CHEMDNER_CORPUS_BIOCREATIVE_4/0000755002344200234200000000000012551146520016720 5ustar mkrallingerBioinfoUnixCHEMDNER_CORPUS_BIOCREATIVE_4/CHEMDNER_TRAIN/0000755002344200234200000000000012551146015021041 5ustar mkrallingerBioinfoUnixCHEMDNER_CORPUS_BIOCREATIVE_4/CHEMDNER_TRAIN/chemdner_ann_training_13-07-31.txt0000644002344200234200000433734412176241433027113 0ustar mkrallingerBioinfoUnix21826085 A 946 957 haloperidol TRIVIAL 22080034 A 1072 1081 aflatoxin FAMILY 22080034 A 1305 1314 aflatoxin FAMILY 22080034 A 1383 1392 aflatoxin FAMILY 22080034 A 190 199 aflatoxin FAMILY 22080034 A 594 603 aflatoxin FAMILY 22080034 A 718 727 aflatoxin FAMILY 22080035 A 1002 1012 superoxide TRIVIAL 22080035 A 1027 1038 glutathione TRIVIAL 22080035 A 1081 1092 glutathione TRIVIAL 22080035 A 1093 1094 S FORMULA 22080035 A 262 268 copper SYSTEMATIC 22080035 A 546 553 cadmium SYSTEMATIC 22080035 A 558 565 arsenic SYSTEMATIC 22080035 A 723 738 malondialdehyde TRIVIAL 22080035 A 964 975 glutathione TRIVIAL 22080037 A 285 297 nitric oxide SYSTEMATIC 22080037 A 340 347 mercury SYSTEMATIC 22080037 A 395 402 mercury SYSTEMATIC 22080037 A 649 656 mercury SYSTEMATIC 22080037 A 769 776 mercury SYSTEMATIC 22080037 T 0 7 Mercury SYSTEMATIC 22080037 T 65 77 nitric oxide SYSTEMATIC 22258629 A 0 8 Chromium SYSTEMATIC 22258629 A 1136 1144 chromium SYSTEMATIC 22258629 A 1452 1460 chromium SYSTEMATIC 22258629 A 1520 1528 chromium SYSTEMATIC 22258629 A 203 211 chromium SYSTEMATIC 22258629 A 428 443 malondialdehyde TRIVIAL 22258629 A 514 522 Chromium SYSTEMATIC 22258629 A 575 583 graphite TRIVIAL 22258629 T 17 25 chromium SYSTEMATIC 22288603 A 336 346 mikanolide TRIVIAL 22288603 A 638 648 mikanolide TRIVIAL 22294443 A 0 32 Polycyclic aromatic hydrocarbons FAMILY 22294443 A 1030 1042 fluoranthene SYSTEMATIC 22294443 A 1047 1061 benzo(a)pyrene SYSTEMATIC 22294443 A 206 211 PCAHs ABBREVIATION 22294443 A 34 39 PCAHs ABBREVIATION 22294443 A 412 417 PCAHs ABBREVIATION 22294443 A 428 434 pyrene SYSTEMATIC 22294443 A 436 454 benzo(a)anthracene SYSTEMATIC 22294443 A 456 470 benzo(e)pyrene SYSTEMATIC 22294443 A 472 490 benzoflouroanthene SYSTEMATIC 22294443 A 496 510 benzo(a)pyrene SYSTEMATIC 22294443 A 563 593 methanolic potassium hydroxide SYSTEMATIC 22294443 A 611 622 cyclohexane SYSTEMATIC 22294443 A 755 760 PCAHs ABBREVIATION 22294443 A 884 889 PCAHs ABBREVIATION 22294443 A 956 961 PCAHs ABBREVIATION 22294443 T 13 45 polycyclic aromatic hydrocarbons FAMILY 22301816 A 198 205 Thiovit TRIVIAL 22301816 A 502 509 Thiovit TRIVIAL 22301816 A 588 594 captan TRIVIAL 22301816 A 599 607 captafol TRIVIAL 22301816 A 898 905 Thiovit TRIVIAL 22301816 T 10 17 Thiovit TRIVIAL 22301818 A 495 498 MTT ABBREVIATION 22301818 A 500 559 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide SYSTEMATIC 22303963 A 380 391 formic acid SYSTEMATIC 22303963 A 417 428 formic acid SYSTEMATIC 22303963 A 432 444 acetonitrile SYSTEMATIC 22303963 A 839 857 steroidal saponins FAMILY 22303963 A 95 113 steroidal saponins FAMILY 22303963 T 23 41 steroidal saponins FAMILY 22304302 A 167 229 (25S)-1β,3β,4β-trihydroxyspirostan-5β-yl-O-β-D-glucopyranoside SYSTEMATIC 22304302 A 235 269 kitigenin-5β-O-β-D-glucopyranoside SYSTEMATIC 22304302 A 31 41 furostanol TRIVIAL 22304302 A 43 80 reinocarnoside A (1), B (2) and C (3) MULTIPLE 22304302 A 449 452 MTT ABBREVIATION 22304302 A 8 20 spirostanols FAMILY 22304302 T 10 30 steroidal glycosides FAMILY 22310169 A 1044 1060 ethoxyresorufine SYSTEMATIC 22310169 A 1061 1062 O FORMULA 22310169 A 1166 1198 polycyclic aromatic hydrocarbons FAMILY 22310169 A 1200 1204 PAHs ABBREVIATION 22310169 A 1237 1240 PAH ABBREVIATION 22310169 A 836 847 glutathione TRIVIAL 22310169 A 866 877 glutathione TRIVIAL 22310169 A 878 879 S FORMULA 22310169 A 932 946 thiobarbituric SYSTEMATIC 22310170 A 1319 1322 TCS ABBREVIATION 22310170 A 1453 1462 phosphate SYSTEMATIC 22310170 A 1588 1591 TCS ABBREVIATION 22310170 A 1670 1673 TCS ABBREVIATION 22310170 A 512 521 triclosan TRIVIAL 22310170 A 523 526 TCS ABBREVIATION 22310170 A 664 667 TCS ABBREVIATION 22310170 A 881 884 TCS ABBREVIATION 22310170 A 930 933 TCS ABBREVIATION 22310170 A 958 961 TCS ABBREVIATION 22310170 T 60 69 triclosan TRIVIAL 22312034 A 209 233 4aα,7β,7aα-nepetalactone SYSTEMATIC 22312034 A 244 254 germacrene TRIVIAL 22312034 A 268 274 elemol TRIVIAL 22312034 A 744 767 sodium dodecyl sulphate SYSTEMATIC 22312034 A 768 782 polyacrylamide SYSTEMATIC 22312034 A 804 807 SDS ABBREVIATION 22317823 A 134 142 aluminum SYSTEMATIC 22317823 A 1452 1454 Al FORMULA 22317823 A 1607 1609 Al FORMULA 22317823 A 1774 1776 Al FORMULA 22317823 A 339 341 Al FORMULA 22317823 A 387 389 Al FORMULA 22317823 A 412 414 Al FORMULA 22317823 A 426 434 Aluminum SYSTEMATIC 22317823 A 448 450 Al FORMULA 22317823 A 637 639 Al FORMULA 22317823 A 883 885 Al FORMULA 22317823 T 46 54 aluminum SYSTEMATIC 22349814 A 1199 1219 phosphatidylinositol TRIVIAL 22349814 A 6 19 monoglyceride SYSTEMATIC 22349814 A 733 750 phosphatidic acid FAMILY 22349814 A 755 779 phosphoinositol(3,4,5)P3 SYSTEMATIC 22349814 A 781 803 phosphoinositol(3,5)P2 SYSTEMATIC 22349814 A 805 827 phosphoinositol(3,4)P2 SYSTEMATIC 22349814 A 846 863 phosphoinositides FAMILY 22349814 A 879 896 phosphoinositides FAMILY 22349814 A 928 939 PI(3,4,5)P3 SYSTEMATIC 22349814 T 36 49 monoglyceride SYSTEMATIC 22360797 A 231 243 morolic acid TRIVIAL 22360797 A 316 323 acetone SYSTEMATIC 22360797 A 397 437 β-sitosteryl and stigmasteryl linoleates MULTIPLE 22360797 A 439 451 β-sitosterol TRIVIAL 22360797 A 453 465 stigmasterol TRIVIAL 22360797 A 467 479 triacontanol TRIVIAL 22360797 A 481 506 squalene, α- and β-amyrin MULTIPLE 22360797 A 508 514 lupeol TRIVIAL 22360797 A 516 524 lupenone TRIVIAL 22360797 A 526 542 betulin aldehyde TRIVIAL 22360797 A 544 560 betulon aldehyde TRIVIAL 22360797 A 562 580 oleanolic aldehyde TRIVIAL 22360797 A 582 596 betulinic acid TRIVIAL 22360797 A 598 612 betulonic acid TRIVIAL 22360797 A 614 626 moronic acid TRIVIAL 22360797 A 628 640 morolic acid TRIVIAL 22360797 A 642 656 oleanolic acid TRIVIAL 22360797 A 658 668 flavonoids FAMILY 22360797 A 669 677 acacetin TRIVIAL 22360797 A 682 705 acacetin 7-methyl ether SYSTEMATIC 22370634 A 1104 1107 RAP ABBREVIATION 22370634 A 1229 1232 RAP ABBREVIATION 22370634 A 1461 1464 RAP ABBREVIATION 22370634 A 421 430 Rapamycin TRIVIAL 22370634 A 432 435 RAP ABBREVIATION 22370634 A 712 715 RAP ABBREVIATION 22370634 A 948 951 RAP ABBREVIATION 22370634 T 46 55 rapamycin TRIVIAL 22370645 A 1199 1205 WP1066 IDENTIFIER 22370645 A 274 283 gefitinib TRIVIAL 22370645 A 951 972 phosphatidyl inositol TRIVIAL 22385272 A 322 330 pulegone TRIVIAL 22385272 A 338 346 menthone TRIVIAL 22385272 A 355 366 isomenthone TRIVIAL 22385272 A 374 385 isopulegone TRIVIAL 22385272 A 397 405 limonene TRIVIAL 22394118 A 154 167 withanolide A TRIVIAL 22394118 A 202 208 carbon SYSTEMATIC 22394118 A 270 283 withanolide A TRIVIAL 22394118 A 342 349 sucrose TRIVIAL 22394118 A 703 716 withanolide A TRIVIAL 22394118 T 0 6 Carbon SYSTEMATIC 22394118 T 104 117 withanolide A TRIVIAL 22397600 A 159 169 nimesulide TRIVIAL 22397600 A 241 251 nimesulide TRIVIAL 22397600 T 49 59 nimesulide TRIVIAL 22397675 A 1132 1135 NMP ABBREVIATION 22397675 A 1219 1222 IVM ABBREVIATION 22397675 A 1487 1490 IVM ABBREVIATION 22397675 A 1615 1618 PLA ABBREVIATION 22397675 A 345 355 ivermectin TRIVIAL 22397675 A 357 360 IVM ABBREVIATION 22397675 A 414 417 PLA ABBREVIATION 22397675 A 462 484 N-methyl-2-pyrrolidone SYSTEMATIC 22397675 A 486 489 NMP ABBREVIATION 22397675 A 492 505 2-pyrrolidone SYSTEMATIC 22397675 A 512 522 triacetine TRIVIAL 22397675 A 532 547 benzyl benzoate SYSTEMATIC 22397675 A 76 93 poly(D,L-lactide) SYSTEMATIC 22397675 A 888 891 IVM ABBREVIATION 22397675 A 95 98 PLA ABBREVIATION 22397675 T 11 14 PLA ABBREVIATION 22397675 T 72 82 Ivermectin TRIVIAL 22401597 A 131 141 triterpene FAMILY 22401597 A 145 211 1α,3β,25-trihydroxy-9(11)-ene-16-one-9,10-seco-9,19-cyclolanostane SYSTEMATIC 22401597 A 227 241 fatty alcohols SYSTEMATIC 22401597 T 0 29 9,10-seco-9,19-cyclolanostane SYSTEMATIC 22401597 T 30 40 triterpene FAMILY 22404642 A 148 161 triterpenoids FAMILY 22404642 A 163 186 3β-O-octadecanoyllupeol SYSTEMATIC 22404642 A 192 207 glut-5-en-3β-ol SYSTEMATIC 22404642 A 213 241 24-methylenecicloartan-3β-ol SYSTEMATIC 22404642 A 250 276 cicloart-23-ene-3β,25-diol SYSTEMATIC 22404642 A 316 328 ellagic acid TRIVIAL 22404642 A 337 365 3,3'-di-O-methylellagic acid SYSTEMATIC 22420410 A 14 30 diketopiperazine FAMILY 22420410 A 479 489 amino acid FAMILY 22420410 A 571 609 trans-cyclo-(D-tryptophanyl-L-tyrosyl) SYSTEMATIC 22420410 A 724 762 Trans-cyclo-(D-tryptophanyl-L-tyrosyl) SYSTEMATIC 22420410 T 39 55 diketopiperazine FAMILY 22424088 A 539 546 eugenol TRIVIAL 22424088 A 617 621 DPPH ABBREVIATION 22424088 A 626 636 superoxide TRIVIAL 22424088 A 735 742 eugenol TRIVIAL 22424117 A 141 159 iridoid glucosides FAMILY 22424117 A 167 199 8-O-trans-cinnamoyl caryoptoside SYSTEMATIC 22424117 A 205 248 8-O-trans-cinnamoyl shanzhiside methylester SYSTEMATIC 22424117 A 254 286 8-O-trans-cinnamoyl mussaenoside SYSTEMATIC 22424117 A 295 318 8-O-cafeoyl massenoside SYSTEMATIC 22424117 A 39 51 ethylacetate SYSTEMATIC 22424117 A 533 541 iridoids FAMILY 22424117 A 747 753 acetyl SYSTEMATIC 22424117 A 816 834 iridoid glucosides FAMILY 22424117 A 869 875 acetyl SYSTEMATIC 22424117 T 44 62 iridoid glucosides FAMILY 22430207 A 460 467 glucose TRIVIAL 22430207 A 933 940 glucose TRIVIAL 22445601 A 1103 1111 LY541850 IDENTIFIER 22445601 A 1234 1242 LY541850 IDENTIFIER 22445601 A 1320 1333 phencyclidine TRIVIAL 22445601 A 1338 1349 amphetamine TRIVIAL 22445601 A 1546 1555 Glutamate TRIVIAL 22445601 A 207 215 LY541850 IDENTIFIER 22445601 A 401 409 LY541850 IDENTIFIER 22445601 A 606 614 LY541850 IDENTIFIER 22445601 A 69 78 glutamate TRIVIAL 22445601 A 865 873 LY541850 IDENTIFIER 22445601 A 970 978 LY541850 IDENTIFIER 22445601 T 61 69 LY541850 IDENTIFIER 22451355 A 307 367 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide SYSTEMATIC 22455800 A 101 134 3-alkyl-2,6-diarylpiperidin-4-one FAMILY 22455800 A 12 55 4-hydroxy-3,4-dialkyl-2,6-diaryl-piperidine FAMILY 22455800 A 145 161 Grignard reagent FAMILY 22455800 A 287 300 piperdin-4-ol SYSTEMATIC 22455800 T 13 56 4-hydroxy-3,4-dialkyl-2,6-diaryl-piperidine FAMILY 22468693 A 151 161 chloroform TRIVIAL 22468693 A 267 280 diethyl ether SYSTEMATIC 22468693 A 285 292 acetone SYSTEMATIC 22468693 A 315 325 chloroform TRIVIAL 22468693 A 544 554 chloroform TRIVIAL 22468693 A 57 65 saponins FAMILY 22468693 A 605 613 eicosane SYSTEMATIC 22468693 A 615 625 oleic acid TRIVIAL 22468693 A 627 639 stigmasterol TRIVIAL 22468693 A 644 653 vitamin E FAMILY 22468741 A 353 391 sodium dodecyl sulphate polyacrylamide SYSTEMATIC 22468741 A 540 550 Isoleucine TRIVIAL 22468741 A 705 712 calcium SYSTEMATIC 22468741 A 714 723 magnesium SYSTEMATIC 22468741 A 728 737 potassium SYSTEMATIC 22468741 A 823 830 arsenic SYSTEMATIC 22469981 A 1025 1036 doxycycline TRIVIAL 22469981 A 382 394 tetracycline FAMILY 22469988 A 114 120 oxygen SYSTEMATIC 22469988 A 1399 1406 glucose TRIVIAL 22469988 A 198 201 ATP ABBREVIATION 22469988 A 206 217 fatty acids FAMILY 22475014 A 0 13 Glaucogenin E TRIVIAL 22475014 A 25 30 C(21) FORMULA 22475014 A 31 38 steroid FAMILY 22475014 T 0 13 Glaucogenin E TRIVIAL 22475014 T 21 24 C21 FORMULA 22475014 T 25 32 steroid FAMILY 22480291 A 123 132 rotenoids FAMILY 22480291 A 134 147 boeravinone E TRIVIAL 22480291 A 152 165 boeravinone B TRIVIAL 22480291 A 340 360 orthophosphoric acid SYSTEMATIC 22480291 A 374 386 acetonitrile SYSTEMATIC 22480291 A 631 650 boeravinone E and B MULTIPLE 22480291 T 52 65 boeravinone E TRIVIAL 22480291 T 70 83 boeravinone B TRIVIAL 22489960 A 309 326 7-ethoxyresorufin SYSTEMATIC 22489960 A 327 328 O FORMULA 22489960 A 348 362 benzo(a)pyrene SYSTEMATIC 22489960 A 414 425 glutathione TRIVIAL 22489960 A 427 430 GSH ABBREVIATION 22489960 A 433 445 testosterone TRIVIAL 22489960 A 447 460 17β-estradiol SYSTEMATIC 22489960 A 497 509 triglyceride FAMILY 22489960 A 630 633 GSH ABBREVIATION 22497567 A 1008 1011 IMC ABBREVIATION 22497567 A 1014 1033 fluoro-indomethacin FAMILY 22497567 A 1035 1040 F-IMC ABBREVIATION 22497567 A 1116 1119 IMC ABBREVIATION 22497567 A 1191 1194 IMC ABBREVIATION 22497567 A 1199 1204 F-IMC ABBREVIATION 22497567 A 1285 1290 F-IMC ABBREVIATION 22497567 A 1314 1317 IMC ABBREVIATION 22497567 A 1322 1327 F-IMC ABBREVIATION 22497567 A 1640 1643 IMC ABBREVIATION 22497567 A 1648 1653 F-IMC ABBREVIATION 22497567 A 1881 1884 IMC ABBREVIATION 22497567 A 1889 1894 F-IMC ABBREVIATION 22497567 A 2043 2050 18F-IMC FORMULA 22497567 A 606 609 18F FORMULA 22497567 A 829 841 indomethacin TRIVIAL 22497567 A 994 1006 indomethacin TRIVIAL 22497567 T 70 89 fluoro-indomethacin FAMILY 22502647 A 10 20 furostanol TRIVIAL 22502647 A 21 29 saponins FAMILY 22502647 A 49 61 polyhydroxyl SYSTEMATIC 22502647 A 62 69 saponin FAMILY 22502647 T 15 23 saponins FAMILY 22502647 T 4 14 furostanol TRIVIAL 22507666 A 1078 1086 dopamine TRIVIAL 22507666 A 1092 1096 cAMP ABBREVIATION 22507666 A 1230 1234 DHPG ABBREVIATION 22507666 A 1358 1361 Ser FORMULA 22507666 A 1392 1396 DHPG ABBREVIATION 22507666 A 1690 1699 Glutamate TRIVIAL 22507666 A 21 30 glutamate TRIVIAL 22507666 A 319 323 AMPA ABBREVIATION 22507666 A 324 333 glutamate TRIVIAL 22507666 A 425 457 (R,S)-3,5-dihydroxyphenylglycine SYSTEMATIC 22507666 A 459 463 DHPG ABBREVIATION 22507666 A 503 507 cAMP ABBREVIATION 22507666 A 545 548 Ser FORMULA 22507666 A 581 629 2-methyl-6-(phenylethynyl)pyridine hydrochloride SYSTEMATIC 22507666 A 631 635 MPEP ABBREVIATION 22507666 A 719 723 DHPG ABBREVIATION 22507666 A 757 766 adenosine TRIVIAL 22507666 A 817 821 cAMP ABBREVIATION 22507666 A 920 929 adenosine TRIVIAL 22507666 A 945 954 adenosine TRIVIAL 22507666 A 981 985 DHPG ABBREVIATION 22507666 T 16 25 glutamate TRIVIAL 22507666 T 26 30 AMPA ABBREVIATION 22510064 A 379 395 sodium hydroxide SYSTEMATIC 22510064 A 397 401 NaOH FORMULA 22510064 A 484 497 Poloxamer 407 TRIVIAL 22510064 A 64 74 rebamipide TRIVIAL 22510064 A 834 847 poloxamer 407 TRIVIAL 22510064 T 102 112 rebamipide TRIVIAL 22510064 T 118 131 poloxamer 407 TRIVIAL 22512590 A 503 515 Nikkomycin Z TRIVIAL 22512590 A 772 782 nikkomycin TRIVIAL 22512590 A 787 795 polyoxin FAMILY 22516666 A 1188 1193 CO(2) FORMULA 22516666 A 1251 1262 venlafaxine TRIVIAL 22516666 A 1287 1297 pregabalin TRIVIAL 22516666 A 1354 1369 benzodiazepines FAMILY 22516666 A 1399 1404 CO(2) FORMULA 22516666 A 1468 1473 CO(2) FORMULA 22516666 A 152 161 lorazepam TRIVIAL 22516666 A 1615 1620 CO(2) FORMULA 22516666 A 187 197 paroxetine TRIVIAL 22516666 A 199 210 Venlafaxine TRIVIAL 22516666 A 215 225 pregabalin TRIVIAL 22516666 A 341 346 CO(2) FORMULA 22516666 A 455 466 venlafaxine TRIVIAL 22516666 A 470 480 pregabalin TRIVIAL 22516666 A 581 592 venlafaxine TRIVIAL 22516666 A 603 613 pregabalin TRIVIAL 22516666 A 621 626 CO(2) FORMULA 22516666 A 677 682 CO(2) FORMULA 22516666 A 774 779 CO(2) FORMULA 22516666 A 866 871 CO(2) FORMULA 22516666 A 94 99 CO(2) FORMULA 22516666 T 29 40 venlafaxine TRIVIAL 22516666 T 45 55 pregabalin TRIVIAL 22516666 T 63 77 carbon dioxide SYSTEMATIC 22533550 A 200 207 Octanal SYSTEMATIC 22533550 A 212 230 2-bromoacetic acid SYSTEMATIC 22533550 A 55 60 amide FAMILY 22533550 A 71 107 N-isobutyl-4,5-epoxy-2(E)-decenamide SYSTEMATIC 22533550 T 32 68 N-isobutyl-4,5-epoxy-2(E)-decenamide SYSTEMATIC 22546615 A 1027 1038 haloperidol TRIVIAL 22546615 A 1083 1092 reserpine TRIVIAL 22546615 A 1104 1108 DCPG ABBREVIATION 22546615 A 1127 1138 haloperidol TRIVIAL 22546615 A 1161 1170 reserpine TRIVIAL 22546615 A 1202 1206 DCPG ABBREVIATION 22546615 A 1296 1310 decanoate salt SYSTEMATIC 22546615 A 13 22 glutamate TRIVIAL 22546615 A 1314 1325 haloperidol TRIVIAL 22546615 A 1358 1362 DCPG ABBREVIATION 22546615 A 1419 1436 6-hydroxydopamine SYSTEMATIC 22546615 A 1464 1472 dopamine TRIVIAL 22546615 A 1628 1636 dopamine TRIVIAL 22546615 A 1672 1680 dopamine TRIVIAL 22546615 A 1902 1911 Glutamate TRIVIAL 22546615 A 822 852 (S)-3,4-dicarboxyphenylglycine SYSTEMATIC 22546615 A 854 858 DCPG ABBREVIATION 22546615 A 954 965 haloperidol TRIVIAL 22546615 A 969 978 reserpine TRIVIAL 22546615 T 17 26 glutamate TRIVIAL 22546615 T 46 58 (S)-3,4-DCPG SYSTEMATIC 22546616 A 0 4 GABA ABBREVIATION 22546616 A 1189 1193 GABA ABBREVIATION 22546616 A 198 202 GABA ABBREVIATION 22546616 A 448 462 benzodiazepine FAMILY 22546616 A 483 499 [(11)C]Ro15-4513 IDENTIFIER 22546616 A 6 30 gamma-amino-butyric-acid SYSTEMATIC 22546616 A 715 731 [(11)C]Ro15-4513 IDENTIFIER 22546616 T 10 14 GABA ABBREVIATION 22546616 T 15 29 benzodiazepine FAMILY 22546616 T 92 108 [(11)C]Ro15-4513 IDENTIFIER 22548348 A 105 113 methanol SYSTEMATIC 22548348 A 19 43 C-geranylated flavonoids FAMILY 22548348 A 258 275 tanariflavanone D TRIVIAL 22548348 A 44 58 tomentomimulol TRIVIAL 22548348 A 67 77 mimulone B TRIVIAL 22548348 T 0 14 Tomentomimulol TRIVIAL 22548348 T 19 29 mimulone B TRIVIAL 22548348 T 39 63 C-geranylated flavonoids FAMILY 22548364 A 202 212 pimprinine TRIVIAL 22548364 A 218 291 (3R,4S,5R,6R)-3,4,5,6-tetrahydro-4-hydroxy-3,5,6-trimethyl-2H-pyran-2-one SYSTEMATIC 22548364 A 297 322 indolyl-3-carboxylic acid SYSTEMATIC 22548364 A 30 119 N-trans-cinnamoyl 2-amino-3a,4,5,6,7,8,9,10,11,12,13,13a-dodecahydrocyclododeca[d]oxazole SYSTEMATIC 22548364 A 328 345 2-phenylacetamide SYSTEMATIC 22548364 A 354 381 di(1H-pyrrol-2-yl)methanone SYSTEMATIC 22548364 T 6 27 cyclododeca[d]oxazole SYSTEMATIC 22551786 A 1367 1374 GRN-529 IDENTIFIER 22551786 A 1419 1426 GRN-529 IDENTIFIER 22551786 A 1592 1599 GRN-529 IDENTIFIER 22551786 A 1709 1713 MTEP ABBREVIATION 22551786 A 2120 2127 GRN-529 IDENTIFIER 22551786 A 508 517 glutamate TRIVIAL 22551786 A 586 593 GRN-529 IDENTIFIER 22551786 A 655 664 glutamate TRIVIAL 22551786 A 721 728 GRN-529 IDENTIFIER 22551786 A 865 872 GRN-529 IDENTIFIER 22551786 T 47 56 glutamate TRIVIAL 22559719 A 165 179 carbon dioxide SYSTEMATIC 22559719 A 277 288 Citronellal TRIVIAL 22559719 A 780 803 oxygenated monoterpenes FAMILY 22559719 A 999 1010 citronellal TRIVIAL 22561337 A 329 337 estrogen FAMILY 22561337 A 388 396 estrogen FAMILY 22561337 A 554 562 estrogen FAMILY 22561337 A 762 770 estrogen FAMILY 22561337 A 822 830 estrogen FAMILY 22561337 A 934 942 estrogen FAMILY 22561337 T 49 57 estrogen FAMILY 22563917 A 1008 1011 BBH ABBREVIATION 22563917 A 1129 1132 BBH ABBREVIATION 22563917 A 1331 1334 BBH ABBREVIATION 22563917 A 134 157 Berberine hydrochloride SYSTEMATIC 22563917 A 159 162 BBH ABBREVIATION 22563917 A 674 689 ethyl linoleate SYSTEMATIC 22563917 A 694 704 oleic acid TRIVIAL 22563917 A 722 730 Tween-80 TRIVIAL 22563917 A 745 753 glycerol TRIVIAL 22563917 A 769 772 BBH ABBREVIATION 22563917 A 854 857 BBH ABBREVIATION 22563917 T 98 121 berberine hydrochloride SYSTEMATIC 22579656 A 1027 1032 THDOC ABBREVIATION 22579656 A 1053 1057 GABA ABBREVIATION 22579656 A 1110 1114 GABA ABBREVIATION 22579656 A 572 581 estrogens FAMILY 22579656 A 586 598 progesterone TRIVIAL 22579656 A 699 715 allopregnanolone TRIVIAL 22579656 A 725 758 allotetrahydrodeoxycorticosterone TRIVIAL 22579656 A 760 765 THDOC ABBREVIATION 22579656 A 882 886 GABA ABBREVIATION 22583008 A 139 149 fatty acid FAMILY 22583008 A 321 342 Saturated fatty acids FAMILY 22583008 A 448 475 monounsaturated fatty acids FAMILY 22583008 A 543 570 polyunsaturated fatty acids FAMILY 22583008 A 605 669 arachidonic (C20 : 4ω-6) and eicosapentaenoic (C20 : 5ω-3) acids MULTIPLE 22583008 A 787 798 fatty acids FAMILY 22583008 T 0 10 Fatty acid FAMILY 22585425 A 0 17 Allylpyrocatechol SYSTEMATIC 22585425 A 19 22 APC ABBREVIATION 22585425 A 258 261 APC ABBREVIATION 22585425 A 263 266 APC ABBREVIATION 22585425 A 287 294 phorbol TRIVIAL 22585425 A 295 304 myristate TRIVIAL 22585425 A 305 312 acetate SYSTEMATIC 22585425 A 344 350 oxygen SYSTEMATIC 22585425 A 363 373 superoxide TRIVIAL 22585425 A 562 578 sodium ascorbate SYSTEMATIC 22585425 A 597 600 APC ABBREVIATION 22585425 A 688 691 APC ABBREVIATION 22585425 A 745 748 GSH ABBREVIATION 22585425 A 812 815 APC ABBREVIATION 22585425 T 28 45 allylpyrocatechol SYSTEMATIC 22585450 A 1031 1068 N-[3(aminomethyl) benzyl]-acetamidine SYSTEMATIC 22585450 A 1070 1085 dihydrochloride SYSTEMATIC 22585450 A 1312 1315 STZ ABBREVIATION 22585450 A 229 243 streptozotocin TRIVIAL 22585450 A 245 248 STZ ABBREVIATION 22585450 A 356 368 nitric oxide SYSTEMATIC 22585450 A 606 619 acetylcholine SYSTEMATIC 22585450 A 642 655 noradrenaline TRIVIAL 22585450 A 777 784 nitrite SYSTEMATIC 22585450 A 785 792 nitrate SYSTEMATIC 22585450 A 798 813 malondialdehite TRIVIAL 22585450 T 60 74 streptozotocin TRIVIAL 22594605 A 176 184 caffeine TRIVIAL 22594605 A 193 232 1,3-dimethylpyrimidine-2,4(1H,3H)-dione SYSTEMATIC 22594605 A 34 74 9-acetyl-1,3,7-trimethyl-pyrimidinedione SYSTEMATIC 22594605 A 6 21 pyrimidinedione FAMILY 22594605 T 6 21 pyrimidinedione FAMILY 22610853 A 1010 1018 curcumin TRIVIAL 22610853 A 1057 1069 curcuminoids FAMILY 22610853 A 106 114 Curcumin TRIVIAL 22610853 A 1117 1128 cholesterol TRIVIAL 22610853 A 1154 1165 cholesterol TRIVIAL 22610853 A 1192 1203 cholesterol TRIVIAL 22610853 A 1410 1423 triglycerides FAMILY 22610853 A 286 294 curcumin TRIVIAL 22610853 A 357 369 curcuminoids FAMILY 22610853 A 490 501 cholesterol TRIVIAL 22610853 A 503 516 triglycerides FAMILY 22610853 A 542 553 cholesterol TRIVIAL 22610853 A 583 594 cholesterol TRIVIAL 22610853 A 959 972 triglycerides FAMILY 22610853 T 32 44 curcuminoids FAMILY 22616559 A 284 294 naringenin TRIVIAL 22616559 A 29 58 apigenin 7-O-β-D-cellobioside SYSTEMATIC 22616559 A 67 120 apigenin 7-O-β-D-cellobiosyl-4'-O-β-D-glucopyranoside SYSTEMATIC 22616559 T 29 82 apigenin 7-O-β-D-cellobiosyl-4'-O-β-D-glucopyranoside SYSTEMATIC 22616577 A 110 124 Arjunolic acid TRIVIAL 22616577 A 130 154 24-hydroxytormentic acid SYSTEMATIC 22616577 A 163 195 3-O-β-D-glucopyranosylsitosterol SYSTEMATIC 22616577 A 205 221 sodium periodate SYSTEMATIC 22616577 A 226 236 silica gel TRIVIAL 22616577 A 246 249 THF ABBREVIATION 22616577 A 289 297 hydroxyl SYSTEMATIC 22616577 A 29 41 vicinal diol FAMILY 22616577 A 347 377 lactol pentacyclic triterpenes FAMILY 22616577 A 391 423 bicyclotriacetal of β-sitosterol TRIVIAL 22616577 A 8 11 C-C FORMULA 22616577 T 133 138 NaIO4 FORMULA 22616577 T 139 143 SiO2 FORMULA 22616577 T 151 154 THF ABBREVIATION 22616577 T 30 48 acetal triterpenes FAMILY 22616577 T 62 74 vicinal diol FAMILY 22619070 A 1105 1112 terpene FAMILY 22619070 A 1114 1127 terpinen-4-ol SYSTEMATIC 22623520 A 0 10 Methiocarb TRIVIAL 22623520 A 1080 1095 malondialdehyde TRIVIAL 22623520 A 1165 1176 glutathione TRIVIAL 22623520 A 1195 1205 superoxide TRIVIAL 22623520 A 1230 1241 glutathione TRIVIAL 22623520 A 130 139 carbamate FAMILY 22623520 A 1301 1312 glutathione TRIVIAL 22623520 A 1553 1562 vitamin E FAMILY 22623520 A 1567 1574 taurine TRIVIAL 22623520 A 1999 2008 vitamin E FAMILY 22623520 A 2013 2020 taurine TRIVIAL 22623520 A 33 42 carbamate FAMILY 22623520 A 473 482 vitamin E FAMILY 22623520 A 487 494 taurine TRIVIAL 22623520 A 632 641 vitamin E FAMILY 22623520 A 704 711 taurine TRIVIAL 22623520 A 883 892 vitamin E FAMILY 22623520 A 914 921 taurine TRIVIAL 22623520 T 17 27 methiocarb TRIVIAL 22623520 T 78 87 vitamin E FAMILY 22623520 T 92 99 taurine TRIVIAL 22625411 A 185 196 sulfonamide SYSTEMATIC 22625411 A 371 383 sulfonamides FAMILY 22625411 A 593 604 sulfonamide SYSTEMATIC 22625411 A 676 688 sulfonamides FAMILY 22625411 T 42 54 sulfonamides FAMILY 22625416 A 156 165 terpenoid FAMILY 22625416 A 198 212 tocochromanols FAMILY 22625416 A 217 224 sterols FAMILY 22625416 A 337 345 terpenes FAMILY 22625416 A 93 112 omega-3 fatty acids FAMILY 22625416 T 5 14 terpenoid FAMILY 22628017 A 117 129 anthocyanins FAMILY 22628017 A 356 364 pyruvate TRIVIAL 22628017 A 370 376 malate TRIVIAL 22628017 A 547 556 Succinate TRIVIAL 22628017 A 591 603 anthocyanins FAMILY 22628017 A 643 663 malvidin-3-glucoside SYSTEMATIC 22628017 A 665 687 malvidin-3-galactoside SYSTEMATIC 22628017 A 693 715 cyanidin-3-galactoside SYSTEMATIC 22628017 A 747 755 pyruvate TRIVIAL 22628017 A 761 767 malate TRIVIAL 22628017 A 809 814 H2 O2 FORMULA 22628017 A 934 945 anthocyanin FAMILY 22628265 A 1036 1043 ethanol SYSTEMATIC 22628265 A 109 118 neolignan FAMILY 22628265 A 1245 1252 ethanol SYSTEMATIC 22628265 A 1399 1406 ethanol SYSTEMATIC 22628265 A 258 265 ethanol SYSTEMATIC 22628265 A 49 57 magnolol TRIVIAL 22628265 A 505 512 ethanol SYSTEMATIC 22628265 A 559 566 ethanol SYSTEMATIC 22628265 A 59 67 honokiol TRIVIAL 22628265 A 69 87 4-O-methylhonokiol SYSTEMATIC 22628265 A 735 742 ethanol SYSTEMATIC 22628265 A 89 97 obovatol TRIVIAL 22628265 A 900 912 nitric oxide SYSTEMATIC 22628265 T 0 7 Ethanol SYSTEMATIC 22634360 A 1047 1091 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine SYSTEMATIC 22634360 A 1093 1097 MPTP ABBREVIATION 22634360 A 1724 1728 MPTP ABBREVIATION 22634360 A 1801 1806 L-AP4 IDENTIFIER 22634360 A 2052 2057 L-AP4 IDENTIFIER 22634360 A 2071 2080 VU0155041 IDENTIFIER 22634360 A 208 225 6-hydroxydopamine SYSTEMATIC 22634360 A 23 32 glutamate TRIVIAL 22634360 A 2347 2352 L-AP4 IDENTIFIER 22634360 A 2391 2400 glutamate TRIVIAL 22634360 A 2661 2670 Glutamate TRIVIAL 22634360 A 866 871 L-AP4 IDENTIFIER 22634360 A 917 926 VU0155041 IDENTIFIER 22634360 T 13 22 glutamate TRIVIAL 22640571 A 0 101 16-Isopropyl-5, 9-dimethyltetracyclo [10.2.2.0(1, 10).0(4, 9)] hexadec-15-ene-5, 14-dicarboxylic acid SYSTEMATIC 22640571 A 189 201 Schiff bases FAMILY 22640571 A 277 281 (1)H FORMULA 22640571 A 370 382 Schiff bases FAMILY 22640571 T 40 52 Schiff bases FAMILY 22640571 T 58 159 16-isopropyl-5, 9-dimethyltetracyclo [10.2.2.0(1, 10).0(4, 9)] hexadec-15-ene-5, 14-dicarboxylic acid SYSTEMATIC 22641218 A 1308 1317 Celastrol TRIVIAL 22641218 A 1577 1586 Celastrol TRIVIAL 22641218 A 2141 2150 Celastrol TRIVIAL 22644836 A 919 926 glucose TRIVIAL 22644836 A 928 941 triglycerides FAMILY 22644836 A 951 962 cholesterol TRIVIAL 22648529 A 1097 1103 hopane TRIVIAL 22648529 A 1112 1120 saponins FAMILY 22648529 A 1207 1215 saponins FAMILY 22648529 A 344 352 methanol SYSTEMATIC 22648529 A 768 776 saponins FAMILY 22648529 A 821 831 flavonoids FAMILY 22648529 A 836 844 oleanane TRIVIAL 22648529 A 850 858 saponins FAMILY 22648529 A 862 870 oleanane TRIVIAL 22648529 A 876 884 saponins FAMILY 22648529 A 932 938 hopane TRIVIAL 22648529 A 944 952 saponins FAMILY 22658648 A 1111 1123 myo-inositol TRIVIAL 22658648 A 1193 1205 Myo-inositol TRIVIAL 22658648 A 161 169 inositol TRIVIAL 22658648 A 387 399 myo-inositol TRIVIAL 22658648 A 433 441 inositol TRIVIAL 22658648 A 454 466 myo-inositol TRIVIAL 22658648 A 567 574 glucose TRIVIAL 22658648 A 641 653 myo-inositol TRIVIAL 22658648 A 956 968 myo-inositol TRIVIAL 22658648 T 23 35 myo-inositol TRIVIAL 22659473 A 108 117 glutamate TRIVIAL 22659473 A 554 563 Glutamate TRIVIAL 22659473 T 51 60 glutamate TRIVIAL 22660443 A 348 354 azoles FAMILY 22660443 A 488 494 azoles FAMILY 22660443 A 522 537 corticosteroids FAMILY 22660443 T 0 5 Azole FAMILY 22661401 A 207 213 Cu(2+) FORMULA 22661401 A 215 221 Zn(2+) FORMULA 22661401 A 223 229 Mn(2+) FORMULA 22661401 A 234 240 Ni(2+) FORMULA 22669363 A 329 350 N-acetylgalactosamine SYSTEMATIC 22670797 A 1012 1019 octanol SYSTEMATIC 22670797 A 107 133 4-tert-butylphenylthiourea SYSTEMATIC 22670797 A 1109 1116 QNT3-18 IDENTIFIER 22670797 A 1150 1157 QNT3-20 IDENTIFIER 22670797 A 1219 1226 QNT3-18 IDENTIFIER 22670797 A 135 142 QNT3-20 IDENTIFIER 22670797 A 1418 1425 QNT3-18 IDENTIFIER 22670797 A 1502 1509 QNT3-18 IDENTIFIER 22670797 A 1608 1615 QNT3-18 IDENTIFIER 22670797 A 38 93 (E)-2-(4-tert-butylbenzylidene) hydrazinecarbothioamide SYSTEMATIC 22670797 A 411 418 QNT3-18 IDENTIFIER 22670797 A 422 429 QNT3-20 IDENTIFIER 22670797 A 576 583 QNT3-18 IDENTIFIER 22670797 A 588 595 QNT3-20 IDENTIFIER 22670797 A 695 702 QNT3-18 IDENTIFIER 22670797 A 726 733 QNT3-20 IDENTIFIER 22670797 A 786 793 QNT3-18 IDENTIFIER 22670797 A 797 804 QNT3-20 IDENTIFIER 22670797 A 95 102 QNT3-18 IDENTIFIER 22670797 T 52 59 QNT3-18 IDENTIFIER 22677475 A 0 21 Tetrabromobisphenol A SYSTEMATIC 22677475 A 23 28 TBBPA ABBREVIATION 22677475 A 265 270 TBBPA ABBREVIATION 22677475 A 356 361 TBBPA ABBREVIATION 22677475 A 91 96 TBBPA ABBREVIATION 22677475 A 944 949 TBBPA ABBREVIATION 22677475 T 10 30 tetrabrombisphenol A SYSTEMATIC 22678994 A 1065 1070 H2 O2 FORMULA 22678994 A 1162 1179 poly (ADP-ribose) SYSTEMATIC 22678994 A 1278 1283 H2 O2 FORMULA 22678994 A 1333 1352 acetoxymethyl ester SYSTEMATIC 22678994 A 433 440 calcium SYSTEMATIC 22678994 A 734 759 Polymethoxylated flavones FAMILY 22678994 A 768 777 nobiletin TRIVIAL 22678994 A 782 792 tangeretin TRIVIAL 22678994 A 87 94 calcium SYSTEMATIC 22678994 A 959 964 H2 O2 FORMULA 22683935 A 706 730 2,4-dinitrochlorobenzene SYSTEMATIC 22683935 A 732 751 paraphenylendiamine SYSTEMATIC 22683935 A 753 767 cinnamaldehyde TRIVIAL 22683935 A 769 779 isoeugenol TRIVIAL 22683935 A 781 795 nickel-sulfate SYSTEMATIC 22683935 A 797 825 tetramethylthiuram disulfide SYSTEMATIC 22683935 A 827 834 eugenol TRIVIAL 22683935 A 836 852 cinnamic-alcohol SYSTEMATIC 22683935 A 854 882 ammonium-hexachloroplatinate SYSTEMATIC 22683935 A 927 948 sodium lauryl sulfate SYSTEMATIC 22683935 A 950 964 salicylic acid TRIVIAL 22683935 A 966 972 phenol SYSTEMATIC 22683935 A 974 987 octanoic acid SYSTEMATIC 22693035 A 1123 1135 ursolic acid TRIVIAL 22693035 A 1137 1151 oleanolic acid TRIVIAL 22693035 A 1153 1161 apigenin TRIVIAL 22693035 A 1163 1171 luteolin TRIVIAL 22693035 A 1176 1185 ixoroside TRIVIAL 22693035 A 1187 1209 Apigenin-7-O-glucoside SYSTEMATIC 22693035 A 1211 1232 8-hydroxycirsimaritin SYSTEMATIC 22693035 A 1237 1249 cirsimaritin TRIVIAL 22693035 A 1296 1309 ethyl acetate SYSTEMATIC 22693035 A 1328 1344 Nepetanudoside B TRIVIAL 22693035 A 1367 1376 n-butanol SYSTEMATIC 22693035 A 260 289 2,2-diphenyl-1-picrylhydrazyl SYSTEMATIC 22693035 A 291 295 DPPH ABBREVIATION 22693035 A 298 353 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) SYSTEMATIC 22693035 A 355 359 ABTS ABBREVIATION 22693035 A 447 455 methanol SYSTEMATIC 22693035 A 503 511 n-hexane SYSTEMATIC 22693035 A 513 526 ethyl acetate SYSTEMATIC 22693035 A 531 540 n-butanol SYSTEMATIC 22693035 A 558 566 methanol SYSTEMATIC 22693035 A 627 633 Fe(II) FORMULA 22693035 A 667 686 butylhydroxytoluene SYSTEMATIC 22693035 A 696 702 Fe(II) FORMULA 22693035 A 733 737 DPPH ABBREVIATION 22693035 A 839 852 ethyl acetate SYSTEMATIC 22693035 A 857 866 n-butanol SYSTEMATIC 22693035 A 892 901 n-Butanol SYSTEMATIC 22694738 A 1081 1179 pelargonidin-3-O-[6-O-(4-O-E-p-coumaroyl-O-α-rhamnopyranosyl)-β-glucopyrano]-5-O-β-glucopyranoside SYSTEMATIC 22694738 A 11 22 anthocyanin FAMILY 22694738 A 172 184 anthocyanins FAMILY 22694738 A 325 346 acylated anthocyanins FAMILY 22694738 A 382 394 Anthocyanins FAMILY 22694738 A 473 485 anthocyanins FAMILY 22694738 A 622 659 -3,5-di-O-β-glucosides of delphinidin SYSTEMATIC 22694738 A 661 669 cyanidin TRIVIAL 22694738 A 671 680 petunidin TRIVIAL 22694738 A 682 690 malvidin TRIVIAL 22694738 A 695 703 peonidin TRIVIAL 22694738 A 715 724 cyanidine TRIVIAL 22694738 A 729 753 peonidin-3-O-β-glucoside SYSTEMATIC 22694738 A 772 866 cyanidin-3-O-[6-O-(4-O-E-p-coumaroyl-O-α-rhamnopyranosyl)-β-glucopyrano]-5-O-β-glucopyranoside SYSTEMATIC 22694738 A 881 892 anthocyanin FAMILY 22694738 A 932 943 anthocyanin FAMILY 22694738 A 985 1076 cyanidin-3-O-[6-O-(4-O-E-caffeoyl-O-α-rhamnopyranosyl)-β-glucopyrano]-5-O-β-glucopyranoside SYSTEMATIC 22694738 T 32 44 anthocyanins FAMILY 22705340 A 1125 1129 MTEP ABBREVIATION 22705340 A 1243 1252 VU0360172 IDENTIFIER 22705340 A 1325 1334 VU0360172 IDENTIFIER 22705340 A 1370 1374 MTEP ABBREVIATION 22705340 A 1669 1678 Glutamate TRIVIAL 22705340 A 743 763 polyphosphoinositide SYSTEMATIC 22705340 T 57 66 VU0360172 IDENTIFIER 22709945 A 1211 1215 CORT ABBREVIATION 22709945 A 384 398 corticosterone TRIVIAL 22709945 A 625 639 corticosterone TRIVIAL 22709945 A 983 997 corticosterone TRIVIAL 22709945 A 999 1003 CORT ABBREVIATION 22709945 T 30 44 corticosterone TRIVIAL 22712581 A 235 248 peristrophine TRIVIAL 22712581 A 743 756 peristrophine TRIVIAL 22712581 A 881 894 peristrophine TRIVIAL 22712581 T 59 70 phenoxazine SYSTEMATIC 22712621 A 815 822 arbutin TRIVIAL 22718275 A 0 20 7-Dehydrocholesterol SYSTEMATIC 22718275 A 1032 1037 IsoPs ABBREVIATION 22718275 A 1042 1049 NeuroPs ABBREVIATION 22718275 A 1151 1156 IsoPs ABBREVIATION 22718275 A 1161 1168 NeuroPs ABBREVIATION 22718275 A 1316 1321 7-DHC SYSTEMATIC 22718275 A 1330 1340 oxysterols FAMILY 22718275 A 1380 1385 IsoPs ABBREVIATION 22718275 A 1390 1397 NeuroPs ABBREVIATION 22718275 A 165 181 3β-hydroxysterol FAMILY 22718275 A 22 27 7-DHC SYSTEMATIC 22718275 A 232 237 7-DHC SYSTEMATIC 22718275 A 332 342 oxysterols FAMILY 22718275 A 392 397 7-DHC SYSTEMATIC 22718275 A 440 445 7-DHC SYSTEMATIC 22718275 A 599 609 oxysterols FAMILY 22718275 A 611 623 isoprostanes FAMILY 22718275 A 625 630 IsoPs ABBREVIATION 22718275 A 637 651 neuroprostanes FAMILY 22718275 A 653 660 NeuroPs ABBREVIATION 22718275 A 700 705 7-DHC SYSTEMATIC 22718275 A 707 723 arachidonic acid TRIVIAL 22718275 A 728 748 docosahexaenoic acid SYSTEMATIC 22718275 A 802 811 oxysterol FAMILY 22718275 A 813 846 3β,5α-dihydroxycholest-7-en-6-one SYSTEMATIC 22718275 A 848 853 DHCEO ABBREVIATION 22718275 A 917 927 oxysterols FAMILY 22724545 A 191 236 6,8-dihydroxy-3-methyl-3,4-dihydroisocoumarin SYSTEMATIC 22724545 A 242 285 (22R)-hydroxylanosta-7,9(11),24-trien-3-one SYSTEMATIC 22724545 A 27 35 methanol SYSTEMATIC 22724545 A 294 304 ergosterol TRIVIAL 22724545 A 599 610 isocoumarin TRIVIAL 22728231 A 1024 1028 DNCB ABBREVIATION 22728231 A 1030 1040 resorcinol TRIVIAL 22728231 A 1042 1045 pPD ABBREVIATION 22728231 A 1069 1080 lactic acid TRIVIAL 22728231 A 1144 1148 DNCB ABBREVIATION 22728231 A 1162 1172 resorcinol TRIVIAL 22728761 A 1067 1074 cocaine TRIVIAL 22728761 A 1166 1174 D-serine TRIVIAL 22728761 A 1277 1285 D-serine TRIVIAL 22728761 A 1345 1353 D-serine TRIVIAL 22728761 A 1481 1488 cocaine TRIVIAL 22728761 A 1531 1539 D-serine TRIVIAL 22728761 A 1647 1654 cocaine TRIVIAL 22728761 A 635 643 D-serine TRIVIAL 22728761 A 735 742 cocaine TRIVIAL 22728761 A 786 794 D-serine TRIVIAL 22728761 A 846 853 cocaine TRIVIAL 22728761 A 920 928 D-serine TRIVIAL 22728761 T 0 8 D-Serine TRIVIAL 22728761 T 92 99 cocaine TRIVIAL 22732443 A 538 547 Ro25-6981 IDENTIFIER 22732443 A 659 663 AMPA ABBREVIATION 22736593 A 169 181 ginsenosides FAMILY 22736593 A 354 366 ginsenosides FAMILY 22736593 A 375 378 UDP ABBREVIATION 22736593 A 456 478 20(S)-protopanaxatriol SYSTEMATIC 22736593 A 480 483 ppt ABBREVIATION 22736593 T 25 47 20(S)-Protopanaxatriol SYSTEMATIC 22736593 T 49 52 ppt ABBREVIATION 22743159 A 1325 1334 Glutamate TRIVIAL 22743159 A 311 320 glutamate TRIVIAL 22743159 T 21 30 glutamate TRIVIAL 22745189 A 465 474 sulpiride TRIVIAL 22745189 A 639 648 sulpiride TRIVIAL 22745189 A 716 725 sulpiride TRIVIAL 22745189 A 932 941 sulpiride TRIVIAL 22745189 A 966 975 Sulpiride TRIVIAL 22745189 T 16 25 sulpiride TRIVIAL 22750050 A 128 131 ATP ABBREVIATION 22750050 A 28 50 adenosine triphosphate SYSTEMATIC 22750050 A 365 371 serine TRIVIAL 22750050 A 372 381 threonine TRIVIAL 22750050 A 450 473 adenosine monophosphate SYSTEMATIC 22750050 A 52 55 ATP ABBREVIATION 22750050 A 793 803 fatty acid FAMILY 22750050 A 808 815 glucose TRIVIAL 22750079 A 186 197 mirtazapine TRIVIAL 22750079 A 268 279 Mirtazapine TRIVIAL 22750079 A 447 458 mirtazapine TRIVIAL 22750079 A 80 91 mirtazapine TRIVIAL 22750079 A 829 840 Mirtazapine TRIVIAL 22750079 T 35 46 mirtazapine TRIVIAL 22751286 A 0 9 Cisplatin TRIVIAL 22751286 A 15 46 cis-diamminedichloroplatinum II SYSTEMATIC 22751286 A 222 252 ω-3 polyunsaturated fatty acid FAMILY 22751286 A 835 845 sulfhydryl FAMILY 22751286 A 968 979 glutathione TRIVIAL 22751286 T 63 72 cisplatin TRIVIAL 22760156 A 28 38 lanthanide FAMILY 22760156 A 358 368 lanthanide FAMILY 22760156 A 871 882 bicarbonate SYSTEMATIC 22760156 A 884 891 lactate FAMILY 22760156 A 893 900 citrate FAMILY 22760156 A 905 910 urate SYSTEMATIC 22760156 T 26 36 lanthanide FAMILY 22765022 A 159 231 5,2',4'-trihydroxy-flavone-8-C-α-arabinopyranoside-7-O-β-glucopyranoside SYSTEMATIC 22765022 A 246 254 apigenin TRIVIAL 22765022 A 256 286 apigenin-7-O-β-glucopyranoside SYSTEMATIC 22765022 A 288 313 apigenin 7-O-gentobioside SYSTEMATIC 22765022 A 315 323 luteolin TRIVIAL 22765022 A 325 355 luteolin-7-O-β-glucopyranoside SYSTEMATIC 22765022 A 357 393 quercetin-3,7-di-O-β-glucopyranoside SYSTEMATIC 22765022 A 395 449 quercetin-3-O-β-glucopyranoside-7-O-α-rhamnopyranoside SYSTEMATIC 22765022 A 454 462 daidzein TRIVIAL 22765022 A 8 17 flavonoid FAMILY 22765022 A 94 154 quercetin-3,7-di-O-β-glucopyranoside 4'-O-α-rhamnopyranoside SYSTEMATIC 22765022 T 0 9 Flavonoid FAMILY 22765159 A 214 231 cyclo-(Gly-L-Ala) SYSTEMATIC 22765159 A 237 256 cyclo-(L-Ala-L-Ala) SYSTEMATIC 22765159 A 262 279 cyclo-(L-Pro-Gly) SYSTEMATIC 22765159 A 285 304 cyclo-(L-Pro-L-Ser) SYSTEMATIC 22765159 A 310 345 cyclo-(L-Ala-trans-4-hydroxy-L-Pro) SYSTEMATIC 22765159 A 352 370 yclo-(L-Val-L-Pro) SYSTEMATIC 22765159 A 376 393 cyclo-(Gly-L-Tyr) SYSTEMATIC 22765159 A 399 418 cyclo-(L-Ala-L-Tyr) SYSTEMATIC 22765159 A 424 459 cyclo-(L-Tyr-trans-4-hydroxy-L-Pro) SYSTEMATIC 22765159 A 465 482 3-methylhydantoin SYSTEMATIC 22765159 A 492 506 2-piperidinone SYSTEMATIC 22765159 A 722 737 cyclodipeptides FAMILY 22766173 A 1687 1693 iodide SYSTEMATIC 22766173 A 1708 1725 terephthalic acid TRIVIAL 22766173 A 271 277 iodide SYSTEMATIC 22766173 A 292 309 terephthalic acid TRIVIAL 22766173 A 409 415 iodide SYSTEMATIC 22766173 A 420 437 terephthalic acid TRIVIAL 22766173 A 593 595 KI FORMULA 22766173 A 664 681 terephthalic acid TRIVIAL 22766173 T 20 26 iodide SYSTEMATIC 22766173 T 41 58 terephthalic acid TRIVIAL 22766394 A 1245 1254 modafinil TRIVIAL 22766394 A 1572 1581 Modafinil TRIVIAL 22766394 A 1752 1761 modafinil TRIVIAL 22766394 A 1863 1872 modafinil TRIVIAL 22766394 A 2034 2043 modafinil TRIVIAL 22766394 A 468 477 modafinil TRIVIAL 22766394 A 634 643 modafinil TRIVIAL 22766394 T 82 91 modafinil TRIVIAL 22771462 A 1062 1066 TBOA ABBREVIATION 22771462 A 1080 1084 TBOA ABBREVIATION 22771462 A 1128 1132 MPEP ABBREVIATION 22771462 A 1138 1145 CPCCOEt FORMULA 22771462 A 1198 1207 glutamate TRIVIAL 22771462 A 13 22 glutamate TRIVIAL 22771462 A 1560 1569 Glutamate TRIVIAL 22771462 A 296 300 DHPG ABBREVIATION 22771462 A 605 609 DHPG ABBREVIATION 22771462 A 709 716 CPCCOEt FORMULA 22771462 A 754 761 CPCCOEt FORMULA 22771462 A 792 807 antagonist MPEP ABBREVIATION 22771462 A 821 830 glutamate TRIVIAL 22771462 A 849 853 TBOA ABBREVIATION 22771462 A 934 938 CNQX ABBREVIATION 22771462 A 952 955 AP5 ABBREVIATION 22776039 A 1029 1036 glucose TRIVIAL 22776039 A 1213 1220 glucose TRIVIAL 22776039 A 1644 1651 glucose TRIVIAL 22776039 A 363 370 glucose TRIVIAL 22776039 A 719 726 glucose TRIVIAL 22776039 A 765 772 glucose TRIVIAL 22776039 A 887 894 glucose TRIVIAL 22776039 A 917 924 glucose TRIVIAL 22776039 T 82 89 glucose TRIVIAL 22780426 A 109 119 octaketide SYSTEMATIC 22780426 A 132 148 dindygulerione D TRIVIAL 22780426 A 165 179 acylresorcinol SYSTEMATIC 22780426 A 191 206 dindyguleranone TRIVIAL 22780426 A 329 345 Dindygulerione C TRIVIAL 22780426 A 392 402 polyketide FAMILY 22780426 A 473 577 (-)-(4S)-2-[(Z)-1'-(6″,7″-dihydroxyphenethyl-amino)octadec-11'-enylidene]-4-hydroxycyclohexane-1,3-dione SYSTEMATIC 22780426 A 56 66 polyketide FAMILY 22780426 A 583 649 (+)-2-heptadecyl-4-hydroxy-3,4,7,8-tetrahydro-2H-chromen-5(6H)-one SYSTEMATIC 22780426 A 658 698 2-(1,3-dihydroxyphenyl)-octacosan-1'-one SYSTEMATIC 22780426 A 79 95 dindygulerione C TRIVIAL 22780563 A 0 14 Hydroxyapatite TRIVIAL 22780563 A 151 157 carbon SYSTEMATIC 22780563 A 331 337 carbon SYSTEMATIC 22780563 A 384 399 Calcium acetate SYSTEMATIC 22780563 A 401 417 Ca (CH(3)COO)(2) FORMULA 22780563 A 423 438 phosphoric acid SYSTEMATIC 22780563 A 440 449 H(3)PO(4) FORMULA 22780563 A 680 682 Ti FORMULA 22780563 A 757 766 n-butanol SYSTEMATIC 22780563 T 21 35 hydroxyapatite TRIVIAL 22780563 T 46 52 carbon SYSTEMATIC 22788542 A 199 204 rutin TRIVIAL 22788542 A 209 218 quercetin TRIVIAL 22788542 A 219 229 flavonoids FAMILY 22788542 A 413 418 rutin TRIVIAL 22788542 A 423 432 quercetin TRIVIAL 22788542 A 624 629 rutin TRIVIAL 22788542 A 634 643 quercetin TRIVIAL 22788700 A 21 32 polyphenols FAMILY 22788700 A 34 45 chlorogenic FAMILY 22788700 A 361 371 polyphenol FAMILY 22788700 A 430 441 polyphenols FAMILY 22788700 A 47 54 caffeic FAMILY 22788700 A 505 516 polyphenols FAMILY 22788700 A 537 542 rutin TRIVIAL 22788700 A 56 59 CaA ABBREVIATION 22788700 A 622 632 polyphenol FAMILY 22788700 A 65 78 ferulic acids FAMILY 22788700 A 756 766 polyphenol FAMILY 22788700 A 817 820 CaA ABBREVIATION 22788700 A 84 89 rutin TRIVIAL 22788700 T 0 10 Polyphenol FAMILY 22788743 A 110 119 vitamin C TRIVIAL 22788743 A 121 127 folate TRIVIAL 22788743 A 132 140 phenolic FAMILY 22789395 A 168 189 p-hydroxybenzoic acid SYSTEMATIC 22789395 A 259 267 parabens FAMILY 22789395 A 68 112 methyl, ethyl, n-propyl and n-butyl parabens MULTIPLE 22789395 A 825 833 parabens FAMILY 22789395 A 882 890 parabens FAMILY 22789395 T 21 29 parabens FAMILY 22799569 A 0 10 Flavonoids FAMILY 22799569 A 295 305 Flavonoids FAMILY 22799569 A 344 354 flavonoids FAMILY 22799569 A 360 383 quercetin 3-O-glucoside SYSTEMATIC 22799569 A 389 413 quercetin 3-O-rhamnoside SYSTEMATIC 22799569 A 419 460 quercetin 3-O-rhamnosyl-(1 → 6)-glucoside SYSTEMATIC 22799569 A 469 530 quercetin 3-O-rhamnosyl-(1 → 2)-[rhamnosyl-(1 → 6)]-glucoside SYSTEMATIC 22799569 A 550 559 Flavonoid FAMILY 22799569 T 0 10 Flavonoids FAMILY 22804459 A 410 417 ethanol SYSTEMATIC 22804459 A 431 438 ethanol SYSTEMATIC 22804459 A 443 451 methanol SYSTEMATIC 22804459 A 557 572 rosmarinic acid TRIVIAL 22804459 A 574 586 caffeic acid TRIVIAL 22804459 A 588 605 lithospermic acid TRIVIAL 22804459 A 610 628 salvianolic acid C TRIVIAL 22804459 A 728 734 Trolox TRIVIAL 22804459 A 751 758 ethanol SYSTEMATIC 22804459 A 824 828 DPPH ABBREVIATION 22804459 A 833 839 ferric SYSTEMATIC 22809021 A 1209 1221 progesterone TRIVIAL 22809021 A 1324 1336 progesterone TRIVIAL 22809021 A 678 690 progesterone TRIVIAL 22809021 A 722 731 estradiol TRIVIAL 22809021 T 117 129 progesterone TRIVIAL 22809387 A 228 245 polyethyleneimine SYSTEMATIC 22809387 A 413 422 LiFePO(4) FORMULA 22809387 A 423 425 Li FORMULA 22809387 A 496 503 LiPF(6) FORMULA 22809387 T 50 53 PEI ABBREVIATION 22809387 T 97 99 Li FORMULA 22813628 A 292 312 phthalate monoesters FAMILY 22813628 A 314 333 monobutyl phthalate SYSTEMATIC 22813628 A 335 339 MBuP FORMULA 22813628 A 342 362 monobenzyl phthalate SYSTEMATIC 22813628 A 364 368 MBzP FORMULA 22813628 A 374 403 mono-(2-ethylhexyl) phthalate SYSTEMATIC 22813628 A 405 409 MEHP ABBREVIATION 22813628 A 435 455 monomethyl phthalate SYSTEMATIC 22813628 A 457 460 MMP ABBREVIATION 22813628 A 663 683 phthalate monoesters FAMILY 22813628 A 851 855 MEHP ABBREVIATION 22813628 A 856 860 MBzP FORMULA 22813628 A 861 865 MBuP FORMULA 22813628 A 866 869 MMP ABBREVIATION 22813628 A 997 1016 phthalate monoester SYSTEMATIC 22813628 T 26 40 monophthalates FAMILY 22815230 A 1011 1015 DPPH ABBREVIATION 22815230 A 361 368 acetone SYSTEMATIC 22815230 A 369 377 methanol SYSTEMATIC 22815230 A 507 537 1,1-diphenyl-2-picryl hydrazyl SYSTEMATIC 22815230 A 569 573 DPPH ABBREVIATION 22815230 A 576 583 ferrous SYSTEMATIC 22815230 A 618 624 ferric SYSTEMATIC 22815230 A 818 829 trypan blue TRIVIAL 22815230 A 977 982 FeSO4 FORMULA 22815248 A 1027 1040 ethylmorphine SYSTEMATIC 22815248 A 1041 1042 N FORMULA 22815248 A 1059 1066 aniline SYSTEMATIC 22815248 A 1127 1131 CCl4 FORMULA 22815248 A 1152 1161 silymarin FAMILY 22815248 A 1337 1341 CCl4 FORMULA 22815248 A 1392 1401 silymarin FAMILY 22815248 A 207 218 paracetamol TRIVIAL 22815248 A 228 248 carbon tetrachloride SYSTEMATIC 22815248 A 250 254 CCl4 FORMULA 22815248 A 296 305 silymarin FAMILY 22815248 A 356 360 CCl4 FORMULA 22815248 A 434 443 silymarin FAMILY 22815248 A 483 492 aspartate TRIVIAL 22815248 A 49 56 saponin FAMILY 22815248 A 511 518 alanine TRIVIAL 22815248 A 537 544 lactate FAMILY 22815248 A 580 591 glutathione TRIVIAL 22815248 A 593 596 GSH ABBREVIATION 22815248 A 624 639 malondialdehyde TRIVIAL 22815248 A 641 644 MDA ABBREVIATION 22815248 A 674 678 CCl4 FORMULA 22815248 A 779 782 MDA ABBREVIATION 22815248 A 833 836 GSH ABBREVIATION 22815248 A 914 918 CCl4 FORMULA 22815248 A 967 976 silymarin FAMILY 22815248 T 33 40 Saponin FAMILY 22818587 A 1118 1128 tryptophan TRIVIAL 22820275 A 0 11 Atomoxetine TRIVIAL 22820275 A 1014 1024 isoflurane TRIVIAL 22820275 A 1044 1047 ATM ABBREVIATION 22820275 A 13 16 ATM ABBREVIATION 22820275 A 1324 1327 ATM ABBREVIATION 22820275 A 1400 1403 ATM ABBREVIATION 22820275 A 1500 1503 ATM ABBREVIATION 22820275 A 1936 1939 ATM ABBREVIATION 22820275 A 2052 2055 ATM ABBREVIATION 22820275 A 2208 2211 ATM ABBREVIATION 22820275 A 2416 2419 ATM ABBREVIATION 22820275 A 247 250 ATM ABBREVIATION 22820275 A 30 44 norepinephrine TRIVIAL 22820275 A 470 473 ATM ABBREVIATION 22820275 A 576 579 ATM ABBREVIATION 22820275 A 735 738 ATM ABBREVIATION 22820275 A 905 908 ATM ABBREVIATION 22820275 T 0 11 Atomoxetine TRIVIAL 22824787 A 244 254 fluoxetine TRIVIAL 22824787 A 256 259 FLX ABBREVIATION 22824787 A 393 396 FLX ABBREVIATION 22824787 A 626 629 FLX ABBREVIATION 22824787 A 780 783 FLX ABBREVIATION 22824787 T 47 57 fluoxetine TRIVIAL 22824788 A 259 266 cadmium SYSTEMATIC 22824788 A 432 439 cadmium SYSTEMATIC 22824788 A 607 614 cadmium SYSTEMATIC 22824788 A 704 711 cadmium SYSTEMATIC 22824788 A 807 814 cadmium SYSTEMATIC 22827445 A 1100 1105 C(60) TRIVIAL 22827445 A 1161 1166 C(60) TRIVIAL 22827445 A 1296 1306 POT-co-DOT ABBREVIATION 22827445 A 1307 1312 C(60) TRIVIAL 22827445 A 1454 1464 POT-co-DOT ABBREVIATION 22827445 A 443 452 thiophene SYSTEMATIC 22827445 A 467 530 poly(3-octylthiophene-2,5-diyl-co-3-decyloxythiophene-2,5-diyl) SYSTEMATIC 22827445 A 532 542 POT-co-DOT ABBREVIATION 22827445 A 639 649 POT-co-DOT ABBREVIATION 22827445 A 722 729 toluene TRIVIAL 22827445 A 758 770 acetonitrile SYSTEMATIC 22827445 A 962 972 POT-co-DOT ABBREVIATION 22827445 A 977 982 C(60) TRIVIAL 22827445 T 34 43 thiophene SYSTEMATIC 22827445 T 84 87 C60 TRIVIAL 22827894 A 1028 1033 oxime SYSTEMATIC 22827894 A 1189 1194 oxime SYSTEMATIC 22827894 A 1265 1270 oxime SYSTEMATIC 22827894 A 128 134 oximes FAMILY 22827894 A 1354 1359 oxime SYSTEMATIC 22827894 A 1555 1561 oximes FAMILY 22827894 A 1602 1607 oxime SYSTEMATIC 22827894 A 286 292 oximes FAMILY 22827894 A 34 50 organophosphorus FAMILY 22827894 A 492 498 oximes FAMILY 22827894 A 721 727 oximes FAMILY 22827894 A 973 993 bispyridinium oximes FAMILY 22827894 T 139 145 oximes FAMILY 22827894 T 38 44 oximes FAMILY 22830982 A 1010 1028 hydroxy-omeprazole SYSTEMATIC 22830982 A 1056 1067 dextrorphan TRIVIAL 22830982 A 1321 1337 dextromethorpahn TRIVIAL 22830982 A 1342 1352 omeprazole TRIVIAL 22830982 A 545 566 Fluorescein diacetate SYSTEMATIC 22830982 A 686 695 midazolam TRIVIAL 22830982 A 697 708 tolbutamide TRIVIAL 22830982 A 710 718 caffeine TRIVIAL 22830982 A 720 730 omeprazole TRIVIAL 22830982 A 732 748 dextromethorphan TRIVIAL 22830982 A 750 763 acetaminophen TRIVIAL 22830982 A 768 779 repaglinide TRIVIAL 22830982 A 874 886 paraxanthine TRIVIAL 22830982 A 901 915 1-OH-midazolam TRIVIAL 22830982 A 921 939 omeprazole sulfone TRIVIAL 22830982 A 964 984 hydroxyl-repaglinide SYSTEMATIC 22832075 A 0 9 Vitamin A FAMILY 22832075 A 1308 1317 vitamin-A FAMILY 22832075 A 1338 1351 retinoic acid TRIVIAL 22832075 A 1471 1480 vitamin A FAMILY 22832075 A 1617 1630 retinoic acid TRIVIAL 22832075 A 243 252 retinoids FAMILY 22832075 A 342 355 retinoic acid TRIVIAL 22832075 A 386 395 vitamin A FAMILY 22832075 A 426 435 vitamin A FAMILY 22832075 A 611 634 all-trans-retinoic acid TRIVIAL 22832075 A 666 673 retinol TRIVIAL 22832075 A 732 741 vitamin-A FAMILY 22832075 A 788 811 all-trans-retinoic acid TRIVIAL 22832075 A 895 904 vitamin-A FAMILY 22832075 T 0 9 Vitamin A FAMILY 22832075 T 158 171 retinoic acid TRIVIAL 22834411 A 198 207 1-butanol SYSTEMATIC 22834411 A 213 241 dodecylbenzenesulphonic acid SYSTEMATIC 22834411 A 28 42 barium ferrite SYSTEMATIC 22834411 T 17 31 barium ferrite SYSTEMATIC 22836659 A 711 714 Gly FORMULA 22836659 A 715 718 Cys FORMULA 22836881 A 889 896 aspirin TRIVIAL 22836881 A 922 930 nitrates FAMILY 22838394 A 10 30 diarylbutane lignans FAMILY 22838394 A 136 161 dihydroclusin monoacetate SYSTEMATIC 22838394 A 254 296 2,3-demethoxy-secoisolintetralin diacetate SYSTEMATIC 22838394 A 305 328 dihydroclusin diacetate SYSTEMATIC 22838394 A 38 77 9-acetyl-9'-pentadecanoil-dihydroclusin SYSTEMATIC 22838394 A 395 399 (1)H FORMULA 22838394 A 404 409 (13)C FORMULA 22838394 A 83 127 2,3-demethoxy-secoisolintetralin monoacetate SYSTEMATIC 22838394 T 10 30 diarylbutane lignans FAMILY 22840199 A 174 185 citronellol TRIVIAL 22840199 A 196 204 geraniol TRIVIAL 22840199 A 384 395 chamazulene TRIVIAL 22840199 A 408 415 camphor TRIVIAL 22840229 A 146 159 cyclonerodiol TRIVIAL 22840229 A 168 188 10(Z)-cyclonerotriol TRIVIAL 22840229 A 6 19 sesquiterpene FAMILY 22840229 T 6 16 cyclonerol TRIVIAL 22841391 A 1147 1160 methylselenol SYSTEMATIC 22841391 A 274 287 methylselenol SYSTEMATIC 22841391 A 33 46 methylselenol SYSTEMATIC 22841391 A 358 371 methylselenol SYSTEMATIC 22841391 A 574 587 methylselenol SYSTEMATIC 22841391 A 61 69 selenium SYSTEMATIC 22841391 A 762 775 methylselenol SYSTEMATIC 22841391 A 995 1008 methylselenol SYSTEMATIC 22841391 T 0 13 Methylselenol SYSTEMATIC 22841391 T 17 25 selenium SYSTEMATIC 22841397 A 1074 1084 acetyl-CoA SYSTEMATIC 22841397 A 1157 1164 glucose TRIVIAL 22841397 A 1189 1196 glucose TRIVIAL 22841397 A 1242 1248 biotin TRIVIAL 22841397 A 1295 1302 glucose TRIVIAL 22841397 A 1332 1338 Biotin TRIVIAL 22841397 A 1654 1660 biotin TRIVIAL 22841397 A 166 172 biotin TRIVIAL 22841397 A 1743 1749 biotin TRIVIAL 22841397 A 1849 1855 biotin TRIVIAL 22841397 A 318 324 biotin TRIVIAL 22841397 A 44 50 biotin TRIVIAL 22841397 A 445 451 biotin TRIVIAL 22841397 A 578 584 biotin TRIVIAL 22841397 A 643 650 glucose TRIVIAL 22841397 A 780 786 biotin TRIVIAL 22841397 T 11 17 biotin TRIVIAL 22841397 T 91 98 glucose TRIVIAL 22841916 A 1131 1139 caffeine TRIVIAL 22841916 A 22 30 caffeine TRIVIAL 22841916 A 309 318 adenosine TRIVIAL 22841916 A 387 395 caffeine TRIVIAL 22841916 A 436 444 caffeine TRIVIAL 22841916 A 641 649 Caffeine TRIVIAL 22841916 A 849 857 caffeine TRIVIAL 22841916 T 8 16 caffeine TRIVIAL 22841917 A 0 39 Omega-(n)-3 polyunsaturated fatty acids FAMILY 22841917 A 113 116 EPA ABBREVIATION 22841917 A 1150 1154 PUFA ABBREVIATION 22841917 A 336 340 PUFA ABBREVIATION 22841917 A 41 46 PUFAs ABBREVIATION 22841917 A 562 566 PUFA ABBREVIATION 22841917 A 59 79 docosahexaenoic acid SYSTEMATIC 22841917 A 81 84 DHA ABBREVIATION 22841917 A 90 111 eicosapentaenoic acid SYSTEMATIC 22841917 A 908 912 PUFA ABBREVIATION 22841917 T 25 44 omega-3 fatty acids FAMILY 22846225 A 1140 1143 ZIP ABBREVIATION 22846225 A 1148 1161 chelerythrine TRIVIAL 22846225 A 1582 1585 ZIP ABBREVIATION 22846225 A 1605 1608 ZIP ABBREVIATION 22846225 A 1778 1791 staurosporine TRIVIAL 22846225 A 182 221 myristoylated ζ-pseudosubstrate peptide TRIVIAL 22846225 A 2063 2076 staurosporine TRIVIAL 22846225 A 223 226 ZIP ABBREVIATION 22846225 A 2267 2270 ZIP ABBREVIATION 22846225 A 2275 2288 chelerythrine TRIVIAL 22846225 A 2314 2317 ZIP ABBREVIATION 22846225 A 2322 2335 staurosporine TRIVIAL 22846225 A 465 468 ZIP ABBREVIATION 22846225 A 545 558 Chelerythrine TRIVIAL 22846225 T 55 58 ZIP ABBREVIATION 22849656 A 159 170 neurotensin TRIVIAL 22849656 A 190 198 tyrosine TRIVIAL 22849972 A 863 870 glucose TRIVIAL 22849972 A 884 895 cholesterol TRIVIAL 22859660 A 1014 1017 ISO ABBREVIATION 22859660 A 104 118 phenylepherine TRIVIAL 22859660 A 1059 1070 fenofibrate TRIVIAL 22859660 A 1100 1103 Ach ABBREVIATION 22859660 A 1105 1108 SNP ABBREVIATION 22859660 A 1113 1116 ISO ABBREVIATION 22859660 A 1176 1187 fenofibrate TRIVIAL 22859660 A 1225 1236 fenofibrate TRIVIAL 22859660 A 1343 1346 Ach ABBREVIATION 22859660 A 1348 1351 SNP ABBREVIATION 22859660 A 1356 1359 ISO ABBREVIATION 22859660 A 167 180 acetylcholine SYSTEMATIC 22859660 A 182 185 Ach ABBREVIATION 22859660 A 188 208 sodium nitroprusside SYSTEMATIC 22859660 A 210 213 SNP ABBREVIATION 22859660 A 219 232 isoproterenol TRIVIAL 22859660 A 234 237 ISO ABBREVIATION 22859660 A 257 265 glycerol TRIVIAL 22859660 A 323 334 fenofibrate TRIVIAL 22859660 A 468 479 fenofibrate TRIVIAL 22859660 A 630 641 fenofibrate TRIVIAL 22859660 A 852 863 fenofibrate TRIVIAL 22859660 A 954 957 Ach ABBREVIATION 22859660 A 959 962 SNP ABBREVIATION 22859660 A 967 970 ISO ABBREVIATION 22859660 T 11 22 fenofibrate TRIVIAL 22859660 T 65 73 glycerol TRIVIAL 22862926 A 195 202 glucose TRIVIAL 22862926 A 325 332 glucose TRIVIAL 22862926 A 377 384 glucose TRIVIAL 22862926 A 423 430 glucose TRIVIAL 22862926 A 906 913 glucose TRIVIAL 22862926 A 983 990 glucose TRIVIAL 22865292 A 1416 1427 chloroquine TRIVIAL 22865292 A 9 13 H(+) FORMULA 22867274 A 436 455 benzothiazole amide SYSTEMATIC 22867274 A 565 575 aryl amine FAMILY 22867274 A 609 610 N FORMULA 22867274 A 708 719 glutathione TRIVIAL 22867274 A 721 724 GSH ABBREVIATION 22867274 A 772 777 amide FAMILY 22867274 A 818 821 GSH ABBREVIATION 22867274 A 856 861 NADPH ABBREVIATION 22867274 A 866 869 GSH ABBREVIATION 22867274 T 48 67 benzothiazole amide SYSTEMATIC 22872141 A 0 12 Formaldehyde SYSTEMATIC 22872141 T 35 47 formaldehyde SYSTEMATIC 22872607 A 0 9 Aldo-keto SYSTEMATIC 22872607 A 1025 1033 cotinine TRIVIAL 22872607 A 111 115 PAHs ABBREVIATION 22872607 A 1239 1243 PAHs ABBREVIATION 22872607 A 1339 1343 PAHs ABBREVIATION 22872607 A 142 152 o-quinones FAMILY 22872607 A 167 173 oxygen SYSTEMATIC 22872607 A 263 267 PAHs ABBREVIATION 22872607 A 529 533 PAHs ABBREVIATION 22872607 A 626 630 PAHs ABBREVIATION 22872607 A 77 109 polycyclic aromatic hydrocarbons FAMILY 22874922 A 752 758 Ca(2+) FORMULA 22876956 A 1146 1159 peroxynitrite SYSTEMATIC 22876956 A 1167 1172 ONOO- FORMULA 22876956 A 1186 1199 peroxynitrite SYSTEMATIC 22876956 A 1230 1240 superoxide TRIVIAL 22876956 A 1242 1247 O2 •- FORMULA 22876956 A 1297 1307 superoxide TRIVIAL 22876956 A 1370 1417 6-nitro-3,4-methylenedioxyphenyl-Nacylhydrazone SYSTEMATIC 22876956 A 1419 1430 LASSBio-881 IDENTIFIER 22876956 A 1435 1450 γ-butyrolactone SYSTEMATIC 22876956 A 197 205 nitrogen SYSTEMATIC 22876956 A 210 216 oxygen SYSTEMATIC 22876956 A 402 413 desipramine TRIVIAL 22876956 A 415 425 duloxetine TRIVIAL 22876956 A 427 437 fluoxetine TRIVIAL 22876956 A 439 449 paroxetine TRIVIAL 22876956 A 451 463 escitalopram TRIVIAL 22876956 A 465 474 phenytoin TRIVIAL 22876956 A 478 491 carbamazepine TRIVIAL 22876956 A 496 509 α-lipoic acid TRIVIAL 22876956 A 644 656 indomethacin TRIVIAL 22876956 A 658 667 meloxicam TRIVIAL 22876956 A 669 678 tenoxicam TRIVIAL 22876956 A 680 690 valdecoxib TRIVIAL 22876956 T 0 8 Nitrogen SYSTEMATIC 22876956 T 10 16 oxygen SYSTEMATIC 22876956 T 20 26 sulfur SYSTEMATIC 22889561 A 557 567 danusertib TRIVIAL 22889561 T 34 44 danusertib TRIVIAL 22889612 A 1017 1020 BaP ABBREVIATION 22889612 A 104 107 BaP ABBREVIATION 22889612 A 1085 1088 BaP ABBREVIATION 22889612 A 1148 1151 RVT ABBREVIATION 22889612 A 1231 1234 BaP ABBREVIATION 22889612 A 1361 1364 RVT ABBREVIATION 22889612 A 1369 1372 BaP ABBREVIATION 22889612 A 1391 1394 RVT ABBREVIATION 22889612 A 1478 1481 BaP ABBREVIATION 22889612 A 1527 1530 RVT ABBREVIATION 22889612 A 1585 1588 BaP ABBREVIATION 22889612 A 26 40 benzo(a)pyrene SYSTEMATIC 22889612 A 369 380 resveratrol TRIVIAL 22889612 A 382 385 RVT ABBREVIATION 22889612 A 390 393 BaP ABBREVIATION 22889612 A 42 45 BaP ABBREVIATION 22889612 A 484 487 BaP ABBREVIATION 22889612 A 602 605 RVT ABBREVIATION 22889612 A 630 633 BaP ABBREVIATION 22889612 A 678 681 RVT ABBREVIATION 22889612 A 719 722 BaP ABBREVIATION 22889612 A 801 804 BaP ABBREVIATION 22889612 A 809 812 RVT ABBREVIATION 22889612 A 899 902 RVT ABBREVIATION 22889612 A 943 946 BaP ABBREVIATION 22889612 A 947 950 RVT ABBREVIATION 22889612 T 19 33 benzo(a)pyrene SYSTEMATIC 22889612 T 73 84 resveratrol TRIVIAL 22889721 A 1078 1089 Hematoxylin TRIVIAL 22889721 A 1094 1099 eosin FAMILY 22889721 A 1742 1749 calcium SYSTEMATIC 22891663 A 0 32 N,β-D-glucopyranosyl vincosamide TRIVIAL 22891663 A 271 274 GPV ABBREVIATION 22891663 A 34 37 GPV ABBREVIATION 22891663 A 514 531 hydrogen peroxide SYSTEMATIC 22891663 A 535 538 GPV ABBREVIATION 22891663 A 601 604 GPV ABBREVIATION 22891663 A 608 619 chlorophyll FAMILY 22891663 A 729 735 oxygen SYSTEMATIC 22891663 A 737 747 superoxide TRIVIAL 22891663 A 759 767 hydroxyl SYSTEMATIC 22891663 A 830 833 GPV ABBREVIATION 22891663 T 10 25 indole alkaloid FAMILY 22891663 T 26 58 N,β-D-glucopyranosyl vincosamide TRIVIAL 22898132 A 472 485 valproic acid TRIVIAL 22898132 A 487 500 retinoic acid TRIVIAL 22898132 A 502 510 caffeine TRIVIAL 22898132 A 512 529 sodium salicylate SYSTEMATIC 22898132 A 531 538 glucose TRIVIAL 22898132 A 540 551 hydroxyurea SYSTEMATIC 22898132 A 553 571 methoxyacetic acid SYSTEMATIC 22898132 A 573 583 boric acid SYSTEMATIC 22898132 A 588 603 paraoxon-methyl SYSTEMATIC 22898132 A 921 952 valproic and methoxyacetic acid MULTIPLE 22903180 T 38 44 silver SYSTEMATIC 22906569 A 1007 1016 bilirubin TRIVIAL 22906569 A 1021 1031 biliverdin TRIVIAL 22906569 A 445 454 bilirubin TRIVIAL 22906569 A 466 476 biliverdin TRIVIAL 22906572 A 1037 1040 ATP ABBREVIATION 22906572 A 1130 1136 Ca(2+) FORMULA 22906572 A 1218 1224 Ca(2+) FORMULA 22906572 A 14 20 Ca(2+) FORMULA 22906572 A 215 221 Ca(2+) FORMULA 22906572 A 589 595 Ca(2+) FORMULA 22906572 A 731 737 Ca(2+) FORMULA 22906572 A 805 810 amine SYSTEMATIC 22906572 A 811 822 heptylamine SYSTEMATIC 22906572 A 888 894 Ca(2+) FORMULA 22906572 A 896 907 Heptylamine SYSTEMATIC 22906572 A 926 929 ATP ABBREVIATION 22906572 A 997 1003 Ca(2+) FORMULA 22906572 T 76 83 calcium SYSTEMATIC 22906573 A 1064 1069 amine SYSTEMATIC 22906573 A 1085 1096 polystyrene SYSTEMATIC 22906573 A 550 561 polystyrene SYSTEMATIC 22906573 A 579 585 carbon SYSTEMATIC 22906573 A 673 684 polystyrene SYSTEMATIC 22906573 A 729 740 polystyrene SYSTEMATIC 22906573 A 897 908 polystyrene SYSTEMATIC 22906573 A 952 958 carbon SYSTEMATIC 22911509 A 267 275 graphene TRIVIAL 22911509 A 304 310 Teflon TRIVIAL 22911509 A 50 58 graphene TRIVIAL 22911509 A 652 660 graphene TRIVIAL 22911509 T 17 25 graphene TRIVIAL 22914985 A 0 17 Mycophenolic acid TRIVIAL 22914985 A 1016 1019 MPA ABBREVIATION 22914985 A 1088 1091 MPA ABBREVIATION 22914985 A 119 143 inosine-5'-monophosphate SYSTEMATIC 22914985 A 1538 1541 MPA ABBREVIATION 22914985 A 1618 1621 MPA ABBREVIATION 22914985 A 19 22 MPA ABBREVIATION 22914985 A 1916 1920 MPAG ABBREVIATION 22914985 A 1997 2000 MPA ABBREVIATION 22914985 A 2156 2160 MPAG ABBREVIATION 22914985 A 2265 2268 MPA ABBREVIATION 22914985 A 240 253 mycophenolate TRIVIAL 22914985 A 2407 2410 MPA ABBREVIATION 22914985 A 2557 2560 MPA ABBREVIATION 22914985 A 2580 2584 MPAG ABBREVIATION 22914985 A 550 553 MPA ABBREVIATION 22914985 A 584 613 mycophenolic acid glucuronide TRIVIAL 22914985 A 615 619 MPAG ABBREVIATION 22914985 A 766 769 MPA ABBREVIATION 22914985 A 849 864 MPA glucuronide TRIVIAL 22914985 A 985 1000 MPA glucuronide TRIVIAL 22914985 T 11 28 mycophenolic acid TRIVIAL 22914985 T 74 103 mycophenolic acid glucuronide TRIVIAL 22917637 A 1136 1147 (-)-cocaine TRIVIAL 22917637 A 1330 1350 (+)- and (-)-cocaine MULTIPLE 22917637 A 1546 1566 (+)- and (-)-cocaine MULTIPLE 22917637 A 1647 1658 (-)-cocaine TRIVIAL 22917637 A 1737 1748 (+)-cocaine TRIVIAL 22917637 A 1802 1813 (-)-cocaine TRIVIAL 22917637 A 183 190 cocaine TRIVIAL 22917637 A 36 43 cocaine TRIVIAL 22917637 A 366 377 (-)-cocaine TRIVIAL 22917637 A 464 475 (+)-cocaine TRIVIAL 22917637 A 558 576 [(11)C](-)-cocaine SYSTEMATIC 22917637 A 581 599 [(11)C](+)-cocaine SYSTEMATIC 22917637 A 632 650 [(11)C](-)-cocaine SYSTEMATIC 22917637 A 701 719 [(11)C](+)-cocaine SYSTEMATIC 22917637 A 837 844 cocaine TRIVIAL 22917637 A 85 92 cocaine TRIVIAL 22917637 A 873 880 cocaine TRIVIAL 22917637 A 935 946 (-)-cocaine TRIVIAL 22917637 A 992 1003 (+)-cocaine TRIVIAL 22917637 T 26 33 cocaine TRIVIAL 22917637 T 96 116 (+)- and (-)-cocaine MULTIPLE 22921987 A 412 425 malonaldehyde TRIVIAL 22921987 A 427 430 MDA ABBREVIATION 22921987 A 739 742 MDA ABBREVIATION 22921987 A 94 102 Psoralen TRIVIAL 22923473 A 161 168 glucose TRIVIAL 22923473 A 272 280 fructose TRIVIAL 22923473 A 402 410 fructose TRIVIAL 22923473 A 558 565 glucose TRIVIAL 22923473 A 645 652 glucose TRIVIAL 22923473 T 109 116 glucose TRIVIAL 22926048 A 1011 1015 HEDS ABBREVIATION 22926048 A 1063 1070 glucose TRIVIAL 22926048 A 1241 1248 glucose TRIVIAL 22926048 A 184 191 glucose TRIVIAL 22926048 A 24 31 glucose TRIVIAL 22926048 A 297 319 hydroxyethyl disulfide SYSTEMATIC 22926048 A 321 325 HEDS ABBREVIATION 22926048 A 330 335 NADPH ABBREVIATION 22926048 A 337 340 GSH ABBREVIATION 22926048 A 342 346 GSSG ABBREVIATION 22926048 A 354 365 glutathione TRIVIAL 22926048 A 525 532 glucose TRIVIAL 22926048 A 536 543 glucose TRIVIAL 22926048 A 565 569 HEDS ABBREVIATION 22926048 A 57 74 pentose phosphate FAMILY 22926048 A 602 609 glucose TRIVIAL 22926048 A 662 669 glucose TRIVIAL 22926048 A 705 710 NADPH ABBREVIATION 22926048 A 736 741 thiol FAMILY 22926048 A 910 914 HEDS ABBREVIATION 22926048 A 98 103 thiol FAMILY 22926048 T 105 112 glucose TRIVIAL 22926048 T 35 52 pentose phosphate FAMILY 22931186 A 1131 1141 creatinine TRIVIAL 22931186 A 1297 1306 etoposide TRIVIAL 22931186 A 182 191 etoposide TRIVIAL 22931186 A 228 237 Etoposide TRIVIAL 22931186 A 332 342 creatinine TRIVIAL 22931186 A 483 492 etoposide TRIVIAL 22931186 T 25 34 etoposide TRIVIAL 22931212 A 1046 1054 thiazole SYSTEMATIC 22931212 A 1076 1082 phenyl SYSTEMATIC 22931212 A 1123 1133 amino acid FAMILY 22931212 A 1195 1201 sulfur SYSTEMATIC 22931212 A 1214 1222 thiazole SYSTEMATIC 22931212 A 1333 1339 ribose TRIVIAL 22931212 A 185 189 NADP ABBREVIATION 22931212 A 191 192 H FORMULA 22931212 A 194 197 NAD ABBREVIATION 22931212 A 199 200 H FORMULA 22931212 A 206 235 β-nicotinamide mononucleotide FAMILY 22931212 A 237 240 NMN ABBREVIATION 22931212 A 282 312 adenine dinucleotide phosphate SYSTEMATIC 22931212 A 324 327 ADP ABBREVIATION 22931212 A 332 339 adenine TRIVIAL 22931212 A 375 390 5-phosphoribose SYSTEMATIC 22931212 A 38 44 ribose TRIVIAL 22931212 A 402 405 Rib ABBREVIATION 22931212 A 471 477 ribose TRIVIAL 22931212 A 490 493 Rib ABBREVIATION 22931212 A 502 508 ribose TRIVIAL 22931212 A 520 523 Rib ABBREVIATION 22931212 A 537 552 carboxylic acid SYSTEMATIC 22931212 A 556 559 Rib ABBREVIATION 22931212 A 564 567 Rib ABBREVIATION 22931212 A 66 70 NADH ABBREVIATION 22931212 A 744 750 ribose TRIVIAL 22931212 A 773 776 NAD ABBREVIATION 22931212 A 778 779 H FORMULA 22931212 A 823 826 Rib ABBREVIATION 22931212 A 834 837 Rib ABBREVIATION 22931212 A 91 99 pyrazole SYSTEMATIC 22931212 A 943 946 Rib ABBREVIATION 22931212 T 32 38 ribose TRIVIAL 22931212 T 56 64 pyrazole SYSTEMATIC 22935104 A 35 45 sildenafil TRIVIAL 22935104 A 50 61 thalidomide TRIVIAL 22940283 A 1122 1140 thiocholine esters FAMILY 22940855 A 1000 1012 thione dimer FAMILY 22940855 A 1016 1027 thiol dimer FAMILY 22940855 A 102 110 hydrogen SYSTEMATIC 22940855 A 1087 1098 thiol dimer FAMILY 22940855 A 1102 1114 thione dimer FAMILY 22940855 A 118 141 thione and thiol dimers MULTIPLE 22940855 A 1276 1284 hydrogen SYSTEMATIC 22940855 A 1470 1471 H FORMULA 22940855 A 1500 1502 S1 FORMULA 22940855 A 1503 1505 H2 FORMULA 22940855 A 1508 1510 N2 FORMULA 22940855 A 1511 1513 N2 FORMULA 22940855 A 1514 1516 H2 FORMULA 22940855 A 1519 1521 S1 FORMULA 22940855 A 1522 1524 N3 FORMULA 22940855 A 1525 1528 H3B FORMULA 22940855 A 1531 1533 O1 FORMULA 22940855 A 155 163 triazole FAMILY 22940855 A 19 31 thione-thiol FAMILY 22940855 A 363 373 chloroform TRIVIAL 22940855 A 375 383 methanol SYSTEMATIC 22940855 A 494 500 thione FAMILY 22940855 A 775 787 thione dimer FAMILY 22940855 A 820 831 thiol dimer FAMILY 22940855 T 127 185 4-amino-5-(2-hydroxyphenyl)-2H-1,2,4-triazole-3(4H)-thione SYSTEMATIC 22940855 T 94 102 hydrogen SYSTEMATIC 22945693 A 1412 1415 CpG ABBREVIATION 22945693 A 837 840 CpG ABBREVIATION 22945693 T 22 35 sodium-iodide SYSTEMATIC 22949511 A 1162 1167 lysyl TRIVIAL 22949511 A 1352 1364 hydroxylates FAMILY 22949511 A 1381 1386 lysyl TRIVIAL 22949511 A 336 342 prolyl TRIVIAL 22949511 T 141 148 lysines FAMILY 22954532 A 1118 1120 WC FORMULA 22954532 A 1248 1254 sodium SYSTEMATIC 22954532 A 141 157 Tungsten carbide SYSTEMATIC 22954532 A 178 180 WC FORMULA 22954532 A 297 299 WC FORMULA 22954532 A 389 391 WC FORMULA 22954532 A 395 407 tetrodotoxin TRIVIAL 22954532 A 409 412 TTX ABBREVIATION 22954532 A 442 448 sodium SYSTEMATIC 22954532 A 460 462 Na FORMULA 22954532 A 546 548 WC FORMULA 22954532 A 585 587 Na FORMULA 22954532 A 699 701 WC FORMULA 22954532 A 780 782 Na FORMULA 22954532 A 868 870 Na FORMULA 22954532 A 913 915 Na FORMULA 22954532 A 965 967 WC FORMULA 22954532 T 21 37 tungsten carbide SYSTEMATIC 22954532 T 69 75 sodium SYSTEMATIC 22955948 A 220 237 hydrogen peroxide SYSTEMATIC 22955948 A 239 247 H(2)O(2) FORMULA 22955948 A 454 463 rapamycin TRIVIAL 22955948 A 500 509 rapamycin TRIVIAL 22955948 A 632 640 H(2)O(2) FORMULA 22955948 A 707 715 H(2)O(2) FORMULA 22955948 A 968 976 H(2)O(2) FORMULA 22955948 T 15 32 hydrogen peroxide SYSTEMATIC 22956629 A 14 30 titanium dioxide SYSTEMATIC 22956629 A 1605 1611 TiO(2) FORMULA 22956629 A 32 38 TiO(2) FORMULA 22956629 T 63 79 titanium dioxide SYSTEMATIC 22956630 A 0 8 Parabens FAMILY 22956630 A 104 117 propylparaben SYSTEMATIC 22956630 A 1060 1081 4-hydroxybenzoic acid SYSTEMATIC 22956630 A 1112 1120 parabens FAMILY 22956630 A 1151 1163 benzoic acid SYSTEMATIC 22956630 A 1177 1179 OH FORMULA 22956630 A 119 131 butylparaben SYSTEMATIC 22956630 A 1251 1259 parabens FAMILY 22956630 A 137 150 benzylparaben SYSTEMATIC 22956630 A 1479 1487 parabens FAMILY 22956630 A 152 182 Paraben esters and their salts MULTIPLE 22956630 A 1563 1571 parabens FAMILY 22956630 A 1573 1597 butyl- and benzylparaben MULTIPLE 22956630 A 1722 1730 parabens FAMILY 22956630 A 1783 1791 parabens FAMILY 22956630 A 24 36 alkyl esters FAMILY 22956630 A 291 299 parabens FAMILY 22956630 A 40 61 p-hydroxybenzoic acid SYSTEMATIC 22956630 A 417 425 parabens FAMILY 22956630 A 467 475 parabens FAMILY 22956630 A 555 563 parabens FAMILY 22956630 A 75 88 methylparaben SYSTEMATIC 22956630 A 778 786 parabens FAMILY 22956630 A 889 895 methyl SYSTEMATIC 22956630 A 899 904 ethyl SYSTEMATIC 22956630 A 90 102 ethylparaben SYSTEMATIC 22956630 A 908 914 propyl SYSTEMATIC 22956630 A 918 930 butylparaben SYSTEMATIC 22956630 A 997 1010 benzylparaben SYSTEMATIC 22956630 T 11 19 parabens FAMILY 22958332 A 1130 1136 oxygen SYSTEMATIC 22958332 A 1153 1167 carbon dioxide SYSTEMATIC 22960471 A 1028 1046 7-aminoactinomycin SYSTEMATIC 22960471 A 1048 1053 7-AAD SYSTEMATIC 22960471 A 416 432 sulforhodamine B TRIVIAL 22960471 A 500 508 nicotine TRIVIAL 22960471 A 599 607 Nicotine TRIVIAL 22961087 A 1045 1058 triglycerides FAMILY 22961200 A 789 806 alanine dipeptide FAMILY 22963367 A 1393 1398 GdOCl FORMULA 22963367 A 1524 1538 Tb-doped GdOCl FORMULA 22963367 A 1552 1568 indium tin oxide SYSTEMATIC 22963367 A 1570 1573 ITO ABBREVIATION 22963367 A 463 468 GdOCl FORMULA 22963367 A 602 607 GdOCl FORMULA 22963367 A 884 889 GdOCl FORMULA 22963367 A 909 920 cyclohexane SYSTEMATIC 22963367 T 39 44 GdOCl FORMULA 22963553 A 1009 1028 Ipratropium bromide TRIVIAL 22963553 A 1105 1123 Oxitropium bromide TRIVIAL 22963553 A 1153 1171 Tiotropium bromide TRIVIAL 22963553 A 1292 1310 aclidinium bromide TRIVIAL 22963553 A 1315 1337 glycopyrrolate bromide TRIVIAL 22963553 A 1498 1508 tiotropium TRIVIAL 22963553 A 945 964 ipratropium bromide TRIVIAL 22963553 A 966 984 oxitropium bromide TRIVIAL 22963553 A 989 1007 tiotropium bromide TRIVIAL 22963554 A 1312 1326 corticosteroid TRIVIAL 22963554 A 1451 1463 theophylline TRIVIAL 22963554 A 1465 1478 nortriptyline TRIVIAL 22963554 A 1483 1493 macrolides FAMILY 22963619 A 104 114 methionine TRIVIAL 22963619 A 151 161 amino acid FAMILY 22963619 A 281 291 methionine TRIVIAL 22963619 A 374 383 Methionin TRIVIAL 22963619 A 389 393 DTPA ABBREVIATION 22963619 A 394 404 Methionine TRIVIAL 22963619 A 454 461 (99m)Tc FORMULA 22963619 A 657 664 (99m)Tc FORMULA 22963619 A 680 689 Methionin TRIVIAL 22963619 A 746 751 99mTc FORMULA 22963619 A 752 756 DTPA ABBREVIATION 22963619 A 757 767 Methionine TRIVIAL 22963619 A 796 803 (99m)Tc FORMULA 22963619 A 819 828 Methionin TRIVIAL 22963619 A 82 93 amino acids FAMILY 22963619 A 832 837 99mTc FORMULA 22963619 A 838 842 DTPA ABBREVIATION 22963619 A 844 854 Methionine TRIVIAL 22963619 T 69 79 methionine TRIVIAL 22966070 A 1002 1006 O(2) FORMULA 22966070 A 1280 1283 tyr FORMULA 22966070 A 1349 1357 tyrosine TRIVIAL 22966070 A 339 346 glucose TRIVIAL 22966070 A 588 596 tyrosine TRIVIAL 22966070 A 620 623 tyr FORMULA 22966070 A 700 708 tyrosine TRIVIAL 22966070 A 955 962 glucose TRIVIAL 22966070 A 976 983 glucose TRIVIAL 22967722 A 1053 1072 phosphoenolpyruvate SYSTEMATIC 22967722 A 1091 1098 glucose TRIVIAL 22967722 A 1157 1166 carnitine TRIVIAL 22967722 A 1232 1241 glabridin TRIVIAL 22967722 A 1246 1255 glabridin TRIVIAL 22967722 A 180 189 glabridin TRIVIAL 22967722 A 194 203 glabridin TRIVIAL 22967722 A 256 265 Glabridin TRIVIAL 22967722 A 72 81 glabridin TRIVIAL 22967722 A 88 97 isoflavan FAMILY 22967722 T 24 33 glabridin TRIVIAL 22967722 T 53 67 carbon dioxide SYSTEMATIC 22968089 A 13 22 glutamate TRIVIAL 22968089 A 438 446 LY379268 IDENTIFIER 22968089 A 479 483 MPEP ABBREVIATION 22968089 A 520 526 AMN082 IDENTIFIER 22968089 A 634 642 LY379268 IDENTIFIER 22968089 A 683 687 MPEP ABBREVIATION 22968089 A 727 733 AMN082 IDENTIFIER 22968089 T 24 33 glutamate TRIVIAL 22972178 A 1099 1107 cortisol TRIVIAL 22972178 A 1113 1120 lactate FAMILY 22972178 A 1641 1649 cortisol TRIVIAL 22972178 A 1722 1730 cortisol TRIVIAL 22972178 A 2056 2064 cortisol TRIVIAL 22972178 A 2159 2167 cortisol TRIVIAL 22972178 A 456 464 cortisol TRIVIAL 22972178 A 570 578 cortisol TRIVIAL 22972178 T 7 15 cortisol TRIVIAL 22972179 A 1277 1280 Ser FORMULA 22972179 A 256 270 2-deoxyglucose SYSTEMATIC 22972179 A 320 329 rapamycin TRIVIAL 22972179 A 430 433 Thr FORMULA 22972179 A 543 557 2-deoxyglucose SYSTEMATIC 22972179 A 907 921 2-deoxyglucose SYSTEMATIC 22972179 A 932 946 2-Deoxyglucose SYSTEMATIC 22972222 A 1125 1132 glucose TRIVIAL 22972222 A 133 140 glucose TRIVIAL 22972222 A 1447 1454 glucose TRIVIAL 22972222 A 1570 1582 vildagliptin TRIVIAL 22972222 A 1590 1597 glucose TRIVIAL 22972222 A 284 296 vildagliptin TRIVIAL 22972222 A 427 439 vildagliptin TRIVIAL 22972222 A 56 63 glucose TRIVIAL 22972222 A 630 642 vildagliptin TRIVIAL 22972222 A 83 95 vildagliptin TRIVIAL 22972222 A 844 856 vildagliptin TRIVIAL 22972222 T 108 115 glucose TRIVIAL 22972222 T 28 35 glucose TRIVIAL 22972222 T 55 67 vildagliptin TRIVIAL 22972396 A 47 55 platinum SYSTEMATIC 22972396 T 20 28 platinum SYSTEMATIC 22975146 A 1019 1028 α-asarone TRIVIAL 22975146 A 1124 1142 pentylenetetrazole SYSTEMATIC 22975146 A 1147 1154 kainate TRIVIAL 22975146 A 1171 1180 α-asarone TRIVIAL 22975146 A 1392 1396 GABA ABBREVIATION 22975146 A 1448 1457 α-asarone TRIVIAL 22975146 A 276 285 α-asarone TRIVIAL 22975146 A 385 403 pentylenetetrazole SYSTEMATIC 22975146 A 407 414 kainate TRIVIAL 22975146 A 540 549 α-asarone TRIVIAL 22975146 A 579 585 Mg(2+) FORMULA 22975146 A 6 17 (α)-asarone TRIVIAL 22975146 A 759 763 GABA ABBREVIATION 22975146 A 784 793 picotoxin TRIVIAL 22975146 A 812 816 GABA ABBREVIATION 22975146 A 840 851 bicuculline TRIVIAL 22975146 A 871 878 glycine TRIVIAL 22975146 A 898 908 strychnine TRIVIAL 22975146 A 931 935 GABA ABBREVIATION 22975146 T 0 13 Alpha-asarone TRIVIAL 22975146 T 77 81 GABA ABBREVIATION 22975155 A 1081 1086 RS41A NO CLASS 22975155 A 1091 1097 RS194B NO CLASS 22975155 A 1316 1322 RS194B NO CLASS 22975155 A 1548 1554 RS194B NO CLASS 22975155 A 1661 1666 oxime SYSTEMATIC 22975155 A 175 180 sarin TRIVIAL 22975155 A 182 192 cyclosarin TRIVIAL 22975155 A 198 206 paraoxon TRIVIAL 22975155 A 211 216 tabun TRIVIAL 22975155 A 218 267 N-substituted 2-hydroxyiminoacetamido alkylamines FAMILY 22975155 A 343 349 oximes FAMILY 22975155 A 351 356 RS41A NO CLASS 22975155 A 361 367 RS194B NO CLASS 22975155 A 416 426 pyridinium SYSTEMATIC 22975155 A 43 48 oxime SYSTEMATIC 22975155 A 441 445 2PAM ABBREVIATION 22975155 A 450 454 MMB4 IDENTIFIER 22975155 A 481 486 RS41A NO CLASS 22975155 A 740 745 RS41A NO CLASS 22975155 A 806 812 RS194B NO CLASS 22975155 A 859 865 RS194B NO CLASS 22975155 A 965 971 RS194B NO CLASS 22977168 A 224 236 diisocyanate SYSTEMATIC 22977168 A 551 563 diisocyanate SYSTEMATIC 22977168 A 776 802 hexamethylene diisocyanate SYSTEMATIC 22977168 T 53 65 diisocyanate SYSTEMATIC 22981737 A 192 193 C FORMULA 22981737 A 262 270 tyrosine TRIVIAL 22981737 A 306 319 acetylcholine SYSTEMATIC 22982206 A 1053 1063 salubrinal TRIVIAL 22982206 A 1473 1479 oxygen SYSTEMATIC 22982206 A 396 408 verrucarin A TRIVIAL 22982206 T 0 12 Verrucarin A TRIVIAL 22982773 A 105 121 organophosphorus FAMILY 22982773 A 1128 1133 sarin TRIVIAL 22982773 A 1137 1147 cyclosarin TRIVIAL 22982773 A 1195 1200 tabun TRIVIAL 22982773 A 1208 1244 O-ethyl isopropylphosphonofluoridate SYSTEMATIC 22982773 A 1289 1294 tabun TRIVIAL 22982773 A 1474 1487 dimethylamine SYSTEMATIC 22982773 A 1496 1502 alkoxy FAMILY 22982773 A 1600 1605 oxime SYSTEMATIC 22982773 A 1661 1670 phosphate SYSTEMATIC 22982773 A 1672 1683 phosphonate SYSTEMATIC 22982773 A 1687 1702 phosphoramidate SYSTEMATIC 22982773 A 18 23 oxime SYSTEMATIC 22982773 A 301 305 HI-6 IDENTIFIER 22982773 A 310 319 obidoxime TRIVIAL 22982773 A 478 483 oxime SYSTEMATIC 22982773 A 581 586 oxime SYSTEMATIC 22982773 A 730 740 phosphates FAMILY 22982773 A 742 754 phosphonates FAMILY 22982773 A 759 775 phosphoramidates FAMILY 22982773 A 805 810 oxime SYSTEMATIC 22982773 A 843 848 oxime SYSTEMATIC 22982773 A 901 938 O-methyl isopropylphosphonofluoridate SYSTEMATIC 22982773 A 945 955 cyclosarin TRIVIAL 22982773 A 966 1004 O-methyl cyclohexylphosphonofluoridate SYSTEMATIC 22982773 T 37 42 oxime SYSTEMATIC 22982773 T 93 109 organophosphorus FAMILY 22983118 A 0 33 3,4-Methylenedioxymethamphetamine SYSTEMATIC 22983118 A 1025 1028 DOI ABBREVIATION 22983118 A 1032 1036 MDMA ABBREVIATION 22983118 A 105 108 DOI ABBREVIATION 22983118 A 1167 1170 DOI ABBREVIATION 22983118 A 129 141 amphetamines FAMILY 22983118 A 1300 1304 5-HT SYSTEMATIC 22983118 A 1410 1413 DOI ABBREVIATION 22983118 A 1417 1421 MDMA ABBREVIATION 22983118 A 1453 1465 amphetamines FAMILY 22983118 A 1653 1657 5-HT SYSTEMATIC 22983118 A 257 268 amphetamine TRIVIAL 22983118 A 320 323 DOI ABBREVIATION 22983118 A 328 332 MDMA ABBREVIATION 22983118 A 35 39 MDMA ABBREVIATION 22983118 A 44 51 Ecstasy TRIVIAL 22983118 A 504 508 MDMA ABBREVIATION 22983118 A 525 528 DOI ABBREVIATION 22983118 A 551 558 lactate FAMILY 22983118 A 58 103 2,5-dimethoxy-4-iodoamphetamine hydrochloride SYSTEMATIC 22983118 A 595 606 tetrazolium SYSTEMATIC 22983118 A 614 617 MTT ABBREVIATION 22983118 A 894 897 DOI ABBREVIATION 22983118 A 963 967 MDMA ABBREVIATION 22983118 T 36 48 amphetamines FAMILY 22983652 A 224 249 Poly(methyl methacrylate) SYSTEMATIC 22983652 A 251 255 PMMA ABBREVIATION 22983652 A 278 284 carbon SYSTEMATIC 22983652 A 410 414 PMMA ABBREVIATION 22983652 A 519 523 PMMA ABBREVIATION 22983652 A 541 547 carbon SYSTEMATIC 22983652 A 671 675 PMMA ABBREVIATION 22983652 A 715 719 PMMA ABBREVIATION 22983652 A 813 819 carbon SYSTEMATIC 22983652 T 59 84 Poly(methyl methacrylate) SYSTEMATIC 22983652 T 85 91 carbon SYSTEMATIC 22985735 A 1096 1104 H(2)O(2) FORMULA 22985735 A 1109 1115 SiO(2) FORMULA 22985735 A 804 807 GSH ABBREVIATION 22985735 A 832 840 H(2)O(2) FORMULA 22985735 A 852 858 SiO(2) FORMULA 22985735 A 966 969 GSH ABBREVIATION 22985735 A 99 105 silica TRIVIAL 22985735 T 124 128 SiO2 FORMULA 22985953 A 0 5 Na(+) FORMULA 22985953 A 1222 1225 MMT ABBREVIATION 22985953 A 1282 1290 glycerol TRIVIAL 22985953 A 1295 1302 xylitol TRIVIAL 22985953 A 1342 1345 MMT ABBREVIATION 22985953 A 381 394 carbohydrates FAMILY 22985953 A 53 56 MMT ABBREVIATION 22985953 A 6 21 montmorillonite TRIVIAL 22985953 A 640 643 MMT ABBREVIATION 22985953 A 712 726 sugar alcohols FAMILY 22985953 A 728 736 glycerol TRIVIAL 22985953 A 738 745 xylitol TRIVIAL 22985953 A 759 767 hydroxyl SYSTEMATIC 22985953 A 825 828 MMT ABBREVIATION 22985953 A 859 862 MMT ABBREVIATION 22985953 A 984 987 MMT ABBREVIATION 22985953 T 38 51 sugar alcohol FAMILY 22985953 T 61 64 Na+ FORMULA 22985953 T 65 80 montmorillonite TRIVIAL 22986217 A 1025 1036 isoflavones FAMILY 22986217 A 1054 1061 glucose TRIVIAL 22986217 A 1157 1168 isoflavones FAMILY 22986217 A 227 238 isoflavones FAMILY 22986217 A 528 539 isoflavones FAMILY 22986217 A 54 65 isoflavones FAMILY 22986217 A 564 575 isoflavones FAMILY 22986217 A 697 708 fatty acids FAMILY 22986217 T 4 15 isoflavones FAMILY 22986456 A 1005 1012 glucose TRIVIAL 22986456 A 1140 1147 glucose TRIVIAL 22986456 A 1177 1188 cholesterol TRIVIAL 22986456 A 1253 1264 cholesterol TRIVIAL 22986456 A 1269 1281 triglyceride FAMILY 22986456 A 1348 1355 glucose TRIVIAL 22989703 A 1079 1102 apo-14'-lycopenoic acid SYSTEMATIC 22989703 A 1147 1170 apo-10'-lycopenoic acid SYSTEMATIC 22989703 A 1214 1222 lycopene TRIVIAL 22989703 A 1257 1277 apo-lycopenoic acids FAMILY 22989703 A 1296 1319 apo-14'-lycopenoic acid SYSTEMATIC 22989703 A 252 260 lycopene TRIVIAL 22989703 A 375 383 lycopene TRIVIAL 22989703 A 41 49 lycopene TRIVIAL 22989703 A 412 435 apo-10'-lycopenoic acid SYSTEMATIC 22989703 A 440 463 apo-14'-lycopenoic acid SYSTEMATIC 22989703 A 506 514 H(2)O(2) FORMULA 22989703 A 576 599 apo-10'-lycopenoic acid SYSTEMATIC 22989703 A 604 627 apo-14'-lycopenoic acid SYSTEMATIC 22989703 A 665 673 H(2)O(2) FORMULA 22989703 A 878 898 apo-lycopenoic acids FAMILY 22989703 A 942 948 8-OHdG SYSTEMATIC 22989703 T 129 133 H2O2 FORMULA 22989703 T 45 68 apo-10'-lycopenoic acid SYSTEMATIC 22989703 T 73 96 apo-14'-lycopenoic acid SYSTEMATIC 22989704 A 0 6 Nickel SYSTEMATIC 22989704 A 1026 1030 atRA ABBREVIATION 22989704 A 1053 1060 NiCl(2) FORMULA 22989704 A 108 131 all-trans retinoid acid SYSTEMATIC 22989704 A 1116 1120 atRA ABBREVIATION 22989704 A 1192 1198 nickel SYSTEMATIC 22989704 A 133 137 atRA ABBREVIATION 22989704 A 251 255 atRA ABBREVIATION 22989704 A 296 302 nickel SYSTEMATIC 22989704 A 417 432 nickel chloride SYSTEMATIC 22989704 A 434 441 NiCl(2) FORMULA 22989704 A 496 502 oxygen SYSTEMATIC 22989704 A 536 543 NiCl(2) FORMULA 22989704 A 643 647 atRA ABBREVIATION 22989704 A 703 710 NiCl(2) FORMULA 22989704 A 794 801 NiCl(2) FORMULA 22989704 A 840 847 NiCl(2) FORMULA 22989704 A 941 948 NiCl(2) FORMULA 22989704 T 12 35 all-trans retinoid acid SYSTEMATIC 22989704 T 50 56 nickel SYSTEMATIC 22989705 A 0 9 Cisplatin TRIVIAL 22989705 A 1005 1016 glutathione TRIVIAL 22989705 A 1018 1021 GSH ABBREVIATION 22989705 A 1119 1124 BADGE ABBREVIATION 22989705 A 1126 1138 Pioglitazone TRIVIAL 22989705 A 1180 1189 cisplatin TRIVIAL 22989705 A 1259 1264 BADGE ABBREVIATION 22989705 A 1328 1340 pioglitazone TRIVIAL 22989705 A 1359 1368 cisplatin TRIVIAL 22989705 A 1477 1489 pioglitazone TRIVIAL 22989705 A 1556 1565 cisplatin TRIVIAL 22989705 A 167 179 pioglitazone TRIVIAL 22989705 A 194 203 cisplatin TRIVIAL 22989705 A 357 366 cisplatin TRIVIAL 22989705 A 407 419 Pioglitazone TRIVIAL 22989705 A 421 449 Bisphenol A diglycidyl ether SYSTEMATIC 22989705 A 451 456 BADGE ABBREVIATION 22989705 A 606 615 cisplatin TRIVIAL 22989705 A 769 781 pioglitazone TRIVIAL 22989705 A 837 852 malondialdehyde TRIVIAL 22989705 A 854 857 MDA ABBREVIATION 22989705 A 948 957 cisplatin TRIVIAL 22989705 T 0 12 Pioglitazone TRIVIAL 22989705 T 30 39 cisplatin TRIVIAL 22991234 A 0 7 Calcium SYSTEMATIC 22991234 A 1197 1204 calcium SYSTEMATIC 22991234 A 1295 1310 calcium citrate SYSTEMATIC 22991234 A 1389 1404 calcium citrate SYSTEMATIC 22991234 A 1653 1660 calcium SYSTEMATIC 22991234 A 1773 1780 calcium SYSTEMATIC 22991234 A 1791 1798 calcium SYSTEMATIC 22991234 A 2025 2032 calcium SYSTEMATIC 22991234 A 2145 2152 calcium SYSTEMATIC 22991234 A 264 271 Calcium SYSTEMATIC 22991234 A 335 342 calcium SYSTEMATIC 22991234 A 453 460 calcium SYSTEMATIC 22991234 A 471 478 calcium SYSTEMATIC 22991234 A 735 742 calcium SYSTEMATIC 22991234 A 837 852 calcium citrate SYSTEMATIC 22991234 T 16 31 calcium citrate SYSTEMATIC 22991234 T 41 48 calcium SYSTEMATIC 22991330 A 0 24 Nitrogen-bisphosphonates FAMILY 22991330 A 1737 1741 n-BP ABBREVIATION 22991330 A 26 30 n-BP ABBREVIATION 22991330 A 275 289 bisphosphonate SYSTEMATIC 22991330 A 335 339 n-BP ABBREVIATION 22991330 A 54 74 aminobisphosphonates FAMILY 22991330 A 624 628 n-BP ABBREVIATION 22991330 A 766 770 n-BP ABBREVIATION 22991330 A 876 880 n-BP ABBREVIATION 22991330 T 126 145 aminobisphosphonate FAMILY 22992330 A 279 287 catechol TRIVIAL 22992330 A 288 289 O FORMULA 22993196 A 1016 1019 TAG ABBREVIATION 22993196 A 1075 1082 glucose TRIVIAL 22993196 A 1185 1192 glucose TRIVIAL 22993196 A 1226 1233 glucose TRIVIAL 22993196 A 1343 1350 glucose TRIVIAL 22993196 A 1383 1390 glucose TRIVIAL 22993196 A 1460 1463 TAG ABBREVIATION 22993196 A 266 273 glucose TRIVIAL 22993196 A 304 311 Glucose TRIVIAL 22993196 A 466 473 Glucose TRIVIAL 22993196 A 54 69 triacylglycerol FAMILY 22993196 A 71 74 TAG ABBREVIATION 22993196 A 772 775 TAG ABBREVIATION 22993196 A 785 792 Glucose TRIVIAL 22993196 A 8 20 triglyceride FAMILY 22993196 A 853 860 glucose TRIVIAL 22993196 A 921 928 glucose TRIVIAL 22993196 T 33 40 glucose TRIVIAL 22995755 A 1057 1060 PEI ABBREVIATION 22995755 A 1123 1132 disulfide SYSTEMATIC 22995755 A 1169 1178 disulfide SYSTEMATIC 22995755 A 12 29 polyethylenimines FAMILY 22995755 A 1259 1262 PEI ABBREVIATION 22995755 A 180 183 PEI ABBREVIATION 22995755 A 31 35 PEIs ABBREVIATION 22995755 A 318 327 disulfide SYSTEMATIC 22995755 A 484 487 PEI ABBREVIATION 22995755 A 519 528 disulfide SYSTEMATIC 22995755 T 19 35 polyethylenimine SYSTEMATIC 22995849 A 442 452 nucleotide FAMILY 22996261 A 1122 1132 Raloxifene TRIVIAL 22996261 A 1179 1183 DACA ABBREVIATION 22996261 A 1230 1240 raloxifene TRIVIAL 22996261 A 130 138 aldehyde SYSTEMATIC 22996261 A 1354 1362 aldehyde SYSTEMATIC 22996261 A 318 366 N-[(2-dimethylamino)ethyl]acridine-4-carboxamide SYSTEMATIC 22996261 A 368 372 DACA ABBREVIATION 22996261 A 375 379 DACA ABBREVIATION 22996261 A 584 588 DACA ABBREVIATION 22996261 A 688 699 phthalazine TRIVIAL 22996261 A 816 820 DACA ABBREVIATION 22996261 A 833 844 phthalazine TRIVIAL 22996261 A 883 893 raloxifene TRIVIAL 22996261 T 69 77 aldehyde SYSTEMATIC 22997060 A 1068 1071 DON ABBREVIATION 22997060 A 1251 1264 trichothecene FAMILY 22997060 A 1334 1340 kaolin TRIVIAL 22997060 A 1611 1614 DON ABBREVIATION 22997060 A 1625 1639 trichothecenes FAMILY 22997060 A 231 251 8-ketotrichothecenes FAMILY 22997060 A 36 49 trichothecene FAMILY 22997060 A 364 367 DON ABBREVIATION 22997060 A 369 392 15-acetyldeoxynivalenol SYSTEMATIC 22997060 A 394 401 15-ADON SYSTEMATIC 22997060 A 404 426 3-acetyldeoxynivalenol SYSTEMATIC 22997060 A 428 434 3-ADON SYSTEMATIC 22997060 A 437 448 fusarenon X TRIVIAL 22997060 A 459 468 nivalenol TRIVIAL 22997060 A 470 473 NIV ABBREVIATION 22997060 A 60 74 deoxynivalenol TRIVIAL 22997060 A 76 79 DON ABBREVIATION 22997060 A 83 92 vomitoxin TRIVIAL 22997060 A 876 879 DON ABBREVIATION 22997060 A 881 888 15-ADON SYSTEMATIC 22997060 A 890 896 3-ADON SYSTEMATIC 22997060 A 906 909 NIV ABBREVIATION 22997060 T 100 122 3-acetyldeoxynivalenol SYSTEMATIC 22997060 T 124 135 fusarenon X TRIVIAL 22997060 T 141 150 nivalenol TRIVIAL 22997060 T 38 73 8-ketotrichothecenes deoxynivalenol SYSTEMATIC 22997060 T 75 98 15-acetyldeoxynivalenol SYSTEMATIC 22998180 A 100 106 carbon SYSTEMATIC 22998180 A 150 153 SiC FORMULA 22998180 A 695 698 SiC FORMULA 22998180 A 73 76 SiC FORMULA 22998180 T 0 3 SiC FORMULA 23000250 A 369 382 acetylcholine SYSTEMATIC 23000250 A 515 528 acetylcholine SYSTEMATIC 23000250 A 89 99 Amino acid FAMILY 23000251 A 0 9 Quercetin TRIVIAL 23000251 A 14 19 rutin TRIVIAL 23000251 A 163 172 quercetin TRIVIAL 23000251 A 177 182 rutin TRIVIAL 23000251 A 265 275 Flavonoids FAMILY 23000251 A 325 335 flavonoids FAMILY 23000251 A 34 44 flavonoids FAMILY 23000251 A 366 375 Quercetin TRIVIAL 23000251 A 406 421 methylquercetin SYSTEMATIC 23000251 A 430 451 quercetin glucuronide TRIVIAL 23000251 A 460 465 rutin TRIVIAL 23000251 A 482 496 rutin sulphate SYSTEMATIC 23000251 A 502 513 methylrutin SYSTEMATIC 23000251 A 522 539 rutin glucuronide TRIVIAL 23000251 A 566 571 rutin TRIVIAL 23000251 A 573 582 quercetin TRIVIAL 23000251 A 620 623 MTT ABBREVIATION 23000251 A 624 635 tetrazolium SYSTEMATIC 23000251 A 659 670 trypan blue TRIVIAL 23000251 A 784 789 rutin TRIVIAL 23000251 A 794 808 rutin sulphate SYSTEMATIC 23000251 A 902 911 quercetin TRIVIAL 23000251 T 17 26 quercetin TRIVIAL 23000251 T 31 36 rutin TRIVIAL 23000442 A 0 8 Mollugin TRIVIAL 23000442 A 261 269 mollugin TRIVIAL 23000442 A 394 402 mollugin TRIVIAL 23000442 A 469 479 phenacetin TRIVIAL 23000442 A 480 481 O FORMULA 23000442 A 584 592 Mollugin TRIVIAL 23000442 A 614 624 phenacetin TRIVIAL 23000442 A 625 626 O FORMULA 23000442 A 805 813 mollugin TRIVIAL 23000442 A 925 933 mollugin TRIVIAL 23000442 T 32 40 mollugin TRIVIAL 23000447 A 1164 1174 glyphosate TRIVIAL 23000447 A 203 213 glyphosate TRIVIAL 23000447 A 305 315 glyphosate TRIVIAL 23000447 T 26 36 glyphosate TRIVIAL 23000449 A 117 126 carbamate FAMILY 23000449 A 947 962 organophosphate FAMILY 23000449 A 99 115 organophosphates FAMILY 23000450 A 1025 1037 triglyceride FAMILY 23000450 A 1101 1114 triglycerides FAMILY 23000450 A 83 94 cholesterol TRIVIAL 23000450 A 918 930 triglyceride FAMILY 23000450 A 99 111 triglyceride FAMILY 23000451 A 0 7 Cocaine TRIVIAL 23000451 A 1124 1131 cocaine TRIVIAL 23000451 A 582 593 (-)-cocaine TRIVIAL 23000451 A 866 877 (-)-cocaine TRIVIAL 23000451 A 942 949 cocaine TRIVIAL 23000451 A 95 102 Cocaine TRIVIAL 23000451 T 75 82 cocaine TRIVIAL 23000507 A 1074 1077 ISO ABBREVIATION 23000507 A 1234 1237 PRO ABBREVIATION 23000507 A 1296 1299 ISO ABBREVIATION 23000507 A 1407 1424 6-hydroxydopamine SYSTEMATIC 23000507 A 1426 1432 6-OHDA SYSTEMATIC 23000507 A 1480 1483 PRO ABBREVIATION 23000507 A 585 593 tyrosine TRIVIAL 23000507 A 816 827 propranolol TRIVIAL 23000507 A 829 832 PRO ABBREVIATION 23000507 A 864 877 isoproterenol TRIVIAL 23000507 A 879 882 ISO ABBREVIATION 23000507 A 920 923 PRO ABBREVIATION 23001627 A 1119 1122 PTU ABBREVIATION 23001627 A 1125 1130 Vit E ABBREVIATION 23001627 A 1206 1209 PTU ABBREVIATION 23001627 A 1239 1242 PTU ABBREVIATION 23001627 A 1245 1249 L-T4 ABBREVIATION 23001627 A 1252 1257 Vit E ABBREVIATION 23001627 A 1326 1329 PTU ABBREVIATION 23001627 A 1332 1336 L-T4 ABBREVIATION 23001627 A 1623 1626 MDA ABBREVIATION 23001627 A 1670 1673 PTU ABBREVIATION 23001627 A 1676 1681 Vit E ABBREVIATION 23001627 A 1686 1689 PTU ABBREVIATION 23001627 A 1692 1696 L-T4 ABBREVIATION 23001627 A 1699 1704 Vit E ABBREVIATION 23001627 A 1721 1724 PTU ABBREVIATION 23001627 A 1729 1732 PTU ABBREVIATION 23001627 A 1735 1739 L-T4 ABBREVIATION 23001627 A 178 187 vitamin E FAMILY 23001627 A 1788 1801 levothyroxine TRIVIAL 23001627 A 1827 1836 vitamin E FAMILY 23001627 A 1889 1892 PTU ABBREVIATION 23001627 A 493 506 levothyroxine TRIVIAL 23001627 A 532 541 vitamin E FAMILY 23001627 A 655 658 PTU ABBREVIATION 23001627 A 666 669 PTU ABBREVIATION 23001627 A 672 677 Vit E ABBREVIATION 23001627 A 685 688 PTU ABBREVIATION 23001627 A 691 695 L-T4 ABBREVIATION 23001627 A 707 710 PTU ABBREVIATION 23001627 A 713 717 L-T4 ABBREVIATION 23001627 A 720 725 Vit E ABBREVIATION 23001627 A 755 770 malondialdehyde TRIVIAL 23001627 A 772 775 MDA ABBREVIATION 23001627 A 810 829 thiobarbituric-acid SYSTEMATIC 23001627 A 88 101 levothyroxine TRIVIAL 23001627 A 880 890 superoxide TRIVIAL 23001627 A 988 1009 nitroblue tetrazolium TRIVIAL 23001627 T 0 13 Levothyroxine TRIVIAL 23001627 T 39 48 vitamin E FAMILY 23002087 A 264 271 statins FAMILY 23007555 A 0 10 Ifenprodil TRIVIAL 23007555 A 1194 1204 ifenprodil TRIVIAL 23007555 A 1274 1278 zinc SYSTEMATIC 23007555 A 1413 1423 ifenprodil TRIVIAL 23007555 A 1473 1483 ifenprodil TRIVIAL 23007555 A 344 355 ifenprodil, TRIVIAL 23007555 A 363 367 zinc SYSTEMATIC 23007555 A 412 417 amino FAMILY 23007555 A 54 74 N-methyl-D-aspartate SYSTEMATIC 23007555 A 663 673 ifenprodil TRIVIAL 23007555 A 841 851 ifenprodil TRIVIAL 23007555 A 977 987 ifenprodil TRIVIAL 23007555 T 10 20 ifenprodil TRIVIAL 23007555 T 37 57 N-methyl-D-aspartate SYSTEMATIC 23007559 A 1095 1097 NO FORMULA 23007559 A 1229 1233 EtOH FORMULA 23007559 A 1317 1319 NO FORMULA 23007559 A 1469 1473 EtOH FORMULA 23007559 A 1671 1673 NO FORMULA 23007559 A 383 390 ethanol SYSTEMATIC 23007559 A 392 396 EtOH FORMULA 23007559 A 503 507 EtOH FORMULA 23007559 A 566 570 EtOH FORMULA 23007559 A 894 898 EtOH FORMULA 23007559 T 32 39 ethanol SYSTEMATIC 23008099 A 0 20 (1R)-Normetanephrine TRIVIAL 23008099 A 239 256 adrenergic amines FAMILY 23008099 A 361 381 (1R)-normetanephrine TRIVIAL 23008099 A 386 406 (1S)-normetanephrine TRIVIAL 23008099 A 463 478 normetanephrine TRIVIAL 23008099 A 511 548 3'-phosphoadenosine-5'-phosphosulfate SYSTEMATIC 23008099 A 722 742 (1R)-normetanephrine TRIVIAL 23008099 A 744 764 (1S)-normetanephrine TRIVIAL 23008099 A 778 793 normetanephrine TRIVIAL 23008099 T 72 87 normetanephrine TRIVIAL 23008229 A 0 10 Fullerenes FAMILY 23008229 A 154 163 fullerene TRIVIAL 23008229 A 231 236 thiol FAMILY 23008229 A 357 362 C(60) TRIVIAL 23008229 A 382 387 C(60) TRIVIAL 23008229 A 446 448 Au FORMULA 23008229 A 453 458 C(60) TRIVIAL 23008229 T 47 56 fullerene TRIVIAL 23008229 T 61 70 fullerene TRIVIAL 23010164 A 45 51 serine TRIVIAL 23010164 T 41 47 serine TRIVIAL 23010165 A 510 522 l-amino acid FAMILY 23010165 T 87 99 l-amino acid FAMILY 23010362 A 112 125 acetylcholine SYSTEMATIC 23010362 A 1188 1202 (-)-reboxetine TRIVIAL 23010362 A 1246 1256 imipramine TRIVIAL 23010362 A 1317 1331 (-)-reboxetine TRIVIAL 23010362 A 1461 1475 (-)-reboxetine TRIVIAL 23010362 A 1534 1544 imipramine TRIVIAL 23010362 A 1697 1711 (-)-reboxetine TRIVIAL 23010362 A 255 261 Ca(2+) FORMULA 23010362 A 291 305 (-)-reboxetine TRIVIAL 23010362 A 33 47 norepinephrine TRIVIAL 23010362 A 550 564 (-)-reboxetine TRIVIAL 23010362 A 67 81 (-)-reboxetine TRIVIAL 23010362 A 717 731 (-)-reboxetine TRIVIAL 23010362 A 753 769 [(3)H]imipramine SYSTEMATIC 23010362 A 812 826 (-)-reboxetine TRIVIAL 23010362 A 984 998 (-)-reboxetine TRIVIAL 23010362 T 41 55 (-)-reboxetine TRIVIAL 23010362 T 86 99 acetylcholine SYSTEMATIC 23010695 A 185 188 VPA ABBREVIATION 23010695 A 309 312 VPA ABBREVIATION 23010695 A 325 354 (S)-2-pentyl-4-pentynoic acid SYSTEMATIC 23010695 A 38 51 valproic acid TRIVIAL 23010695 A 53 56 VPA ABBREVIATION 23010695 A 671 700 (S)-2-pentyl-4-pentynoic acid SYSTEMATIC 23010695 A 746 749 VPA ABBREVIATION 23010695 A 777 806 (R)-2-pentyl-4-pentynoic acid SYSTEMATIC 23010695 A 811 814 VPA ABBREVIATION 23010695 A 931 960 (S)-2-pentyl-4-pentynoic acid SYSTEMATIC 23010695 A 986 989 VPA ABBREVIATION 23010867 A 944 956 sulfonylurea FAMILY 23010867 T 69 81 sulfonylurea FAMILY 23010870 A 1034 1039 (13)C FORMULA 23010870 A 1045 1050 (15)N FORMULA 23010870 A 1145 1147 Hg FORMULA 23010870 A 1305 1307 Hg FORMULA 23010870 A 216 218 Hg FORMULA 23010870 A 461 468 Mercury SYSTEMATIC 23010870 A 67 74 mercury SYSTEMATIC 23010870 A 76 78 Hg FORMULA 23010870 A 888 890 Hg FORMULA 23010870 T 26 33 mercury SYSTEMATIC 23011663 A 1006 1009 MDA ABBREVIATION 23011663 A 1062 1066 zinc SYSTEMATIC 23011663 A 1071 1077 copper SYSTEMATIC 23011663 A 1248 1251 MDA ABBREVIATION 23011663 A 1298 1301 MDA ABBREVIATION 23011663 A 1409 1412 MDA ABBREVIATION 23011663 A 1478 1482 CAPE ABBREVIATION 23011663 A 1562 1566 zinc SYSTEMATIC 23011663 A 1571 1577 copper SYSTEMATIC 23011663 A 1637 1641 CAPE ABBREVIATION 23011663 A 1800 1804 CAPE ABBREVIATION 23011663 A 1997 2001 CAPE ABBREVIATION 23011663 A 2095 2099 CAPE ABBREVIATION 23011663 A 361 365 CAPE ABBREVIATION 23011663 A 408 412 CAPE ABBREVIATION 23011663 A 508 512 CAPE ABBREVIATION 23011663 A 56 84 caffeic acid phenethyl ester SYSTEMATIC 23011663 A 668 672 CAPE ABBREVIATION 23011663 A 792 796 CAPE ABBREVIATION 23011663 A 86 90 CAPE ABBREVIATION 23011663 A 938 948 superoxide TRIVIAL 23011663 A 989 1004 malondialdehyde TRIVIAL 23011663 T 141 147 copper SYSTEMATIC 23011663 T 152 156 zinc SYSTEMATIC 23011663 T 50 78 caffeic acid phenethyl ester SYSTEMATIC 23011663 T 80 84 CAPE ABBREVIATION 23012257 A 0 70 4-(2-Butyl-6,7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid SYSTEMATIC 23012257 A 1027 1032 DCPIB ABBREVIATION 23012257 A 1067 1076 glutamate TRIVIAL 23012257 A 1120 1127 cystine TRIVIAL 23012257 A 1128 1137 glutamate TRIVIAL 23012257 A 1205 1214 glutamate TRIVIAL 23012257 A 1251 1260 glutamate TRIVIAL 23012257 A 1330 1335 DCPIB ABBREVIATION 23012257 A 1473 1478 DCPIB ABBREVIATION 23012257 A 1498 1507 glutamate TRIVIAL 23012257 A 289 294 DCPIB ABBREVIATION 23012257 A 425 434 glutamate TRIVIAL 23012257 A 482 491 glutamate TRIVIAL 23012257 A 590 595 DCPIB ABBREVIATION 23012257 A 641 650 glutamate TRIVIAL 23012257 A 691 708 l-[(3)H]glutamate SYSTEMATIC 23012257 A 710 727 d-[(3)H]aspartate SYSTEMATIC 23012257 A 72 77 DCPIB ABBREVIATION 23012257 A 733 749 l-[(14)C]cystine TRIVIAL 23012257 A 769 779 amino acid FAMILY 23012257 A 868 873 DCPIB ABBREVIATION 23012257 A 893 902 glutamate TRIVIAL 23012257 A 941 950 glutamate TRIVIAL 23012257 A 966 975 glutamate TRIVIAL 23012257 T 0 5 DCPIB ABBREVIATION 23012257 T 91 100 glutamate TRIVIAL 23016524 A 518 522 Ca2+ FORMULA 23016524 A 582 590 inositol TRIVIAL 23017385 A 602 617 Rosmarinic acid TRIVIAL 23017385 A 833 845 caffeic acid TRIVIAL 23017385 A 920 929 flavonoid FAMILY 23017385 A 931 956 luteolin-3'-O-glucuronide SYSTEMATIC 23017388 A 144 149 SB365 IDENTIFIER 23017388 A 151 171 Pulsatilla saponin D TRIVIAL 23017388 A 265 270 SB365 IDENTIFIER 23017388 A 377 382 SB365 IDENTIFIER 23017388 A 526 531 SB365 IDENTIFIER 23017388 A 669 673 5-FU SYSTEMATIC 23017388 A 727 732 SB365 IDENTIFIER 23017388 A 848 853 SB365 IDENTIFIER 23017388 A 994 999 SB365 IDENTIFIER 23017388 T 0 5 SB365 IDENTIFIER 23017388 T 7 27 Pulsatilla saponin D TRIVIAL 23017389 A 1029 1036 ferrous SYSTEMATIC 23017389 A 1042 1048 Fe(2+) FORMULA 23017389 A 1080 1084 DPPH ABBREVIATION 23017389 A 1137 1150 ethyl acetate SYSTEMATIC 23017389 A 1155 1163 methanol SYSTEMATIC 23017389 A 247 260 ethyl acetate SYSTEMATIC 23017389 A 271 281 flavonoids FAMILY 23017389 A 382 392 silica gel TRIVIAL 23017389 A 515 519 (1)H FORMULA 23017389 A 525 530 (13)C FORMULA 23017389 A 597 644 chrysoeriol-7-O-[2″-O-E-feruloyl]-β-d-glucoside SYSTEMATIC 23017389 A 650 661 chrysoeriol TRIVIAL 23017389 A 671 699 isorhamnetin-3-β-d-glucoside SYSTEMATIC 23017389 A 941 959 ferric thiocyanate SYSTEMATIC 23017389 A 968 974 ferric SYSTEMATIC 23017389 A 980 986 Fe(3+) FORMULA 23017389 T 40 48 flavones FAMILY 23017393 A 1031 1039 catechin TRIVIAL 23017393 A 1118 1126 Catechin TRIVIAL 23017393 A 1227 1235 pyruvate TRIVIAL 23017393 A 1271 1279 creatine TRIVIAL 23017393 A 1300 1308 catechin TRIVIAL 23017393 A 1439 1447 catechin TRIVIAL 23017393 A 1524 1532 catechin TRIVIAL 23017393 A 216 228 (+)-catechin TRIVIAL 23017393 A 384 415 fluorescein-5-thiosemicarbazide SYSTEMATIC 23017393 A 417 421 FTSC ABBREVIATION 23017393 A 556 564 pyruvate TRIVIAL 23017393 A 585 593 creatine TRIVIAL 23017393 A 631 645 glyceraldehyde TRIVIAL 23017393 A 893 901 catechin TRIVIAL 23017393 T 95 103 catechin TRIVIAL 23017401 A 162 171 genistein TRIVIAL 23017401 A 173 181 genistin TRIVIAL 23017401 A 183 192 iprodione TRIVIAL 23017401 A 194 205 vinclozolin TRIVIAL 23017401 A 210 221 procymidone TRIVIAL 23017401 A 518 527 iprodione TRIVIAL 23017401 A 626 635 genistein TRIVIAL 23017401 A 697 725 genistin, its β-glycosylated MULTIPLE 23017401 T 0 9 Genistein TRIVIAL 23017401 T 14 27 dicarboximide SYSTEMATIC 23017404 A 368 375 glucose TRIVIAL 23017404 A 380 388 fructose TRIVIAL 23017404 A 414 421 sucrose TRIVIAL 23017404 A 45 50 sugar FAMILY 23017404 A 451 458 sucrose TRIVIAL 23017404 A 643 649 hexose TRIVIAL 23017404 A 669 674 sugar FAMILY 23017404 A 743 750 hexoses FAMILY 23017404 A 769 775 hexose TRIVIAL 23017404 T 0 5 Sugar FAMILY 23017406 A 0 4 GABA ABBREVIATION 23017406 A 145 149 GABA ABBREVIATION 23017406 A 15 24 polyamine FAMILY 23017406 A 234 237 Glu FORMULA 23017406 A 242 251 polyamine FAMILY 23017406 A 325 329 GABA ABBREVIATION 23017406 A 354 358 GABA ABBREVIATION 23017406 A 449 452 Glu FORMULA 23017406 A 457 467 polyamines FAMILY 23017406 A 48 67 γ-aminobutyric acid SYSTEMATIC 23017406 A 69 73 GABA ABBREVIATION 23017406 A 758 762 GABA ABBREVIATION 23017406 A 892 896 GABA ABBREVIATION 23017406 A 959 968 polyamine FAMILY 23017406 T 0 4 GABA ABBREVIATION 23017406 T 15 24 polyamine FAMILY 23017406 T 48 67 γ-aminobutyric acid SYSTEMATIC 23017414 A 334 342 phenolic FAMILY 23017414 A 433 443 isoflavone FAMILY 23017414 A 56 64 phenolic FAMILY 23017414 A 699 713 phenolic acids FAMILY 23017414 A 76 87 isoflavones FAMILY 23017414 A 765 773 phenolic FAMILY 23017414 A 840 851 isoflavones FAMILY 23017414 T 28 39 isoflavones FAMILY 23017414 T 8 16 phenolic FAMILY 23017417 A 319 330 polyphenols FAMILY 23017417 A 520 531 gallic acid TRIVIAL 23017417 A 533 545 (+)-catechin TRIVIAL 23017417 A 547 562 (-)-epicatechin SYSTEMATIC 23017417 A 568 583 (E)-resveratrol TRIVIAL 23017417 A 585 597 Anthocyanins FAMILY 23017417 A 828 838 polyphenol FAMILY 23017423 A 202 209 glucose TRIVIAL 23017423 A 220 225 sugar FAMILY 23017423 A 231 238 sucrose TRIVIAL 23017423 A 445 460 l-ascorbic acid TRIVIAL 23017423 A 561 581 dehydroascorbic acid TRIVIAL 23017423 A 583 586 DHA ABBREVIATION 23017423 A 695 698 DHA ABBREVIATION 23017423 A 991 996 sugar FAMILY 23017423 T 49 54 sugar FAMILY 23017423 T 59 74 l-ascorbic acid TRIVIAL 23018143 A 11 19 estrogen FAMILY 23018143 T 87 95 estrogen FAMILY 23019137 A 1006 1015 Serotonin TRIVIAL 23019137 A 1027 1038 neurotensin TRIVIAL 23019137 A 1118 1211 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4c]carbazole-12-propanenitrile SYSTEMATIC 23019137 A 1213 1219 Gö6976 IDENTIFIER 23019137 A 182 190 dopamine TRIVIAL 23019137 A 493 497 5-HT SYSTEMATIC 23019137 A 504 515 neurotensin TRIVIAL 23019137 A 931 941 quinpirole TRIVIAL 23019137 A 958 967 serotonin TRIVIAL 23019137 A 983 994 neurotensin TRIVIAL 23019137 T 12 20 dopamine TRIVIAL 23019217 A 1100 1104 Mith ABBREVIATION 23019217 A 1229 1233 Mith ABBREVIATION 23019217 A 1456 1460 Mith ABBREVIATION 23019217 A 598 611 mithramycin A TRIVIAL 23019217 A 613 617 Mith ABBREVIATION 23019217 A 863 867 Mith ABBREVIATION 23019217 T 0 13 Mithramycin A TRIVIAL 23019274 A 1333 1343 creatinine TRIVIAL 23019274 A 1357 1361 urea TRIVIAL 23019274 A 1362 1370 nitrogen SYSTEMATIC 23019274 A 1372 1380 N-acetyl SYSTEMATIC 23019274 A 716 733 aristolochic acid FAMILY 23022069 A 285 293 melamine TRIVIAL 23022069 A 295 298 MEL ABBREVIATION 23022069 A 365 368 MEL ABBREVIATION 23022069 A 373 386 cyanuric acid TRIVIAL 23022069 A 388 391 CYA ABBREVIATION 23022069 A 404 412 melamine TRIVIAL 23022069 A 413 422 cyanurate TRIVIAL 23022069 A 692 695 MEL ABBREVIATION 23022069 A 700 703 CYA ABBREVIATION 23022069 T 107 120 cyanuric acid TRIVIAL 23022069 T 94 102 melamine TRIVIAL 23022398 A 1102 1106 PILO ABBREVIATION 23022398 A 1200 1204 NMDA ABBREVIATION 23022398 A 1307 1310 AP7 IDENTIFIER 23022398 A 1421 1425 PILO ABBREVIATION 23022398 A 1440 1443 AP7 IDENTIFIER 23022398 A 1627 1631 PILO ABBREVIATION 23022398 A 381 389 urethane TRIVIAL 23022398 A 503 514 pilocarpine TRIVIAL 23022398 A 516 520 PILO ABBREVIATION 23022398 A 586 590 PILO ABBREVIATION 23022398 A 771 775 NMDA ABBREVIATION 23022398 A 797 800 AP7 IDENTIFIER 23022398 A 851 855 PILO ABBREVIATION 23022398 A 967 971 PILO ABBREVIATION 23022398 T 0 4 NMDA ABBREVIATION 23023024 A 1076 1079 MDA ABBREVIATION 23023024 A 118 128 bile acids FAMILY 23023024 A 130 133 BAs ABBREVIATION 23023024 A 1346 1349 BAs ABBREVIATION 23023024 A 360 370 bile acids FAMILY 23023024 A 495 510 Malondialdehyde TRIVIAL 23023024 A 51 63 α-tocopherol TRIVIAL 23023024 A 512 515 MDA ABBREVIATION 23023024 A 565 575 superoxide TRIVIAL 23023024 A 981 984 MDA ABBREVIATION 23023024 T 15 27 α-tocopherol TRIVIAL 23023136 A 0 16 Arsenic trioxide SYSTEMATIC 23023136 A 1069 1076 arsenic SYSTEMATIC 23023136 A 1141 1150 As(2)O(3) FORMULA 23023136 A 1172 1183 resveratrol TRIVIAL 23023136 A 1195 1204 As(2)O(3) FORMULA 23023136 A 1263 1270 arsenic SYSTEMATIC 23023136 A 1329 1340 resveratrol TRIVIAL 23023136 A 1434 1441 arsenic SYSTEMATIC 23023136 A 1455 1462 arsenic SYSTEMATIC 23023136 A 18 27 As(2)O(3) FORMULA 23023136 A 217 226 As(2)O(3) FORMULA 23023136 A 276 287 Resveratrol TRIVIAL 23023136 A 390 399 As(2)O(3) FORMULA 23023136 A 420 431 resveratrol TRIVIAL 23023136 A 459 466 arsenic SYSTEMATIC 23023136 A 588 597 As(2)O(3) FORMULA 23023136 A 617 628 resveratrol TRIVIAL 23023136 A 665 674 As(2)O(3) FORMULA 23023136 A 795 814 reduced glutathione TRIVIAL 23023136 A 816 819 GSH ABBREVIATION 23023136 A 824 844 oxidized glutathione TRIVIAL 23023136 A 846 850 GSSG ABBREVIATION 23023136 A 857 864 arsenic SYSTEMATIC 23023136 A 899 910 resveratrol TRIVIAL 23023136 A 911 920 As(2)O(3) FORMULA 23023136 A 942 952 superoxide TRIVIAL 23023136 A 986 989 GSH ABBREVIATION 23023136 A 990 994 GSSG ABBREVIATION 23023136 T 0 11 Resveratrol TRIVIAL 23023136 T 57 73 arsenic trioxide SYSTEMATIC 23023933 A 1112 1132 perfluoroalkyl acids FAMILY 23023933 A 256 276 perfluoroalkyl acids FAMILY 23023933 A 650 657 octanol SYSTEMATIC 23026700 A 256 263 ethanol SYSTEMATIC 23026700 A 563 566 AMP ABBREVIATION 23026700 A 644 654 acetyl-CoA SYSTEMATIC 23026700 A 704 723 carnitine palmitoyl TRIVIAL 23026700 A 758 764 sterol FAMILY 23026700 A 806 816 fatty acid FAMILY 23026700 A 937 949 triglyceride FAMILY 23028140 A 1112 1120 imatinib TRIVIAL 23028140 A 1325 1333 imatinib TRIVIAL 23028140 A 1392 1400 imatinib TRIVIAL 23028140 A 1458 1466 imatinib TRIVIAL 23028140 A 1722 1730 imatinib TRIVIAL 23028140 A 197 205 imatinib TRIVIAL 23028140 A 249 257 imatinib TRIVIAL 23028140 A 408 416 imatinib TRIVIAL 23028140 A 47 55 imatinib TRIVIAL 23028140 A 511 519 imatinib TRIVIAL 23028140 A 551 559 imatinib TRIVIAL 23028140 A 651 659 imatinib TRIVIAL 23028140 A 733 741 imatinib TRIVIAL 23028140 A 743 762 N-desmethylimatinib SYSTEMATIC 23028140 A 825 833 imatinib TRIVIAL 23028140 A 890 898 imatinib TRIVIAL 23028140 A 935 943 imatinib TRIVIAL 23028140 T 62 70 imatinib TRIVIAL 23030346 A 1061 1063 Ge FORMULA 23030346 A 1079 1081 Si FORMULA 23030346 A 1226 1228 Si FORMULA 23030346 A 1229 1231 Ge FORMULA 23030346 A 372 374 Ge FORMULA 23030346 A 375 377 Si FORMULA 23030680 A 1099 1117 5-hydroxyelzasonan SYSTEMATIC 23030680 A 18 27 elzasonan TRIVIAL 23030680 A 195 196 N FORMULA 23030680 A 254 271 elzasonan N-oxide SYSTEMATIC 23030680 A 281 299 5-hydroxyelzasonan SYSTEMATIC 23030680 A 331 340 elzasonan TRIVIAL 23030680 A 391 397 indole SYSTEMATIC 23030680 A 463 470 iminium SYSTEMATIC 23030680 A 663 672 elzasonan TRIVIAL 23030680 T 69 78 elzasonan TRIVIAL 23030706 A 336 354 chloroacetaldehyde SYSTEMATIC 23030706 A 392 402 ifosfamide TRIVIAL 23030706 A 412 427 cobalt chloride SYSTEMATIC 23030706 A 464 470 cobalt SYSTEMATIC 23030706 A 510 519 valproate SYSTEMATIC 23030706 A 775 784 carbon 13 SYSTEMATIC 23030766 A 547 557 amino acid FAMILY 23032515 A 1005 1024 8-hydroxycalamenene SYSTEMATIC 23032515 A 123 142 8-hydroxycalamenene SYSTEMATIC 23032515 A 165 171 hexane SYSTEMATIC 23032515 A 221 240 8-hydroxycalamenene SYSTEMATIC 23032515 A 429 459 l-buthionine-(S,R)-sulfoximine SYSTEMATIC 23032515 A 461 464 BSO ABBREVIATION 23032515 A 471 480 glutamate TRIVIAL 23032515 A 496 507 glutathione TRIVIAL 23032515 A 512 523 glutathione TRIVIAL 23032515 A 524 525 S FORMULA 23032515 A 574 593 8-hydroxycalamenene SYSTEMATIC 23032515 A 680 689 glutamate TRIVIAL 23032515 A 690 693 BSO ABBREVIATION 23032515 A 721 741 N-methyl-d-aspartate SYSTEMATIC 23032515 A 880 899 8-hydroxycalamenene SYSTEMATIC 23032515 T 0 19 8-Hydroxycalamenene SYSTEMATIC 23033256 A 671 680 Bisulfite SYSTEMATIC 23034931 A 17 25 nitrogen SYSTEMATIC 23034931 A 463 464 S FORMULA 23034931 A 791 794 oxy SYSTEMATIC 23034931 A 795 800 nitro SYSTEMATIC 23036893 A 1078 1087 genistein TRIVIAL 23036893 A 1092 1103 bisphenol A TRIVIAL 23036893 A 1191 1194 EE2 ABBREVIATION 23036893 A 317 328 bisphenol A TRIVIAL 23036893 A 330 339 genistein TRIVIAL 23036893 A 345 358 4-nonylphenol SYSTEMATIC 23036893 A 372 388 ethinylestradiol SYSTEMATIC 23036893 A 390 393 EE2 ABBREVIATION 23036893 A 416 424 estrogen FAMILY 23036893 A 559 562 EE2 ABBREVIATION 23036893 A 740 743 EE2 ABBREVIATION 23038668 A 0 23 Calcium manganese oxide SYSTEMATIC 23038668 A 224 230 oxygen SYSTEMATIC 23038668 A 310 314 O(2) FORMULA 23038668 T 72 78 oxygen SYSTEMATIC 23038668 T 83 85 H+ FORMULA 23041228 A 257 265 tyrosine TRIVIAL 23041228 A 35 38 ser FORMULA 23041228 A 39 42 thr FORMULA 23041510 A 0 12 Eldecalcitol TRIVIAL 23041510 A 1000 1003 ALN ABBREVIATION 23041510 A 1051 1054 ALN ABBREVIATION 23041510 A 1106 1109 ELD ABBREVIATION 23041510 A 1110 1113 ALN ABBREVIATION 23041510 A 1158 1161 ALF ABBREVIATION 23041510 A 116 128 alfacalcidol TRIVIAL 23041510 A 1162 1165 ALN ABBREVIATION 23041510 A 1223 1226 ELD ABBREVIATION 23041510 A 1231 1234 ALF ABBREVIATION 23041510 A 1294 1297 ELD ABBREVIATION 23041510 A 1298 1301 ALN ABBREVIATION 23041510 A 130 133 ALF ABBREVIATION 23041510 A 1306 1309 ALF ABBREVIATION 23041510 A 1310 1313 ALN ABBREVIATION 23041510 A 1370 1373 ALN ABBREVIATION 23041510 A 14 17 ELD ABBREVIATION 23041510 A 1401 1404 ELD ABBREVIATION 23041510 A 1406 1409 ELD ABBREVIATION 23041510 A 1410 1413 ALN ABBREVIATION 23041510 A 1419 1422 ALF ABBREVIATION 23041510 A 1423 1426 ALN ABBREVIATION 23041510 A 1521 1524 ELD ABBREVIATION 23041510 A 1525 1528 ALN ABBREVIATION 23041510 A 1583 1586 ALN ABBREVIATION 23041510 A 1641 1644 ELD ABBREVIATION 23041510 A 1661 1664 ELD ABBREVIATION 23041510 A 1665 1668 ALN ABBREVIATION 23041510 A 1890 1893 ALF ABBREVIATION 23041510 A 1898 1901 ALF ABBREVIATION 23041510 A 1902 1905 ALN ABBREVIATION 23041510 A 2024 2027 ELD ABBREVIATION 23041510 A 2031 2034 ALF ABBREVIATION 23041510 A 2060 2063 ALN ABBREVIATION 23041510 A 2096 2099 ALN ABBREVIATION 23041510 A 2118 2121 ELD ABBREVIATION 23041510 A 2122 2125 ALN ABBREVIATION 23041510 A 22 41 2β-hydroxypropyloxy SYSTEMATIC 23041510 A 226 237 Alendronate TRIVIAL 23041510 A 2304 2307 ALF ABBREVIATION 23041510 A 2308 2311 ALN ABBREVIATION 23041510 A 239 242 ALN ABBREVIATION 23041510 A 270 284 bisphosphonate SYSTEMATIC 23041510 A 472 475 ELD ABBREVIATION 23041510 A 480 483 ALN ABBREVIATION 23041510 A 492 495 ALF ABBREVIATION 23041510 A 500 503 ALN ABBREVIATION 23041510 A 56 70 1α,25 (OH) 2D3 SYSTEMATIC 23041510 A 677 680 ELD ABBREVIATION 23041510 A 695 698 ALF ABBREVIATION 23041510 A 713 716 ALN ABBREVIATION 23041510 A 731 734 ELD ABBREVIATION 23041510 A 735 738 ALN ABBREVIATION 23041510 A 757 760 ALF ABBREVIATION 23041510 A 761 764 ALN ABBREVIATION 23041510 A 806 809 ELD ABBREVIATION 23041510 A 825 828 ALF ABBREVIATION 23041510 A 848 851 ALN ABBREVIATION 23041510 A 923 926 ELD ABBREVIATION 23041510 A 931 934 ALF ABBREVIATION 23041510 A 984 987 ELD ABBREVIATION 23041510 A 988 991 ALN ABBREVIATION 23041510 A 996 999 ALF ABBREVIATION 23041510 T 169 181 alfacalcidol TRIVIAL 23041510 T 186 197 alendronate TRIVIAL 23041510 T 35 47 eldecalcitol TRIVIAL 23041510 T 52 63 alendronate TRIVIAL 23041538 A 1026 1034 spermine TRIVIAL 23041538 A 1061 1066 NASPM ABBREVIATION 23041538 A 1147 1156 SCH 58261 IDENTIFIER 23041538 A 1310 1319 SCH 58261 IDENTIFIER 23041538 A 1345 1350 NASPM ABBREVIATION 23041538 A 1482 1491 SCH 58261 IDENTIFIER 23041538 A 372 379 calcium SYSTEMATIC 23041538 A 496 505 adenosine TRIVIAL 23041538 A 679 685 oxygen SYSTEMATIC 23041538 A 686 693 glucose TRIVIAL 23041538 T 68 75 calcium SYSTEMATIC 23041661 A 1048 1051 Glu FORMULA 23041661 A 1055 1058 Arg FORMULA 23041661 A 1139 1142 Arg FORMULA 23041661 A 1152 1170 γ-phosphate oxygen SYSTEMATIC 23041661 A 1174 1177 ATP ABBREVIATION 23041661 A 1262 1265 Arg FORMULA 23041661 A 1269 1272 Glu FORMULA 23041661 A 1279 1282 Arg FORMULA 23041661 A 1286 1289 ATP ABBREVIATION 23041661 A 1401 1404 ATP ABBREVIATION 23041661 A 1412 1415 ATP ABBREVIATION 23041661 A 27 52 adenosine-5'-triphosphate SYSTEMATIC 23041661 A 284 287 Glu FORMULA 23041661 A 295 298 Arg FORMULA 23041661 A 352 355 ATP ABBREVIATION 23041661 A 503 506 Glu FORMULA 23041661 A 514 517 Arg FORMULA 23041661 A 54 57 ATP ABBREVIATION 23041661 A 569 578 disulfide SYSTEMATIC 23041661 A 621 624 Glu FORMULA 23041661 A 632 635 Arg FORMULA 23041661 A 695 698 ATP ABBREVIATION 23041661 A 777 780 Glu FORMULA 23041661 A 784 787 Arg FORMULA 23041661 A 953 956 Glu FORMULA 23041661 A 964 967 Arg FORMULA 23041661 T 27 30 Arg FORMULA 23041661 T 34 37 Glu FORMULA 23041661 T 44 47 Arg FORMULA 23041661 T 51 54 ATP ABBREVIATION 23041725 A 0 14 Organochlorine FAMILY 23041725 A 1019 1027 dieldrin TRIVIAL 23041725 A 1247 1255 dieldrin TRIVIAL 23041725 A 1398 1406 dieldrin TRIVIAL 23041725 A 1458 1466 dieldrin TRIVIAL 23041725 A 1604 1612 dieldrin TRIVIAL 23041725 A 265 273 dieldrin TRIVIAL 23041725 A 390 398 dieldrin TRIVIAL 23041725 A 41 49 dieldrin TRIVIAL 23041725 A 485 493 dieldrin TRIVIAL 23041725 A 558 571 17β-estradiol SYSTEMATIC 23041725 A 650 658 dieldrin TRIVIAL 23041725 A 686 694 estrogen FAMILY 23041725 A 696 704 dieldrin TRIVIAL 23041725 T 123 131 dieldrin TRIVIAL 23041725 T 98 112 organochlorine FAMILY 23042728 A 1209 1212 VPD ABBREVIATION 23042728 A 127 137 Valpromide TRIVIAL 23042728 A 139 142 VPD ABBREVIATION 23042728 A 149 154 amide FAMILY 23042728 A 169 172 VPA ABBREVIATION 23042728 A 21 34 valproic acid TRIVIAL 23042728 A 274 277 VPA ABBREVIATION 23042728 A 36 39 VPA ABBREVIATION 23042728 A 362 365 VPA ABBREVIATION 23042728 A 563 566 VPA ABBREVIATION 23042728 A 570 573 VPD ABBREVIATION 23042728 A 604 607 VPA ABBREVIATION 23042728 A 833 836 VPA ABBREVIATION 23042728 A 851 854 VPD ABBREVIATION 23042728 A 976 979 VPA ABBREVIATION 23042728 T 12 25 valproic acid TRIVIAL 23042730 A 0 10 Amiodarone TRIVIAL 23042730 A 1029 1041 α-tocopherol TRIVIAL 23042730 A 1043 1047 TOCO ABBREVIATION 23042730 A 1113 1116 AMD ABBREVIATION 23042730 A 1179 1182 AMD ABBREVIATION 23042730 A 12 15 AMD ABBREVIATION 23042730 A 1200 1206 α-TOCO SYSTEMATIC 23042730 A 1256 1259 AMD ABBREVIATION 23042730 A 1362 1365 AMD ABBREVIATION 23042730 A 1460 1463 AMD ABBREVIATION 23042730 A 216 219 AMD ABBREVIATION 23042730 A 400 403 AMD ABBREVIATION 23042730 A 418 421 AMD ABBREVIATION 23042730 A 555 558 AMD ABBREVIATION 23042730 A 671 677 oxygen SYSTEMATIC 23042730 A 761 764 AMD ABBREVIATION 23042730 A 846 852 trolox TRIVIAL 23042730 A 854 870 N-acetylcysteine SYSTEMATIC 23042730 A 872 883 glutathione TRIVIAL 23042730 A 888 897 ascorbate TRIVIAL 23042730 A 934 937 AMD ABBREVIATION 23042730 A 999 1002 AMD ABBREVIATION 23042730 T 60 70 amiodarone TRIVIAL 23042808 A 1030 1033 CBD ABBREVIATION 23042808 A 113 124 cannabidiol TRIVIAL 23042808 A 126 129 CBD ABBREVIATION 23042808 A 1280 1283 CBD ABBREVIATION 23042808 A 1366 1369 THC ABBREVIATION 23042808 A 1374 1377 CBD ABBREVIATION 23042808 A 246 249 THC ABBREVIATION 23042808 A 254 257 CBD ABBREVIATION 23042808 A 400 403 CBD ABBREVIATION 23042808 A 414 417 THC ABBREVIATION 23042808 A 516 519 CBD ABBREVIATION 23042808 A 587 590 THC ABBREVIATION 23042808 A 606 609 THC ABBREVIATION 23042808 A 657 660 CBD ABBREVIATION 23042808 A 72 95 Δ⁹-tetrahydrocannabinol SYSTEMATIC 23042808 A 844 847 CBD ABBREVIATION 23042808 A 946 949 THC ABBREVIATION 23042808 A 97 100 THC ABBREVIATION 23042808 T 0 11 Cannabidiol TRIVIAL 23042808 T 21 24 THC ABBREVIATION 23042953 A 1084 1097 triglycerides FAMILY 23042953 A 1254 1265 cholesterol TRIVIAL 23042953 A 1648 1659 cholesterol TRIVIAL 23042953 A 370 381 amino acids FAMILY 23042953 A 57 68 cholesterol TRIVIAL 23042953 A 635 646 amino acids FAMILY 23042953 A 889 900 cholesterol TRIVIAL 23042953 A 993 1004 cholesterol TRIVIAL 23042953 T 113 124 cholesterol TRIVIAL 23042953 T 12 23 amino acids FAMILY 23042954 A 1039 1047 LY293558 IDENTIFIER 23042954 A 1133 1141 LY293558 IDENTIFIER 23042954 A 1191 1196 oxime SYSTEMATIC 23042954 A 1197 1201 HI-6 IDENTIFIER 23042954 A 1301 1309 LY293558 IDENTIFIER 23042954 A 1484 1492 LY293558 IDENTIFIER 23042954 A 1692 1700 LY293558 IDENTIFIER 23042954 A 746 798 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid SYSTEMATIC 23042954 A 800 804 AMPA ABBREVIATION 23042954 A 826 914 (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid SYSTEMATIC 23042954 A 916 924 LY293558 IDENTIFIER 23042954 T 22 26 AMPA ABBREVIATION 23042954 T 47 55 LY293558 IDENTIFIER 23043137 A 1001 1005 pVIc ABBREVIATION 23043137 A 192 196 pVIc ABBREVIATION 23043137 A 204 214 amino acid FAMILY 23043137 A 244 245 C FORMULA 23043137 A 875 879 pVIc ABBREVIATION 23043137 A 930 934 pVIc ABBREVIATION 23043137 A 948 957 disulfide SYSTEMATIC 23043441 A 186 195 copper(I) SYSTEMATIC 23043441 A 206 218 azide-alkyne FAMILY 23044047 A 947 957 phalloidin TRIVIAL 23044489 A 0 16 Organophosphorus FAMILY 23044489 A 1403 1406 KET ABBREVIATION 23044489 A 1428 1444 atropine sulfate SYSTEMATIC 23044489 A 1469 1483 benzodiazepine FAMILY 23044489 A 1506 1511 soman TRIVIAL 23044489 A 1625 1630 soman TRIVIAL 23044489 A 1790 1796 MK-801 IDENTIFIER 23044489 A 1798 1801 KET ABBREVIATION 23044489 A 1896 1899 KET ABBREVIATION 23044489 A 768 772 NMDA ABBREVIATION 23044489 A 953 961 Ketamine TRIVIAL 23044489 A 963 966 KET ABBREVIATION 23044489 A 980 984 NMDA ABBREVIATION 23044489 T 0 8 Ketamine TRIVIAL 23044489 T 49 54 soman TRIVIAL 23046872 A 1033 1046 cisplatin(II) TRIVIAL 23046872 A 1051 1064 cisplatin(IV) TRIVIAL 23046872 A 1092 1101 cisplatin TRIVIAL 23046872 A 12 25 cisplatin(IV) TRIVIAL 23046872 A 164 177 cisplatin(IV) TRIVIAL 23046872 A 466 482 sodium ascorbate SYSTEMATIC 23046872 A 484 489 NaAsc FORMULA 23046872 A 622 635 cisplatin(II) TRIVIAL 23046872 A 675 688 cisplatin(II) TRIVIAL 23046872 A 708 719 nucleobases FAMILY 23046872 A 74 80 Pt(IV) FORMULA 23046872 A 773 782 cisplatin TRIVIAL 23046872 A 859 872 cisplatin(II) TRIVIAL 23046872 A 877 890 cisplatin(IV) TRIVIAL 23046872 T 54 67 cisplatin(IV) TRIVIAL 23047001 A 113 116 ATP ABBREVIATION 23047001 A 255 273 benzothiazepinones FAMILY 23047001 A 275 279 BTZs ABBREVIATION 23047001 A 294 297 ATP ABBREVIATION 23047001 A 434 437 BTZ ABBREVIATION 23047001 T 47 65 benzothiazepinones FAMILY 23047001 T 67 71 BTZs ABBREVIATION 23047001 T 86 89 ATP ABBREVIATION 23047024 A 0 16 Organophosphorus FAMILY 23047024 A 1112 1117 tabun TRIVIAL 23047024 A 1391 1396 oxime SYSTEMATIC 23047024 A 1397 1401 K048 IDENTIFIER 23047024 A 1437 1441 K048 IDENTIFIER 23047024 A 1460 1465 tabun TRIVIAL 23047024 A 1612 1618 oximes FAMILY 23047024 A 1727 1733 oximes FAMILY 23047024 A 359 364 tabun TRIVIAL 23047024 A 369 374 oxime SYSTEMATIC 23047024 A 37 43 oximes FAMILY 23047024 A 375 379 K048 IDENTIFIER 23047024 A 863 868 tabun TRIVIAL 23047024 A 869 873 K048 IDENTIFIER 23047024 A 897 902 tabun TRIVIAL 23047024 A 907 911 K048 IDENTIFIER 23047024 T 47 63 organophosphates FAMILY 23047024 T 68 74 oximes FAMILY 23047287 A 1031 1035 β-CD ABBREVIATION 23047287 A 1331 1341 amantadine TRIVIAL 23047287 A 1360 1383 5(6)-carboxyfluorescein SYSTEMATIC 23047287 A 1390 1401 Arg-Gly-Asp FORMULA 23047287 A 1449 1459 adamantine TRIVIAL 23047287 A 1489 1512 5(6)-carboxyfluorescein SYSTEMATIC 23047287 A 1581 1591 cyclic RGD TRIVIAL 23047287 A 38 46 graphene TRIVIAL 23047287 A 429 443 β-cyclodextrin TRIVIAL 23047287 A 617 631 β-cyclodextrin TRIVIAL 23047287 A 633 637 β-CD ABBREVIATION 23047287 A 742 750 graphene TRIVIAL 23047287 A 800 808 graphene TRIVIAL 23047287 A 824 828 β-CD ABBREVIATION 23047287 A 961 969 graphene TRIVIAL 23047287 T 40 54 β-cyclodextrin TRIVIAL 23047287 T 79 87 graphene TRIVIAL 23047912 A 1038 1044 L-BMAA ABBREVIATION 23047912 A 1093 1099 oxygen SYSTEMATIC 23047912 A 1187 1196 vitamin E FAMILY 23047912 A 1198 1204 L-BMAA ABBREVIATION 23047912 A 1263 1269 L-BMAA ABBREVIATION 23047912 A 1336 1342 L-BMAA ABBREVIATION 23047912 A 19 44 β-N-methylamino-L-alanine SYSTEMATIC 23047912 A 281 287 L-BMAA ABBREVIATION 23047912 A 407 413 L-BMAA ABBREVIATION 23047912 A 46 52 L-BMAA ABBREVIATION 23047912 A 512 518 L-BMAA ABBREVIATION 23047912 A 647 653 L-BMAA ABBREVIATION 23047912 A 744 749 (14)C FORMULA 23047912 A 750 756 L-BMAA ABBREVIATION 23047912 A 786 792 L-BMAA ABBREVIATION 23047912 T 0 6 L-BMAA ABBREVIATION 23050902 A 1067 1076 ribavirin TRIVIAL 23050902 A 1110 1119 Ribavirin TRIVIAL 23050902 A 1222 1231 ribavirin TRIVIAL 23050902 A 1254 1257 GTP ABBREVIATION 23050902 A 1450 1459 ribavirin TRIVIAL 23050902 A 174 183 ribavirin TRIVIAL 23050902 A 35 44 vitamin K FAMILY 23050902 A 360 369 ribavirin TRIVIAL 23050902 A 474 477 GTP ABBREVIATION 23050902 A 491 500 ribavirin TRIVIAL 23050902 A 525 549 inosine-5'-monophosphate SYSTEMATIC 23050902 A 585 602 mycophenolic acid TRIVIAL 23050902 A 607 623 6-mercaptopurine TRIVIAL 23050902 A 861 870 Ribavirin TRIVIAL 23050902 A 904 910 lysine TRIVIAL 23050902 A 987 996 ribavirin TRIVIAL 23050902 T 0 9 Ribavirin TRIVIAL 23050902 T 32 35 GTP ABBREVIATION 23052192 A 1158 1160 WC FORMULA 23052192 A 1161 1163 Co FORMULA 23052192 A 1178 1180 Co FORMULA 23052192 A 1230 1237 CoCl(2) FORMULA 23052192 A 1241 1243 WC FORMULA 23052192 A 1545 1547 WC FORMULA 23052192 A 1548 1550 Co FORMULA 23052192 A 233 235 Co FORMULA 23052192 A 24 40 tungsten carbide SYSTEMATIC 23052192 A 309 311 WC FORMULA 23052192 A 312 314 Co FORMULA 23052192 A 42 44 WC FORMULA 23052192 A 428 430 WC FORMULA 23052192 A 431 433 Co FORMULA 23052192 A 475 481 oxygen SYSTEMATIC 23052192 A 59 65 cobalt SYSTEMATIC 23052192 A 67 69 Co FORMULA 23052192 A 752 754 WC FORMULA 23052192 A 755 757 Co FORMULA 23052192 A 805 807 WC FORMULA 23052192 A 808 810 Co FORMULA 23052192 A 818 824 Co(2+) FORMULA 23052192 A 831 838 CoCl(2) FORMULA 23052192 A 942 944 WC FORMULA 23052192 A 945 947 Co FORMULA 23052192 T 12 14 WC FORMULA 23052192 T 15 17 Co FORMULA 23052195 A 1106 1109 PPA ABBREVIATION 23052195 A 1195 1198 PPA ABBREVIATION 23052195 A 148 167 phenylpropanolamine SYSTEMATIC 23052195 A 169 172 PPA ABBREVIATION 23052195 A 320 323 PPA ABBREVIATION 23052195 A 373 384 glutathione TRIVIAL 23052195 A 672 675 PPA ABBREVIATION 23052195 A 75 80 c-AMP ABBREVIATION 23052195 A 853 856 PPA ABBREVIATION 23052195 T 117 136 phenylpropanolamine SYSTEMATIC 23052195 T 48 59 glutathione TRIVIAL 23052195 T 75 80 c-AMP ABBREVIATION 23055393 A 239 245 TiO(2) FORMULA 23055453 A 108 136 oligo(p-phenyleneethynylene) SYSTEMATIC 23055453 A 1144 1147 HCl FORMULA 23055453 A 138 141 OPE ABBREVIATION 23055453 A 159 170 cholesterol TRIVIAL 23055453 A 199 212 ethanediamine SYSTEMATIC 23055453 A 316 319 OPE ABBREVIATION 23055453 A 571 574 HCl FORMULA 23055453 A 687 692 imino SYSTEMATIC 23055453 T 126 129 HCl FORMULA 23055539 A 0 14 Angiotensin IV TRIVIAL 23055539 A 1117 1125 hydrogen SYSTEMATIC 23055539 A 1218 1260 N-hexanoic-Tyr-Ile-(6) aminohexanoic amide SYSTEMATIC 23055539 A 1262 1268 dihexa ABBREVIATION 23055539 A 1324 1335 scopolamine TRIVIAL 23055539 A 1414 1420 dihexa ABBREVIATION 23055539 A 16 21 AngIV ABBREVIATION 23055539 A 459 464 AngIV ABBREVIATION 23055539 A 473 483 norleucine TRIVIAL 23055539 A 487 501 angiotensin IV TRIVIAL 23055539 A 524 525 N FORMULA 23055539 A 535 546 amino acids FAMILY 23055539 A 548 559 Nle-Tyr-Ile FORMULA 23055539 A 616 626 tripeptide FAMILY 23055539 A 804 805 N FORMULA 23055539 A 811 812 C FORMULA 23055539 A 920 931 scopolamine TRIVIAL 23055539 T 39 53 angiotensin IV TRIVIAL 23057615 A 459 473 phenanthroline SYSTEMATIC 23057615 A 544 556 moxifloxacin TRIVIAL 23057615 A 578 587 quinolone FAMILY 23057615 A 630 636 copper SYSTEMATIC 23057615 A 785 797 moxifloxacin TRIVIAL 23057615 T 101 113 moxifloxacin TRIVIAL 23057615 T 78 90 moxifloxacin TRIVIAL 23057692 A 236 246 ciclopirox TRIVIAL 23059626 A 1239 1242 Met FORMULA 23059626 A 675 678 Met FORMULA 23059626 A 964 967 Met FORMULA 23059626 A 976 979 Met FORMULA 23060096 A 102 120 polyethyleneglycol SYSTEMATIC 23060096 A 14 36 Pt(48)Pd(52)-Fe(3)O(4) FORMULA 23060096 A 159 167 H(2)O(2) FORMULA 23060096 A 182 202 tetramethylbenzidine SYSTEMATIC 23060096 A 204 207 TMB ABBREVIATION 23060096 A 248 270 Pt(48)Pd(52)-Fe(3)O(4) FORMULA 23060096 A 271 274 TMB ABBREVIATION 23060096 A 327 335 H(2)O(2) FORMULA 23060096 A 453 461 H(2)O(2) FORMULA 23060096 A 91 101 oleylamine SYSTEMATIC 23060096 T 12 16 H2O2 FORMULA 23060096 T 46 56 PtPd-Fe3O4 FORMULA 23061607 A 165 178 organosilicon FAMILY 23061607 A 21 28 silicon SYSTEMATIC 23061607 A 46 59 organosilicon FAMILY 23061607 T 0 13 Organosilicon FAMILY 23061635 A 0 7 Menthol TRIVIAL 23061635 A 1028 1035 menthol TRIVIAL 23061635 A 1165 1169 GABA ABBREVIATION 23061635 A 1184 1190 sodium SYSTEMATIC 23061635 A 1270 1277 menthol TRIVIAL 23061635 A 1364 1372 nicotine TRIVIAL 23061635 A 1476 1483 Menthol TRIVIAL 23061635 A 276 283 menthol TRIVIAL 23061635 A 490 497 Menthol TRIVIAL 23061635 A 861 868 calcium SYSTEMATIC 23061635 A 87 98 monoterpene FAMILY 23061635 A 884 891 calcium SYSTEMATIC 23061635 T 0 7 Menthol TRIVIAL 23063002 A 103 115 chlorpyrifos TRIVIAL 23063002 A 120 130 penoxsulam TRIVIAL 23063002 A 225 231 oxygen SYSTEMATIC 23063002 A 443 455 chlorpyrifos TRIVIAL 23063002 A 460 470 penoxsulam TRIVIAL 23063002 T 119 131 chlorpyrifos TRIVIAL 23063002 T 136 146 penoxsulam TRIVIAL 23063066 A 344 357 esfenvalerate TRIVIAL 23063066 A 502 515 esfenvalerate TRIVIAL 23063069 A 1005 1008 PCB ABBREVIATION 23063069 A 1013 1016 DDT ABBREVIATION 23063069 A 583 613 polybrominated diphenyl ethers FAMILY 23063069 A 615 620 PBDEs ABBREVIATION 23063069 A 623 648 polychlorinated biphenyls FAMILY 23063069 A 650 654 PCBs ABBREVIATION 23063069 A 660 691 dichlorodiphenyltrichloroethane SYSTEMATIC 23063069 A 878 883 PBDEs ABBREVIATION 23063411 A 0 13 Actinomycin D TRIVIAL 23063411 A 1076 1089 actinomycin D TRIVIAL 23063411 A 1217 1230 actinomycin D TRIVIAL 23063411 A 1293 1306 actinomycin D TRIVIAL 23063411 A 1546 1559 actinomycin D TRIVIAL 23063411 A 1682 1695 actinomycin D TRIVIAL 23063411 A 1799 1812 actinomycin D TRIVIAL 23063411 A 287 300 actinomycin D TRIVIAL 23063411 A 704 717 actinomycin D TRIVIAL 23063411 A 918 931 Actinomycin D TRIVIAL 23063411 T 104 117 actinomycin D TRIVIAL 23063590 A 0 11 Cholesterol TRIVIAL 23063590 A 1015 1026 cholesterol TRIVIAL 23063590 A 1067 1092 hydroxymethylglutaryl CoA SYSTEMATIC 23063590 A 1094 1101 HMG CoA ABBREVIATION 23063590 A 1299 1315 artemisinic acid TRIVIAL 23063590 A 1357 1364 HMG CoA ABBREVIATION 23063590 A 1438 1454 artemisinic acid TRIVIAL 23063590 A 190 206 artemisinic acid TRIVIAL 23063590 A 314 330 artemisinic acid TRIVIAL 23063590 A 530 546 artemisinic acid TRIVIAL 23063590 A 724 740 artemisinic acid TRIVIAL 23063590 A 755 759 cAMP ABBREVIATION 23063590 A 826 842 artemisinic acid TRIVIAL 23063590 A 912 928 artemisinic acid TRIVIAL 23063590 A 960 976 artemisinic acid TRIVIAL 23063590 T 0 16 Artemisinic acid TRIVIAL 23063590 T 98 105 HMG-CoA ABBREVIATION 23063593 A 0 10 Herbacetin TRIVIAL 23063593 A 1046 1049 HER ABBREVIATION 23063593 A 1107 1127 phosphatidylinositol TRIVIAL 23063593 A 1154 1162 LY294002 IDENTIFIER 23063593 A 1198 1201 HER ABBREVIATION 23063593 A 12 15 HER ABBREVIATION 23063593 A 1264 1267 HER ABBREVIATION 23063593 A 225 228 HER ABBREVIATION 23063593 A 30 39 flavonoid FAMILY 23063593 A 400 403 HER ABBREVIATION 23063593 A 470 487 poly (ADP-ribose) SYSTEMATIC 23063593 A 516 519 HER ABBREVIATION 23063593 A 836 839 HER ABBREVIATION 23063593 A 901 920 N-Acetyl-l-cysteine SYSTEMATIC 23063593 A 922 925 NAC ABBREVIATION 23063593 A 977 980 HER ABBREVIATION 23063593 T 0 10 Herbacetin TRIVIAL 23065696 A 1283 1289 (13) C FORMULA 23065696 A 197 203 (13) C FORMULA 23065696 A 359 365 (13) C FORMULA 23065696 A 621 627 carbon SYSTEMATIC 23066090 A 183 187 cAMP ABBREVIATION 23066090 A 389 471 3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile SYSTEMATIC 23066090 A 39 43 cAMP ABBREVIATION 23066090 A 473 479 ESI-09 IDENTIFIER 23066090 A 500 510 nucleotide FAMILY 23066090 A 55 59 cAMP ABBREVIATION 23066821 A 19 32 callylactam A TRIVIAL 23066821 A 41 53 callyimine A TRIVIAL 23066949 A 1083 1095 GlcNAcstatin FAMILY 23066949 A 352 364 GlcNAcstatin FAMILY 23066949 A 4 16 GlcNAcstatin FAMILY 23066949 A 458 467 imidazole SYSTEMATIC 23066949 A 468 476 nitrogen SYSTEMATIC 23066949 A 485 497 GlcNAcstatin FAMILY 23066949 A 57 68 2-acetamino SYSTEMATIC 23066949 A 690 699 aspartate TRIVIAL 23066949 A 849 852 Asp FORMULA 23066949 A 857 860 Asp FORMULA 23066949 A 869 872 Asp FORMULA 23066949 A 893 905 GlcNAcstatin FAMILY 23066949 T 58 70 GlcNAcstatin FAMILY 23068419 A 1262 1270 tyrosine TRIVIAL 23068419 A 1366 1372 6-OHDA SYSTEMATIC 23068419 A 297 310 methylparaben SYSTEMATIC 23068419 A 365 382 6-hydroxydopamine SYSTEMATIC 23068419 A 384 390 6-OHDA SYSTEMATIC 23068419 A 532 538 6-OHDA SYSTEMATIC 23068419 A 544 561 hydrogen peroxide SYSTEMATIC 23068419 A 614 620 oxygen SYSTEMATIC 23068419 A 642 648 6-OHDA SYSTEMATIC 23068419 A 794 800 6-OHDA SYSTEMATIC 23068419 A 901 912 apomorphine TRIVIAL 23068419 A 986 992 6-OHDA SYSTEMATIC 23068419 T 0 13 Methylparaben SYSTEMATIC 23068419 T 23 40 6-hydroxydopamine SYSTEMATIC 23069619 A 132 141 ibuprofen TRIVIAL 23069619 A 887 896 ibuprofen TRIVIAL 23069627 A 1030 1043 palmitic acid TRIVIAL 23069627 A 531 538 calcium SYSTEMATIC 23069627 A 636 643 glucose TRIVIAL 23070981 A 235 239 GeTe FORMULA 23070981 T 52 56 GeTe FORMULA 23071106 A 0 11 Tolbutamide TRIVIAL 23071106 A 1055 1077 8-pCPT-2'-O-Me-cAMP-AM SYSTEMATIC 23071106 A 1159 1165 Ca(2+) FORMULA 23071106 A 1236 1263 2-aminoethoxydiphenylborate SYSTEMATIC 23071106 A 1265 1270 2-APB SYSTEMATIC 23071106 A 1304 1310 Ca(2+) FORMULA 23071106 A 1312 1334 8-pCPT-2'-O-Me-cAMP-AM SYSTEMATIC 23071106 A 1383 1394 tolbutamide TRIVIAL 23071106 A 1421 1426 2-APB SYSTEMATIC 23071106 A 1469 1490 bisindolylmaleimide I SYSTEMATIC 23071106 A 1545 1556 tolbutamide TRIVIAL 23071106 A 1561 1571 gliclazide TRIVIAL 23071106 A 1600 1622 8-pCPT-2'-O-Me-cAMP-AM SYSTEMATIC 23071106 A 1629 1639 gliclazide TRIVIAL 23071106 A 1741 1763 8-pCPT-2'-O-Me-cAMP-AM SYSTEMATIC 23071106 A 1827 1832 2-APB SYSTEMATIC 23071106 A 1843 1849 Ca(2+) FORMULA 23071106 A 205 209 cAMP ABBREVIATION 23071106 A 217 239 8-pCPT-2'-O-Me-cAMP-AM SYSTEMATIC 23071106 A 369 380 tolbutamide TRIVIAL 23071106 A 391 401 gliclazide TRIVIAL 23071106 A 486 498 thapsigargin TRIVIAL 23071106 A 520 526 Ca(2+) FORMULA 23071106 A 543 554 nicardipine TRIVIAL 23071106 A 585 607 8-pCPT-2'-O-Me-cAMP-AM SYSTEMATIC 23071106 A 648 654 Ca(2+) FORMULA 23071106 A 687 698 tolbutamide TRIVIAL 23071106 A 702 712 gliclazide TRIVIAL 23071106 A 731 743 thapsigargin TRIVIAL 23071106 A 747 758 nicardipine TRIVIAL 23071106 A 847 858 tolbutamide TRIVIAL 23071106 A 863 873 gliclazide TRIVIAL 23071106 A 925 935 gliclazide TRIVIAL 23071106 A 976 977 K FORMULA 23071106 A 978 981 ATP ABBREVIATION 23071106 T 115 125 gliclazide TRIVIAL 23071106 T 16 28 sulfonylurea FAMILY 23071106 T 57 61 cAMP ABBREVIATION 23071106 T 99 110 tolbutamide TRIVIAL 23071294 A 763 774 cholesterol TRIVIAL 23071294 A 899 910 cholesterol TRIVIAL 23073171 A 1198 1201 CLA ABBREVIATION 23073171 A 1260 1263 CLA ABBREVIATION 23073171 A 394 397 CLA ABBREVIATION 23073171 A 497 500 CLA ABBREVIATION 23073171 A 65 78 linoleic acid TRIVIAL 23073171 A 654 661 glucose TRIVIAL 23073171 A 80 83 CLA ABBREVIATION 23073171 A 988 991 CLA ABBREVIATION 23073171 T 148 155 glucose TRIVIAL 23073171 T 22 35 linoleic acid TRIVIAL 23074021 A 0 13 Methyleugenol TRIVIAL 23074021 A 1115 1118 MEG ABBREVIATION 23074021 A 1379 1382 MEG ABBREVIATION 23074021 A 15 18 MEG ABBREVIATION 23074021 A 274 277 MEG ABBREVIATION 23074021 A 412 415 MEG ABBREVIATION 23074021 A 547 550 MEG ABBREVIATION 23074021 A 717 720 MEG ABBREVIATION 23074021 A 807 810 MEG ABBREVIATION 23074021 A 877 888 glutathione TRIVIAL 23074021 A 889 890 S FORMULA 23074021 T 24 37 methyleugenol SYSTEMATIC 23074035 A 168 175 PNIPAAm ABBREVIATION 23074035 A 269 276 PNIPAAm ABBREVIATION 23074035 A 281 285 PMMA ABBREVIATION 23074035 A 77 91 PMMA-b-PNIPAAm ABBREVIATION 23074088 A 843 851 carboxyl SYSTEMATIC 23074173 A 0 11 Deferasirox TRIVIAL 23074173 A 1106 1117 deferasirox TRIVIAL 23074173 A 1268 1279 deferasirox TRIVIAL 23074173 A 1584 1600 poly(ADP-ribose) SYSTEMATIC 23074173 A 1649 1660 deferasirox TRIVIAL 23074173 A 186 201 desferrioxamine TRIVIAL 23074173 A 203 206 DFO ABBREVIATION 23074173 A 243 246 DFO ABBREVIATION 23074173 A 322 326 iron SYSTEMATIC 23074173 A 35 39 iron SYSTEMATIC 23074173 A 41 43 Fe FORMULA 23074173 A 516 527 deferasirox TRIVIAL 23074173 A 562 573 Deferasirox TRIVIAL 23074173 A 711 714 DFO ABBREVIATION 23074173 A 729 740 deferasirox TRIVIAL 23074173 A 795 798 DFO ABBREVIATION 23074173 A 822 828 (59)Fe FORMULA 23074173 A 90 94 iron SYSTEMATIC 23074173 A 916 927 deferasirox TRIVIAL 23074173 T 19 30 deferasirox TRIVIAL 23074173 T 4 8 iron SYSTEMATIC 23076553 A 1007 1014 halogen FAMILY 23076553 A 1159 1166 halogen FAMILY 23076553 A 116 125 NHn(X3-n) FAMILY 23076553 A 1240 1247 halogen FAMILY 23076553 A 1379 1389 Lewis base FAMILY 23076553 A 1398 1405 halogen FAMILY 23076553 A 1438 1448 Lewis acid FAMILY 23076553 A 1507 1514 halogen FAMILY 23076553 A 156 159 CH3 FORMULA 23076553 A 162 163 F FORMULA 23076553 A 168 179 Lewis bases FAMILY 23076553 A 1717 1718 N FORMULA 23076553 A 1739 1741 Cl FORMULA 23076553 A 1765 1766 N FORMULA 23076553 A 1767 1769 Cl FORMULA 23076553 A 184 185 F FORMULA 23076553 A 186 188 Cl FORMULA 23076553 A 201 211 Lewis acid FAMILY 23076553 A 452 453 F FORMULA 23076553 A 454 456 Cl FORMULA 23076553 A 459 462 NF3 FORMULA 23076553 A 46 48 Cl FORMULA 23076553 A 486 487 F FORMULA 23076553 A 488 490 Cl FORMULA 23076553 A 493 500 N(CH3)3 FORMULA 23076553 A 51 52 N FORMULA 23076553 T 10 17 halogen FAMILY 23077105 A 1080 1093 actinomycin D TRIVIAL 23077105 A 1189 1276 7α,17β-[9-[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol SYSTEMATIC 23077105 A 1278 1288 ICI182/780 IDENTIFIER 23077105 A 151 167 ethynylestradiol SYSTEMATIC 23077105 A 1606 1616 ICI182/780 IDENTIFIER 23077105 A 198 206 estrogen FAMILY 23077105 A 514 522 estrogen FAMILY 23077105 A 685 695 bile salts FAMILY 23077105 A 700 711 glutathione TRIVIAL 23077105 T 129 137 estrogen FAMILY 23077105 T 66 82 ethynylestradiol SYSTEMATIC 23078542 A 533 541 dopamine TRIVIAL 23079231 A 1071 1080 sirolimus TRIVIAL 23079231 A 1210 1218 curcumin TRIVIAL 23079231 A 1270 1279 sirolimus TRIVIAL 23079231 A 1367 1375 curcumin TRIVIAL 23079231 A 1395 1404 sirolimus TRIVIAL 23079231 A 1473 1481 curcumin TRIVIAL 23079231 A 1500 1509 sirolimus TRIVIAL 23079231 A 1528 1537 sirolimus TRIVIAL 23079231 A 1560 1568 curcumin TRIVIAL 23079231 A 1663 1671 curcumin TRIVIAL 23079231 A 1676 1685 sirolimus TRIVIAL 23079231 A 1756 1764 curcumin TRIVIAL 23079231 A 1769 1778 sirolimus TRIVIAL 23079231 A 205 214 sirolimus TRIVIAL 23079231 A 22 31 sirolimus TRIVIAL 23079231 A 257 265 curcumin TRIVIAL 23079231 A 36 44 curcumin TRIVIAL 23079231 A 705 719 (3)H-thymidine SYSTEMATIC 23079231 A 748 756 curcumin TRIVIAL 23079231 A 877 885 Curcumin TRIVIAL 23079231 A 956 964 curcumin TRIVIAL 23079231 T 60 69 sirolimus TRIVIAL 23079231 T 92 100 curcumin TRIVIAL 23080539 A 1019 1030 doxycycline TRIVIAL 23081912 A 106 110 TCDD ABBREVIATION 23081912 A 1110 1123 salicyl amide TRIVIAL 23081912 A 1145 1149 TCDD ABBREVIATION 23081912 A 1154 1164 prochloraz TRIVIAL 23081912 A 127 136 imidazole SYSTEMATIC 23081912 A 147 157 prochloraz TRIVIAL 23081912 A 1559 1569 prochloraz TRIVIAL 23081912 A 1574 1580 dioxin FAMILY 23081912 A 288 304 aryl hydrocarbon FAMILY 23081912 A 342 348 dioxin FAMILY 23081912 A 586 590 TCDD ABBREVIATION 23081912 A 595 605 prochloraz TRIVIAL 23081912 A 69 104 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23081912 A 758 762 TCDD ABBREVIATION 23081912 A 766 776 prochloraz TRIVIAL 23081912 A 800 814 Hoechst H33342 IDENTIFIER 23081912 A 897 902 Ko143 IDENTIFIER 23081912 T 10 20 prochloraz TRIVIAL 23081912 T 127 142 arylhydrocarbon FAMILY 23081912 T 49 55 dioxin FAMILY 23081947 A 211 219 chlorine SYSTEMATIC 23081947 A 255 259 AuCl FORMULA 23081947 A 342 350 chlorine SYSTEMATIC 23081947 A 418 426 Chlorine SYSTEMATIC 23081947 A 73 75 Au FORMULA 23081947 A 902 910 chlorine SYSTEMATIC 23081947 A 95 103 chlorine SYSTEMATIC 23081947 T 0 8 Chlorine SYSTEMATIC 23081947 T 38 40 Au FORMULA 23085085 A 63 69 acetyl SYSTEMATIC 23085085 A 82 88 lysine TRIVIAL 23085266 A 1014 1024 wortmannin TRIVIAL 23085266 A 1048 1057 GF109203X IDENTIFIER 23085266 A 1114 1117 Ser FORMULA 23085266 A 1125 1128 Ser FORMULA 23085266 A 1133 1141 SB203580 IDENTIFIER 23085266 A 1146 1151 UO126 IDENTIFIER 23085266 A 1249 1252 Ser FORMULA 23085266 A 1316 1325 genistein TRIVIAL 23085266 A 1330 1340 wortmannin TRIVIAL 23085266 A 1368 1376 SB203580 IDENTIFIER 23085266 A 1378 1383 UO126 IDENTIFIER 23085266 A 1388 1397 GF109203X IDENTIFIER 23085266 A 1457 1462 NADPH ABBREVIATION 23085266 A 1566 1574 tyrosine TRIVIAL 23085266 A 429 466 formyl-methionyl-leucyl-phenylalanine SYSTEMATIC 23085266 A 468 472 fMLF ABBREVIATION 23085266 A 482 507 phorbol myristate acetate SYSTEMATIC 23085266 A 509 512 PMA ABBREVIATION 23085266 A 59 64 NADPH ABBREVIATION 23085266 A 712 717 NADPH ABBREVIATION 23085266 A 781 784 Ser FORMULA 23085266 A 789 792 Ser FORMULA 23085266 A 800 803 Ser FORMULA 23085266 A 9 15 oxygen SYSTEMATIC 23085266 A 949 958 genistein TRIVIAL 23085266 A 981 989 tyrosine TRIVIAL 23085266 T 156 164 tyrosine TRIVIAL 23085266 T 16 21 NADPH ABBREVIATION 23085330 A 0 8 Curcumin TRIVIAL 23085330 A 1174 1179 HPβCD ABBREVIATION 23085330 A 1184 1192 curcumin TRIVIAL 23085330 A 1312 1320 curcumin TRIVIAL 23085330 A 1407 1415 curcumin TRIVIAL 23085330 A 143 151 curcumin TRIVIAL 23085330 A 1466 1474 curcumin TRIVIAL 23085330 A 1559 1567 curcumin TRIVIAL 23085330 A 1701 1709 curcumin TRIVIAL 23085330 A 349 357 curcumin TRIVIAL 23085330 A 554 562 curcumin TRIVIAL 23085330 A 648 656 curcumin TRIVIAL 23085330 A 754 782 hydroxypropyl-β-cyclodextrin SYSTEMATIC 23085330 A 784 789 HPβCD ABBREVIATION 23085330 A 791 799 curcumin TRIVIAL 23085330 A 817 830 Hydroxypropyl SYSTEMATIC 23085330 A 867 875 curcumin TRIVIAL 23085330 T 131 139 curcumin TRIVIAL 23085435 A 0 8 Nitrogen SYSTEMATIC 23085435 A 1094 1095 N FORMULA 23085435 A 20 35 bisphosphonates FAMILY 23085435 A 260 261 N FORMULA 23085435 A 262 265 BPs ABBREVIATION 23085435 A 37 38 N FORMULA 23085435 A 39 42 BPs ABBREVIATION 23085435 A 396 424 geranylgeranyl pyrophosphate SYSTEMATIC 23085435 A 426 430 GGPP ABBREVIATION 23085435 A 459 460 N FORMULA 23085435 A 461 464 BPs ABBREVIATION 23085435 A 656 657 N FORMULA 23085435 A 658 661 BPs ABBREVIATION 23085435 A 900 901 N FORMULA 23085435 A 902 905 BPs ABBREVIATION 23085435 T 0 8 Nitrogen SYSTEMATIC 23085435 T 20 35 bisphosphonates FAMILY 23085979 A 1130 1134 TCDD ABBREVIATION 23085979 A 4 20 aryl hydrocarbon FAMILY 23085979 A 716 751 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23085979 A 753 757 TCDD ABBREVIATION 23085979 A 762 794 polycyclic aromatic hydrocarbons FAMILY 23085979 T 0 16 Aryl hydrocarbon FAMILY 23086035 A 639 646 glucose TRIVIAL 23086035 A 718 732 acylcarnitines FAMILY 23086035 A 737 748 sphingosine TRIVIAL 23086035 T 16 23 glucose TRIVIAL 23086038 A 1004 1011 glucose TRIVIAL 23086038 A 596 633 phosphoinositide (3,4,5)-triphosphate SYSTEMATIC 23086197 A 1396 1403 steroid FAMILY 23086197 A 357 362 NADPH ABBREVIATION 23086197 A 502 510 squalene TRIVIAL 23086197 A 531 535 heme FAMILY 23086197 T 0 5 NADPH ABBREVIATION 23086198 A 0 3 UDP ABBREVIATION 23086198 A 1072 1093 1-hydroxy-(OH)-pyrene SYSTEMATIC 23086198 A 1095 1105 1-naphthol SYSTEMATIC 23086198 A 1111 1138 hydroxylated benzo(a)pyrene FAMILY 23086198 A 1257 1261 PAHs ABBREVIATION 23086198 A 1267 1278 1-OH-pyrene SYSTEMATIC 23086198 A 1283 1293 1-naphthol SYSTEMATIC 23086198 A 129 133 PAHs ABBREVIATION 23086198 A 1612 1615 PAH ABBREVIATION 23086198 A 1656 1668 nitrosamines FAMILY 23086198 A 1673 1692 heterocyclic amines FAMILY 23086198 A 1775 1778 PAH ABBREVIATION 23086198 A 1812 1815 PAH ABBREVIATION 23086198 A 1816 1821 diols FAMILY 23086198 A 1916 1936 monohydroxylated PAH FAMILY 23086198 A 193 196 PAH ABBREVIATION 23086198 A 95 127 polycyclic aromatic hydrocarbons FAMILY 23086198 T 14 17 UDP ABBREVIATION 23086703 A 104 123 cyclic pentapeptide FAMILY 23086703 A 124 129 FC131 IDENTIFIER 23086703 A 153 167 dipicolylamine FAMILY 23086703 A 253 279 1,4-phenylenedimethanamine SYSTEMATIC 23086703 A 281 314 naphthalene-2,6-diyldimethanamine SYSTEMATIC 23086703 A 320 358 [1,1'-biphenyl]-4,4'-diyldimethanamine SYSTEMATIC 23086703 A 431 446 2-pyridylmethyl SYSTEMATIC 23086703 A 451 467 1-naphthylmethyl SYSTEMATIC 23086703 A 559 576 1-propylguanidine SYSTEMATIC 23086703 A 581 618 1,1,3,3-tetramethyl-2-propylguanidine SYSTEMATIC 23086703 A 700 708 zinc(II) SYSTEMATIC 23086703 A 725 753 bis(pyridin-2-ylmethyl)amine SYSTEMATIC 23087261 A 1135 1141 lysine TRIVIAL 23087261 A 1264 1267 Lys FORMULA 23087261 A 1424 1427 Lys FORMULA 23087261 T 0 6 Lysine TRIVIAL 23089896 A 1175 1181 Rho123 ABBREVIATION 23089896 A 16 19 ATP ABBREVIATION 23089896 A 230 242 rhodamine123 TRIVIAL 23089896 A 244 250 Rho123 ABBREVIATION 23089896 A 850 862 itraconazole TRIVIAL 23089896 A 909 915 Rho123 ABBREVIATION 23089896 A 998 1004 Rho123 ABBREVIATION 23089896 T 0 3 ATP ABBREVIATION 23091169 A 1083 1093 androstane TRIVIAL 23091169 A 285 298 phenobarbital TRIVIAL 23091169 A 802 811 glutamine TRIVIAL 23091189 A 0 21 Laninamivir octanoate SYSTEMATIC 23091189 A 110 121 laninamivir TRIVIAL 23091189 A 1111 1122 laninamivir TRIVIAL 23091189 A 1346 1357 laninamivir TRIVIAL 23091189 A 1509 1520 laninamivir TRIVIAL 23091189 A 1587 1598 laninamivir TRIVIAL 23091189 A 181 192 laninamivir TRIVIAL 23091189 A 28 34 Inavir TRIVIAL 23091189 A 565 576 laninamivir TRIVIAL 23091189 A 65 70 ester FAMILY 23091189 A 708 719 laninamivir TRIVIAL 23091189 A 824 829 (14)C FORMULA 23091189 T 158 179 laninamivir octanoate SYSTEMATIC 23091189 T 70 81 laninamivir TRIVIAL 23092136 A 1164 1172 hydrogen SYSTEMATIC 23092237 A 141 144 ZnO FORMULA 23092237 T 62 65 ZnO FORMULA 23092395 A 1067 1079 β-sitosterol TRIVIAL 23092395 A 1084 1096 stigmasterol TRIVIAL 23092395 A 208 214 hexane SYSTEMATIC 23092395 A 216 224 methanol SYSTEMATIC 23092395 A 461 491 2,2-diphenyl-1-picryl-hydrazyl SYSTEMATIC 23092395 A 496 502 Fe(3+) FORMULA 23092395 A 503 517 Phenanthroline TRIVIAL 23092395 A 594 604 flavonoids FAMILY 23092395 A 660 668 steroids FAMILY 23092395 A 689 696 tannins FAMILY 23092395 A 786 792 hexane SYSTEMATIC 23092395 A 909 943 3,5,4'-trimethoxy-4-prenylstilbene SYSTEMATIC 23092395 A 945 958 lonchocarpine TRIVIAL 23092395 A 960 982 4-hydroxylonchocarpine SYSTEMATIC 23092395 A 987 998 derricidine TRIVIAL 23092723 A 1217 1225 methanol SYSTEMATIC 23092723 A 1227 1234 ethanol SYSTEMATIC 23092723 A 180 187 hexanes FAMILY 23092723 A 189 197 methanol SYSTEMATIC 23092723 A 202 217 dichloromethane SYSTEMATIC 23092723 A 327 330 MTT ABBREVIATION 23092723 A 405 412 ethanol SYSTEMATIC 23092723 A 588 597 celastrol TRIVIAL 23092723 A 675 683 methanol SYSTEMATIC 23092723 A 685 692 ethanol SYSTEMATIC 23092723 A 790 798 methanol SYSTEMATIC 23092723 A 904 919 dichloromethane SYSTEMATIC 23092877 A 1053 1063 nandrolone TRIVIAL 23092877 A 1552 1559 steroid FAMILY 23092877 A 205 212 steroid FAMILY 23092877 A 213 223 nandrolone TRIVIAL 23092877 A 251 271 nandrolone decanoate SYSTEMATIC 23092877 A 991 1001 nandrolone TRIVIAL 23092894 A 183 192 Glutamate TRIVIAL 23092894 A 32 41 glutamate TRIVIAL 23092894 A 346 355 Glutamate TRIVIAL 23092894 A 433 442 Glutamate TRIVIAL 23092894 A 644 653 Glutamate TRIVIAL 23092894 A 994 1003 glutamate TRIVIAL 23092894 T 26 35 glutamate TRIVIAL 23094599 A 0 7 Silicon SYSTEMATIC 23094599 A 246 253 silicon SYSTEMATIC 23094599 A 467 474 silicon SYSTEMATIC 23094599 A 780 784 Si-C FORMULA 23094599 A 795 801 Si-O-C FORMULA 23094599 A 825 832 silicon SYSTEMATIC 23094599 A 898 902 Si-N FORMULA 23094599 T 0 7 Silicon SYSTEMATIC 23094599 T 44 48 Si-N FORMULA 23094864 A 1115 1120 TSIIA ABBREVIATION 23094864 A 14 28 Tanshinone IIA TRIVIAL 23094864 A 144 175 Sodium tanshinone IIA sulfonate SYSTEMATIC 23094864 A 177 180 STS ABBREVIATION 23094864 A 215 220 TSIIA ABBREVIATION 23094864 A 30 35 TSIIA ABBREVIATION 23094864 A 38 54 cryptotanshinone TRIVIAL 23094864 A 438 443 TSIIA ABBREVIATION 23094864 A 471 481 tanshinone FAMILY 23094864 A 588 593 TSIIA ABBREVIATION 23094864 A 59 71 tanshinone I TRIVIAL 23094864 A 799 804 TSIIA ABBREVIATION 23094864 A 874 879 TSIIA ABBREVIATION 23094864 A 884 896 tanshinone I TRIVIAL 23094864 A 996 1006 tanshinone FAMILY 23094864 T 0 10 Tanshinone FAMILY 23095167 A 144 151 kainate TRIVIAL 23095167 A 171 180 glutamate TRIVIAL 23095167 A 354 361 Kainate TRIVIAL 23095167 A 560 567 kainate TRIVIAL 23095167 A 763 770 kainate TRIVIAL 23095167 T 0 7 Kainate TRIVIAL 23095244 A 0 7 Ecstasy TRIVIAL 23095244 A 1316 1323 ecstasy TRIVIAL 23095244 A 186 193 Ecstasy TRIVIAL 23095244 A 260 267 ecstasy TRIVIAL 23095244 A 397 404 ecstasy TRIVIAL 23095244 A 468 475 ecstasy TRIVIAL 23095244 A 946 953 Ecstasy TRIVIAL 23095244 T 20 27 ecstasy TRIVIAL 23097024 A 1454 1456 NO FORMULA 23097024 A 970 982 nitric oxide SYSTEMATIC 23097351 A 10 17 alcohol FAMILY 23097351 A 121 128 ethanol SYSTEMATIC 23097351 A 266 277 flavonoidal FAMILY 23097351 A 320 330 naringenin TRIVIAL 23097351 A 332 344 aromadendrin TRIVIAL 23097351 A 346 354 apigenin TRIVIAL 23097351 A 359 400 4'-O-methoxy-luteolin-7-O-rhamnoglucoside SYSTEMATIC 23097351 A 515 522 alcohol FAMILY 23097351 A 582 611 1,1-diphenyl,2-picrylhydrazyl SYSTEMATIC 23097351 A 670 711 4'-O-methoxy-luteolin-7-O-rhamnoglucoside SYSTEMATIC 23097351 A 754 761 alcohol FAMILY 23097351 T 56 66 flavonoids FAMILY 23098805 A 1034 1041 cocaine TRIVIAL 23098805 A 1076 1083 cocaine TRIVIAL 23098805 A 117 124 cocaine TRIVIAL 23098805 A 1191 1200 estradiol TRIVIAL 23098805 A 1205 1217 progesterone TRIVIAL 23098805 A 1224 1232 estrogen FAMILY 23098805 A 1284 1296 progesterone TRIVIAL 23098805 A 1393 1400 cocaine TRIVIAL 23098805 A 1568 1575 cocaine TRIVIAL 23098805 A 253 260 cocaine TRIVIAL 23098805 A 546 553 cocaine TRIVIAL 23098805 A 77 84 cocaine TRIVIAL 23098805 A 891 900 estradiol TRIVIAL 23098805 A 905 917 progesterone TRIVIAL 23098805 T 36 43 cocaine TRIVIAL 23098818 A 1028 1035 quinine TRIVIAL 23098818 A 1040 1050 fluoxetine TRIVIAL 23098818 A 1111 1130 5-methoxytryptamine SYSTEMATIC 23098818 A 1134 1143 serotonin TRIVIAL 23098818 A 1287 1296 serotonin TRIVIAL 23098818 A 1302 1321 5-methoxytryptamine SYSTEMATIC 23098818 A 1382 1391 serotonin TRIVIAL 23098818 A 264 265 O FORMULA 23098818 A 283 302 5-methoxytryptamine SYSTEMATIC 23098818 A 306 315 serotonin TRIVIAL 23098818 A 369 378 serotonin TRIVIAL 23098818 A 6 15 serotonin TRIVIAL 23098818 A 752 753 O FORMULA 23098818 A 771 790 5-methoxytryptamine SYSTEMATIC 23098818 A 794 803 serotonin TRIVIAL 23098818 A 934 953 5-methoxytryptamine SYSTEMATIC 23098818 A 957 966 serotonin TRIVIAL 23098818 T 64 73 serotonin TRIVIAL 23098818 T 79 98 5-methoxytryptamine SYSTEMATIC 23098879 A 29 79 1α, 6α-epoxy-9-oxo-10β-hydroxyl-furanoeremophilane SYSTEMATIC 23098879 A 314 319 C1-C6 FORMULA 23098879 A 320 326 oxygen SYSTEMATIC 23098879 A 337 355 furanoeremophilane FAMILY 23098879 A 8 27 furanoeremophilanes FAMILY 23098879 A 89 136 9-oxo-1α, 6β, 10β-trihydroxy-furanoeremophilane SYSTEMATIC 23098879 T 43 49 oxygen SYSTEMATIC 23098879 T 8 26 furanoeremophilane FAMILY 23098993 A 595 604 HC 030031 IDENTIFIER 23098993 A 729 738 capsaicin TRIVIAL 23099337 A 177 184 cadmium SYSTEMATIC 23099337 A 254 262 Caffeine TRIVIAL 23099337 A 275 282 cadmium SYSTEMATIC 23099337 A 333 340 cadmium SYSTEMATIC 23099337 A 381 391 superoxide TRIVIAL 23099337 A 436 444 Caffeine TRIVIAL 23099337 A 482 493 glutathione TRIVIAL 23099337 A 529 536 cadmium SYSTEMATIC 23099337 A 56 64 caffeine TRIVIAL 23099337 A 746 753 cadmium SYSTEMATIC 23099337 A 85 92 cadmium SYSTEMATIC 23099337 A 853 861 Caffeine TRIVIAL 23099337 A 885 892 cadmium SYSTEMATIC 23099337 T 0 8 Caffeine TRIVIAL 23099337 T 17 24 cadmium SYSTEMATIC 23099339 A 110 119 vitamin C TRIVIAL 23099339 A 384 394 folic acid TRIVIAL 23099339 A 399 408 vitamin C TRIVIAL 23099339 A 448 457 resazurin TRIVIAL 23099339 A 598 607 vitamin C TRIVIAL 23099339 A 621 631 folic acid TRIVIAL 23099339 A 778 785 glucose TRIVIAL 23099339 A 786 801 hydroxybutyrate SYSTEMATIC 23099339 A 95 105 folic acid TRIVIAL 23099339 T 122 131 vitamin C TRIVIAL 23099339 T 136 146 folic acid TRIVIAL 23099645 A 1215 1237 5-Aza-2'-deoxycytidine SYSTEMATIC 23099645 A 1343 1357 trichostatin A TRIVIAL 23099811 A 1039 1052 methylmercury SYSTEMATIC 23099811 A 1054 1058 MeHg FORMULA 23099811 A 1087 1088 N FORMULA 23099811 A 1127 1132 (15)N FORMULA 23099811 A 1159 1164 (13)C FORMULA 23099811 A 1340 1345 (13)C FORMULA 23099811 A 1389 1394 (13)C FORMULA 23099811 A 1463 1468 (13)C FORMULA 23099811 A 155 161 carbon SYSTEMATIC 23099811 A 1571 1577 carbon SYSTEMATIC 23099811 A 1778 1784 carbon SYSTEMATIC 23099811 A 2048 2052 MeHg FORMULA 23099811 A 2217 2221 MeHg FORMULA 23099811 A 246 253 mercury SYSTEMATIC 23099811 A 45 52 mercury SYSTEMATIC 23099811 A 492 499 mercury SYSTEMATIC 23099811 A 501 503 Hg FORMULA 23099811 A 528 534 carbon SYSTEMATIC 23099811 A 537 542 (13)C FORMULA 23099811 A 548 556 nitrogen SYSTEMATIC 23099811 A 559 564 (15)N FORMULA 23099811 A 626 630 MeHg FORMULA 23099811 A 650 655 (13)C FORMULA 23099811 A 705 710 (13)C FORMULA 23099811 A 764 768 MeHg FORMULA 23099811 A 820 825 (15)N FORMULA 23099811 A 871 876 (13)C FORMULA 23099811 A 916 918 Hg FORMULA 23099811 T 21 27 carbon SYSTEMATIC 23099811 T 31 38 mercury SYSTEMATIC 23102508 A 1021 1030 miltirone TRIVIAL 23102508 A 1176 1187 tanshinones FAMILY 23102508 A 1225 1234 miltirone TRIVIAL 23102508 A 1252 1269 dihydrotanshinone SYSTEMATIC 23102508 A 1289 1305 cryptotanshinone TRIVIAL 23102508 A 1307 1319 tanshinone I TRIVIAL 23102508 A 1324 1338 tanshinone IIA TRIVIAL 23102508 A 231 240 Miltirone TRIVIAL 23102508 A 250 258 abietane TRIVIAL 23102508 A 264 281 diterpene quinone FAMILY 23102508 A 39 50 tanshinones FAMILY 23102508 A 432 441 miltirone TRIVIAL 23102508 A 548 557 Miltirone TRIVIAL 23102508 A 754 763 miltirone TRIVIAL 23102508 T 68 77 miltirone TRIVIAL 23103297 A 0 11 (-)-Carvone TRIVIAL 23103297 A 1017 1028 (-)-carvone TRIVIAL 23103297 A 1090 1099 carbachol TRIVIAL 23103297 A 1133 1144 (-)-carvone TRIVIAL 23103297 A 1200 1211 (-)-carvone TRIVIAL 23103297 A 1216 1225 verapamil TRIVIAL 23103297 A 1229 1238 carbachol TRIVIAL 23103297 A 1260 1271 (-)-Carvone TRIVIAL 23103297 A 1312 1316 K(+) FORMULA 23103297 A 1359 1368 verapamil TRIVIAL 23103297 A 1376 1387 (-)-carvone TRIVIAL 23103297 A 1465 1476 (-)-carvone TRIVIAL 23103297 A 17 35 monoterpene ketone FAMILY 23103297 A 211 222 (-)-carvone TRIVIAL 23103297 A 304 315 (-)-carvone TRIVIAL 23103297 A 406 417 (-)-carvone TRIVIAL 23103297 A 604 615 (-)-carvone TRIVIAL 23103297 A 656 663 calcium SYSTEMATIC 23103297 A 686 695 verapamil TRIVIAL 23103297 A 730 741 (-)-carvone TRIVIAL 23103297 A 862 866 K(+) FORMULA 23103297 A 927 936 histamine TRIVIAL 23103297 A 948 953 BaCl2 FORMULA 23103297 A 968 977 carbachol TRIVIAL 23103297 T 0 11 (-)-Carvone TRIVIAL 23103426 A 1064 1073 (PhSe)(2) FORMULA 23103426 A 1078 1087 (PhTe)(2) FORMULA 23103426 A 1132 1136 NADH ABBREVIATION 23103426 A 1188 1198 superoxide TRIVIAL 23103426 A 1234 1250 organochalcogens FAMILY 23103426 A 1317 1336 reduced glutathione TRIVIAL 23103426 A 1338 1341 GSH ABBREVIATION 23103426 A 1364 1373 (PhSe)(2) FORMULA 23103426 A 1378 1387 (PhTe)(2) FORMULA 23103426 A 1610 1625 organochalcogen FAMILY 23103426 A 1703 1708 thiol FAMILY 23103426 A 1740 1749 (PhSe)(2) FORMULA 23103426 A 1754 1763 (PhTe)(2) FORMULA 23103426 A 190 209 diphenyl diselenide SYSTEMATIC 23103426 A 1929 1938 (PhSe)(2) FORMULA 23103426 A 1943 1952 (PhTe)(2) FORMULA 23103426 A 211 220 (PhSe)(2) FORMULA 23103426 A 226 246 diphenyl ditelluride SYSTEMATIC 23103426 A 248 257 (PhTe)(2) FORMULA 23103426 A 410 426 organochalcogens FAMILY 23103426 A 440 456 organochalcogens FAMILY 23103426 A 552 561 (PhTe)(2) FORMULA 23103426 A 757 766 (PhSe)(2) FORMULA 23103426 A 897 913 organochalcogens FAMILY 23103426 A 928 944 organochalcogens FAMILY 23103426 T 72 88 organochalcogens FAMILY 23103568 A 1297 1305 estrogen FAMILY 23103568 A 176 185 estrogens FAMILY 23103568 A 257 265 estrogen FAMILY 23103568 A 339 348 lapatinib TRIVIAL 23103568 A 388 396 Estrogen FAMILY 23103568 A 522 530 estrogen FAMILY 23103568 A 64 73 estradiol TRIVIAL 23103568 A 843 851 tyrosine TRIVIAL 23103568 T 0 8 Estrogen FAMILY 23104244 A 1183 1200 7-ethoxyresorufin SYSTEMATIC 23104244 A 1215 1233 7-pentoxyresorufin SYSTEMATIC 23104244 A 1253 1266 chlorzoxazone SYSTEMATIC 23104244 A 807 824 7-ethoxyresorufin SYSTEMATIC 23104244 A 825 826 O FORMULA 23104244 A 839 857 7-pentoxyresorufin SYSTEMATIC 23104244 A 858 859 O FORMULA 23104244 A 877 890 chlorzoxazone SYSTEMATIC 23104244 A 914 923 midazolam TRIVIAL 23104245 A 0 21 Gamma-hydroxybutyrate SYSTEMATIC 23104245 A 1013 1019 1,4-BD SYSTEMATIC 23104245 A 1024 1027 GBL ABBREVIATION 23104245 A 1071 1074 GHB ABBREVIATION 23104245 A 1112 1118 1,4-BD SYSTEMATIC 23104245 A 1123 1126 GBL ABBREVIATION 23104245 A 1132 1135 GHB ABBREVIATION 23104245 A 198 201 GHB ABBREVIATION 23104245 A 214 220 1,4-BD SYSTEMATIC 23104245 A 23 26 GHB ABBREVIATION 23104245 A 236 239 GBL ABBREVIATION 23104245 A 313 316 GHB ABBREVIATION 23104245 A 318 324 1,4-BD SYSTEMATIC 23104245 A 326 329 GBL ABBREVIATION 23104245 A 48 62 1,4-butanediol SYSTEMATIC 23104245 A 590 593 GHB ABBREVIATION 23104245 A 64 70 1,4-BD SYSTEMATIC 23104245 A 828 831 GBL ABBREVIATION 23104245 A 835 841 1,4-BD SYSTEMATIC 23104245 A 97 100 GBL ABBREVIATION 23104245 A 996 999 GHB ABBREVIATION 23104245 T 118 121 GBL ABBREVIATION 23104245 T 40 61 gamma-hydroxybutyrate SYSTEMATIC 23104245 T 63 66 GHB ABBREVIATION 23104245 T 69 83 1,4-butanediol SYSTEMATIC 23104245 T 85 91 1,4-BD SYSTEMATIC 23104245 T 97 116 gamma-butyrolactone SYSTEMATIC 23104419 A 1184 1191 lactate FAMILY 23104419 A 1251 1259 creatine TRIVIAL 23104419 A 1380 1391 methimazole TRIVIAL 23104419 A 273 284 methimazole TRIVIAL 23104419 A 499 507 Androgen FAMILY 23104419 A 59 67 androgen FAMILY 23104419 A 622 634 testosterone TRIVIAL 23104419 A 639 648 estradiol TRIVIAL 23104419 A 710 722 testosterone TRIVIAL 23104419 A 743 752 estradiol TRIVIAL 23104419 A 815 823 Androgen FAMILY 23104419 T 78 86 androgen FAMILY 23104982 A 41 47 serine TRIVIAL 23104982 A 741 782 Ala-Pro-7-amido-4-trifluoromethylcoumarin SYSTEMATIC 23106229 A 863 874 beauvericin TRIVIAL 23106229 A 878 890 depsipeptide FAMILY 23106482 A 213 221 bergenin TRIVIAL 23106482 A 227 233 emodin TRIVIAL 23106482 A 239 251 caffeic acid TRIVIAL 23106482 A 257 266 nobiletin TRIVIAL 23106482 A 272 365 3-O-β-d-galactopyranosyl-hederagenin 28-O-β-d-xylopyranosyl(1 → 6)-β-d-galactopyranosyl ester SYSTEMATIC 23106482 A 30 96 (2R*,3S*,5S*)-N,2-dimethyl-3-hydroxy-5-(10-phenyldecyl)pyrrolidine SYSTEMATIC 23106482 A 371 380 coniferin TRIVIAL 23106482 A 386 403 qingyangshengenin TRIVIAL 23106482 A 409 424 methylconiferin SYSTEMATIC 23106482 A 430 469 syringaresinol 4'-O-β-d-glucopyranoside SYSTEMATIC 23106482 A 476 486 gagaminine TRIVIAL 23106482 A 493 504 perlolyrine TRIVIAL 23106482 A 511 546 (S)-1-(1'-hydroxyethyl)-β-carboline SYSTEMATIC 23106482 A 553 602 1-(β-carboline-1-yl)-3,4,5-trihydroxy-1-pentanone SYSTEMATIC 23106482 A 609 638 1-methoxycarbonyl-β-carboline SYSTEMATIC 23106482 A 645 667 indolo[2,3-α]carbazole SYSTEMATIC 23106482 A 674 709 4-hydroxycinnamic acid methyl ester SYSTEMATIC 23106482 A 720 802 methyl 4-[2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-1-(hydroxymethyl)ethyl] ferulate SYSTEMATIC 23106482 A 8 28 pyrrolidine alkaloid FAMILY 23106482 A 857 865 N-methyl SYSTEMATIC 23108214 A 342 355 carbohydrates FAMILY 23109233 A 1194 1200 Cu(2+) FORMULA 23109233 A 1218 1232 Cu(2+) -Zn(2+) FORMULA 23109233 A 1285 1298 Cu(2+) -Ag(+) FORMULA 23109233 A 170 175 Ag(+) FORMULA 23109233 A 180 186 Zn(2+) FORMULA 23109233 A 193 195 Cu FORMULA 23109233 A 222 224 Ag FORMULA 23109233 A 251 253 Zn FORMULA 23109233 A 396 401 Ag(+) FORMULA 23109233 A 424 426 Ag FORMULA 23109233 A 440 442 Cu FORMULA 23109233 A 456 458 Zn FORMULA 23109233 A 469 475 Cu(2+) FORMULA 23109233 A 534 539 Ag(+) FORMULA 23109233 A 544 550 Zn(2+) FORMULA 23109233 A 653 655 Cu FORMULA 23109233 A 673 675 Ag FORMULA 23109233 A 693 695 Zn FORMULA 23109233 A 823 837 Cu(2+) -Zn(2+) FORMULA 23109233 A 842 855 Cu(2+) -Ag(+) FORMULA 23109233 A 96 102 Cu(2+) FORMULA 23109233 T 44 57 Cu(2+) -Ag(+) FORMULA 23109233 T 60 74 Cu(2+) -Zn(2+) FORMULA 23109279 A 0 8 Fipronil TRIVIAL 23109279 A 1009 1017 fipronil TRIVIAL 23109279 A 1059 1075 fipronil sulfide SYSTEMATIC 23109279 A 1116 1124 fipronil TRIVIAL 23109279 A 1132 1148 fipronil sulfide SYSTEMATIC 23109279 A 1181 1197 fipronil sulfone SYSTEMATIC 23109279 A 1528 1536 fipronil TRIVIAL 23109279 A 196 204 fipronil TRIVIAL 23109279 A 371 379 fipronil TRIVIAL 23109279 A 499 507 fipronil TRIVIAL 23109279 A 568 576 fipronil TRIVIAL 23109279 T 49 57 fipronil TRIVIAL 23110522 A 1032 1040 platinum SYSTEMATIC 23110522 A 150 158 graphite TRIVIAL 23110522 A 178 186 hydrogen SYSTEMATIC 23110522 A 188 202 carbon dioxide SYSTEMATIC 23110522 A 204 219 sulfur trioxide SYSTEMATIC 23110522 A 224 238 carbon dioxide SYSTEMATIC 23110522 A 239 254 sulfur trioxide SYSTEMATIC 23110522 A 309 317 hydrogen SYSTEMATIC 23110522 A 32 40 graphene TRIVIAL 23110522 A 327 342 carboxylic acid SYSTEMATIC 23110522 A 352 365 sulfonic acid SYSTEMATIC 23110522 A 379 394 carboxylic acid SYSTEMATIC 23110522 A 395 408 sulfonic acid SYSTEMATIC 23110522 A 570 576 oxygen SYSTEMATIC 23110522 A 895 903 graphite TRIVIAL 23110522 A 927 933 sulfur SYSTEMATIC 23110522 T 147 153 oxygen SYSTEMATIC 23110522 T 58 66 graphene TRIVIAL 23111282 A 599 609 fatty acid FAMILY 23111282 A 614 625 cholesterol TRIVIAL 23111374 A 0 16 Organophosphorus FAMILY 23111374 A 1024 1030 oximes FAMILY 23111374 A 1031 1035 HI-6 IDENTIFIER 23111374 A 1037 1046 Obidoxime TRIVIAL 23111374 A 1051 1064 2-Pralidoxime SYSTEMATIC 23111374 A 1066 1071 2-PAM SYSTEMATIC 23111374 A 1187 1192 2-PAM SYSTEMATIC 23111374 A 1236 1245 obidoxime TRIVIAL 23111374 A 1250 1254 HI-6 IDENTIFIER 23111374 A 1378 1383 2-PAM SYSTEMATIC 23111374 A 233 236 P-O FORMULA 23111374 A 261 267 serine TRIVIAL 23111374 A 324 363 pyridinium and bis-pyridinium aldoximes MULTIPLE 23111374 A 658 664 oximes FAMILY 23111374 A 748 753 tabun TRIVIAL 23111374 A 868 873 oxime SYSTEMATIC 23111374 T 105 121 organophosphorus FAMILY 23111684 A 140 148 PNTOPAHP ABBREVIATION 23111684 A 32 139 4,8,11,14,15-pentanitro-2,6,9,13-tetraoxa-4,8,11,14,15-pentaazaheptacyclo [5.5.1.1(3,11).1(5,9)]pentadecane SYSTEMATIC 23111684 A 823 877 4,10-dinitro-2,6,8,12-tetraoxa-4,10-diazaisowurtzitane SYSTEMATIC 23111684 A 878 881 TEX ABBREVIATION 23111684 A 959 962 TEX ABBREVIATION 23111684 A 977 984 N-NO(2) FORMULA 23111684 T 64 171 4,8,11,14,15-pentanitro-2,6,9,13-tetraoxa-4,8,11,14,15-pentaazaheptacyclo[5.5.1.1(3,11).1(5,9)] pentadecane SYSTEMATIC 23111879 A 1072 1075 HCl FORMULA 23111879 A 1172 1177 FeCl3 FORMULA 23111879 A 1420 1425 FeCl3 FORMULA 23111879 A 1461 1463 Fe FORMULA 23111879 A 296 311 Ferric chloride SYSTEMATIC 23111879 A 444 451 bromide SYSTEMATIC 23111879 A 453 457 Iron SYSTEMATIC 23111879 A 515 520 FeCl3 FORMULA 23111879 A 564 567 HCl FORMULA 23111879 A 629 641 FeCl3 • 6H2O FORMULA 23111879 A 762 767 FeCl3 FORMULA 23111879 A 826 831 FeCl3 FORMULA 23111879 A 930 935 FeCl3 FORMULA 23111879 A 946 948 Fe FORMULA 23111879 A 978 983 FeCl3 FORMULA 23111879 T 55 70 ferric chloride SYSTEMATIC 23111883 A 153 169 vitamins C and B MULTIPLE 23111883 A 195 197 Cd FORMULA 23111883 A 219 235 Cadmium chloride SYSTEMATIC 23111883 A 237 242 CdCl2 FORMULA 23111883 A 360 367 glucose TRIVIAL 23111883 A 369 382 triglycerides FAMILY 23111883 A 384 395 cholesterol TRIVIAL 23111883 A 431 435 urea TRIVIAL 23111883 A 440 450 creatinine TRIVIAL 23111883 A 496 501 CdCl2 FORMULA 23111883 A 52 59 cadmium SYSTEMATIC 23111883 A 539 548 uric acid TRIVIAL 23111883 A 550 559 aspartate TRIVIAL 23111883 A 578 585 alanine TRIVIAL 23111883 A 61 63 Cd FORMULA 23111883 A 629 638 bilirubin TRIVIAL 23111883 A 879 884 CdCl2 FORMULA 23111883 A 910 926 vitamins C and B MULTIPLE 23111883 A 993 995 Cd FORMULA 23111883 T 12 19 cadmium SYSTEMATIC 23111883 T 56 72 vitamins C and B MULTIPLE 23111884 A 455 462 ethanol SYSTEMATIC 23111884 T 173 184 amphetamine TRIVIAL 23111884 T 186 206 tetrahydrocannabinol SYSTEMATIC 23111885 A 1001 1004 NaC ABBREVIATION 23111885 A 130 138 Tween 61 TRIVIAL 23111885 A 150 161 cholesterol TRIVIAL 23111885 A 212 226 sodium cholate SYSTEMATIC 23111885 A 228 231 NaC ABBREVIATION 23111885 A 237 256 sodium deoxycholate SYSTEMATIC 23111885 A 258 262 NaDC FORMULA 23111885 A 300 307 ethanol SYSTEMATIC 23111885 A 387 396 phosphate SYSTEMATIC 23111885 A 533 542 phosphate SYSTEMATIC 23111885 A 736 740 NaDC FORMULA 23111885 A 750 753 NaC ABBREVIATION 23111885 A 765 772 ethanol SYSTEMATIC 23111885 A 816 819 NaC ABBREVIATION 23111887 A 22 37 dexmedetomidine TRIVIAL 23111887 A 359 374 dexmedetomidine TRIVIAL 23111887 A 415 424 clonidine TRIVIAL 23111887 A 588 597 clonidine TRIVIAL 23111887 A 658 673 dexmedetomidine TRIVIAL 23111887 T 19 34 dexmedetomidine TRIVIAL 23115086 A 1000 1009 midazolam TRIVIAL 23115086 A 1022 1030 fentanyl TRIVIAL 23115086 A 1035 1043 propofol TRIVIAL 23115086 A 1110 1118 fentanyl TRIVIAL 23115086 A 1166 1174 propofol TRIVIAL 23115086 A 1303 1311 morphine TRIVIAL 23115086 A 1380 1388 morphine TRIVIAL 23115086 A 139 147 morphine TRIVIAL 23115086 A 1390 1398 fentanyl TRIVIAL 23115086 A 1404 1412 propofol TRIVIAL 23115086 A 1425 1434 midazolam TRIVIAL 23115086 A 1467 1475 morphine TRIVIAL 23115086 A 1477 1485 fentanyl TRIVIAL 23115086 A 149 158 midazolam TRIVIAL 23115086 A 1491 1499 propofol TRIVIAL 23115086 A 160 168 fentanyl TRIVIAL 23115086 A 174 182 propofol TRIVIAL 23115086 A 376 384 morphine TRIVIAL 23115086 A 389 398 midazolam TRIVIAL 23115086 A 443 451 fentanyl TRIVIAL 23115086 A 456 464 propofol TRIVIAL 23115086 A 684 692 morphine TRIVIAL 23115086 T 45 53 morphine TRIVIAL 23115086 T 55 64 midazolam TRIVIAL 23115086 T 66 74 fentanyl TRIVIAL 23115086 T 80 88 propofol TRIVIAL 23115119 A 115 128 phenylalanine TRIVIAL 23115119 A 142 157 carboxylic acid SYSTEMATIC 23115119 A 182 195 aspartic acid TRIVIAL 23115119 A 199 212 glutamic acid TRIVIAL 23115119 A 475 478 Phe FORMULA 23115119 A 479 482 Glu FORMULA 23115119 A 486 489 Phe FORMULA 23115119 A 490 493 Asp FORMULA 23115119 A 602 605 Phe FORMULA 23115119 A 627 630 Glu FORMULA 23115119 A 634 637 Asp FORMULA 23115324 A 1119 1128 bleomycin FAMILY 23115324 A 1450 1459 bleomycin FAMILY 23115324 A 572 581 bleomycin FAMILY 23115324 T 143 152 bleomycin FAMILY 23115325 A 1121 1125 LEVC ABBREVIATION 23115325 A 1155 1178 sodium hydrogen sulfide SYSTEMATIC 23115325 A 1180 1184 NaHS FORMULA 23115325 A 1202 1203 K FORMULA 23115325 A 1204 1207 ATP ABBREVIATION 23115325 A 1330 1334 NaHS FORMULA 23115325 A 143 155 sulfonylurea FAMILY 23115325 A 1433 1445 sulfonylurea FAMILY 23115325 A 1481 1485 NaHS FORMULA 23115325 A 1592 1593 K FORMULA 23115325 A 1594 1597 ATP ABBREVIATION 23115325 A 18 27 potassium SYSTEMATIC 23115325 A 37 38 K FORMULA 23115325 A 389 390 K FORMULA 23115325 A 39 42 ATP ABBREVIATION 23115325 A 391 394 ATP ABBREVIATION 23115325 A 4 7 ATP ABBREVIATION 23115325 A 538 567 trinitrobenzene sulfonic acid SYSTEMATIC 23115325 A 569 570 K FORMULA 23115325 A 571 574 ATP ABBREVIATION 23115325 A 640 644 K(+) FORMULA 23115325 A 694 707 levcromakalim TRIVIAL 23115325 A 709 713 LEVC ABBREVIATION 23115325 A 718 719 K FORMULA 23115325 A 720 723 ATP ABBREVIATION 23115325 A 865 869 LEVC ABBREVIATION 23115325 T 0 16 Hydrogen sulfide SYSTEMATIC 23115325 T 47 50 ATP ABBREVIATION 23115325 T 61 70 potassium SYSTEMATIC 23116643 A 1168 1174 CCl(4) FORMULA 23116643 A 250 256 CCl(4) FORMULA 23116643 A 271 277 CCl(4) FORMULA 23116643 A 420 435 3-nitrotyrosine SYSTEMATIC 23116643 A 437 441 3-NT SYSTEMATIC 23116643 A 447 466 thiobarbituric acid SYSTEMATIC 23116643 A 535 537 Cu FORMULA 23116643 A 538 540 Zn FORMULA 23116643 A 541 551 superoxide TRIVIAL 23116643 A 578 584 CCl(4) FORMULA 23116643 A 70 85 rosmarinic acid TRIVIAL 23116643 T 0 15 Rosmarinic acid TRIVIAL 23116643 T 67 87 carbon tetrachloride SYSTEMATIC 23117790 A 1191 1198 glucose TRIVIAL 23117790 A 12 19 glucose TRIVIAL 23117790 A 1471 1479 SB334867 IDENTIFIER 23117790 A 1578 1585 glucose TRIVIAL 23117790 A 210 217 glucose TRIVIAL 23117790 A 288 295 glucose TRIVIAL 23117790 A 783 791 SB334867 IDENTIFIER 23117790 A 793 850 N-(2-methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea SYSTEMATIC 23117790 T 33 40 glucose TRIVIAL 23118018 A 1033 1040 alcohol FAMILY 23118018 A 104 111 alcohol FAMILY 23118018 A 119 128 serotonin TRIVIAL 23118018 A 140 159 5-hydroxytryptamine SYSTEMATIC 23118018 A 229 236 alcohol FAMILY 23118018 A 343 350 alcohol FAMILY 23118018 A 473 480 alcohol FAMILY 23118018 A 545 552 alcohol FAMILY 23118018 A 614 618 5-HT SYSTEMATIC 23118018 A 620 643 gamma-aminobutyric acid SYSTEMATIC 23118018 A 645 649 GABA ABBREVIATION 23118018 A 652 660 dopamine TRIVIAL 23118018 A 666 675 glutamate TRIVIAL 23118018 A 795 802 alcohol FAMILY 23118018 A 909 916 alcohol FAMILY 23118018 T 71 78 ethanol SYSTEMATIC 23118018 T 8 27 5-hydroxytryptamine SYSTEMATIC 23118019 A 1231 1237 5'-AMN FORMULA 23118019 A 1242 1249 5'-MABN FORMULA 23118019 A 1341 1348 U50,488 IDENTIFIER 23118019 A 1429 1435 5'-AMN FORMULA 23118019 A 1440 1447 5'-MABN FORMULA 23118019 A 313 343 5'-(2-aminomethyl) naltrindole SYSTEMATIC 23118019 A 345 351 5'-AMN FORMULA 23118019 A 357 401 N-((Naltrindol-5-yl) methyl) pentanimidamide SYSTEMATIC 23118019 A 403 410 5'-MABN FORMULA 23118019 A 454 465 naltrindole TRIVIAL 23118019 A 580 600 [(3)H]-diprenorphine SYSTEMATIC 23118019 A 610 652 guanosine-5'-O-(3-[35S]-thio) triphosphate SYSTEMATIC 23118019 A 654 667 [(35)S]-GTPγS SYSTEMATIC 23118019 A 736 742 5'-AMN FORMULA 23118019 A 747 754 5'-MABN FORMULA 23118019 A 936 942 5'-AMN FORMULA 23118019 A 947 954 5'-MABN FORMULA 23118019 T 41 52 naltrindole TRIVIAL 23121767 A 47 58 bicarbonate SYSTEMATIC 23121934 A 1081 1110 3,4,5-trimethoxycinnamic acid SYSTEMATIC 23121934 A 109 117 morphine TRIVIAL 23121934 A 1195 1205 WAY 100635 IDENTIFIER 23121934 A 12 41 3,4,5-trimethoxycinnamic acid SYSTEMATIC 23121934 A 1250 1279 3,4,5-trimethoxycinnamic acid SYSTEMATIC 23121934 A 238 245 ketones FAMILY 23121934 A 251 257 esters FAMILY 23121934 A 298 304 amides FAMILY 23121934 A 339 361 1-hydroxybenzotriazole SYSTEMATIC 23121934 A 362 401 ethyl(dimethylaminopropryl)carbodiimide SYSTEMATIC 23121934 A 442 450 naloxone TRIVIAL 23121934 A 459 467 morphine TRIVIAL 23121934 A 534 563 3,4,5-trimethoxycinnamic acid SYSTEMATIC 23121934 A 600 629 3,4,5-trimethoxycinnamic acid SYSTEMATIC 23121934 A 701 709 naloxone TRIVIAL 23121934 A 718 726 morphine TRIVIAL 23121934 A 765 777 (+)8-OH-DPAT SYSTEMATIC 23121934 A 858 870 (+)8-OH-DPAT SYSTEMATIC 23121934 A 975 985 WAY 100635 IDENTIFIER 23121934 T 40 69 3,4,5-trimethoxycinnamic acid SYSTEMATIC 23122060 A 1019 1038 quercetin glucoside TRIVIAL 23122060 A 113 140 quercetin-3-O-β-d-glucoside SYSTEMATIC 23122060 A 1187 1190 Q3G SYSTEMATIC 23122060 A 142 145 Q3G SYSTEMATIC 23122060 A 189 198 d-glucose TRIVIAL 23122060 A 231 240 d-glucose TRIVIAL 23122060 A 251 254 Q3G SYSTEMATIC 23122060 A 608 618 saccharide FAMILY 23122060 A 661 670 quercetin TRIVIAL 23122060 A 78 98 quercetin glycosides FAMILY 23122060 A 794 797 Q3G SYSTEMATIC 23122060 A 811 820 quercetin TRIVIAL 23122060 A 932 935 Q3G SYSTEMATIC 23122060 T 39 58 quercetin glycoside FAMILY 23122061 A 191 202 β-carboline TRIVIAL 23122061 A 203 216 glucoalkaloid FAMILY 23122061 A 218 246 harmanyl β-d-glucopyranoside TRIVIAL 23122061 A 289 293 (1)H FORMULA 23122061 A 299 304 (13)C FORMULA 23122061 A 310 314 (1)H FORMULA 23122061 A 315 319 (1)H FORMULA 23122061 A 38 45 ethanol SYSTEMATIC 23122064 A 857 864 cocaine TRIVIAL 23122064 A 870 881 amphetamine TRIVIAL 23122066 A 145 155 silica gel TRIVIAL 23122066 A 299 310 cholesterol TRIVIAL 23122066 A 465 476 cholesterol TRIVIAL 23122066 A 507 518 cholesterol TRIVIAL 23122066 A 586 597 cholesterol TRIVIAL 23122066 A 640 649 bile acid FAMILY 23122066 A 726 739 sphingolipids FAMILY 23122066 A 768 784 triacylglycerols FAMILY 23122066 A 789 802 sterol esters FAMILY 23122066 A 853 866 sphingolipids FAMILY 23122066 A 868 884 triacylglycerols FAMILY 23122066 A 890 903 sterol esters FAMILY 23122068 A 110 122 sulforaphene TRIVIAL 23122068 A 232 244 Sulforaphene TRIVIAL 23122068 A 334 342 methanol SYSTEMATIC 23122068 A 435 447 sulforaphene TRIVIAL 23122068 A 469 481 sulforaphene TRIVIAL 23122068 A 504 516 sulforaphene TRIVIAL 23122068 A 586 598 sulforaphene TRIVIAL 23122068 A 630 642 sulforaphene TRIVIAL 23122068 A 779 783 (1)H FORMULA 23122068 A 792 797 (13)C FORMULA 23122068 A 851 863 sulforaphene TRIVIAL 23122068 A 891 903 sulforaphene TRIVIAL 23122068 T 31 43 sulforaphene TRIVIAL 23122077 A 441 449 H(2)O(2) FORMULA 23122077 A 491 520 2,2-diphenyl-1-picrylhydrazyl SYSTEMATIC 23122077 A 522 526 DPPH ABBREVIATION 23122085 A 1056 1079 monoacylglycerol ethers FAMILY 23122085 A 1092 1115 fatty acid ethyl esters FAMILY 23122085 A 134 154 diacylglycerol ether FAMILY 23122085 A 159 175 triacylglycerols FAMILY 23122085 A 217 237 diacylglycerol ether FAMILY 23122085 A 301 308 ethanol SYSTEMATIC 23122085 A 32 40 squalene TRIVIAL 23122085 A 482 502 diacylglycerol ether FAMILY 23122085 A 743 758 triacylglycerol FAMILY 23122085 A 808 829 diacylglycerol ethers FAMILY 23122085 A 839 862 monoacylglycerol ethers FAMILY 23122085 A 875 898 fatty acid ethyl esters FAMILY 23122085 A 939 946 ethanol SYSTEMATIC 23122085 A 957 978 diacylglycerol ethers FAMILY 23122085 T 23 44 diacylglycerol ethers FAMILY 23122086 A 340 357 galacturonic acid TRIVIAL 23122086 A 359 363 GalA ABBREVIATION 23122089 A 271 277 carbon SYSTEMATIC 23122089 A 281 289 nitrogen SYSTEMATIC 23122089 A 291 292 C FORMULA 23122089 A 293 294 N FORMULA 23122089 A 318 329 amino acids FAMILY 23122089 A 340 344 GABA ABBREVIATION 23122089 A 379 385 sugars FAMILY 23122089 A 397 424 Linoleic and linolenic acid MULTIPLE 23122089 A 448 471 unsaturated fatty acids FAMILY 23122089 A 530 540 tocopherol FAMILY 23122089 A 545 555 isoflavone FAMILY 23122089 A 660 664 GABA ABBREVIATION 23122089 A 666 677 isoflavones FAMILY 23122089 A 682 693 tocopherols FAMILY 23122092 A 1062 1075 1-octen-3-one SYSTEMATIC 23122092 A 976 985 Methional TRIVIAL 23122092 A 995 1002 phenols FAMILY 23122097 A 266 274 alcohols FAMILY 23122097 A 276 285 aldehydes FAMILY 23122097 A 287 299 hydrocarbons FAMILY 23122097 A 301 308 ketones FAMILY 23122097 A 310 325 carboxylic acid SYSTEMATIC 23122097 A 327 332 ester FAMILY 23122097 A 521 533 1-Octen-3-ol SYSTEMATIC 23122097 A 538 550 (2E)-hexenal SYSTEMATIC 23122097 A 886 897 fatty acids FAMILY 23122097 A 902 908 esters FAMILY 23122105 A 153 166 Allura Red AC TRIVIAL 23122105 A 721 734 ascorbic acid TRIVIAL 23122105 A 736 747 citric acid TRIVIAL 23122105 A 749 756 sucrose TRIVIAL 23122105 A 835 858 aromatic amine or amide MULTIPLE 23122105 T 24 37 Allura Red AC TRIVIAL 23122108 A 0 11 Polyphenols FAMILY 23122108 A 130 135 sugar FAMILY 23122108 A 248 261 ginnalins A-C MULTIPLE 23122108 A 454 467 Ginnalins A-C MULTIPLE 23122108 A 560 571 polyphenols FAMILY 23122108 A 573 583 ginnalin A TRIVIAL 23122108 A 58 71 Ginnalins A-C MULTIPLE 23122108 A 635 652 ginnalins B and C MULTIPLE 23122108 A 705 715 Ginnalin A TRIVIAL 23122108 A 76 87 polyphenols FAMILY 23122108 A 895 906 polyphenols FAMILY 23122108 T 19 32 ginnalins A-C MULTIPLE 23122108 T 6 17 polyphenols FAMILY 23122114 A 217 224 mercury SYSTEMATIC 23122114 A 381 388 mercury SYSTEMATIC 23122114 A 399 412 methylmercury SYSTEMATIC 23122114 A 414 418 MeHg FORMULA 23122114 A 502 504 Hg FORMULA 23122114 A 574 578 MeHg FORMULA 23122114 A 669 671 Hg FORMULA 23122114 A 770 772 Hg FORMULA 23122114 T 5 12 mercury SYSTEMATIC 23122116 A 125 137 azoxystrobin TRIVIAL 23122116 A 334 345 strobilurin FAMILY 23122116 A 399 407 methanol SYSTEMATIC 23122116 A 540 548 methanol SYSTEMATIC 23122116 A 591 599 methanol SYSTEMATIC 23122116 A 649 657 methanol SYSTEMATIC 23122116 T 35 47 azoxystrobin TRIVIAL 23122118 A 162 178 organophosphorus FAMILY 23122118 T 23 39 organophosphorus FAMILY 23122129 A 38 48 amino acid FAMILY 23122129 T 28 39 D-galactose TRIVIAL 23122135 A 176 184 methanol SYSTEMATIC 23122135 A 265 294 2,2-diphenyl-1-picrylhydrazyl SYSTEMATIC 23122135 A 296 300 DPPH ABBREVIATION 23122135 A 306 360 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) SYSTEMATIC 23122135 A 362 366 ABTS ABBREVIATION 23122135 A 636 662 caffeic acid-3-O-glucoside SYSTEMATIC 23122135 A 668 680 caffeic acid TRIVIAL 23122135 A 686 708 luteolin-7-O-glucoside SYSTEMATIC 23122135 A 714 736 apigenin-7-O-glucoside SYSTEMATIC 23122135 A 742 771 rosmarinic acid-3-O-glucoside SYSTEMATIC 23122135 A 777 792 rosmarinic acid TRIVIAL 23122135 A 798 806 luteolin TRIVIAL 23122135 A 812 820 apigenin TRIVIAL 23122135 A 830 841 chrysoeriol TRIVIAL 23122135 A 928 957 rosmarinic acid-3-O-glucoside SYSTEMATIC 23122135 A 966 981 rosmarinic acid TRIVIAL 23122136 A 34 46 anthocyanins FAMILY 23122136 T 24 36 anthocyanins FAMILY 23122137 A 0 10 Vescalagin TRIVIAL 23122137 A 123 130 glucose TRIVIAL 23122137 A 317 325 fructose TRIVIAL 23122137 A 427 437 vescalagin TRIVIAL 23122137 A 553 560 glucose TRIVIAL 23122137 A 573 585 fructosamine SYSTEMATIC 23122137 A 587 599 triglyceride FAMILY 23122137 A 609 619 fatty acid FAMILY 23122137 A 745 755 vescalagin TRIVIAL 23122137 A 877 888 cholesterol TRIVIAL 23122137 A 945 955 vescalagin TRIVIAL 23122137 A 988 998 vescalagin TRIVIAL 23122137 T 146 154 fructose TRIVIAL 23122137 T 48 58 vescalagin TRIVIAL 23122140 A 507 511 DPPH ABBREVIATION 23122140 A 683 691 H(2)O(2) FORMULA 23122140 T 119 127 H(2)O(2) FORMULA 23122141 A 160 171 fatty acids FAMILY 23122141 A 216 227 fatty acids FAMILY 23122141 A 284 295 fatty acids FAMILY 23122141 A 30 41 fatty acids FAMILY 23122141 A 673 689 triacylglycerols FAMILY 23122141 A 713 724 fatty acids FAMILY 23122141 T 17 29 behenic acid TRIVIAL 23122145 A 518 526 catechin TRIVIAL 23122145 A 531 542 epicatechin TRIVIAL 23122145 A 552 575 epicatechin-3-O-gallate SYSTEMATIC 23122145 A 615 631 epigallocatechin TRIVIAL 23122145 A 663 674 epicatechin TRIVIAL 23122145 A 679 702 epicatechin-3-O-gallate SYSTEMATIC 23122145 A 71 87 proanthocyanidin FAMILY 23122145 T 96 113 proanthocyanidins FAMILY 23122152 A 366 387 secoiridoid aglycones FAMILY 23122152 A 950 956 phenol SYSTEMATIC 23122155 A 1037 1045 carnosol TRIVIAL 23122155 A 1050 1064 betulinic acid TRIVIAL 23122155 A 117 130 ethyl acetate SYSTEMATIC 23122155 A 140 145 AcOEt FORMULA 23122155 A 155 161 hexane SYSTEMATIC 23122155 A 163 166 HEX ABBREVIATION 23122155 A 274 282 carnosol TRIVIAL 23122155 A 287 301 betulinic acid TRIVIAL 23122155 A 610 615 AcOEt FORMULA 23122155 A 675 678 HEX ABBREVIATION 23122155 A 702 707 AcOEt FORMULA 23122155 A 737 745 carnosol TRIVIAL 23122155 A 786 789 HEX ABBREVIATION 23122155 A 803 817 betulinic acid TRIVIAL 23122155 A 853 858 AcOEt FORMULA 23122155 A 864 869 AcOEt FORMULA 23122155 T 57 65 carnosol TRIVIAL 23122155 T 70 84 betulinic acid TRIVIAL 23122160 A 1412 1423 dinotefuran TRIVIAL 23122160 A 1504 1515 dinotefuran TRIVIAL 23122160 A 42 53 dinotefuran TRIVIAL 23122160 A 501 521 ammonium bicarbonate SYSTEMATIC 23122160 A 671 694 primary secondary amine MULTIPLE 23122160 A 75 78 MNG ABBREVIATION 23122160 A 901 923 acetonitrile and salts MULTIPLE 23122160 T 56 67 dinotefuran TRIVIAL 23122165 A 0 50 Z-2-(β-d-glucopyranosyloxy)-3-phenylpropenoic acid SYSTEMATIC 23122165 A 388 393 sugar FAMILY 23122165 A 439 489 E-2-(β-d-glucopyranosyloxy)-3-phenylpropenoic acid SYSTEMATIC 23122165 A 52 56 PPAG ABBREVIATION 23122165 A 624 628 PPAG ABBREVIATION 23122165 A 815 819 PPAG ABBREVIATION 23122165 T 37 87 Z-2-(β-d-glucopyranosyloxy)-3-phenylpropenoic acid SYSTEMATIC 23122167 A 28 44 nortriterpenoids FAMILY 23122167 A 422 442 Schisarisanlactone A TRIVIAL 23122167 A 46 77 schisarisanlactones A (1) and B MULTIPLE 23122167 T 0 27 Schisarisanlactones A and B MULTIPLE 23122167 T 44 60 nortriterpenoids FAMILY 23122169 A 265 282 16-acetoxylsugiol SYSTEMATIC 23122169 A 288 303 graciliflorin E TRIVIAL 23122169 A 309 324 graciliflorin F TRIVIAL 23122169 A 330 356 15-O-methylgraciliflorin F SYSTEMATIC 23122169 A 362 389 15-hydroxy-20-deoxocarnosol SYSTEMATIC 23122169 A 39 47 abietane TRIVIAL 23122169 A 395 416 3β-hydroxysempervirol SYSTEMATIC 23122169 A 422 449 15-hydroxy-1-oxosalvibretol SYSTEMATIC 23122169 A 455 487 abieta-8,11,13-triene-14,19-diol SYSTEMATIC 23122169 A 48 60 diterpenoids FAMILY 23122169 A 493 541 6,12,15-trihydroxy-5,8,11,13-abietatetraen-7-one SYSTEMATIC 23122169 A 551 562 3α-hinokiol TRIVIAL 23122169 T 0 8 Abietane TRIVIAL 23122169 T 9 21 diterpenoids FAMILY 23123188 A 1219 1225 oxygen SYSTEMATIC 23123188 A 1397 1404 timolol TRIVIAL 23123188 A 513 516 PGT ABBREVIATION 23123188 A 518 550 propoxylated glyceryl triacylate FAMILY 23123188 A 581 588 timolol TRIVIAL 23123188 A 701 708 ethanol SYSTEMATIC 23123188 A 747 754 timolol TRIVIAL 23123188 A 758 767 phosphate SYSTEMATIC 23123188 A 915 922 timolol TRIVIAL 23123188 A 930 933 PGT ABBREVIATION 23123188 T 40 47 timolol TRIVIAL 23123248 A 587 596 carbamate FAMILY 23123248 A 701 713 rivastigmine TRIVIAL 23123248 A 884 894 carbamates FAMILY 23123254 A 440 445 tabun TRIVIAL 23123254 A 452 457 sarin TRIVIAL 23123254 A 464 469 soman TRIVIAL 23123254 A 480 490 cyclosarin TRIVIAL 23123254 A 500 517 chlorpyrifos oxon TRIVIAL 23123254 A 560 572 chlorpyrifos TRIVIAL 23123254 A 743 751 diazoxon TRIVIAL 23123254 A 78 94 organophosphorus FAMILY 23123254 A 794 802 diazinon TRIVIAL 23123331 A 1052 1055 SLB ABBREVIATION 23123331 A 1060 1067 silybin TRIVIAL 23123331 A 1125 1128 SLB ABBREVIATION 23123331 A 1205 1215 Na(2)CO(3) FORMULA 23123331 A 155 161 silica TRIVIAL 23123331 A 539 542 SLB ABBREVIATION 23123331 A 547 554 silybin TRIVIAL 23123331 A 621 631 Na(2)CO(3) FORMULA 23123331 A 663 673 Na(2)CO(3) FORMULA 23123331 A 715 722 silybin TRIVIAL 23123331 A 73 80 silybin TRIVIAL 23123331 A 751 754 SLB ABBREVIATION 23123331 A 858 861 SLB ABBREVIATION 23123331 A 866 873 silybin TRIVIAL 23123331 A 87 90 SLB ABBREVIATION 23123331 A 937 947 Na(2)CO(3) FORMULA 23123331 T 64 71 silybin TRIVIAL 23123331 T 88 94 silica TRIVIAL 23123737 A 421 427 lutein TRIVIAL 23123743 A 1136 1139 PPT ABBREVIATION 23123743 A 1448 1451 PPT ABBREVIATION 23123743 A 1620 1638 inositol phosphate SYSTEMATIC 23123743 A 1695 1703 estrogen FAMILY 23123743 A 220 233 17β-Estradiol SYSTEMATIC 23123743 A 266 269 PPT ABBREVIATION 23123743 A 302 305 DPN ABBREVIATION 23123743 A 341 364 [³H]-inositol phosphate SYSTEMATIC 23123743 A 516 539 [³H]-inositol phosphate SYSTEMATIC 23123743 A 601 612 ICI 182,780 IDENTIFIER 23123743 A 643 647 G-15 IDENTIFIER 23123743 A 667 690 [³H]-inositol phosphate SYSTEMATIC 23123743 A 67 75 estrogen FAMILY 23123743 A 722 725 PPT ABBREVIATION 23123743 A 822 830 tyrosine TRIVIAL 23123743 A 849 852 PP2 ABBREVIATION 23123743 A 871 894 [³H]-inositol phosphate SYSTEMATIC 23123743 A 926 929 PPT ABBREVIATION 23123743 T 0 8 Estrogen FAMILY 23123743 T 53 71 inositol phosphate SYSTEMATIC 23123945 A 0 8 Atrazine TRIVIAL 23123945 A 10 13 ATR ABBREVIATION 23123945 A 1024 1027 ATR ABBREVIATION 23123945 A 1088 1091 ATR ABBREVIATION 23123945 A 1195 1204 monoamine FAMILY 23123945 A 1269 1272 ATR ABBREVIATION 23123945 A 1296 1307 amphetamine TRIVIAL 23123945 A 1355 1358 ATR ABBREVIATION 23123945 A 1457 1460 ATR ABBREVIATION 23123945 A 1514 1517 ATR ABBREVIATION 23123945 A 244 247 ATR ABBREVIATION 23123945 A 352 360 dopamine TRIVIAL 23123945 A 428 431 ATR ABBREVIATION 23123945 A 464 473 monoamine FAMILY 23123945 A 569 572 ATR ABBREVIATION 23123945 A 618 621 ATR ABBREVIATION 23123945 A 746 751 DOPAC ABBREVIATION 23123945 A 757 760 HVA ABBREVIATION 23123945 A 828 830 Mn FORMULA 23123945 A 918 927 monoamine FAMILY 23123945 T 35 43 atrazine TRIVIAL 23124677 A 1110 1117 Cadmium SYSTEMATIC 23124677 A 1259 1266 cadmium SYSTEMATIC 23124677 A 1365 1372 Cadmium SYSTEMATIC 23124677 A 1580 1582 Cd FORMULA 23124677 A 1679 1681 Cd FORMULA 23124677 A 450 457 cadmium SYSTEMATIC 23124677 A 601 608 cadmium SYSTEMATIC 23124677 A 725 727 Cd FORMULA 23124677 A 795 803 nitrogen SYSTEMATIC 23124677 T 0 7 Cadmium SYSTEMATIC 23124905 A 279 287 dicaprin TRIVIAL 23124905 A 465 476 diglyceride FAMILY 23124905 A 478 494 1,2-sn- dicaprin SYSTEMATIC 23124905 A 499 514 2,3-sn-dicaprin SYSTEMATIC 23124905 A 540 555 1,3-sn-dicaprin SYSTEMATIC 23124905 A 640 645 ester FAMILY 23124905 A 660 671 diglyceride FAMILY 23124905 A 681 696 1,2-sn-dicaprin SYSTEMATIC 23124905 A 701 716 2,3-sn-dicaprin SYSTEMATIC 23124905 A 860 868 dicaprin TRIVIAL 23124950 A 175 181 silver SYSTEMATIC 23124950 A 308 315 silicon SYSTEMATIC 23125070 A 0 12 Testosterone TRIVIAL 23125070 A 1317 1332 androstenedione TRIVIAL 23125070 A 1406 1421 androstenedione TRIVIAL 23125070 A 1425 1437 testosterone TRIVIAL 23125070 A 1477 1489 testosterone TRIVIAL 23125070 A 1588 1600 testosterone TRIVIAL 23125070 A 426 438 testosterone TRIVIAL 23125070 A 514 526 testosterone TRIVIAL 23125070 A 557 569 testosterone TRIVIAL 23125070 T 44 56 testosterone TRIVIAL 23127598 A 133 147 Brilliant Blue TRIVIAL 23127598 A 157 168 Patent Blue TRIVIAL 23127598 A 48 64 triphenylmethane SYSTEMATIC 23127598 A 571 578 ethanol SYSTEMATIC 23127598 A 643 650 ethanol SYSTEMATIC 23127598 T 14 30 triphenylmethane SYSTEMATIC 23127598 T 36 50 Brilliant Blue TRIVIAL 23127598 T 55 66 Patent Blue TRIVIAL 23127599 A 1068 1071 Res ABBREVIATION 23127599 A 1125 1128 Res ABBREVIATION 23127599 A 1279 1282 Res ABBREVIATION 23127599 A 227 238 resveratrol TRIVIAL 23127599 A 240 243 Res ABBREVIATION 23127599 A 279 289 fatty acid FAMILY 23127599 A 546 553 sucrose TRIVIAL 23127599 A 581 592 resveratrol TRIVIAL 23127599 A 753 756 Res ABBREVIATION 23127599 A 781 784 Res ABBREVIATION 23127599 A 934 937 Res ABBREVIATION 23127599 T 23 34 resveratrol TRIVIAL 23127601 A 1169 1176 mercury SYSTEMATIC 23127601 A 1279 1286 mercury SYSTEMATIC 23127601 A 278 285 mercury SYSTEMATIC 23127601 A 542 549 mercury SYSTEMATIC 23127601 A 734 741 mercury SYSTEMATIC 23127601 A 922 929 mercury SYSTEMATIC 23127601 T 62 69 mercury SYSTEMATIC 23127826 A 1059 1066 flavone TRIVIAL 23127826 A 121 128 flavone TRIVIAL 23127826 A 287 294 flavone TRIVIAL 23127826 A 327 337 pyridinium SYSTEMATIC 23127826 A 487 494 flavone TRIVIAL 23127826 A 57 64 flavone TRIVIAL 23127826 A 923 930 flavone TRIVIAL 23127826 T 26 33 flavone TRIVIAL 23128829 A 88 95 cocaine TRIVIAL 23131177 A 0 9 Melatonin TRIVIAL 23131177 A 1335 1344 melatonin TRIVIAL 23131177 A 1363 1369 Ca(2+) FORMULA 23131177 A 1681 1690 melatonin TRIVIAL 23131177 A 275 284 melatonin TRIVIAL 23131177 A 304 313 melatonin TRIVIAL 23131177 A 562 598 N-[3-(3-methoxyphenyl)propyl] amides FAMILY 23131177 A 613 622 melatonin TRIVIAL 23131177 A 798 802 cAMP ABBREVIATION 23131177 A 935 945 benzyloxyl SYSTEMATIC 23131177 A 993 1008 3-methoxyphenyl SYSTEMATIC 23131177 T 32 50 phenylpropylamides FAMILY 23131177 T 87 96 melatonin TRIVIAL 23131797 A 1230 1237 octanol SYSTEMATIC 23131798 A 334 405 N-cyclopentyl-4-ethoxy-6-(4-methylpiperidin-1-yl)-1,3,5-triazin-2-amine SYSTEMATIC 23131798 A 517 531 1,3,5-triazine SYSTEMATIC 23131798 A 616 652 2,4,6-trisubstituted-1,3,5-triazines FAMILY 23131798 T 104 140 2,4,6-trisubstituted 1,3,5-triazines FAMILY 23132334 A 0 12 Dolutegravir TRIVIAL 23132334 A 1085 1088 DTG ABBREVIATION 23132334 A 1163 1166 DTG ABBREVIATION 23132334 A 1293 1303 creatinine TRIVIAL 23132334 A 1390 1393 DTG ABBREVIATION 23132334 A 14 17 DTG ABBREVIATION 23132334 A 1536 1539 DTG ABBREVIATION 23132334 A 19 31 S/GSK1349572 IDENTIFIER 23132334 A 253 256 DTG ABBREVIATION 23132334 A 321 324 DTG ABBREVIATION 23132334 A 526 529 DTG ABBREVIATION 23132334 A 555 558 UDP ABBREVIATION 23132334 A 646 649 DTG ABBREVIATION 23132334 A 764 767 DTG ABBREVIATION 23132334 T 129 141 dolutegravir TRIVIAL 23132743 A 353 376 1,25-dihydroxyvitamin D SYSTEMATIC 23132743 A 38 61 1,25-dihydroxyvitamin D SYSTEMATIC 23132743 A 4 13 vitamin D FAMILY 23132743 A 454 477 1,25-dihydroxyvitamin D SYSTEMATIC 23132743 A 665 674 vitamin D FAMILY 23132743 T 32 41 vitamin D FAMILY 23132751 A 26 29 CaO FORMULA 23132751 A 428 431 MgO FORMULA 23132751 A 44 51 CaCO(3) FORMULA 23132751 A 491 498 CaCO(3) FORMULA 23132751 A 535 538 MgO FORMULA 23132751 A 544 551 CaCO(3) FORMULA 23132751 A 626 629 MgO FORMULA 23132751 A 73 78 CO(2) FORMULA 23132751 T 25 28 CaO FORMULA 23132751 T 50 55 CO(2) FORMULA 23132843 A 250 256 iodine SYSTEMATIC 23132843 A 266 304 4-Aryl-3,4-dihydropyrimidin-2(1H)-ones FAMILY 23132843 A 4 17 sodium iodide SYSTEMATIC 23132843 A 516 526 pyrimidone SYSTEMATIC 23132843 A 73 79 iodide SYSTEMATIC 23132843 T 28 59 3,4-dihydropyrimidin-2(1H)-ones FAMILY 23132843 T 63 76 sodium iodide SYSTEMATIC 23135547 A 0 11 Dronedarone TRIVIAL 23135547 A 1063 1074 dronedarone TRIVIAL 23135547 A 119 130 dronedarone TRIVIAL 23135547 A 1272 1283 dronedarone TRIVIAL 23135547 A 1342 1352 amiodarone TRIVIAL 23135547 A 1374 1384 amiodarone TRIVIAL 23135547 A 1386 1397 dronedarone TRIVIAL 23135547 A 1600 1611 fatty acids FAMILY 23135547 A 181 191 Amiodarone TRIVIAL 23135547 A 304 315 dronedarone TRIVIAL 23135547 A 350 360 amiodarone TRIVIAL 23135547 A 49 59 amiodarone TRIVIAL 23135547 A 573 584 dronedarone TRIVIAL 23135547 A 589 599 amiodarone TRIVIAL 23135547 A 65 75 benzofuran SYSTEMATIC 23135547 A 687 690 ATP ABBREVIATION 23135547 A 971 977 oxygen SYSTEMATIC 23135547 T 54 65 dronedarone TRIVIAL 23135547 T 83 93 amiodarone TRIVIAL 23135548 A 1165 1169 TCDD ABBREVIATION 23135548 A 1236 1240 TCDD ABBREVIATION 23135548 A 128 132 TCDD ABBREVIATION 23135548 A 134 140 dioxin FAMILY 23135548 A 1425 1429 TCDD ABBREVIATION 23135548 A 1603 1607 TCDD ABBREVIATION 23135548 A 293 297 TCDD ABBREVIATION 23135548 A 361 365 TCDD ABBREVIATION 23135548 A 470 474 TCDD ABBREVIATION 23135548 A 56 72 aryl hydrocarbon FAMILY 23135548 A 663 667 TCDD ABBREVIATION 23135548 A 669 673 TCDD ABBREVIATION 23135548 A 775 779 TCDD ABBREVIATION 23135548 A 876 880 TCDD ABBREVIATION 23135548 A 91 126 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23135548 A 984 988 TCDD ABBREVIATION 23135548 T 0 6 Dioxin FAMILY 23137833 A 1035 1046 resveratrol TRIVIAL 23137833 A 1252 1265 dexamethasone TRIVIAL 23137833 A 1375 1386 resveratrol TRIVIAL 23137833 A 353 364 resveratrol TRIVIAL 23137833 A 468 479 resveratrol TRIVIAL 23137833 A 706 717 resveratrol TRIVIAL 23137833 A 765 776 resveratrol TRIVIAL 23137833 A 884 897 dexamethasone TRIVIAL 23137833 A 965 976 resveratrol TRIVIAL 23137833 T 13 24 resveratrol TRIVIAL 23137957 A 1195 1209 trichothecenes FAMILY 23137957 A 754 768 deoxynivalenol TRIVIAL 23137957 A 770 773 DON ABBREVIATION 23138333 A 1238 1240 Cu FORMULA 23138333 A 1283 1296 chlorophyll a TRIVIAL 23138333 A 1298 1303 chl a ABBREVIATION 23138333 A 324 330 copper SYSTEMATIC 23138333 A 949 955 copper SYSTEMATIC 23138333 T 14 20 copper SYSTEMATIC 23138381 A 35 47 formaldehyde SYSTEMATIC 23138381 A 541 553 formaldehyde SYSTEMATIC 23138381 A 88 100 Formaldehyde SYSTEMATIC 23138381 T 15 27 formaldehyde SYSTEMATIC 23138381 T 51 63 Formaldehyde SYSTEMATIC 23138972 A 200 202 Pd FORMULA 23138972 A 326 328 Ru FORMULA 23138972 A 330 332 Rh FORMULA 23138972 A 337 339 Ir FORMULA 23138972 A 427 433 imines FAMILY 23138972 A 435 443 enamines FAMILY 23138972 A 445 452 olefins FAMILY 23138972 A 454 461 ketones FAMILY 23138972 A 466 478 heteroarenes FAMILY 23138972 A 503 512 palladium SYSTEMATIC 23138972 A 720 729 palladium SYSTEMATIC 23138972 T 12 21 palladium SYSTEMATIC 23139020 A 1001 1026 epoxyeicosatrienoic acids FAMILY 23139020 A 1031 1070 19- and 20-hydroxyeicosatetraenoic acid MULTIPLE 23139020 A 31 47 arachidonic acid TRIVIAL 23139020 T 30 46 arachidonic acid TRIVIAL 23139378 A 1108 1120 itraconazole TRIVIAL 23139378 A 1149 1160 gemfibrozil TRIVIAL 23139378 A 1194 1217 gemfibrozil glucuronide TRIVIAL 23139378 A 121 133 itraconazole TRIVIAL 23139378 A 1255 1266 repaglinide TRIVIAL 23139378 A 138 149 gemfibrozil TRIVIAL 23139378 A 1448 1459 repaglinide TRIVIAL 23139378 A 1507 1518 gemfibrozil TRIVIAL 23139378 A 1635 1646 repaglinide TRIVIAL 23139378 A 1817 1828 repaglinide TRIVIAL 23139378 A 28 39 repaglinide TRIVIAL 23139378 A 433 445 itraconazole TRIVIAL 23139378 A 447 458 gemfibrozil TRIVIAL 23139378 A 464 487 gemfibrozil glucuronide TRIVIAL 23139378 A 602 613 repaglinide TRIVIAL 23139378 A 736 748 itraconazole TRIVIAL 23139378 A 790 813 gemfibrozil glucuronide TRIVIAL 23139378 A 886 917 gemfibrozil and its glucuronide MULTIPLE 23139378 A 956 967 repaglinide TRIVIAL 23139378 T 63 74 gemfibrozil TRIVIAL 23139378 T 79 91 itraconazole TRIVIAL 23139413 A 1556 1559 Sar ABBREVIATION 23139413 A 1563 1566 Gln FORMULA 23139413 A 1570 1573 Ile FORMULA 23139413 A 741 750 cysteines FAMILY 23139413 A 904 912 losartan TRIVIAL 23139413 A 969 978 cysteines FAMILY 23140132 A 1331 1344 triglycerides FAMILY 23140132 A 1516 1532 triacylglyceride FAMILY 23141425 A 1306 1310 EGCG ABBREVIATION 23141425 A 1468 1472 EGCG ABBREVIATION 23141425 A 363 389 Epigallocatechin-3-gallate TRIVIAL 23141425 A 391 395 EGCG ABBREVIATION 23141425 A 408 418 polyphenol FAMILY 23141425 A 576 580 EGCG ABBREVIATION 23141425 A 675 679 EGCG ABBREVIATION 23141425 A 949 953 EGCG ABBREVIATION 23141425 T 0 4 EGCG ABBREVIATION 23142020 A 1022 1033 BAY 41-8543 IDENTIFIER 23142020 A 1249 1260 BAY 41-8543 IDENTIFIER 23142020 A 201 212 BAY 41-8543 IDENTIFIER 23142020 A 365 376 polystyrene SYSTEMATIC 23142020 A 572 583 BAY 41-8543 IDENTIFIER 23142020 T 40 51 BAY 41-8543 IDENTIFIER 23142538 A 0 35 2,3,7,8-Tetrachlorodibenzo-p-dioxin SYSTEMATIC 23142538 A 167 171 TCDD ABBREVIATION 23142538 A 37 41 TCDD ABBREVIATION 23142538 A 415 419 TCDD ABBREVIATION 23142538 A 617 621 TCDD ABBREVIATION 23142538 A 759 763 TCDD ABBREVIATION 23142538 T 24 30 dioxin FAMILY 23142558 A 1019 1029 oestrogens FAMILY 23142558 A 322 332 Oestrogens FAMILY 23142558 A 807 822 17-β-oestradiol SYSTEMATIC 23142558 A 912 922 oestrogens FAMILY 23142558 T 4 19 17-β-oestradiol SYSTEMATIC 23142699 A 228 237 estradiol TRIVIAL 23142699 A 882 891 estrogens FAMILY 23142699 T 32 40 estrogen FAMILY 23142753 A 0 14 Organochlorine FAMILY 23142753 A 1017 1025 p,p'-DDT ABBREVIATION 23142753 A 1030 1038 p,p'-DDE SYSTEMATIC 23142753 A 334 379 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane SYSTEMATIC 23142753 A 381 389 p,p'-DDT ABBREVIATION 23142753 A 416 462 1,1'-dichloro-2,2'-bis(p-chlorophenyl)ethylene SYSTEMATIC 23142753 A 464 472 p,p'-DDE SYSTEMATIC 23142753 A 495 555 1,1,1-trichloro-2-(p-chlorophenyl)-2-(o-chlorophenyl)-ethane SYSTEMATIC 23142753 A 557 565 o,p'-DDT ABBREVIATION 23142753 A 641 649 p,p'-DDT ABBREVIATION 23142753 A 723 731 p,p'-DDE SYSTEMATIC 23142753 A 736 744 o,p'-DDT ABBREVIATION 23142753 A 766 774 p,p'-DDT ABBREVIATION 23142753 A 785 793 o,p'-DDT ABBREVIATION 23142753 A 798 806 p,p'-DDE SYSTEMATIC 23142753 A 852 860 p,p'-DDE SYSTEMATIC 23142753 A 929 937 p,p'-DDT ABBREVIATION 23142753 A 942 950 o,p'-DDT ABBREVIATION 23142753 T 0 31 Dichlorodiphenyltrichloroethane SYSTEMATIC 23142753 T 33 36 DDT ABBREVIATION 23142753 T 39 42 DDT ABBREVIATION 23143036 A 1217 1236 butylhydroxytoluene SYSTEMATIC 23143036 A 1238 1241 BHT ABBREVIATION 23143036 A 1244 1254 d-mannitol TRIVIAL 23143036 A 1258 1274 N-acetylcysteine SYSTEMATIC 23143036 A 1276 1279 NAC ABBREVIATION 23143036 A 1301 1303 Cd FORMULA 23143036 A 1389 1391 Cd FORMULA 23143036 A 1535 1543 paraquat TRIVIAL 23143036 A 1556 1562 oxygen SYSTEMATIC 23143036 A 1602 1619 hydrogen peroxide SYSTEMATIC 23143036 A 1638 1640 Cd FORMULA 23143036 A 1850 1852 Cd FORMULA 23143036 A 194 201 Cadmium SYSTEMATIC 23143036 A 203 205 Cd FORMULA 23143036 A 2031 2033 Cd FORMULA 23143036 A 373 375 Cd FORMULA 23143036 A 436 438 Cd FORMULA 23143036 A 554 556 Cd FORMULA 23143036 A 725 727 Cd FORMULA 23143036 A 797 799 Cu FORMULA 23143036 A 800 802 Zn FORMULA 23143036 A 803 813 superoxide TRIVIAL 23143036 A 825 827 Cu FORMULA 23143036 A 828 830 Zn FORMULA 23143036 A 956 958 Cd FORMULA 23143036 T 0 7 Cadmium SYSTEMATIC 23143036 T 8 10 Cd FORMULA 23143039 A 1105 1112 glucose TRIVIAL 23143039 A 1134 1143 gluconate TRIVIAL 23143039 A 1162 1173 glutathione TRIVIAL 23143039 A 1304 1311 cadmium SYSTEMATIC 23143039 A 1346 1353 cadmium SYSTEMATIC 23143039 A 1426 1433 cadmium SYSTEMATIC 23143039 A 1540 1547 cadmium SYSTEMATIC 23143039 A 1644 1651 cadmium SYSTEMATIC 23143039 A 1675 1682 cadmium SYSTEMATIC 23143039 A 1716 1724 carbonyl FAMILY 23143039 A 1865 1872 cadmium SYSTEMATIC 23143039 A 189 196 cadmium SYSTEMATIC 23143039 A 337 344 cadmium SYSTEMATIC 23143039 A 538 545 cadmium SYSTEMATIC 23143039 A 606 613 Cadmium SYSTEMATIC 23143039 A 764 771 cadmium SYSTEMATIC 23143039 A 874 882 carbonyl FAMILY 23143039 A 926 941 malondialdehyde TRIVIAL 23143039 T 36 43 cadmium SYSTEMATIC 23143620 A 379 403 2,4-dinitrochlorobenzene SYSTEMATIC 23143674 A 1061 1070 clemizole TRIVIAL 23143674 A 512 521 clemizole TRIVIAL 23143674 A 832 841 clemizole TRIVIAL 23144001 A 16 24 perylene SYSTEMATIC 23144001 T 87 95 perylene SYSTEMATIC 23146662 A 0 12 Bryostatin 1 TRIVIAL 23146662 A 1057 1070 phorbol ester FAMILY 23146662 A 1218 1226 Merle 23 IDENTIFIER 23146662 A 1295 1306 bryostatins FAMILY 23146662 A 132 145 phorbol ester FAMILY 23146662 A 1337 1349 bryostatin 1 TRIVIAL 23146662 A 1358 1371 phorbol ester FAMILY 23146662 A 221 233 bryostatin 1 TRIVIAL 23146662 A 23 37 phorbol esters FAMILY 23146662 A 235 248 phorbol ester FAMILY 23146662 A 258 270 bryostatin 1 TRIVIAL 23146662 A 282 290 Merle 23 IDENTIFIER 23146662 A 339 351 Bryostatin 1 TRIVIAL 23146662 A 378 391 phorbol ester FAMILY 23146662 A 441 449 Merle 23 IDENTIFIER 23146662 A 460 473 phorbol ester FAMILY 23146662 A 496 508 bryostatin 1 TRIVIAL 23146662 A 758 770 bryostatin 1 TRIVIAL 23146662 A 795 808 phorbol ester FAMILY 23146662 A 889 901 bryostatin 1 TRIVIAL 23146662 A 921 933 bryostatin 1 TRIVIAL 23146662 A 949 962 phorbol ester FAMILY 23146662 A 992 1000 Merle 23 IDENTIFIER 23146662 T 42 55 phorbol ester FAMILY 23146662 T 57 69 bryostatin 1 TRIVIAL 23146662 T 75 85 bryostatin FAMILY 23146690 A 1193 1204 resveratrol TRIVIAL 23146690 A 1209 1220 clofarabine TRIVIAL 23146690 A 316 327 clofarabine TRIVIAL 23146690 A 433 444 resveratrol TRIVIAL 23146690 A 449 460 clofarabine TRIVIAL 23146690 A 744 755 clofarabine TRIVIAL 23146690 A 772 783 resveratrol TRIVIAL 23146690 A 920 936 phosphoinositide FAMILY 23146690 A 952 960 Ly294002 IDENTIFIER 23146690 T 35 46 resveratrol TRIVIAL 23146690 T 74 85 clofarabine TRIVIAL 23146692 A 1030 1034 AAPH ABBREVIATION 23146692 A 1086 1092 oxygen SYSTEMATIC 23146692 A 1160 1164 AAPH ABBREVIATION 23146692 A 1221 1225 CAAP ABBREVIATION 23146692 A 673 683 amino acid FAMILY 23146692 A 711 726 Val-Cys-Ser-Val FORMULA 23146692 A 728 732 VCSV ABBREVIATION 23146692 A 738 753 Cys-Ala-Ala-Pro FORMULA 23146692 A 755 759 CAAP ABBREVIATION 23146692 A 838 867 1,1-diphenyl-2-picrylhydrazyl SYSTEMATIC 23146692 A 869 873 DPPH ABBREVIATION 23146692 A 982 1028 2,2-azobis-(2-amidino-propane) dihydrochloride SYSTEMATIC 23146694 A 0 11 Bisphenol A TRIVIAL 23146694 A 1005 1006 N FORMULA 23146694 A 1126 1129 BPA ABBREVIATION 23146694 A 13 16 BPA ABBREVIATION 23146694 A 158 161 BPA ABBREVIATION 23146694 A 476 479 BPA ABBREVIATION 23146694 A 508 511 BPA ABBREVIATION 23146694 A 61 74 polycarbonate FAMILY 23146694 A 641 644 BPA ABBREVIATION 23146694 A 954 957 BPA ABBREVIATION 23146694 T 0 11 Bisphenol A TRIVIAL 23146765 A 1270 1277 glucose TRIVIAL 23146765 A 1279 1286 lactate FAMILY 23146765 A 1288 1295 choline FAMILY 23146765 A 1297 1304 formate SYSTEMATIC 23146765 A 1337 1343 CCl(4) FORMULA 23146765 A 1506 1509 B12 TRIVIAL 23146765 A 1514 1520 folate TRIVIAL 23146765 A 1618 1621 B12 TRIVIAL 23146765 A 1671 1677 CCl(4) FORMULA 23146765 A 22 42 carbon tetrachloride SYSTEMATIC 23146765 A 223 229 CCl(4) FORMULA 23146765 A 407 413 CCl(4) FORMULA 23146765 A 44 50 CCl(4) FORMULA 23146765 A 581 585 (1)H FORMULA 23146765 T 0 2 1H FORMULA 23146766 A 0 14 Aflatoxin B(1) TRIVIAL 23146766 A 1048 1051 AFB ABBREVIATION 23146766 A 1052 1055 Lys FORMULA 23146766 A 1228 1231 AFB ABBREVIATION 23146766 A 1232 1235 Lys FORMULA 23146766 A 15 21 lysine TRIVIAL 23146766 A 240 246 AFB(1) ABBREVIATION 23146766 A 279 282 AFB ABBREVIATION 23146766 A 283 286 Lys FORMULA 23146766 A 30 33 AFB ABBREVIATION 23146766 A 34 37 Lys FORMULA 23146766 A 348 354 AFB(1) ABBREVIATION 23146766 A 371 374 AFB ABBREVIATION 23146766 A 375 378 Lys FORMULA 23146766 A 623 629 AFB(1) ABBREVIATION 23146766 A 660 663 AFB ABBREVIATION 23146766 A 664 667 Lys FORMULA 23146766 A 67 76 aflatoxin FAMILY 23146766 A 729 735 AFB(1) ABBREVIATION 23146766 A 796 799 AFB ABBREVIATION 23146766 A 800 803 Lys FORMULA 23146766 A 869 872 AFB ABBREVIATION 23146766 A 873 876 Lys FORMULA 23146766 T 46 58 aflatoxin B1 TRIVIAL 23146766 T 59 65 lysine TRIVIAL 23146838 A 1112 1121 saccharin TRIVIAL 23146838 A 1144 1151 glucose TRIVIAL 23146838 A 1295 1304 estrogens FAMILY 23146838 A 1349 1360 anastrozole TRIVIAL 23146838 A 1378 1387 saccharin TRIVIAL 23146838 A 1470 1477 glucose TRIVIAL 23146838 A 1614 1623 saccharin TRIVIAL 23146838 A 1734 1743 saccharin TRIVIAL 23146838 A 1758 1765 glucose TRIVIAL 23146838 A 1794 1805 anastrozole TRIVIAL 23146838 A 1983 1991 estrogen FAMILY 23146838 A 403 408 sugar FAMILY 23146838 A 541 550 saccharin TRIVIAL 23146838 A 640 645 sugar FAMILY 23146838 A 794 803 estrogens FAMILY 23146838 T 37 46 estrogens FAMILY 23146871 A 10 19 manganese SYSTEMATIC 23146871 A 1060 1066 Mn(3+) FORMULA 23146871 A 1125 1131 Fe(3+) FORMULA 23146871 A 118 124 Mn(2+) FORMULA 23146871 A 1203 1205 Mn FORMULA 23146871 A 1288 1294 Mn(3+) FORMULA 23146871 A 1343 1349 Fe(3+) FORMULA 23146871 A 1372 1378 Mn(3+) FORMULA 23146871 A 1421 1423 Mn FORMULA 23146871 A 1496 1498 Mn FORMULA 23146871 A 185 191 Mn(3+) FORMULA 23146871 A 21 23 Mn FORMULA 23146871 A 235 239 iron SYSTEMATIC 23146871 A 241 243 Fe FORMULA 23146871 A 290 292 Mn FORMULA 23146871 A 371 373 Mn FORMULA 23146871 A 419 425 Mn(2+) FORMULA 23146871 A 427 433 Mn(3+) FORMULA 23146871 A 560 562 Mn FORMULA 23146871 A 589 595 Fe(3+) FORMULA 23146871 A 647 653 Mn(3+) FORMULA 23146871 A 731 737 Mn(3+) FORMULA 23146871 A 824 835 Alexa green TRIVIAL 23146871 A 869 875 Mn(3+) FORMULA 23146871 A 945 951 Mn(3+) FORMULA 23146871 A 987 989 Mn FORMULA 23146871 T 0 9 Manganese SYSTEMATIC 23147005 A 277 291 phosphodiester SYSTEMATIC 23147005 T 84 98 phosphodiester SYSTEMATIC 23147376 A 1603 1613 Superoxide TRIVIAL 23147376 A 332 346 streptozotocin TRIVIAL 23147376 A 545 557 methacholine TRIVIAL 23147377 A 101 110 Fe(2)O(3) FORMULA 23147377 A 793 803 iron oxide SYSTEMATIC 23147377 A 89 99 iron oxide SYSTEMATIC 23147377 T 0 10 Iron oxide SYSTEMATIC 23147415 A 1044 1053 donepezil TRIVIAL 23147415 A 1077 1090 physostigmine TRIVIAL 23147415 A 1177 1184 glucose TRIVIAL 23147415 A 1267 1276 donepezil TRIVIAL 23147415 A 683 690 choline FAMILY 23147415 A 738 745 choline FAMILY 23147415 A 858 866 BW284c51 IDENTIFIER 23147415 A 937 947 bambuterol TRIVIAL 23147416 A 1245 1253 naloxone TRIVIAL 23147416 A 1258 1297 d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2 FORMULA 23147416 A 1299 1303 CTAP ABBREVIATION 23147416 A 730 755 D-Ala(1)-peptide T-NH(2,) FORMULA 23147416 A 756 761 DAPTA ABBREVIATION 23147475 A 1037 1047 fluorenone SYSTEMATIC 23147475 A 1158 1168 fluorenone SYSTEMATIC 23147475 A 27 37 fluorenone SYSTEMATIC 23147475 A 398 407 zeolite L TRIVIAL 23147475 A 41 50 zeolite L TRIVIAL 23147475 A 582 592 fluorenone SYSTEMATIC 23147475 A 607 611 K(+) FORMULA 23147475 A 614 617 O=C FORMULA 23147475 A 692 696 K(+) FORMULA 23147475 A 705 724 fluorenone carbonyl SYSTEMATIC 23147475 A 771 772 C FORMULA 23147475 A 803 804 O FORMULA 23147475 T 55 65 fluorenone SYSTEMATIC 23147475 T 69 78 zeolite L TRIVIAL 23147567 A 1075 1086 naphthalene SYSTEMATIC 23147567 A 1091 1097 pyrene SYSTEMATIC 23147567 A 1366 1377 naphthalene SYSTEMATIC 23147567 A 1382 1394 phenanthrene SYSTEMATIC 23147567 A 166 188 poly(dimethylsiloxane) SYSTEMATIC 23147567 A 272 304 polycyclic aromatic hydrocarbons FAMILY 23147567 A 306 310 PAHs ABBREVIATION 23147567 A 400 403 PAH ABBREVIATION 23147567 A 411 419 silicone FAMILY 23147567 A 531 542 naphthalene SYSTEMATIC 23147567 A 544 554 anthracene SYSTEMATIC 23147567 A 560 566 pyrene SYSTEMATIC 23147567 A 708 719 naphthalene SYSTEMATIC 23147567 A 721 733 phenanthrene SYSTEMATIC 23147567 A 739 745 pyrene SYSTEMATIC 23147567 T 23 55 polycyclic aromatic hydrocarbons FAMILY 23147715 A 165 171 Cr(VI) FORMULA 23147715 A 17 31 chromium oxide SYSTEMATIC 23147715 A 200 206 Cr(VI) FORMULA 23147715 A 238 245 Cr(III) FORMULA 23147715 A 258 262 H(2) FORMULA 23147715 A 355 361 Cr(VI) FORMULA 23147715 A 383 390 Cr(III) FORMULA 23147715 A 470 477 Cr(III) FORMULA 23147715 A 506 515 Cr(OH)(3) FORMULA 23147715 A 610 618 Cr(2)O(3 FORMULA 23147715 A 677 683 Cr(VI) FORMULA 23147715 A 69 75 Cr(VI) FORMULA 23147715 A 742 751 Cr(OH)(3) FORMULA 23147715 A 77 87 CrO(4)(2-) FORMULA 23147715 A 779 787 chromium SYSTEMATIC 23147715 A 907 914 Cr(III) FORMULA 23147715 A 91 104 Cr(2)O(7)(2-) FORMULA 23147715 A 921 923 OH FORMULA 23147715 A 928 936 H(2)O(2) FORMULA 23147715 A 955 961 Cr(VI) FORMULA 23147715 A 981 989 H(2)O(2) FORMULA 23147715 T 37 51 chromium oxide SYSTEMATIC 23147715 T 81 91 dichromate SYSTEMATIC 23147750 A 1102 1110 HCO 3(-) FORMULA 23147750 A 1112 1120 SO 4(2-) FORMULA 23147750 A 1122 1128 Ca(2+) FORMULA 23147750 A 1134 1140 Mg(2+) FORMULA 23147750 A 669 674 Ca(+) FORMULA 23147750 A 676 681 Mg(+) FORMULA 23147750 A 683 691 HCO 3(-) FORMULA 23147750 A 697 704 SO 4(-) FORMULA 23147750 A 826 830 coal TRIVIAL 23147837 A 0 30 Polybrominated diphenyl ethers FAMILY 23147837 A 1061 1067 BDE-47 ABBREVIATION 23147837 A 1117 1123 BDE-99 ABBREVIATION 23147837 A 1138 1144 BDE-99 ABBREVIATION 23147837 A 1177 1183 BDE-47 ABBREVIATION 23147837 A 1362 1368 BDE-47 ABBREVIATION 23147837 A 258 262 PBDE ABBREVIATION 23147837 A 273 279 BDE-47 ABBREVIATION 23147837 A 284 290 BDE-99 ABBREVIATION 23147837 A 32 37 PBDEs ABBREVIATION 23147837 A 611 617 BDE-47 ABBREVIATION 23147837 A 627 633 BDE-99 ABBREVIATION 23147837 A 759 765 BDE-47 ABBREVIATION 23147837 A 776 782 BDE-99 ABBREVIATION 23147837 A 884 890 BDE-47 ABBREVIATION 23147837 A 922 928 BDE-99 ABBREVIATION 23147837 T 33 63 polybrominated diphenyl ethers FAMILY 23147837 T 64 70 BDE-47 ABBREVIATION 23147837 T 75 81 BDE-99 ABBREVIATION 23149337 A 1022 1031 adenosine TRIVIAL 23149337 A 1099 1108 adenosine TRIVIAL 23149337 A 492 501 histamine TRIVIAL 23149337 A 855 864 adenosine TRIVIAL 23149337 T 11 20 adenosine TRIVIAL 23149908 A 1755 1762 glucose TRIVIAL 23150491 A 1289 1292 BPA ABBREVIATION 23150491 A 1444 1447 BPA ABBREVIATION 23150491 A 382 385 BPA ABBREVIATION 23150491 A 410 425 BPA-glucuronide SYSTEMATIC 23150491 A 46 57 bisphenol A TRIVIAL 23150491 A 537 540 BPA ABBREVIATION 23150491 A 59 62 BPA ABBREVIATION 23150491 A 622 625 BPA ABBREVIATION 23150491 A 855 863 BPA-Gluc ABBREVIATION 23150491 A 921 924 BPA ABBREVIATION 23150491 A 970 973 BPA ABBREVIATION 23150491 T 31 42 bisphenol a TRIVIAL 23151003 A 1076 1085 adenosine TRIVIAL 23151003 A 1108 1141 nucleoside tri- and di-phosphates MULTIPLE 23151003 A 584 590 Purine TRIVIAL 23151003 A 595 605 pyrimidine SYSTEMATIC 23151003 A 606 617 nucleotides FAMILY 23151610 A 0 14 Carbohelicenes FAMILY 23151610 A 108 117 benzenoid FAMILY 23151610 A 1297 1311 carbohelicenes FAMILY 23151610 A 1418 1431 carbohelicene FAMILY 23151610 A 1555 1564 helicenes FAMILY 23151610 A 1659 1668 helicenes FAMILY 23151610 A 317 326 helicenes FAMILY 23151610 A 448 462 carbohelicenes FAMILY 23151610 A 708 716 helicene FAMILY 23151610 A 981 995 carbohelicenes FAMILY 23151610 T 101 115 carbohelicenes FAMILY 23151610 T 21 29 helicene FAMILY 23151611 A 1199 1213 oleanolic acid TRIVIAL 23151611 A 1238 1247 serotonin TRIVIAL 23151611 A 1249 1253 5-HT SYSTEMATIC 23151611 A 1376 1402 5-hydroxyindoleacetic acid SYSTEMATIC 23151611 A 1404 1410 5-HIAA SYSTEMATIC 23151611 A 1412 1416 5-HT SYSTEMATIC 23151611 A 1529 1543 norepinephrine TRIVIAL 23151611 A 1605 1613 dopamine TRIVIAL 23151611 A 1704 1718 oleanolic acid TRIVIAL 23151611 A 1866 1870 5-HT SYSTEMATIC 23151611 A 1937 1951 oleanolic acid TRIVIAL 23151611 A 276 290 oleanolic acid TRIVIAL 23151611 A 61 75 oleanolic acid TRIVIAL 23151611 A 882 896 oleanolic acid TRIVIAL 23151611 T 30 44 oleanolic acid TRIVIAL 23151612 A 705 714 steroidal FAMILY 23151612 A 794 801 aspirin TRIVIAL 23151612 A 803 822 omega-3 fatty acids FAMILY 23151612 A 824 837 neurosteroids FAMILY 23151612 A 842 853 minocycline TRIVIAL 23152186 A 1163 1170 As(III) FORMULA 23152186 A 1288 1295 As(III) FORMULA 23152186 A 1408 1431 sphingosine-1-phosphate SYSTEMATIC 23152186 A 1477 1484 As(III) FORMULA 23152186 A 149 156 Arsenic SYSTEMATIC 23152186 A 1570 1577 As(III) FORMULA 23152186 A 158 165 As(III) FORMULA 23152186 A 1623 1630 arsenic SYSTEMATIC 23152186 A 1720 1727 As(III) FORMULA 23152186 A 1854 1861 arsenic SYSTEMATIC 23152186 A 24 31 glucose TRIVIAL 23152186 A 391 398 As(III) FORMULA 23152186 A 633 640 As(III) FORMULA 23152186 A 809 816 As(III) FORMULA 23152186 A 841 854 dexamethasone TRIVIAL 23152186 T 0 7 Arsenic SYSTEMATIC 23153029 A 1134 1143 estrogens FAMILY 23153029 A 1177 1189 progesterone TRIVIAL 23153029 A 1297 1306 estradiol TRIVIAL 23153029 A 1311 1323 progesterone TRIVIAL 23153029 A 217 229 progesterone TRIVIAL 23153029 A 477 486 estradiol TRIVIAL 23153029 A 534 543 estradiol TRIVIAL 23153029 A 613 622 estradiol TRIVIAL 23153029 A 696 708 progesterone TRIVIAL 23153029 T 4 16 progesterone TRIVIAL 23153054 A 394 404 alprazolam TRIVIAL 23153054 A 406 416 clonazepam TRIVIAL 23153054 A 418 427 diltiazem TRIVIAL 23153054 A 429 438 midazolam TRIVIAL 23153054 A 440 450 nifedipine TRIVIAL 23153054 A 456 465 quinidine TRIVIAL 23153054 A 806 819 dexamethasone TRIVIAL 23153054 A 821 831 nifedipine TRIVIAL 23153054 A 833 842 midazolam TRIVIAL 23153054 A 844 853 quinidine TRIVIAL 23153054 A 855 865 tacrolimus TRIVIAL 23153054 A 871 880 verapamil TRIVIAL 23153057 A 1554 1566 salicylamide TRIVIAL 23153057 A 1693 1705 salicylamide TRIVIAL 23153057 A 325 335 phenacetin TRIVIAL 23153057 A 337 346 bupropion TRIVIAL 23153057 A 348 358 diclofenac TRIVIAL 23153057 A 363 372 midazolam TRIVIAL 23153057 A 483 499 β-naphthoflavone TRIVIAL 23153057 A 509 522 phenobarbital TRIVIAL 23153057 A 536 546 rifampicin TRIVIAL 23153057 A 743 755 salicylamide TRIVIAL 23153322 A 109 112 RAI ABBREVIATION 23153322 A 1514 1517 RAI ABBREVIATION 23153322 A 179 182 RAI ABBREVIATION 23153322 A 1988 1991 RAI ABBREVIATION 23153322 A 2054 2057 RAI ABBREVIATION 23153322 A 379 382 RAI ABBREVIATION 23153322 A 432 435 RAI ABBREVIATION 23153322 A 474 477 RAI ABBREVIATION 23153322 A 89 107 radioactive iodine SYSTEMATIC 23153322 T 38 56 radioactive iodine SYSTEMATIC 23153456 A 722 734 nitric oxide SYSTEMATIC 23153456 A 885 916 polyinosinic:polycytidylic acid MULTIPLE 23153512 A 1024 1027 FEN ABBREVIATION 23153512 A 237 240 FEN ABBREVIATION 23153512 A 374 377 FEN ABBREVIATION 23153512 A 443 457 methylene blue TRIVIAL 23153512 A 522 525 FEN ABBREVIATION 23153512 A 541 544 FEN ABBREVIATION 23153512 A 585 599 methylene blue TRIVIAL 23153512 A 61 73 fenitrothion TRIVIAL 23153512 A 661 665 (1)H FORMULA 23153512 A 682 685 FEN ABBREVIATION 23153512 A 749 754 (31)P FORMULA 23153512 A 75 78 FEN ABBREVIATION 23153512 A 771 774 FEN ABBREVIATION 23153512 A 808 811 NO2 FORMULA 23153512 T 105 110 (31)P FORMULA 23153512 T 116 120 (1)H FORMULA 23153512 T 48 60 fenitrothion TRIVIAL 23154127 A 1127 1146 formamidopyrimidine SYSTEMATIC 23154127 A 1264 1267 AOH FORMULA 23154127 A 1272 1275 AME ABBREVIATION 23154127 A 1391 1394 AOH FORMULA 23154127 A 1399 1402 AME ABBREVIATION 23154127 A 14 25 alternariol TRIVIAL 23154127 A 27 30 AOH FORMULA 23154127 A 286 289 AOH FORMULA 23154127 A 317 332 monomethylether SYSTEMATIC 23154127 A 334 337 AME ABBREVIATION 23154127 A 347 366 dichlorofluorescein SYSTEMATIC 23154127 A 368 371 DCF ABBREVIATION 23154127 A 438 457 dichlorofluorescein SYSTEMATIC 23154127 A 499 510 glutathione TRIVIAL 23154127 A 583 586 DCF ABBREVIATION 23154127 A 594 597 AOH FORMULA 23154127 A 602 605 AME ABBREVIATION 23154127 A 723 741 γ-glutamylcysteine SYSTEMATIC 23154127 A 761 772 glutathione TRIVIAL 23154127 A 773 774 S FORMULA 23154127 A 975 978 DCF ABBREVIATION 23154127 T 65 76 alternariol TRIVIAL 23154127 T 81 109 alternariol monomethyl ether SYSTEMATIC 23154304 A 116 132 indole hydrazone FAMILY 23154304 A 319 335 indole hydrazone FAMILY 23154304 A 424 445 adenosine diphosphate TRIVIAL 23154304 A 447 450 ADP ABBREVIATION 23154304 A 456 472 arachidonic acid TRIVIAL 23154304 A 537 553 arachidonic acid TRIVIAL 23154304 A 624 636 indomethacin TRIVIAL 23154304 A 712 715 ADP ABBREVIATION 23154304 A 81 90 hydrazone FAMILY 23154304 T 19 35 indole hydrazone FAMILY 23154865 A 515 518 BH3 FORMULA 23155201 A 587 601 technetium-99m SYSTEMATIC 23155201 A 603 608 99mTc FORMULA 23155201 A 610 631 methylendiphosphonate SYSTEMATIC 23155201 A 633 636 MDP ABBREVIATION 23157442 A 342 352 Gentamicin FAMILY 23157635 A 334 340 oxygen SYSTEMATIC 23157637 A 1217 1228 haloperidol TRIVIAL 23157637 A 1230 1240 olanzapine TRIVIAL 23157637 A 1242 1252 quetiapine TRIVIAL 23157637 A 1257 1268 risperidone TRIVIAL 23157637 A 1313 1321 dopamine TRIVIAL 23157637 A 139 145 oxygen SYSTEMATIC 23157640 A 1253 1261 platinum SYSTEMATIC 23157640 A 459 468 cisplatin TRIVIAL 23157640 A 470 484 anthracyclines FAMILY 23157640 A 490 497 taxanes FAMILY 23159106 A 1179 1186 ethanol SYSTEMATIC 23159106 A 296 303 ethanol SYSTEMATIC 23159106 A 548 555 ethanol SYSTEMATIC 23159106 A 586 592 oxygen SYSTEMATIC 23159106 A 83 90 ethanol SYSTEMATIC 23159106 A 951 957 Oxygen SYSTEMATIC 23159106 T 0 7 Ethanol SYSTEMATIC 23159331 A 0 15 Methamphetamine TRIVIAL 23159331 A 1238 1253 methamphetamine TRIVIAL 23159331 A 138 153 methamphetamine TRIVIAL 23159331 A 1445 1460 methamphetamine TRIVIAL 23159331 A 1654 1663 serotonin TRIVIAL 23159331 A 1770 1785 methamphetamine TRIVIAL 23159331 A 1905 1914 serotonin TRIVIAL 23159331 A 385 400 methamphetamine TRIVIAL 23159331 A 473 492 (±)-methamphetamine TRIVIAL 23159331 A 884 899 Methamphetamine TRIVIAL 23159331 A 942 950 dopamine TRIVIAL 23159331 A 966 975 serotonin TRIVIAL 23159331 A 977 992 Methamphetamine TRIVIAL 23159331 T 36 51 methamphetamine TRIVIAL 23159396 A 1226 1230 FITC ABBREVIATION 23159396 A 1255 1259 FITC ABBREVIATION 23159396 A 126 130 FITC ABBREVIATION 23159396 A 1539 1543 FITC ABBREVIATION 23159396 A 385 389 FITC ABBREVIATION 23159396 A 427 431 DAPI ABBREVIATION 23159396 A 433 463 4',6'-diamidino-2-phenylindole SYSTEMATIC 23159396 A 469 479 Evans blue TRIVIAL 23159396 A 481 485 FITC ABBREVIATION 23159396 A 571 575 FITC ABBREVIATION 23159396 A 584 588 FITC ABBREVIATION 23159396 A 703 707 FITC ABBREVIATION 23159396 A 716 720 FITC ABBREVIATION 23159396 A 98 124 fluorescein isothiocyanate TRIVIAL 23159397 A 583 631 calcium disodium ethylenediaminetetraacetic acid SYSTEMATIC 23159397 A 633 644 CaNa(2)EDTA FORMULA 23159479 A 310 318 oxytocin TRIVIAL 23159479 A 54 62 oxytocin TRIVIAL 23159479 A 640 648 oxytocin TRIVIAL 23159479 A 704 712 oxytocin TRIVIAL 23159479 A 817 825 Oxytocin TRIVIAL 23159479 T 14 22 oxytocin TRIVIAL 23159529 A 1088 1091 14C FORMULA 23159529 A 204 209 17864 IDENTIFIER 23159529 A 217 225 platinum SYSTEMATIC 23159529 A 232 241 sunitinib TRIVIAL 23159529 A 277 287 methionine TRIVIAL 23159529 A 412 431 polyethylene glycol SYSTEMATIC 23159529 A 438 441 PEG ABBREVIATION 23159529 A 565 568 PEG ABBREVIATION 23159529 A 647 650 14C FORMULA 23159529 A 729 734 17864 IDENTIFIER 23159529 A 752 755 PEG ABBREVIATION 23159529 A 77 91 Glutaraldehyde TRIVIAL 23159529 T 84 89 17864 IDENTIFIER 23159662 A 0 11 Venlafaxine TRIVIAL 23159662 A 1200 1211 venlafaxine TRIVIAL 23159662 A 1540 1551 venlafaxine TRIVIAL 23159662 A 1663 1674 venlafaxine TRIVIAL 23159662 A 318 329 venlafaxine TRIVIAL 23159662 A 394 405 venlafaxine TRIVIAL 23159662 A 527 538 venlafaxine TRIVIAL 23159662 A 586 597 venlafaxine TRIVIAL 23159662 A 833 844 venlafaxine TRIVIAL 23159662 A 898 909 venlafaxine TRIVIAL 23159662 T 38 49 venlafaxine TRIVIAL 23159666 A 196 215 polyethylene glycol SYSTEMATIC 23159666 A 217 220 PEG ABBREVIATION 23159666 A 284 324 5,10,15,20-tetra(m-hydroxyphenyl)chlorin SYSTEMATIC 23159666 A 326 332 Foscan TRIVIAL 23159666 A 574 580 Foscan TRIVIAL 23159666 A 798 804 Foscan TRIVIAL 23159666 A 831 834 PEG ABBREVIATION 23159666 A 948 954 Foscan TRIVIAL 23159666 T 70 76 Foscan TRIVIAL 23159667 A 0 18 8-Chloro-adenosine SYSTEMATIC 23159667 A 126 129 8CA SYSTEMATIC 23159667 A 1260 1263 8CA SYSTEMATIC 23159667 A 1340 1343 8CA SYSTEMATIC 23159667 A 1347 1351 8CAS SYSTEMATIC 23159667 A 1442 1445 8CA SYSTEMATIC 23159667 A 1471 1475 8CAS SYSTEMATIC 23159667 A 1535 1538 8CA SYSTEMATIC 23159667 A 20 23 8CA SYSTEMATIC 23159667 A 269 272 8CA SYSTEMATIC 23159667 A 329 361 8-chloro-adenosine-5'-O-stearate SYSTEMATIC 23159667 A 363 367 8CAS SYSTEMATIC 23159667 A 383 395 octadecanoyl SYSTEMATIC 23159667 A 408 411 8CA SYSTEMATIC 23159667 A 502 521 phosphatidylcholine FAMILY 23159667 A 523 534 cholesterol TRIVIAL 23159667 A 539 561 poly (ethylene glycol) SYSTEMATIC 23159667 A 567 602 distearoyl phosphatidylethanolamine SYSTEMATIC 23159667 A 604 612 PEG-DSPE ABBREVIATION 23159667 A 698 701 MTT ABBREVIATION 23159667 A 741 745 8CAS SYSTEMATIC 23159667 A 775 779 8CAS SYSTEMATIC 23159667 A 906 909 8CA SYSTEMATIC 23159667 A 990 994 8CAS SYSTEMATIC 23159667 T 62 80 8-chloro-adenosine SYSTEMATIC 23159712 A 176 185 lidocaine TRIVIAL 23159712 A 356 364 Carbopol TRIVIAL 23159712 A 366 375 Poloxamer TRIVIAL 23159712 A 420 427 PEG 400 ABBREVIATION 23159712 A 429 445 triethyl citrate SYSTEMATIC 23159712 A 570 579 lidocaine TRIVIAL 23159712 A 580 589 Compritol TRIVIAL 23159712 A 691 700 lidocaine TRIVIAL 23159712 A 95 104 lidocaine TRIVIAL 23159712 T 79 88 lidocaine TRIVIAL 23159729 A 0 16 Naphthenic acids FAMILY 23159729 A 1204 1220 naphthenic acids FAMILY 23159729 A 1250 1265 Naphthenic acid FAMILY 23159729 A 1383 1399 naphthenic acids FAMILY 23159729 A 1430 1444 benzo[a]pyrene SYSTEMATIC 23159729 A 1592 1608 naphthenic acids FAMILY 23159729 A 177 193 naphthenic acids FAMILY 23159729 A 334 350 naphthenic acids FAMILY 23159729 A 606 620 benzo[a]pyrene SYSTEMATIC 23159729 T 41 57 naphthenic acids FAMILY 23159732 A 1013 1016 Trp FORMULA 23159732 A 1027 1030 Trp FORMULA 23159732 A 1049 1052 Trp FORMULA 23159732 A 1082 1085 Trp FORMULA 23159732 A 1185 1188 NFK ABBREVIATION 23159732 A 1383 1385 O2 FORMULA 23159732 A 21 35 methylene blue TRIVIAL 23159732 A 60 66 oxygen SYSTEMATIC 23159732 A 71 73 O2 FORMULA 23159732 A 897 916 N'-formylkynurenine TRIVIAL 23159732 A 918 921 NFK ABBREVIATION 23159732 A 961 964 NFK ABBREVIATION 23159732 T 48 62 methylene blue TRIVIAL 23159790 A 1082 1092 nucleotide FAMILY 23159790 A 1144 1155 amino acids FAMILY 23159790 A 1630 1633 Gly FORMULA 23159790 A 1636 1639 Ser FORMULA 23159790 A 1642 1645 Gly FORMULA 23159790 A 1931 1938 proline TRIVIAL 23159790 A 2024 2031 proline TRIVIAL 23159790 A 972 982 amino acid FAMILY 23159888 A 0 7 Alcohol SYSTEMATIC 23159888 A 191 198 alcohol FAMILY 23159888 A 60 67 alcohol FAMILY 23159888 A 827 838 glutathione TRIVIAL 23159888 A 839 840 S FORMULA 23159888 T 22 29 alcohol FAMILY 23160003 A 533 549 bicyclic phenols FAMILY 23160003 A 558 586 polycyclic cyclohexadienones FAMILY 23160003 A 795 809 dienone-phenol SYSTEMATIC 23160003 A 863 869 phenol SYSTEMATIC 23160089 A 110 142 5,7,3',5'-tetrahydroxy-flavanone SYSTEMATIC 23160089 A 148 204 5,7,3',5'-tetrahydroxy-flavanone-7-O-β-d-glucopyranoside SYSTEMATIC 23160089 A 214 267 5,7,3',5'-tetrahydroxy-flavanone-7-O-neohesperidoside SYSTEMATIC 23160089 A 29 46 drynachromoside A TRIVIAL 23160089 A 52 69 drynachromoside B TRIVIAL 23160089 A 522 532 flavonoids FAMILY 23160089 A 565 568 MTT ABBREVIATION 23160089 A 8 27 chromone glycosides FAMILY 23160089 A 98 108 flavanones FAMILY 23160089 T 8 27 chromone glycosides FAMILY 23160092 A 1107 1118 curcumenone TRIVIAL 23160092 A 1160 1167 alcohol FAMILY 23160092 A 1207 1214 alcohol FAMILY 23160092 A 159 166 alcohol FAMILY 23160092 A 284 291 alcohol FAMILY 23160092 A 322 329 alcohol FAMILY 23160092 A 362 369 ethanol SYSTEMATIC 23160092 A 459 466 alcohol FAMILY 23160092 A 487 495 n-hexane SYSTEMATIC 23160092 A 624 632 n-hexane SYSTEMATIC 23160092 A 703 710 alcohol FAMILY 23160092 A 749 756 alcohol FAMILY 23160092 A 863 870 alcohol FAMILY 23160092 A 918 929 curcumenone TRIVIAL 23160092 A 956 960 (1)H FORMULA 23160092 A 966 971 (13)C FORMULA 23160092 T 102 109 alcohol FAMILY 23160092 T 47 58 curcumenone TRIVIAL 23160419 A 1076 1081 NO(2) FORMULA 23160419 A 1112 1117 NO(2) FORMULA 23160419 A 1128 1133 NO(2) FORMULA 23160419 A 1191 1198 oxygens FAMILY 23160419 A 1305 1310 NO(2) FORMULA 23160419 A 1364 1369 NO(2) FORMULA 23160419 A 1464 1469 NO(2) FORMULA 23160419 A 1530 1534 HONO FORMULA 23160419 A 170 175 NO(2) FORMULA 23160419 A 19 24 NO(2) FORMULA 23160419 A 239 244 NO(2) FORMULA 23160419 A 245 250 H(2)O FORMULA 23160419 A 367 372 NO(2) FORMULA 23160419 A 373 378 H(2)O FORMULA 23160419 A 477 482 NO(2) FORMULA 23160419 A 611 616 NO(2) FORMULA 23160419 A 857 862 NO(2) FORMULA 23160419 A 929 937 nitrogen SYSTEMATIC 23160419 A 951 957 oxygen SYSTEMATIC 23160419 A 980 988 hydrogen SYSTEMATIC 23160419 T 0 16 Nitrogen dioxide SYSTEMATIC 23160527 A 36 43 glucose TRIVIAL 23160527 A 382 389 glucose TRIVIAL 23160527 A 434 441 glucose TRIVIAL 23160529 A 138 142 zinc SYSTEMATIC 23160934 A 1114 1120 Cu(2+) FORMULA 23160934 A 124 139 α-syn12 peptide TRIVIAL 23160934 A 1262 1277 α-syn12 peptide TRIVIAL 23160934 A 1345 1351 Cu(2+) FORMULA 23160934 A 1388 1403 α-syn12 peptide TRIVIAL 23160934 A 15 21 Cu(2+) FORMULA 23160934 A 267 273 Cu(2+) FORMULA 23160934 A 292 307 α-syn12 peptide TRIVIAL 23160934 A 433 448 α-syn12 peptide TRIVIAL 23160934 A 782 797 α-syn12 peptide TRIVIAL 23160934 A 850 856 Cu(2+) FORMULA 23160934 A 863 878 α-syn12 peptide TRIVIAL 23160934 A 960 966 Cu(2+) FORMULA 23160934 A 985 1000 α-syn12 peptide TRIVIAL 23160934 T 48 54 Cu(2+) FORMULA 23160934 T 73 88 α-syn12 peptide TRIVIAL 23160940 A 1050 1092 guanosine 5'-O-(3-[(35)S]thio)triphosphate SYSTEMATIC 23160940 A 1094 1106 [(35)S]GTPγS SYSTEMATIC 23160940 A 1181 1185 cAMP ABBREVIATION 23160940 A 1371 1375 cAMP ABBREVIATION 23160940 A 1481 1490 Org 27569 IDENTIFIER 23160940 A 1495 1504 PSNCBAM-1 IDENTIFIER 23160940 A 225 238 [(3)H]CP55940 IDENTIFIER 23160940 A 507 519 [(35)S]GTPγS SYSTEMATIC 23160940 A 560 569 forskolin TRIVIAL 23160940 A 581 585 cAMP ABBREVIATION 23160940 A 87 96 Org 27569 IDENTIFIER 23160940 A 880 887 CP55940 IDENTIFIER 23160940 A 915 923 WIN55212 IDENTIFIER 23160940 A 952 966 [(3)H]WIN55212 IDENTIFIER 23160940 A 976 985 Org 27569 IDENTIFIER 23160940 A 98 107 PSNCBAM-1 IDENTIFIER 23160961 A 1049 1053 acyl FAMILY 23160961 A 1072 1076 acyl FAMILY 23160961 A 1111 1127 triacylglyceride FAMILY 23160961 A 1275 1279 acyl FAMILY 23160961 A 1319 1323 acyl FAMILY 23160961 A 158 161 Ser FORMULA 23160961 A 919 930 fatty acids FAMILY 23160964 A 1013 1036 1,25-dihydroxyvitamin D SYSTEMATIC 23160964 A 1149 1172 1,25-dihydroxyvitamin D SYSTEMATIC 23160964 A 1253 1262 vitamin D FAMILY 23160964 A 179 188 vitamin D FAMILY 23160964 A 259 268 vitamin D FAMILY 23160964 A 449 458 vitamin D FAMILY 23160964 A 559 568 vitamin D FAMILY 23160964 A 650 659 vitamin D FAMILY 23160964 A 667 677 RO-27-5646 IDENTIFIER 23160964 A 805 828 1,25-dihydroxyvitamin D SYSTEMATIC 23160964 A 94 103 Vitamin D FAMILY 23160964 T 0 24 1,25-Dihydroxyvitamin D3 SYSTEMATIC 23161217 A 1115 1122 Suramin TRIVIAL 23161217 A 1303 1310 Suramin TRIVIAL 23161217 A 1396 1403 phospho SYSTEMATIC 23161217 A 1473 1480 suramin TRIVIAL 23161217 A 1560 1567 suramin TRIVIAL 23161217 A 169 176 suramin TRIVIAL 23161217 A 180 207 polysulfonated naphthylurea FAMILY 23161217 A 287 294 ethanol SYSTEMATIC 23161217 A 394 401 alanine TRIVIAL 23161217 A 435 444 bilirubin TRIVIAL 23161217 A 604 611 Suramin TRIVIAL 23161217 A 761 784 5-bromo-2'-deoxyuridine SYSTEMATIC 23161217 A 786 790 BrdU ABBREVIATION 23161217 A 980 987 Suramin TRIVIAL 23161217 A 998 1002 BrdU ABBREVIATION 23161217 T 0 7 Suramin TRIVIAL 23161217 T 54 61 ethanol SYSTEMATIC 23161424 A 125 135 evodiamine TRIVIAL 23161424 A 208 218 Evodiamine TRIVIAL 23161424 A 359 362 Arg FORMULA 23161424 A 370 373 Asp FORMULA 23161424 A 419 429 evodiamine TRIVIAL 23161424 A 474 484 evodiamine TRIVIAL 23161424 A 536 546 Evodiamine TRIVIAL 23161424 A 744 754 evodiamine TRIVIAL 23161424 T 26 36 evodiamine TRIVIAL 23161648 A 211 215 coal TRIVIAL 23161648 A 534 542 SO (4)2- FORMULA 23161648 A 545 553 HCO (3)- FORMULA 23161648 A 556 561 Cl(-) FORMULA 23161664 A 0 5 Lysyl TRIVIAL 23161664 A 1024 1026 Co FORMULA 23161664 A 1311 1313 Co FORMULA 23161664 A 1380 1387 Cadmium SYSTEMATIC 23161664 A 1389 1391 Cd FORMULA 23161664 A 1417 1423 oxygen SYSTEMATIC 23161664 A 1503 1505 Co FORMULA 23161664 A 1613 1615 Co FORMULA 23161664 A 1620 1622 Cd FORMULA 23161664 A 673 678 CoCl2 FORMULA 23161664 A 680 682 Co FORMULA 23161664 A 886 892 cobalt SYSTEMATIC 23161664 A 894 896 Co FORMULA 23161664 T 112 118 cobalt SYSTEMATIC 23161664 T 123 130 cadmium SYSTEMATIC 23161664 T 78 83 lysyl TRIVIAL 23161673 A 1197 1206 tamoxifen TRIVIAL 23161673 A 1473 1482 tamoxifen TRIVIAL 23161677 A 207 214 guanine TRIVIAL 23161677 A 220 232 nucleic acid FAMILY 23161804 A 0 43 (18-Crown-6)-2,3,11,12-tetracarboxylic acid SYSTEMATIC 23161804 A 105 117 β-amino acid FAMILY 23161804 A 131 142 Isoxazoline FAMILY 23161804 A 176 189 hydrochloride FAMILY 23161804 A 199 207 methanol SYSTEMATIC 23161804 A 285 293 hydrogen SYSTEMATIC 23161804 A 323 328 amine SYSTEMATIC 23161804 A 333 344 crown ether FAMILY 23161804 A 345 351 oxygen SYSTEMATIC 23161804 A 87 98 isoxazoline SYSTEMATIC 23161804 T 31 42 isoxazoline SYSTEMATIC 23161804 T 49 61 β-amino acid FAMILY 23161804 T 80 123 (18-crown-6)-2,3,11,12-tetracarboxylic acid SYSTEMATIC 23163430 A 1026 1045 polyethylene glycol SYSTEMATIC 23163508 A 533 544 chlorophyll FAMILY 23163696 A 1035 1039 H-89 TRIVIAL 23163696 A 1286 1314 inositol 1,4,5-trisphosphate SYSTEMATIC 23163696 A 773 796 cyclo(1-8) [DLeu(5) ]OP FORMULA 23163696 A 838 852 benzodiazepine FAMILY 23163696 A 873 883 flumazenil TRIVIAL 23163696 A 977 984 U-73122 IDENTIFIER 23164613 A 107 116 serotonin TRIVIAL 23164613 A 285 294 8-OH-DPAT SYSTEMATIC 23164613 A 299 305 LP-211 IDENTIFIER 23164613 A 409 418 SB-269970 IDENTIFIER 23164613 A 441 446 U0126 IDENTIFIER 23164613 A 498 509 roscovitine TRIVIAL 23164613 A 525 538 cycloheximide TRIVIAL 23164613 A 70 74 5-HT SYSTEMATIC 23164613 T 4 13 serotonin TRIVIAL 23164615 A 169 179 AZ12216052 IDENTIFIER 23164615 A 229 259 (S)-3,4-dicarboxyphenylglycine SYSTEMATIC 23164615 A 261 265 DCPG ABBREVIATION 23164615 A 394 398 DCPG ABBREVIATION 23164615 A 749 758 glutamate TRIVIAL 23164615 A 865 874 glutamate TRIVIAL 23164615 A 983 987 DCPG ABBREVIATION 23164615 T 108 117 glutamate TRIVIAL 23164711 A 280 284 ZINC SYSTEMATIC 23164711 A 302 309 sulfate SYSTEMATIC 23164711 A 715 739 monosulfated benzofurans FAMILY 23164711 A 852 856 ZINC SYSTEMATIC 23164711 A 970 990 sulfated benzofurans FAMILY 23164931 A 1006 1010 MPEP ABBREVIATION 23164931 A 461 473 procyclidine TRIVIAL 23164931 A 478 488 caramiphen TRIVIAL 23164931 A 509 518 glutamate TRIVIAL 23164931 A 530 536 DCG-IV IDENTIFIER 23164931 A 541 545 MPEP ABBREVIATION 23164931 A 728 738 caramiphen TRIVIAL 23164931 A 871 883 Procyclidine TRIVIAL 23164931 A 996 1002 DCG-IV IDENTIFIER 23164984 A 193 195 Hg FORMULA 23164984 A 197 199 Cd FORMULA 23164984 A 201 203 Pb FORMULA 23164984 A 208 210 As FORMULA 23164984 A 377 379 Hg FORMULA 23164984 A 40 47 mercury SYSTEMATIC 23164984 A 49 51 Hg FORMULA 23164984 A 54 61 cadmium SYSTEMATIC 23164984 A 63 65 Cd FORMULA 23164984 A 74 76 Pb FORMULA 23164984 A 781 783 Hg FORMULA 23164984 A 82 89 arsenic SYSTEMATIC 23164984 A 91 93 As FORMULA 23164984 T 28 35 mercury SYSTEMATIC 23164984 T 43 50 cadmium SYSTEMATIC 23164984 T 56 63 arsenic SYSTEMATIC 23168241 A 1033 1040 sulfite SYSTEMATIC 23168241 A 1094 1101 sulfite SYSTEMATIC 23168241 A 1191 1201 quinacrine TRIVIAL 23168241 A 1277 1284 sulfite SYSTEMATIC 23168241 A 302 322 sodium metabisulfite SYSTEMATIC 23168241 A 336 356 sodium metabisulfite SYSTEMATIC 23168241 A 357 367 quinacrine TRIVIAL 23168241 A 382 402 Sodium metabisulfite SYSTEMATIC 23168241 A 41 48 sulfite SYSTEMATIC 23168241 A 476 486 quinacrine TRIVIAL 23168241 A 683 693 quinacrine TRIVIAL 23168241 A 717 718 S FORMULA 23168241 A 719 728 sulfonate SYSTEMATIC 23168241 A 856 866 Quinacrine TRIVIAL 23168241 A 953 963 Quinacrine TRIVIAL 23168241 T 48 55 sulfite SYSTEMATIC 23168241 T 9 19 quinacrine TRIVIAL 23168915 A 112 115 NiO FORMULA 23168915 A 67 71 H(2) FORMULA 23168915 T 73 85 nickel oxide SYSTEMATIC 23169614 A 1079 1085 carbon SYSTEMATIC 23169614 A 21 29 graphene TRIVIAL 23169614 A 211 219 graphene TRIVIAL 23169614 A 335 343 graphene TRIVIAL 23169614 A 621 627 carbon SYSTEMATIC 23169614 A 923 931 graphene TRIVIAL 23169614 T 36 44 graphene TRIVIAL 23170796 A 1031 1042 minocycline TRIVIAL 23170796 A 1187 1198 minocycline TRIVIAL 23170796 A 1253 1264 minocycline TRIVIAL 23170796 A 283 294 Minocycline TRIVIAL 23170796 A 332 344 tetracycline FAMILY 23170796 A 353 399 7-dimethylamino-6-dimethyl-6-deoxytetracycline SYSTEMATIC 23170796 A 538 549 minocycline TRIVIAL 23170796 A 916 927 minocycline TRIVIAL 23170796 T 0 11 Minocycline TRIVIAL 23170798 A 191 198 ethanol SYSTEMATIC 23170798 A 615 622 ethanol SYSTEMATIC 23170798 A 767 774 ethanol SYSTEMATIC 23170798 A 972 979 ethanol SYSTEMATIC 23170798 T 31 38 ethanol SYSTEMATIC 23171045 A 135 143 biphenyl SYSTEMATIC 23171045 A 31 66 2-(aryloxy)-3-phenylpropanoic acids FAMILY 23171045 A 802 815 acylcarnitine SYSTEMATIC 23171045 A 828 837 carnitine TRIVIAL 23171045 A 838 847 palmitoyl TRIVIAL 23171045 A 905 914 carnitine TRIVIAL 23171045 T 137 146 carnitine TRIVIAL 23171045 T 4 39 2-(aryloxy)-3-phenylpropanoic acids FAMILY 23172038 A 767 783 titanium dioxide SYSTEMATIC 23172121 A 973 986 polyurethanes FAMILY 23172121 T 12 24 polyurethane SYSTEMATIC 23172229 A 1026 1037 cardiolipin TRIVIAL 23172229 A 1092 1103 cardiolipin TRIVIAL 23172229 A 1349 1360 cardiolipin TRIVIAL 23172229 A 1401 1412 cardiolipin TRIVIAL 23172229 A 1447 1458 cardiolipin TRIVIAL 23172229 A 1509 1520 cardiolipin TRIVIAL 23172229 A 1573 1584 cardiolipin TRIVIAL 23172229 A 251 262 cardiolipin TRIVIAL 23172229 A 306 317 cardiolipin TRIVIAL 23172229 A 606 625 phosphatidylcholine FAMILY 23172229 A 630 654 phosphatidylethanolamine SYSTEMATIC 23172229 A 897 908 cardiolipin TRIVIAL 23172229 T 0 11 Cardiolipin TRIVIAL 23174213 A 894 901 calcium SYSTEMATIC 23174457 A 1000 1006 Mn(2+) FORMULA 23174457 A 568 574 Mn(2+) FORMULA 23174457 A 675 681 Mn(2+) FORMULA 23174457 A 823 830 cadmium SYSTEMATIC 23174457 A 854 860 Mn(2+) FORMULA 23174457 A 917 925 paraoxon TRIVIAL 23174457 A 964 970 Cd(2+) FORMULA 23174457 T 0 6 Mn(2+) FORMULA 23174539 A 1037 1041 PERM ABBREVIATION 23174539 A 1217 1225 dopamine TRIVIAL 23174539 A 1266 1275 serotonin TRIVIAL 23174539 A 1277 1281 5-HT SYSTEMATIC 23174539 A 1287 1300 noradrenaline TRIVIAL 23174539 A 1466 1470 PERM ABBREVIATION 23174539 A 1565 1575 pyrethroid FAMILY 23174539 A 1586 1607 3-phenoxybenzoic acid SYSTEMATIC 23174539 A 174 184 permethrin TRIVIAL 23174539 A 186 190 PERM ABBREVIATION 23174539 A 340 344 PERM ABBREVIATION 23174539 A 479 487 dopamine TRIVIAL 23174539 A 669 673 PERM ABBREVIATION 23174539 T 22 32 permethrin TRIVIAL 23174539 T 75 84 monoamine FAMILY 23174746 A 0 7 Ritalin TRIVIAL 23174746 A 10 25 methylphenidate SYSTEMATIC 23174746 A 206 213 Ritalin TRIVIAL 23174746 A 33 44 amphetamine TRIVIAL 23174746 A 505 512 Ritalin TRIVIAL 23174746 T 38 45 Ritalin TRIVIAL 23174746 T 50 65 methylphenidate SYSTEMATIC 23177255 A 137 144 glucose TRIVIAL 23177255 A 156 168 scutellarein TRIVIAL 23177255 A 239 246 glucose TRIVIAL 23177255 A 273 285 scutellarein TRIVIAL 23177255 A 32 43 scutellarin TRIVIAL 23177255 A 358 365 glucose TRIVIAL 23177255 A 377 389 scutellarein TRIVIAL 23177255 A 419 423 DPPH ABBREVIATION 23177255 A 57 68 scutellarin TRIVIAL 23177255 A 631 638 glucose TRIVIAL 23177255 A 692 699 glucose TRIVIAL 23177255 A 710 722 scutellarein TRIVIAL 23177255 A 94 106 scutellarein TRIVIAL 23177255 T 149 160 scutellarin TRIVIAL 23177255 T 47 54 glucose TRIVIAL 23177255 T 66 78 scutellarein TRIVIAL 23177256 A 233 241 arginine TRIVIAL 23177256 A 318 337 7-nitrobenzofurazan SYSTEMATIC 23177256 A 392 406 ortho-biphenyl SYSTEMATIC 23177256 A 432 450 para-carboxyphenyl SYSTEMATIC 23177256 A 486 494 JY-3-094 IDENTIFIER 23177256 A 608 616 JY-3-094 IDENTIFIER 23177256 A 748 756 JY-3-094 IDENTIFIER 23177256 A 75 83 10074-G5 IDENTIFIER 23177256 A 85 149 N-([1,1'-biphenyl]-2-yl)-7-nitrobenzo[c][1,2,5]oxadiazol-4-amine SYSTEMATIC 23177256 T 48 56 10074-G5 IDENTIFIER 23177784 A 103 114 nucleosides FAMILY 23177784 A 171 195 5-amino-2'-deoxycytidine SYSTEMATIC 23177784 A 219 227 diketone SYSTEMATIC 23177784 A 233 242 ruthenium SYSTEMATIC 23177784 A 25 34 ruthenium SYSTEMATIC 23177784 A 295 317 polypyridine ruthenium SYSTEMATIC 23177784 A 39 47 europium SYSTEMATIC 23177784 A 394 402 europium SYSTEMATIC 23177784 A 410 440 1,10-phenanthroline-2,9-diacid SYSTEMATIC 23177784 A 455 465 lanthanide FAMILY 23177784 A 474 484 nucleoside FAMILY 23177784 A 595 609 phenanthroline SYSTEMATIC 23177784 A 623 633 lanthanide FAMILY 23177784 A 642 652 nucleoside FAMILY 23177784 A 72 91 1,10-phenanthroline SYSTEMATIC 23177784 A 744 752 europium SYSTEMATIC 23177784 T 18 32 phenanthroline SYSTEMATIC 23177784 T 41 52 nucleosides FAMILY 23177784 T 65 74 ruthenium SYSTEMATIC 23177784 T 79 87 europium SYSTEMATIC 23178170 A 1025 1031 Ca(2+) FORMULA 23178170 A 1171 1177 Ca(2+) FORMULA 23178170 A 1328 1335 calcium SYSTEMATIC 23178170 A 1428 1434 Ca(2+) FORMULA 23178170 A 445 451 Ca(2+) FORMULA 23178170 A 468 469 C FORMULA 23178170 A 639 640 C FORMULA 23178170 A 728 734 Ca(2+) FORMULA 23178170 A 74 83 potassium SYSTEMATIC 23178170 A 753 754 C FORMULA 23178170 A 832 839 calcium SYSTEMATIC 23178170 A 979 985 Ca(2+) FORMULA 23178170 T 15 21 Ca(2+) FORMULA 23178178 A 1003 1009 TiO(2) FORMULA 23178178 A 1236 1243 lactate FAMILY 23178178 A 1261 1267 TiO(2) FORMULA 23178178 A 1750 1761 glutathione TRIVIAL 23178178 A 1788 1797 Na(+)K(+) FORMULA 23178178 A 183 199 titanium dioxide SYSTEMATIC 23178178 A 215 221 TiO(2) FORMULA 23178178 A 344 350 TiO(2) FORMULA 23178178 A 364 370 TiO(2) FORMULA 23178178 A 394 400 TiO(2) FORMULA 23178178 A 414 430 Titanium dioxide SYSTEMATIC 23178178 A 498 500 Ti FORMULA 23178178 A 595 597 Ti FORMULA 23178178 A 681 687 TiO(2) FORMULA 23178178 A 884 890 TiO(2) FORMULA 23178178 A 947 953 TiO(2) FORMULA 23178178 T 79 95 titanium dioxide SYSTEMATIC 23178179 A 1047 1050 MBT ABBREVIATION 23178179 A 1182 1185 MBT ABBREVIATION 23178179 A 286 309 2-Mercaptobenzothiazole SYSTEMATIC 23178179 A 311 314 MBT ABBREVIATION 23178179 A 544 547 MBT ABBREVIATION 23178179 A 659 662 MBT ABBREVIATION 23178179 A 804 817 sodium-iodide SYSTEMATIC 23178179 A 879 895 iodo-amino acids FAMILY 23178179 A 934 937 MBT ABBREVIATION 23178179 T 63 86 2-mercaptobenzothiazole SYSTEMATIC 23178182 A 10 30 N-Methyl-d-aspartate SYSTEMATIC 23178182 A 1020 1030 UCCB01-125 IDENTIFIER 23178182 A 1035 1041 MK-801 IDENTIFIER 23178182 A 1152 1158 MK-801 IDENTIFIER 23178182 A 1163 1173 UCCB01-125 IDENTIFIER 23178182 A 1281 1291 UCCB01-125 IDENTIFIER 23178182 A 1464 1470 MK-801 IDENTIFIER 23178182 A 1565 1575 UCCB01-125 IDENTIFIER 23178182 A 264 266 NO FORMULA 23178182 A 349 351 NO FORMULA 23178182 A 679 681 NO FORMULA 23178182 A 72 84 nitric oxide SYSTEMATIC 23178182 A 811 821 UCCB01-125 IDENTIFIER 23178182 A 849 855 MK-801 IDENTIFIER 23178182 A 86 88 NO FORMULA 23178182 T 0 10 UCCB01-125 IDENTIFIER 23178182 T 140 144 NMDA ABBREVIATION 23178182 T 165 171 MK-801 IDENTIFIER 23178221 A 10 29 diglycoside taxanes FAMILY 23178221 A 168 170 OH FORMULA 23178221 A 180 187 xylosyl TRIVIAL 23178221 A 200 217 7-xylosyl taxanes FAMILY 23178221 A 61 72 α-d-glucose TRIVIAL 23178221 T 39 65 xylosyl-containing taxanes FAMILY 23178243 A 1331 1338 Printex TRIVIAL 23178243 A 1387 1394 8-OH-dG SYSTEMATIC 23178243 A 1480 1487 Aerosil TRIVIAL 23178243 A 1523 1530 8-OH-dG SYSTEMATIC 23178243 A 1764 1771 8-OH-dG SYSTEMATIC 23178243 A 2052 2068 8-hydroxyguanine SYSTEMATIC 23178243 A 276 292 poly(ADP-ribose) SYSTEMATIC 23178243 A 294 297 PAR ABBREVIATION 23178243 A 330 348 8-hydroxyguanosine SYSTEMATIC 23178243 A 350 357 8-OH-dG SYSTEMATIC 23178243 A 364 376 8-oxoguanine SYSTEMATIC 23178243 A 403 411 paraffin FAMILY 23178243 A 651 657 silica TRIVIAL 23178243 A 659 666 Aerosil TRIVIAL 23178243 A 679 691 carbon black TRIVIAL 23178243 A 693 700 Printex TRIVIAL 23178279 A 684 697 dexamethasone TRIVIAL 23178339 A 112 132 docosahexaenoic acid SYSTEMATIC 23178339 A 1144 1147 DHA ABBREVIATION 23178339 A 1148 1159 doxorubicin TRIVIAL 23178339 A 134 137 DHA ABBREVIATION 23178339 A 142 168 polyunsaturated fatty acid FAMILY 23178339 A 549 552 DHA ABBREVIATION 23178339 A 557 572 triethanolamine SYSTEMATIC 23178339 A 574 577 TEA ABBREVIATION 23178339 A 580 585 amine SYSTEMATIC 23178339 A 621 632 doxorubicin TRIVIAL 23178339 A 72 83 doxorubicin TRIVIAL 23178339 A 733 736 DHA ABBREVIATION 23178339 A 764 775 doxorubicin TRIVIAL 23178339 A 933 944 doxorubicin TRIVIAL 23178339 A 945 948 DHA ABBREVIATION 23178339 A 970 981 doxorubicin TRIVIAL 23178339 A 982 985 DHA ABBREVIATION 23178339 T 64 75 doxorubicin TRIVIAL 23178949 A 1087 1099 formaldehyde SYSTEMATIC 23179351 A 345 360 nickel chloride SYSTEMATIC 23179351 A 605 620 nickel chloride SYSTEMATIC 23179351 A 880 895 nickel chloride SYSTEMATIC 23179351 T 82 97 nickel chloride SYSTEMATIC 23179765 A 1015 1022 benzene SYSTEMATIC 23179765 A 1033 1040 pyrrole SYSTEMATIC 23179765 A 165 173 hydrogen SYSTEMATIC 23179765 A 187 194 benzene SYSTEMATIC 23179765 A 205 212 pyrrole SYSTEMATIC 23179765 T 11 18 benzene SYSTEMATIC 23179765 T 29 36 pyrrole SYSTEMATIC 23179966 A 1059 1067 dopamine TRIVIAL 23179966 A 1315 1323 dopamine TRIVIAL 23179966 A 1325 1334 serotonin TRIVIAL 23179966 A 1340 1349 glutamate TRIVIAL 23179966 A 1422 1431 glutamate TRIVIAL 23179966 A 1432 1440 dopamine TRIVIAL 23179966 A 1441 1450 serotonin TRIVIAL 23179966 A 1619 1628 serotonin TRIVIAL 23179966 A 1629 1638 glutamate TRIVIAL 23179966 A 1643 1652 serotonin TRIVIAL 23179966 A 1653 1661 dopamine TRIVIAL 23179966 A 248 257 glutamate TRIVIAL 23179966 A 281 290 serotonin TRIVIAL 23179966 A 291 295 5-HT SYSTEMATIC 23179966 A 445 449 5-HT SYSTEMATIC 23179966 A 49 58 serotonin TRIVIAL 23179966 A 526 530 5-HT SYSTEMATIC 23179966 A 59 68 glutamate TRIVIAL 23179966 A 73 82 serotonin TRIVIAL 23179966 A 793 813 N-methyl-D-aspartate SYSTEMATIC 23179966 A 815 819 NMDA ABBREVIATION 23179966 A 83 91 dopamine TRIVIAL 23179966 A 831 835 5-HT SYSTEMATIC 23179966 T 0 9 Serotonin TRIVIAL 23179966 T 10 19 glutamate TRIVIAL 23179966 T 24 33 serotonin TRIVIAL 23179966 T 34 42 dopamine TRIVIAL 23180370 A 1004 1012 sulphate SYSTEMATIC 23180370 A 1245 1249 NaCl FORMULA 23180370 A 1251 1254 SO4 FORMULA 23180370 A 412 420 sulphate SYSTEMATIC 23180382 A 165 173 graphene TRIVIAL 23180382 A 286 294 graphene TRIVIAL 23180382 A 40 48 graphene TRIVIAL 23180382 A 491 499 graphene TRIVIAL 23180382 A 645 654 graphenes FAMILY 23180382 A 876 885 graphenes FAMILY 23180382 T 9 18 graphenes FAMILY 23180652 A 402 432 2,4-dichlorophenoxyacetic acid SYSTEMATIC 23180652 A 434 442 atrazine TRIVIAL 23180652 A 444 456 chlorpyrifos TRIVIAL 23180652 A 462 473 gemfibrozil TRIVIAL 23180692 A 1117 1126 malathion TRIVIAL 23180692 A 1171 1180 malathion TRIVIAL 23180692 A 1292 1301 malathion TRIVIAL 23180692 A 896 905 malathion TRIVIAL 23180762 A 587 596 magnesium SYSTEMATIC 23180762 A 69 77 tartrate TRIVIAL 23181488 A 1038 1047 isopropyl SYSTEMATIC 23181488 A 1303 1309 methyl SYSTEMATIC 23181488 A 240 258 diisopropyl ketone SYSTEMATIC 23181488 A 71 89 diisopropyl ketone SYSTEMATIC 23181488 A 91 119 (CH(3))(2)HC-CO-CH(CH(3))(2) FORMULA 23181488 T 28 46 diisopropyl ketone SYSTEMATIC 23183084 A 1099 1111 progesterone TRIVIAL 23183084 A 1228 1240 progesterone TRIVIAL 23183084 A 1244 1265 5α-dihydroprogestrone SYSTEMATIC 23183084 A 1323 1329 3-keto SYSTEMATIC 23183084 A 1334 1341 20-keto SYSTEMATIC 23183084 A 1423 1432 dienogest TRIVIAL 23183084 A 1585 1597 progesterone TRIVIAL 23183084 A 167 179 progesterone TRIVIAL 23183084 A 1698 1725 medroxyprogesterone acetate TRIVIAL 23183084 A 1825 1837 progesterone TRIVIAL 23183084 A 1879 1891 progesterone TRIVIAL 23183084 A 2002 2011 progestin FAMILY 23183084 A 2116 2128 progesterone TRIVIAL 23183084 A 237 249 progesterone TRIVIAL 23183084 A 305 317 progesterone TRIVIAL 23183084 A 355 365 progestins FAMILY 23183084 A 380 392 progesterone TRIVIAL 23183084 A 541 551 progestins FAMILY 23183084 A 552 579 medroxyprogesterone acetate TRIVIAL 23183084 A 581 595 dydrogesterone TRIVIAL 23183084 A 600 609 dienogest TRIVIAL 23183084 A 622 634 progesterone TRIVIAL 23183084 A 686 698 progesterone TRIVIAL 23183084 A 816 826 progestins FAMILY 23183084 A 928 942 dydrogesterone TRIVIAL 23183084 A 947 956 dienogest TRIVIAL 23183084 A 975 989 dydrogesterone TRIVIAL 23183084 T 0 9 Progestin FAMILY 23183186 A 1076 1083 glucose TRIVIAL 23183186 A 1251 1254 Ser FORMULA 23183186 A 1462 1469 glucose TRIVIAL 23183186 A 421 428 glucose TRIVIAL 23183186 A 500 503 Thr FORMULA 23183186 A 653 692 2,2'-dihydroxy-1,1'-dinaphthyldisulfide SYSTEMATIC 23183186 A 694 698 IPA3 ABBREVIATION 23183186 A 744 748 cAMP ABBREVIATION 23183186 A 782 785 Ser FORMULA 23183186 A 958 965 glucose TRIVIAL 23183186 A 996 1003 glucose TRIVIAL 23183186 T 148 155 glucose TRIVIAL 23183413 A 1283 1289 copper SYSTEMATIC 23183413 A 1324 1330 copper SYSTEMATIC 23183413 A 1398 1404 copper SYSTEMATIC 23183413 A 1491 1497 copper SYSTEMATIC 23183413 A 1551 1557 sodium SYSTEMATIC 23183413 A 1597 1602 Na(+) FORMULA 23183413 A 1603 1607 K(+) FORMULA 23183413 A 161 167 copper SYSTEMATIC 23183413 A 1695 1701 oxygen SYSTEMATIC 23183413 A 1767 1773 oxygen SYSTEMATIC 23183413 A 1815 1822 peroxyl SYSTEMATIC 23183413 A 1833 1844 glutathione TRIVIAL 23183413 A 1845 1846 S FORMULA 23183413 A 1879 1890 glutathione TRIVIAL 23183413 A 1892 1895 GSH ABBREVIATION 23183413 A 2011 2017 copper SYSTEMATIC 23183413 A 2108 2110 Cu FORMULA 23183413 A 2280 2282 Cu FORMULA 23183413 A 2390 2396 copper SYSTEMATIC 23183413 A 2438 2444 copper SYSTEMATIC 23183413 A 251 257 copper SYSTEMATIC 23183413 A 2543 2549 copper SYSTEMATIC 23183413 A 2741 2747 copper SYSTEMATIC 23183413 A 2863 2869 copper SYSTEMATIC 23183413 A 357 363 copper SYSTEMATIC 23183413 A 392 398 copper SYSTEMATIC 23183413 A 440 446 oxygen SYSTEMATIC 23183413 A 682 688 copper SYSTEMATIC 23183413 A 797 803 copper SYSTEMATIC 23183413 T 133 139 copper SYSTEMATIC 23183532 A 1080 1091 fatty acids FAMILY 23183532 A 1204 1211 sulfide SYSTEMATIC 23183532 A 1216 1223 ammonia SYSTEMATIC 23183532 A 224 235 amino acids FAMILY 23183532 A 295 306 amino acids FAMILY 23183532 A 329 339 amino acid FAMILY 23183532 A 525 536 amino acids FAMILY 23183532 A 808 819 amino acids FAMILY 23183532 A 845 856 amino acids FAMILY 23183532 T 19 27 nitrogen SYSTEMATIC 23184251 A 1042 1048 Ap(4)A ABBREVIATION 23184251 A 1084 1097 pyrophosphate SYSTEMATIC 23184251 A 1160 1166 Ap(4)A ABBREVIATION 23184251 A 1281 1284 IDP ABBREVIATION 23184251 A 1289 1293 dIDP ABBREVIATION 23184251 A 1297 1329 diphosphoinositol polyphosphates FAMILY 23184251 A 1331 1335 DIPs ABBREVIATION 23184251 A 1406 1409 DIP ABBREVIATION 23184251 A 1441 1467 diadenosine polyphosphates FAMILY 23184251 A 1482 1496 polyphosphates FAMILY 23184251 A 373 393 oxidized nucleotides FAMILY 23184251 A 402 412 8-oxo-dGTP SYSTEMATIC 23184251 A 473 484 nucleotides FAMILY 23184251 A 493 496 ADP ABBREVIATION 23184251 A 497 503 ribose TRIVIAL 23184251 A 507 533 diadenosine tetraphosphate SYSTEMATIC 23184251 A 535 541 Ap(4)A ABBREVIATION 23184951 A 247 250 ATP ABBREVIATION 23184951 A 520 523 ATP ABBREVIATION 23184951 A 665 668 ATP ABBREVIATION 23184951 A 717 720 ATP ABBREVIATION 23184951 T 0 3 ATP ABBREVIATION 23185990 A 0 11 Amino acids FAMILY 23185990 A 1188 1193 2'-OH SYSTEMATIC 23185990 A 224 230 Prolyl TRIVIAL 23185990 A 283 286 Pro FORMULA 23185990 A 293 296 Ala FORMULA 23185990 A 301 304 Cys FORMULA 23185990 A 355 358 Ala FORMULA 23185990 A 378 381 Cys FORMULA 23185990 A 387 390 Pro FORMULA 23185990 A 84 93 aminoacyl SYSTEMATIC 23185990 A 939 942 Cys FORMULA 23185990 A 970 973 Cys FORMULA 23185990 A 979 984 ester FAMILY 23185990 T 0 9 Aminoacyl SYSTEMATIC 23186623 A 1146 1149 TTX ABBREVIATION 23186623 A 1236 1239 TTX ABBREVIATION 23186623 A 1325 1328 TTX ABBREVIATION 23186623 A 1631 1634 TTX ABBREVIATION 23186623 A 1670 1673 TTX ABBREVIATION 23186623 A 62 74 tetrodotoxin TRIVIAL 23186623 A 686 689 TTX ABBREVIATION 23186623 A 76 79 TTX ABBREVIATION 23186623 A 987 990 TTX ABBREVIATION 23186623 T 62 74 tetrodotoxin TRIVIAL 23186624 A 1034 1043 clonidine TRIVIAL 23186624 A 1205 1214 clonidine TRIVIAL 23186624 A 140 144 urea TRIVIAL 23186624 A 1447 1456 clonidine TRIVIAL 23186624 A 145 153 nitrogen SYSTEMATIC 23186624 A 1544 1553 Clonidine TRIVIAL 23186624 A 1592 1602 creatinine TRIVIAL 23186624 A 167 177 creatinine TRIVIAL 23186624 A 1695 1704 clonidine TRIVIAL 23186624 A 46 55 clonidine TRIVIAL 23186624 A 494 503 clonidine TRIVIAL 23186624 A 505 515 Catapresan TRIVIAL 23186624 A 528 532 NaCl FORMULA 23186624 A 632 644 diethylether SYSTEMATIC 23186624 A 802 810 formalin TRIVIAL 23186624 A 915 924 clonidine TRIVIAL 23186624 T 10 19 clonidine TRIVIAL 23188714 A 1013 1030 5F-2'deoxyuridine SYSTEMATIC 23188714 A 1233 1243 pyrimidine SYSTEMATIC 23188714 A 1317 1331 5-fluorouracil SYSTEMATIC 23188714 A 136 147 pyrimidines FAMILY 23188714 A 1442 1451 5F-2'dUrd SYSTEMATIC 23188714 A 1456 1465 5F-2'dCtd SYSTEMATIC 23188714 A 1564 1571 5F-dUMP SYSTEMATIC 23188714 A 1611 1621 pyrimidine SYSTEMATIC 23188714 A 1704 1714 pyrimidine SYSTEMATIC 23188714 A 301 311 pyrimidine SYSTEMATIC 23188714 A 361 371 pyrimidine SYSTEMATIC 23188714 A 41 51 pyrimidine SYSTEMATIC 23188714 A 486 492 uracil TRIVIAL 23188714 A 567 577 pyrimidine SYSTEMATIC 23188714 A 630 637 uridine TRIVIAL 23188714 A 642 656 2'deoxyuridine SYSTEMATIC 23188714 A 674 684 pyrimidine SYSTEMATIC 23188714 A 736 745 thymidine TRIVIAL 23188714 A 791 801 nucleoside FAMILY 23188714 A 850 864 5-fluorouracil SYSTEMATIC 23188714 A 90 101 pyrimidines FAMILY 23188714 A 914 932 5-fluoropyrimidine SYSTEMATIC 23188714 A 997 1011 5F-orotic acid SYSTEMATIC 23188714 T 0 10 Pyrimidine SYSTEMATIC 23188714 T 90 113 halogenated pyrimidines FAMILY 23189968 A 517 521 iron SYSTEMATIC 23190030 A 265 279 (poly)phenolic FAMILY 23190030 A 473 479 oxygen SYSTEMATIC 23190030 A 490 498 nitrogen SYSTEMATIC 23190030 A 592 601 flavonoid FAMILY 23190030 A 940 954 (poly)phenolic FAMILY 23190030 T 0 8 Phenolic FAMILY 23190172 A 228 242 17β-oestradiol SYSTEMATIC 23190172 A 336 345 H(2) O(2) FORMULA 23190172 A 747 756 oestrogen FAMILY 23190172 T 0 14 17β-Oestradiol SYSTEMATIC 23190172 T 71 80 oestrogen FAMILY 23192895 A 122 127 NH(3) FORMULA 23192895 A 158 190 magnesium borohydride ammoniates FAMILY 23192895 A 253 265 Mg(BH(4))(2) FORMULA 23192895 A 274 287 hexaammoniate SYSTEMATIC 23192895 A 3 10 ammonia SYSTEMATIC 23192895 A 371 379 hydrogen SYSTEMATIC 23192895 A 423 428 NH(3) FORMULA 23192895 A 448 467 Mg(BH(4))(2)·xNH(3) FAMILY 23192895 A 510 515 H(δ+) FORMULA 23192895 A 52 80 metal borohydride ammoniates FAMILY 23192895 A 520 525 H(δ-) FORMULA 23192895 A 554 559 H(δ+) FORMULA 23192895 A 564 569 H(δ-) FORMULA 23192895 A 611 620 N:→Mg(2+) FORMULA 23192895 A 643 664 magnesium borohydride SYSTEMATIC 23192895 A 666 684 Mg(BH(4))(2)·NH(3) FORMULA 23192895 A 744 752 hydrogen SYSTEMATIC 23192895 T 115 123 hydrogen SYSTEMATIC 23192895 T 49 81 magnesium borohydride ammoniates FAMILY 23192982 A 1010 1021 cholesterol TRIVIAL 23192982 A 1130 1141 cholesterol TRIVIAL 23192982 A 117 128 cholesterol TRIVIAL 23192982 A 1255 1266 cholesterol TRIVIAL 23192982 A 161 172 cholesterol TRIVIAL 23192982 A 241 254 17β-estradiol SYSTEMATIC 23192982 A 317 325 estrogen FAMILY 23192982 A 409 417 estrogen FAMILY 23192982 A 913 924 cholesterol TRIVIAL 23192982 T 100 111 cholesterol TRIVIAL 23192982 T 72 80 estrogen FAMILY 23193276 A 566 576 amino acid FAMILY 23194502 A 1018 1028 adriamycin TRIVIAL 23194502 A 1033 1045 mitoxantrone TRIVIAL 23194502 A 499 507 glaucine TRIVIAL 23194502 A 718 726 glaucine TRIVIAL 23194502 A 728 736 Glaucine TRIVIAL 23194502 T 3 24 isoquinoline alkaloid FAMILY 23194504 A 196 202 oxygen SYSTEMATIC 23194504 A 259 269 superoxide TRIVIAL 23194504 A 289 325 3',5'-Di-C-β-glucopyranosylphloretin SYSTEMATIC 23194504 A 327 335 naringin TRIVIAL 23194504 A 33 43 flavonoids FAMILY 23194504 A 337 347 hesperidin TRIVIAL 23194504 A 349 358 nobiletin TRIVIAL 23194504 A 364 374 tangeretin TRIVIAL 23194504 A 394 404 flavonoids FAMILY 23194504 A 546 555 nobiletin TRIVIAL 23194504 A 560 570 tangeretin TRIVIAL 23194504 A 754 760 Trolox TRIVIAL 23194504 A 809 817 naringin TRIVIAL 23194504 A 822 832 hesperidin TRIVIAL 23194504 A 942 978 3',5'-di-C-β-glucopyranosylphloretin SYSTEMATIC 23194505 A 150 157 ethanol SYSTEMATIC 23194507 A 100 110 zeaxanthin TRIVIAL 23194507 A 67 77 β-carotene TRIVIAL 23194507 A 670 678 lycopene TRIVIAL 23194507 A 781 791 β-carotene TRIVIAL 23194507 A 79 87 lycopene TRIVIAL 23194507 A 866 876 β-carotene TRIVIAL 23194507 A 89 95 lutein TRIVIAL 23194507 A 910 948 cis-isomers of lycopene and β-carotene MULTIPLE 23194510 A 126 146 4(5)-methylimidazole MULTIPLE 23194510 A 148 152 4-MI SYSTEMATIC 23194510 A 246 254 sulphite SYSTEMATIC 23194510 A 286 290 4-MI SYSTEMATIC 23194510 A 351 359 sulphite SYSTEMATIC 23194510 A 380 388 sulphite SYSTEMATIC 23194510 A 425 429 4-MI SYSTEMATIC 23194510 A 44 53 D-glucose SYSTEMATIC 23194510 A 486 494 sulphite SYSTEMATIC 23194510 A 518 526 sulphite SYSTEMATIC 23194510 A 54 59 NH(3) FORMULA 23194510 A 544 552 sulphite SYSTEMATIC 23194510 A 60 68 sulphite SYSTEMATIC 23194510 A 610 614 4-MI SYSTEMATIC 23194510 A 660 668 sulphite SYSTEMATIC 23194510 A 733 741 sulphite SYSTEMATIC 23194510 A 793 801 Sulphite SYSTEMATIC 23194510 A 873 881 pyrazine SYSTEMATIC 23194510 A 918 926 sulphite SYSTEMATIC 23194510 A 966 970 4-MI SYSTEMATIC 23194510 T 26 46 4(5)-methylimidazole MULTIPLE 23194510 T 83 91 sulphite SYSTEMATIC 23194512 A 105 120 graciliflorin C TRIVIAL 23194512 A 143 151 abietane TRIVIAL 23194512 A 153 168 graciliflorin D TRIVIAL 23194512 A 275 310 podocarpa-8,11,13-triene-3α,13-diol SYSTEMATIC 23194512 A 319 331 micranthin B TRIVIAL 23194512 A 36 48 podocarpanes FAMILY 23194512 A 50 76 graciliflorins A (1) and B MULTIPLE 23194512 A 534 537 MTT ABBREVIATION 23194512 A 559 571 Micranthin B TRIVIAL 23194512 A 85 103 isopimarane acetal SYSTEMATIC 23194512 A 9 21 diterpenoids FAMILY 23194512 T 0 11 Podocarpane TRIVIAL 23194512 T 13 24 isopimarane TRIVIAL 23194512 T 30 38 abietane TRIVIAL 23194512 T 39 51 diterpenoids FAMILY 23194517 A 1173 1183 amino acid FAMILY 23194517 A 613 623 fatty acid FAMILY 23194517 A 628 638 amino acid FAMILY 23194517 A 700 711 astaxanthin TRIVIAL 23194517 A 716 726 tocopherol FAMILY 23194517 A 788 796 carbonyl FAMILY 23194517 A 815 826 amino acids FAMILY 23194517 A 828 838 sulfhydryl FAMILY 23194517 A 874 882 carbonyl FAMILY 23194517 A 932 942 fatty acid FAMILY 23194522 A 1031 1041 polyphenol FAMILY 23194522 A 260 271 polyphenols FAMILY 23194522 A 355 359 ABTS ABBREVIATION 23194522 A 413 423 polyphenol FAMILY 23194522 A 541 551 polyphenol FAMILY 23194522 A 569 583 phenolic acids FAMILY 23194522 A 60 70 polyphenol FAMILY 23194522 A 728 739 polyphenols FAMILY 23194522 A 884 894 polyphenol FAMILY 23194522 T 33 44 polyphenols FAMILY 23194524 A 396 403 acetone SYSTEMATIC 23194524 A 639 649 phloridzin TRIVIAL 23194524 A 704 714 polyphenol FAMILY 23194524 A 910 920 phloridzin TRIVIAL 23194525 A 7 13 Hexose TRIVIAL 23194525 T 34 40 Hexose TRIVIAL 23194526 A 316 327 cholesterol TRIVIAL 23194526 A 390 401 cholesterol TRIVIAL 23194526 A 425 436 cholesterol TRIVIAL 23194526 A 609 620 cholesterol TRIVIAL 23194526 A 674 685 cholesterol TRIVIAL 23194526 A 771 782 cholesterol TRIVIAL 23194526 A 826 837 cholesterol TRIVIAL 23194526 A 979 990 cholesterol TRIVIAL 23194528 A 115 133 3-methyl-1-butanol SYSTEMATIC 23194528 A 138 156 2-methyl-1-butanol SYSTEMATIC 23194528 A 161 166 furan SYSTEMATIC 23194528 A 184 215 5-(hydroxymethyl)-2-furaldehyde SYSTEMATIC 23194528 A 19 25 silver SYSTEMATIC 23194528 A 220 233 2-furaldehyde SYSTEMATIC 23194528 A 271 281 1-propanol SYSTEMATIC 23194528 A 283 296 ethyl acetate SYSTEMATIC 23194528 A 298 317 2-methyl-1-propanol SYSTEMATIC 23194528 A 319 337 3-methyl-1-butanol SYSTEMATIC 23194528 A 342 360 2-methyl-1-butanol SYSTEMATIC 23194528 A 465 496 5-(Hydroxymethyl)-2-furaldehyde SYSTEMATIC 23194528 A 501 514 2-furaldehyde SYSTEMATIC 23194528 A 67 77 1-propanol SYSTEMATIC 23194528 A 79 92 ethyl acetate SYSTEMATIC 23194528 A 94 113 2-methyl-1-propanol SYSTEMATIC 23194531 A 216 223 ethanol SYSTEMATIC 23194531 A 359 370 anthocyanin FAMILY 23194531 A 62 73 anthocyanin FAMILY 23194531 A 751 758 ethanol SYSTEMATIC 23194531 A 963 970 ethanol SYSTEMATIC 23194531 T 45 57 anthocyanins FAMILY 23194533 A 0 11 Fatty acids FAMILY 23194533 A 484 495 fatty acids FAMILY 23194533 A 566 577 lauric acid TRIVIAL 23194533 A 589 600 fatty acids FAMILY 23194533 A 637 648 fatty acids FAMILY 23194533 T 27 48 saturated fatty acids FAMILY 23194540 A 678 686 boscalid TRIVIAL 23194540 A 818 826 boscalid TRIVIAL 23194540 A 922 930 boscalid TRIVIAL 23194543 A 527 533 sodium SYSTEMATIC 23194543 A 73 79 sodium SYSTEMATIC 23194544 A 117 127 acrylamide TRIVIAL 23194544 A 193 203 acrylamide TRIVIAL 23194544 A 407 417 Asparagine TRIVIAL 23194544 A 419 426 glucose TRIVIAL 23194544 A 428 436 fructose TRIVIAL 23194544 A 441 448 sucrose TRIVIAL 23194544 A 517 527 acrylamide TRIVIAL 23194544 A 683 693 acrylamide TRIVIAL 23194544 A 756 766 asparagine TRIVIAL 23194544 A 780 786 sugars FAMILY 23194544 A 867 877 acrylamide TRIVIAL 23194544 T 17 27 acrylamide TRIVIAL 23194555 A 112 118 Hg(II) FORMULA 23194555 A 196 202 Hg(II) FORMULA 23194555 A 693 699 Hg(II) FORMULA 23194555 A 828 835 mercury SYSTEMATIC 23194555 A 896 903 mercury SYSTEMATIC 23194555 A 923 929 Zn(II) FORMULA 23194555 A 934 940 Cd(II) FORMULA 23194555 T 52 58 Hg(II) FORMULA 23194566 A 0 12 Tetrodotoxin TRIVIAL 23194566 A 14 17 TTX ABBREVIATION 23194566 A 360 363 TTX ABBREVIATION 23194566 A 608 611 TTX ABBREVIATION 23194566 A 872 875 TTX ABBREVIATION 23194566 A 914 917 TTX ABBREVIATION 23194566 A 966 969 TTX ABBREVIATION 23194566 T 106 118 tetrodotoxin TRIVIAL 23194750 A 0 18 Thiazolidinediones FAMILY 23194750 A 1002 1008 GW9662 IDENTIFIER 23194750 A 1036 1057 N(G)-nitro-L-arginine SYSTEMATIC 23194750 A 1059 1063 LNNA ABBREVIATION 23194750 A 1081 1083 NO FORMULA 23194750 A 1124 1127 ser FORMULA 23194750 A 1192 1210 thiazolidinediones FAMILY 23194750 A 1212 1220 LY294002 IDENTIFIER 23194750 A 1225 1232 10-DEBC SYSTEMATIC 23194750 A 1474 1492 Thiazolidinediones FAMILY 23194750 A 1598 1608 glitazones FAMILY 23194750 A 258 275 thiazolidinedione FAMILY 23194750 A 40 50 glitazones FAMILY 23194750 A 507 525 thiazolidinediones FAMILY 23194750 A 694 697 KCl FORMULA 23194750 A 701 714 phenylephrine TRIVIAL 23194750 A 751 763 troglitazone TRIVIAL 23194750 A 765 778 rosiglitazone TRIVIAL 23194750 A 780 792 pioglitazone TRIVIAL 23194750 A 794 802 LY294002 IDENTIFIER 23194750 A 824 831 10-DEBC SYSTEMATIC 23194750 A 916 919 KCl FORMULA 23194750 T 45 63 thiazolidinediones FAMILY 23194825 A 1 8 Ecstasy TRIVIAL 23194825 A 1021 1031 superoxide TRIVIAL 23194825 A 1083 1091 dopamine TRIVIAL 23194825 A 11 44 3,4-methylenedioxymethamphetamine SYSTEMATIC 23194825 A 1110 1119 GBR 12909 IDENTIFIER 23194825 A 1175 1181 α-MeDA ABBREVIATION 23194825 A 1218 1229 glutathione TRIVIAL 23194825 A 1231 1234 GSH ABBREVIATION 23194825 A 1321 1339 γ-glutamylcysteine SYSTEMATIC 23194825 A 1431 1453 buthionine sulfoximine SYSTEMATIC 23194825 A 1455 1458 BSO ABBREVIATION 23194825 A 1494 1500 α-MeDA ABBREVIATION 23194825 A 1521 1524 GSH ABBREVIATION 23194825 A 1592 1595 BSO ABBREVIATION 23194825 A 1620 1623 NAC ABBREVIATION 23194825 A 1651 1657 α-MeDA ABBREVIATION 23194825 A 1712 1715 GSH ABBREVIATION 23194825 A 174 178 MDMA ABBREVIATION 23194825 A 1774 1777 BSO ABBREVIATION 23194825 A 1788 1799 N-Me-α-MeDA ABBREVIATION 23194825 A 1850 1853 NAC ABBREVIATION 23194825 A 1886 1890 MDMA ABBREVIATION 23194825 A 1891 1899 catechol TRIVIAL 23194825 A 221 225 MDMA ABBREVIATION 23194825 A 280 284 MDMA ABBREVIATION 23194825 A 293 301 catechol TRIVIAL 23194825 A 315 331 α-methyldopamine SYSTEMATIC 23194825 A 333 339 α-MeDA ABBREVIATION 23194825 A 345 370 N-methyl-α-methyldopamine SYSTEMATIC 23194825 A 372 383 N-Me-α-MeDA ABBREVIATION 23194825 A 441 454 retinoic acid TRIVIAL 23194825 A 459 496 12-O-tetradecanoyl-phorbol-13-acetate SYSTEMATIC 23194825 A 48 52 MDMA ABBREVIATION 23194825 A 571 579 dopamine TRIVIAL 23194825 A 610 618 dopamine TRIVIAL 23194825 A 634 638 MDMA ABBREVIATION 23194825 A 639 647 catechol TRIVIAL 23194825 A 787 791 MDMA ABBREVIATION 23194825 A 887 898 glutathione TRIVIAL 23194825 A 910 926 N-acetylcysteine SYSTEMATIC 23194825 A 928 931 NAC ABBREVIATION 23194825 A 976 980 MDMA ABBREVIATION 23194825 T 18 25 ecstasy TRIVIAL 23195954 A 1077 1083 Ca(2+) FORMULA 23195954 A 1103 1109 Zn(2+) FORMULA 23195954 A 1147 1153 Zn(2+) FORMULA 23195954 A 192 198 serine TRIVIAL 23195954 A 217 220 Ser FORMULA 23195954 A 241 244 Asp FORMULA 23195954 A 267 270 His FORMULA 23195954 A 33 39 Ca(2+) FORMULA 23195954 A 342 343 C FORMULA 23195954 A 393 399 Zn(2+) FORMULA 23195954 A 479 485 Zn(2+) FORMULA 23195954 A 509 510 N FORMULA 23195954 A 561 567 Zn(2+) FORMULA 23195954 A 620 626 serine TRIVIAL 23195954 A 743 749 Ca(2+) FORMULA 23195954 A 906 912 Zn(2+) FORMULA 23195954 T 0 6 Serine TRIVIAL 23195954 T 50 54 Zn2+ FORMULA 23195960 A 1080 1085 Na(+) FORMULA 23195960 A 1109 1116 ouabain TRIVIAL 23195960 A 1380 1385 Na(+) FORMULA 23195960 A 1502 1507 Na(+) FORMULA 23195960 A 290 295 Na(+) FORMULA 23195960 A 50 52 Na FORMULA 23195960 A 502 509 ouabain TRIVIAL 23195960 A 53 54 K FORMULA 23195960 A 558 563 Na(+) FORMULA 23195960 A 580 585 Na(+) FORMULA 23195960 A 702 707 Na(+) FORMULA 23195960 A 871 876 Na(+) FORMULA 23195960 A 917 919 Na FORMULA 23195960 A 920 921 K FORMULA 23195960 A 978 983 Na(+) FORMULA 23195960 T 34 36 Na FORMULA 23195960 T 37 38 K FORMULA 23196320 A 1082 1086 AuAg FORMULA 23196320 A 138 140 Ag FORMULA 23196320 A 89 93 AuAg FORMULA 23196320 A 988 992 AuAg FORMULA 23197649 A 1061 1064 ACh ABBREVIATION 23197649 A 110 123 acetylcholine SYSTEMATIC 23197649 A 1103 1107 BQCA ABBREVIATION 23197649 A 1262 1265 ACh ABBREVIATION 23197649 A 1276 1280 BQCA ABBREVIATION 23197649 A 179 192 acetylcholine SYSTEMATIC 23197649 A 194 197 ACh ABBREVIATION 23197649 A 284 301 clozapine-N-oxide SYSTEMATIC 23197649 A 303 306 CNO ABBREVIATION 23197649 A 489 492 CNO ABBREVIATION 23197649 A 525 528 ACh ABBREVIATION 23197649 A 748 780 benzyl quinolone carboxylic acid SYSTEMATIC 23197649 A 782 786 BQCA ABBREVIATION 23197649 A 824 827 ACh ABBREVIATION 23197649 A 978 981 CNO ABBREVIATION 23197771 A 1057 1063 TAPI-0 IDENTIFIER 23197771 A 1227 1233 TAPI-0 IDENTIFIER 23197771 A 13 21 tyrosine TRIVIAL 23197771 A 1494 1500 TAPI-0 IDENTIFIER 23197771 A 1705 1711 TAPI-0 IDENTIFIER 23197771 A 568 574 TAPI-0 IDENTIFIER 23197771 A 843 849 TAPI-0 IDENTIFIER 23197771 T 29 37 tyrosine TRIVIAL 23198810 A 1005 1012 quinone FAMILY 23198810 A 1062 1069 quinone FAMILY 23198810 A 696 709 naphthalimide FAMILY 23198810 A 750 757 quinone FAMILY 23198810 A 852 859 quinone FAMILY 23198819 A 1003 1006 MTM ABBREVIATION 23198819 A 335 350 Montmorillonite TRIVIAL 23198819 A 352 355 MTM ABBREVIATION 23198819 A 520 523 MTM ABBREVIATION 23198819 A 539 545 quartz TRIVIAL 23198819 A 985 988 MTM ABBREVIATION 23198831 A 240 248 hydrogen SYSTEMATIC 23198831 A 477 481 H(+) FORMULA 23198831 A 482 486 H(2) FORMULA 23198831 T 0 8 Hydrogen SYSTEMATIC 23198831 T 24 26 Pt FORMULA 23198831 T 27 29 Ru FORMULA 23198958 A 188 196 In(Ga)As FORMULA 23198958 A 197 201 GaAs FORMULA 23199028 A 127 139 carbohydrate FAMILY 23199028 A 6 18 glycyrrhizin TRIVIAL 23199028 A 89 94 amine SYSTEMATIC 23199028 A 98 108 amino acid FAMILY 23199028 T 60 72 glycyrrhizin TRIVIAL 23199983 A 1020 1027 lactose TRIVIAL 23199983 A 111 119 fructose TRIVIAL 23199983 A 1132 1140 fructose TRIVIAL 23199983 A 14 25 1-lactulose SYSTEMATIC 23199983 A 186 193 Lactose TRIVIAL 23199983 A 278 289 1-lactulose SYSTEMATIC 23199983 A 30 39 lactulose TRIVIAL 23199983 A 311 320 lactulose TRIVIAL 23199983 A 333 341 fructose TRIVIAL 23199983 A 480 491 1-lactulose SYSTEMATIC 23199983 A 492 501 lactulose TRIVIAL 23199983 A 593 604 1-lactulose SYSTEMATIC 23199983 A 609 618 lactulose TRIVIAL 23199983 A 670 678 fructose TRIVIAL 23199983 A 719 726 Lactose TRIVIAL 23199983 A 771 779 fructose TRIVIAL 23199983 A 965 973 Fructose TRIVIAL 23199983 A 995 1005 galactosyl TRIVIAL 23199983 T 118 126 fructose TRIVIAL 23199983 T 14 25 1-lactulose SYSTEMATIC 23199983 T 30 39 lactulose TRIVIAL 23199984 A 15 22 stearin TRIVIAL 23199984 A 298 314 sodium methoxide SYSTEMATIC 23199984 A 361 376 triacylglycerol FAMILY 23199984 A 378 381 TAG ABBREVIATION 23199984 A 868 875 stearin TRIVIAL 23199984 T 111 118 stearin TRIVIAL 23199992 A 1071 1073 ¹H FORMULA 23199992 A 328 330 ¹H FORMULA 23199992 A 686 701 4-aminobutyrate SYSTEMATIC 23199992 A 703 707 GABA ABBREVIATION 23199992 A 710 717 acetate SYSTEMATIC 23199992 A 719 729 asparagine TRIVIAL 23199992 A 731 738 leucine TRIVIAL 23199992 A 740 750 isoleucine TRIVIAL 23199992 A 752 768 O-phosphocholine SYSTEMATIC 23199992 A 770 783 phenylacetate SYSTEMATIC 23199992 A 785 798 phenylalanine TRIVIAL 23199992 A 800 809 succinate TRIVIAL 23199992 A 811 818 sucrose TRIVIAL 23199992 A 820 828 tyrosine TRIVIAL 23199992 A 834 840 valine TRIVIAL 23199992 T 112 114 ¹H FORMULA 23199999 A 670 685 malondialdehyde TRIVIAL 23200004 A 1012 1024 nitrous acid SYSTEMATIC 23200004 A 1029 1043 nitrous oxides FAMILY 23200004 A 1062 1082 potassium dichromate SYSTEMATIC 23200004 A 1110 1117 mercury SYSTEMATIC 23200004 A 1246 1253 mercury SYSTEMATIC 23200004 A 214 225 nitric acid SYSTEMATIC 23200004 A 230 247 hydrogen peroxide SYSTEMATIC 23200004 A 388 399 nitric acid SYSTEMATIC 23200004 A 404 416 tin chloride SYSTEMATIC 23200004 A 529 536 mercury SYSTEMATIC 23200004 A 68 75 mercury SYSTEMATIC 23200004 A 788 795 mercury SYSTEMATIC 23200004 T 17 24 mercury SYSTEMATIC 23200005 A 0 8 Selenium SYSTEMATIC 23200005 A 169 177 selenium SYSTEMATIC 23200005 A 264 272 selenium SYSTEMATIC 23200005 A 313 321 selenium SYSTEMATIC 23200005 A 375 380 SeMet FORMULA 23200005 A 382 398 selenomethionine SYSTEMATIC 23200005 A 414 422 selenium SYSTEMATIC 23200005 A 470 475 SeMet FORMULA 23200005 A 480 485 SeCys FORMULA 23200005 A 487 507 methylselenocysteine SYSTEMATIC 23200005 A 528 530 Se FORMULA 23200005 A 532 540 selenium SYSTEMATIC 23200005 A 543 545 Zn FORMULA 23200005 A 547 551 zinc SYSTEMATIC 23200005 A 554 556 Fe FORMULA 23200005 A 558 562 iron SYSTEMATIC 23200005 A 598 607 adenosine TRIVIAL 23200005 A 609 619 cordycepin TRIVIAL 23200005 A 699 700 P FORMULA 23200005 A 702 712 phosphorus SYSTEMATIC 23200005 A 718 719 K FORMULA 23200005 A 721 730 potassium SYSTEMATIC 23200005 T 62 70 selenium SYSTEMATIC 23200006 A 28 35 cadmium SYSTEMATIC 23200006 A 576 585 alcoholic FAMILY 23200006 A 66 72 copper SYSTEMATIC 23200006 A 90 98 graphite TRIVIAL 23200006 A 99 105 carbon SYSTEMATIC 23200006 T 38 47 alcoholic FAMILY 23200246 A 139 162 12-hydroxy-scabrolide A SYSTEMATIC 23200246 A 171 190 13-epi-scabrolide C SYSTEMATIC 23200246 A 93 108 norditerpenoids FAMILY 23200246 T 18 33 norditerpenoids FAMILY 23200253 A 154 158 TPBP ABBREVIATION 23200253 A 226 236 piperidine SYSTEMATIC 23200253 A 456 465 VU0357017 IDENTIFIER 23200253 A 89 93 TBPB ABBREVIATION 23200253 A 98 107 VU0357017 IDENTIFIER 23200747 A 0 16 Organophosphorus FAMILY 23200778 A 341 350 bleomycin FAMILY 23200778 A 352 361 etoposide TRIVIAL 23200778 A 367 376 cisplatin TRIVIAL 23200778 A 378 381 BEP ABBREVIATION 23200778 A 481 492 glutathione TRIVIAL 23200778 A 493 494 S FORMULA 23200778 A 526 529 BEP ABBREVIATION 23200778 A 595 603 aldehyde SYSTEMATIC 23200778 A 818 821 BEP ABBREVIATION 23200778 A 905 908 BEP ABBREVIATION 23200778 T 23 34 glutathione TRIVIAL 23200778 T 35 36 S FORMULA 23200887 A 0 11 Resveratrol TRIVIAL 23200887 A 1054 1065 resveratrol TRIVIAL 23200887 A 1099 1110 resveratrol TRIVIAL 23200887 A 1251 1262 resveratrol TRIVIAL 23200887 A 13 45 3,5,4'-trihydroxy-trans stilbene SYSTEMATIC 23200887 A 1344 1355 resveratrol TRIVIAL 23200887 A 344 355 resveratrol TRIVIAL 23200887 A 618 626 H(2)O(2) FORMULA 23200887 A 686 697 Resveratrol TRIVIAL 23200887 A 851 862 resveratrol TRIVIAL 23200887 A 980 983 ADP ABBREVIATION 23200887 T 0 11 Resveratrol TRIVIAL 23200901 A 0 18 Aconitum alkaloids FAMILY 23200901 A 1000 1007 aconine TRIVIAL 23200901 A 1012 1022 mesaconine TRIVIAL 23200901 A 129 143 benzoylaconine SYSTEMATIC 23200901 A 1369 1372 BAC ABBREVIATION 23200901 A 1374 1377 BMA ABBREVIATION 23200901 A 1382 1385 BHA ABBREVIATION 23200901 A 145 148 BAC ABBREVIATION 23200901 A 151 168 benzoylmesaconine SYSTEMATIC 23200901 A 170 173 BMA ABBREVIATION 23200901 A 176 193 benzoylhypaconine TRIVIAL 23200901 A 195 198 BHA ABBREVIATION 23200901 A 201 208 aconine TRIVIAL 23200901 A 214 224 mesaconine TRIVIAL 23200901 A 29 38 aconitine TRIVIAL 23200901 A 45 57 mesaconitine TRIVIAL 23200901 A 584 602 Aconitum alkaloids FAMILY 23200901 A 64 76 hypaconitine TRIVIAL 23200901 A 699 717 Aconitum alkaloids FAMILY 23200901 A 755 769 cyclosporine A TRIVIAL 23200901 A 774 783 verapamil TRIVIAL 23200901 A 792 797 Ko143 IDENTIFIER 23200901 A 809 814 MK571 IDENTIFIER 23200901 A 947 950 BAC ABBREVIATION 23200901 A 952 955 BMA ABBREVIATION 23200901 A 961 964 BHA ABBREVIATION 23200901 T 65 74 aconitine TRIVIAL 23200901 T 76 88 mesaconitine TRIVIAL 23200901 T 90 102 hypaconitine TRIVIAL 23201003 A 1005 1011 JBP485 IDENTIFIER 23201003 A 1023 1038 1,25(OH)(2)D(3) FORMULA 23201003 A 105 132 1α,25-dihydroxyvitamin D(3) SYSTEMATIC 23201003 A 1154 1160 JBP485 IDENTIFIER 23201003 A 1165 1180 1,25(OH)(2)D(3) FORMULA 23201003 A 1249 1255 JBP485 IDENTIFIER 23201003 A 1260 1275 1,25(OH)(2)D(3) FORMULA 23201003 A 1336 1351 1,25(OH)(2)D(3) FORMULA 23201003 A 134 149 1,25(OH)(2)D(3) FORMULA 23201003 A 211 226 1,25(OH)(2)D(3) FORMULA 23201003 A 298 304 JBP485 IDENTIFIER 23201003 A 356 362 JBP485 IDENTIFIER 23201003 A 693 708 1,25(OH)(2)D(3) FORMULA 23201003 A 758 764 JBP485 IDENTIFIER 23201003 A 824 830 JBP485 IDENTIFIER 23201003 A 845 851 JBP485 IDENTIFIER 23201003 A 904 919 1,25(OH)(2)D(3) FORMULA 23201003 A 94 100 JBP485 IDENTIFIER 23201003 A 960 975 1,25(OH)(2)D(3) FORMULA 23201003 T 21 46 1α,25-dihydroxyvitamin D₃ SYSTEMATIC 23201003 T 63 69 JBP485 IDENTIFIER 23201055 A 122 126 PLGA ABBREVIATION 23201055 A 281 285 PLGA ABBREVIATION 23201055 A 491 495 PLGA ABBREVIATION 23201055 A 91 120 Poly(lactic-co-glycolic acid) SYSTEMATIC 23201055 T 61 65 PLGA ABBREVIATION 23201124 A 689 690 N FORMULA 23201309 A 0 10 Nucleoside FAMILY 23201309 A 1043 1053 nucleotide FAMILY 23201309 A 1170 1200 tenofovir mono- or diphosphate MULTIPLE 23201309 A 1433 1456 tenofovir monophosphate SYSTEMATIC 23201309 A 234 245 3'-hydroxyl SYSTEMATIC 23201309 A 367 390 tenofovir monophosphate SYSTEMATIC 23201309 A 433 455 nucleoside diphosphate FAMILY 23201309 A 471 489 3-phosphoglycerate SYSTEMATIC 23201309 A 504 512 creatine TRIVIAL 23201309 A 529 537 pyruvate TRIVIAL 23201309 A 598 621 tenofovir monophosphate SYSTEMATIC 23201309 A 699 702 ADP ABBREVIATION 23201309 A 815 818 ADP ABBREVIATION 23201309 A 892 915 tenofovir monophosphate SYSTEMATIC 23201309 A 980 989 tenofovir TRIVIAL 23201309 T 44 53 tenofovir TRIVIAL 23201331 A 1040 1049 sweroside TRIVIAL 23201331 A 1101 1110 sweroside TRIVIAL 23201331 A 1148 1157 Sweroside TRIVIAL 23201331 A 1380 1389 sweroside TRIVIAL 23201331 A 1457 1466 sweroside TRIVIAL 23201331 A 146 155 Sweroside TRIVIAL 23201331 A 542 551 sweroside TRIVIAL 23201331 A 598 658 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide SYSTEMATIC 23201331 A 660 663 MTT ABBREVIATION 23201331 A 704 713 sweroside TRIVIAL 23201331 A 854 863 Sweroside TRIVIAL 23201331 T 22 31 sweroside TRIVIAL 23201370 A 554 563 aspartate TRIVIAL 23201370 A 588 595 alanine TRIVIAL 23201370 A 596 601 amino FAMILY 23201370 A 776 787 cholesterol TRIVIAL 23201370 A 789 802 triglycerides FAMILY 23201439 A 1125 1141 organophosphorus FAMILY 23201439 A 171 185 β-cyclodextrin TRIVIAL 23201439 A 22 38 organophosphorus FAMILY 23201439 A 495 509 β-cyclodextrin TRIVIAL 23201439 A 728 734 carbon SYSTEMATIC 23201439 A 826 836 cyclosarin TRIVIAL 23201439 T 13 27 β-cyclodextrin TRIVIAL 23201442 A 0 8 Estrogen FAMILY 23201442 A 1006 1016 raloxifene TRIVIAL 23201442 A 1052 1056 H₂O₂ FORMULA 23201442 A 1124 1132 phenoxyl SYSTEMATIC 23201442 A 1156 1166 raloxifene TRIVIAL 23201442 A 1211 1215 NADH ABBREVIATION 23201442 A 1370 1374 NADH ABBREVIATION 23201442 A 1375 1379 NAD⁺ ABBREVIATION 23201442 A 258 268 raloxifene TRIVIAL 23201442 A 282 290 estrogen FAMILY 23201442 A 375 385 fatty acid FAMILY 23201442 A 406 417 Fatty acids FAMILY 23201442 A 574 584 raloxifene TRIVIAL 23201442 A 644 654 raloxifene TRIVIAL 23201442 A 709 720 fatty acids FAMILY 23201442 A 739 756 β-hydroxybutyrate SYSTEMATIC 23201442 A 757 769 acetoacetate SYSTEMATIC 23201442 A 792 797 ¹⁴CO₂ FORMULA 23201442 A 844 850 oxygen SYSTEMATIC 23201442 A 878 888 raloxifene TRIVIAL 23201442 A 911 915 NADH ABBREVIATION 23201442 T 0 10 Raloxifene TRIVIAL 23201442 T 19 29 fatty acid FAMILY 23201451 A 0 12 Moniliformin TRIVIAL 23201451 A 1226 1238 moniliformin TRIVIAL 23201451 A 142 154 moniliformin TRIVIAL 23201451 A 354 366 moniliformin TRIVIAL 23201451 A 478 490 moniliformin TRIVIAL 23201451 A 556 568 Moniliformin TRIVIAL 23201451 A 900 912 moniliformin TRIVIAL 23201451 A 980 992 moniliformin TRIVIAL 23201451 T 74 86 moniliformin TRIVIAL 23202250 A 1407 1413 TiO(2) FORMULA 23202250 A 1571 1577 TiO(2) FORMULA 23202250 A 22 38 titanium dioxide SYSTEMATIC 23202250 A 270 276 TiO(2) FORMULA 23202250 A 55 61 TiO(2) FORMULA 23202250 A 620 626 TiO(2) FORMULA 23202250 A 853 859 carbon SYSTEMATIC 23202585 A 214 215 C FORMULA 23202585 A 570 573 ATP ABBREVIATION 23202880 A 147 151 N(2) FORMULA 23202880 A 168 176 squalane TRIVIAL 23202880 A 180 195 branched alkane FAMILY 23202880 A 199 204 NO(3) FORMULA 23202880 A 241 249 squalene TRIVIAL 23202880 A 283 288 NO(3) FORMULA 23202880 A 40 47 nitrate SYSTEMATIC 23202880 A 443 448 NO(3) FORMULA 23202880 A 463 471 squalene TRIVIAL 23202880 A 57 62 NO(3) FORMULA 23202880 A 633 638 NO(3) FORMULA 23202880 A 661 669 squalene TRIVIAL 23202880 A 696 704 squalene TRIVIAL 23202880 A 84 92 squalane TRIVIAL 23202880 A 944 952 squalene TRIVIAL 23202880 A 97 105 squalene TRIVIAL 23202880 A 983 988 NO(3) FORMULA 23202880 T 53 56 NO3 FORMULA 23202880 T 72 80 squalane TRIVIAL 23202880 T 85 93 squalene TRIVIAL 23203454 A 0 8 Hexamoll TRIVIAL 23203454 A 1045 1055 monoesters FAMILY 23203454 A 1100 1102 OH FORMULA 23203454 A 1103 1108 MINCH ABBREVIATION 23203454 A 113 122 phthalate FAMILY 23203454 A 1130 1133 oxo SYSTEMATIC 23203454 A 1134 1139 MINCH ABBREVIATION 23203454 A 1162 1169 carboxy SYSTEMATIC 23203454 A 1170 1175 MINCH ABBREVIATION 23203454 A 12 17 DINCH ABBREVIATION 23203454 A 1236 1245 monoester SYSTEMATIC 23203454 A 1246 1251 MINCH ABBREVIATION 23203454 A 1289 1294 DINCH ABBREVIATION 23203454 A 1585 1590 DINCH ABBREVIATION 23203454 A 168 173 DINCH ABBREVIATION 23203454 A 1680 1685 DINCH ABBREVIATION 23203454 A 22 62 diisononyl-cyclohexane-1,2-dicarboxylate SYSTEMATIC 23203454 A 259 267 Hexamoll TRIVIAL 23203454 A 271 276 DINCH ABBREVIATION 23203454 A 429 450 di-iso-nonylphthalate SYSTEMATIC 23203454 A 452 456 DINP ABBREVIATION 23203454 A 495 504 monoester SYSTEMATIC 23203454 A 505 548 mono-isononyl-cyclohexane-1,2-dicarboxylate SYSTEMATIC 23203454 A 550 555 MINCH ABBREVIATION 23203454 A 710 743 cyclohexane-1,2-dicarboxylic acid SYSTEMATIC 23203454 A 745 749 CHDA ABBREVIATION 23203454 A 855 859 CHDA ABBREVIATION 23203454 T 34 43 phthalate FAMILY 23203454 T 55 95 diisononyl-cyclohexane-1,2-dicarboxylate SYSTEMATIC 23203454 T 97 102 DINCH ABBREVIATION 23203870 A 209 213 zinc SYSTEMATIC 23203920 A 731 769 N-3-oxododecanoyl-L-homoserine lactone SYSTEMATIC 23203920 A 771 774 OHN ABBREVIATION 23203920 A 883 886 OHN ABBREVIATION 23204325 A 728 735 glucose TRIVIAL 23204443 A 0 23 Sphingosine 1-phosphate SYSTEMATIC 23204443 T 0 23 Sphingosine 1-phosphate SYSTEMATIC 23205571 A 128 129 N FORMULA 23205571 A 165 172 proline TRIVIAL 23205571 A 186 212 indoline-2-carboxylic acid SYSTEMATIC 23205571 A 214 217 Ica ABBREVIATION 23205571 A 223 286 (2S,4R)-4-(naphthalene-2-ylmethyl)pyrrolidine-2-carboxylic acid SYSTEMATIC 23205571 A 434 442 oxytocin TRIVIAL 23205571 A 457 460 Ica ABBREVIATION 23205571 A 546 574 [Mpa(1), Ica(2), D-Arg(8)]VP FORMULA 23205571 A 579 612 [Mpa(1),Ica(2),Val(4),D-Arg(8)]VP FORMULA 23205571 A 694 757 (2S,4R)-4-(naphthalene-2-ylmethyl)pyrrolidine-2-carboxylic acid SYSTEMATIC 23205571 A 869 889 arginine vasopressin TRIVIAL 23205571 A 91 111 arginine vasopressin TRIVIAL 23205571 A 989 1009 arginine vasopressin TRIVIAL 23205571 T 103 110 proline TRIVIAL 23205571 T 61 81 arginine vasopressin TRIVIAL 23205763 A 232 243 metal-oxide FAMILY 23205763 A 330 336 alkyne FAMILY 23205763 A 703 708 azide SYSTEMATIC 23205763 A 718 735 indocyanine green TRIVIAL 23205763 A 887 904 indocyanine green TRIVIAL 23205778 A 1002 1008 purine TRIVIAL 23205778 A 1010 1020 anthracene SYSTEMATIC 23205778 A 1026 1038 phenanthrene SYSTEMATIC 23205778 A 13 21 hydrogen SYSTEMATIC 23205778 A 141 149 benzenes FAMILY 23205778 A 1426 1433 benzene SYSTEMATIC 23205778 A 1434 1446 benzonitrile SYSTEMATIC 23205778 A 1448 1455 benzene SYSTEMATIC 23205778 A 1456 1462 phenol SYSTEMATIC 23205778 A 1468 1479 naphthalene SYSTEMATIC 23205778 A 1480 1488 methanol SYSTEMATIC 23205778 A 1616 1624 hydrogen SYSTEMATIC 23205778 A 203 204 F FORMULA 23205778 A 207 209 Cl FORMULA 23205778 A 212 214 Br FORMULA 23205778 A 217 220 C≡N FORMULA 23205778 A 227 229 OH FORMULA 23205778 A 237 269 polycyclic aromatic hydrocarbons FAMILY 23205778 A 321 327 carbon SYSTEMATIC 23205778 A 364 370 carbon SYSTEMATIC 23205778 A 414 435 aromatic heterocycles FAMILY 23205778 A 466 489 fused-ring heterocycles FAMILY 23205778 A 622 635 fluorobenzene SYSTEMATIC 23205778 A 637 650 chlorobenzene SYSTEMATIC 23205778 A 652 664 bromobenzene SYSTEMATIC 23205778 A 666 698 di-, tri-, and hexachlorobenzene MULTIPLE 23205778 A 708 721 2-chlorofuran SYSTEMATIC 23205778 A 723 740 2-chlorothiophene SYSTEMATIC 23205778 A 742 754 benzonitrile SYSTEMATIC 23205778 A 756 762 phenol SYSTEMATIC 23205778 A 764 780 dihydroxybenzene FAMILY 23205778 A 790 806 1,4-benzoquinone SYSTEMATIC 23205778 A 808 819 naphthalene SYSTEMATIC 23205778 A 821 847 naphthalene-2-carbonitrile SYSTEMATIC 23205778 A 849 864 naphthalen-2-ol SYSTEMATIC 23205778 A 866 875 quinoline SYSTEMATIC 23205778 A 877 894 benzo[b]thiophene SYSTEMATIC 23205778 A 896 913 benzo[c]thiophene SYSTEMATIC 23205778 A 915 926 benzoxazole SYSTEMATIC 23205778 A 928 941 benzisoxazole SYSTEMATIC 23205778 A 943 956 benzimidazole SYSTEMATIC 23205778 A 958 971 benzothiazole SYSTEMATIC 23205778 A 973 979 indole SYSTEMATIC 23205778 A 981 990 isoindole SYSTEMATIC 23205778 A 992 1000 indazole SYSTEMATIC 23205778 T 108 127 polycyclic aromatic FAMILY 23205778 T 59 67 hydrogen SYSTEMATIC 23205778 T 95 103 benzenes FAMILY 23206503 A 0 23 N-palmitoylethanolamine SYSTEMATIC 23206503 A 1063 1069 GW6471 IDENTIFIER 23206503 A 1098 1106 SR141716 IDENTIFIER 23206503 A 1157 1165 SR141716 IDENTIFIER 23206503 A 1171 1174 PEA ABBREVIATION 23206503 A 1178 1181 AEA ABBREVIATION 23206503 A 1246 1252 GW6471 IDENTIFIER 23206503 A 1265 1268 PEA ABBREVIATION 23206503 A 1305 1308 AEA ABBREVIATION 23206503 A 1355 1358 PEA ABBREVIATION 23206503 A 1360 1363 AEA ABBREVIATION 23206503 A 1368 1372 2-AG ABBREVIATION 23206503 A 1374 1396 2-arachidonoylglycerol SYSTEMATIC 23206503 A 1500 1503 PEA ABBREVIATION 23206503 A 1608 1611 PEA ABBREVIATION 23206503 A 25 28 PEA ABBREVIATION 23206503 A 253 265 cannabinoids FAMILY 23206503 A 434 437 PEA ABBREVIATION 23206503 A 45 68 fatty acid ethanolamide FAMILY 23206503 A 510 513 PEA ABBREVIATION 23206503 A 515 525 anandamide TRIVIAL 23206503 A 527 530 AEA ABBREVIATION 23206503 A 554 560 GW6471 IDENTIFIER 23206503 A 619 627 SR141716 IDENTIFIER 23206503 A 788 791 PEA ABBREVIATION 23206503 A 815 823 SR141716 IDENTIFIER 23206503 A 828 834 GW6471 IDENTIFIER 23206503 A 876 879 AEA ABBREVIATION 23206503 A 892 895 PEA ABBREVIATION 23206503 A 963 966 PEA ABBREVIATION 23206503 A 971 974 AEA ABBREVIATION 23206503 T 24 47 N-palmitoylethanolamine SYSTEMATIC 23206861 A 138 148 carbamates FAMILY 23206861 A 39 62 tetrahydro-β-carbolines FAMILY 23206861 T 0 22 Tetrahydro-β-carboline SYSTEMATIC 23206861 T 45 61 fatty acid amide FAMILY 23206990 A 392 400 Estrogen FAMILY 23207166 A 0 11 Misoprostol TRIVIAL 23207166 A 332 343 misoprostol TRIVIAL 23207166 A 641 652 misoprostol TRIVIAL 23207166 A 732 743 misoprostol TRIVIAL 23207166 A 930 941 misoprostol TRIVIAL 23207166 T 32 43 misoprostol TRIVIAL 23207252 A 579 598 thiobarbituric acid SYSTEMATIC 23207252 A 868 911 nicotinamide adenine dinucleotide phosphate SYSTEMATIC 23207252 A 913 918 NADPH ABBREVIATION 23207328 A 1034 1037 AZT ABBREVIATION 23207328 A 1110 1113 AZT ABBREVIATION 23207328 A 123 133 zidovudine TRIVIAL 23207328 A 1253 1268 PPG-5-CETETH-20 FORMULA 23207328 A 1270 1280 oleic acid TRIVIAL 23207328 A 135 138 AZT ABBREVIATION 23207328 A 1403 1406 AZT ABBREVIATION 23207328 A 1464 1467 AZT ABBREVIATION 23207328 A 1562 1565 AZT ABBREVIATION 23207328 A 1596 1599 AZT ABBREVIATION 23207328 A 1884 1887 AZT ABBREVIATION 23207328 A 1956 1959 AZT ABBREVIATION 23207328 A 350 365 PPG-5-CETETH-20 FORMULA 23207328 A 367 377 oleic acid TRIVIAL 23207477 A 1106 1108 Co FORMULA 23207477 A 1336 1338 Co FORMULA 23207477 A 202 208 Cobalt SYSTEMATIC 23207477 A 374 380 cobalt SYSTEMATIC 23207477 A 382 384 Co FORMULA 23207477 A 460 462 Co FORMULA 23207477 A 496 498 Co FORMULA 23207477 A 602 604 Co FORMULA 23207477 A 624 626 Co FORMULA 23207477 A 677 679 Co FORMULA 23207477 A 850 852 Co FORMULA 23207477 A 926 928 Co FORMULA 23207477 A 961 963 Co FORMULA 23207477 T 0 6 Cobalt SYSTEMATIC 23207477 T 102 108 cobalt SYSTEMATIC 23208007 A 94 105 sialic acid TRIVIAL 23208609 A 1025 1038 17ß-estradiol SYSTEMATIC 23208609 A 1043 1050 estrone TRIVIAL 23208609 A 1079 1084 2-ITX SYSTEMATIC 23208609 A 1119 1127 androgen FAMILY 23208609 A 1142 1154 pregnenolone TRIVIAL 23208609 A 1159 1171 progesterone TRIVIAL 23208609 A 1345 1350 2-ITX SYSTEMATIC 23208609 A 1352 1357 4-ITX SYSTEMATIC 23208609 A 1363 1377 2,4-diethyl-TX SYSTEMATIC 23208609 A 1431 1436 2-ITX SYSTEMATIC 23208609 A 1561 1573 thioxanthone SYSTEMATIC 23208609 A 1680 1687 steroid FAMILY 23208609 A 178 183 2-ITX SYSTEMATIC 23208609 A 256 261 2-ITX SYSTEMATIC 23208609 A 263 286 4-isopropylthioxanthone SYSTEMATIC 23208609 A 288 293 4-ITX SYSTEMATIC 23208609 A 296 320 2,4-diethylthio xanthone SYSTEMATIC 23208609 A 322 336 2,4-diethyl-TX SYSTEMATIC 23208609 A 339 359 2-chlorothioxanthone SYSTEMATIC 23208609 A 361 372 2-chloro-TX SYSTEMATIC 23208609 A 379 409 1-chloro-4-propoxythioxanthone SYSTEMATIC 23208609 A 411 432 1-chloro-4-propoxy-TX SYSTEMATIC 23208609 A 457 465 androgen FAMILY 23208609 A 470 478 estrogen FAMILY 23208609 A 52 75 2-isopropylthioxanthone SYSTEMATIC 23208609 A 762 767 2-ITX SYSTEMATIC 23208609 A 769 774 4-ITX SYSTEMATIC 23208609 A 77 82 2-ITX SYSTEMATIC 23208609 A 780 794 2,4-diethyl-TX SYSTEMATIC 23208609 A 804 815 2-chloro-TX SYSTEMATIC 23208609 T 32 44 thioxanthone SYSTEMATIC 23208666 A 469 495 poly(2-nonyl-2-oxazoline)s FAMILY 23208666 A 9 26 poly(2-oxazoline) SYSTEMATIC 23208666 T 0 17 Poly(2-oxazoline) SYSTEMATIC 23209192 A 1139 1147 cotinine TRIVIAL 23209192 A 1374 1382 cotinine TRIVIAL 23209192 A 1605 1613 cotinine TRIVIAL 23209192 A 1669 1677 cotinine TRIVIAL 23209192 A 398 406 cotinine TRIVIAL 23209192 A 489 497 Cotinine TRIVIAL 23209192 A 641 649 Cotinine TRIVIAL 23209192 T 0 8 Cotinine TRIVIAL 23210481 A 0 8 Vizantin TRIVIAL 23210481 A 10 55 6,6'-bis-O-(3-nonyldodecanoyl)-α,α'-trehalose SYSTEMATIC 23210481 A 165 196 trehalose 6,6'-dicorynomycolate SYSTEMATIC 23210481 A 198 202 TDCM ABBREVIATION 23210481 A 235 243 vizantin TRIVIAL 23210481 A 293 297 TDCM ABBREVIATION 23210481 A 424 432 vizantin TRIVIAL 23210481 T 15 23 vizantin TRIVIAL 23210481 T 97 128 trehalose-6,6'-dicorynomycolate SYSTEMATIC 23210547 A 786 792 carbon SYSTEMATIC 23210547 A 79 85 carbon SYSTEMATIC 23210547 T 96 102 carbon SYSTEMATIC 23210662 A 195 202 ethynyl SYSTEMATIC 23210662 A 208 213 PAMAM ABBREVIATION 23210662 A 217 224 ethynyl SYSTEMATIC 23210662 A 230 235 PAMAM ABBREVIATION 23210662 A 459 466 ethynyl SYSTEMATIC 23210662 A 472 477 PAMAM ABBREVIATION 23210662 A 631 636 PAMAM ABBREVIATION 23210662 A 676 687 doxorubicin TRIVIAL 23210662 A 880 891 doxorubicin TRIVIAL 23210851 A 1021 1024 ATP ABBREVIATION 23210851 A 975 978 ATP ABBREVIATION 23211364 A 0 11 Candesartan TRIVIAL 23211364 A 1056 1067 Candesartan TRIVIAL 23211364 A 1151 1162 candesartan TRIVIAL 23211364 A 1262 1273 candesartan TRIVIAL 23211364 A 1358 1367 PD-123319 IDENTIFIER 23211364 A 1517 1528 candesartan TRIVIAL 23211364 A 163 174 candesartan TRIVIAL 23211364 A 674 685 candesartan TRIVIAL 23211364 A 929 940 candesartan TRIVIAL 23211364 A 975 986 candesartan TRIVIAL 23211525 A 224 238 hydroxysteroid FAMILY 23211525 A 306 326 sulfonate bile acids FAMILY 23211525 A 328 342 hydroxysteroid FAMILY 23211525 A 343 365 dehydroepiandrosterone TRIVIAL 23211525 A 379 388 androgens FAMILY 23211525 A 4 12 retinoid FAMILY 23211525 T 24 38 hydroxysteroid FAMILY 23212787 A 227 239 ginsenosides FAMILY 23212787 A 627 639 ginsenosides FAMILY 23212787 A 661 672 Ginsenoside FAMILY 23212787 A 780 813 Ginsenosides Ra1-3, Rb2-3, and Rc MULTIPLE 23212970 A 14 27 polyurethanes FAMILY 23212970 A 149 162 monoglyceride SYSTEMATIC 23212970 A 328 331 MTT ABBREVIATION 23212970 A 50 53 TDI ABBREVIATION 23212970 A 55 63 PCL diol SYSTEMATIC 23212970 A 65 75 butanediol SYSTEMATIC 23212970 A 81 96 pentaerythritol SYSTEMATIC 23212970 T 56 68 polyurethane SYSTEMATIC 23212975 A 0 24 Poly(N-vinylpyrrolidone) SYSTEMATIC 23212975 A 185 188 PVP ABBREVIATION 23212975 A 26 29 PVP ABBREVIATION 23212975 A 310 313 PVP ABBREVIATION 23212975 A 429 432 PVP ABBREVIATION 23212975 A 513 534 poly(ethylene glycol) SYSTEMATIC 23212975 A 536 539 PEG ABBREVIATION 23212975 A 611 614 PVP ABBREVIATION 23212975 A 695 698 PVP ABBREVIATION 23212975 A 782 785 PVP ABBREVIATION 23212975 T 0 24 Poly(N-vinylpyrrolidone) SYSTEMATIC 23214415 A 118 121 PEO ABBREVIATION 23214415 A 1186 1189 PEO ABBREVIATION 23214415 A 1318 1321 PEO ABBREVIATION 23214415 A 1322 1325 PAA ABBREVIATION 23214415 A 1626 1629 PEO ABBREVIATION 23214415 A 1634 1637 PAA ABBREVIATION 23214415 A 223 241 poly(acrylic acid) SYSTEMATIC 23214415 A 243 246 PAA ABBREVIATION 23214415 A 96 116 poly(ethylene oxide) SYSTEMATIC 23214415 T 16 19 PEO ABBREVIATION 23214415 T 20 23 PAA ABBREVIATION 23214423 A 1150 1167 graphite fluoride TRIVIAL 23214423 A 131 137 BrF(3) FORMULA 23214423 A 143 148 Br(2) FORMULA 23214423 A 26 34 graphite TRIVIAL 23214423 A 294 299 Br(2) FORMULA 23214423 A 341 349 graphene TRIVIAL 23214423 A 372 377 C(2)F FORMULA 23214423 A 442 450 graphite TRIVIAL 23214423 A 705 722 graphite fluoride TRIVIAL 23214423 A 775 781 carbon SYSTEMATIC 23214423 A 815 823 fluorine SYSTEMATIC 23214423 A 967 972 C(2)F FORMULA 23214423 A 993 1001 fluorine SYSTEMATIC 23214423 T 50 58 graphite TRIVIAL 23214423 T 59 62 C2F FORMULA 23214430 A 815 817 Au FORMULA 23214430 A 935 941 silica TRIVIAL 23214714 A 103 111 pyridine SYSTEMATIC 23214714 A 1193 1199 PyH(0) FORMULA 23214714 A 1309 1318 PyCOOH(0) FORMULA 23214714 A 1341 1347 PyH(0) FORMULA 23214714 A 1393 1399 PyH(0) FORMULA 23214714 A 1403 1408 CO(2) FORMULA 23214714 A 1489 1494 CO(2) FORMULA 23214714 A 1504 1512 Py·CO(2) FORMULA 23214714 A 154 159 CO(2) FORMULA 23214714 A 1596 1604 PyCOO(-) FORMULA 23214714 A 1637 1645 CO(2)(-) FORMULA 23214714 A 1650 1655 Py(-) ABBREVIATION 23214714 A 1706 1711 CO(2) FORMULA 23214714 A 1749 1757 pyridine SYSTEMATIC 23214714 A 1803 1808 CO(2) FORMULA 23214714 A 1854 1863 PyCOOH(0) FORMULA 23214714 A 191 200 PyCOOH(0) FORMULA 23214714 A 1982 1993 formic acid SYSTEMATIC 23214714 A 1998 2010 formaldehyde SYSTEMATIC 23214714 A 2036 2043 CH(3)OH FORMULA 23214714 A 2123 2128 CO(2) FORMULA 23214714 A 2184 2190 PyH(+) FORMULA 23214714 A 2194 2200 PyH(0) FORMULA 23214714 A 237 243 PyH(+) FORMULA 23214714 A 259 265 PyH(0) FORMULA 23214714 A 271 277 PyH(0) FORMULA 23214714 A 291 296 CO(2) FORMULA 23214714 A 358 359 N FORMULA 23214714 A 377 378 C FORMULA 23214714 A 382 387 CO(2) FORMULA 23214714 A 431 437 PyH(0) FORMULA 23214714 A 441 446 CO(2) FORMULA 23214714 A 456 465 PyCOOH(0) FORMULA 23214714 A 578 584 PyH(0) FORMULA 23214714 A 588 593 CO(2) FORMULA 23214714 A 84 89 CO(2) FORMULA 23214714 T 38 41 CO2 FORMULA 23214714 T 45 53 pyridine SYSTEMATIC 23214926 A 152 155 ADP ABBREVIATION 23214926 A 50 56 AMF-26 IDENTIFIER 23214926 A 866 878 Δ¹,²-octalin TRIVIAL 23214926 T 19 25 AMF-26 IDENTIFIER 23214926 T 92 95 ADP ABBREVIATION 23214979 A 241 278 3-amido-5-cyclopropylpyrrolopyrazines SYSTEMATIC 23214979 T 0 23 3-Amido pyrrolopyrazine SYSTEMATIC 23214990 A 147 175 poly(N-isopropyl acrylamide) SYSTEMATIC 23214990 T 96 124 poly(N-isopropyl acrylamide) SYSTEMATIC 23215007 A 1036 1054 methylated uracils FAMILY 23215007 A 121 177 5,6-dimethyl-, 1,3,5-trimethyl-, and 1,3,5,6-tetramethyl MULTIPLE 23215007 A 624 628 N(2) FORMULA 23215007 A 770 788 5,6-dimethyluracil SYSTEMATIC 23215007 A 790 811 1,3,5-trimethyluracil SYSTEMATIC 23215007 A 817 842 1,3,5,6-tetramethyluracil SYSTEMATIC 23215007 T 19 26 uracils FAMILY 23215007 T 86 149 5,6-dimethyl-, 1,3,5-trimethyl-, and 1,3,5,6-tetramethyluracils MULTIPLE 23215148 A 1196 1200 DPPC ABBREVIATION 23215148 A 1201 1205 DPPC ABBREVIATION 23215148 A 1397 1401 DPPC ABBREVIATION 23215148 A 1402 1406 DPPC ABBREVIATION 23215148 A 1548 1552 DPPC ABBREVIATION 23215148 A 1569 1573 DOPC ABBREVIATION 23215148 A 392 432 1,2-dioleoyl-sn-glycero-3-phosphocholine SYSTEMATIC 23215148 A 434 438 DOPC ABBREVIATION 23215148 A 440 483 1,2-dipalmitoyl-sn-glycero-3-phosphocholine SYSTEMATIC 23215148 A 485 489 DPPC ABBREVIATION 23215148 A 512 516 DOPC ABBREVIATION 23215148 A 517 521 DPPC ABBREVIATION 23215148 A 522 564 1,2-dioleoyl-sn-glycero-3-phospho-L-serine SYSTEMATIC 23215148 A 566 570 DOPS ABBREVIATION 23215148 A 596 605 Texas Red TRIVIAL 23215148 A 606 674 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine triethylammonium SYSTEMATIC 23215148 A 681 688 TR-DHPE ABBREVIATION 23215148 A 754 758 DPPC ABBREVIATION 23215148 A 943 947 DOPC ABBREVIATION 23215148 A 948 952 DPPC ABBREVIATION 23215148 A 958 962 DOPC ABBREVIATION 23215148 A 988 992 DPPC ABBREVIATION 23215238 A 124 141 calcium carbonate SYSTEMATIC 23215238 A 404 421 calcium carbonate SYSTEMATIC 23215238 A 507 524 calcium carbonate SYSTEMATIC 23215238 A 548 552 EDTA ABBREVIATION 23215461 A 381 393 carbohydrate FAMILY 23216335 A 555 564 androgens FAMILY 23217961 A 159 167 retinoid FAMILY 23217961 A 209 222 Cinnamic acid TRIVIAL 23217961 A 241 261 phenylpropionic acid SYSTEMATIC 23217961 A 283 291 retinoid FAMILY 23217961 A 442 457 carboxylic acid SYSTEMATIC 23217961 A 488 501 diphenylamine SYSTEMATIC 23217961 A 534 540 methyl SYSTEMATIC 23217961 A 56 68 benzoic acid SYSTEMATIC 23217961 A 575 583 carboxyl SYSTEMATIC 23217961 A 691 695 Am80 IDENTIFIER 23217961 A 77 90 diphenylamine SYSTEMATIC 23217961 A 97 106 retinoids FAMILY 23217961 T 41 53 benzoic acid SYSTEMATIC 23217961 T 62 75 diphenylamine SYSTEMATIC 23217961 T 82 91 retinoids FAMILY 23218712 A 135 142 glucose TRIVIAL 23218712 A 188 194 YH-GKA IDENTIFIER 23218712 A 265 271 YH-GKA IDENTIFIER 23218712 A 287 294 glucose TRIVIAL 23218712 A 484 491 glucose TRIVIAL 23218712 A 548 554 YH-GKA IDENTIFIER 23218712 A 592 599 glucose TRIVIAL 23218712 A 6 15 benzamide SYSTEMATIC 23218712 A 675 681 YH-GKA IDENTIFIER 23218712 T 21 42 phenylethyl benzamide SYSTEMATIC 23218713 A 284 293 bisulfite SYSTEMATIC 23218713 A 359 379 dipeptidyl aldehydes FAMILY 23218713 A 384 396 α-ketoamides FAMILY 23218713 A 608 617 bisulfite SYSTEMATIC 23218713 A 821 830 bisulfite SYSTEMATIC 23218713 A 890 896 serine TRIVIAL 23218713 A 901 909 cysteine TRIVIAL 23218713 A 929 947 α-ketoheterocycles FAMILY 23218713 A 952 964 α-ketoesters FAMILY 23218713 T 40 49 bisulfite SYSTEMATIC 23218716 A 0 16 Tsitsikammamines FAMILY 23218716 A 306 317 Indoleamine SYSTEMATIC 23218716 A 516 531 tsitsikammamine FAMILY 23218716 A 558 575 Tsitsikammamine A TRIVIAL 23218716 A 70 89 pyrroloiminoquinone SYSTEMATIC 23218716 A 747 757 tryptophan TRIVIAL 23218716 T 0 11 Indoleamine SYSTEMATIC 23218716 T 82 99 tsitsikammamine A TRIVIAL 23218717 A 106 135 N-pyridylpyrazolecarboxamides FAMILY 23218717 A 1084 1089 2-APB SYSTEMATIC 23218717 A 1092 1098 Ca(2+) FORMULA 23218717 A 1161 1168 calcium SYSTEMATIC 23218717 A 1247 1254 calcium SYSTEMATIC 23218717 A 147 152 cyano FAMILY 23218717 A 62 71 ryanodine TRIVIAL 23218717 A 669 676 calcium SYSTEMATIC 23218717 A 779 786 calcium SYSTEMATIC 23218717 A 807 813 Ca(2+) FORMULA 23218717 A 908 914 Ca(2+) FORMULA 23218717 A 946 953 calcium SYSTEMATIC 23218717 A 997 1006 fluo-3 AM TRIVIAL 23218717 T 47 76 N-pyridylpyrazolecarboxamides FAMILY 23218717 T 88 93 cyano FAMILY 23219161 A 361 362 N FORMULA 23219161 A 396 397 C FORMULA 23219325 A 0 7 Leucine TRIVIAL 23219325 A 254 278 cinnoline-3-carboxamides FAMILY 23219325 T 6 15 cinnoline TRIVIAL 23219339 A 0 10 Oxymatrine TRIVIAL 23219339 A 1018 1025 calcium SYSTEMATIC 23219339 A 1081 1085 NMDA ABBREVIATION 23219339 A 1087 1090 OMT ABBREVIATION 23219339 A 1180 1184 NMDA ABBREVIATION 23219339 A 12 15 OMT ABBREVIATION 23219339 A 304 307 OMT ABBREVIATION 23219339 A 396 400 NMDA ABBREVIATION 23219339 A 433 436 OMT ABBREVIATION 23219339 A 606 626 N-methyl-D-aspartate SYSTEMATIC 23219339 A 628 632 NMDA ABBREVIATION 23219339 A 719 722 OMT ABBREVIATION 23219339 A 785 789 NMDA ABBREVIATION 23219339 A 836 839 OMT ABBREVIATION 23219339 A 947 950 OMT ABBREVIATION 23219339 T 114 118 NMDA ABBREVIATION 23219339 T 27 37 oxymatrine TRIVIAL 23219469 A 392 403 cholesterol TRIVIAL 23219469 T 71 82 cholesterol TRIVIAL 23219525 A 1007 1015 bosentan TRIVIAL 23219525 A 1020 1031 ambrisentan TRIVIAL 23219525 A 1100 1110 sildenafil TRIVIAL 23219525 A 1114 1123 tadalafil TRIVIAL 23219525 A 122 132 sildenafil TRIVIAL 23219525 A 136 145 tadalafil TRIVIAL 23219525 A 1400 1409 tadalafil TRIVIAL 23219525 A 1423 1434 ambrisentan TRIVIAL 23219525 A 1447 1457 sildenafil TRIVIAL 23219525 A 1474 1482 pregnane TRIVIAL 23219525 A 1547 1557 sildenafil TRIVIAL 23219525 A 1562 1571 tadalafil TRIVIAL 23219525 A 1618 1626 bosentan TRIVIAL 23219525 A 1631 1642 ambrisentan TRIVIAL 23219525 A 290 298 bosentan TRIVIAL 23219525 A 319 329 sildenafil TRIVIAL 23219525 A 495 505 sildenafil TRIVIAL 23219525 A 510 519 tadalafil TRIVIAL 23219525 A 575 583 bosentan TRIVIAL 23219525 A 58 66 bosentan TRIVIAL 23219525 A 587 598 ambrisentan TRIVIAL 23219525 A 671 679 bosentan TRIVIAL 23219525 A 684 695 ambrisentan TRIVIAL 23219525 A 70 81 ambrisentan TRIVIAL 23219525 A 845 855 sildenafil TRIVIAL 23219525 A 859 868 tadalafil TRIVIAL 23219525 T 102 113 ambrisentan TRIVIAL 23219525 T 13 23 sildenafil TRIVIAL 23219525 T 89 97 bosentan TRIVIAL 23219590 A 1065 1076 Maprotiline TRIVIAL 23219590 A 1130 1136 Ca(2+) FORMULA 23219590 A 224 235 Maprotiline TRIVIAL 23219590 A 301 315 norepinephrine TRIVIAL 23219590 A 348 359 maprotiline TRIVIAL 23219590 A 450 461 Maprotiline TRIVIAL 23219590 A 547 558 maprotiline TRIVIAL 23219590 A 631 642 Maprotiline TRIVIAL 23219590 A 657 663 Ca(2+) FORMULA 23219590 A 727 733 Ca(2+) FORMULA 23219590 A 789 794 BAPTA ABBREVIATION 23219590 A 801 807 Ca(2+) FORMULA 23219590 A 829 840 maprotiline TRIVIAL 23219590 A 914 925 maprotiline TRIVIAL 23219590 A 960 971 maprotiline TRIVIAL 23219590 T 13 24 maprotiline TRIVIAL 23219590 T 53 57 Ca2+ FORMULA 23219658 A 185 205 N-methyl-d-Aspartate SYSTEMATIC 23219658 A 207 211 NMDA ABBREVIATION 23219658 A 408 412 NMDA ABBREVIATION 23219658 T 101 110 glutamate TRIVIAL 23219658 T 80 100 N-methyl-d-aspartate SYSTEMATIC 23219696 A 1017 1025 steroids FAMILY 23219696 A 1348 1356 steroids FAMILY 23219696 A 1491 1500 estradiol TRIVIAL 23219696 A 1660 1669 estradiol TRIVIAL 23219696 A 1847 1855 steroids FAMILY 23219696 A 412 420 steroids FAMILY 23219696 A 485 493 steroids FAMILY 23219696 A 512 520 steroids FAMILY 23219696 A 55 63 steroids FAMILY 23219696 A 573 584 Bisphenol-A TRIVIAL 23219696 A 586 597 nonylphenol SYSTEMATIC 23219696 A 70 82 testosterone TRIVIAL 23219696 A 755 762 steroid FAMILY 23219696 A 84 93 estradiol TRIVIAL 23219696 A 95 107 progesterone TRIVIAL 23219696 T 107 115 steroids FAMILY 23219696 T 31 39 steroids FAMILY 23219778 A 1080 1084 MeOH FORMULA 23219778 A 738 746 methanol SYSTEMATIC 23219778 A 748 752 MeOH FORMULA 23219778 A 884 888 MeOH FORMULA 23219778 A 964 976 nitric oxide SYSTEMATIC 23219979 A 25 49 sciryagarol I (1) and II MULTIPLE 23219979 A 77 82 EtOAc FORMULA 23219979 A 8 23 cis-stilbenoids FAMILY 23219979 T 10 25 cis-stilbenoids FAMILY 23220002 A 1430 1437 glucose TRIVIAL 23220002 A 171 187 organophosphorus FAMILY 23220002 A 193 199 esters FAMILY 23220003 A 1005 1016 gallic acid TRIVIAL 23220003 A 1018 1032 methyl gallate SYSTEMATIC 23220003 A 1034 1047 ethyl gallate SYSTEMATIC 23220003 A 1049 1063 propyl gallate SYSTEMATIC 23220003 A 1065 1070 rutin TRIVIAL 23220003 A 1075 1083 curcumin TRIVIAL 23220003 A 1089 1100 polyphenols FAMILY 23220003 A 1132 1135 GSH ABBREVIATION 23220003 A 1162 1173 polyphenols FAMILY 23220003 A 124 131 glyoxal TRIVIAL 23220003 A 1335 1346 polyphenols FAMILY 23220003 A 1357 1362 rutin TRIVIAL 23220003 A 136 149 methylglyoxal SYSTEMATIC 23220003 A 1427 1432 rutin TRIVIAL 23220003 A 1467 1473 oxygen SYSTEMATIC 23220003 A 1504 1509 rutin TRIVIAL 23220003 A 151 159 Fructose TRIVIAL 23220003 A 1533 1538 alkyl FAMILY 23220003 A 1561 1568 gallate TRIVIAL 23220003 A 1607 1617 polyphenol FAMILY 23220003 A 1636 1644 gallates FAMILY 23220003 A 1657 1662 alkyl FAMILY 23220003 A 1706 1712 oxygen SYSTEMATIC 23220003 A 173 186 glycoaldehyde SYSTEMATIC 23220003 A 188 202 glyceraldehyde TRIVIAL 23220003 A 207 222 hydroxypyruvate SYSTEMATIC 23220003 A 289 297 fructose TRIVIAL 23220003 A 415 423 fructose TRIVIAL 23220003 A 43 51 fructose TRIVIAL 23220003 A 459 469 dicarbonyl SYSTEMATIC 23220003 A 559 575 dihydroxyacetone SYSTEMATIC 23220003 A 579 587 fructose TRIVIAL 23220003 A 653 664 dicarbonyls FAMILY 23220003 A 768 779 polyphenols FAMILY 23220003 A 829 836 glyoxal TRIVIAL 23220003 A 842 855 methylglyoxal SYSTEMATIC 23220003 A 887 893 oxygen SYSTEMATIC 23220003 A 975 986 polyphenols FAMILY 23220003 T 0 7 Glyoxal TRIVIAL 23220003 T 12 25 methylglyoxal SYSTEMATIC 23220003 T 45 61 dihydroxyacetone SYSTEMATIC 23220003 T 66 76 polyphenol FAMILY 23220004 A 1019 1026 retinol TRIVIAL 23220004 A 1031 1044 retinaldehyde TRIVIAL 23220004 A 1063 1071 retinoid FAMILY 23220004 A 1313 1321 4-methyl SYSTEMATIC 23220004 A 1337 1350 retinaldehyde TRIVIAL 23220004 A 1577 1586 retinoids FAMILY 23220004 A 1609 1622 retinoic acid TRIVIAL 23220004 A 1643 1651 retinoid FAMILY 23220004 A 1721 1734 retinaldehyde TRIVIAL 23220004 A 1788 1797 retinoids FAMILY 23220004 A 1829 1836 UVI2008 IDENTIFIER 23220004 A 1941 1949 carboxyl SYSTEMATIC 23220004 A 227 234 retinol TRIVIAL 23220004 A 238 251 retinaldehyde TRIVIAL 23220004 A 303 310 retinol TRIVIAL 23220004 A 31 40 retinoids FAMILY 23220004 A 325 328 NAD ABBREVIATION 23220004 A 458 471 Retinaldehyde TRIVIAL 23220004 A 582 590 aldehyde SYSTEMATIC 23220004 A 67 74 retinol TRIVIAL 23220004 A 724 732 retinoid FAMILY 23220004 A 742 750 retinoid FAMILY 23220004 A 769 776 retinol TRIVIAL 23220004 A 78 91 retinoic acid TRIVIAL 23220004 A 850 858 retinoid FAMILY 23220004 T 24 32 retinoid FAMILY 23220291 A 251 259 limonene TRIVIAL 23220291 A 264 269 ozone TRIVIAL 23220291 A 571 579 limonene TRIVIAL 23220291 A 584 589 ozone TRIVIAL 23220291 A 750 758 limonene TRIVIAL 23220291 A 759 764 ozone TRIVIAL 23220291 A 835 843 limonene TRIVIAL 23220291 A 878 886 limonene TRIVIAL 23220291 A 890 898 limonene TRIVIAL 23220291 A 899 904 ozone TRIVIAL 23220291 T 26 34 limonene TRIVIAL 23220293 A 1032 1041 serotonin TRIVIAL 23220293 A 1046 1060 norepinephrine TRIVIAL 23220293 A 1166 1170 5-HT SYSTEMATIC 23220293 A 1210 1214 5-HT SYSTEMATIC 23220293 A 1510 1520 citalopram TRIVIAL 23220293 A 1553 1564 desipramine TRIVIAL 23220293 A 1727 1736 serotonin TRIVIAL 23220293 A 1740 1753 catecholamine TRIVIAL 23220293 A 187 196 monoamine FAMILY 23220293 A 378 387 serotonin TRIVIAL 23220293 A 392 400 dopamine TRIVIAL 23220293 A 501 510 serotonin TRIVIAL 23220293 A 590 599 serotonin TRIVIAL 23220293 A 619 629 citalopram TRIVIAL 23220293 A 668 677 serotonin TRIVIAL 23220293 A 814 818 5-HT SYSTEMATIC 23220293 A 871 881 citalopram TRIVIAL 23220293 A 980 990 citalopram TRIVIAL 23220293 T 6 16 monoamines FAMILY 23220295 A 1028 1036 dopamine TRIVIAL 23220295 A 1117 1128 amphetamine TRIVIAL 23220295 A 1178 1189 amphetamine TRIVIAL 23220295 A 1198 1206 dopamine TRIVIAL 23220295 A 1279 1290 amphetamine TRIVIAL 23220295 A 1308 1316 dopamine TRIVIAL 23220295 A 1371 1379 dopamine TRIVIAL 23220295 A 1402 1413 amphetamine TRIVIAL 23220295 A 1555 1566 amphetamine TRIVIAL 23220295 A 1622 1630 dopamine TRIVIAL 23220295 A 1755 1766 amphetamine TRIVIAL 23220295 A 1798 1809 amphetamine TRIVIAL 23220295 A 1843 1851 dopamine TRIVIAL 23220295 A 1973 1981 dopamine TRIVIAL 23220295 A 283 291 dopamine TRIVIAL 23220295 A 32 40 dopamine TRIVIAL 23220295 A 348 356 dopamine TRIVIAL 23220295 A 391 399 dopamine TRIVIAL 23220295 A 424 435 amphetamine TRIVIAL 23220295 A 451 462 amphetamine TRIVIAL 23220295 A 511 522 amphetamine TRIVIAL 23220295 A 567 578 amphetamine TRIVIAL 23220295 A 601 609 dopamine TRIVIAL 23220295 A 716 724 dopamine TRIVIAL 23220295 A 909 920 amphetamine TRIVIAL 23220295 A 973 984 amphetamine TRIVIAL 23220295 T 45 56 amphetamine TRIVIAL 23220295 T 96 104 dopamine TRIVIAL 23220412 A 0 11 Metolachlor TRIVIAL 23220412 A 1008 1019 metolachlor TRIVIAL 23220412 A 1125 1136 metolachlor TRIVIAL 23220412 A 1468 1479 glutathione TRIVIAL 23220412 A 15 32 chloroacetanilide SYSTEMATIC 23220412 A 1517 1530 chlorophyll a TRIVIAL 23220412 A 1552 1563 metolachlor TRIVIAL 23220412 A 1646 1657 metolachlor TRIVIAL 23220412 A 1858 1869 metolachlor TRIVIAL 23220412 A 303 314 metolachlor TRIVIAL 23220412 A 412 433 chlorophyll a, b or c MULTIPLE 23220412 A 613 624 metolachlor TRIVIAL 23220412 A 685 696 glutathione TRIVIAL 23220412 A 712 723 metolachlor TRIVIAL 23220412 A 755 766 metolachlor TRIVIAL 23220412 T 64 75 metolachlor TRIVIAL 23220413 A 0 37 Tris(1,3-dichloro-2-propyl) phosphate SYSTEMATIC 23220413 A 1227 1232 TDCPP ABBREVIATION 23220413 A 1531 1536 TDCPP ABBREVIATION 23220413 A 1801 1806 TDCPP ABBREVIATION 23220413 A 301 306 TDCPP ABBREVIATION 23220413 A 39 44 TDCPP ABBREVIATION 23220413 A 583 588 TDCPP ABBREVIATION 23220413 A 810 836 3,3',5-triiodo-l-thyronine SYSTEMATIC 23220413 A 877 890 thyroxin (T4) TRIVIAL 23220413 T 40 45 TDCPP ABBREVIATION 23220513 A 0 13 Methyleugenol TRIVIAL 23220513 A 1249 1252 MEG ABBREVIATION 23220513 A 15 18 MEG ABBREVIATION 23220513 A 199 202 MEG ABBREVIATION 23220513 A 326 339 phenobarbital TRIVIAL 23220513 A 488 493 (32)P FORMULA 23220513 A 560 563 MEG ABBREVIATION 23220513 A 711 714 MEG ABBREVIATION 23220513 A 764 775 glutathione TRIVIAL 23220513 A 776 777 S FORMULA 23220513 A 911 914 MEG ABBREVIATION 23220513 T 0 13 Methyleugenol TRIVIAL 23220514 A 1010 1013 DOX ABBREVIATION 23220514 A 1061 1064 DOX ABBREVIATION 23220514 A 1097 1102 Na(+) FORMULA 23220514 A 1113 1123 nucleoside FAMILY 23220514 A 1155 1158 DOX ABBREVIATION 23220514 A 1232 1235 DOX ABBREVIATION 23220514 A 1248 1256 linalool TRIVIAL 23220514 A 1311 1314 DOX ABBREVIATION 23220514 A 278 289 doxorubicin TRIVIAL 23220514 A 291 294 DOX ABBREVIATION 23220514 A 328 331 DOX ABBREVIATION 23220514 A 384 387 DOX ABBREVIATION 23220514 A 422 430 linalool TRIVIAL 23220514 A 479 482 DOX ABBREVIATION 23220514 A 526 534 linalool TRIVIAL 23220514 A 538 541 DOX ABBREVIATION 23220514 A 594 597 DOX ABBREVIATION 23220514 A 603 611 linalool TRIVIAL 23220514 A 671 674 DOX ABBREVIATION 23220514 A 713 716 DOX ABBREVIATION 23220514 A 742 750 linalool TRIVIAL 23220514 A 821 826 Na(+) FORMULA 23220514 A 884 915 S-(4-nitrobenzyl)-6-thioinosine SYSTEMATIC 23220514 A 945 954 phlorizin TRIVIAL 23220514 A 992 1000 linalool TRIVIAL 23220514 T 10 18 linalool TRIVIAL 23220514 T 56 67 doxorubicin TRIVIAL 23220560 A 1066 1070 MeHg FORMULA 23220560 A 1096 1100 MeHg FORMULA 23220560 A 1208 1212 MeHg FORMULA 23220560 A 1395 1399 MeHg FORMULA 23220560 A 1658 1662 MeHg FORMULA 23220560 A 242 246 MeHg FORMULA 23220560 A 48 52 MeHg FORMULA 23220560 A 507 511 MeHg FORMULA 23220560 A 753 757 MeHg FORMULA 23220560 T 31 44 methylmercury SYSTEMATIC 23220562 A 1089 1100 clopidogrel TRIVIAL 23220562 A 1371 1380 SB-203580 IDENTIFIER 23220562 A 1427 1433 U-0126 IDENTIFIER 23220562 A 1456 1465 SP-600125 IDENTIFIER 23220562 A 1501 1512 clopidogrel TRIVIAL 23220562 A 1736 1747 clopidogrel TRIVIAL 23220562 A 221 232 clopidogrel TRIVIAL 23220562 A 413 424 clopidogrel TRIVIAL 23220562 A 478 481 MTT ABBREVIATION 23220562 A 517 521 DAPI ABBREVIATION 23220562 A 83 94 clopidogrel TRIVIAL 23220562 T 68 79 clopidogrel TRIVIAL 23220586 A 1026 1029 PEG ABBREVIATION 23220586 A 1045 1048 PEG ABBREVIATION 23220586 A 1156 1159 PEG ABBREVIATION 23220586 A 132 148 organophosphorus FAMILY 23220586 A 389 394 soman TRIVIAL 23220586 A 565 584 polyethylene glycol SYSTEMATIC 23220586 A 586 589 PEG ABBREVIATION 23220586 A 702 705 PEG ABBREVIATION 23220586 A 712 715 PEG ABBREVIATION 23220586 T 10 29 polyethylene glycol SYSTEMATIC 23220588 A 0 16 Cyclophosphamide TRIVIAL 23220588 A 1065 1073 Acrolein TRIVIAL 23220588 A 1135 1143 acrolein TRIVIAL 23220588 A 1229 1232 CAA ABBREVIATION 23220588 A 1332 1340 Aldehyde SYSTEMATIC 23220588 A 1409 1412 CAA ABBREVIATION 23220588 A 1506 1515 cyanamide SYSTEMATIC 23220588 A 1626 1634 acrolein TRIVIAL 23220588 A 1726 1734 acrolein TRIVIAL 23220588 A 1738 1741 CAA ABBREVIATION 23220588 A 184 192 acrolein TRIVIAL 23220588 A 1858 1876 sodium borohydride SYSTEMATIC 23220588 A 1878 1894 sodium bisulfite SYSTEMATIC 23220588 A 1896 1901 thiol FAMILY 23220588 A 1924 1940 N-acetylcysteine SYSTEMATIC 23220588 A 1942 1950 cysteine TRIVIAL 23220588 A 1952 1963 glutathione TRIVIAL 23220588 A 1965 1991 2-mercaptoethane sulfonate SYSTEMATIC 23220588 A 197 215 chloroacetaldehyde SYSTEMATIC 23220588 A 1993 1998 MESNA ABBREVIATION 23220588 A 2001 2014 penicillamine TRIVIAL 23220588 A 2016 2024 carbonyl FAMILY 23220588 A 2036 2042 amines FAMILY 23220588 A 2044 2058 aminoguanidine SYSTEMATIC 23220588 A 2060 2071 hydralazine SYSTEMATIC 23220588 A 2073 2086 hydroxylamine SYSTEMATIC 23220588 A 21 31 ifosfamide TRIVIAL 23220588 A 2117 2130 ascorbic acid TRIVIAL 23220588 A 2132 2138 Trolox TRIVIAL 23220588 A 217 220 CAA ABBREVIATION 23220588 A 2197 2205 acrolein TRIVIAL 23220588 A 2210 2213 CAA ABBREVIATION 23220588 A 223 231 Acrolein TRIVIAL 23220588 A 236 239 CAA ABBREVIATION 23220588 A 2401 2409 acrolein TRIVIAL 23220588 A 2413 2416 CAA ABBREVIATION 23220588 A 2420 2436 cyclophosphamide TRIVIAL 23220588 A 2440 2450 ifosfamide TRIVIAL 23220588 A 529 537 acrolein TRIVIAL 23220588 A 542 545 CAA ABBREVIATION 23220588 A 651 662 Trypan blue TRIVIAL 23220588 A 693 699 oxygen SYSTEMATIC 23220588 A 729 733 H2O2 FORMULA 23220588 A 936 944 acrolein TRIVIAL 23220588 A 974 977 CAA ABBREVIATION 23220588 T 0 8 Acrolein TRIVIAL 23220588 T 13 31 chloroacetaldehyde SYSTEMATIC 23220589 A 0 16 Organophosphorus FAMILY 23220589 A 1028 1038 dichlorvos TRIVIAL 23220589 A 1040 1048 paraoxon TRIVIAL 23220589 A 1053 1058 tabun TRIVIAL 23220589 A 1105 1113 paraoxon TRIVIAL 23220589 A 1148 1156 BT-07-4M NO CLASS 23220589 A 1158 1167 obidoxime TRIVIAL 23220589 A 1169 1174 TMB-4 IDENTIFIER 23220589 A 1179 1184 BT-08 NO CLASS 23220589 A 1213 1219 oximes FAMILY 23220589 A 1225 1232 Toxidin NO CLASS 23220589 A 1234 1239 BT-05 NO CLASS 23220589 A 1244 1249 BT-03 NO CLASS 23220589 A 1374 1382 BT-07-4M NO CLASS 23220589 A 1384 1389 TMB-4 IDENTIFIER 23220589 A 1394 1403 obidoxime TRIVIAL 23220589 A 1419 1425 oximes FAMILY 23220589 A 1431 1436 BT-05 NO CLASS 23220589 A 1441 1446 BT-03 NO CLASS 23220589 A 1550 1560 dichlorvos TRIVIAL 23220589 A 714 719 tabun TRIVIAL 23220589 A 721 729 paraoxon TRIVIAL 23220589 A 734 744 dichlorvos TRIVIAL 23220589 A 838 844 oximes FAMILY 23220589 A 846 855 obidoxime TRIVIAL 23220589 A 857 861 HI-6 IDENTIFIER 23220589 A 863 868 2-PAM SYSTEMATIC 23220612 A 1030 1038 H(2)O(2) FORMULA 23220612 A 1107 1119 Arachidonate TRIVIAL 23220612 A 1121 1137 docosahexaenoate SYSTEMATIC 23220612 A 1139 1156 eicosapentaenoate SYSTEMATIC 23220612 A 1161 1172 cholesterol TRIVIAL 23220612 A 1208 1216 H(2)O(2) FORMULA 23220612 A 1246 1258 isoprostanes FAMILY 23220612 A 1260 1274 neuroprostanes FAMILY 23220612 A 1275 1284 5(S)-HETE SYSTEMATIC 23220612 A 1286 1293 20-HETE SYSTEMATIC 23220612 A 1295 1312 7-ketocholesterol SYSTEMATIC 23220612 A 1314 1335 27-hydroxycholesterol SYSTEMATIC 23220612 A 1340 1351 resolvin D1 TRIVIAL 23220612 A 1452 1464 isoprostanes FAMILY 23220612 A 289 316 polyunsaturated fatty acids FAMILY 23220612 A 321 332 cholesterol TRIVIAL 23220612 A 365 373 H(2)O(2) FORMULA 23220612 A 41 47 oxygen SYSTEMATIC 23220612 A 456 468 isoprostanes FAMILY 23220612 A 491 503 isoprostanes FAMILY 23220612 A 505 519 neuroprostanes FAMILY 23220612 A 521 538 7-ketocholesterol SYSTEMATIC 23220612 A 540 561 7β-hydroxycholesterol SYSTEMATIC 23220612 A 589 624 5(S)-, 8(S)-, 12(S)- and 15(S)-HETE MULTIPLE 23220612 A 630 641 resolvin D1 TRIVIAL 23220612 A 667 692 9(S)-, 11(S)- and 20-HETE MULTIPLE 23220612 A 698 718 27-hydroxycholestrol SYSTEMATIC 23220612 A 765 777 Arachidonate TRIVIAL 23220612 A 779 795 docosahexaenoate SYSTEMATIC 23220612 A 797 814 eicosapentaenoate SYSTEMATIC 23220612 A 819 830 cholesterol TRIVIAL 23220612 A 891 903 gluthathione TRIVIAL 23220617 A 2183 2194 doxorubicin TRIVIAL 23220617 A 2199 2215 cyclophosphamide TRIVIAL 23220617 A 359 367 carbonyl FAMILY 23220617 A 379 394 3-nitrotyrosine SYSTEMATIC 23220617 A 705 716 doxorubicin TRIVIAL 23220617 A 721 737 cyclophosphamide TRIVIAL 23220635 A 4 20 aryl hydrocarbon FAMILY 23220644 A 120 136 arachidonic acid TRIVIAL 23220644 A 327 334 JMC08-4 IDENTIFIER 23220644 A 498 505 JMC08-4 IDENTIFIER 23220644 A 607 626 5-hydroxytryptamine SYSTEMATIC 23220644 A 742 749 JMC08-4 IDENTIFIER 23220644 T 16 36 5-hydroxytryptamines FAMILY 23220646 A 130 151 isoxazolecarbaldehyde SYSTEMATIC 23220646 A 260 273 benzimidazole SYSTEMATIC 23220646 A 275 288 benzothiazole SYSTEMATIC 23220646 A 290 301 3H-indazole SYSTEMATIC 23220646 A 307 327 5-phenyl-1H-pyrazole SYSTEMATIC 23220646 A 652 656 TLCK ABBREVIATION 23220646 T 30 47 benzoheterocyclic FAMILY 23221006 A 0 10 Phenformin TRIVIAL 23221006 A 1003 1009 oxygen SYSTEMATIC 23221006 A 1157 1167 phenformin TRIVIAL 23221006 A 1337 1347 phenformin TRIVIAL 23221006 A 1449 1459 phenformin TRIVIAL 23221006 A 237 247 phenformin TRIVIAL 23221006 A 252 277 [(14)C]tetraethylammonium SYSTEMATIC 23221006 A 279 282 TEA ABBREVIATION 23221006 A 312 322 phenformin TRIVIAL 23221006 A 389 399 phenformin TRIVIAL 23221006 A 658 661 TEA ABBREVIATION 23221006 A 682 692 phenformin TRIVIAL 23221006 A 729 738 carnitine TRIVIAL 23221006 A 832 835 TEA ABBREVIATION 23221006 A 989 999 phenformin TRIVIAL 23221006 T 23 32 carnitine TRIVIAL 23221006 T 60 70 phenformin TRIVIAL 23221633 A 456 463 phospho SYSTEMATIC 23221633 A 87 93 oxygen SYSTEMATIC 23222689 A 192 205 valproic acid TRIVIAL 23222689 A 277 290 valproic acid TRIVIAL 23222689 A 95 108 valproic acid TRIVIAL 23222689 T 11 24 valproic acid TRIVIAL 23223023 A 44 55 fatty acids FAMILY 23223023 A 72 85 palmitic acid TRIVIAL 23223023 A 884 906 oleic and stearic acid MULTIPLE 23223023 T 12 25 palmitic acid TRIVIAL 23223234 A 605 616 6-azauracil SYSTEMATIC 23223234 A 73 83 nucleotide FAMILY 23223345 A 1062 1069 glucose TRIVIAL 23223345 A 1350 1354 CARB ABBREVIATION 23223345 A 1417 1421 CARB ABBREVIATION 23223345 A 1466 1478 carbohydrate FAMILY 23223345 A 331 343 carbohydrate FAMILY 23223345 A 355 359 CARB ABBREVIATION 23223345 T 15 27 Carbohydrate FAMILY 23223551 A 1166 1172 oxygen SYSTEMATIC 23223551 A 18 25 methane SYSTEMATIC 23223551 A 240 243 C-H FORMULA 23223551 A 327 330 C-H FORMULA 23223551 A 340 347 methane SYSTEMATIC 23223551 A 358 370 hydrocarbons FAMILY 23223551 A 384 400 transition metal FAMILY 23223551 A 471 477 CuO(+) FORMULA 23223551 A 482 489 CuOH(+) FORMULA 23223551 T 54 61 methane SYSTEMATIC 23223551 T 65 77 copper oxide SYSTEMATIC 23223551 T 82 98 copper hydroxide SYSTEMATIC 23223639 A 325 345 polydimethylsiloxane SYSTEMATIC 23223641 A 103 110 zeolite TRIVIAL 23223641 A 266 274 zeolites FAMILY 23223641 A 893 901 zeolites FAMILY 23223641 T 39 46 zeolite TRIVIAL 23223708 A 0 23 Polyvinylidene fluoride SYSTEMATIC 23223708 A 159 163 PVDF ABBREVIATION 23223708 A 25 29 PVDF ABBREVIATION 23223708 A 304 312 vanadium SYSTEMATIC 23223708 A 618 622 PVDF ABBREVIATION 23223708 A 755 761 Nafion TRIVIAL 23223708 A 97 105 vanadium SYSTEMATIC 23223708 T 39 43 PVDF ABBREVIATION 23223801 A 0 20 Trivalent lanthanide FAMILY 23223801 A 22 28 Ln(3+) FORMULA 23223801 A 402 408 Ln(3+) FORMULA 23223801 T 0 10 Lanthanide FAMILY 23223857 A 0 6 Carbon SYSTEMATIC 23223857 T 18 24 carbon SYSTEMATIC 23224291 A 1034 1056 adenosine triphosphate SYSTEMATIC 23224291 A 1092 1103 glutathione TRIVIAL 23224291 A 1104 1105 S FORMULA 23224291 A 1291 1298 glycine TRIVIAL 23224291 A 780 784 (1)H FORMULA 23224291 A 968 975 glucose TRIVIAL 23224291 A 998 1010 thiosulphate SYSTEMATIC 23224775 A 432 461 carboxyl- and hydroxyl oxygen MULTIPLE 23224775 A 471 477 Ti(IV) FORMULA 23224775 A 500 506 TiO(2) FORMULA 23224775 A 596 604 carboxyl SYSTEMATIC 23224775 A 625 631 Ti(IV) FORMULA 23224775 A 860 866 TiO(2) FORMULA 23224942 A 222 230 graphene TRIVIAL 23224942 A 236 241 epoxy SYSTEMATIC 23224942 A 39 53 graphene oxide SYSTEMATIC 23224942 A 664 672 graphene TRIVIAL 23224942 A 77 91 graphene oxide SYSTEMATIC 23224942 T 55 75 epoxy graphene oxide SYSTEMATIC 23225075 A 585 594 manganese SYSTEMATIC 23225075 A 596 605 aluminium SYSTEMATIC 23225075 A 607 614 cadmium SYSTEMATIC 23225075 A 616 622 cobalt SYSTEMATIC 23225075 A 624 630 copper SYSTEMATIC 23225075 A 632 636 zinc SYSTEMATIC 23225075 A 644 652 vanadium SYSTEMATIC 23225075 A 657 664 uranium SYSTEMATIC 23225241 A 1113 1124 cholesterol TRIVIAL 23225241 A 112 127 triacylglycerol FAMILY 23225241 A 1149 1162 biliary acids FAMILY 23225241 A 129 132 TAG ABBREVIATION 23225241 A 1319 1322 TAG ABBREVIATION 23225241 A 138 149 cholesterol TRIVIAL 23225241 A 1505 1516 cholesterol TRIVIAL 23225241 A 41 50 estrogens FAMILY 23225241 A 442 445 TAG ABBREVIATION 23225241 A 591 594 TAG ABBREVIATION 23225241 A 909 920 cholesterol TRIVIAL 23225241 A 992 1003 cholesterol TRIVIAL 23225241 T 39 50 Cholesterol TRIVIAL 23225365 A 1032 1035 MTT ABBREVIATION 23225365 A 1222 1233 resveratrol TRIVIAL 23225365 A 211 222 resveratrol TRIVIAL 23225365 A 477 488 resveratrol TRIVIAL 23225365 A 65 76 resveratrol TRIVIAL 23225365 A 764 775 Resveratrol TRIVIAL 23225365 A 795 797 NO FORMULA 23225365 A 837 839 NO FORMULA 23225365 A 863 883 sodium nitroprusside SYSTEMATIC 23225365 A 926 937 resveratrol TRIVIAL 23225365 T 37 48 resveratrol TRIVIAL 23225366 A 11 27 9,19-cycloartane SYSTEMATIC 23225366 A 28 39 triterpenes FAMILY 23225366 A 366 375 cimigenol TRIVIAL 23225366 A 518 527 cimigenol TRIVIAL 23225366 A 736 745 cimigenol TRIVIAL 23225366 T 10 21 cycloartane TRIVIAL 23225366 T 22 33 triterpenes FAMILY 23225536 A 1018 1022 PAHs ABBREVIATION 23225536 A 1208 1211 GSH ABBREVIATION 23225536 A 204 236 polycyclic aromatic hydrocarbons FAMILY 23225536 A 238 242 PAHs ABBREVIATION 23225536 A 364 368 PAHs ABBREVIATION 23225536 A 369 381 phenanthrene SYSTEMATIC 23225536 A 383 391 fluorene SYSTEMATIC 23225536 A 393 405 fluoranthene SYSTEMATIC 23225536 A 407 413 pyrene SYSTEMATIC 23225536 A 419 433 benzo[a]pyrene SYSTEMATIC 23225536 A 499 505 Cd(2+) FORMULA 23225536 A 528 534 Cu(2+) FORMULA 23225536 A 557 563 Zn(2+) FORMULA 23225536 A 591 597 Ni(2+) FORMULA 23225536 A 645 658 chlorophyll a TRIVIAL 23225536 A 728 732 PAHs ABBREVIATION 23225536 A 855 866 glutathione TRIVIAL 23225536 A 868 871 GSH ABBREVIATION 23225536 A 895 905 superoxide TRIVIAL 23225536 A 967 971 PAHs ABBREVIATION 23225536 T 21 53 polycyclic aromatic hydrocarbons FAMILY 23225542 A 1156 1159 ICG ABBREVIATION 23225542 A 1339 1342 ICG ABBREVIATION 23225542 A 249 266 indocyanine green TRIVIAL 23225542 A 268 271 ICG ABBREVIATION 23225542 A 435 444 Fe(3)O(4) FORMULA 23225542 A 646 676 poly(allylamine hydrochloride) SYSTEMATIC 23225542 A 678 681 PAH ABBREVIATION 23225542 T 35 40 Fe3O4 FORMULA 23225638 A 1002 1038 1-anilinonaphthalene-8-sulfonic acid SYSTEMATIC 23225638 A 140 163 2-azido-1,3-propanediol SYSTEMATIC 23225638 A 165 179 azido glycerol SYSTEMATIC 23225638 A 185 204 polyethylene glycol SYSTEMATIC 23225638 A 206 209 PEG ABBREVIATION 23225638 A 215 227 diethylester SYSTEMATIC 23225638 A 390 403 polyglycerols FAMILY 23225638 A 420 429 octadecyl SYSTEMATIC 23225638 A 991 997 pyrene SYSTEMATIC 23225671 A 149 155 purine TRIVIAL 23225671 A 156 162 purine TRIVIAL 23225671 A 74 87 nucleic acids FAMILY 23225764 A 100 109 L-lysines FAMILY 23225764 A 58 77 poly(methacrylate)s FAMILY 23225764 T 54 73 poly(methacrylate)s FAMILY 23225764 T 96 105 L-lysines FAMILY 23225770 A 244 251 genipin TRIVIAL 23225770 T 86 93 genipin TRIVIAL 23225780 A 24 44 N-Cyano sulfoximines FAMILY 23225780 T 0 20 N-cyano sulfoximines FAMILY 23227887 A 1392 1395 FDV ABBREVIATION 23227887 A 1618 1621 FDV ABBREVIATION 23227887 A 322 325 FDV ABBREVIATION 23227887 A 38 49 Fosdevirine TRIVIAL 23227887 A 458 461 FDV ABBREVIATION 23227887 A 51 54 FDV ABBREVIATION 23227887 A 68 78 nucleoside FAMILY 23227887 A 736 739 FDV ABBREVIATION 23227887 A 809 817 cysteine TRIVIAL 23227887 A 865 876 glutathione TRIVIAL 23227887 A 878 881 GSH ABBREVIATION 23227887 A 907 933 trans-phenyl acrylonitrile SYSTEMATIC 23227887 A 944 947 FDV ABBREVIATION 23227887 T 53 64 Fosdevirine TRIVIAL 23227887 T 66 76 GSK2248761 IDENTIFIER 23227887 T 85 95 nucleoside FAMILY 23228028 A 1296 1305 In(2)O(3) FORMULA 23228028 A 17 26 In(2)O(3) FORMULA 23228028 A 199 208 In(2)O(3) FORMULA 23228028 A 397 406 In(2)O(3) FORMULA 23228028 A 479 481 Mg FORMULA 23228028 A 483 485 Al FORMULA 23228028 A 491 493 Ga FORMULA 23228028 A 616 618 Mg FORMULA 23228028 A 620 622 Ga FORMULA 23228028 A 628 630 Al FORMULA 23228028 A 960 962 Mg FORMULA 23228028 A 969 978 In(2)O(3) FORMULA 23228028 T 50 55 In2O3 FORMULA 23228193 A 33 45 denbinobin B TRIVIAL 23228193 A 6 25 phenanthrenequinone SYSTEMATIC 23228193 A 77 90 phenanthrenes FAMILY 23228193 T 20 39 phenanthrenequinone SYSTEMATIC 23228469 A 18 120 3,5-bis(4-chlorobenzylidene)-1-[4-{2-(4-morpholinyl)ethoxy}phenyl-carbonyl]-4-piperidone hydrochloride SYSTEMATIC 23228469 A 358 369 glutathione TRIVIAL 23228471 A 151 160 chalcones FAMILY 23228471 A 162 179 thiosemicarbazide SYSTEMATIC 23228471 A 18 80 2-(3,5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-phenylthiazoles FAMILY 23228471 A 184 200 phenacyl bromide FAMILY 23228471 A 379 382 HCl FORMULA 23228471 A 386 390 EtOH FORMULA 23228471 T 51 71 thiazolyl-pyrazoline FAMILY 23228475 A 0 10 Cyprodinil TRIVIAL 23228475 A 1038 1048 Cyprodinil TRIVIAL 23228475 A 1058 1071 dexamethasone TRIVIAL 23228475 A 1165 1178 dexamethasone TRIVIAL 23228475 A 1340 1343 BaP ABBREVIATION 23228475 A 1345 1349 TCDD ABBREVIATION 23228475 A 1377 1387 cyprodinil TRIVIAL 23228475 A 155 169 Benzo[a]pyrene SYSTEMATIC 23228475 A 1568 1578 cyprodinil TRIVIAL 23228475 A 1591 1594 BaP ABBREVIATION 23228475 A 16 30 pyrimidinamine TRIVIAL 23228475 A 171 174 BaP ABBREVIATION 23228475 A 180 215 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23228475 A 217 221 TCDD ABBREVIATION 23228475 A 280 296 aryl hydrocarbon FAMILY 23228475 A 347 357 cyprodinil TRIVIAL 23228475 A 391 394 BaP ABBREVIATION 23228475 A 399 403 TCDD ABBREVIATION 23228475 A 427 437 cyprodinil TRIVIAL 23228475 A 524 540 aryl hydrocarbon FAMILY 23228475 A 566 576 Cyprodinil TRIVIAL 23228475 A 838 848 Cyprodinil TRIVIAL 23228475 A 981 994 Dexamethasone TRIVIAL 23228475 T 0 10 Cyprodinil TRIVIAL 23228475 T 30 46 aryl hydrocarbon FAMILY 23228696 A 0 9 Metformin TRIVIAL 23228696 A 1046 1056 paclitaxel TRIVIAL 23228696 A 1118 1127 metformin TRIVIAL 23228696 A 1162 1172 paclitaxel TRIVIAL 23228696 A 1266 1276 paclitaxel TRIVIAL 23228696 A 1417 1426 metformin TRIVIAL 23228696 A 1431 1441 paclitaxel TRIVIAL 23228696 A 1567 1576 metformin TRIVIAL 23228696 A 1590 1600 paclitaxel TRIVIAL 23228696 A 186 196 paclitaxel TRIVIAL 23228696 A 198 203 Taxol TRIVIAL 23228696 A 509 517 platinum SYSTEMATIC 23228696 A 566 576 paclitaxel TRIVIAL 23228696 A 767 777 paclitaxel TRIVIAL 23228696 A 910 918 SB202190 IDENTIFIER 23228696 T 0 9 Metformin TRIVIAL 23228696 T 194 204 paclitaxel TRIVIAL 23228697 A 0 8 Orlistat TRIVIAL 23228697 A 1001 1009 orlistat TRIVIAL 23228697 A 1047 1050 PPD ABBREVIATION 23228697 A 1382 1390 orlistat TRIVIAL 23228697 A 1405 1413 orlistat TRIVIAL 23228697 A 426 434 orlistat TRIVIAL 23228697 A 678 694 pentyl carbamate SYSTEMATIC 23228697 A 698 721 p-aminobenzyl carbamate SYSTEMATIC 23228697 A 725 737 doxazolidine TRIVIAL 23228697 A 739 742 PPD ABBREVIATION 23228697 A 748 758 irinotecan TRIVIAL 23228697 A 913 921 orlistat TRIVIAL 23228697 T 73 81 orlistat TRIVIAL 23229055 A 158 162 (1)H FORMULA 23229055 A 168 173 (13)C FORMULA 23229055 A 21 52 6-carbethoxy-2-cyclohexen-1-one SYSTEMATIC 23229055 A 295 308 Cyclohexenone SYSTEMATIC 23229055 A 400 409 chalcones FAMILY 23229055 A 428 436 Indazole SYSTEMATIC 23229055 A 57 72 2H-indazol-3-ol SYSTEMATIC 23229055 A 6 14 chalcone FAMILY 23229055 T 126 141 2H-indazol-3-ol SYSTEMATIC 23229055 T 75 83 chalcone FAMILY 23229055 T 90 121 6-carbethoxy-2-cyclohexen-1-one SYSTEMATIC 23229511 A 1086 1092 17-AAG SYSTEMATIC 23229511 A 1212 1218 17-AAG SYSTEMATIC 23229511 A 1233 1239 17-AAG SYSTEMATIC 23229511 A 1369 1376 NAD(P)H ABBREVIATION 23229511 A 1377 1384 quinone FAMILY 23229511 A 1480 1486 17-AAG SYSTEMATIC 23229511 A 1579 1585 17-AAG SYSTEMATIC 23229511 A 1702 1708 17-AAG SYSTEMATIC 23229511 A 1751 1757 17-AAG SYSTEMATIC 23229511 A 183 221 17-Allylamino-17-demethoxygeldanamycin SYSTEMATIC 23229511 A 223 229 17-AAG SYSTEMATIC 23229511 A 26 42 aryl hydrocarbon FAMILY 23229511 A 379 385 17-AAG SYSTEMATIC 23229511 A 676 682 17-AAG SYSTEMATIC 23229511 T 0 16 Aryl hydrocarbon FAMILY 23229511 T 41 79 17-Allylamino-17-demethoxygeldanamycin SYSTEMATIC 23229539 A 1073 1077 iron SYSTEMATIC 23229539 A 1199 1214 malondialdehyde TRIVIAL 23229539 A 1248 1258 superoxide TRIVIAL 23229539 A 207 211 iron SYSTEMATIC 23229539 A 816 820 iron SYSTEMATIC 23229539 A 882 886 iron SYSTEMATIC 23230131 A 0 11 Gemcitabine TRIVIAL 23230131 A 1086 1090 dFdU ABBREVIATION 23230131 A 1205 1209 dFdC ABBREVIATION 23230131 A 1292 1303 gemcitabine TRIVIAL 23230131 A 13 17 dFdC ABBREVIATION 23230131 A 1365 1369 dFdC ABBREVIATION 23230131 A 1409 1413 dFdC ABBREVIATION 23230131 A 19 46 2',2'-difluorodeoxycytidine SYSTEMATIC 23230131 A 485 495 cytarabine TRIVIAL 23230131 A 497 502 Ara-C ABBREVIATION 23230131 A 505 509 dFdC ABBREVIATION 23230131 A 530 556 2',2'-difluorodeoxyuridine SYSTEMATIC 23230131 A 558 562 dFdU ABBREVIATION 23230131 A 637 642 Ara-C ABBREVIATION 23230131 A 647 651 dFdC ABBREVIATION 23230131 A 66 74 cytidine TRIVIAL 23230131 A 746 751 Ara-C ABBREVIATION 23230131 A 829 834 Ara-C ABBREVIATION 23230131 A 839 843 dFdC ABBREVIATION 23230131 A 95 108 deoxycytidine TRIVIAL 23230131 A 979 983 dFdC ABBREVIATION 23230131 T 110 123 deoxycytidine TRIVIAL 23230131 T 20 31 gemcitabine TRIVIAL 23230131 T 87 95 cytidine TRIVIAL 23230274 A 1080 1088 arsenite SYSTEMATIC 23230274 A 376 384 arsenite SYSTEMATIC 23230274 A 686 692 oxygen SYSTEMATIC 23230274 T 55 61 oxygen SYSTEMATIC 23230281 A 1178 1191 peroxynitrite SYSTEMATIC 23230281 A 1416 1429 peroxynitrite SYSTEMATIC 23230281 A 868 881 peroxynitrite SYSTEMATIC 23231350 A 1243 1255 sulfonamides FAMILY 23231350 A 650 664 methyl mercury SYSTEMATIC 23231439 A 112 121 dipeptide FAMILY 23231439 A 256 261 ML188 IDENTIFIER 23231439 A 271 370 (R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide SYSTEMATIC 23231439 A 380 393 CID: 46897844 IDENTIFIER 23231439 T 130 135 ML188 IDENTIFIER 23231439 T 70 128 N-(tert-butyl)-2-(N-arylamido)-2-(pyridin-3-yl) acetamides FAMILY 23231457 A 130 143 poly-L-lysine SYSTEMATIC 23231809 A 14 22 dopamine TRIVIAL 23231809 A 1657 1665 dopamine TRIVIAL 23231809 T 0 8 Dopamine TRIVIAL 23231809 T 112 120 dopamine TRIVIAL 23231967 A 164 173 adenosine TRIVIAL 23231967 A 25 38 methoxyphenyl SYSTEMATIC 23231967 A 339 348 adenosine TRIVIAL 23231967 A 68 105 N-(2,6-diarylpyrimidin-4-yl)acetamide FAMILY 23231967 T 21 30 adenosine TRIVIAL 23231967 T 58 69 methoxyaryl FAMILY 23231967 T 90 127 N-(2,6-diarylpyrimidin-4-yl)acetamide FAMILY 23232056 A 47 66 diphenylpropanamide FAMILY 23232056 T 15 21 amides FAMILY 23232059 A 1054 1066 cynaropicrin TRIVIAL 23232059 A 1215 1227 cynaropicrin TRIVIAL 23232059 A 881 893 cynaropicrin TRIVIAL 23232059 A 906 927 sesquiterpene lactone FAMILY 23232059 T 0 12 Cynaropicrin TRIVIAL 23232150 A 101 109 steroids FAMILY 23232150 A 1483 1490 steroid FAMILY 23232150 A 171 180 estradiol TRIVIAL 23232150 A 518 527 estradiol TRIVIAL 23232150 A 557 566 estradiol TRIVIAL 23232150 A 791 799 glycerol TRIVIAL 23232150 A 823 830 formate SYSTEMATIC 23232150 A 868 888 histidinol-phosphate SYSTEMATIC 23232150 A 995 1002 alcohol FAMILY 23232150 T 39 48 estradiol TRIVIAL 23232150 T 96 103 steroid FAMILY 23232333 A 1017 1031 corticosterone TRIVIAL 23232333 A 1190 1204 corticosterone TRIVIAL 23232333 A 1353 1367 corticosterone TRIVIAL 23232333 A 1490 1504 corticosterone TRIVIAL 23232333 A 1600 1614 corticosterone TRIVIAL 23232333 A 289 303 corticosterone TRIVIAL 23232333 A 50 64 corticosterone TRIVIAL 23232333 A 512 526 corticosterone TRIVIAL 23232333 A 746 760 corticosterone TRIVIAL 23232333 A 820 834 corticosterone TRIVIAL 23232333 A 956 970 corticosterone TRIVIAL 23232333 T 44 58 corticosterone TRIVIAL 23232461 A 1101 1110 organotin FAMILY 23232461 A 1335 1345 organotins FAMILY 23232461 A 159 168 organotin FAMILY 23232461 A 28 37 organotin FAMILY 23232461 A 379 388 organotin FAMILY 23232461 A 607 617 organotins FAMILY 23232461 A 692 701 Organotin FAMILY 23232461 A 912 914 Na FORMULA 23232461 A 915 916 K FORMULA 23232461 T 12 21 organotin FAMILY 23232866 A 1017 1023 Fluo-4 ABBREVIATION 23232866 A 1181 1188 calcium SYSTEMATIC 23232866 A 533 555 poly(dimethylsiloxane) SYSTEMATIC 23232866 A 557 561 PDMS ABBREVIATION 23232866 A 994 1001 calcium SYSTEMATIC 23232941 A 440 445 vinyl FAMILY 23232941 A 447 450 C=C FORMULA 23232941 A 460 465 cyano FAMILY 23232941 A 467 470 C≡N FORMULA 23232941 A 66 79 acrylonitrile SYSTEMATIC 23232941 A 714 717 C=C FORMULA 23232941 A 726 729 C≡N FORMULA 23232941 A 94 101 Cu(100) FORMULA 23232941 T 100 107 Cu(100) FORMULA 23232941 T 74 87 acrylonitrile SYSTEMATIC 23233034 A 1034 1041 citrate FAMILY 23233034 A 1056 1062 silver SYSTEMATIC 23233034 A 1299 1306 citrate FAMILY 23233034 A 490 497 citrate FAMILY 23233034 A 515 521 silver SYSTEMATIC 23233034 A 819 826 citrate FAMILY 23233034 A 841 847 silver SYSTEMATIC 23233456 A 0 25 Dendritic poly(L-lysines) SYSTEMATIC 23233456 A 176 179 DGL ABBREVIATION 23233456 A 27 30 DGL ABBREVIATION 23233456 A 407 410 DGL ABBREVIATION 23233456 A 467 473 jetPEI TRIVIAL 23233456 A 569 572 DGL ABBREVIATION 23233456 A 701 704 DGL ABBREVIATION 23233456 T 46 61 poly(L-lysines) SYSTEMATIC 23234246 A 217 235 benzenesulfonamide SYSTEMATIC 23234246 A 315 323 M(CO)(3) FAMILY 23234246 A 334 336 Re FORMULA 23234246 A 340 347 (99m)Tc FORMULA 23234246 A 417 443 benzenesulfonamide rhenium SYSTEMATIC 23234246 A 617 639 technetium tricarbonyl SYSTEMATIC 23234246 A 641 660 {(99m)Tc(CO)(3)}(+) FORMULA 23234246 A 677 695 (99m)Tc(CO)(3)}(+) FORMULA 23234246 A 740 754 (99m)Tc(CO)(3) FORMULA 23234246 A 902 921 {(99m)Tc(CO)(3)}(+) FORMULA 23234246 T 27 29 Re FORMULA 23234246 T 30 35 99mTc FORMULA 23234246 T 44 62 benzenesulfonamide SYSTEMATIC 23234313 A 433 454 poly(propylene-imine) SYSTEMATIC 23234313 T 31 52 poly(propylene imine) SYSTEMATIC 23234537 A 126 132 carbon SYSTEMATIC 23234537 A 506 512 carbon SYSTEMATIC 23234537 A 56 78 poly(3-hexylthiophene) SYSTEMATIC 23234537 A 657 661 P3HT ABBREVIATION 23234537 A 732 738 carbon SYSTEMATIC 23234537 A 83 87 P3HT ABBREVIATION 23234537 T 7 13 carbon SYSTEMATIC 23234607 A 10 24 2-oxoglutarate SYSTEMATIC 23234607 A 211 214 2OG ABBREVIATION 23234607 A 26 29 2OG ABBREVIATION 23234607 A 315 318 2OG ABBREVIATION 23234607 A 494 497 2OG ABBREVIATION 23234607 T 41 55 2-oxoglutarate SYSTEMATIC 23234812 A 0 18 Strontium Ranelate SYSTEMATIC 23234812 A 1021 1023 NO FORMULA 23234812 A 1035 1041 PGE(2) ABBREVIATION 23234812 A 1093 1098 SrRan FORMULA 23234812 A 1302 1307 SrRan FORMULA 23234812 A 1413 1418 SrRan FORMULA 23234812 A 1513 1518 SrRan FORMULA 23234812 A 1669 1674 SrRan FORMULA 23234812 A 20 25 SrRan FORMULA 23234812 A 275 280 SrRan FORMULA 23234812 A 441 446 SrRan FORMULA 23234812 A 561 573 Nitric oxide SYSTEMATIC 23234812 A 575 577 NO FORMULA 23234812 A 583 601 prostaglandin E(2) TRIVIAL 23234812 A 603 609 PGE(2) ABBREVIATION 23234812 A 874 879 SrRan FORMULA 23234812 A 895 897 NO FORMULA 23234812 A 902 908 PGE(2) ABBREVIATION 23234812 A 958 960 NO FORMULA 23234812 A 972 978 PGE(2) ABBREVIATION 23234812 T 0 18 Strontium Ranelate SYSTEMATIC 23234855 A 111 136 [RuCl(HL)(PPh(3))(2)(CO)] FORMULA 23234855 A 145 171 [RuCl(HL)(AsPh(3))(2)(CO)] FORMULA 23234855 A 182 220 2,2'-bipyridine-4,4'-dicarboxylic acid SYSTEMATIC 23234855 A 26 50 [RuHCl(bpy)(PPh(3))(CO)] FORMULA 23234855 A 56 81 [RuHCl(bpy)(AsPh(3))(CO)] FORMULA 23234855 A 791 795 COOH FORMULA 23234855 A 799 809 bipyridine SYSTEMATIC 23234855 A 843 847 COOH FORMULA 23234855 A 87 90 bpy ABBREVIATION 23234855 A 9 15 Ru(II) FORMULA 23234855 A 93 108 2,2'-bipyridine SYSTEMATIC 23234855 T 13 28 carboxylic acid SYSTEMATIC 23234855 T 48 84 ruthenium (II) polypyridyl complexes FAMILY 23235151 A 1553 1554 C FORMULA 23235151 A 240 249 histamine TRIVIAL 23235151 A 421 428 sulfate SYSTEMATIC 23235151 A 598 599 N FORMULA 23235151 A 668 669 C FORMULA 23235158 A 1008 1016 tyrosine TRIVIAL 23235158 A 1131 1134 Tyr FORMULA 23235158 A 1300 1304 heme FAMILY 23235158 A 377 385 chlorite SYSTEMATIC 23235158 A 487 491 heme FAMILY 23235158 A 513 522 aspartate TRIVIAL 23235158 A 532 535 Asp FORMULA 23235158 A 591 608 hydrogen peroxide SYSTEMATIC 23235158 A 620 624 heme FAMILY 23235158 A 625 629 iron SYSTEMATIC 23235158 A 65 69 heme FAMILY 23235158 A 838 841 Asp FORMULA 23235158 A 905 909 heme FAMILY 23235158 A 96 113 hydrogen peroxide SYSTEMATIC 23235158 A 984 995 amino acids FAMILY 23235435 A 109 126 triazacyclononane SYSTEMATIC 23235435 A 273 279 Co(ii) FORMULA 23235435 A 441 448 Cr(iii) FORMULA 23235435 A 453 459 Co(ii) FORMULA 23235435 A 75 91 transition metal FAMILY 23235435 T 126 142 transition metal FAMILY 23235435 T 69 97 bis(1,4,7-triazacyclononane) SYSTEMATIC 23235742 A 284 286 Pt FORMULA 23235742 A 640 642 Pt FORMULA 23235742 A 71 73 Pt FORMULA 23235742 A 893 907 levulinic acid TRIVIAL 23235742 T 141 143 Pt FORMULA 23237482 A 560 564 GaAs FORMULA 23237482 A 575 577 As FORMULA 23237482 A 578 582 GaAs FORMULA 23237482 T 31 35 GaAs FORMULA 23237546 A 485 492 glucose TRIVIAL 23237546 A 599 601 Au FORMULA 23237546 A 707 714 calcium SYSTEMATIC 23237590 A 27 33 silica TRIVIAL 23237828 A 1151 1164 cycloheximide TRIVIAL 23237828 A 1258 1271 cycloheximide TRIVIAL 23237828 A 201 214 cycloheximide TRIVIAL 23237828 A 305 318 cycloheximide TRIVIAL 23237828 A 407 420 actinomycin D TRIVIAL 23237828 A 431 444 cycloheximide TRIVIAL 23237828 A 510 523 cycloheximide TRIVIAL 23237828 A 559 572 cycloheximide TRIVIAL 23237828 A 710 715 U0126 IDENTIFIER 23237828 A 720 727 PD98059 IDENTIFIER 23237828 A 755 763 SP600125 IDENTIFIER 23237828 A 765 770 U0126 IDENTIFIER 23237828 A 775 782 PD98059 IDENTIFIER 23237828 A 806 819 cycloheximide TRIVIAL 23237828 A 859 867 SP600125 IDENTIFIER 23237828 A 887 900 cycloheximide TRIVIAL 23237828 A 919 932 cycloheximide TRIVIAL 23237828 T 0 13 Cycloheximide TRIVIAL 23237939 A 1208 1214 NU7441 IDENTIFIER 23237939 A 1219 1228 cisplatin TRIVIAL 23237939 A 730 736 NU7441 IDENTIFIER 23237939 A 737 746 cisplatin TRIVIAL 23237974 A 177 191 schisandrin A1 TRIVIAL 23237974 A 222 227 epoxy SYSTEMATIC 23237974 A 30 36 lignan FAMILY 23237974 A 316 330 schisandrin A1 TRIVIAL 23237974 A 339 354 schisantherin A TRIVIAL 23237974 A 44 58 schisandrin A1 TRIVIAL 23237974 A 502 517 schisantherin A TRIVIAL 23237974 A 542 565 6,7-secoschisantherol A SYSTEMATIC 23237974 A 6 24 dibenzocyclooctene SYSTEMATIC 23237974 A 610 617 lignans FAMILY 23237974 A 636 651 schisantherin A TRIVIAL 23237974 T 0 7 Lignans FAMILY 23237974 T 69 84 schisantherin A TRIVIAL 23238233 A 108 129 chikusetsusaponin LM5 TRIVIAL 23238233 A 135 156 chikusetsusaponin LM6 TRIVIAL 23238233 A 179 200 triterpenoid saponins FAMILY 23238233 A 209 224 ginsenoside Rb3 TRIVIAL 23238233 A 230 244 ginsenoside Rc TRIVIAL 23238233 A 24 45 triterpenoid saponins FAMILY 23238233 A 250 264 ginsenoside Rd TRIVIAL 23238233 A 270 284 ginsenoside Re TRIVIAL 23238233 A 290 305 ginsenoside Rg1 TRIVIAL 23238233 A 311 325 ginsenoside F3 TRIVIAL 23238233 A 332 346 ginsenoside F5 TRIVIAL 23238233 A 353 367 ginsenoside F6 TRIVIAL 23238233 A 374 395 chikusetsusaponin IVa TRIVIAL 23238233 A 402 421 chikusetsusaponin V TRIVIAL 23238233 A 428 448 chikusetsusaponin L5 TRIVIAL 23238233 A 455 476 chikusetsusaponin L9a TRIVIAL 23238233 A 483 505 chikusetsusaponin L9bc TRIVIAL 23238233 A 512 533 chikusetsusaponin L10 TRIVIAL 23238233 A 54 75 chikusetsusaponin LM3 TRIVIAL 23238233 A 540 561 chikusetsusaponin FK2 TRIVIAL 23238233 A 568 589 chikusetsusaponin FK6 TRIVIAL 23238233 A 596 617 chikusetsusaponin FK7 TRIVIAL 23238233 A 624 645 chikusetsusaponin FT1 TRIVIAL 23238233 A 652 673 chikusetsusaponin LM1 TRIVIAL 23238233 A 684 705 chikusetsusaponin LM2 TRIVIAL 23238233 A 81 102 chikusetsusaponin LM4 TRIVIAL 23238233 A 836 854 chikusetsusaponins FAMILY 23238233 A 9 18 dammarane TRIVIAL 23238233 T 9 30 triterpenoid saponins FAMILY 23238235 A 1025 1033 acrolein TRIVIAL 23238235 A 1035 1049 crotonaldehyde TRIVIAL 23238235 A 1051 1068 4-hydroxy-hexenal SYSTEMATIC 23238235 A 1070 1075 4-HHE SYSTEMATIC 23238235 A 1081 1096 4-oxo-2-nonenal SYSTEMATIC 23238235 A 1098 1103 4-ONE SYSTEMATIC 23238236 A 556 563 Sterols FAMILY 23238236 A 565 576 triterpenes FAMILY 23238236 A 593 604 fatty acids FAMILY 23238236 A 728 735 DPPH(·) ABBREVIATION 23238236 A 737 747 superoxide TRIVIAL 23238236 A 752 764 nitric oxide SYSTEMATIC 23238352 A 0 10 Zinc oxide SYSTEMATIC 23238352 A 1300 1305 H(2)S FORMULA 23238352 A 1310 1315 H(2)O FORMULA 23238352 A 1354 1357 ZnO FORMULA 23238352 A 1415 1420 H(2)S FORMULA 23238352 A 145 148 ZnO FORMULA 23238352 A 1634 1640 oxygen SYSTEMATIC 23238352 A 1790 1793 ZnO FORMULA 23238352 A 1794 1797 ZnS FORMULA 23238352 A 1943 1946 ZnO FORMULA 23238352 A 1947 1950 ZnS FORMULA 23238352 A 2325 2328 ZnO FORMULA 23238352 A 2329 2332 ZnS FORMULA 23238352 A 303 306 ZnO FORMULA 23238352 A 556 559 ZnS FORMULA 23238352 A 609 617 wurtzite TRIVIAL 23238352 A 693 696 ZnS FORMULA 23238352 A 712 716 zinc SYSTEMATIC 23238352 A 721 727 oxygen SYSTEMATIC 23238352 A 747 750 ZnO FORMULA 23238352 A 751 754 ZnS FORMULA 23238352 A 796 799 ZnS FORMULA 23238352 A 826 829 ZnO FORMULA 23238352 A 845 850 H(2)S FORMULA 23238352 A 984 987 ZnS FORMULA 23238352 T 21 24 ZnO FORMULA 23238352 T 86 89 ZnS FORMULA 23238425 A 1031 1037 SO(3)H FORMULA 23238425 A 1081 1087 Nafion TRIVIAL 23238425 A 1097 1099 Si FORMULA 23238425 A 119 125 SO(3)H FORMULA 23238425 A 1192 1198 SO(3)H FORMULA 23238425 A 1244 1250 oxygen SYSTEMATIC 23238425 A 1289 1295 SO(3)H FORMULA 23238425 A 13 19 Nafion TRIVIAL 23238425 A 1333 1339 Nafion TRIVIAL 23238425 A 1357 1359 Pt FORMULA 23238425 A 1360 1362 Si FORMULA 23238425 A 1449 1455 SO(3)H FORMULA 23238425 A 1524 1532 fluorine SYSTEMATIC 23238425 A 160 167 silicon SYSTEMATIC 23238425 A 1649 1655 Nafion TRIVIAL 23238425 A 169 171 Si FORMULA 23238425 A 1700 1706 Nafion TRIVIAL 23238425 A 174 187 glassy carbon TRIVIAL 23238425 A 197 205 platinum SYSTEMATIC 23238425 A 206 213 silicon SYSTEMATIC 23238425 A 215 217 Pt FORMULA 23238425 A 218 220 Si FORMULA 23238425 A 594 600 Nafion TRIVIAL 23238425 A 611 613 Si FORMULA 23238425 A 680 682 Si FORMULA 23238425 A 693 699 oxygen SYSTEMATIC 23238425 A 734 740 SO(3)H FORMULA 23238425 A 879 885 Nafion TRIVIAL 23238425 A 895 897 Si FORMULA 23238425 T 33 37 SO3H FORMULA 23238425 T 83 89 Nafion TRIVIAL 23238611 A 110 119 magnesium SYSTEMATIC 23238611 A 343 352 magnesium SYSTEMATIC 23238611 A 551 560 magnesium SYSTEMATIC 23238611 A 720 729 magnesium SYSTEMATIC 23238611 T 18 27 magnesium SYSTEMATIC 23238657 A 1099 1106 nitrite SYSTEMATIC 23238657 A 1118 1125 nitrate SYSTEMATIC 23238657 A 1179 1203 N(ε)-carboxymethyllisine SYSTEMATIC 23238657 A 1500 1512 nitric oxide SYSTEMATIC 23238662 A 1252 1259 glucose TRIVIAL 23238662 A 1320 1327 glucose TRIVIAL 23238662 A 204 211 glucose TRIVIAL 23238662 A 550 557 glucose TRIVIAL 23238662 A 903 910 glucose TRIVIAL 23238662 A 931 938 glucose TRIVIAL 23238662 A 972 979 glucose TRIVIAL 23238783 A 1626 1635 bupropion TRIVIAL 23238783 A 1641 1650 bupropion TRIVIAL 23238783 A 1850 1859 bupropion TRIVIAL 23238783 A 403 412 bupropion TRIVIAL 23238783 A 414 427 Wellbutrin SR TRIVIAL 23238783 A 548 557 bupropion TRIVIAL 23238783 A 804 813 bupropion TRIVIAL 23238783 A 823 839 hydroxybupropion SYSTEMATIC 23238783 T 56 65 bupropion TRIVIAL 23238991 A 1154 1158 CFSE ABBREVIATION 23238991 A 354 360 silica TRIVIAL 23238991 A 763 766 MTT ABBREVIATION 23238991 T 44 50 silica TRIVIAL 23239015 A 167 181 graphene oxide SYSTEMATIC 23239015 A 218 224 Pc(8+) FORMULA 23239015 A 38 80 poly-ortho-substituted tetraarylporphycene FAMILY 23239015 A 82 88 Pc(8+) FORMULA 23239015 T 0 47 Poly-Ortho-Functionalizable Tetraarylporphycene FAMILY 23239015 T 142 156 Graphene Oxide SYSTEMATIC 23239015 T 70 82 Octacationic FAMILY 23239601 A 199 207 hydrogen SYSTEMATIC 23239601 A 315 323 hydrogen SYSTEMATIC 23239601 T 63 71 hydrogen SYSTEMATIC 23239639 A 105 109 HPMA ABBREVIATION 23239639 A 184 193 maleimide SYSTEMATIC 23239639 A 209 249 poly(N-(2-hydroxypropyl)-methacrylamide) SYSTEMATIC 23239639 A 251 260 poly-HPMA ABBREVIATION 23239639 A 363 393 pentafluorophenyl methacrylate SYSTEMATIC 23239639 A 436 441 ester FAMILY 23239639 A 719 722 SDS ABBREVIATION 23239639 T 13 22 maleimide SYSTEMATIC 23239639 T 38 42 HPMA ABBREVIATION 23239825 A 311 319 carboxyl SYSTEMATIC 23239825 A 398 404 serine TRIVIAL 23239825 A 558 567 threonine TRIVIAL 23240655 A 416 422 MoS(2) FORMULA 23240655 A 510 518 scandium SYSTEMATIC 23240655 A 554 560 MoS(2) FORMULA 23240655 A 596 605 Al(2)O(3) FORMULA 23240655 A 83 91 graphene TRIVIAL 23240655 T 28 32 MoS2 FORMULA 23240655 T 50 58 scandium SYSTEMATIC 23240993 A 1057 1071 Me(2)DABCO(2+) FORMULA 23240993 A 1105 1107 Ar FORMULA 23240993 A 1108 1113 Ar(l) FORMULA 23240993 A 1132 1139 (129)Xe FORMULA 23240993 A 1241 1248 (129)Xe FORMULA 23240993 A 1341 1348 (129)Xe FORMULA 23240993 A 155 169 Me(2)DABCO(2+) FORMULA 23240993 A 1711 1718 (129)Xe FORMULA 23240993 A 1777 1779 Xe FORMULA 23240993 A 1780 1785 Xe(l) FORMULA 23240993 A 1932 1939 (129)Xe FORMULA 23240993 A 390 397 (129)Xe FORMULA 23240993 A 449 456 (129)Xe FORMULA 23240993 A 466 468 Ar FORMULA 23240993 A 469 474 Ar(l) FORMULA 23240993 A 479 481 Xe FORMULA 23240993 A 482 487 Xe(l) FORMULA 23240993 A 789 793 (1)H FORMULA 23240993 A 795 800 (13)C FORMULA 23240993 A 802 807 (19)F FORMULA 23240993 A 813 819 (29)Si FORMULA 23240993 T 53 58 129Xe FORMULA 23240993 T 80 82 Xe FORMULA 23241030 A 31 66 9-diphenylthiophosphinoylanthracene SYSTEMATIC 23241354 A 105 113 tyrosine TRIVIAL 23241354 A 212 220 tyrosine TRIVIAL 23241354 A 399 407 tyrosine TRIVIAL 23241354 T 82 90 tyrosine TRIVIAL 23243659 A 108 114 nickel SYSTEMATIC 23243659 A 120 126 NH(4)F FORMULA 23243659 A 131 140 H(3)PO(4) FORMULA 23243659 A 19 28 Ni(OH)(2) FORMULA 23243659 A 29 35 NiF(2) FORMULA 23243659 A 450 456 nickel SYSTEMATIC 23243659 T 12 19 Ni(OH)2 FORMULA 23243659 T 20 24 NiF2 FORMULA 23243660 A 123 133 flavonoids FAMILY 23243660 A 134 144 naringenin TRIVIAL 23243660 A 1481 1484 O–H FORMULA 23243660 A 152 161 quercetin TRIVIAL 23243660 A 1652 1656 H(2) FORMULA 23243660 A 171 180 myricetin TRIVIAL 23243660 A 221 229 chromone TRIVIAL 23243660 A 238 245 flavone TRIVIAL 23243660 A 632 642 flavonoids FAMILY 23243660 T 46 56 flavonoids FAMILY 23244178 A 1108 1114 azides FAMILY 23244178 A 1181 1187 azides FAMILY 23244178 A 12 22 aryl azide FAMILY 23244178 A 1239 1252 primary amine FAMILY 23244178 A 1301 1323 oligo(ethylene glycol) SYSTEMATIC 23244178 A 1339 1344 amine SYSTEMATIC 23244178 A 157 171 aluminum oxide SYSTEMATIC 23244178 A 321 330 diazirine SYSTEMATIC 23244178 A 34 40 thiols FAMILY 23244178 A 346 356 aryl thiol FAMILY 23244178 A 45 61 phosphonic acids FAMILY 23244178 A 500 513 primary amine FAMILY 23244178 A 548 559 aryl azides FAMILY 23244178 A 573 582 diazirine SYSTEMATIC 23244178 A 595 609 primary amines FAMILY 23244178 A 649 655 azides FAMILY 23244178 A 841 851 aryl azide FAMILY 23244178 A 909 922 primary amine FAMILY 23244178 A 936 942 amines FAMILY 23244178 T 110 124 primary amines FAMILY 23244178 T 142 153 aryl azides FAMILY 23244178 T 166 180 aluminum oxide SYSTEMATIC 23244521 A 525 532 ethanol SYSTEMATIC 23245188 A 0 7 Silicon SYSTEMATIC 23245188 A 210 218 H(2)O(2) FORMULA 23245188 A 234 240 oxygen SYSTEMATIC 23245188 A 286 304 o-phenylenediamine SYSTEMATIC 23245188 A 306 309 OPD ABBREVIATION 23245188 A 351 359 H(2)O(2) FORMULA 23245188 A 377 379 Si FORMULA 23245188 A 380 381 H FORMULA 23245188 A 524 532 H(2)O(2) FORMULA 23245188 A 593 602 (Si-H)(2) FORMULA 23245188 A 606 607 O FORMULA 23245188 A 618 627 (Si-H)(2) FORMULA 23245188 T 58 65 silicon SYSTEMATIC 23245512 A 115 121 acetyl SYSTEMATIC 23245512 A 123 132 propionyl SYSTEMATIC 23245512 A 134 142 butanoyl SYSTEMATIC 23245512 A 144 153 pentanoyl SYSTEMATIC 23245512 A 155 162 valeryl SYSTEMATIC 23245512 A 167 183 3-methylbutanoyl SYSTEMATIC 23245512 A 18 39 glycopyranosyl azides FAMILY 23245512 A 185 195 isovaleryl TRIVIAL 23245512 A 197 202 ester FAMILY 23245512 A 272 293 glycopyranosyl azides FAMILY 23245512 A 300 306 copper SYSTEMATIC 23245512 A 317 322 azide SYSTEMATIC 23245512 A 323 329 alkyne FAMILY 23245512 A 482 486 acyl FAMILY 23245512 A 534 571 acetyl, propionyl and butanoyl esters MULTIPLE 23245512 A 642 669 mono-, di- and tri-acylated MULTIPLE 23245512 A 69 81 carbohydrate FAMILY 23245512 A 763 800 pentanoyl and 3-methylbutanoyl esters MULTIPLE 23245514 A 103 113 PBI-18-Man TRIVIAL 23245514 A 360 367 mannose TRIVIAL 23245514 A 447 454 mannose TRIVIAL 23245514 A 46 58 α-D-mannoses FAMILY 23245514 A 74 82 perylene SYSTEMATIC 23245514 T 13 30 perylene bisimide FAMILY 23245697 A 1096 1111 ribonucleotides FAMILY 23245697 A 1206 1221 ribonucleotides FAMILY 23245697 A 1262 1277 ribonucleotides FAMILY 23245697 A 1331 1346 ribonucleotides FAMILY 23245697 A 1407 1421 ribonucleotide FAMILY 23245697 A 1554 1568 ribonucleotide FAMILY 23245697 A 1724 1739 ribonucleotides FAMILY 23245697 A 486 501 ribonucleotides FAMILY 23245697 A 53 68 ribonucleotides FAMILY 23245697 A 548 558 nucleotide FAMILY 23245697 A 654 658 rNTP ABBREVIATION 23245697 A 682 687 dNTPs ABBREVIATION 23245697 A 802 817 ribonucleotides FAMILY 23245697 T 0 14 Ribonucleotide FAMILY 23246428 A 0 34 Ergosta-4,6,8(14),22-tetraen-3-one SYSTEMATIC 23246428 A 1143 1152 bile acid FAMILY 23246428 A 1274 1280 ergone TRIVIAL 23246428 A 36 42 ergone TRIVIAL 23246428 A 481 488 adenine TRIVIAL 23246428 A 519 553 ergosta-4,6,8(14),22-tetraen-3-one SYSTEMATIC 23246428 A 555 561 ergone TRIVIAL 23246428 A 689 696 adenine TRIVIAL 23246428 A 719 725 ergone TRIVIAL 23246428 T 133 167 ergosta-4,6,8(14),22-tetraen-3-one SYSTEMATIC 23246428 T 45 52 adenine TRIVIAL 23246436 A 538 539 C FORMULA 23246531 A 1042 1050 diazepam TRIVIAL 23246531 A 1070 1077 KNT-127 IDENTIFIER 23246531 A 1162 1169 ethanol SYSTEMATIC 23246531 A 1293 1300 KNT-127 IDENTIFIER 23246531 A 1406 1421 benzodiazepines FAMILY 23246531 A 187 194 KNT-127 IDENTIFIER 23246531 A 258 265 KNT-127 IDENTIFIER 23246531 A 349 356 KNT-127 IDENTIFIER 23246531 A 519 526 KNT-127 IDENTIFIER 23246531 A 56 61 SNC80 IDENTIFIER 23246531 A 609 617 diazepam TRIVIAL 23246531 A 639 653 benzodiazepine FAMILY 23246531 A 697 704 KNT-127 IDENTIFIER 23246531 A 759 770 naltrindole TRIVIAL 23246531 A 848 855 KNT-127 IDENTIFIER 23246531 T 148 163 benzodiazepines FAMILY 23246531 T 36 43 KNT-127 IDENTIFIER 23246700 A 0 10 Phthalates FAMILY 23246700 A 1084 1088 DEHP ABBREVIATION 23246700 A 1185 1195 phthalates FAMILY 23246700 A 1252 1262 phthalates FAMILY 23246700 A 22 47 di-(2-ethylhexyl) adipate SYSTEMATIC 23246700 A 251 261 phthalates FAMILY 23246700 A 266 270 DEHA ABBREVIATION 23246700 A 408 417 phthalate FAMILY 23246700 A 49 53 DEHA ABBREVIATION 23246700 A 651 676 di-2-ethylhexyl phthalate SYSTEMATIC 23246700 A 678 682 DEHP ABBREVIATION 23246700 A 705 726 di-isobutyl phthalate SYSTEMATIC 23246700 A 728 732 DiBP ABBREVIATION 23246700 A 759 779 di-n-butyl phthalate SYSTEMATIC 23246700 A 781 785 DnBP ABBREVIATION 23246700 A 811 815 DEHA ABBREVIATION 23246700 A 894 898 DEHP ABBREVIATION 23246700 A 919 923 DnBP ABBREVIATION 23246700 A 944 948 DiBP ABBREVIATION 23246700 A 973 994 di-isononyl phthalate SYSTEMATIC 23246700 T 0 9 Phthalate SYSTEMATIC 23246700 T 14 39 di-(2-ethylhexyl) adipate SYSTEMATIC 23246700 T 41 45 DEHA ABBREVIATION 23246701 A 0 25 Perfluorooctane sulfonate SYSTEMATIC 23246701 A 1103 1107 PFOS ABBREVIATION 23246701 A 1159 1167 curcumin TRIVIAL 23246701 A 1217 1221 PFOS ABBREVIATION 23246701 A 27 31 PFOS ABBREVIATION 23246701 A 289 297 Curcumin TRIVIAL 23246701 A 311 323 polyphenolic FAMILY 23246701 A 575 579 PFOS ABBREVIATION 23246701 A 723 731 curcumin TRIVIAL 23246701 A 86 90 PFOS ABBREVIATION 23246701 A 904 908 PFOS ABBREVIATION 23246701 T 23 31 curcumin TRIVIAL 23246701 T 35 60 perfluorooctane sulfonate SYSTEMATIC 23246865 A 1028 1030 Pb FORMULA 23246865 A 1128 1130 Pb FORMULA 23246865 A 1169 1188 amino cupric silver SYSTEMATIC 23246865 A 1279 1282 MUS ABBREVIATION 23246865 A 1317 1321 GABA ABBREVIATION 23246865 A 1337 1348 bicuculline TRIVIAL 23246865 A 1350 1353 BIC ABBREVIATION 23246865 A 1392 1394 Pb FORMULA 23246865 A 1511 1515 GABA ABBREVIATION 23246865 A 183 185 Pb FORMULA 23246865 A 384 391 PbNO(3) FORMULA 23246865 A 56 58 Pb FORMULA 23246865 A 856 858 Pb FORMULA 23246865 A 928 947 γ-aminobutyric acid SYSTEMATIC 23246865 A 961 965 GABA ABBREVIATION 23246865 A 979 987 muscimol TRIVIAL 23246865 A 989 992 MUS ABBREVIATION 23246865 T 81 85 GABA ABBREVIATION 23246867 A 1061 1065 IPA3 ABBREVIATION 23246867 A 1113 1119 ML-141 IDENTIFIER 23246867 A 1133 1140 glucose TRIVIAL 23246867 A 1222 1226 IPA3 ABBREVIATION 23246867 A 1341 1350 PD0325901 IDENTIFIER 23246867 A 1535 1542 glucose TRIVIAL 23246867 A 389 396 glucose TRIVIAL 23246867 A 466 470 IPA3 ABBREVIATION 23246867 A 536 543 glucose TRIVIAL 23246867 A 777 784 glucose TRIVIAL 23246867 A 838 842 IPA3 ABBREVIATION 23246867 A 898 902 IPA3 ABBREVIATION 23246867 A 916 923 glucose TRIVIAL 23247009 A 0 6 Aldose TRIVIAL 23247009 A 170 186 Beta-glucogallin TRIVIAL 23247009 A 188 191 BGG ABBREVIATION 23247009 A 333 336 BGG ABBREVIATION 23247009 A 459 467 sorbitol TRIVIAL 23247009 A 495 498 BGG ABBREVIATION 23247009 A 61 70 aldehydes FAMILY 23247009 A 766 769 BGG ABBREVIATION 23247009 A 80 87 alcohol FAMILY 23247009 A 916 919 BGG ABBREVIATION 23247009 T 0 16 Beta-glucogallin TRIVIAL 23247009 T 108 114 aldose FAMILY 23247010 A 10 18 carbonyl FAMILY 23247010 A 1209 1219 nucleotide FAMILY 23247010 A 151 164 anthracycline FAMILY 23247010 A 184 198 prostaglandins FAMILY 23247010 A 204 210 isatin TRIVIAL 23247010 A 248 257 monoamine FAMILY 23247010 A 473 497 butylated hydroxyanisole SYSTEMATIC 23247010 A 499 502 BHA ABBREVIATION 23247010 A 532 535 BHA ABBREVIATION 23247010 A 809 812 BHA ABBREVIATION 23247010 T 20 28 carbonyl FAMILY 23247040 A 165 196 α-Amino acid-N-carboxyanhydride FAMILY 23247298 A 136 142 serine TRIVIAL 23247298 A 582 584 OH FORMULA 23247298 A 784 790 serine TRIVIAL 23247298 A 973 979 serine TRIVIAL 23247298 T 40 46 serine TRIVIAL 23247504 A 1048 1051 KCl FORMULA 23247504 A 11 21 iron oxide SYSTEMATIC 23247504 A 410 422 carbohydrate FAMILY 23247504 A 430 440 iron oxide SYSTEMATIC 23247504 A 720 729 maghemite TRIVIAL 23247504 A 734 746 ferrihydrite TRIVIAL 23247504 A 919 923 COOH FORMULA 23247504 T 29 39 iron oxide SYSTEMATIC 23247824 A 1141 1149 nicotine TRIVIAL 23247824 A 19 32 acetylcholine SYSTEMATIC 23247824 A 887 895 dopamine TRIVIAL 23248173 A 849 856 glucose TRIVIAL 23248196 A 1090 1102 atorvastatin TRIVIAL 23248196 A 1107 1118 simvastatin TRIVIAL 23248196 A 1228 1234 statin FAMILY 23248196 A 233 239 statin FAMILY 23248196 A 52 59 statins FAMILY 23248196 A 525 532 statins FAMILY 23248196 A 799 805 Statin FAMILY 23248196 T 0 7 Statins FAMILY 23248236 A 1039 1046 Ebselen TRIVIAL 23248236 A 1055 1061 sulfur SYSTEMATIC 23248236 A 1069 1077 ebsulfur TRIVIAL 23248236 A 1100 1103 GSH ABBREVIATION 23248236 A 1124 1132 Ebsulfur TRIVIAL 23248236 A 1358 1374 benzisoselenazol SYSTEMATIC 23248236 A 1379 1393 benzisothiazol SYSTEMATIC 23248236 A 192 197 NADPH ABBREVIATION 23248236 A 367 374 Ebselen TRIVIAL 23248236 A 376 415 2-phenyl-1,2 benzisoselenazol-3(2H)-one SYSTEMATIC 23248236 A 516 527 methicillin TRIVIAL 23248236 A 609 616 ebselen TRIVIAL 23248236 A 736 743 dithiol SYSTEMATIC 23248236 A 776 787 glutathione TRIVIAL 23248236 A 789 792 GSH ABBREVIATION 23248236 T 98 109 glutathione TRIVIAL 23249244 A 242 247 DMABN ABBREVIATION 23249244 A 251 263 acetonitrile SYSTEMATIC 23249244 A 40 45 DMABN ABBREVIATION 23249244 A 876 889 dimethylamino SYSTEMATIC 23249244 T 66 95 4-(dimethylamino)benzonitrile SYSTEMATIC 23249244 T 97 102 DMABN ABBREVIATION 23249338 A 1124 1133 acetylene SYSTEMATIC 23249338 A 1150 1159 porphyrin FAMILY 23249338 A 124 136 chlorophylls FAMILY 23249338 A 1287 1296 porphyrin FAMILY 23249338 A 162 171 porphyrin FAMILY 23249338 A 539 545 Zn(II) FORMULA 23249338 A 546 555 porphyrin FAMILY 23249338 A 563 626 [5,15-dipyridyl-10,20-bis(pentafluorophenyl)porphinato]zinc(II) SYSTEMATIC 23249338 A 631 694 [5,15-bis[4-(pyridyl)ethynyl]-10,20-diphenylporphinato]zinc(II) SYSTEMATIC 23249338 A 881 890 porphyrin FAMILY 23249338 A 99 108 porphyrin FAMILY 23249338 T 51 60 porphyrin FAMILY 23249341 A 302 304 OH FORMULA 23249341 A 339 341 OH FORMULA 23249341 A 401 403 OH FORMULA 23249341 A 44 46 OH FORMULA 23249341 A 554 559 NO(2) FORMULA 23249341 A 624 626 OH FORMULA 23249341 A 896 904 H(2)O(2) FORMULA 23249341 A 909 914 H(2)O FORMULA 23249341 A 965 967 OH FORMULA 23249341 T 15 17 OH FORMULA 23249525 A 1003 1013 quinpirole TRIVIAL 23249525 A 111 120 8-OH-DPAT SYSTEMATIC 23249525 A 1138 1147 8-OH-DPAT SYSTEMATIC 23249525 A 1152 1162 quinpirole TRIVIAL 23249525 A 1304 1314 Quinpirole TRIVIAL 23249525 A 1452 1461 8-OH-DPAT SYSTEMATIC 23249525 A 188 196 dopamine TRIVIAL 23249525 A 220 230 quinpirole TRIVIAL 23249525 A 316 325 8-OH-DPAT SYSTEMATIC 23249525 A 337 347 quinpirole TRIVIAL 23249525 A 36 45 serotonin TRIVIAL 23249525 A 453 462 8-OH-DPAT SYSTEMATIC 23249525 A 466 476 quinpirole TRIVIAL 23249525 A 517 526 8-OH-DPAT SYSTEMATIC 23249525 A 617 627 quinpirole TRIVIAL 23249525 A 679 688 8-OH-DPAT SYSTEMATIC 23249525 A 693 703 quinpirole TRIVIAL 23249525 A 70 109 8-hydroxy-2-(di-n-propylamino) tetralin SYSTEMATIC 23249525 A 812 821 8-OH-DPAT SYSTEMATIC 23249525 A 870 880 quinpirole TRIVIAL 23249525 A 954 964 quinpirole TRIVIAL 23249525 A 989 998 8-OH-DPAT SYSTEMATIC 23249525 T 0 10 Quinpirole TRIVIAL 23249525 T 15 24 8-OH-DPAT SYSTEMATIC 23249745 A 310 321 sparsomycin TRIVIAL 23250357 A 120 127 glucose TRIVIAL 23250357 A 1216 1227 Colesevelam TRIVIAL 23250357 A 1301 1312 Colesevelam TRIVIAL 23250357 A 1428 1435 glucose TRIVIAL 23250357 A 199 210 Colesevelam TRIVIAL 23250357 A 369 378 metformin TRIVIAL 23250357 A 51 60 bile acid FAMILY 23250357 A 520 531 Colesevelam TRIVIAL 23250357 A 645 652 glucose TRIVIAL 23250357 A 675 682 glucose TRIVIAL 23250357 A 80 91 Colesevelam TRIVIAL 23250357 A 843 854 Colesevelam TRIVIAL 23250357 A 958 965 glucose TRIVIAL 23250357 T 16 25 bile acid FAMILY 23250357 T 41 48 glucose TRIVIAL 23250541 A 1003 1005 Fe FORMULA 23250541 A 1202 1204 Cr FORMULA 23250541 A 1237 1244 Cr(III) FORMULA 23250541 A 1420 1439 chromium picolinate SYSTEMATIC 23250541 A 1441 1453 [Cr(pic)(3)] FORMULA 23250541 A 1461 1463 Cr FORMULA 23250541 A 1479 1486 CrCl(3) FORMULA 23250541 A 1493 1495 Cr FORMULA 23250541 A 1515 1557 Cr3 ([Cr(3)O(propionate)(6)(H(2)O)(3)](+)) FORMULA 23250541 A 1574 1576 Cr FORMULA 23250541 A 1662 1669 CrCl(3) FORMULA 23250541 A 1674 1677 Cr3 FORMULA 23250541 A 1687 1699 [Cr(pic)(3)] FORMULA 23250541 A 1709 1711 Cr FORMULA 23250541 A 1771 1773 Cr FORMULA 23250541 A 1878 1880 Cu FORMULA 23250541 A 483 485 Cu FORMULA 23250541 A 487 489 Zn FORMULA 23250541 A 491 493 Fe FORMULA 23250541 A 495 497 Mg FORMULA 23250541 A 503 505 Ca FORMULA 23250541 A 564 566 Cr FORMULA 23250541 A 693 695 Cu FORMULA 23250541 A 697 699 Zn FORMULA 23250541 A 701 703 Fe FORMULA 23250541 A 705 707 Mg FORMULA 23250541 A 895 897 Cu FORMULA 23250541 A 938 940 Ca FORMULA 23250541 T 122 130 chromium SYSTEMATIC 23250541 T 92 102 fatty rats FAMILY 23250811 A 0 8 Curcumin TRIVIAL 23250811 A 1225 1233 curcumin TRIVIAL 23250811 A 1260 1273 sulfasalazine TRIVIAL 23250811 A 1388 1396 curcumin TRIVIAL 23250811 A 1409 1422 sulfasalazine TRIVIAL 23250811 A 1439 1447 Curcumin TRIVIAL 23250811 A 1489 1524 2,4,6-trinitrobenzene sulfonic acid SYSTEMATIC 23250811 A 1564 1577 sulfasalazine TRIVIAL 23250811 A 1612 1620 curcumin TRIVIAL 23250811 A 183 191 curcumin TRIVIAL 23250811 A 354 389 2,4,6-trinitrobenzene sulfonic acid SYSTEMATIC 23250811 A 436 444 curcumin TRIVIAL 23250811 A 448 461 sulfasalazine TRIVIAL 23250811 A 852 860 curcumin TRIVIAL 23250811 T 0 8 Curcumin TRIVIAL 23252421 A 348 358 octylamine SYSTEMATIC 23252481 A 155 164 vindoline TRIVIAL 23252481 A 208 217 vindoline TRIVIAL 23252481 A 46 57 vinblastine TRIVIAL 23252481 A 501 508 Fe(III) FORMULA 23252481 A 532 545 catharanthine TRIVIAL 23252481 A 597 608 vinblastine TRIVIAL 23252481 A 699 708 vindoline TRIVIAL 23252481 A 835 844 vindoline TRIVIAL 23252481 A 998 1009 vinblastine TRIVIAL 23252481 T 111 120 vindoline TRIVIAL 23252481 T 34 45 vinblastine TRIVIAL 23252610 A 1008 1011 HPB ABBREVIATION 23252610 A 1121 1124 HPB ABBREVIATION 23252610 A 270 304 4-hydroxy-1-(3-pyridyl)-1-butanone SYSTEMATIC 23252610 A 306 309 HPB ABBREVIATION 23252610 A 707 710 HPB ABBREVIATION 23252610 A 752 755 HPB ABBREVIATION 23252610 T 12 46 4-Hydroxy-1-(3-pyridyl)-1-butanone SYSTEMATIC 23252610 T 48 51 HPB ABBREVIATION 23252823 A 1140 1149 1-decanol SYSTEMATIC 23252823 A 12 19 glucono TRIVIAL 23252823 A 123 132 methylene SYSTEMATIC 23252823 A 1427 1435 hydrogen SYSTEMATIC 23252823 A 1529 1533 (1)H FORMULA 23252823 A 154 159 amino FAMILY 23252823 A 1573 1581 hydrogen SYSTEMATIC 23252823 A 1598 1605 glucono TRIVIAL 23252823 A 1637 1644 pyrenyl SYSTEMATIC 23252823 A 29 45 1-pyrenesulfonyl SYSTEMATIC 23252823 A 69 86 α,ω-diaminoalkane FAMILY 23252823 A 765 773 naphthyl SYSTEMATIC 23252823 T 0 7 Pyrenyl SYSTEMATIC 23252823 T 15 22 glucono TRIVIAL 23252848 A 25 41 withawrightolide TRIVIAL 23252848 A 261 275 withametelin L TRIVIAL 23252848 A 336 339 MTS ABBREVIATION 23252848 A 358 374 withanolides 1-5 MULTIPLE 23252848 A 6 17 withanolide TRIVIAL 23252848 A 62 74 withanolides FAMILY 23252848 T 18 30 withanolides FAMILY 23253441 A 208 221 oxadiazepines FAMILY 23253441 A 57 67 oxadiazine FAMILY 23253441 T 23 36 oxadiazepines FAMILY 23253856 A 535 546 hydroxyurea SYSTEMATIC 23253856 T 106 117 hydroxyurea SYSTEMATIC 23254196 A 1078 1087 genistein TRIVIAL 23254196 A 1219 1223 cAMP ABBREVIATION 23254196 A 1282 1291 genistein TRIVIAL 23254196 A 1326 1335 genistein TRIVIAL 23254196 A 167 176 genistein TRIVIAL 23254196 A 30 39 genistein TRIVIAL 23254196 A 321 330 Genistein TRIVIAL 23254196 A 466 469 Ser FORMULA 23254196 A 474 477 Thr FORMULA 23254196 A 510 519 Genistein TRIVIAL 23254196 A 560 566 Ca(2+) FORMULA 23254196 A 600 606 Ca(2+) FORMULA 23254196 A 663 675 nitric oxide SYSTEMATIC 23254196 A 688 696 estrogen FAMILY 23254196 A 745 754 genistein TRIVIAL 23254196 A 921 930 genistein TRIVIAL 23254196 T 14 23 genistein TRIVIAL 23255050 A 0 10 Iron oxide SYSTEMATIC 23255050 A 1082 1084 Fe FORMULA 23255050 A 1114 1118 iron SYSTEMATIC 23255050 A 1761 1771 gadolinium SYSTEMATIC 23255050 A 1964 1966 Gd FORMULA 23255050 A 2268 2272 iron SYSTEMATIC 23255050 A 368 388 polyvinylpyrrolidone SYSTEMATIC 23255050 A 863 865 Fe FORMULA 23255050 A 901 912 glutathione TRIVIAL 23255050 A 927 940 acetylcholine SYSTEMATIC 23255050 T 20 30 iron oxide SYSTEMATIC 23255284 A 1013 1023 nucleotide FAMILY 23255284 A 1168 1192 dipeptide-mononucleotide FAMILY 23255284 A 195 207 L-dipeptides FAMILY 23255284 A 221 230 histidine TRIVIAL 23255284 A 250 257 Ser-His FORMULA 23255284 A 532 556 dipeptide-mononucleotide FAMILY 23255284 A 725 734 imidazole SYSTEMATIC 23255284 A 751 760 histidine TRIVIAL 23255284 A 768 776 carboxyl SYSTEMATIC 23255284 A 788 797 dipeptide FAMILY 23255284 T 17 31 phosphodiester SYSTEMATIC 23255284 T 40 49 histidine TRIVIAL 23255284 T 61 71 dipeptides FAMILY 23255384 A 108 127 coniothyrinones A-D MULTIPLE 23255384 A 11 32 hydroxyanthraquinones FAMILY 23255384 A 431 466 coniothyrinones A (5), B (6), and D MULTIPLE 23255384 A 584 600 coniothyrinone C TRIVIAL 23255384 A 614 649 Coniothyrinones A (5), B (6), and D MULTIPLE 23255384 A 754 763 tetralone TRIVIAL 23255384 A 805 819 anthraquinones FAMILY 23255384 A 83 92 tetralone TRIVIAL 23255384 T 41 61 hydroxyanthraquinone SYSTEMATIC 23255471 A 0 16 Tungsten carbide SYSTEMATIC 23255471 A 1037 1039 Na FORMULA 23255471 A 1046 1054 SrTiO(3) FORMULA 23255471 A 1089 1105 tungsten carbide SYSTEMATIC 23255471 A 1176 1184 platinum SYSTEMATIC 23255471 A 145 161 Tungsten carbide SYSTEMATIC 23255471 A 232 240 tungsten SYSTEMATIC 23255471 A 26 34 platinum SYSTEMATIC 23255471 A 278 286 C(3)N(4) FORMULA 23255471 A 292 300 C(3)N(4) FORMULA 23255471 A 557 562 W(2)C FORMULA 23255471 A 566 568 WC FORMULA 23255471 A 630 632 WC FORMULA 23255471 A 709 717 hydrogen SYSTEMATIC 23255471 A 754 756 WC FORMULA 23255471 A 785 793 hydrogen SYSTEMATIC 23255471 A 838 844 oxygen SYSTEMATIC 23255471 A 870 887 tungsten carbides FAMILY 23255471 A 952 956 H(2) FORMULA 23255471 A 961 965 O(2) FORMULA 23255471 A 997 1002 H(2)O FORMULA 23255471 T 0 16 Tungsten carbide SYSTEMATIC 23256442 A 1046 1057 reduced GSH ABBREVIATION 23256442 A 107 117 methionine TRIVIAL 23256442 A 123 130 choline FAMILY 23256442 A 557 564 alanine TRIVIAL 23256442 A 589 601 triglyceride FAMILY 23256442 A 608 623 malondialdehyde TRIVIAL 23256442 A 625 628 MDA ABBREVIATION 23256442 A 635 654 reduced glutathione TRIVIAL 23256442 A 656 659 GSH ABBREVIATION 23256442 A 961 964 MDA ABBREVIATION 23256442 T 64 74 methionine TRIVIAL 23256442 T 80 87 choline FAMILY 23256445 A 1047 1050 TRG ABBREVIATION 23256445 A 149 168 thiobarbituric acid SYSTEMATIC 23256445 A 201 224 8-hydroxydeoxyguanosine SYSTEMATIC 23256445 A 27 39 trigonelline TRIVIAL 23256445 A 318 321 TRG ABBREVIATION 23256445 A 41 44 TRG ABBREVIATION 23256445 A 416 419 TRG ABBREVIATION 23256445 A 583 589 oxygen SYSTEMATIC 23256445 A 614 626 carbohydrate FAMILY 23256445 A 690 701 glutathione TRIVIAL 23256445 A 768 771 TRG ABBREVIATION 23256445 A 832 835 TRG ABBREVIATION 23256445 A 885 890 NADPH ABBREVIATION 23256445 T 0 12 Trigonelline TRIVIAL 23256446 A 1289 1296 glucose TRIVIAL 23256446 A 607 614 glucose TRIVIAL 23256446 A 833 840 glucose TRIVIAL 23256446 A 862 873 cholesterol TRIVIAL 23256446 A 891 904 triglycerides FAMILY 23256510 A 1067 1071 F8BT ABBREVIATION 23256510 A 304 316 polyfluorene SYSTEMATIC 23256510 A 328 419 poly(9,9'-dioctylfluorene-co-bis-N,N'-(4-butylphenyl)-bis-N,N'-phenyl-1,4-phenylene-diamine SYSTEMATIC 23256510 A 422 425 PFB ABBREVIATION 23256510 A 431 476 poly(9,9'-dioctylfluorene-co-benzothiadiazole SYSTEMATIC 23256510 A 479 483 F8BT ABBREVIATION 23256510 A 747 751 F8BT ABBREVIATION 23256510 A 778 781 PFB ABBREVIATION 23256510 A 869 873 F8BT ABBREVIATION 23256510 A 943 946 PFB ABBREVIATION 23256510 A 978 982 F8BT ABBREVIATION 23256609 A 1247 1259 benzoic acid SYSTEMATIC 23256609 A 180 192 Benzoic acid SYSTEMATIC 23256609 A 251 259 hydrogen SYSTEMATIC 23256609 A 481 501 mono- and dihydrates MULTIPLE 23256609 A 83 98 carboxylic acid SYSTEMATIC 23256609 A 852 860 hydrogen SYSTEMATIC 23256609 T 103 115 benzoic acid SYSTEMATIC 23256621 A 0 21 Poly(ethylene glycol) SYSTEMATIC 23256621 A 1005 1009 mPEG ABBREVIATION 23256621 A 1069 1073 PEGs ABBREVIATION 23256621 A 1079 1088 polyether SYSTEMATIC 23256621 A 1241 1262 dibenzylamino ethanol SYSTEMATIC 23256621 A 1287 1291 PEGs ABBREVIATION 23256621 A 1336 1341 amino FAMILY 23256621 A 1392 1397 amino FAMILY 23256621 A 1435 1459 squaric acid ester amide SYSTEMATIC 23256621 A 1543 1546 PEG ABBREVIATION 23256621 A 159 162 PEG ABBREVIATION 23256621 A 1669 1673 mPEG ABBREVIATION 23256621 A 1713 1721 hydroxyl SYSTEMATIC 23256621 A 1761 1782 poly(ethylene glycol) SYSTEMATIC 23256621 A 1857 1863 acetal SYSTEMATIC 23256621 A 1875 1879 PEGs ABBREVIATION 23256621 A 1884 1887 PEG ABBREVIATION 23256621 A 23 26 PEG ABBREVIATION 23256621 A 302 306 PEGs ABBREVIATION 23256621 A 468 474 acetal SYSTEMATIC 23256621 A 486 490 PEGs ABBREVIATION 23256621 A 691 710 acetaldehyde acetal SYSTEMATIC 23256621 A 727 768 (hetero)functional poly(ethylene glycol)s FAMILY 23256621 A 909 923 ethylene oxide SYSTEMATIC 23256621 A 925 936 cholesterol TRIVIAL 23256621 A 938 959 dibenzylamino ethanol SYSTEMATIC 23256621 A 965 1003 poly(ethylene glycol) monomethyl ether SYSTEMATIC 23256621 T 102 124 poly(ethylene glycol)s FAMILY 23256643 A 138 146 pyridine SYSTEMATIC 23256643 A 1483 1491 pyridine SYSTEMATIC 23256643 A 1956 1964 pyridine SYSTEMATIC 23256643 A 2002 2004 Mn FORMULA 23256643 A 2005 2013 pyridine SYSTEMATIC 23256643 A 2125 2131 Mn(II) FORMULA 23256643 A 2177 2185 pyridine SYSTEMATIC 23256643 A 333 350 pyridine nitrogen SYSTEMATIC 23256643 A 39 102 manganese(II) diacetylacetonate and dihexafluoroacetylacetonate MULTIPLE 23256643 A 744 750 m-PyNO FORMULA 23256643 A 811 827 acetyl acetonate SYSTEMATIC 23256643 A 960 976 acetyl acetonate SYSTEMATIC 23256643 T 53 59 Mn(II) FORMULA 23256719 A 1045 1056 glutathione TRIVIAL 23256719 A 1087 1089 NO FORMULA 23256719 A 510 515 Thiol SYSTEMATIC 23256719 A 534 553 N-acetyl-L-cysteine SYSTEMATIC 23256719 A 555 558 NAC ABBREVIATION 23256719 A 561 574 carbocysteine TRIVIAL 23256719 A 576 586 erdosteine TRIVIAL 23256719 A 592 602 fudosteine TRIVIAL 23256719 A 678 681 NAC ABBREVIATION 23256719 A 686 699 carbocysteine TRIVIAL 23256719 A 765 780 corticosteroids FAMILY 23256719 A 858 868 superoxide TRIVIAL 23256724 A 0 10 Clonazepam TRIVIAL 23256724 A 224 234 clonazepam TRIVIAL 23256724 A 373 383 clonazepam TRIVIAL 23256724 A 553 563 clonazepam TRIVIAL 23256724 A 623 626 CO2 FORMULA 23256724 A 780 783 CO2 FORMULA 23256724 A 942 952 clonazepam TRIVIAL 23256724 A 987 996 serotonin TRIVIAL 23256724 T 0 10 Clonazepam TRIVIAL 23256769 A 1008 1016 hematite TRIVIAL 23256769 A 1134 1144 iron oxide SYSTEMATIC 23256769 A 14 22 hematite TRIVIAL 23256769 A 147 155 hematite TRIVIAL 23256769 A 292 299 Fe(III) FORMULA 23256769 A 343 351 hematite TRIVIAL 23256769 A 363 375 ferrihydrite TRIVIAL 23256769 A 455 460 As(V) FORMULA 23256769 A 524 534 iron oxide SYSTEMATIC 23256769 A 62 74 ferrihydrite TRIVIAL 23256769 A 677 689 ferrihydrite TRIVIAL 23256769 A 704 714 iron oxide SYSTEMATIC 23256769 A 812 824 ferrihydrite TRIVIAL 23256769 A 828 836 hematite TRIVIAL 23256769 A 941 946 As(V) FORMULA 23256769 A 991 1003 ferrihydrite TRIVIAL 23256769 T 108 118 iron oxide SYSTEMATIC 23256816 A 121 128 calcium SYSTEMATIC 23256816 A 787 798 pentamidine TRIVIAL 23256819 A 1184 1195 amino acids FAMILY 23256819 A 1322 1331 histidine TRIVIAL 23256819 A 1333 1343 methionine TRIVIAL 23256819 A 1349 1357 cysteine TRIVIAL 23256819 A 1432 1438 lysine TRIVIAL 23256819 A 1498 1503 amino FAMILY 23256819 A 1656 1667 amino acids FAMILY 23256819 A 515 526 amino acids FAMILY 23256819 A 852 882 ((13)C)methyldodecanesulfonate SYSTEMATIC 23256819 T 167 178 Amino Acids FAMILY 23258537 A 1057 1064 ferrous SYSTEMATIC 23258537 A 1144 1159 ribonucleotides FAMILY 23258537 A 847 856 potassium SYSTEMATIC 23258537 A 981 990 Magnesium SYSTEMATIC 23258671 A 10 18 tungsten SYSTEMATIC 23258671 A 116 117 W FORMULA 23258671 A 159 167 tungsten SYSTEMATIC 23258671 A 178 186 nitrogen SYSTEMATIC 23258671 A 487 488 W FORMULA 23258671 A 729 730 W FORMULA 23258671 A 80 93 beta-tungsten SYSTEMATIC 23258671 T 23 36 beta-tungsten SYSTEMATIC 23258742 A 1038 1042 PBDE ABBREVIATION 23258742 A 1171 1175 PBDE ABBREVIATION 23258742 A 1558 1564 BDE-99 ABBREVIATION 23258742 A 185 221 2,2',4,4',5-pentabromodiphenyl ether SYSTEMATIC 23258742 A 223 229 BDE-99 ABBREVIATION 23258742 A 251 268 dimethylsulfoxide SYSTEMATIC 23258742 A 270 274 DMSO ABBREVIATION 23258742 A 47 77 polybrominated diphenyl ethers FAMILY 23258742 A 475 479 PBDE ABBREVIATION 23258742 A 681 687 BDE-99 ABBREVIATION 23258742 A 79 84 PBDEs ABBREVIATION 23258742 A 821 825 PBDE ABBREVIATION 23258742 A 939 943 PBDE ABBREVIATION 23258742 T 49 56 PBDE-99 ABBREVIATION 23258773 A 1040 1044 PCBs ABBREVIATION 23258773 A 1090 1093 PCB ABBREVIATION 23258773 A 1155 1158 PCB ABBREVIATION 23258773 A 1173 1176 PCB ABBREVIATION 23258773 A 1340 1343 PCB ABBREVIATION 23258773 A 1439 1443 PCBs ABBREVIATION 23258773 A 1491 1494 PCB ABBREVIATION 23258773 A 244 256 polyethylene SYSTEMATIC 23258773 A 289 292 PCB ABBREVIATION 23258773 A 460 463 PCB ABBREVIATION 23258773 A 63 88 polychlorinated biphenyls FAMILY 23258773 A 742 746 PCBs ABBREVIATION 23258773 A 879 901 Aroclors 1016 and 1254 MULTIPLE 23258773 A 90 94 PCBs ABBREVIATION 23258773 T 45 70 polychlorinated biphenyls FAMILY 23259536 A 277 286 porphyrin FAMILY 23259536 A 319 328 fullerene TRIVIAL 23259536 A 350 359 quinoline SYSTEMATIC 23259536 A 368 385 dihydroindolizine SYSTEMATIC 23259536 A 405 420 dithienylethene SYSTEMATIC 23259536 A 438 447 porphyrin FAMILY 23259536 A 524 533 fullerene TRIVIAL 23259536 A 681 690 porphyrin FAMILY 23259666 A 0 10 Vancomycin TRIVIAL 23259666 A 1076 1086 vancomycin TRIVIAL 23259666 A 119 129 vancomycin TRIVIAL 23259666 A 1197 1207 vancomycin TRIVIAL 23259666 A 1259 1269 iron oxide SYSTEMATIC 23259666 A 1563 1573 vancomycin TRIVIAL 23259666 A 408 424 poly(amidoamine) SYSTEMATIC 23259666 A 426 431 PAMAM ABBREVIATION 23259666 A 458 468 vancomycin TRIVIAL 23259666 A 476 477 C FORMULA 23259666 A 648 658 vancomycin TRIVIAL 23259666 A 671 686 (D)-Ala-(D)-Ala FORMULA 23259666 A 690 700 vancomycin TRIVIAL 23259666 A 711 726 (D)-Ala-(D)-Lac FORMULA 23259666 A 852 862 vancomycin TRIVIAL 23259666 A 967 977 vancomycin TRIVIAL 23259666 T 28 38 vancomycin TRIVIAL 23259742 A 564 570 oxygen SYSTEMATIC 23259742 A 76 82 carbon SYSTEMATIC 23259742 A 781 787 ZrO(2) FORMULA 23259742 T 62 68 carbon SYSTEMATIC 23259773 A 285 292 silicon SYSTEMATIC 23259773 A 595 601 carbon SYSTEMATIC 23259773 A 623 631 platinum SYSTEMATIC 23259773 A 88 90 Si FORMULA 23259773 T 101 108 silicon SYSTEMATIC 23259865 A 137 149 camptothecin TRIVIAL 23259865 A 272 291 indenoisoquinolines FAMILY 23259865 A 495 514 indenoisoquinolines FAMILY 23259865 T 39 58 indenoisoquinolines FAMILY 23259866 A 214 225 polystyrene SYSTEMATIC 23259866 A 232 245 polybutadiene SYSTEMATIC 23259866 A 256 268 polyisoprene SYSTEMATIC 23259866 A 360 384 poly(1,3-cyclohexadiene) SYSTEMATIC 23259866 A 63 87 poly(1,3-cyclohexadiene) SYSTEMATIC 23259866 A 747 751 PCHD ABBREVIATION 23259866 A 89 93 PCHD ABBREVIATION 23259866 T 57 77 poly(cyclohexadiene) SYSTEMATIC 23259985 A 0 8 Polyplex TRIVIAL 23259985 A 1147 1157 polyplexes FAMILY 23259985 A 1222 1232 polyplexes FAMILY 23259985 A 1335 1345 polyplexes FAMILY 23259985 A 1630 1640 polyplexes FAMILY 23259985 A 264 280 poly((L)-lysine) SYSTEMATIC 23259985 A 282 285 PLL ABBREVIATION 23259985 A 314 317 PLL ABBREVIATION 23259985 A 382 385 PLL ABBREVIATION 23259985 A 423 433 polyplexes FAMILY 23259985 A 580 590 polyplexes FAMILY 23259985 A 60 70 polyplexes FAMILY 23259985 A 722 730 polyplex TRIVIAL 23259985 A 783 786 PLL ABBREVIATION 23259985 A 795 805 polyplexes FAMILY 23259985 A 871 879 polyplex TRIVIAL 23259985 A 945 948 PLL ABBREVIATION 23259985 A 957 967 polyplexes FAMILY 23259985 T 50 58 polyplex TRIVIAL 23260032 A 1028 1035 bismuth SYSTEMATIC 23260032 A 117 124 bismuth SYSTEMATIC 23260032 A 125 135 asparagine TRIVIAL 23260032 T 28 35 Bismuth SYSTEMATIC 23260032 T 36 46 Asparagine TRIVIAL 23260347 A 0 25 Diphenylphosphinic amides FAMILY 23260347 A 115 124 potassium SYSTEMATIC 23260347 A 30 54 diphenylphosphine oxides FAMILY 23260347 T 28 53 diphenylphosphinic amides FAMILY 23260347 T 58 82 diphenylphosphine oxides FAMILY 23260352 A 167 186 hydroxy-ethyl-amine SYSTEMATIC 23260352 A 230 242 Mannich base FAMILY 23260352 A 260 271 amodiaquine TRIVIAL 23260352 A 45 64 hydroxy-ethyl-amine SYSTEMATIC 23260352 T 47 66 hydroxy-ethyl-amine SYSTEMATIC 23261524 A 1015 1023 nutlin-3 TRIVIAL 23261524 A 874 882 nutlin-3 TRIVIAL 23261527 A 11 25 prostaglandins FAMILY 23261528 A 1060 1067 icariin TRIVIAL 23261528 A 1267 1274 icariin TRIVIAL 23261528 A 273 280 steroid FAMILY 23261528 A 445 452 icariin TRIVIAL 23261528 A 594 601 sulfate SYSTEMATIC 23261528 A 602 608 sodium SYSTEMATIC 23261528 A 633 640 icariin TRIVIAL 23261528 A 894 901 icariin TRIVIAL 23261528 T 155 164 flavonoid FAMILY 23261528 T 175 182 icariin TRIVIAL 23261588 A 1409 1414 BPA-f ABBREVIATION 23261588 A 1504 1509 BPA-f ABBREVIATION 23261588 A 1646 1651 BPA-f ABBREVIATION 23261588 A 237 242 BPA-f ABBREVIATION 23261588 A 36 55 boronophenylalanine SYSTEMATIC 23261588 A 415 418 MTT ABBREVIATION 23261588 A 426 436 calcein-AM TRIVIAL 23261588 A 437 453 Propidium Iodide SYSTEMATIC 23261588 A 56 64 fructose TRIVIAL 23261588 A 570 573 MTT ABBREVIATION 23261588 A 653 658 BPA-f ABBREVIATION 23261588 A 66 71 BPA-f ABBREVIATION 23261588 A 882 887 BPA-f ABBREVIATION 23261588 A 905 915 Calcein-AM TRIVIAL 23261588 A 929 934 BPA-f ABBREVIATION 23261588 T 78 83 Boron SYSTEMATIC 23261590 A 1180 1194 neoechinulin A TRIVIAL 23261590 A 1243 1257 neoechinulin A TRIVIAL 23261590 A 1575 1589 neoechinulin A TRIVIAL 23261590 A 1653 1667 neoechinulin A TRIVIAL 23261590 A 358 372 neoechinulin A TRIVIAL 23261590 A 377 383 indole SYSTEMATIC 23261590 A 511 525 Neoechinulin A TRIVIAL 23261590 A 587 593 oxygen SYSTEMATIC 23261590 A 598 606 nitrogen SYSTEMATIC 23261590 A 682 696 neoechinulin A TRIVIAL 23261590 A 857 873 prostaglandin E2 TRIVIAL 23261590 A 875 879 PGE2 ABBREVIATION 23261590 A 990 1002 nitric oxide SYSTEMATIC 23261590 T 0 14 Neoechinulin A TRIVIAL 23261644 A 520 543 methylmethanesulphonate SYSTEMATIC 23261644 A 545 548 MMS ABBREVIATION 23261644 A 612 615 MMS ABBREVIATION 23261644 A 734 737 MMS ABBREVIATION 23261645 A 0 9 Jaspamide TRIVIAL 23261645 A 11 25 jasplakinolide TRIVIAL 23261645 A 1133 1142 jaspamide TRIVIAL 23261645 A 1195 1207 mitoxantrone TRIVIAL 23261645 A 1380 1389 jaspamide TRIVIAL 23261645 A 27 37 NSC-613009 IDENTIFIER 23261645 A 331 340 Jaspamide TRIVIAL 23261645 A 433 442 Jaspamide TRIVIAL 23261645 A 44 61 cyclodepsipeptide FAMILY 23261645 A 486 495 Jaspamide TRIVIAL 23261645 A 790 799 Jaspamide TRIVIAL 23261645 T 15 24 jaspamide TRIVIAL 23261667 A 113 119 copper SYSTEMATIC 23261667 A 1200 1206 copper SYSTEMATIC 23261667 A 191 197 copper SYSTEMATIC 23261667 T 70 76 copper SYSTEMATIC 23261676 A 1086 1096 superoxide TRIVIAL 23261676 A 1101 1109 hydroxyl SYSTEMATIC 23261676 A 1141 1156 (-) epicatechin TRIVIAL 23261676 A 1212 1227 (-) epicatechin TRIVIAL 23261676 A 122 137 (-) epicatechin TRIVIAL 23261676 A 1315 1322 calcium SYSTEMATIC 23261676 A 1363 1381 tricarboxylic acid SYSTEMATIC 23261676 A 1428 1439 glutathione TRIVIAL 23261676 A 1444 1466 adenosine triphosphate SYSTEMATIC 23261676 A 1474 1489 (-) epicatechin TRIVIAL 23261676 A 1525 1538 isoproterenol TRIVIAL 23261676 A 173 186 isoproterenol TRIVIAL 23261676 A 267 282 (-) epicatechin TRIVIAL 23261676 A 368 381 isoproterenol TRIVIAL 23261676 A 506 519 Isoproterenol TRIVIAL 23261676 A 669 676 calcium SYSTEMATIC 23261676 A 753 764 glutathione TRIVIAL 23261676 A 777 788 glutathione TRIVIAL 23261676 A 800 819 reduced glutathione TRIVIAL 23261676 A 821 831 isocitrate TRIVIAL 23261676 A 833 842 succinate TRIVIAL 23261676 A 844 850 malate TRIVIAL 23261676 A 852 867 α-ketoglutarate TRIVIAL 23261676 A 872 876 NADH ABBREVIATION 23261676 A 918 940 adenosine triphosphate SYSTEMATIC 23261676 A 942 957 (-) Epicatechin TRIVIAL 23261676 T 0 15 (-) Epicatechin TRIVIAL 23261676 T 133 140 calcium SYSTEMATIC 23261676 T 144 157 isoproterenol TRIVIAL 23261676 T 97 119 adenosine triphosphate SYSTEMATIC 23261705 A 1029 1038 rapamycin TRIVIAL 23261705 A 629 638 rapamycin TRIVIAL 23261705 A 96 105 rapamycin TRIVIAL 23261715 A 1067 1082 4-oxo-2-nonenal SYSTEMATIC 23261715 A 1176 1180 GSSG ABBREVIATION 23261715 A 1181 1192 glutathione TRIVIAL 23261715 A 121 131 amino acid FAMILY 23261715 A 1260 1268 aldehyde SYSTEMATIC 23261715 A 1352 1356 GSSG ABBREVIATION 23261715 A 1429 1433 GSSG ABBREVIATION 23261715 A 1452 1455 Cys FORMULA 23261715 A 205 220 4-oxo-2-nonenal SYSTEMATIC 23261715 A 298 306 aldehyde SYSTEMATIC 23261715 A 441 443 SH FORMULA 23261715 A 454 488 p-chloromercuriphenylsulfonic acid SYSTEMATIC 23261715 A 493 520 p-chloromercuribenzoic acid SYSTEMATIC 23261715 A 552 557 NADPH ABBREVIATION 23261715 A 62 68 aldose FAMILY 23261715 A 645 666 glutathione disulfide SYSTEMATIC 23261715 A 668 672 GSSG ABBREVIATION 23261715 A 767 781 dithiothreitol SYSTEMATIC 23261715 A 786 797 glutathione TRIVIAL 23261715 A 887 890 Cys FORMULA 23261715 A 944 947 Cys FORMULA 23261715 T 102 122 oxidized glutathione TRIVIAL 23261715 T 127 129 SH FORMULA 23261715 T 59 65 aldose FAMILY 23261820 A 0 9 Triclosan TRIVIAL 23261820 A 11 14 TCS ABBREVIATION 23261820 A 119 122 TCS ABBREVIATION 23261820 A 160 177 ethinyl estradiol TRIVIAL 23261820 A 227 230 TCS ABBREVIATION 23261820 A 266 269 TCS ABBREVIATION 23261820 A 595 603 estrogen FAMILY 23261820 A 645 648 TCS ABBREVIATION 23261820 A 757 760 TCS ABBREVIATION 23261820 A 877 885 estrogen FAMILY 23261820 A 980 983 TCS ABBREVIATION 23261820 T 14 23 triclosan TRIVIAL 23261820 T 74 91 ethinyl estradiol TRIVIAL 23262162 A 0 11 Resveratrol TRIVIAL 23262162 A 1240 1251 resveratrol TRIVIAL 23262162 A 1281 1290 polyamide FAMILY 23262162 A 1380 1391 resveratrol TRIVIAL 23262162 A 1708 1712 DPPH ABBREVIATION 23262162 A 1741 1752 resveratrol TRIVIAL 23262162 A 1978 1989 resveratrol TRIVIAL 23262162 A 2345 2356 resveratrol TRIVIAL 23262162 A 262 273 resveratrol TRIVIAL 23262162 A 277 284 ethanol SYSTEMATIC 23262162 A 388 399 resveratrol TRIVIAL 23262162 A 431 437 trolox TRIVIAL 23262162 A 455 464 Vitamin E FAMILY 23262162 A 607 618 resveratrol TRIVIAL 23262162 A 623 629 trolox TRIVIAL 23262162 A 655 659 DPPH ABBREVIATION 23262162 A 711 715 DPPH ABBREVIATION 23262162 A 842 853 resveratrol TRIVIAL 23262162 A 877 883 trolox TRIVIAL 23262203 A 1022 1026 HPMA ABBREVIATION 23262203 A 255 288 N-(2-hydroxypropyl)methacrylamide SYSTEMATIC 23262203 A 290 294 HPMA ABBREVIATION 23262203 A 456 466 Gadolinium SYSTEMATIC 23262203 A 475 479 HPMA ABBREVIATION 23262203 A 774 778 HPMA ABBREVIATION 23262203 T 71 75 HPMA ABBREVIATION 23262279 A 1019 1107 4-{(Z)-[(2Z)-2-(2-fluorobenzylidene)-4-oxo-1,3-thiazolidin-5-ylidene]methyl}benzoic acid SYSTEMATIC 23262279 A 1464 1470 ML-145 IDENTIFIER 23262279 A 1472 1603 2-hydroxy-4-[4-(5Z)-5-[(E)-2-methyl-3-phenylprop-2-enylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]butanoylamino]benzoic acid SYSTEMATIC 23262390 A 1038 1040 Mn FORMULA 23262390 A 1237 1239 Mn FORMULA 23262390 A 297 306 manganese SYSTEMATIC 23262390 A 308 310 Mn FORMULA 23262390 A 638 640 Mn FORMULA 23262390 A 704 706 Mn FORMULA 23262390 T 0 9 Manganese SYSTEMATIC 23263987 A 110 117 glucose TRIVIAL 23263987 A 200 204 cAMP ABBREVIATION 23263987 A 280 284 cAMP ABBREVIATION 23263987 A 32 42 cyclic AMP TRIVIAL 23263987 A 44 48 cAMP ABBREVIATION 23263987 A 621 628 glucose TRIVIAL 23263987 T 136 146 cyclic AMP TRIVIAL 23263987 T 61 68 glucose TRIVIAL 23264030 A 1135 1145 fluoxetine TRIVIAL 23264030 A 119 129 Fluoxetine TRIVIAL 23264030 A 1259 1269 fluoxetine TRIVIAL 23264030 A 14 23 serotonin TRIVIAL 23264030 A 1459 1469 fluoxetine TRIVIAL 23264030 A 150 159 serotonin TRIVIAL 23264030 A 1519 1529 fluoxetine TRIVIAL 23264030 A 43 53 fluoxetine TRIVIAL 23264030 A 434 444 fluoxetine TRIVIAL 23264030 A 445 458 hydrochloride FAMILY 23264030 A 901 911 fluoxetine TRIVIAL 23264030 T 11 21 fluoxetine TRIVIAL 23264615 A 1211 1219 cortisol TRIVIAL 23264615 A 1295 1304 PF 915275 IDENTIFIER 23264615 A 146 160 prostaglandins FAMILY 23264615 A 1564 1572 cortisol TRIVIAL 23264615 A 1611 1623 progesterone TRIVIAL 23264615 A 1712 1720 cortisol TRIVIAL 23264615 A 196 204 cortisol TRIVIAL 23264615 A 209 223 hydroxysteroid FAMILY 23264615 A 266 278 progesterone TRIVIAL 23264615 A 349 353 keto SYSTEMATIC 23264615 A 573 581 cortisol TRIVIAL 23264615 A 729 737 cortisol TRIVIAL 23264615 A 739 748 PF 915275 IDENTIFIER 23264615 A 789 797 cortisol TRIVIAL 23264615 A 806 815 meloxicam TRIVIAL 23264615 A 850 858 cortisol TRIVIAL 23264615 A 863 872 meloxicam TRIVIAL 23264615 A 964 972 Cortisol TRIVIAL 23264615 T 0 8 Cortisol TRIVIAL 23265282 A 1109 1121 α-thioesters FAMILY 23265282 A 346 357 α-thioester FAMILY 23265282 A 375 376 N FORMULA 23265282 A 386 389 Cys FORMULA 23265282 A 510 522 α-thioesters FAMILY 23265282 A 633 645 α-thioesters FAMILY 23265282 A 804 815 α-thioester FAMILY 23265296 A 1021 1025 PGMA ABBREVIATION 23265296 A 105 132 poly(glycidyl methacrylate) SYSTEMATIC 23265296 A 1173 1179 biotin TRIVIAL 23265296 A 134 138 PGMA ABBREVIATION 23265296 A 155 162 silicon SYSTEMATIC 23265296 A 351 355 PGMA ABBREVIATION 23265296 A 356 363 epoxide SYSTEMATIC 23265296 A 376 381 amino FAMILY 23265296 A 415 421 POEGMA ABBREVIATION 23265296 A 50 91 poly(oligo(ethylene glycol) methacrylate) SYSTEMATIC 23265296 A 873 879 POEGMA ABBREVIATION 23265296 A 93 99 POEGMA ABBREVIATION 23265429 A 1112 1114 as FORMULA 23265429 A 1181 1190 As(2)O(3) FORMULA 23265429 A 12 16 GaAs FORMULA 23265429 A 1206 1210 GaAs FORMULA 23265429 A 1365 1369 GaAs FORMULA 23265429 A 145 152 gallium SYSTEMATIC 23265429 A 154 159 Ga(l) FORMULA 23265429 A 1871 1875 GaAs FORMULA 23265429 A 20 24 GaAs FORMULA 23265429 A 207 212 Ga(l) FORMULA 23265429 A 395 404 As(2)O(3) FORMULA 23265429 A 474 478 GaAs FORMULA 23265429 A 641 650 As(2)O(3) FORMULA 23265429 A 791 800 As(2)O(3) FORMULA 23265429 A 81 90 As(2)O(3) FORMULA 23265429 A 877 879 As FORMULA 23265429 A 908 910 As FORMULA 23265429 T 33 37 GaAs FORMULA 23265429 T 48 55 gallium SYSTEMATIC 23265452 A 0 12 Polyphenolic FAMILY 23265452 A 1079 1087 apigenin TRIVIAL 23265452 A 1393 1407 phenolic acids FAMILY 23265452 A 1432 1441 flavonoid FAMILY 23265452 A 675 685 flavonoids FAMILY 23265452 A 810 817 chrysin TRIVIAL 23265452 A 819 830 pinocembrin TRIVIAL 23265452 A 835 843 galangin TRIVIAL 23265452 A 883 898 p-Coumaric acid TRIVIAL 23265452 A 985 996 gallic acid TRIVIAL 23265456 A 109 120 polyphenols FAMILY 23265456 A 414 425 polyphenols FAMILY 23265456 A 747 758 polyphenols FAMILY 23265456 T 37 48 polyphenols FAMILY 23265458 A 353 360 ABTS(+) ABBREVIATION 23265458 A 879 882 ADP ABBREVIATION 23265462 A 1012 1021 sophorose TRIVIAL 23265462 A 110 115 sugar FAMILY 23265462 A 124 145 6-O-caffeoylsophorose SYSTEMATIC 23265462 A 669 678 phloretin TRIVIAL 23265462 A 696 715 monocarboxylic acid SYSTEMATIC 23265462 A 735 747 Benzoic acid SYSTEMATIC 23265462 A 78 90 caffeic acid TRIVIAL 23265462 A 895 904 quercetin TRIVIAL 23265462 A 982 994 caffeic acid TRIVIAL 23265462 T 29 50 6-O-caffeoylsophorose SYSTEMATIC 23265467 A 125 128 HFO ABBREVIATION 23265467 A 17 22 As(V) FORMULA 23265467 A 234 241 arsenic SYSTEMATIC 23265467 A 315 320 As(V) FORMULA 23265467 A 377 380 HFO ABBREVIATION 23265467 A 385 390 As(V) FORMULA 23265467 A 498 503 As(V) FORMULA 23265467 A 559 562 HFO ABBREVIATION 23265467 A 582 587 As(V) FORMULA 23265467 A 630 633 HCl FORMULA 23265467 A 650 654 NaOH FORMULA 23265467 A 66 87 hydrated ferric oxide SYSTEMATIC 23265467 A 733 741 carboxyl SYSTEMATIC 23265467 A 746 754 hydroxyl SYSTEMATIC 23265467 A 788 793 As(V) FORMULA 23265467 A 89 92 HFO ABBREVIATION 23265467 A 907 912 As(V) FORMULA 23265467 A 969 972 HFO ABBREVIATION 23265467 T 31 51 hydrous ferric oxide SYSTEMATIC 23265467 T 96 101 As(V) FORMULA 23265469 A 324 331 propane SYSTEMATIC 23265469 A 333 341 n-butane SYSTEMATIC 23265469 A 343 348 CO(2) FORMULA 23265469 A 678 685 kestose TRIVIAL 23265469 A 703 710 nystose TRIVIAL 23265469 A 730 747 fructosyl nystose TRIVIAL 23265469 A 769 776 sucrose TRIVIAL 23265469 A 79 86 sucrose TRIVIAL 23265483 A 27 35 selenium SYSTEMATIC 23265483 A 340 342 Se FORMULA 23265483 A 444 446 Se FORMULA 23265483 A 618 620 Se FORMULA 23265483 A 912 920 selenium SYSTEMATIC 23265483 T 42 50 selenium SYSTEMATIC 23265488 A 662 665 ser FORMULA 23265491 A 1032 1042 isoflavone FAMILY 23265491 A 1104 1115 isoflavones FAMILY 23265491 A 158 165 alcohol FAMILY 23265491 A 198 225 genistein-7-O-gentiobioside SYSTEMATIC 23265491 A 470 480 isoflavone FAMILY 23265491 A 51 61 isoflavone FAMILY 23265491 A 63 90 genistein-7-O-gentiobioside SYSTEMATIC 23265491 A 778 789 glutathione TRIVIAL 23265491 A 861 871 isoflavone FAMILY 23265491 A 915 926 glutathione TRIVIAL 23265491 T 102 112 isoflavone FAMILY 23265492 A 151 155 DEAE ABBREVIATION 23265492 A 339 346 mannose TRIVIAL 23265492 A 479 488 arabinose TRIVIAL 23265492 A 563 570 mannose TRIVIAL 23265492 A 698 706 sulphate SYSTEMATIC 23265492 A 779 786 mannose TRIVIAL 23265492 A 794 802 sulphate SYSTEMATIC 23265492 A 867 874 mannose TRIVIAL 23265501 A 377 385 Fructose TRIVIAL 23265501 A 387 394 glucose TRIVIAL 23265501 A 400 407 sucrose TRIVIAL 23265501 A 461 467 sugars FAMILY 23265501 A 510 543 Citric, malic, and ascorbic acids MULTIPLE 23265501 A 707 719 anthocyanins FAMILY 23265501 A 882 893 gallic acid TRIVIAL 23265502 A 0 7 Nitrate SYSTEMATIC 23265502 A 21 34 ascorbic acid TRIVIAL 23265502 A 250 257 Nitrate SYSTEMATIC 23265502 A 259 266 nitrate SYSTEMATIC 23265502 A 271 284 ascorbic acid TRIVIAL 23265502 A 36 45 vitamin C TRIVIAL 23265502 A 551 558 nitrate SYSTEMATIC 23265502 A 563 570 nitrite SYSTEMATIC 23265502 A 667 674 nitrate SYSTEMATIC 23265502 A 768 781 Ascorbic acid TRIVIAL 23265502 A 9 16 nitrite SYSTEMATIC 23265502 T 0 13 Ascorbic acid TRIVIAL 23265502 T 15 22 nitrate SYSTEMATIC 23265502 T 28 35 nitrite SYSTEMATIC 23265504 A 268 275 phenols FAMILY 23265504 A 277 292 ρ-coumaric acid TRIVIAL 23265504 A 294 306 sinapic acid TRIVIAL 23265504 A 308 317 quercetin TRIVIAL 23265504 A 339 350 citric acid TRIVIAL 23265504 A 352 362 malic acid TRIVIAL 23265504 A 364 372 fructose TRIVIAL 23265504 A 405 409 DPPH ABBREVIATION 23265504 A 536 546 β-carotene TRIVIAL 23265504 A 548 569 ρ-hydroxybenzoic acid SYSTEMATIC 23265504 A 571 578 sucrose TRIVIAL 23265504 A 586 591 sugar FAMILY 23265504 A 614 622 catechin TRIVIAL 23265504 A 624 637 succinic acid TRIVIAL 23265504 A 787 794 phenols FAMILY 23265504 A 796 806 β-carotene TRIVIAL 23265506 A 0 7 DPPH(·) ABBREVIATION 23265506 A 103 110 DPPH(·) ABBREVIATION 23265506 A 752 761 quercetin TRIVIAL 23265506 A 763 771 catechin TRIVIAL 23265506 A 773 786 ascorbic acid TRIVIAL 23265506 A 788 800 caffeic acid TRIVIAL 23265506 A 802 818 chlorogenic acid TRIVIAL 23265506 A 823 837 acetylcysteine SYSTEMATIC 23265506 A 882 889 DPPH(·) ABBREVIATION 23265506 T 43 48 DPPH· ABBREVIATION 23265507 A 0 17 Trans fatty acids FAMILY 23265507 A 1045 1048 TFA ABBREVIATION 23265507 A 19 22 TFA ABBREVIATION 23265507 A 252 255 TFA ABBREVIATION 23265507 A 413 416 TFA ABBREVIATION 23265507 A 522 525 TFA ABBREVIATION 23265507 A 592 595 TFA ABBREVIATION 23265507 A 707 718 fatty acids FAMILY 23265507 A 755 766 fatty acids FAMILY 23265507 T 9 26 trans fatty acids FAMILY 23265517 A 258 272 streptozotocin TRIVIAL 23265517 A 746 761 malondialdehyde TRIVIAL 23265517 A 775 785 superoxide TRIVIAL 23265517 A 807 818 glutathione TRIVIAL 23265517 T 140 154 streptozotocin TRIVIAL 23265526 A 592 598 Fe(2+) FORMULA 23265529 A 261 274 ethyl acetate SYSTEMATIC 23265529 A 282 297 sodium sulphate SYSTEMATIC 23265529 A 441 464 primary secondary amine MULTIPLE 23265529 A 489 500 formic acid SYSTEMATIC 23265533 A 307 313 sodium SYSTEMATIC 23265533 A 54 60 sodium SYSTEMATIC 23265533 A 984 990 sodium SYSTEMATIC 23265533 T 32 38 sodium SYSTEMATIC 23265542 A 202 218 artemisia ketone TRIVIAL 23265542 A 228 240 germacrene B TRIVIAL 23265542 A 249 256 borneol TRIVIAL 23265542 A 268 293 cis-chrysanthenyl acetate SYSTEMATIC 23265546 A 563 571 lactones FAMILY 23265843 A 1107 1115 lucidone TRIVIAL 23265843 A 1202 1210 lucidone TRIVIAL 23265843 A 212 220 lucidone TRIVIAL 23265843 A 347 355 Lucidone TRIVIAL 23265843 A 620 628 lucidone TRIVIAL 23265843 A 857 868 cholesterol TRIVIAL 23265843 A 870 882 triglyceride FAMILY 23265843 A 884 891 glucose TRIVIAL 23265843 A 947 955 lucidone TRIVIAL 23265843 T 0 8 Lucidone TRIVIAL 23265880 A 192 205 biphenylthiol SYSTEMATIC 23265880 A 207 216 FLIP-IDAM ABBREVIATION 23265880 A 255 264 FLIP-IDAM ABBREVIATION 23265880 A 325 338 [(125)I]-IDAM SYSTEMATIC 23265880 A 408 425 [(125)I]Flip-IDAM SYSTEMATIC 23265880 A 41 50 serotonin TRIVIAL 23265880 A 730 736 (123)I FORMULA 23265880 T 118 182 (2-((2-((dimethylamino)methyl)-4-iodophenyl)thio)phenyl)methanol SYSTEMATIC 23265880 T 75 84 serotonin TRIVIAL 23265880 T 99 116 [(125)I]Flip-IDAM SYSTEMATIC 23265892 A 122 132 SCH 900229 IDENTIFIER 23265892 A 260 267 4-CF(3) FORMULA 23265892 A 272 276 4-Br FORMULA 23265892 A 289 300 arylsulfone FAMILY 23265892 A 447 454 sulfone SYSTEMATIC 23265892 A 82 89 sulfone SYSTEMATIC 23265892 T 43 69 tricyclic bispyran sulfone FAMILY 23265896 A 119 126 ZSTK474 IDENTIFIER 23265896 A 310 323 benzimidazole SYSTEMATIC 23265896 A 579 620 5- and 6-methoxysubstituted benzimidazole MULTIPLE 23265896 A 636 643 ZSTK474 IDENTIFIER 23265896 A 651 660 5-methoxy SYSTEMATIC 23265896 A 714 723 6-methoxy SYSTEMATIC 23265896 A 925 932 ZSTK474 IDENTIFIER 23265896 T 28 73 5- and 6-methoxybenzimidazole-1,3,5-triazines MULTIPLE 23265899 A 0 48 C5-Ethynylbenzenesulfonamide-modified nucleotide FAMILY 23265899 A 206 210 EBNA ABBREVIATION 23265899 A 213 223 nucleotide FAMILY 23265899 A 347 351 EBNA ABBREVIATION 23265899 A 454 458 EBNA ABBREVIATION 23265899 A 461 472 nucleotides FAMILY 23265899 A 50 54 EBNA ABBREVIATION 23265899 T 45 94 C5-ethynylbenzenesulfonamide-modified nucleotides FAMILY 23265899 T 96 100 EBNA ABBREVIATION 23265901 A 141 156 tertiary amines FAMILY 23265901 A 166 167 N FORMULA 23265901 A 187 194 adenine TRIVIAL 23265901 A 227 232 amino FAMILY 23265901 A 356 364 DSR-6434 IDENTIFIER 23265901 A 80 93 8-oxoadenines FAMILY 23265901 T 28 40 8-oxoadenine FAMILY 23265902 A 130 141 Selectfluor TRIVIAL 23265902 A 196 211 difluoroquinone FAMILY 23265902 A 306 321 difluoroquinone FAMILY 23265902 A 357 364 quinone FAMILY 23265902 A 48 56 9-fluoro SYSTEMATIC 23265902 A 98 108 SCH 900229 IDENTIFIER 23265902 T 23 33 SCH 900229 IDENTIFIER 23265902 T 55 62 sulfone SYSTEMATIC 23265903 A 18 39 C-cinnamoyl glycoside FAMILY 23265903 A 361 448 (E)-1-(2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyl)-4-(3-hydroxyphenyl)but-3-en-2-one SYSTEMATIC 23265903 A 55 61 phenol SYSTEMATIC 23265903 T 77 99 C-cinnamoyl glycosides FAMILY 23265904 A 1001 1023 spirocyclic piperidine FAMILY 23265904 A 106 109 CoA ABBREVIATION 23265904 A 22 55 benzo-fused spirocyclic oxazepine FAMILY 23265904 A 350 359 oxazepine TRIVIAL 23265904 A 369 377 benzylic TRIVIAL 23265904 A 415 425 piperidine SYSTEMATIC 23265904 A 576 586 piperidine SYSTEMATIC 23265904 A 587 595 nitrogen SYSTEMATIC 23265904 A 675 689 glycine amides FAMILY 23265904 A 710 716 amides FAMILY 23265904 A 722 731 thiazoles FAMILY 23265904 A 85 104 stearoyl-coenzyme A TRIVIAL 23265904 A 951 971 5-carboxy-2-thiazole SYSTEMATIC 23265904 T 42 54 stearoyl-CoA TRIVIAL 23266447 A 472 481 rhodamine TRIVIAL 23266452 A 373 394 N-acetylgalactosamine SYSTEMATIC 23266452 A 629 650 N-acetylgalactosamine SYSTEMATIC 23266452 A 666 710 poly(ethylene glycol)-b-poly(ε-caprolactone) SYSTEMATIC 23266452 A 724 784 poly(ε-caprolactone)-b-poly(2-aminoethyl ethylene phosphate) SYSTEMATIC 23266452 A 786 797 PCL-b-PPEEA ABBREVIATION 23266452 A 892 913 poly(ethylene glycol) SYSTEMATIC 23266452 T 0 21 N-acetylgalactosamine SYSTEMATIC 23266453 A 610 629 polyethylene glycol SYSTEMATIC 23266501 A 187 195 Apigenin TRIVIAL 23266501 A 197 221 4',5,7-trihydroxyflavone SYSTEMATIC 23266501 A 406 414 apigenin TRIVIAL 23266501 A 545 551 oxygen SYSTEMATIC 23266501 A 649 657 Apigenin TRIVIAL 23266501 A 957 965 apigenin TRIVIAL 23266501 A 979 987 apigenin TRIVIAL 23266501 T 37 45 apigenin TRIVIAL 23266502 A 0 9 Carbamate SYSTEMATIC 23266502 A 1083 1091 methomyl TRIVIAL 23266502 A 1240 1244 Urea TRIVIAL 23266502 A 1293 1301 methomyl TRIVIAL 23266502 A 150 158 methomyl TRIVIAL 23266502 A 22 30 methomyl TRIVIAL 23266502 A 284 292 methomyl TRIVIAL 23266502 A 614 622 methomyl TRIVIAL 23266502 A 637 645 methomyl TRIVIAL 23266502 A 997 1005 methomyl TRIVIAL 23266502 T 0 9 Carbamate SYSTEMATIC 23266502 T 22 30 methomyl TRIVIAL 23266674 A 1073 1081 androgen FAMILY 23266674 A 1116 1124 androgen FAMILY 23266674 A 1185 1193 androgen FAMILY 23266674 A 1207 1215 androgen FAMILY 23266674 A 1465 1473 androgen FAMILY 23266674 A 1568 1576 androgen FAMILY 23266674 A 167 192 polyaromatic hydrocarbons FAMILY 23266674 A 1676 1684 androgen FAMILY 23266674 A 201 238 2,3,7,8,-tetrachloro-dibenzo-p-dioxin SYSTEMATIC 23266674 A 240 244 TCDD ABBREVIATION 23266674 A 4 20 aryl hydrocarbon FAMILY 23266674 A 620 628 androgen FAMILY 23266674 A 735 743 androgen FAMILY 23266674 A 802 810 androgen FAMILY 23266674 T 27 43 aryl hydrocarbon FAMILY 23266674 T 80 88 androgen FAMILY 23266719 A 84 90 carbon SYSTEMATIC 23266719 T 44 50 carbon SYSTEMATIC 23266722 A 1050 1063 phorbol ester FAMILY 23266722 A 1239 1252 phorbol ester FAMILY 23266722 A 158 189 7,12-dimethylbenz[a]anthrancene SYSTEMATIC 23266722 A 191 195 DMBA ABBREVIATION 23266722 A 205 218 phorbol ester FAMILY 23266722 A 219 255 12-O-tetradecanoylphorbol-13-acetate SYSTEMATIC 23266722 A 257 260 TPA ABBREVIATION 23266722 A 373 377 DMBA ABBREVIATION 23266722 A 382 385 TPA ABBREVIATION 23266731 A 1063 1070 paeonol TRIVIAL 23266731 A 1078 1090 flavan-3-ols FAMILY 23266731 A 1091 1099 catechin TRIVIAL 23266731 A 1106 1129 epicatechin-3-O-gallate SYSTEMATIC 23266731 A 1145 1161 proanthocyanidin FAMILY 23266731 A 1162 1189 epicatechin-(4β→8)-catechin SYSTEMATIC 23266731 A 1206 1225 trigalloyl-glucoses FAMILY 23266731 A 1232 1269 1,2,3,4,6-penta-O-galloyl-β-d-glucose SYSTEMATIC 23266731 A 1271 1274 PGG ABBREVIATION 23266731 A 1283 1299 proanthocyanidin FAMILY 23266731 A 1332 1335 PGG ABBREVIATION 23266731 A 1422 1425 PGG ABBREVIATION 23266731 A 1830 1840 polyphenol FAMILY 23266731 A 229 233 EtOH FORMULA 23266731 A 407 410 MTT ABBREVIATION 23266732 A 1002 1004 NO FORMULA 23266732 A 1010 1036 6-keto prostaglandin F(1α) SYSTEMATIC 23266732 A 1038 1052 6-keto-PGF(1α) SYSTEMATIC 23266732 A 941 957 thromboxane B(2) TRIVIAL 23266732 A 959 965 TXB(2) ABBREVIATION 23266732 A 988 1000 nitric oxide SYSTEMATIC 23266737 A 104 125 triterpenoid saponins FAMILY 23266737 A 158 166 saponins FAMILY 23266737 A 411 419 saponins FAMILY 23266737 A 483 491 creatine TRIVIAL 23266737 A 514 521 lactate FAMILY 23266737 T 0 21 Triterpenoid saponins FAMILY 23267837 A 473 485 somatostatin TRIVIAL 23267837 A 694 706 somatostatin TRIVIAL 23267837 A 755 765 Cetrorelix TRIVIAL 23267855 A 1104 1113 metformin TRIVIAL 23267855 A 152 161 metformin TRIVIAL 23267855 A 357 366 metformin TRIVIAL 23267855 A 41 50 metformin TRIVIAL 23267855 A 418 425 glucose TRIVIAL 23267855 A 446 455 metformin TRIVIAL 23267855 A 511 520 metformin TRIVIAL 23267855 A 560 569 metformin TRIVIAL 23267855 A 735 744 metformin TRIVIAL 23267855 A 745 752 glucose TRIVIAL 23267855 A 989 998 metformin TRIVIAL 23267855 T 105 114 metformin TRIVIAL 23267862 A 1126 1132 Ca(2+) FORMULA 23267862 A 1138 1144 Mg(2+) FORMULA 23267862 A 1355 1361 Ca(2+) FORMULA 23267862 A 1451 1457 Mg(2+) FORMULA 23267862 A 1608 1614 Ca(2+) FORMULA 23267862 A 1658 1664 Mg(2+) FORMULA 23267862 A 364 370 Ca(2+) FORMULA 23267862 A 399 405 Mg(2+) FORMULA 23267862 A 924 930 Ca(2+) FORMULA 23267862 A 935 941 Mg(2+) FORMULA 23268927 A 481 488 glucose TRIVIAL 23268927 A 856 863 glucose TRIVIAL 23270527 A 1158 1166 aminooxy SYSTEMATIC 23270527 A 1265 1271 sugars FAMILY 23270527 A 1369 1374 NIPAm ABBREVIATION 23270527 A 1546 1559 carbohydrates FAMILY 23270527 A 1685 1691 sugars FAMILY 23270527 A 342 350 aminooxy SYSTEMATIC 23270527 A 359 373 methacrylamide SYSTEMATIC 23270527 A 379 400 N-isopropylacrylamide SYSTEMATIC 23270527 A 402 407 NIPAm ABBREVIATION 23270527 A 412 437 N-isopropylmethacrylamide SYSTEMATIC 23270527 A 439 444 NIPMa ABBREVIATION 23270527 A 451 459 aminooxy SYSTEMATIC 23270527 A 769 791 pyridoxal-5'-phosphate SYSTEMATIC 23270527 A 805 811 ketone SYSTEMATIC 23270527 A 878 883 oxime SYSTEMATIC 23270527 A 897 914 benzylalkoxyamine FAMILY 23270527 A 924 945 poly(ethylene glycol) SYSTEMATIC 23270527 A 946 957 alkoxyamine FAMILY 23270704 A 115 118 APO ABBREVIATION 23270704 A 120 128 apocynin TRIVIAL 23270704 A 154 166 raisanberine TRIVIAL 23270704 A 175 182 calcium SYSTEMATIC 23270704 A 358 361 APO ABBREVIATION 23270704 A 524 528 H2O2 FORMULA 23270704 A 592 604 testosterone TRIVIAL 23270704 A 83 88 NADPH ABBREVIATION 23270704 A 840 843 APO ABBREVIATION 23270704 T 0 8 Apocynin TRIVIAL 23270704 T 13 25 raisanberine TRIVIAL 23270704 T 98 110 testosterone TRIVIAL 23270993 A 0 14 Kynurenic acid TRIVIAL 23270993 A 137 150 acetylcholine SYSTEMATIC 23270993 A 16 20 KYNA ABBREVIATION 23270993 A 267 271 KYNA ABBREVIATION 23270993 A 31 41 tryptophan TRIVIAL 23270993 A 350 354 KYNA ABBREVIATION 23270993 A 423 427 KYNA ABBREVIATION 23270993 A 59 68 glutamate TRIVIAL 23270993 A 615 619 KYNA ABBREVIATION 23270993 T 0 14 Kynurenic acid TRIVIAL 23270993 T 48 61 acetylcholine SYSTEMATIC 23271737 A 256 271 acylsulfonamide FAMILY 23271742 A 1009 1016 arsenic SYSTEMATIC 23271742 A 1189 1196 arsenic SYSTEMATIC 23271742 A 1232 1239 arsenic SYSTEMATIC 23271742 A 1379 1386 arsenic SYSTEMATIC 23271742 A 459 475 arsenic trioxide SYSTEMATIC 23271742 A 633 649 arsenic trioxide SYSTEMATIC 23271742 A 809 825 arsenic trioxide SYSTEMATIC 23271742 T 0 7 Arsenic SYSTEMATIC 23273150 A 1011 1019 carbonyl FAMILY 23273150 A 1020 1021 O FORMULA 23273150 A 1037 1040 C=O FORMULA 23273150 A 1059 1064 amide FAMILY 23273150 A 146 148 NH FORMULA 23273150 A 151 154 O H FORMULA 23273150 A 224 241 N-methylacetamide SYSTEMATIC 23273150 A 243 246 NMA ABBREVIATION 23273150 A 319 320 H FORMULA 23273150 A 383 385 NH FORMULA 23273150 A 443 448 amide FAMILY 23273150 A 532 534 CO FORMULA 23273150 A 549 551 NH FORMULA 23273150 A 689 691 NH FORMULA 23273150 A 694 697 O H FORMULA 23273150 A 756 758 CH FORMULA 23273150 A 761 764 O H FORMULA 23273150 A 809 811 CO FORMULA 23273150 A 879 880 O FORMULA 23273150 A 888 890 CO FORMULA 23273150 A 971 972 O FORMULA 23273225 A 141 150 porphyrin FAMILY 23273225 A 162 211 tetrakis(3,5-di-t-butyl-4-hydroxyphenyl)porphyrin SYSTEMATIC 23273225 A 220 248 tetrakis(4-pyridyl)porphyrin SYSTEMATIC 23273225 A 30 39 porphyrin FAMILY 23273225 T 12 21 Porphyrin FAMILY 23273412 A 0 6 Thymol TRIVIAL 23273412 A 106 118 Schiff bases FAMILY 23273412 A 11 20 carvacrol TRIVIAL 23273412 A 122 150 2-iso-propyl-5-methyl-phenol SYSTEMATIC 23273412 A 152 158 thymol TRIVIAL 23273412 A 164 192 2-tert-butyl-5-methyl-phenol SYSTEMATIC 23273412 A 202 230 5-iso-propyl-2-methyl-phenol SYSTEMATIC 23273412 A 232 241 carvacrol TRIVIAL 23273412 A 294 300 thymol TRIVIAL 23273412 A 305 314 carvacrol TRIVIAL 23273412 A 318 322 DPPH ABBREVIATION 23273412 A 460 473 ascorbic acid TRIVIAL 23273412 A 531 535 ABTS ABBREVIATION 23273412 T 38 44 thymol TRIVIAL 23273412 T 49 58 carvacrol TRIVIAL 23273412 T 65 77 Schiff bases FAMILY 23274352 A 1137 1139 Pb FORMULA 23274352 A 128 130 Co FORMULA 23274352 A 132 134 Cu FORMULA 23274352 A 136 138 Pb FORMULA 23274352 A 140 142 Ni FORMULA 23274353 A 1009 1017 peroxide SYSTEMATIC 23274353 A 1030 1038 carbonyl FAMILY 23274353 A 1142 1146 PBDE ABBREVIATION 23274353 A 1375 1386 glutathione TRIVIAL 23274353 A 1387 1388 S FORMULA 23274353 A 1453 1468 ethoxyresorufin SYSTEMATIC 23274353 A 1469 1470 O FORMULA 23274353 A 1535 1539 PBDE ABBREVIATION 23274353 A 1673 1681 carbonyl FAMILY 23274353 A 1780 1784 PBDE ABBREVIATION 23274353 A 1870 1875 PBDEs ABBREVIATION 23274353 A 41 46 PBDEs ABBREVIATION 23274353 A 644 648 PBDE ABBREVIATION 23274353 A 9 39 polybrominated diphenyl ethers FAMILY 23274353 T 125 155 polybrominated diphenyl ethers FAMILY 23274353 T 157 162 PBDEs ABBREVIATION 23274746 A 1108 1118 flavonoids FAMILY 23274746 A 1123 1140 chlorogenic acids FAMILY 23274768 A 0 4 Zinc SYSTEMATIC 23274768 A 1031 1033 Zn FORMULA 23274768 A 1035 1040 ZnSO4 FORMULA 23274768 A 1188 1193 ZnSO4 FORMULA 23274768 A 1317 1321 zinc SYSTEMATIC 23274768 A 170 174 zinc SYSTEMATIC 23274768 A 401 413 zinc sulfate SYSTEMATIC 23274768 A 415 420 ZnSO4 FORMULA 23274768 A 704 716 zinc sulfate SYSTEMATIC 23274768 A 837 844 lactate FAMILY 23274768 A 877 880 ATP ABBREVIATION 23274768 A 988 993 ZnSO4 FORMULA 23274768 T 11 15 zinc SYSTEMATIC 23274903 A 702 708 oxygen SYSTEMATIC 23274903 A 822 829 glucose TRIVIAL 23274903 A 977 984 glucose TRIVIAL 23274917 A 1012 1015 EMS ABBREVIATION 23274917 A 1072 1080 formalin TRIVIAL 23274917 A 1160 1163 EMS ABBREVIATION 23274917 A 1168 1176 formalin TRIVIAL 23274917 A 563 586 ethyl methane sulfonate SYSTEMATIC 23274917 A 588 591 EMS ABBREVIATION 23274917 A 609 617 formalin TRIVIAL 23274917 A 840 843 EMS ABBREVIATION 23275110 A 1000 1007 calcium SYSTEMATIC 23275110 A 1065 1072 calcium SYSTEMATIC 23275110 A 1229 1236 calcium SYSTEMATIC 23275110 A 1528 1546 PHEA-IB-p(MANa(+)) FORMULA 23275110 A 199 217 PHEA-IB-p(MANa(+)) FORMULA 23275110 A 374 392 PHEA-IB-p(MANa(+)) FORMULA 23275110 A 517 535 PHEA-IB-p(MANa(+)) FORMULA 23275110 A 814 821 calcium SYSTEMATIC 23275110 A 87 197 β-poly(N-2-hydroxyethyl)-graft-{N-2-ethylene[2-poly(methacrylic acid sodium salt)isobutyrate]}-d,l-aspartamide SYSTEMATIC 23275110 A 900 918 PHEA-IB-p(MANa(+)) FORMULA 23275110 T 0 27 PHEA-graft-polymethacrylate SYSTEMATIC 23275111 A 1005 1012 lactide TRIVIAL 23275111 A 1070 1073 PTX ABBREVIATION 23275111 A 1102 1109 lactide TRIVIAL 23275111 A 1116 1119 PLA ABBREVIATION 23275111 A 1214 1217 PLA ABBREVIATION 23275111 A 1355 1358 PLA ABBREVIATION 23275111 A 1412 1415 DOX ABBREVIATION 23275111 A 1423 1426 PLA ABBREVIATION 23275111 A 1548 1551 DOX ABBREVIATION 23275111 A 1553 1556 DOX ABBREVIATION 23275111 A 1560 1563 PTX ABBREVIATION 23275111 A 1580 1583 PLA ABBREVIATION 23275111 A 1686 1689 PLA ABBREVIATION 23275111 A 1733 1736 DOX ABBREVIATION 23275111 A 1740 1743 PLA ABBREVIATION 23275111 A 1753 1756 PLA ABBREVIATION 23275111 A 1810 1813 PTX ABBREVIATION 23275111 A 1846 1849 DOX ABBREVIATION 23275111 A 1853 1856 PLA ABBREVIATION 23275111 A 1908 1911 DOX ABBREVIATION 23275111 A 1916 1919 PLA ABBREVIATION 23275111 A 1942 1945 DOX ABBREVIATION 23275111 A 1953 1956 PLA ABBREVIATION 23275111 A 198 209 polylactide FAMILY 23275111 A 2081 2084 PLA ABBREVIATION 23275111 A 2130 2133 DOX ABBREVIATION 23275111 A 2144 2147 PLA ABBREVIATION 23275111 A 2193 2196 PLA ABBREVIATION 23275111 A 369 380 Doxorubicin TRIVIAL 23275111 A 382 385 DOX ABBREVIATION 23275111 A 390 400 paclitaxel TRIVIAL 23275111 A 402 405 PTX ABBREVIATION 23275111 A 424 427 PLA ABBREVIATION 23275111 A 480 499 polyethylene glycol SYSTEMATIC 23275111 A 511 514 PLA ABBREVIATION 23275111 A 516 519 PLA ABBREVIATION 23275111 A 541 544 PLA ABBREVIATION 23275111 A 554 557 PLA ABBREVIATION 23275111 A 680 683 DOX ABBREVIATION 23275111 A 687 690 PLA ABBREVIATION 23275111 A 700 703 PLA ABBREVIATION 23275111 A 758 761 PTX ABBREVIATION 23275111 A 804 807 DOX ABBREVIATION 23275111 A 812 815 PTX ABBREVIATION 23275111 A 821 824 PLA ABBREVIATION 23275111 A 854 857 PLA ABBREVIATION 23275111 A 978 981 DOX ABBREVIATION 23275111 T 92 103 polylactide FAMILY 23275113 A 1242 1250 Neusilin TRIVIAL 23275113 A 340 349 Fujicalin TRIVIAL 23275113 A 355 363 Neusilin TRIVIAL 23275113 A 615 623 Neusilin TRIVIAL 23276135 A 174 176 Au FORMULA 23276135 A 618 630 carbohydrate FAMILY 23276161 A 463 472 silicates FAMILY 23276161 A 474 484 aluminates FAMILY 23276161 A 494 500 oxides FAMILY 23276161 A 502 510 sulfates FAMILY 23276161 A 516 524 apatites FAMILY 23276627 A 10 25 1-methyladenine SYSTEMATIC 23276627 A 1102 1105 MMS ABBREVIATION 23276627 A 27 32 1-meA SYSTEMATIC 23276627 A 38 54 3-methylcytosine SYSTEMATIC 23276627 A 56 61 3-meC SYSTEMATIC 23276627 A 667 690 methyl methanesulfonate SYSTEMATIC 23276627 A 692 695 MMS ABBREVIATION 23276627 A 863 874 nucleotides FAMILY 23276633 A 1007 1019 testosterone TRIVIAL 23276633 A 104 116 testosterone TRIVIAL 23276633 A 1163 1175 testosterone TRIVIAL 23276633 A 12 24 testosterone TRIVIAL 23276633 A 1561 1573 testosterone TRIVIAL 23276633 A 1672 1684 testosterone TRIVIAL 23276633 A 172 184 Testosterone TRIVIAL 23276633 A 218 231 17β-estradiol SYSTEMATIC 23276633 A 257 276 dihydrotestosterone SYSTEMATIC 23276633 A 278 281 DHT ABBREVIATION 23276633 A 415 427 testosterone TRIVIAL 23276633 A 474 486 testosterone TRIVIAL 23276633 A 906 918 testosterone TRIVIAL 23276633 T 0 12 Testosterone TRIVIAL 23277104 A 1026 1030 FICZ ABBREVIATION 23277104 A 1053 1065 Aroclor 1254 TRIVIAL 23277104 A 1080 1084 PCBs ABBREVIATION 23277104 A 1338 1341 BNF ABBREVIATION 23277104 A 1422 1428 PCB126 TRIVIAL 23277104 A 421 437 aryl hydrocarbon FAMILY 23277104 A 895 911 β-naphthoflavone TRIVIAL 23277104 A 913 916 BNF ABBREVIATION 23277104 A 932 968 3,3',4,4',5-polychlorinated biphenyl SYSTEMATIC 23277104 A 970 976 PCB126 TRIVIAL 23277104 A 994 1024 6-formylindolo[3,2-b]carbazole SYSTEMATIC 23277230 A 1119 1126 Fisetin TRIVIAL 23277230 A 1189 1196 glucose TRIVIAL 23277230 A 1286 1298 nitric oxide SYSTEMATIC 23277230 A 1300 1302 NO FORMULA 23277230 A 1479 1486 fisetin TRIVIAL 23277230 A 1516 1520 DPPH ABBREVIATION 23277230 A 1525 1529 ABTS ABBREVIATION 23277230 A 1590 1597 fisetin TRIVIAL 23277230 A 1683 1690 fisetin TRIVIAL 23277230 A 1714 1721 fisetin TRIVIAL 23277230 A 486 493 fisetin TRIVIAL 23277230 A 513 525 bioflavonoid FAMILY 23277230 A 577 580 STZ ABBREVIATION 23277230 A 723 730 fisetin TRIVIAL 23277230 A 821 835 streptozotocin TRIVIAL 23277230 A 860 867 Fisetin TRIVIAL 23277230 T 0 7 Fisetin TRIVIAL 23277230 T 57 71 streptozotocin TRIVIAL 23278398 A 267 269 Cu FORMULA 23278398 A 270 272 Zn FORMULA 23278398 A 273 283 superoxide TRIVIAL 23278398 A 756 759 Trp FORMULA 23278398 A 791 802 quinazoline SYSTEMATIC 23278398 A 887 901 catecholamines FAMILY 23278633 A 257 258 H FORMULA 23278633 A 308 309 H FORMULA 23278633 A 411 422 nucleobases FAMILY 23278633 A 463 464 H FORMULA 23278633 A 497 505 xanthine TRIVIAL 23278633 A 594 595 H FORMULA 23278633 A 621 622 H FORMULA 23278633 A 678 687 xanthines FAMILY 23278633 A 708 709 H FORMULA 23278633 A 838 846 graphite TRIVIAL 23278633 T 17 43 N(3)-Substituted Xanthines FAMILY 23279802 A 11 29 4-aminoquinazoline SYSTEMATIC 23279802 T 46 64 4-aminoquinazoline SYSTEMATIC 23279841 A 593 600 ethanol SYSTEMATIC 23279841 A 849 856 nitrite SYSTEMATIC 23279841 A 861 868 nitrate SYSTEMATIC 23279841 T 107 114 ethanol SYSTEMATIC 23279844 A 110 114 CCl4 FORMULA 23279844 A 1303 1307 CCl4 FORMULA 23279844 A 211 215 CCl4 FORMULA 23279844 A 243 252 aspartate TRIVIAL 23279844 A 276 283 alanine TRIVIAL 23279844 A 31 41 flavonoids FAMILY 23279844 A 572 582 superoxide TRIVIAL 23279844 A 607 618 glutathione TRIVIAL 23279844 A 657 668 glutathione TRIVIAL 23279844 A 698 713 malondialdehyde TRIVIAL 23279844 A 839 843 CCl4 FORMULA 23279844 A 88 108 carbon tetrachloride SYSTEMATIC 23279844 T 18 27 flavonoid FAMILY 23279844 T 77 97 carbon tetrachloride SYSTEMATIC 23279943 A 1153 1156 GSH ABBREVIATION 23279943 A 1191 1194 MDA ABBREVIATION 23279943 A 1230 1232 Al FORMULA 23279943 A 1234 1236 Fe FORMULA 23279943 A 1242 1244 Cu FORMULA 23279943 A 1271 1273 Mn FORMULA 23279943 A 1275 1277 Zn FORMULA 23279943 A 1283 1285 Se FORMULA 23279943 A 1306 1309 GSH ABBREVIATION 23279943 A 1358 1361 MDA ABBREVIATION 23279943 A 1387 1389 Mn FORMULA 23279943 A 1391 1393 Zn FORMULA 23279943 A 1399 1401 Se FORMULA 23279943 A 1427 1429 Al FORMULA 23279943 A 1431 1433 Fe FORMULA 23279943 A 1439 1441 Cu FORMULA 23279943 A 276 285 donepezil TRIVIAL 23279943 A 660 670 superoxide TRIVIAL 23279943 A 688 699 glutathione TRIVIAL 23279943 A 712 715 GSH ABBREVIATION 23279943 A 725 740 malondialdehyde TRIVIAL 23279943 A 742 745 MDA ABBREVIATION 23279943 A 789 791 Al FORMULA 23279943 A 793 795 Fe FORMULA 23279943 A 797 799 Cu FORMULA 23279943 A 801 803 Zn FORMULA 23279943 A 805 807 Se FORMULA 23279943 A 813 815 Mn FORMULA 23280101 A 1079 1085 oxygen SYSTEMATIC 23280101 A 207 224 protoporphyrin IX TRIVIAL 23280101 A 226 230 PpIX ABBREVIATION 23280620 A 1146 1148 Hg FORMULA 23280620 A 133 135 Hg FORMULA 23280620 A 1384 1386 Hg FORMULA 23280620 A 262 264 Hg FORMULA 23280620 A 388 390 Hg FORMULA 23280620 A 441 443 Hg FORMULA 23280620 A 45 52 mercury SYSTEMATIC 23280620 A 54 56 Hg FORMULA 23280620 A 864 866 Hg FORMULA 23280620 A 983 985 Hg FORMULA 23280620 T 81 88 mercury SYSTEMATIC 23280766 A 1184 1194 pyrethroid FAMILY 23280766 A 1491 1501 pyrethroid FAMILY 23280766 A 687 702 organophosphate FAMILY 23280766 A 716 726 pyrethroid FAMILY 23280951 A 137 183 1-(2'-deoxy-β-D-threo-pentofuranosyl)thymidine SYSTEMATIC 23280951 A 32 46 C3'-thymidinyl SYSTEMATIC 23280951 T 88 102 C3'-thymidinyl SYSTEMATIC 23280958 A 196 204 methanol SYSTEMATIC 23280958 A 256 264 hydrogen SYSTEMATIC 23280958 A 56 64 hydrogen SYSTEMATIC 23280958 A 619 636 hydroxyl hydrogen SYSTEMATIC 23280997 A 303 307 CdSe FORMULA 23280997 A 308 311 ZnS FORMULA 23280997 T 30 34 CdSe FORMULA 23280997 T 35 38 ZnS FORMULA 23281069 A 0 49 Diaromatic-substituted ortho- and meta-carboranes MULTIPLE 23281069 A 105 115 carboranes FAMILY 23281069 A 80 93 manassantin A TRIVIAL 23281069 T 39 68 diaryl-substituted carboranes FAMILY 23281101 A 255 264 Organotin FAMILY 23281101 A 443 482 di- and tri-n-butyltin(IV) carboxylates MULTIPLE 23281101 A 731 738 tin(IV) SYSTEMATIC 23281101 A 979 996 di-n-butyltin(IV) SYSTEMATIC 23281101 T 0 22 Butyltin(IV) benzoates FAMILY 23281242 A 177 183 silica TRIVIAL 23281242 A 33 35 Pt FORMULA 23281242 A 36 38 Ru FORMULA 23281242 A 43 45 Pt FORMULA 23281242 T 71 73 pt FORMULA 23281242 T 74 76 ru FORMULA 23281330 A 100 103 HMF ABBREVIATION 23281330 A 1001 1008 glucose TRIVIAL 23281330 A 1136 1153 hydrogen chloride SYSTEMATIC 23281330 A 1154 1165 formic acid SYSTEMATIC 23281330 A 1187 1207 chloromethylfurfural SYSTEMATIC 23281330 A 150 157 FeCl(3) FORMULA 23281330 A 173 176 HMF ABBREVIATION 23281330 A 198 205 toluene TRIVIAL 23281330 A 207 213 xylene FAMILY 23281330 A 219 229 mesitylene TRIVIAL 23281330 A 248 258 CH(2)Cl(2) FORMULA 23281330 A 263 270 MeNO(2) FORMULA 23281330 A 359 364 ether SYSTEMATIC 23281330 A 36 46 mesitylene TRIVIAL 23281330 A 421 427 p-TsOH FORMULA 23281330 A 466 477 formic acid SYSTEMATIC 23281330 A 501 511 mesitylene TRIVIAL 23281330 A 52 64 carbohydrate FAMILY 23281330 A 539 560 mesitylmethylfurfural SYSTEMATIC 23281330 A 562 565 MMF ABBREVIATION 23281330 A 581 589 fructose TRIVIAL 23281330 A 644 652 fructose TRIVIAL 23281330 A 658 669 formic acid SYSTEMATIC 23281330 A 688 698 mesitylene TRIVIAL 23281330 A 73 98 5-(hydroxymethyl)furfural SYSTEMATIC 23281330 A 730 743 formate ester SYSTEMATIC 23281330 A 747 750 HMF ABBREVIATION 23281330 A 808 816 hydroxyl SYSTEMATIC 23281330 A 834 841 mesityl TRIVIAL 23281330 A 847 852 arene FAMILY 23281330 A 934 945 formic acid SYSTEMATIC 23281330 T 49 62 carbohydrates FAMILY 23281330 T 88 99 formic acid SYSTEMATIC 23281578 A 177 190 carbohydrates FAMILY 23281578 A 341 356 glycofullerenes FAMILY 23281578 A 388 396 mannoses FAMILY 23281578 A 41 72 hexakis-adduct of [60]fullerene TRIVIAL 23281578 T 0 15 Glycofullerenes FAMILY 23281613 A 368 388 ent-3,4-seco-labdane SYSTEMATIC 23281613 A 394 404 diterpenes FAMILY 23281613 A 43 61 methylcallicarpate SYSTEMATIC 23281613 A 70 86 callicarpic acid TRIVIAL 23281613 A 8 41 ent-3,4-seco-labdane diterpenoids FAMILY 23281613 T 8 41 ent-3,4-seco-labdane diterpenoids FAMILY 23281636 A 0 12 Paeoniflorin TRIVIAL 23281636 A 385 397 paeoniflorin TRIVIAL 23281636 A 520 532 paeoniflorin TRIVIAL 23281636 A 558 569 cholesterol TRIVIAL 23281636 A 622 625 ATP ABBREVIATION 23281636 A 736 748 paeoniflorin TRIVIAL 23281636 A 815 823 GSK 3987 IDENTIFIER 23281636 A 875 887 paeoniflorin TRIVIAL 23281636 T 0 12 Paeoniflorin TRIVIAL 23281847 A 445 453 hydrogen SYSTEMATIC 23281917 A 1293 1302 acyclovir TRIVIAL 23281917 A 137 146 acyclovir TRIVIAL 23281917 A 246 253 Span-80 TRIVIAL 23281917 A 258 265 Span-83 TRIVIAL 23281917 A 295 302 Brij-35 TRIVIAL 23281917 T 87 96 acyclovir TRIVIAL 23281937 A 1122 1127 (31)P FORMULA 23281937 A 1209 1215 sodium SYSTEMATIC 23281937 A 1322 1332 phosphorus SYSTEMATIC 23281937 A 1337 1342 boron SYSTEMATIC 23281937 A 1360 1367 oxygens FAMILY 23281937 A 1375 1380 P-O-B FAMILY 23281937 A 1704 1709 boron SYSTEMATIC 23281937 A 1718 1719 B FORMULA 23281937 A 1743 1744 B FORMULA 23281937 A 1753 1754 P FORMULA 23281937 A 1773 1774 B FORMULA 23281937 A 1782 1783 P FORMULA 23281937 A 1911 1912 B FORMULA 23281937 A 206 226 sodium borophosphate SYSTEMATIC 23281937 A 231 237 Na(2)O FORMULA 23281937 A 244 273 [xB(2)O(3) + (1 - x)P(2)O(5)] FAMILY 23281937 A 391 396 (11)B FORMULA 23281937 A 401 406 (31)P FORMULA 23281937 A 623 624 B FORMULA 23281937 A 647 648 P FORMULA 23281937 A 704 709 Na(+) FORMULA 23281937 A 778 791 sodium borate SYSTEMATIC 23281937 A 804 820 sodium phosphate SYSTEMATIC 23281937 T 107 110 31P FORMULA 23281937 T 45 49 Na2O FORMULA 23281937 T 56 77 [xB2O3 + (1 - x)P2O5] FAMILY 23281937 T 99 102 11B FORMULA 23282017 A 0 60 Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] SYSTEMATIC 23282017 A 151 157 KP1339 IDENTIFIER 23282017 A 361 370 ruthenium SYSTEMATIC 23282017 A 475 482 citrate FAMILY 23282017 A 513 522 carbonate FAMILY 23282017 A 608 619 glutathione TRIVIAL 23282017 A 65 71 KP1019 IDENTIFIER 23282017 A 660 669 carbonate FAMILY 23282017 A 90 146 sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] SYSTEMATIC 23282017 A 965 974 ruthenium SYSTEMATIC 23282017 T 103 163 indazolium trans-[Tetrachlorobis(1H-indazole)ruthenate(III)] SYSTEMATIC 23282017 T 165 171 KP1019 IDENTIFIER 23282066 A 1020 1023 MDZ ABBREVIATION 23282066 A 1092 1095 TRZ ABBREVIATION 23282066 A 222 231 midazolam TRIVIAL 23282066 A 233 236 MDZ ABBREVIATION 23282066 A 241 250 triazolam TRIVIAL 23282066 A 252 255 TRZ ABBREVIATION 23282066 A 445 448 TRZ ABBREVIATION 23282066 A 625 628 MDZ ABBREVIATION 23282066 A 644 647 TRZ ABBREVIATION 23282066 A 673 676 MDZ ABBREVIATION 23282066 A 815 818 MDZ ABBREVIATION 23282066 T 157 166 midazolam TRIVIAL 23282066 T 171 180 triazolam TRIVIAL 23282101 A 0 23 (Xylyl-phanephos)Pt(2+) FORMULA 23282101 A 102 108 olefin FAMILY 23282101 A 137 144 polyene SYSTEMATIC 23282101 A 324 336 P(2)Pt-alkyl FAMILY 23282101 A 44 50 XeF(2) FORMULA 23282101 T 62 70 polyenes FAMILY 23282576 A 998 1009 metal-oxide FAMILY 23282999 A 1130 1132 Al FORMULA 23282999 A 1214 1225 cholesterol TRIVIAL 23282999 A 1250 1252 Al FORMULA 23282999 A 1345 1357 testosterone TRIVIAL 23282999 A 136 149 zinc sulphate SYSTEMATIC 23282999 A 1472 1474 Al FORMULA 23282999 A 154 163 vitamin E FAMILY 23282999 A 1540 1558 aluminium sulphate SYSTEMATIC 23282999 A 1654 1667 zinc sulphate SYSTEMATIC 23282999 A 1672 1681 vitamin E FAMILY 23282999 A 1748 1750 Al FORMULA 23282999 A 1886 1904 aluminium sulphate SYSTEMATIC 23282999 A 1996 2009 zinc sulphate SYSTEMATIC 23282999 A 2017 2026 vitamin E FAMILY 23282999 A 2074 2083 vitamin E FAMILY 23282999 A 2173 2186 zinc sulphate SYSTEMATIC 23282999 A 230 239 aluminium SYSTEMATIC 23282999 A 241 243 Al FORMULA 23282999 A 387 405 aluminium sulphate SYSTEMATIC 23282999 A 454 472 aluminium sulphate SYSTEMATIC 23282999 A 494 507 zinc sulphate SYSTEMATIC 23282999 A 542 560 aluminium sulphate SYSTEMATIC 23282999 A 581 590 vitamin E FAMILY 23282999 A 625 643 aluminium sulphate SYSTEMATIC 23282999 A 666 679 zinc sulphate SYSTEMATIC 23282999 A 68 86 aluminium sulphate SYSTEMATIC 23282999 A 684 693 vitamin E FAMILY 23282999 A 814 832 aluminium sulphate SYSTEMATIC 23282999 A 928 930 Al FORMULA 23282999 T 0 13 Zinc sulphate SYSTEMATIC 23282999 T 18 27 vitamin E FAMILY 23282999 T 70 88 aluminium sulphate SYSTEMATIC 23284002 A 0 14 Trichostatin A TRIVIAL 23284002 A 1067 1070 DPI ABBREVIATION 23284002 A 1074 1077 NAC ABBREVIATION 23284002 A 1092 1095 TSA ABBREVIATION 23284002 A 1128 1136 H(2)O(2) FORMULA 23284002 A 1202 1205 GSH ABBREVIATION 23284002 A 1266 1269 TSA ABBREVIATION 23284002 A 140 146 oxygen SYSTEMATIC 23284002 A 1448 1451 TSA ABBREVIATION 23284002 A 1557 1560 TSA ABBREVIATION 23284002 A 16 19 TSA ABBREVIATION 23284002 A 175 178 TSA ABBREVIATION 23284002 A 372 375 TSA ABBREVIATION 23284002 A 381 388 NAD(P)H ABBREVIATION 23284002 A 407 426 diphenyleneiodonium TRIVIAL 23284002 A 428 431 DPI ABBREVIATION 23284002 A 450 467 N-acetyl-cysteine SYSTEMATIC 23284002 A 469 472 NAC ABBREVIATION 23284002 A 552 564 sulforaphane TRIVIAL 23284002 A 741 749 H(2)O(2) FORMULA 23284002 A 765 776 glutathione TRIVIAL 23284002 A 778 781 GSH ABBREVIATION 23284002 A 920 923 TSA ABBREVIATION 23284002 T 0 14 Trichostatin A TRIVIAL 23284002 T 70 76 oxygen SYSTEMATIC 23284082 A 1149 1154 amide FAMILY 23284082 A 19 34 prostaglandin E FAMILY 23284082 A 329 333 urea TRIVIAL 23284082 A 338 348 creatinine TRIVIAL 23284082 A 429 444 bis-sulfonamide SYSTEMATIC 23284082 A 482 487 amide FAMILY 23284082 A 683 688 amide FAMILY 23284082 A 822 827 amide FAMILY 23284082 T 0 5 Amide SYSTEMATIC 23284082 T 58 73 prostaglandin E FAMILY 23286198 A 123 157 hexadecyltrimethylammonium bromide SYSTEMATIC 23286198 A 159 163 CTAB ABBREVIATION 23286198 A 169 182 sodium oleate SYSTEMATIC 23286198 A 184 188 NaOL ABBREVIATION 23286198 A 399 403 CTAB ABBREVIATION 23286198 A 444 448 CTAB ABBREVIATION 23286198 A 449 453 NaOL ABBREVIATION 23286198 A 582 586 CTAB ABBREVIATION 23286240 A 181 204 dimeric phloroglucinols FAMILY 23286240 A 205 236 mallotojaponins B (1) and C (2) MULTIPLE 23286240 A 262 276 mallotophenone TRIVIAL 23286240 A 36 43 ethanol SYSTEMATIC 23286240 A 527 538 chloroquine TRIVIAL 23286240 T 37 60 dimeric phloroglucinols FAMILY 23287045 A 0 6 Copper SYSTEMATIC 23287045 A 1051 1053 Cu FORMULA 23287045 A 1224 1226 Cu FORMULA 23287045 A 269 271 Cu FORMULA 23287045 A 484 498 copper sulfate SYSTEMATIC 23287045 A 500 505 CuSO4 FORMULA 23287045 A 510 527 copper (II) oxide SYSTEMATIC 23287045 A 529 532 CuO FORMULA 23287045 A 541 543 Cu FORMULA 23287045 A 562 578 transition metal FAMILY 23287045 A 741 747 oxygen SYSTEMATIC 23287045 A 8 10 Cu FORMULA 23287045 A 834 842 Cu salts FAMILY 23287045 A 847 850 CuO FORMULA 23287045 A 878 883 CuSO4 FORMULA 23287045 A 90 92 Cu FORMULA 23287045 T 12 24 copper salts FAMILY 23287056 A 1100 1116 N-alkylcarbazole FAMILY 23287056 A 32 40 tyrosine TRIVIAL 23287056 A 950 960 carbazoles FAMILY 23287056 T 43 59 N-alkylcarbazole FAMILY 23287389 A 0 20 Perfluoroalkyl acids FAMILY 23287389 A 1041 1045 PFOS ABBREVIATION 23287389 A 1050 1054 PFOA ABBREVIATION 23287389 A 1087 1092 PFHxS ABBREVIATION 23287389 A 1110 1129 perfluoroalkyl acid FAMILY 23287389 A 1346 1357 bisphenol A TRIVIAL 23287389 A 1359 1364 PBDEs ABBREVIATION 23287389 A 1369 1373 PCBs ABBREVIATION 23287389 A 257 262 PFHxS ABBREVIATION 23287389 A 32 57 perfluorohexane sulfonate SYSTEMATIC 23287389 A 409 429 perfluoroalkyl acids FAMILY 23287389 A 431 435 PFOS ABBREVIATION 23287389 A 440 444 PFOA ABBREVIATION 23287389 A 59 64 PFHxS ABBREVIATION 23287389 A 625 630 PFHxS ABBREVIATION 23287389 A 865 870 PFHxS ABBREVIATION 23287389 A 926 934 nicotine TRIVIAL 23287389 T 83 88 PFHxS ABBREVIATION 23287538 A 1024 1031 ethanol SYSTEMATIC 23287538 A 1069 1076 ethanol SYSTEMATIC 23287538 A 1140 1147 ethanol SYSTEMATIC 23287538 A 1211 1218 sucrose TRIVIAL 23287538 A 1242 1253 amphetamine TRIVIAL 23287538 A 1525 1532 ethanol SYSTEMATIC 23287538 A 1771 1778 ethanol SYSTEMATIC 23287538 A 214 221 ethanol SYSTEMATIC 23287538 A 313 320 ethanol SYSTEMATIC 23287538 A 366 373 ethanol SYSTEMATIC 23287538 A 582 589 ethanol SYSTEMATIC 23287538 A 652 659 ethanol SYSTEMATIC 23287538 A 709 716 ethanol SYSTEMATIC 23287538 A 850 857 ethanol SYSTEMATIC 23287538 A 935 942 ethanol SYSTEMATIC 23287700 A 0 11 Cannabinoid FAMILY 23287700 A 1008 1014 AM4113 IDENTIFIER 23287700 A 1060 1066 AM4054 IDENTIFIER 23287700 A 1176 1182 AM4054 IDENTIFIER 23287700 A 1218 1228 rimonabant TRIVIAL 23287700 A 1233 1239 AM4113 IDENTIFIER 23287700 A 506 515 SR141716A IDENTIFIER 23287700 A 517 527 rimonabant TRIVIAL 23287700 A 55 65 rimonabant TRIVIAL 23287700 A 562 568 AM4113 IDENTIFIER 23287700 A 741 747 AM4054 IDENTIFIER 23287700 A 771 777 AM4054 IDENTIFIER 23287700 A 914 939 Δ(9)-tetrahydrocannabinol SYSTEMATIC 23287700 A 970 980 rimonabant TRIVIAL 23287700 T 0 11 Cannabinoid FAMILY 23287710 A 193 203 acrylamide TRIVIAL 23287710 A 329 339 acrylamide TRIVIAL 23287710 A 631 641 acrylamide TRIVIAL 23287710 A 661 672 glycidamide TRIVIAL 23287710 A 752 763 glycidamide TRIVIAL 23287710 A 764 774 acrylamide TRIVIAL 23287710 A 89 99 acrylamide TRIVIAL 23287710 T 36 46 acrylamide TRIVIAL 23287710 T 51 62 glycidamide TRIVIAL 23287728 A 3 15 L-amino acid FAMILY 23287728 A 304 314 amino-acid FAMILY 23287728 A 393 398 L-Leu FORMULA 23287728 T 49 61 L-amino acid FAMILY 23288049 A 0 30 Polybrominated diphenyl ethers FAMILY 23288049 A 1196 1202 BDE-49 ABBREVIATION 23288049 A 1236 1241 PBDEs ABBREVIATION 23288049 A 1534 1538 PBDE ABBREVIATION 23288049 A 195 200 PBDEs ABBREVIATION 23288049 A 319 324 PBDEs ABBREVIATION 23288049 A 32 37 PBDEs ABBREVIATION 23288049 A 334 336 Br FORMULA 23288049 A 358 392 2,2',4,4'-tetrabromodiphenyl ether SYSTEMATIC 23288049 A 394 400 BDE-47 ABBREVIATION 23288049 A 406 440 2,2',4,5'-tetrabromodiphenyl ether SYSTEMATIC 23288049 A 442 448 BDE-49 ABBREVIATION 23288049 A 544 550 BDE-49 ABBREVIATION 23288049 A 657 663 BDE-47 ABBREVIATION 23288049 A 801 807 BDE-49 ABBREVIATION 23288049 A 888 894 BDE-49 ABBREVIATION 23288049 T 32 38 BDE-49 ABBREVIATION 23288052 A 1016 1019 DEN ABBREVIATION 23288052 A 1156 1162 CCl(4) FORMULA 23288052 A 348 366 diethylnitrosamine SYSTEMATIC 23288052 A 368 371 DEN ABBREVIATION 23288052 A 431 451 carbon tetrachloride SYSTEMATIC 23288052 A 453 459 CCl(4) FORMULA 23288052 A 604 607 DEN ABBREVIATION 23288091 A 1423 1436 carbamazepine TRIVIAL 23288091 A 1438 1446 clobazam TRIVIAL 23288091 A 1448 1460 ethosuximide TRIVIAL 23288091 A 1462 1472 gabapentin TRIVIAL 23288091 A 1474 1484 lacosamide TRIVIAL 23288091 A 1486 1497 lamotrigine TRIVIAL 23288091 A 1499 1512 levetiracetam TRIVIAL 23288091 A 1514 1527 oxcarbazepine SYSTEMATIC 23288091 A 1529 1542 phenobarbital TRIVIAL 23288091 A 1544 1553 phenytoin TRIVIAL 23288091 A 1555 1564 primidone TRIVIAL 23288091 A 1566 1576 topiramate TRIVIAL 23288091 A 1582 1592 zonisamide TRIVIAL 23288091 A 1610 1623 valproic acid TRIVIAL 23288091 A 1661 1671 clonazepam TRIVIAL 23288091 A 1673 1696 eslicarbazepine acetate SYSTEMATIC 23288091 A 1698 1707 felbamate TRIVIAL 23288091 A 1709 1719 pregabalin TRIVIAL 23288091 A 1721 1731 retigabine TRIVIAL 23288091 A 1733 1743 rufinamide TRIVIAL 23288091 A 1745 1756 stiripentol TRIVIAL 23288091 A 1758 1767 tiagabine TRIVIAL 23288091 A 1773 1783 vigabatrin TRIVIAL 23288103 A 230 232 Sn FORMULA 23288103 A 234 236 Ti FORMULA 23288103 A 242 244 Si FORMULA 23288103 A 377 383 oxygen SYSTEMATIC 23288103 A 523 529 oxygen SYSTEMATIC 23288103 A 554 556 Sn FORMULA 23288103 A 669 675 oxygen SYSTEMATIC 23288103 A 725 733 hematite TRIVIAL 23288103 A 73 81 hematite TRIVIAL 23288103 A 769 771 Sn FORMULA 23288103 A 83 94 α-Fe(2)O(3) FORMULA 23288103 A 844 850 oxygen SYSTEMATIC 23288103 A 865 867 Sn FORMULA 23288103 T 6 14 hematite TRIVIAL 23288103 T 69 75 oxygen SYSTEMATIC 23288866 A 1013 1023 loperamide TRIVIAL 23288866 A 1305 1315 loperamide TRIVIAL 23288866 A 1504 1522 aminobenzotriazole SYSTEMATIC 23288866 A 1710 1720 loperamide TRIVIAL 23288866 A 531 541 loperamide TRIVIAL 23288866 A 650 660 loperamide TRIVIAL 23288866 A 894 904 loperamide TRIVIAL 23288866 A 953 963 loperamide TRIVIAL 23288866 T 51 61 loperamide TRIVIAL 23289403 A 138 152 poly(l-lysine) SYSTEMATIC 23289403 A 154 157 PLL ABBREVIATION 23289403 A 215 226 vinylbenzyl SYSTEMATIC 23289412 A 1053 1062 triazoles FAMILY 23289412 A 1306 1359 1H-1,2,3-, 2H-1,2,3-, 1H-1,2,4- and 4H-1,2,4-triazole MULTIPLE 23289412 A 1628 1681 1H-1,2,3-, 2H-1,2,3-, 1H-1,2,4- and 4H-1,2,4-triazole MULTIPLE 23289412 A 1793 1802 triazoles FAMILY 23289412 A 18 27 triazoles FAMILY 23289412 A 254 260 carbon SYSTEMATIC 23289412 A 265 273 nitrogen SYSTEMATIC 23289412 A 311 320 triazoles FAMILY 23289412 A 622 675 1H-1,2,3-, 2H-1,2,3-, 1H-1,2,4- and 4H-1,2,4-triazole MULTIPLE 23289412 A 786 795 triazoles FAMILY 23289412 T 6 59 1H-1,2,3-, 2H-1,2,3-, 1H-1,2,4- and 4H-1,2,4-triazole MULTIPLE 23289585 A 1042 1052 nucleobase FAMILY 23289585 A 115 120 dA5'p SYSTEMATIC 23289585 A 1152 1157 dG5'p SYSTEMATIC 23289585 A 1229 1239 nucleobase FAMILY 23289585 A 123 156 2'-deoxycytidine-5'-monophosphate SYSTEMATIC 23289585 A 1402 1417 phosphate ester SYSTEMATIC 23289585 A 158 163 dC5'p SYSTEMATIC 23289585 A 166 200 2'-deoxyguanosine-5'-monophosphate SYSTEMATIC 23289585 A 202 207 dG5'p SYSTEMATIC 23289585 A 214 240 thymidine-5'-monophosphate SYSTEMATIC 23289585 A 242 246 T5'p SYSTEMATIC 23289585 A 445 460 mononucleotides FAMILY 23289585 A 45 68 2'-deoxymononucleotides FAMILY 23289585 A 79 113 2'-deoxyadenosine-5'-monophosphate SYSTEMATIC 23289585 A 941 946 dA5'p SYSTEMATIC 23289585 A 948 953 dC5'p SYSTEMATIC 23289585 A 959 963 T5'p SYSTEMATIC 23289585 A 989 995 ribose TRIVIAL 23289585 T 78 93 mononucleotides FAMILY 23289615 A 279 289 2-propanol SYSTEMATIC 23289615 A 870 877 alcohol FAMILY 23289624 A 205 210 amide FAMILY 23289624 A 324 329 amide FAMILY 23289624 T 55 60 amide FAMILY 23289646 A 405 426 poly(ethylene glycol) SYSTEMATIC 23289710 A 144 147 Ser FORMULA 23289710 A 148 151 Sec FORMULA 23289710 A 225 238 dimethylallyl SYSTEMATIC 23289710 A 245 248 Ser FORMULA 23289710 A 249 252 Sec FORMULA 23289710 A 364 367 Ser FORMULA 23289710 A 368 371 Sec FORMULA 23289710 A 405 439 [(14)C]dimethylallyl pyrophosphate SYSTEMATIC 23289710 A 449 452 Ser FORMULA 23289710 A 453 456 Sec FORMULA 23289710 A 46 56 amino acid FAMILY 23289710 A 471 474 Ser FORMULA 23289710 A 475 478 Sec FORMULA 23289710 A 57 60 Sec FORMULA 23289710 A 62 76 selenocysteine TRIVIAL 23289710 T 27 30 Ser FORMULA 23289710 T 31 34 Sec FORMULA 23289710 T 36 47 isopentenyl SYSTEMATIC 23289872 A 1097 1105 fluorine SYSTEMATIC 23289872 A 1132 1140 hydrogen SYSTEMATIC 23289872 A 1220 1228 hydrogen SYSTEMATIC 23289872 A 283 287 (1)H FORMULA 23289872 A 289 294 (19)F FORMULA 23289872 A 317 322 (15)N FORMULA 23289872 A 43 48 CF(3) FORMULA 23289872 A 454 456 FH FORMULA 23289872 A 465 467 FN FORMULA 23289872 A 480 482 FF FORMULA 23289872 A 536 544 hydrogen SYSTEMATIC 23289872 A 58 61 N-H FORMULA 23289872 A 606 611 CF(3) FORMULA 23289872 A 64 67 F-C FORMULA 23289872 A 654 662 hydrogen SYSTEMATIC 23289872 A 675 683 hydrogen SYSTEMATIC 23289872 A 68 76 hydrogen SYSTEMATIC 23289872 A 747 752 (19)F FORMULA 23289872 A 753 758 (19)F FORMULA 23289872 A 855 857 NH FORMULA 23289872 T 14 17 CF3 FORMULA 23289872 T 27 30 N-H FORMULA 23289872 T 33 36 F-C FORMULA 23289872 T 37 45 hydrogen SYSTEMATIC 23290050 A 188 194 silica TRIVIAL 23290050 A 259 270 indoxyl red TRIVIAL 23290050 A 298 303 (13)C FORMULA 23290050 A 3 9 indole SYSTEMATIC 23290050 A 309 313 (1)H FORMULA 23290050 A 364 375 indoxyl red TRIVIAL 23290050 T 22 33 indoxyl red TRIVIAL 23290262 A 314 326 Alkyladenine FAMILY 23290262 A 973 996 methyl methanesulfonate SYSTEMATIC 23290262 A 998 1001 MMS ABBREVIATION 23290262 T 0 12 Alkyladenine FAMILY 23290724 A 111 117 copper SYSTEMATIC 23290724 A 122 126 zinc SYSTEMATIC 23290724 A 161 162 C FORMULA 23290724 A 485 489 Zn²⁺ FORMULA 23290724 A 497 498 N FORMULA 23290724 A 511 512 C FORMULA 23290724 A 558 559 C FORMULA 23290724 A 70 71 N FORMULA 23290724 T 0 4 Zinc SYSTEMATIC 23291118 A 12 36 5- and 8-methoxypsoralen MULTIPLE 23291118 A 211 215 MOPs ABBREVIATION 23291118 A 221 237 N-bromosaccharin SYSTEMATIC 23291118 A 367 375 acrylate SYSTEMATIC 23291118 A 38 41 MOP ABBREVIATION 23291118 A 380 388 benzoate SYSTEMATIC 23291118 A 393 402 cinnamate SYSTEMATIC 23291118 A 427 432 8-MOP SYSTEMATIC 23291118 A 487 495 psoralen TRIVIAL 23291118 A 506 520 butyl acrylate SYSTEMATIC 23291118 A 526 546 tert-butyl cinnamate SYSTEMATIC 23291118 A 730 742 indomethacin TRIVIAL 23291118 A 782 787 8-MOP SYSTEMATIC 23291118 A 850 862 indomethacin TRIVIAL 23291118 A 901 906 8-MOP SYSTEMATIC 23291118 T 62 77 methoxypsoralen SYSTEMATIC 23291264 A 1085 1094 cisplatin TRIVIAL 23291264 A 1157 1167 creatinine TRIVIAL 23291264 A 1178 1182 urea TRIVIAL 23291264 A 1183 1191 nitrogen SYSTEMATIC 23291264 A 1252 1261 cisplatin TRIVIAL 23291264 A 1395 1404 cisplatin TRIVIAL 23291264 A 1462 1471 cisplatin TRIVIAL 23291264 A 1670 1679 cisplatin TRIVIAL 23291264 A 1836 1845 cisplatin TRIVIAL 23291264 A 185 194 cisplatin TRIVIAL 23291264 A 196 227 cis-diamminedichloroplatinum II SYSTEMATIC 23291264 A 495 504 cisplatin TRIVIAL 23291264 A 628 637 cisplatin TRIVIAL 23291264 A 824 833 cisplatin TRIVIAL 23291264 T 122 131 cisplatin TRIVIAL 23292343 A 1051 1062 amino acids FAMILY 23292343 A 502 528 ribulose-1, 5-bisphosphate SYSTEMATIC 23292343 A 840 850 amino acid FAMILY 23292752 A 1059 1070 rivaroxaban TRIVIAL 23292752 A 1075 1083 apixaban TRIVIAL 23292752 A 1449 1460 rivaroxaban TRIVIAL 23292752 A 1465 1473 apixaban TRIVIAL 23292752 A 1873 1883 argatroban TRIVIAL 23292752 A 1949 1959 dabigatran TRIVIAL 23292752 A 2002 2022 Dabigatran etexilate TRIVIAL 23292752 A 2139 2149 dabigatran TRIVIAL 23292752 A 215 224 vitamin K FAMILY 23292752 A 2193 2203 Dabigatran TRIVIAL 23292752 A 2395 2405 dabigatran TRIVIAL 23292752 A 2546 2556 Dabigatran TRIVIAL 23292752 A 2642 2662 dabigatran etexilate TRIVIAL 23292752 A 2990 3000 dabigatran TRIVIAL 23292752 A 3015 3026 rivaroxaban TRIVIAL 23292752 A 3031 3039 apixaban TRIVIAL 23292752 A 3052 3062 dabigatran TRIVIAL 23292752 A 3115 3125 dabigatran TRIVIAL 23292752 A 3264 3275 rivaroxaban TRIVIAL 23292752 A 3278 3286 apixaban TRIVIAL 23292752 A 3289 3299 dabigatran TRIVIAL 23292752 T 55 64 vitamin K FAMILY 23292753 A 0 5 Sugar FAMILY 23292753 A 135 154 methylcyclopropenes FAMILY 23292753 A 237 249 mannosamines FAMILY 23292753 A 282 287 azide SYSTEMATIC 23292753 A 288 294 alkyne FAMILY 23292753 A 36 55 methylcyclopropenes FAMILY 23292753 A 399 405 sugars FAMILY 23292753 A 80 89 tetrazine FAMILY 23292753 T 70 82 cyclopropene SYSTEMATIC 23292753 T 83 94 mannosamine FAMILY 23292768 A 1002 1003 C FORMULA 23292768 A 1013 1018 CH2OH FORMULA 23292768 A 1030 1033 O-H FORMULA 23292768 A 1132 1140 methanol SYSTEMATIC 23292768 A 179 180 D FORMULA 23292768 A 181 183 OD FORMULA 23292768 A 197 198 D FORMULA 23292768 A 199 201 CD FORMULA 23292768 A 26 43 propargyl alcohol SYSTEMATIC 23292768 A 301 303 OH FORMULA 23292768 A 309 314 C≡C-H FORMULA 23292768 A 428 432 C-OH FORMULA 23292768 A 660 661 D FORMULA 23292768 A 662 664 CD FORMULA 23292768 A 674 675 D FORMULA 23292768 A 676 678 OD FORMULA 23292768 A 923 926 O-H FORMULA 23292768 T 118 121 H-O FORMULA 23292768 T 140 141 C FORMULA 23292768 T 86 103 propargyl alcohol SYSTEMATIC 23292797 A 1177 1185 adenylyl TRIVIAL 23292797 A 1229 1233 cAMP ABBREVIATION 23292797 A 544 563 5-hydroxytryptamine SYSTEMATIC 23292797 A 569 573 5-HT SYSTEMATIC 23292797 A 654 696 [(35)S]guanosine 5'-(3-O-thio)triphosphate SYSTEMATIC 23292797 A 929 933 5-HT SYSTEMATIC 23292881 A 139 147 aluminum SYSTEMATIC 23292881 A 171 179 zeolites FAMILY 23292881 A 271 279 aluminum SYSTEMATIC 23292881 A 347 354 zeolite TRIVIAL 23292881 T 53 61 aluminum SYSTEMATIC 23292881 T 91 99 zeolites FAMILY 23292988 A 199 207 Sm2 CuO4 FORMULA 23292988 A 212 218 LaFeO3 FORMULA 23292988 A 277 285 Sm2 CuO4 FORMULA 23292988 A 329 337 Sm2 CuO4 FORMULA 23292988 A 339 345 LaFeO3 FORMULA 23292988 T 38 44 LaFeO3 FORMULA 23292988 T 45 52 Sm2CuO4 FORMULA 23293000 A 1123 1128 sugar FAMILY 23293000 A 1129 1138 phosphate SYSTEMATIC 23293094 A 73 97 polychlorinated biphenyl FAMILY 23293094 A 99 102 PCB ABBREVIATION 23293950 T 28 34 pyrene SYSTEMATIC 23293962 A 1217 1221 iron SYSTEMATIC 23293962 A 1280 1284 iron SYSTEMATIC 23293962 A 80 84 iron SYSTEMATIC 23293966 A 249 263 quarteranthene TRIVIAL 23293966 A 593 601 peroxide SYSTEMATIC 23293966 A 90 98 graphene TRIVIAL 23293966 T 103 111 graphene TRIVIAL 23293966 T 34 48 quarteranthene TRIVIAL 23293970 A 1027 1029 O₃ FORMULA 23293970 A 1059 1061 O₃ FORMULA 23293970 A 1221 1229 dopamine TRIVIAL 23293970 A 126 128 O₃ FORMULA 23293970 A 1277 1279 O₃ FORMULA 23293970 A 1399 1401 O₃ FORMULA 23293970 A 1459 1461 O₃ FORMULA 23293970 A 1628 1630 O₃ FORMULA 23293970 A 341 343 O₃ FORMULA 23293970 A 570 572 O₃ FORMULA 23293970 A 709 711 O₃ FORMULA 23293970 A 803 805 O₃ FORMULA 23293970 A 81 86 ozone TRIVIAL 23293970 A 88 90 O₃ FORMULA 23293970 A 95 97 O₃ FORMULA 23293970 A 952 962 superoxide TRIVIAL 23293970 A 989 991 O₃ FORMULA 23293970 A 995 997 O₃ FORMULA 23293970 T 24 29 ozone TRIVIAL 23293971 A 1161 1164 NiO FORMULA 23293971 A 200 212 nickel oxide SYSTEMATIC 23293971 A 214 217 NiO FORMULA 23293971 A 620 623 NiO FORMULA 23293971 A 988 991 NiO FORMULA 23293971 T 98 101 NiO FORMULA 23294326 A 1002 1013 ganglioside TRIVIAL 23294326 A 126 137 ganglioside TRIVIAL 23294326 A 161 172 ganglioside TRIVIAL 23294326 A 296 307 ganglioside TRIVIAL 23294326 A 740 751 ganglioside TRIVIAL 23294566 A 0 9 Androgens FAMILY 23294566 A 1005 1013 androgen FAMILY 23294566 A 1031 1040 oestrogen FAMILY 23294566 A 1085 1093 androgen FAMILY 23294566 A 1098 1107 oestrogen FAMILY 23294566 A 1136 1144 androgen FAMILY 23294566 A 1149 1158 oestrogen FAMILY 23294566 A 122 131 androgens FAMILY 23294566 A 1252 1260 androgen FAMILY 23294566 A 1367 1375 androgen FAMILY 23294566 A 14 24 oestrogens FAMILY 23294566 A 1497 1505 androgen FAMILY 23294566 A 1628 1636 Androgen FAMILY 23294566 A 1695 1703 androgen FAMILY 23294566 A 1816 1824 androgen FAMILY 23294566 A 189 198 oestrogen FAMILY 23294566 A 303 312 androgens FAMILY 23294566 A 317 327 oestrogens FAMILY 23294566 A 650 658 androgen FAMILY 23294566 A 695 703 androgen FAMILY 23294566 A 835 845 oestradiol TRIVIAL 23294566 A 891 900 oestrogen FAMILY 23294566 A 973 981 androgen FAMILY 23294566 T 100 109 androgens FAMILY 23294566 T 117 127 oestrogens FAMILY 23294566 T 41 49 androgen FAMILY 23294699 A 129 135 sterol FAMILY 23294699 A 16 45 pentacyclic hemiacetal sterol FAMILY 23294699 A 162 168 acetyl SYSTEMATIC 23294699 A 349 355 sterol FAMILY 23294699 A 46 59 nephthoacetal TRIVIAL 23294699 T 0 29 Pentacyclic hemiacetal sterol FAMILY 23294895 A 0 7 Aspirin TRIVIAL 23294895 A 185 192 aspirin TRIVIAL 23294895 A 222 229 aspirin TRIVIAL 23294895 A 371 378 aspirin TRIVIAL 23294895 A 568 575 aspirin TRIVIAL 23294895 A 699 706 aspirin TRIVIAL 23294895 A 805 812 aspirin TRIVIAL 23294895 T 0 7 Aspirin TRIVIAL 23294895 T 12 19 aspirin TRIVIAL 23295156 A 1046 1052 l-NAME ABBREVIATION 23295156 A 196 207 l-Carnitine TRIVIAL 23295156 A 270 281 fatty acids FAMILY 23295156 A 670 676 l-NAME ABBREVIATION 23295156 A 728 734 l-NAME ABBREVIATION 23295156 A 877 882 NADPH ABBREVIATION 23295156 T 0 11 L-Carnitine TRIVIAL 23295223 A 1147 1155 steroids FAMILY 23295223 A 1159 1165 carbon SYSTEMATIC 23295223 A 1216 1225 estradiol TRIVIAL 23295223 A 1230 1241 cholesterol TRIVIAL 23295223 A 1413 1420 steroid FAMILY 23295223 A 174 194 3,17β-Hydroxysteroid FAMILY 23295223 A 1923 1935 testosterone TRIVIAL 23295223 A 2029 2041 testosterone TRIVIAL 23295223 A 2113 2121 steroids FAMILY 23295223 A 335 342 steroid FAMILY 23295223 A 58 66 steroids FAMILY 23295223 A 71 103 polycyclic aromatic hydrocarbons FAMILY 23295223 A 731 743 testosterone TRIVIAL 23295223 A 752 761 estradiol TRIVIAL 23295223 A 772 783 cholesterol TRIVIAL 23295223 A 865 877 testosterone TRIVIAL 23295223 T 47 54 steroid FAMILY 23295223 T 83 103 3,17β-hydroxysteroid FAMILY 23295224 A 1072 1076 keto SYSTEMATIC 23295224 A 1135 1152 α-hydroxy ketones FAMILY 23295224 A 1206 1210 keto SYSTEMATIC 23295224 A 1327 1341 2,3-butanediol SYSTEMATIC 23295224 A 1347 1354 acetoin TRIVIAL 23295224 A 1477 1486 diketones FAMILY 23295224 A 1491 1498 acetoin TRIVIAL 23295224 A 1589 1606 α-hydroxy ketones FAMILY 23295224 A 1611 1616 diols FAMILY 23295224 A 253 262 diketones FAMILY 23295224 A 4 21 α-hydroxy ketones FAMILY 23295224 A 422 439 α-hydroxy ketones FAMILY 23295224 A 444 449 diols FAMILY 23295224 A 455 472 vicinal diketones FAMILY 23295224 A 540 545 NADPH ABBREVIATION 23295224 A 580 599 glucose-6-phosphate SYSTEMATIC 23295224 A 604 623 glucose-6-phosphate SYSTEMATIC 23295224 T 27 48 alpha-hydroxy ketones FAMILY 23295224 T 53 66 vicinal diols FAMILY 23295229 A 0 8 Aldehyde SYSTEMATIC 23295229 A 1048 1054 NAD(+) ABBREVIATION 23295229 A 1059 1072 butyraldehyde SYSTEMATIC 23295229 A 1109 1113 NADH ABBREVIATION 23295229 A 1158 1162 NADH ABBREVIATION 23295229 A 121 127 Mg(2+) FORMULA 23295229 A 1230 1234 NADH ABBREVIATION 23295229 A 1243 1249 Mg(2+) FORMULA 23295229 A 1370 1376 Mg(2+) FORMULA 23295229 A 1402 1408 Mg(2+) FORMULA 23295229 A 1504 1508 NADH ABBREVIATION 23295229 A 1587 1596 magnesium SYSTEMATIC 23295229 A 1630 1634 NADH ABBREVIATION 23295229 A 1705 1711 Mg(2+) FORMULA 23295229 A 1763 1769 Mg(2+) FORMULA 23295229 A 179 183 NADH ABBREVIATION 23295229 A 1861 1865 NADH ABBREVIATION 23295229 A 1950 1959 magnesium SYSTEMATIC 23295229 A 1984 1988 NADH ABBREVIATION 23295229 A 321 325 NADH ABBREVIATION 23295229 A 370 374 NADH ABBREVIATION 23295229 A 460 466 Mg(2+) FORMULA 23295229 A 487 491 NADH ABBREVIATION 23295229 A 571 575 NADH ABBREVIATION 23295229 A 624 628 NADH ABBREVIATION 23295229 A 68 77 aldehydes FAMILY 23295229 A 690 696 Mg(2+) FORMULA 23295229 A 794 798 NADH ABBREVIATION 23295229 A 81 97 carboxylic acids FAMILY 23295229 A 839 845 Mg(2+) FORMULA 23295229 A 866 872 Mg(2+) FORMULA 23295229 A 910 916 NAD(+) ABBREVIATION 23295229 A 946 950 NADH ABBREVIATION 23295229 A 979 983 NADH ABBREVIATION 23295229 T 45 54 magnesium SYSTEMATIC 23295229 T 74 78 NADH ABBREVIATION 23295229 T 88 96 aldehyde SYSTEMATIC 23295582 A 0 25 Terbinafine hydrochloride TRIVIAL 23295582 A 27 30 TBF ABBREVIATION 23295582 A 296 299 TBF ABBREVIATION 23295582 A 300 303 HCl FORMULA 23295582 A 31 34 HCl FORMULA 23295582 A 719 722 TBF ABBREVIATION 23295582 A 723 726 HCl FORMULA 23295582 A 804 817 poloxamer gel TRIVIAL 23295582 T 30 41 Terbinafine TRIVIAL 23295582 T 42 45 HCl FORMULA 23295739 A 1061 1079 Methylprednisolone SYSTEMATIC 23295739 A 1111 1125 corticosterone TRIVIAL 23295739 A 255 269 corticosterone TRIVIAL 23295739 A 648 662 corticosterone TRIVIAL 23295739 A 918 936 methylprednisolone SYSTEMATIC 23295740 A 1043 1046 TAM ABBREVIATION 23295740 A 1078 1081 TAM ABBREVIATION 23295740 A 1252 1255 TAM ABBREVIATION 23295740 A 1388 1391 TAM ABBREVIATION 23295740 A 146 154 estrogen FAMILY 23295740 A 1546 1549 TAM ABBREVIATION 23295740 A 20 23 TAM ABBREVIATION 23295740 A 246 249 TAM ABBREVIATION 23295740 A 364 367 TAM ABBREVIATION 23295740 A 38 46 estrogen FAMILY 23295740 A 561 564 TAM ABBREVIATION 23295740 A 783 786 TAM ABBREVIATION 23295740 A 814 818 zinc SYSTEMATIC 23295740 A 9 18 tamoxifen TRIVIAL 23295740 T 0 9 Tamoxifen TRIVIAL 23296019 A 522 525 GDP ABBREVIATION 23296019 A 547 550 GTP ABBREVIATION 23296100 A 0 9 Manganese SYSTEMATIC 23296100 A 11 13 Mn FORMULA 23296100 A 1136 1143 thymine TRIVIAL 23296100 A 1276 1292 N-acetylcysteine SYSTEMATIC 23296100 A 1294 1297 NAC ABBREVIATION 23296100 A 1306 1317 glutathione TRIVIAL 23296100 A 1319 1322 GSH ABBREVIATION 23296100 A 1384 1391 thymine TRIVIAL 23296100 A 1523 1525 Mn FORMULA 23296100 A 1838 1844 Mn(2+) FORMULA 23296100 A 1885 1892 thymine TRIVIAL 23296100 A 2045 2051 Mn(2+) FORMULA 23296100 A 305 307 Mn FORMULA 23296100 A 476 478 Mn FORMULA 23296100 A 590 596 Mn(2+) FORMULA 23296100 A 635 641 Mn(2+) FORMULA 23296100 A 764 770 Mn(2+) FORMULA 23296100 A 800 802 Mn FORMULA 23296100 A 840 856 propidium iodide TRIVIAL 23296100 A 951 957 Mn(2+) FORMULA 23296100 A 996 1002 Mn(2+) FORMULA 23296100 T 0 9 Manganese SYSTEMATIC 23296100 T 105 116 glutathione TRIVIAL 23296100 T 121 137 N-acetylcysteine SYSTEMATIC 23296100 T 81 88 thymine TRIVIAL 23296102 A 1188 1196 Acrolein TRIVIAL 23296102 A 1256 1264 Acrolein TRIVIAL 23296102 A 289 297 Acrolein TRIVIAL 23296102 A 351 359 Acrolein TRIVIAL 23296102 A 446 454 Acrolein TRIVIAL 23296102 A 723 731 Acrolein TRIVIAL 23296102 A 85 93 Acrolein TRIVIAL 23296102 A 879 889 superoxide TRIVIAL 23296102 A 938 953 malondialdehyde TRIVIAL 23296102 A 995 1003 Acrolein TRIVIAL 23296102 T 0 8 Acrolein TRIVIAL 23296105 A 0 7 Uranium SYSTEMATIC 23296105 A 1223 1230 uranium SYSTEMATIC 23296105 A 272 279 uranium SYSTEMATIC 23296105 A 349 356 uranium SYSTEMATIC 23296105 A 535 542 uranium SYSTEMATIC 23296105 A 677 684 uranium SYSTEMATIC 23296105 A 755 762 Uranium SYSTEMATIC 23296105 A 920 927 uranium SYSTEMATIC 23296105 A 995 998 UO₂ FORMULA 23296105 T 14 21 uranium SYSTEMATIC 23296122 A 125 142 metalloporphyrins FAMILY 23296122 A 166 175 magnesium SYSTEMATIC 23296122 A 180 184 zinc SYSTEMATIC 23296122 T 29 58 magnesium and zinc porphyrins MULTIPLE 23296156 A 424 435 chromium-51 SYSTEMATIC 23296368 A 1010 1028 3-methylglutaconic SYSTEMATIC 23296368 A 1065 1087 3-methylglutaconyl-CoA SYSTEMATIC 23296368 A 1139 1146 leucine TRIVIAL 23296368 A 1209 1227 3-methylglutaconic SYSTEMATIC 23296368 A 160 183 3-methylglutaconic acid SYSTEMATIC 23296368 A 1644 1662 3-methylglutaconic SYSTEMATIC 23296368 A 1786 1791 3-MGA SYSTEMATIC 23296368 A 18 40 3-methylglutaconic aci SYSTEMATIC 23296368 A 353 376 3-methylglutaconic acid SYSTEMATIC 23296368 A 398 416 3-methylglutaconic SYSTEMATIC 23296368 A 642 660 3-methylglutaconic SYSTEMATIC 23296368 A 914 932 3-methylglutaconic SYSTEMATIC 23296368 T 33 51 3-methylglutaconic SYSTEMATIC 23296837 A 1039 1042 EHT ABBREVIATION 23296837 A 1175 1187 nitric oxide SYSTEMATIC 23296837 A 1200 1203 EHT ABBREVIATION 23296837 A 1292 1298 MPP(+) ABBREVIATION 23296837 A 1463 1466 EHT ABBREVIATION 23296837 A 1527 1530 EHT ABBREVIATION 23296837 A 1539 1543 MPTP ABBREVIATION 23296837 A 244 274 eicosanoyl-5-hydroxytryptamide SYSTEMATIC 23296837 A 276 279 EHT ABBREVIATION 23296837 A 505 508 EHT ABBREVIATION 23296837 A 530 534 MPTP ABBREVIATION 23296837 A 575 578 EHT ABBREVIATION 23296837 A 673 677 MPTP ABBREVIATION 23296837 A 751 759 dopamine TRIVIAL 23296837 A 764 772 tyrosine TRIVIAL 23296837 A 824 827 EHT ABBREVIATION 23296837 A 873 877 MPTP ABBREVIATION 23296837 A 988 991 EHT ABBREVIATION 23296837 T 78 82 MPTP ABBREVIATION 23296902 A 1032 1039 glucose TRIVIAL 23296902 A 1094 1096 Cr FORMULA 23296902 A 1159 1167 graphite TRIVIAL 23296902 A 1215 1217 Cr FORMULA 23296902 A 1231 1238 glucose TRIVIAL 23296902 A 1297 1299 Cr FORMULA 23296902 A 1334 1338 iron SYSTEMATIC 23296902 A 1409 1411 Cr FORMULA 23296902 A 1432 1436 iron SYSTEMATIC 23296902 A 1449 1451 Cr FORMULA 23296902 A 1509 1513 iron SYSTEMATIC 23296902 A 1586 1588 Cr FORMULA 23296902 A 1633 1635 Cr FORMULA 23296902 A 166 168 Cr FORMULA 23296902 A 19 27 chromium SYSTEMATIC 23296902 A 269 271 Cr FORMULA 23296902 A 29 31 Cr FORMULA 23296902 A 353 355 Cr FORMULA 23296902 A 419 421 Cr FORMULA 23296902 A 519 526 glucose TRIVIAL 23296902 A 575 577 Cr FORMULA 23296902 A 626 628 Cr FORMULA 23296902 A 659 661 Cr FORMULA 23296902 A 709 711 Cr FORMULA 23296902 A 844 846 Cr FORMULA 23296902 A 939 941 Cr FORMULA 23296902 T 8 16 chromium SYSTEMATIC 23296902 T 86 94 chromium SYSTEMATIC 23296950 A 0 7 Chrysin TRIVIAL 23296950 A 1064 1067 TGs ABBREVIATION 23296950 A 1083 1094 cholesterol TRIVIAL 23296950 A 1107 1114 chrysin TRIVIAL 23296950 A 1119 1127 luteolin TRIVIAL 23296950 A 1170 1177 chrysin TRIVIAL 23296950 A 12 20 luteolin TRIVIAL 23296950 A 1248 1256 luteolin TRIVIAL 23296950 A 1280 1282 NO FORMULA 23296950 A 1327 1334 chrysin TRIVIAL 23296950 A 1339 1347 luteolin TRIVIAL 23296950 A 1494 1496 NO FORMULA 23296950 A 195 209 streptozotocin TRIVIAL 23296950 A 211 214 STZ ABBREVIATION 23296950 A 233 240 chrysin TRIVIAL 23296950 A 245 253 luteolin TRIVIAL 23296950 A 288 291 STZ ABBREVIATION 23296950 A 366 373 glucose TRIVIAL 23296950 A 415 428 triglycerides FAMILY 23296950 A 430 433 TGs ABBREVIATION 23296950 A 442 453 cholesterol TRIVIAL 23296950 A 45 55 flavonoids FAMILY 23296950 A 482 493 cholesterol TRIVIAL 23296950 A 553 556 KCl FORMULA 23296950 A 558 571 phenylephrine TRIVIAL 23296950 A 578 591 acetylcholine SYSTEMATIC 23296950 A 593 596 ACh ABBREVIATION 23296950 A 602 605 ACh ABBREVIATION 23296950 A 614 616 NO FORMULA 23296950 A 736 743 chrysin TRIVIAL 23296950 A 748 756 luteolin TRIVIAL 23296950 A 890 893 KCl FORMULA 23296950 A 932 935 ACh ABBREVIATION 23296950 A 943 950 chrysin TRIVIAL 23296950 A 955 963 luteolin TRIVIAL 23296950 A 999 1002 ACh ABBREVIATION 23296950 T 0 7 Chrysin TRIVIAL 23296950 T 12 20 Luteolin TRIVIAL 23296950 T 130 132 NO FORMULA 23296979 A 1074 1078 EATN ABBREVIATION 23296979 A 1116 1120 cAMP ABBREVIATION 23296979 A 1167 1173 Ca(2+) FORMULA 23296979 A 1378 1382 EATN ABBREVIATION 23296979 A 251 316 erythro-(7S,8R)-7-acetoxy-3,4,3`,5`-tetramethoxy-8-O-4`-neolignan SYSTEMATIC 23296979 A 318 322 EATN ABBREVIATION 23296979 A 327 336 neolignan FAMILY 23296979 A 394 398 EATN ABBREVIATION 23296979 A 673 677 EATN ABBREVIATION 23296979 A 735 751 arachidonic acid TRIVIAL 23296979 A 753 757 EATN ABBREVIATION 23296979 A 790 799 serotonin TRIVIAL 23296979 A 804 807 ATP ABBREVIATION 23296979 A 821 837 thromboxane B(2) TRIVIAL 23296979 A 878 882 EATN ABBREVIATION 23296979 A 905 915 cyclic AMP TRIVIAL 23296979 A 917 921 cAMP ABBREVIATION 23296979 A 959 965 Ca(2+) FORMULA 23296979 T 26 91 Erythro-(7S,8R)-7-acetoxy-3,4,3`,5`-tetramethoxy-8-O-4`-neolignan SYSTEMATIC 23297346 A 0 16 Hydrogen sulfide SYSTEMATIC 23297346 A 103 118 carbon monoxide SYSTEMATIC 23297346 A 155 168 cystathionine TRIVIAL 23297346 A 178 191 cystathionine TRIVIAL 23297346 A 18 23 H(2)S FORMULA 23297346 A 208 226 3-mercaptopyruvate SYSTEMATIC 23297346 A 246 251 H(2)S FORMULA 23297346 A 446 451 H(2)S FORMULA 23297346 A 598 603 H(2)S FORMULA 23297346 A 757 762 H(2)S FORMULA 23297346 A 86 98 nitric oxide SYSTEMATIC 23297346 A 863 868 H(2)S FORMULA 23297346 T 0 16 Hydrogen sulfide SYSTEMATIC 23297689 A 459 467 sabinene TRIVIAL 23297712 A 216 230 sesquiterpenes FAMILY 23297712 A 240 247 hinesol TRIVIAL 23297712 A 249 264 z-caryophyllene TRIVIAL 23297712 A 266 276 β-maaliene TRIVIAL 23297712 A 278 289 γ-gurjunene TRIVIAL 23297712 A 291 313 silphiperfol-5-en-3-ol SYSTEMATIC 23297712 A 315 320 ledol TRIVIAL 23297712 A 322 335 cubecol-1-epi SYSTEMATIC 23297712 A 341 358 muurola-3,5-diene SYSTEMATIC 23297712 A 441 454 dexamethasone TRIVIAL 23297713 A 559 573 carbon dioxide SYSTEMATIC 23297713 A 742 756 hydroxyproline SYSTEMATIC 23297713 A 884 895 acetic acid SYSTEMATIC 23297755 A 101 111 CH(2)Cl(2) FORMULA 23297755 A 1036 1098 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide SYSTEMATIC 23297755 A 227 249 sesquiterpene lactones FAMILY 23297755 A 257 279 cis-fused guaianolides FAMILY 23297755 A 308 391 1α-hydroxy-3βH-3α,4α-epoxy-4,10-dimethyl-5αH,7αH,8βH,10αH-guai-11(13)-ene-7,8-olide SYSTEMATIC 23297755 A 421 492 1αH-4α-hydroxy-4,10-dimethyl-5αH,7αH,8βH,10αH-guai-11(13)-ene-7,8-olide SYSTEMATIC 23297755 A 935 944 Efavirenz TRIVIAL 23297755 A 946 949 EFV ABBREVIATION 23297755 T 43 64 sesquiterpene lactone FAMILY 23297817 A 103 119 Au(0.75)Pd(0.25) FORMULA 23297817 A 1095 1106 metal oxide FAMILY 23297817 A 1150 1152 Pd FORMULA 23297817 A 1209 1225 Au(0.75)Pd(0.25) FORMULA 23297817 A 1239 1241 Au FORMULA 23297817 A 127 138 metal oxide FAMILY 23297817 A 1300 1316 Au(0.75)Pd(0.25) FORMULA 23297817 A 217 219 CO FORMULA 23297817 A 240 242 CO FORMULA 23297817 A 245 252 1/2O(2) FORMULA 23297817 A 255 260 CO(2) FORMULA 23297817 A 299 306 alumina TRIVIAL 23297817 A 35 61 Au(0.80)Pd(0.20)-Fe(x)O(y) FAMILY 23297817 A 529 555 Au(0.80)Pd(0.20)-Fe(x)O(y) FAMILY 23297817 A 591 607 Au(0.75)Pd(0.25) FORMULA 23297817 A 688 697 Fe(x)O(y) FAMILY 23297817 A 706 722 Au(0.80)Pd(0.20) FORMULA 23297817 A 812 823 metal oxide FAMILY 23297817 A 825 834 Fe(x)O(y) FAMILY 23297817 A 863 879 Au(0.80)Pd(0.20) FORMULA 23297817 T 0 2 CO FORMULA 23297817 T 26 52 Au(0.80)Pd(0.20)-Fe(x)O(y) FAMILY 23298140 A 1245 1252 glucose TRIVIAL 23298140 A 1260 1272 fructosamine SYSTEMATIC 23298140 A 1386 1403 hydrogen peroxide SYSTEMATIC 23298140 A 1412 1420 peroxide SYSTEMATIC 23298140 A 1432 1442 flavonoids FAMILY 23298140 A 1444 1457 methylglyoxal SYSTEMATIC 23298140 A 424 430 sugars FAMILY 23298140 A 451 459 fructose TRIVIAL 23298140 A 470 477 glucose TRIVIAL 23298140 A 521 537 free amino acids FAMILY 23298140 A 561 572 polyphenols FAMILY 23298140 A 580 591 polyphenols FAMILY 23298140 A 593 603 flavonoids FAMILY 23298140 A 967 978 polyphenols FAMILY 23298158 A 133 140 F4-TCNQ FORMULA 23298158 A 186 200 aluminum oxide SYSTEMATIC 23298158 A 332 339 F4-TCNQ FORMULA 23298158 A 377 381 P3HT ABBREVIATION 23298158 A 468 475 F4-TCNQ FORMULA 23298158 A 49 71 poly(3-hexylthiophene) SYSTEMATIC 23298158 A 580 584 P3HT ABBREVIATION 23298158 A 585 592 F4-TNCQ FORMULA 23298158 A 73 77 P3HT ABBREVIATION 23298158 A 79 131 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane SYSTEMATIC 23298158 T 126 133 Alumina TRIVIAL 23298158 T 36 58 Poly(3-hexylthiophene) SYSTEMATIC 23298158 T 59 95 Fluorinated Tetracyanoquinodimethane FAMILY 23298322 A 812 843 2-(dimethylamino)ethyl acrylate SYSTEMATIC 23298322 A 845 850 DMAEA ABBREVIATION 23298322 A 880 892 acrylic acid TRIVIAL 23298810 A 11 29 prostaglandin E(2) TRIVIAL 23298810 A 198 209 PF-04693627 IDENTIFIER 23298810 A 257 268 benzoxazole SYSTEMATIC 23298810 A 286 297 PF-04693627 IDENTIFIER 23298810 A 426 437 PF-04693627 IDENTIFIER 23298810 A 524 536 benzoxazoles FAMILY 23298810 A 673 684 cyclohexane SYSTEMATIC 23298810 T 51 63 benzoxazoles FAMILY 23299191 A 415 430 sodium chloride SYSTEMATIC 23299191 A 78 94 dimethylarginine SYSTEMATIC 23299191 T 22 38 dimethylarginine SYSTEMATIC 23299194 A 1164 1177 nitrofurazone SYSTEMATIC 23299194 A 1355 1369 hydroxyproline SYSTEMATIC 23299194 A 1697 1711 hydroxyproline SYSTEMATIC 23299909 A 817 818 N FORMULA 23299909 A 847 848 N FORMULA 23300000 A 290 299 flavonoid FAMILY 23300000 A 354 360 La(3+) FORMULA 23300000 A 362 368 Ce(3+) FORMULA 23300000 A 374 380 Nd(3+) FORMULA 23300000 A 507 513 Ce(3+) FORMULA 23300000 A 517 523 Nd(3+) FORMULA 23300000 A 640 649 flavonoid FAMILY 23300000 A 70 79 flavonoid FAMILY 23300000 A 730 743 phenylalanine TRIVIAL 23300000 A 744 751 ammonia SYSTEMATIC 23300000 A 919 929 superoxide TRIVIAL 23300056 A 207 215 dopamine TRIVIAL 23300056 A 470 478 dopamine TRIVIAL 23300056 A 629 643 arylpiperazine FAMILY 23300056 T 66 81 arylpiperazines FAMILY 23300056 T 90 98 dopamine TRIVIAL 23300227 A 1191 1197 TRV130 IDENTIFIER 23300227 A 184 192 Morphine TRIVIAL 23300227 A 466 474 morphine TRIVIAL 23300227 A 508 514 TRV130 IDENTIFIER 23300227 A 516 613 [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine SYSTEMATIC 23300227 A 675 681 TRV130 IDENTIFIER 23300227 A 755 763 morphine TRIVIAL 23300227 A 854 860 TRV130 IDENTIFIER 23300227 A 964 972 morphine TRIVIAL 23300227 A 997 1003 TRV130 IDENTIFIER 23300227 T 145 153 morphine TRIVIAL 23300338 A 328 331 Lys FORMULA 23300338 A 79 88 rapamycin TRIVIAL 23301246 A 1097 1100 NiO FORMULA 23301246 A 12 15 NiO FORMULA 23301246 A 1434 1437 NiO FORMULA 23301246 A 1532 1535 NiO FORMULA 23301246 A 1628 1631 NiO FORMULA 23301246 A 174 177 NiO FORMULA 23301246 A 1761 1770 triiodide SYSTEMATIC 23301246 A 1771 1777 iodide SYSTEMATIC 23301246 A 195 203 fluorine SYSTEMATIC 23301246 A 210 219 tin oxide SYSTEMATIC 23301246 A 221 224 FTO ABBREVIATION 23301246 A 652 655 NiO FORMULA 23301246 T 32 44 nickel oxide SYSTEMATIC 23301495 A 116 123 cyanide SYSTEMATIC 23301495 A 253 263 sulfanegen TRIVIAL 23301495 A 264 279 triethanolamine SYSTEMATIC 23301495 A 336 343 cyanide SYSTEMATIC 23301495 T 0 7 Cyanide SYSTEMATIC 23301495 T 66 74 dithiane SYSTEMATIC 23301495 T 76 86 sulfanegen TRIVIAL 23301495 T 93 111 3-mercaptopyruvate SYSTEMATIC 23301701 A 1024 1032 hydrogen SYSTEMATIC 23301701 A 110 146 1-butyl-3-methylimidazolium chloride SYSTEMATIC 23301701 A 148 156 [bmim]Cl FORMULA 23301701 A 159 194 1-ethyl-3-methylimidazolium acetate SYSTEMATIC 23301701 A 1645 1653 [bmim]Cl FORMULA 23301701 A 1658 1669 [dmim][DMP] ABBREVIATION 23301701 A 196 206 [emim][Ac] ABBREVIATION 23301701 A 213 254 1,3-dimethylimidazolium dimethylphosphate SYSTEMATIC 23301701 A 256 267 [dmim][DMP] ABBREVIATION 23301701 T 77 88 imidazolium SYSTEMATIC 23301853 A 254 267 benzoquinones FAMILY 23301853 A 269 280 betulinan A TRIVIAL 23301853 A 289 300 betulinan C TRIVIAL 23301853 A 327 336 terphenyl FAMILY 23301853 A 347 363 BTH-II0204-207:A IDENTIFIER 23301853 T 0 13 Benzoquinones FAMILY 23301853 T 18 27 terphenyl FAMILY 23301948 A 287 292 amide FAMILY 23302583 A 108 126 7-mercaptocoumarin SYSTEMATIC 23302583 A 415 423 prazosin TRIVIAL 23302583 A 582 598 phenylpiperazine SYSTEMATIC 23302583 A 815 833 7-mercaptocoumarin SYSTEMATIC 23302583 T 53 71 7-mercaptocoumarin SYSTEMATIC 23302594 A 10 26 himeic acids E-G MULTIPLE 23302594 A 161 174 himeic acid A TRIVIAL 23302594 T 0 16 Himeic acids E-G MULTIPLE 23302594 T 22 32 4-pyridone SYSTEMATIC 23303191 A 1006 1009 UDP ABBREVIATION 23303191 A 1010 1015 sugar FAMILY 23303191 A 1053 1056 UDP ABBREVIATION 23303191 A 1057 1063 sugars FAMILY 23303191 A 1200 1203 UDP ABBREVIATION 23303191 A 1204 1210 sugars FAMILY 23303191 A 1340 1343 UDP ABBREVIATION 23303191 A 1344 1363 N-acetylhexosamines FAMILY 23303191 A 1368 1371 UDP ABBREVIATION 23303191 A 1372 1387 glucuronic acid TRIVIAL 23303191 A 138 141 UDP ABBREVIATION 23303191 A 142 161 N-acetylglucosamine SYSTEMATIC 23303191 A 1512 1515 UDP ABBREVIATION 23303191 A 1516 1522 sugars FAMILY 23303191 A 166 169 UDP ABBREVIATION 23303191 A 170 185 glucuronic acid TRIVIAL 23303191 A 540 543 UDP ABBREVIATION 23303191 A 544 564 N-acetyl glucosamine SYSTEMATIC 23303191 A 587 598 glucosamine TRIVIAL 23303191 A 678 689 glucosamine TRIVIAL 23303191 A 734 741 Glucose TRIVIAL 23303191 A 783 786 UDP ABBREVIATION 23303191 A 787 793 sugars FAMILY 23303191 T 54 57 UDP ABBREVIATION 23303191 T 58 64 GlcNAc FORMULA 23303198 A 1076 1086 olmesartan TRIVIAL 23303198 A 116 127 telmisartan TRIVIAL 23303198 A 1177 1187 olmesartan TRIVIAL 23303198 A 1298 1308 olmesartan TRIVIAL 23303198 A 1319 1330 telmisartan TRIVIAL 23303198 A 1418 1428 olmesartan TRIVIAL 23303198 A 1536 1546 olmesartan TRIVIAL 23303198 A 346 356 olmesartan TRIVIAL 23303198 A 373 384 telmisartan TRIVIAL 23303198 A 533 540 glucose TRIVIAL 23303198 A 88 98 olmesartan TRIVIAL 23303198 A 941 951 olmesartan TRIVIAL 23303198 A 997 1007 olmesartan TRIVIAL 23303198 T 52 62 olmesartan TRIVIAL 23303198 T 67 78 telmisartan TRIVIAL 23303441 A 0 10 Paroxetine TRIVIAL 23303441 A 1017 1024 sulfate SYSTEMATIC 23303441 A 1113 1123 paroxetine TRIVIAL 23303441 A 1316 1319 ATP ABBREVIATION 23303441 A 298 305 sulfate SYSTEMATIC 23303441 A 358 368 paroxetine TRIVIAL 23303441 A 604 614 paroxetine TRIVIAL 23303441 A 666 682 [(3)H]paroxetine SYSTEMATIC 23303441 T 37 47 paroxetine TRIVIAL 23303486 A 1050 1059 thioether SYSTEMATIC 23303486 A 45 51 biotin TRIVIAL 23303486 A 937 943 biotin TRIVIAL 23303486 A 955 960 amide FAMILY 23303710 A 0 15 Myriaporone 3/4 MULTIPLE 23303710 A 195 210 myriaporone 3/4 MULTIPLE 23303710 A 374 389 myriaporone 3/4 MULTIPLE 23303710 A 458 473 myriaporone 3/4 MULTIPLE 23303710 A 588 603 myriaporone 3/4 MULTIPLE 23303710 T 22 37 myriaporone 3/4 MULTIPLE 23305110 A 207 215 LaAlO(3) FORMULA 23305110 A 216 224 SrTiO(3) FORMULA 23305110 A 337 345 SrTiO(3) FORMULA 23305110 A 377 379 Si FORMULA 23305110 A 77 85 LaAlO(3) FORMULA 23305110 A 90 98 SrTiO(3) FORMULA 23305110 T 27 33 LaAlO3 FORMULA 23305110 T 34 40 SrTiO3 FORMULA 23305294 A 0 7 Lithium SYSTEMATIC 23305294 A 148 155 lithium SYSTEMATIC 23305294 A 392 399 lithium SYSTEMATIC 23305294 A 481 491 Li(3)PS(4) FORMULA 23305294 A 587 594 lithium SYSTEMATIC 23305294 A 630 640 Li(3)PS(4) FORMULA 23305294 A 906 916 Li(3)PS(4) FORMULA 23305444 A 374 399 benzofuran salicylic acid SYSTEMATIC 23305444 A 921 935 salicylic acid TRIVIAL 23305444 T 102 140 6-Hydroxy-benzofuran-5-carboxylic acid SYSTEMATIC 23305444 T 70 78 tyrosine TRIVIAL 23305465 A 101 114 meroterpenoid FAMILY 23305465 A 126 141 albatrelins D-F MULTIPLE 23305465 A 169 268 6a,7,8,9,10,10a-hexahydro-3,6,9-trimethyl-6-(4-methyl-3-penten-1-yl)-1,9-epoxy-6H-dibenzo[b,d]pyran SYSTEMATIC 23305465 A 277 288 confluentin TRIVIAL 23305465 A 546 558 Albatrelin F TRIVIAL 23305465 A 58 73 albatrelins A-C MULTIPLE 23305465 A 6 14 grifolin TRIVIAL 23305465 A 627 638 Confluentin TRIVIAL 23305465 T 0 13 Meroterpenoid FAMILY 23305777 A 101 112 miliumollin TRIVIAL 23305777 A 114 134 7-methoxymiliumollin SYSTEMATIC 23305777 A 136 157 3'-methoxymiliumollin SYSTEMATIC 23305777 A 159 181 4'-O-methylmiliumollin SYSTEMATIC 23305777 A 186 200 miliumollinone TRIVIAL 23305777 A 212 228 8-O-4' neolignan SYSTEMATIC 23305777 A 235 248 miliusamollin TRIVIAL 23305777 A 341 352 Miliumollin TRIVIAL 23305777 A 354 375 3'-methoxymiliumollin SYSTEMATIC 23305777 A 377 391 miliumollinone TRIVIAL 23305777 A 472 486 Miliumollinone TRIVIAL 23305777 A 64 92 dihydrobenzofuran neolignans FAMILY 23305777 T 0 10 Neolignans FAMILY 23305807 A 0 9 Estrogens FAMILY 23305807 A 1027 1038 glutathione TRIVIAL 23305807 A 1119 1131 nitric oxide SYSTEMATIC 23305807 A 1145 1160 malondialdehyde TRIVIAL 23305807 A 1226 1229 RES ABBREVIATION 23305807 A 1311 1314 RES ABBREVIATION 23305807 A 140 149 bile acid FAMILY 23305807 A 1475 1483 estrogen FAMILY 23305807 A 251 262 resveratrol TRIVIAL 23305807 A 264 267 RES ABBREVIATION 23305807 A 368 371 RES ABBREVIATION 23305807 A 49 65 ethinylestradiol SYSTEMATIC 23305807 A 581 590 bile acid FAMILY 23305807 A 638 647 bilirubin TRIVIAL 23305807 A 728 738 superoxide TRIVIAL 23305807 A 750 761 glutathione TRIVIAL 23305807 A 774 785 glutathione TRIVIAL 23305807 A 869 879 sulfhydryl FAMILY 23305807 A 888 891 RES ABBREVIATION 23305807 A 930 937 alanine TRIVIAL 23305807 A 959 970 glutathione TRIVIAL 23305807 A 971 972 S FORMULA 23305807 A 992 1000 glutamyl TRIVIAL 23305807 T 23 34 resveratrol TRIVIAL 23305807 T 43 59 ethinylestradiol SYSTEMATIC 23305918 A 131 150 pyrazine-2-(1H)-one SYSTEMATIC 23305918 A 269 288 ma'edamines A and B MULTIPLE 23305918 A 583 594 ma'edamines FAMILY 23305918 A 631 642 ma'edamines FAMILY 23305918 A 71 95 ma'edamines A (18) and B MULTIPLE 23305918 T 79 98 ma'edamines A and B MULTIPLE 23305993 A 1000 1006 GW9962 IDENTIFIER 23305993 A 1207 1213 LYSO-7 ABBREVIATION 23305993 A 13 96 (5Z)-5-[(5-bromo-1H-indol-3-yl)methylene]-3-(4-chlorobenzyl)-thiazolidine-2,4-dione SYSTEMATIC 23305993 A 490 496 LYSO-7 ABBREVIATION 23305993 A 644 651 LYSO-07 ABBREVIATION 23305993 A 935 947 nitric oxide SYSTEMATIC 23305993 A 949 951 NO FORMULA 23305993 A 98 104 LYSO-7 ABBREVIATION 23306171 A 101 111 diterpenes FAMILY 23306171 A 14 25 diterpenoid FAMILY 23306171 A 27 40 leptoclalin A TRIVIAL 23306171 A 6 13 spatane TRIVIAL 23306171 A 87 100 norcembranoid FAMILY 23306171 T 14 25 diterpenoid FAMILY 23306171 T 6 13 spatane TRIVIAL 23306172 A 16 90 2-hydroxy-5-((6-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-2- propylchroman-4-one SYSTEMATIC 23306172 A 463 470 CD(3)OD FORMULA 23306172 A 509 518 deuterium SYSTEMATIC 23306172 A 572 590 2-hydroxy-γ-pyrone SYSTEMATIC 23306172 A 748 766 4-hydroxy-α-pyrone SYSTEMATIC 23306172 A 771 789 2-hydroxy-γ-pyrone SYSTEMATIC 23306172 A 952 963 methicillin TRIVIAL 23306172 T 107 120 hydroxypyrone SYSTEMATIC 23306790 A 24 36 verrucarin A TRIVIAL 23306790 A 741 752 glutathione TRIVIAL 23306790 A 757 776 N-acetyl-l-cysteine SYSTEMATIC 23306790 A 805 810 MG132 IDENTIFIER 23306790 T 0 12 Verrucarin A TRIVIAL 23306791 A 0 19 Polyethylene glycol SYSTEMATIC 23306791 A 22 39 polyvinyl alcohol SYSTEMATIC 23306791 A 41 48 PEG-PVA ABBREVIATION 23306791 A 578 585 PEG-PVA ABBREVIATION 23306791 A 891 898 PEG-PVA ABBREVIATION 23306791 T 0 19 Polyethylene glycol SYSTEMATIC 23306791 T 22 39 polyvinyl alcohol SYSTEMATIC 23307185 A 804 810 serine TRIVIAL 23307185 A 818 827 threonine TRIVIAL 23307790 A 664 671 glucose TRIVIAL 23311296 A 216 222 carbon SYSTEMATIC 23311296 A 309 315 carbon SYSTEMATIC 23311296 A 69 75 carbon SYSTEMATIC 23311296 A 838 844 carbon SYSTEMATIC 23311296 T 57 63 carbon SYSTEMATIC 23311700 A 1026 1029 RAI ABBREVIATION 23311700 A 937 940 RAI ABBREVIATION 23311718 A 1230 1244 [C(4)mim][AOT] FORMULA 23311718 A 1285 1302 [C(2)mim][TF(2)N] FORMULA 23311718 A 1303 1317 [C(4)mim][AOT] FORMULA 23311718 A 1318 1325 benzene SYSTEMATIC 23311718 A 1363 1380 [C(2)mim][TF(2)N] FORMULA 23311718 A 1383 1400 [C(4)mim][TF(2)N] FORMULA 23311718 A 1403 1420 [C(6)mim][TF(2)N] FORMULA 23311718 A 2423 2427 (1)H FORMULA 23311718 A 2584 2598 [C(4)mim][AOT] FORMULA 23311718 A 2599 2606 benzene SYSTEMATIC 23311718 A 444 458 [C(4)mim][AOT] FORMULA 23311718 A 459 466 benzene SYSTEMATIC 23311718 A 569 573 (1)H FORMULA 23311718 A 753 770 [C(6)mim][TF(2)N] FORMULA 23311718 A 773 790 [C(4)mim][TF(2)N] FORMULA 23311718 A 793 810 [C(2)mim][TF(2)N] FORMULA 23311718 A 913 930 [C(4)mim][TF(2)N] FORMULA 23311718 A 933 949 [C(4)mim][PF(6)] FORMULA 23311718 A 952 968 [C(4)mim][BF(4)] FORMULA 23311754 A 180 185 PEDOT ABBREVIATION 23311754 A 203 209 MnO(2) FORMULA 23311754 A 284 290 MnO(2) FORMULA 23311754 A 314 332 vanadium pentoxide SYSTEMATIC 23311754 A 333 365 poly(3,4-ethylenedioxythiophene) SYSTEMATIC 23311754 A 367 372 PEDOT ABBREVIATION 23311754 A 564 572 V(2)O(5) FORMULA 23311754 A 816 823 lithium SYSTEMATIC 23311754 T 14 18 V2O5 FORMULA 23311754 T 19 51 poly(3,4-ethylenedioxythiophene) SYSTEMATIC 23311754 T 52 56 MnO2 FORMULA 23312946 A 18 24 flavin FAMILY 23312946 A 276 289 monocillin II TRIVIAL 23312946 A 328 349 4-hydroxyisoquinoline SYSTEMATIC 23312946 A 358 379 6-hydroxyisoquinoline SYSTEMATIC 23312946 A 502 510 hydroxyl SYSTEMATIC 23312946 A 562 575 isoquinolines FAMILY 23312946 T 25 38 isoquinolines FAMILY 23312946 T 51 57 flavin FAMILY 23313176 A 1052 1058 carbon SYSTEMATIC 23313176 A 999 1009 dendrimers FAMILY 23313245 A 50 62 diaryl ureas FAMILY 23313245 T 6 18 diaryl ureas FAMILY 23313376 A 1063 1066 PTE ABBREVIATION 23313376 A 108 119 resveratrol TRIVIAL 23313376 A 1127 1130 Tyr FORMULA 23313376 A 1176 1179 PTE ABBREVIATION 23313376 A 1492 1495 PTE ABBREVIATION 23313376 A 155 158 PTE ABBREVIATION 23313376 A 1552 1557 AG490 TRIVIAL 23313376 A 1630 1633 PTE ABBREVIATION 23313376 A 1825 1828 PTE ABBREVIATION 23313376 A 292 295 PTE ABBREVIATION 23313376 A 51 64 Pterostilbene TRIVIAL 23313376 A 536 539 PTE ABBREVIATION 23313376 A 66 69 PTE ABBREVIATION 23313376 A 669 672 PTE ABBREVIATION 23313376 A 674 677 PTE ABBREVIATION 23313376 A 784 787 PTE ABBREVIATION 23313376 A 993 999 oxygen SYSTEMATIC 23313376 T 0 13 Pterostilbene TRIVIAL 23313448 A 1510 1513 ADP ABBREVIATION 23313448 A 368 379 amino acids FAMILY 23313621 A 1076 1094 phorbol dibutyrate SYSTEMATIC 23313621 A 154 176 1-nitro-2-phenylethane SYSTEMATIC 23313621 A 347 350 KCl FORMULA 23313621 A 495 508 phenylephrine TRIVIAL 23313621 A 510 513 PHE ABBREVIATION 23313621 A 710 716 Ca(2+) FORMULA 23313621 A 796 804 caffeine TRIVIAL 23313621 A 829 835 Ca(2+) FORMULA 23313621 A 850 854 K(+) FORMULA 23313621 A 900 907 CaCl(2) FORMULA 23313621 A 911 918 BaCl(2) FORMULA 23313621 T 24 46 1-nitro-2-phenylethane SYSTEMATIC 23313638 A 191 196 amide FAMILY 23313638 A 211 231 D-leucine-D-cysteine TRIVIAL 23313638 A 236 255 D-valine-D-cysteine TRIVIAL 23313638 A 282 291 D-alanine TRIVIAL 23313638 A 296 304 D-valine TRIVIAL 23313638 A 543 562 spiruchostatins A-D MULTIPLE 23313638 A 619 624 FK228 IDENTIFIER 23313638 A 626 636 romidepsin TRIVIAL 23313638 A 64 87 spiruchostatins C and D MULTIPLE 23313638 T 42 65 spiruchostatins C and D MULTIPLE 23313639 A 202 242 4,5,6-trimethoxybiphenyl-2-carbaldehydes FAMILY 23313639 A 28 64 E-2,3,4-trimethoxy-6-styrylbiphenyls FAMILY 23313639 A 370 389 3,4-(1,3-dioxolane) SYSTEMATIC 23313639 A 394 406 3,4-difluoro SYSTEMATIC 23313639 A 69 112 2,3,4-trimethoxy-6-(1-phenylvinyl)biphenyls FAMILY 23313639 A 769 779 colchicine TRIVIAL 23313639 T 24 45 biaryl aryl stilbenes FAMILY 23313639 T 46 55 ethylenes FAMILY 23313712 A 102 143 polyhexamethylene biguanide hydrochloride SYSTEMATIC 23313712 A 145 149 PHMB ABBREVIATION 23313712 A 156 160 PHMB ABBREVIATION 23313712 A 265 269 PHMB ABBREVIATION 23313712 A 328 339 neutral red TRIVIAL 23313712 A 49 68 phosphatidylcholine FAMILY 23313712 A 606 610 PHMB ABBREVIATION 23313712 A 673 677 PHMB ABBREVIATION 23313712 A 760 764 PHMB ABBREVIATION 23313712 A 836 840 PHMB ABBREVIATION 23313712 T 15 56 polyhexamethylene biguanide hydrochloride SYSTEMATIC 23313712 T 58 62 PHMB ABBREVIATION 23313712 T 69 88 phosphatidylcholine FAMILY 23313797 A 1011 1023 nicotinamide TRIVIAL 23313797 A 1110 1116 oxygen SYSTEMATIC 23313797 A 1126 1141 malondialdehyde TRIVIAL 23313797 A 1143 1150 nitrite SYSTEMATIC 23313797 A 1152 1163 glutathione TRIVIAL 23313797 A 1168 1178 superoxide TRIVIAL 23313797 A 1222 1225 Res ABBREVIATION 23313797 A 1273 1276 Res ABBREVIATION 23313797 A 1303 1307 EtOH FORMULA 23313797 A 1331 1334 Res ABBREVIATION 23313797 A 1456 1460 EtOH FORMULA 23313797 A 222 226 EtOH FORMULA 23313797 A 258 269 resveratrol TRIVIAL 23313797 A 271 274 Res ABBREVIATION 23313797 A 30 37 ethanol SYSTEMATIC 23313797 A 39 43 EtOH FORMULA 23313797 A 395 398 Res ABBREVIATION 23313797 A 402 409 ethanol SYSTEMATIC 23313797 A 570 573 Res ABBREVIATION 23313797 A 577 581 EtOH FORMULA 23313797 A 605 608 Res ABBREVIATION 23313797 A 704 717 Hoechst 33342 TRIVIAL 23313797 A 778 782 dUTP ABBREVIATION 23313797 A 826 830 EtOH FORMULA 23313797 A 866 869 Res ABBREVIATION 23313797 A 886 889 Res ABBREVIATION 23313797 A 910 936 5'-adenosine monophosphate SYSTEMATIC 23313797 T 111 118 ethanol SYSTEMATIC 23313797 T 27 38 resveratrol TRIVIAL 23313961 A 1258 1272 benzyl alcohol SYSTEMATIC 23313961 A 1322 1328 folate TRIVIAL 23313961 A 1476 1482 folate TRIVIAL 23313961 A 1483 1486 PEG ABBREVIATION 23313961 A 1487 1490 PCL ABBREVIATION 23313961 A 17 23 folate TRIVIAL 23313961 A 435 441 folate TRIVIAL 23313961 A 457 478 poly(ethylene glycol) SYSTEMATIC 23313961 A 481 497 polycaprolactone SYSTEMATIC 23313961 A 499 505 folate TRIVIAL 23313961 A 506 509 PEG ABBREVIATION 23313961 A 512 515 PCL ABBREVIATION 23313961 A 759 765 folate TRIVIAL 23313961 A 780 803 Triamcinolone acetonide SYSTEMATIC 23313961 A 854 860 folate TRIVIAL 23313961 T 19 25 folate TRIVIAL 23313961 T 36 49 triamcinolone TRIVIAL 23313962 A 1179 1189 temoporfin TRIVIAL 23313962 A 1242 1252 temoporfin TRIVIAL 23313962 A 1326 1336 temoporfin TRIVIAL 23313962 A 1460 1470 temoporfin TRIVIAL 23313962 A 1581 1591 temoporfin TRIVIAL 23313962 A 1685 1695 temoporfin TRIVIAL 23313962 A 205 215 temoporfin TRIVIAL 23313962 A 2052 2062 temoporfin TRIVIAL 23313962 A 2206 2215 glycerols FAMILY 23313962 A 264 275 cholesterol TRIVIAL 23313962 A 366 378 PEG2000-DSPE ABBREVIATION 23313962 A 562 572 temoporfin TRIVIAL 23313962 A 628 644 (14)C-temoporfin SYSTEMATIC 23313962 A 65 75 temoporfin TRIVIAL 23313962 A 688 698 temoporfin TRIVIAL 23313962 A 879 889 temoporfin TRIVIAL 23313962 A 941 951 temoporfin TRIVIAL 23313962 T 20 30 temoporfin TRIVIAL 23313962 T 89 99 temoporfin TRIVIAL 23314045 A 29 33 urea TRIVIAL 23314045 A 34 42 thiourea SYSTEMATIC 23314045 A 341 346 rutin TRIVIAL 23314045 A 415 422 methoxy SYSTEMATIC 23314045 A 427 434 bromine SYSTEMATIC 23314045 A 58 61 Gly FORMULA 23314045 A 62 65 Pro FORMULA 23314045 A 77 90 benzisoxazole SYSTEMATIC 23314045 T 35 39 urea TRIVIAL 23314045 T 44 52 thiourea SYSTEMATIC 23314045 T 68 75 glycine TRIVIAL 23314045 T 76 83 proline TRIVIAL 23314045 T 95 108 benzisoxazole SYSTEMATIC 23314276 A 1081 1089 androgen FAMILY 23314276 A 1090 1104 17β-trenbolone SYSTEMATIC 23314276 A 2165 2173 androgen FAMILY 23314276 A 255 264 androgens FAMILY 23314276 A 762 770 androgen FAMILY 23314276 A 925 933 androgen FAMILY 23314276 T 11 25 17β-trenbolone SYSTEMATIC 23314277 A 115 123 TiSiO(4) FORMULA 23314277 A 207 215 TiSiO(4) FORMULA 23314277 A 319 330 glutathione TRIVIAL 23314277 A 331 332 S FORMULA 23314277 A 347 354 lactate FAMILY 23314277 A 399 406 alanine TRIVIAL 23314277 A 411 418 lactate FAMILY 23314277 A 488 496 TiSiO(4) FORMULA 23314277 A 624 632 TiSiO(4) FORMULA 23314277 A 82 99 titanium silicate SYSTEMATIC 23314277 A 923 931 TiSiO(4) FORMULA 23314277 A 983 991 TiSiO(4) FORMULA 23314277 T 79 96 titanium silicate SYSTEMATIC 23314331 A 0 6 Copper SYSTEMATIC 23314331 A 1275 1277 Cu FORMULA 23314331 A 138 140 Cu FORMULA 23314331 A 354 356 Cu FORMULA 23314331 A 476 478 Cu FORMULA 23314331 A 8 10 Cu FORMULA 23314331 A 841 843 Cu FORMULA 23314331 A 934 936 Cu FORMULA 23314331 T 0 6 Copper SYSTEMATIC 23314757 A 1069 1073 COOH FORMULA 23314757 A 1103 1109 folate TRIVIAL 23314757 A 1250 1256 folate TRIVIAL 23314757 A 1339 1345 folate TRIVIAL 23314757 A 220 228 AgInS(2) FORMULA 23314757 A 229 232 ZnS FORMULA 23314757 A 466 474 carboxyl SYSTEMATIC 23314757 A 476 481 amine SYSTEMATIC 23314757 A 483 491 hydroxyl SYSTEMATIC 23314757 A 497 502 thiol FAMILY 23314757 A 813 821 carboxyl SYSTEMATIC 23314757 A 839 843 COOH FORMULA 23315090 A 1074 1085 cholesterol TRIVIAL 23315090 A 1090 1102 triglyceride FAMILY 23315090 A 706 717 cholesterol TRIVIAL 23315090 A 743 754 cholesterol TRIVIAL 23315090 A 822 833 cholesterol TRIVIAL 23315090 A 962 973 cholesterol TRIVIAL 23315216 A 74 91 pentose phosphate FAMILY 23315496 A 1040 1044 oATP ABBREVIATION 23315496 A 1310 1314 oATP ABBREVIATION 23315496 A 623 626 ATP ABBREVIATION 23315496 A 628 632 oATP ABBREVIATION 23315496 A 764 768 oATP ABBREVIATION 23315496 A 82 85 ATP ABBREVIATION 23315496 A 865 874 rapamycin TRIVIAL 23315496 T 44 47 ATP ABBREVIATION 23315585 A 0 11 Domoic acid TRIVIAL 23315585 A 118 125 kainate TRIVIAL 23315585 A 1256 1260 DomA ABBREVIATION 23315585 A 13 17 DomA ABBREVIATION 23315585 A 137 141 DomA ABBREVIATION 23315585 A 1426 1430 DomA ABBREVIATION 23315585 A 1472 1475 GSH ABBREVIATION 23315585 A 1611 1615 DomA ABBREVIATION 23315585 A 294 298 DomA ABBREVIATION 23315585 A 460 469 glutamate TRIVIAL 23315585 A 470 478 cysteine TRIVIAL 23315585 A 559 570 glutathione TRIVIAL 23315585 A 572 575 GSH ABBREVIATION 23315585 A 610 614 DomA ABBREVIATION 23315585 A 64 117 α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid SYSTEMATIC 23315585 A 680 684 DomA ABBREVIATION 23315585 A 849 853 DomA ABBREVIATION 23315585 A 926 930 DomA ABBREVIATION 23315585 A 950 953 GSH ABBREVIATION 23315585 T 10 21 domoic acid TRIVIAL 23315585 T 98 109 glutathione TRIVIAL 23315601 A 1075 1082 glucose TRIVIAL 23315601 A 1183 1190 glucose TRIVIAL 23315601 A 1276 1283 glucose TRIVIAL 23315601 A 1313 1320 glucose TRIVIAL 23315601 A 1510 1517 glucose TRIVIAL 23315601 A 152 159 glucose TRIVIAL 23315601 A 24 31 glucose TRIVIAL 23315601 A 260 267 glucose TRIVIAL 23315601 A 47 54 glucose TRIVIAL 23315601 A 598 605 glucose TRIVIAL 23315601 A 740 747 glucose TRIVIAL 23315601 A 921 928 glucose TRIVIAL 23315601 T 32 39 Glucose TRIVIAL 23315601 T 9 16 Glucose TRIVIAL 23315683 A 118 140 poly(3-hexylthiophene) SYSTEMATIC 23315683 A 141 147 indene TRIVIAL 23315683 A 148 151 C60 TRIVIAL 23315683 A 152 161 bisadduct FAMILY 23315683 A 163 167 P3HT ABBREVIATION 23315683 A 168 172 ICBA ABBREVIATION 23315683 A 21 24 InP FORMULA 23315683 A 37 38 N FORMULA 23315683 A 57 63 carbon SYSTEMATIC 23315791 A 15 33 poly(benzyl ether) SYSTEMATIC 23315791 A 314 331 (R,R)-G(2)DPENBoc FORMULA 23315791 A 433 437 (1)H FORMULA 23315791 A 666 674 hydrogen SYSTEMATIC 23315791 A 76 119 N-Boc-protected 1,2-diphenylethylenediamine FAMILY 23315791 T 0 43 N-Boc-protected 1,2-diphenylethylenediamine FAMILY 23315938 A 272 279 steroid FAMILY 23315938 A 452 462 fatty acid FAMILY 23315938 A 670 677 glucose TRIVIAL 23315938 A 679 689 fatty acid FAMILY 23315938 A 695 705 amino acid FAMILY 23315938 A 792 803 amino acids FAMILY 23315938 A 805 820 acyl carnitines FAMILY 23315938 T 76 83 steroid FAMILY 23315996 A 157 174 hydrogen peroxide SYSTEMATIC 23315996 A 2 4 Pd FORMULA 23316021 A 225 240 gadolinium(III) SYSTEMATIC 23316021 A 261 275 β-cyclodextrin TRIVIAL 23316021 A 277 285 Gd-F-βCD FORMULA 23316021 A 299 315 titanium dioxide SYSTEMATIC 23316021 A 317 321 TiO2 FORMULA 23316021 A 421 432 Fluorescein TRIVIAL 23316021 A 436 445 rhodamine TRIVIAL 23316021 A 522 537 gadolinium(III) SYSTEMATIC 23316021 T 0 10 Gadolinium SYSTEMATIC 23316913 A 1188 1193 TiCl₄ FORMULA 23316913 A 1232 1235 BSO ABBREVIATION 23316913 A 1334 1337 BSO ABBREVIATION 23316913 A 1394 1398 TiO₂ FORMULA 23316913 A 302 312 perovskite TRIVIAL 23316913 A 313 319 BaSnO₃ FORMULA 23316913 A 321 324 BSO ABBREVIATION 23316913 A 371 376 TiCl₄ FORMULA 23316913 A 449 452 BSO ABBREVIATION 23316913 A 487 492 TiCl₄ FORMULA 23316913 A 534 538 TiO₂ FORMULA 23316913 A 552 555 BSO ABBREVIATION 23316913 A 644 648 TiO₂ FORMULA 23316913 A 8 14 oxides FAMILY 23316913 A 806 811 TiCl₄ FORMULA 23316913 A 866 868 OH FORMULA 23316913 A 94 98 TiO₂ FORMULA 23316913 T 48 58 perovskite TRIVIAL 23316913 T 59 65 BaSnO₃ FORMULA 23316965 A 1343 1354 doxycycline TRIVIAL 23316966 A 1073 1084 doxycycline TRIVIAL 23317100 A 1154 1161 SZ-685C IDENTIFIER 23317100 A 1172 1179 SZ-685C IDENTIFIER 23317100 A 1308 1315 SZ-685C IDENTIFIER 23317100 A 1524 1531 SZ-685C IDENTIFIER 23317100 A 1763 1770 SZ-685C IDENTIFIER 23317100 A 1857 1864 SZ-685C IDENTIFIER 23317100 A 1935 1942 SZ-685C IDENTIFIER 23317100 A 2013 2020 SZ-685C IDENTIFIER 23317100 A 366 373 SZ-685C IDENTIFIER 23317100 A 41 48 SZ-685C IDENTIFIER 23317100 A 541 548 SZ-685C IDENTIFIER 23317100 A 623 626 MTT ABBREVIATION 23317100 A 659 663 FITC ABBREVIATION 23317100 A 773 780 SZ-685C IDENTIFIER 23317100 A 796 803 SZ-685C IDENTIFIER 23317100 A 949 956 SZ-685C IDENTIFIER 23317100 T 21 28 SZ-685C IDENTIFIER 23317159 A 1348 1359 Ruxolitinib TRIVIAL 23317159 A 1514 1522 TG101348 IDENTIFIER 23317159 A 1526 1535 SAR302503 IDENTIFIER 23317159 A 1537 1543 SB1518 IDENTIFIER 23317159 A 1545 1551 CEP701 IDENTIFIER 23317159 A 1556 1565 LY2784544 IDENTIFIER 23317159 A 1627 1638 tasocitinib TRIVIAL 23317159 A 256 264 tyrosine TRIVIAL 23317159 A 945 948 ATP ABBREVIATION 23317163 A 1318 1331 acetylcholine SYSTEMATIC 23317450 A 1094 1125 benzylic and aliphatic alcohols MULTIPLE 23317450 A 1188 1192 O(2) FORMULA 23317450 A 12 14 Cu FORMULA 23317450 A 1219 1236 benzylic alcohols FAMILY 23317450 A 1311 1329 aliphatic alcohols FAMILY 23317450 A 15 20 TEMPO ABBREVIATION 23317450 A 164 171 alcohol FAMILY 23317450 A 213 218 Cu(I) FORMULA 23317450 A 219 224 TEMPO ABBREVIATION 23317450 A 225 228 NMI ABBREVIATION 23317450 A 246 249 NMI ABBREVIATION 23317450 A 252 269 N-methylimidazole SYSTEMATIC 23317450 A 352 360 alcohols FAMILY 23317450 A 39 44 TEMPO ABBREVIATION 23317450 A 47 83 2,2,6,6-tetramethylpiperidine-N-oxyl SYSTEMATIC 23317450 A 470 501 benzylic and aliphatic alcohols MULTIPLE 23317450 A 805 810 Cu(I) FORMULA 23317450 A 815 820 TEMPO ABBREVIATION 23317450 A 821 822 H FORMULA 23317450 A 839 843 O(2) FORMULA 23317450 A 860 869 Cu(2)O(2) FORMULA 23317450 A 925 931 Cu(II) FORMULA 23317450 A 940 948 nitroxyl SYSTEMATIC 23317450 A 972 978 Cu(II) FORMULA 23317450 A 979 987 alkoxide FAMILY 23317450 T 13 22 copper(I) SYSTEMATIC 23317450 T 47 54 alcohol FAMILY 23317497 A 0 19 Pyrroloquinoxalines FAMILY 23317497 A 372 391 pyrroloquinoxalines FAMILY 23317497 A 562 581 pyrroloquinoxalines FAMILY 23317497 T 72 91 pyrroloquinoxalines FAMILY 23317498 A 1040 1051 nucleosides FAMILY 23317498 A 161 171 nucleoside FAMILY 23317498 A 762 772 nucleoside FAMILY 23317498 A 801 812 nucleosides FAMILY 23317498 A 822 833 nucleosides FAMILY 23317572 A 114 127 rotenoisins A FAMILY 23317572 A 171 179 rotenone TRIVIAL 23317572 A 33 54 isoflavonoid rotenone TRIVIAL 23317572 A 423 431 rotenone TRIVIAL 23317572 T 29 37 rotenone TRIVIAL 23318226 A 1141 1146 NADPH ABBREVIATION 23318226 A 1180 1185 NADPH ABBREVIATION 23318226 A 1272 1281 Ro-318220 IDENTIFIER 23318226 A 1283 1289 Gö6983 IDENTIFIER 23318226 A 1294 1303 Rottlerin TRIVIAL 23318226 A 133 144 nucleotides FAMILY 23318226 A 1444 1447 NAC ABBREVIATION 23318226 A 1449 1452 APO ABBREVIATION 23318226 A 1454 1457 DPI ABBREVIATION 23318226 A 1459 1468 Ro-318220 IDENTIFIER 23318226 A 1470 1476 Gö6983 IDENTIFIER 23318226 A 1478 1487 Rottlerin TRIVIAL 23318226 A 154 157 ATP ABBREVIATION 23318226 A 1615 1619 PGE2 ABBREVIATION 23318226 A 1709 1713 PGE2 ABBREVIATION 23318226 A 1750 1755 NADPH ABBREVIATION 23318226 A 297 308 nucleotides FAMILY 23318226 A 496 499 ATP ABBREVIATION 23318226 A 539 543 PGE2 ABBREVIATION 23318226 A 642 647 NADPH ABBREVIATION 23318226 A 657 685 diphenyleneiodonium chloride SYSTEMATIC 23318226 A 687 690 DPI ABBREVIATION 23318226 A 695 703 apocynin TRIVIAL 23318226 A 705 708 APO ABBREVIATION 23318226 A 717 736 N-acetyl-l-cysteine SYSTEMATIC 23318226 A 738 741 NAC ABBREVIATION 23318226 A 754 763 Ro-318220 IDENTIFIER 23318226 A 765 771 Gö6983 IDENTIFIER 23318226 A 776 785 Rottlerin TRIVIAL 23318226 A 937 941 PGE2 ABBREVIATION 23318226 T 0 3 ATP ABBREVIATION 23318226 T 107 112 NADPH ABBREVIATION 23318226 T 15 21 PGE(2) ABBREVIATION 23318425 A 399 405 acetyl SYSTEMATIC 23318425 A 464 470 lysine TRIVIAL 23318445 A 1150 1160 superoxide TRIVIAL 23318445 A 1224 1230 oxygen SYSTEMATIC 23318445 A 919 925 oxygen SYSTEMATIC 23318645 A 779 785 iodine SYSTEMATIC 23318729 A 0 12 Isotretinoin TRIVIAL 23318729 A 1028 1040 isotretinoin TRIVIAL 23318729 A 1191 1203 isotretinoin TRIVIAL 23318729 A 1248 1260 isotretinoin TRIVIAL 23318729 A 18 31 retinoic acid TRIVIAL 23318729 A 286 295 retinoids FAMILY 23318729 A 361 373 isotretinoin TRIVIAL 23318729 A 540 552 isotretinoin TRIVIAL 23318729 A 809 821 isotretinoin TRIVIAL 23318729 A 882 894 isotretinoin TRIVIAL 23318729 T 41 53 isotretinoin TRIVIAL 23318730 A 1056 1071 platinum folate SYSTEMATIC 23318730 A 1555 1565 folic acid TRIVIAL 23318730 A 1601 1611 folic acid TRIVIAL 23318730 A 1727 1737 folic acid TRIVIAL 23318730 A 465 475 folic acid TRIVIAL 23318730 A 612 620 platinum SYSTEMATIC 23318730 A 641 651 folic acid TRIVIAL 23318730 T 0 15 Platinum folate SYSTEMATIC 23318905 A 101 133 benzofuran-3-yl(phenyl)methanone SYSTEMATIC 23318905 A 11 17 NAD(+) ABBREVIATION 23318905 A 233 236 Phe FORMULA 23318905 A 241 244 Phe FORMULA 23318905 A 252 255 Ile FORMULA 23318905 A 272 280 hydroxyl SYSTEMATIC 23318905 A 301 307 phenyl SYSTEMATIC 23318905 A 317 318 H FORMULA 23318905 A 329 332 Asn FORMULA 23318905 A 345 404 (2,5-dihydroxyphenyl)(5-hydroxy-1-benzofuran-3-yl)methanone SYSTEMATIC 23318905 A 428 437 hydroxyls FAMILY 23318905 A 611 623 nicotinamide TRIVIAL 23318905 A 634 640 NAD(+) ABBREVIATION 23318905 A 739 745 NAD(+) ABBREVIATION 23318905 T 18 51 benzofuran-3-yl(phenyl)methanones FAMILY 23319584 A 0 7 Calcium SYSTEMATIC 23319584 A 161 167 Ca(2+) FORMULA 23319584 A 1686 1692 Ca(2+) FORMULA 23319584 A 391 401 nucleotide FAMILY 23319591 T 29 35 lysine TRIVIAL 23319591 T 45 51 lysine TRIVIAL 23320385 A 1095 1106 Delphinidin TRIVIAL 23320385 A 12 24 Anthocyanins FAMILY 23320385 A 1250 1264 anthocyanidins FAMILY 23320385 A 1317 1331 Anthocyanidins FAMILY 23320385 A 1399 1413 anthocyanidins FAMILY 23320385 A 233 247 anthocyanidins FAMILY 23320385 A 249 260 delphinidin TRIVIAL 23320385 A 262 270 cyanidin TRIVIAL 23320385 A 272 280 malvidin TRIVIAL 23320385 A 285 297 pelargonidin TRIVIAL 23320385 A 357 365 carbonyl FAMILY 23320385 A 385 396 glutathione TRIVIAL 23320385 A 397 398 S FORMULA 23320385 A 423 426 UDP ABBREVIATION 23320385 A 44 58 anthocyanidins FAMILY 23320385 A 541 555 anthocyanidins FAMILY 23320385 A 623 632 menadione TRIVIAL 23320385 A 634 661 1-chloro-2,4-dinitrobenzene SYSTEMATIC 23320385 A 666 679 p-nitrophenol SYSTEMATIC 23320385 A 857 871 Anthocyanidins FAMILY 23320385 A 87 97 flavonoids FAMILY 23320385 A 955 963 Cyanidin TRIVIAL 23320385 T 106 114 carbonyl FAMILY 23320385 T 21 35 anthocyanidins FAMILY 23320385 T 47 58 glutathione TRIVIAL 23320385 T 59 60 S FORMULA 23320385 T 74 77 UDP ABBREVIATION 23320412 A 14 21 sulfate SYSTEMATIC 23320521 A 0 38 Dideoxy bicyclic pyrimidine nucleoside FAMILY 23320521 A 382 387 ether SYSTEMATIC 23320521 A 418 443 n-C(9)H(18)-O-n-C(5)H(11) FORMULA 23320521 A 50 57 ddBCNAs ABBREVIATION 23320521 A 530 539 cidofovir TRIVIAL 23320521 A 558 565 ddBCNAs ABBREVIATION 23320521 A 689 696 ddBCNAs ABBREVIATION 23320521 T 28 57 l-dideoxy bicyclic nucleoside FAMILY 23320931 A 266 274 europium SYSTEMATIC 23320931 A 279 286 terbium SYSTEMATIC 23320931 A 32 42 lanthanide FAMILY 23320931 A 334 344 lanthanide FAMILY 23320931 A 453 463 lanthanide FAMILY 23320931 A 501 509 catechol TRIVIAL 23320931 A 68 84 isophthalic acid TRIVIAL 23320931 A 89 97 catechol TRIVIAL 23320931 T 52 62 lanthanide FAMILY 23320940 A 43 64 perdeuterated tempone TRIVIAL 23320940 A 66 69 PDT ABBREVIATION 23320940 A 664 667 PDT ABBREVIATION 23321054 A 0 19 5-Hydroxytryptamine SYSTEMATIC 23321054 A 1097 1105 zolpidem TRIVIAL 23321054 A 1184 1196 eplivanserin TRIVIAL 23321054 A 1222 1230 zolpidem TRIVIAL 23321054 A 21 25 5-HT SYSTEMATIC 23321054 A 257 269 eplivanserin TRIVIAL 23321054 A 271 283 volinanserin TRIVIAL 23321054 A 288 295 AVE8488 NO CLASS 23321054 A 357 365 zolpidem TRIVIAL 23321054 A 461 473 eplivanserin TRIVIAL 23321054 A 506 518 volinanserin TRIVIAL 23321054 A 540 547 AVE8488 NO CLASS 23321054 A 572 580 zolpidem TRIVIAL 23321054 A 652 664 eplivanserin TRIVIAL 23321054 A 685 693 zolpidem TRIVIAL 23321054 A 775 787 Eplivanserin TRIVIAL 23321054 A 863 871 zolpidem TRIVIAL 23321054 A 931 943 Volinanserin TRIVIAL 23321054 A 964 971 AVE8488 NO CLASS 23321054 T 140 148 zolpidem TRIVIAL 23321916 A 181 200 decamethylferrocene SYSTEMATIC 23321916 A 202 206 DmFc ABBREVIATION 23321916 A 289 319 permethylated transition-metal FAMILY 23321916 A 463 472 ferrocene TRIVIAL 23321916 A 477 490 cobaltocenium SYSTEMATIC 23321916 A 48 71 decamethylcobaltocenium SYSTEMATIC 23321916 A 511 515 DmFc ABBREVIATION 23321916 A 599 608 DmFc(0/+) ABBREVIATION 23321916 A 613 622 DmCc(+/0) ABBREVIATION 23321916 A 73 80 DmCc(+) ABBREVIATION 23321916 A 743 747 DmFc ABBREVIATION 23321916 A 845 849 DmFc ABBREVIATION 23321916 T 14 44 permethylated transition-metal FAMILY 23322164 A 0 14 Acylcarnitines FAMILY 23322164 A 1035 1052 octanoylcarnitine SYSTEMATIC 23322164 A 1112 1126 acylcarnitines FAMILY 23322164 A 1221 1238 octanoylcarnitine SYSTEMATIC 23322164 A 1486 1499 acylcarnitine SYSTEMATIC 23322164 A 151 164 acylcarnitine SYSTEMATIC 23322164 A 1672 1681 Carnitine TRIVIAL 23322164 A 1709 1718 carnitine TRIVIAL 23322164 A 1719 1732 acylcarnitine SYSTEMATIC 23322164 A 1803 1817 acylcarnitines FAMILY 23322164 A 216 225 acyl-CoAs FAMILY 23322164 A 460 468 acyl-CoA ABBREVIATION 23322164 A 505 514 carnitine TRIVIAL 23322164 A 547 556 carnitine TRIVIAL 23322164 A 557 570 acylcarnitine SYSTEMATIC 23322164 A 609 618 carnitine TRIVIAL 23322164 A 67 77 fatty acid FAMILY 23322164 A 739 752 decanoic acid SYSTEMATIC 23322164 A 757 766 carnitine TRIVIAL 23322164 A 803 816 acylcarnitine SYSTEMATIC 23322164 A 930 947 octanoylcarnitine SYSTEMATIC 23322164 T 0 9 Carnitine TRIVIAL 23322164 T 131 145 acylcarnitines FAMILY 23322164 T 37 46 carnitine TRIVIAL 23322164 T 47 60 acylcarnitine SYSTEMATIC 23322347 A 1219 1226 calcium SYSTEMATIC 23322347 A 1285 1289 iron SYSTEMATIC 23322347 A 1424 1428 iron SYSTEMATIC 23322347 A 1811 1815 iron SYSTEMATIC 23322347 A 940 946 Ca(++) FORMULA 23322508 A 394 400 copper SYSTEMATIC 23322508 T 0 6 Copper SYSTEMATIC 23322559 A 10 30 monoterpene lactones FAMILY 23322559 A 32 51 cimicifugolides A-C MULTIPLE 23322559 T 4 24 monoterpene lactones FAMILY 23322648 A 33 112 1-O-hexadecyl-2-O-methyl-3-O-(2'-amino-2'-deoxy-β-D-glucopyranosyl)-sn-glycerol SYSTEMATIC 23322648 A 533 612 1-O-Hexadecyl-2-O-methyl-3-O-(2'-amino-2'-deoxy-α-D-glucopyranosyl)-sn-glycerol SYSTEMATIC 23322648 A 765 766 O FORMULA 23322648 A 791 805 thioglycosidic FAMILY 23322648 A 836 841 amino FAMILY 23322648 A 854 859 azide SYSTEMATIC 23322648 A 863 872 guanidino SYSTEMATIC 23322648 A 936 943 glycero SYSTEMATIC 23322648 T 133 140 glycero SYSTEMATIC 23322648 T 36 47 glucosamine TRIVIAL 23322709 A 13 15 CO FORMULA 23322709 A 143 158 carbon monoxide SYSTEMATIC 23322709 A 223 230 olefins FAMILY 23322709 A 248 262 alkyl formates FAMILY 23322709 A 293 302 palladium SYSTEMATIC 23322709 A 356 363 olefins FAMILY 23322709 A 419 425 esters FAMILY 23322709 T 79 86 olefins FAMILY 23322709 T 9 18 palladium SYSTEMATIC 23322709 T 92 100 formates FAMILY 23323677 A 1067 1081 cyanate esters FAMILY 23323677 A 108 132 2-methoxy-4-methylphenol SYSTEMATIC 23323677 A 134 141 creosol TRIVIAL 23323677 A 148 160 formaldehyde SYSTEMATIC 23323677 A 1553 1560 phenols FAMILY 23323677 A 1562 1576 isocyanic acid TRIVIAL 23323677 A 162 174 acetaldehyde SYSTEMATIC 23323677 A 1626 1629 CO2 FORMULA 23323677 A 1665 1667 N2 FORMULA 23323677 A 180 195 propionaldehyde SYSTEMATIC 23323677 A 1820 1827 phenols FAMILY 23323677 A 1829 1836 creosol TRIVIAL 23323677 A 1848 1866 alkylated creosols FAMILY 23323677 A 1982 1988 phenol SYSTEMATIC 23323677 A 1990 1997 creosol TRIVIAL 23323677 A 201 215 cyanate esters FAMILY 23323677 A 22 41 bis(cyanate) esters FAMILY 23323677 A 272 276 (1)H FORMULA 23323677 A 281 286 (13)C FORMULA 23323677 A 610 617 creosol TRIVIAL 23323677 A 626 640 cyanate esters FAMILY 23323677 A 66 76 bisphenols FAMILY 23323677 A 741 755 cyanate esters FAMILY 23323677 A 857 871 cyanate esters FAMILY 23323677 A 989 998 methylene SYSTEMATIC 23323677 T 61 80 bis(cyanate) esters FAMILY 23323677 T 94 118 2-methoxy-4-methylphenol SYSTEMATIC 23323680 A 1109 1111 Si FORMULA 23323680 A 125 130 Li-Si FORMULA 23323680 A 25 27 Si FORMULA 23323680 A 274 276 Si FORMULA 23323680 A 300 302 Si FORMULA 23323680 A 378 380 Si FORMULA 23323680 A 54 56 Li FORMULA 23323680 A 712 717 Si-Si FORMULA 23323680 A 778 780 Si FORMULA 23323680 A 850 852 Li FORMULA 23323680 A 875 877 Si FORMULA 23323680 T 49 56 silicon SYSTEMATIC 23323691 A 235 251 carboxylic acids FAMILY 23323691 A 326 332 aldose FAMILY 23323691 A 8 24 carboxylic acids FAMILY 23323691 T 10 26 carboxylic acids FAMILY 23323763 A 63 82 tuberostemonoxirine TRIVIAL 23323763 A 8 29 pyrrolo[1,2-α]azepine SYSTEMATIC 23323763 A 91 113 9α-epi-tuberospironine TRIVIAL 23323829 A 333 343 anthracene SYSTEMATIC 23323829 A 364 426 9,10-bis[4-(3-sulfonatopropoxyl)-styryl]anthracene sodium salt SYSTEMATIC 23323829 A 428 433 BSPSA ABBREVIATION 23323829 A 643 648 BSPSA ABBREVIATION 23323829 A 685 708 guanidine hydrochloride SYSTEMATIC 23323829 A 855 860 BSPSA ABBREVIATION 23323829 A 964 969 BSPSA ABBREVIATION 23323829 T 26 36 anthracene SYSTEMATIC 23323854 A 1052 1059 adenine TRIVIAL 23323854 A 1061 1069 cytosine TRIVIAL 23323854 A 1075 1082 guanine TRIVIAL 23323854 A 1097 1101 DOPC ABBREVIATION 23323854 A 1102 1107 DOTAP ABBREVIATION 23323854 A 1120 1124 DOPC ABBREVIATION 23323854 A 1125 1130 DC-Ch ABBREVIATION 23323854 A 1152 1156 DOPC ABBREVIATION 23323854 A 1192 1196 DOPC ABBREVIATION 23323854 A 1197 1202 DOTAP ABBREVIATION 23323854 A 1270 1274 DOPC ABBREVIATION 23323854 A 1275 1280 DC-Ch ABBREVIATION 23323854 A 157 198 1,2-dioleoyl-sn-glycerol-3-phosphocholine SYSTEMATIC 23323854 A 199 238 1,2-dioleoyl-3-timethylammonium propane SYSTEMATIC 23323854 A 240 244 DOPC ABBREVIATION 23323854 A 245 250 DOTAP ABBREVIATION 23323854 A 256 260 DOPC ABBREVIATION 23323854 A 261 316 3β-{N-[(N',N'-dimethylamino)ethyl]carbamoyl}cholesterol SYSTEMATIC 23323854 A 318 322 DOPC ABBREVIATION 23323854 A 323 328 DC-Ch ABBREVIATION 23323854 A 484 488 DOPC ABBREVIATION 23323854 A 489 494 DC-Ch ABBREVIATION 23323854 A 592 596 DOPC ABBREVIATION 23323854 A 597 602 DC-Ch ABBREVIATION 23323854 A 650 654 DOPC ABBREVIATION 23323854 A 655 660 DOTAP ABBREVIATION 23323854 A 761 765 DOPC ABBREVIATION 23323854 A 766 771 DOTAP ABBREVIATION 23323854 A 784 788 DOPC ABBREVIATION 23323854 A 789 794 DC-Ch ABBREVIATION 23323854 A 876 880 DOPC ABBREVIATION 23323854 A 942 951 phosphate SYSTEMATIC 23323854 A 954 962 PO(2)(-) FORMULA 23323854 A 969 977 carbonyl FAMILY 23323854 A 980 983 C=O FORMULA 23323854 T 47 102 3β-{N-[(N',N'-dimethylamino)ethyl]carbamoyl}cholesterol SYSTEMATIC 23323987 A 15 26 diterpenoid FAMILY 23323987 A 28 40 acerifolin A TRIVIAL 23323987 A 385 395 cisplantin TRIVIAL 23323987 A 56 67 isopimarane TRIVIAL 23323987 A 6 14 tigliane TRIVIAL 23323987 A 68 79 diterpenoid FAMILY 23323987 A 81 93 acerifolin B TRIVIAL 23323987 T 8 20 diterpenoids FAMILY 23324400 A 1209 1212 LT4 ABBREVIATION 23324400 A 1489 1492 LT4 ABBREVIATION 23324400 A 1830 1833 LT4 ABBREVIATION 23324400 A 254 267 levothyroxine TRIVIAL 23324400 A 269 272 LT4 ABBREVIATION 23324400 T 16 29 LEVOTHYROXINE TRIVIAL 23324437 A 1096 1107 Nateglinide TRIVIAL 23324437 A 1268 1279 Nateglinide TRIVIAL 23324437 A 1395 1402 glucose TRIVIAL 23324437 A 1422 1429 glucose TRIVIAL 23324437 A 143 150 glucose TRIVIAL 23324437 A 1458 1469 Nateglinide TRIVIAL 23324437 A 1473 1481 Acarbose TRIVIAL 23324437 A 1520 1530 Natelinide TRIVIAL 23324437 A 1535 1543 Acarbose TRIVIAL 23324437 A 1648 1655 glucose TRIVIAL 23324437 A 1688 1698 Natelinide TRIVIAL 23324437 A 1702 1710 Acarbose TRIVIAL 23324437 A 319 326 glucose TRIVIAL 23324437 A 466 477 Nateglinide TRIVIAL 23324437 A 481 489 Acarbose TRIVIAL 23324437 A 568 575 glucose TRIVIAL 23324437 A 601 608 glucose TRIVIAL 23324437 A 650 657 glucose TRIVIAL 23324437 A 69 76 glucose TRIVIAL 23324437 A 943 954 Nateglinide TRIVIAL 23324437 A 959 967 Acarbose TRIVIAL 23324437 T 42 53 Nateglinide TRIVIAL 23324437 T 57 65 Acarbose TRIVIAL 23324437 T 89 96 Glucose TRIVIAL 23325046 A 104 110 hexane SYSTEMATIC 23325046 A 1058 1064 oxygen SYSTEMATIC 23325046 A 977 981 DPPH ABBREVIATION 23325046 A 983 1012 α,α-diphenyl-β-picrylhydrazyl SYSTEMATIC 23325050 A 129 135 indole SYSTEMATIC 23325050 A 141 159 aromatic aldehydes FAMILY 23325050 A 18 35 dichlorophosphate SYSTEMATIC 23325050 A 212 233 bis(indolyl) methanes FAMILY 23325050 A 37 49 PEG-OPOCl(2) FORMULA 23325050 T 13 31 bisindolylmethanes FAMILY 23325373 A 1015 1022 glucose TRIVIAL 23325373 A 1027 1035 fructose TRIVIAL 23325373 A 138 145 glucose TRIVIAL 23325373 A 19 26 glucose TRIVIAL 23325373 A 237 244 glucose TRIVIAL 23325373 A 277 284 glucose TRIVIAL 23325373 A 494 502 fructose TRIVIAL 23325373 A 504 511 glucose TRIVIAL 23325373 A 566 574 Fructose TRIVIAL 23325373 A 617 624 glucose TRIVIAL 23325373 A 743 751 fructose TRIVIAL 23325373 A 765 772 glucose TRIVIAL 23325373 A 77 84 glucose TRIVIAL 23325373 A 873 881 fructose TRIVIAL 23325373 A 886 893 glucose TRIVIAL 23325373 T 42 49 glucose TRIVIAL 23325373 T 66 74 fructose TRIVIAL 23325486 A 1207 1210 Glu FORMULA 23325486 A 1250 1260 amino acid FAMILY 23325486 A 1271 1274 Tyr FORMULA 23325486 A 1281 1284 Thr FORMULA 23325489 A 1007 1014 linarin TRIVIAL 23325489 A 1100 1108 acacetin TRIVIAL 23325489 A 210 223 pentobarbital TRIVIAL 23325489 A 251 269 pentylenetetrazole SYSTEMATIC 23325489 A 271 274 PTZ ABBREVIATION 23325489 A 454 462 acacetin TRIVIAL 23325489 A 464 471 linarin TRIVIAL 23325489 A 473 561 acacetin 7-O-β-D-glucopyranosyl-(1 → 2)[α-L-rhamnopyranosyl-(1 → 6)]-β-D-glucopyranoside SYSTEMATIC 23325489 A 563 579 chlorogenic acid TRIVIAL 23325489 A 585 613 3,5-di-O-caffeoylquinic acid SYSTEMATIC 23325489 A 715 722 linarin TRIVIAL 23325489 A 865 872 Linarin TRIVIAL 23325489 A 891 899 acacetin TRIVIAL 23325489 T 69 86 flavone glycoside FAMILY 23325492 A 1146 1153 citrate FAMILY 23325492 A 17 24 citrate FAMILY 23325492 A 32 38 silver SYSTEMATIC 23325492 T 13 20 citrate FAMILY 23325492 T 28 34 silver SYSTEMATIC 23325530 A 0 10 Diclofenac TRIVIAL 23325530 A 1155 1158 DCF ABBREVIATION 23325530 A 1195 1198 DCF ABBREVIATION 23325530 A 12 15 DCF ABBREVIATION 23325530 A 1377 1380 DCF ABBREVIATION 23325530 A 534 537 DCF ABBREVIATION 23325530 A 742 745 DCF ABBREVIATION 23325530 A 883 886 DCF ABBREVIATION 23325530 T 0 10 Diclofenac TRIVIAL 23325631 A 0 5 CO(2) FORMULA 23325631 A 223 228 CO(2) FORMULA 23325631 A 292 303 bicarbonate SYSTEMATIC 23325631 A 481 505 3-nitrophenylacetic acid SYSTEMATIC 23325631 A 535 540 CO(2) FORMULA 23325631 A 705 710 CO(2) FORMULA 23325631 A 762 767 CO(2) FORMULA 23325631 T 42 47 CO(2) FORMULA 23325631 T 6 11 CO(2) FORMULA 23327112 A 19 49 clauexcavatins A (1) and B (2) MULTIPLE 23327112 A 8 17 coumarins FAMILY 23327112 T 0 9 Coumarins FAMILY 23327360 A 1065 1071 TiO(2) FORMULA 23327360 A 1364 1374 amino acid FAMILY 23327360 A 1444 1455 amino acids FAMILY 23327360 A 1512 1522 phosphoryl FAMILY 23327360 A 1597 1603 TiO(2) FORMULA 23327360 A 1793 1799 TiO(2) FORMULA 23327360 A 279 289 phosphoryl FAMILY 23327360 A 301 317 titanium dioxide SYSTEMATIC 23327360 A 319 325 TiO(2) FORMULA 23327360 A 636 642 TiO(2) FORMULA 23327360 A 692 698 quartz TRIVIAL 23327360 A 877 887 amino acid FAMILY 23327360 T 51 67 titanium dioxide SYSTEMATIC 23327360 T 95 101 quartz TRIVIAL 23327494 A 810 824 speciophylline TRIVIAL 23327494 A 826 836 uncarine F TRIVIAL 23327494 A 841 851 uncarine E TRIVIAL 23327494 A 857 866 flavanols FAMILY 23327494 A 868 876 catechin TRIVIAL 23327494 A 881 897 epigallocatechin TRIVIAL 23327532 A 1013 1020 styrene TRIVIAL 23327532 A 1026 1039 4-vinylphenol SYSTEMATIC 23327532 A 1083 1097 Styrene glycol TRIVIAL 23327532 A 331 338 styrene TRIVIAL 23327532 A 376 383 styrene TRIVIAL 23327532 A 549 556 styrene TRIVIAL 23327532 A 597 610 4-nitrophenol SYSTEMATIC 23327532 A 667 674 Styrene TRIVIAL 23327532 A 901 914 Styrene oxide SYSTEMATIC 23327532 A 919 932 4-vinylphenol SYSTEMATIC 23327532 A 972 985 Styrene oxide SYSTEMATIC 23327532 T 46 53 styrene TRIVIAL 23327534 A 551 563 germacrene B TRIVIAL 23327534 A 577 590 viridiflorene TRIVIAL 23327534 A 609 617 globulol TRIVIAL 23327534 A 631 640 α-cadinol TRIVIAL 23327534 A 656 665 τ-cadinol TRIVIAL 23327557 A 1111 1122 procyanidin FAMILY 23327557 A 25 37 procyanidins FAMILY 23327557 A 412 429 galacturonic acid TRIVIAL 23327557 A 469 480 procyanidin FAMILY 23327557 A 501 516 (-)-epicatechin SYSTEMATIC 23327557 A 685 697 procyanidins FAMILY 23327557 A 787 799 procyanidins FAMILY 23327557 A 96 108 Procyanidins FAMILY 23327557 A 998 1010 procyanidins FAMILY 23327557 T 42 54 procyanidins FAMILY 23327580 A 86 97 doxorubicin TRIVIAL 23327668 A 10 18 abietane TRIVIAL 23327668 A 19 31 diterpenoids FAMILY 23327668 A 33 50 isoabietenins A-C MULTIPLE 23327668 A 630 642 nitric oxide SYSTEMATIC 23327668 A 69 83 ent-kauranoids FAMILY 23327668 A 85 100 tenuifolins A-M MULTIPLE 23327668 T 10 18 abietane TRIVIAL 23327668 T 23 34 ent-kaurane TRIVIAL 23327668 T 35 47 diterpenoids FAMILY 23327794 A 144 164 piperidine alkaloids FAMILY 23327794 A 166 186 microgrewiapines A-C MULTIPLE 23327794 A 241 256 microcosamine A TRIVIAL 23327794 A 262 325 7'-(3',4'-dihydroxyphenyl)-N-[4-methoxyphenyl)ethyl]propenamide SYSTEMATIC 23327794 A 335 346 liriodenine TRIVIAL 23327794 A 407 417 chloroform TRIVIAL 23327794 A 514 541 microgrewiapine A 3-acetate SYSTEMATIC 23327794 A 694 707 acetylcholine SYSTEMATIC 23327794 A 828 845 microgrewiapine A TRIVIAL 23327993 A 1128 1131 NAC ABBREVIATION 23327993 A 1133 1136 AD4 IDENTIFIER 23327993 A 1141 1154 ascorbic acid TRIVIAL 23327993 A 1207 1228 NAc-Cys-Pro-Cys amide SYSTEMATIC 23327993 A 590 599 auranofin TRIVIAL 23327993 A 601 604 AuF ABBREVIATION 23327993 A 624 627 AuF ABBREVIATION 23327993 A 735 738 AuF ABBREVIATION 23327993 A 893 902 disulfide SYSTEMATIC 23327993 T 43 52 auranofin TRIVIAL 23328072 A 1544 1555 1,25(OH)₂D₃ SYSTEMATIC 23328072 A 371 381 vitamin D₃ TRIVIAL 23328072 A 383 407 1,25-dihydroxyvitamin D₃ SYSTEMATIC 23328072 A 409 420 1,25(OH)₂D₃ SYSTEMATIC 23328072 A 65 74 vitamin D FAMILY 23328072 A 681 692 1,25(OH)₂D₃ SYSTEMATIC 23328072 A 966 977 1,25(OH)₂D3 SYSTEMATIC 23328072 T 26 35 vitamin D FAMILY 23328126 A 1037 1052 ω-3 fatty acids FAMILY 23328126 A 201 216 ω-3 fatty acids FAMILY 23328126 A 315 340 Omega-3-Acid Ethyl Esters FAMILY 23328126 A 757 771 ω-3 fatty acid FAMILY 23328126 A 958 973 ω-3 fatty acids FAMILY 23328126 T 0 19 Omega-3 Fatty acids FAMILY 23328252 A 0 25 2,4-Dihydroxybenzophenone SYSTEMATIC 23328252 A 1176 1180 BP-1 ABBREVIATION 23328252 A 1273 1277 BP-1 ABBREVIATION 23328252 A 1451 1455 BP-1 ABBREVIATION 23328252 A 1704 1708 BP-1 ABBREVIATION 23328252 A 177 181 BP-1 ABBREVIATION 23328252 A 27 41 benzophenone-1 SYSTEMATIC 23328252 A 407 411 BP-1 ABBREVIATION 23328252 A 43 47 BP-1 ABBREVIATION 23328252 A 458 466 estrogen FAMILY 23328252 A 541 555 17-β estradiol SYSTEMATIC 23328252 A 596 600 BP-1 ABBREVIATION 23328252 A 824 828 BP-1 ABBREVIATION 23328252 A 835 839 BP-1 ABBREVIATION 23328252 A 933 944 ICI 182,780 IDENTIFIER 23328252 A 980 984 BP-1 ABBREVIATION 23328252 T 0 14 Benzophenone-1 SYSTEMATIC 23328252 T 98 106 estrogen FAMILY 23329065 A 1060 1070 quinpirole TRIVIAL 23329065 A 1418 1428 quinpirole TRIVIAL 23329065 A 1544 1554 quinpirole TRIVIAL 23329065 A 1631 1641 quinpirole TRIVIAL 23329065 A 1700 1710 quinpirole TRIVIAL 23329065 A 311 321 quinpirole TRIVIAL 23329065 A 45 55 quinpirole TRIVIAL 23329065 A 484 494 quinpirole TRIVIAL 23329065 A 626 634 urethane TRIVIAL 23329065 A 705 715 quinpirole TRIVIAL 23329065 A 766 776 quinpirole TRIVIAL 23329065 T 11 19 dopamine TRIVIAL 23329065 T 31 41 quinpirole TRIVIAL 23329125 A 1005 1008 PCB ABBREVIATION 23329125 A 1078 1082 tBHQ ABBREVIATION 23329125 A 1206 1210 tBHQ ABBREVIATION 23329125 A 126 142 aryl hydrocarbon FAMILY 23329125 A 1430 1441 glutathione TRIVIAL 23329125 A 1442 1443 S FORMULA 23329125 A 1491 1495 tBHQ ABBREVIATION 23329125 A 1557 1567 superoxide TRIVIAL 23329125 A 1649 1653 PCBs ABBREVIATION 23329125 A 1772 1775 PCB ABBREVIATION 23329125 A 205 230 polychlorinated biphenyls FAMILY 23329125 A 232 236 PCBs ABBREVIATION 23329125 A 242 277 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23329125 A 279 283 TCDD ABBREVIATION 23329125 A 529 532 PCB ABBREVIATION 23329125 A 747 769 tert-butylhydroquinone SYSTEMATIC 23329125 A 771 775 tBHQ ABBREVIATION 23329180 A 1054 1065 theaflavins FAMILY 23329180 A 1181 1191 theaflavin TRIVIAL 23329180 A 1548 1558 theaflavin TRIVIAL 23329180 A 348 359 theaflavins FAMILY 23329180 A 59 67 tyrosine TRIVIAL 23330542 A 1059 1065 azoles FAMILY 23330542 A 1326 1331 azole FAMILY 23330542 A 38 46 pregnane TRIVIAL 23330542 A 464 477 acetaminophen TRIVIAL 23330542 A 939 951 sulforaphane TRIVIAL 23330549 A 103 108 Pt(6) FORMULA 23330549 T 12 20 platinum SYSTEMATIC 23330613 A 1308 1317 ornithine TRIVIAL 23330613 A 1480 1490 spermidine TRIVIAL 23330613 A 412 421 polyamine FAMILY 23330613 A 453 474 5-methylthioadenosine SYSTEMATIC 23330613 A 476 486 putrescine TRIVIAL 23330613 A 491 501 spermidine TRIVIAL 23330613 A 571 580 polyamine FAMILY 23330613 A 6 22 phosphoinositide FAMILY 23330613 A 668 678 spermidine TRIVIAL 23330613 A 777 786 polyamine FAMILY 23330613 A 803 812 ornithine TRIVIAL 23330613 A 928 938 spermidine TRIVIAL 23330613 T 0 9 Polyamine SYSTEMATIC 23330789 A 490 497 silanes FAMILY 23330847 A 1040 1061 carbonyl di-imidazole SYSTEMATIC 23330847 A 1066 1073 hydroxy SYSTEMATIC 23330847 A 1355 1362 hydroxy SYSTEMATIC 23330847 A 1484 1495 cholesterol TRIVIAL 23330847 A 1651 1658 hydroxy SYSTEMATIC 23330847 A 892 899 hydroxy SYSTEMATIC 23330847 A 911 930 polyethylene glycol SYSTEMATIC 23330847 T 0 7 Hydroxy SYSTEMATIC 23330847 T 95 106 cholesterol TRIVIAL 23330848 A 404 411 choline FAMILY 23330848 A 433 434 H FORMULA 23330848 A 470 476 C2H3OH FORMULA 23330848 A 485 486 H FORMULA 23330848 A 567 574 tacrine TRIVIAL 23330848 A 579 591 galanthamine TRIVIAL 23330848 A 633 641 coumarin TRIVIAL 23330848 A 802 810 coumarin TRIVIAL 23330848 A 843 850 tacrine TRIVIAL 23330908 A 100 101 C FORMULA 23330908 A 108 109 C FORMULA 23330908 A 402 411 zanamivir TRIVIAL 23330908 A 594 603 zanamivir TRIVIAL 23330908 A 77 86 zanamivir TRIVIAL 23330908 T 40 41 C FORMULA 23330908 T 49 50 C FORMULA 23330908 T 73 82 zanamivir TRIVIAL 23330971 A 110 113 ZnO FORMULA 23330971 A 14 20 indium SYSTEMATIC 23330971 A 189 192 ZnO FORMULA 23330971 A 239 242 ZnO FORMULA 23330971 A 248 251 ZnO FORMULA 23330971 A 514 530 Cu(In,Ga)(S,Se)₂ FORMULA 23330971 A 532 538 CIGSSe ABBREVIATION 23330971 A 709 714 oxide SYSTEMATIC 23330971 A 721 727 CIGSSe ABBREVIATION 23330971 A 744 747 ZnO FORMULA 23330971 A 753 756 ZnO FORMULA 23330971 A 81 87 silver SYSTEMATIC 23330971 T 34 37 ZnO FORMULA 23330971 T 38 40 Ag FORMULA 23330971 T 50 53 ZnO FORMULA 23331178 A 1027 1035 carbonyl FAMILY 23331178 A 1040 1049 phosphate SYSTEMATIC 23331178 A 1106 1110 DMPE ABBREVIATION 23331178 A 113 149 dimyristoyl phosphatidylethanolamine SYSTEMATIC 23331178 A 151 155 DMPE ABBREVIATION 23331178 A 174 181 Au(111) FORMULA 23331178 A 560 564 DMPE ABBREVIATION 23331178 A 645 676 dimyristoyl phosphatidylcholine SYSTEMATIC 23331178 A 678 682 DMPC ABBREVIATION 23331178 A 818 822 DMPE ABBREVIATION 23331178 A 852 863 hydrocarbon FAMILY 23331178 A 957 968 hydrocarbon FAMILY 23331539 A 133 145 quinazolinon FAMILY 23331539 A 447 459 quinazolinon FAMILY 23331539 A 516 524 hydrogen SYSTEMATIC 23331539 A 647 659 quinazolinon FAMILY 23331539 T 31 43 quinazolinon FAMILY 23331618 A 102 128 4-amino-7-chloroquinolines FAMILY 23331618 A 153 187 7-chloro-4-aminoquinoline-triazine FAMILY 23331618 A 242 253 chloroquine TRIVIAL 23331618 A 273 284 chloroquine TRIVIAL 23331618 A 42 50 triazine FAMILY 23331618 A 501 512 chloroquine TRIVIAL 23331618 A 639 650 chloroquine TRIVIAL 23331618 A 663 674 chloroquine TRIVIAL 23331618 T 0 25 4-Aminoquinoline-Triazine FAMILY 23332347 A 355 366 sibutramine TRIVIAL 23332347 A 418 426 orlistat TRIVIAL 23332347 A 539 545 Belviq TRIVIAL 23332347 A 550 556 Qsymia TRIVIAL 23332762 A 632 638 serine TRIVIAL 23332762 A 643 646 Ser FORMULA 23332762 A 697 700 Ser FORMULA 23333093 A 273 281 catechin TRIVIAL 23333093 A 861 872 cholesterol TRIVIAL 23333093 A 901 912 cholesterol TRIVIAL 23333093 A 960 971 cholesterol TRIVIAL 23333093 T 10 18 catechin TRIVIAL 23333261 A 1011 1019 curcumin TRIVIAL 23333261 A 208 215 glucose TRIVIAL 23333261 A 592 606 streptozotocin TRIVIAL 23333261 A 847 854 glucose TRIVIAL 23333261 A 916 924 Curcumin TRIVIAL 23333575 A 1000 1011 glutathione TRIVIAL 23333575 A 1055 1064 genistein TRIVIAL 23333575 A 1116 1125 genistein TRIVIAL 23333575 A 113 132 uridine diphosphate SYSTEMATIC 23333575 A 1168 1177 genistein TRIVIAL 23333575 A 1210 1214 APAP ABBREVIATION 23333575 A 1263 1267 APAP ABBREVIATION 23333575 A 191 204 acetaminophen TRIVIAL 23333575 A 271 280 genistein TRIVIAL 23333575 A 346 353 alanine TRIVIAL 23333575 A 372 379 alanine TRIVIAL 23333575 A 398 405 lactate FAMILY 23333575 A 424 439 malondialdehyde TRIVIAL 23333575 A 45 54 genistein TRIVIAL 23333575 A 487 491 APAP ABBREVIATION 23333575 A 519 522 GSH ABBREVIATION 23333575 A 561 565 APAP ABBREVIATION 23333575 A 621 630 genistein TRIVIAL 23333575 A 709 718 Genistein TRIVIAL 23333575 A 746 750 APAP ABBREVIATION 23333575 A 794 798 APAP ABBREVIATION 23333575 A 799 810 glucuronide TRIVIAL 23333575 A 876 885 genistein TRIVIAL 23333575 A 952 956 APAP ABBREVIATION 23333575 T 0 9 Genistein TRIVIAL 23333575 T 110 113 UDP ABBREVIATION 23333575 T 29 42 acetaminophen TRIVIAL 23333639 A 463 482 formamidopyrimidine SYSTEMATIC 23333639 A 694 706 8-oxoguanine SYSTEMATIC 23333639 A 708 714 8-oxoG SYSTEMATIC 23333639 A 842 848 oxygen SYSTEMATIC 23333639 A 932 944 α-tocopherol TRIVIAL 23333641 A 0 12 Methoxychlor TRIVIAL 23333641 A 14 17 MXC ABBREVIATION 23333641 A 166 169 MXC ABBREVIATION 23333641 A 189 233 2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane SYSTEMATIC 23333641 A 235 239 HPTE ABBREVIATION 23333641 A 260 278 11β-hydroxysteroid FAMILY 23333641 A 560 563 MXC ABBREVIATION 23333641 A 568 572 HPTE ABBREVIATION 23333641 A 622 626 HPTE ABBREVIATION 23333641 A 684 687 MXC ABBREVIATION 23333641 A 716 719 MXC ABBREVIATION 23333641 A 724 728 HPTE ABBREVIATION 23333641 A 770 774 HPTE ABBREVIATION 23333641 A 889 892 MXC ABBREVIATION 23333641 A 955 958 MXC ABBREVIATION 23333641 A 978 982 HPTE ABBREVIATION 23333641 T 11 23 methoxychlor TRIVIAL 23333641 T 43 89 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane SYSTEMATIC 23333641 T 93 111 11β-hydroxysteroid FAMILY 23333716 A 117 125 phenolic FAMILY 23333716 A 136 155 protocatechuic acid TRIVIAL 23333716 A 405 424 protocatechuic acid TRIVIAL 23333716 T 61 80 protocatechuic acid TRIVIAL 23333834 A 1011 1016 YR-11 IDENTIFIER 23333834 A 1067 1075 cysteine TRIVIAL 23333834 A 1083 1089 serine TRIVIAL 23333834 A 1297 1302 YR-11 IDENTIFIER 23333834 A 1593 1598 YR-11 IDENTIFIER 23333834 A 391 394 Tyr FORMULA 23333834 A 397 400 Asp FORMULA 23333834 A 404 407 Tyr FORMULA 23333834 A 410 413 Glu FORMULA 23333834 A 421 424 Leu FORMULA 23333834 A 428 431 Arg FORMULA 23333834 A 472 475 Leu FORMULA 23333834 A 479 482 Arg FORMULA 23333834 A 988 997 celecoxib TRIVIAL 23333899 A 0 11 Doxorubicin TRIVIAL 23333899 A 1001 1004 Dox ABBREVIATION 23333899 A 1024 1035 Doxorubicin TRIVIAL 23333899 A 1296 1299 Dox ABBREVIATION 23333899 A 1385 1388 Dox ABBREVIATION 23333899 A 1415 1418 Dox ABBREVIATION 23333899 A 1424 1427 Dox ABBREVIATION 23333899 A 147 160 octa-arginine TRIVIAL 23333899 A 1540 1543 Dox ABBREVIATION 23333899 A 1575 1578 Dox ABBREVIATION 23333899 A 1612 1615 Dox ABBREVIATION 23333899 A 1714 1725 doxorubicin TRIVIAL 23333899 A 218 271 polyethylene glycol-dioleoyl phosphatidylethanolamine SYSTEMATIC 23333899 A 273 281 PEG-DOPE ABBREVIATION 23333899 A 321 330 R8-PEG-PE FORMULA 23333899 A 66 71 DOXIL TRIVIAL 23333899 A 751 754 Dox ABBREVIATION 23333899 A 76 83 Lipodox TRIVIAL 23333899 A 824 835 doxorubicin TRIVIAL 23333899 A 950 961 Doxorubicin TRIVIAL 23333899 A 990 993 Dox ABBREVIATION 23333899 T 29 40 doxorubicin TRIVIAL 23333899 T 63 76 octa-arginine TRIVIAL 23333900 A 1032 1045 carbamazepine TRIVIAL 23333900 A 1050 1058 Soluplus TRIVIAL 23333900 A 1248 1251 CBZ ABBREVIATION 23333900 A 1289 1292 CBZ ABBREVIATION 23333900 A 1345 1348 CBZ ABBREVIATION 23333900 A 1517 1520 CBZ ABBREVIATION 23333900 A 1637 1650 carbamazepine TRIVIAL 23333900 A 1654 1662 Soluplus TRIVIAL 23333900 A 382 395 carbamazepine TRIVIAL 23333900 A 397 400 CBZ ABBREVIATION 23333900 A 407 425 polyethyleneglycol SYSTEMATIC 23333900 A 426 447 polyvinyl caprolactam SYSTEMATIC 23333900 A 448 465 polyvinyl acetate SYSTEMATIC 23333900 A 485 493 Soluplus TRIVIAL 23333900 A 849 852 CBZ ABBREVIATION 23333900 A 857 865 Soluplus TRIVIAL 23333900 T 15 28 carbamazepine TRIVIAL 23333900 T 29 37 Soluplus TRIVIAL 23333908 A 1416 1426 Captropril TRIVIAL 23333908 A 1452 1462 Lisinopril TRIVIAL 23333908 A 1470 1481 cholesterol TRIVIAL 23333908 A 1507 1518 cholesterol TRIVIAL 23333908 A 1532 1545 triglycerides FAMILY 23333908 A 1671 1682 cholesterol TRIVIAL 23333908 A 1892 1903 cholesterol TRIVIAL 23333908 A 1912 1925 triglycerides FAMILY 23333908 A 1955 1967 Anthocyanins FAMILY 23333908 A 2171 2182 polyphenols FAMILY 23333908 A 2187 2200 hibiscus acid TRIVIAL 23333908 A 2376 2388 anthocyanins FAMILY 23334176 A 558 563 sugar FAMILY 23334176 A 574 581 glucose TRIVIAL 23334176 A 700 707 glucose TRIVIAL 23334176 A 831 836 sugar FAMILY 23334176 A 847 854 glucose TRIVIAL 23334322 A 0 22 Pyridoxal-5'-phosphate SYSTEMATIC 23334322 A 1033 1043 vitamin B6 TRIVIAL 23334322 A 1105 1117 homocysteine TRIVIAL 23334322 A 1275 1285 vitamin B6 TRIVIAL 23334322 A 1448 1457 pyridoxal TRIVIAL 23334322 A 1498 1508 pyridoxine TRIVIAL 23334322 A 1519 1529 vitamin B6 TRIVIAL 23334322 A 1546 1549 PLP ABBREVIATION 23334322 A 1738 1748 vitamin B6 TRIVIAL 23334322 A 214 224 vitamin B6 TRIVIAL 23334322 A 24 27 PLP ABBREVIATION 23334322 A 375 383 aldehyde SYSTEMATIC 23334322 A 409 419 pyridoxine TRIVIAL 23334322 A 511 514 PLP ABBREVIATION 23334322 A 52 62 vitamin B6 TRIVIAL 23334322 A 529 532 PLP ABBREVIATION 23334322 A 567 579 homocysteine TRIVIAL 23334322 A 638 640 B6 TRIVIAL 23334322 A 661 664 PLP ABBREVIATION 23334322 A 696 706 pyridoxine TRIVIAL 23334322 A 977 987 vitamin B6 TRIVIAL 23334322 T 11 21 vitamin B6 TRIVIAL 23334583 A 1179 1185 Ca(+2) FORMULA 23335034 A 0 6 Carbon SYSTEMATIC 23335034 A 188 194 carbon SYSTEMATIC 23335034 A 258 264 (14) C FORMULA 23335034 A 287 299 phenanthrene SYSTEMATIC 23335034 A 342 348 carbon SYSTEMATIC 23335034 A 413 425 phenanthrene SYSTEMATIC 23335034 A 491 503 phenanthrene SYSTEMATIC 23335034 A 703 715 phenanthrene SYSTEMATIC 23335034 A 969 981 phenanthrene SYSTEMATIC 23335034 T 18 30 phenanthrene SYSTEMATIC 23335034 T 53 59 carbon SYSTEMATIC 23335220 A 247 250 ATP ABBREVIATION 23335220 A 251 257 biotin TRIVIAL 23335220 A 332 338 biotin TRIVIAL 23335220 A 486 492 biotin TRIVIAL 23335220 A 550 566 phosphorylbiotin SYSTEMATIC 23335220 A 900 903 ATP ABBREVIATION 23335220 A 904 910 biotin TRIVIAL 23335220 A 983 986 ATP ABBREVIATION 23335243 A 20 28 terpenes FAMILY 23335243 A 249 263 sesquiterpenes FAMILY 23335243 A 57 70 sesquiterpene FAMILY 23335243 T 22 35 sesquiterpene FAMILY 23335320 A 161 169 pyridine SYSTEMATIC 23335320 A 185 207 N-heterocyclic carbene FAMILY 23335320 A 208 221 palladacycles FAMILY 23335320 A 339 349 amino acid FAMILY 23335320 A 514 516 Pd FORMULA 23335320 A 517 518 N FORMULA 23335320 A 574 582 α-carbon SYSTEMATIC 23335320 A 77 84 carbene FAMILY 23335320 A 91 104 palladacycles FAMILY 23335320 T 102 115 palladacycles FAMILY 23335320 T 135 137 Pd FORMULA 23335320 T 138 139 N FORMULA 23335320 T 64 72 pyridine SYSTEMATIC 23335320 T 73 95 N-heterocyclic carbene FAMILY 23335450 A 205 213 cysteine TRIVIAL 23335450 A 968 972 S-Au FORMULA 23335565 A 389 402 5-azacytidine SYSTEMATIC 23335565 A 461 467 oxygen SYSTEMATIC 23335565 A 740 751 phytic acid TRIVIAL 23335565 T 43 54 phytic Acid TRIVIAL 23335833 A 138 142 DPPC ABBREVIATION 23335833 A 211 236 poly(methyl methacrylate) SYSTEMATIC 23335833 A 316 320 DPPC ABBREVIATION 23335833 A 374 378 DPPC ABBREVIATION 23335833 A 48 57 formamide SYSTEMATIC 23335833 A 62 75 diiodomethane SYSTEMATIC 23335833 A 620 624 DPPC ABBREVIATION 23335833 A 93 136 1,2-dipalmitoyl-sn-glycero-3-phosphocholine SYSTEMATIC 23336337 A 127 132 ester FAMILY 23336337 A 403 413 jolkinol D TRIVIAL 23336337 A 532 551 lathyrane diterpene FAMILY 23336337 A 56 66 jolkinol D TRIVIAL 23336337 A 762 769 octanol SYSTEMATIC 23336337 T 22 32 diterpenes FAMILY 23336337 T 98 108 jolkinol D TRIVIAL 23336368 A 100 110 kaempferol TRIVIAL 23336368 A 119 128 quercetin TRIVIAL 23336368 A 8 20 homoflavanol FAMILY 23336368 A 89 99 flavonoids FAMILY 23336368 T 46 58 homoflavanol FAMILY 23336729 A 194 206 methacrylate TRIVIAL 23336729 A 260 273 acetylcholine SYSTEMATIC 23336729 A 305 336 dimethylaminoethyl methacrylate SYSTEMATIC 23336729 A 345 353 hydroxyl SYSTEMATIC 23336729 A 365 386 poly(ethylene glycol) SYSTEMATIC 23336729 A 775 788 poly-l-lysine SYSTEMATIC 23336729 T 47 60 acetylcholine SYSTEMATIC 23337202 A 567 579 [Au(CN)(2)]- FORMULA 23337202 A 763 775 [Au(CN)(2)]- FORMULA 23337397 A 121 132 Trypan blue TRIVIAL 23337397 A 188 191 MTT ABBREVIATION 23337599 A 134 140 indole SYSTEMATIC 23337599 A 362 370 zileuton TRIVIAL 23337599 A 565 570 tosyl TRIVIAL 23337599 A 588 609 pyrolidinyl-1,2-dione SYSTEMATIC 23337599 A 632 638 indole SYSTEMATIC 23337599 T 21 28 indoles FAMILY 23337600 A 0 15 (Me)FGC(Bz)DEVD FORMULA 23337600 A 191 200 cisplatin TRIVIAL 23337600 A 298 317 (99m)Tc-(Me)FGCDEVD SYSTEMATIC 23337600 A 38 52 technetium-99m SYSTEMATIC 23337600 T 0 17 ⁹⁹mTc-(Me)FGCDEVD SYSTEMATIC 23337925 A 720 729 acetylene SYSTEMATIC 23337941 A 1015 1039 quinoidal oligothiophene TRIVIAL 23337941 A 136 161 quinoidal quaterthiophene SYSTEMATIC 23337941 A 163 171 QQT(CN)4 FORMULA 23337941 A 498 506 QQT(CN)4 FORMULA 23337941 A 658 666 QQT(CN)4 FORMULA 23337941 A 877 885 QQT(CN)4 FORMULA 23338525 A 1036 1038 Ir FORMULA 23338525 A 1231 1237 oxygen SYSTEMATIC 23338525 A 1513 1519 IrO(2) FORMULA 23338525 A 1520 1526 SnO(2) FORMULA 23338525 A 1604 1606 Ir FORMULA 23338525 A 1636 1644 hydrogen SYSTEMATIC 23338525 A 328 330 Ir FORMULA 23338525 A 333 335 Sn FORMULA 23338525 A 340 344 O(2) FORMULA 23338525 A 485 487 Ir FORMULA 23338525 A 505 520 bi-metal oxides FAMILY 23338525 A 566 568 Ir FORMULA 23338525 A 574 576 Sn FORMULA 23338525 A 61 63 Ir FORMULA 23338525 A 66 68 Sn FORMULA 23338525 A 664 670 SnO(2) FORMULA 23338525 A 689 695 IrO(2) FORMULA 23338525 A 73 77 O(2) FORMULA 23338525 A 749 755 IrO(2) FORMULA 23338525 A 797 799 Ir FORMULA 23338525 A 851 853 Ir FORMULA 23338525 A 895 897 Sn FORMULA 23338525 A 918 920 Ir FORMULA 23338525 A 926 928 Sn FORMULA 23338525 A 934 938 O(2) FORMULA 23338525 A 968 974 Nafion TRIVIAL 23338525 T 17 19 Ir FORMULA 23338525 T 22 24 Sn FORMULA 23338525 T 29 31 O2 FORMULA 23338525 T 53 59 oxygen SYSTEMATIC 23338537 A 168 178 cefuroxime TRIVIAL 23338537 A 275 285 cefuroxime TRIVIAL 23338537 A 419 429 cefuroxime TRIVIAL 23338537 A 580 587 Aprokam TRIVIAL 23338537 A 603 613 cefuroxime TRIVIAL 23338537 A 744 751 Aprokam TRIVIAL 23338537 T 13 23 cefuroxime TRIVIAL 23339036 A 250 259 estrogens FAMILY 23339036 A 298 307 tamoxifen TRIVIAL 23339036 A 653 662 estrogens FAMILY 23339547 A 1192 1202 rasagiline TRIVIAL 23339547 A 1305 1315 rasagiline TRIVIAL 23339547 A 1378 1388 rasagiline TRIVIAL 23339547 A 14 24 rasagiline TRIVIAL 23339547 A 157 167 rasagiline TRIVIAL 23339547 A 250 260 rasagiline TRIVIAL 23339547 A 406 416 rasagiline TRIVIAL 23339547 A 521 531 rasagiline TRIVIAL 23339547 A 915 925 rasagiline TRIVIAL 23339547 T 44 54 rasagiline TRIVIAL 23339572 A 1019 1031 sulforaphane TRIVIAL 23339572 A 1033 1049 dimethylfumarate SYSTEMATIC 23339572 A 1051 1059 chalcone FAMILY 23339572 A 1063 1108 (2E)-1-phenyl-3-pyrimidin-2-ylprop-2-en-1-one SYSTEMATIC 23339572 A 1114 1122 chalcone FAMILY 23339572 A 1126 1153 1,3-diphenylprop-2-yn-1-one SYSTEMATIC 23339572 A 1186 1210 α,β-unsaturated carbonyl FAMILY 23339572 A 12 21 Chalcones FAMILY 23339572 A 1234 1240 thiols FAMILY 23339572 A 1514 1517 BAP ABBREVIATION 23339572 A 1519 1535 4-hydroxynonenal SYSTEMATIC 23339572 A 1540 1548 chalcone FAMILY 23339572 A 1552 1601 4-[(1E)-3-oxo-3-phenylprop-1-en-1-yl]benzonitrile SYSTEMATIC 23339572 A 1604 1612 chalcone FAMILY 23339572 A 1616 1675 (2E)-1-phenyl-3-[4-(trifluoromethyl)-phenyl]prop-2-en-1-one SYSTEMATIC 23339572 A 1681 1689 chalcone FAMILY 23339572 A 465 474 chalcones FAMILY 23339572 A 478 483 thiol FAMILY 23339572 A 50 68 benzalacetophenone SYSTEMATIC 23339572 A 617 626 chalcones FAMILY 23339572 A 637 661 α,β-unsaturated carbonyl FAMILY 23339572 A 677 683 thiols FAMILY 23339572 A 70 73 BAP ABBREVIATION 23339572 A 840 845 thiol FAMILY 23339572 A 855 871 N-acetylcysteine SYSTEMATIC 23339572 A 892 928 5,5'-dithiobis-(2-nitrobenzoic acid) SYSTEMATIC 23339572 T 47 56 chalcones FAMILY 23339572 T 67 91 α,β-unsaturated carbonyl FAMILY 23339577 A 105 115 ferrocenyl TRIVIAL 23339577 A 122 128 acetyl SYSTEMATIC 23339577 A 1290 1300 ferrocenyl TRIVIAL 23339577 A 134 165 AcS-C6H4-C≡C-(fc)n-C≡C-C6H4-SAc FORMULA 23339577 A 214 224 ferrocenyl TRIVIAL 23339577 A 292 294 Au FORMULA 23339577 A 508 522 organometallic FAMILY 23339577 A 583 593 ferrocenyl TRIVIAL 23339577 A 772 782 ferrocenyl TRIVIAL 23339577 A 83 98 fc-C≡C-C6H4-SAc FORMULA 23339577 A 982 989 Au(111) FORMULA 23339577 T 26 40 organometallic FAMILY 23339604 A 1230 1245 dodecamanganese SYSTEMATIC 23339604 A 419 470 Mn(III)(8)Mn(IV)(4)O(12)(L(x,y,z-CB))(16)(H(2)O)(4) FAMILY 23339604 T 122 161 Mn(III)8Mn(IV)4O12(L(x,y,z-CB))16(H2O)4 FAMILY 23339604 T 87 96 manganese SYSTEMATIC 23339678 A 1009 1018 ketorolac TRIVIAL 23339678 A 1164 1173 ketorolac TRIVIAL 23339678 A 1306 1315 ketorolac TRIVIAL 23339678 A 250 259 ketorolac TRIVIAL 23339678 A 62 71 ketorolac TRIVIAL 23339678 A 791 800 ketorolac TRIVIAL 23339678 T 10 19 ketorolac TRIVIAL 23339974 A 516 527 gly-gly-lys FORMULA 23340331 A 106 115 hydroxide SYSTEMATIC 23340331 A 120 129 carbonate FAMILY 23340331 A 421 435 carbon dioxide SYSTEMATIC 23340331 A 488 490 Pb FORMULA 23340331 A 592 594 Pb FORMULA 23340331 A 599 605 Pb(2+) FORMULA 23340331 A 700 703 HCl FORMULA 23340332 A 1035 1040 Na(+) FORMULA 23340332 A 1041 1045 K(+) FORMULA 23340332 A 1069 1074 Na(+) FORMULA 23340332 A 1079 1084 Cl(-) FORMULA 23340332 A 1257 1263 Cu(2+) FORMULA 23340332 A 1313 1318 Cl(-) FORMULA 23340332 A 1376 1381 Na(+) FORMULA 23340332 A 1703 1709 copper SYSTEMATIC 23340332 A 489 495 copper SYSTEMATIC 23340332 A 880 886 Cu(2+) FORMULA 23340332 T 35 41 copper SYSTEMATIC 23340333 A 1055 1064 disulfide SYSTEMATIC 23340334 A 379 386 Toluene TRIVIAL 23340334 A 702 708 oxygen SYSTEMATIC 23340334 A 840 847 toluene TRIVIAL 23340334 A 915 922 toluene TRIVIAL 23340334 A 927 933 oxygen SYSTEMATIC 23340646 A 1254 1261 lithium SYSTEMATIC 23340646 A 1373 1382 Fe(3)O(4) FORMULA 23340646 A 1392 1399 lithium SYSTEMATIC 23340646 A 1467 1473 sodium SYSTEMATIC 23340646 A 191 198 lithium SYSTEMATIC 23340646 A 203 209 sodium SYSTEMATIC 23340646 A 295 304 Fe(3)O(4) FORMULA 23340646 A 66 73 lithium SYSTEMATIC 23340646 A 78 84 sodium SYSTEMATIC 23340646 A 819 826 lithium SYSTEMATIC 23340646 A 850 859 Fe(3)O(4) FORMULA 23340646 A 947 955 graphite TRIVIAL 23340646 A 982 997 Li(4)Ti(5)O(12) FORMULA 23340646 T 116 121 Fe3O4 FORMULA 23340646 T 51 58 lithium SYSTEMATIC 23340646 T 67 73 sodium SYSTEMATIC 23340858 A 229 237 GaZnSeAs FORMULA 23340858 T 24 32 GaZnSeAs FORMULA 23340977 A 123 125 Mn FORMULA 23340977 A 130 132 Fe FORMULA 23340977 A 196 198 Mn FORMULA 23340977 A 203 205 Fe FORMULA 23340977 A 329 336 ammonia SYSTEMATIC 23340977 A 338 341 NH3 FORMULA 23340981 A 1050 1058 nicotine TRIVIAL 23340981 A 1204 1212 nicotine TRIVIAL 23340981 A 1308 1316 nicotine TRIVIAL 23340981 A 1455 1463 nicotine TRIVIAL 23340981 A 1619 1627 nicotine TRIVIAL 23340981 A 181 189 nicotine TRIVIAL 23340981 A 435 443 nicotine TRIVIAL 23340981 A 893 901 nicotine TRIVIAL 23340981 T 33 41 nicotine TRIVIAL 23341175 A 11 21 pyrethroid FAMILY 23341175 A 124 137 organophorous FAMILY 23341175 A 139 148 carbamate FAMILY 23341175 A 1500 1511 pyrethroids FAMILY 23341175 A 154 168 organochlorine FAMILY 23341175 A 203 214 Pyrethroids FAMILY 23341175 A 355 366 Pyrethroids FAMILY 23341175 A 765 775 permethrin TRIVIAL 23341175 A 838 848 permethrin TRIVIAL 23341175 A 936 947 pyrethroids FAMILY 23341175 T 51 61 pyrethroid FAMILY 23341248 A 1075 1077 Ag FORMULA 23341248 A 1179 1181 Ag FORMULA 23341248 A 23 29 silver SYSTEMATIC 23341248 A 524 530 oxygen SYSTEMATIC 23341248 A 693 695 Ag FORMULA 23341248 A 984 986 Ag FORMULA 23341248 T 0 6 Silver SYSTEMATIC 23341258 A 0 10 Nonivamide TRIVIAL 23341258 A 1030 1040 nonivamide TRIVIAL 23341258 A 1093 1099 Ca(2+) FORMULA 23341258 A 1209 1219 nonivamide TRIVIAL 23341258 A 178 188 nonivamide TRIVIAL 23341258 A 292 302 nonivamide TRIVIAL 23341258 A 44 53 capsaicin TRIVIAL 23341258 A 473 483 nonivamide TRIVIAL 23341258 A 507 513 oxygen SYSTEMATIC 23341258 A 565 575 nonivamide TRIVIAL 23341258 A 657 667 superoxide TRIVIAL 23341258 A 690 701 glutathione TRIVIAL 23341258 A 703 706 GSH ABBREVIATION 23341258 T 50 60 nonivamide TRIVIAL 23343117 A 1040 1045 OH(-) FORMULA 23343117 A 1058 1060 Zn FORMULA 23343117 A 1090 1098 coumarin TRIVIAL 23343117 A 11 16 amide FAMILY 23343117 A 1146 1154 coumarin TRIVIAL 23343117 A 17 31 dipicolylamine FAMILY 23343117 A 2 10 coumarin TRIVIAL 23343117 A 257 282 amide and amine nitrogens MULTIPLE 23343117 A 304 312 coumarin TRIVIAL 23343117 A 337 343 Zn(2+) FORMULA 23343117 A 347 353 Cd(2+) FORMULA 23343117 A 581 587 Zn(2+) FORMULA 23343117 A 592 598 Cd(2+) FORMULA 23343117 A 624 632 pyridine SYSTEMATIC 23343117 A 633 634 N FORMULA 23343117 A 636 641 amine SYSTEMATIC 23343117 A 642 643 N FORMULA 23343117 A 649 654 amide FAMILY 23343117 A 655 656 O FORMULA 23343117 A 671 677 Zn(2+) FORMULA 23343117 A 712 721 hydroxide SYSTEMATIC 23343117 A 729 734 OH(-) FORMULA 23343117 A 766 768 Zn FORMULA 23343117 A 773 775 Cd FORMULA 23343117 A 912 914 Cd FORMULA 23343117 A 966 968 Cd FORMULA 23343117 T 103 109 Cd(II) FORMULA 23343117 T 51 59 coumarin TRIVIAL 23343117 T 60 65 amide FAMILY 23343117 T 66 80 dipicolylamine FAMILY 23343117 T 92 98 Zn(II) FORMULA 23343172 A 151 161 porphyrins FAMILY 23343172 A 814 823 porphyrin FAMILY 23343324 A 131 138 3 μ-ISF ABBREVIATION 23343324 A 256 263 3 μ-ISF ABBREVIATION 23343324 A 65 77 polyisoprene SYSTEMATIC 23343324 A 82 93 polystyrene SYSTEMATIC 23343324 A 98 129 polyferrocenylethylmethylsilane SYSTEMATIC 23343325 A 207 210 EuS FORMULA 23343325 A 252 255 EuS FORMULA 23343325 A 310 317 Eu(III) FORMULA 23343325 A 318 333 dithiocarbamate SYSTEMATIC 23343325 A 342 410 tetraphenylphosphonium tetrakis(diethyldithiocarbamate)europium(III) SYSTEMATIC 23343325 A 416 432 transition-metal FAMILY 23343325 A 458 461 EuS FORMULA 23343325 A 47 53 Mn(II) FORMULA 23343325 A 55 61 Co(II) FORMULA 23343325 A 6 9 EuS FORMULA 23343325 A 66 72 Fe(II) FORMULA 23343325 A 757 760 EuS FORMULA 23343325 T 53 56 EuS FORMULA 23343325 T 88 104 transition-metal FAMILY 23343474 A 0 32 Penta(tert-butylthio)corannulene SYSTEMATIC 23343474 A 273 279 sulfur SYSTEMATIC 23343474 A 37 80 penta(4-dimethylaminophenylthio)corannulene SYSTEMATIC 23343474 A 392 395 C-S FORMULA 23343474 A 522 531 thioether SYSTEMATIC 23343474 A 708 717 thiolates FAMILY 23343474 T 26 54 corannulene penta-thioethers FAMILY 23343595 A 703 713 olanzapine TRIVIAL 23344429 A 1078 1094 L-pipecolic acid TRIVIAL 23344429 A 1100 1108 L-lysine TRIVIAL 23344429 A 1134 1138 NADH ABBREVIATION 23344429 A 702 706 NADH ABBREVIATION 23344429 A 709 712 FAD ABBREVIATION 23344429 A 718 722 haem TRIVIAL 23344429 A 916 921 amine SYSTEMATIC 23344820 A 1051 1066 malondialdehyde TRIVIAL 23344820 A 1068 1071 MDA ABBREVIATION 23344820 A 1077 1089 nitric oxide SYSTEMATIC 23344820 A 1310 1313 MDA ABBREVIATION 23344820 A 1318 1320 NO FORMULA 23344820 A 138 163 adenosine-5'-triphosphate SYSTEMATIC 23344820 A 1492 1496 DMBA ABBREVIATION 23344820 A 1586 1588 NO FORMULA 23344820 A 1643 1647 2-DG ABBREVIATION 23344820 A 1652 1660 malonate TRIVIAL 23344820 A 189 219 7,12-dimethylbenz(a)anthracene SYSTEMATIC 23344820 A 221 225 DMBA ABBREVIATION 23344820 A 509 513 DMBA ABBREVIATION 23344820 A 52 65 2-deoxglucose SYSTEMATIC 23344820 A 527 531 DMBA ABBREVIATION 23344820 A 615 629 2-deoxyglucose SYSTEMATIC 23344820 A 631 635 2-DG ABBREVIATION 23344820 A 69 77 malonate TRIVIAL 23344820 A 695 710 sodium malonate SYSTEMATIC 23344820 A 790 805 sodium malonate SYSTEMATIC 23344820 A 870 874 DMBA ABBREVIATION 23344820 A 932 943 glutathione TRIVIAL 23344820 A 966 976 superoxide TRIVIAL 23344820 A 994 1005 glutathione TRIVIAL 23344820 T 41 55 2-deoxyglucose SYSTEMATIC 23344820 T 60 68 malonate TRIVIAL 23344820 T 72 102 7,12-dimethylbenz(a)anthracene SYSTEMATIC 23344824 A 1100 1108 saponins FAMILY 23344824 A 1113 1123 terpenoids FAMILY 23344824 A 1171 1178 tannins FAMILY 23344824 A 1180 1190 terpenoids FAMILY 23344825 A 102 104 Cr FORMULA 23344825 A 453 455 Pb FORMULA 23344825 A 47 49 Pb FORMULA 23344825 A 52 56 iron SYSTEMATIC 23344825 A 58 60 Fe FORMULA 23344825 A 63 67 zinc SYSTEMATIC 23344825 A 69 71 Zn FORMULA 23344825 A 74 81 cadmium SYSTEMATIC 23344825 A 83 85 Cd FORMULA 23344825 A 92 100 chromium SYSTEMATIC 23344975 A 0 6 Copper SYSTEMATIC 23344975 A 1105 1110 Cu(+) FORMULA 23344975 A 1182 1188 copper SYSTEMATIC 23344975 A 119 125 copper SYSTEMATIC 23344975 A 1226 1232 copper SYSTEMATIC 23344975 A 1291 1297 copper SYSTEMATIC 23344975 A 166 172 Copper SYSTEMATIC 23344975 A 242 248 copper SYSTEMATIC 23344975 A 575 581 copper SYSTEMATIC 23344975 A 659 665 copper SYSTEMATIC 23344975 A 734 740 copper SYSTEMATIC 23344975 A 80 86 copper SYSTEMATIC 23344975 A 901 906 Cu(+) FORMULA 23344975 T 60 66 copper SYSTEMATIC 23345132 A 1329 1336 steroid FAMILY 23345132 A 1431 1439 androgen FAMILY 23345132 A 1583 1591 androgen FAMILY 23345132 A 189 212 17α-hydroxyprogesterone SYSTEMATIC 23345132 A 254 262 androgen FAMILY 23345132 A 280 299 dihydrotestosterone SYSTEMATIC 23345132 A 301 324 17α-Hydroxyprogesterone SYSTEMATIC 23345132 A 347 366 dihydrotestosterone SYSTEMATIC 23345132 A 371 388 4-androstenedione SYSTEMATIC 23345132 A 429 452 17α-hydroxypregnenolone SYSTEMATIC 23345132 A 457 479 dehydroepiandrosterone TRIVIAL 23345132 A 600 622 dehydroepiandrosterone TRIVIAL 23345132 A 624 641 4-androstenedione SYSTEMATIC 23345132 A 647 659 testosterone TRIVIAL 23345132 A 771 779 androgen FAMILY 23345132 A 862 869 steroid FAMILY 23345132 T 0 8 Androgen FAMILY 23346898 A 113 138 [Ni(Me(6)tren)Cl](ClO(4)) FORMULA 23346898 A 147 168 [Ni(Me(6)tren)Br](Br) FORMULA 23346898 A 561 567 Ni(II) FORMULA 23346898 A 74 101 trigonal bipyramidal Ni(II) FAMILY 23346898 T 40 67 trigonal bipyramidal Ni(II) FAMILY 23347052 A 231 235 DOPA ABBREVIATION 23347052 A 242 247 amine SYSTEMATIC 23347052 A 326 330 iron SYSTEMATIC 23347052 A 410 414 DOPA ABBREVIATION 23347052 A 415 419 iron SYSTEMATIC 23347151 A 1312 1315 C-C FORMULA 23347151 A 390 395 CH3CN FORMULA 23347151 A 44 52 hydrogen SYSTEMATIC 23347151 A 509 512 C═C FORMULA 23347151 A 784 789 CH3CN FORMULA 23347151 A 828 833 CH3OH FORMULA 23347151 A 838 846 CF3CH2OH FORMULA 23347151 T 11 19 hydrogen SYSTEMATIC 23347151 T 84 94 para-amino SYSTEMATIC 23347422 A 1029 1036 DiynePE ABBREVIATION 23347422 A 1100 1119 polydimethylsiloxan SYSTEMATIC 23347422 A 1121 1125 PDMS ABBREVIATION 23347422 A 1427 1434 DiynePC ABBREVIATION 23347422 A 1435 1442 DiynePE ABBREVIATION 23347422 A 196 207 diacetylene SYSTEMATIC 23347422 A 234 291 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine SYSTEMATIC 23347422 A 293 300 DiynePC ABBREVIATION 23347422 A 306 368 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphoethanolamine SYSTEMATIC 23347422 A 370 377 DiynePE ABBREVIATION 23347422 A 380 387 DiynePC ABBREVIATION 23347422 A 435 447 ethanolamine SYSTEMATIC 23347422 A 461 468 DiynePE ABBREVIATION 23347422 A 559 566 DiynePC ABBREVIATION 23347422 A 571 578 DiynePE ABBREVIATION 23347547 A 0 9 Quercetin TRIVIAL 23347547 A 1138 1147 quercetin TRIVIAL 23347547 A 476 487 acetic acid SYSTEMATIC 23347547 A 54 63 flavonoid FAMILY 23347547 T 0 9 Quercetin TRIVIAL 23347683 A 102 116 norepinephrine TRIVIAL 23347683 A 12 49 3-(phenoxy-phenyl-methyl)-pyrrolidine SYSTEMATIC 23347683 A 126 135 serotonin TRIVIAL 23347683 A 137 156 5-hydroxytryptamine SYSTEMATIC 23347683 A 158 162 5-HT SYSTEMATIC 23347683 T 17 55 3-(phenoxy-phenyl-methyl)-pyrrolidines FAMILY 23347683 T 79 93 norepinephrine TRIVIAL 23347683 T 98 107 serotonin TRIVIAL 23347684 A 0 44 2-(4-Chloro-2-cyano-2-phenylbutyl)aziridines FAMILY 23347684 A 113 177 endo- and exo-2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes MULTIPLE 23347684 A 185 202 azaheterobicyclic FAMILY 23347684 A 226 234 LiAlH(4) FORMULA 23347684 A 310 337 1-azabicyclo[2.2.1]heptanes FAMILY 23347684 T 108 152 2-(4-chloro-2-cyano-2-phenylbutyl)aziridines FAMILY 23347684 T 13 63 2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes FAMILY 23347684 T 68 74 LiAlH₄ FORMULA 23347875 A 0 22 Hexabromocyclododecane SYSTEMATIC 23347875 A 1010 1015 HBCDD ABBREVIATION 23347875 A 1161 1166 HBCDD ABBREVIATION 23347875 A 1261 1265 cAMP ABBREVIATION 23347875 A 1291 1295 cAMP ABBREVIATION 23347875 A 1306 1317 cholesterol TRIVIAL 23347875 A 1373 1377 cAMP ABBREVIATION 23347875 A 1422 1427 HBCDD ABBREVIATION 23347875 A 237 242 HBCDD ABBREVIATION 23347875 A 24 29 HBCDD ABBREVIATION 23347875 A 316 321 HBCDD ABBREVIATION 23347875 A 366 375 forskolin TRIVIAL 23347875 A 386 390 cAMP ABBREVIATION 23347875 A 449 453 cAMP ABBREVIATION 23347875 A 528 532 cAMP ABBREVIATION 23347875 A 600 611 cholesterol TRIVIAL 23347875 A 644 661 3β-hydroxysteroid FAMILY 23347875 A 699 704 HBCDD ABBREVIATION 23347875 A 975 999 22(R)-hydroxycholesterol SYSTEMATIC 23347875 T 17 39 hexabromocyclododecane SYSTEMATIC 23347875 T 62 72 nucleotide FAMILY 23348152 A 1059 1066 selenol FAMILY 23348152 A 1082 1086 RSeH FORMULA 23348152 A 1132 1138 thiols FAMILY 23348152 A 1197 1202 NADPH ABBREVIATION 23348152 A 301 319 diaryl diselenides FAMILY 23348152 A 321 351 p-methoxyl-diphenyl diselenide SYSTEMATIC 23348152 A 352 376 (p-CH(3)O-C(6)H(4)Se)(2) FORMULA 23348152 A 386 414 p-chloro-diphenyl diselenide SYSTEMATIC 23348152 A 415 435 (p-Cl-C(6)H(4)Se)(2) SYSTEMATIC 23348152 A 445 451 Cu(2+) FORMULA 23348152 A 747 753 Cu(2+) FORMULA 23348152 A 801 819 diaryl diselenides FAMILY 23348152 T 14 32 diaryl diselenides FAMILY 23348499 A 132 139 glucose TRIVIAL 23348501 A 100 109 disulfide SYSTEMATIC 23348501 A 1017 1026 disulfide SYSTEMATIC 23348501 A 1041 1044 CPT ABBREVIATION 23348501 A 1049 1052 NPT ABBREVIATION 23348501 A 1131 1134 GSH ABBREVIATION 23348501 A 1207 1218 clopidogrel TRIVIAL 23348501 A 124 135 clopidogrel TRIVIAL 23348501 A 1404 1409 thiol FAMILY 23348501 A 1410 1419 disulfide SYSTEMATIC 23348501 A 1442 1445 GSH ABBREVIATION 23348501 A 1504 1513 disulfide SYSTEMATIC 23348501 A 1750 1761 clopidogrel TRIVIAL 23348501 A 211 227 2-oxoclopidogrel SYSTEMATIC 23348501 A 288 293 thiol FAMILY 23348501 A 324 329 thiol FAMILY 23348501 A 348 359 glutathione TRIVIAL 23348501 A 361 364 GSH ABBREVIATION 23348501 A 483 492 disulfide SYSTEMATIC 23348501 A 535 561 6-chloropyridazine-3-thiol SYSTEMATIC 23348501 A 563 566 CPT ABBREVIATION 23348501 A 569 594 2,5-dimethylfuran-3-thiol SYSTEMATIC 23348501 A 600 623 3-nitropyridine-2-thiol SYSTEMATIC 23348501 A 625 628 NPT ABBREVIATION 23348501 A 753 762 disulfide SYSTEMATIC 23348501 A 799 804 thiol FAMILY 23348501 A 857 866 disulfide SYSTEMATIC 23348501 A 905 911 thiols FAMILY 23348501 A 917 920 GSH ABBREVIATION 23348501 T 58 67 disulfide SYSTEMATIC 23348501 T 82 93 clopidogrel TRIVIAL 23348514 A 1044 1053 metformin TRIVIAL 23348514 A 1152 1161 metformin TRIVIAL 23348514 A 1232 1242 fatty acid FAMILY 23348514 A 1304 1313 metformin TRIVIAL 23348514 A 1425 1434 metformin TRIVIAL 23348514 A 393 400 glucose TRIVIAL 23348514 A 414 423 Metformin TRIVIAL 23348514 A 542 551 metformin TRIVIAL 23348514 A 663 672 metformin TRIVIAL 23348514 A 794 803 metformin TRIVIAL 23348514 A 977 984 alanine TRIVIAL 23348514 T 11 20 metformin TRIVIAL 23348754 A 1035 1043 oxytocin TRIVIAL 23348754 A 1072 1105 3,4-methylenedioxymethamphetamine SYSTEMATIC 23348754 A 1107 1111 MDMA ABBREVIATION 23348754 A 1113 1120 Ecstasy TRIVIAL 23348754 A 1210 1218 oxytocin TRIVIAL 23348754 A 1352 1356 MDMA ABBREVIATION 23348754 A 204 212 Oxytocin TRIVIAL 23348754 A 39 47 oxytocin TRIVIAL 23348754 A 509 517 oxytocin TRIVIAL 23348754 A 681 689 oxytocin TRIVIAL 23348754 A 797 805 oxytocin TRIVIAL 23348754 A 872 880 oxytocin TRIVIAL 23348754 A 910 917 cocaine TRIVIAL 23348754 A 922 937 methamphetamine TRIVIAL 23348754 T 19 27 oxytocin TRIVIAL 23349486 A 1034 1046 pioglitazone TRIVIAL 23349486 A 324 342 thiazolidinediones FAMILY 23349486 A 470 482 pioglitazone TRIVIAL 23349486 A 540 552 pioglitazone TRIVIAL 23349486 A 934 946 pioglitazone TRIVIAL 23349486 T 93 110 Thiazolidinedione SYSTEMATIC 23349498 A 204 211 glucose TRIVIAL 23349500 A 1051 1058 calcium SYSTEMATIC 23349500 A 142 149 glucose TRIVIAL 23349500 A 1426 1433 glucose TRIVIAL 23349500 A 225 229 cAMP ABBREVIATION 23349500 A 281 288 glucose TRIVIAL 23349500 A 341 345 cAMP ABBREVIATION 23349500 A 53 60 glucose TRIVIAL 23349500 A 593 600 glucose TRIVIAL 23349500 A 728 735 glucose TRIVIAL 23349500 T 71 78 Glucose TRIVIAL 23349501 A 1090 1097 17-HDHA SYSTEMATIC 23349501 A 1215 1222 glucose TRIVIAL 23349501 A 1375 1382 17-HDHA SYSTEMATIC 23349501 A 1387 1399 protectin D1 TRIVIAL 23349501 A 1466 1473 17-HDHA SYSTEMATIC 23349501 A 367 376 resolvins FAMILY 23349501 A 419 446 polyunsaturated fatty acids FAMILY 23349501 A 447 468 eicosapentaenoic acid SYSTEMATIC 23349501 A 470 473 EPA ABBREVIATION 23349501 A 479 499 docosahexaenoic acid SYSTEMATIC 23349501 A 501 504 DHA ABBREVIATION 23349501 A 603 606 EPA ABBREVIATION 23349501 A 607 610 DHA ABBREVIATION 23349501 A 773 776 DHA ABBREVIATION 23349501 A 785 815 17-hydroxydocosahexaenoic acid SYSTEMATIC 23349501 A 817 824 17-HDHA SYSTEMATIC 23349501 A 826 837 resolvin D1 TRIVIAL 23349501 A 853 865 protectin D1 TRIVIAL 23349501 A 907 910 EPA ABBREVIATION 23349501 A 911 914 DHA ABBREVIATION 23349501 T 74 81 17-HDHA SYSTEMATIC 23350730 A 227 234 calcium SYSTEMATIC 23350730 A 374 381 calcium SYSTEMATIC 23350730 A 506 513 calcium SYSTEMATIC 23350730 A 593 600 calcium SYSTEMATIC 23350730 A 605 614 vitamin D FAMILY 23350730 T 16 23 calcium SYSTEMATIC 23350797 A 438 450 nitric oxide SYSTEMATIC 23350797 A 65 96 7-chloro-4-quinolinyl hydrazone FAMILY 23350797 T 0 32 7-Chloro-4-quinolinyl Hydrazones FAMILY 23350945 A 1025 1029 DMMP ABBREVIATION 23350945 A 111 120 Al(2)O(3) FORMULA 23350945 A 263 267 DMMP ABBREVIATION 23350945 A 293 298 H(2)O FORMULA 23350945 A 318 322 DMMP ABBREVIATION 23350945 A 375 383 hydrogen SYSTEMATIC 23350945 A 39 65 dimethyl methylphosphonate SYSTEMATIC 23350945 A 391 396 H(2)O FORMULA 23350945 A 451 460 Al(2)O(3) FORMULA 23350945 A 469 478 Al(OH)(3) FORMULA 23350945 A 486 493 AlO(OH) FORMULA 23350945 A 499 502 P═O FORMULA 23350945 A 512 516 DMMP ABBREVIATION 23350945 A 546 551 H(2)O FORMULA 23350945 A 600 605 oxide SYSTEMATIC 23350945 A 67 71 DMMP ABBREVIATION 23350945 A 689 694 H(2)O FORMULA 23350945 A 734 739 Al-OH FORMULA 23350945 A 755 762 methoxy SYSTEMATIC 23350945 A 76 81 H(2)O FORMULA 23350945 A 763 764 O FORMULA 23350945 A 774 778 DMMP ABBREVIATION 23350945 A 801 805 DMMP ABBREVIATION 23350945 A 849 854 oxide SYSTEMATIC 23350945 T 38 43 Al2O3 FORMULA 23350945 T 70 96 dimethyl methylphosphonate SYSTEMATIC 23351082 A 332 358 10-hydroxy-2-decenoic acid SYSTEMATIC 23351082 A 523 534 fatty acids FAMILY 23351082 A 576 587 fatty acids FAMILY 23351082 A 608 614 esters FAMILY 23351082 A 621 632 fatty acids FAMILY 23351082 A 643 667 medium-chain fatty acids FAMILY 23351082 A 745 771 mono- or dicarboxylic acid MULTIPLE 23351082 A 846 857 fatty acids FAMILY 23351096 A 250 260 iron oxide SYSTEMATIC 23351096 A 752 820 poly(N-isopropylacrylamide-co-acrylamide)-block-poly(ε-caprolactone) SYSTEMATIC 23351096 A 972 983 doxorubicin TRIVIAL 23351139 A 114 120 AZT-TP ABBREVIATION 23351139 A 23 45 adenosine triphosphate SYSTEMATIC 23351139 A 433 436 ATP ABBREVIATION 23351139 A 437 443 AZT-TP ABBREVIATION 23351139 A 47 50 ATP ABBREVIATION 23351139 A 56 66 nucleotide FAMILY 23351139 A 674 684 nucleotide FAMILY 23351139 A 689 699 nucleotide FAMILY 23351139 A 796 799 ATP ABBREVIATION 23351139 A 804 810 AZT-TP ABBREVIATION 23351139 A 85 112 azidothymidine triphosphate SYSTEMATIC 23351139 A 863 866 ATP ABBREVIATION 23351139 A 874 880 AZT-TP ABBREVIATION 23351139 A 986 989 ATP ABBREVIATION 23351139 A 994 1000 AZT-TP ABBREVIATION 23351139 T 77 88 nucleotides FAMILY 23351139 T 93 103 nucleotide FAMILY 23351961 A 0 8 Curcumin TRIVIAL 23351961 A 1186 1189 SDS ABBREVIATION 23351961 A 1295 1303 curcumin TRIVIAL 23351961 A 1446 1454 curcumin TRIVIAL 23351961 A 157 165 curcumin TRIVIAL 23351961 A 1986 1994 curcumin TRIVIAL 23351961 A 2094 2102 curcumin TRIVIAL 23351961 A 289 350 3-(4,5-dimethyl-thiazol-2-yl)-2-5-diphenyltetrazolium-bromide SYSTEMATIC 23351961 A 352 355 MTT ABBREVIATION 23351961 A 375 383 curcumin TRIVIAL 23351961 A 528 536 curcumin TRIVIAL 23351961 A 734 742 curcumin TRIVIAL 23351961 A 862 870 curcumin TRIVIAL 23351961 T 22 30 curcumin TRIVIAL 23352141 A 501 510 γ-pyrones FAMILY 23352141 A 520 531 nocapyrones FAMILY 23352141 A 758 769 nocapyrones FAMILY 23352141 T 31 49 pyrone polyketides FAMILY 23352430 A 149 157 cytidine TRIVIAL 23352430 A 496 499 CpG ABBREVIATION 23352430 A 500 513 dinucleotides FAMILY 23352430 A 767 778 hydroxyurea SYSTEMATIC 23352650 A 1184 1192 hydrogen SYSTEMATIC 23352650 A 1346 1356 PNU-120596 IDENTIFIER 23352650 A 1573 1574 H FORMULA 23352650 A 254 260 GTS-21 IDENTIFIER 23352650 A 262 272 2,4diMeOBA SYSTEMATIC 23352650 A 27 40 acetylcholine SYSTEMATIC 23352650 A 324 346 benzylidene anabaseine FAMILY 23352650 A 558 564 GTS-21 IDENTIFIER 23352650 A 567 576 dihydroxy SYSTEMATIC 23352650 A 589 598 2,4diOHBA SYSTEMATIC 23352650 A 779 787 hydroxyl SYSTEMATIC 23352650 A 804 815 benzylidene SYSTEMATIC 23352650 A 893 899 serine TRIVIAL 23352650 T 158 181 benzylidene anabaseines FAMILY 23352910 A 202 217 poly-l-arginine SYSTEMATIC 23352910 A 592 655 1, 1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine iodide SYSTEMATIC 23352910 A 656 659 DiR ABBREVIATION 23352929 A 1115 1123 phenolic FAMILY 23352929 A 1182 1196 salicylic acid TRIVIAL 23352929 A 372 384 nitric oxide SYSTEMATIC 23352929 A 386 388 NO FORMULA 23352929 A 429 441 nitric oxide SYSTEMATIC 23352929 A 940 942 NO FORMULA 23353026 A 1136 1138 Mn FORMULA 23353026 A 124 130 oxygen SYSTEMATIC 23353026 A 1256 1259 GSH ABBREVIATION 23353026 A 1278 1282 H2O2 FORMULA 23353026 A 1319 1321 Mn FORMULA 23353026 A 16 25 manganese SYSTEMATIC 23353026 A 188 190 Mn FORMULA 23353026 A 27 29 Mn FORMULA 23353026 A 272 281 manganese SYSTEMATIC 23353026 A 372 374 Mn FORMULA 23353026 A 455 471 propidium iodide TRIVIAL 23353026 A 520 527 lactate FAMILY 23353026 A 600 602 Mn FORMULA 23353026 A 692 702 superoxide TRIVIAL 23353026 A 729 731 Mn FORMULA 23353026 A 822 824 Mn FORMULA 23353026 A 957 959 Mn FORMULA 23353026 T 32 41 manganese SYSTEMATIC 23353027 A 10 17 arsenic SYSTEMATIC 23353027 A 1007 1015 arsenite SYSTEMATIC 23353027 A 1020 1028 thio-DMA SYSTEMATIC 23353027 A 1058 1061 GSH ABBREVIATION 23353027 A 1066 1070 GSSG ABBREVIATION 23353027 A 1162 1166 H2O2 FORMULA 23353027 A 1347 1355 arsenite SYSTEMATIC 23353027 A 1360 1368 thio-DMA SYSTEMATIC 23353027 A 1417 1424 arsenic SYSTEMATIC 23353027 A 157 164 arsenic SYSTEMATIC 23353027 A 253 260 arsenic SYSTEMATIC 23353027 A 334 335 S FORMULA 23353027 A 347 354 arsenic SYSTEMATIC 23353027 A 452 460 arsenite SYSTEMATIC 23353027 A 462 487 thio-dimethylarsinic acid SYSTEMATIC 23353027 A 489 497 thio-DMA SYSTEMATIC 23353027 A 506 533 dimethylarsinic glutathione SYSTEMATIC 23353027 A 535 539 DMAG ABBREVIATION 23353027 A 789 795 oxygen SYSTEMATIC 23353027 A 800 808 nitrogen SYSTEMATIC 23353027 T 110 137 dimethylarsinic glutathione SYSTEMATIC 23353027 T 47 48 S FORMULA 23353027 T 60 67 arsenic SYSTEMATIC 23353027 T 80 105 thio-dimethylarsinic acid SYSTEMATIC 23353058 A 1021 1023 Cu FORMULA 23353058 A 1050 1052 Na FORMULA 23353058 A 1076 1078 Cu FORMULA 23353058 A 1204 1210 copper SYSTEMATIC 23353058 A 1377 1379 Cu FORMULA 23353058 A 1411 1413 Cu FORMULA 23353058 A 1455 1457 Cu FORMULA 23353058 A 1483 1485 Cu FORMULA 23353058 A 1500 1502 Na FORMULA 23353058 A 1503 1504 K FORMULA 23353058 A 1613 1615 Cu FORMULA 23353058 A 1642 1644 Cu FORMULA 23353058 A 1697 1699 Cu FORMULA 23353058 A 1756 1758 Cu FORMULA 23353058 A 1809 1811 Cu FORMULA 23353058 A 1847 1849 Cu FORMULA 23353058 A 1986 1988 Cu FORMULA 23353058 A 2132 2134 Na FORMULA 23353058 A 2135 2136 K FORMULA 23353058 A 2275 2277 Cu FORMULA 23353058 A 2492 2494 Cu FORMULA 23353058 A 301 303 Cu FORMULA 23353058 A 324 326 Cu FORMULA 23353058 A 34 40 copper SYSTEMATIC 23353058 A 379 381 Cu FORMULA 23353058 A 398 400 Cu FORMULA 23353058 A 557 559 Na FORMULA 23353058 A 619 621 Cu FORMULA 23353058 A 652 658 copper SYSTEMATIC 23353058 A 757 759 Na FORMULA 23353058 A 783 785 Cu FORMULA 23353058 A 845 847 Cu FORMULA 23353058 T 14 20 copper SYSTEMATIC 23353658 A 0 9 Coumarins FAMILY 23353658 A 1289 1300 imperatorin TRIVIAL 23353658 A 1302 1316 isoimperatorin TRIVIAL 23353658 A 1321 1329 cnidilin TRIVIAL 23353658 A 1371 1380 coumarins FAMILY 23353658 A 1479 1490 imperatorin TRIVIAL 23353658 A 1495 1509 isoimperatorin TRIVIAL 23353658 A 1599 1607 cnidilin TRIVIAL 23353658 A 1653 1662 coumarins FAMILY 23353658 A 327 336 coumarins FAMILY 23353658 A 348 359 imperatorin TRIVIAL 23353658 A 361 375 isoimperatorin TRIVIAL 23353658 A 380 388 cnidilin TRIVIAL 23353658 A 501 513 acetonitrile SYSTEMATIC 23353658 A 951 962 imperatorin TRIVIAL 23353658 A 964 978 isoimperatorin TRIVIAL 23353658 A 983 991 cnidilin TRIVIAL 23353658 T 101 115 isoimperatorin TRIVIAL 23353658 T 120 128 cnidilin TRIVIAL 23353658 T 88 99 imperatorin TRIVIAL 23353659 A 112 125 curculigine I TRIVIAL 23353659 A 142 160 phenolic glycoside FAMILY 23353659 A 162 174 orcinoside H TRIVIAL 23353659 A 206 225 phenolic glycosides FAMILY 23353659 A 36 49 curculigine E TRIVIAL 23353659 A 389 408 phenolic glycosides FAMILY 23353659 A 487 490 MTT ABBREVIATION 23353659 A 55 68 curculigine F TRIVIAL 23353659 A 74 87 curculigine G TRIVIAL 23353659 A 9 34 chlorophenolic glucosides FAMILY 23353659 A 93 106 curculigine H TRIVIAL 23353659 T 0 19 Phenolic glycosides FAMILY 23353698 A 1050 1059 quercetin TRIVIAL 23353698 A 1149 1156 ABT-737 IDENTIFIER 23353698 A 1161 1170 quercetin TRIVIAL 23353698 A 1268 1277 quercetin TRIVIAL 23353698 A 288 295 ABT-737 IDENTIFIER 23353698 A 345 352 ABT-737 IDENTIFIER 23353698 A 512 521 quercetin TRIVIAL 23353698 A 525 534 flavonoid FAMILY 23353698 A 795 802 ABT-737 IDENTIFIER 23353698 A 807 816 quercetin TRIVIAL 23353698 A 993 1002 quercetin TRIVIAL 23353698 T 0 7 ABT-737 IDENTIFIER 23353698 T 154 163 quercetin TRIVIAL 23353699 A 1050 1053 PP1 IDENTIFIER 23353699 A 1122 1125 PP1 IDENTIFIER 23353699 A 1127 1133 AG1478 IDENTIFIER 23353699 A 1135 1141 AG1296 IDENTIFIER 23353699 A 1146 1154 LY294002 IDENTIFIER 23353699 A 1453 1456 PP1 IDENTIFIER 23353699 A 1458 1464 AG1478 IDENTIFIER 23353699 A 1466 1472 AG1296 IDENTIFIER 23353699 A 1474 1482 LY294002 IDENTIFIER 23353699 A 1484 1492 SB202190 IDENTIFIER 23353699 A 1494 1502 SP600125 IDENTIFIER 23353699 A 1507 1512 U0126 IDENTIFIER 23353699 A 752 755 PP1 IDENTIFIER 23353699 A 764 770 AG1478 IDENTIFIER 23353699 A 780 786 AG1296 IDENTIFIER 23353699 A 795 803 LY294002 IDENTIFIER 23353699 A 811 815 SH-5 IDENTIFIER 23353699 A 826 831 U0126 IDENTIFIER 23353699 A 844 852 SB202190 IDENTIFIER 23353699 A 863 871 SP600125 IDENTIFIER 23353699 A 883 897 Tanshinone IIA TRIVIAL 23353733 A 143 178 1,4-di-substituted 2-aminoimidazole FAMILY 23353733 A 179 188 triazoles FAMILY 23353733 A 190 196 2-AITs FAMILY 23353733 A 373 379 2-AITs FAMILY 23353733 A 38 55 2-aminoimidazoles FAMILY 23353733 A 4 31 pyrrole-imidazole alkaloids FAMILY 23353733 T 125 134 β-lactams FAMILY 23353733 T 23 59 1,4-di-substituted 2-aminoimidazoles FAMILY 23353741 A 171 175 (1)H FORMULA 23353741 A 181 186 (13)C FORMULA 23353741 A 22 39 resveratrol amide SYSTEMATIC 23353741 A 449 465 prostaglandin E2 TRIVIAL 23353741 A 467 471 PGE2 ABBREVIATION 23353741 T 50 67 resveratrol amide SYSTEMATIC 23353743 A 18 48 1,2,3-triazole-dithiocarbamate SYSTEMATIC 23353743 A 513 527 5-fluorouracil SYSTEMATIC 23353743 T 30 60 1,2,3-triazole-dithiocarbamate SYSTEMATIC 23353815 A 1032 1034 Zn FORMULA 23353815 A 1091 1093 Cd FORMULA 23353815 A 218 225 cadmium SYSTEMATIC 23353815 A 227 229 Cd FORMULA 23353815 A 329 337 n-hexane SYSTEMATIC 23353815 A 339 342 Hex ABBREVIATION 23353815 A 378 380 Zn FORMULA 23353815 A 385 387 Fe FORMULA 23353815 A 45 49 zinc SYSTEMATIC 23353815 A 51 53 Zn FORMULA 23353815 A 585 588 Hex ABBREVIATION 23353815 A 597 600 Hex ABBREVIATION 23353815 A 752 754 Cd FORMULA 23353815 A 759 761 Zn FORMULA 23353815 A 81 85 iron SYSTEMATIC 23353815 A 830 832 Cd FORMULA 23353815 A 844 847 Hex ABBREVIATION 23353815 A 87 89 Fe FORMULA 23353815 A 903 906 Hex ABBREVIATION 23353815 A 938 940 Cd FORMULA 23353815 A 957 959 Zn FORMULA 23353815 A 986 988 Fe FORMULA 23353815 T 64 66 Cd FORMULA 23353816 A 10 17 arsenic SYSTEMATIC 23353816 A 1000 1008 DMA(III) FORMULA 23353816 A 1097 1103 oxygen SYSTEMATIC 23353816 A 112 120 MMA(III) ABBREVIATION 23353816 A 1157 1160 GSH ABBREVIATION 23353816 A 126 147 dimethylarsinous acid SYSTEMATIC 23353816 A 1286 1297 glutathione TRIVIAL 23353816 A 1434 1441 arsenic SYSTEMATIC 23353816 A 149 157 DMA(III) FORMULA 23353816 A 188 195 arsenic SYSTEMATIC 23353816 A 19 24 As(V) FORMULA 23353816 A 25 32 As(III) FORMULA 23353816 A 347 354 arsenic SYSTEMATIC 23353816 A 553 575 monomethylarsonic acid SYSTEMATIC 23353816 A 577 583 MMA(V) ABBREVIATION 23353816 A 585 605 dimethylarsinic acid SYSTEMATIC 23353816 A 607 613 DMA(V) FORMULA 23353816 A 615 623 MMA(III) ABBREVIATION 23353816 A 628 636 DMA(III) FORMULA 23353816 A 87 110 monomethylarsonous acid SYSTEMATIC 23353816 A 880 887 As(III) FORMULA 23353816 A 982 990 MMA(III) ABBREVIATION 23353816 T 69 76 arsenic SYSTEMATIC 23354070 A 1050 1059 palinurin TRIVIAL 23354070 A 470 483 sesquiterpene FAMILY 23354070 A 484 493 palinurin TRIVIAL 23354070 A 627 636 palinurin TRIVIAL 23354070 A 663 666 ATP ABBREVIATION 23354070 A 891 900 palinurin TRIVIAL 23354070 T 87 96 palinurin TRIVIAL 23354072 A 117 135 phenolic glycoside FAMILY 23354072 A 137 242 2-(2-benzoyl-β-D-glucopyranosyloxy)-7-(1α,2α,6α-trihydroxy-3-oxocyclohex-4-enoyl)-5-hydroxybenzyl alcohol SYSTEMATIC 23354072 A 261 276 poliothrysoside TRIVIAL 23354072 A 282 345 catechin-[5,6-e]-4β-(3,4-dihydroxyphenyl)dihydro-2(3H)-pyranone SYSTEMATIC 23354072 A 351 456 2-(6-benzoyl-β-D-glucopyranosyloxy)-7-(1α,2α,6α-trihydroxy-3-oxocyclohex-4-enoyl)-5-hydroxybenzyl alcohol SYSTEMATIC 23354072 A 462 497 chrysoeriol-7-O-β-D-glucopyranoside SYSTEMATIC 23354072 A 507 516 mururin A TRIVIAL 23354072 A 587 598 chloroquine TRIVIAL 23354072 A 621 632 chloroquine TRIVIAL 23354072 A 705 712 hematin TRIVIAL 23354072 A 726 735 β-hematin TRIVIAL 23354072 A 786 790 heme FAMILY 23354072 T 32 41 β-hematin TRIVIAL 23354391 A 0 8 Daidzein TRIVIAL 23354391 A 1068 1076 daidzein TRIVIAL 23354391 A 1122 1124 Ca FORMULA 23354391 A 1165 1173 daidzein TRIVIAL 23354391 A 1229 1237 daidzein TRIVIAL 23354391 A 1273 1280 calcium SYSTEMATIC 23354391 A 13 21 estrogen FAMILY 23354391 A 1341 1348 calcium SYSTEMATIC 23354391 A 187 195 estrogen FAMILY 23354391 A 360 368 daidzein TRIVIAL 23354391 A 382 389 calcium SYSTEMATIC 23354391 A 682 690 daidzein TRIVIAL 23354391 A 775 777 Ca FORMULA 23354391 A 839 847 daidzein TRIVIAL 23354391 A 925 927 Ca FORMULA 23354391 A 970 978 daidzein TRIVIAL 23354391 T 21 29 daidzein TRIVIAL 23354391 T 66 73 calcium SYSTEMATIC 23354727 A 511 519 steroids FAMILY 23354755 A 127 131 coal TRIVIAL 23354755 T 40 44 coal TRIVIAL 23355287 A 119 125 carbon SYSTEMATIC 23355287 A 145 149 TiO2 FORMULA 23355287 T 12 16 TiO2 FORMULA 23355287 T 31 37 carbon SYSTEMATIC 23355467 A 1117 1122 sugar FAMILY 23355467 A 1200 1212 carbohydrate FAMILY 23355467 A 170 175 sugar FAMILY 23355467 A 209 216 glucose TRIVIAL 23355467 A 369 374 sugar FAMILY 23355467 A 418 429 fatty acids FAMILY 23355467 A 443 450 glucose TRIVIAL 23355467 A 502 508 carbon SYSTEMATIC 23355467 A 552 562 fatty acid FAMILY 23355467 A 600 613 triglycerides FAMILY 23355467 A 778 783 sugar FAMILY 23355467 A 832 844 carbohydrate FAMILY 23355467 A 881 893 stearoyl-CoA TRIVIAL 23355467 A 937 942 sugar FAMILY 23355488 A 286 296 vancomycin TRIVIAL 23355488 A 319 332 actinomycin D TRIVIAL 23355488 A 337 347 romidepsin TRIVIAL 23355488 A 501 511 vancomycin TRIVIAL 23355488 A 513 526 actinomycin D TRIVIAL 23355488 A 531 541 romidepsin TRIVIAL 23355488 A 875 882 cystine TRIVIAL 23355489 A 1225 1241 poly(ADP-ribose) SYSTEMATIC 23355489 A 163 169 serine TRIVIAL 23355489 A 175 178 Ser FORMULA 23355489 A 297 300 Ser FORMULA 23355489 A 767 783 poly(ADP-ribose) SYSTEMATIC 23355489 A 948 951 Ser FORMULA 23355616 A 1115 1118 CpG ABBREVIATION 23355616 A 22 25 CpG ABBREVIATION 23355616 A 26 39 dinucleotides FAMILY 23355616 A 545 555 nucleotide FAMILY 23355616 A 828 831 CpG ABBREVIATION 23355616 A 832 845 dinucleotides FAMILY 23355616 A 885 889 CpGs ABBREVIATION 23356207 A 475 486 triterpenes FAMILY 23356207 A 737 748 triterpenes FAMILY 23356207 A 900 914 monoglycerides FAMILY 23356207 A 989 999 triterpene FAMILY 23356207 T 101 112 triterpenes FAMILY 23356740 A 1030 1040 cyclic AMP TRIVIAL 23356740 A 119 133 catecholamines FAMILY 23356740 A 135 148 noradrenaline TRIVIAL 23356740 A 1393 1401 tyramine TRIVIAL 23356740 A 1442 1450 Tyramine TRIVIAL 23356740 A 153 163 adrenaline TRIVIAL 23356740 A 22 34 phenolamines FAMILY 23356740 A 223 233 octopamine TRIVIAL 23356740 A 267 277 octopamine TRIVIAL 23356740 A 283 291 tyramine TRIVIAL 23356740 A 308 316 Tyramine TRIVIAL 23356740 A 345 355 Octopamine TRIVIAL 23356740 A 356 364 Tyramine TRIVIAL 23356740 A 36 44 tyramine TRIVIAL 23356740 A 400 408 tyramine TRIVIAL 23356740 A 414 424 octopamine TRIVIAL 23356740 A 451 459 Tyramine TRIVIAL 23356740 A 49 59 octopamine TRIVIAL 23356740 A 555 563 tyramine TRIVIAL 23356740 A 824 832 tyramine TRIVIAL 23356740 A 931 937 amines FAMILY 23356740 A 949 959 octopamine TRIVIAL 23356740 A 961 969 dopamine TRIVIAL 23356740 A 971 984 noradrenaline TRIVIAL 23356740 A 986 996 adrenaline TRIVIAL 23356740 T 49 57 tyramine TRIVIAL 23356791 A 0 12 Formaldehyde SYSTEMATIC 23356791 A 1000 1011 glutathione TRIVIAL 23356791 A 1084 1095 glutathione TRIVIAL 23356791 A 1217 1229 formaldehyde SYSTEMATIC 23356791 A 1267 1278 glutathione TRIVIAL 23356791 A 1327 1339 formaldehyde SYSTEMATIC 23356791 A 181 193 formaldehyde SYSTEMATIC 23356791 A 336 348 formaldehyde SYSTEMATIC 23356791 A 509 521 formaldehyde SYSTEMATIC 23356791 A 576 588 formaldehyde SYSTEMATIC 23356791 A 638 650 formaldehyde SYSTEMATIC 23356791 A 790 797 formate SYSTEMATIC 23356791 A 812 824 formaldehyde SYSTEMATIC 23356791 A 861 868 glucose TRIVIAL 23356791 A 909 916 lactate FAMILY 23356791 T 0 12 Formaldehyde SYSTEMATIC 23356791 T 28 40 formaldehyde SYSTEMATIC 23356791 T 64 71 lactate FAMILY 23356791 T 87 98 glutathione TRIVIAL 23356859 A 844 855 tetrazolium SYSTEMATIC 23356859 A 861 921 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide SYSTEMATIC 23356859 A 923 926 MTT ABBREVIATION 23356867 A 33 45 carbohydrate FAMILY 23356867 A 730 740 saccharide FAMILY 23356867 A 793 805 cellohexaose TRIVIAL 23356867 A 818 831 cellotetraose TRIVIAL 23356867 T 64 76 carbohydrate FAMILY 23356907 A 240 259 zinc phthalocyanine SYSTEMATIC 23356907 A 265 284 acetylenic bombesin SYSTEMATIC 23356907 A 288 296 arginine TRIVIAL 23356907 A 297 304 glycine TRIVIAL 23356907 A 305 318 aspartic acid TRIVIAL 23356907 A 33 52 zinc phthalocyanine SYSTEMATIC 23356907 A 807 821 phthalocyanine TRIVIAL 23356907 A 822 830 bombesin TRIVIAL 23356907 T 0 14 Phthalocyanine TRIVIAL 23356946 A 237 249 glucuronides FAMILY 23356946 A 25 33 sulfates FAMILY 23356946 A 254 262 sulfates FAMILY 23356946 A 293 330 epicatechin glucuronides and sulfates MULTIPLE 23356946 A 4 20 monoglucuronides FAMILY 23356946 A 50 72 3'-O-methylepicatechin SYSTEMATIC 23356946 A 615 626 epicatechin TRIVIAL 23356946 A 78 100 4'-O-methylepicatechin SYSTEMATIC 23356946 T 43 80 epicatechin glucuronides and sulfates MULTIPLE 23356964 A 108 133 benzyl alcohol glycosides FAMILY 23356964 A 203 303 7-O-β-d-glucopyranosyl-(1→2)-β-d-glucopyranosyl-(1→2)-[α-l-rhamnopyranosyl-(1→6)]-β-d-glucopyranosyl SYSTEMATIC 23356964 A 316 341 benzyl alcohol glycosides FAMILY 23356964 A 346 350 acyl FAMILY 23356964 A 367 375 glycosyl SYSTEMATIC 23356964 A 455 459 DPPH ABBREVIATION 23356964 A 505 531 phenylpropanoylquinic acid SYSTEMATIC 23356964 A 75 97 lavone tetraglycosides FAMILY 23356964 T 0 23 Flavone tetraglycosides FAMILY 23356964 T 28 53 benzyl alcohol glycosides FAMILY 23357308 A 435 474 5-acetyl-4-methyl-2-(3-pyridyl)thiazole SYSTEMATIC 23357308 A 523 533 ampicillin TRIVIAL 23357308 A 658 671 amphotricin B TRIVIAL 23357308 A 849 857 thiazole SYSTEMATIC 23357308 A 94 135 2-(3-pyridyl)-4,5-disubstituted thiazoles FAMILY 23357308 T 22 63 2-(3-pyridyl)-4,5-disubstituted thiazoles FAMILY 23357312 A 0 7 Paeonol TRIVIAL 23357312 A 1246 1253 paeonol TRIVIAL 23357312 A 1558 1565 Paeonol TRIVIAL 23357312 A 1635 1642 paeonol TRIVIAL 23357312 A 1765 1772 paeonol TRIVIAL 23357312 A 244 251 paeonol TRIVIAL 23357312 A 429 436 lactate FAMILY 23357312 A 529 542 Hoechst 33342 TRIVIAL 23357312 A 595 601 oxygen SYSTEMATIC 23357312 A 643 678 2',7'-dichlorofluorescein diacetate SYSTEMATIC 23357312 A 680 687 DCFH-DA ABBREVIATION 23357312 T 0 7 Paeonol TRIVIAL 23357362 A 196 209 acetylcholine SYSTEMATIC 23357362 A 213 219 Ba(2+) FORMULA 23357362 A 279 292 acetylcholine SYSTEMATIC 23357362 A 297 303 Ba(2+) FORMULA 23357362 A 98 107 Vicenin 2 TRIVIAL 23357362 T 42 51 Vicenin 2 TRIVIAL 23357565 A 0 9 Silymarin FAMILY 23357565 A 1049 1058 silymarin FAMILY 23357565 A 1113 1115 NO FORMULA 23357565 A 1123 1125 SH FORMULA 23357565 A 1148 1157 capsaicin TRIVIAL 23357565 A 137 146 silymarin FAMILY 23357565 A 192 201 silymarin FAMILY 23357565 A 248 255 ethanol SYSTEMATIC 23357565 A 281 290 Silymarin FAMILY 23357565 A 359 366 aspirin TRIVIAL 23357565 A 493 502 silymarin FAMILY 23357565 A 518 530 nitric oxide SYSTEMATIC 23357565 A 532 534 NO FORMULA 23357565 A 555 561 l-NAME ABBREVIATION 23357565 A 563 565 SH FORMULA 23357565 A 574 590 N-ethylmaleimide SYSTEMATIC 23357565 A 611 622 capsazepine TRIVIAL 23357565 A 626 633 ethanol SYSTEMATIC 23357565 A 703 710 ethanol SYSTEMATIC 23357565 A 761 771 sulfhydryl FAMILY 23357565 A 816 825 silymarin FAMILY 23357565 A 882 891 silymarin FAMILY 23357565 A 895 902 ethanol SYSTEMATIC 23357565 A 971 980 silymarin FAMILY 23357565 T 21 30 silymarin FAMILY 23357565 T 39 46 ethanol SYSTEMATIC 23357565 T 82 93 sulfhydryls FAMILY 23357565 T 95 107 nitric oxide SYSTEMATIC 23357626 A 0 12 Aplyronine A TRIVIAL 23357626 A 21 33 mycalolide B TRIVIAL 23357626 A 410 422 aplyronine A TRIVIAL 23357626 T 62 74 aplyronine A TRIVIAL 23357627 A 438 462 phosphonic glutamic acid SYSTEMATIC 23357627 A 494 526 Boc-Phe-Leu-Glu(P)(OC(6)H(4))(2) FORMULA 23357627 A 608 640 Boc-Phe-Leu-Glu(P)(OC(6)H(4))(2) FORMULA 23357627 T 0 10 Phosphonic SYSTEMATIC 23357627 T 24 37 glutamic acid TRIVIAL 23357628 A 12 52 dimethylaminomethyl-substituted curcumin FAMILY 23357628 A 210 213 MTT ABBREVIATION 23357628 A 288 296 curcumin TRIVIAL 23357628 A 457 461 DPPH ABBREVIATION 23357628 A 466 476 galvinoxyl TRIVIAL 23357628 A 608 616 curcumin TRIVIAL 23357628 T 187 195 curcumin TRIVIAL 23357628 T 24 64 dimethylaminomethyl-substituted curcumin FAMILY 23357629 A 18 26 pyrazole SYSTEMATIC 23357629 A 198 202 (1)H FORMULA 23357629 A 203 207 (1)H FORMULA 23357629 A 214 218 (1)H FORMULA 23357629 A 219 224 (13)C FORMULA 23357629 A 234 238 (1)H FORMULA 23357629 A 239 244 (13)C FORMULA 23357629 A 39 47 flavones FAMILY 23357629 A 400 411 acetic acid SYSTEMATIC 23357629 A 801 805 keto SYSTEMATIC 23357629 A 810 818 phenolic FAMILY 23357629 A 820 822 OH FORMULA 23357629 A 87 135 1-methyl-5-(2,4,6-trimethoxy-phenyl)-1H-pyrazole SYSTEMATIC 23357629 T 78 86 pyrazole SYSTEMATIC 23357629 T 99 107 flavones FAMILY 23357633 A 12 52 C-(3-aminomethyl-cyclohexyl)-methylamine SYSTEMATIC 23357633 A 248 255 t-butyl SYSTEMATIC 23357633 A 280 287 benzene SYSTEMATIC 23357633 A 354 364 ethambutol TRIVIAL 23357633 T 78 118 C-(3-aminomethyl-cyclohexyl)-methylamine SYSTEMATIC 23357976 A 164 171 glucose TRIVIAL 23357976 A 315 322 glucose TRIVIAL 23357976 A 357 364 glucose TRIVIAL 23357976 A 393 400 glucose TRIVIAL 23357976 A 611 618 glucose TRIVIAL 23357976 A 7 25 11β-hydroxysteroid FAMILY 23357976 A 77 85 cortisol TRIVIAL 23357976 A 98 107 cortisone TRIVIAL 23357976 A 980 987 glucose TRIVIAL 23357976 T 37 44 glucose TRIVIAL 23359435 A 18 31 triscarbazole SYSTEMATIC 23359435 A 60 67 oxetane SYSTEMATIC 23359435 A 71 87 benzocyclobutene SYSTEMATIC 23359520 A 303 316 triglycerides FAMILY 23359520 A 331 342 cholesterol TRIVIAL 23359520 A 382 389 glucose TRIVIAL 23359520 A 756 767 cholesterol TRIVIAL 23359520 A 815 822 glucose TRIVIAL 23359538 A 106 113 mercury SYSTEMATIC 23359538 A 115 121 copper SYSTEMATIC 23359538 A 127 134 cadmium SYSTEMATIC 23359538 A 350 363 aluminosilica TRIVIAL 23359538 A 554 560 Cu(2+) FORMULA 23359538 A 563 569 Cd(2+) FORMULA 23359538 A 576 582 Hg(2+) FORMULA 23359555 A 169 174 C(60) TRIVIAL 23359555 A 278 283 C(60) TRIVIAL 23359555 A 355 364 fullerene TRIVIAL 23359555 A 91 107 N-alkylcarbazole FAMILY 23359555 T 53 58 C(60) TRIVIAL 23359587 A 223 237 hydroxyapatite TRIVIAL 23359587 A 242 262 tricalcium phosphate SYSTEMATIC 23360142 A 203 205 CO FORMULA 23360142 A 25 27 CO FORMULA 23360142 A 354 356 CO FORMULA 23360142 A 562 564 CO FORMULA 23360142 A 586 588 CO FORMULA 23360142 A 620 622 CO FORMULA 23360142 A 690 705 carbon monoxide SYSTEMATIC 23360142 A 800 802 CO FORMULA 23360142 A 831 833 CO FORMULA 23360142 A 838 840 CO FORMULA 23360142 A 899 901 CO FORMULA 23360142 T 0 2 CO FORMULA 23360142 T 7 9 CO FORMULA 23360180 A 1020 1026 Oxygen SYSTEMATIC 23360180 A 1035 1039 PLGA ABBREVIATION 23360180 A 1040 1042 Ag FORMULA 23360180 A 1150 1154 PLGA ABBREVIATION 23360180 A 1175 1177 Ag FORMULA 23360180 A 119 121 Ag FORMULA 23360180 A 1201 1207 oxygen SYSTEMATIC 23360180 A 126 130 PLGA ABBREVIATION 23360180 A 235 239 PLGA ABBREVIATION 23360180 A 315 317 Ag FORMULA 23360180 A 355 359 PLGA ABBREVIATION 23360180 A 364 368 PLGA ABBREVIATION 23360180 A 369 371 Ag FORMULA 23360180 A 413 419 oxygen SYSTEMATIC 23360180 A 450 454 PLGA ABBREVIATION 23360180 A 68 74 oxygen SYSTEMATIC 23360180 A 785 789 PLGA ABBREVIATION 23360180 A 828 834 oxygen SYSTEMATIC 23360180 A 928 930 Ag FORMULA 23360180 A 97 103 silver SYSTEMATIC 23360180 T 20 22 Ag FORMULA 23360180 T 41 47 oxygen SYSTEMATIC 23360230 A 553 556 PEG ABBREVIATION 23360230 A 605 607 Au FORMULA 23360230 A 868 871 PEG ABBREVIATION 23360230 T 46 48 Au FORMULA 23360232 A 1162 1165 PEG ABBREVIATION 23360232 A 131 134 PEG ABBREVIATION 23360232 A 78 87 histidine TRIVIAL 23360232 A 88 94 lysine TRIVIAL 23360361 A 1255 1262 DMAPODA ABBREVIATION 23360361 A 1479 1486 DMAPODA ABBREVIATION 23360361 A 1678 1685 DMAPODA ABBREVIATION 23360361 A 168 178 carboxylic SYSTEMATIC 23360361 A 189 200 fatty acids FAMILY 23360361 A 215 220 amino FAMILY 23360361 A 231 273 N-[3-(Dimethylamino)propyl]-Octadecanamide SYSTEMATIC 23360361 A 275 282 DMAPODA ABBREVIATION 23360361 A 394 407 Decanoic acid SYSTEMATIC 23360361 A 414 427 myristic acid TRIVIAL 23360361 A 434 446 stearic acid TRIVIAL 23360361 A 456 468 behenic acid TRIVIAL 23360361 A 522 529 DMAPODA ABBREVIATION 23360361 A 699 706 DMAPODA ABBREVIATION 23360361 A 743 750 DMAPODA ABBREVIATION 23360361 A 833 840 DMAPODA ABBREVIATION 23360361 T 21 31 fatty acid FAMILY 23360361 T 36 78 N-[3-(dimethylamino)propyl]-octadecanamide SYSTEMATIC 23360361 T 90 100 fatty acid FAMILY 23360392 A 1021 1030 flavonols FAMILY 23360392 A 1036 1045 cisplatin TRIVIAL 23360392 A 104 113 cisplatin TRIVIAL 23360392 A 203 212 cisplatin TRIVIAL 23360392 A 217 226 flavonols FAMILY 23360392 A 23 32 cisplatin TRIVIAL 23360392 A 344 352 hydroxyl SYSTEMATIC 23360392 A 377 386 flavonols FAMILY 23360392 A 38 47 flavonols FAMILY 23360392 A 421 430 cisplatin TRIVIAL 23360392 A 445 451 quartz TRIVIAL 23360392 A 562 571 hydroxyls FAMILY 23360392 A 601 610 cisplatin TRIVIAL 23360392 A 675 683 hydroxyl SYSTEMATIC 23360392 A 708 717 flavonols FAMILY 23360392 A 770 779 cisplatin TRIVIAL 23360392 A 913 922 hydroxyls FAMILY 23360392 A 926 935 cisplatin TRIVIAL 23360392 T 49 58 Cisplatin TRIVIAL 23360392 T 63 71 Flavonol FAMILY 23360412 A 1034 1038 DCBN ABBREVIATION 23360412 A 1099 1103 DCBN ABBREVIATION 23360412 A 1161 1165 DCBN ABBREVIATION 23360412 A 118 122 DCBN ABBREVIATION 23360412 A 1245 1249 DCBN ABBREVIATION 23360412 A 14 38 2,6-dichlorobenzonitrile SYSTEMATIC 23360412 A 1454 1458 DCBN ABBREVIATION 23360412 A 1471 1475 DCBN ABBREVIATION 23360412 A 1556 1560 DCBN ABBREVIATION 23360412 A 197 201 DCBN ABBREVIATION 23360412 A 40 44 DCBN ABBREVIATION 23360412 A 405 409 DCBN ABBREVIATION 23360412 A 498 502 DCBN ABBREVIATION 23360412 A 540 551 glutathione TRIVIAL 23360412 A 565 569 DCBN ABBREVIATION 23360412 A 574 578 DCBN ABBREVIATION 23360412 A 616 620 DCBN ABBREVIATION 23360412 A 745 749 DCBN ABBREVIATION 23360412 A 893 910 8-methoxypsoralen SYSTEMATIC 23360412 A 940 944 DCBN ABBREVIATION 23360412 T 36 60 2,6-dichlorobenzonitrile SYSTEMATIC 23360619 A 106 109 UDP ABBREVIATION 23360619 A 327 342 glucuronic acid TRIVIAL 23360619 A 943 985 7-ethyl-10-hydroxycamptothecin glucuronide SYSTEMATIC 23361101 A 502 510 Caffeine TRIVIAL 23361101 A 546 554 caffeine TRIVIAL 23361383 A 1099 1115 N-acetylcysteine SYSTEMATIC 23361383 A 120 134 amphotericin B TRIVIAL 23361383 A 136 139 AmB ABBREVIATION 23361383 A 425 433 mannitol TRIVIAL 23361383 A 503 512 Potassium SYSTEMATIC 23361383 A 540 549 amiloride TRIVIAL 23361383 A 554 568 spironolactone TRIVIAL 23361383 A 661 670 potassium SYSTEMATIC 23361383 A 716 719 AmB ABBREVIATION 23361383 A 749 752 AmB ABBREVIATION 23361383 A 962 965 AmB ABBREVIATION 23361383 T 62 76 amphotericin B TRIVIAL 23361517 A 0 13 Y(2)Ti(2)O(7) FORMULA 23361517 A 144 147 YTO FORMULA 23361517 A 15 18 YTO FORMULA 23361517 A 152 157 EYYTO FORMULA 23361517 A 24 30 Er(3+) FORMULA 23361517 A 253 258 EYYTO FORMULA 23361517 A 31 37 Yb(3+) FORMULA 23361517 A 47 60 Y(2)Ti(2)O(7) FORMULA 23361517 A 477 483 Er(3+) FORMULA 23361517 A 62 67 EYYTO FORMULA 23361517 A 671 676 EYYTO FORMULA 23361517 T 43 47 Er3+ FORMULA 23361517 T 52 56 Yb3+ FORMULA 23361517 T 66 73 Y2Ti2O7 FORMULA 23361587 A 180 186 NAD(+) ABBREVIATION 23361587 A 385 391 NAD(+) ABBREVIATION 23361914 A 121 137 (S)-argininamide TRIVIAL 23361914 A 36 55 [2,3-(3)H]propionyl SYSTEMATIC 23361914 A 99 108 guanidine TRIVIAL 23361914 T 0 15 [(3)H]UR-PLN196 SYSTEMATIC 23362105 A 0 10 Nucleotide FAMILY 23362105 A 173 190 muramyl dipeptide TRIVIAL 23362105 A 192 195 MDP ABBREVIATION 23362105 A 399 417 GlcNAcβ(1→4)MurNAc ABBREVIATION 23362105 A 421 439 MurNAcβ(1→4)GlcNAc ABBREVIATION 23362105 A 468 480 disaccharide FAMILY 23362105 A 484 499 tetrasaccharide FAMILY 23362105 A 798 816 MurNAcβ(1→4)GlcNAc ABBREVIATION 23362105 A 895 913 GlcNAcβ(1→4)MurNAc ABBREVIATION 23362239 A 1025 1029 Ca²⁺ FORMULA 23362239 A 1105 1109 Ca²⁺ FORMULA 23362239 A 1196 1200 Ca²⁺ FORMULA 23362239 A 1330 1334 Ca²⁺ FORMULA 23362239 A 1384 1388 Ca²⁺ FORMULA 23362239 A 1509 1513 Ca²⁺ FORMULA 23362239 A 1557 1561 Ca²⁺ FORMULA 23362239 A 1591 1595 Ca²⁺ FORMULA 23362239 A 1713 1717 Ca²⁺ FORMULA 23362239 A 313 317 Ca²⁺ FORMULA 23362239 A 335 344 ryanodine TRIVIAL 23362239 A 418 422 Ca²⁺ FORMULA 23362239 A 525 529 Ca²⁺ FORMULA 23362239 A 579 583 Ca²⁺ FORMULA 23362239 A 606 610 Ca²⁺ FORMULA 23362239 A 806 810 Ca²⁺ FORMULA 23362239 A 916 920 Ca²⁺ FORMULA 23362239 T 0 4 Ca²⁺ FORMULA 23362239 T 34 38 Ca²⁺ FORMULA 23362239 T 88 92 Ca²⁺ FORMULA 23362923 A 306 326 cyclic pentapeptides FAMILY 23362923 A 566 577 amino acids FAMILY 23362923 T 130 141 Amino Acids FAMILY 23362942 A 17 42 pillar[n]arene (n = 5, 6) SYSTEMATIC 23362942 A 350 361 amino acids FAMILY 23362942 A 487 497 amino acid FAMILY 23362942 A 569 579 amino acid FAMILY 23362942 A 78 82 (1)H FORMULA 23362942 T 44 55 amino acids FAMILY 23362960 A 314 321 biotins FAMILY 23363072 A 0 8 Hydrogen SYSTEMATIC 23363072 A 105 113 hydrogen SYSTEMATIC 23363072 A 128 141 LiNMe(2)BH(3) FORMULA 23363072 A 146 158 KNMe(2)BH(3) FORMULA 23363072 A 201 204 H-B FORMULA 23363072 A 261 262 H FORMULA 23363072 A 265 266 H FORMULA 23363072 T 10 20 dihydrogen SYSTEMATIC 23363072 T 32 57 alkali metal amidoboranes FAMILY 23363335 A 1182 1191 cytosines FAMILY 23363335 A 1389 1392 CpG ABBREVIATION 23363335 A 1525 1535 pyrimidine SYSTEMATIC 23363335 A 1587 1595 cytosine TRIVIAL 23363335 A 167 170 CpG ABBREVIATION 23363335 A 1703 1711 cytosine TRIVIAL 23363335 A 1755 1764 cytosines FAMILY 23363335 A 1783 1792 cytosines FAMILY 23363335 A 1806 1814 cytosine TRIVIAL 23363335 A 1919 1927 hydrogen SYSTEMATIC 23363335 A 1950 1957 guanine TRIVIAL 23363335 A 21 30 cytosines FAMILY 23363335 A 304 312 cytosine TRIVIAL 23363335 A 34 50 CpG dinucleotide FAMILY 23363335 A 442 445 CpG ABBREVIATION 23363335 A 524 533 cytosines FAMILY 23363335 A 541 550 cytosines FAMILY 23363335 A 759 768 cytosines FAMILY 23363335 A 830 839 cytosines FAMILY 23363335 A 947 956 cytosines FAMILY 23363335 T 81 84 CpG ABBREVIATION 23363407 A 182 188 silica TRIVIAL 23363407 A 220 237 6-mercaptohexanol SYSTEMATIC 23363407 A 437 443 silica TRIVIAL 23363407 A 477 483 oxygen SYSTEMATIC 23363407 T 47 53 silica TRIVIAL 23363425 A 1006 1015 phosphate SYSTEMATIC 23363425 A 1093 1099 silica TRIVIAL 23363425 A 11 22 Pro-Hyp-Gly FORMULA 23363425 A 122 128 silica TRIVIAL 23363425 A 158 161 Hyp ABBREVIATION 23363425 A 164 185 (2S,4R)hydroxyproline SYSTEMATIC 23363425 A 332 338 silica TRIVIAL 23363425 A 353 365 silicic acid TRIVIAL 23363425 A 470 482 silicic acid TRIVIAL 23363425 A 94 95 C FORMULA 23363425 A 989 1002 (poly-)amines FAMILY 23363425 T 0 6 Silica TRIVIAL 23363574 A 0 19 Glucose 6-phosphate SYSTEMATIC 23363574 A 1202 1207 Tl(+) FORMULA 23363574 A 239 256 pentose phosphate FAMILY 23363574 A 35 65 d-glucose 6-phosphate SYSTEMATIC 23363574 A 377 399 2',5'-ADP-sepharose-4B SYSTEMATIC 23363574 A 483 505 sodium dodecyl sulfate SYSTEMATIC 23363574 A 506 520 polyacrylamide SYSTEMATIC 23363574 A 67 74 NADP(+) ABBREVIATION 23363574 A 738 752 silver nitrate SYSTEMATIC 23363574 A 754 759 Ag(+) FORMULA 23363574 A 762 779 thallium sulphate SYSTEMATIC 23363574 A 781 786 TI(+) FORMULA 23363574 A 789 808 cobalt (II) nitrate SYSTEMATIC 23363574 A 810 816 Co(2+) FORMULA 23363574 A 822 839 arsenic (V) oxide SYSTEMATIC 23363574 A 841 847 As(5+) FORMULA 23363574 A 942 947 Ag(+) FORMULA 23363574 A 949 955 Co(2+) FORMULA 23363574 A 960 966 As(5+) FORMULA 23363574 T 37 56 glucose 6-phosphate SYSTEMATIC 23363576 A 1120 1137 hydrogen peroxide SYSTEMATIC 23363576 A 1192 1196 EtOH FORMULA 23363576 A 1342 1346 EtOH FORMULA 23363576 A 1533 1537 EtOH FORMULA 23363576 A 156 163 ethanol SYSTEMATIC 23363576 A 165 169 EtOH FORMULA 23363576 A 265 269 EtOH FORMULA 23363576 A 274 278 EtOH FORMULA 23363576 A 443 447 EtOH FORMULA 23363576 A 529 533 EtOH FORMULA 23363576 A 619 628 aspartate TRIVIAL 23363576 A 650 657 alanine TRIVIAL 23363576 A 709 713 EtOH FORMULA 23363576 A 746 761 malondialdehyde TRIVIAL 23363576 A 871 881 superoxide TRIVIAL 23363576 A 906 917 glutathione TRIVIAL 23363576 A 999 1003 EtOH FORMULA 23363576 T 47 54 ethanol SYSTEMATIC 23363577 A 326 328 Se FORMULA 23363577 A 533 535 Se FORMULA 23363577 A 551 585 diethylenetriaminepentaacetic acid SYSTEMATIC 23363577 A 640 642 Se FORMULA 23363577 A 673 675 Se FORMULA 23363577 A 78 86 selenium SYSTEMATIC 23363577 A 88 90 Se FORMULA 23364612 A 1020 1022 1H FORMULA 23364612 A 1024 1027 11B FORMULA 23364612 A 1033 1036 13C FORMULA 23364612 A 1139 1151 thioglycerol SYSTEMATIC 23364612 A 223 228 boron SYSTEMATIC 23364612 A 264 284 1,4-dihydropyridines FAMILY 23364612 A 295 319 3,4-dihydropyrimidinones FAMILY 23364612 A 334 359 formylphenylboronic acids FAMILY 23364612 A 478 485 ethanol SYSTEMATIC 23364612 T 50 55 boron SYSTEMATIC 23364615 A 0 16 Titanium dioxide SYSTEMATIC 23364615 A 1253 1269 titanium dioxide SYSTEMATIC 23364615 A 480 496 titanium dioxide SYSTEMATIC 23364615 A 55 67 metal oxides FAMILY 23364615 T 78 82 TiO2 FORMULA 23364884 A 306 314 cysteine TRIVIAL 23364884 A 491 499 cysteine TRIVIAL 23364884 A 634 644 serotonine TRIVIAL 23364884 A 920 924 E-64 TRIVIAL 23368510 A 135 144 metformin TRIVIAL 23368510 A 493 500 glucose TRIVIAL 23368510 T 151 160 metformin TRIVIAL 23368777 A 1033 1042 aspartate TRIVIAL 23368777 A 1062 1065 Ser FORMULA 23368777 A 1227 1234 sucrose TRIVIAL 23368777 A 164 170 lysine TRIVIAL 23368777 A 511 514 Ser FORMULA 23368777 A 604 607 Tyr FORMULA 23368777 A 880 883 Ser FORMULA 23368777 A 902 911 aspartate TRIVIAL 23368777 A 932 939 alanine TRIVIAL 23368884 A 0 16 Hydroxamic acids FAMILY 23368884 A 180 187 BRD9757 IDENTIFIER 23369033 A 13 28 (-)-tylophorine TRIVIAL 23369033 A 372 396 levorotatory tylophorine TRIVIAL 23369033 T 50 81 phenanthroindolizidine alkaloid FAMILY 23369343 A 1019 1029 sulfhydryl FAMILY 23369343 A 1039 1047 carbonyl FAMILY 23369343 A 1049 1061 nitric oxide SYSTEMATIC 23369343 A 1075 1083 peroxide SYSTEMATIC 23369343 A 1122 1133 d-galactose TRIVIAL 23369343 A 1230 1240 α-santalol TRIVIAL 23369343 A 243 253 α-santalol TRIVIAL 23369343 A 314 321 alloxan TRIVIAL 23369343 A 422 433 d-galactose TRIVIAL 23369343 A 533 543 α-santalol TRIVIAL 23369343 A 648 655 glucose TRIVIAL 23369343 A 663 672 bilirubin TRIVIAL 23369343 A 700 709 peroxides FAMILY 23369343 A 750 757 alloxan TRIVIAL 23369343 A 826 836 α-santalol TRIVIAL 23369343 A 971 980 bilirubin TRIVIAL 23369343 A 982 992 superoxide TRIVIAL 23369343 T 71 81 α-santalol TRIVIAL 23369344 A 1121 1125 cGMP ABBREVIATION 23369344 A 1147 1159 prostacyclin TRIVIAL 23369344 A 592 604 nitric oxide SYSTEMATIC 23369344 A 624 630 l-NAME ABBREVIATION 23369344 A 655 664 guanylate TRIVIAL 23369344 A 888 900 indomethacin TRIVIAL 23369344 A 902 906 Indo ABBREVIATION 23369344 A 941 952 propranolol TRIVIAL 23369344 A 954 958 Prop ABBREVIATION 23369537 T 24 33 chalcones FAMILY 23369833 A 1345 1346 N FORMULA 23369833 A 1390 1420 carbamate and N-sulfocarbamoyl MULTIPLE 23369833 A 1634 1635 N FORMULA 23369833 A 1768 1777 carbamate FAMILY 23369833 A 700 716 N-sulfocarbamoyl SYSTEMATIC 23369833 A 754 763 carbamate FAMILY 23369933 A 0 7 Mercury SYSTEMATIC 23369933 A 1043 1060 mercuric chloride SYSTEMATIC 23369933 A 1149 1164 sodium selenite SYSTEMATIC 23369933 A 1172 1181 vitamin E FAMILY 23369933 A 1201 1218 mercuric chloride SYSTEMATIC 23369933 A 1246 1263 mercuric chloride SYSTEMATIC 23369933 A 1306 1321 sodium selenite SYSTEMATIC 23369933 A 1329 1338 vitamin E FAMILY 23369933 A 154 171 mercuric chloride SYSTEMATIC 23369933 A 275 290 sodium selenite SYSTEMATIC 23369933 A 298 307 vitamin E FAMILY 23369933 A 426 443 mercuric chloride SYSTEMATIC 23369933 A 463 478 sodium selenite SYSTEMATIC 23369933 A 494 503 vitamin E FAMILY 23369933 A 566 583 mercuric chloride SYSTEMATIC 23369933 A 768 775 mercury SYSTEMATIC 23369933 A 865 880 sodium selenite SYSTEMATIC 23369933 A 888 897 vitamin E FAMILY 23369933 A 901 908 mercury SYSTEMATIC 23369933 T 0 17 Mercuric chloride SYSTEMATIC 23369933 T 101 110 vitamin E FAMILY 23369933 T 81 96 sodium selenite SYSTEMATIC 23370006 A 1023 1030 Uranium SYSTEMATIC 23370006 A 1035 1044 manganese SYSTEMATIC 23370006 A 1137 1141 zinc SYSTEMATIC 23370006 A 26 33 uranium SYSTEMATIC 23370006 A 455 462 uranium SYSTEMATIC 23370006 T 65 72 uranium SYSTEMATIC 23370180 A 223 235 testosterone TRIVIAL 23370180 A 667 686 dihydrotestosterone SYSTEMATIC 23370180 A 688 691 DHT ABBREVIATION 23370180 A 696 714 diethylstilbestrol SYSTEMATIC 23370180 A 716 719 DES ABBREVIATION 23370306 A 1009 1021 crotofolanes FAMILY 23370306 A 106 117 crotofolane TRIVIAL 23370306 A 160 176 nor-diterpenoids FAMILY 23370306 A 256 267 crotofolane TRIVIAL 23370306 A 434 443 diterpene FAMILY 23370306 A 51 63 diterpenoids FAMILY 23370306 A 526 535 γ-lactone SYSTEMATIC 23370306 A 577 589 crotofolanes FAMILY 23370306 A 71 89 crotocascarins A-H MULTIPLE 23370306 A 714 734 2-methylbutyric acid SYSTEMATIC 23370306 A 923 937 crotocascarins FAMILY 23370306 T 10 22 Diterpenoids FAMILY 23370306 T 35 51 Nor-Diterpenoids FAMILY 23370795 A 1127 1140 buprenorphine TRIVIAL 23370795 A 478 491 buprenorphine TRIVIAL 23370795 A 624 637 buprenorphine TRIVIAL 23370795 A 718 731 buprenorphine TRIVIAL 23370795 A 781 794 buprenorphine TRIVIAL 23370795 T 9 22 buprenorphine TRIVIAL 23371032 A 301 315 organochlorine FAMILY 23371032 A 317 332 organophosphate FAMILY 23371032 A 334 343 carbamate FAMILY 23371032 A 348 358 pyrethroid FAMILY 23371032 A 374 390 chlorocyclodiene FAMILY 23371032 A 399 415 organophosphates FAMILY 23371032 A 500 510 endosulfan TRIVIAL 23371032 A 566 578 chlorpyrifos TRIVIAL 23371032 A 588 599 pyrethroids FAMILY 23371032 A 608 617 carbamate FAMILY 23371032 A 662 674 cypermethrin TRIVIAL 23371032 A 691 703 deltamethrin TRIVIAL 23371032 A 724 732 methomyl TRIVIAL 23371303 A 0 9 Avibactam TRIVIAL 23371303 A 1039 1050 ceftazidime TRIVIAL 23371303 A 1120 1129 avibactam TRIVIAL 23371303 A 1163 1174 ceftazidime TRIVIAL 23371303 A 1356 1365 avibactam TRIVIAL 23371303 A 1457 1468 ceftazidime TRIVIAL 23371303 A 1577 1586 avibactam TRIVIAL 23371303 A 1757 1768 ceftazidime TRIVIAL 23371303 A 1775 1786 ceftazidime TRIVIAL 23371303 A 1788 1797 avibactam TRIVIAL 23371303 A 1859 1869 creatinine TRIVIAL 23371303 A 1915 1926 ceftazidime TRIVIAL 23371303 A 1927 1936 avibactam TRIVIAL 23371303 A 20 26 NXL104 IDENTIFIER 23371303 A 2038 2049 ceftazidime TRIVIAL 23371303 A 2099 2110 ceftazidime TRIVIAL 23371303 A 2111 2120 avibactam TRIVIAL 23371303 A 2149 2159 carbapenem FAMILY 23371303 A 2280 2293 cephalosporin FAMILY 23371303 A 2359 2370 ceftazidime TRIVIAL 23371303 A 2371 2380 avibactam TRIVIAL 23371303 A 243 254 ceftazidime TRIVIAL 23371303 A 2475 2486 Ceftazidime TRIVIAL 23371303 A 2487 2496 avibactam TRIVIAL 23371303 A 255 264 avibactam TRIVIAL 23371303 A 2669 2678 avibactam TRIVIAL 23371303 A 2713 2724 ceftazidime TRIVIAL 23371303 A 2797 2808 ceftazidime TRIVIAL 23371303 A 28 36 AVE1330A IDENTIFIER 23371303 A 2809 2818 avibactam TRIVIAL 23371303 A 2920 2931 ceftazidime TRIVIAL 23371303 A 2932 2941 avibactam TRIVIAL 23371303 A 3175 3186 ceftazidime TRIVIAL 23371303 A 3187 3196 avibactam TRIVIAL 23371303 A 3230 3243 metronidazole TRIVIAL 23371303 A 3320 3331 ceftazidime TRIVIAL 23371303 A 3332 3341 avibactam TRIVIAL 23371303 A 457 465 β-lactam TRIVIAL 23371303 A 493 502 avibactam TRIVIAL 23371303 A 537 543 cephem TRIVIAL 23371303 A 57 65 β-lactam TRIVIAL 23371303 A 570 579 avibactam TRIVIAL 23371303 A 676 685 avibactam TRIVIAL 23371303 A 728 737 avibactam TRIVIAL 23371303 A 834 845 ceftazidime TRIVIAL 23371303 A 999 1008 avibactam TRIVIAL 23371303 T 0 11 Ceftazidime TRIVIAL 23371303 T 12 21 avibactam TRIVIAL 23371303 T 31 44 cephalosporin FAMILY 23371451 A 1021 1024 GSH ABBREVIATION 23371451 A 1113 1123 cysteamine TRIVIAL 23371451 A 117 127 cysteamine TRIVIAL 23371451 A 1263 1273 cysteamine TRIVIAL 23371451 A 1333 1343 cysteamine TRIVIAL 23371451 A 1394 1397 GSH ABBREVIATION 23371451 A 1448 1458 cysteamine TRIVIAL 23371451 A 1545 1548 GSH ABBREVIATION 23371451 A 1584 1594 Cysteamine TRIVIAL 23371451 A 162 172 cysteamine TRIVIAL 23371451 A 1744 1747 GSH ABBREVIATION 23371451 A 1839 1849 cysteamine TRIVIAL 23371451 A 330 340 cysteamine TRIVIAL 23371451 A 377 387 cysteamine TRIVIAL 23371451 A 461 471 cysteamine TRIVIAL 23371451 A 559 577 tetrazolium salt-1 FAMILY 23371451 A 691 708 bromodeoxyuridine TRIVIAL 23371451 A 710 714 BrdU ABBREVIATION 23371451 A 796 807 glutathione TRIVIAL 23371451 A 809 812 GSH ABBREVIATION 23371451 A 843 853 cysteamine TRIVIAL 23371451 A 895 905 cysteamine TRIVIAL 23371451 T 74 84 cysteamine TRIVIAL 23371488 A 1269 1277 nicotine TRIVIAL 23371488 A 1445 1453 Nicotine TRIVIAL 23371488 A 1701 1709 nicotine TRIVIAL 23371488 A 372 380 nicotine TRIVIAL 23371488 A 502 510 nicotine TRIVIAL 23371488 A 792 805 polycarbonate FAMILY 23371488 A 80 88 nicotine TRIVIAL 23371488 A 923 931 Nicotine TRIVIAL 23371488 T 56 64 nicotine TRIVIAL 23371489 A 1010 1017 cocaine TRIVIAL 23371489 A 186 195 cathinone TRIVIAL 23371489 A 205 215 mephedrone TRIVIAL 23371489 A 220 246 methylenedioxypyrovalerone SYSTEMATIC 23371489 A 248 252 MDPV ABBREVIATION 23371489 A 298 307 cathinone TRIVIAL 23371489 A 379 388 cathinone TRIVIAL 23371489 A 393 406 methcathinone TRIVIAL 23371489 A 457 465 dopamine TRIVIAL 23371489 A 486 496 mephedrone TRIVIAL 23371489 A 501 505 MDPV ABBREVIATION 23371489 A 579 589 mephedrone TRIVIAL 23371489 A 627 635 dopamine TRIVIAL 23371489 A 663 678 methamphetamine TRIVIAL 23371489 A 682 695 methcathinone TRIVIAL 23371489 A 697 701 MDPV ABBREVIATION 23371489 A 715 722 cocaine TRIVIAL 23371489 A 750 758 dopamine TRIVIAL 23371489 A 773 783 Mephedrone TRIVIAL 23371489 A 788 792 MDPV ABBREVIATION 23371489 A 990 1005 methamphetamine TRIVIAL 23371489 T 0 10 Mephedrone TRIVIAL 23371489 T 124 132 dopamine TRIVIAL 23371489 T 15 41 methylenedioxypyrovalerone SYSTEMATIC 23371489 T 43 47 MDPV ABBREVIATION 23371760 A 1035 1046 resin acids FAMILY 23371760 A 147 150 CH FORMULA 23371760 A 240 252 sulfonylurea FAMILY 23371760 A 322 334 vitamin D(3) TRIVIAL 23371760 A 422 433 diterpenoid FAMILY 23371760 A 499 510 resin acids FAMILY 23371760 A 523 535 abietic acid TRIVIAL 23371760 A 537 556 dehydroabietic acid SYSTEMATIC 23371760 A 562 577 isopimaric acid TRIVIAL 23371760 A 719 741 15-hydroxyabietic acid SYSTEMATIC 23371760 A 743 772 15-hydroxydehydroabietic acid SYSTEMATIC 23371760 A 778 804 15,16-epoxyisopimaric acid SYSTEMATIC 23371760 T 0 10 Resin acid FAMILY 23371760 T 110 122 diterpenoids FAMILY 23371763 A 190 196 carbon SYSTEMATIC 23371763 A 42 49 Eu(III) FORMULA 23371763 T 77 84 Eu(III) FORMULA 23371965 A 0 23 Phenethylisothiocyanate SYSTEMATIC 23371965 A 1064 1069 PEITC ABBREVIATION 23371965 A 1085 1088 PIC ABBREVIATION 23371965 A 1287 1293 sulfur SYSTEMATIC 23371965 A 1335 1340 PEITC ABBREVIATION 23371965 A 1424 1429 PEITC ABBREVIATION 23371965 A 1544 1550 sulfur SYSTEMATIC 23371965 A 1581 1590 parathion TRIVIAL 23371965 A 1664 1667 Cys FORMULA 23371965 A 1703 1706 PIC ABBREVIATION 23371965 A 25 30 PEITC ABBREVIATION 23371965 A 272 277 PEITC ABBREVIATION 23371965 A 427 432 PEITC ABBREVIATION 23371965 A 518 523 PEITC ABBREVIATION 23371965 A 525 530 PEITC ABBREVIATION 23371965 A 55 69 isothiocyanate FAMILY 23371965 A 650 661 glutathione TRIVIAL 23371965 A 663 666 GSH ABBREVIATION 23371965 A 735 740 PEITC ABBREVIATION 23371965 A 857 860 GSH ABBREVIATION 23371965 A 872 892 phenethyl isocyanate SYSTEMATIC 23371965 A 894 897 PIC ABBREVIATION 23371965 A 903 917 phenethylamine SYSTEMATIC 23371965 A 989 992 PIC ABBREVIATION 23371965 T 36 60 phenethyl isothiocyanate SYSTEMATIC 23373444 A 1006 1010 H(I) FORMULA 23373444 A 1082 1087 α-ZrP SYSTEMATIC 23373444 A 1230 1236 Zr(IV) FORMULA 23373444 A 1237 1242 α-ZrP SYSTEMATIC 23373444 A 1250 1256 Zr(IV) FORMULA 23373444 A 1257 1262 α-ZrP SYSTEMATIC 23373444 A 1377 1382 α-ZrP SYSTEMATIC 23373444 A 140 158 α-Zr(IV) phosphate SYSTEMATIC 23373444 A 1427 1432 α-ZrP SYSTEMATIC 23373444 A 1452 1458 Mg(II) FORMULA 23373444 A 1461 1466 Na(I) FORMULA 23373444 A 1469 1473 H(I) FORMULA 23373444 A 1476 1483 Cr(III) FORMULA 23373444 A 1486 1492 Ca(II) FORMULA 23373444 A 1495 1501 Zr(IV) FORMULA 23373444 A 160 165 α-ZrP SYSTEMATIC 23373444 A 200 207 glucose TRIVIAL 23373444 A 266 272 Zr(IV) FORMULA 23373444 A 274 281 Cr(III) FORMULA 23373444 A 283 290 Au(III) FORMULA 23373444 A 292 299 Al(III) FORMULA 23373444 A 301 307 Ca(II) FORMULA 23373444 A 309 315 Mg(II) FORMULA 23373444 A 317 323 Zn(II) FORMULA 23373444 A 325 331 Ni(II) FORMULA 23373444 A 333 338 Na(I) FORMULA 23373444 A 344 348 H(I) FORMULA 23373444 A 383 388 α-ZrP SYSTEMATIC 23373444 A 444 450 Zr(IV) FORMULA 23373444 A 459 465 Ca(II) FORMULA 23373444 A 501 507 Zr(IV) FORMULA 23373444 A 510 516 Ca(II) FORMULA 23373444 A 519 526 Cr(III) FORMULA 23373444 A 529 535 Mg(II) FORMULA 23373444 A 538 542 H(I) FORMULA 23373444 A 545 550 Na(I) FORMULA 23373444 A 596 603 Au(III) FORMULA 23373444 A 605 612 Al(III) FORMULA 23373444 A 614 620 Zn(II) FORMULA 23373444 A 622 628 Cu(II) FORMULA 23373444 A 634 640 Ni(II) FORMULA 23373444 A 679 685 Zr(IV) FORMULA 23373444 A 719 724 α-ZrP SYSTEMATIC 23373444 A 782 788 Zr(IV) FORMULA 23373444 A 791 795 H(I) FORMULA 23373444 A 798 804 Mg(II) FORMULA 23373444 A 807 812 Na(I) FORMULA 23373444 A 815 821 Ca(II) FORMULA 23373444 A 824 831 Cr(III) FORMULA 23373444 A 892 897 α-ZrP SYSTEMATIC 23373444 A 933 939 Zr(IV) FORMULA 23373444 A 942 949 Cr(III) FORMULA 23373444 A 952 958 Zn(II) FORMULA 23373444 A 961 967 Ni(II) FORMULA 23373444 A 970 976 Mg(II) FORMULA 23373444 A 979 985 Ca(II) FORMULA 23373444 A 988 995 Au(III) FORMULA 23373444 A 998 1003 Na(I) FORMULA 23373444 T 81 106 α-zirconium(IV) phosphate SYSTEMATIC 23373463 A 149 158 α-Co(OH)2 FORMULA 23373463 A 204 213 β-Co(OH)2 FORMULA 23373463 A 265 274 hydroxide SYSTEMATIC 23373463 A 311 317 cobalt SYSTEMATIC 23373463 A 527 536 α-Co(OH)2 FORMULA 23373463 A 848 857 α-Co(OH)2 FORMULA 23373463 T 77 101 α- to β-cobalt hydroxide MULTIPLE 23373530 A 148 175 poly(2-phenyl-1,4-xylylene) SYSTEMATIC 23373530 A 177 181 PPPX ABBREVIATION 23373530 A 249 253 PPPX ABBREVIATION 23373544 A 12 19 lignans FAMILY 23373544 A 156 172 Deoxyschisandrin TRIVIAL 23373544 A 182 197 schisantherin A TRIVIAL 23373544 A 327 334 lignans FAMILY 23373544 A 518 525 lignans FAMILY 23373544 A 526 534 Eudragit TRIVIAL 23373544 A 581 594 poloxamer 188 TRIVIAL 23373544 T 11 18 lignans FAMILY 23373590 A 1019 1029 iron oxide SYSTEMATIC 23373590 A 1095 1111 poly(AMPS-co-AA) SYSTEMATIC 23373590 A 208 212 NaCl FORMULA 23373590 A 221 226 CaCl2 FORMULA 23373590 A 245 249 NaCl FORMULA 23373590 A 258 263 CaCl2 FORMULA 23373590 A 336 342 Ca(2+) FORMULA 23373590 A 374 386 acrylic acid TRIVIAL 23373590 A 431 438 citrate FAMILY 23373590 A 554 613 poly(2-methyl-2-acrylamidopropanesulfonate-co-acrylic acid) SYSTEMATIC 23373590 A 615 631 poly(AMPS-co-AA) SYSTEMATIC 23373590 A 655 696 poly(styrenesulfonate-block-acrylic acid) SYSTEMATIC 23373590 A 718 756 poly(styrenesulfonate-alt-maleic acid) SYSTEMATIC 23373590 A 847 851 AMPS ABBREVIATION 23373590 A 91 101 iron oxide SYSTEMATIC 23373590 A 959 963 AMPS ABBREVIATION 23373590 T 17 27 iron oxide SYSTEMATIC 23373590 T 50 56 sodium SYSTEMATIC 23373590 T 61 68 calcium SYSTEMATIC 23373613 T 48 58 iron oxide SYSTEMATIC 23373648 A 360 368 tyrosine TRIVIAL 23373648 A 522 530 tyrosine TRIVIAL 23373648 A 847 865 steroidal hormones FAMILY 23373648 T 99 107 tyrosine TRIVIAL 23373724 A 0 29 1β-d-Arabinofuranosylcytosine SYSTEMATIC 23373724 A 108 113 Ara-C ABBREVIATION 23373724 A 1146 1149 PEG ABBREVIATION 23373724 A 1150 1155 Ara-C ABBREVIATION 23373724 A 1295 1300 Ara-C ABBREVIATION 23373724 A 1302 1307 Ara-U ABBREVIATION 23373724 A 1341 1346 Ara-C ABBREVIATION 23373724 A 1413 1418 Ara-C ABBREVIATION 23373724 A 1423 1426 PEG ABBREVIATION 23373724 A 1427 1432 Ara-C ABBREVIATION 23373724 A 1525 1528 PEG ABBREVIATION 23373724 A 1529 1534 Ara-C ABBREVIATION 23373724 A 1618 1623 Ara-C ABBREVIATION 23373724 A 174 182 cytidine TRIVIAL 23373724 A 257 262 Ara-U ABBREVIATION 23373724 A 264 291 1β-d-arabinofuranosyluracil SYSTEMATIC 23373724 A 31 41 Cytarabine TRIVIAL 23373724 A 410 418 hydroxyl SYSTEMATIC 23373724 A 43 48 Ara-C ABBREVIATION 23373724 A 430 435 PAMAM ABBREVIATION 23373724 A 450 452 OH FORMULA 23373724 A 463 466 PEG ABBREVIATION 23373724 A 503 508 Ara-C ABBREVIATION 23373724 A 669 677 hydroxyl SYSTEMATIC 23373724 A 687 692 Ara-C ABBREVIATION 23373724 A 707 710 PEG ABBREVIATION 23373724 A 813 817 (1)H FORMULA 23373724 A 890 895 Ara-C ABBREVIATION 23373724 A 947 952 Ara-C ABBREVIATION 23373724 T 26 31 Ara-C ABBREVIATION 23373724 T 57 62 PAMAM ABBREVIATION 23373724 T 84 87 PEG ABBREVIATION 23373772 A 111 116 CF(3) FORMULA 23373772 A 128 132 MeOH FORMULA 23373772 A 250 265 Ru(bpy)(3)Cl(2) FORMULA 23373772 A 66 73 alkenes FAMILY 23373772 T 51 58 alkenes FAMILY 23373965 A 157 167 1-en-3-one SYSTEMATIC 23373965 A 172 186 9(11),12-diene SYSTEMATIC 23373965 A 191 205 2,20-dinitrile SYSTEMATIC 23373965 A 29 48 glycyrrhetinic acid TRIVIAL 23373965 A 319 321 NO FORMULA 23373965 A 417 419 NO FORMULA 23373965 A 876 878 NO FORMULA 23373965 T 50 105 3-oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile SYSTEMATIC 23374865 A 15 24 bile acid FAMILY 23374865 A 165 182 cresol red sodium TRIVIAL 23374865 A 192 198 pyrene SYSTEMATIC 23374865 A 437 444 acetone SYSTEMATIC 23374865 A 484 493 bile acid FAMILY 23374865 A 59 64 Cu(I) FORMULA 23374865 A 75 87 azide-alkyne FAMILY 23374865 T 43 52 bile acid FAMILY 23374868 A 323 336 [(125)I]-CCL3 SYSTEMATIC 23374868 A 48 102 1-(4-phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanone SYSTEMATIC 23374868 T 0 55 1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanones FAMILY 23374869 A 1049 1050 C FORMULA 23374869 A 1064 1074 phthalides FAMILY 23374869 A 128 137 monoamine FAMILY 23374869 A 236 245 phthalide TRIVIAL 23374869 A 247 269 2-benzofuran-1(3H)-one SYSTEMATIC 23374869 A 282 291 Phthalide TRIVIAL 23374869 A 319 325 isatin TRIVIAL 23374869 A 330 341 phthalimide TRIVIAL 23374869 A 401 410 phthalide TRIVIAL 23374869 A 50 56 isatin TRIVIAL 23374869 A 61 72 phthalimide TRIVIAL 23374869 A 684 694 phthalides FAMILY 23374869 A 748 769 6-benzyloxyphthalides FAMILY 23374869 A 819 825 phenyl SYSTEMATIC 23374869 A 864 869 CF(3) FORMULA 23374869 A 872 873 I FORMULA 23374869 A 876 878 Br FORMULA 23374869 A 881 883 Cl FORMULA 23374869 A 886 887 F FORMULA 23374869 A 890 895 CH(3) FORMULA 23374869 A 898 899 H FORMULA 23374869 A 964 974 phthalides FAMILY 23374869 T 14 23 monoamine FAMILY 23374869 T 35 44 phthalide TRIVIAL 23374871 A 116 125 imidazole SYSTEMATIC 23374871 A 127 144 1-methylimidazole SYSTEMATIC 23374871 A 149 175 2-phenyl-1-methylimidazole SYSTEMATIC 23374871 A 34 45 imidazolium SYSTEMATIC 23374871 T 114 123 imidazole SYSTEMATIC 23374872 A 218 223 (11)C FORMULA 23374872 A 228 233 (18)F FORMULA 23374872 A 52 62 tariquidar TRIVIAL 23374872 T 21 31 tariquidar TRIVIAL 23375260 A 22 40 guanine nucleotide TRIVIAL 23375260 T 43 61 guanine nucleotide TRIVIAL 23375851 A 1091 1094 ACE ABBREVIATION 23375851 A 1099 1102 GEM ABBREVIATION 23375851 A 1274 1277 ACE ABBREVIATION 23375851 A 1398 1401 CBZ ABBREVIATION 23375851 A 1419 1438 11-ketotestosterone SYSTEMATIC 23375851 A 273 286 acetaminophen TRIVIAL 23375851 A 288 291 ACE ABBREVIATION 23375851 A 294 306 venlafaxaine TRIVIAL 23375851 A 308 311 VEN ABBREVIATION 23375851 A 326 339 carbamazepine TRIVIAL 23375851 A 341 344 CBZ ABBREVIATION 23375851 A 350 361 gemfibrozil TRIVIAL 23375851 A 363 366 GEM ABBREVIATION 23375851 A 506 509 CBZ ABBREVIATION 23375851 A 514 517 GEM ABBREVIATION 23376090 A 0 11 Chlordecone TRIVIAL 23376090 A 1070 1081 chlordecone TRIVIAL 23376090 A 1308 1319 chlordecone TRIVIAL 23376090 A 1441 1455 organochlorine FAMILY 23376090 A 28 42 organochlorine FAMILY 23376090 A 510 521 chlordecone TRIVIAL 23376090 A 622 633 chlordecone TRIVIAL 23376090 A 828 839 chlordecone TRIVIAL 23376090 T 15 29 organochlorine FAMILY 23376090 T 41 52 chlordecone TRIVIAL 23376110 A 116 148 1,3-thiazolane-4-carboxylic acid SYSTEMATIC 23376110 A 202 220 trans-androsterone SYSTEMATIC 23376110 A 225 250 trans-dehydroandrosterone SYSTEMATIC 23376110 A 279 397 spiro[5'.2″]acenaphthylene-1″-one-spiro[16.6']-(7'-aryl)-tetrahydro-1H-pyrrolo [1,2-c][1,3]thiazolo-trans-androsterone FAMILY 23376110 A 33 43 azomethine SYSTEMATIC 23376110 A 398 417 dehydroandrosterone SYSTEMATIC 23376110 A 531 548 16-spiro steroids FAMILY 23376110 A 87 111 acenaphthylene-1,2-dione SYSTEMATIC 23376110 T 19 36 16-spiro steroids FAMILY 23376110 T 38 113 Spiro-7'-(aryl)tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazolo-trans-androsterone FAMILY 23376119 A 0 16 Poly(ADP-ribose) SYSTEMATIC 23376119 A 1082 1085 TPT ABBREVIATION 23376119 A 1163 1167 PJ34 IDENTIFIER 23376119 A 1352 1355 TPT ABBREVIATION 23376119 A 1356 1360 PJ34 IDENTIFIER 23376119 A 1500 1503 TPT ABBREVIATION 23376119 A 1504 1508 PJ34 IDENTIFIER 23376119 A 444 456 camptothecin TRIVIAL 23376119 A 489 498 topotecan TRIVIAL 23376119 A 504 508 PJ34 IDENTIFIER 23376119 A 708 711 TPT ABBREVIATION 23376119 A 712 716 PJ34 IDENTIFIER 23376119 A 868 872 PJ34 IDENTIFIER 23376119 A 893 896 TPT ABBREVIATION 23376119 A 965 969 PJ34 IDENTIFIER 23376119 A 987 990 TPT ABBREVIATION 23376119 T 19 35 poly(ADP-ribose) SYSTEMATIC 23376162 A 356 370 [Rh2(OCOCF3)4] FORMULA 23376162 A 40 51 bisabolenes FAMILY 23376162 A 420 432 nitric oxide SYSTEMATIC 23376162 A 52 66 sesquiterpenes FAMILY 23376162 T 0 14 Sesquiterpenes FAMILY 23376162 T 85 97 nitric oxide SYSTEMATIC 23376242 A 1089 1092 MAN ABBREVIATION 23376242 A 230 263 P-aminophenyl-α-d-mannopyranoside SYSTEMATIC 23376242 A 265 268 MAN ABBREVIATION 23376242 A 393 396 MAN ABBREVIATION 23376242 A 398 401 MAN ABBREVIATION 23376242 A 540 543 MAN ABBREVIATION 23376242 A 717 720 MAN ABBREVIATION 23376242 A 844 847 MAN ABBREVIATION 23376242 T 24 57 P-aminophenyl-α-d-mannopyranoside SYSTEMATIC 23376245 A 0 8 Tyrosine TRIVIAL 23376245 A 1057 1061 NMDA ABBREVIATION 23376245 A 106 114 tyrosine TRIVIAL 23376245 A 1175 1178 Tyr FORMULA 23376245 A 1265 1269 NMDA ABBREVIATION 23376245 A 195 203 tyrosine TRIVIAL 23376245 A 270 278 tyrosine TRIVIAL 23376245 A 28 48 N-methyl-d-aspartate SYSTEMATIC 23376245 A 475 488 orthovanadate SYSTEMATIC 23376245 A 492 502 Bpv (phen) ABBREVIATION 23376245 A 50 54 NMDA ABBREVIATION 23376245 A 64 73 glutamate TRIVIAL 23376245 A 747 751 NMDA ABBREVIATION 23376245 A 778 791 orthovanadate SYSTEMATIC 23376245 A 796 806 Bpv (phen) ABBREVIATION 23376245 A 858 862 NMDA ABBREVIATION 23376245 T 22 30 tyrosine TRIVIAL 23376249 A 112 118 acetyl SYSTEMATIC 23376249 A 30 47 1,3,4-thiadiazole SYSTEMATIC 23376249 T 39 56 1,3,4-thiadiazole SYSTEMATIC 23376353 A 195 206 doxorubicin TRIVIAL 23376353 A 231 240 verapamil TRIVIAL 23376353 A 388 392 PLGA ABBREVIATION 23376353 A 482 510 cyclo(Arg-Gly-Asp-D-Phe-Lys) SYSTEMATIC 23376353 A 544 552 carboxyl SYSTEMATIC 23376353 A 567 571 PLGA ABBREVIATION 23376353 A 608 611 DOX ABBREVIATION 23376353 A 612 615 VER ABBREVIATION 23376353 A 620 624 PLGA ABBREVIATION 23376353 A 762 765 DOX ABBREVIATION 23376353 A 770 773 VER ABBREVIATION 23376353 A 819 822 DOX ABBREVIATION 23376353 A 823 826 VER ABBREVIATION 23376353 A 831 835 PLGA ABBREVIATION 23376354 A 208 214 Ca(2+) FORMULA 23376354 A 219 223 K(+) FORMULA 23376354 A 469 475 Ca(2+) FORMULA 23376354 A 480 484 K(+) FORMULA 23376354 A 606 612 Ca(2+) FORMULA 23376354 A 650 654 K(+) FORMULA 23376354 A 696 702 Ca(2+) FORMULA 23376354 A 713 717 K(+) FORMULA 23376412 A 334 350 indole alkaloids FAMILY 23376412 A 448 464 indole alkaloids FAMILY 23376412 T 12 28 indole alkaloids FAMILY 23376437 A 1143 1146 CPZ ABBREVIATION 23376437 A 1489 1492 CPZ ABBREVIATION 23376437 A 280 294 chlorpromazine TRIVIAL 23376437 A 296 299 CPZ ABBREVIATION 23376437 A 452 455 CPZ ABBREVIATION 23376437 A 476 479 CPZ ABBREVIATION 23376437 A 692 695 CPZ ABBREVIATION 23376437 A 719 722 CPZ ABBREVIATION 23376437 A 838 841 CPZ ABBREVIATION 23376437 T 24 38 chlorpromazine TRIVIAL 23376439 A 1096 1103 alkanes FAMILY 23376439 A 1108 1119 hydrocarbon FAMILY 23376439 A 1227 1233 hexane SYSTEMATIC 23376439 A 1241 1247 decane SYSTEMATIC 23376439 A 1256 1266 hexadecane SYSTEMATIC 23376439 A 146 158 hydrocarbons FAMILY 23376439 A 167 180 methyl esters FAMILY 23376439 A 232 239 alkanes FAMILY 23376439 T 25 37 hydrocarbons FAMILY 23376477 A 149 161 xenoestrogen FAMILY 23376477 A 168 179 nonylphenol SYSTEMATIC 23376477 A 336 340 K(+) FORMULA 23376477 A 377 383 Ca(2+) FORMULA 23376477 A 58 62 K(+) FORMULA 23376477 A 83 89 Ca(2+) FORMULA 23376477 T 0 11 Nonylphenol SYSTEMATIC 23376477 T 30 38 estrogen FAMILY 23376477 T 62 64 K⁺ FORMULA 23376477 T 85 89 Ca²⁺ FORMULA 23376608 A 0 8 Apigenin TRIVIAL 23376608 A 166 174 Apigenin TRIVIAL 23376608 A 317 325 apigenin TRIVIAL 23376608 A 359 367 apigenin TRIVIAL 23376608 A 473 481 apigenin TRIVIAL 23376608 A 547 555 apigenin TRIVIAL 23376608 A 670 678 apigenin TRIVIAL 23376608 A 70 78 apigenin TRIVIAL 23376608 A 872 880 apigenin TRIVIAL 23376608 T 0 8 Apigenin TRIVIAL 23376696 A 1007 1015 fluoride SYSTEMATIC 23376696 A 1118 1126 chloride SYSTEMATIC 23376696 A 1276 1284 fluoride SYSTEMATIC 23376696 A 165 173 fluoride SYSTEMATIC 23376696 A 264 272 fluoride SYSTEMATIC 23376696 A 314 322 fluoride SYSTEMATIC 23376696 A 392 400 fluoride SYSTEMATIC 23376696 A 576 584 fluoride SYSTEMATIC 23376696 A 65 73 fluoride SYSTEMATIC 23376696 A 708 713 Na(+) FORMULA 23376696 A 714 718 K(+) FORMULA 23376696 A 730 736 Ca(2+) FORMULA 23376696 A 820 828 fluoride SYSTEMATIC 23376696 A 867 877 superoxide TRIVIAL 23376696 A 941 956 malondialdehyde TRIVIAL 23376696 A 958 961 MDA ABBREVIATION 23376696 T 24 32 fluoride SYSTEMATIC 23376697 A 1005 1019 titanium oxide SYSTEMATIC 23376697 A 1024 1030 cobalt SYSTEMATIC 23376712 A 0 19 γ-Aminobutyric acid SYSTEMATIC 23376712 A 1116 1124 baclofen TRIVIAL 23376712 A 1166 1174 baclofen TRIVIAL 23376712 A 1289 1295 BHF177 IDENTIFIER 23376712 A 1345 1351 BHF177 IDENTIFIER 23376712 A 1523 1531 baclofen TRIVIAL 23376712 A 1536 1542 BHF177 IDENTIFIER 23376712 A 1709 1715 BHF177 IDENTIFIER 23376712 A 479 573 N-([1R,2R,4S]-bicyclo[2.2.1]hept-2-yl)-2-methyl-5-(4-[trifluoromethyl]phenyl)-4-pyrimidinamine SYSTEMATIC 23376712 A 575 581 BHF177 IDENTIFIER 23376712 A 697 703 BHF177 IDENTIFIER 23376712 A 735 743 baclofen TRIVIAL 23376712 A 767 783 chlordiazepoxide TRIVIAL 23376712 A 785 793 baclofen TRIVIAL 23376712 A 843 849 BHF177 IDENTIFIER 23376712 A 987 995 Baclofen TRIVIAL 23376712 T 105 113 baclofen TRIVIAL 23376712 T 67 73 BHF177 IDENTIFIER 23376780 A 1297 1306 β-asarone TRIVIAL 23376780 A 296 303 eugenol TRIVIAL 23376780 A 305 313 rotenone TRIVIAL 23376780 A 315 324 β-asarone TRIVIAL 23376780 A 329 339 pyrethrins FAMILY 23376780 A 473 482 β-asarone TRIVIAL 23376780 A 884 892 rotenone TRIVIAL 23376817 A 1004 1008 BrdU ABBREVIATION 23376817 A 1036 1040 BrdU ABBREVIATION 23376817 A 1157 1165 DMA(III) FORMULA 23376817 A 1435 1443 DMA(III) FORMULA 23376817 A 1551 1558 arsenic SYSTEMATIC 23376817 A 1596 1602 DMA(V) FORMULA 23376817 A 162 168 DMA(V) FORMULA 23376817 A 1682 1690 DMA(III) FORMULA 23376817 A 1724 1730 DMA(V) FORMULA 23376817 A 290 298 DMA(III) FORMULA 23376817 A 30 37 arsenic SYSTEMATIC 23376817 A 348 354 DMA(V) FORMULA 23376817 A 472 480 DMA(III) FORMULA 23376817 A 565 585 methylate arsenicals FAMILY 23376817 A 665 673 DMA(III) FORMULA 23376817 A 826 843 bromodeoxyuridine TRIVIAL 23376817 A 845 849 BrdU ABBREVIATION 23376817 A 967 975 DMA(III) FORMULA 23376817 T 103 110 arsenic SYSTEMATIC 23376817 T 33 54 dimethylarsinous acid SYSTEMATIC 23376817 T 56 64 DMA(III) FORMULA 23376997 A 391 406 arylsulfonamido FAMILY 23376997 A 413 425 hydroxamates FAMILY 23376997 T 0 15 Arylsulfonamide FAMILY 23377100 A 1246 1248 Cd FORMULA 23377100 A 1283 1292 ascorbate TRIVIAL 23377100 A 1343 1349 oxygen SYSTEMATIC 23377100 A 1445 1454 ascorbate TRIVIAL 23377100 A 321 328 cadmium SYSTEMATIC 23377100 A 335 341 Cd(2+) FORMULA 23377100 A 376 399 polytetrafluoroethylene TRIVIAL 23377100 A 401 405 PTFE ABBREVIATION 23377100 A 603 607 PTFE ABBREVIATION 23377100 A 695 701 Cd(2+) FORMULA 23377100 A 894 896 Cd FORMULA 23377100 A 957 963 Cd(2+) FORMULA 23377100 T 27 36 ascorbate TRIVIAL 23377115 A 106 125 calcium diglutamate SYSTEMATIC 23377115 A 127 149 monoammonium glutamate SYSTEMATIC 23377115 A 155 176 magnesium diglutamate SYSTEMATIC 23377115 A 59 79 monosodium glutamate SYSTEMATIC 23377115 A 81 104 monopotassium glutamate SYSTEMATIC 23377115 T 59 69 glutamates FAMILY 23377609 A 1038 1042 EDTA ABBREVIATION 23377609 A 1046 1053 cadmium SYSTEMATIC 23377609 A 133 140 cadmium SYSTEMATIC 23377609 A 1532 1539 cadmium SYSTEMATIC 23377609 A 17 24 cadmium SYSTEMATIC 23377609 A 228 235 cadmium SYSTEMATIC 23377609 A 395 462 1-(4-isothiocyanobenzyl) ethylenediamine N,N,N',N'-tetraacetic acid SYSTEMATIC 23377609 A 464 469 ITCBE ABBREVIATION 23377609 A 494 499 ITCBE ABBREVIATION 23377609 A 566 626 1-(4-aminobenzyl) ethylenediamine N,N,N',N'-tetraacetic acid SYSTEMATIC 23377609 A 628 644 aminobenzyl-EDTA SYSTEMATIC 23377609 A 653 660 cadmium SYSTEMATIC 23377609 A 708 724 aminobenzyl-EDTA SYSTEMATIC 23377609 A 847 854 cadmium SYSTEMATIC 23377609 T 60 67 cadmium SYSTEMATIC 23377617 A 1122 1124 Zn FORMULA 23377617 A 1263 1266 GSH ABBREVIATION 23377617 A 1291 1293 Zn FORMULA 23377617 A 13 17 zinc SYSTEMATIC 23377617 A 1367 1370 GSH ABBREVIATION 23377617 A 1429 1431 Zn FORMULA 23377617 A 1457 1460 GSH ABBREVIATION 23377617 A 1597 1600 GSH ABBREVIATION 23377617 A 1658 1660 Zn FORMULA 23377617 A 19 21 Zn FORMULA 23377617 A 219 221 Zn FORMULA 23377617 A 246 257 glutathione TRIVIAL 23377617 A 259 262 GSH ABBREVIATION 23377617 A 411 414 GSH ABBREVIATION 23377617 A 436 444 dopamine TRIVIAL 23377617 A 451 454 GSH ABBREVIATION 23377617 A 542 544 Zn FORMULA 23377617 A 579 581 Zn FORMULA 23377617 A 606 624 γ-Glutamylcysteine SYSTEMATIC 23377617 A 667 670 GSH ABBREVIATION 23377617 A 705 707 Zn FORMULA 23377617 A 828 830 Zn FORMULA 23377617 T 10 14 zinc SYSTEMATIC 23377617 T 36 47 glutathione TRIVIAL 23378200 A 114 122 Baicalin TRIVIAL 23378200 A 1542 1550 Baicalin TRIVIAL 23378200 A 1626 1634 baicalin TRIVIAL 23378200 A 211 219 baicalin TRIVIAL 23378200 A 323 331 baicalin TRIVIAL 23378200 A 631 639 baicalin TRIVIAL 23378200 T 11 19 baicalin TRIVIAL 23378608 A 1138 1147 celecoxib TRIVIAL 23378608 A 859 870 Fatty acids FAMILY 23378626 A 1098 1105 CS-1036 IDENTIFIER 23378626 A 1118 1125 CS-1036 IDENTIFIER 23378626 A 1333 1340 CS-1036 IDENTIFIER 23378626 A 1379 1386 glucose TRIVIAL 23378626 A 1472 1479 CS-1036 IDENTIFIER 23378626 A 153 160 CS-1036 IDENTIFIER 23378626 A 344 351 CS-1036 IDENTIFIER 23378626 A 45 151 (2R,3R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-deoxy-β-d-glucopyranosyl)-α-d-glucopyranoside SYSTEMATIC 23378626 A 507 521 [(14)C]CS-1036 IDENTIFIER 23378626 T 179 186 glucose TRIVIAL 23378626 T 43 50 CS-1036 IDENTIFIER 23378627 A 19 29 androstane TRIVIAL 23378627 T 95 105 androstane TRIVIAL 23378820 A 11 19 selenate SYSTEMATIC 23378820 A 140 151 bicarbonate SYSTEMATIC 23378820 A 160 164 Iron SYSTEMATIC 23378820 A 180 197 ferrous hydroxide SYSTEMATIC 23378820 A 241 249 selenate SYSTEMATIC 23378820 A 265 269 Iron SYSTEMATIC 23378820 A 407 413 oxygen SYSTEMATIC 23378820 A 526 534 selenate SYSTEMATIC 23378820 A 572 580 selenate SYSTEMATIC 23378820 A 684 691 ferrous SYSTEMATIC 23378820 A 696 705 hydroxide SYSTEMATIC 23378820 A 842 848 oxygen SYSTEMATIC 23378820 A 903 911 selenate SYSTEMATIC 23378820 A 98 102 iron SYSTEMATIC 23378820 T 27 35 Selenate SYSTEMATIC 23379362 A 19 32 polyacetylene SYSTEMATIC 23379362 A 297 311 Petroacetylene TRIVIAL 23379362 A 53 67 petroacetylene TRIVIAL 23379362 T 0 14 Petroacetylene TRIVIAL 23379362 T 22 35 polyacetylene SYSTEMATIC 23379369 A 33 52 2-fluoroethyl azide SYSTEMATIC 23379369 A 54 63 FCH2CH2N3 FORMULA 23379369 A 619 626 F-C-C-N FORMULA 23379369 A 631 638 C-C-N-N FORMULA 23379369 A 668 676 fluorine SYSTEMATIC 23379369 A 690 695 azido SYSTEMATIC 23379369 T 64 83 2-fluoroethyl azide SYSTEMATIC 23379369 T 85 94 FCH2CH2N3 FORMULA 23379686 A 112 125 [C10C10mim]Cl FORMULA 23379686 A 1401 1414 [C10C10mim]Cl FORMULA 23379686 A 1505 1538 4-methoxybenzenesulfonyl chloride SYSTEMATIC 23379686 A 1540 1544 MBSC ABBREVIATION 23379686 A 545 551 pyrene SYSTEMATIC 23379686 A 556 564 Nile red TRIVIAL 23379686 A 617 628 rhodamine B TRIVIAL 23379686 A 659 663 (1)H FORMULA 23379686 A 672 675 D2O FORMULA 23379686 A 70 110 1,3-didecyl-2-methylimidazolium chloride SYSTEMATIC 23379686 T 44 84 1,3-didecyl-2-methylimidazolium chloride SYSTEMATIC 23379723 A 169 179 spiropyran FAMILY 23379723 A 400 407 toluene TRIVIAL 23379723 A 409 424 tetrahydrofuran SYSTEMATIC 23379723 A 426 433 acetone SYSTEMATIC 23379723 A 435 447 acetonitrile SYSTEMATIC 23379723 A 449 456 ethanol SYSTEMATIC 23379723 A 462 470 methanol SYSTEMATIC 23379723 A 55 65 spiropyran FAMILY 23379723 A 6 12 silica TRIVIAL 23379723 A 632 642 spiropyran FAMILY 23379723 A 662 673 merocyanine FAMILY 23379723 A 840 850 spiropyran FAMILY 23379723 T 0 10 Spiropyran FAMILY 23379784 A 0 11 Polystyrene SYSTEMATIC 23379784 A 830 831 H FORMULA 23379784 A 959 970 polystyrene SYSTEMATIC 23379784 A 973 993 poly(ethylene oxide) SYSTEMATIC 23379784 T 27 38 polystyrene SYSTEMATIC 23379962 A 1032 1037 PFH-A ABBREVIATION 23379962 A 187 193 carbon SYSTEMATIC 23379962 A 287 356 poly[(9,9-dioctylfluorenyl-2,7-diyl)-alt-co-(6,6'-{2,2'-bipyridine})] SYSTEMATIC 23379962 A 358 365 PFO-BPy ABBREVIATION 23379962 A 371 429 poly[(9,9-dihexylfluorenyl-2,7-diyl)-co-(9,10-anthracene)] SYSTEMATIC 23379962 A 431 436 PFH-A ABBREVIATION 23379962 A 51 59 fluorene SYSTEMATIC 23379962 T 70 76 carbon SYSTEMATIC 23380082 A 278 292 phenolic acids FAMILY 23380082 A 294 309 rosmarinic acid TRIVIAL 23380082 A 316 328 caffeic acid TRIVIAL 23380082 A 338 350 ferulic acid TRIVIAL 23380082 A 564 578 phenolic acids FAMILY 23380082 A 689 703 phenolic acids FAMILY 23380082 T 77 91 phenolic acids FAMILY 23380243 A 930 937 arsenic SYSTEMATIC 23380305 A 0 9 Histamine TRIVIAL 23380305 A 1047 1054 ABT-239 IDENTIFIER 23380305 A 1073 1082 histamine TRIVIAL 23380305 A 1184 1191 ABT-239 IDENTIFIER 23380305 A 1202 1211 histamine TRIVIAL 23380305 A 1305 1312 ABT-239 IDENTIFIER 23380305 A 1438 1445 ABT-239 IDENTIFIER 23380305 A 158 167 histamine TRIVIAL 23380305 A 1679 1688 histamine TRIVIAL 23380305 A 1835 1844 histamine TRIVIAL 23380305 A 510 519 histamine TRIVIAL 23380305 A 543 613 4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile SYSTEMATIC 23380305 A 615 622 ABT-239 IDENTIFIER 23380305 A 801 814 acetylcholine SYSTEMATIC 23380305 A 819 828 histamine TRIVIAL 23380305 T 103 116 acetylcholine SYSTEMATIC 23380305 T 121 130 histamine TRIVIAL 23380305 T 37 46 histamine TRIVIAL 23380305 T 86 93 ABT-239 IDENTIFIER 23380477 A 459 474 cobalt chloride SYSTEMATIC 23380477 A 561 567 oxygen SYSTEMATIC 23380477 A 597 602 CoCl2 FORMULA 23380477 A 831 836 CoCl2 FORMULA 23380477 T 88 95 CoCl(2) FORMULA 23380917 A 1064 1067 PCP ABBREVIATION 23380917 A 1262 1265 PCP ABBREVIATION 23380917 A 1439 1442 PCP ABBREVIATION 23380917 A 1596 1599 PCP ABBREVIATION 23380917 A 21 34 phencyclidine TRIVIAL 23380917 A 227 246 γ-aminobutyric acid SYSTEMATIC 23380917 A 248 252 GABA ABBREVIATION 23380917 A 36 39 PCP ABBREVIATION 23380917 A 430 434 GABA ABBREVIATION 23380917 A 531 534 PCP ABBREVIATION 23380917 A 726 729 PCP ABBREVIATION 23380917 A 74 94 N-methyl D-aspartate SYSTEMATIC 23380917 T 10 23 phencyclidine TRIVIAL 23381681 A 1128 1130 Se FORMULA 23381681 A 1188 1190 Se FORMULA 23381681 A 1216 1222 seleno SYSTEMATIC 23381681 A 1261 1264 GSH ABBREVIATION 23381681 A 1294 1309 sodium selenite SYSTEMATIC 23381681 A 1311 1320 Thyroxine TRIVIAL 23381681 A 1327 1343 triiodothyronine TRIVIAL 23381681 A 1538 1540 Se FORMULA 23381681 A 1572 1574 Se FORMULA 23381681 A 1617 1632 sodium selenite SYSTEMATIC 23381681 A 1697 1703 seleno SYSTEMATIC 23381681 A 1711 1719 Selenium SYSTEMATIC 23381681 A 1808 1811 GSH ABBREVIATION 23381681 A 1827 1833 seleno SYSTEMATIC 23381681 A 1845 1847 Se FORMULA 23381681 A 1871 1886 sodium selenite SYSTEMATIC 23381681 A 374 382 selenium SYSTEMATIC 23381681 A 384 386 Se FORMULA 23381681 A 415 417 Se FORMULA 23381681 A 423 438 sodium selenite SYSTEMATIC 23381681 A 483 485 Se FORMULA 23381681 A 491 497 seleno SYSTEMATIC 23381681 A 756 758 Se FORMULA 23381681 A 794 796 Se FORMULA 23381681 A 822 833 glutathione TRIVIAL 23381681 A 857 860 GSH ABBREVIATION 23381681 A 901 903 Se FORMULA 23381681 A 914 920 seleno SYSTEMATIC 23381681 A 969 984 sodium selenite SYSTEMATIC 23381681 A 990 993 GSH ABBREVIATION 23381681 T 25 33 selenium SYSTEMATIC 23381882 A 1048 1058 saquinavir TRIVIAL 23381882 A 143 152 midazolam TRIVIAL 23381882 A 171 183 fexofenadine TRIVIAL 23381882 A 199 210 pravastatin TRIVIAL 23381882 A 280 290 saquinavir TRIVIAL 23381882 A 34 43 ritonavir TRIVIAL 23381882 A 439 448 ritonavir TRIVIAL 23381882 A 572 582 saquinavir TRIVIAL 23381882 A 739 748 midazolam TRIVIAL 23381882 A 753 765 fexofenadine TRIVIAL 23381882 A 922 933 pravastatin TRIVIAL 23381882 A 99 109 saquinavir TRIVIAL 23381882 T 107 116 Midazolam TRIVIAL 23381882 T 127 139 Fexofenadine TRIVIAL 23381882 T 162 173 Pravastatin TRIVIAL 23381882 T 50 59 Ritonavir TRIVIAL 23381882 T 64 74 Saquinavir TRIVIAL 23381951 A 0 11 Allopurinol TRIVIAL 23381951 A 571 582 allopurinol TRIVIAL 23381951 A 701 709 abacavir TRIVIAL 23381951 A 714 727 carbamazepine TRIVIAL 23381951 A 844 855 allopurinol TRIVIAL 23381951 T 20 31 Allopurinol TRIVIAL 23382013 A 1017 1024 octanol SYSTEMATIC 23382105 A 1051 1054 MMF ABBREVIATION 23382105 A 1089 1101 cyclosporine TRIVIAL 23382105 A 1119 1122 MPA ABBREVIATION 23382105 A 1238 1259 mycophenolate mofetil TRIVIAL 23382105 A 1276 1279 MPA ABBREVIATION 23382105 A 138 141 MPA ABBREVIATION 23382105 A 220 223 MPA ABBREVIATION 23382105 A 465 468 MPA ABBREVIATION 23382105 A 600 603 MPA ABBREVIATION 23382105 A 65 82 mycophenolic acid TRIVIAL 23382105 A 759 771 cyclosporine TRIVIAL 23382105 A 830 833 MPA ABBREVIATION 23382105 A 84 87 MPA ABBREVIATION 23382105 A 960 970 tacrolimus TRIVIAL 23382105 T 104 125 mycophenolate mofetil TRIVIAL 23382105 T 53 70 mycophenolic acid TRIVIAL 23382380 A 0 4 AMPA ABBREVIATION 23382380 A 28 37 glutamate TRIVIAL 23383423 A 121 131 amino acid FAMILY 23383594 A 430 444 carbon dioxide SYSTEMATIC 23383594 A 449 456 methane SYSTEMATIC 23383594 A 520 527 zeolite TRIVIAL 23383594 A 550 556 carbon SYSTEMATIC 23383594 A 598 601 CO2 FORMULA 23383594 A 602 605 CH4 FORMULA 23383710 A 137 143 DMAAPS ABBREVIATION 23383710 A 157 173 polyethylenimine SYSTEMATIC 23383710 A 175 178 PEI ABBREVIATION 23383710 A 315 318 PEI ABBREVIATION 23383710 A 338 341 PEI ABBREVIATION 23383710 A 342 348 DMAAPS ABBREVIATION 23383710 A 353 356 PEI ABBREVIATION 23383710 A 357 363 DMAAPS ABBREVIATION 23383710 A 372 375 PEI ABBREVIATION 23383710 A 376 382 DMAAPS ABBREVIATION 23383710 A 462 465 PEI ABBREVIATION 23383710 A 558 561 PEI ABBREVIATION 23383710 A 633 636 PEI ABBREVIATION 23383710 A 748 751 PEI ABBREVIATION 23383710 A 752 758 DMAAPS ABBREVIATION 23383710 A 772 775 PEI ABBREVIATION 23383710 A 776 782 DMAAPS ABBREVIATION 23383710 A 79 135 N,N-dimethyl(acrylamidopropyl)ammonium propane sulfonate SYSTEMATIC 23383710 A 939 942 PEI ABBREVIATION 23383710 A 985 988 PEI ABBREVIATION 23383723 A 0 9 Pluronics FAMILY 23383723 A 1034 1043 bile salt FAMILY 23383723 A 1057 1070 Pluronic F127 TRIVIAL 23383723 A 1112 1121 bile salt FAMILY 23383723 A 1214 1227 Pluronic F127 TRIVIAL 23383723 A 1270 1279 bile salt FAMILY 23383723 A 200 210 bile salts FAMILY 23383723 A 323 343 Pluronic F127 or F68 MULTIPLE 23383723 A 352 361 bile salt FAMILY 23383723 A 362 367 NaTDC ABBREVIATION 23383723 A 464 472 Pluronic FAMILY 23383723 A 529 537 Pluronic FAMILY 23383723 A 741 754 Pluronic F127 TRIVIAL 23383723 A 805 814 bile salt FAMILY 23383723 A 820 823 F68 IDENTIFIER 23383723 A 934 943 Pluronics FAMILY 23383723 T 21 45 Pluronics (F127 and F68) MULTIPLE 23383723 T 50 60 bile salts FAMILY 23383723 T 62 67 NaTDC ABBREVIATION 23383746 A 102 108 LA-Tam ABBREVIATION 23383746 A 1034 1040 Prodan ABBREVIATION 23383746 A 1118 1124 LA-Tam ABBREVIATION 23383746 A 1135 1142 DCA-Tam ABBREVIATION 23383746 A 117 133 deoxycholic acid TRIVIAL 23383746 A 134 143 tamoxifen TRIVIAL 23383746 A 1415 1422 TamNHMe FORMULA 23383746 A 1427 1433 CA-Tam ABBREVIATION 23383746 A 1449 1455 LA-Tam ABBREVIATION 23383746 A 145 152 DCA-Tam ABBREVIATION 23383746 A 1466 1473 DCA-Tam ABBREVIATION 23383746 A 1554 1558 DPPC ABBREVIATION 23383746 A 1620 1629 bile acid FAMILY 23383746 A 1630 1639 tamoxifen TRIVIAL 23383746 A 165 176 cholic acid TRIVIAL 23383746 A 177 186 tamoxifen TRIVIAL 23383746 A 1780 1789 tamoxifen TRIVIAL 23383746 A 1805 1815 bile acids FAMILY 23383746 A 188 194 CA-Tam ABBREVIATION 23383746 A 218 227 tamoxifen TRIVIAL 23383746 A 248 253 amine SYSTEMATIC 23383746 A 275 279 DPPC ABBREVIATION 23383746 A 308 333 N-desmethylated tamoxifen TRIVIAL 23383746 A 335 342 TamNHMe FORMULA 23383746 A 350 353 DPH ABBREVIATION 23383746 A 385 391 Prodan ABBREVIATION 23383746 A 42 51 bile acid FAMILY 23383746 A 456 459 DPH ABBREVIATION 23383746 A 497 506 bile acid FAMILY 23383746 A 507 516 tamoxifen TRIVIAL 23383746 A 52 61 tamoxifen TRIVIAL 23383746 A 596 605 tamoxifen TRIVIAL 23383746 A 630 639 bile acid FAMILY 23383746 A 672 681 bile acid FAMILY 23383746 A 682 691 tamoxifen TRIVIAL 23383746 A 710 714 DPPC ABBREVIATION 23383746 A 74 90 lithocholic acid TRIVIAL 23383746 A 781 790 bile acid FAMILY 23383746 A 791 800 tamoxifen TRIVIAL 23383746 A 816 820 DPPC ABBREVIATION 23383746 A 857 863 CA-Tam ABBREVIATION 23383746 A 872 879 DCA-Tam ABBREVIATION 23383746 A 888 894 LA-Tam ABBREVIATION 23383746 A 903 910 TamNHMe FORMULA 23383746 A 91 100 tamoxifen TRIVIAL 23383746 A 929 938 bile acid FAMILY 23383746 A 939 948 tamoxifen TRIVIAL 23383746 T 78 87 bile acid FAMILY 23383750 A 1302 1309 PS-P4VP ABBREVIATION 23383750 A 1310 1313 PDP ABBREVIATION 23383750 A 1398 1405 PS-P4VP ABBREVIATION 23383750 A 241 275 polystyrene-poly(4-vinyl pyridine) SYSTEMATIC 23383750 A 277 284 PS-P4VP ABBREVIATION 23383750 A 530 550 3-n-pentadecylphenol SYSTEMATIC 23383750 A 552 555 PDP ABBREVIATION 23383750 A 598 606 hydrogen SYSTEMATIC 23383750 T 100 107 PS-P4VP ABBREVIATION 23383750 T 112 119 PS-P4VP ABBREVIATION 23383750 T 120 123 PDP ABBREVIATION 23383871 A 1829 1836 steroid FAMILY 23383871 A 1911 1922 cyclohexene SYSTEMATIC 23383871 A 88 96 estrogen FAMILY 23383871 A 908 916 estrogen FAMILY 23384042 A 233 241 perylene SYSTEMATIC 23384042 A 242 248 CH2Cl2 FORMULA 23384042 T 40 48 perylene SYSTEMATIC 23384363 A 253 261 nitrogen SYSTEMATIC 23384363 T 67 75 nitrogen SYSTEMATIC 23384387 A 101 124 elaidoyl-L-valinolamide SYSTEMATIC 23384387 A 130 153 elaidoyl-D-valinolamide SYSTEMATIC 23384387 A 158 181 stearoyl-L-valinolamide SYSTEMATIC 23384387 A 18 34 acylethanolamide FAMILY 23384387 A 191 215 palmitoyl-L-valinolamide SYSTEMATIC 23384387 A 47 68 oleoyl-L-valinolamide SYSTEMATIC 23384387 A 74 95 oleoyl-D-valinolamide SYSTEMATIC 23384387 A 785 806 Oleoyl-L-valinolamide SYSTEMATIC 23384387 A 857 864 glucose TRIVIAL 23384387 A 937 958 oleoyl-L-valinolamide SYSTEMATIC 23384387 T 6 22 acylethanolamide FAMILY 23384446 A 1012 1017 NADPH ABBREVIATION 23384446 A 1036 1044 apocynin TRIVIAL 23384446 A 1144 1146 NO FORMULA 23384446 A 1178 1181 CPA ABBREVIATION 23384446 A 1186 1189 ACh ABBREVIATION 23384446 A 1209 1217 arsenite SYSTEMATIC 23384446 A 1219 1227 Arsenite SYSTEMATIC 23384446 A 1236 1244 apocynin TRIVIAL 23384446 A 1408 1416 arsenite SYSTEMATIC 23384446 A 1491 1508 hydrogen peroxide SYSTEMATIC 23384446 A 1553 1563 superoxide TRIVIAL 23384446 A 1583 1588 NADPH ABBREVIATION 23384446 A 1628 1630 NO FORMULA 23384446 A 172 180 arsenite SYSTEMATIC 23384446 A 1775 1783 arsenite SYSTEMATIC 23384446 A 1836 1838 NO FORMULA 23384446 A 284 296 nitric oxide SYSTEMATIC 23384446 A 298 300 NO FORMULA 23384446 A 460 473 acetylcholine SYSTEMATIC 23384446 A 475 478 ACh ABBREVIATION 23384446 A 487 505 cyclopiazonic acid TRIVIAL 23384446 A 507 510 CPA ABBREVIATION 23384446 A 543 549 Ca(2+) FORMULA 23384446 A 621 627 oxygen SYSTEMATIC 23384446 A 765 780 dihydroethidium SYSTEMATIC 23384446 A 8 15 arsenic SYSTEMATIC 23384446 A 821 829 arsenite SYSTEMATIC 23384446 A 889 892 CPA ABBREVIATION 23384446 A 897 900 ACh ABBREVIATION 23384446 A 955 965 superoxide TRIVIAL 23384446 A 984 1003 manganese porphyrin SYSTEMATIC 23384446 T 24 31 arsenic SYSTEMATIC 23384446 T 77 82 NADPH ABBREVIATION 23384446 T 95 112 hydrogen peroxide SYSTEMATIC 23384967 A 0 11 Bisphenol A TRIVIAL 23384967 A 13 16 BPA ABBREVIATION 23384967 A 189 196 steroid FAMILY 23384967 A 22 40 diethylstilbestrol SYSTEMATIC 23384967 A 321 324 BPA ABBREVIATION 23384967 A 329 332 DES ABBREVIATION 23384967 A 42 45 DES ABBREVIATION 23384967 A 483 486 BPA ABBREVIATION 23384967 A 491 494 DES ABBREVIATION 23384967 A 607 610 BPA ABBREVIATION 23384967 A 783 786 BPA ABBREVIATION 23384967 A 847 850 DES ABBREVIATION 23384967 T 110 128 diethylstilbestrol SYSTEMATIC 23384967 T 94 105 bisphenol A TRIVIAL 23384996 A 1045 1052 ammonia SYSTEMATIC 23384996 A 1153 1160 ammonia SYSTEMATIC 23384996 A 121 128 ammonia SYSTEMATIC 23384996 A 1289 1298 glutamine TRIVIAL 23384996 A 1344 1353 glutamine TRIVIAL 23384996 A 1429 1438 glutamine TRIVIAL 23384996 A 1504 1513 glutamate TRIVIAL 23384996 A 1545 1554 glutamate TRIVIAL 23384996 A 1642 1651 glutamate TRIVIAL 23384996 A 1690 1699 glutamine TRIVIAL 23384996 A 2009 2018 aspartate TRIVIAL 23384996 A 2023 2030 alanine TRIVIAL 23384996 A 205 212 ammonia SYSTEMATIC 23384996 A 2069 2076 alanine TRIVIAL 23384996 A 2105 2112 ammonia SYSTEMATIC 23384996 A 216 225 glutamine TRIVIAL 23384996 A 2171 2182 amino acids FAMILY 23384996 A 2239 2246 ammonia SYSTEMATIC 23384996 A 2315 2322 ammonia SYSTEMATIC 23384996 A 241 252 amino acids FAMILY 23384996 A 331 338 ammonia SYSTEMATIC 23384996 A 384 391 ammonia SYSTEMATIC 23384996 A 441 450 glutamate TRIVIAL 23384996 A 454 463 glutamine TRIVIAL 23384996 A 493 502 glutamate TRIVIAL 23384996 A 51 58 ammonia SYSTEMATIC 23384996 A 538 547 aspartate TRIVIAL 23384996 A 576 583 alanine TRIVIAL 23384996 A 613 622 glutamine TRIVIAL 23384996 A 685 696 amino acids FAMILY 23384996 A 917 924 ammonia SYSTEMATIC 23384996 A 929 936 NH4HCO3 FORMULA 23384996 T 136 143 ammonia SYSTEMATIC 23384996 T 14 24 amino acid FAMILY 23385211 A 133 144 desipramine TRIVIAL 23385211 A 203 228 lithium aluminium hydride SYSTEMATIC 23385211 A 32 47 ethylene glycol SYSTEMATIC 23385211 A 456 461 amine SYSTEMATIC 23385211 A 48 49 N FORMULA 23385211 A 522 532 Imipramine TRIVIAL 23385211 A 537 548 desipramine TRIVIAL 23385211 A 62 72 imipramine TRIVIAL 23385211 A 661 671 Imipramine TRIVIAL 23385211 A 734 743 serotonin TRIVIAL 23385211 A 963 974 imipramines FAMILY 23385211 T 20 31 imipramines FAMILY 23385211 T 6 7 N FORMULA 23385214 A 244 246 OH FORMULA 23385214 A 259 260 H FORMULA 23385214 A 268 270 OH FORMULA 23385214 A 523 525 OH FORMULA 23385214 A 651 653 OH FORMULA 23386250 A 1071 1077 FK-506 IDENTIFIER 23386250 A 1079 1089 tacrolimus TRIVIAL 23386250 A 1207 1213 FK-506 IDENTIFIER 23386250 A 1310 1316 Ca(2+) FORMULA 23386250 A 1327 1331 K(+) FORMULA 23386250 A 308 314 Ca(2+) FORMULA 23386468 A 0 27 2'-Fluoro-2'-deoxyguanosine SYSTEMATIC 23386468 A 1047 1054 guanine TRIVIAL 23386468 A 1099 1108 adenosine TRIVIAL 23386468 A 1153 1181 nucleoside 5'-monophosphates FAMILY 23386468 A 186 213 2'-fluoro-2'-deoxyguanosine SYSTEMATIC 23386468 A 248 263 phosphoramidate SYSTEMATIC 23386468 A 334 345 nucleosides FAMILY 23386468 A 418 451 5'-O-naphthyl(methoxy-L-alaninyl) SYSTEMATIC 23386468 A 475 513 6-O-methyl-2'-fluoro-2'-deoxyguanosine SYSTEMATIC 23386468 A 515 552 6-O-ethyl-2'-fluoro-2'-deoxyguanosine SYSTEMATIC 23386468 A 558 594 2'-deoxy-2'-fluoro-6-chloroguanosine SYSTEMATIC 23386468 A 604 636 5'-O-naphthyl(ethoxy-L-alaninyl) SYSTEMATIC 23386468 A 648 685 6-O-ethyl-2'-fluoro-2'-deoxyguanosine SYSTEMATIC 23386468 A 816 826 L-alaninyl TRIVIAL 23386468 A 858 902 2'-fluoro-2'-deoxyguanosine 5'-monophosphate SYSTEMATIC 23386468 T 39 72 purine 2'-fluoro-2'-deoxyriboside SYSTEMATIC 23386597 A 1040 1049 ezogabine TRIVIAL 23386597 A 1230 1239 ezogabine TRIVIAL 23386597 A 332 341 Ezogabine TRIVIAL 23386597 A 352 362 retigabine TRIVIAL 23386597 A 380 441 ethyl N-(2-amino-4-[{fluorophenyl}methlamino]phenylcarbamate) SYSTEMATIC 23386597 A 618 627 Ezogabine TRIVIAL 23386597 A 685 694 potassium SYSTEMATIC 23386597 A 847 856 ezogabine TRIVIAL 23386597 T 0 9 Ezogabine TRIVIAL 23386599 A 133 139 esters FAMILY 23386599 A 1358 1365 statins FAMILY 23386599 A 141 147 amides FAMILY 23386599 A 149 159 thioesters FAMILY 23386599 A 165 175 carbamates FAMILY 23386599 A 448 453 ester FAMILY 23386599 A 545 560 carboxylic acid SYSTEMATIC 23386616 A 33 38 NADPH ABBREVIATION 23386616 A 948 954 oxygen SYSTEMATIC 23386616 T 62 67 NADPH ABBREVIATION 23386704 A 1002 1011 vitamin D FAMILY 23386704 A 105 126 4β-hydroxycholesterol SYSTEMATIC 23386704 A 1099 1118 25-hydroxyvitamin D SYSTEMATIC 23386704 A 1123 1144 4β-hydroxycholesterol SYSTEMATIC 23386704 A 1235 1256 4β-hydroxycholesterol SYSTEMATIC 23386704 A 1338 1357 25-hydroxyvitamin D SYSTEMATIC 23386704 A 1400 1409 vitamin D FAMILY 23386704 A 1414 1435 4β-hydroxycholesterol SYSTEMATIC 23386704 A 1530 1551 4β-hydroxycholesterol SYSTEMATIC 23386704 A 556 565 vitamin D FAMILY 23386704 A 737 756 25-hydroxyvitamin D SYSTEMATIC 23386704 A 81 100 25-hydroxyvitamin D SYSTEMATIC 23386704 A 828 847 25-hydroxyvitamin D SYSTEMATIC 23386704 A 882 903 4β-hydroxycholesterol SYSTEMATIC 23386704 T 16 35 25-hydroxyvitamin D SYSTEMATIC 23386704 T 60 81 4β-hydroxycholesterol SYSTEMATIC 23386704 T 97 106 vitamin D FAMILY 23386780 A 0 15 Epichlorohydrin TRIVIAL 23386780 A 17 20 ECH ABBREVIATION 23386780 A 302 305 ECH ABBREVIATION 23386780 A 318 321 ECH ABBREVIATION 23386780 A 404 408 dUTP ABBREVIATION 23386780 A 934 939 amino FAMILY 23386780 T 49 64 epichlorohydrin TRIVIAL 23387796 A 1029 1039 geralcin C TRIVIAL 23387796 A 115 132 geralcins A and B MULTIPLE 23387796 A 12 22 hydrazides FAMILY 23387796 A 236 252 Amberlite XAD-16 TRIVIAL 23387796 A 24 37 geralcins C-E MULTIPLE 23387796 A 577 585 methanol SYSTEMATIC 23387796 A 625 629 (1)H FORMULA 23387796 A 631 636 (13)C FORMULA 23387796 A 642 647 (15)N FORMULA 23387796 A 881 898 geralcins D and E MULTIPLE 23387796 A 900 910 Geralcin C TRIVIAL 23387796 T 42 52 hydrazides FAMILY 23387851 A 1211 1217 SA4503 IDENTIFIER 23387851 A 1222 1233 ANAVEX 2-73 IDENTIFIER 23387851 A 1256 1263 E-52862 IDENTIFIER 23387865 A 0 23 Hydroxysafflor yellow A SYSTEMATIC 23387865 A 25 29 HSYA ABBREVIATION 23387865 A 356 365 DMSO-d(6) ABBREVIATION 23387865 A 367 380 pyridine-d(5) SYSTEMATIC 23387865 A 386 393 CD(3)OH FORMULA 23387865 A 438 442 HSYA ABBREVIATION 23387865 A 495 512 3-enol-1,7-diketo SYSTEMATIC 23387865 A 541 550 keto-enol SYSTEMATIC 23387865 A 591 608 1-enol-3,7-diketo SYSTEMATIC 23387865 A 688 713 quinochalcone C-glycoside FAMILY 23387865 A 767 772 (13)C FORMULA 23387865 A 789 809 (E)-olefinic carbons FAMILY 23387865 A 813 839 quinochalcone C-glycosides FAMILY 23387865 A 971 980 keto-enol SYSTEMATIC 23387865 T 61 84 hydroxysafflor yellow A SYSTEMATIC 23387865 T 95 121 quinochalcone C-glycosides FAMILY 23389039 A 1124 1132 curcumin TRIVIAL 23389039 A 1273 1281 curcumin TRIVIAL 23389045 A 0 7 Pyridyl SYSTEMATIC 23389045 A 1211 1220 4-pyridyl SYSTEMATIC 23389045 A 1225 1245 bis(2-hydroxy-ethyl) SYSTEMATIC 23389045 A 1261 1272 lipoic acid TRIVIAL 23389045 A 176 183 ethanol SYSTEMATIC 23389045 A 537 546 4-pyridyl SYSTEMATIC 23389045 A 553 572 bis(2-hydroxyethyl) SYSTEMATIC 23389045 A 587 598 lipoic acid TRIVIAL 23389045 A 98 112 thyroxine (T4) TRIVIAL 23389045 T 17 25 pyridine SYSTEMATIC 23389045 T 35 46 lipoic Acid TRIVIAL 23389045 T 94 108 thyroxine (t4) TRIVIAL 23389625 A 101 110 LiFePO(4) FORMULA 23389625 A 152 159 lithium SYSTEMATIC 23389625 A 179 188 LiFePO(4) FORMULA 23389625 A 271 277 carbon SYSTEMATIC 23389625 A 330 336 carbon SYSTEMATIC 23389625 A 359 366 sucrose TRIVIAL 23389625 A 372 373 C FORMULA 23389625 A 374 383 LiFePO(4) FORMULA 23389625 A 60 66 carbon SYSTEMATIC 23389625 A 640 641 C FORMULA 23389625 A 642 651 LiFePO(4) FORMULA 23389625 A 74 83 LiFePO(4) FORMULA 23389625 A 752 758 carbon SYSTEMATIC 23389625 A 774 780 carbon SYSTEMATIC 23389625 A 825 831 carbon SYSTEMATIC 23389625 A 91 97 carbon SYSTEMATIC 23389625 A 916 925 LiFePO(4) FORMULA 23389625 A 99 100 C FORMULA 23389625 T 0 6 Carbon SYSTEMATIC 23389625 T 14 21 LiFePO4 FORMULA 23389625 T 29 35 carbon SYSTEMATIC 23389625 T 72 79 lithium SYSTEMATIC 23389738 A 1139 1143 ETBE ABBREVIATION 23389738 A 19 45 ethyl tertiary-butyl ether SYSTEMATIC 23389738 A 200 204 ETBE ABBREVIATION 23389738 A 47 51 ETBE ABBREVIATION 23389738 T 24 50 ethyl tertiary-butyl ether SYSTEMATIC 23389956 A 271 274 sGC ABBREVIATION 23389956 A 41 49 cortisol TRIVIAL 23389956 A 449 457 cortisol TRIVIAL 23389956 A 663 671 cortisol TRIVIAL 23389956 A 777 790 betamethasone TRIVIAL 23389956 A 941 949 cortisol TRIVIAL 23391096 A 0 10 Paclitaxel TRIVIAL 23391096 A 1098 1108 paclitaxel TRIVIAL 23391096 A 1120 1125 PAMAM ABBREVIATION 23391096 A 12 17 Taxol TRIVIAL 23391096 A 221 231 paclitaxel TRIVIAL 23391096 A 243 257 polyamidoamine FAMILY 23391096 A 259 264 PAMAM ABBREVIATION 23391096 A 437 447 paclitaxel TRIVIAL 23391096 A 493 503 paclitaxel TRIVIAL 23391096 A 588 598 paclitaxel TRIVIAL 23391096 A 850 860 paclitaxel TRIVIAL 23391096 A 924 934 paclitaxel TRIVIAL 23391096 A 989 1004 tertiary amines FAMILY 23391096 T 0 10 Paclitaxel TRIVIAL 23391096 T 22 27 PAMAM ABBREVIATION 23391133 A 298 303 ester FAMILY 23391133 A 305 318 monophosphate SYSTEMATIC 23391133 A 329 334 amide FAMILY 23391162 A 23 47 DO3A-N-α-aminopropionate SYSTEMATIC 23391162 A 246 248 Gd FORMULA 23391162 A 4 11 Gd(III) FORMULA 23391162 A 49 59 Gd(DOTAla) FORMULA 23391162 T 101 103 Gd FORMULA 23391162 T 90 100 Amino Acid FAMILY 23391254 A 231 236 taxol TRIVIAL 23391254 A 577 580 ATP ABBREVIATION 23391441 A 1081 1096 Alexa Fluor 488 TRIVIAL 23391441 A 1108 1118 phalloidin TRIVIAL 23391441 A 388 421 biotin-fluorescein isothiocyanate FAMILY 23391441 A 434 440 biotin TRIVIAL 23391441 A 441 445 FITC ABBREVIATION 23391441 A 574 580 biotin TRIVIAL 23391441 A 581 585 FITC ABBREVIATION 23391441 A 663 669 biotin TRIVIAL 23391441 A 670 674 FITC ABBREVIATION 23391441 A 794 804 gentamicin FAMILY 23391441 A 864 874 gentamicin FAMILY 23391441 A 875 884 Texas Red TRIVIAL 23391441 A 888 898 gentamicin FAMILY 23391442 A 47 53 oxygen SYSTEMATIC 23391443 A 783 787 cAMP ABBREVIATION 23391484 A 0 22 Perfluorooctanoic acid SYSTEMATIC 23391484 A 1099 1103 PFOA ABBREVIATION 23391484 A 1295 1299 PFCA ABBREVIATION 23391484 A 1315 1321 carbon SYSTEMATIC 23391484 A 1362 1366 PFOA ABBREVIATION 23391484 A 221 227 carbon SYSTEMATIC 23391484 A 24 28 PFOA ABBREVIATION 23391484 A 289 293 PFOA ABBREVIATION 23391484 A 316 320 PFOA ABBREVIATION 23391484 A 437 468 perfluorinated carboxylic acids FAMILY 23391484 A 470 474 PFCA ABBREVIATION 23391484 A 483 489 carbon SYSTEMATIC 23391484 A 531 537 carbon SYSTEMATIC 23391484 A 62 76 fluoropolymers FAMILY 23391484 A 688 694 carbon SYSTEMATIC 23391484 A 726 730 PFCA ABBREVIATION 23391484 A 78 81 PFT ABBREVIATION 23391484 A 835 839 PFCA ABBREVIATION 23391484 A 917 921 PFOA ABBREVIATION 23391484 A 977 981 PFCA ABBREVIATION 23391484 T 43 74 perfluorinated carboxylic acids FAMILY 23391484 T 90 96 carbon SYSTEMATIC 23391485 A 1094 1097 BPA ABBREVIATION 23391485 A 1234 1237 BPA ABBREVIATION 23391485 A 1382 1385 BPA ABBREVIATION 23391485 A 333 336 BPA ABBREVIATION 23391485 A 37 48 Bisphenol A TRIVIAL 23391485 A 50 53 BPA ABBREVIATION 23391485 A 776 779 BPA ABBREVIATION 23391485 A 842 846 DMSO ABBREVIATION 23391485 A 874 888 17-β-estrodiol SYSTEMATIC 23391485 A 961 964 BPA ABBREVIATION 23391485 T 19 30 Bisphenol A TRIVIAL 23391598 A 1099 1101 As FORMULA 23391598 A 1112 1114 Fe FORMULA 23391598 A 239 241 Co FORMULA 23391598 A 243 245 Cr FORMULA 23391598 A 247 249 Cu FORMULA 23391598 A 251 253 Fe FORMULA 23391598 A 255 256 I FORMULA 23391598 A 258 260 Mn FORMULA 23391598 A 262 264 Mo FORMULA 23391598 A 266 268 Ni FORMULA 23391598 A 270 272 Se FORMULA 23391598 A 277 279 Zn FORMULA 23391598 A 292 294 As FORMULA 23391598 A 296 298 Cd FORMULA 23391598 A 300 302 Hg FORMULA 23391598 A 307 309 Pb FORMULA 23391598 A 699 701 Cu FORMULA 23391598 A 770 772 Zn FORMULA 23391598 A 794 795 I FORMULA 23391598 A 817 819 Se FORMULA 23391631 A 1230 1236 Pb(2+) FORMULA 23391631 A 1334 1341 lactate FAMILY 23391631 A 1360 1368 creatine TRIVIAL 23391631 A 1428 1434 Pb(2+) FORMULA 23391631 A 1587 1593 Pb(2+) FORMULA 23391631 A 176 182 Pb(2+) FORMULA 23391631 A 1958 1964 Pb(2+) FORMULA 23391631 A 2013 2024 resveratrol TRIVIAL 23391631 A 2055 2061 Pb(2+) FORMULA 23391631 A 265 271 Pb(2+) FORMULA 23391631 A 390 396 Pb(2+) FORMULA 23391631 A 509 525 aryl hydrocarbon FAMILY 23391631 A 593 599 Pb(2+) FORMULA 23391631 A 6 12 Pb(2+) FORMULA 23391631 A 682 688 Pb(2+) FORMULA 23391631 A 938 944 Pb(2+) FORMULA 23391631 T 12 28 aryl hydrocarbon FAMILY 23391632 A 1005 1023 11β-hydroxysteroid FAMILY 23391632 A 1259 1262 EDS ABBREVIATION 23391632 A 1415 1419 DEHP ABBREVIATION 23391632 A 1648 1651 EDS ABBREVIATION 23391632 A 1668 1672 DEHP ABBREVIATION 23391632 A 1794 1798 DEHP ABBREVIATION 23391632 A 1847 1851 DEHP ABBREVIATION 23391632 A 318 322 DEHP ABBREVIATION 23391632 A 399 424 ethane dimethanesulfonate SYSTEMATIC 23391632 A 426 429 EDS ABBREVIATION 23391632 A 464 476 testosterone TRIVIAL 23391632 A 578 581 EDS ABBREVIATION 23391632 A 59 85 di(2-ethylhexyl) phthalate SYSTEMATIC 23391632 A 646 649 EDS ABBREVIATION 23391632 A 683 695 testosterone TRIVIAL 23391632 A 709 726 3β-hydroxysteroid FAMILY 23391632 A 803 807 DEHP ABBREVIATION 23391632 A 852 864 testosterone TRIVIAL 23391632 A 87 91 DEHP ABBREVIATION 23391632 T 40 66 di(2-ethylhexyl) phthalate SYSTEMATIC 23391637 A 593 598 Na(+) FORMULA 23391637 A 600 604 K(+) FORMULA 23391637 A 609 615 Ca(2+) FORMULA 23391637 A 746 751 Na(+) FORMULA 23391637 A 763 769 Ca(2+) FORMULA 23392568 A 1157 1159 Hg FORMULA 23392568 A 121 123 Hg FORMULA 23392568 A 1264 1266 Hg FORMULA 23392568 A 1355 1357 Hg FORMULA 23392568 A 14 19 HgCl2 FORMULA 23392568 A 1635 1637 Hg FORMULA 23392568 A 233 235 Hg FORMULA 23392568 A 284 286 Hg FORMULA 23392568 A 555 557 Hg FORMULA 23392568 A 621 623 Hg FORMULA 23392568 A 818 820 Hg FORMULA 23392568 A 920 922 Hg FORMULA 23392568 T 21 37 mercury chloride SYSTEMATIC 23392606 A 1074 1077 PVP ABBREVIATION 23392606 A 1087 1091 PLLA ABBREVIATION 23392606 A 1092 1095 PVP ABBREVIATION 23392606 A 1135 1138 PVP ABBREVIATION 23392606 A 1162 1166 PLLA ABBREVIATION 23392606 A 1362 1365 PVP ABBREVIATION 23392606 A 1370 1374 PLLA ABBREVIATION 23392606 A 1532 1535 PVP ABBREVIATION 23392606 A 1597 1601 PLLA ABBREVIATION 23392606 A 1704 1708 PLLA ABBREVIATION 23392606 A 578 598 polyvinylpyrrolidone SYSTEMATIC 23392606 A 600 603 PVP ABBREVIATION 23392606 A 609 628 poly(l-lactic acid) SYSTEMATIC 23392606 A 630 634 PLLA ABBREVIATION 23393163 A 0 11 Vesnarinone TRIVIAL 23393163 A 27 38 quinolinone SYSTEMATIC 23393163 A 281 292 vesnarinone TRIVIAL 23393163 A 477 488 vesnarinone TRIVIAL 23393163 A 662 673 vesnarinone TRIVIAL 23393163 A 702 713 vesnarinone TRIVIAL 23393163 T 0 11 Vesnarinone TRIVIAL 23393209 A 1137 1150 triglycerides FAMILY 23393209 A 1285 1298 triglycerides FAMILY 23393209 A 1353 1362 metformin TRIVIAL 23393209 A 1442 1455 triglycerides FAMILY 23393209 A 1472 1479 glucose TRIVIAL 23393209 A 1554 1563 metformin TRIVIAL 23393209 A 159 166 glucose TRIVIAL 23393209 A 1635 1644 metformin TRIVIAL 23393209 A 1690 1697 glucose TRIVIAL 23393209 A 1710 1723 triglycerides FAMILY 23393209 A 209 218 Metformin TRIVIAL 23393209 A 272 285 triglycerides FAMILY 23393209 A 366 375 metformin TRIVIAL 23393209 A 493 506 triglycerides FAMILY 23393209 A 53 65 triglyceride FAMILY 23393209 A 580 589 metformin TRIVIAL 23393209 A 628 637 metformin TRIVIAL 23393209 A 674 687 triglycerides FAMILY 23393209 A 761 774 triglycerides FAMILY 23393209 A 838 850 triglyceride FAMILY 23393209 A 917 930 Triglycerides FAMILY 23393209 A 978 987 metformin TRIVIAL 23393209 T 25 38 Triglycerides FAMILY 23393209 T 90 99 Metformin TRIVIAL 23393216 A 1017 1028 cholesterol TRIVIAL 23393216 A 102 109 glucose TRIVIAL 23393216 A 1030 1043 triglycerides FAMILY 23393216 A 1236 1242 25-OHD SYSTEMATIC 23393216 A 1421 1427 25-OHD SYSTEMATIC 23393216 A 1488 1494 25-OHD SYSTEMATIC 23393216 A 1616 1625 Vitamin D FAMILY 23393216 A 414 439 25-hydroxycholecalciferol SYSTEMATIC 23393216 A 43 52 vitamin D FAMILY 23393216 A 441 447 25-OHD SYSTEMATIC 23393216 A 552 558 25-OHD SYSTEMATIC 23393216 A 982 991 vitamin D FAMILY 23393216 T 130 137 glucose TRIVIAL 23393216 T 34 59 25-hydroxycholecalciferol SYSTEMATIC 23393219 A 0 11 Repaglinide TRIVIAL 23393219 A 1048 1059 repaglinide TRIVIAL 23393219 A 1087 1097 rifampicin TRIVIAL 23393219 A 1375 1386 repaglinide TRIVIAL 23393219 A 1417 1428 repaglinide TRIVIAL 23393219 A 1473 1483 rifampicin TRIVIAL 23393219 A 1636 1647 repaglinide TRIVIAL 23393219 A 1844 1855 repaglinide TRIVIAL 23393219 A 1856 1866 rifampicin TRIVIAL 23393219 A 288 299 repaglinide TRIVIAL 23393219 A 305 315 rifampicin TRIVIAL 23393219 A 373 384 repaglinide TRIVIAL 23393219 A 606 617 repaglinide TRIVIAL 23393219 A 737 748 repaglinide TRIVIAL 23393219 A 806 816 rifampicin TRIVIAL 23393219 A 914 924 rifampicin TRIVIAL 23393219 T 199 209 Rifampicin TRIVIAL 23393219 T 27 38 Repaglinide TRIVIAL 23393219 T 39 49 Rifampicin TRIVIAL 23394218 A 138 145 AZD5363 IDENTIFIER 23394218 T 126 133 AZD5363 IDENTIFIER 23394218 T 13 124 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide SYSTEMATIC 23394309 A 1026 1027 O FORMULA 23394309 A 1032 1033 O FORMULA 23394309 A 160 172 Hydrocarbons FAMILY 23394309 A 252 270 [Nb6O19Hx]((8-x)-) FAMILY 23394309 A 586 590 H(+) FORMULA 23394309 A 595 600 OH(-) FORMULA 23394309 A 656 674 [Nb6O19Hx]((8-x)-) FAMILY 23394309 A 765 766 H FORMULA 23394309 A 852 858 oxygen SYSTEMATIC 23394309 A 881 882 H FORMULA 23394309 T 58 76 [Nb6O19Hx]((8-x)-) FAMILY 23394318 A 150 165 petroleum ether TRIVIAL 23394318 A 17 29 diterpenoids FAMILY 23394318 A 170 177 ethanol SYSTEMATIC 23394318 A 31 55 aquilarabietic acids A-J MULTIPLE 23394318 A 479 493 norepinephrine TRIVIAL 23394318 A 74 85 podocarpane TRIVIAL 23394318 A 8 16 abietane TRIVIAL 23394318 A 86 97 diterpenoid FAMILY 23394318 A 99 120 aquilarabietic acid K TRIVIAL 23394318 T 15 23 abietane TRIVIAL 23394318 T 24 36 diterpenoids FAMILY 23394432 A 831 846 cadmium sulfide SYSTEMATIC 23394432 A 848 851 CdS FORMULA 23394469 A 1059 1067 graphite TRIVIAL 23394469 A 610 624 met-enkephalin TRIVIAL 23394469 A 625 637 pentapeptide FAMILY 23394469 A 649 657 graphite TRIVIAL 23394480 A 1112 1114 Ge FORMULA 23394480 A 116 118 Ge FORMULA 23394480 A 164 166 Ge FORMULA 23394480 A 279 281 Si FORMULA 23394480 A 84 86 Ge FORMULA 23394480 A 87 89 Si FORMULA 23394480 A 916 918 Ge FORMULA 23394480 A 983 985 Ge FORMULA 23394480 T 58 60 Ge FORMULA 23394480 T 61 63 Si FORMULA 23394542 A 244 249 (31)P FORMULA 23394542 A 394 402 chlorine SYSTEMATIC 23394542 A 504 508 CdSe FORMULA 23394542 A 516 522 carbon SYSTEMATIC 23394542 T 53 61 chlorine SYSTEMATIC 23395165 A 107 113 serine TRIVIAL 23395165 A 194 200 purine TRIVIAL 23395165 A 217 228 glutathione TRIVIAL 23395165 T 48 54 serine TRIVIAL 23395652 A 232 247 (-)-huperzine A TRIVIAL 23395652 A 393 417 (+)- and (-)-huperzine A MULTIPLE 23395652 A 460 464 NMDA ABBREVIATION 23395652 A 610 621 huperzine A TRIVIAL 23395652 T 22 33 huperzine A TRIVIAL 23395656 A 12 43 indazolo[4,3-gh]isoquinolinones FAMILY 23395656 A 132 144 Mitoxantrone TRIVIAL 23395656 T 53 83 indazolo[4,3-gh]isoquinolinone SYSTEMATIC 23395663 A 36 43 lactose TRIVIAL 23395663 A 505 512 lactose TRIVIAL 23395663 A 525 544 zinc phthalocyanine SYSTEMATIC 23395663 A 56 75 zinc phthalocyanine SYSTEMATIC 23395663 A 77 188 [2,9(10),16(17),23(24)-tetrakis((1-(β-d-lactose-2-yl)-1H-1,2,3-triazol-4-yl)methoxyl)phthalocyaninato] zinc(II) SYSTEMATIC 23395663 T 0 7 Lactose TRIVIAL 23395663 T 20 39 zinc phthalocyanine SYSTEMATIC 23395665 A 108 118 azomethine SYSTEMATIC 23395665 A 140 146 isatin TRIVIAL 23395665 A 151 160 sarcosine TRIVIAL 23395665 A 184 248 3-(1H-indol-3-yl)-3-oxo-2-(2-oxoindolin-3-ylidene)propanenitrile SYSTEMATIC 23395665 A 277 296 acenaphthenequinone SYSTEMATIC 23395665 A 6 33 dispirooxindole-pyrrolidine SYSTEMATIC 23395665 T 34 61 dispirooxindole-pyrrolidine SYSTEMATIC 23395689 A 0 10 Gadolinium SYSTEMATIC 23395689 A 106 112 Gd(3+) FORMULA 23395689 A 12 14 Gd FORMULA 23395689 A 1267 1278 doxorubicin TRIVIAL 23395689 A 247 256 manganese SYSTEMATIC 23395689 A 258 260 Mn FORMULA 23395689 A 423 425 Mn FORMULA 23395689 A 611 619 Mn oxide SYSTEMATIC 23395689 A 686 696 Oleic acid TRIVIAL 23395689 A 704 707 MnO FORMULA 23395689 A 764 783 polyethylene glycol SYSTEMATIC 23395689 A 785 793 PEG-2000 ABBREVIATION 23395689 A 796 820 phosphatidylethanolamine SYSTEMATIC 23395689 A 830 841 cholesterol TRIVIAL 23395689 A 847 880 dioleoyl-phosphatidylethanolamine SYSTEMATIC 23395689 A 882 886 DOPE ABBREVIATION 23395689 T 0 9 Manganese SYSTEMATIC 23395717 A 0 14 Xestospongin C TRIVIAL 23395717 A 1150 1157 PD98059 IDENTIFIER 23395717 A 53 76 bis-1-oxaquinolizidines FAMILY 23395717 A 632 653 nitroblue tetrazolium TRIVIAL 23395717 T 0 14 Xestospongin C TRIVIAL 23395719 A 104 112 phenolic FAMILY 23395719 A 370 378 phenolic FAMILY 23395719 A 681 697 coumaroyl hexose FAMILY 23395719 A 716 737 dihydroxybenzoic acid SYSTEMATIC 23395719 A 739 755 caffeoyl glucose TRIVIAL 23395719 A 757 796 dihydroferulic acid 4-O-β-d-glucuronide SYSTEMATIC 23395719 A 798 830 methoxyquercetin 3-O-galactoside SYSTEMATIC 23395719 A 832 842 scopoletin TRIVIAL 23395719 A 844 853 myricetin TRIVIAL 23395719 A 858 867 quercetin TRIVIAL 23395719 T 18 29 polyphenols FAMILY 23395783 A 0 7 Cadmium SYSTEMATIC 23395783 A 1020 1025 δ-ALA SYSTEMATIC 23395783 A 1050 1057 cadmium SYSTEMATIC 23395783 A 1131 1134 ORY ABBREVIATION 23395783 A 1157 1164 cadmium SYSTEMATIC 23395783 A 185 192 cadmium SYSTEMATIC 23395783 A 238 248 γ-oryzanol TRIVIAL 23395783 A 250 253 ORY ABBREVIATION 23395783 A 314 319 CdCl2 FORMULA 23395783 A 343 346 ORY ABBREVIATION 23395783 A 487 500 ascorbic acid TRIVIAL 23395783 A 502 509 cadmium SYSTEMATIC 23395783 A 526 532 thiols FAMILY 23395783 A 569 579 superoxide TRIVIAL 23395783 A 613 624 glutathione TRIVIAL 23395783 A 643 654 glutathione TRIVIAL 23395783 A 655 656 S FORMULA 23395783 A 679 698 δ-aminolevulic acid SYSTEMATIC 23395783 A 712 717 δ-ALA SYSTEMATIC 23395783 A 722 729 Cadmium SYSTEMATIC 23395783 A 850 857 cadmium SYSTEMATIC 23395783 A 896 899 ORY ABBREVIATION 23395783 A 996 999 ORY ABBREVIATION 23395783 T 0 10 γ-Oryzanol TRIVIAL 23395783 T 34 41 cadmium SYSTEMATIC 23395914 A 1151 1160 darunavir TRIVIAL 23395914 A 1249 1258 darunavir TRIVIAL 23395914 A 1264 1276 ketoconazole TRIVIAL 23395914 A 1327 1339 ketoconazole TRIVIAL 23395914 A 1401 1410 darunavir TRIVIAL 23395914 A 378 387 darunavir TRIVIAL 23395914 A 495 507 ketoconazole TRIVIAL 23395914 A 540 549 darunavir TRIVIAL 23395914 A 758 767 darunavir TRIVIAL 23395914 A 851 860 darunavir TRIVIAL 23395914 A 897 906 darunavir TRIVIAL 23395914 A 931 941 zosuquidar TRIVIAL 23395914 A 958 968 zosuquidar TRIVIAL 23395914 T 40 49 darunavir TRIVIAL 23395914 T 75 87 ketoconazole TRIVIAL 23396041 A 1077 1081 AZAs ABBREVIATION 23396041 A 1252 1256 AZAs ABBREVIATION 23396041 A 1379 1383 AZA1 ABBREVIATION 23396041 A 1409 1414 AZA17 ABBREVIATION 23396041 A 1427 1431 AZA3 ABBREVIATION 23396041 A 152 163 AZA1 and -2 MULTIPLE 23396041 A 171 175 AZA3 ABBREVIATION 23396041 A 25 36 azaspiracid TRIVIAL 23396041 A 308 319 AZA1 and -2 MULTIPLE 23396041 A 501 504 AZA ABBREVIATION 23396041 A 554 558 AZA1 ABBREVIATION 23396041 A 607 611 AZAs ABBREVIATION 23396041 A 623 631 AZA1 + 2 MULTIPLE 23396041 A 684 690 AZA1+2 MULTIPLE 23396041 A 864 872 AZA1 + 2 MULTIPLE 23396041 A 994 998 AZAs ABBREVIATION 23396041 T 10 22 azaspiracids FAMILY 23396116 A 112 115 TTX ABBREVIATION 23396116 A 1295 1298 TTX ABBREVIATION 23396116 A 1377 1380 TTX ABBREVIATION 23396116 A 1592 1595 TTX ABBREVIATION 23396116 A 463 466 TTX ABBREVIATION 23396116 A 571 574 TTX ABBREVIATION 23396116 A 60 72 tetrodotoxin TRIVIAL 23396116 A 614 617 TTX ABBREVIATION 23396116 A 683 686 TTX ABBREVIATION 23396116 A 74 77 TTX ABBREVIATION 23396116 A 801 804 TTX ABBREVIATION 23396116 T 54 66 tetrodotoxin TRIVIAL 23396441 A 141 148 sucrose TRIVIAL 23396441 A 177 180 ATP ABBREVIATION 23396442 A 864 882 dimethyl sulfoxide SYSTEMATIC 23396442 A 884 888 DMSO ABBREVIATION 23396442 A 893 905 acetonitrile SYSTEMATIC 23396442 A 907 910 ACN ABBREVIATION 23397032 A 1163 1176 Dexamethasone TRIVIAL 23397032 A 1300 1313 dexamethasone TRIVIAL 23397032 A 1441 1454 dexamethasone TRIVIAL 23397032 A 1740 1753 dexamethasone TRIVIAL 23397049 A 1011 1023 paliperidone TRIVIAL 23397049 A 1109 1121 paliperidone TRIVIAL 23397049 A 1249 1261 Paliperidone TRIVIAL 23397049 A 1385 1397 paliperidone TRIVIAL 23397049 A 151 163 paliperidone TRIVIAL 23397049 A 1610 1622 paliperidone TRIVIAL 23397049 A 314 326 paliperidone TRIVIAL 23397049 T 34 46 paliperidone TRIVIAL 23398290 A 0 9 Vitamin A FAMILY 23398290 A 1067 1070 Dex ABBREVIATION 23398290 A 21 34 retinoic acid TRIVIAL 23398290 A 610 623 dexamethasone TRIVIAL 23398290 A 625 628 Dex ABBREVIATION 23398290 T 0 9 Retinoids FAMILY 23399323 A 259 260 O FORMULA 23399323 T 22 23 O FORMULA 23399639 A 1088 1104 taccalonolide AJ TRIVIAL 23399639 A 1230 1246 taccalonolide AJ TRIVIAL 23399639 A 1350 1361 Laulimalide TRIVIAL 23399639 A 1366 1376 paclitaxel TRIVIAL 23399639 A 300 316 taccalonolide AJ TRIVIAL 23399639 A 318 329 laulimalide TRIVIAL 23399639 A 330 343 fijianolide B TRIVIAL 23399639 A 348 358 paclitaxel TRIVIAL 23399639 A 662 678 Taccalonolide AJ TRIVIAL 23399639 A 762 772 paclitaxel TRIVIAL 23399639 A 776 787 laulimalide TRIVIAL 23399641 A 1058 1064 CB1954 IDENTIFIER 23399641 A 605 611 CB1954 IDENTIFIER 23399641 A 616 623 PR-104A IDENTIFIER 23399641 T 160 166 CB1954 IDENTIFIER 23399641 T 171 178 PR-104A IDENTIFIER 23400262 A 254 260 TiO(2) FORMULA 23400262 A 821 827 TiO(2) FORMULA 23400262 A 884 890 TiO(2) FORMULA 23400262 A 941 944 MgO FORMULA 23400262 T 22 26 TiO2 FORMULA 23400270 A 166 172 silica TRIVIAL 23400270 A 18 24 silica TRIVIAL 23400270 A 282 288 silica TRIVIAL 23400270 A 578 584 silica TRIVIAL 23400270 A 854 861 silicas TRIVIAL 23400270 T 47 53 silica TRIVIAL 23400782 A 122 123 C FORMULA 23400782 A 410 413 ATP ABBREVIATION 23400782 A 55 58 ATP ABBREVIATION 23400782 A 594 597 ADP ABBREVIATION 23400782 A 697 698 N FORMULA 23400782 A 80 83 ATP ABBREVIATION 23400782 A 814 815 C FORMULA 23400782 A 861 862 N FORMULA 23400782 A 898 901 ADP ABBREVIATION 23400782 T 103 106 ADP ABBREVIATION 23400782 T 66 69 ATP ABBREVIATION 23400795 A 1041 1052 tributyltin SYSTEMATIC 23400795 A 191 200 organotin FAMILY 23400795 A 43 52 organotin FAMILY 23400795 A 947 968 triphenyltin chloride SYSTEMATIC 23400796 A 1030 1032 Mn FORMULA 23400796 A 1037 1039 Zn FORMULA 23400796 A 105 107 Zn FORMULA 23400796 A 1060 1062 Co FORMULA 23400796 A 1294 1296 Mn FORMULA 23400796 A 1301 1303 Cr FORMULA 23400796 A 643 645 Mn FORMULA 23400796 A 648 650 Zn FORMULA 23400796 A 653 655 Cr FORMULA 23400796 A 658 660 Cu FORMULA 23400796 A 663 665 Co FORMULA 23400796 A 670 672 Mn FORMULA 23400796 A 675 677 Cr FORMULA 23400796 A 680 682 Zn FORMULA 23400796 A 685 687 Cu FORMULA 23400796 A 690 692 Co FORMULA 23400796 A 779 781 Mn FORMULA 23400796 A 86 88 Co FORMULA 23400796 A 90 92 Cr FORMULA 23400796 A 94 96 Cu FORMULA 23400796 A 98 100 Mn FORMULA 23400796 T 27 29 Co FORMULA 23400796 T 31 33 Cr FORMULA 23400796 T 35 37 Cu FORMULA 23400796 T 39 41 Mn FORMULA 23400796 T 46 48 Zn FORMULA 23400888 A 34 47 acetylcholine SYSTEMATIC 23400925 A 1157 1159 Hg FORMULA 23400925 A 123 125 Hg FORMULA 23400925 A 1345 1347 Hg FORMULA 23400925 A 1385 1387 Hg FORMULA 23400925 A 205 212 mercury SYSTEMATIC 23400925 A 220 237 monomethylmercury SYSTEMATIC 23400925 A 239 243 MMHg FORMULA 23400925 A 256 264 selenium SYSTEMATIC 23400925 A 331 333 Hg FORMULA 23400925 A 44 46 Hg FORMULA 23400925 A 468 474 carbon SYSTEMATIC 23400925 A 477 483 (13) C FORMULA 23400925 A 489 497 nitrogen SYSTEMATIC 23400925 A 500 506 (15) N FORMULA 23400925 A 51 53 Se FORMULA 23400925 A 535 537 Hg FORMULA 23400925 A 620 626 (15) N FORMULA 23400925 A 688 694 (15) N FORMULA 23400925 A 724 728 MMHg FORMULA 23400925 A 737 739 Hg FORMULA 23400925 A 908 914 (15) N FORMULA 23400925 T 40 47 mercury SYSTEMATIC 23400925 T 52 60 selenium SYSTEMATIC 23400943 A 795 808 valproic acid TRIVIAL 23400943 A 814 824 clonazepam TRIVIAL 23400943 A 862 875 valproic acid TRIVIAL 23400943 A 877 888 stiripentol TRIVIAL 23400943 A 894 902 clobazam TRIVIAL 23400943 A 971 981 vigabatrin TRIVIAL 23401139 A 0 22 Petroleum hydrocarbons FAMILY 23401139 A 164 167 PHC ABBREVIATION 23401139 A 24 28 PHCs ABBREVIATION 23401139 A 359 366 C10-C16 MULTIPLE 23401139 A 375 382 C16-C23 MULTIPLE 23401139 A 395 402 C23-C34 MULTIPLE 23401139 T 54 75 petroleum hydrocarbon FAMILY 23401211 A 1017 1019 Hg FORMULA 23401211 A 129 131 Hg FORMULA 23401211 A 18 20 Hg FORMULA 23401211 A 470 472 Hg FORMULA 23401211 A 69 71 Hg FORMULA 23401211 A 858 866 nitrogen SYSTEMATIC 23401211 A 9 16 mercury SYSTEMATIC 23401211 T 38 45 mercury SYSTEMATIC 23401217 A 561 568 alloxan TRIVIAL 23401244 A 1025 1028 C60 TRIVIAL 23401244 A 1050 1053 DDE ABBREVIATION 23401244 A 1093 1096 DDE ABBREVIATION 23401244 A 1119 1128 fullerene TRIVIAL 23401244 A 1217 1226 fullerene TRIVIAL 23401244 A 1241 1244 DDE ABBREVIATION 23401244 A 1358 1361 C60 TRIVIAL 23401244 A 1396 1399 DDE ABBREVIATION 23401244 A 1473 1476 DDE ABBREVIATION 23401244 A 1519 1529 fullerenes FAMILY 23401244 A 1606 1609 DDE ABBREVIATION 23401244 A 1714 1717 DDE ABBREVIATION 23401244 A 1745 1748 C60 TRIVIAL 23401244 A 352 355 C60 TRIVIAL 23401244 A 356 366 fullerenes FAMILY 23401244 A 400 432 dichlorodiphenyldichloroethylene SYSTEMATIC 23401244 A 434 442 p,p'-DDE SYSTEMATIC 23401244 A 444 447 DDT ABBREVIATION 23401244 A 670 673 DDE ABBREVIATION 23401244 A 706 709 C60 TRIVIAL 23401244 A 710 720 fullerenes FAMILY 23401244 A 828 831 DDE ABBREVIATION 23401244 A 836 839 C60 TRIVIAL 23401244 A 912 922 fullerenes FAMILY 23401244 T 10 13 C60 TRIVIAL 23401244 T 14 24 FULLERENES FAMILY 23401244 T 58 66 p,p'-DDE SYSTEMATIC 23401262 A 1152 1161 phenytoin TRIVIAL 23401262 A 211 220 phenytoin TRIVIAL 23401262 A 263 272 Phenytoin TRIVIAL 23401262 A 630 639 phenytoin TRIVIAL 23401262 T 77 86 Phenytoin TRIVIAL 23401281 A 125 127 Cd FORMULA 23401281 A 1268 1270 Al FORMULA 23401281 A 1272 1274 Fe FORMULA 23401281 A 1280 1282 Mn FORMULA 23401281 A 129 131 Cu FORMULA 23401281 A 133 135 Pb FORMULA 23401281 A 141 143 Zn FORMULA 23401281 A 373 379 carbon SYSTEMATIC 23401281 A 525 527 Pb FORMULA 23401281 A 530 532 Cu FORMULA 23401281 A 535 537 Zn FORMULA 23401281 A 540 542 Cd FORMULA 23401281 A 737 739 Al FORMULA 23401291 A 0 10 Fatty acid FAMILY 23401291 A 247 257 β-ketoacyl SYSTEMATIC 23401291 A 258 262 acyl FAMILY 23401291 A 372 382 fatty acid FAMILY 23401291 A 683 694 Schiff base FAMILY 23401291 A 838 915 (E)-N-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methylene)hexadecan-1-amine SYSTEMATIC 23401291 T 6 17 Schiff-base FAMILY 23401303 A 1132 1138 carbon SYSTEMATIC 23401303 A 1168 1178 carboxylic SYSTEMATIC 23401303 A 1182 1190 phenolic FAMILY 23401303 A 357 363 carbon SYSTEMATIC 23401303 A 386 392 carbon SYSTEMATIC 23401303 A 433 443 pyrethroid FAMILY 23401303 A 621 632 pyrethroids FAMILY 23401303 T 31 42 pyrethroids FAMILY 23401323 A 163 166 MNG ABBREVIATION 23401323 T 16 40 maltose-neopentyl glycol SYSTEMATIC 23401323 T 45 48 MNG ABBREVIATION 23401324 A 343 368 polychlorinated biphenyls FAMILY 23401324 A 370 374 PCBs ABBREVIATION 23401324 A 396 426 polybrominated diphenyl ethers FAMILY 23401324 A 721 725 PCBs ABBREVIATION 23401324 A 730 744 organochlorine FAMILY 23401324 T 105 135 polybrominated diphenyl ethers FAMILY 23401324 T 141 155 organochlorine FAMILY 23401324 T 78 103 polychlorinated biphenyls FAMILY 23401355 A 11 14 MnO FORMULA 23401355 A 131 134 MnO FORMULA 23401355 A 167 169 Co FORMULA 23401355 A 233 235 Li FORMULA 23401355 A 391 394 MnO FORMULA 23401355 A 396 398 Mn FORMULA 23401355 A 404 408 Li2O FORMULA 23401355 A 476 478 Co FORMULA 23401355 A 48 50 Co FORMULA 23401355 A 526 528 Li FORMULA 23401355 A 602 605 MnO FORMULA 23401355 A 626 628 Co FORMULA 23401355 A 708 710 Li FORMULA 23401355 A 84 89 MnCO3 FORMULA 23401355 T 115 122 lithium SYSTEMATIC 23401355 T 28 31 MnO FORMULA 23401355 T 32 34 Co FORMULA 23401470 A 653 654 N FORMULA 23401472 A 1024 1046 5-aza-2'-deoxycytidine SYSTEMATIC 23401472 A 1048 1056 5-Aza-dC SYSTEMATIC 23401472 A 1361 1369 5-Aza-dC SYSTEMATIC 23401472 A 142 151 bilirubin TRIVIAL 23401472 A 156 161 SN-38 IDENTIFIER 23401472 A 387 396 Bisulfite SYSTEMATIC 23401472 A 433 436 CpG ABBREVIATION 23401472 A 6 9 UDP ABBREVIATION 23401602 A 162 173 fatty acids FAMILY 23401602 A 274 285 fatty acids FAMILY 23401602 A 291 304 linoleic acid TRIVIAL 23401602 A 370 383 linoleic acid TRIVIAL 23401602 A 511 524 linoleic acid TRIVIAL 23401602 A 77 90 linoleic acid TRIVIAL 23401602 T 11 24 linoleic acid TRIVIAL 23402270 A 116 127 polystyrene SYSTEMATIC 23402270 A 168 212 poly(2-aminoethylmethacrylate hydrochloride) SYSTEMATIC 23402270 A 214 219 PAEMH ABBREVIATION 23402341 A 0 14 Mefenamic acid TRIVIAL 23402341 A 1034 1041 MFA-CoA ABBREVIATION 23402341 A 1177 1186 MFA-1-O-G SYSTEMATIC 23402341 A 1331 1342 glutathione TRIVIAL 23402341 A 1344 1347 GSH ABBREVIATION 23402341 A 1387 1394 MFA-AMP ABBREVIATION 23402341 A 1417 1420 GSH ABBREVIATION 23402341 A 1453 1460 MFA-CoA ABBREVIATION 23402341 A 1468 1477 MFA-1-O-G SYSTEMATIC 23402341 A 152 176 MFA-1-O-acyl-glucuronide FAMILY 23402341 A 1535 1546 glutathione TRIVIAL 23402341 A 1547 1548 S FORMULA 23402341 A 1568 1575 MFA-AMP ABBREVIATION 23402341 A 1598 1605 MFA-GSH ABBREVIATION 23402341 A 1630 1637 MFA-CoA ABBREVIATION 23402341 A 1660 1667 MFA-GSH ABBREVIATION 23402341 A 17 20 MFA ABBREVIATION 23402341 A 1726 1735 MFA-1-O-G SYSTEMATIC 23402341 A 1768 1782 mefenamic acid TRIVIAL 23402341 A 178 187 MFA-1-O-G SYSTEMATIC 23402341 A 1811 1819 acyl-CoA ABBREVIATION 23402341 A 1914 1921 MFA-AMP ABBREVIATION 23402341 A 1926 1933 MFA-CoA ABBREVIATION 23402341 A 193 207 MFA-S-acyl-CoA FAMILY 23402341 A 1985 1988 GSH ABBREVIATION 23402341 A 209 216 MFA-CoA ABBREVIATION 23402341 A 25 40 carboxylic acid SYSTEMATIC 23402341 A 265 287 MFA-S-acyl-glutathione FAMILY 23402341 A 289 296 MFA-GSH ABBREVIATION 23402341 A 433 437 acyl FAMILY 23402341 A 494 501 MFA-GSH ABBREVIATION 23402341 A 556 559 MFA ABBREVIATION 23402341 A 592 596 acyl FAMILY 23402341 A 616 625 mefenamyl TRIVIAL 23402341 A 626 635 adenylate TRIVIAL 23402341 A 637 644 MFA-AMP ABBREVIATION 23402341 A 692 695 MFA ABBREVIATION 23402341 A 773 780 MFA-AMP ABBREVIATION 23402341 A 824 831 MFA-AMP ABBREVIATION 23402341 A 918 925 MFA-GSH ABBREVIATION 23402341 T 24 28 acyl FAMILY 23402341 T 29 38 adenylate TRIVIAL 23402341 T 60 74 mefenamic Acid TRIVIAL 23402364 A 1015 1027 Nitric oxide SYSTEMATIC 23402364 A 1040 1045 VP-16 IDENTIFIER 23402364 A 1198 1210 nitric oxide SYSTEMATIC 23402364 A 1254 1259 VP-16 IDENTIFIER 23402364 A 1307 1312 (·)NO FORMULA 23402364 A 1361 1366 VP-16 IDENTIFIER 23402364 A 1476 1481 (·)NO FORMULA 23402364 A 1535 1540 VP-16 IDENTIFIER 23402364 A 1578 1583 VP-16 IDENTIFIER 23402364 A 187 192 (·)NO FORMULA 23402364 A 286 295 Etoposide TRIVIAL 23402364 A 297 302 VP-16 IDENTIFIER 23402364 A 328 333 VP-16 IDENTIFIER 23402364 A 365 370 VP-16 IDENTIFIER 23402364 A 374 379 (·)NO FORMULA 23402364 A 457 485 o-quinone- and nitroso-VP-16 MULTIPLE 23402364 A 46 58 nitric oxide SYSTEMATIC 23402364 A 534 544 chloroform TRIVIAL 23402364 A 552 558 oxygen SYSTEMATIC 23402364 A 60 65 (·)NO FORMULA 23402364 A 620 625 VP-16 IDENTIFIER 23402364 A 650 655 VP-16 IDENTIFIER 23402364 A 683 687 H2O2 FORMULA 23402364 A 713 718 (·)NO FORMULA 23402364 A 722 732 chloroform TRIVIAL 23402364 A 752 758 oxygen SYSTEMATIC 23402364 A 796 801 VP-16 IDENTIFIER 23402364 A 890 897 phenoxy SYSTEMATIC 23402364 A 914 923 o-quinone SYSTEMATIC 23402364 A 927 932 VP-16 IDENTIFIER 23402364 A 954 963 nitroxide SYSTEMATIC 23402364 A 965 973 iminoxyl SYSTEMATIC 23402364 A 985 999 nitrogen oxide SYSTEMATIC 23402364 T 65 74 etoposide TRIVIAL 23402364 T 76 85 VP-16,213 IDENTIFIER 23402364 T 8 20 nitric oxide SYSTEMATIC 23402423 A 288 292 CdTe FORMULA 23402423 A 378 382 CdTe FORMULA 23402423 A 466 470 CdTe FORMULA 23402423 A 678 682 CdTe FORMULA 23402423 A 794 803 monothiol FAMILY 23402636 A 216 232 γ-linolenic acid TRIVIAL 23402636 A 252 259 sterols FAMILY 23402636 A 401 412 cholesterol TRIVIAL 23402636 A 417 429 triglyceride FAMILY 23402636 A 488 499 cholesterol TRIVIAL 23402638 A 107 115 iron(II) SYSTEMATIC 23402638 A 202 216 amino alcohols FAMILY 23402638 A 296 304 iron(II) SYSTEMATIC 23402638 A 361 375 iron nitrenoid FAMILY 23402638 A 43 50 olefins FAMILY 23402638 A 73 86 hydroxylamine SYSTEMATIC 23402638 T 0 8 Iron(II) SYSTEMATIC 23402638 T 56 63 olefins FAMILY 23402638 T 84 98 hydroxylamines FAMILY 23402647 A 185 202 diethylene glycol SYSTEMATIC 23402647 A 224 244 lanthanide chlorides FAMILY 23402647 A 266 273 1-Butyl SYSTEMATIC 23402647 A 275 312 2-methylimidazolium tetrafluoroborate SYSTEMATIC 23402647 A 317 325 fluoride SYSTEMATIC 23402647 A 460 464 GdF3 FORMULA 23402647 A 49 62 europium(III) SYSTEMATIC 23402647 A 628 630 Eu FORMULA 23402647 A 631 635 GdF3 FORMULA 23402647 A 69 93 gadolinium(III) fluoride SYSTEMATIC 23402647 A 913 915 Eu FORMULA 23402647 A 916 920 GdF3 FORMULA 23402647 A 95 97 Eu FORMULA 23402647 A 98 102 GdF3 FORMULA 23402647 T 87 89 Eu FORMULA 23402647 T 90 94 GdF3 FORMULA 23402855 A 1214 1228 pheophorbide a TRIVIAL 23402855 A 1233 1245 pheophytin a TRIVIAL 23402855 A 1354 1356 NO FORMULA 23402855 A 166 178 nitric oxide SYSTEMATIC 23402855 A 180 182 NO FORMULA 23402855 A 206 218 nitric oxide SYSTEMATIC 23402855 A 542 544 NO FORMULA 23402855 A 591 597 CH2Cl2 FORMULA 23402855 A 694 700 CH2Cl2 FORMULA 23402855 A 774 783 porphyrin FAMILY 23402855 A 797 811 pheophorbide a TRIVIAL 23402855 A 816 828 pheophytin a TRIVIAL 23402855 A 856 867 fucoxanthin TRIVIAL 23402855 A 884 895 fucoxanthin TRIVIAL 23402855 A 897 911 pheophorbide a TRIVIAL 23402855 A 916 928 pheophytin a TRIVIAL 23402855 A 982 984 NO FORMULA 23402855 T 108 120 pheophytin a TRIVIAL 23402855 T 89 103 pheophorbide a TRIVIAL 23402859 A 0 12 Chlorpyrifos TRIVIAL 23402859 A 1008 1023 malondialdehyde TRIVIAL 23402859 A 1034 1046 chlorpyrifos TRIVIAL 23402859 A 1091 1099 catechin TRIVIAL 23402859 A 1100 1112 chlorpyrifos TRIVIAL 23402859 A 1131 1140 quercetin TRIVIAL 23402859 A 1141 1153 chlorpyrifos TRIVIAL 23402859 A 1206 1214 catechin TRIVIAL 23402859 A 1219 1228 quercetin TRIVIAL 23402859 A 1339 1351 chlorpyrifos TRIVIAL 23402859 A 1415 1423 catechin TRIVIAL 23402859 A 1424 1436 chlorpyrifos TRIVIAL 23402859 A 1441 1450 quercetin TRIVIAL 23402859 A 1451 1463 chlorpyrifos TRIVIAL 23402859 A 1519 1527 catechin TRIVIAL 23402859 A 1532 1541 quercetin TRIVIAL 23402859 A 1563 1575 chlorpyrifos TRIVIAL 23402859 A 188 196 catechin TRIVIAL 23402859 A 19 35 organophosphorus FAMILY 23402859 A 198 207 quercetin TRIVIAL 23402859 A 209 221 chlorpyrifos TRIVIAL 23402859 A 223 231 catechin TRIVIAL 23402859 A 232 244 chlorpyrifos TRIVIAL 23402859 A 246 255 quercetin TRIVIAL 23402859 A 256 268 chlorpyrifos TRIVIAL 23402859 A 350 359 aspartate TRIVIAL 23402859 A 378 385 alanine TRIVIAL 23402859 A 426 433 lactate FAMILY 23402859 A 449 461 trigliceride FAMILY 23402859 A 469 480 cholesterol TRIVIAL 23402859 A 512 522 superoxide TRIVIAL 23402859 A 544 555 glutathione TRIVIAL 23402859 A 568 579 glutathione TRIVIAL 23402859 A 609 624 malondialdehyde TRIVIAL 23402859 A 840 848 catechin TRIVIAL 23402859 A 853 862 quercetin TRIVIAL 23402859 T 0 12 Chlorpyrifos TRIVIAL 23402859 T 78 87 quercetin TRIVIAL 23402859 T 92 100 catechin TRIVIAL 23402860 A 0 11 (-)-Cubebin TRIVIAL 23402860 A 1016 1019 CUB ABBREVIATION 23402860 A 1209 1212 DXR ABBREVIATION 23402860 A 1216 1219 URE ABBREVIATION 23402860 A 13 16 CUB ABBREVIATION 23402860 A 193 204 doxorubicin TRIVIAL 23402860 A 206 209 DXR ABBREVIATION 23402860 A 23 29 lignan FAMILY 23402860 A 231 239 urethane TRIVIAL 23402860 A 241 244 URE ABBREVIATION 23402860 A 326 329 CUB ABBREVIATION 23402860 A 417 420 CUB ABBREVIATION 23402860 A 474 477 DXR ABBREVIATION 23402860 A 579 582 CUB ABBREVIATION 23402860 A 819 822 CUB ABBREVIATION 23402860 A 839 842 URE ABBREVIATION 23402860 T 49 60 (-)-cubebin TRIVIAL 23402938 A 1162 1168 IR3535 IDENTIFIER 23402938 A 1176 1182 IR3535 IDENTIFIER 23402938 A 1279 1285 IR3535 IDENTIFIER 23402938 A 1333 1339 IR3535 IDENTIFIER 23402938 A 1448 1454 IR3535 IDENTIFIER 23402938 A 1472 1478 IR3535 IDENTIFIER 23402938 A 1527 1533 IR3535 IDENTIFIER 23402938 A 1613 1619 IR3535 IDENTIFIER 23402938 A 194 200 IR3535 IDENTIFIER 23402938 A 225 231 IR3535 IDENTIFIER 23402938 A 338 344 IR3535 IDENTIFIER 23402938 A 373 379 IR3535 IDENTIFIER 23402938 A 470 476 IR3535 IDENTIFIER 23402938 A 53 59 IR3535 IDENTIFIER 23402938 A 541 547 IR3535 IDENTIFIER 23402938 A 865 871 IR3535 IDENTIFIER 23402938 A 879 885 IR3535 IDENTIFIER 23402938 A 952 958 IR3535 IDENTIFIER 23402938 A 992 998 IR3535 IDENTIFIER 23402938 T 61 67 IR3535 IDENTIFIER 23402971 A 113 125 benztriazole SYSTEMATIC 23402971 A 99 112 benzimidazole SYSTEMATIC 23402971 T 80 93 benzimidazole SYSTEMATIC 23402971 T 98 110 benztriazole SYSTEMATIC 23402972 A 1043 1052 ritonavir TRIVIAL 23402972 A 1117 1126 indinavir TRIVIAL 23402972 A 504 513 indinavir TRIVIAL 23402972 A 640 649 indinavir TRIVIAL 23402972 A 783 792 indinavir TRIVIAL 23402972 A 900 909 indinavir TRIVIAL 23402972 T 26 35 indinavir TRIVIAL 23403080 A 13 35 hydrazino-1,3-thiazole SYSTEMATIC 23403080 A 132 139 indolyl SYSTEMATIC 23403080 A 161 170 hydrazone FAMILY 23403080 A 303 319 (S)-2-aminoethyl SYSTEMATIC 23403080 A 333 341 thiazole SYSTEMATIC 23403080 T 45 69 2-hydrazino-1,3-thiazole SYSTEMATIC 23403395 A 1118 1127 docetaxel TRIVIAL 23403395 A 1128 1137 cisplatin TRIVIAL 23403395 A 135 139 TPGS ABBREVIATION 23403395 A 141 150 cisplatin TRIVIAL 23403395 A 198 207 cisplatin TRIVIAL 23403395 A 209 218 docetaxel TRIVIAL 23403395 A 362 384 poly(lactic acid)-TPGS SYSTEMATIC 23403395 A 386 394 PLA-TPGS ABBREVIATION 23403395 A 400 408 carboxyl SYSTEMATIC 23403395 A 426 430 TPGS ABBREVIATION 23403395 A 432 436 TPGS ABBREVIATION 23403395 A 437 441 COOH FORMULA 23403395 A 602 611 docetaxel TRIVIAL 23403395 A 619 628 cisplatin TRIVIAL 23403395 A 75 133 d-alpha-tocopheryl-co-poly(ethylene glycol) 1000 succinate SYSTEMATIC 23403395 A 823 831 Taxotere TRIVIAL 23403395 A 837 846 cisplatin TRIVIAL 23403395 A 869 878 docetaxel TRIVIAL 23403395 A 886 895 cisplatin TRIVIAL 23403395 A 968 977 docetaxel TRIVIAL 23403395 A 985 994 cisplatin TRIVIAL 23403395 T 24 33 docetaxel TRIVIAL 23403395 T 35 44 cisplatin TRIVIAL 23403395 T 62 71 vitamin E FAMILY 23403395 T 72 76 TPGS ABBREVIATION 23403395 T 77 86 cisplatin TRIVIAL 23403537 A 103 116 tetrapeptides FAMILY 23403537 T 39 51 tetrapeptide FAMILY 23404062 A 1211 1219 SCH23390 IDENTIFIER 23404062 A 1240 1249 sulpiride TRIVIAL 23404062 A 1271 1279 naloxone TRIVIAL 23404062 A 1377 1386 sulpiride TRIVIAL 23404062 A 1392 1400 naloxone TRIVIAL 23404062 A 362 370 dopamine TRIVIAL 23404062 A 700 708 SCH23390 IDENTIFIER 23404062 A 795 803 naloxone TRIVIAL 23404062 A 874 883 sulpiride TRIVIAL 23404062 T 46 54 dopamine TRIVIAL 23404443 A 1384 1392 arginine TRIVIAL 23404443 A 1534 1542 arginine TRIVIAL 23404443 A 888 895 glucose TRIVIAL 23404443 A 897 904 glucose TRIVIAL 23404443 A 911 918 glucose TRIVIAL 23404443 A 934 941 glucose TRIVIAL 23404443 A 966 974 arginine TRIVIAL 23404458 A 1001 1003 Ca FORMULA 23404458 A 1004 1006 Zn FORMULA 23404458 A 1011 1013 Ca FORMULA 23404458 A 1014 1016 Cu FORMULA 23404458 A 1053 1060 calcium SYSTEMATIC 23404458 A 1320 1342 calcium hydroxyapatite SYSTEMATIC 23404458 A 1347 1358 cholesterol TRIVIAL 23404458 A 1572 1574 Mg FORMULA 23404458 A 1576 1577 P FORMULA 23404458 A 1582 1584 Ca FORMULA 23404458 A 1702 1724 calcium hydroxyapatite SYSTEMATIC 23404458 A 1729 1740 cholesterol TRIVIAL 23404458 A 686 688 Ni FORMULA 23404458 A 690 692 Pt FORMULA 23404458 A 694 696 Hg FORMULA 23404458 A 698 700 Sn FORMULA 23404458 A 702 704 Pb FORMULA 23404458 A 706 707 W FORMULA 23404458 A 709 711 Au FORMULA 23404458 A 713 715 Al FORMULA 23404458 A 717 719 Si FORMULA 23404458 A 757 759 Ca FORMULA 23404458 A 761 763 Sr FORMULA 23404458 A 765 767 Cr FORMULA 23404458 A 769 770 P FORMULA 23404458 A 859 861 Mg FORMULA 23404458 A 863 865 Ca FORMULA 23404458 A 869 870 P FORMULA 23404739 A 0 12 Sipholenol A TRIVIAL 23404739 A 1063 1072 carbamate FAMILY 23404739 A 1100 1143 19,20-anhydrosipholenol A 4β-benzoate ester SYSTEMATIC 23404739 A 1197 1205 tyrosine TRIVIAL 23404739 A 1351 1361 sipholanes FAMILY 23404739 A 1498 1530 sipholenol A 4β-4-chlorobenzoate SYSTEMATIC 23404739 A 1535 1580 19,20-anhydrosipholenol A 4β-4-chlorobenzoate SYSTEMATIC 23404739 A 1581 1587 esters FAMILY 23404739 A 16 36 sipholane triterpene FAMILY 23404739 A 1823 1845 sipholenol A succinate TRIVIAL 23404739 A 1924 1947 sipholane triterpenoids FAMILY 23404739 A 235 247 sipholenol A TRIVIAL 23404739 A 372 384 Sipholenol A TRIVIAL 23404739 A 389 402 sipholenone A TRIVIAL 23404739 A 593 598 ester FAMILY 23404739 A 600 605 ether SYSTEMATIC 23404739 A 607 612 oxime SYSTEMATIC 23404739 A 618 627 carbamate FAMILY 23404739 A 771 803 Sipholenol A 4β-4-chlorobenzoate SYSTEMATIC 23404739 A 808 853 19,20-anhydrosipholenol A 4β-4-chlorobenzoate SYSTEMATIC 23404739 A 854 860 esters FAMILY 23404739 T 23 33 triterpene FAMILY 23404739 T 34 45 sipholenols FAMILY 23404750 A 991 994 Phe FORMULA 23404750 T 74 77 Phe FORMULA 23405943 A 147 160 4-aminophenol SYSTEMATIC 23405943 A 165 175 salicylate SYSTEMATIC 23405943 A 319 348 1,1-diphenyl-2-picrylhydrazyl SYSTEMATIC 23405943 A 365 384 thiobarbituric acid SYSTEMATIC 23405943 A 444 450 Fe(2+) FORMULA 23405943 A 455 468 ascorbic acid TRIVIAL 23405943 A 562 576 salicylic acid TRIVIAL 23405943 A 588 595 benzoyl SYSTEMATIC 23405943 A 645 656 paracetamol TRIVIAL 23405943 T 25 38 4-aminophenol SYSTEMATIC 23405943 T 43 53 salicylate SYSTEMATIC 23406166 A 120 152 2'-hydroxy-3,4-dimethoxychalcone SYSTEMATIC 23406166 A 158 169 biochanin A TRIVIAL 23406166 A 178 212 kaempferol-3-O-β-d-glucopyranoside SYSTEMATIC 23406166 A 29 77 3',4'-dimethoxy-7-(γ,γ-dimethylallyloxy)flavonol SYSTEMATIC 23406166 A 6 27 O-prenylated flavonol FAMILY 23406166 T 6 27 O-prenylated flavonol FAMILY 23406277 A 1152 1161 ruthenium SYSTEMATIC 23406277 A 12 31 poly(vinyl alcohol) SYSTEMATIC 23406277 A 33 36 PVA ABBREVIATION 23406277 A 450 453 PVA ABBREVIATION 23406277 A 541 544 PVA ABBREVIATION 23406277 A 627 660 [μ-(11,11'-bidppz)(phen)4Ru2](4+) FORMULA 23406277 A 765 774 ruthenium SYSTEMATIC 23406277 T 26 39 ruthenium(II) SYSTEMATIC 23406348 A 1004 1013 methylene SYSTEMATIC 23406348 A 1024 1040 n-butyl acrylate SYSTEMATIC 23406348 A 1370 1378 hydrogen SYSTEMATIC 23406348 A 146 161 alkyl acrylates FAMILY 23406348 A 163 198 methyl, ethyl, and n-butyl acrylate MULTIPLE 23406348 A 1702 1710 hydrogen SYSTEMATIC 23406348 A 1755 1761 methyl SYSTEMATIC 23406348 A 1771 1786 methyl acrylate SYSTEMATIC 23406348 A 1791 1800 methylene SYSTEMATIC 23406348 A 1813 1837 ethyl (n-butyl) acrylate SYSTEMATIC 23406348 A 880 888 hydrogen SYSTEMATIC 23406348 A 928 934 methyl SYSTEMATIC 23406348 A 944 959 methyl acrylate SYSTEMATIC 23406348 A 965 974 methylene SYSTEMATIC 23406348 A 984 998 ethyl acrylate SYSTEMATIC 23406348 T 97 112 alkyl acrylates FAMILY 23406429 A 167 187 triaryl sulfonamides FAMILY 23406429 A 281 288 triaryl FAMILY 23406429 T 6 25 triaryl sulfonamide FAMILY 23406469 A 137 143 silica TRIVIAL 23406469 A 287 304 protoporphyrin IX TRIVIAL 23406469 A 306 310 PpIX ABBREVIATION 23406469 A 890 894 PpIX ABBREVIATION 23406469 T 95 101 silica TRIVIAL 23407893 A 0 9 Imogolite TRIVIAL 23407893 A 1093 1102 imogolite TRIVIAL 23407893 A 1279 1287 silicate FAMILY 23407893 A 1291 1300 phosphate SYSTEMATIC 23407893 A 1302 1311 phosphite SYSTEMATIC 23407893 A 131 147 aluminogermanate TRIVIAL 23407893 A 1313 1321 arsenate SYSTEMATIC 23407893 A 1326 1334 arsenite SYSTEMATIC 23407893 A 217 222 H3PO4 FORMULA 23407893 A 224 229 H3PO3 FORMULA 23407893 A 231 237 H3AsO3 FORMULA 23407893 A 239 245 H3AsO4 FORMULA 23407893 A 279 288 imogolite TRIVIAL 23407893 A 29 44 aluminosilicate TRIVIAL 23407893 A 429 438 imogolite TRIVIAL 23407893 A 548 564 aluminogermanate TRIVIAL 23407893 A 588 596 silicate FAMILY 23407893 A 620 629 germanate SYSTEMATIC 23407893 A 656 664 silicate FAMILY 23407893 A 691 700 phosphate SYSTEMATIC 23407893 A 702 711 phosphite SYSTEMATIC 23407893 A 713 721 arsenate SYSTEMATIC 23407893 A 726 734 arsenite SYSTEMATIC 23407893 A 748 757 imogolite TRIVIAL 23407893 A 942 951 imogolite TRIVIAL 23407893 T 0 9 Imogolite TRIVIAL 23407893 T 108 115 arsenic SYSTEMATIC 23407893 T 92 103 phosphorous SYSTEMATIC 23408116 A 0 13 Acetaminophen TRIVIAL 23408116 A 113 116 UDP ABBREVIATION 23408116 A 1254 1267 acetaminophen TRIVIAL 23408116 A 1618 1631 acetaminophen TRIVIAL 23408116 A 1827 1840 acetaminophen TRIVIAL 23408116 A 1899 1912 acetaminophen TRIVIAL 23408116 A 200 213 acetaminophen TRIVIAL 23408116 A 271 284 acetaminophen TRIVIAL 23408116 A 355 368 acetaminophen TRIVIAL 23408116 A 422 435 acetaminophen TRIVIAL 23408116 A 653 666 acetaminophen TRIVIAL 23408116 A 733 746 acetaminophen TRIVIAL 23408116 A 799 812 acetaminophen TRIVIAL 23408116 A 99 112 acetaminophen TRIVIAL 23408116 T 114 127 Acetaminophen TRIVIAL 23408116 T 235 248 Acetaminophen TRIVIAL 23408116 T 4 7 UDP ABBREVIATION 23408270 A 1070 1090 (+)-limonene epoxide SYSTEMATIC 23408270 A 1205 1225 (+)-limonene epoxide SYSTEMATIC 23408270 A 243 255 praziquantel TRIVIAL 23408270 A 275 287 praziquantel TRIVIAL 23408270 A 490 510 (+)-Limonene epoxide SYSTEMATIC 23408270 A 837 857 (+)-limonene epoxide SYSTEMATIC 23408270 A 943 955 praziquantel TRIVIAL 23408270 T 46 66 (+)-limonene epoxide SYSTEMATIC 23408434 A 1183 1189 Ca(2+) FORMULA 23408434 A 1361 1367 Ca(2+) FORMULA 23408434 T 29 36 calcium SYSTEMATIC 23408851 A 1285 1286 N FORMULA 23408851 A 1337 1338 C FORMULA 23408851 A 291 301 amino acid FAMILY 23409716 A 507 516 capsaicin TRIVIAL 23409716 A 520 527 menthol TRIVIAL 23409716 A 605 613 SB705498 IDENTIFIER 23409716 A 615 621 JTS653 IDENTIFIER 23409716 A 623 634 JNJ17203212 IDENTIFIER 23409716 A 636 640 AP18 IDENTIFIER 23409716 A 642 649 A967079 IDENTIFIER 23409716 A 651 669 Chembridge-5861528 IDENTIFIER 23409719 A 0 20 Farnesyl diphosphate SYSTEMATIC 23409719 A 122 136 sesquiterpenes FAMILY 23409719 A 183 186 FPP ABBREVIATION 23409719 A 209 219 isoprenoid FAMILY 23409719 A 22 25 FPP ABBREVIATION 23409719 A 280 283 FPP ABBREVIATION 23409719 A 430 433 FPP ABBREVIATION 23409719 A 582 585 FPP ABBREVIATION 23409719 A 632 643 aryl azides FAMILY 23409719 A 645 670 diazotrifluoropropionates FAMILY 23409719 A 675 688 benzophenones FAMILY 23409719 T 129 139 isoprenoid FAMILY 23409719 T 23 43 farnesyl diphosphate SYSTEMATIC 23409719 T 56 67 isoprenoids FAMILY 23409765 A 1007 1020 phenylalanine TRIVIAL 23409765 A 1049 1057 pyruvate TRIVIAL 23409765 A 443 458 porphobilinogen TRIVIAL 23409842 A 1230 1233 Arg FORMULA 23409842 A 394 399 (13)C FORMULA 23409842 A 401 406 (15)N FORMULA 23409842 A 429 448 polyethylene glycol SYSTEMATIC 23409842 A 577 581 (1)H FORMULA 23409842 A 582 587 (15)N FORMULA 23409842 A 711 715 (1)H FORMULA 23409842 A 773 787 amide nitrogen SYSTEMATIC 23409842 A 810 814 (1)H FORMULA 23409925 A 253 266 carboxymethyl SYSTEMATIC 23409925 A 441 447 folate TRIVIAL 23409925 A 500 506 folate TRIVIAL 23409925 A 548 552 5-FU SYSTEMATIC 23409925 A 665 669 5-FU SYSTEMATIC 23409925 A 701 705 FITC ABBREVIATION 23409925 A 78 91 carboxymethyl SYSTEMATIC 23409925 T 16 29 carboxymethyl SYSTEMATIC 23409925 T 95 101 folate TRIVIAL 23409952 A 0 5 Azide SYSTEMATIC 23409952 A 1034 1045 metal azide FAMILY 23409952 A 1239 1243 DMSO ABBREVIATION 23409952 A 185 190 azide SYSTEMATIC 23409952 A 235 252 dimethylsulfoxide SYSTEMATIC 23409952 A 254 258 DMSO ABBREVIATION 23409952 A 266 271 azide SYSTEMATIC 23409952 A 465 470 azide SYSTEMATIC 23409952 A 498 502 LiN3 FORMULA 23409952 A 504 508 NaN3 FORMULA 23409952 A 510 515 NH4N3 FORMULA 23409952 A 517 524 MgN3(+) FORMULA 23409952 A 530 537 CaN3(+) FORMULA 23409952 A 542 546 DMSO ABBREVIATION 23409952 A 582 593 metal azide FAMILY 23409952 A 661 666 azide SYSTEMATIC 23409952 A 824 829 azide SYSTEMATIC 23409952 A 894 899 azide SYSTEMATIC 23409952 A 924 935 metal azide FAMILY 23409952 T 23 34 metal azide FAMILY 23409952 T 48 65 dimethylsulfoxide SYSTEMATIC 23410078 A 198 208 pyrimidine SYSTEMATIC 23410078 A 209 219 diterpenes FAMILY 23410078 A 231 265 axistatins 1 (1), 2 (2), and 3 (3) MULTIPLE 23410078 A 305 315 formamides FAMILY 23410078 A 326 337 agelasine F TRIVIAL 23410078 A 507 521 Axistatins 1-3 MULTIPLE 23410078 A 529 538 formamide SYSTEMATIC 23410078 A 546 557 agelasine F TRIVIAL 23410078 T 28 42 axistatins 1-3 MULTIPLE 23410105 A 388 393 X-NO2 FAMILY 23410105 A 693 698 nitro SYSTEMATIC 23410105 A 77 82 nitro SYSTEMATIC 23410168 A 668 689 phenylaminopyrimidine SYSTEMATIC 23410168 A 691 704 anthracycline FAMILY 23410168 A 709 722 naphthalimide FAMILY 23410172 A 0 16 Arachidonic acid TRIVIAL 23410172 A 1068 1071 ARA ABBREVIATION 23410172 A 1250 1260 eicosanoid FAMILY 23410172 A 18 21 ARA ABBREVIATION 23410172 A 640 648 oxylipin FAMILY 23410172 A 699 702 ARA ABBREVIATION 23410172 A 812 815 ARA ABBREVIATION 23410634 A 1085 1096 glutathione TRIVIAL 23410634 A 136 142 oxygen SYSTEMATIC 23410634 A 603 612 menadione TRIVIAL 23410634 A 614 631 hydrogen peroxide SYSTEMATIC 23410634 A 636 660 tert-butyl hydroperoxide SYSTEMATIC 23410634 A 738 746 carbonyl FAMILY 23410745 A 712 723 Cholesterol TRIVIAL 23410745 A 947 957 creatinine TRIVIAL 23410745 A 962 971 uric acid TRIVIAL 23411075 A 12 23 arylglycine FAMILY 23411075 A 317 323 icilin TRIVIAL 23411075 T 0 11 Arylglycine FAMILY 23411076 A 1083 1090 (99m)Tc FORMULA 23411076 A 117 119 Re FORMULA 23411076 A 139 146 (99m)Tc FORMULA 23411076 A 148 168 2-arylbenzothiazoles FAMILY 23411076 A 258 260 Re FORMULA 23411076 A 339 346 (99m)Tc FORMULA 23411076 A 475 498 Re 2-arylbenzothiazoles FAMILY 23411076 A 50 57 (99m)Tc FORMULA 23411076 A 683 704 2-phenylbenzothiazole FAMILY 23411076 A 786 809 Re 2-arylbenzothiazoles FAMILY 23411076 A 954 977 Re 2-arylbenzothiazoles FAMILY 23411076 T 57 85 rhenium 2-arylbenzothiazoles FAMILY 23411079 A 1013 1015 NO FORMULA 23411079 A 358 367 steroidal FAMILY 23411079 A 379 390 longipenane TRIVIAL 23411079 A 396 432 longipenane 26-O-β-d-glucopyranoside SYSTEMATIC 23411079 A 441 534 neogitogenin 3-O-α-l-rhamnopyranosyl-(1→2)-O-[β-d-glucopyranosyl-(1→4)]-β-d-galactopyranoside SYSTEMATIC 23411079 A 561 579 steroidal saponins FAMILY 23411079 A 799 811 nitric oxide SYSTEMATIC 23411079 A 813 815 NO FORMULA 23411079 T 0 9 Steroidal FAMILY 23411079 T 89 101 nitric oxide SYSTEMATIC 23411082 A 15 28 Hypocrellin A TRIVIAL 23411082 A 168 174 Al(3+) FORMULA 23411082 A 236 242 oxygen SYSTEMATIC 23411082 A 244 249 (1)O2 FORMULA 23411082 A 339 345 Al(3+) FORMULA 23411082 A 34 40 Al(3+) FORMULA 23411082 T 16 29 Hypocrellin A TRIVIAL 23411082 T 35 39 Al3+ FORMULA 23411168 A 439 444 diene SYSTEMATIC 23411168 A 494 497 AOT ABBREVIATION 23411168 A 502 511 isooctane SYSTEMATIC 23411168 A 557 570 linoleic acid TRIVIAL 23411168 A 618 621 AOT ABBREVIATION 23411168 A 693 696 AOT ABBREVIATION 23411168 A 697 706 isooctane SYSTEMATIC 23411168 A 792 795 AOT ABBREVIATION 23411168 A 809 812 AOT ABBREVIATION 23411168 T 73 76 AOT ABBREVIATION 23411168 T 77 86 isooctane SYSTEMATIC 23411173 A 1045 1052 phytate TRIVIAL 23411173 A 1054 1061 oxalate SYSTEMATIC 23411173 A 1066 1073 saponin FAMILY 23411173 A 271 284 carbohydrates FAMILY 23411173 A 366 374 Palmitic TRIVIAL 23411173 A 383 390 stearic TRIVIAL 23411173 A 399 404 oleic TRIVIAL 23411173 A 417 425 linoleic TRIVIAL 23411173 A 511 518 oxalate SYSTEMATIC 23411173 A 534 541 saponin FAMILY 23411173 A 580 587 phytate TRIVIAL 23411175 A 252 262 polyphenol FAMILY 23411175 A 306 320 polyacrylamide SYSTEMATIC 23411175 A 351 362 polyphenols FAMILY 23411175 A 4 15 polyphenols FAMILY 23411175 A 623 634 polyphenols FAMILY 23411175 T 43 53 polyphenol FAMILY 23411177 A 533 570 eicosapentaenoic-docosahexaenoic acid MULTIPLE 23411177 A 602 629 polyunsaturated fatty acids FAMILY 23411177 A 669 690 saturated fatty acids FAMILY 23411177 A 755 773 cholesterol oxides FAMILY 23411177 A 789 807 cholesterol oxides FAMILY 23411178 A 111 116 2-NAP SYSTEMATIC 23411178 A 260 263 KOH FORMULA 23411178 A 590 595 2-NAP SYSTEMATIC 23411178 A 600 605 1-HOP SYSTEMATIC 23411178 A 701 706 2-NAP SYSTEMATIC 23411178 A 71 86 l-hydroxypyrene SYSTEMATIC 23411178 A 878 883 2-NAP SYSTEMATIC 23411178 A 88 93 1-HOP SYSTEMATIC 23411178 A 99 109 2-naphthol SYSTEMATIC 23411178 T 30 40 2-naphthol SYSTEMATIC 23411178 T 45 60 1-hydroxypyrene SYSTEMATIC 23411181 A 397 417 furanosesquiterpenes FAMILY 23411181 A 513 516 MTT ABBREVIATION 23411181 A 553 557 DPPH ABBREVIATION 23411181 A 559 563 ABTS ABBREVIATION 23411181 A 904 918 Isofuranodiene SYSTEMATIC 23411181 A 923 955 1β-acetoxyfuranoeudesm-4(15)-ene SYSTEMATIC 23411181 T 60 80 furanosesquiterpenes FAMILY 23411182 A 422 454 ascorbic, citric and malic acids MULTIPLE 23411182 A 561 574 ascorbic acid TRIVIAL 23411182 A 591 593 Ni FORMULA 23411182 A 598 600 Ag FORMULA 23411182 A 613 615 Ag FORMULA 23411182 A 620 622 Ir FORMULA 23411182 A 709 731 citric and malic acids MULTIPLE 23411182 A 765 767 Ir FORMULA 23411182 A 769 771 Rh FORMULA 23411182 A 773 775 Pt FORMULA 23411182 A 777 779 Ag FORMULA 23411182 A 784 786 Cu FORMULA 23411183 A 92 103 polyphenols FAMILY 23411184 A 201 213 acetonitrile SYSTEMATIC 23411184 A 472 484 acetonitrile SYSTEMATIC 23411184 A 656 667 avermectins FAMILY 23411185 A 0 4 Iron SYSTEMATIC 23411185 A 101 105 iron SYSTEMATIC 23411185 A 122 126 iron SYSTEMATIC 23411185 A 614 618 iron SYSTEMATIC 23411185 A 623 627 zinc SYSTEMATIC 23411185 T 68 72 iron SYSTEMATIC 23411189 A 185 192 Fe(III) FORMULA 23411189 A 220 227 Fe(III) FORMULA 23411189 A 234 238 EDTA ABBREVIATION 23411189 A 334 341 Citrate TRIVIAL 23411189 A 346 352 malate TRIVIAL 23411189 A 399 406 Fe(III) FORMULA 23411189 A 477 481 EDTA ABBREVIATION 23411189 A 519 523 EDTA ABBREVIATION 23411189 A 63 67 EDTA ABBREVIATION 23411189 A 761 765 EDTA ABBREVIATION 23411189 A 92 96 EDTA ABBREVIATION 23411189 T 17 48 ethylenediaminetetraacetic acid SYSTEMATIC 23411191 A 0 12 Ginsenosides FAMILY 23411191 A 1019 1033 ginsenoside Re TRIVIAL 23411191 A 1034 1040 lysine TRIVIAL 23411191 A 1123 1135 ginsenosides FAMILY 23411191 A 241 255 Ginsenoside Re TRIVIAL 23411191 A 274 279 triol SYSTEMATIC 23411191 A 285 297 ginsenosides FAMILY 23411191 A 387 392 sugar FAMILY 23411191 A 405 412 carbons FAMILY 23411191 A 533 547 ginsenoside Re TRIVIAL 23411191 A 572 586 Ginsenoside Re TRIVIAL 23411191 A 619 661 ginsenosides, namely Rg(2), Rg(6) and F(4) MULTIPLE 23411191 A 722 736 ginsenoside Re TRIVIAL 23411191 A 737 743 lysine TRIVIAL 23411191 A 84 88 diol SYSTEMATIC 23411191 A 913 921 glucosyl TRIVIAL 23411191 A 94 106 ginsenosides FAMILY 23411191 A 944 950 carbon SYSTEMATIC 23411191 A 957 971 ginsenoside Re TRIVIAL 23411191 A 976 982 lysine TRIVIAL 23411191 T 50 64 ginsenoside Re TRIVIAL 23411191 T 65 71 lysine TRIVIAL 23411194 A 19 30 quinic acid TRIVIAL 23411194 A 917 928 quinic acid TRIVIAL 23411195 A 184 210 polyunsaturated fatty acid FAMILY 23411195 A 212 216 PUFA ABBREVIATION 23411195 A 544 548 PUFA ABBREVIATION 23411199 A 101 112 polyphenols FAMILY 23411199 A 1196 1207 polyphenols FAMILY 23411199 A 241 253 anthocyanins FAMILY 23411199 A 426 437 polyphenols FAMILY 23411199 A 442 454 anthocyanins FAMILY 23411199 A 459 468 flavonols FAMILY 23411199 A 472 492 hydroxybenzoic acids FAMILY 23411199 A 497 518 hydroxycinnamic acids FAMILY 23411199 A 522 532 flavanones FAMILY 23411199 A 536 552 dihydrochalcones FAMILY 23411199 A 556 568 flavan-3-ols FAMILY 23411199 A 575 584 stilbenes FAMILY 23411199 A 600 610 polyphenol FAMILY 23411199 A 658 668 polyphenol FAMILY 23411199 A 720 731 polyphenols FAMILY 23411199 A 783 794 polyphenols FAMILY 23411199 A 881 892 polyphenols FAMILY 23411199 T 44 55 polyphenols FAMILY 23411206 A 165 182 ammonium sulphate SYSTEMATIC 23411206 A 184 197 dicyandiamide SYSTEMATIC 23411206 A 199 207 melamine TRIVIAL 23411206 A 213 217 urea TRIVIAL 23411208 A 179 191 α-tocopherol TRIVIAL 23411208 A 234 243 vitamin E FAMILY 23411208 A 245 257 α-Tocopherol TRIVIAL 23411208 A 316 328 α-tocopherol TRIVIAL 23411208 A 691 713 α-tocopheryl succinate SYSTEMATIC 23411208 A 715 720 α-TOS ABBREVIATION 23411208 A 749 761 α-tocopherol TRIVIAL 23411208 A 798 809 doxorubicin TRIVIAL 23411208 A 926 935 vitamin E FAMILY 23411208 T 14 26 α-tocopherol TRIVIAL 23411210 A 1009 1015 6-OHDA SYSTEMATIC 23411210 A 170 181 gallic acid TRIVIAL 23411210 A 286 303 6-hydroxydopamine SYSTEMATIC 23411210 A 305 311 6-OHDA SYSTEMATIC 23411210 A 464 470 6-OHDA SYSTEMATIC 23411210 A 556 561 thiol FAMILY 23411210 A 578 589 glutathione TRIVIAL 23411210 A 656 671 malondialdehyde TRIVIAL 23411210 A 673 676 MDA ABBREVIATION 23411210 A 869 874 thiol FAMILY 23411210 A 911 914 MDA ABBREVIATION 23411210 T 32 43 gallic acid TRIVIAL 23411210 T 80 97 6-hydroxydopamine SYSTEMATIC 23411211 A 159 171 cannabisin B TRIVIAL 23411211 A 361 373 cannabisin B TRIVIAL 23411211 A 430 442 Cannabisin B TRIVIAL 23411211 A 525 540 3-methyladenine SYSTEMATIC 23411211 A 53 65 cannabisin B TRIVIAL 23411211 A 542 546 3-MA SYSTEMATIC 23411211 A 595 607 cannabisin B TRIVIAL 23411211 A 641 653 cannabisin B TRIVIAL 23411211 A 726 738 cannabisin B TRIVIAL 23411211 A 864 873 rapamycin TRIVIAL 23411211 A 910 922 cannabisin B TRIVIAL 23411211 T 0 12 Cannabisin B TRIVIAL 23411212 A 104 123 25-hydroxyvitamin D SYSTEMATIC 23411212 A 125 135 25OH-Vit D SYSTEMATIC 23411212 A 434 439 Vit D ABBREVIATION 23411212 A 444 454 25OH-Vit D SYSTEMATIC 23411212 A 496 505 Deuterium SYSTEMATIC 23411212 A 515 520 Vit D ABBREVIATION 23411212 A 525 535 25OH-Vit D SYSTEMATIC 23411212 A 82 91 vitamin D FAMILY 23411212 A 93 98 Vit D ABBREVIATION 23411212 T 0 9 Vitamin D FAMILY 23411212 T 14 33 25-hydroxyvitamin D SYSTEMATIC 23411213 A 105 119 aflatoxin B(1) TRIVIAL 23411213 A 124 136 ochratoxin A TRIVIAL 23411213 A 438 450 acetonitrile SYSTEMATIC 23411213 A 474 490 ammonium acetate SYSTEMATIC 23411213 T 30 44 aflatoxin B(1) TRIVIAL 23411213 T 49 61 ochratoxin A TRIVIAL 23411217 A 144 148 GalA ABBREVIATION 23411217 A 150 154 GlcA ABBREVIATION 23411217 A 156 159 Ara ABBREVIATION 23411217 A 161 164 Gal ABBREVIATION 23411217 A 169 172 Rha ABBREVIATION 23411217 A 203 207 GalA ABBREVIATION 23411217 A 218 222 Araf ABBREVIATION 23411217 A 260 263 Ara ABBREVIATION 23411217 A 274 277 Gal ABBREVIATION 23411217 A 305 308 Rha ABBREVIATION 23411219 A 20 36 triacylglycerols FAMILY 23411219 A 261 271 fatty acid FAMILY 23411219 A 289 306 hexacosanoic acid SYSTEMATIC 23411219 A 321 339 heneicosanoic acid SYSTEMATIC 23411219 A 360 376 triacylglycerols FAMILY 23411219 A 457 472 triacylglycerol FAMILY 23411219 A 517 535 dioleoyl linoleoyl TRIVIAL 23411219 A 537 540 OOL ABBREVIATION 23411219 A 543 557 1,2,3-trioleyl SYSTEMATIC 23411219 A 559 562 OOO ABBREVIATION 23411219 A 565 588 1,2-dioleyl-3-palmitoyl SYSTEMATIC 23411219 A 590 593 POO ABBREVIATION 23411219 A 596 619 1,2-dilinoleoyl-3-oleyl SYSTEMATIC 23411219 A 621 624 OLL ABBREVIATION 23411219 A 630 663 1-oleoyl-2-linoleoyl-3-linolenoyl SYSTEMATIC 23411219 A 665 669 OLLn ABBREVIATION 23411219 A 806 809 OOO ABBREVIATION 23411219 A 844 847 OOL ABBREVIATION 23411219 A 857 860 OOO ABBREVIATION 23411219 A 873 876 POO ABBREVIATION 23411219 A 905 908 OLL ABBREVIATION 23411219 A 918 921 OOO ABBREVIATION 23411219 A 934 937 OLL ABBREVIATION 23411219 T 58 74 triacylglycerols FAMILY 23411220 A 105 113 H(2)O(2) FORMULA 23411220 A 1058 1066 H(2)O(2) FORMULA 23411220 A 322 330 H(2)O(2) FORMULA 23411220 A 394 402 H(2)O(2) FORMULA 23411220 A 568 576 H(2)O(2) FORMULA 23411220 A 739 747 H(2)O(2) FORMULA 23411220 A 86 103 hydrogen peroxide SYSTEMATIC 23411220 A 892 900 H(2)O(2) FORMULA 23411220 A 996 1004 H(2)O(2) FORMULA 23411220 T 91 108 hydrogen peroxide SYSTEMATIC 23411223 A 1002 1004 Co FORMULA 23411223 A 1010 1011 V FORMULA 23411223 A 913 915 Ni FORMULA 23411223 A 917 919 Ag FORMULA 23411223 A 921 923 Cr FORMULA 23411223 A 925 927 Sr FORMULA 23411223 A 929 931 Zn FORMULA 23411223 A 937 939 Cu FORMULA 23411223 A 964 966 Rb FORMULA 23411223 A 968 970 Zn FORMULA 23411223 A 976 978 Mn FORMULA 23411223 A 998 1000 Pb FORMULA 23411232 A 11 23 vitamin D(3) TRIVIAL 23411232 A 377 389 Vitamin D(3) TRIVIAL 23411232 A 394 417 25-hydroxy vitamin D(3) SYSTEMATIC 23411232 A 527 539 vitamin D(3) TRIVIAL 23411232 A 563 586 25-hydroxy vitamin D(3) SYSTEMATIC 23411232 A 644 671 1,25 dihydroxy vitamin D(3) SYSTEMATIC 23411232 T 18 28 vitamin D3 TRIVIAL 23411236 A 540 551 chitotriose TRIVIAL 23411236 A 553 563 chitobiose TRIVIAL 23411236 A 585 604 N-acetylglucosamine SYSTEMATIC 23411239 A 134 150 Organophosphorus FAMILY 23411239 A 155 165 pyrethroid FAMILY 23411239 A 881 889 diazinon TRIVIAL 23411239 A 913 925 fenitrothion TRIVIAL 23411239 A 949 961 cypermethrin TRIVIAL 23411239 A 989 999 permethrin TRIVIAL 23411239 T 72 88 organophosphorus FAMILY 23411239 T 93 103 pyrethroid FAMILY 23411248 A 280 284 zinc SYSTEMATIC 23411248 A 380 384 zinc SYSTEMATIC 23411248 A 495 499 zinc SYSTEMATIC 23411248 T 62 66 zinc SYSTEMATIC 23411250 A 139 150 polyphenols FAMILY 23411250 A 203 218 pyrogallic acid TRIVIAL 23411250 A 287 294 Fe(III) FORMULA 23411250 A 298 304 Fe(II) FORMULA 23411250 A 332 335 NRS ABBREVIATION 23411250 A 35 42 Fe(III) FORMULA 23411250 A 390 396 Fe(II) FORMULA 23411250 A 397 400 NRS ABBREVIATION 23411250 A 43 93 3-hydroxy-4-nitroso-2,7-naphthalenedisulfonic acid SYSTEMATIC 23411250 A 830 837 Fe(III) FORMULA 23411250 A 838 841 NRS ABBREVIATION 23411250 A 95 98 NRS ABBREVIATION 23411250 T 124 135 polyphenols FAMILY 23411250 T 31 37 Fe(II) FORMULA 23411250 T 38 88 3-hydroxy-4-nitroso-2,7-naphthalenedisulfonic acid SYSTEMATIC 23411252 A 115 124 vitamin A FAMILY 23411252 A 447 455 phytoene TRIVIAL 23411252 A 457 468 phytofluene TRIVIAL 23411252 A 470 476 lutein TRIVIAL 23411252 A 478 488 zeaxanthin TRIVIAL 23411252 A 490 505 β-cryptoxanthin TRIVIAL 23411252 A 507 517 α-carotene TRIVIAL 23411252 A 519 529 β-carotene TRIVIAL 23411252 A 534 542 lycopene TRIVIAL 23411255 A 1017 1026 ascorbate TRIVIAL 23411255 A 1027 1038 glutathione TRIVIAL 23411255 A 1167 1180 ascorbic acid TRIVIAL 23411255 A 1185 1196 glutathione TRIVIAL 23411255 A 1313 1326 ascorbic acid TRIVIAL 23411255 A 1342 1353 glutathione TRIVIAL 23411255 A 1464 1477 ascorbic acid TRIVIAL 23411255 A 1482 1493 glutathione TRIVIAL 23411255 A 1683 1692 peroxides FAMILY 23411255 A 1702 1711 carbonyls FAMILY 23411255 A 1794 1807 ascorbic acid TRIVIAL 23411255 A 1812 1823 glutathione TRIVIAL 23411255 A 260 273 ascorbic acid TRIVIAL 23411255 A 278 289 glutathione TRIVIAL 23411255 A 420 433 ascorbic acid TRIVIAL 23411255 A 438 449 glutathione TRIVIAL 23411255 A 637 650 ascorbic acid TRIVIAL 23411255 A 655 666 glutathione TRIVIAL 23411255 A 66 79 ascorbic acid TRIVIAL 23411255 A 799 812 ascorbic acid TRIVIAL 23411255 A 84 95 glutathione TRIVIAL 23411255 A 848 859 glutathione TRIVIAL 23411255 A 919 932 ascorbic acid TRIVIAL 23411255 A 937 948 glutathione TRIVIAL 23411255 T 33 46 ascorbic acid TRIVIAL 23411255 T 51 62 glutathione TRIVIAL 23411265 A 0 12 Phytosterols FAMILY 23411265 A 1045 1066 phytosteryl sinapates FAMILY 23411265 A 1105 1118 vanillic acid SYSTEMATIC 23411265 A 1123 1138 vinyl vanillate SYSTEMATIC 23411265 A 1179 1191 phytosterols FAMILY 23411265 A 1197 1221 sinapic or vanillic acid MULTIPLE 23411265 A 1298 1319 phytosteryl sinapates FAMILY 23411265 A 1324 1334 vanillates FAMILY 23411265 A 236 248 phytosterols FAMILY 23411265 A 253 286 phytosteryl esters of fatty acids FAMILY 23411265 A 315 337 phytosteryl phenolates FAMILY 23411265 A 353 365 phytosterols FAMILY 23411265 A 371 385 phenolic acids FAMILY 23411265 A 403 425 phytosteryl phenolates FAMILY 23411265 A 434 455 phytosteryl sinapates FAMILY 23411265 A 460 470 vanillates FAMILY 23411265 A 843 864 phytosteryl sinapates FAMILY 23411265 A 889 895 oxygen SYSTEMATIC 23411265 A 983 1005 phytosteryl vanillates FAMILY 23411265 T 0 21 Phytosteryl sinapates FAMILY 23411265 T 26 36 vanillates FAMILY 23411268 A 151 155 (1)H FORMULA 23411268 T 37 39 1H FORMULA 23411271 A 1014 1019 thiol FAMILY 23411271 A 1031 1053 methyl dihydrocaffeate SYSTEMATIC 23411271 A 1119 1128 caffeates FAMILY 23411271 A 123 126 azo SYSTEMATIC 23411271 A 192 197 thiol FAMILY 23411271 A 24 39 methyl caffeate SYSTEMATIC 23411271 A 279 288 caffeates FAMILY 23411271 A 437 452 methyl caffeate SYSTEMATIC 23411271 A 44 66 methyl dihydrocaffeate SYSTEMATIC 23411271 A 566 571 thiol FAMILY 23411271 A 619 641 methyl dihydrocaffeate SYSTEMATIC 23411271 A 709 714 thiol FAMILY 23411271 A 88 103 cysteinyl thiol SYSTEMATIC 23411271 A 961 966 thiol FAMILY 23411271 A 977 992 methyl caffeate SYSTEMATIC 23411271 T 50 65 cysteinyl thiol SYSTEMATIC 23411271 T 97 130 caffeic and dihydrocaffeic esters MULTIPLE 23411272 A 297 304 glucose TRIVIAL 23411272 A 37 49 procyanidins FAMILY 23411272 A 627 635 catechin TRIVIAL 23411272 A 697 710 methylglyoxal SYSTEMATIC 23411272 A 736 744 carbonyl FAMILY 23411272 A 826 839 methylglyoxal SYSTEMATIC 23411272 A 850 858 carbonyl FAMILY 23411272 T 11 23 procyanidins FAMILY 23411272 T 122 131 carbonyls FAMILY 23411283 A 0 10 Biguanides FAMILY 23411283 A 115 124 guanidine TRIVIAL 23411283 A 19 28 metformin TRIVIAL 23411283 A 219 229 biguanides FAMILY 23411283 A 262 272 biguanides FAMILY 23411283 A 351 360 biguanide TRIVIAL 23411283 A 960 969 biguanide TRIVIAL 23411283 T 0 9 Biguanide TRIVIAL 23411284 A 0 10 β-Carotene TRIVIAL 23411284 A 111 121 β-Carotene TRIVIAL 23411284 A 178 184 oxygen SYSTEMATIC 23411284 A 268 278 β-carotene TRIVIAL 23411284 A 408 418 β-carotene TRIVIAL 23411284 A 637 647 β-carotene TRIVIAL 23411284 A 82 91 vitamin A FAMILY 23411284 T 22 32 β-carotene TRIVIAL 23411306 A 102 111 sulfonate SYSTEMATIC 23411306 A 118 129 Ponceau 4RC TRIVIAL 23411306 A 131 144 Sunset yellow TRIVIAL 23411306 A 146 156 Allura red TRIVIAL 23411306 A 158 169 Azophloxine TRIVIAL 23411306 A 171 187 Ponceau xylidine TRIVIAL 23411306 A 189 200 Erythrosine TRIVIAL 23411306 A 205 214 Orange II TRIVIAL 23411306 A 339 346 Ethanol SYSTEMATIC 23411306 A 347 354 ammonia SYSTEMATIC 23411307 A 321 324 SFA ABBREVIATION 23411307 A 326 330 MUFA ABBREVIATION 23411307 A 335 339 PUFA ABBREVIATION 23411307 A 39 49 fatty acid FAMILY 23411307 A 476 486 fatty acid FAMILY 23411307 A 789 800 fatty acids FAMILY 23411307 A 973 983 fatty acid FAMILY 23411307 T 0 10 Fatty acid FAMILY 23411311 A 221 233 dienoic acid SYSTEMATIC 23411311 A 247 258 p-anisidine SYSTEMATIC 23411311 A 358 363 C11:0 FORMULA 23411311 A 374 397 unsaturated fatty acids FAMILY 23411311 A 399 403 UFAs ABBREVIATION 23411311 A 409 430 saturated fatty acids FAMILY 23411311 A 432 436 SFAs ABBREVIATION 23411311 A 525 528 SFA ABBREVIATION 23411311 A 552 555 UFA ABBREVIATION 23411311 A 605 618 caprylic acid TRIVIAL 23411311 A 620 624 C8:0 FORMULA 23411311 A 736 759 unsaturated fatty acids FAMILY 23411311 A 761 765 SFAs ABBREVIATION 23411311 A 766 770 UFAs ABBREVIATION 23411311 A 775 788 caprylic acid TRIVIAL 23411311 A 790 794 C8:0 FORMULA 23411311 A 801 805 UFAs ABBREVIATION 23411311 A 892 899 sesamol TRIVIAL 23411311 A 961 972 fatty acids FAMILY 23411311 A 98 109 fatty acids FAMILY 23411311 T 92 103 fatty acids FAMILY 23411312 A 1389 1395 sugars FAMILY 23411312 A 1565 1576 polyphenols FAMILY 23411312 A 1669 1672 HMF ABBREVIATION 23411312 A 287 290 ACs ABBREVIATION 23411312 A 724 747 5-hydroxymethylfurfural SYSTEMATIC 23411312 A 749 752 HMF ABBREVIATION 23411312 A 82 93 anthocyanin FAMILY 23411312 T 21 33 anthocyanins FAMILY 23411314 A 205 212 proline TRIVIAL 23411314 A 214 228 phloroglucinol TRIVIAL 23411314 A 230 238 mannitol TRIVIAL 23411314 A 242 253 fatty acids FAMILY 23411314 A 260 267 sterols FAMILY 23411314 A 423 427 DPPH ABBREVIATION 23411314 A 429 441 nitric oxide SYSTEMATIC 23411314 A 443 453 superoxide TRIVIAL 23411314 A 458 466 hydroxyl SYSTEMATIC 23411314 A 917 931 phloroglucinol TRIVIAL 23411314 A 933 941 mannitol TRIVIAL 23411314 A 943 988 oleic, arachidonic and eicosapentaenoic acids MULTIPLE 23411314 A 994 1004 fucosterol TRIVIAL 23411334 A 1075 1083 l-5-MTHF SYSTEMATIC 23411334 A 1169 1177 l-5-MTHF SYSTEMATIC 23411334 A 130 156 l-5-methyltetrahydrofolate SYSTEMATIC 23411334 A 158 166 l-5-MTHF SYSTEMATIC 23411334 A 188 212 epigallocatechin-gallate TRIVIAL 23411334 A 303 311 l-5-MTHF SYSTEMATIC 23411334 A 326 334 catechin TRIVIAL 23411334 A 375 383 l-5-MTHF SYSTEMATIC 23411334 A 599 607 l-5-MTHF SYSTEMATIC 23411334 A 634 642 l-5-MTHF SYSTEMATIC 23411334 A 763 772 catechins FAMILY 23411334 A 812 816 EGCG ABBREVIATION 23411334 A 892 900 hydrogen SYSTEMATIC 23411334 A 930 939 catechins FAMILY 23411334 A 983 991 l-5-MTHF SYSTEMATIC 23411334 T 20 29 catechins FAMILY 23411334 T 83 109 L-5-methyltetrahydrofolate SYSTEMATIC 23411335 A 136 145 natamycin TRIVIAL 23411335 A 245 250 sugar FAMILY 23411335 A 261 266 sugar FAMILY 23411335 A 268 281 ascorbic acid TRIVIAL 23411335 A 364 373 natamycin TRIVIAL 23411335 A 589 594 sugar FAMILY 23411335 A 599 612 ascorbic acid TRIVIAL 23411335 T 131 140 natamycin TRIVIAL 23411340 A 174 187 ascorbic acid TRIVIAL 23411340 A 200 214 manganese(III) SYSTEMATIC 23411340 A 248 262 manganese(III) SYSTEMATIC 23411340 A 268 281 diphenylamine SYSTEMATIC 23411340 A 285 316 barium diphenylamine sulphonate SYSTEMATIC 23411340 A 46 59 ascorbic acid TRIVIAL 23411340 A 462 471 vitamin C TRIVIAL 23411340 A 736 750 manganese(III) SYSTEMATIC 23411340 A 755 768 diphenylamine SYSTEMATIC 23411340 A 774 787 ascorbic acid TRIVIAL 23411340 T 137 150 ascorbic acid TRIVIAL 23411340 T 69 92 manganese(III) sulphate SYSTEMATIC 23411340 T 98 111 diphenylamine SYSTEMATIC 23411342 A 1084 1090 Pb(II) FORMULA 23411342 A 128 158 ethylene glycol dimethacrylate SYSTEMATIC 23411342 A 180 208 2,2'- azobisisobutyronitrile SYSTEMATIC 23411342 A 227 244 diphenylcarbazone SYSTEMATIC 23411342 A 260 271 acetonitril SYSTEMATIC 23411342 A 292 304 Pb(NO(3))(2) FORMULA 23411342 A 44 50 Pb(II) FORMULA 23411342 A 442 445 HCl FORMULA 23411342 A 647 653 Pb(II) FORMULA 23411342 A 87 102 2-vinylpyridine SYSTEMATIC 23411351 A 1176 1184 carbaryl TRIVIAL 23411351 A 1444 1456 carbohydrate FAMILY 23411351 A 1618 1626 carbaryl TRIVIAL 23411351 A 1774 1782 carbaryl TRIVIAL 23411351 A 605 613 carbaryl TRIVIAL 23411351 A 732 740 carbaryl TRIVIAL 23411351 A 969 977 carbaryl TRIVIAL 23411351 T 145 153 carbaryl TRIVIAL 23411351 T 64 72 carbaryl TRIVIAL 23412078 A 1046 1053 glucose TRIVIAL 23412078 A 1129 1142 Canagliflozin TRIVIAL 23412078 A 1302 1315 canagliflozin TRIVIAL 23412078 A 1464 1477 acetaminophen TRIVIAL 23412078 A 1602 1609 glucose TRIVIAL 23412078 A 164 177 canagliflozin TRIVIAL 23412078 A 1670 1683 Canagliflozin TRIVIAL 23412078 A 1712 1719 glucose TRIVIAL 23412078 A 26 32 sodium SYSTEMATIC 23412078 A 285 292 glucose TRIVIAL 23412078 A 33 40 glucose TRIVIAL 23412078 A 385 398 canagliflozin TRIVIAL 23412078 A 413 420 glucose TRIVIAL 23412078 A 494 507 canagliflozin TRIVIAL 23412078 A 584 591 glucose TRIVIAL 23412078 A 593 605 (3)H-glucose SYSTEMATIC 23412078 A 607 620 (14)C-glucose SYSTEMATIC 23412078 A 708 715 glucose TRIVIAL 23412078 A 746 753 glucose TRIVIAL 23412078 A 770 777 glucose TRIVIAL 23412078 A 817 830 canagliflozin TRIVIAL 23412078 A 869 876 glucose TRIVIAL 23412078 A 9 22 Canagliflozin TRIVIAL 23412078 T 0 13 Canagliflozin TRIVIAL 23412078 T 130 137 Glucose TRIVIAL 23412078 T 34 41 Glucose TRIVIAL 23412078 T 77 84 Glucose TRIVIAL 23412396 A 1120 1126 JZL184 IDENTIFIER 23412396 A 1211 1217 JZL184 IDENTIFIER 23412396 A 1335 1341 JZL184 IDENTIFIER 23412396 A 1408 1414 JZL184 IDENTIFIER 23412396 A 1442 1448 JZL184 IDENTIFIER 23412396 A 1516 1541 Δ(9)-tetrahydrocannabinol SYSTEMATIC 23412396 A 154 160 JZL184 IDENTIFIER 23412396 A 1543 1546 THC ABBREVIATION 23412396 A 1593 1603 rimonabant TRIVIAL 23412396 A 4 20 monoacylglycerol SYSTEMATIC 23412396 A 45 51 JZL184 IDENTIFIER 23412396 A 552 558 JZL184 IDENTIFIER 23412396 A 795 801 JZL184 IDENTIFIER 23412396 A 908 923 [(3)H]SR141716A SYSTEMATIC 23412396 A 936 944 CP55,940 IDENTIFIER 23412396 A 957 962 (35)S FORMULA 23412396 T 40 56 Monoacylglycerol SYSTEMATIC 23412396 T 74 80 JZL184 IDENTIFIER 23412992 A 1253 1256 ATP ABBREVIATION 23412992 A 1393 1396 NaK FORMULA 23412992 A 271 277 sodium SYSTEMATIC 23412992 A 278 287 potassium SYSTEMATIC 23412992 A 298 301 Na+ FORMULA 23412992 A 302 304 K+ FORMULA 23412992 A 319 322 NaK FORMULA 23412992 A 376 384 steroids FAMILY 23412992 A 588 591 Na+ FORMULA 23412992 A 592 594 K+ FORMULA 23412992 A 712 715 Na+ FORMULA 23412992 A 716 718 K+ FORMULA 23412992 A 762 765 Na+ FORMULA 23412992 A 766 768 K+ FORMULA 23412992 A 833 840 steroid FAMILY 23412992 T 30 33 Na+ FORMULA 23412992 T 34 36 K+ FORMULA 23413033 A 887 896 potassium SYSTEMATIC 23413033 T 48 57 Potassium SYSTEMATIC 23413101 A 516 528 nitric oxide SYSTEMATIC 23414252 A 648 654 methyl SYSTEMATIC 23414252 A 992 1000 hydrogen SYSTEMATIC 23414433 A 1175 1179 METH ABBREVIATION 23414433 A 1181 1185 METH ABBREVIATION 23414433 A 1186 1190 METH ABBREVIATION 23414433 A 1263 1267 METH ABBREVIATION 23414433 A 1361 1365 METH ABBREVIATION 23414433 A 146 154 dopamine TRIVIAL 23414433 A 198 202 METH ABBREVIATION 23414433 A 23 38 methamphetamine TRIVIAL 23414433 A 272 276 METH ABBREVIATION 23414433 A 40 44 METH ABBREVIATION 23414433 A 422 426 METH ABBREVIATION 23414433 A 687 691 METH ABBREVIATION 23414433 A 747 751 METH ABBREVIATION 23414433 A 753 757 METH ABBREVIATION 23414433 A 766 770 METH ABBREVIATION 23414433 A 771 775 METH ABBREVIATION 23414433 A 853 857 METH ABBREVIATION 23414433 A 953 957 METH ABBREVIATION 23414433 A 958 962 METH ABBREVIATION 23414433 T 34 49 methamphetamine TRIVIAL 23414802 A 169 189 2-hydroxydiarylamide FAMILY 23414802 A 256 262 serine TRIVIAL 23414802 A 391 397 serine TRIVIAL 23414802 T 19 39 2-hydroxydiarylamide FAMILY 23414841 A 13 24 Arg-Gly-Asp FORMULA 23414841 A 349 356 (99m)Tc FORMULA 23414841 A 412 426 [(99m)TcN](+2) FORMULA 23414841 A 445 460 dithiocarbamate SYSTEMATIC 23414841 A 494 505 G3-c(RGDfK) FORMULA 23414841 A 507 521 G3=Gly-Gly-Gly FORMULA 23414841 A 523 528 f=Phe FORMULA 23414841 A 530 535 K=Lys FORMULA 23414841 A 575 589 [(99m)TcN](+2) FORMULA 23414841 A 615 638 (99m)TcN-[G3-c(RGDfK)]2 FORMULA 23414841 T 39 46 (99m)Tc FORMULA 23415714 A 1025 1034 flutamide TRIVIAL 23415714 A 1069 1072 DHT ABBREVIATION 23415714 A 1257 1265 androgen FAMILY 23415714 A 1339 1347 androgen FAMILY 23415714 A 1454 1462 androgen FAMILY 23415714 A 26 34 androgen FAMILY 23415714 A 303 311 androgen FAMILY 23415714 A 35 43 androgen FAMILY 23415714 A 554 562 androgen FAMILY 23415714 A 710 718 androgen FAMILY 23415714 A 720 742 5α-dihydrotestosterone SYSTEMATIC 23415714 A 744 747 DHT ABBREVIATION 23415714 A 750 753 DHT ABBREVIATION 23415714 A 831 844 prostaglandin FAMILY 23415714 T 0 8 Androgen FAMILY 23415714 T 9 17 androgen FAMILY 23415893 A 104 115 glucosamine TRIVIAL 23415893 A 138 151 2-glucosamine SYSTEMATIC 23415893 A 81 103 prednisolone carbamate SYSTEMATIC 23415893 A 822 834 prednisolone TRIVIAL 23415893 A 892 905 2-glucosamine SYSTEMATIC 23415893 A 966 978 prednisolone TRIVIAL 23415893 T 77 90 2-glucosamine SYSTEMATIC 23416001 A 128 139 spirocycles FAMILY 23416001 A 156 162 isatin TRIVIAL 23416001 A 163 169 ketone SYSTEMATIC 23416001 T 33 39 isatin TRIVIAL 23416011 A 0 9 Celecoxib TRIVIAL 23416011 A 357 390 nitro-substituted acylsulfonamide FAMILY 23416011 A 412 421 celecoxib TRIVIAL 23416011 A 428 454 nitro-substituted 21-ester FAMILY 23416011 A 513 518 nitro SYSTEMATIC 23416011 T 2 12 nitropheny SYSTEMATIC 23416011 T 61 73 prednisolone TRIVIAL 23416011 T 75 85 budesonide TRIVIAL 23416011 T 90 99 celecoxib TRIVIAL 23416070 A 143 150 glucose TRIVIAL 23416070 A 934 944 fatty acid FAMILY 23416115 A 0 16 Chlorogenic acid TRIVIAL 23416115 A 1011 1014 CGA ABBREVIATION 23416115 A 1115 1122 glucose TRIVIAL 23416115 A 1138 1148 fatty acid FAMILY 23416115 A 1247 1250 CGA ABBREVIATION 23416115 A 1260 1267 glucose TRIVIAL 23416115 A 18 21 CGA ABBREVIATION 23416115 A 276 279 CGA ABBREVIATION 23416115 A 283 290 glucose TRIVIAL 23416115 A 385 392 glucose TRIVIAL 23416115 A 460 463 CGA ABBREVIATION 23416115 A 484 491 glucose TRIVIAL 23416115 A 507 517 fatty acid FAMILY 23416115 A 51 58 glucose TRIVIAL 23416115 A 593 596 CGA ABBREVIATION 23416115 A 683 686 CGA ABBREVIATION 23416115 A 698 705 glucose TRIVIAL 23416115 A 744 747 CGA ABBREVIATION 23416115 A 872 879 glucose TRIVIAL 23416115 A 919 926 glucose TRIVIAL 23416115 A 934 941 glucose TRIVIAL 23416115 T 44 60 chlorogenic acid TRIVIAL 23416191 A 552 559 HJC0123 IDENTIFIER 23416191 A 885 893 estrogen FAMILY 23416191 T 49 56 HJC0123 IDENTIFIER 23416192 A 136 162 3-(2-bromoacetyl)coumarins FAMILY 23416192 A 18 100 2-(5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-yl)-4-(coumarin-3-yl)thiazoles FAMILY 23416192 A 180 245 5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-thiocarboxamides FAMILY 23416192 A 279 296 thiosemicarbazide SYSTEMATIC 23416192 A 302 329 trifluoromethyl-β-diketones FAMILY 23416192 A 460 472 indomethacin TRIVIAL 23416192 A 609 617 cefixime TRIVIAL 23416192 T 55 137 2-(5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-yl)-4-(coumarin-3-yl)thiazoles FAMILY 23416229 A 271 284 acetylcholine SYSTEMATIC 23416262 A 390 396 oxygen SYSTEMATIC 23416264 A 1013 1025 hydroquinone SYSTEMATIC 23416264 A 1041 1049 nicotine TRIVIAL 23416264 A 1065 1073 acrolein TRIVIAL 23416264 A 1202 1219 2,5-dimethylfuran SYSTEMATIC 23416264 A 122 131 aldehydes FAMILY 23416264 A 1230 1238 aldehyde SYSTEMATIC 23416264 A 147 159 formaldehyde SYSTEMATIC 23416264 A 1507 1516 aldehydes FAMILY 23416264 A 161 173 acetaldehyde SYSTEMATIC 23416264 A 178 186 acrolein TRIVIAL 23416264 A 304 316 formaldehyde SYSTEMATIC 23416264 A 318 326 acrolein TRIVIAL 23416264 A 331 343 acetaldehyde SYSTEMATIC 23416264 A 403 412 aldehydes FAMILY 23416264 A 421 429 aldehyde SYSTEMATIC 23416264 A 441 449 nicotine TRIVIAL 23416264 A 451 463 hydroquinone SYSTEMATIC 23416264 A 468 485 2,5-dimethylfuran SYSTEMATIC 23416264 A 630 639 aldehydes FAMILY 23416264 A 661 670 aldehydes FAMILY 23416264 A 708 717 aldehydes FAMILY 23416264 A 802 814 Formaldehyde SYSTEMATIC 23416264 A 988 1000 acetaldehyde SYSTEMATIC 23416264 T 20 29 aldehydes FAMILY 23416326 A 115 120 (32)P FORMULA 23416326 A 235 238 PAH ABBREVIATION 23416326 A 265 269 PAHs ABBREVIATION 23416326 A 37 40 PAH ABBREVIATION 23416326 A 439 442 PAH ABBREVIATION 23416326 A 499 510 nucleotides FAMILY 23416326 A 549 560 nucleotides FAMILY 23416326 A 563 566 PAH ABBREVIATION 23416326 A 676 679 PAH ABBREVIATION 23416326 A 730 733 PAH ABBREVIATION 23416326 A 841 844 PAH ABBREVIATION 23416326 A 995 998 PAH ABBREVIATION 23416326 T 10 13 PAH ABBREVIATION 23416409 A 0 7 Mercury SYSTEMATIC 23416409 A 1193 1195 Hg FORMULA 23416409 A 1319 1321 Hg FORMULA 23416409 A 1447 1449 Hg FORMULA 23416409 A 180 197 mercuric chloride SYSTEMATIC 23416409 A 199 204 HgCl2 FORMULA 23416409 A 344 346 Hg FORMULA 23416409 A 411 413 Hg FORMULA 23416409 A 690 692 Hg FORMULA 23416409 A 9 11 Hg FORMULA 23416409 T 71 78 mercury SYSTEMATIC 23416650 A 57 65 urushiol TRIVIAL 23416930 A 607 616 rapamycin TRIVIAL 23416930 A 618 629 resveratrol TRIVIAL 23416930 A 633 643 spermidine TRIVIAL 23417420 A 1010 1013 DHT ABBREVIATION 23417420 A 1094 1097 DHT ABBREVIATION 23417420 A 1423 1426 DHT ABBREVIATION 23417420 A 1615 1623 androgen FAMILY 23417420 A 534 542 androgen FAMILY 23417420 A 699 707 androgen FAMILY 23417420 A 786 794 androgen FAMILY 23417420 A 976 984 androgen FAMILY 23417420 A 986 1008 5α-dihydrotestosterone SYSTEMATIC 23417420 T 7 15 androgen FAMILY 23417717 A 331 337 copper SYSTEMATIC 23417717 A 373 379 copper SYSTEMATIC 23417717 A 630 636 copper SYSTEMATIC 23417717 T 36 42 copper SYSTEMATIC 23417790 A 1070 1072 Hg FORMULA 23417790 A 111 113 Hg FORMULA 23417790 A 1156 1169 methylmercury SYSTEMATIC 23417790 A 1204 1206 Hg FORMULA 23417790 A 1239 1241 Hg FORMULA 23417790 A 1256 1258 Hg FORMULA 23417790 A 13 15 Hg FORMULA 23417790 A 1330 1332 Hg FORMULA 23417790 A 1444 1446 Hg FORMULA 23417790 A 1526 1528 Hg FORMULA 23417790 A 1600 1602 Hg FORMULA 23417790 A 249 251 Hg FORMULA 23417790 A 471 473 Hg FORMULA 23417790 A 571 573 Hg FORMULA 23417790 A 603 605 Hg FORMULA 23417790 A 791 793 Hg FORMULA 23417790 A 898 900 Hg FORMULA 23417790 A 988 1001 methylmercury SYSTEMATIC 23417790 T 17 24 mercury SYSTEMATIC 23417790 T 65 72 mercury SYSTEMATIC 23418006 A 135 143 catechol TRIVIAL 23418006 A 308 316 catechol TRIVIAL 23418006 A 505 513 catechol TRIVIAL 23418006 A 71 79 catechol TRIVIAL 23418006 T 73 82 Catechols FAMILY 23418011 A 1036 1048 γ-thialysine SYSTEMATIC 23418011 A 1088 1096 pyruvate TRIVIAL 23418011 A 1127 1139 γ-thialysine SYSTEMATIC 23418011 A 1183 1189 lysine TRIVIAL 23418011 A 1237 1247 thialysine SYSTEMATIC 23418011 A 127 130 Lys FORMULA 23418011 A 1344 1354 thialysine SYSTEMATIC 23418011 A 148 171 N-acetylneuraminic acid SYSTEMATIC 23418011 A 1512 1522 amino acid FAMILY 23418011 A 1714 1726 γ-thialysine SYSTEMATIC 23418011 A 404 412 cysteine TRIVIAL 23418011 A 480 488 cysteine TRIVIAL 23418011 A 501 504 Lys FORMULA 23418011 A 594 602 cysteine TRIVIAL 23418011 A 608 620 γ-thialysine SYSTEMATIC 23418011 A 629 643 dehydroalanine SYSTEMATIC 23418011 A 63 73 amino acid FAMILY 23418011 A 645 648 Dha ABBREVIATION 23418011 A 74 86 γ-thialysine SYSTEMATIC 23418011 A 745 757 γ-thialysine SYSTEMATIC 23418011 A 961 969 pyruvate TRIVIAL 23418011 T 135 141 lysine TRIVIAL 23418011 T 147 159 γ-thialysine SYSTEMATIC 23418011 T 62 85 N-acetylneuraminic acid SYSTEMATIC 23418059 A 1317 1342 polychlorinated biphenyls FAMILY 23418059 A 1432 1460 polybrominated diphenylether FAMILY 23418087 A 0 11 Bisphenol A TRIVIAL 23418087 A 1016 1023 phospho SYSTEMATIC 23418087 A 1141 1148 calcium SYSTEMATIC 23418087 A 1179 1186 calcium SYSTEMATIC 23418087 A 122 125 BPA ABBREVIATION 23418087 A 13 16 BPA ABBREVIATION 23418087 A 1305 1308 BPA ABBREVIATION 23418087 A 1319 1322 BPA ABBREVIATION 23418087 A 1350 1353 BPA ABBREVIATION 23418087 A 1407 1410 BPA ABBREVIATION 23418087 A 1436 1439 BPA ABBREVIATION 23418087 A 1453 1456 BPA ABBREVIATION 23418087 A 1514 1517 CpG ABBREVIATION 23418087 A 1608 1611 BPA ABBREVIATION 23418087 A 167 174 calcium SYSTEMATIC 23418087 A 284 287 BPA ABBREVIATION 23418087 A 419 422 BPA ABBREVIATION 23418087 A 580 583 BPA ABBREVIATION 23418087 A 679 682 BPA ABBREVIATION 23418087 A 873 876 BPA ABBREVIATION 23418087 A 890 897 calcium SYSTEMATIC 23418087 A 967 973 sodium SYSTEMATIC 23418087 A 974 981 calcium SYSTEMATIC 23418087 T 21 32 bisphenol a TRIVIAL 23418674 A 773 782 berberine TRIVIAL 23418674 A 856 861 EtOAc FORMULA 23418674 A 874 883 berberine TRIVIAL 23418674 A 989 998 berberine TRIVIAL 23418859 A 1136 1147 salidroside TRIVIAL 23418859 A 1165 1173 LY294002 IDENTIFIER 23418859 A 1273 1284 salidroside TRIVIAL 23418859 A 375 386 Salidroside TRIVIAL 23418859 A 390 401 salidroside TRIVIAL 23418859 A 418 426 LY294002 IDENTIFIER 23418859 A 47 58 salidroside TRIVIAL 23418859 A 556 560 dUTP ABBREVIATION 23418859 A 824 835 salidroside TRIVIAL 23418859 T 0 11 Salidroside TRIVIAL 23418880 A 117 143 (-)-sukhodianine-β-N-oxide SYSTEMATIC 23418880 A 149 158 palmatine TRIVIAL 23418880 A 164 175 corydalmine TRIVIAL 23418880 A 181 199 dehydrocorydalmine SYSTEMATIC 23418880 A 209 221 corynoxidine TRIVIAL 23418880 A 297 318 demethylaristofolin C SYSTEMATIC 23418880 A 32 53 demethylaristofolin C SYSTEMATIC 23418880 A 496 507 methicillin TRIVIAL 23418880 A 6 30 denitroaristolochic acid TRIVIAL 23418880 A 94 111 crebanine N-oxide SYSTEMATIC 23418880 T 20 44 denitroaristolochic acid TRIVIAL 23418960 A 1096 1099 PGN ABBREVIATION 23418960 A 1116 1121 CO(2) FORMULA 23418960 A 1152 1155 PGN ABBREVIATION 23418960 A 1214 1217 PGN ABBREVIATION 23418960 A 1234 1237 PGN ABBREVIATION 23418960 A 1301 1304 PGN ABBREVIATION 23418960 A 1376 1379 PGN ABBREVIATION 23418960 A 1466 1469 PGN ABBREVIATION 23418960 A 1523 1526 PGN ABBREVIATION 23418960 A 1604 1607 PGN ABBREVIATION 23418960 A 326 338 progesterone TRIVIAL 23418960 A 340 343 PGN ABBREVIATION 23418960 A 373 378 CO(2) FORMULA 23418960 A 407 410 PGN ABBREVIATION 23418960 A 474 493 polyethylene glycol SYSTEMATIC 23418960 A 495 498 PEG ABBREVIATION 23418960 A 518 526 Gelucire TRIVIAL 23418960 A 537 570 D-α-tocopheryl PEG 1000 succinate SYSTEMATIC 23418960 A 572 576 TPGS ABBREVIATION 23418960 A 604 607 PGN ABBREVIATION 23418960 A 911 914 PGN ABBREVIATION 23418960 T 36 48 progesterone TRIVIAL 23418960 T 81 95 carbon dioxide SYSTEMATIC 23419007 A 498 509 ketosteroid FAMILY 23419139 A 106 115 midazolam TRIVIAL 23419139 A 182 191 midazolam TRIVIAL 23419139 A 291 302 thalidomide TRIVIAL 23419139 A 374 393 1'-hydroxymidazolam SYSTEMATIC 23419139 A 423 434 thalidomide TRIVIAL 23419139 A 43 54 thalidomide TRIVIAL 23419139 A 557 575 4-hydroxymidazolam SYSTEMATIC 23419139 A 625 636 thalidomide TRIVIAL 23419139 A 781 792 thalidomide TRIVIAL 23419139 A 862 873 thalidomide TRIVIAL 23419139 T 43 54 thalidomide TRIVIAL 23419139 T 60 69 midazolam TRIVIAL 23419143 A 1031 1037 copper SYSTEMATIC 23419143 A 118 124 copper SYSTEMATIC 23419143 A 143 145 Si FORMULA 23419143 A 208 210 Pd FORMULA 23419143 A 440 442 Pd FORMULA 23419143 A 581 583 Au FORMULA 23419143 A 589 591 Cu FORMULA 23419143 A 774 780 copper SYSTEMATIC 23419143 A 921 923 Cu FORMULA 23419143 T 34 40 copper SYSTEMATIC 23419593 A 1511 1515 K(+) FORMULA 23419638 A 1044 1055 delphinidin TRIVIAL 23419638 A 1073 1085 pelargonidin TRIVIAL 23419638 A 1123 1137 anthocyanidins FAMILY 23419638 A 1178 1190 pelargonidin TRIVIAL 23419638 A 118 134 aryl hydrocarbon FAMILY 23419638 A 1263 1275 pelargonidin TRIVIAL 23419638 A 1280 1291 delphinidin TRIVIAL 23419638 A 27 41 anthocyanidins FAMILY 23419638 A 330 342 pelargonidin TRIVIAL 23419638 A 398 410 pelargonidin TRIVIAL 23419638 A 43 51 cyanidin TRIVIAL 23419638 A 522 554 2,3,7,8-tetrachlorodibenzodioxin SYSTEMATIC 23419638 A 53 64 delphinidin TRIVIAL 23419638 A 556 560 TCDD ABBREVIATION 23419638 A 644 656 pelargonidin TRIVIAL 23419638 A 66 74 malvidin TRIVIAL 23419638 A 722 726 TCDD ABBREVIATION 23419638 A 76 84 peonidin TRIVIAL 23419638 A 86 95 petunidin TRIVIAL 23419638 A 910 922 pelargonidin TRIVIAL 23419638 A 97 109 pelargonidin TRIVIAL 23419638 T 0 12 Pelargonidin TRIVIAL 23419783 A 1144 1156 sulfonylurea FAMILY 23419783 A 1199 1211 sulfonylurea FAMILY 23419783 A 1550 1559 metformin TRIVIAL 23419783 A 1579 1591 sulfonylurea FAMILY 23419783 A 217 226 metformin TRIVIAL 23419783 A 258 271 sulfonylureas FAMILY 23419783 A 528 537 metformin TRIVIAL 23419783 A 545 557 sulfonylurea FAMILY 23419783 A 558 571 sulfonylureas FAMILY 23419783 A 831 840 metformin TRIVIAL 23419783 A 883 892 metformin TRIVIAL 23419783 T 0 9 Metformin TRIVIAL 23419783 T 14 27 Sulfonylureas FAMILY 23419813 A 0 19 Polyethylene glycol SYSTEMATIC 23419813 A 262 274 ketoconazole TRIVIAL 23419813 A 57 64 acrylic SYSTEMATIC 23419813 A 850 853 PEG ABBREVIATION 23419813 A 86 95 6-carboxy SYSTEMATIC 23419814 A 310 318 fentanyl TRIVIAL 23419814 A 4 12 fentanyl TRIVIAL 23419814 A 568 576 fentanyl TRIVIAL 23419814 A 634 642 fentanyl TRIVIAL 23419814 T 28 36 fentanyl TRIVIAL 23419950 A 1004 1011 methoxy SYSTEMATIC 23419950 A 1023 1026 PEG ABBREVIATION 23419950 A 1161 1170 mannoside FAMILY 23419950 A 1182 1185 PEG ABBREVIATION 23419950 A 1200 1203 PEG ABBREVIATION 23419950 A 1237 1244 mannose TRIVIAL 23419950 A 1341 1350 mannoside FAMILY 23419950 A 1362 1365 PEG ABBREVIATION 23419950 A 1465 1472 methoxy SYSTEMATIC 23419950 A 1484 1487 PEG ABBREVIATION 23419950 A 1515 1522 methoxy SYSTEMATIC 23419950 A 1534 1537 PEG ABBREVIATION 23419950 A 1590 1597 methoxy SYSTEMATIC 23419950 A 1609 1612 PEG ABBREVIATION 23419950 A 166 173 mannose TRIVIAL 23419950 A 375 382 mannose TRIVIAL 23419950 A 650 653 PEG ABBREVIATION 23419950 A 731 739 hydroxyl SYSTEMATIC 23419950 A 741 748 methoxy SYSTEMATIC 23419950 A 753 762 mannoside FAMILY 23419950 A 914 922 hydroxyl SYSTEMATIC 23419950 A 934 937 PEG ABBREVIATION 23420115 A 12 23 Theobromine TRIVIAL 23420115 A 27 41 methylxanthine SYSTEMATIC 23420115 A 281 292 theobromine TRIVIAL 23420115 A 356 364 caffeine TRIVIAL 23420115 A 411 419 Caffeine TRIVIAL 23420115 A 516 527 Theobromine TRIVIAL 23420115 A 53 61 caffeine TRIVIAL 23420115 A 935 946 theobromine TRIVIAL 23420115 A 983 994 theobromine TRIVIAL 23420115 T 22 33 theobromine TRIVIAL 23420400 A 0 42 Trinitromethyl-substituted aminotetrazoles FAMILY 23420400 A 373 378 nitro SYSTEMATIC 23420400 A 402 411 tetrazole FAMILY 23420400 A 49 54 NH(2) FORMULA 23420400 A 57 62 NO(2) FORMULA 23420400 A 65 69 N(3) FORMULA 23420400 A 76 89 NHC(NO(2))(3) FORMULA 23420400 A 783 786 HMX ABBREVIATION 23420400 A 788 826 1,3,5,7-tetranitro-1,3,5,7-tetrazocine SYSTEMATIC 23420400 A 949 956 C-NO(2) FORMULA 23420400 T 115 156 trinitromethyl-substituted aminotetrazole FAMILY 23420471 A 1014 1018 TiO2 FORMULA 23420471 A 384 388 TiO2 FORMULA 23420471 A 584 588 P3HT ABBREVIATION 23420471 A 589 593 PCBM ABBREVIATION 23420471 A 636 640 TiO2 FORMULA 23420471 A 679 683 TiO2 FORMULA 23420471 A 952 956 TiO2 FORMULA 23420471 T 0 4 TiO2 FORMULA 23421331 A 1584 1593 metformin TRIVIAL 23421331 A 164 173 metformin TRIVIAL 23421331 A 370 379 metformin TRIVIAL 23421331 A 483 490 glucose TRIVIAL 23421331 T 52 61 metformin TRIVIAL 23421617 A 1071 1076 LAS-6 ABBREVIATION 23421617 A 1077 1085 linalool TRIVIAL 23421617 A 108 121 phenylethanol SYSTEMATIC 23421617 A 1104 1109 LAS-6 ABBREVIATION 23421617 A 1110 1118 linalool TRIVIAL 23421617 A 176 210 sodium dodecyl 6-benzene sulfonate SYSTEMATIC 23421617 A 212 217 LAS-6 ABBREVIATION 23421617 A 795 800 LAS-6 ABBREVIATION 23421617 A 865 873 linalool TRIVIAL 23421617 A 90 98 linalool TRIVIAL 23421617 A 962 967 LAS-6 ABBREVIATION 23421617 T 77 111 sodium dodecyl 6-benzene sulfonate SYSTEMATIC 23421714 A 0 18 (M)-Bicelaphanol A TRIVIAL 23421714 A 148 160 celaphanol A TRIVIAL 23421714 A 27 45 (P)-bicelaphanol A TRIVIAL 23421714 A 436 453 hydrogen peroxide SYSTEMATIC 23421714 T 0 27 (M)- and (P)-Bicelaphanol A MULTIPLE 23421714 T 37 53 Trinorditerpenes FAMILY 23421737 A 178 206 3-keton-desacetylcinobufagin SYSTEMATIC 23421737 A 212 238 3-epi-desacetylcinobufagin SYSTEMATIC 23421737 A 244 259 bufadienolide A TRIVIAL 23421737 A 269 300 15β,16α-dihydroxyl-17βH-bufalin SYSTEMATIC 23421737 A 47 67 desacetylcinobufagin TRIVIAL 23421737 T 34 54 desacetylcinobufagin TRIVIAL 23421743 A 239 246 CHCl(3) FORMULA 23421743 A 337 382 dorsamin-A763, -A737, -A765, -A739, and -A767 MULTIPLE 23421743 A 395 445 1,2-diacyl-sn-glycero-3-dehydrophenylalanine ester SYSTEMATIC 23421743 A 468 472 ABTS ABBREVIATION 23421743 A 508 518 dorsamin-A FAMILY 23421743 A 566 572 Trolox TRIVIAL 23421743 A 71 75 ABTS ABBREVIATION 23421743 T 0 10 Dorsamin-A FAMILY 23421743 T 39 59 Dehydrophenylalanine SYSTEMATIC 23421743 T 60 65 Ester SYSTEMATIC 23421877 A 210 230 sodium phenobarbital SYSTEMATIC 23421877 A 25 43 atractylenolide II TRIVIAL 23421877 A 533 565 4(R),15-epoxy-atractylenolide II SYSTEMATIC 23421877 A 573 615 4(R),15-epoxy-13-hydroxyatractylenolide II SYSTEMATIC 23421877 A 623 665 4(R),15-epoxy-1β-hydroxyatractylenolide II SYSTEMATIC 23421877 A 677 712 4(R),15-dihydroxyatractylenolide II SYSTEMATIC 23421877 A 753 771 atractylenolide II TRIVIAL 23421877 T 24 48 sesquiterpenoid lactones FAMILY 23421877 T 54 72 atractylenolide II TRIVIAL 23421877 T 9 18 eudesmane TRIVIAL 23422033 A 1132 1143 resveratrol TRIVIAL 23422033 A 203 214 resveratrol TRIVIAL 23422033 A 307 318 resveratrol TRIVIAL 23422033 A 420 431 resveratrol TRIVIAL 23422033 A 472 483 resveratrol TRIVIAL 23422033 A 586 597 resveratrol TRIVIAL 23422033 A 612 615 AMP ABBREVIATION 23422033 A 895 906 resveratrol TRIVIAL 23422033 T 0 11 Resveratrol TRIVIAL 23422034 A 386 392 phenol SYSTEMATIC 23422034 A 764 771 phenols FAMILY 23422226 A 121 128 steroid FAMILY 23422226 A 130 164 6-O-acyl-β-d-glucosyl-β-sitosterol SYSTEMATIC 23422226 A 171 187 klainedoxasterol TRIVIAL 23422226 A 240 253 triterpenoids FAMILY 23422226 A 265 273 steroids FAMILY 23422226 A 290 296 tanins FAMILY 23422226 A 30 75 2-hydroxy-24-methylenelanostan-1,8-dien-3-one SYSTEMATIC 23422226 A 423 432 lanostane TRIVIAL 23422226 A 438 451 triterpenoids FAMILY 23422226 A 6 28 lanostane triterpenoid FAMILY 23422226 A 610 618 xanthine TRIVIAL 23422226 A 726 734 xanthine TRIVIAL 23422226 A 82 103 klainedoxalanostenone TRIVIAL 23422226 T 0 9 Lanostane TRIVIAL 23422226 T 15 27 triterpenoid FAMILY 23422226 T 32 39 steroid FAMILY 23422227 A 123 137 sesquiterpenes FAMILY 23422227 A 31 41 chloroform TRIVIAL 23422227 T 10 24 sesquiterpenes FAMILY 23422263 A 1091 1099 E2-3,4-Q SYSTEMATIC 23422263 A 111 119 estrogen FAMILY 23422263 A 1242 1250 estrogen FAMILY 23422263 A 1321 1329 E2-3,4-Q SYSTEMATIC 23422263 A 134 142 E2-3,4-Q SYSTEMATIC 23422263 A 146 154 E2-2,3-Q SYSTEMATIC 23422263 A 204 212 estrogen FAMILY 23422263 A 300 317 estrogen quinones FAMILY 23422263 A 32 40 E2-2,3-Q SYSTEMATIC 23422263 A 46 71 17β-estradiol-3,4-quinone SYSTEMATIC 23422263 A 5 30 17β-estradiol-2,3-quinone SYSTEMATIC 23422263 A 507 516 cysteinyl TRIVIAL 23422263 A 528 536 E2-2,3-Q SYSTEMATIC 23422263 A 549 557 E2-3,4-Q SYSTEMATIC 23422263 A 691 699 E2-2,3-Q SYSTEMATIC 23422263 A 712 720 E2-3,4-Q SYSTEMATIC 23422263 A 73 81 E2-3,4-Q SYSTEMATIC 23422263 A 909 917 E2-3,4-Q SYSTEMATIC 23422263 A 987 995 E2-3,4-Q SYSTEMATIC 23422263 T 47 67 estrogen-3,4-quinone FAMILY 23422733 A 1086 1094 Soluplus TRIVIAL 23422733 A 1097 1113 polycaprolactone SYSTEMATIC 23422733 A 1119 1122 PEO ABBREVIATION 23422733 A 1128 1144 polycaprolactone SYSTEMATIC 23422733 A 1145 1148 PEO ABBREVIATION 23422733 A 1240 1248 Soluplus TRIVIAL 23422733 A 284 301 Diclofenac sodium SYSTEMATIC 23422733 A 896 904 Soluplus TRIVIAL 23422733 A 917 933 polycaprolactone SYSTEMATIC 23422733 A 946 949 PEO ABBREVIATION 23422872 A 205 214 peramivir TRIVIAL 23422872 T 69 78 peramivir TRIVIAL 23423243 A 1093 1113 acetylsalicylic acid SYSTEMATIC 23423243 A 1421 1429 warfarin TRIVIAL 23423243 A 1700 1720 acetylsalicylic acid SYSTEMATIC 23423243 A 51 59 warfarin TRIVIAL 23423243 A 612 620 warfarin TRIVIAL 23423243 T 24 32 warfarin TRIVIAL 23423353 A 384 397 Hoechst 33258 TRIVIAL 23423468 A 1019 1023 DAPI ABBREVIATION 23423468 A 22 51 4',6-diamidino-2-phenylindole SYSTEMATIC 23423468 A 53 57 DAPI ABBREVIATION 23423468 A 818 825 amidine SYSTEMATIC 23423468 T 88 92 DAPI ABBREVIATION 23423695 A 1042 1049 glucose TRIVIAL 23423695 A 1099 1106 glucose TRIVIAL 23423695 A 1196 1209 triglycerides FAMILY 23423695 A 1521 1528 glucose TRIVIAL 23423695 A 813 820 glucose TRIVIAL 23423710 A 1376 1383 Aza-CdR SYSTEMATIC 23423710 A 1635 1642 Aza-CdR SYSTEMATIC 23423710 A 362 384 5-Aza-2'-deoxycytidine SYSTEMATIC 23423710 A 386 393 Aza-CdR SYSTEMATIC 23423710 A 638 641 MTT ABBREVIATION 23423710 A 828 835 Aza-CdR SYSTEMATIC 23423710 A 946 953 Aza-CdR SYSTEMATIC 23423710 T 0 22 5-Aza-2'-deoxycytidine SYSTEMATIC 23423942 A 763 776 17β-estradiol SYSTEMATIC 23423942 A 780 794 17β-trenbolone SYSTEMATIC 23423942 T 105 115 trenbolone TRIVIAL 23423942 T 119 128 estradiol TRIVIAL 23423972 A 1227 1246 γ-aminobutyric acid SYSTEMATIC 23423972 A 1288 1297 N-nitroso SYSTEMATIC 23423972 A 1890 1899 N-nitroso SYSTEMATIC 23423972 A 233 272 hexahydro-1,3,5-trinitro-1,3,5-triazine SYSTEMATIC 23423972 A 418 464 hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine SYSTEMATIC 23423972 A 472 518 hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine SYSTEMATIC 23423972 A 530 571 hexahydro-1,3,5-trinitroso-1,3,5-triazine SYSTEMATIC 23423972 T 51 90 hexahydro-1,3,5-trinitro-1,3,5-triazine SYSTEMATIC 23424012 A 183 191 saponins FAMILY 23424012 A 325 333 oleanane TRIVIAL 23424012 A 339 347 saponins FAMILY 23424012 A 353 358 sugar FAMILY 23424012 A 37 56 longicarposides A-I MULTIPLE 23424012 A 429 437 saponins FAMILY 23424012 A 546 549 MTT ABBREVIATION 23424012 A 9 30 triterpenoid saponins FAMILY 23424012 A 90 98 saponins FAMILY 23424012 T 10 31 triterpenoid saponins FAMILY 23424028 A 1095 1105 permethrin TRIVIAL 23424028 A 1198 1208 permethrin TRIVIAL 23424028 A 190 210 pyrethoid permethrin TRIVIAL 23424028 A 376 386 Permethrin TRIVIAL 23424028 A 450 456 carbon SYSTEMATIC 23424028 T 55 65 permethrin TRIVIAL 23424207 A 0 7 Cadmium SYSTEMATIC 23424207 A 1027 1030 RUT ABBREVIATION 23424207 A 1035 1037 Se FORMULA 23424207 A 1047 1049 Cd FORMULA 23424207 A 1128 1130 Cd FORMULA 23424207 A 1192 1194 Se FORMULA 23424207 A 1203 1206 RUT ABBREVIATION 23424207 A 1211 1213 Se FORMULA 23424207 A 1291 1293 Cd FORMULA 23424207 A 1332 1334 Se FORMULA 23424207 A 135 140 rutin TRIVIAL 23424207 A 1356 1359 RUT ABBREVIATION 23424207 A 1379 1391 testosterone TRIVIAL 23424207 A 142 145 RUT ABBREVIATION 23424207 A 1432 1435 RUT ABBREVIATION 23424207 A 1440 1442 Se FORMULA 23424207 A 1480 1482 Cd FORMULA 23424207 A 161 169 selenium SYSTEMATIC 23424207 A 171 173 Se FORMULA 23424207 A 217 219 Cd FORMULA 23424207 A 368 370 Cd FORMULA 23424207 A 446 458 testosterone TRIVIAL 23424207 A 460 467 lactate FAMILY 23424207 A 560 577 3β-hydroxysteroid FAMILY 23424207 A 673 676 RUT ABBREVIATION 23424207 A 681 683 Se FORMULA 23424207 A 758 760 Cd FORMULA 23424207 A 850 860 superoxide TRIVIAL 23424207 A 894 905 glutathione TRIVIAL 23424207 A 9 11 Cd FORMULA 23424207 A 918 921 GSH ABBREVIATION 23424207 A 927 938 glutathione TRIVIAL 23424207 A 955 966 glutathione TRIVIAL 23424207 A 968 971 GSH ABBREVIATION 23424207 A 978 989 glutathione TRIVIAL 23424207 A 990 991 S FORMULA 23424207 T 0 5 Rutin TRIVIAL 23424207 T 11 19 Selenium SYSTEMATIC 23424207 T 31 38 cadmium SYSTEMATIC 23424208 A 1064 1074 Triparanol TRIVIAL 23424208 A 1085 1096 cholesterol TRIVIAL 23424208 A 1250 1258 probucol TRIVIAL 23424208 A 1312 1323 cholesterol TRIVIAL 23424208 A 1423 1434 cholesterol TRIVIAL 23424208 A 1446 1457 simvastatin TRIVIAL 23424208 A 1462 1472 triparanol TRIVIAL 23424208 A 265 273 probucol TRIVIAL 23424208 A 407 418 cholesterol TRIVIAL 23424208 A 436 444 probucol TRIVIAL 23424208 A 461 472 cholesterol TRIVIAL 23424208 A 481 492 simvastatin TRIVIAL 23424208 A 496 522 3-hydroxy-3-methylglutaryl SYSTEMATIC 23424208 A 559 569 triparanol TRIVIAL 23424208 A 573 589 3β-hydroxysterol FAMILY 23424208 A 61 70 potassium SYSTEMATIC 23424208 A 618 629 cholesterol TRIVIAL 23424208 A 765 773 Probucol TRIVIAL 23424208 A 790 801 cholesterol TRIVIAL 23424208 A 887 898 Simvastatin TRIVIAL 23424208 A 909 920 cholesterol TRIVIAL 23424208 T 0 8 Probucol TRIVIAL 23424208 T 17 28 cholesterol TRIVIAL 23424208 T 50 61 simvastatin TRIVIAL 23424208 T 66 76 triparanol TRIVIAL 23424212 A 1067 1070 MTX ABBREVIATION 23424212 A 1207 1210 MTX ABBREVIATION 23424212 A 1227 1230 RVT ABBREVIATION 23424212 A 1265 1268 MTX ABBREVIATION 23424212 A 1388 1391 RVT ABBREVIATION 23424212 A 1500 1503 MTX ABBREVIATION 23424212 A 153 164 resveratrol TRIVIAL 23424212 A 1547 1550 RVT ABBREVIATION 23424212 A 1588 1591 MTX ABBREVIATION 23424212 A 166 197 trans-3,5,4'-trihydroxystilbene SYSTEMATIC 23424212 A 1689 1692 RVT ABBREVIATION 23424212 A 1741 1744 MTX ABBREVIATION 23424212 A 199 202 RVT ABBREVIATION 23424212 A 212 215 MTX ABBREVIATION 23424212 A 296 299 MTX ABBREVIATION 23424212 A 384 387 MTX ABBREVIATION 23424212 A 390 393 RVT ABBREVIATION 23424212 A 428 431 RVT ABBREVIATION 23424212 A 455 458 RVT ABBREVIATION 23424212 A 495 498 MTX ABBREVIATION 23424212 A 52 64 methotrexate TRIVIAL 23424212 A 594 603 Aspartate TRIVIAL 23424212 A 628 635 alanine TRIVIAL 23424212 A 66 69 MTX ABBREVIATION 23424212 A 727 730 MTX ABBREVIATION 23424212 A 769 788 thiobarbituric acid SYSTEMATIC 23424212 A 922 933 glutathione TRIVIAL 23424212 A 934 935 S FORMULA 23424212 T 0 11 Resveratrol TRIVIAL 23424212 T 24 36 methotrexate TRIVIAL 23424213 A 1055 1058 GSH ABBREVIATION 23424213 A 1167 1170 MDA ABBREVIATION 23424213 A 1175 1177 NO FORMULA 23424213 A 433 440 alanine TRIVIAL 23424213 A 465 474 aspartate TRIVIAL 23424213 A 505 514 bilirubin TRIVIAL 23424213 A 529 533 urea TRIVIAL 23424213 A 534 542 nitrogen SYSTEMATIC 23424213 A 615 630 malondialdehyde TRIVIAL 23424213 A 632 635 MDA ABBREVIATION 23424213 A 638 649 glutathione TRIVIAL 23424213 A 651 654 GSH ABBREVIATION 23424213 A 663 673 superoxide TRIVIAL 23424213 A 694 706 nitric oxide SYSTEMATIC 23424213 A 708 710 NO FORMULA 23424213 A 823 834 hematoxylin TRIVIAL 23424213 A 839 844 eosin FAMILY 23425339 A 104 108 iron SYSTEMATIC 23425339 A 117 124 acetone SYSTEMATIC 23425339 A 144 149 FeCl2 FORMULA 23425339 A 180 186 Fe(II) FORMULA 23425339 A 269 281 Fe(H2O)6(2+) FORMULA 23425339 A 297 307 [FeCl4](-) FORMULA 23425339 A 317 324 acetone SYSTEMATIC 23425339 A 354 360 Fe(II) FORMULA 23425339 A 361 368 Fe(III) FORMULA 23425339 A 527 537 [FeCl4](-) FORMULA 23425339 A 549 556 acetone SYSTEMATIC 23425339 T 13 17 iron SYSTEMATIC 23425339 T 31 38 acetone SYSTEMATIC 23425601 A 176 220 3β, 7β, 21β-trihydroxy-urs-12-en-28-oic acid SYSTEMATIC 23425601 A 226 276 3β, 21β-dihydroxy-urs-11-en-28-oic acid-13-lactone SYSTEMATIC 23425601 A 28 40 ursolic acid TRIVIAL 23425601 A 282 326 1β, 3β, 21β-trihydroxy-urs-12-en-28-oic acid SYSTEMATIC 23425601 A 332 386 3β, 7β, 21β-trihydroxy-urs-1-en-28-oic acid-13-lactone SYSTEMATIC 23425601 A 396 441 21-oxo-1β, 3β-dihydroxy-urs-12-en-28-oic acid SYSTEMATIC 23425601 A 46 78 3β-hydroxy-urs-12-en-28-oic acid SYSTEMATIC 23425601 T 21 33 ursolic acid TRIVIAL 23425604 A 1131 1143 acetaldehyde SYSTEMATIC 23425604 A 1269 1281 acetaldehyde SYSTEMATIC 23425604 A 1381 1393 acetaldehyde SYSTEMATIC 23425604 A 204 225 [(13)C2]-acetaldehyde SYSTEMATIC 23425604 A 319 338 N (2)-ethylidene-dG SYSTEMATIC 23425604 A 59 77 N(2)-ethylidene-dG SYSTEMATIC 23425604 T 78 97 [13C2]-Acetaldehyde SYSTEMATIC 23425605 A 1003 1007 MeHg FORMULA 23425605 A 1032 1040 tyrosine TRIVIAL 23425605 A 1063 1079 α-methyltyrosine SYSTEMATIC 23425605 A 1114 1118 MeHg FORMULA 23425605 A 1139 1143 MeHg FORMULA 23425605 A 1216 1240 3-hydroxybenzylhydrazine SYSTEMATIC 23425605 A 1264 1268 MeHg FORMULA 23425605 A 1279 1287 tyrosine TRIVIAL 23425605 A 1347 1351 MeHg FORMULA 23425605 A 217 221 MeHg FORMULA 23425605 A 361 365 MeHg FORMULA 23425605 A 386 390 MeHg FORMULA 23425605 A 405 409 MeHg FORMULA 23425605 A 46 59 methylmercury SYSTEMATIC 23425605 A 464 468 MeHg FORMULA 23425605 A 550 554 MeHg FORMULA 23425605 A 61 65 MeHg FORMULA 23425605 A 618 622 MeHg FORMULA 23425605 A 707 714 calcium SYSTEMATIC 23425605 A 75 83 dopamine TRIVIAL 23425605 A 803 807 MeHg FORMULA 23425605 A 879 886 calcium SYSTEMATIC 23425605 A 888 892 MeHg FORMULA 23425605 T 20 33 catecholamine TRIVIAL 23425605 T 57 70 methylmercury SYSTEMATIC 23425605 T 89 97 dopamine TRIVIAL 23426609 A 456 469 phenobarbital TRIVIAL 23426609 A 471 480 phenytoin TRIVIAL 23426609 A 482 494 ethosuximide TRIVIAL 23426609 A 496 509 valproic acid TRIVIAL 23426609 A 511 521 vigabatrin TRIVIAL 23426609 A 523 531 tiagabin TRIVIAL 23426609 A 533 546 levitiracetam TRIVIAL 23426609 A 548 558 zonisamide TRIVIAL 23426609 A 564 574 lacosamide TRIVIAL 23426718 A 103 115 Paricalcitol TRIVIAL 23426718 A 1239 1251 paricalcitol TRIVIAL 23426718 A 129 138 vitamin D FAMILY 23426718 A 1448 1460 paricalcitol TRIVIAL 23426718 A 428 438 calcitriol TRIVIAL 23426718 A 480 492 paricalcitol TRIVIAL 23426718 T 29 41 paricalcitol TRIVIAL 23426954 A 1087 1095 CP55,940 IDENTIFIER 23426954 A 1188 1196 CP55,940 IDENTIFIER 23426954 A 1276 1284 CP55,940 IDENTIFIER 23426954 A 1290 1419 (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]-pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)-methanone mesylate SYSTEMATIC 23426954 A 1421 1432 WIN55,212-2 IDENTIFIER 23426954 A 1487 1494 alanine TRIVIAL 23426954 A 1584 1592 CP55,940 IDENTIFIER 23426954 A 1597 1608 WIN55,212-2 IDENTIFIER 23426954 A 65 74 aspartate TRIVIAL 23426954 A 725 760 guanosine 5'-3-O-(thio)triphosphate TRIVIAL 23426954 A 862 973 N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride SYSTEMATIC 23426954 A 975 984 SR141716A IDENTIFIER 23426954 A 989 1085 (-)-3cis -[2-hydroxyl-4-(1,1-dimethyl-heptyl)phenyl]-trans-4-[3-hydroxyl-propyl] cyclohexan-1-ol SYSTEMATIC 23426982 A 0 30 Polybrominated diphenyl ethers FAMILY 23426982 A 1053 1061 nona-BDE ABBREVIATION 23426982 A 1097 1105 octa-BDE ABBREVIATION 23426982 A 1128 1130 Br FORMULA 23426982 A 1164 1173 octa-BDEs ABBREVIATION 23426982 A 1201 1203 Br FORMULA 23426982 A 32 37 PBDEs ABBREVIATION 23426982 A 337 346 nona-BDEs ABBREVIATION 23426982 A 350 358 methanol SYSTEMATIC 23426982 A 573 581 octa-BDE ABBREVIATION 23426982 A 625 634 nona-BDEs ABBREVIATION 23426982 A 759 768 nona-BDEs ABBREVIATION 23426982 A 874 882 nona-BDE ABBREVIATION 23426982 A 892 894 Br FORMULA 23426982 A 905 907 Br FORMULA 23426982 A 960 968 penta-Br FORMULA 23426982 A 973 981 tetra-Br FORMULA 23426982 A 994 1001 phenyls FAMILY 23426982 T 55 64 Nona-BDEs ABBREVIATION 23426982 T 68 76 Methanol SYSTEMATIC 23427007 A 1293 1298 25OHD SYSTEMATIC 23427007 A 138 147 vitamin D FAMILY 23427007 A 1440 1449 vitamin D FAMILY 23427007 A 1587 1592 25OHD SYSTEMATIC 23427007 A 291 300 vitamin D FAMILY 23427007 A 319 338 25-hydroxyvitamin D SYSTEMATIC 23427007 A 340 345 25OHD SYSTEMATIC 23427007 A 372 384 vitamin D(3) TRIVIAL 23427007 A 57 66 vitamin D FAMILY 23427007 A 660 672 vitamin D(3) TRIVIAL 23427007 A 786 798 vitamin D(3) TRIVIAL 23427007 A 868 873 25OHD SYSTEMATIC 23427007 A 974 986 vitamin D(3) TRIVIAL 23427007 T 54 66 vitamin D(3) TRIVIAL 23427007 T 86 105 25-hydroxyvitamin D SYSTEMATIC 23427056 A 1101 1111 creatinine TRIVIAL 23427056 A 129 136 glucose TRIVIAL 23427063 A 201 228 poly(methyl metha-acrylate) SYSTEMATIC 23427063 A 232 246 Disperse Red 1 TRIVIAL 23427064 A 227 234 cadmium SYSTEMATIC 23427064 A 385 387 Cd FORMULA 23427064 A 561 563 Cd FORMULA 23427064 A 744 746 Cd FORMULA 23427064 A 879 881 Cd FORMULA 23427064 A 953 955 Cd FORMULA 23427064 T 109 116 cadmium SYSTEMATIC 23427074 A 191 206 1,3- and 1,5-DP MULTIPLE 23427074 A 64 79 Dechlorane Plus TRIVIAL 23427074 A 847 853 carbon SYSTEMATIC 23427074 T 0 15 Dechlorane plus TRIVIAL 23427076 A 230 234 SiO2 FORMULA 23427076 A 250 252 Au FORMULA 23427088 A 1649 1665 Titanium dioxide SYSTEMATIC 23427088 A 211 224 pyrophosphate SYSTEMATIC 23427137 A 154 171 4-cyanoresorcinol SYSTEMATIC 23427137 A 186 196 azobenzene SYSTEMATIC 23427850 A 272 276 PDMS ABBREVIATION 23428155 A 1036 1045 linezolid TRIVIAL 23428155 A 159 185 benzoxazinyl-oxazolidinone SYSTEMATIC 23428155 A 285 294 linezolid TRIVIAL 23428155 A 436 443 pyridyl SYSTEMATIC 23428155 A 49 91 (pyridin-3-yl) benzoxazinyl-oxazolidinones FAMILY 23428155 A 556 569 Oxazolidinone SYSTEMATIC 23428155 A 595 602 pyridyl SYSTEMATIC 23428155 A 668 683 imidazolidinone SYSTEMATIC 23428155 T 34 76 (pyridin-3-yl) benzoxazinyl-oxazolidinones FAMILY 23428212 A 117 123 carbon SYSTEMATIC 23428212 A 146 182 2,2,6,6-tetramethylpiperidine-1-oxyl SYSTEMATIC 23428212 A 184 189 TEMPO ABBREVIATION 23428212 A 244 259 sodium carboxyl SYSTEMATIC 23428212 A 763 771 graphene TRIVIAL 23428212 T 64 69 TEMPO ABBREVIATION 23428212 T 97 103 Carbon SYSTEMATIC 23428325 A 172 187 brassinosteroid FAMILY 23428325 T 19 35 brassinosteroids FAMILY 23428347 A 1043 1053 bortezomib TRIVIAL 23428347 A 1217 1227 bortezomib TRIVIAL 23428347 A 1576 1586 bortezomib TRIVIAL 23428347 A 336 346 bortezomib TRIVIAL 23428347 A 718 728 bortezomib TRIVIAL 23428347 A 948 958 bortezomib TRIVIAL 23428347 T 0 10 Bortezomib TRIVIAL 23428841 A 0 17 Tamoxifen citrate SYSTEMATIC 23428841 A 1212 1221 Tamoxifen TRIVIAL 23428841 A 1316 1333 tamoxifen citrate SYSTEMATIC 23428841 A 1495 1498 TAM ABBREVIATION 23428841 A 178 187 tamoxifen TRIVIAL 23428841 A 19 22 TAM ABBREVIATION 23428841 A 314 323 tamoxifen TRIVIAL 23428841 A 350 353 TAM ABBREVIATION 23428841 A 390 399 tamoxifen TRIVIAL 23428841 A 418 421 TAM ABBREVIATION 23428841 A 583 586 TAM ABBREVIATION 23428841 A 644 653 tamoxifen TRIVIAL 23428841 A 674 682 lecithin FAMILY 23428841 A 810 819 tamoxifen TRIVIAL 23428841 A 87 95 lecithin FAMILY 23428841 A 902 905 TAM ABBREVIATION 23428841 A 954 971 tamoxifen citrate SYSTEMATIC 23428841 T 0 8 Lecithin FAMILY 23428841 T 57 74 tamoxifen citrate SYSTEMATIC 23429043 A 0 26 1,2-Benzisothiazolin-3-one SYSTEMATIC 23429043 A 1005 1008 BIT ABBREVIATION 23429043 A 1020 1023 BIT ABBREVIATION 23429043 A 1105 1108 BIT ABBREVIATION 23429043 A 114 117 BIT ABBREVIATION 23429043 A 1375 1378 BIT ABBREVIATION 23429043 A 28 31 BIT ABBREVIATION 23429043 A 313 316 BIT ABBREVIATION 23429043 A 39 48 2634-33-5 IDENTIFIER 23429043 A 662 665 BIT ABBREVIATION 23429043 T 62 88 1,2-benzisothiazolin-3-one SYSTEMATIC 23429043 T 90 93 BIT ABBREVIATION 23429184 A 518 519 N FORMULA 23429184 A 792 798 Ca(2+) FORMULA 23429184 A 816 820 PMSF ABBREVIATION 23429184 A 824 831 lactose TRIVIAL 23429184 A 868 874 serine TRIVIAL 23429231 A 1056 1059 NVP ABBREVIATION 23429231 A 1384 1393 RhodaminB TRIVIAL 23429231 A 1420 1423 NVP ABBREVIATION 23429231 A 322 365 poly[acrylonitrile-co-(N-vinylpyrrolidone)] SYSTEMATIC 23429231 A 471 489 N-vinylpyrrolidone SYSTEMATIC 23429231 A 491 494 NVP ABBREVIATION 23429231 A 570 573 NVP ABBREVIATION 23429231 A 791 794 NVP ABBREVIATION 23429282 A 263 279 sesquiterpenoids FAMILY 23429282 A 281 287 avarol TRIVIAL 23429282 A 822 848 avarol and its monoacetate MULTIPLE 23429889 A 1130 1142 rosuvastatin TRIVIAL 23429889 A 1301 1313 Rosuvastatin TRIVIAL 23429889 A 131 143 rosuvastatin TRIVIAL 23429889 A 1459 1471 rosuvastatin TRIVIAL 23429889 A 147 158 cholesterol TRIVIAL 23429889 A 1549 1561 rosuvastatin TRIVIAL 23429889 A 1793 1805 rosuvastatin TRIVIAL 23429889 A 1854 1866 rosuvastatin TRIVIAL 23429889 A 372 384 rosuvastatin TRIVIAL 23429889 A 489 501 rosuvastatin TRIVIAL 23429889 T 45 57 rosuvastatin TRIVIAL 23429911 A 1149 1187 7-hydroxy-N,N-dipropyl-2-aminotetralin SYSTEMATIC 23429911 A 1189 1198 7-OH-DPAT SYSTEMATIC 23429911 A 4 12 dopamine TRIVIAL 23429911 A 467 480 retinoic acid TRIVIAL 23429911 A 628 641 dexamethasone TRIVIAL 23429911 T 49 57 dopamine TRIVIAL 23430408 A 1020 1032 thiamethoxam TRIVIAL 23430408 A 1273 1285 thiamethoxam TRIVIAL 23430408 A 544 556 thiamethoxam TRIVIAL 23430408 A 872 877 (14)C FORMULA 23430408 T 26 38 thiamethoxam TRIVIAL 23430761 A 1021 1032 ondansetron TRIVIAL 23430761 A 311 321 poloxamers FAMILY 23430761 A 323 327 P407 IDENTIFIER 23430761 A 33 44 ondansetron TRIVIAL 23430761 A 332 336 P188 IDENTIFIER 23430761 A 342 361 hydroxypropylmethyl SYSTEMATIC 23430761 A 755 766 ondansetron TRIVIAL 23430761 A 844 848 P407 IDENTIFIER 23430761 A 850 854 P188 IDENTIFIER 23430761 T 25 36 ondansetron TRIVIAL 23432004 A 497 507 gadolinium SYSTEMATIC 23432004 A 509 511 Gd FORMULA 23432004 A 576 578 Gd FORMULA 23432004 A 778 780 Gd FORMULA 23432004 A 975 977 Gd FORMULA 23432004 T 0 2 Gd FORMULA 23432007 A 200 206 (89)Zr FORMULA 23432007 A 277 283 (89)Zr FORMULA 23432007 A 300 315 desferrioxamine TRIVIAL 23432007 A 317 320 DFO ABBREVIATION 23432007 A 34 40 (89)Zr FORMULA 23432007 A 488 494 lysine TRIVIAL 23432007 A 589 595 lysine TRIVIAL 23432007 A 614 623 N-suc-DFO FORMULA 23432007 A 627 637 DFO-Bz-NCS FORMULA 23432007 A 758 764 (89)Zr FORMULA 23432007 A 913 919 (89)Zr FORMULA 23432007 T 0 6 (89)Zr FORMULA 23432061 A 154 158 Ca2+ FORMULA 23432061 A 303 307 Ca2+ FORMULA 23432095 A 135 143 androgen FAMILY 23432095 A 167 175 androgen FAMILY 23432095 A 224 232 androgen FAMILY 23432095 A 320 329 androgens FAMILY 23432095 A 454 476 5α-dihydrotestosterone SYSTEMATIC 23432095 A 478 490 Indomethacin TRIVIAL 23432095 A 655 667 indomethacin TRIVIAL 23432095 A 914 926 testosterone TRIVIAL 23432095 A 971 978 NADP(+) ABBREVIATION 23432095 A 979 1005 2'-des-methyl-indomethacin SYSTEMATIC 23432095 T 36 48 indomethacin TRIVIAL 23432095 T 96 114 17β-hydroxysteroid SYSTEMATIC 23432151 A 271 281 Silica gel TRIVIAL 23432151 A 353 366 ethyl acetate SYSTEMATIC 23432151 A 368 380 acetonitrile SYSTEMATIC 23432151 A 385 405 carbon tetrachloride SYSTEMATIC 23432151 A 447 467 benzopranyl capriate TRIVIAL 23432151 A 469 533 9H-1-isoprenyl-benzopyran-5-isopropanoic acid-6-ol-6-n-decanoate SYSTEMATIC 23432151 A 536 552 shorghumoic acid TRIVIAL 23432151 A 554 590 n-octadec-8,11-dien-7α-ol-1-oic acid SYSTEMATIC 23432151 A 596 611 sorghumflavin A TRIVIAL 23432151 A 613 662 2-n-butyloxo-6-β-hydroxy-7-β-isoprenyl ankaflavin SYSTEMATIC 23432151 A 706 721 hordeumflavin B TRIVIAL 23432151 A 723 764 2-n-undecanyloxo-7-β-isoprenyl ankaflavin SYSTEMATIC 23432151 A 770 783 vulgaredilone TRIVIAL 23432151 A 785 824 2-dodecanyl-7-β isopranyl monoscodilone SYSTEMATIC 23432203 A 330 337 α-amino SYSTEMATIC 23432203 A 36 37 N FORMULA 23432203 A 47 58 amino acids FAMILY 23432203 A 912 931 p-chloroamphetamine SYSTEMATIC 23432335 A 119 155 (Z)-13,15-hexadecadien-2,4-diyn-1-ol SYSTEMATIC 23432335 A 42 59 montiporic acid D TRIVIAL 23432335 A 6 35 polyacetylene carboxylic acid FAMILY 23432335 A 96 117 polyacetylene alcohol FAMILY 23432335 T 0 17 Montiporic acid D TRIVIAL 23432335 T 25 54 polyacetylene carboxylic acid FAMILY 23432582 A 0 27 Bisacylimidoselenocarbamate SYSTEMATIC 23432582 A 1074 1077 BSC ABBREVIATION 23432582 A 1122 1125 BSC ABBREVIATION 23432582 A 158 176 phosphatidylserine FAMILY 23432582 A 221 224 BSC ABBREVIATION 23432582 A 373 376 BSC ABBREVIATION 23432582 A 41 44 BSC ABBREVIATION 23432582 A 477 480 BSC ABBREVIATION 23432582 A 824 827 BSC ABBREVIATION 23432582 A 936 945 z-VAD-fmk ABBREVIATION 23432582 T 0 28 Bisacylimidoselenocarbamates FAMILY 23432586 A 1410 1416 Ca(2+) FORMULA 23432586 A 179 183 Ca2+ FORMULA 23432586 A 348 352 Ca2+ FORMULA 23432586 A 440 450 tacrolimus TRIVIAL 23432586 A 452 457 FK506 IDENTIFIER 23432586 A 463 472 sirolimus TRIVIAL 23432586 A 474 483 rapamycin TRIVIAL 23432586 A 493 497 Ca2+ FORMULA 23432586 A 920 925 FK506 IDENTIFIER 23432586 A 970 976 Ca(2+) FORMULA 23432587 A 1002 1012 technetium SYSTEMATIC 23432587 A 1014 1021 rhenium SYSTEMATIC 23432587 A 1023 1031 samarium SYSTEMATIC 23432587 A 1036 1046 gadolinium SYSTEMATIC 23432587 A 1198 1209 phosphonate SYSTEMATIC 23432587 A 1462 1478 aminophosphonate SYSTEMATIC 23432587 A 562 583 aminophosphonic acids FAMILY 23432587 A 825 841 aminophosphonate SYSTEMATIC 23432587 A 855 863 platinum SYSTEMATIC 23432587 T 0 16 Aminophosphonate SYSTEMATIC 23432708 A 0 18 Carbon monosulfide SYSTEMATIC 23432708 A 1290 1292 CS FORMULA 23432708 A 20 22 CS FORMULA 23432708 A 207 209 CS FORMULA 23432708 A 386 388 CS FORMULA 23432708 A 814 816 CS FORMULA 23433812 A 0 3 ATP ABBREVIATION 23433812 A 226 234 arsenate SYSTEMATIC 23433812 A 271 274 ATP ABBREVIATION 23433812 A 563 567 dNTP ABBREVIATION 23433812 A 611 619 arsenate SYSTEMATIC 23433812 A 658 662 dNTP ABBREVIATION 23433812 A 863 867 dNTP ABBREVIATION 23433812 T 13 17 dNTP ABBREVIATION 23434226 A 500 503 Tyr FORMULA 23434226 A 570 578 tyrosine TRIVIAL 23434228 A 105 110 DEACM ABBREVIATION 23434228 A 113 138 6-bromo-7-hydroxycoumarin SYSTEMATIC 23434228 A 140 143 BHC ABBREVIATION 23434228 A 149 174 6-bromo-7-methoxycoumarin SYSTEMATIC 23434228 A 176 180 BMCM ABBREVIATION 23434228 A 23 31 coumarin TRIVIAL 23434228 A 264 267 BHC ABBREVIATION 23434228 A 268 279 cholesterol TRIVIAL 23434228 A 38 50 cholesterols FAMILY 23434228 A 81 103 6-diethylaminocoumarin SYSTEMATIC 23434228 T 40 48 coumarin TRIVIAL 23434228 T 55 66 cholesterol TRIVIAL 23434322 A 117 120 caC ABBREVIATION 23434322 A 161 169 cytosine TRIVIAL 23434322 A 21 37 5-methylcytosine SYSTEMATIC 23434322 A 283 286 hmC ABBREVIATION 23434322 A 55 70 5-hydroxymethyl SYSTEMATIC 23434322 A 678 681 hmC ABBREVIATION 23434322 A 72 75 hmC ABBREVIATION 23434322 A 731 734 hmC ABBREVIATION 23434322 A 78 86 5-formyl SYSTEMATIC 23434322 A 97 115 5-carboxylcytosine SYSTEMATIC 23434322 T 20 45 5-(hydroxy)methylcytosine SYSTEMATIC 23434422 A 17 31 sesquiterpenes FAMILY 23434422 A 177 205 bicyclic furanosesquiterpene SYSTEMATIC 23434422 A 285 310 α,β-unsaturated-γ-lactone SYSTEMATIC 23434422 A 33 49 euryspongins A-C MULTIPLE 23434422 A 331 336 furan SYSTEMATIC 23434422 A 625 645 dehydroeuryspongin A SYSTEMATIC 23434422 T 0 16 Euryspongins A-C MULTIPLE 23434422 T 35 49 sesquiterpenes FAMILY 23434491 A 1012 1014 E2 FORMULA 23434491 A 1061 1068 steroid FAMILY 23434491 A 1212 1215 KTC ABBREVIATION 23434491 A 1277 1280 KTC ABBREVIATION 23434491 A 1392 1395 KTC ABBREVIATION 23434491 A 1477 1480 KTC ABBREVIATION 23434491 A 1501 1503 E2 FORMULA 23434491 A 306 319 17β-estradiol SYSTEMATIC 23434491 A 321 323 E2 FORMULA 23434491 A 329 341 ketoconazole TRIVIAL 23434491 A 343 346 KTC ABBREVIATION 23434491 A 536 553 7-ethoxyresorufin SYSTEMATIC 23434491 A 554 555 O FORMULA 23434491 A 605 607 E2 FORMULA 23434491 A 749 751 E2 FORMULA 23434491 A 859 867 estrogen FAMILY 23434491 A 947 949 E2 FORMULA 23434491 A 954 957 KTC ABBREVIATION 23434491 T 15 28 17β-estradiol SYSTEMATIC 23434491 T 33 45 ketoconazole TRIVIAL 23434641 A 1023 1033 rifampicin TRIVIAL 23434641 A 139 202 5-(2-benzylsulfanyl-pyridin-3-yl)-3H-[1,3,4]oxadiazole-2-thione SYSTEMATIC 23434641 A 18 94 5-(2-benzylsulfanyl-pyridin-3-yl)-2-(substituted)-sulfanyl-1,3,4-oxadiazoles FAMILY 23434641 A 285 296 haloacetate FAMILY 23434641 A 301 310 haloalkyl FAMILY 23434641 A 422 423 C FORMULA 23434641 A 425 426 H FORMULA 23434641 A 428 429 N FORMULA 23434641 A 779 792 benzothiazole SYSTEMATIC 23434641 A 883 893 ampicillin TRIVIAL 23434641 A 920 928 triazole FAMILY 23434641 A 933 943 morpholine SYSTEMATIC 23434641 T 4 35 2-benzylsulfanyl-nicotinic acid SYSTEMATIC 23434641 T 42 59 1,3,4-oxadiazoles FAMILY 23434648 A 1052 1053 C FORMULA 23434648 A 1137 1140 LPA ABBREVIATION 23434648 A 1292 1295 LPA ABBREVIATION 23434648 A 427 430 LPA ABBREVIATION 23434648 A 632 635 LPA ABBREVIATION 23434648 A 786 789 LPA ABBREVIATION 23434669 A 24 33 rapamycin TRIVIAL 23434669 A 506 515 Rapamycin TRIVIAL 23434669 A 842 845 ATP ABBREVIATION 23434669 T 76 85 Rapamycin TRIVIAL 23434929 A 1097 1111 Corticosterone TRIVIAL 23434929 A 1215 1228 Catecholamine FAMILY 23434929 A 1354 1368 corticosterone TRIVIAL 23434929 A 24 36 somatostatin TRIVIAL 23434929 A 344 358 Streptozotocin TRIVIAL 23434929 A 86 100 corticosterone TRIVIAL 23434929 T 33 45 Somatostatin TRIVIAL 23434931 A 601 612 tunicamycin TRIVIAL 23434931 A 932 938 oxygen SYSTEMATIC 23434934 A 122 132 nucleotide FAMILY 23435179 A 483 492 disulfide SYSTEMATIC 23435179 A 925 938 acetylcholine SYSTEMATIC 23435356 A 0 9 Serotonin TRIVIAL 23435356 A 1008 1012 5-HT SYSTEMATIC 23435356 A 1057 1061 5-HT SYSTEMATIC 23435356 A 11 15 5-HT SYSTEMATIC 23435356 A 166 170 5-HT SYSTEMATIC 23435356 A 235 245 Tryptophan TRIVIAL 23435356 A 295 299 5-HT SYSTEMATIC 23435356 A 94 98 5-HT SYSTEMATIC 23435356 T 0 10 Tryptophan TRIVIAL 23435615 A 1008 1026 omeprazole sulfone TRIVIAL 23435615 A 1105 1128 (R)-5-hydroxyomeprazole SYSTEMATIC 23435615 A 1220 1243 (S)-5-hydroxyomeprazole SYSTEMATIC 23435615 A 1256 1270 (R)-omeprazole TRIVIAL 23435615 A 1422 1436 (S)-omeprazole TRIVIAL 23435615 A 1483 1497 (R)-omeprazole TRIVIAL 23435615 A 1553 1571 racemic-omeprazole SYSTEMATIC 23435615 A 235 249 (R)-omeprazole TRIVIAL 23435615 A 278 296 racemic omeprazole SYSTEMATIC 23435615 A 676 686 omeprazole TRIVIAL 23435615 A 715 725 omeprazole TRIVIAL 23435615 A 871 894 (R)- and (S)-omeprazole MULTIPLE 23435615 A 9 19 Omeprazole TRIVIAL 23435615 T 4 18 (R)-omeprazole TRIVIAL 23435910 A 0 12 Sinapic acid TRIVIAL 23435910 A 1006 1018 sinapic acid TRIVIAL 23435910 A 1078 1081 DMN ABBREVIATION 23435910 A 1292 1304 sinapic acid TRIVIAL 23435910 A 249 261 sinapic acid TRIVIAL 23435910 A 265 284 dimethylnitrosamine SYSTEMATIC 23435910 A 286 289 DMN ABBREVIATION 23435910 A 32 47 phenylpropanoid SYSTEMATIC 23435910 A 329 341 Sinapic acid TRIVIAL 23435910 A 363 366 DMN ABBREVIATION 23435910 A 462 469 alanine TRIVIAL 23435910 A 484 493 aspartate TRIVIAL 23435910 A 518 533 malondialdehyde TRIVIAL 23435910 A 556 568 sinapic acid TRIVIAL 23435910 A 585 599 hydroxyproline SYSTEMATIC 23435910 A 913 925 sinapic acid TRIVIAL 23435910 A 927 939 Sinapic acid TRIVIAL 23435910 T 10 22 sinapic acid TRIVIAL 23435910 T 31 50 dimethylnitrosamine SYSTEMATIC 23435913 A 1094 1103 tadalafil TRIVIAL 23435913 A 141 150 tadalafil TRIVIAL 23435913 A 204 213 Tadalafil TRIVIAL 23435913 A 218 228 acebutolol TRIVIAL 23435913 A 297 320 tert-butyl methyl ether SYSTEMATIC 23435913 A 437 448 formic acid SYSTEMATIC 23435913 A 453 465 acetonitrile SYSTEMATIC 23435913 A 918 927 Tadalafil TRIVIAL 23435913 T 98 107 tadalafil TRIVIAL 23435916 A 0 11 Pristimerin TRIVIAL 23435916 A 15 42 quinonemethide triterpenoid FAMILY 23435916 A 243 254 pristimerin TRIVIAL 23435916 A 281 292 Pristimerin TRIVIAL 23435916 A 331 343 nitric oxide SYSTEMATIC 23435916 A 345 347 NO FORMULA 23435916 A 353 369 prostaglandin E2 TRIVIAL 23435916 A 408 410 NO FORMULA 23435916 A 524 535 pristimerin TRIVIAL 23435916 A 716 727 pristimerin TRIVIAL 23435916 T 28 39 pristimerin TRIVIAL 23435942 A 1049 1056 tacrine TRIVIAL 23435942 A 1058 1067 donepezil TRIVIAL 23435942 A 1069 1081 rivastigmine TRIVIAL 23435942 A 1083 1094 galantamine TRIVIAL 23435942 A 1096 1110 xanthostigmine TRIVIAL 23435942 A 1112 1134 para-aminobenzoic acid SYSTEMATIC 23435942 A 1136 1144 coumarin TRIVIAL 23435942 A 1146 1155 flavonoid FAMILY 23435942 A 1161 1178 pyrrolo-isoxazole SYSTEMATIC 23435942 A 530 543 acetylcholine SYSTEMATIC 23435942 A 896 909 acetylcholine SYSTEMATIC 23435948 A 1024 1049 3,5-dicaffeoylquinic acid SYSTEMATIC 23435948 A 1051 1089 3,5-dicaffeoylquinic acid methyl ester SYSTEMATIC 23435948 A 1091 1116 4,5-dicaffeoylquinic acid SYSTEMATIC 23435948 A 1118 1139 3-caffeoylquinic acid SYSTEMATIC 23435948 A 1150 1158 chromone TRIVIAL 23435948 A 1160 1172 capillarisin TRIVIAL 23435948 A 1198 1207 esculetin TRIVIAL 23435948 A 1209 1219 scopoletin TRIVIAL 23435948 A 1221 1230 quercetin TRIVIAL 23435948 A 1232 1242 hyperoside TRIVIAL 23435948 A 1244 1256 isorhamnetin TRIVIAL 23435948 A 1258 1296 3,5-dicaffeoylquinic acid methyl ester SYSTEMATIC 23435948 A 1298 1323 3,4-dicaffeoylquinic acid SYSTEMATIC 23435948 A 1329 1354 1,5-dicaffeoylquinic acid SYSTEMATIC 23435948 A 136 144 methanol SYSTEMATIC 23435948 A 1444 1452 acarbose TRIVIAL 23435948 A 1467 1476 esculetin TRIVIAL 23435948 A 1481 1504 6-methoxy artemicapin C SYSTEMATIC 23435948 A 1570 1592 dicaffeoylquinic acids FAMILY 23435948 A 1897 1906 coumarins FAMILY 23435948 A 1908 1918 flavonoids FAMILY 23435948 A 1924 1946 dicaffeoylquinic acids FAMILY 23435948 A 226 234 tyrosine TRIVIAL 23435948 A 263 271 methanol SYSTEMATIC 23435948 A 379 387 methanol SYSTEMATIC 23435948 A 656 665 coumarins FAMILY 23435948 A 667 676 esculetin TRIVIAL 23435948 A 678 685 esculin TRIVIAL 23435948 A 687 695 scopolin TRIVIAL 23435948 A 697 708 isoscopolin TRIVIAL 23435948 A 710 719 daphnetin TRIVIAL 23435948 A 721 734 umbelliferone TRIVIAL 23435948 A 736 754 7-methoxy coumarin SYSTEMATIC 23435948 A 756 765 scoparone TRIVIAL 23435948 A 767 777 scopoletin TRIVIAL 23435948 A 779 802 6-methoxy artemicapin C SYSTEMATIC 23435948 A 807 817 flavonoids FAMILY 23435948 A 819 829 hyperoside TRIVIAL 23435948 A 831 840 quercetin TRIVIAL 23435948 A 842 854 isorhamnetin TRIVIAL 23435948 A 856 867 cirsilineol TRIVIAL 23435948 A 869 879 arcapillin TRIVIAL 23435948 A 881 909 isorhamnetin 3-robinobioside SYSTEMATIC 23435948 A 911 918 linarin TRIVIAL 23435948 A 920 945 isorhamnetin 3-glucoiside SYSTEMATIC 23435948 A 950 958 phenolic FAMILY 23435948 A 970 995 1,5-dicaffeoylquinic acid SYSTEMATIC 23435948 A 997 1022 3,4-dicaffeoylquinic acid SYSTEMATIC 23435948 T 33 41 tyrosine TRIVIAL 23436129 A 1101 1112 acamprosate TRIVIAL 23436129 A 1396 1407 Acamprosate TRIVIAL 23436129 A 1660 1671 acamprosate TRIVIAL 23436129 A 1747 1758 acamprosate TRIVIAL 23436129 A 391 400 glutamate TRIVIAL 23436129 A 415 438 gamma-aminobutyric acid SYSTEMATIC 23436129 A 440 444 GABA ABBREVIATION 23436129 A 529 540 acamprosate TRIVIAL 23436129 A 611 622 Acamprosate TRIVIAL 23436129 T 10 21 acamprosate TRIVIAL 23436266 A 0 11 Allopurinol TRIVIAL 23436266 A 1076 1083 statins FAMILY 23436266 A 1172 1183 allopurinol TRIVIAL 23436266 A 1223 1233 colchicine TRIVIAL 23436266 A 1237 1244 statins FAMILY 23436266 A 1284 1295 allopurinol TRIVIAL 23436266 A 140 151 allopurinol TRIVIAL 23436266 A 223 234 allopurinol TRIVIAL 23436266 A 328 339 allopurinol TRIVIAL 23436266 A 43 52 uric acid TRIVIAL 23436266 A 476 487 allopurinol TRIVIAL 23436266 A 654 665 cholesterol TRIVIAL 23436266 A 688 697 aspartate TRIVIAL 23436266 A 730 737 alanine TRIVIAL 23436266 A 850 861 colchicines FAMILY 23436266 A 888 895 statins FAMILY 23436266 A 995 1006 colchicines FAMILY 23436266 T 44 55 allopurinol TRIVIAL 23436544 A 0 11 Vemurafenib TRIVIAL 23436544 A 136 147 vemurafenib TRIVIAL 23436544 A 203 214 vemurafenib TRIVIAL 23436544 A 412 423 Vemurafenib TRIVIAL 23436544 A 774 785 vemurafenib TRIVIAL 23436544 T 0 11 Vemurafenib TRIVIAL 23436791 A 1049 1052 ATP ABBREVIATION 23436791 A 1069 1072 ATP ABBREVIATION 23436791 A 11 17 serine TRIVIAL 23436791 A 1240 1250 paclitaxel TRIVIAL 23436791 A 18 27 threonine TRIVIAL 23436791 A 351 354 ATP ABBREVIATION 23436791 A 367 384 indolyl-pyrrolone SYSTEMATIC 23436791 A 545 548 ATP ABBREVIATION 23436791 A 595 610 2-aminothiazole SYSTEMATIC 23436791 A 670 673 ATP ABBREVIATION 23436791 A 846 862 2-aminothiazoles FAMILY 23436791 A 957 960 ATP ABBREVIATION 23436791 T 78 81 ATP ABBREVIATION 23437766 A 189 199 amantadine TRIVIAL 23437766 A 22 32 amantadine TRIVIAL 23437766 A 37 48 rimantadine TRIVIAL 23437766 A 715 721 benzyl SYSTEMATIC 23437766 A 734 744 amantadine TRIVIAL 23437766 A 809 855 4-(adamantan-1-ylaminomethyl)-benzene-1,3-diol SYSTEMATIC 23437926 A 0 9 Hecogenin TRIVIAL 23437926 A 1012 1023 naltrindole TRIVIAL 23437926 A 1068 1081 glibenclamide TRIVIAL 23437926 A 1083 1086 ATP ABBREVIATION 23437926 A 1097 1101 K(+) FORMULA 23437926 A 194 211 hecogenin acetate SYSTEMATIC 23437926 A 854 862 naloxone TRIVIAL 23437926 A 915 919 CTOP ABBREVIATION 23437926 A 961 968 nor-BNI ABBREVIATION 23437926 T 103 120 Hecogenin Acetate SYSTEMATIC 23438500 A 178 183 Br(-) FORMULA 23438500 A 209 211 Pd FORMULA 23438500 A 230 235 Br(-) FORMULA 23438500 A 267 269 Pd FORMULA 23438500 A 345 347 Pd FORMULA 23438500 A 370 375 Br(-) FORMULA 23438500 A 528 530 Pd FORMULA 23438500 A 694 699 Br(-) FORMULA 23438500 A 733 735 Pd FORMULA 23438500 A 792 797 Br(-) FORMULA 23438500 T 117 119 Pd FORMULA 23438500 T 49 52 Br- FORMULA 23438500 T 61 63 Pd FORMULA 23438503 A 1077 1088 atomoxetine TRIVIAL 23438503 A 1125 1140 methylphenidate SYSTEMATIC 23438503 A 1386 1401 methylphenidate SYSTEMATIC 23438503 A 1443 1454 atomoxetine TRIVIAL 23438503 A 160 171 atomoxetine TRIVIAL 23438503 A 254 265 atomoxetine TRIVIAL 23438503 A 417 428 atomoxetine TRIVIAL 23438503 A 493 504 atomoxetine TRIVIAL 23438503 A 579 590 atomoxetine TRIVIAL 23438503 A 793 804 Atomoxetine TRIVIAL 23438503 T 21 32 atomoxetine TRIVIAL 23439033 A 565 581 hydrofluoroether SYSTEMATIC 23439131 A 133 154 poly(ethylene glycol) SYSTEMATIC 23439131 A 156 159 PEG ABBREVIATION 23439131 A 312 315 PEG ABBREVIATION 23439223 A 257 264 steroid FAMILY 23439223 A 486 498 testosterone TRIVIAL 23439223 A 500 509 estradiol TRIVIAL 23439223 A 515 523 cortisol TRIVIAL 23439223 T 81 88 steroid FAMILY 23439241 A 974 984 phenacetin TRIVIAL 23439241 A 989 998 bupropion TRIVIAL 23439561 A 1265 1274 thymidine TRIVIAL 23439561 A 1294 1298 PGE2 ABBREVIATION 23439561 A 141 157 prostaglandin E2 TRIVIAL 23439561 A 1475 1479 PGE2 ABBREVIATION 23439561 A 159 163 PGE2 ABBREVIATION 23439561 A 272 276 PGE2 ABBREVIATION 23439561 A 293 308 prostaglandin E FAMILY 23439561 A 354 358 PGE2 ABBREVIATION 23439561 A 729 733 PGE2 ABBREVIATION 23439561 A 749 758 thymidine TRIVIAL 23439561 A 787 792 NADPH ABBREVIATION 23439561 A 828 835 calcium SYSTEMATIC 23439561 A 935 944 thymidine TRIVIAL 23439561 A 964 968 PGE2 ABBREVIATION 23439561 T 0 5 NADPH ABBREVIATION 23439561 T 76 91 Prostaglandin E FAMILY 23439649 A 1129 1138 thioester SYSTEMATIC 23439649 A 1346 1349 Phe FORMULA 23439649 A 14 20 (125)I FORMULA 23439649 A 680 688 oxyester SYSTEMATIC 23439660 A 1291 1300 oxycodone TRIVIAL 23439660 A 1327 1339 noroxycodone TRIVIAL 23439660 A 1344 1355 oxymorphone TRIVIAL 23439660 A 1366 1375 oxycodone TRIVIAL 23439660 A 1522 1531 oxycodone TRIVIAL 23439660 A 1576 1585 oxycodone TRIVIAL 23439660 A 1794 1803 oxycodone TRIVIAL 23439660 A 276 286 androstane TRIVIAL 23439660 A 307 323 Aryl hydrocarbon FAMILY 23439660 A 489 498 oxycodone TRIVIAL 23439660 T 82 91 oxycodone TRIVIAL 23440404 A 1008 1011 BDT ABBREVIATION 23440404 A 1294 1300 Au-S-C FORMULA 23440404 A 1315 1323 Au-S-C-C FORMULA 23440404 A 275 277 Au FORMULA 23440404 A 292 304 thiol sulfur SYSTEMATIC 23440404 A 66 89 gold-1,4-benzenedithiol SYSTEMATIC 23440404 A 91 94 BDT ABBREVIATION 23440404 A 974 977 C=C FORMULA 23440664 A 300 304 cGMP ABBREVIATION 23440664 A 481 493 Nikkomycin Z TRIVIAL 23440664 A 50 62 Nikkomycin Z TRIVIAL 23440664 A 63 66 HCl FORMULA 23440664 T 73 85 Nikkomycin Z TRIVIAL 23440956 A 0 7 Silicon SYSTEMATIC 23440956 A 1008 1016 graphene TRIVIAL 23440956 A 1121 1123 Si FORMULA 23440956 A 1145 1153 graphene TRIVIAL 23440956 A 1202 1204 Si FORMULA 23440956 A 1305 1307 Si FORMULA 23440956 A 1324 1332 graphene TRIVIAL 23440956 A 1406 1414 graphene TRIVIAL 23440956 A 1419 1421 Si FORMULA 23440956 A 152 154 Si FORMULA 23440956 A 1569 1577 graphene TRIVIAL 23440956 A 1591 1593 Si FORMULA 23440956 A 1708 1715 lithium SYSTEMATIC 23440956 A 357 359 Si FORMULA 23440956 A 396 404 graphene TRIVIAL 23440956 A 471 473 Si FORMULA 23440956 A 492 506 graphene oxide SYSTEMATIC 23440956 A 559 561 Si FORMULA 23440956 A 608 622 graphene oxide SYSTEMATIC 23440956 A 632 634 Si FORMULA 23440956 A 656 670 graphene oxide SYSTEMATIC 23440956 A 69 76 lithium SYSTEMATIC 23440956 A 695 697 Si FORMULA 23440956 A 761 763 Si FORMULA 23440956 A 790 798 graphene TRIVIAL 23440956 A 812 814 Si FORMULA 23440956 A 897 905 graphene TRIVIAL 23440956 A 9 11 Si FORMULA 23440956 T 0 8 Graphene TRIVIAL 23440956 T 34 36 Si FORMULA 23440956 T 55 62 Lithium SYSTEMATIC 23441753 A 1030 1037 pNIPAAm ABBREVIATION 23441753 A 19 55 hydrated poly(N-isopropylacrylamide) SYSTEMATIC 23441753 A 226 235 Isoniazid TRIVIAL 23441753 A 390 399 Isoniazid TRIVIAL 23441753 A 577 586 Isoniazid TRIVIAL 23441753 A 82 91 Isoniazid TRIVIAL 23441753 T 59 86 poly(N-isopropylacrylamide) SYSTEMATIC 23441816 A 299 305 Ca(2+) FORMULA 23441816 A 4 10 Ca(2+) FORMULA 23441816 A 537 543 Ca(2+) FORMULA 23441816 T 0 6 Ca(2+) FORMULA 23441829 A 195 199 V2O5 FORMULA 23441829 A 20 24 V2O5 FORMULA 23441829 A 215 223 n-butane SYSTEMATIC 23441829 A 225 230 C4H10 FORMULA 23441829 A 244 250 V2O5H2 FORMULA 23441829 A 270 278 hydrogen SYSTEMATIC 23441829 A 298 303 C4H10 FORMULA 23441829 A 307 311 V2O5 FORMULA 23441829 A 323 327 C4H8 FORMULA 23441829 A 374 378 V2O5 FORMULA 23441829 A 441 446 C4H10 FORMULA 23441829 A 533 537 V2O5 FORMULA 23441829 A 557 562 C4H10 FORMULA 23441829 A 597 601 V2O5 FORMULA 23441829 A 736 742 V2O5H2 FORMULA 23441829 A 825 829 V2O5 FORMULA 23441829 A 842 846 V2O5 FORMULA 23441829 A 867 871 C2H6 FORMULA 23441829 A 880 886 V2O5H2 FORMULA 23441829 A 891 895 C2H4 FORMULA 23441829 A 979 983 V2O5 FORMULA 23441829 A 984 988 C2H6 FORMULA 23441829 T 30 42 hydrocarbons FAMILY 23441829 T 66 71 oxide SYSTEMATIC 23441829 T 7 10 C-H FORMULA 23441843 A 1070 1073 Lig ABBREVIATION 23441843 A 1178 1181 Lig ABBREVIATION 23441843 A 1287 1290 Lig ABBREVIATION 23441843 A 1592 1595 Lig ABBREVIATION 23441843 A 535 548 Z-Ligustilide SYSTEMATIC 23441843 A 550 553 Lig ABBREVIATION 23441843 A 631 634 Lig ABBREVIATION 23441843 A 726 729 Lig ABBREVIATION 23441843 A 863 872 Bisulfite SYSTEMATIC 23441843 A 906 909 Lig ABBREVIATION 23441843 T 99 112 Z-ligustilide SYSTEMATIC 23441878 A 104 109 CHBr3 FORMULA 23441878 A 1140 1142 Br FORMULA 23441878 A 1165 1170 CHBr3 FORMULA 23441878 A 120 124 CHI3 FORMULA 23441878 A 1270 1275 CHBr2 FORMULA 23441878 A 1276 1278 Br FORMULA 23441878 A 135 139 CCl4 FORMULA 23441878 A 205 206 C FORMULA 23441878 A 207 208 H FORMULA 23441878 A 243 259 polyhalomethanes FAMILY 23441878 A 308 309 C FORMULA 23441878 A 310 311 H FORMULA 23441878 A 375 382 halogen FAMILY 23441878 A 406 407 C FORMULA 23441878 A 470 475 CHBr2 FORMULA 23441878 A 476 478 Br FORMULA 23441878 A 506 510 CHI2 FORMULA 23441878 A 511 512 I FORMULA 23441878 A 929 934 CHBr3 FORMULA 23441878 T 34 39 CHBr3 FORMULA 23441878 T 44 48 CHI3 FORMULA 23442005 A 1022 1039 amino sulfonamide SYSTEMATIC 23442005 A 1044 1051 proline TRIVIAL 23442005 A 153 162 aldehydes FAMILY 23442005 A 308 315 enamine SYSTEMATIC 23442005 A 339 357 aliphatic aldehyde FAMILY 23442005 A 449 464 3-methylbutanal SYSTEMATIC 23442005 A 471 478 enamine SYSTEMATIC 23442005 A 493 510 α-chloroaldehydes FAMILY 23442005 A 516 524 carbonyl FAMILY 23442005 A 52 59 proline TRIVIAL 23442005 A 602 603 C FORMULA 23442005 A 604 605 C FORMULA 23442005 A 633 640 enamine SYSTEMATIC 23442005 A 670 678 aldehyde SYSTEMATIC 23442005 A 692 699 proline TRIVIAL 23442005 A 711 728 amino sulfonamide SYSTEMATIC 23442005 A 79 96 amino sulfonamide SYSTEMATIC 23442005 A 883 902 aliphatic aldehydes FAMILY 23442005 A 916 927 α-methylene SYSTEMATIC 23442005 T 78 97 Aliphatic Aldehydes FAMILY 23442025 A 136 141 argon SYSTEMATIC 23442025 A 319 332 Fe(CN)(6)(3–) FORMULA 23442025 A 337 343 methyl SYSTEMATIC 23442025 A 71 72 H FORMULA 23442025 A 75 80 OH(–) FORMULA 23442025 A 83 88 H(2)O FORMULA 23442151 A 0 6 Phenol SYSTEMATIC 23442151 A 1031 1038 benzene SYSTEMATIC 23442151 A 1139 1145 phenol SYSTEMATIC 23442151 A 1165 1171 phenol SYSTEMATIC 23442151 A 138 145 benzene SYSTEMATIC 23442151 A 166 185 sodium hypochlorite SYSTEMATIC 23442151 A 260 279 sodium hypochlorite SYSTEMATIC 23442151 A 296 315 sodium hypochlorite SYSTEMATIC 23442151 A 342 348 phenol SYSTEMATIC 23442151 A 412 431 sodium hypochlorite SYSTEMATIC 23442151 A 445 451 phenol SYSTEMATIC 23442151 A 51 58 benzene SYSTEMATIC 23442151 A 521 540 sodium hypochlorite SYSTEMATIC 23442151 A 555 561 phenol SYSTEMATIC 23442151 A 567 586 sodium hypochlorite SYSTEMATIC 23442151 A 672 678 oxygen SYSTEMATIC 23442151 A 715 718 •OH FORMULA 23442151 A 726 727 H FORMULA 23442151 A 729 731 H2 FORMULA 23442151 A 737 741 H2O2 FORMULA 23442151 A 760 766 phenol SYSTEMATIC 23442151 A 772 791 sodium hypochlorite SYSTEMATIC 23442151 A 79 98 sodium hypochlorite SYSTEMATIC 23442151 A 807 811 NaCl FORMULA 23442151 A 862 868 phenol SYSTEMATIC 23442151 A 874 881 benzene SYSTEMATIC 23442151 A 896 915 sodium hypochlorite SYSTEMATIC 23442151 A 958 966 chlorine SYSTEMATIC 23442151 A 974 993 Sodium hypochlorite SYSTEMATIC 23442151 T 0 6 Phenol SYSTEMATIC 23442151 T 48 55 benzene SYSTEMATIC 23442151 T 70 89 sodium hypochlorite SYSTEMATIC 23442197 A 0 7 A-74528 IDENTIFIER 23442197 A 13 27 C30 polyketide FAMILY 23442197 A 322 329 A-74528 IDENTIFIER 23442197 A 471 485 fredericamycin TRIVIAL 23442197 A 592 599 A-74528 IDENTIFIER 23442197 A 709 716 A-74528 IDENTIFIER 23442197 A 965 972 A-74528 IDENTIFIER 23442197 A 991 1005 fredericamycin TRIVIAL 23442197 T 32 39 A-74528 IDENTIFIER 23443405 A 1104 1111 silicon SYSTEMATIC 23443405 A 201 204 ZnO FORMULA 23443405 A 45 52 silicon SYSTEMATIC 23443405 A 668 675 silicon SYSTEMATIC 23443405 A 676 679 ZnO FORMULA 23443405 A 77 87 zinc oxide SYSTEMATIC 23443405 A 89 92 ZnO FORMULA 23443405 A 939 942 ZnO FORMULA 23443405 T 72 74 Si FORMULA 23443405 T 75 78 ZnO FORMULA 23443408 A 0 16 Titanium dioxide SYSTEMATIC 23443408 A 265 269 TiO2 FORMULA 23443408 A 32 36 TiO2 FORMULA 23443408 A 335 339 TiO2 FORMULA 23443408 A 576 580 TiO2 FORMULA 23443408 A 748 758 nucleotide FAMILY 23443408 A 765 771 O-Ti-O FORMULA 23443408 A 987 993 oxygen SYSTEMATIC 23443408 T 46 62 titanium dioxide SYSTEMATIC 23443628 A 1172 1181 donepezil TRIVIAL 23443628 A 1186 1195 memantine TRIVIAL 23443628 A 1393 1402 donepezil TRIVIAL 23443628 A 1407 1416 memantine TRIVIAL 23443628 A 1664 1676 rivastigmine TRIVIAL 23443628 A 1681 1690 donepezil TRIVIAL 23443628 A 2025 2034 memantine TRIVIAL 23443628 A 2058 2067 donepezil TRIVIAL 23443628 A 39 48 memantine TRIVIAL 23443628 A 585 594 donepezil TRIVIAL 23443628 A 596 608 rivastigmine TRIVIAL 23443628 A 610 621 galantamine TRIVIAL 23443628 A 626 635 memantine TRIVIAL 23443957 A 1168 1174 oxygen SYSTEMATIC 23443957 A 1240 1246 oxygen SYSTEMATIC 23443957 A 292 298 oxygen SYSTEMATIC 23443957 A 42 48 oxygen SYSTEMATIC 23443957 A 544 550 oxygen SYSTEMATIC 23443957 A 573 644 platinum(ii)-5,10,15,20-tetrakis-(2,3,4,5,6-pentafluorphenyl)-porphyrin SYSTEMATIC 23443957 A 646 652 PtTFPP ABBREVIATION 23443957 A 817 823 oxygen SYSTEMATIC 23443957 A 97 103 oxygen SYSTEMATIC 23443957 T 13 19 oxygen SYSTEMATIC 23444256 A 105 112 Truvada TRIVIAL 23444256 A 1169 1172 FTC ABBREVIATION 23444256 A 1173 1176 TDF ABBREVIATION 23444256 A 1482 1485 FTC ABBREVIATION 23444256 A 1486 1489 TDF ABBREVIATION 23444256 A 1707 1710 FTC ABBREVIATION 23444256 A 1711 1714 TDF ABBREVIATION 23444256 A 1831 1834 FTC ABBREVIATION 23444256 A 1835 1838 TDF ABBREVIATION 23444256 A 273 276 FTC ABBREVIATION 23444256 A 277 280 TDF ABBREVIATION 23444256 A 30 43 emtricitabine TRIVIAL 23444256 A 45 48 FTC ABBREVIATION 23444256 A 564 567 FTC ABBREVIATION 23444256 A 568 571 TDF ABBREVIATION 23444256 A 61 90 tenofovir disoproxil fumarate TRIVIAL 23444256 A 743 746 FTC ABBREVIATION 23444256 A 747 750 TDF ABBREVIATION 23444256 A 92 95 TDF ABBREVIATION 23444256 T 0 13 Emtricitabine TRIVIAL 23444256 T 14 43 tenofovir disoproxil fumarate TRIVIAL 23444284 A 1090 1100 nevirapine TRIVIAL 23444284 A 1143 1153 nevirapine TRIVIAL 23444284 A 12 22 nevirapine TRIVIAL 23444284 A 1277 1287 nevirapine TRIVIAL 23444284 A 1370 1380 nevirapine TRIVIAL 23444284 A 241 251 nevirapine TRIVIAL 23444284 A 573 583 nevirapine TRIVIAL 23444284 A 837 847 nevirapine TRIVIAL 23444284 T 41 51 nevirapine TRIVIAL 23444335 A 302 306 iron SYSTEMATIC 23444335 A 587 591 zinc SYSTEMATIC 23444335 A 596 604 selenium SYSTEMATIC 23444335 A 766 774 selenium SYSTEMATIC 23444335 A 779 783 zinc SYSTEMATIC 23444335 T 35 39 iron SYSTEMATIC 23444387 A 1014 1023 menadione TRIVIAL 23444387 A 1050 1058 carbonyl FAMILY 23444387 A 482 493 haloperidol TRIVIAL 23444387 A 495 506 mebendazole TRIVIAL 23444387 A 512 523 ziprasidone TRIVIAL 23444387 A 821 832 haloperidol TRIVIAL 23444387 A 837 848 mebendazole TRIVIAL 23444387 A 889 894 NADPH ABBREVIATION 23444387 A 903 907 NADH ABBREVIATION 23444389 A 1084 1087 Rb1 ABBREVIATION 23444389 A 1134 1137 Rb1 ABBREVIATION 23444389 A 1175 1178 ATP ABBREVIATION 23444389 A 1182 1185 ADP ABBREVIATION 23444389 A 1218 1226 Ca(2)(+) FORMULA 23444389 A 1266 1271 azide SYSTEMATIC 23444389 A 1304 1313 diazoxide SYSTEMATIC 23444389 A 1332 1340 Ca(2)(+) FORMULA 23444389 A 1357 1367 nifedipine TRIVIAL 23444389 A 1399 1402 Rb1 ABBREVIATION 23444389 A 1469 1481 ginsenosides FAMILY 23444389 A 1563 1575 ginsenosides FAMILY 23444389 A 296 303 glucose TRIVIAL 23444389 A 422 430 saponins FAMILY 23444389 A 498 513 Ginsenoside Rb1 TRIVIAL 23444389 A 515 518 Rb1 ABBREVIATION 23444389 A 58 70 Ginsenosides FAMILY 23444389 A 721 735 streptozotocin TRIVIAL 23444389 A 954 961 glucose TRIVIAL 23444389 T 87 99 ginsenosides FAMILY 23444429 A 1055 1071 poly(ADP-ribose) SYSTEMATIC 23444773 A 334 345 mitomycin C TRIVIAL 23444773 A 347 350 MMC ABBREVIATION 23444773 A 353 362 cisplatin TRIVIAL 23444782 A 588 598 sibutramin TRIVIAL 23444782 A 672 679 alanine TRIVIAL 23444782 A 707 716 aspartate TRIVIAL 23444783 A 1175 1178 Glu FORMULA 23444783 A 1309 1312 Glu FORMULA 23444783 A 518 527 glutamate TRIVIAL 23444783 A 529 532 Glu FORMULA 23444783 A 629 632 Glu FORMULA 23444783 A 647 650 Glu FORMULA 23444783 T 140 149 glutamate TRIVIAL 23444785 A 429 444 Malondialdehyde TRIVIAL 23444785 A 446 449 MDA ABBREVIATION 23444785 A 452 462 superoxide TRIVIAL 23444785 A 658 661 MDA ABBREVIATION 23444785 A 724 727 MDA ABBREVIATION 23444833 A 141 165 lystabactins A, B, and C MULTIPLE 23444833 A 255 265 amino acid FAMILY 23444833 A 289 301 lystabactins FAMILY 23444833 A 318 324 serine TRIVIAL 23444833 A 326 329 Ser FORMULA 23444833 A 332 342 asparagine TRIVIAL 23444833 A 344 347 Asn FORMULA 23444833 A 354 388 formylated/hydroxylated ornithines MULTIPLE 23444833 A 390 396 FOHOrn ABBREVIATION 23444833 A 399 421 dihydroxy benzoic acid SYSTEMATIC 23444833 A 423 426 Dhb ABBREVIATION 23444833 A 448 475 nonproteinogenic amino acid NO CLASS 23444833 A 477 511 4,8-diamino-3-hydroxyoctanoic acid SYSTEMATIC 23444833 A 513 518 LySta ABBREVIATION 23444833 T 38 42 Iron SYSTEMATIC 23444833 T 65 77 Lystabactins FAMILY 23445125 A 499 511 erythromycin TRIVIAL 23445125 A 662 668 amines FAMILY 23445125 A 763 775 erythromycin TRIVIAL 23445362 A 101 103 Zn FORMULA 23445362 A 104 114 superoxide TRIVIAL 23445362 A 31 51 aryloxanylpyrazolone FAMILY 23445362 A 4 26 arylsulfanylpyrazolone FAMILY 23445362 A 403 424 arylazanylpyrazolones FAMILY 23445362 A 534 544 pyrazolone SYSTEMATIC 23445362 A 639 645 phenol SYSTEMATIC 23445362 A 668 678 pyrazolone SYSTEMATIC 23445362 A 722 742 arylazanylpyrazolone FAMILY 23445362 A 98 100 Cu FORMULA 23445362 T 0 20 Arylazanylpyrazolone FAMILY 23445362 T 57 67 superoxide TRIVIAL 23445497 A 131 143 camptothecin TRIVIAL 23445497 A 145 155 paclitaxel TRIVIAL 23445497 A 157 168 doxorubicin TRIVIAL 23445497 A 173 182 docetaxel TRIVIAL 23445497 A 226 251 phenyl O-carboxyanhydride SYSTEMATIC 23445497 A 253 260 Phe-OCA ABBREVIATION 23445497 A 282 289 Phe-OCA ABBREVIATION 23445497 A 329 334 PheLA ABBREVIATION 23445497 A 695 706 polylactide FAMILY 23445497 A 716 721 PheLA ABBREVIATION 23445497 A 99 107 hydroxyl SYSTEMATIC 23445497 T 105 129 poly(O-carboxyanhydride) FAMILY 23445497 T 46 65 O-carboxyanhydrides FAMILY 23446230 A 1012 1016 EETs ABBREVIATION 23446230 A 106 110 EETs ABBREVIATION 23446230 A 1440 1444 EETs ABBREVIATION 23446230 A 212 216 EETs ABBREVIATION 23446230 A 53 70 arachidonic acids FAMILY 23446230 A 572 576 EETs ABBREVIATION 23446230 A 79 104 epoxyeicosatrienoic acids FAMILY 23446230 A 903 907 EETs ABBREVIATION 23446230 T 32 36 EETs ABBREVIATION 23446276 A 1051 1057 Mg(2+) FORMULA 23446276 A 1281 1285 urea TRIVIAL 23446276 A 533 540 adenine TRIVIAL 23446276 A 948 955 adenine TRIVIAL 23447132 A 1108 1112 cAMP ABBREVIATION 23447132 A 1182 1186 cAMP ABBREVIATION 23447132 A 148 152 cAMP ABBREVIATION 23447132 A 1656 1660 cAMP ABBREVIATION 23447132 A 220 227 calcium SYSTEMATIC 23447132 A 41 45 cAMP ABBREVIATION 23447132 A 429 433 cAMP ABBREVIATION 23447132 A 462 466 cAMP ABBREVIATION 23447132 A 507 511 cAMP ABBREVIATION 23447132 A 566 576 nucleotide FAMILY 23447132 A 827 831 cAMP ABBREVIATION 23447132 A 857 861 cAMP ABBREVIATION 23447132 T 39 43 cAMP ABBREVIATION 23447132 T 66 70 cAMP ABBREVIATION 23447427 A 192 198 Cu(2+) FORMULA 23447427 A 206 214 ZnIn2 S4 FORMULA 23447427 A 329 331 H2 FORMULA 23447427 A 38 46 sulphide SYSTEMATIC 23447427 A 95 101 copper SYSTEMATIC 23447427 T 140 148 hydrogen SYSTEMATIC 23447427 T 52 60 sulphide SYSTEMATIC 23447538 A 1538 1545 tryptic FAMILY 23447538 A 1915 1921 serine TRIVIAL 23447538 A 39 45 serine TRIVIAL 23447538 T 92 98 serine TRIVIAL 23448196 A 267 274 glucose TRIVIAL 23448196 A 288 295 glucose TRIVIAL 23448202 T 112 129 cadmium telluride SYSTEMATIC 23448384 A 1042 1049 ethanol SYSTEMATIC 23448384 A 1059 1067 methanol SYSTEMATIC 23448384 A 1069 1073 MeOH FORMULA 23448384 A 1122 1128 Hfa(-) ABBREVIATION 23448384 A 1189 1201 [dppz][H2fa] ABBREVIATION 23448384 A 1222 1246 [H-dppz(+)][Hfa(-)]·MeOH FORMULA 23448384 A 133 141 hydrogen SYSTEMATIC 23448384 A 1393 1412 [H-dppz(+)][Hfa(-)] FORMULA 23448384 A 1486 1498 [dppz][H2fa] ABBREVIATION 23448384 A 21 33 anilic acids FAMILY 23448384 A 213 226 [H-dppz][Hca] ABBREVIATION 23448384 A 231 244 [H-dppz][Hba] ABBREVIATION 23448384 A 246 250 H2ca ABBREVIATION 23448384 A 253 269 chloranilic acid TRIVIAL 23448384 A 271 275 H2ba ABBREVIATION 23448384 A 278 293 bromanilic acid TRIVIAL 23448384 A 35 39 H2xa ABBREVIATION 23448384 A 406 414 hydrogen SYSTEMATIC 23448384 A 45 72 2,3-di(2-pyridinyl)pyrazine SYSTEMATIC 23448384 A 598 606 hydrogen SYSTEMATIC 23448384 A 731 735 dppz ABBREVIATION 23448384 A 74 78 dppz ABBREVIATION 23448384 A 740 744 H2ba ABBREVIATION 23448384 A 816 836 [H(1.5)-dppz]2[Hba]3 FORMULA 23448384 A 868 889 [H-dppz]2[Hba]2[H2ba] FORMULA 23448384 A 910 914 dppz ABBREVIATION 23448384 A 936 952 fluoranilic acid TRIVIAL 23448384 A 954 958 H2fa ABBREVIATION 23448384 A 993 997 H2fa ABBREVIATION 23448384 T 101 113 anilic acids FAMILY 23448384 T 118 145 2,3-di(2-pyridinyl)pyrazine SYSTEMATIC 23448384 T 58 66 hydrogen SYSTEMATIC 23448620 A 527 557 carbazochrome sodium sulfonate SYSTEMATIC 23448620 A 690 700 tinidazole TRIVIAL 23448682 A 284 293 tetrazine FAMILY 23448682 A 294 304 norbornene TRIVIAL 23448682 A 565 568 PEG ABBREVIATION 23448682 A 569 578 tetrazine FAMILY 23448682 A 607 619 dinorbornene TRIVIAL 23448682 A 786 795 tetrazine FAMILY 23448682 A 796 806 norbornene TRIVIAL 23448682 A 877 882 thiol FAMILY 23448682 A 883 886 ene SYSTEMATIC 23448682 A 970 979 tetrazine FAMILY 23448682 T 88 97 tetrazine FAMILY 23448682 T 98 108 norbornene TRIVIAL 23448860 A 1016 1025 manganese SYSTEMATIC 23448860 A 128 137 manganese SYSTEMATIC 23448860 A 139 141 Mn FORMULA 23448860 A 294 296 Mn FORMULA 23448860 A 421 423 Mn FORMULA 23448860 A 619 621 Mn FORMULA 23448860 A 758 760 Mn FORMULA 23448860 A 810 812 Mn FORMULA 23448860 A 844 846 Mn FORMULA 23448860 A 901 903 Mn FORMULA 23448860 A 931 933 Mn FORMULA 23448860 T 47 56 manganese SYSTEMATIC 23448861 A 1124 1132 ethenone SYSTEMATIC 23448861 A 1137 1151 crotonaldehyde TRIVIAL 23448861 A 248 256 ethenone SYSTEMATIC 23448861 A 261 275 crotonaldehyde TRIVIAL 23448861 A 385 393 ethenone SYSTEMATIC 23448861 A 398 412 crotonaldehyde TRIVIAL 23448861 A 688 694 oxygen SYSTEMATIC 23448861 A 782 788 oxygen SYSTEMATIC 23448861 T 85 93 ethenone SYSTEMATIC 23448861 T 98 112 crotonaldehyde TRIVIAL 23449201 A 1057 1064 lactose TRIVIAL 23449201 A 124 131 Lactose TRIVIAL 23449201 A 1258 1265 lactose TRIVIAL 23449201 A 213 226 hydroxypropyl SYSTEMATIC 23449201 A 238 258 hydroxypropyl methyl SYSTEMATIC 23449201 A 274 294 polyvinylpyrrolidone SYSTEMATIC 23449201 A 449 456 lactose TRIVIAL 23449205 A 124 156 (3R),(5S)-5-hydroxylasiodiplodin SYSTEMATIC 23449205 A 184 188 EtOH FORMULA 23449205 A 23 30 lactone FAMILY 23449205 A 32 64 (3S),(6R)-6-hydroxylasiodiplodin SYSTEMATIC 23449205 A 96 114 (3R)-lasiodiplodin TRIVIAL 23449205 T 0 13 Lasiodiplodin TRIVIAL 23449220 A 1034 1037 FdU ABBREVIATION 23449220 A 1050 1055 FdUMP ABBREVIATION 23449220 A 316 330 deoxythymidine SYSTEMATIC 23449220 A 649 673 5-fluoro-2'-deoxyuridine SYSTEMATIC 23449220 A 675 678 FdU ABBREVIATION 23449220 A 873 876 FdU ABBREVIATION 23449220 A 891 894 FdU ABBREVIATION 23449220 T 54 78 5-fluoro-2'-deoxyuridine SYSTEMATIC 23450151 A 230 237 cadmium SYSTEMATIC 23450151 A 255 257 Zn FORMULA 23450151 A 258 260 Ag FORMULA 23450151 A 261 263 In FORMULA 23450151 A 264 265 S FORMULA 23450151 A 267 271 ZAIS ABBREVIATION 23450151 A 494 498 ZAIS ABBREVIATION 23450151 A 553 560 cadmium SYSTEMATIC 23450151 A 599 607 DHLA-PEG ABBREVIATION 23450151 A 704 710 folate TRIVIAL 23450151 A 839 841 Cd FORMULA 23450151 T 44 46 Zn FORMULA 23450151 T 47 49 Ag FORMULA 23450151 T 50 52 In FORMULA 23450151 T 53 54 S FORMULA 23450752 A 1024 1036 tetraproline FAMILY 23450752 A 1094 1102 hydrogen SYSTEMATIC 23450752 A 136 178 4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidines FAMILY 23450752 A 204 216 tetraproline FAMILY 23450752 A 272 284 tetraproline FAMILY 23450752 A 350 395 4-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidines FAMILY 23450752 A 408 450 4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidines FAMILY 23450752 A 41 68 4-aryl-1,4-dihydropyridines FAMILY 23450752 A 499 534 racemic 4-aryl-1,4-dihydropyridines FAMILY 23450752 A 542 554 tetraproline FAMILY 23450752 A 593 605 5,5-dimethyl SYSTEMATIC 23450752 A 674 686 5,5-dimethyl SYSTEMATIC 23450752 A 712 754 4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidines FAMILY 23450752 A 77 122 4-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidines FAMILY 23450752 A 773 779 sulfur SYSTEMATIC 23450752 A 826 871 4-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidines FAMILY 23450752 A 982 994 tetraproline FAMILY 23450752 T 116 128 tetraproline FAMILY 23450752 T 35 62 4-aryl-1,4-dihydropyridines FAMILY 23450752 T 67 103 4-aryl-1,2,3,4-tetrahydropyrimidines FAMILY 23450777 A 0 24 Graphitic carbon nitride SYSTEMATIC 23450777 A 126 131 C3 N4 FORMULA 23450777 A 187 188 N FORMULA 23450777 A 189 190 C FORMULA 23450777 A 253 267 carbon nitride SYSTEMATIC 23450777 A 345 353 hydrogen SYSTEMATIC 23450777 T 11 35 graphitic carbon nitride SYSTEMATIC 23450777 T 74 82 hydrogen SYSTEMATIC 23450829 A 125 129 TiO2 FORMULA 23450829 A 13 17 TiO2 FORMULA 23450829 A 43 45 Ti FORMULA 23451707 A 178 208 sulfated quinazolin-4(3H)-ones FAMILY 23451707 A 210 214 QAOs ABBREVIATION 23451758 A 1189 1193 C2-D FORMULA 23451758 A 1214 1223 imidazole SYSTEMATIC 23451758 A 1245 1246 H FORMULA 23451758 A 1335 1339 C2-D FORMULA 23451758 A 1374 1375 H FORMULA 23451758 A 1405 1408 His FORMULA 23451758 A 1462 1468 Cu(2+) FORMULA 23451758 A 1483 1487 C2-D FORMULA 23451758 A 15 24 histidine TRIVIAL 23451758 A 1765 1768 His FORMULA 23451758 A 1786 1789 His FORMULA 23451758 A 212 215 His FORMULA 23451758 A 218 241 4-substituted imidazole FAMILY 23451758 A 248 251 His FORMULA 23451758 A 26 29 His FORMULA 23451758 A 319 322 His FORMULA 23451758 A 4 14 amino acid FAMILY 23451758 A 514 517 His FORMULA 23451758 A 562 571 deuterium SYSTEMATIC 23451758 A 605 609 C2-H FORMULA 23451758 A 610 618 hydrogen SYSTEMATIC 23451758 A 631 634 His FORMULA 23451758 A 635 644 imidazole SYSTEMATIC 23451758 A 655 664 deuterium SYSTEMATIC 23451758 A 695 699 C2-D FORMULA 23451758 A 793 802 imidazole SYSTEMATIC 23451758 A 911 915 C2-D FORMULA 23451758 A 966 969 His FORMULA 23451758 A 993 997 C2-D FORMULA 23451797 A 33 53 racemosalactones A-E MULTIPLE 23451797 A 81 102 sesquiterpene latones FAMILY 23451797 A 870 881 alantolides FAMILY 23451797 A 9 31 sesquiterpene lactones FAMILY 23451797 T 52 74 Sesquiterpene Lactones FAMILY 23451803 A 146 148 Au FORMULA 23451803 A 45 53 Fe-PTCDA FORMULA 23451803 A 505 510 PTCDA ABBREVIATION 23451803 A 518 526 Fe-PTCDA FORMULA 23451803 A 55 109 perylene-3,4,9,10-tetracarboxylic-3,4,9,10-dianhydride SYSTEMATIC 23451823 A 17 41 cryptocapsin-5,6-epoxide SYSTEMATIC 23451823 A 178 202 Cryptocapsin-5,6-epoxide SYSTEMATIC 23451823 A 256 268 cryptocapsin TRIVIAL 23451823 A 43 73 3'-deoxycapsanthin-5,6-epoxide SYSTEMATIC 23451823 A 472 496 cryptocapsin-5,8-epoxide SYSTEMATIC 23451823 A 616 641 cryptocapsin-5,8-epoxides FAMILY 23451823 A 79 104 cryptocapsin-5,8-epoxides FAMILY 23451823 T 0 19 Cryptocapsinepoxide FAMILY 23451983 A 101 105 PFCE ABBREVIATION 23451983 A 110 118 fluorine SYSTEMATIC 23451983 A 141 145 PFCE ABBREVIATION 23451983 A 262 266 PFCE ABBREVIATION 23451983 A 74 99 perfluoro-1,5-crown ether SYSTEMATIC 23452042 A 20 26 NAD(+) ABBREVIATION 23452042 A 356 374 N-hydroxyarylamine FAMILY 23452042 A 375 376 O FORMULA 23452042 A 521 527 lysine TRIVIAL 23452042 A 632 638 lysine TRIVIAL 23452042 A 785 791 lysine TRIVIAL 23452042 A 826 827 O FORMULA 23452042 A 850 851 N FORMULA 23452042 A 969 975 lysine TRIVIAL 23452042 T 105 123 N-hydroxyarylamine FAMILY 23452042 T 124 125 O FORMULA 23452042 T 22 28 lysine TRIVIAL 23452147 A 1096 1097 N FORMULA 23452147 A 1155 1156 C FORMULA 23452147 A 1272 1273 N FORMULA 23452147 A 1279 1280 C FORMULA 23452147 A 1423 1424 N FORMULA 23452147 A 1565 1566 C FORMULA 23452147 A 745 746 N FORMULA 23452147 A 774 775 C FORMULA 23452147 A 851 852 N FORMULA 23452147 A 858 859 C FORMULA 23452219 A 191 203 Theophylline TRIVIAL 23452219 A 352 364 theophylline TRIVIAL 23452219 A 387 395 caffeine TRIVIAL 23452219 A 423 429 methyl SYSTEMATIC 23452219 A 478 490 theophylline TRIVIAL 23452219 A 585 591 Purine TRIVIAL 23452219 A 695 702 guanine TRIVIAL 23452219 A 706 713 adenine TRIVIAL 23452219 A 812 818 purine TRIVIAL 23452254 A 102 118 polyoxometalates FAMILY 23452254 A 1020 1026 oxygen SYSTEMATIC 23452254 A 120 124 POMs ABBREVIATION 23452254 A 126 152 (R, R)-[(R*PO3)2M5O15](2-) FAMILY 23452254 A 1319 1335 transition metal FAMILY 23452254 A 1427 1431 POMs ABBREVIATION 23452254 A 159 169 CH3CH(NH3) FORMULA 23452254 A 176 178 Mo FORMULA 23452254 A 180 181 W FORMULA 23452254 A 624 650 (R, R)-[(R*PO3)2W5O15](2-) FAMILY 23452254 A 657 667 CH3CH(NH3) FORMULA 23452855 A 310 317 glycine TRIVIAL 23452855 A 321 330 glutamate TRIVIAL 23452857 A 18 38 N-methyl-D-aspartate SYSTEMATIC 23452857 A 582 588 serine TRIVIAL 23452857 T 65 69 NMDA ABBREVIATION 23453039 A 1024 1031 glucose TRIVIAL 23453039 A 1162 1169 glucose TRIVIAL 23453039 A 1300 1312 triglyceride FAMILY 23453039 A 1320 1331 cholesterol TRIVIAL 23453039 A 136 143 calcium SYSTEMATIC 23453039 A 396 403 calcium SYSTEMATIC 23453039 A 69 76 calcium SYSTEMATIC 23453039 A 873 887 streptozotocin TRIVIAL 23453039 A 963 970 glucose TRIVIAL 23453067 A 1009 1019 nucleotide FAMILY 23453067 A 1066 1073 guanine TRIVIAL 23453067 A 265 275 6-O-methyl SYSTEMATIC 23453067 A 333 352 guanine nucleosides FAMILY 23453067 A 389 420 2'-C-methyl-6-O-methylguanosine SYSTEMATIC 23453067 A 548 571 2'-C-methyl-6-O-methyl- SYSTEMATIC 23453067 A 579 588 guanosine TRIVIAL 23453067 A 659 660 N FORMULA 23453067 A 670 680 nucleobase FAMILY 23453067 A 732 763 2'-C-methyl-6-O-methylguanosine SYSTEMATIC 23453067 A 74 94 2'-C-methylguanosine FAMILY 23453067 A 902 925 2'-C-methyl-6-O-methyl- SYSTEMATIC 23453067 A 933 942 guanosine TRIVIAL 23453067 T 123 155 L-Alanine ester phosphoramidates FAMILY 23453067 T 75 118 2'-C-methyl-6-O-methyl guanosine nucleoside FAMILY 23453068 A 13 20 leucine TRIVIAL 23453068 A 339 376 4-alkylamino-7-aryl-3-cyanoquinolines FAMILY 23453068 A 635 638 Ser FORMULA 23453068 T 13 49 4-alkylamino-7-aryl-3-cyanoquinoline FAMILY 23453303 A 1165 1168 MDA ABBREVIATION 23453303 A 726 729 MDA ABBREVIATION 23453831 A 1604 1622 iridoid glucosides FAMILY 23453831 A 1624 1632 iridoids FAMILY 23453831 A 1637 1649 secoiridoids FAMILY 23453831 A 1652 1661 xanthones FAMILY 23453831 A 1666 1676 flavonoids FAMILY 23453831 A 1678 1696 Iridoid glucosides FAMILY 23453831 A 1744 1756 Loganic acid TRIVIAL 23453831 A 1758 1767 Sweroside TRIVIAL 23453831 A 1769 1781 Swertiamarin TRIVIAL 23453831 A 1783 1798 Gentiopicroside TRIVIAL 23453831 A 1800 1808 Gentisin TRIVIAL 23453831 A 1810 1821 Isogentisin TRIVIAL 23453831 A 1823 1833 Gentioside TRIVIAL 23453831 A 1835 1850 Norswertianolin TRIVIAL 23453831 A 1852 1864 Swertianolin TRIVIAL 23453831 A 1866 1927 4″-O-β-d-glucosyl-6'-O-(4-O-β-d-glucosylcaffeoyl)-linearoside SYSTEMATIC 23453831 A 1932 1941 Swertisin TRIVIAL 23453831 A 1986 1994 methanol SYSTEMATIC 23453831 A 341 345 DPPH ABBREVIATION 23453831 A 347 355 hydroxyl SYSTEMATIC 23453831 A 486 498 α-tocopherol TRIVIAL 23453831 A 500 508 catechin TRIVIAL 23453831 A 513 516 BHT ABBREVIATION 23453831 A 633 642 flavonoid FAMILY 23453831 A 781 798 sulphorhodamine B TRIVIAL 23453831 A 800 803 SRB ABBREVIATION 23454011 A 1042 1050 vitamins FAMILY 23454011 A 1092 1102 vitamin D3 TRIVIAL 23454011 A 1232 1242 vitamin D3 TRIVIAL 23454011 A 149 160 cholesterol TRIVIAL 23454011 A 26 43 aluminum silicate TRIVIAL 23454011 A 325 342 vitamin D3 and K1 MULTIPLE 23454011 A 537 547 vitamin D3 TRIVIAL 23454011 A 559 569 vitamin K1 TRIVIAL 23454011 A 606 616 vitamin D3 TRIVIAL 23454011 A 631 641 vitamin K1 TRIVIAL 23454011 A 67 82 montmorillonite TRIVIAL 23454011 A 726 738 stigmastanol TRIVIAL 23454011 A 768 778 vitamin D3 TRIVIAL 23454011 A 906 916 vitamin K1 TRIVIAL 23454011 T 145 163 vitamins D3 and K1 MULTIPLE 23454011 T 57 74 aluminum silicate TRIVIAL 23454011 T 76 87 cholesterol TRIVIAL 23454052 A 1140 1143 ZnO FORMULA 23454052 A 1315 1318 ZnO FORMULA 23454052 A 173 176 ZnO FORMULA 23454052 A 227 230 ZnO FORMULA 23454052 A 27 37 zinc oxide SYSTEMATIC 23454052 A 338 341 ZnO FORMULA 23454052 A 39 42 ZnO FORMULA 23454052 A 703 706 ZnO FORMULA 23454052 A 839 842 ZnO FORMULA 23454052 A 876 879 ZnO FORMULA 23454052 A 995 998 ZnO FORMULA 23454052 T 68 78 zinc oxide SYSTEMATIC 23454054 A 205 217 indomethacin TRIVIAL 23454054 A 222 231 saccharin TRIVIAL 23454054 A 233 236 IMC ABBREVIATION 23454054 A 237 240 SAC ABBREVIATION 23454054 A 480 488 methanol SYSTEMATIC 23454054 A 564 567 IMC ABBREVIATION 23454054 A 568 571 SAC ABBREVIATION 23454054 A 662 665 IMC ABBREVIATION 23454054 A 666 669 SAC ABBREVIATION 23454054 A 684 687 IMC ABBREVIATION 23454054 T 19 31 indomethacin TRIVIAL 23454054 T 32 41 saccharin TRIVIAL 23454054 T 43 46 IMC ABBREVIATION 23454054 T 47 50 SAC ABBREVIATION 23454133 A 1154 1155 H FORMULA 23454133 A 259 269 olanzapine TRIVIAL 23454133 A 274 285 simvastatin TRIVIAL 23454133 A 945 955 olanzapine TRIVIAL 23454133 A 960 971 simvastatin TRIVIAL 23454148 A 105 119 5-fluorouracil SYSTEMATIC 23454148 A 1279 1295 prostaglandin E2 TRIVIAL 23454148 A 129 140 mitomycin C TRIVIAL 23454148 A 1313 1316 MMC ABBREVIATION 23454148 A 1376 1379 MMC ABBREVIATION 23454148 A 142 145 MMC ABBREVIATION 23454148 A 1516 1519 MMC ABBREVIATION 23454148 A 436 439 MMC ABBREVIATION 23454148 A 442 451 Cisplatin TRIVIAL 23454148 A 456 459 MMC ABBREVIATION 23454148 A 551 565 5-Fluorouracil SYSTEMATIC 23454148 A 677 688 glutathione TRIVIAL 23454148 A 689 690 S FORMULA 23454148 A 719 720 N FORMULA 23454148 A 725 733 cysteine TRIVIAL 23454148 A 734 735 S FORMULA 23454148 A 843 860 dihydropyrimidine SYSTEMATIC 23454148 A 89 98 cisplatin TRIVIAL 23454148 A 919 922 MMC ABBREVIATION 23454148 A 942 949 quinone FAMILY 23454148 A 973 981 xanthine TRIVIAL 23454148 T 65 74 cisplatin TRIVIAL 23454148 T 76 90 5-fluorouracil SYSTEMATIC 23454148 T 95 106 mitomycin C TRIVIAL 23454208 A 1033 1041 luteolin TRIVIAL 23454208 A 1189 1197 luteolin TRIVIAL 23454208 A 1279 1287 luteolin TRIVIAL 23454208 A 160 168 luteolin TRIVIAL 23454208 A 319 327 luteolin TRIVIAL 23454208 A 504 505 N FORMULA 23454208 A 58 66 luteolin TRIVIAL 23454208 A 583 591 luteolin TRIVIAL 23454208 A 617 625 luteolin TRIVIAL 23454208 A 84 93 flavonoid FAMILY 23454208 A 857 871 bafilomycin A1 TRIVIAL 23454208 A 918 926 luteolin TRIVIAL 23454208 T 92 100 luteolin TRIVIAL 23454297 A 1058 1070 caffeic acid TRIVIAL 23454297 A 1178 1190 caffeic acid TRIVIAL 23454297 A 1260 1272 caffeic acid TRIVIAL 23454297 A 152 162 nucleotide FAMILY 23454297 A 219 228 adenosine TRIVIAL 23454297 A 36 48 caffeic acid TRIVIAL 23454297 A 401 413 caffeic acid TRIVIAL 23454297 A 428 440 caffeic acid TRIVIAL 23454297 A 458 470 caffeic acid TRIVIAL 23454297 A 508 520 caffeic acid TRIVIAL 23454297 A 562 574 caffeic acid TRIVIAL 23454297 A 589 592 ATP ABBREVIATION 23454297 A 618 621 ADP ABBREVIATION 23454297 A 837 849 Caffeic acid TRIVIAL 23454297 A 97 120 nucleoside triphosphate FAMILY 23454297 T 0 12 Caffeic acid TRIVIAL 23454297 T 48 66 adenine nucleotide TRIVIAL 23454308 A 1569 1575 Al(3+) FORMULA 23454308 A 170 185 aluminium oxide SYSTEMATIC 23454308 A 461 468 alumina TRIVIAL 23454308 A 48 63 aluminium oxide SYSTEMATIC 23454308 A 616 622 Al(3+) FORMULA 23454308 T 16 31 aluminium oxide SYSTEMATIC 23454309 A 1072 1078 methyl SYSTEMATIC 23454309 A 1079 1081 Hg FORMULA 23454309 A 1349 1351 Hg FORMULA 23454309 A 139 145 methyl SYSTEMATIC 23454309 A 146 148 Hg FORMULA 23454309 A 1477 1479 Hg FORMULA 23454309 A 1513 1515 Hg FORMULA 23454309 A 1689 1691 Hg FORMULA 23454309 A 1812 1814 Hg FORMULA 23454309 A 202 207 (15)N FORMULA 23454309 A 422 424 Hg FORMULA 23454309 A 537 539 Hg FORMULA 23454309 A 545 550 (15)N FORMULA 23454309 A 652 654 Hg FORMULA 23454309 A 715 717 Hg FORMULA 23454309 A 723 728 (15)N FORMULA 23454309 A 766 772 methyl SYSTEMATIC 23454309 A 773 775 Hg FORMULA 23454309 A 81 88 mercury SYSTEMATIC 23454309 A 847 853 methyl SYSTEMATIC 23454309 A 854 856 Hg FORMULA 23454309 A 862 867 (15)N FORMULA 23454309 A 90 92 Hg FORMULA 23454309 A 908 910 Hg FORMULA 23454309 T 43 50 mercury SYSTEMATIC 23454310 A 1425 1431 silver SYSTEMATIC 23454310 A 1725 1731 silver SYSTEMATIC 23454310 A 190 196 silver SYSTEMATIC 23454310 A 44 50 silver SYSTEMATIC 23454310 T 36 42 silver SYSTEMATIC 23454529 A 112 123 quinazoline SYSTEMATIC 23454529 A 223 231 hydrogen SYSTEMATIC 23454529 A 264 275 quinazoline SYSTEMATIC 23454529 A 30 45 indoloquinoline SYSTEMATIC 23454529 A 406 444 N-(2-(quinazolin-2-yl)phenyl)benzamide SYSTEMATIC 23454529 A 446 449 QPB ABBREVIATION 23454529 A 473 484 quinazoline SYSTEMATIC 23454529 A 49 67 benzofuroquinoline SYSTEMATIC 23454529 A 522 528 phenyl SYSTEMATIC 23454529 A 615 618 QPB ABBREVIATION 23454529 A 719 724 LZ-11 IDENTIFIER 23454529 A 766 777 quinazoline SYSTEMATIC 23454529 A 829 832 QPB ABBREVIATION 23454529 T 4 15 quinazoline SYSTEMATIC 23454529 T 80 86 phenyl SYSTEMATIC 23454648 A 0 14 Polyamidoamine SYSTEMATIC 23454648 A 1112 1117 amino FAMILY 23454648 A 1153 1158 PAMAM ABBREVIATION 23454648 A 16 21 PAMAM ABBREVIATION 23454648 A 294 300 oxygen SYSTEMATIC 23454648 A 465 470 PAMAM ABBREVIATION 23454648 A 707 712 amino FAMILY 23454648 A 883 888 amino FAMILY 23454648 T 101 115 polyamidoamine FAMILY 23454648 T 117 122 PAMAM ABBREVIATION 23454648 T 37 43 oxygen SYSTEMATIC 23454829 A 0 106 (2R,3R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside SYSTEMATIC 23454829 A 1008 1015 alanine TRIVIAL 23454829 A 1021 1028 proline TRIVIAL 23454829 A 1066 1077 amino acids FAMILY 23454829 A 108 115 CS-1036 IDENTIFIER 23454829 A 1108 1119 amino acids FAMILY 23454829 A 1232 1243 fatty acids FAMILY 23454829 A 1314 1325 fatty acids FAMILY 23454829 A 1365 1378 palmitic acid TRIVIAL 23454829 A 1380 1390 oleic acid TRIVIAL 23454829 A 1396 1423 8,11,14-eicosatrienoic acid SYSTEMATIC 23454829 A 1459 1466 CS-1036 IDENTIFIER 23454829 A 1586 1597 amino acids FAMILY 23454829 A 1602 1613 fatty acids FAMILY 23454829 A 1620 1634 [(14)C]CS-1036 IDENTIFIER 23454829 A 1678 1692 [(14)C]CS-1036 IDENTIFIER 23454829 A 1733 1744 amino acids FAMILY 23454829 A 1768 1779 fatty acids FAMILY 23454829 A 206 220 [(14)C]CS-1036 IDENTIFIER 23454829 A 405 412 CS-1036 IDENTIFIER 23454829 A 642 652 amino acid FAMILY 23454829 A 771 785 [(14)C]CS-1036 IDENTIFIER 23454829 A 957 967 amino acid FAMILY 23454829 A 978 991 glutamic acid TRIVIAL 23454829 A 993 1006 aspartic acid TRIVIAL 23454829 T 117 129 [14C]CS-1036 IDENTIFIER 23455056 A 121 130 palladium SYSTEMATIC 23455056 A 159 181 bis(pinacolato)diboron SYSTEMATIC 23455056 A 18 26 oleanane TRIVIAL 23455056 A 187 202 vinyl triflates FAMILY 23455056 A 434 459 oleanolic vinyl boronates FAMILY 23455056 A 44 57 triterpenoids FAMILY 23455056 A 68 82 boronate ester FAMILY 23455056 A 792 797 boron SYSTEMATIC 23455056 A 805 819 oleanolic acid TRIVIAL 23455056 A 855 860 amide FAMILY 23455056 T 6 31 oleanolic vinyl boronates FAMILY 23455057 A 12 31 arene ruthenium(II) FAMILY 23455057 A 130 139 p-NMe2PIP FORMULA 23455057 A 1307 1312 arene FAMILY 23455057 A 1313 1319 Ru(II) FORMULA 23455057 A 148 156 p-MeOPIP FORMULA 23455057 A 165 172 p-HOPIP FORMULA 23455057 A 181 190 p-COOHPIP FORMULA 23455057 A 199 207 p-CF3PIP FORMULA 23455057 A 216 223 p-BrPIP FORMULA 23455057 A 482 485 MTT ABBREVIATION 23455057 A 532 537 arene FAMILY 23455057 A 538 544 Ru(II) FORMULA 23455057 A 57 76 phenanthroimidazole FAMILY 23455057 A 815 820 arene FAMILY 23455057 A 821 827 Ru(II) FORMULA 23455057 A 88 110 [(C6H6)Ru(L)Cl]Cl·2H2O FORMULA 23455057 T 32 51 arene ruthenium(II) FAMILY 23455229 A 104 106 Au FORMULA 23455229 A 306 308 Au FORMULA 23455229 A 868 870 Au FORMULA 23455312 A 1007 1011 HENA ABBREVIATION 23455312 A 1169 1176 steroid FAMILY 23455312 A 1191 1195 HENA ABBREVIATION 23455312 A 1355 1358 LCA ABBREVIATION 23455312 A 1360 1364 HENA ABBREVIATION 23455312 A 1456 1460 HENA ABBREVIATION 23455312 A 1505 1509 HENA ABBREVIATION 23455312 A 1735 1742 steroid FAMILY 23455312 A 25 29 K(+) FORMULA 23455312 A 252 259 steroid FAMILY 23455312 A 260 276 lithocholic acid TRIVIAL 23455312 A 278 281 LCA ABBREVIATION 23455312 A 393 396 Thr FORMULA 23455312 A 4 9 Ca(2+ FORMULA 23455312 A 616 619 LCA ABBREVIATION 23455312 A 678 713 sodium 3-hydroxyolean-12-en-30-oate SYSTEMATIC 23455312 A 715 719 HENA ABBREVIATION 23455312 A 722 726 HENA ABBREVIATION 23455312 A 918 921 LCA ABBREVIATION 23455312 A 928 932 HENA ABBREVIATION 23455312 T 56 63 Cholane TRIVIAL 23455312 T 64 71 Steroid FAMILY 23455314 A 0 20 N-methyl-d-aspartate SYSTEMATIC 23455314 A 1063 1066 CIQ ABBREVIATION 23455314 A 1305 1309 NMDA ABBREVIATION 23455314 A 1385 1389 NMDA ABBREVIATION 23455314 A 1454 1458 NMDA ABBREVIATION 23455314 A 22 26 NMDA ABBREVIATION 23455314 A 231 235 NMDA ABBREVIATION 23455314 A 507 511 NMDA ABBREVIATION 23455314 A 640 741 (3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone SYSTEMATIC 23455314 A 743 746 CIQ ABBREVIATION 23455314 A 815 818 CIQ ABBREVIATION 23455314 A 840 845 amino FAMILY 23455314 A 869 873 NMDA ABBREVIATION 23455314 T 109 129 N-methyl-d-aspartate SYSTEMATIC 23455373 A 0 36 Polyhedral oligomeric silsesquioxane FAMILY 23455373 A 101 106 T8C18 FORMULA 23455373 A 112 164 octakis(n-octadecyldimethylsiloxy)octasilsesquioxane SYSTEMATIC 23455373 A 1193 1199 OSiMe2 FORMULA 23455373 A 167 172 Q8C18 FORMULA 23455373 A 227 233 C18H37 FORMULA 23455373 A 38 42 POSS ABBREVIATION 23455373 A 64 98 octa-n-octadecyloctasilsesquioxane SYSTEMATIC 23455373 T 122 126 POSS ABBREVIATION 23455373 T 83 120 polyhedral oligomeric silsesquioxanes FAMILY 23455513 A 572 573 O FORMULA 23455513 A 825 837 carbohydrate FAMILY 23455513 A 896 897 O FORMULA 23455995 A 1025 1033 spinosad FAMILY 23455995 A 1146 1159 λ-cyhalothrin FAMILY 23455995 A 1274 1287 λ-cyhalothrin FAMILY 23455995 A 1332 1340 spinosad FAMILY 23455995 A 1416 1424 spinosad FAMILY 23455995 A 1454 1462 spinosad FAMILY 23455995 A 1495 1508 λ-cyhalothrin FAMILY 23455995 A 1528 1536 spinosad FAMILY 23455995 A 1593 1606 λ-cyhalothrin FAMILY 23455995 A 185 193 spinosad FAMILY 23455995 A 198 211 λ-cyhalothrin FAMILY 23455995 A 388 396 spinosad FAMILY 23455995 A 401 414 λ-cyhalothrin FAMILY 23455995 A 740 748 Spinosad FAMILY 23455995 A 848 861 λ-cyhalothrin FAMILY 23455995 T 11 19 spinosad FAMILY 23455995 T 24 37 λ-cyhalothrin FAMILY 23456038 A 1303 1310 phospho SYSTEMATIC 23456038 A 1470 1477 phospho SYSTEMATIC 23456038 A 1565 1574 phosphate SYSTEMATIC 23456038 A 1585 1592 phospho SYSTEMATIC 23456038 A 1620 1627 phospho SYSTEMATIC 23456038 A 433 439 serine TRIVIAL 23456038 A 440 449 threonine TRIVIAL 23456038 A 816 820 (1)H FORMULA 23456038 A 821 826 (15)N FORMULA 23456038 A 827 832 amide FAMILY 23456097 A 1305 1306 N FORMULA 23456248 A 137 145 nitrogen SYSTEMATIC 23456248 A 498 508 amino acid FAMILY 23456248 A 656 676 phosphatidylinositol TRIVIAL 23456735 A 1390 1397 glucose TRIVIAL 23456735 A 1431 1438 glucose TRIVIAL 23456735 A 557 564 glucose TRIVIAL 23456814 A 1089 1092 MDA ABBREVIATION 23456814 A 1142 1145 GSH ABBREVIATION 23456814 A 489 504 malondialdehyde TRIVIAL 23456814 A 506 509 MDA ABBREVIATION 23456814 A 512 522 superoxide TRIVIAL 23456814 A 543 554 glutathione TRIVIAL 23456814 A 556 559 GSH ABBREVIATION 23456814 A 751 776 deoxyuridine triphosphate SYSTEMATIC 23456816 A 414 429 sodium chloride SYSTEMATIC 23456816 A 476 492 sodium hydroxide SYSTEMATIC 23456892 A 0 13 Rosiglitazone TRIVIAL 23456892 A 1034 1037 RSG ABBREVIATION 23456892 A 1062 1079 deoxypyridinoline SYSTEMATIC 23456892 A 1228 1231 RSG ABBREVIATION 23456892 A 1423 1426 RSG ABBREVIATION 23456892 A 1431 1434 ALN ABBREVIATION 23456892 A 1475 1478 RSG ABBREVIATION 23456892 A 15 18 RSG ABBREVIATION 23456892 A 1513 1516 RSG ABBREVIATION 23456892 A 1624 1627 RSG ABBREVIATION 23456892 A 1816 1819 ALN ABBREVIATION 23456892 A 1869 1872 RSG ABBREVIATION 23456892 A 202 205 RSG ABBREVIATION 23456892 A 321 324 RSG ABBREVIATION 23456892 A 607 610 RSG ABBREVIATION 23456892 A 612 623 alendronate TRIVIAL 23456892 A 625 628 ALN ABBREVIATION 23456892 A 633 636 RSG ABBREVIATION 23456892 A 642 645 ALN ABBREVIATION 23456892 A 757 760 RSG ABBREVIATION 23456892 T 14 27 rosiglitazone TRIVIAL 23456892 T 96 107 alendronate TRIVIAL 23457119 A 1123 1129 MK-801 IDENTIFIER 23457119 A 1146 1157 Scopolamine TRIVIAL 23457119 A 1190 1200 [(18)F]FDG SYSTEMATIC 23457119 A 1225 1231 MK-801 IDENTIFIER 23457119 A 1334 1340 MK-801 IDENTIFIER 23457119 A 1369 1379 [(18)F]FDG SYSTEMATIC 23457119 A 1483 1493 [(18)F]FDG SYSTEMATIC 23457119 A 161 192 [(18)F]fluoro-2-deoxy-d-glucose SYSTEMATIC 23457119 A 1634 1638 NMDA ABBREVIATION 23457119 A 1702 1708 MK-801 IDENTIFIER 23457119 A 194 204 [(18)F]FDG SYSTEMATIC 23457119 A 244 251 glucose TRIVIAL 23457119 A 377 397 N-methyl-d-aspartate SYSTEMATIC 23457119 A 399 403 NMDA ABBREVIATION 23457119 A 581 588 glucose TRIVIAL 23457119 A 637 647 [(18)F]FDG SYSTEMATIC 23457119 A 707 711 NMDA ABBREVIATION 23457119 A 733 739 MK-801 IDENTIFIER 23457119 A 747 757 [(18)F]FDG SYSTEMATIC 23457119 A 792 799 glucose TRIVIAL 23457119 A 850 856 MK-801 IDENTIFIER 23457119 A 878 888 [(18)F]FDG SYSTEMATIC 23457119 T 0 8 [18F]FDG SYSTEMATIC 23457119 T 40 44 NMDA ABBREVIATION 23458167 A 39 46 silicon SYSTEMATIC 23458385 A 228 238 saccharide FAMILY 23458385 A 836 859 poly(styrene sulfonate) SYSTEMATIC 23458422 A 1009 1012 PNB ABBREVIATION 23458422 A 1211 1214 PNB ABBREVIATION 23458422 A 1314 1317 PNB ABBREVIATION 23458422 A 15 64 poly(N-isopropylacrylamide-co-butyl methacrylate) SYSTEMATIC 23458422 A 279 282 PNB ABBREVIATION 23458422 A 394 407 sulfuric acid SYSTEMATIC 23458422 A 522 525 PNB ABBREVIATION 23458422 A 562 565 PNB ABBREVIATION 23458422 A 597 600 PNB ABBREVIATION 23458422 A 66 69 PNB ABBREVIATION 23458422 A 664 667 PNB ABBREVIATION 23458422 A 873 876 PNB ABBREVIATION 23458422 A 941 944 PNB ABBREVIATION 23458422 T 45 63 Poly(NIPAM-co-BMA) SYSTEMATIC 23458573 A 156 163 cocaine TRIVIAL 23458573 A 219 226 cocaine TRIVIAL 23458573 A 277 284 cocaine TRIVIAL 23458573 A 425 432 cocaine TRIVIAL 23458573 A 448 455 Cocaine TRIVIAL 23458573 A 629 636 cocaine TRIVIAL 23458573 T 42 49 cocaine TRIVIAL 23458575 A 358 364 oxygen SYSTEMATIC 23458617 A 1148 1163 cis-imidazoline SYSTEMATIC 23458617 A 1173 1181 Nutlin-3 TRIVIAL 23458621 A 606 612 silica TRIVIAL 23458621 A 616 622 silica TRIVIAL 23458621 A 907 913 silica TRIVIAL 23458621 T 12 18 silica TRIVIAL 23458727 A 149 152 A12 ABBREVIATION 23458727 A 37 86 N-(4-carboxy-3-hydroxyphenyl)-2,5-dimethylpyrrole SYSTEMATIC 23458727 A 430 434 NB-2 ABBREVIATION 23458727 A 439 442 A12 ABBREVIATION 23458727 A 88 92 NB-2 ABBREVIATION 23458727 A 98 147 N-(3-carboxy-4-hydroxyphenyl)-2,5-dimethylpyrrole SYSTEMATIC 23458730 A 0 8 Baicalin TRIVIAL 23458730 A 1094 1102 baicalin TRIVIAL 23458730 A 1215 1223 baicalin TRIVIAL 23458730 A 1316 1324 baicalin TRIVIAL 23458730 A 1352 1355 DXM ABBREVIATION 23458730 A 203 211 baicalin TRIVIAL 23458730 A 233 249 dextromethorphan TRIVIAL 23458730 A 251 254 DXM ABBREVIATION 23458730 A 349 357 baicalin TRIVIAL 23458730 A 492 500 baicalin TRIVIAL 23458730 A 522 525 DXM ABBREVIATION 23458730 A 694 697 DXM ABBREVIATION 23458730 A 774 777 DXM ABBREVIATION 23458730 A 832 840 baicalin TRIVIAL 23458730 A 895 903 baicalin TRIVIAL 23458730 A 950 953 DXM ABBREVIATION 23458730 T 46 54 baicalin TRIVIAL 23458730 T 76 92 dextromethorphan TRIVIAL 23458895 A 0 7 NAD(P)H ABBREVIATION 23458895 A 126 140 streptozotocin TRIVIAL 23458895 A 142 145 STZ ABBREVIATION 23458895 A 278 281 STZ ABBREVIATION 23458895 A 374 381 glucose TRIVIAL 23458895 A 617 620 STZ ABBREVIATION 23458895 A 8 15 quinone FAMILY 23458895 T 75 82 NAD(P)H ABBREVIATION 23458895 T 83 90 quinone FAMILY 23459146 A 1173 1176 NaF FORMULA 23459146 A 1265 1268 NaF FORMULA 23459146 A 1290 1293 NaF FORMULA 23459146 A 1340 1343 NaF FORMULA 23459146 A 181 184 NaF FORMULA 23459146 A 299 302 NaF FORMULA 23459146 A 329 332 NaF FORMULA 23459146 A 396 399 NaF FORMULA 23459146 A 56 71 sodium fluoride SYSTEMATIC 23459146 A 569 581 testosterone TRIVIAL 23459146 A 587 599 progesterone TRIVIAL 23459146 A 608 617 estradiol TRIVIAL 23459146 A 73 76 NaF FORMULA 23459146 A 770 781 hematoxylin TRIVIAL 23459146 A 782 787 eosin FAMILY 23459146 A 854 857 NaF FORMULA 23459146 A 990 993 NaF FORMULA 23459146 T 11 26 sodium fluoride SYSTEMATIC 23459233 A 0 10 Phosphorus SYSTEMATIC 23459233 A 1001 1002 P FORMULA 23459233 A 12 13 P FORMULA 23459233 A 1308 1309 P FORMULA 23459233 A 436 437 P FORMULA 23459233 A 570 572 N2 FORMULA 23459233 A 633 634 P FORMULA 23459233 A 724 726 N2 FORMULA 23459233 A 898 900 N2 FORMULA 23459233 A 908 910 H+ FORMULA 23459233 A 944 953 succinate TRIVIAL 23459233 T 98 108 Phosphorus SYSTEMATIC 23460347 A 187 223 poly(ethylene glycol)-dimethacrylate SYSTEMATIC 23460347 A 225 232 PEG-DMA ABBREVIATION 23460347 A 480 487 PEG-DMA ABBREVIATION 23460347 A 582 589 PEG-DMA ABBREVIATION 23460347 T 29 36 PEG-DMA ABBREVIATION 23460383 A 126 140 1,4-butanediol SYSTEMATIC 23460383 A 141 176 4,4'-methylenebis(phenylisocyanate) SYSTEMATIC 23460383 A 23 36 polyurethanes FAMILY 23460383 A 519 523 diol SYSTEMATIC 23460383 A 63 79 undecylenic acid SYSTEMATIC 23460383 A 88 104 telechelic diols FAMILY 23460383 T 14 27 Polyurethanes FAMILY 23460383 T 33 49 Undecylenic Acid SYSTEMATIC 23461617 A 106 121 6-nitrochrysene SYSTEMATIC 23461617 A 1154 1158 6-NC SYSTEMATIC 23461617 A 1163 1175 1,2-DHD-6-NC SYSTEMATIC 23461617 A 123 127 6-NC SYSTEMATIC 23461617 A 1332 1336 6-NC SYSTEMATIC 23461617 A 1345 1357 1,2-DHD-6-NC SYSTEMATIC 23461617 A 1446 1450 6-NC SYSTEMATIC 23461617 A 1506 1510 6-NC SYSTEMATIC 23461617 A 1515 1527 1,2-DHD-6-NC SYSTEMATIC 23461617 A 1603 1607 6-NC SYSTEMATIC 23461617 A 203 207 6-NC SYSTEMATIC 23461617 A 288 339 (±)-trans-1,2-dihydroxy-1,2-dihydro-6-nitrochrysene SYSTEMATIC 23461617 A 341 353 1,2-DHD-6-NC SYSTEMATIC 23461617 A 402 418 (±)-1,2-DHD-6-NC SYSTEMATIC 23461617 A 424 461 (-)-[R,R]- and (+)-[S,S]-1,2-DHD-6-NC MULTIPLE 23461617 A 767 771 6-NC SYSTEMATIC 23461617 A 903 907 6-NC SYSTEMATIC 23461617 A 913 925 1,2-DHD-6-NC SYSTEMATIC 23461617 A 962 966 6-NC SYSTEMATIC 23461617 A 971 983 1,2-DHD-6-NC SYSTEMATIC 23461617 T 124 190 (-)-[R,R]- and (+)-[S,S]-1,2-Dihydroxy-1,2-dihydro-6-nitrochrysene MULTIPLE 23461617 T 88 103 6-Nitrochrysene SYSTEMATIC 23461650 A 19 26 cyanine TRIVIAL 23461784 A 183 190 lithium SYSTEMATIC 23461784 A 272 281 germanium SYSTEMATIC 23461784 A 436 445 germanium SYSTEMATIC 23461784 A 581 588 silicon SYSTEMATIC 23461784 A 675 682 silicon SYSTEMATIC 23461784 A 733 742 germanium SYSTEMATIC 23461784 A 856 865 germanium SYSTEMATIC 23461784 A 989 996 lithium SYSTEMATIC 23461784 T 6 15 Germanium SYSTEMATIC 23461821 A 125 131 Silver SYSTEMATIC 23461821 A 168 196 polyguanidino oxanorbornenes FAMILY 23461821 A 222 246 polyamino oxanorbornenes FAMILY 23461821 A 310 316 silver SYSTEMATIC 23461821 A 327 332 NaBH4 FORMULA 23461821 A 397 403 silver SYSTEMATIC 23461821 A 55 61 silver SYSTEMATIC 23461821 A 661 667 silver SYSTEMATIC 23461821 A 843 856 4-nitrophenol SYSTEMATIC 23461821 A 860 873 4-aminophenol SYSTEMATIC 23461821 A 893 898 NaBH4 FORMULA 23461821 A 90 100 norbornene TRIVIAL 23461821 T 112 125 4-nitrophenol SYSTEMATIC 23461821 T 20 26 silver SYSTEMATIC 23461821 T 64 79 polynorbornenes FAMILY 23461841 A 1045 1059 spironolactone TRIVIAL 23461841 A 1166 1180 spironolactone TRIVIAL 23461841 A 273 288 magnesium oxide SYSTEMATIC 23461841 A 340 354 spironolactone TRIVIAL 23461841 A 378 385 glucose TRIVIAL 23461841 A 411 418 glucose TRIVIAL 23461841 A 45 60 magnesium oxide SYSTEMATIC 23461841 A 512 519 glucose TRIVIAL 23461841 A 529 540 aldosterone TRIVIAL 23461841 A 65 79 spironolactone TRIVIAL 23461841 A 820 835 magnesium oxide SYSTEMATIC 23461841 A 840 854 spironolactone TRIVIAL 23461841 A 959 974 magnesium oxide SYSTEMATIC 23461841 A 97 108 fatty acids FAMILY 23461841 T 11 21 fatty acid FAMILY 23461841 T 71 86 magnesium oxide SYSTEMATIC 23461841 T 91 105 spironolactone TRIVIAL 23461969 A 1004 1007 Pro FORMULA 23461969 A 1012 1015 Ala FORMULA 23461969 A 1020 1023 Asp FORMULA 23461969 A 1028 1031 Arg FORMULA 23461969 A 1036 1039 His FORMULA 23461969 A 1048 1051 Tyr FORMULA 23461969 A 806 812 phenyl SYSTEMATIC 23461969 A 865 871 phenyl SYSTEMATIC 23461969 A 945 948 Gln FORMULA 23461969 A 952 955 Ile FORMULA 23461969 A 959 962 Asp FORMULA 23461969 A 966 969 Trp FORMULA 23461969 A 973 976 His FORMULA 23461969 A 980 983 Ile FORMULA 23461969 A 988 991 Tyr FORMULA 23461969 A 996 999 Glu FORMULA 23462104 A 237 248 Cholesterol TRIVIAL 23462104 A 339 350 cholesterol TRIVIAL 23462104 A 378 389 cholesterol TRIVIAL 23462104 A 549 560 Cholesterol TRIVIAL 23462104 A 575 586 Cholesterol TRIVIAL 23462104 A 600 611 Cholesterol TRIVIAL 23462104 A 626 637 Cholesterol TRIVIAL 23462104 T 64 75 cholesterol TRIVIAL 23462193 A 0 7 Glucose TRIVIAL 23462194 A 1049 1059 nevirapine TRIVIAL 23462194 A 1192 1202 nevirapine TRIVIAL 23462194 A 1338 1348 nevirapine TRIVIAL 23462194 A 1406 1412 iodine SYSTEMATIC 23462194 A 1450 1460 nevirapine TRIVIAL 23462194 A 172 182 Nevirapine TRIVIAL 23462194 A 350 360 nevirapine TRIVIAL 23462194 A 498 508 nevirapine TRIVIAL 23462194 A 598 626 methly thiazolyl tetrazolium SYSTEMATIC 23462194 A 628 631 MTT ABBREVIATION 23462194 A 671 684 Hoechst 33258 TRIVIAL 23462194 A 840 846 Iodine SYSTEMATIC 23462194 A 872 878 (125)I FORMULA 23462194 A 948 958 nevirapine TRIVIAL 23462194 T 52 62 nevirapine TRIVIAL 23462212 A 109 124 chebulinic acid TRIVIAL 23462212 A 182 197 Chebulinic acid TRIVIAL 23462212 A 242 249 aspirin TRIVIAL 23462212 A 256 263 alcohol FAMILY 23462212 A 366 381 chebulinic acid TRIVIAL 23462212 A 497 507 omeprazole TRIVIAL 23462212 A 609 619 Sucralfate TRIVIAL 23462212 A 713 728 Chebulinic acid TRIVIAL 23462212 A 862 877 chebulinic acid TRIVIAL 23462212 A 902 906 H(+) FORMULA 23462212 A 907 911 K(+) FORMULA 23462212 A 994 1004 omeprazole TRIVIAL 23462212 T 46 61 chebulinic acid TRIVIAL 23462213 A 1082 1085 VPA ABBREVIATION 23462213 A 1110 1113 VPA ABBREVIATION 23462213 A 1225 1236 fluorescein TRIVIAL 23462213 A 1330 1333 VPA ABBREVIATION 23462213 A 241 254 Valproic acid TRIVIAL 23462213 A 256 259 VPA ABBREVIATION 23462213 A 407 410 VPA ABBREVIATION 23462213 A 429 444 monocarboxylate SYSTEMATIC 23462213 A 487 490 VPA ABBREVIATION 23462213 A 558 561 VPA ABBREVIATION 23462213 A 577 580 VPA ABBREVIATION 23462213 A 712 715 VPA ABBREVIATION 23462213 A 744 747 VPA ABBREVIATION 23462213 A 870 873 VPA ABBREVIATION 23462213 A 994 997 VPA ABBREVIATION 23462213 T 37 52 monocarboxylate SYSTEMATIC 23462213 T 88 101 valproic acid TRIVIAL 23462281 A 1011 1019 thiamine TRIVIAL 23462281 A 273 281 thiamine TRIVIAL 23462281 A 381 389 thiamine TRIVIAL 23462281 A 395 403 thiamine TRIVIAL 23462281 A 526 534 thiamine TRIVIAL 23462281 A 637 645 tyrosine TRIVIAL 23462281 A 839 882 nicotinamide adenine dinucleotide phosphate SYSTEMATIC 23462281 A 931 939 thiamine TRIVIAL 23462281 T 23 31 Thiamine TRIVIAL 23462379 A 151 152 N FORMULA 23462380 A 2038 2049 neostigmine TRIVIAL 23462505 A 0 8 Estrogen FAMILY 23462505 A 1284 1297 17β-estradiol SYSTEMATIC 23462505 A 1343 1352 tamoxifen TRIVIAL 23462505 A 1354 1364 raloxifene TRIVIAL 23462505 A 1366 1378 bazedoxifene TRIVIAL 23462505 A 1383 1394 fulvestrant TRIVIAL 23462505 A 68 76 estrogen FAMILY 23462505 T 82 90 estrogen FAMILY 23462666 A 1234 1241 glucose TRIVIAL 23462666 A 1395 1402 glucose TRIVIAL 23462666 A 1424 1431 glucose TRIVIAL 23462666 A 227 234 glucose TRIVIAL 23463333 A 1223 1233 robenidine TRIVIAL 23463333 A 296 308 acetonitrile SYSTEMATIC 23463333 A 309 320 formic acid SYSTEMATIC 23463333 A 351 357 hexane SYSTEMATIC 23463333 A 450 458 methanol SYSTEMATIC 23463333 A 485 505 trifluoroacetic acid SYSTEMATIC 23463333 A 71 81 robenidine TRIVIAL 23463333 T 17 27 robenidine TRIVIAL 23463334 A 176 197 polyvinyl pyrrolidone SYSTEMATIC 23463334 A 202 214 stearic acid TRIVIAL 23463334 A 248 258 nifedipine TRIVIAL 23463334 T 86 96 nifedipine TRIVIAL 23463336 A 749 760 acetic acid SYSTEMATIC 23463609 A 48 54 carbon SYSTEMATIC 23463609 T 38 44 carbon SYSTEMATIC 23463634 A 11 19 graphene TRIVIAL 23463634 A 53 61 graphene TRIVIAL 23463634 A 93 101 graphene TRIVIAL 23463634 T 4 12 graphene TRIVIAL 23463732 A 1173 1177 PFBV ABBREVIATION 23463732 A 411 442 polyfluorene-bis-vinylphenylene SYSTEMATIC 23463732 A 444 448 PFBV ABBREVIATION 23463732 A 487 491 PMMA ABBREVIATION 23463732 A 579 583 PFBV ABBREVIATION 23463732 A 708 712 PMMA ABBREVIATION 23463732 A 752 756 PFBV ABBREVIATION 23463732 A 796 800 PMMA ABBREVIATION 23463732 A 904 908 PFBV ABBREVIATION 23463898 A 779 789 daunomycin TRIVIAL 23464618 A 0 6 Carbon SYSTEMATIC 23464618 A 182 188 carbon SYSTEMATIC 23464618 T 51 57 carbon SYSTEMATIC 23464667 A 313 327 Liquiritigenin TRIVIAL 23464667 A 521 535 liquiritigenin TRIVIAL 23464667 A 626 640 liquiritigenin TRIVIAL 23464667 A 757 764 lactate FAMILY 23464667 A 801 815 liquiritigenin TRIVIAL 23464667 T 0 14 Liquiritigenin TRIVIAL 23464789 A 137 156 lithium borohydride SYSTEMATIC 23464789 A 177 205 oligo(hydroxyalkanoate)diols FAMILY 23464789 A 221 265 poly(3-hydroxybutyrate-co-4-hydroxybutyrate) SYSTEMATIC 23464789 A 280 296 poly(3HB-co-4HB) SYSTEMATIC 23464789 A 325 354 poly[(R,S)-3-hydroxybutyrate] SYSTEMATIC 23464789 A 358 361 PHB ABBREVIATION 23464789 A 417 445 oligo(hydroxyalkanoate)diols FAMILY 23464789 A 565 573 hydroxyl SYSTEMATIC 23464789 A 619 624 ester FAMILY 23464789 A 74 95 polyhydroxyalkanoates FAMILY 23464789 A 754 763 polyester FAMILY 23464789 A 826 829 PHA ABBREVIATION 23464789 A 97 100 PHA ABBREVIATION 23464789 T 23 26 PHA ABBREVIATION 23464789 T 88 91 PHA ABBREVIATION 23464859 A 820 827 silicon SYSTEMATIC 23464990 A 1062 1066 SiO2 FORMULA 23464990 A 373 375 O2 FORMULA 23464990 A 430 436 Pt(II) FORMULA 23464990 A 437 448 tetraphenyl SYSTEMATIC 23464990 A 449 468 tetrabenzoporphyrin SYSTEMATIC 23464990 A 470 476 PtTPBP ABBREVIATION 23464990 A 482 488 BODIPY ABBREVIATION 23464990 A 495 500 BDP-G NO CLASS 23464990 A 505 510 BDP-Y NO CLASS 23465066 A 10 13 GaS FORMULA 23465066 A 1073 1076 GaS FORMULA 23465066 A 1225 1228 GaS FORMULA 23465066 A 1321 1328 silicon SYSTEMATIC 23465066 A 145 148 GaS FORMULA 23465066 A 285 288 GaS FORMULA 23465066 A 322 326 SiO2 FORMULA 23465066 A 327 329 Si FORMULA 23465066 A 354 380 polyethylene terephthalate SYSTEMATIC 23465066 A 382 385 PET ABBREVIATION 23465066 A 506 514 graphene TRIVIAL 23465066 A 516 520 MoS2 FORMULA 23465066 A 615 619 SiO2 FORMULA 23465066 A 620 622 Si FORMULA 23465066 A 627 630 PET ABBREVIATION 23465066 A 958 961 GaS FORMULA 23465066 T 28 31 GaS FORMULA 23465072 A 130 140 [(3)H]EBOB SYSTEMATIC 23465072 A 231 235 GABA ABBREVIATION 23465072 A 242 250 chloride SYSTEMATIC 23465072 A 322 328 phenyl SYSTEMATIC 23465072 A 337 348 [(3)H]A1443 SYSTEMATIC 23465072 A 35 46 isoxazoline SYSTEMATIC 23465072 A 516 526 [(3)H]EBOB SYSTEMATIC 23465072 A 552 563 isoxazoline SYSTEMATIC 23465072 A 59 64 A1443 IDENTIFIER 23465072 A 604 614 avermectin FAMILY 23465072 A 615 619 GABA ABBREVIATION 23465072 A 620 629 glutamate TRIVIAL 23465072 A 630 638 chloride SYSTEMATIC 23465072 A 708 712 GABA ABBREVIATION 23465072 A 713 722 glutamate TRIVIAL 23465072 A 95 128 [(3)H]ethynylbicycloorthobenzoate SYSTEMATIC 23465072 T 39 56 [(3)H]Isoxazoline SYSTEMATIC 23465072 T 4 8 GABA ABBREVIATION 23465072 T 9 18 Glutamate TRIVIAL 23465594 A 1013 1016 Ser FORMULA 23465594 A 106 113 ethanol SYSTEMATIC 23465594 A 1063 1066 Thr FORMULA 23465594 A 1113 1116 Ser FORMULA 23465594 A 1144 1151 ethanol SYSTEMATIC 23465594 A 1204 1210 sterol FAMILY 23465594 A 1251 1263 carbohydrate FAMILY 23465594 A 1335 1342 ethanol SYSTEMATIC 23465594 A 1401 1409 acyl-CoA ABBREVIATION 23465594 A 1443 1451 acyl-CoA ABBREVIATION 23465594 A 1493 1501 acyl-CoA ABBREVIATION 23465594 A 1611 1621 fatty acid FAMILY 23465594 A 1641 1648 ethanol SYSTEMATIC 23465594 A 1695 1707 stearoyl CoA TRIVIAL 23465594 A 1725 1735 fatty acid FAMILY 23465594 A 175 178 AMP ABBREVIATION 23465594 A 1851 1858 ethanol SYSTEMATIC 23465594 A 247 254 ethanol SYSTEMATIC 23465594 A 492 499 ethanol SYSTEMATIC 23465594 A 538 545 ethanol SYSTEMATIC 23465594 A 602 609 alanine TRIVIAL 23465594 A 680 693 triglycerides FAMILY 23465594 A 752 759 Ethanol SYSTEMATIC 23465594 A 887 894 ethanol SYSTEMATIC 23465594 A 938 941 Thr FORMULA 23465594 A 956 966 acetyl CoA SYSTEMATIC 23465594 A 994 1001 ethanol SYSTEMATIC 23465594 T 129 136 ethanol SYSTEMATIC 23465612 A 214 229 carboxylic acid SYSTEMATIC 23465612 A 326 334 hydrogen SYSTEMATIC 23465612 A 51 70 dihydroisoquinoline SYSTEMATIC 23465612 T 103 113 aspartates FAMILY 23465612 T 32 51 dihydroisoquinoline SYSTEMATIC 23466228 A 0 10 Olanzapine TRIVIAL 23466228 A 104 127 1-fluoro-2-nitrobenzene SYSTEMATIC 23466228 A 145 155 piperazine SYSTEMATIC 23466228 A 246 263 [(11)C]Olanzapine SYSTEMATIC 23466228 A 308 321 [(11)C]CH3OTf SYSTEMATIC 23466228 A 330 331 N FORMULA 23466228 A 333 338 (11)C FORMULA 23466228 A 454 464 [(11)C]CO2 SYSTEMATIC 23466228 A 599 616 [(11)C]Olanzapine SYSTEMATIC 23466228 A 72 85 malononitrile TRIVIAL 23466228 A 87 102 propionaldehyde SYSTEMATIC 23466228 T 0 15 [11C]olanzapine SYSTEMATIC 23466231 A 154 199 17α-bromo-21-iodo-3β-acetoxypregn-5-en-20-one SYSTEMATIC 23466231 A 20 79 [17(20)Z]- and [17(20)E]-pregna-5,17(20)-dien-21-oyl amides MULTIPLE 23466231 A 298 304 sterol FAMILY 23466231 A 309 321 triglyceride FAMILY 23466231 A 385 406 25-hydroxycholesterol SYSTEMATIC 23466231 A 414 458 [17(20)E]-pregna-5,17(20)-dien-21-oyl amides FAMILY 23466231 A 532 544 triglyceride FAMILY 23466231 A 618 623 amide FAMILY 23466231 A 645 689 [17(20)Z]-pregna-5,17(20)-dien-21-oyl amides FAMILY 23466231 T 0 34 Pregna-5,17(20)-dien-21-oyl amides FAMILY 23466231 T 45 51 sterol FAMILY 23466231 T 56 68 triglyceride FAMILY 23466235 A 598 606 hydrogen SYSTEMATIC 23466235 A 638 641 Asp FORMULA 23466235 A 649 652 Asp FORMULA 23466444 A 632 638 oxygen SYSTEMATIC 23466459 A 100 119 heterocyclic amines FAMILY 23466459 A 1257 1261 PhIP ABBREVIATION 23466459 A 17 64 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine SYSTEMATIC 23466459 A 173 177 PhIP ABBREVIATION 23466459 A 336 340 PhIP ABBREVIATION 23466459 A 410 414 PhIP ABBREVIATION 23466459 A 521 525 PhIP ABBREVIATION 23466459 A 629 633 PhIP ABBREVIATION 23466459 A 66 70 PhIP ABBREVIATION 23466459 A 769 773 PhIP ABBREVIATION 23466459 A 955 959 PhIP ABBREVIATION 23466459 T 151 155 PhIP ABBREVIATION 23466459 T 35 53 heterocyclic amine FAMILY 23466461 A 1080 1083 FB1 ABBREVIATION 23466461 A 1088 1091 FB2 ABBREVIATION 23466461 A 147 157 Fumonisins FAMILY 23466461 A 62 82 fumonisins B1 and B2 MULTIPLE 23466461 A 761 780 fumonisin B1 and B2 MULTIPLE 23466461 A 84 87 FB1 ABBREVIATION 23466461 A 900 903 FB1 ABBREVIATION 23466461 A 916 919 FB2 ABBREVIATION 23466461 A 92 95 FB2 ABBREVIATION 23466461 T 14 24 fumonisins FAMILY 23466488 A 0 11 l-glutamine TRIVIAL 23466488 A 1080 1085 amide FAMILY 23466488 A 1247 1258 glutathione TRIVIAL 23466488 A 1260 1275 malondialdehyde TRIVIAL 23466488 A 1277 1288 glutathione TRIVIAL 23466488 A 1301 1312 glutathione TRIVIAL 23466488 A 1402 1409 glucose TRIVIAL 23466488 A 1432 1443 sitagliptin TRIVIAL 23466488 A 1465 1476 l-glutamine TRIVIAL 23466488 A 1499 1510 l-glutamine TRIVIAL 23466488 A 1535 1546 l-glutamine TRIVIAL 23466488 A 1573 1580 glucose TRIVIAL 23466488 A 1602 1607 amide FAMILY 23466488 A 1661 1668 glucose TRIVIAL 23466488 A 1710 1721 l-glutamine TRIVIAL 23466488 A 1750 1761 l-glutamine TRIVIAL 23466488 A 1779 1786 glucose TRIVIAL 23466488 A 186 197 l-glutamine TRIVIAL 23466488 A 1878 1883 amide FAMILY 23466488 A 1935 1949 streptozotocin TRIVIAL 23466488 A 1950 1962 nicotinamide TRIVIAL 23466488 A 247 252 amide FAMILY 23466488 A 266 280 streptozotocin TRIVIAL 23466488 A 281 293 nicotinamide TRIVIAL 23466488 A 295 298 STZ ABBREVIATION 23466488 A 299 302 NTM ABBREVIATION 23466488 A 31 41 amino acid FAMILY 23466488 A 537 549 nicotinamide TRIVIAL 23466488 A 609 623 streptozotocin TRIVIAL 23466488 A 62 67 sugar FAMILY 23466488 A 715 726 sitagliptin TRIVIAL 23466488 A 747 758 l-glutamine TRIVIAL 23466488 A 780 791 l-glutamine TRIVIAL 23466488 A 817 828 l-glutamine TRIVIAL 23466488 A 852 863 l-glutamine TRIVIAL 23466488 A 868 879 sitagliptin TRIVIAL 23466488 A 908 915 glucose TRIVIAL 23466488 T 111 123 nicotinamide TRIVIAL 23466488 T 47 52 amide FAMILY 23466488 T 5 16 l-glutamine TRIVIAL 23466488 T 96 110 stretpozotocin TRIVIAL 23466874 A 267 280 phlorotannins FAMILY 23466874 A 289 300 polyphenols FAMILY 23466874 A 454 467 phlorotannins FAMILY 23466874 A 602 609 glucose TRIVIAL 23466874 A 652 660 tyrosine TRIVIAL 23466874 A 927 940 phlorotannins FAMILY 23466874 T 45 58 phlorotannins FAMILY 23466874 T 67 78 polyphenols FAMILY 23468099 T 56 63 choline FAMILY 23468099 T 90 97 glucose TRIVIAL 23468310 A 250 259 flavonoid FAMILY 23468310 A 260 269 sarothrin TRIVIAL 23468310 A 271 312 5,7,4'-trihydroxy-3,6,8-trimethoxyflavone SYSTEMATIC 23468310 A 538 547 sarothrin TRIVIAL 23468310 A 717 726 sarothrin TRIVIAL 23468310 T 0 9 Sarothrin TRIVIAL 23468426 A 0 15 Isopenicillin N TRIVIAL 23468426 A 1038 1043 AhCmC ABBREVIATION 23468426 A 106 109 ACV ABBREVIATION 23468426 A 1123 1129 Fe(II) FORMULA 23468426 A 1130 1134 AhCV ABBREVIATION 23468426 A 125 140 isopenicillin N TRIVIAL 23468426 A 1333 1339 Fe(II) FORMULA 23468426 A 1340 1345 AhCmC ABBREVIATION 23468426 A 1368 1377 thioether SYSTEMATIC 23468426 A 1394 1398 iron SYSTEMATIC 23468426 A 1400 1405 AhCmC ABBREVIATION 23468426 A 142 145 IPN ABBREVIATION 23468426 A 1492 1495 ACV ABBREVIATION 23468426 A 1531 1540 methylene SYSTEMATIC 23468426 A 190 200 penicillin FAMILY 23468426 A 205 218 cephalosporin FAMILY 23468426 A 362 369 valinyl TRIVIAL 23468426 A 446 455 cysteinyl TRIVIAL 23468426 A 513 558 δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-valine SYSTEMATIC 23468426 A 560 564 AhCV ABBREVIATION 23468426 A 570 621 δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-allylglycine SYSTEMATIC 23468426 A 623 628 AhCaG ABBREVIATION 23468426 A 63 104 δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine SYSTEMATIC 23468426 A 635 660 monocyclic hydroxy-lactam SYSTEMATIC 23468426 A 705 714 methylene SYSTEMATIC 23468426 A 819 825 lactam SYSTEMATIC 23468426 A 907 949 δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-Xaa FAMILY 23468426 A 972 976 AhCV ABBREVIATION 23468426 A 981 1036 δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-S-methylcysteine SYSTEMATIC 23468426 T 19 34 isopenicillin N TRIVIAL 23468426 T 81 123 δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-Xaa FAMILY 23469688 A 1047 1055 LY294002 IDENTIFIER 23469688 A 1060 1065 U0126 IDENTIFIER 23469688 A 1133 1137 8-TQ SYSTEMATIC 23469688 A 1148 1152 8-TQ SYSTEMATIC 23469688 A 1317 1321 8-TQ SYSTEMATIC 23469688 A 20 43 8-(tosylamino)quinoline SYSTEMATIC 23469688 A 201 205 8-TQ SYSTEMATIC 23469688 A 45 49 8-TQ SYSTEMATIC 23469688 A 487 491 8-TQ SYSTEMATIC 23469688 A 77 88 BAY 11-7082 IDENTIFIER 23469688 A 775 779 8-TQ SYSTEMATIC 23469688 A 998 1002 8-TQ SYSTEMATIC 23469688 T 0 23 8-(Tosylamino)quinoline SYSTEMATIC 23469781 A 34 44 quinolines FAMILY 23469781 A 412 422 quinolines FAMILY 23469781 A 492 501 quinoline SYSTEMATIC 23469781 A 508 521 sitamaquinine TRIVIAL 23469781 A 526 535 Imiquimod TRIVIAL 23469781 T 0 10 Quinolines FAMILY 23469924 A 0 8 Androgen FAMILY 23469924 A 121 129 androgen FAMILY 23469924 A 1400 1408 androgen FAMILY 23469924 A 805 813 androgen FAMILY 23469924 A 916 924 androgen FAMILY 23469924 T 57 65 Androgen FAMILY 23470034 A 133 192 3,7-dioxo-11β-hydroxy-5α-tirucalla-8,24(Z)-dien-26-oic acid SYSTEMATIC 23470034 A 49 68 mastichinoic acid A TRIVIAL 23470034 A 6 30 tetracyclic triterpenoid FAMILY 23470034 T 6 30 tetracyclic triterpenoid FAMILY 23470076 A 200 208 cysteine TRIVIAL 23470076 A 52 62 amino acid FAMILY 23470076 A 695 704 cysteinyl TRIVIAL 23470080 A 289 290 N FORMULA 23470080 A 657 665 arginine TRIVIAL 23470104 A 1202 1215 hydroxymethyl SYSTEMATIC 23470104 A 134 136 CH FORMULA 23470104 A 306 308 CH FORMULA 23470104 A 321 326 CH2OH FORMULA 23470104 A 408 421 hydroxymethyl SYSTEMATIC 23470104 A 518 523 CH3OH FORMULA 23470104 A 532 537 CH2OH FORMULA 23470104 A 563 566 Cl2 FORMULA 23470104 A 591 592 H FORMULA 23470104 A 618 620 Cl FORMULA 23470104 A 623 628 CH3OH FORMULA 23470104 A 631 634 HCl FORMULA 23470104 A 637 642 CH2OH FORMULA 23470104 A 74 87 hydroxymethyl SYSTEMATIC 23470104 A 97 102 CH2OH FORMULA 23470104 T 50 63 Hydroxymethyl SYSTEMATIC 23470104 T 79 81 CH FORMULA 23470105 A 429 436 guanine TRIVIAL 23470105 A 704 711 guanine TRIVIAL 23470152 A 120 139 phenyleneethynylene SYSTEMATIC 23470152 A 168 176 trithiol FAMILY 23470152 A 227 234 Au(111) FORMULA 23470152 A 318 324 sulfur SYSTEMATIC 23470152 A 37 45 trithiol FAMILY 23470152 A 54 64 adamantane TRIVIAL 23470152 A 549 559 ferrocenyl TRIVIAL 23470152 A 85 95 ferrocenyl TRIVIAL 23470152 T 125 134 ferrocene TRIVIAL 23470152 T 93 100 au(111) FORMULA 23470280 A 1108 1111 ISO ABBREVIATION 23470280 A 1171 1184 catecholamine TRIVIAL 23470280 A 1317 1326 glutamate TRIVIAL 23470280 A 1408 1417 glutamate TRIVIAL 23470280 A 272 285 catecholamine TRIVIAL 23470280 A 536 544 dopamine TRIVIAL 23470280 A 588 601 isoproterenol TRIVIAL 23470280 A 603 606 ISO ABBREVIATION 23470280 A 760 769 glutamate TRIVIAL 23470280 A 942 956 catecholamines FAMILY 23470280 T 35 49 catecholamines FAMILY 23470359 A 1061 1066 PFAAs ABBREVIATION 23470359 A 1151 1163 carboxylates FAMILY 23470359 A 1168 1178 sulfonates FAMILY 23470359 A 1397 1402 PFAAs ABBREVIATION 23470359 A 169 189 perfluoroalkyl acids FAMILY 23470359 A 191 196 PFAAs ABBREVIATION 23470359 A 411 416 PFAAs ABBREVIATION 23470359 A 657 662 PFAAs ABBREVIATION 23470359 A 853 858 PFAAs ABBREVIATION 23470359 T 54 74 perfluoroalkyl acids FAMILY 23470359 T 76 81 PFAAs ABBREVIATION 23470418 A 0 11 Bisphenol A TRIVIAL 23470418 A 1166 1169 BPA ABBREVIATION 23470418 A 157 169 para-hydroxy SYSTEMATIC 23470418 A 184 191 benzene SYSTEMATIC 23470418 A 199 210 Bisphenol A TRIVIAL 23470418 A 212 215 BPA ABBREVIATION 23470418 A 475 478 BPA ABBREVIATION 23470418 A 54 70 diphenylmethanes FAMILY 23470418 A 738 749 glutathione TRIVIAL 23470418 A 764 767 BPA ABBREVIATION 23470418 A 785 788 BPF ABBREVIATION 23470418 A 790 794 BPAF ABBREVIATION 23470418 A 796 799 BPZ ABBREVIATION 23470418 A 804 809 DMBPA ABBREVIATION 23470418 A 895 900 NADPH ABBREVIATION 23470418 A 90 97 benzene SYSTEMATIC 23470418 A 905 908 GSH ABBREVIATION 23470418 A 953 956 BPA ABBREVIATION 23470418 T 17 28 bisphenol A TRIVIAL 23470418 T 46 49 BPF ABBREVIATION 23470418 T 51 55 BPAF ABBREVIATION 23470418 T 57 60 BPZ ABBREVIATION 23470418 T 65 70 DMBPA ABBREVIATION 23470922 A 1049 1053 NADH ABBREVIATION 23470922 A 742 785 nicotinamide adenine dinucleotide phosphate SYSTEMATIC 23470922 A 787 792 NADPH ABBREVIATION 23470922 A 812 825 plastoquinone TRIVIAL 23471029 A 0 9 Resolvins FAMILY 23471029 A 1004 1031 cis-1,4,7,10-undecatetraene SYSTEMATIC 23471029 A 126 145 omega-3 fatty acids FAMILY 23471029 A 146 188 all-cis-5,8,11,14,17-eicosapentaenoic acid SYSTEMATIC 23471029 A 190 193 EPA ABBREVIATION 23471029 A 199 243 all-cis-4,7,10,13,16,19-docosahexaenoic acid SYSTEMATIC 23471029 A 245 248 DHA ABBREVIATION 23471029 A 323 331 resolvin FAMILY 23471029 A 359 369 fatty acid FAMILY 23471029 A 477 496 mono- and dihydroxy MULTIPLE 23471029 A 660 690 omega-3 and omega-6 fatty acid MULTIPLE 23471029 A 703 722 Mono- and dihydroxy MULTIPLE 23471029 A 961 988 polyunsaturated fatty acids FAMILY 23471029 T 24 53 mono- and dihydroxy-resolvins FAMILY 23471029 T 59 62 EPA ABBREVIATION 23471029 T 67 70 DHA ABBREVIATION 23471156 A 227 239 metal oxides FAMILY 23471156 A 362 374 metal oxides FAMILY 23471156 A 383 386 ZnO FORMULA 23471156 A 388 391 NiO FORMULA 23471156 A 393 396 CuO FORMULA 23471156 A 398 403 Co3O4 FORMULA 23471156 A 408 412 CeO2 FORMULA 23471156 A 499 510 metal oxide FAMILY 23471156 A 723 735 metal oxides FAMILY 23471156 A 737 740 NiO FORMULA 23471156 A 796 802 silver SYSTEMATIC 23471156 A 897 909 metal oxides FAMILY 23471156 T 11 23 metal oxides FAMILY 23471218 A 1128 1134 oxygen SYSTEMATIC 23471218 A 194 200 oxygen SYSTEMATIC 23471440 A 1338 1348 quinolones FAMILY 23471440 A 1417 1431 propionic acid SYSTEMATIC 23471440 A 1668 1678 quinolones FAMILY 23471440 A 1683 1697 propionic acid SYSTEMATIC 23471440 T 34 44 quinolones FAMILY 23471488 A 1159 1166 glucose TRIVIAL 23471488 A 1565 1572 glucose TRIVIAL 23471488 A 287 298 lauric acid TRIVIAL 23471488 A 505 514 metformin TRIVIAL 23471488 A 965 972 glucose TRIVIAL 23471504 A 0 20 Olmesartan medoxomil TRIVIAL 23471504 A 138 148 olmesartan TRIVIAL 23471504 T 77 97 olmesartan medoxomil TRIVIAL 23471539 A 674 685 amino acids FAMILY 23471561 A 130 143 Anthraquinone SYSTEMATIC 23471561 A 287 304 bis-anthraquinone SYSTEMATIC 23471561 T 19 36 bis-anthraquinone SYSTEMATIC 23471710 A 116 126 omeprazole TRIVIAL 23471710 A 1251 1258 glucose TRIVIAL 23471710 A 252 266 clarithromycin TRIVIAL 23471710 A 268 279 amoxicillin TRIVIAL 23471710 A 285 295 omeprazole TRIVIAL 23471710 A 649 661 carbohydrate FAMILY 23471710 A 710 724 clarithromycin TRIVIAL 23471710 A 743 754 amoxicillin TRIVIAL 23471710 A 777 787 omeprazole TRIVIAL 23471710 A 905 919 clarithromycin TRIVIAL 23471710 A 97 111 clarithromycin TRIVIAL 23471969 A 293 303 amino acid FAMILY 23471969 A 642 653 amino acids FAMILY 23472709 A 101 103 N2 FORMULA 23472709 A 133 149 Iron aminoimides FAMILY 23472709 A 199 201 N2 FORMULA 23472709 A 230 233 E-H FAMILY 23472709 A 245 251 PhSiH3 FORMULA 23472709 A 256 258 H2 FORMULA 23472709 A 336 337 H FORMULA 23472709 A 346 347 B FORMULA 23472709 A 38 58 Fe-diphosphineborane SYSTEMATIC 23472709 A 385 391 Fe-BPh FORMULA 23472709 T 0 3 H-H FORMULA 23472709 T 30 37 Fe≡NNR2 FAMILY 23472709 T 65 67 N2 FORMULA 23472709 T 8 12 Si-H FORMULA 23472738 A 1159 1171 [Au25L18](-) FORMULA 23472738 A 473 506 trialkylacryloylphosphonium salts FAMILY 23472738 A 776 788 [Au25L18](-) FORMULA 23472738 A 794 803 SCH2CH2Ph FORMULA 23472738 A 958 962 Au25 FORMULA 23472745 A 1347 1359 anthocyanins FAMILY 23472745 A 392 445 2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid SYSTEMATIC 23472745 A 450 497 N,N-dimethyl-p-phenylenediamine dihydrochloride SYSTEMATIC 23472745 A 58 70 polyphenolic FAMILY 23472745 A 583 612 2,2-diphenyl-1-picrylhydrazyl SYSTEMATIC 23472745 A 642 654 polyphenolic FAMILY 23472745 A 675 687 polyphenolic FAMILY 23472745 A 692 703 anthocyanin FAMILY 23472745 A 75 86 anthocyanin FAMILY 23472745 A 980 992 polyphenolic FAMILY 23472803 A 324 326 Au FORMULA 23472803 A 36 38 Au FORMULA 23472803 A 505 507 Au FORMULA 23472803 A 587 598 polystyrene SYSTEMATIC 23472803 A 605 630 poly(methyl methacrylate) SYSTEMATIC 23472803 A 637 641 PMMA ABBREVIATION 23472803 A 832 834 Au FORMULA 23472803 A 917 919 Au FORMULA 23472803 T 31 33 au FORMULA 23472840 A 13 22 ibuprofen TRIVIAL 23472840 A 24 31 aspirin TRIVIAL 23472840 A 37 49 erythromycin TRIVIAL 23472840 A 81 94 Pluronic F127 TRIVIAL 23472840 T 38 51 Pluronic F127 TRIVIAL 23472886 A 439 458 indenoisoquinolines FAMILY 23472886 A 605 633 indenoisoquinoline rexinoids FAMILY 23472886 A 667 685 indenoisoquinoline SYSTEMATIC 23472886 A 726 734 carboxyl SYSTEMATIC 23472886 T 48 76 indenoisoquinoline rexinoids FAMILY 23473024 A 1027 1029 Au FORMULA 23473024 A 1086 1090 H2O2 FORMULA 23473024 A 123 125 Au FORMULA 23473024 A 1278 1280 Au FORMULA 23473024 A 262 279 hydrogen peroxide SYSTEMATIC 23473024 A 281 285 H2O2 FORMULA 23473024 A 345 352 citrate FAMILY 23473024 A 434 438 H2O2 FORMULA 23473024 A 450 452 Au FORMULA 23473024 A 489 491 Au FORMULA 23473024 A 548 550 Au FORMULA 23473024 A 604 606 Au FORMULA 23473024 A 714 716 Au FORMULA 23473024 A 754 760 thiols FAMILY 23473024 A 837 841 H2O2 FORMULA 23473024 A 858 871 poly-l-lysine SYSTEMATIC 23473024 A 909 911 Au FORMULA 23473024 T 130 147 hydrogen peroxide SYSTEMATIC 23473030 A 0 4 Iron SYSTEMATIC 23473030 A 196 200 iron SYSTEMATIC 23473030 A 228 232 Iron SYSTEMATIC 23473030 A 345 349 Iron SYSTEMATIC 23473030 A 466 470 iron SYSTEMATIC 23473030 A 62 66 iron SYSTEMATIC 23473030 T 0 4 Iron SYSTEMATIC 23473037 A 717 724 leucine TRIVIAL 23473037 A 728 735 proline TRIVIAL 23473037 A 844 856 nitric oxide SYSTEMATIC 23473444 A 100 104 GdIO FORMULA 23473444 A 353 363 gadolinium SYSTEMATIC 23473444 A 391 395 GdIO FORMULA 23473444 A 475 479 GdIO FORMULA 23473444 A 641 659 dopamine sulfonate SYSTEMATIC 23473444 A 68 78 gadolinium SYSTEMATIC 23473444 A 682 686 GdIO FORMULA 23473444 A 88 98 iron oxide SYSTEMATIC 23473444 A 925 935 iron-oxide SYSTEMATIC 23473444 T 11 21 iron-oxide SYSTEMATIC 23473664 A 137 146 glutamate TRIVIAL 23473664 T 14 23 glutamate TRIVIAL 23473681 A 1036 1044 thiourea SYSTEMATIC 23473681 A 306 314 MAC13243 IDENTIFIER 23473681 A 432 440 MAC13243 IDENTIFIER 23473681 A 466 495 S-(4-chlorobenzyl)isothiourea SYSTEMATIC 23473681 A 684 692 MAC13243 IDENTIFIER 23473681 A 701 709 thiourea SYSTEMATIC 23473681 A 935 943 thiourea SYSTEMATIC 23473681 A 967 975 MAC13243 IDENTIFIER 23473681 T 15 23 MAC13243 IDENTIFIER 23473681 T 68 76 thiourea SYSTEMATIC 23473801 A 0 10 Hinokitiol TRIVIAL 23473801 A 1000 1010 hinokitiol TRIVIAL 23473801 A 1059 1069 Hinokitiol TRIVIAL 23473801 A 1190 1193 ODQ ABBREVIATION 23473801 A 1198 1205 SQ22536 IDENTIFIER 23473801 A 1233 1243 hinokitiol TRIVIAL 23473801 A 1304 1314 hinokitiol TRIVIAL 23473801 A 1387 1395 hydroxyl SYSTEMATIC 23473801 A 145 155 hinokitiol TRIVIAL 23473801 A 1496 1506 hinokitiol TRIVIAL 23473801 A 329 339 hinokitiol TRIVIAL 23473801 A 418 428 hinokitiol TRIVIAL 23473801 A 591 607 arachidonic acid TRIVIAL 23473801 A 613 616 ADP ABBREVIATION 23473801 A 618 628 Hinokitiol TRIVIAL 23473801 A 841 848 calcium SYSTEMATIC 23473801 A 866 874 hydroxyl SYSTEMATIC 23473801 A 884 886 OH FORMULA 23473801 A 899 909 Hinokitiol TRIVIAL 23473801 T 0 10 Hinokitiol TRIVIAL 23473802 A 1138 1144 sodium SYSTEMATIC 23473802 A 1226 1232 sodium SYSTEMATIC 23473802 A 274 283 disulfide SYSTEMATIC 23473802 A 466 475 disulfide SYSTEMATIC 23473802 A 511 518 cystine TRIVIAL 23473802 A 547 556 disulfide SYSTEMATIC 23473802 A 843 849 sodium SYSTEMATIC 23473804 A 1002 1005 7KC SYSTEMATIC 23473804 A 1014 1019 7βOHC SYSTEMATIC 23473804 A 1072 1077 27OHC SYSTEMATIC 23473804 A 1136 1148 α-tocopherol TRIVIAL 23473804 A 1158 1170 ellagic acid TRIVIAL 23473804 A 116 121 7βOHC SYSTEMATIC 23473804 A 1175 1186 resveratrol TRIVIAL 23473804 A 1211 1214 7KC SYSTEMATIC 23473804 A 1220 1225 7βOHC SYSTEMATIC 23473804 A 1280 1283 7KC SYSTEMATIC 23473804 A 1288 1293 27OHC SYSTEMATIC 23473804 A 1346 1356 oxysterols FAMILY 23473804 A 1481 1487 Ca(2+) FORMULA 23473804 A 330 340 oxysterols FAMILY 23473804 A 459 462 7KC SYSTEMATIC 23473804 A 466 471 7βOHC SYSTEMATIC 23473804 A 52 63 cholesterol TRIVIAL 23473804 A 65 82 7-ketocholesterol SYSTEMATIC 23473804 A 713 734 27-hydroxycholesterol SYSTEMATIC 23473804 A 805 811 Fura-2 TRIVIAL 23473804 A 828 834 Ca(2+) FORMULA 23473804 A 84 87 7KC SYSTEMATIC 23473804 A 869 879 oxysterols FAMILY 23473804 A 923 932 ionomycin TRIVIAL 23473804 A 93 114 7β-hydroxycholesterol SYSTEMATIC 23473804 T 31 40 oxysterol FAMILY 23473804 T 82 89 calcium SYSTEMATIC 23474013 A 1884 1891 cocaine TRIVIAL 23474013 A 32 39 cocaine TRIVIAL 23474013 A 932 939 cocaine TRIVIAL 23474013 T 109 116 cocaine TRIVIAL 23474217 A 1110 1123 camptothecine TRIVIAL 23474217 A 33 46 camptothecine TRIVIAL 23474217 A 470 483 camptothecine TRIVIAL 23474217 A 590 603 camptothecine TRIVIAL 23474217 A 644 667 10-hydroxycamptothecine SYSTEMATIC 23474217 A 669 691 9-methoxycamptothecine SYSTEMATIC 23474217 A 693 714 20-deoxycamptothecine SYSTEMATIC 23474217 A 989 1002 camptothecine TRIVIAL 23474217 T 47 60 camptothecine TRIVIAL 23474319 A 0 6 Copper SYSTEMATIC 23474319 A 1049 1051 Cu FORMULA 23474319 A 1068 1076 carbonyl FAMILY 23474319 A 1102 1104 Cu FORMULA 23474319 A 1182 1184 Cu FORMULA 23474319 A 1211 1221 superoxide TRIVIAL 23474319 A 1403 1405 Cu FORMULA 23474319 A 1438 1457 reduced glutathione TRIVIAL 23474319 A 1459 1462 GSH ABBREVIATION 23474319 A 1523 1534 glutathione TRIVIAL 23474319 A 1553 1564 glutathione TRIVIAL 23474319 A 1565 1566 S FORMULA 23474319 A 1589 1600 glutathione TRIVIAL 23474319 A 1636 1638 Cu FORMULA 23474319 A 165 177 myo-inositol TRIVIAL 23474319 A 1836 1839 MDA ABBREVIATION 23474319 A 1884 1886 Cu FORMULA 23474319 A 1940 1942 Cu FORMULA 23474319 A 1997 2007 superoxide TRIVIAL 23474319 A 206 208 Cu FORMULA 23474319 A 2246 2248 Cu FORMULA 23474319 A 2283 2294 reduced GSH ABBREVIATION 23474319 A 2425 2427 Cu FORMULA 23474319 A 2523 2525 Cu FORMULA 23474319 A 2634 2636 Cu FORMULA 23474319 A 434 436 Cu FORMULA 23474319 A 580 582 Cu FORMULA 23474319 A 673 675 Cu FORMULA 23474319 A 762 764 Cu FORMULA 23474319 A 8 10 Cu FORMULA 23474319 A 802 809 lactate FAMILY 23474319 A 839 854 malondialdehyde TRIVIAL 23474319 A 856 859 MDA ABBREVIATION 23474319 T 48 60 myo-inositol TRIVIAL 23474319 T 69 75 copper SYSTEMATIC 23474320 A 999 1001 Cu FORMULA 23474321 A 1649 1654 Na(+) FORMULA 23474321 A 1655 1659 K(+) FORMULA 23474321 T 116 121 Na(+) FORMULA 23474321 T 122 126 K(+) FORMULA 23474323 A 1265 1275 creatinine TRIVIAL 23474323 A 696 703 tannins FAMILY 23474323 A 717 728 polyphenols FAMILY 23474323 A 892 903 cholesterol TRIVIAL 23474323 A 909 920 cholesterol TRIVIAL 23474323 A 929 940 cholesterol TRIVIAL 23474356 A 0 10 Macrolones FAMILY 23474356 A 1004 1016 azithromycin TRIVIAL 23474356 A 101 130 4-quinolone-3-carboxylic acid SYSTEMATIC 23474356 A 1065 1075 macrolones FAMILY 23474356 A 1140 1147 octanol SYSTEMATIC 23474356 A 1208 1216 hydrogen SYSTEMATIC 23474356 A 1233 1248 secondary amide FAMILY 23474356 A 1281 1290 macrolone FAMILY 23474356 A 142 143 C FORMULA 23474356 A 162 171 macrolide FAMILY 23474356 A 176 186 macrolides FAMILY 23474356 A 410 419 macrolone FAMILY 23474356 A 548 558 macrolones FAMILY 23474356 A 610 619 macrolide FAMILY 23474356 A 620 632 azithromycin TRIVIAL 23474356 A 70 79 macrolide FAMILY 23474356 A 707 716 macrolide FAMILY 23474356 A 727 736 quinolone FAMILY 23474356 A 822 831 macrolide FAMILY 23474356 A 833 845 azithromycin TRIVIAL 23474356 A 890 904 clarithromycin TRIVIAL 23474356 A 912 922 macrolones FAMILY 23474356 A 927 941 clarithromycin TRIVIAL 23474356 T 61 71 macrolones FAMILY 23474357 A 1059 1069 certramide FAMILY 23474357 A 1074 1077 IPM ABBREVIATION 23474357 A 1220 1231 certramides FAMILY 23474357 A 1244 1247 IPM ABBREVIATION 23474357 A 368 387 isopropyl myristate SYSTEMATIC 23474357 A 389 392 IPM ABBREVIATION 23474357 A 395 406 certramides FAMILY 23474357 A 490 498 caffeine TRIVIAL 23474357 A 500 509 cortisone TRIVIAL 23474357 A 511 528 diclofenac sodium SYSTEMATIC 23474357 A 530 538 mannitol TRIVIAL 23474357 A 540 554 salicylic acid TRIVIAL 23474357 A 559 571 testosterone TRIVIAL 23474357 A 583 599 propylene glycol SYSTEMATIC 23474357 A 611 618 ethanol SYSTEMATIC 23474357 A 894 904 certramide FAMILY 23474357 A 909 912 IPM ABBREVIATION 23474382 A 1057 1068 alcian blue TRIVIAL 23474382 A 299 306 HMG-CoA ABBREVIATION 23474382 A 367 374 statins FAMILY 23474382 A 470 477 statins FAMILY 23474382 T 19 30 simvastatin TRIVIAL 23474386 A 134 140 amides FAMILY 23474386 A 145 160 benzoimidazoles FAMILY 23474386 A 18 49 5-(benzyloxy)pyridin-2(1H)-ones SYSTEMATIC 23474386 T 6 36 5-(benzyloxy)pyridin-2(1H)-one SYSTEMATIC 23474441 A 306 315 estradiol TRIVIAL 23474645 A 108 124 titanium dioxide SYSTEMATIC 23474645 A 126 130 TiO2 FORMULA 23474645 A 253 281 4,4-N,N-dicarbazole-biphenyl SYSTEMATIC 23474645 A 283 286 CBP ABBREVIATION 23474645 A 292 335 4,4',4''-tris(carbazol-9-yl)-triphenylamine SYSTEMATIC 23474645 A 337 341 TCTA ABBREVIATION 23474645 A 44 48 CdSe FORMULA 23474645 A 442 446 TCTA ABBREVIATION 23474645 A 49 52 CdS FORMULA 23474645 A 53 56 ZnS FORMULA 23474645 A 567 571 TCTA ABBREVIATION 23474645 T 14 17 CdS FORMULA 23474645 T 18 21 ZnS FORMULA 23474645 T 62 78 titanium dioxide SYSTEMATIC 23474645 T 9 13 CdSe FORMULA 23474688 A 1048 1050 Pt FORMULA 23474688 A 1051 1052 C FORMULA 23474688 A 143 149 carbon SYSTEMATIC 23474688 A 381 389 nitrogen SYSTEMATIC 23474688 A 419 427 graphene TRIVIAL 23474688 A 452 460 graphene TRIVIAL 23474688 A 566 574 Nitrogen SYSTEMATIC 23474688 A 692 700 graphene TRIVIAL 23474688 A 874 883 hydrazine SYSTEMATIC 23474688 A 958 960 Pt FORMULA 23474688 A 961 962 C FORMULA 23474688 A 977 983 oxygen SYSTEMATIC 23474688 T 0 8 Nitrogen SYSTEMATIC 23474688 T 102 111 hydrazine SYSTEMATIC 23474688 T 126 132 oxygen SYSTEMATIC 23474688 T 21 29 graphene TRIVIAL 23474899 A 26 46 tetrahydroquinolines FAMILY 23474899 A 358 393 tricyclic pyrimido[4,5-b]quinolines FAMILY 23474899 A 48 83 tetrahydropyrimido[4,5-b]quinolines FAMILY 23474899 A 89 131 tetrahydropentaazacyclopenta[a]anthracenes FAMILY 23474899 T 72 92 tetrahydroquinolines FAMILY 23474972 A 253 261 hydrogen SYSTEMATIC 23474972 A 27 31 NaCl FORMULA 23474972 A 454 462 hydrogen SYSTEMATIC 23474972 A 67 73 carbon SYSTEMATIC 23474972 T 104 112 hydrogen SYSTEMATIC 23475901 A 0 7 Calcium SYSTEMATIC 23475901 A 1293 1299 Ca(2+) FORMULA 23475901 A 159 166 calcium SYSTEMATIC 23475901 A 182 189 calcium SYSTEMATIC 23475901 A 208 215 calcium SYSTEMATIC 23475901 A 403 409 Ca(2+) FORMULA 23475901 A 597 603 Ca(2+) FORMULA 23477344 A 58 64 carbon SYSTEMATIC 23477344 A 598 605 proline TRIVIAL 23477344 T 22 28 Carbon SYSTEMATIC 23477344 T 43 50 Proline TRIVIAL 23477419 A 126 160 α-methylene-β-aminopropanoic acids FAMILY 23477419 A 162 165 Map ABBREVIATION 23477419 A 206 210 EM-1 ABBREVIATION 23477419 A 232 235 Dmt ABBREVIATION 23477419 A 240 250 (R/S)-βPro ABBREVIATION 23477419 A 259 266 (ph)Map ABBREVIATION 23477419 A 270 282 (2-furyl)Map SYSTEMATIC 23477419 A 437 440 Dmt ABBREVIATION 23477419 A 444 452 (R)-βPro ABBREVIATION 23477419 A 456 459 Trp FORMULA 23477419 A 463 475 (2-furyl)Map SYSTEMATIC 23477419 A 578 587 Forskolin TRIVIAL 23477419 A 596 600 cAMP ABBREVIATION 23477419 A 67 80 endomorphin-1 TRIVIAL 23477419 A 82 86 EM-1 ABBREVIATION 23477419 A 869 877 morphine TRIVIAL 23477419 T 65 78 Endomorphin-1 TRIVIAL 23477451 A 107 123 penicimarins D-F MULTIPLE 23477451 A 140 151 benzofurans FAMILY 23477451 A 153 169 penicifurans A-D MULTIPLE 23477451 A 204 215 isocoumarin TRIVIAL 23477451 A 44 61 hydroisocoumarins FAMILY 23477451 A 63 79 penicimarins A-C MULTIPLE 23477451 A 711 722 isocoumarin TRIVIAL 23477451 A 900 913 penicifuran A TRIVIAL 23477451 A 93 105 isocoumarins FAMILY 23477451 T 0 11 Isocoumarin TRIVIAL 23477451 T 28 39 Benzofurans FAMILY 23477623 A 100 129 2,2-diphenyl-1-picrylhydrazyl SYSTEMATIC 23477623 A 1006 1011 Sal B ABBREVIATION 23477623 A 131 135 DPPH ABBREVIATION 23477623 A 15 33 salvianolic acid B TRIVIAL 23477623 A 166 172 Fe(2+) FORMULA 23477623 A 219 227 phenolic FAMILY 23477623 A 243 248 Sal B ABBREVIATION 23477623 A 35 40 Sal B ABBREVIATION 23477623 A 363 394 cholesteryl ester hydroperoxide SYSTEMATIC 23477623 A 396 402 CE-OOH FORMULA 23477623 A 439 444 Sal B ABBREVIATION 23477623 A 530 535 Sal B ABBREVIATION 23477623 A 613 619 CE-OOH FORMULA 23477623 A 667 672 Sal B ABBREVIATION 23477623 A 738 743 Sal B ABBREVIATION 23477623 A 923 928 Sal B ABBREVIATION 23477623 T 116 134 salvianolic acid B TRIVIAL 23477623 T 44 50 copper SYSTEMATIC 23478800 A 1223 1237 cucurbitacin I TRIVIAL 23478800 A 1312 1326 cucurbitacin I TRIVIAL 23478800 A 1351 1357 oxygen SYSTEMATIC 23478800 A 1391 1410 N-acetyl l-cysteine SYSTEMATIC 23478800 A 1489 1503 cucurbitacin I TRIVIAL 23478800 A 1719 1733 cucurbitacin I TRIVIAL 23478800 A 226 244 guanine nucleotide TRIVIAL 23478800 A 282 290 tyrosine TRIVIAL 23478800 A 571 585 cucurbitacin I TRIVIAL 23478800 A 822 836 cucurbitacin I TRIVIAL 23478800 A 882 896 Cucurbitacin I TRIVIAL 23478800 A 992 1006 cucurbitacin I TRIVIAL 23478800 T 0 14 Cucurbitacin I TRIVIAL 23478800 T 138 146 tyrosine TRIVIAL 23478800 T 77 83 oxygen SYSTEMATIC 23479193 A 104 117 Mannich bases FAMILY 23479193 A 121 128 S-alkyl FAMILY 23479193 A 25 88 4-phenyl-5-pyridin-4-yl-2,3-dihydro-3H-1,2,4-triazole-3-thiones FAMILY 23479193 A 309 318 celocoxib TRIVIAL 23479193 T 40 54 diaryltriazole FAMILY 23479194 A 1183 1194 Lupinifolin TRIVIAL 23479194 A 171 182 lupinifolin TRIVIAL 23479194 A 188 223 8-methoxy-7,3',4'-trihydroxyflavone SYSTEMATIC 23479194 A 233 262 7,8,3',4'-tetrahydroxyflavone SYSTEMATIC 23479194 A 270 282 triterpenoid FAMILY 23479194 A 283 289 lupeol TRIVIAL 23479194 A 310 317 sterols FAMILY 23479194 A 318 331 β-sitosterone TRIVIAL 23479194 A 337 362 stigmasta-5,22-dien-3-one SYSTEMATIC 23479194 A 368 380 β-sitosterol TRIVIAL 23479194 A 390 402 stigmasterol TRIVIAL 23479194 A 815 826 lupinifolin TRIVIAL 23479194 A 912 923 Lupinifolin TRIVIAL 23479318 A 19 26 cadmium SYSTEMATIC 23479318 A 28 30 Cd FORMULA 23479318 A 378 380 Cd FORMULA 23479318 A 385 387 Pb FORMULA 23479318 A 42 44 Pb FORMULA 23479318 A 529 531 Cd FORMULA 23479318 A 533 535 Pb FORMULA 23479318 A 701 703 Cd FORMULA 23479318 A 708 710 Pb FORMULA 23479318 T 15 22 cadmium SYSTEMATIC 23479389 A 457 469 [6]-Gingerol TRIVIAL 23479389 A 805 817 [6]-gingerol TRIVIAL 23479389 T 0 12 [6]-gingerol TRIVIAL 23479390 A 212 223 ophioglonin TRIVIAL 23479390 A 238 255 2-phenoxychromone SYSTEMATIC 23479390 A 269 287 3'-O-β-D-glucoside SYSTEMATIC 23479390 A 35 50 dichloromethane SYSTEMATIC 23479390 A 405 416 ophioglonin TRIVIAL 23479390 A 820 828 estrogen FAMILY 23479390 T 0 12 Peltogynoids FAMILY 23479390 T 17 35 2-Phenoxychromones FAMILY 23479407 A 0 9 Gefitinib TRIVIAL 23479407 A 1249 1257 afatinib TRIVIAL 23479407 A 1262 1273 dacomitinib TRIVIAL 23479407 A 14 23 erlotinib TRIVIAL 23479407 A 54 62 tyrosine TRIVIAL 23479455 A 1005 1015 EMD 386088 IDENTIFIER 23479455 A 1085 1094 clozapine TRIVIAL 23479455 A 1146 1154 ketamine TRIVIAL 23479455 A 1259 1267 ketamine TRIVIAL 23479455 A 34 53 5-hydroxytryptamine SYSTEMATIC 23479455 A 55 64 serotonin TRIVIAL 23479455 A 588 598 EMD 386088 IDENTIFIER 23479455 A 607 615 ketamine TRIVIAL 23479455 A 782 792 EMD 386088 IDENTIFIER 23479455 A 906 914 ketamine TRIVIAL 23479455 A 945 953 ketamine TRIVIAL 23479455 T 25 34 serotonin TRIVIAL 23479455 T 4 23 5-hydroxytryptamine SYSTEMATIC 23479455 T 55 65 EMD 386088 IDENTIFIER 23479455 T 78 86 ketamine TRIVIAL 23479738 A 0 15 S-Nitrosothiols FAMILY 23479738 A 101 105 H2O2 FORMULA 23479738 A 1120 1122 NO FORMULA 23479738 A 1123 1126 SNO FORMULA 23479738 A 1201 1218 S-nitrosocysteine SYSTEMATIC 23479738 A 129 135 oxygen SYSTEMATIC 23479738 A 1354 1371 S-nitrosocysteine SYSTEMATIC 23479738 A 1425 1442 S-nitrosocysteine SYSTEMATIC 23479738 A 1488 1490 NO FORMULA 23479738 A 1491 1494 SNO FORMULA 23479738 A 17 21 SNOs FAMILY 23479738 A 282 286 SNOs FAMILY 23479738 A 291 295 H2O2 FORMULA 23479738 A 317 322 thiol FAMILY 23479738 A 34 46 nitric oxide SYSTEMATIC 23479738 A 472 474 NO FORMULA 23479738 A 475 478 SNO FORMULA 23479738 A 48 50 NO FORMULA 23479738 A 569 572 Cys FORMULA 23479738 A 61 62 S FORMULA 23479738 A 687 689 NO FORMULA 23479738 A 690 693 SNO FORMULA 23479738 A 709 726 S-nitrosocysteine SYSTEMATIC 23479738 A 731 751 S-nitrosoglutathione SYSTEMATIC 23479738 A 772 773 S FORMULA 23479738 A 82 99 hydrogen peroxide SYSTEMATIC 23479738 A 882 891 disulfide SYSTEMATIC 23479738 A 934 943 cysteines FAMILY 23479738 A 945 948 Cys FORMULA 23479738 A 956 959 Cys FORMULA 23479738 T 27 30 cys FORMULA 23480196 A 1278 1282 COOH FORMULA 23480196 A 1563 1565 Ni FORMULA 23480196 A 1600 1604 COOH FORMULA 23480196 A 199 202 HCl FORMULA 23480196 A 287 293 carbon SYSTEMATIC 23480196 A 361 363 Ni FORMULA 23480196 A 391 397 carbon SYSTEMATIC 23480196 A 489 492 HCl FORMULA 23480196 A 612 615 HCl FORMULA 23480196 A 668 672 COOH FORMULA 23480196 A 683 689 HNO(3) FORMULA 23480196 A 763 767 COOH FORMULA 23480196 A 77 83 carbon SYSTEMATIC 23480196 A 795 799 COOH FORMULA 23480196 T 59 65 carbon SYSTEMATIC 23480279 A 55 65 colchicine TRIVIAL 23480279 A 70 84 thiocolchicine SYSTEMATIC 23480279 T 65 78 colchicinoids FAMILY 23480348 A 0 14 Polyallylamine SYSTEMATIC 23480348 A 142 145 PAH ABBREVIATION 23480348 A 16 19 PAH ABBREVIATION 23480348 A 267 270 PAH ABBREVIATION 23480348 A 275 277 Pd FORMULA 23480348 A 327 329 Pd FORMULA 23480348 A 342 355 Pd icosahedra FORMULA 23480348 A 36 49 Pd icosahedra FORMULA 23480348 A 384 387 PAH ABBREVIATION 23480348 A 434 436 Pd FORMULA 23480348 A 483 496 Pd icosahedra FORMULA 23480348 A 532 535 PAH ABBREVIATION 23480348 A 551 564 Pd icosahedra FORMULA 23480348 A 612 619 ethanol SYSTEMATIC 23480348 A 648 654 oxygen SYSTEMATIC 23480348 A 719 727 Pt black FORMULA 23480348 A 815 828 Pd icosahedra FORMULA 23480348 A 874 882 Pt black FORMULA 23480348 A 950 952 Pd FORMULA 23480348 T 0 14 Polyallylamine SYSTEMATIC 23480348 T 131 138 ethanol SYSTEMATIC 23480348 T 30 50 palladium icosahedra SYSTEMATIC 23480446 A 203 213 amino acid FAMILY 23480446 A 367 378 amino acids FAMILY 23480446 A 424 444 aromatic amino acids FAMILY 23480446 A 445 458 phenylalanine TRIVIAL 23480446 A 460 468 tyrosine TRIVIAL 23480446 A 474 484 tryptophan TRIVIAL 23480446 A 632 640 hydrogen SYSTEMATIC 23480446 A 661 669 hydrogen SYSTEMATIC 23480532 A 1254 1261 lactose TRIVIAL 23480532 A 239 258 lactose monohydrate TRIVIAL 23480597 A 534 543 polyamine FAMILY 23480798 A 104 110 phenol SYSTEMATIC 23480798 A 1095 1103 hydrogen SYSTEMATIC 23480798 A 1112 1132 carbon tetrachloride SYSTEMATIC 23480798 A 116 117 F FORMULA 23480798 A 119 121 Cl FORMULA 23480798 A 1258 1266 hydrogen SYSTEMATIC 23480798 A 1311 1317 phenol SYSTEMATIC 23480798 A 1450 1460 trihydrate SYSTEMATIC 23480798 A 1485 1495 2F-ethanol SYSTEMATIC 23480798 A 1640 1648 hydrogen SYSTEMATIC 23480798 A 1703 1704 F FORMULA 23480798 A 1709 1711 Cl FORMULA 23480798 A 713 733 carbon tetrachloride SYSTEMATIC 23480798 A 89 96 ethanol SYSTEMATIC 23480798 A 919 923 OCCF FORMULA 23480798 A 947 957 2F-ethanol SYSTEMATIC 23480798 T 23 26 o-h FORMULA 23480798 T 29 30 f FORMULA 23480798 T 35 38 o-h FORMULA 23480798 T 41 43 cl FORMULA 23480798 T 44 52 hydrogen SYSTEMATIC 23480848 A 103 106 SNP ABBREVIATION 23480848 A 108 127 Na2[Fe(CN)5NO]·2H2O FORMULA 23480848 A 1118 1120 NO FORMULA 23480848 A 1124 1127 SNP ABBREVIATION 23480848 A 1370 1374 heme FAMILY 23480848 A 1453 1455 NO FORMULA 23480848 A 1459 1462 SNP ABBREVIATION 23480848 A 1566 1574 nitrosyl SYSTEMATIC 23480848 A 1579 1586 cyanide SYSTEMATIC 23480848 A 1645 1653 trans-CN SYSTEMATIC 23480848 A 1717 1722 Fe-NO FORMULA 23480848 A 1731 1734 SNP ABBREVIATION 23480848 A 204 206 NO FORMULA 23480848 A 210 213 SNP ABBREVIATION 23480848 A 245 253 nitrosyl SYSTEMATIC 23480848 A 354 366 nitric oxide SYSTEMATIC 23480848 A 368 370 NO FORMULA 23480848 A 42 50 nitrosyl SYSTEMATIC 23480848 A 439 441 NO FORMULA 23480848 A 476 491 deuterium oxide SYSTEMATIC 23480848 A 493 501 methanol SYSTEMATIC 23480848 A 503 510 ethanol SYSTEMATIC 23480848 A 512 527 ethylene glycol SYSTEMATIC 23480848 A 529 538 formamide SYSTEMATIC 23480848 A 544 562 dimethyl sulfoxide SYSTEMATIC 23480848 A 586 588 NO FORMULA 23480848 A 681 699 dimethyl sulfoxide SYSTEMATIC 23480848 A 74 76 NO FORMULA 23480848 A 763 765 NO FORMULA 23480848 A 81 101 sodium nitroprusside SYSTEMATIC 23480848 A 892 894 NO FORMULA 23480848 A 898 901 SNP ABBREVIATION 23480848 A 984 986 2D FORMULA 23480848 T 72 80 Nitrosyl SYSTEMATIC 23480848 T 95 101 Fe(II) FORMULA 23481139 A 12 26 nicotinic acid TRIVIAL 23481139 A 131 135 TBTU ABBREVIATION 23481139 T 0 14 Nicotinic acid TRIVIAL 23481236 A 1009 1017 tyrosine TRIVIAL 23481236 A 1033 1059 palmitic and stearic acids MULTIPLE 23481236 A 1070 1079 ceramides FAMILY 23481236 A 1142 1145 Ser FORMULA 23481236 A 1312 1322 wortmannin TRIVIAL 23481236 A 1373 1382 ceramides FAMILY 23481236 A 1437 1440 Ser FORMULA 23481236 A 1663 1666 Ser FORMULA 23481236 A 295 303 tyrosine TRIVIAL 23481236 A 417 430 triglycerides FAMILY 23481236 A 432 436 TAGs ABBREVIATION 23481236 A 439 451 diglycerides FAMILY 23481236 A 453 457 DAGs ABBREVIATION 23481236 A 464 473 ceramides FAMILY 23481236 A 656 667 fatty acids FAMILY 23481236 A 7 14 glucose TRIVIAL 23481236 A 730 740 wortmannin TRIVIAL 23481236 A 758 778 phosphatidylinositol TRIVIAL 23481236 A 841 845 DAGs ABBREVIATION 23481236 A 847 851 TAGs ABBREVIATION 23481236 A 89 96 glucose TRIVIAL 23481236 A 980 986 serine TRIVIAL 23481236 A 988 991 Ser FORMULA 23481236 A 997 1000 Ser FORMULA 23481281 A 0 17 Aphanamgrandiol A TRIVIAL 23481281 A 31 43 triterpenoid FAMILY 23481281 A 369 386 Aphanamgrandiol A TRIVIAL 23481281 A 51 71 bicyclo[3,2,1]octane SYSTEMATIC 23481281 T 0 17 Aphanamgrandiol A TRIVIAL 23481281 T 25 37 triterpenoid FAMILY 23481281 T 52 58 carbon SYSTEMATIC 23481650 A 203 209 indole SYSTEMATIC 23481650 A 237 243 indole SYSTEMATIC 23481650 A 248 257 azaindole FAMILY 23481650 A 295 306 5-azaindole SYSTEMATIC 23481650 A 597 608 7-azaindole SYSTEMATIC 23481650 T 0 24 N-substituted azaindoles FAMILY 23481677 A 209 226 chloroazaphilones FAMILY 23481677 A 273 290 chloroazaphilones FAMILY 23481677 A 375 386 helicusin A TRIVIAL 23481677 A 395 415 deacetylsclerotiorin TRIVIAL 23481677 A 432 449 chloroazaphilones FAMILY 23481677 A 451 462 helicusin E TRIVIAL 23481677 A 468 486 isochromophilone X TRIVIAL 23481677 A 495 514 isochromophilone XI TRIVIAL 23481677 A 532 543 pentaketide FAMILY 23481677 A 545 556 bartanolide TRIVIAL 23481677 T 0 11 Helicusin E TRIVIAL 23481677 T 13 31 Isochromophilone X TRIVIAL 23481677 T 36 55 Isochromophilone XI TRIVIAL 23481677 T 61 78 Chloroazaphilones FAMILY 23483327 A 1227 1239 phenanthrene SYSTEMATIC 23483327 A 1541 1548 cadmium SYSTEMATIC 23483327 A 1552 1564 phenanthrene SYSTEMATIC 23483327 A 246 253 cadmium SYSTEMATIC 23483327 A 258 270 phenanthrene SYSTEMATIC 23483327 A 853 860 cadmium SYSTEMATIC 23483327 A 865 877 phenanthrene SYSTEMATIC 23483327 T 121 128 cadmium SYSTEMATIC 23483327 T 133 145 phenanthrene SYSTEMATIC 23484490 A 32 38 carbon SYSTEMATIC 23484490 T 59 65 Carbon SYSTEMATIC 23484546 A 1055 1063 hydrogen SYSTEMATIC 23484546 A 161 169 graphene TRIVIAL 23484546 A 487 495 graphene TRIVIAL 23484546 A 611 619 graphene TRIVIAL 23484546 A 742 751 acetylene SYSTEMATIC 23484546 A 799 807 graphene TRIVIAL 23484546 A 856 867 hydrocarbon FAMILY 23484546 A 94 102 graphene TRIVIAL 23484546 A 977 985 graphene TRIVIAL 23484546 T 70 78 graphene TRIVIAL 23484622 A 1159 1162 ZnO FORMULA 23484622 A 256 270 benzo[a]pyrene SYSTEMATIC 23484622 A 341 355 p-benzoquinone SYSTEMATIC 23484622 A 468 478 zinc oxide SYSTEMATIC 23484622 A 480 483 ZnO FORMULA 23484622 A 56 62 oxygen SYSTEMATIC 23484622 T 73 87 Benzo[a]pyrene SYSTEMATIC 23484851 A 108 121 phenylalanine TRIVIAL 23484851 A 123 126 Phe FORMULA 23484851 A 1486 1492 pyrene SYSTEMATIC 23484851 A 1550 1553 Phe FORMULA 23484851 A 207 210 Asp FORMULA 23484851 A 215 218 Phe FORMULA 23484851 A 517 520 Asp FORMULA 23484851 A 645 648 Asp FORMULA 23484851 A 654 657 Asp FORMULA 23484851 A 72 85 aspartic acid TRIVIAL 23484851 A 87 90 Asp FORMULA 23484851 A 938 941 Asp FORMULA 23484851 A 951 954 Phe FORMULA 23484851 A 993 996 Asp FORMULA 23484974 A 316 322 quartz TRIVIAL 23485065 A 789 797 dopamine TRIVIAL 23485151 A 106 110 LiCl FORMULA 23485151 A 126 130 H(+) FORMULA 23485151 A 2 8 Ca(2+) FORMULA 23485151 A 272 276 H(+) FORMULA 23485151 A 321 326 Li(+) FORMULA 23485151 T 63 67 LiCl FORMULA 23485151 T 79 81 H+ FORMULA 23485441 A 0 16 Poly(ADP-ribose) SYSTEMATIC 23485441 A 1016 1022 NAD(+) ABBREVIATION 23485441 A 176 179 ADP ABBREVIATION 23485441 A 180 186 ribose TRIVIAL 23485441 A 207 217 amino acid FAMILY 23485441 A 254 257 ADP ABBREVIATION 23485441 A 258 264 ribose TRIVIAL 23485441 A 318 321 ADP ABBREVIATION 23485441 A 322 329 ribosyl TRIVIAL 23485441 A 445 448 ADP ABBREVIATION 23485441 A 449 455 ribose TRIVIAL 23485441 A 62 65 ADP ABBREVIATION 23485441 A 66 73 ribosyl TRIVIAL 23485441 T 36 39 ADP ABBREVIATION 23485450 A 1100 1102 Fe FORMULA 23485450 A 244 255 doxorubicin TRIVIAL 23485450 A 257 260 DOX ABBREVIATION 23485450 A 280 301 poly(ethylene glycol) SYSTEMATIC 23485450 A 303 306 PEG ABBREVIATION 23485450 A 329 342 acylhydrazone SYSTEMATIC 23485450 A 462 465 DOX ABBREVIATION 23485450 A 49 59 iron-oxide SYSTEMATIC 23485450 A 625 628 DOX ABBREVIATION 23485450 A 776 779 DOX ABBREVIATION 23485450 A 904 907 DOX ABBREVIATION 23485450 A 913 916 DOX ABBREVIATION 23485450 T 47 57 iron-oxide SYSTEMATIC 23485613 A 0 8 Gossypol TRIVIAL 23485613 A 1033 1041 gossypol TRIVIAL 23485613 A 1120 1128 gossypol TRIVIAL 23485613 A 1171 1179 gossypol TRIVIAL 23485613 A 1296 1304 gossypol TRIVIAL 23485613 A 143 151 gossypol TRIVIAL 23485613 A 253 261 gossypol TRIVIAL 23485613 A 325 333 gossypol TRIVIAL 23485613 A 435 443 gossypol TRIVIAL 23485613 A 594 602 gossypol TRIVIAL 23485613 A 810 818 gossypol TRIVIAL 23485613 T 36 44 gossypol TRIVIAL 23485613 T 72 80 gossypol TRIVIAL 23485991 A 444 453 disulfide SYSTEMATIC 23485991 A 483 484 N FORMULA 23485991 A 642 659 hydrogen peroxide SYSTEMATIC 23485991 A 670 685 methyl viologen SYSTEMATIC 23486187 A 392 395 Trp FORMULA 23487486 A 1357 1369 progesterone TRIVIAL 23487486 A 1392 1395 MPA ABBREVIATION 23487486 A 1633 1645 progesterone TRIVIAL 23487486 A 4 12 steroids FAMILY 23487486 A 493 505 progesterone TRIVIAL 23487486 A 531 540 progestin FAMILY 23487486 A 541 568 medroxyprogesterone acetate TRIVIAL 23487486 A 570 573 MPA ABBREVIATION 23487486 A 717 720 MPA ABBREVIATION 23487486 T 11 23 progesterone TRIVIAL 23487486 T 28 47 medroxyprogesterone TRIVIAL 23488728 A 1113 1120 citrate FAMILY 23488728 A 1158 1171 ascorbic acid TRIVIAL 23488728 A 151 158 silicon SYSTEMATIC 23488728 A 50 57 silicon SYSTEMATIC 23488728 A 58 65 Si(111) FORMULA 23488728 A 596 603 silicon SYSTEMATIC 23488728 A 835 841 carbon SYSTEMATIC 23488728 A 906 911 amine SYSTEMATIC 23488728 A 967 974 Si(111) FORMULA 23488728 T 22 27 oxide SYSTEMATIC 23488728 T 33 40 silicon SYSTEMATIC 23488739 A 102 110 glycidol TRIVIAL 23488739 A 1020 1028 hydrogen SYSTEMATIC 23488739 A 173 188 ethylene glycol SYSTEMATIC 23488739 A 230 244 poly(glycidol) SYSTEMATIC 23488739 A 391 401 oleic acid TRIVIAL 23488739 A 402 408 octane SYSTEMATIC 23488739 A 41 48 diamond TRIVIAL 23488739 A 480 486 octane SYSTEMATIC 23488739 A 496 506 oleic acid TRIVIAL 23488739 A 58 75 dimethylsulfoxide SYSTEMATIC 23488739 A 722 725 H2O FORMULA 23488739 A 741 748 toluene TRIVIAL 23488748 A 1300 1308 hydrogen SYSTEMATIC 23488987 A 101 107 oxygen SYSTEMATIC 23488987 A 1058 1064 oxygen SYSTEMATIC 23488987 A 1112 1121 nitroaryl FAMILY 23488987 A 1153 1158 amino FAMILY 23488987 A 1247 1255 xanthine TRIVIAL 23488987 A 1279 1304 6-nitroquinolin-2(1H)-one SYSTEMATIC 23488987 A 138 147 Nitroaryl FAMILY 23488987 A 1784 1793 nitroaryl FAMILY 23488987 A 1803 1809 oxygen SYSTEMATIC 23488987 A 290 299 nitroaryl FAMILY 23488987 A 309 316 nitroso SYSTEMATIC 23488987 A 318 331 hydroxylamino SYSTEMATIC 23488987 A 337 342 amino FAMILY 23488987 A 377 383 oxygen SYSTEMATIC 23488987 A 481 497 6-nitroquinoline SYSTEMATIC 23488987 A 660 668 xanthine TRIVIAL 23488987 A 669 677 xanthine TRIVIAL 23488987 A 759 775 6-aminoquinoline SYSTEMATIC 23488987 A 871 895 6-hydroxylaminoquinoline SYSTEMATIC 23488987 A 952 960 xanthine TRIVIAL 23488987 A 961 969 xanthine TRIVIAL 23488987 T 24 40 6-Nitroquinoline SYSTEMATIC 23488987 T 60 76 6-Aminoquinoline SYSTEMATIC 23489135 A 111 116 OZ277 IDENTIFIER 23489135 A 121 126 OZ439 IDENTIFIER 23489135 A 193 206 1,2-dioxolane SYSTEMATIC 23489135 A 208 222 1,2,4-trioxane SYSTEMATIC 23489135 A 228 246 1,2,4,5-tetraoxane SYSTEMATIC 23489135 A 294 304 dioxolanes FAMILY 23489135 A 352 357 OZ277 IDENTIFIER 23489135 A 370 378 trioxane FAMILY 23489135 A 485 495 trioxolane FAMILY 23489135 A 499 509 tetraoxane FAMILY 23489135 A 529 534 OZ439 IDENTIFIER 23489135 A 61 77 1,2,4-trioxolane SYSTEMATIC 23489135 A 642 652 trioxolane FAMILY 23489135 A 655 663 trioxane FAMILY 23489135 A 666 676 tetraoxane FAMILY 23489135 A 713 718 OZ439 IDENTIFIER 23489135 A 726 731 OZ277 IDENTIFIER 23489135 A 737 742 OZ439 IDENTIFIER 23489135 A 750 759 peroxides FAMILY 23489135 A 833 838 OZ277 IDENTIFIER 23489135 A 846 855 peroxides FAMILY 23489135 A 94 110 dispiro ozonides FAMILY 23489135 T 110 123 1,2-dioxolane SYSTEMATIC 23489135 T 125 139 1,2,4-trioxane SYSTEMATIC 23489135 T 145 163 1,2,4,5-tetraoxane SYSTEMATIC 23489135 T 57 65 ozonides FAMILY 23489135 T 67 84 1,2,4-trioxolanes FAMILY 23489135 T 86 91 OZ277 IDENTIFIER 23489135 T 93 98 OZ439 IDENTIFIER 23489301 A 1042 1052 alogliptin TRIVIAL 23489301 A 1246 1256 alogliptin TRIVIAL 23489301 A 1360 1370 alogliptin TRIVIAL 23489301 A 1512 1521 aloglipin TRIVIAL 23489301 A 200 210 alogliptin TRIVIAL 23489301 A 286 296 alogliptin TRIVIAL 23489301 A 380 390 alogliptin TRIVIAL 23489301 A 593 603 alogliptin TRIVIAL 23489301 A 774 783 metformin TRIVIAL 23489301 A 785 798 sulfonylureas FAMILY 23489301 A 803 821 thiazolidinediones FAMILY 23489301 T 61 71 alogliptin TRIVIAL 23489623 A 0 12 (R)-Bgugaine TRIVIAL 23489623 A 182 193 norbgugaine TRIVIAL 23489623 A 224 232 bgugaine TRIVIAL 23489623 A 26 46 pyrrolidine alkaloid FAMILY 23489623 A 379 390 norbgugaine TRIVIAL 23489623 A 495 504 pyocyanin TRIVIAL 23489623 T 13 28 (R)-norbgugaine TRIVIAL 23489624 A 252 255 MTT ABBREVIATION 23489629 A 0 33 N-(Pyridin-2-yl) arylsulfonamides FAMILY 23489629 A 199 210 glutathione TRIVIAL 23489629 A 317 326 PF-915275 IDENTIFIER 23489629 A 43 52 PF-915275 IDENTIFIER 23489629 A 545 578 N-(pyridin-2-yl) arylsulfonamides FAMILY 23489629 A 620 638 11β-hydroxysteroid FAMILY 23489629 A 94 112 11β-hydroxysteroid FAMILY 23489629 T 0 32 N-(Pyridin-2-yl) arylsulfonamide FAMILY 23489629 T 47 65 11β-hydroxysteroid FAMILY 23489976 A 1410 1418 cortisol TRIVIAL 23489976 A 1605 1613 cortisol TRIVIAL 23489976 T 40 48 Cortisol TRIVIAL 23490078 A 0 10 Haloalkane FAMILY 23490078 A 1200 1208 tyrosine TRIVIAL 23490078 A 1214 1224 tryptophan TRIVIAL 23490078 A 1234 1240 halide FAMILY 23490078 A 1322 1330 hydrogen SYSTEMATIC 23490078 A 1606 1616 haloalkane FAMILY 23490078 A 1699 1707 hydrogen SYSTEMATIC 23490078 A 172 178 halide FAMILY 23490078 A 290 296 halide FAMILY 23490078 A 313 321 hydrogen SYSTEMATIC 23490078 A 355 365 haloalkane FAMILY 23490078 A 417 428 tryptophans FAMILY 23490078 A 434 444 tryptophan TRIVIAL 23490078 A 445 455 asparagine TRIVIAL 23490078 A 481 491 haloalkane FAMILY 23490078 A 52 58 carbon SYSTEMATIC 23490078 A 577 583 halide FAMILY 23490078 A 59 66 halogen FAMILY 23490078 A 596 604 tyrosine TRIVIAL 23490078 A 649 659 tryptophan TRIVIAL 23490078 A 980 988 hydrogen SYSTEMATIC 23490078 T 23 29 halide FAMILY 23490078 T 81 91 haloalkane FAMILY 23491602 A 782 788 Mn(2+) FORMULA 23491602 A 810 822 5'-phosphate SYSTEMATIC 23491602 A 872 882 amino acid FAMILY 23492810 A 1256 1265 fadrozole TRIVIAL 23492810 A 1374 1377 VTG ABBREVIATION 23492810 A 453 462 fadrozole TRIVIAL 23492810 A 587 596 fadrozole TRIVIAL 23492810 A 712 725 17β-estradiol SYSTEMATIC 23492810 A 735 747 vitellogenin TRIVIAL 23492810 A 749 752 VTG ABBREVIATION 23492810 A 863 872 fadrozole TRIVIAL 23492810 A 911 914 VTG ABBREVIATION 23493317 A 1181 1188 glucose TRIVIAL 23493317 A 243 250 glucose TRIVIAL 23493317 A 308 344 adenosine-3',5'-cyclic monophosphate SYSTEMATIC 23493317 A 346 350 cAMP ABBREVIATION 23493317 A 360 370 nucleotide FAMILY 23493317 A 423 427 cAMP ABBREVIATION 23493317 A 82 89 glucose TRIVIAL 23493374 A 1109 1116 (m)CpGs ABBREVIATION 23493374 A 1310 1316 (m)CpG ABBREVIATION 23493374 A 1370 1392 5-aza-2'-deoxycytidine SYSTEMATIC 23493374 A 1429 1443 trichostatin A TRIVIAL 23493374 A 1452 1458 (m)CpG ABBREVIATION 23493374 A 1591 1598 (m)CpGs ABBREVIATION 23493374 A 1760 1766 (m)CpG ABBREVIATION 23493374 A 1831 1837 (m)CpG ABBREVIATION 23493374 A 199 202 CpG ABBREVIATION 23493374 A 290 299 bisulfite SYSTEMATIC 23493374 A 33 40 glucose TRIVIAL 23493374 A 342 345 CpG ABBREVIATION 23493374 A 347 353 (m)CpG ABBREVIATION 23493374 A 662 669 (m)CpGs ABBREVIATION 23493374 A 779 786 (m)CpGs ABBREVIATION 23493374 A 860 866 methyl SYSTEMATIC 23493374 A 913 920 (m)CpGs ABBREVIATION 23493374 T 12 18 (m)CpG ABBREVIATION 23493374 T 68 75 glucose TRIVIAL 23493449 A 103 109 indole SYSTEMATIC 23493449 A 345 349 SAHA ABBREVIATION 23493449 A 575 579 SAHA ABBREVIATION 23493449 A 59 79 N-hydroxycinnamamide SYSTEMATIC 23493449 A 745 749 SAHA ABBREVIATION 23493449 T 15 35 N-Hydroxycinnamamide SYSTEMATIC 23493449 T 78 84 Indole SYSTEMATIC 23494106 A 1316 1323 JWH-210 IDENTIFIER 23494106 A 1328 1335 JWH-122 IDENTIFIER 23494106 A 30 42 cannabinoids FAMILY 23494106 A 330 345 naphthoylindole FAMILY 23494106 A 357 364 JWH-018 IDENTIFIER 23494106 A 366 373 JWH-073 IDENTIFIER 23494106 A 375 382 JWH-122 IDENTIFIER 23494106 A 387 394 JWH-210 IDENTIFIER 23494106 A 407 420 benzoylindole FAMILY 23494106 A 422 428 AM-694 IDENTIFIER 23494106 A 482 502 tetrahydrocannabinol SYSTEMATIC 23494106 A 842 849 JWH-073 IDENTIFIER 23494106 A 854 861 JWH-122 IDENTIFIER 23494106 A 967 974 JWH-210 IDENTIFIER 23494106 T 45 57 cannabinoids FAMILY 23494106 T 97 108 cannabinoid FAMILY 23494232 A 1114 1122 ketamine TRIVIAL 23494232 A 1143 1151 Ketamine TRIVIAL 23494232 A 1352 1360 SCH23390 IDENTIFIER 23494232 A 1377 1385 Ketamine TRIVIAL 23494232 A 1547 1555 SCH23390 IDENTIFIER 23494232 A 1598 1606 ketamine TRIVIAL 23494232 A 1667 1675 SCH23390 IDENTIFIER 23494232 A 1778 1786 ketamine TRIVIAL 23494232 A 1870 1874 AMPA ABBREVIATION 23494232 A 34 42 ketamine TRIVIAL 23494232 A 377 385 dopamine TRIVIAL 23494232 A 406 462 alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid SYSTEMATIC 23494232 A 464 468 AMPA ABBREVIATION 23494232 A 558 566 ketamine TRIVIAL 23494232 A 618 626 ketamine TRIVIAL 23494232 A 790 798 SCH23390 IDENTIFIER 23494232 A 806 810 AMPA ABBREVIATION 23494232 A 918 926 ketamine TRIVIAL 23494232 T 6 14 ketamine TRIVIAL 23494232 T 93 101 dopamine TRIVIAL 23494233 A 1002 1006 TRIM ABBREVIATION 23494233 A 1032 1044 nitric oxide SYSTEMATIC 23494233 A 1071 1135 N-([3-(aminomethyl)phenyl]methyl) ethanimidamide dihydrochloride SYSTEMATIC 23494233 A 11 23 Nitric oxide SYSTEMATIC 23494233 A 1137 1142 1400W IDENTIFIER 23494233 A 1235 1247 Carboxy-PTIO SYSTEMATIC 23494233 A 1258 1264 L-NAME ABBREVIATION 23494233 A 1277 1281 TRIM ABBREVIATION 23494233 A 1297 1302 1400W IDENTIFIER 23494233 A 1361 1368 ethanol SYSTEMATIC 23494233 A 1420 1422 NO FORMULA 23494233 A 1433 1443 L-arginine TRIVIAL 23494233 A 1468 1474 L-NAME ABBREVIATION 23494233 A 1489 1491 NO FORMULA 23494233 A 1553 1560 ethanol SYSTEMATIC 23494233 A 1638 1640 NO FORMULA 23494233 A 169 176 Ethanol SYSTEMATIC 23494233 A 1751 1758 ethanol SYSTEMATIC 23494233 A 25 27 NO FORMULA 23494233 A 329 331 NO FORMULA 23494233 A 378 385 ethanol SYSTEMATIC 23494233 A 555 562 ethanol SYSTEMATIC 23494233 A 655 662 ethanol SYSTEMATIC 23494233 A 724 726 NO FORMULA 23494233 A 737 802 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide SYSTEMATIC 23494233 A 804 816 carboxy-PTIO SYSTEMATIC 23494233 A 832 844 nitric oxide SYSTEMATIC 23494233 A 864 899 N (G)-nitro-L-arginine methyl ester SYSTEMATIC 23494233 A 901 907 L-NAME ABBREVIATION 23494233 A 929 941 nitric oxide SYSTEMATIC 23494233 A 961 1000 1-(2-[trifluoromethyl]phenyl) imidazole SYSTEMATIC 23494233 T 11 23 nitric oxide SYSTEMATIC 23494233 T 94 101 ethanol SYSTEMATIC 23494732 A 0 10 Ascorbigen TRIVIAL 23494732 A 12 15 ABG ABBREVIATION 23494732 A 141 144 ABG ABBREVIATION 23494732 A 324 327 ABG ABBREVIATION 23494732 A 36 42 indole SYSTEMATIC 23494732 A 437 448 hematoxylin TRIVIAL 23494732 A 453 458 eosin FAMILY 23494732 A 531 534 ABG ABBREVIATION 23494732 A 622 625 ABG ABBREVIATION 23494732 A 731 734 ABG ABBREVIATION 23494732 A 832 835 ABG ABBREVIATION 23494732 T 0 10 Ascorbigen TRIVIAL 23494763 A 1013 1021 safranal TRIVIAL 23494763 A 1050 1058 safranal TRIVIAL 23494763 A 1184 1192 safranal TRIVIAL 23494763 A 1194 1202 Safranal TRIVIAL 23494763 A 228 236 safranal TRIVIAL 23494763 A 443 451 safranal TRIVIAL 23494763 A 477 485 safranal TRIVIAL 23494763 A 502 555 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium SYSTEMATIC 23494763 A 557 560 MTT ABBREVIATION 23494763 A 653 669 propidium iodide TRIVIAL 23494763 A 717 720 MTT ABBREVIATION 23494763 A 894 902 safranal TRIVIAL 23494763 T 38 46 Safranal TRIVIAL 23494763 T 65 73 Safranal TRIVIAL 23494802 A 0 12 Curcuminoids FAMILY 23494802 A 1016 1028 curcuminoids FAMILY 23494802 A 203 214 curcuminoid FAMILY 23494802 A 416 428 curcuminoids FAMILY 23494802 A 784 795 Curcuminoid FAMILY 23494802 T 0 12 Curcuminoids FAMILY 23494810 A 1016 1023 pyridyl SYSTEMATIC 23494810 A 1040 1047 pyridyl SYSTEMATIC 23494810 A 1197 1204 pyridyl SYSTEMATIC 23494810 A 1359 1374 (S)-nornicotine TRIVIAL 23494810 A 1398 1410 (S)-nicotine TRIVIAL 23494810 A 1521 1536 (S)-nornicotine TRIVIAL 23494810 A 1580 1592 (S)-nicotine TRIVIAL 23494810 A 337 345 nicotine TRIVIAL 23494810 A 479 491 (S)-nicotine TRIVIAL 23494810 A 69 90 (R)- and (S)-nicotine MULTIPLE 23494810 A 722 729 pyridyl SYSTEMATIC 23494810 A 95 110 (S)-nornicotine TRIVIAL 23494810 A 986 996 pyrrolidyl SYSTEMATIC 23494810 A 997 998 N FORMULA 23494810 T 25 33 Nicotine TRIVIAL 23494810 T 38 49 Nornicotine TRIVIAL 23494831 A 0 6 Ca(2+) FORMULA 23494831 A 122 128 Ca(2+) FORMULA 23494831 A 226 240 coelenterazine TRIVIAL 23494831 A 255 261 oxygen SYSTEMATIC 23494831 A 331 345 coelenterazine TRIVIAL 23494831 A 462 476 coelenterazine TRIVIAL 23494831 A 534 536 N7 FORMULA 23494831 A 552 557 C2(-) FORMULA 23494831 A 58 85 2-hydroperoxycoelenterazine SYSTEMATIC 23494831 A 582 588 oxygen SYSTEMATIC 23494831 A 628 633 C2(-) FORMULA 23494831 A 655 661 peroxy SYSTEMATIC 23494831 A 699 701 N7 FORMULA 23494831 A 729 735 peroxy SYSTEMATIC 23494831 A 773 800 2-hydroperoxycoelenterazine SYSTEMATIC 23494831 A 846 849 His FORMULA 23494831 A 889 892 His FORMULA 23494831 A 971 977 Ca(2+) FORMULA 23494831 T 0 6 Oxygen SYSTEMATIC 23494831 T 32 46 Coelenterazine TRIVIAL 23494834 A 0 8 Graphene TRIVIAL 23494834 A 255 263 graphene TRIVIAL 23494834 A 444 452 Graphene TRIVIAL 23494834 A 821 829 graphene TRIVIAL 23494834 T 28 36 graphene TRIVIAL 23495001 A 247 258 cholesterol TRIVIAL 23495001 A 310 324 Glucosinolates FAMILY 23495001 A 408 423 isothiocyanates FAMILY 23495001 A 522 533 cholesterol TRIVIAL 23495001 A 596 607 cholesterol TRIVIAL 23495001 A 765 779 glucosinolates FAMILY 23495001 A 843 854 cholesterol TRIVIAL 23495001 T 82 93 Cholesterol TRIVIAL 23495151 A 112 117 H(2)O FORMULA 23495151 A 203 204 H FORMULA 23495151 A 217 226 hydronium SYSTEMATIC 23495151 A 244 245 H FORMULA 23495151 A 269 270 H FORMULA 23495151 A 324 325 O FORMULA 23495151 A 371 380 hydronium SYSTEMATIC 23495151 A 38 39 H FORMULA 23495151 A 382 390 H(3)O(+) FORMULA 23495151 A 456 465 hydronium SYSTEMATIC 23495151 A 470 475 H(2)O FORMULA 23495151 A 50 59 hydronium SYSTEMATIC 23495151 A 538 543 H(2)O FORMULA 23495151 A 638 643 H(2)O FORMULA 23495151 A 72 73 H FORMULA 23495151 A 88 89 O FORMULA 23495161 A 284 317 acarviostatins III0(-1) and III23 MULTIPLE 23495161 A 392 406 acarviostatins FAMILY 23495161 A 524 557 acarviostatins III0(-1) and III23 MULTIPLE 23495161 T 57 71 acarviostatins FAMILY 23495163 A 1075 1084 n-alkanes FAMILY 23495163 A 172 178 hexane SYSTEMATIC 23495163 A 366 381 nonacosan-10-ol SYSTEMATIC 23495163 A 597 606 n-alkanes FAMILY 23495163 A 662 663 C FORMULA 23495163 A 671 672 C FORMULA 23495163 A 696 705 n-alkanes FAMILY 23495163 A 70 79 n-alkanes FAMILY 23495163 A 711 712 C FORMULA 23495163 A 718 719 C FORMULA 23495163 A 729 730 C FORMULA 23495163 A 785 791 carbon SYSTEMATIC 23495163 A 820 829 n-alkanes FAMILY 23495163 A 84 99 nonacosan-10-ol SYSTEMATIC 23495163 T 15 24 n-alkanes FAMILY 23495163 T 29 44 nonacosan-10-ol SYSTEMATIC 23495190 A 217 228 artemisinin TRIVIAL 23495190 A 229 240 polypyrrole FAMILY 23495190 A 35 47 Artemisinins FAMILY 23495190 T 0 11 Artemisinin TRIVIAL 23495190 T 12 23 polypyrrole FAMILY 23495719 A 182 190 furfural TRIVIAL 23495719 A 201 223 hydroxymethyl furfural SYSTEMATIC 23495719 A 225 228 HMF ABBREVIATION 23495719 A 719 722 HMF ABBREVIATION 23495769 A 1297 1303 silver SYSTEMATIC 23495769 A 643 645 Ag FORMULA 23495769 A 709 711 Au FORMULA 23495911 A 1029 1037 chromium SYSTEMATIC 23495911 A 1290 1298 chromium SYSTEMATIC 23495911 A 181 189 chromium SYSTEMATIC 23495911 A 278 286 chromium SYSTEMATIC 23495911 T 0 8 Chromium SYSTEMATIC 23496305 A 298 309 fluorescein TRIVIAL 23496349 A 1065 1067 W3 FORMULA 23496349 A 1099 1105 W3(2-) FORMULA 23496349 A 122 133 tritungsten SYSTEMATIC 23496349 A 144 146 W3 FORMULA 23496349 A 148 153 W3(-) FORMULA 23496349 A 155 161 W3(2-) FORMULA 23496349 A 167 184 tritungsten oxide SYSTEMATIC 23496349 A 194 203 W3Ox(-/0) FAMILY 23496349 A 350 357 W3Ox(-) FAMILY 23496349 A 508 519 tritungsten SYSTEMATIC 23496349 A 632 634 W3 FORMULA 23496349 A 636 641 W3(-) FORMULA 23496349 A 646 652 W3(2-) FORMULA 23496349 A 672 678 W3O(-) FORMULA 23496349 A 683 686 W3O FORMULA 23496349 A 701 707 oxygen SYSTEMATIC 23496349 A 762 768 oxygen SYSTEMATIC 23496349 A 812 819 W3O2(-) FORMULA 23496349 A 824 828 W3O2 FORMULA 23496349 A 990 995 W3(-) FORMULA 23496349 A 999 1006 W3O2(-) FORMULA 23496349 T 104 110 W3(2-) FORMULA 23496349 T 37 46 W3Ox(-/0) FAMILY 23496349 T 61 67 W3(2-) FORMULA 23496349 T 97 99 W3 FORMULA 23496412 A 268 279 metal oxide FAMILY 23496412 A 439 456 calcium carbonate SYSTEMATIC 23496412 A 468 477 kaolinite TRIVIAL 23496412 A 597 606 kaolinite TRIVIAL 23496412 T 48 57 Kaolinite TRIVIAL 23496412 T 72 89 Calcium Carbonate SYSTEMATIC 23497227 A 104 112 tyrosine TRIVIAL 23497227 A 12 31 pyrido-quinazolines FAMILY 23497227 A 174 204 Alkylideno/arylideno-bis-ureas MULTIPLE 23497227 A 300 302 1H FORMULA 23497227 T 37 63 N-Aryl pyrido-quinazolines FAMILY 23497860 A 1012 1022 β-carotene TRIVIAL 23497860 A 972 983 astaxanthin TRIVIAL 23497860 A 985 991 lutein TRIVIAL 23497860 A 993 1006 canthaxanthin TRIVIAL 23497864 A 115 133 phenolic glycoside FAMILY 23497864 A 144 166 monoterpene glycosides FAMILY 23497864 A 178 211 1-O-β-d-(4-hydroxybenzoyl)glucose SYSTEMATIC 23497864 A 217 236 pyridylpaeoniflorin SYSTEMATIC 23497864 A 242 286 (8R)-piperitone-4-en-9-O-β-d-glucopyranoside SYSTEMATIC 23497864 A 292 307 oxypaeoniflorin SYSTEMATIC 23497864 A 313 344 6'-O-β-glucopyranosylalbiflorin SYSTEMATIC 23497864 A 350 360 albiflorin TRIVIAL 23497864 A 366 392 β-gentiobiosylpaeoniflorin TRIVIAL 23497864 A 402 414 paeoniflorin TRIVIAL 23497864 A 602 613 formic acid SYSTEMATIC 23497864 A 618 626 methanol SYSTEMATIC 23497864 T 41 76 phenolic and monoterpene glycosides MULTIPLE 23497866 A 131 141 flavonoids FAMILY 23497866 A 202 212 flavonoids FAMILY 23497866 A 301 311 flavonoids FAMILY 23497866 A 321 330 quercetin TRIVIAL 23497866 A 332 342 kaempferol TRIVIAL 23497866 A 347 359 isorhamnetin TRIVIAL 23497866 A 599 606 ethanol SYSTEMATIC 23497866 A 843 853 flavonoids FAMILY 23497866 T 70 80 flavonoids FAMILY 23497867 A 528 531 Thr FORMULA 23497867 A 544 547 Ser FORMULA 23497875 A 140 144 iron SYSTEMATIC 23497875 A 273 275 Fe FORMULA 23497875 A 302 308 FeEDTA FORMULA 23497875 A 357 359 Fe FORMULA 23497875 A 384 390 FeEDTA FORMULA 23497875 A 395 397 Fe FORMULA 23497875 A 434 440 FeEDTA FORMULA 23497875 A 460 462 Fe FORMULA 23497875 A 498 505 nitrate SYSTEMATIC 23497875 A 555 557 Fe FORMULA 23497875 A 646 655 ascorbate TRIVIAL 23497875 A 664 666 Fe FORMULA 23497875 A 705 707 Fe FORMULA 23497875 A 776 780 DPPH ABBREVIATION 23497875 A 809 811 Fe FORMULA 23497875 A 863 865 Fe FORMULA 23497875 A 919 921 Fe FORMULA 23497875 A 984 986 Fe FORMULA 23497875 T 5 7 Fe FORMULA 23497876 A 133 174 reduced nicotinamide adenine dinucleotide TRIVIAL 23497876 A 176 180 NADH ABBREVIATION 23497876 A 222 229 ethanol SYSTEMATIC 23497876 A 259 263 NADH ABBREVIATION 23497876 A 349 353 NADH ABBREVIATION 23497876 A 377 391 graphene oxide SYSTEMATIC 23497876 A 424 430 carbon SYSTEMATIC 23497876 A 596 602 Al(3+) FORMULA 23497876 A 623 645 tridecameric aluminium SYSTEMATIC 23497876 A 665 671 Al(13) FORMULA 23497876 A 706 712 Al(3+) FORMULA 23497876 A 722 728 Al(13) FORMULA 23497876 A 77 84 alcohol FAMILY 23497876 A 929 933 NADH ABBREVIATION 23497876 A 945 951 Al(3+) FORMULA 23497876 A 961 967 Al(13) FORMULA 23497876 T 118 125 alcohol FAMILY 23497876 T 23 37 graphene oxide SYSTEMATIC 23497876 T 42 48 carbon SYSTEMATIC 23497878 A 246 259 ethyl-acetate SYSTEMATIC 23497878 A 455 466 cholesterol TRIVIAL 23497879 A 784 789 MeAαC ABBREVIATION 23497879 A 916 920 HCAs ABBREVIATION 23497879 T 139 146 Trp-P-1 ABBREVIATION 23497879 T 148 155 Trp-P-2 ABBREVIATION 23497879 T 157 160 AαC ABBREVIATION 23497879 T 165 170 MeAαC ABBREVIATION 23497881 A 479 491 l-malic acid SYSTEMATIC 23497881 A 633 641 alcohols FAMILY 23497881 A 653 659 esters FAMILY 23497881 A 743 751 alcohols FAMILY 23497882 A 329 336 glucose TRIVIAL 23497882 A 338 347 galactose TRIVIAL 23497882 A 352 359 mannose TRIVIAL 23497882 A 461 468 glucose TRIVIAL 23497882 A 562 568 oxygen SYSTEMATIC 23497882 A 630 636 Trolox TRIVIAL 23497882 A 86 90 DEAE ABBREVIATION 23497887 A 246 254 carbonyl FAMILY 23497887 A 635 643 peroxide SYSTEMATIC 23497887 A 675 692 organic peroxides FAMILY 23497887 A 694 698 ROOH FAMILY 23497887 A 725 742 hydrogen peroxide SYSTEMATIC 23497887 A 744 748 H2O2 FORMULA 23497887 A 800 809 vitamin E FAMILY 23497887 A 814 823 carnosine TRIVIAL 23497887 T 120 129 peroxides FAMILY 23497894 A 150 172 short-chain fatty acid FAMILY 23497894 A 174 178 SCFA ABBREVIATION 23497894 A 631 639 hydroxyl SYSTEMATIC 23497894 A 660 670 superoxide TRIVIAL 23497894 A 691 721 1,1-diphenyl-2-picryl-hydrazyl SYSTEMATIC 23497894 A 822 826 SCFA ABBREVIATION 23497894 A 828 842 propionic acid SYSTEMATIC 23497894 A 847 861 n-butyric acid SYSTEMATIC 23497894 T 64 86 short-chain fatty acid FAMILY 23497896 A 0 6 Citral TRIVIAL 23497896 A 373 379 citral TRIVIAL 23497896 A 417 423 citral TRIVIAL 23497896 A 588 594 citral TRIVIAL 23497896 A 689 715 polyoxyethylene alkylether FAMILY 23497896 A 859 865 citral TRIVIAL 23497896 T 14 20 citral TRIVIAL 23497896 T 69 95 polyoxyethylene alkylether FAMILY 23497898 A 448 467 phosphatidylcholine FAMILY 23497908 A 46 53 mercury SYSTEMATIC 23499236 A 232 241 rhodanine FAMILY 23499236 A 60 65 enoyl FAMILY 23499236 T 57 62 enoyl FAMILY 23499237 A 335 339 zinc SYSTEMATIC 23499237 A 372 422 UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine SYSTEMATIC 23499237 A 512 515 UDP ABBREVIATION 23499237 A 636 647 hydroxamate SYSTEMATIC 23499237 A 722 725 UDP ABBREVIATION 23499237 A 761 773 α-amino acid FAMILY 23499237 T 14 17 UDP ABBREVIATION 23499237 T 41 51 amino acid FAMILY 23499664 A 0 15 Levomilnacipran TRIVIAL 23499664 A 1025 1028 LVM ABBREVIATION 23499664 A 1219 1229 Duloxetine TRIVIAL 23499664 A 1234 1245 venlafaxine TRIVIAL 23499664 A 127 138 milnacipran TRIVIAL 23499664 A 1346 1349 LVM ABBREVIATION 23499664 A 1430 1433 LVM ABBREVIATION 23499664 A 1477 1481 5-HT SYSTEMATIC 23499664 A 17 20 LVM ABBREVIATION 23499664 A 22 27 F2695 IDENTIFIER 23499664 A 222 225 LVM ABBREVIATION 23499664 A 267 277 duloxetine TRIVIAL 23499664 A 282 293 venlafaxine TRIVIAL 23499664 A 353 356 LVM ABBREVIATION 23499664 A 413 417 5-HT SYSTEMATIC 23499664 A 489 493 5-HT SYSTEMATIC 23499664 A 543 546 LVM ABBREVIATION 23499664 A 578 592 norepinephrine TRIVIAL 23499664 A 605 614 serotonin TRIVIAL 23499664 A 644 648 5-HT SYSTEMATIC 23499664 A 66 75 serotonin TRIVIAL 23499664 A 749 760 venlafaxine TRIVIAL 23499664 A 76 90 norepinephrine TRIVIAL 23499664 A 765 775 duloxetine TRIVIAL 23499664 A 791 794 LVM ABBREVIATION 23499664 A 849 852 LVM ABBREVIATION 23499664 A 903 907 5-HT SYSTEMATIC 23499664 A 92 96 5-HT SYSTEMATIC 23499664 T 0 15 Levomilnacipran TRIVIAL 23499664 T 17 22 F2695 IDENTIFIER 23499664 T 27 41 norepinephrine TRIVIAL 23499758 A 0 10 Raloxifene TRIVIAL 23499758 A 105 115 raloxifene TRIVIAL 23499758 A 1072 1082 raloxifene TRIVIAL 23499758 A 1144 1154 raloxifene TRIVIAL 23499758 A 1258 1268 raloxifene TRIVIAL 23499758 A 1333 1343 raloxifene TRIVIAL 23499758 A 1437 1447 raloxifene TRIVIAL 23499758 A 1538 1548 raloxifene TRIVIAL 23499758 A 1634 1651 mycophenolic acid TRIVIAL 23499758 A 191 194 UDP ABBREVIATION 23499758 A 2130 2140 raloxifene TRIVIAL 23499758 A 503 513 amino acid FAMILY 23499758 A 541 551 raloxifene TRIVIAL 23499758 A 704 714 Raloxifene TRIVIAL 23499758 A 982 992 raloxifene TRIVIAL 23499758 T 10 13 UDP ABBREVIATION 23499758 T 58 68 raloxifene TRIVIAL 23499823 A 117 133 4'-hydroxymethyl SYSTEMATIC 23499823 A 148 166 4'-methoxycarbonyl SYSTEMATIC 23499823 A 216 261 17α-bromo-21-iodo-3β-acetoxypregn-5-en-20-one SYSTEMATIC 23499823 A 24 104 (4'R)- and (4'S)- 2'-{[(E)-3β-hydroxyandrost-5-en-17-ylidene]-methyl} oxazolines MULTIPLE 23499823 A 274 297 (L)-serine methyl ester SYSTEMATIC 23499823 A 302 325 (D)-serine methyl ester SYSTEMATIC 23499823 A 338 405 methyl N-[3β-acetoxy-21-oxopregna-5,17(20)-dien-21-yl]-(L)-serinate SYSTEMATIC 23499823 A 410 477 methyl N-[3β-acetoxy-21-oxopregna-5,17(20)-dien-21-yl]-(D)-serinate SYSTEMATIC 23499823 A 561 567 amides FAMILY 23499823 A 575 681 methyl 2'-{[(E)-3β-acetoxyandrost-5-en-17-ylidene]methyl}-(4'S)-4',5'-dihydro-1',3'-oxazole-4'-carboxylate SYSTEMATIC 23499823 A 686 792 methyl 2'-{[(E)-3β-acetoxyandrost-5-en-17-ylidene]methyl}-(4'R)-4',5'-dihydro-1',3'-oxazole-4'-carboxylate SYSTEMATIC 23499823 T 36 120 (4'R)- and (4'S)- 4'-substituted 2'-{[(E)-androst-5-en-17-ylidene]-methyl}oxazolines MULTIPLE 23499925 A 1986 1987 N FORMULA 23500061 A 407 415 tyrosine TRIVIAL 23500061 A 562 579 polyethyleneimine SYSTEMATIC 23500061 A 594 610 deoxycholic acid TRIVIAL 23500061 T 108 124 deoxycholic acid TRIVIAL 23500061 T 155 172 polyethyleneimine SYSTEMATIC 23500065 A 105 121 proanthocyanidin FAMILY 23500065 A 626 629 Lys FORMULA 23500065 T 41 57 proanthocyanidin FAMILY 23500115 A 1051 1061 ketoprofen TRIVIAL 23500115 A 1152 1162 ketoprofen TRIVIAL 23500115 A 1186 1195 phosphate SYSTEMATIC 23500115 A 1236 1246 Ketoprofen TRIVIAL 23500115 A 1446 1456 ketoprofen TRIVIAL 23500115 A 1510 1520 ketoprofen TRIVIAL 23500115 A 161 171 Ketoprofen TRIVIAL 23500115 A 437 441 (1)H FORMULA 23500115 A 446 451 (31)P FORMULA 23500115 A 499 509 Ketoprofen TRIVIAL 23500115 A 599 609 ketoprofen TRIVIAL 23500115 A 73 83 ketoprofen TRIVIAL 23500115 A 760 770 Ketoprofen TRIVIAL 23500115 A 956 966 ketoprofen TRIVIAL 23500115 A 979 989 ketoprofen TRIVIAL 23500115 T 40 50 ketoprofen TRIVIAL 23500335 A 0 11 Bisphenol A TRIVIAL 23500335 A 1226 1229 BPA ABBREVIATION 23500335 A 1237 1240 BPA ABBREVIATION 23500335 A 13 16 BPA ABBREVIATION 23500335 A 1359 1362 BPA ABBREVIATION 23500335 A 1427 1430 BPA ABBREVIATION 23500335 A 1565 1568 BPA ABBREVIATION 23500335 A 188 191 BPA ABBREVIATION 23500335 A 320 323 BPA ABBREVIATION 23500335 A 394 397 BPA ABBREVIATION 23500335 A 624 633 estradiol TRIVIAL 23500335 A 63 76 polycarbonate FAMILY 23500335 A 781 784 BPA ABBREVIATION 23500335 A 87 92 epoxy SYSTEMATIC 23500335 A 949 957 tyrosine TRIVIAL 23500335 T 33 44 bisphenol A TRIVIAL 23500335 T 46 49 BPA ABBREVIATION 23500411 A 175 177 OH FORMULA 23500411 A 25 38 ritterazine G TRIVIAL 23500411 A 69 86 hecogenin acetate SYSTEMATIC 23500411 A 8 10 OH FORMULA 23500411 T 17 19 OH FORMULA 23500411 T 34 47 ritterazine G TRIVIAL 23500411 T 78 95 hecogenin acetate SYSTEMATIC 23500537 A 1036 1046 sitosterol TRIVIAL 23500537 A 1051 1062 campesterol TRIVIAL 23500537 A 107 121 oxyphytosterol FAMILY 23500537 A 1108 1121 oxysitosterol FAMILY 23500537 A 1126 1140 oxycampesterol FAMILY 23500537 A 1220 1234 oxyphytosterol FAMILY 23500537 A 1373 1387 oxyphytosterol FAMILY 23500537 A 1518 1522 iron SYSTEMATIC 23500537 A 1523 1529 copper SYSTEMATIC 23500537 A 1538 1550 α-tocopherol TRIVIAL 23500537 A 1675 1689 oxyphytosterol FAMILY 23500537 A 195 208 sterol esters FAMILY 23500537 A 276 288 stanol ester FAMILY 23500537 A 28 43 oxyphytosterols FAMILY 23500537 A 324 338 oxyphytosterol FAMILY 23500537 A 493 507 oxyphytosterol FAMILY 23500537 A 591 597 sterol FAMILY 23500537 A 599 605 stanol FAMILY 23500537 A 636 650 oxyphytosterol FAMILY 23500537 A 685 709 butylated hydroxytoluene SYSTEMATIC 23500537 A 711 714 BHT ABBREVIATION 23500537 A 725 729 EDTA ABBREVIATION 23500537 A 838 844 Trolox TRIVIAL 23500537 A 892 904 α-tocopherol TRIVIAL 23500537 A 924 928 iron SYSTEMATIC 23500537 A 929 935 copper SYSTEMATIC 23500537 T 0 14 Oxyphytosterol FAMILY 23500547 A 314 325 cholesterol TRIVIAL 23500547 A 72 83 cholesterol TRIVIAL 23500550 A 1037 1038 N FORMULA 23500550 A 1085 1086 C FORMULA 23500550 A 872 873 N FORMULA 23500768 A 0 11 Astaxanthin TRIVIAL 23500768 A 174 185 astaxanthin TRIVIAL 23500768 A 271 282 astaxanthin TRIVIAL 23500768 A 329 338 bleomycin FAMILY 23500768 A 412 423 astaxanthin TRIVIAL 23500768 A 557 568 astaxanthin TRIVIAL 23500768 A 664 678 hydroxyproline SYSTEMATIC 23500768 A 798 809 Astaxanthin TRIVIAL 23500768 A 958 969 astaxanthin TRIVIAL 23500768 T 0 11 Astaxanthin TRIVIAL 23500770 A 1071 1074 DON ABBREVIATION 23500770 A 42 56 deoxynivalenol TRIVIAL 23500770 A 431 434 DON ABBREVIATION 23500770 A 462 465 DON ABBREVIATION 23500770 A 58 61 DON ABBREVIATION 23500770 A 633 636 DON ABBREVIATION 23500770 A 816 819 DON ABBREVIATION 23500770 A 972 975 DON ABBREVIATION 23500770 T 40 54 deoxynivalenol TRIVIAL 23500772 A 143 150 ethanol SYSTEMATIC 23500772 A 152 156 EtOH FORMULA 23500772 A 207 211 EtOH FORMULA 23500772 A 293 297 EtOH FORMULA 23500772 A 354 361 glucose TRIVIAL 23500772 A 513 517 EtOH FORMULA 23500772 A 723 727 EtOH FORMULA 23500772 A 812 815 MDA ABBREVIATION 23500772 A 958 962 EtOH FORMULA 23500772 A 989 992 MDA ABBREVIATION 23500772 T 25 32 ethanol SYSTEMATIC 23500778 A 1057 1068 Hirsutenone TRIVIAL 23500778 A 1101 1105 NMDA ABBREVIATION 23500778 A 1164 1175 hirsutenone TRIVIAL 23500778 A 264 294 l-buthionine-(S,R)-sulfoximine SYSTEMATIC 23500778 A 296 299 BSO ABBREVIATION 23500778 A 30 41 hirsutenone TRIVIAL 23500778 A 306 315 glutamate TRIVIAL 23500778 A 372 388 propidium iodide TRIVIAL 23500778 A 445 448 MTT ABBREVIATION 23500778 A 467 478 hirsutenone TRIVIAL 23500778 A 549 552 BSO ABBREVIATION 23500778 A 569 580 Hirsutenone TRIVIAL 23500778 A 608 628 sodium nitroprusside SYSTEMATIC 23500778 A 630 633 SNP ABBREVIATION 23500778 A 718 729 hirsutenone TRIVIAL 23500778 A 747 767 N-methyl-d-aspartate SYSTEMATIC 23500778 A 769 773 NMDA ABBREVIATION 23500778 A 820 824 NMDA ABBREVIATION 23500778 A 968 972 dUTP ABBREVIATION 23501108 A 16 74 2-pyridyl hexahydrocycloocta [4,5]thieno[2,3-d]pyrimidines FAMILY 23501108 A 566 577 doxorubicin TRIVIAL 23501108 T 43 93 2-pyridyl hexahyrocyclooctathieno[2,3-d]pyrimidine SYSTEMATIC 23501109 A 18 31 pleuromutilin TRIVIAL 23501109 A 185 196 methicillin TRIVIAL 23501109 A 230 241 methicillin TRIVIAL 23501109 A 418 487 14-O-[(4-methoxybenzamide-2- methylpropane-2-yl) thioacetate] mutilin SYSTEMATIC 23501109 A 492 558 14-O-[(2-aminobenzamide-2-methylpropane-2-yl) thioacetate] mutilin SYSTEMATIC 23501109 A 566 632 14-O-[(4-aminobenzamide-2-methylpropane-2-yl) thioacetate] mutilin SYSTEMATIC 23501109 T 48 61 pleuromutilin TRIVIAL 23503472 A 1054 1066 cyclosporine TRIVIAL 23503472 A 1685 1697 cyclosporine TRIVIAL 23503472 A 1799 1811 cyclosporine TRIVIAL 23503472 A 265 277 cyclosporine TRIVIAL 23503472 A 4 16 Cyclosporine TRIVIAL 23503472 A 441 453 cyclosporine TRIVIAL 23503472 A 579 591 Cyclosporine TRIVIAL 23503472 A 694 706 cyclosporine TRIVIAL 23503472 A 818 830 cyclosporine TRIVIAL 23503472 T 66 78 cyclosporine TRIVIAL 23503923 A 473 499 poly(lactide-co-glycolide) SYSTEMATIC 23503923 A 501 505 PLGA ABBREVIATION 23503923 A 531 535 PLGA ABBREVIATION 23503923 A 599 617 poly(acrylic acid) SYSTEMATIC 23503923 A 619 622 PAA ABBREVIATION 23503923 A 834 837 PAA ABBREVIATION 23503927 A 1008 1017 potassium SYSTEMATIC 23503927 A 1042 1049 lithium SYSTEMATIC 23503927 A 109 112 DNB ABBREVIATION 23503927 A 1097 1103 tBuCQN ABBREVIATION 23503927 A 1114 1123 potassium SYSTEMATIC 23503927 A 113 124 S/R-leucine TRIVIAL 23503927 A 1170 1176 tBuCQN ABBREVIATION 23503927 A 158 163 Li(+) FORMULA 23503927 A 165 170 Na(+) FORMULA 23503927 A 172 176 K(+) FORMULA 23503927 A 28 62 (8S,9R)-tert-butylcarbamoylquinine SYSTEMATIC 23503927 A 298 309 carboxylate SYSTEMATIC 23503927 A 319 322 DNB ABBREVIATION 23503927 A 323 326 Leu FORMULA 23503927 A 377 403 [tBuCQN·DNB-S/R-Leu·Na](+) FORMULA 23503927 A 513 519 tBuCQN ABBREVIATION 23503927 A 570 573 DNB ABBREVIATION 23503927 A 574 579 S-Leu FORMULA 23503927 A 64 70 tBuCQN ABBREVIATION 23503927 A 73 107 N-3,5-dinitrobenzoyl-(S,R)-leucine SYSTEMATIC 23503927 A 744 747 DNB ABBREVIATION 23503927 A 748 753 R-Leu FORMULA 23503927 A 817 824 lithium SYSTEMATIC 23503927 A 853 859 sodium SYSTEMATIC 23503927 A 901 925 [tBuCQN·DNB-R-Leu·Li](+) FORMULA 23503927 A 934 958 [tBuCQN·DNB-S-Leu·Li](+) FORMULA 23504247 A 124 134 devazepide TRIVIAL 23504247 A 139 149 asperlicin TRIVIAL 23504247 A 19 45 1,3,4-benzotriazepin-5-one SYSTEMATIC 23504247 A 203 237 2-amino-1,3,4-benzotriazepin-5-one SYSTEMATIC 23504247 T 17 43 1,3,4-benzotriazepin-5-one SYSTEMATIC 23504356 A 405 417 fenfluramine TRIVIAL 23504356 A 655 663 oxytocin TRIVIAL 23504645 A 208 211 SO2 FORMULA 23504645 A 27 30 SO2 FORMULA 23504645 A 76 83 benzene SYSTEMATIC 23504923 A 0 10 BMS-690514 IDENTIFIER 23504923 A 1020 1032 ketoconazole TRIVIAL 23504923 A 1178 1190 ketoconazole TRIVIAL 23504923 A 1278 1290 ketoconazole TRIVIAL 23504923 A 357 369 ketoconazole TRIVIAL 23504923 A 373 383 BMS-690514 IDENTIFIER 23504923 A 440 450 BMS-690514 IDENTIFIER 23504923 A 476 486 BMS-690514 IDENTIFIER 23504923 A 492 504 ketoconazole TRIVIAL 23504923 A 556 566 BMS-690514 IDENTIFIER 23504923 A 599 611 ketoconazole TRIVIAL 23504923 A 642 652 BMS-690514 IDENTIFIER 23504923 A 697 707 BMS-690514 IDENTIFIER 23504923 A 724 734 BMS-690514 IDENTIFIER 23504923 A 742 754 ketoconazole TRIVIAL 23504923 A 836 846 BMS-690514 IDENTIFIER 23504923 T 103 113 BMS-690514 IDENTIFIER 23504923 T 21 33 Ketoconazole TRIVIAL 23504923 T 77 85 Tyrosine TRIVIAL 23505091 A 988 994 oxygen SYSTEMATIC 23505146 A 255 256 N FORMULA 23505146 A 463 470 glucose TRIVIAL 23505146 A 518 525 mannose TRIVIAL 23505344 A 242 244 CO FORMULA 23505344 A 288 291 H2O FORMULA 23505344 A 39 42 H2O FORMULA 23505344 A 420 423 Leu FORMULA 23505344 A 47 49 CO FORMULA 23505344 A 568 573 xenon SYSTEMATIC 23505344 A 599 602 H2O FORMULA 23505344 A 639 644 xenon SYSTEMATIC 23505344 A 655 658 Xe4 FORMULA 23505344 A 660 663 Xe2 FORMULA 23505344 A 669 672 Xe3 FORMULA 23505344 A 773 776 H2O FORMULA 23505344 A 794 803 histidine TRIVIAL 23505344 A 831 833 CO FORMULA 23505344 A 917 919 Xe FORMULA 23505344 A 978 980 CO FORMULA 23505344 T 35 37 CO FORMULA 23506052 A 1034 1039 TEMPO ABBREVIATION 23506052 A 1066 1071 TEMPO ABBREVIATION 23506052 A 1083 1086 DPH ABBREVIATION 23506052 A 1157 1160 DPH ABBREVIATION 23506052 A 122 126 DOPC ABBREVIATION 23506052 A 1244 1248 DOPC ABBREVIATION 23506052 A 1249 1253 DPPC ABBREVIATION 23506052 A 1263 1267 DOPC ABBREVIATION 23506052 A 1268 1272 DPPC ABBREVIATION 23506052 A 127 131 DPPC ABBREVIATION 23506052 A 1282 1286 DOPC ABBREVIATION 23506052 A 1303 1307 DOPC ABBREVIATION 23506052 A 1308 1312 DPPC ABBREVIATION 23506052 A 137 141 DOPC ABBREVIATION 23506052 A 142 153 cholesterol TRIVIAL 23506052 A 212 251 (2,2,6,6-tetramethylpiperidin-1-yl)oxyl SYSTEMATIC 23506052 A 253 258 TEMPO ABBREVIATION 23506052 A 307 311 DOPC ABBREVIATION 23506052 A 312 316 DPPC ABBREVIATION 23506052 A 352 381 1,6-diphenyl-1,3,5-hexatriene SYSTEMATIC 23506052 A 36 76 1,2-dioleoyl-sn-glycero-3-phosphocholine SYSTEMATIC 23506052 A 383 386 DPH ABBREVIATION 23506052 A 483 520 6-lauroyl-2-dimethylamino naphthalene SYSTEMATIC 23506052 A 522 529 Laurdan ABBREVIATION 23506052 A 593 597 DOPC ABBREVIATION 23506052 A 598 602 DPPC ABBREVIATION 23506052 A 77 120 1,2-dipalmitoyl-sn-glycero-3-phosphocholine SYSTEMATIC 23506052 A 799 803 DOPC ABBREVIATION 23506052 A 804 808 DPPC ABBREVIATION 23506052 A 813 817 DOPC ABBREVIATION 23506052 A 945 949 DOPC ABBREVIATION 23506052 A 950 954 DPPC ABBREVIATION 23506052 T 42 46 DOPC ABBREVIATION 23506052 T 47 51 DPPC ABBREVIATION 23506052 T 56 60 DOPC ABBREVIATION 23506073 A 1004 1007 FMN ABBREVIATION 23506073 A 1095 1103 quinones FAMILY 23506073 A 1139 1146 glyoxal TRIVIAL 23506073 A 1303 1311 quinones FAMILY 23506073 A 1316 1324 glyoxals FAMILY 23506073 A 264 280 N-ethylmaleimide SYSTEMATIC 23506073 A 32 40 glyoxals FAMILY 23506073 A 485 493 quinones FAMILY 23506073 A 498 506 glyoxals FAMILY 23506073 A 624 632 quinones FAMILY 23506073 A 637 645 glyoxals FAMILY 23506073 A 80 88 carbonyl FAMILY 23506073 A 815 825 disulphide SYSTEMATIC 23506073 A 931 938 glyoxal TRIVIAL 23506497 A 1093 1107 catecholamines FAMILY 23506497 A 1165 1175 dobutamine TRIVIAL 23506497 A 1207 1221 catecholamines FAMILY 23506497 A 1444 1456 levosimendan TRIVIAL 23506497 A 1458 1468 istaroxime TRIVIAL 23506497 A 1472 1490 omecamtiv mecarbil TRIVIAL 23506497 A 1527 1533 oxygen SYSTEMATIC 23506497 A 1569 1579 ivabradine TRIVIAL 23506497 A 1599 1605 oxygen SYSTEMATIC 23506497 A 1780 1788 pyruvate TRIVIAL 23506497 A 1790 1799 succinate TRIVIAL 23506497 A 710 717 calcium SYSTEMATIC 23506497 A 742 749 calcium SYSTEMATIC 23506497 A 995 1009 norepinephrine TRIVIAL 23506741 A 1076 1081 Fc11a FORMULA 23506741 A 1125 1132 Fc11a-2 FORMULA 23506741 A 1339 1346 Fc11a-2 FORMULA 23506741 A 269 315 1-ethyl-5-methyl-2-phenyl-1H-benzo[d]imidazole SYSTEMATIC 23506741 A 365 372 Fc11a-2 FORMULA 23506741 A 403 410 sulfate SYSTEMATIC 23506741 A 411 417 sodium SYSTEMATIC 23506741 A 745 752 Fc11a-2 FORMULA 23506741 A 926 933 Fc11a-2 FORMULA 23506741 T 79 85 sodium SYSTEMATIC 23506741 T 8 25 benzo[d]imidazole SYSTEMATIC 23507565 T 118 125 cocaine TRIVIAL 23507565 T 130 136 heroin TRIVIAL 23507573 A 455 463 tyrosine TRIVIAL 23508304 A 100 107 glucose TRIVIAL 23508304 T 109 116 glucose TRIVIAL 23508887 A 1198 1221 5-hydroxymethylcytosine SYSTEMATIC 23508887 A 1241 1257 5-methylcytosine SYSTEMATIC 23508961 A 1332 1341 leupeptin TRIVIAL 23508961 A 450 461 cholesterol TRIVIAL 23508961 A 782 793 cholesterol TRIVIAL 23509039 A 27 40 aminothiazole SYSTEMATIC 23509039 A 46 104 (4-biphenyl-4-ylthiazol-2-yl)-(6-methylpyridin-2-yl)-amine SYSTEMATIC 23509039 A 664 731 (6-methylpyridin-2-yl)-[4-(4-pyridin-3-yl-phenyl)thiazol-2-yl]amine SYSTEMATIC 23509039 A 736 793 cyclopropanecarboxylic acid (4-biphenylthiazol-2-yl)amide SYSTEMATIC 23509039 T 0 16 2-aminothiazoles FAMILY 23509853 A 1107 1117 pivalamido SYSTEMATIC 23509853 A 1148 1154 Cu(II) FORMULA 23509853 A 1155 1160 Cu(I) FORMULA 23509853 A 1256 1265 CF3COO(-) FORMULA 23509853 A 1364 1374 pivalamido SYSTEMATIC 23509853 A 1631 1635 H2O2 FORMULA 23509853 A 1765 1767 O2 FORMULA 23509853 A 18 42 [(PV-tmpa)Cu(II)](ClO4)2 FORMULA 23509853 A 190 192 O2 FORMULA 23509853 A 196 215 decamethylferrocene SYSTEMATIC 23509853 A 2 8 copper SYSTEMATIC 23509853 A 241 261 trifluoroacetic acid SYSTEMATIC 23509853 A 263 270 CF3COOH FORMULA 23509853 A 275 282 acetone SYSTEMATIC 23509853 A 318 324 copper SYSTEMATIC 23509853 A 343 353 pivalamido SYSTEMATIC 23509853 A 361 382 [(tmpa)Cu(II)](ClO4)2 FORMULA 23509853 A 388 392 tmpa ABBREVIATION 23509853 A 395 421 tris(2-pyridylmethyl)amine SYSTEMATIC 23509853 A 465 486 decamethylferrocenium SYSTEMATIC 23509853 A 48 55 PV-tmpa ABBREVIATION 23509853 A 544 546 O2 FORMULA 23509853 A 58 118 bis(pyrid-2-ylmethyl){[6-(pivalamido)pyrid-2-yl]methyl}amine SYSTEMATIC 23509853 A 588 595 CF3COOH FORMULA 23509853 A 600 602 O2 FORMULA 23509853 A 783 790 CF3COOH FORMULA 23509853 A 794 796 O2 FORMULA 23509853 A 941 943 O2 FORMULA 23509853 A 970 977 CF3COOH FORMULA 23509853 T 106 116 Copper(II) SYSTEMATIC 23509853 T 33 41 Dioxygen SYSTEMATIC 23509853 T 43 45 O2 FORMULA 23509853 T 64 81 Hydrogen Peroxide SYSTEMATIC 23509853 T 83 87 H2O2 FORMULA 23509904 A 654 662 aspartyl TRIVIAL 23510192 A 1255 1264 phosphate SYSTEMATIC 23510192 A 1671 1681 nucleotide FAMILY 23510479 A 254 273 poly(1,2-butadiene) SYSTEMATIC 23511016 A 302 304 Gd FORMULA 23511016 A 363 367 DOTA ABBREVIATION 23511016 A 375 387 pantoprazole TRIVIAL 23511016 A 491 495 DOTA ABBREVIATION 23511016 A 565 577 pantoprazole TRIVIAL 23511016 T 15 19 DOTA ABBREVIATION 23511016 T 21 27 Gd(3+) FORMULA 23511016 T 64 76 pantoprazole TRIVIAL 23511018 A 45 61 (+)-lycoricidine TRIVIAL 23511018 A 737 753 (+)-lycoricidine TRIVIAL 23511018 T 49 65 (+)-lycoricidine TRIVIAL 23511022 A 109 151 dimethoxyP(V)tetraphenylporphyrin chloride SYSTEMATIC 23511022 A 1124 1133 DMP(V)TPP ABBREVIATION 23511022 A 1163 1169 oxygen SYSTEMATIC 23511022 A 153 162 DMP(V)TPP ABBREVIATION 23511022 A 242 248 oxygen SYSTEMATIC 23511022 A 263 272 DMP(V)TPP ABBREVIATION 23511022 A 316 325 porphyrin FAMILY 23511022 A 421 430 DMP(V)TPP ABBREVIATION 23511022 A 498 507 DMP(V)TPP ABBREVIATION 23511022 A 520 530 amino acid FAMILY 23511022 A 628 638 tryptophan TRIVIAL 23511022 A 681 687 oxygen SYSTEMATIC 23511022 A 698 710 sodium azide SYSTEMATIC 23511022 A 870 876 oxygen SYSTEMATIC 23511022 A 934 943 DMP(V)TPP ABBREVIATION 23511022 A 94 107 P(V)porphyrin SYSTEMATIC 23511022 T 34 77 dimethoxyphosphorus(V) tetraphenylporphyrin SYSTEMATIC 23511088 A 285 298 alkylphenones FAMILY 23511088 A 645 651 butoxy SYSTEMATIC 23511125 A 1002 1011 donepezil TRIVIAL 23511125 A 1249 1258 donepezil TRIVIAL 23511125 A 1314 1323 donepezil TRIVIAL 23511125 A 1449 1458 Donepezil TRIVIAL 23511125 A 1519 1531 mecamylamine TRIVIAL 23511125 A 1540 1558 methyllycaconitine TRIVIAL 23511125 A 1650 1659 glutamate TRIVIAL 23511125 A 35 48 acetylcholine SYSTEMATIC 23511125 A 363 376 acetylcholine SYSTEMATIC 23511125 A 428 437 glutamate TRIVIAL 23511125 A 515 524 glutamate TRIVIAL 23511125 T 75 84 glutamate TRIVIAL 23511311 A 581 588 glucose TRIVIAL 23511711 A 1001 1010 midazolam TRIVIAL 23511711 A 1056 1065 midazolam TRIVIAL 23511711 A 158 167 midazolam TRIVIAL 23511711 A 222 231 midazolam TRIVIAL 23511711 A 419 431 ketoconazole TRIVIAL 23511711 A 482 491 midazolam TRIVIAL 23511711 A 627 639 Ketoconazole TRIVIAL 23511711 A 648 657 midazolam TRIVIAL 23511711 A 781 790 midazolam TRIVIAL 23511711 A 827 839 ketoconazole TRIVIAL 23511711 A 878 887 midazolam TRIVIAL 23511711 T 45 54 Midazolam TRIVIAL 23511718 A 1002 1005 PEG ABBREVIATION 23511718 A 1179 1182 PEG ABBREVIATION 23511718 A 1316 1319 PEG ABBREVIATION 23511718 A 1439 1442 PEG ABBREVIATION 23511718 A 516 535 polyethylene glycol SYSTEMATIC 23511718 A 537 540 PEG ABBREVIATION 23511718 A 640 643 PEG ABBREVIATION 23511718 A 833 836 PEG ABBREVIATION 23511718 A 874 877 PEG ABBREVIATION 23511718 T 0 3 PEG ABBREVIATION 23512337 A 113 127 polyamidoamine FAMILY 23512337 A 500 517 polyethyleneimine SYSTEMATIC 23512337 T 15 18 PAA ABBREVIATION 23512409 A 113 126 polythiophene FAMILY 23512409 A 458 471 polythiophene FAMILY 23512409 T 55 68 Polythiophene FAMILY 23512438 A 1030 1043 monocrotophos TRIVIAL 23512438 A 1048 1060 imidacloprid TRIVIAL 23512438 A 1149 1162 gluconic acid TRIVIAL 23512438 A 1175 1198 citric and acetic acids MULTIPLE 23512438 A 1369 1382 monocrotophos TRIVIAL 23512438 A 1387 1399 imidacloprid TRIVIAL 23512438 A 264 273 phosphate SYSTEMATIC 23512438 A 60 69 phosphate SYSTEMATIC 23512438 A 606 618 alphamethrin TRIVIAL 23512438 A 642 652 endosulfan TRIVIAL 23512438 A 743 756 monocrotophos TRIVIAL 23512438 A 761 773 imidacloprid TRIVIAL 23512438 A 920 933 gluconic acid TRIVIAL 23512438 T 23 33 phosphorus SYSTEMATIC 23512754 A 1007 1010 CDM ABBREVIATION 23512754 A 1134 1137 CDM ABBREVIATION 23512754 A 13 50 1-cinnamoyl-3,11-dihydroxymeliacarpin SYSTEMATIC 23512754 A 217 220 CDM ABBREVIATION 23512754 A 292 295 CDM ABBREVIATION 23512754 A 394 397 CDM ABBREVIATION 23512754 A 403 406 MTT ABBREVIATION 23512754 A 501 504 CDM ABBREVIATION 23512754 A 52 55 CDM ABBREVIATION 23512754 A 703 706 CDM ABBREVIATION 23512754 A 953 956 CDM ABBREVIATION 23512754 T 31 68 1-Cinnamoyl-3,11-Dihydroxymeliacarpin SYSTEMATIC 23512824 A 1064 1069 azide SYSTEMATIC 23512824 A 1086 1096 phosphines FAMILY 23512824 A 1132 1149 2,4-dinitrophenyl SYSTEMATIC 23512824 A 1151 1154 DNP ABBREVIATION 23512824 A 1317 1320 DNP ABBREVIATION 23512824 A 1356 1359 DNP ABBREVIATION 23512824 A 521 526 azide SYSTEMATIC 23512824 A 595 600 azide SYSTEMATIC 23512824 A 708 746 peracetylated N-azidoacetylglucosamine SYSTEMATIC 23512824 A 748 758 Ac4 GlcNAz FORMULA 23512824 A 803 813 Ac4 GlcNAz FORMULA 23512824 A 954 960 azides FAMILY 23512824 A 965 975 phosphines FAMILY 23512927 A 122 225 poly(ethylene glycol)-b-poly[styrene-co-(2-(1,2,3,4,5-pentaphenyl-1H-silol-1-yloxy)ethyl methacrylate)] SYSTEMATIC 23512927 A 227 247 PEG-b-P(S-co-PPSEMA) ABBREVIATION 23512927 A 278 289 doxorubicin TRIVIAL 23512927 A 291 294 DOX ABBREVIATION 23512927 A 454 460 PPSEMA ABBREVIATION 23512927 A 464 467 DOX ABBREVIATION 23512927 A 483 486 DOX ABBREVIATION 23512927 A 568 571 DOX ABBREVIATION 23512927 A 779 782 DOX ABBREVIATION 23512927 T 112 123 Doxorubicin TRIVIAL 23514378 A 104 113 serotonin TRIVIAL 23514378 A 115 119 5-HT SYSTEMATIC 23514378 A 1277 1281 5-HT SYSTEMATIC 23514378 A 627 631 5-HT SYSTEMATIC 23514378 A 706 710 5-HT SYSTEMATIC 23514378 T 32 41 serotonin TRIVIAL 23514599 A 12 50 4-(1-methyl-1H-pyrrol-3-yl)benzenamine SYSTEMATIC 23514599 A 195 228 pyrrolo[2,1-c][1,4]benzodiazepine SYSTEMATIC 23514599 A 230 233 PBD ABBREVIATION 23514599 A 265 272 PBD-MPB ABBREVIATION 23514599 A 52 55 MPB ABBREVIATION 23514599 A 661 670 KMR-28-39 IDENTIFIER 23514599 T 22 43 Pyrrolobenzodiazepine FAMILY 23514599 T 44 50 Biaryl FAMILY 23515282 A 1242 1253 cholesterol TRIVIAL 23515282 A 519 530 cholesterol TRIVIAL 23515282 A 52 63 cholesterol TRIVIAL 23515282 A 735 746 cholesterol TRIVIAL 23515497 A 1063 1067 PCBs ABBREVIATION 23515497 A 1157 1164 PCB 180 IDENTIFIER 23515497 A 1169 1174 mirex TRIVIAL 23515497 A 1296 1303 PCB 180 IDENTIFIER 23515497 A 1308 1318 endosulfan TRIVIAL 23515497 A 1386 1393 PCB 180 IDENTIFIER 23515497 A 1395 1407 Aroclor 1221 TRIVIAL 23515497 A 1412 1422 endosulfan TRIVIAL 23515497 A 384 394 oestradiol TRIVIAL 23515497 A 412 419 PCB 180 IDENTIFIER 23515497 A 421 433 Aroclor 1221 TRIVIAL 23515497 A 435 445 endosulfan TRIVIAL 23515497 A 450 455 mirex TRIVIAL 23515497 A 46 71 polychlorinated biphenyls FAMILY 23515497 A 634 646 formaldehyde SYSTEMATIC 23515497 A 73 77 PCBs ABBREVIATION 23515497 A 823 828 mirex TRIVIAL 23515497 A 83 100 organochlorinated FAMILY 23515497 A 924 936 Aroclor 1221 TRIVIAL 23515497 A 941 951 endosulfan TRIVIAL 23515497 T 36 61 polychlorinated biphenyls FAMILY 23515497 T 66 83 organochlorinated FAMILY 23515582 A 1135 1147 escitalopram TRIVIAL 23515582 A 1197 1209 escitalopram TRIVIAL 23515582 A 1411 1423 escitalopram TRIVIAL 23515582 A 1544 1556 Escitalopram TRIVIAL 23515582 A 456 465 serotonin TRIVIAL 23515582 A 485 497 escitalopram TRIVIAL 23515582 A 614 626 Escitalopram TRIVIAL 23515582 T 6 18 escitalopram TRIVIAL 23515934 A 1001 1009 formalin TRIVIAL 23515934 A 1027 1036 glutamate TRIVIAL 23515934 A 1093 1107 oleanolic acid TRIVIAL 23515934 A 207 218 acetic acid SYSTEMATIC 23515934 A 307 321 oleanolic acid TRIVIAL 23515934 A 31 45 oleanolic acid TRIVIAL 23515934 A 506 515 glutamate TRIVIAL 23515934 A 542 556 oleanolic acid TRIVIAL 23515934 A 599 607 naloxone TRIVIAL 23515934 A 640 652 methysergide TRIVIAL 23515934 A 654 658 5-HT SYSTEMATIC 23515934 A 73 87 Oleanolic acid TRIVIAL 23515934 A 738 752 oleanolic acid TRIVIAL 23515934 A 784 793 yohimbine TRIVIAL 23515934 A 869 883 oleanolic acid TRIVIAL 23515934 A 911 925 oleanolic acid TRIVIAL 23515934 T 74 88 oleanolic acid TRIVIAL 23517008 A 103 109 carbon SYSTEMATIC 23517008 A 1241 1247 carbon SYSTEMATIC 23517008 A 143 149 carbon SYSTEMATIC 23517008 A 256 264 graphene TRIVIAL 23517008 A 431 437 carbon SYSTEMATIC 23517008 A 571 579 graphite TRIVIAL 23517008 A 908 916 graphene TRIVIAL 23517008 T 67 73 carbon SYSTEMATIC 23517010 A 334 336 Au FORMULA 23517028 A 198 212 arylpiperazine FAMILY 23517028 A 486 492 indole SYSTEMATIC 23517028 A 500 509 quinoline SYSTEMATIC 23517028 T 94 108 Arylpiperazine FAMILY 23517093 A 1045 1059 thailanstatins FAMILY 23517093 A 128 136 FR901464 IDENTIFIER 23517093 A 393 407 thailanstatins FAMILY 23517093 A 503 517 Thailanstatins FAMILY 23517093 A 667 675 hydroxyl SYSTEMATIC 23517093 A 705 713 carboxyl SYSTEMATIC 23517093 A 746 760 thailanstatins FAMILY 23517093 A 820 829 phosphate SYSTEMATIC 23517093 A 876 890 thailanstatins FAMILY 23517093 T 29 55 Thailanstatins A, B, and C MULTIPLE 23517126 A 176 192 sesquiterpenoids FAMILY 23517126 A 194 228 1β-p-hydroxy-E-cinnamoyldrimeninol SYSTEMATIC 23517126 A 234 279 1β-p-hydroxy-E-cinnamoyl-5α-hydroxydrimeninol SYSTEMATIC 23517126 A 289 351 methyl ether of 1β-p-hydroxy-E-cinnamoyl-12α-methoxydrimeninol SYSTEMATIC 23517126 A 385 412 1β-p-coumaroyloxypolygodial SYSTEMATIC 23517126 A 439 449 tetralones FAMILY 23517126 A 451 472 3'-deoxyisozygolone A SYSTEMATIC 23517126 A 481 495 calothyrlone A TRIVIAL 23517126 A 525 538 isozygolone A TRIVIAL 23517126 A 544 554 zygolone A TRIVIAL 23517126 A 564 585 4'-O-methylzygolone A SYSTEMATIC 23517126 A 603 614 cinnamolide TRIVIAL 23517126 T 52 68 Sesquiterpenoids FAMILY 23517126 T 73 83 Tetralones FAMILY 23517145 A 106 159 3,11,15,23-tetraoxo-27ξ-lanosta-8,16-dien-26-oic acid SYSTEMATIC 23517145 A 177 184 lactone FAMILY 23517145 A 198 249 5-hydroxy-5-(methoxymethyl)-4-methylfuran-2(5H)-one SYSTEMATIC 23517145 A 23 41 ethyl lucidenate A SYSTEMATIC 23517145 A 258 305 3-(4-methoxy-2-oxo-2H-pyran-6-yl)propanoic acid SYSTEMATIC 23517145 A 347 400 11α-hydroxy-3,7-dioxolanost-8,24(E)-dien-26- oic acid SYSTEMATIC 23517145 A 406 455 3,7,11-trioxo-5α-lanosta-8,24(E)-dien-26-oic acid SYSTEMATIC 23517145 A 461 514 methyl 3,7,11,12,15,23-hexaoxo-5α-lanost-8-en-26-oate SYSTEMATIC 23517145 A 47 65 ethyl lucidenate F SYSTEMATIC 23517145 A 524 576 ethyl 3,7,11,12,15,23-hexaoxo-5α-lanost-8-en-26-oate SYSTEMATIC 23517145 A 71 96 15-O-acetylganolucidate A SYSTEMATIC 23517145 A 869 871 NO FORMULA 23517145 A 9 21 lanostanoids FAMILY 23517145 A 996 998 NO FORMULA 23517145 T 18 30 Lanostanoids FAMILY 23517145 T 35 42 Lactone FAMILY 23517379 A 101 109 graphene TRIVIAL 23517379 A 28 61 2,5-dialkoxy-phenylene-thienylene SYSTEMATIC 23517379 A 383 392 thiophene SYSTEMATIC 23517470 A 153 159 Ca(2+) FORMULA 23517470 A 237 243 Ca(2+) FORMULA 23517470 A 701 707 Ca(2+) FORMULA 23517470 A 95 101 Ca(2+) FORMULA 23517470 T 54 60 Ca(2+) FORMULA 23517474 A 1117 1122 amide FAMILY 23517474 A 1229 1235 Ca(2+) FORMULA 23517474 A 1238 1244 Mg(2+) FORMULA 23517474 A 1247 1252 Li(+) FORMULA 23517474 A 1255 1260 Na(+) FORMULA 23517474 A 1263 1267 K(+) FORMULA 23517474 A 1323 1329 Ca(2+) FORMULA 23517474 A 1410 1431 amide carbonyl oxygen SYSTEMATIC 23517474 A 1464 1469 Na(+) FORMULA 23517474 A 1474 1478 K(+) FORMULA 23517474 A 1567 1573 amides FAMILY 23517474 A 163 171 chloride SYSTEMATIC 23517474 A 309 314 amide FAMILY 23517474 A 39 49 butyramide SYSTEMATIC 23517474 A 546 552 Ca(2+) FORMULA 23517474 A 554 560 Mg(2+) FORMULA 23517474 A 562 567 Li(+) FORMULA 23517474 A 626 632 amides FAMILY 23517474 A 709 715 amides FAMILY 23517474 A 846 856 butyramide SYSTEMATIC 23517474 A 945 950 amide FAMILY 23517474 T 28 34 Amides FAMILY 23517541 A 1117 1125 nor-NOHA TRIVIAL 23517541 A 1318 1326 nor-NOHA TRIVIAL 23517541 A 357 365 nor-NOHA TRIVIAL 23517541 A 49 76 N(ω)-hydroxy-nor-L-arginine SYSTEMATIC 23517541 A 493 501 nor-NOHA TRIVIAL 23517541 A 78 86 nor-NOHA TRIVIAL 23517541 A 939 947 nor-NOHA TRIVIAL 23517541 T 32 59 N(ω)-hydroxy-nor-L-arginine SYSTEMATIC 23517546 A 1016 1020 GaAs FORMULA 23517546 A 1021 1030 (Ga,Mn)As FORMULA 23517546 A 115 124 (Ga,Mn)As FORMULA 23517546 A 158 169 zinc-blende SYSTEMATIC 23517546 A 175 179 GaAs FORMULA 23517546 A 180 189 (Ga,Mn)As FORMULA 23517546 A 214 216 Si FORMULA 23517546 A 241 245 GaAs FORMULA 23517546 A 319 321 Ga FORMULA 23517546 A 406 415 (Ga,Mn)As FORMULA 23517546 A 471 475 GaAs FORMULA 23517546 A 538 542 GaAs FORMULA 23517546 A 54 58 GaAs FORMULA 23517546 A 543 552 (Ga,Mn)As FORMULA 23517546 A 722 726 GaAs FORMULA 23517546 A 727 736 (Ga,Mn)As FORMULA 23517546 A 805 807 Mn FORMULA 23517546 T 16 20 GaAs FORMULA 23517546 T 21 30 (Ga,Mn)As FORMULA 23517546 T 4 15 Zinc-Blende SYSTEMATIC 23517565 A 455 475 dihydroquinazolinone SYSTEMATIC 23517565 T 0 28 N-Methyldihydroquinazolinone SYSTEMATIC 23517621 A 0 36 2,2,6,6-Tetramethylpiperidine-1-oxyl SYSTEMATIC 23517621 A 1120 1125 TEMPO ABBREVIATION 23517621 A 1280 1285 TEMPO ABBREVIATION 23517621 A 174 179 TEMPO ABBREVIATION 23517621 A 318 323 TEMPO ABBREVIATION 23517621 A 38 43 TEMPO ABBREVIATION 23517621 A 464 469 TEMPO ABBREVIATION 23517621 A 630 635 TEMPO ABBREVIATION 23517621 A 873 878 TEMPO ABBREVIATION 23517621 A 896 902 oxygen SYSTEMATIC 23517621 A 925 936 glutathione TRIVIAL 23517621 A 998 1003 TEMPO ABBREVIATION 23517621 T 0 9 Nitroxide SYSTEMATIC 23517621 T 10 15 TEMPO ABBREVIATION 23517636 A 1008 1023 androstenedione TRIVIAL 23517636 A 1025 1055 dehydroepiandrosterone sulfate SYSTEMATIC 23517636 A 1057 1063 DHEA-S ABBREVIATION 23517636 A 1151 1159 androgen FAMILY 23517636 A 14 26 Testosterone TRIVIAL 23517636 A 521 529 androgen FAMILY 23517636 A 984 1006 17-hydroxyprogesterone SYSTEMATIC 23517636 T 0 12 Testosterone TRIVIAL 23517729 A 1200 1211 Py3MeO-TBPo ABBREVIATION 23517729 A 140 151 Py3MeO-TBPo ABBREVIATION 23517729 A 1805 1816 Py3MeO-TBPo ABBREVIATION 23517729 A 1919 1925 oxygen SYSTEMATIC 23517729 A 2051 2057 oxygen SYSTEMATIC 23517729 A 2068 2080 sodium azide SYSTEMATIC 23517729 A 2151 2162 Py3MeO-TBPo ABBREVIATION 23517729 A 2500 2511 Py3MeO-TBPo ABBREVIATION 23517729 A 289 300 Py3MeO-TBPo ABBREVIATION 23517729 A 601 611 porphycene TRIVIAL 23517729 A 66 138 2,7,12-tris(α-pyridinio-p-tolyl)-17-(p-(methoxymethyl)phenyl) porphycene SYSTEMATIC 23517729 A 745 756 Py3MeO-TBPo ABBREVIATION 23517729 A 812 823 Py3MeO-TBPo ABBREVIATION 23517729 T 67 77 porphycene TRIVIAL 23518155 A 1121 1128 glucose TRIVIAL 23518155 A 1253 1260 glucose TRIVIAL 23518155 A 1393 1400 glucose TRIVIAL 23518155 A 1627 1634 glucose TRIVIAL 23518155 A 399 400 N FORMULA 23518155 A 657 661 cAMP ABBREVIATION 23518155 A 873 880 glucose TRIVIAL 23518155 A 996 1003 glucose TRIVIAL 23518321 A 0 13 Acetaminophen TRIVIAL 23518321 A 1167 1180 acetaminophen TRIVIAL 23518321 A 215 228 acetaminophen TRIVIAL 23518321 A 352 365 acetaminophen TRIVIAL 23518321 A 465 478 acetaminophen TRIVIAL 23518321 A 533 558 phorbol myristate acetate SYSTEMATIC 23518321 A 688 701 acetaminophen TRIVIAL 23518321 A 727 731 HOCl FORMULA 23518321 A 736 740 H2O2 FORMULA 23518321 A 808 821 Acetaminophen TRIVIAL 23518321 A 852 863 glutathione TRIVIAL 23518321 A 990 1003 acetaminophen TRIVIAL 23518321 T 0 13 Acetaminophen TRIVIAL 23518599 A 0 10 Rare-earth FAMILY 23518599 A 1168 1188 rare-earth phosphate FAMILY 23518599 A 1316 1319 P-O FORMULA 23518599 A 1324 1325 P FORMULA 23518599 A 1356 1357 O FORMULA 23518599 A 1375 1395 rare-earth phosphate FAMILY 23518599 A 1535 1555 rare-earth phosphate FAMILY 23518599 A 214 234 rare-earth phosphate FAMILY 23518599 A 244 272 (R2O3)x(R'2O3)y(P2O5)1-(x+y) FAMILY 23518599 A 297 299 Ce FORMULA 23518599 A 301 303 Er FORMULA 23518599 A 309 311 La FORMULA 23518599 A 313 315 Nd FORMULA 23518599 A 341 351 rare-earth FAMILY 23518599 A 395 408 metaphosphate FAMILY 23518599 A 410 415 RP3O9 FAMILY 23518599 A 421 435 ultraphosphate FAMILY 23518599 A 437 443 RP5O14 FAMILY 23518599 A 471 481 rare-earth FAMILY 23518599 A 726 736 rare-earth FAMILY 23518599 A 989 1009 rare-earth phosphate FAMILY 23518599 T 58 78 rare-earth phosphate FAMILY 23518857 A 203 215 formaldehyde SYSTEMATIC 23518857 A 228 231 FCF FORMULA 23518857 A 241 256 difluoromethane SYSTEMATIC 23518857 A 275 279 C-HF FORMULA 23518857 A 297 301 CH2O FORMULA 23518857 A 307 315 hydrogen SYSTEMATIC 23518857 A 463 475 formaldehyde SYSTEMATIC 23518857 A 75 90 difluoromethane SYSTEMATIC 23518857 A 95 107 formaldehyde SYSTEMATIC 23518857 T 50 59 CH2F2H2CO FORMULA 23519059 A 372 431 bis(4,6-difluorophenyl) pyridinato-N,C [dfppy] iridium(iii) SYSTEMATIC 23519059 A 509 524 acetylacetonate SYSTEMATIC 23519059 A 526 536 picolinate TRIVIAL 23519059 A 542 559 pyridylpyrazolate SYSTEMATIC 23519059 T 67 79 iridium(iii) SYSTEMATIC 23519153 A 1063 1067 iron SYSTEMATIC 23519153 A 1174 1196 S-adenosylhomocysteine TRIVIAL 23519153 A 1298 1320 S-adenosylhomocysteine TRIVIAL 23519153 A 1519 1525 Copper SYSTEMATIC 23519153 A 1598 1600 Fe FORMULA 23519153 A 1605 1625 adenosylhomocysteine TRIVIAL 23519153 A 265 271 copper SYSTEMATIC 23519153 A 691 697 copper SYSTEMATIC 23519153 A 989 995 copper SYSTEMATIC 23520074 A 101 107 serine TRIVIAL 23520074 A 1063 1070 phospho SYSTEMATIC 23520074 A 219 224 amino FAMILY 23520074 A 452 453 N FORMULA 23520074 A 501 502 C FORMULA 23520074 A 987 994 (125) I FORMULA 23521014 A 0 6 Carbon SYSTEMATIC 23521014 T 41 47 carbon SYSTEMATIC 23521318 A 489 500 α-terpineol TRIVIAL 23521318 A 810 821 α-terpineol TRIVIAL 23521360 A 10 40 methylated flavonol glucosides FAMILY 23521360 A 102 161 3,4'-dimethoxy-7-O-β-(6″-galloyl-glucopyranoside) quercetin SYSTEMATIC 23521360 A 170 225 3-methoxy-7-O-β-(6″-galloylgluco-pyranoside) kaempferol SYSTEMATIC 23521360 A 256 265 flavonols FAMILY 23521360 A 290 303 ethyl acetate SYSTEMATIC 23521360 A 42 96 3-methoxy-7-O-β-(6″-galloylgluco-pyranoside) quercetin SYSTEMATIC 23521360 T 4 34 methylated flavonol glucosides FAMILY 23521567 A 357 400 1,2-dipalmitoyl-sn-glycero-3-phosphocholine SYSTEMATIC 23521567 A 402 406 DPPC ABBREVIATION 23521567 A 522 526 DPPC ABBREVIATION 23521567 A 578 582 DPPC ABBREVIATION 23521567 T 34 38 DPPC ABBREVIATION 23522182 A 1044 1051 AZD1656 IDENTIFIER 23522182 A 1214 1221 AZD1656 IDENTIFIER 23522182 A 1322 1329 glucose TRIVIAL 23522182 A 1408 1415 AZD1656 IDENTIFIER 23522182 A 293 300 AZD1656 IDENTIFIER 23522182 A 496 503 glucose TRIVIAL 23522182 A 611 618 AZD1656 IDENTIFIER 23522182 A 705 712 AZD1656 IDENTIFIER 23522182 A 809 816 AZD1656 IDENTIFIER 23522182 A 90 97 AZD1656 IDENTIFIER 23522182 A 988 995 AZD1656 IDENTIFIER 23522182 T 50 57 AZD1656 IDENTIFIER 23522564 A 126 127 N FORMULA 23522564 A 246 247 C FORMULA 23522564 A 464 474 amino acid FAMILY 23522564 A 669 675 lysine TRIVIAL 23522564 A 680 683 Ile FORMULA 23522564 A 695 706 cholesterol TRIVIAL 23522564 A 723 724 C FORMULA 23522564 A 823 834 cholesterol TRIVIAL 23522833 A 0 8 Cu(OTf)2 FORMULA 23522833 A 138 144 isatin TRIVIAL 23522833 A 146 156 kojic acid TRIVIAL 23522833 A 168 178 methylenes FAMILY 23522833 A 42 76 spiropyrano[3,2-b]pyran-4(8H)-ones FAMILY 23522833 T 0 8 Cu(OTf)2 FORMULA 23522833 T 68 106 spiro[indoline-3,4'-pyrano[3,2-b]pyran SYSTEMATIC 23523142 A 0 9 Ginkgetin TRIVIAL 23523142 A 23 34 biflavonoid FAMILY 23523142 A 283 292 ginkgetin TRIVIAL 23523142 A 369 378 ginkgetin TRIVIAL 23523142 A 431 440 Ginkgetin TRIVIAL 23523142 A 602 611 Ginkgetin TRIVIAL 23523142 A 790 800 Z-DEVD-fmk ABBREVIATION 23523142 A 876 885 ginkgetin TRIVIAL 23523142 A 938 947 ginkgetin TRIVIAL 23523142 T 0 9 Ginkgetin TRIVIAL 23523258 A 1031 1040 midazolam TRIVIAL 23523258 A 111 116 Sch B ABBREVIATION 23523258 A 1189 1209 1'-hydroxy midazolam SYSTEMATIC 23523258 A 1427 1432 Sch B ABBREVIATION 23523258 A 1546 1551 Sch B ABBREVIATION 23523258 A 236 245 midazolam TRIVIAL 23523258 A 348 360 ketoconazole TRIVIAL 23523258 A 414 419 Sch B ABBREVIATION 23523258 A 565 574 midazolam TRIVIAL 23523258 A 579 599 1'-hydroxy midazolam SYSTEMATIC 23523258 A 678 683 Sch B ABBREVIATION 23523258 A 875 880 Sch B ABBREVIATION 23523258 A 96 109 Schisandrin B TRIVIAL 23523258 A 960 969 midazolam TRIVIAL 23523258 A 971 976 Sch B ABBREVIATION 23523258 T 18 31 Schisandrin B TRIVIAL 23523546 A 1104 1107 ITZ ABBREVIATION 23523546 A 121 124 ITZ ABBREVIATION 23523546 A 1224 1227 ITZ ABBREVIATION 23523546 A 20 23 ITZ ABBREVIATION 23523546 A 387 390 ITZ ABBREVIATION 23523546 A 496 499 ITZ ABBREVIATION 23523546 A 563 566 ITZ ABBREVIATION 23523546 A 6 18 Itraconazole TRIVIAL 23523546 A 90 98 mannitol TRIVIAL 23523546 T 48 60 itraconazole TRIVIAL 23523557 A 1211 1220 HC 030031 IDENTIFIER 23523557 A 1277 1293 cyclophosphamide TRIVIAL 23523557 A 1481 1497 cyclophosphamide TRIVIAL 23523557 A 161 177 cyclophosphamide TRIVIAL 23523557 A 264 280 cyclophosphamide TRIVIAL 23523557 A 417 426 HC 030031 IDENTIFIER 23523557 A 604 613 HC 030031 IDENTIFIER 23523557 A 673 689 cyclophosphamide TRIVIAL 23523557 A 818 834 cyclophosphamide TRIVIAL 23523557 A 867 876 HC 030031 IDENTIFIER 23523557 A 958 974 cyclophosphamide TRIVIAL 23523557 T 125 141 cyclophosphamide TRIVIAL 23523780 A 104 110 Ca(2+) FORMULA 23523780 A 1325 1336 bicuculline TRIVIAL 23523780 A 176 182 Ca(2+) FORMULA 23523780 A 40 46 Ca(2+) FORMULA 23523781 A 1320 1364 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine SYSTEMATIC 23523781 A 1366 1370 MPTP ABBREVIATION 23523781 A 1444 1449 DOPAC ABBREVIATION 23523781 A 1687 1691 MPTP ABBREVIATION 23523781 A 1745 1749 MPTP ABBREVIATION 23523781 A 2309 2317 dopamine TRIVIAL 23523781 A 403 411 dopamine TRIVIAL 23523781 A 418 435 homovanillic acid TRIVIAL 23523781 A 42 61 paraquat dichloride SYSTEMATIC 23523781 A 437 440 HVA ABBREVIATION 23523781 A 445 475 3,4-dihydroxyphenylacetic acid SYSTEMATIC 23523781 A 477 482 DOPAC ABBREVIATION 23523781 A 497 505 dopamine TRIVIAL 23523781 A 668 676 tyrosine TRIVIAL 23523781 A 900 906 silver SYSTEMATIC 23523781 A 942 950 tyrosine TRIVIAL 23523781 T 104 112 paraquat TRIVIAL 23523906 A 1044 1058 hydroxyproline SYSTEMATIC 23523906 A 1092 1101 bleomycin FAMILY 23523906 A 1138 1147 histamine TRIVIAL 23523906 A 1185 1194 berberine TRIVIAL 23523906 A 1196 1205 Berberine TRIVIAL 23523906 A 1342 1351 Berberine TRIVIAL 23523906 A 1366 1375 bleomycin FAMILY 23523906 A 1499 1511 nitric oxide SYSTEMATIC 23523906 A 1541 1550 berberine TRIVIAL 23523906 A 1755 1764 berberine TRIVIAL 23523906 A 1773 1782 bleomycin FAMILY 23523906 A 332 341 Berberine TRIVIAL 23523906 A 524 533 berberine TRIVIAL 23523906 A 542 551 bleomycin FAMILY 23523906 A 695 704 bleomycin FAMILY 23523906 A 715 724 Berberine TRIVIAL 23523906 A 805 814 Berberine TRIVIAL 23523906 A 860 869 bleomycin FAMILY 23523906 A 958 967 Berberine TRIVIAL 23523906 T 0 9 Berberine TRIVIAL 23523906 T 21 30 bleomycin FAMILY 23523949 A 1136 1142 Crocin TRIVIAL 23523949 A 1163 1172 vitamin E FAMILY 23523949 A 1219 1222 MDA ABBREVIATION 23523949 A 1244 1247 GSH ABBREVIATION 23523949 A 130 138 diazinon TRIVIAL 23523949 A 1381 1384 DZN ABBREVIATION 23523949 A 1398 1401 DZN ABBREVIATION 23523949 A 140 143 DZN ABBREVIATION 23523949 A 1497 1503 Crocin TRIVIAL 23523949 A 1558 1561 DZN ABBREVIATION 23523949 A 275 281 crocin TRIVIAL 23523949 A 318 321 DZN ABBREVIATION 23523949 A 323 332 vitamin E FAMILY 23523949 A 376 379 DZN ABBREVIATION 23523949 A 384 390 crocin TRIVIAL 23523949 A 456 464 Creatine TRIVIAL 23523949 A 491 506 malondealdehyde TRIVIAL 23523949 A 508 511 MDA ABBREVIATION 23523949 A 517 528 glutathione TRIVIAL 23523949 A 530 533 GSH ABBREVIATION 23523949 A 57 63 crocin TRIVIAL 23523949 A 792 795 DZN ABBREVIATION 23523949 A 923 926 MDA ABBREVIATION 23523949 A 957 960 GSH ABBREVIATION 23523949 T 21 27 crocin TRIVIAL 23523949 T 31 39 diazinon TRIVIAL 23523991 A 1051 1059 naloxone TRIVIAL 23523991 A 1064 1067 FNA ABBREVIATION 23523991 A 1376 1384 naloxone TRIVIAL 23523991 A 1633 1637 urea TRIVIAL 23523991 A 1649 1659 creatinine TRIVIAL 23523991 A 268 276 naloxone TRIVIAL 23523991 A 346 350 urea TRIVIAL 23523991 A 351 359 nitrogen SYSTEMATIC 23523991 A 377 387 creatinine TRIVIAL 23523991 A 524 532 naloxone TRIVIAL 23523991 A 611 621 creatinine TRIVIAL 23523991 A 638 646 naloxone TRIVIAL 23523991 A 694 702 morphine TRIVIAL 23523991 A 738 754 β-funaltrexamine TRIVIAL 23523991 A 756 759 FNA ABBREVIATION 23523991 A 844 854 creatinine TRIVIAL 23523991 A 866 874 tyrosine TRIVIAL 23523991 T 10 18 naloxone TRIVIAL 23524160 A 12 50 3-(1H-indol-3-yl)pyrrolidine-2,5-dione SYSTEMATIC 23524160 A 198 202 (1)H FORMULA 23524160 A 208 213 (13)C FORMULA 23524160 A 306 315 serotonin TRIVIAL 23524160 T 45 66 pyrrolidine-2,5-dione SYSTEMATIC 23524188 A 1070 1073 Dox ABBREVIATION 23524188 A 1131 1134 Dox ABBREVIATION 23524188 A 1199 1202 Dox ABBREVIATION 23524188 A 1309 1312 Dox ABBREVIATION 23524188 A 1338 1341 Dox ABBREVIATION 23524188 A 1390 1393 Dox ABBREVIATION 23524188 A 1428 1431 Dox ABBREVIATION 23524188 A 1480 1483 Dox ABBREVIATION 23524188 A 1537 1540 Dox ABBREVIATION 23524188 A 1595 1598 Dox ABBREVIATION 23524188 A 1658 1661 Dox ABBREVIATION 23524188 A 1718 1721 Dox ABBREVIATION 23524188 A 1769 1772 Dox ABBREVIATION 23524188 A 1820 1823 Dox ABBREVIATION 23524188 A 1907 1910 Dox ABBREVIATION 23524188 A 198 201 PEG ABBREVIATION 23524188 A 212 223 doxorubicin TRIVIAL 23524188 A 225 228 Dox ABBREVIATION 23524188 A 365 368 Dox ABBREVIATION 23524188 A 387 390 Dox ABBREVIATION 23524188 A 446 449 PEG ABBREVIATION 23524188 A 515 518 Dox ABBREVIATION 23524188 A 625 628 Dox ABBREVIATION 23524188 A 823 826 Dox ABBREVIATION 23524188 A 837 840 Dox ABBREVIATION 23524188 A 909 912 Dox ABBREVIATION 23524188 T 28 39 doxorubicin TRIVIAL 23524189 A 372 415 meso-tetrakis (4-sulfonatophenyl) porphyrin SYSTEMATIC 23524189 A 417 421 TPPS ABBREVIATION 23524189 A 709 713 TPPS ABBREVIATION 23524189 A 760 766 oxygen SYSTEMATIC 23524189 T 46 55 porphyrin FAMILY 23524254 A 1139 1146 PVP-K30 IDENTIFIER 23524254 A 1164 1167 PVP ABBREVIATION 23524254 A 1224 1229 (13)C FORMULA 23524254 A 1231 1236 (15)N FORMULA 23524254 A 1241 1245 (1)H FORMULA 23524254 A 1364 1373 vincamine TRIVIAL 23524254 A 141 150 vincamine TRIVIAL 23524254 A 1459 1466 PVP-K30 IDENTIFIER 23524254 A 1480 1488 hydrogen SYSTEMATIC 23524254 A 1576 1579 PVP ABBREVIATION 23524254 A 1622 1629 PVP-K30 IDENTIFIER 23524254 A 1688 1697 vincamine TRIVIAL 23524254 A 262 265 PVP ABBREVIATION 23524254 A 578 585 PVP-K30 IDENTIFIER 23524254 A 933 937 (1)H FORMULA 23524254 T 30 39 vincamine TRIVIAL 23524305 A 257 263 oxygen SYSTEMATIC 23524983 A 365 390 trifluoromethyloxadiazole SYSTEMATIC 23524983 A 392 396 TFMO ABBREVIATION 23524983 A 466 478 hydroxamates FAMILY 23524983 A 519 523 TFMO ABBREVIATION 23524983 A 631 635 TFMO ABBREVIATION 23524983 A 657 668 hydroxamate SYSTEMATIC 23524983 T 70 74 zinc SYSTEMATIC 23525092 A 910 922 levoglucosan TRIVIAL 23525092 A 938 966 phenyl α- and β-d-glucosides MULTIPLE 23525092 T 130 158 phenyl α- and β-d-glucosides MULTIPLE 23525092 T 91 107 1,6-anhydrosugar FAMILY 23525112 A 1010 1013 PMA ABBREVIATION 23525112 A 1122 1126 H2O2 FORMULA 23525112 A 118 124 oxygen SYSTEMATIC 23525112 A 1326 1329 PMA ABBREVIATION 23525112 A 1393 1396 PMA ABBREVIATION 23525112 A 1598 1612 trichostatin A TRIVIAL 23525112 A 1625 1629 H2O2 FORMULA 23525112 A 205 209 H2O2 FORMULA 23525112 A 314 318 H2O2 FORMULA 23525112 A 324 355 phorbol 12-myristate 13-acetate SYSTEMATIC 23525112 A 357 360 PMA ABBREVIATION 23525112 A 520 526 Ca(2+) FORMULA 23525112 A 645 651 Ca(2+) FORMULA 23525112 A 705 708 PMA ABBREVIATION 23525112 A 738 767 4α-phorbol 12, 13-didecanoate SYSTEMATIC 23525112 A 769 775 4α-PDD SYSTEMATIC 23525112 A 885 888 PMA ABBREVIATION 23525112 A 951 957 Gö6976 IDENTIFIER 23525112 T 106 112 Oxygen SYSTEMATIC 23525167 A 103 122 formoterol fumarate TRIVIAL 23525167 A 218 224 phenyl SYSTEMATIC 23525167 A 243 249 methyl SYSTEMATIC 23525167 A 306 311 (13)C FORMULA 23525167 A 356 360 (2)H FORMULA 23525167 A 365 370 (13)C FORMULA 23525167 A 474 482 fumarate TRIVIAL 23525167 A 56 63 ethanol SYSTEMATIC 23525167 T 63 82 formoterol fumarate TRIVIAL 23525215 A 1013 1017 CORT ABBREVIATION 23525215 A 1116 1120 CORT ABBREVIATION 23525215 A 1157 1161 CORT ABBREVIATION 23525215 A 1171 1175 CORT ABBREVIATION 23525215 A 1279 1283 CORT ABBREVIATION 23525215 A 1528 1532 zinc SYSTEMATIC 23525215 A 736 750 corticosterone TRIVIAL 23525215 A 752 756 CORT ABBREVIATION 23525215 A 912 916 CORT ABBREVIATION 23525215 A 974 978 CORT ABBREVIATION 23525330 A 1022 1057 Para-chloromercuribenzene sulfonate SYSTEMATIC 23525330 A 1059 1064 pCMBS ABBREVIATION 23525330 A 1104 1115 sulfhydryls FAMILY 23525330 A 1139 1143 GABA ABBREVIATION 23525330 A 1162 1171 Etomidate TRIVIAL 23525330 A 1294 1303 etomidate TRIVIAL 23525330 A 1350 1360 suflhydryl SYSTEMATIC 23525330 A 1446 1455 etomidate TRIVIAL 23525330 A 1533 1537 GABA ABBREVIATION 23525330 A 1609 1618 etomidate TRIVIAL 23525330 A 1759 1768 etomidate TRIVIAL 23525330 A 230 238 cysteine TRIVIAL 23525330 A 400 409 Etomidate TRIVIAL 23525330 A 637 641 GABA ABBREVIATION 23525330 A 673 682 etomidate TRIVIAL 23525330 A 693 697 GABA ABBREVIATION 23525330 A 729 738 etomidate TRIVIAL 23525330 A 905 914 etomidate TRIVIAL 23525330 T 82 90 Cysteine TRIVIAL 23525662 A 127 134 steroid FAMILY 23525674 A 1016 1028 polyethylene SYSTEMATIC 23525674 A 119 131 polyethylene SYSTEMATIC 23525674 A 463 475 polyethylene SYSTEMATIC 23525674 A 825 838 polypropylene SYSTEMATIC 23525674 A 88 101 polypropylene SYSTEMATIC 23525674 A 932 944 polyethylene SYSTEMATIC 23525674 T 67 80 polypropylene SYSTEMATIC 23525674 T 98 110 polyethylene SYSTEMATIC 23525786 A 1051 1067 methacrylic acid TRIVIAL 23525786 A 1238 1242 HEMA ABBREVIATION 23525786 A 1360 1364 HEMA ABBREVIATION 23525786 A 446 499 poly(2-hydroxyethyl methacrylate-co-methacrylic acid) SYSTEMATIC 23525786 A 501 517 poly(HEMA-co-MA) SYSTEMATIC 23525786 A 541 555 hydroxyapatite TRIVIAL 23525786 A 656 713 dimethacrylated poly(lactide-b-ethylene glycol-b-lactide) SYSTEMATIC 23525786 A 805 810 pHEMA ABBREVIATION 23525786 T 84 89 PHEMA ABBREVIATION 23525786 T 94 108 Hydroxyapatite TRIVIAL 23525902 A 1116 1122 RO3306 IDENTIFIER 23525902 A 547 557 phosphates FAMILY 23525902 A 814 817 ATP ABBREVIATION 23525902 A 838 844 1NMPP1 IDENTIFIER 23525902 A 873 879 RO3306 IDENTIFIER 23525902 A 888 894 1NMPP1 IDENTIFIER 23526144 A 1053 1055 Ca FORMULA 23526144 A 1060 1062 Mg FORMULA 23526144 A 1101 1103 Cu FORMULA 23526144 A 1149 1151 Cu FORMULA 23526144 A 1152 1154 Fe FORMULA 23526144 A 1212 1214 Mg FORMULA 23526144 A 1220 1222 Zn FORMULA 23526144 A 1240 1242 Mg FORMULA 23526144 A 1248 1250 Fe FORMULA 23526144 A 623 625 Ca FORMULA 23526144 A 627 629 Mg FORMULA 23526144 A 631 633 Cu FORMULA 23526144 A 635 637 Zn FORMULA 23526144 A 642 644 Fe FORMULA 23526144 A 851 853 Ca FORMULA 23526144 A 858 860 Mg FORMULA 23526144 A 917 919 Cu FORMULA 23526144 A 924 926 Zn FORMULA 23526144 A 970 972 Ca FORMULA 23526144 A 974 976 Mg FORMULA 23526144 A 981 983 Cu FORMULA 23526231 A 115 149 (+)-N-methoxylcarbonyl-nandigerine SYSTEMATIC 23526231 A 155 188 (+)-N-methoxycarbonyl-lindcarpine SYSTEMATIC 23526231 A 194 226 (+)-10-O-methylhernovine N-oxide SYSTEMATIC 23526231 A 236 273 (+)-3-hydroxy-anhydrolycorine N-oxide SYSTEMATIC 23526231 A 35 42 ethanol SYSTEMATIC 23526231 A 377 381 (1)H FORMULA 23526231 A 382 386 (1)H FORMULA 23526571 A 247 255 thiazole SYSTEMATIC 23526571 T 25 33 Thiazole SYSTEMATIC 23526674 A 1105 1115 vancomycin TRIVIAL 23526674 A 1169 1179 vancomycin TRIVIAL 23526674 A 1341 1351 vancomycin TRIVIAL 23526674 A 1568 1572 urea TRIVIAL 23526674 A 1573 1581 nitrogen SYSTEMATIC 23526674 A 1605 1615 vancomycin TRIVIAL 23526674 A 1721 1731 vancomycin TRIVIAL 23526674 A 1760 1770 vancomycin TRIVIAL 23526674 A 1880 1890 vancomycin TRIVIAL 23526674 A 361 371 vancomycin TRIVIAL 23526674 A 384 394 vancomycin TRIVIAL 23526674 A 490 500 vancomycin TRIVIAL 23526674 A 589 599 creatinine TRIVIAL 23526674 A 677 687 vancomycin TRIVIAL 23526674 A 69 79 vancomycin TRIVIAL 23526674 A 902 912 vancomycin TRIVIAL 23526674 T 27 37 Vancomycin TRIVIAL 23526745 A 171 183 thiostrepton TRIVIAL 23526745 A 195 204 cobalamin FAMILY 23526745 A 212 218 4Fe-4S FORMULA 23526745 A 240 258 2-methyltryptophan SYSTEMATIC 23526745 A 264 274 tryptophan TRIVIAL 23526745 A 75 85 tryptophan TRIVIAL 23526745 T 30 39 Cobalamin FAMILY 23526814 A 112 131 tert-butylcarbamate SYSTEMATIC 23526814 A 23 30 pyrrole SYSTEMATIC 23526814 A 291 303 hydroxamates FAMILY 23526814 A 36 43 benzene SYSTEMATIC 23526814 A 492 496 SAHA ABBREVIATION 23526814 A 50 62 hydroxamates FAMILY 23526814 A 515 530 pyrrole anilide SYSTEMATIC 23526814 A 75 91 2'-aminoanilides FAMILY 23526814 T 0 19 tert-Butylcarbamate SYSTEMATIC 23526919 T 13 25 Carbocyanine TRIVIAL 23527317 A 12 13 N FORMULA 23527317 A 146 155 monoamine FAMILY 23527317 A 206 220 [(3)H]dopamine SYSTEMATIC 23527317 A 26 34 lobelane TRIVIAL 23527317 A 261 285 N-1,2(R)-dihydroxypropyl SYSTEMATIC 23527317 A 368 383 methamphetamine TRIVIAL 23527317 A 85 111 [(3)H]dihydrotetrabenazine SYSTEMATIC 23527317 T 147 162 methamphetamine TRIVIAL 23527317 T 24 25 N FORMULA 23527317 T 42 54 nor-lobelane TRIVIAL 23527551 A 1123 1137 aryl diazonium FAMILY 23527551 A 183 197 aryl diazonium FAMILY 23527551 A 258 264 SO3(-) FORMULA 23527551 A 269 278 N(+)(Me)3 FORMULA 23527551 A 345 358 glassy carbon TRIVIAL 23527551 A 482 496 aryl diazonium FAMILY 23527551 A 680 694 aryl diazonium FAMILY 23527551 A 815 829 aryl diazonium FAMILY 23527551 A 922 928 phenyl SYSTEMATIC 23527551 T 205 219 Aryl Diazonium FAMILY 23527585 A 0 6 Copper SYSTEMATIC 23527585 A 1047 1053 copper SYSTEMATIC 23527585 A 1090 1096 PCB126 TRIVIAL 23527585 A 1229 1240 glutathione TRIVIAL 23527585 A 1277 1283 copper SYSTEMATIC 23527585 A 1377 1385 selenium SYSTEMATIC 23527585 A 1387 1396 manganese SYSTEMATIC 23527585 A 1398 1402 zinc SYSTEMATIC 23527585 A 1408 1412 iron SYSTEMATIC 23527585 A 143 149 copper SYSTEMATIC 23527585 A 1604 1610 PCB126 TRIVIAL 23527585 A 1678 1684 copper SYSTEMATIC 23527585 A 1714 1720 copper SYSTEMATIC 23527585 A 1773 1779 PCB126 TRIVIAL 23527585 A 1781 1787 PCB126 TRIVIAL 23527585 A 213 221 hydroxyl SYSTEMATIC 23527585 A 232 248 Aryl-hydrocarbon FAMILY 23527585 A 300 324 polychlorinated biphenyl FAMILY 23527585 A 326 329 PCB ABBREVIATION 23527585 A 341 372 3,3',4,4',5-pentachlorobiphenyl SYSTEMATIC 23527585 A 374 380 PCB126 TRIVIAL 23527585 A 392 398 copper SYSTEMATIC 23527585 A 517 520 PCB ABBREVIATION 23527585 A 604 610 copper SYSTEMATIC 23527585 A 793 799 PCB126 TRIVIAL 23527585 A 994 1000 copper SYSTEMATIC 23527585 T 13 19 Copper SYSTEMATIC 23527619 A 113 115 Au FORMULA 23527619 A 150 163 carboxylethyl SYSTEMATIC 23527619 A 239 245 Hg(2+) FORMULA 23527619 A 250 252 Au FORMULA 23527619 A 317 319 Au FORMULA 23527619 A 369 371 Au FORMULA 23527619 A 422 425 Cys FORMULA 23527619 A 472 474 Au FORMULA 23527619 A 593 599 Hg(2+) FORMULA 23527619 A 60 68 cysteine TRIVIAL 23527619 A 629 635 thiols FAMILY 23527619 A 641 643 Au FORMULA 23527619 A 673 676 Cys FORMULA 23527619 A 689 691 Au FORMULA 23527619 A 70 73 Cys FORMULA 23527619 A 79 85 Hg(2+) FORMULA 23527619 A 824 827 Cys FORMULA 23527619 A 832 838 Hg(2+) FORMULA 23527619 A 890 893 Cys FORMULA 23527619 A 898 904 Hg(2+) FORMULA 23527619 T 106 114 Cysteine TRIVIAL 23527619 T 119 130 Mercury(II) SYSTEMATIC 23528109 A 124 131 silicon SYSTEMATIC 23528109 A 195 207 organosilane FAMILY 23528109 A 216 221 Si3N4 FORMULA 23528109 A 27 31 POPC ABBREVIATION 23528109 A 769 774 CaCl2 FORMULA 23528109 A 88 103 silicon nitride SYSTEMATIC 23528109 A 970 977 silicon SYSTEMATIC 23528109 T 36 51 silicon nitride SYSTEMATIC 23528251 A 140 150 androstane TRIVIAL 23528251 A 215 221 5'-AMP SYSTEMATIC 23528251 A 35 41 5'-AMP SYSTEMATIC 23528251 A 367 380 Phenobarbital TRIVIAL 23528251 A 702 717 Cobalt chloride SYSTEMATIC 23528251 T 32 42 androstane TRIVIAL 23528252 A 1042 1050 androgen FAMILY 23528252 A 1141 1144 BPA ABBREVIATION 23528252 A 138 141 BPA ABBREVIATION 23528252 A 36 47 bisphenol A TRIVIAL 23528252 A 413 416 BPA ABBREVIATION 23528252 A 49 52 BPA ABBREVIATION 23528252 A 532 544 testosterone TRIVIAL 23528252 A 673 676 BPA ABBREVIATION 23528252 A 782 790 androgen FAMILY 23528252 A 961 964 BPA ABBREVIATION 23528252 T 10 18 androgen FAMILY 23528252 T 121 132 bisphenol A TRIVIAL 23528300 A 12 23 benzoxazole SYSTEMATIC 23528300 A 45 56 oxamic acid TRIVIAL 23528300 T 24 50 2-substituted benzoxazoles FAMILY 23528390 A 0 10 Quinolones FAMILY 23528390 A 159 169 quinolones FAMILY 23528390 A 227 237 Quinolones FAMILY 23528390 A 489 498 quinolone FAMILY 23528390 A 587 593 oxygen SYSTEMATIC 23528390 A 794 803 quinolone FAMILY 23528390 T 24 34 quinolones FAMILY 23528611 A 1125 1132 PKI-166 IDENTIFIER 23528611 A 1220 1227 PKI-166 IDENTIFIER 23528611 A 1232 1242 lisinopril TRIVIAL 23528611 A 1314 1327 phenylephrine TRIVIAL 23528611 A 445 452 PKI-166 IDENTIFIER 23528611 A 570 577 PKI-166 IDENTIFIER 23528611 A 581 591 lisinopril TRIVIAL 23528611 A 683 690 PKI-166 IDENTIFIER 23528611 A 718 725 PKI-166 IDENTIFIER 23528611 A 837 847 creatinine TRIVIAL 23528611 A 925 935 lisinopril TRIVIAL 23528611 A 993 1000 PKI-166 IDENTIFIER 23528611 T 43 50 PKI-166 IDENTIFIER 23529571 A 530 536 carbon SYSTEMATIC 23529571 A 548 556 graphene TRIVIAL 23529571 A 561 567 carbon SYSTEMATIC 23529671 A 1094 1101 glucose TRIVIAL 23529671 A 631 638 glucose TRIVIAL 23529894 A 167 178 flinderoles FAMILY 23529894 A 236 245 borrerine TRIVIAL 23529894 A 273 284 flinderoles FAMILY 23529894 A 290 302 borreverines FAMILY 23529894 A 347 358 flinderoles FAMILY 23529894 A 387 396 borrerine TRIVIAL 23529894 A 492 515 Flinderoles A, B, and C MULTIPLE 23529894 A 540 554 isoborreverine TRIVIAL 23529894 A 560 582 dimethylisoborreverine TRIVIAL 23529894 A 627 637 tryptamine TRIVIAL 23529894 A 708 731 flinderoles A, B, and C MULTIPLE 23529894 A 819 825 indole SYSTEMATIC 23529894 A 835 840 enone SYSTEMATIC 23529898 A 105 109 TiO2 FORMULA 23529898 A 326 330 TiO2 FORMULA 23529898 A 341 344 PHB ABBREVIATION 23529898 A 45 68 poly(3-hydroxybutyrate) SYSTEMATIC 23529898 A 70 73 PHB ABBREVIATION 23529898 A 86 90 TiO2 FORMULA 23529898 T 38 61 Poly(3-Hydroxybutyrate) SYSTEMATIC 23529898 T 63 67 TiO2 FORMULA 23529905 A 117 133 polycaprolactone SYSTEMATIC 23529905 A 134 160 poly(α,β)-DL-aspartic acid SYSTEMATIC 23529905 A 622 625 PCL ABBREVIATION 23529905 A 626 629 PAA ABBREVIATION 23530011 A 1111 1122 cholesterol TRIVIAL 23530011 A 1184 1191 glucose TRIVIAL 23530011 A 1208 1219 cholesterol TRIVIAL 23530011 A 1225 1236 cholesterol TRIVIAL 23530011 A 1238 1251 triglycerides FAMILY 23530011 A 1261 1272 fatty acids FAMILY 23530011 A 1433 1440 glucose TRIVIAL 23530011 A 1766 1773 glucose TRIVIAL 23530011 A 636 643 glucose TRIVIAL 23530011 A 763 775 Carbohydrate FAMILY 23530011 A 809 822 carbohydrates FAMILY 23530018 A 1066 1069 CGP ABBREVIATION 23530018 A 1210 1219 chalcogen FAMILY 23530018 A 1226 1228 Se FORMULA 23530018 A 1236 1238 Te FORMULA 23530018 A 1313 1320 methine SYSTEMATIC 23530018 A 1324 1334 trimethine SYSTEMATIC 23530018 A 1369 1377 pyrylium FAMILY 23530018 A 1538 1547 chalcogen FAMILY 23530018 A 182 200 chalcogenopyrylium FAMILY 23530018 A 207 211 CGPs ABBREVIATION 23530018 A 270 297 [(3)H]estradiol glucuronide SYSTEMATIC 23530018 A 299 305 E217βG SYSTEMATIC 23530018 A 405 409 CGPs ABBREVIATION 23530018 A 458 465 calcein TRIVIAL 23530018 A 49 52 ATP ABBREVIATION 23530018 A 494 498 CGPs ABBREVIATION 23530018 A 523 529 E217βG SYSTEMATIC 23530018 A 571 575 CGPs ABBREVIATION 23530018 A 704 708 CGPs ABBREVIATION 23530018 A 744 751 calcein TRIVIAL 23530018 A 849 853 CGPs ABBREVIATION 23530018 A 869 881 [(3)H]E217βG SYSTEMATIC 23530018 A 971 977 E217βG SYSTEMATIC 23530018 T 0 18 Chalcogenopyrylium FAMILY 23530019 A 0 8 Nicotine TRIVIAL 23530019 A 1000 1008 nicotine TRIVIAL 23530019 A 1013 1022 bupropion TRIVIAL 23530019 A 1049 1057 coumarin TRIVIAL 23530019 A 1077 1085 Nicotine TRIVIAL 23530019 A 1105 1113 cotinine TRIVIAL 23530019 A 1161 1169 Nicotine TRIVIAL 23530019 A 1174 1183 bupropion TRIVIAL 23530019 A 1213 1225 C-8-xanthate TRIVIAL 23530019 A 1365 1373 nicotine TRIVIAL 23530019 A 1399 1408 bupropion TRIVIAL 23530019 A 1473 1481 nicotine TRIVIAL 23530019 A 149 157 nicotine TRIVIAL 23530019 A 1565 1573 nicotine TRIVIAL 23530019 A 196 204 Nicotine TRIVIAL 23530019 A 209 217 cotinine TRIVIAL 23530019 A 289 297 nicotine TRIVIAL 23530019 A 364 372 nicotine TRIVIAL 23530019 A 448 456 nicotine TRIVIAL 23530019 A 542 550 nicotine TRIVIAL 23530019 A 561 569 Nicotine TRIVIAL 23530019 A 701 709 nicotine TRIVIAL 23530019 A 765 773 nicotine TRIVIAL 23530019 A 867 875 nicotine TRIVIAL 23530019 A 879 887 cotinine TRIVIAL 23530019 T 0 8 Nicotine TRIVIAL 23530020 A 0 10 Prilocaine TRIVIAL 23530020 A 1020 1049 bis-(4-nitrophenyl) phosphate SYSTEMATIC 23530020 A 1134 1144 prilocaine TRIVIAL 23530020 A 1149 1158 lidocaine TRIVIAL 23530020 A 1305 1316 o-toluidine SYSTEMATIC 23530020 A 1321 1333 2,6-xylidine SYSTEMATIC 23530020 A 1415 1426 o-Toluidine SYSTEMATIC 23530020 A 1431 1443 2,6-xylidine SYSTEMATIC 23530020 A 1482 1510 4- and 6-hydroxy-o-toluidine MULTIPLE 23530020 A 15 24 lidocaine TRIVIAL 23530020 A 1515 1537 4-hydroxy-2,6-xylidine SYSTEMATIC 23530020 A 168 178 prilocaine TRIVIAL 23530020 A 1781 1791 prilocaine TRIVIAL 23530020 A 1797 1806 lidocaine TRIVIAL 23530020 A 180 191 o-toluidine SYSTEMATIC 23530020 A 197 206 lidocaine TRIVIAL 23530020 A 208 220 2,6-xylidine SYSTEMATIC 23530020 A 421 431 prilocaine TRIVIAL 23530020 A 43 48 amide FAMILY 23530020 A 437 446 lidocaine TRIVIAL 23530020 A 504 514 prilocaine TRIVIAL 23530020 A 595 604 lidocaine TRIVIAL 23530020 A 668 678 prilocaine TRIVIAL 23530020 A 683 692 lidocaine TRIVIAL 23530020 A 843 853 prilocaine TRIVIAL 23530020 A 858 869 o-toluidine SYSTEMATIC 23530020 A 920 929 lidocaine TRIVIAL 23530020 A 934 946 2,6-xylidine SYSTEMATIC 23530020 A 988 1015 diisopropyl fluorophosphate SYSTEMATIC 23530020 T 0 10 Prilocaine TRIVIAL 23530020 T 16 25 Lidocaine TRIVIAL 23530036 A 577 585 tyrosine TRIVIAL 23530765 A 130 165 bis(l-histidinato)cadmium dihydrate SYSTEMATIC 23530765 A 204 210 copper SYSTEMATIC 23530765 A 453 459 copper SYSTEMATIC 23530765 A 610 619 histidine TRIVIAL 23530765 A 69 75 Cu(II) FORMULA 23530765 A 809 815 copper SYSTEMATIC 23530765 T 55 61 Copper SYSTEMATIC 23530765 T 79 114 Bis(l-histidinato)cadmium Dihydrate SYSTEMATIC 23531107 A 1153 1156 PbS FORMULA 23531107 A 1216 1219 PbS FORMULA 23531107 A 1220 1223 ZnO FORMULA 23531107 A 1309 1312 ZnO FORMULA 23531107 A 1322 1326 PbSe FORMULA 23531107 A 1330 1333 ZnO FORMULA 23531107 A 138 149 metal oxide FAMILY 23531107 A 1652 1663 metal oxide FAMILY 23531107 A 422 425 ZnO FORMULA 23531107 A 433 438 oxide SYSTEMATIC 23531107 A 487 490 ZnO FORMULA 23531107 A 623 626 PbS FORMULA 23531107 A 630 633 ZnO FORMULA 23531107 A 684 687 ZnO FORMULA 23531107 A 693 701 nitrogen SYSTEMATIC 23531107 A 763 766 ZnO FORMULA 23531107 A 801 805 PbSe FORMULA 23531107 A 809 812 ZnO FORMULA 23531107 T 88 99 Metal Oxide FAMILY 23531119 A 0 7 Uridine TRIVIAL 23531119 A 167 174 5-bromo SYSTEMATIC 23531119 A 179 187 5-fluoro SYSTEMATIC 23531119 A 208 214 uracil TRIVIAL 23531119 A 231 234 NHN FORMULA 23531119 A 235 243 hydrogen SYSTEMATIC 23531119 A 290 301 nucleosides FAMILY 23531119 A 315 323 halogens FAMILY 23531119 A 415 426 halouracils FAMILY 23531119 A 471 481 2-carbonyl SYSTEMATIC 23531119 A 515 523 hydrogen SYSTEMATIC 23531119 A 611 618 guanine TRIVIAL 23531119 A 63 71 hydrogen SYSTEMATIC 23531119 A 640 647 thymine TRIVIAL 23531119 A 664 669 (15)N FORMULA 23531119 A 678 692 5-bromouridine SYSTEMATIC 23531119 A 728 732 enol SYSTEMATIC 23531119 T 68 88 5-substituted uracil SYSTEMATIC 23531160 A 1054 1057 TRP ABBREVIATION 23531160 A 1062 1066 5-HT SYSTEMATIC 23531160 A 1076 1086 monoamines FAMILY 23531160 A 183 192 monoamine FAMILY 23531160 A 226 235 serotonin TRIVIAL 23531160 A 237 241 5-HT SYSTEMATIC 23531160 A 898 909 indoleamine SYSTEMATIC 23531160 A 963 973 tryptophan TRIVIAL 23531160 A 975 978 TRP ABBREVIATION 23531160 T 14 23 serotonin TRIVIAL 23531217 A 105 120 organophosphate FAMILY 23531217 A 122 139 organophosphonate FAMILY 23531217 A 24 52 bis-pyridinium mono-aldoxime SYSTEMATIC 23531217 A 358 374 octadecyl silica SYSTEMATIC 23532446 A 1256 1269 polypropylene SYSTEMATIC 23532446 A 180 196 titanium dioxide SYSTEMATIC 23532897 A 397 404 proline TRIVIAL 23532897 A 761 773 thiazolidine SYSTEMATIC 23532897 A 862 880 inositol phosphate SYSTEMATIC 23532897 T 14 21 Proline TRIVIAL 23533220 A 1139 1151 testosterone TRIVIAL 23533220 A 1405 1409 cAMP ABBREVIATION 23533220 A 1421 1425 cAMP ABBREVIATION 23533220 A 1563 1576 17β-estradiol SYSTEMATIC 23533220 A 332 345 17β-estradiol SYSTEMATIC 23533220 A 356 369 catecholamine TRIVIAL 23533220 A 619 627 dopamine TRIVIAL 23534412 A 144 151 seselin TRIVIAL 23534412 A 334 345 epinephrine TRIVIAL 23534412 A 407 423 arachidonic acid TRIVIAL 23534412 A 538 553 ferric chloride SYSTEMATIC 23534412 A 698 701 ADP ABBREVIATION 23534412 A 973 976 ADP ABBREVIATION 23534412 T 47 55 coumarin TRIVIAL 23534412 T 67 188 3-(5-hydroxy-2,2-dimethyl-chroman-6-yl)-N-{2-[3-(5-hydroxy-2,2-dimethyl-chroman-6-yl)-propionylamino]-ethyl}-propionamide SYSTEMATIC 23534413 A 1026 1036 flavonoids FAMILY 23534413 A 1067 1075 xanthine TRIVIAL 23534413 A 210 219 uric acid TRIVIAL 23534413 A 24 35 allopurinol TRIVIAL 23534413 A 302 310 xanthine TRIVIAL 23534413 A 40 53 benzbromarone TRIVIAL 23534413 A 409 419 flavonoids FAMILY 23534413 A 473 483 flavonoids FAMILY 23534413 A 530 538 xanthine TRIVIAL 23534413 A 674 682 xanthine TRIVIAL 23534413 A 713 722 Myricetin TRIVIAL 23534413 A 727 735 luteolin TRIVIAL 23534413 A 786 794 xanthine TRIVIAL 23534413 A 872 880 xanthine TRIVIAL 23534413 T 108 116 xanthine TRIVIAL 23534413 T 73 83 flavonoids FAMILY 23534413 T 88 99 isoflavones FAMILY 23534440 A 1144 1151 guanine TRIVIAL 23534440 A 1192 1200 cytosine TRIVIAL 23534440 A 1466 1476 nucleotide FAMILY 23534440 A 1555 1565 nucleotide FAMILY 23534440 A 1992 1997 sugar FAMILY 23534440 A 2003 2004 H FORMULA 23534440 A 2082 2088 Mg(2+) FORMULA 23534440 A 2209 2215 Mg(2+) FORMULA 23534440 A 834 841 guanine TRIVIAL 23534442 A 1025 1054 nitrooxyalkyl ester and ether MULTIPLE 23534442 A 12 44 3-substituted 1,5-diarylpyrroles FAMILY 23534442 A 138 145 pyrrole SYSTEMATIC 23534442 A 154 167 nitrooxyalkyl FAMILY 23534442 A 176 182 esters FAMILY 23534442 A 184 194 carbonates FAMILY 23534442 A 200 206 ethers FAMILY 23534442 A 248 250 NO FORMULA 23534442 A 351 371 nitrooxyalkyl ethers FAMILY 23534442 A 399 407 alcohols FAMILY 23534442 A 450 458 Nitrooxy SYSTEMATIC 23534442 A 478 480 NO FORMULA 23534442 A 55 68 nitrooxyalkyl FAMILY 23534442 A 922 926 (1)H FORMULA 23534442 A 932 937 (13)C FORMULA 23534442 T 134 146 nitric oxide SYSTEMATIC 23534442 T 42 80 1,5-diarylpyrrole nitrooxyalkyl ethers FAMILY 23534827 A 1009 1020 C-(N)-A-S-H ABBREVIATION 23534827 A 103 128 calcium (alumino)silicate SYSTEMATIC 23534827 A 1255 1263 silicate FAMILY 23534827 A 1268 1277 aluminate TRIVIAL 23534827 A 1377 1407 calcium-sodium aluminosilicate SYSTEMATIC 23534827 A 196 207 tobermorite TRIVIAL 23534827 A 347 385 calcium-sodium aluminosilicate hydrate SYSTEMATIC 23534827 A 387 398 C-(N)-A-S-H ABBREVIATION 23534827 A 507 518 C-(N)-A-S-H ABBREVIATION 23534827 A 573 584 tobermorite TRIVIAL 23534827 A 632 643 tobermorite TRIVIAL 23534827 A 992 1003 tobermorite TRIVIAL 23534827 T 112 123 tobermorite TRIVIAL 23534827 T 38 76 calcium-sodium aluminosilicate hydrate SYSTEMATIC 23535167 A 10 20 methionine TRIVIAL 23535167 A 1012 1020 ethylene SYSTEMATIC 23535167 A 1022 1035 nicotianamine SYSTEMATIC 23535167 A 1150 1153 Met FORMULA 23535167 A 188 191 Met FORMULA 23535167 A 26 29 SAM ABBREVIATION 23535167 A 293 299 sulfur SYSTEMATIC 23535167 A 31 51 S-adenosylmethionine TRIVIAL 23535167 A 341 350 aspartate TRIVIAL 23535167 A 359 370 amino acids FAMILY 23535167 A 404 407 SAM ABBREVIATION 23535167 A 409 412 SAM ABBREVIATION 23535167 A 424 432 ethylene SYSTEMATIC 23535167 A 434 447 nicotianamine SYSTEMATIC 23535167 A 5 8 Met FORMULA 23535167 A 501 507 methyl SYSTEMATIC 23535167 A 631 634 SAM ABBREVIATION 23535167 A 76 79 Met FORMULA 23535167 A 837 840 Met FORMULA 23535167 A 895 898 Met FORMULA 23535167 A 934 937 MTA ABBREVIATION 23535167 A 939 961 5'-methylthioadenosine SYSTEMATIC 23535167 A 964 967 MTA ABBREVIATION 23535167 T 0 10 Methionine TRIVIAL 23535167 T 23 43 S-adenosylmethionine TRIVIAL 23535167 T 69 75 sulfur SYSTEMATIC 23535167 T 77 85 ethylene SYSTEMATIC 23535185 A 1053 1061 galangin TRIVIAL 23535185 A 1084 1092 cromolyn TRIVIAL 23535185 A 1146 1154 galangin TRIVIAL 23535185 A 1232 1241 histamine TRIVIAL 23535185 A 1365 1373 galangin TRIVIAL 23535185 A 298 306 galangin TRIVIAL 23535185 A 378 386 Galangin TRIVIAL 23535185 A 397 406 histamine TRIVIAL 23535185 A 449 456 calcium SYSTEMATIC 23535185 A 460 489 phorbol 12-mystate 13-acetate SYSTEMATIC 23535185 A 495 502 calcium SYSTEMATIC 23535185 A 557 565 Galangin TRIVIAL 23535185 A 719 727 galangin TRIVIAL 23535185 A 788 789 N FORMULA 23535185 A 897 905 galangin TRIVIAL 23535185 A 982 991 histamine TRIVIAL 23535185 T 0 8 Galangin TRIVIAL 23535186 A 109 124 d-galactosamine TRIVIAL 23535186 A 1145 1151 d-GalN ABBREVIATION 23535186 A 1188 1197 scoparone TRIVIAL 23535186 A 1224 1233 scoparone TRIVIAL 23535186 A 1245 1251 d-GalN ABBREVIATION 23535186 A 126 132 d-GalN ABBREVIATION 23535186 A 264 270 d-GalN ABBREVIATION 23535186 A 338 347 scoparone TRIVIAL 23535186 A 358 364 d-GalN ABBREVIATION 23535186 A 395 401 d-GalN ABBREVIATION 23535186 A 559 568 scoparone TRIVIAL 23535186 A 585 591 d-GalN ABBREVIATION 23535186 A 756 757 N FORMULA 23535186 A 950 959 scoparone TRIVIAL 23535186 A 96 105 scoparone TRIVIAL 23535186 T 0 9 Scoparone TRIVIAL 23535186 T 21 36 d-galactosamine TRIVIAL 23535288 A 1195 1198 BHA ABBREVIATION 23535288 A 562 578 sulfadimethoxine TRIVIAL 23535288 A 580 583 SDM ABBREVIATION 23535288 A 603 629 phenylethyl isothiocyanate SYSTEMATIC 23535288 A 645 669 butylated hydroxyanisole SYSTEMATIC 23535288 A 671 674 BHA ABBREVIATION 23535288 A 696 704 catechol TRIVIAL 23535288 A 722 769 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine SYSTEMATIC 23535288 A 774 795 chenodeoxycholic acid TRIVIAL 23535288 A 846 857 caprolactam TRIVIAL 23535320 A 120 135 1,2,3-triazoles FAMILY 23535320 A 142 157 nor-β-lapachone TRIVIAL 23535320 A 164 179 1,2,3-triazoles FAMILY 23535320 A 188 199 α-lapachone TRIVIAL 23535320 A 206 221 1,2,3-triazoles FAMILY 23535320 A 622 637 Nor-α-lapachone TRIVIAL 23535320 A 89 108 1,4-naphthoquinones FAMILY 23535320 T 106 128 α- and nor-α-lapachone MULTIPLE 23535320 T 135 150 1,2,3-triazoles FAMILY 23535320 T 154 160 copper SYSTEMATIC 23535320 T 171 176 azide SYSTEMATIC 23535320 T 177 183 alkyne FAMILY 23535320 T 7 22 naphthoquinones FAMILY 23535321 A 107 123 diphenyl sulfone SYSTEMATIC 23535321 A 12 56 heterocyclic organobismuth(III) carboxylates FAMILY 23535321 A 174 185 carboxylate SYSTEMATIC 23535321 A 441 457 diphenyl sulfone SYSTEMATIC 23535321 A 470 497 ClBi(5-RC6H3-2-SO2C6H4-1'-) FAMILY 23535321 A 66 92 RCO2Bi(C6H4-2-SO2C6H4-1'-) FAMILY 23535321 A 699 706 bismuth SYSTEMATIC 23535321 A 732 743 carboxylate SYSTEMATIC 23535321 A 765 772 bismuth SYSTEMATIC 23535321 T 0 33 Heterocyclic bismuth carboxylates FAMILY 23535321 T 45 61 diphenyl sulfone SYSTEMATIC 23535326 A 307 315 BP1.4160 IDENTIFIER 23535326 A 317 329 cyclohexanol SYSTEMATIC 23535326 A 358 365 alcohol FAMILY 23535326 A 46 55 histamine TRIVIAL 23535326 A 96 104 hydroxyl SYSTEMATIC 23535326 T 24 33 histamine TRIVIAL 23535326 T 66 73 alcohol FAMILY 23535334 A 173 190 hydroxycinnamates FAMILY 23535334 A 234 276 p-coumaryl, coniferyl and sinapyl alcohols MULTIPLE 23535351 A 1236 1245 Asenapine TRIVIAL 23535351 A 1354 1363 asenapine TRIVIAL 23535351 A 411 420 Asenapine TRIVIAL 23535351 A 967 976 asenapine TRIVIAL 23535351 T 54 63 asenapine TRIVIAL 23535360 A 1239 1247 cysteine TRIVIAL 23535360 A 1252 1260 cysteine TRIVIAL 23535360 A 1261 1267 lysine TRIVIAL 23535360 A 1342 1348 lysine TRIVIAL 23535360 A 1588 1596 cysteine TRIVIAL 23535360 A 411 422 amino acids FAMILY 23535360 A 875 883 cysteine TRIVIAL 23535360 A 885 891 lysine TRIVIAL 23535360 A 896 904 cysteine TRIVIAL 23535360 A 905 911 lysine TRIVIAL 23535360 T 42 53 Amino Acids FAMILY 23535394 A 1014 1023 saxitoxin TRIVIAL 23535394 A 1063 1069 sodium SYSTEMATIC 23535394 A 1185 1194 saxitoxin TRIVIAL 23535394 A 156 162 sodium SYSTEMATIC 23535394 A 164 173 potassium SYSTEMATIC 23535394 A 178 185 calcium SYSTEMATIC 23535394 A 376 385 Saxitoxin TRIVIAL 23535394 A 950 959 saxitoxin TRIVIAL 23535394 T 38 47 saxitoxin TRIVIAL 23535516 A 1092 1095 Nle FORMULA 23535516 A 1100 1105 D-Phe FORMULA 23535516 A 1839 1844 AG490 TRIVIAL 23535516 A 1849 1854 U0126 IDENTIFIER 23535516 A 827 828 N FORMULA 23535870 T 12 21 potassium SYSTEMATIC 23535915 A 1056 1064 atrazine TRIVIAL 23535915 A 1165 1173 atrazine TRIVIAL 23535915 A 1283 1291 atrazine TRIVIAL 23535915 A 1492 1500 atrazine TRIVIAL 23535915 A 162 170 atrazine TRIVIAL 23535915 A 243 251 atrazine TRIVIAL 23535915 A 424 432 atrazine TRIVIAL 23535915 A 532 540 atrazine TRIVIAL 23535915 A 704 712 atrazine TRIVIAL 23535915 A 933 941 atrazine TRIVIAL 23535915 A 996 1004 atrazine TRIVIAL 23535915 T 80 88 atrazine TRIVIAL 23536271 A 0 8 β-Ionone TRIVIAL 23536271 A 1176 1184 β-ionone TRIVIAL 23536271 A 191 199 β-ionone TRIVIAL 23536271 A 575 583 β-ionone TRIVIAL 23536271 A 641 649 β-ionone TRIVIAL 23536271 A 789 794 amino FAMILY 23536271 A 842 850 β-Ionone TRIVIAL 23536271 T 0 8 β-Ionone TRIVIAL 23536315 A 1092 1095 ASA ABBREVIATION 23536315 A 1099 1110 BAY 11-7082 IDENTIFIER 23536315 A 1194 1207 dexamethasone TRIVIAL 23536315 A 1316 1319 ASA ABBREVIATION 23536315 A 329 342 dexamethasone TRIVIAL 23536315 A 363 383 acetylsalicylic acid SYSTEMATIC 23536315 A 385 388 ASA ABBREVIATION 23536315 A 471 482 BAY 11-7082 IDENTIFIER 23536315 A 487 498 Ro 106-9920 IDENTIFIER 23536315 A 587 590 ASA ABBREVIATION 23536315 A 592 603 BAY-11-7082 IDENTIFIER 23536315 A 608 619 Ro 106-9920 IDENTIFIER 23536582 A 224 231 glucose TRIVIAL 23536582 A 56 63 glucose TRIVIAL 23536582 T 15 22 Glucose TRIVIAL 23536584 A 1044 1051 glucose TRIVIAL 23536584 A 1192 1199 glucose TRIVIAL 23536584 A 1856 1865 metformin TRIVIAL 23536584 A 202 211 metformin TRIVIAL 23536584 T 123 132 Metformin TRIVIAL 23536728 T 56 64 Pregnane TRIVIAL 23537133 A 109 121 acetonitrile SYSTEMATIC 23537133 A 143 160 tetraalkyammonium FAMILY 23537133 A 220 221 C FORMULA 23537133 A 238 251 glassy carbon TRIVIAL 23537133 A 253 261 graphite TRIVIAL 23537133 A 266 275 fullerene TRIVIAL 23537133 A 346 348 Ag FORMULA 23537133 A 349 353 AgCl FORMULA 23537133 A 410 426 trimethylsilanes FAMILY 23537133 A 427 433 RSiMe3 FAMILY 23537133 A 459 473 trimethylsilyl SYSTEMATIC 23537133 A 481 487 TMS(+) ABBREVIATION 23537133 A 60 66 carbon SYSTEMATIC 23537133 A 761 767 benzyl SYSTEMATIC 23537133 A 772 777 allyl SYSTEMATIC 23537133 A 91 104 glassy carbon TRIVIAL 23537133 T 47 54 carbons FAMILY 23537133 T 61 66 allyl SYSTEMATIC 23537133 T 71 77 benzyl SYSTEMATIC 23537133 T 78 94 trimethylsilanes FAMILY 23537315 A 202 217 phosphoranimide SYSTEMATIC 23537315 A 260 268 nitrogen SYSTEMATIC 23537315 A 31 42 hydrocarbon FAMILY 23537315 A 354 365 hydrocarbon FAMILY 23537315 A 450 458 nitrogen SYSTEMATIC 23537315 A 89 94 Co(I) FORMULA 23537315 A 932 956 unsaturated hydrocarbons FAMILY 23537315 A 99 104 Ni(I) FORMULA 23537315 T 0 11 Hydrocarbon FAMILY 23537321 A 15 22 silicon SYSTEMATIC 23537321 A 184 191 silicon SYSTEMATIC 23537321 A 301 308 silicon SYSTEMATIC 23537321 A 487 494 silicon SYSTEMATIC 23537321 A 495 501 carbon SYSTEMATIC 23537321 A 531 538 silicon SYSTEMATIC 23537321 A 576 582 carbon SYSTEMATIC 23537321 A 632 638 carbon SYSTEMATIC 23537321 A 64 71 lithium SYSTEMATIC 23537321 A 676 683 silicon SYSTEMATIC 23537321 A 736 743 silicon SYSTEMATIC 23537321 T 57 64 silicon SYSTEMATIC 23537321 T 88 90 li FORMULA 23537339 A 164 185 α-azido-β-keto esters FAMILY 23537339 A 21 23 Fe FORMULA 23537339 A 255 284 3-substitued 3-azidooxindoles FAMILY 23537339 A 65 78 β-keto esters FAMILY 23537339 A 83 92 oxindoles FAMILY 23537339 T 17 21 Iron SYSTEMATIC 23537339 T 45 58 β-Keto Esters FAMILY 23537339 T 63 72 Oxindoles FAMILY 23537597 A 1056 1077 δ-aminolevulinic acid SYSTEMATIC 23537597 A 1144 1159 protoporphyrins FAMILY 23537597 A 174 183 vitamin C TRIVIAL 23537597 A 190 205 calcium lactate SYSTEMATIC 23537597 A 207 212 CaLac ABBREVIATION 23537597 A 215 230 ferrous sulfate SYSTEMATIC 23537597 A 232 237 FeSO4 FORMULA 23537597 A 243 255 zinc sulfate SYSTEMATIC 23537597 A 257 262 ZnSO4 FORMULA 23537599 A 106 116 methanabol TRIVIAL 23537599 A 92 101 turinabol TRIVIAL 23537599 A 943 953 methanabol TRIVIAL 23537661 A 1021 1037 PC-dibenzofurans FAMILY 23537661 A 623 648 polychlorinated biphenyls FAMILY 23537661 A 650 654 PCBs ABBREVIATION 23537661 A 657 671 organochlorine FAMILY 23537661 A 688 701 methylmercury SYSTEMATIC 23537661 A 946 957 hydrocarbon FAMILY 23537661 A 983 996 non-ortho PCB FAMILY 23537661 A 999 1016 PC-dibenzodioxins FAMILY 23537700 A 0 10 Oxysterols FAMILY 23537700 A 148 173 7 beta-hydroxycholesterol SYSTEMATIC 23537700 A 175 180 7b-HC SYSTEMATIC 23537700 A 404 409 7b-HC SYSTEMATIC 23537700 A 472 480 pyruvate TRIVIAL 23537700 A 506 526 phosphoenol pyruvate TRIVIAL 23537700 A 561 570 glutamine TRIVIAL 23537700 T 63 84 7β-hydroxycholesterol SYSTEMATIC 23537700 T 8 16 pyruvate TRIVIAL 23537700 T 89 98 glutamine TRIVIAL 23537747 A 1098 1107 nobiletin TRIVIAL 23537747 A 291 299 apigenin TRIVIAL 23537747 A 301 309 tricetin TRIVIAL 23537747 A 311 321 tangeretin TRIVIAL 23537747 A 327 336 nobiletin TRIVIAL 23537747 A 402 411 nobiletin TRIVIAL 23537747 A 628 637 nobiletin TRIVIAL 23537747 A 750 759 nobiletin TRIVIAL 23537747 A 897 906 nobiletin TRIVIAL 23537747 A 945 952 phospho SYSTEMATIC 23537747 A 962 969 phospho SYSTEMATIC 23537747 T 0 9 Nobiletin TRIVIAL 23537748 A 0 11 Methicillin TRIVIAL 23537748 A 1077 1080 CCM ABBREVIATION 23537748 A 1134 1137 CCM ABBREVIATION 23537748 A 1225 1228 CCM ABBREVIATION 23537748 A 1274 1283 oxacillin TRIVIAL 23537748 A 1285 1288 OXI ABBREVIATION 23537748 A 1291 1301 ampicillin TRIVIAL 23537748 A 1303 1306 AMP ABBREVIATION 23537748 A 1309 1322 ciprofloxacin TRIVIAL 23537748 A 1324 1327 CIP ABBREVIATION 23537748 A 1334 1345 norfloxacin TRIVIAL 23537748 A 1347 1350 NOR ABBREVIATION 23537748 A 1415 1418 CCM ABBREVIATION 23537748 A 1423 1426 OXI ABBREVIATION 23537748 A 1537 1540 CCM ABBREVIATION 23537748 A 1600 1603 OXI ABBREVIATION 23537748 A 1605 1608 AMP ABBREVIATION 23537748 A 1610 1613 CIP ABBREVIATION 23537748 A 1619 1622 NOR ABBREVIATION 23537748 A 1633 1636 CCM ABBREVIATION 23537748 A 505 513 Curcumin TRIVIAL 23537748 A 515 518 CCM ABBREVIATION 23537748 A 531 553 polyphenolic flavonoid FAMILY 23537748 A 746 754 curcumin TRIVIAL 23537748 A 825 828 CCM ABBREVIATION 23537748 A 890 893 CCM ABBREVIATION 23537748 T 36 44 curcumin TRIVIAL 23537748 T 53 64 methicillin TRIVIAL 23537942 A 168 190 thiazolidine-2,4-dione SYSTEMATIC 23537942 A 406 457 N-3-substituted-5-arylidene thiazolidine-2,4-diones FAMILY 23537942 A 471 491 α-bromoacryloylamido SYSTEMATIC 23537942 A 536 542 phenyl SYSTEMATIC 23537942 A 550 559 arylidene FAMILY 23537942 T 57 93 5-benzylidene thiazolidine-2,4-dione SYSTEMATIC 23538843 A 595 608 carbohydrates FAMILY 23538843 A 621 628 proline TRIVIAL 23538868 A 133 220 (3Z,6E)-1-N-methyl-3-benzylidene-6-(2R-methyl-3-hydroxypropylidene)piperazine-2,5-dione SYSTEMATIC 23538868 A 226 295 (3Z,6Z)-3- (4-hydroxybenzylidene)-6-isobutylidenepiperazine-2,5-dione SYSTEMATIC 23538868 A 301 377 (3Z,6Z)-3-((1H-imidazol-5-yl)-methylene)-6-isobutylidenepiperazine-2,5-dione SYSTEMATIC 23538868 A 387 444 (3Z,6S)-3-benzylidene-6-(2S-but-2-yl)piperazine-2,5-dione SYSTEMATIC 23538868 A 39 127 (3Z,6E)-1-N-methyl-3-benzy lidene-6-(2S-methyl-3-hydroxypropylidene)piperazine-2,5-dione SYSTEMATIC 23538868 A 9 25 diketopiperazine FAMILY 23538868 A 979 982 13C FORMULA 23538868 A 995 1047 (3Z,6S)-3-benzylidene-6-isobutylpiperazine-2,5-dione SYSTEMATIC 23538868 T 0 16 Diketopiperazine FAMILY 23538871 A 1010 1019 thiazolyl SYSTEMATIC 23538871 A 775 786 methicillin TRIVIAL 23538871 A 981 988 kocurin TRIVIAL 23538871 T 66 75 Thiazolyl SYSTEMATIC 23538871 T 95 102 Kocurin TRIVIAL 23539511 A 839 849 creatinine TRIVIAL 23539547 A 1336 1347 glutathione TRIVIAL 23539547 A 1348 1349 S FORMULA 23539547 A 1364 1365 N FORMULA 23539547 A 1391 1394 UDP ABBREVIATION 23539641 A 140 150 orvepitant TRIVIAL 23539641 A 152 160 GW823296 IDENTIFIER 23539641 A 401 416 [(11)C]GR205171 SYSTEMATIC 23539641 A 445 455 orvepitant TRIVIAL 23539641 A 658 668 orvepitant TRIVIAL 23539641 A 680 690 orvepitant TRIVIAL 23539641 T 98 108 orvepitant TRIVIAL 23540754 A 120 129 l-lactide SYSTEMATIC 23540754 A 407 416 l-lactide SYSTEMATIC 23540754 A 468 472 PLLA ABBREVIATION 23540754 A 48 63 poly(l-lactide) SYSTEMATIC 23540754 A 493 497 PLLA ABBREVIATION 23540754 A 65 69 PLLA ABBREVIATION 23540754 A 708 712 PLLA ABBREVIATION 23540754 A 733 737 PLLA ABBREVIATION 23540754 T 14 25 Polylactide SYSTEMATIC 23540754 T 50 61 Polylactide SYSTEMATIC 23541399 A 319 327 androgen FAMILY 23541399 A 41 53 testosterone TRIVIAL 23541399 A 589 597 androgen FAMILY 23541399 T 0 8 Androgen FAMILY 23541436 A 358 366 limonene TRIVIAL 23541436 A 380 391 γ-terpinene TRIVIAL 23541436 A 431 443 nitric oxide SYSTEMATIC 23541436 A 445 447 NO FORMULA 23541436 A 453 469 prostaglandin E2 TRIVIAL 23541436 A 471 475 PGE2 ABBREVIATION 23541436 A 528 540 nitric oxide SYSTEMATIC 23541637 A 0 11 Aldosterone TRIVIAL 23541637 A 1032 1037 Na(+) FORMULA 23541637 A 1038 1042 K(+) FORMULA 23541637 A 169 174 Na(+) FORMULA 23541637 A 175 179 K(+) FORMULA 23541637 A 197 208 Aldosterone TRIVIAL 23541637 A 22 27 Na(+) FORMULA 23541637 A 411 431 phosphatidylinositol TRIVIAL 23541637 A 700 707 ouabain TRIVIAL 23541637 A 756 761 Na(+) FORMULA 23541637 A 762 766 K(+) FORMULA 23541637 A 864 875 aldosterone TRIVIAL 23541637 A 935 946 aldosterone TRIVIAL 23541637 T 0 11 Aldosterone TRIVIAL 23541637 T 35 40 Na(+) FORMULA 23541637 T 41 45 K(+) FORMULA 23541637 T 87 107 phosphatidylinositol TRIVIAL 23541646 A 1055 1065 octylamide SYSTEMATIC 23541646 A 1169 1174 amide FAMILY 23541646 A 365 384 glycyrrhetinic acid TRIVIAL 23541646 A 646 649 MTT ABBREVIATION 23541646 A 765 777 benzyl amide SYSTEMATIC 23541646 A 873 876 MTT ABBREVIATION 23541646 T 0 19 Glycyrrhetinic acid TRIVIAL 23541670 A 107 132 5H-pyrrolo[2,3-b]pyrazine SYSTEMATIC 23541670 A 45 48 ATP ABBREVIATION 23541670 T 31 72 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers FAMILY 23541768 T 33 42 histidine TRIVIAL 23541949 A 0 25 RFamide-related peptide-3 SYSTEMATIC 23541949 A 179 185 RFRP-3 ABBREVIATION 23541949 A 239 245 RFRP-3 ABBREVIATION 23541949 A 27 33 RFRP-3 ABBREVIATION 23541949 A 467 473 RFRP-3 ABBREVIATION 23541949 A 545 551 RFRP-3 ABBREVIATION 23541949 A 567 574 steroid FAMILY 23541949 A 778 784 RFRP-3 ABBREVIATION 23541949 A 875 882 steroid FAMILY 23541949 T 15 21 RFRP-3 ABBREVIATION 23541950 A 311 341 dehydroepiandrosterone sulfate SYSTEMATIC 23541950 A 343 355 testosterone TRIVIAL 23541950 A 42 49 steroid FAMILY 23541950 A 520 527 steroid FAMILY 23541950 A 728 735 steroid FAMILY 23541950 T 45 52 steroid FAMILY 23542008 A 1070 1079 2'-fluoro SYSTEMATIC 23542008 A 1410 1418 hydrogen SYSTEMATIC 23542008 A 379 387 hydrogen SYSTEMATIC 23542008 A 403 414 2'-hydroxyl SYSTEMATIC 23542008 A 604 612 hydrogen SYSTEMATIC 23542008 A 825 834 2'-fluoro SYSTEMATIC 23542008 A 872 880 hydrogen SYSTEMATIC 23542039 A 137 148 Neutral Red TRIVIAL 23542039 A 491 499 glycerol TRIVIAL 23542039 A 651 662 polyphenols FAMILY 23542041 A 1214 1216 NO FORMULA 23542041 A 418 430 nitric oxide SYSTEMATIC 23542041 A 457 462 O2(-) FORMULA 23542041 A 844 846 NO FORMULA 23542041 A 865 870 O2(-) FORMULA 23542126 A 1126 1129 GSH ABBREVIATION 23542126 A 1156 1159 GSH ABBREVIATION 23542126 A 167 186 Thiobarbituric-acid TRIVIAL 23542126 A 244 253 carbonyls FAMILY 23542126 A 283 294 glutathione TRIVIAL 23542126 A 683 686 GSH ABBREVIATION 23542126 A 725 734 carbonyls FAMILY 23542126 A 953 962 carbonyls FAMILY 23542239 A 104 107 PEG ABBREVIATION 23542239 A 113 130 poly(amino acid)s FAMILY 23542239 A 484 494 iron oxide SYSTEMATIC 23542239 A 81 102 poly(ethylene glycol) SYSTEMATIC 23542440 A 0 9 Serotonin TRIVIAL 23542440 A 11 15 5-HT SYSTEMATIC 23542440 A 1256 1260 CORT ABBREVIATION 23542440 A 1345 1354 SB-656104 IDENTIFIER 23542440 A 1401 1405 CORT ABBREVIATION 23542440 A 1461 1470 SB-656104 IDENTIFIER 23542440 A 1539 1543 CORT ABBREVIATION 23542440 A 1817 1821 5-HT SYSTEMATIC 23542440 A 1826 1832 5-HIAA SYSTEMATIC 23542440 A 1889 1895 5-HIAA SYSTEMATIC 23542440 A 1896 1900 5-HT SYSTEMATIC 23542440 A 1946 1950 5-HT SYSTEMATIC 23542440 A 2229 2233 CORT ABBREVIATION 23542440 A 2367 2371 5-HT SYSTEMATIC 23542440 A 250 264 corticosterone TRIVIAL 23542440 A 266 270 CORT ABBREVIATION 23542440 A 317 326 SB-656104 IDENTIFIER 23542440 A 518 522 5-HT SYSTEMATIC 23542440 A 527 552 5-hydroxyindolacetic acid ABBREVIATION 23542440 A 554 560 5-HIAA SYSTEMATIC 23542440 A 567 573 5-HIAA SYSTEMATIC 23542440 A 574 578 5-HT SYSTEMATIC 23542440 A 607 611 5-HT SYSTEMATIC 23542440 A 635 639 5-HT SYSTEMATIC 23542440 A 654 664 tryptophan TRIVIAL 23542440 A 840 849 SB-656104 IDENTIFIER 23542440 T 35 49 corticosterone TRIVIAL 23542513 A 1007 1009 NO FORMULA 23542513 A 1035 1054 zinc protoporphyrin SYSTEMATIC 23542513 A 1056 1060 ZnPP FORMULA 23542513 A 1129 1134 5HHMF SYSTEMATIC 23542513 A 1150 1152 NO FORMULA 23542513 A 1174 1179 5HHMF SYSTEMATIC 23542513 A 1291 1296 5HHMF SYSTEMATIC 23542513 A 1305 1307 NO FORMULA 23542513 A 1415 1420 5HHMF SYSTEMATIC 23542513 A 1432 1434 NO FORMULA 23542513 A 160 162 NO FORMULA 23542513 A 217 219 NO FORMULA 23542513 A 267 272 5HHMF SYSTEMATIC 23542513 A 29 70 5-hydroxy-3,6,7,8,3'4'-hexamethoxyflavone SYSTEMATIC 23542513 A 507 534 Pyrrolidine dithiocarbamate SYSTEMATIC 23542513 A 536 540 PDTC ABBREVIATION 23542513 A 698 703 5HHMF SYSTEMATIC 23542513 A 72 77 5HHMF SYSTEMATIC 23542513 A 785 790 5HHMF SYSTEMATIC 23542513 A 915 936 cobalt protoporphyrin SYSTEMATIC 23542513 A 938 942 CoPP FORMULA 23542513 T 0 41 5-Hydroxy-3,6,7,8,3'4'-hexamethoxyflavone SYSTEMATIC 23542513 T 51 63 nitric oxide SYSTEMATIC 23542608 A 0 6 Carbon SYSTEMATIC 23542608 A 333 339 carbon SYSTEMATIC 23542652 A 1128 1137 estrogens FAMILY 23542652 A 210 213 EE2 ABBREVIATION 23542652 A 24 45 17-α-ethinylestradiol SYSTEMATIC 23542652 A 369 372 EE2 ABBREVIATION 23542652 A 420 423 EE2 ABBREVIATION 23542652 A 47 50 EE2 ABBREVIATION 23542652 A 528 537 estradiol TRIVIAL 23542652 A 563 566 EE2 ABBREVIATION 23542652 A 619 622 EE2 ABBREVIATION 23542652 A 750 753 EE2 ABBREVIATION 23542652 T 15 36 17-α-ethinylestradiol SYSTEMATIC 23542652 T 38 41 EE2 ABBREVIATION 23543321 A 0 10 Polyamines FAMILY 23543321 A 1100 1109 polyamine FAMILY 23543321 A 1490 1500 polyamines FAMILY 23543321 A 176 196 S-adenosylmethionine TRIVIAL 23543321 A 243 252 polyamine FAMILY 23543321 T 38 58 S-adenosylmethionine TRIVIAL 23543413 A 0 9 Cisplatin TRIVIAL 23543413 A 1071 1079 platinum SYSTEMATIC 23543413 A 1099 1105 copper SYSTEMATIC 23543413 A 11 15 cDDP ABBREVIATION 23543413 A 1218 1226 platinum SYSTEMATIC 23543413 A 1560 1566 copper SYSTEMATIC 23543413 A 313 319 copper SYSTEMATIC 23543413 A 364 368 cDDP ABBREVIATION 23543413 A 763 767 cDDP ABBREVIATION 23543413 A 820 826 copper SYSTEMATIC 23543413 A 886 890 cDDP ABBREVIATION 23543413 A 958 960 Pt FORMULA 23543413 T 62 64 Cu FORMULA 23543413 T 80 82 Pt FORMULA 23543460 A 0 11 Radioiodide SYSTEMATIC 23543460 A 1194 1200 (131)I FORMULA 23543460 A 13 19 (131)I FORMULA 23543460 A 1429 1435 (131)I FORMULA 23543460 A 1569 1575 (131)I FORMULA 23543460 A 545 551 (131)I FORMULA 23543460 A 604 610 (131)I FORMULA 23543460 A 677 683 (131)I FORMULA 23543460 A 833 836 MTT ABBREVIATION 23543460 A 844 855 Radioiodide SYSTEMATIC 23543460 T 0 11 Radioiodide SYSTEMATIC 23544667 A 812 820 hydroxyl SYSTEMATIC 23544667 A 838 846 sulfates FAMILY 23544698 A 270 283 (NaNO3,1H2O)x FORMULA 23544698 A 528 541 (NaNO3,nH2O)3 FORMULA 23544698 A 74 79 NaNO3 SYSTEMATIC 23544698 A 88 102 (NaNO3, nH2O)x FORMULA 23544698 T 150 166 Hydrated Nitrate SYSTEMATIC 23545002 A 121 134 1,3-diketones FAMILY 23545002 A 35 40 steel TRIVIAL 23545002 A 407 420 1,3-diketones FAMILY 23545002 A 480 484 iron SYSTEMATIC 23545002 A 485 491 diketo SYSTEMATIC 23545002 A 565 575 1,3 diketo SYSTEMATIC 23545002 A 871 875 iron SYSTEMATIC 23545002 T 90 95 steel TRIVIAL 23545108 A 22 32 nucleoside FAMILY 23545108 T 35 45 nucleoside FAMILY 23545161 A 0 13 Acetaminophen TRIVIAL 23545161 A 1283 1299 prostaglandin E2 TRIVIAL 23545161 A 1318 1331 acetaminophen TRIVIAL 23545161 A 1370 1383 acetaminophen TRIVIAL 23545161 A 1396 1403 aspirin TRIVIAL 23545161 A 1566 1582 prostaglandin E2 TRIVIAL 23545161 A 171 184 acetaminophen TRIVIAL 23545161 A 346 359 prostaglandin FAMILY 23545161 A 722 737 prostaglandin E FAMILY 23545161 A 857 870 acetaminophen TRIVIAL 23545161 A 979 992 acetaminophen TRIVIAL 23545161 T 0 13 Acetaminophen TRIVIAL 23545348 A 892 895 ACh ABBREVIATION 23545348 A 913 916 KCl FORMULA 23545348 A 977 990 acetylcholine SYSTEMATIC 23545458 T 6 14 saponins FAMILY 23545806 A 1090 1099 methylone TRIVIAL 23545806 A 1132 1141 methylone TRIVIAL 23545806 A 263 272 methylone TRIVIAL 23545806 A 362 371 methylone TRIVIAL 23545806 A 37 46 methylone TRIVIAL 23545806 A 471 493 dihydroxymethcathinone SYSTEMATIC 23545806 A 48 75 methylenedioxymethcathinone SYSTEMATIC 23545806 A 526 545 N-hydroxy-methylone SYSTEMATIC 23545806 A 566 583 dihydro-methylone SYSTEMATIC 23545806 T 44 53 Methylone TRIVIAL 23545999 A 139 213 7-(2,3-dihydroxy-3-methylbutoxy)-3,5-dimethoxy-3',4'-methylenedioxyflavone SYSTEMATIC 23545999 A 21 76 5,8-dihydroxy-3,7-dimethoxy-3',4'-methylenedioxyflavone SYSTEMATIC 23545999 A 219 281 7-(2,3-dihydroxy-3-methylbutoxy)-3,3',4',5-tetramethoxyflavone SYSTEMATIC 23545999 A 291 355 7-(2,3-dihydroxy-3-methylbutoxy)-3,3',4',5,8-pentamethoxyflavone SYSTEMATIC 23545999 A 437 447 flavonoids FAMILY 23545999 A 463 505 3,4',5-trihydroxy-3',7,8-trimethoxyflavone SYSTEMATIC 23545999 A 511 562 5,7-dihydroxy-3-methoxy-3',4'-methylenedioxyflavone SYSTEMATIC 23545999 A 568 607 4',5,7-trihydroxy-3,3'-dimethoxyflavone SYSTEMATIC 23545999 A 613 656 4',7-dihydroxy-3,3',5,8-tetramethoxyflavone SYSTEMATIC 23545999 A 662 701 4',7-dihydroxy-3,3',5-trimethoxyflavone SYSTEMATIC 23545999 A 712 754 4',5,7-trihydroxy-3,3',8-trimethoxyflavone SYSTEMATIC 23545999 A 82 133 7-hydroxy-3,5-dimethoxy-3',4'-methylenedioxyflavone SYSTEMATIC 23545999 A 9 19 flavonoids FAMILY 23545999 T 22 32 Flavonoids FAMILY 23546003 A 0 11 Quinoxaline SYSTEMATIC 23546003 A 31 48 bis(fluoromethyl) SYSTEMATIC 23546003 A 422 433 quinoxaline SYSTEMATIC 23546003 A 488 498 halomethyl FAMILY 23546003 A 50 67 bis(chloromethyl) SYSTEMATIC 23546003 A 72 87 bis(iodomethyl) SYSTEMATIC 23546003 T 13 43 2,3-Bis(halomethyl)quinoxaline FAMILY 23546004 A 131 137 aldose FAMILY 23546004 A 187 204 acylated sucroses FAMILY 23546004 A 206 218 mumeoses F-J MULTIPLE 23546004 A 436 442 aldose FAMILY 23546004 A 477 497 Acylated quinic acid FAMILY 23546004 A 611 617 aldose FAMILY 23546004 A 644 657 mumeic acid-A TRIVIAL 23546004 T 42 59 Acylated Sucroses FAMILY 23546395 A 1085 1096 gallic acid TRIVIAL 23546395 A 1101 1116 (-)-epicatechin SYSTEMATIC 23546395 A 568 584 cyclophosphamide TRIVIAL 23546395 A 934 953 Thiobarbituric acid TRIVIAL 23546525 A 0 14 Azidoacetylene SYSTEMATIC 23546525 A 238 252 azidoacetylene SYSTEMATIC 23546525 T 0 14 Azidoacetylene SYSTEMATIC 23546600 A 1379 1387 androgen FAMILY 23546600 A 1634 1642 androgen FAMILY 23546600 A 256 264 androgen FAMILY 23546600 A 440 448 androgen FAMILY 23546600 T 115 123 androgen FAMILY 23546601 A 1017 1026 tamoxifen TRIVIAL 23546601 A 1074 1083 tamoxifen TRIVIAL 23546601 A 1111 1120 tamoxifen TRIVIAL 23546601 A 1317 1325 estrogen FAMILY 23546601 A 1509 1518 tamoxifen TRIVIAL 23546601 A 1595 1604 tamoxifen TRIVIAL 23546601 A 176 185 tamoxifen TRIVIAL 23546601 A 22 31 tamoxifen TRIVIAL 23546601 A 231 240 tamoxifen TRIVIAL 23546601 A 427 436 tamoxifen TRIVIAL 23546601 A 577 586 tamoxifen TRIVIAL 23546601 A 672 681 tamoxifen TRIVIAL 23546601 A 708 717 tamoxifen TRIVIAL 23546601 A 754 763 tamoxifen TRIVIAL 23546601 A 981 990 tamoxifen TRIVIAL 23546601 T 0 8 Estrogen FAMILY 23546601 T 52 61 Tamoxifen TRIVIAL 23546601 T 77 85 Estrogen FAMILY 23546605 A 1174 1186 progesterone TRIVIAL 23546605 A 1358 1371 estradiol-17β SYSTEMATIC 23546605 A 513 521 estrogen FAMILY 23546867 A 673 679 oxygen SYSTEMATIC 23546879 A 1107 1108 O FORMULA 23546879 A 1159 1165 GalNAc FORMULA 23546879 A 1180 1186 GalNAc FORMULA 23546879 A 1262 1268 GalNAc FORMULA 23546879 A 1392 1398 GalNAc FORMULA 23546879 A 1449 1450 C FORMULA 23546879 A 1472 1481 threonine TRIVIAL 23546879 A 1761 1762 O FORMULA 23546879 A 568 569 O FORMULA 23546879 A 633 641 cysteine TRIVIAL 23546879 A 647 648 N FORMULA 23546879 A 654 655 C FORMULA 23546879 A 868 869 N FORMULA 23546879 T 107 115 cysteine TRIVIAL 23546879 T 14 15 O FORMULA 23547584 A 142 151 hβ(3) Phe SYSTEMATIC 23547584 A 164 167 Phe FORMULA 23547584 A 47 55 Biphalin TRIVIAL 23547584 A 91 112 homo-β(3) amino acids FAMILY 23547584 T 50 58 Biphalin TRIVIAL 23547652 A 212 227 hydroxamic acid SYSTEMATIC 23547652 A 337 362 3-hydroxypyridin-2-thione SYSTEMATIC 23547652 A 364 369 3-HPT SYSTEMATIC 23547652 A 427 432 3-HPT SYSTEMATIC 23547652 A 47 51 zinc SYSTEMATIC 23547652 A 519 524 3-HPT SYSTEMATIC 23547652 A 601 605 3HPT SYSTEMATIC 23547652 T 0 25 3-Hydroxypyridin-2-thione SYSTEMATIC 23547652 T 35 39 Zinc SYSTEMATIC 23547706 A 123 130 PI-1833 IDENTIFIER 23547706 A 401 408 PI-1840 IDENTIFIER 23547706 A 482 487 amide FAMILY 23547706 A 505 511 phenyl SYSTEMATIC 23547706 A 584 590 propyl SYSTEMATIC 23547706 A 594 599 butyl SYSTEMATIC 23547706 A 662 674 meta-pyridyl SYSTEMATIC 23547706 A 94 119 oxadiazole-isopropylamide FAMILY 23547706 T 0 26 Oxadiazole-isopropylamides FAMILY 23547757 A 20 32 belactosin A TRIVIAL 23547757 A 44 62 trans-cyclopropane SYSTEMATIC 23547757 A 464 480 cis-cyclopropane SYSTEMATIC 23547757 A 938 947 threonine TRIVIAL 23547757 A 964 973 β-lactone SYSTEMATIC 23547757 T 56 72 Cis-Cyclopropane SYSTEMATIC 23547757 T 83 95 Belactosin A TRIVIAL 23547776 A 483 493 LDN-212854 IDENTIFIER 23547776 A 689 699 LDN-212854 IDENTIFIER 23547776 A 898 908 LDN-212854 IDENTIFIER 23547786 A 100 103 PGS ABBREVIATION 23547786 A 131 168 dodecyl triphenyl phosphonium bromide SYSTEMATIC 23547786 A 170 173 DTP ABBREVIATION 23547786 A 182 185 DTP ABBREVIATION 23547786 A 186 189 PGS ABBREVIATION 23547786 A 350 353 DTP ABBREVIATION 23547786 A 390 393 PGS ABBREVIATION 23547786 A 438 441 DTP ABBREVIATION 23547786 A 442 445 PGS ABBREVIATION 23547786 A 45 72 quaternary phosphonium salt FAMILY 23547786 A 482 485 PGS ABBREVIATION 23547786 A 490 493 DTP ABBREVIATION 23547786 A 638 641 PGS ABBREVIATION 23547786 A 86 98 palygorskite TRIVIAL 23547786 T 18 30 palygorskite TRIVIAL 23547786 T 46 73 quaternary phosphonium salt FAMILY 23548149 A 1117 1120 Ser FORMULA 23548149 A 113 123 Fru-2,6-P2 SYSTEMATIC 23548149 A 125 150 fructose-2,6-bisphosphate SYSTEMATIC 23548149 A 1350 1360 Fru-2,6-P2 SYSTEMATIC 23548149 A 275 287 carbohydrate FAMILY 23548149 A 509 513 NaCl FORMULA 23548149 A 515 519 H2O2 FORMULA 23548149 A 538 548 anisomycin TRIVIAL 23548896 A 298 313 phosphotyrosine SYSTEMATIC 23548896 A 332 343 amino acids FAMILY 23548896 A 460 461 C FORMULA 23548896 A 63 71 tyrosine TRIVIAL 23548896 A 693 708 phosphotyrosine SYSTEMATIC 23548896 T 84 85 C FORMULA 23548974 A 1038 1045 mercury SYSTEMATIC 23548974 A 1138 1145 mercury SYSTEMATIC 23548974 A 1338 1345 mercury SYSTEMATIC 23548974 A 1466 1479 methylmercury SYSTEMATIC 23548974 A 1664 1668 PUFA ABBREVIATION 23548974 A 21 34 methylmercury SYSTEMATIC 23548974 A 319 332 methylmercury SYSTEMATIC 23548974 A 428 441 methylmercury SYSTEMATIC 23548974 A 740 747 mercury SYSTEMATIC 23548974 A 935 962 polyunsaturated fatty acids FAMILY 23548974 A 964 969 PUFAs ABBREVIATION 23548974 T 59 72 methylmercury SYSTEMATIC 23549285 A 775 787 Spongiatriol TRIVIAL 23549285 A 798 815 furanoditerpenoid FAMILY 23549285 T 0 12 Spongiatriol TRIVIAL 23549672 A 623 641 11β-hydroxysteroid FAMILY 23549672 A 712 721 cortisone TRIVIAL 23549672 A 745 753 cortisol TRIVIAL 23549672 A 788 796 cortisol TRIVIAL 23549673 A 119 131 testosterone TRIVIAL 23549673 A 203 211 androgen FAMILY 23549673 A 351 374 testosterone propionate SYSTEMATIC 23549673 A 51 60 androgens FAMILY 23550066 A 0 8 Ketamine TRIVIAL 23550066 A 1262 1270 ThioTEPA SYSTEMATIC 23550066 A 1348 1362 troleandomycin TRIVIAL 23550066 A 1441 1449 ketamine TRIVIAL 23550066 A 1658 1666 ketamine TRIVIAL 23550066 A 1750 1758 ketamine TRIVIAL 23550066 A 324 332 ketamine TRIVIAL 23550066 A 37 48 norketamine TRIVIAL 23550066 A 391 399 ketamine TRIVIAL 23550066 A 658 669 norketamine TRIVIAL 23550066 A 958 966 ketamine TRIVIAL 23550066 T 64 72 Ketamine TRIVIAL 23550656 A 0 3 CO2 FORMULA 23550656 A 1057 1058 H FORMULA 23550656 A 1061 1064 CO2 FORMULA 23550656 A 1151 1154 CO2 FORMULA 23550656 A 130 133 CO2 FORMULA 23550656 A 1314 1317 CO2 FORMULA 23550656 A 1446 1449 HCO FORMULA 23550656 A 1513 1515 CO FORMULA 23550656 A 1525 1526 H FORMULA 23550656 A 1563 1566 H2O FORMULA 23550656 A 1612 1613 H FORMULA 23550656 A 1643 1646 H2O FORMULA 23550656 A 1670 1672 CO FORMULA 23550656 A 1705 1708 HCO FORMULA 23550656 A 247 249 CO FORMULA 23550656 A 250 253 H2O FORMULA 23550656 A 344 346 CO FORMULA 23550656 A 354 356 OH FORMULA 23550656 A 381 384 H2O FORMULA 23550656 A 463 466 CO2 FORMULA 23550656 A 666 670 HOCO FORMULA 23550656 A 705 708 CO2 FORMULA 23550656 A 785 787 CO FORMULA 23550656 A 823 826 CO2 FORMULA 23550656 A 832 834 CO FORMULA 23550656 A 87 90 H2O FORMULA 23550656 A 878 882 HOCO FORMULA 23550656 A 938 948 trans-HOCO SYSTEMATIC 23550656 A 95 97 CO FORMULA 23550656 T 34 37 CO2 FORMULA 23550722 A 119 122 NO2 FORMULA 23550722 A 166 183 C6F13CH2C(O)OONO2 FORMULA 23550722 A 17 36 CxF2x+1CH2C(O)OONO2 FAMILY 23550722 A 367 382 CF3CH2C(O)OONO2 FORMULA 23550722 A 539 559 peroxy acyl nitrates FAMILY 23550722 A 74 89 CxF2x+1CH2C(O)H FAMILY 23550722 T 114 117 NO2 FORMULA 23550722 T 21 41 Peroxy Acyl Nitrates FAMILY 23550722 T 69 84 CxF2x+1CH2C(O)H FAMILY 23551856 A 1343 1355 Pioglitazone TRIVIAL 23551856 A 140 147 glucose TRIVIAL 23551856 A 161 173 pioglitazone TRIVIAL 23551856 A 175 178 TZD ABBREVIATION 23551856 A 41 53 pioglitazone TRIVIAL 23551856 A 631 643 pioglitazone TRIVIAL 23551856 A 743 755 pioglitazone TRIVIAL 23551856 A 856 868 pioglitazone TRIVIAL 23551856 T 10 22 pioglitazone TRIVIAL 23552101 A 1004 1041 phosphatidylinositol-4,5-bisphosphate SYSTEMATIC 23552101 A 1043 1052 PI(4,5)P2 FORMULA 23552101 A 1136 1145 PI(4,5)P2 FORMULA 23552101 A 157 164 glucose TRIVIAL 23552101 A 807 839 phosphatidylinositol 4-phosphate SYSTEMATIC 23552101 A 950 982 phosphatidylinositol 4-phosphate SYSTEMATIC 23552101 A 984 990 PI(4)P FORMULA 23552264 A 14 20 carbon SYSTEMATIC 23552264 T 65 71 carbon SYSTEMATIC 23552268 A 0 7 Carvone TRIVIAL 23552268 A 1204 1207 CVN ABBREVIATION 23552268 A 1209 1269 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide SYSTEMATIC 23552268 A 1288 1291 CVN ABBREVIATION 23552268 A 1445 1448 CVN ABBREVIATION 23552268 A 19 41 monocyclic monoterpene FAMILY 23552268 A 285 288 CVN ABBREVIATION 23552268 A 432 435 CVN ABBREVIATION 23552268 A 598 601 CVN ABBREVIATION 23552268 A 687 690 CVN ABBREVIATION 23552268 A 851 854 CVN ABBREVIATION 23552268 A 9 12 CVN ABBREVIATION 23552268 T 33 40 carvone TRIVIAL 23552398 A 1286 1292 oxygen SYSTEMATIC 23552398 A 1398 1401 C-O FORMULA 23552398 A 151 159 hydrogen SYSTEMATIC 23552398 A 333 336 CO2 FORMULA 23552398 A 340 347 Pt(111) FORMULA 23552398 A 373 376 CO2 FORMULA 23552398 A 398 402 COOH FORMULA 23552398 A 405 407 CO FORMULA 23552398 A 410 413 H2O FORMULA 23552398 A 416 419 COH FORMULA 23552398 A 438 439 C FORMULA 23552398 A 442 445 H2O FORMULA 23552398 A 562 564 CO FORMULA 23552398 A 569 572 COH FORMULA 23552398 A 674 677 C-O FORMULA 23552398 A 77 80 CO2 FORMULA 23552398 A 84 91 Pt(111) FORMULA 23552398 T 26 33 Pt(111) FORMULA 23552398 T 9 12 CO2 FORMULA 23552482 A 1298 1300 RX FAMILY 23552482 A 1640 1651 cyclohexane SYSTEMATIC 23552482 A 1707 1712 ether SYSTEMATIC 23552482 A 1725 1731 phenol SYSTEMATIC 23552482 A 1733 1751 allyl phenyl ether SYSTEMATIC 23552482 A 1779 1781 RO FAMILY 23552482 A 1782 1787 allyl SYSTEMATIC 23552482 A 306 316 thiophenol SYSTEMATIC 23552482 A 318 336 p-methylthiophenol SYSTEMATIC 23552482 A 341 352 thioanisole SYSTEMATIC 23552482 A 354 373 p-methylthioanisole SYSTEMATIC 23552482 A 379 385 phenol SYSTEMATIC 23552482 A 404 415 cyclohexane SYSTEMATIC 23552482 A 468 472 RX-Y FAMILY 23552482 A 478 479 O FORMULA 23552482 A 481 482 S FORMULA 23552482 A 488 489 H FORMULA 23552482 A 491 494 CH3 FORMULA 23552482 A 971 982 cyclohexane SYSTEMATIC 23552830 A 849 859 amino acid FAMILY 23552843 A 262 268 silica TRIVIAL 23552843 A 346 352 silica TRIVIAL 23552843 A 372 381 disulfide SYSTEMATIC 23552843 A 400 439 poly(2-dimethylaminoethyl methacrylate) SYSTEMATIC 23552843 A 441 448 PDMAEMA ABBREVIATION 23552843 A 856 865 disulfide SYSTEMATIC 23552843 A 890 897 PDMAEMA ABBREVIATION 23552843 A 940 947 PDMAEMA ABBREVIATION 23552843 T 24 63 poly(2-dimethylaminoethyl methacrylate) SYSTEMATIC 23552843 T 90 96 silica TRIVIAL 23552852 A 1011 1022 flusilazole TRIVIAL 23552852 A 1141 1152 fluconazole TRIVIAL 23552852 A 233 239 azoles FAMILY 23552852 A 26 31 azole FAMILY 23552852 A 653 664 triadimefon TRIVIAL 23552852 A 669 677 imazalil TRIVIAL 23552852 A 688 699 triadimefon TRIVIAL 23552852 A 701 709 imazalil TRIVIAL 23552852 A 735 746 fluconazole TRIVIAL 23552852 A 942 953 triadimefon TRIVIAL 23552852 A 955 963 imazalil TRIVIAL 23552852 A 965 976 triadimenol TRIVIAL 23552852 A 978 991 cyproconazole TRIVIAL 23552852 A 993 1005 tebuconazole TRIVIAL 23552852 T 23 28 azole FAMILY 23552899 A 172 175 ZnO FORMULA 23552899 A 189 197 graphene TRIVIAL 23552899 A 353 361 graphene TRIVIAL 23552899 A 66 77 metal oxide FAMILY 23552899 A 91 99 graphene TRIVIAL 23552899 T 66 69 ZnO FORMULA 23552899 T 83 91 graphene TRIVIAL 23552908 A 136 139 DFA ABBREVIATION 23552908 A 177 184 benzene SYSTEMATIC 23552908 A 200 207 benzene SYSTEMATIC 23552908 A 333 342 acetylene SYSTEMATIC 23552908 A 378 388 ferrocenes FAMILY 23552908 A 40 61 diferrocenylacetylene SYSTEMATIC 23552908 A 593 596 DFA ABBREVIATION 23552908 A 63 66 DFA ABBREVIATION 23552908 A 804 807 DFA ABBREVIATION 23552908 A 84 91 benzene SYSTEMATIC 23552908 A 923 932 ferrocene TRIVIAL 23552908 A 95 102 Au(111) FORMULA 23552908 A 972 988 cyclopentadienyl SYSTEMATIC 23552908 T 14 35 diferrocenylacetylene SYSTEMATIC 23552908 T 39 46 Au(111) FORMULA 23553560 A 0 8 Axitinib TRIVIAL 23553560 A 1249 1257 axitinib TRIVIAL 23553560 A 1326 1334 axitinib TRIVIAL 23553560 A 180 188 Axitinib TRIVIAL 23553560 A 474 482 axitinib TRIVIAL 23553560 T 0 8 Axitinib TRIVIAL 23553595 A 437 459 fluticasone propionate SYSTEMATIC 23553595 A 504 510 Diskus TRIVIAL 23553595 A 819 825 Diskus TRIVIAL 23553632 A 458 464 biotin TRIVIAL 23553632 A 735 741 biotin TRIVIAL 23553632 A 815 816 N FORMULA 23553632 A 822 823 C FORMULA 23553655 A 1003 1012 nilotinib TRIVIAL 23553655 A 1014 1023 dasatinib TRIVIAL 23553655 A 1029 1038 bosutinib TRIVIAL 23553655 A 1322 1330 imatinib TRIVIAL 23553655 A 1332 1341 nilotinib TRIVIAL 23553655 A 1343 1352 dasatinib TRIVIAL 23553655 A 1358 1367 bosutinib TRIVIAL 23553655 A 153 161 imatinib TRIVIAL 23553655 A 163 172 nilotinib TRIVIAL 23553655 A 174 183 dasatinib TRIVIAL 23553655 A 189 198 bosutinib TRIVIAL 23553655 A 42 50 tyrosine TRIVIAL 23553655 A 993 1001 imatinib TRIVIAL 23553655 T 91 99 Tyrosine TRIVIAL 23553677 A 183 189 silver SYSTEMATIC 23553677 A 360 366 silver SYSTEMATIC 23553677 T 116 122 Silver SYSTEMATIC 23553679 A 1424 1434 gabapentin TRIVIAL 23553679 A 437 447 gabapentin TRIVIAL 23553679 A 503 513 gabapentin TRIVIAL 23553679 A 676 686 gabapentin TRIVIAL 23553679 A 811 821 gabapentin TRIVIAL 23553679 T 83 93 Gabapentin TRIVIAL 23553708 A 1127 1137 sildenafil TRIVIAL 23553708 A 1267 1277 sildenafil TRIVIAL 23553708 A 162 172 sildenafil TRIVIAL 23553708 A 43 53 sildenafil TRIVIAL 23553708 A 553 563 sildenafil TRIVIAL 23553708 A 633 643 sildenafil TRIVIAL 23553708 A 818 828 sildenafil TRIVIAL 23553708 A 979 989 sildenafil TRIVIAL 23553708 T 10 20 Sildenafil TRIVIAL 23553811 A 1163 1170 alcohol FAMILY 23553811 A 1354 1362 warfarin TRIVIAL 23553811 A 1405 1416 clopidogrel TRIVIAL 23553811 A 1422 1429 aspirin TRIVIAL 23553811 A 1485 1495 dabigatran TRIVIAL 23553811 A 1497 1508 rivaroxaban TRIVIAL 23553811 A 1514 1522 apixaban TRIVIAL 23553811 A 1524 1535 Vernakalant TRIVIAL 23553811 A 1666 1677 dronedarone TRIVIAL 23553811 A 1852 1863 aldosterone TRIVIAL 23553811 A 1872 1879 statins FAMILY 23553811 A 1885 1912 polyunsaturated fatty acids FAMILY 23553905 A 761 773 Alizarin red TRIVIAL 23553905 A 801 812 Alcian blue TRIVIAL 23553961 A 10 12 CO FORMULA 23553961 A 102 104 Pt FORMULA 23553961 A 297 299 Pt FORMULA 23553961 A 322 323 O FORMULA 23553961 A 353 359 oxides FAMILY 23553961 A 86 88 CO FORMULA 23553961 T 17 19 CO FORMULA 23553961 T 48 50 Pt FORMULA 23554029 A 797 812 malondialdehyde TRIVIAL 23554029 A 852 862 superoxide TRIVIAL 23554029 A 877 888 glutathione TRIVIAL 23554215 A 150 161 fluoroximes FAMILY 23554215 A 358 366 fluorine SYSTEMATIC 23554215 A 371 379 nitrogen SYSTEMATIC 23554215 T 76 87 fluoroximes FAMILY 23554335 A 1127 1145 2,4-dinitroaniline SYSTEMATIC 23554335 A 1324 1341 2,4-dinitrophenyl SYSTEMATIC 23554335 A 306 319 dodecanethiol SYSTEMATIC 23554335 A 323 325 Pt FORMULA 23554335 A 47 64 2,4-dinitrophenyl SYSTEMATIC 23554335 A 518 520 CH FORMULA 23554335 A 618 636 2,4-dinitroaniline SYSTEMATIC 23554335 A 692 694 CH FORMULA 23554335 T 51 68 2,4-dinitrophenyl SYSTEMATIC 23556445 A 250 261 hydroxyurea SYSTEMATIC 23556445 T 91 102 hydroxyurea SYSTEMATIC 23556446 T 15 18 ATP ABBREVIATION 23556448 A 1225 1240 methamphetamine TRIVIAL 23556448 A 1408 1423 methamphetamine TRIVIAL 23556448 A 1552 1567 methamphetamine TRIVIAL 23556448 A 360 375 methamphetamine TRIVIAL 23556448 A 388 403 methamphetamine TRIVIAL 23556448 A 549 564 methamphetamine TRIVIAL 23556448 A 989 1004 methamphetamine TRIVIAL 23556448 T 51 66 methamphetamine TRIVIAL 23557487 A 1040 1051 nitric acid SYSTEMATIC 23557487 A 1066 1068 OH FORMULA 23557487 A 1094 1097 NO2 FORMULA 23557487 A 1774 1785 nitric acid SYSTEMATIC 23557487 A 373 384 nitric acid SYSTEMATIC 23557487 A 57 68 nitric acid SYSTEMATIC 23557487 A 70 74 HNO3 FORMULA 23557487 T 39 43 HNO3 FORMULA 23557931 A 100 103 MPA ABBREVIATION 23557931 A 1041 1044 MPA ABBREVIATION 23557931 A 1046 1049 MPA ABBREVIATION 23557931 A 1464 1467 MPA ABBREVIATION 23557931 A 197 200 MPA ABBREVIATION 23557931 A 447 450 MPA ABBREVIATION 23557931 A 535 538 MPA ABBREVIATION 23557931 A 81 98 mycophenolic acid TRIVIAL 23557931 A 924 936 cyclosporine TRIVIAL 23557931 A 940 950 tacrolimus TRIVIAL 23557931 T 35 52 mycophenolic acid TRIVIAL 23557933 A 1395 1398 RES ABBREVIATION 23557933 A 1621 1624 RES ABBREVIATION 23557933 A 1744 1747 RES ABBREVIATION 23557933 A 234 237 RES ABBREVIATION 23557933 A 33 44 resveratrol TRIVIAL 23557933 A 431 434 RES ABBREVIATION 23557933 A 46 49 RES ABBREVIATION 23557933 A 468 471 RES ABBREVIATION 23557933 A 705 708 RES ABBREVIATION 23557933 A 751 754 RES ABBREVIATION 23557933 A 916 919 RES ABBREVIATION 23557933 A 964 971 glucose TRIVIAL 23557933 T 57 68 resveratrol TRIVIAL 23558233 A 105 109 MPTP ABBREVIATION 23558233 A 1209 1213 MPTP ABBREVIATION 23558233 A 251 255 MPTP ABBREVIATION 23558233 A 358 366 dopamine TRIVIAL 23558233 A 393 398 DOPAC ABBREVIATION 23558233 A 403 406 HVA ABBREVIATION 23558233 A 412 421 serotonin TRIVIAL 23558233 A 442 449 5-HIAAA ABBREVIATION 23558233 A 505 510 DOPAC ABBREVIATION 23558233 A 518 521 HVA ABBREVIATION 23558233 A 542 550 tyrosine TRIVIAL 23558233 A 612 616 iron SYSTEMATIC 23558233 A 666 674 dopamine TRIVIAL 23558233 A 774 778 MPTP ABBREVIATION 23558233 A 780 789 Serotonin TRIVIAL 23558233 A 884 888 MPTP ABBREVIATION 23558233 A 898 903 DOPAC ABBREVIATION 23558233 A 905 908 HVA ABBREVIATION 23558233 T 41 45 MPTP ABBREVIATION 23558236 A 257 260 MTT ABBREVIATION 23558236 A 37 50 rotundic acid TRIVIAL 23558236 T 62 75 rotundic acid TRIVIAL 23558446 A 69 77 tyrosine TRIVIAL 23558646 A 201 209 melamine TRIVIAL 23558646 A 214 237 N(3)-alkylated xanthine FAMILY 23558646 T 117 125 melamine TRIVIAL 23558646 T 126 134 xanthine TRIVIAL 23558646 T 15 16 H FORMULA 23558682 A 1055 1063 arginine TRIVIAL 23558682 A 1243 1251 carbonyl FAMILY 23558682 A 1292 1300 hydrogen SYSTEMATIC 23558682 A 1328 1337 histidine TRIVIAL 23558682 A 1380 1388 cysteine TRIVIAL 23558682 A 267 275 cysteine TRIVIAL 23558682 A 607 608 N FORMULA 23558682 A 683 691 cysteine TRIVIAL 23558682 A 772 777 sugar FAMILY 23558682 T 96 104 cysteine TRIVIAL 23558686 A 562 563 C FORMULA 23558747 A 11 17 methyl SYSTEMATIC 23558747 A 164 170 methyl SYSTEMATIC 23558747 A 634 635 N FORMULA 23558747 T 73 79 methyl SYSTEMATIC 23559221 A 1096 1103 glucose TRIVIAL 23559221 A 1193 1200 glucose TRIVIAL 23559221 A 1233 1240 glucose TRIVIAL 23559221 A 1373 1380 glucose TRIVIAL 23559221 A 140 147 glucose TRIVIAL 23559221 A 1481 1488 glucose TRIVIAL 23559221 A 1531 1538 glucose TRIVIAL 23559221 A 1657 1664 glucose TRIVIAL 23559221 A 238 245 glucose TRIVIAL 23559221 A 495 502 glucose TRIVIAL 23559221 A 56 63 glucose TRIVIAL 23559221 A 583 590 glucose TRIVIAL 23559221 A 617 624 glucose TRIVIAL 23559221 A 920 927 glucose TRIVIAL 23559221 T 0 7 Glucose TRIVIAL 23559436 A 161 173 hydrocarbons FAMILY 23559436 A 193 199 oxygen SYSTEMATIC 23559436 A 26 34 peroxide SYSTEMATIC 23559436 A 462 476 alkyl peroxide FAMILY 23559436 A 515 516 H FORMULA 23559436 A 531 559 (di)unsaturated hydrocarbons FAMILY 23559436 T 17 25 Peroxide SYSTEMATIC 23560557 A 1481 1494 catecholamine TRIVIAL 23560844 A 1031 1038 phospho SYSTEMATIC 23560844 A 1098 1105 phospho SYSTEMATIC 23560844 A 1245 1258 pThr-Glu-pTyr FORMULA 23560844 A 1281 1284 Lys FORMULA 23560844 A 1292 1295 Arg FORMULA 23560844 A 1374 1377 Gln FORMULA 23560844 A 1385 1388 Arg FORMULA 23560844 A 1466 1469 Arg FORMULA 23560844 A 1486 1489 Glu FORMULA 23560844 A 1508 1515 phospho SYSTEMATIC 23560844 A 1553 1560 phospho SYSTEMATIC 23560844 A 428 431 Thr FORMULA 23560844 A 439 442 Tyr FORMULA 23560989 A 0 21 Poly(ethylene glycol) SYSTEMATIC 23560989 A 217 252 2-(dimethylamino)ethyl methacrylate SYSTEMATIC 23560989 A 23 26 PEG ABBREVIATION 23560989 A 254 260 DMAEMA ABBREVIATION 23560989 A 266 296 ethylene glycol dimethacrylate SYSTEMATIC 23560989 A 298 303 EGDMA ABBREVIATION 23561072 A 128 131 DNJ ABBREVIATION 23561072 A 193 196 DNJ ABBREVIATION 23561072 A 286 289 DNJ ABBREVIATION 23561072 A 42 60 1-deoxynojirimycin SYSTEMATIC 23561072 A 452 455 DNJ ABBREVIATION 23561072 A 552 567 triacylglycerol FAMILY 23561072 A 62 65 DNJ ABBREVIATION 23561072 A 759 762 DNJ ABBREVIATION 23561072 A 797 800 DNJ ABBREVIATION 23561072 A 909 912 DNJ ABBREVIATION 23561075 A 0 16 Proanthocyanidin FAMILY 23561075 A 293 301 Catechin TRIVIAL 23561075 A 306 321 (epi)afzelechin TRIVIAL 23561075 A 337 348 flavan-3-ol FAMILY 23561075 A 563 575 flavan-3-ols FAMILY 23561075 A 630 652 catechin-7-O-glucoside SYSTEMATIC 23561075 T 0 16 Proanthocyanidin FAMILY 23561075 T 63 83 catechin-O-glucoside SYSTEMATIC 23561076 A 437 448 anthocyanin FAMILY 23561076 A 44 55 anthocyanin FAMILY 23561076 A 478 489 anthocyanin FAMILY 23561076 A 665 676 anthocyanin FAMILY 23561076 A 719 730 anthocyanin FAMILY 23561076 T 64 76 anthocyanins FAMILY 23561079 A 316 324 nitrogen SYSTEMATIC 23561079 A 466 474 nitrogen SYSTEMATIC 23561089 A 22 30 phenolic FAMILY 23561089 A 306 318 polyphenolic FAMILY 23561089 A 394 402 methanol SYSTEMATIC 23561089 A 404 411 ethanol SYSTEMATIC 23561089 A 549 557 methanol SYSTEMATIC 23561089 A 597 608 Gallic acid TRIVIAL 23561089 A 860 866 trolox TRIVIAL 23561091 A 10 22 eriocaulin A TRIVIAL 23561091 A 2 8 flavan FAMILY 23561091 A 251 259 flavones FAMILY 23561091 A 270 281 isoflavones FAMILY 23561091 A 298 308 flavonoids FAMILY 23561091 A 328 379 (2S)-3',4'-methylenedioxy-5-methoxy-7-hydroxyflavan SYSTEMATIC 23561091 A 38 61 flavone acyl glucosides FAMILY 23561091 A 385 434 hispidulin 7-O-β-d-(6-O-cinnamoyl)glucopyranoside SYSTEMATIC 23561091 A 440 491 jaceosidin 7-O-β-d-(6-O-p-coumaroyl)glucopyranoside SYSTEMATIC 23561091 A 497 553 jaceosidin 7-O-β-d-(6-O-p-hydroxybenzoyl)glucopyranoside SYSTEMATIC 23561091 A 604 614 flavonoids FAMILY 23561091 A 63 81 eriocaulosides A-C MULTIPLE 23561091 A 855 858 MTT ABBREVIATION 23561091 T 0 10 Flavonoids FAMILY 23561093 A 672 683 astaxanthin TRIVIAL 23561093 A 725 738 palmitic acid TRIVIAL 23561093 A 743 753 tocopherol FAMILY 23561093 A 828 849 eicosapentaenoic acid SYSTEMATIC 23561093 A 851 854 EPA ABBREVIATION 23561093 A 887 907 docosahexaenoic acid SYSTEMATIC 23561093 A 909 912 DHA ABBREVIATION 23561093 A 940 949 Anisidine TRIVIAL 23561093 A 954 973 thiobarbituric acid SYSTEMATIC 23561103 A 0 9 Vitamin A FAMILY 23561103 A 196 205 vitamin A FAMILY 23561103 A 484 494 β-carotene TRIVIAL 23561103 A 643 653 β-carotene TRIVIAL 23561103 A 693 703 β-carotene TRIVIAL 23561103 A 863 873 β-carotene TRIVIAL 23561103 A 984 993 vitamin A FAMILY 23561103 T 16 26 β-carotene TRIVIAL 23561109 A 722 726 DPPH ABBREVIATION 23561109 A 755 759 ABTS ABBREVIATION 23561113 A 501 514 Hoechst 33342 TRIVIAL 23561120 A 0 6 Phenol SYSTEMATIC 23561120 A 1224 1228 IPTG ABBREVIATION 23561120 A 146 153 tyrosol TRIVIAL 23561120 A 189 203 hydroxytyrosol SYSTEMATIC 23561120 A 222 228 Phenol SYSTEMATIC 23561120 A 326 330 NADH ABBREVIATION 23561120 A 335 338 FAD ABBREVIATION 23561120 A 514 520 phenol SYSTEMATIC 23561120 A 525 532 tyrosol TRIVIAL 23561120 A 539 543 IPTG ABBREVIATION 23561120 A 545 580 isopropyl-β-d-thiogalactopyranoside SYSTEMATIC 23561120 A 729 733 IPTG ABBREVIATION 23561120 A 779 785 phenol SYSTEMATIC 23561120 A 902 913 monophenols FAMILY 23561120 T 28 42 hydroxytyrosol SYSTEMATIC 23561120 T 95 101 phenol SYSTEMATIC 23561124 A 142 148 amines FAMILY 23561124 A 150 162 anthocyanins FAMILY 23561124 A 164 175 polyphenols FAMILY 23561124 A 590 595 amine SYSTEMATIC 23561124 A 702 711 histamine TRIVIAL 23561124 A 713 721 tyramine TRIVIAL 23561124 A 726 736 putrescine TRIVIAL 23561124 A 818 830 anthocyanins FAMILY 23561124 A 906 917 polyphenols FAMILY 23561124 T 23 28 amine SYSTEMATIC 23561124 T 33 43 polyphenol FAMILY 23561128 A 125 139 sodium nitrite SYSTEMATIC 23561128 A 545 551 sulfur SYSTEMATIC 23561128 A 668 675 nitrite SYSTEMATIC 23561128 A 790 796 sulfur SYSTEMATIC 23561128 T 10 17 nitrite SYSTEMATIC 23561131 A 102 111 minutin B TRIVIAL 23561131 A 1099 1113 clauslactone E TRIVIAL 23561131 A 1144 1153 minutin B TRIVIAL 23561131 A 1187 1222 8-hydroxyisocapnolactone-2',3'-diol SYSTEMATIC 23561131 A 183 192 coumarins FAMILY 23561131 A 194 245 8,4″-dihydroxy-3″,4″-dihydrocapnolactone-2',3'-diol SYSTEMATIC 23561131 A 247 282 8-hydroxyisocapnolactone-2',3'-diol SYSTEMATIC 23561131 A 284 330 8-hydroxy-3″,4″-dihydrocapnolactone-2',3'-diol SYSTEMATIC 23561131 A 336 350 clauslactone E TRIVIAL 23561131 A 375 384 minutin A TRIVIAL 23561131 A 386 395 minutin B TRIVIAL 23561131 A 397 432 8-hydroxyisocapnolactone-2',3'-diol SYSTEMATIC 23561131 A 437 451 clauslactone E TRIVIAL 23561131 A 586 636 8,4″-dihydroxy-3″4″-dihydrocapnolactone-2',3'-diol SYSTEMATIC 23561131 A 641 687 8-hydroxy-3″,4″-dihydrocapnolactone-2',3'-diol SYSTEMATIC 23561131 A 65 86 monoterpene coumarins FAMILY 23561131 A 88 97 minutin A TRIVIAL 23561131 A 887 901 clauslactone E TRIVIAL 23561131 A 903 912 minutin B TRIVIAL 23561131 A 917 952 8-hydroxyisocapnolactone-2',3'-diol SYSTEMATIC 23561131 T 17 38 monoterpene coumarins FAMILY 23561135 A 116 124 coumarin TRIVIAL 23561135 A 1163 1192 coumarinyl thiosemicarbazides FAMILY 23561135 A 271 297 7-hydroxy-4-methylcoumarin SYSTEMATIC 23561135 A 30 47 thiosemicarbazide SYSTEMATIC 23561135 A 382 400 thiosemicarbazides FAMILY 23561135 A 443 447 DPPH ABBREVIATION 23561135 A 452 462 galvinoxyl TRIVIAL 23561135 A 481 498 4-thiazolidinones FAMILY 23561135 A 52 66 thiazolidinone SYSTEMATIC 23561135 A 562 575 ascorbic acid TRIVIAL 23561135 A 787 795 coumarin TRIVIAL 23561135 A 932 949 4-thiazolidinones FAMILY 23561135 A 993 1011 thiosemicarbazides FAMILY 23561135 T 0 26 4-Methyl-7-hydroxycoumarin SYSTEMATIC 23561135 T 118 132 thiazolidinone SYSTEMATIC 23561135 T 96 113 thiosemicarbazide SYSTEMATIC 23561137 A 276 291 petroleum ether TRIVIAL 23561137 A 296 309 ethyl acetate SYSTEMATIC 23561137 A 373 375 NO FORMULA 23561137 A 634 644 lanosterol TRIVIAL 23561137 A 650 676 3β-hydroxy-8,24-dien-21-al SYSTEMATIC 23561137 A 682 692 ergosterol TRIVIAL 23561137 A 698 707 inotodiol TRIVIAL 23561137 A 713 732 ergosterol peroxide TRIVIAL 23561137 A 741 758 trametenolic acid TRIVIAL 23561137 A 773 783 ergosterol TRIVIAL 23561137 A 785 804 ergosterol peroxide TRIVIAL 23561137 A 809 826 trametenolic acid TRIVIAL 23561137 A 867 886 ergosterol peroxide TRIVIAL 23561137 A 891 908 trametenolic acid TRIVIAL 23561138 A 351 361 6-gingerol SYSTEMATIC 23561138 A 473 480 acetone SYSTEMATIC 23561138 A 530 538 gingerol TRIVIAL 23561138 A 600 608 gingerol TRIVIAL 23561138 A 685 692 ethanol SYSTEMATIC 23561138 A 718 726 gingerol TRIVIAL 23561138 A 818 825 ethanol SYSTEMATIC 23561138 A 88 98 6-Gingerol SYSTEMATIC 23561138 A 882 892 polyphenol FAMILY 23561138 A 924 934 6-gingerol SYSTEMATIC 23561138 A 936 945 6-paradol SYSTEMATIC 23561138 A 957 981 6- and 8-methyl shogaols MULTIPLE 23561139 A 583 591 vitamins FAMILY 23561139 A 596 606 acrylamide TRIVIAL 23561139 A 666 679 ascorbic acid TRIVIAL 23561139 A 694 708 glucosinolates FAMILY 23561139 A 769 779 acrylamide TRIVIAL 23561139 A 835 845 vitamins B FAMILY 23561140 A 550 561 anthocyanin FAMILY 23561140 A 618 630 anthocyanins FAMILY 23561140 A 632 652 quercetin rutinoside TRIVIAL 23561140 A 657 669 procyanidins FAMILY 23561140 A 776 788 procyanidins FAMILY 23561140 A 793 805 anthocyanins FAMILY 23561140 A 883 894 anthocyanin FAMILY 23561140 T 11 21 polyphenol FAMILY 23561141 A 1009 1020 astaxanthin TRIVIAL 23561141 A 13 24 astaxanthin TRIVIAL 23561141 A 184 195 astaxanthin TRIVIAL 23561141 A 601 612 astaxanthin TRIVIAL 23561141 A 669 680 astaxanthin TRIVIAL 23561141 A 694 705 astaxanthin TRIVIAL 23561141 A 790 801 astaxanthin TRIVIAL 23561141 A 881 892 astaxanthin TRIVIAL 23561141 A 90 101 astaxanthin TRIVIAL 23561141 A 979 990 astaxanthin TRIVIAL 23561141 T 22 33 astaxanthin TRIVIAL 23561147 A 0 10 Fatty acid FAMILY 23561147 A 170 173 FAs ABBREVIATION 23561147 A 283 286 FAs ABBREVIATION 23561147 T 60 71 fatty acids FAMILY 23561152 A 0 7 Annatto TRIVIAL 23561152 A 185 193 norbixin TRIVIAL 23561152 A 227 233 sodium SYSTEMATIC 23561152 A 454 462 Norbixin TRIVIAL 23561152 A 591 599 norbixin TRIVIAL 23561152 A 628 636 norbixin TRIVIAL 23561152 A 717 725 norbixin TRIVIAL 23561152 A 792 800 norbixin TRIVIAL 23561152 A 9 17 norbixin TRIVIAL 23561152 T 28 36 norbixin TRIVIAL 23561157 A 205 208 KOH FORMULA 23561157 A 283 294 fatty acids FAMILY 23561157 A 317 327 oleic acid TRIVIAL 23561157 A 341 349 peroxide SYSTEMATIC 23561157 A 369 371 O2 FORMULA 23561157 A 396 400 (1)H FORMULA 23561157 A 429 433 (1)H FORMULA 23561157 A 484 490 iodine SYSTEMATIC 23561157 A 569 579 oleic acid TRIVIAL 23561157 A 602 615 palmitic acid TRIVIAL 23561157 A 626 638 stearic acid TRIVIAL 23561157 A 649 667 palmitelaidic acid TRIVIAL 23561157 A 680 693 myristic acid TRIVIAL 23561158 A 1206 1209 EPA ABBREVIATION 23561158 A 1214 1217 DHA ABBREVIATION 23561158 A 1247 1250 DHA ABBREVIATION 23561158 A 1307 1310 DHA ABBREVIATION 23561158 A 1322 1326 TAGs ABBREVIATION 23561158 A 1342 1345 EPA ABBREVIATION 23561158 A 1701 1705 TAGs ABBREVIATION 23561158 A 1768 1772 TAGs ABBREVIATION 23561158 A 1822 1836 diacylglycerol FAMILY 23561158 A 189 202 lithiated TAG ABBREVIATION 23561158 A 279 295 triacylglycerols FAMILY 23561158 A 297 301 TAGs ABBREVIATION 23561158 A 327 343 eicosapentaenoic SYSTEMATIC 23561158 A 345 348 EPA ABBREVIATION 23561158 A 360 381 docosahexaenoic acids FAMILY 23561158 A 383 386 DHA ABBREVIATION 23561158 A 492 502 fatty acid FAMILY 23561158 A 573 599 α,β-unsaturated fatty acid FAMILY 23561158 A 652 656 TAGs ABBREVIATION 23561158 A 719 728 Li-RACOOH FAMILY 23561158 A 729 740 R'BCHCHCOOH FAMILY 23561158 A 754 763 Li-RACOOH FAMILY 23561158 A 764 775 R'ACHCHCOOH FAMILY 23561158 A 850 854 acyl FAMILY 23561158 A 891 895 TAGs ABBREVIATION 23561158 T 51 83 polyunsaturated triacylglycerols FAMILY 23561161 A 105 116 fatty acids FAMILY 23561161 A 209 220 fatty acids FAMILY 23561161 A 25 32 calcium SYSTEMATIC 23561161 A 350 360 fatty acid FAMILY 23561161 A 409 416 calcium SYSTEMATIC 23561161 A 503 510 calcium SYSTEMATIC 23561161 A 554 563 phosphate SYSTEMATIC 23561161 A 573 580 calcium SYSTEMATIC 23561161 A 596 613 calcium gluconate SYSTEMATIC 23561161 A 615 630 calcium acetate SYSTEMATIC 23561161 A 635 640 CaCl2 FORMULA 23561161 A 693 703 fatty acid FAMILY 23561161 A 746 749 CaO FORMULA 23561161 A 754 759 CaSO4 FORMULA 23561161 A 796 803 calcium SYSTEMATIC 23561161 A 875 882 calcium SYSTEMATIC 23561161 A 933 944 fatty acids FAMILY 23561161 T 10 17 calcium SYSTEMATIC 23561161 T 42 52 fatty acid FAMILY 23561165 A 396 406 sulphydryl FAMILY 23561165 A 461 469 carbonyl FAMILY 23561169 A 293 303 β-carotene TRIVIAL 23561169 A 308 319 chlorophyll FAMILY 23561169 A 32 43 chlorophyll FAMILY 23561169 A 337 348 xanthophyll FAMILY 23561169 A 349 355 lutein TRIVIAL 23561169 A 426 432 lutein TRIVIAL 23561169 A 504 515 fatty acids FAMILY 23561169 A 521 527 C8-C16 MULTIPLE 23561169 A 590 596 lutein TRIVIAL 23561169 A 60 71 tocopherols FAMILY 23561169 A 609 615 lutein TRIVIAL 23561169 A 621 632 tocopherols FAMILY 23561169 A 761 772 tocopherols FAMILY 23561169 A 903 914 isoprenoids FAMILY 23561169 T 16 27 tocopherols FAMILY 23561171 A 1001 1013 ginsenosides FAMILY 23561171 A 294 302 saponins FAMILY 23561171 A 304 316 ginsenosides FAMILY 23561171 A 399 407 saponins FAMILY 23561171 A 464 465 H FORMULA 23561171 A 477 479 Na FORMULA 23561171 A 591 596 sugar FAMILY 23561171 A 664 672 saponins FAMILY 23561171 A 778 790 ginsenosides FAMILY 23561171 A 799 803 acyl FAMILY 23561171 A 823 830 malonyl SYSTEMATIC 23561171 A 843 845 OH FORMULA 23561171 A 850 860 di-malonyl SYSTEMATIC 23561171 A 949 964 protopanaxadiol TRIVIAL 23561171 A 979 995 protopanaxatriol TRIVIAL 23561171 T 28 36 saponins FAMILY 23561176 A 102 105 EGC ABBREVIATION 23561176 A 111 141 (-)-epigallocatechin-3-gallate TRIVIAL 23561176 A 143 147 EGCG ABBREVIATION 23561176 A 153 177 butylated hydroxytoluene SYSTEMATIC 23561176 A 179 182 BHT ABBREVIATION 23561176 A 221 240 phosphatidylcholine FAMILY 23561176 A 246 259 sphingomyelin FAMILY 23561176 A 49 61 (+)-catechin TRIVIAL 23561176 A 63 78 (-)-epicatechin SYSTEMATIC 23561176 A 645 646 H FORMULA 23561176 A 763 775 (+)-catechin TRIVIAL 23561176 A 777 792 (-)-epicatechin SYSTEMATIC 23561176 A 794 797 EGC ABBREVIATION 23561176 A 799 803 EGCG ABBREVIATION 23561176 A 80 100 (-)-epigallocatechin TRIVIAL 23561176 A 808 811 BHT ABBREVIATION 23561176 A 913 921 hydrogen SYSTEMATIC 23561176 A 935 938 BTH ABBREVIATION 23561176 T 10 19 flavonoid FAMILY 23561177 A 0 7 Folates FAMILY 23561177 A 1031 1038 folates FAMILY 23561177 A 125 132 folates FAMILY 23561177 A 318 325 folates FAMILY 23561177 A 429 436 folates FAMILY 23561177 A 561 568 Folates FAMILY 23561177 A 843 849 folate TRIVIAL 23561177 T 36 42 folate TRIVIAL 23561178 A 400 413 hydroperoxide FAMILY 23561178 A 430 443 linoleic acid TRIVIAL 23561178 A 448 462 linolenic acid TRIVIAL 23561178 A 816 827 amino acids FAMILY 23561183 A 1041 1044 PAC ABBREVIATION 23561183 A 225 243 Methylene chloride SYSTEMATIC 23561183 A 244 257 ethyl acetate SYSTEMATIC 23561183 A 258 269 formic acid SYSTEMATIC 23561183 A 311 332 vanillin hydrochloric SYSTEMATIC 23561183 A 39 47 catechin TRIVIAL 23561183 A 441 449 catechin TRIVIAL 23561183 A 451 457 PAC-A2 ABBREVIATION 23561183 A 462 468 PAC-B1 ABBREVIATION 23561183 A 49 65 proanthocyanidin FAMILY 23561183 A 663 671 Catechin TRIVIAL 23561183 A 67 70 PAC ABBREVIATION 23561183 A 673 679 PAC-A2 ABBREVIATION 23561183 A 684 690 PAC-B1 ABBREVIATION 23561183 A 753 756 PAC ABBREVIATION 23561183 A 79 85 PAC-B1 ABBREVIATION 23561185 A 1071 1081 β-carotene TRIVIAL 23561185 A 297 309 triglyceride FAMILY 23561185 A 330 342 triglyceride FAMILY 23561185 A 478 488 β-carotene TRIVIAL 23561185 A 675 691 triacylglycerols FAMILY 23561185 A 710 721 fatty acids FAMILY 23561185 A 877 887 β-carotene TRIVIAL 23561185 T 11 21 β-carotene TRIVIAL 23561188 A 1014 1042 C-20 oxygenated ent-kauranes FAMILY 23561188 A 1099 1110 Effusanin E TRIVIAL 23561188 A 1112 1120 lasiodin TRIVIAL 23561188 A 1125 1136 effusanin F TRIVIAL 23561188 A 123 130 ethanol SYSTEMATIC 23561188 A 201 216 petroleum ether TRIVIAL 23561188 A 218 231 ethyl acetate SYSTEMATIC 23561188 A 233 240 butanol SYSTEMATIC 23561188 A 280 287 ethanol SYSTEMATIC 23561188 A 486 499 ethyl acetate SYSTEMATIC 23561188 A 702 717 rosmarinic acid TRIVIAL 23561188 A 719 737 methyl rosmarinate SYSTEMATIC 23561188 A 742 751 pedalitin TRIVIAL 23561188 A 762 790 C-20 oxygenated ent-kauranes FAMILY 23561188 A 792 803 effusanin E TRIVIAL 23561188 A 805 813 lasiodin TRIVIAL 23561188 A 815 831 rabdosichuanin D TRIVIAL 23561188 A 858 869 effusanin F TRIVIAL 23561188 T 73 100 C-20 oxygenated ent-kaurane FAMILY 23561190 A 210 218 n-hexane SYSTEMATIC 23561190 A 219 231 acetonitrile SYSTEMATIC 23561190 A 265 286 cycloartenyl ferulate TRIVIAL 23561190 A 288 291 CAF ABBREVIATION 23561190 A 297 331 24-methylene cycloartanyl ferulate SYSTEMATIC 23561190 A 333 340 24-mCAF SYSTEMATIC 23561190 A 381 384 CAF ABBREVIATION 23561190 A 402 409 24-mCAF SYSTEMATIC 23561190 A 47 65 triterpene alcohol FAMILY 23561190 A 761 765 (1)H FORMULA 23561190 A 767 772 (13)C FORMULA 23561190 A 871 874 CAF ABBREVIATION 23561190 A 879 886 24-mCAF SYSTEMATIC 23561190 T 26 44 triterpene alcohol FAMILY 23561191 A 0 16 Alkylresorcinols FAMILY 23561191 A 26 34 phenolic FAMILY 23561191 A 444 469 3,5-dihydroxybenzoic acid SYSTEMATIC 23561191 A 474 514 3-(3,5-dihydroxyphenyl)-1-propanoic acid SYSTEMATIC 23561191 A 516 521 DHPPA ABBREVIATION 23561191 A 801 806 DHPPA ABBREVIATION 23561191 T 29 45 alkylresorcinols FAMILY 23561192 A 291 302 Anthocyanin FAMILY 23561192 A 30 45 sodium chloride SYSTEMATIC 23561192 A 470 476 sugars FAMILY 23561192 A 477 484 glucose TRIVIAL 23561192 A 486 494 fructose TRIVIAL 23561192 A 499 506 sucrose TRIVIAL 23561192 A 565 572 glucose TRIVIAL 23561192 A 577 585 fructose TRIVIAL 23561192 A 730 754 tartaric and malic acids MULTIPLE 23561192 A 882 886 NaCl FORMULA 23561192 T 59 63 NaCl FORMULA 23561194 A 14 20 Ca(2+) FORMULA 23561194 A 163 169 Ca(2+) FORMULA 23561194 A 352 363 oxalic acid TRIVIAL 23561194 A 383 394 quinic acid TRIVIAL 23561194 A 417 430 tartaric acid TRIVIAL 23561194 A 450 461 Oxalic acid TRIVIAL 23561194 A 489 495 Ca(2+) FORMULA 23561194 A 527 538 polyphenols FAMILY 23561194 A 575 581 Ca(2+) FORMULA 23561194 A 705 711 Ca(2+) FORMULA 23561194 A 739 750 oxalic acid TRIVIAL 23561194 A 752 763 quinic acid TRIVIAL 23561194 A 768 781 tartaric acid TRIVIAL 23561194 A 783 789 Ca(2+) FORMULA 23561194 A 794 801 oxalate SYSTEMATIC 23561194 T 14 20 Ca(2+) FORMULA 23561197 A 104 112 xanthine TRIVIAL 23561197 A 119 127 xanthine TRIVIAL 23561197 A 205 210 Fe3O4 FORMULA 23561197 A 823 836 ascorbic acid TRIVIAL 23561197 A 838 842 urea TRIVIAL 23561197 A 847 854 sucrose TRIVIAL 23561197 T 65 73 xanthine TRIVIAL 23561198 A 173 184 lactic acid TRIVIAL 23561198 A 487 493 carbon SYSTEMATIC 23561198 A 495 503 nitrogen SYSTEMATIC 23561198 A 76 82 carbon SYSTEMATIC 23561198 A 851 858 lactose TRIVIAL 23561198 A 871 879 thiamine TRIVIAL 23561198 A 896 901 FeCl3 FORMULA 23561198 A 92 100 nitrogen SYSTEMATIC 23561198 T 77 88 lactic acid TRIVIAL 23561203 A 147 157 Pyronine B TRIVIAL 23561203 A 163 169 Se(IV) FORMULA 23561203 A 194 217 sodium dodecyl sulphate SYSTEMATIC 23561203 A 219 222 SDS ABBREVIATION 23561203 A 450 456 Se(IV) FORMULA 23561203 A 505 511 Se(IV) FORMULA 23561203 A 74 82 selenium SYSTEMATIC 23561203 A 764 772 selenium SYSTEMATIC 23561203 T 44 52 selenium SYSTEMATIC 23561208 A 398 410 anthocyanins FAMILY 23561208 A 412 429 proanthocyanidins FAMILY 23561208 A 615 623 Vanillin TRIVIAL 23561208 A 625 639 syringaldehyde TRIVIAL 23561208 A 644 660 furfuryl alcohol TRIVIAL 23561208 A 781 798 proanthocyanidins FAMILY 23561213 A 104 120 chlorogenic acid TRIVIAL 23561213 A 1045 1052 neo-ChA TRIVIAL 23561213 A 1122 1141 feruloyl octopamine TRIVIAL 23561213 A 1153 1177 5-O-feruloyl quinic acid SYSTEMATIC 23561213 A 1189 1196 cis-ChA TRIVIAL 23561213 A 1208 1227 caffeoyl putrescine TRIVIAL 23561213 A 122 125 ChA ABBREVIATION 23561213 A 1239 1254 sinapoyl hexose FAMILY 23561213 A 1266 1307 N(1),N(14)-bis-(dihydrocaffeoyl) spermine SYSTEMATIC 23561213 A 128 138 crypto-ChA TRIVIAL 23561213 A 1319 1362 N(1),N(10)-bis-(dihydrocaffeoyl) spermidine SYSTEMATIC 23561213 A 1378 1425 N(1),N(5),N(14)-tris-(dihydrocaffeoyl) spermine SYSTEMATIC 23561213 A 144 151 neo-ChA TRIVIAL 23561213 A 158 169 anthocyanin FAMILY 23561213 A 17 29 caffeic acid TRIVIAL 23561213 A 177 181 HCAs ABBREVIATION 23561213 A 320 347 didydrohydroxycinnamic acid SYSTEMATIC 23561213 A 47 67 hydroxycinnamic acid SYSTEMATIC 23561213 A 629 633 HCAs ABBREVIATION 23561213 A 69 72 HCA ABBREVIATION 23561213 A 867 871 HCAs ABBREVIATION 23561213 T 13 43 (dihydro) hydroxycinnamic acid SYSTEMATIC 23561222 A 0 28 Caffeic acid phenethyl ester SYSTEMATIC 23561222 A 234 238 CAPE ABBREVIATION 23561222 A 30 34 CAPE ABBREVIATION 23561222 A 388 392 CAPE ABBREVIATION 23561222 A 40 52 caffeic acid TRIVIAL 23561222 A 576 580 CAPE ABBREVIATION 23561222 A 810 814 CAPE ABBREVIATION 23561222 T 58 86 caffeic acid phenethyl ester SYSTEMATIC 23561222 T 91 103 caffeic acid TRIVIAL 23562076 A 805 812 glucose TRIVIAL 23562245 A 123 131 cysteine TRIVIAL 23562245 A 163 178 iodoacetanilide SYSTEMATIC 23562245 A 180 183 IAA ABBREVIATION 23562245 A 192 198 (13)C7 FORMULA 23562245 A 207 222 iodoacetanilide SYSTEMATIC 23562245 A 224 230 (13)C7 FORMULA 23562245 A 231 234 IAA ABBREVIATION 23562245 A 243 259 N-ethylmaleimide SYSTEMATIC 23562245 A 261 264 NEM ABBREVIATION 23562245 A 273 275 d5 FORMULA 23562245 A 284 300 N-ethylmaleimide SYSTEMATIC 23562245 A 302 304 d5 FORMULA 23562245 A 305 308 NEM ABBREVIATION 23562245 T 36 42 (13)C7 FORMULA 23562245 T 51 66 iodoacetanilide SYSTEMATIC 23562245 T 71 73 d5 FORMULA 23562245 T 82 98 N-ethylmaleimide SYSTEMATIC 23562369 A 1109 1112 LPC ABBREVIATION 23562369 A 1163 1166 LPA ABBREVIATION 23562369 A 1322 1340 phosphatidylserine FAMILY 23562369 A 427 450 lysophosphatidylcholine FAMILY 23562369 A 452 455 LPC ABBREVIATION 23562369 A 462 483 lysophosphatidic acid TRIVIAL 23562369 A 485 488 LPA ABBREVIATION 23562369 A 494 501 choline FAMILY 23562369 A 589 602 sphingomyelin FAMILY 23562369 A 611 630 phosphatidylcholine FAMILY 23562369 A 887 891 EDTA ABBREVIATION 23562369 A 893 897 EGTA ABBREVIATION 23562369 A 903 922 1, 10-phenantroline SYSTEMATIC 23562597 A 0 12 Ilicicolin H TRIVIAL 23562597 A 395 407 ilicicolin H TRIVIAL 23562597 A 416 426 19-hydroxy SYSTEMATIC 23562597 A 495 504 4'-esters SYSTEMATIC 23562597 A 526 527 N FORMULA 23562597 A 533 534 O FORMULA 23562597 A 618 633 4',19-Diacetate SYSTEMATIC 23562597 A 638 660 19-cyclopropyl acetate SYSTEMATIC 23562597 T 96 108 ilicicolin H TRIVIAL 23562633 A 1226 1232 PEG-FA ABBREVIATION 23562633 A 1432 1438 PEG-FA ABBREVIATION 23562633 A 1577 1583 PEG-FA ABBREVIATION 23562633 A 1632 1638 PEG-FA ABBREVIATION 23562633 A 1831 1838 alanine TRIVIAL 23562633 A 1856 1865 aspartate TRIVIAL 23562633 A 1989 1992 PEG ABBREVIATION 23562633 A 2069 2075 PEG-FA ABBREVIATION 23562633 A 2183 2189 PEG-FA ABBREVIATION 23562633 A 546 565 polyethylene glycol SYSTEMATIC 23562633 A 567 570 PEG ABBREVIATION 23562633 A 579 589 folic acid TRIVIAL 23562633 A 693 696 PEG ABBREVIATION 23562633 A 714 720 PEG-FA ABBREVIATION 23562633 A 800 806 PEG-FA ABBREVIATION 23562633 A 817 823 folate TRIVIAL 23562633 A 916 919 PEG ABBREVIATION 23562633 A 935 941 PEG-FA ABBREVIATION 23562633 T 34 37 PEG ABBREVIATION 23562633 T 38 44 folate TRIVIAL 23562634 A 1319 1328 DP-TAT-59 IDENTIFIER 23562634 A 431 451 miproxifen phosphate TRIVIAL 23562634 A 453 459 TAT-59 IDENTIFIER 23562634 A 711 717 TAT-59 IDENTIFIER 23562634 A 812 818 TAT-59 IDENTIFIER 23562634 A 845 854 DP-TAT-59 IDENTIFIER 23562634 A 928 937 DP-TAT-59 IDENTIFIER 23562706 A 1045 1048 DON ABBREVIATION 23562706 A 1049 1052 NIV ABBREVIATION 23562706 A 1054 1057 DON ABBREVIATION 23562706 A 1058 1061 ZEA ABBREVIATION 23562706 A 1063 1066 DON ABBREVIATION 23562706 A 1067 1070 NIV ABBREVIATION 23562706 A 1071 1074 FB1 ABBREVIATION 23562706 A 1076 1079 DON ABBREVIATION 23562706 A 1080 1083 ZEA ABBREVIATION 23562706 A 1084 1087 FB1 ABBREVIATION 23562706 A 1089 1092 NIV ABBREVIATION 23562706 A 1093 1096 ZEA ABBREVIATION 23562706 A 1097 1100 FB1 ABBREVIATION 23562706 A 315 329 deoxynivalenol TRIVIAL 23562706 A 331 334 DON ABBREVIATION 23562706 A 337 346 nivalenol TRIVIAL 23562706 A 348 351 NIV ABBREVIATION 23562706 A 354 365 zearalenone TRIVIAL 23562706 A 367 370 ZEA ABBREVIATION 23562706 A 376 388 fumonisin B1 TRIVIAL 23562706 A 390 393 FB1 ABBREVIATION 23562706 A 533 536 MTT ABBREVIATION 23562706 A 831 834 NIV ABBREVIATION 23562706 A 835 838 DON ABBREVIATION 23562706 A 839 842 ZEA ABBREVIATION 23562706 A 843 846 FB1 ABBREVIATION 23562706 T 105 118 fumonisins B1 TRIVIAL 23562706 T 62 76 deoxynivalenol TRIVIAL 23562706 T 78 87 nivalenol TRIVIAL 23562706 T 89 100 zearalenone TRIVIAL 23562707 A 1086 1095 Sudan III TRIVIAL 23562707 A 1126 1129 azo SYSTEMATIC 23562707 A 148 163 aromatic amines FAMILY 23562707 A 206 209 azo SYSTEMATIC 23562707 A 284 297 ironporphyrin SYSTEMATIC 23562707 A 449 458 Sudan III TRIVIAL 23562707 A 46 55 Sudan III TRIVIAL 23562707 A 542 549 aniline SYSTEMATIC 23562707 A 551 562 o-anisidine TRIVIAL 23562707 A 564 589 2-methoxi-5-methylaniline SYSTEMATIC 23562707 A 591 606 4-aminobiphenyl SYSTEMATIC 23562707 A 608 625 4,4'-oxydianiline SYSTEMATIC 23562707 A 627 654 4,4'-diaminodiphenylmethane SYSTEMATIC 23562707 A 659 678 2,6-dimethylaniline SYSTEMATIC 23562707 A 775 784 Sudan III TRIVIAL 23562707 A 970 985 aromatic amines FAMILY 23562707 T 104 113 Sudan III TRIVIAL 23562707 T 56 71 aromatic amines FAMILY 23562707 T 96 99 azo SYSTEMATIC 23562765 A 0 11 Bisphenol A TRIVIAL 23562765 A 1053 1056 BPA ABBREVIATION 23562765 A 1061 1065 BPAF ABBREVIATION 23562765 A 1224 1227 BPA ABBREVIATION 23562765 A 1232 1236 BPAF ABBREVIATION 23562765 A 13 16 BPA ABBREVIATION 23562765 A 1315 1323 androgen FAMILY 23562765 A 1324 1329 R1881 IDENTIFIER 23562765 A 1331 1334 BPS ABBREVIATION 23562765 A 1404 1409 R1881 IDENTIFIER 23562765 A 1471 1474 BPA ABBREVIATION 23562765 A 1569 1582 17β-estradiol SYSTEMATIC 23562765 A 1615 1618 BPA ABBREVIATION 23562765 A 1715 1718 BPA ABBREVIATION 23562765 A 1792 1795 BPA ABBREVIATION 23562765 A 1908 1911 BPA ABBREVIATION 23562765 A 259 262 BPA ABBREVIATION 23562765 A 575 583 estrogen FAMILY 23562765 A 609 617 androgen FAMILY 23562765 A 649 652 BPA ABBREVIATION 23562765 A 711 714 BPA ABBREVIATION 23562765 A 914 917 BPA ABBREVIATION 23562765 A 927 939 bisphenol AF TRIVIAL 23562765 A 941 945 BPAF ABBREVIATION 23562765 A 951 962 bisphenol S TRIVIAL 23562765 A 964 967 BPS ABBREVIATION 23562765 T 0 11 Bisphenol A TRIVIAL 23562765 T 20 28 androgen FAMILY 23562995 A 284 287 ZnO FORMULA 23562995 A 8 11 ZnO FORMULA 23562995 T 22 25 ZnO FORMULA 23563049 A 0 10 Ketoprofen TRIVIAL 23563049 A 1220 1230 ketoprofen TRIVIAL 23563049 A 1319 1329 ketoprofen TRIVIAL 23563049 A 1404 1414 ketoprofen TRIVIAL 23563049 A 158 171 prostaglandin FAMILY 23563049 A 209 219 ketoprofen TRIVIAL 23563049 A 772 782 ketoprofen TRIVIAL 23563049 T 88 98 Ketoprofen TRIVIAL 23563055 A 1140 1169 2,2-diphenyl-1-picrylhydrazyl SYSTEMATIC 23563205 T 114 132 thiazolidinediones FAMILY 23563356 A 1005 1014 serotonin TRIVIAL 23563356 A 629 638 serotonin TRIVIAL 23563356 A 715 724 serotonin TRIVIAL 23563356 T 20 29 serotonin TRIVIAL 23564211 A 1108 1118 cetirizine TRIVIAL 23564211 A 1124 1133 verapamil TRIVIAL 23564211 A 1158 1168 cetirizine TRIVIAL 23564211 A 1238 1248 cetirizine TRIVIAL 23564211 A 1458 1468 cetirizine TRIVIAL 23564211 A 1473 1482 verapamil TRIVIAL 23564211 A 1541 1547 oxygen SYSTEMATIC 23564211 A 713 723 cetirizine TRIVIAL 23564211 A 750 759 verapamil TRIVIAL 23564211 A 802 812 cetirizine TRIVIAL 23564211 A 815 824 verapamil TRIVIAL 23564329 A 16 18 CO FORMULA 23564329 A 221 223 CO FORMULA 23564329 A 284 293 graphenes FAMILY 23564329 A 353 355 Al FORMULA 23564329 A 361 363 Si FORMULA 23564329 A 409 411 CO FORMULA 23564329 A 590 592 Al FORMULA 23564329 A 599 607 graphene TRIVIAL 23564329 A 650 652 CO FORMULA 23564329 A 728 736 graphene TRIVIAL 23564329 A 74 76 Al FORMULA 23564329 A 757 759 Al FORMULA 23564329 A 771 773 CO FORMULA 23564329 A 82 84 Si FORMULA 23564329 A 92 101 graphenes FAMILY 23564329 T 23 31 graphene TRIVIAL 23564329 T 61 63 CO FORMULA 23564329 T 71 73 Al FORMULA 23564643 A 0 30 Polybrominated diphenyl ethers FAMILY 23564643 A 111 118 PBDE-47 ABBREVIATION 23564643 A 1168 1180 6-OH-PBDE-47 SYSTEMATIC 23564643 A 1298 1310 6-OH-PBDE-47 SYSTEMATIC 23564643 A 1448 1460 6-OH-PBDE-47 SYSTEMATIC 23564643 A 148 152 PBDE ABBREVIATION 23564643 A 1660 1672 6-OH-PBDE-47 SYSTEMATIC 23564643 A 1754 1758 PBDE ABBREVIATION 23564643 A 249 261 6-OH-PBDE-47 SYSTEMATIC 23564643 A 294 301 PBDE-47 ABBREVIATION 23564643 A 32 37 PBDEs ABBREVIATION 23564643 A 392 397 PBDEs ABBREVIATION 23564643 A 469 474 PBDEs ABBREVIATION 23564643 A 54 67 organobromine FAMILY 23564643 A 616 621 PBDEs ABBREVIATION 23564643 A 755 767 6-OH-PBDE-47 SYSTEMATIC 23564643 A 797 804 PBDE-47 ABBREVIATION 23564643 A 911 923 6-OH-PBDE-47 SYSTEMATIC 23564643 T 45 52 PBDE-47 ABBREVIATION 23564646 A 1029 1033 DNCB ABBREVIATION 23564646 A 1213 1217 DNCB ABBREVIATION 23564646 A 1276 1280 CinA ABBREVIATION 23564646 A 155 161 oxygen SYSTEMATIC 23564646 A 700 708 cysteine TRIVIAL 23564646 A 719 743 2,4-dinitrochlorobenzene SYSTEMATIC 23564646 A 745 749 DNCB ABBREVIATION 23564646 A 755 769 cinnamaldehyde TRIVIAL 23564646 A 771 775 CinA ABBREVIATION 23564646 A 830 838 cysteine TRIVIAL 23564646 A 843 849 lysine TRIVIAL 23564646 A 860 883 isophorone diisocyanate SYSTEMATIC 23564646 A 885 889 IPDI ABBREVIATION 23564646 A 927 933 lysine TRIVIAL 23564646 A 944 965 trimellitic anhydride SYSTEMATIC 23564646 A 967 970 TMA ABBREVIATION 23564918 A 26 29 NH2 FORMULA 23564918 T 0 3 NH2 FORMULA 23565585 A 1019 1022 PLA ABBREVIATION 23565585 A 1023 1027 PLGA ABBREVIATION 23565585 A 214 233 polyethylene glycol SYSTEMATIC 23565585 A 235 238 PEG ABBREVIATION 23565585 A 288 295 glucose TRIVIAL 23565585 A 323 349 poly(lactide-co-glycolide) SYSTEMATIC 23565585 A 351 355 PLGA ABBREVIATION 23565585 A 360 377 poly(lactic acid) SYSTEMATIC 23565585 A 379 382 PLA ABBREVIATION 23565585 A 384 388 PLGA ABBREVIATION 23565585 A 740 743 PLA ABBREVIATION 23565585 A 754 758 PLGA ABBREVIATION 23565749 A 105 111 halide FAMILY 23565749 A 126 130 NaCl FORMULA 23565749 A 243 247 NaCl FORMULA 23565749 A 255 261 polyol FAMILY 23565749 A 275 277 Ag FORMULA 23565749 A 287 292 AgNO3 FORMULA 23565749 A 296 311 ethylene glycol SYSTEMATIC 23565749 A 346 350 AgCl FORMULA 23565749 A 38 44 polyol FAMILY 23565749 A 416 418 Ag FORMULA 23565749 A 440 442 Ag FORMULA 23565749 A 559 563 AgCl FORMULA 23565749 A 58 64 silver SYSTEMATIC 23565749 A 76 78 Ag FORMULA 23565749 T 0 15 Silver Chloride SYSTEMATIC 23565749 T 62 68 Silver SYSTEMATIC 23565753 A 0 9 Androgens FAMILY 23565753 A 1333 1341 androgen FAMILY 23565753 A 160 169 androgens FAMILY 23565753 A 18 26 androgen FAMILY 23565753 A 249 257 androgen FAMILY 23565753 A 553 561 androgen FAMILY 23565753 A 587 595 androgen FAMILY 23565753 A 808 816 androgen FAMILY 23565753 A 987 995 androgen FAMILY 23565753 T 0 8 Androgen FAMILY 23565754 A 1108 1109 N FORMULA 23565754 A 136 145 androgens FAMILY 23565754 A 155 164 androgens FAMILY 23565754 A 188 196 androgen FAMILY 23565754 A 311 320 androgens FAMILY 23565754 A 54 62 androgen FAMILY 23565754 A 579 588 androgens FAMILY 23565754 A 820 829 androgens FAMILY 23565754 T 38 46 androgen FAMILY 23565776 A 211 221 amino acid FAMILY 23565776 A 222 232 nucleotide FAMILY 23565776 A 259 272 phenylalanine TRIVIAL 23565776 A 277 286 thymidine TRIVIAL 23565776 A 300 340 saturated or unsaturated diacyl glycerol MULTIPLE 23565776 A 398 407 aminoacid FAMILY 23565776 A 591 604 phenylanaline TRIVIAL 23565776 A 605 616 amino acids FAMILY 23565776 A 652 662 nucleotide FAMILY 23565776 A 773 783 nucleotide FAMILY 23565776 T 0 10 Amino Acid FAMILY 23565776 T 11 21 nucleotide FAMILY 23565776 T 40 50 amino Acid FAMILY 23565822 A 119 129 perovskite TRIVIAL 23565822 A 142 152 perovskite TRIVIAL 23565822 A 28 34 oxygen SYSTEMATIC 23565822 A 479 483 LSCO ABBREVIATION 23565822 A 68 97 lanthanum strontium cobaltite SYSTEMATIC 23565822 A 99 103 LSCO ABBREVIATION 23565822 T 30 36 Oxygen SYSTEMATIC 23566174 A 116 124 bis-urea SYSTEMATIC 23566174 A 534 542 hydrogen SYSTEMATIC 23566174 A 83 91 hydrogen SYSTEMATIC 23566174 T 29 37 Hydrogen SYSTEMATIC 23566174 T 45 53 Bis-urea SYSTEMATIC 23566269 A 0 12 d-Amino acid FAMILY 23566269 A 1010 1038 3-hydroxy-pyridine-2(1H)-one SYSTEMATIC 23566269 A 1070 1130 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one SYSTEMATIC 23566269 A 108 128 N-methyl-d-aspartate SYSTEMATIC 23566269 A 1165 1171 MK-801 IDENTIFIER 23566269 A 165 193 4-hydroxypyridazin-3(2H)-one SYSTEMATIC 23566269 A 536 539 Tyr FORMULA 23566269 A 55 68 d-amino acids FAMILY 23566269 A 630 658 3-hydroxy-pyridine-2(1H)-one SYSTEMATIC 23566269 A 730 775 3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one SYSTEMATIC 23566269 A 79 87 d-serine TRIVIAL 23566269 A 940 968 4-hydroxypyridazin-3(2H)-one SYSTEMATIC 23566269 T 0 28 4-Hydroxypyridazin-3(2H)-one SYSTEMATIC 23566269 T 50 62 d-Amino Acid FAMILY 23566299 A 67 80 acetylcholine SYSTEMATIC 23566299 A 941 949 hydrogen SYSTEMATIC 23566299 T 75 88 Acetylcholine SYSTEMATIC 23566514 A 101 118 pyrrolopyrimidine SYSTEMATIC 23566514 A 178 191 benzimidazole SYSTEMATIC 23566514 A 212 225 benzimidazole SYSTEMATIC 23566514 A 252 277 4-amino-pyrrolopyrimidine SYSTEMATIC 23566514 A 291 301 ketophenyl SYSTEMATIC 23566514 A 340 350 ketophenyl SYSTEMATIC 23566514 A 452 485 ketophenyl pyrrolopyrimidine urea SYSTEMATIC 23566514 T 33 57 4-aminopyrrolopyrimidine SYSTEMATIC 23566899 A 628 641 acetaminophen TRIVIAL 23566899 T 144 157 acetaminophen TRIVIAL 23567034 A 1023 1031 methanol SYSTEMATIC 23567034 A 1042 1045 MTT ABBREVIATION 23567034 A 1090 1098 methanol SYSTEMATIC 23567034 A 1176 1184 methanol SYSTEMATIC 23567034 A 1442 1453 citronellol TRIVIAL 23567034 A 1458 1466 geraniol TRIVIAL 23567034 A 1510 1521 E-β-ocimene TRIVIAL 23567034 A 1582 1603 7,8-dimethoxycoumarin SYSTEMATIC 23567034 A 1608 1620 sinapic acid TRIVIAL 23567034 A 1628 1636 methanol SYSTEMATIC 23567034 A 1707 1715 methanol SYSTEMATIC 23567037 A 158 164 oxygen SYSTEMATIC 23567037 A 932 942 superoxide TRIVIAL 23567041 A 1203 1214 fluorescein TRIVIAL 23567041 A 1224 1235 Fluorescein TRIVIAL 23567041 A 1552 1563 fluorescein TRIVIAL 23567041 A 475 483 Nile red TRIVIAL 23567041 A 504 515 fluorescein TRIVIAL 23567041 A 897 908 fluorescein TRIVIAL 23567041 A 982 993 fluorescein TRIVIAL 23567045 A 254 301 N-lactobionyl-dioleoyl phosphatidylethanolamine SYSTEMATIC 23567045 A 303 311 Lac-DOPE ABBREVIATION 23567046 A 154 164 iron oxide SYSTEMATIC 23567046 A 222 224 Au FORMULA 23567046 A 660 671 doxorubicin TRIVIAL 23567046 A 673 676 DOX ABBREVIATION 23567046 A 780 783 DOX ABBREVIATION 23567046 A 928 931 DOX ABBREVIATION 23567046 T 47 58 doxorubicin TRIVIAL 23567046 T 68 78 iron oxide SYSTEMATIC 23567242 A 0 11 Bisphenol A TRIVIAL 23567242 A 1205 1208 BPA ABBREVIATION 23567242 A 1290 1293 BPA ABBREVIATION 23567242 A 13 16 BPA ABBREVIATION 23567242 A 173 176 BPA ABBREVIATION 23567242 A 267 270 BPA ABBREVIATION 23567242 A 36 49 polycarbonate FAMILY 23567242 A 430 433 BPA ABBREVIATION 23567242 A 63 68 epoxy SYSTEMATIC 23567242 A 632 635 BPA ABBREVIATION 23567242 A 681 684 BPA ABBREVIATION 23567242 A 787 790 BPA ABBREVIATION 23567242 A 837 840 BPA ABBREVIATION 23567242 T 0 11 Bisphenol A TRIVIAL 23567269 A 323 329 oxygen SYSTEMATIC 23567314 A 1223 1233 androstane TRIVIAL 23567314 A 1305 1310 PFAAs ABBREVIATION 23567314 A 155 175 perfluoroalkyl acids FAMILY 23567314 A 177 182 PFAAs ABBREVIATION 23567314 A 1928 1933 PFAAs ABBREVIATION 23567314 A 2146 2150 PFAA ABBREVIATION 23567314 A 2151 2163 carboxylates FAMILY 23567314 A 2241 2245 PFDA ABBREVIATION 23567314 A 2250 2254 PFOS ABBREVIATION 23567314 A 2309 2313 PFOA ABBREVIATION 23567314 A 30 34 PFOA ABBREVIATION 23567314 A 324 329 PFAAs ABBREVIATION 23567314 A 40 65 perfluorooctane sulfonate SYSTEMATIC 23567314 A 528 533 PFAAs ABBREVIATION 23567314 A 6 28 perfluorooctanoic acid SYSTEMATIC 23567314 A 67 71 PFOS ABBREVIATION 23567314 A 699 704 PFAAs ABBREVIATION 23567314 A 708 716 Wy14,643 IDENTIFIER 23567314 T 14 33 perfluoroalkyl acid FAMILY 23567318 A 1097 1109 carbohydrate FAMILY 23567318 A 334 335 N FORMULA 23567318 A 773 784 xylohexaose FAMILY 23567318 A 789 801 xylopentaose FAMILY 23567318 A 807 819 xylotetraose FAMILY 23567318 A 821 831 xylotriose FAMILY 23567318 A 836 845 xylobiose FAMILY 23567486 A 410 422 hydroxyethyl SYSTEMATIC 23567486 A 430 455 hydroxyethyl methacrylate SYSTEMATIC 23567486 A 457 465 HES-HEMA ABBREVIATION 23567486 A 468 480 hydroxyethyl SYSTEMATIC 23567486 A 488 500 methacrylate TRIVIAL 23567486 A 502 508 HES-MA ABBREVIATION 23567486 A 515 527 hydroxyethyl SYSTEMATIC 23567486 A 535 567 polyethylene glycol methacrylate SYSTEMATIC 23567486 A 569 581 HES-P(EG)6MA FORMULA 23567486 A 584 603 polyethylene glycol SYSTEMATIC 23567486 A 612 615 PEG ABBREVIATION 23567486 A 769 772 PEG ABBREVIATION 23567486 A 849 852 PEG ABBREVIATION 23567486 T 14 33 polyethylene glycol SYSTEMATIC 23567861 A 1384 1390 sterol FAMILY 23567861 A 1486 1498 nitric oxide SYSTEMATIC 23567861 A 1591 1592 N FORMULA 23567861 A 545 552 glucose TRIVIAL 23567861 A 632 645 triglycerides FAMILY 23567861 A 653 664 cholesterol TRIVIAL 23567861 A 681 692 fatty acids FAMILY 23567861 A 71 98 7-O-galloyl-d-sedoheptulose SYSTEMATIC 23567861 A 719 730 cholesterol TRIVIAL 23567861 A 761 772 cholesterol TRIVIAL 23567861 A 797 808 cholesterol TRIVIAL 23567861 A 819 825 oxygen SYSTEMATIC 23567861 A 845 864 thiobarbituric acid SYSTEMATIC 23567861 T 14 41 7-O-galloyl-d-sedoheptulose SYSTEMATIC 23567954 A 12 24 polysulfones FAMILY 23567954 A 300 304 iron SYSTEMATIC 23567954 A 305 314 ascorbate TRIVIAL 23567954 A 347 351 H2O2 FORMULA 23567954 A 372 383 polysulfone FAMILY 23567954 A 387 437 2,2-diallyl-1,1,3,3-tetraethylguanidinium chloride SYSTEMATIC 23567954 A 480 497 hydrogen peroxide SYSTEMATIC 23567954 A 647 658 polysulfone FAMILY 23567954 A 65 79 azanorbornenes FAMILY 23567954 A 662 688 N-benzyl-2-azanorbornene-5 SYSTEMATIC 23567954 A 81 182 2,2-diallyl-1,1,3,3-tetraethylguanidiniumchloride and tris(diethylamino)diallylaminophosphonium salts MULTIPLE 23567954 T 0 12 Polysulfones FAMILY 23567959 A 140 175 5-substituted-2-aminobenzimidazoles FAMILY 23567959 A 319 323 (1)H FORMULA 23567959 A 329 334 (13)C FORMULA 23567959 A 588 597 hydrazone FAMILY 23567959 A 768 775 acetate SYSTEMATIC 23567959 A 9 61 1,3,5-substituted-2,3-dihydro-2-imino-benzimidazoles FAMILY 23567959 A 978 987 hydrazone FAMILY 23567959 T 63 97 5-substituted-2-iminobenzimidazole FAMILY 23567999 A 1011 1017 τ-CnVA TRIVIAL 23567999 A 1230 1236 τ-CnVA TRIVIAL 23567999 A 569 575 τ-CnVA TRIVIAL 23567999 A 604 612 cysteine TRIVIAL 23567999 T 67 73 τ-CnVA TRIVIAL 23568274 A 1146 1154 tyrosine TRIVIAL 23568429 A 96 103 tritium SYSTEMATIC 23568429 T 44 51 tritium SYSTEMATIC 23568455 A 107 115 LY294002 IDENTIFIER 23568455 A 217 227 tetrazolyl SYSTEMATIC 23568455 A 60 80 phosphatidylinositol TRIVIAL 23568455 T 21 41 Phosphatidylinositol TRIVIAL 23568508 A 292 298 oxygen SYSTEMATIC 23568508 A 30 59 Rhenium(I) indolato complexes FAMILY 23568508 T 0 7 Rhenium SYSTEMATIC 23568512 A 0 10 Acrylamide TRIVIAL 23568512 A 1025 1031 AA-GSH ABBREVIATION 23568512 A 1037 1041 AAMA ABBREVIATION 23568512 A 1047 1051 GAMA ABBREVIATION 23568512 A 1129 1138 N7-GA-Gua FORMULA 23568512 A 1273 1279 AA-GSH ABBREVIATION 23568512 A 1509 1515 AA-GSH ABBREVIATION 23568512 A 1594 1603 N7-GA-Gua FORMULA 23568512 A 191 204 carbohydrates FAMILY 23568512 A 209 219 asparagine TRIVIAL 23568512 A 360 371 glycidamide TRIVIAL 23568512 A 447 485 N7-(2-carbamoyl-2-hydroxyethyl)guanine SYSTEMATIC 23568512 A 487 496 N7-GA-Gua FORMULA 23568512 A 613 624 glutathione TRIVIAL 23568512 A 626 629 GSH ABBREVIATION 23568512 A 636 639 GSH ABBREVIATION 23568512 A 711 728 mercapturic acids FAMILY 23568512 A 735 772 N-acetyl-S-(2-carbamoylethyl)cysteine SYSTEMATIC 23568512 A 774 778 AAMA ABBREVIATION 23568512 A 785 832 N-acetyl-S-(2-hydroxy-2-carbamoylethyl)cysteine SYSTEMATIC 23568512 A 834 838 GAMA ABBREVIATION 23568512 T 110 121 glycidamide TRIVIAL 23568512 T 18 28 acrylamide TRIVIAL 23568512 T 69 80 glutathione TRIVIAL 23568578 A 1022 1031 glutamine TRIVIAL 23568578 A 1097 1101 GABA ABBREVIATION 23568578 A 1103 1112 glutamine TRIVIAL 23568578 A 1118 1127 glutamate TRIVIAL 23568578 A 1202 1211 threonine TRIVIAL 23568578 A 1293 1300 alanine TRIVIAL 23568578 A 1460 1464 GABA ABBREVIATION 23568578 A 29 48 γ-aminobutyric acid SYSTEMATIC 23568578 A 419 430 amino acids FAMILY 23568578 A 50 54 GABA ABBREVIATION 23568578 A 716 726 amino acid FAMILY 23568578 A 860 864 GABA ABBREVIATION 23568578 A 929 938 glutamine TRIVIAL 23568578 T 29 40 amino acids FAMILY 23568579 A 1053 1060 cocaine TRIVIAL 23568579 A 1189 1196 cocaine TRIVIAL 23568579 A 1271 1278 cocaine TRIVIAL 23568579 A 1473 1480 cocaine TRIVIAL 23568579 A 1562 1569 cocaine TRIVIAL 23568579 A 203 210 cocaine TRIVIAL 23568579 A 508 515 cocaine TRIVIAL 23568579 A 571 578 cocaine TRIVIAL 23568579 A 98 105 cocaine TRIVIAL 23568579 T 22 29 cocaine TRIVIAL 23570266 A 51 57 silica TRIVIAL 23570266 T 40 46 silica TRIVIAL 23570328 A 275 292 4-acetamido-TEMPO SYSTEMATIC 23570328 A 303 308 TEMPO ABBREVIATION 23570328 A 311 347 2,2,6,6-tetramethylpiperidine-N-oxyl SYSTEMATIC 23570328 A 369 373 HNO3 FORMULA 23570328 A 378 381 HCl FORMULA 23570328 A 511 514 C-C FORMULA 23570328 A 86 103 benzylic alcohols FAMILY 23570394 A 268 276 graphene TRIVIAL 23570394 A 290 292 Ru FORMULA 23570394 A 322 330 graphene TRIVIAL 23570394 A 334 337 SiC FORMULA 23570394 A 339 340 O FORMULA 23570394 A 341 343 Ru FORMULA 23570394 A 354 358 SiO2 FORMULA 23570394 A 359 361 Ru FORMULA 23570394 A 397 399 Ru FORMULA 23570394 A 410 417 Pt(111) FORMULA 23570394 A 527 529 Ru FORMULA 23570394 A 594 596 Ru FORMULA 23570394 A 597 598 C FORMULA 23570394 A 61 69 graphene TRIVIAL 23570394 A 643 645 Ru FORMULA 23570394 A 707 715 graphene TRIVIAL 23570394 A 768 776 graphene TRIVIAL 23570394 T 39 47 Graphene TRIVIAL 23570451 A 285 310 poly(methyl methacrylate) SYSTEMATIC 23570451 A 312 316 PMMA ABBREVIATION 23570451 A 355 362 acetone SYSTEMATIC 23570500 A 1102 1106 (1)H FORMULA 23570500 A 1191 1196 PEO45 ABBREVIATION 23570500 A 1251 1256 PEO45 ABBREVIATION 23570500 A 1437 1448 doxorubicin TRIVIAL 23570500 A 1450 1453 DOX ABBREVIATION 23570500 A 1474 1500 fluorescein isothiocyanate TRIVIAL 23570500 A 1511 1515 FITC ABBREVIATION 23570500 A 1620 1624 FITC ABBREVIATION 23570500 A 1633 1636 DOX ABBREVIATION 23570500 A 164 209 trans-N-(2-ethoxy-1,3-dioxan-5-yl) acrylamide SYSTEMATIC 23570500 A 1802 1805 DOX ABBREVIATION 23570500 A 211 215 tNEA ABBREVIATION 23570500 A 225 245 poly(ethylene oxide) SYSTEMATIC 23570500 A 247 252 PEO45 ABBREVIATION 23570500 A 570 575 PtNEA ABBREVIATION 23570500 A 62 67 PEO45 ABBREVIATION 23570500 A 735 740 PtNEA ABBREVIATION 23570500 A 848 853 PtNEA ABBREVIATION 23570514 A 41 47 NAD(+) ABBREVIATION 23570514 A 683 694 carboxamide SYSTEMATIC 23570514 A 708 720 nicotinamide TRIVIAL 23570514 T 13 51 Thieno[3,2-d]pyrimidine-6-carboxamides FAMILY 23570533 A 1093 1099 Quartz TRIVIAL 23570533 A 171 177 lignin FAMILY 23570533 A 561 593 dodecyl 3,4,5-trihydroxybenzoate SYSTEMATIC 23570533 A 595 601 HB-C12 ABBREVIATION 23570533 A 821 827 HB-C12 ABBREVIATION 23570533 A 974 980 HB-C12 ABBREVIATION 23570552 A 0 14 Cinnamaldehyde TRIVIAL 23570552 A 434 448 cinnamaldehyde TRIVIAL 23570552 A 518 532 cinnamaldehyde TRIVIAL 23570552 A 628 642 Cinnamaldehyde TRIVIAL 23570552 T 25 39 Cinnamaldehyde TRIVIAL 23570561 A 358 362 urea TRIVIAL 23570561 A 791 795 urea TRIVIAL 23570561 T 39 43 Urea TRIVIAL 23570609 A 1076 1083 PEG-LαC ABBREVIATION 23570609 A 1236 1243 PEG-LαC ABBREVIATION 23570609 A 178 192 α-cyclodextrin TRIVIAL 23570609 A 194 213 polyethylene glycol SYSTEMATIC 23570609 A 215 218 PEG ABBREVIATION 23570609 A 249 256 lactose TRIVIAL 23570609 A 258 266 PEG-LαCs ABBREVIATION 23570609 A 350 357 PEG-LαC ABBREVIATION 23570609 A 394 397 PEG ABBREVIATION 23570609 A 464 472 PEG-LαCs ABBREVIATION 23570609 A 685 692 PEG-LαC ABBREVIATION 23570609 A 75 89 polyamidoamine FAMILY 23570609 A 779 793 α-cyclodextrin TRIVIAL 23570609 A 833 842 Lac-α-CDE ABBREVIATION 23570609 A 869 872 PEG ABBREVIATION 23570609 A 934 941 PEG-LαC ABBREVIATION 23570609 T 25 39 polyamidoamine FAMILY 23570609 T 65 68 PEG ABBREVIATION 23570609 T 70 84 α-cyclodextrin TRIVIAL 23570609 T 89 96 lactose TRIVIAL 23570839 A 227 235 n-hexane SYSTEMATIC 23570839 A 237 242 CHCl3 FORMULA 23570839 A 244 249 AcOEt FORMULA 23570839 A 251 256 CH3OH FORMULA 23570839 A 27 35 coumarin TRIVIAL 23570839 A 54 69 Daphneretusin A TRIVIAL 23570839 A 74 89 Daphneretusin B TRIVIAL 23570839 T 25 33 coumarin TRIVIAL 23570840 A 223 231 methanol SYSTEMATIC 23570840 A 266 274 n-hexane SYSTEMATIC 23570840 A 276 286 chloroform TRIVIAL 23570840 A 291 298 butanol SYSTEMATIC 23570840 A 386 413 goniolandrene-A (1), -B (2) MULTIPLE 23570840 A 445 460 goniolandrene B TRIVIAL 23570840 A 601 614 Goniothalamin TRIVIAL 23570840 T 0 21 Goniolandrene A and B MULTIPLE 23570914 A 1110 1138 caffeic acid phenethyl ester SYSTEMATIC 23570914 A 1168 1177 bleomycin FAMILY 23570914 A 380 389 bleomycin FAMILY 23570914 A 551 561 superoxide TRIVIAL 23570914 A 596 607 glutathione TRIVIAL 23570914 A 612 631 thiobarbituric acid SYSTEMATIC 23570914 A 682 691 bleomycin FAMILY 23570914 A 809 815 oxygen SYSTEMATIC 23570914 A 947 956 bleomycin FAMILY 23570914 T 116 125 bleomycin FAMILY 23570992 A 1046 1060 hydroxysteroid FAMILY 23570992 A 1147 1154 arsenic SYSTEMATIC 23570992 A 1234 1241 arsenic SYSTEMATIC 23570992 A 150 157 arsenic SYSTEMATIC 23570992 A 242 249 arsenic SYSTEMATIC 23570992 A 460 467 arsenic SYSTEMATIC 23570992 A 556 571 sodium arsenite SYSTEMATIC 23570992 A 94 101 arsenic SYSTEMATIC 23570992 T 22 29 Arsenic SYSTEMATIC 23570993 A 37 43 carbon SYSTEMATIC 23570993 T 108 114 Carbon SYSTEMATIC 23570998 A 0 9 Quercetin TRIVIAL 23570998 A 1166 1176 flavonoids FAMILY 23570998 A 1182 1187 rutin TRIVIAL 23570998 A 1192 1201 quercetin TRIVIAL 23570998 A 14 19 rutin TRIVIAL 23570998 A 141 151 flavonoids FAMILY 23570998 A 31 41 flavonoids FAMILY 23570998 A 373 383 flavonoids FAMILY 23570998 A 385 394 quercetin TRIVIAL 23570998 A 399 404 rutin TRIVIAL 23570998 A 456 465 quercetin TRIVIAL 23570998 A 470 475 rutin TRIVIAL 23570998 A 538 547 quercetin TRIVIAL 23570998 A 552 557 rutin TRIVIAL 23570998 A 704 713 Quercetin TRIVIAL 23570998 A 718 723 rutin TRIVIAL 23570998 A 928 938 flavonoids FAMILY 23570998 T 26 36 flavonoids FAMILY 23571415 A 634 652 sodium fluorescein SYSTEMATIC 23572409 A 0 12 Pomalidomide TRIVIAL 23572409 A 1010 1022 pomalidomide TRIVIAL 23572409 A 14 22 Pomalyst TRIVIAL 23572409 A 187 199 Pomalidomide TRIVIAL 23572409 A 286 299 dexamethasone TRIVIAL 23572409 A 432 444 lenalidomide TRIVIAL 23572409 A 449 459 bortezomib TRIVIAL 23572409 A 488 500 pomalidomide TRIVIAL 23572409 A 59 70 thalidomide TRIVIAL 23572409 A 754 766 Pomalidomide TRIVIAL 23572409 T 0 12 Pomalidomide TRIVIAL 23572520 A 0 1 S FORMULA 23572520 A 1051 1052 S FORMULA 23572520 A 1127 1130 GSH ABBREVIATION 23572520 A 1146 1148 NO FORMULA 23572520 A 1207 1209 NO FORMULA 23572520 A 1248 1250 NO FORMULA 23572520 A 1264 1276 nitric oxide SYSTEMATIC 23572520 A 430 441 glutathione TRIVIAL 23572520 A 555 556 S FORMULA 23572520 A 62 70 cysteine TRIVIAL 23572520 A 730 731 S FORMULA 23572520 A 998 1003 CysNO FORMULA 23572520 T 0 1 S FORMULA 23572520 T 17 28 glutathione TRIVIAL 23573957 A 24 34 E-stilbene TRIVIAL 23573957 A 281 292 prolinamide TRIVIAL 23573957 A 35 47 prolinamides FAMILY 23573990 A 1015 1018 PEO ABBREVIATION 23573990 A 102 120 polyethylene oxide SYSTEMATIC 23573990 A 1147 1150 PEO ABBREVIATION 23573990 A 122 125 PEO ABBREVIATION 23573990 A 177 180 sPS ABBREVIATION 23573990 A 348 351 sPS ABBREVIATION 23573990 A 44 68 syndiotactic polystyrene FAMILY 23573990 A 445 448 sPS ABBREVIATION 23573990 A 500 515 tetrahydrofuran SYSTEMATIC 23573990 A 535 538 PEO ABBREVIATION 23573990 A 674 682 nitrogen SYSTEMATIC 23573990 A 70 73 sPS ABBREVIATION 23573990 A 707 713 helium SYSTEMATIC 23573990 A 889 892 PEO ABBREVIATION 23573990 A 981 984 sPS ABBREVIATION 23573990 T 50 74 syndiotactic polystyrene FAMILY 23574008 A 1088 1099 C4-C-N-PEG9 NO CLASS 23574008 A 1200 1211 C4-C-N-PEG9 NO CLASS 23574008 A 1278 1289 C4-C-N-PEG9 NO CLASS 23574008 A 1343 1349 C12EO4 FORMULA 23574008 A 1363 1374 C4-C-N-PEG9 NO CLASS 23574008 A 1582 1593 C4-C-N-PEG9 NO CLASS 23574008 A 1621 1629 coumarin TRIVIAL 23574008 A 1657 1672 polyoxyethylene SYSTEMATIC 23574008 A 1758 1766 coumarin TRIVIAL 23574008 A 1803 1814 C4-C-N-PEG9 NO CLASS 23574008 A 187 195 coumarin TRIVIAL 23574008 A 1924 1939 polyoxyethylene SYSTEMATIC 23574008 A 1990 1997 PhyEO20 FORMULA 23574008 A 208 233 7-butoxy-2H-chromen-2-one SYSTEMATIC 23574008 A 251 266 polyoxyethylene SYSTEMATIC 23574008 A 314 325 C4-C-N-PEG9 NO CLASS 23574008 A 33 46 cinnamic acid TRIVIAL 23574008 A 444 477 polyoxyethylene phytosterol ether SYSTEMATIC 23574008 A 479 486 PhyEO20 FORMULA 23574008 A 492 522 tetraoxyethylene dodecyl ether SYSTEMATIC 23574008 A 524 530 C12EO4 FORMULA 23574008 A 546 553 PhyEO20 FORMULA 23574008 A 554 557 H2O FORMULA 23574008 A 569 575 C12EO4 FORMULA 23574008 A 676 687 C4-C-N-PEG9 NO CLASS 23574008 A 79 90 C4-C-N-PEG9 NO CLASS 23574008 A 798 809 C4-C-N-PEG9 NO CLASS 23574008 A 860 871 C4-C-N-PEG9 NO CLASS 23574008 A 899 910 C4-C-N-PEG9 NO CLASS 23574008 A 982 993 C4-C-N-PEG9 NO CLASS 23574014 A 147 151 DTPA ABBREVIATION 23574014 A 153 187 diethylenetriaminepentaacetic acid SYSTEMATIC 23574014 A 215 224 maleimide SYSTEMATIC 23574014 A 585 594 maleimide SYSTEMATIC 23574014 A 62 85 poly(N-alkylacrylamide) SYSTEMATIC 23574534 A 115 119 SnO2 FORMULA 23574534 A 1323 1327 SnO2 FORMULA 23574534 A 1448 1452 SnO2 FORMULA 23574534 A 254 256 He FORMULA 23574534 A 257 259 Cd FORMULA 23574534 A 326 330 SnO2 FORMULA 23574534 A 478 482 SnO2 FORMULA 23574534 A 689 693 SnO2 FORMULA 23574534 A 934 938 SnO2 FORMULA 23574534 T 71 75 SnO2 FORMULA 23574984 A 526 537 acetic acid SYSTEMATIC 23574984 A 688 704 prostaglandin E2 TRIVIAL 23574984 A 706 710 PGE2 ABBREVIATION 23574984 A 825 833 Naloxone TRIVIAL 23575765 A 1301 1307 carbon SYSTEMATIC 23575765 A 437 440 ZnO FORMULA 23575765 A 644 654 zinc oxide SYSTEMATIC 23575765 A 655 661 silver SYSTEMATIC 23575765 A 66 82 indium tin oxide SYSTEMATIC 23575765 A 84 87 ITO ABBREVIATION 23575765 A 848 858 zinc oxide SYSTEMATIC 23575765 T 19 29 zinc oxide SYSTEMATIC 23575765 T 42 48 silver SYSTEMATIC 23576174 A 27 49 dimeric alkenylphenols FAMILY 23576174 A 490 505 sarmentosumol A TRIVIAL 23576174 A 58 79 sarmentosumols A to F MULTIPLE 23576174 T 0 21 Sarmentosumols A to F MULTIPLE 23576174 T 27 59 Mono- and Dimeric Alkenylphenols MULTIPLE 23576286 A 114 150 oligo(poly(ethylene glycol)fumarate) SYSTEMATIC 23576286 A 152 155 OPF ABBREVIATION 23576286 A 212 236 calcium glycerophosphate SYSTEMATIC 23576286 A 238 243 Ca-GP FORMULA 23576286 A 471 483 alizarin red TRIVIAL 23576286 A 600 607 calcium SYSTEMATIC 23576286 A 883 895 alizarin red TRIVIAL 23576286 T 58 94 Oligo(poly(ethylene glycol) Fumarate SYSTEMATIC 23576297 A 172 174 Pd FORMULA 23576297 A 192 201 porphyrin FAMILY 23576297 A 340 351 formic acid SYSTEMATIC 23576297 A 47 49 Pd FORMULA 23576297 A 75 84 porphyrin FAMILY 23576297 T 36 45 Palladium SYSTEMATIC 23576297 T 59 68 Porphyrin FAMILY 23576297 T 82 93 Formic Acid SYSTEMATIC 23576306 A 0 19 Tetramethylammonium SYSTEMATIC 23576306 A 130 136 amines FAMILY 23576306 A 142 157 methyl acrylate SYSTEMATIC 23576306 A 228 257 tetramethylammonium hydroxide SYSTEMATIC 23576306 A 263 266 CO2 FORMULA 23576306 A 346 349 CO2 FORMULA 23576306 A 382 389 alcohol FAMILY 23576306 A 400 406 (13) C FORMULA 23576306 A 467 470 CO2 FORMULA 23576306 A 49 61 β-amino acid FAMILY 23576306 A 497 500 CO2 FORMULA 23576306 A 575 586 bicarbonate SYSTEMATIC 23576306 A 616 637 hydroxyethylcarbonate SYSTEMATIC 23576306 A 642 657 methylcarbonate SYSTEMATIC 23576306 A 683 698 ethylene glycol SYSTEMATIC 23576306 A 703 711 methanol SYSTEMATIC 23576306 A 768 779 carboxylate SYSTEMATIC 23576306 A 854 857 CO2 FORMULA 23576306 A 874 882 hydrogen SYSTEMATIC 23576306 A 913 921 hydrogen SYSTEMATIC 23576306 A 935 940 amino FAMILY 23576306 T 0 11 Carboxylate SYSTEMATIC 23576306 T 103 115 β-Amino Acid FAMILY 23576306 T 34 48 Alkylcarbonate FAMILY 23576306 T 62 65 CO2 FORMULA 23576306 T 70 89 Tetramethylammonium SYSTEMATIC 23576341 A 1087 1095 biphenyl SYSTEMATIC 23576341 A 1379 1387 biphenyl SYSTEMATIC 23576341 A 300 308 biphenyl SYSTEMATIC 23576341 A 34 37 ATP ABBREVIATION 23576341 A 439 442 MTT ABBREVIATION 23576341 A 445 509 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide SYSTEMATIC 23576341 A 674 682 biphenyl SYSTEMATIC 23576341 A 787 795 biphenyl SYSTEMATIC 23576341 A 901 905 urea TRIVIAL 23576341 T 28 36 biphenyl SYSTEMATIC 23576355 A 10 21 tirucallane TRIVIAL 23576355 A 104 157 (23R,24S)-23,24,25-trihydroxytirucall-7-ene-3,6-dione SYSTEMATIC 23576355 A 163 175 piscidinol A TRIVIAL 23576355 A 181 199 24-epipiscidinol A SYSTEMATIC 23576355 A 205 226 21α-methylmelianodiol SYSTEMATIC 23576355 A 22 35 triterpenoids FAMILY 23576355 A 236 257 21β-methylmelianodiol SYSTEMATIC 23576355 A 285 289 EtOH FORMULA 23576355 A 37 53 brumollisols A-C MULTIPLE 23576355 A 696 698 NO FORMULA 23576355 T 0 11 Tirucallane TRIVIAL 23576355 T 12 25 Triterpenoids FAMILY 23576378 A 180 191 methicillin TRIVIAL 23576378 A 232 242 gentamicin FAMILY 23576378 A 25 43 demethylvancomycin SYSTEMATIC 23576378 A 282 293 methicillin TRIVIAL 23576378 A 340 350 vancomycin TRIVIAL 23576378 A 427 463 N-(6-phenylheptyl)demethylvancomycin SYSTEMATIC 23576378 A 533 543 vancomycin TRIVIAL 23576378 A 548 566 demethylvancomycin SYSTEMATIC 23576378 A 634 644 vancomycin TRIVIAL 23576378 A 870 880 vancomycin TRIVIAL 23576378 T 49 67 Demethylvancomycin SYSTEMATIC 23577042 A 147 153 biotin TRIVIAL 23577589 A 904 911 glucose TRIVIAL 23577701 A 138 147 friedelin TRIVIAL 23577701 A 153 165 apetalactone TRIVIAL 23577701 A 171 183 inophyllum C TRIVIAL 23577701 A 192 203 canophyllol TRIVIAL 23577701 A 24 46 α-hydroxytomentolide A TRIVIAL 23577701 A 298 302 (1)H FORMULA 23577701 A 308 313 (13)C FORMULA 23577701 A 6 22 dipyranocoumarin FAMILY 23577701 T 4 20 dipyranocoumarin FAMILY 23577749 A 545 556 gallic acid TRIVIAL 23577749 A 829 839 terpenoids FAMILY 23577749 A 841 848 phenols FAMILY 23577749 A 853 863 flavonoids FAMILY 23577749 A 879 887 phenolic FAMILY 23577749 A 902 912 flavonoids FAMILY 23578584 A 764 767 ATP ABBREVIATION 23578584 A 775 782 calcium SYSTEMATIC 23578610 A 886 895 baicalein TRIVIAL 23578623 A 551 555 NaCl FORMULA 23578627 A 0 25 3,4-Dihydroxyphenylglycol SYSTEMATIC 23578627 A 1008 1017 β-hydroxy SYSTEMATIC 23578627 A 1033 1045 verbascoside TRIVIAL 23578627 A 1050 1065 isoverbascoside TRIVIAL 23578627 A 1067 1085 β-hydroxyacteoside SYSTEMATIC 23578627 A 1090 1111 β-hydroxyisoacteoside SYSTEMATIC 23578627 A 1118 1138 2″-hydroxyoleuropein SYSTEMATIC 23578627 A 1163 1167 DHPG ABBREVIATION 23578627 A 120 124 DHPG ABBREVIATION 23578627 A 1242 1250 phenolic FAMILY 23578627 A 255 259 DHPG ABBREVIATION 23578627 A 27 31 DHPG ABBREVIATION 23578627 A 440 444 DHPG ABBREVIATION 23578627 A 528 532 DHPG ABBREVIATION 23578627 T 53 85 phenol 3,4-dihydroxyphenylglycol SYSTEMATIC 23578632 A 0 11 Polyphenols FAMILY 23578632 A 1070 1081 polyphenols FAMILY 23578632 A 115 149 omega-3 polyunsaturated fatty acid FAMILY 23578632 A 1176 1188 α-tocopherol TRIVIAL 23578632 A 1190 1214 butylated hydroxytoluene SYSTEMATIC 23578632 A 151 158 ω3 PUFA ABBREVIATION 23578632 A 310 317 ethanol SYSTEMATIC 23578632 A 558 564 ferric SYSTEMATIC 23578632 A 603 632 1,1-diphenyl-2-picrylhydrazyl SYSTEMATIC 23578632 A 642 646 DPPH ABBREVIATION 23578632 A 722 741 thiobarbituric acid SYSTEMATIC 23578632 A 777 788 Polyphenols FAMILY 23578632 A 872 879 DPPH(·) ABBREVIATION 23578633 A 236 261 perfluorooctane sulfonate SYSTEMATIC 23578633 A 263 267 PFOS ABBREVIATION 23578633 A 273 295 perfluorooctanoic acid SYSTEMATIC 23578633 A 297 301 PFOA ABBREVIATION 23578633 A 435 439 PFOS ABBREVIATION 23578633 A 509 513 PFOA ABBREVIATION 23578633 A 558 562 PFOS ABBREVIATION 23578633 A 829 833 PFOS ABBREVIATION 23578633 T 25 54 perfluorooctane sulfonic acid SYSTEMATIC 23578633 T 56 60 PFOS ABBREVIATION 23578633 T 66 88 perfluorooctanoic acid SYSTEMATIC 23578633 T 90 94 PFOA ABBREVIATION 23578634 A 344 348 NaCl FORMULA 23578634 A 350 353 KCl FORMULA 23578634 A 355 368 Ca-propionate SYSTEMATIC 23578634 A 373 409 FeNa-ethylenediaminetetraacetic acid SYSTEMATIC 23578634 A 411 420 FeNa-EDTA FORMULA 23578634 A 805 809 NaCl FORMULA 23578636 A 1209 1218 alcoholic FAMILY 23578636 A 1268 1275 alcohol FAMILY 23578636 A 1475 1487 Anthocyanins FAMILY 23578636 A 1567 1574 tannins FAMILY 23578636 A 684 692 phenolic FAMILY 23578642 A 256 273 ammonium sulphate SYSTEMATIC 23578643 A 1085 1090 5-HMF SYSTEMATIC 23578643 A 139 146 glucose TRIVIAL 23578643 A 235 242 glucose TRIVIAL 23578643 A 329 335 oxygen SYSTEMATIC 23578643 A 518 525 glucose TRIVIAL 23578643 A 552 557 5-HMF SYSTEMATIC 23578643 A 622 629 glucose TRIVIAL 23578643 A 66 71 5-HMF SYSTEMATIC 23578643 A 703 708 5-HMF SYSTEMATIC 23578643 A 732 739 glucose TRIVIAL 23578643 A 879 886 glucose TRIVIAL 23578643 A 994 1001 glucose TRIVIAL 23578643 T 10 33 5-hydroxymethylfurfural SYSTEMATIC 23578643 T 102 109 glucose TRIVIAL 23578651 A 144 160 ethylenethiourea SYSTEMATIC 23578651 A 162 165 ETU ABBREVIATION 23578651 A 286 289 ETU ABBREVIATION 23578651 A 331 339 methanol SYSTEMATIC 23578651 A 355 362 alumina TRIVIAL 23578651 T 30 46 ethylenethiourea SYSTEMATIC 23578651 T 76 84 methanol SYSTEMATIC 23578652 A 303 313 superoxide TRIVIAL 23578652 A 321 334 peroxynitrite SYSTEMATIC 23578652 A 346 353 peroxyl SYSTEMATIC 23578652 A 432 440 hydroxyl SYSTEMATIC 23578652 A 476 482 oxygen SYSTEMATIC 23578652 A 682 696 S-allylcystein SYSTEMATIC 23578652 A 85 99 hydroethanolic FAMILY 23578652 A 851 855 NMDA ABBREVIATION 23578652 A 949 952 ATP ABBREVIATION 23578652 T 38 52 hydroethanolic FAMILY 23578690 A 131 136 amine SYSTEMATIC 23578690 A 49 55 oxygen SYSTEMATIC 23578690 A 835 846 doxorubicin TRIVIAL 23578690 A 851 861 cytarabine TRIVIAL 23578690 T 37 51 tethered amine FAMILY 23578763 A 498 508 prednisone TRIVIAL 23578968 A 1052 1056 MEHP ABBREVIATION 23578968 A 1154 1161 steroid FAMILY 23578968 A 123 135 testosterone TRIVIAL 23578968 A 1283 1292 phthalate FAMILY 23578968 A 185 195 phthalates FAMILY 23578968 A 197 201 MEHP ABBREVIATION 23578968 A 203 206 MBP ABBREVIATION 23578968 A 222 232 phthalates FAMILY 23578968 A 234 237 MMP ABBREVIATION 23578968 A 242 245 MEP ABBREVIATION 23578968 A 373 385 testosterone TRIVIAL 23578968 A 438 441 MBP ABBREVIATION 23578968 A 450 454 MEHP ABBREVIATION 23578968 A 462 465 MEP ABBREVIATION 23578968 A 470 473 MMP ABBREVIATION 23578968 A 503 515 testosterone TRIVIAL 23578968 A 610 622 testosterone TRIVIAL 23578968 A 637 640 MBP ABBREVIATION 23578968 A 645 649 MEHP ABBREVIATION 23578968 A 804 814 monoesters FAMILY 23578968 A 844 848 MEHP ABBREVIATION 23578968 A 850 860 Monoesters FAMILY 23578968 A 883 890 carbons FAMILY 23578968 A 929 941 testosterone TRIVIAL 23578968 A 964 970 carbon SYSTEMATIC 23578968 T 80 96 phthalate esters FAMILY 23579044 A 1097 1104 cocaine TRIVIAL 23579044 A 1168 1171 MPD ABBREVIATION 23579044 A 1224 1231 cocaine TRIVIAL 23579044 A 1288 1295 cocaine TRIVIAL 23579044 A 1348 1351 MPD ABBREVIATION 23579044 A 1423 1430 cocaine TRIVIAL 23579044 A 153 160 cocaine TRIVIAL 23579044 A 1589 1592 MPD ABBREVIATION 23579044 A 1639 1648 monoamine FAMILY 23579044 A 1658 1671 d-amphetamine TRIVIAL 23579044 A 1736 1745 monoamine FAMILY 23579044 A 1769 1772 MPD ABBREVIATION 23579044 A 1793 1800 cocaine TRIVIAL 23579044 A 293 306 d-amphetamine TRIVIAL 23579044 A 320 327 cocaine TRIVIAL 23579044 A 427 442 methylphenidate SYSTEMATIC 23579044 A 444 447 MPD ABBREVIATION 23579044 A 501 508 cocaine TRIVIAL 23579044 A 598 605 cocaine TRIVIAL 23579044 A 65 73 dopamine TRIVIAL 23579044 A 755 762 cocaine TRIVIAL 23579044 A 83 97 norepinephrine TRIVIAL 23579044 A 858 865 cocaine TRIVIAL 23579044 A 991 994 MPD ABBREVIATION 23579044 T 19 34 methylphenidate SYSTEMATIC 23579044 T 38 45 cocaine TRIVIAL 23579182 A 643 644 N FORMULA 23579333 A 144 163 potassium phosphate SYSTEMATIC 23579333 A 208 210 Co FORMULA 23579333 A 211 213 Ni FORMULA 23579333 A 291 293 Co FORMULA 23579333 A 294 296 Ni FORMULA 23579333 A 297 306 hydroxide SYSTEMATIC 23579333 A 322 328 iodine SYSTEMATIC 23579333 A 34 36 Co FORMULA 23579333 A 37 39 Ni FORMULA 23579333 A 423 430 Co(iii) FORMULA 23579333 A 431 440 hydroxide SYSTEMATIC 23579333 A 55 65 hydroxides FAMILY 23579333 A 633 635 Co FORMULA 23579333 A 636 638 Ni FORMULA 23579333 A 782 788 oxygen SYSTEMATIC 23579333 A 852 854 Co FORMULA 23579333 A 855 857 Ni FORMULA 23579333 A 900 902 Co FORMULA 23579333 T 0 2 Co FORMULA 23579333 T 21 31 hydroxides FAMILY 23579333 T 3 5 Ni FORMULA 23579427 A 1011 1018 alcohol FAMILY 23579427 A 1044 1051 alcohol FAMILY 23579427 A 1134 1141 alcohol FAMILY 23579427 A 1217 1224 alcohol FAMILY 23579427 A 1307 1314 alcohol FAMILY 23579427 A 1428 1435 alcohol FAMILY 23579427 A 1493 1500 alcohol FAMILY 23579427 A 1614 1621 alcohol FAMILY 23579427 A 326 333 alcohol FAMILY 23579427 A 363 370 alcohol FAMILY 23579427 A 39 46 alcohol FAMILY 23579427 A 446 453 alcohol FAMILY 23579427 A 459 466 alcohol FAMILY 23579427 A 779 786 alcohol FAMILY 23579427 A 875 882 alcohol FAMILY 23579427 T 6 13 alcohol FAMILY 23579427 T 65 72 alcohol FAMILY 23579486 A 1084 1089 RU486 IDENTIFIER 23579486 A 1104 1109 APR19 IDENTIFIER 23579486 A 1159 1165 serine TRIVIAL 23579486 A 1347 1359 progesterone TRIVIAL 23579486 A 1361 1366 APR19 IDENTIFIER 23579486 A 1398 1406 hydrogen SYSTEMATIC 23579486 A 1543 1548 APR19 IDENTIFIER 23579486 A 1554 1559 RU486 IDENTIFIER 23579486 A 20 32 progesterone TRIVIAL 23579486 A 529 540 homosteroid FAMILY 23579486 A 541 546 APR19 IDENTIFIER 23579486 A 604 609 APR19 IDENTIFIER 23579486 A 619 631 progesterone TRIVIAL 23579486 A 68 80 mifepristone TRIVIAL 23579486 A 788 795 steroid FAMILY 23579486 A 82 87 RU486 IDENTIFIER 23579486 A 948 953 APR19 IDENTIFIER 23579486 T 42 54 Progesterone TRIVIAL 23579487 A 192 199 glucose TRIVIAL 23579487 A 933 953 phosphatidylinositol TRIVIAL 23580169 A 1035 1043 europium SYSTEMATIC 23580169 A 1198 1200 Eu FORMULA 23580169 A 191 193 Eu FORMULA 23580169 A 363 371 europium SYSTEMATIC 23580169 A 383 395 (Ca,Eu)2SiS4 FORMULA 23580169 A 42 50 europium SYSTEMATIC 23580169 A 57 64 Ca2SiS4 FORMULA 23580169 A 582 590 europium SYSTEMATIC 23580169 A 652 660 europium SYSTEMATIC 23580169 A 781 789 europium SYSTEMATIC 23580169 A 833 835 Ca FORMULA 23580169 A 960 978 monoclinic Eu2SiS4 FORMULA 23580169 T 31 33 Eu FORMULA 23580169 T 45 57 thiosilicate SYSTEMATIC 23580257 A 274 287 dexamethasone TRIVIAL 23580257 A 446 457 hematoxylin TRIVIAL 23580257 A 462 467 eosin FAMILY 23580257 A 70 78 baicalin TRIVIAL 23580257 T 26 34 Baicalin TRIVIAL 23580402 A 1281 1287 sodium SYSTEMATIC 23580402 A 1336 1342 sugars FAMILY 23580402 A 1344 1355 cholesterol TRIVIAL 23580402 A 837 846 vitamin C TRIVIAL 23580402 A 848 857 vitamin E FAMILY 23580402 A 863 873 β-carotene TRIVIAL 23580402 A 879 883 zinc SYSTEMATIC 23580404 A 0 3 PbS FORMULA 23580404 A 473 476 PbS FORMULA 23580404 T 78 81 PbS FORMULA 23580421 A 41 45 MnO2 FORMULA 23580421 T 53 67 Graphene Oxide SYSTEMATIC 23580421 T 68 85 Manganese Dioxide SYSTEMATIC 23580652 A 839 846 glycine TRIVIAL 23580652 A 861 874 aspartic acid TRIVIAL 23580652 A 915 922 calcium SYSTEMATIC 23581295 A 146 150 VCl4 FORMULA 23581295 A 156 168 superhydride TRIVIAL 23581295 A 170 177 LiBHEt3 FORMULA 23581295 A 198 220 4-octylphenyldiazonium SYSTEMATIC 23581295 A 415 423 V-N═N-Ar FORMULA 23581295 A 48 70 4-octylphenyldiazenido SYSTEMATIC 23581295 A 9 17 vanadium SYSTEMATIC 23581295 T 13 22 diazenido SYSTEMATIC 23581295 T 31 39 vanadium SYSTEMATIC 23581492 A 1164 1171 Arg-Arg FORMULA 23581492 A 1243 1250 Arg-Arg FORMULA 23581492 A 1264 1275 Arg-Arg-Asp FORMULA 23581492 A 1276 1279 Glu FORMULA 23581492 A 135 143 arginine TRIVIAL 23581492 A 144 152 arginine TRIVIAL 23581492 A 1457 1464 Arg-Arg FORMULA 23581492 A 154 161 Arg-Arg FORMULA 23581492 A 178 184 carbon SYSTEMATIC 23581492 A 187 193 carbon SYSTEMATIC 23581492 A 248 255 Arg-Arg FORMULA 23581492 A 454 461 Arg-Arg FORMULA 23581492 A 501 508 Arg-Arg FORMULA 23581492 A 561 572 Arg-Arg-Asp FORMULA 23581492 A 573 576 Glu FORMULA 23581492 A 720 727 Arg-Arg FORMULA 23581492 A 950 957 Arg-Arg FORMULA 23581492 T 52 70 acidic amino acids FAMILY 23581492 T 74 82 arginine TRIVIAL 23581492 T 83 91 arginine TRIVIAL 23581965 A 1173 1181 hematite TRIVIAL 23581965 A 1203 1206 ATO ABBREVIATION 23581965 A 222 230 hematite TRIVIAL 23581965 A 310 321 polystyrene SYSTEMATIC 23581965 A 48 72 antimony-doped tin oxide SYSTEMATIC 23581965 A 559 564 oxide SYSTEMATIC 23581965 A 572 580 hematite TRIVIAL 23581965 A 77 80 ATO ABBREVIATION 23581965 A 813 821 hematite TRIVIAL 23581965 A 936 939 ATO ABBREVIATION 23581965 A 979 987 hematite TRIVIAL 23581965 T 48 72 Antimony-Doped Tin Oxide SYSTEMATIC 23581965 T 9 17 Hematite TRIVIAL 23581993 A 222 225 ATP ABBREVIATION 23581993 A 818 824 carbon SYSTEMATIC 23582235 A 1066 1070 zinc SYSTEMATIC 23582235 A 1138 1142 zinc SYSTEMATIC 23582235 A 1178 1182 zinc SYSTEMATIC 23582235 A 1401 1405 zinc SYSTEMATIC 23582235 A 1588 1592 zinc SYSTEMATIC 23582235 A 184 188 zinc SYSTEMATIC 23582235 A 36 40 zinc SYSTEMATIC 23582235 A 371 375 zinc SYSTEMATIC 23582235 A 622 635 zinc chloride SYSTEMATIC 23582235 A 689 705 Poly(ADP-ribose) SYSTEMATIC 23582235 A 812 816 zinc SYSTEMATIC 23582235 A 938 942 zinc SYSTEMATIC 23582235 T 0 4 Zinc SYSTEMATIC 23582235 T 125 141 Poly(ADP-ribose) SYSTEMATIC 23582330 A 0 7 Glucose TRIVIAL 23582330 A 117 122 sugar FAMILY 23582330 A 162 175 phosphosugars FAMILY 23582330 A 249 257 haloacid FAMILY 23582330 A 359 372 phosphosugars FAMILY 23582330 A 490 497 glucose TRIVIAL 23582330 T 33 38 Sugar FAMILY 23582330 T 66 73 Glucose TRIVIAL 23582779 A 91 98 glucose TRIVIAL 23583168 A 403 413 fatty-acid FAMILY 23583203 A 1008 1011 TPP ABBREVIATION 23583203 A 141 150 celastrol TRIVIAL 23583203 A 317 326 celastrol TRIVIAL 23583203 A 381 384 TPP ABBREVIATION 23583203 A 684 687 TPP ABBREVIATION 23583203 A 766 769 TPP ABBREVIATION 23583203 A 872 881 celastrol TRIVIAL 23583203 A 970 979 celastrol TRIVIAL 23583437 A 146 275 (3β, 7β, 12β, 25R)-spirost-5-ene-3, 7, 12-triol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl-(1→4)]-O-β-d-glucopyranoside SYSTEMATIC 23583437 A 281 410 (2α, 3β, 12β, 25R)-spirost-5-ene-2, 3, 12-triol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl-(1→4)]-O-β-d-glucopyranoside SYSTEMATIC 23583437 A 440 560 (3β, 12β, 25R)-spirost-5-ene-3,12-diol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl-(1→4)]-O-β-d-glucopyranoside SYSTEMATIC 23583437 A 5 23 steroidal saponins FAMILY 23583437 A 567 682 (1α, 3β, 25R)-spirost-5-ene-2-diol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl(1→4)]-O-β-d-glucopyranoside SYSTEMATIC 23583437 A 79 83 EtOH FORMULA 23583437 A 894 912 steroidal saponins FAMILY 23583437 T 8 26 steroidal saponins FAMILY 23583454 A 1073 1077 METH ABBREVIATION 23583454 A 1082 1086 MDMA ABBREVIATION 23583454 A 1097 1118 4-fluoromethcathinone SYSTEMATIC 23583454 A 1156 1160 METH ABBREVIATION 23583454 A 1180 1194 methcathinones FAMILY 23583454 A 1286 1295 monoamine FAMILY 23583454 A 138 153 methamphetamine TRIVIAL 23583454 A 1515 1528 methcathinone TRIVIAL 23583454 A 1543 1552 serotonin TRIVIAL 23583454 A 155 159 METH ABBREVIATION 23583454 A 1554 1558 5-HT SYSTEMATIC 23583454 A 1649 1657 dopamine TRIVIAL 23583454 A 165 197 3,4-methylendioxymethamphetamine SYSTEMATIC 23583454 A 1780 1789 serotonin TRIVIAL 23583454 A 1791 1799 dopamine TRIVIAL 23583454 A 199 203 MDMA ABBREVIATION 23583454 A 21 35 methcathinones FAMILY 23583454 A 408 419 amphetamine TRIVIAL 23583454 A 434 464 3,4-Methylenedioxypyrovalerone SYSTEMATIC 23583454 A 469 478 naphyrone TRIVIAL 23583454 A 548 556 dopamine TRIVIAL 23583454 A 565 574 serotonin TRIVIAL 23583454 A 587 601 norepinephrine TRIVIAL 23583454 A 642 648 [(3)H] FORMULA 23583454 A 683 690 cocaine TRIVIAL 23583454 A 737 745 Butylone TRIVIAL 23583454 A 798 819 4-fluoromethcathinone SYSTEMATIC 23583454 A 821 831 mephedrone TRIVIAL 23583454 A 836 845 methylone TRIVIAL 23583454 A 949 955 [(3)H] FORMULA 23583454 T 12 26 methcathinones FAMILY 23583513 A 1029 1072 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione SYSTEMATIC 23583513 A 22 65 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione SYSTEMATIC 23583513 A 530 539 diazepine TRIVIAL 23583513 A 578 625 1,5-dihydro-benzo[f][1,3,5]triazepine-2,4-dione SYSTEMATIC 23583513 A 747 790 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione SYSTEMATIC 23583513 T 18 61 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione SYSTEMATIC 23583641 A 1024 1027 MTT ABBREVIATION 23583641 A 552 564 polyurethane SYSTEMATIC 23583641 A 760 768 methanol SYSTEMATIC 23583641 A 995 997 NO FORMULA 23583735 A 1121 1128 Realgar TRIVIAL 23583735 A 1229 1236 Realgar TRIVIAL 23583735 A 1345 1349 (1)H FORMULA 23583735 A 2167 2174 realgar TRIVIAL 23583735 A 2176 2181 As2S2 FORMULA 23583735 A 2247 2254 realgar TRIVIAL 23583735 A 2256 2261 As2S2 FORMULA 23583735 A 2440 2447 choline FAMILY 23583735 A 2460 2470 amino acid FAMILY 23583735 A 2517 2524 realgar TRIVIAL 23583735 A 2526 2531 As2S2 FORMULA 23583735 A 544 551 realgar TRIVIAL 23583735 A 553 558 As2S2 FORMULA 23583735 A 638 642 (1)H FORMULA 23583735 A 720 727 realgar TRIVIAL 23583735 A 729 734 As2S2 FORMULA 23583735 A 888 895 Realgar TRIVIAL 23583735 A 921 928 Realgar TRIVIAL 23583735 T 0 4 (1)H FORMULA 23583882 A 483 492 parathion TRIVIAL 23583882 A 497 512 organophosphate FAMILY 23583882 A 526 538 methoxychlor TRIVIAL 23583882 A 543 557 organochlorine FAMILY 23583882 A 600 618 piperonyl butoxide SYSTEMATIC 23583882 T 65 77 methoxychlor TRIVIAL 23583882 T 79 88 parathion TRIVIAL 23583882 T 93 111 piperonyl butoxide SYSTEMATIC 23583910 A 12 30 aminopropylindenes FAMILY 23583910 A 152 168 2,3-oxidosqualen TRIVIAL 23583910 A 172 182 lanosterol TRIVIAL 23583910 A 201 219 Grundmann's ketone TRIVIAL 23583910 A 347 370 N,N-dimethylaminopropyl SYSTEMATIC 23583910 A 509 520 cholesterol TRIVIAL 23583910 A 97 110 oxidosqualene FAMILY 23583910 T 0 18 Aminopropylindenes FAMILY 23583910 T 32 50 Grundmann's ketone TRIVIAL 23583928 A 1273 1281 VUF 8430 IDENTIFIER 23583928 A 1286 1298 JNJ 10191584 IDENTIFIER 23583928 A 4 13 histamine TRIVIAL 23583928 A 427 435 VUF 8430 IDENTIFIER 23583928 A 559 571 JNJ 10191584 IDENTIFIER 23583928 A 678 687 histamine TRIVIAL 23583928 A 859 867 diazepam TRIVIAL 23583928 A 934 942 VUF 8430 IDENTIFIER 23583928 A 956 967 scopolamine TRIVIAL 23583928 T 22 31 histamine TRIVIAL 23583929 A 597 612 quinolinic acid TRIVIAL 23584090 A 722 725 CpG ABBREVIATION 23584277 A 389 406 hydrogen peroxide SYSTEMATIC 23584277 A 4 10 oxygen SYSTEMATIC 23584277 A 95 142 diethylmethylammonium trifluoromethanesulfonate SYSTEMATIC 23584277 T 26 32 oxygen SYSTEMATIC 23584358 A 0 11 Paracetamol TRIVIAL 23584358 A 1098 1107 aspartate TRIVIAL 23584358 A 1126 1133 alanine TRIVIAL 23584358 A 121 130 melatonin TRIVIAL 23584358 A 1227 1241 8-iso-prostane TRIVIAL 23584358 A 1276 1286 superoxide TRIVIAL 23584358 A 1310 1321 glutathione TRIVIAL 23584358 A 1348 1359 paracetamol TRIVIAL 23584358 A 1379 1390 agomelatine TRIVIAL 23584358 A 1395 1398 NAC ABBREVIATION 23584358 A 1463 1474 agomelatine TRIVIAL 23584358 A 1516 1527 paracetamol TRIVIAL 23584358 A 294 303 melatonin TRIVIAL 23584358 A 390 401 agomelatine TRIVIAL 23584358 A 405 416 paracetamol TRIVIAL 23584358 A 517 528 agomelatine TRIVIAL 23584358 A 682 693 agomelatine TRIVIAL 23584358 A 709 725 N-acetylcysteine SYSTEMATIC 23584358 A 727 730 NAC ABBREVIATION 23584358 A 744 755 paracetamol TRIVIAL 23584358 A 768 779 paracetamol TRIVIAL 23584358 A 792 795 NAC ABBREVIATION 23584358 A 808 819 paracetamol TRIVIAL 23584358 A 831 842 agomelatine TRIVIAL 23584358 A 859 870 paracetamol TRIVIAL 23584358 A 882 893 agomelatine TRIVIAL 23584358 A 90 101 Agomelatine TRIVIAL 23584358 A 902 913 Paracetamol TRIVIAL 23584358 T 0 11 Agomelatine TRIVIAL 23584358 T 75 86 paracetamol TRIVIAL 23584418 A 0 9 Aluminium SYSTEMATIC 23584418 A 140 146 Al(3+) FORMULA 23584418 T 65 74 aluminium SYSTEMATIC 23584426 A 0 5 Fe3O4 FORMULA 23584426 A 1024 1029 Fe3O4 FORMULA 23584426 A 1098 1103 As(V) FORMULA 23584426 A 1108 1113 Fe3O4 FORMULA 23584426 A 1212 1217 As(V) FORMULA 23584426 A 1229 1234 Fe3O4 FORMULA 23584426 A 1315 1320 Fe3O4 FORMULA 23584426 A 137 144 arsenic SYSTEMATIC 23584426 A 1544 1549 Fe3O4 FORMULA 23584426 A 1566 1571 As(V) FORMULA 23584426 A 1589 1594 As(V) FORMULA 23584426 A 1644 1652 arsenics FAMILY 23584426 A 1699 1706 arsenic SYSTEMATIC 23584426 A 213 220 arsenic SYSTEMATIC 23584426 A 359 364 Fe3O4 FORMULA 23584426 A 389 394 As(V) FORMULA 23584426 A 51 58 arsenic SYSTEMATIC 23584426 A 559 564 As(V) FORMULA 23584426 A 613 618 As(V) FORMULA 23584426 A 650 655 Fe3O4 FORMULA 23584426 A 853 858 Fe3O4 FORMULA 23584426 A 894 899 As(V) FORMULA 23584426 A 93 98 Fe3O4 FORMULA 23584426 A 958 963 Fe3O4 FORMULA 23584426 T 21 38 ferroferric oxide SYSTEMATIC 23584426 T 57 64 arsenic SYSTEMATIC 23584427 A 0 19 Hexavalent chromium SYSTEMATIC 23584427 A 1304 1306 Cr FORMULA 23584427 A 1670 1672 Cr FORMULA 23584427 A 1786 1788 Cr FORMULA 23584427 A 1824 1830 oxygen SYSTEMATIC 23584427 A 20 26 Cr(VI) FORMULA 23584427 A 249 251 Cr FORMULA 23584427 A 393 395 Cr FORMULA 23584427 A 520 522 Cr FORMULA 23584427 A 602 608 Cr(VI) FORMULA 23584427 A 682 684 Cr FORMULA 23584427 A 746 752 Cr(VI) FORMULA 23584427 T 64 83 hexavalent chromium SYSTEMATIC 23584427 T 85 91 Cr(VI) FORMULA 23584541 A 209 223 betulinic acid TRIVIAL 23584541 A 241 255 1,2,3-triazole SYSTEMATIC 23584541 A 298 299 C FORMULA 23584541 A 517 582 3{1N(2-cyanophenyl)-1H-1,2,3-triazol-4yl}methyloxy betulinic acid SYSTEMATIC 23584541 A 591 663 3{1N(5-hydroxy-naphth-1yl)-1H-1,2,3-triazol-4yl}methyloxy betulinic acid SYSTEMATIC 23584541 T 13 69 3-O-propargylated betulinic acid and its 1,2,3-triazoles MULTIPLE 23584545 A 118 127 quinoline SYSTEMATIC 23584545 A 27 36 quinoline SYSTEMATIC 23584545 A 387 396 quinoline SYSTEMATIC 23584545 A 604 617 Schiff's base FAMILY 23584545 T 57 66 quinoline SYSTEMATIC 23584556 A 1178 1179 N FORMULA 23584556 A 1230 1231 C FORMULA 23584556 A 1780 1784 zinc SYSTEMATIC 23584556 A 2165 2175 amino acid FAMILY 23584556 A 979 989 amino acid FAMILY 23584636 A 112 115 ZnO FORMULA 23584636 A 195 200 Al2O3 FORMULA 23584636 A 357 359 Au FORMULA 23584636 A 364 380 indium-tin-oxide SYSTEMATIC 23584636 A 382 385 ITO ABBREVIATION 23584636 T 12 15 ZnO FORMULA 23584857 A 1063 1077 2-deoxyglucose SYSTEMATIC 23584886 A 0 12 Ketoconazole TRIVIAL 23584886 A 1125 1137 Ketoconazole TRIVIAL 23584886 A 1254 1263 midazolam TRIVIAL 23584886 A 1461 1473 ketoconazole TRIVIAL 23584886 A 310 322 ketoconazole TRIVIAL 23584886 A 397 409 ketoconazole TRIVIAL 23584886 A 410 419 midazolam TRIVIAL 23584886 A 765 774 midazolam TRIVIAL 23584886 A 804 813 midazolam TRIVIAL 23584886 A 997 1009 ketoconazole TRIVIAL 23584948 A 1252 1262 Vandetanib TRIVIAL 23584948 A 246 256 Vandetanib TRIVIAL 23584948 A 258 266 Caprelsa TRIVIAL 23584948 A 305 313 tyrosine TRIVIAL 23584948 A 403 411 tyrosine TRIVIAL 23584948 T 0 10 Vandetanib TRIVIAL 23585058 A 1023 1026 APV ABBREVIATION 23585058 A 1035 1039 NMDA ABBREVIATION 23585058 A 1086 1093 calcium SYSTEMATIC 23585058 A 1102 1110 BAPTA-AM ABBREVIATION 23585058 A 1147 1152 UO126 IDENTIFIER 23585058 A 1172 1176 NMDA ABBREVIATION 23585058 A 1215 1219 NMDA ABBREVIATION 23585058 A 1296 1300 Ca2+ FORMULA 23585058 A 456 460 NMDA ABBREVIATION 23585058 A 54 74 γ amino-butyric acid SYSTEMATIC 23585058 A 620 624 NMDA ABBREVIATION 23585058 A 829 833 NMDA ABBREVIATION 23585058 T 0 4 NMDA ABBREVIATION 23585058 T 75 79 GABA ABBREVIATION 23585235 A 1039 1041 HD FORMULA 23585235 A 1125 1133 hydrogen SYSTEMATIC 23585235 A 1244 1252 hydrogen SYSTEMATIC 23585235 A 1385 1393 hydrogen SYSTEMATIC 23585235 A 1471 1479 hydrogen SYSTEMATIC 23585235 A 1594 1602 hydrogen SYSTEMATIC 23585235 A 1659 1667 hydrogen SYSTEMATIC 23585235 A 166 168 H2 FORMULA 23585235 A 17 25 hydrogen SYSTEMATIC 23585235 A 170 172 D2 FORMULA 23585235 A 291 299 hydrogen SYSTEMATIC 23585235 A 353 361 hydrogen SYSTEMATIC 23585235 A 363 365 HD FORMULA 23585235 A 382 384 H2 FORMULA 23585235 A 389 391 D2 FORMULA 23585235 A 397 399 Pd FORMULA 23585235 A 45 52 Pd(111) FORMULA 23585235 A 526 528 HD FORMULA 23585235 A 620 628 hydrogen SYSTEMATIC 23585235 A 742 750 hydrogen SYSTEMATIC 23585235 A 827 835 hydrogen SYSTEMATIC 23585235 A 85 87 Pd FORMULA 23585235 A 861 863 HD FORMULA 23585235 T 105 112 Pd(111) FORMULA 23585235 T 66 67 H FORMULA 23585235 T 68 69 D FORMULA 23585235 T 84 86 Pd FORMULA 23585358 A 175 178 C-H FORMULA 23585358 A 353 362 diazonium SYSTEMATIC 23585380 A 101 132 poly(L-lactic-co-glycolic acid) SYSTEMATIC 23585380 A 1127 1131 PLGA ABBREVIATION 23585380 A 1164 1168 PLGA ABBREVIATION 23585380 A 134 138 PLGA ABBREVIATION 23585380 A 269 273 PLGA ABBREVIATION 23585380 A 362 366 PLGA ABBREVIATION 23585380 A 722 726 PLGA ABBREVIATION 23585383 A 232 234 Ag FORMULA 23585383 A 30 32 Ag FORMULA 23585383 A 33 39 Fe2 O3 FORMULA 23585383 A 331 333 Ag FORMULA 23585383 A 355 365 iron oxide SYSTEMATIC 23585383 A 391 393 Ag FORMULA 23585383 A 55 57 Ag FORMULA 23585383 A 58 64 Fe2 O3 FORMULA 23585383 T 62 64 Ag FORMULA 23585383 T 65 71 Fe2 O3 FORMULA 23585770 A 589 591 Ni FORMULA 23585770 T 31 33 Ni FORMULA 23586441 A 1063 1073 acridinium SYSTEMATIC 23586441 A 1240 1258 aliphatic ammonium FAMILY 23586441 A 1281 1289 acridine TRIVIAL 23586441 A 1304 1312 acridine TRIVIAL 23586441 A 1313 1321 nitrogen SYSTEMATIC 23586441 A 139 147 acridine TRIVIAL 23586441 A 438 442 (1)H FORMULA 23586441 A 597 607 tetraamine SYSTEMATIC 23586441 A 625 633 acridine TRIVIAL 23586441 A 634 642 nitrogen SYSTEMATIC 23586441 A 720 728 acridine TRIVIAL 23586441 A 76 96 triethylentetraamine SYSTEMATIC 23586441 T 93 101 Acridine TRIVIAL 23586519 A 1004 1007 THF ABBREVIATION 23586519 A 105 108 PFS ABBREVIATION 23586519 A 1146 1149 PFS ABBREVIATION 23586519 A 1268 1272 PDMS ABBREVIATION 23586519 A 1275 1295 polydimethylsiloxane SYSTEMATIC 23586519 A 1319 1329 2-propanol SYSTEMATIC 23586519 A 1331 1335 P2VP ABBREVIATION 23586519 A 1338 1358 poly(2-vinylpyridine SYSTEMATIC 23586519 A 1500 1503 PFS ABBREVIATION 23586519 A 1723 1726 PFS ABBREVIATION 23586519 A 719 722 PFS ABBREVIATION 23586519 A 73 103 poly(ferrocenyldimethylsilane) SYSTEMATIC 23586519 A 848 854 decane SYSTEMATIC 23586519 A 910 913 THF ABBREVIATION 23586519 A 919 922 PFS ABBREVIATION 23586638 A 0 13 Vinyl acetate SYSTEMATIC 23586638 A 1065 1066 H FORMULA 23586638 A 1085 1103 CH3C(O)O(•)CHCH2OH FORMULA 23586638 A 1114 1134 CH3C(O)OCH(OH)(•)CH2 FORMULA 23586638 A 1141 1143 OH FORMULA 23586638 A 1201 1203 O2 FORMULA 23586638 A 1216 1218 NO FORMULA 23586638 A 1894 1917 formic acetic anhydride SYSTEMATIC 23586638 A 19 29 CH3COOC2H3 FORMULA 23586638 A 1919 1930 acetic acid SYSTEMATIC 23586638 A 1936 1948 formaldehyde SYSTEMATIC 23586638 A 1956 1958 OH FORMULA 23586638 A 2004 2006 O2 FORMULA 23586638 A 2011 2013 NO FORMULA 23586638 A 206 208 OH FORMULA 23586638 A 322 324 OH FORMULA 23586638 A 360 362 O2 FORMULA 23586638 A 367 369 NO FORMULA 23586638 A 487 496 ethylenic SYSTEMATIC 23586638 A 497 498 C FORMULA 23586638 A 635 636 H FORMULA 23586638 A 708 710 OH FORMULA 23586638 A 997 999 OH FORMULA 23586638 T 56 69 Vinyl Acetate SYSTEMATIC 23586638 T 83 85 OH FORMULA 23586839 A 1096 1097 C FORMULA 23586839 A 1098 1100 2H FORMULA 23586839 A 1188 1189 H FORMULA 23586839 A 1191 1193 2H FORMULA 23586839 A 1210 1212 Ir FORMULA 23586839 A 1213 1214 C FORMULA 23586839 A 1215 1217 2H FORMULA 23586839 A 1364 1366 Pt FORMULA 23586839 A 1382 1389 carbene FAMILY 23586839 A 1405 1407 Ta FORMULA 23586839 A 1412 1413 W FORMULA 23586839 A 1415 1422 carbene FAMILY 23586839 A 1484 1491 carbyne FAMILY 23586839 A 1510 1512 Ir FORMULA 23586839 A 1526 1528 Ir FORMULA 23586839 A 1529 1536 carbyne FAMILY 23586839 A 162 169 Methane SYSTEMATIC 23586839 A 18 25 methane SYSTEMATIC 23586839 A 239 240 C FORMULA 23586839 A 241 243 2H FORMULA 23586839 A 250 252 H2 FORMULA 23586839 A 39 55 transition metal FAMILY 23586839 A 396 403 carbene FAMILY 23586839 A 430 433 CH2 FORMULA 23586839 A 469 472 CH2 FORMULA 23586839 A 480 487 carbyne FAMILY 23586839 A 489 508 hydrido-methylidyne SYSTEMATIC 23586839 A 532 534 CH FORMULA 23586839 A 541 549 hydrogen SYSTEMATIC 23586839 A 581 582 H FORMULA 23586839 A 586 588 CH FORMULA 23586839 A 707 714 carbene FAMILY 23586839 A 719 726 carbyne FAMILY 23586839 A 770 771 C FORMULA 23586839 A 772 774 2H FORMULA 23586839 A 782 784 Ta FORMULA 23586839 A 786 787 W FORMULA 23586839 A 789 791 Ir FORMULA 23586839 A 793 795 Pt FORMULA 23586839 T 46 53 Methane SYSTEMATIC 23586839 T 71 87 Transition Metal FAMILY 23587048 A 0 33 3-Hydroperoxy-N-nitrosomorpholine SYSTEMATIC 23587048 A 1012 1019 iminium SYSTEMATIC 23587048 A 1080 1085 imine SYSTEMATIC 23587048 A 1117 1130 hydroperoxide FAMILY 23587048 A 1150 1157 NaNCBH3 FORMULA 23587048 A 1468 1480 nicotinamide TRIVIAL 23587048 A 1495 1504 ascorbate TRIVIAL 23587048 A 160 180 α-hydroxynitrosamine SYSTEMATIC 23587048 A 196 205 diazonium SYSTEMATIC 23587048 A 281 288 hydride SYSTEMATIC 23587048 A 392 453 6-(2-{2-[(9H-purin-6-yl)amino]ethoxy}ethoxy)-9H-purin-2-amine SYSTEMATIC 23587048 A 510 519 diazonium SYSTEMATIC 23587048 A 530 543 3-oxapentanal SYSTEMATIC 23587048 A 556 557 O FORMULA 23587048 A 561 564 Gua ABBREVIATION 23587048 A 588 589 N FORMULA 23587048 A 593 596 Ade ABBREVIATION 23587048 A 769 780 borohydride SYSTEMATIC 23587048 A 793 800 NaNCBH3 FORMULA 23587048 A 878 885 hydride SYSTEMATIC 23587048 A 909 914 NaBH4 FORMULA 23587048 A 918 928 Na(AcO)3BH FORMULA 23587048 A 948 955 NaNCBH3 FORMULA 23587048 T 43 49 Purine TRIVIAL 23587048 T 91 110 N-Nitrosomorpholine SYSTEMATIC 23587423 A 98 104 lysine TRIVIAL 23587426 A 160 182 4-alkyloxybenzaldehyde FAMILY 23587426 A 188 228 2-amino-2-hydroxymethyl-propane-1,3-diol SYSTEMATIC 23587426 A 424 435 methicillin TRIVIAL 23587426 A 98 121 aromatic amino alcohols FAMILY 23587426 T 58 81 aromatic amino alcohols FAMILY 23587660 A 1102 1109 alcohol FAMILY 23587660 A 1206 1213 alcohol FAMILY 23587660 A 277 284 alcohol FAMILY 23587660 A 335 342 alcohol FAMILY 23587660 A 525 532 alcohol FAMILY 23587660 A 66 73 alcohol FAMILY 23587660 T 87 94 alcohol FAMILY 23588093 A 1042 1048 l-NAME ABBREVIATION 23588093 A 1050 1062 indomethacin TRIVIAL 23588093 A 1064 1082 tetraethylammonium SYSTEMATIC 23588093 A 1087 1100 glibenclamide TRIVIAL 23588093 A 1230 1235 CaCl2 FORMULA 23588093 A 1428 1442 norepinephrine TRIVIAL 23588093 A 1576 1582 Ca(2+) FORMULA 23588093 A 1659 1674 p-coumaric acid TRIVIAL 23588093 A 1676 1686 isovitexin TRIVIAL 23588093 A 1688 1696 luteolin TRIVIAL 23588093 A 1701 1712 chrysoeriol TRIVIAL 23588093 A 1725 1733 Luteolin TRIVIAL 23588093 A 1752 1763 chrysoeriol TRIVIAL 23588093 A 1786 1801 p-coumaric acid TRIVIAL 23588093 A 1919 1932 phenylephrine TRIVIAL 23588093 A 2206 2212 Ca(2+) FORMULA 23588093 A 2235 2242 calcium SYSTEMATIC 23588093 A 2294 2302 luteolin TRIVIAL 23588093 A 2304 2315 chrysoeriol TRIVIAL 23588093 A 2320 2335 p-coumaric acid TRIVIAL 23588093 A 771 784 phenylephrine TRIVIAL 23588093 A 826 845 5-hydroxytriptamine SYSTEMATIC 23588093 A 887 890 KCl FORMULA 23588093 A 963 976 phenylephrine TRIVIAL 23588094 A 1411 1418 styrene TRIVIAL 23588094 A 1428 1444 cinnamyl alcohol TRIVIAL 23588094 A 1456 1464 α-pinene TRIVIAL 23588094 A 698 708 chloroform TRIVIAL 23588094 A 713 722 n-butanol SYSTEMATIC 23588094 A 754 761 ethanol SYSTEMATIC 23588312 A 0 14 5-Fluorouracil SYSTEMATIC 23588312 A 1023 1027 5-FU SYSTEMATIC 23588312 A 136 140 5-FU SYSTEMATIC 23588312 A 16 20 5-FU SYSTEMATIC 23588312 A 284 301 dihydropyrimidine SYSTEMATIC 23588312 A 712 716 5-FU SYSTEMATIC 23588390 A 1227 1231 BrdU ABBREVIATION 23588390 A 1294 1306 GEM-C18-PLGA FORMULA 23588390 A 1558 1566 stearoyl TRIVIAL 23588390 A 407 418 gemcitabine TRIVIAL 23588390 A 608 619 gemcitabine TRIVIAL 23588390 A 627 641 4-(N)-stearoyl SYSTEMATIC 23588390 A 654 661 GEM-C18 FORMULA 23588390 A 714 718 PLGA ABBREVIATION 23588390 A 812 824 GEM-C18-PLGA FORMULA 23588390 T 134 154 stearoyl gemcitabine TRIVIAL 23588390 T 90 94 PLGA ABBREVIATION 23588558 T 24 30 statin FAMILY 23588560 A 10 20 Tacrolimus TRIVIAL 23588560 A 1247 1250 TAC ABBREVIATION 23588560 A 1360 1363 TAC ABBREVIATION 23588560 A 1479 1482 TAC ABBREVIATION 23588560 A 206 209 TAC ABBREVIATION 23588560 A 22 25 TAC ABBREVIATION 23588560 A 323 326 TAC ABBREVIATION 23588560 A 432 435 TAC ABBREVIATION 23588560 A 627 630 TAC ABBREVIATION 23588560 A 808 811 TAC ABBREVIATION 23588560 T 39 49 tacrolimus TRIVIAL 23588562 A 1582 1602 tetrahydrocannabinol SYSTEMATIC 23588562 A 1604 1607 THC ABBREVIATION 23588562 A 1613 1624 cannabidiol TRIVIAL 23588562 A 1626 1629 CBD ABBREVIATION 23588681 A 394 418 emodin-6-O-β-D-glucoside SYSTEMATIC 23588681 A 620 651 phorbol-12-myristate 13-acetate SYSTEMATIC 23588681 A 653 656 PMA ABBREVIATION 23588681 A 796 799 PMA ABBREVIATION 23588681 T 0 24 Emodin-6-O-β-D-glucoside SYSTEMATIC 23588682 A 1058 1069 venlafaxine TRIVIAL 23588682 A 1341 1352 venlafaxine TRIVIAL 23588682 A 246 257 venlafaxine TRIVIAL 23588682 A 316 327 venlafaxine TRIVIAL 23588682 A 520 527 carboxy SYSTEMATIC 23588682 A 548 569 polyvinyl pyrrolidone SYSTEMATIC 23588682 T 23 34 venlafaxine TRIVIAL 23588796 A 1045 1056 polyaniline SYSTEMATIC 23588796 A 1187 1198 polyaniline SYSTEMATIC 23588997 A 116 125 zirconium FAMILY 23588997 A 271 279 hydrogen SYSTEMATIC 23588997 A 45 63 zirconium hydrides FAMILY 23588997 A 564 568 ZrH2 FORMULA 23588997 T 10 28 zirconium hydrides FAMILY 23589223 A 1174 1183 fullerene TRIVIAL 23589223 A 534 543 fullerene TRIVIAL 23589223 A 545 548 C60 TRIVIAL 23589223 A 785 794 fullerene TRIVIAL 23589223 T 0 9 Fullerene TRIVIAL 23589329 A 1034 1038 tBHQ ABBREVIATION 23589329 A 1049 1056 arsenic SYSTEMATIC 23589329 A 1144 1151 arsenic SYSTEMATIC 23589329 A 1390 1397 arsenic SYSTEMATIC 23589329 A 516 523 Arsenic SYSTEMATIC 23589329 A 688 695 arsenic SYSTEMATIC 23589329 A 849 861 sulforaphane TRIVIAL 23589329 A 866 888 tert-butylhydroquinone SYSTEMATIC 23589329 A 976 980 tBHQ ABBREVIATION 23589329 T 0 7 Arsenic SYSTEMATIC 23589462 A 299 305 (13) C FORMULA 23589462 A 377 380 N-C FORMULA 23589462 A 40 45 (1) H FORMULA 23589462 A 46 52 (15) N FORMULA 23589462 A 59 65 (15) N FORMULA 23589462 A 647 658 amino acids FAMILY 23589462 A 66 72 (13) C FORMULA 23589462 A 690 696 Zn(II) FORMULA 23589462 A 717 723 Cu(II) FORMULA 23589462 A 726 732 Zn(II) FORMULA 23589462 T 0 6 (13) C FORMULA 23589476 A 206 213 glucose TRIVIAL 23589501 A 103 109 pyrene SYSTEMATIC 23589501 A 1032 1036 NaCl FORMULA 23589501 A 114 125 neocuproine TRIVIAL 23589501 A 232 234 Cu FORMULA 23589501 A 296 304 dioxygen SYSTEMATIC 23589501 A 323 325 Cu FORMULA 23589501 A 384 392 hydrogen SYSTEMATIC 23589501 A 530 532 O2 FORMULA 23589501 A 535 537 Cu FORMULA 23589501 A 687 693 pyrene SYSTEMATIC 23589501 A 699 710 neocuproine TRIVIAL 23589501 A 824 830 oxygen SYSTEMATIC 23589501 A 850 852 Cu FORMULA 23589501 T 31 33 O2 FORMULA 23589624 A 107 118 amino acids FAMILY 23589624 A 390 413 p-azido-l-phenylalanine SYSTEMATIC 23589624 A 415 419 pAzF ABBREVIATION 23589624 A 424 454 p-propargyloxy-l-phenylalanine SYSTEMATIC 23589624 A 456 460 pPaF ABBREVIATION 23589624 T 100 110 amino acid FAMILY 23590189 A 1042 1045 PVO ABBREVIATION 23590189 A 192 200 Vanillin TRIVIAL 23590189 A 404 412 vanillin TRIVIAL 23590189 A 421 443 poly(vanillin oxalate) SYSTEMATIC 23590189 A 445 448 PVO ABBREVIATION 23590189 A 462 465 PVO ABBREVIATION 23590189 A 47 64 hydrogen peroxide SYSTEMATIC 23590189 A 479 483 H2O2 FORMULA 23590189 A 493 509 peroxalate ester SYSTEMATIC 23590189 A 530 538 vanillin TRIVIAL 23590189 A 559 565 acetal SYSTEMATIC 23590189 A 652 655 PVO ABBREVIATION 23590189 A 66 70 H2O2 FORMULA 23590189 A 755 763 vanillin TRIVIAL 23590189 A 765 768 PVO ABBREVIATION 23590189 A 835 839 H2O2 FORMULA 23590189 A 88 92 H2O2 FORMULA 23590189 A 887 893 oxygen SYSTEMATIC 23590189 T 82 90 Vanillin TRIVIAL 23590386 A 1099 1103 P3AT SYSTEMATIC 23590386 A 143 166 poly(3-alkylthiophene)s FAMILY 23590386 A 168 173 P3ATs SYSTEMATIC 23590386 A 176 200 poly(3-dodecylthiophene) SYSTEMATIC 23590386 A 202 207 P3DDT SYSTEMATIC 23590386 A 210 246 poly(3,3‴-didodecyl-quaterthiophene) SYSTEMATIC 23590386 A 248 253 PQT12 ABBREVIATION 23590386 A 260 319 poly(2,5-bis(3-dodecylthiophen-2-yl)thieno[3,2-b]thiophene) SYSTEMATIC 23590386 A 321 328 pBTTT12 ABBREVIATION 23590386 A 366 381 dichloromethane SYSTEMATIC 23590386 A 383 393 chloroform TRIVIAL 23590386 A 395 410 tetrahydrofuran SYSTEMATIC 23590386 A 416 432 carbon disulfide SYSTEMATIC 23590386 A 434 437 CS2 FORMULA 23590386 A 440 443 CS2 FORMULA 23590386 A 544 548 P3AT SYSTEMATIC 23590386 A 596 599 CS2 FORMULA 23590386 A 714 718 P3AT SYSTEMATIC 23590386 A 771 776 P3DDT SYSTEMATIC 23590386 A 787 792 PQT12 ABBREVIATION 23590386 A 875 882 pBTTT12 ABBREVIATION 23590386 A 936 939 CS2 FORMULA 23590386 T 39 62 Poly(3-alkylthiophene)s FAMILY 23590473 A 638 645 alcohol FAMILY 23590667 A 12 16 MoS2 FORMULA 23590667 A 437 441 MoS2 FORMULA 23590667 T 10 14 MoS2 FORMULA 23590689 A 1132 1139 ClFn(+) FAMILY 23590689 A 1192 1195 SFn FAMILY 23590689 A 1286 1293 ClFn(+) FAMILY 23590689 A 1298 1301 SFn FAMILY 23590689 A 132 135 SFn FAMILY 23590689 A 1348 1355 ClFn(+) FAMILY 23590689 A 137 141 ClFn FAMILY 23590689 A 1404 1407 SFn FAMILY 23590689 A 143 146 PFn FAMILY 23590689 A 1460 1467 ClF2(+) FORMULA 23590689 A 148 152 SCln FAMILY 23590689 A 1511 1514 SF2 FORMULA 23590689 A 1563 1565 HF FORMULA 23590689 A 158 163 SFnCl FAMILY 23590689 A 1581 1588 ClFn(+) FAMILY 23590689 A 1593 1596 SFn FAMILY 23590689 A 1623 1624 F FORMULA 23590689 A 1709 1710 F FORMULA 23590689 A 1805 1806 F FORMULA 23590689 A 1816 1823 ClFn(+) FAMILY 23590689 A 1832 1835 SFn FAMILY 23590689 A 1860 1865 Cl(+) FORMULA 23590689 A 1897 1898 F FORMULA 23590689 A 1930 1935 Cl(+) FORMULA 23590689 A 1946 1947 S FORMULA 23590689 A 2042 2049 ClFn(+) FAMILY 23590689 A 636 643 ClFn(+) FAMILY 23590689 A 810 817 ClFn(+) FAMILY 23590689 A 861 865 ClFn FAMILY 23590689 T 38 45 ClFn(+) FAMILY 23590882 A 1192 1203 amino acids FAMILY 23590882 A 1290 1296 Ca(2+) FORMULA 23590882 A 148 158 amino acid FAMILY 23590882 A 165 171 Ca(2+) FORMULA 23590882 T 12 21 Glutamate TRIVIAL 23590892 A 0 8 Paraquat TRIVIAL 23590892 A 1020 1023 DHA ABBREVIATION 23590892 A 130 150 Docosahexaenoic acid SYSTEMATIC 23590892 A 152 155 DHA ABBREVIATION 23590892 A 298 301 DHA ABBREVIATION 23590892 A 506 509 DHA ABBREVIATION 23590892 A 600 603 DHA ABBREVIATION 23590892 A 748 762 hydroxyproline SYSTEMATIC 23590892 A 891 894 DHA ABBREVIATION 23590892 T 0 20 Docosahexaenoic acid SYSTEMATIC 23590892 T 22 25 DHA ABBREVIATION 23590892 T 39 47 paraquat TRIVIAL 23591044 A 1010 1017 ethanol SYSTEMATIC 23591044 A 1022 1029 ethanol SYSTEMATIC 23591044 A 1030 1039 melatonin TRIVIAL 23591044 A 1116 1123 ethanol SYSTEMATIC 23591044 A 1180 1189 melatonin TRIVIAL 23591044 A 1204 1211 Ethanol SYSTEMATIC 23591044 A 1216 1225 melatonin TRIVIAL 23591044 A 1318 1325 steroid FAMILY 23591044 A 192 199 ethanol SYSTEMATIC 23591044 A 211 220 melatonin TRIVIAL 23591044 A 282 289 steroid FAMILY 23591044 A 338 345 ethanol SYSTEMATIC 23591044 A 463 471 androgen FAMILY 23591044 A 473 481 estrogen FAMILY 23591044 A 483 495 progesterone TRIVIAL 23591044 A 500 509 melatonin TRIVIAL 23591044 A 582 591 Melatonin TRIVIAL 23591044 A 602 611 estradiol TRIVIAL 23591044 A 631 643 progesterone TRIVIAL 23591044 A 653 673 6-sulfatoxymelatonin SYSTEMATIC 23591044 A 675 680 6-STM SYSTEMATIC 23591044 A 692 699 ethanol SYSTEMATIC 23591044 A 700 709 melatonin TRIVIAL 23591044 A 8 15 ethanol SYSTEMATIC 23591044 A 830 837 ethanol SYSTEMATIC 23591044 A 838 847 melatonin TRIVIAL 23591044 A 927 934 ethanol SYSTEMATIC 23591044 A 938 947 melatonin TRIVIAL 23591044 A 94 103 melatonin TRIVIAL 23591044 T 0 9 Melatonin TRIVIAL 23591044 T 126 133 steroid FAMILY 23591044 T 14 21 ethanol SYSTEMATIC 23591044 T 67 76 estradiol TRIVIAL 23591044 T 81 93 progesterone TRIVIAL 23591111 A 122 126 zinc SYSTEMATIC 23591111 A 135 150 hydroxamic acid SYSTEMATIC 23591111 A 22 36 β-cyclodextrin TRIVIAL 23591111 A 275 279 SAHA ABBREVIATION 23591111 A 281 291 vorinostat TRIVIAL 23591111 A 38 41 βCD ABBREVIATION 23591111 A 396 400 SAHA ABBREVIATION 23591660 A 1142 1145 C60 TRIVIAL 23591660 A 1210 1213 C60 TRIVIAL 23591660 A 1229 1231 Ga FORMULA 23591660 A 408 411 C60 TRIVIAL 23591660 A 561 567 carbon SYSTEMATIC 23591777 A 1024 1027 MSM ABBREVIATION 23591777 A 1072 1076 CCl4 FORMULA 23591777 A 152 156 CCl4 FORMULA 23591777 A 246 250 CCl4 FORMULA 23591777 A 289 304 malondialdehyde TRIVIAL 23591777 A 306 309 MDA ABBREVIATION 23591777 A 342 352 superoxide TRIVIAL 23591777 A 35 56 methylsulfonylmethane SYSTEMATIC 23591777 A 58 61 MSM ABBREVIATION 23591777 A 594 598 CCl4 FORMULA 23591777 A 636 640 CCl4 FORMULA 23591777 A 66 86 carbon tetrachloride SYSTEMATIC 23591777 A 741 744 MSM ABBREVIATION 23591777 A 832 835 MDA ABBREVIATION 23591777 A 88 92 CCl4 FORMULA 23591777 A 880 884 CCl4 FORMULA 23591777 A 919 922 MSM ABBREVIATION 23591777 T 27 48 methylsulfonylmethane SYSTEMATIC 23591777 T 57 77 carbon tetrachloride SYSTEMATIC 23591995 A 1011 1021 ramiprilat TRIVIAL 23592429 A 31 39 androgen FAMILY 23592429 A 323 332 androgens FAMILY 23592429 A 375 384 androgens FAMILY 23592429 A 420 439 Abiraterone acetate SYSTEMATIC 23592429 A 444 452 androgen FAMILY 23592429 A 478 490 enzalutamide TRIVIAL 23592429 A 501 509 androgen FAMILY 23592429 A 574 583 androgens FAMILY 23592429 A 671 679 androgen FAMILY 23592429 A 797 805 androgen FAMILY 23592429 T 12 20 androgen FAMILY 23592516 A 1089 1096 choline FAMILY 23592516 A 1107 1119 L-amino acid FAMILY 23592516 A 1240 1243 OPZ ABBREVIATION 23592516 A 1247 1253 NK-252 IDENTIFIER 23592516 A 598 603 thiol FAMILY 23592516 A 619 627 oltipraz TRIVIAL 23592516 A 629 632 OPZ ABBREVIATION 23592516 A 693 697 urea TRIVIAL 23592516 A 715 721 NK-252 IDENTIFIER 23592516 A 723 729 NK-252 IDENTIFIER 23592516 A 780 783 OPZ ABBREVIATION 23592516 A 837 843 NK-252 IDENTIFIER 23592516 A 921 924 OPZ ABBREVIATION 23592516 A 963 969 NK-252 IDENTIFIER 23592516 A 990 993 OPZ ABBREVIATION 23592568 A 43 62 trimethine cyanines FAMILY 23592568 T 47 65 Trimethine Cyanine SYSTEMATIC 23592779 A 93 104 vitamin B12 TRIVIAL 23593923 A 594 600 serine TRIVIAL 23593960 A 148 172 toluene-2,4-diisocyanate SYSTEMATIC 23593960 A 174 177 TDI ABBREVIATION 23593960 A 31 39 diacetyl SYSTEMATIC 23593960 A 389 392 TDI ABBREVIATION 23593960 A 481 484 TDI ABBREVIATION 23593960 T 3 11 Diacetyl SYSTEMATIC 23594296 A 1005 1018 ethyl acetate SYSTEMATIC 23594296 A 1043 1048 taxol TRIVIAL 23594296 A 1103 1108 taxol TRIVIAL 23594296 A 1116 1131 dichloromethane SYSTEMATIC 23594296 A 1140 1150 chloroform TRIVIAL 23594296 A 1191 1192 C FORMULA 23594296 A 1193 1195 Cl FORMULA 23594296 A 1210 1218 hydrogen SYSTEMATIC 23594296 A 1236 1244 hydroxyl SYSTEMATIC 23594296 A 1260 1265 taxol TRIVIAL 23594296 A 182 191 phosphate SYSTEMATIC 23594296 A 237 245 methanol SYSTEMATIC 23594296 A 251 258 ethanol SYSTEMATIC 23594296 A 264 292 hydroxypropyl β-cyclodextrin SYSTEMATIC 23594296 A 294 300 HP-βCD ABBREVIATION 23594296 A 306 320 sodium citrate SYSTEMATIC 23594296 A 328 336 Tween 80 TRIVIAL 23594296 A 378 385 octanol SYSTEMATIC 23594296 A 391 406 dichloromethane SYSTEMATIC 23594296 A 412 422 chloroform TRIVIAL 23594296 A 431 444 ethyl acetate SYSTEMATIC 23594296 A 468 473 taxol TRIVIAL 23594296 A 56 61 taxol TRIVIAL 23594296 A 682 687 taxol TRIVIAL 23594296 A 775 783 Tween 80 TRIVIAL 23594296 A 837 842 taxol TRIVIAL 23594296 A 878 884 HP-βCD ABBREVIATION 23594296 A 899 904 taxol TRIVIAL 23594296 T 38 43 taxol TRIVIAL 23594789 A 0 16 Thyroid hormones FAMILY 23594789 A 639 642 PTU ABBREVIATION 23594789 A 644 667 6-n-propyl-2-thiouracil SYSTEMATIC 23594789 A 750 766 triiodothyronine TRIVIAL 23594789 A 781 784 PTU ABBREVIATION 23594789 A 884 887 PTU ABBREVIATION 23594789 T 30 45 thyroid hormone FAMILY 23595055 A 1093 1100 bromine SYSTEMATIC 23595055 A 1123 1127 MeOH FORMULA 23595055 A 1403 1410 bromine SYSTEMATIC 23595055 A 339 358 brominated tyrosine TRIVIAL 23595055 A 706 719 bromotyrosine SYSTEMATIC 23595055 A 928 932 MeOH FORMULA 23595419 A 1041 1048 lithium SYSTEMATIC 23595419 A 1159 1161 Na FORMULA 23595419 A 1162 1164 Li FORMULA 23595419 A 1173 1174 K FORMULA 23595419 A 1175 1177 Li FORMULA 23595419 A 1185 1187 Mg FORMULA 23595419 A 1188 1190 Li FORMULA 23595419 A 119 126 lithium SYSTEMATIC 23595419 A 15 22 lithium SYSTEMATIC 23595419 A 173 180 lithium SYSTEMATIC 23595419 A 310 317 lithium SYSTEMATIC 23595419 A 343 365 lithium iron phosphate SYSTEMATIC 23595419 A 434 441 lithium SYSTEMATIC 23595419 A 446 452 sodium SYSTEMATIC 23595419 A 511 520 magnesium SYSTEMATIC 23595419 A 656 663 lithium SYSTEMATIC 23595419 A 730 734 MnO2 FORMULA 23595419 A 760 768 chloride SYSTEMATIC 23595419 A 834 841 lithium SYSTEMATIC 23595419 A 877 886 magnesium SYSTEMATIC 23595419 A 941 948 lithium SYSTEMATIC 23595419 T 17 24 lithium SYSTEMATIC 23595419 T 55 59 MnO2 FORMULA 23595419 T 60 62 Ag FORMULA 23595510 A 1194 1199 (13)C FORMULA 23595510 A 1201 1205 (1)H FORMULA 23595510 A 1276 1282 carbon SYSTEMATIC 23595510 A 279 286 carbide FAMILY 23595510 A 295 302 carbons FAMILY 23595510 A 568 574 carbon SYSTEMATIC 23595510 A 57 63 carbon SYSTEMATIC 23595510 A 771 777 carbon SYSTEMATIC 23595510 T 66 73 carbide FAMILY 23595510 T 82 88 carbon SYSTEMATIC 23595554 A 477 487 difenacoum TRIVIAL 23595554 A 492 504 bromadiolone TRIVIAL 23595692 A 1030 1039 capsaicin TRIVIAL 23595692 A 1146 1154 pine-oil TRIVIAL 23595692 A 25 33 pine oil TRIVIAL 23595692 A 988 1010 adenosine triphosphate SYSTEMATIC 23595692 T 0 8 Pine Oil TRIVIAL 23596084 A 258 270 benzophenone SYSTEMATIC 23596084 A 75 96 poly(alkylacrylamide) FAMILY 23596084 T 57 81 Poly(N-alkyl Acrylamide) FAMILY 23596091 A 0 26 Fluorescein isothiocyanate SYSTEMATIC 23596091 A 144 152 mPEG-PCL ABBREVIATION 23596091 A 166 187 FITC-labeled mPEG-PCL ABBREVIATION 23596091 A 28 32 FITC ABBREVIATION 23596091 A 397 401 FITC ABBREVIATION 23596091 A 82 142 monomethoxy poly(ethylene glycol)-block-poly(ε-caprolactone) SYSTEMATIC 23596325 A 1096 1118 unsaturated fatty acid FAMILY 23596325 A 204 214 fatty acid FAMILY 23596325 A 419 426 glucose TRIVIAL 23596325 A 519 526 sucrose TRIVIAL 23596359 A 0 20 Cyclic tetrapeptides FAMILY 23596359 A 572 585 d-amino acids FAMILY 23596359 A 589 596 proline TRIVIAL 23596359 A 812 832 cyclic tetrapeptides FAMILY 23596359 A 928 936 hydrogen SYSTEMATIC 23596359 T 35 55 Cyclic Tetrapeptides FAMILY 23596972 A 1128 1132 VA64 IDENTIFIER 23596972 A 1677 1681 VA64 IDENTIFIER 23596972 A 659 663 VA64 IDENTIFIER 23597047 A 0 9 Adenosine TRIVIAL 23597047 A 1221 1232 nucleotides FAMILY 23597047 A 81 98 nucleosides/tides MULTIPLE 23597047 T 119 128 Adenosine TRIVIAL 23597071 A 488 494 biotin TRIVIAL 23597099 A 255 260 EtOAc FORMULA 23597099 A 289 305 2-methoxyjuglone SYSTEMATIC 23597099 A 606 622 propidium iodide TRIVIAL 23597099 A 64 71 ethanol SYSTEMATIC 23597099 A 747 763 propidium iodide TRIVIAL 23597099 T 0 16 2-Methoxyjuglone SYSTEMATIC 23597133 A 1027 1030 HCO FORMULA 23597133 A 1138 1141 HCO FORMULA 23597133 A 1147 1148 H FORMULA 23597133 A 1151 1153 CO FORMULA 23597133 A 1337 1338 H FORMULA 23597133 A 1339 1341 CO FORMULA 23597133 A 1362 1364 CO FORMULA 23597133 A 142 143 H FORMULA 23597133 A 148 150 CO FORMULA 23597133 A 42 55 H-CO(X̃(2)A') FAMILY 23597133 A 614 615 H FORMULA 23597133 A 616 618 CO FORMULA 23597133 A 77 79 CO FORMULA 23597133 T 57 70 H-CO(X̃(2)A') FAMILY 23597450 A 0 8 Prunetin TRIVIAL 23597450 A 1022 1030 prunetin TRIVIAL 23597450 A 1179 1187 prunetin TRIVIAL 23597450 A 1388 1396 prunetin TRIVIAL 23597450 A 148 156 prunetin TRIVIAL 23597450 A 15 38 O-methylated isoflavone FAMILY 23597450 A 212 220 prunetin TRIVIAL 23597450 A 324 336 nitric oxide SYSTEMATIC 23597450 A 781 789 prunetin TRIVIAL 23597450 A 862 870 prunetin TRIVIAL 23597450 A 892 904 nitric oxide SYSTEMATIC 23597450 A 909 925 prostaglandin E2 TRIVIAL 23597450 T 28 36 prunetin TRIVIAL 23597490 A 0 7 Embelin TRIVIAL 23597490 A 1174 1181 embelin TRIVIAL 23597490 A 1204 1211 embelin TRIVIAL 23597490 A 149 163 streptozotocin TRIVIAL 23597490 A 165 168 STZ ABBREVIATION 23597490 A 198 205 embelin TRIVIAL 23597490 A 252 255 STZ ABBREVIATION 23597490 A 346 353 glucose TRIVIAL 23597490 A 557 572 malondialdehyde TRIVIAL 23597490 A 592 603 glutathione TRIVIAL 23597490 A 626 636 superoxide TRIVIAL 23597490 A 706 709 STZ ABBREVIATION 23597490 A 745 752 embelin TRIVIAL 23597490 A 778 785 Embelin TRIVIAL 23597490 A 803 806 STZ ABBREVIATION 23597490 A 9 21 benzoquinone SYSTEMATIC 23597490 A 910 917 embelin TRIVIAL 23597490 T 26 33 embelin TRIVIAL 23597507 A 1090 1098 SB366791 IDENTIFIER 23597507 A 1136 1145 capsaicin TRIVIAL 23597507 A 1154 1160 Ca(2+) FORMULA 23597507 A 1233 1241 SB366791 IDENTIFIER 23597507 A 1256 1265 capsaicin TRIVIAL 23597507 A 1274 1280 Ca(2+) FORMULA 23597507 A 1395 1404 capsaicin TRIVIAL 23597507 A 275 282 calcium SYSTEMATIC 23597507 A 463 472 capsaicin TRIVIAL 23597507 A 518 524 Ca(2+) FORMULA 23597507 A 754 763 capsaicin TRIVIAL 23597507 A 796 804 SB366791 IDENTIFIER 23597507 A 846 856 nifedipine TRIVIAL 23597507 A 861 871 mibefradil TRIVIAL 23597507 A 935 944 capsaicin TRIVIAL 23597507 A 997 1003 Ca(2+) FORMULA 23597507 T 21 30 capsaicin TRIVIAL 23597510 A 1033 1041 nicotine TRIVIAL 23597510 A 1077 1084 cocaine TRIVIAL 23597510 A 109 117 nicotine TRIVIAL 23597510 A 1100 1108 nicotine TRIVIAL 23597510 A 1147 1155 nicotine TRIVIAL 23597510 A 1181 1188 cocaine TRIVIAL 23597510 A 121 128 alcohol FAMILY 23597510 A 1232 1240 nicotine TRIVIAL 23597510 A 1244 1251 cocaine TRIVIAL 23597510 A 1366 1374 nicotine TRIVIAL 23597510 A 1426 1457 Suberoylanilide hydroxamic acid SYSTEMATIC 23597510 A 1459 1463 SAHA ABBREVIATION 23597510 A 1531 1539 nicotine TRIVIAL 23597510 A 1607 1615 nicotine TRIVIAL 23597510 A 1816 1824 nicotine TRIVIAL 23597510 A 1828 1835 cocaine TRIVIAL 23597510 A 195 202 cocaine TRIVIAL 23597510 A 460 468 nicotine TRIVIAL 23597510 A 515 522 cocaine TRIVIAL 23597510 A 538 546 nicotine TRIVIAL 23597510 A 632 639 cocaine TRIVIAL 23597510 A 707 715 nicotine TRIVIAL 23597510 A 719 726 cocaine TRIVIAL 23597510 A 874 882 nicotine TRIVIAL 23597510 A 945 952 cocaine TRIVIAL 23597510 T 0 8 Nicotine TRIVIAL 23597510 T 30 37 cocaine TRIVIAL 23597793 A 1004 1007 Asp FORMULA 23597793 A 1030 1042 nicotinamide TRIVIAL 23597793 A 1051 1058 NADP(+) ABBREVIATION 23597793 A 146 150 (1)H FORMULA 23597793 A 152 157 (13)C FORMULA 23597793 A 2 11 tetrazole FAMILY 23597793 A 257 275 11β-hydroxysteroid FAMILY 23597793 A 34 48 clofibric acid TRIVIAL 23597793 A 424 434 clofibrate TRIVIAL 23597793 A 439 453 clofibric acid TRIVIAL 23597793 A 647 654 glucose TRIVIAL 23597793 A 986 989 Ser FORMULA 23597793 A 995 998 Tyr FORMULA 23597793 T 47 56 tetrazole FAMILY 23597793 T 69 83 clofibric acid TRIVIAL 23598462 A 305 313 graphene TRIVIAL 23598462 T 40 48 graphene TRIVIAL 23598904 A 1174 1180 Cd(2+) FORMULA 23598904 A 1185 1191 Mn(2+) FORMULA 23598904 A 162 169 cadmium SYSTEMATIC 23598904 A 174 183 manganese SYSTEMATIC 23598904 A 252 259 cadmium SYSTEMATIC 23598904 A 264 273 manganese SYSTEMATIC 23598904 A 292 294 Cd FORMULA 23598904 A 309 311 Mn FORMULA 23598904 A 388 393 CdCl2 FORMULA 23598904 A 398 403 MnCl2 FORMULA 23598904 A 435 437 Cd FORMULA 23598904 A 462 464 Mn FORMULA 23598904 A 538 543 CdCl2 FORMULA 23598904 A 548 553 MnCl2 FORMULA 23598904 A 659 666 cadmium SYSTEMATIC 23598904 A 671 680 manganese SYSTEMATIC 23598904 A 77 82 CdCl2 FORMULA 23598904 A 802 807 HgCl2 FORMULA 23598904 A 812 817 AgNO3 FORMULA 23598904 A 87 92 MnCl2 FORMULA 23598904 A 932 938 Cd(2+) FORMULA 23598904 A 943 949 Mn(2+) FORMULA 23598904 T 54 61 cadmium SYSTEMATIC 23598904 T 76 85 manganese SYSTEMATIC 23599006 A 1111 1118 alanine TRIVIAL 23599006 A 1140 1149 aspartate TRIVIAL 23599006 A 766 799 7-O-(β-D-glucopyranosyl)-galactin SYSTEMATIC 23599431 A 1013 1020 TC14012 IDENTIFIER 23599433 A 139 145 serine TRIVIAL 23599433 A 146 155 threonine TRIVIAL 23599433 T 62 68 serine TRIVIAL 23599433 T 69 78 threonine TRIVIAL 23600432 A 63 79 arachidonic acid TRIVIAL 23600432 A 789 808 1,5-diarylpyrazoles FAMILY 23600432 A 810 821 indolizines FAMILY 23600432 A 826 833 indoles FAMILY 23600486 A 181 186 ZnCl2 FORMULA 23600486 A 206 230 cyclic alkylaminocarbene FAMILY 23600486 A 232 236 cAAC ABBREVIATION 23600486 A 294 297 KC8 ABBREVIATION 23600486 A 302 315 LiB(sec-Bu)3H FORMULA 23600486 A 345 359 dicarbene zinc SYSTEMATIC 23600486 A 369 378 (cAAC)2Zn FORMULA 23600486 A 414 418 zinc SYSTEMATIC 23600486 A 428 438 (cAACH)2Zn FORMULA 23600486 A 751 754 CO2 FORMULA 23600486 A 795 799 cAAC ABBREVIATION 23600486 A 800 803 CO2 FORMULA 23600486 T 23 27 Zinc SYSTEMATIC 23600612 A 141 148 lignans FAMILY 23600612 A 150 157 visanol TRIVIAL 23600612 A 166 184 9-aldehydevibsanol SYSTEMATIC 23600612 A 19 43 8-dehydroxymethylvisanol SYSTEMATIC 23600612 A 217 221 EtOH FORMULA 23600612 A 374 381 lignans FAMILY 23600612 A 52 111 9-O-[3-O-acetyl-β-d-glucopyranosyl]-4-hydroxy-cinnamic acid SYSTEMATIC 23600626 A 235 242 polyHis ABBREVIATION 23600626 A 247 254 polyAsp ABBREVIATION 23600626 A 280 300 poly-l-glutamic acid SYSTEMATIC 23600626 A 302 309 polyGlu ABBREVIATION 23600626 A 335 342 polyHis ABBREVIATION 23600626 A 34 53 poly(aspartic acid) SYSTEMATIC 23600626 A 379 386 polyHis ABBREVIATION 23600626 A 387 394 polyAsp ABBREVIATION 23600626 A 462 469 polyHis ABBREVIATION 23600626 A 470 477 polyGlu ABBREVIATION 23600626 A 513 520 PolyHis ABBREVIATION 23600626 A 521 528 polyAsp ABBREVIATION 23600626 A 55 62 polyAsp ABBREVIATION 23600626 A 562 569 polyHis ABBREVIATION 23600626 A 570 577 polyGlu ABBREVIATION 23600626 A 68 84 poly-l-histidine SYSTEMATIC 23600626 A 831 846 ethylene glycol SYSTEMATIC 23600626 A 86 93 polyHis ABBREVIATION 23600646 A 140 144 TiO2 FORMULA 23600646 A 244 255 bisphenol A TRIVIAL 23600646 A 260 277 dibutyl phthalate SYSTEMATIC 23600646 A 34 39 Fe3O4 FORMULA 23600646 A 40 44 TiO2 FORMULA 23600646 A 492 497 Fe3O4 FORMULA 23600646 A 498 502 TiO2 FORMULA 23600646 A 786 790 TiO2 FORMULA 23600646 A 874 885 bisphenol A TRIVIAL 23600646 A 890 907 dibutyl phthalate SYSTEMATIC 23600646 A 987 992 Fe3O4 FORMULA 23600646 T 28 33 Fe3O4 FORMULA 23600646 T 34 38 TiO2 FORMULA 23600648 A 342 365 quinochalcone glycoside FAMILY 23600648 A 35 52 saffloquinoside C TRIVIAL 23600648 A 389 404 dioxaspirocycle FAMILY 23600648 A 61 136 (-)-4-hydroxybenzoic acid-4-O-[6'-O-(2″-methylbutyryl)-β-D-glucopyranoside] SYSTEMATIC 23600656 A 1236 1240 DPPC ABBREVIATION 23600656 A 1565 1569 DPPC ABBREVIATION 23600656 A 1582 1586 DPPC ABBREVIATION 23600656 A 223 242 phosphatidylcholine FAMILY 23600656 A 254 297 1,2-dipalmitoyl-sn-glycero-3-phosphacholine SYSTEMATIC 23600656 A 299 303 DPPC ABBREVIATION 23600656 A 354 361 Brucine TRIVIAL 23600656 A 442 446 DPPC ABBREVIATION 23600656 A 476 483 brucine TRIVIAL 23600656 A 655 659 DPPC ABBREVIATION 23600656 A 756 760 DPPC ABBREVIATION 23600656 A 865 869 DPPC ABBREVIATION 23600656 A 925 929 DPPC ABBREVIATION 23600656 T 0 7 Brucine TRIVIAL 23600717 A 106 118 fawcettimine TRIVIAL 23600717 A 146 163 lycobscurines A-C MULTIPLE 23600735 A 236 250 Anthraquinones FAMILY 23600735 A 252 262 flavonoids FAMILY 23600735 A 268 278 terpenoids FAMILY 23600754 A 129 209 3,4-secocycloarta-4(28),17(20),24(Z)-triene-7β-hydroxy-16β,26-lactone-3-oic acid SYSTEMATIC 23600754 A 218 303 3,4-secocycloarta-4(28),17(20)(Z),24(Z)-triene-7β-hydroxy-16β-methoxy-3,26-dioic acid SYSTEMATIC 23600754 A 53 67 nigranoic acid TRIVIAL 23600754 A 556 561 ester FAMILY 23600754 A 601 608 lactone FAMILY 23600754 A 638 657 3,4-secocycloartane SYSTEMATIC 23600754 A 69 120 3,4-secocycloarta-4(28),24(Z)-diene-3,26-dioic acid SYSTEMATIC 23600754 T 49 63 nigranoic acid TRIVIAL 23600800 A 0 3 ATP ABBREVIATION 23600800 A 1006 1012 MG-132 IDENTIFIER 23600800 A 249 256 calcium SYSTEMATIC 23600800 A 278 284 serine TRIVIAL 23600800 A 647 653 serine TRIVIAL 23600807 A 161 178 diketopiperazines FAMILY 23600807 A 19 31 rhodostegone FAMILY 23600807 A 85 104 cyclo-(l-Val-l-Leu) SYSTEMATIC 23600887 A 104 114 furostanol TRIVIAL 23600887 A 115 123 saponins FAMILY 23600887 A 158 176 steroidal saponins FAMILY 23600887 A 298 470 (25R)-26-O-[β-d-glucopyranosyl-(1 → 2)-β-d-glucopyranosyl]-5-ene-furost-1β,3β,22α,26-tetraol-3-O-α-l-rhamnopyranosyl-(1 → 2)-[β-d-xylopyranosyl-(1 → 4)]-β-d-glucopyranoside SYSTEMATIC 23600887 A 475 489 ophiopogonin P TRIVIAL 23600887 A 495 667 (25R)-26-O-[β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranosyl]-5-ene-furost-1β,3β,22α,26-tetraol-3-O-α-l-rhamnopyranosyl-(1 → 2)-[β-d-xylopyranosyl-(1 → 4)]-β-d-glucopyranoside SYSTEMATIC 23600887 A 672 686 ophiopogonin Q TRIVIAL 23600887 A 689 699 Furostanol TRIVIAL 23600887 A 700 708 saponins FAMILY 23600887 A 718 730 disaccharide FAMILY 23600887 A 747 759 C-26 hydroxy SYSTEMATIC 23600887 T 10 20 furostanol TRIVIAL 23600887 T 21 29 saponins FAMILY 23600914 A 1201 1207 24-OHC SYSTEMATIC 23600914 A 1262 1268 24-OHC SYSTEMATIC 23600914 A 130 154 24(S)-hydroxycholesterol SYSTEMATIC 23600914 A 156 162 24-OHC SYSTEMATIC 23600914 A 363 369 24-OHC SYSTEMATIC 23600914 A 39 50 cholesterol TRIVIAL 23600914 A 488 494 24-OHC SYSTEMATIC 23600914 A 5 16 cholesterol TRIVIAL 23600914 A 507 515 TO901317 IDENTIFIER 23600914 A 520 533 retinoic acid TRIVIAL 23600914 A 639 645 24-OHC SYSTEMATIC 23600914 A 993 999 24-OHC SYSTEMATIC 23600914 T 0 24 24(S)-hydroxycholesterol SYSTEMATIC 23600925 A 177 192 diaminothiazole FAMILY 23600925 A 36 42 serine TRIVIAL 23600925 A 43 52 threonine TRIVIAL 23600925 T 43 58 Diaminothiazole FAMILY 23601387 A 162 172 vitamin D3 TRIVIAL 23601387 A 177 198 25-hydroxy-vitamin D3 SYSTEMATIC 23601387 A 200 206 25OHD3 SYSTEMATIC 23601387 A 316 325 vitamin D FAMILY 23601387 A 35 44 vitamin D FAMILY 23601387 A 438 448 vitamin D3 TRIVIAL 23601387 A 465 471 25OHD3 SYSTEMATIC 23601387 A 516 526 vitamin D3 TRIVIAL 23601387 A 538 544 25OHD3 SYSTEMATIC 23601387 A 593 603 vitamin D3 TRIVIAL 23601387 A 616 622 25OHD3 SYSTEMATIC 23601387 A 760 770 vitamin D3 TRIVIAL 23601387 T 50 60 vitamin D3 TRIVIAL 23601387 T 65 86 25-hydroxy-vitamin D3 SYSTEMATIC 23601391 A 30 35 sugar FAMILY 23601393 A 157 170 ascorbic acid TRIVIAL 23601393 A 401 414 Ascorbic acid TRIVIAL 23601393 A 521 525 zinc SYSTEMATIC 23601393 A 530 536 copper SYSTEMATIC 23601393 A 549 556 calcium SYSTEMATIC 23601393 A 558 567 magnesium SYSTEMATIC 23601393 A 572 583 phosphorous SYSTEMATIC 23601393 A 627 636 Potassium SYSTEMATIC 23601393 A 765 778 ascorbic acid TRIVIAL 23601396 A 156 169 carbohydrates FAMILY 23601396 A 219 223 iron SYSTEMATIC 23601396 A 225 229 zinc SYSTEMATIC 23601396 A 231 240 magnesium SYSTEMATIC 23601396 A 242 249 calcium SYSTEMATIC 23601396 A 251 261 phosphorus SYSTEMATIC 23601396 A 263 269 copper SYSTEMATIC 23601396 A 271 280 manganese SYSTEMATIC 23601396 A 282 291 potassium SYSTEMATIC 23601396 A 293 299 sodium SYSTEMATIC 23601396 A 304 312 selenium SYSTEMATIC 23601396 A 799 803 iron SYSTEMATIC 23601396 A 805 809 zinc SYSTEMATIC 23601396 A 814 823 magnesium SYSTEMATIC 23601409 A 1196 1203 ethanol SYSTEMATIC 23601409 A 724 738 monosaccharide FAMILY 23601409 A 803 810 Glucose TRIVIAL 23601409 A 840 854 monosaccharide FAMILY 23601409 A 868 877 arabinose TRIVIAL 23601409 A 879 888 galactose TRIVIAL 23601409 A 890 896 xylose TRIVIAL 23601409 A 901 908 mannose TRIVIAL 23601709 A 0 4 EMPA ABBREVIATION 23601709 A 1093 1104 [(11)C]EMPA SYSTEMATIC 23601709 A 337 341 EMPA ABBREVIATION 23601709 A 347 353 carbon SYSTEMATIC 23601709 A 376 478 [(11)C]N-ethyl-2-(N-(6-methoxypyridin-3-yl)-2-methylphenylsulfonamido)-N-(pyridin-3-ylmethyl)acetamide SYSTEMATIC 23601709 A 480 491 [(11)C]EMPA SYSTEMATIC 23601709 A 611 612 O FORMULA 23601709 A 651 655 EMPA ABBREVIATION 23601709 A 661 674 sodium iodide SYSTEMATIC 23601709 A 679 700 chlorotrimethylsilane SYSTEMATIC 23601709 A 712 713 O FORMULA 23601709 A 732 743 [(11)C]CH3I SYSTEMATIC 23601709 A 763 779 cesium carbonate SYSTEMATIC 23601709 A 783 787 DMSO ABBREVIATION 23601709 A 810 821 [(11)C]EMPA SYSTEMATIC 23601709 A 85 96 [(3)H]-EMPA SYSTEMATIC 23601709 A 881 892 [(11)C]CH3I SYSTEMATIC 23601709 T 33 44 [(11)C]EMPA SYSTEMATIC 23601710 A 134 177 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione SYSTEMATIC 23601710 A 417 432 benzotriazepine FAMILY 23601710 A 437 456 spirobenzodiazepine FAMILY 23601710 A 52 58 phenyl SYSTEMATIC 23601710 T 155 161 phenyl SYSTEMATIC 23601710 T 18 61 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione SYSTEMATIC 23601711 A 221 227 S14161 IDENTIFIER 23601711 A 28 75 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene SYSTEMATIC 23601711 A 342 351 l-proline SYSTEMATIC 23601711 A 356 369 triethylamine SYSTEMATIC 23601711 A 434 470 6-bromo-8-ethoxy-3-nitro-2H-chromene SYSTEMATIC 23601711 A 472 480 BENC-511 IDENTIFIER 23601711 A 587 593 S14161 IDENTIFIER 23601711 A 595 603 BENC-511 IDENTIFIER 23601711 A 692 700 BENC-511 IDENTIFIER 23601711 A 77 83 S14161 IDENTIFIER 23601711 T 15 21 S14161 IDENTIFIER 23601711 T 61 97 6-bromo-8-ethoxy-3-nitro-2H-chromene SYSTEMATIC 23602400 A 0 57 2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine SYSTEMATIC 23602400 A 195 202 4-amino SYSTEMATIC 23602400 A 235 246 pyrimidines FAMILY 23602400 A 278 330 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine SYSTEMATIC 23602400 A 410 427 N-propylacetamide SYSTEMATIC 23602400 T 37 63 4-amino-2-phenylpyrimidine SYSTEMATIC 23602442 A 253 264 diarylureas FAMILY 23602442 A 285 290 amine SYSTEMATIC 23602442 A 57 67 diarylurea FAMILY 23602442 T 13 23 diarylurea FAMILY 23602516 A 0 9 Cisplatin TRIVIAL 23602516 A 1135 1144 Cisplatin TRIVIAL 23602516 A 1361 1370 cisplatin TRIVIAL 23602516 A 1459 1468 cisplatin TRIVIAL 23602516 A 1544 1553 cisplatin TRIVIAL 23602516 A 1579 1588 cisplatin TRIVIAL 23602516 A 1687 1696 cisplatin TRIVIAL 23602516 A 1785 1794 cisplatin TRIVIAL 23602516 A 416 425 cisplatin TRIVIAL 23602516 A 851 860 cisplatin TRIVIAL 23602516 A 961 970 cisplatin TRIVIAL 23602516 T 0 9 Cisplatin TRIVIAL 23602732 A 353 364 Salidroside TRIVIAL 23602732 A 369 376 tyrosol TRIVIAL 23602732 A 65 76 salidroside TRIVIAL 23602732 A 778 789 salidroside TRIVIAL 23602732 A 794 801 tyrosol TRIVIAL 23602732 A 81 88 tyrosol TRIVIAL 23602891 A 235 238 HCQ ABBREVIATION 23602891 A 43 61 hydroxychloroquine SYSTEMATIC 23602891 A 63 66 HCQ ABBREVIATION 23602891 A 845 848 HCQ ABBREVIATION 23602891 A 900 903 HCQ ABBREVIATION 23602891 T 49 67 Hydroxychloroquine SYSTEMATIC 23602903 A 0 21 Scrophularianines A-C MULTIPLE 23602903 A 406 426 monoterpene pyridine FAMILY 23602903 A 441 449 iridoids FAMILY 23602903 A 47 77 monoterpene pyridine alkaloids FAMILY 23602903 A 630 634 H2O2 FORMULA 23602903 A 83 106 cyclopenta [c] pyridine SYSTEMATIC 23602903 T 0 30 Monoterpene pyridine alkaloids FAMILY 23602903 T 35 44 phenolics FAMILY 23602986 A 1070 1078 nicotine TRIVIAL 23602986 A 114 117 MLA ABBREVIATION 23602986 A 1148 1156 nicotine TRIVIAL 23602986 A 123 147 dihydro-beta-eritroidine SYSTEMATIC 23602986 A 1264 1272 cotinine TRIVIAL 23602986 A 1279 1287 cotinine TRIVIAL 23602986 A 1288 1296 nicotine TRIVIAL 23602986 A 149 153 DHβE ABBREVIATION 23602986 A 42 50 nicotine TRIVIAL 23602986 A 52 55 NIC ABBREVIATION 23602986 A 58 66 cotinine TRIVIAL 23602986 A 604 612 nicotine TRIVIAL 23602986 A 633 641 Cotinine TRIVIAL 23602986 A 677 685 nicotine TRIVIAL 23602986 A 68 71 COT ABBREVIATION 23602986 A 74 86 mecamylamine TRIVIAL 23602986 A 792 800 cotinine TRIVIAL 23602986 A 809 817 nicotine TRIVIAL 23602986 A 88 91 MEC ABBREVIATION 23602986 A 94 112 methyllycaconitine TRIVIAL 23602986 A 991 999 Cotinine TRIVIAL 23602986 T 23 31 cotinine TRIVIAL 23602989 A 1018 1023 KN-62 IDENTIFIER 23602989 A 1090 1094 K(+) FORMULA 23602989 A 1176 1186 [(3)H]GABA FORMULA 23602989 A 1230 1235 KN-62 IDENTIFIER 23602989 A 1297 1307 PD 128,907 IDENTIFIER 23602989 A 1344 1353 SKF 38393 IDENTIFIER 23602989 A 1371 1376 KN-62 IDENTIFIER 23602989 A 1406 1414 dopamine TRIVIAL 23602989 A 1441 1451 [(3)H]GABA FORMULA 23602989 A 1461 1466 KN-62 IDENTIFIER 23602989 A 1484 1492 dopamine TRIVIAL 23602989 A 1512 1517 KN-62 IDENTIFIER 23602989 A 1670 1676 Ca(2+) FORMULA 23602989 A 1731 1735 GABA ABBREVIATION 23602989 A 1873 1881 dopamine TRIVIAL 23602989 A 425 431 Ca(2+) FORMULA 23602989 A 516 522 Ca(2+) FORMULA 23602989 A 524 533 ionomycin TRIVIAL 23602989 A 538 542 K(+) FORMULA 23602989 A 597 601 cAMP ABBREVIATION 23602989 A 650 658 dopamine TRIVIAL 23602989 A 702 707 KN-62 IDENTIFIER 23602989 A 742 751 ionomycin TRIVIAL 23602989 A 756 760 K(+) FORMULA 23602989 A 798 803 Ca(2) FORMULA 23602989 A 842 848 Ca(2+) FORMULA 23602989 A 857 867 nifedipine TRIVIAL 23602989 A 907 911 K(+) FORMULA 23602989 A 959 963 K(+) FORMULA 23602989 T 111 117 Ca(2+) FORMULA 23602989 T 30 38 dopamine TRIVIAL 23603053 A 0 30 Polybrominated diphenyl ethers FAMILY 23603053 A 1003 1011 OH-PBDEs FAMILY 23603053 A 1143 1151 OH-PBDEs FAMILY 23603053 A 1288 1295 OH-PBDE FORMULA 23603053 A 1378 1386 OH-PBDEs FAMILY 23603053 A 191 195 PBDE ABBREVIATION 23603053 A 197 204 OH-PBDE FORMULA 23603053 A 255 263 OH-PBDEs FAMILY 23603053 A 32 37 PBDEs ABBREVIATION 23603053 A 397 405 OH-PBDEs FAMILY 23603053 A 529 541 6-OH-BDE-047 SYSTEMATIC 23603053 A 542 555 4'-OH-BDE-049 SYSTEMATIC 23603053 A 556 569 4'-OH-BDE-017 SYSTEMATIC 23603053 A 570 583 6'-OH-BDE-099 SYSTEMATIC 23603053 A 584 597 5'-OH-BDE-099 SYSTEMATIC 23603053 A 598 611 2'-OH-BDE-007 SYSTEMATIC 23603053 A 612 625 3'-OH-BDE-028 SYSTEMATIC 23603053 A 686 694 OH-PBDEs FAMILY 23603053 A 69 77 estrogen FAMILY 23603053 A 824 837 4'-OH-BDE-049 SYSTEMATIC 23603053 A 838 851 4'-OH-BDE-017 SYSTEMATIC 23603053 A 852 865 2'-OH-BDE-007 SYSTEMATIC 23603053 A 866 879 3'-OH-BDE-028 SYSTEMATIC 23603053 A 880 892 3-OH-BDE-047 SYSTEMATIC 23603053 A 893 906 3'-OH-BDE-007 SYSTEMATIC 23603053 T 34 77 hydroxylated polybrominated diphenyl ethers FAMILY 23603053 T 87 95 estrogen FAMILY 23603059 A 1044 1053 SP6001325 IDENTIFIER 23603059 A 1213 1220 arsenic SYSTEMATIC 23603059 A 1289 1296 arsenic SYSTEMATIC 23603059 A 168 175 arsenic SYSTEMATIC 23603059 A 17 24 arsenic SYSTEMATIC 23603059 A 553 568 sodium arsenite SYSTEMATIC 23603059 A 663 669 oxygen SYSTEMATIC 23603059 A 803 804 N FORMULA 23603059 A 901 917 N-acetylcysteine SYSTEMATIC 23603059 A 919 922 NAC ABBREVIATION 23603059 T 0 7 Arsenic SYSTEMATIC 23603112 A 1143 1148 TMPCP ABBREVIATION 23603112 A 1153 1161 TMPCP-4P ABBREVIATION 23603112 A 1313 1323 porphyrins FAMILY 23603112 A 1523 1532 porphyrin FAMILY 23603112 A 237 309 tri-cationic meso-tri(4-N-methylpyridyl)-mono-(4-carboxyphenyl)porphyrin SYSTEMATIC 23603112 A 311 316 TMPCP ABBREVIATION 23603112 A 322 335 tetrapeptides FAMILY 23603112 A 347 352 TMPCP ABBREVIATION 23603112 A 354 362 TMPCP-4P ABBREVIATION 23603112 A 368 448 bi-cationic meso-5,10-bis(4-N-methylpyridyl)-15,20-di-(4-carboxyphenyl)porphyrin SYSTEMATIC 23603112 A 44 53 porphyrin FAMILY 23603112 A 450 459 BMPCP-4P2 ABBREVIATION 23603112 A 548 560 tetrapeptide FAMILY 23603112 A 584 594 porphyrins FAMILY 23603112 A 974 983 BMPCP-4P2 ABBREVIATION 23603112 T 24 33 porphyrin FAMILY 23603112 T 34 46 tetrapeptide FAMILY 23603193 A 1027 1030 Val ABBREVIATION 23603193 A 1152 1155 PTZ ABBREVIATION 23603193 A 1237 1240 Val ABBREVIATION 23603193 A 1273 1276 Val ABBREVIATION 23603193 A 1294 1306 nitric oxide SYSTEMATIC 23603193 A 1308 1310 NO FORMULA 23603193 A 1369 1372 PTZ ABBREVIATION 23603193 A 1424 1426 NO FORMULA 23603193 A 1443 1446 Val ABBREVIATION 23603193 A 1494 1497 MDA ABBREVIATION 23603193 A 1516 1519 PTZ ABBREVIATION 23603193 A 1579 1581 NO FORMULA 23603193 A 1713 1716 PTZ ABBREVIATION 23603193 A 1808 1811 Val ABBREVIATION 23603193 A 1844 1846 NO FORMULA 23603193 A 525 542 pentylenetetrazol TRIVIAL 23603193 A 544 547 PTZ ABBREVIATION 23603193 A 714 717 PTZ ABBREVIATION 23603193 A 785 788 PTZ ABBREVIATION 23603193 A 898 901 PTZ ABBREVIATION 23603193 A 941 950 Valproate TRIVIAL 23603193 A 952 955 Val ABBREVIATION 23603193 T 95 112 pentylenetetrazol TRIVIAL 23603293 A 0 10 Toluquinol TRIVIAL 23603293 A 1341 1351 toluquinol TRIVIAL 23603293 A 14 32 methylhydroquinone SYSTEMATIC 23603293 A 1630 1640 toluquinol TRIVIAL 23603293 A 212 222 toluquinol TRIVIAL 23603293 A 358 368 toluquinol TRIVIAL 23603293 A 448 458 Toluquinol TRIVIAL 23603293 A 673 683 Toluquinol TRIVIAL 23603293 A 931 941 toluquinol TRIVIAL 23603293 T 0 10 Toluquinol TRIVIAL 23603339 A 1019 1027 estrogen FAMILY 23603339 A 1040 1044 DHEA ABBREVIATION 23603339 A 1281 1285 DHEA ABBREVIATION 23603339 A 1376 1389 actinomycin D TRIVIAL 23603339 A 144 148 DHEA ABBREVIATION 23603339 A 1537 1541 DHEA ABBREVIATION 23603339 A 1565 1569 DHEA ABBREVIATION 23603339 A 1657 1661 DHEA ABBREVIATION 23603339 A 30 52 dehydroepiandrosterone TRIVIAL 23603339 A 392 396 DHEA ABBREVIATION 23603339 A 54 58 DHEA ABBREVIATION 23603339 A 554 558 DHEA ABBREVIATION 23603339 A 604 621 7-ethoxyresorufin SYSTEMATIC 23603339 A 622 623 O FORMULA 23603339 A 641 651 phenacetin TRIVIAL 23603339 A 652 653 O FORMULA 23603339 A 704 724 3-methylcholanthrene SYSTEMATIC 23603339 A 786 794 androgen FAMILY 23603339 A 829 833 DHEA ABBREVIATION 23603339 A 917 929 bicalutamide TRIVIAL 23603339 A 935 943 androgen FAMILY 23603339 T 0 22 Dehydroepiandrosterone TRIVIAL 23603339 T 82 90 androgen FAMILY 23603380 A 1006 1015 anabasine TRIVIAL 23603380 A 1020 1028 myosmine TRIVIAL 23603380 A 1056 1074 alpha conotoxin GI TRIVIAL 23603380 A 186 195 anabasine TRIVIAL 23603380 A 197 205 lobeline TRIVIAL 23603380 A 211 219 myosmine TRIVIAL 23603380 A 327 340 acetylcholine SYSTEMATIC 23603380 A 623 641 alpha conotoxin GI TRIVIAL 23603380 A 685 694 anabasine TRIVIAL 23603380 A 699 707 myosmine TRIVIAL 23603380 A 804 812 lobeline TRIVIAL 23603380 A 869 878 anabasine TRIVIAL 23603380 A 967 975 lobeline TRIVIAL 23603380 A 980 988 myosmine TRIVIAL 23603380 T 0 10 Piperidine SYSTEMATIC 23603380 T 12 29 pyridine alkaloid FAMILY 23603381 A 18 21 BLM ABBREVIATION 23603381 A 27 43 cyclophosphamide TRIVIAL 23603381 A 339 351 Ellagic acid TRIVIAL 23603381 A 620 623 BLM ABBREVIATION 23603381 A 7 16 bleomycin FAMILY 23603381 A 703 717 hydroxyproline SYSTEMATIC 23603381 A 771 783 nitric oxide SYSTEMATIC 23603381 A 807 815 carbonyl FAMILY 23603381 A 909 912 GSH ABBREVIATION 23603381 A 974 977 BLM ABBREVIATION 23603381 T 0 12 Ellagic acid TRIVIAL 23603381 T 24 33 bleomycin FAMILY 23603381 T 38 54 cyclophosphamide TRIVIAL 23603385 A 1665 1681 titanium dioxide SYSTEMATIC 23603385 A 1750 1754 TiO2 FORMULA 23603385 A 1970 1974 TiO2 FORMULA 23603385 A 2203 2207 TiO2 FORMULA 23603385 A 41 57 titanium dioxide SYSTEMATIC 23603385 A 464 468 TiO2 FORMULA 23603385 A 547 551 TiO2 FORMULA 23603385 A 750 766 titanium dioxide SYSTEMATIC 23603385 A 840 856 titanium dioxide SYSTEMATIC 23603385 T 79 95 titanium dioxide SYSTEMATIC 23603635 A 271 284 benzoquinones FAMILY 23603635 A 286 294 vanadium SYSTEMATIC 23603635 A 469 477 tyrosine TRIVIAL 23604140 A 1175 1181 Bodipy TRIVIAL 23604140 A 1182 1193 pirenzepine TRIVIAL 23604140 A 196 207 pirenzepine TRIVIAL 23604140 A 257 273 Bodipy [558/568] IDENTIFIER 23604140 A 724 730 Bodipy TRIVIAL 23604140 A 909 918 gallamine TRIVIAL 23604140 A 958 973 indocarbazolole SYSTEMATIC 23604592 A 1456 1458 As FORMULA 23604592 A 1460 1462 Cd FORMULA 23604592 A 1467 1469 Pb FORMULA 23604592 A 283 289 oxygen SYSTEMATIC 23604592 A 409 411 As FORMULA 23604592 A 422 424 Pb FORMULA 23604592 A 439 441 Cd FORMULA 23604592 A 59 61 As FORMULA 23604592 A 63 65 Cd FORMULA 23604592 A 70 72 Pb FORMULA 23604592 T 26 28 As FORMULA 23604592 T 30 32 Cd FORMULA 23604592 T 37 39 Pb FORMULA 23604719 A 115 119 β-CD ABBREVIATION 23604719 A 266 270 β-CD ABBREVIATION 23604719 A 373 383 flavonoids FAMILY 23604719 A 47 57 flavonoids FAMILY 23604719 A 502 506 β-CD ABBREVIATION 23604719 A 607 611 β-CD ABBREVIATION 23604719 A 99 113 β-cyclodextrin TRIVIAL 23604719 T 35 45 flavonoids FAMILY 23604721 A 232 240 methanol SYSTEMATIC 23604721 A 396 402 flavan FAMILY 23604721 T 35 44 flavonoid FAMILY 23604819 A 0 52 1-Substituted-N-tosyl-1,2,3,4-tetrahydroisoquinoline FAMILY 23604819 A 1109 1132 tetrahydroisoquinolines FAMILY 23604819 A 166 189 tetrahydroisoquinolines FAMILY 23604819 A 251 260 p-methoxy SYSTEMATIC 23604819 A 291 300 o-hydroxy SYSTEMATIC 23604819 A 467 477 Trimethoxy SYSTEMATIC 23604819 A 913 922 p-methoxy SYSTEMATIC 23604819 T 42 80 N-tosyl-1,2,3,4-tetrahydroisoquinoline SYSTEMATIC 23605905 A 706 714 thyroxin TRIVIAL 23605905 A 84 100 triiodothyronine TRIVIAL 23605905 T 132 148 triiodothyronine TRIVIAL 23606243 A 0 4 TiO2 FORMULA 23606243 A 143 147 TiO2 FORMULA 23606243 A 186 189 FTO ABBREVIATION 23606243 A 273 277 TiO2 FORMULA 23606243 A 332 336 TiO2 FORMULA 23606243 A 503 507 TiO2 FORMULA 23606243 A 761 765 CdSe FORMULA 23606243 A 780 784 TiO2 FORMULA 23606243 T 23 27 TiO2 FORMULA 23606278 A 115 126 cholesterol TRIVIAL 23606278 A 34 45 cholesterol TRIVIAL 23606278 A 515 522 statins FAMILY 23606278 T 7 14 Statins FAMILY 23606301 A 185 205 polydimethylsiloxane SYSTEMATIC 23606301 A 207 211 PDMS ABBREVIATION 23606301 A 341 347 oxygen SYSTEMATIC 23606301 T 98 104 Oxygen SYSTEMATIC 23606318 A 20 30 dabigatran TRIVIAL 23606318 A 35 46 rivaroxaban TRIVIAL 23606318 A 540 548 warfarin TRIVIAL 23606318 A 550 560 dabigatran TRIVIAL 23606318 A 566 577 rivaroxaban TRIVIAL 23606318 A 938 946 warfarin TRIVIAL 23606318 A 976 986 dabigatran TRIVIAL 23606318 A 991 1002 rivaroxaban TRIVIAL 23606463 A 284 292 carbonyl FAMILY 23606463 A 302 307 amino FAMILY 23606463 A 37 45 carbonyl FAMILY 23606463 A 514 522 carbonyl FAMILY 23606629 A 203 219 phosphoramidates FAMILY 23606629 A 321 336 phosphoramidate SYSTEMATIC 23606629 A 369 378 thymidine TRIVIAL 23606629 A 416 426 nucleoside FAMILY 23606629 A 438 453 Phosphoramidate SYSTEMATIC 23606629 A 469 505 (E)-5-(2-bromovinyl)-2'-deoxyuridine SYSTEMATIC 23606629 A 507 511 BVDU ABBREVIATION 23606629 A 526 535 L-alanine TRIVIAL 23606629 A 539 571 pivaloyloxymethyl iminodiacetate SYSTEMATIC 23606629 A 54 79 nucleoside monophosphates FAMILY 23606629 A 573 580 IDA-POM ABBREVIATION 23606629 A 735 746 nucleosides FAMILY 23606629 A 757 772 phosphoramidate SYSTEMATIC 23606629 A 816 827 nucleosides FAMILY 23606629 A 838 862 phosphoramidate triester FAMILY 23606629 A 945 955 nucleotide FAMILY 23606629 A 96 111 phosphoramidate SYSTEMATIC 23606629 A 976 992 phosphoramidates FAMILY 23606629 T 40 55 Phosphoramidate SYSTEMATIC 23607523 A 1043 1045 C7 FORMULA 23607523 A 1046 1054 cyclitol FAMILY 23607523 A 214 225 pyralomicin TRIVIAL 23607523 A 359 377 benzopyranopyrrole FAMILY 23607523 A 38 49 pyralomicin TRIVIAL 23607523 A 457 458 O FORMULA 23607523 A 485 486 N FORMULA 23607523 A 571 572 N FORMULA 23607523 A 625 632 glucose TRIVIAL 23607523 A 651 659 cyclitol FAMILY 23607523 A 703 705 C7 FORMULA 23607523 A 706 714 cyclitol FAMILY 23607523 A 767 785 benzopyranopyrrole FAMILY 23607523 A 846 847 N FORMULA 23607523 A 885 896 pyralomicin TRIVIAL 23607523 A 986 991 sugar FAMILY 23607523 A 992 1001 phosphate SYSTEMATIC 23607523 T 22 33 Pyralomicin TRIVIAL 23607578 A 164 170 carbon SYSTEMATIC 23607578 A 88 100 carbon black TRIVIAL 23607578 T 38 44 Carbon SYSTEMATIC 23607669 A 152 161 HB(C6F5)2 FORMULA 23607669 A 218 224 amines FAMILY 23607669 A 75 81 imines FAMILY 23607669 A 95 101 dienes FAMILY 23607669 T 31 37 borane SYSTEMATIC 23607669 T 7 13 dienes FAMILY 23607669 T 87 93 imines FAMILY 23607866 A 1089 1098 docetaxel TRIVIAL 23607866 A 1294 1304 paclitaxel TRIVIAL 23607866 A 1381 1391 paclitaxel TRIVIAL 23607866 A 1479 1481 1H FORMULA 23607866 A 1634 1644 paclitaxel TRIVIAL 23607866 A 387 423 N-(2-benzoyloxypropyl methacrylamide SYSTEMATIC 23607866 A 456 465 naphthoyl SYSTEMATIC 23607866 A 492 538 N-(2-hydroxypropyl) methacrylamide monolactate SYSTEMATIC 23607866 A 548 567 polyethylene glycol SYSTEMATIC 23607866 A 877 887 Paclitaxel TRIVIAL 23607866 A 892 901 docetaxel TRIVIAL 23607866 A 958 965 ethanol SYSTEMATIC 23607869 T 139 142 C-h FORMULA 23607869 T 144 147 C-C FORMULA 23607869 T 153 156 C-f FORMULA 23608109 A 577 587 crizotinib TRIVIAL 23608241 A 1099 1103 cAMP ABBREVIATION 23608241 A 1124 1132 foskolin TRIVIAL 23608241 A 1191 1199 morphine TRIVIAL 23608241 A 1205 1216 mitragynine TRIVIAL 23608241 A 1297 1305 morphine TRIVIAL 23608241 A 1361 1372 mitragynine TRIVIAL 23608241 A 1434 1442 morphine TRIVIAL 23608241 A 1486 1490 cAMP ABBREVIATION 23608241 A 1572 1583 mitragynine TRIVIAL 23608241 A 31 42 Mitragynine TRIVIAL 23608241 A 339 350 mitragynine TRIVIAL 23608241 A 365 373 morphine TRIVIAL 23608241 A 387 397 cyclic AMP TRIVIAL 23608241 A 399 403 cAMP ABBREVIATION 23608241 A 49 64 indole alkaloid FAMILY 23608241 A 518 529 Mitragynine TRIVIAL 23608241 A 620 624 cAMP ABBREVIATION 23608241 A 636 645 forskolin TRIVIAL 23608241 A 848 856 morphine TRIVIAL 23608241 A 861 872 mitragynine TRIVIAL 23608241 A 913 917 cAMP ABBREVIATION 23608241 A 952 960 nitrogen SYSTEMATIC 23608241 T 14 25 mitragynine TRIVIAL 23608241 T 29 33 cAMP ABBREVIATION 23608613 A 363 380 albuterol sulfate SYSTEMATIC 23608613 A 389 397 mannitol TRIVIAL 23608613 A 423 432 l-leucine TRIVIAL 23608613 A 459 472 poloxamer 188 TRIVIAL 23608699 A 1019 1022 EE2 ABBREVIATION 23608699 A 1034 1046 testosterone TRIVIAL 23608699 A 1114 1131 25-OH-cholesterol SYSTEMATIC 23608699 A 1140 1152 pregnenolone TRIVIAL 23608699 A 1160 1172 testosterone TRIVIAL 23608699 A 12 32 17α-ethinylestradiol SYSTEMATIC 23608699 A 1259 1264 11-KT ABBREVIATION 23608699 A 1375 1380 11-KT ABBREVIATION 23608699 A 1473 1476 EE2 ABBREVIATION 23608699 A 1596 1599 EE2 ABBREVIATION 23608699 A 310 313 EE2 ABBREVIATION 23608699 A 34 37 EE2 ABBREVIATION 23608699 A 491 494 EE2 ABBREVIATION 23608699 A 52 60 estrogen FAMILY 23608699 A 552 555 EE2 ABBREVIATION 23608699 A 688 691 EE2 ABBREVIATION 23608699 A 734 747 17β-estradiol SYSTEMATIC 23608699 A 878 883 11-KT ABBREVIATION 23608699 A 885 904 11-ketotestosterone SYSTEMATIC 23608699 A 918 921 EE2 ABBREVIATION 23608699 T 11 31 17α-ethinylestradiol SYSTEMATIC 23608699 T 33 36 EE2 ABBREVIATION 23608896 A 136 140 Cu2O FORMULA 23608896 A 141 143 Ni FORMULA 23608896 A 16 27 polystyrene SYSTEMATIC 23608896 A 202 206 Cu2O FORMULA 23608896 A 207 209 Ni FORMULA 23608896 T 40 44 Cu2O FORMULA 23608896 T 45 47 Ni FORMULA 23609128 A 1221 1230 hydronium SYSTEMATIC 23609128 A 1369 1380 (H2 O)5 (+) FORMULA 23609128 A 1443 1447 H2 O FORMULA 23609128 A 251 258 (H2 O)n FAMILY 23609128 A 746 755 hydronium SYSTEMATIC 23609128 A 771 778 H3 O(+) FORMULA 23609128 A 789 797 hydroxyl SYSTEMATIC 23609145 A 1031 1038 citrate FAMILY 23609145 A 1043 1050 glycine TRIVIAL 23609145 A 1279 1290 bicarbonate SYSTEMATIC 23609145 A 19 25 folate TRIVIAL 23609145 A 202 208 folate TRIVIAL 23609145 A 306 317 bicarbonate SYSTEMATIC 23609145 A 410 419 Bisulfite SYSTEMATIC 23609145 A 424 431 nitrite SYSTEMATIC 23609145 A 484 491 sulfate SYSTEMATIC 23609145 A 493 500 nitrate SYSTEMATIC 23609145 A 505 514 phosphate SYSTEMATIC 23609145 A 564 573 bisulfite SYSTEMATIC 23609145 A 578 585 nitrite SYSTEMATIC 23609145 A 654 661 sulfate SYSTEMATIC 23609145 A 666 673 nitrate SYSTEMATIC 23609145 A 713 722 bisulfite SYSTEMATIC 23609145 A 727 734 nitrite SYSTEMATIC 23609145 A 76 82 folate TRIVIAL 23609145 A 922 938 Monocarboxylates FAMILY 23609145 A 947 955 pyruvate TRIVIAL 23609145 A 960 967 acetate SYSTEMATIC 23609145 T 33 39 Folate TRIVIAL 23609145 T 70 81 Bicarbonate SYSTEMATIC 23609438 A 1110 1116 Ca(2+) FORMULA 23609438 A 1641 1647 Ca(2+) FORMULA 23609438 A 29 36 calcium SYSTEMATIC 23609438 A 47 56 potassium SYSTEMATIC 23609438 A 482 488 Ca(2+) FORMULA 23609438 A 505 511 Ca(2+) FORMULA 23609438 A 546 552 Ca(2+) FORMULA 23609438 A 637 643 Ca(2+) FORMULA 23609438 A 695 699 cAMP ABBREVIATION 23609438 A 852 858 Ca(2+) FORMULA 23609438 T 140 147 Calcium SYSTEMATIC 23609438 T 29 36 Calcium SYSTEMATIC 23609438 T 47 56 Potassium SYSTEMATIC 23609606 A 1076 1081 UDPGA ABBREVIATION 23609606 A 1107 1112 UDPGA ABBREVIATION 23609606 A 1171 1185 fenclozic acid TRIVIAL 23609606 A 1537 1551 fenclozic acid TRIVIAL 23609606 A 26 40 fenclozic acid TRIVIAL 23609606 A 372 394 [(14)C]-fenclozic acid SYSTEMATIC 23609606 A 4 19 carboxylic acid SYSTEMATIC 23609606 A 512 517 NADPH ABBREVIATION 23609606 A 910 917 taurine TRIVIAL 23609606 A 966 982 acyl glucuronide SYSTEMATIC 23609606 T 87 101 fenclozic acid TRIVIAL 23609769 A 1121 1128 ecstasy TRIVIAL 23609769 A 1139 1146 ecstasy TRIVIAL 23609769 A 1149 1160 amphetamine TRIVIAL 23609769 A 1228 1235 ecstasy TRIVIAL 23609769 A 1245 1252 ecstasy TRIVIAL 23609769 A 1255 1266 amphetamine TRIVIAL 23609769 A 1306 1317 Amphetamine TRIVIAL 23609769 A 1328 1335 ecstasy TRIVIAL 23609769 A 1538 1545 ecstasy TRIVIAL 23609769 A 1548 1559 amphetamine TRIVIAL 23609769 A 1665 1672 ecstasy TRIVIAL 23609769 A 1688 1697 serotonin TRIVIAL 23609769 A 229 236 ecstasy TRIVIAL 23609769 A 238 266 methylendioxymethamphetamine SYSTEMATIC 23609769 A 300 309 serotonin TRIVIAL 23609769 A 366 377 amphetamine TRIVIAL 23609769 A 473 482 serotonin TRIVIAL 23609769 A 517 524 ecstasy TRIVIAL 23609769 A 692 703 amphetamine TRIVIAL 23609769 A 714 721 ecstasy TRIVIAL 23609769 A 72 79 ecstasy TRIVIAL 23609769 T 39 46 ecstasy TRIVIAL 23609769 T 48 52 MDMA ABBREVIATION 23609770 A 1535 1547 remifentanil TRIVIAL 23609770 A 1685 1697 remifentanil TRIVIAL 23609770 A 456 468 remifentanil TRIVIAL 23609770 A 635 647 remifentanil TRIVIAL 23609770 T 33 45 remifentanil TRIVIAL 23609782 A 2040 2045 BG-12 IDENTIFIER 23609782 A 2264 2274 Laquinimod TRIVIAL 23609782 A 2299 2304 BG-12 IDENTIFIER 23609782 A 2368 2381 Teriflunomide TRIVIAL 23609782 A 706 716 Fingolimod TRIVIAL 23609944 A 468 479 amino acids FAMILY 23609944 A 545 555 amino acid FAMILY 23609944 A 729 740 amino acids FAMILY 23609944 T 12 23 amino acids FAMILY 23609963 A 1266 1277 cholesterol TRIVIAL 23609963 A 1282 1292 fatty acid FAMILY 23609963 A 251 262 cholesterol TRIVIAL 23609963 A 367 378 cholesterol TRIVIAL 23609963 A 48 59 cholesterol TRIVIAL 23609963 A 638 649 cholesterol TRIVIAL 23609963 A 664 675 cholesterol TRIVIAL 23609963 A 684 694 fatty acid FAMILY 23609963 A 730 741 cholesterol TRIVIAL 23610077 A 0 7 Silanol SYSTEMATIC 23610077 A 20 26 silica TRIVIAL 23610077 A 227 234 silanol SYSTEMATIC 23610077 A 318 331 alkoxysilanes FAMILY 23610077 A 333 347 bis-silylamine SYSTEMATIC 23610077 A 358 371 chlorosilanes FAMILY 23610077 A 665 671 SBA-15 IDENTIFIER 23610077 A 821 833 nitrobenzene SYSTEMATIC 23610077 A 863 869 SBA-15 IDENTIFIER 23610077 T 19 25 SBA-15 IDENTIFIER 23610086 A 1066 1077 glutathione TRIVIAL 23610086 A 1104 1123 glutathione-S-oxide SYSTEMATIC 23610086 A 1151 1181 2-methylimidazo[2,1-b]thiazole SYSTEMATIC 23610086 A 1192 1203 glutathione TRIVIAL 23610086 A 1284 1292 thiazole SYSTEMATIC 23610086 A 1394 1397 18O FORMULA 23610086 A 1433 1450 potassium cyanide SYSTEMATIC 23610086 A 1621 1629 thiazole SYSTEMATIC 23610086 A 1642 1659 1,2,4-thiadiazole SYSTEMATIC 23610086 A 1675 1809 -(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethanone SYSTEMATIC 23610086 A 219 344 1-(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b]thiazol-6-yl)ethanone SYSTEMATIC 23610086 A 369 391 imidazo[2,1-b]thiazole SYSTEMATIC 23610086 A 470 475 NADPH ABBREVIATION 23610086 A 481 492 glutathione TRIVIAL 23610086 A 538 549 glutathione TRIVIAL 23610086 A 719 731 glutathionyl TRIVIAL 23610086 A 746 751 thiol FAMILY 23610086 A 774 782 thiazole SYSTEMATIC 23610086 A 812 823 glutathione TRIVIAL 23610086 A 859 881 imidazo[2,1-b]thiazole SYSTEMATIC 23610086 A 93 210 1-(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(imidazo[2,1-b]thiazol-6-yl)ethanone SYSTEMATIC 23610086 A 948 959 glutathione TRIVIAL 23610086 A 974 981 S-oxide SYSTEMATIC 23610086 T 40 83 Imidazo- and 2-Methylimidazo[2,1-b]thiazole MULTIPLE 23611120 A 118 129 polystyrene SYSTEMATIC 23611120 A 16 25 D-glucose SYSTEMATIC 23611120 A 281 290 D-glucose SYSTEMATIC 23611120 A 313 321 hydrogen SYSTEMATIC 23611120 A 432 440 hydrogen SYSTEMATIC 23611120 A 495 504 D-glucose SYSTEMATIC 23611120 A 575 584 D-glucose SYSTEMATIC 23611120 A 67 69 Ru FORMULA 23611120 A 731 739 hydrogen SYSTEMATIC 23611120 T 0 11 D - Glucose TRIVIAL 23611120 T 31 33 Ru FORMULA 23611120 T 88 99 Polystyrene SYSTEMATIC 23611124 A 448 468 indole-2-carboxamide SYSTEMATIC 23611124 T 95 112 Indolecarboxamide FAMILY 23611338 A 1042 1074 o-MitoPhB(OH)2 FORMULA 23611338 A 1079 1095 ONOO- FORMULA 23611338 A 1118 1124 phenyl SYSTEMATIC 23611338 A 1185 1231 o-MitoPhB(OH)2O•- FORMULA 23611338 A 1288 1294 phenyl SYSTEMATIC 23611338 A 1308 1334 •NO2 FORMULA 23611338 A 1451 1497 o-MitoPhB(OH)2O•- FORMULA 23611338 A 149 165 ONOO- FORMULA 23611338 A 1548 1594 m-MitoPhB(OH)2O•- FORMULA 23611338 A 1599 1645 p-MitoPhB(OH)2O•- FORMULA 23611338 A 1695 1711 ONOO- FORMULA 23611338 A 1717 1753 ortho-MitoPhB(OH)2 FORMULA 23611338 A 1790 1819 o-MitoPhNO2 FORMULA 23611338 A 1849 1857 phenolic FAMILY 23611338 A 1867 1884 o-MitoPhOH FORMULA 23611338 A 1946 1962 ONOO- FORMULA 23611338 A 247 263 ONOO- FORMULA 23611338 A 268 281 arylboronates FAMILY 23611338 A 283 302 PhB(OH)2 FORMULA 23611338 A 313 321 phenolic FAMILY 23611338 A 365 398 PhB(OH)2O•- FORMULA 23611338 A 399 425 •NO2 FORMULA 23611338 A 4 26 Aromatic boronic acids FAMILY 23611338 A 46 59 peroxynitrite SYSTEMATIC 23611338 A 555 575 triphenylphosphonium SYSTEMATIC 23611338 A 577 580 TPP ABBREVIATION 23611338 A 61 77 ONOO- FORMULA 23611338 A 612 628 ONOO- FORMULA 23611338 A 655 667 arylboronate FAMILY 23611338 A 677 735 o-, m-, and p-MitoPhB(OH)2 MULTIPLE 23611338 A 858 864 phenyl SYSTEMATIC 23611338 A 88 95 phenols FAMILY 23611338 A 979 1008 o-MitoPhNO2 FORMULA 23611338 T 17 30 peroxynitrite SYSTEMATIC 23611338 T 35 84 triphenylphosphonium-substituted arylboronic acid FAMILY 23611508 A 542 553 polystyrene SYSTEMATIC 23611538 A 1149 1153 EGCG ABBREVIATION 23611538 A 1178 1182 EGCG ABBREVIATION 23611538 A 1237 1241 EGCG ABBREVIATION 23611538 A 1268 1274 amines FAMILY 23611538 A 1326 1338 Schiff bases FAMILY 23611538 A 1534 1538 EGCG ABBREVIATION 23611538 A 1607 1611 EGCG ABBREVIATION 23611538 A 327 353 Epigallocatechin-3-gallate TRIVIAL 23611538 A 355 359 EGCG ABBREVIATION 23611538 A 376 386 polyphenol FAMILY 23611538 A 681 685 EGCG ABBREVIATION 23611538 A 776 780 EGCG ABBREVIATION 23611538 A 856 860 EGCG ABBREVIATION 23611538 A 886 890 EGCG ABBREVIATION 23611538 A 943 955 thioflavin T TRIVIAL 23611538 T 43 47 EGCG ABBREVIATION 23611809 A 1055 1076 tertiary cyclic amine MULTIPLE 23611809 A 1080 1095 trifluoperazine TRIVIAL 23611809 A 110 115 amine SYSTEMATIC 23611809 A 1170 1183 amitriptyline TRIVIAL 23611809 A 1185 1195 imipramine TRIVIAL 23611809 A 1201 1216 diphenhydramine TRIVIAL 23611809 A 1559 1567 nicotine TRIVIAL 23611809 A 1572 1581 hecogenin TRIVIAL 23611809 A 1708 1723 tertiary amines FAMILY 23611809 A 40 43 UDP ABBREVIATION 23611809 A 439 452 amitriptyline TRIVIAL 23611809 A 454 464 imipramine TRIVIAL 23611809 A 466 475 ketotifen TRIVIAL 23611809 A 477 486 pizotifen TRIVIAL 23611809 A 488 498 olanzapine TRIVIAL 23611809 A 500 515 diphenhydramine TRIVIAL 23611809 A 517 526 tamoxifen TRIVIAL 23611809 A 528 540 ketoconazole TRIVIAL 23611809 A 545 554 midazolam TRIVIAL 23611809 A 683 708 tertiary aliphatic amines FAMILY 23611809 A 710 723 cyclic amines FAMILY 23611809 A 731 740 imidazole SYSTEMATIC 23611809 A 795 806 desipramine TRIVIAL 23611809 A 808 821 nortriptyline TRIVIAL 23611809 A 823 836 carbamazepine TRIVIAL 23611809 A 841 852 afloqualone TRIVIAL 23611809 A 883 910 secondary or primary amines MULTIPLE 23611809 A 973 988 tertiary amines FAMILY 23612242 A 1161 1172 glutathione TRIVIAL 23612242 A 1173 1174 S FORMULA 23612242 A 646 678 polycyclic aromatic hydrocarbons FAMILY 23612242 A 764 775 glutathione TRIVIAL 23612242 A 950 960 superoxide TRIVIAL 23612421 A 1440 1447 adenine TRIVIAL 23612421 A 1463 1473 amino acid FAMILY 23612421 A 1532 1539 adenine TRIVIAL 23612421 A 1541 1558 L-acetylcarnitine SYSTEMATIC 23612421 A 1560 1576 8-hydroxyadenine SYSTEMATIC 23612421 A 1578 1590 hypoxanthine TRIVIAL 23612421 A 1592 1600 creatine TRIVIAL 23612421 A 1602 1612 methionine TRIVIAL 23612421 A 1614 1630 phytosphingosine TRIVIAL 23612421 A 1635 1648 phenylalanine TRIVIAL 23612421 A 1730 1750 2,8-dihydroxyadenine SYSTEMATIC 23612421 A 1752 1776 indole-3-carboxylic acid SYSTEMATIC 23612421 A 1778 1798 3-methyldioxyindole, SYSTEMATIC 23612421 A 1799 1828 ethyl-N2-acetyl-L-argininate, SYSTEMATIC 23612421 A 1829 1843 3-O-methyldopa SYSTEMATIC 23612421 A 1848 1864 xanthurenic acid TRIVIAL 23612421 A 2135 2142 adenine TRIVIAL 23612421 A 2158 2168 amino acid FAMILY 23612421 A 630 637 adenine TRIVIAL 23612423 A 1259 1262 MDA ABBREVIATION 23612423 A 1290 1298 creatine TRIVIAL 23612423 A 1307 1313 malate TRIVIAL 23612423 A 1329 1332 ATP ABBREVIATION 23612423 A 1435 1447 nitric oxide SYSTEMATIC 23612423 A 1764 1771 ethanol SYSTEMATIC 23612423 A 1852 1864 nitric oxide SYSTEMATIC 23612423 A 276 286 chloroform TRIVIAL 23612423 A 336 343 ethanol SYSTEMATIC 23612423 A 491 503 nitric oxide SYSTEMATIC 23612423 A 913 917 DPPH ABBREVIATION 23612487 A 0 23 Sphingosine-1-phosphate SYSTEMATIC 23612487 A 1104 1107 S1P ABBREVIATION 23612487 A 1292 1295 S1P ABBREVIATION 23612487 A 130 133 S1P ABBREVIATION 23612487 A 210 213 S1P ABBREVIATION 23612487 A 25 28 S1P ABBREVIATION 23612487 A 320 323 S1P ABBREVIATION 23612487 A 399 402 S1P ABBREVIATION 23612487 A 413 433 phosphatidylinositol TRIVIAL 23612487 A 56 68 sphingolipid FAMILY 23612487 A 751 754 S1P ABBREVIATION 23612487 T 0 23 Sphingosine-1-phosphate SYSTEMATIC 23612709 A 317 324 calcium SYSTEMATIC 23612720 A 185 194 graphenes FAMILY 23612720 A 212 220 graphene TRIVIAL 23612720 A 228 236 hydrogen SYSTEMATIC 23612720 A 384 392 graphene TRIVIAL 23612720 A 467 475 graphene TRIVIAL 23612720 A 571 579 graphane TRIVIAL 23612720 A 580 588 graphene TRIVIAL 23612720 A 61 69 graphene TRIVIAL 23612720 A 638 643 ferro TRIVIAL 23612720 A 782 791 graphenes FAMILY 23612720 A 929 938 graphenes FAMILY 23612720 T 40 48 graphene TRIVIAL 23613012 A 1108 1120 testosterone TRIVIAL 23613012 A 1304 1315 cholesterol TRIVIAL 23613012 A 1321 1332 cholesterol TRIVIAL 23613012 A 1556 1568 testosterone TRIVIAL 23613012 A 393 405 testosterone TRIVIAL 23613012 A 675 694 testosterone esters FAMILY 23613012 A 920 932 triglyceride FAMILY 23613012 A 982 993 cholesterol TRIVIAL 23613012 T 4 15 Cholesterol TRIVIAL 23613012 T 47 59 Testosterone TRIVIAL 23613080 A 120 123 FTO ABBREVIATION 23613080 A 53 56 NiO FORMULA 23613080 A 552 555 NiO FORMULA 23613080 A 592 595 WO3 FORMULA 23613080 T 13 16 NiO FORMULA 23613312 A 136 148 cyclopropane SYSTEMATIC 23613312 A 162 168 alkene FAMILY 23613312 A 187 199 cyclopropane SYSTEMATIC 23613312 A 21 33 cyclopropane SYSTEMATIC 23613312 A 248 271 4-benzyloxybenzaldehyde SYSTEMATIC 23613312 A 308 316 estrogen FAMILY 23613312 A 346 358 cyclopropane SYSTEMATIC 23613312 A 406 414 estrogen FAMILY 23613312 A 44 52 stilbene TRIVIAL 23613312 A 475 483 stilbene TRIVIAL 23613312 A 500 509 tamoxifen TRIVIAL 23613312 A 514 524 raloxifene TRIVIAL 23613312 A 536 548 cyclopropane SYSTEMATIC 23613312 A 591 599 estrogen FAMILY 23613312 A 86 94 estrogen FAMILY 23613312 T 142 150 estrogen FAMILY 23613312 T 48 59 cyclopropyl SYSTEMATIC 23613312 T 73 81 stilbene TRIVIAL 23613312 T 87 97 raloxifene TRIVIAL 23613425 A 220 231 doxorubicin TRIVIAL 23613425 A 233 236 DOX ABBREVIATION 23613425 A 269 276 methoxy SYSTEMATIC 23613425 A 277 298 poly(ethylene glycol) SYSTEMATIC 23613425 A 305 326 poly(D,L-lactic acid) SYSTEMATIC 23613425 A 328 332 mPEG ABBREVIATION 23613425 A 335 338 PLA ABBREVIATION 23613425 A 427 430 DOX ABBREVIATION 23613425 T 56 67 Doxorubicin TRIVIAL 23614379 A 254 292 ( - )-nectandrin B-β-d-glucopyranoside SYSTEMATIC 23614379 A 298 390 ( - )-(7R,7'R,8S,8'R)-4,4'-dihydroxy-3,3'-dimethoxy-7,7'-epoxylignan-4-O-β-d-glucopyranoside SYSTEMATIC 23614379 A 396 489 ( - )-(7R,7'R,8S,8'R)-4,4'-dihydroxy-3,3'-dimethoxy-7,7'-epoxylignan-4'-O-β-d-glucopyranoside SYSTEMATIC 23614379 A 495 574 ( - )-(8S,8'R)-4,4'-dihydroxy-3,3',5'-trimethoxylignan-4'-O-β-d-glucopyranoside SYSTEMATIC 23614379 A 580 634 ( - )-(7R,8R)-syringylglycerol-8-O-β-d-glucopyranoside SYSTEMATIC 23614379 A 644 729 ( - )-3-hydroxy-2-methyl-4-pyrone-3-O-β-d-xylopyranosyl-(1 → 6)-O-β-d-glucopyranoside SYSTEMATIC 23614492 A 10 18 pimarane TRIVIAL 23614492 A 128 160 11α-hydroxypimara-8(14),15-diene SYSTEMATIC 23614492 A 171 192 2,3-secoaromadendrane SYSTEMATIC 23614492 A 198 214 sesquiterpenoids FAMILY 23614492 A 237 260 ethyoxyplagiochiline A2 SYSTEMATIC 23614492 A 24 36 diterpenoids FAMILY 23614492 A 282 293 fusicoccane FAMILY 23614492 A 299 311 diterpenoids FAMILY 23614492 A 38 75 7β,11α-dihydroxypimara-8(14),15-diene SYSTEMATIC 23614492 A 81 118 1β,11α-dihydroxypimara-8(14),15-diene SYSTEMATIC 23614492 T 0 10 Terpenoids FAMILY 23614571 A 1015 1019 NMDA ABBREVIATION 23614571 A 119 129 (S)-CCG-IV ABBREVIATION 23614571 A 348 352 NMDA ABBREVIATION 23614571 A 54 58 NMDA ABBREVIATION 23614571 A 568 572 NMDA ABBREVIATION 23614571 A 719 723 NMDA ABBREVIATION 23614571 A 75 117 (2S,1'R,2'S)-2-(carboxycyclopropyl)glycine SYSTEMATIC 23614571 A 944 954 (S)-CCG-IV ABBREVIATION 23614571 T 15 72 2'-substituted (2S,1'R,2'S)-2-(carboxycyclopropyl)glycine FAMILY 23614571 T 93 117 N-methyl-D-aspartic acid SYSTEMATIC 23614635 A 333 341 estrogen FAMILY 23614635 A 371 386 bisphosphonates FAMILY 23614635 A 402 420 strontium ranelate SYSTEMATIC 23614643 A 1163 1169 SU5402 IDENTIFIER 23614643 A 1274 1282 xyloside FAMILY 23614643 A 1515 1524 xylosides FAMILY 23614643 A 481 504 bis- and tris-xylosides MULTIPLE 23614643 A 725 748 bis- and tris-xylosides MULTIPLE 23614643 A 758 772 mono-xylosides FAMILY 23614652 A 0 19 Aristolochic acid I TRIVIAL 23614652 A 132 136 AA-I ABBREVIATION 23614652 A 177 182 nitro SYSTEMATIC 23614652 A 206 214 cysteine TRIVIAL 23614652 A 21 25 AA-I ABBREVIATION 23614652 A 218 229 glutathione TRIVIAL 23614652 A 238 252 aristolic acid TRIVIAL 23614652 A 440 444 AA-I ABBREVIATION 23614652 T 14 33 Aristolochic Acid I TRIVIAL 23614652 T 39 53 Aristolic Acid TRIVIAL 23614652 T 71 79 Cysteine TRIVIAL 23614652 T 84 95 Glutathione TRIVIAL 23614728 A 1184 1192 phosgene TRIVIAL 23614728 A 1378 1386 phosgene TRIVIAL 23614728 A 1515 1523 phosgene TRIVIAL 23614728 A 1671 1679 phosgene TRIVIAL 23614728 A 30 38 phosgene TRIVIAL 23614728 A 347 355 phosgene TRIVIAL 23614728 A 448 456 phosgene TRIVIAL 23614728 A 641 653 Haematoxylin TRIVIAL 23614728 A 654 659 Eosin FAMILY 23614728 T 50 58 phosgene TRIVIAL 23614815 A 604 614 disulphide SYSTEMATIC 23614815 A 752 762 amino-acid FAMILY 23614827 A 15 145 (7S,8R,7'R,8'R)-7-(3,4-methylenedioxyphenyl)-8,8'-dimethyl-8'-hydroxyl-7'-methoxyl-7'-(3',4'-methylenedioxyphenyl)-tetrahydrofuran SYSTEMATIC 23614827 A 173 206 2-hydroxy-11,12-dehydrocalamenene SYSTEMATIC 23614827 A 236 316 erythro-1-(3,4-dimethoxyphenyl)-4-(3,4-methylenedioxyphenyl)-2,3-dimethyl-butane SYSTEMATIC 23614827 A 336 343 lignans FAMILY 23614827 A 344 446 (+)-anwulignan(erythro-1-(4-hydroxy-3-methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-2,3-dimethyl-butane) SYSTEMATIC 23614827 A 455 469 ( - )-zuonin-A TRIVIAL 23614831 A 1024 1042 N-vinylpyrrolidone SYSTEMATIC 23614831 A 1271 1279 Soluplus TRIVIAL 23614831 A 1281 1284 PVP ABBREVIATION 23614831 A 1286 1289 PVP ABBREVIATION 23614831 A 1417 1425 hydrogen SYSTEMATIC 23614831 A 1547 1550 PVP ABBREVIATION 23614831 A 1555 1563 Soluplus TRIVIAL 23614831 A 18 29 Cilnidipine TRIVIAL 23614831 A 299 302 PVP ABBREVIATION 23614831 A 304 307 PVP ABBREVIATION 23614831 A 315 323 Soluplus TRIVIAL 23614831 A 46 61 dihydropyridine SYSTEMATIC 23614831 A 62 69 calcium SYSTEMATIC 23614831 A 815 823 Soluplus TRIVIAL 23614831 A 825 828 PVP ABBREVIATION 23614831 A 833 836 PVP ABBREVIATION 23614831 A 985 993 hydrogen SYSTEMATIC 23614831 T 88 99 cilnidipine TRIVIAL 23614904 A 1042 1051 bile acid FAMILY 23614904 A 1163 1174 cholesterol TRIVIAL 23614904 A 1179 1188 bile acid FAMILY 23614904 A 1327 1338 cholesterol TRIVIAL 23614904 A 1344 1354 bile acids FAMILY 23614904 A 215 226 cholesterol TRIVIAL 23614904 A 231 240 bile acid FAMILY 23614904 A 359 371 atorvastatin TRIVIAL 23614904 A 384 396 Atorvastatin TRIVIAL 23614904 A 473 484 cholesterol TRIVIAL 23614904 A 486 503 cholesterol ester FAMILY 23614904 A 514 523 bile acid FAMILY 23614904 A 559 568 bile acid FAMILY 23614904 A 600 612 atorvastatin TRIVIAL 23614904 A 635 645 bile acids FAMILY 23614904 A 668 679 cholesterol TRIVIAL 23614904 A 785 795 bile acids FAMILY 23614904 A 922 931 bile acid FAMILY 23614904 A 993 1005 atorvastatin TRIVIAL 23614904 T 0 9 Bile Acid FAMILY 23614904 T 14 20 Sterol FAMILY 23615074 A 347 357 flavanoids FAMILY 23615074 A 374 384 flavanoids FAMILY 23615074 A 508 518 flavanoids FAMILY 23615074 A 566 572 oxygen SYSTEMATIC 23616238 A 1103 1106 Met FORMULA 23616238 A 1424 1433 metformin TRIVIAL 23616238 A 1437 1452 triacylglycerol FAMILY 23616238 A 1522 1537 triacylglycerol FAMILY 23616238 A 1556 1565 metformin TRIVIAL 23616238 A 384 393 metformin TRIVIAL 23616376 A 95 103 DPh-DNTT ABBREVIATION 23616387 A 134 142 triazole FAMILY 23616387 A 21 33 azide-alkyne FAMILY 23616387 A 294 303 triazoles FAMILY 23616387 A 4 10 copper SYSTEMATIC 23616387 A 426 435 triazoles FAMILY 23616387 A 556 565 triazoles FAMILY 23617226 A 126 137 [Cu(dmp)2]+ FORMULA 23617226 A 139 142 dmp ABBREVIATION 23617226 A 145 177 2,9-dimethyl-1,10-phenanthroline SYSTEMATIC 23617226 A 192 204 acetonitrile SYSTEMATIC 23617226 A 209 224 dichloromethane SYSTEMATIC 23617226 A 272 287 dichloromethane SYSTEMATIC 23617226 A 292 304 acetonitrile SYSTEMATIC 23617226 A 65 67 Cu FORMULA 23617226 A 78 124 Bis(2,9-dimethyl-1,10-phenanthroline)copper(I) SYSTEMATIC 23617226 A 933 945 acetonitrile SYSTEMATIC 23617226 T 100 124 Copper(I) Phenanthroline SYSTEMATIC 23617279 A 107 117 resorcinol TRIVIAL 23617279 A 1110 1116 carbon SYSTEMATIC 23617279 A 122 134 formaldehyde SYSTEMATIC 23617279 A 1239 1245 carbon SYSTEMATIC 23617279 A 1275 1281 carbon SYSTEMATIC 23617279 A 154 173 potassium carbonate SYSTEMATIC 23617279 A 454 460 carbon SYSTEMATIC 23617279 A 774 780 Carbon SYSTEMATIC 23617279 A 979 985 carbon SYSTEMATIC 23617279 T 0 6 Carbon SYSTEMATIC 23617279 T 47 57 Resorcinol TRIVIAL 23617279 T 58 70 Formaldehyde SYSTEMATIC 23617430 A 22 44 3-carboranyl thymidine SYSTEMATIC 23617430 A 628 652 N3-substituted thymidine FAMILY 23617430 A 67 72 boron SYSTEMATIC 23617430 A 761 770 carborane SYSTEMATIC 23617430 A 799 804 boron SYSTEMATIC 23617430 A 93 98 boron SYSTEMATIC 23617430 T 0 24 N3-substituted thymidine FAMILY 23617439 A 208 211 PZQ ABBREVIATION 23617439 A 35 47 praziquantel TRIVIAL 23617439 A 354 357 PZQ ABBREVIATION 23617439 A 441 448 bromine SYSTEMATIC 23617439 A 49 52 PZQ ABBREVIATION 23617439 A 493 505 praziquantel TRIVIAL 23617439 A 554 566 praziquentel TRIVIAL 23617439 T 0 12 Praziquantel TRIVIAL 23617462 A 101 111 bile salts FAMILY 23617462 A 1019 1023 NaTC FORMULA 23617462 A 1028 1033 NaGDC FORMULA 23617462 A 113 127 sodium cholate SYSTEMATIC 23617462 A 1201 1211 bile salts FAMILY 23617462 A 129 132 NaC ABBREVIATION 23617462 A 1342 1345 NaC ABBREVIATION 23617462 A 135 148 dexocycholate TRIVIAL 23617462 A 150 154 NaDC FORMULA 23617462 A 157 169 taurocholate TRIVIAL 23617462 A 1589 1599 bile salts FAMILY 23617462 A 171 175 NaTC FORMULA 23617462 A 181 198 glycodeoxycholate TRIVIAL 23617462 A 200 205 NaGDC FORMULA 23617462 A 311 321 amino acid FAMILY 23617462 A 323 327 NaTC FORMULA 23617462 A 332 337 NaGDC FORMULA 23617462 A 512 515 NaC ABBREVIATION 23617462 A 520 524 NaDC FORMULA 23617462 A 610 621 amino acids FAMILY 23617462 A 625 629 NaTC FORMULA 23617462 A 634 639 NaGDC FORMULA 23617462 A 69 75 sodium SYSTEMATIC 23617462 A 946 956 bile salts FAMILY 23617462 A 964 970 decane SYSTEMATIC 23617462 T 26 63 Di-hydroxy and Tri-hydroxy Bile Salts MULTIPLE 23617753 A 285 293 naphthyl SYSTEMATIC 23617753 A 299 308 quinoline SYSTEMATIC 23617753 A 40 47 BRD0476 IDENTIFIER 23617807 A 16 23 benzene SYSTEMATIC 23617807 A 28 47 hexahalogenbenzenes FAMILY 23617807 A 600 609 dihalogen FAMILY 23617807 A 634 667 hexachloro- and hexabromobenzenes MULTIPLE 23617807 A 805 814 dihalogen FAMILY 23617807 A 865 898 hexachloro- and hexabromobenzenes MULTIPLE 23617807 T 45 52 Benzene SYSTEMATIC 23617807 T 57 76 Hexahalogenbenzenes FAMILY 23618528 A 1378 1385 ethanol SYSTEMATIC 23618624 A 0 10 Squalamine TRIVIAL 23618624 A 193 202 polyamine FAMILY 23618624 A 21 32 aminosterol FAMILY 23618624 A 225 231 sterol FAMILY 23618624 A 262 270 hydroxyl SYSTEMATIC 23618624 A 305 337 tetraammonium spermine polyamine SYSTEMATIC 23618624 A 391 424 trisammonium spermidine polyamine SYSTEMATIC 23618624 A 456 464 hydroxyl SYSTEMATIC 23618624 A 603 617 7β-OH spermine SYSTEMATIC 23618624 T 36 47 aminosterol FAMILY 23618921 A 0 11 Glutathione TRIVIAL 23618921 A 1061 1068 fisetin TRIVIAL 23618921 A 1252 1259 fisetin TRIVIAL 23618921 A 1282 1285 GSH ABBREVIATION 23618921 A 13 16 GSH ABBREVIATION 23618921 A 1375 1378 GSH ABBREVIATION 23618921 A 146 149 GSH ABBREVIATION 23618921 A 1494 1497 GSH ABBREVIATION 23618921 A 1538 1545 fisetin TRIVIAL 23618921 A 1594 1597 GSH ABBREVIATION 23618921 A 22 25 GSH ABBREVIATION 23618921 A 244 247 GSH ABBREVIATION 23618921 A 413 416 GSH ABBREVIATION 23618921 A 645 648 GSH ABBREVIATION 23618921 A 691 700 flavonoid FAMILY 23618921 A 701 708 fisetin TRIVIAL 23618921 A 744 747 GSH ABBREVIATION 23618921 A 767 770 GSH ABBREVIATION 23618921 A 913 920 fisetin TRIVIAL 23618921 T 119 128 Flavonoid FAMILY 23618921 T 129 136 Fisetin TRIVIAL 23618921 T 93 104 Glutathione TRIVIAL 23619019 A 1583 1635 ginsenosides Rb1, Rg1, Rf, Rh1, Rc, Rb2, Ro, and Rg3 MULTIPLE 23619019 A 1694 1708 ginsenoside Ro TRIVIAL 23619019 A 1951 1963 ginsenosides FAMILY 23619019 A 800 809 Captopril TRIVIAL 23619611 A 1013 1024 rivaroxaban TRIVIAL 23619611 A 102 112 dabigatran TRIVIAL 23619611 A 1028 1036 apixaban TRIVIAL 23619611 A 1170 1178 Apixaban TRIVIAL 23619611 A 1235 1246 rivaroxaban TRIVIAL 23619611 A 1251 1261 dabigatran TRIVIAL 23619611 A 1463 1472 vitamin K FAMILY 23619611 A 1548 1559 rivaroxaban TRIVIAL 23619611 A 1561 1569 apixaban TRIVIAL 23619611 A 1571 1579 edoxaban TRIVIAL 23619611 A 1585 1595 dabigatran TRIVIAL 23619611 A 210 218 edoxaban TRIVIAL 23619611 A 297 308 rivaroxaban TRIVIAL 23619611 A 430 441 rivaroxaban TRIVIAL 23619611 A 443 451 apixaban TRIVIAL 23619611 A 457 467 dabigatran TRIVIAL 23619611 A 742 753 Rivaroxaban TRIVIAL 23619611 A 75 86 rivaroxaban TRIVIAL 23619611 A 755 763 apixaban TRIVIAL 23619611 A 769 779 dabigatran TRIVIAL 23619611 A 88 96 apixaban TRIVIAL 23619611 A 965 975 Dabigatran TRIVIAL 23619613 A 1131 1138 polySia ABBREVIATION 23619613 A 1160 1167 polySia ABBREVIATION 23619613 A 1399 1406 polySia ABBREVIATION 23619613 A 335 342 polySia ABBREVIATION 23619613 A 422 429 polySia ABBREVIATION 23619613 A 631 638 polySia ABBREVIATION 23619613 A 765 774 bleomycin FAMILY 23619613 A 78 93 polysialic acid SYSTEMATIC 23619613 A 907 914 polySia ABBREVIATION 23619613 A 95 102 polySia ABBREVIATION 23620060 A 1024 1031 glucose TRIVIAL 23620060 A 1159 1173 Diacylglycerol FAMILY 23620060 A 1359 1372 sphingomyelin FAMILY 23620060 A 391 398 glucose TRIVIAL 23620060 A 612 619 Glucose TRIVIAL 23620162 A 1058 1064 oxygen SYSTEMATIC 23620162 A 38 43 Al2O3 FORMULA 23620162 A 48 52 Y2O3 FORMULA 23620162 A 518 522 Y2O3 FORMULA 23620162 A 524 529 AlY20 FORMULA 23620162 A 783 789 Al(3+) FORMULA 23620162 A 794 799 Y(3+) FORMULA 23620162 A 847 852 Y(3+) FORMULA 23620162 A 853 858 Y(3+) FORMULA 23620162 T 34 39 Al2O3 FORMULA 23620162 T 40 44 Y2O3 FORMULA 23620199 A 1469 1475 taxane FAMILY 23620199 A 208 218 mertansine TRIVIAL 23620199 A 222 232 maytansine TRIVIAL 23620199 A 259 262 DM1 ABBREVIATION 23620199 A 386 396 mertansine TRIVIAL 23620199 A 542 551 thioether SYSTEMATIC 23620199 A 560 622 N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate SYSTEMATIC 23620199 A 624 628 SMCC ABBREVIATION 23620199 A 641 644 MCC ABBREVIATION 23620200 A 230 237 glucose TRIVIAL 23620200 A 341 348 glucose TRIVIAL 23620256 A 1516 1523 glucose TRIVIAL 23620256 A 1712 1719 glucose TRIVIAL 23620256 A 2114 2121 glucose TRIVIAL 23620256 A 802 810 yo pro-1 TRIVIAL 23620256 A 815 831 propidium iodide TRIVIAL 23620256 A 995 1002 glucose TRIVIAL 23620266 A 1005 1014 ibuprofen TRIVIAL 23620266 A 1016 1024 Naproxen TRIVIAL 23620266 A 258 263 amide FAMILY 23620266 A 317 339 (R)-1-phenylethylamine SYSTEMATIC 23620266 A 341 344 PEA ABBREVIATION 23620266 A 35 55 2-arylpropionic acid FAMILY 23620266 A 57 62 2-APA ABBREVIATION 23620266 A 572 581 ibuprofen TRIVIAL 23620266 A 71 80 ibuprofen TRIVIAL 23620266 A 722 732 ketoprofen TRIVIAL 23620266 A 82 90 naproxen TRIVIAL 23620266 A 893 903 ketoprofen TRIVIAL 23620266 A 96 106 ketoprofen TRIVIAL 23620266 T 39 60 2-arylpropionic acids FAMILY 23620283 A 1056 1057 C FORMULA 23620283 A 198 204 serine TRIVIAL 23620283 A 205 214 threonine TRIVIAL 23620487 A 1031 1041 omeprazole TRIVIAL 23620487 A 1292 1302 omeprazole TRIVIAL 23620487 A 148 158 omeprazole TRIVIAL 23620487 A 230 249 5-hydroxyomeprazole SYSTEMATIC 23620487 A 251 275 5'-O-desmethylomeprazole SYSTEMATIC 23620487 A 277 295 omeprazole sulfone TRIVIAL 23620487 A 300 317 carboxyomeprazole SYSTEMATIC 23620487 A 433 443 omeprazole TRIVIAL 23620487 A 535 545 omeprazole TRIVIAL 23620487 A 547 565 omeprazole sulfone TRIVIAL 23620487 A 570 594 5'-O-desmethylomeprazole SYSTEMATIC 23620487 A 650 660 omeprazole TRIVIAL 23620487 A 665 689 5'-O-desmethylomeprazole SYSTEMATIC 23620487 A 887 897 omeprazole TRIVIAL 23620487 T 36 46 Omeprazole TRIVIAL 23621358 A 1037 1040 GAL ABBREVIATION 23621358 A 114 126 carbohydrate FAMILY 23621358 A 181 221 galactosylated polylactide-polyaminoacid SYSTEMATIC 23621358 A 282 354 alpha,beta-poly(N-2-hydroxyethyl) (2-aminoethylcarbamate)-DL-aspartamide SYSTEMATIC 23621358 A 356 364 PHEA-EDA ABBREVIATION 23621358 A 371 386 polylactic acid SYSTEMATIC 23621358 A 388 391 PLA ABBREVIATION 23621358 A 423 430 lactose TRIVIAL 23621358 A 442 458 PHEA-EDA-PLA-GAL ABBREVIATION 23621358 A 540 543 RBV ABBREVIATION 23621358 A 558 574 RBV tripalmitate TRIVIAL 23621358 A 62 71 ribavirin TRIVIAL 23621358 A 622 625 RBV ABBREVIATION 23621358 A 709 725 RBV tripalmitate TRIVIAL 23621358 A 73 76 RBV ABBREVIATION 23621358 A 780 796 PHEA-EDA-PLA-GAL ABBREVIATION 23621358 A 893 909 RBV tripalmitate TRIVIAL 23621358 A 917 933 PHEA-EDA-PLA-GAL ABBREVIATION 23621358 T 30 39 RIBAVIRIN TRIVIAL 23621493 A 0 13 Tetracyclines FAMILY 23621493 A 189 208 anhydrotetracycline SYSTEMATIC 23621493 A 218 233 oxytetracycline SYSTEMATIC 23621493 A 918 930 tetracycline FAMILY 23621493 T 56 71 Oxytetracycline SYSTEMATIC 23621616 A 13 21 graphene TRIVIAL 23621616 A 226 234 graphene TRIVIAL 23621616 A 365 373 graphene TRIVIAL 23621616 A 450 458 graphene TRIVIAL 23621616 A 551 559 graphene TRIVIAL 23621616 A 657 665 graphene TRIVIAL 23621616 A 829 837 graphene TRIVIAL 23621616 T 51 59 Graphene TRIVIAL 23621857 A 0 11 Brefeldin A TRIVIAL 23621857 A 1063 1066 BFA ABBREVIATION 23621857 A 13 16 BFA ABBREVIATION 23621857 A 201 204 BFA ABBREVIATION 23621857 A 276 284 hydroxyl SYSTEMATIC 23621857 A 370 373 BFA ABBREVIATION 23621857 A 431 462 monoacylated and diacylated BFA MULTIPLE 23621857 A 632 648 BFA 7-O-benzoate SYSTEMATIC 23621857 A 650 670 BFA 4,7-O-dibenzoate SYSTEMATIC 23621857 A 676 702 BFA 7-O-biotin carboxylate SYSTEMATIC 23621857 A 926 944 guanine nucleotide TRIVIAL 23621857 T 38 58 Acylated Brefeldin A TRIVIAL 23623416 A 0 13 Echinocandins FAMILY 23623416 A 18 31 pneumocandins FAMILY 23623416 A 314 325 caspofungin TRIVIAL 23623416 A 327 337 micafungin TRIVIAL 23623416 A 342 355 anidulafungin TRIVIAL 23623416 A 373 390 hydroxy-glutamine SYSTEMATIC 23623416 A 398 407 threonine TRIVIAL 23623416 A 412 441 unsaturated linear fatty acid FAMILY 23623416 A 449 484 branched chain saturated fatty acid FAMILY 23623416 A 47 68 lipocyclohexapeptides FAMILY 23623416 A 646 663 cyclohexapeptides FAMILY 23623416 A 700 704 acyl FAMILY 23623416 A 840 844 acyl FAMILY 23623416 A 859 876 hydroxy-glutamine SYSTEMATIC 23623416 T 39 49 pentyloxyl SYSTEMATIC 23623416 T 50 69 diphenylisoxazoloyl SYSTEMATIC 23623416 T 70 83 pneumocandins FAMILY 23623416 T 88 101 echinocandins FAMILY 23623419 A 136 151 1,2,3-triazoles FAMILY 23623419 A 700 708 diazepam TRIVIAL 23623419 A 76 105 2-arylimidazo[1,2-a]pyridines FAMILY 23623419 T 24 47 imidazo[1,2-a]pyridines FAMILY 23623419 T 57 72 1,2,3-triazoles FAMILY 23623493 A 18 28 titanocene TRIVIAL 23623493 T 81 96 half-titanocene TRIVIAL 23623743 A 1017 1031 polyacrylamide SYSTEMATIC 23623743 A 192 210 1,3-dinitrobenzene SYSTEMATIC 23623743 A 212 219 1,3-DNB SYSTEMATIC 23623743 A 222 243 3-nitropropionic acid SYSTEMATIC 23623743 A 245 250 3-NPA SYSTEMATIC 23623743 A 257 276 3-chloropropanediol SYSTEMATIC 23623743 A 278 283 3-CPD SYSTEMATIC 23623743 A 781 815 tetramethyl rhodamine methyl ester SYSTEMATIC 23623743 A 817 821 TMRM ABBREVIATION 23623743 A 903 915 deferoxamine TRIVIAL 23623743 A 953 957 TMRM ABBREVIATION 23623743 T 100 118 1,3-dinitrobenzene SYSTEMATIC 23623743 T 120 141 3-nitropropionic acid SYSTEMATIC 23623743 T 147 166 3-chloropropanediol SYSTEMATIC 23623751 A 103 118 Methylphenidate SYSTEMATIC 23623751 A 1055 1063 dopamine TRIVIAL 23623751 A 1142 1157 Methylphenidate SYSTEMATIC 23623751 A 1230 1245 methylphenidate SYSTEMATIC 23623751 A 1284 1299 methylphenidate SYSTEMATIC 23623751 A 1357 1372 methylphenidate SYSTEMATIC 23623751 A 136 144 dopamine TRIVIAL 23623751 A 149 163 norepinephrine TRIVIAL 23623751 A 1559 1574 methylphenidate SYSTEMATIC 23623751 A 1716 1723 cocaine TRIVIAL 23623751 A 358 373 methylphenidate SYSTEMATIC 23623751 A 411 418 cocaine TRIVIAL 23623751 A 698 705 cocaine TRIVIAL 23623751 A 839 854 methylphenidate SYSTEMATIC 23623751 T 101 109 Dopamine TRIVIAL 23623751 T 12 27 methylphenidate SYSTEMATIC 23623795 A 657 673 sodium phosphate SYSTEMATIC 23623843 A 1032 1036 CCl4 FORMULA 23623843 A 201 205 CCl4 FORMULA 23623843 A 339 354 monosaccharides FAMILY 23623843 A 388 394 ferric SYSTEMATIC 23623843 A 453 457 DPPH ABBREVIATION 23623843 A 459 461 OH FORMULA 23623843 A 466 471 O2(-) FORMULA 23623843 A 548 552 CCl4 FORMULA 23623843 A 595 599 CCl4 FORMULA 23623843 A 664 667 MDA ABBREVIATION 23623843 A 672 683 8-iso-PGF2a SYSTEMATIC 23623843 A 801 804 GSH ABBREVIATION 23623843 A 843 847 CCl4 FORMULA 23623843 T 64 84 carbon tetrachloride SYSTEMATIC 23624029 A 103 110 steroid FAMILY 23624029 A 240 248 androgen FAMILY 23624029 A 362 384 17-hydroxyprogesterone SYSTEMATIC 23624240 A 574 586 cobalt oxide SYSTEMATIC 23624240 A 588 593 Co3O4 FORMULA 23624240 A 731 737 cobalt SYSTEMATIC 23624240 T 23 35 cobalt oxide SYSTEMATIC 23624376 A 375 387 borosilicate SYSTEMATIC 23624376 A 405 437 linear methoxylated polyglycerol SYSTEMATIC 23624376 A 439 465 hyperbranched polyglycerol SYSTEMATIC 23624376 A 471 510 hyperbranched methoxylated polyglycerol SYSTEMATIC 23624376 T 0 12 Polyglycerol SYSTEMATIC 23624419 A 1134 1146 vildagliptin TRIVIAL 23624419 A 1147 1156 metformin TRIVIAL 23624419 A 1158 1170 Vildagliptin TRIVIAL 23624419 A 1187 1196 metformin TRIVIAL 23624419 A 220 231 vildaglipin TRIVIAL 23624419 A 263 272 metformin TRIVIAL 23624419 A 37 49 vildagliptin TRIVIAL 23624419 A 585 597 vildagliptin TRIVIAL 23624419 A 65 74 metformin TRIVIAL 23624419 A 698 706 arginine TRIVIAL 23624419 A 720 732 Vildagliptin TRIVIAL 23624419 A 733 742 metformin TRIVIAL 23624419 A 776 785 metformin TRIVIAL 23624419 A 892 904 Vildagliptin TRIVIAL 23624419 A 905 914 metformin TRIVIAL 23624419 T 112 121 metformin TRIVIAL 23624419 T 84 96 vildagliptin TRIVIAL 23624423 A 1125 1128 OHT FORMULA 23624423 A 131 144 17β-Estradiol SYSTEMATIC 23624423 A 1321 1324 OHT FORMULA 23624423 A 1436 1439 OHT FORMULA 23624423 A 228 237 Tamoxifen TRIVIAL 23624423 A 269 277 estrogen FAMILY 23624423 A 454 463 tamoxifen TRIVIAL 23624423 A 533 541 estrogen FAMILY 23624423 A 636 644 estrogen FAMILY 23624423 A 663 681 4-Hydroxytamoxifen SYSTEMATIC 23624423 A 683 686 OHT FORMULA 23624423 A 688 697 tamoxifen TRIVIAL 23624423 A 857 860 OHT FORMULA 23624423 T 0 18 4-Hydroxytamoxifen SYSTEMATIC 23624706 A 1002 1006 SnO2 FORMULA 23624706 A 1011 1016 Fe2O3 FORMULA 23624706 A 1017 1021 SnO2 FORMULA 23624706 A 1022 1023 C FORMULA 23624706 A 1045 1052 lithium SYSTEMATIC 23624706 A 1195 1202 lithium SYSTEMATIC 23624706 A 159 161 Li FORMULA 23624706 A 163 175 carbon black TRIVIAL 23624706 A 248 255 lithium SYSTEMATIC 23624706 A 333 344 molten salt FAMILY 23624706 A 40 45 Fe2O3 FORMULA 23624706 A 46 50 SnO2 FORMULA 23624706 A 51 52 C FORMULA 23624706 A 81 86 Fe2O3 FORMULA 23624706 A 91 95 SnO2 FORMULA 23624706 A 996 1001 Fe2O3 FORMULA 23624706 T 28 33 Fe2O3 FORMULA 23624706 T 34 38 SnO2 FORMULA 23624706 T 39 40 C FORMULA 23624706 T 9 16 lithium SYSTEMATIC 23624810 A 1140 1148 oxytocin TRIVIAL 23624810 A 1324 1332 oxytocin TRIVIAL 23624810 A 1722 1730 oxytocin TRIVIAL 23624810 A 342 350 oxytocin TRIVIAL 23624810 A 648 656 oxytocin TRIVIAL 23624810 A 661 669 oxytocin TRIVIAL 23624810 A 73 81 oxytocin TRIVIAL 23624810 A 746 754 oxytocin TRIVIAL 23624810 A 889 897 oxytocin TRIVIAL 23624810 T 35 43 oxytocin TRIVIAL 23624862 A 479 482 GTP ABBREVIATION 23624862 A 489 492 GTP ABBREVIATION 23624862 A 772 775 GTP ABBREVIATION 23624862 A 906 909 GDP ABBREVIATION 23625160 A 1010 1012 Fe FORMULA 23625160 A 106 110 iron SYSTEMATIC 23625160 A 133 137 iron SYSTEMATIC 23625160 A 312 315 MSG ABBREVIATION 23625160 A 411 413 Fe FORMULA 23625160 A 571 573 Fe FORMULA 23625160 A 68 90 monosodium L-glutamate SYSTEMATIC 23625160 A 697 700 MSG ABBREVIATION 23625160 A 711 713 Fe FORMULA 23625160 A 913 916 MSG ABBREVIATION 23625160 A 92 95 MSG ABBREVIATION 23625160 A 996 999 MSG ABBREVIATION 23625160 T 33 55 Monosodium L-Glutamate SYSTEMATIC 23625194 A 1101 1109 orlistat TRIVIAL 23625194 A 1322 1330 orlistat TRIVIAL 23625194 A 947 955 orlistat TRIVIAL 23625194 A 957 968 sibutramine TRIVIAL 23625194 A 974 984 rimonabant TRIVIAL 23625745 A 739 750 cholesterol TRIVIAL 23625745 A 758 769 cholesterol TRIVIAL 23625745 A 807 818 cholesterol TRIVIAL 23625745 A 824 837 triglycerides FAMILY 23625745 A 977 988 Cholesterol TRIVIAL 23625750 A 1118 1125 IB-MECA IDENTIFIER 23625750 A 12 21 adenosine TRIVIAL 23625750 A 1369 1376 IB-MECA IDENTIFIER 23625750 A 1497 1504 IB-MECA IDENTIFIER 23625750 A 1562 1571 adenosine TRIVIAL 23625750 A 1614 1633 sodium taurocholate SYSTEMATIC 23625750 A 208 217 adenosine TRIVIAL 23625750 A 398 407 adenosine TRIVIAL 23625750 A 445 464 sodium taurocholate SYSTEMATIC 23625750 A 678 687 adenosine TRIVIAL 23625750 A 708 715 IB-MECA IDENTIFIER 23625750 A 716 801 (1-deoxy-1-6[[(3-iodophenyl) methyl]amino]-9H-purin-9-yl)-N-methyl-B-D-ribofuronamide SYSTEMATIC 23625750 A 900 919 sodium taurocholate SYSTEMATIC 23625750 T 19 28 adenosine TRIVIAL 23625750 T 49 56 IB-MECA IDENTIFIER 23625750 T 60 79 sodium taurocholate SYSTEMATIC 23625769 A 1114 1124 furosemide TRIVIAL 23625769 A 1221 1231 furosemide TRIVIAL 23625769 A 439 449 furosemide TRIVIAL 23625769 A 668 678 furosemide TRIVIAL 23625769 A 839 849 furosemide TRIVIAL 23625769 A 907 917 furosemide TRIVIAL 23625769 A 935 944 torsemide TRIVIAL 23625769 A 986 996 furosemide TRIVIAL 23625769 T 17 27 Furosemide TRIVIAL 23625779 A 1032 1040 saponins FAMILY 23625779 A 1593 1599 MCM-41 IDENTIFIER 23625779 A 1600 1606 silica TRIVIAL 23625779 A 199 204 amino FAMILY 23625779 A 300 305 Amino SYSTEMATIC 23625779 A 321 327 MCM-41 IDENTIFIER 23625779 A 475 481 MCM-41 IDENTIFIER 23625779 A 495 501 MCM-41 IDENTIFIER 23625779 A 80 86 MCM-41 IDENTIFIER 23625779 A 98 104 silica TRIVIAL 23625779 T 11 17 Silica TRIVIAL 23625787 A 1320 1328 warfarin TRIVIAL 23625787 A 1541 1549 warfarin TRIVIAL 23625787 A 1803 1811 warfarin TRIVIAL 23625787 A 181 189 warfarin TRIVIAL 23625787 A 441 449 warfarin TRIVIAL 23625787 A 652 660 warfarin TRIVIAL 23625787 A 865 873 warfarin TRIVIAL 23625787 T 79 87 Warfarin TRIVIAL 23625887 A 14 41 5'-triphenylmethyl (trityl) SYSTEMATIC 23625887 A 299 365 3'-O-(isoleucylisoleucyl)-5'-O-(3,3,3-triphenylpropanoyl)thymidine SYSTEMATIC 23625887 A 527 543 tritylthymidines FAMILY 23625887 A 54 63 thymidine TRIVIAL 23625887 A 635 645 superoxide TRIVIAL 23625887 T 0 9 5'-Trityl SYSTEMATIC 23625887 T 22 31 Thymidine TRIVIAL 23625905 A 1084 1103 thiobarbituric acid SYSTEMATIC 23625905 A 1169 1180 glutathione TRIVIAL 23625905 A 1182 1185 GSH ABBREVIATION 23625905 A 1228 1239 glutathione TRIVIAL 23625905 A 1302 1304 Cr FORMULA 23625905 A 1337 1341 zinc SYSTEMATIC 23625905 A 1343 1349 copper SYSTEMATIC 23625905 A 1355 1359 iron SYSTEMATIC 23625905 A 1378 1384 Cr(VI) FORMULA 23625905 A 143 149 Cr(VI) FORMULA 23625905 A 1515 1518 GSH ABBREVIATION 23625905 A 1652 1658 Cr(VI) FORMULA 23625905 A 1738 1744 Cr(VI) FORMULA 23625905 A 188 194 Cr(VI) FORMULA 23625905 A 1946 1952 Cr(VI) FORMULA 23625905 A 25 44 hexavalent chromium SYSTEMATIC 23625905 A 327 333 Cr(VI) FORMULA 23625905 A 396 402 Cr(VI) FORMULA 23625905 A 453 464 glutathione TRIVIAL 23625905 A 46 52 Cr(VI) FORMULA 23625905 A 572 578 Cr(VI) FORMULA 23625905 A 808 814 Cr(VI) FORMULA 23625905 A 839 845 Cr(VI) FORMULA 23625905 A 86 88 Cr FORMULA 23625905 A 887 894 K2Cr2O7 FORMULA 23625905 T 10 23 chromium (VI) SYSTEMATIC 23625909 A 1140 1144 alum FAMILY 23625909 A 894 898 alum FAMILY 23625912 A 0 8 Aluminum SYSTEMATIC 23625912 A 10 12 Al FORMULA 23625912 A 1043 1045 Cu FORMULA 23625912 A 1065 1067 Fe FORMULA 23625912 A 1211 1213 Al FORMULA 23625912 A 258 260 Al FORMULA 23625912 A 548 559 Al chloride SYSTEMATIC 23625912 A 561 566 AlCl3 FORMULA 23625912 A 674 676 Al FORMULA 23625912 A 678 682 iron SYSTEMATIC 23625912 A 684 686 Fe FORMULA 23625912 A 689 695 copper SYSTEMATIC 23625912 A 697 699 Cu FORMULA 23625912 A 706 710 zinc SYSTEMATIC 23625912 A 712 714 Zn FORMULA 23625912 A 934 936 Al FORMULA 23625912 A 985 987 Al FORMULA 23625912 A 992 994 Fe FORMULA 23625912 T 11 28 aluminum chloride SYSTEMATIC 23627275 A 132 169 2-(2-methoxyethoxy)ethyl methacrylate SYSTEMATIC 23627275 A 171 177 MEO2MA ABBREVIATION 23627275 A 183 218 oligo(ethylene glycol) methacrylate SYSTEMATIC 23627275 A 220 225 OEGMA ABBREVIATION 23627275 A 232 244 polydopamine TRIVIAL 23627275 A 246 250 Pdop ABBREVIATION 23627275 A 259 263 SiO2 FORMULA 23627275 A 373 377 SiO2 FORMULA 23627275 A 563 575 rhodamine 6G TRIVIAL 23627275 A 577 581 Rh6G ABBREVIATION 23627275 A 677 681 Rh6G ABBREVIATION 23627275 A 853 866 methyl orange TRIVIAL 23627396 A 271 282 tyroscherin TRIVIAL 23627396 A 287 306 N-methyltyroscherin SYSTEMATIC 23627396 A 378 389 tyroscherin TRIVIAL 23627396 A 421 440 N-methyltyroscherin SYSTEMATIC 23627438 A 171 183 thioflavin-T TRIVIAL 23627438 A 204 217 sciadopitysin TRIVIAL 23627438 A 347 360 sciadopitysin TRIVIAL 23627438 A 46 53 ethanol SYSTEMATIC 23627438 A 5 24 taxane diterpenoids FAMILY 23627438 A 574 587 sciadopitysin TRIVIAL 23627438 T 0 13 Sciadopitysin TRIVIAL 23627443 A 2138 2152 amphotericin B TRIVIAL 23627443 A 371 385 amphotericin B TRIVIAL 23627443 A 47 61 amphotericin B TRIVIAL 23627443 A 527 532 Tween FAMILY 23627443 A 795 809 amphotericin B TRIVIAL 23627597 A 153 184 1,6-diyne carbonates and esters MULTIPLE 23627597 A 30 55 2,4a-dihydro-1H-fluorenes FAMILY 23627597 A 363 375 cyclopropene SYSTEMATIC 23627597 A 594 596 Au FORMULA 23627597 A 73 80 gold(I) SYSTEMATIC 23627597 A 91 102 1,2-acyloxy SYSTEMATIC 23627597 T 37 68 1,6-Diyne Carbonates and Esters MULTIPLE 23627597 T 72 97 2,4a-Dihydro-1H-fluorenes FAMILY 23627605 A 1051 1059 graphene TRIVIAL 23627605 A 161 169 graphene TRIVIAL 23627605 A 245 253 graphene TRIVIAL 23627605 A 333 341 graphene TRIVIAL 23627605 A 399 407 graphene TRIVIAL 23627605 A 630 634 SiO2 FORMULA 23627605 A 674 682 graphene TRIVIAL 23627605 A 718 726 graphene TRIVIAL 23627605 A 73 81 graphene TRIVIAL 23627605 A 816 824 graphene TRIVIAL 23627605 A 872 880 graphene TRIVIAL 23627605 T 103 107 SiO2 FORMULA 23627605 T 4 12 Graphene TRIVIAL 23627605 T 90 98 Graphene TRIVIAL 23627685 A 114 120 carbon SYSTEMATIC 23627685 A 140 148 hydrogen SYSTEMATIC 23627685 A 337 342 oxide SYSTEMATIC 23627685 A 459 461 Zn FORMULA 23627685 A 57 59 Zn FORMULA 23627685 A 60 63 ZnO FORMULA 23627685 A 808 810 Zn FORMULA 23627685 A 938 940 Zn FORMULA 23627685 T 49 53 Zinc SYSTEMATIC 23627717 A 101 138 octaethylene glycol monododecyl ether SYSTEMATIC 23627717 A 1033 1062 cyclodextrin (i.e. ,  or ) MULTIPLE 23627717 A 61 96 di-n-decyldimethylammonium chloride SYSTEMATIC 23627717 T 59 94 di-n-decyldimethylammonium chloride SYSTEMATIC 23627717 T 95 132 octaethylene glycol monododecyl ether SYSTEMATIC 23627806 A 102 112 iron oxide SYSTEMATIC 23627806 A 190 202 acrylic acid TRIVIAL 23627806 A 207 235 2-methacryloylethyl acrylate SYSTEMATIC 23627806 A 262 283 poly(ethylene glycol) SYSTEMATIC 23627806 A 288 315 poly(N-isopropylacrylamide) SYSTEMATIC 23627806 A 477 480 MEA ABBREVIATION 23627806 A 65 76 citric acid TRIVIAL 23627834 A 1019 1022 Dox ABBREVIATION 23627834 A 1052 1072 p(NIPAM)55-b-p(His)n FAMILY 23627834 A 1283 1286 Dox ABBREVIATION 23627834 A 143 163 p(NIPAM)55-b-p(His)n FAMILY 23627834 A 291 296 NIPAM ABBREVIATION 23627834 A 341 373 α-amino acid N-carboxyanhydrides FAMILY 23627834 A 464 484 p(NIPAM)55-b-p(His)n FAMILY 23627834 A 645 665 p(NIPAM)55-b-p(His)n FAMILY 23627834 A 752 763 doxorubicin TRIVIAL 23627834 A 765 768 Dox ABBREVIATION 23627834 A 834 837 Dox ABBREVIATION 23627834 A 87 141 poly(N-isopropylacrylamide)55-block-poly(l-histidine)n FAMILY 23627834 A 939 942 Dox ABBREVIATION 23627834 T 122 133 Doxorubicin TRIVIAL 23627834 T 24 71 Poly(N-isopropylacrylamide)-b-poly(l-histidine) SYSTEMATIC 23627902 A 1071 1076 (13)C FORMULA 23627902 A 114 120 phenyl SYSTEMATIC 23627902 A 1187 1192 (13)C FORMULA 23627902 A 1193 1197 (1)H FORMULA 23627902 A 144 149 cyano FAMILY 23627902 A 173 179 phenyl SYSTEMATIC 23627902 A 204 211 dodecyl SYSTEMATIC 23627902 A 275 280 cyano FAMILY 23627902 A 43 48 (13)C FORMULA 23627902 T 110 115 (13)C FORMULA 23628154 A 1082 1091 berberine TRIVIAL 23628154 A 1093 1102 palmatine TRIVIAL 23628154 A 1104 1112 baicalin TRIVIAL 23628154 A 1117 1126 baicalein TRIVIAL 23628154 A 1197 1208 gardenoside TRIVIAL 23628154 A 163 172 berberine TRIVIAL 23628154 A 174 182 baicalin TRIVIAL 23628154 A 187 198 gardenoside TRIVIAL 23628154 A 457 466 berberine TRIVIAL 23628154 A 468 477 palmatine TRIVIAL 23628154 A 479 487 baicalin TRIVIAL 23628154 A 489 498 baicalein TRIVIAL 23628154 A 503 514 gardenoside TRIVIAL 23628154 A 944 953 berberine TRIVIAL 23628154 A 955 964 palmatine TRIVIAL 23628154 A 966 974 baicalin TRIVIAL 23628154 A 976 985 baicalein TRIVIAL 23628154 A 990 1001 gardenoside TRIVIAL 23628332 A 1156 1166 idescarpin TRIVIAL 23628332 A 1341 1351 idescarpin TRIVIAL 23628332 A 287 295 methanol SYSTEMATIC 23628332 A 477 553 6-(oxymethyl)-2-hydroxyphenyl-O-β-d-glucopyranosyl-(1→6)-β-d-glucopyranoside SYSTEMATIC 23628332 A 624 629 CHCl3 FORMULA 23628332 A 634 640 n-BuOH FORMULA 23628332 A 658 666 methanol SYSTEMATIC 23628332 A 711 721 idescarpin TRIVIAL 23628332 A 731 771 1-hydroxy-6-oxo-2-cyclohexenecarboxylate SYSTEMATIC 23628332 A 879 889 Idescarpin TRIVIAL 23628333 A 372 376 NADH ABBREVIATION 23628333 A 73 80 lactate FAMILY 23628333 A 8 42 2-thio-6-oxo-1,6-dihydropyrimidine SYSTEMATIC 23628333 T 30 65 2-thio-6-oxo-1,6-dihydropyrimidines FAMILY 23628333 T 89 96 lactate FAMILY 23628455 A 1086 1097 aldosterone TRIVIAL 23628455 A 1304 1310 sodium SYSTEMATIC 23628455 A 277 281 NaCl FORMULA 23628455 A 392 405 acetylcholine SYSTEMATIC 23628455 A 407 410 ACh ABBREVIATION 23628455 A 442 448 L-NAME ABBREVIATION 23628455 A 460 472 enalaprilate TRIVIAL 23628455 A 481 489 losartan TRIVIAL 23628455 A 502 516 spironolactone TRIVIAL 23628455 A 753 765 enalaprilate TRIVIAL 23628455 A 770 778 losartan TRIVIAL 23628455 A 892 900 losartan TRIVIAL 23628455 A 925 928 ACh ABBREVIATION 23628455 A 957 971 Spironolactone TRIVIAL 23628508 A 0 10 Aspidin BB TRIVIAL 23628508 A 1014 1024 aspidin BB TRIVIAL 23628508 A 1196 1206 aspidin BB TRIVIAL 23628508 A 211 221 aspidin BB TRIVIAL 23628508 A 25 39 phloroglucinol TRIVIAL 23628508 A 266 276 Aspidin BB TRIVIAL 23628508 A 469 479 aspidin BB TRIVIAL 23628508 A 610 626 propidium iodide TRIVIAL 23628508 A 694 704 aspidin BB TRIVIAL 23628508 A 919 934 poly ADP-ribose SYSTEMATIC 23628508 T 0 10 Aspidin BB TRIVIAL 23628508 T 14 28 phloroglucinol TRIVIAL 23628509 A 1092 1099 CP[c]Ph ABBREVIATION 23628509 A 1171 1185 benzo[a]pyrene SYSTEMATIC 23628509 A 1187 1192 B[a]P ABBREVIATION 23628509 A 1248 1255 CP[c]Ph ABBREVIATION 23628509 A 1393 1400 CP[c]Ph ABBREVIATION 23628509 A 1420 1425 B[a]P ABBREVIATION 23628509 A 1536 1544 estrogen FAMILY 23628509 A 1609 1616 CP[c]Ph ABBREVIATION 23628509 A 1700 1708 CP[c]Phs ABBREVIATION 23628509 A 1873 1880 CP-PAHs ABBREVIATION 23628509 A 282 308 cyclopenta[c]phenanthrenes FAMILY 23628509 A 310 317 CP[c]Ph ABBREVIATION 23628509 A 474 481 CP-PAHs ABBREVIATION 23628509 A 516 523 CP[c]Ph ABBREVIATION 23628509 A 59 66 CP-PAHs ABBREVIATION 23628509 A 591 598 CP[c]Ph ABBREVIATION 23628509 A 659 671 cyclopentane SYSTEMATIC 23628509 A 747 753 B[c]Ph ABBREVIATION 23628509 A 763 775 phenanthrene SYSTEMATIC 23628509 A 8 57 cyclopenta-fused polycyclic aromatic hydrocarbons FAMILY 23628509 A 809 814 alkyl FAMILY 23628509 A 932 939 CP[c]Ph ABBREVIATION 23628509 T 0 26 Cyclopenta[c]phenanthrenes FAMILY 23628605 A 1282 1293 cholesterol TRIVIAL 23628605 A 1342 1353 cholesterol TRIVIAL 23628605 A 1574 1585 cholesterol TRIVIAL 23628605 A 161 172 cholesterol TRIVIAL 23628605 A 315 326 cholesterol TRIVIAL 23628605 A 330 342 pregnenolone TRIVIAL 23628605 A 37 44 steroid FAMILY 23628605 A 496 513 3β-hydroxysteroid FAMILY 23628605 A 549 560 aldosterone TRIVIAL 23628605 A 725 734 vitamin D FAMILY 23628605 A 750 761 cholesterol TRIVIAL 23628605 T 0 7 Steroid FAMILY 23628621 A 1358 1369 cholesterol TRIVIAL 23628621 A 847 858 cholesterol TRIVIAL 23628674 A 1271 1281 tacrolimus TRIVIAL 23628674 A 1304 1314 tacrolimus TRIVIAL 23628674 A 1368 1378 tacrolimus TRIVIAL 23628674 A 1422 1431 tacolimus TRIVIAL 23628674 A 1485 1495 Tacrolimus TRIVIAL 23628674 A 150 161 schisandrin TRIVIAL 23628674 A 1614 1623 tacolimus TRIVIAL 23628674 A 163 176 schisandrol B TRIVIAL 23628674 A 1747 1757 tacrolimus TRIVIAL 23628674 A 178 193 schisantherin A TRIVIAL 23628674 A 1801 1811 tacrolimus TRIVIAL 23628674 A 195 207 schisanhenol TRIVIAL 23628674 A 212 227 deoxyshisandrin TRIVIAL 23628674 A 237 247 tacrolimus TRIVIAL 23628674 A 43 50 ethanol SYSTEMATIC 23628674 A 450 460 tacrolimus TRIVIAL 23628674 A 559 569 tacrolimus TRIVIAL 23628674 A 694 704 tacrolimus TRIVIAL 23628674 A 777 787 tacrolimus TRIVIAL 23628674 A 821 831 tacrolimus TRIVIAL 23628674 A 979 989 tacrolimus TRIVIAL 23628674 T 77 87 Tacrolimus TRIVIAL 23629055 A 103 150 meta di-tert-butylphenyl-substituted porphyrins FAMILY 23629055 A 1192 1206 ortho-octyloxy SYSTEMATIC 23629055 A 1225 1237 meso-phenyls FAMILY 23629055 A 15 24 porphyrin FAMILY 23629055 A 1671 1688 cyanoacrylic acid SYSTEMATIC 23629055 A 432 459 meta-substituted porphyrins FAMILY 23629055 A 500 510 dioctyloxy SYSTEMATIC 23629055 A 554 565 meso-phenyl SYSTEMATIC 23629055 A 592 600 carboxyl SYSTEMATIC 23629055 A 608 625 cyanoacrylic acid SYSTEMATIC 23629055 A 795 804 porphyrin FAMILY 23629055 A 829 830 C FORMULA 23629055 A 85 97 meso-phenyls FAMILY 23629055 A 861 862 C FORMULA 23629055 T 0 9 Porphyrin FAMILY 23629516 A 0 33 Tris(1-chloro-2-propyl) phosphate SYSTEMATIC 23629516 A 1040 1044 TCPP ABBREVIATION 23629516 A 1052 1057 TDCPP ABBREVIATION 23629516 A 1195 1199 TCPP ABBREVIATION 23629516 A 1203 1208 TDCPP ABBREVIATION 23629516 A 1325 1329 TCPP ABBREVIATION 23629516 A 1334 1339 TDCPP ABBREVIATION 23629516 A 1476 1481 TDCPP ABBREVIATION 23629516 A 274 278 TCPP ABBREVIATION 23629516 A 282 287 TDCPP ABBREVIATION 23629516 A 35 39 TCPP ABBREVIATION 23629516 A 45 82 tris(1,3-dichloro-2-propyl) phosphate SYSTEMATIC 23629516 A 646 650 TCPP ABBREVIATION 23629516 A 745 750 TDCPP ABBREVIATION 23629516 A 84 89 TDCPP ABBREVIATION 23629516 T 22 37 organophosphate FAMILY 23629516 T 56 60 TCPP ABBREVIATION 23629516 T 65 70 TDCPP ABBREVIATION 23629675 A 1054 1061 proline TRIVIAL 23629675 A 1201 1208 proline TRIVIAL 23629675 A 1562 1569 proline TRIVIAL 23629675 A 333 339 lysine TRIVIAL 23629675 A 383 391 ethylene SYSTEMATIC 23629675 A 621 627 lysine TRIVIAL 23629675 A 741 747 lysine TRIVIAL 23629675 A 86 92 lysine TRIVIAL 23629675 A 912 916 NaCl FORMULA 23629675 A 97 107 tryptophan TRIVIAL 23629675 T 113 119 Lysine TRIVIAL 23630043 A 106 138 5-(1,2,4-triazol-3-yl)tetrazoles FAMILY 23630043 A 1120 1128 triazole FAMILY 23630043 A 1139 1142 CC FORMULA 23630043 A 1159 1167 triazole FAMILY 23630043 A 1251 1260 tetrazole FAMILY 23630043 A 183 188 nitro SYSTEMATIC 23630043 A 190 199 nitrimino SYSTEMATIC 23630043 A 205 210 azido SYSTEMATIC 23630043 T 34 66 5-(1,2,4-Triazol-3-yl)tetrazoles FAMILY 23631351 A 119 141 biflavonoid glycosides FAMILY 23631351 A 143 236 5,3',5″,4″'-tetrahydroxy-3″',5″'dimethoxy-biflavone (4' → 8″)-7-O-((2-rhamnoside) rhamnoside) SYSTEMATIC 23631351 A 264 277 ethyl acetate SYSTEMATIC 23631351 A 302 310 methanol SYSTEMATIC 23631351 A 37 104 trans-2',6'-dihydroxy-4'-O-(4″-acetyl-rhamnoside)-4-methoxychalcone SYSTEMATIC 23631351 A 472 476 (1)H FORMULA 23631351 A 485 490 (13)C FORMULA 23631351 A 552 565 ethyl acetate SYSTEMATIC 23631351 A 591 620 1,1-diphenyl-2-picrylhydrazyl SYSTEMATIC 23631351 A 6 35 acetylated chalcone glycoside FAMILY 23631351 A 655 668 ethyl acetate SYSTEMATIC 23631351 T 30 52 biflavonoid glycosides FAMILY 23631351 T 6 25 acetylated chalcone FAMILY 23631427 A 16 25 adenosine TRIVIAL 23631427 A 240 256 benzothiazinones FAMILY 23631427 A 263 326 2-(3-chlorophenoxy)-N-(4-oxo-4H-3,1-benzothiazin-2-yl)acetamide SYSTEMATIC 23631427 A 422 438 Benzothiazinones TRIVIAL 23631427 A 487 494 methoxy SYSTEMATIC 23631427 A 495 509 cinnamoylamino SYSTEMATIC 23631427 A 511 529 phenylbutyrylamino SYSTEMATIC 23631427 A 534 566 chlorobenzylpiperazinylbenzamido SYSTEMATIC 23631427 A 63 72 monoamine FAMILY 23631427 A 687 703 benzothiazinones FAMILY 23631427 A 785 793 xanthine TRIVIAL 23631427 A 844 897 N-(4-oxo-4H-3,1-benzothiazin-2-yl)-4-phenylbutanamide SYSTEMATIC 23631427 T 22 31 Adenosine TRIVIAL 23631427 T 50 59 Monoamine SYSTEMATIC 23631490 A 55 66 polyphenols FAMILY 23631490 T 10 21 Polyphenols FAMILY 23631493 A 1036 1044 lycopene TRIVIAL 23631493 A 1089 1097 Lycopene TRIVIAL 23631493 A 1225 1233 Lycopene TRIVIAL 23631493 A 1367 1375 lycopene TRIVIAL 23631493 A 142 150 lycopene TRIVIAL 23631493 A 347 355 lycopene TRIVIAL 23631493 A 829 837 lycopene TRIVIAL 23631493 A 9 17 Lycopene TRIVIAL 23631493 T 10 18 Lycopene TRIVIAL 23631499 A 1036 1049 acetylcholine SYSTEMATIC 23631499 A 1280 1285 AlCl3 FORMULA 23631499 A 642 654 rivastigmine TRIVIAL 23631553 A 1251 1266 Polybenzoxazine FAMILY 23631553 A 180 191 benzoxazine FAMILY 23631553 A 253 264 bisphenol-A TRIVIAL 23631553 A 271 293 tetraethylenepentamine SYSTEMATIC 23631553 A 295 299 TEPA ABBREVIATION 23631553 A 305 313 formalin TRIVIAL 23631553 A 415 417 1H FORMULA 23631553 A 563 574 acetic acid SYSTEMATIC 23631553 A 694 705 benzoxazine FAMILY 23631553 A 71 82 benzoxazine FAMILY 23631553 A 891 902 benzoxazine FAMILY 23631553 A 904 912 Hydrogen SYSTEMATIC 23631553 A 929 944 polybenzoxazine FAMILY 23631553 T 19 34 Polybenzoxazine FAMILY 23632007 A 229 290 1,5-bis(4-allyldimethylammoniumphenyl) pentan-3-one dibromide SYSTEMATIC 23632007 A 292 324 tetraisopropyl pyrophosphoramide SYSTEMATIC 23632007 A 329 340 neostigmine TRIVIAL 23632007 A 378 394 organophosphorus FAMILY 23632007 A 396 406 dichlorvos TRIVIAL 23632007 A 408 420 chlorpyrifos TRIVIAL 23632007 A 425 433 diazinon TRIVIAL 23632007 A 443 452 carbamate FAMILY 23632007 A 454 462 carbaryl TRIVIAL 23632007 A 467 477 carbofuran TRIVIAL 23632007 A 658 668 dichlorvos TRIVIAL 23632007 A 681 693 chlorpyrifos TRIVIAL 23632007 A 707 715 carbaryl TRIVIAL 23632007 A 730 740 carbofuran TRIVIAL 23632081 A 0 9 Serotonin TRIVIAL 23632081 A 1182 1191 serotonin TRIVIAL 23632081 A 1237 1246 serotonin TRIVIAL 23632081 A 1313 1322 serotonin TRIVIAL 23632081 A 1381 1419 3,4-methylenedioxy-N-methylamphetamine SYSTEMATIC 23632081 A 1421 1425 MDMA ABBREVIATION 23632081 A 374 383 serotonin TRIVIAL 23632081 A 528 539 amino acids FAMILY 23632081 A 755 762 leucine TRIVIAL 23632081 A 90 99 serotonin TRIVIAL 23632081 T 45 54 Serotonin TRIVIAL 23632082 A 1044 1049 Na(+) FORMULA 23632082 A 1258 1263 2-APB SYSTEMATIC 23632082 A 1265 1280 flufenamic acid TRIVIAL 23632082 A 1285 1290 ML204 IDENTIFIER 23632082 A 1304 1310 La(3+) FORMULA 23632082 A 136 147 thyrotropin TRIVIAL 23632082 A 1378 1389 capsazepine TRIVIAL 23632082 A 1395 1400 Na(+) FORMULA 23632082 A 1402 1408 Ca(2+) FORMULA 23632082 A 1427 1435 KB-R7943 IDENTIFIER 23632082 A 1437 1440 TRH ABBREVIATION 23632082 A 1562 1567 2-APB SYSTEMATIC 23632082 A 1571 1576 ML204 IDENTIFIER 23632082 A 1612 1615 TRH ABBREVIATION 23632082 A 167 170 TRH ABBREVIATION 23632082 A 1719 1723 K(+) FORMULA 23632082 A 257 260 TRH ABBREVIATION 23632082 A 420 423 TRH ABBREVIATION 23632082 A 460 463 TRH ABBREVIATION 23632082 A 483 486 TTX ABBREVIATION 23632082 A 543 546 TRH ABBREVIATION 23632082 A 630 633 TRH ABBREVIATION 23632082 A 772 775 TRH ABBREVIATION 23632082 A 821 826 Na(+) FORMULA 23632082 A 843 847 K(+) FORMULA 23632082 A 950 956 Ba(2+) FORMULA 23632082 A 999 1008 SCH 23390 IDENTIFIER 23632082 T 45 56 thyrotropin TRIVIAL 23632158 A 1200 1209 glutamate TRIVIAL 23632309 A 1307 1316 flavonoid FAMILY 23633521 A 226 233 glucose TRIVIAL 23633529 A 1019 1028 phosphate SYSTEMATIC 23633529 A 1069 1079 phosphates FAMILY 23633529 A 1162 1171 oxymethyl SYSTEMATIC 23633529 A 1398 1417 ritonavir phosphate SYSTEMATIC 23633529 A 1531 1543 fosphenytoin TRIVIAL 23633529 A 1548 1569 clindamycin phosphate SYSTEMATIC 23633529 A 267 276 phosphate SYSTEMATIC 23633529 A 755 767 fosphenytoin TRIVIAL 23633529 A 769 790 clindamycin phosphate SYSTEMATIC 23633529 A 792 815 dexamethasone phosphate SYSTEMATIC 23633529 A 817 836 ritonavir phosphate SYSTEMATIC 23633529 A 841 870 ritonavir oxymethyl phosphate SYSTEMATIC 23633532 A 1133 1147 corticosterone TRIVIAL 23633532 A 1149 1153 CORT ABBREVIATION 23633532 A 1159 1164 11DHC SYSTEMATIC 23633532 A 1193 1197 CORT ABBREVIATION 23633532 A 1207 1212 11DHC SYSTEMATIC 23633532 A 1255 1259 CORT ABBREVIATION 23633532 A 1264 1269 11DHC SYSTEMATIC 23633532 A 1298 1302 CORT ABBREVIATION 23633532 A 1312 1317 11DHC SYSTEMATIC 23633532 A 1362 1365 Ser FORMULA 23633532 A 1383 1386 Thr FORMULA 23633532 A 1417 1432 diacylglyderide FAMILY 23633532 A 1638 1653 diacylglyderide FAMILY 23633532 A 450 468 11β-hydroxysteroid FAMILY 23633532 A 542 555 Dexamethasone TRIVIAL 23633532 A 642 645 Ser FORMULA 23633532 A 656 666 acetyl-CoA SYSTEMATIC 23633532 A 709 712 Thr FORMULA 23633532 A 720 723 AMP ABBREVIATION 23633532 A 786 799 dexamethasone TRIVIAL 23633532 A 842 855 dexamethasone TRIVIAL 23633532 A 921 945 11-dehydrocorticosterone SYSTEMATIC 23633532 A 947 952 11DHC SYSTEMATIC 23633563 A 1053 1060 glucose TRIVIAL 23633563 A 1683 1690 glucose TRIVIAL 23633563 A 298 305 glucose TRIVIAL 23633563 A 391 398 glucose TRIVIAL 23633563 A 517 524 glucose TRIVIAL 23633563 A 805 812 glucose TRIVIAL 23633563 A 89 96 glucose TRIVIAL 23634786 A 174 178 MeOH FORMULA 23634786 A 289 312 lanostane triterpenoids FAMILY 23634786 A 477 503 3-hydroxy-3-methylglutaryl SYSTEMATIC 23634786 A 640 652 fasciculol G TRIVIAL 23634786 A 876 888 nitric oxide SYSTEMATIC 23634786 T 0 23 Lanostane Triterpenoids FAMILY 23634899 A 22 24 OH FORMULA 23634899 A 291 300 $^{17}$OH FORMULA 23634899 A 433 442 $^{17}$OH FORMULA 23634899 A 544 546 OH FORMULA 23634899 T 24 32 Hydroxyl SYSTEMATIC 23635005 A 1004 1016 carbohydrate FAMILY 23635005 A 1196 1208 carbohydrate FAMILY 23635005 A 269 281 carbohydrate FAMILY 23635005 A 388 396 β-D-Galp ABBREVIATION 23635005 A 444 452 β-D-Galp ABBREVIATION 23635005 A 547 555 α-L-Araf ABBREVIATION 23635005 A 593 601 α-L-Araf ABBREVIATION 23635005 A 606 614 β-D-Galp ABBREVIATION 23635005 A 639 664 esterified phenolic acids FAMILY 23635005 A 757 769 carbohydrate FAMILY 23635005 A 851 864 phenolic acid FAMILY 23635005 T 17 29 Carbohydrate FAMILY 23635023 A 30 34 GaAs FORMULA 23635023 A 328 334 AlGaAs FORMULA 23635023 A 361 365 GaAs FORMULA 23635023 T 76 80 GaAs FORMULA 23636303 A 1055 1063 MDL72222 IDENTIFIER 23636303 A 1111 1123 methiothepin TRIVIAL 23636303 A 1141 1151 citalopram TRIVIAL 23636303 A 1174 1182 MDL72222 IDENTIFIER 23636303 A 1266 1276 citalopram TRIVIAL 23636303 A 1358 1366 MDL72222 IDENTIFIER 23636303 A 1390 1400 citalopram TRIVIAL 23636303 A 1485 1494 serotonin TRIVIAL 23636303 A 21 30 serotonin TRIVIAL 23636303 A 315 324 serotonin TRIVIAL 23636303 A 503 513 citalopram TRIVIAL 23636303 A 541 554 noradrenaline TRIVIAL 23636303 A 722 729 RS79948 IDENTIFIER 23636303 A 747 757 citalopram TRIVIAL 23636303 A 836 846 citalopram TRIVIAL 23636303 A 975 985 citalopram TRIVIAL 23636303 T 15 24 serotonin TRIVIAL 23636303 T 92 101 serotonin TRIVIAL 23636446 A 588 602 hydrocortisone TRIVIAL 23636584 A 552 558 biotin TRIVIAL 23636886 A 870 877 glucose TRIVIAL 23636886 A 898 903 MgCl2 FORMULA 23637306 A 144 151 benzene SYSTEMATIC 23637306 A 153 160 toluene TRIVIAL 23637306 A 165 171 xylene FAMILY 23637306 A 384 391 benzene SYSTEMATIC 23637306 A 393 400 toluene TRIVIAL 23637306 A 405 411 xylene FAMILY 23637306 A 705 715 superoxide TRIVIAL 23637306 A 841 848 alanine TRIVIAL 23637306 A 870 879 aspartate TRIVIAL 23637306 A 967 977 creatinine TRIVIAL 23637306 A 982 993 cholesterol TRIVIAL 23638641 A 0 8 Shogaols FAMILY 23638641 A 1053 1059 thiols FAMILY 23638641 A 1099 1125 5-glutathionyl-[6]-shogaol SYSTEMATIC 23638641 A 1449 1454 thiol FAMILY 23638641 A 1586 1616 5-N-acetylcystenyl-[6]-shogaol SYSTEMATIC 23638641 A 180 196 mercapturic acid TRIVIAL 23638641 A 1863 1871 cysteine TRIVIAL 23638641 A 1897 1908 [6]-shogaol TRIVIAL 23638641 A 206 229 5-cysteinyl-[6]-shogaol SYSTEMATIC 23638641 A 304 315 [6]-shogaol TRIVIAL 23638641 A 478 483 thiol FAMILY 23638641 A 906 917 glutathione TRIVIAL 23638641 T 0 8 Cysteine TRIVIAL 23638641 T 51 62 [6]-shogaol TRIVIAL 23638641 T 86 97 [6]-shogaol TRIVIAL 23638658 A 0 7 CuInSe2 FORMULA 23638658 A 266 273 CuInSe2 FORMULA 23638658 A 675 677 Cu FORMULA 23638658 A 678 680 In FORMULA 23638658 A 681 683 Se FORMULA 23638658 A 771 777 copper SYSTEMATIC 23638658 A 786 792 indium SYSTEMATIC 23638658 T 35 47 Chalcopyrite TRIVIAL 23638658 T 48 72 Copper Indium Diselenide SYSTEMATIC 23638985 A 154 162 saponins FAMILY 23638985 A 163 177 ginsenoside Rf TRIVIAL 23638985 A 18 28 triterpene FAMILY 23638985 A 186 201 ginsenoside Re5 TRIVIAL 23638985 A 206 219 panajaponol A TRIVIAL 23638985 A 275 279 (1)H FORMULA 23638985 A 280 284 (1)H FORMULA 23638985 A 29 36 saponin FAMILY 23638985 A 363 370 saponin FAMILY 23638985 A 389 482 3β,12β,20S,26-tetrahydroxydammar-24E-en-6α-O-β-d-glucopyranosyl-(1 → 2)-O-β-d-glucopyranoside SYSTEMATIC 23638985 A 43 56 ginsenjilinol TRIVIAL 23638985 A 512 520 saponins FAMILY 23638985 A 532 544 nitric oxide SYSTEMATIC 23638985 A 642 650 saponins FAMILY 23638985 A 8 17 dammarane TRIVIAL 23638985 A 912 924 indomethacin TRIVIAL 23638985 T 0 13 Ginsenjilinol TRIVIAL 23638985 T 21 37 protopanaxatriol TRIVIAL 23638985 T 43 50 saponin FAMILY 23638985 T 93 95 NO FORMULA 23639075 A 218 237 patriheterdoid B, C NO CLASS 23639075 A 30 49 patriheterdoid B, C NO CLASS 23639075 A 327 331 (1)H FORMULA 23639075 A 336 341 (13)C FORMULA 23639075 A 8 22 iridoid esters FAMILY 23639075 T 18 32 iridoid esters FAMILY 23639096 A 1223 1231 catechol TRIVIAL 23639096 A 1386 1393 calcium SYSTEMATIC 23639096 A 575 583 dopamine TRIVIAL 23639096 A 685 693 catechol TRIVIAL 23639096 A 712 721 catechols FAMILY 23639096 A 861 869 catechol TRIVIAL 23639096 A 993 1001 catechol TRIVIAL 23639096 T 14 21 Calcium SYSTEMATIC 23639188 A 230 241 anthranoids FAMILY 23639188 A 438 450 altersolanol FAMILY 23639188 T 28 39 anthranoids FAMILY 23639192 A 0 8 Puerarin TRIVIAL 23639192 A 1112 1120 puerarin TRIVIAL 23639192 A 1237 1245 puerarin TRIVIAL 23639192 A 1416 1424 estrogen FAMILY 23639192 A 1437 1445 puerarin TRIVIAL 23639192 A 19 39 isoflavone glycoside FAMILY 23639192 A 231 239 puerarin TRIVIAL 23639192 A 372 380 puerarin TRIVIAL 23639192 A 562 570 puerarin TRIVIAL 23639192 A 627 636 cisplatin TRIVIAL 23639192 A 704 712 estrogen FAMILY 23639192 A 737 745 Puerarin TRIVIAL 23639192 A 813 821 puerarin TRIVIAL 23639192 A 932 943 ICI 182,780 IDENTIFIER 23639192 A 975 983 puerarin TRIVIAL 23639192 T 0 8 Puerarin TRIVIAL 23639248 A 1063 1069 silica TRIVIAL 23639248 A 1246 1252 silica TRIVIAL 23639248 A 1402 1408 silica TRIVIAL 23639248 A 1475 1481 silica TRIVIAL 23639248 A 219 225 silica TRIVIAL 23639248 A 355 361 silica TRIVIAL 23639248 A 481 487 silica TRIVIAL 23639248 A 503 509 silica TRIVIAL 23639248 A 543 549 silica TRIVIAL 23639248 A 587 593 silica TRIVIAL 23639248 A 747 761 hydroxyproline SYSTEMATIC 23639248 A 886 900 hydroxyproline SYSTEMATIC 23639248 A 968 974 silica TRIVIAL 23639248 T 38 44 silica TRIVIAL 23639361 A 1043 1051 naringin TRIVIAL 23639361 A 1057 1067 naringenin TRIVIAL 23639361 A 1076 1083 calcium SYSTEMATIC 23639361 A 1108 1116 naringin TRIVIAL 23639361 A 1121 1131 naringenin TRIVIAL 23639361 A 1290 1298 naringin TRIVIAL 23639361 A 1303 1313 naringenin TRIVIAL 23639361 A 622 629 calcium SYSTEMATIC 23639361 A 801 808 calcium SYSTEMATIC 23639361 A 869 877 naringin TRIVIAL 23639361 A 882 892 naringenin TRIVIAL 23639361 A 918 925 calcium SYSTEMATIC 23639361 A 975 988 cortistatin-8 TRIVIAL 23639361 T 33 41 naringin TRIVIAL 23639361 T 46 56 naringenin TRIVIAL 23639430 A 1044 1051 quinine TRIVIAL 23639430 A 1194 1201 cocaine TRIVIAL 23639430 A 1478 1485 cocaine TRIVIAL 23639430 A 1578 1585 quinine TRIVIAL 23639430 A 1698 1705 cocaine TRIVIAL 23639430 A 1847 1855 dopamine TRIVIAL 23639430 A 1887 1894 cocaine TRIVIAL 23639430 A 1984 1991 quinine TRIVIAL 23639430 A 2042 2049 cocaine TRIVIAL 23639430 A 2076 2083 cocaine TRIVIAL 23639430 A 2170 2178 dopamine TRIVIAL 23639430 A 2203 2210 cocaine TRIVIAL 23639430 A 2358 2365 cocaine TRIVIAL 23639430 A 24 31 cocaine TRIVIAL 23639430 A 757 766 saccharin TRIVIAL 23639430 A 809 816 cocaine TRIVIAL 23639430 A 977 984 cocaine TRIVIAL 23639430 T 136 143 cocaine TRIVIAL 23639437 A 0 8 Nicotine TRIVIAL 23639437 A 412 420 nicotine TRIVIAL 23639437 A 966 974 nicotine TRIVIAL 23639437 T 26 34 Nicotine TRIVIAL 23639437 T 64 72 Nicotine TRIVIAL 23639537 A 6 44 indeno[1,2-d]thiazole hydroxamic acids FAMILY 23639537 T 47 68 indeno[1,2-d]thiazole SYSTEMATIC 23639543 A 0 26 Ribonucleoside phosphonate FAMILY 23639543 A 151 171 diphosphophosphonate SYSTEMATIC 23639543 A 173 185 triphosphate SYSTEMATIC 23639543 A 198 205 adenine TRIVIAL 23639543 A 210 218 cytidine TRIVIAL 23639543 A 387 410 nucleoside phosphonates FAMILY 23639543 A 48 59 2'-α-fluoro SYSTEMATIC 23639543 T 14 27 2'-α-fluorine SYSTEMATIC 23639543 T 37 60 nucleoside phosphonates FAMILY 23639545 A 102 107 amino FAMILY 23639545 A 108 117 acetamido FAMILY 23639545 A 183 187 (1)H FORMULA 23639545 A 384 407 l-α-phosphatidylcholine FAMILY 23639545 A 46 64 p-phenylenediamine SYSTEMATIC 23639545 A 583 588 amino FAMILY 23639545 A 6 18 bis(choloyl) FAMILY 23639545 A 640 645 Na(+) FORMULA 23639545 A 646 651 Li(+) FORMULA 23639545 A 65 90 p-bis(aminomethyl)benzene SYSTEMATIC 23639545 A 652 656 K(+) FORMULA 23639545 A 657 662 Rb(+) FORMULA 23639545 A 663 668 Cs(+) FORMULA 23639545 A 693 702 acetamido FAMILY 23639545 A 736 741 Li(+) FORMULA 23639545 A 742 747 Na(+) FORMULA 23639545 A 748 752 K(+) FORMULA 23639545 A 753 758 Rb(+) FORMULA 23639545 A 759 764 Cs(+) FORMULA 23639545 T 54 66 bis(choloyl) FAMILY 23639627 A 0 13 Anthracycline TRIVIAL 23639627 A 521 532 doxorubicin TRIVIAL 23639627 A 534 537 DXR ABBREVIATION 23639627 A 786 789 DXR ABBREVIATION 23639627 A 953 956 DXR ABBREVIATION 23639627 A 993 996 DXR ABBREVIATION 23639627 T 0 11 Doxorubicin TRIVIAL 23639652 A 391 399 chalcone FAMILY 23639652 A 420 431 sulfonamide SYSTEMATIC 23639652 T 10 19 chalcones FAMILY 23639652 T 24 36 sulfonamides FAMILY 23639652 T 84 92 tyrosine TRIVIAL 23639738 A 0 11 Cholesterol TRIVIAL 23639738 A 106 109 PEC ABBREVIATION 23639738 A 335 338 PEC ABBREVIATION 23639738 A 408 411 PEC ABBREVIATION 23639738 A 436 439 PEC ABBREVIATION 23639738 A 448 451 PEC ABBREVIATION 23639738 A 475 478 PEC ABBREVIATION 23639738 A 529 532 PEC ABBREVIATION 23639738 A 53 77 poly(ethylene carbonate) SYSTEMATIC 23639738 A 579 582 PEC ABBREVIATION 23639738 A 647 650 PEC ABBREVIATION 23639738 A 772 775 PEC ABBREVIATION 23639738 A 79 82 PEC ABBREVIATION 23639738 A 800 803 PEC ABBREVIATION 23639738 A 914 917 PEC ABBREVIATION 23639738 T 37 61 poly(ethylene carbonate) SYSTEMATIC 23639739 A 736 742 6-OHDA SYSTEMATIC 23639741 A 202 208 sodium SYSTEMATIC 23639741 A 213 222 potassium SYSTEMATIC 23639741 A 871 874 HCl FORMULA 23639741 T 34 36 Na FORMULA 23639741 T 41 42 K FORMULA 23639992 A 239 259 polydimethylsiloxane SYSTEMATIC 23639992 A 261 265 PDMS ABBREVIATION 23640282 A 244 249 Fe3O4 FORMULA 23640282 A 254 258 FePt FORMULA 23640471 A 150 177 1-butyl-3-methylimidazolium SYSTEMATIC 23640471 A 179 189 [C4MIM](+) FORMULA 23640471 A 329 334 C4MIM ABBREVIATION 23640471 A 353 360 [Cl](-) FORMULA 23640471 A 362 370 [BF4](-) FORMULA 23640471 A 372 380 [PF6](-) FORMULA 23640471 A 382 390 [OTf](-) FORMULA 23640471 A 392 401 [NTf2](-) FORMULA 23640471 A 406 419 [B(hfip)4](-) FORMULA 23640471 A 922 932 [C4MIM](+) FORMULA 23640722 A 334 380 2-chloro-3-(4-methylpiperazin-1-yl)quinoxaline SYSTEMATIC 23640722 A 382 390 VUF10166 IDENTIFIER 23640722 A 458 476 [(3) H]granisetron SYSTEMATIC 23640722 A 575 583 VUF10166 IDENTIFIER 23640722 A 588 629 3-(4-methylpiperazin-1-yl)quinoxalin-2-ol SYSTEMATIC 23640722 A 872 917 2-amino-3-(4-methylpiperazin-1-yl)quinoxaline SYSTEMATIC 23640722 A 982 1019 2-(4-methylpiperazin-1-yl)quinoxaline SYSTEMATIC 23640722 T 36 47 Quinoxaline SYSTEMATIC 23640867 A 252 260 arginine TRIVIAL 23640867 A 316 324 arginine TRIVIAL 23640867 A 569 576 trypsin TRIVIAL 23640867 A 752 762 citrulline TRIVIAL 23640872 A 286 293 tropane TRIVIAL 23640872 A 297 306 scopoline TRIVIAL 23640872 A 32 39 scopine TRIVIAL 23640872 A 352 359 scopine TRIVIAL 23640872 A 45 54 scopoline TRIVIAL 23640872 A 527 536 scopoline TRIVIAL 23640872 A 56 62 oscine TRIVIAL 23640872 A 607 614 scopine TRIVIAL 23640872 A 642 647 epoxy SYSTEMATIC 23640872 A 691 708 7β-hydroxytropane SYSTEMATIC 23640872 A 728 735 hydroxy SYSTEMATIC 23640872 A 780 783 OH FORMULA 23640872 A 786 787 N FORMULA 23640872 A 803 811 hydrogen SYSTEMATIC 23640872 A 845 853 N-methyl SYSTEMATIC 23640872 T 14 21 Tropane TRIVIAL 23640872 T 25 34 Scopoline TRIVIAL 23640962 A 1166 1179 isoflavonoids FAMILY 23640962 A 1190 1198 saponins FAMILY 23640962 A 628 640 nitric oxide SYSTEMATIC 23640962 A 927 943 prostaglandin E2 TRIVIAL 23641017 A 1100 1111 cholesterol TRIVIAL 23641017 A 1117 1129 triglyceride FAMILY 23641017 A 722 733 cholesterol TRIVIAL 23641017 A 755 768 triglycerides FAMILY 23641017 A 801 812 cholesterol TRIVIAL 23641685 A 1185 1188 HMP ABBREVIATION 23641685 A 145 156 hydroperoxy SYSTEMATIC 23641685 A 1519 1522 HMP ABBREVIATION 23641685 A 166 169 HO2 FORMULA 23641685 A 175 187 formaldehyde SYSTEMATIC 23641685 A 189 193 HCHO FORMULA 23641685 A 1943 1946 HMP ABBREVIATION 23641685 A 215 217 OH FORMULA 23641685 A 2231 2234 HMP ABBREVIATION 23641685 A 2277 2281 OCOH FORMULA 23641685 A 2287 2291 OOCO FORMULA 23641685 A 2639 2642 HMP ABBREVIATION 23641685 A 271 274 HMP ABBREVIATION 23641685 A 2749 2752 HMP ABBREVIATION 23641685 A 2910 2913 HMP ABBREVIATION 23641685 A 2994 2997 HMP ABBREVIATION 23641685 A 3006 3009 HMP ABBREVIATION 23641685 A 413 416 HMP ABBREVIATION 23641685 A 455 459 HCHO FORMULA 23641685 A 465 468 HO2 FORMULA 23641685 A 52 74 hydroxyl-methyl-peroxy SYSTEMATIC 23641685 A 544 547 Cl2 FORMULA 23641685 A 567 571 HCHO FORMULA 23641685 A 576 578 O2 FORMULA 23641685 A 84 91 HOCH2OO FORMULA 23641685 A 96 99 HMP ABBREVIATION 23641685 A 984 988 HOOH FORMULA 23641685 A 993 998 HCOOH FORMULA 23641685 T 36 57 Hydroxy-Methyl-Peroxy SYSTEMATIC 23641955 A 118 137 uridine diphosphate SYSTEMATIC 23641955 A 444 455 laropiprant TRIVIAL 23641955 A 51 67 prostaglandin D2 TRIVIAL 23641955 A 520 531 laropiprant TRIVIAL 23641955 A 795 806 laropiprant TRIVIAL 23641955 A 90 101 laropiprant TRIVIAL 23641955 T 134 145 laropiprant TRIVIAL 23641955 T 147 154 MK-0524 IDENTIFIER 23641955 T 24 27 UDP ABBREVIATION 23642029 A 0 12 Brevetoxin B FAMILY 23642029 A 1066 1076 brevetoxin FAMILY 23642029 A 123 147 α,β-unsaturated aldehyde SYSTEMATIC 23642029 A 1364 1374 brevetoxin FAMILY 23642029 A 14 19 BTX-B ABBREVIATION 23642029 A 1404 1417 dihydro-BTX-B SYSTEMATIC 23642029 A 1474 1489 S-desoxy-BTX-B2 SYSTEMATIC 23642029 A 1543 1570 N-palmitoyl-S-desoxy-BTX-B2 SYSTEMATIC 23642029 A 1706 1716 brevetoxin FAMILY 23642029 A 1756 1766 amino acid FAMILY 23642029 A 1783 1793 fatty acid FAMILY 23642029 A 1806 1811 BTX-B ABBREVIATION 23642029 A 342 352 brevetoxin FAMILY 23642029 A 423 428 BTX-B ABBREVIATION 23642029 A 451 456 BTX-B ABBREVIATION 23642029 A 485 503 [3H] dihydro-BTX-B SYSTEMATIC 23642029 A 505 525 [3H] S-desoxy-BTX-B2 SYSTEMATIC 23642029 A 527 548 cysteine brevetoxin B TRIVIAL 23642029 A 576 581 BTX-B ABBREVIATION 23642029 A 600 608 cysteine TRIVIAL 23642029 A 620 628 olefinic FAMILY 23642029 A 641 645 [3H] FORMULA 23642029 A 666 674 aldehyde SYSTEMATIC 23642029 A 686 719 [14C] N-palmitoyl-S-desoxy-BTX-B2 SYSTEMATIC 23642029 A 739 754 S-desoxy-BTX-B2 SYSTEMATIC 23642029 A 801 806 [14C] FORMULA 23642029 A 820 830 fatty acid FAMILY 23642029 A 839 847 cysteine TRIVIAL 23642029 A 848 853 amide FAMILY 23642029 A 909 929 [3H] S-desoxy-BTX-B2 SYSTEMATIC 23642029 A 931 964 [14C] N-palmitoyl-S-desoxy-BTX-B2 SYSTEMATIC 23642029 A 969 987 [3H] dihydro-BTX-B SYSTEMATIC 23642029 T 31 41 amino acid FAMILY 23642029 T 52 62 brevetoxin FAMILY 23642965 A 6 39 7-oxabicyclo[2.2.1]hept-5-en-2-yl SYSTEMATIC 23642965 A 80 114 boron trifluoride diethyl etherate SYSTEMATIC 23642965 T 13 46 7-oxabicyclo[2.2.1]hept-5-en-2-yl SYSTEMATIC 23643542 A 1634 1646 glycyrrhizin TRIVIAL 23643542 A 1685 1691 18β-GA FORMULA 23643542 A 2489 2495 18β-GA FORMULA 23643542 A 867 879 glycyrrhizin TRIVIAL 23643542 A 884 907 18β-glycyrrhetinic acid SYSTEMATIC 23643542 A 909 915 18β-GA FORMULA 23643664 A 1052 1060 tyrosine TRIVIAL 23643664 A 1218 1222 MPTP ABBREVIATION 23643664 A 1567 1571 MPTP ABBREVIATION 23643664 A 166 174 dopamine TRIVIAL 23643664 A 285 329 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine SYSTEMATIC 23643664 A 32 40 dopamine TRIVIAL 23643664 A 331 335 MPTP ABBREVIATION 23643664 A 376 380 MPTP ABBREVIATION 23643664 A 445 452 carboxy SYSTEMATIC 23643664 A 556 560 MPTP ABBREVIATION 23643664 A 594 598 MPTP ABBREVIATION 23643664 A 670 674 MPTP ABBREVIATION 23643664 A 816 820 MPTP ABBREVIATION 23643664 A 904 908 MPTP ABBREVIATION 23643664 T 30 34 MPTP ABBREVIATION 23643664 T 60 68 dopamine TRIVIAL 23643700 A 1042 1051 vitamin C TRIVIAL 23643700 A 1156 1165 vitamin C TRIVIAL 23643700 A 1255 1264 vitamin C TRIVIAL 23643700 A 207 220 Ascorbic acid TRIVIAL 23643700 A 356 369 ascorbic acid TRIVIAL 23643700 A 452 461 vitamin C TRIVIAL 23643700 A 651 660 vitamin C TRIVIAL 23643700 A 738 747 vitamin C TRIVIAL 23643700 A 974 983 vitamin C TRIVIAL 23643700 T 0 9 Vitamin C TRIVIAL 23643725 A 1340 1351 oxyfluorfen TRIVIAL 23643725 A 1416 1427 oxyfluorfen TRIVIAL 23643725 A 274 285 oxyfluorfen TRIVIAL 23643725 A 418 427 ascorbate TRIVIAL 23643725 A 532 543 glutathione TRIVIAL 23643725 A 620 631 oxyfluorfen TRIVIAL 23643725 A 856 867 oxyfluorfen TRIVIAL 23643725 A 903 908 chl-a ABBREVIATION 23643730 A 0 7 Juglone TRIVIAL 23643730 A 1017 1024 juglone TRIVIAL 23643730 A 1074 1082 androgen FAMILY 23643730 A 117 124 juglone TRIVIAL 23643730 A 1236 1255 dihydrotestosterone SYSTEMATIC 23643730 A 1257 1260 DHT ABBREVIATION 23643730 A 1308 1315 juglone TRIVIAL 23643730 A 1433 1440 juglone TRIVIAL 23643730 A 1482 1490 androgen FAMILY 23643730 A 404 411 juglone TRIVIAL 23643730 A 415 423 androgen FAMILY 23643730 A 463 466 MTT ABBREVIATION 23643730 A 531 538 juglone TRIVIAL 23643730 A 580 593 Hoechst 33342 TRIVIAL 23643730 A 650 657 juglone TRIVIAL 23643730 A 689 696 juglone TRIVIAL 23643730 A 817 824 juglone TRIVIAL 23643730 A 852 865 Hoechst 33342 TRIVIAL 23643730 T 0 7 Juglone TRIVIAL 23643737 A 254 260 acetyl SYSTEMATIC 23643737 A 347 360 acetylcholine SYSTEMATIC 23643737 A 558 601 1,4-substituted 4-(1H)-pyridylene-hydrazone FAMILY 23643737 T 0 43 1,4-Substituted 4-(1H)-pyridylene-hydrazone FAMILY 23643739 A 1181 1189 glycerol TRIVIAL 23643739 A 1194 1198 urea TRIVIAL 23643739 A 1311 1319 glycerol TRIVIAL 23643739 A 1325 1329 urea TRIVIAL 23643739 A 141 149 Glycerol TRIVIAL 23643739 A 154 158 urea TRIVIAL 23643739 A 294 302 glycerol TRIVIAL 23643739 A 307 311 urea TRIVIAL 23643739 A 349 362 metronidazole TRIVIAL 23643739 A 925 933 glycerol TRIVIAL 23643739 A 938 942 urea TRIVIAL 23643739 T 0 8 Glycerol TRIVIAL 23643739 T 13 17 urea TRIVIAL 23643744 A 106 110 NMDA ABBREVIATION 23643744 A 1186 1190 THIP ABBREVIATION 23643744 A 1202 1205 PCP ABBREVIATION 23643744 A 1306 1310 THIP ABBREVIATION 23643744 A 1328 1336 ADX47273 IDENTIFIER 23643744 A 1378 1382 THIP ABBREVIATION 23643744 A 1448 1456 ADX47273 IDENTIFIER 23643744 A 1461 1470 SSR180711 IDENTIFIER 23643744 A 1651 1659 ADX47273 IDENTIFIER 23643744 A 1663 1672 SSR180711 IDENTIFIER 23643744 A 1737 1740 PCP ABBREVIATION 23643744 A 367 371 NMDA ABBREVIATION 23643744 A 398 411 phencyclidine TRIVIAL 23643744 A 413 416 PCP ABBREVIATION 23643744 A 578 587 glutamate TRIVIAL 23643744 A 663 676 acetylcholine SYSTEMATIC 23643744 A 698 707 SSR180711 IDENTIFIER 23643744 A 750 753 PCP ABBREVIATION 23643744 A 906 914 ADX47273 IDENTIFIER 23643744 A 918 927 SSR180711 IDENTIFIER 23643744 T 184 197 phencyclidine TRIVIAL 23643744 T 199 202 PCP ABBREVIATION 23643744 T 42 51 glutamate TRIVIAL 23643744 T 89 102 acetylcholine SYSTEMATIC 23643745 A 109 117 dopamine TRIVIAL 23643745 A 1287 1298 pramipexole TRIVIAL 23643745 A 1509 1517 dopamine TRIVIAL 23643745 A 435 443 SCH23390 IDENTIFIER 23643745 A 453 463 raclopride TRIVIAL 23643745 A 465 476 amisulpride TRIVIAL 23643745 A 486 492 S33084 IDENTIFIER 23643745 A 705 715 raclopride TRIVIAL 23643745 A 756 767 amisulpride TRIVIAL 23643745 A 769 780 Amisulpride TRIVIAL 23643745 A 854 865 pramipexole TRIVIAL 23643745 A 870 878 dopamine TRIVIAL 23643745 A 889 917 L-3,4-dihydroxyphenylalanine SYSTEMATIC 23643745 A 927 937 raclopride TRIVIAL 23643745 A 943 949 S33084 IDENTIFIER 23643748 A 1041 1049 oxytocin TRIVIAL 23643748 A 1197 1205 oxytocin TRIVIAL 23643748 A 1554 1562 oxytocin TRIVIAL 23643748 A 32 40 oxytocin TRIVIAL 23643748 A 646 654 oxytocin TRIVIAL 23643748 A 706 714 oxytocin TRIVIAL 23643748 A 779 787 oxytocin TRIVIAL 23643748 A 915 923 oxytocin TRIVIAL 23643748 A 970 978 oxytocin TRIVIAL 23643748 T 21 29 oxytocin TRIVIAL 23643792 A 1123 1131 Tween 80 TRIVIAL 23643792 A 1402 1410 Tween-80 TRIVIAL 23643792 A 352 371 poly(-caprolactone) SYSTEMATIC 23643792 A 731 739 Tween 80 TRIVIAL 23643839 A 179 186 glucose TRIVIAL 23643839 A 202 208 serine TRIVIAL 23643839 A 209 218 threonine TRIVIAL 23643839 A 52 58 serine TRIVIAL 23643839 A 59 68 threonine TRIVIAL 23643933 A 1013 1016 TSA ABBREVIATION 23643933 A 1028 1031 TSA ABBREVIATION 23643933 A 1273 1276 TSA ABBREVIATION 23643933 A 1362 1365 TSA ABBREVIATION 23643933 A 1454 1457 TSA ABBREVIATION 23643933 A 1501 1504 TSA ABBREVIATION 23643933 A 197 211 Trichostatin A TRIVIAL 23643933 A 213 216 TSA ABBREVIATION 23643933 A 345 348 TSA ABBREVIATION 23643933 T 84 96 trichostatin TRIVIAL 23644192 A 207 214 rhenium SYSTEMATIC 23644192 A 417 424 (99m)Tc FORMULA 23644192 A 5 41 (99m)Tc-labeled dibenzylideneacetone SYSTEMATIC 23644192 A 677 684 (99m)Tc FORMULA 23644192 A 72 79 rhenium SYSTEMATIC 23644192 T 0 36 (99m)Tc-labeled dibenzylideneacetone SYSTEMATIC 23644195 A 1017 1028 carboxylate SYSTEMATIC 23644195 A 1032 1039 RVX-208 IDENTIFIER 23644195 A 1136 1140 (1)H FORMULA 23644195 A 1266 1282 primary hydroxyl FAMILY 23644195 A 1292 1299 RVX-208 IDENTIFIER 23644195 A 1303 1318 carboxylic acid SYSTEMATIC 23644195 A 344 351 RVX-208 IDENTIFIER 23644195 A 532 539 RVX-208 IDENTIFIER 23644195 A 65 72 RVX-208 IDENTIFIER 23644195 A 708 712 (1)H FORMULA 23644195 A 784 800 primary hydroxyl FAMILY 23644195 A 810 817 RVX-208 IDENTIFIER 23644195 A 822 837 glucuronic acid TRIVIAL 23644195 T 161 168 RVX-208 IDENTIFIER 23644195 T 83 159 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one SYSTEMATIC 23644200 A 248 255 mannose TRIVIAL 23644200 A 260 269 galactose TRIVIAL 23644200 A 28 57 glycosylated isomalyngamide A FAMILY 23644200 A 476 483 lactose TRIVIAL 23644200 A 548 562 monosaccharide FAMILY 23644200 A 575 587 disaccharide FAMILY 23644200 A 606 622 isomalyngamide A TRIVIAL 23644200 T 56 72 isomalyngamide A TRIVIAL 23644201 A 118 159 2-oxo-1,2-dihydroquinoline-3-carbaldehyde SYSTEMATIC 23644201 A 171 172 H FORMULA 23644201 A 178 180 Me FORMULA 23644201 A 186 188 Et FORMULA 23644201 A 197 199 Ph FORMULA 23644201 A 45 67 [Ni(H2-Qtsc-R)2](NO3)2 FAMILY 23644201 A 69 78 H2-Qtsc-R FAMILY 23644201 A 81 114 4N-substituted thiosemicarbazones FAMILY 23644201 A 9 15 Ni(II) FORMULA 23644201 T 109 142 4N-substituted thiosemicarbazones FAMILY 23644201 T 146 187 2-oxo-1,2-dihydroquinoline-3-carbaldehyde SYSTEMATIC 23644201 T 89 95 Ni(II) FORMULA 23644214 A 102 106 PCl5 FORMULA 23644214 A 125 126 C FORMULA 23644214 A 148 155 nitrile SYSTEMATIC 23644214 A 273 279 chloro SYSTEMATIC 23644214 A 298 304 amines FAMILY 23644214 A 327 372 4-aminothieno[2,3-d]pyrimidine-6-carbonitrile SYSTEMATIC 23644214 A 44 84 oxothieno[2,3-d]pyrimidine-6-carboxamide SYSTEMATIC 23644214 A 830 840 ampicillin TRIVIAL 23644214 A 908 920 greseofulvin TRIVIAL 23644214 A 92 97 POCl3 FORMULA 23644214 T 34 79 4-aminothieno[2,3-d]pyrimidine-6-carbonitrile SYSTEMATIC 23644256 A 1406 1409 IBU ABBREVIATION 23644256 A 1410 1414 ISDN ABBREVIATION 23644256 A 298 301 IBU ABBREVIATION 23644256 A 306 310 ISDN ABBREVIATION 23644256 A 33 42 ibuprofen TRIVIAL 23644256 A 44 47 IBU ABBREVIATION 23644256 A 497 500 IBU ABBREVIATION 23644256 A 514 518 ISDN ABBREVIATION 23644256 A 53 73 isosorbide dinitrate SYSTEMATIC 23644256 A 75 79 ISDN ABBREVIATION 23644256 A 946 949 IBU ABBREVIATION 23644256 A 950 954 ISDN ABBREVIATION 23644256 T 0 9 Ibuprofen TRIVIAL 23644256 T 15 35 Isosorbide Dinitrate SYSTEMATIC 23644525 A 245 251 carbon SYSTEMATIC 23645248 A 1014 1031 17beta-oestradiol SYSTEMATIC 23645248 A 1195 1208 sodium iodide SYSTEMATIC 23645248 A 1251 1268 17beta-oestradiol SYSTEMATIC 23645248 A 1284 1293 oestrogen FAMILY 23645248 A 139 148 oestrogen FAMILY 23645248 A 1511 1520 oestrogen FAMILY 23645248 A 334 343 oestrogen FAMILY 23645248 A 429 446 17beta-oestradiol SYSTEMATIC 23645248 A 498 507 oestrogen FAMILY 23645248 A 536 553 17beta-oestradiol SYSTEMATIC 23645248 A 675 688 sodium iodide SYSTEMATIC 23645248 A 726 743 17beta-oestradiol SYSTEMATIC 23645248 A 869 878 oestrogen FAMILY 23645248 A 945 954 oestrogen FAMILY 23645248 T 0 9 Oestrogen FAMILY 23645249 A 1077 1086 genistein TRIVIAL 23645249 A 1134 1146 triglyceride FAMILY 23645249 A 1175 1185 fatty acid FAMILY 23645249 A 1214 1223 Genistein TRIVIAL 23645249 A 1291 1299 estrogen FAMILY 23645249 A 1388 1427 2,3-bis (4-hydroxyphenyl)-propionitrile SYSTEMATIC 23645249 A 1429 1432 DPN ABBREVIATION 23645249 A 1606 1615 genistein TRIVIAL 23645249 A 1624 1627 DPN ABBREVIATION 23645249 A 1653 1662 genistein TRIVIAL 23645249 A 1847 1856 genistein TRIVIAL 23645249 A 605 615 isoflavone FAMILY 23645249 A 616 625 genistein TRIVIAL 23645249 A 784 793 genistein TRIVIAL 23645249 A 898 907 genistein TRIVIAL 23645249 T 38 47 genistein TRIVIAL CHEMDNER_CORPUS_BIOCREATIVE_4/CHEMDNER_TRAIN/Readme.txt0000644002344200234200000001266412176243316023015 0ustar mkrallingerBioinfoUnixCHEMDNER task training data annotation (Version 1.0 31st July 2013) ------------------------------------------------------------------- This directory contains the training abstracts, manual annotations and updated annotation guidelines. 1) chemdner_abs_training.txt : Training set abstracts This file contains plain-text, UTF8-encoded PubMed abstracts in a tab-separated format with the following three columns: 1- Article identifier (PMID, PubMed identifier) 2- Title of the article 3- Abstract of the article In total 3,500 abstracts are provided in this training set. Note that the test set will be provided in the same format. 2) Annotation Guidelines: chemdner_data_preparation_v17july31.pdf This document describes the article selection process as well as the updated manual data annotation guidelines used for the CHEMDNER task. 3) Training data annotations: chemdner_ann_training_13-07-31.txt This file contains manually generated annotations of chemical entities of the training dataset. It consists of tab-separated fields containing: 1- Article identifier (PMID) 2- Type of text from which the annotation was derived (T: Title, A: Abstract) 3- Start offset 4- End offset 5- Text string of the entity mention 6- Type of chemical entity mention (ABBREVIATION,FAMILY,FORMULA,IDENTIFIERS,MULTIPLE,SYSTEMATIC,TRIVIAL) 4) Training data Gold Standard file for the Chemical document indexing (CDI) sub-task: cdi_ann_training_13-07-31.txt Given a set of documents, for this subtask, the participants are asked to return for each of them a ranked list of chemical entities described within each of these documents. You are not required to provide the specific type of chemical entity class. It consists of tab-separated fields containing: 1- Article identifier (PMID) 2- Text string of the entity mention An example is shown below: 22258629 malondialdehyde 22288603 mikanolide 5) Training data Gold Standard file for the Chemical entity mention recognition (CEM) sub-task: cem_ann_training_13-07-31.txt Given a set of documents, for this subtask, the participants have to return the start and end indices corresponding to all the chemical entities mentioned in this document. You are not requested to provide the specific type of chemical entity subclass. It consists of tab-separated columns containing: 1- Article identifier (PMID) 2- Offset string consisting in a triplet joined by the ':' character. You have to provide the text type (T: Title, A:Abstract), the start offset and the end offset. An example illustrating the format is shown below: 21826085 A:946:957 22080034 A:1072:1081 22080034 A:1305:1314 22080034 A:1383:1392 22080034 A:190:199 Additional comments ------------------- To evaluate the performance of your system we recommend you to use the BioCreative evaluation library scripts. You can also directly download it from the BioCreative Resources page at: http://www.biocreative.org/resources/biocreative-ii5/evaluation-library/ This webpage explains in detail how to install the library and how it works. For both of the tasks you should use the --INT evaluation option like shown below: bc-evaluate --INT prediction_file evaluation_file As the --INT option is chosen by default, you can also run this script without the argument: bc-evaluate prediction_file evaluation_file Example evaluation files for both subtasks were described above. A) Prediction format for the CDI subtask Please make sure that your predictions are compliant with the formatting information provided for the --INT option of the evaluation library (The webpage and the bc-evaluate -h and bc-evaluate -d option provide you with more details.) In short, you have to provide a tab-separated file with: 1- Article identifier 2- The chemical entity mention string 3- The rank of the chemical entity returned for this document 4- A confidence score Example cases are provided online in the CHEMDNER sample set (June 25, 2013) (http://www.biocreative.org/resources/corpora/bc-iv-chemdner-corpus/#bc-iv-chemdner-corpus:downloads) An example prediction for the sample set is shown below: 6780324 LHRH 1 0.9 6780324 FSH 2 0.857142857143 6780324 3H2O 3 0.75 6780324 (Bu)2cAMP 4 0.75 6780324 vitro 5 0.666666666667 6780324 plasminogen 6 0.5 6780324 ethylamide 7 0.5 6780324 beta-3H]testosterone 8 0.5 6780324 NIH-FSH-S13 9 0.5 6780324 D-Ser-(But),6 10 0.5 6780324 4-h 11 0.5 6780324 3-isobutyl-l-methylxanthine 12 0.5 2231607 thymidylate 1 0.666666666667 2231607 acid 2 0.666666666667 2231607 TS 3 0.666666666667 B) Prediction format for the CEM subtask Please make sure that your predictions are compliant with the formatting information provided for the --INT option of the evaluation library (The webpage and the bc-evaluate -h and bc-evaluate -d option provide you with more details.) In short, you have to provide a tab-separated file with: 1- Article identifier (PMID) 2- Offset string consisting in a triplet joined by the ':' character. You have to provide the text type (T: Title, A:Abstract), the start offset and the end offset. 3- The rank of the chemical entity returned for this document 4- A confidence score Example from the sample set (from June 25, 2013) is shown below: 6780324 A:104:107 1 0.5 6780324 A:1136:1147 2 0.5 6780324 A:1497:1500 3 0.5 6780324 A:162:167 4 0.5 6780324 A:17:21 5 0.5 6780324 A:319:330 6 0.5 6780324 A:448:452 7 0.5 CHEMDNER_CORPUS_BIOCREATIVE_4/CHEMDNER_TRAIN/chemdner_abs_training.txt0000644002344200234200002261561512176224371026136 0ustar mkrallingerBioinfoUnix23104419 Transient gestational and neonatal hypothyroidism-induced specific changes in androgen receptor expression in skeletal and cardiac muscles of adult rat. The present study aims to identify the association between androgen status and metabolic activity in skeletal and cardiac muscles of adult rats with transient gestational/neonatal-onset hypothyroidism. Pregnant and lactating rats were made hypothyroid by exposing to 0.05% methimazole in drinking water; gestational exposure was from embryonic day 9-14 (group II) or 21 (group III), lactational exposure was from postnatal day 1-14 (group IV) or 29 (group V). Serum was collected for hormone assay. Androgen receptor status, Glu-4 expression, and enzyme activities were assessed in the skeletal and cardiac muscles. Serum testosterone and estradiol levels decreased in adult rats of groups II and III, whereas testosterone remained normal but estradiol increased in group IV and V, when compared to coeval control. Androgen receptor ligand binding activity increased in both muscle phenotypes with a consistent increase in the expression level of its mRNA and protein expressions except in the forelimb of adult rats with transient hypothyroidism (group II-V). Glut-4 expression remained normal in skeletal and cardiac muscle of experimental rats. Specific activity of hexokinase and lactate dehydrogenase increased in both muscle phenotypes whereas, creatine kinase activity increased in skeletal muscles alone. It is concluded that transient gestational/lactational exposure to methimazole results in hypothyroidism during prepuberal life whereas it increases AR status and glycolytic activity in skeletal and cardiac muscles even at adulthood. Thus, the present study suggests that euthyroid status during prenatal and early postnatal life is essential to have optimal AR status and metabolic activity at adulthood. 23550066 The CYP2B6*6 Allele Significantly Alters the N-demethylation of Ketamine Enantiomers In Vitro. Ketamine is primarily metabolized to norketamine by hepatic cytochrome P450 (CYP) 2B6 and CYP3A4-mediated N-demethylation. However, the relative contribution from each enzyme remains controversial. The CYP2B6*6 allele is associated with reduced enzyme expression and activity that may lead to interindividual variability in ketamine metabolism. We examined the N-demethylation of individual ketamine enantiomers using human liver microsomes (HLMs) genotyped for the CYP2B6*6 allele, insect cell expressed recombinant CYP2B6 and CYP3A4 enzymes and COS-1 cell expressed recombinant CYP2B6.1 and CYP2B6.6 protein variant. Effects of CYP-selective inhibitors on norketamine formation were also determined in HLMs. The two-enzyme Michaelis-Menten model best fitted the HLM kinetic data. The Km value for the high affinity enzyme and the low affinity enzyme were similar to those for the expressed CYP2B6 and CYP3A4, respectively. The intrinsic clearance for both ketamine enantiomers by the high affinity enzyme in HLMs with CYP2B6*1/*1 genotype were at least 2-fold and 6-fold higher, respectively, than those for CYP2B6*1/*6 genotype and CYP2B6*6/*6 genotype. The Vmax and Km values for CYP2B6.1 were approximately 160% and 70% of those for CYP2B6.6, respectively. ThioTEPA (CYP2B6 inhibitor, 25 μM) and the monoclonal antibody against CYP2B6 but not troleandomycin (CYP3A4 inhibitor, 25 μM) or the monoclonal antibody against CYP3A4 inhibited ketamine N-demethylation at clinically relevant concentrations. The degree of inhibition was significantly reduced in HLMs with the CYP2B6*6 allele (gene-dose P<0.05). These results indicate a major role of CYP2B6 in ketamine N-demethylation in vitro and a significant impact of the CYP2B6*6 allele on enzyme-ketamine binding and catalytic activity. 23164152 Metal-mediated targeting in the body. Metal ions are important for many biological processes and are steadily available in the human body. Metal concentrations can be extremely high in diseased areas of various pathological conditions. Some synthetic and natural drugs need to be activated by metal ions as prodrugs. In this review, we provide a few examples to illustrate how metal ions activate and mediate drug targeting in the body. This knowledge may be helpful for the development of more effective drugs and pharmaceutical formulations. 23477346 Follicular Variant of Papillary Thyroid Carcinoma is a Unique Clinical Entity: A Population-Based Study of 10,740 Cases. Background: Follicular variant of papillary thyroid carcinoma (FV-PTC) has been increasingly diagnosed in recent years. However, little is known about its clinical behavior. The purpose of this study was to determine the disease characteristics of FV-PTC, and to compare it with classical papillary thyroid carcinoma (C-PTC) and follicular thyroid carcinoma (FTC). Methods: All cases of C-PTC, FV-PTC and FTC larger than 1 cm in the Surveillance, Epidemiology and End Results (SEER) Cancer Database from 1988 to 2007 were identified. Tumor behavior and patient survival were compared among these three groups. Different risk factors for disease-specific mortality in each group were evaluated by multivariate analysis. Results: A total over 36,000 surgical cases were identified including 21,796 C-PTCs, 10,740 FV-PTCs and 3,958 FTCs. Extrathyroidal extension and lymph node metastases were more common in FV-PTC than in FTC, but significantly less common than in C-PTC (p<0.0001). Distant metastasis rate were present in 2% of patients with FV-PTC, 1% in C-PTC and 4% in FTC (p<0.0001). The 10-year disease-specific survival for patients with FV-PTC was 98%, similar to C-PTC (97%), but better than FTC (94%, p<0.0001). Age greater than 45 years remained a strong risk factor for disease-specific mortality in both FV-PTC and C-PTC, while the presence of extrathyroidal extension and distant metastases were stronger predictors of disease-specific mortality in FV-PTC than in C-PTC. Conclusions: FV-PTC is a common variant of PTC. Its clinical behavior is unique and represents an intermediate entity with clinical features that are between C-PTC and FTC. Interestingly, despite the variations in clinical behavior, the long-term outcome of these patients remains excellent and similar to C-PTC. 23530020 Prilocaine- and Lidocaine-induced Methemoglobinemia is Caused by Human Carboxylesterase-, CYP2E1- and CYP3A4-mediated Metabolic Activation. Prilocaine and lidocaine are classified as amide-type local anesthetics whose serious adverse effects include methemoglobinemia. Although the hydrolyzed metabolites of prilocaine (o-toluidine) and lidocaine (2,6-xylidine) have been suspected to induce methemoglobinemia, the metabolic enzymes that are involved remain uncharacterized. In the present study, we aimed to identify the human enzymes that are responsible for prilocaine- and lidocaine-induced methemoglobinemia. Our experiments revealed that prilocaine was hydrolyzed by recombinant human carboxylesterase (CES) 1A and CES2, whereas lidocaine was hydrolyzed only by human CES1A. When the parent compounds (prilocaine and lidocaine) were incubated with HLM, Met-Hb formation was lower than when the hydrolyzed metabolites were incubated with HLM. In addition, Met-Hb formation when prilocaine and o-toluidine were incubated with HLM was higher than that when lidocaine and 2,6-xylidine were incubated with HLM. Incubation with diisopropyl fluorophosphate and bis-(4-nitrophenyl) phosphate, which are general inhibitors of CES, significantly decreased Met-Hb formation when prilocaine and lidocaine were incubated with HLM. An anti-CYP3A4 antibody further decreased the residual formation of Met-Hb. Met-Hb formation following the incubation of o-toluidine and 2,6-xylidine with HLM was only markedly decreased by incubation with an anti-CYP2E1 antibody. o-Toluidine and 2,6-xylidine were further metabolized by CYP2E1 to 4- and 6-hydroxy-o-toluidine and 4-hydroxy-2,6-xylidine, respectively, and these metabolites were shown to more efficiently induce Met-Hb formation than the parent compounds. Collectively, we found that the metabolites produced by human CES-, CYP2E1- and CYP3A4-mediated metabolism were involved in prilocaine- and lidocaine-induced methemoglobinemia. 23122105 Non-target screening of Allura Red AC photodegradation products in a beverage through ultra high performance liquid chromatography coupled with hybrid triple quadrupole/linear ion trap mass spectrometry. The study deals with the identification of the degradation products formed by simulated sunlight photoirradiation in a commercial beverage that contains Allura Red AC dye. An UHPLC-MS/MS method, that makes use of hybrid triple quadrupole/linear ion trap, was developed. In the identification step the software tool information dependent acquisition (IDA) was used to automatically obtain information about the species present and to build a multiple reaction monitoring (MRM) method with the MS/MS fragmentation pattern of the species considered. The results indicate that the identified degradation products are formed from side-reactions and/or interactions among the dye and other ingredients present in the beverage (ascorbic acid, citric acid, sucrose, aromas, strawberry juice, and extract of chamomile flowers). The presence of aromatic amine or amide functionalities in the chemical structures proposed for the degradation products might suggest potential hazards to consumer health. 23494810 Spectroscopic Studies on Nicotine and Nornicotine in the UV Region. The UV absorption and electronic circular dichroism (ECD) spectra of (R)- and (S)-nicotine and (S)-nornicotine in aqueous solution were measured to a significantly lower wavelength range than previously reported, allowing the identification of four previously unobserved electronic transitions. The ECD spectra of the two enantiomers of nicotine were equal in magnitude and opposite in sign, while the UV absorption spectra were coincidental. In line with previous observations, (S)-nicotine exhibited a negative cotton effect centered on 263 nm with vibronic structure (π-π1 * transition) and a broad, positive ECD signal at around 240 nm associated with the n-π1 * transition. As expected this band disappeared when the pyridyl aromatic moiety was protonated. Four further electronic transitions are reported between 215 and 180 nm; it is proposed the negative maxima around 206 nm is either an n-σ* transition or a charge transfer band resulting from the movement of charge from the pyrrolidyl N lone pair to the pyridyl π* orbital. The pyridyl π-π2 * transition may be contained within the negative ECD signal envelope at around 200 nm. Another negative maximum at 188 nm is thought to be the pyridyl π-π3 * transition, while the lowest wavelength end-absorption and positive ECD may be associated with the π-π4 * transition. The UV absorption spectra of (S)-nornicotine was similar to that of (S)-nicotine in the range 280-220 nm and acidification of the aqueous solution enhanced the absorption. The ECD signals of (S)-nornicotine were considerably less intense compared to (S)-nicotine and declined further on acidification; in the far UV region the ECD spectra diverge considerably. Chirality 25:288-293, 2013. © 2013 Wiley Periodicals, Inc. 23567486 Variations in polyethylene glycol brands and their influence on the preparation process of hydrogel microspheres. Hydrogel microspheres, e.g. for the use as protein carriers, can be prepared without the use of organic solvents via an emulsified aqueous two-phase system (ATPS) that is based on two immiscible polymer solutions. The type and concentration of the polymers can affect the ATPS and finally the distribution of incorporated drugs between the aqueous phases. For the preparation of hydrogel microspheres based on hydroxyethyl starch-hydroxyethyl methacrylate (HES-HEMA), hydroxyethyl starch-methacrylate (HES-MA), and hydroxyethyl starch-polyethylene glycol methacrylate (HES-P(EG)6MA), polyethylene glycol 12,000 (PEG 12,000) was used as second polymer. The particle size distribution and encapsulation efficiency of the microspheres depended dramatically on the type of PEG 12,000 that was used in the second phase of the ATPS. Analysis of different PEG 12,000 brands by various methods revealed differences in the salt composition and molecular weight distribution of the polymers which can explain the results from the production process. The results illustrate that the range of product specifications may not always be tight enough to avoid variability in pharmaceutical processes like the preparation of hydrogel microspheres by an aqueous two-phase preparation process. 23639096 Bio-inspired, Calcium-free Alginate Hydrogels with Tunable Physical and Mechanical Properties and Improved Biocompatibility. Alginate hydrogels are for various biomedical applications including tissue engineering, cell therapy, and drug delivery. However, it is not easy to control swelling, or viscoelastic and biophysical properties of alginate hydrogels prepared by conventional crosslinking methods (ionic interaction using divalent cations). In this study, we describe a bio-inspired approach for preparing divalent ion-free alginate hydrogels that exhibit tunable physical and mechanical properties and improved biocompatibility due to the absence of cations in the gel matrices. We conjugated dopamine, a minimalized adhesive motif found in the holdfast pads of mussels, to alginate backbones (alginate-catechol) and the tethered catechols underwent oxidative crosslinking. This resulted in divalent cation-free alginate hydrogels. The swelling ratios and moduli of the alginate-catechol hydrogels are readily tunable, which is difficult to achieve in ionic bond-based alginate hydrogels. Furthermore, alginate-catechol hydrogels enhanced the survival of various human primary cells including stem cells in the three-dimensional gel matrix, indicating that intrinsic cytotoxicity caused by divalent cations becomes negligible when employing catechol oxidation for alginate crosslinking. The inflammatory response in vivo was also significantly attenuated compared to conventional alginate hydrogels with calcium crosslinking. This biomimetic approach for the preparation of alginate hydrogels may provide a novel platform technology to develop tunable, functional, biocompatible three-dimensional scaffolds for tissue engineering and cell therapy. 23198831 Hydrogen evolution from Pt/Ru-coated p-type WSe2 photocathodes. Crystalline p-type WSe(2) has been grown by a chemical vapor transport method. After deposition of noble metal catalysts, p-WSe(2) photocathodes exhibited thermodynamically based photoelectrode energy-conversion efficiencies of >7% for the hydrogen evolution reaction under mildly acidic conditions, and were stable under cathodic conditions for at least 2 h in acidic as well as in alkaline electrolytes. The open circuit potentials of the photoelectrodes in contact with the H(+)/H(2) redox couple were very close to the bulk recombination/diffusion limit predicted from the Shockley diode equation. Only crystals with a prevalence of surface step edges exhibited a shift in flat-band potential as the pH was varied. Spectral response data indicated effective minority-carrier diffusion lengths of ∼1 μm, which limited the attainable photocurrent densities in the samples to ∼15 mA cm(-2) under 100 mW cm(-2) of Air Mass 1.5G illumination. 23376090 Exposure to an organochlorine pesticide (chlordecone) and development of 18-month-old infants. Chlordecone is a persistent organochlorine pesticide that was used in the French West Indies until the early 1990s for banana weevil borer control. Human exposure to this chemical in this area still occurs nowadays due to consumption of contaminated food. Although adverse effects on neurodevelopment, including tremors and memory deficits, have been documented in experimental studies conducted with rodents exposed during the gestational and neonatal periods, no study has been conducted yet to determine if chlordecone alters child development. This study examines the relation of gestational and postnatal exposure to chlordecone to infant development at 18 months of age in a birth-cohort of Guadeloupean children. In a prospective longitudinal study conducted in Guadeloupe (Timoun mother-child cohort study), exposure to chlordecone was measured at birth from an umbilical cord blood sample (n=141) and from a breast milk sample collected at 3 months postpartum (n=75). Toddlers were assessed using an adapted version of the Ages and Stages Questionnaire. Higher chlordecone concentrations in cord blood were associated with poorer fine motor scores. When analyses were conducted separately for boys and girls, this effect was only observed among boys. These results suggest that prenatal exposure to chlordecone is associated with specific impairments in fine motor function in boys, and add to the growing evidence that exposure to organochlorine pesticides early in life impairs child development. 23530033 The Hyaluronan Receptor for Endocytosis (HARE) activates NF-κB mediated gene expression in response to 40-400 kDa, but not smaller or larger, hyaluronan. The Hyaluronan (HA) Receptor for Endocytosis (HARE) binds and clears 14 different ligands, including HA and heparin, via clathrin-mediated endocytosis. HA binding to HARE stimulates ERK1/2 activation (Kyosseva et al. J. Biol. Chem. 283, 15047, 2008). To assess a possible HA size-dependence for signaling, we tested purified HA fractions of different weight-average molar mass (Mw) and with narrow size distributions and Select-HA for stimulation of HARE-mediated gene expression using an NF-κB promoter-driven luciferase reporter system. Human HARE-mediated gene expression was stimulated in a dose-dependent manner with small HA (SHA) >40 kDa and intermediate HA (IHA) <400 kDa. The hyperbolic dose-response saturated at 20-50 nM with an apparent Km ~10 nM, identical to the Kd for HA-HARE binding. Activation was not detected with oligomeric HA (OHA), SHA <40 kDa, IHA >400 kDa or large HA (LHA). Similar responses occurred with rat HARE. Activation by SHA-IHA was blocked by excess nonsignaling SHA, IHA or LHA, deletion of the HA-binding LINK domain, or HA-blocking antibody. Endogenous NF-κB activation also occurred in the absence of luciferase plasmids, as assessed by degradation of IκB-α. ERK1/2 activation was also HA-size dependent. The results show that HA-HARE interactions stimulate NF-κB activated gene expression and that HARE senses a narrow size-range of HA degradation products. We propose a model in which optimal length HA binds multiple HARE proteins to allow cytoplasmic domain interactions that stimulate intracellular signaling. This HARE signaling system during continuous HA clearance could monitor the homeostasis of tissue biomatrix turnover throughout the body. 23223708 Hydrophobic asymmetric ultrafiltration PVDF membranes: an alternative separator for VFB with excellent stability. Polyvinylidene fluoride (PVDF) ultrafiltration membranes were investigated for the first time in vanadium redox flow battery (VFB) applications. Surprisingly, PVDF ultrafiltration membranes with hydrophobic pore walls and relatively large pore sizes of several tens of nanometers proved able to separate vanadium ions and protons efficiently, thus being suitable as a VFB separator. The ion selectivity of this new type of VFB membrane could be tuned readily by controlling the membrane morphology via changes in the composition of the membrane casting solution, and the casting thickness. The results showed that the PVDF membranes offered good performances and excellent stability in VFB applications, where it could, performance-wise, truly substitute Nafion in VFB applications, but at a much lower cost. 23499423 EBF2 Determines and Maintains Brown Adipocyte Identity. The master transcription factor Pparγ regulates the general differentiation program of both brown and white adipocytes. However, it has been unclear whether Pparγ also controls fat lineage-specific characteristics. Here, we show that early B cell factor-2 (Ebf2) regulates Pparγ binding activity to determine brown versus white adipocyte identity. The Ebf DNA-binding motif was highly enriched within brown adipose-specific Pparγ binding sites that we identified by genome-wide ChIP-Seq. Of the Ebf isoforms, Ebf2 was selectively expressed in brown relative to white adipocytes and was bound at brown adipose-specific Pparγ target genes. When expressed in myoblasts or white preadipose cells, Ebf2 recruited Pparγ to its brown-selective binding sites and reprogrammed cells to a brown fat fate. Brown adipose cells and tissue from Ebf2-deficient mice displayed a loss of brown-specific characteristics and thermogenic capacity. Together, these results identify Ebf2 as a key transcriptional regulator of brown fat cell fate and function. 23429043 Estimation of the safe use concentrations of the preservative 1,2-benzisothiazolin-3-one (BIT) in consumer cleaning products and sunscreens. 1,2-Benzisothiazolin-3-one (BIT; CAS # 2634-33-5) is a preservative used in consumer products. Dermal exposure to BIT at sufficient dose and duration can produce skin sensitization and allergic contact dermatitis in animals and susceptible humans.The purpose of this study is to derive a maximal concentration of BIT in various consumer products that would result in exposures below the No Expected Sensitization Induction Level (NESIL), a dose below which skin sensitization should not occur. A screening level exposure estimate was performed for several product use scenarios with sunscreen, laundry detergent, dish soap, and spray cleaner. We calculated that BIT concentrations below the following concentrations of 0.0075%, 0.035%, 0.035%, 0.021% in sunscreen, laundry detergent, dish soap, and spray cleaner, respectively, are unlikely to induce skin sensitization. We completed a pilot study consisting of bulk sample analysis of one representative product from each category labelled as containing BIT, and found BIT concentrations of 0.0009% and 0.0027% for sunscreen and dish soap, respectively. BIT was not detected in the laundry detergent and spray cleaner products above the limit of detection of 0.0006%. Based on publically available data for product formulations and our results, we were able to establish that cleaning products and sunscreens likely contain BIT at concentrations similar to or less than our calculated maximal safe concentrations and that exposures are unlikely to induce skin sensitization in most users. 23371488 Effect of wheel-running during abstinence on subsequent nicotine-seeking in rats. RATIONALE: Exercise appears to be a promising non-pharmacological treatment for nicotine addiction that may be useful for the vulnerable adolescent population. OBJECTIVES: The aim of this study is to determine if wheel-running, an animal model of aerobic exercise, during an abstinence period would decrease subsequent nicotine-seeking in rats that had extended access to nicotine self-administration during adolescence. METHODS: Male adolescent rats (n = 55) were trained to self-administer saline or nicotine infusions (5 or 10 μg/kg) under a fixed ratio 1 schedule with a maximum of 20 infusions/day beginning on postnatal day 30. After 5 days, access was extended to 23 h/day with unlimited infusions for a total of 10 days. After the last self-administration session, rats were moved to polycarbonate cages for a 10-day abstinence period where they either had access to a locked or unlocked running wheel for 2 h/day. Nicotine-seeking was examined following the 10th day of abstinence under a within-session extinction/cue-induced reinstatement paradigm. RESULTS: Intake was higher at the 10 μg/kg dose as compared to the 5 μg/kg dose; however, intake did not differ within doses prior to wheel assignment. Compared to saline controls, rats that self-administered nicotine at either dose showed a significant increase in drug-seeking during extinction, and consistent with our hypothesis, exercise during abstinence attenuated this effect. Nicotine led to modest but significant levels of cue-induced reinstatement; however, in this adolescent-onset model, levels were variable and not affected by exercise. CONCLUSIONS: Exercise may effectively reduce relapse vulnerability for adolescent-onset nicotine addiction. 23454299 Prediction and characterization of the linear IgE epitopes for the major soybean allergen β-conglycinin using immunoinformatics tools. The α subunit of β-conglycinin is a major allergen in soybean. The objective of this study was to predict and identify the linear immunoglobulin (Ig)E epitopes of the soybean α subunit of β-conglycinin. Three immunoinformatics tools were used to predict the potential epitopes and were confirmed by dot-blot inhibition using sera from soybean allergic subjects. As a result, 15 peptides were predicted and assembled by solid-phase synthesis. Eleven epitopes were identified by the dot-blot inhibition test. Moreover, peptide 3 had IgE binding capability with all sera(5/5) tested, while peptide 1, 4, 6, 8 and12 could bind to 4/5 of the sera samples. Secondary structure prediction of peptide 3 and circular dichroism test validated that the structure of peptide 3 was a random coil. 23537597 Antioxidant and micronutrient-rich milk formula reduces lead poisoning and related oxidative damage in lead-exposed mice. Lead poisoning is a global environmental disease that induces lifelong adverse health effects. The effect of a milk formula consisting of antioxidant of bamboo leaves (AOB), vitamin C (Vc), calcium lactate (CaLac), ferrous sulfate (FeSO4) and zinc sulfate (ZnSO4) on the reduction of lead and lead-induced oxidative damage in lead-exposed mice was studied. The lead-reducing effect of milk formula was investigated via a 7-week toxicokinetics study and a tissue distribution level examination. The ameliorating effect of milk formula on lead-induced oxidative damage was investigated. Results demonstrated current milk formula could effectively reduce blood lead levels (BLLs) and lead distribution levels of liver, kidneys, thighbones and brain in mice based on metal ion-mediated antagonism and chelation mechanisms. This milk formula could not only protect lead-susceptible tissues against lead poisoning, but also maintain normal absorption and distribution of essential elements in vivo. Meanwhile, current milk formula could prevent the reduction of δ-aminolevulinic acid dehydratase (δ-ALAD) activity and enhancement of free erythrocyte protoporphyrins (FEP) levels in blood erythrocytes of mice. Also, this formula could indirectly protect blood cell membranes against lead-induced lipid peroxidation. We conclude that current optimized milk formula effectively reduces lead poisoning and lead-induced in vivo oxidative damage in lead-exposed mice. 23511311 SEVERE HYPOGLYCEMIC EPISODES: A PERSISTENT THREAT FOR CHILDREN WITH TYPE 1 DIABETES MELLITUS AND THEIR FAMILIES. Background: As lowering HbA1c levels is still the main goal of insulin treatment, severe hypoglycaemia (SH) remains a common experience in children with type 1 diabetes mellitus (T1DM) and their families. Aim: This study aims to evaluate the incidence and the clinical features of SH episodes in our Centre in the last 20 years. Subjects and Methods: We analysed SH incidence in 269 patients diagnosed from 1990 to 2010 (total follow-up 2212.9 patient-years). Inclusion criteria: at least 3 visits/year and 1 year of follow-up. SH episode was defined as any condition of low blood glucose requiring third-party assistance. Results: 50.2% of patients experienced at least 1 SH episode for a total of 345 episodes. Whole incidence was 15.6/100 pts/yr, slightly different between first and second decade (12.6 vs 16.5, p=0.047). HbA1c at the time of SH was lower in the non-BB group (7.4±1.3 vs 8.2±1.4; p=0.0001) and worsened 3 months later (p=0.0001). Impaired awareness was the main or only symptom in 43.5%. SH occurred at night in 32% of patients and they were significantly younger than those with SH at other times. 5 SH episodes or more occurred in 8.1% of patients who presented a lower HbA1c, a younger age and shorter disease duration than the other patients. HbA1c at first SH was negatively correlated with number of SH (r=-0.20; p=0.05). Conclusions: Despite the advent of new insulin regimens, we confirm that SH still represents a relevant risk and a current threat for patients with T1DM and their families. 23568512 Toxicokinetics of acrylamide in primary rat hepatocytes: coupling to glutathione is faster than conversion to glycidamide. Acrylamide (AA), classified as class 2A carcinogen (probably carcinogenic to humans) by the International Agency for Research on Cancer (IARC), is formed during heating of food from reducing carbohydrates and asparagine by Maillard reaction chemistry. After dietary uptake, AA is in part metabolically converted into the proximate genotoxic phase I metabolite glycidamide (GA). GA reacts with nucleophilic base positions in DNA, primarily forming N7-(2-carbamoyl-2-hydroxyethyl)guanine (N7-GA-Gua) adducts. In a competing phase II biotransformation pathway AA, as well as its phase I metabolite GA, is coupled to glutathione (GSH). The GSH coupling products are further biotransformed and excreted via urine as mercapturic acids (MA), N-acetyl-S-(2-carbamoylethyl)cysteine (AAMA), and N-acetyl-S-(2-hydroxy-2-carbamoylethyl)cysteine (GAMA). In the present study, hepatic biotransformation pathways and DNA adduct formation were studied in primary rat hepatocytes, incubated with AA (0.2-2,000 μM) for up to 24 h. Contents of AA-GSH, GA, AAMA, and GAMA were measured in the cell culture medium after solid phase extraction (SPE). N7-GA-Gua adducts in DNA of hepatocytes were determined by HPLC-ESI-MS/MS after lysis of the cells and neutral thermal hydrolysis. Formation of AA-GSH was linear with AA concentration and incubation time and became detectable already at 0.2 μM (4 h). In contrast to AA, GA was not detected before 16 h incubation at 10-fold higher AA concentration (2 μM). In summary, the rate of AA-GSH formation was found to be about 1.5-3 times higher than that of GA formation. N7-GA-Gua adducts were found only at the highest AA concentration tested (2,000 μM). 23632158 Attack of the nervous system by Clostridium perfringens Epsilon toxin: From disease to mode of action on neural cells. Epsilon toxin (ET), produced by Clostridium perfringens types B and D, ranks among the four most potent poisonous substances known so far. ET-intoxication is responsible for enterotoxaemia in animals, mainly sheep and goats. This disease comprises several manifestations indicating the attack of the nervous system. This review aims to summarize the effects of ET on central nervous system. ET binds to endothelial cells of brain capillary vessels before passing through the blood-brain barrier. Therefore, it induces perivascular oedema and accumulates into brain. ET binding to different brain structures and to different component in the brain indicates regional susceptibility to the toxin. Histological examination has revealed nerve tissue and cellular lesions, which may be directly or indirectly caused by ET. The naturally occurring disease caused by ET-intoxication can be reproduced experimentally in rodents. In mice and rats, ET recognizes receptor at the surface of different neural cell types, including certain neurons (e.g. the granule cells in cerebellum) as well as oligodendrocytes, which are the glial cells responsible for the axons myelination. Moreover, ET induces release of glutamate and other transmitters, leading to firing of neural network. The precise mode of action of ET on neural cells remains to be determined. 23462380 Non-front-fanged colubroid snakes: A current evidence-based analysis of medical significance. Non-front-fanged colubroid snakes (NFFC; formerly and artificially taxonomically assembled as "colubrids") comprise about 70% of extant snake species and include several taxa now known to cause lethal or life threatening envenoming in humans. Although the medical risks of bites by only a handful of species have been documented, a growing number of NFFC are implicated in medically significant bites. The majority of these snakes have oral products (Duvernoy's secretions, or venoms) with unknown biomedical properties and their potential for causing harm in humans is unknown. Increasingly, multiple NFFC species are entering the commercial snake trade posing an uncertain risk. Published case reports describing NFFC bites were assessed for evidence-based value, clinical detail and verified species identification. These data were subjected to meta-analysis and a hazard index was generated for select taxa. Cases on which we consulted or personally treated were included and subjected to the same assessment criteria. Cases involving approximately 120 species met the selection criteria, and a small subset designated Hazard Level 1 (most hazardous), contained 5 species with lethal potential. Recommended management of these cases included antivenom for 3 species, Dispholidus typus, Rhabdophis tiginis, Rhabdophis subminiatus, whereas others in this subset without commercially available antivenoms (Thelotornis spp.) were treated with plasma/erythrocyte replacement therapy and supportive care. Heparin, antifibrinolytics and/or plasmapheresis/exchange transfusion have been used in the management of some Hazard Level 1 envenomings, but evidence-based analysis positively contraindicates the use of any of these interventions. Hazard Level 2/3 species were involved in cases containing mixed quality data that implicated these taxa (e.g. Boiga irregularis, Philodryas olfersii, Malpolon monspessulanus) with bites that caused rare systemic effects. Recommended management may include use of acetylcholinesterase inhibitors (e.g. neostigmine) and wound care on a case-by-case basis. Hazard level 3 species comprised a larger group capable of producing significant local effects only, often associated with a protracted bite (eg Heterodon nasicus, Borikenophis (Alsophis) portoricensis, Platyceps (Coluber) rhodorachis). Management is restricted to wound care. Bites by Hazard level 4 species comprised the majority of surveyed taxa and these showed only minor effects of no clinical importance. This study has produced a comprehensive evidence-based listing of NFFC snakes tabulated against medical significance of bites, together with best-practice management recommendations. This analysis assumes increasing importance, as there is growing exposure to lesser-known NFFC snakes, particularly in captive collections that may uncover further species of significance in the future. Careful and accurate documentation of bites by verified species of NFFC snakes is required to increase the evidence base and establish the best medical management approach for each species. 23463336 Effects of dried Citrus unshiu peels on gastrointestinal motility in rodents. Aqueous extracts of the dried mature (ANP-W) and immature Citrus unshiu peels (CUP-W) have been used as a traditional folk medicine for the treatment of gastrointestinal (GI) motility disorders in Korea. In the present study, neither ANP-W nor CUP-W exhibited significant toxicity even at an oral dose of 5 g/kg to mice. The effects of ANP-W and CUP-W on GI motor function were investigated by measuring the intestinal transit rate (ITR) of Evans blue in normal mice and rats with experimental GI motility dysfunctions (GMDs). In normal mice, the ITR was significantly increased by ANP-W (0.1-1 g/kg) in a dose dependent manner, whereas CUP-W elicited no significant change. GMD was induced by appropriate surgery or an intraperitoneal injection of acetic acid to the rats. The ITR in the GMD rats was significantly retarded compared to that in normal rats. However, the retardation was significantly inhibited by ANP-W (0.1-1 g/kg) in a dose dependent manner. The above results suggest that ANP-W has the potential for development as a prokinetic agent that may prevent or alleviate GMD in human patients. 23497898 Stability of sunflower 2S albumins and LTP to physiologically relevant in vitro gastrointestinal digestion. In order for a protein to elicit a systemic allergic response it must reach the circulatory system through the intestinal mucosa as a sufficiently large fragment with adequate structural integrity. Sunflower LTP and 2S albumins (SFA8 and three mixed fractions of Alb1 and Alb2) were digested in simulated gastric fluid (SGF) for 2h and the conditions were then changed to mimic the intestinal environment for a further 2h digestion. The effects of phosphatidylcholine (PC) and emulsification on the digestibility of the proteins were investigated. PC protected all of the proteins studied against both gastric and intestinal digestive enzymes but to different extents. Emulsification of SFA8 resulted in strong protection against digestion, which was further enhanced by the presence of PC in the SGF. These results highlight the importance of considering real food structures such as emulsified systems and also the gastrointestinal environment that proteins are exposed to once consumed when assessing allergenicity. 23122085 Discrimination against diacylglycerol ethers in lipase-catalysed ethanolysis of shark liver oil. Lipase-catalysed ethanolysis of squalene-free shark liver oil was investigated. The mentioned shark liver oil was comprised mainly of diacylglycerol ether and triacylglycerols. In order to test discrimination against diacylglycerol ether, up to 10 different lipases were compared. The ratio of oil to ethanol and lipase stability were also evaluated. Surprisingly, lipase from Pseudomonas stutzeri was the fastest biocatalyst among all assayed, although poor discrimination against diacylglycerol ether was observed. The best results in terms of selectivity and stability were obtained with immobilised lipase from Candida antarctica (Novozym 435). Ethanolysis reaction after 24h in the presence of Novozym 435 produced total disappearance of triacylglycerol and a final reaction mixture comprised mainly of diacylglycerol ethers (10.6%), monoacylglycerol ethers (32.9%) and fatty acid ethyl esters (46.0%). In addition, when an excess of ethanol was used, diacylglycerol ethers completely disappeared after 15 h, giving a final product mainly composed of monoacylglycerol ethers (36.6%) and fatty acid ethyl esters (46.4%). 23250357 The effect of a bile acid sequestrant on glucose metabolism in subjects with type 2 diabetes. We designed an experiment to examine the effect of bile acid sequestration with Colesevelam on fasting and postprandial glucose metabolism in type 2 diabetes. To do so, we tested the hypothesis that Colesevelam increases the disposition index (DI), and this increase is associated with increased glucagon-like peptide-1 (GLP-1) concentrations. Thirty-eight subjects on metformin monotherapy were studied using a double-blind, placebo-controlled, parallel-group design. Subjects were studied before and after 12 weeks of Colesevelam or placebo using a labeled triple-tracer mixed meal to measure the rate of meal appearance (Meal Ra), endogenous glucose production (EGP), and glucose disappearance (Rd). Insulin sensitivity and β-cell responsivity indices were estimated using the oral minimal model and then used to calculate DI. Therapy with Colesevelam was associated with a decrease in fasting (7.0 ± 0.2 vs. 6.6 ± 0.2 mmol/L; P = 0.004) and postprandial glucose concentrations (3,145 ± 138 vs. 2,896 ± 127 mmol/6 h; P = 0.01) in the absence of a change in insulin concentrations. Minimal model-derived indices of insulin secretion and action were unchanged. Postprandial GLP-1 concentrations were not altered by Colesevelam. Although EGP and Rd were unchanged, integrated Meal Ra was decreased by Colesevelam (5,191 ± 204 vs. 5,817 ± 204 μmol/kg/6 h; P = 0.04), suggesting increased splanchnic sequestration of meal-derived glucose. 23334583 Effects of aging on apoptosis gene expression in oral mucosal tissues. Apoptotic processes are important for physiologic renewal of an intact epithelial barrier and contribute some antimicrobial resistance for bacteria and viruses, as well as anti-inflammatory effects that benefits the mucosa. The oral cavity presents a model of host-bacterial interactions at mucosal surfaces, in which a panoply of microorganisms colonizes various niches in the oral cavity and creates complex multispecies biofilms that challenge the gingival tissues. This report details gene expression in apoptotic pathways that occur in oral mucosal tissues across the lifespan, using a nonhuman primate model. Macaca mulatta primates from 2 to 23 years of age (n = 23) were used in a cross-sectional study to obtain clinical healthy gingival tissues specimens. Further, mRNA was prepared and evaluated using the Affymetrix Rhesus GeneChip and 88 apoptotic pathway genes were evaluated. The results identified significant positive correlations with age in 12 genes and negative correlations with an additional five genes. The gene effects were predicted to alter apoptosis receptor levels, extrinsic apoptotic pathways through caspases, cytokine effects on apoptotic events, Ca(+2)-induced death signaling, cell cycle checkpoints, and potential effects of survival factors. Both the positively and negatively correlated genes within the apoptotic pathways provided evidence that healthy tissues in aging animals exhibit decreased apoptotic potential compared to younger animals. The results suggested that decreased physiologic apoptotic process in the dynamic septic environment of the oral mucosal tissues could increase the risk of aging tissues to undergo destructive disease processes through dysregulated inflammatory responses to the oral microbial burden. 23493569 Adipose Tissue Macrophages Function as Antigen Presenting Cells and Regulate Adipose Tissue CD4+ T Cells in Mice. The pro-inflammatory activation of leukocytes in adipose tissue contributes to metabolic disease. How crosstalk between immune cells initiates and sustains adipose tissue inflammation remains an unresolved question. We have examined the hypothesis that adipose tissue macrophages (ATMs) interact with and regulate the function of T cells. Dietary obesity was shown to activate the proliferation of effector memory CD4(+) T cells in adipose tissue. Our studies further demonstrate that ATMs are functional antigen presenting cells that promote the proliferation of IFN-γ producing CD4(+) T cells in adipose tissue. ATMs from both lean and obese visceral fat process and present MHC class II-restricted antigens. ATMs were sufficient to promote proliferation and IFN-γ production from antigen-specific CD4(+) T cells in vitro and in vivo. Diet-induced obesity increased the expression of MHC II and T cell costimulatory molecules on ATMs in visceral fat, which correlated with an induction of T cell proliferation in that depot. Collectively, these data indicate that ATMs provide a functional link between the innate and adaptive immune systems within visceral fat in mice. 23085994 Actinin-4 in keratinocytes regulates motility via an effect on lamellipodia stability and matrix adhesions. During wound repair, epidermal cells at the edge of an injury establish front-rear polarity through orchestrated changes in their cytoskeleton and adhesion structures. The polarity and directed migration of such cells is determined by the assembly, extension, and stabilization of a lamellipodium. Actinin-4 associates with lamellipodia and has been implicated in regulating lamellipodial structure, function and assembly. To study the functions of actinin-4 in human keratinocytes, we used shRNA to generate knockdown cells and compared their motility behavior and matrix adhesion assembly to scrambled shRNA treated control keratinocytes. Actinin-4 knockdown keratinocytes lack polarity, assemble multiple lamellipodia with a 2× increased area over controls, display reduced activity of the actin remodeling protein cofilin, and fail to migrate in a directional manner. This motility defect is rescued by plating knockdown cells on preformed laminin-332 matrix. In actinin-4-knockdown keratinocytes, focal contact area is increased by 25%, and hemidesmosome proteins are mislocalized. Specifically, α6β4 integrin localizes to large lamellipodial extensions, displays reduced dynamics, and fails to recruit its bullous pemphigoid antigen binding partners. Together, our data indicate a role for actinin-4 in regulating the steering mechanism of keratinocytes via profound effects on their matrix adhesion sites. 23214926 Total synthesis of AMF-26, an antitumor agent for inhibition of the Golgi system, targeting ADP-ribosylation factor 1. An effective method for the total synthesis of 1 (AMF-26), a potentially promising new anticancer drug that disrupts the Golgi system by inhibiting the ADP-ribosylation factor 1 (Arf1) activation, has been developed for the first time. The construction of the chiral linear precursor (a key to the synthesis) was achieved by the asymmetric aldol reaction followed by the computer-assisted predictive stereoselective intramolecular Diels-Alder reaction. The global antitumor activity of the totally synthetic 1 against a variety of human cancer cells was assessed using a panel of 39 human cancer cell lines (JFCR39), and it was shown that the synthetic 1 strongly inhibited the growth of several cancer cell lines at concentrations of less than 0.04 μM. Biological assays of novel derivatives, 26 and 31, which have different side-chains at the C-4 positions in the Δ¹,²-octalin backbone, disclosed the importance of the suitable structure of the side-chain containing conjugated multidouble bonds. 22728761 D-Serine facilitates the effectiveness of extinction to reduce drug-primed reinstatement of cocaine-induced conditioned place preference. Addiction is a disease that is characterized by compulsive drug-seeking and use despite negative health and social consequences. One obstacle in treating addiction is a high susceptibility for relapse which persists despite prolonged periods of abstinence. Relapse can be triggered by drug predictive stimuli such as environmental context and drug associated cues, as well as the addictive drug itself. The conditioned place preference (CPP) behavioral model is a useful paradigm for studying the ability of these drug predictive stimuli to reinstate drug-seeking behavior. The present study investigated the dose-dependent effects of D-serine (10 mg/kg, 30 mg/kg and 100 mg/kg) on extinction training and drug-primed reinstatement in cocaine-conditioned rats. In the first experiment, D-serine had no effect on the acquisition or development of cocaine-induced locomotor sensitization or CPP. In the second experiment, D-serine treatment resulted in significantly decreased time spent in the drug-paired compartment following completion of an extinction protocol. A cocaine-primed reinstatement test indicated that the combination of extinction training along with D-serine treatment resulted in a significant reduction of drug-seeking behavior. The third experiment assessed D-serine's long-term effects to diminish drug-primed reinstatement. D-serine treatment given during extinction was effective in reducing drug-seeking for more than four weeks of abstinence after the last cocaine exposure. These findings demonstrate that D-serine may be an effective adjunct therapeutic agent along with cognitive behavioral therapy for the treatment of cocaine addiction. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23229055 Microwave synthesis, characterization and bio-efficacy evaluation of novel chalcone based 6-carbethoxy-2-cyclohexen-1-one and 2H-indazol-3-ol derivatives. Novel chalcone based 6-carbethoxy-2-cyclohexen-1-one and 2H-indazol-3-ol derivatives were synthesized and characterized by using spectral techniques like IR, (1)H NMR, (13)C NMR, COSY, DEPT, and GC-MS. All these compounds were screened for anti-fungal, anti-bacterial and anti-oxidant activity. Cyclohexenone derivatives, in general, showed better anti-fungal and anti-bacterial activity than parent chalcones. Whereas, all the Indazole derivatives showed very good anti-oxidant activity and some were also found to be active as anti-bacterial agent. Among the screened compounds, 15 was found to be most active as anti-fungal agent (against Rhizoctonia solani, LC(50) = 2.36 μg mL(-1)), 15b was found to be most active anti-bacterial agent (against Klebsiella pneumonia, MIC = 24.68 μg mL(-1)) and 14b emerged as most active anti-oxidant (IC(50) = 19.81 μg mL(-1)). 23474382 Multiple dosing of simvastatin inhibits airway mucus production of epithelial cells: Implications in the treatment of chronic obstructive airway pathologies. BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by mucus hyper-production. This pathology, together with other inflammatory contributions, leads to airway obstruction and breathing complications. Newer therapeutic approaches are of increased interest, including the use of HMG-CoA reductase inhibitors. Retrospective studies have shown that statins are effective in reducing patient mortality and blood cytokines levels. These findings suggest statins may also provide a new therapeutic approach in COPD treatment. PURPOSE: The aim of the present work was to study the transport of SV across Calu-3 epithelial cells and to investigate its pharmacological action with respect to reduction in mucus production. METHODS: Calu-3 cells were grown under liquid covered culture (LCC) conditions for transport studies in order to demonstrate the ability of SV to transport across the monolayer. For mucus detection, cells were grown under air interface culture (AIC) conditions. Samples collected for microscope analysis were stained with alcian blue; images of the stained cell surface were acquired and the mucus was quantified as the RGBB ratio. RESULTS: SV was transported through the cell monolayer and 'retained' inside the Calu-3 cells. Colour analysis of stained Calu-3 monolayers microscope-images showed that chronic administration of SV for 14days caused a significant inhibition in mucus production. CONCLUSION: These findings suggest that local delivery of SV directly to the lungs may provide a promising treatment and potential disease management approach of COPD, with significant effects on mucus reduction. 23193183 Transferability and fine mapping of type 2 diabetes loci in African Americans: the Candidate Gene Association Resource Plus Study. Type 2 diabetes (T2D) disproportionally affects African Americans (AfA) but, to date, genetic variants identified from genome-wide association studies (GWAS) are primarily from European and Asian populations. We examined the single nucleotide polymorphism (SNP) and locus transferability of 40 reported T2D loci in six AfA GWAS consisting of 2,806 T2D case subjects with or without end-stage renal disease and 4,265 control subjects from the Candidate Gene Association Resource Plus Study. Our results revealed that seven index SNPs at the TCF7L2, KLF14, KCNQ1, ADCY5, CDKAL1, JAZF1, and GCKR loci were significantly associated with T2D (P < 0.05). The strongest association was observed at TCF7L2 rs7903146 (odds ratio [OR] 1.30; P = 6.86 × 10⁻⁸). Locus-wide analysis demonstrated significant associations (P(emp) < 0.05) at regional best SNPs in the TCF7L2, KLF14, and HMGA2 loci as well as suggestive signals in KCNQ1 after correction for the effective number of SNPs at each locus. Of these loci, the regional best SNPs were in differential linkage disequilibrium (LD) with the index and adjacent SNPs. Our findings suggest that some loci discovered in prior reports affect T2D susceptibility in AfA with similar effect sizes. The reduced and differential LD pattern in AfA compared with European and Asian populations may facilitate fine mapping of causal variants at loci shared across populations. 23614652 Conversion of Aristolochic Acid I into Aristolic Acid by Reaction with Cysteine and Glutathione: Biological Implications. Aristolochic acid I (AA-I), naturally occurring in Aristolochia plants, is a potent nephrotoxin and carcinogen. Here we report that AA-I suffers hydrogenolysis with loss of the nitro group by reaction with cysteine or glutathione to give aristolic acid. Since the reaction can proceed in aqueous solutions at pH 7.0 and 37 °C, it is inferred that it may also occur in biological systems and contribute to the nephrotoxic effects induced by AA-I. 23355489 Ataxia telangiectasia mutated (ATM) is dispensable for endonuclease I-SceI-induced homologous recombination in mouse embryonic stem cells. Ataxia telangiectasia mutated (ATM) is activated upon DNA double strand breaks (DSBs) and phosphorylates numerous DSB response proteins, including histone H2AX on serine 139 (Ser-139) to form γ-H2AX. Through interaction with MDC1, γ-H2AX promotes DSB repair by homologous recombination (HR). H2AX Ser-139 can also be phosphorylated by DNA-dependent protein kinase catalytic subunit and ataxia telangiectasia- and Rad3-related kinase. Thus, we tested whether ATM functions in HR, particularly that controlled by γ-H2AX, by comparing HR occurring at the euchromatic ROSA26 locus between mouse embryonic stem cells lacking either ATM, H2AX, or both. We show here that loss of ATM does not impair HR, including H2AX-dependent HR, but confers sensitivity to inhibition of poly(ADP-ribose) polymerases. Loss of ATM or H2AX has independent contributions to cellular sensitivity to ionizing radiation. The ATM-independent HR function of H2AX requires both Ser-139 phosphorylation and γ-H2AX/MDC1 interaction. Our data suggest that ATM is dispensable for HR, including that controlled by H2AX, in the context of euchromatin, excluding the implication of such an HR function in genomic instability, hypersensitivity to DNA damage, and poly(ADP-ribose) polymerase inhibition associated with ATM deficiency. 23624862 Coordinated conformational and compositional dynamics drive ribosome translocation. During translation elongation, the ribosome compositional factors elongation factor G (EF-G; encoded by fusA) and tRNA alternately bind to the ribosome to direct protein synthesis and regulate the conformation of the ribosome. Here, we use single-molecule fluorescence with zero-mode waveguides to directly correlate ribosome conformation and composition during multiple rounds of elongation at high factor concentrations in Escherichia coli. Our results show that EF-G bound to GTP (EF-G-GTP) continuously samples both rotational states of the ribosome, binding with higher affinity to the rotated state. Upon successful accommodation into the rotated ribosome, the EF-G-ribosome complex evolves through several rate-limiting conformational changes and the hydrolysis of GTP, which results in a transition back to the nonrotated state and in turn drives translocation and facilitates release of both EF-G-GDP and E-site tRNA. These experiments highlight the power of tracking single-molecule conformation and composition simultaneously in real time. 23444833 Isolation, Structure Elucidation, and Iron-Binding Properties of Lystabactins, Siderophores Isolated from a Marine Pseudoalteromonas sp. The marine bacterium Pseudoalteromonas sp. S2B, isolated from the Gulf of Mexico after the Deepwater Horizon oil spill, was found to produce lystabactins A, B, and C (1-3), three new siderophores. The structures were elucidated through mass spectrometry, amino acid analysis, and NMR. The lystabactins are composed of serine (Ser), asparagine (Asn), two formylated/hydroxylated ornithines (FOHOrn), dihydroxy benzoic acid (Dhb), and a very unusual nonproteinogenic amino acid, 4,8-diamino-3-hydroxyoctanoic acid (LySta). The iron-binding properties of the compounds were investigated through a spectrophotometric competition. 23208007 Polysialic acid enhances the migration and invasion of human cytotrophoblasts. Polysialic acid (polySia) is a large, cell-surface linear homopolymer composed of α2,8-linked sialic acid residues. Most extensively studied in the nervous system, this unique glycan modulates development by enhancing cell migration and regulating differentiation. PolySia also functions in developing and adult immune systems and is a signature of many cancers. In this study, we demonstrated that human placental trophoblasts, an epithelial lineage, also display this glycan. Cytotrophoblasts and syncytiotrophoblasts expressed polySia in the first trimester and downregulated it during the course of pregnancy. PolySia promoted cytotrophoblast migration in an explant model of chorionic villous growth. Removal of this glycan also reduced cytotrophoblast penetration of basement membranes in an in vitro model of invasion. Finally, we showed that polySia was overexpressed in biopsies from patients with gestational trophoblastic diseases, including benign molar pregnancies and malignant choriocarcinomas. These results demonstrated, for the first time, functional roles for polySia during normal human placental development and implicated these unusual oligosaccharides in the unrestrained invasion of trophoblast tumors. 22991234 Acute effect of calcium citrate on serum calcium and cardiovascular function. Calcium supplements have been associated with an increased risk of cardiovascular events. However, the validity of these findings has been questioned. A major concern is that the mechanism underlying an increase in cardiovascular events has not been demonstrated. Calcium initiates cardiac and vascular contraction following influx of calcium into cardiac and smooth muscle from extracellular fluid. We have investigated whether the acute rise in serum calcium following calcium supplement administration is associated with adverse changes in cardiovascular function. In an open interventional study, we recruited 25 volunteers (16 female, age 60.3 ± 6.5 years, body mass index 25.7 ± 2.7 kg/m2) from the community who were not taking calcium supplements. Participants were studied before and 3 hours after a single oral dose of 1000 mg calcium citrate. We assessed well-validated markers of arterial stiffness (pulse wave velocity [PWV]), arterial wave reflection (augmentation index [AIx]), and myocardial perfusion (subendocardial viability ratio [SEVR]) by pulse wave analysis and endothelial function (reactive hyperemia index [RHI]) by peripheral arterial tonometry. Total and ionized serum calcium were acutely increased by 0.10 ± 0.07 and 0.06 ± 0.03 mmol/L, respectively, 3 hours after calcium citrate administration (p < 0.0001 for both comparisons). Following administration of calcium citrate there was a fall in AIx from a median of 29.7% (23.8% to 34.0%) to 26.4% (22.7% to 34.0%, p = 0.03) and an increase in SEVR from 163% (148% to 174%) to 170% (149% to 185%, p = 0.007). PWV and RHI were not significantly altered. The change in total calcium was negatively correlated with the change in AIx (r = -0.48, p = 0.02). In summary, the acute increase in serum calcium following calcium supplement administration is associated with reduced arterial wave reflection and a marker of increased myocardial perfusion. If maintained long-term, these changes would be expected to reduce cardiovascular risk. Acute serum calcium-mediated changes in these parameters of cardiovascular function are unlikely to underlie an association between calcium supplementation and cardiovascular events. 23256503 Ballistic InAs nanowire transistors. Ballistic transport of electrons at room temperature in top-gated InAs nanowire (NW) transistors is experimentally observed and theoretically examined. From length dependent studies, the low-field mean free path is directly extracted as ~150 nm. The mean free path is found to be independent of temperature due to the dominant role of surface roughness scattering. The mean free path was also theoretically assessed by a method that combines Fermi's golden rule and a numerical Schrödinger-Poisson simulation to determine the surface scattering potential with the theoretical calculations being consistent with experiments. Near ballistic transport (~80% of the ballistic limit) is demonstrated experimentally for transistors with a channel length of ~60 nm, owing to the long mean free path of electrons in InAs NWs. 23429282 Sources of secondary metabolite variation in Dysidea avara (Porifera: Demospongiae): the importance of having good neighbors. Several studies report temporal, geographical, and intra-individual variation in sponge metabolite yields. However, the internal and/or external factors that regulate the metabolite production remain poorly understood. Dysidea avara is a demosponge that produces sesquiterpenoids (avarol and derivatives) with interesting medical properties, which has prompted addressed studies to obtain enough amounts of these metabolites for research on drug discovery. Within this framework, specimens of Dysidea avara from a population of the Northwest Mediterranean were sampled and their secondary metabolites quantified to assess their variability and the possible relationship with external (seasonality, interactions with neighbors) and internal (reproductive stages) factors. The results show a variation of the amount of both avarol and its monoacetate derivative with time, with no clear relationship with seawater temperature. A trade-off with sponge reproduction was not found either. However, our results showed for the first time that sponges are able to increase production or accumulation of secondary metabolites in their peripheral zone depending on the nature of their neighbors. This finding could explain part of the high variability in the amount of secondary metabolites usually found in chemical ecology studies on sponges and opens new biotechnological approaches to enhance the metabolite yield in sponge cultures. 23418059 Forty-seven days of decay does not change persistent organic pollutant levels in loggerhead sea turtle eggs. Reptile and bird eggs are priority samples for specimen banking programs that assess spatial and temporal trends of environmental contaminants. From endangered species, such as sea turtles, nonlethal sampling is required (e.g., unhatched eggs collected postemergence). Previous contaminant monitoring studies have used unhatched sea turtle eggs, but no study has tested whether their concentrations represent levels found in fresh eggs (e.g., eggs collected within 24 h of oviposition). The author analyzed three fresh eggs from different nest depths and up to three unhatched eggs from 10 loggerhead sea turtle (Caretta caretta) nests in South Carolina, USA, for a suite of persistent organic pollutants (POPs). Lipid-normalized POP concentrations were not significantly different (p > 0.05) between fresh and unhatched eggs or among different depths from the same nest. The POP concentrations in loggerhead eggs from South Carolina were higher than previously measured concentrations in eggs from Florida and slightly lower than concentrations in eggs from North Carolina. This pattern agrees with previously observed trends of increasing POP concentrations in loggerhead turtles inhabiting northern latitudes along the U.S. East Coast. Contaminant profiles are discussed, including a higher chlorinated pattern of polychlorinated biphenyls possibly associated with a Superfund site in nearby Brunswick, Georgia, USA, and unusual polybrominated diphenylether patterns seen in this and previous sea turtle studies. Concentrations correlated with one of eight measurements of reproductive success; levels were negatively correlated with egg mass (p < 0.05), which may have implications for hatchling fitness. The present study suggests that unhatched eggs can be used for POP-monitoring projects. 23214990 Protein adsorption mechanisms determine the efficiency of thermally controlled cell adhesion on poly(N-isopropyl acrylamide) brushes. This study investigated the impact of the protein adsorption mechanism(s) on the efficiency of thermally controlled cell adhesion and release from poly(N-isopropyl acrylamide) brushes. Large format polymer gradients were used to screen for grafting densities and substrate chemistries that alter both cell adhesion at 37 °C and rapid cell release at 25 °C. In particular, the grafting conditions investigated allowed protein adsorption to the underlying substrate, penetration of the brush only, or adsorption to the outer edge of the film. At an average molecular weight of 30 kDa (degree of polymerization N ∼ 270), the results show that robust protein adsorption to polymer brushes impairs rapid cell release below the lower critical solution temperature. Conversely, grafting conditions that permit protein penetration of the brush but block strong adsorption to the underlying substrate support cell adhesion above the transition temperature and ensure efficient cell recovery at lower temperature. These findings demonstrate the impact of protein adsorption mechanisms, surface chemistry, and polymer properties on thermally controlled cell capture and release. 23524195 Compound promiscuity: what can we learn from current data? The specificity paradigm that assigns central relevance to achieving target specificity of drug candidates has recently been revisited. Evidence is mounting that polypharmacological drug behavior is often responsible for therapeutic efficacy suggesting the consideration of new drug development strategies. Target promiscuity of compounds is at the origin of polypharmacology. For many bioactive compounds, multiple target annotations are available indicating that compound promiscuity is a general phenomenon. However, careful analysis of compound activity data reveals that the degree of apparent promiscuity is strongly influenced by data selection criteria and the type of activity measurements that are considered. Furthermore, promiscuity involving unrelated targets is less common. Apparent target promiscuity might often better be interpreted as activity promiscuity in different assays. 23588312 A DPYD Variant (Y186C) in Individuals of African Ancestry Is Associated With Reduced DPD Enzyme Activity. 5-Fluorouracil (5-FU) is used to treat many aggressive cancers, such as those of the colon, breast, and head and neck. The responses to 5-FU, with respect to both toxicity and efficacy, vary among racial groups, potentially because of variability in the activity levels of the enzyme dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene). In this study, the genetic associations between DPYD variations and circulating mononuclear-cell DPD enzyme activity were evaluated in 94 African-American and 81 European-American volunteers. The DPYD-Y186C variant was unique to individuals of African ancestry, and DPD activity was 46% lower in carriers as compared with noncarriers (279 ± 35 vs. 514 ± 168 pmol 5-FU min(-1) mg(-1); P = 0.00029). In this study, 26% of the African Americans with reduced DPD activity were carriers of Y186C. In the African-American cohort, after excluding Y186C carriers, homozygous carriers of C29R showed 27% higher DPD activity as compared with noncarriers (609 ± 152 and 480 ± 152 pmol 5-FU min(-1) mg(-1), respectively; P = 0.013).Clinical Pharmacology & Therapeutics (2013); advance online publication 1 May 2013. doi:10.1038/clpt.2013.69. 23554335 Vibrational sum-frequency generation activity of a 2,4-dinitrophenyl phospholipid hybrid bilayer: retrieving orientational parameters from a DFT analysis of experimental data. The vibrational nonlinear activity of films of 2,4-dinitrophenyl phospholipid (DNP) at the solid interface is measured by sum-frequency generation spectroscopy (SFG). Hybrid bilayers are formed by a Langmuir-Schaefer approach in which the lipid layer is physisorbed on top of a self-assembled monolayer of dodecanethiol on Pt with the polar heads pointing out from the surface. The SFG response is investigated in two vibrational frequency domains, namely, 3050-2750 and 1375-1240 cm(-1) . The first region probes the CH stretching modes of DNP films, and the latter explores the vibrational nonlinear activity of the 2,4-dinitroaniline moiety of the polar head of the lipid. Analysis of the CH stretching vibrations suggests substantial conformational order of the aliphatic chains with only a few gauche defects. To reliably assign the detected SFG signals to specific molecular vibrations, DFT calculations of the IR and Raman activities of molecular models are performed and compared to experimental solid-state spectra. This allows unambiguous assignment of the observed SFG vibrations to molecular modes localized on the 2,4-dinitroaniline moiety of the polar head of DNP. Then, SFG spectra of DNP in the 1375-1240 cm(-1) frequency range are simulated and compared with experimental ones, and thus the 1,4-axis of the 2,4-dinitrophenyl head is estimated to have tilt and rotation angles of 45±5° and 0±30°, respectively. 23095244 Subacute effects of ecstasy on mood: an exploration of associated risk factors. Ecstasy use may result in lowered mood, anxiety or aggression in the days following use. Yet, few studies have investigated what factors increase the risk of experiencing such symptoms. Ecstasy users (at least once in the last 12 months) who subsequently took ecstasy (n=35) over the period of one week, were compared on measures of mood, sleep, stress and drug use, with those who abstained from ecstasy (n=21) that week. Measures were administered the week prior to ecstasy use and one and three days following use, or the equivalent day for abstainers. Mood symptoms were assessed using the Kessler-10 self-report psychological distress scale, a subjective mood rating (1-10), and using the depression, anxiety and hostility items from the clinician-rated Brief Psychiatric Rating Scale. Timeline Followback methods were used to collect information on drug use and life stress in the past month. Self-reported sleep quality was also assessed. Ecstasy use was not associated with subacute depressive, anxiety or aggressive symptoms. Rather, lowered mood and increased psychological distress were associated with self-reported hours and quality of sleep obtained during the three-day follow-up. These findings highlight the importance of considering sleep disruption in understanding the short-term mood effects of ecstasy use. 23443165 Regulation of Translation Initiation under Biotic and Abiotic Stresses. Plants have developed versatile strategies to deal with the great variety of challenging conditions they are exposed to. Among them, the regulation of translation is a common target to finely modulate gene expression both under biotic and abiotic stress situations. Upon environmental challenges, translation is regulated to reduce the consumption of energy and to selectively synthesize proteins involved in the proper establishment of the tolerance response. In the case of viral infections, the situation is more complex, as viruses have evolved unconventional mechanisms to regulate translation in order to ensure the production of the viral encoded proteins using the plant machinery. Although the final purpose is different, in some cases, both plants and viruses share common mechanisms to modulate translation. In others, the mechanisms leading to the control of translation are viral- or stress-specific. In this paper, we review the different mechanisms involved in the regulation of translation initiation under virus infection and under environmental stress in plants. In addition, we describe the main features within the viral RNAs and the cellular mRNAs that promote their selective translation in plants undergoing biotic and abiotic stress situations. 23282576 A micro-cantilever sensor chip based on contact angle analysis for a label-free troponin I immunoassay. Cantilever sensors have been extensively explored as a promising technique for real-time and label-free analyses in biological systems. A major sensing principle utilized by state-of-the-art cantilever sensors is based on analyte-induced surface stress changes, which result in static bending of a cantilever. The sensor performance, however, suffers from the intrinsically small change in surface stress induced by analytes, especially for molecular recognition such as antigen-antibody binding. Through the contact angle change on a tailored solid surface, it is possible to convert a tiny surface stress into a capillary force-a much larger physical quantity needed for a practical sensor application. In this work, a micro-cantilever sensor based on contact angle analysis (CAMCS) was proposed to effectively enhance the sensitivity of a sensor in proportion to the square of the length to thickness ratio of the cantilever structure. CAMCS chips were fabricated using a standard complementary-metal-oxide-semiconductor (CMOS) process to demonstrate a 1250-fold enhancement in the sensitivity of surface stress to bioanalyte adsorption using a piezoresistive sensing method. A real-time and label-free troponin I (cTnI) immunoassay, which is now widely used in clinics and considered a gold standard for the early diagnosis and prognosis of cardiovascular disease, was performed to demonstrate cTnI detection levels as low as 1 pg mL(-1). The short detection time of this assay was within several minutes, which matches the detection time of commercially available instruments that are based on fluorescence-labeling techniques. 23581993 Engineering bacterial efflux pumps for solar-powered bioremediation of surface waters. Antibiotics are difficult to selectively remove from surface waters by present treatment methods. Bacterial efflux pumps have evolved the ability to discriminately expel antibiotics and other noxious agents via proton and ATP driven pathways. Here, we describe light-dependent removal of antibiotics by engineering the bacterial efflux pump AcrB into a proteovesicle system. We have created a chimeric protein with the requisite proton motive force by coupling AcrB to the light-driven proton pump Delta-rhodopsin (dR) via a glycophorin A transmembrane domain. This creates a solar powered protein material capable of selectively capturing antibiotics from bulk solutions. Using environmental water and direct sunlight, our AcrB-dR vesicles removed almost twice as much antibiotic as the treatment standard, activated carbon. Altogether, the AcrB-dR system provides an effective means of extracting antibiotics from surface waters as well as potential antibiotic recovery through vesicle solubilization. 23210790 Plant metabolomics: from holistic data to relevant biomarkers. Metabolomics is playing an increasingly important role in plant science. It aims at the comprehensive analysis of the plant metabolome which consists both of primary and secondary metabolites. The goal of metabolomics is ultimately to identify and quantify this wide array of small molecules in biological samples. This new science is included in several systems biology approaches and is based primarily on the unbiased acquisition of mass spectrometric (MS) or nuclear magnetic resonance (NMR) data from carefully selected samples. This approach provides the most ''functional'' information of the 'omics' technologies of a given organism since metabolites are the end products of the cellular regulatory processes. The application of state-of-the-art data mining, that includes various untargeted and targeted multivariate data analysis methods, to the vast amount of data generated by this data-driven approach leads to sample classification and the identification of relevant biomarkers. The biological areas that have been successfully studied by this holistic approach include global metabolite composition assessment, mutant and phenotype characterisation, taxonomy, developmental processes, stress response, interaction with the environment, quality control assessment, lead finding and mode of action of botanicals. This review summarises the main MS- and NMR-based approaches that are used to perform these studies and discusses the potential and current limitations of the various methods. The intent is not to provide an exhaustive overview of the field, which has grown considerably over the past decade, but to summarise the main strategies that are used and to discuss the potential and limitations of the different approaches as well as future trends. 23335565 Mimicking native extracellular matrix with phytic Acid-crosslinked protein nanofibers for cardiac tissue engineering. A functional scaffold fabricated is developed from natural polymers, favoring regeneration of the ischemic myocardium. Hemoglobin/gelatin/fibrinogen (Hb/gel/fib) nanofibers are fabricated by electrospinning and are characterized for morphology, scaffold composition, functional groups and hydrophilicity. It is hypothesized that ex vivo pretreatment of mesenchymal stem cells (MSCs) using 5-azacytidine and such a functional nanofibrous construct having a high oxygen-carrying potential could lead to enhanced cardiomyogenic differentiation of MSCs and result in superior biological and functional effects. The combination of a functional nanofibrous scaffold composed of natural polymers and crosslinked with a natural crosslinking agent, phytic acid, and stem cell biology may prove to be a novel therapeutic device for treatment of myocardial infarction. 23258742 A three-generational study of In ovo exposure to PBDE-99 in the zebra finch. Based on a literature review of avian data for polybrominated diphenyl ethers (PBDEs), ecologically relevant doses, low (10 ng/egg), medium (100 ng/egg), and high (1,000 ng/egg) of the 2,2',4,4',5-pentabromodiphenyl ether (BDE-99) congener along with dimethylsulfoxide (DMSO) control were injected into the yolk sac of un-incubated eggs of zebra finch, Taeniopygia guttata. Offspring development and adult phenotype were followed over three generations. No effects of in ovo PBDE exposure on hatching success, chick growth, thyroid hormone levels, or hematological traits were measured at sexual maturity (90 d posthatching). However, the authors did detect significant effects of BDE-99 treatment on adult phenotype of in ovo-exposed birds by breeding observations, in which clutch size was significantly smaller in all PBDE-dosed birds (low, medium, and high) compared with controls. A trend was also seen for longer laying intervals in PBDE-dosed birds (13-14 d) compared with control birds (8 d). In addition, a significant effect of PBDE was found on growth of the second-generation offspring of in ovo-treated females; body mass was significantly lower in the high-PBDE dosed birds compared with controls from hatch through to fledging (day 30). The authors found no evidence of effects over the longer term and in successive generations, whether in adult, reproductive phenotype of the second-generation offspring of in ovo-treated birds, or in the growth of their (third-generation) offspring. Their results suggest that egg levels as low as 10 ng/g BDE-99 may affect reproduction in small passerines by reducing clutch size. 23252421 Lightweight and strong cellulose materials made from aqueous foams stabilized by nanofibrillated cellulose. A lightweight and strong porous cellulose material has been prepared by drying aqueous foams stabilized with surface-modified nanofibrillated cellulose (NFC). This material differs from other dry, particle stabilized foams in that renewable cellulose is used as stabilizing particles. Confocal microscopy and high speed video imaging show that the octylamine-coated, rod-shaped NFC nanoparticles residing at the air-liquid interface prevent the air bubbles from collapsing or coalescing. Stable wet foams can be achieved at solids content around 1% by weight. Careful removal of the water results in a cellulose-based material with a porosity of 98% and a density of 30 mg cm(-3). These porous cellulose materials have a higher Young's modulus than porous cellulose materials made from freeze-drying, at comparable densities, and have a compressive energy absorption of 56 kJ m(-3) at 80% strain. Measurement with the aid of an autoporosimeter revealed that most pores are in the range of 300 to 500 μm. 22836881 Hospitalized osteoporotic vertebral fracture increases the risk of stroke: a population-based cohort study. The association between osteoporosis and cardiovascular diseases has been demonstrated. Higher cardiovascular risk has also been correlated with vertebral fractures. However, the association between osteoporotic vertebral fracture and the possibly higher risk of stroke remains uncertain. This study aimed to evaluate the incidence, risk, and type of stroke in patients with osteoporotic vertebral fracture. Patients with osteoporotic vertebral fracture were identified (n = 380) and 10 age- and sex-matched controls per case (comparison group, n = 3795) were chosen from a nationwide representative cohort of 999,997 people from 1998 to 2005. Both groups were followed-up for stroke events for 3 years, matched by propensity scores with adjustments for covariates such as comorbidities (ie, hypertension, diabetes, arrhythmia, or coronary heart diseases) and exposure to medications (ie, aspirin, lipid lowering drug, or nitrates), and assessed by Kaplan-Meier and Cox regression analyses. The incidence rate of stroke in the osteoporotic vertebral fracture group (37.5 per 1000 person-years; 95% confidence interval [CI], 27.5-51.2) was significantly higher than in the comparison group (14.0 per 1000 person-years; 95% CI, 12.0-16.4, p < 0.001). Stroke was more likely to occur in the osteoporotic vertebral fracture patients than in the normal controls (crude hazard ratio [HR] 2.68, 95% CI 1.89-3.79, p < 0.001; adjusted HR 2.71, 95% CI 1.90-3.86, p < 0.001). In conclusion, patients with osteoporotic vertebral fracture have a higher risk of stroke (ie, both ischemic and hemorrhagic) and require stroke prevention strategies. 23044047 The early mouse 3D osteocyte network in the presence and absence of mechanical loading. Osteocytes are considered to act as mechanosensory cells in bone. They form a functional synctia in which their processes become interconnected to constitute a three-dimensional (3D) network. Previous studies reported that in mice, the two-dimensional osteocyte network becomes progressively more regular as they grow, although the key factors governing the arrangement of the osteocyte network during bone growth remain unknown. In this study, we characterized the 3D formation of the osteocyte network during bone growth. Morphological skeletal changes have been reported to occur in response to mechanical loading and unloading. In order to evaluate the effect of mechanical unloading on osteocyte network formation, we subjected newborn mice to sciatic neurectomy in order to immobilize their left hind limb as an unloading model. The osteocyte network was visualized by staining osteocyte cell bodies and processes with fluorescently labeled phalloidin. First, we compared the osteocyte network in the femora of embryonic and 6-week-old mice in order to understand the morphological changes that occur with normal growth and mechanical loading. In embryonic mice, the osteocyte network in the femur cortical bone displayed a random cell body distribution, non-directional orientation of cell processes, and irregularly shaped cells. In 6-week-old mice, the 3D network contained spindle-shaped osteocytes, which were arranged parallel to the longitudinal axis of the femur. In addition, more and longer cell processes radiated from each osteocyte. Second, we compared the cortical osteocyte networks of 6-week-old mice that had or had not undergone sciatic neurectomy in order to evaluate the effect of unloading on osteocyte network formation. The osteocyte network formation in both cortical bone and cancellous bone was affected by mechanical loading. However, there were differences in the extent of network formation between cortical bone and cancellous bone in response to mechanical loading with regard to the orientation, nuclear shape and branch formation. 23418674 Development of a cell-based high-throughput peroxisome proliferator-activated receptors (PPARs) screening model and its application for evaluation of the extracts from Rhizoma Coptis. To date, peroxisome proliferator-activated receptors (PPARs) are becoming the new therapeutic targets for the treatment of metabolic diseases, such as Type 2 diabetes, obesity, and cardiovascular disease. In this study, a cell-based high-throughput PPARs (PPARα/β/γ) model was developed for the screening of PPARs agonists. The screening conditions were evaluated through analyzing the expression value of luciferase. Finally, 24 h of drug acting time, 5 times of the dilution factor of luciferase zymolyte, and about 2 × 10(4) cells/ well on HeLa cells in 96-well plates were used, respectively. Furthermore, the quality of high-throughput screening (HTS) in stability and reliability was evaluated by the Z'-factor. Additionally, different extracts of Rhizoma Coptis and berberine were tested by the developed method. The results suggested that both the EtOAc extract and berberine were able to activate PPARα/β/γ, and Rhizoma Coptis contains potential natural agonists of PPARs besides berberine. In conclusion, the developed HTS assay is a simple, rapid, stable, and specific method for the screening of PPARs natural agonists. 23518040 The life history of a botulinum toxin molecule. There is an emerging literature describing the absorption, distribution, metabolism and elimination of botulinum toxin. This work reveals that the toxin can be absorbed by both the oral and inhalation routes. The primary mechanism for absorption is binding and transport across epithelial cells. Toxin that enters the body undergoes a distribution phase, which is quite short, and an elimination phase, which is comparatively long. During the distribution phase, botulinum toxin migrates to the peri-neuronal microcompartment in the vicinity of vulnerable cells, such as cholinergic nerve endings. Only these cells have the ability to selectively accumulate the molecule. When the toxin moves from the cell membrane to the cell interior, it undergoes programmed death. This is coincident with release of the catalytically active light chain that paralyzes transmission. Intraneuronal metabolism of light chain is via the ubiquitination-proteasome pathway. Systemic metabolism and elimination is assumed to be via the liver. The analysis of absorption, distribution, metabolism and elimination of the toxin helps to create a life history of the molecule in the body. This has many benefits, including: a) clarifying the mechanisms that underlie the disease botulism, b) providing insights for development of medical countermeasures against the toxin, and c) helping to explain the meaning of a lethal dose of toxin. It is likely that work intended to enhance understanding of the fate of botulinum toxin in the body will intensify. These efforts will include new and powerful analytic tools, such as single molecule-single cell analyses in vitro and real time, 3-dimensional pharmacokinetic studies in vivo. 23500334 Sphaerospora sensu stricto: Taxonomy, diversity and evolution of a unique lineage of myxosporeans (Myxozoa). Myxosporeans (Myxozoa) are eukaryotic parasites, primarily of fish, whose classification is in a state of flux as taxonomists attempt to synthesize the traditional morphology-based system with emerging DNA sequence-based phylogenies. The genus Sphaerospora Thélohan, 1892, which includes pathogenic species that cause significant impacts on fisheries and aquaculture, is one of the most polyphyletic taxa and exemplifies the current challenges facing myxozoan taxonomists. The type species, S. elegans, clusters within the Sphaerospora sensu stricto clade, members of which share similar tissue tropism and long insertions in their variable rRNA gene regions. However, other morphologically similar sphaerosporids lie in different branches of myxozoan phylogenetic trees. Herein, we significantly extend taxonomic sampling of sphaerosporids with SSU+LSU rDNA and EF-2 sequence data for 12 taxa including three representatives of the morphologically similar genus Polysporoplasma Sitjà-Bobadilla et Álvarez-Pellitero, 1995. These taxa were sampled from different vertebrate host groups, biogeographic realms and environments. Our phylogenetic analyses and statistical tests of single and concatenated datasets revealed Sphaerospora s. s. as a strongly supported monophyletic lineage, that clustered sister to the whole myxosporean clade (freshwater+marine lineages). Generally, Sphaerospora s. s. rDNA sequences (up to 3.7kb) are the longest of all myxozoans and indeed metazoans. The sphaerosporid clade has two lineages, which have specific morphological, biological and sequence traits. Lineage A taxa (marine Sphaerospora spp.) have a single binucleate sporoplasm and shorter AT-rich rDNA inserts. Lineage B taxa (freshwater/brackish Sphaerospora spp.+marine/brackish Polysporoplasma spp.) have 2-12 uninucleate sporoplasms and longer GC-rich rDNA inserts. Lineage B has four subclades that correlate with host group and habitat; all Polysporoplasma species, including the type species, cluster together in one of these subclades. We thus suppress the genus Polysporoplasma and the family Polysporoplasmidae and emend the generic diagnosis of the genus Sphaerospora. The combination of morphological, biological and DNA sequence data applied in this study helped to elucidate an important part of the taxonomic puzzle within the phylum Myxozoa. 23528390 Antibacterial action of quinolones: From target to network. Quinolones are widely used broad-spectrum antibacterials with incomplete elucidated mechanism of action. Here, molecular basis for the antibacterial action of quinolones, from target to network, is fully discussed and updated. Quinolones trap DNA gyrase or topoisomerase IV to form reversible drug-enzyme-DNA cleavage complexes, resulting in bacteriostasis. Cell death arises from chromosome fragmentation in protein synthesis-dependent or -independent pathways according to distinguished quinolone structures. In the former pathway, irreversible oxidative DNA damage caused by reactive oxygen species kills bacteria eventually. Toxin-antitoxin mazEF is triggered as an additional lethal action. Bacteria survive and develop resistance by SOS and other stress responses. Enlarged knowledges of quinolone actions and bacterial response will provide new targets for drug design and approaches to prevent bacterial resistance. 23545458 Total saponins of Panax notoginseng enhance VEGF and relative receptors signals and promote angiogenesis derived from rat bone marrow mesenchymal stem cells. ETHNOPHARMACOLOGICAL RELEVANCE: Total saponins of Panax notoginseng (tPNS), main constituents extracted from Panax Notoginseng, a highly valued traditional Chinese medicine, has been shown to increase protein expression and the secretion of vascular endothelial growth factor (VEGF) in human umbilical vein endothelial cells. AIMS OF THE STUDY: The effects of tPNS on angiogenesis were studied in rat bone marrow mesenchymal stem cells (rBMSCs). MATERIALS AND METHODS: rBMSCs were stimulated by tPNS of 48h. The mRNA expression levels of VEGF-A, Flt-1 and Kdr in rBMSCs were determined by quantitative real time PCR (qRT-PCR). rBMSCs were induced to differentiate into endothelial-like cells and the effects of tPNS on the angiogenesis ability of rBMSCs and rBMSCs after endothelial differentiation were assayed by a Matrigel model in vivo and in vitro. RESULTS: tPNS (100μg/ml) significantly enhanced the mRNA expression level of VEGF-A and Kdr compared to the control group, while they had no obvious effect on the expression of Flt-1. tPNS (1μg/ml and 100μg/ml) significantly increased capillary network forming of rBMSCs after endothelial differentiation in Matrigel in vitro. tPNS (50μg/kg, 100μg/kg and 150μg/kg) also significantly increased angiogenesis induced by the combination with implantation of rBMSCs and Matrigel in vivo. CONCLUSION: tPNS up-regulate VEGF-A and Kdr expression, and promote angiogenesis in rat bone marrow mesenchymal stem cells. 23320521 Novel antiviral activity of l-dideoxy bicyclic nucleoside analogues versus vaccinia and measles viruses in vitro. Dideoxy bicyclic pyrimidine nucleoside analogues (ddBCNAs) with d-chirality have previously been described by us to inhibit replication of human cytomegalovirus. We herein report for the first time that activity against vaccinia virus (VACV) was achieved using novel l-analogues. A structure-activity relationship was established: Antiviral activity versus VACV was highest with an ether side chain with an optimum of n-C(9)H(18)-O-n-C(5)H(11). This gave an IC(50) of 190 nM, a 60-fold enhancement over the FDA-approved antiviral cidofovir. Interestingly, l-ddBCNAs also inhibit wild type measles virus syncytia formation with a TCID(50) of 7.5 μM for the lead compound. We propose that l-ddBCNAs represent significant innovative antiviral candidates versus measles and poxviruses, and we suggest a mechanism of action versus one or more cellular targets that are essential for viral replication. 23511016 Synthesis of a DOTA (Gd(3+))-conjugate of proton-pump inhibitor pantoprazole for gastric wall imaging studies. Magnetic resonance imaging (MRI) is used to evaluate gastrointestinal (GI) structure and functions in humans. Despite filling the viscus lumen with a contrast agent, visualization of the viscus wall is limited. To overcome this limitation, we de novo synthesized a conjugate that covalently combines a Gd-based MRI contrast agent, encaged with a chelating agent (DOTA), with pantoprazole, which is a widely used proton pump inhibitor that binds to proton pumps in the stomach and colon. The DOTA linkage was installed at a mechanism-based strategic location in the pantoprazole molecule to minimize a possible negative effect of the structural modification on the drug. It is anticipated that by defining the wall of the stomach and colon, this compound will facilitate functional MRI of the GI tract in humans. 23537661 Effects of lactational and/or in utero exposure to environmental contaminants on the glucocorticoid stress-response and DNA methylation of the glucocorticoid receptor promoter in male rats. Perinatal events can reprogram the hypothalamo-pituitary-adrenal axis for the entire lifespan leading to abnormal glucocorticoid stress-response (GSR) in adulthood: a phenomenon reported to be mediated by changes in DNA methylation of the glucocorticoid receptor (GR) gene promoter. We examined whether in utero and/or lactational exposure to mixtures of environmental contaminants can also induce abnormal GSR during adulthood. The experiment included nine treatment groups. From gestation day (GD) 0 until postnatal day (PND) 20, dams were fed daily with a cookie laced with corn oil (control) or a chemical mixture (M) [polychlorinated biphenyls (PCBs), organochlorine pesticides, and methylmercury] at 0.5 or 1.0mg/kg/day (0.5M, and M). At birth, some control (C) and M litters were cross-fostered to create four groups with the following in utero/postnatal exposure: C/C, M/C, C/M, M/M. Other dams received 1.8ng/kg/day of a mixture of aryl hydrocarbon receptor (AhR) agonists (non-ortho PCBs, PC-dibenzodioxins and PC-dibenzofurans) without or with 0.5M (0.5MAhR). In adult male offspring the abundance of GR in treated groups was not different from the control, but the AhR and M groups were significantly different from each other with opposite effects in the hippocampus and liver. There was no change in DNA methylation of the GR promoter (exon-17 and -110). Abnormal GSRs were detected in the AhR, 0.5MAhR, CM, and MM groups. The literature associates abnormal GSR with metabolic and mental health impairments, thus these results support further investigation of the influence of developmental exposure to environmental contaminants and predisposition to stress-induced diseases. 23416326 Levels of PAH-DNA adducts in placental tissue and the risk of fetal neural tube defects in a Chinese population. We examined the relationship between PAH-DNA adduct levels in the placental tissue, measured by a highly sensitive (32)P-postlabeling assay, and the risk of fetal neural tube defects (NTDs). We further explored the interaction between PAH-DNA adducts and placental PAHs with respect to NTD risk. Placental tissues from 80 NTD-affected pregnancies and 50 uncomplicated normal pregnancies were included in this case-control study. Levels of PAH-DNA adducts were lower in the NTD group (8.12 per 10(8) nucleotides) compared to controls (9.92 per 10(8) nucleotides). PAH-DNA adduct concentrations below the median was associated with a 3-fold increased NTD risk. Women with a low PAH-DNA adduct level in concert with a high placental PAH level resulted in a 10-fold elevated risk of having an NTD-complicated pregnancy. A low level of placental PAH-DNA adducts was associated with an increased risk of NTDs; this risk increased dramatically when a low adduct level was coupled with a high placental PAH concentration. 23311700 Poorly differentiated thyroid carcinoma presenting with gross extrathyroidal extension: 1986-2009 Memorial Sloan-Kettering Cancer Center experience. To describe the outcome of patients with poorly differentiated thyroid cancer (PDTC) presenting with gross extrathyroidal extension (ETE). After IRB approval we performed retrospective review of consecutive series of thyroid cancer patients treated by primary surgical resection with or without adjuvant therapy at MSKCC from 1986-2009. Out of 91 PDTC patients, 27 (30%) had gross ETE (T4a) and they formed the basis of our study. Of 27 patients, 52% were female. The median age was 70 (range 27-87). Ten patients (37%) presented with distant metastases; four to the bone, three to lung and three had both bone and lung metastases. All patients had extended total thyroidectomy except two who had subtotal thyroidectomy. 20 patients (74%) had central compartment neck dissection and 11 also had lateral neck dissection. Four patients had pN0, 6 (30%) pN1a and 10 (50%) pN1b neck disease. 21 patients (77%) had adjuvant therapy: 15 (55%) RAI only, 3 (11%) postoperative external beam radiation (PORT) only and 3 (11%) had both RAI and PORT. Overall survival (OS), disease specific survival (DSS), local recurrence free survival (LRFS) and regional recurrence free survival (RRFS) were calculated by the Kaplan Meier method. Median follow-up time was 57 months (range 1-197 months). The 5 year OS and DSS were 47% and 49% respectively. This poor outcome was due to distant metastatic disease; 10 patients had distant metastases at presentation and a further 6 developed distant metastases during follow up. Locoregional control was good with 5 year LRFS and RRFS of 70% and 62% respectively. Overall, 8 patients (30%) had recurrences: 2 had distant alone, 2 regional, 2 regional and distant, 1 local and distant, and 1 had local, regional and distant recurrence. Aggressive surgery in patients with PDTC showing gross ETE resulted in satisfactory locoregional control. Due to the small proportion of patients who received PORT (22%), it is not possible to analyze its benefit on locoregional control. Of significance is the observation that the majority of patients (60%) who presented with or subsequently developed distant metastases eventually died of distant disease. New systemic therapies to target distant metastatic disease are required for improvements in outcome. 23474972 Energetic contribution to hydration shells in one-dimensional aqueous electrolyte solution by anomalous hydrogen bonds. The hydration structure of NaCl aqueous solution was elucidated in carbon nanotubes (CNTs) on the basis of canonical ensemble Monte Carlo simulations. Hydration shells were preferentially formed even in narrow CNTs to gain stabilization energy, whereas hydrogen bonding between water molecules in such CNTs was sacrificed. Nanoscale-confined aqueous electrolyte solutions therefore prioritize hydration shell formation between ions and water rather than hydrogen-bond formation between water molecules. 23357311 Introducing new dimensions in MIA-QSAR: A case for chemokine receptor inhibitors. Multivariate image analysis applied to quantitative structure-activity relationships (MIA-QSAR) is a very simple correlative method that uses pixels (binaries) of chemical structures built from 2D viewer programs as descriptors; structural changes correspond to different pixel coordinates, which explain the variance in the bioactivities block. The MIA-QSAR method has shown to be predictive and capable of encoding some chemical information, but introduction of more descriptive information, such as atom size and colors to differentiate atom types, would improve predictability and interpretability. The bioactivities of a series of chemokine receptor (CCR2) inhibitors have been modeled using both conventional and atom color/size-dependent MIA-QSAR (namely aug-MIA-QSAR); the latter showed to be better. Moreover, the results were comparable to those obtained by 3D methodologies, indicating that 2D shape and substituent size are more significant descriptors than the conformational profiles required by field fit techniques. 23588316 Regulatory and Scientific Issues Regarding Use of Foreign Data in Support of New Drug Applications in the United States: An FDA Perspective. Globalization of clinical research has led to an increase in clinical trials conducted outside of the United States that are submitted to the US Food and Drug Administration (FDA) in new drug applications. This article discusses the FDA's experience with these submissions in specific therapeutic areas, including the extent of this practice, differences between the effectiveness and safety outcomes of studies conducted inside and outside the United States, and the FDA's approach to acceptance of these trials.Clinical Pharmacology & Therapeutics (2013); advance online publication 1 May 2013. doi:10.1038/clpt.2013.70. 22838394 Three new diarylbutane lignans from the resin of Bursera fagaroides. Three new diarylbutane lignans, named 9-acetyl-9'-pentadecanoil-dihydroclusin (1), 2,3-demethoxy-secoisolintetralin monoacetate (4) and dihydroclusin monoacetate (5), have been isolated from the resin of Bursera fagaroides, together with two known ones, 2,3-demethoxy-secoisolintetralin diacetate (2) and dihydroclusin diacetate (3). The complete structure assignments were obtained by means of (1)H and (13)C NMR spectra. 23085368 In vivo-in vitro comparison of acute respiratory tract toxicity using human 3D airway epithelial models and human A549 and murine 3T3 monolayer cell systems. The usefulness of in vitro systems to predict acute inhalation toxicity was investigated. Nineteen substances were tested in three-dimensional human airway epithelial models, EpiAirway™ and MucilAir™, and in A549 and 3T3 monolayer cell cultures. IC(50) values were compared to rat four-hour LC(50) values classified according to EPA and GHS hazard categories. Best results were achieved with a prediction model distinguishing toxic from non-toxic substances, with satisfactory specificities and sensitivities. Using a self-made four-level prediction model to classify substances into four in vitro hazard categories, in vivo-in vitro concordance was mediocre, but could be improved by excluding substances causing pulmonary edema and emphysema in vivo. None of the test systems was outstanding, and there was no evidence that tissue or monolayer systems using respiratory tract cells provide an added value. However, the test systems only reflected bronchiole epithelia and alveolar cells and investigated cytotoxicity. Effects occurring in other cells by other mechanisms could not be recognised. Further work should optimise test protocols and expand the set of substances tested to define applicability domains. In vivo respiratory toxicity data for in vitro comparisons should distinguish different modes of action, and their relevance for human health effects should be ensured. 23412078 Canagliflozin Lowers Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption in Addition to Increasing Urinary Glucose Excretion: Results of a randomized, placebo-controlled study. OBJECTIVECanagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, is also a low-potency SGLT1 inhibitor. This study tested the hypothesis that intestinal canagliflozin levels postdose are sufficiently high to transiently inhibit intestinal SGLT1, thereby delaying intestinal glucose absorption.RESEARCH DESIGN AND METHODSThis two-period, crossover study evaluated effects of canagliflozin on intestinal glucose absorption in 20 healthy subjects using a dual-tracer method. Placebo or canagliflozin 300 mg was given 20 min before a 600-kcal mixed-meal tolerance test. Plasma glucose, (3)H-glucose, (14)C-glucose, and insulin were measured frequently for 6 h to calculate rates of appearance of oral glucose (R(a)O) in plasma, endogenous glucose production, and glucose disposal.RESULTSCompared with placebo, canagliflozin treatment reduced postprandial plasma glucose and insulin excursions (incremental 0- to 2-h area under the curve [AUC(0-2h)] reductions of 35% and 43%, respectively; P < 0.001 for both), increased 0- to 6-h urinary glucose excretion (UGE(0-6h), 18.2 ± 5.6 vs <0.2 g; P < 0.001), and delayed R(a)O. Canagliflozin reduced AUC R(a)O by 31% over 0 to 1 h (geometric means, 264 vs. 381 mg/kg; P < 0.001) and by 20% over 0 to 2 h (576 vs. 723 mg/kg; P = 0.002). Over 2 to 6 h, canagliflozin increased R(a)O such that total AUC R(a)O over 0 to 6 h was <6% lower versus placebo (960 vs. 1,018 mg/kg; P = 0.003). A modest (∼10%) reduction in acetaminophen absorption was observed over the first 2 h, but this difference was not sufficient to explain the reduction in R(a)O. Total glucose disposal over 0 to 6 h was similar across groups.CONCLUSIONSCanagliflozin reduces postprandial plasma glucose and insulin by increasing UGE (via renal SGLT2 inhibition) and delaying R(a)O, likely due to intestinal SGLT1 inhibition. 23433812 Reduction of dNTP levels enhances DNA replication fidelity in vivo. ATP is the most important energy source for the maintenance and growth of living cells. Here we report that the impairment of the aerobic respiratory chain by inactivation of the ndh gene, or the inhibition of glycolysis with arsenate, both of which reduce intracellular ATP, result in a significant decrease in spontaneous mutagenesis in Escherichia coli. The genetic analyses and mutation spectra in the ndh strain revealed that the decrease in spontaneous mutagenesis resulted from an enhanced accuracy of the replicative DNA polymerase. Quantification of the dNTP content in the ndh mutant cells and in the arsenate-treated cells showed reduction of the dNTP pool, which could explain the observed broad antimutator effects. In conclusion, our work indicates that the cellular energy supply could affect spontaneous mutation rates and that a reduction of the dNTP levels can be antimutagenic. 23364884 Anti-inflammatory activity of Bromelia hieronymi: comparison with bromelain. Some plant proteases (e. g., papain, bromelain, ficin) have been used as anti-inflammatory agents for some years, and especially bromelain is still being used as alternative and/or complementary therapy to glucocorticoids, nonsteroidal antirheumatics, and immunomodulators. Bromelain is an extract rich in cysteine endopeptidases obtained from Ananas comosus. In this study the anti-inflammatory action of a partially purified extract of Bromelia hieronymi fruits, whose main components are cysteine endopeptidases, is presented. Different doses of a partially purified extract of B. hieronymi were assayed on carrageenan-induced and serotonine-induced rat paw edema, as well as in cotton pellet granuloma model. Doses with equal proteolytic activity of the partially purified extract and bromelain showed significantly similar anti-inflammatory responses. Treatment of the partially purified extract and bromelain with E-64 provoked loss of anti-inflammatory activity on carrageenan-induced paw edema, a fact which is consistent with the hypothesis that the proteolytic activity would be responsible for the anti-inflammatory action. 23515934 Mechanisms involved in the antinociceptive effects of orally administered oleanolic acid in the mouse. The antinociceptive effects of oleanolic acid were examined in ICR mice. Oleanolic acid administered orally (1, 5 and 10 mg/kg) showed an antinociceptive effect in a dose-dependent manner as measured in the acetic acid-induced writhing test. In the time- course study, duration of antinociceptive action of oleanolic acid maintained at least for 60 min. In addition, the cumulative nociceptive response time for intraplantar formalin injection (2nd phase), intrathecal injection of substance P (0.7 μg) or glutamate (20 μg) was diminished by oleanolic acid. Intraperitoneal (i.p.) pretreatment with naloxone (opioid receptor antagonist) or methysergide (5-HT serotonergic receptor antagonist) attenuated antinociceptive effect induced by oleanolic acid in the writhing test. However, yohimbine (adrenergic receptor antagonist) did not affect antinociception induced by oleanolic acid. The results indicate that oleanolic acid shows an antinociceptive property in various pain models such as writhing, formalin, substance P and glutamate pain tests. Furthermore, this antinociceptive effect of oleanolic acid may be mediated by opioidergic and serotonergic receptors, but not adrenergic receptors. 23449308 Targeting pathological B cell receptor signalling in lymphoid malignancies. Signalling through the B cell receptor (BCR) is central to the development and maintenance of B cells. In light of the numerous proliferative and survival pathways activated downstream of the BCR, it comes as no surprise that malignant B cells would co-opt this receptor to promote their own growth and survival. However, direct evidence for BCR signalling in human lymphoma has only come to light recently. Roles for antigen-dependent and antigen-independent, or tonic, BCR signalling have now been described for several different lymphoma subtypes. Furthermore, correlative data implicate antigen-dependent BCR signalling in many other forms of lymphoma. A host of therapeutic agents targeting effectors of the BCR signalling pathway are now in clinical trials and have shown initial success against multiple forms of lymphoma. 23470867 Human induced pluripotent stem cells and their use in drug discovery for toxicity testing. Predicting human safety risks of novel xenobiotics remains a major challenge, partly due to the limited availability of human cells to evaluate tissue-specific toxicity. Recent progress in the production of human induced pluripotent stem cells (hiPSCs) may fill this gap. hiPSCs can be continuously expanded in culture in an undifferentiated state and then differentiated to form most cell types. Thus, it is becoming technically feasible to generate large quantities of human cell types and, in combination with relatively new detection methods, to develop higher-throughput in vitro assays that quantify tissue-specific biological properties. Indeed, the first wave of large scale hiSC-differentiated cell types including patient-derived hiPSCS are now commercially available. However, significant improvements in hiPSC production and differentiation processes are required before cell-based toxicity assays that accurately reflect mature tissue phenotypes can be delivered and implemented in a cost-effective manner. In this review, we discuss the promising alignment of hiPSCs and recently emerging technologies to quantify tissue-specific functions. We emphasize liver, cardiovascular, and CNS safety risks and highlight limitations that must be overcome before routine screening for toxicity pathways in hiSC-derived cells can be established. 23340331 Implications of pH manipulation methods for metal toxicity: not all acidic environments are created equal. The toxicity of many metals is impacted by environmental pH, through both competition and complexation by hydroxide and carbonate ions. To establish safe environmental regulation it is important to properly define the relationship between pH and metal toxicity, a process that involves manipulating the pH of test water in the lab. The current study compares the effects of the three most common pH manipulation methods (carbon dioxide, acid-base addition, and chemical buffers) on acute Pb toxicity of a model fish species, Pimephales promelas. Acidification of test water revealed that the Pb and Pb(2+) LC50 values were impacted by the pH manipulation method, with the following order of effects: HCl stems (16.4 μg g(-1)) > roots (15.5 μg g(-1)). The accumulation potential was fourfold higher than the plant available concentration of 15.2 μg g(-1) of Se g(-1) of soil (diethylenetriaminepentaacetic acid extracted). Although the plant was able to accumulate Se in their tissues, increase in Se concentrations in soil caused a concentration-dependent decrease in the growth rate of plants (regeneration of leaves, number of leaves, number of roots, root length, stem length and biomass). 23412841 Computational Investigation of Cancer-Associated Molecular Mechanism in Aurora A (S155R) Mutation. Centrosomes are the key-regulating element of cell cycle progression. Aberrations in their functional mechanism lead to several cancer-related disorders. Aurora A protein is a centrosome-associated protein that regulates the centriole duplication and its abberations are associated with multiple cases of aneuploidy and cancer-related disorders. S155R mutation in Aurora A is reported to induce cancer like phenotype and disrupt its binding with TPX2 protein. In this study, we have demonstrated the structural consequences of Aurora A S155R mutation and the atomic changes that influenced the loss of TPX2-binding affinity. Docking and molecular dynamics simulation results suggested significant loss in atomic contacts between mutant Aurora A and TPX2 protein. Further, we observed a notable changes in conformation of mutant Aurora A-TPX2 docked complex as compared to the native. Loss of binding affinity rendered the TPX2 domain free which then induced unfolding in its coiled region and enabled the overall expansion of mutant complex as compared to the native. The significant outcomes obtained from this study will facilitate in future cancer researches and in developing the potent drug therapies. 23391096 Paclitaxel-conjugated PAMAM dendrimers adversely affect microtubule structure through two independent modes of action. Paclitaxel (Taxol) is an anticancer drug that induces mitotic arrest via microtubule hyperstabilization but causes side effects due to its hydrophobicity and cellular promiscuity. The targeted cytotoxicity of hydrophilic paclitaxel-conjugated polyamidoamine (PAMAM) dendrimers has been demonstrated in cultured cancer cells. Mechanisms of action responsible for this cytotoxicity are unknown, that is, whether the cytotoxicity is due to paclitaxel stabilization of microtubules, as is whether paclitaxel is released intracellularly from the dendrimer. To determine whether the conjugated paclitaxel can bind microtubules, we used a combination of ensemble and single microtubule imaging techniques in vitro. We demonstrate that these conjugates adversely affect microtubules by (1) promoting the polymerization and stabilization of microtubules in a paclitaxel-dependent manner, and (2) bundling preformed microtubules in a paclitaxel-independent manner, potentially due to protonation of tertiary amines in the dendrimer interior. Our results provide mechanistic insights into the cytotoxicity of paclitaxel-conjugated PAMAM dendrimers and uncover unexpected risks of using such conjugates therapeutically. 23278633 Self-Assembly of N(3)-Substituted Xanthines in the Solid State and at the Solid-Liquid Interface. The self-assembly of small molecular modules interacting through noncovalent forces is increasingly being used to generate functional structures and materials for electronic, catalytic, and biomedical applications. The greatest control over the geometry in H-bond supramolecular architectures, especially in H-bonded supramolecular polymers, can be achieved by exploiting the rich programmability of artificial nucleobases undergoing self-assembly through strong H bonds. Here N(3)-functionalized xanthine modules are described, which are capable of self-associating through self-complementary H-bonding patterns to form H-bonded supramolecular ribbons. The self-association of xanthines through directional H bonding between neighboring molecules allows the controlled generation of highly compact 1D supramolecular polymeric ribbons on graphite. These architectures have been characterized by scanning tunneling microscopy at the solid-liquid interface, corroborated by dispersion-corrected density functional theory (DFT) studies and X-ray diffraction. 23274746 Artichoke induces genetic toxicity in the cytokinesis-block micronucleus (CBMN) cytome assay. Artichoke leaves are used in traditional medicine as an herbal medicament for the treatment of hepatic related diseases, as well as choleretic and diuretic. The aim of the present study was to evaluate the capacity of Cynara scolymus L. leaves extract (LE) to cause chromosomal instability and cytotoxicity in Chinese hamster ovary cells (CHO) employing the cytokinesis-block micronucleus (CBMN) cytome assay. Cells were treated with four concentrations of C. scolymus for two exposure times: 1h and 24h. Our findings showed that LE did not increase the frequencies of nucleoplasmic bridges (NPBs) and nuclear bud (NBUD). However, all concentrations of the extract produced increments in micronuclei frequencies (MNi) in both exposure times, when compared to the negative control. No significant differences were observed in the nuclear division cytotoxicity index (NDCI), reflecting the absence of cytotoxic effects associated to LE. The results demonstrated the ability of C. scolymus LE to promote chromosomal mutations which are, probably, a result of the pro-oxidant activity of LE constituents such as flavonoids and chlorogenic acids. The data obtained in this study suggests that high concentrations of artichoke can pose a risk associated to its consumption. 23289403 Influence of polyelectrolyte film stiffness on bacterial growth. Photo-cross-linkable polyelectrolyte films, whose nanomechanical properties can be varied under UV light illumination, were prepared from poly(l-lysine) (PLL) and a hyaluronan derivative modified with photoreactive vinylbenzyl groups (HAVB). The adhesion and the growth of two model bacteria, namely Escherichia coli and Lactococcus lactis , were studied on non-cross-linked and cross-linked films to investigate how the film stiffness influences the bacterial behavior. While the Gram positive L. lactis was shown to grow slowly on both films, independently of their rigidity, the Gram negative E. coli exhibited a more rapid growth on non-cross-linked softer films compared to the stiffer ones. Experiments performed on photopatterned films showing both soft and stiff regions, confirmed a faster development of E. coli colonies on softer regions. Interestingly, this behavior is opposite to the one reported before for mammalian cells. Therefore, the photo-cross-linked (PLL/HAVB) films are interesting coatings for tissue engineering since they promote the growth of mammalian cells while limiting the bacterial colonization. 23384042 Two-photon circular-linear dichroism of perylene in solution: a theoretical-experimental study. Herein, we report on the theoretical-experimental analysis of the two-photon absorption (TPA) and two-photon circular-linear dichroism (TPCLD) spectra of a highly conjugated, rigid, and centrosymmetric molecule in solution, that is, perylene/CH2Cl2. We show how a three-energy-level diagram, under the sum-over-essential states approach, assists in the determination of the magnitude of transition electric dipole moments and the angle between them for the main TPA transitions. We demonstrate the potential of TPCLD to reveal the symmetry of excited states and the angles between their transition electric dipole moments and that of the ground state. By means of TPCLD, we explain how the overwhelming contribution of certain TPA transitions can mask important spectral features in regions where the transition electric dipole moments are perpendicular. TPCLD is expected to enhance the understanding of the photophysical properties of materials that are not accessible using conventional linear and two-photon spectroscopy. TPA and TPCLD measurements were performed employing the open-aperture Z-scan technique using an amplified femtosecond system. Time-dependent density functional theory (TD-DFT) calculations were carried out using response theory at the B3LYP level with the aug-cc-pVDZ basis set. Solvent effects were included through the polarizable continuum model (PCM). 23561147 The effect of interesterification on the bioavailability of fatty acids in structured lipids. Fatty acid (FA) profile is a critical factor in the nutritional properties of fats, but, stereochemistry may also play a fundamental role in the rate and extent to which FAs are absorbed and become available. To better understand this phenomenon, we evaluated the bioavailability of FAs in linseed-oil and palm-stearin blends compared to their interesterified mix, using a sn-1,3 stereospecific lipase, to determine if there was any difference in terms of FA availability when using this technology. Test meals were fed through an intragastric feeding tube on Sprague-Dawley male rats after 18h fasting. Postprandial blood samples were collected after meal or physiological serum (control) administration and the FA profile of plasma lipids was determined. Results showed that modification of the melting profile through interesterification, without altering the bioavailability determined by sn-2 stereochemistry, could delay lipid absorption at the beginning, but had no effect on total lipid absorption. 23453067 Synthesis and evaluation against hepatitis C virus of 7-deaza analogues of 2'-C-methyl-6-O-methyl guanosine nucleoside and L-Alanine ester phosphoramidates. 7-Deazapurines are known to possess broad antiviral activity, however the 2'-C-methylguanosine analogue displays poor cell permeation and limited phosphorylation, thus is not an efficient inhibitor of hepatitis C virus (HCV) replication. We previously reported the 6-O-methyl entity as a prodrug moiety to increase liphophilicity of guanine nucleosides and the ProTide approach applied to 2'-C-methyl-6-O-methylguanosine has lead to potent HCV inhibitors now in clinical trials. In this Letter, we report the synthesis and biological evaluation of 2'-C-methyl-6-O-methyl-7-deaza guanosine and ProTide derivatives. In contrast to prior studies, removal of the N-7 of the nucleobase entirely negates anti-HCV activity compared to the 2'-C-methyl-6-O-methylguanosine analogues. To understand better this significant loss of activity, enzymatic assays and molecular modeling were carried out and suggested 2'-C-methyl-6-O-methyl-7-deaza guanosine and related ProTides do not act as efficient prodrugs of the free nucleotide, in marked contrast to the case of the parent guanine analogue. 23434445 Mucous hypersecretion and relationship to cough. A variety of foreign "invaders" such as viruses, bacteria and other particulates e.g., cigarette smoke, are inhaled, deposit on the airway surface and invade the "host." Mucins produced by the surface airway epithelium and by the submucosal glands are secreted into the airway lumen. Deposited particulates adhere to the mucus and are cleared via mucociliary transport and via cough. Mucins are major constituents of mucus, which is important in the clearance of inhaled materials. Normally, secreted mucus is cleared without symptoms or interference with lung function. However, in obstructive airway diseases such as COPD, asthma, and cystic fibrosis, excessive mucus is produced. Because of the prominence of mucous hypersecretion as a cause of cough, this discussion focuses on mechanisms regulating normal production of mucins and the mechanisms underlying exaggerated mucin secretion in chronic obstructive airway diseases. Mucins are produced by airway epithelial cells via a cascade of signals (the Epidermal Growth Factor Cascade) and secreted on the luminal epithelial surface, often in response to the deposition of inhaled irritants. Normally, only minimal amounts of mucins are secreted, which assist in clearance of the inhaled particulates. However, in disease, additional pathways are induced via positive feedback systems, which lead to mucous hypersecretion. In the large conducting airways, where cough receptors are concentrated, mucous hypersecretion causes stimulation of neural receptors that result in cough. However, in small airways (e.g., bronchioles), because of their small diameters, mucous hypersecretion leads to plugging of the airways. Because there are so many small airways, their plugging is difficult to detect early, and this locus is known as a "silent zone." In chronic obstructive airway diseases, plugging of small airways may persist and increase over time, finally resulting in severe airway obstruction. Different obstructive airway diseases induce inflammatory signaling (including mucous hypersecretion) via different stimuli, but often via similar signaling pathways. Application of present knowledge of signaling that occurs with mucous hypersecretion can lead to novel therapies for hypersecretion and cough induced in conducting airways and could prevent plugging in small airways that can lead to clinical deterioration and death. 22766173 Correlation between iodide dosimetry and terephthalic acid dosimetry to evaluate the reactive radical production due to the acoustic cavitation activity. Acoustic cavitation plays an important role in sonochemical processes and the rate of sonochemical reaction is influenced by sonication parameters. There are several methods to evaluate cavitation activity such as chemical dosimetry. In this study, to comparison between iodide dosimetry and terephthalic acid dosimetry, efficacy of sonication parameters in reactive radical production has been considered by iodide and terephthalic acid dosimetries. For this purpose, efficacy of different exposure parameters on cavitations production by 1 MHz ultrasound has been studied. The absorbance of KI dosimeter was measured by spectrophotometer and the fluorescence of terephthalic acid dosimeter was measured using spectrofluorometer after sonication. The result of experiments related to sonication time and intensity showed that with increasing time of sonication or intensity, the absorbance is increased. It has been shown that the absorbance for continuous mode is remarkably higher than for pulsing mode (p-value < 0.05). Also results show that with increasing the duty cycles of pulsed field, the inertial cavitation activity is increased. With compensation of sonication time or intensity in different duty cycles, no significant absorbance difference were observed unless 20% duty cycle. A significant correlation between the absorbance and fluorescence intensities (count) at different intensity (R = 0.971), different sonication time (R = 0.999) and different duty cycle (R = 0.967) were observed (p-value < 0.05). It is concluded that the sonication parameters having important influences on reactive radical production. These results suggest that there is a correlation between iodide dosimetry and terephthalic acid dosimetry to examine the acoustic cavitation activity in ultrasound field. 22594605 A new pyrimidinedione derivative from the gorgonian coral Verrucella umbraculum. A new pyrimidinedione derivative, 9-acetyl-1,3,7-trimethyl-pyrimidinedione (1), was isolated from the gorgonian coral Verrucella umbraculum, together with two known compounds, caffeine (2) and 1,3-dimethylpyrimidine-2,4(1H,3H)-dione (3). The structure of 1 was elucidated by the aid of 1D, 2D NMR and MS experiments. The structures of the known compounds were identified by comparison of their spectroscopic data with those reported in the literature. 23297762 Risk of completed suicide after bariatric surgery: a systematic review. Bariatric surgery is one of the most effective treatments for morbid obesity, and a large body of research indicates significant long-term weight loss. While overall mortality decreases in patients who received bariatric surgery, a number of studies have shown that suicide rates are higher in bariatric patients than in control groups. The objective of this study was to present a systematic review of suicide mortality after bariatric surgery and calculate an estimate for the suicide rate. Literature researches of the databases PubMed, Web of Knowledge, PsychInfo, ScienceDirect and Google Scholar were conducted. Thirty studies concerning bariatric surgery and completed suicides met the inclusion criteria. We included 28 studies in the estimation of a suicide rate for the bariatric population. Only one study (Tindle et al.) put a main focus on suicide after bariatric surgery; this was therefore chosen as an adequate reference figure for comparison. The other 27 chosen studies were compared with World Health Organization data and the suicide rate reported by Tindle et al. Twenty-three thousand eight hundred eighty-five people were included in the analysis. In the literature, we found a total of 95 suicides when examining 190,000 person-years of post-bariatric surgery data. Little information was provided describing the reasons for suicide and the time-point of these events after surgery. We estimated a suicide rate of 4.1/10,000 person-years (95% confidence interval [3.2, 5.1]/10,000 person-years). A comparison with Tindle et al. demonstrates that their rate is significantly higher than our estimate (P = 0.03). Bariatric surgery patients show higher suicide rates than the general population. Therefore, there is a great need to identify persons at risk and post-operative psychological monitoring is recommended. 23206990 ESR1 polymorphisms, daily hassles, anger expression, and depressive symptoms in adolescent boys and girls. Studies reporting associations between genetic factors and mood-related traits have often been criticized (i) for failing to take into account the role of the social environment in which individuals act and (ii) for not maintaining a 'transparent narrative connection' between genes and outcomes. In a sample of adolescents, we analyzed whether PvuII and XbaI, two polymorphisms on the ESR1 (Estrogen Receptor Gene α) were related to depressive symptoms, and considered whether daily hassles moderated this relationship and whether anger expression style mediated this relationship. Analyses suggested that ESR1 polymorphisms are relevant to the intra-sexual variability in depressive symptoms in boys and that the experience of daily hassles moderated this relationship. No such relationships were found in girls. Additionally, ESR1 polymorphisms are related to anger expression styles in girls. Anger-related variables, however, did not mediate the relationship between ESR1 polymorphisms and depressive symptoms, in boys nor in girls. 23410163 The economics of polypharmacology: fixed dose combinations and drug cocktails. The history of Fixed Dose Combination (FDC) oral drug products has been tumultuous over its history. Some FDCs were prepared for marketing purposes and others for clinical improvements. Often, the products prepared for marketing advantage ended up causing negative outcomes. However, in recent years, there has been a resurgence of FDCs as clinicians have found them adventitious for treatment of AIDS/HIV and for oral contraceptives, just to name two examples. International regulatory Agencies and most major drug regulatory agencies have established guidelines along with regulations concerning preparation, labeling and marketing for FDCs. The advantages of FDCs are said to be in the clinical realm where simplified therapy regimens are thought to enhance patient's medication taking compliance. On the financial side, health insurers and other payers normally save money from a decreased number of dispensing fees, the use of fewer bottles, labels, etc., and from the possible situation where the price of the FDC is less than the medication price of the two separate ingredients dispensed individually. Overall, there is a great deal of evidence in favor of appropriate FDCs. 23125070 Contribution of Leydig and Sertoli cells to testosterone production in mouse fetal testes. Testosterone is a final product of androgenic hormone biosynthesis, and Leydig cells are known to be the primary source of androgens. In the mammalian testis, two distinct populations of Leydig cells, the fetal and the adult Leydig cells, develop sequentially, and these two cell types differ both morphologically and functionally. It is well known that the adult Leydig cells maintain male reproductive function by producing testosterone. However, it has been controversial whether fetal Leydig cells can produce testosterone, and the synthetic pathway of testosterone in the fetal testis is not fully understood. In the present study, we generated transgenic mice in which enhanced green fluorescence protein was expressed under the control of a fetal Leydig cell-specific enhancer of the Ad4BP/SF-1 (Nr5a1) gene. The transgene construct was prepared by mutating the LIM homeodomain transcription factor (LHX9)-binding sequence in the promoter, which abolished promoter activity in the undifferentiated testicular cells. These transgenic mice were used to collect highly pure fetal Leydig cells. Gene expression and steroidogenic enzyme activities in the fetal Leydig cells as well as in the fetal Sertoli cells and adult Leydig cells were analyzed. Our results revealed that the fetal Leydig cells synthesize only androstenedione because they lack expression of Hsd17b3, and fetal Sertoli cells convert androstenedione to testosterone, whereas adult Leydig cells synthesize testosterone by themselves. The current study demonstrated that both Leydig and Sertoli cells are required for testosterone synthesis in the mouse fetal testis. 23451797 Structural Investigation and Biological Activity of Sesquiterpene Lactones from the Traditional Chinese Herb Inula racemosa. Five new sesquiterpene lactones, racemosalactones A-E (1-5), along with 19 known sesquiterpene latones (6-24), were isolated from the roots of Inula racemosa. Their structures were elucidated by extensive spectroscopic analysis, and the absolute configuration of 2 was deduced from X-ray diffraction analysis. Compounds 1, 6, 8, 10, 12, 14, and 17 exhibited antiproliferative activities with IC50 values ranging from 0.38 to 4.19 μg/mL against human non-small-cell lung cancer A549, hepatocellular carcinoma HepG2, and human fibrosarcoma HT1080 cells. Compounds 6 and 8 exhibited antiproliferative activities against endothelial cells with IC50 values of 2.4 and 2.5 μg/mL, respectively. Furthermore, compounds 6 and 8 both inhibited endothelial cell tube formation at 1.0 μg/mL. A method for the rapid and straightforward preparative-scale isolation of compound 6 from alantolides is described. 23111282 Analysis of gene expression changes to elucidate the mechanism of chilling injury in precision-cut liver slices. The exact mechanism of chilling injury (by a decrease of temperature to sub-physiological values), especially in the intact organ, is yet unknown. Precision-cut liver slices (PCLS), which closely resemble the organ from which they are derived, are an ideal in vitro model to study the mechanism of chilling injury in the intact organ. In the present study we were able to separate chilling injury from other damaging events such as cryoprotectant toxicity and ice-crystal injury and performed micro-array analysis of regulated genes. Pathway analysis revealed that different stress responses, lipid/fatty acid and cholesterol biosynthesis and metabolism were affected by chilling. This indicates that the cell-membrane might be the primary site and sensor for chilling, which may initiate and amplify downstream intracellular signaling events. Most importantly, we were able to identify gene expression responses from stellate cells and Kupffer cells suggesting the involvement of all liver cell types in the injury. In conclusion, a broad spectrum of previously unknown gene expression changes induced by chilling was identified in the tissue. This is the first report of a systematic investigation on the mechanism of chilling injury in integrated tissue by micro-array analysis under conditions in which other sources of injury are minimal. 23402364 Role of nitric oxide in the chemistry and anticancer activity of etoposide (VP-16,213). Originally identified as an innate cytotoxin, nitric oxide ((·)NO) formation in tumors can influence chemotherapy and exacerbate cancer progression. Here, we examined the hypothesis that (·)NO generation contributes to cancer cell drug resistance toward the widely used anticancer drug Etoposide (VP-16). The UV-vis spectrum of VP-16 was not changed by exposure of VP-16 to (·)NO in aqueous buffer. In contrast, reddish-orange compound(s) characteristic of o-quinone- and nitroso-VP-16 were readily generated in a hydrophobic medium (chloroform) in an oxygen-dependent manner. Similar products were also formed when the VP-16 radical, generated from VP-16 and horseradish peroxidase/H2O2, was exposed directly to (·)NO in chloroform in the presence of oxygen. Separation and spectral analysis of VP-16 reaction extracts by electron spin resonance and UV-vis indicated the generation of the phenoxy radical and the o-quinone of VP-16, as well as putative nitroxide, iminoxyl, and other nitrogen oxide intermediates. Nitric oxide products of VP-16 displayed significantly diminished topoisomerase II-dependent cleavage of DNA and cytotoxicity to human HL-60 leukemia cells. LPS-mediated induction of nitric oxide synthase in murine macrophages resulted in VP-16 resistance compared to Raw cells. Furthermore, (·)NO products derived from iNOS rapidly reacted with VP-16 leading to decreased DNA damage and cytotoxicity. Together, these observations suggest that the formation of (·)NO in tumors (associated macrophages) can contribute to VP-16 resistance via the detoxification of VP-16. 23416070 Glucagon-induced acetylation of Foxa2 regulates hepatic lipid metabolism. Circulating levels of insulin and glucagon reflect the nutritional state of animals and elicit regulatory responses in the liver that maintain glucose and lipid homeostasis. The transcription factor Foxa2 activates lipid metabolism and ketogenesis during fasting and is inhibited via insulin-PI3K-Akt signaling-mediated phosphorylation at Thr156 and nuclear exclusion. Here we show that, in addition, Foxa2 is acetylated at the conserved residue Lys259 following inhibition of histone deacetylases (HDACs) class I-III and the cofactors p300 and SirT1 are involved in Foxa2 acetylation and deacetylation, respectively. Physiologically, fasting states and glucagon stimulation are sufficient to induce Foxa2 acetylation. Introduction of the acetylation-mimicking (K259Q) or -deficient (K259R) mutations promotes or inhibits Foxa2 activity, respectively, and adenoviral expression of Foxa2-K259Q augments expression of genes involved in fatty acid oxidation and ketogenesis. Our study reveals a molecular mechanism by which glucagon signaling activates a fasting response through acetylation of Foxa2. 22579656 Neuroendocrine aspects of catamenial epilepsy. This review describes the neuroendocrinological aspects of catamenial epilepsy, a menstrual cycle-related seizure disorder in women with epilepsy. Catamenial epilepsy is a multifaceted neuroendocrine condition in which seizures are clustered around specific points in the menstrual cycle, most often around perimenstrual or periovulatory period. Three types of catamenial seizures (perimenstrual, periovulatory and inadequate luteal) have been identified. The molecular pathophysiology of catamenial epilepsy remains unclear. Cyclical changes in the circulating levels of estrogens and progesterone (P) play a central role in the development of catamenial epilepsy. Endogenous neurosteroids such as allopregnanolone (AP) and allotetrahydrodeoxycorticosterone (THDOC) that modulate seizure susceptibility could play a critical role in catamenial epilepsy. In addition, plasticity in GABA-A receptor subunits could play a role in the enhanced seizure susceptibility in catamenial epilepsy. P-derived neurosteroids such as AP and THDOC potentiate synaptic GABA-A receptor function and also activate extrasynaptic GABA-A receptors in the hippocampus and thus may represent endogenous regulators of catamenial seizure susceptibility. Experimental studies have shown that neurosteroids confer greater seizure protection in animal models of catamenial epilepsy, especially without evident tolerance to their actions during chronic therapy. In the recently completed NIH-sponsored, placebo controlled phase 3 clinical trial, P therapy proved to be beneficial only in women with perimenstrual catamenial epilepsy but not in non-catamenial subjects. Neurosteroid analogs with favorable profile may be useful in the treatment of catamenial epilepsy. 23552264 Evaluation of in vitro and in vivo genotoxicity of single-walled carbon nanotubes. Single-walled carbon nanotubes (SWCNTs) have extensive potential industrial applications due to their unique physical and chemical properties; yet this also increases the chance of human and environment exposure to SWCNTs. Due to the current lack of hazardous effect information on SWNCTs, a standardized genotoxicity battery test was conducted to clarify the genetic toxicity potential of SWCNTs (diameter: 1-1.2 nm, length: ∼20 μm) according to Organization for Economic Cooperation and Development test guidelines 471 (bacterial reverse mutation test), 473 (in vitro chromosome aberration test), and 474 (in vivo micronuclei test) with a good laboratory practice system. The test results showed that the SWCNTs did not induce significant bacterial reverse mutations at 31.3-500 μg/plate in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 or in Escherichia coli strain WP2uvrA, with and without a metabolic activation system. Furthermore, the in vitro chromosome aberration test showed no significant increase in structural or numerical chromosome aberration frequencies at SWCNT dose levels of 12.5-50 μg/ml in the presence and absence of metabolic activation. However, dose-dependent cell growth inhibition was found at all the SWCNT dose levels and statistically significant cytotoxic effects observed at certain concentrations in the presence and absence of metabolic activation. Finally, the SWCNTs did not evoke significant in vivo micronuclei frequencies in the polychromatic erythrocytes of an imprinting control region mice at 25-100 mg/kg. Thus, according to the results of the present study, the SWCNTs were not found to have a genotoxic effect on the in vitro and in vivo test systems. 23184951 ATP hydrolysis enhances RNA recognition and antiviral signal transduction by the innate immune sensor, laboratory of genetics and physiology 2 (LGP2). Laboratory of genetics and physiology 2 (LGP2) is a member of the RIG-I-like receptor family of cytoplasmic pattern recognition receptors that detect molecular signatures of virus infection and initiate antiviral signal transduction cascades. The ATP hydrolysis activity of LGP2 is essential for antiviral signaling, but it has been unclear how the enzymatic properties of LGP2 regulate its biological response. Quantitative analysis of the dsRNA binding and enzymatic activities of LGP2 revealed high dsRNA-independent ATP hydrolysis activity. Biochemical assays and single-molecule analysis of LGP2 and mutant variants that dissociate basal from dsRNA-stimulated ATP hydrolysis demonstrate that LGP2 utilizes basal ATP hydrolysis to enhance and diversify its RNA recognition capacity, enabling the protein to associate with intrinsically poor substrates. This property is required for LGP2 to synergize with another RIG-I-like receptor, MDA5, to potentiate IFNβ transcription in vivo during infection with encephalomyocarditis virus or transfection with poly(I:C). These results demonstrate previously unrecognized properties of LGP2 ATP hydrolysis and RNA interaction and provide a mechanistic basis for a positive regulatory role for LGP2 in antiviral signaling. 23608109 Novel therapeutic targets in non-small cell lung cancer. Oncogenic driver mutations frequently occur in lung cancer and play role in carcinogenesis. These mutations are usually associated with distinct clinical and histological features and are attractive targets for anticancer therapy. Recently, several molecularly distinct phenotypes of NSCLC based on specific and mutually exclusive genetic derangements have been described. Few targets like epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements have successfully been targeted with EGFR tyrosine kinase inhibitors (TKIs) and crizotinib, respectively. Many more inhibitors of specific driver mutations involving genes like ROS, c-MET, FGFR, mTOR, IGFR and RET are currently under development. However, efforts to target some mutated genes like K-RAS have been unsuccessful. Moreover, the emerging challenge of acquired resistance to initially effective therapy is becoming another major concern. In this review recent data on novel molecular targets and their future prospects are discussed. 22788700 Polyphenol distribution in plant organs of tomato introgression lines. The content of total polyphenols, chlorogenic, caffeic (CaA) and ferulic acids, and rutin, was investigated in plant organs of three introgression lines (IL7-3, IL10-1 and IL12-4) of Solanum pennellii in Solanum lycopersicum cv M82 and compared with that of cropped parental. Such study aims to evidence factors associated to the introgressions that can affect polyphenol distribution in plant. Among genotypes few differences in polyphenols were recorded on fresh weight basis. IL7-3 showed higher total polyphenols in fruits and lower rutin in leaves than the other genotypes. IL12-4 showed an increasing trend of total polyphenol concentration in fresh vegetative organs; however, this seems to depend on the lower water content rather than on a higher polyphenol biosynthesis in the genotype. IL10-1 sowed higher CaA and lignin contents in leaves. Such differences agree with the morphological and physiological traits of the genotypes. 22956630 Effects of parabens on adipocyte differentiation. Parabens are a group of alkyl esters of p-hydroxybenzoic acid that include methylparaben, ethylparaben, propylparaben, butylparaben, and benzylparaben. Paraben esters and their salts are widely used as preservatives in cosmetics, toiletries, food, and pharmaceuticals. Humans are exposed to parabens through the use of such products from dermal contact, ingestion, and inhalation. However, research on the effects of parabens on health is limited, and the effects of parabens on adipogenesis have not been systematically studied. Here, we report that (1) parabens promote adipogenesis (or adipocyte differentiation) in murine 3T3-L1 cells, as revealed by adipocyte morphology, lipid accumulation, and mRNA expression of adipocyte-specific markers; (2) the adipogenic potency of parabens is increased with increasing length of the linear alkyl chain in the following potency ranking order: methyl- < ethyl- < propyl- < butylparaben. The extension of the linear alkyl chain with an aromatic ring in benzylparaben further augments the adipogenic ability, whereas 4-hydroxybenzoic acid, the common metabolite of all parabens, and the structurally related benzoic acid (without the OH group) are inactive in promoting 3T3-L1 adipocyte differentiation; (3) parabens activate glucocorticoid receptor and/or peroxisome proliferator-activated receptor γ in 3T3-L1 preadipocytes; however, no direct binding to, or modulation of, the ligand binding domain of the glucocorticoid receptor by parabens was detected by glucocorticoid receptor competitor assays; and lastly, (4) parabens, butyl- and benzylparaben in particular, also promote adipose conversion of human adipose-derived multipotent stromal cells. Our results suggest that parabens may contribute to obesity epidemic, and the role of parabens in adipogenesis in vivo needs to be examined further. 23123945 Repeated exposure to the herbicide atrazine alters locomotor activity and the nigrostriatal dopaminergic system of the albino rat. Atrazine (ATR) is used as a pre- and post-emergent herbicide; although banned in several countries of the European Community, it is still used extensively around the world. A recent study in rats has shown that chronic, daily exposure to 10 mg ATR/kg BW causes hyperactivity, disrupts motor coordination and learning of behavioral tasks, and decreases dopamine levels in the brain. In order to evaluate the short-term effect of ATR exposure on locomotor activity, monoamine markers, and antioxidants, adult male Sprague-Dawley rats received six IP injections of 100 mg ATR/kg BW or vehicle over two weeks. After every ATR injection we found hypoactivity that lasted up to five days, and it was accompanied by reductions in levels of striatal DA, DOPAC, and HVA without any alteration in the striatal expression of the mRNAs for Mn-SOD, Trx-1, DAR-D(1), or DAR-D(2). In contrast, in the nucleus accumbens no changes in monoamine markers were observed, and a down-regulation of Trx-1 expression was detected shortly after the ATR treatment. Moreover, in the ventral midbrain, we found that ATR induced a down-regulation of mRNA for Th and DAT, but it increased VMAT2 mRNA expression. Decreases of monoamine levels and of locomotor activity disappeared three months after ATR treatment; however, an amphetamine challenge (1 mg/kg) given two months after the ATR treatment resulted in a significant stimulation in the exposed group, revealing hidden effects of ATR on dopaminergic systems. These results indicate that ATR exposure differentially modifies the dopaminergic systems, and these modifications may underlie the behavioral changes observed. 23347684 Synthesis of 2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes via LiAlH₄-induced reductive cyclization of 2-(4-chloro-2-cyano-2-phenylbutyl)aziridines and evaluation of their antimalarial activity. 2-(4-Chloro-2-cyano-2-phenylbutyl)aziridines were employed for the one-step stereoselective construction of both endo- and exo-2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes as new azaheterobicyclic scaffolds via a double LiAlH(4)-induced reductive cyclization protocol. Antiplasmodial assessment of these 1-azabicyclo[2.2.1]heptanes revealed moderate to good activities in the micromolar range, with the exo-isomers being the most promising structures. Furthermore, the proposed mode of action was supported by ligand docking studies, pointing to a strong binding interaction with the enzyme plasmepsin II. 23362923 Biselectivity of isoDGR Peptides for Fibronectin Binding Integrin Subtypes α5β1 and αvβ6: Conformational Control through Flanking Amino Acids. Integrins are the major class of cell adhesion proteins. Their interaction with different ligands of the extracellular matrix is diverse. To get more insight into these interactions, artificial ligands endowed with a well-defined activity/selectivity profile are necessary. Herein, we present a library of cyclic pentapeptides, based on our previously reported peptide motif c(-phg-isoDGR-X-), in which high activity toward fibronectin binding integrins α5β1 and αvβ6 and not on vitronectin binding integrins αvβ3 and αvβ5 has been achieved by changing the flanking amino acids. The structure of the most promising candidates has been determined using a combined approach of NMR, distance geometry, and molecular dynamics simulations, and docking studies have been further used to elucidate the peptide-integrin interactions at the molecular level. The peptides' binding affinity has been characterized by enzyme linked immunosorbent assay experiments, and the results have been verified by cell adhesion experiments on specifically functionalized surfaces. 23464990 A General Strategy for Biocompatible, High-Effective Upconversion Nanocapsules Based on Triplet-Triplet Annihilation. A general strategy for constructing high-effective upconversion nanocapsules based on triplet-triplet annihilation (TTA) was developed by loading both sensitizer and annihilator into BSA-dextran stabilized oil droplets. This strategy can maintain high translational mobility of the chromophores, avoid luminescence quenching of chromophore by aggregation, and decrease the O2-induced quenching of TTA-based upconversion emission. Pt(II)-tetraphenyl-tetrabenzoporphyrin (PtTPBP) and BODIPY dyes (BDP-G and BDP-Y with the maximal fluorescence emission at 528 and 546 nm, respectively) were chosen as sensitizer/annihilator couples to fabricate green and yellow upconversion luminescent emissive nanocapsules, named UCNC-G and UCNC-Y, respectively. In water under the atmospheric environment, interestingly, UCNC-G and UCNC-Y exhibit intense upconversion luminescence (UCL) emission (λex = 635 nm) with the quantum efficiencies (ΦUCL) of 1.7% and 4.8%, respectively, whereas very weak UCL emission (ΦUCL < 0.1%) was observed for the corresponding previous reported SiO2-coating nanosystems because of aggregation-induced fluorescence quenching of annihilators. Furthermore, application of theses upconversion nanocapsules for high-contrast UCL bioimaging in vivo of living mice without removing the skin was demonstrated under 635-nm excitation with low power density of 12.5 mW cm(-2). 23469688 8-(Tosylamino)quinoline inhibits tumour progression through targeting phosphoinositide-3-kinase/Akt pathway. We examined whether 8-(tosylamino)quinoline (8-TQ), a structural analogue of BAY 11-7082, is able to modulate various tumourigenic responses using various in vitro and in vivo experimental conditions. 8-TQ exhibited the strongest suppressive activity on the proliferation of C6, A431, HeLa and MDA-MB-231 cells with IC550 values ranging from 10 to 30 microM. According to the analysis of level of active caspase-3, and morphologies of C6, HeLa and MDA-MB-231 cells, it was revealed that 8-TQ is able to induce apoptosis. Furthermore, this compound strongly diminished the invasion of MDA-MB-231 cells, the migration of HeLa cells, and the new generation of blood vessels under non-toxic conditions. Reduction of the phospho-form levels of intracellular signalling enzymes by 8-TQ strongly indicated that molecular signalling machineries composed of phosphoinositide 3-kinase (PI3K)/phosphoinositide-dependent kinase-1 (PDK1)/Akt and extracellular-signal-regulated kinase (ERK) could be targeted by 8-TQ treatment. Indeed, the specific inhibitors (LY294002 and U0126) of PI3K/PDK1/Akt and ERK showed similar anti-cancer properties to 8-TQ. Finally, 8-TQ intraperitoneally injected suppressed the increase of tumour volume up to 40% compared to vehicle-treated control. Taken together, our results clearly suggest that 8-TQ might have applications as a novel anti-cancer drug or may be served as a lead compound to be further optimized. 23411342 Synthesis and characterisation of nano structure lead (II) ion-imprinted polymer as a new sorbent for selective extraction and preconcentration of ultra trace amounts of lead ions from vegetables, rice, and fish samples. This paper describes the preparation of new Pb(II)-imprinted polymeric particles using 2-vinylpyridine as a functional monomer, ethylene glycol dimethacrylate as the cross-linker, 2,2'- azobisisobutyronitrile as the initiator, diphenylcarbazone as the ligand, acetonitril as the solvent, and Pb(NO(3))(2) as the template ion, through bulk polymerisation technique. The imprinted lead ions were removed from the polymeric matrix using 5 mL of HCl (2 mol.L(-1)) as the eluting solvent. The lead ion concentration was determined by flame atomic absorption spectrometry. Optimum pH for maximum sorption was obtained at 6.0. Sorption and desorption of Pb(II) ions on the IIP particles were quite fast and achieved fully over 5 min. In the proposed method, the maximum sorbent capacity of the ion-imprinted polymer was calculated to be 75.4 mg g(-1). The preconcentration factor, relative standard deviation, and limit of detection of the method were found to be 245, 2.1%, and 0.42 ng mL(-1), respectively. The prepared ion-imprinted polymer particles have an increased selectivity toward Pb(II) ions over a range of competing metal ions with the same charge and similar ionic radius. This ion-imprinted polymer is an efficient solid phase for extraction and preconcentration of lead ions in complex matrixes. For proving that the proposed method is reliable, a wide range of food samples with different and complex matrixes was used. 23633529 Characterization of Recombinantly Expressed Rat and Monkey Intestinal Alkaline Phosphatases: In Vitro Studies and In Vivo Correlations. Intestinal alkaline phosphatases (IALPs) are widely expressed in the brush border of epithelial cells of the intestinal mucosa. Although their physiological role is unclear, they are very significant when it comes to the release of bioactive parent from orally dosed phosphate prodrugs. Such prodrugs can be resistant to cleavage by IALP, or alternatively undergo rapid cleavage leading to the release and precipitation of the less soluble parent. Because purified IALPs from pre-clinical species are not commercially available, and species differences have not been investigated to date, an effort was made to recombinantly express, purify and characterize rat and cynomolgus monkey IALP (rIALP). Specifically, rIALP-catalyzed cleavage of five prodrugs (fosphenytoin, clindamycin phosphate, dexamethasone phosphate, ritonavir phosphate and ritonavir oxymethyl phosphate) was tested in vitro and parent exposure was assessed in vivo (rat only) following an oral dose of each prodrug. It was determined that the rate of phosphate cleavage in vitro varied widely; direct phosphates were more resistant to bioconversion, whereas faster conversion was observed with oxymethyl linked prodrugs. Overall, the rat rIALP-derived data were qualitatively consistent with in-vivo data; prodrugs that were readily cleaved in vitro rendered higher parent drug exposure in vivo. Of the five prodrugs tested, one (ritonavir phosphate) showed no conversion in vitro and minimal parent exposure in vivo. Finally, the apparent Km values obtained for fosphenytoin and clindamycin phosphate in vitro suggest that IALP is not likely to be saturated at therapeutic doses. 23624240 In vitro assessment of cobalt oxide particle toxicity: Identifying and circumventing interference. The continuing development of nanotechnology necessitates the reliable assessment of potential adverse health consequences associated with human exposures. The physicochemical properties of nanomaterials can be responsible for unexpected interactions with components of classical toxicity assays, which may generate erroneous interpretations. In this paper, we describe how particle interference can be observed in in vitro toxicity tests (CellTiter Blue, CyQUANT, WST-1 and CellTiter-Glo assay) and in cell biology tests using flow cytometry (cell cycle analysis). We used cobalt oxide (Co3O4) particles as an example, but these assays can be performed, in principle, regardless of the nanoparticle considered. We have shown that cobalt particles interfere with most of these tests. We adapted the protocol of the CellTiter-Glo assay to circumvent this interference and demonstrated that, using this protocol, the toxicity level is consistent with results obtained using the clonogenic assay, which is considered to be the reference test. Before assessing particle toxicity using in vitro toxicity tests, interference testing should be performed to avoid false interpretations. Furthermore, in some cases of interference, protocol adaptation can be considered to allow the reliable use of these quick and convenient in vitro tests. 23606278 Beyond Statins: Lipid Management to Reduce Cardiovascular Risk. The discovery that elevated total cholesterol levels and the subsequent understanding that low-density lipoprotein cholesterol levels are associated with higher risk for cardiovascular disease (CVD) has led to the development of lipid management strategies that seek to reduce the burden of CVD. Although substantive progress has been made in reducing death and cardiovascular events, questions remain regarding the optimal approach to further reduce CVD-associated death and disability. Based on current evidence, statins are the clear first-line agents for the management of hyperlipidemia in patients at high risk for cardiovascular events. However, due to the failure of recent clinical trials evaluating antihyperlipidemic drugs, the most appropriate lipid management strategy in patients who cannot tolerate statin therapy or who warrant antihyperlipidemic therapies in addition to statins is a major therapeutic controversy. In this review, we summarize the clinical trial evidence evaluating the efficacy of second-line antihyperlipidemic drug classes for reducing cardiovascular risk, provide recommendations for appropriate use of nonstatin lipid-altering drugs, and identify key areas of future research to support evidence-based lipid management. Given the complexity, magnitude, and burden of CVD, opportunities to improve processes of care and identify new therapeutic options clearly exist. 23584541 Synthesis of 3-O-propargylated betulinic acid and its 1,2,3-triazoles as potential apoptotic agents. Cytotoxic agents from nature are presently the mainstay of anticancer chemotherapy, and the need to reinforce the arsenal of anticancer agents is highly desired. Chemical transformation studies carried out on betulinic acid, through concise 1,2,3-triazole synthesis via click chemistry approach at C-3position in ring A have been evaluated for their cytotoxic potentiation against nine human cancer cell lines. Most of the derivatives have shown higher cytotoxic profiles than the parent molecule. Two compounds i.e. 3{1N(2-cyanophenyl)-1H-1,2,3-triazol-4yl}methyloxy betulinic acid (7) and 3{1N(5-hydroxy-naphth-1yl)-1H-1,2,3-triazol-4yl}methyloxy betulinic acid (13) displayed impressive IC50 values (2.5 and 3.5 μM respectively) against leukemia cell line HL-60 (5-7-fold higher potency than betulinic acid). As evident from various biological end points, inhibition of cell migration and colony formation, mitochondrial membrane disruption followed by DNA fragmentation and apoptosis, is demonstrated. 22903180 RETRACTED: Effects of nanometer-sized silver materials on survival response of Caspian roach (Rutilus rutilus caspicus). RETRACTED. 23426718 Anti-inflammatory profile of paricalcitol in hemodialysis patients: a prospective, open-label, pilot study. Inflammation is a strong predictor of increased morbidity and mortality in hemodialysis (HD) patients. Paricalcitol, a selective vitamin D receptor activator used for prevention and treatment of secondary hyperparathyroidism, has shown anti-inflammatory properties in experimental studies, although clinical data are scarce. In an open-label, prospective, single center, pilot study, 25 stable HD patients, previously receiving calcitriol, completed 12 weeks of therapy with oral paricalcitol. Serum and peripheral blood mononuclear cell (PBMC) expression profiles of inflammatory cytokines were analyzed. Serum interleukin (IL)-1, IL-10, and IL-18 did not change, unlike high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), and IL-6, which experienced a significant mean percent decrease of 14.3%, 4.7%, and 5%, respectively. There was a significant reduction in the TNF-α/IL-10 and the IL-6/IL-10 ratios (P < .05). Serum intact parathyroid hormone concentration experienced a mild but significant reduction. In addition, expression levels of TNF-α and IL-6 decreased by 19.1% (P < .01) and 17.5% (P < .001), respectively, whereas expression of IL-10 increased by 17.7% (P < .01) after treatment. In conclusion, paricalcitol administration to HD patients is associated with a beneficial effect on the inflammatory cytokine serum and gene expression profile of PBMC. This effect may contribute to the survival benefits of paricalcitol observed in clinical studies. 23232461 Toxicity of organotin compounds: shared and unshared biochemical targets and mechanisms in animal cells. Most biochemical effects of organotin compounds leading to toxicity are astonishingly similar in different animal species. In vitro tests, designed to explore organotin action modes at cell level by minimizing interfering factors, point out akin responses to these man-made environmental pollutants from prokaryotes to mammals. On the other hand, a broad susceptibility range to organotin toxicants of animal cells and variegated action mechanisms of these compounds have been reported both in vitro and in vivo studies. Endocrine and lipid homeostasis perturbations span from mollusks to mammals, in which organotins mainly favor fat accumulation. Lipid changes were also found in Bacteria. Organotin are immunotoxic both in invertebrates and humans. Mitochondria and membrane functions seem to be a preferred target of these lipophilic pollutants. The inhibition of key membrane-bound enzyme complexes such as Na,K-and F0F1-ATPases, accompanied by perturbation of hydromineral balance, membrane potential and bioenergetics, has been widely reported. Highly conserved mechanisms could be involved in organotin binding to nuclear receptors, membrane components and intracellular proteins as well as in promoting DNA damage, all widely shared action modes of these toxicants. Accordingly, the different responsiveness/refractoriness to organotins, here overviewed, may mirror the biochemical-physiological selectivity of biomembranes, signalling pathways and intracellular protein components. 23286198 Using binary surfactant mixtures to simultaneously improve the dimensional tunability and monodispersity in the seeded growth of gold nanorods. We report a dramatically improved synthesis of colloidal gold nanorods (NRs) using a binary surfactant mixture composed of hexadecyltrimethylammonium bromide (CTAB) and sodium oleate (NaOL). Both thin (diameter <25 nm) and thicker (diameter >30 nm) gold NRs with exceptional monodispersity and broadly tunable longitudinal surface plasmon resonance can be synthesized using seeded growth at reduced CTAB concentrations (as low as 0.037 M). The CTAB-NaOL binary surfactant mixture overcomes the difficulty of growing uniform thick gold NRs often associated with the single-component CTAB system and greatly expands the dimensions of gold NRs that are accessible through a one-pot seeded growth process. Gold NRs with large overall dimensions and thus high scattering/absorption ratios are ideal for scattering-based applications such as biolabeling as well as the enhancement of optical processes. 23395826 Support vector machine: Classifying and predicting mutagenicity of complex mixtures based on pollution profiles. Powerful, robust in silico approaches offer great promise for classifying and predicting biological effects of complex mixtures and for identifying the constituents of greatest concern. Support vector machine (SVM) methods can deal with high dimensional data and small sample size and examine multiple interrelationships among samples. In this work, we applied SVM methods to examine pollution profiles and mutagenicity of 60 water samples obtained from 6 cities in China during 2006-2011. Pollutant profiles were characterized in water extracts by gas chromatography-mass spectrometry (GC/MS) and mutagenicity examined by Ames assays. We encoded feature vectors of GS-MS peaks in the mixtures and used 48 samples as the training set, reserving 12 samples as the test set. The SVM model and regression were constructed from whole pollution profiles that ranked compounds in relation to their correlation to the mutagenicity. Both classification and prediction performance were evaluated. The SVM model based on whole pollution profiles showed lower performance (sensitivity, specificity, accuracy and correlation coefficient were 69.5-70.7%, 70.6-73.2%, 69.9-72.1%, and 0.55-0.59%, respectively) than one based on compounds with highest association with mutagenicity. A SVM model with the top 10 compounds had the highest performance (sensitivity, specificity, accuracy, and correlation coefficient were 89.8-90.3%, 90.1-92.1%, 90.1-91.3%, and 0.80-0.82%, respectively), with negligible decreases in performance between the test and training set. SVM can be a powerful, robust classifier of the relationship of pollutants and mutagenicity in complex real-world mixtures. The top 14 compounds have the greatest contribution to mutagenicity and deserve further studies to identify these constituents. 23603293 Toluquinol, a marine fungus metabolite, is a new angiosuppresor that interferes the Akt pathway. Toluquinol, a methylhydroquinone produced by a marine fungus, was selected in the course of a blind screening for new potential inhibitors of angiogenesis. In the present study we provide the first evidence that toluquinol is a new anti-angiogenic-compound. In a variety of experimental systems, representing the sequential events of the angiogenic process, toluquinol treatment of activated endothelial cells resulted in strong inhibitory effect. Toluquinol inhibited the growth of endothelial and tumor cells in culture in the micromolar range. Our results indicate that the observed growth inhibitory effect could be due, at least in part, to an induction of apoptosis. Toluquinol induced endothelial cell death is mediated via apoptosis after a cell cycle block and caspase activation. Capillary tube formation on Matrigel and migratory, invasive and proteolytic capabilities of endothelial cells were inhibited by addition of toluquinol at subtoxic concentrations. Inhibition of the mentioned essential steps of in vitro angiogenesis agrees with the observed inhibition of the in vivo angiogenesis, substantiated by using the chick chorioallatoic membrane assay and confirmed by the murine Matrigel plug, the zebrafish embryo neovascularization and the zebrafish caudal fin regeneration assays. Data here shown altogether indicate that toluquinol has antiangiogenic effects both in vitro and in vivo that are exerted partly by suppression of the VEGF and FGF-induced Akt activation of endothelial cells. These effects are carried out at lower concentrations to those required for other inhibitors of angiogenesis, what makes toluquinol a promising drug candidate for further evaluation in the treatment of cancer and other angiogenesis-related pathologies. 23447132 Exchange protein directly activated by cAMP (epac): a multidomain cAMP mediator in the regulation of diverse biological functions. Since the discovery nearly 60 years ago, cAMP is envisioned as one of the most universal and versatile second messengers. The tremendous feature of cAMP to tightly control highly diverse physiologic processes, including calcium homeostasis, metabolism, secretion, muscle contraction, cell fate, and gene transcription, is reflected by the award of five Nobel prizes. The discovery of Epac (exchange protein directly activated by cAMP) has ignited a new surge of cAMP-related research and has depicted novel cAMP properties independent of protein kinase A and cyclic nucleotide-gated channels. The multidomain architecture of Epac determines its activity state and allows cell-type specific protein-protein and protein-lipid interactions that control fine-tuning of pivotal biologic responses through the "old" second messenger cAMP. Compartmentalization of cAMP in space and time, maintained by A-kinase anchoring proteins, phosphodiesterases, and β-arrestins, contributes to the Epac signalosome of small GTPases, phospholipases, mitogen- and lipid-activated kinases, and transcription factors. These novel cAMP sensors seem to implement certain unexpected signaling properties of cAMP and thereby to permit delicate adaptations of biologic responses. Agonists and antagonists selective for Epac are developed and will support further studies on the biologic net outcome of the activation of Epac. This will increase our current knowledge on the pathophysiology of devastating diseases, such as diabetes, cognitive impairment, renal and heart failure, (pulmonary) hypertension, asthma, and chronic obstructive pulmonary disease. Further insights into the cAMP dynamics executed by the Epac signalosome will help to optimize the pharmacological treatment of these diseases. 23568274 Pediatric relapsed or refractory leukemia: new pharmacotherapeutic developments and future directions. Over the past 50 years, numerous advances in treatment have produced dramatic increases in the cure rates of pediatric leukemias. Despite this progress, the majority of children with relapsed leukemia are not expected to survive. With current chemotherapy regimens, approximately 15 % of children with acute lymphoblastic leukemia and 45 % of children with acute myeloid leukemia will have refractory disease or experience a relapse. Advances in the treatment of pediatric relapsed leukemia have not mirrored the successes of upfront therapy, and newer treatments are desperately needed in order to improve survival in these challenging patients. Recent improvements in our knowledge of cancer biology have revealed an extensive number of targets that have the potential to be exploited for anticancer therapy. These advances have led to the development of a number of new treatments that are now being explored in children with relapsed or refractory leukemia. Novel agents seek to exploit the same molecular aberrations that contribute to leukemia development and resistance to therapy. Newer classes of drugs, including monoclonal antibodies, tyrosine kinase inhibitors and epigenetic modifiers are transforming the treatment of patients who are not cured with conventional therapies. As the side effects of many new agents are distinct from those seen with conventional chemotherapy, these treatments are often explored in combination with each other or combined with conventional treatment regimens. This review discusses the biological rationale for the most promising new agents and the results of recent studies conducted in pediatric patients with relapsed leukemia. 23552899 High responsivity, fast ultraviolet photodetector fabricated from ZnO nanoparticle-graphene core-shell structures. We report a simple, efficient and versatile method for assembling metal oxide nanomaterial-graphene core-shell structures. An ultraviolet photodetector fabricated from the ZnO nanoparticle-graphene core-shell structures showed high responsivity and fast transient response, which are attributed to the improved carrier transport efficiency arising from graphene encapsulation. 23147837 Experimental exposure of eggs to polybrominated diphenyl ethers BDE-47 and BDE-99 in red-eared sliders (Trachemys scripta elegans) and snapping turtles (Chelydra serpentina) and possible species-specific differences in debromination. Polybrominated diphenyl ethers (PBDEs) are a bioaccumulative, persistent, and toxic class of flame retardants that can potentially impact turtles in natural habitats via exposure through maternal transfer. To simulate maternal transfer in the present study, PBDE congeners BDE-47 and BDE-99 were topically applied to the eggshell and were allowed to diffuse into the egg contents of the red-eared slider (Trachemys scripta elegans) and snapping turtle (Chelydra serpentina). Eggs were topically dosed over 8 d to achieve a target concentration of 40 ng/g in the egg contents. Transfer efficiency was higher for BDE-47 than for BDE-99 in the red-eared sliders (25.8 ± 1.9% vs 9.9 ± 1.1%) and snapping turtles (31.3 ± 1.6% vs 12.5 ± 1.4%), resulting in greater BDE-47 and lower BDE-99 egg content concentrations relative to the 40 ng/g target. However, only 25.8 and 31.3% of the total BDE-47 and 9.9 and 12.5% of the total BDE-99 dose applied could be accounted for in the red-eared slider and snapping turtle egg contents, respectively. Additionally, increased BDE-47 in red-eared slider egg contents dosed with only BDE-99 indicate that BDE-99 might have been debrominated to BDE-47. The efficacy of topical dosing for administering desired embryonic exposures is clearly affected by the chemical properties of the applied compounds and was more successful for BDE-47 in both species. 23512409 Impact of DNA Sequence and Oligonucleotide Length on a Polythiophene-Based Fluorescent DNA Biosensor. DNA hybridization is a universal and specific mechanism for the recognition of biological targets. Some cationic polythiophene transducers sensitive to DNA structure have been previously utilized to detect such biomolecules. Further characterization of these systems indicates that both DNA sequence composition and length modulate the biosensor performance. It appears that different repeated sequence patterns cause different conformational changes of the polythiophene, from a more relaxed form to an extremely rigid one. A length difference between the DNA oligonucleotide probe and target has a detrimental effect on the fluorescent signal, but it can be attenuated by changing the sequence composition of the protruding target sequence. This demonstrates that the nature of DNA can be critical for hybridization-based detection systems. 23631732 Hydrodynamic Effects on the Relative Rotational Velocity of Associating Proteins. Hydrodynamic steering effects on the barnase-barstar association were studied through the analysis of the proteins' relative rotational velocity. We considered the two proteins approaching each other in a response to their electrostatic attraction and employed a method that accounts for the long range and the many-body character of hydrodynamic interactions as well as complicated shapes of proteins. Hydrodynamic steering effects are clearly seen when attractive forces are applied to proteins geometric centers (resulting in zero torques) and the attraction acts along the line that connects centers of geometry of proteins in their crystallographic complex. When we rotate barstar relative to barnase around this line by an angle in the range of (-90(o),60(o)), the rotational velocity arising solely due to hydrodynamic interactions restores orientation of proteins that is observed in the crystal structure. However, as in reality both electrostatic forces and torques act on proteins, and these forces and torques depend on protein-protein distance and the relative orientation of binding partners, we investigated also more realistic situations employing continuum electrostatics calculations based on atomistic proteins models. Overall, we conclude that hydrodynamic interactions aid barnase and barstar in assuming a proper relative orientation upon complex formation. 23542720 Leptin as regulator of pulmonary immune responses: Involvement in respiratory diseases. Leptin is an adipocyte-derived hormone, recognized as a critical mediator of the balance between food intake and energy expenditure by signalling through its functional receptor (Ob-Rb) in the hypothalamus. Structurally, leptin belongs to the long-chain helical cytokine family, and is now known to have pleiotropic functions in both innate and adaptive immunity. The presence of the functional leptin receptor in the lung together with evidence of increased airspace leptin levels arising during pulmonary inflammation, suggests an important role for leptin in lung development, respiratory immune responses and eventually pathogenesis of inflammatory respiratory diseases. The purpose of this article is to review our current understanding of leptin and its functional role on the different resident cell types of the lung in health as well as in the context of three major respiratory conditions being chronic obstructive pulmonary disease (COPD), asthma, and pneumonia. 23238783 The influence of sex, ethnicity, and CYP2B6 genotype on bupropion metabolism as an index of hepatic CYP2B6 activity in humans. The effects of sex, ethnicity, and genetic polymorphism on hepatic CYP2B6 (cytochrome P450 2B6) expression and activity were previously demonstrated in vitro. Race/ethnic differences in CYP2B6 genotype and phenotype were observed only in women. To identify important covariates associated with interindividual variation in CYP2B6 activity in vivo, we evaluated these effects in healthy volunteers using bupropion (Wellbutrin SR GlaxoSmithKline, Research Triangle Park, NC) as a CYP2B6 probe substrate. A fixed 150-mg oral sustained-release dose of bupropion was administered to 100 healthy volunteers comprising four sex/ethnicity cohorts (n = 25 each): Caucasian men and Caucasian, African American, and Hispanic women. Blood samples were obtained at 0 and 6 hours postdose for the measurement of serum bupropion (BU) and hydroxybupropion (HB) concentrations. Whole blood was obtained at baseline for CYP2B6 genotyping. To characterize the relationship between CYP2B6 activity and ethnicity, sex, and genotype when accounting for serum BU concentrations (dose-adjusted log(10)-transformed), analysis of covariance model was fitted in which the dependent variable was CYP2B6 activity represented as the log(10)-transformed, metabolic ratio of HB to BU concentrations. Several CYP2B6 polymorphisms were associated with CYP2B6 activity. Evidence of dependence of CYP2B6 activity on ethnicity or genotype-by-ethnicity interactions was not detected in women. These results suggest that CYP2B6 genotype is the most important patient variable for predicting the level of CYP2B6 activity in women, when measured by the metabolism of bupropion. The bupropion metabolic ratio appears to detect known differences in CYP2B6 activity associated with genetic polymorphism, across different ethnic groups. Prospective studies will be needed to validate the use of bupropion as a probe substrate for clinical use. 23238235 Mutagenic/recombinogenic effects of four lipid peroxidation products in Drosophila. The human diet is an important factor in the development of different diseases. Lipid peroxidation during frying in edible vegetable liquid oils of food components is a mechanism leading to the formation of free radicals. Such radicals induce tissue damage and are implicated in diverse pathological conditions, including aging, atherosclerosis, brain disorders, cancer, lung disorders and various liver disorders. In the present study, we decided to investigate the genotoxic effects of four lipid peroxidation products in the in vivo Drosophila wing somatic mutation and recombination test. In this test, point mutation, chromosome breakage and mitotic recombination produce single spots; while twin spots are produced only by mitotic recombination. Drosophila is a suitable eukaryotic organism for mutagenicity studies and also its metabolism is quite similar to that of mammalians. Since conflicting data exist on the possible risk of several lipid peroxidation products for humans, we have selected four of them, namely acrolein, crotonaldehyde, 4-hydroxy-hexenal (4-HHE) and 4-oxo-2-nonenal (4-ONE). Especially at the highest concentrations tested all exert both mutagenic and recombinogenic effects in the Drosophila SMART assay, showing a direct dose-effect relationship. This is the first study reporting genotoxicity data in Drosophila for these compounds. 23578610 Inhibitory effect of skullcap (Scutellaria baicalensis) extract on ovalbumin permeation in vitro and in vivo. Scutellaria baicalensis Georgi (skullcap) has been widely used as a dietary ingredient. The purpose of this study was to reveal novel function of skullcap and its mechanism on allergen permeation in intestinal epithelial cells. Intestinal epithelial Caco-2 cell monolayers were used to evaluate the inhibitory effect of skullcap on ovalbumin (OVA) permeation by measuring transepithelial electrical resistance (TEER) and the quantity of permeated OVA. TEER increased and the OVA flux decreased in a dose-dependent manner through up-regulating tight junction-related proteins in cells incubated with increasing concentrations of skullcap extract. In the in vivo study, the amounts of OVA from orally ingested albumen reduced on administration of the skullcap extract. We also revealed for the first time that the active component of skullcap extract for inhibition of OVA permeation was baicalein. These findings demonstrated that skullcap extract might attenuate a food allergic response by inhibiting allergen permeation in vitro and in vivo. 23376712 Comparison of the effects of the GABAB receptor positive modulator BHF177 and the GABAB receptor agonist baclofen on anxiety-like behavior, learning, and memory in mice. γ-Aminobutyric acid B (GABAB) receptor activation is a potential therapeutic approach for the treatment of drug addiction, pain, anxiety, and depression. However, full agonists of this receptor induce side-effects, such as sedation, muscle relaxation, tolerance, and cognitive disruption. Positive allosteric modulators (PAMs) of the GABAB receptor may have similar therapeutic effects as agonists with superior side-effect profiles. The present study behaviorally characterized N-([1R,2R,4S]-bicyclo[2.2.1]hept-2-yl)-2-methyl-5-(4-[trifluoromethyl]phenyl)-4-pyrimidinamine (BHF177), a GABAB receptor PAM, in mouse models of anxiety-like behavior, learning and memory. In addition, the effects of BHF177 were compared with the agonist baclofen. Unlike the anxiolytic chlordiazepoxide, baclofen (0.5, 1.5, and 2.5 mg/kg, intraperitoneally) and BHF177 (10, 20, and 40 mg/kg, orally) had no effect on anxiety-like behavior in the elevated plus maze, light/dark box, or Vogel conflict test. Baclofen increased punished drinking in the Vogel conflict test, but this effect may be attributable to the analgesic actions of baclofen. At the highest dose tested (2.5 mg/kg), baclofen-treated mice exhibited sedation-like effects (i.e., reduced locomotor activity) across many of the tests, whereas BHF177-treated mice exhibited no sedation-like effects. BHF177 exhibited pro-convulsion properties only in mice, but not in rats, indicating that this effect may be species-specific. At doses that were not sedative or pro-convulsant, baclofen and BHF177 had no selective effects on fear memory retrieval in contextual and cued fear conditioning or spatial learning and memory in the Barnes maze. These data suggest that BHF177 has little sedative activity, no anxiolytic-like profile, and minimal impairment of learning and memory in mice. 23373544 Schisandra lignans-loaded enteric nanoparticles: preparation, characterization, and in vitro-in vivo evaluation. Schisandrae lignans (SL) have been well proven to possess hepatoprotective effect against the hepatic dysfunction induced by various chemical hepatotoxins. Deoxyschisandrin (DA) and schisantherin A (SA) are both considered as the major active components in SL. The objective of the study was to prepare and evaluate Schisandra lignans (composed of DA and SA)-loaded enteric nanoparticles produced by a novel toxic solvent-free modified spontaneous emulsification solvent diffusion (SESD) method. An organic Schisandra lignans/Eudragit(®) S100 solution was injected into an aqueous poloxamer 188 solution under a agitation. The nanoparticles were characterized with respect to particle size distribution, morphology, encapsulation efficiency (EE) and physical stability of the drug, wettability, in vitro release and in vivo bioavailability. Nanoparticles with a smooth surface and dense structure were obtained with high EE (EE(DA) >90%; EE(SA) >85%). The drug was in a noncrystalline state in the matrix and physically stable for 120 days at room temperature. In vitro drug release study, the drug dissolution rate from the nanoparticles was significantly enhanced compared to the physical mixture and to the pure drug; the release profile of the nanoparticles was stable after 120 days. The appropriate size of nanoparticles (~93 nm), the solubilization of the surfactant, the noncrystalline state of the drug in the matrix and the fast dissolution rate contributed to a significantly enhanced oral bioavailability from the nanoparticles when compared to pure drug suspension. 23602903 Monoterpene pyridine alkaloids and phenolics from Scrophularia ningpoensis and their cardioprotective effect. Scrophularianines A-C (1-3), three new unusual monoterpene pyridine alkaloids with cyclopenta [c] pyridine skeleton reported from the genus Scrophularia for the first time, together with 15 known compounds (4-18), were isolated from the extract of Scrophularia ningpoensis. Their structures were elucidated on the basis of extensive analyses of spectroscopic evidences. The biogenetic relationship between monoterpene pyridine alkaloids and iridoids was proposed preliminarily. The myocardial protective bioassay indicated that compounds 13 and 14 with a concentration of 10(-4)M exhibited significantly protective effect against H2O2-induced apoptosis in cardiomyocytes. 23603339 Dehydroepiandrosterone post-transcriptionally modifies CYP1A2 induction involving androgen receptor. The pharmacological dosage of dehydroepiandrosterone (DHEA) protects against chemically induced carcinogenesis. The chemoprotective activity of DHEA is attributed to its inhibitory potential for the expression of CYP1A enzymes, which are highly responsible for metabolic activation of several mutagenic and carcinogenic chemicals. The present work investigated whether the chemoprevention by DHEA was due to diminished transcriptional activation of CYP1A genes or to the post-transcriptional modulation of CYP1A expression. In primary human hepatocytes, DHEA diminished the increase in CYP1A activities (7-ethoxyresorufin O-dealkylation and phenacetin O-dealkylation) and in CYP1A2 mRNA level induced by 3-methylcholanthrene, but did not alter the amount of CYP1A1 and CYP1B1 mRNA. The androgen receptor seemed to be involved in DHEA-mediated diminishment of CYP1A2 induction, which was attenuated in the presence of bicalutamide, the androgen receptor antagonist. The potential role of the glucocorticoid receptor and estrogen receptor in DHEA-mediated decrease in CYP1A2 induction was excluded. The developed computational model of CYP1A2 induction kinetics and CYP1A2 mRNA degradation proposed that a post-transcriptional mechanism was likely to be the primary mechanism of the DHEA-mediated diminishment of CYP1A2 induction. The hypothesis was confirmed by the results of actinomycin D-chase experiments in MCF-7 and LNCaP cells, displaying that the degradation rates of CYP1A2 mRNA were significantly higher in the cells exposed to DHEA. The novel findings on DHEA-mediated modulation of CYP1A2 mRNA stability may account for the beneficial effects of DHEA by decreasing the metabolic activation of pro-carcinogenic compounds. 23296100 Manganese-induced oxidative DNA damage in neuronal SH-SY5Y cells: attenuation of thymine base lesions by glutathione and N-acetylcysteine. Manganese (Mn) is an essential trace element required for normal function and development. However, exposure to this metal at elevated levels may cause manganism, a progressive neurodegenerative disorder with neurological symptoms similar to idiopathic Parkinson's disease (IPD). Elevated body burdens of Mn from exposure to parental nutrition, vapors in mines and smelters and welding fumes have been associated with neurological health concerns. The underlying mechanism of Mn neurotoxicity remains unclear. Accordingly, the present study was designed to investigate the toxic effects of Mn(2+) in human neuroblastoma SH-SY5Y cells. Mn(2+) caused a concentration dependent decrease in SH-SY5Y cellular viability compared to controls. The LD50 value was 12.98 μM Mn(2+) (p<0.001 for control vs. 24h Mn treatment). Both TUNEL and annexin V/propidium iodide (PI) apoptosis assays confirmed the induction of apoptosis in the cells following exposure to Mn(2+) (2 μM, 62 μM or 125 μM). In addition, Mn(2+) induced both the formation and accumulation of DNA single strand breaks (via alkaline comet assay analysis) and oxidatively modified thymine bases (via gas chromatography/mass spectrometry analysis). Pre-incubation of the cells with characteristic antioxidants, either 1mM N-acetylcysteine (NAC) or 1mM glutathione (GSH) reduced the level of DNA strand breaks and the formation of thymine base lesions, suggesting protection against oxidative cellular damage. Our findings indicate that (1) exposure of SH-SY5Y cells to Mn promotes both the formation and accumulation of oxidative DNA damage, (2) SH-SY5Y cells with accumulated DNA damage are more likely to die via an apoptotic pathway and (3) the accumulated levels of DNA damage can be abrogated by the addition of exogenous chemical antioxidants. This is the first known report of Mn(2+)-induction and antioxidant protection of thymine lesions in this SH-SY5Y cell line and contributes new information to the potential use of antioxidants as a therapeutic strategy for protection against Mn(2+)-induced oxidative DNA damage. 23147415 Mice heterozygous for AChE are more sensitive to AChE inhibitors but do not respond to BuChE inhibition. An impaired central cholinergic system is at least partly involved in Alzheimer's disease (AD) pathogenesis, with cholinergic markers such as acetylcholinesterase (AChE) activity and protein levels decreasing as cognitive decline progresses. AD patients receive AChE inhibitor drugs to enhance cholinergic responses in the brain. The present study characterises the cholinergic system of mice heterozygous for AChE (HZ) as a suitable in vivo model for permanently reduced AChE activity. In comparison to homozygous, wild type (WT) mice, HZ mice show a 40% reduction of AChE activity in the brain, while their hippocampal ACh levels are increased by 56% as measured by microdialysis; choline acetyltransferase levels remain unaltered, and choline uptake increases 2-fold. We demonstrate that HZ mice are significantly more sensitive to local AChE inhibition (BW284c51), but remain insensitive to butyrylcholinesterase (BuChE) inhibition (bambuterol). HZ mice are also more sensitive to the peripheral application of the selective AChE inhibitor donepezil or the mixed inhibitor physostigmine; extracellular ACh levels rise significantly after administration of both drugs; also glucose levels are moderately increased indicating potentially non-cholinergic effects of donepezil. Behavioural tests show comparable cognitive function in both mouse strains. Our results are discussed in relation to the use of AChE/BuChE inhibitors in AD patients. 23017389 Studies on the antioxidant potential of flavones of Allium vineale isolated from its water-soluble fraction. The aim of this work was to examine the chemical constituents and antioxidant potential of water-soluble fractions from the commonly consumed vegetable, Allium vineale. The water-soluble fraction, containing phenolic compounds, was extracted with ethyl acetate to obtain flavonoids which were separated and purified by repeated column chromatography over Sephadex LH-20, RP C18 and silica gel. The isolated compounds were identified according to their physicochemical properties and spectral data (UV, HPLC-TOF/MS, (1)H NMR, (13)C NMR and 2D NMR). Three flavonoids were isolated and identified as chrysoeriol-7-O-[2″-O-E-feruloyl]-β-d-glucoside (1), chrysoeriol (2), and isorhamnetin-3-β-d-glucoside (3). Antioxidant studies of the aqueous extract and three isolated compounds, 1, 2, 3, were undertaken and they were found to have significant antioxidant activity. Antioxidant activities were evaluated for total antioxidant activity by the ferric thiocyanate method, ferric ion (Fe(3+)) reducing antioxidant power assay (FRAP), ferrous ion (Fe(2+)) metal chelating activity, and DPPH free radical-scavenging activity. The water-soluble ethyl acetate and methanol extraction methods were also compared using HPLC-TOF/MS. 23290724 Zinc drives a tertiary fold in the prion protein with familial disease mutation sites at the interface. The cellular prion protein PrP(C) consists of two domains--a flexible N-terminal domain, which participates in copper and zinc regulation, and a largely helical C-terminal domain that converts to β sheet in the course of prion disease. These two domains are thought to be fully independent and noninteracting. Compelling cellular and biophysical studies, however, suggest a higher order structure that is relevant to both PrP(C) function and misfolding in disease. Here, we identify a Zn²⁺-driven N-terminal to C-terminal tertiary interaction in PrP(C). The C-terminal surface participating in this interaction carries the majority of the point mutations that confer familial prion disease. Investigation of mutant PrPs finds a systematic relationship between the type of mutation and the apparent strength of this domain structure. The structural features identified here suggest mechanisms by which physiologic metal ions trigger PrP(C) trafficking and control prion disease. 23465066 Highly Responsive Ultrathin GaS Nanosheet Photodetectors on Rigid and Flexible Substrates. The first GaS nanosheet-based photodetectors are demonstrated on both mechanically rigid and flexible substrates. Highly crystalline, exfoliated GaS nanosheets are promising for optoelectronics due to strong absorption in the UV-visible wavelength region. Photocurrent measurements of GaS nanosheet photodetectors made on SiO2/Si substrates and flexible polyethylene terephthalate (PET) substrates exhibit a photoresponsivity at 254 nm up to 4.2 AW(-1) and 19.2 AW(-1), respectively, which exceeds that of graphene, MoS2, or other 2D material-based devices. Additionally, the linear dynamic range of the devices on SiO2/Si and PET substrates are 97.7 dB and 78.73 dB, respectively. Both surpass that of currently exploited InGaAs photodetectors (66 dB). Theoretical modeling of the electronic structures indicates that the reduction of the effective mass at the valence band maximum (VBM) with decreasing sheet thickness enhances the carrier mobility of the GaS nanosheets, contributing to the high photocurrents. Double-peak VBMs are theoretically predicted for ultrathin GaS nanosheets (thickness less than five monolayers), which is found to promote photon absorption. These theoretical and experimental results show that GaS nanosheets are promising materials for high-performance photodetectors on both conventional silicon and flexible substrates. 23069619 A case study of real-time monitoring of solid-state phase transformations in acoustically levitated particles using near infrared and Raman spectroscopy. The objective of this study was to monitor the amorphous-to-crystalline solid-state phase transformation kinetics of the model drug ibuprofen with spectroscopic methods during acoustic levitation. Chemical and physical information was obtained by real-time near infrared (NIRS) and Raman spectroscopy measurements. The recrystallisation kinetic parameters (overall recrystallisation rate constant β and the time needed to reach 50% of the equilibrated level t(50)), were determined using a multivariate curve resolution approach. The acoustic levitation device coupled with non-invasive spectroscopy enabled monitoring of the recrystallisation process of the difficult-to-handle (adhesive) amorphous sample. The application of multivariate curve resolution enabled isolation of the underlying pure spectra, which corresponded well with the reference spectra of amorphous and crystalline ibuprofen. The recrystallisation kinetic parameters were estimated from the recrystallisation profiles. While the empirical recrystallisation rate constant determined by NIR and Raman spectroscopy were comparable, the lag time for recrystallisation was significantly lower with Raman spectroscopy as compared to NIRS. This observation was explained by the high energy density of the Raman laser beam, which might have led to local heating effects of the sample and thus reduced the recrystallisation onset time. It was concluded that acoustic levitation with NIR and Raman spectroscopy combined with multivariate curve resolution allowed direct determination of the recrystallisation kinetics of amorphous drugs and thus is a promising technique for monitoring solid-state phase transformations of adhesive small-sized samples during the early phase of drug development. 23216335 Platelet-derived microparticles in overweight/obese women with the polycystic ovary syndrome. A substantial proportion of women with the polycystic ovary syndrome (PCOS) are obese and obesity is considered as a prothrombotic state. Platelet-derived microparticles (PMPs) might be implicated in the activation of the coagulation cascade. We aimed to assess plasma PMPs in overweight/obese women with PCOS. We measured plasma PMPs and determined anthropometric, metabolic, hormonal and ultrasonographic features of PCOS in 67 overweight/obese women with PCOS (with body mass index [BMI] >25.0 kg/m(2)) and in 21 BMI-matched healthy women. Circulating androgens and markers of insulin resistance (IR) were higher in women with PCOS than in controls. Plasma PMPs were also higher in women with PCOS than in controls (p = 0.046). In women with PCOS, plasma PMPs correlated with the mean number of follicles in the ovaries (r = 0.343; p = 0.006). In controls, plasma PMPs did not correlate with any of the studied parameters. In conclusion, plasma PMPs are elevated in overweight/obese women with PCOS compared with BMI-matched controls. The cause of this increase is unclear but both IR and hyperandrogenemia might be implicated. More studies are required to elucidate the pathogenesis of the elevation of PMPs in PCOS and to assess its implications on the cardiovascular risk of these patients. 23408270 Anthelmintic activity of the natural compound (+)-limonene epoxide against Schistosoma mansoni. Blood fluke of the genus Schistosoma are the etiological agents of human schistosomiasis, an important neglected tropical disease that afflicts over 200 million people worldwide. The treatment for this disease relies heavily on a single drug, praziquantel. Recent reports of praziquantel resistance raise concerns about future control of the disease and show the importance of developing new antischistosomal drugs. Currently, natural products have been a good source for drug development. (+)-Limonene epoxide is a mixture of cis and trans isomers found in many plants. Here, we report the in vitro effect of this natural compound on the survival time of Schistosoma mansoni adult worms. In addition, we examined alterations on the tegumental surface of adult schistosomes by means of confocal laser scanning microscopy. The effects of (+)-limonene epoxide at 25 µg/mL on S. mansoni adult worms were similar to those of the positive control (praziquantel), with reduction in motility and death of all worms after 120 h. Confocal laser scanning microscopy revealed that (+)-limonene epoxide-mediated worm killing was associated with tegumental destruction. Our results, along with the low toxicity of the (+)-limonene epoxide, suggest that this natural compound might be promising for the development of new schistosomicidal agents. 23644200 Glycosylation enhances the anti-migratory activities of isomalyngamide A analogs. Three, new, fully synthetic glycosylated isomalyngamide A analogs 4-6 were prepared and evaluated for their anti-migratory activities in human breast cancer cells. The results of the study show that two glycosylated derivatives 4 and 5, containing mannose and galactose appendages, suppress metastatic events (e.g., migration, invasion and adhesion) in human breast adenocarcinoma MDA-MB-231 cells at "nontoxic" concentration levels. In contrast, derivative 6 that contains a lactose moiety, displays a less potent activity. The findings show that monosaccharide rather than disaccharide appendages to the isomalyngamide A backbone more greatly influence cell migration and invasive ability. Evidence has been gained for a mechanism for inhibition of metastatic activities in MDA-MB-231 cells by 4 and 5, involving inactivation of the expression of p-FAK and paxillin through the integrin-mediated antimetastatic pathway. 23361383 Role of diuretics and lipid formulations in the prevention of amphotericin B-induced nephrotoxicity. PURPOSE: To collect available clinical data to define the role of diuretics and lipid formulations in the prevention of amphotericin B (AmB)-induced nephrotoxicity (AIN) in human populations. METHOD: A literature search was performed in the following databases: Scopus, Medline, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. RESULTS AND CONCLUSION: Co-administration of mannitol failed to show any clinically significant benefit in preventing AIN. Potassium-sparing diuretics, such as amiloride and spironolactone, have been shown to have beneficial effects as an alternative or adjunct to oral/parenteral potassium supplements in preventing hypokalemia due to AmB. Lipid-based formulations of AmB are clinically effective and safe in preventing AIN. However, due to their high cost and limited accessibility, these formulations are generally used as second-line antifungal therapy in cases of conventional AmB refractoriness and/or intolerance or pre-existing renal dysfunction. The potential effects of other nephroprotective agents, such as N-acetylcysteine, AIN merit further considerations and investigations. 23295582 Novel topical formulations of Terbinafine-HCl for treatment of onychomycosis. Terbinafine hydrochloride (TBF-HCl) is an active substance that is using for treatment of onychomycosis. Onychomycosis is a fungal infection which is the most common disease of nail plate. The nail plate is a barrier which prevents effective topical treatment of ungual disorders. In this study, TBF-HCl loaded liposome and ethosome formulations and also gel form of these formulations were prepared. The formulations were characterized and in vitro and ex vivo release studies were performed. Nail characterization studies were also performed to examine the effect of formulations and experimental conditions on nail surface. As a result, all formulations can serve as efficient formulations for ungual application of TBF-HCl. By the way, the results of the accumulation studies suggested that liposome poloxamer gel formulation could be promising system for ungual drug delivery due to the better accumulation and easier application of the formulation. 23609445 YidC occupies the lateral gate of the SecYEG translocon and is sequentially displaced by a nascent membrane protein. Most membrane proteins are co-translationally inserted into the lipid bilayer via the universally conserved SecY complex and they access the lipid phase presumably via a lateral gate in SecY. In bacteria, the lipid transfer of membrane proteins from the SecY channel is assisted by the SecY-associated protein YidC, but details on the SecY-YidC interaction are unknown. By employing an in vivo and in vitro site-directed cross-linking approach, we have mapped the SecY-YidC interface and found YidC in contact with all four transmembrane domains of the lateral gate. This interaction did not require the SecDFYajC complex and was not influenced by SecA binding to SecY. In contrast, ribosomes dissociated the YidC contacts to lateral gate helices 2b and 8. The major contact between YidC and the lateral gate was lost in the presence of ribosome-nascent chains and new SecY-YidC contacts appeared. These data demonstrate that the SecY-YidC interaction is influenced by nascent-membrane induced lateral gate movements. 23220412 Comparative responses of two species of marine phytoplankton to metolachlor exposure. Metolachlor, a chloroacetanilide herbicide, has been frequently detected in coastal waters. This study examined the growth, photosynthesis, and detoxification responses of chlorophyte Dunaliella tertiolecta (DT) and brown tide alga Aureococcus anophagefferens (AA) upon 5-day exposure to 0.5-5 mg L(-1) metolachlor. Growth was assessed with exponential growth rate, and 5th day in vivo chlorophyll fluorescence, chlorophyll a, b or c, cell density and cell size. The photosynthesis function was assessed with photochemical parameters of photosystem II (PSII) during the mid-exponential growth phase (i.e. 2-4 day metolachlor exposure). The biochemical detoxification was analyzed with glutathione production and metolachlor degradation. Results show that metolachlor caused up to ∼9% inhibition in growth rate in both species and an expected ∼35% and 25% inhibition in chlorophyll based endpoints in DT and AA respectively. DT had an up to 70% inhibition in cell density, but AA a 35% hormesis at 1 mg L(-1) metolachlor and no significant inhibition, as compared to the controls. Both DT and AA's cell sizes were enlarged by metolachlor exposure, but greater in DT (1.2% per mg L(-1)) than in AA (0.68% per mg L(-1)). On PSII photochemistry, maximum quantum yield was not affected in both species; PSII optical cross section and connectivity factor increased in DT but decreased in AA, suggesting species specific impact on PSII function. On detoxification responses, glutathione production, when normalized to total chlorophyll a, was not affected by metolachlor in both species; further, despite of heterotrophic capacity of A. anophagefferens metolachlor was not significantly degraded by this alga during the 5-day incubation. The species specific effects on algal growth have ecological implications of potential selective inhibition of chlorophytes by metolachlor herbicide. 23466874 Anti-diabetic effects of brown algae derived phlorotannins, marine polyphenols through diverse mechanisms. Marine algae are popular and abundant food ingredients mainly in Asian countries, and also well known for their health beneficial effects due to the presence of biologically active components. The marine algae have been studied for biologically active components and phlorotannins, marine polyphenols are among them. Among marine algae, brown algae have extensively studied for their potential anti-diabetic activities. Majority of the investigations on phlorotannins derived from brown algae have exhibited their various anti-diabetic mechanisms such as α-glucosidase and α-amylase inhibitory effect, glucose uptake effect in skeletal muscle, protein tyrosine phosphatase 1B (PTP 1B) enzyme inhibition, improvement of insulin sensitivity in type 2 diabetic db/db mice, and protective effect against diabetes complication. In this review, we have made an attempt to discuss the various anti-diabetic mechanisms associated with phlorotannins from brown algae that are confined to in vitro and in vivo. 23338525 Highly effective Ir(x)Sn(1-x)O2 electrocatalysts for oxygen evolution reaction in the solid polymer electrolyte water electrolyser. We developed an advanced surfactant-assistant method for the Ir(x)Sn(1-x)O(2) (0 < x ≤ 1) nanoparticle (NP) preparation, and examined the OER performances by a series of half-cell and full-cell tests. In contrast to the commercial Ir black, the collective data confirmed the outstanding activity and stability of the fabricated Ir(x)Sn(1-x)O(2) (x = 1, 0.67 and 0.52) NPs, which could be ascribed to the amorphous structure, good dispersion, high pore volume, solid-solution state and Ir-rich surface for bi-metal oxides, and relatively large size (10-11 nm), while Ir(0.31)Sn(0.69) exhibited poor electro-catalytic activity because of the separated two phases, a SnO(2)-rich phase and an IrO(2)-rich phase. Furthermore, compared with highly active IrO(2), the improved durability, precious-metal Ir utilization efficiency and correspondingly reduced Ir loading were realized by the addition of Sn component. When the Ir(0.52)Sn(0.48)O(2) cell operated at 80 °C using Nafion® 115 membrane and less than 0.8 mg cm(-2) of the noble-metal Ir loading, the cell voltages we achieved were 1.631 V at 1000 mA cm(-2), and 1.821 V at 2000 mA cm(-2). The IR-free voltage at the studied current density was very close to the onset voltage of oxygen evolution. The only 50 μV h(-1) of voltage increased for the 500 h durability test at 500 mA cm(-2). In fact, these results are exceptional compared to the performances for OER in SPEWE cells known so far. This work highlights the potential of using highly active and stable IrO(2)-SnO(2) amorphous NPs to enhance the electrolysis efficiency, reduce the noble-metal Ir loading and thus the cost of hydrogen production from the solid polymer electrolyte water electrolysis. 23427064 Interactive effects of contaminants and climate-related stressors: High temperature increases sensitivity to cadmium. An emerging issue in environmental toxicology is in understanding how climate change will alter responses of organisms to chemical contaminants. The objective of the present study was to characterize the interactive effects of cadmium and elevated temperature on life-stage-specific responses in the freshwater snail Physa pomilia. We exposed developing eggs, juveniles, and adults to Cd (5 µg/L, 15 µg/L, and 25 µg/L for eggs, and 250 µg/L for juveniles and adults) and 2 temperatures of 25 °C (control) and 35 °C (upper range of tolerance). In the absence of Cd, time to hatch was shorter at 35 °C compared with 25 °C, demonstrating a stimulatory effect of the higher temperature. However, when egg masses were reared at 35 °C and exposed to Cd, hatching success was significantly lower, and time-to-hatching was significantly longer. The effects of the higher temperature and Cd on newly hatched neonate survival were additive, except at the highest Cd concentration, at which effects of the 2 stressors were greater than additive. Overall, within the combined stressor treatments, adult snails generally survived significantly longer than did juvenile snails, and both were more tolerant than developing snails. Many climate projection models predict future increases in global temperatures. The present study shows that combined stressors may produce greater-than-additive effects, challenging predictive power. More studies are needed to better characterize the interactive effects of chemical contaminants and stressors related to climate change. Environ Toxicol Chem 2013;32:1337-1343. © 2013 SETAC. 23290050 On the preparation of indoxyl red from indican and some new characteristics. An indole compound with a strong purple-red color was produced by boiling a solution of indican under acidic conditions and purified by chromatographies on DEAE-650S Toyopearl TSK-gel and silica-gel columns. The purple-red compound purified was identified as indoxyl red, on the basis of FAB Mass, (13)C NMR, (1)H NMR, UV-visible spectra, and IR spectra. Although indoxyl red was first synthesized by Seidel(9) 70 years ago, very little information has been available on its characteristics. We repot here that the compound was purple-red colored at acidic pH and green at pH 13, and showed antiproliferative and cytotoxic activities to the mouse B cell lymphoma cell line NSF202. 22507666 mGlu5R promotes glutamate AMPA receptor phosphorylation via activation of PKA/DARPP-32 signaling in striatopallidal medium spiny neurons. Group I metabotropic glutamate receptors (mGluRs), which comprise mGlu1Rs and mGlu5Rs, are enriched in striatal medium spiny neurons (MSNs), where they modulate glutamatergic transmission. Here, we have examined the effect of group I mGluRs on the regulation of the state of phosphorylation of the GluA1 subunit of the AMPA glutamate receptor. We found that incubation of mouse striatal slices with the group I mGluR agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) promotes GluA1 phosphorylation at the cAMP-dependent protein kinase (PKA) site, Ser845. This effect is prevented by 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), a selective mGlu5R antagonist. The increase in GluA1 phosphorylation produced by DHPG is also prevented by blockade of adenosine A2A receptors (A2ARs), which are known to promote cAMP signaling specifically in striatopallidal MSNs, as well as by enzymatic degradation of endogenous adenosine, achieved with adenosine deaminase. The ability of DHPG to increase PKA-dependent phosphorylation of GluA1 depends on concomitant activation of the dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32). Thus, inactivation of the PKA phosphorylation site of DARPP-32 abolishes the effect of DHPG. Moreover, cell-specific knock out of DARPP-32 in striatopallidal, but not in striatonigral, MSNs prevents the increase in Ser845 phosphorylation induced by DHPG. These results indicate that activation of mGlu5Rs promotes PKA/DARPP-32-dependent phosphorylation of downstream target proteins in striatopallidal MSNs and that this effect is exerted via potentiation of tonic A2AR transmission. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23641955 Using human recombinant UDP-glucuronosyltransferase isoforms and a relative activity factor approach to model total body clearance of laropiprant (MK-0524) in humans. Abstract 1.  A major pathway of elimination of the prostaglandin D2 receptor 1 antagonist laropiprant in humans is by uridine diphosphate-glucuronosyltransferase (UGT)-mediated biotransformation. In this study, liver and kidney relative activity factors were developed for UGT1A1, 1A9 and 2B7 to allow for in vitro-in vivo extrapolation of intrinsic clearance data to whole organ clearance using recombinant human UGT isoforms applying this to laropiprant as a model substrate. 2.  The total body metabolic clearance of laropiprant determined using this approach (5.0 L/hr) agreed well with the value determined in vivo following intravenous administration to healthy human volunteers (5.1 L/hr). 3.  The results suggest that approximately 36%, 36% and 28% of the hepatic metabolic clearance of laropiprant was mediated by UGT1A1, 1A9 and 2B7, respectively. Likewise, 80% and 20% of the renal metabolic clearance was mediated by UGT1A9 and 2B7, respectively. Furthermore, the data suggested that the contribution of the kidney to the overall total metabolic clearance was minor relative to the liver (∼ 12%). 23206503 Antiepileptic action of N-palmitoylethanolamine through CB1 and PPAR-α receptor activation in a genetic model of absence epilepsy. N-palmitoylethanolamine (PEA), an endogenous fatty acid ethanolamide, plays a key role in the regulation of the inflammatory response and pain through, among others, activation of nuclear peroxisome proliferator-activated receptors (PPAR-α). Endogenous cannabinoids play a protective role in several central nervous system (CNS) disorders, particularly those associated with neuronal hyperexcitability. We investigated the effects of PEA and the role of PPAR-α in absence epilepsy using the WAG/Rij rat model. PEA, anandamide (AEA), a PPAR-α antagonist (GW6471) and a synthetic CB1 receptor antagonist/inverse agonist (SR141716) were administered to WAG/Rij rats in order to evaluate the effects on epileptic spike-wave discharges (SWDs) on EEG recordings. We studied also the effects of PEA co-administration with SR141716 and GW6471 and compared these effects with those of AEA to evaluate PEA mechanism of action and focusing on CB1 receptors and PPAR-α. Both PEA and AEA administration significantly decreased SWDs parameters (absence seizures). In contrast, GW6471 was devoid of effects while SR141716 had pro-absence effects. The co-administration of SR141716 with PEA or AEA completely blocked the anti-absence effects of these compounds. GW6471 antagonized PEA's effects whereas it did not modify AEA's effects. Furthermore, we have also measured PEA, AEA and 2-AG (2-arachidonoylglycerol) brain levels identifying significant differences between epileptic and control rats such as decreased PEA levels in both thalamus and cortex that might contribute to absence epilepsy. Our data demonstrate that PEA has anti-absence properties in the WAG/Rij rat model and that such properties depend on PPAR-α and indirect activation of CB1 receptors. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'. 23530765 Electron Paramagnetic Resonance Spectroscopic Study of Copper Hopping in Doped Bis(l-histidinato)cadmium Dihydrate. Electron paramagnetic resonance (EPR) spectroscopy was used to study Cu(II) dynamic behavior in a doped biological model crystal, bis(l-histidinato)cadmium dihydrate, in order to gain better insight into copper site stability in metalloproteins. Temperature-dependent changes in the low temperature X-band EPR spectra became visible around 100 K and continued up to room temperature. The measured 298 K g-tensor (principal values: 2.17, 2.16, 2.07) and copper hyperfine coupling tensor (principal values: -260, -190, -37 MHz) were similar to the average of the 77 K tensor values pertaining to two neighboring histidine binding sites. The observed temperature dependence was interpreted using Anderson's theory of motional narrowing, where the magnetic parameters for the different states are averaged as the copper rapidly hops between sites. The EPR pattern was also found to undergo a sharp sigmoidal-shaped, temperature-dependent conversion between two species with a critical temperature Tc ≈ 160 K. The species below Tc hops between the two low temperature site patterns, and the one above Tc represents an average of the molecular spin Hamiltonian coupling tensors of the two 77 K sites. In addition, the low and high temperature species hop between one another, contributing to the dynamic averaging. Spectral simulations using this 4-state model determined a hop rate between the two low temperature sites νh4 = 4.5 × 10(8) s(-1) and between the low and high temperature states νh2 = 1.7 × 10(8) s(-1) at 160 K. An Arrhenius relationship of hop rate and temperature gave energy barriers of ΔE4 = 389 cm(-1) and ΔE2 = 656 cm(-1) between the two low temperature sites and between the low and high temperature states, respectively. 22985953 Ultrasonic treatment and synthesis of sugar alcohol modified Na+-montmorillonite clay. Na(+)-montmorillonite clay (generally referred to as MMT) is very useful for reinforcing polymeric matrix at very low concentrations (typically, 2-5% wt). These clay particles are typically exfoliated before they can demonstrate the significant gains in heat deflection temperature, modulus, and elongation properties. In the case of hydrophilic biopolymer based matrices, such as carbohydrates and chitosan, exfoliating these nanoclay particles needs greater attention because the exfoliation is typically carried out using hydrophobic oligomers through ion-exchange. This study reports a new method of synthesizing completely hydrophilic MMT-assemblages using hydrophilic plasticizers for biopolymers. We used sugar alcohols (glycerol, xylitol with 3 and 5 hydroxyl groups) and polysaccharide maltodextrin to exfoliate the MMT. Sonication was conducted for MMT nanoclay and plasticizers at different weight ratios. It was confirmed that all plasticizer/modifier led to expansion of MMT gallery spacing (d-spacing) and the change in d-spacing could be related to the molecular structure of the plasticizer. Meanwhile, the extent of exfoliation was maximum with maltodextrin (fully exfoliation with 1:10 and 1:20 ratio of MMT:plasticizer) across all test samples and interestingly, glycerol and xylitol samples quickly established within the MMT galleries and exhibited minimal influence with further increase in relative concentrations. 23327557 Interactions between pectic compounds and procyanidins are influenced by methylation degree and chain length. The interactions between procyanidins and pectic compounds are of importance in food chemistry. Procyanidins with low (9) and high (30) average degrees of polymerization (DP9 and DP30) were extracted from two cider apple varieties. Commercial apple and citrus pectins, as well as three pectin subfractions (homogalacturonans, partially methylated homogalacturonans with degree of methylation 30 and 70) at 30 mM galacturonic acid equivalent, were titrated with the two procyanidin fractions (at 30 mM (-)-epicatechin equivalent) by isothermal titration calorimetry and UV-vis spectrophotometry. Slightly stronger affinities were recorded between commercial apple or citrus pectins and procyanidins of DP30 (Ka = 1460 and 1225 M(-1) respectively, expressed per monomer units) compared to procyanidins of DP9 (Ka = 1240 and 1085 M(-1), respectively), but stoichiometry and absorbance maxima differed between apple and citrus pectins. It was proposed that methylated homogalacturonans interacted with procyanidins DP30 mainly through hydrophobic interactions. The stronger association was obtained with the longer procyanidin molecules interacting with highly methylated pectins. 23538868 Diketopiperazine Derivatives from the Marine-Derived Actinomycete Streptomyces sp. FXJ7.328. Five new diketopiperazine derivatives, (3Z,6E)-1-N-methyl-3-benzy lidene-6-(2S-methyl-3-hydroxypropylidene)piperazine-2,5-dione (1), (3Z,6E)-1-N-methyl-3-benzylidene-6-(2R-methyl-3-hydroxypropylidene)piperazine-2,5-dione (2), (3Z,6Z)-3- (4-hydroxybenzylidene)-6-isobutylidenepiperazine-2,5-dione (3), (3Z,6Z)-3-((1H-imidazol-5-yl)-methylene)-6-isobutylidenepiperazine-2,5-dione (4), and (3Z,6S)-3-benzylidene-6-(2S-but-2-yl)piperazine-2,5-dione (5), were isolated from the marine-derived actinomycete Streptomyces sp. FXJ7.328. The structures of 1-5 were determined by spectroscopic analysis, CD exciton chirality, the modified Mosher's, Marfey's and the C3 Marfey's methods. Compound 3 showed modest antivirus activity against influenza A (H1N1) virus with an IC50 value of 41.5 ± 4.5 μM. In addition, compound 6 and 7 displayed potent anti-H1N1 activity with IC50 value of 28.9 ± 2.2 and 6.8 ± 1.5 μM, respectively. Due to the lack of corresponding data in the literature, the 13C NMR data of (3Z,6S)-3-benzylidene-6-isobutylpiperazine-2,5-dione (6) were also reported here for the first time. 23571308 Quantification of the Young's modulus of the primary plant cell wall using Bending-Lab-On-Chip (BLOC). Biomechanical and mathematical modeling of plant developmental processes requires quantitative information about the structural and mechanical properties of living cells, tissues and cellular components. A crucial mechanical property of plant cells is the mechanical stiffness or Young's modulus of its cell wall. Measuring this property in situ at single cell wall level is technically challenging. Here, a bending test is implemented in a chip, called Bending-Lab-On-a-Chip (BLOC), to quantify this biomechanical property for a widely investigated cellular model system, the pollen tube. Pollen along with culture medium is introduced into a microfluidic chip and the growing pollen tube is exposed to a bending force created through fluid loading. The flexural rigidity of the pollen tube and the Young's modulus of the cell wall are estimated through finite element modeling of the observed fluid-structure interaction. An average value of 350 MPa was experimentally estimated for the Young's modulus in longitudinal direction of the cell wall of Camellia pollen tubes. This value is in agreement with the result of an independent method based on cellular shrinkage after plasmolysis and with the mechanical properties of in vitro reconstituted cellulose-callose material. 23507573 Minireview: Nuclear Insulin and Insulin-like Growth Factor-1 Receptors: A Novel Paradigm in Signal Transduction. The specificity of the insulin receptor (InsR) and insulin-like growth factor-1 receptor (IGF1R) signaling pathways has been the focus of significant debate over the past few years. Recent evidence showing nuclear import and a direct transcriptional role for both InsR and IGF1R adds a new layer of complexity to this dialog. Hence, in addition to the classical roles associated with cell-surface receptors (eg, ligand binding, autophosphorylation of the tyrosine kinase domain, activation of insulin receptor substrate 1 (IRS-1) and additional substrates, protein-protein interactions with membrane and cytoplasm components), new data are consistent with nuclear (genomic) role(s) for both InsR and IGF1R. The present review provides a brief overview of the physical and functional similarities and differences between InsR and IGF1R and describes data from a number of laboratories providing evidence for a new layer of signaling regulation (ie, the ability of InsR and IGF1R to translocate to the cell nucleus and to elicit genomic activities usually associated with transcription factors). The ability of InsR and IGF1R to function as transcription factors, although poorly understood, constitutes a new paradigm in signal transduction. Although research on the role of nuclear InsR/IGF1R is still in its infancy, we believe that this rapidly developing area may have a major basic and translational impact on the fields of metabolism, diabetes, and cancer. 23261590 Neoechinulin A suppresses amyloid-β oligomer-induced microglia activation and thereby protects PC-12 cells from inflammation-mediated toxicity. A pathological hallmark of Alzheimer's disease (AD), aggregation and deposition of amyloid-β peptides, has been recognized as a potent activator of microglia-mediated neuroinflammation and neuronal dysfunction. Therefore, downregulation of microglial activation has a significant therapeutic demand. In this study, focus was given to evaluate the ability of neoechinulin A, an indole alkaloid isolated from marine-derived Microsporum sp., to attenuate microglial activation by oligomeric amyloid-β 1-42 (Aβ42). Neoechinulin A treatment significantly inhibited the generation of reactive oxygen and nitrogen species in Aβ42-activated BV-2 microglia cells. In addition, we found that neoechinulin A significantly suppressed the production of neurotoxic inflammatory mediator tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and prostaglandin E2 (PGE2) in activated BV-2 cells. Moreover, the treatment downregulated the protein and gene expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, IL-1β and IL-6. Further, activated microglia-mediated apoptosis of PC-12 pheochromocytoma cells was significantly repressed by neoechinulin A. The molecular mechanism studies suggested that neoechinulin A may block the phosphorylation of mitogen-activated protein kinase (MAPK) molecule p38, apoptosis signal-regulating kinase 1 (ASK-1) and nuclear translocation of nuclear factor-κB (NF-κB) p65 and p50 subunits. Regulation of these signalling pathways have most probably contributed to the anti-inflammatory activity of neoechinulin A. Collectively, these results suggest that with further studies neoechinulin A have a potential to be developed as a modulator of neuroinflammatory process in AD. 23611338 Reaction between peroxynitrite and triphenylphosphonium-substituted arylboronic acid isomers - Identification of diagnostic marker products and biological implications. Aromatic boronic acids react rapidly with peroxynitrite (ONOO-) to yield phenols as major products. This reaction was used to monitor ONOO- formation in cellular systems. Previously, we proposed that the reaction between ONOO- and arylboronates (PhB(OH)2) yields a phenolic product (major pathway) and a radical pair PhB(OH)2O•-…•NO2 (minor pathway). [Sikora A. et al., Chem Res Toxicol 24, 687-97]. In this study, we investigated the influence of a bulky triphenylphosphonium (TPP) group on the reaction between ONOO- and mitochondria-targeted arylboronate isomers (o-, m-, and p-MitoPhB(OH)2). Results from the electron paramagnetic resonance (EPR) spin-trapping experiments unequivocally showed the presence of a phenyl radical intermediate from meta and para isomers, and not from the ortho isomer. The yield of o-MitoPhNO2 formed from the reaction between o-MitoPhB(OH)2 and ONOO- was not diminished by phenyl radical scavengers, suggesting a rapid fragmentation of the o-MitoPhB(OH)2O•- radical anion with subsequent reaction of the resulting phenyl radical with •NO2 in the solvent cage. The DFT quantum mechanical calculations showed that the energy barrier for the dissociation of o-MitoPhB(OH)2O•- radical anion is significantly lower than that of m-MitoPhB(OH)2O•- and p-MitoPhB(OH)2O•- radical anions. We conclude that the reaction of ONOO- with ortho-MitoPhB(OH)2 forming the minor nitrated product, o-MitoPhNO2, and the corresponding major phenolic product (o-MitoPhOH) can be employed as a diagnostic tool to specifically detect ONOO- in biological systems. 23578633 Pilot study on levels of perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in selected foodstuffs and human milk from Italy. Despite the health risks associated with perfluorinated compounds (PFC) exposure and the detection of these compounds in many countries around the world, little is known on their occurrence in Italy. The results of a study on levels of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), analysed by HPLC-ESI-MS, in human milk and food samples from the city of Siena and its province (central Italy) are here reported. PFOS was found in 13 out of 49 breast milk samples (0.76±1.27ng/g), while PFOA was detected in one sample (8.04ng/g). Only PFOS was found in food samples. Fish were the most contaminated samples (7.65±34.2ng/g); mean concentrations in meat and milk and dairy products were similar (1.43±7.21ng/g and 1.35±3.45ng/g, respectively). In all cereal-based food, eggs, vegetables, honey and beverages PFOS concentration was 10-fold) in the absence of Oatp1a/1b transporters. After intravenous administration (5 mg/kg), systemic exposure was 3-fold higher in Oatp1a/1b-null mice than in the wild-type mice. Liver, small intestinal, and kidney exposure were slightly, but not significantly, increased in Oatp1a/1b-null mice. The biliary excretion of rosuvastatin was very fast, with 60% of the dose eliminated within 15 minutes after intravenous administration, and also not significantly altered in Oatp1a/1b-null mice. Rosuvastatin renal clearance, although still minor, was increased ∼15-fold in Oatp1a/1b-null males, suggesting a role of Oatp1a1 in the renal reabsorption of rosuvastatin. Absence of Oatp1a/1b uptake transporters increases the systemic exposure of rosuvastatin by reducing its hepatic extraction ratio. However, liver concentrations are not significantly affected, most likely due to the compensatory activity of high-capacity, low-affinity alternative uptake transporters at higher systemic rosuvastatin levels and the absence of efficient alternative rosuvastatin clearance mechanisms. 22989703 Comparative antioxidant effects of lycopene, apo-10'-lycopenoic acid and apo-14'-lycopenoic acid in human macrophages exposed to H2O2 and cigarette smoke extract. Much of the beneficial effects of tomato lycopene in the prevention of chronic diseases has been attributed to its antioxidant properties, which could be mediated by its metabolites and/or oxidation products. However, the biological functions of these lycopene derivatives remain still unknown. In the present study, we evaluated and compared the antioxidant efficacy of the lycopene eccentric cleavage products apo-10'-lycopenoic acid and apo-14'-lycopenoic acid in counteracting the oxidative effects of H(2)O(2) and cigarette smoke extract (CSE) in THP-1 macrophages. Both apo-10'-lycopenoic acid and apo-14'-lycopenoic acid were able to inhibit spontaneous and H(2)O(2)-induced ROS production in a dose-dependent manner. Such an effect was accompanied by an inhibition of MAPK phosphorylation, by NF-κB inactivation, and by inhibition of hsp-70 and hsp-90 expressions. Both apo-lycopenoic acids also decreased CSE-induced ROS production, 8-OHdG formation and reduced the increase in NOX-4 and COX-2 expressions caused by CSE. However, in both the models of oxidative stress, apo-14'-lycopenoic acid was much more potent as an antioxidant than apo-10'-lycopenoic acid, showing antioxidant properties similar to lycopene. These data strongly suggest that apo-lycopenoic acids, and particularly apo-14'-lycopenoic acid, may mediate some of the antioxidant functions of lycopene in cells. 23548896 Identification of a new interaction mode between the Src homology 2 (SH2) domain of C-terminal Src kinase (Csk) and Csk-binding protein (Cbp)/phosphoprotein associated with glycosphingolipid microdomains (PAG). Proteins with Src homology 2 (SH2) domains play major roles in tyrosine kinase signaling. Structures of many SH2 domains have been studied, and the regions involved in their interactions with ligands have been elucidated. However, these analyses have been performed using short peptides comprising phosphotyrosine followed by a few amino acids, which are described as the canonical recognition sites. Here we report the solution structure of the SH2 domain of C-terminal Src kinase (Csk) in complex with a longer phosphopeptide from Csk-binding protein (Cbp). This structure, together with biochemical experiments, revealed the existence of a novel binding region in addition to the canonical phosphotyrosine-314 binding site of Cbp. Mutational analysis of this second region in cells showed that both canonical and novel binding sites are required for tumor suppression through the Cbp-Csk interaction. Furthermore, the data indicate an allosteric connection between Cbp binding and Csk activation that arises from residues in the βB/βC loop of the SH2 domain. 23443025 The influence of clan structure on the genetic variation in a single Ghanaian village. Socioeconomic and cultural factors are thought to have an important role in influencing human population genetic structure. To explain such population structure differences, most studies analyse genetic differences among widely dispersed human populations. In contrast, we have studied the genetic structure of an ethnic group occupying a single village in north-eastern Ghana. We found a markedly skewed male population substructure because of an almost complete lack of male gene flow among Bimoba clans in this village. We also observed a deep male substructure within one of the clans in this village. Among all males, we observed only three Y-single-nucleotide polymorphism (SNP) haplogroups: E1b1a*-M2, E1b1a7a*-U174 and E1b1a8a*-U209, P277, P278. In contrast to the marked Y-chromosomal substructure, mitochondrial DNA HVS-1 sequence variation and autosomal short-tandem repeats variation patterns indicate high genetic diversities and a virtually random female-mediated gene flow among clans. On the extreme micro-geographical scale of this single Bimoba village, correspondence between the Y-chromosome lineages and clan membership could be due to the combined effects of the strict patrilocal and patrilineal structure. If translated to larger geographic scales, our results would imply that the extent of variation in uniparentally inherited genetic markers, which are typically associated with historical migration on a continental scale, could equally likely be the result of many small and different cumulative effects of social factors such as clan membership that act at a local scale. Such local scale effects should therefore be considered in genetic studies, especially those that use uniparental markers, before making inferences about human history at large.European Journal of Human Genetics advance online publication, 27 February 2013; doi:10.1038/ejhg.2013.12. 23368884 Potent and Selective Inhibition of Histone Deacetylase 6 (HDAC6) Does Not Require a Surface-Binding Motif. Hydroxamic acids were designed, synthesized, and evaluated for their ability to selectively inhibit human histone deacetylase 6 (HDAC6). Several inhibitors, including compound 14 (BRD9757), exhibited excellent potency and selectivity despite the absence of a surface-binding motif. The binding of these highly efficient ligands for HDAC6 is rationalized via structure-activity relationships. These results demonstrate that high selectivity and potent inhibition of HDAC6 can be achieved through careful choice of linker element only. 23109068 Proximal femoral density distribution and structure in relation to age and hip fracture risk in women. Hip fracture risk rises exponentially with age, but there is little knowledge about how fracture-related alterations in hip structure differ from those of aging. We employed computed tomography (CT) imaging to visualize the three-dimensional (3D) spatial distribution of bone mineral density (BMD) in the hip in relation to age and incident hip fracture. We used intersubject image registration to integrate 3D hip CT images into a statistical atlas comprising women aged 21 to 97 years (n = 349) and a group of women with (n = 74) and without (n = 148) incident hip fracture 4 to 7 years after their imaging session. Voxel-based morphometry was used to generate Student's t test statistical maps from the atlas, which indicated regions that were significantly associated with age or with incident hip fracture. Scaling factors derived from intersubject image registration were employed as measures of bone size. BMD comparisons of young, middle-aged, and older American women showed preservation of load-bearing cortical and trabecular structures with aging, whereas extensive bone loss was observed in other trabecular and cortical regions. In contrast, comparisons of older Icelandic fracture women with age-matched controls showed that hip fracture was associated with a global cortical bone deficit, including both the superior cortical margin and the load-bearing inferior cortex. Bone size comparisons showed larger dimensions in older compared to younger American women and in older Icelandic fracture women compared to controls. The results indicate that older Icelandic women who sustain incident hip fracture have a structural phenotype that cannot be described as an accelerated pattern of normal age-related loss. The fracture-related cortical deficit noted in this study may provide a biomarker of increased hip fracture risk that may be translatable to dual-energy X-ray absorptiometry (DXA) and other clinical images. 23589501 Direct Bio-electrocatalysis of O2 Reduction by Streptomyces coelicolor Laccase Orientated at Promoter-Modified Graphite Electrodes. Bacterial laccase from Streptomyces coelicolor (SLAC) has been immobilised and orientated at promoter (pyrene and neocuproine)-modified electrodes productively both for direct electron transfer (ET) between the electrode and the T1 Cu site of SLAC and direct (unmediated) bio-electrocatalysis of dioxygen reduction. Its T1 Cu potential ranges between 471 and 318 mV versus the normal hydrogen electrode, at pH 5.5 and 8, respectively; this value is dependent both on the solution pH and electrode modification. In the presence of O2 , Cu of the T2/T3 trinuclear centre is distinguished electrochemically at 748-623 mV. Depending on the promoter nature, different orientations of SLAC at pyrene- and neocuproine-modified electrodes can be followed from the kinetic analysis of the ET rates. Bio-electrocatalytic reduction of oxygen starts from the T1 Cu potentials of SLAC, and is most efficient at the promoter-modified electrodes, thereby demonstrating good performance both in neutral and basic media and in solutions with a high NaCl content, such as sea water. The obtained results allow consideration of a broader bioenergetic application of laccases as biocathodes operating directly in such environmental media as sea water and physiological fluids. 23404509 α1A-Adrenergic Receptors Regulate Cardiac Hypertrophy In Vivo Through Interleukin-6 Secretion. The role of α1-adrenergic receptors (ARs) in the regulation of cardiac hypertrophy is still unclear, because transgenic mice demonstrated hypertrophy or the lack of it despite high receptor overexpression. To further address the role of the α1-ARs in cardiac hypertrophy, we analyzed unique transgenic mice that overexpress constitutively active mutation (CAM) α1A-ARs or CAM α1B-ARs under the regulation of large fragments of their native promoters. These constitutively active receptors are expressed in all tissues that endogenously express their wild-type counterparts as opposed to only myocyte-targeted transgenic mice. In this study, we discovered that CAM α1A-AR mice in vivo have cardiac hypertrophy independent of changes in blood pressure, corroborating earlier studies, but in contrast to myocyte-targeted α1A-AR mice. We also found cardiac hypertrophy in CAM α1B-AR mice, in agreement with previous studies, but hypertrophy only developed in older mice. We also discovered unique α1-AR-mediated hypertrophic signaling that was AR subtype-specific with CAM α1A-AR mice secreting atrial naturietic factor and interleukin-6 (IL-6), whereas CAM α1B-AR mice expressed activated nuclear factor-κB (NF-κB). These particular hypertrophic signals were blocked when the other AR subtype was coactivated. We also discovered that crossbreeding the two CAM models (double CAM α1A/B-AR) inhibited the development of hypertrophy and was reversible with single receptor activation, suggesting that coactivation of the receptors can lead to novel antagonistic signal transduction. This was confirmed by demonstrating antagonistic signals that were even lower than normal controls in the double CAM α1A/B-AR mice for p38, NF-κB, and the IL-6/glycoprotein 130/signal transducer and activator of transcription 3 pathway. Because α1A/B double knockout mice fail to develop hypertrophy in response to IL-6, our results suggest that IL-6 is a major mediator of α1A-AR cardiac hypertrophy. 23389956 Glucocorticoid programming of the fetal male hippocampal epigenome. The late-gestation surge in fetal plasma cortisol is critical for maturation of fetal organ systems. As a result, synthetic glucocorticoids (sGCs) are administered to pregnant women at risk of delivering preterm. However, animal studies have shown that fetal exposure to sGC results in increased risk of behavioral, endocrine, and metabolic abnormalities in offspring. Here, we test the hypothesis that prenatal GC exposure resulting from the fetal cortisol surge or after sGC exposure results in promoter-specific epigenetic changes in the hippocampus. Fetal guinea pig hippocampi were collected before (gestational day [GD52]) and after (GD65) the fetal plasma cortisol surge (Term∼GD67) and 24 hours after (GD52) and 14 days after (GD65) two repeat courses of maternal sGC (betamethasone) treatment (n = 3-4/gp). We identified extensive genome-wide alterations in promoter methylation in late fetal development (coincident with the fetal cortisol surge), whereby the majority of the affected promoters exhibited hypomethylation. Fetuses exposed to sGC in late gestation exhibited substantial differences in DNA methylation and histone h3 lysine 9 (H3K9) acetylation in specific gene promoters; 24 hours after the sGC treatment, the majority of genes affected were hypomethylated or hyperacetylated. However, 14 days after sGC exposure these differences did not persist, whereas other promoters became hypermethylated or hyperacetylated. These data support the hypothesis that the fetal GC surge is responsible, in part, for significant variations in genome-wide promoter methylation and that prenatal sGC treatment profoundly changes the epigenetic landscape, affecting both DNA methylation and H3K9 acetylation. This is important given the widespread use of sGC in the management of women in preterm labor. 23386597 Ezogabine: a novel antiepileptic for adjunctive treatment of partial-onset seizures. Epilepsy is defined as a tendency toward recurrent seizures unprovoked by any systemic or acute neurologic insults. It is a disruption of the electrical conductivity or activity in the brain, resulting in a seizure. In the United States, approximately 120 of every 100,000 people seek medical attention due to new seizure activity. Ezogabine, known as retigabine in Europe, is an ethyl N-(2-amino-4-[{fluorophenyl}methlamino]phenylcarbamate). The drug has been approved by the United States Food and Drug Administration (FDA) and European Medicines Agency for adjunctive treatment of partial-onset seizures in adults. Ezogabine exerts its therapeutic effect by enhancing transmembrane potassium channels (KCNQ ion channels), which is a novel mechanism in comparison with other antiepileptics. There are no specific documented contraindications to ezogabine. Warnings target patients that have benign prostatic hyperplasia or are receiving concomitant anticholinergic drugs due to a risk of urinary retention (2%). The FDA has required that ezogabine be part of a risk evaluation and mitigation strategy program in order to inform health care professionals of the risk of urinary retention. Prescribers should inform patients that ezogabine can cause urinary retention, including urinary hesitation, and instruct them to seek immediate medical attention if these symptoms occur. A medication guide has been developed for distribution to patients. 23017423 Light exposure during storage preserving soluble sugar and l-ascorbic acid content of minimally processed romaine lettuce (Lactuca sativa L.var. longifolia). Minimally processed romaine lettuce (MPRL) leaves were stored in light condition (2500lux) or darkness at 4°C for 7d. Light exposure significantly delayed the degradation of chlorophyll and decrease of glucose, reducing sugar, and sucrose content, and thus preserved more total soluble solid (TSS) content at the end of storage in comparison with darkness. While, it did not influenced starch content that progressively decreased over time. The l-ascorbic acid (AA) accumulated in light-stored leaves, but deteriorated in dark-stored leaves during storage. The dehydroascorbic acid (DHA) increased in all leaves stored in both light and dark condition, of which light condition resulted in less DHA than darkness. In addition, the fresh weight loss and dry matter significantly increased and these increases were accelerated by light exposure. Conclusively, light exposure in applied intensity effectively alleviated MPRL quality deterioration by delaying the decreases of pigments, soluble sugar, TSS content and accumulating AA. 22889612 Chemoprevention of benzo(a)pyrene-induced colon polyps in ApcMin mice by resveratrol. Human dietary exposure to benzo(a)pyrene (BaP) has generated interest with regard to the association of BaP with gastrointestinal carcinogenesis. Since colon cancer ranks third among cancer-related mortalities, it is necessary to evaluate the effect of phytochemicals on colon cancer initiation and progression. In this study, we investigated the preventive effects of resveratrol (RVT) on BaP-induced colon carcinogenesis in Apc(Min) mouse model. For the first group of mice, 100 μg BaP/kg body weight was administered to mice in peanut oil via oral gavage over a 60-day period. For the second group, RVT was coadministered with BaP at a dose of 45 μg/kg. For the third group, RVT was administered for 1 week prior to BaP exposure for 60 days. Jejunum, colon and liver were collected at 60 days post BaP and RVT exposure; adenomas in jejunum and colon were counted and subjected to histopathology. RVT reduced the number of colon adenomas in BaP+RVT-treated mice significantly compared to that in mice that received BaP alone. While dysplasia of varying degrees was noted in colon of BaP-treated mice, the dysplasias were of limited occurrence in RVT-treated mice. To ascertain whether the tumor inhibition is a result of altered BaP-induced toxicity of tumor cells, growth, apoptosis and proliferation of adenocarcinoma cells were assessed posttreatment with RVT and BaP. Cotreatment with RVT increased apoptosis and decreased cell proliferation to a greater extent than with BaP alone. Overall, our observations reveal that RVT inhibits colon tumorigenesis when given together with BaP and holds promise as a therapeutic agent. 23403184 The PprA protein is required for accurate cell division of γ-irradiated Deinococcus radiodurans bacteria. Deinococcus radiodurans, one of the most radioresistant organisms known to date is able to reconstruct an intact genome from hundreds of DNA fragments. Here, we investigate the in vivo role of PprA, a radiation-induced Deinococcus specific protein. We report that DNA double strand break repair in cells devoid of PprA and exposed to 3800Gy γ-irradiation takes place efficiently with a delay of only 1h as compared to the wild type, whereas massive DNA synthesis begins 90min after irradiation as in the wild type, a phenotype insufficient to explain the severe radiosensitivity of the ΔpprA mutant. We show that the slow kinetics of reassembly of DNA fragments in a ΔpprA ΔrecA double mutant was the same as that observed in a ΔrecA single mutant demonstrating that PprA does not play a major role in DNA repair through RecA-independent pathways. Using a tagged PprA protein and immunofluorescence microscopy, we show that PprA is recruited onto the nucleoid after γ-irradiation before DNA double strand break repair completion, and then is found as a thread across the septum in dividing cells. Moreover, whereas untreated cells devoid of PprA displayed a wild type morphology, they showed a characteristic cell division abnormality after irradiation not found in other radiosensitive mutants committed to die, as DNA is present equally in the two daughter cells but not separated at the division septum. We propose that PprA may play a crucial role in the control of DNA segregation and/or cell division after DNA double strand break repair. 23640962 Anti-inflammatory Activities of an Active Fraction Isolated from the root of Astragalus membranaceus in RAW 264.7 Macrophages. The root of Astragalus membranaceus (AR), which has been widely used in Traditional Chinese herbal formulae for treating foot ulcer, was found to exhibit anti-inflammatory property, but its molecular mechanism still remains unknown. We previously identified the anti-inflammatory sub-fraction using bioassay-guided fractionation. The objective of the present study was to investigate the anti-inflammatory mechanism of the major active fraction (MAF) (0.039 to 0.156 mg/mL) using lipopolysaccharide (LPS)-stimulated mouse macrophage RAW 264.7 cells. MAF was shown to inhibit LPS-induced mRNA and protein expression of inducible nitric oxide synthase by 54.7% and 65.1%, respectively. Additionally, MAF down-regulated the protein expression of cyclooxygenase-2 and MAPK regulator by 45.0% to 74.6%, as well as the reduction of DNA binding activity of nuclear factor kappa B (NFκB) by 66.5%. It also attenuated the production of prostaglandin E2 , interleukin-1 beta (IL-1β), IL-6 and tumor necrosis factor alpha by 21.2% to 86.2%. Furthermore, the chemical constituents of MAF were identified. A total of 13 known chemical compounds were found in MAF, including five isoflavonoids and eight saponins. In conclusion, a bioactive fraction of AR was identified which possessed anti-inflammatory property by reducing the release of inflammatory mediators and inactivation of NFκB through MAPK signalling pathway. Copyright © 2013 John Wiley & Sons, Ltd. 23256819 HR-MAS NMR Spectroscopy of Reconstructed Human Epidermis: Potential for the in Situ Investigation of the Chemical Interactions between Skin Allergens and Nucleophilic Amino Acids. High-resolution magic angle spinning (HR-MAS) is a nuclear magnetic resonance (NMR) technique that enables the characterization of metabolic phenotypes/metabolite profiles of cells, tissues, and organs, under both normal and pathological conditions, without resorting to time-consuming extraction techniques. In this article, we explore a new domain of application of HR-MAS, namely, reconstructed human epidermis (RHE) and the in situ observation of chemical interactions between skin sensitizers and nucleophilic amino acids. First, the preparation, storage, and analysis of RHE were optimized, and this work demonstrated that HR-MAS NMR was well adapted for investigating RHE with spectra of good quality allowing qualitative as well as quantitative studies of metabolites. Second, in order to study the response of RHE to chemical sensitizers, the ((13)C)methyldodecanesulfonate was chosen as an NMR probe, and we compared adducts formed on human serum albumin (HSA) in solution and adducts formed in RHE. Thus, while the modification of proteins or peptides in solution takes several days to lead to a significant amount of modification, in RHE the modifications of nucleophilic amino acids were observable already at 24 h. The chemioselectivity also appeared to be different with major modifications taking place on histidine, methionine, and cysteine residues in RHE, while on HSA, significant modifications were observed on lysine residues with the formation of methylated and dimethylated amino groups. We thus demonstrated that RHE could be used to investigate in situ chemical interactions taking place between skin sensitizers and nucleophilic amino acids. This opens perspectives for the molecular understanding of the skin immune system activation by sensitizing chemicals. 23525662 The nuclear receptors COUP-TF: a long-lasting experience in forebrain assembly. Chicken ovalbumin upstream promoter transcription factors (COUP-TFs) are nuclear receptors belonging to the superfamily of the steroid/thyroid hormone receptors. Members of this family are internalized to the nucleus both in a ligand-dependent or -independent manner and act as strong transcriptional regulators by binding to the DNA of their target genes. COUP-TFs are defined as orphan receptors, since ligands regulating their activity have not so far been identified. From the very beginning of metazoan evolution, these molecules have been involved in various key events during embryonic development and organogenesis. In this review, we will mainly focus on their function during development and maturation of the central nervous system, which has been well characterized in various animal classes ranging from ctenophores to mammals. We will start by introducing the current knowledge on COUP-TF mechanisms of action and then focus our discussion on the crucial processes underlying forebrain ontogenesis, with special emphasis on mammalian development. Finally, the conserved roles of COUP-TFs along phylogenesis will be highlighted, and some hypotheses, worth exploring in future years to gain more insight into the mechanisms controlled by these factors, will be proposed. 23625750 The effects of the adenosine A3 receptor agonist IB-MECA on sodium taurocholate-induced experimental acute pancreatitis. The role of adenosine A3 receptors and their distribution in the gastrointestinal tract have been widely investigated. Most of the reports discuss their role in intestinal inflammations. However, the role of adenosine A3 receptor agonist in pancreatitis has not been well established. The aim of this study is (Ed note: Purpose statements should be in present tense) to evaluate the effects of the adenosine A3 receptor agonist on the course of sodium taurocholate-induced experimental acute pancreatitis (EAP). The experiments were performed on 80 male Wistar rats, 58 of which survived, subdivided into 3 groups: C-control rats, I-EAP group, and II-EAP group treated with the adenosine A3 receptor agonist IB-MECA (1-deoxy-1-6[[(3-iodophenyl) methyl]amino]-9H-purin-9-yl)-N-methyl-B-D-ribofuronamide at a dose of 0.75 mg/kg b.w. i.p. at 48, 24, 12 and 1 h before and 1 h after the injection of 5 % sodium taurocholate solution into the biliary-pancreatic duct. Serum for α-amylase and lipase determinations and tissue samples for morphological examinations were collected at 2, 6, and 24 h of the experiment. In the IB-MECA group, α-amylase activity was decreased with statistically high significance compared to group I. The activity of lipase was not significantly different among the experimental groups but higher than in the control group. The administration of IB-MECA attenuated the histological parameters of inflammation as compared to untreated animals. The use of A3 receptor agonist IB-MECA attenuates EAP. Our findings suggest that stimulation of adenosine A3 receptors plays a positive role in the sodium taurocholate-induced EAP in rats. 23603385 How to measure hazards/risks following exposures to nanoscale or pigment-grade titanium dioxide particles. Due to its multifunctional applications, titanium dioxide particles have widespread use in commerce. The particle-types function as sources of pigment color, in food products, anti-bacterial components, ultraviolet radiation scavengers, catalysts, as well as in cosmetics. Because of its inherent properties in a diverse number of products, exposures may occur via any of the major point-of-entry routes, i.e., inhalation, oral or dermal. Although the majority of TiO2 applications are known to exist in the pigment-grade form, nanoscale forms of TiO2 are also common components in several products. This brief review is designed to identify relevant toxicology and risk-related issues which inform health effects assessments on the various forms of titanium dioxide particles. While there has been an abundance of hazard data generated on titanium dioxide particulates, many of the published reports have limited informational value for assessing health effects due, in large part, to shortcomings in experimental design issues, such as: (1) inadequate material characterization of test samples; (2) questionable relevance of experimental systems employed to simulate human exposures; (3) applications of generally high doses, exclusive focus on acute toxicity endpoints, and a lack of reference benchmark control materials, to afford interpretation of measured results; and/or (4) failure to recognize fundamental differences between hazard and risk concepts. Accordingly, a number of important toxicology issues are identified and integrated herein to provide a more comprehensive assessment of the health risks of different forms of pigment-grade and nanoscale titanium dioxide particles. It is important to note that particle-types of different TiO2 compositions may have variable toxicity potencies, depending upon crystal structure, particle size, particle surface characteristics and surface coatings. In order to develop a more robust health risk evaluation of TiO2 particle exposures, this review focuses on the following issues: A comprehensive evaluation of the existing animal and human health data is a necessary prerequisite for facilitating accurate assessments of human health risks to TiO2 exposures. 23239015 Poly-Ortho-Functionalizable Tetraarylporphycene Platform-Synthesis of Octacationic Derivatives Towards the Layer-by-Layer Design of Versatile Graphene Oxide Photoelectrodes. The most highly charged water-soluble poly-ortho-substituted tetraarylporphycene (Pc(8+) ) has been synthetized. The latter, which interacts in aqueous solutions with graphene oxide (GO) forming a photoactive ensemble Pc(8+) /GO, is immobilized by means of the Layer-by-Layer (LbL) technique onto ITO electrodes to afford novel solar energy conversion devices. 23287045 Toxicity of copper salts is dependent on solubility profile and cell type tested. Copper (Cu) is considered an essential metal for living organisms. However, disruption of Cu homeostasis is toxic and can lead to disorders such as Menkes and Wilson's diseases. The brain appears to be a vulnerable target organ. This study investigated the toxicity of Cu based on its solubility profile and cell type tested. Human A-172 (glioblastoma), SK-N-SH (neuroblastoma) and CCF-STTG1 (astrocytoma) cells were assessed after exposure to different concentrations (0.5-500μM) of copper sulfate (CuSO4) or copper (II) oxide (CuO). Since Cu is a redox active transition metal, we hypothesized that oxidative stress would be the main mechanism underlying cell toxicity. Therefore, cell viability was correlated with the extent of reactive oxygen species (ROS) formation. Cell viability decreased at the higher concentrations of the Cu salts and CuO was more toxic compared to CuSO4. The astrocytoma and glioblastoma cells were more vulnerable compared to the neuronal cells. Furthermore, it appears that oxidative stress only partially accounts for Cu-induced cell toxicity. Further studies are needed to better understand the unique susceptibility of glial cells and determine the physicochemical properties of insoluble Cu which accounts for its enhanced toxicity. 23239045 Perspectives and potential applications of nanomedicine in breast and prostate cancer. Nanomedicine is a branch of nanotechnology that includes the development of nanostructures and nanoanalytical systems for various medical applications. Among these applications, utilization of nanotechnology in oncology has captivated the attention of many research endeavors in recent years. The rapid development of nano-oncology raises new possibilities in cancer diagnosis and treatment. It also holds great promise for realization of point-of-care, theranostics, and personalized medicine. In this article, we review advances in nano-oncology, with an emphasis on breast and prostate cancer because these organs are amenable to the translation of nanomedicine from small animals to humans. As new drugs are developed, the incorporation of nanotechnology approaches into medicinal research becomes critical. Diverse aspects of nano-oncology are discussed, including nanocarriers, targeting strategies, nanodevices, as well as nanomedical diagnostics, therapeutics, and safety. The review concludes by identifying some limitations and future perspectives of nano-oncology in breast and prostate cancer management. 23561178 Home conservation strategies for tomato (Solanum lycopersicum): Storage temperature vs. duration - Is there a compromise for better aroma preservation? Expression of dissatisfaction with tomato aroma prompted us to lead this study on the impact of domestic storage conditions on volatile compounds. Two storage modalities (20 and 4°C) and two cultivars (Levovil and LCx) were used. Volatile compounds were analysed by gas chromatography-mass spectrometry detection after accelerated solvent extraction. Physical characteristics, lipoxygenase activity, hydroperoxide lyase activity; linoleic acid and linolenic acid were monitored. Storing tomatoes at 4°C induced a drastic loss in volatiles, whatever their biosynthetic origin. After 30days at 4°C, the concentration of volatiles had decreased by 66%. Reconditioning for 24h at 20°C was able to recover some aroma production after up to 6days storage at 4°C. Volatile degradation products arising from carotenoids and amino acids increased when tomatoes were kept at 20°C, while lipid degradation products did not vary. Storing tomatoes at fridge temperature, even for short durations, was detrimental for their aroma. This should be taken into account to formulate practical advice for consumers. 23411208 Alteration of α-tocopherol-associated protein (TAP) expression in human breast epithelial cells during breast cancer development. Breast cancer is the most common malignancy among women and has an age-specific incidence profile. Over the last decade, many studies have demonstrated the anticancer activity of α-tocopherol, the main and most active form of natural vitamin E. α-Tocopherol-associated protein (TAP) was found to be one of the major α-tocopherol binding proteins in human serum and in liver, brain, and prostate tissues. In this study, we found that reduced TAP expression was significantly correlated with Her2/neu receptor expression, breast cancer stage and nodal stage in paired normal and cancerous breast tissue samples from 93 patients using real-time PCR analysis. A cell viability assay showed that α-tocopheryl succinate (α-TOS), a synthetic derivative of α-tocopherol, enhanced the cells' sensitivity to doxorubicin and resulted in a reduction in cell viability in breast cancers. Taken together, these data suggest that the use of vitamin E or its analogue as a dietary supplement may be beneficial for the treatment of cancer. 23296368 Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature. Increased urinary 3-methylglutaconic acid excretion is a relatively common finding in metabolic disorders, especially in mitochondrial disorders. In most cases 3-methylglutaconic acid is only slightly elevated and accompanied by other (disease specific) metabolites. There is, however, a group of disorders with significantly and consistently increased 3-methylglutaconic acid excretion, where the 3-methylglutaconic aciduria is a hallmark of the phenotype and the key to diagnosis. Until now these disorders were labelled by roman numbers (I-V) in the order of discovery regardless of pathomechanism. Especially, the so called "unspecified" 3-methylglutaconic aciduria type IV has been ever growing, leading to biochemical and clinical diagnostic confusion. Therefore, we propose the following pathomechanism based classification and a simplified diagnostic flow chart for these "inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature". One should distinguish between "primary 3-methylglutaconic aciduria" formerly known as type I (3-methylglutaconyl-CoA hydratase deficiency, AUH defect) due to defective leucine catabolism and the-currently known-three groups of "secondary 3-methylglutaconic aciduria". The latter should be further classified and named by their defective protein or the historical name as follows: i) defective phospholipid remodelling (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome) and ii) mitochondrial membrane associated disorders (OPA3 defect or Costeff syndrome, DNAJC19 defect or DCMA syndrome, TMEM70 defect). The remaining patients with significant and consistent 3-methylglutaconic aciduria in whom the above mentioned syndromes have been excluded, should be referred to as "not otherwise specified (NOS) 3-MGA-uria" until elucidation of the underlying pathomechanism enables proper (possibly extended) classification. 23222849 Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma. Low-grade brain tumors (pilocytic astrocytomas) arising in the neurofibromatosis type 1 (NF1) inherited cancer predisposition syndrome are hypothesized to result from a combination of germline and acquired somatic NF1 tumor suppressor gene mutations. However, genetically engineered mice (GEM) in which mono-allelic germline Nf1 gene loss is coupled with bi-allelic somatic (glial progenitor cell) Nf1 gene inactivation develop brain tumors that do not fully recapitulate the neuropathological features of the human condition. These observations raise the intriguing possibility that, while loss of neurofibromin function is necessary for NF1-associated low-grade astrocytoma development, additional genetic changes may be required for full penetrance of the human brain tumor phenotype. To identify these potential cooperating genetic mutations, we performed whole-genome sequencing (WGS) analysis of three NF1-associated pilocytic astrocytoma (PA) tumors. We found that the mechanism of somatic NF1 loss was different in each tumor (frameshift mutation, loss of heterozygosity, and methylation). In addition, tumor purity analysis revealed that these tumors had a high proportion of stromal cells, such that only 50%-60% of cells in the tumor mass exhibited somatic NF1 loss. Importantly, we identified no additional recurrent pathogenic somatic mutations, supporting a model in which neuroglial progenitor cell NF1 loss is likely sufficient for PA formation in cooperation with a proper stromal environment. 23337941 Exciton diffusion in near-infrared absorbing solution-processed organic thin films. We report on singlet-singlet annihilation and exciton diffusion in as-prepared p-type and annealed n-type thin films of the low-bandgap quinoidal quaterthiophene [QQT(CN)4] using ultrafast transient absorption measurements. The decay dynamics of exciton populations are well described by a one-dimensional diffusion-limited bimolecular recombination, indicating that the singlet excitons migrate preferentially along the stacking direction. Our results show that the exciton diffusion constants in QQT(CN)4 films do not vary significantly upon thermal annealing. Exciton diffusion lengths are measured to be as high as 4 and 5 nm in as-prepared and annealed QQT(CN)4 films, respectively. We also observe an influence of the excitation densities on the singlet exciton diffusion, which is attributed to phonon scattering. Because of the possibility of patterning p-n regions in QQT(CN)4 films by thermal nanolithography techniques, this study provides important insight not only into the photophysical properties of quinoidal oligothiophene derivatives but also for their future integration into high-performance p-n nanostructured near infrared light-sensing devices. 23256816 The evolution of S100B inhibitors for the treatment of malignant melanoma. Malignant melanoma continues to be an extremely fatal cancer due to a lack of viable treatment options for patients. The calcium-binding protein S100B has long been used as a clinical biomarker, aiding in malignant melanoma staging and patient prognosis. However, the discovery of p53 as a S100B target and the consequent impact on cell apoptosis redirected research efforts towards the development of inhibitors of this S100B-p53 interaction. Several approaches, including computer-aided drug design, fluorescence polarization competition assays, NMR, x-ray crystallography and cell-based screens have been performed to identify compounds that block the S100B-p53 association, reactivate p53 transcriptional activities and induce cancer cell death. Eight promising compounds, including pentamidine, are presented in this review and the potential for future modifications is discussed. Synthesis of compound derivatives will likely exhibit increased S100B affinity and mimic important S100B-target dynamic properties that will result in high specificity. 23473664 Variations on glutamate binding in channel-gated receptors. In this issue of Structure, Lomash and colleagues report on the crystal structure and ligand binding properties of a primitive eukaryote glutamate-gated ion channel: AvGluR1. 23194559 Suitability of elemental fingerprinting for assessing the geographic origin of pumpkin (Cucurbita pepo var. styriaca) seed oil. An analytical method was developed and validated for the classification of the geographical origin of pumpkin seeds and oil from Austria, China and Russia. The distribution of element traces in pumpkin seed and pumpkin seed oils in relation to the geographical origin of soils of several agricultural farms in Austria was studied in detail. Samples from several geographic origins were taken from parts of the pumpkin, pumpkin flesh, seeds, the oil extracted from the seeds and the oil-extraction cake as well as the topsoil on which the plants were grown. Plants from different geographical origin show variations of the elemental patterns that are significantly large, reproducible over the years and ripeness period and show no significant influence of oil production procedure, to allow to a discrimination of geographical origin. A successful differentiation of oils from different regions in Austria, China and Russia classified with multivariate data analysis is demonstrated. 23508106 Loss of an igκ gene enhancer in mature B cells results in rapid gene silencing and partial reversible dedifferentiation. We address here whether there is cellular memory of a transcriptional enhancer once it has served its purpose to establish an active chromatin state. We have previously shown that the mouse Igκ gene's downstream enhancers, E3' and Ed, are essential but play redundant roles for establishing transcriptional activity in the locus during B cell development. To determine whether these enhancers are also necessary for the maintenance of transcriptional activity, we conditionally deleted E3' in mature B cells that possessed Ed(-/-) alleles. Upon E3' deletion, the locus became rapidly silenced and lost positive histone epigenetic marks, and the mature B cells partially dedifferentiated, induced RAG-1 and -2 along with certain other pro-B cell makers, and then redifferentiated after triggering Igλ gene rearrangements. We conclude that the Igκ gene's downstream enhancers are essential for both the establishment and maintenance of transcriptional activity and that there is no cellular memory of previous transcriptional activity in this locus. Furthermore, upon enhancer loss, the mature B cells unexpectedly underwent reversible retrograde differentiation. This result establishes that receptor editing can occur in mature B cells and raises the possibility that this may provide a tolerance mechanism for eliminating autoreactive B cells in the periphery. 23402549 Polymerase chain reaction-free variable-number tandem repeat typing using gold nanoparticle-DNA monoconjugates. In this work, we report a novel polymerase chain reaction (PCR)-free variable-number tandem repeat (VNTR) typing method using a T-shaped gold nanoparticle-DNA monoconjugate, called the "watching-gene assay". The T-shaped DNA probe was synthesized by "click" chemistry and linked with the gold nanoparticle to form the gold nanoparticle-DNA monoconjugate (a VNTR probe). Through a simple annealing and ligation reaction of the VNTR probe on a synthetic DNA template mimicking the human D1S80 VNTR locus, the number of tandem repeat units could be deciphered by counting the self-assembled gold nanoparticles. The number of tandem repeat units could be identified with more than 50% yield if the repeat number was less than four. In the case of the real human genomic DNA, the 18 repeat unit number could be successfully revealed by observing the 18-gold-nanoparticle cluster, which exactly corresponded to the number of tandem repeats of the real sample. Our "watching-gene assay" is rapid, simple, and direct for data interpretation, thereby providing an advanced PCR-free genetic polymorphism analysis platform. 23616238 Common variation in PPARGC1A/B and progression to diabetes or change in metabolic traits following preventive interventions: the Diabetes Prevention Program. AIMS/HYPOTHESIS: PPARGC1A and PPARGC1B encode transcriptional coactivators that regulate numerous type 2 diabetes-related metabolic processes. Common genetic variation across PPARGC1A/B was characterised by genotyping tagging variants. We then tested associations of these variants with diabetes incidence or change in quantifiable metabolic traits directly or via interactions (with metformin treatment or intensive lifestyle modification) in the Diabetes Prevention Program (DPP), a randomised controlled trial in persons at high risk of type 2 diabetes. METHODS: We used Tagger software to select 75 PPARGC1A and 94 PPARGC1B tag single nucleotide polymorphisms (SNPs) for analysis. These SNPs were tested for association with diabetes incidence using Cox proportional hazards regression models, and a range of relevant metabolic quantifiable traits, using generalised linear models. RESULTS: Eight PPARGC1A variants were nominally (p < 0.05) associated with diabetes incidence, of which one (rs3736265/Thr612Met) was associated with diabetes in the DPP (HR 1.31, 95% CI 1.05, 1.63 per copy of the 612Met allele) and in the DIAGRAM database (OR 1.11, 95% CI 1.01, 1.21). Consistent with earlier reports, the Gly482Ser (rs8192678) variant showed nominally significant effects on 1 year accumulation of adiposity and worsening insulin resistance (both p < 0.05). A third PPARGC1A variant (rs2970852) modified the effects of metformin on triacylglycerol levels (p interaction = 0.04; p = 0.0001 for association of SNP with triacylglycerol concentrations in metformin-treated participants). A number of other PPARGC1A/B variants were nominally directly associated with diabetes incidence or modified treatment effects on diabetes incidence. CONCLUSIONS/INTERPRETATION: These findings provide some novel and confirmatory insights into the roles of PPARGC1A/B variation in type 2 diabetes and related metabolic traits. TRIAL REGISTRATION: ClinicalTrials.gov NCT00004992. 23643933 Induction of the liver cancer-down-regulated long noncoding RNA uc002mbe.2 mediates trichostatin-induced apoptosis of liver cancer cells. Differential expression of long non-coding RNAs (lncRNAs) plays critical roles in hepatocarcinogenesis. Considerable attention has focused on the antitumor effect of histone deacetylase inhibitor (Trichostatin A, TSA) as well as the coding gene expression-induced apoptosis of cancer cells. However, it is not known whether lncRNA has a role in TSA-induced apoptosis of human hepatocellular carcinoma (HCC) cells. The global expression of lncRNAs and coding genes was analyzed with the Human LncRNA Array V2.0 after 24h treatment. Expression was verified in cell lines and tissues by quantitative real-time PCR. The data showed that 4.8% (959) of lncRNA and 6.1% (1849) of protein coding gene were significantly differentially expressed. The differential expressions of lncRNA and protein coding genes had distinguishable hierarchical clustering expression profiling pattern. Among these differentially expressed lncRNAs, the greatest change was noted for uc002mbe.2, which had more than 300 folds induction upon TSA treatment. TSA selectively induced uc002mbe.2 in four studied HCC cell lines. Compared with normal human hepatocytes and adjacent noncancerous tissues, uc002mbe.2 expression level was significantly lower in the HCC cell lines and liver cancer tissues. The TSA-induced uc002mbe.2 expression was positively correlated with the apoptotic effect of TSA in HCC cells. In addition, knockdown the expression of uc002mbe.2 significantly reduced TSA-induced apoptosis of Huh7cells. Therefore, TSA-induced apoptosis of HCC cells is uc002mbe.2 dependent and reduced expression of uc002mbe.2 may be associated with liver carcinogenesis. 23504356 Pharmacotherapy for the core symptoms in autistic disorder: current status of the research. The current review covers extant literature on pharmacotherapy for core symptoms of autism. The core symptoms of autism include impairments in social interaction and communication, as well as the presence of restricted and repetitive behaviors. There are no known efficacious treatments for the core social symptoms, although effects on repetitive behaviors are indicated with some data. While studies of fenfluramine, secretin, opiates, and mood stabilizers generally find no effect, mixed results suggest more research is needed on antidepressants and atypical antipsychotics. Newer lines of research, including cholinergic and glutamatergic agents and oxytocin, will be of considerable interest in the future. However, research on the treatment of core symptoms is plagued by limitations in study design, statistical power, and other issues inherent to the study of treatments for autism (e.g., heterogeneity of the disorder) that continue to prevent the elucidation of efficacious treatments. 23471561 Synthesis of novel bis-anthraquinone derivatives and their biological evaluation as antitumor agents. Cancer has become a major worldwide problem and drug resistance now is one of the most important problems in treatment of cancer. Anthraquinone derivatives represent one of the most important drugs that can be used in treatment of many types of cancer. In this study two series of novel bis-anthraquinone derivatives have been synthesized. Five of these compounds were chosen to be evaluated for their antitumor activity against human cancer cell lines by the National Cancer Institute (NCI, USA). Marked activity was shown for the tested compounds(2-6). The most active one was compound 6 with mean value -67.00 against all cell lines. Compounds 7 and 8 were found inactive. 22945305 Type 2 diabetes and cardiovascular disease in women. Cardiovascular disease is the leading cause of death in both men and women. This is also true for patients with diabetes. In general, differences between the sexes are present in several areas, such as epidemiology, pathophysiology, diagnostics, treatment response and prognosis, as well as the way in which disease is experienced and expressed. Cardiovascular disease presents later in life in women, who are therefore more likely to suffer from comorbidities. However, this age-related difference is attenuated in women with diabetes, who suffer their first myocardial infarction at about the same age as men with diabetes. Diabetes mellitus increases the risk of cardiovascular disease by three to four times in women and two to three times in men, after adjusting for other risk factors. This paper describes the differences in cardiovascular disease in men and women and the special situation of women with type 2 diabetes when it comes to risk factors, symptoms and the setting of acute coronary syndromes. Furthermore, it highlights the importance of sex-specific analyses in clinical research to improve our knowledge of cardiovascular disease in women in general and in women with diabetes in particular. The importance of taking sex into account when treating women and men at risk of cardiovascular disease is discussed. 23421331 Once-daily initiation of basal insulin as add-on to metformin: a 26-week, randomized, treat-to-target trial comparing insulin detemir with insulin glargine in patients with type 2 diabetes. AIMS: This study assessed the efficacy and safety of once-daily insulin initiation using insulin detemir (detemir) or insulin glargine (glargine) added to existing metformin in type 2 diabetes (T2D). METHODS: This 26-week, multinational, randomized, treat-to-target trial involved 457 insulin-naïve adults with T2D (HbA1c 7-9%). Detemir or glargine was added to current metformin therapy [any second oral antidiabetic drug (OAD) discontinued] and titrated to a target fasting plasma glucose (FPG) ≤90 mg/dl (≤5.0 mmol/l). Primary efficacy endpoint was change in HbA1c. RESULTS: Mean (s.d.) HbA1c decreased with detemir and glargine by 0.48 and 0.74%-points, respectively, to 7.48% (0.91%) and 7.13% (0.72%) [estimated between-treatment difference, 0.30 (95% CI: 0.14-0.46)]. Non-inferiority for detemir at the a priori level of 0.4%-points was not established. The proportions of patients reaching HbA1c ≤ 7% at 26 weeks were 38% and 53% (p = 0.026) with detemir and glargine, respectively. FPG decreased ∼43.2 mg/dl (∼2.4 mmol/l) in both groups [non-significant (NS)]. Treatment satisfaction was good for both insulins. Hypoglycaemia, which occurred infrequently, was observed less with detemir than glargine [rate ratio 0.73 (95% CI 0.54-0.98)]. The proportions of patients reaching HbA1c ≤ 7% without hypoglycaemia in the detemir and glargine groups were 32% and 38% (NS), respectively. Weight decreased with detemir [-0.49 (3.3) kg] and increased with glargine [+1.0 (3.1) kg] (95% CI for difference: -2.17 to -0.89 kg). CONCLUSION: While both detemir and glargine, when added to metformin therapy, improved glycaemic control, glargine resulted in greater reductions in HbA1c, while detemir demonstrated less weight gain and hypoglycaemia. 23000250 Three-finger toxins, a deadly weapon of elapid venom--milestones of discovery. Three-finger toxins (TFTs) are the main venom components of snakes from Elapidae family. Amino acid sequences of more than five hundreds TFTs are determined; these toxins form one of the largest protein families present in snake venoms. The first TFT α-bungarotoxin was isolated almost half a century ago and so far it remains a valuable tool in the study of nicotinic acetylcholine receptors. TFTs possess diverse biological activities; for example, α-neurotoxins bind specifically with high affinity to nicotinic acetylcholine receptors, while cytotoxins induce non-specific lysis in great variety of cells. These toxins are widely used as instruments in different branches of life sciences. In this review the main landmarks in TFT study are considered. These are the discovery and isolation of TFTs, determination of their structure and mode of action as well as evolution and relationship within the family. 23010165 A brief review of the scientific history of several lesser-known snake venom proteins: l-amino acid oxidases, hyaluronidases and phosphodiesterases. When considering the proteins and toxins in snake venom one's thoughts generally migrate to the proteinases, neurotoxins and phospholipases since these families of proteins are comprised by many of the toxins found in venom. However as modern proteomic and transcriptomic venom research has abundantly shown snake venoms are complex and containing numerous families of protein beyond the "big three". In this brief review we will discuss three of the lesser discussed proteins typically found in snake venoms: l-amino acid oxidases (LAAO); hyaluronidases and phosphodiesterases. These proteins have long been known to be part of many venoms' proteomes with reports appearing in the literature as early as 1944 for LAAO, 1947 for hyaluronidase (spreading factor), and 1932 for venom phosphodiesterase. These are more or less contemporary with the first reports (circa 1950) on snake venom proteases. Thus, the relatively modest literature on these snake venom proteins stems not from lack of early discovery but rather more likely to their ostensibly minor role in snake venom pathophysiology. In this review we will provide an overview of the experimental history of these venom proteins, their biochemical and structural features and their role in snake venom toxinology with the aim of bringing a fuller, more comprehensive, understanding of the history of laboratory research on snake venoms. In addition, there are some comments on these proteins from investigators who were actively engaged in their investigation. 23017404 Sugar metabolism in relation to chilling tolerance of loquat fruit. The relationship between chilling injury and sugar metabolism was investigated in loquat fruit stored at 1°C for 35days. No symptoms of chilling injury occurred in the fruit, of 'Ninghaibai' cultivar, during the whole storage whereas, in 'Dahongpao' fruit, severe chilling symptoms were observed after 20days of storage at 1°C. 'Ninghaibai' fruit had higher levels of glucose and fructose and higher activities of sucrose hydrolyzing enzymes, such as sucrose synthase-cleavage and invertase, than had 'Dahongpao'. Furthermore, the chilling resistant 'Ninghaibai' fruit also showed higher activities of hexokinase and fructokinase, involved in hexose phoshorylation and sugar signal generation. These results suggest that the higher content of hexoses and activities of hexose sensors were likely part of the mechanism for chilling tolerance of loquat fruit. 23623416 Synthesis and antifungal evaluation of pentyloxyl-diphenylisoxazoloyl pneumocandins and echinocandins. Echinocandins and pneumocandins are classes of lipocyclohexapeptides that are broad spectrum antifungal agents. They inhibit fungal specific 1,3-β-glucan synthase activity which is an essential component of the fungal cell wall. Chemical modifications of these two leads have produced three clinical agents namely caspofungin, micafungin and anidulafungin. The presence of hydroxy-glutamine versus threonine and unsaturated linear fatty acid versus branched chain saturated fatty acid differentiate the two classes of compounds with profound differences in their hemolytic properties. In the current study, we have replaced the side chain of the cyclohexapeptides with a common aromatic heterocyclic acyl side chain and compared the biological activities of the cores head-to-head and for the first time demonstrated the role played by the acyl chain and the hydroxy-glutamine for the antifungal potency. 23333900 Preparation of carbamazepine-Soluplus® solid dispersions by hot-melt extrusion, and prediction of drug-polymer miscibility by thermodynamic model fitting. Hot-melt extrusion (HME) is a dust- and solvent-free continuous process enabling the preparation of a variety of solid dosage forms containing solid dispersions of poorly soluble drugs into thermoplastic polymers. Miscibility of drug and polymer is a prerequisite for stable solid dispersion formation. The present study investigates the feasibility of forming solid dispersions of carbamazepine (CBZ) into polyethyleneglycol-polyvinyl caprolactam-polyvinyl acetate grafted copolymer (Soluplus®) by hot-melt extrusion. Physicochemical properties of the raw materials, extrudates, co-melted products, and corresponding physical mixtures were characterized by thermo-gravimetric analysis (TGA), differential scanning calorimetry (DSC), attenuated total reflectance infrared (ATR-FTIR) spectroscopy and hot stage microscopy (HSM), while miscibility of CBZ and Soluplus® was estimated on the basis of the Flory-Huggins theory, Hansen solubility parameters, and solid-liquid equilibrium equation. It was found that hot-melt extrusion of carbamazepine and Soluplus® is feasible on a single-screw hot-melt extruder without the addition of plasticizers. DSC analysis and FTIR spectroscopy revealed that a molecular dispersion is formed when the content of CBZ does not exceed ∼5% w/w while higher CBZ content results in a microcrystalline dispersion of CBZ form III crystals, with the molecularly dispersed percentage increasing with extrusion temperature, at the risk of inducing transformation to the undesirable form I of CBZ. Thermodynamic modeling elucidated potential limitations and temperature dependence of solubility/dispersibility of carbamazepine in Soluplus® hot-melt extrudates. The results obtained by thermodynamic models are in agreement with the findings of the HME processing, encouraging therefore their further application in the HME process development. 23153959 Three-dimensional imaging of collagen fibril organization in rat circumferential lamellar bone using a dual beam electron microscope reveals ordered and disordered sub-lamellar structures. Lamellar bone is a major component of most mammalian skeletons. A prominent component of individual lamellae are parallel arrays of mineralized type I collagen fibrils, organized in a plywood like motif. Here we use a dual beam microscope and the serial surface view (SSV) method to investigate the three dimensional collagen organization of circumferential lamellar bone from rat tibiae after demineralization and osmium staining. Fast Fourier transform analysis is used to quantitatively identify the mean collagen array orientations and local collagen fibril dispersion. Based on collagen fibril array orientations and variations in fibril dispersion, we identify 3 distinct sub-lamellar structural motifs: a plywood-like fanning sub-lamella, a unidirectional sub-lamella and a disordered sub-lamella. We also show that the disordered sub-lamella is less mineralized than the other sub-lamellae. The hubs and junctions of the canalicular network, which connect radially oriented canaliculi, are intimately associated with the disordered sub-lamella. We also note considerable variations in the proportions of these 3 sub-lamellar structural elements among different lamellae. This new application of Serial Surface View opens the way to quantitatively compare lamellar bone from different sources, and to clarify the 3-dimensional structures of other bone types, as well as other biological structural materials. 23614904 Bile Acid and Sterol Metabolism with Combined HMGCoA Reductase and PCSK9 Suppression. PCSK9 inhibition markedly augments the LDL lowering action of statins. The combination is being evaluated for long-term effects on atherosclerotic disease outcomes. However, effects of combined treatment on hepatic cholesterol and bile acid metabolism have not yet been reported. To study this, PCSK9-Y119X mutant (knockout) and wild type mice were treated ± atorvastatin for 12 wks. Atorvastatin progressively lowered plasma LDL in each group, but no differences in liver cholesterol, cholesterol ester, or total bile acid concentrations, or in plasma total bile acid levels were seen. In contrast, atorvastatin increased fecal total bile acids (~2-fold, P<0.01) and cholesterol concentrations (~3-fold, P<0.01) vs. controls for both PCSK9-Y119X and wild type mice. All 14 individual bile acids resolved by LC-MS, including primary, secondary, and conjugated species, reflected similar increases. Expression of key liver bile acid synthesis genes CYP7A1 and CYP8B1 were ~2.5-fold higher with atorvastatin in both strains, but mRNA for liver bile acid export and reuptake transporters and conjugating enzymes were not unaffected. The data suggest that hepatocyte cholesterol and bile acid homeostasis is maintained with combined PCSK9 and HMGCoA reductase inhibition through efficient liver enzymatic conversion of LDL-derived cholesterol into bile acids and excretion of both, with undisturbed enterohepatic recycling. 23553944 Bone stiffness and failure load are related with clinical parameters in men with chronic obstructive pulmonary disease. Osteoporosis is frequently seen in patients with chronic obstructive pulmonary disease (COPD). Since research on bone structure and bone strength in COPD patients is limited, the objectives of this pilot study were: 1. To compare bone structure, stiffness and failure load, measured at the peripheral skeleton, between men with and without COPD after stratification for areal bone mineral density (aBMD), and 2. To relate clinical parameters with bone stiffness and failure load in men with COPD. We included 30 men with COPD (normal aBMD n = 18, osteoporosis n = 12) and 17 men without COPD (normal aBMD n = 9, osteoporosis n = 8). We assessed pack-years of smoking, body mass index (BMI), fat free mass index (FFMI), pulmonary function (FEV1 , FEV1 /FVC, DLCO and KCO) and extent of emphysema. Bone structure of the distal radius and tibia was assessed by high resolution peripheral quantitative computed tomography (HR-pQCT), and bone stiffness and failure load of the distal radius and tibia were estimated from micro finite element analysis (µFEA). After stratification for aBMD and COPD, men with osteoporosis showed abnormal bone structure (p < 0.01), lower bone stiffness (p < 0.01) and lower failure load (p < 0.01) compared with men with normal aBMD, and men with COPD had comparable bone structure, stiffness and failure load compared with men without COPD. In men with COPD, lower FFMI was related with lower bone stiffness and failure load of the radius and tibia and lower DLCO and KCO were related with lower bone stiffness and failure load of the tibia after normalization with respect to femoral neck aBMD. Thus, this pilot study could not detect differences in bone structure, stiffness and failure load between men with and without COPD after stratification for aBMD. FFMI and gas transfer capacity of the lung were significantly related with bone stiffness and failure load in men with COPD after normalization with respect to femoral neck aBMD. © 2013 American Society for Bone and Mineral Research. 23474321 Effects of salinity stress on Bufo balearicus and Bufo bufo tadpoles: Tolerance, morphological gill alterations and Na(+)/K(+)-ATPase localization. Freshwater habitats are globally threatened by human-induced secondary salinization. Amphibians are generally poorly adapted to survive in saline environments. We experimentally investigated the effects of chronic exposure to various salinities (5%, 10%, 15%, 20%, 25%, 30% and 35% seawater, SW) on survival, larval growth and metamorphosis of tadpoles from two amphibian populations belonging to two species: the green toad Bufo balearicus and the common toad Bufo bufo. In addition, gill morphology of tadpoles of both species after acute exposure to hypertonic conditions (20%, 25%, and 30% SW) was examined by light and electron microscopy. Tadpoles experienced 100% mortality above 20% SW in B. balearicus while above 15% SW in B. bufo. We detected also sublethal effects of salinity stress on growth and metamorphosis. B. bufo cannot withstand chronic exposure to salinity above 5% SW, tadpoles grew slower and were significantly smaller than those in control at metamorphosis. B. balearicus tolerated salinity up to 20% SW without apparent effects during larval development, but starting from 15% SW tadpoles metamorphosed later and at a smaller size compared with control. We also revealed a negative relation between increasing salt concentration and gill integrity. The main modifications were increased mucous secretion, detachment of external layer, alteration of epithelial surface, degeneration phenomena, appearance of residual bodies, and macrophage immigration. These morphological alterations of gill epithelium can interfere with respiratory function and both osmotic and acid-base regulation. Significant variations in branchial Na(+)/K(+)-ATPase activity were also observed between two species; moreover an increase in enzyme activity was evident in response to SW exposure. Epithelial responses to increasing salt concentration were different in the populations belonging to two species: the intensity of histological and ultrastructural pathology in B. bufo was greater and we noticed the appearance in exposed samples of the tubular vesicle cells (TVCs). Taken together, our results demonstrated that increased salinity of freshwater may give cause for concern and must be considered a stressor for amphibians as well as other pollutants. 23609606 In vitro exploration of potential mechanisms of toxicity of the human hepatotoxic drug fenclozic acid. The carboxylic acid NSAID fenclozic acid exhibited an excellent preclinical safety profile and promising clinical efficacy, yet was withdrawn from clinical development in 1971 due to hepatotoxicity observed in clinical trials. A variety of modern in vitro approaches have been used to explore potential underlying mechanisms. Covalent binding studies were undertaken with [(14)C]-fenclozic acid to investigate the possible role of reactive metabolites. Time-dependent covalent binding to protein was observed in NADPH-supplemented liver microsomes, although no metabolites were detected in these incubations or in reactive metabolite trapping experiments. In human hepatocytes, covalent binding was observed at lower levels than in microsomes and a minor uncharacterizable metabolite was also observed. In addition, covalent binding was observed in incubations undertaken with dog and rat hepatocytes, where a taurine conjugate of the drug was detected. Although an acyl glucuronide metabolite was detected when liver microsomes from human, rat and dog were supplemented with UDPGA, there was no detectable UDPGA-dependent covalent binding. No effects were observed when fenclozic acid was assessed for P450-dependent and P450-independent cytotoxicity to THLE cell lines, time-dependent inhibition of five major human cytochrome P450 enzymes, inhibition of the biliary efflux transporters BSEP and MRP2 or mitochondrial toxicity to THLE or HepG2 cells. These data suggest that Phase 1 bioactivation plays a role in the hepatotoxicity of fenclozic acid and highlight the unique insight into mechanisms of human drug toxicity that can be provided by investigations of biotransformation and covalent binding to proteins. 23448202 Large enhancement of nonlinear optical response in a hybrid nanobiomaterial consisting of bacteriorhodopsin and cadmium telluride quantum dots. We report wavelength-dependent enormous enhancement of the nonlinear refractive index of wild-type bacteriorhodopsin in the presence of semiconductor quantum dots. The effect is strongest in the region just below the absorption edge of both constituents of this hybrid material and in samples that show strong Förster resonance energy transfer. We show that enhancements of up to 4000% can be achieved by controlled engineering of the hybrid structure involving variations of the molar ratio of the constituents. This new hybrid material with exceptional nonlinear properties will have numerous photonic and optoelectronic applications employing its photochromic, energy transfer, and conversion properties. 23410078 Isolation and structures of axistatins 1-3 from the Republic of Palau marine sponge Agelas axifera Hentschel . An investigation begun in 1979 directed at the Republic of Palau marine sponge Agelas axifera Hentschel for cancer cell growth inhibitory constituents subsequently led to the isolation of three new pyrimidine diterpenes designated axistatins 1 (1), 2 (2), and 3 (3), together with the previously reported formamides 4, 5, and agelasine F (6). The structures were elucidated by analysis of 2D-NMR spectra and by HRMS. All of the isolated compounds were found to be moderate inhibitors of cancer cell growth. Axistatins 1-3 (1-3), formamide 4, and agelasine F (6) also exhibited antimicrobial activity. 23435179 Botulinum toxins: Mechanisms of action, antinociception and clinical applications. Botulinum toxin (BoNT) is a potent neurotoxin that is produced by the gram-positive, spore-forming, anaerobic bacterium, Clostridum botulinum. There are 7 known immunologically distinct serotypes of BoNT: types A, B, C1, D, E, F, and G. Clostridum neurotoxins are produced as a single inactive polypeptide chain of 150kDa, which is cleaved by tissue proteinases into an active di-chain molecule: a heavy chain (H) of ∼100kDa and a light chain (L) of ∼50kDa held together by a single disulfide bond. Each serotype demonstrates its own varied mechanisms of action and duration of effect. The heavy chain of each BoNT serotype binds to its specific neuronal ecto-acceptor, whereby, membrane translocation and endocytosis by intracellular synaptic vesicles occurs. The light chain acts to cleave SNAP-25, which inhibits synaptic exocytosis, and therefore, disables neural transmission. The action of BoNT to block the release of acetylcholine botulinum toxin at the neuromuscular junction is best understood, however, most experts acknowledge that this effect alone appears inadequate to explain the entirety of the neurotoxin's apparent analgesic activity. Consequently, scientific and clinical evidence has emerged that suggests multiple antinociceptive mechanisms for botulinum toxins in a variety of painful disorders, including: chronic musculoskeletal, neurological, pelvic, perineal, osteoarticular, and some headache conditions. 23111374 Syntheses and in vitro evaluations of uncharged reactivators for human acetylcholinesterase inhibited by organophosphorus nerve agents. Organophosphorus nerve agents (OPNAs) are highly toxic compounds that represent a threat to both military and civilian populations. They cause an irreversible inhibition of acetylcholinesterase (AChE), by the formation of a covalent P-O bond with the catalytic serine. Among the present treatment of nerve agents poisoning, pyridinium and bis-pyridinium aldoximes are used to reactivate this inhibited enzyme but these compounds do not readily cross the blood brain barrier (BBB) due to their permanent cationic charge and thus cannot efficiently reactivate cholinesterases in the central nervous system (CNS). In this study, a series of seven new uncharged oximes reactivators have been synthesized and their in vitro ability to reactivate VX and tabun-inhibited human acetylcholinesterase (hAChE) has been evaluated. The dissociation constant KD of inhibited enzyme-oxime complex, the reactivity rate constant kr and the second order reactivation rate constant kr2 have been determined and have been compared to reference oximes HI-6, Obidoxime and 2-Pralidoxime (2-PAM). Regarding the reactivation of VX-inhibited hAChE, all compounds show a better reactivation potency than those of 2-PAM, nevertheless they are less efficient than obidoxime and HI-6. Moreover, one of seven described compounds presents an ability to reactivate tabun-inhibited hAChE equivalent to those of 2-PAM. 23214430 Structure enhancement factor relationships in single gold nanoantennas by surface-enhanced Raman excitation spectroscopy. Determining the existence of any direct spectral relationship between the far-field scattering properties and the near-field Raman-enhancing properties of surface-enhanced Raman spectroscopy (SERS) substrates has been a challenging task with only a few significant results to date. Here, we prove that hot spot dominated systems show little dependence on the far-field scattering properties because of differences between near- and far-field localized surface plasmon resonance (LSPR) effects as well as excitation of new plasmon modes via a localized emitter. We directly probe the relationship between the near- and far-field light interactions using a correlated LSPR-transmission electron microscopy (TEM) surface-enhanced Raman excitation spectroscopy (SERES) technique. Fourteen individual SERS nanoantennas, Au nanoparticle aggregates ranging from dimers to undecamers, coated in a reporter molecule and encased in a protective silica shell, were excited using eight laser wavelengths. We observed no correlation between the spectral position of the LSPR maxima and the maximum enhancement factor (EF). The single nanoantenna data reveal EFs ranging from (2.5 ± 0.6) × 10(4) to (4.5 ± 0.6) × 10(8) with maximum enhancement for excitation wavelengths of 785 nm and lower energy. The magnitude of maximum EF was not correlated to the number of cores in the nanoantenna or the spectral position of the LSPR, suggesting a separation between near-field SERS enhancement and far-field Rayleigh scattering. Computational electrodynamics confirms the decoupling of maximum SERS enhancement from the peak of the scattering spectrum. It also points to the importance of a localized emitter for radiating Raman photons to the far-field which, in nonsymmetric systems, allows for the excitation of radiative plasmon modes that are difficult to excite with plane waves. Once these effects are considered, we are able to fully explain the hot spot dominated SERS response of the nanoantennas. 23411311 Determination of the degree of oxidation in highly-oxidised lipids using profile changes of fatty acids. The degree of highly oxidised lipids was determined by a modified method using profile changes of fatty acids in lard and soybean oil heated at 180°C. The usefulness of the modified method was compared through conjugated dienoic acid (CDA) and/or p-anisidine value (p-AV) methods. Absolute values, which were expressed as equivalent to an internal standard (C11:0), of both unsaturated fatty acids (UFAs) and saturated fatty acids (SFAs) decreased significantly during thermal oxidation (p<0.05) while relative percentage of SFA increased and those of UFA decreased significantly (p<0.05). The content of caprylic acid (C8:0) increased significantly (p<0.05) as thermal oxidation time increased. The ratio of total saturated over total unsaturated fatty acids (SFAs/UFAs) or caprylic acid (C8:0) over UFAs could be useful markers to determine the degree of oxidation. Antioxidant capacity of sesamol, a free radical scavenger, was determined using the ratio of fatty acids. The modified method can be applied to determine the quality control of fried foods containing highly oxidised and abused oils, which may not be measured correctly using CDA and p-AV. 23369343 Evaluation of in vivo anti-hyperglycemic and antioxidant potentials of α-santalol and sandalwood oil. Sandalwood finds numerous mentions across diverse traditional medicinal systems in use worldwide. The objective of this study was to evaluate the in vivo anti-hyperglycemic and antioxidant potential of sandalwood oil and its major constituent α-santalol. The in vivo anti-hyperglycemic experiment was conducted in alloxan-induced diabetic male Swiss albino mice models. The in vivo antioxidant experiment was performed in d-galactose mediated oxidative stress induced male Swiss albino mice models. Intraperitoneal administration of α-santalol (100mg/kg BW) and sandalwood oil (1g/kg BW) for an week modulated parameters such as body weight, blood glucose, serum bilirubin, liver glycogen, and lipid peroxides contents to normoglycemic levels in the alloxan-induced diabetic mice. Similarly, intraperitoneal administration of α-santalol (100mg/kg BW) and sandalwood oil (1g/kg BW) for two weeks modulated parameters such as serum aminotransferases, alkaline phosphatase, bilirubin, superoxide dismutase, catalase, free sulfhydryl, protein carbonyl, nitric oxide, liver lipid peroxide contents, and antioxidant capacity in d-galactose mediated oxidative stress induced mice. Besides, it was observed that the beneficial effects of α-santalol were well complimented, differentially by other constituents present in sandalwood oil, thus indicating synergism in biological activity of this traditionally used bioresource. 23174746 Orofacial dyskinesia induced by nasal Ritalin(R) (methylphenidate) sniffing: a rare case report from Switzerland. Ritalin® (methylphenidate) is an amphetamine-like prescription stimulant commonly used in the treatment of attention deficit hyperactivity disorder in children and adults. Recently, the recreational use of Ritalin has increased, particularly among young adults. Well-known symptoms of intoxication include signs of sympathetic nervous stimulation, such as agitation, anxiety, tachycardia, hypertension, headache, tremor, and dizziness. This case report describes oral dyskinesia as a rare presentation of Ritalin intoxication, with the review of pathophysiology and some epidemiological data. 23416191 Fragment-based drug design and identification of HJC0123, a novel orally bioavailable STAT3 inhibitor for cancer therapy. Fragment-based drug design (FBDD) is a promising approach for the generation of lead molecules with enhanced activity and especially drug-like properties against therapeutic targets. Herein, we report the fragment-based drug design, systematic chemical synthesis and pharmacological evaluation of novel scaffolds as potent anticancer agents by utilizing six privileged fragments from known STAT3 inhibitors. Several new molecules such as compounds 5, 12, and 19 that may act as advanced chemical leads have been identified. The most potent compound 5 (HJC0123) has demonstrated to inhibit STAT3 promoter activity, downregulate phosphorylation of STAT3, increase the expression of cleaved caspase-3, inhibit cell cycle progression and promote apoptosis in breast and pancreatic cancer cells with low micromolar to nanomolar IC50 values. Furthermore, compound 5 significantly suppressed estrogen receptor (ER)-negative breast cancer MDA-MB-231 xenograft tumor growth in vivo (p.o.), indicating its great potential as an efficacious and orally bioavailable drug candidate for human cancer therapy. 23305127 Enhanced redifferentiation of chondrocytes on microperiodic silk/gelatin scaffolds: toward tailor-made tissue engineering. Direct-write assembly allows rapid fabrication of complex three-dimensional (3D) architectures, such as scaffolds simulating anatomical shapes, avoiding the need for expensive lithographic masks. However, proper selection of polymeric ink composition and tailor-made viscoelastic properties are critically important for smooth deposition of ink and shape retention. Deposition of only silk solution leads to frequent clogging due to shear-induced β-sheet crystallization, whereas optimized viscoelastic property of silk-gelatin blends facilitate the flow of these blends through microcapillary nozzles of varying diameter. This study demonstrates that induction of controlled changes in scaffold surface chemistry, by optimizing silk-gelatin ratio, can govern cell proliferation and maintenance of chondrocyte morphology. Microperiodic silk-gelatin scaffolds can influence postexpansion redifferentiation of goat chondrocytes by enhancing Sox-9 gene expression, aggregation, and driving cartilage matrix production, as evidenced by upregulation of collagen type II and aggrecan expression. The strategy for optimizing redifferentiation of chondrocytes can offer valuable consideration in scaffold-based cartilage repair strategies. 23357633 Antimycobacterial activity evaluation, time-kill kinetic and 3D-QSAR study of C-(3-aminomethyl-cyclohexyl)-methylamine derivatives. A series of C-(3-aminomethyl-cyclohexyl)-methylamine derivatives were synthesized and evaluated for their antitubercular activity. Some of the compounds exhibited potent activity against Mycobacterium tuberculosis H37Rv. One of the compound having t-butyl at para position of the benzene ring showed excellent activity even better than the standard drug ethambutol with MIC value 1.1 ± 0.2 μM. The time-kill kinetics study of two most active compounds showed rapid killing of the M. tuberculosis within 4 days. Additionally atom-based quantitative structure-activity relationship (QSAR) model was developed that gave a statistically satisfying result (R(2))=0.92, Q(2)=0.75, Pearson-R=0.96 and effectively predicts the anti-tuberculosis activity of training and test set compounds. 23598462 Sub-picometer structural information of graphene hidden in a 50 pm resolved image. In a 2D self-organized crystalline structure more than 1000 unit-cells can be observed in a single image. Here we exploit the benefits from having a large number of observations of the same unit cell utilizing an image processing methodology. We obtain sub-picometer resolution data from a 50 pm image of graphene, revealing a 1% axial elongation and a 3 fold symmetry, indicating a chair conformation. 23313379 The effects of natural disturbances, reef state, and herbivorous fish densities on ciguatera poisoning in Rarotonga, southern Cook Islands. Ciguatera poisoning is a critical public-health issue among Pacific island nations. Accurately predicting ciguatera outbreaks has become a priority, particularly in Rarotonga in the southern Cook Islands, which has reported the highest incidence of ciguatera poisoning globally. Since 2006, however, cases of ciguatera poisoning have declined, and in 2011 ciguatera cases were the lowest in nearly 20 years. Here we examined the relationships between cases of ciguatera poisoning, from 1994 to 2011, and: (i) coral cover, used as a proxy of reef state, (ii) the densities of herbivorous fishes, and (iii) reef disturbances. We found that coral cover was not a good predictor of cases of ciguatera poisoning, but high densities of the herbivorous fish Ctenochaetus striatus and reef disturbances were both strong predictors of ciguatera poisoning. Yet these two predictors were correlated, because the densities of C. striatus increased only after major cyclones had disturbed the reefs. Since 2006, the number of cyclones has decreased considerably in Rarotonga, because of the climatic shift toward the negative phase of the Pacific Decadal Oscillation. We suggest that fewer cyclones have led to decreases in both the densities of C. striatus and of the number of reported cases of ciguatera poisoning in Rarotonga. 23354727 Osteoporosis in men: recent progress. As osteoporosis in men has been recognized as an important clinical problem, new information is being accumulated on its scope, pathophysiology, evaluation, and treatment. Fracture risk calculators, such as FRAX, identify a large proportion of the older male population to be at heightened risk for fracture. The classification of osteoporosis into primary and secondary forms, while still useful, is affected by the fact that many men have multiple contributing factors to their fracture risk. The role of sex steroids is being better defined as other risk factors for fracture are delineated. As longevity continues to increase in men and until osteoporotic fracture is truly recognized as a potentially fatal disorder, many men will be undiagnosed and untreated. Two recent studies provide more evidence that treatments which decrease fracture risk in women do the same in men. With the publication of guidelines and increasing strength of evidence for treatment efficacy, it is hoped that more men will be evaluated and treated for this often neglected disorder. 23644525 Solution-processed organic spin-charge converter. Conjugated polymers and small organic molecules are enabling new, flexible, large-area, low-cost optoelectronic devices, such as organic light-emitting diodes, transistors and solar cells. Owing to their exceptionally long spin lifetimes, these carbon-based materials could also have an important impact on spintronics, where carrier spins play a key role in transmitting, processing and storing information. However, to exploit this potential, a method for direct conversion of spin information into an electric signal is indispensable. Here we show that a pure spin current can be produced in a solution-processed conducting polymer by pumping spins through a ferromagnetic resonance in an adjacent magnetic insulator, and that this generates an electric voltage across the polymer film. We demonstrate that the experimental characteristics of the generated voltage are consistent with it being generated through an inverse spin Hall effect in the conducting polymer. In contrast with inorganic materials, the conducting polymer exhibits coexistence of high spin-current to charge-current conversion efficiency and long spin lifetimes. Our discovery opens a route for a new generation of molecular-structure-engineered spintronic devices, which could lead to important advances in plastic spintronics. 23066949 Protein-ligand interaction study of CpOGA in complex with GlcNAcstatin. The GlcNAcstatin is a potent inhibitor of O-glycoprotein 2-acetamino-2-deoxy-β-D-glucopyranosidase, which has been related with type II diabetes and neurodegenerative disorders. Herein, hybrid quantum mechanics/molecular mechanics, molecular dynamics simulations, and potential of mean force were employed to study the interactions established between GlcNAcstatin and a bacterial O-GlcNAcase enzyme from Clostridium perfringens. The results reveal that the imidazole nitrogen atom of GlcNAcstatin has shown a better interaction with the active site of Clostridium perfringens in its protonated form, which is compatible with a substrate-assisted reaction mechanism involving two conserved aspartate residues (297 and 298). Furthermore, the quantum mechanics/molecular mechanics-molecular dynamics simulations appointed a strong interaction between Asp401, Asp298, and Asp297 residues and the GlcNAcstatin inhibitor, which is in accordance with experimental data. Lastly, these results may contribute to understand the molecular mechanism of inhibition of Clostridium perfringens by GlcNAcstatin inhibitor and, consequently, this study might be useful to design new molecules with more interesting inhibitory activity. 23401139 Toxicity and toxicokinetics of binary combinations of petroleum hydrocarbon distillates with the earthworm Eisenia andrei. Petroleum hydrocarbons (PHCs) act via narcosis and are expected to have additive toxicity. However, previous work has demonstrated less-than-additive toxicity with PHC distillates and earthworms. A study was initiated to investigate this through toxicity and toxicokinetic studies with the earthworm Eisenia andrei. Three petroleum distillate fractions, F2 (>C10-C16), F3a (>C16-C23), and F3b (>C23-C34), were used in two binary combinations, F2F3a and F3aF3b. In the toxicity study, clean soil was spiked with equitoxic combinations of the two distillates ranging from 0.5 to 2.5 toxic units. In the toxicokinetic study, a binary combination consisting of one concentration of each distillate was used. On a soil concentration basis, the toxicity of the binary combinations of distillates was less than additive. Accumulation of the individual distillates, however, was generally reduced when a second distillate was present, resulting in lower body burden. This is thought to be due to the presence of a nonaqueous-phase liquid at the soil concentrations used. On a tissue concentration basis, toxicity was closer to additive. The results demonstrate that tissue concentrations are the preferred metric for toxicity for earthworms. They also demonstrate that the Canada-wide soil standards based on individual distillates are likely protective. Environ. Toxicol. Chem. 2013;32:1016-1026. © 2013 SETAC. 23220586 Effect of polyethylene glycol conjugation on the circulatory stability of plasma-derived human butyrylcholinesterase in mice. Exogenously administered human serum butyrylcholinesterase (Hu BChE) was demonstrated to function as a bioscavenger of highly toxic organophosphorus (OP) compounds in several animal species. Since the enzyme is isolated from human serum, it is currently the most suitable pretreatment for human use. A dose of 200-300mg/70kg human adult is projected to provide protection from 2 X LD50 of soman. Due to the limited supply of Hu BChE, strategies aimed at reducing the dose of enzyme are being explored. In this study, we investigated the effect of modification with polyethylene glycol (PEG) on the in vivo stability of Hu BChE. Mice were given two injections of either Hu BChE or Hu BChE modified with PEG-5K or PEG-20K, six weeks apart. Pharmacokinetic parameters, such as mean residence time (MRT), maximal concentration (Cmax), elimination half-life (T1/2), and area under the plasma concentration time curve extrapolated to infinity (AUC), were determined. For the first injection, values for MRT, T1/2, Cmax, and AUC for PEG-5K-Hu BChE and PEG-20K-Hu BChE were similar to those for Hu BChE. These values for the second injection of Hu BChE as well as PEG-Hu BChEs were lower as compared to those for the first injections, likely due to antibody-mediated clearance. 23401291 Novel Schiff-base-derived FabH inhibitors with dioxygenated rings as antibiotic agents. Fatty acid biosynthesis plays a vital role in bacterial survival and several key enzymes involved in this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. Of these promising targets, β-ketoacyl-acyl carrier protein (ACP) synthase III (FabH) is the most attractive target that could trigger the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and -negative bacteria. Designing small molecules with FabH inhibitory activity displays great significance for developing antibiotic agents, which should be highly selective, nontoxic and broad-spectrum. In this manuscript, a series of novel Schiff base compounds were designed and synthesized, and their biological activities were evaluated as potential inhibitors. Among these 21 new compounds, (E)-N-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methylene)hexadecan-1-amine (10) showed the most potent antibacterial activity with a MIC value of 3.89-7.81 μM(-1) against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with an IC(50) value of 1.6 μM. Docking simulation was performed to position compound 10 into the E. coli FabH active site to determine the probable binding conformation. 23281242 Mesoporous metallic cells: design of uniformly sized hollow mesoporous pt-ru particles with tunable shell thicknesses. A new class of hollow mesoporous Pt-Ru and Pt particles with uniform size, named 'mesoporous metallic cells', are synthesized through a dual-templating approach using colloidal silica particles and non-ionic surfactants. To realize the full potential of mesoporous metals as electrocatalysts, the shell thicknesses, compositions, and hollow cavity sizes are precisely controlled. 23297346 Hydrogen sulfide, the next potent preventive and therapeutic agent in aging and age-associated diseases. Hydrogen sulfide (H(2)S) is the third endogenous signaling gasotransmitter, following nitric oxide and carbon monoxide. It is physiologically generated by cystathionine-γ-lyase, cystathionine-β-synthase, and 3-mercaptopyruvate sulfurtransferase. H(2)S has been gaining increasing attention as an important endogenous signaling molecule because of its significant effects on the cardiovascular and nervous systems. Substantial evidence shows that H(2)S is involved in aging by inhibiting free-radical reactions, activating SIRT1, and probably interacting with the age-related gene Klotho. Moreover, H(2)S has been shown to have therapeutic potential in age-associated diseases. This article provides an overview of the physiological functions and effects of H(2)S in aging and age-associated diseases, and proposes the potential health and therapeutic benefits of H(2)S. 23417790 Determination of mercury speciation in fish tissue with a direct mercury analyzer. Knowledge of Hg speciation in tissue is valuable for assessing potential toxicological effects in fish. Direct Hg analyzers, which use thermal decomposition and atomic absorption spectrometry, have recently gained popularity for determining organic Hg after procedural solvent extraction from some environmental media, although quantitative recovery from lipid-rich materials, such as fish liver, has been problematic. The authors developed a new method by which organic Hg in fish liver and muscle is estimated by the difference between direct measurements of inorganic Hg in an acid extract and total Hg in whole tissue. The method was validated by analysis of a certified reference material (DOLT-4 dogfish liver) and naturally contaminated fish tissues with comparison to an established Hg speciation method (gas chromatography cold vapor atomic fluorescence spectrometry). Recovery of organic Hg from DOLT-4, estimated by difference, averaged 99 ± 5% of the mean certified value for methylmercury. In most liver samples and all muscle samples, estimates of organic Hg from the proposed method were indiscernible from direct speciation measurements of methylmercury (99% ± 6%). Estimation of organic Hg by the difference between total Hg and inorganic Hg was less accurate in liver samples with a high percentage of inorganic Hg (90%). This was because of the increased uncertainty that results from estimating a third value (i.e., organic Hg) by using the difference between two large concentrations (inorganic and total Hg). The proposed method is a useful tool for examining the speciation of Hg in fish muscle and liver, and by extension, potentially other tissues and environmental media. Environ Toxicol Chem 2013;32:1237-1241. © 2013 SETAC. 23379353 Impairment of regulatory T cell function in autoimmune thyroid disease. Background: Autoimmune thyroid disease (AITD) pathogenesis may result from a loss of immune tolerance to thyroid antigens. Regulatory T cells (Tregs) control immune responses, prevent excessive inflammation, and may be dysfunctional in AITD. We investigated the role of Tregs in Hashimoto's thyroiditis (HT) and Graves' disease (GD). Our goal was to identify differences in CD4+CD25hi Treg function or number in patients with GD and HT, compared to healthy controls (HC). Methods: Treg number was assessed by flow cytometric analysis in samples from twenty AITD patients (7 GD, 13 HT), 9 HC, and 7 individuals with Down syndrome (DS), a genetic disorder associated with multiple autoimmune disorders including AITD. Treg function was assessed by the inhibition of proliferation (radioactive thymidine incorporation into DNA) of blood-derived T effector cells (Teff) by Tregs in a co-culture. Various methods of stimulation were contrasted. Cytokine levels were determined in conditioned media from the co-cultures. Results: No differences were found in the frequency of Tregs as a percentage of CD4+ cells between AITD and HC. AITD Tregs were less capable of inhibiting the proliferation of Teff cells when compared to HC, however, the impairment was dependent on the type of stimulation used. DS patients without AITD exhibited normal Treg function. We observed few differences in cytokine production between HC and AITD patients. Conclusions: Tregs from AITD patients are partly dysfunctional, possibly explaining their autoimmunity. Future work will elucidate the diagnostic potential and pathophysiology of Tregs in AITD. 23151611 Antidepressant-like effect of oleanolic acid in mice exposed to the repeated forced swimming test. The study aimed to explore the antidepressant-like effect of oleanolic acid and its possible mechanism related to the monoaminergic system and neurotrophin in mice exposed to the repeated forced swimming test (FST). Both the duration and the latency of immobility affected by oleanolic acid (10, 20 and 40 mg/kg) were evaluated in the FST repeated at intervals on days 1, 7 and 14, followed by neurochemical and brain-derived neurotrophic factor (BDNF) analyses in the mouse brain regions of frontal cortex and whole hippocampus. A repeated analysis of variance (ANOVA) indicated that over retesting the immobility time increased, whereas latency to immobility tended to decrease. Minute-by-minute analysis showed that immobility time also increased during the 4-min course of the test. In addition, post-hoc Dunnett's test demonstrated that sub-chronic and chronic, but not acute, oleanolic acid treatment reduced the immobility time (sub-chronic: 20 mg/kg, 43.5%; chronic: 10 mg/kg, 19.3%; 20 mg/kg, 31.8%) and increased the latency to immobility (sub-chronic: 10 mg/kg, 60.6%; 20 mg/kg, 80.1%; chronic: 10 mg/kg, 121.8%; 20 mg/kg, 140.8%; 40 mg/kg, 80.0%). Furthermore, chronic administration of oleanolic acid significantly increased serotonin (5-HT) levels (frontal cortex: 44.5%, 41.9%, 27.5% for 10, 20, 40 mg/kg; hippocampus: 57.2%, 80.9% for 10, 20 mg/kg), decreased 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio (frontal cortex: 31.6%, 30.1%, 23.5%; hippocampus: 40.6%, 47.7%, 29.2% for 10, 20, 40 mg/kg) and elevated norepinephrine (NE) levels (hippocampus: 20 mg/kg, 45.4%) but did not alter dopamine (DA) levels. Moreover, BDNF levels in the two brain regions were also elevated by chronic oleanolic acid treatment (frontal cortex: 20 mg/kg, 67.2%; hippocampus: 10 mg/kg, 36.4%; 20 mg/kg, 55.1%). Taken together, these findings imply that functions of 5-HT, NE and BDNF may be involved in the antidepressant-like effect of oleanolic acid. 23561171 Rapid chemical profiling of saponins in the flower buds of Panax notoginseng by integrating MCI gel column chromatography and liquid chromatography/mass spectrometry analysis. The flower buds of Panax notoginseng (Notoginseng flower, FBP) are used as the traditional Chinese medicine San-Qi-Hua. In this study, we conducted column chromatography fractionation and liquid chromatography/mass spectrometry (LC/MS) analysis to comprehensively profile bioactive notoginseng saponins (ginsenosides) in FBP. MCI gel column chromatography allowed separation and enrichment of minor saponins. Electrospray ionization tandem mass spectrometry of [M-H](-) and [M+Na](+) precursor ions of the saponins provided reliable structural information for the sapogenin, and sequence of sugar chains. Confirmed by high-accuracy Q-TOF analysis, 170 notoginseng saponins were characterized from FBP, and 91 of them were reported from Panax species for the first time. The new ginsenosides contain acyl groups on α-chain, malonyl group at 20-OH, or di-malonyl groups. This study also indicated that the flower buds of P. notoginseng contained more protopanaxadiol-type but less protopanaxatriol-type ginsenosides than the roots. 23489629 N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11β-hydroxysteroid dehydrogenase type 1: strategies to eliminate reactive metabolites. N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11β-hydroxysteroid dehydrogenase type 1. A screen for bioactivation revealed that these compounds formed glutathione conjugates. This communication presents the results of a risk benefit analysis carried out to progress 2 (PF-915275) to a clinical study and the strategies used to eliminate reactive metabolites in this series of inhibitors. Based on the proposed mechanism of bioactivation and structure-activity relationships, design efforts led to N-(pyridin-2-yl) arylsulfonamides such as 18 and 20 that maintained potent 11β-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were negative in the reactive metabolite assay. 23561089 The enhancement of antioxidant compounds extracted from Thymus vulgaris using enzymes and the effect of extracting solvent. We evaluate the total phenolic compounds (TPC) content and the antioxidant activity (AA) of extracts obtained from ground fresh thyme (FT) and depleted thyme (DT), a by-product of the process of essential oil extraction. In addition, enzymatic treatments were evaluated to improve the extraction yields of polyphenolic compounds from thyme. Extractions were performed using several solvents as methanol, ethanol, and water. Enzymes were applied prior to extraction or during the extraction process. The best results were obtained using a mixture of methanol and water, resulting in 2790 and 220mg Gallic acid equivalent (GAE)/L of TPC for FT and DT, respectively. A similar result was observed for AA. With regard to enzymatic treatment, application of Grindamyl CA 150 enzyme as a pre-treatment resulted in the production of an extract from DT with 614mg TE (trolox equivalent)/L of AA, 70% more than the control, and an AA of 621mg TE/L (74% more than the control sample) was obtained using Grindamyl CA 150 during the extraction process. These results suggest that enzymatic treatment is an interesting alternative for producing antioxidant extracts from DT. 23497882 Structural characterisation of polysaccharides from Tricholoma matsutake and their antioxidant and antitumour activities. In this study, polysaccharides from Tricholoma matsutake (TM-P) were purified using a DEAE-Sepharose fast flow column and three polysaccharide fractions (TM-P1, TM-P2 and TM-P3) were obtained. The chemical composition and structural characteristics of TM-P2 were quite different from those of TM-P1 and TM-P3. TM-P2 consisted of glucose, galactose and mannose with a molar ratio of 5.9:1.1:1.0. The glycosidic linkages were mainly composed of 1,6- and 1-linked glucose. Furthermore, TM-P2 showed the strongest in vitro antioxidant and antitumour activities. The oxygen radical absorbance capacity (ORAC) of TM-P2 was 2100.44 μmol Trolox/g. The antiproliferative activities of TM-P2 (4.0mg/ml) on the growth of HepG2 and A549 cells were 67.98% and 59.04%, respectively. 23194528 Characterisation of tequila according to their major volatile composition using multilayer perceptron neural networks. Differentiation of silver, gold, aged and extra-aged tequila using 1-propanol, ethyl acetate, 2-methyl-1-propanol, 3-methyl-1-butanol and 2-methyl-1-butanol and furan derivatives like 5-(hydroxymethyl)-2-furaldehyde and 2-furaldehyde has been carried out. The content of 1-propanol, ethyl acetate, 2-methyl-1-propanol, 3-methyl-1-butanol and 2-methyl-1-butanol was determined by means of head space solid phase microextraction gas chromatography mass-spectrometry. 5-(Hydroxymethyl)-2-furaldehyde and 2-furaldehyde were determined by high performance liquid chromatography with diode array detection. Kruskal-Wallis test was used to highlight significant differences between types of tequila. Principal component analysis was applied as visualisation technique. Linear discriminant analysis and multilayer perceptron artificial neural networks were used to construct classification models. The best classification performance was obtained when multilayer perceptron model was applied. 23537897 The birth and early years of INA, the International Neurotoxicology Association. The International Neurotoxicology Association (INA) is a scientific society whose members have interest and expertise in the discipline of neurotoxicology. The idea of forming INA was born in 1984, as a follow-up to a NATO-sponsored meeting on Toxicology of the Nervous System. INA held its first meeting in the Netherlands in 1987 and has had continuous meetings every other year since then. INA is registered as a scientific society in the Netherlands, and is an affiliated society of IUTOX. This paper presents a personal account of the events that led to the birth of INA, and of the first fifteen years of this association. 23352748 Rhododendron tomentosum (Ledum palustre). A review of traditional use based on current research. Rhododendron tomentosum Harmaja (previously: Ledum palustre) is a fragrant evergreen shrub found in peaty soils in northern Europe, Asia and North America, commonly referred to as wild rosemary, marsh tea, marsh rosemary or northern Labrador tea. At least since the eighteenth century it has been used in ethnomedicine for the treatment of various ailments, such as rheumatism, cough, cold and insect bites, as well as a repellent. The essential oil of wild rosemary with the rich polyphenolic fraction possesses analgesic, anti-inflammatory, antimicrobial, antiviral, antifungal and insecticidal potential, demonstrated by in vivo and in vitro studies. In addition, recent scientific research reported the promising antidiabetic, antioxidant and anticancer properties. This review summarizes the information concerning taxonomy, botany, ecology, chemical composition, biological activities, toxicology and traditional and contemporary application of Rhododendron tomentosum plants. 23460347 Arraying Cell Cultures Using PEG-DMA Micromolding in Standard Culture Dishes. A robust and effortless procedure is presented, which allows for the microstructuring of standard cell culture dishes. Cell adhesion and proliferation are controlled by three-dimensional poly(ethylene glycol)-dimethacrylate (PEG-DMA) microstructures. The spacing between microwells can be extended to millimeter size in order to enable the combination with robotic workstations. Cell arrays of microcolonies can be studied under boundary-free growth conditions by lift-off of the PEG-DMA layer in which the growth rate is accessible via the evolution of patch areas. Alternatively, PEG-DMA stencils can be used as templates for plasma-induced patterning. 23225780 N-cyano sulfoximines: COX inhibition, anticancer activity, cellular toxicity, and mutagenicity. From insects to cancer: N-Cyano sulfoximines were evaluated for COX inhibition and antiproliferative activity against a panel of cancer cell lines. The most active compound exhibited potent COX-2 inhibition, some selectivity for COX-2 over COX-1, only slight cytotoxicity towards healthy cells (HaCaT skin cells), and no mutagenic potential (as determined by an Ames assay). 23454308 Cytotoxicity of aluminium oxide nanoparticles towards fresh water algal isolate at low exposure concentrations. The growing commercial applications had brought aluminium oxide nanoparticles under toxicologists' purview. In the present study, the cytotoxicity of two different sized aluminium oxide nanoparticles (ANP(1), mean hydrodynamic diameter 82.6±22nm and ANP(2), mean hydrodynamic diameter 246.9±39nm) towards freshwater algal isolate Chlorella ellipsoids at low exposure levels (≤1μg/mL) using sterile lake water as the test medium was assessed. The dissolution of alumina nanoparticles and consequent contribution towards toxicity remained largely unexplored owing to its presumed insoluble nature. Herein, the leached Al(3+) ion mediated toxicity has been studied along with direct particulate toxicity to bring out the dynamics of toxicity through colloidal stability, biochemical, spectroscopic and microscopic analyses. The mean hydrodynamic diameter increased with time both for ANP(1) [82.6±22nm (0h) to 246.3±59nm (24h), to 1204±140nm (72h)] and ANP(2) [246.9±39nm (0h) to 368.28±48nm (24h), to 1225.96±186nm (72h)] signifying decreased relative abundance of submicron sized particles (<1000nm). The detailed cytotoxicity assays showed a significant reduction in the viability dependent on dose and exposure. A significant increase in ROS and LDH levels were noted for both ANPs at 1μg/mL concentration. The zeta potential and FT-IR analyses suggested surface chemical interaction between nanoparticles and algal cells. The substantial morphological changes and cell wall damage were confirmed through microscopic analyses (SEM, TEM, and CLSM). At 72h, significant Al(3+) ion release in the test medium [0.092μg/mL for ANP(1), and 0.19μg/mL for ANP(2)] was noted, and the resulting suspension containing leached ions caused significant cytotoxicity, revealing a substantial ionic contribution. This study indicates that both the nano-size and ionic dissolution play a significant role in the cytotoxicity of ANPs towards freshwater algae, and the exposure period largely determines the prevalent mode of nano-toxicity. 23543014 Commentary to Gebel 2012: a quantitative review should apply meta-analytical methods. Gebel (2012) performed a quantitative review of inhalation rat studies on the association of granular biopersistent dust exposures and lung cancer risk. The analytical methods applied are unreliable because they do not fulfil the requirements of current meta-analytical methods. 22982206 Verrucarin A sensitizes TRAIL-induced apoptosis via the upregulation of DR5 in an eIF2α/CHOP-dependent manner. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising candidates for new cancer therapeutics. However, resistance to TRAIL in some cancers remains a current problem in recent. The protein-folding compartment of the endoplasmic reticulum (ER) is particularly sensitive to disturbances, which, if severe, may trigger apoptosis. Therefore, we examined whether verrucarin A (VA) sensitize TRAIL-induced apoptosis in cancer cells by induction of ER stress. We first found that VA induces a major molecule of ER stress, CCAAT/enhancer binding protein homologous protein (CHOP)-dependent DR5 induction and subsequently increases TRAIL-induced cleavage of caspases and PARP in TRAIL-resistant Hep3B cells. Importantly, the transient knockdown using siRNA for CHOP abrogated VA-induced DR5 expression and attenuated TRAIL-induced apoptosis. Treatment with VA also increased the levels of phosphorylation of eukaryotic translation initiation factor-2α (eIF2α), which is a common cellular response of ER stress. Furthermore, salubrinal, a specific eIF2α phosphorylation-inducing agent, increased CHOP and DR5 expression in the presence of VA. In contrast, transfection of mutant-eIF2α significantly reversed VA-induced apoptosis with downregulation of CHOP-dependent DR5 expression. Therefore, VA-induced eIF2α phosphorylation seemed to be important for CHOP and DR5 upregulation and TRAIL-induced apoptosis. In addition, generation of reactive oxygen species (ROS) is an effector molecular in sensitization of VA-induced ER stress. We concluded that VA triggers TRAIL-induced apoptosis by eIF2α/CHOP-dependent DR5 induction via ROS generation. 23265880 A new single-photon emission computed tomography (SPECT) imaging agent for serotonin transporters: [(125)I]Flip-IDAM, (2-((2-((dimethylamino)methyl)-4-iodophenyl)thio)phenyl)methanol. New ligands for in vivo brain imaging of serotonin transporter (SERT) with single photon emission tomography (SPECT) were prepared and evaluated. An efficient synthesis and radiolabeling of a biphenylthiol, FLIP-IDAM, 4, was accomplished. The affinity of FLIP-IDAM was evaluated by an in vitro inhibitory binding assay using [(125)I]-IDAM as radioligand in rat brain tissue homogenates (K(i) = 0.03 nM). New [(125)I]Flip-IDAM exhibited excellent binding affinity to SERT binding sites with a high hypothalamus to cerebellum ratio of 4 at 30 min post iv injection. The faster in vivo kinetics for brain uptake and a rapid washout from non-specific regions provide excellent signal to noise ratio. This new agent, when labeled with (123)I, may be a useful imaging agent for mapping SERT binding sites in the human brain. 22986217 Soy isoflavones modulate adipokines and myokines to regulate lipid metabolism in adipose tissue, skeletal muscle and liver of male Huanjiang mini-pigs. Although a growing body of evidence suggests that soy isoflavones help regulate lipid metabolism, the underlying mechanism has not yet been thoroughly clarified. The present study was undertaken to determine the effects of soy isoflavones on the expression of genes involved in lipid metabolism in different adipose tissue depots, skeletal muscle and liver of male Huanjiang mini-pigs, as well as the expression of adipokines and myokines. A total of 36 male Huanjiang mini-pigs were fed basal diet (control, Con), low-dose soy isoflavones (LSI) and high-dose soy isoflavones (HSI). The results showed that LSI and HSI regulated the expression of genes involved in the anabolism and catabolism of fatty acids in dorsal subcutaneous (DSA), abdominal subcutaneous (ASA) and perirenal (PRA) adipose tissue depots, as well as longissimus dorsi muscle (LDM) and liver. LSI and HSI also regulated the expression of adipokines in DSA, ASA and PRA, and the expression of myokines in LDM in male Huanjiang mini-pigs. In addition, soy isoflavones regulated plasma glucose, leptin and adiponectin contents after treatment for two months. Our results indicate that soy isoflavones, by regulating the expression of adipokines and myokines, may regulate the metabolism of lipids and could have potential therapeutic applications in lipid abnormalities. 23210851 Recent advances in the development of catalytic inhibitors of human DNA topoisomerase IIα as novel anticancer agents. DNA topoisomerases comprise an important family of enzymes that catalyse the induction of topological changes (e.g. relaxation/ supercoiling, catenation/decatenation and knotting/unknotting) in the DNA molecule. These enzymes perform their functions by creating transient either single-stranded or double-stranded breaks in the DNA molecule. Due to their ability to modulate the topology of the DNA molecule, DNA topoisomerases play vital roles in replication, transcription, chromosome separation and segregation, and thus represent an important collection of design targets for novel anticancer drugs. The aim of this review is to provide an overview of the development of catalytic inhibitors of the human topoisomerase IIα enzyme--an important member of the DNA topoisomerase family--as potential novel anticancer agents. The group of catalytic topoII inhibitors is classified into four types according to their molecular mechanism of action: inhibitors that bind to the ATP binding site, inhibitors that prevent the ATP hydrolysis step and trap the enzyme in a closed clamp, inhibitors that block the DNA cleavage and inhibitors that prevent the enzyme binding to the DNA. One of the important considerations highlighted throughout this review is the structure-based perspective of inhibitor design, giving the reader a medicinal chemist's perspective on this vibrant and active field of drug design research. 23217961 Structure-activity relationship study on benzoic acid part of diphenylamine-based retinoids. Based on structure-activity relationship studies of the benzoic acid part of diphenylamine-based retinoids, the potent RXR agonist 4 was derivatized to obtain retinoid agonists, synergists, and an antagonist. Cinnamic acid derivatives 5 and phenylpropionic acid derivatives 6 showed retinoid agonistic and synergistic activities, respectively. The difference of the activities is considered to be due to differences in the flexibility of the carboxylic acid-containing substituent on the diphenylamine skeleton. Compound 7, bearing a methyl group at the meta position to the carboxyl group, was an antagonist, dose-dependently inhibiting HL-60 cell differentiation induced by 3.3 × 10(-10)M Am80. 23106482 Chemical constituents of Arisaema franchetianum tubers. A novel pyrrolidine alkaloid, (2R*,3S*,5S*)-N,2-dimethyl-3-hydroxy-5-(10-phenyldecyl)pyrrolidine (1), and 17 known compounds were isolated from Arisaema franchetianum Engl. (Araceae) tubers. The 17 compounds were bergenin (2), emodin (3), caffeic acid (4), nobiletin (5), 3-O-β-d-galactopyranosyl-hederagenin 28-O-β-d-xylopyranosyl(1 → 6)-β-d-galactopyranosyl ester (6), coniferin (7), qingyangshengenin (8), methylconiferin (9), syringaresinol 4'-O-β-d-glucopyranoside (10), gagaminine (11), perlolyrine (12), (S)-1-(1'-hydroxyethyl)-β-carboline (13), 1-(β-carboline-1-yl)-3,4,5-trihydroxy-1-pentanone (14), 1-methoxycarbonyl-β-carboline (15), indolo[2,3-α]carbazole (16), 4-hydroxycinnamic acid methyl ester (17), and methyl 4-[2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-1-(hydroxymethyl)ethyl] ferulate (18). The inhibitory activities of compound 1 and its N-methyl derivative (1a) against porcine respiratory and reproductive syndrome virus (PRRSV), human leukemic K562 cells, and human breast cancer MCF-7 cells were evaluated. Compounds 1 [50% inhibited concentration (IC(50)) = 12.5 ± 0.6 μM] and 1a (IC(50) = 15.7 ± 0.9 μM) were cytotoxic against K562 cells. Compound 1a also had a weak effect on PRRSV with an IC(50) value of 31.9 ± 6.0 μM [selectivity index (SI) = 18.7]. 23122140 Carotenoid compositions of coloured tomato cultivars and contribution to antioxidant activities and protection against H(2)O(2)-induced cell death in H9c2. The carotenoid compositions, antioxidant activities and the potential cardio-protective role of 13 tomato cultivars with distinct colour were studied. Colour coordinates were evaluated by colorimeter and the carotenoid compositions were analysed by UPLC. Red tomatoes had the highest total carotenoid contents (TCC) and antioxidant activities, followed by purple, orange, pink and yellow ones. The TCC were 120.5-278.0 μg/gDW, and the antioxidant activities were 21.32-40.07 μmolTE/gDW (PCL), 64.42-89.98% (DPPH) and 10.47-13.76 μmolTE/g DW (ORAC), respectively. The lipophilic extracts were also found to prevent cell death in a cell-based model system using cardiac H9c2 cells and H(2)O(2), via attenuation of the caspase-3 and matrix metalloproteinase-2 activities. The extracts of different tomatoes showed strong but different antioxidant activities. Roles of total and individual carotenoids in the antioxidant activities were studied and lycopene showed the highest correlation. Results of this study can be used to guide the development of new tomato cultivars and functional foods, and benefit the consumers. 23207477 Cobalt whole blood concentrations in healthy adult male volunteers following two-weeks of ingesting a cobalt supplement. Recently, there has been an increase in the marketing and sales of dietary supplements, energy drinks, and other consumer products that may contain relatively high concentrations of essential elements. Cobalt-containing supplements are readily available in the U.S. and have been marketed to consumers as energy enhancers. However, little information is available regarding cobalt (Co) body burden and steady-state blood concentrations following the intake of Co dietary supplements. We assessed Co whole blood concentrations in four healthy adult male volunteers who ingested a commercially available Co supplement (0.4 mg Co/day) for 15 or 16 days. Pre-supplementation blood Co concentrations were less than the reporting limit of 0.5 μg/L, consistent with background concentrations reported to range between 0.1 and 0.4 μg/L. The mean whole blood Co concentration in the volunteers after 15 or 16 days of dosing was 3.6 μg Co/L and ranged from 1.8 to 5.1 μg Co/L. The mean observed concentration in the study group was approximately 9-36 times greater than background concentrations. Further studies of Co whole blood concentrations following supplementation over longer time periods with additional monitoring of physiological parameters may provide useful information for evaluating the health of persons who take various doses of Co. 23580169 A XAS study of the luminescent Eu centers in thiosilicate phosphors. Due to its bright yellow-to-red emission, europium doped Ca2SiS4 is a very interesting material for phosphor converted light emitting diodes. The emission spectrum is highly dependent on the Eu concentration and can consist of more than one emission band. We combined X-ray absorption fine structure and photoluminescence measurements to analyze the structure of europium centers in (Ca,Eu)2SiS4 luminescent powders. This paper provides an explanation for the concentration dependency of the emission spectra. We find that at low dopant concentrations a large fraction of trivalent europium ions is unexpectedly present in the powders. These trivalent europium ions tend to form defect clusters in the luminescent powders. Furthermore we observe a preferential substitution of the europium ions over the two different substitutional Ca sites, which changes upon increasing the dopant concentration. At high dopant concentration, the powder crystallizes in the monoclinic Eu2SiS4 structure. Once more a preferential substitution of the europium ions is observed. Summarizing, the influence of the concentration on the emission spectrum is explained by a difference in preferential occupation of the Eu ions in the lattice. 23540713 Asymmetric Collapse in Biomimetic Complex Coacervates Revealed by Local Polymer and Water Dynamics. Complex coacervation is a phenomenon characterized by the association of oppositely charged polyelectrolytes into micrometer-scale liquid condensates. This process is the purported first step in the formation of underwater adhesives by sessile marine organisms, as well as the process harnessed for the formation of new synthetic and protein-based contemporary materials. Efforts to understand the physical nature of complex coacervates are important for developing robust adhesives, injectable materials, or novel drug delivery vehicles for biomedical applications; however, their internal fluidity necessitates the use of in situ characterization strategies of their local dynamic properties, capabilities not offered by conventional techniques such as X-ray scattering, microscopy, or bulk rheological measurements. Herein, we employ the novel magnetic resonance technique Overhauser dynamic nuclear polarization enhanced nuclear magnetic resonance (DNP), together with electron paramagnetic resonance (EPR) line shape analysis, to concurrently quantify local molecular and hydration dynamics, with species- and site-specificity. We observe striking differences in the structure and dynamics of the protein-based biomimetic complex coacervates from their synthetic analogues, which is an asymmetric collapse of the polyelectrolyte constituents. From this study we suggest charge heterogeneity within a given polyelectrolyte chain to be an important parameter by which the internal structure of complex coacervates may be tuned. Acquiring molecular-level insight to the internal structure and dynamics of dynamic polymer complexes in water through the in situ characterization of site- and species-specific local polymer and hydration dynamics should be a promising general approach that has not been widely employed for materials characterization. 23490078 The effect of a unique halide-stabilizing residue on the catalytic properties of haloalkane dehalogenase DatA from Agrobacterium tumefaciens C58. Haloalkane dehalogenases catalyze the hydrolysis of carbon-halogen bonds in various chlorinated, brominated and iodinated compounds. These enzymes have a conserved pair of halide-stabilizing residues that are important in substrate binding and stabilization of the transition state and the halide ion product via hydrogen bonding. In all previously known haloalkane dehalogenases, these residues are either a pair of tryptophans or a tryptophan-asparagine pair. The newly-isolated haloalkane dehalogenase DatA from Agrobacterium tumefaciens C58 (EC 3.8.1.5) possesses a unique halide-stabilizing tyrosine residue, Y109, in place of the conventional tryptophan. A variant of DatA with the Y109W mutation was created and the effects of this mutation on the structure and catalytic properties of the enzyme were studied using spectroscopy and pre-steady-state kinetic experiments. Quantum mechanical and molecular dynamics calculations were used to obtain a detailed analysis of the hydrogen-bonding patterns within the active sites of the wild-type and the mutant, as well as of the stabilization of the ligands as the reaction proceeds. Fluorescence quenching experiments suggested that replacing the tyrosine with tryptophan improves halide binding by 3.7-fold, presumably as a result of the introduction of an additional hydrogen bond. Kinetic analysis revealed that the mutation affected the substrate specificity of the enzyme and reduced its K0.5 for selected halogenated substrates by a factor of 2-4, without impacting the rate-determining hydrolytic step. We conclude that DatA is the first natural haloalkane dehalogenase that stabilizes its substrate in the active site using only a single hydrogen bond, which is a new paradigm in catalysis by this enzyme family. 22424117 Antioxidant and lipoxygenase inhibiting new iridoid glucosides from Caryopteris odorata. The phytochemical investigation of the ethylacetate-soluble fraction of Caryopteris odorata (Ham. ex Roxb.) led to the isolation of four new iridoid glucosides (1-4): 8-O-trans-cinnamoyl caryoptoside (1), 8-O-trans-cinnamoyl shanzhiside methylester (2), 8-O-trans-cinnamoyl mussaenoside (3) and 8-O-cafeoyl massenoside (4). The structures of these compounds were determined by FAB-MS, IR, 1D and 2D-NMR spectroscopy and by comparing with the published data of the closely related compounds. The antioxidant potential of the isolated iridoids (1-4) was evaluated relative to conventionally used standards and these molecules exhibited good antioxidant potential. Moreover, their inhibitory potential was also screened against three enzymes, namely acetyl cholinesterase, butyrylcholinesterase and lipoxygenase. These iridoid glucosides were found to be inactive against acetyl and butyrylcholinesterases but active against lipoxygenase. 23530018 Chalcogenopyrylium Dyes as Differential Modulators of Organic Anion Transport by MRP1, MRP2 and MRP4. Multidrug resistance proteins (MRPs) mediate the ATP-dependent efflux of structurally diverse compounds, including anticancer drugs and physiological organic anions. Five classes of chalcogenopyrylium dyes (CGPs) were examined for their ability to modulate transport of [(3)H]estradiol glucuronide (E217βG) (a prototypical MRP substrate) into MRP-enriched inside-out membrane vesicles. Additionally, some CGPs were tested in intact transfected cells using a calcein efflux assay. Sixteen of 34 CGPs inhibited MRP1-mediated E217βG uptake by >50% (IC50's 0.7-7.6 μM). Of 9 CGPs with IC50's ≤2 μM, two belonged to Class I, two to Class III and five to Class V. When tested in the intact cells, only 4 of 16 CGPs (at 10 μM) inhibited MRP1-mediated calcein efflux by >50% (III-1, V-3, -4, -6) while a fifth (I-5) inhibited efflux by just 23%. These five CGPs also inhibited [(3)H]E217βG uptake by MRP4. In contrast, their effects on MRP2 varied with two (V-4, V-6) inhibiting E217βG transport (IC50's 2.0, 9.2 μM), two (V-3, III-1) stimulating transport (>2-fold), while CGP I-5 had no effect. Strikingly, although V-3 and V-4 had opposite effects on MRP2 activity, they are structurally identical except for their chalcogen atom (Se versus Te). This study is the first to identify Class V CGPs with their distinctive methine or trimethine linkage between two disubstituted pyrylium moieties as a particularly potent class of MRP modulators and also show that within this core structure, differences in the electronegativity associated with a chalcogen atom can be the sole determinant of whether a compound will stimulate or inhibit MRP2. 23639430 When a good taste turns bad: Neural mechanisms underlying the emergence of negative affect and associated natural reward devaluation by cocaine. An important feature of cocaine addiction in humans is the emergence of negative affect (e.g., dysphoria, irritability, anhedonia), postulated to play a key role in craving and relapse. Indeed, the DSM-IV recognizes that social, occupational and/or recreational activities become reduced as a consequence of repeated drug use where previously rewarding experiences (e.g., food, job, family) become devalued as the addict continues to seek and use drug despite serious negative consequences. Here, research in the Carelli laboratory is reviewed that examined neurobiological mechanisms that may underlie these processes using a novel animal model. Oromotor responses (taste reactivity) were examined as rats learned that intraoral infusion of a sweet (e.g., saccharin) predicts impending but delayed access to cocaine self-administration. We showed that rats exhibit aversive taste reactivity (i.e., gapes/rejection responses) during infusion of the sweet paired with impending cocaine, similar to aversive responses observed during infusion of quinine, a bitter tastant. Critically, the expression of this pronounced aversion to the sweet predicted the subsequent motivation to self-administer cocaine. Electrophysiology studies show that this shift in palatability corresponds to an alteration in nucleus accumbens (NAc) cell firing; neurons that previously responded with inhibition during infusion of the palatable sweet shifted to excitatory activity during infusion of the cocaine-devalued tastant. This excitatory response profile is typically observed during infusion of quinine, indicating that the once palatable sweet becomes aversive following its association with impending but delayed cocaine, and NAc neurons encode this aversive state. We also review electrochemical studies showing a shift (from increase to decrease) in rapid NAc dopamine release during infusion of the cocaine-paired tastant as the aversive state developed, again, resulting in responses similar to quinine infusion. Collectively, our findings suggest that cocaine-conditioned cues elicit a cocaine-need state that is aversive, is encoded by a distinct subset of NAc neurons and rapid dopamine signaling, and promotes cocaine-seeking behavior. Finally, we present data showing that experimentally induced abstinence (30 days) exacerbates this natural reward devaluation by cocaine, and this effect is correlated with a greater motivation to lever press during extinction. Dissecting the neural mechanisms underlying these detrimental consequences of addiction is critical since it may lead to novel treatments that ameliorate negative affective states associated with drug use and decrease the drive (craving) for the drug. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. 23201442 Raloxifene affects fatty acid oxidation in livers from ovariectomized rats by acting as a pro-oxidant agent. Estrogen deficiency accelerates the development of several disorders including visceral obesity and hepatic steatosis. The predisposing factors can be exacerbated by drugs that affect hepatic lipid metabolism. The aim of the present work was to determine if raloxifene, a selective estrogen receptor modulator (SERM) used extensively by postmenopausal women, affects hepatic fatty acid oxidation pathways. Fatty acids oxidation was measured in the livers, mitochondria and peroxisomes of ovariectomized (OVX) rats. Mitochondrial and peroxisomal β-oxidation was inhibited by raloxifene at a concentration range of 2.5-25 μM. In perfused livers, raloxifene reduced the ketogenesis from endogenous and exogenous fatty acids and increased the β-hydroxybutyrate/acetoacetate ratio. An increase in ¹⁴CO₂ production without a parallel increase in the oxygen consumption indicated that raloxifene caused a diversion of NADH from the mitochondrial respiratory chain to another oxidative reaction. It was found that raloxifene has a strong ability to react with H₂O₂ in the presence of peroxidase. It is likely that the generation of phenoxyl radical derivatives of raloxifene in intact livers led to the co-oxidation of NADH and a shift of the cellular redox state to an oxidised condition. This change can perturb other important liver metabolic processes dependent on cellular NADH/NAD⁺ ratio. 22780426 New long-chain aliphatic compounds from Peperomia dindygulensis. Three long-chain aliphatic compounds, including one new polyketide derivative, dindygulerione C (1), one new octaketide derivative, dindygulerione D (2) and one new acylresorcinol derivative dindyguleranone (3) were isolated from the whole plant of the Chinese anticancer folk medicine Peperomia dindygulensis Miq. (Piperaceae). Dindygulerione C is an unprecedented example of a N-containing polyketide. The chemical structures and configurations of 1-3 were elucidated as (-)-(4S)-2-[(Z)-1'-(6″,7″-dihydroxyphenethyl-amino)octadec-11'-enylidene]-4-hydroxycyclohexane-1,3-dione (1), (+)-2-heptadecyl-4-hydroxy-3,4,7,8-tetrahydro-2H-chromen-5(6H)-one (2) and 2-(1,3-dihydroxyphenyl)-octacosan-1'-one (3), respectively, by comparing with the literature data and extensive spectroscopic methods, including 2-D NMR and circular dichroism spectroscopic analysis. The cytotoxicity of 1-3 was evaluated against Hep3B and HepG2 liver cancer cell lines. 23116112 Stem cell lineage commitment by electrical fields and the potential application in drug discovery. Stem cells may be applied to improve the efficiency of drug discovery, but more effective protocols are first required to control the differentiation. Recent researches have revealed that physical stimulation is an important avenue for stem cell lineage commitment, such as electrical field stimulation. Here, we review literatures about stem cell differentiation by electrical field stimulation. Various forms of electrical fields with soluble induction factors have shown to produce a synergistic effect in order to enhance the osteogenic commitment. Moreover, electrical field stimulation alone shows marked effects of pre-commitment to cardiomyocyte and neuron. However, the related precise molecular regulatory mechanism is unclear. As cardiomyocyte and neuron are crucial factors in drug development process, electrical field stimulation may be proposed as an effect important for stem cell differentiation, exhibiting a potential application in drug discovery. 23497866 Application of response surface methodology to optimise extraction of flavonoids from fructus sophorae. Response surface methodology (RSM) based on a central composite design (CCD) was applied to optimise the extraction conditions for flavonoids from fructus sophorae with advantages in terms of resisting flavonoids during the whole process and maximising of extraction yield. Three aglycon forms of the flavonoids, namely, quercetin, kaempferol and isorhamnetin were quantified by high-performance liquid chromatography with ultraviolet detection (HPLC-UV) to estimate extraction yield. The combined effects of independent variables were studied and the optimal extraction conditions were obtained as ethanol concentration, 74.47%; solid-liquid ratio, 17.99 ml/g; temperature, 89.13°C; and extraction time, 2.10h. The reliability of the method was confirmed by recovery experiments, performed under optimal conditions. Recoveries indicated that flavonoids resisted the extraction conditions. The experimental extraction yield under optimal conditions was found to be 10.459%, which was well matched with the predicted values of 10.461%. 23561137 Anti-inflammatory and anticancer activities of extracts and compounds from the mushroom Inonotus obliquus. Mushroom Inonotus obliquus (I. obliquus) has been used as functional food and traditional Chinese herbs for long time. An efficient method for bioassay-guided preparative isolation was used for identifying the anti-inflammatory and anticancer constituents in I. obliquus. The petroleum ether and ethyl acetate fractions were found to have significant inhibition effects on NO production and NF-κB luciferase activity in macrophage RAW 264.7 cells and cytotoxicity against human prostatic carcinoma cell PC3 and breast carcinoma cell MDA-MB-231. Six main constituents were isolated from these two fractions and they were identified as lanosterol (1), 3β-hydroxy-8,24-dien-21-al (2), ergosterol (3), inotodiol (4), ergosterol peroxide (5) and trametenolic acid (6). Compound ergosterol, ergosterol peroxide and trametenolic acid showed anti-inflammatory activities and ergosterol peroxide and trametenolic acid showed obviously cytotoxicity on human prostatic carcinoma cell PC3 and breast carcinoma MDA-MB-231 cell. The results obtained in this work might contribute to understanding the biological activity of mushroom I. obliquus for food and drug application. 23552398 Modeling CO2 reduction on Pt(111). Density functional theory was used to model the electrochemical reduction of CO2 on Pt(111) with an explicit solvation layer and the presence of extra hydrogen atoms to represent a negatively charged electrode. We focused on the electronic energy barriers for the first four lowest energy proton-electron transfer steps for reducing CO2 on Pt(111) beginning with adsorbed *CO2 and continuing with *COOH, *CO + H2O, *COH, and ending with *C + H2O. We find that simple elementary steps in which a proton is transferred to an adsorbate (such as the protonation of *CO to *COH) have small barriers on the order of 0.1 eV. Elementary steps in which a proton is transferred and a C-O bond is simultaneously cleaved show barriers on the order of 0.5 eV. All barriers calculated for these steps show no sign of being insurmountable at room temperature. To explain why these barriers are so small, we analyze the charge density and the density of states plots to see that first, the electron transfer is decoupled from the proton transfer so that in the initial state, the surface and adsorbate are already charged up and can easily accept the proton from solution. Also, we see that in the cases where barriers are on the order of 0.1 eV, electron density in the initial state localizes on the oxygen end of the adsorbate, while electron density is more spread out on the surface for initial states of the C-O bond cleaving elementary steps. 23458422 Thermoresponsive Bacterial Cellulose Whisker/Poly(NIPAM-co-BMA) Nanogel Complexes: Synthesis, Characterization, and Biological Evaluation. Dispersions of poly(N-isopropylacrylamide-co-butyl methacrylate) (PNB) nanogels are known to exhibit reversible thermosensitive sol-gel phase behavior and can consequently be used in a wide range of biomedical applications. However, some dissatisfactory mechanical properties of PNB nanogels can limit their applications. In this paper, bacterial cellulose (BC) whiskers were first prepared by sulfuric acid hydrolysis and then nanosized by high-pressure homogenization for subsequent use in the preparation of BC whisker/PNB nanogel complexes (designated as BC/PNB). The mechanical properties of PNB was successfully enhanced, resulting in good biosafety. The BC/PNB nanogel dispersions exhibited phase transitions from swollen gel to shrunken gel with increasing temperature. In addition, differential scanning calorimetry (DSC) data showed that the thermosensitivity of PNB nanogels was retained. Rheological tests also indicated that BC/PNB nanogel complexes had stronger gel strengths when compared with PNB nanogels. The concentrated dispersions showed shear thinning behavior and improved toughness, both of which can play a key role in the medical applications of nanogel complexes. Furthermore, the BC/PNB nanogel complexes were noncytotoxic according to cytotoxicity and hemolysis tests. Concentrated BC/PNB nanogel dispersion displayed gel a forming capacity in situ by catheter injection, which indicates potential for a wide range of medical applications. 22304302 Three new steroidal glycosides from roots of Reineckia carnea. Two new spirostanols and a new furostanol, reinocarnoside A (1), B (2) and C (3), were isolated from the roots of Reineckia carnea, together with two known compounds, (25S)-1β,3β,4β-trihydroxyspirostan-5β-yl-O-β-D-glucopyranoside (4), kitigenin-5β-O-β-D-glucopyranoside (5). The structures of three new compounds were elucidated by spectroscopic methods including 1-D NMR, 2-D NMR and MS spectrums, and their anticancer activities were evaluated by MTT method. 23327360 Physicochemical characterization of phosphopeptide/titanium dioxide interactions employing the quartz crystal microbalance technique. The rapidly growing field of phosphoproteomics has led to a strong demand for procedures enabling fast and reliable isolation and enrichment of phosphorylated proteins and peptides. During the past decade, several novel phosphopeptide enrichment methods based on the affinity of phosphoryl groups for titanium dioxide (TiO(2)) have been developed and tested. The ultimate goal of obtaining comprehensive phosphoproteomes has, however, been found difficult to achieve and the obtained results often vary, dependent on the enrichment method and protocol used. In the present study, the physical chemistry of the phosphopeptide binding to TiO(2) is investigated by means of measurements using a quartz crystal microbalance with dissipation monitoring (QCM-D). Special emphasis is put on the effect of the degree of phosphorylation of the phosphopeptide, the impact of the primary amino acid structure, and the role of electrostatic interactions. The results show that, in general, adsorption of phosphopeptides follows the Langmuir model and that the affinity for the TiO(2) surface increases in a nonlinear fashion with increasing degree of phosphorylation. An exception was detected, however, where positive cooperativity between the peptides existed and the Langmuir model no longer applied. The source behind the cooperativity could be traced back to the primary amino acid structure and, more specifically, the presence of positively charged amino acids in positions that enable electrostatic interaction with phosphoryl groups on neighboring peptides. Regardless of the net peptide charge, the TiO(2)-phosphopeptide interaction was for all phosphopeptides investigated found to be mainly of electrostatic origin. This study highlights and explains some of the most common problems with the TiO(2)-based enrichment methods used today. 22940283 Relation between dynamics, activity and thermal stability within the cholinesterase family. Incoherent neutron scattering is one of the most powerful tools for studying dynamics in biological matter. Using the cold neutron backscattering spectrometer IN16 at the Institut Laue Langevin (ILL, Grenoble, France), temperature dependence of cholinesterases' dynamics (human butyrylcholinesterase from plasma: hBChE; recombinant human acetylcholinesterase: hAChE and recombinant mouse acetylcholinesterase: mAChE) was examined using elastic incoherent neutron scattering (EINS). The dynamics was characterized by the averaged atomic mean square displacement (MSD), associated with the sample flexibility at a given temperature. We found MSD values of hAChE above the dynamical transition temperature (around 200K) larger than for mAChE and hBChE, implying that hAChE is more flexible than the other ChEs. Activation energies for thermodynamical transition were extracted through the frequency window model (FWM) (Becker et al. 2004) [1] and turned out to increase from hBChE to mAChE and finally to hAChE, inversely to the MSDs relations. Between 280 and 316K, catalytic studies of these enzymes were carried out using thiocholine esters: at the same temperature, the hAChE activity was systematically higher than the mAChE or hBChE ones. Our results thus suggest a strong correlation between dynamics and activity within the ChE family. We also studied and compared the ChEs thermal inactivation kinetics. Here, no direct correlation with the dynamics was observed, thus suggesting that relations between enzyme dynamics and catalytic stability are more complex. Finally, the possible relation between flexibility and protein ability to grow in crystals is discussed. 23350621 Leptin levels and adipose tissue percentage in adolescents with polycystic ovary syndrome. The main purpose of the research is to compare serum leptin (Lep) levels and adipose tissue percentage in adolescents diagnosed with polycystic ovary syndrome (PCOS) and those in healthy subjects. The results showed a greater percentage of patients with increased adipose tissue and significantly higher serum Lep levels in the PCOS group compared to the healthy controls. It was proved that there is a correlation between Lep and body mass index, body adipose tissue, waist circumference and HOMA index. PCOS in adolescents is a condition related to highly predominant overweight and obesity with exceeding level of body adipose tissue and higher serum Lep levels compared to healthy age-matched controls. 23294895 Aspirin and aspirin resistance in coronary artery disease. Aspirin is still the mainstay of antiplatelet therapy in the secondary prevention of coronary artery disease. However certain patients do not benefit from the antithrombotic effects of aspirin. The phenomenon of so-called aspirin resistance can be considered from the clinical and laboratory perspective. A variety of methods have emerged for the laboratory diagnosis of aspirin resistance. None of them is considered ideal as they provide conflicting information with significant inter-individual variability and weak correlation between them. With the mechanisms of aspirin resistance not fully understood and the phenomenon commonly observed in individuals with poor compliance, the existence of aspirin resistance has been challenged. The aim of this review is to present recent data on the impact of aspirin resistance in primary and secondary prevention of coronary artery disease. 23174519 An unusual marine envenomation following a rope contact: a report on nine cases of dermatitis caused by Pennaria disticha. We would like to present the clinical course of nine patients who had an acute, painful dermatitis following contact with a rope used as a swimming area liner in the sea. The macroscopic and microscopic analysis of the fouling on the rope retrospectively, revealed Pennaria disticha as the causative organism. To our knowledge, there is no previous report on P. disticha envenomation in medical literature. P. disticha is a benthic hydrozoa belonging to Cnidaria phylum. Cnidaria are well known for their envenomation with their venomous organelle, "cnidocyst". The contact with cnidaria can result in a wide range of cytotoxic or anaphylactic reactions. While there is a large body of data in the literature from studies at molecular and cellular levels, there is limited data about the in vivo effects of cnidaria toxins. We think the clinical aspects of the dermatologic reactions caused by P. disticha and the diagnostic work-up to reveal the contamination on this unusual medium would be of interest to the readers. 23633532 Regulation of Lipid Metabolism by Glucocorticoids and 11β-HSD1 in Skeletal Muscle. The prevalence of insulin resistance and type 2 diabetes mellitus are rising dramatically and as a consequence there is an urgent need to understand the pathogenesis underpinning these conditions to develop new and more efficacious treatments.We have tested the hypothesis that glucocorticoid-mediated changes in insulin sensitivity may be associated with changes in lipid flux. Furthermore, pre-receptor modulation of glucocorticoid availability by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may represent a critical regulatory step.Dexamethasone decreased lipogenesis in both murine C2C12 and human LHC-NM2 myotubes. Inactivating p-Ser-79/218 of acetyl-CoA carboxylase 1/2 (ACC1/2) and activating p-Thr-172 of AMP-activated protein kinase (AMPK) were both increased following dexamethasone treatment in C2C12 myotubes. By contrast, dexamethasone increased β-oxidation. Selective 11β-HSD1 inhibition blocked the 11-dehydrocorticosterone (11DHC)-mediated decrease in lipogenic, and increase in lipolytic gene expression. Lipogenic gene expression was decreased, whilst lipolytic and β-oxidative genes expression increased in corticosterone (CORT) and 11DHC treated wild-type mice, and CORT (but not 11DHC) treated 11β-HSD1(-/-) mice. Furthermore, CORT and 11DHC treated wild-type mice, and CORT (but not 11DHC) treated 11β-HSD1(-/-) mice had increased p-Ser-79/218 ACC1/2, p-Thr-172 AMPK and intramyocellular diacylglyderide content.In summary, we have shown that glucocorticoids have potent actions upon intramyocellular lipid homeostasis by decreasing lipid storage, increasing lipid mobilisation and utilisation and increasing diacylglyderide content. It is plausible that dysregulated intramyocellular lipid metabolism may underpin GC-induced insulin resistance of skeletal muscle. 23444429 Defective DNA damage response and repair in liver cells expressing hepatitis B virus surface antigen. Hepatitis B virus (HBV) is implicated in liver cancer. The aim of this study was to find out whether HBV or its components [HBV surface antigen (HBsAg), HBV core protein (HBc), and HBV X protein (HBx)] could interfere with the host DNA damage response and repair pathway. The full HBV genome or individual HBV open-reading frame (ORF) was introduced into HepG2 cells to examine the effect on host genomic stability, DNA repair efficacy in response to double-strand DNA damage, and DNA damage-induced cell death. Responses to apoptosis induction in the HBV ORF-transfected HepG2 cells were also compared with those in HBV-positive and HBV-negative human hepatocellular carcinoma (HCC) cells. In the absence of HBV replication, accumulation of HBsAg in liver cells without other HBV proteins enhanced DNA repair protein and tumor suppressor promyelocytic leukemia (PML) degradation, which resulted in resistance to apoptosis induction and deficient double-strand DNA repair. However, HBsAg-positive cells exhibited increased cell death with exposure to the poly(ADP-ribose) polymerase inhibitor that blocks single-strand DNA repair. These results indicate that suppression of PML by HBsAg disrupts cellular mechanisms that respond to double-strand DNA damage for DNA repair or apoptosis induction, which may facilitate hepatocarcinogenesis and open up a synthetic lethality strategy for HBsAg-positive HCC treatment.-Chung, Y.-L. Defective DNA damage response and repair in liver cells expressing hepatitis B virus surface antigen. 23327532 Cooperative effects for CYP2E1 differ between styrene and its metabolites. Abstract 1. Cooperative interactions are frequently observed in the metabolism of drugs and pollutants by cytochrome P450s; nevertheless, the molecular determinants for cooperativity remain elusive. Previously, we demonstrated that steady-state styrene metabolism by CYP2E1 exhibits positive cooperativity. 2. We hypothesized that styrene metabolites have lower affinity than styrene toward CYP2E1 and limited ability to induce cooperative effects during metabolism. To test the hypothesis, we determined the potency and mechanism of inhibition for styrene and its metabolites toward oxidation of 4-nitrophenol using CYP2E1 Supersomes® and human liver microsomes. 3. Styrene inhibited the reaction through a mixed cooperative mechanism with high affinity for the catalytic site (67 µM) and lower affinity for the cooperative site (1100 µM), while increasing substrate turnover at high concentrations. Styrene oxide and 4-vinylphenol possessed similar affinity for CYP2E1. Styrene oxide behaved cooperatively like styrene, but 4-vinylphenol decreased turnover at high concentrations. Styrene glycol was a very poor competitive inhibitor. Among all compounds, there was a positive correlation with binding and hydrophobicity. 4. Taken together, these findings for CYP2E1 further validate contributions of cooperative mechanisms to metabolic processes, demonstrate the role of molecular structure on those mechanisms and underscore the potential for heterotropic cooperative effects between different compounds. 23633651 Prevalence of MAGI in patients with type 2 diabetes mellitus. Background. MAGI is an acronym that identifies the "male accessory gland inflammations/infections", a potential cause of male infertility. Type 2 diabetes mellitus (DM2) prevalence is going to increase among men of reproductive age. Due to the high prevalence of these two conditions, we could suppose that they might appear together in the same patient. Aim. To evaluate MAGI prevalence in patients with DM2 in fertile age. Subjects and Methods. A cross-sectional study carried out on patients with DM2 of fertile age. All patients underwent andrological evaluation for the identification of conventional MAGI diagnostic criteria. Results. DM2 patients showed a frequency of MAGI about 43%, significantly lower (p<0.05) than in infertile patients of the same age without diabetes, which showed a MAGI overall frequency of 61%. Among examined diabetic patients the prevalence of MAGI did not significantly differ between patients attending for diabetes care problems (glycemic control) and patients with andrological disorders. Finally, no significant difference in seminal inflammatory signs frequency was detected between patients with DM2 and infertile patients without diabetes. Finally, the correlation analysis showed a significant direct correlation between duration of diabetes and glycemic control with the prevalence of MAGI. Conclusion. MAGI prevalence in DM2 is lower than the one detected in age matched infertile non-diabetic patients, however, as in infertile patients, there is a high frequency of seminal inflammatory signs. Moreover, the observed prevalence among diabetic patients with diabetes care problems and diabetic patients with andrological problems is not statistically different. 23239825 Differentiation of opioid drug effects by hierarchical multi-site phosphorylation. Differences in the ability of opioid drugs to promote regulated endocytosis of μ-opioid receptors are related to their tendency to produce drug tolerance and dependence. Here we show that drug-specific differences in receptor internalization are determined by a conserved, 10-residue sequence in the receptor's carboxyl-terminal cytoplasmic tail. Diverse opioids induce receptor phosphorylation at serine (S)375, present in the middle of this sequence, but opioids differ markedly in their ability to drive higher-order phosphorylation on flanking residues [threonine (T)370, T376, and T379]. Multi-phosphorylation is required for the endocytosis-promoting activity of this sequence and occurs both sequentially and hierarchically, with S375 representing the initiating site. Higher-order phosphorylation involving T370, T376, and T379 specifically requires GRK2/3 isoforms, and the same sequence controls opioid receptor internalization in neurons. These results reveal a biochemical mechanism differentiating the endocytic activity of opioid drugs. 23578634 Effect of salt solutions applied during wheat conditioning on lipase activity and lipid stability of whole wheat flour. Lipolytic activity in whole wheat flour (WWF) is largely responsible for the loss in baking quality during storage. Metal ions affect the activity of seed lipases; however, no previous studies have applied this information to WWF in a way that reduces lipase activity, is practical for commercial manufacture, and uses common food ingredients. NaCl, KCl, Ca-propionate, or FeNa-ethylenediaminetetraacetic acid (FeNa-EDTA) were applied to hard red winter (HRW) and hard white spring (HWS) wheats during conditioning as aqueous solutions at concentrations that would be acceptable in baked goods. Salts affected lipase activity to different degrees depending on the type of wheat used. Inhibition was greater in HRW compared with HWS WWF, probably due to higher lipase activity in HRW wheat. In HRW WWF, 1% NaCl (flour weight) reduced hydrolytic and oxidative rancidity and resulted in higher loaf volume and lower firmness than untreated WWF after 24weeks of storage. 23411248 Antioxidant and antimicrobial activity of xylan-chitooligomer-zinc complex. In this study, a ternary complex based on natural polysaccharides was explored as a novel food preservative. Chitooligomer was obtained by enzyme hydrolysis of chitosan with immobilised neutral protease, and the degree of polymerisation (DP) was mainly from 2 to 5. Chitooligomer-zinc complex (CGZC) was first produced and then co-heated with xylan to prepare xylan-chitooligomer-zinc complex (XCGZC). XCGZC showed higher antioxidant and antibacterial activity than chitooligomer, chitooligomer-zinc and xylan-chitooligomer. The IC(50) of XCGZC was 5.37 mg/mL, which was equal to the antioxidant ability of 3.28 mg/mL BHT. The diameter of the inhibition zone for XCGZC against Escherichia coli and Staphylococcus aureus was 17.2 ± 0.4 and 30.3 ± 0.6mm vs. control of 6.0mm. Besides, XCGZC had excellent antibacterial activity against Bacillus subtilis, Salmonella typhimurium, Bacillus megaterium. Therefore, XCGZC can be used as a novel promising preservative with antibacterial and antioxidant properties in the food industry. 23611507 Links between obesity, diabetes and ethnic disparities in breast cancer among Hispanic populations. Breast cancer is the most prevalent malignancy in women worldwide and is a growing concern due to rising incidence and ongoing ethnic disparities in both incidence and mortality. A number of factors likely contribute to these trends including rising rates of obesity and diabetes across the globe and differences in genetic predisposition. Here, we emphasize Hispanic populations and summarize what is currently known about obesity, diabetes and individual genetic predisposition as they relate to ethnic disparities in breast cancer incidence and mortality. In addition, we discuss potential contributions to breast cancer aetiology from molecular mechanisms associated with obesity and diabetes including dyslipidemia, hyperglycaemia, hyperinsulinaemia, endocrine dysfunction and inflammation. We propose that unique differences in diet and lifestyle coupled with individual genetic predisposition and endocrine/immune dysfunction explain most of the ethnic disparities seen in breast cancer incidence and mortality. 23194540 Method development and validation for boscalid in blueberries by solid-phase microextraction gas chromatography, and their degradation kinetics. Analytical method for the residues of boscalid in blueberries was developed. Fungicide residues were determined by solid-phase microextraction (SPME) coupled to gas chromatography with micro-electron capture (μ-ECD) detector. The effect of pH values and fiber coatings were studied. The SPME fiber coating selected was 100 μm PDMS. The method is selective with adequate precision and high accuracy and sensitivity. Recoveries ranged within the 98-104% range, and detection and quantification limits were 1.33 and 4.42 μg/kg, respectively. Statistical parameters indicated the occurrence of matrix effect; consequently calibration was performed on spiked samples. Degradation of boscalid was studied in a blueberry field located in Concordia, Argentina, with fruits from Emerald and Jewel varieties. The degradation of boscalid in both blueberry varieties studied followed a first order rate kinetics and the half-life for boscalid was 5.3 and 6.3 days for Emerald and Jewel cultivars, respectively. 23359520 Pycnogenol® Supplementation Improves Health Risk Factors in Subjects with Metabolic Syndrome. This open, controlled study evaluated the effects of 6 month supplementation with Pycnogenol® maritime pine bark extract on health risk factors in subjects with metabolic syndrome. Pycnogenol® was used with the aim of improving risk factors associated with metabolic syndrome, central obesity, elevated triglycerides (TG), low HDL cholesterol, high blood pressure and fasting blood glucose. Sixty-four subjects (range 45-55 years) presenting with all five risk factors of metabolic syndrome were included, and Pycnogenol® was administered for 6 months. A group of 66 equivalent subjects were followed up as controls. In the 6-month study Pycnogenol® supplementation 150 mg/day decreased waist circumference, TG levels, blood pressure and increased the HDL cholesterol levels in subjects. Pycnogenol lowered fasting glucose from baseline 123 ± 8.6 mg/dl to 106.4 ± 5.3 after 3 months and to 105.3 ± 2.5 at the end of the study (p < 0.05 vs controls). Men's waist circumference decreased with Pycnogenol from 106.2 ± 2.2 cm to 98.8 ± 2.3 cm and to 98.3 ± 2.1 after 3 and 6 months. Women's waist decreased from 90.9 ± 1.6 cm to 84.6 ± 2.1 cm and to 83.6 ± 2.2 cm after 3 and 6 months. Both genders waist circumference reduction was significant as compared to controls at both time points. In addition, plasma free radicals decrease in the Pycnogenol group was more effective than in the control group (-34.6%; p < 0.05). In conclusion, this study indicates a role for Pycnogenol® for improving health risk factors in subjects with metabolic syndrome. Copyright © 2013 John Wiley & Sons, Ltd. 23361517 Structural and up-conversion properties of Er3+ and Yb3+ co-doped Y2Ti2O7 phosphors. Y(2)Ti(2)O(7) (YTO) and Er(3+)/Yb(3+) co-doped Y(2)Ti(2)O(7) (EYYTO) phosphors have been prepared by solid-state reaction method. Structures of YTO and EYYTO phosphors are identified as face centered cubic pyrochlores. Up-conversion emission spectra of EYYTO under 976 nm excitation is studied, which revealed three prominent emission lines at ~524, 548 and 661 nm originating from (2)H(11/2)→(4)I(15/2), (4)S(3/2)→(4)I(15/2) and (4)F(9/2)→(4)I(15/2) electronic transitions of Er(3+) ion, respectively in green and red regions. The power dependence study suggests that these bands arise due to two photon absorption. The monodispersed laser ablated colloidal solution of EYYTO shows strong red and green emissions on excitation with 976 nm laser. The variation of luminescence intensity at different laser excitation powers is observed and thus a color can be tuned. The photoluminescence lifetime of green band at 548 nm ((4)S(3/2) level) has been found to be ~446 μs. 22628265 Ethanol extract of Magnolia officinalis prevents lipopolysaccharide-induced memory deficiency via its antineuroinflammatory and antiamyloidogenic effects. Magnolia bark contains several compounds such as magnolol, honokiol, 4-O-methylhonokiol, obovatol, and other neolignan compounds. These compounds have been reported to have various beneficial effects in various diseases. There is sufficient possibility that ethanol extract of Magnolia officinalis is more effective in amyloidogenesis via synergism of these ingredients. Neuroinflammation has been known to play a critical role in the pathogenesis of Alzheimer's disease (AD). We investigated whether the ethanol extract of M. officinalis (10 mg/ kg in 0.05% ethanol) prevents memory dysfunction and amyloidogenesis in AD mouse model by intraperitoneal lipopolysaccharide (LPS, 250 µg/ kg/day for seven times) injection. We found that ethanol extract of M. officinalis prevented LPS-induced memory deficiency as well as inhibited the LPS-induced elevation of inflammatory proteins, such as inducible nitric oxide synthase and cyclooxygenase 2, and activation of astrocytes and microglia. In particular, administration of M. officinalis ethanol extract inhibited LPS-induced amyloidogenesis, which resulted in the inhibition of amyloid precursor protein, beta-site amyloid-precursor-protein-cleaving enzyme 1 and C99. Thus, this study shows that ethanol extract of M. officinalis prevents LPS-induced memory impairment as well as amyloidogenesis via inhibition of neuroinflammation and suggests that ethanol extract of M. officinalis might be a useful intervention for neuroinflammation-associated diseases such as AD. Copyright © 2012 John Wiley & Sons, Ltd. 23404739 Optimization of marine triterpene sipholenols as inhibitors of breast cancer migration and invasion. Sipholenol A, a sipholane triterpene isolated from the Red Sea sponge Callyspongia siphonella, has the ability to reverse multidrug resistance in cancer cells that overexpress P-glycoprotein (P-gp). Here, the antimigratory activity of sipholenol A and analogues are reported against the highly metastatic human breast cancer cell line MDA-MB-231 in a wound-healing assay. Sipholenol A and sipholenone A were semisynthetically optimized using ligand-based strategies to generate structurally diverse analogues in an attempt to maximize their antimigratory activity. A total of 22 semisynthetic ester, ether, oxime, and carbamate analogues were generated and identified by extensive one- and two-dimensional NMR spectroscopy and high-resolution mass spectrometry analyses. Sipholenol A 4β-4-chlorobenzoate and 19,20-anhydrosipholenol A 4β-4-chlorobenzoate esters were the most potent of all tested analogues in the wound-healing assay, with IC(50) values of 5.3 and 5.9 μM, respectively. Generally, ester derivatives showed better antimigratory activities than the carbamate analogues. A KINOMEscan of 19,20-anhydrosipholenol A 4β-benzoate ester against 451 human protein kinases identified protein tyrosine kinase 6 (PTK6) as a potential target. In breast tumor cells, PTK6 promotes growth factor signaling and migration, and as such the semisynthetic sipholanes were evaluated for their ability to inhibit PTK6 phosphorylation in vitro. The two analogues with the highest antimigratory activities, sipholenol A 4β-4-chlorobenzoate and 19,20-anhydrosipholenol A 4β-4-chlorobenzoate esters, also exhibited the most potent inhibition of PTK6 phosphorylation inhibition. None of the compounds exhibited cytotoxicity in a normal epithelial breast cell line. These derivatives were evaluated in an in vitro invasion assay, where sipholenol A succinate potently inhibited MDA-MB-231 cell invasion at 10 μM. These results highlight sipholane triterpenoids as novel antimigratory marine natural products with potential for further development as agents for the control of metastatic breast malignancies. 23432151 Five new secondary metabolites from Monascus purpureus-fermented Hordeum vulgare and Sorghum bicolor. Long grains of Hordeum vulgare and Sorghum bicolor were individually fermented with Monascus purpureus MTCC 369 under solid state fermentation. The aqueous extract of Monascus which fermented H. vulgare and S. bicolor was found to contain five different new metabolites. Silica gel column chromatography of the aqueous extract with a linear gradient of ethyl acetate, acetonitrile and carbon tetrachloride (v/v) yielded five new metabolites named benzopranyl capriate (9H-1-isoprenyl-benzopyran-5-isopropanoic acid-6-ol-6-n-decanoate), shorghumoic acid (n-octadec-8,11-dien-7α-ol-1-oic acid) and sorghumflavin A (2-n-butyloxo-6-β-hydroxy-7-β-isoprenyl ankaflavin) from Monascus-fermented S. bicolor, while hordeumflavin B (2-n-undecanyloxo-7-β-isoprenyl ankaflavin) and vulgaredilone (2-dodecanyl-7-β isopranyl monoscodilone) from Monascus-fermented H. vulgare. 23535394 An overview on the marine neurotoxin, saxitoxin: genetics, molecular targets, methods of detection and ecological functions. Marine neurotoxins are natural products produced by phytoplankton and select species of invertebrates and fish. These compounds interact with voltage-gated sodium, potassium and calcium channels and modulate the flux of these ions into various cell types. This review provides a summary of marine neurotoxins, including their structures, molecular targets and pharmacologies. Saxitoxin and its derivatives, collectively referred to as paralytic shellfish toxins (PSTs), are unique among neurotoxins in that they are found in both marine and freshwater environments by organisms inhabiting two kingdoms of life. Prokaryotic cyanobacteria are responsible for PST production in freshwater systems, while eukaryotic dinoflagellates are the main producers in marine waters. Bioaccumulation by filter-feeding bivalves and fish and subsequent transfer through the food web results in the potentially fatal human illnesses, paralytic shellfish poisoning and saxitoxin pufferfish poisoning. These illnesses are a result of saxitoxin's ability to bind to the voltage-gated sodium channel, blocking the passage of nerve impulses and leading to death via respiratory paralysis. Recent advances in saxitoxin research are discussed, including the molecular biology of toxin synthesis, new protein targets, association with metal-binding motifs and methods of detection. The eco-evolutionary role(s) PSTs may serve for phytoplankton species that produce them are also discussed. 23397032 Parathyroid hormone (1-34) counteracts the suppression of interleukin-11 expression by glucocorticoid in murine osteoblasts: a possible mechanism for stimulating osteoblast differentiation against glucocorticoid excess. Glucocorticoid (GC) excess causes a rapid loss of bone with a reduction in bone formation. Intermittent PTH (1-34) administration stimulates bone formation and counteracts the inhibition of bone formation by GC excess. We have previously demonstrated that mechanical strain enhances interleukin (IL)-11 gene transcription by a rapid induction of ΔFosB expression and protein kinase C (PKC)-δ-mediated phosphorylation of phosphorylated mothers against decapentaplegic (Smad)-1. Because IL-11 suppresses the expression of dickkopf-1 and -2 and stimulates Wnt signaling, IL-11 appears to mediate at least a part of the effect of mechanical strain on osteoblast differentiation and bone formation. The present study was undertaken to examine the effect of PTH(1-34) and GCs on IL-11 expression in murine primary osteoblasts (mPOBs). PTH(1-34) treatment of mPOBs enhanced IL-11 expression in a time- and dose-dependent manner. PTH(1-34) also stimulated ΔFosB expression and Smad1 phosphorylation, which cooperatively stimulated IL-11 gene transcription. PTH(1-34)-induced Smad1 phosphorylation was mediated via PKCδ and was abrogated in mPOBs from PKCδ knockout mice. Dexamethasone suppressed IL-11 gene transcription enhanced by PTH(1-34) without affecting ΔFosB expression or Smad1 phosphorylation, and dexamethasone-GC receptor complex was bound to JunD, which forms heterodimers with ΔFosB. High doses of PTH(1-34) counteracted the effect of dexamethasone on apoptosis of mPOBs, which was blunted by neutralizing anti-IL-11 antibody or IL-11 small interfering RNA. These results demonstrate that PTH(1-34) and GCs interact to regulate IL-11 expression in parallel with osteoblast differentiation and apoptosis and suggest that PTH(1-34) and dexamethasone may regulate osteoblast differentiation and apoptosis via their effect on IL-11 expression. 22743159 Role of metabotropic glutamate receptors in persistent forms of hippocampal plasticity and learning. Storage and processing of information at the synaptic level is enabled by the ability of synapses to persistently alter their efficacy. This phenomenon, known as synaptic plasticity, is believed to underlie multiple forms of long-term memory in the mammalian brain. It has become apparent that the metabotropic glutamate (mGlu) receptor is critically required for both persistent forms of memory and persistent synaptic plasticity. Persistent forms of synaptic plasticity comprise long-term potentiation (LTP) and long-term depression (LTD) that last at least for 4 h but can be followed in vivo for days and weeks. These types of plasticity are believed to be analogous to forms of memory that persist for similar time-spans. The mGlu receptors are delineated into three distinct groups based on their G-protein coupling and agonist affinity and also exercise distinct roles in the way they regulate both long-term plasticity and long-term hippocampus-dependent memory. Here, the mGlu receptors will be reviewed both in general, and in the particular context of their role in persistent (>4 h) forms of hippocampus-dependent synaptic plasticity and memory, as well as forms of synaptic plasticity that have been shown to be directly regulated by memory events. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23194750 Reversible inhibition of vasoconstriction by thiazolidinediones related to PI3K/Akt inhibition in vascular smooth muscle cells. Thiazolidinediones (also referred to as glitazones), agonists for Peroxisome Proliferator-Activated Receptor gamma (PPARγ), are used for treating type 2 diabetes mellitus, where they decrease insulin resistance and cardiovascular risk. Compounds bearing the thiazolidinedione structure have also been shown to inhibit phosphoinositide 3-kinase (PI3K). Here we tried to elucidate the poorly defined role of PI3K/Akt in the physiology of vascular smooth muscle cell contraction and tested the hypothesis that thiazolidinediones, by affecting the PI3K/Akt pathway, may influence vascular physiology. Isolated rat femoral arteries segments were mounted in a wire myograph and challenged with 100mM KCl or phenylephrine (PE), in the absence or presence of troglitazone, rosiglitazone, pioglitazone, LY294002 (PI3K inhibitor) and 10-DEBC (Akt inhibitor). All these compounds dose-dependently inhibited vasoconstriction to KCl or PE; their effect was reversible (after 60-120 min washout) and not affected by GW9662 (a PPARγ antagonist) or by N(G)-nitro-L-arginine (LNNA, an inhibitor of NO biosynthesis). Analysis of phospho-Akt (ser 473) in lysates from rat arteries (by immunoblot) revealed that thiazolidinediones, LY294002 and 10-DEBC, at the same concentration and kinetics inhibiting vasoconstriction, produced a similar decrease of Akt phosphorylation. PI3K/Akt pathway therefore appears to be an important, fast acting, modulator of contraction of vascular smooth muscle. Thiazolidinediones decrease vasoconstriction of isolated vessels possibly by inhibiting PI3K/Akt pathway. Such an effect of glitazones, if occurring in vivo, may impact cardiovascular syndromes related to vasospasm in diabetic patients. 23298158 Enhanced Electrical Conductivity in Poly(3-hexylthiophene)/Fluorinated Tetracyanoquinodimethane Nanowires Grown with a Porous Alumina Template. We report on improved electrical conductivity in poly(3-hexylthiophene) (P3HT)/2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4-TCNQ) composite nanowires grown using an anodized aluminum oxide (AAO) template. The electrical conductivity of individual nanowire measured by four-probe scanning tunneling microscopy shows that F4-TCNQ molecules are effectively doped into P3HT by capillary force. The resistivity is tuned in the 0.1-10 Ω cm range by changing the F4-TCNQ concentration from 10 to 0.1 wt % and is 2-4 orders of magnitude smaller than that of the corresponding P3HT/F4-TNCQ thin film composites. The AAO template-assisted synthesis approach thus appears to be effective for high chemical doping and for improving the electrical conductivity of the molecular wires. 23266447 Depth-resolved characterization of diffusion properties within and across minimally-perturbed skin layers. We examine by both experimental and computational means the diffusion of macromolecules through the skin strata (both the epidermis and dermis). Using mouse skin as a test case, we present a novel high-resolution technique to characterize the diffusion properties of heterogeneous biomaterials using 3D imaging of fluorescent probes, precisely-deposited in minimally-perturbed in vivo skin layers. We find the diffusivity of the delivered macromolecules (70 kDa and 2 MDa rhodamine-dextrans) low within the packed cellular arrangement of the epidermis, while gradually increasing (by ~an order of magnitude) through the dermis--as pores in the fibrillar network enlarge from the papillary to the reticular dermis. Our experimental and computational approaches for investigating the diffusion through skin strata help in the assessment and optimization of controlled delivery of drugs (e.g. vaccines) to specific sites (e.g. antigen presenting cells). 23585235 Kinetic Evidence for a Non-Langmuir-Hinshelwood Surface Reaction: H/D Exchange over Pd Nanoparticles and Pd(111). The mechanism of hydrogen recombination on a Pd(111) single crystal and well-defined Pd nanoparticles is studied using pulsed multi-molecular beam techniques and the H2 /D2 isotope exchange reaction. The focus of this study is to obtain a microscopic understanding of the role of subsurface hydrogen in enhancing the associative desorption of molecular hydrogen. HD production from H2 and D2 over Pd is investigated using pulsed molecular beams, and the temperature dependence and reaction orders are obtained for the rate of HD production under various reaction conditions designed to modulate the amount of subsurface hydrogen present. The experimental data are compared to the results of kinetic modeling based on different mechanisms for hydrogen recombination. We found that under conditions where virtually no subsurface hydrogen species are present, the HD formation rate can be described exceptionally well by a classic Langmuir-Hinshelwood model. However, this model completely fails to reproduce the experimentally observed high HD formation rates and the reaction orders under reaction conditions where subsurface hydrogen is present. To analyze this phenomenon, we develop two kinetic models that account for the role of subsurface hydrogen. First, we investigate the possibility of a change in the reaction mechanism, where recombination of one subsurface and one surface hydrogen species (known as a breakthrough mechanism) becomes dominant when subsurface hydrogen is present. Second, we investigate the possibility of the modified Langmuir-Hinshelwood mechanism with subsurface hydrogen lowering the activation energy for recombination of two hydrogen species adsorbed on the surface. We show that the experimental reaction kinetics can be well described by both kinetic models based on non-Langmuir-Hinshelwood-type mechanisms. 23238236 Chemical assessment and antioxidant capacity of pepper (Capsicum annuum L.) seeds. Capsicum annuum L. is reported to be the most widely cultivated species. Recently, waste of vegetable processing, like seeds, has been the subject of many studies as an attempt to find new, alternative and cheap resources of bioactive compounds with application in several industries. Despite their chemical, biological and ecological importance, C. annuum seeds are still poorly studied. To improve the knowledge on the metabolic profile of this matrix, a targeted metabolite analysis was performed in "sweet Italian" and "Reus long pairal" pepper seeds. Sterols, triterpenes, organic acids, fatty acids and volatile compounds were determined by different chromatographic methods. The antioxidant activity was assessed against DPPH(·), superoxide and nitric oxide radicals. A concentration-dependent activity was noticed against all radicals. Acetylcholinesterase inhibitory capacity was also evaluated, but no effect was found. Data provide evidence of great similarities between "sweet Italian" and "Reus long pairal" pepper seeds. The present study indicates that C. annuum seeds are a potential source of valuable bioactive compounds that could be used in food industry. 23223857 Biofunctionalized carbon nanotubes in neural regeneration: a mini-review. Carbon nanotubes (CNTs) have become an intriguing and promising biomaterial platform for the regeneration and functional recovery of damaged nerve tissues. The unique electrical, structural and mechanical properties, diversity of available surface chemistry and cell-penetrating ability of CNTs have made them useful implantable matrices or carriers for the delivery of therapeutic molecules. Although there are still challenges being faced in the clinical applications of CNTs mainly due to their toxicity, many studies to overcome this issue have been published. Modification of CNTs with chemical groups to ensure their dissolution in aqueous media is one possible solution. Functionalization of CNTs with biologically relevant and effective molecules (biofunctionalization) is also a promising strategy to provide better biocompatibility and selectivity for neural regeneration. Here, we review recent advances in the use of CNTs to promote neural regeneration. 22788542 Quality assessment and scavenging activity of Siamese neem flower extract. Young leaves and flowers of Siamese neem tree (Azadirachta indica A. Juss. var. siamensis Valeton) are commonly consumed as a bitter tonic vegetable. Active antioxidant components in the flowers are rutin and quercetin flavonoids. The aqueous extracts of young flowers collected from 14 different locations in Thailand were quantitatively analysed using high-performance liquid chromatography for the contents of rutin and quercetin, and were determined for the loss on drying, heavy metals and pesticide residues, microbial contamination, solubility, chromatographic fingerprints and acute toxicity. The extracts contained rutin and quercetin in the ranges from 388 to 1178 mg% dry weight (average 772 mg%), and 1 to 10 mg% dry weight (average 5 mg%), respectively. EC50 of the scavenging activity of all extracts was found in the range of 27-133 µg mL(-1). Loss on drying of the extracts was less than 7% w/w and no sign of toxicity (LD50 > 5 g kg(-1)) was found. 23330789 Facile fabrication of "dual click" one- and two-dimensional orthogonal Peptide concentration gradients. Peptides, proteins, and extracellular matrix act synergistically to influence cellular function at the biotic-synthetic interface. However, identifying the individual and cooperative contributions of the various combinations and concentration regimes is extremely difficult. The confined channel deposition method we describe affords highly tunable orthogonal reactive concentration gradients that greatly expand the dynamic range, spatial control, and chemical versatility of the reactive silanes that can be controllably deposited. Using metal-free "dual click" immobilization chemistries, multiple peptides with a variety of functionality can be immobilized efficiently and reproducibly enabling optimal concentration profiling and the assessment of synergistic interactions. 23305993 Chemical synthesis, docking studies and biological effects of a pan peroxisome proliferator-activated receptor agonist and cyclooxygenase inhibitor. The compound (5Z)-5-[(5-bromo-1H-indol-3-yl)methylene]-3-(4-chlorobenzyl)-thiazolidine-2,4-dione (LYSO-7) was synthesised in order to obtain a new type of anti-inflammatory drug, designed with hybrid features to inhibit cyclooxygenase (COX) and also to activate peroxisome proliferator-activated receptor (PPAR). Results obtained from docking (in silico) studies corroborated with experimental data, showing the potential affinity between the studied ligand and targets. The specificity of LYSO-7 for COX-enzymes was detected by the inhibition of COX-1 and COX-2 activities by 30% and 20%, respectively. In transactivation reporter gene assays LYSO-07 showed a pan partial agonist effect on the three PPAR subtypes (PPARγ, PPARα and PPARβ/δ). The agonist action on PPARγ was also observed by a pharmacological approach, as the reduction in the Escherichia coli lipopolysaccharide (LPS)-induced interleukin 1 beta (IL-1β) secretion and nitric oxide (NO) production by mouse neutrophils was blocked by GW9962, a specific PPARγ antagonist. Additionally, the in vivo effect was measured by reduced carrageenan-induced neutrophil influx into the subcutaneous tissue of mice. Taken together, these data show that LYSO-7 displays a potent in vivo anti-inflammatory effect during the innate acute response, which is dependent on its associated COX inhibitory activities and PPAR activation. 23041510 Effects of combined treatment with eldecalcitol and alendronate on bone mass, mechanical properties, and bone histomorphometry in ovariectomized rats: a comparison with alfacalcidol and alendronate. Eldecalcitol (ELD), a 2β-hydroxypropyloxy derivative of 1α,25 (OH) 2D3, inhibits bone resorption more potently than alfacalcidol (ALF) while maintaining osteoblastic function in an ovariectomized (OVX) osteoporosis rat model. Alendronate (ALN), which is the most common bisphosphonate used for the treatment of osteoporosis, increases the bone mineral density (BMD) by suppressing bone resorption. In this study, we investigated the effects of combination treatments with ELD and ALN or with ALF and ALN on bone mass and strength in OVX rats. Seventy female rats, 32 weeks old, were assigned to seven groups: (1) a sham-operated control group; (2) an OVX-control group; (3) an ELD group; (4) an ALF group; (5) an ALN group; (6) an ELD+ALN group; and (7) an ALF+ALN group. OVX rats were orally treated with ELD (0.015 μg/kg), ALF (0.0375 μg/kg), or ALN (0.2mg/kg) daily for 12 weeks. In both the lumbar spine and the femur, ELD and ALF monotherapy significantly increased the BMD, and ELD+ALN and ALF+ALN significantly increased the BMD, compared with ALN monotherapy, as an additive effect. In particular, ELD+ALN resulted in a significantly higher BMD than ALF+ALN in the femur. On mechanical testing of the lumbar spine, ELD and ALF monotherapy significantly increased the ultimate load, and ELD+ALN and ALF+ALN significantly increased the ultimate load compared with ALN monotherapy. In the femur, ELD, ELD+ALN, and ALF+ALN treatment significantly increased the ultimate load, compared with the OVX-control group, and ELD+ALN resulted in a significantly higher ultimate load than ALN monotherapy. A histomorphometric analysis showed that ELD monotherapy and ELD+ALN combination therapy had a potent inhibitory effect on bone resorption parameters (osteoclast surface and eroded surface), while maintaining bone formation parameters (osteoblast surface and osteoid surface). By contrast, ALF and ALF+ALN significantly lowered the histological parameters of both bone resorption and formation. These results suggested that ELD or ALF used in combination with ALN has therapeutic advantages over ALN monotherapy, with ELD+ALN combination treatment producing an especially beneficial anti-osteoporotic effect by inhibiting osteoclastic bone resorption and maintaining osteoblastic function, compared with ALF+ALN combination treatment. 23411255 Understanding the degradation of ascorbic acid and glutathione in relation to the levels of oxidative stress biomarkers in broccoli (Brassica oleracea L. italica cv. Bellstar) during storage and mechanical processing. The purpose of this research was to understand the degradation of ascorbic acid and glutathione content in broccoli florets (Brassica oleracea L. italica cv. Bellstar) during prolonged storage and subsequent mechanical processing. The initial content of total ascorbic acid and glutathione in broccoli florets averaged at 5.18 ± 0.23 and 0.70 ± 0.03 μmol/g fresh weight, respectively. Results showed that the content of ascorbic acid and glutathione in broccoli degraded during storage at 23°C, for at least 4.5-fold after 6 days of storage. On each day of storage, broccoli florets were mechanically processed, but the content of total ascorbic acid and glutathione was not significantly affected. When the mechanically processed broccoli florets were further incubated for up to 6h, the amount of ascorbic acid was greatly reduced as compared to glutathione. To obtain an in-depth understanding on the degradation of ascorbic acid and glutathione, the activity of enzymes involved in plant antioxidative system via ascorbate-glutathione cycle, as a response towards oxidative stress that took place during storage was determined in this study. The content of total ascorbic acid and glutathione in broccoli florets before and after mechanical processing were found to decrease concurrently with the activity of ascorbic acid peroxidase and glutathione reductase over the experimental storage duration. Meanwhile, the effect of oxidative stress on the content of ascorbic acid and glutathione was apparent during the 6h of incubation after mechanical processing. This phenomenon was demonstrated by the level of oxidative stress biomarkers examined, in which the formation of lipid peroxides, protein carbonyls and DNA oxidised products was positively associated with the degradation of total ascorbic acid and glutathione. 23517470 Light-Triggered Cross-Linking of Alginates with Caged Ca(2+) A strategy to light-trigger ionic cross-linking of alginates by incorporating a photosensitive Ca(2+) cage (nitr-T) is presented. Upon irradiation, free Ca(2+) was released, and this caused gelation of the alginate solution. Addition of Ca(2+) "on-demand" allowed us to obtain homogeneous alginate (ALG) gels using concentrated initial ALG solutions (10%), not possible with other ionic gelation approaches. The cross-linking degree and derived mechanical properties of the hydrogel were modulated by the exposure dose. The light-mediated cross-linked alginate hydrogel displayed a significant improvement in the mechanical properties and homogeneity when compared to mixtures of alginate and soluble Ca(2+) at comparable concentrations. 23163696 The octadecaneuropeptide stimulates somatolactin release from cultured goldfish pituitary cells. The present study aimed to investigate the distribution of the octadecaneuropeptide (ODN) in the goldfish brain and to look for a possible effect of ODN on somatolactin (SL) release from pituitary cells. A discrete population of ODN-immunoreactive neurones was localised in the lateral part of the nucleus lateralis tuberis. These neurones sent projections through the neurohypophyseal tract towards the neurohypophysis, and nerve fibres were seen in the close vicinity of SL-producing cells in the pars intermedia. Incubation of cultured goldfish pituitary cells with graded concentrations of ODN (10(-9) -10(-5 ) m) induced a dose-dependent stimulation of SL-β, but not SL-α, release. ODN-evoked SL release was blocked by the metabotrophic endozepine receptor antagonist cyclo(1-8) [DLeu(5) ]OP but was not affected by the central-type benzodiazepine receptor antagonist flumazenil. ODN-induced SL release was suppressed by treatment with the phospholipase C (PLC) inhibitor U-73122 but not with the protein kinase A (PKA) inhibitor H-89. These results indicate that, in fish, ODN produced by hypothalamic neurones acts as a hypophysiotrophic neuropeptide stimulating SL release. The effect of ODN is mediated through a metabotrophic endozepine receptor positively coupled to the PLC/inositol 1,4,5-trisphosphate/protein kinase C-signalling pathway. 23411181 In vitro biological activity of essential oils and isolated furanosesquiterpenes from the neglected vegetable Smyrnium olusatrum L. (Apiaceae). Smyrnium olusatrum, better known as Alexanders or wild celery, is a biennal herb used in cuisine for many centuries by Romans in many dishes, where it has now been replaced by celery. In order to provide additional evidences so that this forgotten vegetable can be reconsidered in the human diet, as well as in pharmaceutics, the essential oils obtained from different parts and its main isolated furanosesquiterpenes were in vitro biologically assayed for antiproliferative activity on human tumor cell lines by MTT assay, for antioxidant potential by DPPH, ABTS and FRAP assays, and for antimicrobial activity by the agar disc diffusion method. The essential oils showed cytotoxic effects on tested human tumor cell lines, related to the furanosesquiterpenoid content; the IC(50) values on colon carcinoma, glioblastoma, and breast adenocarcinoma cells were 8.51, 13.35, and 14.81 μg/ml, respectively. Isofuranodiene and 1β-acetoxyfuranoeudesm-4(15)-ene resulted the most active constituents. The essential oils possessed also radical scavenging activity. 23458621 Luminescent silica nanoparticles for cancer diagnosis. Fluorescence imaging techniques are becoming essential for preclinical investigations, necessitating the development of suitable tools for in vivo measurements. Nanotechnology entered this field to help overcome many of the current technical limitations, and luminescent nanoparticles (NPs) are one of the most promising materials proposed for future diagnostic implementation. NPs also constitute a versatile platform that can allow facile multi-functionalization to perform multimodal imaging or theranostics (simultaneous diagnosis and therapy). In this contribution we have mainly focused on dye doped silica or silica-based NPs conjugated with targeting moieties to enable imaging of specific cancer cells. We also cite and briefly discuss a few non-targeted systems for completeness. We summarize common synthetic approaches to these materials, and then survey the most recent imaging applications of silica-based nanoparticles in cancer. The field of theranostics is particularly important and stimulating, so, even though it is not the central topic of this paper, we have included some significant examples. We conclude with a short section on NP-based systems already in clinical trials and examples of specific applications in childhood tumors. This review aims to describe and discuss, through focused examples, the great potential of these materials in the medical field, with the aim to encourage further research to implement applications, which today are still rare. 23281340 Chemerin and vaspin: possible targets to treat obesity? Obesity is one of the main human epidemics today. The increase in fat accumulation, which is associated with obesity, may significantly change the expression of several bioactive molecules known as adipokines. These adipokines interact not only with adipose tissue, but also with metabolically relevant organs such as liver and muscle. Understanding the molecular basics of potential novel targets might help to improve the therapeutic treatment of people who suffer from obesity. Herein we summarize the state of the art of two novel adipokines and their impaired or protective action in obesity: chemerin and vaspin. Their expression patterns, signal transduction activity, and resulting functions within the human body are introduced. We also discuss various possibilities to target these adipokines, which may represent promising new targets for the treatment of obesity by small and synthetic compounds. 23104982 Identification of inhibitory scFv antibodies targeting fibroblast activation protein utilizing phage display functional screens. Fibroblast activation protein (FAP) is a serine protease selectively expressed on tumor stromal fibroblasts in epithelial carcinomas and is important in cancer growth, adhesion, and metastases. As FAP enzymatic activity is a potent therapeutic target, we aimed to identify inhibitory antibodies. Using a competitive inhibition strategy, we used phage display techniques to identify 53 single-chain variable fragments (scFvs) after three rounds of panning against FAP. These scFvs were expressed and characterized for binding to FAP by surface plasmon resonance and flow cytometry. Functional assessment of these antibodies yielded an inhibitory scFv antibody, named E3, which could attenuate 35% of FAP cleavage of the fluorescent substrate Ala-Pro-7-amido-4-trifluoromethylcoumarin compared with nonfunctional scFv control. Furthermore, a mutant E3 scFv was identified by yeast affinity maturation. It had higher affinity (4-fold) and enhanced inhibitory effect on FAP enzyme activity (3-fold) than E3. The application of both inhibitory anti-FAP scFvs significantly affected the formation of 3-dimensional FAP-positive cell matrix, as demonstrated by reducing the fibronectin fiber orientation from 41.18% (negative antibody control) to 34.06% (E3) and 36.15% (mutant E3), respectively. Thus, we have identified and affinity-maturated the first scFv antibody capable of inhibiting FAP function. This scFv antibody has the potential to disrupt the role of FAP in tumor invasion and metastasis. 23300000 Influence of rare earth elements on metabolism and related enzyme activity and isozyme expression in Tetrastigma hemsleyanum cell suspension cultures. The effects of rare earth elements (REEs) not only on cell growth and flavonoid accumulation of Tetrastigma hemsleyanum suspension cells but also on the isoenzyme patterns and activities of related enzymes were studied in this paper. There were no significant differences in enhancement of flavonoid accumulation in T. hemsleyanum suspension cells among La(3+), Ce(3+), and Nd(3+). Whereas their inductive effects on cell proliferation varied greatly. The most significant effects were achieved with 100 μM Ce(3+)and Nd(3+). Under treatment over a 25-day culture period, the maximal biomass levels reached 1.92- and 1.74-fold and the total flavonoid contents are 1.45- and 1.49-fold, than that of control, respectively. Catalase, phenylalanine ammonia-lyase (PAL), and peroxidase (POD) activity was activated significantly when the REE concentration range from 0 to 300 μM, whereas no significant changes were found in superoxide dismutase activity. Differences of esterase isozymes under REE treatment only laid in expression level, and there were no specific bands. The expression level of some POD isozymes strengthened with increasing concentration of REEs within the range of 50-200 μM. When REE concentration was higher than 300 μM, the expression of some POD isozymes was inhibited; meanwhile, some other new POD isozymes were induced. Our results also showed REEs did not directly influence PAL activity. So, we speculated that 50-200 μM REEs could activate some of antioxidant enzymes, adjust some isozymes expression, trigger the defense responses of T. hemsleyanum suspension cells, and stimulate flavonoid accumulation by inducing PAL activity. 23267862 Simultaneous addition of two ligands: a potential strategy for estimating divalent ion affinities in EF-hand proteins by isothermal titration calorimetry. Capable of providing a detailed thermodynamic picture of noncovalent association reactions, isothermal titration calorimetry (ITC) has become a popular method for studying protein-ligand interactions. We routinely employ the technique to study divalent ion-binding by two-site EF-hand proteins from the parvalbumin- and polcalcin lineages. The combination of high Ca(2+) affinity and relatively low Mg(2+) affinity, and the attendant complication of parameter correlation, conspire to make the simultaneous extraction of binding constants and -enthalpies for both ions challenging. Although global analysis of multiple ITC experiments can overcome these hurdles, our current experimental protocol includes upwards of 10 titrations - requiring a substantial investment in labor, machine time, and material. This paper explores the potential for using a smaller suite of experiments that includes simultaneous titrations with Ca(2+) and Mg(2+) at different ratios of the two ions. The results obtained for four proteins, differing substantially in their divalent ion-binding properties, suggest that the approach has merit. The Ca(2+)- and Mg(2+)-binding constants afforded by the streamlined analysis are in reasonable agreement with those obtained from the standard analysis protocol. Likewise, the abbreviated analysis provides comparable values for the Ca(2+)-binding enthalpies. However, the streamlined analysis can yield divergent values for the Mg(2+)-binding enthalpies - particularly those for lower affinity sites. This shortcoming can be remedied, in large measure, by including data from a direct Ca(2+) titration in the presence of a high, fixed Mg(2+) concentration. 23273225 Controlling Porphyrin Nanoarchitectures at Solid Interfaces. Two complementary examples of porphyrin nanoarchitectonics are presented. The fabrication of binary molecular monolayers using two different porphyrin molecules, tetrakis(3,5-di-t-butyl-4-hydroxyphenyl)porphyrin (1) and tetrakis(4-pyridyl)porphyrin (2), by deposition in ultrahigh vacuum was demonstrated. Two unusual heteromolecular monolayer structures were observed, with one exhibiting good separation of 1 molecules within the monolayer. Also, a synthetic nanoarchitectonic approach was used to prepare self-assembled molecular nanowires at a mica substrate. The nanowires could be observed to grow using atomic force microscopy (AFM), and the network structures of the nanowires could be influenced by manipulation using the AFM probe tip. 23570998 Assessment of the role of flavonoids for inducing osteoblast differentiation in isolated mouse bone marrow derived mesenchymal stem cells. Quercetin and rutin are common flavonoids in fruit and vegetables, and have been reported to affect bone development. However, the effect of flavonoids on osteoblast differentiation remains a matter of controversy. In the present study, mouse bone marrow mesenchymal stem cells (BMMSCs) were isolated and characterized for their use in osteoblast differentiation using two flavonoids, quercetin and rutin. BMMSCs were cultured in various concentrations of quercetin and rutin during the osteoblast differentiation period of 10 days. Both quercetin and rutin were found to up regulate the osteoblast differentiation in dose dependent manner, albeit to lesser extent in case of former than that of latter. Quercetin and rutin also increased alkaline phosphatase activity by about 150 and 240% and demonstrated mineralization up to 110 and 200% respectively as compared to control (which was considered as 100%). Further, both the flavonoids were also found to increase the expression of some of the prominent markers for differentiation of osteoblast like osteopontin, osterix, RunX2, osteoprotegerin and osteocalcin. The current data suggests that certain classes of flavonoids like rutin and quercetin can be used in the cure and management of osteodegenerative disorders due to their osteoblast specific differentiation activities. 23122137 Hypotriglyceridemic and hypoglycemic effects of vescalagin from Pink wax apple [Syzygium samarangense (Blume) Merrill and Perry cv. Pink] in high-fructose diet-induced diabetic rats. Vescalagin, an active component from Pink wax apple [Syzygium samarangense (Blume) Merrill and Perry cv. Pink] fruit, with glucose uptake enhancing ability in insulin-resistant FL83B mouse hepatocytes, as shown in our previous study, was further evaluated for its hypotriglyceridemic and hypoglycemic effects in high-fructose diet (HFD)-induced diabetic rats. Wistar rats were fed HFD for 16 weeks and orally administered with vescalagin from Pink wax apple daily during the last 4 weeks. The results of biochemical parameters showed that fasting blood glucose, C-peptide, fructosamine, triglyceride and free fatty acid contents decreased by 44.7%, 46.2%, 4.0%, 42.5%, and 10.8%, respectively, in the HFD-induced diabetic rats administered with vescalagin at 30 mg/kg body weight in comparison with those of control HFD-induced diabetic rats. However, high-density-lipoprotein-cholesterol content increased by 14.4% in the HFD rats treated with vescalagin. The present study reveals that vescalagin could have therapeutic value against diabetic progression via its anti-hypertriglyceridemic and anti-hyperglycemic effects. 23215238 Encapsulation of living E. coli cells in hollow polymer microspheres of highly defined size. Here, we report the preparation and characterization of hollow polymer microspheres based on the preprecipitation of porous calcium carbonate cores with an average size of 5 μm and their use for encapsulation of living microorganisms. The microspheres filled with individual living E. coli cells were prepared by layer-by-layer (LbL) deposition of different polyelectrolytes and proteins onto the porous calcium carbonate cores leading to the formation of matrix-like complexes of the compounds followed by calcium carbonate core dissolution using EDTA. Both the influence of the encapsulation process as well as of the used polyelectrolytes on the survival rate of the cells were determined by confocal laser scanning microscopy (CLSM) and microtiter plate fluorescence tests. After the encapsulation process ~40% of the cells were alive. Cultivation tests indicated that the lag phase of cells treated with polyelectrolytes increases and the encapsulated E. coli cells were able to produce green fluorescent protein inside the microcapsules. 23549285 Spongiatriol inhibits nuclear factor kappa B activation and induces apoptosis in pancreatic cancer cells. Pancreatic cancer, the fourth leading cause of cancer death in the US, is highly resistant to all current chemotherapies, and its growth is facilitated by chronic inflammation. The majority of pro-inflammatory cytokines initiate signaling cascades that converge at the activation of the Nuclear Factor Kappa B (NFκB), a signal transduction molecule that promotes cell survival, proliferation and angiogenesis. In an effort to identify novel inhibitors of NFκB, the HBOI library of pure compounds was screened using a reporter cell line that produces luciferin under the transcriptional control of NFκB. Seven compounds were identified through this screen, but in the case of five of them, their reported mechanism of action made them unlikely to be specific NFκB inhibitors. Spongiatriol, a marine furanoditerpenoid that was first isolated in the 1970s, is shown here to inhibit NFκB transcriptional activity in a reporter cell line, to reduce levels of phosphorylated (active) NFκB in the AsPC-1 cell line, to have an IC50 for cytotoxicity in the low micromolar range against the AsPC-1, BxPC-3, MiaPaCa-2 and Panc-1 pancreatic cancer cell lines, and to induce moderate but significant apoptosis in both the AsPC-1 and the Panc-1 cell lines. 23296837 Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson's disease. Consumption of coffee is associated with reduced risk of Parkinson's disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of α-synuclein transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if EHT has an effect in the MPTP model of PD. Mice fed a diet containing EHT for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed. Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with EHT treatment. The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with EHT. In cultured primary microglia and astrocytes, EHT had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NFκB activation, iNOS induction, and nitric oxide production. EHT also exhibited a robust anti-oxidant activity in vitro. Additionally, in SH-SY5Y cells, MPP(+)-induced demethylation of phosphoprotein phosphatase 2A (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by EHT. These findings indicate that the neuroprotective effect of EHT against MPTP is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of PP2A. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD. 23500537 Oxyphytosterol formation in humans: Identification of high vs. low oxidizers. Animal studies suggest that oxyphytosterols are atherogenic. However, we have previously shown that plasma oxyphytosterol concentrations did not increase after consuming a diet enriched in plant sterol esters (3g/day), while minor reductions were seen after consuming a plant stanol ester-enriched diet. Large variations in oxyphytosterol concentrations between individuals however existed. The aim of this study was to identify factors that may explain inter-individual differences in plasma oxyphytosterol concentrations. For this, 43 subjects consumed for 4 weeks in random order a plant sterol, stanol and control margarine. Plasma oxyphytosterol concentrations were determined in butylated hydroxytoluene (BHT)-enriched EDTA plasma via GC-MS and serum oxidized low-density lipoprotein (oxLDL) concentrations were analyzed via ELISA. Trolox equivalent antioxidant capacity (TEAC) values, α-tocopherol concentrations and iron/copper status were determined to assess plasma oxidative and anti-oxidative capacity. Serum (non-oxidized) sitosterol and campesterol concentrations did not correlate with plasma oxysitosterol and oxycampesterol concentrations during any of the three dietary interventions. Moreover, plasma oxyphytosterol concentrations remained relatively stable over time. Six subjects could be arbitrarily classified as having consistent low or high plasma oxyphytosterol concentrations, which was also reflected in oxLDL concentrations. However, oxidative and anti-oxidative capacity markers, such as iron/copper status, α-tocopherol concentrations and TEAC values, could not explain these differences. In conclusion, subjects seem to have consistent plasma oxyphytosterol concentrations, which resulted in the identification of 'low and high oxidizers'. Differences, however, could not be attributed to the oxidative and anti-oxidative capacity markers analyzed. 23590189 Inflammation-Responsive Antioxidant Nanoparticles Based on a Polymeric Prodrug of Vanillin. Oxidative stress is induced by accumulation of hydrogen peroxide (H2O2), and therefore, H2O2 could serve as a potential biomarker of various oxidative stress-associated inflammatory diseases. Vanillin is one of the major components of natural vanilla and has potent antioxidant and anti-inflammatory activities. In this work, we developed a novel inflammation-responsive antioxidant polymeric prodrug of vanillin, termed poly(vanillin oxalate) (PVO). In design, PVO incorporates H2O2-reacting peroxalate ester bonds and bioactive vanillin via acid-responsive acetal linkages in its backbone. Therefore, in cells undergoing damages by oxidative stress, PVO readily degrades into three nontoxic components, one of which is antioxidant and anti-inflammatory vanillin. PVO nanoparticles exhibit potent antioxidant activities by scavenging H2O2 and inhibiting the generation of ROS (reactive oxygen species) and also reduce the expression of pro-inflammatory cytokines in activated macrophages in vitro and in vivo. We, therefore, anticipate that PVO nanoparticles have great potential as novel antioxidant therapeutics and drug delivery systems for ROS-associated inflammatory diseases. 22818587 Influence of low ultrasound intensity on the degradation of dextran catalyzed by dextranase. In our current research work, the effect of ultrasound irradiation on the enzymatic activity and enzymatic hydrolysis kinetic parameters of dextran catalysis by dextranase were investigated. Furthermore, the effects of ultrasound irradiation on the structure of dextranase were investigated with the aid of fluorescence spectroscopy and circular dichroism (CD) spectroscopy. The maximum activity of dextranase was observed when the sample was treated with ultrasound at 25 kHz, 40 W for 15 min, under which the enzyme activity increased by 13.43% compared the routine thermal incubation at 50 °C. Experimental Kinetics results, demonstrated that, both the V(max) and K(M) values of dextranase increased with ultrasound-treated compared with the incubation at 50 °C. Likewise, both the catalytic and specificity constants were higher under the effects of an ultrasonic field, indicating that, the substrate is converted into the product at an increased rate when compared with the incubation at 50 °C. On the other hand, fluorescence and CD spectra reflected that the ultrasound irradiation had increased the number of tryptophan on dextranase surface with increased α-helix by 15.74% and reduced random coil by 5.41% upon ultrasound-treated dextranase protein compared to the control, which were helpful for the improvement of its activity. 23317498 Small-molecule inhibitors for the treatment of hepatitis B virus documented in patents. Hepatitis B virus (HBV) infection is a serious health problem worldwide, and the current treatment methods including vaccines, immunomodulators, interferons and nucleoside analogs are far from satisfactory. For the search of new anti-HBV agents, much investigation has revealed a large number of small-molecule compounds with various skeletons and promising anti-HBV activities. Although some reviews on anti-HBV progress have been published, they are mainly concentrated on the results reported in journal articles. This review provides an overview of the structural features and anti-HBV properties of the small-molecule anti-HBV inhibitors claimed in recent patents (from 2001 to 2010). These small-molecules can be structurally classified as two main types, nucleoside analogs (cyclic and acyclic nucleosides) and non-nucleosides (natural and synthesized compounds), which are declared with the activity inhibiting the secretion of HBsAg and HBeAg and HBV DNA replication in vitro, as well as anti-DHBV DNA in vivo. Especially, the non-nucleosides with diverse skeletons and novel mechanism offer prolific candidates for anti-HBV drug discovery, which are preferred to be used as adjuvant therapy for HBV infection. This paper will provide valuable information for understanding the current anti-HBV investigation and developing new anti-HBV agents. 23434669 Chemical Inhibitors and microRNAs (miRNA) Targeting the Mammalian Target of Rapamycin (mTOR) Pathway: Potential for Novel Anticancer Therapeutics. The mammalian target of rapamycin (mTOR) is a critical regulator of many fundamental features in response to upstream cellular signals, such as growth factors, energy, stress and nutrients, controlling cell growth, proliferation and metabolism through two complexes, mTORC1 and mTORC2. Dysregulation of mTOR signalling often occurs in a variety of human malignant diseases making it a crucial and validated target in the treatment of cancer. Tumour cells have shown high susceptibility to mTOR inhibitors. Rapamycin and its derivatives (rapalogs) have been tested in clinical trials in several tumour types and found to be effective as anticancer agents in patients with advanced cancers. To block mTOR function, they form a complex with FKBP12 and then bind the FRB domain of mTOR. Furthermore, a new generation of mTOR inhibitors targeting ATP-binding in the catalytic site of mTOR showed potent and more selective inhibition. More recently, microRNAs (miRNA) have emerged as modulators of biological pathways that are essential in cancer initiation, development and progression. Evidence collected to date shows that miRNAs may function as tumour suppressors or oncogenes in several human neoplasms. The mTOR pathway is a promising target by miRNAs for anticancer therapy. Extensive studies have indicated that regulation of the mTOR pathway by miRNAs plays a major role in cancer progression, indicating a novel way to investigate the tumorigenesis and therapy of cancer. Here, we summarize current findings of the role of mTOR inhibitors and miRNAs in carcinogenesis through targeting mTOR signalling pathways and determine their potential as novel anti-cancer therapeutics. 23606629 Synthesis and Anti-herpetic Activity of Phosphoramidate ProTides. Among the many prodrug approaches aimed at delivering nucleoside monophosphates into cells, the phosphoramidate ProTide approach is one that has shown success, which has made it possible for some of the phosphoramidates to enter into clinical trials. Herein, we report the synthesis and antiviral activity of a series of phosphoramidate ProTides designed to bypass the thymidine kinase (TK) dependence of the parent nucleoside analogues. Phosphoramidate derivatives of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) that contain L-alanine or pivaloyloxymethyl iminodiacetate (IDA-POM) exhibit anti-HSV-1 and anti-VZV activity in cell cultures, but they largely lost antiviral potency against TK-deficient virus strains. Among deazapurine nucleosides and their phosphoramidate derivatives, the 7-deazaadenine containing nucleosides and their phosphoramidate triester derivatives showed weak antiviral activity against VZV. Apparently, intracellular nucleotide delivery with these phosphoramidates is partly successful. However, none of the compound prodrugs showed superior activity to their parent drugs. 23139019 The utility of modeling and simulation approaches to evaluate immunogenicity effect on the therapeutic protein pharmacokinetics. While therapeutic proteins (TP), particularly recombinant human proteins and fully human monoclonal antibodies, are designed to have a low immunogenic potential in humans, a clinical immune response does sometimes occur and cannot be predicted from preclinical studies. Changes in TP pharmacokinetics may be perceived as an early indication of antibody formation and serve as a surrogate for later changes in efficacy and safety in individual subjects. Given the substantial increase in number of biological products, including biosimilars, there is an urgent need to quantitatively predict and quantify the immune response and any consequential changes in TP pharmacokinetics. The purpose of this communication is to review the utility of population-based modeling and simulation approaches developed to date for investigating the development of an immune response and assessing its impact on TP pharmacokinetics. Two examples of empirical modeling approaches for pharmacokinetic assessment are presented. The first example presents methods to analyze pharmacokinetic data in the presence of anti-drug antibody (ADA) and confirm the effect of immunogenicity on TP pharmacokinetics in early phases of drug development. The second example provides a framework to analyze pharmacokinetic data in the absence or with very low incidence of ADA and confirm with enough power the lack of an immunogenicity effect on TP pharmacokinetics in late phases of drug development. Finally, a theoretical mechanism-based modeling framework is presented to mathematically relate the complex interaction among TP, their targets, and ADA. 22929022 Genetic perspectives on the origin of clicks in Bantu languages from southwestern Zambia. Some Bantu languages spoken in southwestern Zambia and neighboring regions of Botswana, Namibia, and Angola are characterized by the presence of click consonants, whereas their closest linguistic relatives lack such clicks. As clicks are a typical feature not of the Bantu language family, but of Khoisan languages, it is highly probable that the Bantu languages in question borrowed the clicks from Khoisan languages. In this paper, we combine complete mitochondrial genome sequences from a representative sample of populations from the Western Province of Zambia speaking Bantu languages with and without clicks, with fine-scaled analyses of Y-chromosomal single nucleotide polymorphisms and short tandem repeats to investigate the prehistoric contact that led to this borrowing of click consonants. Our results reveal complex population-specific histories, with female-biased admixture from Khoisan-speaking groups associated with the incorporation of click sounds in one Bantu-speaking population, while concomitant levels of potential Khoisan admixture did not result in sound change in another. Furthermore, the lack of sequence sharing between the Bantu-speaking groups from southwestern Zambia investigated here and extant Khoisan populations provides an indication that there must have been genetic substructure in the Khoisan-speaking indigenous groups of southern Africa that did not survive until the present or has been substantially reduced. 23095167 Kainate receptor signaling in pain pathways. Receptors and channels that underlie nociceptive signaling constitute potential sites of intervention for treatment of chronic pain states. The kainate receptor family of glutamate-gated ion channels represents one such candidate set of molecules. They have a prominent role in modulation of excitatory signaling between sensory and spinal cord neurons. Kainate receptors are also expressed throughout central pain neuraxis, where their functional contributions to neural integration are less clearly defined. Pharmacological inhibition or genetic ablation of kainate receptor activity reduces pain behaviors in a number of animal models of chronic pain, and small clinical trials have been conducted using several orthosteric antagonists. This review will cover kainate receptor function and participation in pain signaling as well as the pharmacological studies supporting further consideration as potential targets for therapeutic development. 23497875 Mild Fe-deficiency improves biomass production and quality of hydroponic-cultivated spinach plants (Spinacia oleracea L.). It is of great practical importance to improve yield and quality of vegetables in soilless cultures. This study investigated the effects of iron-nutrition management on yield and quality of hydroponic-cultivated spinach (Spinacia oleracea L.). The results showed that mild Fe-deficient treatment (1 μM FeEDTA) yielded a greater biomass of edible parts than Fe-omitted treatment (0 μM FeEDTA) or Fe-sufficient treatments (10 and 50 μM FeEDTA). Conversely, mild Fe-deficient treatment had the lowest nitrate concentration in the edible parts out of all the Fe treatments. Interestingly, all the concentrations of soluble sugar, soluble protein and ascorbate in mild Fe-deficient treatments were higher than Fe-sufficient treatments. In addition, both phenolic concentration and DPPH scavenging activity in mild Fe-deficient treatments were comparable with those in Fe-sufficient treatments, but were higher than those in Fe-omitted treatments. Therefore, we concluded that using a mild Fe-deficient nutrition solution to cultivate spinach not only would increase yield, but also would improve quality. 23255050 Intrinsically green iron oxide nanoparticles? From synthesis via (eco-)toxicology to scenario modelling. Iron oxide nanoparticles (IONP) are currently being studied as green magnet resonance imaging (MRI) contrast agents. They are also used in huge quantities for environmental remediation and water treatment purposes, although very little is known on the consequences of such applications for organisms and ecosystems. In order to address these questions, we synthesised polyvinylpyrrolidone-coated IONP, characterised the particle dispersion in various media and investigated the consequences of an IONP exposure using an array of biochemical and biological assays. Several theoretical approaches complemented the measurements. In aqueous dispersion IONP had an average hydrodynamic diameter of 25 nm and were stable over six days in most test media, which could also be predicted by stability modelling. The particles were tested in concentrations of up to 100 mg Fe per L. The activity of the enzymes glutathione reductase and acetylcholine esterase was not affected, nor were proliferation, morphology or vitality of mammalian OLN-93 cells although exposure of the cells to 100 mg Fe per L increased the cellular iron content substantially. Only at this concentration, acute toxicity tests with the freshwater flea Daphnia magna revealed slightly, yet insignificantly increased mortality. Two fundamentally different bacterial assays, anaerobic activated sludge bacteria inhibition and a modified sediment contact test with Arthrobacter globiformis, both rendered results contrary to the other assays: at the lowest test concentration (1 mg Fe per L), IONP caused a pronounced inhibition whereas higher concentrations were not effective or even stimulating. Preliminary and prospective risk assessment was exemplified by comparing the application of IONP with gadolinium-based nanoparticles as MRI contrast agents. Predicted environmental concentrations were modelled in two different scenarios, showing that IONP could reduce the environmental exposure of toxic Gd-based particles by more than 50%. Application of the Swiss "Precautionary Matrix for Synthetic Nanomaterials" rendered a low precautionary need for using our IONP as MRI agents and a higher one when using them for remediation or water treatment. Since IONP and (considerably more reactive) zerovalent iron nanoparticles are being used in huge quantities for environmental remediation purposes, it has to be ascertained that these particles pose no risk to either human health or to the environment. 23601409 Improvement of the AOAC 2009.01 total dietary fibre method for bread and other high starch containing matrices. The dietary fibre (DF) content in wheat grain based food products have been established with both the classical AOAC 985.29 dietary fibre and the new AOAC 2009.01 total dietary fibre protocol. There is a good agreement between the high molecular weight dietary fibre (HMWDF) contents measured with the AOAC 2009.01 method and (DF) content measured with the classical AOAC 985.29 method in wheat grain based food products. With the AOAC 2009.01 method also a significant amount of low molar weight dietary fibre (LMWDF), ranging from 1% to 3% w/w, was measured which is not quantified with the AOAC 985.29 method. With semi-preparative GPC the LMWDF (DP⩾3) fractions in the wheat grain based food products were isolated. The monosaccharide composition of the dissolved LMWDF constituents was determined. Glucose was by far the most abundant monosaccharide present with arabinose, galactose, xylose and mannose as minor constituents. It appeared that the LMWDF contains still not fully converted digestible starch/malto-oligosaccharide fragments with DP⩾3, which are erroneously quantified as LMWDF. By introducing an extra AMG hydrolysis step in the AOAC 2009.01 protocol after evaporation of the ethanol and dissolving the residue in deionised water, these malto-oligosaccharides are fully hydrolysed resulting in that way in a correct and lower LMWDF content. 23153054 A new approach to predicting human hepatic clearance of CYP3A4 substrates using monkey pharmacokinetic data. 1. Focusing on the genetic similarity of CYP3A subfamily enzymes (CYP3A4 and CYP3A5) between monkeys and humans, we have attempted to provide a single-species approach to predicting human hepatic clearance (CLh) of CYP3A4 substrates using pharmacokinetic parameters in cynomolgus monkeys following intravenous administrations. 2. Hepatic intrinsic clearance (CLint,h) of six CYP3A4 substrates (alprazolam, clonazepam, diltiazem, midazolam, nifedipine, and quinidine), covering a wide range of clearance, in monkeys correlated well with that cited in literature for humans (R = 0.90) with a simple equation of Y = 0.165X (Y: human CLint,h, X: monkey CLint,h, represented in mL/min/kg). 3. To verify the predictability of human CLint,h, monkey CLint,h of a test set of CYP3A4 substrates cited in literature (dexamethasone, nifedipine, midazolam, quinidine, tacrolimus, and verapamil) was applied to the equation and human CLint,h was calculated. The human CLint,h of all the substrates was predicted within 3-fold error (fold error: 0.35-2.77). 4. The predictability of human CLh by our method was superior to common in vivo prediction methods (allometry and liver blood flow method). These results suggest that human hepatic clearance of CYP3A4 substrates can be predicted by applying cynomolgus monkey CLint,h obtained following intravenous administrations in each laboratory to the simple equation. 23178182 UCCB01-125, a dimeric inhibitor of PSD-95, reduces inflammatory pain without disrupting cognitive or motor performance: comparison with the NMDA receptor antagonist MK-801. Excessive N-Methyl-d-aspartate receptor (NMDAR)-dependent production of nitric oxide (NO) is involved in the development and maintenance of chronic pain states, and is mediated by postsynaptic density protein-95 (PSD-95). By binding to both the NMDAR and neuronal NO synthase (nNOS), PSD-95 mediates a specific coupling between NMDAR activation and NO production. NMDAR antagonism shows anti-nociceptive action in humans and animal models of chronic pain but is associated with severe disturbances of cognitive and motor functions. An alternative approach to modulate the NMDAR-related activity is to perturb the NMDAR/PSD-95/nNOS complex by targeting PSD-95, thereby decreasing NO production without interfering with the NMDAR ion channel function. Here, we compared the effects of a dimeric PSD-95 inhibitor, UCCB01-125, and the NMDAR antagonist, MK-801, on mechanical hypersensitivity in the complete Freund's adjuvant (CFA) model of inflammatory pain. To examine side-effect profiles we also compared the effects of UCCB01-125 and MK-801 in tests of attention, long-term memory, and motor performance. When administered concurrently with CFA, both MK-801 and UCCB01-125 prevented the development of CFA-induced mechanical hypersensitivity 1 and 24 h after treatment. Moreover, UCCB01-125 was found to reverse CFA-induced hypersensitivity when administered 24 h after CFA treatment, an effect lasting for at least 3 days. At the dose reducing hypersensitivity, MK-801 disrupted attention, long-term memory, and motor performance. By contrast, even high doses of UCCB01-125 were devoid of side-effects in these tests. The data suggest that PSD-95 inhibition is a feasible strategy to prevent both development and maintenance of chronic inflammatory pain, while avoiding NMDAR antagonism-related side-effects. 23411265 Phytosteryl sinapates and vanillates: chemoenzymatic synthesis and antioxidant capacity assessment. Phytosterols and their derivatives have attracted much attention because of their health benefits to humans and are widely used in food, pharmaceuticals, and cosmetics in the past decades. While most of the research has focused on free phytosterols and phytosteryl esters of fatty acids, few researches reported on phytosteryl phenolates, the esters of phytosterols with phenolic acids. Two novel group phytosteryl phenolates, namely phytosteryl sinapates and vanillates, were successfully chemoenzymatically synthesised in this work and their structures confirmed. Fourier transform infrared (FTIR) and high performance chromatography-mass spectrometry/mass spectrometry (HPLC-MS/MS) using atmospheric pressure chemical ionisation (APCI) under both positive and negative ion modes were employed for this purpose. High antioxidant capacity of phytosteryl sinapates was observed using both oxygen radical absorbance capacity (ORAC) assay and cooked ground meat model system. Although phytosteryl vanillates showed lower antioxidant capacity than phytosteryl sinapates, they were stronger antioxidants than vanillic acid and vinyl vanillate in both assays employed. Conjugation of phytosterols with sinapic or vanillic acid rendered higher antioxidant capacity. Further studies on health benefits of phytosteryl sinapates and vanillates are necessary. 23389625 Carbon-coated LiFePO4-porous carbon composites as cathode materials for lithium ion batteries. This work introduces a facile strategy for the synthesis of carbon-coated LiFePO(4)-porous carbon (C-LiFePO(4)-PC) composites as a cathode material for lithium ion batteries. The LiFePO(4) particles obtained are about 200 nm in size and homogeneously dispersed in porous carbon matrix. These particles are further coated with the carbon layers pyrolyzed from sucrose. The C-LiFePO(4)-PC composites display a high initial discharge capacity of 152.3 mA h g(-1) at 0.1 C, good cycling stability, as well as excellent rate capability (112 mA h g(-1) at 5 C). The likely contributing factors to the excellent electrochemical performance of the C-LiFePO(4)-PC composites could be related to the combined effects of enhancement of conductivity by the porous carbon matrix and the carbon coating layers. It is believed that further carbon coating is a facile and effective way to improve the electrochemical performance of LiFePO(4)-PC. 23497864 Determination of chemical variability of phenolic and monoterpene glycosides in the seeds of Paeonia species using HPLC and profiling analysis. A rapid, sensitive, and accurate HPLC-DAD method was developed and validated for simultaneous determination of one phenolic glycoside and seven monoterpene glycosides, including 1-O-β-d-(4-hydroxybenzoyl)glucose (1), pyridylpaeoniflorin (2), (8R)-piperitone-4-en-9-O-β-d-glucopyranoside (3), oxypaeoniflorin (4), 6'-O-β-glucopyranosylalbiflorin (5), albiflorin (6), β-gentiobiosylpaeoniflorin (7), and paeoniflorin (8), in 44 batches of peony seeds from nine Paeonia species collected from different areas. Using the optimised method, separations were conducted with a YMC-pack ODS-A column with water/formic acid and methanol as the mobile phase. All eight analytes demonstrated good linearity (r(2)>0.9993). The recoveries, measured at three concentration levels, varied from 98.20% to 103.81%. Six compounds including 1 and 4-8 occur ubiquitously in all the seeds of nine Paeonia species, and compounds 2 and 3 showed undetectable levels or very low content in several samples. The seed samples were classified into several groups, which coincide with the taxonomy of Paeonia at the section level. Peony seed might be a useful resource in developing new herbal or food products. 22862926 Incretin and pancreatic hormone secretion in Caucasian non-diabetic carriers of the TCF7L2 rs7903146 risk T allele. We characterised 62 non-diabetic, middle-aged, Caucasians with and without the T risk allele of rs7903146 in transcription factor 7-like 2 (TCF7L2) with regard to secretion of insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) as well as insulin sensitivity and endogenous glucose production. All participants had a 3-h oral glucose tolerance test (OGTT), an intravenous glucose tolerance test and a euglycaemic, hyperinsulinaemic clamp. After adjustment for age and sex, risk T allele carriers had higher haemoglobin A1c levels (p = 0.030), reduced first-phase insulin response (p = 0.048), higher peripheral insulin sensitivity (p = 0.050) and lower fasting GIP concentrations (p = 0.003) than CC allele carriers. The latter was also reflected by lower total GIP secretion during the OGTT (p = 0.018). We found no significant differences in endogenous glucose production, hepatic insulin sensitivity or fasting concentrations of glucose, insulin, glucagon and GLP-1 between the groups. The findings suggest that the effect of TCF7L2 on diabetes risk may include reduced secretion of GIP. 23313380 Preclinical assessment of a polyspecific antivenom against the venoms of Cerrophidion sasai, Porthidium nasutum and Porthidium ophryomegas: Insights from combined antivenomics and neutralization assays. A polyspecific antivenom is used in Central America for the treatment of envenomings by viperid snakes. This antivenom is generated in horses hyperimmunized with a mixture of venoms from Bothrops asper, Crotalus simus and Lachesis stenophrys. The present study analyzed the ability of this antivenom to neutralize the venoms of three Central American viperid species of the 'Porthidium group', i.e. Porthidium nasutum, Porthidium ophryomegas and Cerrophidion sasai, formerly classified as Cerrophidion godmani. In addition, the immunorecognition of the components of these venoms was assessed by immunoaffinity antivenomics. The antivenom proved effective in neutralizing the lethal, hemorrhagic, myotoxic, phospholipase A(2) (PLA(2)) and proteinase activities of the three venoms, albeit exhibiting quantitative differences in the values of the Median Effective Doses (ED(50)). Excepting for certain low molecular mass bands corresponding to disintegrins, and some PLA(2)s and PI-metalloproteinases, Western blotting and immunoaffinity chromatography revealed immunorecognition of most Porthidium and Cerrophidion venom proteins. In agreement with in vivo neutralization assays, immobilized antivenom IgGs showed higher immunocapturing activity of toxins from both Porthidium taxa than from C. sasai. Overall our results demonstrate a significant paraspecific protection of the Costa Rican polyspecific antivenom against the three venoms sampled. They also stress the need to search for novel ways to enhance the immune response of horses against several weakly immunogenic venom components. 23411177 Influence of seasonality on the chemical composition of oysters (Crassostrea rhizophorae). This paper aimed to evaluate the influence of seasonality on the chemical composition of oysters (Crassostrea rhizophorae). Samples were collected during summer and winter from the estuary and lagoon complex of the municipality of Barra de São Miguel, Alagoas, Brazil. Statistical differences (p<0.05) between summer and winter were observed in relation to chemical composition. The oysters cultivated in the winter presented some nutritional advantages because of the higher levels of proteins and functional nutrients, such as the eicosapentaenoic-docosahexaenoic acid combination and percentages of polyunsaturated fatty acids (n-3 and n-6), and the lower levels of saturated fatty acids. Therefore, the animals in winter presented a higher content of cholesterol oxides. The levels of cholesterol oxides found in these products during winter may encourage researchers to investigate the composition of oysters cultivated in different climates all over the world. 23295223 A novel transcriptional repressor PhaR for the steroid-inducible expression of the 3,17β-hydroxysteroid dehydrogenase gene in Comamonas testosteroni ATCC11996. Comamonas testosteroni is able to catabolize a variety of steroids and polycyclic aromatic hydrocarbons and might be used in the bioremediation of contaminated environments. 3,17β-Hydroxysteroid dehydrogenase (3,17β-HSD) from C. testosteroni is a member of the short-chain dehydrogenase/reductase (SDR) superfamily and a key enzyme in steroid degradation. The genome of C. testosteroni ATCC11996 was sequenced in our previous work. In addition to the gene coding for 3,17β-HSD (βhsd), a novel transcriptional repressor phaR gene (phaR) which locates 2290 bp upstream of the βhsd gene was found. PhaR knock-out mutants of C. testosteroni were prepared and shown to grow better than wild-type C. testosteroni in the presence of 1 mM testosterone, 0.5 mM estradiol or 0.5 mM cholesterol in both Standard 1 Nutrient (SIN) medium and 1:10 diluted SIN medium. After 1 mM testosterone induction, 3,17β-HSD expression in the mutant was 2.5 times higher than in wild type C. testosteroni. Accordingly, PhaR is a repressor that controls 3,17β-HSD expression. Moreover, phaR knock-out mutants grow at higher rates and produce more protein in the presence of steroids as carbon source. However, ELISA results showed that 0.5 mM estradiol and cholesterol could not induce βhsd gene expression in both wild-type and mutant C. testosteroni. Probably, in addition to the βhsd gene, PhaR regulates some other genes that relate to steroid degradation. The genes coding for PhaR and 3,17β-HSD together with their promoter domains were cloned into plasmids pK18 and pUC19. Escherichia coli HB101 was co-transformed with these plasmids. The results suggest that PhaR is a repressor, which might bind on a special βhsd promoter domain (214 bp). A 2509 bp DNA fragment that contained a putative promoter for the βhsd gene (without the phaR gene) was cloned into plasmid pUC2.5-3. The plasmid was transformed into HB101 (E. coli) and induced with testosterone. As a result, 3,17β-HSD expression was at a high level, but could not be further enhanced by testosterone. Taken together, phaR knock-out mutants have better ability to degrade steroids than wild-type C. testosteroni ATCC11996 and might therefore be used in bioremediation. 23517474 Cations Bind Only Weakly to Amides in Aqueous Solutions. We investigated salt interactions with butyramide as a simple mimic of cation interactions with protein backbones. The experiments were performed in aqueous metal chloride solutions using two spectroscopic techniques. In the first, which provided information about contact pair formation, the response of the amide I band to the nature and concentration of salt was monitored in bulk aqueous solutions via attenuated total reflection Fourier transform infrared spectroscopy. It was found that molar concentrations of well-hydrated metal cations (Ca(2+), Mg(2+), Li(+)) led to the rise of a peak assigned to metal cation-bound amides (1645 cm(-1)) and a decrease in the peak associated with purely water-bound amides (1620 cm(-1)). In a complementary set of experiments, the effect of cation identity and concentration was investigated at the air/butyramide/water interface via vibrational sum frequency spectroscopy. In these studies, metal ion-amide binding led to the ordering of the adjacent water layer. Such experiments were sensitive to the interfacial partitioning of cations in either a contact pair with the amide or as a solvent separated pair. In both experiments, the ordering of the interactions of the cations was: Ca(2+) > Mg(2+) > Li(+) > Na(+) ≈ K(+). This is a direct cationic Hofmeister series. Even for Ca(2+), however, the apparent equilibrium dissociation constant of the cation with the amide carbonyl oxygen was no tighter than ∼8.5 M. For Na(+) and K(+), no evidence was found for any binding. As such, the interactions of metal cations with amides are far weaker than the analogous binding of weakly hydrated anions. 23450752 Enantiomeric separation of racemic 4-aryl-1,4-dihydropyridines and 4-aryl-1,2,3,4-tetrahydropyrimidines on a chiral tetraproline stationary phase. The chromatographic chiral resolution of 4-aryl-1,4-dihydropyridines (1-32), 4-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidines (33-38), and 4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidines (39-41) was studied on a tetraproline-immobilized chiral column synthesized in our lab. This tetraproline chiral stationary phase can resolve most of these compounds. The 4-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidines (33-38) and 4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidines (39-41) were more efficiently resolved than the racemic 4-aryl-1,4-dihydropyridines on the tetraproline chiralstationary phase. Analytes with 5,5-dimethyl groups (39-41) were less efficiently resolved than analytes without 5,5-dimethyl substituents (1-16). The 4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidines (39-41) without a sulfur atom were much more efficiently resolved than 4-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidines (33-38). No obvious electronic effects on the resolution of any of these analytes (1-41) were observed on the tetraproline chiral stationary phase. The tetraproline chiral stationary phase separated enantiomers mainly via hydrogen bonding interactions. 23292768 Microwave spectroscopic and atoms in molecules theoretical investigations on the Ar···propargyl alcohol complex: Ar···H-O, Ar···π, and Ar···C interactions. The structure of the Ar···propargyl alcohol (Ar···PA) complex is determined from the rotational spectra of the parent complex and its two deuterated isotopologues, namely Ar···PA-D(OD) and Ar···PA-D(CD). The spectra confirm a geometry in which PA exists in the gauche form with Ar located in between -OH and -C≡C-H groups. All a, b and c types of transitions show small splitting due to some large-amplitude motion dominated by C-OH torsion, as in the monomer. Splittings in a- and b-type transitions are of the order of a few kilohertz, whereas splitting in the c-type transitions is relatively larger (0.9-2.6 MHz) and decreases in the order Ar···PA>Ar···PA-D(CD)>Ar···PA-D(OD). The assignments are well supported by ab initio calculations. Atoms in molecules (AIM) and electrostatic potential calculations are used to explore the nature of the interactions in this complex. AIM calculations not only reveal the expected O-H···Ar and π···Ar interactions in the Ar···gauche-PA complex, but also novel C···Ar (of CH2OH group) and O-H···Ar interactions in the Ar···trans-PA complex. Similar interactions are also present in the Ar···methanol complex. 23002087 Arterial stiffness is inversely related to plasma adiponectin levels in young normotensive patients with type 1 diabetes. OBJECTIVE This study investigated the association between arterial stiffness and plasma adiponectin in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS Participants were normotensive patients with type 1 diabetes who were up to age 40 years. Subjects on statins with macrovascular disease or overt nephropathy were excluded. Large artery stiffness was assessed by measurement of carotid-femoral pulse wave velocity (PWV), whereas plasma adiponectin was measured by radioimmunoassay. RESULTS Data from 80 patients (age 27.1 ± 6.1 years, BMI 24.2 ± 3.1 kg/m(2), HbA(1c) 7.5 ± 1.6%, 39 men, adiponectin 13.9 ± 6.7 μg/mL, and PWV 5.6 ± 0.9 m/s) were analyzed. Log adiponectin inversely correlated with age-adjusted PWV (r = -0.291, P = 0.009) and waist circumference (r = -0.427, P < 0.001). In a fully adjusted model, age, expiration/inspiration index, and log adiponectin were independently associated with PWV, explaining 39.6% of its variance. CONCLUSIONS Arterial stiffness is inversely related to adiponectin concentration in young patients with type 1 diabetes without major complications. 23192982 MLL histone methylases regulate expression of HDLR-SR-B1 in presence of estrogen and control plasma cholesterol in vivo. High-density lipoprotein receptors scavenger receptor class B type I [HDLR-SR-B1 (SR-B1)] is a key player in reverse cholesterol transport and maintaining blood cholesterol. We demonstrated that human SR-B1 is transcriptionally activated by 17β-estradiol (E2) in HEPG2 and JAR cells. SR-B1 promoter contains multiple estrogen response elements (ERE half-sites) along with some Sp1 binding sites. Knockdown of estrogen receptor (ER)α and ERβ down-regulated E2-induced SR-B1 expression. ERs were bound to SR-B1 promoter EREs in an E2-dependent manner. Along with ERs, mixed-lineage leukemia (MLL) histone methylases, especially MLL1 and MLL2, play key roles in E2-mediated SR-B1 activation. MLL1 and MLL2 bind to SR-B1 promoter in an E2-dependent manner and control the assembly of transcription pre-initiation complex and RNA polymerase II (RNAPII) recruitment. ERs and MLLs play critical roles in determining the cholesterol uptake by steroidogenic tissues/cells, and their knockdown suppressed the E2-induced cholesterol uptake efficiencies of the cells. Intriguingly, MLL2 knockdown in mice resulted in a 33% increase in plasma cholesterol level and also reduced SR-B1 expression in mice liver, demonstrating its crucial functions in controlling plasma cholesterol in vivo. 23172038 Predicting isosteric heats for gas adsorption. A method for predicting the isosteric heat of gas adsorption on solid materials is developed which requires the measurement of a single isotherm - where previous methods, such as the Clausius-Clapeyron approach, require either multiple isotherms or complex calorimetric measurement. The Tóth potential function, stemming from the Polanyi potential function, is evaluated using the Langmuir and Tóth isotherm equations to generate new equations for the isosteric heat. These new isosteric heat equations share common parameters with the isotherm equations and are determined from isotherm fitting. This method is demonstrated in the literature for gas adsorption onto solid adsorbates including zeolites of various surface charge character and non-porous rutile phase titanium dioxide. Predictions are made using the new isosteric heat equations and then compared to calorimetric data. 23087261 Lysine 48-linked polyubiquitination of organic anion transporter-1 is essential for its protein kinase C-regulated endocytosis. Organic anion transporter-1 (OAT1) mediates the body's disposition of a diverse array of environmental toxins and clinically important drugs. Therefore, understanding the regulation of this transporter has profound clinical significance. We had previously established that OAT1 undergoes constitutive internalization from and recycling back to the cell surface and that acute activation of protein kinase C (PKC) inhibits OAT1 activity by reducing OAT1 cell-surface expression through accelerating its internalization from cell surface to intracellular compartments. However, the underlying mechanisms are poorly understood. In the current study, we provide novel evidence that acute activation of PKC significantly enhances OAT1 ubiquitination both in vitro and ex vivo. We further show that ubiquitination of cell-surface OAT1 increases in cells transfected with dominant negative mutant of dynamin-2, a maneuver blocking OAT1 internalization, which suggests that OAT1 ubiquitination proceeds before OAT1 internalization. Mass spectroscopy has revealed that ubiquitination of OAT1 consists of polyubiquitin chains, primarily through lysine 48 linkage. Transfection of cells with the dominant negative mutant of ubiquitin Ub-K48R, which prevents the formation of Lys48-linked polyubiquitin chains, abolishes PKC-stimulated OAT1 ubiquitination and internalization. Together, our findings demonstrate for the first time that Lys48-linked polyubiquitination is essential for PKC-regulated OAT1 trafficking. 23320412 An adhesive bone marrow scaffold and bone morphogenetic-2 protein carrier for cartilage tissue engineering. A chondroitin sulfate-bone marrow (CS-BM) adhesive hydrogel was used to localize rhBMP-2 to enhance articular cartilage tissue formation. Chondrocyte pellet culture revealed that 0.1 and 1 μg/mL of rhBMP-2 enhanced sulfated-GAG content. rhBMP-2 localization within the hydrogels was investigated, and it was found that BM, CS-NHS, and rhBMP-2 levels and time affected rhBMP-2 retention. Retention was modulated from 82 to 99% over a 3-week period for the material formulations investigated. To evaluate carrier efficacy, rhBMP-2 and bovine articular chondrocytes were encapsulated within CS-BM, and biochemical evaluation revealed significant increases in total collagen production with rhBMP-2. Histological analysis revealed more robust tissue formation and greater type-II collagen production with encapsulated rhBMP-2. Subsequently, a subcutaneous culture of hydrogels revealed increased total collagen, type-II to type-I collagen ratio, and sulfated GAG in samples carrying rhBMP-2. These findings indicate the development of a multifunctional system capable of localizing rhBMP-2 to enhance repair tissue quality. 22510064 Physicochemical, pharmacokinetic and pharmacodynamic evaluations of novel ternary solid dispersion of rebamipide with poloxamer 407. This study was conducted primarily to improve the solubility of rebamipide, a poorly water-soluble anti-ulcer drug, using novel ternary solid dispersion (SD) systems and secondly to evaluate the effect of solubility enhancement on its pharmacokinetic (PK) and pharmacodynamic (PD) profile. After dissolving the three components in aqueous medium, ternary SD containing the drug, sodium hydroxide (NaOH) and PVP-VA 64 was achieved by spray drying method, which was used as primary SD. Poloxamer 407, a surfactant polymer, was incorporated in this primary SD by four different methods: co-grinding, physical mixing, melting or spray drying. SD was then characterized by dissolution test, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR). The spray dried SD of poloxamer 407 together with primary SD displayed highest dissolution rate of the drug of about 70% after 2 h. DSC, PXRD and FT-IR characterized the amorphous state and molecular dispersion of the drug in the SD. PK and PD studies in Sprague-Dawley rats revealed that the bioavailability of the drug using optimal SD was about twofold higher than that of reference product, and the irritation area of stomach was significantly reduced in the ulcer-induced rat model using optimal SD as compared to the reference product. 23265467 Sugarcane bagasse treated with hydrous ferric oxide as a potential adsorbent for the removal of As(V) from aqueous solutions. The mechanism of As(V) removal from aqueous solutions by means of hydrated ferric oxide (HFO)-treated sugarcane bagasse (SCB-HFO) (Saccharum officinarum L.) was investigated. Effects of different parameters, such as pH value, initial arsenic concentration, adsorbent dosage, contact time and ionic strength, on the As(V) adsorption were studied. The adsorption capacity of SCB-HFO for As(V) was found to be 22.1 mg/g under optimum conditions of pH 4, contact time 3h and temperature 22 °C. Initial As(V) concentration influenced the removal efficiency of SCB-HFO. The desorption of As(V) from the adsorbent was 17% when using 30% HCl and 85% with 1M NaOH solution. FTIR analyses evidenced two potential binding sites associated with carboxyl and hydroxyl groups which are responsible for As(V) removal. Adsorption, surface precipitation, ion exchange and complexation can be suggested as mechanisms for the As(V) removal from the solution phase onto the surface of SCB-HFO. 23147567 Uptake and toxicity of polycyclic aromatic hydrocarbons in terrestrial springtails--studying bioconcentration kinetics and linking toxicity to chemical activity. Passive dosing applies a polymer loaded with test compound(s) to establish and maintain constant exposure in laboratory experiments. Passive dosing with the silicone poly(dimethylsiloxane) was used to control exposure of the terrestrial springtail Folsomia candida to six polycyclic aromatic hydrocarbons (PAHs) in bioconcentration and toxicity experiments. Folsomia candida could move freely on the PAH-loaded silicone, resulting in exposure via air and direct contact. The bioconcentration kinetics indicated efficient uptake of naphthalene, anthracene, and pyrene through air and (near) equilibrium partitioning of these PAHs to lipids and possibly the waxy layer of the springtail cuticle. Toxicities of naphthalene, phenanthrene, and pyrene were related to chemical activity, which quantifies the energetic level and drives spontaneous processes including diffusive biouptake. Chemical activity-response relationships yielded effective lethal chemical activities (La50s) well within the expected range for baseline toxicity (0.01-0.1). Effective lethal body burdens for naphthalene and pyrene exceeded the expected range of 2 to 8 mmol kg(-1) fresh weight, which again indicated the waxy layer to be a sorbing phase. Finally, chemical activities were converted into equilibrium partitioning concentrations in lipids yielding effective lethal concentrations for naphthalene and phenanthrene in good correspondence with the lethal membrane burden for baseline toxicity (40-160 mmol kg(-1) lipid). Passive dosing was a practical approach for tightly controlling PAH exposure, which in turn provided new experimental possibilities and findings. 23500610 Pharmacokinetics and the drug-target residence time concept. The concept of drug-target residence time has been in focus in recent drug discovery literature. However, few studies consider the combined effect of pharmacokinetics (PK) and binding kinetics (BK) on the duration of effect of a drug. Using a simple model that takes both PK and BK into account, we found that prolongation of binding owing to a long drug-target residence time can only occur when the binding dissociation is slower than the PK elimination. Data for several drugs and/or drug candidates in the literature indicate that the opposite is observed, that is, they have a slower elimination compared with dissociation. These observations greatly reduce the usability of drug-target residence times for estimating the duration of effect of a drug in vivo. 23452254 TDDFT studies on the determination of the absolute configurations and chiroptical properties of Strandberg-type polyoxometalates. The electronic circular dichroism (ECD) and UV-visible absorption (UV-vis) spectra of Strandberg-type polyoxometalates (POMs) (R, R)-[(R*PO3)2M5O15](2-) (R* = CH3CH(NH3), (M = Mo, W)) have been explored using the time-dependent density functional theory (TDDFT) method. It demonstrates that the absolute configurations of chiral systems can be determined by chiroptical spectroscopic methods combined with DFT calculations. The calculated ECD spectra of the Strandberg-type molybdate were produced over the range of 3.3-6.5 eV, which are generally in agreement with the experimental spectra. In addition, the ECD spectra of (R, R)-[(R*PO3)2W5O15](2-) (R* = CH3CH(NH3)) were produced over the range of 4.5-8.5 eV. The Becke's half-and-half hybrid exchange-correlation functional (BHandHLYP) with the HF exchange fraction to 55% hybrid functional was found to well predict the excitation energies of studied systems. The origins of the ECD bands of two systems are mainly ascribed to charge-transfer (CT) transitions from oxygen atoms to metal atoms in polyanion. The results suggest that the polyanion are chiroptical chromophores. The polyanion plays a role as an optically active chromophore and contribute to the absorptions of ECD spectra. The difference of the UV-vis/ECD spectra between two systems shows that the transition metal atom significantly influences on the chiroptical properties of the studied Strandberg-type POMs. 23275110 PHEA-graft-polymethacrylate supramolecular aggregates for protein oral delivery. Salmon calcitonin (sCT) is characterized by a poor oral availability. A new copolymer, β-poly(N-2-hydroxyethyl)-graft-{N-2-ethylene[2-poly(methacrylic acid sodium salt)isobutyrate]}-d,l-aspartamide (PHEA-IB-p(MANa(+))), was designed for the oral administration of sCT through the formation of supramolecular aggregates (SAs) based on electrostatic interactions. Several sCT/PHEA-IB-p(MANa(+)) weight ratios were characterized by turbidimetry, DLS, zeta potential, and microscopy analysis. After the incubation of sCT/PHEA-IB-p(MANa(+)) complex with digestive enzymes, 10% (w/w) of loaded sCT was released in the native form. In vitro investigation was carried out to determine the copolymer effect on the permeability of sCT in Caco-2 cell monolayers. sCT pharmacokinetic profile and the pharmacodynamic effect on calcium plasma level were determined following an oral administration of the lead sCT/PHEA-IB-p(MANa(+)) SA (1/5 ratio) in rats. The SA yielded a marked prolongation of the sCT lowering calcium effect. The maximum decrease, 35% with respect the basal calcium plasma level at time 0h, was achieved after 4h post-administration, and after 7h, a decrease of 20% was still present. Differently, sCT yielded a transient calcium decrease that was completely restored after 5h. The higher bioavailability of sCT administered as SA was confirmed by the pharmacokinetic studies. In fact, the AUC and the Cmax were about 15 times higher for the sCT formulated as SA than the free sCT. This study indicates the potentials of PHEA-IB-p(MANa(+)) as carrier of sCT for oral delivery. 23294277 Hedgehog pathway inhibitors: a patent review (2009--present). INTRODUCTION: The hedgehog (Hh) pathway is a developmental signaling pathway that plays a key role in directing cellular growth and tissue patterning during embryonic development. Dysregulation of Hh signaling has been linked to the development of a variety of human tumors, and numerous drug development programs in both academia and industry are actively exploring inhibitors of the pathway as anti-cancer agents. AREAS COVERED: This review surveys the recent patent literature (2009 - 2012) for Hh pathway inhibitors as treatments for a variety of human malignancies. EXPERT OPINION: To date, all of the pathway inhibitors that have entered clinical trials and the majority of compounds identified via high-throughput screens target smoothened (Smo), a transmembrane protein that is essential for pathway signaling. While these compounds have shown initial promise in preclinical and clinical trials, several mechanisms of resistance to Smo inhibitors have been identified. Even with this knowledge, the majority of small-molecule pathway inhibitors disclosed in the recent patent literature directly target Smo. The continued identification of Hh pathway inhibitors that function either upstream or downstream is warranted not only to combat these emerging resistance mechanisms, but also to help elucidate the various cellular mechanisms that control both normal and oncogenic pathway signaling. 22658648 Chronic treatment with myo-inositol reduces white adipose tissue accretion and improves insulin sensitivity in female mice. Type 2 diabetes is a complex disease characterized by a state of insulin resistance in peripheral tissues such as skeletal muscle, adipose tissue or liver. Some inositol isomers have been reported to possess insulin-mimetic activity and to be efficient in lowering blood glucose level. The aim of the present study was to assess in mice the metabolic effects of a chronic treatment with myo-inositol, the most common stereoisomer of inositol. Mice given myo-inositol treatment (0.9 or 1.2 mg g(-1) day(-1), 15 days, orally or intraperitoneally) exhibited an improved glucose tolerance due to a greater insulin sensitivity. Mice treated with myo-inositol exhibited a decreased white adipose tissue accretion (-33%, P<.005) compared with controls. The decrease in white adipose tissue deposition was due to a decrease in adipose cell volume (-33%, P<.05), while no change was noticed in total adipocyte number. In skeletal muscle, in vivo as well as ex vivo myo-inositol treatment increased protein kinase B/Akt phosphorylation under baseline and insulin-stimulated conditions, suggesting a synergistic action of myo-inositol treatment and insulin on proteins of the insulin signalling pathway. Myo-inositol could therefore constitute a viable nutritional strategy for the prevention and/or treatment of insulin resistance and type 2 diabetes. 23470079 MicroRNAs and the Heart: Small Things Do Matter. MicroRNAs are small RNA molecules and constitute a relatively novel class of gene expression regulators, found in the great majority of eukaryotic cells. Their role in human physiology and pathology is actively being researched with new exciting discoveries continuously coming to the forefront. MicroRNAs play a crucial role in the biogenesis and function of the cardiovascular system and act as important regulators of various metabolic and signaling pathways in cardiovascular disease. In this review there will be a summary on current knowledge about the expression, regulation and function of microRNAs in the most common diseases of the cardiovascular system as well as a presentation of and discussion about their promising future role as new biomarkers and therapeutic targets. 23265899 Synthesis of DNA oligonucleotides containing C5-ethynylbenzenesulfonamide-modified nucleotides (EBNA) by polymerases towards the construction of base functionalized nucleic acids. C5-Ethynylbenzenesulfonamide-modified nucleotide (EBNA) was investigated as substrate of various DNA polymerases. The experiments revealed that KOD, Phusion and Klenow DNA polymerases successfully accepted EBNA-T nucleotide as a substrate and yielded the fully extended DNA. KOD DNA polymerase was found to be the most efficient enzyme to furnish EBNA-T containing DNA in good yields. Phusion DNA polymerase efficiently amplified the template containing EBNA-T nucleotides by PCR. 23589462 (13) C-Detected Through-Bond Correlation Experiments for Protein Resonance Assignment by Ultra-Fast MAS Solid-State NMR. We present two sequences which combine ((1) H,(15) N) and ((15) N,(13) C) selective cross-polarization steps with an efficient variant of the J-based homonuclear transfer scheme, in which a spin-state-selective (S(3) E) block is incorporated to improve both resolution and sensitivity in the direct (13) C dimension. We propose these two sequences as a part of a suite of four N-C correlation experiments allowing for the assignment of protein backbone resonances in the solid state. We illustrate these experiments under ultra-fast magic angle spinning conditions on two samples of microcrystalline dimeric human superoxide dismutase (SOD, 153×2 amino acids), in its diamagnetic ("empty", Zn(II) ) and paramagnetic (Cu(II) , Zn(II) ) states. 23290262 Alkyladenine DNA glycosylase (AAG) localizes to mitochondria and interacts with mitochondrial single-stranded binding protein (mtSSB). Due to a harsh environment mitochondrial genomes accumulate high levels of DNA damage, in particular oxidation, hydrolytic deamination, and alkylation adducts. While repair of alkylated bases in nuclear DNA has been explored in detail, much less is known about the repair of DNA alkylation damage in mitochondria. Alkyladenine DNA glycosylase (AAG) recognizes and removes numerous alkylated bases, but to date AAG has only been detected in the nucleus, even though mammalian mitochondria are known to repair DNA lesions that are specific substrates of AAG. Here we use immunofluorescence to show that AAG localizes to mitochondria, and we find that native AAG is present in purified human mitochondrial extracts, as well as that exposure to alkylating agent promotes AAG accumulation in the mitochondria. We identify mitochondrial single-stranded binding protein (mtSSB) as a novel interacting partner of AAG; interaction between mtSSB and AAG is direct and increases upon methyl methanesulfonate (MMS) treatment. The consequence of this interaction is specific inhibition of AAG glycosylase activity in the context of a single-stranded DNA (ssDNA), but not a double-stranded DNA (dsDNA) substrate. By inhibiting AAG-initiated processing of damaged bases, mtSSB potentially prevents formation of DNA breaks in ssDNA, ensuring that base removal primarily occurs in dsDNA. In summary, our findings suggest the existence of AAG-initiated BER in mitochondria and further support a role for mtSSB in DNA repair. 23535334 Impact of cell wall composition on maize resistance to pests and diseases. In cereals, the primary cell wall is built of a skeleton of cellulosic microfibrils embedded in a matrix of hemicelluloses and smaller amounts of pectins, glycoproteins and hydroxycinnamates. Later, during secondary wall development, p-coumaryl, coniferyl and sinapyl alcohols are copolymerized to form mixed lignins. Several of these cell wall components show a determinative role in maize resistance to pest and diseases. However, defense mechanisms are very complex and vary among the same plant species, different tissues or even the same tissue at different developmental stages. Thus, it is important to highlight that the role of the cell wall components needs to be tested in diverse genotypes and specific tissues where the feeding or attacking by the pathogen takes place. Understanding the role of cell wall constituents as defense mechanisms may allow modifications of crops to withstand pests and diseases. 23438860 A network model of the molecular organization of chromatin in Drosophila. Chromatin governs gene regulation and genome maintenance, yet a substantial fraction of the chromatin proteome is still unexplored. Moreover, a global model of the chromatin protein network is lacking. By screening >100 candidates we identify 42 Drosophila proteins that were not previously associated with chromatin, which all display specific genomic binding patterns. Bayesian network modeling of the binding profiles of these and 70 known chromatin components yields a detailed blueprint of the in vivo chromatin protein network. We demonstrate functional compartmentalization of this network, and predict functions for most of the previously unknown chromatin proteins, including roles in DNA replication and repair, and gene activation and repression. 23143674 Using chimeric mice with humanized livers to predict human drug metabolism and a drug-drug interaction. Interspecies differences in drug metabolism have made it difficult to use preclinical animal testing data to predict the drug metabolites or potential drug-drug interactions (DDIs) that will occur in humans. Although chimeric mice with humanized livers can produce known human metabolites for test substrates, we do not know whether chimeric mice can be used to prospectively predict human drug metabolism or a possible DDI. Therefore, we investigated whether they could provide a more predictive assessment for clemizole, a drug in clinical development for the treatment of hepatitis C virus (HCV) infection. Our results demonstrate, for the first time, that analyses performed in chimeric mice can correctly identify the predominant human drug metabolite before human testing. The differences in the rodent and human pathways for clemizole metabolism were of importance, because the predominant human metabolite was found to have synergistic anti-HCV activity. Moreover, studies in chimeric mice also correctly predicted that a DDI would occur in humans when clemizole was coadministered with a CYP3A4 inhibitor. These results demonstrate that using chimeric mice can improve the quality of preclinical drug assessment. 23210481 Development of vizantin, a safe immunostimulant, based on the structure-activity relationship of trehalose-6,6'-dicorynomycolate. Vizantin, 6,6'-bis-O-(3-nonyldodecanoyl)-α,α'-trehalose, was developed as a safe immunostimulator on the basis of a structure-activity relationship (SAR) study with trehalose 6,6'-dicorynomycolate (TDCM). It was possible to synthesize vizantin on a large scale more easily than in the case of TDCM, and the compound exhibited more potent prophylactic effect on experimental lung metastasis of B16-F0 melanoma cells. Because vizantin stimulated human macrophages, it is a promising candidate for clinical application. 23553677 A Localized Surface Plasmon Resonance-Based Multicolor Electrochromic Device with Electrochemically Size-Controlled Silver Nanoparticles. The first localized surface plasmon resonance (LSPR)-based multicolor electrochromic device with reversible five optical states is demonstrated. In this device, the size of deposited silver nanoparticles is electrochemically controlled using a voltage-step method in which two different voltages are applied successively. The electrochemically size-controlled silver nanoparticles enable a reversible multiple-color change by a shift of the LSPR band. 22980124 Something's got to give: psychiatric disease on the rise and novel drug development on the decline. Research and development of drugs for psychiatric disease is currently in a state of decline. Despite the increasing prevalence and healthcare costs of psychiatric disease, the costly and unpredictable drug development process has led to decreased public and investor confidence in the abilities of companies to develop safe and efficacious drugs. Industrial research in this disease area is therefore being scaled back owing to various scientific, corporate, financial and legal factors. This review will consider how these factors contribute to the current status of psychiatric drug development and offer several avenues forward to spur reinvestment in this type of research. Such a shift is needed to reduce the burden psychiatric disease imposes on the healthcare system and its patient populations. 23544463 Aqua Mediated Synthesis of Bio-active Compounds. Recently the aqueous medium has attracted the interest of organic chemists, and many. Moreover, in the past 20 years, the drug-discovery process has undergone extraordinary changes, and high-throughput biological screening of potential drug candidates has led to an ever-increasing demand for novel drug-like compounds. Noteworthy advantages were observed during the course of study on aqua mediated synthesis of compounds of medicinal importance. The established advantages of water as a solvent for reactions are, water is the most abundant and available resource on the planet and many biochemical processes occur in aqueous medium. This review will focus on describing new developments in the application of water in medicinal chemistry for the synthesis of bio-active compounds possessing various biological properties. 23437766 Discovery of Novel Dual Inhibitors of the Wild-Type and the Most Prevalent Drug-Resistant Mutant, S31N, of the M2 Proton Channel from Influenza A Virus. Anti-influenza drugs, amantadine and rimantadine, targeting the M2 channel from influenza A virus are no longer effective because of widespread drug resistance. S31N is the predominant and amantadine-resistant M2 mutant, present in almost all of the circulating influenza A strains as well as in the pandemic 2009 H1N1 and the highly pathogenic H5N1 flu strains. Thus, there is an urgent need to develop second-generation M2 inhibitors targeting the S31N mutant. However, the S31N mutant presents a huge challenge to drug discovery, and it has been considered undruggable for several decades. Using structural information, classical medicinal chemistry approaches, and M2-specific biological testing, we discovered benzyl-substituted amantadine derivatives with activity against both S31N and WT, among which 4-(adamantan-1-ylaminomethyl)-benzene-1,3-diol (44) is the most potent dual inhibitor. These inhibitors demonstrate that S31N is a druggable target and provide a new starting point to design novel M2 inhibitors that address the problem of drug-resistant influenza A infections. 23210662 Dendronized albumin core-shell transporters with high drug loading capacity. We describe the synthesis of a core-shell biohybrid consisting of a human serum albumin (HSA) core that serves as a reservoir for lipophilic molecules and a cationized shell region consisting of ethynyl-G2.0-PAMAM or ethynyl-G3.0-PAMAM dendrons. The binding capacity of lipophilic guests was quantified applying electron paramagnetic resonance (EPR) spectroscopy, and five to six out of seven pockets were still available compared with HSA. The attachment of ethynyl-G2.0-PAMAM dendrons to HSA yielded a nontoxic core-shell macromolecule that was clearly uptaken by A549 human epithelial cells due to the presence of the dendritic PAMAM shell. Significantly higher loading of doxorubicin was observed for dendronized G2-DHSA compared with the native protein due to the availability of binding pockets of the HSA core, and interaction with the dendritic shell. Dendronized G2-DHSA-doxorubicin displayed significant cytotoxicity resulting from high drug loading and high stability under different conditions, thus demonstrating its great potential as a transporter for drug molecules. 23010695 Enantioselective apoptosis induction in histiocytic lymphoma cells and acute promyelocytic leukemia cells. The aim of this study was to identify valproic acid (VPA) analogs with a broad spectrum of anti-cancer activities and an increased apoptosis-inducing potential compared with the parent VPA, which is enrolled as histone deacetylase (HDAC) inhibitor in a large number of clinical trials. We identified a chiral VPA derivative, (S)-2-pentyl-4-pentynoic acid, previously characterized as HDAC inhibitor that induced massive programmed cell death in a strongly enantioselective manner in U937 histiocytic lymphoma cells and NB4 acute promyelocytic leukemia cells. By performing fluorescence-activated cell sorting and Western blotting analyses, we established that enantiomer (S)-2-pentyl-4-pentynoic acid has higher apoptosis-inducing potential than VPA itself. The optic antipode (R)-2-pentyl-4-pentynoic acid and VPA caused under the same conditions only a weak growth inhibition without inducing cell differentiation and apoptosis. (S)-2-pentyl-4-pentynoic acid is more apoptogenic than VPA and displays enantioselective anti-cancer properties that warrant further research regarding the mechanistic basis of its activity and its potential use in cancer therapy. 23220560 Low level prenatal exposure to methylmercury disrupts neuronal migration in the developing rat cerebral cortex. We determined the effects of low-level prenatal MeHg exposure on neuronal migration in the developing rat cerebral cortex using in utero electroporation. We used offspring rats born to dams that had been exposed to saline or various doses of MeHg (0.01 mg/kg/day, 0.1 mg/kg/day, and 1 mg/kg/day) from gestational day (GD) 11-21. Immunohistochemical examination of the brains of the offspring was conducted on postnatal day (PND) 0, PND3, and PND7. Our results showed that prenatal exposure to low levels of MeHg (0.1 mg/kg/day or 1 mg/kg/day) during the critical stage in neuronal migration resulted in migration defects of the cerebrocortical neurons in offspring rats. Importantly, our data revealed that the abnormal neuronal distribution induced by MeHg was not caused by altered proliferation of neural progenitor cells (NPCs), induction of apoptosis of NPCs and/or newborn neurons, abnormal differentiation of NPCs, and the morphological changes of radial glial scaffold, indicating that the defective neuronal positioning triggered by exposure to low-dose of MeHg is due to the impacts of MeHg on the process of neuronal migration itself. Moreover, we demonstrated that in utero exposure to low-level MeHg suppresses the expression of Rac1, Cdc42, and RhoA, which play key roles in the migration of cerebrocortical neurons during the early stage of brain development, suggesting that the MeHg-induced migratory disturbance of cerebrocortical neurons is likely associated with the Rho GTPases signal pathway. In conclusion, our results provide a novel perspective on clarifying the mechanisms underlying the impairment of neuronal migration induced by MeHg. 23362942 Chiral selective transmembrane transport of amino acids through artificial channels. Peptide-appended pillar[n]arene (n = 5, 6) derivatives have been synthesized. (1)H NMR and IR studies revealed that the molecules adopt a tubular conformation in solution and lipid bilayer membranes. Kinetic measurements using the fluorescent labeling method with lipid vesicles revealed that these molecules can efficiently mediate the transport of amino acids across lipid membranes at a very low channel-to-lipid ratio (EC(50) = 0.002 mol %). In several cases, chiral selectivity for amino acid enantiomers was achieved, which is one of the key functions of natural amino acid channels. 23584426 Combined toxicity of ferroferric oxide nanoparticles and arsenic to the ciliated protozoa Tetrahymena Pyriformis. Fe3O4 nanoparticles (NPs) have a high affinity for arsenic. As a result of this association, Fe3O4 NPs loaded with high concentration of arsenic can enter into organisms and produce locally high concentrations of arsenic, which may lead to some unexpected toxicity to aquatic organisms. The objectives of this research were to investigate the toxic effect of Fe3O4 NPs in combination with As(V). Cultured Tetrahymena pyriformis was chosen as a research model organism to evaluate the toxic effects of the combined agents. The results showed that after 24h of As(V) exposure, the median effective concentration of As(V) to T. pyriformis was 1.29mg/L. Fe3O4 NPs alone were not only non-toxic, but actually promoted the growth of T. pyriformis at the experimental doses. After 24h exposure, the cell number increased by 32.2% at an exposure level of 3mg/L Fe3O4 NPs. After 24h exposure to 1.0mg/L As(V), the survival rate increased from 60.5% in the absence of Fe3O4 NPs to 73.8% and 83.8% in the presence of 13mg/L and 19mg/L Fe3O4 NPs, respectively. However, after 30h, the combined toxic effect of As(V) and Fe3O4 NPs on T. pyriformis was significantly enhanced and the survival rates for co-exposure to 1.5mg/L As(V) and 13mg/L Fe3O4 NPs decreased from 92.3% after 18h to 45.3% after 30h. After 18h of exposure to Fe3O4 NPs alone, the intracellular ROS levels were markedly increased and achieved steady state. Compared with the control group, the intracellular ROS levels were significantly increased (2.56-fold) by the combination of 19mg/L Fe3O4 NPs and 1.0mg/L As(V). Accumulation of As(V) in T. pyriformis led to an increase in trivalent arsenics as a result of the saturation of the cellular arsenic methylation capability or/and redox reactions. These exposures also resulted in an imbalance between oxidants and antioxidants, resulting in oxidative damage and cell death. 22906569 Extracellular and intracellular anti-mutagenic effects of bile pigments in the Salmonella typhimurium reverse mutation assay. In vitro anti-genotoxic properties of bile pigments have been explored and confirmed recently. Despite these reports mechanisms to explain DNA protection by endogenous bile pigments remain unclear. Surprisingly, the quantification of cellular pigment absorption which could represent a fundamental prerequisite for intracellular (e.g., anti-mutagenic) effects, has not been explored. Therefore, we aimed to measure the amounts of un-/conjugated bilirubin as well as biliverdin absorbed into colonies of Salmonella typhimurium, utilising HPLC analyses, and to observe whether intracellular compound concentrations could predict anti-genotoxic effects. HPLC analyses confirmed that bacterial bile pigment absorption was concentration-dependent. Plate bile pigment concentrations were inversely associated with genotoxicity of all tested mutagens, irrespective of strain and test conditions. However, protection against frame-shift mutation in strain TA98 most strongly depended on the bacterial absorption of bilirubin and biliverdin, which indicates that bile pigments can protect by intercepting mutations extracellularly and specifically inhibit frame-shift mutations intracellularly. 23611538 Toward the Molecular Mechanism(s) by Which EGCG Treatment Remodels Mature Amyloid Fibrils. Protein misfolding and/or aggregation has been implicated as the cause of several human diseases, such as Alzheimer's and Parkinson's diseases and familial amyloid polyneuropathy. These maladies are referred to as amyloid diseases, named after the cross-β-sheet amyloid fibril aggregates or deposits common to these disorders. Epigallocatechin-3-gallate (EGCG), the principal polyphenol present in green tea, has been shown to be effective at preventing aggregation and is able to remodel amyloid fibrils comprising different amyloidogenic proteins, although the mechanistic underpinnings are unclear. Herein, we work toward an understanding of the molecular mechanism(s) by which EGCG remodels mature amyloid fibrils made up of Aβ1-40, IAPP8-24, or Sup35NM7-16. We show that EGCG amyloid remodeling activity in vitro is dependent on auto-oxidation of the EGCG. Oxidized and unoxidized EGCG binds to amyloid fibrils, preventing the binding of thioflavin T. This engagement of the hydrophobic binding sites in Aβ1-40, IAPP8-24, or Sup35NMAc7-16 Y→F amyloid fibrils seems to be sufficient to explain the majority of the amyloid remodeling observed by EGCG treatment, although how EGCG oxidation drives remodeling remains unclear. Oxidized EGCG molecules react with free amines within the amyloid fibril through the formation of Schiff bases, cross-linking the fibrils, which may prevent dissociation and toxicity, but these aberrant post-translational modifications do not appear to be the major driving force for amyloid remodeling by EGCG treatment. These insights into the molecular mechanism of action of EGCG provide boundary conditions for exploring amyloid remodeling in more detail. 23360142 CO and CO-releasing molecules in medicinal chemistry. Since the discovery that CO acts as a cytoprotective and homeostatic molecule, increasing research efforts have been devoted to the exploitation of its therapeutic effects. Both endogenous and exogenous CO improves experimental lung, vascular and cardiac injuries and protects against several inflammatory states. The technology is now in place to bring CO to clinical applications, but the use of the gaseous molecule poses several problems. The challenges associated with the clinical implementation of the gas have in part been answered by the development of CO-releasing molecules (CO-RMs). As stable solid forms of CO, these molecules represent an alternative to the administration of carbon monoxide (orally or by injection). In this article, we present insights into the biochemical action of CO and discuss the efficacy of CO and CO-RMs in preclinical disease models. Recent advances in the CO-RMs field are critically addressed. 23331618 4-Aminoquinoline-Triazine-Based Hybrids with Improved In Vitro Antimalarial Activity Against CQ-Sensitive and CQ-Resistant Strains of Plasmodium falciparum. A systematic chemical modification in the triazine moiety covalently attached via suitable linkers to 4-amino-7-chloroquinolines yielded a series of new 7-chloro-4-aminoquinoline-triazine hybrids exhibiting high in vitro activity against W2 (chloroquine-resistant) and D6 (chloroquine-sensitive) strains of Plasmodium falciparum without any toxicity against mammalian cell lines (Vero, LLC-PK11, HepG2). Many of the compounds (6, 8, 10, 11, 13, 14, 16, 27, 29 and 33) showed excellent potency against chloroquine sensitive and resistant strains. In particular, compounds 6, 8, 14, 16 and 29 were found to be significantly more active than chloroquine against the chloroquine-resistant strains (W2 clone) of P. falciparum. 23607869 Hierarchy of relative bond dissociation enthalpies and their use to efficiently compute accurate absolute bond dissociation enthalpies for C-h, C-C, and C-f bonds. We have used the high-level W1X-2 and G4(MP2)-6X procedures to examine the performance of a variety of computationally less demanding quantum chemistry methods for the calculation of absolute bond dissociation enthalpies (BDEs) and a hierarchy of relative bond dissociation enthalpies. These include relative bond dissociation enthalpies (RBDEs), deviations from additivity of RBDEs (DARBDEs), and deviations from pairwise additivity of RBDEs (DPARBDEs). The absolute magnitudes of these quantities decrease in the order BDE > RBDE > DARBDE > DPARBDE, and overall, theoretical procedures are better able to describe these quantities in the same order. In general, the performance of the various types of procedures improves in the order pure DFT → hybrid DFT → double-hybrid DFT → composite procedures, as expected. Overall, we find M06-L to be the best-performing pure DFT procedure and M06-2X to be the best among the hybrid DFT methods. A promising observation is that even many pure and hybrid DFT procedures give DARBDE and DPARBDE values that are reasonably accurate. This can be exploited by using reference BDEs calculated at a higher-level of theory, in combination with DARBDE or DPARBDE values obtained at a lower level, to produce BDEs and RBDEs with an accuracy that is close to the directly calculated higher-level values. Strongly π-electron-withdrawing or π-electron-donating groups, however, sometimes represent challenges to these approximation methods when the substrate contains several of these substituents. 23271742 Arsenic suppresses cell survival via Pirh2-mediated proteasomal degradation of ΔNp63 protein. Transcription factor p63, a member of the p53 family, shares a high degree of sequence similarity with p53. Because of transcription from two distinct promoters, the p63 gene encodes two isoforms, TAp63 and ΔNp63. Although TAp63 acts as a tumor suppressor, ΔNp63 functions as an oncogene and is often overexpressed in squamous cell carcinomas. Thus, therapeutic agents targeting ΔNp63 might be used to manage tumors that overexpress ΔNp63. Here we found that arsenic trioxide, a frontline agent for acute promyelocytic leukemia, inhibits ΔNp63 but not TAp63 expression in time- and dose-dependent manners. In addition, we found that arsenic trioxide decreases the stability of ΔNp63 protein via a proteasome-dependent pathway but has little effect on the level of ΔNp63 transcript. Furthermore, we found that arsenic trioxide activates the Pirh2 promoter and consequently induces Pirh2 expression. Consistent with this, we found that knockdown of Pirh2 inhibits, whereas ectopic expression of Pirh2 enhances, arsenic-induced degradation of ΔNp63 protein. Importantly, we found that knockdown of ΔNp63 sensitizes, whereas ectopic expression of ΔNp63 inhibits, growth suppression induced by arsenic. Together, these data suggest that arsenic degrades ΔNp63 protein at least in part via Pirh2-dependent proteolysis and that inhibition of ΔNp63 expression facilitates tumor cells to arsenic-induced death. 23586839 Structures of the Dehydrogenation Products of Methane Activation by 5d Transition Metal Cations. The activation of methane by gas-phase transition metal cations (M+) has been studied extensively, both experimentally and using density functional theory (DFT). Methane is exothermically dehydrogenated by several 5d metal ions to form [M,C,2H]+ and H2. However, the structure of the dehydrogenation product has not been established unambiguously. Two types of structures have been considered: a carbene structure where an intact CH2 fragment is bound to the metal (M+-CH2) and a carbyne (hydrido-methylidyne) structure with both a CH and a hydrogen bound to the metal separately (H-M+-CH). For metal ions with empty d-orbitals, an agostic interaction can occur that could influence the competition between carbene and carbyne structures. In this work, the gas phase [M,C,2H]+ (M = Ta, W, Ir, Pt) products are investigated by infrared multiple-photon dissociation (IR-MPD) spectroscopy using the Free Electron Laser for IntraCavity Experiments (FELICE). Metal cations are formed in a laser ablation source and react with methane pulsed into a reaction channel downstream. IRMPD spectra of the [M,C,2H]+ species are measured in the 300 - 3500 cm-1 spectral range by monitoring the loss of H (2H in the case of [Ir,C,2H]+). For each system, the experimental spectrum closely resembles the calculated spectrum of the lowest energy structure calculated using DFT: for Pt, a classic C2v carbene structure; for Ta and W, carbene structures that are distorted by agostic interactions; and a carbyne structure for the Ir complex. The Ir carbyne structure was not considered previously. To obtain this agreement, the calculated harmonic frequencies are scaled with a scaling factor of 0.939, which is fairly low and can be attributed to the strong redshift induced by the IR multiple-photon excitation process of these small molecules. These four-atomic species are among the smallest systems studied by IR-FEL based IR-MPD spectroscopy and their spectra demonstrate the power of IR spectroscopy in resolving long-standing chemical questions. 23146871 Manganese transport via the transferrin mechanism. Excessive manganese (Mn) uptake by brain cells, particularly in regions like the basal ganglia, can lead to toxicity. Mn(2+) is transported into cells via a number of mechanisms, while Mn(3+) is believed to be transported similarly to iron (Fe) via the transferrin (Tf) mechanism. Cellular Mn uptake is therefore determined by the activity of the mechanisms transporting Mn into each type of cell and by the amounts of Mn(2+), Mn(3+) and their complexes to which these cells are exposed; this complicates understanding the contributions of each transporter to Mn toxicity. While uptake of Fe(3+) via the Tf mechanism is well understood, uptake of Mn(3+) via this mechanism has not been systematically studied. The stability of the Mn(3+)Tf complex allowed us to form and purify this complex and label it with a fluorescent (Alexa green) tag. Using purified and labeled Mn(3+)Tf and biophysical tools, we have developed a novel approach to study Mn(3+)Tf transport independently of other Mn transport mechanisms. This approach was used to compare the uptake of Mn(3+)Tf into neuronal cell lines with published descriptions of Fe(3+) uptake via the Tf mechanism, and to obtain quantitative information on Mn uptake via the Tf mechanism. Results confirm that in these cell lines significant Mn(3+) is transported by the Tf mechanism similarly to Fe(3+)Tf transport; although Mn(3+)Tf transport is markedly slower than other Mn transport mechanisms. This novel approach may prove useful for studying Mn toxicity in other systems and cell types. 22698957 An optogenetic approach in epilepsy. Optogenetic tools comprise a variety of different light-sensitive proteins from single-cell organisms that can be expressed in mammalian neurons and effectively control their excitability. Two main classes of optogenetic tools allow to either depolarize or hyperpolarize, and respectively generate or inhibit action potentials in selective populations of neurons. This opens unprecedented possibilities for delineating the role of certain neuronal populations in brain processing and diseases. Moreover, optogenetics may be considered for developing potential treatment strategies for brain diseases, particularly for excitability disorders such as epilepsy. Expression of the inhibitory halorhodopsin NpHR in hippocampal principal cells has been recently used as a tool to effectively control chemically and electrically induced epileptiform activity in slice preparations, and to reduce in vivo spiking induced by tetanus toxin injection in the motor cortex. In this review we give a comprehensive summary of what has been achieved so far in the field of epilepsy using optogenetics, and discuss some of the possible strategies that could be envisaged in the future. We also point out some of the challenges and pitfalls in relation to possible outcomes of using optogenetics for controlling network excitability, and associated brain diseases. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'. 23292753 Fluorescent live-cell imaging of metabolically incorporated unnatural cyclopropene-mannosamine derivatives. Sugar coated: We recently developed methylcyclopropenes as low-molecular-weight tetrazine coupling partners. Here, we demonstrate that methylcyclopropenes can meet the stringent steric demands required for metabolic imaging of unnatural mannosamines on live cells. Using sequential azide-alkyne chemistry, we also demonstrate multicolor imaging of two different metabolically incorporated unnatural sugars. 23567046 Recent advances in theranostic nanocarriers of doxorubicin based on iron oxide and gold nanoparticles. Hybrid (organic/inorganic) nanoparticles emerged as a simple solution to build "theranostic" systems. Due to their physical properties, superparamagnetic iron oxide nanoparticles (SPIONs) and plasmonic gold nanoparticles (Au-NPs) are extensively studied as a part of diagnostic and therapeutic strategies in cancer treatments. They can be used as agents for in vitro or in vivo imaging, for magnetic drug targeting and/or thermal therapy. Their functionalization with organic shells enhances their potential performance in tumor targeting and drug delivery. The advances in such hybrid nanocarriers are well illustrated with the example of the anticancer drug doxorubicin (DOX). The aim of this review is to give a multidisciplinary overview of such smart nanosystems loaded with DOX, based on examples taken from recent publications. From a physico-chemical point of view, we discuss the choices for the strategies for loading DOX and the consequences on drug release. From a biological point of view, we analyze the in vitro and in vivo assays concerning tumor imaging, targeted drug delivery and anticancer efficiency. Future opportunities and challenges are also addressed. 23638985 Ginsenjilinol, a new protopanaxatriol-type saponin with inhibitory activity on LPS-activated NO production in macrophage RAW 264.7 cells from the roots and rhizomes of Panax ginseng. One new dammarane triterpene saponin named ginsenjilinol (1) was isolated from the roots and rhizomes of Panax ginseng C.A. Mey., together with two known saponins ginsenoside Rf (2) and ginsenoside Re5 ( = panajaponol A, 3). Based on IR, HR-ESI-MS, and 1D as well as 2D NMR ((1)H-(1)H COSY, NOESY, HSQC, and HMBC) spectral data, the chemical structure of the new saponin was elucidated as 3β,12β,20S,26-tetrahydroxydammar-24E-en-6α-O-β-d-glucopyranosyl-(1 → 2)-O-β-d-glucopyranoside. The ability of the isolated saponins to inhibit nitric oxide production by lipopolysaccharide-activated RAW 264.7 cells was also assayed. All of the isolated saponins exhibited the significant activity in a concentration-dependent manner at concentrations of 60-200 μM with the half maximal inhibitory concentration (IC50) values of 70.96 ± 2.05 μM for 1, 74.14 ± 2.65 μM for 2, and 79.83 ± 1.78 μM for 3, respectively, whereas indomethacin had an IC50 of 63.75 ± 3.33 μM as a positive control drug. 23535360 Reactivity of Chemical Sensitizers Toward Amino Acids In Cellulo Plays a Role in the Activation of the Nrf2-ARE Pathway in Human Monocyte Dendritic Cells and the THP-1 Cell Line. Allergic contact dermatitis resulting from skin sensitization is an inflammatory skin disease linked to the use of chemicals termed haptens. Chemical reactivity is necessary for a chemical to be a sensitizer, allowing both covalent binding to proteins and maturation of dendritic cells (DCs) by mimicking "danger signals." The aim of this study was to evaluate how the reactivity of chemical sensitizers toward amino acids translates into a biological response using the activation of the nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway, which was assessed by the induction of three Nrf2 target genes (ho-1, nqo1, and il-8) and Nrf2 protein accumulation. Nrf2 activation is known to play a role in numerous detoxification mechanisms that could regulate danger signal outcomes in myeloid cells. Monocyte-derived DCs and THP-1 cells were exposed to (a) haptens with cysteine, lysine, or cysteine/lysine reactivity, (b) pro-/prehaptens, and (c) nonsensitizing molecules with reducing or oxidative properties (17 molecules in total). Chemicals were classified as "Nrf2 pathway activators" when at least two Nrf2 target genes associated with Nrf2 protein expression were induced. Results showed that most chemical sensitizers having cysteine and cysteine/lysine affinities were inducers of the Nrf2 pathway in both cell models, whereas lysine-reactive chemicals were less efficient. In THP-1 cells, the Nrf2 pathway was also activated by pro-/prehaptens. Regression analysis revealed that ho-1 and nqo1 expressions were found to be associated with chemical sensitizer reactivity to cysteine, providing evidence of the importance of chemical reactivity, as a part of danger signals, in DC biology. 23411315 Near-infrared hyperspectral imaging and partial least squares regression for rapid and reagentless determination of Enterobacteriaceae on chicken fillets. Bacterial pathogens are the main culprits for outbreaks of food-borne illnesses. This study aimed to use the hyperspectral imaging technique as a non-destructive tool for quantitative and direct determination of Enterobacteriaceae loads on chicken fillets. Partial least squares regression (PLSR) models were established and the best model using full wavelengths was obtained in the spectral range 930-1450 nm with coefficients of determination R(2)≥ 0.82 and root mean squared errors (RMSEs) ≤ 0.47 log(10)CFUg(-1). In further development of simplified models, second derivative spectra and weighted PLS regression coefficients (BW) were utilised to select important wavelengths. However, the three wavelengths (930, 1121 and 1345 nm) selected from BW were competent and more preferred for predicting Enterobacteriaceae loads with R(2) of 0.89, 0.86 and 0.87 and RMSEs of 0.33, 0.40 and 0.45 log(10)CFUg(-1) for calibration, cross-validation and prediction, respectively. Besides, the constructed prediction map provided the distribution of Enterobacteriaceae bacteria on chicken fillets, which cannot be achieved by conventional methods. It was demonstrated that hyperspectral imaging is a potential tool for determining food sanitation and detecting bacterial pathogens on food matrix without using complicated laboratory regimes. 23583641 Seasonal variation in the toxicological properties of size-segregated indoor and outdoor air particulate matter. Ambient air particulate matter (PM) as well as microbial contaminants in the indoor air are known to cause severe adverse health effects. It has been shown that there is a clear seasonal variation in the potency of outdoor air particles to evoke inflammation and cytotoxicity. However, the role of outdoor sources in the indoor air quality, especially on its toxicological properties, remains largely unknown. In this study, we collected size segregated (PM10-2.5, PM2.5-0.2 and PM0.2) particulate samples with a high volume cascade impactor (HVCI) on polyurethane foam and fluoropore membrane filters. The samples were collected during four different seasons simultaneously from indoor and outdoor air. Thereafter, the samples were weighed and extracted with methanol from the filters before undergoing toxicological analyses. Mouse macrophages (RAW264.7) were exposed to particulate sample doses of 50, 150 and 300μg/ml for 24h. Thereafter, the levels of the proinflammatory cytokine (TNF-α), NO-production, cytotoxicity (MTT-test) and changes in the cell cycle (SubG1, G1, S and G2/M phases) were investigated. PM10-2.5 particles evoked the highest inflammatory and cytotoxic responses. Instead, PM2.5-0.2 samples exerted the greatest effect on apoptotic activity in the macrophages. With respect to the outdoor air samples, particles collected during warm seasons had a stronger potency to induce inflammatory and cytotoxic responses, whereas no such clear effect was seen with the corresponding indoor air samples. Outdoor air samples were associated with higher inflammatory potential, whereas indoor air samples had overall higher cytotoxic properties. This indicates that the outdoor air has a limited influence on the indoor air quality in a modern house. Thus, the indoor sources dominate the toxicological responses obtained from samples collected inside house. 23295943 Apoptotic transcriptional profile remains activated in late remodeled left ventricle after myocardial infarction in swine infarcted hearts with preserved ejection fraction. Apoptosis is involved in both acute and chronic loss of cardiomyocytes after myocardial infarction (MI). To date, the pathophysiological significance of an apoptotic transcriptional profile activated in the post-ischemic remodeled myocardium, in the absence of hemodynamic factors secondary to left ventricular (LV) dysfunction, still remains to be determined. The mRNA expression of pro- and anti-apoptotic factors was determined in a swine model of non-reperfused MI with preserved LV ejection fraction. The extent of cell death was evaluated by histological analysis. Male adult farm pigs with MI (n=5), induced by permanent surgical ligation of the left anterior descending coronary artery and sham-operated adult farm pigs as control (n=7) were studied. Tissue samples were collected from the border (BZ) and remote zone (RZ) of the infarcted area to identify possible regional effects. After 4 weeks post-MI, the infarct size was 13±1% of the LV wall mass in absence of contractile dysfunction. In BZ, there was increased mRNA expression of Casp-3 (BZ vs Controls: 0.51±0.15 vs 1.39±0.04, p<0.001), a significant decrease in Bcl-2 (by 63%), associated with an increase in apoptotic cells, as revealed by TUNEL staining and cleaved-Casp-3 presence. In contrast, in the RZ there was a significant reduction of pro-apoptotic factors compared to BZ (by 80% for Casp-3), in presence of scattered apoptotic cells, increased gene expression of Hsp72 (1.82±0.21 vs 1.34±0.08, p=0.037) and iNOS (1.51±0.14 vs 1.19±0.05, p<0.05) compared to control. In conclusion, the LV distribution of apoptotic transcriptional profile revealed that apoptotic cell death is highly detectable in BZ, possibly explaining the local abnormalities of myocardial cell survival in a porcine model of MI with normal overall function. 23402270 Binding between proteins and cationic spherical polyelectrolyte brushes: effect of pH, ionic strength, and stoichiometry. Cationic spherical polyelectrolyte brushes (SPBs) were synthesized by photoemulsion polymerization, consisting of a polystyrene core with a diameter around 80 nm and a poly(2-aminoethylmethacrylate hydrochloride) (PAEMH) shell with a thickness from 10 to 50 nm densely grafted on the core surface. The binding of various proteins onto SPBs was observed by turbidimetric titration, dynamic light scattering (DLS), zeta potential, and isothermal titration calorimetry (ITC). The binding, aggregation, and releasing of proteins by SPB can be tuned by modulating pH. The pH regions of binding for bovine serum albumin (BSA), β-lactoglobulin (BLG), and papain onto SPBs are markedly different and tunable by ionic strength and stoichiometry between protein and SPB. Binding energetics, affinity, and amount of various proteins onto cationic SPBs were determined by ITC. These findings lay the foundation for SPB applications in the protein purification and selective immobilization of different proteins, enzymes, and antibodies. 22616577 Cytotoxicity of semisynthetic acetal triterpenes from one-pot vicinal diol cleavage following by lactolization: Reaction promoted by NaIO4/SiO2 gel in THF. In situ C-C bond cleavage of vicinal diol following by the lactolisation resulted from separated treatment of Arjunolic acid (1), 24-hydroxytormentic acid (2) and 3-O-β-D-glucopyranosylsitosterol (3) with sodium periodate and silica gel in dried THF according to the strategic position of hydroxyl functions in the molecule. The reaction led to a lactol pentacyclic triterpenes 1A, 2A and a bicyclotriacetal of β-sitosterol 3A. These products were further acetylated and the cytotoxicity of all molecules was evaluated against human fibrosarcoma HT1080 cancer cells lines. 23030680 In vitro metabolism of the 5-hydroxytryptamine1B receptor antagonist elzasonan. The metabolism of elzasonan has been examined in vitro using hepatic microsomes from human and recombinant heterologously expressed P450 enzymes (rCYP). Metabolism occurs primarily via oxidative N-demethylation to form M4 and oxidation reactions to form elzasonan N-oxide (M5) and 5-hydroxyelzasonan metabolite (M3). Additionally, elzasonan was shown to be metabolized to the novel cyclized indole metabolite (M6) which undergoes subsequent oxidation to form the iminium ion metabolite (M3a). The rCYP data was normalized relative to the levels of each CYP form in native human liver microsomes to better assess the contribution of each rCYP in the metabolism of elzasonan. Results demonstrated the involvement of CYP3A4 in the pathways leading to M3a, M3, M5 and M6 and CYP2C8 in the formation of M4. Kinetic constants for the formation of M3 were determined and correlation and inhibition studies suggested that CYP3A4 is primarily responsible for the formation of M3 and CYP2C19 plays a very minor role in its formation. Cytochrome b5 has shown to be an essential component in P450 3A4 catalyzed 5-hydroxyelzasonan formation and provides insights on the disconnect between human liver microsomes data and that of rCYP. Furthermore, rCYP3A4 containing b5 are useful models for predicting the rates for liver microsomes P450-dependent drug oxidations and should be utilized routinely. 23123743 Estrogen receptor ESR1 regulates the phospholipase C-inositol phosphate signaling in the hippocampus from rats in proestrous and estrous phases. The aim of the present study was to investigate the involvement of estrogen receptors in the activation of phospholipase C (PLC)-phosphoinositide hydrolysis in the hippocampus from rats in estrous and proestrous phases. 17β-Estradiol (E2) and ESR1-selective agonist PPT, but not ESR2-selective agonist DPN, induced a rapid increase on total [³H]-inositol phosphate accumulation in the hippocampus from both rats. These effects are mediated by PLC activation, since the inhibition of this protein decreased the total [³H]-inositol phosphate accumulation. The pretreatment with ESR1 and ESR2 antagonist ICI 182,780, but not with GPER antagonist G-15, blocked the total [³H]-inositol phosphate accumulation induced by E2 and PPT, confirming that ESR1 is upstream component regulating this rapid effect. SRC family of protein tyrosine kinases inhibitor PP2 blocked the total [³H]-inositol phosphate accumulation induced by E2 and PPT in hippocampus, suggesting that ESR1 undergoes translocation from the nuclei to the plasma membrane region via SRC to activate rapid signaling pathways. Furthermore, the magnitude of the response to E2 and PPT was higher in hippocampus from rats in proestrous than in estrous. On the other hand, the expression of the ESR1 is higher in hippocampus from rats in estrous than in proestrous, indicating that the regulation of this receptor by estrous cycle does not play a role in the magnitude of the response to E2 and PPT in hippocampus. In conclusion, our results indicate that E2 activates SRC-mediated translocation of ESR1 to the plasma membrane, which results in the activation of PLC-inositol phosphate signaling pathway in rat hippocampus. Thus, these rapid estrogen actions in hippocampus might be a key step mediating cellular events important for learning and memory. 22981737 Specific binding of collagen Q to the neuromuscular junction is exploited to cure congenital myasthenia and to explore bases of myasthenia gravis. Acetylcholinesterase (AChE) at the neuromuscular junction (NMJ) is anchored to the synaptic basal lamina via a triple helical collagen Q (ColQ) in the form of asymmetric AChE (AChE/ColQ). The C-terminal domain of ColQ binds to MuSK, the muscle-specific receptor tyrosine kinase, that mediates a signal for acetylcholine receptor (AChR) clustering at the NMJ. ColQ also binds to heparan sulfate proteoglycans including perlecan. Congenital defects of ColQ cause endplate AChE deficiency. A single intravenous administration of adeno-associated virus serotype 8 (AAV8)-COLQ to Colq-/- mice rescued motor functions, synaptic transmission, and the ultrastructure of NMJ. We also injected AAV1-COLQ-IRES-EGFP to the left tibialis anterior and observed colocalization of AChE/ColQ at all the examined NMJs of the non-injected limbs. Additionally, injection of purified recombinant AChE/ColQ protein complex into gluteus maximus accumulated AChE in non-injected forelimbs. These observations suggest that the tissue-targeting signal of ColQ can be exploited to specifically deliver the transgene product to the target tissue. MuSK antibody-positive myasthenia gravis (MG) accounts for 5-15% of autoimmune MG. As AChR deficiency is typically mild and as cholinesterase inhibitors are generally ineffective or worsen myasthenic symptoms, we asked if the patient's MuSK-IgG interferes with binding of ColQ to MuSK. In vitro overlay of AChE/ColQ to muscle sections of Colq-/- mice revealed that MuSK-IgG blocks binding of ColQ to the NMJ. In vitro plate-binding of MuSK to ColQ disclosed that MuSK-IgG exerts a dose-dependent block of MuSK-ColQ interaction. In addition, passive transfer of MuSK-IgG to mice reduced the size and density of ColQ to ∼10% of controls and had a lesser effect on the sizes and densities of AChR and MuSK. Elucidation of molecular mechanisms of specific binding of ColQ to the NMJ enabled us to ameliorate devastating myasthenic symptoms of Colq-/- mice and to reveal bases of anti-MuSK MG. 23363574 Purification and characterization of glucose 6-phosphate dehydrogenase enzyme from rainbow trout (Oncorhynchus mykiss) liver and investigation of the effects of some metal ions on enzyme activity. Glucose 6-phosphate dehydrogenase (d-glucose 6-phosphate: NADP(+) oxidoreductase, EC 1.1.1.49; G6PD) is a key enzyme that is localized in all mammal tissues, especially in cytoplasmic sections and that catalyzes the first step of pentose phosphate metabolic pathway. In this study, G6PD enzyme was purified 1444-fold with a yield of 77% from rainbow trout liver using 2',5'-ADP-sepharose-4B affinity chromatography. Moreover, a purity check of the enzyme was performed with sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Some characteristic features like optimal pH, stable pH, optimal temperature and optimal ionic strength were determined for the purified enzyme. In addition to this, in vitro effects of ions like silver nitrate (Ag(+)), thallium sulphate (TI(+)), cobalt (II) nitrate (Co(2+)) and arsenic (V) oxide (As(5+)) on enzyme activity were researched. Half-maximal inhibitory concentration (IC(50)) values of Ag(+), Co(2+) and As(5+) metal ions, which showed an inhibitory effect, were found to be 0.0044, 0.084 and 4.058 mM, respectively; and their inhibition constants (K(i)) were found to be 0.0052 ± 0.00042, 0.087 ± 0.015700 and 4.833 ± 1.753207 mM, respectively. Tl(+) not exhibited inhibitory effect on the enzyme activity. 23354755 Impact assessment of dredging to remove coal fly ash at the Tennessee Valley Authority Kingston Fossil plant using fathead minnow elutriate exposures. On December 22, 2008, failure of an earthen containment structure resulted in the release of approximately 4.1 million m(3) of coal fly ash into the Emory River and the surrounding area from the Tennessee Valley Authority Kingston Fossil Plant near Kingston, Tennessee, USA. The purpose of the present study was to assess the potential of dredging activities performed to remove the fly ash from the river to result in increased risk to pelagic fish, with special consideration of mobilization of metals. Elutriates were created using two sources of fly ash by bubbling with air over 10 d. This elutriate preparation method was designed to represent worst-case conditions for oxidation, metal release, and dissolution. Larval and juvenile Pimephales promelas underwent 10-d exposures to these elutriates. Larval end points included survival and biomass, and juvenile end points included survival, length, biomass, liver somatic index, and bioaccumulation. No significant toxicity was observed. Bioaccumulation of metals in juveniles was found to be primarily attributable to metals associated with particles in the gut. Results suggest little potential for toxicity to related fish species due to fly ash removal dredging activities given the extreme conditions represented by the elutriates in the present study. 23524254 Mechanochemical activation of vincamine mediated by linear polymers: Assessment of some "critical" steps. The aim of the research was to investigate three "critical steps" that deserve particular attention during the mechanochemical activation of vincamine. The first step consisted in the selection of the best polymeric carrier/most affine stabiliser between linear PVP and NaCMC by using the GRID and the GRID based AutoDock software packages which permit to calculate their surface features and interactions. Moreover, the calculation of the partial and total solubility parameters supported the results obtained by GRID and AutoDock software. Then, after the selection of linear PVP-K30 as the suitable carrier, the influence of process and formulation variables on the amorphisation degree and solubility enhancement was studied, to select the most suitable process conditions and formulation parameters. Subsequently, the best performing samples were widely characterised using XRPD, TEM and SSNMR (including the proton relaxation ((1)H T1 NMR) time) techniques. These studies highlighted that all the coground samples were nanocrystalline solid dispersions indicating a dramatic difference between the amorphisation capacities of linear PVP-K30 and cross-linked PVP, used in previous analogous experiences. In particular, (13)C, (15)N and (1)H T1 NMR data point to a description of the system as a dispersion of nanocrystals in the polymer. In these dispersions vincamine is in a disordered crystalline state due to extensive interactions and contacts with PVP-K30 but the main hydrogen bonding motif characterising its packing remains. Again, differently from cross-linked PVP, dissolution studies revealed that linear PVP-K30 was able to promote a complete in vitro solubilisation of vincamine in some coground samples. What is more important, by using a linear polymer, drug-to-polymer and milling time variables appeared less influent on the solid state and in vitro properties of the composites. Finally, stability studies conducted for a period of 1year highlighted the high physical stability of the selected samples. 23538998 A simple and versatile microfluidic cell density gradient generator for quantum dot cytotoxicity assay. In this work, a simple and versatile microfluidic cell density gradient generator was successfully developed for cytotoxicity of quantum dots (QDs) assay. The microfluidic cell density gradient generator is composed of eight parallel channels which are respectively surrounded by 1-8 microwells with optimized length and width. The cells fall into microwells by gravity and the cell densities are obviously dependent of microwell number. In a case study, HepG2 and MCF-7 cells were successfully utilized for generating cell density gradients on the microfluidic chip. The microfluidic cell density gradient generator was proved to be easily handled, cell-friendly and could be used to conduct the subsequent cell-based assay. As a proof-of-concept, QD cytotoxicity was evaluated and the results exhibited obvious cell density-dependence. For comparison, QD cytotoxicity was also investigated with a series of cell densities infused by pipette tips. Higher reproducibility was observed on the microfluidic cell density gradient generator and cell density was demonstrated to be a vital factor in cytotoxic study. With higher efficiency, controllability and reproducibility, the microfluidic cell density gradient generator could be integrated into microfluidic analysis systems to promote chip-based biological assay. 23480597 A Novel CUG(exp)·MBNL1 Inhibitor with Therapeutic Potential for Myotonic Dystrophy Type 1. Myotonic dystrophy type 1 (DM1) is caused by an expanded CUG repeat (CUG(exp)) that sequesters muscleblind-like 1 protein (MBNL1), a protein that regulates alternative splicing. CUG(exp) RNA is a validated drug target for this currently untreatable disease. Herein, we develop a bioactive small molecule (1) that targets CUG(exp) RNA and is able to inhibit the CUG(exp)·MBNL1 interaction in cells that model DM1. The core of this small molecule is based on ligand 2, which was previously reported to be active in an in vitro assay. A polyamine-derivative side chain was conjugated to this core to make it aqueous-soluble and cell-penetrable. In a DM1 cell model this conjugate was found to disperse CUG(exp) ribonuclear foci, release MBNL1, and partially reverse the mis-splicing of the insulin receptor pre-mRNA. Direct evidence for ribonuclear foci dispersion by this ligand was obtained in a live DM1 cell model using time-lapse confocal microscopy. 23631351 Novel acetylated chalcone and biflavonoid glycosides from Trigonosciadium brachytaenium (Boiss.) Alava. A new acetylated chalcone glycoside, trans-2',6'-dihydroxy-4'-O-(4″-acetyl-rhamnoside)-4-methoxychalcone (1) and a new biflavonoid glycosides, 5,3',5″,4″'-tetrahydroxy-3″',5″'dimethoxy-biflavone (4' → 8″)-7-O-((2-rhamnoside) rhamnoside) (2) were isolated from the ethyl acetate soluble fraction of the methanol extract obtained from Trigonosciadium brachytaenium and have been purified by column chromatography and preparative TLC. Those structures were elucidated by UV, (1)H NMR and (13)C NMR, HMBC, EI-MS and IR spectra. The antioxidant activity of ethyl acetate extract was evaluated by 1,1-diphenyl-2-picrylhydrazyl method. The results indicate that ethyl acetate extract from aerial part of T. brachytaenium possesses considerable antioxidant activity. 23500065 The interaction of a polymeric persimmon proanthocyanidin fraction with Chinese cobra PLA2 and BSA. To elucidate the anti-venom mechanism of persimmon tannin, the interaction between a polymeric persimmon proanthocyanidin fraction (PT40) and phospholipase A2 (PLA2) or bovine serum albumin (BSA) were studied using a competitive binding assay and spectroscopic methods including Fourier transform infrared spectroscopy (FT-IR), circular dichroism (CD), and resonance light scattering (RLS) spectroscopy. The results revealed that PT40 has a higher affinity for PLA2 than for BSA at physiological pH and induced greater conformational changes in PLA2 than in BSA. PT40 covalently bound to PLA2 in a reaction probably involving Lys residues. We propose that the high affinity of PT40 for PLA2 and the covalent modification of PLA2 by PT40 may be responsible for the ability of the tannin to irreversibly inhibit PLA2 catalytic activity, to prevent edema, and to neutralize the lethality of Chinese cobra PLA2in vivo. 23587048 Trapping of a Cross-Link Formed by a Major Purine Adduct of a Metabolite of the Carcinogen N-Nitrosomorpholine by Inorganic and Biological Reductants. 3-Hydroperoxy-N-nitrosomorpholine in buffered aqueous media in the presence of calf thymus DNA was treated with a phosphine reductant to generate the transient α-hydroxynitrosamine and subsequent diazonium ion that alkylated the DNA, as previously reported. Subsequent addition of hydride donors, for 30 min, followed by acid hydrolysis of the mixture allowed detection and quantification of 6-(2-{2-[(9H-purin-6-yl)amino]ethoxy}ethoxy)-9H-purin-2-amine, the reduced cross-link formed from deposition, via the diazonium ion, of a 3-oxapentanal fragment on O(6)-Gua, and condensation with N(6)-Ade, presumably in the vicinity. Decreasing the temperature of the reaction mixtures and decreasing the pH modestly increased the yields of the trapped cross-link. Among three borohydride reductants, NaNCBH3 is superior, being ∼4 times more effective on a molar basis, as opposed to a hydride equivalent basis, than NaBH4 or Na(AcO)3BH. For trapping with NaNCBH3, it is deduced that the reaction likely occurs with the iminium ion that is in protonic equilibrium with its conjugate base imine. In an experiment in which the hydroperoxide was decomposed and NaNCBH3 was introduced after various periods of time, the amount of cross-link was observed to increase, nearly linearly, by ∼4-fold over 1 week. These data indicate that there are a minimum of two populations of cross-links, one that forms rapidly, in minutes, and another that grows in with time, over days. Reduced nicotinamide cofactors and ascorbate are observed to effect reduction (over 3 days) of the cross-links, confirming the possibility that otherwise reversible cross-links might be immortalized under biological conditions. 23161866 Effects of mutated pregnancy-associated plasma protein-a on atherosclerotic lesion development in mice. Pregnancy-associated plasma protein-A (PAPP-A) is a large multidomain metalloprotease involved in cleavage of IGF binding protein (IGFBP)-4 and -5 thereby causing release of bioactive IGF. Individual domains of PAPP-A have been characterized in vitro, including the metzincin proteolytic domain important for IGFBP proteolytic activity, short consensus repeats critical for cell surface association, and Lin-12/Notch repeat module demonstrated to determine IGFBP substrate specificity. To test the hypothesis that specific cleavage of IGFBP-4 by PAPP-A in close proximity to the cell surface is required for development of lesions in a murine model of atherosclerosis, the following PAPP-A transgenic (Tg) mice were generated: Tg(E483A), which lacks all PAPP-A proteolytic activity; Tg(D1499A), which selectively lacks proteolytic activity against IGFBP-4; and Tg(K1296A/K1316A), in which cell surface binding is compromised. Following cross-breeding with apolipoprotein E (ApoE) knockout (KO) mice, ApoE KO/Tg mice were fed a high-fat diet to promote aortic lesion development. Lesion area was increased 2-fold in aortas from ApoE KO/Tg wild-type compared with ApoE KO mice (P < 0.001). However, there was no significant increase in the lesion area in any of the ApoE KO/Tg mutant mice. We conclude that PAPP-A proteolytic activity is required for the lesion-promoting effect of PAPP-A and that its specificity must be directed against IGFBP-4. Furthermore, our data demonstrate that cleavage of IGFBP-4 at a distance from the cell surface, and hence from the IGF receptor, is not effective in promoting the development of the atherosclerotic lesions. Thus, PAPP-A exerts its effect while bound to the cell surface in vivo. 23440959 Associations of gender and age with the reporting of drug-induced hepatic failure: data from the VigiBase™. Patient gender and age are considered to be the risk factors for developing drug-induced liver injury (DILI). The aim of this study was to analyze gender and age differences in reporting of drug-induced hepatic failure (HF) to the VigiBase™. VigiBase™ was screened for the HF reports submitted from 2000 to 2009. The information retrieved referred to the suspected drug, age, gender, and a reporting country. Variables were examined by using descriptive statistics and the binomial test. During the 10-year period there were in total 6,370 HF reports from 38 countries. After the exclusion of cases with missing gender data (379 cases), females counted for 54.03%. The largest portion of HF cases referred to age <55 (42.57%) with female predominance (56.81%), whereas age ≥55 (32.57%) showed almost even gender distribution. Overall, there were 941 different drugs or their combinations reported. Females significantly predominated in HF cases associated with analgesics, antiepileptics, antiinflamatory and antirheumatic drugs, psychoanaleptics, antibacterials for systemic use, and antidiabetic drugs. Males were significantly overrepresented in HF cases associated with antivirals for systemic use. Differences between genders and/or age groups in the reporting of drug-induced HF depend on drug and/or drug class but may be influenced by multiple factors. 23545846 Determination of the mutagenic and genotoxic potential of simulated leachate from an automobile workshop soil on eukaryotic system. Contamination of soil and water bodies with spent engine oil and petroleum products is a serious ecological problem, primarily in the automobile workshops and garages. This has potential short and chronic adverse health risks. Information is currently scarce on the potential mutagenicity and genotoxicity of such wastes. In this study, the potential mutagenic and genotoxic effects of simulated leachate from automobile workshop soil in Sagamu, Ogun state, Nigeria, were investigated. The assays utilized were bone marrow micronucleus (MN) and chromosome aberration (CA), sperm morphology and sperm count in mice. The physicochemical analysis of the leachate was also carried out. Experiments were carried out at concentrations of 1, 5, 10, 25, 50, 75 and 100% (volume per volume; leachate:distilled water) of the leachate sample. MN analysis showed a concentration-dependent induction of micronucleated polychromatic erythrocytes across the treatment groups. In the CA test, there was concentration-dependent significant reduction in mitotic index and induction of different types of CAs. Assessment of sperm shape showed a significant increase in sperm abnormalities with significant decrease in mean sperm count in treated groups. Heavy metals analyzed in the tested sample are believed to contribute significantly to the observed genetic damage. This indicates that automobile workshop soil-simulated leachate contains potential genotoxic agents and constitutes a genetic risk in exposed human population. 23420400 Theoretical studies on the thermodynamic properties, densities, detonation properties, and pyrolysis mechanisms of trinitromethyl-substituted aminotetrazole compounds. Trinitromethyl-substituted aminotetrazoles with -NH(2), -NO(2), -N(3), and -NHC(NO(2))(3) groups were investigated at the B3LYP/6-31G(d) level of density functional theory. Their sublimation enthalpies, thermodynamic properties, and heats of formation were calculated. The thermodynamic properties of these compounds increase with temperature as well as with the number of nitro groups attached to the tetrazole ring. In addition, the detonation velocities and detonation pressures of these compounds were successfully predicted using the Kamlet-Jacobs equations. It was found that these compounds exhibit good detonation properties, and that compound G (D = 9.2 km/s, P = 38.8 GPa) has the most powerful detonation properties, which are similar to those of the well-known explosive HMX (1,3,5,7-tetranitro-1,3,5,7-tetrazocine). Finally, the electronic structures and bond dissociation energies of these compounds were calculated. The BDEs of their C-NO(2) bonds were found to range from 101.9 to 125.8 kJ/mol(-1). All of these results should provide useful fundamental information for the design of novel HEDMs. 23441843 Epigenetic reactivation of Nrf2 in murine prostate cancer TRAMP C1 cells by natural phytochemicals Z-ligustilide and Radix angelica sinensis via promoter CpG demethylation. Cancer development has been linked to epigenetic modifications of cancer oncogenes and tumor suppressor genes; in advanced metastatic cancers, severe epigenetic modifications are present. We previously demonstrated that the progression of prostate tumors in TRAMP mice is associated with methylation silencing of the Nrf2 promoter and a reduced level of transcription of Nrf2 and Nrf2 target genes. Radix Angelicae Sinensis (RAS; Danggui) is a medicinal herb and health food supplement that has been widely used in Asia for centuries. Z-Ligustilide (Lig) is one of the bioactive components of RAS. We investigated the potential of Lig and RAS to restore Nrf2 gene expression through epigenetic modification in TRAMP C1 cells. Lig and RAS induced the mRNA and protein expression of endogenous Nrf2 and Nrf2 downstream target genes, such as HO-1, NQO1, and UGT1A1. Bisulfite genomic sequencing revealed that Lig and RAS treatment decreased the level of methylation of the first five CpGs of the Nrf2 promoter. A methylation DNA immunoprecipitation assay demonstrated that Lig and RAS significantly decreased the relative amount of methylated DNA in the Nrf2 gene promoter region. Lig and RAS also inhibited DNA methyltransferase activity in vitro. Collectively, these results suggest that Lig and RAS are able to demethylate the Nrf2 promoter CpGs, resulting in the re-expression of Nrf2 and Nrf2 target genes. Epigenetic modifications of genes, including Nrf2, may therefore contribute to the overall health benefits of RAS, including the anticancer effect of RAS and its bioactive component, Lig. 23499237 Exploring the UDP pocket of LpxC through amino acid analogs. Lipopolysaccharide (LPS) biosynthesis is an attractive antibacterial target as it is both conserved and essential for the survival of key pathogenic bacteria. Lipid A is the hydrophobic anchor for LPS and a key structural component of the outer membrane of Gram-negative bacteria. Lipid A biosynthesis is performed in part by a unique zinc dependent metalloamidase, LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase), which catalyzes the first non-reversible step in lipid A biosynthesis. The UDP portion of the LpxC substrate-binding pocket has been relatively unexplored. We have designed and evaluated a series of hydroxamate based inhibitors which explore the SAR of substitutions directed into the UDP pocket with a range of substituted α-amino acid based linkers. We also provide the first wild type structure of Pseudomonas aeruginosa LpxC which was utilized in the design of many of these analogs. 22670797 Preformulation and formulation of newly synthesized QNT3-18 for development of a skin whitening agent. New molecules having the structure of (E)-2-(4-tert-butylbenzylidene) hydrazinecarbothioamide (QNT3-18) or 4-tert-butylphenylthiourea (QNT3-20) was synthesized and presupposed to inhibit melanogenesis through the inhibition of tyrosinase, which is involved in melanin formation. Therefore, we seek to develop these new molecules as skin whitening agents in topical formulations based on preformulation studies. QNT3-18 or QNT3-20 showed a strong single endothermic peak at 159.34°C with 10.79 μm-sized or at 150.69°C with 9.0 μm-sized aggregated particles, respectively. Both QNT3-18 and QNT3-20 did not show cytotoxicity at effective concentration range (0.4 µM) against keratinocyte cells and QNT3-18 was more retained than QNT3-20 in the skin instead of permeating through the skin. QNT3-18 or QNT3-20 was practically insoluble in water; the aqueous solubility was 3.8 ± 0.37 or 130.6 ± 2.52 μg/mL, respectively. Also, the partition coefficient value (log P) corresponding to the quotient between aqueous and octanol concentration of the molecule was 3.9 or 2.6, respectively. The skin retention amount of QNT3-18 was 1.7-fold higher than that of QNT3-20. When the optimal SLN cream (J3 formulation) containing 4 μM QNT3-18 was applied on the backs of hairless rats for 4 days after UV irradiation for 7 days and the skin color was checked by reflectance spectrophotometer, the rat skin treated with SLN cream with QNT3-18 quickly recovered to normal compared to skin treated with SLN cream without QNT3-18. Taken together, this study suggests that topical formulations such as creams including SLNs with QNT3-18 might be appropriate carriers for skin whitening agents. 23411182 Quantification of organic acids using voltammetric tongues. Recently, electronic tongues (ET) have appeared as an excellent alternative to traditional techniques for the evaluation of food quality and processes. ET systems are based on arrays of low selectivity sensors that are simultaneously sensitive to several components in a measured sample (cross-sensitivity). The aim of this study was to determine the ability of an ET based on pulse voltammetry to quantify organic acids (ascorbic, citric and malic acids) in simple (SS) and binary solutions (BS) using different electrodes. The most significant electrodes for ascorbic acid prediction were Ni and Ag for SS, and Ag and Ir for BS where positive pulses were more suitable than negative ones. The prediction of citric and malic acids in SS and BS were suitable using Ir, Rh, Pt, Ag and Cu electrodes, using both positive and negative pulses. 23333575 Genistein protection against acetaminophen-induced liver injury via its potential impact on the activation of UDP-glucuronosyltransferase and antioxidant enzymes. The purpose of this study was to investigate genistein's influence on the relationship between the activation of uridine diphosphate glucuronosyltransferase (UGTs) and the protection against acetaminophen-induced liver toxicity. Animal experimental results revealed that genistein (50, 100 or 200mg/BWkg) significantly ameliorated the biomarkers alanine aminotransferase, alanine aminotransferase, lactate dehydrogenase and malondialdehyde, as indicators of acute liver damage caused by APAP (200mg/BWkg). The level of GSH declined sharply after treatment with APAP within 1h in both the liver and blood with and without genistein. However, after 16h, the levels approached or returned to the original level. Genistein may accelerate and promote APAP glucuronidation as the results showed that APAP-glucuronide increased by 18.44%, 46.79%, and 66.49% for 4h of treatment with genistein dosages of 50, 100 or 200mg/BWkg, respectively, compared with the APAP-only treatment. The activation of UGTs and glutathione peroxidase and the inhibition of CYP2E1 by genistein were observed, and UGTs mRNA expression level with genistein was measured. These findings suggest that genistein can prevent and protect against APAP-induced liver toxicity due to the inhibition of APAP biotransformation and the resistance to oxidative stress via the modulation of the activities of metabolism and the antioxidant enzyme. 23402859 Chlorpyrifos induced hepatotoxic and hematologic changes in rats: the role of quercetin and catechin. Chlorpyrifos is an organophosphorus insecticide which is widely used throughout in the world and it caused toxic effects on nontarget organisms especially mammalian. In the present study, catechin, quercetin, chlorpyrifos, catechin+chlorpyrifos, quercetin+chlorpyrifos were given to male rats through gavage for 4weeks. Serum total protein, albumin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, trigliceride, total cholesterol levels, hematological changes, superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase activities and malondialdehyde content in liver tissues and also histopathological changes of liver were investigated in the rats compared to control group. No significant differences in all investigated parameters were observed between control, catechin and quercetin groups. There were statistically significantly changes in liver function tests, some hematological parameters, antioxidant enzyme activities and malondialdehyde levels in chlorpyrifos treated group compared to control group. In catechin+chlorpyrifos treated group and quercetin+chlorpyrifos treated group we observed the protective effects of catechin and quercetin on examining parameters but not completely. While some histopathological changes detected in liver tissues in chlorpyrifos treated group, less histopathological changes were observed in catechin+chlorpyrifos and quercetin+chlorpyrifos treated groups at the end of the 4thweek. As a result, catechin and quercetin significantly reduce chlorpyrifos induced hepatotoxicity in rats. 23395689 Manganese-loaded lipid-micellar theranostics for simultaneous drug and gene delivery to lungs. Gadolinium (Gd) contrast agents are predominantly used for T(1) MR imaging. However, the high toxicity of Gd(3+) and potential side effects including nephrogenic systemic fibrosis have led to the search for alternative T(1) contrast agents. Since manganese (Mn) has paramagnetic properties with five unpaired electrons that permit high spin number, long electronic relaxation times, and labile water exchange, we evaluated Mn as a T(1) magnetic resonance imaging (MRI) contrast agent for lung imaging. Here we report on the design and synthesis of multifunctional lipid-micellar nanoparticles (LMNs) containing Mn oxide (M-LMNs) for MRI that can also be used for DNA and drug delivery. Oleic acid-coated MnO nanoparticles were encapsulated in micelles composed of polyethylene glycol (PEG-2000), phosphatidylethanolamine (PE), DC-cholesterol, and dioleoyl-phosphatidylethanolamine (DOPE). The particles are taken up in vitro by human embryonic kidney (HEK293), Lewis lung carcinoma (LLC1), and A549 cells and are devoid of cytotoxicity. When administered to mice intranasally, they preferentially accumulate in the lungs. In vitro phantom and ex vivo lung MRI results confirmed that M-LMNs are able to enhance T(1) MRI contrast. M-LMNs loaded with plasmid DNA and/or doxorubicin are efficiently taken up by HEK293 cells in vitro and by target cells in vivo. Taken together, these results demonstrate that M-LMNs are capable of simultaneously providing MRI contrast and DNA and/or drug delivery to target cells in the lung and therefore may prove useful as a lung theranostic, especially for lung cancers. 22981667 Oral delivery of anticancer drugs III: formulation using drug delivery systems. In the past few years, the growth of nanometric size drug delivery systems (DDS) has burst into challenging innovations enabling real progresses to achieve oral delivery of anticancer drugs. DDS, such as polymeric nanoparticles, micelles, dendrimers and lipid-based formulations enable physico-chemical properties of cytotoxic agents to be improved and oral bioavailability to be enhanced. In this review we highlight current DDS used for the oral delivery of anticancer drugs. 23047001 Design, synthesis and biological evaluation of benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of glycogen synthase kinase-3β (GSK-3β). Glycogen synthase kinase-3β (GSK-3β) plays a key role in type II diabetes and Alzheimer's diseases, to which non-ATP competitive inhibitors represent an effectively therapeutical approach due to their good specificity. Herein, a series of small molecules benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of GSK-3β have been designed and synthesized. The in vitro evaluation performed by luminescent assay showed most BTZ derivatives have inhibitory effects in micromolar scale. Among them compounds 6l, 6t and 6v have the IC50 values of 25.0 μM, 27.8 μM and 23.0 μM, respectively. Moreover 6v is devoid of any inhibitory activity in the assays to other thirteen protein kinases. Besides, SAR is analyzed and a hypothetical enzymatic binding mode is proposed by molecular docking study, which would be useful for new candidates design. 23265458 Defatted Jatropha curcas flour and protein isolate as materials for protein hydrolysates with biological activity. Jatropha curcas L. protein hydrolysates were produced by treatment of a non-toxic genotype with Alcalase as well as the digestive enzymes pepsin and pancreatin. The J. curcas protein hydrolysate produced with the pepsin-pancreatin system from protein isolate had the highest TEAC value and was shown to undergo single-electron transfer reactions in the ABTS(+) reduction assay, demonstrating its antioxidant capacity. Testing of antimicrobial activity in the J. curcas protein hydrolysates against seven bacterial pathogens showed no growth inhibitory effect in Gram-negative and Gram-positive bacteria. More ACE-I inhibitory active peptides were produced in the Alcalase hydrolysates obtained from J. curcas protein isolate. The protein hydrolysate obtained with Alcalase from defatted J. curcas flour as well as from the protein isolate showed the highest inhibitory effect of ADP-induced aggregation of human platelets in platelet-rich plasma. It is expected that the information collated will facilitate new applications of proteins present in Jatropha plant. 23479318 Association of cadmium and lead with antioxidant status and incidence of benign prostatic hyperplasia in patients of Western India. The association of cadmium (Cd) and lead (Pb) in the pathophysiology and progression of benign prostate hyperplasia (BPH) has been evaluated in an epidemiological study with 116 BPH patients of the western part of India. The prostatic acid phosphatase activity, prostate-specific antigen, maximum urinary flow rate (Q max), and redox status of BPH patients were correlated with Cd and Pb contents. Additionally, patients were also separated on the basis of their age, genetic lineage, and additive habits and correlated with the Cd, Pb, and Q max levels. Our results suggest that the accumulation of toxic metals in prostate tissue has a significant positive correlation with the pathogenesis of BPH. Cd and Pb exert their effects through altered antioxidant defense mechanisms, ultimately leading to increased BPH severity. Progression of the pathogenesis also depends on other factors such as additive habits, genetic lineage, and age of the patients. 23291503 Embryonic stem cell-derived trophoblast differentiation: a comparative review of the biology, function, and signaling mechanisms. The development of the placenta is imperative for successful pregnancy establishment, yet the earliest differentiation events of the blastocyst-derived trophectoderm that forms the placenta remain difficult to study in humans. Human embryonic stem cells (hESC) display a unique ability to form trophoblast cells when induced to differentiate either by the addition of exogenous BMP4 or by the formation of cellular aggregates called embryoid bodies. While mouse trophoblast stem cells (TSC) have been isolated from blastocyst outgrowths, mouse ESC do not spontaneously differentiate into trophoblast cells. In this review, we focus on addressing the similarities and differences between mouse TSC differentiation and hESC-derived trophoblast differentiation. We discuss the functional and mechanistic diversity that is found in different species models. Of central importance are the unique signaling events that trigger downstream gene expression that create specific cellular fate decisions. We support the idea that we must understand the nuances that hESC differentiation models display so that investigators can choose the appropriate model system to fit experimental needs. 23127599 Alleviative effects of resveratrol on nonalcoholic fatty liver disease are associated with up regulation of hepatic low density lipoprotein receptor and scavenger receptor class B type I gene expressions in rats. Lipid metabolic disorders are widely considered to be one of the most critical and basic link in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to illustrate the alleviation function of resveratrol (Res) on NAFLD and the roles of hepatic fatty acid synthase (FAS), low density lipoprotein receptor (LDLr), scavenger receptor class B type I (SR-BI), and thyroid hormone receptor β1 (TRβ1), which are the key molecules involved in lipid metabolism. Adult male Wistar rats were fed a normal diet or high fat/sucrose diet (HFS) with or without resveratrol for 13 weeks. HFS induced NAFLD formation and increased the lipids concentrations in serum and livers of rats, while noticeable improvement has been reached by Res intervention. Moreover, Res protected against HFS-induced decrease in hepatic LDLr and SR-BI mRNA and protein expressions, whereas TRβ1 expressions were impervious with/without Res. Unexpectedly, hepatic FAS gene expressions were markedly diminished in NAFLD rats and were gradually increased by treatment with Res. These data indicate that the alleviative effects of Res on NAFLD are associated with up regulation of hepatic LDLr and SR-BI gene expressions, which provide new insights into the pharmacological targets of Res in the prevention of NAFLD. 23525112 Nuclear Factor κB Mediates Suppression of Canonical Transient Receptor Potential 6 Expression by Reactive Oxygen Species and Protein Kinase C in Kidney Cells. This study was carried out to explore the molecular mechanism for down-regulation of TRPC6 expression in the reactive oxygen species (ROS)/PKC signaling in kidney cells. In cultured human mesangial cells, H2O2 and TNF-α inhibited TRPC6 mRNA expression in a time-dependent manner. Inhibition of NF-κB reversed both H2O2- and phorbol 12-myristate 13-acetate (PMA)-induced decrease in TRPC6 protein expression. Activation of NF-κB by knocking down IκBα using siRNA could mimic the suppressive effect of ROS/PKC on TRPC6. a Ca(2+) imaging study showed that activation and inhibition of NF-κB significantly decreased and increased the TRPC6-mediated Ca(2+) entry, respectively. Further experiments showed that PMA, but not its inactive analog 4α-phorbol 12, 13-didecanoate (4α-PDD), caused phosphorylation of IκBα and stimulated the nuclear translocation of NF-κB p50 and p65 subunits. The PMA-dependent IκBα phosphorylation was significantly inhibited by Gö6976. Electrophoretic mobility shift assay revealed that PMA stimulated DNA binding activity of NF-κB. Furthermore, specific knockdown of p65, but not p50, prevented an H2O2 inhibitory effect on TRPC6 protein expression, suggesting p65 as a predominant NF-κB subunit repressing TRPC6. In agreement with a major role of p65, chromatin immunoprecipitation assays showed that PMA treatment induced p65 binding to the TRPC6 promoter. Moreover, PMA treatment increased the association of p65 with histone deacetylase (HDAC) and decreased histone acetylation at the TRPC6 promoter. Consistently, knockdown of HDAC2 by siRNA or inhibition of HDAC with trichostatin A prevented a H2O2-induced decrease in TRPC6 mRNA and protein expressions, respectively. Taken together, our findings imply an important role of NF-κB in a negative regulation of TRPC6 expression at the gene transcription level in kidney cells. 23194518 Development and characterisation of composite films made of kefiran and starch. In this study, new edible composite films were prepared by blending kefiran with corn starch. Film-forming solutions of different ratios of kefiran to corn starch (100/0, 70/30, 50/50, 30/70) were cast at room temperature. The effects of starch addition on the resulting films' physical, mechanical and water-vapor permeability (WVP) properties were investigated. Increasing starch content from 0% to 50% (v/v) decreased the WVP of films; however, with further starch addition the WVP increased. Also, this increase in starch content increased the tensile strength and extensibility of the composite films. However, these mechanical properties decreased at higher starch contents. Dynamic mechanical thermal analysis (DMTA) curves showed that addition of starch at all levels increased the glass transition temperature of films. The electron scanning micrograph for the composite film was homogeneous, without signs of phase separation between the components. Thus, it was observed that these two film-forming components were compatible, and that an interaction existed between them. 23368091 Primary hepatocyte cultures as prominent in vitro tools to study hepatic drug transporters. Abstract Before any drug can be placed on the market, drug efficacy and safety must be ensured through rigorous testing. Animal models are used for this purpose, though currently increasing attention goes to the use of alternative in vitro systems. In particular, liver-based testing platforms that allow the prediction of pharmacokinetic (PK) and pharmacotoxicological properties during the early phase of drug development are of interest. They also enable the screening of potential effects on hepatic drug transporters. The latter are known to affect drug metabolism and disposition, thereby possibly underlying drug-drug interactions, which, in turn, may result in liver toxicity. Clearly, stable in vivo-like functional expression of drug transporters in hepatic in vitro settings is a prerequisite to be applicable in routine PK and pharmacotoxicological testing. In the first part of the article, an updated overview of hepatic drug transporters is provided, followed by a state-of-the-art review of drug-transporter production and activity in primary hepatocyte cultures (PHCs), being the gold-standard in vitro system. Specific focus is hereby put on strategies to maintain long-term functional expression, in casu of drug transporters, in these systems. In the second part, the use of PHCs to assess hepatobiliary transport and transporter-mediated interactions is outlined. 23132334 In vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir, a HIV integrase inhibitor. Dolutegravir (DTG; S/GSK1349572) is a potent HIV-1 integrase inhibitor with a distinct resistance profile and a once-daily dose regimen that does not require pharmacokinetic boosting. This work investigated the in vitro drug transport and metabolism of DTG and assessed the potential for clinical drug-drug interactions. DTG is a substrate for the efflux transporters P-glycoprotein (Pgp) and human breast cancer resistance protein (BCRP). Its high intrinsic membrane permeability limits the impact these transporters have on DTG's intestinal absorption. UDP-glucuronosyltransferase (UGT) 1A1 is the main enzyme responsible for the metabolism of DTG in vivo, with cytochrome P450 (P450) 3A4 being a notable pathway and UGT1A3 and UGT1A9 being only minor pathways. DTG demonstrated little or no inhibition (IC(50) values > 30 μM) in vitro of the transporters Pgp, BCRP, multidrug resistance protein 2, organic anion transporting polypeptide 1B1/3, organic cation transporter (OCT) 1, or the drug metabolizing enzymes CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, UGT1A1, or 2B7. Further, DTG did not induce CYP1A2, 2B6, or 3A4 mRNA in vitro using human hepatocytes. DTG does inhibit the renal OCT2 (IC(50) = 1.9 μM) transporter, which provides a mechanistic basis for the mild increases in serum creatinine observed in clinical studies. These in vitro studies demonstrate a low propensity for DTG to be a perpetrator of clinical drug interactions and provide a basis for predicting when other drugs could result in a drug interaction with DTG. 23583928 Pleiotropic effect of histamine H4 receptor modulation in the central nervous system. The histamine H4 receptor (H4R) is expressed primarily on cells involved in inflammation and immune responses. Recently, it has been reported the functional expression of H4R within neurons of the central nervous system, but their role has been poorly understood. The present study aimed to elucidate the physiopathological role of cerebral H4R in animal models by the intracerebroventricular administration of the H4R agonist VUF 8430 (20-40 μg per mouse). Selectivity of results was confirmed by the prevention of the effects produced by the H4R antagonist JNJ 10191584 (3-9 mg/kg p.o.). Neuronal H4R activation induced acute thermal antinociception, indicating that neuronal histamine H4R might be involved in the production of antinociception in the absence of an inflammatory process. An anxiolytic-like effect of intensity comparable to that exerted by diazepam, used as reference drug, was produced in the light-dark box test. VUF 8430 reversed the scopolamine-induced amnesia in the passive avoidance test and showed anorexant activity in food deprived mice. Conversely, the H4R activation did not modify the immobility time in the tail suspension test. Rotarod performance test was employed to demonstrate that the effects observed following the administration of VUF 8430 and JNJ 10191584 were not due to impaired motor function of animals. Furthermore, both compounds did not alter spontaneous mobility and exploratory activity in the hole board test. These results show the antinociceptive, antiamnesic, anxiolytic and anorexant effects induced by neuronal H4R agonism, suggesting that H4 modulators may have broader utility further the control of inflammatory and immune processes. 23378627 Identification and characterization of novel alternative splice variants of human constitutive androstane receptor in liver samples of Koreans and Caucasians. Human constitutive androstane receptor (hCAR, NR1I3) is a member of the orphan nuclear receptor family and regulates the transcription of many drug-metabolizing enzymes and drug transporters. Previous studies have shown that the hCAR gene produces a number of different kinds of mRNA splicing variants (SVs) in non-Asian ethnicities. In the present study, we identified 18 hCAR SVs (SV1-SV18), including four novel SVs in Korean human livers. Among the four novel SVs, SV2 showed enhanced transactivation activity when cotransfected with CYP2B6 reporter gene, whereas other SVs were nonfunctional. When profiles of major hCAR SVs were compared among 30 livers from Korean patients and 20 livers from Caucasian patients, the relative composition of each SV showed interethnic variation as well as interindividual variation. The most predominant form of hCAR SV was not wild type, but either SV4 or SV7. The summed relative amounts of SV4 and SV7 ranged from 34.5 to 57.6% in the 30 Korean livers and from 47.2 to 82.6% in the 20 Caucasian livers, suggesting large interindividual variation. The mean relative amount of nonfunctional SV9 was significantly higher in Koreans (29.8%) than in Caucasians (12.8%). The mean relative amount of novel SV2 was 9.7% in Korean livers and 3.5% in Caucasian livers. Expression profiling of hCAR proteins in human livers also supported large interindividual variation in the expressional ratio of wild-type and SVs. Our results describe for the first time the direct comparison of hCAR SV profiles between Koreans and Caucasians. The functional relevance of these interindividual and interethnic variations of hCAR mRNA expression needs to be further characterized. 23403537 Accurate quantum chemical energies for tetrapeptide conformations: why MP2 data with an insufficient basis set should be handled with caution. High-level quantum chemical calculations have been carried out for biologically-relevant conformers of tetrapeptides. Our results indicate potential problems if the widely-applied MP2 approach is used in such situations with basis sets of insufficient size. Efficient alternatives are discussed. 23542041 In vivo and in vitro anti-inflammatory activity of Lentinus polychrous extract. ETHNOPHARMACOLOGICAL RELEVANCE: Lentinus polychrous is a Thai local edible mushroom, traditionally used for the treatments of fever and inflammation due to snake or scorpion envenomation. AIM OF STUDY: The present study aimed to investigate an anti-inflammatory effect of Lentinus polychrous mycelial extract (LPME) both in vitro and in vivo. MATERIALS AND METHODS: The cytotoxicity and suppressive effects of LPME on nitric oxide production, intracellular O2(-) production, pro-inflammatory mediator expression, TNF-α production were determined by using LPS-activated RAW 264.7 cells. In addition, Anti-inflammatory effect of LPME was evaluated by using carageenan-induced paw edema in rats. RESULTS: The LPME exhibited cytotoxicity with 50% inhibitory concentration (IC50) of 280.25±10.10μg/ml and significantly suppressed the productions of NO and intracellular O2(-) with dose-dependent manner. LPME decreased the expressions of iNOS, IL-1β, IL-6, TNF-α and COX-2 and significantly decreased the TNF-α production in LPS-activated macrophage with dose-dependent manners. Moreover, LPME showed significant suppressive effect on paw edema in rats. CONCLUSION: The results clearly revealed that the LPME inhibited NO and pro-inflammatory productions by down-regulating the gene expressions of pro-inflammatory mediators leading to the decrease paw edema in rat which support the traditional use. 22080037 Mercury induces the expression of cyclooxygenase-2 and inducible nitric oxide synthase. Nuclear factor-κB (NF-κB) is a transcription factor that mediates the inducible expression of a variety of genes involved in immune and inflammatory responses. NF-κB activation induces numerous proinflammatory gene products including cytokines, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). The divalent heavy metal mercury has been used for thousands of years. Although mercury is clearly toxic to most mammalian organ systems, especially the immune system, exposure has still increased in some areas of the world. However, the underlying toxic mechanism is not clearly identified. Here, we report biochemical evidence that mercury alone induces NF-κB activation, resulting in the induced expression of COX-2 and iNOS. The results suggest that mercury can induce inflammatory diseases by lowering host defense. 23219658 Immunotherapy blocking the tissue plasminogen activator-dependent activation of N-methyl-d-aspartate glutamate receptors improves hemorrhagic stroke outcome. Ischemic and hemorrhagic strokes have different etiologies, but share some pathogenic mechanisms, including a pro-neurotoxic effect of endogenous tissue plasminogen activator (tPA) via N-methyl-d-Aspartate (NMDA) receptors. Thus, in a model of intracerebral hemorrhage in rats, we investigated the therapeutic value of a strategy of immunotherapy (αATD-GluN1 antibody) preventing the interaction of tPA with NMDA receptors. We found that a single intravenous injection of αATD-GluN1 reduced brain edema, neuronal death, microglial activation and functional deficits following intracerebral hemorrhage, without affecting the hematoma volume. 23294566 Anterior gradient 2 and 3--two prototype androgen-responsive genes transcriptionally upregulated by androgens and by oestrogens in prostate cancer cells. Androgens and oestrogens have been implicated in prostatic carcinogenesis and tumour progression. Although the actions of androgens have been studied extensively, the mechanisms underlying oestrogen signalling in prostate cancer are not fully understood. In the present study, we analyzed the effect of androgens and oestrogens on the expression of anterior gradient 2 (AGR2) and anterior gradient 3 (AGR3), comprising two highly-related genes encoding secretory proteins that are expressed in prostate cancer and one of which (AGR2) has been associated with tumour metastasis. Quantitative reverse-transcriptase PCR and western blot analysis showed androgen induction of AGR2 and AGR3 in three androgen receptor positive cell lines, starting at concentrations of 0.1 nm. Both AGR genes were also transcriptionally activated by ≥ 5 nM oestradiol but not by isotype selective or nonselective oestrogen receptor agonists in DUCaP cells that harbour a high-level of wild-type androgen receptor. A functional androgen receptor but not oestrogen receptor turned out to be required for both androgen and oestrogen regulation. This pattern of androgen and oestrogen regulation was confirmed in VCaP cells and was also observed for FKBP5, a well-characterized androgen-regulated gene. Genome-wide chromatin-immunoprecipitation studies coupled with deep sequencing identified androgen receptor binding sites localized in the distal promoter and intron regions of the AGR2 and AGR3 genes, respectively. The androgen responsiveness of these enhancers was verified by luciferase reporter gene assays and site-directed mutagenesis analysis. Androgen treatment also induced p300 and RNA Pol II recruitment to androgen receptor enhancers of AGR2 and initiated local chromatin remodelling and the formation of RNA Pol II-containing androgen receptor transcription complexes. 23362960 DNA origami nanopillars as standards for three-dimensional superresolution microscopy. Nanopillars are promising nanostructures composed of various materials that bring new functionalities for applications ranging from photovoltaics to analytics. We developed DNA nanopillars with a height of 220 nm and a diameter of ~14 nm using the DNA origami technique. Modifying the base of the nanopillars with biotins allowed selective, upright, and rigid immobilization on solid substrates. With the help of site-selective dye labels, we visualized the structure and determined the orientation of the nanopillars by three-dimensional fluorescence superresolution microscopy. Because of their rigidity and nanometer-precise addressability, DNA origami nanopillars qualify as scaffold for the assembly of plasmonic devices as well as for three-dimensional superresolution standards. 23537133 Efficient anodic allylation and benzylation of carbons using allyl and benzyl trimethylsilanes. An easy process for allylation and benzylation of different carbon materials, primarily of glassy carbon, in acetonitrile solutions containing tetraalkyammonium salts is described. The method relies on the capability of C(sp(2)) zones of glassy carbon (graphite and fullerene-like inclusions) to be anodically charged at potentials >1.5 V versus Ag/AgCl to form electrophilic centers reacting with substituted trimethylsilanes RSiMe3. Great propensity of the trimethylsilyl group (TMS(+)) to act as a cationic leaving group facilitates electrophilic reactions of the charged anodic surface with R-carrying silylated precursors, permitting efficient grafting of a large variety of R groups. The present preliminary work focuses only on the efficient grafting of benzyl and allyl moieties. 23609070 Similarities and differences between sexes in regional loss of cortical and trabecular bone in the mid-femoral neck: The AGES-Reykjavik Longitudinal Study. The risk of hip fracture rises rapidly with age, and is notably higher in women. After falls and prior fragility fractures, the main clinically recognized risk factor for hip fracture is reduced bone density. To better understand the extent to which femoral neck density and structure change with age in each sex, we have carried out a longitudinal study in subjects not treated with agents known to influence bone mineral density to investigate changes in regional cortical thickness, as well as cortical and trabecular bone mineral density at the mid-femoral neck. Segmental QCT analysis was used to assess bone measurements in two anatomic sub-regions, the supero-lateral (superior) and infero-medial (inferior). A total of 400 older individuals (100 men and 300 women, aged 66-90 years) who were participants in the AGES-Reykjavik study, were studied. Participants had two QCT scans of the hip over a median follow-up of 5.1 yr. (mean baseline age 74 yr.). Changes in bone values during follow-up were estimated from mixed effects regression models. At baseline women had lower bone values in the superior region than men. At follow-up all bone values were lower in women, except cortical vBMD inferiorly. The relative losses in all bone values estimated in the superior region were substantially (about threefold) and significantly greater compared to those estimated in the inferior region in both sexes. Women lost cortical thickness and cortical vBMD more rapidly than men in both regions; and this was only weakly reflected in total femoral neck DXA-like results. The higher rate of bone loss in women at critical locations may contribute materially to the greater femoral neck fracture incidence among women than men. 23223023 Increase of palmitic acid concentration impairs endothelial progenitor cell and bone marrow-derived progenitor cell bioavailability: role of the STAT5/PPARγ transcriptional complex. Metabolic profiling of plasma nonesterified fatty acids discovered that palmitic acid (PA), a natural peroxisome proliferator-activated receptor γ (PPARγ) ligand, is a reliable type 2 diabetes biomarker. We investigated whether and how PA diabetic (d-PA) concentrations affected endothelial progenitor cell (EPC) and bone marrow-derived hematopoietic cell (BM-HC) biology. PA physiologic (n-PA) and d-PA concentrations were used. Proliferating cell nuclear antigen content and signal transducer and activator of transcription 5 (STAT5), PPARγ, cyclin D1, and p21(Waf) expression were evaluated. Small interfering RNA technology, gene reporter luciferase assay, electrophoretic mobility shift assay, chromatin immunoprecipitation assay, and coimmunoprecipitation were exploited. In vivo studies and migration assays were also performed. d-PA, unlike n-PA or physiological and diabetic oleic and stearic acid concentrations, impaired EPC migration and EPC/BM-HC proliferation through a PPARγ-mediated STAT5 transcription inhibition. This event did not prevent the formation of a STAT5/PPARγ transcriptional complex but was crucial for gene targeting, as p21(Waf) gene promoter, unlike cyclin D1, was the STAT5/PPARγ transcriptional target. Similar molecular events could be detected in EPCs isolated from type 2 diabetic patients. By expressing a constitutively activated STAT5 form, we demonstrated that STAT5 content is crucial for gene targeting and EPC fate. Finally, we also provide in vivo data that d-PA-mediated EPC dysfunction could be rescued by PPARγ blockade. These data provide first insights on how mechanistically d-PA drives EPC/BM-HC dysfunction in diabetes. 23420770 Potential Genotoxicity of Traditional Chinese Medicinal Plants and Phytochemicals: An Overview. In the last decades, cases of poisoning due to herbal medicines have occurred in many countries; Chinese herbal medicines (CHMs) are occasionally involved. The experience gained from traditional use is efficient to detect immediate or near-immediate relationship between administration and toxic effects but is quite unlikely to detect medium- to long-term toxicities; thorough investigations of herbal medicines (toxicity assessments, active pharmacovigilance) appear then essential for their safe use. Genotoxicity is an especially insidious toxicity that may result in carcinoma development years after exposure; it can arise from multiple compounds, with or without metabolic activation. The present work reviews traditional CHMs and phytochemicals that have been shown to present a genotoxic hazard. Copyright © 2013 John Wiley & Sons, Ltd. 23249181 Progress of pharmacological studies on alkaloids from Apocynaceae. Alkaloid was a kind of biological active ingredient. There were various types of alkaloids in Apocynaceae. This paper reviewed the progress on alkaloids from Apocynaceae, which contained origin, structure, and pharmacological activity. 23620162 Structural changes in supercooled Al2O3-Y2O3 liquids. Structural changes in liquids between Al2O3 and Y2O3 are investigated as a function of the composition and during supercooling using high energy X-ray diffraction (HEXRD) techniques combined with containerless aerodynamic levitation. Many-body molecular dynamics simulation techniques utilizing potential models that incorporate anion polarization effects are applied to study the same liquid systems. The X-ray scattering experiments indicate a change in liquid structure during supercooling around a composition 20% Y2O3 (AlY20) that occurs over a narrow temperature interval. We have associated this change in structure with the onset of a liquid-liquid phase transformation. Analysis of the MD simulated structures has allowed the structure changes to be interpreted in terms of Al(3+) and Y(3+) coordination environments and particularly the Y(3+)-Y(3+) structural correlations. We show that the incipient liquid-liquid phase transition behaviour is correlated with local density fluctuations that represent different coordination polyhedra surrounding oxygen ions. The difference in energy and volume associated with this sampling of high and low density basins in the underlying energy landscape is consistent with independent verifications of the volume and enthalpy differences between different amorphous forms. The differences in the high- and low-density configurations match the difference in diffraction patterns observed experimentally. 23044045 A temporary decrease in mineral density in perinatal mouse long bones. Fetal and postnatal bone development in humans is traditionally viewed as a process characterized by progressively increasing mineral density. Yet, a temporary decrease in mineral density has been described in the long bones of infants in the immediate postnatal period. The mechanism that underlies this phenomenon, as well as its causes and consequences, remain unclear. Using daily μCT scans of murine femora and tibiae during perinatal development, we show that a temporary decrease in tissue mineral density (TMD) is evident in mice. By monitoring spatial and temporal structural changes during normal growth and in a mouse strain in which osteoclasts are non-functional (Src-null), we show that endosteal bone resorption is the main cause for the perinatal decrease in TMD. Mechanical testing revealed that this temporary decrease is correlated with reduced stiffness of the bones. We also show, by administration of a progestational agent to pregnant mice, that the decrease in TMD is not the result of parturition itself. This study provides a comprehensive view of perinatal long bone development in mice, and describes the process as well as the consequences of density fluctuation during this period. 23561177 Effects of industrial processing on folate content in green vegetables. Folates are described to be sensitive to different physical parameters such as heat, light, pH and leaching. Most studies on folates degradation during processing or cooking treatments were carried out on model solutions or vegetables only with thermal treatments. Our aim was to identify which steps were involved in folates loss in industrial processing chains, and which mechanisms were underlying these losses. For this, the folates contents were monitored along an industrial canning chain of green beans and along an industrial freezing chain of spinach. Folates contents decreased significantly by 25% during the washing step for spinach in the freezing process, and by 30% in the green beans canning process after sterilisation, with 20% of the initial amount being transferred into the covering liquid. The main mechanism involved in folate loss during both canning green beans and freezing spinach was leaching. Limiting the contact between vegetables and water or using steaming seems to be an adequate measure to limit folates losses during processing. 22625411 Recent advances in medicinal chemistry of sulfonamides. Rational design as anti-tumoral, anti-bacterial and anti-inflammatory agents. Now-a-days, cancer is becoming one of the major problems of public health in the world. Pharmacology treatment is a way to increase quality and long life. Predominantly, in last decade sulfonamide derivatives have been described as potential carbonic anhydrase inhibitors. In the present work, we describe recent advances during the last decade in medicinal chemistry of sulfonamides derivatives with some examples of rational design as anti-tumoral, antibacterial and anti-inflammatory agents. We show strategy design, structure-activity relationship, biological activity and advances of new sulfonamide compounds that have more health significance than some clinically used sulfonamides. 23496349 Probing the Electronic Properties of W3Ox(-/0) (x = 0-2) and W3(2-) Clusters: The Aromaticity of W3 and W3(2-). Density functional theory (DFT) calculations are employed to investigate the structural and electronic properties of bare tritungsten clusters (W3, W3(-), W3(2-)) and tritungsten oxide clusters W3Ox(-/0) (x = 1, 2). Generalized Koopmans' theorem is applied to predict the vertical detachment energies and simulate the photoelectron spectra (PES) for W3Ox(-) (x = 0-2) clusters. Extensive DFT calculations are performed in search of the lowest energy structures for both the anions and the neutrals. The bare tritungsten clusters are predicted to be triangular structures with D3h ((3)A1'), C2v ((2)A1) and D3h ((1)A1') symmetry for W3, W3(-) and W3(2-), respectively. For W3O(-) and W3O clusters, the oxygen atom occupies the terminal site, while the next added oxygen atom is found to be a bridging one in both W3O2(-) and W3O2 clusters. Molecular orbital analyses are carried out to elucidate the chemical bonding of these clusters and provide insights into the sequential oxidation from W3(-) to W3O2(-). Partial σ- and δ-aromaticity are revealed in the neutral W3 (D3h, (3)A1'), while the anion W3(2-) (D3h, (1)A1') possesses only δ-aromaticity. 23606463 Regulation of Conjugated Hemoglobin on Micelles through Copolymer Chain Sequences and the Protein's Isoelectric Aggregation. Amphiphilic triblock copolymers with carbonyl groups located either in the middle segment or in the third side block are synthesized by adjusting feeding sequence of the comonomers. The conjugation of hemoglobin (Hb) on the copolymer micelles is realized by condensation reactions of carbonyl with the amino groups of Hb, and the gas-binding capacity of Hb is well preserved. Interestingly, the reassembly behavior of Hb-conjugated micelles (HbM) is explored by adjusting the pH. As for triblock copolymers with a carbonyl-functionalized segment as the third block, Hb is rearranged into the inner core of micelles when the pH is adjusted close to the isoelectric point of Hb. Therefore, it may provide a new needed route for fabrication of protein carriers, which is different from the traditional encapsulation technique. 23439131 Microfluidic synthesis of cell-type-specific artificial extracellular matrix hydrogels. Droplet microfluidic technology is applied for the high-throughput synthesis via Michael-type addition of reactive, micrometer-sized poly(ethylene glycol) (PEG) hydrogels ("microgels") with precisely controlled dimension and physicochemical properties. A versatile chemical scheme is used to modify the reactive PEG microgels with tethered biomolecules to tune their bioactive properties for the bioreactor culture and manipulation of various (stem) cell types. 23634899 Isotopic Spectra of the Hydroxyl Radical. Rotational spectra of OH and its isotopologues have been precisely measured using high efficiency Terahertz (THz) sources. The measurements are compared with existing data and are useful for global modeling. For the first time microwave measurements of the $\Lambda$-doubling transitions of $^{17}$OH isotopologue are combined with THz data successfully. Precise rotational, fine-structure and hyperfine structure parameters for the $^{17}$OH isotopologue are reported. An isotopically independent Dunham model for all isotopologues of $^2\Pi$ OH v $ < $ 3 is presented. 23448620 Multiple targeted drugs carrying biodegradable membrane barrier: anti-adhesion, hemostasis, and anti-infection. A multiple targeted drug carrying bilayer membrane for preventing an abdominal adhesion is prepared by electrospinning. Two bioactive drugs were successfully incorporated into this bilayer membrane and can be independently released from nanofibrous scaffolds without losing structural integrity and functionality of the anti-adhesion membrane. Besides, the drug release profile could be easily adjusted by optimizing the swelling behavior of the fibrous scaffold. The inner layer of the bilayered fibrous membranes loaded with carbazochrome sodium sulfonate (CA) showed an excellent vascular hemostatic efficacy and formed little clot during in vivo experiment. The outer layer loaded with tinidazole (TI) had outstanding antibacterial effect against the anaerobe. We believe this approach could serve as a model technique to guide the design of implants with drug delivery functions. 23488748 Molecular dynamics simulation of nanosized water droplet spreading in an electric field. Molecular dynamics (MD) simulations are performed for the spreading of a nanosized water droplet on a solid substrate subject to a parallel electric field. A combined electrostatic and Lennard-Jones potential is employed to represent the intermolecular interactions. Results show that in response to the applied field, polar water molecules realign themselves and this microscopic reorientation of molecular dipoles combines with the intermolecular forces to produce a macroscopic deformation of a free spherical water droplet into an ellipsoid. The applied field has a strong effect on the spreading of the water droplet on a solid substrate. For a weaker parallel field, the droplet spreading is asymmetric with the leading contact angle being greater than the trailing contact angle. With an increase in field strength, this asymmetry continues to increase, culminates, and then decreases until it disappears. The symmetric spreading remains with a further increase in the field strength until the saturation point is reached. This transition from the asymmetric to symmetric spreading is a manifestation of the interaction of the electric field with polar water molecules and the intermolecular forces within the droplet and between the water and solid; the interaction also leads to a change in hydrogen bonds along the droplet surface. The dynamics of the droplet spreading is entailed by the electrically induced motion of molecules along the liquid surface toward the solid substrate and is controlled by a competing mechanism among the electric, water-water, and water-solid intermolecular forces. 23292985 Structural aspects of gut peptides with therapeutic potential for type 2 diabetes. Gut hormones represent a niche subset of pharmacologically active agents that are rapidly gaining importance in medicine. Due to their exceptional specificity for their receptors, these hormones along with their analogues have attracted considerable pharmaceutical interest for the treatment of human disorders including type 2 diabetes. With the recent advances in the structural biology, a significant amount of structural information for these hormones is now available. This Minireview presents an overview of the structural aspects of these hormones, which have roles in physiological processes such as insulin secretion, as well as a discussion on the relevant structural modifications used to improve these hormones for the treatment of type 2 diabetes. 23444785 Incision wound healing activity of pine bark extract containing topical formulations: a study with histopathological and biochemical analyses in albino rats. The present study was designed to identify and compare the in vivo wound healing capacity of a bark extract from Pinus brutia and Pycnogenol in an incision wound model in rats. O/W cream formulations were prepared incorporating 2% Pycnogenol and P. brutia bark extract. The rats were divided into three groups (n = 8). Subsequently placebo and test formulations were applied to animals once a day from day "0" until the 9th day. Malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) were studied in addition to histopathological examinations. Treatment with F. brutia extract containing cream inhibited lipid peroxidation by a 35% decrease in MDA and 46.8% increase in SOD activity, whereas 19.3% decrease in MDA and 34.7% increase in SOD activity were attained with Pynogenol compared to control. The histological data revealed a better performance of P. brutia extract enriched formulation in terms of degeneration of hair roots, increased vascularization and a decrease in necrotic area. Consequently, a high wound healing activity was observed in animals treated with P. brutia extract significantly accelerating the wound healing process. 23019139 A comparative analysis of computational approaches to relative protein quantification using peptide peak intensities in label-free LC-MS proteomics experiments. Liquid chromatography coupled with mass spectrometry (LC-MS) is widely used to identify and quantify peptides in complex biological samples. In particular, label-free shotgun proteomics is highly effective for the identification of peptides and subsequently obtaining a global protein profile of a sample. As a result, this approach is widely used for discovery studies. Typically, the objective of these discovery studies is to identify proteins that are affected by some condition of interest (e.g. disease, exposure). However, for complex biological samples, label-free LC-MS proteomics experiments measure peptides and do not directly yield protein quantities. Thus, protein quantification must be inferred from one or more measured peptides. In recent years, many computational approaches to relative protein quantification of label-free LC-MS data have been published. In this review, we examine the most commonly employed quantification approaches to relative protein abundance from peak intensity values, evaluate their individual merits, and discuss challenges in the use of the various computational approaches. 23357627 Phosphonic analogues of glutamic acid as irreversible inhibitors of Staphylococcus aureus endoproteinase GluC: an efficient synthesis and inhibition of the human IgG degradation. Endoproteinase GluC (V8 protease) is one of many virulence factors released by the Staphylococcus aureus species in vivo. The V8 protease is able to hydrolyze some serpins and all classes of mammalian immunoglobulins. The application of specific and potent inhibitors of V8 protease may lead to the development of new antibacterial agents. Herein, we present the synthesis and the inhibitory properties of novel peptidyl derivatives of a phosphonic glutamic acid analogue. One of the compounds Boc-Phe-Leu-Glu(P)(OC(6)H(4))(2) displayed an apparent second-order inhibition rate value of 8540 M(-1)s(-1). The Boc-Phe-Leu-Glu(P)(OC(6)H(4))(2) compound with the highest inhibitory potency showed the ability to prevent V8-mediated human IgG proteolysis in vitro. 23454309 Food web analysis reveals effects of pH on mercury bioaccumulation at multiple trophic levels in streams. Biomagnification processes and the factors that govern them, including those for mercury (Hg), are poorly understood in streams. Total and methyl Hg concentrations and relative trophic position (using δ(15)N) were analyzed in biofilm and invertebrates from 21 streams in New Brunswick, Canada to assess food web biomagnification leading to the common minnow blacknose dace (Rhinichthys atratulus), a species known to have Hg concentrations that are higher in low pH waters. Biomagnification slopes within stream food webs measured using Hg vs. δ(15)N or corresponding trophic levels (TL) differed depending on the chemical species analyzed, with total Hg exhibiting increases of 1.3-2.5 per TL (mean slope of total Hg vs. δ(15)N=0.14±0.06 S.D., range=0.06-0.20) and methyl Hg showing a more pronounced increase of 2.8 to 6.0 per TL (mean slope of methyl Hg vs. δ(15)N=0.30±0.08 S.D., range=0.22-0.39). While Hg biomagnification slopes through the entire food web (Trophic Magnification Factors, TMFs) were not influenced by water chemistry (pH), dietary concentrations of methyl Hg strongly influenced biomagnification factors (BMFs) for consumer-diet pairs within the food web at lower trophic levels, and BMFs between dace and predatory invertebrates were significantly higher in low pH waters. These analyses, coupled with observations of higher Hg in primary producers in streams with low pH, suggest that pH influences both baseline concentrations and biomagnification of Hg in these systems. Because higher Hg concentrations in the diets of primary consumers and predatory insects in lower pH waters led to lower BMFs, these feeding groups showed insignificant relationships between Hg and pH; thus, altered BMFs associated with dietary concentrations can dampen the effects of environmental conditions on Hg concentrations. 22859660 Effects of fenofibrate, a PPAR-α ligand, on the haemodynamics of glycerol-induced renal failure in rats. The modulating effect of peroxisome proliferator-activated receptor α ligand on haemodynamic effects of phenylepherine (PE), angiotensin II (AII), endothelin 1 (ET1), acetylcholine (Ach), sodium nitroprusside (SNP) and isoproterenol (ISO) were evaluated in glycerol-induced acute kidney injury in rats. The effect of PE on fenofibrate-treated animals was a dose-dependent increase in mean arterial blood pressure (MAP). For AII and ET1, MAP was also increased for the fenofibrate group but not in a dose-dependent fashion. On the medullary blood flow (MBF), while the lower doses of PE and AII increased the perfusion unit on the fenofibrate-treated group, the higher doses decreased the perfusion unit. The ET1 increased the perfusion unit on this group but not in dose-dependent fashion. The effects of PE and AII on the cortical blood flow (CBF) of fenofibrate-treated group is similar to that of MBF for the same group but not for ET1. The effect of Ach, SNP and ISO in all the groups was the decrease in MAP. ISO caused dose-dependent increase in MBF of fenofibrate-treated group. The effect of Ach, SNP and ISO on the CBF perfusion unit was that of the increase for the fenofibrate-treated group. The study showed that fenofibrate did not attenuate increased blood pressure induced by PE, AII and ET1 but caused enhanced vasodilation by Ach, SNP and ISO. 23333093 Green tea catechin leads to global improvement among Alzheimer's disease-related phenotypes in NSE/hAPP-C105 Tg mice. Amyloid β (Αβ) has been reported to be responsible for the functional and structural abnormalities of Alzheimer's disease (AD) through the induction of oxidative stress. The aim of this study was to determine whether or not treatment of transgenic (Tg) mice with green tea catechin (GTC), a radical scavenger, improves AD phenotypes. To test this, 7-month-old Tg mice were treated with a low (1 mg) or high (10 mg) dose of GTC for 6 months. Surprisingly, GTC-treated Tg mice exhibited significant decreases in behavioral impairment, Aβ-42 production, APP-C99/89 expression, γ-secretase component and Wnt protein levels, γ-secretase activity and MAPK activation. In contrast, the levels of APP-C83 protein and enzyme activities (α-secretase, neprilysin and Pin1) were elevated in the GTC-treated groups. Moreover, GTC-treated groups showed lower levels of total cholesterol and low-density lipoprotein cholesterol, whereas the level of high-density lipoprotein cholesterol increased. These results provide the first experimental evidence that GTC improves AD phenotypes, thereby suggesting that GTC can be used in the prevention of AD or treatment of AD patients. 23625779 Mesoporous Silica Nanoparticles Act as a Self-Adjuvant for Ovalbumin Model Antigen in Mice. Immunization to the model protein antigen ovalbumin (OVA) is investigated using MCM-41 mesoporous silica nanoparticles as a novel vaccine delivery vehicle and adjuvant system in mice. The effects of amino surface functionalization and adsorption time on OVA adsorption to nanoparticles are assessed. Amino-functionalized MCM-41 (AM-41) shows an effect on the amount of OVA binding, with 2.5-fold increase in binding capacity (72 mg OVA/g AM-41) compared to nonfunctionalized MCM-41 (29 mg OVA/g MCM-41). Immunization studies in mice with a 10 μg dose of OVA adsorbed to AM-41 elicits both antibody and cell-mediated immune responses following three subcutaneous injections. Immunizations at a lower 2 μg dose of OVA adsorbed to AM-41 particles results in an antibody response but not cell-mediated immunity. The level of antibody responses following immunization with nanoformulations containing either 2 μg or 10 μg of OVA are only slightly lower than that in mice which receive 50 μg OVA adjuvanted with QuilA, a crude mixture of saponins extracted from the bark of the Quillaja saponaria Molina tree. This is a significant result, since it demonstrates that AM-41 nanoparticles are self-adjuvanting and elicit immune responses at reduced antigen doses in vivo compared to a conventional delivery system. Importantly, there are no local or systemic negative effects in animals injected with AM-41. Histopathological studies of a range of tissue organs show no changes in histopathology of the animals receiving nanoparticles over a six week period. These results establish the biocompatible MCM-41 silica nanoparticles as a new method for vaccine delivery which incorporates a self-adjuvant effect. 23464520 Microvascular complications and diabetic retinopathy: recent advances and future implications. Retinal microvascular alterations have been observed during diabetic retinopathy (DR) due to the retinal susceptibility towards subtle pathological alterations. Therefore, retinal microvascular pathology is essential to understand the nature of retinal degenerations during DR. In this review, the role of retinal microvasculature complications during progression of DR, along with recent efforts to normalize such alterations for better therapeutic outcome, will be underlined. In addition, current therapeutics and future directions for advancement of standard treatment for DR patients will be discussed. 23179351 Changes of the serum cytokine contents in broilers fed on diets supplemented with nickel chloride. Cytokines are immunoregulatory proteins which play an important role in the immune system. The purpose of this study was to examine the serum cytokine contents including interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), interferon gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α) induced by dietary nickel chloride in broilers by enzyme-linked immunospecific assay. A total of 240 one-day-old avian broilers were divided into four groups and fed on a corn-soybean basal diet as control diet or the same basal diet supplemented with 300, 600, and 900 mg/kg of nickel chloride. During the experimental period of 42 days, the results showed that the serum IL-2, IL-4, IL-6, IL-10, IFN-γ and TNF-α contents were lower (p < 0.05 or p < 0.01) in the 300, 600, 900 mg/kg groups than those in the control group. It was concluded that dietary nickel chloride in the range of 300 to 900 mg/kg could reduce the serum cytokine contents, which could finally impact the immune function in broilers. 23155052 Matrix metalloproteinase-1-mediated up-regulation of vascular endothelial growth factor-2 in endothelial cells. Matrix metalloproteinase-1 (MMP-1) is a collagenase that is highly active in extracellular matrix and vascular remodeling, angiogenesis, and tumor progression. Vascular endothelial growth factor receptor-2 (VEGFR2), the main receptor for VEGF-A, is expressed on endothelial cells and promotes cell survival, proliferation, and other functions. Although MMP-1 and VEGFR2 co-exist in many normal and pathophysiological conditions, the effect of MMP-1 on cellular VEGFR2 that can promote the above processes is unknown. In this study we test the hypothesis that stimulation of endothelial cells with MMP-1 increases their levels of VEGFR2. The increased VEGFR2 is then available to bind VEGF-A, resulting in increased response. Indeed we found that endothelial cells incubated with active MMP-1 had higher mRNA and protein levels of VEGFR2. Furthermore, VEGF-A-dependent phosphorylation of intracellular signaling molecules and endothelial proliferation were elevated after MMP-1 treatment. MMP-1 caused activation of the nuclear factor-κB (NF-κB) pathway (p65/RelA) in endothelial cells, and this response was dependent upon activation of protease activated receptor-1 (PAR-1). Chromatin immunoprecipitation was used to confirm NF-κB-mediated active transcription of the VEGFR2 (KDR) gene. Elevation in VEGFR2 after MMP-1 stimulation was inhibited by PAR-1 knockdown and NF-κB specific inhibition. We conclude that MMP-1 promotes VEGFR2 expression and proliferation of endothelial cells through stimulation of PAR-1 and activation of NF-κB. These results suggest a mechanism by which MMP-1 may prime or sensitize endothelial cell functions. 23535821 Global increases in both common and rare copy number load associated with autism. Children with autism have an elevated frequency of large, rare copy number variants (CNVs). However, the global load of deletions or duplications, per se, and their size, location and relationship to clinical manifestations of autism have not been documented. We examined CNV data from 516 individuals with autism or typical development from the population-based Childhood Autism Risks from Genetics and Environment (CHARGE) study. We interrogated 120 regions flanked by segmental duplications (genomic hotspots) for events >50 kbp and the entire genomic backbone for variants >300 kbp using a custom targeted DNA microarray. This analysis was complemented by a separate study of five highly dynamic hotspots associated with autism or developmental delay syndromes, using a finely tiled array platform (>1 kbp) in 142 children matched for gender and ethnicity. In both studies, a significant increase in the number of base pairs of duplication, but not deletion, was associated with autism. Significantly elevated levels of CNV load remained after the removal of rare and likely pathogenic events. Further, the entire CNV load detected with the finely tiled array was contributed by common variants. The impact of this variation was assessed by examining the correlation of clinical outcomes with CNV load. The level of personal and social skills, measured by Vineland Adaptive Behavior Scales, negatively correlated (Spearman's r = -0.13, P = 0.034) with the duplication CNV load for the affected children; the strongest association was found for communication (P = 0.048) and socialization (P = 0.022) scores. We propose that CNV load, predominantly increased genomic base pairs of duplication, predisposes to autism. 23295740 Tamoxifen represses miR-200 microRNAs and promotes epithelial-to-mesenchymal transition by up-regulating c-Myc in endometrial carcinoma cell lines. Although tamoxifen (TAM), a selective estrogen receptor modulator, has been widely used in the treatment of hormone-responsive breast cancer, its estrogen-like effect increases the risk of endometrial cancer. However, the molecular mechanisms of TAM-induced endometrial carcinoma still remain unclear. In this report, we explored the role of microRNAs (miRNAs) in TAM-induced epithelial-mesenchymal transition (EMT) in ECC-1 and Ishikawa endometrial cancer cell lines and found miR-200 is involved in this process via the regulation of c-Myc. When treated with TAM, ECC-1 and Ishikawa cells were characterized by higher invasiveness and motility and underwent EMT. miR-200, a miRNA family with tumor suppressive functions in a wide range of cancers, was found reduced in response to TAM treatment. Consistent with zinc finger E-box binding homeobox 2, which was confirmed as a direct target of miR-200b in endometrial cancer cell lines, some other key factors of EMT such as Snail and N-cadherin increased, whereas E-cadherin decreased in the TAM-treated cells, contributing to TAM-induced EMT in these endometrial cancer cells. In addition, we showed that c-Myc directly binds to and represses the promoter of miR-200 miRNAs, and its up-regulation in TAM-treated endometrial cancer cells leads to the down-regulation of miR-200 and eventually to EMT. Collectively, our data suggest that TAM can repress the miR-200 family and induce EMT via the up-regulation of c-Myc in endometrial cancer cells. These findings describe a possible mechanism of TAM-induced EMT in endometrial cancer and provide a potential new therapeutic strategy for it. 23413033 Fine-tuning of Voltage Sensitivity of the Kv1.2 Potassium Channel by Interhelix Loop Dynamics. Many proteins function by changing conformation in response to ligand binding or changes in other factors in their environment. Any change in the sequence of a protein, for example during evolution, which alters the relative free energies of the different functional conformations changes the conditions under which the protein will function. Voltage-gated ion channels are membrane proteins that open and close an ion-selective pore in response to changes in transmembrane voltage. The charged S4 transmembrane helix transduces changes in transmembrane voltage into a change in protein internal energy by interacting with the rest of the channel protein through a combination of non-covalent interactions between adjacent helices and covalent interactions along the peptide backbone. However, the structural basis for the wide variation in the V50 value between different voltage-gated potassium channels is not well defined. To test the role of the loop linking the S3 helix and the S4 helix in voltage sensitivity, we have constructed a set of mutants of the rat Kv1.2 channel that vary solely in the length and composition of the extracellular loop that connects S4 to S3. We evaluated the effect of these different loop substitutions on the voltage sensitivity of the channel and compared these experimental results with molecular dynamics simulations of the loop structures. Here, we show that this loop has a significant role in setting the precise V50 of activation in Kv1 family channels. 23200246 Anti-inflammatory norditerpenoids from the soft coral Sinularia maxima. Chemical investigation of the soft coral Sinularia maxima resulted in the isolation of seven norditerpenoids, including two new compounds, 12-hydroxy-scabrolide A (2) and 13-epi-scabrolide C (6). The structures of the isolated compounds were elucidated based on extensive spectroscopic evidence including Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS) and both one- and two-dimensional nuclear magnetic resonance (1D and 2D NMR, respectively), in comparison with reported data. Compound 6 potently inhibited IL-12 and IL-6 production in LPS-stimulated bone marrow derived dendritic (BMDCs) with IC(50) values of 5.30 ± 0.21 and 13.12 ± 0.64 μM, respectively. Compound 1 exhibited moderate inhibitory activity against IL-12 and IL-6 production with IC(50) values of 23.52 ± 1.37 and 69.85 ± 4.11 μM, respectively. 23514620 Hyaluronic Acid nanoparticles titrate the viscoelastic properties of viscosupplements. Hyaluronic acid (HA) is a glycosaminoglycan with diverse biomedical applications including viscosupplementation of synovial fluid for the treatment osteoarthritis. Current HA viscosupplements such as Synvisc, Orthovisc, and Hyalgan have shown positive effects of reducing pain and improving joint function. The therapeutic efficacy, however, is highly transient, and these viscous fluids suffer from poor injectability. HA nanoparticles were found to modify the rheological properties of a model of the HA viscosupplement Orthovisc. Nanoparticles were successfully synthesized from 17 and 1500 kDa HA. Nanoparticle suspensions of HA were studied at different concentrations and in blends with the model viscosupplement. Nanoparticles made from 1500 kDa HA reduced the viscosupplement viscosity and elasticity to a much greater degree than nanoparticles made from 17 kDa HA. The difference in the nanoparticle effect on viscoelasticity suggested that nanoparticles made from 17 kDa HA may have dangling surface polymers that facilitated interactions with HA in solution. This hypothesis was supported by the greater compressibility of 17 kDa nanoparticles as determined by ultrasonic vibrational spectroscopy. Rheological investigations showed that the viscoelasticity of viscosupplements could be discretely titrated by modulating the concentration and type of HA nanoparticle additive (hard sphere or hairy). Thus, the injectability of viscosupplements may be enhanced while maintaining high elasticity. 22824788 Telomere shortening and DNA damage of embryonic stem cells induced by cigarette smoke. Embryonic stem cells (ESCs) provide a valuable in vitro model for testing toxicity of chemicals and environmental contaminants including cigarette smoke. Mouse ESCs were acutely or chronically exposed to smoke components, cigarette smoke condensate (CSC), or cadmium, an abundant component of CSC, and then evaluated for their self-renewal, apoptosis, DNA damage and telomere function. Acute exposure of ESCs to high dose of CSC or cadmium increased DNA damage and apoptosis. Yet, ESCs exhibited a remarkable capacity to recover following absence of exposure. Chronic exposure of ESCs to low dose of CSC or cadmium resulted in shorter telomeres and DNA damage. Together, acute exposure of ESCs to CSC or cadmium causes immediate cell death and reduces pluripotency, while chronic exposure of ESCs to CSC or cadmium leads to DNA damage and telomere shortening. Notably, a sub-proportion of ESCs during passages is selected to resist to smoke-induced oxidative damage to telomeres. 23330984 Development of a natural products database from the biodiversity of Brazil. We describe herein the design and development of an innovative tool called the NuBBE database (NuBBEDB), a new Web-based database, which incorporates several classes of secondary metabolites and derivatives from the biodiversity of Brazil. This natural product database incorporates botanical, chemical, pharmacological, and toxicological compound information. The NuBBEDB provides specialized information to the worldwide scientific community and can serve as a useful tool for studies on the multidisciplinary interfaces related to chemistry and biology, including virtual screening, dereplication, metabolomics, and medicinal chemistry. The NuBBEDB site is at http://nubbe.iq.unesp.br/nubbeDB.html . 23546601 Estrogen Receptor-α Variant, ER-α36, is Involved in Tamoxifen Resistance and Estrogen Hypersensitivity. Antiestrogens such as tamoxifen provided a successful treatment for ER-positive breast cancer for the past two decades. However, most breast tumors are eventually resistant to tamoxifen therapy. The molecular mechanisms underlying tamoxifen resistance have not been well established. Recently, we reported that breast cancer patients with tumors expressing high concentrations of ER-α36, a variant of ER-α, benefited less from tamoxifen therapy than those with low concentrations of ER-α36, suggesting that increased ER-α36 concentration is one of the underlying mechanisms of tamoxifen resistance. Here, we investigated the function and underlying mechanism of ER-α36 in tamoxifen resistance. We found that tamoxifen increased ER-α36 concentrations and tamoxifen-resistant MCF7 cells expressed high concentrations of ER-α36. In addition, MCF7 cells with forced expression of recombinant ER-α36 and H3396 cells expressing high concentrations of endogenous ER-α36 were resistant to tamoxifen. ER-α36 downregulation in tamoxifen-resistant cells with the shRNA method restored tamoxifen sensitivity. We also found tamoxifen acted as a potent agonist by activating phosphorylation of the AKT kinase in ER-α36 expressing cells. Finally, we found that cells with high concentration of ER-α36 protein were hypersensitive to estrogen; activating ERK phosphorylation at pM range. Our results thus demonstrated that elevated ER-α36 concentration is one of the mechanisms by which ER-positive breast cancer cells escape tamoxifen therapy and provided a rational to develop novel therapeutic approaches for tamoxifen resistant patients by targeting ER-α36. 23361914 [(3)H]UR-PLN196: a selective nonpeptide radioligand and insurmountable antagonist for the neuropeptide Y Y(2) receptor. Radioing in on NPY: Attachment of a [2,3-(3)H]propionyl group through an appropriate linker to the guanidine group of an (S)-argininamide-type neuropeptide Y (NPY) Y(2) receptor antagonist resulted in a subtype-selective radioligand. 23228193 A new antibacterial phenanthrenequinone from Dendrobium sinense. A new phenanthrenequinone, named denbinobin B (1), together with three known phenanthrenes was isolated from the whole plant of Dendrobium sinense T. Tang et F.T. Wang, an endemic and endangered orchid to Hainan Island. The new compound was elucidated using a combination of 1D, 2D NMR (COSY, HMQC, and HMBC) techniques, and HR-ESI-MS analyses. Compound 1 exhibited moderate antibacterial activity against Staphylococcus aureus with the diameter of the inhibition zone of 16.5 mm. 23160003 Biomimetic diversity-oriented synthesis of benzannulated medium rings via ring expansion. Nature has exploited medium-sized 8- to 11-membered rings in a variety of natural products to address diverse and challenging biological targets. However, owing to the limitations of conventional cyclization-based approaches to medium-ring synthesis, these structures remain severely underrepresented in current probe and drug discovery efforts. To address this problem, we have established an alternative, biomimetic ring expansion approach to the diversity-oriented synthesis of medium-ring libraries. Oxidative dearomatization of bicyclic phenols affords polycyclic cyclohexadienones that undergo efficient ring expansion to form benzannulated medium-ring scaffolds found in natural products. The ring expansion reaction can be induced using three complementary reagents that avoid competing dienone-phenol rearrangements and is driven by rearomatization of a phenol ring adjacent to the scissile bond. Cheminformatic analysis of the resulting first-generation library confirms that these molecules occupy chemical space overlapping with medium-ring natural products and distinct from that of synthetic drugs and drug-like libraries. 23265456 Fast HPLC-DAD quantification of nine polyphenols in honey by using second-order calibration method based on trilinear decomposition algorithm. This paper describes the use of second-order calibration for development of HPLC-DAD method to quantify nine polyphenols in five kinds of honey samples. The sample treatment procedure was simplified effectively relative to the traditional ways. Baselines drift was also overcome by means of regarding the drift as additional factor(s) as well as the analytes of interest in the mathematical model. The contents of polyphenols obtained by the alternating trilinear decomposition (ATLD) method have been successfully used to distinguish different types of honey. This method shows good linearity (r>0.99), rapidity (t<7.60 min) and accuracy, which may be extremely promising as an excellent routine strategy for identification and quantification of polyphenols in the complex matrices. 23439241 pH-gradient PAMPA-based in vitro model assay for drug-induced phospholipidosis in early stage of drug discovery. In the present study we validated a widely used, high-throughput in vitro permeability model (PAMPA) to be used at the early stage of drug discovery for the phospholipidosis (PLD) prediction of drug-like compounds. Regarding the mechanism of action of PLD, our pH-gradient PAMPA system is the first noncell based model to mimic one-way transport of cationic amphiphilic drugs (CADs) from cytosol to the lysosome. Moreover, due to the fact that PLD can mainly occur in lung, liver, brain, kidney and heart, we have used similar commercially available original tissue-derived lipid fractions (heart, liver, brain), and in the case mimicking membrane of kidney and lung tissue we prepared tissue-mimetic artificial lipid mixtures in house. Metabolism of a drug can change the degree of PLD depending on the physicochemical properties of metabolites and the rate of metabolism. Our data from 57 drugs and 4 metabolites of earlier and 2 metabolites of newly recognized outliers (phenacetin and bupropion) using our pH-gradient PAMPA system show a good correlation with in vivo PLD data. Moreover, predictive ability of our best system, the lung specific pH-gradient PAMPA model was significantly better than widely used in silico models and it was also slightly better than that of the known noncell based models on our selection of compounds. Our pH-gradient PAMPA systems therefore offer mechanistically alternative, accurate and cost-effective screening tools for the early prediction of PLD potential of drug-like compounds. 23558950 E2f2 induces cone photoreceptor apoptosis independent of E2f1 and E2f3. The 'activating' E2fs (E2f1-3) are transcription factors that potently induce quiescent cells to divide. Work on cultured fibroblasts suggested they were essential for division, but in vivo analysis in the developing retina and other tissues disproved this notion. The retina, therefore, is an ideal location to assess other in vivo adenovirus E2 promoter binding factor (E2f) functions. It is thought that E2f1 directly induces apoptosis, whereas other activating E2fs only induce death indirectly by upregulating E2f1 expression. Indeed, mouse retinoblastoma (Rb)-null retinal neuron death requires E2f1, but not E2f2 or E2f3. However, we report an entirely distinct mechanism in dying cone photoreceptors. These neurons survive Rb loss, but undergo apoptosis in the cancer-prone retina lacking both Rb and its relative p107. We show that while E2f1 killed Rb/p107 null rod, bipolar and ganglion neurons, E2f2 was required and sufficient for cone death, independent of E2f1 and E2f3. Moreover, whereas E2f1-dependent apoptosis was p53 and p73-independent, E2f2 caused p53-dependent cone death. Our in vivo analysis of cone photoreceptors provides unequivocal proof that E2f-induces apoptosis independent of E2f1, and reveals distinct E2f1- and E2f2-activated death pathways in response to a single tumorigenic insult.Cell Death and Differentiation advance online publication, 5 April 2013; doi:10.1038/cdd.2013.24. 23396442 Structural and mechanical properties of individual human telomeric G-quadruplexes in molecularly crowded solutions. Recent experiments provided controversial observations that either parallel or non-parallel G-quadruplex exists in molecularly crowded buffers that mimic cellular environment. Here, we used laser tweezers to mechanically unfold structures in a human telomeric DNA fragment, 5'-(TTAGGG)4TTA, along three different trajectories. After the end-to-end distance of each unfolding geometry was measured, it was compared with PDB structures to identify the best-matching G-quadruplex conformation. This method is well-suited to identify biomolecular structures in complex settings not amenable to conventional approaches, such as in a solution with mixed species or at physiologically significant concentrations. With this approach, we found that parallel G-quadruplex coexists with non-parallel species (1:1 ratio) in crowded buffers with dehydrating cosolutes [40% w/v dimethyl sulfoxide (DMSO) or acetonitrile (ACN)]. In crowded solutions with steric cosolutes [40% w/v bovine serum albumin (BSA)], the parallel G-quadruplex constitutes only 10% of the population. This difference unequivocally supports the notion that dehydration promotes the formation of parallel G-quadruplexes. Compared with DNA hairpins that have decreased unfolding forces in crowded (9 pN) versus diluted (15 pN) buffers, those of G-quadruplexes remain the same (20 pN). Such a result implies that in a cellular environment, DNA G-quadruplexes, instead of hairpins, can stop DNA/RNA polymerases with stall forces often <20 pN. 22677475 Effect of tetrabrombisphenol A on induction of apoptosis in the testes and changes in expression of selected testicular genes in CD1 mice. Tetrabromobisphenol A (TBBPA) is a substance widely used in industry as a flame retardant. TBBPA was found in the environment and was detected even in the human body. The effect of this chemical was observed in different cell lines in vitro and it is supposed that TBBPA may affect various hormonal systems in vivo. In this study we examined the effect of TBBPA on the reproductive parameters of two generations of outbred mice in vivo. Experimental and control animals of F1 generation were bred in various conditions to enable evaluation of the possible trans-generational effect. An increased incidence of apoptosis in the testes and changes in the morphometry of seminiferous tubules was detected in the experimental animals. In addition, changes in the expression pattern of selected genes encoding proteins that play an important role during spermatogenesis were observed. In contrast, sperm quality and reproduction were not affected by TBBPA. 23590386 Fibrillar Morphology of Derivatives of Poly(3-alkylthiophene)s by Solvent Vapor Annealing: Effects of Conformational Transition and Conjugate Length. A fibrillar morphology was obtained, compared to the featherless pristine films, via solvent annealing the films of a series of derivatives of poly(3-alkylthiophene)s (P3ATs): poly(3-dodecylthiophene) (P3DDT), poly(3,3‴-didodecyl-quaterthiophene) (PQT12), and poly(2,5-bis(3-dodecylthiophen-2-yl)thieno[3,2-b]thiophene) (pBTTT12). Among the solvents used, including dichloromethane, chloroform, tetrahydrofuran, and carbon disulfide (CS2), CS2 was the best to induce fibril formation because its solubility parameter is closest to those of the P3AT derivatives. It was found that higher critical CS2 vapor pressures were needed to form crystal nuclei with increasing conjugation length and molecular weight of the P3AT derivatives; i.e., the critical vapor pressures for P3DDT 13.9k and PQT12 15.5k were 59.0% and 80.7%, respectively, and there were no nuclei of fibrils for pBTTT12 15.6k with the highest conjugation length, even at a CS2 vapor pressure of 98.3%. Meanwhile, at the highest vapor pressure, the fibril density decreased with increasing conjugation length and molecular weight of the P3AT derivatives. This is attributed to the rod-like conformation prevailing for polymers with larger conjugation length and higher molecular weight during solvent annealing, making the conformational transition toward coils more difficult and hindering diffusion of molecules. The results presented here are expected to be helpful for the design and processing of conjugated semiconductor polymers. 22628017 Direct Effects of Vaccinium myrtillus L. Fruit Extracts on Rat Heart Mitochondrial Functions. In this study, the direct influence of bilberry (Vaccinium myrtillus) fruit extracts (aqueous and ethanolic) rich in anthocyanins on the oxidative phosphorylation of isolated rat heart mitochondria was investigated in vitro. Higher concentrations of bilberry extracts concentration-dependently inhibited mitochondrial state 3 respiration (by 23%-61%) with pyruvate plus malate, mildly (by 1.2- to 1.3-fold) uncoupled the oxidative phosphorylation, and increased (by 30%-87%) the state 4 respiration rate in the presence of exogenous cytochrome c. Succinate oxidation was less affected. Pure anthocyanins, the main components of used extracts, malvidin-3-glucoside, malvidin-3-galactoside, and cyanidin-3-galactoside, had no effect on oxidation of pyruvate plus malate. A statistically significant decrease in H2 O2 production by mitochondria was found in the presence of bilberry fruit extracts. Our findings show that bilberry fruit anthocyanin-rich extracts possess direct effects on rat heart mitochondrial function in vitro. These findings give the first insights into the mechanism(s) of their action on cellular energy metabolism. Copyright © 2012 John Wiley & Sons, Ltd. 23355287 Electrospun TiO2 nanorods with carbon nanotubes for efficient electron collection in dye-sensitized solar cells. A high power conversion efficiency of 10.24% can be obtained in a dye-sensitized solar cell by incorporating multiwall carbon nanotubes inside a TiO2 nanorod photoanode. The multiwall carbon nanotubes in the nanorod can effectively collect and transport photogenerated electrons reducing the recombination as well as improving efficiency of the device. 23500768 Astaxanthin ameliorates lung fibrosis in vivo and in vitro by preventing transdifferentiation, inhibiting proliferation, and promoting apoptosis of activated cells. Astaxanthin, a member of the carotenoid family, is the only known ketocarotenoid transported into the brain by transcytosis through the blood-brain barrier. However, whether astaxanthin has antifibrotic functions is unknown. In this study, we investigated the effects of astaxanthin on transforming growth factor β1-mediated and bleomycin-induced pulmonary fibrosis in vitro and in vivo. The results showed that astaxanthin significantly improved the structure of the alveoli and alleviated collagen deposition in vivo. Compared with the control group, the astaxanthin-treated groups exhibited downregulated protein expressions of α-smooth muscle actin, vimentin, hydroxyproline, and B cell lymphoma/leukemia-2 as well as upregulated protein expressions of E-cadherin and p53 in vitro and in vivo. Astaxanthin also inhibited the proliferation of activated A549 and MRC-5 cells at median inhibitory concentrations of 40 and 30μM, respectively. In conclusion, astaxanthin could relieve the symptoms and halt the progression of pulmonary fibrosis, partly by preventing transdifferentiation, inhibiting proliferation, and promoting apoptosis of activated cells. 23474323 Evaluation of some selected blood parameters and histopathology of liver and kidney of rats fed protein-substituted mucuna flour and derived protein rich product. This comparative study reports the nutritional and toxicological characteristics of Mucuna pruriens flour and a protein-rich product developed from it. The protein-rich mucuna product (PRMP) was obtained by the three steps procedure: protein solubilization, heat-coagulation and sieving. Three weeks rats (n=6 per group) were fed for 28days on standard protein-substituted rat feed with mucuna flour or PRMP. The experimental design was a factorial design with three mucuna accessions (Velvet, Black and White) and two treatments (flour and PRMP). The protein content ranged 27.2-31.5g/100g for flour and 58.8-61.1% for PRMP. Processing flour into PRMP led to a significant (p<0.05) reduction of tannins (50%), total polyphenols (50%) and trypsin inhibitors (94%). The rats fed PMRP diets witnessed weight gain similar to casein, while those fed mucuna flour lost weight. The levels of total cholesterol, HDL-cholesterol and LDL-cholesterol observed in animals groups fed mucuna flour and PRMP were significantly lower (p<0.05) than the control group. In addition lymphocytes, granulocytes, red blood cells, hemoglobin and hematocrit of rats fed mucuna flour were significantly (p<0.05) lower than values in other rats groups. Kidneys glomerular sclerosis and high creatinine levels were observed in group fed mucuna flour. PRMP then represents a good alternative of using mucuna proteins for human nutrition. 23023024 The effects of α-tocopherol on oxidative damage and serum levels of Clara cell protein 16 in aspiration pneumonitis induced by bile acids. Our aim in this study is to examine the effects of α-tocopherol (AT) on rats with aspiration pneumonitis induced with bile acids (BAs). The animals were divided in to four groups, namely saline group (n = 7), saline + AT group (n = 7), BA group (n = 7), and BA + AT group (n = 7). Saline and BA groups aspirated intratracheally with 1 ml/kg saline and 1 ml/kg bile acids, respectively. AT was given at 20 mg/kg/day dosage for 7 days to the groups. AT group was given 20 mg/kg/day AT for 7 days. Malondialdehyde (MDA), Clara cell protein 16 (CC-16), catalase (CAT), superoxide dismutase (SOD), as well as peribronchial inflammatory cell infiltration, alveolar septal infiltration, alveolar edema, alveolar exudate, alveolar histiocytes, and necrosis were evaluated. The CAT activity of the BA group was significantly lower than the saline group. In the BA + AT group, there was a significant increase in SOD and CAT activities when compared with that of the BA group. The CC-16 and MDA contents in the BA group were significantly higher than in the saline group. The CC-16 and MDA levels of the BA + AT group were significantly lower than BA group. Histopathologic changes were seen in BA group, and there was a significant decrease in the BA + AT group. In conclusion, AT might be beneficial in the treatment of aspiration pneumonitis induced by BAs because AT decreased oxidative damage and resulted in a decrease in CC-16 levels. 23237305 Influence of glass scaffolds macroporosity on the bioactive process. Little is known about the ideal morphology for three-dimensional (3D) porous scaffolds to be used in bone tissue engineering. The present study will supply useful data about the dependence of the mineralization process upon macroporous features of bioactive glass scaffolds. It also points out the difficulty in distinguishing between the bioactive properties of scaffolds if using common characterization techniques often considered as standard techniques to assess in vitro bioactivity. Here, two bioactive glass foams with different porosities (porous diameters and interconnection sizes) were successfully synthesized by varying the surfactant quantity in the sol-gel foaming process. The two foams had porosities apparently sufficient to serve as a bone tissue engineering scaffold and exhibited no significant difference when studied for the releasing or the taking up of ionic species when immersed in simulated body fluid (SBF). However, thanks to microion beam analysis, it was possible to highlight key differences in the mineralization reaction taking place at the surface of the pores. It is clearly evident that the homogeneity of reaction inside the 3D-scaffolds is particularly dependent upon porosity. In particular, it is demonstrated that inadequate porous features can result in limited circulation of the fluid inside the pores. Careful attention must be paid to the pore size distribution and interconnection sizes when designing scaffolds for bone tissue engineering, in order to induce homogeneous mineralization inside the porous material and for the scaffold to be efficiently alimented with nutrients or growth factors while allowing a free circulation of the bone cells. 23178178 Subtle alterations in swimming speed distributions of rainbow trout exposed to titanium dioxide nanoparticles are associated with gill rather than brain injury. The effects of engineered nanomaterials on fish behaviours are poorly understood. The present study aimed to determine the locomotor behaviours of trout during waterborne exposure to titanium dioxide nanoparticles (TiO(2) NPs) as well as inform on the underlying physiological mechanisms involved. Trout were exposed to either control (without TiO(2)), 1 mg l(-1) TiO(2) NPs or 1 mg l(-1) bulk TiO(2) for 14 days. Titanium dioxide exposure resulted in 31 (bulk) and 22 fold (nano) increases in the Ti concentrations of gill tissue compared to controls, but there were no measurable increases of Ti in the internal organs including the brain. Gill pathologies were observed in both TiO(2) treatments. Locomotor behaviours were quantified using video tracking software and the proportion of time spent swimming at high speed (>20 cms(-1)) was significantly decreased in fish exposed to TiO(2) NPs, compared to controls, but not fish exposed to bulk TiO(2). The shift in swimming speed distribution in the TiO(2) NP-exposed fish was associated with decreased area of red pulp in the spleen, increases in haematocrit and whole blood haemoglobin, all consistent with a compensation for respiratory hypoxia without the accumulation of plasma lactate. Fish exposed to TiO(2) NPs also retained competitive abilities when paired with controls in aggressive social encounters. The duration of competitive contests, the level of aggression and contest outcome were not affected by NP exposure. Neurological injury did not explain the changes in locomotor behaviour, although there was some apparent enlargement of the blood vessels on the brain. Whole brain homogenates showed a statistically significant increase in oxidative stress defences such as the total glutathione pool, but without loss of Na(+)K(+)-ATPase or acetylcholinesterase activities. 23238352 New insight into the ZnO sulfidation reaction: mechanism and kinetics modeling of the ZnS outward growth. Zinc oxide based materials are commonly used for the final desulfurization of synthesis gas in Fischer-Tropsch based XTL processes. Although the ZnO sulfidation reaction has been widely studied, little is known about the transformation at the crystal scale, its detailed mechanism and kinetics. A model ZnO material with well-determined characteristics (particle size and shape) has been synthesized to perform this study. Characterizations of sulfided samples (using XRD, TEM and electron diffraction) have shown the formation of oriented polycrystalline ZnS nanoparticles with a predominant hexagonal form (wurtzite phase). TEM observations also have evidenced an outward development of the ZnS phase, showing zinc and oxygen diffusion from the ZnO-ZnS internal interface to the surface of the ZnS particle. The kinetics of ZnO sulfidation by H(2)S has been investigated using isothermal and isobaric thermogravimetry. Kinetic tests have been performed that show that nucleation of ZnS is instantaneous compared to the growth process. A reaction mechanism composed of eight elementary steps has been proposed to account for these results, and various possible rate laws have been determined upon approximation of the rate-determining step. Thermogravimetry experiments performed in a wide range of H(2)S and H(2)O partial pressures have shown that the ZnO sulfidation reaction rate has a nonlinear variation with H(2)S partial pressure at the same time no significant influence of water vapor on reaction kinetics has been observed. From these observations, a mixed kinetics of external interface reaction with water desorption and oxygen diffusion has been determined to control the reaction kinetics and the proposed mechanism has been validated. However, the formation of voids at the ZnO-ZnS internal interface, characterized by TEM and electron tomography, strongly slows down the reaction rate. Therefore, the impact of the decreasing ZnO-ZnS internal interface on reaction kinetics has been taken into account in the reaction rate expression. In this way the void formation at the interface has been modeled considering a random nucleation followed by an isotropic growth of cavities. Very good agreement has been observed between both experimental and calculated rates after taking into account the decrease in the ZnO-ZnS internal interface. 23439561 NADPH Oxidase NOX5-S and Nuclear Factor κB1 Mediate Acid-Induced Microsomal Prostaglandin E Synthase-1 Expression in Barrett's Esophageal Adenocarcinoma Cells. The mechanisms of progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA) are not known. Cycloxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) has been shown to be important in esophageal tumorigenesis. We have shown that COX-2 mediates acid-induced PGE2 production. The prostaglandin E synthase (PGES) responsible for acid-induced PGE2 production in BE, however, is not known. We found that microsomal PGES1 (mPGES1), mPGES2, and cytosolic PGES (cPGES) were present in FLO EA cells. Pulsed acid treatment significantly increased mPGES1 mRNA and protein levels but had little or no effect on mPGES2 or cPGES mRNA. Knockdown of mPGES1 by mPGES1 small interfering RNA (siRNA) blocked acid-induced increase in PGE2 production and thymidine incorporation. Knockdown of NADPH oxidase, NOX5-S, a variant lacking calcium-binding domains, by NOX5 siRNA significantly inhibited acid-induced increase in mPGES1 expression, thymidine incorporation, and PGE2 production. Overexpression of NOX5-S significantly increased the luciferase activity in FLO cells transfected with a nuclear factor κB (NF-κB) in vivo activation reporter plasmid pNF-κB-Luc. Knockdown of NF-κB1 p50 by p50 siRNA significantly decreased acid-induced increase in mPGES1 expression, thymidine incorporation, and PGE2 production. Two novel NF-κB binding elements, GGAGTCTCCC and CGGGACACCC, were identified in the mPGES1 gene promoter. We conclude that mPGES1 mediates acid-induced increase in PGE2 production and cell proliferation. Acid-induced mPGES1 expression depends on activation of NOX5-S and NF-κB1 p50. Microsomal PGES1 may be a potential target to prevent or treat EA. 23194510 Formation of carcinogenic 4(5)-methylimidazole in caramel model systems: a role of sulphite. Aqueous caramel model systems consisted the D-glucose/NH(3)/sulphite were heated at 100°C for 2 h and amounts of carcinogenic 4(5)-methylimidazole (4-MI) formed were determined. The amount formed ranged from 7.0 to 155.0 ppm. A system with 0.1 M sulphite yielded the greatest amount of 4-MI, which was 54% more than that yielded from a system without sulphite. When the amount of sulphite increased over 0.1 M, the amount of 4-MI reduced. The greatest reduction was achieved with 0.2 M sulphite by 68% compared to 0 M sulphite, suggesting that sulphite plays an important role in the formation of carcinogenic 4-MI in caramel colour. Also, a system with 0.1 M sulphite yielded the most intense caramel colour but the other levels of sulphite did not change the colour intensity significantly. Sulphite contributed slightly to the level of flavour chemicals evaluated using pyrazine formation. The results suggest that sulphite addition at appropriate amount reduces 4-MI formation in caramel colour without sacrificing flavour and colour formation. 23376608 Apigenin induces c-Myc-mediated apoptosis in FRO anaplastic thyroid carcinoma cells. Apigenin promotes apoptosis in cancer cells. We studied the effect of apigenin on cell survival and c-Myc expression in FRO anaplastic thyroid carcinoma (ATC) cells. Apigenin caused apoptosis via the elevation of c-Myc levels in conjunction with the phosphorylation of p38 and p53. In the c-Myc siRNA-transfected and apigenin-treated cells, compared with the apigenin-treated control cells, apoptosis and phosphorylation of p38 and p53 were ameliorated. In the presence of apigenin, diminution of p38 and p53 did not affect cell survival although apigenin activated the phosphorylation of p38 and p53 via increased c-Myc levels. In conclusion, our results indicate that apigenin induces apoptosis mediated via c-Myc with concomitant phosphorylation of p53 and p38 in FRO ATC cells. These findings suggest that augmented c-Myc acts as a core regulator and is necessary for apigenin-induced apoptosis in FRO ATC cells. 23214439 Fibril formation by pH and temperature responsive silk-elastin block copolymers. In this report, we study the self-assembly of two silk-elastin-like proteins: one is a diblock S(24)E(40) composed of 24 silk-like (S) repeats and 40 elastin-like (E) repeats; the other is a triblock S(12)C(4)E(40), in which the S and E blocks are separated by a random coil block (C(4)). Upon lowering the pH, the acidic silk-like blocks fold and self-assemble into fibrils by a nucleation-and-growth process. While silk-like polymers without elastin-like blocks form fibrils by heterogeneous nucleation, leading to monodisperse populations, the elastin-like blocks allow for homogeneous nucleation, which gives rise to polydisperse length distributions, as well as a concentration-dependent fibril length. Moreover, the elastin-like blocks introduce temperature sensitivity: at high temperature, the fibrils become sticky and tend to bundle and aggregate in an irreversible manner. Concentrated solutions of S(12)C(4)E(40) form weak gels at low pH that irreversibly lose elasticity in temperature cycling; this is also attributed to fibril aggregation. 23512438 Pesticide tolerant and phosphorus solubilizing Pseudomonas sp. strain SGRAJ09 isolated from pesticides treated Achillea clavennae rhizosphere soil. In this study, an attempt was made to identify an effective phosphate solubilizing bacteria from pesticide polluted field soil. Based on the formation of solubilization halo on Pikovskaya's agar, six isolates were selected and screened for pesticide tolerance and phosphate (P) solubilization ability through liquid assay. The results showed that only one strain (SGRAJ09) obtained from Achillea clavennae was found to tolerate maximum level of the pesticides tested and it was phylogenetically identified as Pseudomonas sp. It possessed a wide range of pesticide tolerance, ranging from 117 μg mL(-1) for alphamethrin to 2,600 μg mL(-1) for endosulfan. The available P concentrations increased with the maximum and double the maximum dose of monocrotophos and imidacloprid, respectively. On subjected to FT-IR and HPLC analysis, the presence of organic acids functional group in the culture broth and the production of gluconic acid as dominant acid aiding the P solubilization were identified. On comparison with control broth, monocrotophos and imidacloprid added culture broth showed quantitatively high organic acids production. In addition to gluconic acid production, citric and acetic acids were also observed in the pesticide amended broth. Furthermore, the Pseudomonas sp. strain SGRAJ09 possessed all the plant growth promoting traits tested. In presence of monocrotophos and imidacloprid, its plant growth promoting activities were lower than that of the pesticides unamended treatment. 23360230 Surface-enhanced Raman scattering dye-labeled Au nanoparticles for triplexed detection of leukemia and lymphoma cells and SERS flow cytometry. The labeling of cell surface receptors by fluorescent markers is an established method for the identification of cell phenotype in both research and clinical settings. Fluorescence dye labeling has inherent constraints, most notably the upper limit of labels per cell that may be probed using a single excitation source, in addition to a physical limit to the number of broad emission spectra that can be distinctly collected within the visible wavelength region. SERS labeling has the potential to mitigate these shortfalls. Herein, antibody-targeted, PEG-coated surface-enhanced Raman scattering (SERS) Au nanoparticles are used simultaneously to label three cell surface markers of interest on malignant B cells from the LY10 lymphoma cell line. The SERS probes were characterized by multiple methods to confirm their monodispersity and functionalization with both PEG and monoclonal antibodies. The specificity of the particles' cell labeling was demonstrated on both primary chronic lymphocytic leukemia and LY10 cells using SERS from cell suspensions and confocal Raman mapping, respectively. Fluorescence flow cytometry was employed to confirm the binding of SERS probes to LY10 over large cell populations, and the particles' SERS was collected directly from labeled cells using a commercial flow cytometer. To the best of our knowledge, this is the first demonstration of SERS flow cytometry from cells tagged with targeted SERS probes. 23560989 Star Polymers with a Cationic Core Prepared by ATRP for Cellular Nucleic Acids Delivery. Poly(ethylene glycol) (PEG)-based star polymers with a cationic core were prepared by atom transfer radical polymerization (ATRP) for in vitro nucleic acid (NA) delivery. The star polymers were synthesized by ATRP of 2-(dimethylamino)ethyl methacrylate (DMAEMA) and ethylene glycol dimethacrylate (EGDMA). Star polymers were characterized by gel permeation chromatography, zeta potential, and dynamic light scattering. These star polymers were combined with either plasmid DNA (pDNA) or short interfering RNA (siRNA) duplexes to form polyplexes for intracellular delivery. These polyplexes with either siRNA or pDNA were highly effective in NA delivery, particularly at relatively low star polymer weight or molar ratios, highlighting the importance of NA release in efficient delivery systems. 23244178 Generic methods for micrometer- and nanometer-scale surface derivatization based on photochemical coupling of primary amines to monolayers of aryl azides on gold and aluminum oxide surfaces. A series of aryl azide terminated thiols and phosphonic acids has been synthesized, and used to prepare self-assembled monolayers on (respectively) gold and aluminum oxide surfaces. The rates of photoactivation were determined using contact angle measurement and X-ray photoelectron spectroscopy (XPS). The behavior of a diazirine functionalized aryl thiol was also studied. The rates of activation were found to be similar for all five adsorbates. However, the extent of photochemical coupling of a primary amine was significantly greater for the aryl azides than for the diazirine. A range of primary amines was successfully coupled to all of the azides with high yield. Little difference in reactivity was observed following perfluorination of the aromatic ring. Micrometer-scale patterns were fabricated by carrying out exposures of the aryl azide terminated SAMs through a mask submerged under a film of primary amine. Contrasting amines could be introduced to unreacted regions in a subsequent maskless step. A scanning near-field optical microscope was used to fabricate nanopatterns. Exposure of the azides to irradiation at 325 nm in air enabled selective deactivation of azides. The surrounding surface was functionalized with a primary amine in a maskless process; when a protein-resistant oligo(ethylene glycol) functionalized amine was used it was possible to produce protein nanopatterns, by adsorbing protein to features defined using near-field exposure. 23190172 17β-Oestradiol anti-inflammatory effects in primary astrocytes require oestrogen receptor β-mediated neuroglobin up-regulation. Neuroglobin (Ngb), so named after its initial discovery in brain neurones, has received great attention as a result of its neuroprotective effects both in vitro and in vivo. Recently, we demonstrated that, in neurones, Ngb is a 17β-oestradiol (E(2) ) inducible protein that is pivotal for hormone-induced anti-apoptotic effects against H(2) O(2) toxicity. The involvement of Ngb in other brain cell populations, as well as in other neuroprotective effects of E(2) , is completely unknown at present. We demonstrate Ngb immunoreactivity in reactive astrocytes located in the proximity of a penetrating cortical injury in vivo and the involvement of Ngb in the E(2) -mediated anti-inflammatory effect in primary cortical astrocytes. Upon binding to oestrogen receptor (ER)β, E(2) enhances Ngb levels in a dose-dependent manner. Although with a lesser degree than E(2) , the pro-inflammatory stimulation with lipopolysaccharide (LPS) also induces the increase of Ngb protein levels via nuclear factor-(NF)κB signal(s). Moreover, a negative cross-talk between ER subtypes and NFκB signal(s) has been demonstrated. In particular, ERα-activated signals prevent the NFκB-mediated Ngb increase, whereas LPS impairs the ERβ-induced up-regulation of Ngb. Therefore, the co-expression of both ERα and ERβ is pivotal for mediating E(2) -induced Ngb expression in the presence of NFκB-activated signals. Interestingly, Ngb silencing prevents the effect of E(2) on the expression of inflammatory markers (i.e. interleukin 6 and interferon γ-inducible protein 10). Ngb can be regarded as a key mediator of the different protective effects of E(2) in the brain, including protection against oxidative stress and the control of inflammation, both of which are at the root of several neurodegenerative diseases. 23548025 Artificial Neural Networks for Efficient Clustering of Conformational Ensembles and their Potential for Medicinal Chemistry. The biological function of proteins is strictly related to their molecular flexibility and dynamics: enzymatic activity, protein-protein interactions, ligand binding and allosteric regulation are important mechanisms involving protein motions. Computational approaches, such as Molecular Dynamics (MD) simulations, are now routinely used to study the intrinsic dynamics of target proteins as well as to complement molecular docking approaches. These methods have also successfully supported the process of rational design and discovery of new drugs. Identification of functionally relevant conformations is a key step in these studies. This is generally done by cluster analysis of the ensemble of structures in the MD trajectory. Recently Artificial Neural Network (ANN) approaches, in particular methods based on Self-Organising Maps (SOMs), have been reported performing more accurately and providing more consistent results than traditional clustering algorithms in various data-mining problems. In the specific case of conformational analysis, SOMs have been successfully used to compare multiple ensembles of protein conformations demonstrating a potential in efficiently detecting the dynamic signatures central to biological function. Moreover, examples of the use of SOMs to address problems relevant to other stages of the drug-design process, including clustering of docking poses, have been reported. In this contribution we review recent applications of ANN algorithms in analysing conformational and structural ensembles and we discuss their potential in computer-based approaches for medicinal chemistry. 23348754 A brief history of oxytocin and its role in modulating psychostimulant effects. Over the past century, the polypeptide oxytocin has played an important role in medicine with major highlights including the identification of its involvement in parturition and the milk let-down reflex. Oxytocin is now implicated in an extensive range of psychological phenomena including reward and memory processes and has been investigated as a treatment for several psychiatric disorders including addiction, anxiety, autism, and schizophrenia. In this review, we first provide an historical overview of oxytocin and describe key aspects of its physiological activity. We then outline some pharmacological limitations in this field of research before highlighting the role of oxytocin in a wide range of behavioral and neuronal processes. Finally, we review evidence for a modulatory role of oxytocin with regard to psychostimulant effects. Key findings suggest that oxytocin attenuates a broad number of cocaine and methamphetamine induced behaviors and associated neuronal activity in rodents. Evidence also outlines a role for oxytocin in the prosocial effects of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) in both rodents and humans. Clinical trials should now investigate the effectiveness of oxytocin as a novel intervention for psychostimulant addiction and should aim to determine its specific role in the therapeutic properties of MDMA that are currently being investigated. 23302583 Design, synthesis and biological evaluation of novel 7-mercaptocoumarin derivatives as α(1)-adrenoceptor antagonists. Study on the pharmacophore model of α(1)-adrenoceptor (α(1)-AR) antagonists led to design a series of novel 7-mercaptocoumarin derivatives as α(1)-AR antagonists. All designed compounds have been synthesized and biologically evaluated. The results showed that most of them exhibited strong antagonistic activity. Especially compound 6 showed excellent activity, which was better than that of the reference compound prazosin. Structure-activity relationship studies revealed that small hydrophobic group at the terminal heterocyclic ring and ortho substituents on the phenyl ring of phenylpiperazine moiety were the essential structural factors for α(1)-AR antagonistic activity. The pharmacophore modeling studies further clarified their structural contributions to antagonistic activity and also demonstrated that 7-mercaptocoumarin moiety could be a useful scaffold for design of α(1)-AR antagonists. 23636584 A tuneable array of unique steady-state microfluidic gradients. We report an on-chip gradient generator that has been designed, modelled, fabricated, and characterized to facilitate temporal tuning of several unique gradients in parallel for multiple applications. This design allows for steady state programming of the intensities across multiple orders of magnitude while producing exponential, linear, and logarithmic gradient profiles. The magnitude of the gradients is controlled through regulating the ratio of the two on-chip flow inlets without the need for valves or other active mixers. On-chip binding of biotin by a fluorescent streptavidin complex creates a diffusive barrier that regulates access to the gradient inlets, providing a second orthogonal mechanism for regulating the microgradient intensities. The device is also characterized using an on-chip enzymatic reaction to produce an array of tuneable product concentrations within the various microchannels. 23537339 Enantioselective Iron-Catalyzed Azidation of β-Keto Esters and Oxindoles. The first example of Fe-catalyzed enantioselective azidations of β-keto esters and oxindoles using a readily available N3-transfer reagent is reported. A number of α-azido-β-keto esters were obtained with up to 93% ee, and this methodology also generates 3-substitued 3-azidooxindoles with high enantioselectivities (up to 94%). 23333899 Surface functionalization of doxorubicin-loaded liposomes with octa-arginine for enhanced anticancer activity. Doxorubicin-loaded PEGylated liposomes (commercially available as DOXIL® or Lipodox®) were surface functionalized with a cell-penetrating peptide, octa-arginine (R8). For this purpose, R8-peptide was conjugated to the polyethylene glycol-dioleoyl phosphatidylethanolamine (PEG-DOPE) amphiphilic co-polymer. The resultant R8-PEG-PE conjugate was introduced into the lipid bilayer of liposomes at 2mol% of total lipid amount via spontaneous micelle-transfer technique. The liposomal modification did not alter the particle size distribution, as measured by Particle Size Analyzer and transmission electron microscopy (TEM). However, surface-associated cationic peptide increased zeta potential of the modified liposomes. R8-functionalized liposomes (R8-Dox-L) markedly increased the intracellular and intratumoral delivery of doxorubicin as measured by flow cytometry and visualizing by confocal laser scanning microscopy (CLSM) compared to unmodified Doxorubicin-loaded PEGylated liposomes (Dox-L). R8-Dox-L delivered loaded Doxorubicin to the nucleus, being released from the endosomes at higher efficiency compared to unmodified liposomes, which had marked entrapment in the endosomes at tested time point of 1h. The significantly higher accumulation of loaded drug to its site of action for R8-Dox-L resulted in improved cytotoxic activity in vitro (cell viability of 58.5±7% for R8-Dox-L compared to 90.6±2% for Dox-L at Dox dose of 50μg/mL for 4h followed by 24h incubation) and enhanced suppression of tumor growth (348±53mm(3) for R8-Dox-L, compared to 504±54mm(3) for Dox-L treatment) in vivo compared to Dox-L. R8-modification has the potential for broadening the therapeutic window of pegylated liposomal doxorubicin treatment, which could lead to lower non-specific toxicity. 23295999 Poor definitions threaten drug trial safety in India. India has become a hotbed of clinical trials, but recent reports of safety lapses have prompted calls for better regulation in this area. Currently, trial requirements can be relaxed if doing so is in the 'public interest', but a clearer definition of what this means is needed before this provision should be used. 23033256 DNA methylation and histone modification profiles of mouse organic anion transporting polypeptides. Organic anion transporting polypeptides (rodents, Oatps; human, OATPs) are primarily involved in the transmembrane transportation of a wide range of endogenous and exogenous compounds. Multiple mouse Oatp1 isoforms are closely located on chromosome 6, where each isoform shows distinct tissue distribution; Oatp1b2, Oatp1a6, and Oatp1c1 are expressed exclusively in the liver, kidney, and cerebrum, respectively; Oatp1a1 in the liver and kidney; and Oatp1a4 in the liver and cerebrum. We have identified tissue-dependent differentially methylated region (T-DMR) around the transcriptional start site (TSS) of Oatp1b2, which correlates with its liver-specific expression. Bisulfite sequencing also demonstrated the presence of T-DMRs around the TSS in other Oatp1 genes: CpG dinucleotides at +149 relative to the TSS for Oatp1c1; -48, +101, and +356 for Oatp1a4; -572 and -550 for Oatp1a1; and -122 and +216 for Oatp1a6 were differentially methylated among the liver, kidney, and cerebrum. These methylation profiles were largely consistent with the tissue distribution of Oatp1 mRNAs. Chromatin immunoprecipitation assay revealed that the mRNA expression of Oatp1 genes was accompanied by acetylated histone H3. Human OATP1B1 and OATP1B3 are located on chromosome 12p12 in the OATP1 cluster; both show predominant expression in the liver. These genes also contained T-DMRs that were hypomethylated in the liver, compared with kidney cortex: -511, -411, and +92 relative to the TSS for OATP1B1 and -331, +70, and +73 for OATP1B3. These results suggest that the difference in epigenetic profiles comprising DNA methylation and histone acetylation determines the distinct tissue distribution of Oatp/OATP mRNAs. 23518857 Non-bonding interactions and internal dynamics in CH2F2H2CO: a rotational and model calculations study. The rotational spectra of three isotopologues of the 1 : 1 complex between difluoromethane and formaldehyde have been observed and assigned using pulsed jet Fourier transform microwave spectroscopy. The formaldehyde lies in the FCF plane of difluoromethane, linked through a C-HF and a bifurcated CH2O weak hydrogen bonds. The rotational transitions are split into two component lines with a relative intensity ratio of 1 : 3, due to the internal rotation of the formaldehyde moiety along its symmetry axis. The barrier to this motion has been estimated by using a flexible model to be V2 = 180(10) cm(-1). 23265902 A-ring modification of SCH 900229 and related chromene sulfone γ-secretase inhibitors. Attempts to block metabolism by incorporating a 9-fluoro substituent at the A-ring of compound 1 (SCH 900229) using electrophilic Selectfluor™ led to an unexpected oxidation of the A-ring to give difluoroquinone analog 1a. Oxidation of other related chromene γ-secretase inhibitors 2-8 resulted in similar difluoroquinone analogs 2a-8a, respectively. These quinone products exhibited comparable in vitro potency in a γ-scretase membrane assay, but were several fold less potent in a cell-based assay in lowering Aβ40-42, compared to their parent compounds. 23017385 Phenolic profiles of cultivated, in vitro cultured and commercial samples of Melissa officinalis L. infusions. Melissa officinalis L. (lemon balm) is normally consumed as an infusion and presents therapeutic properties, such as sedative, carminative and antispasmodic, also being included in some pharmaceutical preparations. The phenolic profiles of different samples of lemon balm, prepared as infusions, were evaluated by HPLC-DAD-ESI/MS. The profiles were compared in order to understand the differences between cultivated, in vitro cultured and commercial (bags and granulated) samples. All the samples showed a similar phenolic profile, presenting differences only in the quantities found of each compound. Rosmarinic acid was the most abundant compound, being higher in commercial samples, especially in tea bag sample (55.68mg/g of infusion) and lower in in vitro cultured sample (15.46mg/g). Moreover, dimers, trimers and tetramers of caffeic acid were identified and quantified for the first time in lemon balm. Only one flavonoid, luteolin-3'-O-glucuronide was found in all the samples, ranging from 8.43mg/g in commercial granulate sample to 1.22mg/g in in vitro cultured sample. Overall, cultivated and in vitro cultured samples presented the lowest amounts of phenolic compounds (59.59 and 30.21mg/g, respectively); otherwise, commercial samples showed the highest contents (109.24mg/g for tea bag and 101.03mg/g for granulate sample). The present study shows that infusion of lemon balm can be a source of phenolic compounds, known for their bioactive effects. 23401324 Plant consumption by grizzly bears reduces biomagnification of salmon-derived polychlorinated biphenyls, polybrominated diphenyl ethers, and organochlorine pesticides. The present study characterizes the uptake and loss of persistent organic pollutants (POPs) in grizzly bears (Ursus arctos horribilis) by sampling and analyzing their terrestrial and marine foods and fecal material from a remote coastal watershed in British Columbia, Canada. The authors estimate that grizzly bears consume 341 to 1,120 µg of polychlorinated biphenyls (PCBs) and 3.9 to 33 µg of polybrominated diphenyl ethers daily in the fall when they have access to an abundant supply of returning salmon. The authors also estimate that POP elimination by grizzly bears through defecation is very low following salmon consumption (typically <2% of intake) but surprisingly high following plant consumption (>100% for PCBs and organochlorine pesticides). Excretion of individual POPs is largely driven by a combination of fugacity (differences between bear and food concentrations) and the digestibility of the food. The results of the present study are substantiated by a principal components analysis, which also demonstrates a strong role for log KOW in governing the excretion of different POPs in grizzly bears. Collectively, the present study's results reveal that grizzly bears experience a vegetation-associated drawdown of POPs previously acquired through the consumption of salmon, to such an extent that net biomagnification is reduced. Environ. Toxicol. Chem. 2013;32:995-1005. © 2013 SETAC. 23543321 RNAi silencing of three homologues of S-adenosylmethionine decarboxylase gene in tapetal tissue of tomato results in male sterility. Polyamines play very important role in various cellular metabolic functions, including floral induction, floral differentiation and fertility regulation. In the present study, S-adenosylmethionine decarboxylase (SAMDC), a key gene involved in polyamine biosynthesis, has been targeted in tapetal tissue of tomato using RNAi to examine its effect on tapetum development and pollen viability. The target SAMDC gene fragments of three homologues were cloned in a hairpin RNA construct under the control of tapetal-specific A9 promoter, which was used to generate several RNAi tomato plants. These RNAi lines expressed the intended small interfering RNAs in the anther and showed the aborted and sterile pollen exhibiting shrunken and distorted morphology. These RNAi tomato plants having sterile pollen, failed to set fruits but female fertility of the plants remained unaffected as cross pollination resulted in fruit setting. Expression profiling of SAMDC genes showed considerable decrease in transcripts of SAMDC1 (5-8 fold) and SAMDC2 and SAMDC3 (2-3 fold) in the anthers of RNAi plants. The other polyamine biosynthesis genes, ADC and SPDSYN exhibited ~1.5 fold decrease in their transcript levels. Presence of siRNA molecules specific to SAMDC homologues in anther and tapetal-specific activity of A9 promoter as shown with GUS reporter system of RNAi plants suggested down-regulation of the target genes in tapetum by RNAi. These observations indicate the importance of SAMDC, in turn polyamines in pollen development, and thus tapetum-specific down-regulation of SAMDC genes using RNAi can be used for developing male sterile plants. 23210547 An explicit formula for optical oscillator strength of excitons in semiconducting single-walled carbon nanotubes: family behavior. The sensitive structural dependence of the optical properties of single-walled carbon nanotubes, which are dominated by excitons and tunable by changing diameter and chirality, makes them excellent candidates for optical devices. Because of strong many-electron interaction effects, the detailed dependence of the optical oscillator strength f(s) of excitons on nanotube diameter d, chiral angle θ, and electronic subband index P (the so-called family behavior), however, has been unclear. In this study, based on results from an extended Hubbard Hamiltonian with parameters derived from ab initio GW plus Bethe-Salpeter equation (GW-BSE) calculations, we have obtained an explicit formula for the family behavior of the oscillator strengths of excitons in semiconducting single-walled carbon nanotubes (SWCNTs), incorporating environmental screening. The formula explains recent measurements well and is expected to be useful in the understanding and design of possible SWCNT optical and optoelectronic devices. 23529571 Recent progress in nanosensors for sensitive detection of biomolecules. Developing sensitive, rapid, and cost-effective methods for detection of biomolecules is important for both clinical and numerous non-clinical applications. During the last two decades, functional nanomaterials with unique physical and chemical properties have provided significant advantages for biological detection. In this feature article, we introduce recent progress in nanobiosensor development by exploiting the optical, electrical and catalytic properties of a range of nanomaterials, with a focus on gold nanoparticles, carbon nanotubes, graphene and carbon dots. In addition, the perspectives on future opportunities and unsolved challenges are also discussed. 23330848 Acetylcholinesterase immobilized capillary reactors-tandem mass spectrometry: an on-flow tool for ligand screening. The use of immobilized capillary enzyme reactors (ICERs) for online ligand screening has been adopted as a new technique for high-throughput screening (HTS). In this work, the selected target was the enzyme acetylcholinesterase (AChE), and the AChE-ICERs produced were used in a liquid chromatograph-tandem ion-trap mass spectrometer. The activity and kinetic parameters were evaluated by monitoring the choline's precursor ion (M + H)(+)m/z 104.0 and its ion fragment (C2H3OH) - (M + H)(+)m/z 60.0. The assay method was validated using the reference AChE inhibitors tacrine and galanthamine. Two new ligands, out of a library of 17 coumarin derivatives, were identified, and the half-maximal inhibitory concentration (IC50), inhibition constant (K(i)), and the inhibition mechanism were determined. A coumarin derivative with IC50 similar to tacrine was highlighted. 23099811 Influence of dietary carbon on mercury bioaccumulation in streams of the Adirondack Mountains of New York and the Coastal Plain of South Carolina, USA. We studied lower food webs in streams of two mercury-sensitive regions to determine whether variations in consumer foraging strategy and resultant dietary carbon signatures accounted for observed within-site and among-site variations in consumer mercury concentration. We collected macroinvertebrates (primary consumers and predators) and selected forage fishes from three sites in the Adirondack Mountains of New York, and three sites in the Coastal Plain of South Carolina, for analysis of mercury (Hg) and stable isotopes of carbon (δ(13)C) and nitrogen (δ(15)N). Among primary consumers, scrapers and filterers had higher MeHg and more depleted δ(13)C than shredders from the same site. Variation in δ(13)C accounted for up to 34 % of within-site variation in MeHg among primary consumers, beyond that explained by δ(15)N, an indicator of trophic position. Consumer δ(13)C accounted for 10 % of the variation in Hg among predatory macroinvertebrates and forage fishes across these six sites, after accounting for environmental aqueous methylmercury (MeHg, 5 % of variation) and base-N adjusted consumer trophic position (Δδ(15)N, 22 % of variation). The δ(13)C spatial pattern within consumer taxa groups corresponded to differences in benthic habitat shading among sites. Consumers from relatively more-shaded sites had more enriched δ(13)C that was more similar to typical detrital δ(13)C, while those from the relatively more-open sites had more depleted δ(13)C. Although we could not clearly attribute these differences strictly to differences in assimilation of carbon from terrestrial or in-channel sources, greater potential for benthic primary production at more open sites might play a role. We found significant variation among consumers within and among sites in carbon source; this may be related to within-site differences in diet and foraging habitat, and to among-site differences in environmental conditions that influence primary production. These observations suggest that different foraging strategies and habitats influence MeHg bioaccumulation in streams, even at relatively small spatial scales. Such influence must be considered when selecting lower trophic level consumers as sentinels of MeHg bioaccumulation for comparison within and among sites. 23601371 Physicochemical and biological characterization of Pep-1/elastin complexes. Transdermal drug delivery of proteins is challenging because the skin acts as a natural and protective barrier. Several techniques including using the cell penetrating peptides (CPPs) have been studied to increase the penetration of therapeutic proteins into and through the skin. CPPs facilitate and improve the transduction of large and hydrophilic cargo molecules through plasma membrane. We have recently reported an efficient skin delivery of elastin protein in complex with a CPP called Pep-1. Since the biophysical characteristics of CPP/protein complexes have been linked with their biological responses, in the present study, we investigated biophysical properties of Pep-1/elastin complexes (ratio 10:1) stored in three temperatures (-20°C, 4°C and 25°C) by Photon Correlation Spectroscopy (PCS), Circular Dichroism (CD) and isothermal denaturation. We also evaluated the ability of transduction of this complex into cells and skin tissue using both fluorescence microscopy and Kodak In-Vivo FX Pro Imaging System. This article is protected by copyright. All rights reserved. 23427076 Addressable organic structure by anisotropic wetting. The anisotropic wetting of functional organic molecules on a patterned surface and the development of a photolithography-compatible method to fabricate addressable organic structures is reported. For example, DtCDQA is grown on a SiO2 surface with a Au prepattern, achieving a high resolution cross-over organic structure. 23447427 Ion-induced synthesis of uniform single-crystalline sulphide-based quaternary-alloy hexagonal nanorings for highly efficient photocatalytic hydrogen evolution. Uniform single-crystalline quaternary sulphide nanoring photocatalysts are synthesized via the copper-ion-induced Kirkendall effect and is followed by a cation exchange reaction. The obtained Cu(2+) -doped ZnIn2 S4 nanorings show highly preserved morphology, and demonstrate high visible-light-driven photocatalytic activity for H2 evolution in water splitting. 23585311 The effect of PTH(1-34) on fracture healing during different loading conditions. Parathyroid hormone (PTH) and PTH(1-34) have been shown to promote bone healing in several animal studies. It is known that the mechanical environment is important in fracture healing. Furthermore, PTH and mechanical loading has been suggested to have synergistic effects on intact bone. The aim of the present study was to investigate whether the effect of PTH(1-34) on fracture healing in rats was influenced by reduced mechanical loading. For this purpose we used female, 25-week-old ovariectomized rats. Animals were subjected to closed midshaft fracture of the right tibia ten weeks after ovariectomy. Five days before fracture, half of the animals received Botulinum Toxin A-injections in the muscles of the fractured leg to induce muscle paralysis (unloaded group), while the other half received saline injections (control group). For the following eight weeks, half of the animals in each group received injections of hPTH(1-34) (20 µg/kg/day) and the other half received vehicle treatment. Fracture healing was assessed by radiology, DXA, histology and bone strength analysis. We found that unloading reduced callus area significantly, while no effects of PTH(1-34) on callus area were seen in neither normally nor unloaded animals. PTH(1-34) increased callus bone mineral density (BMD) and bone mineral content (BMC) significantly, while unloading decreased callus BMD and BMC significantly. PTH(1-34)-treatment increased bone volume of the callus in both unloaded and control animals. PTH(1-34)-treatment increased ultimate force of the fracture by 63% in both control and unloaded animals and no interaction of the two interventions could be detected. PTH(1-34) was able to stimulate bone formation in normally loaded as well as unloaded intact bone. In conclusion, the study confirms the stimulatory effect of PTH(1-34) on fracture healing and our data suggest that PTH(1-34) is able to promote fracture healing, as well as intact bone formation during conditions of reduced mechanical loading. 23160964 1,25-Dihydroxyvitamin D3 upregulates leptin expression in mouse adipose tissue. Leptin is an adipose tissue-derived hormone that plays a critical role in energy homeostasis. Vitamin D has been shown to regulate energy metabolism, but the relationship between vitamin D and leptin is unclear. Leptin expression and secretion was reduced in vitamin D receptor (VDR)-null mice and increased in transgenic (Tg) mice overexpressing the VDR in adipocytes; however, as leptin is mainly determined by fat mass, it is unclear whether the vitamin D hormone directly regulates leptin expression. To address this question, we determined the effect of vitamin D on leptin expression in vivo and ex vivo. One-week treatment of WT mice with the vitamin D analog RO-27-5646 led to a significant increase in adipose leptin mRNA transcript and serum leptin levels. Moreover, in adipose tissue cultures, 1,25-dihydroxyvitamin D markedly stimulated mRNA expression and secretion of leptin, but not resistin, in adipose tissues obtained from WT mice, but not from VDR-null mice, and leptin upregulation induced by 1,25-dihydroxyvitamin D was more robust in adipose tissues obtained from VDR Tg mice compared with WT mice. These data demonstrate that 1,25-dihydroxyvitamin D stimulates adipose leptin production in a VDR-dependent manner, suggesting that vitamin D may affect energy homeostasis through direct regulation of leptin expression. 22641218 TGF-β and NF-κB signal pathway cross-talk is mediated through TAK1 and SMAD7 in a subset of head and neck cancers. Transforming growth factor-beta (TGF-β) has a dual role in epithelial malignancies, including head and neck squamous cell carcinoma (HNSCC). Attenuation of canonical TGF-β signaling enhances de novo tumor development, whereas TGF-β overexpression and signaling paradoxically promotes malignant progression. We recently observed that TGF-β-induced growth arrest response is attenuated, in association with aberrant activation of nuclear factor-κB (NF-κB), a transcription factor, which promotes malignant progression in HNSCC. However, what role cross-talk between components of the TGF-β and NF-κB pathways plays in altered activation of these pathways has not been established. Here, we show TGF-β receptor II and TGF-β-activated kinase 1 (TAK1) are predominantly expressed in a subset of HNSCC tumors with nuclear activation of NF-κB family member RELA (p65). Further, TGF-β1 treatment induced sequential phosphorylation of TAK1, IKK, IκBα and RELA in human HNSCC lines. TAK1 enhances TGF-β-induced NF-κB activation, as TAK1 siRNA knockdown decreased TGF-β1-induced phosphorylation of IKK, IκB and RELA, degradation of IκBα, RELA nuclear translocation and DNA binding, and NF-κB-induced reporter and target gene transcription. Functionally, TAK1 siRNA inhibited cell proliferation, migration and invasion. Celastrol, a TAK1 inhibitor and anti-inflammatory compound used in traditional Chinese medicine, also decreased TGF-β1-induced phosphorylation of TAK1 and RELA, and suppressed basal, TGF-β1- and tumor necrosis factor-alpha (TNF-α)-induced NF-κB reporter gene activity. Celastrol also inhibited cell proliferation, while increasing sub-G0 DNA fragmentation and Annexin V markers of apoptosis. Furthermore, TGF-β and RELA activation promoted SMAD7 expression. In turn, SMAD7 preferentially suppressed TGF-β-induced SMAD and NF-κB reporters when compared with constitutive or TNF-α-induced NF-κB reporter gene activation. Thus, cross-talk by TGF-β via TAK1 and NF-κB promotes the malignant phenotype of HNSCC. Moreover, NF-κB may contribute to the downstream attenuation of canonical TGF-β signaling through increased SMAD7 expression. Celastrol highlights the therapeutic potential of agents targeting TAK1 as a key node in this pro-oncogenic TGF-β-NF-κB signal pathway. 23098993 The role of transient receptor potential A 1 (TRPA1) in the development and maintenance of carrageenan-induced hyperalgesia. Transient receptor potential ankyrin 1 (TRPA1) is a nonselective cation channel important in setting nociceptive threshold. It is expressed in nociceptive C-fibers and in non-neuronal cells involved in pro-inflammatory mediators' release. We asked whether TRPA1 contributes to carrageenan-induced hyperalgesia in rats, and if so, whether this contribution is mediated by mechanisms involved in inflammation such as cytokine release and neutrophil migration and/or by a direct sensitization of the primary afferent nociceptors. Pharmacological blockade of local TRPA1 by its selective antagonist HC 030031 prevented and reversed carrageenan-induced hyperalgesia, which was detected either by a mechanical or chemical (low dose of capsaicin) stimulus. However, it did not affect either carrageenan-induced cytokines expression or neutrophil migration. The neuronal TRPA1 gene silencing induced by intrathecal pre-treatment with antisense oligodoexynucleotide completely prevented carrageenan-induced hyperalgesia over 24 h and significantly reduced TRPA1 expression in the dorsal root ganglia cells (L5-6), which was not affected by carrageenan treatment. We conclude that TRPA1 plays an important role in the development and maintenance of carrageenan-induced inflammatory hyperalgesia by directly contributing to nociceptor excitability. 23499925 The importance of early bedside echocardiography in children with scorpion envenomation. Scorpion sting may cause myocardial injury and heart failure (HF). Clinical signs of failure may develop several hours or even days after the sting, while electrocardiography (ECG) and blood examination soon after the sting may be normal. We sought to examine whether normal echocardiographic (echo) examination performed shortly after hospital arrival would exclude subsequent HF. We also sought to check if blood troponin and natriuretic peptide values measured shortly after arrival may predict or exclude subsequent HF. Natriuretic peptide activities have not been measured in scorpion sting victims. We also wanted to check if HF occurs in envenomated young infants. In a 3-year prospective study we looked at the demographic, clinical, laboratory, ECG, and echo data of all patients with general envenomation who arrived at the emergency department (ED) after scorpion sting. Clinical, laboratory, ECG, and echo results on arrival and 24 h after arrival were checked and compared between groups of patients with normal and abnormal echo on arrival. We then looked for differences in clinical course, therapy, and outcome between groups. The study included 98 children aged 80 days to 19 years (median 53.1 months), 25 were below the age of 2 years. Envenomation by the "yellow scorpion"Leiurus quinquestriatus was suspected in 74 cases. Median time between sting and ED arrival was 80 min. Echo was performed on arrival in 93 of the 98 patients, (in 5 occasions it was not performed or not recorded) 74 were normal and 19 were abnormal. Abnormal echo included hypokinesia and low fractional shortening and ejection fraction of the left ventricle. Clinical signs, abnormal ECG, and laboratory results were not discriminative between groups on arrival. Mean troponin T was higher in patients with abnormal echo, but within normal range in 13 of the 19 patients with abnormal echo and above normal in 2 of the 74 patients with normal echo - missing sensitivity and specificity. Mean N-terminal pro B-type natriuretic peptide was above normal in both groups but within normal range in 5 patients with abnormal echo and above normal range in 24 patients with normal echo - missing sensitivity and specificity. None of the patients with normal echo had subsequent HF and none of the children younger than 2 years of age had HF. All patients survived the intoxication and were discharged home without sequel. We conclude that early echo examination is an important procedure. In our study, normal examination excluded subsequent HF. Abnormal examination accelerated cardiac therapy which might have contributed to our favorable outcome. HF did not occur in infants younger than two years of age. 23570993 Additional Histopathologic Examination of the Lungs from a 3-Month Inhalation Toxicity Study with Multiwall Carbon Nanotubes in Rats. For hazard assessment of multiwalled carbon nanotubes (MWCNTs), a 90-day inhalation toxicity study has been performed with Nanocyl NC 7000 in accordance with OECD 413 test guideline. MWCNTs produced no systemic toxicity. However, increased lung weights, multifocal granulomatous inflammation, diffuse histiocytic and neutrophilic infiltrates, and intra-alveolar lipoproteinosis were observed in lung and lung-associated lymph nodes at 0.5 and 2.5mg/m(3). Additional investigations of the lungs were performed, including special stains for examination of connective tissue, and electron microscopy was performed to determine the location of the MWCNTs. The alveolar walls revealed no increase of collagen fibers, whereas within the microgranulomas a slight increase of collagen fibers was observed. The pleura did not reveal any increase in collagen fibers. Only a slight increase in reticulin fibers in the alveolar walls in animals of the 0.5 and 2.5mg/m(3) concentration group was noted. In the 0.1mg/m(3) group, the only animal revealing minimal granulomas exhibited a minimal increase in collagen within the granuloma. No increase in reticulin was observed. Electron microscopy demonstrated entangled MWCNTs within alveolar macrophages. Occasionally electron dense particles/detritus were observed within membrane-bound vesicles (interpreted as phagosomes), which could represent degraded MWCNTs. If so, MWCNTs were degradable by alveolar macrophages and not persistent within the lung. Inhalation of MWCNTs caused granulomatous inflammation within the lung parenchyma but not the pleura in any of the concentration groups. Thus, there are some similarities to effects caused by inhaled asbestos, but the hallmark effects, namely pleural inflammation and/or fibrosis leading to mesotheliomas, are absent. 23416264 In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Tobacco smoke consists of thousands of harmful components. A major class of chemicals found in tobacco smoke is formed by aldehydes, in particular formaldehyde, acetaldehyde and acrolein. The present study investigates the gene expression changes in human lung alveolar epithelial cells upon exposure to formaldehyde, acrolein and acetaldehyde at sub-cytotoxic levels. We exposed A549 cells in vitro to aldehydes and non-aldehyde chemicals (nicotine, hydroquinone and 2,5-dimethylfuran) present in tobacco smoke and used microarrays to obtain a global view of the transcriptomic responses. We compared responses of the individual aldehydes with that of the non-aldehydes. We also studied the response of the aldehydes when present in a mixture at relative concentrations as present in cigarette smoke. Formaldehyde gave the strongest response; a total of 66 genes were more than 1.5-fold differentially expressed mostly involved in apoptosis and DNA damage related processes, followed by acetaldehyde (57 genes), hydroquinone (55 genes) and nicotine (8 genes). For acrolein and the mixture only one gene was upregulated involved in oxidative stress. No gene expression effect was found for exposure to 2,5-dimethylfuran. Overall, aldehyde responses are primarily indicative for genotoxicity and oxidative stress. These two toxicity mechanisms are linked to respiratory diseases such as cancer and COPD, respectively. The present findings could be important in providing further understanding of the role of aldehydes emitted from cigarette smoke in the onset of pulmonary diseases. 23609452 TIP60 Positively Regulates ThPOK-Mediated Repression of Eomesodermin in Human CD4+ T Cells. The abundant expression of IFNγ in ThPOK-deficient CD4+ T cells requires the activation of Eomesodermin (Eomes); however, the underlying mechanism of this phenomenon remains unclear. Here we report that ThPOK directly binds to the promoter region of the Eomes gene to repress its expression in CD4+ T cells. We identified the histone acetyltransferase TIP60 as a corepressor of ThPOK-target genes, where ectopically expressed TIP60 increased ThPOK protein stability by promoting its acetylation at its K360 residue to then augment the transcriptional repression of Eomes. Moreover, knockdown of endogenous TIP60 abolished the stabilization of ThPOK in CD4+ T cells, which led to the transcriptional activation of Eomes and increased production of IFNγ. Our results reveal a novel pathway by which TIP60 and ThPOK synergistically suppresses Eomes function and IFNγ production, which could contribute to the regulation of inflammation. 23617226 Solvent Induced Luminescence Quenching: Static and Time-Resolved X-Ray Absorption Spectroscopy of a Copper(I) Phenanthroline Complex. We present a static and picosecond X-ray absorption study at the Cu K-edge of Bis(2,9-dimethyl-1,10-phenanthroline)copper(I) ([Cu(dmp)2]+; dmp = 2,9-dimethyl-1,10-phenanthroline) dissolved in acetonitrile and dichloromethane. The steady state photoluminescence spectra in dichloromethane and acetonitrile are also presented and show a shift to longer wavelengths for the latter, which points to a stronger stabilisation of the excited complex. The fine structure features of the static and transient X-ray spectra allow an unambiguous assignment of the electronic and geometric structure of the molecule in both its ground and excited 3MLCT states. Importantly, the transient spectra are remarkably similar for both solvents and the spectral changes can be rationalised using the optimised ground and excited state structures of the complex. The proposed assignment of the lifetime shortening of the excited state in donor solvents (acetonitrile) to a metal centred exciplex is not corroborated here. Molecular dynamics simulations confirm the lack of complexation, however in both solvents the molecules come close to the metal but undergo rapid exchange with the bulk. The shortening of the lifetime of the title complex and nine additional related complexes can be rationalised by the decrease of the 3MLCT energy. Deviations from this trend may be explained by means of the effects of the dihedral angle between the ligand planes, the solvent and the 3MLCT-1MLCT energy gap. 23434422 Euryspongins A-C, three new unique sesquiterpenes from a marine sponge Euryspongia sp. Three new unique sesquiterpenes, euryspongins A-C (1-3), were isolated from a marine sponge Euryspongia sp. collected at Iriomote Island, Okinawa, Japan. Compound 1 possessed a bicyclic furanosesquiterpene structure with six- and eight-membered rings, whereas compounds 2 and 3 had an α,β-unsaturated-γ-lactone ring instead of the furan ring in 1. Only five natural products in this class have been reported, and compounds 1-3 are the sixth-eighth examples of natural products. Compounds 1-3 had no inhibition effect against PTP1B, an important target enzyme for the treatment of diabetes, while the dehydro derivative of 1 [dehydroeuryspongin A (4)] exhibited inhibitory activity (IC(50)=3.6 μM). 23391207 Controllable adhesive superhydrophobic surfaces based on PDMS microwell arrays. This paper presents a one-step method to fabricate superhydrophobic surfaces with extremely controllable adhesion based on PDMS microwell arrays. The microwell array structures are rapidly produced on PDMS films by a point-by-point femtosecond laser scanning process. The as-prepared superhydrophobic surfaces show water controllable adhesion that ranges from ultrahigh to ultralow by adjusting the extent of overlap of the adjacent microwells, on which the sliding angle can be controlled from 180° (a water droplet can not slide down even when the as-prepared surface is turned upside down) to 3°. A "micro-airbag effect" is introduced to explain the adhesion transition phenomenon of the microwell array structures. This work provides a facile and promising strategy to fabricate superhydrophobic surfaces with controllable adhesion. 23258537 The RNA polymerase of marine cyanophage Syn5. A single subunit DNA-dependent RNA polymerase was identified and purified to apparent homogeneity from cyanophage Syn5 that infects the marine cyanobacteria Synechococcus. Syn5 is homologous to bacteriophage T7 that infects Escherichia coli. Using the purified enzyme its promoter has been identified by examining transcription of segments of Syn5 DNA and sequencing the 5'-termini of the transcripts. Only two Syn5 RNAP promoters, having the sequence 5'-ATTGGGCACCCGTAA-3', are found within the Syn5 genome. One promoter is located within the Syn5 RNA polymerase gene and the other is located close to the right genetic end of the genome. The purified enzyme and its promoter have enabled a determination of the requirements for transcription. Unlike the salt-sensitive bacteriophage T7 RNA polymerase, this marine RNA polymerase requires 160 mm potassium for maximal activity. The optimal temperature for Syn5 RNA polymerase is 24 °C, much lower than that for T7 RNA polymerase. Magnesium is required as a cofactor although some activity is observed with ferrous ions. Syn5 RNA polymerase is more efficient in utilizing low concentrations of ribonucleotides than T7 RNA polymerase. 22585425 The antioxidant activity of allylpyrocatechol is mediated via decreased generation of free radicals along with escalation of antioxidant mechanisms. Allylpyrocatechol (APC) is responsible for the antiinflammatory activity exhibited by the methanolic extract of leaves of Piper betle. As antiinflammatory compounds may display antioxidant properties and vice versa, we investigated the antioxidant effect of APC. APC effectively reduced phorbol-myristate-acetate-induced generation of reactive oxygen species and superoxide in murine peritoneal macrophages as well as inhibited Escherichia-coli-induced phagocytic activity of macrophages. Furthermore, pBluescript SK(+) plasmid DNA damage induced by addition of sodium ascorbate was attenuated by APC as it inhibited transformation of the supercoiled form to a relaxed form. In addition, APC increased the enzymatic (catalase) and nonenzymatic (GSH) antioxidant components of murine macrophages. Taken together, APC exhibited an antioxidant activity which was mediated both via decreased generation of free radicals along with increase in cellular antioxidants. Copyright © 2012 John Wiley & Sons, Ltd. 23600646 Cyclodextrin-Functionalized Fe3O4@TiO2: Reusable, Magnetic Nanoparticles for Photocatalytic Degradation of Endocrine-Disrupting Chemicals in Water Supplies. Water-dispersible, photocatalytic Fe3O4@TiO2 core-shell magnetic nanoparticles have been prepared by anchoring cyclodextrin cavities to the TiO2 shell, and their ability to capture and photocatalytically destroy endocrine-disrupting chemicals, bisphenol A and dibutyl phthalate, present in water, has been demonstrated. The functionalized nanoparticles can be magnetically separated from the dispersion after photocatalysis and hence reused. Each component of the cyclodextrin-functionalized Fe3O4@TiO2 core-shell nanoparticle has a crucial role in its functioning. The tethered cyclodextrins are responsible for the aqueous dispersibility of the nanoparticles and their hydrophobic cavities for the capture of the organic pollutants that may be present in water samples. The amorphous TiO2 shell is the photocatalyst for the degradation and mineralization of the organics, bisphenol A and dibutyl phthalate, under UV illumination, and the magnetism associated with the 9 nm crystalline Fe3O4 core allows for the magnetic separation from the dispersion once photocatalytic degradation is complete. An attractive feature of these "capture and destroy" nanomaterials is that they may be completely removed from the dispersion and reused with little or no loss of catalytic activity. 23631493 Effect of Lycopene Supplementation on Oxidative Stress: An Exploratory Systematic Review and Meta-Analysis of Randomized Controlled Trials. Abstract Lycopene is a potentially useful compound for preventing and treating cardiovascular diseases and cancers. Studies on the effects of lycopene on oxidative stress offer insights into its mechanism of action and provide evidence-based rationale for its supplementation. In this analysis, randomized controlled trials of the effects of oral lycopene supplementation on any valid outcomes of oxidative stress were identified and pooled through a search of international journal databases and reference lists of relevant publications. Two reviewers extracted data from each of the identified studies. Only studies of sufficient quality were included. Twelve parallel trials and one crossover trial were included in the systematic review, and six trials provided data for quantitative meta-analysis. Our results indicate that lycopene supplementation significantly decreases the DNA tail length, as determined using comet assays, with a mean difference (MD) of -6.27 [95% confidence interval (CI) -10.74, -1.90] (P=.006) between the lycopene intervention groups and the control groups. Lycopene supplementation does not significantly prolong the lag time of low-density lipoprotein (MD 3.76 [95% CI -2.48, 10.01]; P=.24). Lycopene possibly alleviates oxidative stress; however, biomarker research for oxidative stress needs be more consistent with the outcomes in lycopene intervention trials for disease prevention. 23627275 Dual-Responsive Capsules with Tunable Low Critical Solution Temperatures and Their Loading and Release Behavior. Dual-responsive capsules sensitive to pH and temperature changes were successfully prepared by grafting random copolymer brushes of 2-(2-methoxyethoxy)ethyl methacrylate (MEO2MA) and oligo(ethylene glycol) methacrylate (OEGMA) from polydopamine (Pdop)-coated SiO2 via a surface-initiated atom-transfer radical polymerization (SI-ATRP) method with subsequent removal of the SiO2 core. The uptake and release properties of the resulting capsules are highly affected by changes in the pH values and temperature of the solution. The capsules can take up cationic dye rhodamine 6G (Rh6G) at high pH and T < LCST but not at low pH and T > LCST. In contrast, the capsules can release Rh6G at pH < 7 and temperature below the LCST, but release is less efficient under the opposite conditions. This dual-responsive property was also observed for the anionic dye methyl orange. 23303785 A Myc-microRNA network promotes exit from quiescence by suppressing the interferon response and cell-cycle arrest genes. The transition of mammalian cells from quiescence to proliferation is accompanied by the differential expression of several microRNAs (miRNAs) and transcription factors. However, the interplay between transcription factors and miRNAs in modulating gene regulatory networks involved in human cell proliferation is largely unknown. Here we show that the miRNA miR-22 promotes proliferation in primary human cells, and through a combination of Argonaute-2 immunoprecipitation and reporter assays, we identified multiple novel targets of miR-22, including several cell-cycle arrest genes that mediate the effects of the tumor-suppressor p53. In addition, we found that miR-22 suppresses interferon gene expression by directly targeting high mobility group box-1 and interferon regulatory factor (IRF)-5, preventing activation of IRF3 and NF-κB, which are activators of interferon genes. The expression of interferon genes is elevated in quiescent cells and their expression is inhibitory for cell proliferation. In addition, we find that miR-22 is activated by the transcription factor Myc when quiescent cells enter proliferation and that miR-22 inhibits the Myc transcriptional repressor MXD4, mediating a feed-forward loop to elevate Myc expression levels. Our results implicate miR-22 in downregulating the anti-proliferative p53 and interferon pathways and reveal a new transcription factor-miRNA network that regulates the transition of primary human cells from quiescence to proliferation. 22664910 Nuclear Receptors in atherosclerosis: a superfamily with many 'Goodfellas'. Nuclear Receptors form a superfamily of 48 transcription factors that exhibit a plethora of functions in steroid hormone signaling, regulation of metabolism, circadian rhythm and cellular differentiation. In this review, we describe our current knowledge on the role of Nuclear Receptors in atherosclerosis, which is a multifactorial disease of the vessel wall. Various cell types are involved in this chronic inflammatory pathology in which multiple cellular processes and numerous genes are dysregulated. Systemic risk factors for atherosclerosis are among others adverse blood lipid profiles, enhanced circulating cytokine levels, as well as increased blood pressure. Since many Nuclear Receptors modulate lipid profiles or regulate blood pressure they indirectly affect atherosclerosis. In the present review, we focus on the functional involvement of Nuclear Receptors within the atherosclerotic vessel wall, more specifically on their modulation of cellular functions in endothelial cells, smooth muscle cells and macrophages. Collectively, this overview shows that most of the Nuclear Receptors are athero-protective in atherosclerotic lesions. 23554463 Comprehensive prediction in 78 human cell lines reveals rigidity and compactness of transcription factor dimers. The binding of transcription factors (TFs) to their specific motifs in genomic regulatory regions is commonly studied in isolation. However, in order to elucidate the mechanisms of transcriptional regulation, it is essential to determine which TFs bind DNA cooperatively as dimers, and to infer the precise nature of these interactions. So far, only a small number of such dimeric complexes are known. Here, we present an algorithm for predicting cell-type-specific TF-TF dimerization on DNA on a large scale, using DNase I hypersensitivity data from 78 human cell lines. We represented the universe of possible TF complexes by their corresponding motif complexes, and analyzed their occurrence at cell-type-specific DNase I hypersensitive sites. Based on ~1.4 billion tests for motif complex enrichment, we predicted 603 highly significant cell-type-specific TF dimers, the vast majority of which are novel. Our predictions included 76% (19/25) of the known dimeric complexes and showed significant overlap with an experimental database of protein-protein interactions. They were also independently supported by evolutionary conservation, as well as quantitative variation in DNase I digestion patterns. Notably, the known and predicted TF dimers were almost always highly compact and rigidly spaced, suggesting that TFs dimerize in close proximity to their partners, which results in strict constraints on the structure of the DNA-bound complex. Overall, our results indicate that chromatin openness profiles are highly predictive of cell-type-specific TF-TF interactions. Moreover, cooperative TF dimerization seems to be a widespread phenomenon, with multiple TF complexes predicted in most cell types. 22660443 Azole interactions with multidrug therapy in pediatric oncology. Patients with cancer receive multidrug therapy. Antineoplastic agents and supportive care drugs are often administered together, leading to potential drug-drug interactions. These interactions may have significant clinical implications in terms of toxicity or a decrease in the efficacy of the treatment administered. Here, we focus on the role of azoles and their main pharmacokinetic interactions with the principal classes of drugs used in pediatric oncology. The co-administration of azoles and antineoplastic agents, corticosteroids, immunosuppressants, antacids, antiemetics, antiepileptic drugs and analgesics was investigated, and a practical guide on the management of these drugs when administered together is provided. 23599006 Pharmacological and Chemical Study to Identify Wound-Healing Active Compounds in Ageratina pichinchensis. The aerial parts of Ageratina pichinchensis are used in Mexican traditional medicine for the treatment of skin wounds. Recently, it was demonstrated that the aqueous extract of this plant reduced the time required to cicatrize a wound induced in the rat. The same extract showed a capability to induce overgrowth in normal fetal lung cells (MRC-5). The objective of the present study was isolating and identifying the active compounds in A. pichinchensis that are capable of inducing cellular overgrowth, as well as performing a preliminary evaluation of their anti-inflammatory and toxic effects. By means of bioguided chemical separation of an aqueous extract of A. pichinchensis, the most active compound capable of inducing cellular overgrowth was identified as 7-O-(β-D-glucopyranosyl)-galactin. In vivo inflammation induced with carrageenan in mice was significantly reduced by the aqueous extract of A. pichinchensis, reaching a decrease of up to 60.6 %. Acute (2 g/kg) and subchronic (1 g/kg for 28 days) oral administration of the aqueous extract of this plant did not affect hepatic function (through alanine aminotransferase and aspartate aminotransferase activity evaluation), while no alterations of the histologic samples of liver and kidney were evidenced. 23504645 Solar-Powered Nanomechanical Transduction from Crystalline Molecular Rotors. A photoinduced solid-state SO2 isomerism drives a larger mechanical change (benzene-ring rotation) in a neighbouring ion (i.e., the system acts as a solar-powered molecular transducer). The ring rotation and SO2 photoisomerisation are observed using in situ X-ray crystallography and are controllable, reproducible, and metastable at low temperatures. This discovery presents a new range of materials for solar-energy-based molecular transduction. 23497881 Evaluation of sequential inoculation of Saccharomyces cerevisiae and Oenococcus oeni strains on the chemical and aromatic profiles of cherry wines. The current study was carried out to elucidate the effect of sequential inoculation of Saccharomyces cerevisiae (RC212, D254) and Oenococcus oeni (SG26, Lalvin 31 and Uvaferm Alpha) on the production of cherry wines, especially on the chemical and aromatic characteristics. SI-D culture required the shortest period (23 d) to complete the fermentation, while other inoculations needed longer time. Analysis from chemical composition showed that titratable acidity and content of l-malic acid exhibited evident differences among the samples after MLF. For volatile compounds, 49 major components were identified, mostly comprising of alcohols, acids and esters. Cherry wines obtained from SI-B and SI-C showed higher contents of total volatile alcohols, and SI-D wines produced the greatest amount of volatile acids. According to the odour active value (OAV), 9 out of 49 studied volatile components had OAV >1 in all the analyzed wines, while six volatile components showed OAV >1 only for some of them. Furthermore, a sensory analysis was performed to compare the sensory profile of these cherry wines, and results evidenced that wines resulting from different inoculations presented diverse sensory profiles. These findings suggest that sequential inoculations posed a great potential in affecting and modulating the aromatic profile of cherry wines. 23052195 Neuropeptide Y Y1 receptor knockdown can modify glutathione peroxidase and c-AMP response element-binding protein in phenylpropanolamine-treated rats. It has been reported that antioxidative enzymes, neuropeptide Y (NPY), and c-AMP response element-binding protein (CREB) are involved in regulating phenylpropanolamine (PPA)-mediated appetite suppression. Here, we investigated whether Y1 receptor (Y1R) might be involved in this regulation. Rats were daily treated with PPA for 4 days. Changes in the contents of NPY, Y1R, glutathione peroxidase (GP), and CREB were assessed and compared. Results showed that Y1R, GP, and CREB increased, with a maximal increase about 100, 200, and 150 %, respectively, on Day 2. By contrast, NPY decreased with a biggest reduction about 48 % on Day 2 and the pattern of expression during PPA treatment was opposite to those of Y1R, GP, and CREB. Central knockdown (using antisense) or inhibition (using antagonist) of Y1R expression modulated the anorectic response of PPA and the reciprocal regulation between NPY and GP (or CREB), revealing an essential role of Y1R in regulating NPY, GP, and CREB. These results suggest that Y1R participates in the reciprocal regulation of NPY, GP, and CREB in the hypothalamus during PPA treatment in conscious rats. The present results may aid the therapeutic research of PPA and related antiobesity drugs. 23356987 Male mice housed in groups engage in frequent fighting and show a lower response to additional bone loading than females or individually housed males that do not fight. Experiments to investigate bone's physiological adaptation to mechanical loading frequently employ models that apply dynamic loads to bones in vivo and assess the changes in mass and architecture that result. It is axiomatic that bones will only show an adaptive response if the applied artificial loading environment differs in a significant way from that to which the bones have been habituated by normal functional loading. It is generally assumed that this normal loading is similar between experimental groups. In the study reported here we found that this was not always the case. Male and female 17-week-old C57BL/6 mice were housed in groups of six, and a single episode (40 cycles) of non-invasive axial loading, engendering 2,200 με on the medial surface of the proximal tibiae in sample mice, was applied to right tibiae on alternate days for two weeks. This engendered an adaptive increase in bone mass in females, but not males. Observation revealed the main difference in behaviour between males and females was that males were involved in fights 1.3 times per hour, whereas the females never fought. We therefore housed all mice individually. In females, there was a similar significant osteogenic response to loading in cortical and trabecular bone of both grouped and individual mice. In contrast, in males, adaptive increases in the loaded compared with non-loaded control bones was only apparent in animals housed individually. Our interpretation of these findings is that the frequent vigorous fighting that occurs between young adult males housed in groups could be sufficient to engender peak strains and strain rates that equal or exceed the stimulus derived from artificial loading. This indicates the importance of ensuring that physical activity is consistent between groups. Reducing the background level of the naturally engendered strain environment allows adaptive responses to artificial loading to be demonstrated at lower loads. 23159662 Ex vivo permeation characteristics of venlafaxine through sheep nasal mucosa. Venlafaxine, a dual acting antidepressant is a new therapeutic option for chronic depression. Depression is a common mental disorder associated with the abnormalities in neuronal transport in the brain. Since the nose-to-brain pathway has been indicated for delivering drugs to the brain, we analyzed the transport of venlafaxine through sheep nasal mucosa. Transmucosal permeation kinetics of venlafaxine were examined using sheep nasal mucosa mounted onto static vertical Franz diffusion cells. Nasal mucosa was treated with venlafaxine in situ gel (100 μl; 1% w/v) for 7h. Amount of venlafaxine diffused through mucosa was measured using validated RP-HPLC method. After the completion of the study histopathological investigation of mucosa was carried out. Ex vivo studies through sheep nasal mucosa showed sustained diffusion of venlafaxine with 66.5% permeation in 7h. Transnasal transport of venlafaxine followed a non-Fickian diffusion process. Permeability coefficient and steady state flux were found to be 21.11×10(-3) cmh(-1) and 21.118 μg cm(-2)h(-1) respectively. Cumulative amount permeated through mucosa at 7h was found to be 664.8 μg through an area of 3.14 cm(2). Total recovery of venlafaxine at the end of the permeation study was 87.3% of initial dose distributed (i) at the mucosal surface (208.4 μg; 20.8%) and (ii) through mucosa (664.8 μg; 66.5%). Histopathological examinations showed no significant adverse effects confirming that the barrier function of nasal mucosa remains unaffected even after treatment with venlafaxine in situ gel. Permeation through sheep nasal mucosa using in situ gel demonstrated a harmless nasal delivery of venlafaxine, providing new dimension to the treatment of chronic depression. 23484490 High Purity Isolation and Quantification of Semiconducting Carbon Nanotubes via Column Chromatography. The isolation of semiconducting carbon nanotubes (CNTs) to ultrahigh (ppb) purity is a prerequisite for their integration into high-performance electronic devices. Here, a method employing column chromatography is used to isolate semiconducting nanotubes to 99.9% purity. The study finds that by modifying the solution preparation step, both the metallic and semiconducting fraction are resolved and elute using a single surfactant system, allowing for multiple iterations. Iterative processing enables a far more rapid path to achieving the level of purities needed for high performance computing. After a single iteration, the metallic peak in the absorption spectra is completely attenuated. Although absorption spectroscopy is typically used to characterize CNT purity, it is found to be insufficient in quantifying solutions of high purity (>98 to 99%) due to low signal-to-noise in the metallic region of ultrahigh purity solutions. Therefore, a high throughput electrical testing method was developed to quantify the degree of separation by characterizing ∼4000 field-effect transistors fabricated from the separated nanotubes after multiple iterations of the process. The separation and characterization methods described here provide a path to produce the ultrahigh purity semiconducting CNT solutions needed for high performance electronics. 23194825 Neurotoxicity of "ecstasy" and its metabolites in human dopaminergic differentiated SH-SY5Y cells. "Ecstasy" (3,4-methylenedioxymethamphetamine or MDMA) is a widely abused recreational drug, reported to produce neurotoxic effects, both in laboratory animals and in humans. MDMA metabolites can be major contributors for MDMA neurotoxicity. This work studied the neurotoxicity of MDMA and its catechol metabolites, α-methyldopamine (α-MeDA) and N-methyl-α-methyldopamine (N-Me-α-MeDA) in human dopaminergic SH-SY5Y cells differentiated with retinoic acid and 12-O-tetradecanoyl-phorbol-13-acetate. Differentiation led to SH-SY5Y neurons with higher ability to accumulate dopamine and higher resistance towards dopamine neurotoxicity. MDMA catechol metabolites were neurotoxic to SH-SY5Y neurons, leading to caspase 3-independent cell death in a concentration- and time-dependent manner. MDMA did not show a concentration- and time-dependent death. Pre-treatment with the antioxidant and glutathione precursor, N-acetylcysteine (NAC), resulted in strong protection against the MDMA metabolites' neurotoxicity. Neither the superoxide radical scavenger, tiron, nor the inhibitor of the dopamine (DA) transporter, GBR 12909, prevented the metabolites' toxicity. Cells exposed to α-MeDA showed an increase in intracellular glutathione (GSH) levels, which, at the 48 h time-point, was not dependent in the activity increase of γ-glutamylcysteine synthetase (γ-GCS), revealing a possible transient effect. Importantly, pre-treatment with buthionine sulfoximine (BSO), an inhibitor of γ-GCS, prevented α-MeDA induced increase in GSH levels, but did not augment this metabolite cytotoxicity. Even so, BSO pre-treatment abolished NAC protective effects against α-MeDA neurotoxicity, which were, at least partially, due to GSH de novo synthesis. Inversely, pre-treatment of cells with BSO augmented N-Me-α-MeDA-induced neurotoxicity, but only slightly affected NAC neuroprotection. In conclusion, MDMA catechol metabolites promote differential toxic effects to differentiated dopaminergic human SH-SY5Y cells. 23561203 A micellar improved method for trace levels selenium quantification in food samples, alcoholic and nonalcoholic beverages through CPE/FAAS. A useful preconcentration and determination method was proposed for trace selenium in food samples. The procedure is based on complex formation of Pyronine B with Se(IV) ions in the presence of sodium dodecyl sulphate (SDS) and Ponpe 7.5. The variables affecting complex formation, extraction and phase separation were studied and optimised. Under the experimental conditions used, the calibration graph was linear in the range of 20-1700μgL(-1) for Se(IV) ions. The limit of detection was 3.81μgL(-1) of Se(IV) and the relative standard deviation for 5 replicate determinations at 250μgL(-1)concentration level was 2.45%. Recovery values were obtained between 97.8% and 102.8% for spiked samples. The method was successfully applied to the determination of total selenium in some food samples and alcoholic and nonalcoholic beverages. Its validity was checked by the analysis of four certified reference materials. The results obtained by the proposed method were quantitatively in good agreement with the certified values. 23394286 Resolving stable axial trapping points of nanowires in an optical tweezers using photoluminescence mapping. Axially resolved microphotoluminescence mapping of semiconductor nanowires held in an optical tweezers reveals important new experimental information regarding equilibrium trapping points and trapping stability of high aspect ratio nanostructures. In this study, holographic optical tweezers are used to scan trapped InP nanowires along the beam direction with respect to a fixed excitation source and the luminescent properties are recorded. It is observed that nanowires with lengths on the range of 3-15 μm are stably trapped near the tip of the wire with the long segment positioned below the focus in an inverted trapping configuration. Through the use of trap multiplexing we investigate the possibility of improving the axial stability of the trapped nanowires. Our results have important implication for applications of optically assisted nanowire assembly and optical tweezers based scanning probes microscopy. 23635023 Monolithic Barrier-All-Around High Electron Mobility Transistor with Planar GaAs Nanowire Channel. High quality growth of planar GaAs nanowires (NWs) with widths as small as 35 nm is realized by comprehensively mapping the parameter space of group III flow, V/III ratio, and temperature as the size of the NWs scale down. Using a growth mode modulation scheme for the NW and thin film barrier layers, monolithically integrated AlGaAs barrier-all-around planar GaAs NW high electron mobility transistors (NW-HEMTs) are achieved. The peak extrinsic transconductance, drive current, and effective electron velocity are 550 µS/µm, 435 µA/µm, and ~2.9 ×〖10〗^7 cm/s, respectively, at 2V supply voltage with a gate length of 120 nm. The excellent DC performance demonstrated here shows the potential of this bottom-up planar NW technology for low-power high-speed very-large-scale-integration (VLSI) circuits. 23198958 Triggered indistinguishable single photons with narrow line widths from site-controlled quantum dots. In this Letter, we present narrow line width (7 μeV), nearly background-free single-photon emission (g((2))(0) = 0.02) and highly indistinguishable photons (V = 0.73) from site-controlled In(Ga)As/GaAs quantum dots. These excellent properties have been achieved by combining overgrowth on ex situ pit-patterned substrates with vertical stacking of spectrally distinct quantum dot layers. Our study paves the way for large-scale integration of quantum dots into quantum photonic circuits as indistinguishable single-photon sources. 23535934 Challenges and approaches for the development of safer immunomodulatory biologics. Immunomodulatory biologics, which render their therapeutic effects by modulating or harnessing immune responses, have proven their therapeutic utility in several complex conditions including cancer and autoimmune diseases. However, unwanted adverse reactions--including serious infections, malignancy, cytokine release syndrome, anaphylaxis and hypersensitivity as well as immunogenicity--pose a challenge to the development of new (and safer) immunomodulatory biologics. In this article, we assess the safety issues associated with immunomodulatory biologics and discuss the current approaches for predicting and mitigating adverse reactions associated with their use. We also outline how these approaches can inform the development of safer immunomodulatory biologics. 23455057 Microwave-assisted synthesis of arene ruthenium(II) complexes that induce S-phase arrest in cancer cells by DNA damage-mediated p53 phosphorylation. A series of arene ruthenium(II) complexes coordinated by phenanthroimidazole derivates, [(C6H6)Ru(L)Cl]Cl·2H2O (1b L = IP, 2b L = p-NMe2PIP, 3b L = p-MeOPIP, 4b L = p-HOPIP, 5b L = p-COOHPIP, 6b L = p-CF3PIP, 7b L = p-BrPIP) have been synthesized in yields of 89-92% under microwave irradiation in 30 min, and the crystal structure of 1b by XRD gives a typical "piano stool" conformation. The antitumor activity of these complexes against various tumor cells have been evaluated by MTT assay, and the results show that this type of arene Ru(II) complexes exhibit acceptable inhibitory effect against all of these tumor cells, especially osteosarcoma MG-63 cells, but with low toxicity toward HK-2 human normal cells. Studies on the mechanism revealed that cell cycle arrest at S-phase in MG-63 cells induced by the arene Ru(II) complex 2b, which was confirmed by the increase in the percentage of cells at S-phase and down-regulator of cyclin A. The further studies by Comet assay at single cell level indicated that DNA damage in MG-63 cells was triggered by 2b, following with the up-regulation of phosphorylated p53 and histone. The studies by spectroscopy in vitro also indicate that 2b bind to DNA molecule by intercalative mode to disturb the bio-function of tumor cells. In conclusion, the synthetic arene Ru(II) complexes could serve as novel p53 activator with potential application in cancer chemotherapy. 23628332 Anti-adipogenic activity of compounds isolated from Idesia polycarpa on 3T3-L1 cells. Recently, obesity is a complex multifactorial chronic disease increasing the risk for type 2 diabetes, coronary heart disease and hypertension, and has become a major worldwide health problem. In the course of screening natural products employing 3T3-L1 cells as an in vitro system, the methanol extract of Idesia polycarpa Maxim. Fruits (Flacourtiaceae) significantly inhibited adipocyte differentiation by measuring lipid contents using oil red O staining. One new compound, 6-(oxymethyl)-2-hydroxyphenyl-O-β-d-glucopyranosyl-(1→6)-β-d-glucopyranoside (8), was isolated along with nine known compounds (1-7 and 9-10) from CHCl3 and n-BuOH fractions of the methanol extract of I. polycarpa fruits. Among them, idescarpin (1) with 1-hydroxy-6-oxo-2-cyclohexenecarboxylate moiety showed the most potent inhibitory activity on adipocyte differentiation with IC50 values of 23.2μM. Idescarpin (1) dramatically suppressed the induction of C/EBPα expression, whereas it significantly increased the induction of PPARγ expression, supported by quantitative real time PCR and Western blot analysis. The down-regulation in mRNA levels of SREBP1c, SCD-1, and FAS by idescarpin (1) during adipocyte differentiation revealed that the inhibition of adipocyte differentiation was mediated by the regulation of lipogenesis. Taken together, we suggest that idescarpin (1) shows a great potential against obesity and diabetes though the anti-adipogenic activity and the up-regulation of PPARγ. 23091169 Identification of Dlk1-Dio3 imprinted gene cluster noncoding RNAs as novel candidate biomarkers for liver tumor promotion. The molecular events during nongenotoxic carcinogenesis and their temporal order are poorly understood but thought to include long-lasting perturbations of gene expression. Here, we have investigated the temporal sequence of molecular and pathological perturbations at early stages of phenobarbital (PB) mediated liver tumor promotion in vivo. Molecular profiling (mRNA, microRNA [miRNA], DNA methylation, and proteins) of mouse liver during 13 weeks of PB treatment revealed progressive increases in hepatic expression of long noncoding RNAs and miRNAs originating from the Dlk1-Dio3 imprinted gene cluster, a locus that has recently been associated with stem cell pluripotency in mice and various neoplasms in humans. PB induction of the Dlk1-Dio3 cluster noncoding RNA (ncRNA) Meg3 was localized to glutamine synthetase-positive hypertrophic perivenous hepatocytes, suggesting a role for β-catenin signaling in the dysregulation of Dlk1-Dio3 ncRNAs. The carcinogenic relevance of Dlk1-Dio3 locus ncRNA induction was further supported by in vivo genetic dependence on constitutive androstane receptor and β-catenin pathways. Our data identify Dlk1-Dio3 ncRNAs as novel candidate early biomarkers for mouse liver tumor promotion and provide new opportunities for assessing the carcinogenic potential of novel compounds. 23592747 EPITOPE RECOGNITION IN HLA-DR3 TRANSGENIC MICE IMMUNIZED TO TSH-R PROTEIN OR PEPTIDES. Development of Graves' disease (GD) is related to HLA-DR3. The extracellular domain (ECD) of human TSH receptor (hTSH-R) is a crucial antigen in GD. hTSH-R peptide 37 (AA 78-94) is an important immunogenic peptide in DR3 transgenic mice immunized to hTSH-R. This study 1) examines epitope recognition in DR3 transgenic mice immunized to hTSH-R protein, and 2) evaluates ability of a mutant hTSH-R peptide to attenuate immunogenicity of hTSH-R peptide 37.DR3 transgenic mice were immunized to recombinant hTSH-R-ECD protein or peptides. A mutant hTSH-R 37 peptide (ISRIYVSIDATLSQLES: 37m), in which DR3 binding motif position 5 was mutated V>A, and position 8 Q>S, was synthesized. 37m should bind to HLA-DR3, but not bind T-cell receptors. DR3 transgenic mice were immunized to hTSH-R 37 and 37m.Mice immunized to hTSH-R-ECD protein developed strong anti hTSH-R antibody, and antisera reacted strongly with hTSH-R peptides 1-5 (20-94), 21(258-277), 41(283-297), 36(376-389), and 31(399-418). Strikingly, antisera raised to hTSH-R peptide 37 bound to hTSH-R peptides 1-7(20-112), 10(132-50), 33(137-150), 41, 23(286-305), 24(301-320), 36, and 31, as well as to hTSH-R-ECD protein. Both antibody titers to hTSH-R 37, and reaction of splenocytes to hTSH-R 37, were significantly reduced in mice immunized to hTSH-R 37 plus 37m, compare to mice immunized to hTSH-R 37 alone.The ability of immunization to a single peptide to induce antibodies that bind hTSH-R-ECD protein, and multiple unrelated peptides, is a unique observation. Immunogenic reaction to hTSH-R peptide 37 was partially suppressed by 37m, and this may contribute to immunotherapy of AITD. 22625416 Flax terpenoid pathway as a source of health promoting compounds. Flax is an important crop plant grown mainly for its fiber and seeds, which are also rich in omega-3 fatty acids and valuable antioxidants derived from the terpenoid pathways including carotenoids, tocochromanols and sterols. Many of those components found in flax have been recently shown to positively influence human health. Although terpenes vary greatly in their chemical structure, mainly two mechanisms of their biological activity can be considered: direct antioxidation, and a recently explored one, connected to specific receptor and cell signaling pathway activation. Recent studies show that many of the health promoting agents derived from flax act through both of the mentioned mechanisms, resulting in synergistic physiological effects. The work summarizes the two mechanisms, focusing mainly on the one involving cell signaling, as a promising target for medicine and pharmacotherapy. 23363576 Hepatoprotective effect of carob against acute ethanol-induced oxidative stress in rat. The present study was undertaken to determine whether subacute treatment with aqueous extract of carob (Ceratonia siliqua L.) pods (AECPs) protects against ethanol (EtOH)-induced oxidative stress in rat liver. Animals were divided into four groups: control, carob, EtOH and EtOH + carob. Wistar rats were intraperitoneally pretreated with AECP (600 mg/kg body weight (bw)) during 7 days and intoxicated for 6 h by acute oral administration of EtOH (6 g/kg bw) 24 h after the last injection. We found that acute administration of EtOH leads to hepatotoxicity as monitored by the increase in the levels of hepatic marker aspartate aminotransferase and alanine aminotransferase as well as hepatic tissue injury. EtOH also increased the formation of malondialdehyde in the liver, indicating an increase in lipid peroxidation and depletion of antioxidant enzyme activities as superoxide dismutase, catalase and glutathione peroxidase. Subacute carob pretreatment prevented all the alterations induced by EtOH and returned their levels to near normal. Importantly, we showed that acute alcohol increased hepatic and plasmatic hydrogen peroxide and free iron levels. The carob pretreatment reversed EtOH effects to near control levels. These data suggest that carob could have a beneficial effect in inhibiting the oxidative damage induced by acute EtOH administration and that its mode of action may involve an opposite effect on plasma and tissue-free iron accumulation. Indeed, carob can be offered as a food additive to protect against EtOH-induced oxidative damage. 23611124 Preliminary Structure-Activity Relationships and Biological Evaluation of Novel Antitubercular Indolecarboxamide Derivatives Against Drug-Susceptible and Drug-Resistant Mycobacterium tuberculosis Strains. Tuberculosis (TB) remains one of the leading causes of mortality and morbidity worldwide, with approximately one-third of the world's population infected with latent TB. This is further aggravated by HIV coinfection and the emergence of multidrug- and extensively drug-resistant (MDR and XDR, respectively) TB; hence the quest for highly effective antitubercular drugs with novel modes of action is imperative. We report herein the discovery of an indole-2-carboxamide analogue, 3, as a highly potent antitubercular agent, and the subsequent chemical modifications aimed at establishing a preliminary body of structure-activity relationships (SARs). These efforts led to the identification of three molecules (12-14) possessing an exceptional activity in the low nanomolar range against actively replicating Mycobacterium tuberculosis , with minimum inhibitory concentration (MIC) values lower than those of the most prominent antitubercular agents currently in use. These compounds were also devoid of apparent toxicity to Vero cells. Importantly, compound 12 was found to be active against the tested XDR-TB strains and orally active in the serum inhibition titration assay. 23295739 Adaptive changes in basal and stress-induced HPA activity in lactating and post-lactating female rats. Lactation represents a period of marked adaptation of the hypothalamo-pituitary-adrenal HPA axis. We characterized basal and stress-induced HPA activity during lactation and experimental weaning using dynamic blood sampling in rats. Pulsatile and diurnal corticosterone release occurred at all reproductive stages studied (virgin; day 10 of lactation; 3 and 14 days after experimental weaning on day 10 of lactation). However, in lactating rats the diurnal peak was significantly reduced, resulting in a flattened rhythm, and three days after weaning, basal HPA activity was markedly suppressed: the number of pulses and underlying basal levels of corticosterone were reduced and the diurnal rise phase delayed. Marked changes in the HPA response to 10 min noise stress also occurred at these times: being completely absent in lactating animals, but restored and highly prolonged in early weaned animals. Injection of methylprednisolone (2 mg, iv) was used to determine whether changes in fast glucocorticoid suppression correlated with these adaptive changes. Methylprednisolone induced a rapid suppression of corticosterone in virgin animals, but this effect was markedly attenuated in lactating and early weaned animals and was accompanied by significant changes in relative expression of hippocampal glucocorticoid and mineralocorticoid receptor mRNA. All effects were reversed or partially reversed 14 days after experimental weaning. Thus, the presence of the pups has an important influence on regulation of the HPA axis, and while postpartum adaptations are reversible, acute weaning evokes marked reorganisation of basal and stress-induced HPA activity. 23556446 Association of ATP-binding cassette transporter variants with the risk of Alzheimer's disease. Aim: A number of studies have demonstrated that ABCB1 and BCRP (ABCG2) actively transport Aβ. We aimed to investigate the association of genetic variants of selected multidrug transporters with Alzheimer's disease (AD) in histopathologically confirmed AD cases and controls. Materials & methods: DNA from brain tissue of 71 AD cases with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropathological stages B/C and 81 controls was genotyped for selected variants in ABCA1, ABCA7, ABCB1, ABCC2 and ABCG2. In addition, the APOE4 status was analyzed. Results: The novel ABCA7 SNP, rs3752246, tended to be associated with AD in our study. Variants in ABCB1 were significantly less frequent in AD cases older than 65 years of age and among females. This association of ABCB1 2677G>T (rs2032582) was more pronounced in APOE4-negative cases (p = 0.005). However, only ABCC2 3972C>T (rs3740066) was significantly associated with AD risk after logistic regression analysis including all variants. Other transporters showed a lack of association. Conclusion: Our results support the hypothesis that ABCB1 and possibly other ABC-transporters are involved in the process of Aβ accumulation in the aging brain and may modulate the risk for AD in an allele-specific manner, and thus might represent a new target for prevention and treatment of AD. Original submitted 8 October 2012; Revision submitted 22 January 2013. 23484622 UVA Radiation Induced Ultrafast Electron Transfer from a Food Carcinogen Benzo[a]pyrene to Organic Molecules, Biological Macromolecules, and Inorganic Nano Structures. Reactions involving electron transfer (ET) and reactive oxygen species (ROS) play a pivotal role in carcinogenesis and cancer biochemistry. Our present study emphasizes UVA radiation induced ET reaction as one of the key aspects of a potential carcinogen, benzo[a]pyrene (BP), in the presence of a wide variety of molecules covering organic p-benzoquinone (BQ), biological macromolecules like calf-thymus DNA (CT-DNA), human serum albumin (HSA) protein, and inorganic zinc oxide (ZnO) nanorods (NRs). Steady-state and picosecond-resolved fluorescence spectroscopy have been used to monitor such ET reactions. Physical consequences of BP association with CT-DNA have been investigated through temperature-dependent circular dichroism (CD) spectroscopy. The temperature-dependent steady-state, picosecond-resolved fluorescence lifetime and anisotropy studies reveal the effect of temperature on the perturbation of such ET reactions from BP to biological macromolecules, highlighting their temperature-dependent association. Furthermore, the electron-donating property of BP has been corroborated by measuring wavelength-dependent photocurrent in a BP-anchored ZnO NR-based photodevice, offering new physical insights for the carcinogenic study of BP. 23275440 Ribosomal protein S25 dependency reveals a common mechanism for diverse internal ribosome entry sites and ribosome shunting. During viral infection or cellular stress, cap-dependent translation is shut down. Proteins that are synthesized under these conditions use alternative mechanisms to initiate translation. This study demonstrates that at least two alternative translation initiation routes, internal ribosome entry site (IRES) initiation and ribosome shunting, rely on ribosomal protein S25 (RPS25). This suggests that they share a mechanism for initiation that is not employed by cap-dependent translation, since cap-dependent translation is not affected by the loss of RPS25. Furthermore, we demonstrate that viruses that utilize an IRES or a ribosome shunt, such as hepatitis C virus, poliovirus, or adenovirus, have impaired amplification in cells depleted of RPS25. In contrast, viral amplification of a virus that relies solely on cap-dependent translation, herpes simplex virus, is not hindered. We present a model that explains how RPS25 can be a nexus for multiple alternative translation initiation pathways. 23449201 Influence of binder droplet dimension on granulation rate during fluidized bed granulation. Here, we statistically identified the critical factor of the granulation rate during the fluidized bed granulation process. Lactose was selected as the excipient and was granulated with several binders, including hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone. The viscosity, density, and surface tension of the binder solution, contact angle, and the work done during adhesion and cohesion between the binder and lactose, mist diameter, Stokes number, and the dimension of the droplet were considered. The Stokes number was defined as the ratio of the inertial force to the viscous-damping force of a particle. We confirmed that droplet diameter after adhesion had the highest correlation coefficient with the granulation rate constant in our investigated parameters. Partial least squares regression revealed two critical principal components of the granulation rate: one relating to the droplet dimension, which is composed of mist diameter and diameter and thickness of the droplet after adhesion of the binder to the lactose surface; and the other relating to wettability, which involves the work done during adhesion and cohesion, surface tension, and the thickness of the droplet after adhesion of the binder to the lactose surface. 23553679 Validation of a Novel Approach for Dose Individualization in Pharmacotherapy Using Gabapentin in a Proof of Principles Study. STUDY OBJECTIVE: To demonstrate the premise of individualized dosing charts (IDCs) as a clinical-bedside decision-support tool to individualize dosage regimens for drugs in which the interpatient variability is controlled by the pharmacokinetic (PK) behavior of the patient, to calculate the optimal sampling schedule (OSS), which minimizes the number of blood samples per patient. The approach is illustrated with available PK data for gabapentin. DESIGN: Retrospective proof of principles study using gabapentin PK data from a published clinical trial. PATIENTS: Nineteen subjects in a trial designed to uncover the importance of the genetic contributions to variability in gabapentin absorption, renal elimination, and transport; subjects were monitored for 36 hours after administration of a single dose of gabapentin 400 mg, and plasma concentrations were determined at 14 time points. MEASUREMENTS AND MAIN RESULTS: When the PK profiles were different between subjects, the IDCs are dramatically different from each other and from the IDC for an "average" patient representing the patient population. The dose amount and dosing interval must be adjusted to maximize the probability of staying within the target concentration range. An optimal sampling methodology based on the assumption-free Bayesian approach is used to distinguish the PK profile of an individual patient from the patient population. In the case of gabapentin, only two optimally selected test blood samples, at 1.5 and 6 hours after administration of a single doses, were necessary. The average sensitivity and the average specificity of the OSS was 99% and 96%, respectively. CONCLUSION: IDCs display the risk of a patient violating the target concentration range for any dosage regimen. They can be used as a clinical-bedside decision-support tool in a patient-physician partnership to decide on a dose amount and dosing interval that are medically acceptable while practical and convenient to ensure compliance. By using the assumption-free Bayesian approach and the OSS, the number of samples required from a new patient to individualize the dosage regimen can be reduced significantly while preserving high levels of sensitivity and specificity. Prospective studies are being planned to validate the encouraging results. This approach can be extended to any drug if PK data and a target concentration range are available for either therapeutic drug monitoring or target concentration intervention. 23296122 A RASSCF study of free base, magnesium and zinc porphyrins: accuracy versus efficiency. The restricted-active-space self-consistent-field methodology is successfully applied to the study of free base- and regular metalloporphyrins, the latter containing magnesium and zinc central ions. It is shown that inclusion of all excitations involving the Gouterman frontier orbitals in the RAS2 subspace results in a numerically stable approach, producing highly accurate results at a fraction of the computational cost of the complete-active-space self-consistent-field method, whereas increasing RAS2 beyond this size leads to only modest improvement. Topological and orbital analysis shows that the approach is also able to give a highly accurate description of the electronic wavefunction. Inclusion of the entire π-conjugated subsystem in the active space results in more accurate excitation energies and a reduction in the dependence on the exact form of the perturbational Hamiltonian used to include dynamic correlation. The larger active space also resolves a quantitative disagreement in results obtained with and without the inclusion of dynamic correlation. 23521014 Barriers to superfast water transport in carbon nanotube membranes. Carbon nanotube (CNT) membranes hold the promise of extraordinary fast water transport for applications such as energy efficient filtration and molecular level drug delivery. However, experiments and computations have reported flow rate enhancements over continuum hydrodynamics that contradict each other by orders of magnitude. We perform large scale molecular dynamics simulations emulating for the first time the micrometer thick CNTs membranes used in experiments. We find transport enhancement rates that are length dependent due to entrance and exit losses but asymptote to 2 orders of magnitude over the continuum predictions. These rates are far below those reported experimentally. The results suggest that the reported superfast water transport rates cannot be attributed to interactions of water with pristine CNTs alone. 23253441 The discovery of fused oxadiazepines as gamma secretase modulators for treatment of Alzheimer's disease. In an attempt to further improve overall profiles of the oxadiazine series of GSMs, in particular the hERG activity, conformational modifications of the core structure resulted in the identification of fused oxadiazepines such as 7i which had an improved hERG inhibition profile and was a highly efficacious GSM in vitro and in vivo in rats. These SAR explorations offer opportunities to identify potential drugs to treat Alzheimer's disease. 23588997 Modelling zirconium hydrides using the special quasirandom structure approach. The study of the structure and properties of zirconium hydrides is important for understanding the embrittlement of zirconium alloys used as cladding in light water nuclear reactors. Simulation of the defect processes is complicated due to the random distribution of the hydrogen atoms. We propose the use of the special quasirandom structure approach as a computationally efficient way to describe this random distribution. We have generated six special quasirandom structure cells based on face centered cubic and face centered tetragonal unit cells to describe ZrH2-x (x = 0.25-0.5). Using density functional theory calculations we investigate the mechanical properties, stability, and electronic structure of the alloys. 23218713 Inhibition of norovirus 3CL protease by bisulfite adducts of transition state inhibitors. Noroviruses are the most common cause of acute viral gastroenteritis, accounting for >21 million cases annually in the US alone. Norovirus infections constitute an important health problem for which there are no specific antiviral therapeutics or vaccines. In this study, a series of bisulfite adducts derived from representative transition state inhibitors (dipeptidyl aldehydes and α-ketoamides) was synthesized and shown to exhibit anti-norovirus activity in a cell-based replicon system. The ED(50) of the most effective inhibitor was 60 nM. This study demonstrates for the first time the utilization of bisulfite adducts of transition state inhibitors in the inhibition of norovirus 3C-like protease in vitro and in a cell-based replicon system. The approach described herein can be extended to the synthesis of the bisulfite adducts of other classes of transition state inhibitors of serine and cysteine proteases, such as α-ketoheterocycles and α-ketoesters. 23118019 In vivo and in vitro characterization of naltrindole-derived ligands at the κ-opioid receptor. Accumulating evidence supports a role for κ-opioid receptor antagonists in the treatment of mood disorders. Standard κ-antagonists have an unusual pharmacodynamic action, with a single injection blocking receptor signaling for several weeks. Here, we have characterized the κ-selective properties of two ligands, 5'-(2-aminomethyl) naltrindole (5'-AMN) and N-((Naltrindol-5-yl) methyl) pentanimidamide (5'-MABN), to identify whether modifications of the naltrindole side chain produces short-acting κ-antagonists. Opioid receptor binding affinity and activity were assessed using [(3)H]-diprenorphine binding, guanosine-5'-O-(3-[35S]-thio) triphosphate ([(35)S]-GTPγS) binding and isolated guinea-pig ileum. Pharmacodynamic profiles of 5'-AMN and 5'-MABN (1-10 mg/kg) were investigated using the tail-withdrawal assay and diuresis. Efficacy was also determined in depression- and anxiety-related behavioral paradigms in CD-1 mice. Both 5'-AMN and 5'-MABN had high affinity for κ-receptors (K (i) 1.36 ± 0.98 and 0.27 ± 0.08, respectively) and were revealed as potent κ-antagonists (pA(2) 7.43 and 8.18, respectively) and μ-receptor antagonists (pA(2) 7.62 and 7.85, respectively) in the ileum. Contrary to our hypothesis, in vivo, 5'-AMN and 5'-MABN displayed long-lasting antagonist effects in mice, reducing the antinociceptive actions of U50,488 (10 mg/kg) at 28 and 21 days post-injection, respectively. Interestingly, while 5'-AMN and 5'-MABN were not κ-selective, both compounds did show significant antidepressant- and anxiolytic-like effects at 7-14 days post-injection in mice. 23232059 Cynaropicrin from Cynara scolymus L. suppresses photoaging of skin by inhibiting the transcription activity of nuclear factor-kappa B. Aging of skin is characterized by skin wrinkling, laxity, and pigmentation induced by several environmental stress factors. Histological changes during the photoaging of skin include hyperproliferation of keratinocytes and melanocytes causing skin wrinkles and pigmentation. Nuclear factor kappa B (NF-κB) is one of the representative transcription factors active in conjunction with inflammation. NF-κB is activated by stimulation such as ultraviolet rays and inflammatory cytokines and induces the expression of various genes such as those of basic fibroblast growth factor (bFGF) and matrix metalloprotease-1 (MMP-1). We screened several plant extracts for their possible inhibitory effect on the transcriptional activity of NF-κB. One of them, an extract from Cynara scolymus L., showed a greatest effect on the suppression of NF-κB transactivation. As a result, we found that cynaropicrin, which is a sesquiterpene lactone, inhibited the NF-κB-mediated transactivation of bFGF and MMP-1. Furthermore, it was confirmed that in an in vivo mouse model cynaropicrin prevented skin photoaging processes leading to the hyperproliferation of keratinocytes and melanocytes. These findings taken together indicate that cynaropicrin is an effective antiphotoaging agent that acts by inhibiting NF-κB-mediated transactivation. 23583036 Structure and T Cell Inhibition Properties of B7 Family Member, B7-H3. T cell activity is controlled by a combination of antigen-dependent signaling through the T cell receptor and a set of auxiliary signals delivered through antigen-independent interactions, including the recognition of the B7 family of ligands. B7-H3 is a recently identified B7 family member that is strongly overexpressed in a range of cancers and correlates with poor prognosis. We report the crystal structure of murine B7-H3 at a 3 Å resolution, which provides a model for the organization of the IgV and IgC domains within the ectodomain. We demonstrate that B7-H3 inhibits T cell proliferation and show that the FG loop of the IgV domain plays a critical role in this function. B7-H3 crystallized as an unusual dimer arising from the exchange of the G strands in the IgV domains of partner molecules. This arrangement, in combination with previous reports, highlights the dynamic nature and plasticity of the immunoglobulin fold. 23346898 Giant Ising-type magnetic anisotropy in trigonal bipyramidal Ni(II) complexes: experiment and theory. This paper reports the experimental and theoretical investigations of two trigonal bipyramidal Ni(II) complexes, [Ni(Me(6)tren)Cl](ClO(4)) (1) and [Ni(Me(6)tren)Br](Br) (2). High-field, high-frequency electron paramagnetic resonance spectroscopy performed on a single crystal of 1 shows a giant uniaxial magnetic anisotropy with an experimental D(expt) value (energy difference between the M(s) = ± 1 and M(s) = 0 components of the ground spin state S = 1) estimated to be between -120 and -180 cm(-1). The theoretical study shows that, for an ideally trigonal Ni(II) complex, the orbital degeneracy leads to a first-order spin-orbit coupling that results in a splitting of the M(s) = ± 1 and M(s) = 0 components of approximately -600 cm(-1). Despite the Jahn-Teller distortion that removes the ground term degeneracy and reduces the effects of the first-order spin-orbit interaction, the D value remains very large. A good agreement between theoretical and experimental results (theoretical D(theor) between -100 and -200 cm(-1)) is obtained. 23562597 Structure-activity relationship of cytochrome bc1 reductase inhibitor broad spectrum antifungal ilicicolin H. Ilicicolin H is a broad spectrum antifungal agent showing sub micro g/mL MICs against Candida spp., Aspergillus fumigatus and Cryptococcus spp. It is a potent inhibitor (C50 2-3ng/mL) of the mitochondrial cytochrome bc1 reductase with over 1000-fold selectivity against rat liver cytochrome bc1 reductase. Structure-activity relationship of semisynthetic derivatives by chemical modification of ilicicolin H and its 19-hydroxy derivative produced by biotransformation have been described. Basic 4'-esters and moderately polar N- and O-alkyl derivatives retained antifungal and the cytochrome bc1 reductase activities. 4',19-Diacetate and 19-cyclopropyl acetate retained antifungal and enzyme activity and selectivity with over 20-fold improvement of plasma protein binding. 23340646 A rationally designed dual role anode material for lithium-ion and sodium-ion batteries: case study of eco-friendly Fe3O4. Identifying dual role electrode materials capable of storing both lithium and sodium are thought to be highly relevant, as these materials could find potential applications simultaneously in lithium and sodium ion batteries. In this regard, the concept of dual alkali storage is demonstrated in Fe(3)O(4) anode material undergoing conversion reaction. To enable improved storage, a rational active material and electrode design is proposed. Accordingly, the following features were simultaneously incorporated into the design: (i) an optimal particle size, (ii) a conducting matrix, (iii) adequately large active material surface area and (iv) strong electrode material-current collector integrity. Electrodes incorporating this rational design exhibit excellent high rate performance and impressive cyclability during lithium storage. For instance, Fe(3)O(4) electrodes deliver a charge capacity of 950 mAh g(-1) at 1.2 C (~2.6 times higher than graphite and 5.4 times higher than Li(4)Ti(5)O(12)). Further, these electrodes show no signs of capacity fade even up to 1100 cycles. Impressively, the cells could also be charged-discharged to 65% of their theoretical capacity in just 5 min or 12 C (11.11 A g(-1)). The rate performance and cyclability of lithium storage achieved here are amongst the highest reported values in the literature for the conversion reaction in Fe(3)O(4). Besides lithium storage, the dual role of this anode is shown by demonstrating its sodium storage ability by conversion reaction for the first time. 23579333 Co-Ni layered double hydroxides for water oxidation in neutral electrolyte. The electrochemical properties of Co-Ni layered double hydroxides (LDHs) as efficient electrocatalysts for water oxidation were investigated in potassium phosphate electrolyte under neutral pH condition. The Co-Ni LDHs with a core-shell structure were fabricated using a facile route from a Co-Ni hydroxide precursor with iodine as a topotactic oxidizer. The unique core-shell morphology is likely due to the enrichment of Co(iii) hydroxide in the inner core indicated by selected area electron diffraction and energy-dispersive spectroscopy. Through a self-assembling process at the organic/inorganic interface and dip-coating, the Co-Ni LDHs were deposited onto FTO glass substrates to prepare composite electrodes. Low over-potential and high current density was achieved in the oxygen evolution reaction. The excellent electrocatalytic activity of Co-Ni LDHs may be attributed to more accessible Co active sites and rapid movement of interlayer ions within their layered structure. 23411335 Physicochemical responses and microbial characteristics of shiitake mushroom (Lentinus edodes) to gum arabic coating enriched with natamycin during storage. Physicochemical responses and microbial characteristics of shiitake mushroom (Lentinus edodes) to gum arabic (GA) coating incorporating natamycin (NA) during storage were investigated. Mushroom weight loss, firmness, total soluble solids, total sugar, reducing sugar, ascorbic acid, and microbial and sensory quality were measured. Mushroom coated with gum arabic+natamycin (GANA) maintained tissue firmness and showed reduction in microbial counts from yeasts and moulds compared with the control. In addition, GANA coating also delayed changes in the soluble solids concentration, total sugar and ascorbic acid. Sensory evaluation proved the efficacy of GANA coating by maintaining the overall quality of shiitake mushroom during the storage period. The efficiency was better than that of GA or NA treatment alone. Our study suggests that GANA has the potential to improve the quality of shiitake mushroom and extend its shelf-life up to 16d. 23435649 Marine ecosystem health status assessment through integrative biomarker indices: a comparative study after the Prestige oil spill "Mussel Watch". Five integrative biomarker indices are compared: Bioeffects Assessment Index (BAI), Health Status Index (HSI), integrated biological response (IBR), ecosystem health condition chart (EHCC) and Integrative Biomarker Index (IBI). They were calculated on the basis of selected biomarker data collected in the framework of the Prestige oil spill (POS) Mussel Watch monitoring (2003-2006) carried out in Galicia and the Bay of Biscay. According to the BAI, the health status of mussels was severely affected by POS and signals of recovery were evidenced in Galicia after April-04 and in Biscay Bay after April-05. The HSI (computed by an expert system) revealed high levels of environmental stress in 2003 and a recovery trend from April-04 to April-05. In July-05, the health status of mussels worsened but in October-05 and April-06 healthy condition was again recorded in almost all localities. IBR/n and IBI indicated that mussel health was severely affected in 2003 and improved from 2004 onwards. EHCC reflected a deleterious environmental condition in 2003 and a recovery trend after April-04, although a healthy ecosystem condition was not achieved in April-06 yet. Whereas BAI and HSI provide a basic indication of the ecosystem health status, star plots accompanying IBR/n and IBI provide complementary information concerning the mechanisms of biological response to environmental insult. Overall, although the integrative indices based on biomarkers show different sensitivity, resolution and informative output, all of them provide coherent information, useful to simplify the interpretation of biological effects of pollution in marine pollution monitoring. Each others' advantages, disadvantages and applicability for ecosystem health assessment are discussed. 23122141 Medium chain and behenic acid incorporated structured lipids from sal, mango and kokum fats by lipase acidolysis. Medium chain (MC) and behenic fatty acids were incorporated into kokum, sal and mango fats using 1,3-specific lipase catalysed acidolysis. The incorporation of fatty acids increased with increase in concentration of fatty acids and duration of reaction. The order of incorporation of fatty acids was C22:0>C10:0>C8:0, to the extent of 53%, 42.5%, 35.8%, respectively, after 16 h, using kokum as substrate. The same trend was observed with sal or mango fats as substrates though the percentages incorporated were different. The modified products with higher contents of MC were liquids with no solid fats, even at 0°C, and which showed low cloud point due to an increase in triacylglycerols containing lower chain fatty acids. The modified products after incorporating both MC and C22:0 showed long melting ranges and were suitable for use in bakery, confectionery, etc. as vanaspati substitutes. 23509853 Enhanced Catalytic Four-Electron Dioxygen (O2) and Two-Electron Hydrogen Peroxide (H2O2) Reduction with a Copper(II) Complex Possessing a Pendant Ligand Pivalamido Group. A copper complex, [(PV-tmpa)Cu(II)](ClO4)2 (1) [PV-tmpa = bis(pyrid-2-ylmethyl){[6-(pivalamido)pyrid-2-yl]methyl}amine], acts as a more efficient catalyst for the four-electron reduction of O2 by decamethylferrocene (Fc*) in the presence of trifluoroacetic acid (CF3COOH) in acetone as compared with the corresponding copper complex without a pivalamido group, [(tmpa)Cu(II)](ClO4)2 (2) (tmpa = tris(2-pyridylmethyl)amine). The rate constant (kobs) of formation of decamethylferrocenium ion (Fc*(+)) in the catalytic four-electron reduction of O2 by Fc* in the presence of a large excess CF3COOH and O2 obeyed first-order kinetics. The kobs value was proportional to the concentration of catalyst 1 or 2, whereas the kobs value remained constant irrespective of the concentration of CF3COOH or O2. This indicates that electron transfer from Fc* to 1 or 2 is the rate-determining step in the catalytic cycle of the four-electron reduction of O2 by Fc* in the presence of CF3COOH. The second-order catalytic rate constant (kcat) for 1 is 4 times larger than the corresponding value determined for 2. With the pivalamido group in 1 compared to 2, the Cu(II)/Cu(I) potentials are -0.23 and -0.05 V vs SCE, respectively. However, during catalytic turnover, the CF3COO(-) anion present readily binds to 2 shifting the resulting complex's redox potential to -0.35 V. The pivalamido group in 1 is found to inhibit anion binding. The overall effect is to make 1 easier to reduce (relative to 2) during catalysis, accounting for the relative kcat values observed. 1 is also an excellent catalyst for the two-electron two-proton reduction of H2O2 to water and is also more efficient than is 2. For both complexes, reaction rates are greater than for the overall four-electron O2-reduction to water, an important asset in the design of catalysts for the latter. 23348514 Effects of metformin on burn-induced hepatic endoplasmic reticulum stress in male rats. Severe burn injury causes hepatic dysfunction that results in major metabolic derangements including insulin resistance and hyperglycemia and is associated with hepatic endoplasmic reticulum (ER) stress. We have recently shown that insulin reduces ER stress and improves liver function and morphology; however, it is not clear whether these changes are directly insulin mediated or are due to glucose alterations. Metformin is an antidiabetic agent that decreases hyperglycemia by different pathways than insulin; therefore, we asked whether metformin affects postburn ER stress and hepatic metabolism. The aim of the present study is to determine the effects of metformin on postburn hepatic ER stress and metabolic markers. Male rats were randomized to sham, burn injury and burn injury plus metformin and were sacrificed at various time points. Outcomes measured were hepatic damage, function, metabolism and ER stress. Burn-induced decrease in albumin mRNA and increase in alanine transaminase (p < 0.01 versus sham) were not normalized by metformin treatment. In addition, ER stress markers were similarly increased in burn injury with or without metformin compared with sham (p < 0.05). We also found that gluconeogenesis and fatty acid metabolism gene expressions were upregulated with or without metformin compared with sham (p < 0.05). Our results indicate that, whereas thermal injury results in hepatic ER stress, metformin does not ameliorate postburn stress responses by correcting hepatic ER stress. 23363407 Highly luminescent and photostable quantum dot-silica monolith and its application to light-emitting diodes. A highly luminescent and photostable quantum dot-silica monolith (QD-SM) substance was prepared by preliminary surface exchange of the QDs and base-catalyzed sol-gel condensation of silica. The SM was heavily doped with 6-mercaptohexanol exchanged QDs up to 12 vol % (26 wt %) without particle aggregation. Propylamine catalyst was important in maintaining the original luminescence of the QDs in the SM during sol-gel condensation. The silica layer was a good barrier against oxygen and moisture, so that the QD-SM maintained its initial luminescence after high-power UV radiation (∼1 W) for 200 h and through the 150 °C LED encapsulant curing process. Green and red light-emitting QD-SMs were applied as color-converting layers on blue LEDs, and the external quantum efficiency reached up to 89% for the green QD-SM and 63% for the red one. A white LED made with a mixture of green and red QDs in the SM, in which the color coordinate was adjusted at (0.23, 0.21) in CIE1931 color space for a backlight application, showed an efficacy of 47 lm/W, the highest value yet reported. 23161804 Enantiomeric discrimination of isoxazoline fused β-amino acid derivatives using (18-crown-6)-2,3,11,12-tetracarboxylic acid as a chiral NMR solvating agent. (18-Crown-6)-2,3,11,12-tetracarboxylic acid is a useful chiral NMR solvating agent for isoxazoline-fused β-amino acid derivatives. Isoxazoline substrates are analyzed as their hydrochloride salts in methanol-d(4). The crown ether and substrate associate through the formation of three hydrogen bonds between the protonated amine and crown ether oxygen atoms. Enantiomeric discrimination is observed for two or more resonances of every substrate. At least one of these resonances is free of overlap with other resonances in the spectrum and has large enough enantiomeric discrimination to enable the determination of enantiomeric purity. 2D COSY methods can be used to identify additional resonances that exhibit enantiomeric discrimination in the NMR spectrum. 23600648 Two new glycosides from the florets of Carthamus tinctorius. Two new glycoside compounds, named saffloquinoside C (1) and (-)-4-hydroxybenzoic acid-4-O-[6'-O-(2″-methylbutyryl)-β-D-glucopyranoside] (2), were isolated from the florets of Carthamus tinctorius. Their structures were elucidated by detailed spectroscopic means including UV, IR, HR-ESI-MS, 1D and 2D NMR, and CD data. Compound 1 was a rare quinochalcone glycoside with six five-membered dioxaspirocycle. 23631553 Bio-based Chitosan/Polybenzoxazine Crosslinked Films: Preparation in Aqueous Media and Synergistic Improvements in Thermal and Mechanical Properties. A novel class of polymer blends has been prepared from main-chain type benzoxazine polymer (MCBP) and chitosan (CTS), a modified biomacromolecule. A water-soluble, main-chain type benzoxazine polymer, MCBP(BA-tepa), was synthesized from the reaction of bisphenol-A (BA), tetraethylenepentamine (TEPA) and formalin. The structure of the MCBP(BA-tepa) was confirmed by proton nuclear magnetic resonance spectroscopy (1H-NMR) and Fourier transform infrared spectroscopy (FT-IR). The polymer blends were prepared by mixing MCBP(BA-tepa) and chitosan (CTS) in aqueous acetic acid solution (1%). The CTS/MCBP(BA-tepa) films are crosslinked by thermal treatment via the ring-opening polymerization of benzoxazine structures in the main chain to produce AB-crosslinked network. Differential scanning calorimetry and FT-IR were used to study the effects of chitosan on the polymerization behavior of benzoxazine. Hydrogen bonding between polybenzoxazine and chitosan structures was also observed. The mechanical and thermal properties of crosslinked CTS/MCBP(BA-tepa) films were evaluated and the results show unusual levels of synergism. In particular, the tensile strength and thermal stability were significantly enhanced in a non-linear fashion. Keywords: Polybenzoxazine; chitosan; crosslinked films; mechanical and thermal properties. 23643528 Cross-protection by co-immunization with influenza hemagglutinin DNA and inactivated virus vaccine using coated microneedles. The need for annual revaccination against influenza is a burden on the healthcare system, leads to low vaccination rates and makes timely vaccination difficult against pandemic strains, such as during the 2009 H1N1 influenza pandemic. In an effort toward achieving a broadly protective vaccine that provides cross-protection against multiple strains of influenza, this study developed a microneedle patch to co-immunize with A/PR8 influenza hemagglutinin DNA and A/PR8 inactivated virus vaccine. We hypothesize that this dual component vaccination strategy administered to the skin using microneedles will provide cross-protection against other strains of influenza. To test this hypothesis, we developed a novel coating formulation that did not require additional excipients to increase coating solution viscosity by using the DNA vaccine itself to increase viscosity and thereby enable thick coatings of DNA vaccine and inactivated virus vaccine on metal microneedles. Co-immunization in this way not only generated robust antibody responses against A/PR8 influenza but also generated robust heterologous antibody responses against pandemic 2009 H1N1 influenza in mice. Challenge studies showed complete cross-protection against lethal challenge with live pandemic 2009 H1N1 virus. Control experiments using A/PR8 inactivated influenza virus vaccine with placebo DNA coated onto microneedles produced lower antibody titers and provided incomplete protection against challenge. Overall, this is the first study showing DNA solution as a microneedle coating agent and demonstrating cross-protection by co-immunization with inactivated virus and DNA vaccine using coated microneedles. 23394542 Interfacing quantum dots and graphitic surfaces with chlorine atomic ligands. The performance of devices based on semiconductor nanocrystals (NCs) improves both with stronger interface interactions among NCs and between NCs and solid electrode surfaces. The combination of X-ray photoelectron spectroscopy (XPS) and solid (31)P CP/MAS NMR (cross-polarization/magic angle spinning nuclear magnetic resonance) shows that the selective substitution of long organic chains by chlorine atomic ligands during the colloidal synthesis by the hot injection method promotes the adsorption of CdSe NCs to carbon sp(2) surfaces, leading to the formation of well-ordered NC monolayers on graphitic materials. 23565060 Promoter Sequence Determines the Relationship between Expression Level and Noise. The ability of cells to accurately control gene expression levels in response to extracellular cues is limited by the inherently stochastic nature of transcriptional regulation. A change in transcription factor (TF) activity results in changes in the expression of its targets, but the way in which cell-to-cell variability in expression (noise) changes as a function of TF activity, and whether targets of the same TF behave similarly, is not known. Here, we measure expression and noise as a function of TF activity for 16 native targets of the transcription factor Zap1 that are regulated by it through diverse mechanisms. For most activated and repressed Zap1 targets, noise decreases as expression increases. Kinetic modeling suggests that this is due to two distinct Zap1-mediated mechanisms that both change the frequency of transcriptional bursts. Notably, we found that another mechanism of repression by Zap1, which is encoded in the promoter DNA, likely decreases the size of transcriptional bursts, producing a unique transcriptional state characterized by low expression and low noise. In addition, we find that further reduction in noise is achieved when a single TF both activates and represses a single target gene. Our results suggest a global principle whereby at low TF concentrations, the dominant source of differences in expression between promoters stems from differences in burst frequency, whereas at high TF concentrations differences in burst size dominate. Taken together, we show that the precise amount by which noise changes with expression is specific to the regulatory mechanism of transcription and translation that acts at each gene. 23462379 Ribosome-inactivating proteins: From toxins to useful proteins. Ribosome-inactivating proteins (RIPs) either single-chain (type 1) or two-chain (type 2) are frequent in plants, often in multiple forms. They are RNA N-glycosidases, have antiviral, antifungal and insecticidal activity. Their expression in plants is increased under stressful conditions. They are investigated for practical applications in medicine and in agriculture. In medicine, RIPs have been linked to, or fused with, appropriate antibodies or other carriers to form "immunotoxins" or other conjugates specifically toxic to the cells target of the carrier, with the aim of eliminating malignant or other undesired cells. In agriculture, it has been observed that an enhanced expression of RIPs confers to plants an increased resistance to viruses, fungi, insects, and also to drought and salinity. 23147032 Understanding the role of gut microbes and probiotics in obesity: how far are we? Obesity has been associated with structural alterations in the gut microbiota, suggesting potential causality between specific microbial taxa and this disorder. Studies in animal models have also provided evidence for plausible gut microbiota mechanisms of action underlying body weight regulation. Yet evidence identifying which specific microbes contribute to or predict obesity is not completely consistent across studies. More recently, diet has also been shown to be primarily involved in regulating the microbiota structure initially related to obesity, suggesting that the role of microbes in energy balance is under the influence of diet. Controversy over the role of components of the gut microbiota in obesity has extended to bacteria, which although weakly related to body weight in observational and human intervention studies, are of interest due to their use as probiotics. This review focuses exclusively on human observational studies and probiotic intervention trials, excluding animal studies and studies in infants at early developmental stages, since such results cannot be extrapolated to human obesity at later stages in life. In this context, evidence for relationships between the gut microbiota composition and obesity and the possible role of probiotics is reviewed, discussing the strengths and weaknesses of the studies conducted to date. 23322648 Structure-activity relationships of glucosamine-derived glycerolipids: the role of the anomeric linkage, the cationic charge and the glycero moiety on the antitumor activity. The potent antitumor activity of 1-O-hexadecyl-2-O-methyl-3-O-(2'-amino-2'-deoxy-β-D-glucopyranosyl)-sn-glycerol (1) was previously shown to arise through an apoptosis-independent pathway. Here, a systematic structure-activity study in which the effects of the anomeric linkage, the cationic charge and the glycero moiety on the antitumor activity is described. Eight analogues of 1 were synthesized, and their antitumor activity against breast (JIMT1 and BT549), pancreas (MiaPaCa2) and prostate (DU145, PC3) cancer was determined. 1-O-Hexadecyl-2-O-methyl-3-O-(2'-amino-2'-deoxy-α-D-glucopyranosyl)-sn-glycerol (2) consistently displayed the most potent activity against all five cell lines with CC(50) values in the range of 6-10 μM. However, replacement of the O-glycosidic linkage by a thioglycosidic linkage or replacement of the amino group by an azide or guanidino group leads to a threefold or greater decrease in potency. The glycero moiety also contributes to the overall activity of 1 and 2 but its effects are of lesser importance. Investigation into the mode of action of this class of compounds revealed that, in agreement with previous findings, the cytotoxic effects arise through induction of large acid vacuoles. 23432203 Development and characterization of monomeric N-end rule inhibitors through in vitro model substrates. In the N-end rule pathway, a set of N-terminal amino acids, called N-degrons, are recognized and ubiquitinated by the UBR proteins. Here we examined various N-end rule inhibitors to identify essential structural components of the system. Our study using in vitro biochemical assay indicated that the l-conformation and protonated α-amino group of the first residue were critical for N-degrons to properly interact with the UBR proteins. The monomeric molecules with minimum interacting motifs showed endopeptidase resistance and better inhibitory activities than traditional dipeptide inhibitors. Collectively, our study identifies a pharmacophore of N-end rule inhibitors, which provides a structural platform to improve the efficiency and druggable properties of inhibitors. Considering that the N-end rule has been implicated in many pathophysiological processes in cells, inhibitors of this pathway, such as p-chloroamphetamine, are potentially of clinical interest in a novel aspect of action mechanisms. 23391441 Ultrasound-aided microbubbles facilitate the delivery of drugs to the inner ear via the round window membrane. The round window membrane (RWM) acts as a barrier between the middle ear and cochlea and can serve as a crucial route for therapeutic medications entering the inner ear via middle ear applications. In this study, we targeted the practical application of microbubbles (MBs) ultrasound on increasing the RWM permeability for facilitating drug or medication delivery to the inner ear. Using biotin-fluorescein isothiocyanate conjugates (biotin-FITC) as delivery agents and guinea pig animal models, we showed that MB ultrasound exposure can improve the inner ear system use of biotin-FITC delivery via the RWM by approximately 3.5 to 38 times that of solely soaking biotin-FITC around the RWM for spontaneous diffusion. We also showed that there was significant enhancement of hair cell uptake of gentamicin in animals whose tympanic bullas were soaked with MB-mixed gentamicin-Texas Red or gentamicin and exposed to ultrasound. Furthermore, increased permeability of the RWM from acoustic cavitation of MBs could also be visualized immediately following ultrasound exposure by using Alexa Fluor 488-conjugated phalloidin as a tracer. Most importantly, such applications had no resulting damage to the integrity of the RWM or deterioration of the hearing thresholds assessed by auditory brainstem responses. We herein provide a basis for MB ultrasound-mediated techniques with therapeutic medication delivery to the inner ear for future application in humans. 23600735 Chemical and preclinical studies on Hedyotis diffusa with anticancer potential. This paper presents the chemical and preclinical anticancer research on Hedyotis diffusa Willd. in detail, one of the most renowned herbs often prescribed in the polyherbal formulas for cancer treatment in traditional Chinese medicine. Anthraquinones, flavonoids, and terpenoids constitute the majority of the 69 compounds that have been isolated and identified from H. diffusa. The anticancer effects of the methanolic, ethanolic, and aqueous extracts in various preclinical cancer models have been described. This review also summarized the anticancer activity of constituents of the herb and the mechanisms of action. All the studies suggest that H. diffusa has enormous potential in the therapy of cancer and warrants further chemical and pharmacological investigation. 23348501 Formation, reactivity, and antiplatelet activity of mixed disulfide conjugates of clopidogrel. In this work, we investigated the formation, reactivity, and antiplatelet activity of various mixed disulfide conjugates of clopidogrel. Our results showed that the production of the active metabolite (AM) from 2-oxoclopidogrel by human liver microsomes (HLMs) is greatly affected by the thiol reductants used. Among the 10 thiol compounds tested, glutathione (GSH) is most efficient in producing the AM at a rate of 167 pmoles AM/min/mg HLM. Interestingly, no AM but only the mixed disulfide conjugates were formed in the presence of 6-chloropyridazine-3-thiol (CPT), 2,5-dimethylfuran-3-thiol, and 3-nitropyridine-2-thiol (NPT). The mass spectrometry (MS) and MS(2) spectra of the conjugates of these thiol compounds confirmed the presence of a mixed disulfide bond linkage between the AM and the thiol reductants. Kinetic studies revealed that the mixed disulfide conjugates were capable of exchanging thiols with GSH to release the AM with second order rate constants ranging from 1.2 to 28 M(-1)s(-1). The mixed disulfide conjugates of CPT and NPT showed potent inhibition of platelet aggregation after pretreatment with 1 mM GSH, confirming that the AM is responsible for the antiplatelet activity of clopidogrel. Collectively, our results provide strong support for a cytochrome P450 (P450)-mediated bioactivation mechanism involving the initial formation of a glutathionyl conjugate, followed by thiol-disulfide exchange with another GSH molecule to release the AM. Furthermore, the stable mixed disulfide conjugates identified in this study provide a platform to quantitatively generate the therapeutic AM without the need for P450-mediated bioactivation. This property can be further explored to overcome the interindividual variability in clopidogrel therapy. 23616387 Click To Bind: Metal Sensors. The copper-catalyzed azide-alkyne "click" cycloaddition reaction is an efficient coupling reaction that results in the formation of a triazole ring. The wide range of applicable substrates for this reaction allows the construction of a variety of conjugated systems. The additional function of triazoles as metal-ion ligands has led to the click reaction being used for the construction of optical sensors for metal ions. The triazoles are integral binding elements, which are formed in an efficient modular synthesis. Herein, we review recent examples of triazoles as a metal-binding element in conjugated metal-ion sensors. 23480798 Are the intramolecular o-h···f and o-h···cl hydrogen bonds maintained in solution? A theoretical study. The present case study aims at calculating the equilibrium conformer compositions for 2X-ethanol and 2X-phenol (X = F, Cl) in solution, and exploring the effect of the applied theoretical method and basis set on the obtained results, as well as considering the usefulness of the continuum solvent approach in comparison with the explicit solvent Monte Carlo model utilizing the free energy perturbation method. Gas-phase optimizations at the DFT/B97D/aug-cc-pvtz and ab initio MP2/aug-cc-pvtz levels predicted structures in good agreement with the available experimental data for three test molecules. Because in-solution geometries change only slightly according to the IEF-PCM continuum solvent calculations in carbon tetrachloride and water, the two theoretical levels were applied further on, and complete basis set (CBS) relative internal free energies were estimated for the conformers under study. The predicted OCCF gauche/trans ratio for 2F-ethanol was well reproduced in comparison with available experimental compositions. The predominant gauche structure maintains an intramolecular hydrogen bond in carbon tetrachloride (HB structure), whereas HB and NoHB gauche conformers appear in nearly the same fraction in aqueous solution. The internally hydrogen-bonded conformer is predominant also for 2X-phenol species, as calculated on the basis of relative CBS internal free energies and IEF-PCM and FEP/MC solvation free energies. Use of a trihydrate supermolecule model for 2F-ethanol conformers leads to the prediction of the aqueous-solution composition in contrast to the experiment. Solution structure modeling predicts weak hydrogen-bond formation capacity for both the covalently bound F and Cl atoms, even in conformations where they are fully exposed to hydration. 23333650 A success in Toxinology translational research in Brazil: Bridging the gap. Basic research is fundamental for discovering potential diagnostic and therapeutic tools, including drugs, vaccines and new diagnostic techniques. On this basis, diagnosis and treatment methods for many diseases have been developed. Presently, discovering new candidate molecules and testing them in animals are relatively easy tasks that require modest resources and responsibility. However, crossing the animal-to-human barrier is still a great challenge that most researchers tend to avoid. Thus, bridging this current gap between clinical and basic research must be encouraged and elucidated in training programmes for health professionals. This project clearly shows the challenges faced by a group of Brazilian researchers who, after discovering a new fibrin sealant through 20 years of painstaking basic work, insisted on having the product applied clinically. The Brazilian government has recently become aware of this challenge and has accordingly defined the product as strategic to the public health of the country. Thus, in addition to financing research and development laboratories, resources were invested in clinical trials and in the development of a virtual platform termed the Virtual System to Support Clinical Research (SAVPC); this platform imparts speed, reliability and visibility to advances in product development, fostering interactions among sponsors, physicians, students and, ultimately, the research subjects themselves. This pioneering project may become a future model for other public institutions in Brazil, principally in overcoming neglected diseases, which unfortunately continue to afflict this tropical country. 23521567 Molecular Dynamics Simulations of DPPC Bilayers Using "LIME", a New Coarse-Grained Model. A new intermediate resolution model for phospholipids, LIME, designed for use with discontinuous molecular dynamics (DMD) simulations is presented. The implicit-solvent model was developed using a multiscale modeling approach in which the geometric and energetic parameters are obtained by collecting data from atomistic simulations of a system composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) molecules and explicit water. In the model, 14 coarse-grained sites that are classified as 1 of 6 types represent DPPC. DMD simulations performed on a random solution of DPPC resulted in the formation of a defect-free bilayer in less than 4 h. The bilayer formed quantitatively reproduces the main structural properties (e.g., area per lipid, bilayer thickness, bond order parameters) that are observed experimentally. In addition, the bilayer transitions from a liquid-crystalline phase to a tilted gel phase when the temperature is reduced. Transbilayer movement of a lipid from the bottom leaflet to the top leaflet is observed when the temperature is increased. 23122168 Optimisation of resistant starch II and III levels in durum wheat pasta to reduce in vitro digestibility while maintaining processing and sensory characteristics. Foods with elevated levels of resistant starch (RS) may have beneficial effects on human health. Pasta was enriched with commercial resistant starches (RSII, Hi Maize™ 1043; RSIII, Novelose 330™) at 10%, 20% and 50% substitution of semolina for RSII and 10% and 20% for RSIII and compared with pasta made from 100% durum wheat semolina to investigate technological, sensory, in vitro starch digestibility and structural properties. The resultant RS content of pasta increased from 1.9% to ∼21% and was not reduced on cooking. Significantly, the results indicate that 10% and 20% RSII and RSIII substitution of semolina had no significant effects on pasta cooking loss, texture and sensory properties, with only a minimal reduction in pasta yellowness. Both RS types lowered the extent of in vitro starch hydrolysis compared to that of control pasta. X-ray diffraction and small-angle scattering verified the incorporation of RS and, compared to the control sample, identified enhanced crystallinity and a changed molecular arrangement following digestion. These results can be contrasted with the negative impact on pasta resulting from substitution with equivalent amounts of more traditional dietary fibre such as bran. The study suggests that these RS-containing formulations may be ideal sources for the preparation of pasta with reduced starch digestibility. 22445601 Differentiating the roles of mGlu2 and mGlu3 receptors using LY541850, an mGlu2 agonist/mGlu3 antagonist. Despite the potential therapeutic relevance of group II metabotropic glutamate (mGlu) receptors, there has been a lack of pharmacological tools for separating the roles of mGlu2 and mGlu3 receptor subtypes. LY541850 was claimed from human mGlu receptors expressed in non-neuronal cells to be a selective orthosteric mGlu2 agonist and mGlu3 antagonist. We have verified this pharmacological profile of LY541850 in hippocampal slices. Field excitatory post-synaptic potentials (fEPSPs) evoked by stimulation of the temporo-ammonic path (TAP) input to CA1 stratum lacunosum moleculare (SLM) were inhibited by LY541850 in mGlu3-/- mice (EC(50) 38 nM) and wild-type littermates (EC(50) 42 nM) to a similar extent but were not significantly affected in mGlu2-/- mice. The group II agonist, DCG-IV, inhibited the fEPSP in all three genotypes. Co-application of DCG-IV and LY541850 in mGlu3-/- and wild-type littermates resulted in an additive effect, whereas in mGlu2-/- mice, LY541850 reversed the inhibitory action of DCG-IV. These results confirm the selective mGlu2 agonist and mGlu3 antagonist actions of LY541850. A similar profile of activity was seen in medial perforant path synapse to the dentate gyrus. Systemic administration of LY541850 to wild-type mice, reduced the increase in locomotor activity following both phencyclidine and amphetamine administration. These data support the hypothesis that mGlu2 receptors mediate the antipsychotic effects of mixed group II agonists. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23521318 Bioassay-guided isolation and identification of antitermitic active compound from the leaf of Chinese cedar (Cryptomeria fortunei Hooibrenk). The persistent use of synthetic termiticides is at present of environmental concern and has resulted in the need to search for plant-derived compounds as an alternative for termite control. Antitermitic activity of Chinese cedar (Cryptomeria fortunei Hooibrenk) against Reticulitermes chinensis was demonstrated in laboratory tests. Bioactivity tests against the termite R. chinensis demonstrate that the lethal concentration (LC50) value of leaf essential oil is 2.80 mg/mL. Furthermore, α-terpineol, which was responsible for the antitermitic property and isolated from Chinese cedar that exhibited very strong antitermitic activity, was found to be significantly effective against R. chinensis with median LC50 values of 0.86 mg/mL. The findings suggested that the essential oil from Chinese cedar leaf and α-terpineol might be considered as a potent source for the production of effective, environmentally friendly and safe termiticides. 23146692 Purification and determination of two novel antioxidant peptides from flounder fish (Paralichthys olivaceus) using digestive proteases. We investigated the effects of bioactive-peptides from hydrolysates of flounder fish muscle (FFM) on antioxidant activity. The hydrolysates were prepared by enzymatic reactions of FFM using eight commercial proteases such as papain, pepsin, trypsin, neutrase, alcalase, kojizyme, protamex, and α-chymotrypsin. The α-chymotrypsin hydrolysate showed the strongest antioxidant activity among the eight enzymatic hydrolysates. Further separation of the α-chymotrypsin hydrolysate was performed by ultrafiltration, gel filtration, and reverse-phase high performance liquid chromatography. Consequently, two novel peptides with high antioxidant activity were purified, and their amino acid sequences were determined (Val-Cys-Ser-Val [VCSV] and Cys-Ala-Ala-Pro [CAAP], respectively). The two peptides showed good scavenging activity against the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical (IC(50) values, 111.32 and 26.89 μM, respectively) and high cytoprotective activities against 2,2-azobis-(2-amidino-propane) dihydrochloride (AAPH) without cytotoxicity and scavenged total reactive oxygen species in Vero cells. In particular, apoptotic bodies produced by AAPH dose-dependently decreased following treatment with the CAAP peptide. These results revealed firstly the two peptides with strong antioxidative effects from FFM. 23454208 Induction of endoplasmic reticulum stress-mediated apoptosis and non-canonical autophagy by luteolin in NCI-H460 lung carcinoma cells. In this study, we investigated the anti-cancer effects of luteolin, a member of the flavonoid family, in NCI-H460 human lung carcinoma cells. It was shown that luteolin induces apoptotic cell death through modulating both the extrinsic pathway and intrinsic pathways, which are suppressed by z-VAD-fmk, indicating that luteolin triggers caspase-dependant apoptosis. Furthermore, we found that the α subunit of the eukaryotic initiation factor 2 (eIF2α/C/EBP homologous protein pathway, but not the c-Jun N-terminal kinase pathway, played a critical role in induction of apoptosis by luteolin. The data indicated that luteolin also induces autophagy; evidence for this is the accumulation of microtubule-associated protein light chain-3 (LC3) II protein, the increase of LC3 puncta as well as an enhanced autophagy flux. In addition, inhibiting autophagy by bafilomycin A1 reduced apoptotic cell death, suggesting that luteolin-induced autophagy functions as a cell death mechanism. Notably, the activated caspases that appeared with luteolin treatment cleaved Beclin-1, and the expression of LC3II remained the same even after cells were challenged with Beclin-1 siRNA, demonstrating that luteolin induces Beclin-1-independent autophagy. Taken together, our findings showed that luteolin triggers both endoplasmic reticulum stress-related apoptosis and non-canonical autophagy, which function as a cell death mechanism in NCI-H460 human lung cancer cells. 22370634 MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells. When mTOR inhibitor rapalogs prevent cap-dependent translation of cell-cycle proteins like c-myc, continuing tumor cell growth depends on cap-independent translation, which is mediated by internal ribosome entry sites (IRESes) located in the 5'-UTR (untranslated region) of transcripts. To investigate if rapalog-induced activation of MNK kinases had a role in such IRES activity, we studied multiple myeloma (MM) cells. Rapamycin (RAP)-activated MNK1 kinase activity in MM cell lines and primary specimens by a mitogen-activated protein kinase-dependent mechanism. Pharmacological inhibition of MNK activity or genetic silencing of MNK1 prevented a rapalog-induced upregulation of c-myc IRES activity. Although RAP, used alone, had little effect on myc protein expression, when combined with a MNK inhibitor, myc protein expression was abrogated. In contrast, there was no inhibition of myc RNA, consistent with an effect on myc translation. In a RAP-resistant MM cell lines as well as a resistant primary MM specimen, co-exposure to a MNK inhibitor or MNK1 knockdown significantly sensitized cells for RAP-induced cytoreduction. Studies in MNK-null murine embryonic fibroblasts additionally supported a role for MNK kinases in RAP-induced myc IRES stimulation. These results indicate that MNK kinase activity has a critical role in the fail-safe mechanism of IRES-dependent translation when mTOR is inhibited. As kinase activity also regulated sensitivity to RAP, the data also provide a rationale for therapeutically targeting MNK kinases for combined treatment with mTOR inhibitors. 23143039 Temperature dependence of long-term cadmium toxicity in the zebrafish is not explained by liver oxidative stress: evidence from transcript expression to physiology. Standard ecotoxicity tests are performed at species' specific standard temperatures, but temperature is known to affect chemical toxicity. A temperature increase has been shown to increase cadmium toxicity in several aquatic species but information in fish is scarce. Based on literature we hypothesize that with increasing temperature, cadmium accumulation and oxidative stress increase, resulting in increased toxicity. In this study zebrafish acclimated to 12, 18, 26 (standard temperature) or 34°C for one month, were exposed to 5 μM cadmium for 4 or 28 days at the respective acclimation temperature. Cadmium toxicity (mortality) increased with increasing temperature. PCA showed that the high mortality at 34°C was closely correlated to an increasing tissue cadmium accumulation with increasing temperature, but not to liver oxidative damage under the form of protein carbonyl content or lipid peroxidation (measured as malondialdehyde levels) or liver antioxidative potential. Instead, acclimation to 12°C induced the highest oxidative damage to liver proteins and lipids, and transcript levels of glucose-6P-dehydrogenase, 6P-gluconate-dehydrogenase and glutathione peroxidase were particularly good markers of cold-induced oxidative stress. At this low temperature there was no interaction with cadmium exposure and there was no sign of cadmium sensitivity. Contrastingly, the combined effect of high temperature and cadmium exposure on mortality proved synergistic. Therefore we conclude that interactions between temperature and cadmium toxicity increased with increasing temperature and that this probably played part in increasing cadmium sensitivity. Increased cadmium compartmentalization and protein carbonyl content in liver of zebrafish acclimated to the standard temperature of 26°C probably played part in increased sensitivity towards the same cadmium body burden compared to lower temperatures. On the one hand we recognize and this study even confirms the importance of applying standard temperatures in standard ecotoxicity tests to ensure inter-study comparability. On the other hand temperatures in the field may deviate from standard temperatures and accounting for deviating temperatures, which can alter chemical sensitivity, in regulation can improve environmental protection. 23314276 Effects of 17β-trenbolone on Eastern and Western mosquitofish (Gambusia holbrooki and G. affinis) anal fin growth and gene expression patterns. The Eastern and Western mosquitofish (Gambusia holbrooki and G. affinis) are potential bioindicator organisms for endocrine disruptors. Male mosquitofish have an elongated anal fin (gonopodium) used for internal fertilization whose formation is driven by androgens. Normal female mosquitofish have a normal, rounded anal fin which undergoes elongation into a gonopodium structure when female mosquitofish are exposed to androgenic chemicals. Significant issues with using mosquitofish as a bioindicator include the lack of knowledge on how anal fin growth in females corresponds to endpoints relevant to biological integrity and the lack of information on the molecular pathways that regulate anal fin growth. The objectives of this study were to understand how androgen-induced anal fin elongation relates to changes in endpoints related to the female reproductive system and to understand how anal fin elongation occurs in androgen-exposed female mosquitofish. To achieve these objectives, adult female G. holbrooki were exposed to a vehicle control or one of three doses of the androgen 17β-trenbolone (TB) at nominal concentrations of 0.1, 1 or 10 μg TB/L. Anal fin measurements were taken and livers were used for quantitative polymerase chain reaction analysis of vitellogenin (vtg) mRNA expression at multiple time points. 10 μg TB/L induced anal fin elongation after 7 days of treatment (one-way ANOVA, p<0.05) as did 0.1 and 1 μg TB/L at later time points (one-way ANOVA, p<0.05). 10 μg TB/L significantly reduced hepatic vtg gene expression at all time points assessed (one-way ANOVA, p<0.05). There was no correlation between anal fin elongation levels and vtg gene expression (Spearman's ρ, p>0.05). In a separate experiment, female G. holbrooki and G. affinis were exposed to the vehicle control or 1 μg TB/L. Anal fins were used for qualitative gene expression analysis of the genes sonic hedgehog (shh), muscle segment homeobox C (msxC), and fibroblast growth factor receptor 1 (fgfr1) by in situ hybridization. Shh was expressed in the distal tip of the gonopodium while msxC and fgfr1 were more widely expressed along the same anal fin rays during androgen exposure. These data provide insight into the molecular pathways involved in anal fin elongation and pave the way for future work toward developing the mosquitofish into a bioindicator organism for endocrine disruptors. 22750050 AMPK signalling and the control of substrate use in the heart. All mammalian cells rely on adenosine triphosphate (ATP) to maintain function and for survival. The heart has the highest basal ATP demand of any organ due to the necessity for continuous contraction. As such, the ability of the cardiomyocyte to monitor cellular energy status and adapt the supply of substrates to match the energy demand is crucial. One important serine/threonine protein kinase that monitors cellular energy status in the heart is adenosine monophosphate activated protein kinase (AMPK). AMPK is also a key enzyme that controls multiple catabolic and anabolic biochemical pathways in the heart and indirectly plays a crucial role in regulating cardiac function in both physiological and pathophysiological conditions. Herein, we review the involvement of AMPK in myocardial fatty acid and glucose transport and utilization, as it relates to basal cardiac function. We also assess the literature amassed on cardiac AMPK and discuss the controversies surrounding the role of AMPK in physiological and pathophysiological processes in the heart. The work reviewed herein also emphasizes areas that require further investigation for the purpose of eventually translating this information into improved patient care. 23411075 Arylglycine derivatives as potent transient receptor potential melastatin 8 (TRPM8) antagonists. A series of arylglycine-based analogs was synthesized and tested for TRPM8 antagonism in a cell-based functional assay. Following structure-activity relationship studies in vitro, a number of compounds were identified as potent TRPM8 antagonists and were subsequently evaluated in an in vivo pharmacodynamic assay of icilin-induced 'wet-dog' shaking in which compound 12 was fully effective. TRPM8 antagonists of the type described here may be useful in treating pain conditions wherein cold hypersensitivity is a dominant feature. 23393216 Decreased serum concentrations of 25-hydroxycholecalciferol are associated with increased risk of progression to impaired fasting glucose and diabetes. OBJECTIVE To study the association between vitamin D status and the risk of incident impaired fasting glucose (IFG) and diabetes in a population-based cohort of diabetes-free subjects. RESEARCH DESIGN AND METHODS In a historical prospective cohort study of subjects from the Clalit Health Services database, which includes information on nearly 4 million people, diabetes-free subjects aged 40-70 years with serum 25-hydroxycholecalciferol (25-OHD) measurements available were followed for 2 years to assess the development of IFG and diabetes in five 25-OHD subgroups: ≥25, 25.1-37.5, 37.6-50, 50.1-75, and >75 nmol/L. RESULTS The baseline cohort included 117,960 adults: 83,526 normoglycemic subjects and 34,434 subjects with IFG. During follow-up, 8,629 subjects (10.3% of the normoglycemic group) developed IFG, and 2,162 subjects (1.8% of the total cohort) progressed to diabetes. A multivariable model adjusted for age, sex, population group, immigrant status, BMI, season of vitamin D measurement, LDL and HDL cholesterol, triglycerides, estimated glomerular filtration rate, history of hypertension or cardiovascular disease, Charlson comorbidity index, smoking, and socioeconomic status revealed an inverse association between 25-OHD and the risk of progression to IFG and diabetes. The odds of transitioning from normoglycemia to IFG, from normoglycemia to diabetes, and from IFG to diabetes in subjects with a 25-OHD level ≤25 nmol/L were greater than those of subjects with a 25-OHD level >75 nmol/L [odds ratio 1.13 (95% CI 1.03-1.24), 1.77 (1.11-2.83), and 1.43 (1.16-1.76), respectively]. CONCLUSIONS Vitamin D deficiency appears to be an independent risk factor for the development of IFG and diabetes. 23195960 A specific and essential role for Na,K-ATPase α3 in neurons co-expressing α1 and α3. Most neurons co-express two catalytic isoforms of Na,K-ATPase, the ubiquitous α1, and the more selectively expressed α3. Although neurological syndromes are associated with α3 mutations, the specific role of this isoform is not completely understood. Here, we used electrophysiological and Na(+) imaging techniques to study the role of α3 in central nervous system neurons expressing both isoforms. Under basal conditions, selective inhibition of α3 using a low concentration of the cardiac glycoside, ouabain, resulted in a modest increase in intracellular Na(+) concentration ([Na(+)](i)) accompanied by membrane potential depolarization. When neurons were challenged with a large rapid increase in [Na(+)](i), similar to what could be expected following suprathreshold neuronal activity, selective inhibition of α3 almost completely abolished the capacity to restore [Na(+)](i) in soma and dendrite. Recordings of Na,K-ATPase specific current supported the notion that when [Na(+)](i) is elevated in the neuron, α3 is the predominant isoform responsible for rapid extrusion of Na(+). Low concentrations of ouabain were also found to disrupt cortical network oscillations, providing further support for the importance of α3 function in the central nervous system. The α isoforms express a well conserved protein kinase A consensus site, which is structurally associated with an Na(+) binding site. Following activation of protein kinase A, both the α3-dependent current and restoration of dendritic [Na(+)](i) were significantly attenuated, indicating that α3 is a target for phosphorylation and may participate in short term regulation of neuronal function. 23639739 In vivo administration of VEGF- and GDNF-releasing biodegradable polymeric microspheres in a severe lesion model of Parkinson's disease. In this work, the neuroregenerative potentials of microencapsulated VEGF, GDNF and their combination on a severely lesioned rat model were compared with the aim of developing a new strategy to treat advanced stages of Parkinson's disease. Both neurotrophic factors were separately encapsulated into polymeric microspheres (MS) to obtain a continuous drug release over time. The regenerative effects of these growth factors were evaluated using a rotation behaviour test and quantified by the number of surviving TH+ cells. The biological activities of encapsulated vascular endothelial growth factor (VEGF) and glial cell line derived neurotrophic factor (GDNF) were investigated in HUVEC and PC12 cells, respectively. The treatment of 6-OHDA-lesioned rats with GDNF microspheres and with both VEGF and GDNF microspheres resulted in improved results in the rotation behaviour test. Both groups also showed higher levels of neuroregeneration/neuroreparation in the substantia nigra than the control group did. These results were confirmed by the pronounced TH + neuron recovery in the group receiving VEGF+GDNF-MS, demonstrating regenerative effects. 23328072 Dose-dependent effects of vitamin D on transdifferentiation of skeletal muscle cells to adipose cells. Fat infiltration within muscle is one of a number of features of vitamin D deficiency, which leads to a decline in muscle functionality. The origin of this fat is unclear, but one possibility is that it forms from myogenic precursor cells present in the muscle, which transdifferentiate into mature adipocytes. The current study examined the effect of the active form of vitamin D₃, 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), on the capacity of the C2C12 muscle cell line to differentiate towards the myogenic and adipogenic lineages. Cells were cultured in myogenic or adipogenic differentiation media containing increasing concentrations (0, 10⁻¹³, 10⁻¹¹, 10⁻⁹, 10⁻⁷ or 10⁻⁵  M) of 1,25(OH)₂D₃ for up to 6 days and markers of muscle and fat development measured. Mature myofibres were formed in both adipogenic and myogenic media, but fat droplets were only observed in adipogenic media. Relative to controls, low physiological concentrations (10⁻¹³ and 10⁻¹¹  M) of 1,25(OH)₂D3 increased fat droplet accumulation, whereas high physiological (10⁻⁹  M) and supraphysiological concentrations (≥10⁻⁷  M) inhibited fat accumulation. This increased accumulation of fat with low physiological concentrations (10⁻¹³ and 10⁻¹¹  M) was associated with a sequential up-regulation of PPARγ2 (PPARG) and FABP4 mRNA, indicating formation of adipocytes, whereas higher concentrations (≥10⁻⁹  M) reduced all these effects, and the highest concentration (10⁻⁵  M) appeared to have toxic effects. This is the first study to demonstrate dose-dependent effects of 1,25(OH)₂D₃ on the transdifferentiation of muscle cells into adipose cells. Low physiological concentrations (possibly mimicking a deficient state) induced adipogenesis, whereas higher (physiological and supraphysiological) concentrations attenuated this effect. 23223551 Quantum chemical study of the catalytic activation of methane by copper oxide and copper hydroxide cations. The activation of methane and its subsequent conversion into more valuable feedstocks under ambient conditions are regarded as one of the major challenges in contemporary catalysis, due to its thermodynamically strong and kinetically inert C-H bond. Several enzymes and synthetic bioinorganic systems perform the activation of C-H bonds in methane and small hydrocarbons, mediated by transition metal mononuclear centers. Among them, monocopper cores and, in particular, CuO(+) and CuOH(+) have been suggested as efficient catalytic centers; this activity has not been experimentally proven until very recently, mainly due to the difficulty to produce sufficient amounts of active species to demonstrate the bond activation processes. The theoretical study presented here provides a thorough quantum chemical description of the activity of both species, together with molecular level insight into the elementary steps of the experimentally observed reactions. Post-HF (CCSD(T), CASPT2) and Density Functional Theory (DFT) methods have been used to unravel detailed electronic and mechanistic aspects of the reaction paths. Our study reveals the decisive role of the oxygen-centered radical in the reactivity of both species, and the improvement of the reactivity as a result of the protonation of the active species. 23375004 Chemometrics-Based Approach to Feature Selection of Chromatographic Profiles and its Application to Search Active Fraction of Herbal Medicine. In our previous report (J Pharmaceut Biomed 56 (2011) 443-447), a support vector machine (SVM)-based pharmacodynamic model was established for predicting active fractions of herbal medicines (HMs), where information contents embedded in the chromatograms of the fractions were represented with the peak areas. However, in this representation the global characteristics of the chromatograms were completely missed, which is definitely contrary to the global and holistic views in theories of HMs and undoubtedly reduce the success rate of this model. To deal with the challenge, two chemometrics methods, that is, minimum redundancy maximum relevance (mRMR) and particle swarm optimizer (PSO), were applied in this article for feature selection of the whole chromatograms, and the PSO was also used to tune the SVM parameters. As a case, a sample HM, that is, Xiangdan injection, was investigated. The predictive accuracy was fully evaluated and compared with those by other popular and reported methods. Furthermore, the confirmation on the independent predicting set exhibited that the predicted bioactivities were well consistent with the experimental values. The important potential application of the present model is to be extended to help search active fractions of other HMs. 23643542 Water extract of licorice had anti-viral activity against human respiratory syncytial virus in human respiratory tract cell lines. ETHNOPHARMACOLOGICAL RELEVANCE: Licorice (Glycyrrhiza uralensis Fisch., Leguminosae) has been used in herbal medicine and food supplement worldwide for centuries. Licorice is a common ingredient of several prescriptions of traditional Chinese medicine which have been proved to inhibit infection of human respiratory syncytial virus (HRSV). There are two preparations of licorice, Radix Glycyrrhizae and Radix Glycyrrhizae Preparata. However, it is unknown whether licorice or which preparation of licorice is effective against HRSV, nor is its active constituent. AIM OF THE STUDY: We tested the hypothesis that Radix Glycyrrhizae can effectively decrease HRSV-induced plaque formation in respiratory mucosal cell lines. We also tried to find out the active constituent. MATERIALS AND METHODS: Anti-HRSV activities of hot water extracts of preparations of licorice, glycyrrhizin and 18β-glycyrrhetinic acid (18β-GA), the active constituents of licorice, were examined by plaque reduction assay in both human upper (HEp-2) and low (A549) respiratory tract cell lines. Abilities of crude licorice to inhibit viral replication and to stimulate IFN-β were evaluated by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. RESULTS: Radix Glycyrrhizae and Radix Glycyrrhizae Preparata dose-dependently inhibited HRSV-induced plaque formation in both HEp-2 and A549 cell lines (p<0.0001). The effect of Radix Glycyrrhizae was better than that of Radix Glycyrrhizae Preparata on HEp-2 cells. However, there was no difference of their anti-HRSV effects on A549 cells. Besides, glycyrrhizin was ineffective at all. Nevertheless, 18β-GA showed a potent anti-HRSV activity. Radix Glycyrrhizae was more effective when given before viral inoculation (p<0.0001) which may be due to its inhibition of viral attachment on (p<0.0001) and penetration (p<0.0001) into the host cells. The anti-HRSV activity of Radix Glycyrrhizae was further confirmed by RT-PCR and qRT-PCR. 300μg/ml Radix Glycyrrhizae markedly decreased the viral amounts within the cells and in the suspension. Radix Glycyrrhizae might further stimulate mucosal cells to secrete IFN-β to counteract viral infection. CONCLUSIONS: Both Radix Glycyrrhizae and Radix Glycyrrhizae Preparata are effective against HRSV infection on airway epithelial cells. Radix Glycyrrhizae inhibited HRSV mainly by preventing viral attachment, internalization, and by stimulating IFN secretion. 18β-GA may be one of its active constituents. 23587426 Synthesis and antimicrobial activity of novel amphiphilic aromatic amino alcohols. We report in this work the preparation and in vitro antimicrobial evaluation of novel amphiphilic aromatic amino alcohols synthesized by reductive amination of 4-alkyloxybenzaldehyde with 2-amino-2-hydroxymethyl-propane-1,3-diol. The antibacterial activity was determined against four standard strains (Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa) and 21 clinical isolates of methicillin-resistant Staphylococcus aureus. The antifungal activity was evaluated against four yeast (Candida albicans, Candida tropicalis, Candida glabrata and Candida parapsilosis). The results obtained showed a strong positive correlation between the lipophilicity and the antibiotic activity of the tested compounds. The best activities were obtained against the Gram-positive bacteria (MIC=2-16μgml(-1)) for the five compounds bearing longer alkyl chains (4c-g; 8-14 carbons), which were also the most active against Candida (MIC=2-64μgml(-1)). Compound 4e exhibited the highest levels of inhibitory activity (MIC=2-16μgml(-1)) against clinical isolates of MRSA. A concentration of twice the MIC resulted in bactericidal activity of 4d against 19 of the 21 clinical isolates. 23625769 A 7-Year Case of Furosemide-Induced Immune Thrombocytopenia. Immune thrombocytopenia has been attributed to many causes. Several drugs have been implicated as culprits in causing drug-induced thrombocytopenia. Although the mechanism for this type of thrombocytopenia is not well understood, at least three types of antibodies appear to be involved: drug-dependent antibodies, hapten-dependent antibodies, and drug-induced platelet-reactive autoantibodies. In this report, we describe a case in which furosemide was identified as the probable cause of drug-induced thrombocytopenia in an 84-year-old man with chronic symptomatic idiopathic thrombocytopenia for seven years before discovery. The patient's platelet count and daily furosemide dose, both intravenous and oral, were documented throughout his medical history. A dose-dependent change in platelet count was observed in association with the furosemide dose. His platelet count increased on discontinuation of furosemide and beginning of torsemide. Several months after discontinuation of furosemide, his platelet count increased to a 9-year high of 206 × 10(3) /mm(3) from a low of 36 × 10(3) /mm(3) while receiving furosemide therapy. Based on the observations of this case report, clinicians should more readily consider furosemide as a potential cause of thrombocytopenia. 23325631 Caged CO(2) for the direct observation of CO(2)-consuming reactions. CO(2)-consuming reactions, in particular carboxylations, play important roles in technical processes and in nature. Their kinetic behavior and the reaction mechanisms of carboxylating enzymes are difficult to study because CO(2) is inconvenient to handle as a gas, exists in equilibrium with bicarbonate in aqueous solution, and typically yields products that show no significant spectroscopic differences from the reactants in the UV/Vis range. Here we demonstrate the utility of 3-nitrophenylacetic acid and related compounds (caged CO(2)) in conjunction with infrared spectroscopy as widely applicable tools for the investigation of such reactions, permitting convenient measurement of the kinetics of CO(2) consumption. The use of isotopically labeled caged CO(2) provides a tool for the assignment of infrared absorption bands, thus aiding insight into reaction intermediates and mechanisms. 23356791 Formaldehyde metabolism and formaldehyde-induced stimulation of lactate production and glutathione export in cultured neurons. Formaldehyde is endogenously produced in the human body and brain levels of this compound are elevated in neurodegenerative conditions. Although the toxic potential of an excess of formaldehyde has been studied, little is known on the molecular mechanisms underlying its neurotoxicity as well as on the ability of neurons to metabolize formaldehyde. To address these topics, we have used cerebellar granule neuron cultures as model system. These cultures express mRNAs of various enzymes that are involved in formaldehyde metabolism and were remarkably resistant toward acute formaldehyde toxicity. Cerebellar granule neurons metabolized formaldehyde with a rate of around 200 nmol/(h × mg) which was accompanied by significant increases in the cellular and extracellular concentrations of formate. In addition, formaldehyde application significantly increased glucose consumption, almost doubled the rate of lactate release from viable neurons and strongly accelerated the export of the antioxidant glutathione. The latter process was completely prevented by inhibition of the known glutathione exporter multidrug resistance protein 1. These data indicate that cerebellar granule neurons are capable of metabolizing formaldehyde and that the neuronal glycolysis and glutathione export are severely affected by the presence of formaldehyde. 23057692 A comprehensive study to evaluate the effect of constant low voltage iontophoresis on transungual delivery. Treatment of nail diseases by topical drug delivery continues to draw much attention in the recent days. This study aims to systematically investigate the effect of constant voltage iontophoresis in the transungual drug delivery, using ciclopirox as a model drug. Preliminary permeation studies were carried out by applying constant voltage (6 V for 24 h) using a gel formulation across the human nail plate in a Franz diffusion cell. Different protocols have been studied to authenticate the potential of the proposed technique. Antifungal studies were carried out to assess the pharmacodynamic effect of drug depot formed in the nail plate. Initial studies revealed that application of constant voltage iontophoresis enhanced the permeation by an order of magnitude (p = 0.019) and delivered significant amount of drug into the deeper nail layers. Noticeably higher permeation was observed during the active phase in on-off studies. Excellent correlation was observed in permeation (r(2) = 0.98) and drug load (r(2) = 0.97) with the increase in applied voltage (3-12 V), indicating that the current technique is predictable. The data observed suggest that any further increase in voltage could eventually lead to increase in the permeation and drug load, as the saturation level is very distant. Furthermore, the enhancement in permeation with the applied voltage (3-12 V) was found to be 6-20 folds, compared to the passive process. Results of step up and step down studies substantiated the viability of the current technique. Zone of inhibition measured during the antifungal studies demonstrated that the drug molecules loaded into the nail plate by low voltage iontophoresis is active and releases over an extended period of time (~32 days). Given the excellent results, the current technique could be used as an effective approach for the delivery of antimycotics, which would localize the drug at the infection site and potentially offer higher patient compliance. 23357362 Testing of Perilla frutescens extract and Vicenin 2 for their antispasmodic effect. Gastrointestinal discomfort is frequently observed. The effects of Perilla frutescens extract and Vicenin 2 (a compound in this extract) were assayed in rat ileum with or without stimulation with acetylcholine or Ba(2+). Both had no direct spasmolytic effect, but both decreased acetylcholine- or Ba(2+)-induced contraction of rat ileum indicating an antispasmodic effect. This is valuable because effects were only observed when spasms were induced and may disturb the patient. The extract and the compound may be used to maintain and improve gut health. 22989705 Pioglitazone protects against cisplatin induced nephrotoxicity in rats and potentiates its anticancer activity against human renal adenocarcinoma cell lines. Cisplatin-induced nephrotoxicity is a serious problem that limits its use in cancer treatment. The present study aimed to investigate the renal protective capacity of pioglitazone to reduce the cisplatin- induced nephrotoxicity. The underlying suggested mechanism(s) and whether this nephroprotective effect (if any) interferes with the cytotoxic effect of cisplatin on cancer cells were also investigated. Pioglitazone, Bisphenol A diglycidyl ether, BADGE, IP injected (Peroxisome proliferator- activated receptor gamma (PPAR-γ) antagonist), or their combination were administered to rats one hour before cisplatin injection. Moreover, their effects on the cell viability of human renal adenocarcinoma cell models (ACHN) were studied. The obtained results showed that pioglitazone improved the renal function, structural changes, renal malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-κB) genes expression in cisplatin injected rats. It increased both renal reduced glutathione (GSH) content and PPAR-γ gene expression. In contrast to the data obtained by prior administration of BADGE. Pioglitazone also potentiated the cytotoxic effect of cisplatin on human renal adenocarcinoma cells and this effect was abolished by BADGE co administration. In conclusion, these results suggested that pioglitazone protected against cisplatin- induced nephrotoxicity through its interaction with PPAR-γ receptors and antioxidant effects. Furthermore, pioglitazone did not interfere but rather potentiated the cytotoxic effects of cisplatin on human renal adenocarcinoma cells. 23503923 Composite dissolving microneedles for coordinated control of antigen and adjuvant delivery kinetics in transcutaneous vaccination. Transcutaneous administration has the potential to improve therapeutics delivery, providing an approach that is safer and more convenient than traditional alternatives, while offering the opportunity for improved therapeutic efficacy through sustained/controlled drug release. To this end, we demonstrate a microneedle materials platform for rapid implantation of controlled-release polymer depots into the cutaneous tissue. Arrays of microneedles comprised of drug-loaded poly(lactide-co-glycolide) (PLGA) microparticles or solid PLGA tips were prepared with a supporting and rapidly water-soluble poly(acrylic acid) (PAA) matrix. Upon application of microneedle patches to the skin of mice, the microneedles perforated the stratum corneum and epidermis. Penetration of the outer skin layers was followed by rapid dissolution of the PAA binder on contact with the interstitial fluid of the epidermis, implanting the microparticles or solid polymer microneedles in the tissue, which were retained following patch removal. These polymer depots remained in the skin for weeks following application and sustained the release of encapsulated cargos for systemic delivery. To show the utility of this approach we demonstrated the ability of these composite microneedle arrays to deliver a subunit vaccine formulation. In comparison to traditional needle-based vaccination, microneedle delivery gave improved cellular immunity and equivalent generation of serum antibodies, suggesting the potential of this approach for vaccine delivery. However, the flexibility of this system should allow for improved therapeutic delivery in a variety of diverse contexts. 23518472 Estrogenic and androgenic effects in mosquitofish (Gambusia affinis) from streams contaminated by municipal effluent in Guangzhou, China. The study reported in this paper used mosquitofish to investigate the estrogenic and androgenic effects of municipal wastewater contamination on the stream system in Guangzhou, China. Western mosquitofish collected from a reference site and five study sites in streams forming part of the Pearl River network were dissected and analyzed for their morphological characteristics (anal fin and hemal spine characteristics) and target mRNA expression of genes (VTGα and ERα mRNA expression). Increased VTGα mRNA expression in males and decreased VTGα mRNA expression in females were observed in samples taken from four of the five study sites, with no such observations being made at the reference site. Correlation analysis indicated a significant correlation between the hemal spine morphology index and the gene transcription relative to the reference site. The multiple index also indicated that both male and female mosquitofish in contaminated streams were altered by discharged wastewater, as reflected in their morphological changes and relative induction of mRNA expression of genes in comparison to fish collected from the reference site. 23000449 Characterization of acetylcholinesterase in Hong Kong oyster (Crassostrea hongkongensis) from South China Sea. Acetylcholinesterase (AChE) activity has been used to evaluate the exposure of mollusk bivalves to organophosphates, carbamate pesticides, and heavy metals. Crassostrea hongkongensis is a Hong Kong endemic oyster, and has a high commercial value along the coastal area of South China. The use of this species as a bio-indicator of the marine environment, and the use of AChE activity measurements in tissues of C. hongkongensis require prior characterization of AChE in this species. Here, we report that gill tissue contains the highest AChE activity in C. hongkongensis, and that the molecular form of AChE is most likely to be a dimeric form. In addition, the effect of the pesticide acephate on AChE activity in the gill of C. hongkongensis was analyzed, and the mean inhibition concentration (IC50) value was determined. This study suggests that AChE activity in the gill tissue of C. hongkongensis might be used as a biomarker in monitoring organophosphate contamination in the marine fauna of South China. 23279802 Synthesis and quantum chemical studies of new 4-aminoquinazoline derivatives as Aurora A/B kinase inhibitors. Nine novel 4-aminoquinazoline derivatives were designed and synthesized. Biochemical and cellular analyses demonstrated that most of the derivatives exhibited a strong activity to inhibit Aurora A and B kinases and to suppress the proliferation of a panel of human tumor cell lines (U937, K562, A549, LoVo, and HT29). Quantum chemical studies were also carried out to determine the structural features of these compounds engaged in the inhibition of Aurora kinases. 23536315 Regulation of neutrophil extracellular trap formation by anti-inflammatory drugs. The formation of neutrophil extracellular traps (NETs) is a newly described phenomenon that increases the bacteria killing ability and the inflammatory response of neutrophils. Because NET generation occurs in an inflammatory microenvironment, we examined its regulation by anti-inflammatory drugs. Treatment of neutrophils with dexamethasone had no effect while acetylsalicylic acid (ASA) treatment prevented NET formation. NETosis was also abrogated by the presence of BAY 11-7082 and Ro 106-9920, two structurally unrelated NF-κB inhibitors. The decrease in NET formation mediated by ASA, BAY-11-7082 and Ro 106-9920 was correlated with a significant reduction in the phosphorylation of NF-κB p65 subunit, indicating that the activation of this transcription factor is a relevant signaling pathway involved in the generation of DNA traps. The inhibitory effect of these drugs was also observed when NET generation was induced under acidic or hyperthermic conditions, two stress signals of the inflammatory microenvironment. In a mouse peritonitis model, while pretreatment of animals with ASA or BAY 11-7082 resulted in a marked suppression of NET formation along with increased bacteremia, dexamethasone had no effect. Our results show that NETs have an important role in the local control of infection and that ASA and NF-κB blockade could be useful therapies to avoid undesired effect of persistent neutrophil activation. 23563049 Molecular dynamics in liquid and glassy states of non-steroidal anti-inflammatory drug: Ketoprofen. Ketoprofen is a well known nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic effects. It acts by inhibiting the body's production of prostaglandin. The molecular mobility of amorphous ketoprofen has been investigated by broadband dielectric spectroscopy (BDS) covering wide temperature and frequency range. Multiple relaxation processes were observed. Besides the primary α-relaxation, one secondary relaxation, γ-have been identified. The γ-process visible in the dielectric spectra at very low temperature is non-JG relaxation, and has an activation energy E=37.91kJ/mol typical for local mobility. Based on Ngai's coupling model smaller n or a larger Kohlrausch exponent (1-n) of the α-relaxation associated with larger τβ (Tg). In the case of ketoprofen we conclude that the secondary relaxation (β) emerging from intermolecular motions, is hidden under the dominant α-peak. The temperature dependence of the relaxation time of the α-process can be described over the entire measured range by a single Vogel-Fulcher-Tammann (VFT) equation. From VFT fits, the glass transition temperature (Tg) was estimated as 267.07K, and a fragility or steepness index m=86.57 was calculated, showing that ketoprofen is a fragile glass former. Our differential scanning calorimetry (DSC) study shows that ketoprofen is a non-crystallizing compound. To confirm the hydrogen bond patterns of ketoprofen FTIR spectroscopy was applied in both crystalline and amorphous phases. Solubility test performed at 37°C proved that amorphous phase is more soluble than the crystalline phase. 23561091 Flavonoids from the capitula of Eriocaulon australe. A flavan, eriocaulin A (1), and three flavone acyl glucosides, eriocaulosides A-C (2-4) were isolated from the capitula of Eriocaulon australe R. Br. (Eriocaulaceae), a Chinese medicine and an herb for health care beverages, together with seven known flavones and three isoflavones (5-14). The new flavonoids were elucidated as (2S)-3',4'-methylenedioxy-5-methoxy-7-hydroxyflavan (1), hispidulin 7-O-β-d-(6-O-cinnamoyl)glucopyranoside (2), jaceosidin 7-O-β-d-(6-O-p-coumaroyl)glucopyranoside (3), jaceosidin 7-O-β-d-(6-O-p-hydroxybenzoyl)glucopyranoside (4) based on their spectroscopic data. All the 14 flavonoids were obtained from this species for the first time. The in vitro cytotoxicity of compounds 1-14 against human lung adenocarcinoma A549, human breast adenocarcinoma MCF-7, and human cervical carcinoma HeLa cell lines was evaluated using the MTT colourimetric assay. Compounds 1, 7, and 9 were cytotoxic to A549, compounds 1, 2, 7, 9, 12, and 14 to MCF-7, and compounds 7, 9, and 14 to HeLa cells, with IC50 values ranging from 7.17 to 29.57μg/ml, while the others were inactive (IC50>50μg/ml). 23281847 Spreading and structuring of water on superhydrophilic polyelectrolyte brush surfaces. The wetting behavior of superhydrophilic polyelectrolyte brushes was investigated. Reflection interference contrast microscopy demonstrated that the contact angles of water on the polyelectrolyte brushes were extremely low but remained finite in the range of <3°. The presence of water molecules was evident, even outside the macroscopic water droplet. These water molecules were confined to the thin brush layers and contained a highly ordered hydrogen bond network, which was identified as structural water. The presence of the thin film and the structural water changed the surface energies, which prevented the complete wetting of the surface. 23461825 Signal transducer and activator of transcription 6 directly regulates human ORMDL3 expression. Orosomucoid-like 3 (ORMDL3) has been associated with asthma and a series of autoimmune disorders, and is involved in endoplasmic reticulum-mediated inflammatory responses. However, its clinical significance and the molecular mechanism underlying its expression are still largely unclear. To elucidate the mechanisms of human ORMDL3 transcriptional regulation, we cloned a 1.5 kb genomic DNA fragment containing the putative promoter region and evaluated its transcriptional activity in a luciferase reporter system by deletion analysis. We identified a 68 bp region that functions as a minimal promoter. Bioinformatics analysis predicted that the -64 to -56 bp region contained a signal transducer and activator of transcription 6 (STAT6) binding site. Electrophoretic mobility shift assay and chromatin immunoprecipitation demonstrated that STAT6 bound to its binding site within the ORMDL3 promoter. STAT6 over-expression or knockdown trans-activated or trans-inhibited, respectively, the ORMDL3 promoter containing the STAT6-binding motif. Treatment with interleukins 4 or 13 increased ORMDL3 promoter activity as well as endogenous ORMDL3 expression. Immunoprecipitation and ChIP/Re-ChIP assays revealed that STAT6 and p300 exist in the same protein complex that binds to the ORMDL3 promoter. Our study confirmed that STAT6 plays important roles in regulating the expression of human ORMDL3 by directly binding to the promoter region, which may shed light on a possible role in various human diseases. STRUCTURED DIGITAL ABSTRACT: p300 physically interacts with STAT6 by anti bait coimmunoprecipitation (View Interaction: 1, 2). 23584358 Agomelatine: An antidepressant with new potent hepatoprotective effects on paracetamol-induced liver damage in rats. Paracetamol was shown to induce hepatotoxicity or more severe fatal acute hepatic damage. Agomelatine, commonly known as melatonin receptor agonist, is a new antidepressant, which resynchronizes circadian rhythms with subjective and objective improvements in sleep quality and architecture, as melatonin does. In the present study, it was aimed to evaluate the hepatoprotective activity of agomelatine on paracetamol-induced hepatotoxicity and to understand the relationship between the hepatoprotective mechanism of agomelatine and antioxidant system and proinflammatory cytokines. A total of 42 rats were divided into 7 groups as each composed of 6 rats: (1) intact, (2) 40 mg/kg agomelatine, (3) 140 mg/kg N-acetylcysteine (NAC), (4) 2 g/kg paracetamol, (5) 2 g/kg paracetamol + 140 mg/kg NAC, (6) 2 g/kg paracetamol + 20 mg/kg agomelatine, and (7) 2 g/kg paracetamol + 40 mg/kg agomelatine groups. Paracetamol-induced hepatotoxicity was applied and liver and blood samples were analyzed histopathologically and biochemically. There were statistically significant increases in the activities of aspartate aminotransferase, alanine aminotransferase, levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) and 8-iso-prostane, and decreases in the activity of superoxide dismutase and level of glutathione in the group treated with paracetamol. Administration of agomelatine and NAC separately reversed these changes significantly. In conclusion, agomelatine administration protects liver cells from paracetamol-induced hepatotoxicity via antioxidant activity and reduced proinflammatory cytokines, such as TNF-α and IL-6. 23278398 X-ray crystallography and computational docking for the detection and development of protein-ligand interactions. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterised by the selective dysfunction and death of the upper and lower motor neurons. Median survival rates are between 3 and 5 years after diagnosis. Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) have been linked to a subset of familial forms of ALS (fALS). Herein, we describe a fragment- based drug discovery (FBDD) approach for the investigation of small molecule binding sites in SOD1. X-ray crystallography has been used as the primary screening method and has been shown to directly detect protein-ligand interactions which cannot be unambiguously identified using other biophysical methods. The structural requirements for effective binding at Trp32 are detailed for a series of quinazoline-containing compounds. The investigation of an additional site that binds a range of catecholamines and the use of computational modelling to assist fragment evolution is discussed. This study also highlights the importance of ligand solubility for successful Xray crystallographic campaigns in lead compound design. 23200901 The role of efflux transporters on the transport of highly toxic aconitine, mesaconitine, hypaconitine, and their hydrolysates, as determined in cultured Caco-2 and transfected MDCKII cells. Aconitum alkaloids including aconitine (AC), mesaconitine (MA), hypaconitine (HA), are highly toxic. Their hydrolysates, such as benzoylaconine (BAC), benzoylmesaconine (BMA), benzoylhypaconine (BHA), aconine, and mesaconine, are considerably less toxic. Efflux transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein isoform 2 (MRP2), act as a first line of defence and play key roles in toxicity prevention. The aim of the present study was to determine the role of efflux transporters in the transport of Aconitum alkaloids using cultured Caco-2, MDR1-MDCKII and BCRP-MDCKII cells. Bidirectional transport assays of the Aconitum alkaloids were performed with or without P-gp (cyclosporine A and verapamil), BCRP (Ko143) and MRP2 (MK571) inhibitors. The efflux ratios (Er) of AC, MA, and HA in Caco-2 cells were 34.6±4.2, 29.7±2.1, and 15.6±2.1, respectively; those of BAC, BMA, and BHA were approximately 4, and those of aconine and mesaconine were equal to 1. The Er values of AC, MA, and HA in MDR1-MDCKII and BCRP-MDCKII cells were significantly higher than those in parental MDCKII cells. Taken together the results of Er values and intracellular amounts in the presence of inhibitors, P-gp and BCRP were involved in the transport of AC, MA and HA; and MRP2 might transport AC, MA, HA, BAC, BMA and BHA. 23373463 Reaction-diffusion framework: the mechanism of the polymorphic transition of α- to β-cobalt hydroxide. A new and simple method is proposed to explore the mechanism of the intercalation/deintercalation of a variety of anions throughout the formation of α-Co(OH)2 crystals and their polymorphic conversion to β-Co(OH)2. This method is based on the reaction-diffusion of hydroxide ions in a gel matrix containing the cobalt salt. The spatiotemporal evolution of each polymorph and their interaction is revealed by tracking the location of the two sharp interfaces between the two polymorphs (conversion zone) and between the gel and α-Co(OH)2 (formation zone) and by measuring the weight composition of each zone. We thereby find that the dynamics of the transformation reaction are correctly described by the two-dimensional Avrami-Erofe'ev equation at different temperatures. The data suggest that the structural redistribution of the atoms inside the α-Co(OH)2 particles plays the fundamental role in establishing the overall rate of the reaction. On the other hand, we notice that other factors such as the nature of the intercalated anions and the concentration of the polymer matrix alter considerably the final rate of the transition reaction through increasing the stability of the α phase. 22397600 Comparison of pharmacokinetics in beagle dogs of nimesulide bilayer tablets with dispersible tablets. The purpose of this study was to compare the in vitro release and the in vivo pharmacokinetics of bilayer tablets with the conventional dispersible tablets of nimesulide. The tablets were administered to beagle dogs and the plasma levels of nimesulide were determined by high-performance liquid chromatography-MS/MS. The pharmacokinetic parameters were calculated using a noncompartmental model. The bilayer tablets showed a biphasic in vitro release pattern with initial burst release and sustained release following the quasi-Fickian diffusion-based release mechanism. The C(max), t(max), mean residence time (MRT), and area under the curve from 0 to 36 h were 10.8 ± 4.2 μg/mL, 2.3 ± 1.0 h, 6.7 ± 2.1 h, 81.5 ± 26.7 μg·h/mL for the bilayer tablets and 14.8 ± 5.8 μg/mL, 2.7 ± 0.8 h, 5.6 ± 0.9 h, 95.4 ± 44.2 μg·h/mL for the dispersible tablets. Compared with the dispersible tablets, the bilayer tablets have lower C(max), similar t(max), and longer MRT. The aforementioned pharmacokinetic parameters, especially the MRT demonstrated to be valuable for evaluating the biphasic characteristics. This study provides a promising in vivo evaluation method for the bilayer tablets with biphasic release pattern. 23547757 Potent Proteasome Inhibitors Derived from the Unnatural Cis-Cyclopropane Isomer of Belactosin A: Synthesis, Biological Activity, and Mode of Action. The natural product belactosin A (1) with a trans-cyclopropane structure is a useful prototype compound for developing potent proteasome (core particle, CP) inhibitors. To date, 1 and its analogs are the only CP ligands bind to both the non-primed S1 pocket as well as the primed substrate binding channel, however, these molecules harbor a high IC50 value of more than 1 µM. We have performed structure activity relationship studies, hereby elucidating unnatural cis-cyclopropane derivatives of 1 that exhibit high potency to primarily block the chymotrypsin-like active site of the human constitutive (cCP) and immunoproteasome (iCP). The most active compound 3e reversibly inhibits cCP and iCP similarly with an IC50 of 5.7 nM. X-ray crystallographic analysis of the yeast proteasome in complex with 3e revealed that the ligand accommodates predominantly to the primed substrate binding channel and covalently binds to the active site threonine residue via its β-lactone ring-opening. 23558747 Impaired in vivo binding of MeCP2 to chromatin in the absence of its DNA methyl-binding domain. MeCP2 is a methyl-CpG-binding protein that is a main component of brain chromatin in vertebrates. In vitro studies have determined that in addition to its specific methyl-CpG-binding domain (MBD) MeCP2 also has several chromatin association domains. However, the specific interactions of MeCP2 with methylated or non-methylated chromatin regions and the structural characteristics of the resulting DNA associations in vivo remain poorly understood. We analysed the role of the MBD in MeCP2-chromatin associations in vivo using an MeCP2 mutant Rett syndrome mouse model (Mecp2(tm)(1)(.)(1)(Jae)) in which exon 3 deletion results in an N-terminal truncation of the protein, including most of the MBD. Our results show that in mutant mice, the truncated form of MeCP2 (ΔMeCP2) is expressed in different regions of the brain and liver, albeit at 50% of its wild-type (wt) counterpart. In contrast to the punctate nuclear distribution characteristic of wt MeCP2, ΔMeCP2 exhibits both diffuse nuclear localization and a substantial retention in the cytoplasm, suggesting a dysfunction of nuclear transport. In mutant brain tissue, neuronal nuclei are smaller, and ΔMeCP2 chromatin is digested faster by nucleases, producing a characteristic nuclease-resistant dinucleosome. Although a fraction of ΔMeCP2 is found associated with nucleosomes, its interaction with chromatin is transient and weak. Thus, our results unequivocally demonstrate that in vivo the MBD of MeCP2 together with its adjacent region in the N-terminal domain are critical for the proper interaction of the protein with chromatin, which cannot be replaced by any other of its protein domains. 23265469 Enzymatic synthesis of fructooligosaccharides by inulinases from Aspergillus niger and Kluyveromyces marxianus NRRL Y-7571 in aqueous-organic medium. This work is focused on the synthesis of the fructooligosaccharides (FOS) from sucrose and inulin, using free, immobilized and pre-treated immobilized inulinase from Kluyveromyces marxianus NRRL Y 7571 and Aspergillus niger in an aqueous-organic system. Initially, the influence of pre-treatment using four different gases, propane, n-butane, CO(2) and liquefied petroleum gas (LPG), was investigated towards FOS production and best results were found when both enzymes were previously treated with LPG. The best reaction yields were obtained when the immobilized enzymes were treated with LPG. Considering FOS synthesis using the enzyme from A. niger, yields of 26.62% of GF2 (kestose), 30.62% of GF3 (nystose) and 8.47% of GF4 (fructosyl nystose) were achieved using sucrose as substrate. Using inulinases from K. marxianus NRRL Y 7571, 11.89% of GF2 and 20.83% of GF3 were obtained, using inulin as substrate. However, promising results were achieved using the free form of inulinase from A. niger (77.19% of GF2; 14.03% of GF3 and 0.07% of GF4) using inulin as substrate. 23265506 EC50 estimation of antioxidant activity in DPPH· assay using several statistical programs. DPPH(·) assay is a reliable method to determine the antioxidant capacity of biological substrates. The DPPH(·) radical scavenging activity is generally quantified in terms of inhibition percentage of the pre-formed free radical by antioxidants, and the EC(50) (concentration required to obtain a 50% antioxidant effect) is a typically employed parameter to express the antioxidant capacity and to compare the activity of different compounds. In this study, the EC(50) estimation was performed using a comparative approach based on various regression models implemented in six specialized computer programs: GraphPad Prism® version 5.01, BLeSq, OriginPro® 8.5.1, SigmaPlot® 12, BioDataFit® 1.02, and IBM SPSS Statistics® Desktop 19.0. For this project, quercetin, catechin, ascorbic acid, caffeic acid, chlorogenic acid and acetylcysteine were screened as antioxidant standards with DPPH(·) assay to define the EC(50) parameters. All the statistical programs gave similar EC(50) values, but GraphPad Prism® five-parameter analysis pointed out a best performance, also showing a minor variance in relation to the actual EC(50). 22610853 Effects of supplementation with curcuminoids on dyslipidemia in obese patients: a randomized crossover trial. Dyslipidemia is a leading risk factor for cardiovascular disease and is also a common feature of obesity. Curcumin is a bioactive phytochemical with well-known antioxidant, anti-inflammatory, and cardioprotective properties. The present study investigated the hypolipidemic activity of curcumin in obese individuals. Participants (n = 30) were treated with curcuminoids (1 g/day), or placebo in a randomized, double-blind, placebo-controlled, crossover trial. Serum concentrations of total cholesterol, triglycerides, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, together with anthropometric parameters and high-sensitivity C-reactive protein were measured before and after each treatment period. Anthropometric parameters including weight, BMI, waist circumference, hip circumference, arm circumference, and body fat remained statistically unchanged by the end of trial (p > 0.05). As for the lipid profile parameters, serum triglycerides were significantly reduced following curcumin supplementation (p = 0.009). However, curcuminoids were not found to affect serum levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and high-sensitivity C-reactive protein (p > 0.05). In summary, the findings of the present study indicated that curcuminoid supplementation (1 g/day for 30 days) leads to a significant reduction in serum triglycerides concentrations but do not have a significant influence on other lipid profile parameters as well as body mass index and body fat. Copyright © 2012 John Wiley & Sons, Ltd. 23323763 Two new stemona alkaloids from Stemona tuberosa Lour. Two new pyrrolo[1,2-α]azepine-type stemona alkaloids, named as tuberostemonoxirine (1) and 9α-epi-tuberospironine (2), were isolated from the roots of Stemona tuberosa. The structures and relative configurations of new compounds were established on the basis of extensive spectroscopic evidences, especially 1D and 2D NMR and HR-MS experiments. 23428347 Bortezomib enhances antigen-specific cytotoxic T cell responses against immune-resistant cancer cells generated by STAT3-ablated dendritic cells. Dendritic cell (DC)-based vaccines have received attention as a new therapeutic modality against cancer. However, increased STAT3 activity in the tumor microenvironment makes DCs tolerogenic and suppresses their antitumor activity. In this study, we explored the effects of a combination treatment consisting of a proteasome inhibitor, bortezomib, and an antigen specific STAT3-ablated (STAT3(-/-)) DC-based vaccine on the control of TC-1(P3) tumors, a p53-degraded immune resistant cancer cells. We found that E7-antigen expressing STAT3(-/-) DC (E7-DC-1STAT3(-/-)) vaccination enhanced generation of E7-specific CD8(+) T cells, but was not enough to control TC-1(P3) cancer cells. Therefore, we investigated whether bortezomib could create a synergistic effect with E7-DC-1STAT3(-/-) vaccination. We found that apoptosis via down-regulation of STAT3 and NF-κB and up-regulation of Fas and death receptor 5 (DR5) expression in TC-1(P3) induced by bortezomib was independent of p53 status. We also observed that TC-1(P3) cells pretreated with bortezomib had markedly enhanced anti-tumor effects on E7-specific CD8(+) T cells through a Fas/DR5-mediated mechanism. In addition, TC-1(P3) tumor-bearing mice treated with bortezomib prior to vaccination with E7-DC-1STAT3(-/-) demonstrated enhanced generation of E7-specific CD8(+) T cells and prolonged survival compared to those treated with monotherapy. These results suggest that the anti-tumor effects against a p53-degraded immune resistant variant generated by antigen-expressing STAT3-ablated mature DCs may be enhanced by bortezomib via death receptor-mediated apoptosis. 23494187 Brentuximab vedotin: a review of its use in patients with hodgkin lymphoma and systemic anaplastic large cell lymphoma following previous treatment failure. Brentuximab vedotin (ADCETRIS(®)) is an antibody-drug conjugate that is specifically targeted against CD30-positive cancer cells such as those in Hodgkin lymphoma or systemic anaplastic large cell lymphoma (ALCL). Intravenous brentuximab vedotin was associated with an overall objective response rate (primary endpoint) of 75 % in 102 patients with Hodgkin lymphoma who had relapsed after high-dose chemotherapy and autologous haematopoietic stem cell transplantation, in a noncomparative, multicentre, phase II trial. In 58 patients with relapsed systemic ALCL after at least one prior treatment, intravenous brentuximab vedotin was associated with an overall objective response rate (primary endpoint) of 86 % in a noncomparative, multicentre, phase II trial. Tumour reductions were observed in 94 % of patients with Hodgkin lymphoma and 97 % of patients with systemic ALCL, and most tumours decreased in size by >65 % and >85 %, respectively. The estimated 12-month survival rates were 89 % and 52 %, respectively. Brentuximab vedotin was generally well tolerated in these trials. The most common adverse event was peripheral neuropathy; approximately one-half of patients with this adverse event experienced complete resolution. 23258708 The comprehensive epigenome map of piRNA clusters. PIWI-interacting RNA (piRNA) clusters act as anti-transposon/retrovirus centers. Integration of selfish jumping elements into piRNA clusters generates de novo piRNAs, which in turn exert trans-silencing activity against these elements in animal gonads. To date, neither genome-wide chromatin modification states of piRNA clusters nor a mode for piRNA precursor transcription have been well understood. Here, to understand the chromatin landscape of piRNA clusters and how piRNA precursors are generated, we analyzed the transcriptome, transcription start sites (TSSs) and the chromatin landscape of the BmN4 cell line, which harbors the germ-line piRNA pathway. Notably, our epigenomic map demonstrated the highly euchromatic nature of unique piRNA clusters. RNA polymerase II was enriched for TSSs that transcribe piRNA precursors. piRNA precursors possessed 5'-cap structures as well as 3'-poly A-tails. Collectively, we envision that the euchromatic, opened nature of unique piRNA clusters or piRNA cluster-associated TSSs allows piRNA clusters to capture new insertions efficiently. 23597490 Anti-diabetic activity of embelin: Involvement of cellular inflammatory mediators, oxidative stress and other biomarkers. Embelin (benzoquinone), an active constituent of methanolic extracts of the fruit of Embelia basal (Myrsinaceae), was studied in high fat diet (HFD)+streptozotocin (STZ) diabetic rats. Treatment of embelin (25 and 50mg/kg/day, p.o.) for 3 weeks to HFD+STZ diabetic rats elicited insignificant increase in body weight, reduced the elevated plasma glucose, glycosylated haemoglobin and pro-inflammatory mediators (interleukin 6 and tumour necrosis factor α) significantly. Furthermore, embelin treatment at both the doses significantly decreased the elevated malondialdehyde, restored depleted glutathione, antioxidant enzymes, superoxide dismutase and catalase in liver. The increased lipid profiles in HFD+STZ diabetic rats were also reduced by embelin treatment significantly. Embelin treatment to HFD+STZ diabetic rats also improved the altered histoarchitecture of β-islets of pancreas and hepatocytes. The embelin effect on progression of type 2 diabetes mellitus in rats appears to be through the inhibition of intracellular pro-inflammatory mediators, lowering of lipid profile and amelioration of oxidative stress. Considering the pharmacological activity profile of embelin, it is suggested that embelin be a useful diabetic modulator or adjuvant along with clinically effective anti-diabetic drugs in the treatment of type 2 diabetes mellitus and needs to be clinically evaluated on human subjects. 23146765 1H NMR-based metabonomics approach in a rat model of acute liver injury and regeneration induced by CCl4 administration. The administration of carbon tetrachloride (CCl(4)) has been established as a model of toxin-induced acute and chronic liver injury. In the present study, we investigate the progression of the biochemical response to acute CCl(4)-induced liver injury, capturing metabolic variations during both toxic insult and regeneration using NMR-based metabonomic analysis of liver tissue and plasma. A single dose of CCl(4) (1 mL/kg BW) was intraperitoneally administered to male Wister rats sacrificed every 12h up to 72 h post treatment, while healthy animals served as controls. Acquired (1)H NMR spectra of liver tissue extracts and plasma samples were explored with multivariate analysis and the resulted models were correlated with conventional biochemical and histopathological indices of toxicity for monitoring the progression of experimental injury. The metabonomic analysis resulted in discrimination between the subjects under toxic insult (up to 36 h) and those at the regenerative phase (peaked at 48 h). At 72 h normalization of liver's pathology similar to the controls group was apparent. Principal component analysis (PCA) trajectories highlighted the time points of the greater degree of toxic insult and the regenerative state. A number of metabolites such as glucose, lactate, choline, formate exhibited variations suggesting CCl(4) induced impairment in essential biochemical pathways as energy metabolism, lipid biosynthesis and transmethylation reactions. The latter provides new evidence of B12 and folate pathways deficiency, indicative of new mechanistic implications possibly by direct inhibition of B12 dependent enzymes by the chlorinated radicals of CCl(4) metabolism. 23524983 Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group. In contrast to studies on class I histone deacetylase (HDAC) inhibitors, the elucidation of the molecular mechanisms and therapeutic potential of class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) is impaired by the lack of potent and selective chemical probes. Here we report the discovery of inhibitors that fill this void with an unprecedented metal-binding group, trifluoromethyloxadiazole (TFMO), which circumvents the selectivity and pharmacologic liabilities of hydroxamates. We confirm direct metal binding of the TFMO through crystallographic approaches and use chemoproteomics to demonstrate the superior selectivity of the TFMO series relative to a hydroxamate-substituted analog. We further apply these tool compounds to reveal gene regulation dependent on the catalytic active site of class IIa HDACs. The discovery of these inhibitors challenges the design process for targeting metalloenzymes through a chelating metal-binding group and suggests therapeutic potential for class IIa HDAC enzyme blockers distinct in mechanism and application compared to current HDAC inhibitors. 23065696 Rapid estimation of nuclear magnetic resonance experiment time in low-concentration environmental samples. Nuclear magnetic resonance (NMR) spectroscopy is an essential tool for studying environmental samples but is often hindered by low sensitivity, especially for the direct detection of nuclei such as(13) C. In very heterogeneous samples with NMR nuclei at low abundance, such as soils, sediments, and air particulates, it can take days to acquire a conventional(13) C spectrum. The present study describes a prescreening method that permits the rapid prediction of experimental run time in natural samples. The approach focuses the NMR chemical shift dispersion into a single spike, and, even in samples with extremely low carbon content, the spike can be observed in two to three minutes, or less. The intensity of the spike is directly proportional to the total concentration of nuclei of interest in the sample. Consequently, the spike intensity can be used as a powerful prescreening method that answers two key questions: (1) Will this sample produce a conventional NMR spectrum? (2) How much instrument time is required to record a spectrum with a specific signal-to-noise (S/N) ratio? The approach identifies samples to avoid (or pretreat) and permits additional NMR experiments to be performed on samples producing high-quality NMR data. Applications in solid- and liquid-state(13) C NMR are demonstrated, and it is shown that the technique is applicable to a range of nuclei. 23194531 Pulsed-electric-field-assisted extraction of anthocyanins from purple-fleshed potato. The influence of pulsed electric field (PEF) treatment on the anthocyanin extraction yield (AEY) from purple-fleshed potato (PFP) at different extraction times (60-480 min) and temperatures (10-40°C) using water and ethanol (48% and 96%) as solvents has been investigated. Response surface methodology was used to determine optimal PEF treatment and optimise anthocyanin extraction. A PEF treatment of 3.4 kV/cm and 105 μs (35 pulses of 3 μs) resulted in the highest cell disintegration index (Z(p)=1) at the lowest specific energy requirements (8.92 kJ/kg). This PEF treatment increased the AEY, the effect being higher at lower extraction temperature with water as solvent. After 480 min at 40°C, the AEY obtained for the untreated sample using 96% ethanol as the solvent (63.9 mg/100 g fw) was similar to that obtained in the PEF-treated sample using water (65.8 mg/100 g fw). Therefore, PEF was possible with water, a more environmental-friendly solvent than ethanol, without decreasing the AEY from PFP. 23357308 Synthesis of some new 2-(3-pyridyl)-4,5-disubstituted thiazoles as potent antimicrobial agents. As a part of ongoing studies in developing new potent antimicrobial agents, a series of novel 2-(3-pyridyl)-4,5-disubstituted thiazoles was efficiently synthesized and characterized by spectral and elemental analyses. The newly synthesized compounds were evaluated for their in vitro antimicrobial activity against ten bacterial and five fungal human pathogenic strains using the disc diffusion assay. Among the synthesized compounds, 5-acetyl-4-methyl-2-(3-pyridyl)thiazole (5) exhibited twofold antibacterial activity of ampicillin in inhibiting the growth of Staphylococcus epidermidis (MIC 0.24 μg/mL) and also showed equipotent antifungal activity with amphotricin B against Geotricum candidum (MIC 0.48 μg/mL). From structure-activity relationship (SAR) point of view, increasing the size of the substitutions either at position 4 or 5 on the thiazole nucleus decreased the antimicrobial activity. 23331539 Fragment-based design of novel quinazolinon derivatives as human acrosin inhibitors. Human acrosin is a promising target for the male contraceptives. On the basis of the active site of human acrosin, a series of novel quinazolinon compounds were designed by a fragment docking and growing strategy. In vitro anti-acrosin assay revealed that all the compounds showed potent human acrosin inhibitory activities. In particular, compounds 5c and 5g are more active than the known inhibitors. Molecular docking studies revealed that the quinazolinon inhibitors interacted with human acrosin mainly through hydrogen bonding and hydrophobic interactions. The binding mode was also consistent with the structure-activity relationships. The quinazolinon derivatives in this study can serve as new lead structure for the development of novel male contraceptives. 23564211 The role of P-glycoprotein in CNS antihistamine effects. RATIONALE: P-glycoprotein (P-gp) is a drug efflux pump expressed, amongst others, on the luminal surface of the cerebral endothelial cells forming the blood-brain barrier. Studies in rodents have demonstrated that antihistamines that are substrates of the P-gp transporter display no or minor central nervous system (CNS) effects as compared to antihistamines that are not P-gp transporter substrates. OBJECTIVES: The present study explored whether P-gp contributes in similar ways to the occurrence of sedative effects of antihistamines in humans. METHODS: An fMRI study was conducted according to a double-blind, randomized, placebo-controlled, cross-over design in 13 healthy volunteers. Participants received cetirizine 15 mg (an antihistamine), verapamil 120 mg (a P-gp blocker), a combination of cetirizine + verapamil, and a placebo. Brain activity was assessed while conducting the attention network test (ANT) in a 3T magnetic resonance scanner. The ANT measures three independent attention domains: i.e., alerting, orienting, and executive attention. It was expected that the combined treatment of cetirizine with verapamil would prevent efflux of cetirizine from the CNS, thus increasing attentional impairment, as compared to cetirizine administered alone. RESULTS: The present study provides evidence that the P-gp transporter is involved in central antihistamine effects in humans. Participants were less alert during the combined treatment of cetirizine and verapamil as indicated by longer reaction times and decreased blood oxygen level-dependent response in the right superior temporal gyrus. CONCLUSION: It is concluded that the affinity for the P-gp transporter may contribute to the lower incidence of CNS side effects of certain antihistamines. 23509904 Structure-Based Design of β-Site APP Cleaving Enzyme 1 (BACE1) Inhibitors for the Treatment of Alzheimer's Disease. The amyloid hypothesis asserts that excess production or reduced clearance of the amyloid-β (Aβ) peptides in the brain initiates a sequence of events that ultimately lead to Alzheimer's disease and dementia. The Aβ hypothesis has identified BACE1 as a therapeutic target to treat Alzheimer's and led to medicinal chemistry efforts to design its inhibitors both in the pharmaceutical industry and in academia. This review summarizes two distinct categories of inhibitors designed based on conformational states of "closed" and "open" forms of the enzyme. In each category the inhibitors are classified based on the core catalytic interaction group or the aspartyl binding motif (ABM). This review covers the description of inhibitors in each ABM class with X-ray crystal structures of key compounds, their binding modes, related structure-activity data highlighting potency advances, and additional properties such as selectivity profile, P-gp efflux, pharmacokinetic, and pharmacodynamic data. 23260032 Exploring the Toxicity of a Bismuth-Asparagine Coordination Polymer on the Early Development of Zebrafish Embryos. Nanoparticles are widely used in nanomedicine, raising concerns about their toxicity. In this study, the toxicity of bismuth-asparagine coordination polymer spheres (BACP-2) was assessed in zebrafish embryos. Injection of 1-4 cell stage embryos with BACP-2 resulted in smaller head size (particularly smaller eye size), shorter body length, and pericardial edemas. The severity and occurrence of the resulting phenotype were concentration-dependent. The expression of genes such as krox20, orthodenticle homeobox 2 (otx2), and cardiac myosin light chain-2 (cmlc2) indicates that the effects of BACP-2 on the head and heart were related to changes in gene expression patterns. A delay in epiboly was observed, and the expression levels of the no tail (ntl) gene indicated that the delay in epiboly resulted both from the effect of BACP-2 on cell migration during epiboly and from slow growth. These findings indicate that BACP-2 exhibits concentration-dependent developmental toxicity, providing insight into the nanotoxicity of bismuth derivatives, which must be rigorously evaluated with respect to toxicity before their application in nanomedicine. 22497567 Evaluation of the physicochemical and biopharmaceutical properties of fluoro-indomethacin. Drug nanocarriers have shown great potential in therapy and as diagnostic probes, e.g. in imaging of cancer and inflammation. Imaging can be applied to localize the carrier or the drug itself in the body and/or tissues. In this particular case it is important that drug molecules have the characteristics for possible detection, e.g. after modification with positron emission tomography compliant radioisotopes, without affecting their pharmacological behavior. In order to easily and efficiently follow the ADME profile of the drug after loaded into nanocarriers, the drug can be radiolabelled with, e.g. 18F-label, in order to assess its biodistribution after enteral and parenteral administration in rats. However, this is only possible if the derivative compound behaves similarly to the parent drug compound. In this study, indomethacin (a poorly water-soluble drug) was chosen as a model compound and aimed to evaluate the physicochemical and biopharmaceutical properties of an analog of indomethacin (IMC), fluoro-indomethacin (F-IMC). Although some of the physicochemical and biopharmaceutical properties of IMC are already known, in order to establish a feasible comparison between IMC and F-IMC, the behavior of the former was also investigated in the same conditions as for F-IMC. In this context, both IMC and F-IMC were thermally and morphologically studied. Furthermore, the following properties were also studied for both compounds: pKa and logP, solubility and dissolution profiles at physiological pH values, and toxicity at different concentrations in Caco-2 cells. Finally, the transport across Caco- 2 monolayers of the IMC and F-IMC at physiological pH range was also investigated. The results obtained showed similar values in pKalogP, solubility, dissolution, cytotoxicity, and permeability for both compounds. Thus, there might be strong evidence that both IMC and F-IMC should have a similar ADME behavior and profiles in vivo. The results provide fundamental tools and ideas for further research with nanocarriers of 18F-IMC. 23333641 Effects of methoxychlor and its metabolite 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane on 11β-hydroxysteroid dehydrogenase activities in vitro. Methoxychlor (MXC) is primarily used as a pesticide and widely present in the environment. The objective of the present study is to investigate the direct effects of MXC and its metabolite 2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE) on two isoforms of 11β-hydroxysteroid dehydrogenase (11β-HSD1 and 11β-HSD2) in vitro. Human liver microsome, rat testis microsome and adult Leydig cells were used for the measurement of 11β-HSD1 activity. Human placental and rat kidney microsomes were used for 11β-HSD2 activity. The IC(50) values on human 11β-HSD1 by MXC and HPTE were 1.91±0.07 and 8.88 ± 0.08 μM, respectively. HPTE inhibited rat 11β-HSD1 with IC(50) of 9.15±0.05μM, while MXC did not inhibit the enzyme. MXC and HPTE were competitive inhibitors of 11β-HSD1. HPTE also inhibited human and rat 11β-HSD2 with IC(50) values of 55.57 ± 0.08 and 12.96 ± 0.11 μM, respectively, while MXC did not inhibit 11β-HSD2. In summary, our results showed that MXC and its metabolite HPTE inhibited both isoforms of 11β-HSD in a species- and chemical structure-dependent manner. 23567040 Photochemical internalization (PCI) of immunotoxins targeting CD133 is specific and highly potent at femtomolar levels in cells with cancer stem cell properties. CD133 is a putative cancer stem cell (CSC) marker for a number of different cancers and is suggested to be a therapeutic target. Since also normal stem cells express CD133 it is of paramount importance that targeting strategies provide a specific and efficient delivery of cytotoxic drugs in only CD133-positive CSCs. In this study, we have employed photochemical internalization (PCI), a minimally invasive method for light-controlled, specific delivery of membrane-impermeable macromolecules from endocytic vesicles to the cytosol, to specifically target CD133-positive cancer cells. We demonstrate that PCI increases the cytotoxic effect of an immunotoxin (IT) targeting CD133-expressing cancer cells of colon (WiDr and HCT116) and pancreas (BxPC-3) origin. The IT consisted of the mAb CD133/1 (AC133) bound to the ribosome inactivating plant toxin saporin (anti-CD133/1-sap). We show that TPCS2a-PCI of anti-CD133/1-sap is specific, and highly cytotoxic at femto-molar concentrations. Specific binding and uptake of CD133/1, was shown by fluorescence microscopy and co-localization with TPCS2a in endosomes/lysosomes was determined by confocal microscopy. CD133(high) WiDr cells, isolated by fluorescence activated cell sorting, had a 7-fold higher capacity to initiate spheroids than CD133(low) cells (P<0.001) and were resistant to photodynamic therapy (PDT). However, PDT-resistance was bypassed by the PCI strategy. Tumor initiation and aggressive growth in athymic nude mice was obtained with only 10 CD133(high) cells in contrast to CD133(low) cells where substantially higher cell numbers were needed. The excellent high efficacy and selectivity of eliminating CD133-expressing cells by PCI warrant further pre-clinical evaluations of this novel therapeutic approach. 23523949 Protective effect of crocin on diazinon induced cardiotoxicity in rats in subchronic exposure. This study was designed to evaluate the effectiveness of crocin, main component of Crocus sativus L. (Saffron) against subchronic diazinon (DZN) induced cardiotoxicity in rats. METHODS: Rats were divided into 7 groups; control (corn oil, gavage), DZN (15mg/kg/day, gavage,), crocin (12.5, 25 or 50mg/kg/day, i.p) plus DZN, vitamin E (200IU/kg, i.p, three times per week) plus DZN and crocin (50mg/kg/day, i.p) groups. Treatments were continued for 4weeks. Creatine phosphokinase MB (CK-MB), malondealdehyde (MDA) and glutathione (GSH) levels were evaluated in heart tissue at the end of treatments. Levels of apoptotic proteins (Bax, Bcl2, caspase 3) and cytosolic cytochrome c were analyzed by Western blotting. Transcript levels of Bax and Bcl2 were also determined using qRT PCR. RESULTS: DZN induced histophatological damages and elevated the level of cardiac marker CK-MB. These effects were associated with increased MDA level, lower level of reduced GSH and induction of apoptosis through elevation of Bax/Bcl2 ratio (both protein and mRNA levels), cytochrome c release to the cytosol and activation caspase 3 in cardiac tissue. Crocin (25 and 50mg/kg) or vitamin E improved histopathological damages, decreased MDA and CK-MB, increased GSH content and attenuated the increase of Bax/Bcl2 ratio, activation of caspase 3 and release of cytochrome c to the cytosol induced by DZN. In summary, DZN induced mitochondrial-mediated apoptosis in heart tissue of rat following subchronic exposure. Crocin, as an antioxidant, showed protective effects against DZN cardiotoxicity by reducing lipid peroxidation and alleviating apoptosis. 23535915 Comparing the sensitivity of geographically distinct Lemna minor populations to atrazine. The objectives of this study were to compare the sensitivities of field populations and a laboratory culture of a duckweed species (Lemna minor) to the herbicide atrazine using three different endpoints and to determine whether sensitivity to atrazine was affected by past exposure to the herbicide. L. minor cultures were purchased commercially or collected from field sites within an agricultural watershed and exposed to atrazine for 7 days under greenhouse conditions. Populations differed significantly in their sensitivity to atrazine. Biomass was more sensitive than frond number, while chlorophyll fluorescence was not a sensitive endpoint. Overall, the sensitivity of the various populations to atrazine was not strongly related to measures of past exposure to agriculture stressors. Positive correlations between biomass twenty-five percent inhibition concentrations (IC25s), biomass estimated marginal means and in-stream atrazine concentrations were observed, providing evidence that atrazine exposure is linked to a decrease in sensitivity to atrazine. However, IC25s generated for each population were similar, ranging from 19 to 40 and 57 to 92 μg/L atrazine for biomass and frond data respectively, and likely do not represent biologically significant differences in atrazine sensitivity. Given the small range in sensitivity observed between populations, commercial laboratory cultures appear to provide a good estimate of the sensitivity of field populations of L. minor to atrazine and should continue to be used in regulatory phytotoxicity testing. 23061607 Organosilicon molecules with medicinal applications. The incorporation of silicon and synthesis of organosilicon small molecules provide unique opportunities for medicinal applications. The biological investigation of organosilicon small molecules is particularly interesting because of differences in their chemical properties that can contribute to enhanced potency and improved pharmacological attributes. Applications such as inhibitor design, imaging, drug release technology, and mapping inhibitor binding are discussed. 23391598 Essential trace and toxic element concentrations in organic and conventional milk in NW Spain. Dietary composition and husbandry practices largely determine essential trace element status and toxic element exposure of livestock, and consequently their concentrations in animal products. This study evaluates the main essential trace (Co, Cr, Cu, Fe, I, Mn, Mo, Ni, Se and Zn) and toxic (As, Cd, Hg and Pb) element concentrations in milk from organic and conventional farms in NW Spain (n=50). Milk samples were acid digested and analyzed by ICP-MS. Essential trace element concentrations in organic milk were significantly lower compared to conventional milk, this was especially evident for elements that are routinely supplemented at high concentrations in the conventional concentrate feed: Cu (41.0 and 68.9μg/L in organic and conventional milk, respectively), Zn (3326 and 3933μg/L), I (78 and 265μg/L) and Se (9.4 and 19.2μg/L). Toxic metal concentrations in milk were in general very low and no statistically significant differences were observed between organic and conventional milk. In addition, the mineral content of organic milk showed a seasonal pattern, the significantly higher As (65%) and Fe (13%) concentrations found in the winter sampling possibly being related to a higher consumption of concentration feed and soil ingestion when grazing. 23318730 Platinum folate nanoparticles toxicity: cancer vs. normal cells. Almost for two decades metallic nanoparticles are successfully used for cancer detection, imaging and treatment. Due to their high electron density they can be easily observed by electron microscopy and used in laser and radiofrequency therapy as energy releasing agents. However, the limitation for this practice is an inability to generate tumor-specific heating in a minimally invasive manner to the healthy tissue. To overcome this restraint we proposed to use folic acid coated metallic nanoparticles and determine whether they preferentially penetrate cancer cells. We developed technique for synthesizing platinum nanoparticles using folic acid as stabilizing agent which produced particles of relatively narrow size distribution, having d=2.3 ± 0.5 nm. High resolution TEM and zeta potential analysis indicated that the particles produced by this method had a high degree of crystalline order with no amorphous outer shell and a high degree of colloidal stability. The keratinocytes and mammary breast cells (cancer and normal) were incubated with platinum folate nanoparticles, and the results showed that the IC50 was significantly higher for the normal cells than the cancer cells in both cases, indicating that these nanoparticles preferentially target the cancer cells. TEM images of thin sections taken from the two types of cells indicated that the number of vacuoles and morphology changes after incubation with nanoparticles was also larger for the cancer cells in both types of tissue studied. No preferential toxicity was observed when folic acid receptors were saturated with free folic acid prior to exposure to nanoparticles. These results confirm our hypothesis regarding the preferential penetration of folic acid coated nanoparticles to cancer cells due to receptor mediated endocytosis. 23109183 Microfluidic investigation of BDNF-enhanced neural stem cell chemotaxis in CXCL12 gradients. In vivo studies have suggested that gradients of CXCL12 (aka stromal cell-derived factor 1α) may be critical for neural stem cell (NSC) migration during brain development and neural tissue regeneration. However, traditional in vitro chemotaxis tools are limited by unstable concentration gradients and the inability to decouple cell migration directionality and speed. These limitations have restricted the reproducible and quantitative analysis of neuronal migration, which is required for mechanism-based studies. Using a microfluidic gradient generator, nestin and Sox-2 positive human embryonic NSC chemotaxis is quantified within a linear and stable CXCL12 gradient. While untreated NSCs are not able to chemotax within CXCL12 gradients, pre-treatment of the cells with brain-derived neurotrophic factor (BDNF) results in significant chemotactic, directional migration. BDNF pre-treatment has no effect on cell migration speed, which averages about 1 μm min(-1). Quantitative analysis determines that CXCL12 concentrations above 9.0 nM are above the minimum activation threshold, while concentrations below 14.7 nM are below the saturation threshold. Interestingly, although inhibitor studies with AMD 3100 revealed that CXCL12 chemotaxis requires receptor CXCR4 activation, BDNF pre-treatment is found to have no profound effects on the mRNA levels or surface presentation of CXCR4 or the putative CXCR7 scavenger receptor. The microfluidic study of NSC migration within stable chemokine concentration profiles provides quantitative analysis as well as new insight into the migratory mechanism underlying BDNF-induced chemotaxis towards CXCL12. 23584484 miR-194 suppresses metastasis of non-small cell lung cancer through regulating expression of BMP1 and p27(kip1.) MicroRNAs (miRNAs) are increasingly implicated in regulating tumor malignance through their capacity to coordinately repress expression of tumor-related genes. Here, we show that overexpression of miR-194 in lung cancer cell lines, results in suppressing metastasis of lung cancer cells, while inhibiting its expression through 'miRNA sponge' promotes the cancer cells to metastasize. miR-194 expression is also found to be in strongly negative association with metastasis in clinical specimens of non-small cell lung cancer. We demonstrate that miR-194 directly targets both BMP1 and p27(kip1). The resulting downregulation of BMP1 leads to suppression of TGFβ activity and, thus, to downregulation of the expression of key oncogenic genes (matrix metalloproteinases MMP2 and MMP9). This leads, in turn, to decreased tumor invasion. In addition, the miRNA-194-induced suppression of p27(kip1) activates the RhoA pathway, producing enhanced development of actin stress fibers and impaired migration of cancer cells. These findings reveal two structurally independent but functionally linked branches of the regulatory and signaling pathway that together provide a bridge between the metastasis-depressing miRNA and the key genes that govern the malignancy of lung cancers.Oncogene advance online publication, 15 April 2013; doi:10.1038/onc.2013.108. 23470152 Ideal redox behavior of the high-density self-assembled monolayer of a molecular tripod on a au(111) surface with a terminal ferrocene group. A dyad consisting of a tripod-shaped trithiol with an adamantane core and a terminal ferrocenyl group linked through ap-phenyleneethynylene bridge was synthesized. The trithiol formed a stable self-assembled monolayer (SAM) on Au(111), wherein each molecule is bound to the surface by three-point adsorption using all sulfur atoms, with confirmation by PM-IRRAS and XPS analyses. Cyclic voltammetry of the SAM showed a line shape typical of an ideal adsorbed system, that is, a monolayer with negligible electrostatic interaction among the terminal ferrocenyl groups. Thus, a rare SAM was achieved, in which the component molecules were isolated from adjacent molecules without the coadsorption of nonelectroactive molecules. 23473066 Going where traditional markers have not gone before: utility of and promise for RAD sequencing in marine invertebrate phylogeography and population genomics. Characterization of large numbers of single-nucleotide polymorphisms (SNPs) throughout a genome has the power to refine the understanding of population demographic history and to identify genomic regions under selection in natural populations. To this end, population genomic approaches that harness the power of next-generation sequencing to understand the ecology and evolution of marine invertebrates represent a boon to test long-standing questions in marine biology and conservation. We employed restriction-site-associated DNA sequencing (RAD-seq) to identify SNPs in natural populations of the sea anemone Nematostella vectensis, an emerging cnidarian model with a broad geographic range in estuarine habitats in North and South America, and portions of England. We identified hundreds of SNP-containing tags in thousands of RAD loci from 30 barcoded individuals inhabiting four locations from Nova Scotia to South Carolina. Population genomic analyses using high-confidence SNPs resulted in a highly-resolved phylogeography, a result not achieved in previous studies using traditional markers. Plots of locus-specific FST against heterozygosity suggest that a majority of polymorphic sites are neutral, with a smaller proportion suggesting evidence for balancing selection. Loci inferred to be under balancing selection were mapped to the genome, where 90% were located in gene bodies, indicating potential targets of selection. The results from analyses with and without a reference genome supported similar conclusions, further highlighting RAD-seq as a method that can be efficiently applied to species lacking existing genomic resources. We discuss the utility of RAD-seq approaches in burgeoning Nematostella research as well as in other cnidarian species, particularly corals and jellyfishes, to determine phylogeographic relationships of populations and identify regions of the genome undergoing selection. 23288589 Electrolyte-gated organic field-effect transistor sensors based on supported biotinylated phospholipid bilayer. Anchored, biotinylated phospholipids forming the capturing layers in an electrolyte-gated organic field-effect transistor (EGOFET) allow label-free electronic specific detection at a concentration level of 10 nM in a high ionic strength solution. The sensing mechanism is based on a clear capacitive effect across the PL layers involving the charges of the target molecules. 23371965 The inactivation of human CYP2E1 by phenethyl isothiocyanate, a naturally occurring chemopreventive agent, and its oxidative bioactivation. Phenethylisothiocyanate (PEITC), a naturally occurring isothiocyanate and potent cancer chemopreventive agent, works by multiple mechanisms, including the inhibition of cytochrome P450 (P450) enzymes, such as CYP2E1, that are involved in the bioactivation of carcinogens. PEITC has been reported to be a mechanism-based inactivator of some P450s. We describe here the possible mechanism for the inactivation of human CYP2E1 by PEITC, as well as the putative intermediate that might be involved in the bioactivation of PEITC. PEITC inactivated recombinant CYP2E1 with a partition ratio of 12, and the inactivation was not inhibited in the presence of glutathione (GSH) and not fully recovered by dialysis. The inactivation of CYP2E1 by PEITC is due to both heme destruction and protein modification, with the latter being the major pathway for inactivation. GSH-adducts of phenethyl isocyanate (PIC) and phenethylamine were detected during the metabolism by CYP2E1, indicating formation of PIC as a reactive intermediate following P450-catalyzed desulfurization of PEITC. Surprisingly, PIC bound covalently to CYP2E1 to form protein adducts but did not inactivate the enzyme. Liquid chromatography mass spectroscopy analysis of the inactivated CYP2E1 apo-protein suggests that a reactive sulfur atom generated during desulfurization of PEITC is involved in the inactivation of CYP2E1. Our data suggest that the metabolism of PEITC by CYP2E1 that results in the inactivation of CYP2E1 may occur by a mechanism similar to that observed with other sulfur-containing compounds, such as parathion. Digestion of the inactivated enzyme and analysis by SEQUEST showed that Cys 268 may be the residue modified by PIC. 23265896 Regioselective synthesis of 5- and 6-methoxybenzimidazole-1,3,5-triazines as inhibitors of phosphoinositide 3-kinase. Phosphoinositide 3-kinases (PI3K) hold significant therapeutic potential as novel targets for the treatment of cancer. ZSTK474 (4a) is a potent, pan-PI3K inhibitor currently under clinical evaluation for the treatment of cancer. Structural studies have shown that derivatisation at the 5- or 6-position of the benzimidazole ring may influence potency and isoform selectivity. However, synthesis of these derivatives by the traditional route results in a mixture of the two regioisomers. We have developed a straightforward regioselective synthesis that gave convenient access to 5- and 6-methoxysubstituted benzimidazole derivatives of ZSTK474. While 5-methoxy substitution abolished activity at all isoforms, the 6-methoxy substitution is consistently 10-fold more potent. This synthesis will allow convenient access to further 6-position derivatives, thus allowing the full scope of the structure-activity relationships of ZSTK474 to be probed. 22310170 Drought episode modulates the response of river biofilms to triclosan. The consequences of global change on rivers include altered flow regime, and entrance of compounds that may be toxic to biota. When water is scarce, a reduced dilution capacity may amplify the effects of chemical pollution. Therefore, studying the response of natural communities to compromised water flow and to toxicants is critical for assessing how global change may affect river ecosystems. This work aims to investigate how an episode of drought might influence the response of river biofilms to pulses of triclosan (TCS). The objectives were to assess the separate and combined effects of simulated drought (achieved through drastic flow alteration) and of TCS exposure on biofilms growing in artificial channels. Thus, three-week-old biofilms were studied under four conditions: Control (normal water flow); Simulated Drought (1 week reduced flow+2 days interrupted flow); TCS only (normal water flow plus a 48-h pulse of TCS); and Simulated Drought+TCS. All channels were then left for 2 weeks under steady flow conditions, and their responses and recovery were studied. Several descriptors of biofilms were analyzed before and after each step. Flow reduction and subsequent interruption were found to provoke an increase in extracellular phosphatase activity, bacterial mortality and green algae biomass. The TCS pulses severely affected biofilms: they drastically reduced photosynthetic efficiency, the viability of bacteria and diatoms, and phosphate uptake. Latent consequences evidenced significant combined effects caused by the two stressors. The biofilms exposed only to TCS recovered far better than those subjected to both altered flow and subsequent TCS exposure: the latter suffered more persistent consequences, indicating that simulated drought amplified the toxicity of this compound. This finding has implications for river ecosystems, as it suggests that the toxicity of pollutants to biofilms may be exacerbated following a drought. 23116643 Rosmarinic acid ameliorates acute liver damage and fibrogenesis in carbon tetrachloride-intoxicated mice. The aim of this study was to investigate the therapeutic potential of rosmarinic acid (RA), a natural phenolic, in the treatment of acute liver toxicity. RA at 10, 25 and 50mg/kg was administered by gavage once daily for 2 consecutive days, 6h after CCl(4) intoxication. CCl(4) intoxication caused hepatic necrosis and increased serum ALT activity. In the livers, oxidative/nitrosative stress was evidenced by increased 3-nitrotyrosine (3-NT) and thiobarbituric acid reactive substances (TBARS) formation and a significant decrease in Cu/Zn superoxide dismutase (SOD) activity. CCl(4) administration triggered inflammatory response in mice livers by activating nuclear factor-kappaB (NF-κB), which coincided with the induction of tumor necrosis factor-alpha (TNF-α) and cyclooxygenase-2 (COX-2). RA improved histological and serum markers of liver damage and significantly ameliorated oxidative/nitrosative stress and inflammatory response in liver tissue. Additionally, RA prevented transforming growth factor-beta1 (TGF-β1) and alpha-smooth muscle actin (α-SMA) expression, suggesting suppression of profibrotic response. Furthermore, RA significantly inhibited the CCl(4)-induced apoptosis, which was evident from decreased cleavage of caspase-3. The hepatoprotective activity of RA coincided with enhanced NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression. The results of this study indicates that RA possesses antioxidant, anti-inflammatory, antiapoptotic and antifibrotic activity against acute liver toxicity. 23644214 Synthetic tactics of new class of 4-aminothieno[2,3-d]pyrimidine-6-carbonitrile derivatives acting as antimicrobial agents. Thermal selective reactions were studied on oxothieno[2,3-d]pyrimidine-6-carboxamide 3 with POCl3 and PCl5. At 25-50 °C, the C7-amide rearranges to nitrile furnished compound 4 in 85-90% yield, while at 80-110 °C furnished mixture of products 4 and 5 in 28-68% yields. The chloro displacement with amines in compound 5 yielded 4-aminothieno[2,3-d]pyrimidine-6-carbonitrile derivatives 8(a-h) and 9(a-e). Antimicrobial activity of new compounds was studied against several bacteria such as Staphylococcus aureus MTCC-96, Escherichia coli MTCC-443, Pseudomonas aeruginosa MTCC-4 41, Streptococcus pyogenes MTCC-442 and fungi Aspergillus niger MTCC-282, Aspergillus clavatus MTCC-1323, Candida albicans MTCC-227 using broth microdilution method. Compounds 4, 8b, 8d, 8e, 8h and 9a showed promising antibacterial activity compared to ampicillin and compounds 8b, 8h showed better antifungal activity compared to greseofulvin. 23086198 Importance of UDP-glucuronosyltransferases 2A2 and 2A3 in tobacco carcinogen metabolism. UDP-glucuronosyltransferase A1 (UGT2A1) is expressed in the lung and exhibits activity against polycyclic aromatic hydrocarbons (PAHs), suggesting UGT2A1 involvement in the local metabolism of PAH tobacco carcinogens. The goal of the present study was to investigate the importance of two additional UGT2A enzymes, UGT2A2 and UGT2A3, in tobacco carcinogen metabolism. Real-time polymerase chain reaction suggested that wild-type UGT2A2 had the highest expression in the breast, followed by trachea > larynx > kidney. A novel splice variant of UGT2A2 lacking exon 3 (termed UGT2A2Δexon3) was investigated, with UGT2A2Δexon3 expression determined to be 25-50% that of wild-type UGT2A2 in all tissues examined. UGT2A3 was determined to be well expressed in the liver and colon, followed by pancreas > kidney > lung > tonsil > trachea > larynx. Cell homogenates prepared from human embryonic kidney (HEK)293 cells overexpressing wild-type UGT2A2 (termed UGT2A2_i1) exhibited glucuronidation activity, as observed by reverse-phase ultra-pressure liquid chromatography, against 1-hydroxy-(OH)-pyrene, 1-naphthol, and hydroxylated benzo(a)pyrene metabolites, whereas homogenates prepared from HEK293 cells overexpressing UGT2A3 only showed activity against simple PAHs like 1-OH-pyrene and 1-naphthol. Activity assays showed the UGT2A2Δexon3 protein (termed UGT2A2_i2) exhibited no detectable glucuronidation activity against all substrates examined; however, coexpression studies suggested that UGT2A2_i2 negatively modulates UGT2A2_i1 activity. Both UGT2A2 and UGT2A3 exhibited no detectable activity against complex PAH proximate carcinogens, tobacco-specific nitrosamines, or heterocyclic amines. These data suggest that, although UGT2A1 is the only UGT2A enzyme active against PAH proximate carcinogens (including PAH diols), both UGTs 2A1 and 2A2 play an important role in the local detoxification of procarcinogenic monohydroxylated PAH metabolites. 23307548 Ambulatory blood pressure monitoring: recent evidence and clinical pharmacy applications. Conventional office blood pressure readings are a well-established surrogate for the prediction of cardiovascular risk. It is assumed that these readings reflect an underlying average level of blood pressure exposure occurring in an individual over a period of time. But because blood pressure is not static, important additional prognostic information about the diurnal blood pressure profile, including within-day and between-day variability, is not easily ascertained from conventional measurements. Ambulatory blood pressure monitoring provides a more thorough depiction of the underlying blood pressure level and predicts cardiovascular risk more robustly than do conventional blood pressure measurements. Although the technology has been available for more than 30 years, there has been an expansion of the research base in the past decade supporting its role in the evaluation and management of patients with hypertension and as an important surrogate in research trials. This review summarizes recent evidence supporting the predictive ability of ambulatory blood pressure monitoring and briefly highlights opportunities for clinical pharmacists to adopt this important clinical and research tool. 22294443 Detection of polycyclic aromatic hydrocarbons in different types of processed foods. Polycyclic aromatic hydrocarbons (PCAHs), particularly those with a high molecular weight, have been classified as probable carcinogens to humans. The aim of the present study is to determine the levels of PCAHs in samples of meat, fish, chicken, fried potato, and toasted bread, which will be thermally processed using conventional and microwave ovens. Different samples will be collected and analyzed for five PCAHs including pyrene, benzo(a)anthracene, benzo(e)pyrene, benzoflouroanthene, and benzo(a)pyrene. The analytical method involves saponification with methanolic potassium hydroxide, extraction with cyclohexane, and determination by high-performance liquid chromatography. The obtained results showed that there is a variation in the detected PCAHs in different foodstuffs. Fried potato processed by conventional oven or microwave oven showed none of the selected studied PCAHs. It was found that, chicken showed higher content levels of total PCAHs than the meat and fish. Data are the highest mean concentrations of fluoranthene and benzo(a)pyrene but within low limit. The obtained results were compared with international permissible levels to avoid pollution, which may cause hazardous effects on individual and society. 22972222 Factors associated with the glucose-lowering effect of vildagliptin identified from the results of the oral glucose tolerance test in Japanese patients with type 2 diabetes. In order to investigate the factors contributing to the glucose-lowering effect of vildagliptin, we analyzed the results of the oral glucose tolerance test together with several clinical parameters in Japanese patients with type 2 diabetes before and after 24 weeks of treatment with vildagliptin. The data of the 13 patients who satisfactorily completed the follow-up examinations were included. After 24 weeks treatment with vildagliptin, the patients were classified into a responder group (69.2%) and a non-responder group (30.8%); the responders consisting of subjects whose HbA1c decreased following 24 weeks treatment with vildagliptin, and the non-responders consisting of subjects who did not show any significant decrease of HbA1c. There were no differences in baseline characteristics between the two groups before administration of vildagliptin. After 24 weeks of treatment, HbA1c was significantly reduced from 7.3 ± 0.5% to 6.7 ± 0.5% in the responder group (P = 0.0077), while it tended to rather increased from 7.1 ± 0.6% to 7.5 ± 0.7% in the non-responder group (P = 0.0679). Also, parameters reflecting the glucose-stimulated insulin secretion, such as the insulinogenic index and oral disposition index, were significantly higher in the responder group than in the non-responder group, whereas insulin sensitivity was similar between the two groups. These results suggest that the difference in the degree of improvement of the glucose tolerance between the responder group and non-responder group in this study could be associated with the effect of vildagliptin on the glucose-stimulated insulin secretion, but not on the insulin sensitivity. 22687520 Non-invasive brain stimulation in neurological diseases. Non-invasive brain stimulation has shown its potential to modulate brain plasticity in humans. Endeavour has been made to utilize brain stimulation in neurological diseases to enhance adaptive processes and prevent potential maladaptive ones. In stroke for instance both sensorimotor and higher cognitive impairment, such as aphasia and neglect, has been addressed to facilitate functional recovery. In Parkinson's disease, brain stimulation has been evaluated to improve motor and non-motor symptoms. In the present review we provide an update of the field of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) as non-invasive brain stimulation techniques to improve motor and higher cognitive functions in patients suffering from stroke and Parkinson's disease. Rather than attempting to be comprehensive in regard of the reviewed scientific field, this article may be considered as a present day's framework of the application of non-invasive brain stimulation on selected examples of common neurological diseases. At the end we will briefly discuss open controversies and future directions of the field which has to be addressed in upcoming studies. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23042728 Exposure to valproic acid inhibits chondrogenesis and osteogenesis in mid-organogenesis mouse limbs. In utero exposure to valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, causes neural tube, heart, and limb defects. Valpromide (VPD), the amide derivative of VPA, does not inhibit HDAC activity and is a weak teratogen in vivo. The detailed mechanism of action of VPA as a teratogen is not known. The goal of this study was to test the hypothesis that VPA disrupts regulation of the expression of genes that are critical in chondrogenesis and osteogenesis during limb development. Murine gestation day-12 embryonic forelimbs were excised and exposed to VPA or VPD in a limb bud culture system. VPA caused a significant concentration- dependent increase in limb abnormalities, which was correlated with its HDAC inhibitory effect. The signaling of both Sox9 and Runx2, key regulators of chondrogenesis, was downregulated by VPA. In contrast, VPD had little effect on limb morphology and no significant effect on HDAC activity or the expression of marker genes. Thus, VPA exposure dysregulated the expression of target genes directly involved in chondrogenesis and osteogenesis in the developing limb. Disturbances in these signaling pathways are likely to be a consequence of HDAC inhibition because VPD did not affect their expressions. 23578627 A study of the precursors of the natural antioxidant phenol 3,4-dihydroxyphenylglycol in olive oil waste. 3,4-Dihydroxyphenylglycol (DHPG) is a potent antioxidant recently found in the free form in olive oil and table olives. DHPG can be recovered from olive oil solid waste by a hydrothermal treatment. It was observed that an increase in the concentration of DHPG occurred when alperujo aqueous extracts were subjected to mild thermal conditions (post-treatment). This fact indicates that certain solubilized compounds or precursors containing DHPG which is released with the post-treatment. In the present study, the precursors of DHPG were identified and characterized after extraction from alperujo using thermal treatment and purification by fractionation on Amberlite® XAD16 polyamide and semi-preparative reverse-phase HPLC columns. Their structures were elucidated using HPLC coupled to diode array detector (DAD) and electrospray ionization mass spectrometry (ESI-MS). The results identified three compounds as precursors, and their structures can be attributed to the diastereoisomeric forms of the two β-hydroxy derivatives of verbascoside and isoverbascoside (β-hydroxyacteoside and β-hydroxyisoacteoside), and 2″-hydroxyoleuropein, all of which contain a DHPG moiety, potentially explaining the increases in the concentration of this phenolic compound in olive oil waste. 23420471 TiO2 nanowire electron transport pathways inside organic photovoltaics. Charge transport is one of the five main steps in the operation of organic photovoltaics, but achieving balanced hole and electron transport with high mobility has been challenging in devices. Here, we report improved charge transport in organic photovoltaics via incorporation of nanostructured inorganic electron transport materials into the active layers of devices. Co-depositing TiO2 nanowires with the organic active layer solution embeds the nanowires directly within active layers of the solar cell. The ability of these nanowires to transport electrons is compared with neat P3HT:PCBM active layers and also devices containing TiO2 nanotube aggregates. Incorporation of TiO2 nanowires yields a six-fold increase in the electron mobility relative to unmodified devices, leading to a 19% improvement in the power conversion efficiency. Lower energetic disorder of the film and more balanced charge transport are also observed upon incorporating TiO2 nanowires. These advantageous effects correlate with the TiO2 nanowire length. 23416847 A review of mouse critical size defect models in weight bearing bones. Current and future advances in orthopedic treatment are aimed at altering biological interactions to enhance bone healing. Currently, several clinical scenarios exist for which there is no definitive treatment, specifically segmental bone loss from high-energy trauma or surgical resection - and it is here that many are aiming to find effective solutions. To test experimental interventions and better understand bone healing, researchers employ critical size defect (CSD) models in animal studies. Here, an overview of CSDs is given that includes the specifications of varying models, a discussion of current scaffold and bone graft designs, and current outcome measures used to determine the extent of bone healing. Many promising graft designs have been discovered along with promising adjunctive treatments, yet a graft that offers biomechanical support while allowing for neovascularization with eventual complete resorption and remodeling remains to be developed. An overview of this important topic is needed to highlight current advances and provide a clear understanding of the ultimate goal in CSD research - develop a graft for clinical use that effectively treats the orthopedic conundrum of segmental bone loss. 23350972 Laboratory adapted Escherichia coli K-12 becomes a pathogen of Caenorhabditis elegans upon restoration of O antigen biosynthesis. Escherichia coli has been the leading model organism for many decades. It is a fundamental player in modern biology, facilitating the molecular biology revolution of the last century. The acceptance of E. coli as model organism is predicated primarily on the study of one E. coli lineage; E. coli K-12. However, the antecedents of today's laboratory strains have undergone extensive mutagenesis to create genetically tractable offspring but which resulted in loss of several genetic traits such as O antigen expression. Here we have repaired the wbbL locus, restoring the ability of E. coli K-12 strain MG1655 to express the O antigen. We demonstrate that O antigen production results in drastic alterations of many phenotypes and the density of the O antigen is critical for the observed phenotypes. Importantly, O antigen production enables laboratory strains of E. coli to enter the gut of the Caenorhabditis elegans worm and to kill C. elegans at rates similar to pathogenic bacterial species. We demonstrate C. elegans killing is a feature of other commensal E. coli. We show killing is associated with bacterial resistance to mechanical shear and persistence in the C. elegans gut. These results suggest C. elegans is not an effective model of human-pathogenic E. coli infectious disease. 23128829 Induction of nuclear anomalies in exfoliated buccal cells of coca chewers: results of a field study. The leaves of coca (Erythroxylum coca var. coca), a South American shrub which contains cocaine, other alkaloids and phenolics are widely used by indigenous populations of the Andes. It is currently not known if coca consumption causes genotoxic effects in humans. This information is important to predict potential long-term toxic effects such as cancer induction. Therefore, the buccal cytome assay was used to analyze oral cells from 45 uni- and bilateral chewers and 23 controls living in the Altiplano of the Peruvian Andes. In total, 123,471 cells were evaluated from chewers and 57,916 from controls. Information concerning the consumption levels and habits and also use of lime were collected with questionnaires. Chewing of the leaves did not induce nuclear anomalies reflecting genetic damage such as micronuclei (MNi) and nuclear buds; in the highest exposure group (but not in the overall group) even a significant decrease in the frequencies of cells with MNi (by 64 %) was observed. However, we found significantly elevated levels of other nuclear anomalies (karyorrhexis and karyolysis) which reflect cytotoxic effects in the coca users. The frequencies of these anomalies increased with the daily consumption and when lime was used to improve the release of the alkaloids. In contrast to other chewing habits (betel, tobacco and khat), consumption of coca leaves does not induce genetic instability in cells from the oral cavity and our findings indicate that no adverse health effects take place in chewers which are associated with DNA damage. However, the significant increase in certain anomalies shows that acute toxic effects are caused by coca consumption. 22301816 Effect of Thiovit(R) Jet on the structure of thoracic microtrichia/trichomes in Drosophila melanogaster. Widely used fungicides and pesticides are known to have profound effect on several nontarget organisms, which is a cause of concern. The present study aims to demonstrate the effect of a fungicide, Thiovit(®) Jet on the structure of epidermal microtrichia (trichome) of the dorsal thorax in Drosophila melanogaster. External morphology and structural variations of thoracic appendages have been extensively studied using scanning electron microscope from flies treated with different concentrations of Thiovit Jet (20, 30, 40 or 200 μg/ml). Similar to the effect of other fungicides like captan and captafol which are reported to produce somatic mutations in the same organism, the present study successfully demonstrates variation in the trichome/microtrichia structure of the dorsal thorax of D. melanogaster. Structural variations were observed to be associated with different concentrations of Thiovit Jet (30, 40 and 200 μg/ml), but the maximum notable change was found with 40 μg/ml treatment. The gross abnormality in the trichome structure may be due to mutation in proteins associated with normal cuticular deposition. 23374872 Potent and selective tariquidar bioisosters as potential PET radiotracers for imaging P-gp. Compounds 8a-d have been designed as bioisosters of tariquidar for imaging P-gp expression and density by PET. The results displayed that compounds 8b and 8d could be considered potential P-gp/BCRP ligands suitable as (11)C and (18)F radiotracers, respectively. 23645248 Oestrogen action on thyroid progenitor cells: relevant for the pathogenesis of thyroid nodules? Benign and malignant thyroid nodules are more prevalent in females than in men. Experimental data suggest that the proliferative effect of oestrogen rather than polymorphisms is responsible for this gender difference. This study analysed whether both differentiated thyroid cells and thyroid stem and progenitor cells are a target of oestrogen action. In thyroid stem/progenitor cells derived from nodular goitres the ability of 17beta-oestradiol to induce thyrosphere formation, the expression of oestrogen receptors and the effect of 17beta-oestradiol on growth, expression of marker of stem cells and thyroid differentiation (TSH receptor, thyroperoxidase, thyroglobulin, sodium iodide symporter expression) were analysed. 17beta-oestradiol induced thyrosphere formation, albeit to lower extent than other growth factors. Thyroid stem and progenitor cells expressed oestrogen receptor alpha and beta with an 8 time higher expression level of oestrogen receptor alpha mRNA compared to differentiated thyrocytes. 17beta-oestradiol was a potent stimulator of thyroid stem/ progenitor cell growth. In contrast, TSH-induced differentiation of progenitor cells, in particular the expression of the sodium iodide symporter, was significantly inhibited by 17beta-oestradiol.In conclusion, oestrogen stimulated growth and simultaneously inhibited differentiation of thyroid nodules derived stem/progenitor cells. From these data and based on the concept of cellular heterogeneity, we hypothesize a supportive role of oestrogen in the propagation of thyroid stem/progenitor cells leading to a selection of a progeny of growth-prone cells with a decreased differentiation. These cells may be the origin of hypo- or non-functioning thyroid nodules in females. 23375260 Structural basis for autoinhibition of the guanine nucleotide exchange factor FARP2. FARP2 is a Dbl-family guanine nucleotide exchange factor (GEF) that contains a 4.1, ezrin, radixin and moesin (FERM) domain, a Dbl-homology (DH) domain and two pleckstrin homology (PH) domains. FARP2 activates Rac1 or Cdc42 in response to upstream signals, thereby regulating processes such as neuronal axon guidance and bone homeostasis. How the GEF activity of FARP2 is regulated remained poorly understood. We have determined the crystal structures of the catalytic DH domain and the DH-PH-PH domains of FARP2. The structures reveal an auto-inhibited conformation in which the GEF substrate-binding site is blocked collectively by the last helix in the DH domain and the two PH domains. This conformation is stabilized by multiple interactions among the domains and two well-structured inter-domain linkers. Our cell-based activity assays confirm the suppression of the FARP2 GEF activity by these auto-inhibitory elements. 23489976 Light at Night Alters Daily Patterns of Cortisol and Clock Proteins in Female Siberian Hamsters. Humans and other organisms have adapted to a 24-h solar cycle in response to life on Earth. The rotation of the planet on its axis and its revolution around the sun cause predictable daily and seasonal patterns in day length. In order to successfully anticipate and adapt to these patterns in the environment, a variety of biological processes oscillate with a daily rhythm approximately 24 h in length. These rhythms arise from hierarchally-coupled cellular clocks generated by positive and negative transcription factors of core circadian clock gene expression. From these endogenous cellular clocks, overt rhythms in activity and patterns in hormone secretion and other homeostatic processes emerge. These circadian rhythms in physiology and behavior can be organized by a variety of cues, but they are most potently entrained by light. In recent history, there has been a major change from naturally occurring light cycles set by the sun, to artificial and sometimes erratic light cycles determined by the use of electric lighting. Virtually every individual living in an industrialized country experiences light at night (LAN), but despite its prevalence, the biological effects of such unnatural lighting have not been fully considered. Using female Siberian hamsters (Phodopus sungorus), we investigated the effects of chronic nightly exposure to dim light on daily rhythms in locomotor activity, serum cortisol concentrations, and brain expression of circadian clock proteins (i.e., PER1, PER2, BMAL1). Although locomotor activity remained entrained to the light cycle, the diurnal fluctuation of cortisol concentrations was blunted and the expression patterns of clock proteins in the SCN and hippocampus were altered. These results demonstrate that chronic exposure to dim LAN can dramatically affect fundamental cellular function and emergent physiology. © 2013 British Society for Neuroendocrinology. 22424088 Comparative chemical composition and in vitro antioxidant activities of essential oil isolated from the leaves of Cinnamomum tamala and Pimenta dioica. Cinnamomum tamala Nees and Eberm (tejpat) and Pimenta dioica (L.) Merr (pimento) leaves are commonly used for flavouring food and widely used in pharmaceutical preparations because of their hypoglycemic, carminative and stimulant properties. In this study, we compared the chemical composition and antioxidant activities of tejpat and pimento essential oils by employing various in vitro methods. GC and GC-MS analyses were done to find out the chemical composition, and the main constituent identified in tejpat and pimento leaf oils was eugenol. Both the oils showed significant radical scavenging activity against DPPH and superoxide radicals with a potent metal chelating activity and were compared with that of standard compound, eugenol. Among the two oils, tejpat oil showed better activity in terms of antioxidative potential. 23360361 Vesicles composed of fatty acid and N-[3-(dimethylamino)propyl]-octadecanamide: effect of fatty acid chain length on physicochemical properties of vesicles. Abstract Background and objectives: Vesicles, recently claimed as drug delivery carriers, were prepared by taking advantage of an electrostatic interaction between the carboxylic groups of fatty acids (FAs) and the amino groups of N-[3-(Dimethylamino)propyl]-Octadecanamide (DMAPODA). The study is to find out the effect of FAs' chain length on physicochemical properties of vesicles. Methods: Decanoic acid (DA), myristic acid (MA), stearic acid (SA) and behenic acid (BA) were used as FAs. Vesicles composed of them and DMAPODA were studied about formation on microscope, calorimetric analysis, size and zeta potential. Results: On microphotographs, all of FAs could form vesicles when mixed with DMAPODA in an equi-molar ratio. However, DA/DMAPODA vesicles were disintegrated during the homogenization. Due to the asymmetry of DA/DMAPODA associate, it seems to hardly form a stable and well-packed bilayer. On thermograms, the vesicles exhibited one strong peak, indicating that FAs can be homogeneously mixed with the cationic amphiphile. The sizes of the four kinds of vesicles suspended in an aqueous solution (final pH 7.5) were in the same order (hundreds of nanometer) on microphotographs. But, on a light scattering machine, the mean size of MA/DMAPODA vesicle was measured to be much greater than those of the other vesicles, possibly because of the low absolute value of the zeta potential. In addition, the medium pH value had a significant effect on the size of BA/DMAPODA vesicle possibly because the zeta potential was strongly dependent on the pH value. Conclusion: FAs' chain length would affect the physicochemical properties of vesicles composed of them and DMAPODA. 23616376 Flexible Low-Voltage Organic Transistors with High Thermal Stability at 250 °C. Low-operating-voltage flexible organic thin-film transistors with high thermal stability using DPh-DNTT and SAM gate dielectrics are reported. The mobility of the transistors are decreased by 23% after heating to 250 °C for 30 min. Furthermore, flexible organic pseudo-CMOS inverter circuits, which are functional after heating to 200 °C. 23458575 Targeting mitochondria for cardiac protection. The critical role of mitochondria in cardiomyocyte survival and death has become an exciting field of research in cardiac biology. Indeed, it is accepted that mitochondrial dysfunction plays a crucial role in the pathogenesis of multiple cardiac diseases. Besides the obvious relevance of mitochondria in energy production, calcium homeostasis, and reactive oxygen species (ROS) production, new processes like mitochondrial fusion/fission, phosphorylation and nitrosylation modifications in mitochondrial proteins have been suggested to form part of a cast of key players in cardiac disease. This review describes currently studied drugs and compounds that target mitochondria in the scenario of cardiovascular diseases. 23092136 A metabolomic study reveals novel plasma lyso-Gb3 analogs as Fabry disease biomarkers. Fabry disease is an X-linked, multisystemic lysosomal storage disorder due to alpha-galactosidase A deficiency. It is characterized by the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb(3)), in biological fluids, vascular endothelium, heart, and kidneys. Treatment by enzyme replacement therapy has been shown to be beneficial in both males and females affected with the disease. In addition to Gb(3), increased concentrations of globotriaosylsphingosine (lyso-Gb(3)) have recently been reported in urine and plasma of Fabry patients. The overall objective of this metabolomic study was to identify and characterize new potential plasma biomarkers in treated and untreated males and females affected with Fabry disease which might better reflect disease severity and progression. We employed a time-of-flight mass spectrometry metabolomic approach using plasma samples of Fabry patients compared to age-matched controls. We found three new lyso-Gb(3) analogs in Fabry patients presenting m/z ratios at 802, 804, and 820. As previously detected by our group, we also found a m/z ratio of 784 corresponding to the lyso-Gb(3) molecule minus two hydrogen atoms. Using exact mass measurements and tandem mass spectrometry, we confirmed that these analogs result from modifications of the lyso-Gb(3) sphingosine moiety. We evaluated the relative plasma concentration by measuring area counts for each lyso-Gb(3) analog. None of these analogs was detected in the majority of healthy controls. The relative concentration of each analog was higher in males compared to female Fabry patients. We demonstrated that mass spectrometry combined to a metabolomic approach is a powerful tool to detect and identify new potential biomarkers. 23099645 Association of NDRG1 Gene Promoter Methylation with Reduced NDRG1 Expression in Gastric Cancer Cells and Tissue Specimens. NDRG1 (N-myc downstream-regulated gene 1) plays a role in cell differentiation and suppression of tumor metastasis. This study aims to determine the expression of NDRG1 mRNA and protein in gastric cancer cell lines and tissue specimens and then assess the possible cause of its aberrant expression. Six gastric cancer cell lines and 20 pairs of normal and gastric cancer tissue samples were used to assess NDRG1 expression using Real-time PCR and Western blot. High-resolution melting analysis (HRM) and methylation-specific PCR (MSP) were performed to detect gene mutation and methylation, respectively, in cell lines and tissues samples. Expression of NDRG1 mRNA and protein was downregulated in gastric cancer cell lines and tissues. Specifically, expression of NDRG1 mRNA and protein was lower in all six gastric cancer cell lines than that of normal gastric cells, while 15 out of 20 cases of gastric cancer tissues had the reduced levels of NDRG1 mRNA and protein. HRM data showed that there was no mutation in NDRG1 gene, but MSP data showed high levels of NDRG1 gene promoter methylation in the CpG islands in both cell lines and tissue samples. Moreover, treatment with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine upregulated NDRG1 expression in gastric cancer HGC27 cells, but not in the histone deacetylase inhibitor trichostatin A-treated HGC27 cells. In conclusion, this study has shown that expression of NDRG1 mRNA and protein was reduced in gastric cancer cell lines and tissues, which is due to methylation of NDRG1 gene promoter. Further study will unearth the clinical significance of the reduced NDRG1 protein in gastric cancer. 23418006 Versatile Nanostructured Materials via Direct Reaction of Functionalized Catechols. A facile one-step polymerization strategy is explored to achieve novel catechol-based materials. Depending on the functionality of the catechol, the as-prepared product can be used to modify at will the surface tension of nano and bulk structures, from oleo-/hydrophobic to highly hydrophilic. A hydrophobic catechol prepared thus polymerized shows the ability to self-assemble as solid nanoparticles with sticky properties in polar solvent media. Such a versatile concept is ideal for the development of catechol-based multifunctional materials. 23484974 Preferential adsorption and activity of monocomponent cellulases on lignocellulose thin films with varying lignin content. Understanding the enzymatic hydrolysis of cellulose and the influence of lignin in the process are critical for viable production of fuels and chemicals from lignocellulosic biomass. The interactions of monocomponent cellulases with cellulose and lignin substrates were investigated by using thin films supported on quartz crystal microgravimetry (QCM) resonators. Trichoderma reesei exoglucanase (CBH-I) and endoglucanase (EG-I) bound strongly to both cellulose and lignin but EG-I exhibited a distinctive higher affinity with lignin, causing a more extensive inhibition of the cellulolytic reactions. CBH-I was found to penetrate into the bulk of the cellulose substrate increasing the extent of hydrolysis and film deconstruction. In the absence of a cellulose binding domain (CBD) and a linker, the CBH-I core adsorbed slowly and was not able to penetrate into the film. Conversely to CBH-I, EG-I exhibited activity only on the surface of the lignocellulose substrate even when containing a CBD and a linker. Interestingly, EG-I displayed a clearly different interaction profile as a function of contact time registered by QCM. 23375049 Activity cliffs: facts or artifacts? The fact that similar compounds may have very different properties has a large impact in several areas of chemistry. In drug discovery, almost every medicinal chemist working on lead optimization has faced unexpected large 'jumps' in activity due to small changes in structure, that is, activity cliffs. A number of computational approaches have been developed to detect and quantify activity cliffs and help to understand, and eventually predict, structure-activity relationships (SAR) in compound data sets. Although activity cliffs do exist, the identification and quantification of cliffs have to proceed with caution because one may identify 'false positive cliffs'. In addition to apparent cliffs due to inaccurate determinations of activity, computationally identified cliffs can be artifacts attributed to the molecular representation and quantitative definition of 'high' structural similarity. This paper brings together and discusses, in a brief and integrated manner, some of the major aspects that raise the question whether all the activity cliffs detected in compound data sets are facts or artifacts. 22830982 Evaluation of seven drug metabolisms and clearances by cryopreserved human primary hepatocytes cultivated in microfluidic biochips. We present characterization of the metabolic performance of human cryopreserved hepatocytes cultivated in a platform of parallelized microfluidic biochips. The RTqPCR analysis revealed that the mRNA levels of the cytochromes P450 (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4) were reduced after the adhesion period (when compared to the post-thawing step). The microfluidic perfusion played a part in stabilizing and partially recovering the levels of the HNF4α, PXR, OAPT2, CYP 1A2, 2B6, 2C19 and 3A4 mRNA on contrary to non-perfused cultures. Fluorescein diacetate staining and P-gp mRNA level illustrated the hepatocytes' polarity in the biochips. Drug metabolism was assessed using midazolam, tolbutamide, caffeine, omeprazole, dextromethorphan, acetaminophen and repaglinide as probes. Metabolite detection and quantification revealed that CYP1A2 (via the detection of paraxanthine), CYP3A4 (via 1-OH-midazolam, and omeprazole sulfone detection), CYP2C8 (via hydroxyl-repaglinide detection), CYP2C19 (via hydroxy-omeprazole detection) and CYP2D6 (via dextrorphan detection) were functional in our microfluidic configurations. Furthermore, the RTqPCR analysis showed that the drugs acted as inductors leading to overexpression of mRNA levels when compared to post-thawing values (such as for HNF4α, PXR and CYP3A4 by dextromethorpahn and omeprazole). Finally, intrinsic in vitro biochip clearances were extracted using a PBPK model for predictions. The biochip predictions were compared to literature in vitro data and in vivo situations. 23337397 Inhibition of leukemic U937 cell growth by induction of apoptosis, cell cycle arrest and suppression of VEGF, MMP-2 and MMP-9 activities by cytotoxin protein NN-32 purified from Indian spectacled cobra (Naja naja) venom. A cytotoxin NN-32 (6.7 kDa) from Indian cobra (Naja naja) venom inhibited human leukemic U937 cell growth as observed by Trypan blue dye exclusion method and cytotoxicity was confirmed by MTT assay. NN-32 induced apoptosis of U937 cell and cell cycle arrest of sub-G1 phase were revealed by FACS analysis. Increased Bax/Bcl-2 ratio, increased caspase 3 and 9 activities, cleaved PARP, decreased VEGF, MMP-2 and MMP-9 activities were observed after NN-32 treatment of U937 cell. Antileukemic activity of NN-32 on U937 cell may be due to activation of apoptosis, arresting cell cycle and antiangiogenesis activities. 23042953 Hydrophobic amino acids in the hinge region of the 5A apolipoprotein mimetic peptide are essential for promoting cholesterol efflux by the ABCA1 transporter. The bihelical apolipoprotein mimetic peptide 5A effluxes cholesterol from cells and reduces inflammation and atherosclerosis in animal models. We investigated how hydrophobic residues in the hinge region between the two helices are important in the structure and function of this peptide. By simulated annealing analysis and molecular dynamics modeling, two hydrophobic amino acids, F-18 and W-21, in the hinge region were predicted to be relatively surface-exposed and to interact with the aqueous solvent. Using a series of 5A peptide analogs in which F-18 or W-21 was changed to either F, W, A, or E, only peptides with hydrophobic amino acids in these two positions were able to readily bind and solubilize phospholipid vesicles. Compared with active peptides containing F or W, peptides containing E in either of these two positions were more than 10-fold less effective in effluxing cholesterol by the ABCA1 transporter. Intravenous injection of 5A in C57BL/6 mice increased plasma-free cholesterol (5A: 89.9 ± 13.6 mg/dl; control: 38.7 ± 4.3 mg/dl (mean ± S.D.); P < 0.05) and triglycerides (5A: 887.0 ± 172.0 mg/dl; control: 108.9 ± 9.9 mg/dl; P < 0.05), whereas the EE peptide containing E in both positions had no effect. Finally, 5A increased cholesterol efflux approximately 2.5-fold in vivo from radiolabeled macrophages, whereas the EE peptide was inactive. These results provide a rationale for future design of therapeutic apolipoprotein mimetic peptides and provide new insights into the interaction of hydrophobic residues on apolipoproteins with phospholipids in the lipid microdomain created by the ABCA1 transporter during the cholesterol efflux process. 23347547 Quercetin-loaded microcapsules ameliorate experimental colitis in mice by anti-inflammatory and antioxidant mechanisms. Quercetin (1) is an anti-inflammatory and antioxidant flavonoid. However, the oral administration of 1 did not lead to beneficial effects in experimental animal colitis models, which involve cytokines and oxidative stress. A possible explanation is that the absorption profile of 1 prevents its activity. Therefore, it was reasoned that the controlled release of 1 would improve its therapeutic effect. Thus, the therapeutic effect and mechanisms of 1-loaded microcapsules in acetic acid-induced colitis in mice were evaluated. Microcapsules were prepared using pectin/casein polymer and 1. The oral administration of 1-loaded microcapsules decreased neutrophil recruitment, attenuated histological alterations, and reduced macroscopical damage, edema, and IL-1β and IL-33 production in the colon samples. Microcapsules loaded with 1 also prevented the reduction of anti-inflammatory cytokine IL-10 and the antioxidant capacity of the colon. These preclinical data indicate that pectin/casein polymer microcapsules loaded with 1 improved the anti-inflammatory and antioxidant effects of 1 compared to the nonencapsulated drug. Therefore, quercetin seems to be a promising active molecule in inflammatory bowel disease if provided with adequate controlled release. 23458730 Concentration-dependent inhibitory effects of baicalin on the metabolism of dextromethorphan, a dual probe of CYP2D and CYP3A, in rats. Baicalin has been shown to possess many pharmacological effects, including antiviral, antioxidant, anti-cancer and anti-inflammatory properties. In the current study, we reveal the inhibitory effects of baicalin on the metabolism of dextromethorphan (DXM), a dual probe substrate of CYP2D and CYP3A, in rats. Lineweaver-Burk plots demonstrated that baicalin inhibited the activities of CYP2D and CYP3A in a non-competitive manner in rat liver microsomes (RLMs). Concomitant administration of baicalin (0.90g/kg, i.v.) and DXM (10mg/kg, i.v.) increased the maximum drug concentration (Cmax) (37%) and the area under concentration-time curve (AUC) (42%) and decreased the clearance (CL) (27%) of DXM in a randomised, crossover study in rats (P<0.01). The change in the AUC of DXM was significantly correlated with the Cmax and AUC of baicalin (P<0.05). The inhibitory effects of multiple doses of baicalin (0.90g/kg, i.v., 12days) on the metabolism of DXM were similar to those observed following a single dose in rats. The activity of CYP3A in excised liver samples from rats following multiple baicalin treatment was significantly decreased compared to that of the control group (P<0.05), whereas multiple doses of baicalin had no obvious effect on the activity of CYP2D. Taken together, these data demonstrate that baicalin inhibits the metabolism of DXM in a concentration-dependent manner in rats, possibly through inhibiting hepatic CYP2D and CYP3A activities. 23411272 Oligomeric procyanidins of lotus seedpod inhibits the formation of advanced glycation end-products by scavenging reactive carbonyls. It has been reported that oligomeric procyanidins of lotus seedpod (LSOPC) is effective in the alleviation of Alzheimer's disease and diabetes through its antioxidant and insulin-potentiating activities. This study investigated the anti-glycative activity of LSOPC in a bovine serum albumin (BSA)-glucose model. The level of glycation and conformational alterations were assessed by specific fluorescence, Congo red binding assay and circular dichroism. The results show that LSOPC has a significant anti-glycative activity in vitro and it can also effectively protect the secondary structure of BSA during glycation. LSOPC or catechin (a major constituent unit of LSOPC), were used to react with methylglyoxal. The structures of their carbonyl adducts were tentatively identified using HPLC-MS(2). Their capacity to scavenge methylglyoxal suggested carbonyl scavenging as a major mechanism of antiglycation. Therefore, LSOPC could be helpful to prevent AGEs-associated diseases, and with the potential to be used as functional food ingredients. 23413803 Tumor necrosis factor receptor-associated factor 5 is an essential mediator of ischemic brain infarction. Tumor necrosis factor receptor-associated factor 5 (TRAF5) is an adaptor protein of the tumor necrosis factor (TNF) receptor superfamily and the interleukin-1 receptor/Toll-like receptor superfamily and plays important roles in regulating multiple signaling pathways. This study was conducted to investigate the role of TRAF5 in the context of brain ischemia/reperfusion (I/R) injury. Transient occlusion of the middle cerebral artery was performed on TRAF5 knockout mice (KO), neuron-specific TRAF5 transgene (TG), and the appropriate controls. Compared with the WT mice, the TRAF5 KO mice showed lower infarct volumes and better outcomes in the neurological tests. A low neuronal apoptosis level, an attenuated blood-brain barrier (BBB) disruption and an inhibited inflammatory response were exhibited in TRAF5 KO mice. TRAF5 TG mice exhibited an opposite phenotype. Moreover, the Akt/FoxO1 signaling pathway was enhanced in the ischemic brains of the TRAF5 KO mice. These results provide the first demonstration that TRAF5 is a critical mediator of I/R injury in an experimental stroke model. The Akt /FoxO1 signaling pathway probably plays an important role in the biological function of TRAF5 in this model. 23261667 Long-term incubation of adult Nereis virens (Annelida: Polychaeta) in copper-spiked sediment: the effects on adult mortality, gametogenesis, spawning and embryo development. Late gametogenic Nereis virens were incubated for up to 2.5 months in environmentally relevant concentrations of copper-spiked sediment. Sequential extraction confirmed that much more labile copper (in actual and percentage terms) was present as spiked concentrations increased, although the residual fractions contained similar amounts across concentrations. This is also reflected in the tissue concentration of the worms which increased in line with the sediment concentrations. Adult mortality was not dependent on the exposure time, but higher concentrations usually induced greater mortality for both sexes. Oocytes were significantly smaller at higher concentrations although pairwise comparisons did not show specific differences. Spawning of males occurred a number of days earlier in the higher concentrations. Differences in the number of embryos developing normally after in vitro fertilizations of oocytes fertilized with sperm from exposed males and non-exposed males showed that sperm were more susceptible to toxicity, but oocytes were also affected at the highest concentration. These results show that there are direct and indirect reproductive consequences of parental exposure to copper with implications for recruitment and subsequent colonization of polluted sediments for this ecologically and commercially important species. 23585383 Surface Matters: Enhanced Bactericidal Property of Core-Shell Ag-Fe2 O3 Nanostructures to Their Heteromer Counterparts from One-Pot Synthesis. A facile one-pot synthesis of Ag@Fe2 O3 core-shell and Ag-Fe2 O3 heteromer nanoparticles is developed, and the core-shell nanoparticles have shown superior antibacterial properties compared to their heteromer counterparts and plain Ag nanoparticles. The mechanism for the increased efficiency is proposed to be due to the enhanced Ag ion release from the iron oxide shell-protected pristine Ag surface. 23277230 Fisetin averts oxidative stress in pancreatic tissues of streptozotocin-induced diabetic rats. Persistent hyperglycemia is associated with chronic oxidative stress which contributes to the development and progression of diabetes-associated complications. The sensitivity of pancreatic β-cells to oxidative stress has been attributed to their low content of antioxidants compared with other tissues. Bioactive compounds with potent antidiabetic properties have been shown to ameliorate hyperglycemia mediated oxidative stress. Recently, we have reported that oral administration of fisetin (10 mg/Kg b.w.), a bioflavonoid found to be present in strawberries, persimmon, to STZ-induced experimental diabetic rats significantly improved normoglycemia. The present study was aimed to evaluate the antioxidant potential of fisetin in both in vitro and in vivo. Diabetes was induced by single intraperitoneal injection of streptozotocin (50 mg/kg body weight). Fisetin was administered orally for 30 days. At the end of the study, all animals were killed. Blood samples were collected for the biochemical estimations. The antioxidant status was evaluated. Histological examinations were performed on pancreatic tissues. Fisetin treatment showed a significant decline in the levels of blood glucose, glycosylated hemoglobin (HbA1c), NF-kB p65 unit (in pancreas) and IL-1β (plasma), serum nitric oxide (NO) with an elevation in plasma insulin. The treatment also improved the antioxidant status in pancreas as well as plasma of diabetic rats indicating the antioxidant potential of fisetin. In addition, the results of DPPH and ABTS assays substantiate the free radical scavenging activity of fisetin. Histological studies of the pancreas also evidenced the tissue protective nature of fisetin. It is concluded that, fisetin possesses antioxidant and anti-inflammatory property and may be considered as an adjunct for the treatment of diabetes. 23588562 The prevalence and incidence of medicinal cannabis on prescription in The Netherlands. BACKGROUND: A growing number of countries are providing pharmaceutical grade cannabis to chronically ill patients. However, little published data is known about the extent of medicinal cannabis use and the characteristics of patients using cannabis on doctor's prescription. This study describes a retrospective database study of The Netherlands. METHODS: Complete dispensing histories were obtained of all patients with at least one medicinal cannabis prescription gathered at pharmacies in The Netherlands in the period 2003-2010. Data revealed prevalence and incidence of use of prescription cannabis as well as characteristics of patients using different cannabis varieties. RESULTS: Five thousand five hundred forty patients were identified. After an initial incidence of about 6/100,000 inhabitants/year in 2003 and 2004, the incidence remained stable at 3/100,000/year in 2005-2010. The prevalence rate ranged from 5 to 8 per 100,000 inhabitants. Virtually all patients used some form of prescription medication in the 6 months preceding start of cannabis use, most particularly psycholeptics (45.5 %), analgesics (44.3 %), anti-ulcer agents (35.9 %) and NSAIDs (30.7 %). We found no significant association between use of medication of common indications for cannabis (pain, HIV/AIDS, cancer, nausea, glaucoma) and variety of cannabis used. CONCLUSIONS: This is the first nationwide study into the extent of prescription of medicinal cannabis. Although the cannabis varieties studied are believed to possess different therapeutic effects based on their different content of tetrahydrocannabinol (THC) and cannabidiol (CBD), no differences in choice of variety was found associated with indication. 23463634 All-graphene core-sheath microfibers for all-solid-state, stretchable fibriform supercapacitors and wearable electronic textiles. Unique all-graphene core-sheath fibers composed of a graphene fiber core with a sheath of 3D graphene network have been developed. Used as flexible electrodes, all-solid-state fiber supercapacitors have been fabricated, which can be managed to highly compressible and stretchable spring supercapacitors and can also be woven into a textile for wearable electronics. 23418880 A new antibacterial denitroaristolochic acid from the tubers of Stephania succifera. A new denitroaristolochic acid, demethylaristofolin C (1), together with six known alkaloids, crebanine N-oxide (2), (-)-sukhodianine-β-N-oxide (3), palmatine (4), corydalmine (5), dehydrocorydalmine (6), and corynoxidine (7), was isolated from the tubers of Stephania succifera. The structure of demethylaristofolin C was elucidated by spectroscopic techniques (UV, IR, 1D, and 2D NMR) and HR-ESI-MS analyses. These compounds exhibited antibacterial activities against Staphylococcus aureus and methicillin-resistant S. aureus strains in different degrees. 23460508 Association of polymorphisms in the leptin and leptin receptor genes with inflammatory mediators in patients with osteoporosis. Bone mass and inflammation are implicated in the pathogenesis of osteoporosis. We hypothesized that leptin and leptin receptor gene might be associated with osteoporosis by activating the inflammatory pathway. Therefore, we analyzed polymorphisms of the leptin (gene symbol, LEP) and leptin receptor (gene symbol, LEPR) genes and determined their associations with proinflammatory cytokine levels in patients with osteoporosis. We assessed polymorphisms in LEP (-2548G > A) and LEPR (Lys109Arg, Gln223Arg, and Lys656Asn) and calculated odds ratios for the genotype and allele distributions between patients and controls. Serum leptin, soluble leptin receptor, interleukin (IL)-1, IL-6, IL-7, and tumor necrosis factor (TNF) levels were measured by enzyme-linked immunosorbent assays (ELISA) and were verified by in vitro lymphocyte proliferation assays and ELISAs. We found a higher frequency of the A allele for LEP at -2548 in patients with osteoporosis compared with the control group. The A allele was associated with differences in serum leptin, soluble leptin receptor, IL-1, IL-6, and TNF levels compared with the wild-type G allele (p < 0.05). The G allele in Lys109Arg and Gln223Arg was associated with increased risk of osteoporosis and with differences in serum leptin, soluble leptin receptor, IL-1, IL-6, and TNF levels compared with the wild-type A allele (p < 0.05). The Lys656Asn genotype was not associated with the risk of osteoporosis. In vitro lymphocyte proliferation assays and ELISAs confirmed these results. Polymorphisms in LEP and LEPR are associated with increased risk of osteoporosis, possibly by increasing the expression of proinflammatory cytokines. 23559276 Kinetics of Apoptosis and Expression of Apoptosis-Related Proteins in Rat CA3 Hippocampus Cells After Experimental Diffuse Brain Injury. The present study examined kinetics of apoptosis and expression of apoptosis-related proteins Bcl-2, Bax, and caspase-3 in the CA3 hippocampus cells after diffuse brain injury (DBI) induced experimentally in rats. Percentage of apoptotic cells and expressions of above proteins were examined by flow cytometry and immunohistochemistry. Substantial neuronal apoptosis was documented in the CA3 hippocampus cells after DBI (22.26 ± 2.97 % at 72 h after DBI vs. 2.92 ± 0.88 % in sham-operated animals). Expression of Bc1-2 decreased, while expression of Bax and caspase-3 increased after DBI, with caspase-3 expression peaking after that of Bax (72 vs. 48 h, respectively). Further, the Bc1-2/Bax expression ratio decreased prior to increase of caspase-3 expression. In conclusion, cell apoptosis and altered expressions of Bcl-2, Bax, and caspase-3 are present in the CA3 region of hippocampus after experimental DBI. Changes in the Bc1-2/Bax expression ratio may facilitate activation of caspase-3 and aggravate neuronal apoptosis after brain injury. 23600914 24(S)-hydroxycholesterol is actively eliminated from neuronal cells by ABCA1. High cholesterol turnover catalyzed by cholesterol 24-hydroxylase is essential for neural functions, especially learning. Because 24(S)-hydroxycholesterol (24-OHC), produced by 24-hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH-SY5Y neuron-like cells as a model, we examined whether 24-OHC is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and ABCG1 was induced by 24-OHC, as well as TO901317 and retinoic acid, which are ligands of the nuclear receptors LXR/RXR. When the expression of ABCA1 and ABCG1 was induced, 24-OHC efflux was stimulated in the presence of high density lipoprotein (HDL), whereas apolipoprotein A-I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against ABCA1, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed HEK293 cells stably expressing human ABCA1 or ABCG1; we clearly observed 24-OHC efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A-I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of 24-OHC. These results suggest that ABCA1 actively eliminates 24-OHC in the presence of HDL as a lipid acceptor and protects neuronal cells. This article is protected by copyright. All rights reserved. 23523991 Effect of naloxone on ischemic acute kidney injury in the mouse. Renal ischemia produces sympathoexcitation, which is responsible for the development of ischemic acute kidney injury. Stimulation of central opioid receptors activates the renal sympathetic nerve. The present study examined the effect of an opioid receptor antagonist naloxone on the ischemia/reperfusion-induced renal dysfunction in mice. Blood urea nitrogen (BUN) and plasma creatinine increased 24 h after the renal ischemia/reperfusion. Intraperitoneal or intracerebroventricular, but not intrathecal, pretreatment with naloxone suppressed the renal ischemia/reperfusion-induced increases in BUN and plasma creatinine. This effect of naloxone was reversed by subcutaneous pretreatment with morphine. Selective MOP receptor antagonist β-funaltrexamine (FNA) also suppressed the renal ischemia/reperfusion-induced increases in BUN and plasma creatinine. Moreover, tyrosine hydroxylase expression in the renal tissue increased 24 h after renal ischemia/reperfusion, which was abolished by intraperitoneal or intracerebroventricular pretreatment with naloxone and FNA. Immunohistochemical experiments revealed a significant increase in the number of the Fos family proteins (c-Fos, FosB, Fra-1, and Fra-2) positive cells in the paraventricular nucleus of hypothalamus and supraoptic nucleus 24 h after the renal ischemia/reperfusion. Intracerebroventricular pretreatment with naloxone attenuated the renal ischemia/reperfusion-induced increase in the number of the Fos family proteins positive cells in these areas. Finally, we observed that i.c.v. pretreatment with antiserum against β-endorphin also suppressed the increased blood urea and plasma creatinine. These results suggest that the blockade of central opioid receptors can attenuate the ischemic acute kidney injury through the inhibition of renal sympathoexcitation. The central opioid receptors may thus be a new target for the treatment of ischemic organ failures. 23546003 Synthesis of 2,3-Bis(halomethyl)quinoxaline Derivatives and Evaluation of Their Antibacterial and Antifungal Activities. Quinoxaline derivatives having bis(fluoromethyl), bis(chloromethyl), or bis(iodomethyl) groups at the 2- and 3-positions, and various electron-donating/withdrawing substituents at the 6- and/or 7-positions, were synthesized. Their antibacterial and antifungal activities were evaluated by means of minimum inhibitory concentration assays. The relationships between the substituents and the antimicrobial activities of the quinoxaline derivatives indicate that the electrophilicity of the halomethyl units plays an important role in generating the antimicrobial activity. 23174457 Mn(2+) modulates the kinetic properties of an archaeal member of the PLL family. Recently we reported on the characterization of an archaeal member of the amidohydrolase superfamily, namely Sulfolobus acidocaldarius lactonase, showing low but significant and extremely thermostable paraoxonase activity. This enzyme, that we have named SacPox, is a member of the new described family of phosphotriesterase-like lactonases (PLLs). In this family the binuclear metal centre, which is involved in the catalytic machinery, has been poorly studied up to now. In this work we describe the expression of the protein in presence of different metals showing Mn(2+) to support the higher activity. The enzyme has been over-expressed, purified and characterized as a Mn(2+)-containing enzyme by inductive plasma coupled mass spectrometry (ICP-MS), showing also surprising kinetic differences in comparison with the cadmium-containing enzyme. The Mn(2+) containing enzyme was about 30-fold more efficient with paraoxon as substrate and more stable than the Cd(2+) counterpart, even though the Mn(2+) affinity for the binuclear metal centre is apparently lower. These results increase our knowledge of the biochemical characteristics of SacPox mainly with regard to the metal-ions modulation of function. 23327534 Characterisation of the essential oil from different aerial parts of Lindera chunii Merr. (Lauraceae). The essential oils from three organs (i.e. flowers, leaves and stems) of wild Lindera chunii Merr. in Dinghu Mountain (China) were obtained by microwave-assisted hydrodistillation. The essential oils were analysed by gas chromatography with flame ionisation detection and gas chromatography with mass spectrometry. The yields of essential oil varied from 0.06% to 0.59% and showed a remarkable variation among the plant organs. A total of 43 compounds accounting for 95.4-96.3% of the total essential oil were identified, and the major compounds were germacrene B (0.7-43.2%), viridiflorene (trace to 14.6%), globulol (6.3-11.6%), α-cadinol (1.7-8.6%) and τ-cadinol (0.5-7.3%). This study shows that the chemical compositions of the essential oils from the different organs of L. chunii are very variable. 22780563 Hydrothermally mixed hydroxyapatite-multiwall carbon nanotubes composite coatings on biomedical alloys by electrophoretic deposition. Hydroxyapatite (HA) coatings have been used to improve biological and mechanical fixation of metallic prosthesis. Because of extraordinary features of carbon nanotubes (CNTs), they have a lot of facilities, such as extremely strong nanoreinforcement materials for composites. HA powders were synthesized and mixed with multiwalled carbon nanotubes (MWCNTs) by a hydrothermal process. Calcium acetate (Ca (CH(3)COO)(2)) and phosphoric acid (H(3)PO(4)) were used as starting materials for synthesizing nano-HA powders. HA-MWCNTs were treated together hydrothermally at 200 °C for 2 h to synthesize nano-HA powders mixed homogeneously with MWCNTs. Cathodic deposits were obtained on Ti-based alloys using suspensions containing nano-HA and MWCNTs dispersed in n-butanol solvent. It was shown that MWCNTs interacted with HA powders during hydrothermal processing, and therefore, they can easily be dispersed within aqueous-based suspensions. It was also shown that hydrothermal surface modification of MWCNTs with functional groups was achievable, which was a significant step toward eliminating nonwetting surface behavior of MWCNTs, resulting in obtaining homogeneous dispersion of them in liquids. 23228696 Metformin-mediated downregulation of p38 mitogen-activated protein kinase-dependent excision repair cross-complementing 1 decreases DNA repair capacity and sensitizes human lung cancer cells to paclitaxel. Metformin, an extensively used and well-tolerated drug for treating individuals with type 2 diabetes, has recently gained significant attention as an anticancer drug. On the other hand, paclitaxel (Taxol) is a new antineoplastic drug that has shown promise in the treatment of non-small cell lung cancer (NSCLC). High expression levels of excision repair cross-complementary 1 (ERCC1) in cancers have been positively associated with the DNA repair capacity and a poor prognosis in NSCLC patients treated with platinum-containing chemotherapy. In this current study, paclitaxel was found to increase phosphorylation of mitogen-activated protein kinase (MAPK) kinase 3/6 (MKK3/6)-p38 MAPK as well as protein and mRNA levels of ERCC1 in H1650 and H1703 cells. Moreover, paclitaxel-induced ERCC1 protein and mRNA levels significantly decreased via the downregulation of p38 activity by either a p38 MAPK inhibitor SB202190 or p38 knockdown with specific small interfering RNA (siRNA). Specific inhibition of ERCC1 with siRNA was found to enhance the paclitaxel-induced cytotoxic effect and growth inhibition. Furthermore, metformin was able to not only decrease the paclitaxel-induced p38 MAPK-mediated ERCC1 expression, but also augment the cytotoxic effect induced by paclitaxel. Finally, expression of constitutive activate MKK6 or HA-p38 MAPK vectors in lung cancer cells was able to abrogate ERCC1 downregulation by metformin and paclitaxel as well as cell viability and DNA repair capacity. Overall, our results suggest that inhibition of the p38 MAPK signaling by metformin coupled with paclitaxel therapy in human NSCLC cells may be a clinically useful combination, which however will require further validation. 23398145 White light from a single-emitter light-emitting electrochemical cell. We report a novel and generic approach for attaining white light from a single-emitter light-emitting electrochemical cell (LEC). With an active-layer comprising a multifluorophoric conjugated copolymer (MCP) and an electrolyte designed to inhibit MCP energy-transfer interactions during LEC operation, we are able to demonstrate LECs that emit broad-band white light with a color rendering index of 82, a correlated-color temperature of 4000 K, and a current conversion efficacy of 3.8 cd/A. It is notable that this single-emitter LEC configuration eliminates color-drift problems stemming from phase separation, which are commonly observed in conventional blended multiemitter devices. Moreover, the key role of the electrolyte in limiting undesired energy-transfer reactions is highlighted by the observation that an electrolyte-free organic light-emitting diode comprising the same MCP emits red light. 23449618 MAP/microtubule affinity-regulating kinases, microtubule dynamics, and spermatogenesis. During spermatogenesis, spermatids derived from meiosis simultaneously undergo extensive morphological transformation, to become highly specialized and metabolically quiescent cells, and transport across the seminiferous epithelium. Spermatids are also transported back-and-forth across the seminiferous epithelium during the epithelial cycle until they line up at the luminal edge of the tubule to prepare for spermiation at stage VIII of the cycle. Spermatid transport thus requires the intricate coordination of the cytoskeletons in Sertoli cells (SCs) as spermatids are nonmotile cells lacking the ultrastructures of lamellipodia and filopodia, as well as the organized components of the cytoskeletons. In the course of preparing this brief review, we were surprised to see that, except for some earlier eminent morphological studies, little is known about the regulation of the microtubule (MT) cytoskeleton and the coordination of MT with the actin-based cytoskeleton to regulate spermatid transport during the epithelia cycle, illustrating that this is a largely neglected area of research in the field. Herein, we summarize recent findings in the field regarding the significance of actin- and tubulin-based cytoskeletons in SCs that support spermatid transport; we also highlight specific areas of research that deserve attention in future studies. 22661401 Bioremoval of heavy metals from industrial effluent by fixed-bed column of red macroalgae. Three different species of nonliving red algal biomass Laurancia obtusa, Geldiella acerosa and Hypnea sp. were used to build three types of fixed-bed column for the removal of toxic heavy metal ions such as Cu(2+), Zn(2+), Mn(2+) and Ni(2+) from industrial effluent. In general, the highest efficiency of metal ion bioremoval was recorded for algal column of L. obtusa followed by G. acerosa and the lowest one was recorded for Hypnea sp., with mean removal values of 94%, 85% and 71%, respectively. The obtained results showed that biological treatments of industrial effluents with these algal columns, using standard algal biotest, Pseudokirchneriella subcapitata, were capable of reducing effluent toxicities from 75% to 15%, respectively. Red algal column may be considered as an inexpensive and efficient alternative treatment for conventional removal technology, for sequestering heavy metal ions from industrial effluents. 23147750 Assessing causation of the extirpation of stream macroinvertebrates by a mixture of ions. Increased ionic concentrations are associated with the impairment of benthic invertebrate assemblages. However, the causal nature of that relationship must be demonstrated so that it can be used to derive a benchmark for conductivity. The available evidence is organized in terms of six characteristics of causation: co-occurrence, preceding causation, interaction, alteration, sufficiency, and time order. The inferential approach is to weight the lines of evidence using a consistent scoring system, weigh the evidence for each causal characteristic, and then assess the body of evidence. Through this assessment, the authors found that a mixture containing the ions Ca(+), Mg(+), HCO 3(-), and SO 4(-), as measured by conductivity, is a common cause of extirpation of aquatic macroinvertebrates in Appalachia where surface coal mining is prevalent. The mixture of ions is implicated as the cause rather than any individual constituent of the mixture. The authors also expect that ionic concentrations sufficient to cause extirpations would occur with a similar salt mixture containing predominately HCO 3(-), SO 4(2-), Ca(2+), and Mg(2+) in other regions with naturally low conductivity. This case demonstrates the utility of the method for determining whether relationships identified in the field are causal. 23160961 Plasma ghrelin is positively associated with body fat, liver fat and milk fat content but not with feed intake of dairy cows after parturition. Ghrelin is a gastrointestinal peptide hormone that is present in blood mostly in a non-posttranslationally modified form, with a minor proportion acylated at Ser(3). Both ghrelin forms were initially assigned a role in the control of food intake but there is accumulating evidence for their involvement in fat allocation and utilization. We investigated changes in the ghrelin system in dairy cows, exhibiting differences in body fat mobilization and fatty liver, from late pregnancy to early lactation. Sixteen dairy cows underwent liver biopsy and were retrospectively grouped based on high (H) or low (L) liver fat content post-partum. Both groups had a comparable feed intake in week -6 (before parturition) and week 2 (after parturition). Only before parturition was preprandial total ghrelin concentration higher in L than in H cows and only after parturition was the basal plasma concentration of non-esterified fatty acids higher in H than in L cows. Both before and after parturition, H cows had higher preprandial plasma concentrations of acyl ghrelin, a higher acyl:total ghrelin ratio, lower plasma triacylglyceride concentrations and a lower respiratory quotient compared with L cows. These group differences could not be attributed to an allelic variant of the acyl ghrelin receptor. Rather, the ratio of acyl:total ghrelin correlated with several aspects of fat metabolism and with respiratory quotient but not with feed intake. These results show that endogenous ghrelin forms are associated with fat allocation, fatty liver, and utilization of fat during the periparturient period. 23194507 Analysis of Anabaena vaginicola and Nostoc calcicola from Northern Iran, as rich sources of major carotenoids. Four major carotenoids of high nutritional significance, including β-carotene, lycopene, lutein and zeaxanthin were determined in three isolates of heterocystous cyanobacteria, belonging to the genera Anabaena and Nostoc, isolated from Iranian terrestrial and aquatic ecosystems, for the first time. The ultrasonically extracted carotenoids were identified and quantified by a rapid and sensitive isocratic HPLC method and identification was further confirmed by spiking authentic standards and the pattern of the UV-Vis spectra obtained from photo-diode array detector. The results showed that these isolates contain large amounts of four major carotenoids, especially lycopene (up to 24,570 μg/g dry weight, DW) which appears to be the highest reported amount until present; and β-carotene (up to 8133 μg/g DW) which is comparable with the best natural sources of β-carotene. Meanwhile, they are rich in the cis-isomers of lycopene and β-carotene which is important in their bioavailability and health benefits. 23248196 Statins and Risk of Diabetes: An analysis of electronic medical records to evaluate possible bias due to differential survival. OBJECTIVE Two meta-analyses of randomized trials of statins found increased risk of type 2 diabetes. One possible explanation is bias due to differential survival when patients who are at higher risk of diabetes survive longer under statin treatment. RESEARCH DESIGN AND METHODS We used electronic medical records from 500 general practices in the U.K. and included data from 285,864 men and women aged 50-84 years from January 2000 to December 2010. We emulated the design and analysis of a hypothetical randomized trial of statins, estimated the observational analog of the intention-to-treat effect, and adjusted for differential survival bias using inverse-probability weighting. RESULTS During 1.2 million person-years of follow-up, there were 13,455 cases of type 2 diabetes and 8,932 deaths. Statin initiation was associated with increased risk of type 2 diabetes. The hazard ratio (95% CI) of diabetes was 1.45 (1.39-1.50) before adjusting for potential confounders and 1.14 (1.10-1.19) after adjustment. Adjusting for differential survival did not change the estimates. Initiating atorvastatin and simvastatin was associated with increased risk of type 2 diabetes. CONCLUSIONS In this sample of the general population, statin therapy was associated with 14% increased risk of type 2 diabetes. Differential survival did not explain this increased risk. 23303786 Space exploration by the promoter of a long human gene during one transcription cycle. An RNA polymerase has been thought to transcribe by seeking out a promoter, initiating and then tracking down the template. We add tumor necrosis factor α to primary human cells, switch on transcription of a 221-kb gene and monitor promoter position during the ensuing transcription cycle (using RNA fluorescence in situ hybridization coupled to super-resolution localization, chromosome conformation capture and Monte Carlo simulations). Results are consistent with a polymerase immobilized in a 'factory' capturing a promoter and reeling in the template, as the transcript and promoter are extruded. Initially, the extruded promoter is tethered close to the factory and so likely to re-initiate; later, the tether becomes long enough to allow re-initiation in another factory. We suggest close tethering underlies enhancer function and transcriptional 'bursting'. 23041661 Salt bridge switching from Arg290/Glu167 to Arg290/ATP promotes the closed-to-open transition of the P2X2 receptor. P2X receptors are trimeric adenosine-5'-triphosphate (ATP)-gated cation channels involved in fast signal transduction in many cell types. In this study, we used homology modeling of the rat P2X2 receptor with the zebrafish P2X4 X-ray template to determine that the side chains of the Glu167 and Arg290 residues are in close spatial vicinity within the ATP-binding pocket when the rat P2X2 channel is closed. Through charge reversal mutation analysis and mutant cycle analysis, we obtained evidence that Glu167 and Arg290 form an electrostatic interaction. In addition, disulfide trapping indicated the close proximity of Glu167 and Arg290 when the channel is in the closed state, but not in the ATP-bound open state. Consistent with a gating-induced movement that disrupts the Glu167/Arg290 salt bridge, a comparison of the closed and open rat P2X2 receptor models revealed a significant rearrangement of the protein backbone and the side chains of the Glu167 and Arg290 residues during the closed-to-open transition. The associated release of the Glu167/Arg290 salt bridge during channel opening allows a strong ionic interaction between Arg290 and a γ-phosphate oxygen of ATP. We conclude from these results that the state-dependent salt bridge switching from Arg290/Glu167 to Arg290/ATP fulfills a dual role: to destabilize the closed state of the receptor and to promote the ionic coordination of ATP in the ATP-binding pocket. 23159529 Nanobody-albumin nanoparticles (NANAPs) for the delivery of a multikinase inhibitor 17864 to EGFR overexpressing tumor cells. A novel, EGFR-targeted nanomedicine has been developed in the current study. Glutaraldehyde crosslinked albumin nanoparticles with a size of approximately 100nm were loaded with the multikinase inhibitor 17864-L(x)-a platinum-bound sunitinib analogue-which couples the drug to methionine residues of albumin and is released in a reductive environment. Albumin nanoparticles were surface-coated with bifunctional polyethylene glycol 3500 (PEG) and a nanobody-the single variable domain of an antibody-(Ega1) against the epidermal growth factor receptor (EGFR). EGa1-PEG functionalized nanoparticles showed a 40-fold higher binding to EGFR-positive 14C squamous head and neck cancer cells in comparison to PEGylated nanoparticles. 17864-L(x) loaded EGa1-PEG nanoparticles were internalized by clathrin-mediated endocytosis and ultimately digested in lysosomes. The intracellular routing of EGa1 targeted nanoparticles leads to a successful release of the kinase inhibitor in the cell and inhibition of proliferation whereas the non-targeted formulations had no antiproliferative effects on 14C cells. The drug loaded targeted nanoparticles were as effective as the free drug in vitro. These results demonstrate that multikinase inhibitor loaded nanoparticles are interesting nanomedicines for the treatment of EGFR-positive cancers. 23234313 Influence of surface groups on poly(propylene imine) dendrimers antiprion activity. Prion diseases are characterized by the accumulation of PrP(Sc), an aberrantly folded isoform of the host protein PrP(C). Specific forms of synthetic molecules known as dendrimers are able to eliminate protease-resistant PrP(Sc) in both an intracellular and in vitro setting. The properties of a dendrimer which govern this ability are unknown. We addressed the issue by comparing the in vitro antiprion ability of numerous modified poly(propylene-imine) dendrimers, which varied in size, structure, charge, and surface group composition. Several of the modified dendrimers, including an anionic glycodendrimer, reduced the level of protease resistant PrP(Sc) in a prion strain-dependent manner. This led to the formulation of a new working model for dendrimer/prion interactions which proposes dendrimers eliminate PrP(Sc) by destabilizing the protein and rendering it susceptible to proteolysis. This ability is not dependent on any particular charge of dendrimer, but does require a high density of reactive surface groups. 23127698 Conjunctival modifications induced by medical and surgical therapies in patients with glaucoma. Lowering intra-ocular pressure, either medically or surgically, is the proven strategy to control glaucoma, though profound changes to the ocular surface and conjunctiva are caused. Toxicity and allergy initiated by medical therapy induce modifications, which progressively worsen with the length of treatment and number of drugs. Conjunctival changes lead to symptoms of ocular surface disease, reduced quality of life, reduced therapeutic compliance and increased risk of surgical failure. Surgery modifies conjunctiva by inducing bleb formation in fistulizing techniques, and by activating secondary aqueous humour outflow pathways, such as trans-scleral routes, in both filtration and bleb-less approaches. The use of unpreserved medications, limitation of intra-operative conjunctival damage and development of bleb-less surgery are advisable. 23196320 Laser synthesis of ligand-free bimetallic nanoparticles for plasmonic applications. A picosecond laser ablation approach has been developed for the synthesis of ligand-free AuAg bimetallic NPs where the relative amount of Ag is controlled in situ through a laser shielding effect. Various measurements, such as optical spectroscopy, transmission electron microscopy combined with energy dispersive X-ray spectroscopy and inductively coupled plasma optical emission spectrometry, revealed the generation of homogenous 15 nm average size bimetallic NPs with different compositions and tunable localized surface plasmon resonance. Furthermore, ligand-free metallic nanoparticles with respect to chemically synthesized nanoparticles display outstanding properties, i.e. featureless Raman background spectrum, which is a basic requirement in many plasmonic applications such as Surface Enhanced Raman Spectroscopy. Various molecules were chemisorbed on the nanoparticle and SERS investigations were carried out, by varying the laser wavelength. The SERS enhancement factor for AuAg bimetallic NPs shows an enhancement factor of about 5.7 × 10(5) with respect to the flat AuAg surface. 23610077 Surface-Passivated SBA-15-Supported Gold Nanoparticles: Highly Improved Catalytic Activity and Selectivity toward Hydrophobic Substrates. Silanol groups on a silica surface affect the activity of immobilized catalysts because they can influence the hydrophilicity/hydrophobicity, matter transfer, or even transition state in a catalytic reaction. Previously, these silanol groups have usually been passivated by using surface-passivation reagents, such as alkoxysilanes, bis-silylamine reagents, chlorosilanes, etc., and surface passivation has typically been found in mesoporous-silicas-supported molecular catalysts and heteroatomic catalysts. However, this property has rarely been reported in mesoporous-silicas-supported metal-nanoparticle catalysts. Herein, we prepared an almost-superhydrophobic SBA-15-supported gold-nanoparticle catalyst by using surface passivation, in which the catalytic activity increased more than 14 times for the reduction of nitrobenzene compared with non-passivated SBA-15. In addition, this catalyst can selectively catalyze hydrophobic molecules under our experimental conditions, owing to its high (almost superhydrophobic) hydrophobic properties. 23223345 The Effects of Carbohydrate, Unsaturated Fat, and Protein Intake on Measures of Insulin Sensitivity: Results from the OmniHeart Trial. OBJECTIVE Impaired insulin sensitivity increases the risk of cardiovascular disease. Although calorie restriction and weight loss increase insulin sensitivity, the effects of modifying macronutrient composition on insulin sensitivity are uncertain. The purpose of this study is to determine the effects on insulin sensitivity of a carbohydrate-rich diet (CARB; similar to the Dietary Approaches to Stop Hypertension [DASH] diet), a protein-rich diet (PROT; protein predominantly from plant sources), and an unsaturated fat-rich diet (UNSAT; predominantly monounsaturated). RESEARCH DESIGN AND METHODS This study was a randomized, controlled, three-period, crossover feeding study. The study participants were 164 individuals with prehypertension or stage 1 hypertension without diabetes. Diets were administered for 6 weeks each, with a washout period between diets of 2-4 weeks. Weight was held constant throughout the study. For our primary outcome, we calculated the quantitative insulin sensitivity check index (QUICKI) using the end-of-period fasting serum glucose and insulin. QUICKI is a validated measure of insulin sensitivity. The primary analyses used generalized estimating equations. RESULTS At baseline, mean (SD) BMI was 30.2 (6.1) kg/m(2), and mean (SD) QUICKI was 0.35 (0.04). The UNSAT diet increased QUICKI by 0.005, more than the CARB diet (P = 0.04). PROT had no significant effect compared with CARB. CONCLUSIONS A diet that partially replaces carbohydrate with unsaturated fat may improve insulin sensitivity in a population at risk for cardiovascular disease. Given the well-recognized challenges of sustaining weight loss, our results suggest an alternative approach for improving insulin sensitivity. 23228028 Controllable electrical properties of metal-doped In2O3 nanowires for high-performance enhancement-mode transistors. In recent years, In(2)O(3) nanowires (NWs) have been widely explored in many technological areas due to their excellent electrical and optical properties; however, most of these devices are based on In(2)O(3) NW field-effect transistors (FETs) operating in the depletion mode, which induces relatively higher power consumption and fancier circuit integration design. Here, n-type enhancement-mode In(2)O(3) NW FETs are successfully fabricated by doping different metal elements (Mg, Al, and Ga) in the NW channels. Importantly, the resulting threshold voltage can be effectively modulated through varying the metal (Mg, Ga, and Al) content in the NWs. A series of scaling effects in the mobility, transconductance, threshold voltage, and source-drain current with respect to the device channel length are also observed. Specifically, a small gate delay time (0.01 ns) and high on-current density (0.9 mA/μm) are obtained at 300 nm channel length. Furthermore, Mg-doped In(2)O(3) NWs are then employed to fabricate NW parallel array FETs with a high saturation current (0.5 mA), on/off ratio (>10(9)), and field-effect mobility (110 cm(2)/V·s), while the subthreshold slope and threshold voltage do not show any significant changes. All of these results indicate the great potency for metal-doped In(2)O(3) NWs used in the low-power, high-performance thin-film transistors. 23588390 Synergistic targeting/prodrug strategies for intravesical drug delivery - Lectin-modified PLGA microparticles enhance cytotoxicity of stearoyl gemcitabine by contact-dependent transfer. The direct access to the urothelial tissue via intravesical therapy has emerged as a promising means for reducing the high recurrence rate of bladder cancer. However, few advanced delivery concepts have so far been evaluated to overcome critical inherent efficacy limitations imposed by short exposure times, low tissue permeability, and extensive washout. This study reports on a novel strategy to enhance gemcitabine treatment impact on urothelial cells by combining a pharmacologically advantageous prodrug approach with the pharmacokinetic benefits of a glycan-targeted carrier system. The conversion of gemcitabine to its 4-(N)-stearoyl derivative (GEM-C18) allowed for stable, homogeneous incorporation into PLGA microparticles (MP) without compromising intracellular drug activation. Fluorescence-labeled GEM-C18-PLGA-MP were surface-functionalized with wheat germ agglutinin (WGA) or human serum albumin (HSA) to assess in direct comparison the impact of biorecognitive interaction on binding rate and anchoring stability. MP adhesion on urothelial cells of non-malignant origin (SV-HUC-1), and low- (5637) or high-grade (HT-1376) carcinoma was correlated to the resultant antiproliferative and antimetabolic effect in BrdU and XTT assays. More extensive and durable binding of the WGA-GEM-C18-PLGA-MP induced a change in the pharmacological profile and substantially higher cytotoxicity, allowing for maximum response within the temporal restrictions of instillative administration (120min). Mechanistically, a direct, contact-dependent transfer of stearoyl derivatives from the particle matrix to the urothelial membrane was found to account for this effect. With versatile options for future application, our results highlight the potential offered by the synergistic implementation of targeting/prodrug strategies in delivery systems tailored to the intravesical route. 23295156 L-Carnitine protects against arterial hypertension-related cardiac fibrosis through modulation of PPAR-γ expression. Cardiac fibrosis is a pathogenic factor in a variety of cardiovascular diseases and is characterized by an abnormal accumulation of extracellular matrix protein that leads to cardiac dysfunction. l-Carnitine (LC) plays an essential role in the β-oxidation of long-chain fatty acids in lipid metabolism. We have previously demonstrated the beneficial effects of LC in hypertensive rats. The aim of this study was to analyze the effect of LC on arterial hypertension-associated cardiac fibrosis and to explore the mechanisms of LC action. To this end, four groups of rats were used: Wistar (control), rats treated with 400mg/kg/day of LC, rats treated with 25mg/kg/day of l-NAME (to induce hypertension), and rats treated with LC+l-NAME simultaneously. We found an elevation in the myocardial expression of profibrotic factors (TGF-β1 and CTGF), types I and III of collagen, and NADPH oxidase subunits (NOX2 and NOX4), in hypertensive rats when compared with normotensive ones. In addition, an increase in myocardial fibrosis was also found in the l-NAME group. These results were accompanied by a down-regulation of PPAR-γ in the heart of hypertensive animals. When hypertensive rats were treated with LC, all these alterations were reversed. Moreover, a significant negative correlation was observed between myocardial interstitial fibrosis and mRNA expression of PPAR-γ. In conclusion, the reduction of cardiac fibrosis and the down-regulation of NOX2, NOX4, TGF-β1 and CTGF induced by LC might be, at least in part, mediated by an upregulation of PPAR-γ, which leads to a reduction on hypertension-related cardiac fibrosis. 23547776 Development of an ALK2-Biased BMP Type I Receptor Kinase Inhibitor. The bone morphogenetic protein (BMP) signaling pathway has essential functions in development, homeostasis, and the normal and pathophysiologic remodeling of tissues. Small molecule inhibitors of the BMP receptor kinase family have been useful for probing physiologic functions of BMP signaling in vitro and in vivo and may have roles in the treatment of BMP-mediated diseases. Here we describe the development of a selective and potent inhibitor of the BMP type I receptor kinases, LDN-212854, which in contrast to previously described BMP receptor kinase inhibitors exhibits nearly 4 orders of selectivity for BMP versus the closely related TGF-β and Activin type I receptors. In vitro, LDN-212854 exhibits some selectivity for ALK2 in preference to other BMP type I receptors, ALK1 and ALK3, which may permit the interrogation of ALK2-mediated signaling, transcriptional activity, and function. LDN-212854 potently inhibits heterotopic ossification in an inducible transgenic mutant ALK2 mouse model of fibrodysplasia ossificans progressiva. These findings represent a significant step toward developing selective inhibitors targeting individual members of the highly homologous BMP type I receptor family. Such inhibitors would provide greater resolution as probes of physiologic function and improved selectivity against therapeutic targets. 23561222 Separation and purification of the antioxidant compounds, caffeic acid phenethyl ester and caffeic acid from mushrooms by molecularly imprinted polymer. Caffeic acid phenethyl ester (CAPE) and caffeic acid (CA), two naturally occurring phenolic antioxidants, have been reported to have a diversity of biological activities. In this investigation, a novel approach to separate and enrich CAPE and CA from 25 species of mushrooms using molecularly imprinted polymers (MIPs) as the sorbent material is reported. The MIPs were synthesized using CAPE as the template, and its adsorption behavior was investigated in detail. In comparison with C18-solid phase extraction (SPE), MIP-SPE displayed high selectivity and good affinity for CAPE and CA. The antioxidant potential of the mushroom extracts, before and after preconcentration using MIPs, was assayed by inhibition of erythrocyte hemolysis and lipid peroxidation. Application of MIPs with a high affinity toward CAPE and CA provides a novel method for obtaining active compounds from natural products. 23416262 A cell-based, multiparametric sensor approach characterises drug-induced cytotoxicity in human liver HepG2 cells. Drug-induced toxicity is of considerable concern in drug discovery and development, placing emphasis on the need for predictive in vitro technologies that identify potential cytotoxic side effects of drugs. A label-free, real-time, multiparametric cytosensor system has therefore been established for in vitro assessment of drug-induced toxicity. The system is based on monitoring cellular oxygen consumption, acidification and impedance of human hepatocarcinoma-derived HepG2 cells. The read-out derived from the multiparametric cytosensor system has been optimised and permits sensitive, reliable, and simultaneous recording of cell physiological signals, such as metabolic activity, cellular respiration and morphological changes and cell adhesion upon exposure to a drug. Analysis of eight prototypic reference drugs revealed distinct patterns of drug-induced physiological signals. Effects proved to be rigidly concentration-dependent. Based on signal patterns and reversibility of the observed effects, compounds could be classified based as triggering mechanisms of respiratory or metabolic stress or conditions leading to cell death (necrosis-like and apoptosis-like). A test-flag-risk mitigation strategy is proposed to address potential risks for drug-induced cytotoxicity. 23389991 Impaired Postural Balance in Turner Syndrome. An impaired body balance has been found in Turner syndrome (TS) in clinical tests like Rombergs's test and walking on a balance beam. The aim of the study was to assess postural balance in TS subjects with specific balance testing using dynamic posturography and relate to body composition. Nineteen TS subjects (20-57 years) were included. Balance was measured with dynamic posturography (Equitest) and compared with 19 sex and age-matched controls (22-59 years). Equitest, visual, vestibular, and somatosensory systems were provoked with increasing difficulty (6 tests, SO1-SO6) and body sway was measured with a dual forceplate. Body composition was measured with DXA. No difference was found between the TS subjects and the controls on fixed platform with open eyes (SO1), with closed eyes (SO2), with stable platform and visual disorientation (SO3), or on unstable platform with open eyes (SO4). In the difficult tests on unstable platform the TS subjects did worse compared with controls both in the test with eyes closed (SO5), p<0.01, and in the test with visual disorientation (SO6), p<0.05. Composite (a merge of all six recordings) was significantly lower in the TS-group, p<0.05. In the TS group high total body weight was related to worse outcome on tests SO5, SO6, and composite, while total bone mass, age, height, or waist showed no significant association with balance scores. Our findings indicate that TS could have an increased risk for falling due to impaired ability to manage complex coordination tasks. 23201370 Acute and subchronic toxicity as well as mutagenic evaluation of essential oil from turmeric (Curcuma longa L). The present study investigated the acute, subchronic and genotoxicity of turmeric essential oil (TEO) from Curcuma longa L. Acute administration of TEO was done as single dose up to 5 g of TEO per kg body weight and subchronic toxicity study for thirteen weeks was done by daily oral administration of TEO at doses 0.1, 0.25 and 0.5 g/kg b.wt. in Wistar rats. There were no mortality, adverse clinical signs or changes in body weight; water and food consumption during acute as well as subchronic toxicity studies. Indicators of hepatic function such as aspartate aminotransferase (AST), alanine amino transferase (ALT) and alkaline phosphatase (ALP) were unchanged in treated animals compared to untreated animals. Oral administration of TEO for 13 weeks did not alter total cholesterol, triglycerides, markers of renal function, serum electrolyte parameters and histopathology of tissues. TEO did not produce any mutagenicity to Salmonella typhimurium TA-98, TA-100, TA-102 and TA-1535 with or without metabolic activation. Administration of TEO to rats (1 g/kg b.wt.) for 14 days did not produce any chromosome aberration or micronuclei in rat bone marrow cells and did not produce any DNA damage as seen by comet assay confirming the non toxicity of TEO. 23264030 Effects of fluoxetine on the swimming and behavioural responses of the Arabian killifish. The selective serotonin reuptake inhibitor fluoxetine has frequently been detected in surface waters around the world. Fluoxetine modulates levels of serotonin, a neurotransmitter that regulates several important physiological and behavioural processes including fear and anxiety, aggression, locomotion and feeding. In this study, groups of sub-adult Arabian killifish (Aphanius dispar) were exposed to either 0, 0.03, 0.3 or 3 μg/L fluoxetine hydrochloride for 7 days and their swimming behaviour and social interactions videotaped in a circular arena. The fish were subsequently exposed to a predator alarm chemical (from dragonfly larvae fed with A. dispar) and their short-term responses recorded. The video was analysed using the open-sourced software program Ctrax which objectively quantified swimming and social behaviours. Aggression (chasing behaviour was significantly reduced at 3.0 μg/L fluoxetine. After the addition of the predator alarm chemicals fish responded quickly, increasing the percentage of time spent drifting or motionless and reducing average swimming velocity. Controls and fish exposed to 0.03 or 3 μg/L fluoxetine reduced swimming speed by 20-30 % but returned to pre-exposure velocities within 6 min. Fish exposed to 0.3 μg/L fluoxetine reduced swimming speed by 38 % after addition of the predator alarm and did not return to pre-exposure speeds during the recording period (19 min). Schooling behaviour was also affected by fluoxetine and predator alarm with fish exposed to 0.3 μg/L fluoxetine significantly reducing nearest neighbour distance and swimming speed relative to nearest neighbour the following addition of the predator alarm. 23528252 Decreased androgen receptor expression may contribute to spermatogenesis failure in rats exposed to low concentration of bisphenol A. To investigate the effects of a low bisphenol A (BPA) concentration on male reproduction, adult rats were administered a concentration of BPA that was less than the no observable adverse effect level (0.0005-5mg/kg/bw) for 8 weeks. General toxicity, reproductive hormones, and spermatogenesis were then determined. The expression of genes related to hormone synthesis and spermatogenesis was also analyzed. These BPA concentrations generated no general toxicity and no significant changes on serum hormones. However, the testicular testosterone, hormone synthesis-related genes StAR and Cyp450scc increased, whereas 3β-HSD, 17β-HSD, and Cyp450arom decreased. Additionally, BPA significantly decreased the epithelial height and round spermatids in seminiferous tubules, sperm count, androgen receptor expression, and the expression of the spermatogenesis-related genes outer dense fiber protein 1 (ODF1) and transition protein 1. Our results indicate that a low BPA concentration can induce spermatogenesis disorders mainly through decreasing androgen receptor expression. The present results may bring attention to the risk of environmental BPA exposure. 23180382 Solvated graphenes: an emerging class of functional soft materials. From a materials science point of view, graphene is essentially a polymer having a giant, two-dimensional molecular configuration. In this Progress Report, solvated graphene and its derivatives are illustrated from the perspective of soft matter. Firstly, the key appealing features of graphene as a molecular building block for assembling bulk soft materials are highlighed. It is then demonstrated how the intersheet interactions in solution are correlated with the molecular structure of graphene, and how a combination of the unique molecular structure and colloidal interactions can lead to simple, solution-phase approaches for assembling graphenes into a variety of macroscopic nanoarchitectures. A number of new exciting functions and applications are also highlighted, which are enabled by the solvation effect and in particular, it is discussed why and how solvated graphenes can offer exciting functions that are unattainable with the dried, hard counterpart. The discussion is concluded with some personal perspectives on the future directions in which this emerging class of functional soft materials could be pursued. 23403904 Comparative study of artificial chromosome centromeres in human and murine cells. Human artificial chromosomes (HAC) are a valuable tool in the analysis of complex chromatin structures such as the human centromere because of their small size and relative simplicity compared with normal human chromosomes. This report includes a comprehensive study of the centromere and chromatin composition of HAC, expressing human genes, generated in human cells and transferred to murine cells. The analysis involved chromatin immuno-precipitation and immuno-FISH on metaphase chromosomes and chromatin fibres. In both the cell types, the HAC consisted of alphoid and non-alphoid DNA and were mainly euchromatic in composition, although a pericentromeric heterochromatic region was present on all the HAC. Fibre-FISH and chromatin immuno-precipitation data indicated that the position of the centromere differed between HAC in human cells and in murine cells. Our work highlights the importance and utilisation of HAC for understanding the epigenetic aspects of chromosome biology.European Journal of Human Genetics advance online publication, 13 February 2013; doi:10.1038/ejhg.2012.296. 23526231 Alkaloids from Lycoris caldwellii and their particular cytotoxicities against the astrocytoma and glioma cell lines. Phytochemical investigation of the ethanol extract of the bulbs of Lycoris caldwellii afforded four new alkaloids, (+)-N-methoxylcarbonyl-nandigerine (1), (+)-N-methoxycarbonyl-lindcarpine (2), (+)-10-O-methylhernovine N-oxide (3), and (+)-3-hydroxy-anhydrolycorine N-oxide (4). Structural elucidation of all the compounds were performed by spectral methods such as 1D and 2D ((1)H-(1)H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. All the alkaloids were in vitro evaluated for their cytotoxic activities against eight tumor cell lines (BEN-MEN-1, CCF-STTG1, CHG-5, SHG-44, U251, BGC-823, HepG2, and SK-OV-3). Alkaloids 1 and 2 exhibited particular cytotoxic activities against astrocytoma and glioma cell lines with IC50 of 9.2-11.3 μM and 10.4-12.2 μM respectively. 23624029 Diagnosis and management of classical congenital adrenal hyperplasia. Congenital adrenal hyperplasia (CAH) is among the most common genetic disorders. Deficiency of adrenal steroid 21-hydroxylase deficiency due to mutations in the CYP21A2 gene accounts for about 95% cases of CAH. This disorder manifests with androgen excess with or without salt wasting. It also is a potentially life threatening disorder; neonatal screening with 17-hydroxyprogesterone measurement can diagnose the condition in asymptomatic children. Carefully monitored therapy with glucocorticoid and mineralocorticoid supplementation will ensure optimal growth and development for children with CAH. Genital surgery may be required for girls with CAH. Continued care is required for individuals with CAH as adults to prevent long-term adverse consequences of the disease, including infertility, metabolic syndrome and osteoporosis. 23578583 The potential role of T cell migration and chemotaxis as targets of glucocorticoids in multiple sclerosis and experimental autoimmune encephalomyelitis. Glucocorticoids (GCs) are the most commonly prescribed drugs for the treatment of acute disease bouts in multiple sclerosis (MS) patients. While T lymphocytes were shown to be essential targets of GC therapy, at least in animal models of MS, the mechanisms by which GCs modulate T cell function are less clear. Until now, apoptosis induction and repression of pro-inflammatory cytokines in T cells have been considered the most critical mechanisms in ameliorating disease symptoms. However, this notion is being challenged by increasing evidence that the control of T cell migration and chemotaxis by GCs might be even more important for the treatment of neuroinflammatory diseases. In this review we aim to provide an overview of how GCs impact the morphological alterations that T cells undergo during activation and migration as well as the influences that GCs have on the directed movement of T cells under the influence of chemokines. A deeper understanding of these processes should not only help to advance our understanding of how GCs exert their beneficial effects in MS therapy but may reveal future strategies to intervene in the pathogenesis of neuroinflammatory diseases. 23461784 Tough Germanium Nanoparticles under Electrochemical Cycling. Mechanical degradation of the electrode materials during electrochemical cycling remains a serious issue that critically limits the capacity retention and cyclability of rechargeable lithium-ion batteries. Here we report the highly reversible expansion and contraction of germanium nanoparticles under lithiation-delithiation cycling with in situ transmission electron microscopy (TEM). During multiple cycles to the full capacity, the germanium nanoparticles remained robust without any visible cracking despite ∼260% volume changes, in contrast to the size-dependent fracture of silicon nanoparticles upon the first lithiation. The comparative in situ TEM study of fragile silicon nanoparticles suggests that the tough behavior of germanium nanoparticles can be attributed to the weak anisotropy of the lithiation strain at the reaction front. The tough germanium nanoparticles offer substantial potential for the development of durable, high-capacity, and high-rate anodes for advanced lithium-ion batteries. 23468426 The interaction of isopenicillin N synthase with homologated substrate analogues δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-Xaa characterised by protein crystallography. Isopenicillin N synthase (IPNS) converts the linear tripeptide δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine (ACV) into bicyclic isopenicillin N (IPN) in the central step in the biosynthesis of penicillin and cephalosporin antibiotics. Solution-phase incubation experiments have shown that IPNS turns over analogues with a diverse range of side chains in the third (valinyl) position of the substrate, but copes less well with changes in the second (cysteinyl) residue. IPNS thus converts the homologated tripeptides δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-valine (AhCV) and δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-allylglycine (AhCaG) into monocyclic hydroxy-lactam products; this suggests that the additional methylene unit in these substrates induces conformational changes that preclude second ring closure after initial lactam formation. To investigate this and solution-phase results with other tripeptides δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-Xaa, we have crystallised AhCV and δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-S-methylcysteine (AhCmC) with IPNS and solved crystal structures for the resulting complexes. The IPNS:Fe(II):AhCV complex shows diffuse electron density for several regions of the substrate, revealing considerable conformational freedom within the active site. The substrate is more clearly resolved in the IPNS:Fe(II):AhCmC complex, by virtue of thioether coordination to iron. AhCmC occupies two distinct conformations, both distorted relative to the natural substrate ACV, in order to accommodate the extra methylene group in the second residue. Attempts to turn these substrates over within crystalline IPNS using hyperbaric oxygenation give rise to product mixtures. 23474356 Structure-property relationship for cellular accumulation of macrolones in human polymorphonuclear leukocytes (PMNs). Macrolones are a new class of antimicrobial compounds consisting of a macrolide scaffold linked to a 4-quinolone-3-carboxylic acid moiety via C(4″) position of a macrolide. As macrolides are known to possess favorable pharmacokinetic properties by accumulating in inflammatory cells, in this study we determined the intensity of accumulation in human polymorphonuclear leukocytes (PMNs) of 57 compounds of the macrolone class and analyzed the relationship between the molecular structure and this cellular pharmacokinetic property. Accumulation of macrolones ranged from 0 to 5.5-fold higher than the standard macrolide azithromycin. Distinct structural features in all three considered molecule parts: the macrolide scaffold, quinolone moiety and the linker, affect cellular accumulation. Interestingly, while the parent macrolide, azithromycin, accumulates approximately 3-fold more than clarithromycin, among macrolones all clarithromycin derivatives accumulated in PMNs significantly more than their azithromycin counterparts. Modeling cellular accumulation of macrolones with simple molecular descriptors, as well as with the measured octanol-water distribution coefficient, revealed that the number of hydrogen bond donors and secondary amide groups negatively contribute to macrolone accumulation, while lipophilicity makes a positive contribution. 23444335 A study on the effects of pica and iron-deficiency anemia on oxidative stress, antioxidant capacity and trace elements. Pica is defined as developmentally inappropriate consumption of nonnutritive substances for at least 1 month. There are a few studies on serum trace element levels of patients with pica. The literature contains contracting data on the levels of oxidative stress and antioxidant levels in patients with iron-deficiency anemia (IDA). The effect of pica on oxidative stress and antioxidant capacity has not been investigated yet. The present study evaluated the effects of pica and IDA on oxidative stress and antioxidant capacity as well as on the levels of trace elements including serum zinc and selenium in 47 children with IDA plus pica, 22 children with IDA only and 21 nonanemic children as controls. The results demonstrated significantly lower levels of serum selenium and zinc in pica and IDA groups compared to the control group. Total oxidant levels were highest in the pica group and consistently, the lowest total antioxidant capacity was observed again in the pica group. Comparison of pica and IDA groups yielded significantly lower levels of total antioxidant levels and significantly higher oxidative stress index in the pica group. Consequently, it is thought that the detrimental effects of pica within the organism were mediated by adverse impacts on antioxidant capacity and oxidative stress. These effects should be kept in mind while managing patients with pica. 23592779 Cubilin, a high affinity receptor for fibroblast growth factor 8, is required for cell survival in the developing vertebrate head. Cubilin (Cubn) is a multiligand endocytic receptor critical for the intestinal absorption of vitamin B12 and renal protein reabsorption. During mouse development Cubn is expressed in both embryonic and extra-embryonic tissues and Cubn gene inactivation results in early embryo-lethality most likely due to the impairment of the function of extra-embryonic Cubn. We here focus on the developmental role of Cubn expressed in the embryonic head. We report that Cubn is a novel, interspecies conserved Fgf receptor. Epiblast-specific inactivation of Cubn in the mouse embryo as well as Cubn silencing in the anterior head of frog or the cephalic neural crest of chick embryos show that Cubn is required during early somite stages to convey survival signals in the developing vertebrate head. Surface Plasmon resonance analysis reveals that fibroblast growth factor 8 (Fgf8), a key mediator of cell survival, migration, proliferation and patterning in the developing head is a high affinity ligand for Cubn. Cell uptake studies show that binding to Cubn is necessary for the phosphorylation of the Fgf signaling mediators MAPK and Smad1. Although Cubn may not form stable ternary complexes with Fgf receptors (FgfRs) it acts together with and/or is necessary for optimal FgfR activity. We propose that plasma membrane binding of Fgf8, and most likely of the Fgf8 family members Fgf17 and Fgf18, to Cubn improves Fgf ligand endocytosis and availability to FgfRs, thus modulating Fgf signaling activity. 23480196 Purification and sidewall functionalization of multiwalled carbon nanotubes and resulting bioactivity in two macrophage models. This study examined the consequences of surface carboxylation of multiwalled carbon nanotubes (MWCNT) on bioactivity. Since commercial raw MWCNT contain impurities that may affect their bioactivity, HCl refluxing was exploited to purify raw "as-received" MWCNT by removing the amorphous carbon layer on the MWCNT surface and reducing the metal impurities (e.g. Ni). The removal of amorphous carbon layer was confirmed by Raman spectroscopy and thermogravimetric analysis. Furthermore, the HCl-purified MWCNT provided more available reaction sites, leading to enhanced sidewall functionalization. The sidewall of HCl-purified MWCNT was further functionalized with the -COOH moiety by HNO(3) oxidation. This process resulted in four distinct MWCNT: raw, purified, -COOH-terminated raw MWCNT, and -COOH-terminated purified MWCNT. Freshly isolated alveolar macrophages from C57Bl/6 mice were exposed to these nanomaterials to determine the effects of the surface chemistry on the bioactivity in terms of cell viability and inflammasome activation. Inflammasome activation was confirmed using inhibitors of cathepsin B and Caspase-1. Purification reduced the cell toxicity and inflammasome activation slightly compared to raw MWCNT. In contrast, functionalization of MWCNT with the -COOH group dramatically reduced the cytotoxicity and inflammasome activation. Similar results were seen using THP-1 cells supporting their potential use for high-throughput screening. This study demonstrated that the toxicity and bioactivity of MWCNT were diminished by removal of the Ni contamination and/or addition of -COOH groups to the sidewalls. 23585058 NMDA Receptor Activation Down-Regulates Expression of δ Subunit-Containing GABA-A Receptors in Cultured Hippocampal Neurons. Neurosteroids are endogenous allosteric modulators of γ amino-butyric acid type A receptors (GABARs), and enhance GABAR-mediated inhibition. However, GABARs expressed on hippocampal dentate granule neurons of epileptic animals are modified such that their neurosteroid sensitivity is reduced and δ subunit expression is diminished. The molecular mechanisms triggering this GABAR plasticity were explored. In the cultured hippocampal neurons treatment with NMDA (10 μM) for 48 hrs reduced surface expression of δ and α4 subunits, but did not increase expression of γ2 subunits. The tonic current recorded from neurons in NMDA-treated cultures was reduced, and its neurosteroid modulation was also diminished. In contrast, synaptic inhibition and its modulation by neurosteroids were preserved in these neurons. The time course of NMDA effects on surface and total δ subunit expression were distinct; shorter (6 hrs) treatment decreased surface expression, whereas longer treatment reduced both surface and total expression. APV blocked NMDA effects on δ subunit expression. Chelation of calcium ions by BAPTA-AM or blockade of ERK1/2 activation by UO126 also prevented the NMDA effects. Thus prolonged activation of NMDA receptors in hippocampal neurons reduced GABAR δ subunit expression through Ca2+ entry and at least in part by ERK1/2 activation. 23458573 PET studies in nonhuman primate models of cocaine abuse: Translational research related to vulnerability and neuroadaptations. The current review highlights the utility of positron emission tomography (PET) imaging to study the neurobiological substrates underlying vulnerability to cocaine addiction and subsequent adaptations following chronic cocaine self-administration in nonhuman primate models of cocaine abuse. Environmental (e.g., social rank) and sex-specific influences on dopaminergic function and sensitivity to the reinforcing effects of cocaine are discussed. Cocaine-related cognitive deficits have been hypothesized to contribute to high rates of relapse and are described in nonhuman primate models. Lastly, the long-term consequences of cocaine on neurobiology are discussed. PET imaging and longitudinal, within-subject behavioral studies in nonhuman primates have provided a strong framework for designing pharmacological and behavioral treatment strategies to aid drug-dependent treatment seekers. Non-invasive PET imaging will allow for individualized treatment strategies. Recent advances in radiochemistry of novel PET ligands and other imaging modalities can further advance our understanding of stimulant use on the brain. This article is part of a Special Issue entitled 'Neuroimaging'. 23151003 Metabotropic purinergic receptors in lipid membrane microdomains. There is broad evidence that association of transmembrane receptors and signalling molecules with lipid rafts/caveolae provides an enriched environment for protein-protein interactions necessary for signal transduction, and a mechanism for the modulation of neurotransmitter and/or growth factor receptor function. Several receptors translocate into submembrane compartments after ligand binding, while others move in the opposite direction. The role of such a dynamic localization and functional facilitation is signalling modulation and receptor desensitization or internalization. Purine and pyrimidine nucleotides have been viewed as primordial precursors in the evolution of all forms of intercellular communication, and they are now regarded as fundamental extracellular signalling molecules. They propagate the purinergic signalling by binding to ionotropic and metabotropic receptors expressed on the plasma membrane of almost all cell types, tissues and organs. Here, we have illustrated the localization in lipid rafts/caveolae of G protein-coupled P1 receptors for adenosine and P2Y receptors for nucleoside tri- and di-phosphates. We have highlighted that microdomain partitioning of these purinergic GPCRs is cell-specific, as is the overall expression levels of these same receptors. Moreover, we have described that disruption of submembrane compartments can shift the purinergic receptors from raft/caveolar to non-raft/non-caveolar fractions, and then abolish their ability to activate lipid signalling pathways and to integrate with additional lipid-controlled signalling events. This modulates the biological response to purinergic ligands and most of all indicates that the topology of the various purinergic components at the cell surface not only organizes the signal transduction machinery, but also controls the final cellular response. 23565776 Amino Acid-nucleotide-lipids: effect of amino Acid on the self-assembly properties. Hybrid amphiphiles composed of a lipid covalently linked to biomolecules are attracting considerable attention, owing to their unique physicochemical and biological properties. Herein, we have synthesized novel amino acid-nucleotide-lipids (ANLs), presenting phenylalanine and thymidine residues and saturated or unsaturated diacyl glycerol lipid moieties to investigate the effect of the specific aminoacid moieties on both aggregation properties and interactions of ANLs with single strand polyA RNA. Physicochemical studies (DLS, cryo-TEM, and small angle X-ray scattering) indicate that phenylanaline amino acids inserted at the 5' position of the nucleotide-lipids stabilize multilamellar systems, whereas unilamellar vesicles are formed preferentially in the case of nucleotide-lipids (NLs). Both NLs and ANLs exhibit weak interactions with complementary polyA RNA as revealed by isothermal titration calorimetry investigations. The multilamellar vesicles obtained with ANLs could be used as a versatile carrier, suitable for both hydrophobic and hydrophilic therapeutic molecules. 23220635 The AhR twist: ligand-dependent AhR signaling and pharmaco-toxicological implications. The aryl hydrocarbon receptor (AhR) is a transcription factor which is activated by diverse compounds and regulates the expression of xenobiotic metabolism genes. Recent studies have unraveled unsuspected physiological roles and novel alternative ligand-specific pathways for this receptor. In this review, we discuss these novel aspects and focus on the different responses elicited by the diverse endogenous and/or exogenous AhR ligands. In addition to challenging the relevance of the 'agonist/antagonist' classification of ligands, we introduce the concept of AhR plasticity as a primordial factor in the generation of these pathways. Finally, we suggest several promising perspectives for the pharmacological modulation of these responses. 23246700 Phthalate and di-(2-ethylhexyl) adipate (DEHA) intake by German infants based on the results of a duplicate diet study and biomonitoring data (INES 2). Phthalates as well as di-(2-ethylhexyl) adipate (DEHA) are used as plasticizers in diverse applications and are of toxicological concern. The study was conducted with a study population of 25 German subjects aged between 15 and 21 months. Overall, 16 phthalates and DEHA were measured by gas chromatography-mass spectrometry in a total of 171 duplicate diet samples collected over 7 consecutive days, and 20 phthalate metabolites were analyzed in the urine samples collected over 7 consecutive days using a liquid chromatography-tandem mass spectrometry method. The median "high" daily dietary intake based on 95th percentiles was 4.66 μg/kg b.w. for di-2-ethylhexyl phthalate (DEHP), 1.03 μg/kg b.w. for di-isobutyl phthalate (DiBP), and 0.70 μg/kg b.w. for di-n-butyl phthalate (DnBP), and 1.0 μg/kg b.w. for DEHA. The "high" daily total intake from biomonitoring data was 4.9 μg/kg b.w. for DEHP, 2.2 μg/kg b.w. for DnBP, 3.9 μg/kg b.w. for DiBP, and 2.6 μg/kg b.w. for di-isononyl phthalate. The comparison of the two intake estimates indicates that the dominant intake source of DEHP was food ingestion, whereas other sources considerably contributed to the total intake of other phthalates. Using our "high" intake scenario, none of the analyzed phthalates reached the recommended tolerable daily intake levels. 23291927 Small-scale heat detection using catalytic microengines irradiated by laser. We demonstrate a novel approach to modulating the motion speed of catalytic microtubular engines via laser irradiation/heating with regard to small-scale heat detection. Laser irradiation on the engines leads to a thermal heating effect and thus enhances the engine speed. During a laser on/off period, the motion behaviour of a microengine can be repeatable and reversible, demonstrating a regulation of motion speeds triggered by laser illumination. Also, the engine velocity exhibits a linear dependence on laser power in various fuel concentrations, which implies an application potential as local heat sensors. Our work may hold great promise in applications such as lab on a chip, micro/nano factories, and environmental detection. 22766394 Association of a deficit of arousal with fatigue in multiple sclerosis: effect of modafinil. Multiple sclerosis (MS) is a multifocal demyelinating disease of the central nervous system, leading to chronic disability. Fatigue is a common and distressing symptom of MS which is unrelated to its clinical form, stage of development, the degree of disability, or the lesion load on magnetic resonance imaging. Fatigue in MS is associated with excessive daytime sleepiness and autonomic dysfunction. Recently it has been reported that the wakefulness-promoting drug modafinil may relieve fatigue in MS patients and ameliorate the associated cognitive difficulties. However, it is not clear to what extent the anti-fatigue effect of modafinil may be related to its alerting and sympathetic activating effects. We addressed this question by comparing three groups of subjects, MS patients with fatigue, MS patients without fatigue and healthy controls, matched for age and sex, on measures of alertness (self-ratings on the Epworth and Stanford Sleepiness Scales and on a battery of visual analogue scales; critical flicker fusion frequency; Pupillographic Sleepiness Test; choice reaction time) and autonomic function (systolic and diastolic blood pressure, heart rate, pupil diameter), and by examining the effect of a single dose (200 mg) of modafinil on these measures. MS patients with fatigue, compared with healthy controls, had reduced level of alertness on all the tests used; MS patients without fatigue did not differ from healthy controls. MS patients with fatigue had a reduced level of cardiovascular sympathetic activation compared to the other two groups. Modafinil displayed alerting and sympathomimetic effects in all three groups of subjects. As fatigue in MS is associated with reduced levels of alertness and sympathetic activity, modafinil may exert its anti-fatigue effect in MS by correcting these deficiencies. The anti-fatigue effect of modafinil may reflect the activation of the noradrenergic locus coeruleus (LC), since there is evidence that this wakefulness-promoting nucleus is damaged in MS, and that modafinil, probably via the dopaminergic system, can stimulate the LC. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23292881 3D nanoscale chemical imaging of the distribution of aluminum coordination environments in zeolites with soft X-ray microscopy. Which side are you on? Scanning transmission X-ray microscopy is used for the first time to elucidate the coordination and distribution of aluminum in industrial-relevant zeolites at the single-particle level. Extended regions of a few hundred nanometers, rich in higher aluminum coordination environments, are heterogeneously embedded within the zeolite particle, before and after a steaming post-treatment. 23047912 L-BMAA induced ER stress and enhanced caspase 12 cleavage in human neuroblastoma SH-SY5Y cells at low nonexcitotoxic concentrations. The cyanobacterial β-N-methylamino-L-alanine (L-BMAA) is described as a low-potency excitotoxin, possibly a factor in the increased incidence of amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia complex (PDC) in Guam. The latter association is intensively disputed, as L-BMAA concentrations required for toxic effects exceed those assumed to occur via food. The question thus was raised whether L-BMAA leads to neurodegeneration at nonexcitotoxic conditions. Using human SH-SY5Y neuroblastoma cells, L-BMAA-transport, incorporation into proteins, and subsequent impairment of cellular protein homeostasis were investigated. Binding of L-BMAA to intracellular proteins, but no clear protein incorporation was detected in response to (14)C-L-BMAA exposures. Nevertheless, low L-BMAA concentrations (≥ 0.1mM, 48 h) increased protein ubiquitination, 20S proteasomal and caspase 12 activity, expression of the endoplasmic reticulum (ER) stress marker CHOP, and enhanced phosphorylation of elf2α in SH-SY5Y cells. In contrast, high L-BMAA concentrations (≥ 1mM, 48 h) increased reactive oxygen species and protein oxidization, which were partially ameliorated by coincubation with vitamin E. L-BMAA-mediated cytotoxicity was observable 48 h following ≥ 2mM L-BMAA treatment. Consequently, the data presented here suggest that low L-BMAA concentrations result in a dysregulation of the cellular protein homeostasis with ensuing ER stress that is independent from high-concentration effects such as excitotoxicity and oxidative stress. Thus, the latter could be a contributing factor in the onset and slow progression of ALS/PDC in Guam. 23340977 Two-dimensional supramolecular electron spin arrays. A bottom-up approach is introduced to fabricate two-dimensional self-assembled layers of molecular spin-systems containing Mn and Fe ions arranged in a chessboard lattice. We demonstrate that the Mn and Fe spin states can be reversibly operated by their selective response to coordination/decoordination of volatile ligands like ammonia (NH3 ). 23466459 Dietary Chlorella protects against heterocyclic amine-induced aberrant gene expression in the rat colon by increasing fecal excretion of unmetabolized PhIP. The food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is one of the most abundant heterocyclic amines formed by cooking meat and fish at high temperature. PhIP induces colorectal adenoma risk in male rats when administered orally. This study used male Fisher 344 rats to investigate the impact of dietary Chlorella on PhIP metabolism and aberrant colonic gene expression following short-term PhIP treatment. High-performance liquid chromatography analysis revealed that fecal excretion of unmetabolized PhIP was significantly increased in rats whose diets were supplemented with Chlorella compared to rats in a PhIP-only group (P<0.001). Quantitative realtime PCR confirmed that the increase in beta-catenin and cyclin D1 mRNA in the colon induced by PhIP was ameliorated in rats pre-fed with Chlorella (P=0.052 for beta-catenin; P=0.005 for cyclin D1). The increase in DNA shearing that is a hallmark of caspase-8-mediated apoptosis by PhIP was also significantly diminished in the colons of rats pre-fed Chlorella (P=0.012). These results suggested that administering dietary Chlorella with a Western-style diet concomitantly or immediately before mutagen exposure might be beneficial in blocking the absorption of food mutagens such as PhIP. 23265502 Ascorbic acid, nitrate, and nitrite concentration relationship to the 24hour light/dark cycle for spinach grown in different conditions. Nitrate, nitrite and ascorbic acid (vitamin C) concentrations were determined for spinach (Spinacia oleracea L.) over a 24 h period to determine if light intensity (including dark periods) at time of harvest impacts concentrations in raw vegetables. Nitrate, nitrate and ascorbic acid concentrations varied significantly over the 24 h period and appeared to be related to changes in light intensity. Light intensity at the time an experimental sample is collected may affect the concentration of some constituents that a researcher is studying. Also, nitrate and nitrite concentrations in raw spinach can be reduced by harvesting at the best time of day. The highest nitrate concentrations in spinach occurred in the dark just prior to an increase in light intensity. Ascorbic acid was near its highest level for the 24 h period when the light intensity initially increased, then decreased to its lowest level around 3-6 h later. 23589365 Crop seed oil bodies: From challenges in protein identification to an emerging picture of the oil body proteome. Oleaginous seeds store lipids in specialized structures called oil bodies (OBs). These organelles consist of a core of neutral lipids bound by proteins embedded in a phospholipid monolayer. OB proteins are well conserved in plants and have long been grouped into only two categories: structural proteins or enzymes. Recent work, however, which identified other classes of proteins associated with OBs, clearly shows that this classification is obsolete. Proteomics-mediated OB protein identification is facilitated in plants for which the genome is sequenced and annotated. However, it is not clear whether this knowledge can be dependably transposed to less well characterized plants, including the well-established commercial sources of seed oil as well as the many others being proposed as novel sources for biodiesel, especially in Africa and Asia. Towards an update of the current data available on OB proteins this review discusses (i) the specific difficulties for proteomic studies of organelles; (ii) a 2012 census of the proteins found in seed OBs from various crops; (iii) the oleosin composition of OBs and their role in organelle stability; (iv) post translational modification of OB proteins as an emerging field of investigation; and finally we describe the emerging model of the OB proteome from oilseed crops. 23246867 A p21-activated kinase (PAK1) signaling cascade coordinately regulates F-actin remodeling and insulin granule exocytosis in pancreatic β cells. Human islet studies implicate an important signaling role for the Cdc42 effector protein p21-activated kinase (PAK1) in the sustained/second-phase of insulin secretion. Because human islets from type 2 diabetic donors lack ∼80% of normal PAK1 protein levels, the mechanistic requirement for PAK1 signaling in islet function was interrogated. Similar to MIN6 β cells, human islets elicited glucose-stimulated PAK1 activation that was sensitive to the PAK1 inhibitor, IPA3. Given that sustained insulin secretion has been correlated with glucose-induced filamentous actin (F-actin) remodeling, we tested the hypothesis that a Cdc42-activated PAK1 signaling cascade is required to elicit F-actin remodeling to mobilize granules to the cell surface. Live-cell imaging captured the glucose-induced cortical F-actin remodeling in MIN6 β cells; IPA3-mediated inhibition of PAK1 abolished this remodeling. IPA3 also ablated glucose-stimulated insulin granule accumulation at the plasma membrane, consistent with its role in sustained/second-phase insulin release. Both IPA3 and a selective inhibitor of the Cdc42 GTPase, ML-141, blunted the glucose-stimulated activation of Raf-1, suggesting Raf-1 to be downstream of Cdc42→PAK1. IPA3 also inhibited MEK1/2 activation, implicating the MEK1/2→ERK1/2 cascade to occur downstream of PAK1. Importantly, PD0325901, a new selective inhibitor of MEK1/2→ERK1/2 activation, impaired F-actin remodeling and the sustained/amplification pathway of insulin release. Taken together, these data suggest that glucose-mediated activation of Cdc42 leads to activation of PAK1 and prompts activation of its downstream targets Raf-1, MEK1/2 and ERK1/2 to elicit F-actin remodeling and recruitment of insulin granules to the plasma membrane to support the sustained phase of insulin release. 23401039 Guidelines for Resident Teaching Experiences. Postgraduate year one (PGY1) and postgraduate year two (PGY2) residencies serve to develop pharmacists into skillful clinicians who provide advanced patient-centered care in various general and specialized areas of pharmacy practice. Pharmacy residencies are a minimum requirement for many clinical pharmacy positions, as well as for positions in academia. The role of clinical pharmacists typically includes teaching, regardless of whether they pursue an academic appointment. Common teaching duties of pharmacist-clinicians include giving continuing education or other invited presentations, providing education to colleagues regarding clinical initiatives, precepting pharmacy students (early and advanced experiences) and residents, and educating other health care professionals. Although ASHP provides accreditation standards for PGY1 and PGY2 residencies, the standards pertaining to teaching or education training are vague. Through the years, teaching certificate programs that develop residents' teaching skills and better prepare residents for a diverse pharmacy job market have increased in popularity; moreover, teaching certificate programs serve as an attractive recruitment tool. However, the consistency of requirements for teaching certificate programs is lacking, and standardization is needed. The Task Force on Residencies developed two sets of guidelines to define teaching experiences within residencies. The first guideline defines the minimum standards for teaching experiences in any residency-training program. The second guideline is for programs offering a teaching certificate program to provide standardization, ensuring similar outcomes and quality on program completion. One of the main differences between the guidelines is the recommendation that residency programs offering a teaching certificate program be affiliated with an academic institution to provide the pedagogy and variety of teaching experiences for the resident. Residency program directors should consider adopting these guidelines to offer consistent teaching experiences. In addition, residents should inquire about the elements of teaching in a program as an aid to selecting the training best suited to their needs. 23597133 Three-Dimensional Ab Initio Potential Energy Surface for H-CO(X̃(2)A'). We present an ab initio potential for the H-CO(X̃(2)A') complex in which the CO bond length is varied and the long-range interactions between H and CO are accurately represented. It was computed using the spin-unrestricted open-shell single and double excitation coupled cluster method with perturbative triples [RHF-UCCSD(T)]. Three doubly augmented correlation-consistent basis sets were utilized to extrapolate the correlation energy to the complete basis set limit. More than 4400 data points were calculated and used for an analytic fit of the potential: long-range terms with inverse power dependence on the H-CO distance R were fit to the data points for large R, the reproducing kernel Hilbert space (RKHS) method was applied to the data at smaller distances. Our potential was compared with previous calculations and with some data extracted from spectroscopy. Furthermore, it was used in three-dimensional discrete variable representation (DVR) calculations of the vibrational frequencies and rotational constants of HCO, which agree very well with the most recently measured data. Also the dissociation energy D0 = 0.623 eV of HCO into H + CO obtained from these calculations agrees well with experimental values. Finally, we made preliminary two-dimensional (2D) calculations of the cross sections for rotationally inelastic H-CO collisions with the CO bond length fixed and obtained good agreement with recently published 2D results. 23124950 Transparent nanowire network electrode for textured semiconductors. This work presents an inexpensive and easily manufacturable, highly conductive and transparent nanowire network electrode for textured semiconductors. It is based on lines of silver nanoparticles transformed into a nanowire network by microwave or furnace sintering. The nanonetwork electrode on crystalline silicon is demonstrated experimentally, with the nanoparticles self-assembling in the valleys between the pyramids of the textured surface. Optical experiments show that this conductive nanowire network electrode can be essentially 'invisible' when covered with the conventional anti-reflection coating (ARC), and thus could be employed in photovoltaic applications. 23318455 Axl/Gas6/NFκB signalling in schwannoma pathological proliferation, adhesion and survival. TAM family receptor tyrosine kinases comprising Tyro3 (Sky), Axl, and Mer are overexpressed in some cancers, correlate with multidrug resistance and contribute to tumourigenesis by regulating invasion, angiogenesis, cell survival and tumour growth. Mutations in the gene coding for a tumour suppressor merlin cause development of multiple tumours of the nervous system such as schwannomas, meningiomas and ependymomas occurring spontaneously or as part of a hereditary disease neurofibromatosis type 2. The benign character of merlin-deficient tumours makes them less responsive to chemotherapy. We previously showed that, amongst other growth factor receptors, TAM family receptors (Tyro3, Axl and Mer) are significantly overexpressed in schwannoma tissues. As Axl is negatively regulated by merlin and positively regulated by E3 ubiquitin ligase CRL4DCAF1, previously shown to be a key regulator in schwannoma growth we hypothesized that Axl is a good target to study in merlin-deficient tumours. Moreover, Axl positively regulates the oncogene Yes-associated protein, which is known to be under merlin regulation in schwannoma and is involved in increased proliferation of merlin-deficient meningioma and mesothelioma. Here, we demonstrated strong overexpression and activation of Axl receptor as well as its ligand Gas6 in human schwannoma primary cells compared to normal Schwann cells. We show that Gas6 is mitogenic and increases schwannoma cell-matrix adhesion and survival acting via Axl in schwannoma cells. Stimulation of the Gas6/Axl signalling pathway recruits Src, focal adhesion kinase (FAK) and NFκB. We showed that NFκB mediates Gas6/Axl-mediated overexpression of survivin, cyclin D1 and FAK, leading to enhanced survival, cell-matrix adhesion and proliferation of schwannoma. We conclude that Axl/FAK/Src/NFκB pathway is relevant in merlin-deficient tumours and is a potential therapeutic target for schwannoma and other merlin-deficient tumours.Oncogene advance online publication, 14 January 2013; doi:10.1038/onc.2012.587. 23001862 Gold nanoprisms as optoacoustic signal nanoamplifiers for in vivo bioimaging of gastrointestinal cancers. Early detection of cancer greatly increases the chances of a simpler and more effective treatment. Traditional imaging techniques are often limited by shallow penetration, low sensitivity, low specificity, poor spatial resolution or the use of ionizing radiation. Hybrid modalities, like optoacoustic imaging, an emerging molecular imaging modality, contribute to improving most of these limitations. However, this imaging method is hindered by relatively low signal contrast. Here, gold nanoprisms (AuNPrs) are used as signal amplifiers in multispectral optoacoustic tomography (MSOT) to visualize gastrointestinal cancer. PEGylated AuNPrs are successfully internalized by HT-29 gastrointestinal cancer cells in vitro. Moreover, the particles show good biocompatibility and exhibit a surface plasmon band centered at 830 nm, a suitable wavelength for optoacoustic imaging purposes. These findings extend well to an in vivo setting, in which mice are injected with PEGylated AuNPrs in order to visualize tumor angiogenesis in gastrointestinal cancer cells. Overall, both our in vitro and in vivo results show that PEGylated AuNPrs have the capacity to penetrate tumors and provide a high-resolution signal amplifier for optoacoustic imaging. The combination of PEGylated AuNPrs and MSOT represents a significant advance for the in vivo imaging of cancers. 23631427 Dual Targeting of the Adenosine A2A Receptors and Monoamine Oxidase B by 4H-3,1-Benzothiazin-4-ones. Blockade of A2A adenosine receptors (A2AARs) and inhibition of monoamine oxidase B (MAO-B) in brain are considered attractive strategies for the treatment of neurodegenerative diseases such as Parkinson's disease (PD). In the present study benzothiazinones, e.g. 2-(3-chlorophenoxy)-N-(4-oxo-4H-3,1-benzothiazin-2-yl)acetamide (13), were identified as a novel class of potent MAO-B inhibitors (IC50 human MAO-B: 1.63 nM). Benzothiazinones with large substituents in the 2-position, e.g. methoxy-cinnamoylamino, phenylbutyrylamino, or chlorobenzylpiperazinylbenzamido residues (14, 17, 27, 28) showed high affinity and selectivity for A2AARs (Ki human A2AAR: 39.5-69.5 nM). By optimizing benzothiazinones for both targets the first potent, dual-acting A2AAR/MAO-B inhibitors with a non-xanthine structure were developed. The best derivative was N-(4-oxo-4H-3,1-benzothiazin-2-yl)-4-phenylbutanamide (17, Ki human A2A 39.5 nM, IC50 human MAO-B 34.9 nM; selective versus other AR subtypes and MAO-A), which inhibited A2AAR-induced cAMP accumulation and showed competitive, reversible MAO B inhibition. The new compounds may be useful tools for validating the A2AAR/MAO-B dual target approach in PD. 23582235 Zinc Promotes the Death of Hypoxic Astrocytes by Upregulating Hypoxia-Induced Hypoxia-Inducible Factor-1alpha Expression via Poly(ADP-ribose) Polymerase-1. AIM: Pathological release of excess zinc ions has been implicated in ischemic brain cell death. However, the underlying mechanisms remain to be elucidated. In stroke, ischemia-induced zinc release and hypoxia-inducible factor-1 (HIF-1) accumulation concurrently occur in the ischemic tissue. The present study tests the hypothesis that the presence of high intracellular zinc concentration is a major cause of modifications to PARP-1 and HIF-1α during hypoxia, which significantly contributes to cell death during ischemia. METHODS: Primary cortical astrocytes and C8-D1A cells were exposed to different concentrations of zinc chloride. Cell death rate and protein expression of HIF-1 and Poly(ADP-ribose) polymerase (PARP)-1 were examined after 3-h hypoxic treatment. RESULTS: Although 3-h hypoxia or 100 μM of zinc alone did not induce noticeable cytotoxicity, their combination led to a dramatic increase in astrocytic cell death in a zinc-concentration-dependent manner. Exposure of astrocytes to hypoxia for 3 h remarkably increased the levels of intracellular zinc and HIF-1α protein, which was further augmented by added exogenous zinc. Notably, HIF-1α knockdown blocked zinc-induced astrocyte death. Moreover, knockdown of PARP-1, another important protein in the response of hypoxia, attenuated the overexpression of HIF-1α and reduced the cell death rate. CONCLUSIONS: Our studies show that zinc promotes hypoxic cell death through overexpression of the hypoxia response factor HIF-1α via the cell fate determine factor PARP-1 modification, which provides a novel mechanism for zinc-mediated ischemic brain injury. 23313961 Specific uptake of folate-decorated triamcinolone-encapsulating nanoparticles by retinal pigment epithelium cells enhances and prolongs antiangiogenic activity. We are proposing folate-decorated polymeric nanoparticles as carriers of poorly soluble drug molecules for intracellular and prolonged delivery to retinal pigment epithelium (RPE) cells. RPE is a monolayer of epithelial cells that forms the outer blood-retinal barrier in the posterior segment of the eye, and is also implicated in the pathology of, such as neovascularization in age-related macular degeneration (AMD). In this study, folate-functionalized poly(ethylene glycol)-b-polycaprolactone (folate-PEG-b-PCL) were synthesized for assembling into nanoparticles of ~130nm. These nanoparticles were internalized into ARPE-19 (human RPE cell line) via receptor-mediated endocytosis, and the cellular uptake was significantly higher than particles without folate modification. Triamcinolone acetonide (TA) was efficiently encapsulated (>97%) into the folate-decorated nanoparticles and was slowly released over a period of 4 weeks at pH 5.5 and 8 weeks at pH 7.4. The enhanced uptake and controlled release resulted in prolonged anti-angiogenic gene expression of RPE cells. In cell culture, the down-regulation of vascular endothelial growth factor (VEGF) and up-regulation of pigment epithelium derived factor (PEDF) lasted for at least 3 weeks. Unlike benzyl alcohol, the surfactant found in commercial formulation, folate-modified nanoparticles were non-toxic. Furthermore, TA became less cytotoxic by being encapsulated in the nanoparticles. Our findings suggest that folate-PEG-PCL nanoparticles are promising drug carriers for RPE targeting. 23470359 Testing for departures from additivity in mixtures of perfluoroalkyl acids (PFAAs). This study is a follow-up to a paper by Carr et al. that determined a design structure to optimally test for departures from additivity in a fixed ratio mixture of four perfluoroalkyl acids (PFAAs) using an in vitro transiently-transfected COS-1 PPARα reporter model with a mixing ratio that is based on average serum levels in NHANES subjects. Availability of information regarding potential for additivity of PFAAs in mixtures is critically important for risk assessors who are concerned with the ability of the compounds to affect human health and impact ecological systems. It is clear that exposures are not to single compounds, but to mixtures of the PFAAs. This paper presents the results from the data collected using the design from Carr et al. along with subsequent analyses that were performed to classify the relationships among mixtures of PFAAs. A non-linear logistic additivity model was employed to predict relative luciferase units (RLU), an indicator of PPARα activation. The results indicated a less than additive relationship among the four PFAAs. To determine if the possible "antagonism" is from the competition among or between carboxylates and sulfonates, four different binary mixtures were also studied. There was a less than additive relationship in all four binary mixtures. These findings are generally similar to two other reports of interfering interactions between PFAAs in mixtures. The most conservative interpretation for our data would be an assumption of additivity (and lack of a greater than additive interaction), with a potential for antagonistic interactions. 23175443 Oncogenic FGFR3 gene fusions in bladder cancer. FGF receptor 3 (FGFR3) is activated by mutation or over-expression in many bladder cancers. Here, we identify an additional mechanism of activation via chromosomal re-arrangement to generate constitutively activated fusion genes. FGFR3-transforming acid coiled coil 3 (TACC3) fusions resulting from 4p16.3 re-arrangements and a t(4;7) that generates a FGFR3-BAI1-associated protein 2-like 1 (BAIAP2L1) fusion were identified in 4 of 43 bladder tumour cell lines and 2 of 32 selected tissue samples including the tumour from which one of the cell lines was derived. These are highly activated and transform NIH-3T3 cells. The FGFR3 component is identical in all cases and lacks the final exon that includes the phospholipase C gamma 1 (PLCγ1) binding site. Expression of the fusions in immortalized normal human urothelial cells (NHUC) induced activation of the mitogen-activated protein kinase pathway but not PLCγ1. A protein with loss of the terminal region alone was not as highly activated as the fusion proteins, indicating that the fusion partners are essential. The TACC3 fusions retain the TACC domain that mediates microtubule binding and the BAIAP2L1 fusion retains the IRSp53/MIM domain (IMD) that mediates actin binding and Rac interaction. As urothelial cell lines with FGFR3 fusions are extremely sensitive to FGFR-selective agents, the presence of a fusion gene may aid in selection of patients for FGFR-targeted therapy. 23220589 In vitro investigation of efficacy of new reactivators on OPC inhibited rat brain acetylcholinesterase. Organophosphorus compounds (OPC) were developed as warfare nerve agents. They are also widely used as pesticides. The drug therapy of intoxication with OPC includes mainly combination of cholinesterase (ChE) reactivators and cholinolytics. There is no single ChE reactivator having an ability to reactivate sufficiently the inhibited enzyme due to the high variability of chemical structure of the inhibitors. The difficulties in reactivation of ChE activity and slight antidote effect regarding intoxication with some OPC are some of the reasons for continuous efforts to obtain new reactivators of ChE. The aim of the present study was to evaluate the efficacy of some ChE reactivators against OPC intoxication (tabun, paraoxon and dichlorvos) in in vitro experiments and to compare their activity to that known for some currently used oximes (obidoxime, HI-6, 2-PAM). Experiments were carried out using rat brain acetylcholinesterase (AChE). Reactivators showed different activity in the reactivation of rat brain AChE after dichlorvos, paraoxon and tabun inhibition. AChE was easier reactivated after paraoxon treatment. The best effect showed BT-07-4M, obidoxime, TMB-4 and BT-08 from the group of symmetric oximes, and Toxidin, BT-05 and BT-03 from asymmetric compounds. The reactivation of brain AChE inhibited with tabun demonstrated better activity of new compound BT-07-4M, TMB-4 and obidoxime from symmetric oximes, and BT-05 and BT-03 possessing asymmetric structure. All compounds showed low activity toward inhibition of AChE caused by dichlorvos. Comparison of two main structure types (symmetric/asymmetric) showed that the symmetric compounds reactivated better AChE, inhibited with this OPC, than asymmetric ones. 23496412 Formation of Aragonitic Layered Structures from Kaolinite and Amorphous Calcium Carbonate Precursors. Clay materials have been an ever-present accoutrement of modern civilization; improvements to process these materials have quickened their utilization for use in complex multiaxial load-bearing structures. Specifically, with better methods to organize the constituent metal oxide components in clay, the distribution of characteristic nematic and smectic phases can be controlled. In this work, we utilize the interactions of an amorphous calcium carbonate phase with kaolinite to form a complex composite that can be organized into distinct hierarchical structures. We demonstrate that these ACC-kaolinite composites can maintain characteristic long-range-ordered layer-by-layer structures across many length scales, from nano- to millimeter, through convenient and economical processing at room temperature. 23233034 Synthesis and NIR optical properties of hollow gold nanospheres with LSPR greater than one micrometer. Optical analysis in the near infrared region is of significant biological importance due to better tissue penetration and reduced autofluorescence. In this work, an improved synthesis of hollow gold nanospheres (HGNs), which provides a tunable localized surface plasmon resonance (LSPR) from 610 nm up to 1320 nm, is demonstrated. The scattering properties of these nanoparticles are shown using surface enhanced Raman scattering (SERS) at 1064 nm excitation wavelength and are compared to citrate reduced gold and silver nanoparticles of similar physical sizes and surface properties. After the addition of salts, a strong signal was observed from hollow gold with a LSPR of 650 nm and a weaker, yet observable, signal from HGNs with a LSPR of 775 nm. However, no obvious signals were observed in the case of standard citrate reduced gold, silver or HGNs with a LSPR of 1080 nm. The absorption properties of HGNs were investigated by monitoring their photothermal activity. In this case, different nanoparticle suspensions including citrate reduced gold, silver, and HGNs were illuminated by a continuous laser at 785 nm excitation wavelength and the absorption efficiency of HGNs with a LSPR of 775 nm was calculated to be 0.81% which is more than 5 times higher than the absorption efficiency of citrate reduced gold nanoparticles under similar conditions. 23613425 A Biodegradable Polymersome Containing Bcl-xL siRNA and Doxorubicin as a Dual Delivery Vehicle for a Synergistic Anticancer Effect. Combined cancer treatment via co-delivery of siRNAs and an anticancer drug can be a promising strategy due to the synergistic effect of simultaneously minimizing gene/drug administration. In this study, Bcl-xL siRNA and doxorubicin (DOX) are encapsulated into designed methoxy-poly(ethylene glycol)-block-poly(D,L-lactic acid) (mPEG-b-PLA) block copolymer polymersomes (PSomes). A study of the cytotoxicity of Bcl-xL siRNA and DOX co-encapsulated PSomes (CPSomes) shows more inhibited proliferation of MKN-45 and MKN-28 human gastric cancer cell lines than only gene- and drug-loaded ones. Consequently, these results demonstrate that co-delivery of genes and drugs using PSomes results in a synergistic efficacy and indicates the potential of PSomes as efficient nanocarriers for combined cancer therapy. 22644836 Insulin resistance is not necessarily an essential element of metabolic syndrome. Type 2 diabetes is frequently associated with metabolic syndrome (MetS). Insulin resistance (IR) is thought to be the underlying pathophysiology of MetS. The purpose of this study is to examine the association of MetS with IR and beta cell function. This is a cross-sectional study in NHANES 1999-2000 participants who were at least 18 years old, including 911 non-Hispanic whites (NHW), 398 non-Hispanic blacks (NHB), and 595 Mexican-Americans (MA). MetS was defined based on the revised ATP III. IR and beta cell function were calculated using homeostasis model assessment (HOMA-IR and HOMA-B). The high-risk tertile was defined as the highest HOMA-IR and lowest HOMA-B. The odds ratio (OR) was calculated against the other two tertiles. The relationship of HOAM-IR and HOMA-B with the components of MetS was also examined. IR was a risk factor of MetS in all three ethnic groups (OR 4.17-12.01, P < 0.0001). Fasting glucose, triglycerides, and HDL cholesterol were associated with IR (P < 0.001) and correlated with HOMA-IR (P < 0.001), while inconsistent results were noted in blood pressure and waist circumference among three racial/ethnic groups. However, in the MetS subjects, 32 % of NHW, 28 % of NHB, and 44 % of MA were not in the IR tertile and in the IR subjects, 25 % of NHW, 36 % NHB, and 30 % of MA did not have MetS. No relationship was found between beta cell function and MetS. Although IR is a risk factor for MetS, IR is neither necessary nor required for MetS. 23273993 Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell-type plasticity within a tumor has recently been suggested to cause a bidirectional conversion between tumor-initiating stem cells and nonstem cells triggered by an inflammatory stroma. NF-κB represents a key transcription factor within the inflammatory tumor microenvironment. However, NF-κB's function in tumor-initiating cells has not been examined yet. Using a genetic model of intestinal epithelial cell (IEC)-restricted constitutive Wnt-activation, which comprises the most common event in the initiation of colon cancer, we demonstrate that NF-κB modulates Wnt signaling and show that IEC-specific ablation of RelA/p65 retards crypt stem cell expansion. In contrast, elevated NF-κB signaling enhances Wnt activation and induces dedifferentiation of nonstem cells that acquire tumor-initiating capacity. Thus, our data support the concept of bidirectional conversion and highlight the importance of inflammatory signaling for dedifferentiation and generation of tumor-initiating cells in vivo. 23410172 Rationally designed multitarget agents against inflammation and pain. Arachidonic acid (ARA) undergoes enzyme-mediated oxidative metabolism, resulting in the formation of a number of biologically active metabolites. For over a century, these biochemical transformations have been the target of numerous pharmacological drugs for inflammation and pain. In particular, non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) selective inhibitors (coxibs) are widely used in the treatment of inflammation and pain. However, gastrointestinal (GI) and cardiovascular adverse effects of NSAIDs and coxibs, and recent findings demonstrating that there are significant risks from the disruption of oxylipin levels when pharmacologically inhibiting a single ARA cascade metabolic pathway, have led to studies involving the simultaneous inhibition of multiple pathways in ARA cascade. These studies suggest that multitarget inhibition represents a new and valuable option to enhance efficacy or reduce side-effects in the treatment of inflammation and pain. This review focuses on the crosstalk within the three pathways of the ARA cascade (cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450)), and summarizes the current and future approaches of multitarget inhibitors for the treatment of eicosanoid driven inflammation and pain. 23454529 New quinazoline derivatives for telomeric G-quadruplex DNA: Effects of an added phenyl group on quadruplex binding ability. To improve the selectivity of indoloquinoline or benzofuroquinoline derivatives, we previously reported several quinazoline derivatives [17]. These compounds could mimic a tetracyclic aromatic system through intramolecular hydrogen bond. Studies showed that these quinazoline derivatives were effective and selective telomeric G-quadruplex ligands. With this encouragement, here we synthesized a series of N-(2-(quinazolin-2-yl)phenyl)benzamide (QPB) compounds as modified quinazoline derivatives. In this modification, a phenyl group was introduced to the aromatic core. The evaluation results showed that part of QPB derivatives had stronger binding ability and better selectivity for telomeric G-quadruplex DNA than LZ-11, the most potential compound of reported quinazoline derivatives. Furthermore, telomerase inhibition of QPB derivatives and their cellular effects were studied. 23468310 Sarothrin from Alkanna orientalis is an antimicrobial agent and efflux pump inhibitor. An Alkanna orientalis leaf and flower extract inhibited the growth of Staphylococcus aureus, a pathogen that causes an estimated 478 000 hospitalizations in the US annually. Bioassay-guided fractionation of A. orientalis resulted in isolation of the flavonoid sarothrin (5,7,4'-trihydroxy-3,6,8-trimethoxyflavone), which inhibited the growth of Mycobacterium smegmatis (MIC 75 µM) and S. aureus (MIC > 800 µM), and possessed efflux pump inhibitory activity. This is the first report of antimicrobial or efflux pump inhibitory activity of sarothrin, and of its presence in A. orientalis. Our findings suggest that the effectiveness of A. orientalis extracts is due to a combination of multiple constituents, including sarothrin. 23517729 Efficient induction of apoptosis in HeLa cells by a novel cationic porphycene photosensitizer. In the present study we analyze the photobiological properties of 2,7,12-tris(α-pyridinio-p-tolyl)-17-(p-(methoxymethyl)phenyl) porphycene (Py3MeO-TBPo) in Hela cells, in order to assess its potential as a new photosensitizer for photodynamic therapy of cultured tumor cells. Using 0.5 μM Py3MeO-TBPo, flow cytometry studies demonstrated an increase of intracellular drug levels related to the incubation time, reaching a maximum at 18 h. LysoTracker(®) Green (LTG) and MitoTracker(®) Green (MTG) probes were used to identify the subcellular localization. Upon exposure to ultraviolet excitation, red porphycene fluorescence was detected as red granules in the cytoplasm that colocalized with LTG. No significant toxic effects were detected for Py3MeO-TBPo in the dark at concentrations below 1 μM. In contrast, Py3MeO-TBPo combined with red-light irradiation induced concentration- and fluence-dependent HeLa cells inactivation. Besides, all photodynamic protocols assayed induced a clear effect of cell detachment inhibition after trypsin treatment. Both apoptotic and necrotic cell death mechanisms can occur in HeLa cells depending on the experimental protocol. After 18 h incubation with 0.5 μM Py3MeO-TBPo and subsequent red light irradiation (3.6 J/cm(2)), a high number of cells die by apoptosis, as evaluated by morphological alterations, immunofluorescent relocalization of Bax from cytosol to mitochondria, and TUNEL assay. Likewise, immunofluorescence techniques showed that cytochrome c is released from mitochondria into cytosol in cells undergoing apoptosis, which occurs immediately after relocation of Bax in mitochondria. The highest amount of apoptosis appeared 24 h after treatment (70%) and this cell death occurred without cell detachment to the substrate. In contrast, with 0.75 μM Py3MeO-TBPo and 3.6 J/cm(2) irradiation, morphological changes showed a preferential necrotic cell death. Singlet oxygen was identified as the cytotoxic agent involved in cell photoinactivation. Moreover, cell cultures pre-exposed to the singlet oxygen scavenger sodium azide showed pronounced protection against the loss of viability induced by Py3MeO-TBPo and light. Different changes in distribution and organization of cytoskeletal elements (microtubules and actin microfilaments) as well as the protein vinculin, after apoptotic and necrotic photodynamic treatments have been analyzed. Neither of these two cell death mechanisms (apoptosis or necrosis) induced cell detachment. In summary, Py3MeO-TBPo appears to meet the requirements for further scrutiny as a very good photosensitizer for photodynamic therapy: it is water soluble, has a high absorption in the red spectral region (where light penetration in tissue is higher), and is able to induce effective high apoptotic rate (70%) related to the more widely studied photosensitizers. 22634360 Metabotropic glutamate receptor 4 in the basal ganglia of parkinsonian monkeys: ultrastructural localization and electrophysiological effects of activation in the striatopallidal complex. Group III metabotropic glutamate receptors (mGluR4,7,8) are widely distributed in the basal ganglia. Injection of group III mGluR agonists into the striatopallidal complex alleviates parkinsonian symptoms in 6-hydroxydopamine-treated rats. In vitro rodent studies have suggested that this may be partly due to modulation of synaptic transmission at striatopallidal and corticostriatal synapses through mGluR4 activation. However, the in vivo electrophysiological effects of group III mGluRs activation upon basal ganglia neurons activity in nonhuman primates remain unknown. Thus, in order to examine the anatomical substrates and physiological effects of group III mGluRs activation upon striatal and pallidal neurons in monkeys, we used electron microscopy immunohistochemistry to localize mGluR4, combined with local administration of the group III mGluR agonist L-AP4, or the mGluR4 positive allosteric modulator VU0155041, to assess the effects of group III mGluR activation on the firing rate and pattern of striatal and pallidal neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian monkeys. At the ultrastructural level, striatal mGluR4 immunoreactivity was localized in pre- (60%) and post-synaptic (30%) elements, while in the GPe, mGluR4 was mainly expressed pre-synaptically (90%). In the putamen, terminals expressing mGluR4 were evenly split between putative excitatory and inhibitory terminals, while in the GPe, most labeled terminals displayed the ultrastructural features of striatal-like inhibitory terminals, though putative excitatory boutons were also labeled. No significant difference was found between normal and parkinsonian monkeys. Extracellular recordings in awake MPTP-treated monkeys revealed that local microinjections of small volumes of L-AP4 resulted in increased firing rates in one half of striatal cells and one third of pallidal cells, while a significant number of neurons in both structures showed either opposite effects, or did not display any significant rate changes following L-AP4 application. VU0155041 administration had little effect on firing rates. Both compounds also had subtle effects on bursting and oscillatory properties, acting to increase the irregularity of firing. The occurrence of pauses in firing was reduced in the majority (80%) of GPe neurons after L-AP4 injection. Our findings indicate that glutamate can mediate multifarious physiological effects upon striatal and pallidal neurons through activation of pre-synaptic group III mGluRs at inhibitory and excitatory synapses in parkinsonian monkeys. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 22809387 Development and characterization of composite YSZ-PEI electrophoretically deposited membrane for Li-ion battery. In this work, the electrophoretic-deposition (EPD) method was used to fabricate pristine and composite ceramic-polymer membranes for application in planar and 3D microbattery configurations. The major focus was on the effect of polyethyleneimine additive on the morphology, composition, and electrochemical properties of the membrane. The ionic conductivity, cycleability, and charge/discharge behavior of planar LiFePO(4)/Li cells comprising composite porous YSZ-based membrane with impregnated LiPF(6) EC:DEC electrolyte were found to be similar to the cells with commercial Celgard membrane. Conformal EPD coating of the electrode materials by a thin-film ceramic separator is advantageous for high-power operation and safety of batteries. 22898132 Assessment of developmental delay in the zebrafish embryo teratogenicity assay. In this study we analyzed some aspects of the assessment of developmental delay in the zebrafish embryotoxicity/teratogenicity test and explored the suitability of acetylcholinesterase (AChE) activity as a biochemical marker and as a higher throughput alternative to morphological endpoints such as head-trunk angle, tail length and morphological score. Embryos were exposed from 4 to 52 h post-fertilization (hpf) to a selection of known embryotoxic/teratogen compounds (valproic acid, retinoic acid, caffeine, sodium salicylate, glucose, hydroxyurea, methoxyacetic acid, boric acid and paraoxon-methyl) over a concentration range. They were evaluated for AChE activity, head-trunk angle, tail length and several qualitative parameters integrated in a morphological score. In general, the different patterns of the concentration-response curves allowed distinguishing between chemicals that produced growth retardation (valproic and methoxyacetic acid) and chemicals that produced non-growth-delay related malformations. An acceptable correlation between the morphological score, AChE activity and head-trunk angle as markers of developmental delay was observed, being AChE activity particularly sensitive to detect delay in the absence of malformations. 23159479 The impact of oxytocin administration and maternal love withdrawal on event-related potential (ERP) responses to emotional faces with performance feedback. This is the first experimental study on the effect of oxytocin administration on the neural processing of facial stimuli conducted with female participants that uses event-related potentials (ERPs). Using a double-blind, placebo-controlled within-subjects design, we studied the effects of 16 IU of intranasal oxytocin on ERPs to pictures combining performance feedback with emotional facial expressions in 48 female undergraduate students. Participants also reported on the amount of love withdrawal they experienced from their mothers. Vertex positive potential (VPP) and late positive potential (LPP) amplitudes were more positive after oxytocin compared to placebo administration. This suggests that oxytocin increased attention to the feedback stimuli (LPP) and enhanced the processing of emotional faces (VPP). Oxytocin heightened processing of the happy and disgusted faces primarily for those reporting less love withdrawal. Significant associations with LPP amplitude suggest that more maternal love withdrawal relates to the allocation of attention toward the motivationally relevant combination of negative feedback with a disgusted face. 23561190 Preparative separation of triterpene alcohol ferulates from rice bran oil using a high performance counter-current chromatography. A novel method for the separation of two major triterpene alcohol ferulates from rice bran oil (RBO) was developed using a high performance counter-current chromatography (HPCCC). A two-phase solvent system of n-hexane-acetonitrile (1:1, v/v) was applied to purify cycloartenyl ferulate (CAF) and 24-methylene cycloartanyl ferulate (24-mCAF) from RBO. The yields were 20.50±2.60mg CAF and 12.62±1.15mg 24-mCAF from 390mg RBO through a two-step separation procedure. The purities of the two compounds were 97.97±0.90% and 95.50±0.75%, respectively, as determined by high performance liquid chromatography (HPLC). Their chemical structures were confirmed by ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS), and (1)H, (13)C and 2D nuclear magnetic resonance (NMR). This represents the first report on direct separation of CAF and 24-mCAF from RBO by HPCCC. 23201309 Selectivity of kinases on the activation of tenofovir, an anti-HIV agent. Nucleoside analogues, used in HIV-therapy, need to be phosphorylated by cellular enzymes in order to become potential substrates for HIV reverse transcriptase. After incorporation into the viral DNA chain, because of lacking of their 3'-hydroxyl groups, they stop the elongation process and lead to the death of the virus. Phosphorylation of the HIV-drug derivative, tenofovir monophosphate was tested with the recombinant mammalian nucleoside diphosphate kinase (NDPK), 3-phosphoglycerate kinase (PGK), creatine kinase (CK) and pyruvate kinase (PK). Among them, only CK was found to phosphorylate tenofovir monophosphate with a reasonable rate (about 45-fold lower than with its natural substrate, ADP), while PK exhibits even lower, but still detectable activity (about 1000-fold lower compared to the value with ADP). On the other hand, neither NDPK nor PGK has any detectable activity on tenofovir monophosphate. The absence of activity with PGK is surprising, since the drug tenofovir competitively inhibits both CK and PGK towards their nucleotide substrates, with similar inhibitory constants, K(I) of 2.9 and 4.8mM, respectively. Computer modelling (docking) of tenofovir mono- or diphosphate forms to these four kinases suggests that the requirement of large-scale domain closure for functioning (as for PGK) may largely restrict their applicability for phosphorylation/activation of pro-drugs having a structure similar to tenofovir monophosphate. 23568578 Differential levels of brain amino acids in rat models presenting learned helplessness or non-learned helplessness. RATIONALE: Glutamatergic and γ-aminobutyric acid (GABA)ergic abnormalities have recently been proposed to contribute to depression. The learned helplessness (LH) paradigm produces a reliable animal model of depression that expresses a deficit in escape behavior (LH model); an alternative phenotype that does not exhibit LH is a model of resilience to depression (non-LH model). OBJECTIVES: We measured the contents of amino acids in the brain to investigate the mechanisms involved in the pathology of depression. METHODS: LH and non-LH models were subjected to inescapable electric footshocks at random intervals following a conditioned avoidance test to determine acquirement of predicted escape deficits. Tissue amino acid contents in eight brain regions were measured via high-performance liquid chromatography. RESULTS: The non-LH model showed increased GABA levels in the dentate gyrus and nucleus accumbens and increased glutamine levels in the dentate gyrus and the orbitofrontal cortex. The LH model had reduced glutamine levels in the medial prefrontal cortex. Changes in the ratios of GABA, glutamine, and glutamate were detected in the non-LH model, but not in the LH model. Reductions in threonine levels occurred in the medial prefrontal cortex in both models, whereas elevated alanine levels were detected in the medial prefrontal cortex in non-LH animals. CONCLUSIONS: The present study demonstrates region-specific compensatory elevations in GABA levels in the dentate gyrus and nucleus accumbens of non-LH animals, supporting the implication of the GABAergic system in the recovery of depression. 23329588 Operationalizing value-based pricing of medicines : a taxonomy of approaches. The UK Government is proposing a novel form of price regulation for branded medicines, which it has dubbed 'value-based pricing' (VBP). The specifics of how VBP will work are unclear. We provide an account of the possible means by which VBP of medicines might be operationalized, and a taxonomy to describe and categorize the various approaches. We begin with a brief discussion of the UK Government's proposal for VBP and proceed to define a taxonomy of approaches to VBP. The taxonomy has five main dimensions: (1) what is identified as being of value, (2) how each element is measured, (3) how it is valued, (4) how the different elements of value are aggregated, and (5) how the result is then used to determine the price of a medicine. We take as our starting point that VBP will include a measure of health gain and that, as proposed by the UK Government, this will be built on the QALY. Our principal interest is in the way criteria other than QALYs are taken into account, including severity of illness, the extent of unmet need, and wider societal considerations such as impacts on carers. We set out to: (1) identify and describe the full range of alternative means by which 'value' might be measured and valued, (2) identify and describe the options available for aggregating the different components of value to establish a maximum price, and (3) note the challenges and relative advantages associated with these approaches. We review the means by which aspects of VBP are currently operationalized in a selection of countries and place these, and proposals for the UK, in the context of our taxonomy. Finally, we give an initial assessment of the challenges, pros and cons of each approach. We conclude that identifying where VBP should lie on each of the five dimensions entails value judgements: there are no simple 'right or wrong' solutions. If a wider definition of value than incremental QALYs gained is adopted, as is desirable, then a pragmatic way to aggregate the different elements of value, including both QALYs and benefits unrelated to QALYs, is to use a multi-criteria decision analysis (MCDA) approach. All approaches to VBP ultimately require the conversion of value, however assessed, into a monetary price. This requires assessment of the marginal values of all types of benefit, not just of QALYs. All stages of the VBP process are subject to uncertainty and margins of error. Consequently, the assessment of overall value can provide bounds to a price negotiation but cannot be expected to identify a precise value-based price. 23524305 Binding pattern and toxicological effects of lectins from genus Canavalia on bovine sperm. The aim of this study was to determine the binding patterns of Canavalia ensiformis (ConA), Canavalia boliviana (ConBol) and Canavalia brasiliensis (ConBr) lectins to bovine sperm and their effects on sperm motility, viability, lipid peroxidation, reactive oxygen species production and fertilization ability. ConA bound to whole spermatozoa, with the exception of the equatorial segment, ConBol did not interact with the acrosome region and ConBr exhibited a fragmented binding pattern. The three lectins decreased sperm motility but did not affect cell viability or lipid peroxidation. Nevertheless, ROS production was increased in comparison to controls and a reduction in the cleavage and blastocyst ratio was induced in comparison to controls. In conclusion, this study determined that structurally similar lectins interact differently with bovine sperm and affect sperm motility, viability, lipid peroxidation, ROS production and fertilization ability in various ways. 23391443 An intra-articular salmon calcitonin-based nanocomplex reduces experimental inflammatory arthritis. Prolonged inappropriate inflammatory responses contribute to the pathogenesis of rheumatoid arthritis (RA) and to aspects of osteoarthritis (OA). The orphan nuclear receptor, NR4A2, is a key regulator and potential biomarker for inflammation and represents a potentially valuable therapeutic target. Both salmon calcitonin (sCT) and hyaluronic acid (HA) attenuated activated mRNA expression of NR4A1, NR4A2, NR4A3, and matrix metalloproteinases (MMPs) 1, 3 and 13 in three human cell lines: SW1353 chondrocytes, U937 and THP-1 monocytes. Ad-mixtures of sCT and HA further down-regulated expression of NR4A2 compared to either agent alone at specific concentrations, hence the rationale for their formulation in nanocomplexes (NPs) using chitosan. The sCT released from NP stimulated cAMP production in human T47D breast cancer cells expressing sCT receptors. When NP were injected by the intra-articular (I.A.) route to the mouse knee during on-going inflammatory arthritis of the K/BxN serum transfer model, joint inflammation was reduced together with NR4A2 expression, and local bone architecture was preserved. These data highlight remarkable anti-inflammatory effects of sCT and HA at the level of reducing NR4A2 mRNA expression in vitro. Combining them in NP elicits anti-arthritic effects in vivo following I.A. delivery. 23468099 Effects of chronic social defeat stress on behavior and choline acetyltransferase, 78-kDa glucose-regulated protein, and CCAAT/enhancer-binding protein (C/EBP) homologous protein in adult mice. RATIONALE: Social defeat stress induces physiological and behavioral symptoms, including anxiety, anhedonia, immune deficits, and altered expression of key brain genes. OBJECTIVES: The present study investigated the effects of social defeat stress on the behaviors and expressions of Chat, Grp78, and chop in the brains of adult mice. METHODS: Adult mice were divided into susceptible and unsusceptible groups after 10 days of social defeat stress. In experiment 1, behavioral tests were conducted, and brains were processed for Western blotting at day 27 after stress. In experiment 2, social avoidance tests were conducted, and brains were processed for Western blotting at day 12 after stress. RESULTS: The results indicate decreased and increased locomotion and anxiety behavior in all defeated mice. Decrease in social interaction, increased immobility, and impaired memory performance were only observed in susceptible mice. A decrease in the Chat level at days 12 and 27 was noted in the prefrontal cortex (PFC), amygdala (Amyg), and dorsal hippocampus (HIP) in defeated mice. The expression levels of Grp78 and chop measured on days 12 and 27 were significantly greater in the Amyg of susceptible mice. In the PFC and HIP, defeated mice displayed different patterns in the levels of Grp78 and chop expressions measured on days 12 and 27. CONCLUSIONS: The present study demonstrated that chronic social defeat stress in mice produces stress-related behaviors. Different response patterns were noted for Grp78 and chop expression among the groups in terms of brain regions and time-course effects. 23161217 Suramin decreases injury and improves regeneration of ethanol-induced steatotic partial liver grafts. Steatotic grafts are excluded for use in partial liver transplantation (LT) because of the increased risk of primary nonfunction. This study investigated the effects of suramin, a polysulfonated naphthylurea, on the outcome of steatotic partial LT. Rat livers were harvested after acute ethanol treatment (6 g/kg, intragastric administration), reduced in size to ≈ 1/3, and transplanted. Serum alanine aminotransferase (ALT) and total bilirubin levels as well as hepatic necrosis and apoptosis were significantly higher after transplantation of fatty partial grafts (FPG) than lean partial grafts (LPG). Suramin (5 mg/kg, i.p.) decreased ALT by ≈ 60%, hyperbilirubinemia by 75%, necrosis by 83%, and apoptosis by 70% after FPG transplantation. Hepatic cellular 5-bromo-2'-deoxyuridine (BrdU) incorporation increased to 28% in LPG but was only 2% in FPG at 48 hours, and the mitotic index increased to 7% in LPG but was only 0.2% in FPG, indicating suppressed regeneration in FPG. Suramin increased BrdU incorporation and the mitotic index to 43% and 9%, respectively, in FPG. All FPG recipients died within 5 days. Suramin recovered survival of FPG to 62%. Tumor necrosis factor-α (TNF-α) mRNA was 2.2-fold higher in FPG than in LPG and was associated with activation of caspase-8 and caspase-3 in FPG. Suramin decreased TNF-α and caspase activation in FPG. Transforming growth factor-β (TGF-β), phospho-Smad2/3 and p21Cip1 were significantly higher in FPG than in LPG and suramin blocked TGF-β formation and its down-stream signaling pathway. Taken together, suramin improves the outcome of FPG transplantation, most likely by inhibition of TNF-α and TGF-β formation. 22397675 Injectable PLA-based in situ forming implants for controlled release of Ivermectin a BCS Class II drug: solvent selection based on physico-chemical characterization. In situ forming implants (ISI) prepared from biodegradable polymers such as poly(D,L-lactide) (PLA) and biocompatible solvents can be used to obtain sustained drug release after parenteral administration. The aim of this work was to study the effect of several biocompatible solvents with different physico-chemical properties on the release of ivermectin (IVM), an antiparasitic BCS II drug, from in situ forming PLA-based implants. The solvents evaluated were N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone (2P), triacetine (TA) and benzyl benzoate (BB). Hansen's solubility parameters of solvents were used to explain polymer/solvent interactions leading to different rheological behaviours. The stability of the polymer and drug in the solvents were also evaluated by size exclusion and high performance liquid chromatography, respectively. The two major factors determining the rate of IVM release from ISI were miscibility of the solvent with water and the viscosity of the polymer solutions. In general, the release rate increased with increasing water miscibility of the solvent and decreasing viscosity in the following order NMP>2P>TA>BB. Scanning electron microscopy revealed a relationship between the rate of IVM release and the surface porosity of the implants, release being higher as implant porosity increased. Finally, drug and polymer stability in the solvents followed the same trends, increasing when polymer-solvent affinities and water content in solvents decreased. IVM degradation was accelerated by the acid environment generated by the degradation of the polymer but the drug did not affect PLA stability. 23620478 Diabetic Retinopathy and Microalbuminuria Can Predict Macroalbuminuria and Renal Function Decline in Japanese Type 2 Diabetic Patients: Japan Diabetes Complications Study. OBJECTIVETo examine the interactive relationship between diabetic retinopathy (DR) and diabetic nephropathy (DN) in type 2 diabetic patients, and to elucidate the role of DR and microalbuminuria on the onset of macroalbuminuria and renal function decline.RESEARCH DESIGN AND METHODSWe explored the effects of DR and microalbuminuria on the progression of DN from normoalbuminuria and low microalbuminuria (<150 mg/gCr) to macroalbuminuria or renal function decline in the Japan Diabetes Complications Study (JDCS), which is a nationwide randomized controlled study of type 2 diabetic patients focusing on lifestyle modification. Patients were divided into four groups according to presence or absence of DR and MA: normoalbuminuria without DR [NA(DR-)] (n = 773), normoalbuminuria with DR [NA(DR+)] (n = 279), microalbuminuria without DR [MA(DR-)] (n = 277), and microalbuminuria with DR [MA(DR+)] (n = 146). Basal urinary albumin-to-creatinine ratio and DR status were determined at baseline and followed for a median of 8.0 years.RESULTSAnnual incidence rates of macroalbuminuria were 1.6/1,000 person-years (9 incidences), 3.9/1,000 person-years (8 incidences), 18.4/1,000 person-years (34 incidences), and 22.1/1,000 person-years (22 incidences) in the four groups, respectively. Multivariate-adjusted hazard ratios of the progression to macroalbuminuria were 2.48 (95% CI 0.94-6.50; P = 0.07), 10.40 (4.91-22.03; P < 0.01), and 11.55 (5.24-25.45; P < 0.01) in NA(DR+), MA(DR-), and MA(DR+), respectively, in comparison with NA(DR-). Decline in estimated glomerular filtration rate (GFR) per year was two to three times faster in MA(DR+) (-1.92 mL/min/1.73 m(2)/year) than in the other groups.CONCLUSIONSIn normo- and low microalbuminuric Japanese type 2 diabetic patients, presence of microalbuminuria at baseline was associated with higher risk of macroalbuminuria in 8 years. Patients with microalbuminuria and DR showed the fastest GFR decline. Albuminuria and DR should be considered as risk factors of renal prognosis in type 2 diabetic patients. An open sharing of information will benefit both ophthalmologists and diabetologists. 23317572 Radiolytic transformation of rotenone with potential anti-adipogenic activity. Radiolytic transformation of the isoflavonoid rotenone (1) with γ-irradiation afforded two new degraded products, rotenoisins A (2) and (3). The structures of the two new rotenone derivatives were elucidated on the basis of spectroscopic methods. The new products 2 and 3 exhibited significantly enhanced inhibitory activities against pancreatic lipase and adipocyte differentiation in 3T3-L1 cells when compared to parent rotenone. 23629515 Mitochondria as a Target of Environmental Toxicants. Enormous strides have recently been made in our understanding of the biology and pathobiology of mitochondria. Many diseases have been identified as caused by mitochondrial dysfunction, and many pharmaceuticals have been identified as previously unrecognized mitochondrial toxicants. A much smaller but growing literature indicates that mitochondria are also targeted by environmental pollutants. We briefly review the importance of mitochondrial function and maintenance for health, based on the genetics of mitochondrial diseases and the toxicities resulting from pharmaceutical exposure. We then discuss how the principles of mitochondrial vulnerability illustrated by those fields might apply to environmental contaminants, with particular attention to factors that may modulate vulnerability including genetic differences, epigenetic interactions, tissue characteristics, and developmental stages. Finally, we review the literature related to environmental mitochondrial toxicants, with a particular focus on those toxicants that target mitochondrial DNA. We conclude that the fields of environmental toxicology and environmental health should focus more strongly on mitochondria. 23604592 Developmental exposure to As, Cd and Pb-mixture diminishes skeletal growth and causes osteopenia at maturity via osteoblast and chondrocyte malfunctioning in female rats. We studied the effect of metal mixture (MM), comprising of As, Cd and Pb, in developing female rat skeleton from gestation day-5 until postnatal day-60 (P-60). MM resulted in synergistic inhibition in viability and differentiation of osteoblasts in vitro, likely induced by reactive oxygen species. MM, administered at their most frequently occurring concentrations present in the ground-water of India, i.e. As: 0.38ppm, Pb: 0.22 ppm and Cd: 0.098 ppm or 10× of the ratio to developing rats exhibited a synergistic decrease in ex vivo mineralization of bone marrow stromal (osteoprogenitor) cells. MM group showed a dose-dependent attenuation in weight and axial lengths, and shortening of tibias at P-60. Furthermore, the growth plate was shortened, which was associated with shorter proliferative- and hypertrophic zones, decreased parathyroid hormone-related protein and Indian hedgehog expression in the chondrocytes, reduced primary- and secondary spongiosa, and hypomineralized osteoids - a major characteristic of osteomalacia. In addition, compared to the control, MM treated rats were clearly osteopenic based on BMD, micro-architecture, biomechanical strength, and particularly the biochemical profile, that suggested high turnover bone loss. Finally, in comparison to the control, the fracture healing ability of MM group was delayed and accompanied by inferior quality of the healed bone. Together, these data demonstrated that the mixture of As, Cd and Pb induced synergistic toxicity to developing skeleton thereby diminishing modeling-directed bone accrual, inducing osteopenia and dampening fracture healing. 23497860 Pigment production by a new thermotolerant microalga Coelastrella sp. F50. Microalgae are good crops to produce natural pigments because of their high growth rates. Tropical zones are better locations than temperate areas for microalgal cultivation because they have longer duration of daylight and more stable temperatures throughout the year, but the high temperatures pose a challenge to microalgal cultivation. A newly isolated thermotolerant microalga produces reddish pigments under environmental stress. Morphological and molecular evidence including meridional ribs on the cell wall, pigment production, and its 18S rDNA sequence suggests that this microalga belongs to the genus Coelastrella. Salt stress and high light intensity accelerated biosynthesis of the pigments, and significant quantities of oil accumulated as the cells experienced stress due to nutrient deficiency. This microalga could withstand temperature of 50°C for more than 8h, which is a necessary trait for outdoor cultivation in tropical areas. The pigments contain astaxanthin, lutein, canthaxanthin, and β-carotene as analysed by using HPLC. 23552101 Cis-silencing of PIP5K1B evidenced in Friedreich's ataxia patient cells results in cytoskeleton anomalies. Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease characterized by ataxia, variously associating heart disease, diabetes mellitus and/or glucose intolerance. It results from intronic expansion of GAA triplet repeats at the FXN locus. Homozygous expansions cause silencing of the FXN gene and subsequent decreased expression of the encoded mitochondrial frataxin. Detailed analyses in fibroblasts and neuronal tissues from FRDA patients have revealed profound cytoskeleton anomalies. So far, however, the molecular mechanism underlying these cytoskeleton defects remains unknown. We show here that gene silencing spreads in cis over the PIP5K1B gene in cells from FRDA patients (circulating lymphocytes and primary fibroblasts), correlating with expanded GAA repeat size. PIP5K1B encodes phosphatidylinositol 4-phosphate 5-kinase β type I (pip5k1β), an enzyme functionally linked to actin cytoskeleton dynamics that phosphorylates phosphatidylinositol 4-phosphate [PI(4)P] to generate phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. Accordingly, loss of pip5k1β function in FRDA cells was accompanied by decreased PI(4,5)P2 levels and was shown instrumental for destabilization of the actin network and delayed cell spreading. Knockdown of PIP5K1B in control fibroblasts using shRNA reproduced abnormal actin cytoskeleton remodeling, whereas over-expression of PIP5K1B, but not FXN, suppressed this phenotype in FRDA cells. In addition to provide new insights into the consequences of the FXN gene expansion, these findings raise the question whether PIP5K1B silencing may contribute to the variable manifestation of this complex disease. 23584556 Gene identification and comparative molecular modeling of a Trypanosoma rangeli major surface protease. Trypanosoma rangeli is a hemoflagellate parasite which is able to infect humans. Distinct from Trypanosoma cruzi, the causative agent of Chagas disease, T. rangeli is non-pathogenic to the vertebrate host. The manner by which the T. rangeli interacts with the host is still unknown, but it certainly depends on the surface molecules. Major surface proteins (MSP) are GPI-anchored, zinc-dependent metalloproteases present in the surface of all trypanosomatids studied so far, which are implicated as virulence factors in pathogenic trypanosomatids, such as Leishmania spp and T. cruzi. The aims of this work were to generate the complete sequence of a T. rangeli MSP (TrMSP) gene and to determine the 3D-structure of the predicted protein by homology modeling. The plasmid bearing a complete copy of a TrMSP gene was completely sequenced and the predicted protein was modeled using Modeller software. Results indicate that TrMSP open reading frame (ORF) codes for a predicted 588 amino acid protein and shows all elements required for its posttranslational processing. Multiple sequence alignment of TrMSP with other trypanosomatids' MSPs showed an extensive conservation of the N-terminal and central regions and a more divergent C-terminal region. Leishmania major MSP (LmMSP), which had its crystal structure previously determined, has an overall 35 % identity with TrMSP. This identity allowed the comparative molecular modeling of TrMSP, which demonstrated a high degree of structural conservation between MSPs from other trypanosomatids (TrypMSPs). All modeled MSPs have a conserved folding pattern, apart from structural divergences in the C-domain and discrete differences of charge and topology in the catalytic cleft, and present the same geometry of the canonical HEXXH zinc-binding motif. The determination of surface charges of the molecules revealed that TrMSP is a predominantly positive protein, whereas LmMSP and Trypanosoma cruzi MSP (TcMSP) are negative proteins, suggesting that substrates recognized by TcMSP and LmMSP could not interact with TrMSP. Moreover, the comparison between TrMSP and TcMSP protein sequences has revealed 45 non-neutral amino acid substitutions, which can be further assessed through protein engineering. The characteristics of TrMSP could explain, at least in part, the lack of pathogenicity of T. rangeli to humans and point to the necessity of identifying the biological targets of this enzyme. 23445497 Drug-initiated ring-opening polymerization of O-carboxyanhydrides for the preparation of anticancer drug-poly(O-carboxyanhydride) nanoconjugates. We report a novel synthetic strategy of polymer-drug conjugates for nanoparticulate drug delivery: hydroxyl-containing drug (e.g., camptothecin, paclitaxel, doxorubicin and docetaxel) can initiate controlled polymerization of phenyl O-carboxyanhydride (Phe-OCA) to afford drug-poly(Phe-OCA) conjugated nanoparticles, termed drug-PheLA nanoconjugates (NCs). Our new NCs have well-controlled physicochemical properties, including high drug loading, quantitative drug loading efficiency, controlled particle size with narrow particle size distribution, and sustained drug release profile over days without "burst" release effect as observed in conventional polymer/drug encapsulates. Compared with polylactide NCs, the PheLA NCs have increased noncovalent hydrophobic interchain interactions and thereby result in remarkable stability in human serum with negligible particle aggregation. Such distinctive properties can reduce the premature disassembly of NCs upon dilution in the bloodstream and prolong NCs' in vivo circulation with the enhancement of intratumoral accumulation of NCs, which has a bearing on therapeutic effectiveness. 22940855 Quantum chemical investigation of the intra- and intermolecular proton transfer reactions and hydrogen bonding interactions in 4-amino-5-(2-hydroxyphenyl)-2H-1,2,4-triazole-3(4H)-thione. The intramolecular thione-thiol tautomerism and intermolecular double proton transfer reaction of the hydrogen-bonded thione and thiol dimers in the title triazole compound were studied at the B3LYP level of theory using 6-311++G(d,p) basis function. The influence of the solvent on the single and double proton transfer reactions was examined in three solvents (chloroform, methanol and water) using the polarizable continuum model (PCM) approximation. The computational results show that the thione tautomer is the most stable isomer with a very high tautomeric energy barrier both in the gas phase and in solution phase, indicating a quite disfavored process. The solvent effect is found to be sizable with increasing polarity. In the double proton transfer reaction, the thione dimer is found to be more stable than thiol dimer both in the gas phase and in solution phase. The energetic and thermodynamic parameters of the double proton transfer process show that the double proton exchange from thione dimer to thiol dimer is thermodynamically unfavored. However, the exchange from thiol dimer to thione dimer for the gas phase and water phase seems to be feasible with a low barrier height and with a negative value in enthalpy and free energy changes. In addition, the hydrogen bonding interactions were analyzed in the gas phase regarding their geometries and energies. It is found that all complex formations are enthalpically favored, and the stability of the H-bonds comes in the order of S1-H2···N2>N2-H2···S1>N3-H3B···O1. Finally, non-linear optical properties were carried out at the same calculation level in the gas phase. 23587422 Recent advances in malaria drug discovery. This digest covers some of the most relevant progress in malaria drug discovery published between 2010 and 2012. There is an urgent need to develop new antimalarial drugs. Such drugs can target the blood stage of the disease to alleviate the symptoms, the liver stage to prevent relapses, and the transmission stage to protect other humans. The pipeline for the blood stage is becoming robust, but this should not be a source of complacency, as the current therapies set a high standard. Drug discovery efforts directed towards the liver and transmission stages are in their infancy but are receiving increasing attention as targeting these stages could be instrumental in eradicating malaria. 23586519 Self-Seeding in One Dimension: A Route to Uniform Fiber-like Nanostructures from Block Copolymers with a Crystallizable Core-Forming Block. One-dimensional micelles formed by the self-assembly of crystalline-coil poly(ferrocenyldimethylsilane) (PFS) block copolymers exhibit self-seeding behavior when solutions of short micelle fragments are heated above a certain temperature and then cooled back to room temperature. In this process, a fraction of the fragments (the least crystalline fragments) dissolves at elevated temperature, but the dissolved polymer crystallizes onto the ends of the remaining seed fragments upon cooling. This process yields longer nanostructures (up to 1 μm) with uniform width (ca. 15 nm) and a narrow length distribution. In this paper, we describe a systematic investigation of factors that affect the self-seeding behavior of PFS block copolymer micelle fragments. For PI1000-PFS50 (the subscripts refer to the number average degree of polymerization) in decane, these factors include the presence of a good solvent (THF) for PFS and the effect of annealing the fragments prior to the self-seeding experiments. THF promoted the dissolution of the micelle fragments, while preannealing improved their stability. We also extended our experiments to other PFS block copolymers with different corona-forming blocks. These included PI637-PFS53 in decane, PFS60-PDMS660 in decane (PDMS = polydimethylsiloxane), and PFS30-P2VP300 in 2-propanol (P2VP = poly(2-vinylpyridine)). The most remarkable result of these experiments is our finding that the corona-forming chain plays an important role in affecting how the PFS chains crystallize in the core of the micelles and, subsequently, the range of temperatures over which the micelle fragments dissolve. Our results also show that self-seeding is a versatile approach to generate uniform PFS fiber-like nanostructures, and in principle, the method should be extendable to a wide variety of crystalline-coil block copolymers. 23567269 A Review of the "Omics" Approach to Biomarkers of Oxidative Stress in Oryza sativa. Physiological and ecological constraints that cause the slow growth and depleted production of crops have raised a major concern in the agriculture industry as they represent a possible threat of short food supply in the future. The key feature that regulates the stress signaling pathway is always related to the reactive oxygen species (ROS). The accumulation of ROS in plant cells would leave traces of biomarkers at the genome, proteome, and metabolome levels, which could be identified with the recent technological breakthrough coupled with improved performance of bioinformatics. This review highlights the recent breakthrough in molecular strategies (comprising transcriptomics, proteomics, and metabolomics) in identifying oxidative stress biomarkers and the arising opportunities and obstacles observed in research on biomarkers in rice. The major issue in incorporating bioinformatics to validate the biomarkers from different omic platforms for the use of rice-breeding programs is also discussed. The development of powerful techniques for identification of oxidative stress-related biomarkers and the integration of data from different disciplines shed light on the oxidative response pathways in plants. 23201003 Inhibitory effect of 1α,25-dihydroxyvitamin D₃ on excretion of JBP485 via organic anion transporters in rats. The aim of this study was to investigate the pharmacokinetic mechanism of interaction between JBP485 and 1α,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. Rats were injected intraperitoneally with 0.64 nmol/kg/day 1,25(OH)(2)D(3) in 1 ml/kg corn oil for 5 days. The plasma and urine concentrations of JBP485 after intravenous administration and the uptake of JBP485 in kidney slices in vitro were determined by liquid chromatography/tandem mass spectrometry. Quantitative polymerase chain reaction, western blotting, immunohistochemical analysis and immunofluorescence were used to determine the changes in the expression of organic anion transporter (Oat)1 and Oat3 in rat kidney in response to 1,25(OH)(2)D(3) treatment. The plasma concentrations and AUCs of JBP485 were significantly increased, while the renal clearance of JBP485 and uptake of JBP485 in kidney slices were significantly decreased after 1,25(OH)(2)D(3) treatment. These results confirmed that 1,25(OH)(2)D(3) inhibited renal excretion of JBP485. Moreover, 1,25(OH)(2)D(3) decreased expression of Oat1 and Oat3 in rat kidney. Our results are novel in demonstrating an interaction between JBP485 and 1,25(OH)(2)D(3) when they are co-administered. The mechanism of interaction between JBP485 and 1,25(OH)(2)D(3) could be explained at least in part by inhibitory effect of 1,25(OH)(2)D(3) on expression of Oats in rat kidney. 23339572 Chemical reactivity and biological activity of chalcones and other α,β-unsaturated carbonyl compounds. Abstract 1. Chalcones are structural analogues of benzalacetophenone (BAP). Several derivatives have been identified in plants and anticarcinogenic and anti-inflammatory properties were attributed to the compounds, probably related to their direct antioxidant activity or stimulatory effects on the expression of endogenous defence enzymes like hemeoxygenase-1 (HO-1). HO-1 expression is triggered by the Nrf2-Keap1 signalling pathway, initiated by the addition of chalcones to thiol groups of Keap1 via Michael-type reaction. 2. The present study used a model system estimating the reactivity of different synthetic chalcones and other α,β-unsaturated carbonyl compounds with thiols and compared the chemical reactivity with the biological activity, measured by HO-1 expression in human dermal fibroblasts. 3. Chemical reactivity with the thiol group of N-acetylcysteine was determined with 5,5'-dithiobis-(2-nitrobenzoic acid) and followed chemical principles of structure-reactivity relationship. Most reactive were sulforaphane, dimethylfumarate, chalcone 3 ((2E)-1-phenyl-3-pyrimidin-2-ylprop-2-en-1-one) and chalcone 7 (1,3-diphenylprop-2-yn-1-one). This result demonstrates that α,β-unsaturated carbonyl derivatives react with thiols differently. All compounds were also biologically active; however, expression of HO-1 was not only related to the chemical reactivity but also to the lipophilicity of the molecules which likely affected transmembrane uptake. Most efficient inducers of HO-1 expression were BAP, 4-hydroxynonenal and chalcone 1 (4-[(1E)-3-oxo-3-phenylprop-1-en-1-yl]benzonitrile), chalcone 5 ((2E)-1-phenyl-3-[4-(trifluoromethyl)-phenyl]prop-2-en-1-one) and chalcone 7. 23558446 Inhibition of PDGFRα by MEDI-575 Reduces Tumor Growth and Stromal Fibroblast Content in a Model of Non-Small Cell Lung Cancer. Platelet-derived growth factor receptor alpha (PDGFRα) is a receptor tyrosine kinase that promotes cell survival and is expressed in both the tumor and the stromal components of human cancers. We have developed a fully human monoclonal antibody, MEDI-575, that selectively binds to human PDGFRα with high affinity, with no observable affinity for murine PDGFRα. To more fully characterize the role of PDGFRα in the regulation of tumor stroma, we evaluated the in vivo antitumor effects of MEDI-575 in tumor-bearing SCID mice and in genetically altered SCID mice expressing human PDGFRα in place of murine PDGFRα. We utilized the Calu-6 non-small cell lung cancer model, because it lacks an in vitro proliferative response to PDGFRα activation. Antitumor activity was observed when the study was performed in mice expressing the human receptor, but no activity was observed in the mice expressing the murine receptor. Immunohistological analysis of tumors from mice expressing human PDGFRα showed a highly significant reduction in stromal fibroblast content and only minor changes in tumor proliferative index in tumors exposed to MEDI-575 compared to the results seen in vehicle-treated tumors or tumors from mice expressing murine PDGFRα. Additional in vitro studies indicated that exposure of primary cancer-associated fibroblasts to MEDI-575 can directly affect proliferation and key signaling pathways in these cells. These results highlight the potential for observing antitumor activity with MEDI-575 through modulation of the stromal component of tumors and confirm that the PDGFRα pathway can play a role in maintaining a tumor microenvironment conducive to tumor growth. 23469781 Quinolines as chemotherapeutic agents for leishmaniasis. The development of leishmanicidal quinolines and their in vitro (promastigote and amastigote) and, where applicable, in vivo activities are reviewed. This survey provides a direct comparison of bioactivity across different species(e.g. L. donovani, L. amazonensis, L. chagasi, L infantum), and in different animal models (e.g. L. donovani Balb/c mice and L. donovani infected hamsters). The progress of selected quinolines through pre-clinical development and phase I/II trials, and the lead quinoline drugs sitamaquinine and Imiquimod, are discussed in conjunction with delivery systems and combination therapies. 23524189 Mesenchymal stem cells as delivery vehicle of porphyrin loaded nanoparticles: Effective photoinduced in vitro killing of osteosarcoma. Mesenchymal stem cells (MSC) have the unique ability to home and engraft in tumor stroma. These features render them potentially a very useful tool as targeted delivery vehicles which can deliver therapeutic drugs to the tumor stroma. In the present study, we investigate whether fluorescent core-shell PMMA nanoparticles (FNPs) post-loaded with a photosensitizer, namely meso-tetrakis (4-sulfonatophenyl) porphyrin (TPPS) and uploaded by MSC could trigger osteosarcoma (OS) cell death in vitro upon specific photoactivation. In co-culture studies we demonstrate using laser confocal microscopy and time lapse imaging, that only after laser irradiation MSC loaded with photosensitizer-coated fluorescent NPs (TPPS@FNPs) undergo cell death and release reactive oxygen species (ROS) which are sufficient to trigger cell death of all OS cells in the culture. These results encourage further studies aimed at proving the efficacy of this novel tri-component system for PDT applications. 23471440 Exposure to phototoxic NSAIDs and quinolones is associated with an increased risk of melanoma. PURPOSE: Ultraviolet radiation exposure is the most important exogenous risk factor for cutaneous malignancies. It is possible that phototoxic drugs promote the development of cutaneous melanoma (CM) by intensifying the effect of ultraviolet light on the skin. We investigated the association between the use of common systemic phototoxic drugs and development of CM. METHODS: This study was a case-control study in a Dutch population-based cohort. The drug dispensing data was obtained from PHARMO, a Dutch drug dispensing and hospital admissions registry, and linked to PALGA, the nationwide pathology network of the Netherlands. The cases were patients diagnosed with pathologically confirmed primary CM between 1991 and 2004. Controls were sampled from the PHARMO population. Exposure to systemic phototoxic drugs was measured and included antimicrobial agents, diuretics, antipsychotic drugs, antidiabetic drugs, cardiac drugs, antimalarials and nonsteroidal anti-inflammatory drugs (NSAIDs). A multivariate conditional logistic regression analysis was performed to study the association between exposure to phototoxic drugs and CM. RESULTS: The study population included 1,318 cases and 6,786 controls. Any phototoxic drug during the study period was dispensed for 46 % of the cases and 43 % of the controls (p = 0.012). The use of quinolones [odds ratio (OR) 1.33, 95 % confidence interval (CI) 1.01-1.76] and propionic acid derivative NSAIDs (OR 1.33, 95 % CI 1.14-1.54) had a positive association with CM. CONCLUSIONS: Our study shows that the use of phototoxic drugs is associated with an increased risk of developing CM. Even a short-term use of phototoxic quinolones and propionic acid derivative NSAIDs may increase the risk for CM. Patient education to promote sun-protective behaviour is essential to avoid immediate adverse effects and possible long-term effects of phototoxic drugs. 23594296 Investigation of aqueous stability of taxol in different release media. Abstract In the present study, the aqueous stability of taxol in different aqueous media and immiscible aqueous/organic systems at 37 °C was investigated. The aqueous media included phosphate buffered saline (PBS) and PBS containing 10% methanol, 10% ethanol, 10% hydroxypropyl β-cyclodextrin (HP-βCD), 1% sodium citrate and 1% Tween 80. The immiscible systems consisted of PBS/octanol, PBS/dichloromethane, PBS/chloroform and PBS/ethyl acetate. The concentrations of taxol and related derivatives in each of the media were determined through the high-performance liquid chromatography assay. Results showed that hydrolysis and epimerization were two major types of degradation for taxol in the aqueous media starting from the initial hours of contact (6 hours). Addition of Tween 80 to PBS moderately increased the aqueous stability of taxol. As well, using PBS containing 10% HP-βCD inhibited the taxol hydrolysis, while epimerization still in process. In the case of immiscible systems, except for PBS/ethyl acetate system, no evidences of taxol hydrolysis were observed. Meanwhile, epimerization of taxol in PBS/dichloromethane and PBS/chloroform systems underwent due to the ability of C-Cl bonds to form hydrogen bonding with the hydroxyl group of C7 of taxol. 23529898 Multifunctional Hybrid Materials From Poly(3-Hydroxybutyrate), TiO2 Nanoparticles, and Chitosan Oligomers by Combining Electrospinning/Electrospraying and Impregnation. Several types of fibrous material containing poly(3-hydroxybutyrate) (PHB), nanosized TiO2 -anatase (nanoTiO2 ), and chitosan oligomers are prepared by combining the electrospinning, electrospraying, and impregnation techniques. Simultaneous electrospinning/electrospraying provides uniform distribution of electrosprayed nanoTiO2 along the PHB fibers and throughout the mat. Hybrid materials of different design manifest excellent photocatalytic activity, even after repeated use. They exhibit high bactericidal activity against Escherichia coli. In addition, the fibrous scaffolds are compatible with human mesenchymal stem cells and provide a favorable environment for their development. 23351040 How do metabolites differ from their parent molecules and how are they excreted? Understanding which physicochemical properties, or property distributions, are favorable for successful design and development of drugs, nutritional supplements, cosmetics, and agrochemicals is of great importance. In this study we have analyzed molecules from three distinct chemical spaces (i) approved drugs, (ii) human metabolites, and (iii) traditional Chinese medicine (TCM) to investigate four aspects determining the disposition of small organic molecules. First, we examined the physicochemical properties of these three classes of molecules and identified characteristic features resulting from their distinctive biological functions. For example, human metabolites and TCM molecules can be larger and more hydrophobic than drugs, which makes them less likely to cross membranes. We then quantified the shifts in physicochemical property space induced by metabolism from a holistic perspective by analyzing a data set of several thousand experimentally observed metabolic trees. Results show how the metabolic system aims to retain nutrients/micronutrients while facilitating a rapid elimination of xenobiotics. In the third part we compared these global shifts with the contributions made by individual metabolic reactions. For better resolution, all reactions were classified into phase I and phase II biotransformations. Interestingly, not all metabolic reactions lead to more hydrophilic molecules. We were able to identify biotransformations leading to an increase of logP by more than one log unit, which could be used for the design of drugs with enhanced efficacy. The study closes with the analysis of the physicochemical properties of metabolites found in the bile, faeces, and urine. Metabolites in the bile can be large and are often negatively charged. Molecules with molecular weight >500 Da are rarely found in the urine, and most of these large molecules are charged phase II conjugates. 23383594 An adsorbent performance indicator as a first step evaluation of novel sorbents for gas separations: application to metal-organic frameworks. An adsorbent performance indicator (API) is proposed in an effort to initially highlight porous materials of potential interest for PSA separation processes. This expression takes into account working capacities, selectivities, and adsorption energies and additionally uses weighting factors to reflect the specific requirements of a given process. To demonstrate the applicability of the API, we have performed the adsorption of carbon dioxide and methane at room temperature on a number of metal-organic frameworks, a zeolite and a molecular sieve carbon. The API is calculated for two different CO2/CH4 separation case scenarios: "bulk separation" and "natural gas purification". This comparison highlights how the API can be more versatile than previously proposed comparison factors for an initial indication of potential adsorbent performance. 23104245 Comparative study of equimolar doses of gamma-hydroxybutyrate (GHB), 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL) on catalepsy after acute and chronic administration. Gamma-hydroxybutyrate (GHB), and its precursors 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL) are known drugs of abuse. The ability of acute and chronic administration of equimolar doses of GHB (200mg/kg), 1,4-BD (174mg/kg) and GBL (166mg/kg) to produce catalepsy in male Swiss Webster mice was examined. GHB, 1,4-BD, GBL produced catalepsy when injected acutely. Drug treatment was then continued for 14days. Tolerance development was determined on days 6, 14, and challenged with a higher dose on day 15 in those chronically pretreated mice, and compared with naïve mice. Chronic GHB produced tolerance to catalepsy, as evidenced from area under the curve (AUC) of catalepsy versus time (min-sec) on days 6 (678±254), 14 (272±247), which were less than those on day 1 (1923±269). However, less tolerance was seen from GBL or 1,4-BD, as AUCs on days 6 and 14 were not significantly lower than that of day 1. In conclusion, although equimolar doses were used, expecting similar levels of GHB in the body, 1,4-BD and GBL shared only some of the in vivo effects of GHB. The rate of metabolic conversion of 1,4-BD and GBL into GHB might be responsible for the differences in the tolerance development to these drugs. 23122167 Schisarisanlactones A and B: a new class of nortriterpenoids from the fruits of Schisandra arisanensis. Two novel highly oxygenated nortriterpenoids, schisarisanlactones A (1) and B (2), have been isolated from the fruits of Schisandra arisanensis, an endemic plant of Taiwan. Compounds 1 and 2 possess an unprecedented 5/5/7/5/5-fused pentacyclic ring system. The structures of both compounds were determined on the basis of spectroscopic analyses, especially 2D NMR and MS. A plausible biogenetic pathway of 1 was proposed. Schisarisanlactone A (1) showed significant anti-HIV activity. 23430000 Inflammation and immune system interactions in atherosclerosis. Cardiovascular disease (CVD) is the leading cause of mortality worldwide, accounting for 16.7 million deaths each year. The underlying cause of the majority of CVD is atherosclerosis. In the past, atherosclerosis was considered to be the result of passive lipid accumulation in the vessel wall. Today's picture is far more complex. Atherosclerosis is considered a chronic inflammatory disease that results in the formation of plaques in large and mid-sized arteries. Both cells of the innate and the adaptive immune system play a crucial role in its pathogenesis. By transforming immune cells into pro- and anti-inflammatory chemokine- and cytokine-producing units, and by guiding the interactions between the different immune cells, the immune system decisively influences the propensity of a given plaque to rupture and cause clinical symptoms like myocardial infarction and stroke. In this review, we give an overview on the newest insights in the role of different immune cells and subtypes in atherosclerosis. 22614018 Promotion of DNA repair by nuclear IKKβ phosphorylation of ATM in response to genotoxic stimuli. Ataxia-telangiectasia mutated (ATM) is one of the key molecules involved in the cellular response to DNA damage. A portion of activated ATM is exported from the nucleus into the cytoplasm, where it activates the I kappa B kinase/nuclear factor kappa B (IKK/NF-κB) signaling pathway. It has been thought that activated IKKβ, which is a critical kinase for NF-κB activation, generally resides in the cytoplasm and phosphorylates cytoplasmic downstream molecules, such as IκBα. Here, we identified a new role for IKKβ during the response to DNA damage. ATM phosphorylation in response to alkylating agents consisted of two phases: the early phase (up to 3 h) and late phase (after 6 h). A portion of the activated IKKβ generated during the DNA damage response was found to translocate into the nucleus and directly phosphorylate ATM in the late phase. Furthermore, the phosphorylation of ATM by nuclear IKKβ was suggested to promote DNA repair. In parallel, activated IKKβ induced classical NF-κB activation and was involved in anti-apoptosis. Our findings define the function of IKKβ during the response to DNA damage, which promotes cell survival and DNA repair, and maintains cellular homeostasis. 23393217 Nurse-Community Health Worker Team Improves Diabetes Care in American Samoa: Results of a randomized controlled trial. OBJECTIVETo evaluate the effectiveness of a culturally adapted, primary care-based nurse-community health worker (CHW) team intervention to support diabetes self-management on diabetes control and other biologic measures.RESEARCH DESIGN AND METHODSTwo hundred sixty-eight Samoan participants with type 2 diabetes were recruited from a community health center in American Samoa and were randomly assigned by village clusters to the nurse-CHW team intervention or to a wait-list control group that received usual care.RESULTSParticipants had a mean age of 55 years, 62% were female, mean years of education were 12.5 years, 41% were employed, and mean HbA(1c) was 9.8% at baseline. At 12 months, mean HbA(1c) was significantly lower among CHW participants, compared with usual care, after adjusting for confounders (b = -0.53; SE = 0.21; P = 0.03). The odds of making a clinically significant improvement in HbA(1c) of at least 0.5% in the CHW group was twice the odds in the usual care group after controlling for confounders (P = 0.05). There were no significant differences in blood pressure, weight, or waist circumference at 12 months between groups.CONCLUSIONSA culturally adapted nurse-CHW team intervention was able to significantly improve diabetes control in the U.S. Territory of American Samoa. This represents an important translation of an evidence-based model to a high-risk population and a resource-poor setting. 23327794 Alkaloids from Microcos paniculata with cytotoxic and nicotinic receptor antagonistic activities. Microcos paniculata is a large shrub or small tree that grows in several countries in South and Southeast Asia. In the present study, three new piperidine alkaloids, microgrewiapines A-C (1-3), as well as three known compounds, inclusive of microcosamine A (4), 7'-(3',4'-dihydroxyphenyl)-N-[4-methoxyphenyl)ethyl]propenamide (5), and liriodenine (6), were isolated from cytotoxic fractions of the separate chloroform-soluble extracts of the stem bark, branches, and leaves of M. paniculata. Compounds 1-6 and 1a (microgrewiapine A 3-acetate) showed a range of cytotoxicity values against the HT-29 human colon cancer cell line. When evaluated for their effects on human α3β4 or α4β2 nicotinic acetylcholine receptors (nAChRs), several of these compounds were shown to be active as nAChR antagonists. As a result of this study, microgrewiapine A (1) was found to be a selective cytotoxic agent for colon cancer cells over normal colon cells and to exhibit nicotinic receptor antagonistic activity for both the hα3β4 and hα4β2 receptor subtypes. 23517379 Generating Long Supramolecular Pathways with a Continuous Density of States by Physically Linking Conjugated Molecules via Their End Groups. Self-assembly of conjugated 2,5-dialkoxy-phenylene-thienylene-based oligomers on epitaxial monolayer graphene was studied in ultrahigh vacuum by low-temperature scanning tunneling microscopy (STM). The formation of long one-dimensional (1D) supramolecular chain-like structures has been observed, associated to a physical linking of their ends which involved the rotation of the end thiophene rings in order to allow π-π stacking of these end-groups. dI/dV maps taken at an energy corresponding to the excited states showed a continuous electronic density of states, which tentatively suggests that within such molecular chains conjugation of electrons is preserved even across physically linked molecules. Thus, in a self-organization process conjugation may be extended by appropriately adapting conformations of neighboring molecules. Our STM results on such self-organized end-linked molecules potentially represent a direct visualization of J-aggregates. 23328127 Allele-Specific Transcriptional Activity at Type 2 Diabetes-Associated Single Nucleotide Polymorphisms in Regions of Pancreatic Islet Open Chromatin at the JAZF1 Locus. Translation of noncoding common variant association signals into meaningful molecular and biological mechanisms explaining disease susceptibility remains challenging. For the type 2 diabetes association signal in JAZF1 intron 1, we hypothesized that the underlying risk variants have cis-regulatory effects in islets or other type 2 diabetes-relevant cell types. We used maps of experimentally predicted open chromatin regions to prioritize variants for functional follow-up studies of transcriptional activity. Twelve regions containing type 2 diabetes-associated variants were tested for enhancer activity in 832/13 and MIN6 insulinoma cells. Three regions exhibited enhancer activity and only rs1635852 displayed allelic differences in enhancer activity; the type 2 diabetes risk allele T showed lower transcriptional activity than the nonrisk allele C. This risk allele showed increased binding to protein complexes, suggesting that it functions as part of a transcriptional repressor complex. We applied DNA affinity capture to identify factors in the complex and determined that the risk allele preferentially binds the pancreatic master regulator PDX1. These data suggest that the rs1635852 region in JAZF1 intron 1 is part of a cis-regulatory complex and that maps of open chromatin are useful to guide identification of variants with allelic differences in regulatory activity at type 2 diabetes loci. 22865292 The R740S mutation in the V-ATPase a3 subunit increases lysosomal pH, impairs NFATc1 translocation, and decreases in vitro osteoclastogenesis. Vacuolar H(+) -ATPase (V-ATPase), a multisubunit enzyme located at the ruffled border and in lysosomes of osteoclasts, is necessary for bone resorption. We previously showed that heterozygous mice with an R740S mutation in the a3 subunit of V-ATPase (+/R740S) have mild osteopetrosis resulting from an ∼90% reduction in proton translocation across osteoclast membranes. Here we show that lysosomal pH is also higher in +/R740S compared with wild-type (+/+) osteoclasts. Both osteoclast number and size were decreased in cultures of +/R740S compared with +/+ bone marrow cells, with concomitant decreased expression of key osteoclast markers (TRAP, cathepsin K, OSCAR, DC-STAMP, and NFATc1), suggesting that low lysosomal pH plays an important role in osteoclastogenesis. To elucidate the molecular mechanism of this inhibition, NFATc1 activation was assessed. NFATc1 nuclear translocation was significantly reduced in +/R740S compared with +/+ cells; however, this was not because of impaired enzymatic activity of calcineurin, the phosphatase responsible for NFATc1 dephosphorylation. Protein and RNA expression levels of regulator of calcineurin 1 (RCAN1), an endogenous inhibitor of NFATc1 activation and a protein degraded in lysosomes, were not significantly different between +/R740S and +/+ osteoclasts, but the RCAN1/NFATc1 ratio was significantly higher in +/R740S versus +/+ cells. The lysosomal inhibitor chloroquine significantly increased RCAN1 accumulation in +/+ cells, consistent with the hypothesis that higher lysosomal pH impairs RCAN1 degradation, leading to a higher RCAN1/NFATc1 ratio and consequently NFATc1 inhibition. Our data indicate that increased lysosomal pH in osteoclasts leads to decreased NFATc1 signaling and nuclear translocation, resulting in a cell autonomous impairment of osteoclastogenesis in vitro. 23293964 Single-molecule force spectroscopy identifies a small cold shock protein as being mechanically robust. Single-molecule force spectroscopy has emerged as a powerful approach to examine the stability and dynamics of single proteins. We have completed force extension experiments on the small cold shock protein B from Thermotoga maritima, using a specially constructed chimeric polyprotein. The protein's simple topology, which is distinct from the mechanically well-characterized β-grasp and immunoglobulin (Ig)-like folds, in addition to the wide range of structural homologues resulting from its ancient origin, provides an attractive model protein for single-molecule force spectroscopy studies. We have determined that the protein has mechanical stability, unfolding at greater than 70 pN at a pulling velocity of 100 nm s(-1). We reveal features of the unfolding energy landscape by measuring the dependence of the mechanical stability on pulling velocity, in combination with Monte Carlo simulations. We show that the cold shock protein has mechanically robust, yet malleable, features that may be important in providing the protein with stability and flexibility to function over a range of environmental conditions. These results provide insights into the relationship between the secondary structure and topology of a protein and its mechanical strength. This lays the foundation for the investigation of the effects of changes in environmental conditions on the mechanical and dynamic properties of cold shock proteins. 23438106 Consequences of Membrane Topography. The surface of mammalian cells is neither smooth nor flat and cells have several times more plasma membrane than the minimum area required to accommodate their shape. We discuss the biological function of this apparent excess membrane that allows the cells to migrate, undergo shape changes and probably plays a role in signal transduction. Methods for studying membrane folding and topography; atomic force microscopy, scanning ion conductance microscopy, fluorescence polarisation microscopy and linear dichroism, are described and evaluated. Membrane folding and topography is frequently ignored when interpreting microscopy data. This has resulted in several misconceptions for instance regarding colocalisation, membrane organisation and molecular clustering. We suggest simple ways to avoid these pitfalls and invoke Occam's razor - that simple explanations are preferable to complex ones. Topography, i. e. deviations from a smooth surface, should always be ruled out as the cause of anomalous data before other explanations are presented. © 2013 The Authors Journal compilation © 2013 FEBS. 22846225 Matching biochemical and functional efficacies confirm ZIP as a potent competitive inhibitor of PKMζ in neurons. PKMζ is an autonomously active, atypical protein kinase C (aPKC) isoform that is both necessary and sufficient for maintaining long-term potentiation (LTP) and long-term memory. The myristoylated ζ-pseudosubstrate peptide, ZIP, potently inhibits PKMζ biochemically in vitro, within cultured cells, and within neurons in hippocampal slices, and reverses LTP maintenance and erases long-term memory storage. A recent study (Wu-Zhang et al., 2012), however, suggested ZIP was not effective on a PKMζ fusion protein overexpressed in cultured cells. Chelerythrine, a redox-sensitive PKC inhibitor that inhibits PKMζ and disrupts LTP maintenance and memory storage, was also reported by Wu-Zhang et al. (2012) not to inhibit the expressed PKMζ fusion protein. However, the efficacy of inhibitors on endogenous enzymes in cells may not be adequately assessed in expression systems in which levels of expression of exogenous enzymes greatly exceed those of endogenous enzymes. Thus, we show, biochemically, that when PKMζ reaches a level beyond that necessary for substrate phosphorylation such that much of the enzyme is excess or 'spare' kinase, ZIP and chelerythrine do not effectively block substrate phosphorylation. We also show that the cellular overexpression techniques used by Wu-Zhang et al. (2012) increase kinase levels ~30-40 fold above normal levels in transfected cells. Using a mathematical model we show that at such level of overexpression, standard concentrations of inhibitor should have no noticeable effect. Furthermore, we demonstrate the standard concentrations of ZIP, but not scrambled ZIP, inhibit the ability of PKMζ to potentiate AMPAR responses at postsynaptic sites, the physiological function of the kinase. Wu-Zhang et al. (2012) had also claimed that staurosporine, a general kinase inhibitor that does not effectively inhibit PKMζ biochemically in vitro, nonetheless indirectly blocked the PKMζ fusion protein overexpressed in cultured cells by inhibiting phosphoinositide-dependent protein kinase-1 (PDK1). However, here we show that staurosporine does not affect PDK1 phosphorylation of the endogenous PKMζ in hippocampal slices. Thus, the biochemical in vitro effects of PKMζ inhibitors correspond with their intracellular effects, and ZIP and chelerythrine, together with scrambled ZIP and staurosporine as controls, are effective tools to examine the function of PKMζ in neurons. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23638621 A prospective, randomised, investigator-blind, controlled, clinical study on the clinical efficacy and tolerability of two highly purified hMG preparations administered subcutaneously in women undergoing IVF. Abstract The aim of this multicentre, prospective, randomised, investigator blind, controlled clinical trial was to evaluate the clinical efficacy and tolerability of a highly purified human menopausal gonadotrophin (hMG) preparation (Merional-HG) when administered to patients undergoing controlled ovarian stimulation (COS) for in-vitro fertilisation (IVF) procedure enrolled in hospital departments. One hundred fifty-seven patients were randomised in two parallel groups: 78 started COS with Merional-HG and 79 with Menopur. Results of the study showed that both highly purified hMG preparations were equivalent in terms of number of oocytes retrieved (primary endpoint: 8.8 ± 3.9 versus 8.4 ± 3.8, p = 0.54). In the patients treated with Merional-HG, we observed a higher occurrence of mature oocytes (78.3% versus 71.4%, p = 0.005) and a reduced quantity of gonadotrophins administered per cycle (2.556 ± 636 IU versus 2.969 ± 855 IU, p < 0.001). Fertilisation, cleavage, implantation rates and the number of positive β-human chorionic gonadotrophin (hCG; pregnancy) tests and the clinical pregnancy rate were comparable in the two groups. Both treatments were well tolerated. In conclusion, the results of this study support the efficacy and safety of Merional-HG administered subcutaneously for assisted reproduction techniques. Efficiency of Merional-HG appears to be higher due to reduced quantity of drug used and the higher yield of mature oocytes retrieved. 23395663 Lactose substituted zinc phthalocyanine: a near infrared fluorescence imaging probe for liver cancer targeting. A near infrared fluorescence probe, lactose substituted zinc phthalocyanine, [2,9(10),16(17),23(24)-tetrakis((1-(β-d-lactose-2-yl)-1H-1,2,3-triazol-4-yl)methoxyl)phthalocyaninato] zinc(II), was synthesized via click reaction. Structural characterization and optical experiment demonstrated its excellent biocompatibility and fluorescence imaging ability. Near infrared fluorescence imaging in vivo for liver cancer, lung cancer and melanoma cancer with tumor bearing nude mice as models demonstrated that lactose substituted zinc phthalocyanine has specifically targeting ability to liver cancer while no targeting to lung cancer or melanoma, which implied its potential in liver cancer diagnosis as a near infrared optical probe. 22966070 Tub has a key role in insulin and leptin signaling and action in vivo in hypothalamic nuclei. Mutation of tub gene in mice induces obesity, suggesting that tub could be an important regulator of energy balance. In the current study, we investigated whether insulin, leptin, and obesity can modulate Tub in vivo in hypothalamic nuclei, and we investigated possible consequences on energy balance, neuropeptide expression, and hepatic glucose metabolism. Food intake, metabolic characteristics, signaling proteins, and neuropeptide expression were measured in response to fasting and refeeding, intracerebroventricular insulin and leptin, and Tub antisense oligonucleotide (ASO). Tub tyrosine phosphorylation (Tub-p-tyr) is modulated by nutritional status. Tub is a substrate of insulin receptor tyrosine kinase (IRTK) and leptin receptor (LEPR)-Janus kinase 2 (JAK2) in hypothalamic nuclei. After leptin or insulin stimulation, Tub translocates to the nucleus. Inhibition of Tub expression in hypothalamus by ASO increased food intake, fasting blood glucose, and hepatic glucose output, decreased O(2) consumption, and blunted the effect of insulin or leptin on proopiomelanocortin, thyroid-releasing hormone, melanin-concentrating hormone, and orexin expression. In hypothalamus of mice administered a high-fat diet, there is a reduction in leptin and insulin-induced Tub-p-tyr and nuclear translocation, which is reversed by reducing protein tyrosine phosphatase 1B expression. These results indicate that Tub has a key role in the control of insulin and leptin effects on food intake, and the modulation of Tub may contribute to insulin and leptin resistance in DIO mice. 23154865 Enhanced heterodimerization of Bax by Bcl-2 mutants improves irradiated cell survival. B Cell Lymphoma-2 (Bcl-2) protein suppresses ionizing radiation-induced apoptosis in hemato-lymphoid system. To enhance the survival of irradiated cells, we have compared the effects and mechanism of Bcl-2 and its functional variants, D34A (caspase-3 resistant) and S70E (mimics phosphorylation on S70). Bcl-2 and its mutants were transfected into hematopoietic cell line and assessed for cell survival, clonogenicity and cell cycle perturbations upon exposure to ionizing radiation. The electrostatic potential of BH3 cleft of Bcl-2/mutants and their heterodimerization with Bcl-2 associated X protein (Bax) were computationally evaluated. Correspondingly, these results were verified by co-immunoprecipitation and western blotting. The mutants afford higher radioprotective effect than Bcl-2 in apoptotic and clonogenic assays at D(0) (radiation dose at which 37 % cell survival was observed). The computational and functional analysis indicates that mutants have higher propensity to neutralize Bax protein by heterodimerization and have increased caspase-9 suppression capability, which is responsible for enhanced survival. This study implies potential of Bcl-2 mutants or their chemical/peptide mimics to elicit radioprotective effect in cells exposed to radiation. 23566269 4-Hydroxypyridazin-3(2H)-one Derivatives as Novel d-Amino Acid Oxidase Inhibitors. d-Amino acid oxidase (DAAO) catalyzes the oxidation of d-amino acids including d-serine, a coagonist of the N-methyl-d-aspartate receptor. We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel DAAO inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information. 3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human DAAO in enzyme- and cell-based assays. We further designed and synthesized 4-hydroxypyridazin-3(2H)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze. 23349498 A link between GIP and osteopontin in adipose tissue and insulin resistance. Low grade inflammation in obesity is associated with accumulation of the macrophagederived cytokine osteopontin in adipose tissue and induction of local as well as systemic insulin resistance. Since GIP (glucose-dependent insulinotropic polypeptide) is a strong stimulator of adipogenesis and may play a role in the development of obesity, we explored whether GIP directly would stimulate osteopontin (OPN) expression in adipose tissue and thereby induce insulin resistance. GIP stimulated OPN protein expression in a dose-dependent fashion in rat primary adipocytes. The level of OPN mRNA was higher in adipose tissue of obese individuals (0.13±}0.04 vs 0.04±}0.01, P<0.05) and correlated inversely with measures of insulin sensitivity (r=-0.24, P=0.001). A common variant of the GIP receptor (GIPR) (rs10423928) gene was associated with lower amount of the exon 9 containing isoform required for transmembrane activity. Carriers of the A-allele with a reduced receptor function showed lower adipose tissue OPN mRNA levels and better insulin sensitivity. Together, these data suggest a role for GIP not only as an incretin hormone, but also as a trigger of inflammation and insulin resistance in adipose tissue. Carriers of GIPR rs10423928 A-allele showed protective properties via reduced GIP effects. Identification of this unprecedented link between GIP and OPN in adipose tissue might open new avenues for therapeutic interventions. 23266311 The venom optimization hypothesis revisited. Animal venoms are complex chemical mixtures that typically contain hundreds of proteins and non-proteinaceous compounds, resulting in a potent weapon for prey immobilization and predator deterrence. However, because venoms are protein-rich, they come with a high metabolic price tag. The metabolic cost of venom is sufficiently high to result in secondary loss of venom whenever its use becomes non-essential to survival of the animal. The high metabolic cost of venom leads to the prediction that venomous animals may have evolved strategies for minimizing venom expenditure. Indeed, various behaviors have been identified that appear consistent with frugality of venom use. This has led to formulation of the "venom optimization hypothesis" (Wigger et al. (2002) Toxicon 40, 749-752), also known as "venom metering", which postulates that venom is metabolically expensive and therefore used frugally through behavioral control. Here, we review the available data concerning economy of venom use by animals with either ancient or more recently evolved venom systems. We conclude that the convergent nature of the evidence in multiple taxa strongly suggests the existence of evolutionary pressures favoring frugal use of venom. However, there remains an unresolved dichotomy between this economy of venom use and the lavish biochemical complexity of venom, which includes a high degree of functional redundancy. We discuss the evidence for biochemical optimization of venom as a means of resolving this conundrum. 23295229 Fluorescence lifetime analysis and effect of magnesium ions on binding of NADH to human aldehyde dehydrogenase 1. Aldehyde dehydrogenase 1 (ALDH1A1) catalyzes the oxidation of toxic aldehydes to carboxylic acids. Physiologic levels of Mg(2+) ions decrease ALDH1 activity in part by increasing NADH binding affinity to the enzyme. By using time-resolved fluorescence spectroscopy, we have resolved the fluorescent lifetimes (τ) of free NADH in solution (τ=0.4 ns) and two enzyme-bound NADH states (τ=2.0 ns and τ=7.7 ns). We used this technique to investigate the effects of Mg(2+) ions on the ALDH1A1-NADH binding characteristics and enzyme catalysis. From the resolved free and bound NADH fluorescence signatures, the KD values for both NADH conformations in ALDH1A1 ranged from about 24 μM to 1 μM for Mg(2+) ion concentrations of 0-6000 μM, respectively. The rate constants for dissociation of the enzyme-NADH complex ranged from 0.03 s(-1) (6000 μM Mg(2+)) to 0.30s(-1) (0 μM Mg(2+)) as determined by addition of excess NAD(+) to prevent re-association of NADH and resolving the real-time NADH fluorescence signal. During the initial reaction of enzyme with NAD(+) and butyraldehyde, there was an immediate rise in the NADH fluorescence, due to the formation of bound NADH complexes, with a constant steady-state rate of production of free NADH. As the Mg(2+) ion concentration was increased, there was a consistent decrease of the enzyme catalytic turnover from 0.31 s(-1) (0 μM Mg(2+)) to 0.050 s(-1) (6000 μM Mg(2+)) and a distinct shift in steady-state conformational population from one that favors the ALDH1-NADH complex with the shorter fluorescence lifetime (33% excess) in the absence of magnesium ion to one that favors the ALDH1-NADH complex with the longer fluorescence lifetime (13% excess) at 6000 μM Mg(2+). This shift in conformational population at higher Mg(2+) ion concentrations and to lower enzyme activity may be due to longer residence time of the NADH in the ALDH1 pocket. The results from monitoring enzyme catalysis in the absence of magnesium suggests that the ALDH1-NADH complex with the shorter fluorescence lifetime is the form initially produced, and the complex with the longer fluorescence lifetime is produced through isomerization. 23382380 Reconstitution of homomeric GluA2(flop) receptors in supported lipid membranes: functional and structural properties. AMPA receptors (AMPARs) are glutamate-gated ion channels ubiquitous in the vertebrate central nervous system, where they mediate fast excitatory neurotransmission and act as molecular determinants of memory formation and learning. Together with detailed analyses of individual AMPAR domains, structural studies of full-length AMPARs by electron microscopy and x-ray crystallography have provided important insights into channel assembly and function. However, the correlation between the structure and functional states of the channel remains ambiguous particularly because these functional states can be assessed only with the receptor bound within an intact lipid bilayer. To provide a basis for investigating AMPAR structure in a membrane environment, we developed an optimized reconstitution protocol using a receptor whose structure has previously been characterized by electron microscopy. Single-channel recordings of reconstituted homomeric GluA2(flop) receptors recapitulate key electrophysiological parameters of the channels expressed in native cellular membranes. Atomic force microscopy studies of the reconstituted samples provide high-resolution images of membrane-embedded full-length AMPARs at densities comparable to those in postsynaptic membranes. The data demonstrate the effect of protein density on conformational flexibility and dimensions of the receptors and provide the first structural characterization of functional membrane-embedded AMPARs, thus laying the foundation for correlated structure-function analyses of the predominant mediators of excitatory synaptic signals in the brain. 23194543 Effect of dry heating with ionic gums on physicochemical properties of starch. Corn starch, potato starch, pea starch were impregnated with ionic gums (sodium alginate, CMC, and xanthan, 1% based on starch solids) and heat-treated in a dry state for 0, 2, or 4 h at 130°C. Effects of the dry heating on paste viscosity (RVA), microstructure and thermal properties were examined. Dry heat treatment with ionic gums reduced the pasting temperature of the three starches. Heating with xanthan increased the paste viscosity of corn and potato starch. With heat treatment, the paste viscosity of all the starch-sodium alginate mixtures decreased. Heating with CMC increased the paste viscosity of potato starch, but decreased that of corn and pea starch. After dry-heating, To, Tp and Tc of potato starch with ionic gums decreased significantly. SEM of potato starch with CMC showed that the gel structure got compacter after drying-heating. Heat treatment obviously improved the functional properties of the three starches. 22614019 The Grainyhead transcription factor Grhl3/Get1 suppresses miR-21 expression and tumorigenesis in skin: modulation of the miR-21 target MSH2 by RNA-binding protein DND1. Epidermal differentiation and stratification, crucial for barrier formation, are regulated by a complex interplay of transcription factors, including the evolutionarily conserved Grainyhead-like 3 (Grhl3/Get1); Grhl3-deleted mice exhibit impaired epidermal differentiation and decreased expression of multiple differentiation genes. To test whether Grhl3 regulates epidermal genes indirectly by controlling the expression of specific microRNAs (miRs), we performed miR profiling and identified 11 miRs that are differentially regulated in Grhl3(-/-) skin, one of which is miR-21, previously shown to be upregulated in diseased skin, including in psoriasis and squamous cell skin cancer. We found that miR-21 is normally expressed in the post-mitotic suprabasal layers of the epidermis, overlapping with Grhl3. The miR-21 promoter is bound and repressed by Grhl3 indicating that these two factors are involved in a regulatory loop maintaining homeostasis in the epidermis. Although miR-21 overexpression in normal keratinocytes had mild effects on the expression of several known miR-21 targets, an enhanced downregulation of the miR-21 tumor-related targets, including MSH2, was observed in Ras-transformed keratinocytes. The increased sensitivity of transformed keratinocytes to miR-21's effects occurs in part through downregulation of the RNA-binding protein DND1 during the transformation process. Additionally, we observed increased tumorigenesis in mice subcutaneously injected with transformed keratinocytes lacking Grhl3. These findings indicate that decreased Grhl3 expression contributes to tumor progression and upregulation of the oncomir miR-21 in squamous cell carcinoma of the skin. 23356740 A comparison of the signalling properties of two tyramine receptors from Drosophila. In invertebrates, the phenolamines, tyramine and octopamine, mediate many functional roles usually associated with the catecholamines, noradrenaline and adrenaline, in vertebrates. The α- and β-adrenergic classes of insect octopamine receptor are better activated by octopamine than tyramine. Similarly, the Tyramine 1 subgroup of receptors (or Octopamine/Tyramine receptors) are better activated by tyramine than octopamine. However, recently, a new Tyramine 2 subgroup of receptors was identified, which appears to be activated highly preferentially by tyramine. We examined immunocytochemically the ability of CG7431, the founding member of this subgroup from Drosophila melanogaster, to be internalized in transfected Chinese hamster ovary (CHO) cells by different agonists. It was only internalized after activation by tyramine. Conversely, the structurally related receptor, CG16766, was internalized by a number of biogenic amines, including octopamine, dopamine, noradrenaline, adrenaline, which also were able to elevate cyclic AMP levels. Studies with synthetic agonists and antagonists confirm that CG16766 has a different pharmacological profile to that of CG7431. Species orthologues of CG16766 were only found in Drosophila species, whereas orthologues of CG7431 could be identified in the genomes of a number of insect species. We propose that CG16766 represents a new group of tyramine receptors, which we have designated the Tyramine 3 receptors. 23441878 Probing the Photoisomerization of CHBr3 and CHI3 in Solution with Transient Vibrational and Electronic Spectroscopy. Transient infrared absorption spectroscopy monitors condensed-phase photodissociation dynamics of 30 mM CHBr3 and 50 mM CHI3 in liquid CCl4. The experiments have picosecond time resolution and monitor the C-H stretch region of both the parent polyhalomethanes and their photolytically generated isomers. The C-H stretching transitions of these isomers, in which the emergent halogen atom returns to form a C-X-X bonding motif, appear about 9 ps after photolysis for iso-CHBr2-Br and in about 46 ps for iso-CHI2-I. These time scales are consistent with, but differ from, the time evolution of the transient electronic absorption spectra of the same samples, highlighting the subtle differences between monitoring the vibrational and electronic chromophores. The specificity of using vibrational transitions to track condensed-phase reaction dynamics permits reassessment of the transient electronic spectrum of photolysis in neat CHBr3, which has an additional prompt feature near 400 nm. Calculations show that this feature, which arises from a precursor to the isomer, is a charge-transfer transition of a contact pair between the nascent Br fragment and a nearby CHBr3 molecule. Dilution and solvent studies show that transition is independent of the solvent. The iso-CHBr2-Br transition wavelength, however, shifts over the range of 400 to 510 nm depending on the solvent. Time-dependent density functional calculations faithfully reproduce these trends. 23122136 Degradation kinetics of anthocyanins in acerola pulp: comparison between ohmic and conventional heat treatment. Degradation kinetics of monomeric anthocyanins in acerola pulp during thermal treatment by ohmic and conventional heating was evaluated at different temperatures (75-90°C). Anthocyanin degradation fitted a first-order reaction model and the rate constants ranged from 5.9 to 19.7 × 10(-3)min(-1). There were no significant differences between the rate constants of the ohmic and the conventional heating processes at all evaluated temperatures. D-Values ranged from 116.7 to 374.5 for ohmic heating and from 134.9 to 390.4 for conventional heating. Values of the free energy of inactivation were within the range of 100.19 and 101.35 kJ mol(-1). The enthalpy of activation presented values between 71.79 and 71.94 kJ mol(-1) and the entropy of activation ranged from -80.15 to -82.63 J mol(-1)K(-1). Both heating technologies showed activation energy of 74.8 kJ mol(-1) and close values for all thermodynamic parameters, indicating similar mechanisms of degradation. 23261527 Emerging targets in lipid-based therapy. The use of prostaglandins and NSAIDS in the clinic has proven that lipid mediators and their associated pathways make attractive therapeutic targets. When contemplating therapies involving lipid pathways, several basic agents come to mind. There are the enzymes and accessory proteins that lead to the metabolism of lipid substrates, provided through diet or through actions of lipases, the subsequent lipid products, and finally the lipid sensors or receptors. There is abundant evidence that molecules along this lipid continuum can serve as prognostic and diagnostic indicators and are in fact viable therapeutic targets. Furthermore, lipids themselves can be used as therapeutics. Despite this, the vernacular dialog pertaining to "biomarkers" does not routinely include mention of lipids, though this is rapidly changing. Collectively these agents are becoming more appreciated for their respective roles in diverse disease processes from cancer to preterm labor and are receiving their due appreciation after decades of ground work in the lipid field. By relating examples of disease processes that result from dysfunction along the lipid continuum, as well as examples of lipid therapies and emerging technologies, this review is meant to inspire further reading and discovery. 23563055 A possible role of partially pyrolysed essential oils in Australian Aboriginal traditional ceremonial and medicinal smoking applications of Eremophila longifolia (R. Br.) F. Muell (Scrophulariaceae). ETHNOPHARMACOLOGICAL SIGNIFICANCE: Eremophila longifolia is one of the most respected of the traditional medicines used by Australian Aboriginal people. Customary use involves smoldering the leaves over hot embers of a fire to produce an acrid smoke, believed to have therapeutic effects broadly consistent with antimicrobial, antifungal and anti-inflammatory capacity. AIM OF THE STUDY: The current study aims to examine the contribution of partially pyrolysed and non-pyrolysed essential oils in traditional usage of Eremophila longifolia. MATERIALS AND METHODS: Non-pyrolysed and partially pyrolysed essential oils were produced by hydrodistillation and part-wet/part-dry distillation, respectively. All samples were tested for antimicrobial activity by broth dilution. Some of these samples were further treated to an incrementally stepped temperature profile in a novel procedure employing a commercial thermocycler in an attempt to mimic the effect of temperature gradients produced during smoking ceremonies. Components from the pyrodistilled oils were compared with the non-pyrodistilled oils, using GC-MS, GC-FID and HPLC-PAD. The 2,2-diphenyl-1-picrylhydrazyl method, was used to compare free radical scavenging ability. RESULTS: Partially pyrolysed oils had approximately three or more times greater antimicrobial activity, enhanced in cultures warmed incrementally to 60°C and held for 30s and further enhanced if held for 2min. Partially pyrolysed oils showed a radical scavenging capacity 30-700 times greater than the corresponding non-pyrolysed oils. HPLC-PAD revealed the presence of additional constituents not present in the fresh essential oil. CONCLUSION: These results, by showing enhanced antimicrobial and antioxidant activities, provide the first known Western scientific justification for the smoking ceremonies involving leaves of Eremophila longifolia. During customary use, both partially pyrolysed as well as non-pyrolysed essential oils may contribute significantly to the overall intended medicinal effect. 23411076 Design, synthesis and structure-activity relationship of rhenium 2-arylbenzothiazoles as β-amyloid plaque binding agents. To continue our efforts toward the development of (99m)Tc PiB analogs, we have synthesized 24 neutral and lipophilic Re (as a surrogate of (99m)Tc) 2-arylbenzothiazoles, and explored their structure-activity relationship for binding to Aβ1-40 fibrils. These Re complexes were designed and synthesized via the integrated approach, so their (99m)Tc analogs would have a greater chance of crossing the blood-brain barrier. While the lipophilicities (logPC18=1.59-3.53) of these Re 2-arylbenzothiazoles were all within suitable range, their binding affinities (Ki=30-617nM) to Aβ1-40 fibrils varied widely depending on the selection and integration of the tetradentate chelator into the 2-phenylbenzothiazole pharmacophore. For potential clinical applications, further refinement to obtain Re 2-arylbenzothiazoles with better binding affinities (<10nM) will likely be needed. The integrated approach reported here to generate compact, neutral and lipophilic Re 2-arylbenzothiazoles could be applied to other potent pharmacophores as well to convert other current Aβ PET tracers to their (99m)Tc analogs for more widespread application via the use of SPECT scanners. 23395165 The Hunger Games: p53 regulates metabolism upon serine starvation. Cancer cells reprogram their metabolism to support a high proliferative rate. A new study shows that, upon serine starvation, the tumor suppressor p53 activates p21 to shift metabolic flux from purine biosynthesis to glutathione production, which enhances cellular proliferation and viability by combating ROS (Maddocks et al., 2013). 23153057 Assessment of cytochrome P450 (1A2, 2B6, 2C9 and 3A4) induction in cryopreserved human hepatocytes cultured in 48-well plates using the cocktail strategy. 1. A fast, straightforward and cost-effective assay was validated for the assessment of CYP induction in cryopreserved human hepatocytes cultured in 48-well plates. The cocktail strategy (in situ incubation) was used to assess the induction of CYP1A2, CYP2B6, CYP2C9 and CYP3A4 by using the recommended probe substrate, i.e. phenacetin, bupropion, diclofenac and midazolam, respectively. 2. Cryopreserved human hepatocytes were treated for 72 h with prototypical reference inducers, β-naphthoflavone (25 µM), phenobarbital (500 µM) and rifampicin (10 µM) as positive controls for CYP induction. The use of a cocktail strategy has been validated and compared to the classical approach (single incubation). The need of using phase II inhibitor (salicylamide) in CYP induction assay was also investigated. 3. By using three different batches of cryopreserved human hepatocytes and our conditions of incubations, we showed that there was no relevant drug-drug interaction using the cocktail strategy. The same conclusions were observed when a broad range of enzyme activity has to be assessed (wide range of reference inducers, i.e. EC50-Emax experiment). In addition, the interassay reproducibility assessment showed that the day-to-day variability was minimal. 4. In summary, the study showed that the conditions used (probe substrates, concentration of probe substrate and time of incubation) for the cocktail approach were appropriate for investigations of CYP induction potential of new chemical entities. In addition, it was also clear that the use of salicylamide in the incubation media was not mandatory and could generate drug-drug interactions. For this reason, we recommend to not use salicylamide in CYP induction assay. 23567293 Inhibition of proteases as a novel therapeutic strategy in the treatment of metabolic, inflammatory and functional diseases of the gastrointestinal tract. Proteases are widely distributed in the human body and are crucially involved in the modulation of physiological processes in the gastrointestinal (GI) tract. They also have a major role in the etiology and the course of GI diseases. This review discusses the pharmacology of proteases and medical application of their inhibitors in the GI tract. In particular, we focus on metabolic disorders, such as diabetes type 2, inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS) and abdominal pain. Based on recent papers in the field of pharmacology and documented clinical trials, we suggest future treatment options employing protease inhibitors. 23463732 Cyclodextrin Insulation Prevents Static Quenching of Conjugated Polymer Fluorescence at the Single Molecule Level. Conjugated polymers (CPs) are promising materials for fluorescence imaging application. However, a significant problem in this field is the unexplained abnormally low fluorescence brightness (or number of fluorescence photons detected per one excitation photon) exhibited by most of CP single chains in solid polymer hosts. Here it is shown that this detrimental effect can be fully avoided for short chains of polyfluorene-bis-vinylphenylene (PFBV) embedded in a host polymer matrix of PMMA, if the conjugated backbone is insulated by cyclodextrin rings to form a polyrotaxane (PFBV-Rtx). Fluorescence kinetics and quantum yields are measured for the polymers in liquid solutions, pristine films, and solid PMMA blends. The fluorescence brightness of PFBV-Rtx single chains dispersed in a solid PMMA is very close to that expected for a chain with 100% fluorescence quantum yield, while the unprotected PFBV chains of the same length possess 4 times lower brightness. Despite this, the fluorescence decay kinetics are the same for both polymers, suggesting the presence of static or ultrafast fluorescence quenching in the unprotected polymer. About 80% of an unprotected PFBV chain is estimated to be completely quenched. The hypothesis is that the cyclodextrin rings prevent the quenching by working as 'bumpers' reducing the mechanical forces applied by the host polymer to the conjugated backbone and help retaining its conformational freedom. While providing a recipe for making CP fluorescence bright at the single-molecule level, these results identify a lack of fundamental understanding in the community of the influence of the environment on excited states in conjugated materials. 23400796 The accumulation of metal (Co, Cr, Cu, Mn and Zn) in freshwater Ulva (Chlorophyta) and its habitat. The possibility of using freshwater Ulva (Chlorophyta) as a bioaccumulator of metals (Co, Cr, Cu, Mn and Zn) in lake and river water was examined weekly in the summer of 2010 in three types of samples: the water, the sediment and the thalli of Ulva. Samples of freshwater Ulva were collected from two aqueous ecosystems lie 250 km away from the basin of the Baltic Sea and 53 km from each other. A flow lake located in the centre of the big city was the first water reservoir (ten sites) and second, the suburban river (six sites). The mean metal concentrations in the Ulva tissue from the river and the lake decreased in the following order: Mn > Zn > Cr > Cu > Co and Mn > Cr > Zn > Cu > Co, respectively. Moreover, a negative and statistically significant correlation between Mn concentrations in the Ulva thalli and the river water was observed. Additionally, numerous correlations were noted between the different concentrations of metals within the Ulva thalli, in the water and in the sediment. The great concentrations of Mn and Zn and the smallest of Co were found in thalli of Ulva, irrespective of the type of the ecosystem from which samples of algal thalli originated. Freshwater Ulva populations examined in this study were clearly characterized a dozen or so times by the higher Mn and Cr accumulation than taxa from that genera coming from sea ecosystems. The calculated bioconcentration factor confirm the high potential for freshwater Ulva to be a bioaccumulator of trace metals in freshwater ecosystems. 23262203 Plasmonic photothermal therapy increases the tumor mass penetration of HPMA copolymers. Effective drug delivery to tumors requires both transport through the vasculature and tumor interstitium. Previously, it was shown that gold nanorod (GNR) mediated plasmonic photothermal therapy (PPTT) is capable of increasing the overall accumulation of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers in prostate tumors. In the present study, it is demonstrated that PPTT is also capable of increasing the distribution of these conjugates in tumors. Gadolinium labeled HPMA copolymers were administered to mice bearing prostate tumors immediately before treatment of the right tumor with PPTT. The left tumor served as internal, untreated control. Magnetic resonance imaging (MRI) of both tumors showed that PPTT was capable of improving the tumor mass penetration of HPMA copolymers. Thermal enhancement of delivery, roughly 1.5-fold, to both the tumor center and periphery was observed. Confocal microscopy of fluorescently labeled copolymers corroborates these findings in that PPTT is capable of delivering more HPMA copolymers to the tumor's center and periphery. These results further demonstrate that PPTT is a useful tool to improve the delivery of polymer-drug conjugates. 23001428 Chronic toxicity of tire and road wear particles to water- and sediment-dwelling organisms. Tire and road wear particles (TRWP) consist of a complex mixture of rubber, and pavement released from tires during use on road surfaces. Subsequent transport of the TRWP into freshwater sediments has raised some concern about the potential adverse effects on aquatic organisms. Previous studies have shown some potential for toxicity for tread particles, however, toxicity studies of TRWP collected from a road simulator system revealed no acute toxicity to green algae, daphnids, or fathead minnows at concentrations up to 10,000 mg/kg under conditions representative of receiving water bodies. In this study, the chronic toxicity of TRWP was evaluated in four aquatic species. Test animals were exposed to whole sediment spiked with TRWP at concentrations up to 10,000 mg/kg sediment or elutriates from spiked sediment. Exposure to TRWP spiked sediment caused mild growth inhibition in Chironomus dilutus but had no adverse effect on growth or reproduction in Hyalella azteca. Exposure to TRWP elutriates resulted in slightly diminished survival in larval Pimephales promelas but had no adverse effect on growth or reproduction in Ceriodaphnia dubia. No other endpoints in these species were affected. These results, together with previous studies demonstrating no acute toxicity of TRWP, indicate that under typical exposure conditions TRWP in sediments pose a low risk of toxicity to aquatic organisms. 22623520 Acute effects of methiocarb on oxidative damage and the protective effects of vitamin E and taurine in the liver and kidney of Wistar rats. Methiocarb (MC) is a widely used carbamate pesticide in agriculture and health programs. Although the main molecular mechanism of carbamate toxicity involves acetylcholinesterase inhibition, studies have also implicated the induction of oxidative stress. Therefore, the present study was aimed to evaluate the effect of acute MC exposure on lipid peroxidation, antioxidant defense systems, histological changes in Wistar rats and the protective effect of pretreatment with vitamin E and taurine. A total of 48 rats were randomly divided into six groups. Rats in group I were given corn oil, while those in group III were dosed with vitamin E (100 mg/kg body weight (b.w.)) and in group V were dosed with taurine (50 mg/kg b.w.). Rats in group II were administered with MC only (25 mg/kg b.w., 1/4 of median lethal dose (LD(50))), while those in groups IV and VI were pretreated with vitamin E (100 mg/kg b.w.) and taurine (50 mg/kg b.w.) for 20 days, respectively, and then exposed to MC (25 mg/kg b.w.). The rats administered with MC showed significant increase in the levels of malondialdehyde in the liver and kidney as an index of lipid peroxidation. Levels of glutathione and activities of superoxide dismutase, catalase and glutathione peroxidase were significantly increased, while activity of glutathione reductase remained unchanged in both the tissues after MC treatment. Mild degenerative histological changes were observed in liver tissue, while the changes in kidney tissue were more severe then liver after MC treatment. Pretreatment with vitamin E and taurine resulted in a significant decrease in the lipid peroxidation and alleviating effects on antioxidant defense systems in both the tissues, while protective effects on the histological changes were shown only in kidney when compared with liver. In conclusion, the study has demonstrated that the acute MC exposure in Wistar rats caused oxidative damage on liver and kidney, which were partly ameliorated by the pretreatment of vitamin E and taurine. 23419950 Optimization of cell receptor-specific targeting through multivalent surface decoration of polymeric nanocarriers. Treatment of tuberculosis is impaired by poor drug bioavailability, systemic side effects, patient non-compliance, and pathogen resistance to existing therapies. The mannose receptor (MR) is known to be involved in the recognition and internalization of Mycobacterium tuberculosis. We present a new assembly process to produce nanocarriers with variable surface densities of mannose targeting ligands in a single step, using kinetically-controlled, block copolymer-directed assembly. Nanocarrier association with murine macrophage J774 cells expressing the MR is examined as a function of incubation time and temperature, nanocarrier size, dose, and PEG corona properties. Amphiphilic diblock copolymers are prepared with terminal hydroxyl, methoxy, or mannoside functionality and incorporated into nanocarrier formulations at specific ratios by Flash NanoPrecipitation. Association of nanocarriers protected by a hydroxyl-terminated PEG corona with J774 cells is size dependent, while nanocarriers with methoxy-terminated PEG coronas do not associate with cells, regardless of size. Specific targeting of the MR is investigated using nanocarriers having 0-75% mannoside-terminated PEG chains in the PEG corona. This is a wider range of mannose densities than has been previously studied. Maximum nanocarrier association is attained with 9% mannoside-terminated PEG chains, increasing uptake more than 3-fold compared to non-targeted nanocarriers with a 5kgmol(-1) methoxy-terminated PEG corona. While a 5kgmol(-1) methoxy-terminated PEG corona prevents non-specific uptake, a 1.8kgmol(-1) methoxy-terminated PEG corona does not sufficiently protect the nanocarriers from nonspecific association. There is continuous uptake of MR-targeted nanocarriers at 37°C, but a saturation of association at 4°C. The majority of targeted nanocarriers associated with J774E cells are internalized at 37°C and uptake is receptor-dependent, diminishing with competitive inhibition by dextran. This characterization of nanocarrier uptake and targeting provides promise for optimizing drug delivery to macrophages for TB treatment and establishes a general route for optimizing targeted formulations of nanocarriers for specific delivery at targeted sites. 23547786 Bacteria-adsorbed palygorskite stabilizes the quaternary phosphonium salt with specific-targeting capability, long-term antibacterial activity, and lower cytotoxicity. In order to extend the antibacterial time of quaternary phosphonium salt in bacteria, palygorskite (PGS) is used as the carrier of dodecyl triphenyl phosphonium bromide (DTP), and a DTP-PGS hybrid is prepared. Antibacterial performance of this novel hybrid is investigated for both Gram-positive and Gram-negative bacteria. The results show that the DTP could be absorbed on the surface of PGS which had bacteria-adsorbed capability. The DTP-PGS hybrid, combining the advantages of PGS and DTP, display specific-targeting capability, long-term antibacterial activity, and lower cytotoxicity, suggesting the great potential application as PGS-based antibacterial powder. 23315683 Exciton Dissociation and Charge-Transport Enhancement in Organic Solar Cells with Quantum-Dot/N-doped CNT Hybrid Nanomaterials. The incorporation of InP quantum-dot/N-doped multiwalled carbon nanotube (QD:NCNT) nanohybrids in the active layer of poly(3-hexylthiophene)/indene-C60 bisadduct (P3HT/ICBA) bulk-heterojuction solar cells enhances VOC and JSC . The QDs encourage exciton dissociation by promoting electron transfer, while the NCNTs enhance the transport of the separated electrons and eventual charge collection. Such a synergistic effect successfully improves the power conversion efficiency (PCE) from 4.68% (reference cells) to 6.11%. 23411211 Cannabisin B induces autophagic cell death by inhibiting the AKT/mTOR pathway and S phase cell cycle arrest in HepG2 cells. This study investigates the anticancer properties of cannabisin B, purified from hempseed hull, in HepG2 human hepatoblastoma cells. The results indicate that cannabisin B significantly inhibited cell proliferation by inducing autophagic cell death rather than typical apoptosis. Cell viability transiently increased upon the addition of a low concentration of cannabisin B but decreased upon the addition of high concentrations. Cannabisin B-induced changes in cell viability were completely inhibited by pre-treatment with 3-methyladenine (3-MA), indicating that the induction of autophagy by cannabisin B caused cell death. Additionally, cannabisin B induced S phase cell cycle arrest in a dose-dependent manner. Moreover, cannabisin B was found to inhibit survival signaling by blocking the activation of AKT and down-stream targets of the mammalian target of rapamycin (mTOR). These findings suggest that cannabisin B possesses considerable antiproliferative activity and that it may be utilised as a promising chemopreventive agent against hepatoblastoma disease. 23561208 Effect of Saccharomyces strains on the quality of red wines aged on lees. Ageing on lees involves ageing the wine in contact with yeast cells after fermentation. If combined with the addition of oak chips, it can soften the wood flavour and increase the aromatic complexity of wine. The aim of the present work is to optimise both ageing techniques through selection of an adequate Saccharomyces cerevisiae strain. The study lasted 6months and content of polysaccharides, anthocyanins, proanthocyanidins, volatile compounds, colour parameters and sensory analysis, were periodically evaluated. Among the strains tested, G37 showed the highest release of polysaccharides (24.4±5.5mgl(-1)). Vanillin, syringaldehyde and furfuryl alcohol increased with ageing time in 7VA2 treatment. The wine aged with CTPL14 strain presented fewer monomeric and oligomeric proanthocyanidins (12.4±0.6 and 83.4±8.3mgl(-1), respectively), and showed the lowest astringency and bitterness sensations. Results show an improvement in the sensory profile of the red wine aged with a combination of these two techniques. 23373724 Enhancing the efficacy of Ara-C through conjugation with PAMAM dendrimer and linear PEG: a comparative study. 1β-d-Arabinofuranosylcytosine (Cytarabine, Ara-C) is a key drug in the treatment of acute myeloid leukemia. Ara-C has a number of limitations such as a rapid deactivation by cytidine deaminase leading to the formation of a biologically inactive metabolite, Ara-U (1β-d-arabinofuranosyluracil), a low lipophilicity, and fast clearance from the body. To address these problems, we developed a conjugate in which hydroxyl-terminated PAMAM dendrimer, G4-OH ["D"] and PEG were used as carriers for the drug (Ara-C). The conjugates were synthesized using an efficient multistep protection/deprotection method resulting in the formation of a covalent bond between the primary hydroxyl group of Ara-C and dendrimer/PEG. The structure, physicochemical properties, and drug release kinetics were characterized extensively. (1)H NMR and MALDI-TOF mass spectrometry suggested covalent attachment of 10 Ara-C molecules to the dendrimer. The release profile of Ara-C in human plasma and in PBS buffer (pH 7.4) showed that the conjugates released the drug over 14 days in PBS, with the release sped up in plasma. In PBS, while most of the drug is released from PEG-Ara-C, the dendrimer continues to release the drug in a sustained fashion. The results also suggested that the formation of the inactive form of Ara-C (Ara-U) was delayed upon conjugation of Ara-C to the polymers. The inhibition of cancer growth by the dendrimer-Ara-C and PEG-Ara-C conjugates was evaluated in A549 human adenocarcinoma epithelial cells. Both dendrimer- and PEG-Ara-C conjugates were 4-fold more effective in inhibition of A549 cells compared to free Ara-C after 72 h of treatment. 23259742 Short-channel transistors constructed with solution-processed carbon nanotubes. We develop short-channel transistors using solution-processed single-walled carbon nanotubes (SWNTs) to evaluate the feasibility of those SWNTs for high-performance applications. Our results show that even though the intrinsic field-effect mobility is lower than the mobility of CVD nanotubes, the electrical contact between the nanotube and metal electrodes is not significantly affected. It is this contact resistance which often limits the performance of ultrascaled transistors. Moreover, we found that the contact resistance is lowered by the introduction of oxygen treatment. Therefore, high-performance solution-processed nanotube transistors with a 15 nm channel length were obtained by combining a top-gate structure and gate insulators made of a high-dielectric-constant ZrO(2) film. The combination of these elements yields a performance comparable to that obtained with CVD nanotube transistors, which indicates the potential for using solution-processed SWNTs for future aggressively scaled transistor technology. 23542126 Oxidative status in ICU patients with septic shock. The aim of this pilot study was to investigate variability of oxidative stress during sepsis evolution. ICU patients with the diagnosis of septic shock were included. Thiobarbituric-acid reactive substances, total antioxidant capacity, protein carbonyls in plasma, reduced, oxidized glutathione and catalase activity in erythrocyte lysate were assessed in the 1st, 3rd, 5th and 8thday after sepsis appearance. A total of 17 patients were divided in two groups: survivors (n=7) and non-survivors (n=10). APACHE II was 11.5±5.4 and 19.9±4.97 in survivors and non-survivors respectively (p=0.005), while mean age and SOFA score at sepsis diagnosis, were similar between the two groups. GSH levels, catalase activity and protein carbonyls presented significant different course in time between survivors and non-survivors (p<0.05). Catalase activity was significantly higher in survivors (238.8±51.5) than non-survivors (166.4±40.2; p=0.005), while protein carbonyls levels were significantly lower in survivors (0.32±0.09) than non-survivors (0.48±0.16; p=0.036) on the 1stday. Yet, non-survivors exhibited a declining course in GSH levels during time, while GSH levels were maintained in survivors. Conclusively, a longstanding antioxidant deficiency in non-surviving patients was noted. This phenomenon was clearly prominent in patients' erythrocytes. 23180762 The nucleoid-associated protein Dan organizes chromosomal DNA through rigid nucleoprotein filament formation in E. coli during anoxia. Dan is a transcription factor that regulates the ttd operon encoding tartrate dehydratase. During anaerobic conditions, its copy number increases by 100-fold, making Dan an abundant nucleoid-associated protein. However, little is known about the mode of Dan-DNA interaction. To understand its cellular functions, we used single-molecule manipulation and imaging techniques to show that Dan binds cooperatively along DNA, resulting in formation of a rigid periodic nucleoprotein filament that strongly restricts accessibility to DNA. Furthermore, in the presence of physiologic levels of magnesium, these filaments interact with each other to cause global DNA condensation. Overall, these results shed light on the architectural role of Dan in the compaction of Escherichia coli chromosomal DNA under anaerobic conditions. Formation of the nucleoprotein filament provides a basis in understanding how Dan may play roles in both chromosomal DNA protection and gene regulation. 23447538 Mutational tail loss is an evolutionary mechanism for liberating marapsins and other type I serine proteases from transmembrane anchors. Human and mouse marapsins (Prss27) are serine proteases preferentially expressed by stratified squamous epithelia. However, mouse marapsin contains a transmembrane anchor absent from the human enzyme. To gain insights into physical forms, activities, inhibition, and roles in epithelial differentiation, we traced tail loss in human marapsin to a nonsense mutation in an ancestral ape, compared substrate preferences of mouse and human marapsins with those of the epithelial peptidase prostasin, designed a selective substrate and inhibitor, and generated Prss27-null mice. Phylogenetic analysis predicts that most marapsins are transmembrane proteins. However, nonsense mutations caused membrane anchor loss in three clades: human/bonobo/chimpanzee, guinea pig/degu/tuco-tuco/mole rat, and cattle/yak. Most marapsin-related proteases, including prostasins, are type I transmembrane proteins, but the closest relatives (prosemins) are not. Soluble mouse and human marapsins are tryptic with subsite preferences distinct from those of prostasin, lack general proteinase activity, and unlike prostasins resist antiproteases, including leupeptin, aprotinin, serpins, and α2-macroglobulin, suggesting the presence of non-canonical active sites. Prss27-null mice develop normally in barrier conditions and are fertile without overt epithelial defects, indicating that marapsin does not play critical, non-redundant roles in development, reproduction, or epithelial differentiation. In conclusion, marapsins are conserved, inhibitor-resistant, tryptic peptidases. Although marapsins are type I transmembrane proteins in their typical form, they mutated independently into anchorless forms in several mammalian clades, including one involving humans. Similar pathways appear to have been traversed by prosemins and tryptases, suggesting that mutational tail loss is an important means of evolving new functions of tryptic serine proteases from transmembrane ancestors. 23591111 A cyclodextrin-capped histone deacetylase inhibitor. We have synthesized a β-cyclodextrin (βCD)-capped histone deacetylase (HDAC) inhibitor 3 containing an alkyl linker and a zinc-binding hydroxamic acid motif. Biological evaluation (HDAC inhibition studies) of 3 enabled us to establish the effect of replacing an aryl cap (in SAHA (vorinostat,)) 1 by a large saccharidic scaffold "cap". HDAC inhibition was observed for 3, to a lesser extent than SAHA, and rationalized by molecular docking into the active site of HDAC8. However, compound 3 displayed no cellular activity. 23399931 The fundamental chemical equation of aromaticity. In the search for the chemical measure of molecular aromaticity, namely the energetic gain of a cyclic delocalized structure for just being cyclic, the numerous definitions of generic aromatic stabilisation energies proposed hitherto stand as approximates of the conceptual limit devised within the framework of spectral graph theory, i.e. the topological resonance energy (TRE). After a 36 year challenge, the TRE acyclic reference of any π-cyclic molecule, originally merely defined by an abstract matching polynomial, is now given a real chemical structure: the Möbius-twisted head-to-tail metathesis cyclo-dimer of the parent ring. The original treatment at the Hückel molecular orbital level of theory can now be extended to DFT or ab initio levels. The corresponding ring opening-closing-twisting chemical transformation provides the observable basis for the measure of aromaticity under either vertical or adiabatic conditions. 23440664 A practical and scalable manufacturing process for an anti-fungal agent, Nikkomycin Z. A scalable and reliable manufacturing process for Nikkomycin Z HCl on a 170 g scale has been developed and optimized. The process is characterized by a 2.3 g/L fermentation yield, 79% purification yield, and >98% relative purity of the final product. This method is suitable for further scale up and cGMP production. The Streptomyces tendae ΔNikQ strain developed during the course of this study is superior to any previously reported strain in terms of higher yield and purity of Nikkomycin Z. 23472840 Encapsulation of Hydrophobic Drugs in Pluronic F127 Micelles: Effects of Drug Hydrophobicity, Solution Temperature, and pH. Three drugs, ibuprofen, aspirin, and erythromycin, are encapsulated in spherical Pluronic F127 micelles. The shapes and the size distributions of the micelles in dilute, aqueous solutions, with and without drugs, are ascertained using cryo-scanning electron microscopy and dynamic light scattering (DLS) experiments, respectively. Uptake of drugs above a threshold concentration is seen to reduce the critical micellization temperature of the solution. The mean hydrodynamic radii and polydispersities of the micelles are found to increase with decrease in temperature and in the presence of drug molecules. The hydration of the micellar core at lower temperatures is verified using fluorescence measurements. Increasing solution pH leads to the ionization of the drugs incorporated in the micellar cores. This causes rupture of the micelles and release of the drugs into the solution at the highest solution pH value of 11.36 investigated here and is studied using DLS and fluorescence spectrocopy. 23305777 Neolignans from leaves of Miliusa mollis. From the leaves of Miliusa mollis Pierre (Annonaceae), five new dihydrobenzofuran neolignans, namely miliumollin, 7-methoxymiliumollin, 3'-methoxymiliumollin, 4'-O-methylmiliumollin and miliumollinone, and a new 8-O-4' neolignan named miliusamollin were isolated, and their structures were elucidated through analysis of spectroscopic data. Miliumollin, 3'-methoxymiliumollin, miliumollinone and decurrenal exhibited weak cytotoxicity against KB, MCF7 and NCI-H187 cells. Miliumollinone possessed weak inhibitory effects against herpes simplex virus types 1 and 2. None of the isolates displayed inhibitory activity against avian influenza H5N1 neuraminidase. 23584857 Induction of the metabolic regulator Txnip in fasting-induced and natural torpor. Torpor is a physiological state characterised by controlled lowering of metabolic rate and core body temperature, allowing substantial energy savings during periods of reduced food availability or harsh environmental conditions. The hypothalamus coordinates energy homeostasis and thermoregulation, and plays a key role in directing torpor. We recently showed that mice lacking the orphan G protein coupled receptor Gpr50 readily enter torpor in response to fasting, and have now used these mice to conduct a microarray analysis of hypothalamic gene expression changes related to the torpor state. This revealed a strong induction of thioredoxin interacting protein (Txnip) in the hypothalamus of torpid mice, which was confirmed by quantitative RT-PCR and Western blot analyses. In situ hybridisation identified the ependyma lining the third ventricle as the principal site of torpor-related expression of Txnip. To characterise further the relationship between Txnip and torpor, we profiled Txnip expression in mice during prolonged fasting, cold exposure, and 2-deoxyglucose-induced hypometabolism, as well as in naturally occurring torpor bouts in the Siberian hamster. Strikingly, pronounced upregulation of Txnip expression was only observed in WT mice when driven into torpor, and during torpor in the Siberian hamster. Increase of Txnip was not limited to the hypothalamus, with exaggerated expression in white adipose tissue, brown adipose tissue, and liver also demonstrated in torpid mice. Given the recent identification of Txnip as a molecular nutrient sensor important in the regulation of energy metabolism, our data suggest that elevated Txnip expression is critical to regulating energy expenditure and fuel utilisation during the extreme hypometabolic state of torpor. 23428841 Lecithin/chitosan controlled release nanopreparations of tamoxifen citrate: Loading, enzyme-trigger release and cell uptake. Tamoxifen citrate (TAM), an anticancer drug with amphiphilic properties, was loaded in lecithin/chitosan nanoparticles (LCN) with a view to oral administration. The influence of tamoxifen loading on the physico-chemical properties of nanoparticles was studied. Size, surface charge and morphological properties of tamoxifen-loaded nanoparticles (LCN-TAM) were assessed. The increase in the tamoxifen amount in the LCN-TAM preparation up to 60mg/100ml maintained the positive zeta potential value of about +45mV. A statistically significant decrease in particle size was observed for TAM amounts between 5 and 20mg. A strong influence of loaded tamoxifen on the structure of lecithin/chitosan nanoparticles was observed, supported by the quantification of free chitosan and morphological analysis. A loading of tamoxifen in nanoparticles of around 19% was obtained. The release of the drug from the LCN-TAM colloidal dispersion was measured, showing that tamoxifen citrate was released very slowly in simulated gastro-intestinal fluids without enzymes. When enzymes able to dismantle the nanoparticle structure were added to the dissolution medium, drug release was triggered and continued in a prolonged manner. Tamoxifen-loaded nanoparticles showed cytotoxicity towards MCF-7 cells comparable to that obtained with tamoxifen citrate solution, but the rate of this toxic effect was dependent on drug release. Caco-2 cells, used as a model of the intestinal epithelium, were shown to take up the TAM loaded nanoparticles extensively. 23470104 High-Resolution Direct-Absorption Spectroscopy of Hydroxymethyl Radical in the CH Symmetric Stretching Region. High-resolution, fully rotationally resolved direct absorption spectra of hydroxymethyl radical, CH2OH, are presented in the infrared CH stretching region. As a result of low rotational temperatures and sub-Doppler linewidths obtained in the slit supersonic expansion, the Ka = 0 ← 0 band of the symmetric CH stretch for CH2OH has been unambiguously identified and analyzed. By way of chemical confirmation, hydroxymethyl radical is generated via two different slit jet discharge syntheses: (i) direct dissociation of CH3OH to form CH2OH and (ii) dissociation of Cl2 followed by the radical H atom extraction reaction Cl + CH3OH → HCl + CH2OH. The identified transitions are fit to a Watson A-reduced symmetric top Hamiltonian to yield first precision experimental values for the ground state rotational constants as well as improved values for the symmetric stretch rotational constants and vibrational band origin. The results both complement and substantially improve upon spectral efforts via previous double resonance ionization detected infrared methods by Feng et al. [J. Phys. Chem. A, 2004, 108, 7093], as well as offer high-resolution predictions for laboratory and astronomical detection of hydroxymethyl radical in the millimeter-wave region. 23561120 A new process for obtaining hydroxytyrosol using transformed Escherichia coli whole cells with phenol hydroxylase gene from Geobacillus thermoglucosidasius. Phenol hydroxylase gene cloning from the thermophilic bacteria Geobacillus thermoglucosidasius was used to develop an effective method to convert tyrosol into the high-added-value compound hydroxytyrosol by hydroxylation. Phenol hydroxylase is a two-component enzyme encoded by pheA1 and pheA2 genes and strictly dependent on NADH and FAD. These two genes were subcloned together as a 2kb fragment into Escherichia coli Rosetta cells, and the transformants were able to grow and effectively transform up to 5mM of phenol and tyrosol using IPTG (isopropyl-β-d-thiogalactopyranoside) as inducer. In addition, when a new fragment with a 340pb upstream pheA1 gene was subcloned, a similar biotransformation rate was attained without IPTG, confirming that this fragment encodes for a phenol hydroxylase promoter that can be recognised by E. coli. Both transformants brought about the total bioconversion of monophenols at a high concentration (5mM), which represents an increase, both in concentration and in yield, compared with that previously described in the bibliography. The use of the transformant with its constitutive promoter was more interesting from a biotechnological point of view, since it is not necessary to use IPTG. It also gave rise to greater operational stability. 23139378 Analysis of the repaglinide concentration increase produced by gemfibrozil and itraconazole based on the inhibition of the hepatic uptake transporter and metabolic enzymes. The plasma concentration of repaglinide is reported to increase greatly when given after repeated oral administration of itraconazole and gemfibrozil. The present study analyzed this interaction based on a physiologically based pharmacokinetic (PBPK) model incorporating inhibition of the hepatic uptake transporter and metabolic enzymes involved in repaglinide disposition. Firstly, the plasma concentration profiles of inhibitors (itraconazole, gemfibrozil, and gemfibrozil glucuronide) were reproduced by a PBPK model to obtain their pharmacokinetic parameters. The plasma concentration profiles of repaglinide were then analyzed by a PBPK model, together with those of the inhibitors, assuming a competitive inhibition of CYP3A4 by itraconazole, mechanism-based inhibition of CYP2C8 by gemfibrozil glucuronide, and inhibition of organic anion transporting polypeptide (OATP) 1B1 by gemfibrozil and its glucuronide. The plasma concentration profiles of repaglinide were well reproduced by the PBPK model based on the above assumptions, and the optimized values for the inhibition constants (0.0676 nM for itraconazole against CYP3A4; 14.2 μM for gemfibrozil against OATP1B1; and 5.48 μM for gemfibrozil glucuronide against OATP1B1) and the fraction of repaglinide metabolized by CYP2C8 (0.801) were consistent with the reported values. The validity of the obtained parameters was further confirmed by sensitivity analyses and by reproducing the repaglinide concentration increase produced by concomitant gemfibrozil administration at various timings/doses. The present findings suggested that the reported concentration increase of repaglinide, suggestive of synergistic effects of the coadministered inhibitors, can be quantitatively explained by the simultaneous inhibition of the multiple clearance pathways of repaglinide. 23473030 Iron and diabetes risk. Iron overload is a risk factor for diabetes. The link between iron and diabetes was first recognized in pathologic conditions-hereditary hemochromatosis and thalassemia-but high levels of dietary iron also impart diabetes risk. Iron plays a direct and causal role in diabetes pathogenesis mediated both by β cell failure and insulin resistance. Iron also regulates metabolism in most tissues involved in fuel homeostasis, with the adipocyte in particular serving an iron-sensing role. The underlying molecular mechanisms mediating these effects are numerous and incompletely understood but include oxidant stress and modulation of adipokines and intracellular signal transduction pathways. 23296019 Combined analytical ultracentrifugation, light scattering and fluorescence spectroscopy studies on the functional associations of the bacterial division FtsZ protein. The combined application of different biophysical techniques - analytical ultracentrifugation, light scattering and fluorescence-based assays - to study the ligand-linked self-association and assembly properties of the cell division protein FtsZ from Escherichia coli is described. These reactions are thought to be important for the formation of the dynamic division ring that drives bacterial cytokinesis. In addition, the use of this orthogonal experimental approach to measure the interactions between FtsZ oligomers (GDP forms) and polymers (GTP forms) with two variants (a soluble form and a full-length protein incorporated in phospholipid bilayer nanodiscs) of the ZipA protein, which provides membrane tethering to FtsZ, is described as well. The power of a global analysis of the results obtained from complementary biophysical methods to discriminate among alternative self- and hetero-associating schemes and to propose a more robust description of the association reactions involved is emphasized. This orthogonal approach will contribute to complete our quantitative understanding of the initial events of bacterial division. 23385211 Basic N-interlinked imipramines show apoptotic activity against malignant cells including Burkitt's lymphoma. We here report the synthesis of ethylene glycol N-interlinked imipramine dimers of various lengths from the tricyclic antidepressant desipramine via an amide coupling reaction followed by reduction with lithium aluminium hydride. The target molecules were found to be potent inhibitors of cellular viability while inducing cell type specific death mechanisms in three cancer cell lines including a highly chemoresistant Burkitt's lymphoma cell line. Basic amine analogues were found to be important for increased potency. Imipramine and desipramine were also tested for apoptotic activity and were found to be much less active than the novel dimeric compounds. Imipramine dimers were only found to be moderate inhibitors of the human serotonin transporter (hSERT) having IC(50) values in the micromolar region whilst the induction of cell death occurred independently of hSERT expression. These results demonstrate the potential of newly designed and synthesised imipramines derivatives for use against malignant cells, including those resistant to standard chemotherapy. 23533220 Enhanced Striatal β1-Adrenergic Receptor Expression Following Hormone Loss in Adulthood Is Programmed by Both Early Sexual Differentiation and Puberty: A Study of Humans and Rats. After reproductive senescence or gonadectomy, changes occur in neural gene expression, ultimately altering brain function. The endocrine mechanisms underlying these changes in gene expression beyond immediate hormone loss are poorly understood. To investigate this, we measured changes in gene expression the dorsal striatum, where 17β-estradiol modulates catecholamine signaling. In human caudate, quantitative PCR determined a significant elevation in β1-adrenergic receptor (β1AR) expression in menopausal females when compared with similarly aged males. No differences were detected in β2-adrenergic and D1- and D2-dopamine receptor expression. Consistent with humans, adult ovariectomized female rats exhibited a similar increase in β1AR expression when compared with gonadectomized males. No sex difference in β1AR expression was detected between intact adults, prepubertal juveniles, or adults gonadectomized before puberty, indicating the necessity of pubertal development and adult ovariectomy. Additionally, increased β1AR expression in adult ovariectomized females was not observed if animals were masculinized/defeminized with testosterone injections as neonates. To generate a model system for assessing functional impact, increased β1AR expression was induced in female-derived cultured striatal neurons via exposure to and then removal of hormone-containing serum. Increased β1AR action on cAMP formation, cAMP response element-binding protein phosphorylation and gene expression was observed. This up-regulation of β1AR action was eliminated with 17β-estradiol addition to the media, directly implicating this hormone as a regulator of β1AR expression. Beyond having implications for the known sex differences in striatal function and pathologies, these data collectively demonstrate that critical periods early in life and at puberty program adult gene responsiveness to hormone loss after gonadectomy and potentially reproductive senescence. 23201223 Emerging role of primary cilia as mechanosensors in osteocytes. The primary cilium is a solitary, immotile microtubule-based extension present on nearly every mammalian cell. This organelle has established mechanosensory roles in several contexts including kidney, liver, and the embryonic node. Mechanical load deflects the cilium, triggering biochemical responses. Defects in cilium function have been associated with numerous human diseases. Recent research has implicated the primary cilium as a mechanosensor in bone. In this review, we discuss the cilium, the growing evidence for its mechanosensory role in bone, and areas of future study. This article is part of a Special Issue entitled "The Osteocyte". 23159888 Analysis of mammalian alcohol dehydrogenase 5 (ADH5): characterisation of rat ADH5 with comparisons to the corresponding human variant. Alcohol dehydrogenase 5 (ADH5) is a member of the mammalian alcohol dehydrogenase family of yet undefined functions. ADH5 was first identified at the DNA level in human and deer mouse. A rat alcohol dehydrogenase structure of similar type has been isolated at the cDNA level using human ADH5 as a screening probe, where the rat cDNA structure displayed several atypical properties. mRNA for rat ADH5 was found in multiple tissues, especially in the kidney. In vitro translation experiments indicated that rat ADH5 is expressed as efficiently as ADH1 and furthermore, rat ADH5 was readily expressed in COS cells fused to Green Fluorescent Protein. However, no soluble ADH5 protein could be heterologously expressed in Escherichia coli cells with expression systems successfully used for other mammalian ADHs, including fused to glutathione-S-transferase. Molecular modelling of the enzyme indicated that the protein does not fold in a productive way, which can be the explanation why no stable and active ADH5 has been isolated. These results indicate that ADH5, while readily expressed at the mRNA level, does not behave similarly to other mammalian ADHs investigated. The results, in vitro and in silico, suggest an unstable ADH5 structure, which can explain for why no active and stable protein can be isolated. Further possibilities are conceivable: the ADH5 protein may have to interact with a stabiliser, or the gene is actually a pseudogene. 23546004 Medicinal Flowers. XXXVIII. Structures of Acylated Sucroses and Inhibitory Effects of Constituents on Aldose Reducatase from the Flower Buds of Prunus mume. The methanolic extract from the flower buds of Prunus mume, cultivated in Zhejiang province, China, showed an inhibitory effect on aldose reductase. From the methanolic extract, five new acylated sucroses, mumeoses F-J, were isolated together with 29 known compounds. The chemical structures of the new compounds were elucidated on the basis of chemical and physicochemical evidence. The inhibitory effects of the isolated compounds on aldose reductase were also investigated. Acylated quinic acid analogs, which are one of the major compounds of the flower buds of P. mume, were shown to substantially inhibit aldose reductase. In particular, mumeic acid-A was found to exhibit a potent inhibitory effect [IC50=0.4 µm]. 23265901 Synthesis and evaluation of 8-oxoadenine derivatives as potent Toll-like receptor 7 agonists with high water solubility. We report the discovery of novel series of highly potent TLR7 agonists based on 8-oxoadenines, 1 and 2 by introducing and optimizing various tertiary amines onto the N(9)-position of the adenine moiety. The introduction of the amino group resulted in not only improved water solubility but also enhanced TLR7 agonistic activity. In particular compound 20 (DSR-6434) indicated an optimal balance between the agonistic potency and high water solubility. It also demonstrated a strong antitumor effect in vivo by intravenous administration in a tumor bearing mice model. 23154304 Synthesis of novel indole hydrazone derivatives and evaluation of their antiplatelet aggregation activity. Based on the existing reports regarding the antiplatelet aggregation activity of hydrazone derivatives, a series of indole hydrazone derivatives were considered as potential antiplatelet agents and synthesized. The structures of the synthesized compounds were confirmed by spectral data and elemental analysis. The new indole hydrazone derivatives were evaluated for their ability to inhibit platelet aggregation induced by adenosine diphosphate (ADP) and arachidonic acid (AA). Compounds 1h and 3h exhibited remarkable activity against arachidonic acid induced platelet aggregation with IC(50) values comparable to that of indomethacin and compound 1i efficiently inhibited platelet aggregation induced by both ADP and AA. 23474386 Novel 5-(benzyloxy)pyridin-2(1H)-one derivatives as potent c-Met inhibitors. A series of novel 5-(benzyloxy)pyridin-2(1H)-ones were designed, synthesized and biologically evaluated for c-Met inhibition. Various amides and benzoimidazoles at C-3 position were investigated. A potent compound 12b with a c-Met IC50 of 12nM was identified. This compound exhibited potent inhibition of EBC-1 cell associated with c-Met constitutive activation and showed high selectivity for c-Met than other tested 11 kinases. The binding model 12b with c-Met was disclosed by docking analysis. 23561165 Chemical, rheological and surface morphologic characterisation of spent hen proteins extracted by pH-shift processing with or without the presence of cryoprotectants. The chemical and rheological properties of spent hen proteins recovered by acid and alkaline extraction have been studied with/without cryoprotectants (CP) after 3weeks of frozen storage. Four pH values (2.0, 2.5, 11.5, and 12.0) were used for extraction. CP addition prevented freeze-induced denaturation and oxidation in all extracted proteins, as revealed by significant increases in reactive sulphydryl groups (p<0.0001), and a decrease in the formation of carbonyl groups (p<0.0001). The alkaline extracted proteins with CP formed more viscoelastic gels compared to the others, while samples without CP failed to form a gel network. FTIR of the protein isolates with CP showed a protective effect on the secondary structure of the isolated proteins. Scanning electron micrographs showed a protective shield of CP around the isolated proteins. 23345171 Adjustment of Born-Oppenheimer electronic wave functions to simplify close coupling calculations. Technical problems connected with use of the Born-Oppenheimer clamped-nuclei approximation to generate electronic wave functions, potential energy surfaces (PES), and associated properties are discussed. A computational procedure for adjusting the phases of the wave functions, as well as their order when potential crossings occur, is presented which is based on the calculation of overlaps between sets of molecular orbitals and configuration interaction eigenfunctions obtained at neighboring nuclear conformations. This approach has significant advantages for theoretical treatments describing atomic collisions and photo-dissociation processes by means of ab initio PES, electronic transition moments, and nonadiabatic radial and rotational coupling matrix elements. It ensures that the electronic wave functions are continuous over the entire range of nuclear conformations considered, thereby greatly simplifying the process of obtaining the above quantities from the results of single-point Born-Oppenheimer calculations. The overlap results are also used to define a diabatic transformation of the wave functions obtained for conical intersections that greatly simplifies the computation of off-diagonal matrix elements by eliminating the need for complex phase factors. 23423243 Characterisation of non-warfarin-associated bleeding events reported to the Norwegian spontaneous reporting system. OBJECTIVE: The aim of the study was to analyse non-warfarin-associated bleeding adverse drug events reported to the Norwegian spontaneous reporting system, with characterisation of the bleeding locations, outcome and drug interactions. In addition, concordance in assessments between reporters and evaluators, trend shifts in reporting, and detection of potentially new adverse drug interaction signals were studied. METHODS: Data on bleeding events reported between 1 January 2003 and 31 December 2005 were retrieved from the Norwegian spontaneous reporting system database. RESULTS: Of 327 case reports of non-warfarin-associated bleeding events, 270 reports (82.6 %) were characterised as serious and 69 (21.1 %) had a fatal outcome. One hundred and eighty-seven bleeds (57.5 %) were gastrointestinal, 57 (17.4 %) were cerebral, and 81 (24.8 %) were from other bleeding sites. The bleeding sites differed with respect to the patient's age, drug use, diagnoses and outcomes. Of drugs associated with bleeding, nonsteroidal anti-inflammatory drugs (NSAIDs)/COX-2 inhibitors (145 reports) and acetylsalicylic acid (128 reports) were most frequently used. Only fibrinolytics were associated with increased mortality. There was a 67.4 % correlation between reporters and evaluators in assessment of drugs associated with bleeding (P < 0.001), with considerable variation in concordance between drug groups. CONCLUSION: Non-warfarin-associated bleeding events are associated with substantial mortality. Old age, cerebral bleeds, number of drugs used, and use of fibrinolytics are all independently associated with increased mortality. The recognition of the bleeding risk of commonly used drugs such as acetylsalicylic acid and heparins may be insufficient among prescribers. 23161648 Derivation of a benchmark for freshwater ionic strength. Because increased ionic strength has caused deleterious ecological changes in freshwater streams, thresholds for effects are needed to inform resource-management decisions. In particular, effluents from surface coal mining raise the ionic strength of receiving streams. The authors developed an aquatic life benchmark for specific conductance as a measure of ionic strength that is expected to prevent the local extirpation of 95% of species from neutral to alkaline waters containing a mixture of dissolved ions in which the mass of SO (4)2- + HCO (3)- ≥ Cl(-). Extirpation concentrations of specific conductance were estimated from the presence and absence of benthic invertebrate genera from 2,210 stream samples in West Virginia. The extirpation concentration is the 95th percentile of the distribution of the probability of occurrence of a genus with respect to specific conductance. In a region with a background of 116 µS/cm, the 5th percentile of the species sensitivity distribution of extirpation concentrations for 163 genera is 300 µS/cm. Because the benchmark is not protective of all genera and protects against extirpation rather than reduction in abundance, this level may not fully protect sensitive species or higher-quality, exceptional waters. 23344824 Phytotoxicity evaluation and phytochemical analysis of three medicinally important plants from Pakistan. This work examines the crude methanolic extracts of three medicinally important plants native to Pakistan for potent phytotoxic activities and important phytochemicals. These plants include Euphorbia wallichii, Bergenia ciliata and Phytolacca latbenia. The phytotoxic effects were checked at 10,000, 1000, and 100 µg/ml against two economically important standard target species, Triticum aestivum (monocot representative) and Brassica napus (dicot representative). The phytotoxicity effects on seed germination, seedling growth and seedling weight were checked. A simple, cost-effective in vitro phytotoxicity assay (that uses petri plates) was used to evaluate the allelopathic properties of crude extracts. At highest concentration, extracts from all the three plants showed phytotoxic activities such that P. latbenia > E. wallichii > B. ciliata. In seedling growth, root length was affected more than shoot length, whereas among the target species B. napus was found to be more sensitive towards extracts when compared with T. aestivum. Phytochemical analysis showed that P. latbenia is rich in saponins and terpenoids, while E. wallichii and B. ciliata are rich in tannins, terpenoids and cardiac glycoside. P. latbenia also carries a moderate amount of cardiac glycosides. 23556445 Genomic variation in the MAP3K5 gene is associated with β-thalassemia disease severity and hydroxyurea treatment efficacy. Aim: In this study we explored the association between genetic variations in MAP3K5 and PDE7B genes, residing on chromosome 6q23, and disease severity in β-hemoglobinopathy patients, as well as the association between these variants with response to hydroxyurea (HU) treatment. Furthermore, we examined MAP3K5 expression in the context of high fetal hemoglobin (HbF) and upon HU treatment in erythroid progenitor cells from healthy and KLF1 haploinsufficient individuals. Materials & methods: For this purpose, we genotyped β-thalassemia intermedia and major patients and healthy controls, as well as a cohort of compound heterozygous sickle cell disease/β-thalassemia patients receiving HU as HbF augmentation treatment. Furthermore, we examined MAP3K5 expression in the context of high HbF and upon HU treatment in erythroid progenitor cells from healthy and KLF1 haploinsufficient individuals. Results: A short tandem repeat in the MAP3K5 promoter and two intronic MAP3K5 gene variants, as well as a PDE7B variant, are associated with low HbF levels and a severe disease phenotype. Moreover, MAP3K5 mRNA expression levels are altered in the context of high HbF and are affected by the presence of HU. Lastly, the abovementioned MAP3K5 variants are associated with HU treatment efficacy. Conclusion: Our data suggest that these MAP3K5 variants are indicative of β-thalassemia disease severity and response to HU treatment. Original submitted 24 September 2012; Revision submitted 4 February 2013. 23449220 Development of modified siRNA molecules incorporating 5-fluoro-2'-deoxyuridine residues to enhance cytotoxicity. Therapeutic small interfering RNAs (siRNAs) are composed of chemically modified nucleotides, which enhance RNA stability and increase affinity in Watson-Crick base pairing. However, the precise fate of such modified nucleotides once the siRNA is degraded within the cell is unknown. Previously, we demonstrated that deoxythymidine release from degraded siRNAs reversed the cytotoxicity of thymidylate synthase (TS)-targeted siRNAs and other TS inhibitor compounds. We hypothesized that siRNAs could be designed with specific nucleoside analogues that, once released, would enhance siRNA cytotoxicity. TS-targeted siRNAs were designed that contained 5-fluoro-2'-deoxyuridine (FdU) moieties at various locations within the siRNA. After transfection, these siRNAs suppressed TS protein and messenger RNA expression with different efficiencies depending on the location of the FdU modification. FdU was rapidly released from the siRNA as evidenced by formation of the covalent inhibitory ternary complex formed between TS protein and the FdU metabolite, FdUMP. These modified siRNAs exhibited 10-100-fold greater cytotoxicity and induced multiple DNA damage repair and apoptotic pathways when compared with control siRNAs. The strategy of designing siRNA molecules that incorporate cytotoxic nucleosides represents a potentially novel drug development approach for the treatment of cancer and other human diseases. 23303441 Evaluation of hepatic disposition of paroxetine using sandwich-cultured rat and human hepatocytes. Paroxetine, a selective serotonin reuptake inhibitor, is metabolized in the liver and excreted into bile and urine as metabolites, but species differences have been observed in hepatic disposition between rats and humans. A major metabolite in rats is M1-glucuronide, whereas M1-glucuronide and M1-sulfate are found in humans. The primary excretion route of paroxetine-derived radioactivity in rats and humans is bile and urine, respectively. The aim of this study was to examine the usefulness of sandwich-cultured hepatocytes (SCH) to evaluate in vivo species differences of the hepatic disposition of paroxetine between rats and humans. The metabolite profile of [(3)H]paroxetine in SCH was similar to that in hepatocytes in suspension, and the in vitro metabolite profiles were similar to the published in vivo metabolic pathways for both species. Furthermore, the biliary excretion index (BEI) of formed M1-glucuronide in rat SCH (25.8-50.9%) was higher than that in human SCH (15.1-16.7%). The BEI of formed M1-sulfate (16.4-29.1%) was comparable to that of M1-glucuronide in human SCH, whereas the BEIs of paroxetine were negligible in SCH of both species. Moreover, M1-glucuronide was demonstrated to be a multidrug resistance-associated protein 2 substrate in both species, as determined by its uptake into ATP-binding cassette transporter-expressing membrane vesicles. SCH should prove to be useful to evaluate the processes of hepatic uptake and metabolism of parent drugs and the simultaneous examination of the biliary excretion of both parent drug and liver-derived metabolites. 23591660 Computer simulations of cluster impacts: effects of the atomic masses of the projectile and target. Cluster secondary ion mass spectrometry is now widely used for the characterization of nanostructures. In order to gain a better understanding of the physics of keV cluster bombardment of surfaces and nanoparticles (NPs), the effects of the atomic masses of the projectile and of the target on the energy deposition and induced sputtering have been studied by means of molecular dynamics simulations. 10 keV C60 was used as a model projectile and impacts on both a flat polymer surface and a metal NP were analyzed. In the first case, the mass of the impinging carbon atoms was artificially varied and, in the second case, the mass of the NP atoms was varied. The results can be rationalized on the basis of the different atomic mass ratios of the projectile and target. In general, the emission is at its maximum, when the projectile and target have the same atomic masses. In the case of the supported NP, the emission of the underlying organic material increases as the atomic mass of the NP decreases. However, it is always less than that calculated for the bare organic surface, irrespective of the mass ratio. The results obtained with C60 impacts on the flat polymer are also compared to simulations of C60 and monoatomic Ga impacts on the NP. 23219339 Neuroprotective effects of oxymatrine against excitotoxicity partially through down-regulation of NR2B-containing NMDA receptors. Oxymatrine (OMT) is a major bioactive component derived from Sophora flavescens Ait (kushen), which is widely used in Chinese medicine. Recent studies have shown that it has neuroprotective effects; however, its underlying mechanisms remain unclear. We focus on the mechanisms of pharmacologic action in OMT by detecting its pharmacological properties against focal cerebral ischemia in vivo and NMDA-induced neurotoxicity in vitro. OMT prevented cerebral ischemic injury in mice induced via a 2 h middle cerebral artery occlusion and a 24 h reperfusion, in vivo. In vitro cultured neurons challenged with N-methyl-D-aspartate (NMDA, 200 μM) for 30 min showed significant decrease in the viability of neurons; however, OMT was able to protect neurons against induced neurotoxicity via NMDA exposure. Western blot analysis revealed that OMT decreased the expression of Bax and repaired the balance of pro- and anti-apoptotic proteins. Furthermore, OMT significantly reversed the up-regulation of NR2B and inhibited the calcium overload in the cultured neurons after challenging the NMDA. OMT showed partial protection in the cortical neurons via down-regulation of NR2B containing NMDA receptors and up-regulation of Bcl-2 family. Our results provide new insights into the development of natural therapeutic anti-oxidants against ischemia. 23159790 Purification and structural characterisation of phospholipase A1 (Vespapase, Ves a 1) from Thai banded tiger wasp (Vespa affinis) venom. The Thai banded tiger wasp (Vespa affinis) is one of the most dangerous vespid species in Southeast Asia, and stinging accidents involving this species still cause fatalities. In the present study, four forms of V. affinis phospholipase A(1) were identified through a proteomics approach. Two of these enzymes were purified by reverse-phase chromatography, and their biochemical properties were characterised. These enzymes, designated Ves a 1s, are not glycoproteins and exist as 33441.5 and 33474.4 Da proteins, which corresponded with the 34-kDa band observed via SDS-PAGE. The thermal stabilities of these enzymes were stronger than snake venom. Using an in vivo assay, no difference was found in the toxicities of the different isoforms. Furthermore, the toxicity of these enzymes does not appear to be correlated with their PLA(1) activity. The cDNAs of the full-length version of Ves a 1s revealed that the Ves a 1 gene consists of a 1005-bp ORF, which encodes 334 amino acid residues, and 67- and 227-bp 5' and 3' UTRs, respectively. The two isoforms are different by three nucleotide substitutions, resulting in the replacement of two amino acids. Through sequence alignment, these enzymes were classified as members of the pancreatic lipase family. The structural modelling of Ves a 1 used the rat pancreatic lipase-related protein 2 (1bu8A) as a template because it has PLA(1) activity, which demonstrated that this enzyme belongs to the α/β hydrolase fold family. The Ves a 1 structure, which is composed of seven α-helixes and eleven β-strands, contains the β-strand/ɛSer/α-helix structural motif, which contains the Gly-X-Ser-X-Gly consensus sequence. The typical surface structures that play important roles in substrate selectivity (the lid domain and the β9 loop) were shortened in the Ves a 1 structure, which suggests that this enzyme may only exhibit phospholipase activity. Moreover, the observed insertion of proline into the lid domain of the Ves a 1 structure is rare. We therefore propose that this proline residue might be involved in the stability and activity of Ves a 1s. 23246531 The novel δ opioid receptor agonist KNT-127 produces distinct anxiolytic-like effects in rats without producing the adverse effects associated with benzodiazepines. We previously reported that a δ opioid receptor agonist SNC80 produced potent anxiolytic-like effects in rodents. Recently, we succeeded in synthesizing a novel δ opioid receptor agonist KNT-127. In this study, we investigated the anxiolytic-like effects of KNT-127 using three different rat models of innate anxiety. In an elevated plus-maze test, KNT-127 (0.3, 1, and 3.0 mg/kg, s.c.) significantly and dose-dependently increased the time rats spent in the open arms 30 min after administration. The magnitude of the KNT-127 (3.0 mg/kg, s.c.)-induced anxiolytic-like effects was similar to that produced by diazepam (1.0 mg/kg, s.c.), a benzodiazepine anxiolytic. The anxiolytic-like effects of KNT-127 (3.0 mg/kg, s.c.) were abolished by pretreatment with naltrindole (0.1 mg/kg, s.c.), a selective δ opioid receptor antagonist, suggesting that KNT-127-induced anxiolytic-like effects are mediated by δ opioid receptors. These findings were supported by results obtained from light/dark and open-field tests. Interestingly, in contrast to diazepam (1.0 mg/kg, s.c.), KNT-127 (3.0 mg/kg, s.c.) caused no significant performance changes in the Y-maze test, the ethanol-induced sleeping test, and footprint test. This is the first study to demonstrate that the novel δ opioid receptor agonist KNT-127 produces distinct anxiolytic-like effects in rats, without producing the adverse effects associated with benzodiazepines. 23131798 Discovery of novel cannabinoid receptor ligands by a virtual screening approach: further development of 2,4,6-trisubstituted 1,3,5-triazines as CB2 agonists. 3D ligand-based virtual screening was employed to identify novel scaffolds for cannabinoid receptor ligand development. A total of 112 compounds with diverse structures were purchased from commercial vendors. 12 CB1 receptor antagonists/inverse agonists and 10 CB2 receptor agonists were identified in vitro. One of the CB2 agonists, N-cyclopentyl-4-ethoxy-6-(4-methylpiperidin-1-yl)-1,3,5-triazin-2-amine (19, -logEC(50)=7.5, E(max)=255%) was selected for further development. As far as we are aware, the compound's 1,3,5-triazine scaffold represents a new core structure for CB2 agonists. A library of fifty-seven 2,4,6-trisubstituted-1,3,5-triazines was created to clarify the structure-activity relationship study of the analogs. 23228471 Facile regioselective synthesis of novel bioactive thiazolyl-pyrazoline derivatives via a three-component reaction and their antimicrobial activity. A series of novel 2-(3,5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-phenylthiazoles have been prepared by a three-component cyclo-condensation of various chalcones, thiosemicarbazide and phenacyl bromide. The easy work-up of the products, rapid reaction, and mild conditions are notable features of this protocol. The reaction was efficiently catalyzed in one-pot by a few drops of HCl in EtOH under reflux conditions providing the title compounds in moderate to high yields. The antibacterial activity of the selected products was examined. Some products exhibit promising activities. 23259866 Morphologies of ABC triblock terpolymer melts containing poly(cyclohexadiene): effects of conformational asymmetry. We have synthesized linear ABC triblock terpolymers containing poly(1,3-cyclohexadiene), PCHD, as an end block and characterized their morphologies in the melt. Specifically, we have studied terpolymers containing polystyrene (PS), polybutadiene (PB), and polyisoprene (PI) as the other blocks. Systematically varying the ratio of 1,2- /1,4-microstructures of poly(1,3-cyclohexadiene), we have studied the effects of conformational asymmetry among the three blocks on the morphologies using transmission electron microscopy (TEM), small-angle X-ray scattering (SAXS), and self-consistent field theory (SCFT) performed with PolySwift++. Our work reveals that the triblock terpolymer melts containing a high percentage of 1,2-microstructures in the PCHD block are disordered at 110 °C for all the samples, independent of sequence and volume fraction of the blocks. In contrast, the triblock terpolymer melts containing a high percentage of 1,4-microstructure form regular morphologies known from the literature. The accuracy of the SCFT calculations depends on calculating the χ parameters that quantify the repulsive interactions between different monomers. Simulations using χ values obtained from solubility parameters and group contribution methods are unable to reproduce the morphologies as seen in the experiments. However, SCFT calculations accounting for the enhancement of the χ parameter with an increase in the conformational asymmetry lead to an excellent agreement between theory and experiments. These results highlight the importance of conformational asymmetry in tuning the χ parameter and, in turn, morphologies in block copolymers. 23406348 Computational study of chain transfer to monomer reactions in high-temperature polymerization of alkyl acrylates. This article presents a computational study of chain transfer to monomer (CTM) reactions in self-initiated high-temperature homopolymerization of alkyl acrylates (methyl, ethyl, and n-butyl acrylate). Several mechanisms of CTM are studied. The effects of the length of live polymer chains and the type of monoradical that initiated the live polymer chains on the energy barriers and rate constants of the involved reaction steps are investigated theoretically. All calculations are carried out using density functional theory. Three types of hybrid functionals (B3LYP, X3LYP, and M06-2X) and four basis sets (6-31G(d), 6-31G(d,p), 6-311G(d), and 6-311G(d,p)) are applied to predict the molecular geometries of the reactants, products and transition sates, and energy barriers. Transition state theory is used to estimate rate constants. The results indicate that abstraction of a hydrogen atom (by live polymer chains) from the methyl group in methyl acrylate, the methylene group in ethyl acrylate, and methylene groups in n-butyl acrylate are the most likely mechanisms of CTM. Also, the rate constants of CTM reactions calculated using M06-2X are in good agreement with those estimated from polymer sample measurements using macroscopic mechanistic models. The rate constant values do not change significantly with the length of live polymer chains. Abstraction of a hydrogen atom by a tertiary radical has a higher energy barrier than abstraction by a secondary radical, which agrees with experimental findings. The calculated and experimental NMR spectra of dead polymer chains produced by CTM reactions are comparable. This theoretical/computational study reveals that CTM occurs most likely via hydrogen abstraction by live polymer chains from the methyl group of methyl acrylate and methylene group(s) of ethyl (n-butyl) acrylate. 23617753 Small-Molecule Inhibitors of Cytokine-Mediated STAT1 Signal Transduction In β-Cells With Improved Aqueous Solubility. We previously reported the discovery of BRD0476 (1), a small molecule generated by diversity-oriented synthesis that suppresses cytokine-induced β-cell apoptosis. Herein, we report the synthesis and biological evaluation of 1 and analogs with improved aqueous solubility. By replacing naphthyl with quinoline moieties, we prepared active analogs with up to a 1400-fold increase in solubility from 1. In addition, we demonstrated that compound 1 and analogs inhibit STAT1 signal transduction induced by IFN-γ. 23353659 Phenolic glycosides from Curculigo orchioides Gaertn. Five new chlorophenolic glucosides, curculigine E (1), curculigine F (2), curculigine G (3), curculigine H (5), curculigine I (6) and one new phenolic glycoside, orcinoside H (4), together with eight known phenolic glycosides (7-14) were isolated from the Curculigo orchioides Gaertn. Their structures were established by spectroscopic techniques (IR, UV, MS, 1D and 2D NMR). The isolated phenolic glycosides were evaluated for antiosteoporotic activity against MC3T3-E1 cell line using MTT assays. Compounds 1, 2, 3, and 5 showed moderate antiosteoporotic activity with the proliferation rate of 10.1-14.1%. 23487179 Rotational spectroscopy meets theory. Rotational spectroscopy is known to be a technique that is widely used to infer information on molecular structure and dynamics. In the last few decades, its role in the field of atmospheric and astrophysical investigations has rapidly grown. However, several are the challenging aspects in rotational spectroscopy, since the detection and analysis of spectra as well as interpretation of obtained results are not at all straightforward. Quantum chemistry has reached such an accuracy that can be used to disentangle these challenging situations by guiding the experimental investigation, assisting in the determination of the spectroscopic parameters, and extracting information of chemical interest. This perspective provides an overview of the theoretical background and computational requirements needed for the accurate evaluation of the spectroscopic parameters of relevance to rotational spectroscopy. The role of theory in guiding and supporting experiment is detailed through a few examples, and the interplay of experiment and theory is discussed in terms of the information of physical and chemical interest that can be derived. 23409842 Mechanistic insights into water-protein interactions of filamentous bacteriophage. Water plays a major structural and functional role around proteins. In an attempt to explore this mechanistic structural aspect of proteins, we present site-specific interaction of hydration water with the major coat protein subunit of filamentous virus Pf1 by magic angle spinning (MAS) solid-state NMR. The interaction of surrounding water with 36 MDa Pf1 virion is investigated in uniformly (13)C, (15)N isotopically labeled; polyethylene glycol precipitated fully hydrated samples by solid-state nuclear magnetic resonance spectroscopy. Dipolar edited two-dimensional (2D) (1)H-(15)N heteronuclear correlation (HETCOR) experiments lead to unambiguous assignments of cross-peaks originating exclusively from (1)H resonances of water molecules correlating to the protein amide nitrogen. An enhanced resolved (1)H chemical shift dimension in these experiments also precludes the need of perdeuteration. We report seven residues spanning the 40-residue continuous α-helical conformation assembly of Pf1 interacting with surrounding water. It shows a highly hydrated inner core inside this viral filamentous assembly. The results obtained also suggest the first evidence of a water-mediated interface cluster formed at the site of Arg44 with the single-stranded DNA genome of the filamentous phage supramolecular assembly. 23423942 Use of gene expression data to determine effects on gonad phenotype in japanese medaka after exposure to trenbolone or estradiol. Various aquatic bioassays using one of several fish species have been developed or are in the process of being developed by organizations like the US Environmental Protection Agency and the Office of Economic Cooperation and Development for testing potential endocrine-disrupting chemicals (EDCs). Often, these involve assessment of the gonad phenotype of individuals as a key endpoint that is inputted into a risk or hazard assessment. Typically, gonad phenotype is determined histologically, which involves specialized and time-consuming techniques. The methods detailed here utilize an entirely different methodology, reverse-transcription quantitative polymerase chain reaction, to determine the relative expression levels of 4 genes after exposure to either 17β-estradiol or 17β-trenbolone and, by extension, the effects of EDCs on the phenotypic status of the gonad. The 4 genes quantified, Sox9b, protamine, Fig1α, and ZPC1, are all involved in gonad development and maintenance in Japanese medaka (Oryzias latipes); these data were then inputted into a permutational multivariate analysis of variance to determine whether significant differences exist between treatment groups. This information in conjunction with the sexual genotype, which can be determined in medaka, can be used to determine adverse effects of exposure to EDCs in a similar fashion to the histologically determined gonad phenotype. Environ Toxicol Chem 2013;32:1344-1353. © 2013 SETAC. 23609438 The Intermediate-conductance Calcium-activated Potassium Channel KCa3.1 Regulates Vascular Smooth Muscle Cell Proliferation via Controlling Calcium-dependent Signaling. The intermediate-conductance calcium-activated potassium channel KCa3.1 contributes to a variety of cell activation processes in pathologies such as inflammation, carcinogenesis and vascular remodeling. We examined the electrophysiological and transcriptional mechanisms by which KCa3.1 regulates vascular smooth muscle cell (VSMC) proliferation. Platelet-derived growth factor-BB (PDGF)-induced proliferation of human coronary artery VSMCs was attenuated by lowering intracellular Ca(2+) concentration ([Ca(2+)]i) and was enhanced by elevating [Ca(2+)]i. KCa3.1 blockade or knockdown inhibited proliferation by suppressing the rise in [Ca(2+)]i and attenuating the expression of phosphorylated cAMP response element binding protein (CREB), c-fos and neuron-derived orphan receptor-1 (NOR-1). This anti-proliferative effect was abolished by elevating [Ca(2+)]i. KCa3.1 overexpression induced VSMC proliferation, and potentiated PDGF-induced proliferation, by inducing CREB phosphorylation, c-fos and NOR-1. Pharmacological stimulation of KCa3.1 unexpectedly suppressed proliferation by inhibiting the rise in [Ca(2+)]i and abolishing the expression and activity of KCa3.1 and PDGF β-receptors. The stimulation also attenuated the levels of phosphorylated CREB, c-fos and cyclins expression. After KCa3.1 blockade, the characteristic round shape of VSMCs expressing high l-caldesmon and low calponin-1 (dedifferentiation state) was maintained, whereas KCa3.1 stimulation induced a spindle-shape cellular appearance, with low l-caldesmon and high calponin-1. In conclusion, KCa3.1 plays an important role in VSMC proliferation via controlling Ca(2+)-dependent signaling pathways and its modulation may therefore constitute a new therapeutic target for cell proliferative diseases such as atherosclerosis. 23602400 Identification of the fused bicyclic 4-amino-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors. 2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine derivative (2) was found to be a new PDE4 inhibitor with moderate PDE4B activity (IC50=150nM). A number of derivatives with a variety of 4-amino substituents and fused bicyclic pyrimidines were synthesized. Among these, 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative (18) showed potent PDE4B inhibitory activity (IC50=25 nM). Finally, N-propylacetamide derivative (31b) was determined as a potent inhibitor for both PDE4B (IC50=7.5nM) and TNF-α production in mouse splenocytes (IC50=9.8nM) and showed good in vivo anti-inflammatory activity in the LPS-induced lung inflammation model in mice (ID50=18mg/kg). The binding mode of the new inhibitor (31e) in the catalytic site of PDE4B is presented based on an X-ray crystal structure of the ligand-enzyme complex. 22397835 Toxic effects of 50 Hz electromagnetic field on memory consolidation in male and female mice. In this study, the effect of exposure to an 8 mT, 50 Hz extremely low-frequency electromagnetic field (ELF EMF) on memory consolidation of adult male and female mice was studied. For this purpose male and female mice were randomly distributed among six groups (n = 10 in each group). Using passive avoidance task, despite its natural tendency, mouse learns to stay on a small platform to avoidant electric shock. Immediately after the learning session, laboratory animals in the experimental groups were placed in an 8 mT, 50 Hz sinusoidal EMF for 4 h. The second male and female groups were sham exposed (exposure device off) and the third groups were considered as the controls. Twenty-four hours after the learning session, the animals were placed on small platform again and step-down latency was measured as the memory consolidation index. Significant (p < 0.05) decreases were determined among groups in memory function and results showed that exposure to an 8 mT, 50 Hz EMF for 4 h has devastating effects on memory consolidation in male and female mice. 23435916 Anti-inflammatory effect of pristimerin on lipopolysaccharide-induced inflammatory responses in murine macrophages. Pristimerin, a quinonemethide triterpenoid derived from Celastraceae and Hippocrateaceae, has recently been found to suppress tumor promotion, metastasis and angiogenesis. In the present study, we evaluated the anti-inflammatory potentials of pristimerin in a cell culture system. Pristimerin suppressed not only the generation of nitric oxide (NO) and prostaglandin E2, but also the expression of inducible NO synthase and cyclooxygenase-2 induced by lipopolysacharide (LPS) in murine macrophage RAW264.7 cells. Similarly, pristimerin inhibited the release of pro-inflammatory cytokines, namely, tumor necrosis factor-α and interleukin-6, induced by LPS. The underlying mechanism of the anti-inflammatory action of pristimerin was correlated with down-regulation of nuclear factor-κB and the mitogen-activated protein kinase signal pathway. 23445362 Arylazanylpyrazolone derivatives as inhibitors of mutant superoxide dismutase 1 dependent protein aggregation for the treatment of amyotrophic lateral sclerosis. The arylsulfanylpyrazolone and aryloxanylpyrazolone scaffolds previously were reported to inhibit Cu/Zn superoxide dismutase 1 dependent protein aggregation and to extend survival in the ALS mouse model. However, further evaluation of these compounds indicated weak pharmacokinetic properties and a relatively low maximum tolerated dose. On the basis of an ADME analysis, a new series of compounds, the arylazanylpyrazolones, has been synthesized, and structure-activity relationships were determined. The SAR results showed that the pyrazolone ring is critical to cellular protection. The NMR, IR, and computational analyses suggest that phenol-type tautomers of the pyrazolone ring are the active pharmacophore with the arylazanylpyrazolone analogues. A comparison of experimental and calculated IR spectra is shown to be a valuable method to identify the predominant tautomer. 23511711 A Nanogram Dose of the CYP3A Probe Substrate Midazolam to Evaluate Drug Interactions. The objective of the study was to establish an in vivo method for assessing cytochrome P450 3A (CYP3A) activity using therapeutically inert nanogram doses of midazolam. We administered four escalating single doses of oral midazolam (0.0001-3 mg) to 12 healthy participants, stratified according to CYP3A5 carrier status, to assess pharmacokinetics linearity. We then evaluated the interactions with the CYP3A inhibitor ketoconazole (400 mg q.d.) after nanogram and regular doses of midazolam. Area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) were linear over the entire range of doses. Ketoconazole reduced midazolam oral clearance by 92.8%. AUC and Cmax increased by 1,540 and 363%, respectively. CYP3A5 carrier status had no influence on midazolam oral clearance or its inhibition by ketoconazole. This is the first study showing that midazolam pharmacokinetics is linear in a 30,000-fold concentration range, and therefore that nano- and microgram doses of midazolam can reliably predict the pharmacokinetics of midazolam in therapeutic doses and can be used to assess CYP3A activity even in the presence of strong CYP3A inhibitors.Clinical Pharmacology & Therapeutics (2013); advance online publication 20 March 2013. doi:10.1038/clpt.2013.27. 23405943 Design and evaluation of 4-aminophenol and salicylate derivatives as free-radical scavenger. This theoretical and experimental study describes the design and evaluation of the free-radical scavenging effect for the molecular association of 4-aminophenol and salicylate derivatives. For this purpose, we employed theoretical methods for the selection of antioxidant drugs and the rapid methods of evaluation: the 1,1-diphenyl-2-picrylhydrazyl radical and the thiobarbituric acid reactive substances in the lipid peroxidation initiated by Fe(2+) and ascorbic acid in human erythrocytes. The associate derivatives exhibited a more potent inhibition than the salicylic acid, while the benzoyl compound exhibited a more potent inhibition than paracetamol. The molecular parameters related to the electron distribution and structure (ionization potential and energy of the highest occupied molecular orbital) correlated very well with the antioxidant action of the compounds studied here in different tests. 23471504 Interindividual variability of carboxymethylenebutenolidase homolog, a novel olmesartan medoxomil hydrolase, in the human liver and intestine. Olmesartan medoxomil (OM) is a prodrug-type angiotensin II type 1 receptor antagonist. OM is rapidly converted into its active metabolite olmesartan by multiple hydrolases in humans, and we recently identified carboxymethylenebutenolidase homolog (CMBL) as one of the OM bioactivating hydrolases. In the present study, we further investigated the interindividual variability of mRNA and protein expression of CMBL and OM-hydrolase activity using 40 individual human liver and 30 intestinal specimens. In the intestinal samples, OM-hydrolase activity strongly correlated with the CMBL protein expression, clearly indicating that CMBL is a major contributor to the prodrug bioactivation in human intestine. The protein and activity were highly distributed in the proximal region (duodenum and jejunum) and decreased to the distal region of the intestine. Although there was high interindividual variability (16-fold) in both the protein and activity in the intestinal segments from the duodenum to colon, the interindividual variability in the duodenum and jejunum was relatively small (3.0- and 2.4-fold, respectively). In the liver samples, the interindividual variability in the protein and activity was 4.1- and 6.8-fold, respectively. No sex differences in the protein and activity were shown in the human liver or intestine. A genetically engineered Y155C mutant of CMBL, which was caused by a single nucleotide polymorphism rs35489000, showed significantly lower OM-hydrolase activity than the wild-type protein although no minor allele was genotyped in the 40 individual liver specimens. 23411210 Neuroprotective effects of oral gallic acid against oxidative stress induced by 6-hydroxydopamine in rats. Free radical-induced neural damage is implicated in neurodegenerative diseases and antioxidants have protective activity. In the present study, we examined the effect of gallic acid (GA; 50, 100 and 200mg/kg, p.o. for 10 days) on memory deficit and cerebral oxidative stress induced by 6-hydroxydopamine (6-OHDA; 8 μg/2 μL) injected into the medial forebrain bundle (MFB, full nigral lesion) as an animal model of Parkinson's disease (PD). The results showed that 6-OHDA significantly reduced the passive avoidance memory performance, non-enzymatic (total thiol) and enzymatic [glutathione peroxidase (GPx)] antioxidant contents and increased the level of malondialdehyde (MDA) in the hippocampus and striatum of vehicle-treated group as compared to sham-operated rats. Furthermore, oral administration of GA significantly increased the passive avoidance memory, total thiol and GPx contents and also decreased MDA levels in the above tissues. The results suggest that GA has neuroprotective activity against 6-OHDA-induced oxidative stress via enhancement of cerebral antioxidant defence. 23561197 Development of electrochemical biosensor with nano-interface for xanthine sensing - A novel approach for fish freshness estimation. Highly sensitive, selective and mediator-free electrochemical biosensor with nano-interface for sensing xanthine using xanthine oxidase (XOx) has been developed. Towards the preparation of nano-interface, Fe3O4 nanoparticles were synthesized by thermal co-precipitation method and structural, morphological characterizations were carried out using X-ray diffraction (XRD), field emission scanning electron microscope (FE-SEM) and field emission transmission electron microscope (FE-TEM) respectively. The modified electrode with the covalently linked XOx was confirmed by FT-IR. With the modified electrode as working electrode, electrochemical studies were carried out. The linear range was found to be from 0.4 to 2.4nM. The biosensor exhibited an optimum response in less than 2s and was not prone to interferences from ascorbic acid, urea and sucrose. The Michaelis-Menten constant (Km) was found to be 1.3nM. The limit of detection is found to be 2.5pM and limit of quantification as 8.3pM. The developed biosensor was used for the real time measurement of fish freshness. 23426954 Novel Insights into CB1 Cannabinoid Receptor Signaling: A Key Interaction Identified between the Extracellular-3 Loop and Transmembrane Helix 2. Activation of the cannabinoid CB1 receptor (CB1) is modulated by aspartate residue D2.63(176) in transmembrane helix (TMH) 2. Interestingly, D2.63 does not affect the affinity for ligand binding at the CB1 receptor. Studies in class A G protein-coupled receptors have suggested an ionic interaction between residues of TMH2 and 7. In this report, modeling studies identified residue K373 in the extracellular-3 (EC-3) loop in charged interactions with D2.63. We investigated this possibility by performing reciprocal mutations and biochemical studies. D2.63(176)A, K373A, D2.63(176)A-K373A, and the reciprocal mutant with the interacting residues juxtaposed D2.63(176)K-K373D were characterized using radioligand binding and guanosine 5'-3-O-(thio)triphosphate functional assays. None of the mutations resulted in a significant change in the binding affinity of N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A) or (-)-3cis -[2-hydroxyl-4-(1,1-dimethyl-heptyl)phenyl]-trans-4-[3-hydroxyl-propyl] cyclohexan-1-ol (CP55,940). Modeling studies indicated that binding-site interactions and energies of interaction for CP55,940 were similar between wild-type and mutant receptors. However, the signaling of CP55,940, and (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]-pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)-methanone mesylate (WIN55,212-2) was impaired at the D2.63(176)A-K373A and the single-alanine mutants. In contrast, the reciprocal D2.63(176)K-K373D mutant regained function for both CP55,940 and WIN55,212-2. Computational results indicate that the D2.63(176)-K373 ionic interaction strongly influences the conformation(s) of the EC-3 loop, providing a structure-based rationale for the importance of the EC-3 loop to signal transduction in CB1. The putative ionic interaction results in the EC-3 loop pulling over the top (extracellular side) of the receptor; this EC-3 loop conformation may serve protective and mechanistic roles. These results suggest that the ionic interaction between D2.63(176) and K373 is important for CB1 signal transduction. 23122152 The influence of the malaxation temperature on the activity of polyphenoloxidase and peroxidase and on the phenolic composition of virgin olive oil. The effect of the malaxation temperature under sealed conditions on the qualitative and quantitative composition of the phenolic compounds in virgin olive oils produced from four Italian cultivars was assessed for two atmospheric conditions. In both cases, the results show a positive relationship between temperature and the concentration of the derivatives of the secoiridoid aglycones; the effect of the temperature on the oxidoreductases that promote oxidation (polyphenoloxidase and peroxidase) was investigated to determine their optimal temperatures and thermal stability. While olive peroxidase (POD) showed the highest activity at 37°C and high stability in the temperature range tested, polyphenoloxidase (PPO) exhibited the optimum activity at approximately 50°C, but showed low stability at 40°C, with a large variation in stability according to the olive cultivar. These results may contribute to an understanding of the increase in the phenol concentration found in virgin olive oils obtained following higher temperatures of malaxation. 23428212 Transparent, Conductive, and Printable Composites Consisting of TEMPO-Oxidized Nanocellulose and Carbon Nanotube. Ultrastrong, transparent, conductive and printable nanocomposites were successfully prepared by mixing single-walled carbon nanotubes (CNTs) with 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-oxidized cellulose nanofibrils (TOCNs) with abundant sodium carboxyl groups on the crystalline nanocellulose surfaces. The surface-anionic cellulose nanofibrils had reinforcing and nanodispersing effects on the CNTs both in water used as the dispersed medium and in the dried composite film, providing highly conductive and printable nanocomposites with a small amount of CNTs. TOCNs are therefore expected as an effective flexible matrix that can be used as an alternative to conventional polymers for various electrical materials, when nanocomposited with CNTs and also graphene. Our findings provide a promising route to realize green and flexible electronics. 22733134 The Hedgehog processing pathway is required for NSCLC growth and survival. Considerable interest has been generated from the results of recent clinical trials using smoothened (SMO) antagonists to inhibit the growth of hedgehog (HH) signaling-dependent tumors. This interest is tempered by the discovery of SMO mutations mediating resistance, underscoring the rationale for developing therapeutic strategies that interrupt HH signaling at levels distinct from those inhibiting SMO function. Here, we demonstrate that HH-dependent non-small cell lung carcinoma (NSCLC) growth is sensitive to blockade of the HH pathway upstream of SMO, at the level of HH ligand processing. Individually, the use of different lentivirally delivered shRNA constructs targeting two functionally distinct HH-processing proteins, skinny hedgehog (SKN) or dispatched-1 (DISP-1), in NSCLC cell lines produced similar decreases in cell proliferation and increased cell death. Further, providing either an exogenous source of processed HH or a SMO agonist reverses these effects. The attenuation of HH processing, by knocking down either of these gene products, also abrogated tumor growth in mouse xenografts. Finally, we extended these findings to primary clinical specimens, showing that SKN is frequently overexpressed in NSCLC and that higher DISP-1 expression is associated with an unfavorable clinical outcome. Our results show a critical role for HH processing in HH-dependent tumors, identifies two potential druggable targets in the HH pathway, and suggest that similar therapeutic strategies could be explored to treat patients harboring HH ligand-dependent cancers. 23536728 Tumor Suppressor Protein p53 Negatively Regulates Human Pregnane X Receptor Activity. The human pregnane X receptor (PXR) regulates genes involved in drug metabolism and disposition. PXR associates with multiple corepressors that attenuate, and coactivators that enhance its activity. PXR plays a vital role in the drug metabolism pathway, and a comprehensive examination of PXR-associated proteins will provide greater insight into the regulation of the receptor and possible therapeutic implications. We performed a mass spectrometric screen to identify PXR-associated proteins. Here we report that the tumor suppressor protein p53 can associate with PXR and downregulate its activity. A loss-of-function p53 mutant (R175H) interacts with PXR but does not repress its activity. Mutant p53 can relieve the suppressive effect of wild-type p53 by competing with its interaction with PXR, suggesting that protein-protein interaction is required but not sufficient for p53 to repress PXR activity. Interestingly, a PXR variant with a naturally occurring deletion of a conserved, unique sequence in the ligand binding domain (PXR174-210) did not interact with p53, indicating that the PXR-p53 interaction is specific. Using a chromatin immunoprecipitation assay, we showed that p53 inhibits the binding of PXR to the CYP3A4 promoter. The loss of p53 function in tumor cells leads to aberrant cell proliferation, apoptosis, carcinogenesis, and altered sensitivity to chemotherapeutic drugs, while PXR contributes to chemoresistance in many cancer cells. Our findings show for the first time that wild-type p53 can negatively regulate PXR by physically associating with it. Thus, PXR and p53 appear to play important yet opposing roles in the sensitivity of tumor cells to chemotherapy. 23444284 Population pharmacokinetic analysis of a nevirapine-based HIV-1 prevention of mother-to-child transmission program in Uganda to assess the impact of different dosing regimens for newborns. Single-dose nevirapine for mothers and newborns at delivery is the simplest prevention strategy for vertical HIV-1 transmission and hence widely used in resource-constrained settings. HIV-1-positive mothers and newborns received single-dose nevirapine in a prevention of mother-to-child HIV-1 transmission (PMTCT) program in Uganda. In a pharmacokinetic investigation, breast milk and plasma samples of mothers and newborns were collected. The nonlinear mixed-effects modeling approach was suitable for analysis (average: 1.8 samples/matrix/individual). For describing the nevirapine pharmacokinetics in mothers and newborns, a 1-compartment model was demonstrated to be sufficient. The plasma-placenta transfer could be quantified, revealing a transfer fraction of 11% to 25% (with a significant influence of time span between maternal nevirapine intake and birth) and a high transfer rate constant from maternal drug administration. Interindividual variability was moderate between mothers and high between newborns. Simulations revealed that newborns born early (<1 hour) after maternal nevirapine intake would benefit from a 3-fold higher nevirapine dosage (6 mg/kg) after birth for analogous protective plasma concentrations over the first 2 weeks. In contrast, postnatal nevirapine dosage seemed to be dispensable for newborns born late (>24 hours) after maternal nevirapine intake. These dosing recommendations should be evaluated in prospective studies, including additional antiretroviral drugs in accordance with current PMTCT guidelines. 23549672 Is There Visceral Adipose Tissue (VAT) Intracellular Hypercortisolism in Human Obesity? The fact that obesity is a prominent feature of Cushing's syndrome (systemic hypercortisolism of adrenocortical origin) stimulated a 40-year search for evidence of systemic hypercortisolism in human obesity. That search has failed to find such evidence. For the past 15 years, however, studies have been done to evaluate a possible alternative type of hypercortisolism in obesity, namely visceral adipose tissue (VAT) intracellular hypercortisolism. The current review summarizes the evidence published so far about this possibility. There have been three types of evidence studied: direct measurement of the VAT levels of 11β-hydroxysteroid dehydrogenase type I (11-HSD-1), which converts biologically inactive cortisone to biologically active cortisol; direct measurement of splanchnic cortisol production; and evaluation of the effect of a specific inhibitor of 11-HSD-1 on metabolic abnormalities associated with obesity, particularly diabetes mellitus. The results are complex and difficult to interpret. Our conclusion is that the presence of VAT intracellular hypercortisolism in human obesity is possible but unlikely. 23411202 Effects of amylosucrase treatment on molecular structure and digestion resistance of pre-gelatinised rice and barley starches. Structural modification of rice and barley starches with Neisseria polysaccharea amylosucrase (NpAS) was conducted, and relationship between structural characteristics and resistant starch (RS) contents of NpAS-treated starches was investigated. Pre-gelatinised rice and barley starches were treated with NpAS. NpAS-treated starches were characterised with respect to morphology, X-ray diffraction pattern, amylopectin branch-chain distribution, and RS content, and their structural characteristics were correlated to RS contents. Regardless of amylose contents of native starches, NpAS-treated (relative to native) starches possessed lower and higher proportions of shorter (DP 6-12) and intermediate (DP 13-36) amylopectin (AP) branch-chains, respectively. RS contents were higher for NpAS-treated starches relative to native starches, and maximum RS contents were obtained for NpAS-treated starches of waxy rice and barley genotypes. Amylose contents were not associated with RS contents of NpAS-treated starches. However, shorter and intermediate AP branch-chain portions were negatively and positively correlated to RS contents of NpAS-treated starches, respectively. 23597450 Anti-inflammatory effect of prunetin via the suppression of NF-κB pathway. Prunetin is an O-methylated isoflavone, which is found in Prunus yedoensis. To date no report has been published on anti-inflammatory activities of prunetin. In the present study, the anti-inflammatory effect of prunetin on LPS-stimulated RAW 264.7 macrophage and LPS-induced septic shock model were investigated. Inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) expressions were determined by western blot and or realtime-PCR (RT-PCR). To elucidate its underlying mechanism, nuclear factor-kappa B (NF-κb) activation and its downstream pathways were investigated by NF-κB transcription factor assay, reporter gene expression, and western blot. In vivo anti-inflammatory effects of prunetin were evaluated in LPS-induced endotoxemia. Promoter assay revealed that prunetin inhibits LPS-induced nitric oxide and prostaglandin E2 production through the suppression of iNOS and COX-2 at the transcriptional level. In addition, prunetin inhibits NF-κB-dependent inflammatory responses by modulating IκB kinase (IKK)-inhibitor κBα (IκBα)-NF-κB signaling. Consistent with these results, prunetin significantly reduced serum levels of inflammatory cytokines and mortality in mice challenged with lipopolysaccharide. These findings offer a potential mechanism for the anti-inflammatory activity of prunetin. 22659473 Molecular mechanisms that desensitize metabotropic glutamate receptor signaling: an overview. The purpose of the present article is to review our actual knowledge on the desensitization of metabotropic glutamate receptors based on the literature available so far, with the attempt to emphasize all converging data and to give a possible explanation to those evidences that still remain controversial. 1. We review our knowledge on the regulation of mGlu receptors based on the available literature 2. We report converging data and we comment on issues that still remain controversial. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23341208 Simulations in evolution. III. Randomness as a generator of opportunities. In Neo-Darwinism, variation and natural selection are the two evolutionary mechanisms which propel biological evolution. Our previous reports presented a histogram model to simulate the evolution of populations of individuals classified into bins according to an unspecified, quantifiable phenotypic character, and whose number in each bin changed generation after generation under the influence of fitness, while the total population was maintained constant. The histogram model also allowed Shannon entropy (SE) to be monitored continuously as the information content of the total population decreased or increased. Here, a simple Perl (Practical Extraction and Reporting Language) application was developed to carry out these computations, with the critical feature of an added random factor in the percent of individuals whose offspring moved to a vicinal bin. The results of the simulations demonstrate that the random factor mimicking variation increased considerably the range of values covered by Shannon entropy, especially when the percentage of changed offspring was high. This increase in information content is interpreted as facilitated adaptability of the population. 23603053 Structure-dependent activities of hydroxylated polybrominated diphenyl ethers on human estrogen receptor. Polybrominated diphenyl ethers (PBDEs) have been shown to affect the estrogen receptor (ER) signaling pathway, and one of the proposed disruption mechanisms is direct binding of hydroxylated PBDE (OH-PBDE) to ER. In this paper, the binding affinity of 22 OH-PBDEs with different degrees of bromination to ER was assessed quantitatively using a surface plasmon resonance biosensor technique. Seven OH-PBDEs were found to bind directly with ER with KD ranging from 1.46×10(-7)M to 7.90×10(-6)M, and the affinity is in the order of 6-OH-BDE-047≧4'-OH-BDE-049>4'-OH-BDE-017>6'-OH-BDE-099≧5'-OH-BDE-099>2'-OH-BDE-007>3'-OH-BDE-028. In MVLN luciferase gene reporter assays, 10 low-brominated OH-PBDEs induced luciferase activity alone, but are 10(5) to 10(7) fold less potent than E2. Their estrogenic activity is in the order of 4'-OH-BDE-049>4'-OH-BDE-017>2'-OH-BDE-007>3'-OH-BDE-028>3-OH-BDE-047≧3'-OH-BDE-007. The good correlation between estrogenic activity and ER binding affinity of the low-brominated OH-PBDEs strongly suggest that these compounds induce ER transcriptional activity by binding directly with ER. The other 12 high-brominated OH-PBDEs inhibited luciferase activity of E2 to various degrees, demonstrating their antagonistic activity. Molecular docking analysis of the ER/OH-PBDE complexes revealed two distinctive binding modes between low- and high-brominated OH-PBDEs which provided rationale for the difference in their ER activity. 23238991 Snake (Walterinnesia aegyptia) venom-loaded silica nanoparticles induce apoptosis and growth arrest in human prostate cancer cells. Prostate cancer (PCa) is the most commonly diagnosed cancer in men. The progression and invasion of PCa are normally mediated by the overexpression of chemokine receptors (CKRs) and the interaction between CKRs and their cognate ligands. We recently demonstrated that venom extracted from Walterinnesia aegyptia (WEV) either alone or in combination with silica nanoparticles (WEV+NP) mediated the growth arrest and apoptosis of breast cancer cells. In the present study, we evaluated the impact of WEV alone and WEV+NP on the migration, invasion, proliferation and apoptosis of prostate cancer cells. We found that WEV alone and WEV+NP decreased the viability of all cell types tested (PCa cells isolated from patient samples, PC3 cells and LNCaP cells) using an MTT assay. The IC(50) values were determined to be 10 and 5 μg/mL for WEV alone and WEV+NP, respectively. WEV+NP decreased the surface expression of the CKRs CXCR3, CXCR4, CXCR5 and CXCR6 to a greater extent than WEV alone and subsequently reduced migration and the invasion response of the cells to the cognate ligands of the CKRs (CXCL10, CXCL12, CXCL13 and CXCL16, respectively). Using a CFSE proliferation assay, we found that WEV+NP strongly inhibited epidermal growth factor-mediated PCa cell proliferation. Furthermore, analysis of the cell cycle indicated that WEV+NP strongly altered the cell cycle of PCa cells and enhanced the induction of apoptosis. Finally, we demonstrated that WEV+NP robustly decreased the expression of anti-apoptotic effectors, such as B cell Lymphoma-2 (Bcl-2), B cell Lymphoma-extra large (Bcl-(XL)) and myeloid cell leukemia sequence-1 (Mcl-1), and increased the expression of pro-apoptotic effectors, such as Bcl-2 homologous antagonist/killer (Bak), Bcl-2-associated X protein (Bax) and Bcl-2-interacting mediator of cell death (Bim). WEV+NP also altered the membrane potential of mitochondria in the PCa cells. Our data reveal the potential of nanoparticle-sustained delivery of snake venom as effective treatments for prostate cancer. 23494834 Prospects and challenges of graphene in biomedical applications. Graphene materials have entered a phase of maturity in their development that is characterized by their explorative utilization in various types of applications and fields from electronics to biomedicine. Herein, we describe the recent advances made with graphene-related materials in the biomedical field and the challenges facing these exciting new tools both in terms of biological activity and toxicological profiling in vitro and in vivo. Graphene materials today have mainly been explored as components of biosensors and for construction of matrices in tissue engineering. Their antimicrobial activity and their capacity to act as drug delivery platforms have also been reported, however, not as coherently. This report will attempt to offer some perspective as to which areas of biomedical applications can expect graphene-related materials to constitute a tool offering improved functionality and previously unavailable options. 23456892 The effect of rosiglitazone on bone mass and fragility is reversible and can be attenuated with alendronate. Rosiglitazone (RSG) is an anti-diabetic drug that has been associated with increased peripheral fractures primarily in postmenopausal women. In this report, we investigated the underlying mechanisms of RSG-associated bone loss in ovariectomized (OVX) rats and determine whether changes in bone parameters associated with RSG administration are reversible on treatment cessation or preventable by co-administration with an antiresorptive agent. Nine-month-old Sprague-Dawley rats underwent OVX or sham operation. Sham-operated rats received oral vehicle only; OVX animals were randomized to receive vehicle, RSG, alendronate (ALN) or RSG plus ALN for 12 weeks. All treatment started the day after ovariectomy. After the 12 week treatment period, the OVX and RSG groups also underwent an 8-week treatment-free recovery period. Bone densitometry measurements, bone turnover markers, biomechanical testing and histomorphometric analysis were conducted. Micro-computed tomography was also used to investigate changes in microarchitecture. RSG significantly increased deoxypyridinoline levels compared with OVX. Significant exacerbation of OVX-induced loss of bone mass, strength and microarchitectural deteriorations was observed in RSG-treated OVX animals compared with OVX controls. These effects were observed predominantly at sites rich in trabecular bone with less pronounced effects in cortical bone. Co-administration of RSG and ALN prevented the bone loss associated with RSG treatment. Following cessation of RSG treatment, effects on bone mass and strength showed evidence of reversal. Thus, treatment of OVX rats with RSG results in loss of bone mass and strength, primarily at sites rich in trabecular bone mainly due to increased bone resorption. These effects can be prevented by concomitant treatment with ALN and may be reversed following discontinuation of RSG. © 2013 American Society for Bone and Mineral Research. 23535185 Galangin attenuates mast cell-mediated allergic inflammation. A great number of people are suffering from allergic inflammatory disease such as asthma, atopic dermatitis, and sinusitis. Therefore discovery of drugs for the treatment of these diseases is an important subject in human health. In this study, we investigated anti-allergic inflammatory effect of galangin and underlying mechanisms of action using in vitro and in vivo models. Galangin inhibited histamine release by the reduction of intracellular calcium in phorbol 12-mystate 13-acetate plus calcium ionophore A23187-stimulated human mast cells (HMC-1). Galangin decreased expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and IL-8. The inhibitory effect of galangin on theses pro-inflammatory cytokines was related with c-Jun N-terminal kinases, and p38 mitogen-activated protein kinase, nuclear factor-κB, and caspase-1. Furthermore, galangin attenuated IgE-mediated passive cutaneous anaphylaxis and the expression of histamine receptor 1 at the inflamed tissue. The inhibitory effects of galangin were more potent than cromolyn, a known anti-allergic drug. Our results showed that galangin down-regulates mast cell-derived allergic inflammatory reactions by blocking histamine release and expression of pro-inflammatory cytokines. In light of in vitro and in vivo anti-allergic inflammatory effects, galangin could be a beneficial anti-allergic inflammatory agent. 23552908 Adsorption of diferrocenylacetylene on Au(111) studied by scanning tunneling microscopy. Scanning tunneling microscopy images of diferrocenylacetylene (DFA) coadsorbed with benzene on Au(111) show individual and close-packed DFA molecules, either adsorbed alongside benzene or on top of a benzene monolayer. Images acquired over a range of positive and negative tip-sample bias voltages show a shift in contrast, with the acetylene linker appearing brighter than the ferrocenes at positive sample bias (where unoccupied states primarily contribute) and the reverse contrast at negative bias. Density functional theory was used to calculate the electronic structure of the gas-phase DFA molecule, and simulated images produced through two-dimensional projections of these calculations approximate the experimental images. The symmetry of both experimental and calculated molecular features for DFA rules out a cis adsorption geometry, and comparison of experiment to simulation indicates torsion around the inter-ferrocene axis between 90° and 180° (trans); the cyclopentadienyl rings are thus angled with respect to the surface. 23542239 SPIO-PICsome: Development of a highly sensitive and stealth-capable MRI nano-agent for tumor detection using SPIO-loaded unilamellar polyion complex vesicles (PICsomes). Size controllable polyion complex vesicles (PICsomes), composed of biocompatible poly(ethylene glycol) (PEG) and poly(amino acid)s, have an extremely prolonged lifetime in the bloodstream that enables them to accumulate effectively in tumors via the enhanced permeability and retention (EPR) effect. The purpose of this study was to use PICsomes to synthesize a highly sensitive MRI contrast agent for more precise tumor detection. We synthesized SPIO-Cy5-PICsomes (superparamagnetic iron oxide nanoparticle-loaded Cy5-cross-linked Nano-PICsomes) and characterized them using dynamic light scattering and transmission electron microscopy in vitro and evaluated their ability to detect subcutaneously grafted tumors in vivo with MRI. The transverse relaxivity (r2) of the SPIO-Cy5-PICsomes (r2=663±28mM(-1)s(-1)) was 2.54 times higher than that of bare clinically-used SPIO. In in vivo MRI experiments on mice subcutaneously grafted with colon-26 tumor cells, the tumor signal was significantly altered at 3h after SPIO-Cy5-PICsome administration and persisted for at least 24h. Small and early-stage in vivo tumors (3days after grafting, approximately 4mm(3)) were also clearly detected with MRI. SPIO-loaded PICsomes are sensitive MRI contrast agents that can act as a powerful nanocarrier to detect small tumors for early diagnosis. 23234607 Reporter ligand NMR screening method for 2-oxoglutarate oxygenase inhibitors. The human 2-oxoglutarate (2OG) dependent oxygenases belong to a family of structurally related enzymes that play important roles in many biological processes. We report that competition-based NMR methods, using 2OG as a reporter ligand, can be used for quantitative and site-specific screening of ligand binding to 2OG oxygenases. The method was demonstrated using hypoxia inducible factor hydroxylases and histone demethylases, and K(D) values were determined for inhibitors that compete with 2OG at the metal center. This technique is also useful as a screening or validation tool for inhibitor discovery, as exemplified by work with protein-directed dynamic combinatorial chemistry. 23586638 Kinetics and Mechanism of the Tropospheric Oxidation of Vinyl Acetate Initiated by OH Radical: A Theoretical Study. Vinyl acetate [VA (CH3COOC2H3)] is an important unsaturated and oxygenated volatile organic compound responsible for atmospheric pollution. In this work, possible reaction mechanisms for the degradation of OH-initiated atmospheric oxidation of VA are investigated. The potential energy surfaces (PESs) for the reaction of OH radical with VA in the presence of O2 and NO have been studied using the M06-2X/6-311++G(d,p) method. The initial addition reactions of more and less substituted ethylenic C-atoms of VA are treated separately, followed by a conventional transition state theory (TST) calculation for reaction rates. The direct H-abstraction mechanism and kinetics have also been studied. The initial OH addition occurs through a prereactive complex, and the calculated rate constants in the temperature range 250-350 K for both the addition reactions are found to have negative temperature dependence. The calculation indicates that the reaction proceeds predominantly via the addition of OH radical to the double bond rather than the direct abstraction of H-atoms in VA. IM1 [CH3C(O)O(•)CHCH2OH] and IM2 [CH3C(O)OCH(OH)(•)CH2], the OH adduct complexes formed initially, react with ubiquitous O2 followed by NO before their rearrangement. The formation of the prereactive complex plays an important role in reaction mechanism and kinetics. The calculated rate constant, k298K = 1.61 × 10(-11) cm(3) molecule(-1) s(-1), is well harmonized with the previous experimental data, k298K = (2.48 ± 0.61) × 10(-11) cm(3) molecule(-1) s(-1) (Blanco et al.) and k298K = (2.3 ± 0.3) × 10(-11) cm(3) molecule(-1) s(-1) (Picquet-Varrult et al.). Additionally, consistent and reliable enthalpies of formation at 298.15 K (ΔfH°298.15) have been computed for all the species involved in the title reaction using the composite CBS-QB3 method. The theoretical results confirm that the major products are formic acetic anhydride, acetic acid, and formaldehyde in the OH-initiated oxidation of VA in the presence of O2 and NO, which are in excellent agreement with the experimental findings. 23643700 Vitamin C and Lifespan in Model Organisms. The process of ageing has been repeatedly associated with increasing oxidative damage which has led to the hypothesis that reducing oxidative stress through antioxidant dietary factors may prolong lifespan. Ascorbic acid is an essential antioxidant in human diets and is widely used for supplementation. However, it is rather unclear if and to what extent ascorbic acid may affect lifespan in humans and model organisms. In our review of literature on vitamin C supplementation and its effect on lifespan in different model organisms we found that some studies suggest an increase in lifespan, other studies failed to observe any beneficial effect of vitamin C on longevity and some studies even reported a decrease in lifespan following vitamin C supplementation. Of the 14 studies included in our analysis, 3 were carried out in worms, 4 in flies and 7 in rodents. The discrepancies between the studies may be related to species-specific differences, the concentration of vitamin C administered, the duration of supplementation and whether vitamin C was used alone or as part of a combined antioxidant diet. Potential underlying mechanisms through which vitamin C may influence lifespan and differences amongst species regarding the capacity to produce vitamin C endogenously are discussed. 23330564 Recent developments in emerging microimmunoassays. Creative and novel microimmunoassay approaches continue to proliferate across many platforms originating from several fields of study. These efforts are aimed at improving one or more metrics for clinical tests, including improved sensitivity, increased speed, reduced cost, smaller sample size, the ability to analyze multiple antigens in parallel and ease of use. Many approaches focus on the production of microarrays that accomplish standard assays in parallel, or mobile solid-support formats to overcome issues of high background noise and long incubation times. In this article, innovative developments beyond existing commercial tests in the microimmunoassay arena are reviewed, covering January 2008 to April 2012. These developing experimental platforms are discussed in terms of their ability to augment or replace current commercial approaches. 23223801 Lanthanide-doped luminescent nano-bioprobes: from fundamentals to biodetection. Trivalent lanthanide (Ln(3+))-doped luminescent inorganic nanoparticles (NPs), characterized by long-lived luminescence, large Stokes and/or anti-Stokes shifts, narrow emission bands and high photochemical stability, are considered to be promising candidates as luminescent bioprobes in biomedicine and biotechnology. In this feature article, we provide a brief overview of the most recent advances in Ln(3+)-doped luminescent inorganic NPs as sensors, which covers from their chemical and physical fundamentals to biodetection, such as controlled synthesis methodology, surface modification chemistry, optical physics, and their promising applications in diverse bioassays, with an emphasis on heterogeneous and homogeneous in vitro biodetection. Finally, some of the most important emerging trends and future efforts toward this active research field are also proposed. 23099339 Teratogenic effects of diabetic conditions in chick heart in ovo and in micromass culture may be prevented by addition of vitamin C and folic acid. Maternal diseases like diabetes mellitus may cause developmental defects. Supplementation with folic acid and vitamin C during the periconceptional period has been shown to prevent some neural tube and congenital heart defects. Hearts were dissected from 5 days-old White Leghorn chick embryos, the cells isolated and cultured in micromass under diabetic conditions, with and without folic acid and vitamin C. Contractile activity, cell viability (resazurin reduction) and protein assays were performed. Results indicated diabetic conditions reduced contractile activity and cell viability, whilst vitamin C (100 μM) and folic acid (1 mM) administered concurrently significantly improved them to values comparable with the control. Day 3 chick embryos in ovo were injected with glucose+hydroxybutyrate or a combination of these and vitamins. Diabetic conditions caused gross and histological malformations, but these effects were abrogated by vitamin supplement. Teratogenic effects on heart development could possibly be prevented by vitamin supplementation during pregnancy. 23479455 The 5-hydroxytryptamine (serotonin) receptor 6 agonist EMD 386088 ameliorates ketamine-induced deficits in attentional set shifting and novel object recognition, but not in the prepulse inhibition in rats. Preclinical data suggest that the 5-hydroxytryptamine (serotonin) 6 (5-HT6) receptor may be a potential target for the development of new therapies for treating cognitive dysfunctions in schizophrenia and other central nervous system disorders. Recent evidence indicates that not only blockade but also activation of 5-HT6 receptors exerts procognitive effects. Nevertheless, little is known about the potential efficacy of 5-HT6 receptor agonists in models of schizophrenia-like cognitive deficits. The aim of the present study was to evaluate the effects of the 5-HT6 receptor agonist, EMD 386088, on the ketamine-induced deficits in the attentional set-shifting task (ASST), novel object recognition (NOR) task and prepulse inhibition (PPI) task in rats. Acute administration of EMD 386088 (2.5 and 5 mg/kg, intraperitoneally) to Sprague-Dawley rats reversed the deficit in the ASST induced by repeated ketamine administration. Moreover, the ketamine-induced deficit in the NOR task was ameliorated by EMD 386088 at a dose of 5 mg/kg. However, in contrast to the antipsychotic drug clozapine, the 5-HT6 agonist did not affect PPI disrupted by ketamine. The present study demonstrated the beneficial effects of the 5-HT6 agonist in ameliorating some of the ketamine-induced deficits relevant to schizophrenia. It thus seems likely that the 5-HT6 receptor activation may represent a useful pharmacological approach to the treatment of cognitive disturbances observed in this disorder. 23149337 Gs-coupled adenosine receptors differentially limit antigen-induced mast cell activation. Mast cell activation results in the immediate release of proinflammatory mediators prestored in cytoplasmic granules, as well as initiation of lipid mediator production and cytokine synthesis by these resident tissue leukocytes. Allergen-induced mast cell activation is central to the pathogenesis of asthma and other allergic diseases. Presently, most pharmacological agents for the treatment of allergic disease target receptors for inflammatory mediators. Many of these mediators, such as histamine, are released by mast cells. Targeting pathways that limit antigen-induced mast cell activation may have greater therapeutic efficacy by inhibiting the synthesis and release of many proinflammatory mediators produced in the mast cell. In vitro studies using cultured human and mouse mast cells, and studies of mice lacking A(2B) receptors, suggest that adenosine receptors, specifically the G(s)-coupled A(2A) and A(2B) receptors, might provide such a target. Here, using a panel of mice lacking various combinations of adenosine receptors, and mast cells derived from these animals, we show that adenosine receptor agonists provide an effective means of inhibition of mast cell degranulation and induction of cytokine production both in vitro and in vivo. We identify A(2B) as the primary receptor limiting mast cell degranulation, whereas the combined activity of A(2A) and A(2B) is required for the inhibition of cytokine synthesis. 23077105 Induction of hepatic multidrug resistance-associated protein 3 by ethynylestradiol is independent of cholestasis and mediated by estrogen receptor. Multidrug resistance-associated protein 3 (Mrp3; Abcc3) expression and activity are up-regulated in rat liver after in vivo repeated administration of ethynylestradiol (EE), a cholestatic synthetic estrogen, whereas multidrug resistance-associated protein 2 (Mrp2) is down-regulated. This study was undertaken to determine whether Mrp3 induction results from a direct effect of EE, independent of accumulation of any endogenous common Mrp2/Mrp3 substrates resulting from cholestasis and the potential mediation of estrogen receptor (ER). In in vivo studies, male rats were given a single, noncholestatic dose of EE (5 mg/kg s.c.), and basal bile flow and the biliary excretion rate of bile salts and glutathione were measured 5 hours later. This treatment increased Mrp3 mRNA by 4-fold, detected by real-time polymerase chain reaction, despite the absence of cholestasis. Primary culture of rat hepatocytes incubated with EE (1-10 µM) for 5 hours exhibited a 3-fold increase in Mrp3 mRNA (10 µM), consistent with in vivo findings. The increase in Mrp3 mRNA by EE was prevented by actinomycin D, indicating transcriptional regulation. When hepatocytes were incubated with an ER antagonist [7α,17β-[9-[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol (ICI182/780), 1 µM], in addition to EE, induction of Mrp3 mRNA was abolished, implicating ER as a key mediator. EE induced an increase in ER-α phosphorylation at 30 minutes and expression of c-Jun, a well-known ER target gene, at 60 minutes, as detected by Western blotting of nuclear extracts. These increases were prevented by ICI182/780. In summary, EE increased the expression of hepatic Mrp3 transcriptionally and independently of any cholestatic manifestation and required participation of an ER, most likely ER-α, through its phosphorylation. 23434648 Structural Characterization of an LPA1 Second Extracellular Loop Mimetic with a Self-Assembling Coiled-Coil Folding Constraint. G protein-coupled receptor (GPCR) structures are of interest as a means to understand biological signal transduction and as tools for therapeutic discovery. The growing number of GPCR crystal structures demonstrates that the extracellular loops (EL) connecting the membrane-spanning helices show tremendous structural variability relative to the more structurally-conserved seven transmembrane α-helical domains. The EL of the LPA(1) receptor have not yet been conclusively resolved, and bear limited sequence identity to known structures. This study involved development of a peptide to characterize the intrinsic structure of the LPA(1) GPCR second EL. The loop was embedded between two helices that assemble into a coiled-coil, which served as a receptor-mimetic folding constraint (LPA(1)-CC-EL2 peptide). The ensemble of structures from multi-dimensional NMR experiments demonstrated that a robust coiled-coil formed without noticeable deformation due to the EL2 sequence. In contrast, the EL2 sequence showed well-defined structure only near its C-terminal residues. The NMR ensemble was combined with a computational model of the LPA(1) receptor that had previously been validated. The resulting hybrid models were evaluated using docking. Nine different hybrid models interacted with LPA 18:1 as expected, based on prior mutagenesis studies, and one was additionally consistent with antagonist affinity trends. 23614728 Adenovirus-delivered angiopoietin-1 treatment for phosgene-induced acute lung injury. Abstract Context: Exposure to phosgene can result in an acute lung injury, leading to pulmonary edema and even death. Angiopoietin-1 (Ang1) is a critical factor for vascular stabilization due to its ability to reduce endothelial permeability and inflammation. Objective: In this study, the histopathological changes of the lungs after exposure to phosgene and the effect of Ang1 treatment were examined. Materials and methods: Rats were exposed to phosgene gas at 8.33 g/m(3) for 5 min. Ang1 overexpressing rats were established by an intravenous injection of adenovirus-Ang1 (Ad/Ang1). The histological changes of the lung were examined by Haematoxylin-Eosin (H&E) staining and fluorescence microscopy. The inferior lobe was used for the determination of the ratio of wet weight to dry weight of the lung. The concentration of cytokines in the serum and bronchoalveolar lavage fluid was determined by enzyme-linked immunosorbent assay. Results: The pathological analysis showed signs of inflammation and edema, evident from a significant increase in the number of leukocytes in bronchoalveolar lavage fluid and the ratio of wet to dry weight of the lungs. The lung injury induced by phosgene was markedly reduced after the injection of Ad/Ang1. The increase of IL-1β and IL-17 and decrease of vascular endothelial growth factor in the serum and bronchoalveolar lavage fluid of phosgene-exposed animals were abolished by the administration of Ad/Ang1. Discussion and conclusions: Ang1 has the beneficial effects on phosgene-induced lung injury. The adenovirus-delivered Ang1 may have the potential as a novel approach for the treatment of the acute lung injury caused by phosgene gas inhalation in humans. 23230274 Stress granules inhibit apoptosis by reducing reactive oxygen species production. Cells can undergo two alternative fates following exposure to environmental stress: they either induce apoptosis or inhibit apoptosis and then repair the stress-induced alterations. These processes minimize cell loss and prevent the survival of cells with aberrant DNA and protein alterations. These two alternative fates are partly controlled by stress granules (SGs). While arsenite, hypoxia, and heat shock induce the formation of SGs that inhibit apoptosis, X-ray irradiation and genotoxic drugs do not induce SGs, and they are more prone to trigger apoptosis. However, it is unclear precisely how SGs control apoptosis. This study found that SGs suppress the elevation of reactive oxygen species (ROS), and this suppression is essential for inhibiting ROS-dependent apoptosis. This antioxidant activity of SGs is controlled by two SG components, GTPase-activating protein SH3 domain binding protein 1 (G3BP1) and ubiquitin-specific protease 10 (USP10). G3BP1 elevates the steady-state ROS level by inhibiting the antioxidant activity of USP10. However, following exposure to arsenite, G3BP1 and USP10 induce the formation of SGs, which uncovers the antioxidant activity of USP10. We also found that the antioxidant activity of USP10 requires the protein kinase activity of ataxia telangiectasia mutated (ATM). This work reveals that SGs are critical redox regulators that control cell fate under stress conditions. 23508887 DNA Methylation and Cancer Development: Molecular Mechanism. DNA methylation is a significant regulator of gene expression, and its role in carcinogenesis recently has been a subject of remarkable interest. The aim of this review is to analyze the mechanism and cell regulatory effects of both hypo- and hyper-DNA methylation on cancer. In this review, we report new developments and their implications regarding the effects of DNA methylation on cancer development. Indeed, alteration of the pattern of DNA methylation has been a constant finding in cancer cells of the same type and differences in the pattern of DNA methylation not only occur in a variety of tumor types, but also in developmental processes Furthermore, the pattern of histone modification appears to be a predicator of the risk of recurrence of human cancers. It is well known that hypermethylation represses transcription of the promoter sections of tumor-suppressor genes leading to gene silencing. However, hypomethylation also has been identified as a cause of oncogenesis. Furthermore, experiments concerning the mechanism of methylation and its control have led to the discovery of many regulatory enzymes and proteins. This review reports on methods developed for the detection of 5-hydroxymethylcytosine methylation at the 5-methylcytosine of protein domains in the CpG context compared to non-methylated DNA, histone modification, and microRNA change. 23265504 Physico-chemical and antioxidant properties of four mango (Mangifera indica L.) cultivars in China. Four principal mango cultivars (Tainong No.1, Irwin, JinHwang and Keitt) grown in southern China were selected, and their physico-chemical and antioxidant properties were characterized and compared. Of all the four cultivars, Tainong No.1 had highest content of total phenols, ρ-coumaric acid, sinapic acid, quercetin, titratable acidity, citric acid, malic acid, fructose, higher antioxidant activities (DPPH, FRAP) and L(*), lower pH, PPO activity and individual weight. Keitt mangoes showed significantly (p<0.05) higher contents of β-carotene, ρ-hydroxybenzoic acid, sucrose, total sugar, total soluble solid, catechin, succinic acid and higher PPO activity. JinHwang mangoes exhibited significantly (p<0.05) higher individual weight and PPO activity, but had lower content of total phenols, β-carotene and lower antioxidant activity. Principal component analysis (PCA) allowed the four mango cultivars to be differentiated clearly based on all these physico-chemical and antioxidant properties determined in the study. 23452042 Reversibly acetylated lysine residues play important roles in the enzymatic activity of Escherichia coli N-hydroxyarylamine O-acetyltransferase. CobB is a bacterial NAD(+) -dependent protein deacetylase. Although progress has been made in functional studies of this protein in recent years, its substrates and biological functions are still largely unclear. Using proteome microarray technology, potential substrates of Escherichia coli CobB were screened and nine proteins were identified, including N-hydroxyarylamine O-acetyltransferase (NhoA). In vitro acetylation/deacetylation of NhoA was verified by western blotting and mass spectrometry, and two acetylated lysine residues were identified. Site-specific mutagenesis experiments showed that mutation of each acetylated lysine decreased the acetylation level of NhoA in vitro. Further analysis showed that variant NhoA proteins carrying substitutions at the two acetylated lysine residues are involved in both the O-acetyltransferase and N-acetyltransferase activity of NhoA. Structural analyses were also performed to explore the effects of the acetylated lysine residues on the activity of NhoA. These results suggest that reversible acetylation may play a role in the activity of Escherichia coli NhoA. 23293921 Analytical model for the deformation of a fluid-fluid interface beneath an AFM probe. We present an analytical solution for the shape of a fluid-fluid interface near a nanoscale solid sphere, which is a configuration motivated by common measurements with an atomic force microscope. The forces considered are surface tension, gravity, and the van der Waals attraction. The nonlinear governing equation has been solved previously using the method of matched asymptotic expansions, and this requires that the surface tension forces far exceed those of gravity, i.e., the Bond number is much less than one. We first present this method using a physically relevant scaling of the equations, then offer a new analytical solution valid for all Bond numbers. We show that one configuration with a large effective Bond number, and thus one requiring our new solution, is a nanothick liquid film spread over a solid substrate. The scaling implications of both analytical methods are considered, and both are compared with numerical solutions of the full equation. 23159667 A novel approach to improve the pharmacokinetic properties of 8-chloro-adenosine by the dual combination of lipophilic derivatisation and liposome formulation. 8-Chloro-adenosine (8CA) has shown promise in hematologic and solid tumor models and is in a phase I clinical trial. However, 8CA is intensively metabolized shortly after i.v. administration, with a t(1/2β) of approximately 1h. Many carriers have failed to encapsulate 8CA efficiently. To improve its pharmacokinetic properties, 8-chloro-adenosine-5'-O-stearate (8CAS), a lipophilic octadecanoyl analogue of 8CA, was synthesized and incorporated into pegylated liposomes. The liposomes, comprising egg phosphatidylcholine, cholesterol and poly (ethylene glycol) 2000-distearoyl phosphatidylethanolamine (PEG-DSPE), had mean diameters of approximately 100 nm and an entrapment efficiency of 69-86%. MTT assays showed that the cytotoxicity of 8CAS and its pegylated liposomes (8CAS-PL) were retained, with IC(50) values of 1.0 μM and 1.9 μM at 72 h on MCF-7 cells, respectively, slightly higher than that of 8CA (0.6 μM). Pharmacokinetic studies in rats after i.v. injection showed that both 8CAS and 8 CAS-PL had increased elimination half-lives (t(1/2), 128.4, 249.2 vs. 74.7 min), decreased clearance rates (Cl, 0.0135, 0.00875 vs. 0.2398 L/min/kg) and increased area under the concentration-time curve (AUC(0-∞), 741.4, 1163.6 vs. 42.0 mg min/L) compared to 8CA. No obvious hematological toxicity was seen for Kunming mice receiving i.v. 8CA or 8CAS-PL at a dosage of 10mg/kg daily. These results indicate that the lipophilic derivation of 8CA and the incorporation of 8CAS is an effective strategy to improve the bioavailability of 8CA. 23565749 Silver Chloride as a Heterogeneous Nucleant for the Growth of Silver Nanowires. Various additives are employed in the polyol synthesis of silver nanowires (Ag NWs), which are typically halide salts such as NaCl. A variety of mechanistic roles have been suggested for these additives. We now show that the early addition of NaCl in the polyol synthesis of Ag NWs from AgNO3 in ethylene glycol results in the rapid formation of AgCl nanocubes, which induce the heterogeneous nucleation of metallic Ag upon their surfaces. Ag NWs subsequently grow from these nucleation sites. The conclusions are supported by studies using ex situ generated AgCl nanocubes. 23592516 Nrf2-activators Attenuate the Progression of Nonalcoholic Steatohepatitis-Related Fibrosis in a Dietary Rat Model. Oxidative stress is considered to be a key mechanism of hepatocellular injury and disease progression in patients with nonalcoholic steatohepatitis (NASH). The transcription factor Nrf2 plays a central role in stimulating expression of various antioxidant-associated genes in the cellular defense against oxidative stress. As the cytosolic repressor Keap1 negatively regulates Nrf2, activation of Nrf2 facilitated by its release from Keap1 may represent a promising strategy in the treatment of NASH. To test this hypothesis, we utilized two chemically distinct types of Nrf2-activator. One is the thiol-reactive agent oltipraz (OPZ), a typical Nrf2-activator, and the other is a novel biaryl urea compound, termed NK-252. NK-252 exhibits a greater Nrf2-activating potential than OPZ. Furthermore, in vitro binding studies revealed that NK-252 interacts with the domain containing the Nrf2-binding site of Keap1, whereas OPZ does not. This finding indicates that NK-252 is more potent than OPZ due to its unique mechanism of action. For in vivo animal model studies, we employed rats on a choline-deficient L-amino acid-defined (CDAA)-diet, which demonstrate pathological findings similar to those seen in human NASH. The administration of OPZ or NK-252 significantly attenuated the progression of histological abnormalities in rats on a CDAA diet, especially hepatic fibrosis. In conclusion, by using Nrf2-activators with independent mechanisms of action, we show in a rat model of NASH that the activation of Nrf2 is responsible for the anti-fibrotic effects of these drugs. This strategy of Nrf2 activation presents new opportunities for treatment of NASH patients with hepatic fibrosis. 23258773 Assessing ongoing sources of dissolved-phase polychlorinated biphenyls in a contaminated stream. Few studies assess the potential of ongoing sources of "fresh" polychlorinated biphenyls (PCBs) to aquatic systems when direct discharge to the environment has been eliminated. In the present study, the authors used single-layered, low-density polyethylene samplers (PEs) to measure total PCB concentrations, congener profiles, and enantiomeric fractions (EFs) in a contaminated stream and to provide multiple lines of evidence for assessing ongoing inputs of PCB. Concentrations were well above background levels that have been monitored for years. Concentrations significantly increased with distance, the farthest downstream PE concentrations being almost five times greater than those at 79 m downstream of a historical point source. The PCBs in the PEs at 79 m downstream of the contamination source were dominated by low K(OW) congeners, similar to those in the mixture of Aroclors 1016 and 1254 (4:1 v/v) historically released from the former capacitor manufacturer. The only two chiral congeners detected in the PEs downstream were PCBs 91 and 95. The EF values were nonracemic for PCB 91, while the values were either racemic or near racemic for PCB 95. Increased PCB concentrations with distance and a congener composition of predominantly low-weight congeners in the PEs at 79 m downstream of the plant site suggested an ongoing PCB source from the plant site. Chiral signatures suggested aerobic biotransformation of dissolved PCBs but did not shed any light on possible ongoing PCB inputs. 23335243 Genetic dissection of sesquiterpene biosynthesis by Fusarium fujikuroi. A treasure trove of terpenes: The products of two fungal sesquiterpene synthases from the rice pathogen Fusarium fujikuroi were identified by gene-knockout experiments, genetic engineering of the fungus for production optimization, isolation of the sesquiterpenes, and structure elucidation by spectroscopic methods. 23628333 Identification of substituted 2-thio-6-oxo-1,6-dihydropyrimidines as inhibitors of human lactate dehydrogenase. A novel 2-thio-6-oxo-1,6-dihydropyrimidine-containing inhibitor of human lactate dehydrogenase (LDH) was identified by high-throughput screening (IC50=8.1μM). Biochemical, surface plasmon resonance, and saturation transfer difference NMR experiments indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of the screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50=0.48μM). A crystal structure of an optimized compound bound to human LDHA was obtained and explained many of the observed structure-activity relationships. 23017406 GABA shunt and polyamine degradation pathway on γ-aminobutyric acid accumulation in germinating fava bean (Vicia faba L.) under hypoxia. GABA shunt and polyamine degradation pathway on γ-aminobutyric acid (GABA) accumulation in germinating fava bean under hypoxia was investigated. GABA content, GAD and DAO activity were significantly increased under hypoxia treatment. Glu and polyamine contents enhanced largely and thus supplied as sufficient substrates for GABA formation. In contrast, GABA content decreased, mainly in the embryo, after removing the hypoxia stress. DAO activity, Glu and polyamines contents decreased, while an increment of GAD activity was observed. This indicated that GAD activity can be not only regulated by hypoxia, but by the rapid growth of embryo after the recovery from hypoxia stress. When treated with AG, DAO activity was almost inhibited completely, and the GABA content decreased by 32.96% and 32.07% after treated for 3 and 5 days, respectively. Hence, it can be inferred that about 30% of GABA formed in germinating fava bean under hypoxia was supplied by polyamine degradation pathway. 23553811 Clinical update on the management of atrial fibrillation. Atrial fibrillation (AF) is a cardiac arrhythmia associated with significant morbidity and mortality, affecting more than 3 million people in the United States and 1-2% of the population worldwide. Its estimated prevalence is expected to double within the next 50 years. During the past decade, there have been significant advances in the treatment of AF. Studies have demonstrated that a rate control strategy, with a target resting heart rate between 80 and 100 beats/minute, is recommended over rhythm control in the vast majority of patients. The CHA2 DS2 ≥ (congestive heart failure, hypertension, age ≥ 65 yrs, diabetes mellitus, stroke or transient ischemic attack, vascular disease, female gender) scoring system is a potentially useful stroke risk stratification tool that incorporates additional risk factors to the commonly used CHADS2 (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke transient ischemic attack) scoring tool. Similarly, a convenient scheme, termed HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly), to assess bleeding risk has emerged that may be useful in select patients. Furthermore, new antithrombotic strategies have been developed as potential alternatives to warfarin, including dual-antiplatelet therapy with clopidogrel plus aspirin and the development of new oral anticoagulants such as dabigatran, rivaroxaban, and apixaban. Vernakalant has emerged as another potential option for pharmacologic conversion of AF, whereas recent trials have better defined the role of dronedarone in the maintenance of sinus rhythm. Finally, catheter ablation represents another alternative to manage AF, whereas upstream therapy with inhibitors of the renin-angiotensin-aldosterone system, statins, and polyunsaturated fatty acids could potentially prevent the occurrence of AF. Despite substantial progress in the management of AF, significant uncertainty surrounds the optimal treatment of this condition. 23573990 Tailoring of morphology and surface properties of syndiotactic polystyrene aerogels. This study evaluates a method for rendering syndiotactic polystyrene (sPS) aerogels hydrophilic using polyethylene oxide (PEO) of different molecular weights. The highly porous sPS aerogels are inherently hydrophobic although applications involving absorption of moisture and removal of particulate solids may benefit from the high surface area of sPS aerogels provided some degree of hydrophilicity is induced in these materials. In this work, sPS gels are prepared by thermo-reversible gelation in tetrahydrofuran in the presence of PEO. The gels are dried under supercritical conditions to obtain aerogels. The aerogels are characterized by scanning electron microscopy, nitrogen-adsorption porosimetry, helium pycnometry, and contact angle measurements. The data reveal that the pore structures and surface energy can be controlled by varying the concentration and molecular weight of PEO and using different cooling rates during thermo-reversible gelation. In the first case, sPS aerogels, aerogels containing PEO of a low molecular weight or low concentration show superhydrophobic surface presenting the "lotus effect". In the second case, PEO at a higher concentration or with higher molecular weight forms phase-separated domains yielding new hydrophilic macropores (>10 μm) in the aerogel structures. These macropores contribute to the superhydrophobic surface with the "petal effect". The cooling rate during gelation shows a strong influence on these two cases. 23573957 HCV NS5A Replication Complex Inhibitors. Part 4. (1) Optimization for Genotype 1a Replicon Inhibitory Activity. A series of symmetrical E-stilbene prolinamides that originated from the library-synthesized lead 3 was studied with respect to HCV genotype 1a (G-1a) and genotype 1b (G-1b) replicon inhibition and selectivity against BVDV and cytotoxicity. SAR emerging from an examination of the prolinamide cap region revealed 11 to be a selective HCV NS5A inhibitor exhibiting submicromolar potency against both G-1a and G-1b replicons. Additional structural refinements resulted in the identification of 30 as a potent, dual G-1a/1b HCV NS5A inhibitor. 22872100 The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. The clinical understanding of the CDKL5 disorder remains limited, with most information being derived from small patient groups seen at individual centres. This study uses a large international data collection to describe the clinical profile of the CDKL5 disorder and compare with Rett syndrome (RTT). Information on individuals with cyclin-dependent kinase-like 5 (CDKL5) mutations (n=86) and females with MECP2 mutations (n=920) was sourced from the InterRett database. Available photographs of CDKL5 patients were examined for dysmorphic features. The proportion of CDKL5 patients meeting the recent Neul criteria for atypical RTT was determined. Logistic regression and time-to-event analyses were used to compare the occurrence of Rett-like features in those with MECP2 and CDKL5 mutations. Most individuals with CDKL5 mutations had severe developmental delay from birth, seizure onset before the age of 3 months and similar non-dysmorphic features. Less than one-quarter met the criteria for early-onset seizure variant RTT. Seizures and sleep disturbances were more common than in those with MECP2 mutations whereas features of regression and spinal curvature were less common. The CDKL5 disorder presents with a distinct clinical profile and a subtle facial, limb and hand phenotype that may assist in differentiation from other early-onset encephalopathies. Although mutations in the CDKL5 gene have been described in association with the early-onset variant of RTT, in our study the majority did not meet these criteria. Therefore, the CDKL5 disorder should be considered separate to RTT, rather than another variant. 22512590 Chitin synthase inhibitors as antifungal agents. Increased risk of fungal diseases in immunocompromised patients, emerging fungal pathogens, limited repertoire of antifungal drugs and resistance development against the drugs demands for development of new and effective antifungal agents. With greater knowledge of fungal metabolism efforts are being made to inhibit specific enzymes involved in different biochemical pathways for the development of antifungal drugs. Chitin synthase is one such promising target as it is absent in plants and mammals. Nikkomycin Z, a chitin synthase inhibitor is under clinical development. Chitin synthesis in fungi, chitin synthase as a target for antifungal agent development, different chitin synthase inhibitors isolated from natural sources, randomly synthesized and modified from nikkomycin and polyoxin are discussed in this review. 23561128 Effect of nitrite on the odourant volatile fraction of cooked ham. The aim of this work was to reliably identify the key odour compounds in cooked ham and acquire new knowledge on the role of sodium nitrite on the formation of its aroma. Gas chromatography coupled with mass spectrometry and (or) olfactometry was used. In all, 24 odourants were identified in the volatile fraction of cooked ham. Their main origins are discussed. Orthonasal sniffing of the hams was used to study how these substances contributed to the overall aroma of the product. The aroma of cooked ham is a balance between that of certain sulfur compounds produced during cooking and that of oxidation compounds commonly found in cooked meats. In the absence of nitrite, this balance is disturbed by extensive formation of oxidation compounds that mask the meaty notes induced by the sulfur compounds. 23360180 Combined effects of Ag nanoparticles and oxygen plasma treatment on PLGA morphological, chemical, and antibacterial properties. The purpose of this study is to investigate the combined effects of oxygen plasma treatments and silver nanoparticles (Ag) on PLGA in order to modulate the surface antimicrobial properties through tunable bacteria adhesion mechanisms. PLGA nanocomposite films, produced by solvent casting with 1 wt % and 7 wt % of Ag nanoparticles were investigated. The PLGA and PLGA/Ag nanocomposite surfaces were treated with oxygen plasma. Surface properties of PLGA were investigated by field emission scanning electron microscopy (FESEM), atomic force microscopy (AFM), static contact angle (CA), and high resolution X-ray photoelectron spectroscopy (XPS). Antibacterial tests were performed using an Escherichia coli RB (a Gram negative) and Staphylococcus aureus 8325-4 (a Gram positive). The PLGA surface becomes hydrophilic after the oxygen treatment and its roughness increases with the treatment time. The surface treatment and the Ag nanoparticle introduction have a dominant influence on the bacteria adhesion and growth. Oxygen-treated PLGA/Ag systems promote higher reduction of the bacteria viability in comparison to the untreated samples and neat PLGA. The combination of Ag nanoparticles with the oxygen plasma treatment opens new perspectives for the studied biodegradable systems in biomedical applications. 23451707 Discovery of allosteric modulators of factor XIa by targeting hydrophobic domains adjacent to its heparin-binding site. To discover promising sulfated allosteric modulators (SAMs) of glycosaminoglycan-binding proteins (GBPs), such as human factor XIa (FXIa), we screened a library of 26 synthetic, sulfated quinazolin-4(3H)-ones (QAOs) resulting in the identification of six molecules that reduced the Vmax of substrate hydrolysis without influencing the KM. Mutagenesis of residues of the heparin-binding site (HBS) of FXIa introduced a nearly 5-fold loss in inhibition potency supporting recognition of an allosteric site. Fluorescence studies showed a sigmoidal binding profile indicating highly cooperative binding. Competition with a positively charged, heparin-binding polymer did not fully nullify inhibition suggesting importance of hydrophobic forces to binding. This discovery suggests the operation of a dual-element recognition process, which relies on an initial Coulombic attraction of anionic SAMs to the cationic HBS of FXIa that forms a locked complex through tight interaction with an adjacent hydrophobic patch. The dual-element strategy may be widely applicable for discovering SAMs of other GBPs. 23632082 GIRK-like and TRPC-like conductances mediate thyrotropin-releasing hormone-induced increases in excitability in thalamic paraventricular nucleus neurons. The thalamic paraventricular nucleus (PVT), reported to participate in arousal and motivated behaviors, contains abundant receptors for thyrotropin-releasing hormone (TRH), a neuropeptide also known to modulate arousal and mood. To test the hypothesis that TRH could influence the excitability of PVT neurons, whole call patch clamp recordings obtained in rat brain slice preparations were evaluated during bath applied TRH. In the majority of neurons tested, TRH induced reversible TTX-resistant membrane depolarization. Under voltage-clamp, TRH induced a concentration-dependent G protein- mediated inward current. The mean net TRH-induced current exhibited a decrease in membrane conductance. Further analyses identified two concurrent conductances contributing to the TRH-induced response. One conductance featured a Na(+)-independent and K(+)-dependent net current that displayed rectification and was suppressed by micromolar concentrations of Ba(2+) and two GIRK antagonists, tertiapin Q and SCH 23390. The second conductance featured a Na(+)-dependent net inward current with an I-V relationship that exhibited double rectification with a negative slope conductance below -40 mV. This conductance was suppressed by nonselective TRPC channel blockers 2-APB, flufenamic acid and ML204, enhanced by La(3+) in a subpopulation of cells, and unchanged by the TRPV1 antagonist capsazepine or a Na(+) /Ca(2+) exchanger blocker KB-R7943. TRH also enhanced hyperpolarization-activated low threshold spikes, a feature that was sensitive to pretreatment with either 2-APB or ML204. Collectively, the data imply that TRH enhances excitability in PVT neurons via concurrently decreasing a G-protein-gated inwardly rectifying K(+) conductance and activating a cationic conductance with characteristics reminiscent of TRPC-like channels, possibly involving TRPC4/C5 subunits. 23395656 Synthesis and biological evaluation of new cytotoxic indazolo[4,3-gh]isoquinolinone derivatives. A series of indazolo[4,3-gh]isoquinolinones derivatives have been synthesized to decrease cardiotoxic side effects in comparison to Mitoxantrone. The antiproliferative effects of different side chains were investigated and tested on at least four different cell lines of cervix, ovarian, CNS, NSCLC (non-small-cell lung cancer) and colon carcinoma. In addition to antiproliferative activities, influence on cell cycle and intercalation behavior have been tested. 23523258 In vivo effect of Schisandrin B on cytochrome P450 enzyme activity. To investigate the possible drug interaction, this study is designed to evaluate the ability of Schisandrin B (Sch B) to modulate cytochrome P450 3A activity (CYP3A) in vivo and to alter the pharmacokinetic profiles of CYP3A substrate (midazolam) in treated rats. Rats were repeated administered with physiological saline (negative control group), ketoconazole (75mg/kg, positive control group) or varied doses of Sch B (experimental groups) for three consecutive days. Subsequently, changes in hepatic microsomal CYP3A activity and the pharmacokinetic profiles of midazolam and 1'-hydroxy midazolam in plasma were studied to evaluate CYP3A activity. The results indicated that Sch B significantly dose-dependently inhibited rat hepatic microsomal CYP3A activity with Ki value of 16.64mg/kg and showed the characteristic of a noncompetitive inhibitor. Oral administration of Sch B for 3 days in rats produced significant effect on the pharmacokinetics of oral midazolam. Sch B resulted in a significant, dose-dependent increase in midazolam AUC0-∞ except at the dose of 2mg/kg, while AUC0-∞ increased by 26.1% (8mg/kg) and 60.6% (16mg/kg), respectively. In the pharmacokinetic profiles of 1'-hydroxy midazolam, the significant, dose-dependent decrease in AUC0-∞ was observed except at the dose of 2mg/kg, while AUC0-∞ reduced by 44.5% (8mg/kg) and 49.2% (16mg/kg), respectively. These results suggested that 3-day treatment of Sch B could increase concentration and oral bioavailability of drug metabolized by CYP3A. When the drug, consisting of Sch B, is used in the clinic for more than 3 days, the possible drug-drug interactions should be taken into consideration. 23225764 Preparation of functional water-soluble low-cytotoxic poly(methacrylate)s with pendant cationic L-lysines for efficient gene delivery. In this work, we present the preparation of water-soluble poly(methacrylate)s with pendant cationic L-lysines PHMLs(6-30 K). Plasmid DNA binding affinity as well as particle sizes and zeta potentials of the polyplexes were examined for these PHML vectors, and their cytotoxicities were assayed with HeLa cells by CCK-8 and lactate dehydrogenase kits. Gene transfection efficacy and intracellular uptake of the polyplexes by the PHML vectors were also studied with HeLa cells. As a result, it was revealed that the low cytotoxic PHMLs tended to exhibit gene transfection efficiencies significantly higher than those of the linear structural PLL (15-30 K) control, in particular the molecular weight of a PHML vector remarkably influenced its pDNA binding affinity, transfection efficacy and intracellular uptake of the polyplexes. 23335320 Synthesis and characterization of conformationally rigid chiral pyridine-N-heterocyclic carbene-based palladacycles with an unexpected Pd-N bond cleavage. The versatility of a previously developed method for the synthesis of chiral carbene-based palladacycles is demonstrated through the synthesis of two new chiral pyridine-functionalized N-heterocyclic carbene palladacycles with different wingtip groups. The efficiency in their resolution with different counter anions and different chiral amino acid salt auxiliaries has been studied. The absolute stereochemistries of all the chiral compounds were confirmed by single crystal X-ray crystallography. An unexpected Pd-N bond cleavage that resulted in the racemization of the α-carbon center in these complexes has also been investigated. 23425605 The role of de novo catecholamine synthesis in mediating methylmercury-induced vesicular dopamine release from rat pheochromocytoma (PC12) cells. The purpose of this study was to characterize methylmercury (MeHg)-induced dopamine (DA) release from undifferentiated pheochromocytoma (PC12) cells and to examine the potential role for DA synthesis in this process. MeHg caused a significant increase in DA release that was both concentration- and time-dependent. DA release was significantly increased by 2µM MeHg at 60min and by 5µM MeHg at 30min; 1µM MeHg was without effect. Because DA release induced by 5µM MeHg was associated with a significant percentage of cell death at 60 and 120min, 2µM MeHg was chosen for further characterization of release mechanisms. MeHg-induced DA release was attenuated but not abolished in the absence of extracellular calcium, whereas the vesicular content depleting drug reserpine (50nM) abolished release. Thus, MeHg-induced DA release requires vesicular exocytosis but not extracellular calcium. MeHg also increased intracellular DA and the rate of DA storage utilization, suggesting a role for DA synthesis in MeHg-induced DA release. The tyrosine hydroxylase inhibitor α-methyltyrosine (300µM, 24h) completely abolished MeHg-induced DA release. MeHg significantly increased DA precursor accumulation in cells treated with 3-hydroxybenzylhydrazine (10µM), revealing that MeHg increases tyrosine hydroxylase activity. Overall, these data demonstrate that MeHg facilitates DA synthesis, increases intracellular DA, and augments vesicular exocytosis. 23633521 Loss of Kruppel-like Factor 3 (KLF3/BKLF) leads to upregulation of the insulin-sensitizing factor adipolin (FAM132A/CTRP12/C1qdc2). Krüppel-like Factor 3 (KLF3) is a transcriptional regulator that we have shown to be involved in the regulation of adipogenesis in vitro. Here we report that KLF3 null mice are lean and protected from diet-induced obesity and glucose intolerance. On a chow diet, plasma levels of leptin are decreased, and adiponectin is increased. Despite significant reductions in body weight and adiposity, wildtype and knockout animals show equivalent energy intake, expenditure and excretion. To investigate the molecular events underlying these observations, we used microarray analysis to compare gene expression in Klf3(+/+) and Klf3(-/-) tissues. We found that mRNA expression of Fam132a, which encodes a newly identified insulin-sensitizing adipokine, adipolin, is significantly upregulated in the absence of KLF3. We confirmed that KLF3 binds the Fam132a promoter in vitro and in vivo and that this leads to repression of promoter activity. Further, plasma adipolin levels were significantly increased in Klf3(-/-) mice compared to wild-type littermates. Boosting levels of adipolin via targeting of KLF3 offers a novel potential therapeutic strategy for the treatment of insulin resistance. 23495190 Artemisinin-polypyrrole conjugates: synthesis, DNA binding studies and preliminary antiproliferative evaluation. Greater than the sum of its parts: Artemisinins are currently in phase I-II clinical trials against breast, colorectal and non-small-cell lung cancers. In an attempt to offer increased specificity, a series of hybrid artemisinin-polypyrrole minor groove binder conjugates are described. DNA binding/modelling studies and preliminary biological evaluation give insights into their mechanism of action and the potential of this strategy. 23207328 Nasal administration of liquid crystal precursor mucoadhesive vehicle as an alternative antiretroviral therapy. The purpose of this study was to develop a mucoadhesive stimuli-sensitive drug delivery system for nasal administration of zidovudine (AZT). The system was prepared by formulating a low viscosity precursor of a liquid crystal phase, taking advantage of its lyotropic phase behavior. Flow rheology measurements showed that the formulation composed of PPG-5-CETETH-20, oleic acid and water (55, 30, 15% w/w), denominated P, has Newtonian flow behavior. Polarized light microscopy (PLM) revealed that formulation P is isotropic, whereas its 1:1 (w/w) dilution with artificial nasal mucus (ANM) changed the system to an anisotropic lamellar phase (PD). Oscillatory frequency sweep analysis showed that PD has a high storage modulus (G') at nasal temperatures. Measurement of the mucoadhesive force against excised porcine nasal mucosa or a mucin disk proved that the transition to the lamellar phase tripled the work of mucoadhesion. Ex vivo permeation studies across porcine nasal mucosa exhibited an 18-fold rise in the permeability of AZT from the formulation. The Weibull mathematical model suggested that the AZT is released by Fickian diffusion mechanisms. Hence, the physicochemical characterization, combined with ex vivo studies, revealed that the PPG-5-CETETH-20, oleic acid, and water formulation could form a mucoadhesive matrix in contact with nasal mucus that promoted nasal absorption of the AZT. For an in vivo assessment, the plasma concentrations of AZT in rats were determined by HPLC method following intravenous and intranasal administration of AZT-loaded P formulation (PA) and AZT solution, respectively, at a dose of 8mg/kg. The intranasal administration of PA resulted in a fast absorption process (Tmax=6.7min). Therefore, a liquid crystal precursor formulation administered by the nasal route might represent a promising novel tool for the systemic delivery of AZT and other antiretroviral drugs. In the present study, the uptake of AZT absorption in the nasal mucosa was demonstrated, providing new foundations for clinical trials in patients with AIDS. 23379346 Introduction of Target Cliffs as a Concept To Identify and Describe Complex Molecular Selectivity Patterns. The study of target specificity or selectivity of small molecules is an important task in drug design. In an ideal situation, a compound would exclusively interact with an individual target and hence be target specific. However, such exclusive binding events are likely to be rare, as increasing evidence suggests. Because many compounds are active against more than one target, apparent selectivity often results from potency differences, i.e., a compound that is highly potent against a given target and weakly potent against one or more others displays target selectivity. In a simple case, a compound might have known activity against a pair of targets and be selective for one over the other. Then, selectivity is straightforward to rationalize. However, there are many more complex selectivity relationships associated with multi-target activities of compounds that are difficult to analyze and compare in a consistent manner. For this purpose, we introduce herein target cliffs as a concept to describe complex selectivity patterns. A target cliff is defined as a pair of targets against which at least one compound displays a large difference in potency. As such, target cliffs are distinct from activity cliffs. However, qualifying target pairs (target cliffs) and compound pairs (activity cliffs) can be systematically extracted from the same data structure termed target-compound matrices. Furthermore, these two types of cliffs can be compared to identify and prioritize compounds that are selective and reveal structure-activity relationship (SAR) information. 23531160 Inflammation, serotonin and major depression. The understanding of the neurobiological processes leading to major depressive disorder (MDD) is an active field of research in the scientific community. For years, the alteration of monoamine neurotransmission, in particular serotonin (5-HT), has been considered the most significant pathophysiological mechanism of the disorder. However, biological data supporting the postulated MDD-related monoamine alterations have been inconclusive, and the use of monoaminergic antidepressants has not yielded the expected results. In the last few years, it has been demonstrated that inflammatory pathways have a significant role in the pathophysiology of MDD. According to the cytokine hypothesis, the disorder would be due to a stress-related increased production of cytokines, including interleukins, tumor necrosis factor- α and interferon- α and γ . These, in turns, would cause the activation of the indoleamine 2,3 dioxygenase (IDO), with subsequent production of tryptophan (TRP) catabolites along the IDO pathway (TRYCATs) and decreased availability of TRP and 5-HT. Besides monoamines, other molecular mechanisms, as those within the inflammatory pathways, should be taken into account in the attempt to clarify the pathophysiology of MDD and to improve its treatment. 23564918 NH2-Terminal Probrain Natriuretic Peptide Is a Stronger Predictor of Cardiovascular Mortality Than C-Reactive Protein and Albumin Excretion Rate in Elderly Patients With Type 2 Diabetes: The Casale Monferrato population-based study. OBJECTIVETo study whether NH2-terminal probrain natriuretic peptide (NT-proBNP) is a short-term independent predictor of both all-cause and cardiovascular (CV) mortality in type 2 diabetic patients and to establish whether albuminuria and C-reactive protein (CRP) affect this relationship.RESEARCH DESIGN AND METHODSThe prospective study included 1,825 type 2 diabetic patients from the population-based cohort of the Casale Monferrato study. CV risk factors, preexisting CVD, and NT-proBNP levels were evaluated at baseline. All-cause and CV mortality were assessed 5.5 years after baseline examination. Multivariate Cox proportional hazards modeling was used to estimate mortality hazard ratios (HRs).RESULTSDuring the follow-up period, 390 people died (175 for CVD) out of 9,101 person-years of observations. A significantly increased mortality risk by quartiles of NT-proBNP was observed (test for trend, P < 0.001). NT-proBN P values >91 pg/mL conferred HRs of 2.05 (95% CI 1.47-2.86) for all-cause and 4.47 (2.38-8.39) for CV mortality, independently of CV risk factors, including CRP and albumin excretion rate (AER). The association was also significant for modest rises in NT-proBNP levels and in patients without microalbuminuria and CVD at baseline (upper quartiles HRs 3.82 [95% CI 1.24-13.75]) and 3.14 [1.00-9.94]). Albuminuria and NT-proBNP had an additive effect on mortality, though the association was stronger for NT-proBNP.CONCLUSIONSNT-proBNP is a strong independent predictor of short-term CV mortality risk in elderly people with type 2 diabetes, including those without preexisting CVD. This association is evident even in people with slightly increased values, is not modified by CRP, and is additive to that provided by AER. 23500778 Protective effects of a compound isolated from Alnus japonica on oxidative stress-induced death in transformed retinal ganglion cells. Here, we investigated whether hirsutenone, a compound isolated from Alnus japonica, was able to attenuate oxidative stress-induced death in transformed retinal ganglion (RGC-5) cells. Hirsutenone effectively protected RGC-5 cells from oxidative insult induced by, l-buthionine-(S,R)-sulfoximine (BSO) plus glutamate in a concentration-dependent manner, as demonstrated by propidium iodide (PI)/Hoechst 33342 double staining, flow cytometry, and MTT assays. Moreover, hirsutenone inhibited the increase in apoptotic protein expression resulting from BSO plus glutamate. Hirsutenone also effectively inhibited sodium nitroprusside (SNP)-induced lipid peroxidation in rat brain homogenates. To investigate the effects of hirsutenone in vivo, we used N-methyl-d-aspartate (NMDA) as a negative insult on the retinas of rats. NMDA affects the thinning of the inner plexiform layer (IPL) and causes an increase in the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive ganglion cells in the ganglion cell layer (GCL). Hirsutenone treatment led to a reduction in NMDA-induced IPL and TUNEL staining of the GCL. In conclusion, hirsutenone isolated from A. japonica may act as neuroprotective agent for conditions such as glaucoma. 23400888 Abo-, inco-, ona-, and rima-botulinum toxins in clinical therapy: a primer. Botulinum neurotoxin (BoNT) is an acetylcholine release inhibitor and a neuromuscular-blocking agent used for the treatment of a variety of medical and cosmetic indications. Currently, in the United States, there are four BoNT formulations licensed for use: abobotulinumtoxinA, incobotulinumtoxinA, onabotulinumtoxinA, and rimabotulinumtoxinB. These revised name designations were established to reinforce the understanding that each BoNT product has an individual potency and is not interchangeable with any other BoNT product. The therapeutic use of BoNTs is expanding and new formulations are on the horizon. This article is a primer that describes distinctions among currently available, licensed BoNT formulations. Toxin pharmacology, product characteristics, storage, handling, preparation, and dosages will be reviewed. In addition, issues related to dose equivalency ratios, immunogenicity, potency, and toxin spread will be discussed. Therapeutic indications and safety are discussed briefly. Knowledge of the available and licensed BoNT formulations and the ability to make distinctions in toxin pharmacology, product characteristics, and indications are vital for product selection, preparation, drug information, avoidance of drug errors, quality assurance, and patient safety. 23411268 Characterization of oils and fats by 1H NMR and GC/MS fingerprinting: classification, prediction and detection of adulteration. The correct identification of oils and fats is important to consumers from both commercial and health perspectives. Proton nuclear magnetic resonance ((1)H NMR) spectroscopy, gas chromatography-mass spectrometry (GC/MS) fingerprinting and chemometrics were employed successfully for the quality control of oils and fats. Principal component analysis (PCA) of both techniques showed group clustering of 14 types of oils and fats. Partial least squares discriminant analysis (PLS-DA) and orthogonal projections to latent structures discriminant analysis (OPLS-DA) using GC/MS data had excellent classification sensitivity and specificity compared to models using NMR data. Depending on the availability of the instruments, data from either technique can effectively be applied for the establishment of an oils and fats database to identify unknown samples. Partial least squares (PLS) models were successfully established for the detection of as low as 5% of lard and beef tallow spiked into canola oil, thus illustrating possible applications in Islamic and Jewish countries. 23639545 Synthesis and ionophoric activities of functionalized bis(choloyl) conjugates with a rigid core. Three bis(choloyl) conjugates bearing a rigid p-phenylenediamine/p-bis(aminomethyl)benzene linker and amino/acetamido groups were synthesized, and fully characterized on the basis of (1)H NMR, ESI-MS and HRMS. Their ionophoric activities were investigated by means of pH discharge assay. The results indicate that these conjugates exhibit potent ionophoric activities across egg-yolk l-α-phosphatidylcholine (EYPC)-based liposomal membranes, via a cation/proton antiport mechanism. They show moderate ion selectivity among alkali metal ions. Of the three conjugates, the ones having amino groups transport alkali metal ions in the order of Na(+)>Li(+)>K(+)≈Rb(+)≈Cs(+), whereas the one having acetamido groups functions in the order of Li(+)>Na(+)>K(+)≈Rb(+)≈Cs(+). 23489624 Novel small molecules as apoptosis inducers: synthesis, preliminary structure-activity relationships, and in vitro biological evaluation. Inducing apoptosis is a promising therapeutic approach to overcome cancer. In this study, 30 compounds were synthesized and evaluated for their antiproliferative activity against three tumor cell lines in vitro: A875, H460 and Hela cancer cells by the MTT assay. The most potent analogue 7a, a novel compound was first reported by our group, inhibited the proliferation of A875 cells with an IC50 value of 98 nM. Flow cytometry analysis and morphological analysis suggested that compound 7a had potential anticancer efficacy via G2/M cell cycle arrest, which could be attributed to its proliferation and apoptosis, and also in a concentration-dependent manner. The SAR analysis indicated that the substituents R(2) played a crucial role in the antiproliferation activity. 23299909 Interruption or deferral of antiretroviral therapy reduces markers of bone turnover compared with continuous therapy: The SMART Body Composition substudy. Bone mineral density (BMD) declines significantly in HIV patients on antiretroviral therapy (ART). We compared the effects of intermittent versus continuous ART on markers of bone turnover in the Body Composition substudy of the Strategies for Management of AntiRetroviral Therapy (SMART) trial and determined whether early changes in markers predicted subsequent change in BMD. For 202 participants (median age 44 years, 17% female, 74% on ART) randomised to continuous or intermittent ART, plasma markers of inflammation and bone turnover were evaluated at baseline, months 4 and 12; BMD at the spine (dual X-ray absorptiometry [DXA] and computed tomography) and hip (DXA) was evaluated annually. Compared to the continuous ART group, mean bone-specific alkaline phosphatase (bALP), osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), N-terminal cross-linking telopeptide of type 1 collagen (NTX), and C-terminal cross-linking telopeptide of type 1 collagen (βCTX) decreased significantly in the intermittent ART group, whereas RANKL and the RANKL:osteoprotegerin (OPG) ratio increased (all p<0.002 at month 4 and month 12). Increases in bALP, osteocalcin, P1NP, NTX, and βCTX at month 4 predicted decrease in hip BMD at month 12, while increases in RANKL and the RANKL:OPG ratio at month 4 predicted increase in hip and spine BMD at month 12. This study has shown that compared with continuous ART, interruption of ART results in a reduction in markers of bone turnover and increase in BMD at hip and spine, and that early changes in markers of bone turnover predict BMD changes at 12 months. © 2013 American Society for Bone and Mineral Research. 23529671 Evaluation of body weight, insulin resistance, leptin and adiponectin levels in premenopausal women with hyperprolactinemia. The effects of hyperprolactinemia on metabolic parameters are not clear and a few data evaluating adiponectin levels in prolactinoma and idiopathic hyperprolactinemia exist. The aim of this study was to evaluate the effects of hyperprolactinemia on body weight, insulin resistance, beta cell function, and leptin and adiponectin levels in premenopausal women with hyperprolactinemia. Forty premenopausal women with prolactinoma or idiopathic hyperprolactinemia were compared to 41 age-matched healthy premenopausal women with regard to body weight, body mass index, waist and hip circumferences, waist to hip ratio, fasting plasma glucose, insulin levels, insulin resistance measured by homeostasis model assessment (HOMA)-insulin resistance index, beta cell function measured by HOMA-β index, leptin and adiponectin levels. Plasma insulin levels and HOMA indexes (both insulin resistance and beta indexes) were significantly higher in hyperprolactinemic women. The other parameters were similar between both groups. There was a positive correlation between prolactin levels and fasting plasma glucose in hyperprolactinemic women. The results of this study showed that high prolactin levels may be associated with hyperinsulinemia and insulin resistance in premenopausal women. This effect seems to be independent of body weight, leptin and adiponectin levels. High prolactin levels may directly stimulate insulin secretion from pancreas and directly cause hepatic and whole-body insulin resistance. 23412992 Cardiotonic steroids-mediated Na+/K+-ATPase targeting could circumvent various chemoresistance pathways. Many cancer patients fail to respond to chemotherapy because of the intrinsic resistance of their cancer to pro-apoptotic stimuli or the acquisition of the multidrug resistant phenotype during chronic treatment. Previous data from our groups and from others point to the sodium/potassium pump (the Na+/K+-ATPase, i.e., NaK) with its highly specific ligands (i.e., cardiotonic steroids) as a new target for combating cancers associated with dismal prognoses, including gliomas, melanomas, non-small cell lung cancers, renal cell carcinomas, and colon cancers. Cardiotonic steroid-mediated Na+/K+-ATPase targeting could circumvent various resistance pathways. The most probable pathways include the involvement of Na+/K+-ATPase β subunits in invasion features and Na+/K+-ATPase α subunits in chemosensitisation by specific cardiotonic steroid-mediated apoptosis and anoïkis-sensitisation; the regulation of the expression of multidrug resistant-related genes; post-translational regulation, including glycosylation and ubiquitinylation of multidrug resistant-related proteins; c-Myc downregulation; hypoxia-inducible factor downregulation; NF-κB downregulation and deactivation; the inhibition of the glycolytic pathway with a reduction of intra-cellular ATP levels and an induction of non-apoptotic cell death. The aims of this review are to examine the various molecular pathways by which the NaK targeting can be more deleterious to biologically aggressive cancer cells than to normal cells. 23265492 Three sulphated polysaccharides isolated from the mucilage of mud snail, Bullacta exarata philippi: characterization and antitumour activity. Three sulphated polysaccharides, coded as BEMPA, BEMPB(1), BEMPB(2), were extracted from the mucilage of mud snail of Bullacta exarata and purified by DEAE-cellulose ion-exchange and size-exclusion chromatography. Structural analysis of purified polysaccharides by chemical and biochemical methods revealed BEMPA was a high (1→3,4)-linked mannose-containing polysaccharide with molecular weight of 22,977 Da. BEMPB(1), with molecular weight of 64,117 Da, was a high (1→3)-linked arabinose-containing polysaccharide. BEMPB(2) was mainly composed of (1→3,4)-linked mannose with molecular weight of 47,507Da. The comparison between sulphated polysaccharides and their desulphated products showed that sulphate substitutions of BEMPB(1) were deduced to be at the C-3 of (1→4)-linked mannose, while sulphate substitutions of BEMPA and BEMPB(2) were at C-4 of (1→3)-linked mannose. Furthermore, BEMPA exhibited highest inhibitory effects on growth of B-16 melanoma cells, and IC(50) were 31.1 μg/mL. 22986456 Decreased serum chemerin levels in male Japanese patients with type 2 diabetes: sex dimorphism. Chemerin, a recently discovered adipocytokine plays an important role in obesity and obesity-associated metabolic complications. However, the role of chemerin in the pathogenesis of type 2 diabetes mellitus (T2DM) has not fully been elucidated. We compared the serum chemerin levels and metabolic parameters between 88 control subjects, 86 patients with metabolic syndrome (MS), and 147 patients with T2DM in a Japanese population and further analyzed their correlation. Enzyme-linked immunosorbent assay was used to measure the serum chemerin levels. The chemerin levels were significantly higher in male than in female control subjects (p < 0.005), with significant decreases in patients with T2DM compared with those with MS and control subjects (164.9 ± 6.3 ng/mL vs. 209.8 ± 7.7 and 218.7 ± 7.3 ng/mL; p < 0.0001 vs. p < 0.0001, respectively) but no significant differences in female subjects. The multiple regression analysis revealed that the chemerin levels negatively correlated with the fasting glucose and HbA1c levels in total and male subjects. In the patients with T2DM, the chemerin levels negatively correlated with fasting glucose and high-density lipoprotein cholesterol but positively correlated with body mass index (BMI), and total cholesterol and triglyceride levels. The negative correlation between the chemerin and fasting glucose levels remained significant after adjustment for age, sex, and BMI in the total and male subjects and those with T2DM. These results suggest the role of chemerin in sex dimorphism and a potential link between chemerin levels and T2DM pathogenesis in a Japanese population. 23394394 Uncertain prognosis for high-quality diagnostics: clinical challenges, economic barriers and needed reforms. Quality healthcare, as measured by outcomes and costs, needs high-quality diagnostics whose use governs the evidence-based flow of patients from screening to treatment to outcomes monitoring. The current patent, regulatory and reimbursement environment may be inadequate to spur their development, thereby placing in jeopardy the goals of healthcare reform and the aspirations of personalized medicine. Policy actions to ensure consistent quality standards and to increase development incentives through research support, reimbursement reform, increased intellectual property protection and market-making activities may be required to obtain the well-characterized, clinically proven diagnostics that US healthcare requires. 23540609 Molar Mass, Entanglement, and Associations of the Biofilm Polysaccharide of Staphylococcus epidermidis. Biofilms are microbial communities that are characterized by the presence of a viscoelastic extracellular polymeric substance (EPS). Studies have shown that polysaccharides, along with proteins and DNA, are a major constituent of the EPS and play a dominant role in mediating its microstructure and rheological properties. Here, we investigate the possibility of entanglements and associative complexes in solutions of extracellular polysaccharide intercellular adhesin (PIA) extracted from Staphylococcus epidermidis biofilms. We report that the weight average molar mass and radius of gyration of PIA isolates are 2.01 × 10(5) ± 1200 g/mol and 29.2 ± 1.2 nm, respectively. The coil overlap concentration, c*, was thus determined to be (32 ± 4) × 10(-4) g/mL. Measurements of the in situ concentration of PIA (cPIA,biofilm) was found to be (10 ± 2) × 10(-4) g/mL . Thus, cPIA,biofilm < c* and the amount of PIA in the biofilm is too low to cause polymer chain entanglements. In the pH range 3.0-5.5, PIA was found to both self-associate and to form complexes with bovine serum albumin (BSA). By static light scattering, both self-association and complex formation with 0.5% (w/v) BSA were found to occur at PIA concentrations of 0.30 × 10(-4) g/mL and greater, which is about 30 times lower than the measured cPIA,biofilm. These results suggest that the microscopic origin of EPS viscoelasticity is unlikely to be due to polysaccharide entanglements. Furthermore, the onset of self-association and protein complexation of PIA occurs at concentrations far lower than the native PIA concentration in biofilms. This finding therefore suggests a critical role for those two association mechanisms in mediating biofilm viscoelasticity. 23374869 Inhibition of monoamine oxidase by phthalide analogues. Based on recent reports that the small molecules, isatin and phthalimide, are suitable scaffolds for the design of high potency monoamine oxidase (MAO) inhibitors, the present study examines the MAO inhibitory properties of a series of phthalide [2-benzofuran-1(3H)-one] analogues. Phthalide is structurally related to isatin and phthalimide and it is demonstrated here that substitution at C6 of the phthalide moiety yields compounds endowed with high binding affinities to both human MAO isoforms. Among the nineteen homologues evaluated, the lowest IC(50) values recorded for the inhibition of MAO-A and -B were 0.096 and 0.0014 μM, respectively. In most instances, C6-substituted phthalides exhibit MAO-B specific inhibition. Among a series of 6-benzyloxyphthalides bearing substituents on the para position of the phenyl ring the general order of potency was CF(3) > I > Br > Cl > F > CH(3) > H. The results also show that the binding modes of representative phthalides are reversible and competitive at both MAO isoforms. Based on these data, C6-substituted phthalides may serve as leads for the development of therapies for neurodegenerative disorders such as Parkinson's disease. 23580404 Low Driving Voltage and High Mobility Ambipolar Field-Effect Transistors with PbS Colloidal Nanocrystals. PbS colloidal nanocrystals (NCs) are promising materials for optoelectronic devices, due to their size-tunable properties. However, there is still minimal understanding of their charge transport mechanism. Through a combination of ligand selections, ambipolar transistor structure optimization, and electrochemical gating usage, high carrier mobility is achieved. The outstanding device characteristics open possibility to investigate the intrinsic transport properties of PbS NCs. 23484851 Effect of sequence on the ionization behavior of a series of amphiphilic polypeptides. The behavior of five polypeptides made of hydrophilic and pH-responsive aspartic acid (Asp) and hydrophobic phenylalanine (Phe), which had been prepared by stitching together short well-defined sequences of Asp and Phe, was studied as a function of pH. The effect of pH on these polypeptides referred to as (Asp3Phe1)n, (Asp2Phe1)n, (Asp1Phe1)n, (Asp1Phe2)n, and (Asp1Phe3)n varied dramatically depending on their constituting sequence. The more hydrophobic polypeptides (Asp1Phe2)n and (Asp1Phe3)n behaved as if the Asp's were isolated from each other and showed an apparent pKa (pKa(app)) that remained constant with level of ionization (α = [Asp(-)]/[Asp]total) and equaled 5.4 and 6.4, respectively. The more hydrophilic polypeptides (Asp3Phe1)n and (Asp2Phe1)n behaved like weak polyacids showing a linear increase in pKa(app) with increasing α. The pKa(app) of (Asp1Phe1)n showed a trend as a function of α intermediate between the Asp-rich and Phe-rich polypeptides, behaving as if the Asp's were isolated at low α values (<0.35) but acting as a weak polyacid for large α values (>0.35). The effect that α, and thus the charge density of the polypeptides, had on the collapse and aggregation of the polypeptides was characterized by conducting static light scattering and fluorescence measurements. Static light scattering measurements demonstrated that all polypeptides precipitated and aggregated in solution at a critical charge density of 0.2. Fluorescence measurements with pyrene indicated that this behavior was due to the formation of Phe aggregates in water. Together, these experiments provide a complete description of how pH affects the behavior of a series of unique amphiphilic polypeptides designed with a well-defined sequence. 23399641 Creation and screening of a multi-family bacterial oxidoreductase library to discover novel nitroreductases that efficiently activate the bioreductive prodrugs CB1954 and PR-104A. Two potentially complementary approaches to improve the anti-cancer strategy gene-directed enzyme prodrug therapy (GDEPT) are discovery of more efficient prodrug-activating enzymes, and development of more effective prodrugs. Here we demonstrate the utility of a flexible screening system based on the Escherichia coli SOS response to evaluate novel nitroreductase enzymes and prodrugs in concert. To achieve this, a library of 47 candidate genes representing 11 different oxidoreductase families was created and screened to identify the most efficient activators of two different nitroaromatic prodrugs, CB1954 and PR-104A. The most catalytically efficient nitroreductases were found in the NfsA and NfsB enzyme families, with NfsA homologues generally more active than NfsB. Some members of the AzoR, NemA and MdaB families also exhibited low-level activity with one or both prodrugs. The results of SOS screening in our optimised E. coli reporter strain SOS-R2 were generally predictive of the ability of nitroreductase candidates to sensitise E. coli to CB1954, and of the kcat/Km for each prodrug substrate at a purified protein level. However, we also found that not all nitroreductases express stably in human (HCT-116 colon carcinoma) cells, and that activity at a purified protein level did not necessarily predict activity in stably transfected HCT-116. These results highlight a need for all enzyme-prodrug partners for GDEPT to be assessed in the specific context of the vector and cell line that they are intended to target. Nonetheless, our oxidoreductase library and optimised screens provide valuable tools to identify preferred nitroreductase-prodrug combinations to advance to preclinical evaluation. 23410634 Time series analysis of oxidative stress response patterns in HepG2: A toxicogenomics approach. Oxidative stress plays an important role in chemically induced liver injury, however, our insight into molecular responses to different oxygen radicals is fragmentary. Since these cellular responses will differ over time, examining time-dependent changes in gene expression, and correlating these with markers for oxidative stress, may provide new insights into responses to oxidants. We used the human hepatoma cell line HepG2 to investigate the effects of oxidative stress on the transcriptome level by micro-arrays at seven time points (0.5, 1, 2, 4, 6, 8 and 24h) following exposure to the oxidants menadione, hydrogen peroxide and tert-butyl hydroperoxide including the effects on cell cycle and apoptosis by flow cytometry, protein carbonyl formation by spectrophotometry and oxidative DNA damage by FPG-comet. In total, 3429 genes were differentially expressed, including 136 genes that were significantly modified by all oxidants. Time-dependent biological pathway analysis showed that these genes were particularly involved in inflammatory responses, cell cycle processes and glutathione signaling. These responses were confirmed and supported by phenotypic anchoring to the different cellular endpoints. In addition, using an innovative temporal analysis we established an oxidative stress-related gene expression time cluster. Altogether, this study provides new insights in temporal oxidative stress mechanisms and demonstrates sequential cellular responses that may contribute to a better hazard identification and the mechanisms of toxicological responses in the liver induced by oxidative stress. 23017399 Can the dietary element content of virgin argan oils really be used for adulteration detection? Levels of eight dietary elements were assessed by ICP-AES in virgin edible and beauty argan oil samples prepared from four remote locations of the argan forest, and over a three-year period. The data showed sufficiently little variability to assess that all argan oil samples present, in terms of dietary elements, a similar composition, independently from the tree location within the argan forest. Therefore, adulteration detection by trace element analysis in edible and beauty argan oil is a method that can be generalised. 23261524 Live-cell imaging of p53 interactions using a novel Venus-based bimolecular fluorescence complementation system. p53 plays an important role in regulating a wide variety of cellular processes, such as cell cycle arrest and/or apoptosis. Dysfunction of p53 is frequently associated with several pathologies, such as cancer and neurodegenerative diseases. In recent years substantial progress has been made in developing novel p53-activating molecules. Importantly, modulation of p53 interaction with its main inhibitor, Mdm2, has been highlighted as a promising therapeutic target. In this regard, bimolecular fluorescence complementation (BiFC) analysis, by providing direct visualization of protein interactions in living cells, offers a straightforward method to identify potential modulators of protein interactions. In this study, we developed a simple and robust Venus-based BiFC system to screen for modulators of p53-p53 and p53-Mdm2 interactions in live mammalian cells. We used nutlin-3, a well-known disruptor of p53-Mdm2 interaction, to validate the specificity of the assay. The reduction of BiFC signal mediated by nutlin-3 was correlated with an increase in Puma transactivation, PARP cleavage, and cell death. Finally, this novel BiFC approach was exploited to identify potential modulators of p53-Mdm2 complex formation among a commercially available chemical library of 33 protein phosphatase inhibitors. Our results constitute "proof-of-concept" that this model has strong potential as an alternative to traditional target-based drug discovery strategies. Identification of new modulators of p53-p53 and p53-Mdm2 interactions will be useful to achieve synergistic drug efficacy with currently used anti-tumor therapies. 23448196 The need for better insulin therapy. Insulin replacement therapy corrects a core defect of diabetes pathophysiology. Since its introduction as a therapeutic modality almost 100 years ago, insulin therapy has undergone remarkable changes in purity and ability to provide more physiologic control of blood glucose levels. With glucose-lowering potential limited only by risks of hypoglycaemia, which remains the major limitation in our ability to achieve glycaemic goals, insulin replacement therapy remains a cornerstone of therapy. Major progress in reducing the risks of hypoglycemia has occurred with the development of insulin analogs. This review article briefly chronicles the evolution of insulin replacement strategies, highlighting both challenges in pharmaceutical development and patient acceptance, underscoring achievements, as well as denoting what improvements are still needed. 23210485 Qualitative studies among obese children and adolescents: a systematic review of the literature. Childhood obesity is a complex condition involving medical, social, moral and cultural issues. Qualitative approaches are of great value in understanding this complexity. This meta-synthesis of 45 qualitative studies deals specifically with the issue of obesity in children and adolescents from different perspectives - those of obese children and adolescents, of parents, and of health professionals providing support to the family. Our aim was to obtain a coherent view of child and adolescent obesity, focused on clinical and personal experience. The themes derived from the synthesis process fall under three main axes: 'Seeing others, seeing oneself', 'Understanding others, understanding oneself', and 'Treating others, treating oneself'. It emerges that participants in all three groups had equal difficulty in perceiving and labelling obesity, mainly because of their lack of any real common ground. The insufficiency of shared representations destabilizes the therapeutic relationship and its construction: an important issue in the doctor-child-parent relationship in this context is the need to exchange their viewpoints of obesity. Health workers may also expand their understanding of obesity by incorporating the personal experiences of obese children and their parents in order to match treatment plans to their needs and expectations. 23456978 Plasminogen plays a crucial role in bone repair. The further development in research of bone regeneration is necessary to meet the clinical demand for bone reconstruction. Plasminogen is a critical factor of the tissue fibrinolytic system, which mediates tissue repair in the skin and liver. However, the role of the fibrinolytic system in bone regeneration remains unknown. Herein, we investigated bone repair and ectopic bone formation using plasminogen deficient (Plg(-/-) ) mice. Bone repair of the femur is delayed in Plg(-/-) mice, unlike that in the wild-type (Plg(+/+) ) mice. The deposition of cartilage matrix and osteoblast formation were both decreased in Plg(-/-) mice. Vessel formation, macrophage accumulation, and the levels of vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β) were decreased at the site of bone damage in Plg(-/-) mice. Conversely, heterotopic ossification was not significantly different between Plg(+/+) and Plg(-/-) mice. Moreover, angiogenesis, macrophage accumulation, and the levels of VEGF and TGF-β were comparable between Plg(+/+) and Plg(-/-) mice in heterotopic ossification. Our data provide novel evidence that plasminogen is essential for bone repair. The present study indicates that plasminogen contributes to angiogenesis related to macrophage accumulation, TGF-β, and VEGF, thereby leading to the enhancement of bone repair. © 2013 American Society for Bone and Mineral Research. 23568579 On the persistence of cocaine-induced place preferences and aversions in rats. RATIONALE: Rats develop preferences for places associated with the immediate rewarding effects of cocaine and aversions for places paired with the drug's delayed negative effects. The motivation to seek cocaine should therefore depend upon the relative magnitude of these two opposing effects of the drug. OBJECTIVE: The current study tested this notion by assessing the relative persistence of the positive and negative associations formed between environmental cues and the immediate or delayed effects of cocaine. METHODS: Rats were administered 1.0 mg/kg intravenous cocaine and placed into a distinctive environment either immediately or 15-min after injection, alternating daily with pairings of a second environment with saline. After four drug-place and four saline-place pairings, rats were returned to their home cages for 1, 7, or 21 days after which a 15-min place preference test was conducted. In a second experiment, the effectiveness of a single reconditioning session (one drug-place and one saline-place pairing) to reactivate learned cocaine-place associations was assessed after 1 or 3 weeks of drug abstinence. RESULTS: Places associated with the immediate effects of cocaine were preferred (CPP), while places associated with the delayed effects of cocaine were avoided (CPA). The persistence of these effects differed with CPP remaining viable at 3 weeks of withdrawal, while CPA was no longer present after 1 week. Reconditioning with an additional cocaine-place pairing failed to reinstate the CPA. CONCLUSIONS: Cue-induced "relapse" of cocaine-seeking behavior may be fueled in part by an increased persistence of positive relative to negative associations with drug-paired stimuli. 22949397 Oral intake of beet extract provides protection against skin barrier impairment in hairless mice. The epidermis acts as a functional barrier against the external environment. Disturbances in the function of this barrier cause water loss and increase the chances of penetration by various irritable stimuli, leading to skin diseases such as dry skin, atopic dermatitis, and psoriasis. Ceramides are a critical natural element of the protective epidermal barrier. The aim of this study was to evaluate whether the oral intake of beet (Beta vulgaris) extract, a natural product rich in glucosylceramide (GlcCer), may prevent disturbance in skin barrier function. When HR-1 hairless mice were fed a special diet (HR-AD), transepidermal water loss (TEWL) from the dorsal skin increased, with a compensatory increase in water intake after 5 weeks. Mice fed with HR-AD had dry skin with erythema and showed increased scratching behaviour. Histological examinations revealed a remarkable increase in the thickness of the skin at 8 weeks. Supplemental addition of beet extract, which contained GlcCer at a final concentration of 0.1%, significantly prevented an increase TEWL, water intake, cumulative scratching time, and epidermal thickness at 8 weeks. These results indicate that oral intake of beet extract shows potential for preventing skin diseases associated with impaired skin barrier function. Copyright © 2012 John Wiley & Sons, Ltd. 23311718 Phase boundaries, structural characteristics, and NMR spectra of ionic liquid-in-oil microemulsions containing double chain surface active ionic liquid: a comparative study. A method developed for the first time, to create a huge number of ionic liquid (IL)-in-oil microemulsions has been discussed in our earlier publication (Rao, V. G.; Ghosh, S.; Ghatak, C.; Mandal, S.; Brahmachari, U.; Sarkar, N. J. Phys. Chem. B 2012, 116, 2850-2855). Here, we present facile methods to adjust the structural parameters of microemulsions using different ionic liquids (ILs) as additives (polar phase). We have characterized ILs/[C(4)mim][AOT]/benzene ternary system by performing a phase behavior study, dynamic light scattering (DLS) measurements, and (1)H NMR measurements. The IL loading capacity of microemulsions (area of single phase region) (i) increases with increase in alkyl chain length of cation of ILs and follows the trend [C(6)mim][TF(2)N] > [C(4)mim][TF(2)N] > [C(2)mim][TF(2)N], (ii) increases with decrease in cation anion interaction strength of added ILs and follows the trend [C(4)mim][TF(2)N] > [C(4)mim][PF(6)] > [C(4)mim][BF(4)]. So depending on the IL used, the amount of IL within the core of microemulsions can be easily manipulated to directly affect the size of aggregates in microemulsions. The size increase with increasing R value (R value is defined as the molar ratio of RTILs to [C(4)mim][AOT]) was found to be maximum in the case of [C(2)mim][TF(2)N]/[C(4)mim][AOT]/benzene microemulsions and follows the trend [C(2)mim][TF(2)N] > [C(4)mim][TF(2)N] > [C(6)mim][TF(2)N]. However, the size increase was almost the same with increase in R value in the case of ILs with different anions. The most promising fact about IL-in-oil microemulsions is their high thermal stability compared to that of aqueous microemulsions, so we investigated the effect of temperature on size of aggregates in microemulsions at R = 1.0. It is evident from dynamic light scattering measurements that the aggregates in microemulsions remain monodisperse in nature with increasing temperature, and in all the cases, the size of aggregates in microemulsions decreases with increasing temperature. The effect of water addition on IL-in-oil (IL/O) microemulsions was also studied in detail. By far, this is the first report where the effect of water addition on microemulsions containing hydrophobic ILs is being reported and compared with microemulsions containing hydrophilic ILs. We observed that the added water has a prominent effect on the microstructure of the microemulsions. In all the cases, (1)H NMR spectra provide more detailed information about intra/intermolecular interactions thus affording a clear picture of locations of (i) the RTILs in RTILs/[C(4)mim][AOT]/benzene microemulsions and (ii) the added water molecules in microemulsions. 23465072 New GABA/Glutamate Receptor Target for [(3)H]Isoxazoline Insecticide. The highly effective and selective isoxazoline insecticide A1443 is known to potently displace [(3)H]ethynylbicycloorthobenzoate ([(3)H]EBOB) binding to house fly head membranes with an IC50 of 0.2 nM in a manner characteristic of GABA-gated chloride channel antagonists. To further define its mode of action, we prepared phenyl-labeled [(3)H]A1443 as described with a specific activity of 14 Ci/mmol. This new radioligand with an apparent IC50 of about 0.4 nM is poorly displaced by most insecticides acting at the [(3)H]EBOB site. Interestingly, the isoxazoline binding site is directly coupled to the avermectin GABA/glutamate chloride channel activator site. These findings revive interest in the insect GABA/glutamate receptor as an insecticide target. 23288866 P-glycoprotein increases portal bioavailability of loperamide in mouse by reducing first-pass intestinal metabolism. P-glycoprotein (P-gp) and CYP3A (cytochrome P450 3A, generally; Cyp3a, rodent enzyme) in the intestine can attenuate absorption of orally administered drugs. While some suggest that P-gp enhances intestinal metabolism by CYP3A/Cyp3a during absorption of a dual substrate, others suggest that P-gp reduces the metabolism in the intestine when substrates are at subsaturating concentrations. Hence, to elucidate the cellular mechanisms that can address these divergent reports, we studied intestinal absorption of the dual substrate loperamide in portal vein-cannulated P-gp-competent and P-gp-deficient mice. These studies showed that at low doses of loperamide, which produced intestinal concentrations near the apparent K(m) for oxidative metabolism, the bioavailability across the intestine (F(G)) was 6-fold greater in the P-gp-competent mice than in P-gp-deficient mice. The higher F(G) of loperamide in the presence of P-gp was attributed to lower loperamide intestinal metabolism. However, at high doses of loperamide, the sparing of first-pass metabolism by P-gp was balanced against the attenuation of absorption by apical efflux, resulting in no net effect on F(G). In vitro studies with intestinal tissue from P-gp-competent and -deficient mice confirmed that P-gp reduced the metabolic rate of loperamide during absorptive flux at concentrations near K(m) but had little effect on metabolism at higher (saturating) concentrations. Further, studies in which Cyp3a was chemically inactivated by aminobenzotriazole in P-gp-competent and -deficient mice, showed that P-gp and Cyp3a individually attenuated F(G) by 8-fold and 70-fold, respectively. These results confirmed that P-gp effectively protects loperamide at low doses from intestinal first-pass metabolism during intestinal absorption. 23401281 Soluble metal pool as affected by soil addition with organic inputs. The potential impact of diverse inputs of organic matter (hay, maize straw, and peat) on the mobility and bioavailability of Cd, Cu, Pb, and Zn was examined at laboratory scale for three soils with contrasting properties and for two moisture regimes: field capacity and saturated conditions. Soil solution was characterized for total soluble metals, dissolved soil organic carbon, and ultraviolet absorbance at 254 nm. Speciation analyses were performed with WHAM VI. For field capacity conditions, metal mobility increased (Pb > Cu > Zn > Cd) for all soils and treatments compared with controls and was significantly correlated (p < 0.05) with dissolved organic matter (r = 0.540). Solubilization of organic matter was mostly driven by Al mobilization (r = 0.580, p < 0.05) and variations in solution pH. The bioavailable pool of metals, estimated as free ion activities, decreased with the increasing occurrence of metal-organic matter complexes, which was accompanied by an increase in solution of highly aromatic organic matter. Soil saturation generally decreased metal mobility and the ratio of metal-organo matter complexes in solution. Consistently, such effects were accompanied by a decrease in the solubilization of organic matter and lower mobilization of Al, Fe, and Mn. Environ Toxicol Chem 2013;32:1027-1032. © 2013 SETAC. 23241059 Pseudostatic and dynamic nanomechanics of the tunica adventitia in elastic arteries using atomic force microscopy. Tunica adventitia, the outer layer of blood vessels, is an important structural feature, predominantly consisting of collagen fibrils. This study uses pseudostatic atomic force microscopy (AFM) nanoindentation at physiological conditions to show that the distribution of indentation modulus and viscous creep for the tunica adventitia of porcine aorta and pulmonary artery are distinct. Dynamic nanoindentation demonstrates that the viscous dissipation of the tunica adventitia of the aorta is greater than the pulmonary artery. We suggest that this mechanical property of the aortic adventitia is functionally advantageous due to the higher blood pressure within this vessel during the cardiac cycle. The effects on pulsatile deformation and dissipative energy losses are discussed. 23387901 Tubulin inhibitors from an endophytic fungus isolated from Cedrus deodara. From an endophytic fungus, a close relative of Talaromyces sp., found in association with Cedrus deodara, four compounds including two new ones (2 and 4) were isolated and characterized. The structures of two compounds (1 and 4) were confirmed by X-ray crystallography. The compounds displayed a range of cytotoxicities against human cancer cell lines (HCT-116, A-549, HEP-1, THP-1, and PC-3). All the compounds were found to induce apoptosis in HL-60 cells, as evidenced by fluorescence and scanning electron microscopy studies. Also, the compounds caused significant microtubule inhibition in HL-60 cells. 23465594 Increased dietary fat contributes to dysregulation of the LKB1/AMPK pathway and increased damage in a mouse model of early-stage ethanol-mediated steatosis. OBJECTIVE: The objective of the study was to examine the interaction of moderate and high dietary fat and ethanol with respect to formation of steatosis and regulation of the AMP-activated protein kinase (AMPK) pathway in a mouse model of chronic ethanol consumption. METHODS: Male C57BL/6J mice were pair-fed a modified Lieber-DeCarli diet composed of either moderate fat [30% fat-derived calories (MF)] or high fat [45% fat-derived calories (HF)] combined with increasing concentrations of ethanol (2%-6%) for 6 weeks. RESULTS: Chronic ethanol consumption resulted in significant increases in plasma alanine aminotransferase in MF (1.84-fold) and HF mice (2.33-fold), yet liver triglycerides only increased significantly in the HF model (1.62-fold). Ethanol addition significantly increased plasma adiponectin under conditions of MF but not HF. In combination with MF, the addition of ethanol significantly decreased total and hepatic pThr(172)AMPKα and acetyl CoA Carboxylase (ACC). HF plus ethanol decreased pSer(108)AMPKβ, yet a marked 1.5-fold increase in pThr(172)AMPKα occurred. No change was evident in pSer(79)ACC under conditions of ethanol and HF ingestion. In both models, nuclear levels of sterol response element binding protein 1c and carbohydrate response element binding protein were decreased. Surprisingly, MF plus ethanol significantly elevated protein expression of medium-chain acyl-CoA dehydrogenase (MCAD), long-chain acyl-CoA dehydrogenase (LCAD) and very long chain acyl-CoA dehydrogenase but did not significantly affect mRNA expression of other proteins involved in β-oxidation and fatty acid synthesis. HF plus ethanol significantly reduced mRNA expression of both stearoyl CoA desaturase 1 and fatty acid elongase 5, but did not have an effect on MCAD or LCAD. CONCLUSION: These data suggest that, when co-ingested with ethanol, dietary fat differentially contributes to dysregulation of adiponectin-dependent activation of the AMPK pathway in the liver of mice. 23537700 Similar pyruvate kinase modifications in glioblastoma cells by 7β-hydroxycholesterol and glutamine withdrawal. Oxysterols possess anti-proliferative properties that may be used with much effect in the treatment of cancer. We have demonstrated previously that 7 beta-hydroxycholesterol (7b-HC) provokes both metabolic stress, as witnessed by AMPK activation, and changes in lipid raft composition in C6 glioblastoma cells. These observations suggested that glycolysis might have been changed. Here we will show that 7b-HC increases cell cycle time and that it changes the affinity of pyruvate kinase to its substrate, phosphoenol pyruvate. The latter effect is mimicked by glutamine withdrawal. 23524160 Synthesis and biological evaluation of novel pyrrolidine-2,5-dione derivatives as potential antidepressant agents. Part 1. A series of 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives was synthesized and their biological activity was evaluated. The chemical structures of the newly prepared compounds were confirmed by (1)H NMR, (13)C NMR and ESI-HRMS spectra data. All tested compounds proved to be potent 5-HT1A receptor and serotonin transporter protein (SERT) ligands. Among them, compounds 15, 18, 19 and 30 showed significant affinity for 5-HT1A and SERT. Computer docking simulations carried out for compounds 15, 31 and 32 to models of 5-HT1A receptor and SERT confirm the results of biological tests. Due to high affinity for the 5-HT1A receptor and moderate affinity for SERT, compounds 31, 32, 35, and 37 were evaluated for their affinity for D2L, 5-HT6, 5-HT7 and 5-HT2A receptors. In vivo tests, in turn, resulted in determining the functional activity of compounds 15, 18, 19 and 30 to the 5-HT1A receptor. The results of these tests indicate that all of the ligands possess properties characteristic of 5-HT1A receptor agonists. 23381882 Mechanisms of Pharmacokinetic Enhancement Between Ritonavir and Saquinavir; Micro/Small Dosing Tests Using Midazolam (CYP3A4), Fexofenadine (p-Glycoprotein), and Pravastatin (OATP1B1) as Probe Drugs. We investigated the mechanisms of ritonavir-mediated enhancement effect on the pharmacokinetics of saquinavir using in vivo probes for CYP3A4 (midazolam), p-glycoprotein (fexofenadine), and OATP1B1 (pravastatin) following oral micro/small dosing. A cocktail of the drugs (2 mg of saquinavir, 100 µg of each probe) was administered to eight healthy volunteers (phase 1), and then coadministered with 20 mg (phase 2) and 100 mg (phase 3) of ritonavir. Plasma concentrations of the drugs were measured by validated LC-MS/MS methods. The mean plasma AUC(0-24) (pg hour/mL) of saquinavir at phases 1, 2, and 3 was 101, 2 540, and 23 900 (P < .01), respectively. The relative area under the plasma concentration-time curve (AUC)(0-24) ratios of midazolam and fexofenadine at phases 1, 2, and 3 were 1:5.9:14.7 (P < .01), and 1:1.4:2.2 (P < .01-.05), respectively. In contrast, there was no difference in the pharmacokinetics of pravastatin. Inhibition of intestinal and hepatic CYP3A-mediated metabolism, and intestinal p-glycoprotein-mediated efflux of saquinavir, but not OATP1B1, is involved in the enhancement mechanism. Micro/small dosing is useful for examining the mechanism of drug interactions without safety concern. 23369833 Transformation of paralytic shellfish poisoning toxins in UK surf clams (Spisula solida) for targeted production of reference materials. The periodic occurrence of Paralytic Shellfish Poisoning (PSP) toxins in UK surf clams and the recent move away from biological assays for PSP testing resulted in the need to determine method performance characteristics for the replacement analytical method in this species. With the requirement for laboratory reference materials to aid this validation together with known issues relating to toxin transformation in live clams and homogenised tissue, there was the need to assess the toxin transformation characteristics of PSP toxins in surf clam tissue. Initial work examined the rates of toxin transformation in UK surf clam tissue incubated with toxin standards, showing rapid transformation of N-sulfocarbamoyl toxins with slower transformation of carbamate toxins. Full transformational pathways were determined using a combination of three different analytical methods and confirmed the major expected transformations involving decarbamoylation, with some evidence for additional reaction pathways. Results obtained from the analysis of surf clam and oyster tissues incubated with varying concentrations of toxic Alexandrium algae highlighted expected transformation reactions, although significant differences were observed in the extent of the transformations amongst the range of toxins studied, with less efficient transformation of N-hydroxylated toxins as compared with other carbamate and N-sulfocarbamoyl toxins. Analysis of PSP-toxic incurred oyster, scallop and mussel tissues incubated with variable proportions of surf clam tissue showed large differences in the extent of the transformations. Total conversion of N-sulfocarbamoyl toxins was confirmed at low relative proportions of surf clam tissue in all three species, whereas transformation of carbamate toxins was found to occur only in the presence of higher proportions of surf clam tissue in oysters and mussels in comparison with scallops. Results enabled the production of three laboratory reference materials prepared following incubation of incurred homogenates with optimum proportions of surf clam tissue, resulting in materials containing a large number of PSP toxins. Stability experiments provided good preliminary evidence for the stability of these targeted materials under storage conditions. The work therefore provides both additional information relating to the transformational activity in UK surf clams and highlights a good potential method for the targeted production of reference materials which include a wider range of toxins than normally present in naturally incurred shellfish. 23041538 Ischemia-induced synaptic plasticity drives sustained expression of calcium-permeable AMPA receptors in the hippocampus. Long lasting enhancement of synaptic transmission can be triggered by brief bursts of afferent stimulation, underlying long-term potentiation (LTP), and also by brief ischemia in a process known as i-LTP. The extent to which LTP and i-LTP rely on comparable cellular mechanisms remains unclear. Under physiological conditions, LTP induction drives transient expression of calcium-permeable AMPARs (CP-AMPARs) at synapses, whose ability to undergo plasticity is primed by endogenous activation of adenosine A(2A) receptors (A(2A)Rs). The present work thus addressed the contribution of CP-AMPARs and A(2A)Rs to i-LTP, which was induced in rat hippocampal slices by brief (10 min) oxygen/glucose deprivation (OGD). The amplitude of afferent-evoked excitatory postsynaptic currents (EPSCs) recorded from CA1 pyramidal neurons was decreased during OGD but gradually recovered toward values significantly above (157 ± 17%) the baseline (100%) 40-50 min after re-oxygenation. This i-LTP was precluded by CP-AMPAR blockade (internal spermine (500 μM) or extracellular NASPM (20 μM) application) as well as by A(2A)R blockade with a selective antagonist (SCH 58261, 100 nM). OGD prompted sustained (>70 min) facilitation of mEPSC amplitude and frequency, and decreased mEPSC decay time, all of which were prevented by SCH 58261 (100 nM). The ability of NASPM (20 μM) to acutely inhibit EPSCs 1 h after OGD, but not in control conditions nor in OGD-challenged slices when in the presence of SCH 58261 (100 nM), further supports sustained CP-AMPAR recruitment by i-LTP in an A(2A)R-dependent way. We propose that although i-LTP may initially mimic LTP, failure of auto-regulated CP-AMPAR removal from synapses could constitute an early divergent event between these forms of plasticity. 23258671 Super-stable ultrafine beta-tungsten nanocrystals with metastable phase and related magnetism. Ultrafine tungsten nanocrystals (average size of 3 nm) with a metastable phase (beta-tungsten with A15 structure, β-W) have been prepared by laser ablation of tungsten in liquid nitrogen. The as-prepared metastable nanocrystals exhibited super-stablity, and can keep the same metastable structure over a period of 6 months at room temperature. This super-stability is attributed to the nanosized confinement effect of ultrafine nanocrystals. The magnetism measurements showed that the β-W nanocrystals have weak ferromagnetic properties at 2 K, which may arise from surface defects and unpaired electrons on the surface of the ultrafine nanocrystals. These findings provided useful information for the application of ultrafine β-W nanocrystals in microelectronics and spintronics. 23315090 Hypolipidemic effect of fruit fibers in rats fed with high dietary fat. The hypolipidemic effect of 10% fruit fibers in rats fed with high-fat diet (HFD) was evaluated. This study was conducted on a total of 50 male Albino rats divided into 10 equal groups fed with different types of dietary fruits. The feeding period lasted for 24 weeks. Fasting blood samples were collected and sera separated and subjected to lipid profile assay and atherogenic index. In addition, total antioxidant activity of different fruits was determined. The results obtained showed that pomegranate had higher content of antioxidants followed by apple, strawberry and guava compared with other fruits. Rats fed with 20% coconut oil showed a highly significant elevation in the levels of serum total cholesterol, low-density lipoprotein cholesterol and atherogenic factor while the level of high-density lipoprotein cholesterol was significantly decreased when compared with control rats. Histological examination revealed that there was a large lipid and cholesterol deposition in the livers of rats fed with HFD. The potential in lowering the levels of plasma total cholesterol and triglyceride is in the following order: pomegranate > apple > strawberry > guava > papaya > mandarin and orange. Accumulation of hepatic lipid droplets was diminished when compared with the HFD group. Also, antiatherogenic is better than the untreated groups. Accordingly these hypolipidemic effects may be due to high-fiber content and antioxidant activity of these fruits. 23434934 From SNP to Transcriptional Mechanism: A Model for FRMD3 in Diabetic Nephropathy. Genome wide association studies (GWAS) have proven to be highly effective at defining causal relationships between single nucleotide polymorphisms (SNP) and clinical phenotypes in complex diseases. Establishing a mechanistic link between a non-coding SNP and the clinical outcome is a significant hurdle in translating associations into biological insight. We demonstrate an approach to assess the functional context of a diabetic nephropathy (DN) associated SNP located in the promoter region of the gene FRMD3. The approach integrates pathway analyses with transcriptional regulatory pattern based promoter modeling and allows the identification of a transcriptional framework impacted by the DN-associated SNP in the FRMD3 promoter. This framework provides a testable hypothesis for mechanisms of genomic variation and transcriptional regulation in the context of DN. Our model proposes a possible transcriptional link through which the polymorphism in the FRMD3 promoter could influence transcriptional regulation within the bone morphogenetic protein (BMP) signaling pathway. These findings provide the rationale to interrogate the biological link between FRMD3 and the BMP pathway, and serve as an example of functional genomics-based hypothesis generation. 23386616 Toll-like receptor 2 mediates peripheral nerve injury-induced NADPH oxidase 2 expression in spinal cord microglia. We have previously reported that NADPH oxidase 2 (Nox2) is up-regulated in spinal cord microglia after spinal nerve injury, demonstrating that it is critical for microglia activation and subsequent pain hypersensitivity. However, the mechanisms and molecules involved in Nox2 induction have not been elucidated. Previous studies have shown that Toll-like receptors (TLRs) are involved in nerve injury-induced spinal cord microglia activation. In this study, we investigated the role of TLR in Nox2 expression in spinal cord microglia after peripheral nerve injury. Studies using TLR knock-out mice have shown that nerve injury-induced microglial Nox2 up-regulation is abrogated in TLR2 but not in TLR3 or -4 knock-out mice. Intrathecal injection of lipoteichoic acid, a TLR2 agonist, induced Nox2 expression in spinal cord microglia both at the mRNA and protein levels. Similarly, lipoteichoic acid stimulation induced Nox2 expression and reactive oxygen species production in primary spinal cord glial cells in vitro. Studies on intracellular signaling pathways indicate that NF-κB and p38 MAP kinase activation is required for TLR2-induced Nox2 expression in glial cells. Conclusively, our data show that TLR2 mediates nerve injury-induced Nox2 gene expression in spinal cord microglia via NF-κB and p38 activation and thereby may contribute to spinal cord microglia activation. 23363425 Silica precipitation by synthetic minicollagens. Oligomeric Pro-Hyp-Gly- (POG-) peptides, wherein the collagenous triple helix is supported by C-terminal capping, exhibit silica precipitation properties (O, Hyp = (2S,4R)hydroxyproline). As quantified by a molybdate assay, the length of the covalently tethered triple helix (number of POG units) determines the amount of amorphous silica obtained from silicic acid solution. Although lacking charged side chains, the synthetic collagens precipitate large quantities of silicic acid resulting in micrometer-sized spheres of varying surface morphologies as analyzed by scanning electron microscopy. Similar precipitation efficiencies on a fast time scale of less than 10 min were previously described only for biogenic diatom proteins and sponge collagen, respectively, which have a considerably higher structural complexity and limited accessibility. The minicollagens described here provide an unexpected alternative to the widely used precipitation conditions, which generally depend on (poly-)amines in phosphate buffer. Collagen can form intimate connections with inorganic matter. Hence, silica-enclosed collagens have promising perspectives as composite materials. 22788743 The potential impact of strawberry on human health. The strawberry (Fragaria X ananassa, Duch.) represents a relevant source of micronutrients, such as minerals, vitamin C, folate and phenolic substances, most of which are natural antioxidants and contribute to the high nutritional quality of the fruit. All these compounds are essential for health and, in particular, strawberry phenolics are best known for their antioxidant and anti-inflammatory action, and possess directly and indirectly antimicrobial, anti-allergy and anti-hypertensive properties, as well as the capacity to inhibit the activities of some physiological enzymes and receptor properties. The main objective of this article is to review and update the current knowledge on the potential impact of the strawberry on human health, with particular attention on compounds and their possible mechanisms of action. 22580610 miR-34a functions as a tumor suppressor modulating EGFR in glioblastoma multiforme. Chromosome 1p36.23 is frequently deleted in glioblastoma multiforme (GBM). miR-34a localizes in this region. Our experiments found that miR-34a was often deleted and epidermal growth factor receptor (EGFR) was frequently amplified in genomic DNA of 55 GBMs using single-nucleotide polymorphism DNA microarray. Notably, we found that the mean survival time was significantly shortened for patients whose GBMs had both EGFR amplification and miR-34a deletion. Expression of miR-34a was significantly lower in GBM samples compared with normal brain tissue. Forced expression of miR-34a in GBM cells decreased their ability to migrate and profoundly decreased their levels of cyclin-A1, -B1, -D1, and -D3, as well as cyclin-dependent kinase and increased expression of cyclin kinase inhibitor proteins (p21, p27). Also, human GBM cells (U251) stable overexpressing mir-34a formed smaller tumors when growing as xenografts in immunodeficient mice compared with wild-type U251 GBM cells. Furthermore, the protein expression of EGFR decreased in the cells with forced overexpression of miR-34a. Additional studies showed that mir-34a targeted Yin Yang-1 (YY1) and YY1 is a transcription factor that can stimulate the expression of EGFR. Thus, our data suggest that miR-34a acts as a tumor suppressor by inhibiting growth of GBM cells in vitro and in vivo associated with moderating the expression of cell-cycle proteins and EGFR. Moreover, we discovered for the first time that both deletion of miR-34a and amplification of EGFR were associated with significantly decreased overall survival of GBM patients. 23374865 Synthesis and micellar mimic properties of bile acid trimers. Two fan-shaped bile acid trimers have been synthesized via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) 'click chemistry', and their extraction experiments of cresol red sodium (CR) and pyrene were investigated in the polar and non-polar solvents, respectively. The transmission electron microscopy (TEM) results showed that the homogenous hollow capsules formed with the diameter size range of 40-70 nm in a solution of water and acetone. Thus the amphiphilicity of fan-shaped bile acid trimers might be used as the promising candidate in biological and drug delivery applications. 23603112 Binding of new cationic porphyrin-tetrapeptide conjugates to nucleoprotein complexes. Ongoing research on DNA binding of cationic porphyrin derivatives and their conjugates is a subject of growing interest because of their possible DNA binding and demonstrated biological properties. In this study nucleoprotein binding of tri-cationic meso-tri(4-N-methylpyridyl)-mono-(4-carboxyphenyl)porphyrin (TMPCP) and tetrapeptides conjugated TMPCP (TMPCP-4P) and bi-cationic meso-5,10-bis(4-N-methylpyridyl)-15,20-di-(4-carboxyphenyl)porphyrin (BMPCP-4P2) was investigated with comprehensive spectroscopic methods. The key observation is that tetrapeptide-conjugates of cationic porphyrins with two or three positive charges bind to encapsidated DNA in T7 phage nucleoprotein complex. The binding modes were analyzed by fluorescent energy transfer, fluorescent life time and CD measurements. Intercalative binding is most feasible when tricationic ligands complex with DNA, especially when it is in close connection with protein capsid. It was found that larger ligand BMPCP-4P2 binds externally to encapsidated T7 DNA, and complex externally as well as by intercalation when the DNA accommodate to relaxed B-conformation. In the case of TMPCP and TMPCP-4P the intercalation is the predominant binding form both in nucleoprotein (NP) and preheated complexes. Further, melting experiments revealed that bound porphyrins do not influence the capsid stability or protein-DNA interactions, but efficiently stabilize the double helical structure of DNA without respect to binding form. A good correlation was found between porphyrin/base pair ration and DNA strand separation temperature. 23178170 Structure of a Ca(2+)/CaM:Kv7.4 (KCNQ4) B-helix complex provides insight into M current modulation. Calmodulin (CaM) is an important regulator of Kv7.x (KCNQx) voltage-gated potassium channels. Channels from this family produce neuronal M currents and cardiac and auditory I(KS) currents and harbor mutations that cause arrhythmias, epilepsy, and deafness. Despite extensive functional characterization, biochemical and structural details of the interaction between CaM and the channel have remained elusive. Here, we show that both apo-CaM and Ca(2+)/CaM bind to the C-terminal tail of the neuronal channel Kv7.4 (KCNQ4), which is involved in both hearing and mechanosensation. Interactions between apo-CaM and the Kv7.4 tail involve two C-terminal tail segments, known as the A and B segments, whereas the interaction between Ca(2+)/CaM and the Kv7.4 C-terminal tail requires only the B segment. Biochemical studies show that the calcium dependence of the CaM:B segment interaction is conserved in all Kv7 subtypes. X-ray crystallographic determination of the structure of the Ca(2+)/CaM:Kv7.4 B segment complex shows that Ca(2+)/CaM wraps around the Kv7.4 B segment, which forms an α-helix, in an antiparallel orientation that embodies a variation of the classic 1-14 Ca(2+)/CaM interaction motif. Taken together with the context of prior studies, our data suggest a model for modulation of neuronal Kv7 channels involving a calcium-dependent conformational switch from an apo-CaM form that bridges the A and B segments to a Ca(2+)/CaM form bound to the B-helix. The structure presented here also provides a context for a number of disease-causing mutations and for further dissection of the mechanisms by which CaM controls Kv7 function. 23159397 Systemic effects induced by the venom of the snake Bothrops caribbaeus in a murine model. Snakebite envenoming by Bothrops caribbaeus, an endemic viperid from the Lesser Antillean island of Saint Lucia, is clinically characterized by local tissue damage and systemic thrombosis that can lead to cerebral, myocardial or pulmonary infarctions and venous thromboses. Systemic effects (lethality, pulmonary hemorrhage, thrombocytopenia and coagulopathy) induced by intravenous (i.v.) administration of B. caribbaeus venom were studied in mice. The role of snake venom metalloproteinases (SVMPs) in these systemic alterations was assessed by inhibition with the chelating agent calcium disodium ethylenediaminetetraacetic acid (CaNa(2)EDTA). A snake C-type lectin-like (snaclec) and a type P-III hemorrhagic SVMP were isolated and characterized from this venom, and the effect of venom and the isolated snaclec on human platelet aggregation was studied in vitro. Results indicate that SVMPs play an important role in the overall toxicity of B. caribbaeus venom, being responsible for systemic hemorrhage and lethality, but not thrombocytopenia, whereas the isolated snaclec is involved in the thrombocytopenic effect. Both venom and snaclec induce platelet aggregation/agglutination. Moreover, the snaclec binds directly to glycoprotein Ib (GPIb) and induces agglutination in washed fixed platelets. On the other hand, B. caribbaeus venom hydrolyzed fibrinogen in vitro and induced a partial drop of fibrinogen levels with an increase in fibrin/fibrinogen degradation products (FDP) levels in vivo. The negative result for D-dimer (DD) in plasma is consistent with the lack of microscopic evidence of pulmonary thrombosis and endothelial cell damage. Likewise, no increments in plasma sE-selectin levels were detected. The absence of thrombosis in this murine model suggests that this effect may be species-specific. 23228697 Carboxylesterase-2 is a highly sensitive target of the antiobesity agent orlistat with profound implications in the activation of anticancer prodrugs. Orlistat has been the most used anti-obesity drug and the mechanism of its action is to reduce lipid absorption by inhibiting gastrointestinal lipases. These enzymes, like carboxylesterases (CESs), structurally belong to the α/β hydrolase fold superfamily. Lipases and CESs are functionally related as well. Some CESs (e.g., human CES1) have been shown to hydrolyze lipids. This study was designed to test the hypothesis that orlistat inhibits CESs with higher potency toward CES1 than CES2, a carboxylesterase with little lipase activity. Liver microsomes and recombinant CESs were tested for the inhibition of the hydrolysis of standard substrates and the anticancer prodrugs pentyl carbamate of p-aminobenzyl carbamate of doxazolidine (PPD) and irinotecan. Contrary to the hypothesis, orlistat at 1 nM inhibited CES2 activity by 75% but no inhibition on CES1, placing CES2 one of the most sensitive targets of orlistat. The inhibition varied among some CES2 polymorphic variants. Pretreatment with orlistat reduced the cell killing activity of PPD. Certain mouse but not rat CESs were also highly sensitive. CES2 is responsible for the hydrolysis of many common drugs and abundantly expressed in the gastrointestinal track and liver. Inhibition of this carboxylesterase probably presents a major source for altered therapeutic activity of these medicines if co-administered with orlistat. In addition, orlistat has been linked to various types of organ toxicities, and this study provides an alternative target potentially involved in these toxicological responses. 23466235 Discovery of non-peptide inhibitors of Plasmepsin II by structure-based virtual screening. Plasmepsin II (PM II) is an attractive target for anti-malaria drug discovery, which involves in host hemoglobin degradation in the acidic food vacuole. In this study, we demonstrated the successful use of structure-based virtual screening to identify inhibitors of PM II from two chemical database. Five novel non-peptide inhibitors were identified and revealed moderate inhibitory potencies with IC50 ranged from 4.62 ± 0.39 to 9.47 ± 0.71 μM. The detailed analysis of binding modes using docking simulations for five inhibitors showed that the inhibitors could be stabilized by forming multiple hydrogen bonds with catalytic residues (Asp 34 and Asp 214) and also with other key residues. 23146662 Comparison of transcriptional response to phorbol ester, bryostatin 1, and bryostatin analogs in LNCaP and U937 cancer cell lines provides insight into their differential mechanism of action. Bryostatin 1, like the phorbol esters, binds to and activates protein kinase C (PKC) but paradoxically antagonizes many but not all phorbol ester responses. Previously, we have compared patterns of biological response to bryostatin 1, phorbol ester, and the bryostatin 1 derivative Merle 23 in two human cancer cell lines, LNCaP and U937. Bryostatin 1 fails to induce a typical phorbol ester biological response in either cell line, whereas Merle 23 resembles phorbol ester in the U937 cells and bryostatin 1 in the LNCaP cells. Here, we have compared the pattern of their transcriptional response in both cell lines. We examined by qPCR the transcriptional response as a function of dose and time for a series of genes regulated by PKCs. In both cell lines bryostatin 1 differed primarily from phorbol ester in having a shorter duration of transcriptional modulation. This was not due to bryostatin 1 instability, since bryostatin 1 suppressed the phorbol ester response. In both cell lines Merle 23 induced a pattern of transcription largely like that of phorbol ester although with a modest reduction at later times in the LNCaP cells, suggesting that the difference in biological response of the two cell lines to Merle 23 lies downstream of this transcriptional regulation. For a series of bryostatins and analogs which ranged from bryostatin 1-like to phorbol ester-like in activity on the U937 cells, the duration of transcriptional response correlated with the pattern of biological activity, suggesting that this may provide a robust platform for structure activity analysis. 23570572 Self-Repair of a Biological Fiber Guided by an Ordered Elastic Framework. Incorporating sacrificial cross-links into polymers represents an exciting new avenue for the development of self-healing materials, but it is unclear to what extent their spatial arrangement is important for this functionality. In this respect, self-healing biological materials, such as mussel byssal threads, can provide important chemical and structural insights. In this study, we employ in situ small-angle X-ray scattering (SAXS) measurements during mechanical deformation to show that byssal threads consist of a partially crystalline protein framework capable of large reversible deformations via unfolding of tightly folded protein domains. The long-range structural order is destroyed by stretching the fiber but reappears rapidly after removal of load. Full mechanical recovery, however, proceeds more slowly, suggesting the presence of strong and slowly reversible sacrificial cross-links. One likely role of the highly ordered elastic framework is to bring sacrificial binding sites back into register upon stress release, facilitating bond reformation and self-repair. 23558682 Porphyromonas gingivalis virulence factor gingipain RgpB shows a unique zymogenic mechanism for cysteine peptidases. Zymogenicity is a regulatory mechanism which prevents inadequate catalytic activity in the wrong context. It plays a central role in maintaining microbial virulence factors in an inactive form inside the pathogen until secretion. Among these virulence factors is the cysteine peptidase gingipain B (RgpB), which is the major virulence factor secreted by the periodontopathogen Porphyromonas gingivalis that attacks host vasculature and defense proteins. The structure of the complex between soluble mature RgpB, consisting of a catalytic domain and an immunoglobulin-superfamily domain, and its 205-residue N-terminal pro-domain, the largest structurally characterized to date for a cysteine peptidase, reveals a novel fold for the pro-domain that is distantly related to sugar-binding lectins. It attaches laterally to the catalytic domain through a large concave surface. The main determinant for latency is a surface inhibitory loop, which approaches the active-site cleft of the enzyme on its non-primed side in a substrate-like manner. It inserts an arginine (R126) into the S1 pocket, thus matching the substrate specificity of the enzyme. Downstream of R126, the polypeptide leaves the cleft, thereby preventing cleavage. Moreover, the carbonyl group of R126 establishes a very strong hydrogen bond with the co-catalytic histidine, H440, pulling it away from the catalytic cysteine, C473, and towards E381, which probably plays a role orienting the side chain of H440 during catalysis. The present results provide the structural determinants of zymogenic inhibition of RgpB by way of a novel inhibitory mechanism for peptidases in general and open the field for the design of novel inhibitory strategies in the treatment of human periodontal disease. 21826085 DPP6 as a candidate gene for neuroleptic-induced tardive dyskinesia. We implemented a two-step approach to detect potential predictor gene variants for neuroleptic-induced tardive dyskinesia (TD) in schizophrenic subjects. First, we screened associations by using a genome-wide (Illumina HumanHapCNV370) SNP array in 61 Japanese schizophrenia patients with treatment-resistant TD and 61 Japanese schizophrenia patients without TD. Next, we performed a replication analysis in 36 treatment-resistant TD and 138 non-TD subjects. An association of an SNP in the DPP6 (dipeptidyl peptidase-like protein-6) gene, rs6977820, the most promising association identified by the screen, was significant in the replication sample (allelic P=0.008 in the replication sample, allelic P=4.6 × 10(-6), odds ratio 2.32 in the combined sample). The SNP is located in intron-1 of the DPP6 gene and the risk allele was associated with decreased DPP6 gene expression in the human postmortem prefrontal cortex. Chronic administration of haloperidol increased Dpp6 expression in mouse brains. DPP6 is an auxiliary subunit of Kv4 and regulates the properties of Kv4, which regulates the activity of dopaminergic neurons. The findings of this study indicate that an altered response of Kv4/DPP6 to long-term neuroleptic administration is involved in neuroleptic-induced TD. 23219525 Influence of sildenafil and tadalafil on the enzyme- and transporter-inducing effects of bosentan and ambrisentan in LS180 cells. The combinations of the endothelin-1 receptor antagonists bosentan or ambrisentan with the phosphodiesterase 5 inhibitors sildenafil or tadalafil are current standard therapies of advanced pulmonary arterial hypertension. However, these drugs have a number of drug interactions. Changes of bosentan pharmacokinetics by sildenafil are attributed to reduced hepatic uptake as a consequence of inhibition of organic anion transporting polypeptides. We therefore tested in vitro the hypothesis that sildenafil and tadalafil reduce the enzyme- and transporter-inducing effects of bosentan or ambrisentan by preventing cellular access. Although intracellular concentrations of bosentan and ambrisentan (measured by high pressure liquid chromatography coupled with tandem mass-spectrometry) after four days of incubation of LS180 cells were lower when sildenafil or tadalafil were present, quantification of mRNA expression in these cells by real-time reverse transcription polymerase chain reaction revealed that bosentan and ambrisentan-mediated induction was stable or even increased in combination with sildenafil or tadalafil. For the drug transporter P-glycoprotein this was confirmed at the protein and functional level with highly significant correlations between P-gp mRNA, protein, and function. Moreover, using a reporter gene assay in LS180 cells, our study demonstrates for the first time that tadalafil is a potent, ambrisentan a weak, and sildenafil no activator of pregnane X receptor. In conclusion, our study demonstrates that although sildenafil and tadalafil indeed reduce intracellular concentrations of bosentan and ambrisentan in LS180 cells, they do not mitigate the inducing effects of these endothelin-1 receptor antagonists. 23359555 Electrochemical Synthesis of Transparent, Amorphous, C(60) -Rich, Photoactive, and Low-Doped Film with an Interconnected Structure. An electrochemical synthesis is developed through quantitative electrochemical reaction of N-alkylcarbazole leading to a novel class of structurally interconnected high-C(60) content (60 wt%) polymer films with negligible doping and intrinsic physicochemical properties of pure C(60) . This strategy allows preparation of previously unavailable low-doped fullerene-containing non-conjugated polymers and broadens the potential applications of electrochemical synthesis for controlled polymer film structures. 23223234 The fidelity of transcription: RPB1 (RPO21) mutations that increase transcriptional slippage in S. cerevisiae. The fidelity of RNA synthesis depends on both accurate template-mediated nucleotide selection and proper maintenance of register between template and RNA. Loss of register, or transcriptional slippage, is particularly likely on homopolymeric runs in the template. Transcriptional slippage can alter the coding capacity of mRNAs and is used as a regulatory mechanism. Here we describe mutations in the largest subunit of Saccharomyces cerevisiae RNA polymerase II that substantially increase the level of transcriptional slippage. Alleles of RPB1 (RPO21) with elevated slippage rates were identified among 6-azauracil-sensitive mutants and were also isolated using a slippage-dependent reporter gene. Biochemical characterization of polymerase II isolated from these mutants confirms elevated levels of transcriptional slippage. 22317825 RETRACTED: Biochemical changes in the Beluga Huso huso exposed to acute crude diesel oil. RETRACTED. 23499823 Synthesis and molecular modeling of (4'R)- and (4'S)- 4'-substituted 2'-{[(E)-androst-5-en-17-ylidene]-methyl}oxazolines. Synthesis of four novel (4'R)- and (4'S)- 2'-{[(E)-3β-hydroxyandrost-5-en-17-ylidene]-methyl} oxazolines, comprising 4'-hydroxymethyl (1 and 2) and 4'-methoxycarbonyl (3 and 4) substituents is presented. Reaction of 17α-bromo-21-iodo-3β-acetoxypregn-5-en-20-one with either (L)-serine methyl ester, or (D)-serine methyl ester resulted in methyl N-[3β-acetoxy-21-oxopregna-5,17(20)-dien-21-yl]-(L)-serinate and methyl N-[3β-acetoxy-21-oxopregna-5,17(20)-dien-21-yl]-(D)-serinate (as mixtures of related [17(20)E]- and [17(20)Z]-isomers). Cyclization of obtained amides led to methyl 2'-{[(E)-3β-acetoxyandrost-5-en-17-ylidene]methyl}-(4'S)-4',5'-dihydro-1',3'-oxazole-4'-carboxylate and methyl 2'-{[(E)-3β-acetoxyandrost-5-en-17-ylidene]methyl}-(4'R)-4',5'-dihydro-1',3'-oxazole-4'-carboxylate which were transformed to titled compounds 1-4. The molecular docking of compounds 1-4 to ligand binding site of nuclear receptor LXRβ revealed significant differences due to stereochemical configuration of 4' atom and structure of 4'-substituent. 23416011 A nitrophenyl-based prodrug type for colorectal targeting of prednisolone, budesonide and celecoxib. Celecoxib is a COX-2 inhibitor drug that can be used to reduce the risk of colorectal adenocarcinoma. Glucocorticoids are used in the treatment of inflammatory bowel disease. A limitation to the use of both drug types is that they undergo absorption from the intestinal tract with serious side effects. The prodrug systems introduced here involve forming a nitro-substituted acylsulfonamide group in the case of celecoxib and a nitro-substituted 21-ester for the glucocorticoids. Drug release is triggered by the nitro reductase action of the colonic microflora, liberating a cyclization competent species. The release of the active parent drugs was evaluated in vitro using Clostridium perfringens and epithelial transport through Caco-2 monolayer evaluation was carried out to estimate the absorption properties of the prodrugs compared to the parental drugs. 23248191 Impact of restricted maternal weight gain on fetal growth and perinatal morbidity in obese women with type 2 diabetes. OBJECTIVE Since January 2008, obese women with type 2 diabetes were advised to gain 0-5 kg during pregnancy. The aim with this study was to evaluate fetal growth and perinatal morbidity in relation to gestational weight gain in these women. RESEARCH DESIGN AND METHODS A retrospective cohort comprised the records of 58 singleton pregnancies in obese women (BMI ≥30 kg/m(2)) with type 2 diabetes giving birth between 2008 and 2011. Birth weight was evaluated by SD z score to adjust for gestational age and sex. RESULTS Seventeen women (29%) gained ≤5 kg, and the remaining 41 gained >5 kg. The median (range) gestational weight gains were 3.7 kg (-4.7 to 5 kg) and 12.1 kg (5.5-25.5 kg), respectively. Prepregnancy BMI was 33.5 kg/m(2) (30-53 kg/m(2)) vs. 36.8 kg/m(2) (30-48 kg/m(2)), P = 0.037, and median HbA1c was 6.7% at first visit in both groups and decreased to 5.7 and 6.0%, P = 0.620, in late pregnancy, respectively. Gestational weight gain ≤5 kg was associated with lower birth weight z score (P = 0.008), lower rates of large-for-gestational-age (LGA) infants (12 vs. 39%, P = 0.041), delivery closer to term (268 vs. 262 days, P = 0.039), and less perinatal morbidity (35 vs. 71%, P = 0.024) compared with pregnancies with maternal weight gain >5 kg. CONCLUSIONS In this pilot study in obese women with type 2 diabetes, maternal gestational weight gain ≤5 kg was associated with a more proportionate birth weight and less perinatal morbidity. 23256719 Antioxidants and mucolytics in COPD management: when (if ever) and in whom? Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Oxidative stress is an important mechanism in the pathogenesis of this disease. The oxidant/ antioxidant imbalance occurring in smokers and patients with COPD is well established. Thus, therapeutic strategies targeting oxidative stress with pharmacological antioxidant agents or boosting the endogenous levels of antioxidants is likely to be beneficial as an adjunctive tool in the treatment of COPD patients. Thiol compounts such as N-acetyl-L-cysteine (NAC), carbocysteine, erdosteine, and fudosteine have been extensively studied. Although some results remain controversial, NAC and carbocysteine seem to have beneficial effect in patients not receiving inhaled corticosteroids who suffer from frequent exacerbations. In addition, other antioxidants like superoxide dismutase (SOD) mimetics and nuclear factor-erythroid 2 related factor 2 (Nrf2) are shown to decrease markers of oxidative stress in patients with emphysema, while others like glutathione peroxidase (GPx) mimetics and NO synthase (iNOS) can prevent both inflammation and oxidative stress in clinical trials in vivo (or in mouse models). In this article we review the effectiveness of various antioxidant factors in COPD and their potential beneficial effect in the treatment of the disease. 23341143 Regional inhibition of cholinesterase in free-ranging western pond turtles (Emys marmorata) occupying California mountain streams. The present study investigated the potential effects of cholinesterase (ChE)-inhibiting pesticides on western pond turtles (Emys marmorata) occupying streams in two regions of California, USA. The southern region was suspected of having increased exposure to atmospheric deposition of contaminants originating from Central Valley agriculture. The northern region represented reference ChE activities because this area was located outside of the prominent wind patterns that deposit pesticides into the southern region. Total ChE activity was measured in plasma from a total of 81 turtles from both regions. Cholinesterase activity of turtles was significantly depressed by 31% (p = 0.005) in the southern region after accounting for additional sources of variation in ChE activity. Male turtles had significantly increased ChE activity compared with females (p = 0.054). Cloaca temperature, length, mass, handling time, body condition, and lymph presence were not significant predictors of turtle ChE activity. In the southern region, 6.3% of the turtles were below the diagnostic threshold of two standard deviations less than the reference site mean ChE activity. Another diagnostic threshold determined that 75% of the turtles from the southern region had ChE activities depressed by 20% of the reference mean. The decrease in ChE activity in the southern region suggests sublethal effects of pesticide exposure, potentially altering neurotransmission, which can result in various deleterious behaviors. 23305444 Discovery and evaluation of novel inhibitors of mycobacterium protein tyrosine phosphatase B from the 6-Hydroxy-benzofuran-5-carboxylic acid scaffold. Mycobacterium tuberculosis (Mtb) protein tyrosine phosphatase B (mPTPB) is a virulence factor secreted by the pathogen and mediates mycobacterial survival in macrophages by targeting host cell immune responses. Consequently, mPTPB represents an exciting new target to combat tuberculosis (TB) infection. We describe a medicinal chemistry oriented approach that transforms a benzofuran salicylic acid scaffold into a highly potent (IC(50) = 38 nM) and selective mPTPB inhibitor (>50 fold against a large panel of PTPs). Importantly, the inhibitor is capable of reversing the altered host immune responses induced by the bacterial phosphatase and restoring the macrophage's full capacity to secrete IL-6 and undergo apoptosis in response to interferon-γ stimulation, validating the concept that chemical inhibition of mPTPB may be therapeutically useful for novel TB treatment. The study further demonstrates that bicyclic salicylic acid pharmacophores can be used to deliver PTP inhibitors with high potency, selectivity, and cellular efficacy. 23410164 Polypharmacology in a single drug: multitarget drugs. Polypharmacology offers a model for the way drug discovery must evolve to develop therapies most suited to treating currently incurable diseases. It is driven by a worldwide demand for safer, more effective, and affordable medicines against the most complex diseases, and by the failures of modern drug discovery to provide these. Polypharmacology can involve combinations and/or multitarget drugs (MTD). Although not mutually exclusive, my premise is that MTDs have inherent advantages over combinations. This review article focuses on MTDs from a medicinal chemistry perspective. I will explore their use in current clinical practice, their likely application in the future, and the challenges to be overcome to achieve this goal. 23411312 Thermal stability of anthocyanins and colourless phenolics in pomegranate (Punica granatum L.) juices and model solutions. The present study aimed at a systematic assessment of the factors influencing the anthocyanin (AC) stability and colour retention of pomegranate juices and less complex model solutions with particular focus on the effects of colourless phenolic copigments (CP). The thermal stability of ACs in three pomegranate juices obtained from isolated arils and the entire fruit with and without previous steaming, in model solutions with AC:CP ratios ranging from 1:0 to 1:4 (m/m), and in two purified extracts from pomegranate juices characterised by different phenolic profiles, respectively, was investigated upon heating at 60, 70, 80 and 90°C for 15 min to 5h. The thermal impact on the AC and CP contents, and the formation of 5-hydroxymethylfurfural (HMF) and AC degradation products were monitored using HPLC-DAD-MS(n). Total phenolic contents, antioxidant capacity and colour properties were determined spectrophotometrically. Heating at 90°C for 5h resulted in total AC losses ranging from 76% to 87% of the initial AC levels in the juices, 78% in both extracts as well as 57% and ∼78% in the model solutions, showing the best stability at an AC:CP ratio of 1:2 and in juices having the highest initial AC contents, respectively. In contrast, the AC stability was independent of total phenolic contents, and low and high molecular pomegranate matrix components (such as organic acids and sugars). Good correlation of the AC contents with red colour (a(∗)) was observed for all samples at elevated temperatures (70-90°C). The stability of putative health-promoting polyphenols of pomegranate juices was not markedly affected by the thermal treatment. Unexpectedly, the HMF contents only slightly increased upon forced heating. Therefore, the visual appearance does not adequately reflect the quality and storage stability of pomegranate juices. 23000447 A 90-day feeding study of glyphosate-tolerant maize with the G2-aroA gene in Sprague-Dawley rats. Maize is not only a staple food crop but also an important raw material for feed and industry; however, the threat of weeds leads to a serious decline in its output and quality. The G2-aroA gene confers glyphosate herbicide tolerance to crops. In this study, the food safety of genetically modified (GM), glyphosate-tolerant maize with the G2-aroA gene was evaluated in a 90-day feeding study in Sprague-Dawley (SD) rats. Maize grain from GM or non-GM isogenic control lines were separately formulated into rodent diets at concentrations of 12.5% (low level), 25% (middle level), and 50% (high level). An additional group of rats were fed a commercialized diet as a control. The toxicological response variables, including body weights, food consumption, serum biochemistry, hematology, and absolute and relative organ weights, were compared between rats fed GM maize and those fed non-GM maize after consumption of test diets for 90days. In addition, gross and microscopic pathology were conducted among treatment groups. No adverse effects related to the consumption of GM maize were detected in the subchronic feeding study. These results indicated that the GM glyphosate-tolerant maize was as safe and nutritious as conventional maize. 23382105 Population pharmacokinetics and dose optimization of mycophenolic acid in HCT recipients receiving oral mycophenolate mofetil. We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. Four thousand four hundred ninety-six MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance (CL) and volume of the central compartment were 24.2 L/hour and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA CL by 33.8%. The optimal LSS was immediately before and at 0.25 hours, 1.25 hours, 2 hours, and 4 hours after oral mycophenolate mofetil administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation. 23347616 5' C-rich telomeric overhangs are an outcome of rapid telomere truncation events. A subset of human tumors ensures indefinite telomere length maintenance by activating a telomerase-independent mechanism known as Alternative Lengthening of Telomeres (ALT). Most tumor cells of ALT origin share a constellation of unique characteristics, which include large stores of extra-chromosomal telomeric material, chronic telomere dysfunction and a peculiar enrichment in chromosome ends with 5' C-rich overhangs. Here we demonstrate that acute telomere de-protection and the subsequent DNA damage signal are not sufficient to facilitate formation of 5' C-overhangs at the chromosome end. Rather chromosome ends bearing 5' C-overhangs are a by-product of rapid cleavage events, processing of which occurs independently of the DNA damage response and is partly mediated through the XRCC3 endonuclease. 23448384 High-temperature and pressure-induced ferroelectricity in hydrogen-bonded supramolecular crystals of anilic acids and 2,3-di(2-pyridinyl)pyrazine. Cocrystallization of anilic acids (H2xa) and 2,3-di(2-pyridinyl)pyrazine (dppz) affords a variety of molecular geometries, including hydrogen-bonding and supramolecular structures. Proton-transferred 1:1 salts of [H-dppz][Hca] and [H-dppz][Hba] (H2ca = chloranilic acid, H2ba = bromanilic acid) were found to host room-temperature ferroelectricity with a spontaneous polarization of 3-4 μC/cm(2) along the hydrogen-bonded chains. Compared with the Curie points of other supramolecular ferroelectrics, those of the salts are relatively high (402 K and >420 K, respectively) because of the elongated hydrogen bonds, which stabilize the proton-ordered state against thermal agitation. In addition to the ferroelectric black (α) form, dppz and H2ba gave two different crystal forms with a 2:3 ratio: the brown β form of [H(1.5)-dppz]2[Hba]3 and the brownish-red γ form of [H-dppz]2[Hba]2[H2ba]. Mixed solutions of dppz with the less acidic fluoranilic acid (H2fa) exhibit valence instability; the H2fa molecules remain mostly neutral in absolute ethanol, whereas methanol (MeOH) solution apparently increases the deprotonated Hfa(-) content. Crystallizations of these solutions gave a neutral [dppz][H2fa] cocrystal and ionic [H-dppz(+)][Hfa(-)]·MeOH salt, respectively. The ferroelectricity induced by a modest hydrostatic pressure corroborates the conclusion that the ionic state with a dipolar [H-dppz(+)][Hfa(-)] chain is energetically close to the nonpolar neutral ground state of the [dppz][H2fa] crystal. 23422227 Cytotoxic sesquiterpenes from Hedychium spicatum: Isolation, structure elucidation and structure-activity relationship studies. Phytochemical investigation of chloroform extract from rhizomes of Hedychium spicatum resulted in the isolation of six new sesquiterpenes (1-6) along with fifteen known compounds (7-21). Their structures were elucidated on the basis of the extensive spectroscopic analyses (IR, Mass and NMR) and by comparison of the data with those reported in the literature. Further, cytotoxic activities of all the isolates were evaluated by determining their inhibitory effects against A-549, B-16, Hela, HT-29, NCI-H460, PC-3, IEC-6 and L-6 cancer cell lines. Results indicated that compounds 1 and 3 may serve as an important natural lead compounds for future development as they showed potent cytotoxic activity against Hela cell lines with an IC50 value of 0.3μg/mL and 1.80μg/mL, respectively. 23411217 Peyer's patch-mediated intestinal immune system modulating activity of pectic-type polysaccharide from peel of Citrus unshiu. An intestinal immune system modulating polysaccharide (CUI-3IIb-3-2, 18kDa) was purified from Citrus unshiu peel. CUI-3IIb-3-2 mainly comprised GalA, GlcA, Ara, Gal and Rha, and it consisted of 4-linked GalA, terminal Araf, 4- or 5-linked/3,4- or 3,5-branched Ara, terminal Gal, and 2-linked/2,4-branched Rha. After CUI-3IIb-3-2 digestion by endo-α-d-(1→4)-polygalacturonase, its hydrolysate was fractionated into PG-1 and PG-2. Methylation analyses of PG-1 and PG-2 using base-catalysed β-elimination suggested that CUI-3IIb-3-2 be assumed as pectic-type polysaccharide. Since the activities of PG-1 and PG-2 were potently decreased, the whole polysaccharide structure of CUI-3IIb-3-2 would be essential to maintain the activity. Meanwhile, when CUI-3IIb was orally administered in mice, bone marrow cell proliferation and GM-CSF/IL-6 production from Peyer's patch cell were significantly higher (1.76- and 2.03/2.51-fold, respectively) than a saline. Therefore, a pectic-type polysaccharide from citrus peel could stimulate Peyer's patches and produce hematopoietic growth factors resulted in bone marrow cell proliferation. 23317159 JAK inhibitors: pharmacology and clinical activity in chronic myeloprolipherative neoplasms. The Janus family kinases (JAKs), JAK1, JAK2, JAK3, and TYK2, are involved in cell growth, survival, development, and differentiation of a variety of cells, particularly immune cells and hematopoietic cells. They form a subgroup of the non-receptor protein tyrosine kinases. Activating mutations within each of the JAKs is associated with malignant transformations; the most common are mutations of JAK2 in polycythemia vera (PV) and other myeloproliferative neoplasms (MPN). Identification of the V617F mutation of the JAK2 gene (JAK2 V617F) led to an important breakthrough in the understanding of MPN disease pathogenesis. The JAK2 V617F mutation is present in the majority of PV patients, and about 50% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) are affected. This mutation leads to hyperactivation of JAK2, cytokine-independent signaling, and subsequent activation of downstream signaling networks. JAK2 ATP-competitive inhibitors that indirectly inhibit the JAK-STAT pathway are new candidates for the treatment of MPN. JAK2 inhibitors in development for the treatment of MPN have demonstrated clinical activity with minimal toxicity. These agents consistently alleviate constitutional symptoms and reduce spleen size in PMF and other MPN. However, some of these inhibitors have additional unique effects. Ruxolitinib causes a significant reduction in the level of pro-inflammatory cytokines. Another inhibitor, CYT387, improves anemia. Many other JAK2 inhibitors such as TG101348 or SAR302503, SB1518, CEP701 and LY2784544 are now under investigation for MPN development. In contrast tasocitinib, a predominantly JAK3 inhibitor, is being evaluated in a number of inflammatory and immunological diseases, including rheumatoid arthritis, psoriasis, ulcerative colitis, dry eye disease and in kidney transplant patients. In conclusion the use of JAK inhibitors in MPN and some of the immune-mediated disorders is a promising new strategy for therapy. However, definitive data from ongoing and future preclinical and clinical trials will aid in better defining the status of these drugs in the treatment of these diseases. 23639361 Ghrelin receptor is activated by naringin and naringenin, constituents of a prokinetic agent Poncirus fructus. ETHNOPHARMACOLOGICAL RELEVANCE: Poncirus fructus (PF), also known as a dried immature fruit of Poncirus trifoliata (L.) Raf, has long been traditionally used for the various gastrointestinal disorders in Eastern Asia. AIM OF STUDY: The aqueous extract of PF (PF-W) has the strong prokinetic effect, yet the underlying mechanism is still elusive. The present study investigated whether PF-W has any effect on motilin receptor or ghrelin receptor, since these receptors enhance intestinal motility when activated. MATERIALS AND METHODS: The effect of PF-W and its components on motilin or ghrelin receptor was determined by calcium imaging and whole-cell patch clamp methods. RESULTS: PF-W activates the ghrelin receptor, but not the motilin receptor, resulting in a transient increase of intracellular calcium levels. Furthermore, among various constituents of PF, only naringin and naringenin evoked the intracellular calcium augmentation via the ghrelin receptor. Moreover, cortistatin-8 - a ghrelin receptor inhibitor - specifically blocked naringin- and naringenin-induced calcium increases. In addition, naringin and naringenin induced inward currents in ghrelin receptor-expressing cells under whole-cell patch clamp configuration. CONCLUSION: PF-W activates the ghrelin receptor, and naringin and naringenin are key constituents responsible for the activation of ghrelin receptor. Therefore, the present study suggests that the ghrelin receptor is a molecular entity responsible for the strong prokinetic activity of PF-W. 23347937 Olfactory evolution: mice rethink stink. Animals use a vast array of chemicals to communicate with others. How such signals originate is poorly known. Now a study traces the emergence of a signal from a metabolic product and the evolution of its behavioural significance. 23423710 5-Aza-2'-deoxycytidine inhibited PDGF-induced rat airway smooth muscle cell phenotypic switching. Airway smooth muscle (ASM) cell phenotypic switching played an important role in airway remodeling in asthma. In vitro platelet-derived growth factor (PDGF) induced ASM cell phenotypic switching from a mature to pro-remodeling phenotype, but the mechanism remained incompletely understood. This study was to explore the effect of DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (Aza-CdR) on PDGF-induced rat ASM cell phenotypic switching and biological behaviors. Rat airway smooth muscle (RASM) cells were obtained by primary explant techniques. Western blot, 3-dimensional gel contraction, transwell and wound healing assay, and MTT were applied to detect cell phenotypic switching, contractility, migration and proliferation, respectively. Cytoskeleton rearrangement was observed by immunofluorescence. Results showed Aza-CdR inhibited PDGF-induced down-regulation of contractile markers in RASM cells and increased cell contractility. Aza-CdR inhibited PDGF-induced RASM cell migration by abrogating cell morphology change and cytoskeletal reorganization and attenuated the effect of PDGF on proliferating cell nuclear antigen expression and cell cycle progression, ultimately cell proliferation. PDGF-induced DNA methyltransferase 1 (DNMT1) expression was mediated by activation of PI3K/Akt and ERK signaling in RASM cells. Selective depletion of DNMT1 protein by Aza-CdR inhibited PDGF-induced RASM cell phenotypic switching, revealing DNMT1-mediated DNA methylation was implicated in asthmatic ASM remodeling. We proposed for the first time that DNMT1 played a key role in PDGF-induced RASM cell phenotypic switching and Aza-CdR is promising in intervening ASM remodeling in asthma. Although study of abnormal DNA methylation in PDGF-stimulated ASM cells is in its infancy, this work contributes to providing new insights into the mechanism of ASM remodeling and may be helpful for developing effective treatments for airway remodeling in asthma. 23491602 Evidence that YycJ is a novel 5'-3' double-stranded DNA exonuclease acting in Bacillus anthracis mismatch repair. The most important system for correcting replication errors that survive the built in editing system of DNA polymerase is the mismatch repair (MMR) system. We have identified a novel mutator strain yycJ in Bacillus anthracis. Mutations in the yycJ gene result in a spontaneous mutator phenotype with a mutational frequency and specificity comparable to that of MMR-deficient strains such as those with mutations in mutL or mutS. YycJ was annotated as a metallo-β-lactamase (MβL) super family member with unknown activity. In this study we carried out a biochemical characterization of YycJ and demonstrated that a recombinant YycJ protein possesses a 5'-3' exonuclease activity at the 5' termini and at nicks of double-stranded DNA. This activity requires a divalent metal cofactor Mn(2+) and is stimulated by 5'-phosphate ends of duplex DNA. The mutagenesis of conserved amino acid residues revealed that in addition to the five MβL family conserved motifs, YycJ appears to have its specific motifs that can be used to distinguish YycJ from other closely related MβL family members. A phylogenetic survey showed that putative YycJ homologs are present in several bacterial phyla as well as in members of the Methanomicrobiales and Thermoplasmales from Archaea. We propose that YycJ represents a new group of MβL fold exonucleases, which is likely to act in the recognition of MMR entry point and subsequent removal of the mismatched base in certain MutH-less bacterial species. 23495163 Variability of n-alkanes and nonacosan-10-ol in natural populations of Picea omorika. This is the first report of population variability of the contents of n-alkanes and nonacosan-10-ol in the needle epicuticular waxes of Serbian spruce (Picea omorika). The hexane extracts of needle samples originated from three natural populations in Serbia (Vranjak, Zmajevački potok, and Mileševka Canyon) were investigated by GC and GC/MS analyses. The amount of nonacosan-10-ol varied individually from 50.05 to 74.42% (65.74% in average), but the differences between the three investigated populations were not statistically confirmed. The results exhibited variability of the composition of n-alkanes in the epicuticular waxes with their size ranging from C(18) to C(35). The most abundant n-alkanes were C(29), C(31), and C(27) (35.22, 13.77, and 12.28% in average, resp.). The carbon preference index of all the n-alkanes (CPI(total)) of the P. omorika populations (average of populations I-III) ranged from 3.3 to 11.5 (mean of 5.9), while the average chain length (ACL) ranged from 26.6 to 29.2. The principal component and cluster analyses of the contents of nine n-alkanes showed the greatest difference for the population growing in the Mileševka Canyon. The obtained results were compared with previous literature data given for other Picea species, and this comparison was briefly discussed. 23092894 PET and SPECT tracers for glutamate receptors. Radioligands for PET imaging of glutamate receptors will have the potential for studying neurological and neuropsychiatric disorders and their diagnosis and therapeutic intervention. Glutamate is the major excitatory neurotransmitter in the brain and is implicated in the pathophysiology of many neurodegenerative and neuropsychiatric disorders. Glutamate and its receptors are potential targets in the treatment of these disorders. Glutamate signaling is mediated through ionotropic and metabotropic receptors. The abundant concentration of these receptors can facilitate their in vivo quantification using positron emission tomography (PET). Glutamate receptors are a potentially important set of targets for monitoring disease progression, for evaluating the effect of therapy and for new treatment development based on the quantification of receptor occupancy. Here, we review the PET and single-photon emission computed tomography (SPECT) radioligands that have been developed for imaging glutamate receptors in living brain. 23537748 Synergistic antibacterial effect of curcumin against methicillin-resistant Staphylococcus aureus. Methicillin-resistant Staphylococcus aureus (MRSA) are spread among infected patients, with infection rates increasing at an alarming rate. Furthermore, increased resistance to antibiotics has resulted in serious challenges in the treatment of infectious diseases worldwide. Under the selection pressure of exposure to antibiotics, microorganisms evolve to survive against the new conditions imposed by therapy. Therefore, there exists a need to develop alternative natural or combination drug therapies. Curcumin (CCM), a natural polyphenolic flavonoid isolated from the rhizome of a plant, Curcuma longa Linné., has been found to possess many beneficial biological activities. The aim of this study was to investigate the synergistic effect of curcumin and antibiotics as well as to determine the antibacterial activity of CCM against specific MRSA strains. The antibacterial activity of CCM was assessed by the broth microdilution method (by calculating the minimal inhibitory concentration [MIC]), checkerboard dilution test, and time-kill assay. Antimicrobial activity of CCM was observed against all tested strains. The MICs of CCM against 10 strains of S. aureus ranged from 125 to 250μg/ml. In the checkerboard test, CCM markedly reduced the MICs of the antibiotics oxacillin (OXI), ampicillin (AMP), ciprofloxacin (CIP), and norfloxacin (NOR) used against MRSA. The time-kill curves showed that a combined CCM and OXI treatment reduced the bacterial counts below the lowest detectable limit after 24h. This study suggested that CCM reduced the MICs of several antibiotics tested, notably of OXI, AMP, CIP, and NOR, and that CCM in combination with antibiotics could lead to the development of new combination of antibiotics against MRSA infection. 23353027 In vitro toxicological characterisation of the S-containing arsenic metabolites thio-dimethylarsinic acid and dimethylarsinic glutathione. Inorganic arsenic is a well-documented, exposure relevant human carcinogen. A promising starting point to further understand the mechanisms behind inorganic arsenic carcinogenicity might be a formation of reactive, highly toxic metabolites during human arsenic metabolism. This study characterises the toxicity of recently identified S-containing arsenic metabolites in cultured human A549 lung adenocarcinoma epithelium cells. In direct comparison to arsenite, thio-dimethylarsinic acid (thio-DMA(V)) and dimethylarsinic glutathione (DMAG) exerted a 5- to 20-fold stronger cytotoxicity and showed a 2- to 20-fold higher cellular bioavailability, respectively. All three arsenicals disturbed cell cycle progression at cytotoxic concentrations, but failed to increase the level of reactive oxygen and nitrogen species (RONS) in healthy A549 cells. However, a strong disturbance of the oxidative defense system was observed after incubation with absolutely sub-cytotoxic, pico- to nanomolar concentrations of arsenite and thio-DMA(V), respectively. Thus, both GSH and GSSG levels were significantly decreased by up to 40%. Accordingly, RONS levels of oxidatively (H2O2) stressed cells were strongly increased by the arsenicals. Since in vivo RONS are permanently endogenously and exogenously produced, this boost of the existing oxidative stress by arsenite and thio-DMA(V) might contribute to the process of inorganic arsenic induced carcinogenicity. 23000442 Selective inhibitory effects of mollugin on CYP1A2 in human liver microsomes. Mollugin originally isolated from Rubia cordifolia is a pharmacological compound for its anti-inflammation, anti-cancer, and anti-viral activity. In the present study, a cocktail probe assay was performed for determination of the selective inhibitory effect of mollugin on cytochrome P450 (CYP) enzymes in human liver microsomes (HLM). Incubation of isoform-specific substrate probes CYPs with mollugin (0-25μM) in HLM resulted in strong inhibition of CYP1A2-catalyzed phenacetin O-deethylation, showing IC(50) values of 1.03 and 3.55μM without and with pre-incubation, respectively. Mollugin-caused inhibition of phenacetin O-deethylation was concentration-dependent in HLMs, but not time-dependent. In addition, the Lineweaver-Burk plot indicated a typical competitive inhibition. Inhibitory effects of mollugin on human recombinant cDNA-expressed CYP1A1 and 1A2 were comparable. Taken together, the results suggested that mollugin might cause herb-drug interaction through selective inhibition of CYP1A2 in humans receiving herbal medications, including R. cordifolia. 23494831 Oxygen Activation of Apo-obelin-Coelenterazine Complex. Ca(2+) -regulated photoproteins use a noncovalently bound 2-hydroperoxycoelenterazine ligand to emit light in response to Ca(2+) binding. To better understand the mechanism of formation of active photoprotein from apoprotein, coelenterazine and molecular oxygen, we investigated the spectral properties of the anaerobic apo-obelin-coelenterazine complex and the kinetics of its conversion into active photoprotein after exposure to air. Our studies suggest that coelenterazine bound within the anaerobic complex might be a mixture of N7-protonated and C2(-) anionic forms, and that oxygen shifts the equilibrium in favor of the C2(-) anion as a result of peroxy anion formation. Proton removal from N7 and further protonation of peroxy anion and the resulting formation of 2-hydroperoxycoelenterazine in obelin might occur with the assistance of His175. It is proposed that this conserved His residue might play a key role both in formation of active photoprotein and in Ca(2+) -triggering of the bioluminescence reaction. 23017401 Genistein and dicarboximide fungicides in infant formulae from the EU market. A method based on ultrasonic extraction and purification by solid phase extraction followed by LC-MS/MS and GC-MS analysis was developed for the determination of genistein, genistin, iprodione, vinclozolin and procymidone in infant powdered formulas. The method was tested for different formulations: milk, soy and hypoallergenic, and was applied to European pooled samples. Spike recoveries ranged from 53.1% to 91.5% and the relative standard deviation values for repeatability ranged from 9.6% to 17.7%, except for iprodione in milk formula (22.3%). None of the fungicides were found in the European pooled formulae, while genistein was found at 9.7μg/g in soy formula and the concentration of genistin, its β-glycosylated form, was respectively 31.4ng/g and 476ng/g in milk and soy formula. 22815230 The antioxidant and anticancer effects of wild carrot oil extract. Daucus carota L. ssp. carota (Apiacea) is used in traditional medicine in Lebanon and in different regions throughout the world. The present study investigates the in vitro anticancer activities of Daucus carota oil extract (DCOE) on four human cancer cell lines as well as its in vitro antioxidant activity. DCOE was extracted from the dried umbels with 50:50 acetone-methanol. The oil extract was analyzed by gas chromatography-mass spectrometry and screened for its antioxidant properties in vitro using 1,1-diphenyl-2-picryl hydrazyl free radical scavenging assay (DPPH), ferrous ion chelating assay (FIC) and the ferric reducing antioxidant power assay (FRAP). The anticancer activity of the oil extract against human colon (HT-29, Caco-2) and breast (MCF-7, MDA-MB-231) cancer cell lines was evaluated using the trypan blue exclusion method and the WST-1 cell proliferation assay. DCOE exhibited antioxidant activity in all assays used. The FRAP value was 164 ± 5.5 µmol FeSO4 /g, and the IC50 values for DPPH and FIC assays were 2.1 ± 0.03 mg/ml and 0.43 ± 0.02 mg/ml, respectively. Also, DCOE demonstrated a significant increase in cell death and decrease in cell proliferation. The effect of DCOE on the cell lines exhibited time and dose-dependent responses. The present study established that DCOE possesses both antioxidant and promising anticancer activities. Copyright © 2012 John Wiley & Sons, Ltd. 23079231 Synergistic immunosuppressive effects of the mTOR inhibitor sirolimus and the phytochemical curcumin. The immunosuppressant sirolimus and curcumin, the main principle of the turmeric spice, have shown antiproliferative effects on many human and not-human cell lines. Whereas the antiproliferative effect of sirolimus is mainly mediated by inhibition of mTOR, curcumin is described to affect many molecular targets which makes it unpredictable to appraise if the effects of these both substances on cell proliferation and especially on immunosuppression are additive or synergistic. To answer this question we investigated the interaction of both these substances on OKT3-induced human peripheral blood mononuclear cell (PBMC) proliferation. OKT3-induced human PBMC proliferation was determined by measuring (3)H-thymidine incorporation. Influence of curcumin on interleukin-2 (IL-2) release and IκB-phosphorylation in PBMC was determined by ELISA and western blot, respectively. Curcumin-induced apoptosis and necrosis was analyzed by FACS analysis. Whereas curcumin completely inhibited OKT3-induced PBMC proliferation in a dose-dependent manner with an IC(50) of 2.8 μM, sirolimus could reduce PBMC proliferation dose-dependently only to a minimum of 28% at a concentration of 5 ng/ml (IC(50) 1.1 ng/ml). When curcumin was combined at concentrations of 1.25-2.5 μM with sirolimus at concentrations from 0.63 to 1.25 ng/ml the effects were synergistic. Combination of curcumin (1.25-2.5 μM) with sirolimus (5 ng/ml) showed additive effects. The effects after combination of curcumin at 5 μM with each sirolimus concentration and sirolimus at 10 ng/ml with each curcumin concentration were presumably antagonistic. We conclude that the immunosuppressive effects of curcumin and sirolimus in low concentrations are synergistic in OKT3-activated PBMC. Whether curcumin and sirolimus have also synergistic antiproliferative effects in tumor cells has to be shown in further experiments including animal models. 23480848 Effect of Solvent Polarity on the Vibrational Dephasing Dynamics of the Nitrosyl Stretch in an Fe(II) Complex Revealed by 2D IR Spectroscopy. The vibrational dephasing dynamics of the nitrosyl stretching vibration (νNO) in sodium nitroprusside (SNP, Na2[Fe(CN)5NO]·2H2O) are investigated using two-dimensional infrared (2D IR) spectroscopy. The νNO in SNP acts as a model system for the nitrosyl ligand found in metalloproteins which play an important role in the transportation and detection of nitric oxide (NO) in biological systems. We perform a 2D IR line shape study of the νNO in the following solvents: water, deuterium oxide, methanol, ethanol, ethylene glycol, formamide, and dimethyl sulfoxide. The frequency of the νNO exhibits a large vibrational solvatochromic shift of 52 cm(-1), ranging from 1884 cm(-1) in dimethyl sulfoxide to 1936 cm(-1) in water. The vibrational anharmonicity of the νNO varies from 21 to 28 cm(-1) in the solvents used in this study. The frequency-frequency correlation functions (FFCFs) of the νNO in SNP in each of the seven solvents are obtained by fitting the experimentally obtained 2D IR spectra using nonlinear response theory. The fits to the 2D IR line shape reveal that the spectral diffusion time scale of the νNO in SNP varies from 0.8 to 4 ps and is negatively correlated with the empirical solvent polarity scales. We compare our results with the experimentally determined FFCFs of other charged vibrational probes in polar solvents and in the active sites of heme proteins. Our results suggest that the vibrational dephasing dynamics of the νNO in SNP reflect the fluctuations of the nonhomogeneous electric field created by the polar solvents around the nitrosyl and cyanide ligands. The solute solvent interactions occurring at the trans-CN ligand are sensed through the π-back-bonding network along the Fe-NO bond in SNP. 23506624 BACE2 as a new diabetes target: a patent review (2010 - 2012). Introduction: When two novel aspartyl proteases were published in 1999 and 2000, beta-site APP-cleaving enzyme 1 (BACE1) was confirmed as the long sought after beta-secretase and Alzheimer's disease drug target. However, the role of its paralogue, BACE2, proved elusive until a 2011 publication implicated it as a Collectrin (TMEM27) secretase controlling pancreatic beta-cell proliferation and a new therapeutic intervention for diabetes. Areas covered: This review, using SureChemOpen, encompasses early validation compounds and small-molecule BACE2 inhibitors for diabetes. Since 2010, one assay patent and several chemical series have been published by Roche but these were followed by filings from Novartis and Schering in 2012. The patents from these three companies include BACE2-only filings but also some specifying both BACE1 and BACE2 inhibitors. Expert opinion: Roche's early collaborative target validation has given them a lead in BACE2 medicinal chemistry. However, the extensive data output for BACE1 in patents and papers over the last decade, plus liganded crystal structures for both proteases, should expedite the design of BACE2 inhibitors by other organisations. This may also shorten the development time for clinical candidates that, unlike those now entering Phase I trials for BACE1, would not need to be brain-penetrant. 23562073 Raggin' on T-bet. Although increasing adiposity is usually associated with adipose tissue infiltration by inflammatory cells and systemic insulin resistance, Stolarczyk et al. (2013) report in this issue that mice deficient in the T-box transcription factor, T-bet, display a dissociated phenotype with enhanced perigonadal adipose but enhanced insulin sensitivity. 23468408 Cell-Laden Hydrogels in Integrated Microfluidic Devices for Long-Term Cell Culture and Tubulogenesis Assays. A hydrogel biochip combining microfluidic mixing and orthogonal supplementation strategies is developed and validated to allow facile generation of libraries of optically transparent 3D culture microenvironments. Live, on-chip tracing of embryonic stem cell differentiation and endothelial cell tubulogenesis confirms that the platform can be used to both create communities of discrete 3D microenvironments as well as to locally monitor subsequent divergent responses at both single cell and multi-cell scales. 23570840 Goniolandrene A and B from Goniothalamus macrophyllus. Goniothalamus macrophyllus (Blume) Hook. f. & Thoms. is a plant widely distributed in Malaysia. The aim of this study is to identify compounds from the roots of G. macrophyllus. The ground roots were extracted with aqueous methanol and partitioned sequentially with n-hexane, chloroform and butanol. Purification from this extracts afforded six compounds with two new compounds, namely goniolandrene-A (1), -B (2). The absolute configuration of goniolandrene B (2) was established by circular dichrosim. The compounds were cytotoxic against the P388 cells with IC50 values ranging from 0.42 to 160μM. Goniothalamin (3) exhibited the highest inhibition of 0.42μM. 23612709 Signaling mechanisms in Mammalian myoblast fusion. Myoblast fusion is a critical process that contributes to the growth of muscle during development and to the regeneration of myofibers upon injury. Myoblasts fuse with each other as well as with multinucleated myotubes to enlarge the myofiber. Initial studies demonstrated that myoblast fusion requires extracellular calcium and changes in cell membrane topography and cytoskeletal organization. More recent studies have identified several cell-surface and intracellular proteins that mediate myoblast fusion. Furthermore, emerging evidence suggests that myoblast fusion is also regulated by the activation of specific cell-signaling pathways that lead to the expression of genes whose products are essential for the fusion process and for modulating the activity of molecules that are involved in cytoskeletal rearrangement. Here, we review the roles of the major signaling pathways in mammalian myoblast fusion. 23230281 Increased oxidized low-density lipoprotein causes blood-brain barrier disruption in early-onset preeclampsia through LOX-1. Early-onset preeclampsia (EPE) is a severe form of preeclampsia that involves life-threatening neurological complications. However, the underlying mechanism by which EPE affects the maternal brain is not known. We hypothesized that plasma from women with EPE increases blood-brain barrier (BBB) permeability vs. plasma from women with late-onset preeclampsia (LPE) or normal pregnancy (NP) and investigated its underlying mechanism by perfusing cerebral veins from nonpregnant rats (n=6-7/group) with human plasma from women with EPE, LPE, or NP and measuring permeability. We show that plasma from women with EPE significantly increased BBB permeability vs. plasma from women with LPE or NP (P<0.001). BBB disruption in response to EPE plasma was due to a 260% increase of circulating oxidized LDL (oxLDL) binding to its receptor, LOX-1, and subsequent generation of peroxynitrite (P<0.001). A rat model with pathologically high lipid levels in pregnancy showed symptoms of preeclampsia, including elevated blood pressure, growth-restricted fetuses, and LOX-1-dependent BBB disruption, similar to EPE (P<0.05). Thus, we have identified LOX-1 activation by oxLDL and subsequent peroxynitrite generation as a novel mechanism by which disruption of the BBB occurs in EPE. As increased BBB permeability is a primary means by which seizure and other neurological symptoms ensue, our findings highlight oxLDL, LOX-1, and peroxynitrite as important therapeutic targets in EPE. 23450777 Exfoliated graphitic carbon nitride nanosheets as efficient catalysts for hydrogen evolution under visible light. Graphitic carbon nitride nanosheets are extracted, produced via simple liquid-phase exfoliation of a layered bulk material, g-C3 N4 . The resulting nanosheets, having ≈2 nm thickness and N/C atomic ratio of 1.31, show an optical bandgap of 2.65 eV. The carbon nitride nanosheets are demonstrated to exhibit excellent photocatalytic activity for hydrogen evolution under visible light. 23289615 Freezing continuous-flow self-assembly in a microfluidic device: toward imaging of liposome formation. A new method is described that combines a microfluidic device for the controlled formation of liposomes with instantaneous immobilization by means of ultrarapid cooling. The microfluidic device is composed of capillaries to hydrodynamically focus a stream of lipids dissolved in 2-propanol by two adjacent aqueous buffer streams before rapidly cooling by propane jet-freezing. The capillary containing the frozen sheath-flow is subsequently separated from the flow-focusing unit and trimmed with cryo-ultramicrotomy for imaging with cryo-scanning electron microscopy (SEM). The emergence of liposomes could be visualized by cryo-SEM without the need for chemical fixation or labeling. We demonstrate that the method is capable of revealing in more detail the formation of nonequilibrium liposomes. Partially and completely formed liposomes were observed at the miscible alcohol-buffer interface. The number density of lipid vesicles varied along the focused interface, and we frequently found clusters of liposomes. Additionally, evidence for the formation of disclike transient intermediates is presented. The method is not limited to studying self-assembly processes only. It can be extended to other biochemical reactions, crystallization processes, and even systematic interfacial mixing studies between different solvents. 23439223 Post-partum variation in the expression of paternal care is unrelated to urinary steroid metabolites in marmoset fathers. The organization and activation of maternal care are known to be highly regulated by hormones and there is growing evidence that expression of paternal care is also related to endocrine substrates. We examined the relationship between paternal behavior and steroid hormones in marmoset fathers (Callithrix geoffroyi) and evaluated whether hormone-paternal behavior relationships were altered by previous offspring-care experience in males. Based on previous findings, we predicted that testosterone, estradiol, and cortisol would decrease following the birth of offspring and would be lowest during the period of maximal infant carrying. Furthermore, we predicted that post-partum changes in carrying effort and hormone levels would be influenced by the level of offspring-care experience. Carrying effort and other paternal care behaviors underwent temporal changes over the post-partum period, but these patterns were not related to variation in hormone concentrations over the same period. There was a limited effect of offspring-care experience on hormone concentrations, but experience was found to play a role in the expression of paternal care, with experienced fathers engaging in significantly more infant allogrooming than inexperienced fathers. Furthermore, inexperienced fathers increased the frequency of food sharing in response to infant begging across the post-partum period, while experienced fathers displayed consistently low levels. We posit that a combination of experiential factors and an increased role for alloparents in offspring-care led to these changes. However, it appears that hormonal changes may not influence paternal responsiveness in white-faced marmoset fathers and that hormone-paternal behavior relationships are not critically dependent on a male's previous offspring-care experience. 23028140 Autoinhibition of CYP3A4 leads to important role of CYP2C8 in imatinib metabolism: variability in CYP2C8 activity may alter plasma concentrations and response. Recent data suggest that the role of CYP3A4 in imatinib metabolism is smaller than presumed. This study aimed to evaluate the quantitative importance of different cytochrome P450 (P450) enzymes in imatinib pharmacokinetics. First, the metabolism of imatinib was investigated using recombinant P450 enzymes and human liver microsomes with P450 isoform-selective inhibitors. Thereafter, an in silico model for imatinib was constructed to perform pharmacokinetic simulations to assess the roles of P450 enzymes in imatinib elimination at clinically used imatinib doses. In vitro, CYP2C8 inhibitors and CYP3A4 inhibitors inhibited the depletion of 0.1 µM imatinib by 45 and 80%, respectively, and the formation of the main metabolite of imatinib, N-desmethylimatinib, by >50%. Likewise, recombinant CYP2C8 and CYP3A4 metabolized imatinib extensively, whereas other isoforms had minor effect on imatinib concentrations. In the beginning of imatinib treatment, the fractions of its hepatic clearance mediated by CYP2C8 and CYP3A4 were predicted to approximate 40 and 60%, respectively. During long-term treatment with imatinib 400 mg once or twice daily, up to 65 or 75% of its hepatic elimination was predicted to occur via CYP2C8, and only about 35 or 25% by CYP3A4, due to dose- and time-dependent autoinactivation of CYP3A4 by imatinib. Thus, although CYP2C8 and CYP3A4 are the main enzymes in imatinib metabolism in vitro, in silico predictions indicate that imatinib inhibits its own CYP3A4-mediated metabolism, assigning a key role for CYP2C8. During multiple dosing, pharmacogenetic polymorphisms and drug interactions affecting CYP2C8 activity may cause marked interindividual variation in the exposure and response to imatinib. 23520074 Opposite modulation of cell migration by distinct subregions of urokinase connecting Peptide. Functional analysis of isolated protein domains may uncover cryptic activities otherwise missed. The serine protease urokinase (uPA) has a clear-cut motogen activity that is catalytically independent and resides in its amino-terminal growth factor domain (GFD, residues 1-49) and connecting peptide region (CP, residues 132-158). To functionally dissect the CP region, we analysed the biological activity of two synthetic peptides corresponding to the N-terminal [uPA-(135-143), residues 135-143] and C-terminal [uPA-(144-158), residues 144-158] CP subregions. Most of the chemotactic activity of connecting peptide-derived peptide (CPp, [uPA-(135-158)]) for embryonic kidney HEK293/uPAR-25 cells is retained by uPA-(144-158) at nanomolar concentrations. In contrast, uPA-(135-143) inhibits basal, CPp -, vitronectin- and fibronectin-induced cell migration. Radioreceptor binding assays on intact HEK293 cells revealed that uPA-(135-143) and uPA-(144-158) are both able to compete with [(125) I]-CPp, albeit with different binding affinities. The consequences of phospho-mimicking, S138E substitution, were studied using [138E]uPA-(135-158) and [138E]uPA-(135-143) peptides. Unlike CPp, [138E]uPA-(135-158) and [138E]uPA-(135-143) exhibit remarkable inhibitory properties. Finally, analysis of the conformational preferences of the peptides allowed to identify secondary structure elements exclusively characterising the stimulatory CPp and uPA-(144-158) versus the inhibitory uPA-(135-143), [138E]uPA-(135-158) and [138E]uPA-(135-143) peptides. In conclusion, these data shed light on the cryptic activities of uPA connecting peptide, revealing the occurrence of two adjacent regions, both competing for binding to cell surface but conveying opposite signalling on cell migration. 23627282 Development and Therapeutic Implications of Selective Histone Deacetylase 6 Inhibitors. The ensuing Perspective provides an in depth look at the numerous disease states in which histone deacetylase 6 (HDAC6) has been implicated. The physiological pathways, protein-protein interactions and non-histone substrates relating to different pathological conditions are discussed with regard to HDAC6. Furthermore, the compounds and methods used to modulate HDAC6 activity are profiled. The latter half of this Perspective analyzes reported HDAC6 selective inhibitors in terms of structure, potency and selectivity over the other HDAC isoforms with the intent of providing a comprehensive overview of the molecular tools available. Potential obstacles and future directions of HDAC6 research are also presented. 23238233 Four new triterpenoid saponins from the leaves of Panax japonicus grown in southern Miyazaki Prefecture (4). Four new dammarane-type triterpenoid saponins such as chikusetsusaponin LM3 (1), chikusetsusaponin LM4 (2), chikusetsusaponin LM5 (3), chikusetsusaponin LM6 (4), and twenty known triterpenoid saponins such as ginsenoside Rb3 (5), ginsenoside Rc (6), ginsenoside Rd (7), ginsenoside Re (8), ginsenoside Rg1 (9), ginsenoside F3 (10), ginsenoside F5 (11), ginsenoside F6 (12), chikusetsusaponin IVa (13), chikusetsusaponin V (14), chikusetsusaponin L5 (15), chikusetsusaponin L9a (16), chikusetsusaponin L9bc (17), chikusetsusaponin L10 (18), chikusetsusaponin FK2 (19), chikusetsusaponin FK6 (20), chikusetsusaponin FK7 (21), chikusetsusaponin FT1 (22), chikusetsusaponin LM1 (23), and chikusetsusaponin LM2 (24), were isolated from the leaves of Panax japonicus C. A. MEYER collected in Miyazaki prefecture, Japan. The structures of new chikusetsusaponins were elucidated on the basis of spectral and physicochemical evidences. 23197296 RNF4 is required for DNA double-strand break repair in vivo. Unrepaired DNA double-strand breaks (DSBs) cause genetic instability that leads to malignant transformation or cell death. Cells respond to DSBs with the ordered recruitment of signaling and repair proteins to the sites of DNA lesions. Coordinated protein SUMOylation and ubiquitylation have crucial roles in regulating the dynamic assembly of protein complexes at these sites. However, how SUMOylation influences protein ubiquitylation at DSBs is poorly understood. We show herein that Rnf4, an E3 ubiquitin ligase that targets SUMO-modified proteins, accumulates in DSB repair foci and is required for both homologous recombination (HR) and non-homologous end joining repair. To establish a link between Rnf4 and the DNA damage response (DDR) in vivo, we generated an Rnf4 allelic series in mice. We show that Rnf4-deficiency causes persistent ionizing radiation-induced DNA damage and signaling, and that Rnf4-deficient cells and mice exhibit increased sensitivity to genotoxic stress. Mechanistically, we show that Rnf4 targets SUMOylated MDC1 and SUMOylated BRCA1, and is required for the loading of Rad51, an enzyme required for HR repair, onto sites of DNA damage. Similarly to inactivating mutations in other key regulators of HR repair, Rnf4 deficiency leads to age-dependent impairment in spermatogenesis. These findings identify Rnf4 as a critical component of the DDR in vivo and support the possibility that Rnf4 controls protein localization at DNA damage sites by integrating SUMOylation and ubiquitylation events. 23293966 Synthesis and characterization of quarteranthene: elucidating the characteristics of the edge state of graphene nanoribbons at the molecular level. The characteristics of the edge state, which is a peculiar magnetic state in zigzag-edged graphene nanoribbons (ZGNRs) that originates from electron-electron correlation in an edge-localized π-state, are investigated by preparing and characterizing quarteranthene molecules. The molecular geometry that was determined from the X-ray analysis is consistent with a zigzag-edge-localized structure of unpaired electrons. The localized electrons are responsible for the peculiar magnetic (room-temperature ferromagnetic correlation), optical (the lowest-lying doubly excited state), and chemical (peroxide bond formation) behaviors. On the basis of these distinguishing properties and a careful consideration of the valence bonding, insight into the edge state of ZGNRs can be gained. 23455373 Properties and self-assembled packing morphology of long alkyl-chained substituted polyhedral oligomeric silsesquioxanes (POSS) cages. Polyhedral oligomeric silsesquioxane (POSS) cubic cage systems (octa-n-octadecyloctasilsesquioxane, (T8C18) and octakis(n-octadecyldimethylsiloxy)octasilsesquioxane, (Q8C18)) were synthesised with eight long n-alkyl chain (R = C18H37) substituent arms, as model nano-functionalized compounds. The crystalline packing morphology of the cages was studied using time-resolved Small- and Wide-angle X-ray scattering (SAXS/WAXS), thermal and optical techniques. From thermal analysis the melting and crystallization temperatures of the Q8 cage were significantly less than those for the T8 cage. X-ray scattering showed that both cage systems have long-range crystalline ordering where the alkyl chains align in a parallel axial disposition from the POSS core giving a 'rod-like' self-assembled packing morphology. The packing length-scale can be directly related to the overall dimensions of the POSS molecules. Compared to the T8 cages, the Q8 cages pack more efficiently allowing the interdigitation of the alkyl chain arms. Different packing modes and thermal behaviour observed for the T8 and Q8 cages is directly attributed to their structural chemistry. For the Q8 cage, the presence of the OSiMe2 spacer groups which tether the alkyl chain arms to the cage (absent in the T8 cages) allows greater flexibility of the arms letting them interdigitate with each other when packing which is not observed for the analogous T8 cages. 23411351 Interactive effects of a bacterial parasite and the insecticide carbaryl to life-history and physiology of two Daphnia magna clones differing in carbaryl sensitivity. Natural and chemical stressors occur simultaneously in the aquatic environment. Their combined effects on biota are usually difficult to predict from their individual effects due to interactions between the different stressors. Several recent studies have suggested that synergistic effects of multiple stressors on organisms may be more common at high compared to low overall levels of stress. In this study, we used a three-way full factorial design to investigate whether interactive effects between a natural stressor, the bacterial parasite Pasteuria ramosa, and a chemical stressor, the insecticide carbaryl, were different between two genetically distinct clones of Daphnia magna that strongly differ in their sensitivity to carbaryl. Interactive effects on various life-history and physiological endpoints were assessed as significant deviations from the reference Independent Action (IA) model, which was implemented by testing the significance of the two-way carbaryl×parasite interaction term in two-way ANOVA's on log-transformed observational data for each clone separately. Interactive effects (and thus significant deviations from IA) were detected in both the carbaryl-sensitive clone (on survival, early reproduction and growth) and in the non-sensitive clone (on growth, electron transport activity and prophenoloxidase activity). No interactions were found for maturation rate, filtration rate, and energy reserve fractions (carbohydrate, protein, lipid). Furthermore, only antagonistic interactions were detected in the non-sensitive clone, while only synergistic interactions were observed in the carbaryl sensitive clone. Our data clearly show that there are genetically determined differences in the interactive effects following combined exposure to carbaryl and Pasteuria in D. magna. 23455314 Contribution of the m1 transmembrane helix and pre-m1 region to positive allosteric modulation and gating of N-methyl-d-aspartate receptors. N-methyl-d-aspartate (NMDA) receptors are glutamate-gated ion channels whose function is critical for normal excitatory synaptic transmission in the brain and whose dysfunction has been implicated in several neurologic conditions. NMDA receptor function is subject to extensive allosteric regulation both by endogenous compounds and by exogenous small molecules. Elucidating the structural determinants and mechanism of action by which allosteric regulators control gating will enhance our understanding of NMDA receptor activation and facilitate the development of novel therapeutics. Here, we investigated the structural determinants for (3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (CIQ), a GluN2C/2D-selective positive allosteric modulator. We show that CIQ does not bind to the amino-terminal domain of the NMDA receptor and does not share structural determinants with modulators acting at the agonist-binding domain dimer interface or ion channel pore. Rather, we identified critical determinants of CIQ modulation in the region near the first transmembrane helix of GluN2D, including in a putative pre-M1 cuff helix that may influence channel gating. We also show that mutations within the GluN2D pre-M1 region alter open probability of the NMDA receptor. These results suggest a novel site of action for potentiation of NMDA receptors by small molecules and implicate the pre-M1 region in NMDA receptor gating. 23203454 Metabolism of the plasticizer and phthalate substitute diisononyl-cyclohexane-1,2-dicarboxylate (DINCH(®)) in humans after single oral doses. Hexamoll(®) DINCH(®) (diisononyl-cyclohexane-1,2-dicarboxylate) is a new high-molecular-weight plasticizer and a phthalate substitute. In this study, the metabolism of DINCH(®) was investigated by oral dosage of three male volunteers with approximately 50 mg Hexamoll(®) DINCH(®) (resulting in individual doses between 0.552 and 0.606 mg/kg body weight). Their urine samples were consecutively collected over 48 h. In analogy to di-iso-nonylphthalate (DINP) metabolism, we quantified the simple monoester mono-isononyl-cyclohexane-1,2-dicarboxylate (MINCH) and its secondary oxidized metabolites with HPLC-MS/MS via isotope dilution analysis. Additionally, we quantified the unspecific full breakdown product, cyclohexane-1,2-dicarboxylic acid (CHDA), via standard addition. All postulated metabolites were present in all samples analyzed. The unspecific CHDA was identified as the major urinary metabolite representing 23.7 % of the dose as the mean of the three volunteers (range 20.0-26.5 %). 14.8 % (11.3-16.7 %) of the dose was excreted as monoesters with oxidative modifications, in particular OH-MINCH 10.7 % (7.7-12.9 %), oxo-MINCH 2.0 % (1.5-2.6 %) and carboxy-MINCH 2.0 % (1.8-2.3 %). Less than 1 % was excreted as the simple monoester MINCH. In sum, 39.2 % (35.9-42.4 %) of the DINCH(®) dose was excreted as these metabolites in urine within 48 h. Over 90 % of the metabolites investigated were excreted within 24 h after application. The secondary oxidized metabolites, with elimination half-times between 10 and 18 h, proved to be apt and specific biomarkers to determine DINCH(®) exposure. With this study, we provide reliable urinary excretion factors to calculate DINCH(®) intakes based on these metabolites in environmental and occupational studies. 23588558 Adherence to preventive statin therapy according to socioeconomic position. AIM: To explore whether long-term adherence to preventive statin therapy depends on socioeconomic position (SEP). METHODS: A cohort of individuals without established cardiovascular disease (CVD) or diabetes initiating preventive statin therapy during 2002-2005 was followed in the individual-level Danish registries for 4 years or until censoring events (death, emigration, CVD or diabetes). Only individuals aged 40-84 years for whom information was available on the SEP indicators, education and income were included (N = 76,038). Two different aspects of poor adherence were applied as outcome measures: (1) Proportion of days covered (PDC) with medication below 80 %, assuming a daily dose of one tablet (continuity); (2) Discontinuation defined as a gap between two consecutive prescriptions exceeding 365 days (persistence). Stratum-specific logistic regression analyses were applied to estimate the odds ratio (OR) for PDC <80 % across SEP, adjusting for age and hypertension. Hazard ratio (HR) for discontinuation was estimated by Cox regression analyses. RESULTS: Adjusting mutually for income and education, the OR for PDC <80 % decreased with increasing income. Comparing the highest income quintile with the lowest, the OR were 0.64 (95 % Confidence Interval 0.64-0.65) and 0.73 (0.73-0.74) in men aged 40-64 and 65-84 years, respectively; in women, the figures were 0.79 (0.79-0.79) and 0.95 (0.94-0.95), respectively. While observed increases in adherence with longer education in unadjusted analyses were attenuated after adjustment for income among men, the potential inverse relationship between length of education and adherence was enhanced among women. Applying discontinuation as outcome, analogous differences were demonstrated. CONCLUSION: Adherence to preventive statin therapy in Denmark decreases with decreasing income-especially in men aged 40-64 years. 23232866 Integration of pre-aligned liquid metal electrodes for neural stimulation within a user-friendly microfluidic platform. Electrical stimulation of nervous tissue is used clinically for the treatment of multiple neurological disorders and experimentally for basic research. With the increase of optical probes to record neuronal activity, simple and user-friendly methods are desired to stimulate neurons and their subcellular compartments for biological experimentation. Here we describe the novel integration of liquid metal electrodes with microfluidic culture platforms to accomplish this goal. We integrated electrode and cell channels into a single poly(dimethylsiloxane) (PDMS) chip, eliminating entirely the need to align electrodes with microchannels. We designed the electrode channels such that the metal can be injected by hand and when the device is non-covalently bound to glass. We demonstrated the biocompatibility of the electrodes for long-term cultures (12 days) using hippocampal neurons. We demonstrated the use of these electrodes to depolarize neurons and recorded neuronal activity using the calcium indicator dye, Fluo-4. We established optimal stimulation parameters that induce neuronal spiking without inducing damage. We showed that the liquid metal electrode evoked larger calcium responses in somata than bath electrodes using the same stimulus parameters. Lastly we demonstrated the use of these liquid metal electrodes to target and depolarize axons. In summary, the integration of liquid metal electrodes with neuronal culture platforms provides a user-friendly and targeted method to stimulate neurons and their subcellular compartments, thus providing a novel tool for future biological investigations. 23335561 Shrinking hydrogel-DNA spots generates 3D microdots arrays. This report describes a straightforward approach for the achievement of sub-100 micrometers size hydrogel dots supporting DNA immobilization. Hydrogel-DNA spots are arrayed and UV-crosslinked on PolyShrink, an innovative polymer material having the remarkable property of isotropically shrinking under high temperature. Curing the microarray enables then spot miniaturization, resulting in 6 µm thick and 60 µm wide hydrogel dots in which oligonucleotides are immobilized in a 3D hydrophilic environment. The probe immobilization within the hydrogel network and its capacity to detect targets specifically and quantitatively is demonstrated using chemiluminescent as well as colorimetric detection techniques. The hydrogel material improves probe accessibility within the spot, leading to an enhanced sensitivity. 23411250 A critical study of use of the Fe(II)/3-hydroxy-4-nitroso-2,7-naphthalenedisulfonic acid complexes in the quantification of polyphenols in medicinal plants. A critical study of the use of the Fe(III)/3-hydroxy-4-nitroso-2,7-naphthalenedisulfonic acid (NRS) complexes on the quantification of the polyphenols content in aqueous extracts of plants, expressed as pyrogallic acid, [PA], is presented. The reaction used is based on the reduction of Fe(III) to Fe(II) by [PA] in the presence of NRS in a buffered medium (Tris; pH 8.0) with formation of Fe(II)/NRS complexes. A calibration curve of absorbance (at 730 nm) vs. [PA] is linear (r=0.998; n=7) from 1.0 to 7.0 μmolL(-1) [PA]. LD and RSD were 0.5 μmolL(-1) and 2.5% (6.0 μmolL(-1) [PA], n=10), respectively. The influence of pH, type of buffer solution and interfering species possibly present in the samples were evaluated. Aqueous extracts of twelve medicinal plants used in the Brazilian folk medicine were analysed by using both Fe(III)/NRS complexes and the Folin-Ciocalteu reagent. 23164711 On scaffold hopping: challenges in the discovery of sulfated small molecules as mimetics of glycosaminoglycans. The design of sulfated, small, nonsaccharide molecules as modulators of proteins is still in its infancy as standard drug discovery tools such as library of diverse sulfated molecules and in silico docking and scoring protocol have not been firmly established. Databases, such as ZINC, contain too few sulfate-containing nonsaccharide molecules, which severely limits the identification of new hits. Lack of a generally applicable protocol for scaffold hopping limits the development of sulfated small molecules as synthetic mimetics of the highly sulfated glycosaminoglycans. We explored a sequential ligand-based (LBVS) and structure-based virtual screening (SBVS) approach starting from our initial discovery of monosulfated benzofurans to discover alternative scaffolds as allosteric modulators of thrombin, a key coagulation enzyme. Screening the ZINC database containing nearly 1 million nonsulfated small molecules using a pharmacophore developed from the parent sulfated benzofurans followed by a genetic algorithm-based dual-filter docking and scoring screening identified a group of 10 promising hits, of which three top-scoring hits were synthesized. Each was found to selectively inhibit human alpha-thrombin suggesting the possibility of this approach for scaffold hopping. Michaelis-Menten kinetics showed allosteric inhibition mechanism for the best molecule and human plasma studies confirmed good anticoagulation potential as expected. Our simple sequential LBVS and SBVS approach is likely to be useful as a general strategy for identification of sulfated small molecules hits as modulators of glycosaminoglycan-protein interactions. 23517145 Anti-inflammatory Lanostanoids and Lactone Derivatives from Antrodia camphorata. Four new lanostanoids, ethyl lucidenate A (1), ethyl lucidenate F (2), 15-O-acetylganolucidate A (3), and 3,11,15,23-tetraoxo-27ξ-lanosta-8,16-dien-26-oic acid (4), and two new lactone derivatives, 5-hydroxy-5-(methoxymethyl)-4-methylfuran-2(5H)-one (5) and 3-(4-methoxy-2-oxo-2H-pyran-6-yl)propanoic acid (6), together with four known compounds, 11α-hydroxy-3,7-dioxolanost-8,24(E)-dien-26- oic acid (7), 3,7,11-trioxo-5α-lanosta-8,24(E)-dien-26-oic acid (8), methyl 3,7,11,12,15,23-hexaoxo-5α-lanost-8-en-26-oate (9), and ethyl 3,7,11,12,15,23-hexaoxo-5α-lanost-8-en-26-oate (10), were characterized from Antrodia camphorata. The structures of these new compounds were determined by analysis of their spectroscopic data, including 1D and 2D NMR experiments. Ten components were evaluated for anti-inflammatory activity by examining their effect on LPS-iNOS-dependent NO production in murine macrophage (RAW 264.7) cells. Among them, compounds 1, 3, 7, 8, 9, and 10 significantly suppressed the NO concentration in LPS-treated RAW 264.7 cells with IC50 values ≤ 10 μM. 23541950 Genome-wide association studies on serum sex steroid levels. Even though the levels of circulating sex steroid hormones are to a large extent heritable, their genetic determinants are largely unknown. With the advent of genome-wide association studies (GWAS), much progress has been made and several genetic loci have been identified to be associated with serum levels of dehydroepiandrosterone sulfate, testosterone and sex hormone-binding globulin. The variants identified so far only explain a small amount of the overall heritability, but may help to elucidate the role of sex steroid hormones in common disorders such as hypogonadism, type 2 diabetes and hormone-sensitive cancers. This review provides an overview of the current state of knowledge of the genetic determinants of sex steroid hormones, with a focus on recent GWAS and brief directions for elucidating the remaining heritability. 23262390 Manganese exposure induces α-synuclein aggregation in the frontal cortex of non-human primates. Aggregation of α-synuclein (α-syn) in the brain is a defining pathological feature of neurodegenerative disorders classified as synucleinopathies. They include Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Occupational and environmental exposure to manganese (Mn) is associated with a neurological syndrome consisting of psychiatric symptoms, cognitive impairment and parkinsonism. In this study, we examined α-syn immunoreactivity in the frontal cortex of Cynomolgus macaques as part of a multidisciplinary assessment of the neurological effects produced by exposure to moderate levels of Mn. We found increased α-syn-positive cells in the gray matter of Mn-exposed animals, typically observed in pyramidal and medium-sized neurons in deep cortical layers. Some of these neurons displayed loss of Nissl staining with α-syn-positive spherical aggregates. In the white matter we also observed α-syn-positive glial cells and in some cases α-syn-positive neurites. These findings suggest that Mn exposure promotes α-syn aggregation in neuronal and glial cells that may ultimately lead to degeneration in the frontal cortex gray and white matter. To our knowledge, this is the first report of Mn-induced neuronal and glial cell α-syn accumulation and aggregation in the frontal cortex of non-human primates. 23527317 Exploring the effect of N-substitution in nor-lobelane on the interaction with VMAT2: discovery of a potential clinical candidate for treatment of methamphetamine abuse. A series of N-substituted lobelane analogues was synthesized and evaluated for their [(3)H]dihydrotetrabenazine binding affinity at the vesicular monoamine transporter and for their inhibition of vesicular [(3)H]dopamine uptake. Compound 19a, which contains an N-1,2(R)-dihydroxypropyl group, had been identified as a potential clinical candidate for the treatment of methamphetamine abuse. 23141425 EGCG inhibits CTGF expression via blocking NF-κB activation in cardiac fibroblast. Connective tissue growth factor (CTGF) has been reported to play an important role in tissue fibrosis and presents a promising therapeutic target for fibrotic diseases. In heart, inappropriate increase in level of CTGF promotes fibroblast proliferation and extracellular matrix (ECM) accumulation, thereby exacerbating cardiac hypertrophy and subsequent failure. Epigallocatechin-3-gallate (EGCG), the major polyphenol found in green tea, possesses multiple protective effects on the cardiovascular system including cardiac fibrosis. However, the molecular mechanism by which EGCG exerts its anti-fibrotic effects has not been well investigated. In this study, we found that EGCG could significantly reduce collagen synthesis, fibronectin (FN) expression and cell proliferation in rat cardiac fibroblasts stimulated with angiotensinII (AngII). It also ameliorated cardiac fibrosis in rats submitted to abdominal aortic constriction (AAC). Moreover, EGCG attenuated the excessive expression of CTGF induced by AAC or AngII, and reduced the nuclear translocation of NF-κB p65 subunit and degradation of IκB-α. Subsequently, we demonstrated that in cardiac fibroblasts NF-κB inhibition could suppress AngII-induced CTGF expression. Taken together, these findings provide the first evidence that the effect of EGCG against cardiac fibrosis may be attributed to its inhibition on NF-κB activation and subsequent CTGF overexpression, suggesting the therapeutic potential of EGCG on the prevention of cardiac remodeling in patients with pressure overload hypertrophy. 23506052 Detection of Nanosized Ordered Domains in DOPC/DPPC and DOPC/Ch Binary Lipid Mixture Systems of Large Unilamellar Vesicles Using a TEMPO Quenching Method. Nanosized ordered domains formed in 1,2-dioleoyl-sn-glycero-3-phosphocholine/1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DOPC/DPPC) and DOPC/cholesterol (Ch) liposomes were characterized using a newly developed (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) quenching method. The membrane fluidity of the DOPC/DPPC liposomes, evaluated by the use of 1,6-diphenyl-1,3,5-hexatriene (DPH), increased significantly above their phase-transition temperature. The fluorescence spectra of 6-lauroyl-2-dimethylamino naphthalene (Laurdan) indicated the formation of an immiscible ordered phase in the DOPC/DPPC (50/50) liposomal membrane at 30 °C. The analysis of the membrane polarity indicated that the surface of the liquid-disordered phase was hydrated whereas that of the ordered phase was dehydrated. DOPC/DPPC and DOPC/Ch (70/30) liposomes exhibited heterogeneous membranes, indicating that nanosized ordered domains formed on the surface of the DOPC/DPPC liposomes. The size of these nanosized ordered domains was estimated using the TEMPO quenching method. Because TEMPO can quench DPH distributed in the disordered phases, the remaining fluorescence from DPH is proportional to the size of the ordered domain. The domain sizes calculated for DOPC/DPPC (50/50), DOPC/DPPC (25/75), DOPC/Ch (70/30), and DOPC/DPPC/Ch (40/40/20) were 13.9, 36.2, 13.2, and 35.5 Å, respectively. 23350797 7-Chloro-4-quinolinyl Hydrazones: A Promising and Potent Class of Antileishmanial Compounds. In this work, we report the antileishmanial evaluation of twenty 7-chloro-4-quinolinyl hydrazone derivatives (1-20). Firstly, the compounds were tested against promastigotes of four different Leishmania species. After that, all derivatives were assayed against L. braziliensis amastigotes and murine macrophages. Furthermore, it was investigated whether the antiamastigote L. braziliensis effect of the compounds could be associated with nitric oxide production. Compounds 6 and 7 showed a strong leishmanicidal activity against intracellular parasite with IC50 in nanogram levels (30 and 20 ng/mL, respectively). Appreciable activity of three compounds tested can be considered an important finding for the rational design of new leads for antileishmanial compounds. 23291435 Thyroid disturbance related to chronic hepatitis C infection: role of CXCL10. Association between autoimmune thyroid diseases (AITD) and hepatitis C is controversial, but may occur or worsen during alpha-interferon treatment. The mechanism responsible for autoimmune diseases in infected patients has not been fully elucidated. This study aims to evaluate the frequency of AITD in chronic hepatitis C and the association of CXCL10 and AITD. One hundred and three patients with chronic hepatitis C and 96 controls were prospectively selected to clinical, hormonal, thyroid autoimmunity and ultrasound exams, besides thyroxine-binding globulin (TBG) and CXCL10 measurements and hepatic biopsies. The frequency of AITD among infected subjects was similar to controls. TT3 and TT4 distributions were right shifted, as was TBG, which correlated to both of them. Thyroid heterogeneity and hypoechogenicity were associated with AITD. Increased vascularization was more prevalent in chronic hepatitis C.CXCL10 was higher in infected patients (p=0.007) but was not related to thyroid dysfunction. Increase in CXCL10 levels were consistent with hepatic necroinflammatory activity (p=0.011). In summary, no association was found between chronic hepatitis C and AITD. Infected subjects had higher TT3 and TT4 which were correlated to TBG. Increased CXCL10 was not associated to thyroid dysfunction in HCV-infected population. 23289412 Novel 1H-1,2,3-, 2H-1,2,3-, 1H-1,2,4- and 4H-1,2,4-triazole derivatives: a patent review (2008 - 2011). INTRODUCTION: The triazoles represent a class of five-membered heterocyclic compounds of great importance for the preparation of new drugs with diverse biological activities because they may present several structural variations with the same numbers of carbon and nitrogen atoms. Due to the success of various triazoles that entered the pharmaceutical market and are still being used in medicines, many companies and research groups have shown interest in developing new methods of synthesis and biological evaluation of potential uses for these compounds. In this review, the authors explored aspects of patents for the 1H-1,2,3-, 2H-1,2,3-, 1H-1,2,4- and 4H-1,2,4-triazole families, including prototypes being considered in clinical studies between 2008 and 2011. AREAS COVERED: The triazoles have been studied for over a century as an important class of heterocyclic compounds and still attract considerable attention due to their broad range of biological activities. More recently, there has been considerable interest in the development of novel triazoles with anti-inflammatory, antiplatelet, antimicrobial, antimycobacterial, antitumoral and antiviral properties and activity against several neglected diseases. This review emphasizes recent perspective and advances in the therapeutically active 1H-1,2,3-, 2H-1,2,3-, 1H-1,2,4- and 4H-1,2,4-triazole derivative patents between 2008 and 2011, covering the development of new chemical entities and new pharmaceuticals. Many studies have focused on these compounds as target structures and evaluated them in several biological targets. EXPERT OPINION: The preparation of 1H-1,2,3-, 2H-1,2,3-, 1H-1,2,4- and 4H-1,2,4-triazole derivatives brings to light several issues. There is a need to find new, more efficient preparations for these triazoles that take into consideration current issues in green chemistry, energy saving and sustainability. New diseases are discovered and new viruses and bacteria continue to challenge mankind, so it is imperative to find new prototypes for these new diseases. Of great urgency is finding prototypes against bacteria that continue to increase resistance and for neglected diseases that affect a large part of humanity, especially the poor and vulnerable. 23287700 Cannabinoid discrimination and antagonism by CB(1) neutral and inverse agonist antagonists. Cannabinoid receptor 1 (CB(1)) inverse agonists (e.g., rimonabant) have been reported to produce adverse effects including nausea, emesis, and anhedonia that limit their clinical applications. Recent laboratory studies suggest that the effects of CB(1) neutral antagonists differ from those of such inverse agonists, raising the possibility of improved clinical utility. However, little is known regarding the antagonist properties of neutral antagonists. In the present studies, the CB(1) inverse agonist SR141716A (rimonabant) and the CB(1) neutral antagonist AM4113 were compared for their ability to modify CB(1) receptor-mediated discriminative stimulus effects in nonhuman primates trained to discriminate the novel CB(1) full agonist AM4054. Results indicate that AM4054 serves as an effective CB(1) discriminative stimulus, with an onset and time course of action comparable with that of the CB(1) agonist Δ(9)-tetrahydrocannabinol, and that the inverse agonist rimonabant and the neutral antagonist AM4113 produce dose-related rightward shifts in the AM4054 dose-effect curve, indicating that both drugs surmountably antagonize the discriminative stimulus effects of AM4054. Schild analyses further show that rimonabant and AM4113 produce highly similar antagonist effects, as evident in comparable pA(2) values (6.9). Taken together with previous studies, the present data suggest that the improved safety profile suggested for CB(1) neutral antagonists over inverse agonists is not accompanied by a loss of antagonist action at CB(1) receptors. 23265462 Transepithelial transport of 6-O-caffeoylsophorose across Caco-2 cell monolayers. The aim of this study was to clarify the transport behaviour and mechanism of caffeic acid analogue bearing a sugar-moiety, 6-O-caffeoylsophorose (CS), in Caco-2 cells. The absorption of CS was investigated by its transport across Caco-2 cell monolayers using a high-performance liquid chromatography-time-of-flight-mass spectrometry (LC-TOF-MS). The permeation of CS was concentration-dependent and reached the plateau at >6 mM. The apparent permeability (P(app)) of CS in the apical-to-basolateral direction was 5.4×10(-7) cm/s, while in the reversed direction the P(app) value was significantly reduced (1.9×10(-7) cm/s). CS transport was competitively inhibited by phloretin, an inhibitor of monocarboxylic acid transporter (MCT). Benzoic acid, an MCT substrate, also reduced CS transport. A less significant change of CS transport was observed across Caco-2 cell monolayers pretreated with quercetin, a suppressor of tight-junction. These findings strongly indicate that CS, a caffeic acid analogue bearing sophorose moiety, can be transported across Caco-2 cell monolayers via the MCT pathway. 23318645 Papillary thyroid carcinoma arising from a thyroglossal duct cyst: a single institution experience. Thyroid cancers arising from a thyroglossal duct cyst (TGDC) are rarely reported. No clear consensus exists regarding optimal management. In this light, TGDC carcinomas recently treated at Asan Medical Center, as well as previously reported cases in the literature, were reviewed. There were ten patients who were diagnosed with TGDC carcinoma at our institution. All patients underwent pre-operative fine-needle aspiration biopsy (FNAB). Nine patients were suspected of having papillary carcinoma following cytology. The Sistrunk operation (SO) was performed in four patients, SO with total thyroidectomy (SO/TT) was performed in three patients, and SO/TT with neck dissection was performed in three patients. Six patients who received total thyroidectomy underwent radioactive iodine (RAI) therapy and T4 suppression. With a median follow-up period of 28.5 months, two patients showed recurrence and one of them died of the disease. We analyzed 163 cases from 1990 to 2012 with three or more cases TGDC carcinoma, including the present study. Among 48 patients who underwent FNAB, 75% had papillary thyroid carcinoma (PTC). SO, SO/TT, or SO/TT with neck dissection was performed in 27%, 41%, and 32% of patients, respectively. Among 119 patients who received total thyroidectomy, 36% had concomitant PTC in the thyroid. Among 52 patients who received neck dissection, 69% had cervical nodal involvement. The results of our review suggest that when TGDC carcinoma is suspected, ultrasonography and, if necessary, FNAB should be performed. If these tests reveal a suspected lesion in the thyroid or lymph node, SO/TT and lymph node dissection should be performed. 23168915 Nanostructural transformations during the reduction of hollow and porous nickel oxide nanoparticles. Size-dependent nanostructural transformations occurring during the H(2)-mediated reduction of hollow and porous NiO nanoparticles were investigated for controlled nanoparticle sizes of ~10 to 100 nm. Transmission electron microscopy reveals that the location and number of reduction sites strongly depend on the nanoparticle size and structure. 23194517 Oxidative changes during ice storage of rainbow trout (Oncorhynchus mykiss) fed different ratios of marine and vegetable feed ingredients. Recently fish meal and oil have increasingly been replaced with proteins and oils from vegetable sources in the diets of farmed salmonids, but the consequences for the oxidative stability of the resulting fish products have not been investigated. The aim of the present study was to evaluate the influence of feeding regime on composition of rainbow trout fillets, as well as on lipid and protein oxidation during storage on ice. Rainbow trout were fed six different diets, which differed in their levels of marine oil and proteins vs. vegetable oil and protein. Fish fillets were characterised by measurement of fatty acid and amino acid composition, primary and secondary lipid oxidation products, astaxanthin and tocopherol content. Protein oxidation was assessed by measuring protein carbonyl content, oxidised amino acids, sulfhydryl groups and immuno-blotting against carbonyl groups. Feeding regimes significantly influenced fatty acid composition. Replacement of fish oil with vegetable oil reduced formation of primary oxidation products, but the effect on secondary oxidation products differed between different types of volatiles. The differences in protein and amino acid composition were not significant, and there were no clear effects of diets on protein oxidation, but data indicated that compounds present in the marine ingredients might have had an effect on protein oxidation. 22949511 Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen. Although biallelic mutations in non-collagen genes account for <10% of individuals with osteogenesis imperfecta, the characterization of these genes has identified new pathways and potential interventions that could benefit even those with mutations in type I collagen genes. We identified mutations in FKBP10, which encodes the 65 kDa prolyl cis-trans isomerase, FKBP65, in 38 members of 21 families with OI. These include 10 families from the Samoan Islands who share a founder mutation. Of the mutations, three are missense; the remainder either introduce premature termination codons or create frameshifts both of which result in mRNA instability. In four families missense mutations result in loss of most of the protein. The clinical effects of these mutations are short stature, a high incidence of joint contractures at birth and progressive scoliosis and fractures, but there is remarkable variability in phenotype even within families. The loss of the activity of FKBP65 has several effects: type I procollagen secretion is slightly delayed, the stabilization of the intact trimer is incomplete and there is diminished hydroxylation of the telopeptide lysyl residues involved in intermolecular cross-link formation in bone. The phenotype overlaps with that seen with mutations in PLOD2 (Bruck syndrome II), which encodes LH2, the enzyme that hydroxylates the telopeptide lysyl residues. These findings define a set of genes, FKBP10, PLOD2 and SERPINH1, that act during procollagen maturation to contribute to molecular stability and post-translational modification of type I procollagen, without which bone mass and quality are abnormal and fractures and contractures result. 23578763 Personalized medicine: predicting responses to therapy in patients with RA. Personalized medicine where each patient receives the right drug and the right intensity of drug treatment for as long as needed or safe is the goal of medicine. The identification of predictors of response is the first step toward this. In rheumatoid arthritis (RA), several prediction matrices were designed to predict the risk of rapid radiological progression (RRP) in the first year of treatment, on either disease modifying anti-rheumatic drug (DMARD) monotherapy or combination therapy with prednisone or a biological agent. Both clinical markers and biomarkers of response to either anti-TNF or different mode of action biological agents, and of successful discontinuation of these agents once the treatment goal has been achieved, have been identified in different studies. Most of these markers need validation in other cohorts. Research into combining clinical markers and biomarkers of response could lead to identification of risk profiles resulting in a new step toward personalized medicine in RA. 23619567 Zebrafish as a model organism to study host-pathogen interactions. Zebrafish have been extensively used in biomedical research as a model to study vertebrate development but it is only recently that it has also been adopted into varied fields such as immunology and host-pathogen interactions. Zebrafish have a rapid life cycle, small size and the adults exhibit no territorial behavior in relatively dense cages. Under standard conditions each female lays an average of a hundred eggs per clutch, providing a large number of larvae per week. Their transparency during early life stages allows real time visualization of the different organs, which makes them especially suitable for the study of bacterial host-pathogen interactions. Traditionally, these studies have been technically challenging in higher organisms, given the loss of control over the bacteria once the pathogen infects its host. Here we describe an emerging approach to monitor Salmonella typhimurium infection progression using in vivo fluorescence upon parenteral infection. We have engineered Salmonella with the Cascade expression system; an efficient method to voluntarily activate bacterial heterologous gene expression at any point during infection once inside the Zebrafish macrophages, using a non-toxic inducer. 23494232 Acute ketamine induces hippocampal synaptic depression and spatial memory impairment through dopamine D1/D5 receptors. RATIONALE: Subanesthetic doses of ketamine have been reported to induce psychotic states that may mimic positive and negative symptoms as well as cognitive and memory deficits similar to those observed in schizophrenia. The cognitive and memory deficits are persistent, and their underlying cellular mechanisms remain unclear. OBJECTIVES: We sought to investigate the roles of dopamine D1/D5 receptors and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in hippocampal synaptic transmission and spatial memory impairment induced by ketamine. METHODS: We examined the effects of subanesthetic ketamine on hippocampal synaptic transmission in freely moving rats. Spatial memory was tested with the Morris water maze. Pretreatment with the D1/D5 receptors antagonist SCH23390 or the AMPA receptors endocytosis interfering peptide Tat-GluR23Y was conducted to examine their capacities to reverse ketamine-induced electrophysiological and behavioral alterations. A series of behavioral observations, including locomotion, prepulse inhibition, and social interaction, were also conducted after ketamine treatment. RESULTS: Ketamine induced synaptic depression lasting at least 4 h at hippocampal Schaffer collateral-CA1 synapses in freely moving rats and long-term spatial memory impairment. Both the effects were blocked by either SCH23390 or Tat-GluR23Y. Ketamine also elicited transient behavioral changes lasting less than 90 min, such as hyperlocomotion and prepulse inhibition deficits. These changes were ameliorated by SCH23390 but not by Tat-GluR23Y. Rats treated with ketamine showed social withdrawal that was also attenuated by either SCH23390 or Tat-GluR23Y. CONCLUSIONS: Our results indicate that hippocampal synaptic depression is involved in ketamine-induced memory impairment, and this is modulated by D1/D5 receptors activation and AMPA receptors endocytosis. 23122160 Feasibility and application of an HPLC/UVD to determine dinotefuran and its shorter wavelength metabolites residues in melon with tandem mass confirmation. A new analytical method was developed for dinotefuran and its metabolites, MNG, UF, and DN, in melon using high-performance liquid chromatography (HPLC) coupled with an ultraviolet detector (UVD). Due to shorter wavelength, lower sensitivity to UV detection, and high water miscibility of some metabolites, QuEChERs acetate-buffered version was modified for extraction and purification. Mobile phases with different ion pairing or ionisation agents were tested in different reverse phase columns, and ammonium bicarbonate buffer was found as the best choice to increase the sensitivity of target analytes to the UV detector. After failure of dispersive SPE clean-up with primary secondary amine, different solid phase extraction cartridges (SPE) were used to check the protecting capability of analytes against matrix interference. Finally, samples were extracted with a simple and rapid method using acetonitrile and salts, and purified through C(18)SPE. The method was validated at two spiking levels (three replicates for each) in the matrix. Good recoveries were observed for all of the analytes and ranged between 70.6% and 93.5%, with relative standard deviations of less than 10%. Calibration curves were linear over the calibration ranges for all the analytes with r(2)≥ 0.998. Limits of detection ranged from 0.02 to 0.05 mg kg(-1), whereas limits of quantitation ranged from 0.06 to 0.16 mg kg(-1) for dinotefuran and its metabolites. The method was successfully applied to real samples, where dinotefuran and UF residues were found in the field-incurred melon samples. Residues were confirmed via LC-tandem mass spectrometry (LC-MS/MS) in positive-ion electrospray ionisation (ESI(+)) mode. 23485441 Activity-based assay for human mono-ADP-ribosyltransferases ARTD7/PARP15 and ARTD10/PARP10 aimed at screening and profiling inhibitors. Poly(ADP-ribose) polymerases (PARPs) or diphtheria toxin like ADP-ribosyl transferases (ARTDs) are enzymes that catalyze the covalent modification of proteins by attachment of ADP-ribose units to the target amino acid residues or to the growing chain of ADP-ribose. A subclass of the ARTD superfamily consists of mono-ADP-ribosyl transferases that are thought to modify themselves and other substrate proteins by covalently adding only a single ADP-ribose moiety to the target. Many of the ARTD enzymes are either established or potential drug targets and a functional activity assay for them will be a valuable tool to identify selective inhibitors for each enzyme. Existing assays are not directly applicable for screening of inhibitors due to the different nature of the reaction and different target molecules. We modified and applied a fluorescence-based assay previously described for PARP1/ARTD1 and tankyrase/ARTD5 for screening of PARP10/ARTD10 and PARP15/ARTD7 inhibitors. The assay measures the amount of NAD(+) present after chemically converting it to a fluorescent analog. We demonstrate that by using an excess of a recombinant acceptor protein the performance of the activity-based assay is excellent for screening of compound libraries. The assay is homogenous and cost effective, making it possible to test relatively large compound libraries. This method can be used to screen inhibitors of mono-ARTDs and profile inhibitors of the enzyme class. The assay was optimized for ARTD10 and ARTD7, but it can be directly applied to other mono-ARTDs of the ARTD superfamily. Profiling of known ARTD inhibitors against ARTD10 and ARTD7 in a validatory screening identified the best inhibitors with submicromolar potencies. Only few of the tested ARTD inhibitors were potent, implicating that there is a need to screen new compound scaffolds. This is needed to create small molecules that could serve as biological probes and potential starting points for drug discovery projects against mono-ARTDs. 23336337 Enhancing macrocyclic diterpenes as multidrug-resistance reversers: structure-activity studies on jolkinol D derivatives. The phytochemical study of Euphorbia piscatoria yielded jolkinol D (1) in a large amount, whose derivatization gave rise to 12 ester derivatives (2-13) and hydrolysis to compound 14. The in vitro modulation of P-gp of compounds 1-14 was evaluated through a combination of transport and chemosensitivity assays, using the L5178 mouse T lymphoma cell line transfected with the human MDR1 gene. Apart from jolkinol D, all derivatives (2-14) showed potential as MDR reversal agents. In this small library of novel bioactive macrocyclic lathyrane diterpene derivatives, designed to evaluate structure-activity relationships essential in overcoming multidrug resistance (MDR), some correlations between MDR reversal and molecular weight, accessible solvent areas, and octanol/water partition coefficient were identified that can contribute to the development of new selective P-gp reversal agents. 23623743 A comparative study of protein carbonylation and mitochondrial dysfunction using the neurotoxicants 1,3-dinitrobenzene, 3-nitropropionic acid, and 3-chloropropanediol. This comparative evaluation of neurotoxicants previously identified as models of chemical-induced mitochondrial dysfunction and energy deprivation demonstrated that subtoxic concentrations of 1,3-dinitrobenzene (1,3-DNB), 3-nitropropionic acid (3-NPA), and 3-chloropropanediol (3-CPD) each led to concentration-dependent loss of the mitochondrial membrane potential (ΔΨm) associated with similar patterns of protein carbonylation. Subtoxic concentrations of each neurotoxicant were determined by measuring DI TNC1 cell viability using the MTS cell proliferation assay. Although exposure 1μM, 10μM, and 100μM concentrations of each toxicant did not result in loss of cell viability after 48h, exposure to each toxicant at these concentrations led to concentration-dependent loss of tetramethyl rhodamine methyl ester (TMRM) fluorescence over the same exposure period. Preincubation with the antioxidant, deferoxamine, was effective in preventing loss of TMRM flurorescence. Through the combined use of two-dimensional polyacrylamide gel electrophoresis (2D PAGE) and Oxyblot analysis, this study demonstrated that exposure to each toxicant resulted in the formation of distinctly similar patterns of protein carbonylation comprised of specific proteins identified with tandem MS/MS. Our results provide insight as to how exposure to different neurotoxicants that enhance oxidative stress may, in fact, lead to mitochondrial injury and subsequent toxicity through selective, yet shared, pathways of protein modification by oxidative carbonylation. 23561075 Proanthocyanidin profile of cowpea (Vigna unguiculata) reveals catechin-O-glucoside as the dominant compound. Proanthocyanidin (PA) profile and content can have important nutritional and health implications on plant foods. Six diverse cowpea phenotypes (black, red, green, white, light-brown and golden-brown) were investigated for PA composition using normal-phase HPLC and reversed-phase UPLC-TQD-MS. Catechin and (epi)afzelechin were the major flavan-3-ol units. Unusual composition was observed in all cowpea phenotypes with significant degrees of glycosylation in the monomers and dimers. The PA content of cowpea (dry basis) ranged between 2.2 and 6.3mg/g. Monomeric flavan-3-ols were the largest group of PA (36-69%) in cowpea, with catechin-7-O-glucoside accounting for most (about 88%) of the monomers. The oligomers with degree of polymerization (DP) 2-4 ranged from 0.41 to 1.3mg/g (15-20%), whereas DP>10 polymers accounted for only 13.5% of PA. Future studies that highlight the impact of the unusual cowpea PA profile on nutritional and bioactive properties of this important legume are warranted. 23265452 The determination of phenolic profiles of Serbian unifloral honeys using ultra-high-performance liquid chromatography/high resolution accurate mass spectrometry. Polyphenolic profiles of 44 unifloral Serbian honeys were analyzed using ultra-high-performance liquid chromatography (UHPLC) coupled with hybrid mass spectrometer which combines the Linear Trap Quadrupole (LTQ) and OrbiTrap mass analyzer. Rapid UHPLC method was developed in combination with a high sensitivity accurate mass scan and a simultaneous data dependent scan. The honey samples were of different botanical origin: acacia (Robinia pseudoacacia), sunflower (Helianthus annuus), linden (Tilia cordata), basil (Ocimum basilicum), buckwheat (Fagopyrum esculentum), oilseed rape (Brassica napus), and goldenrod (Solidago virgaurea). The presence of 43 compounds, mainly flavonoids, was proven in all honey samples by their characteristic mass spectra and fragmentation pattern. Relatively high amounts of chrysin, pinocembrin and galangin were identified in all honey extracts. p-Coumaric acid was not detected in basil, buckwheat and goldenrod honey extracts. A larger amount of gallic acid (max value 1.45 mg/kg) was found in the sunflower honey, while a larger amount of apigenin (0.97 mg/kg) was determined in the buckwheat honey in comparison with other honeys. The samples were classified according to the botanical origin using pattern recognition technique, Principal Component Analysis (PCA). The LTQ OrbiTrap technique was proven to be reliable for the unambiguous detection of phenolic acids, their derivatives, and flavonoid aglycones based on their molecular masses and fragmentation pattern. 23644884 HDAC6 and Ovarian Cancer. The special class IIb histone deacetylase, HDAC6, plays a prominent role in many cellular processes related to cancer, including oncogenesis, the cell stress response, motility, and myriad signaling pathways. Many of the lessons learned from other cancers can be applied to ovarian cancer as well. HDAC6 interacts with diverse proteins such as HSP90, cortactin, tubulin, dynein, p300, Bax, and GRK2 in both the nucleus and cytoplasm to carry out these cancerous functions. Not all pro-cancer interactions of HDAC6 involve deacetylation. The idea of using HDAC6 as a target for cancer treatment continues to expand in recent years, and more potent and specific HDAC6 inhibitors are required to effectively down-regulate the tumor-prone cell signaling pathways responsible for ovarian cancer. 23435913 Simple and sensitive liquid chromatography-tandem mass spectrometry methods for quantification of tadalafil in rat plasma: application to pharmacokinetic study in rats. A simple and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated in rat plasma for quantification of tadalafil, a novel therapeutic agent for erectile dysfunction. Tadalafil and acebutolol (internal standard) were extracted by liquid-liquid extraction with tert-butyl methyl ether. The chromatographic separation was performed on a reverse phase C18 column with a mobile phase consisting of 0.1 % formic acid and acetonitrile (45:55, v/v) at a flow rate of 0.3 mL/min. The protonated analyte was quantitated by multiple reaction monitoring with a Waters Quattro micro™ API mass spectrometer. The calibration curve was linear over a concentration range of 2-2000 ng/mL, and the lower limit of quantification was 2 ng/mL with a precision (CV %) of 10.9 %. Acceptable intra-day and inter-day precision and accuracy were obtained at 3 concentration levels (3, 200, and 1500 ng/mL). Tadalafil was found to be stable in a battery of studies, including bench top, freeze-thaw, and autosampler conditions. The validated method was successfully used to determine tadalafil concentration in rat plasma samples after oral administration at a dose of 1 mg/kg. 23530011 Metabolic Effects of Chronic Cannabis Smoking. OBJECTIVEWe examined if chronic cannabis smoking is associated with hepatic steatosis, insulin resistance, reduced β-cell function, or dyslipidemia in healthy individuals.RESEARCH DESIGN AND METHODSIn a cross-sectional, case-control study, we studied cannabis smokers (n = 30; women, 12; men, 18; 27 ± 8 years) and control subjects (n = 30) matched for age, sex, ethnicity, and BMI (27 ± 6). Abdominal fat depots and intrahepatic fat content were quantified by magnetic resonance imaging and proton magnetic resonance spectroscopy, respectively. Insulin-sensitivity indices and various aspects of β-cell function were derived from oral glucose tolerance tests (OGTT).RESULTSSelf-reported cannabis use was: 9.5 (2-38) years; joints/day: 6 (3-30) [median (range)]. Carbohydrate intake and percent calories from carbohydrates, but not total energy intake, were significantly higher in cannabis smokers. There were no group differences in percent total body fat, or hepatic fat, but cannabis smokers had a higher percent abdominal visceral fat (18 ± 9 vs. 12 ± 5%; P = 0.004). Cannabis smokers had lower plasma HDL cholesterol (49 ± 14 vs. 55 ± 13 mg/dL; P = 0.02), but fasting levels of glucose, insulin, total cholesterol, LDL cholesterol, triglycerides, or free fatty acids (FFA) were not different. Adipocyte insulin resistance index and percent FFA suppression during an OGTT was lower (P < 0.05) in cannabis smokers. However, oral glucose insulin sensitivity index, measures of β-cell function, or incretin concentrations did not differ between the groups.CONCLUSIONSChronic cannabis smoking was associated with visceral adiposity and adipose tissue insulin resistance but not with hepatic steatosis, insulin insensitivity, impaired pancreatic β-cell function, or glucose intolerance. 23499236 Discovery of new potential hits of Plasmodium falciparum enoyl-ACP reductase through ligand- and structure-based drug design approaches. We here report the discovery of novel Plasmodium falciparum enoyl-ACP reductase (PfENR) inhibitors as new antimalarial hits through ligand- and structure-based drug design approaches. We performed 2D and 3D QSAR studies on a set of rhodanine analogues using hologram QSAR (HQSAR), comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Statistical and satisfactory results were obtained for the best HQSAR (r(2) of 0.968 and qLOO(2) of 0.751), CoMFA (r(2) of 0.955 and qLOO(2) of 0.806) and CoMSIA (r(2) of 0.965 and qLOO(2) of 0.659) models. The information gathered from the QSAR models guided us to design new PfENR inhibitors. Three new hits were predicted with potency in the submicromolar range and presented drug-like properties. 23500547 HDL particle functionality as a primary pharmacological target for HDL-based therapies. Despite all existing pharmaceuticals aiming at effectively reducing LDL cholesterol, the steadily increasing prevalence of coronary heart disease (CHD) worldwide shifted focus on HDL as an alternative therapeutic target for the treatment of CHD. Indeed, based on the results from epidemiological studies, high HDL cholesterol (HDL-C) levels have been traditionally associated to atheroprotection. Therefore, current drug design considers plasma HDL-C levels as a primary pharmacological target for combating CHD. However, this approach does not take into consideration the fact that HDL is a rather heterogeneous mixture of lipoprotein particles with distinct apolipoprotein and lipid composition that dictate their atheroprotective or proatherogenic function. This may explain why simply raising HDL-C levels by pharmacological means has yet to yield the expected atheroprotection in recent clinical trials. In this review we argue that HDL particle functionality rather than HDL-C levels should be the primary target in the rational design of new HDL-based pharmaceuticals aiming at successfully treating CHD. 23256640 Enhancing biocompatibility of D-oligopeptide hydrogels by negative charges. Oligopeptide hydrogels are emerging as useful matrices for cell culture with commercial products on the market, but L-oligopeptides are labile to proteases. An obvious solution is to create D-oligopeptide hydrogels, which lack enzymatic recognition. However, D-oligopeptide matrices do not support cell growth as well as L-oligopeptide matrices. In addition to chiral interactions, many cellular activities are strongly governed by charge-charge interactions. In this work, the effects of chirality and charge on human mesenchymal stem cell (hMSC) behavior were studied using hydrogels assembled from oppositely charged oligopeptides. It was found that negative charges significantly improved hMSC viability and proliferation in D-oligopeptide gels but had little effect on their interactions with L-oligopeptide gels. This result points to the possibility of using charge and other factors to engineer biomaterials whose chirality is distinct from that of natural biomaterials, but whose performance is close to that of natural biomaterials. 23534695 Electrohydrodynamic Bubbling: An Alternative Route to Fabricate Porous Structures of Silk Fibroin Based Materials. Conventional fabrication techniques and structures employed in the design of silk fibroin (SF) based porous materials provide only limited control over pore size and require several processing stages. In this study, it is shown that, by utilizing electrohydrodynamic bubbling, not only can new hollow spherical structures of SF be formed in a single step by means of bubbles, but the resulting bubbles can serve as pore generators when dehydrated. The bubble characteristics can be controlled through simple adjustments to the processing parameters. Bubbles with diameters in the range of 240-1000 μm were fabricated in controlled fashion. FT-IR characterization confirmed that the rate of air infused during processing enhanced β-sheet packing in SF at higher flow rates. Dynamic mechanical analysis also demonstrated a correlation between air flow rate and film tensile strength. Results indicate that electrohydrodynamically generated SF and their composite bubbles can be employed as new tools to generate porous structures in a controlled manner with a range of potential applications in biocoatings and tissue engineering scaffolds. 23434491 Interaction of 17β-estradiol and ketoconazole on endocrine function in goldfish (Carassius auratus). An understanding of the effects of toxic mixtures of endocrine disrupting chemicals (EDCs) on aquatic organisms is challenging as these organisms are exposed to multiple classes of contaminants in their natural habitat. The aim of the present study was to evaluate the interactions of two classes of EDCs, 17β-estradiol (E2) and ketoconazole (KTC), on endocrine function in male goldfish (Carassius auratus), including vitellogenesis, metabolic capability and serum steroid synthesis. Changes in vitellogenin (VTG) concentration, liver 7-ethoxyresorufin-O-deethylase (EROD) activity and circulating serum E2 level were examined. The expression of related genes was also determined using quantitative real-time polymerase chain reaction. Exposure to E2 caused a significant increase in VTG concentrations which corresponded with the gene expression of VTG and estrogen receptor (ER) in males, which were further elevated after combined exposure to E2 and KTC, indicative of a synergetic relationship. Exposure to E2 also resulted in a distinct increase in serum steroid biosynthesis and associated cytochrome P450 (CYP) aromatase expression after 10 days. However, these changes were inhibited by the presence of KTC, which acted as a steroidogenic inhibitor in fish. Moreover, KTC significantly decreased liver EROD activity and increased the related gene expression of CYP1A. However, these KTC-mediated metabolic reactions in goldfish were up-regulated following exposure to KTC in combination with E2. These findings reveal complex interactions on endocrine functions in male goldfish when exposed to multiple contaminations and may provide a better understanding of the effects of toxic mixtures. 23330908 Structure-based design and synthesis of C-1- and C-4-modified analogs of zanamivir as neuraminidase inhibitors. In order to exploit the 430-cavity in the active sites of neuraminidases, 22 zanamivir analogs with C-1 and C-4 modification were synthesized, and their inhibitory activities against both group-1 (H5N1, H1N1) and group-2 neuraminidases (H3N2) were determined. Compound 9f exerts the most potency, with IC(50) value of 0.013, 0.001, and 0.09 μM against H3N2, H5N1, and H1N1, which is similar to that of zanamivir (H3N2 IC(50) = 0.0014 μM, H5N1 IC(50) = 0.012 μM, H1N1 IC(50) = 0.001 μM). Pharmacokinetic studies of compound 9f in rats showed a much longer plasma half-life (t(1/2)) than that of zanamivir following administration (po dose). Molecular modeling provided information about the binding model between the new inhibitors and neuraminidase, with the elongated groups at the C-1-position being projected toward the 430-loop region. This study may represent a novel starting point for the future development of improved antiflu agents. 23416229 Alpha neurotoxins. α-Neurotoxins have been isolated from hydrophid, elapid and, more recently, colubrid snake venoms. Also referred to as postsynaptic neurotoxins or 'curare mimetic' neurotoxins, they play an important role in the capture and/or killing of prey by binding to the nicotinic acetylcholine receptor on the skeletal muscle disrupting neurotransmission. They are also thought to cause respiratory paralysis in envenomed humans. This review will discuss the historical background into the discovery, isolation, structure and mechanism of action of the α-neurotoxins, including targets and cellular outcomes, and then will examine the potential uses of α-neurotoxins as pharmacological tools and/or as drug leads. 22516666 Evaluation of the effects of venlafaxine and pregabalin on the carbon dioxide inhalation models of Generalised Anxiety Disorder and panic. Previous studies have shown that subjective and objective symptoms of anxiety induced by 7.5% CO(2) inhalation can be attenuated by anxiolytics such as lorazepam and, to a lesser extent, paroxetine. Venlafaxine and pregabalin, two other licensed treatments for Generalised Anxiety Disorder, were used to further investigate the 7.5% and 35% CO(2) models of anxiety in healthy volunteers. Fifty-four participants were randomised to receive either placebo, venlafaxine or pregabalin. Study treatments were dosed incrementally over a three week period, to reach daily doses of 150 mg venlafaxine and 200mg pregabalin by the CO(2) challenge test day. Participants inhaled air 7.5% CO(2) for 20 minutes (single-blind presentation), and a non-blinded single vital capacity of 35% CO(2). Subjective ratings were recorded before and after each inhalation. Both 7.5% and 35% CO(2) inhalations produced the expected effects of increased ratings of symptoms of panic and anxiety, with increased blood pressure and heart rate. No significant treatment effects were found, although there were trends towards a reduction in feeling tense and nervous by both drugs compared with placebo during the 7.5% CO(2) challenge, and a reduction in alertness generally in the venlafaxine group compared with the pregabalin group. In contrast with the clear anxiolytic effects of benzodiazepines reported in several previous CO(2) studies, these findings suggest that the anxiogenic effects of CO(2) challenges are not significantly influenced by these serotonergic and GABAergic anxiolytics. This may be due to a lack of sensitivity of the CO(2) challenges in healthy volunteers to these drug types. 23402423 Conducting the temperature-dependent conformational change of macrocyclic compounds to the lattice dilation of quantum dots for achieving an ultrasensitive nanothermometer. We report a ligand decoration strategy to enlarge the lattice dilation of quantum dots (QDs), which greatly enhances the characteristic sensitivity of a QD-based thermometer. Upon a multiple covalent linkage of macrocyclic compounds with QDs, for example, thiolated cyclodextrin (CD) and CdTe, the conformation-related torsional force of CD is conducted to the inner lattice of CdTe under altered temperature. The combination of the lattice expansion/contraction of CdTe and the stress from CD conformation change greatly enhances the shifts of both UV-vis absorption and photoluminescence (PL) spectra, thus improving the temperature sensitivity. As an example, β-CD-decorated CdTe QDs exhibit the 0.28 nm shift of the spectra per degree centigrade (0.28 nm/°C), 2.4-fold higher than those of monothiol-ligand-decorated QDs. 23432004 Gd-based Macromolecules and Nanoparticles as Magnetic Resonance Contrast Agents for Molecular Imaging. As we move towards an era of personalized medicine, molecular imaging contrast agents are likely to see an increasing presence in routine clinical practice. Magnetic resonance (MR) imaging has garnered particular interest as a platform for molecular imaging applications due its ability to monitor anatomical changes concomitant with physiologic and molecular changes. One promising new direction in the development of MR contrast agents involves the labeling and/or loading of nanoparticles with gadolinium (Gd). These nanoplatforms are capable of carrying large payloads of Gd, thus providing the requisite sensitivity to detect molecular signatures within disease pathologies. In this review, we discuss some of the progress that has recently been made in the development of Gd-based macromolecules and nanoparticles and outline some of the physical and chemical properties that will be important to incorporate into the next generation of contrast agents, including high Gd chelate stability, high "relaxivity per particle" and "relaxivity density", and biodegradability. 23232056 Small molecule amides as potent ROR-γ selective modulators. The structure-activity relationship study of a diphenylpropanamide series of ROR-γ selective modulators is reported. Compounds were screened using chimeric receptor Gal4 DNA-binding domain (DBD)-NR ligand binding domain cotransfection assay in a two-step format. Three different regions of the scaffold were modified to assess the effects on repression of ROR-γ transcriptional activity and potency. The lead compound 1 exhibits modest mouse pharmacokinetics and an acceptable in vitro profile which makes it a suitable in vivo probe to interrogate the functions of ROR-γ in animal models of disease. 23455056 Novel oleanolic vinyl boronates: Synthesis and antitumor activity. A series of novel oleanane-type pentacyclic triterpenoids bearing a boronate ester moiety at C3 have been synthesized by palladium-catalyzed cross-coupling of bis(pinacolato)diboron with vinyl triflates, in the presence of base, and these compounds were fully characterized by 1D and 2D NMR techniques. Evaluation of their antiproliferative effects on a panel of hematological-based and solid tumor cell lines identified three active oleanolic vinyl boronates that inhibited the growth of leukemia (Jurkat, K562), Burkitt's lymphoma (Jijoye), cervix (Hela), colon (SW480), and ovary (SKOV-3) cancer cells without concomitant inhibition of non-tumoral human fibroblasts. Their mechanisms of action were investigated on the leukemia Jurkat cell line. The results show that the incorporation of boron in the oleanolic acid core combined with the presence of amide bonds afforded compounds with desirable biological effects such as apoptosis induction and inhibition of proteasomal activity on tumor cells, which makes them potential templates for further development in the anticancer drug setting. 23256643 Magnetostructural correlation for rational design of Mn(II) hybrid-spin complexes. The magnetic properties of a series of manganese(II) diacetylacetonate and dihexafluoroacetylacetonate hybrid-spin complexes with neutral pyridine-based organic radicals were characterized theoretically by DFT calculations. Three stable radicals, in which a radical group is bound in either para or meta position with respect to the pyridine nitrogen atom, were considered. The correct stable structures and multiplets of the complexes were obtained by full geometry optimization starting from an ideal structure. A total of three important geometry descriptors of the complexes were monitored and related to their magnetic characteristics. These structural parameters are (i) the torsion angle governing the conjugation of the organic radical m-PyNO (anti versus gauche), (ii) the coordination geometry of the acetyl acetonate ligands around the metal ion (square versus rhombic), and (iii) the relative orientation of the organic radical with respect to the acetyl acetonate plane (parallel versus perpendicular). It was found that the magnetic properties are not sensitive to the orientation of the radicals with respect to the equatorial plane but do depend on the conformation of the organic radicals. Even a spin switch between the ferromagnetic (S = (7)/(2)) and antiferromagnetic (S = (3)/(2)) ground state was found to be feasible for one of the complexes upon variation of the organic radical geometry, namely, the dihedral angle between the organic radical moiety and the pyridine ring. The pattern of molecular orbital overlap was determined to be the key factor governing the exchange coupling in the modeled systems. Bonding π-type overlap provides antiferromagnetic coupling in all complexes of the para radicals. In the meta analogues, the spins are coupled through the σ orbitals. A low-spin ground state occurs whenever a continuous σ-overlap pathway is present in the complex. Ferromagnetic interaction requires σ-π orthogonality of the pyridine atomic orbitals and/or π-antibonding Mn-pyridine natural orbital overlap. Using an estimate of the donor-acceptor energy stabilization, the affinity of a given Mn(II) d-orbital to mix with the sp(2) orbital from pyridine can be predicted. 23499758 Effect of UDP-glucuronosyltransferase 1A8 polymorphism on raloxifene glucuronidation. Raloxifene is an antiestrogen marketed for the treatment of osteoporosis. The major metabolic pathway of raloxifene is glucuronidation at 6- and/or 4'-positions, which is mainly catalyzed by UDP-glucuronosyltransferase 1A8 (UGT1A8) expressed in extrahepatic tissues such as the small intestine and colon. Two non-synonymous allelic variants, termed UGT1A8*2 (518C>G, A173G) and UGT1A8*3 (830G>A, C277Y), have been found in Caucasian, African-American and Asian populations. In this study, the effect of amino acid substitutions in UGT1A8 on raloxifene glucuronidation was studied using recombinant UGT1A8 enzymes of wild-type (UGT1A8.1) and variant UGT1A8 (UGT1A8.2 and UGT1A8.3) expressed in Sf9 cells. Raloxifene 6- and 4'-glucuronidation by UGT1A8.1 exhibited negative allosteric kinetics. The Km and Vmax values of UGT1A8.1 were 15.0μM and 111pmol/min/mg protein for 6-glucuronidation, and 9.35μM and 232pmol/min/mg protein for 4'-glucuronidation, respectively. The kinetics of raloxifene 6-glucuronidation by UGT1A8.2 was positive allosteric, whereas the kinetics of raloxifene 4'-glucuronidation was negative allosteric. The S50 value of raloxifene 6-glucuronidation was markedly low (1.2%) compared with the Km value of UGT1A8.1, and the Km value for raloxifene 4'-glucuronidation was 29% that of UGT1A8.1. The Vmax value for raloxifene 6-glucuronidation by UGT1A8.2 was comparable to that of UGT1A8.1, whereas the Vmax value for raloxifene 4'-glucuronidation was significantly lower (54%) than that of UGT1A8.1. The activities of raloxifene 6- and 4'-glucuronidation in UGT1A8.3 were markedly lower than those of UGT1A8.1. In mycophenolic acid glucuronidation, the kinetics by wild-type and variant UGT1A8s fitted the Michaelis-Menten model. The Km and Vmax values of UGT1A8.1 were 123μM and 4820pmol/min/mg protein, respectively. The Km and Vmax values of UGT1A8.2 were comparable to those of UGT1A8.1. The Km value of UGT1A8.3 was similar to that of UGT1A8.1, whereas the Vmax value was reduced to 2.4% of UGT1A8.1. These findings suggest that A173G and C277Y substitutions of UGT1A8 change the metabolic ability toward raloxifene, and that the polymorphic alleles of UGT1A8 may influence the clinical response and bioavailability of medicines metabolized mainly by UGT1A8. 23263987 Enhanced leptin sensitivity, reduced adiposity, and improved glucose homeostasis in mice lacking exchange protein directly activated by cyclic AMP isoform 1. The prototypic second messenger cyclic AMP (cAMP) is essential for controlling cellular metabolism, including glucose and lipid homeostasis. In mammals, the majority of cAMP functions are mediated by cAMP-dependent protein kinase (PKA) and exchange proteins directly activated by cAMP (Epacs). To explore the physiological functions of Epac1, we generated Epac1 knockout mice. Here we report that Epac1 null mutants have reduced white adipose tissue and reduced plasma leptin levels but display heightened leptin sensitivity. Epac1-deficient mice are more resistant to high-fat diet-induced obesity, hyperleptinemia, and glucose intolerance. Furthermore, pharmacological inhibition of Epac by use of an Epac-specific inhibitor reduces plasma leptin levels in vivo and enhances leptin signaling in organotypic hypothalamic slices. Taken together, our results demonstrate that Epac1 plays an important role in regulating adiposity and energy balance. 23601711 Preparation of S14161 and its analogues and the discovery of 6-bromo-8-ethoxy-3-nitro-2H-chromene as a more potent antitumor agent in vitro. The small chemical compound 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161) was recently identified as an inhibitor of the phosphoinositide 3-kinase (PI3K). In the present study, we designed a novel synthesis of S14161 and prepared a series of its analogues via the oxa-Michael-Henry reaction in the presence of catalytic amounts of l-proline and triethylamine. Further structural simplification led to the identification of 6-bromo-8-ethoxy-3-nitro-2H-chromene (BENC-511) that exhibited potent antiproliferative activities against a panel of 12 tumor cell lines. Compared with S14161, BENC-511 was more potent in blocking the AKT phosphorylation and inducing cancer cell apoptosis. BENC-511 also displayed more potent effects on human umbilical vein epithelial cells (HUVEC) migration, suggesting its anti-angiogenesis activity. 23074021 In vivo genotoxicity of methyleugenol in gpt delta transgenic rats following medium-term exposure. Methyleugenol (MEG), which is commonly used as a fragrance and flavoring agent, has been shown to induce hepatocellular tumors in rodents. However, the role of genotoxicity as a possible mechanism of action is not fully understood even though the DNA-reactive metabolite of MEG has been identified. In this study, a gpt delta transgenic rat model was used to clarify whether genotoxic mechanisms are involved in MEG-induced hepatocarcinogenesis following medium-term exposure. F344 gpt delta rats were subjected to repeated oral administration of MEG at dosages of 0, 10, 30, or 100mg/kg (a carcinogenic dose) for 13 weeks. The relative weight of the liver of the male and female rats that were administered 100mg/kg MEG and the absolute weight of the liver of the male rats that were administered 100mg/kg MEG were significantly increased. In addition, the number and area of glutathione S-transferase placental form (GST-P) positive foci and proliferating cell nuclear antigen (PCNA) positive cell ratios in the hepatocytes were significantly increased in the male and female rats that were administered 100mg/kg MEG compared with the control animals. In the in vivo mutation assays, a significant increase in the gpt and Spi(-) mutant frequencies was observed in both sexes at the carcinogenic dose. These results suggest the possible participation of genotoxic mechanisms in MEG-induced hepatocarcinogenesis. 23111879 Emergency do not consume/do not use concentrations for ferric chloride in drinking water. The U.S. Congress [PL 107-188] amended the Safe Drinking Water Act and required each community water system serving more than 3,000 people to conduct vulnerability assessments. These assessments address potential circumstances that could compromise the safety and reliability of municipal water. Ferric chloride is used in coagulation and flocculation, and it is used to treat raw water with high viral loads, elevated dissolved solids or high bromide. Iron is an essential nutrient, but elevated concentrations of FeCl3 are corrosive as a result of hydrolysis to HCl. Based on a no-observed-adverse effect level (NOAEL) of 0.5% FeCl3 • 6H2O administered in drinking water to male and female F344 rats for up to 2 years, a do not consume concentration of 200 mg FeCl3 /L can be derived. Since instillation of 0.3 M (48.7 g/L) FeCl3 in saline to rodent vagina failed to elicit damage, a topical do not use concentration of 2000 mg FeCl3/L (600 mg Fe/L) can be assigned. The only FeCl3 data available to quantify ocular toxicity involved a pH 1 solution in rabbit eyes, but HCl instillation (pH 2.5) to rabbit eyes found permanent corneal ulceration after 10 min. The pH of FeCl3 in water at the do not use limit (2.4-2.6) is near the pH (2.0) considered corrosive by regulatory agencies. As direct eye contact with water at pH 4.5 or below increases complaints of ocular discomfort, emergency response plans that address FeCl3 in drinking water must account for Fe levels and the pH of the affected water. 23386250 Upregulation of nuclear factor of activated T-cells by nerve injury contributes to development of neuropathic pain. Nerve injury induces long-term changes in gene expression in the nociceptive circuitry and can lead to chronic neuropathic pain. However, the transcriptional mechanism involved in neuropathic pain is poorly understood. Nuclear factor of activated T-cells (NFATc) is a transcriptional factor regulated by the Ca(2+)-dependent protein phosphatase calcineurin. In this study, we determined nerve injury-induced changes in the expression of NFATc1-c4 in the dorsal root ganglia (DRG) and spinal cords and their role in the development of neuropathic pain. The mRNA of NFATc1-c4 was detected in the rat DRG and dorsal spinal cord. Nerve injury transiently elevated NFATc1-c3 mRNA levels and persistently increased NFATc4 and C-C chemokine receptor type 2 (CCR2) mRNA levels in the DRG. However, NFATc1-c4 mRNA levels in the spinal cord were not altered significantly by nerve injury. Nerve injury also significantly increased the protein level of dephosphorylated NFATc4 in the DRG. Intrathecal injection of the specific NFATc inhibitor 11R-VIVIT or the calcineurin inhibitor FK-506 (tacrolimus) early after nerve injury significantly attenuated the development of tactile allodynia. In addition, treatment with FK-506 or 11R-VIVIT significantly reduced the mRNA levels of NFATc4 and CCR2 but not large-conductance Ca(2+)-activated K(+) channels, in the DRG after nerve injury. Our findings suggest that peripheral nerve injury causes a time-dependent change in NFATc1-c4 expression in the DRG. Calcineurin-NFATc-mediated expression of pronociceptive cytokines contributes to the transition from acute to chronic pain after nerve injury. 23541399 Androgen deprivation from pre-puberty to peripuberty interferes in proteins expression in pubertal and adult rat epididymis. Few studies have focused on experimental testosterone deprivation in immature animals. Therefore, this study used sexually immature rats aiming to evaluate the testes and epididymis histology and proteins expression in these organs on PND50 and 75, after premature antiandrogen exposure, from PND21 to 44. Although the androgen deprivation from pre-puberty up to peripuberty did not alter the histological organization of the testes and epididymis either at puberty or at adulthood, the treatment impaired the expression of specific proteins in epididymal tissue at puberty and adulthood (androgen receptor, calmodulin, Rab11A). These changes may be related to impaired epididymal function, sperm quality and fertility capacity as observed in a previous study. Further studies are necessary to better investigate the molecular mechanisms involved in the impairment on reproductive competence of male rats after precocious hormonal injury. 23582327 Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration. In vertebrates, activation of innate immunity is an early response to injury, implicating it in the regenerative process. However, the mechanisms by which innate signals might regulate stem cell functionality are unknown. Here, we demonstrate that type 2 innate immunity is required for regeneration of skeletal muscle after injury. Muscle damage results in rapid recruitment of eosinophils, which secrete IL-4 to activate the regenerative actions of muscle resident fibro/adipocyte progenitors (FAPs). In FAPs, IL-4/IL-13 signaling serves as a key switch to control their fate and functions. Activation of IL-4/IL-13 signaling promotes proliferation of FAPs to support myogenesis while inhibiting their differentiation into adipocytes. Surprisingly, type 2 cytokine signaling is also required in FAPs, but not in myeloid cells, for rapid clearance of necrotic debris, a process that is necessary for timely and complete regeneration of tissues. 23245188 Catalase-like and peroxidase-like catalytic activities of silicon nanowire arrays. Silicon nanowire arrays (SiNWAs) were found to have catalytic activities similar to those of biological enzymes catalase and peroxidase. Thus not only can these materials catalyze the decomposition reaction of H(2)O(2) into water and oxygen, but they can also catalyze the oxidation of o-phenylenediamine (OPD), a common substrate for peroxidases, by H(2)O(2). The presence of Si-H bonds and the morphology of the SiNWAs are found to be crucial to the occurrence of such catalytic activity. When the SiNWAs are reacted with H(2)O(2), the data from Raman spectroscopy suggests the formation of (Si-H)(2)···(O species) ((Si-H)(2)···Os), which is presumably responsible for the catalytic activity. These findings suggest the potential use of SiNWAs as enzyme mimics in medicine, biotechnology, and environmental chemistry. 23008099 Lack of enantioselectivity in the SULT1A3-catalyzed sulfoconjugation of normetanephrine enantiomers: an in vitro and computational study. (1R)-Normetanephrine is the natural stereoisomeric substrate for sulfotransferase 1A3 (SULT1A3)-catalyzed sulfonation. Nothing appears known on the enantioselectivity of the reaction despite its potential significance in the metabolism of adrenergic amines and in clinical biochemistry. We confronted the kinetic parameters of the sulfoconjugation of synthetic (1R)-normetanephrine and (1S)-normetanephrine by recombinant human SULT1A3 to a docking model of each normetanephrine enantiomer with SULT1A3 and the 3'-phosphoadenosine-5'-phosphosulfate cofactor on the basis of molecular modeling and molecular dynamics simulations of the stability of the complexes. The K(M), V(max), and k(cat) values for the sulfonation of (1R)-normetanephrine, (1S)-normetanephrine, and racemic normetanephrine were similar. In silico models were consistent with these findings as they showed that the binding modes of the two enantiomers were almost identical. In conclusion, SULT1A3 is not substrate-enantioselective toward normetanephrine, an unexpected finding explainable by a mutual adaptability between the ligands and SULT1A3 through an "induced-fit model" in the catalytic pocket. 23541670 Discovery of a series of novel 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers, as potent JAK3 kinase inhibitors. We report the discovery of a novel series of ATP-competitive Janus kinase 3 (JAK3) inhibitors based on the 5H-pyrrolo[2,3-b]pyrazine scaffold. The initial leads in this series, compounds 1a and 1h, showed promising potencies, but a lack of selectivity against other isoforms in the JAK family. Computational and crystallographic analysis suggested that the phenyl ether moiety possessed a favorable vector to achieve selectivity. Exploration of this vector resulted in the identification of 12b and 12d, as potent JAK3 inhibitors, demonstrating improved JAK family and kinase selectivity. 23381681 Effects of supplementary selenium source on the blood parameters in beef cows and their nursing calves. Over 2 years, 32 beef cows nursing calves in southwest Arkansas were randomly selected from a herd of 120 that were managed in six groups and were assigned to six 5.1-ha bermudagrass (Cynodon dactylon [L.] Pers.) pastures. Treatments were assigned to pastures (two pastures/treatment) and cows had ad libitum access to one of three free-choice minerals: (1) no supplemental selenium (Se), (2) 26 mg of supplemental Se from sodium selenite per kilogram, and (3) 26 mg of supplemental Se from seleno-yeast per kilogram (designed mineral intake = 113 g/cow daily). Data were analyzed using a mixed model; year and pasture were the random effects and treatment was the fixed effect. At the beginning of the calving and breeding seasons, cows supplemented with Se had greater (P < 0.01) whole blood Se concentration (WBSe) and glutathione peroxidase activities (GSH-Px) than cows receiving no supplemental Se; cows fed seleno-yeast had greater (P ≤ 0.05) WBSe than cows fed sodium selenite, but GSH-Px did not differ (P ≥ 0.25) between the two sources. At birth and near peak lactation (late May), calves from cows supplemented with Se had greater (P < 0.01) WBSe than calves from cows fed no Se and calves from cows fed seleno-yeast had greater (P ≤ 0.01) WBSe and GSH-Px than calves from cows fed sodium selenite. Thyroxine (T4), triiodothyronine (T3), and the T4:T3 ratio in calves did not differ among treatments (P ≥ 0.35). At birth, insulin-like growth factor 1 (IGF-1) was greater (P = 0.02) in calves nursing cows with no supplemental Se than in ones with supplemental Se; in calves nursing cows with supplemental sodium selenite, IGF-1 did not differ (P = 0.96) from ones offered supplemental seleno-yeast. Selenium supplementation of gestating beef cows benefited cows and calves by increasing WBSe and GSH-Px. The use of seleno-yeast as a Se supplement compared to sodium selenite increased the WBSe of both cows and their calves without affecting the T4 to T3 conversion or IGF-1 concentrations. 23231809 Dopamine facilitates dendritic spine formation by cultured striatal medium spiny neurons through both D1 and D2 dopamine receptors. Variations of dopamine (DA) levels induced by drugs of abuse or in the context of Parkinson's disease modulate the number of dendritic spines in medium spiny neurons (MSNs) of the striatum, showing that DA plays a major role in the structural plasticity of MSNs. However, little is presently known regarding early spine development in MSNs occurring before the arrival of cortical inputs and in particular about the role of DA and D1 (D1R) and D2 (D2R) DA receptors. A cell culture model reconstituting early cellular interactions between MSNs, intrinsic cholinergic interneurons and DA neurons was used to study the role of DA in spine formation. After 5 or 10 days in vitro, the presence of DA neurons increased the number of immature spine-like protrusions. In MSN monocultures, chronic activation of D1R or D2R also increased the number of spines and spinophilin expression in MSNs, suggesting a direct role for these receptors. In DA-MSN cocultures, chronic blockade of D1R or D2R reduced the number of dendritic spines. Interestingly, the combined activation or blockade of both D1R and D2R failed to elicit more extensive spine formation, suggesting that both receptors act through a mechanism that is not additive. Finally, we found increased ionotropic glutamate receptor responsiveness and miniature excitatory postsynaptic current (EPSC) frequency in DA-MSN co-cultures, in parallel with a higher number of spines containing PSD-95, suggesting that the newly formed spines present functional post-synaptic machinery preparing the MSNs to receive additional glutamatergic contacts. These results represent a first step in the understanding of how dopamine neurons promote the structural plasticity of MSNs during the development of basal ganglia circuits. 23643824 Therapeutic cell encapsulation: Ten steps towards clinical translation. Since the conception of cell microencapsulation, many scientists bet on this biotechnology as they saw in it a promising alternative to protect transplanted cells from host immunoresponse. Some decades later, this initial enthusiasm is giving rise to a phase of certain conformism and lack of novel advances in the field. This perspective critically discusses current challenges needed to help this approach become a realistic clinical proposal. Alginate seems to be well established as the biomaterial of choice, but additional efforts are needed regarding current cross-linkers and coatings. Biofunctionalization of the matrices may provide the necessary biomimetic microenvironment to control cell behavior. Different alginate degradation rates would allow widening the applications of this biotechnology from drug delivery to cell delivery. In this sense, stem cells from stromal tissues could be the most suitable cell source due to their intrinsic hypoimmunogenicity, their immunomodulatory effets and their capacity to cell homing. The incorporation of suicide and reporter genes in the genome of enclosed cells may overcome some of the existing biosafety concerns. Administration and extraction by means of less invasive procedures also need to be developed to succeed in clinical translation. Finally, improving cost-effectiveness for the scale-up, together with establishing and fulfilling a series of strict regulatory aspects will be indispensable to make the final step to the clinic. 23262162 Antioxidant cosmeto-textiles: Skin assessment. Resveratrol, a natural product, has been reported to have antioxidant activities such as the scavenging of free radicals. This compound could be used in the dermocosmetic field to protect the skin from oxidative stress. In this work, the percutaneous profile of resveratrol in ethanol solutions through pig skin was determinated by an in vitro methodology. The percutaneous absorption of resveratrol was measured and compared with trolox, an analogous of Vitamin E. Both antioxidants were found in all skin sections (stratum corneum, epidermis, and dermis). Besides, the free radical scavenging activity of resveratrol and trolox has been evaluated using DPPH method. The effective dose (ED50) of compounds and DPPH radical inhibition in each skin layer were evaluated. Under the conditions used for these experiments, it can be deduced that resveratrol is more efficient than trolox as an antioxidant, also in the inner skin layers. The cosmeto-textiles with an active substance incorporated into their structure are increasingly used in the cosmetics and pharmaceutical industries. The action of several cosmeto-textiles on the skin was assessed by in vitro and in vivo methodologies. Samples of these cosmeto-textiles were prepared with resveratrol incorporated into cotton and polyamide fabrics. An in vitro percutaneous absorption was used to demonstrate the delivery of the resveratrol from the textile to the different skin layers (stratum corneum, epidermis, and dermis). Additionally, these cosmeto-textiles containing the antioxidant were applied onto the forearms of volunteers to evaluate the textiles' efficacy in skin penetration. The antioxidant's antiradical capacity was evaluated using the DPPH method. Results showed that resveratrol could be detected in the dermis, epidermis, and stratum corneum (SC) by an in vitro percutaneous absorption method and was also detected in the outermost layers of the SC by an in vivo method (stripping). A smaller amount of resveratrol was penetrated through the skin layers when cosmeto-textiles were used compared to direct topical application of the antioxidant solution. The cosmeto-textiles investigated can act as a reservoir system capable of progressively deliver the active substance to the skin layers. From the skin penetration profiles and the antioxidant efficacy assessment of resveratrol, it is possible to ameliorate the inherent antioxidant capacity of skin. 23273150 Preferred configurations of peptide-peptide interactions. The natural and fundamental proclivities of interaction between a pair of peptide units are examined using high-level ab initio calculations. The NH···O H-bonded structure is found to be the most stable configuration of the N-methylacetamide (NMA) model dimer, but only slightly more so than a stacked arrangement. The H-bonded geometry is destabilized by only a small amount if the NH group is lifted out of the plane of the proton-accepting amide. This out-of-plane motion is facilitated by a stabilizing charge transfer from the CO π bond to the NH σ* antibonding orbital. The parallel and antiparallel stacked dimers are nearly equal in energy, both only slightly less stable than the NH···O H-bonded structure. Both are stabilized by a combination of CH···O H-bonding and a π→π* transfer between the two CO bonds. There are no minima on the surface that are associated with O(lp)→π*(CO) transfers, due in large part to strong electrostatic repulsion between the two O atoms, which resists an approach of a carbonyl O from above the C=O bond of the other amide. 23570533 Laccase-mediated coupling of nonpolar chains for the hydrophobization of lignocellulose. We investigate the use of laccase enzymes for coupling short nonpolar chains containing aromatic rings onto flax fibers and nanofibrillated cellulose (NFC) with different lignin contents. Trametes villosa, Pycnoporus cinnabarinus and Myceliophthora thermophila were used to facilitate surface coupling and to produce materials with different levels of hydrophobicity. Heat treatment of fiber webs after lacccase-mediated coupling markedly increased the resistance to water absorption. The highest hydrophobization levels of flax fibers was achieved by coupling dodecyl 3,4,5-trihydroxybenzoate (HB-C12), which yielded water contact angles (WCA) of 80-96 degrees and water absorption times (drop tests) of ca. 73 min. The results from apparent aromatic content and FTIR analyses confirmed the laccase-mediated coupling of HB-C12 onto the cellulose fibers. Substrates consisting of ultrathin films of NFC were also used as substrates for enzyme-mediated hydrophobization with HB-C12. In these cases water contact angles in the range of 87-104 degrees were achieved, depending on the conditions. Quartz crystal microgravimetry (QCM) was used to study the dynamics and the extent of the coupling process onto cellulose. The results help to better understand the mechanisms involved in laccase-mediated hydrophobization and provide a proof of a biotechnological platform for the development of added-value fiber products. 23493374 Creb1-Mecp2-(m)CpG complex transactivates postnatal murine neuronal glucose transporter isoform 3 expression. The murine neuronal facilitative glucose transporter isoform 3 (Glut3) is developmentally regulated, peaking in expression at postnatal day (PN)14. In the present study, we characterized a canonical CpG island spanning the 5'-flanking region of the glut3 gene. Methylation-specific PCR and bisulfite sequencing identified methylation of this CpG ((m)CpG) island of the glut3 gene, frequency of methylation increasing 2.5-fold with a 1.6-fold increase in DNA methyl transferase 3a concentrations noted with advancing postnatal age (PN14 vs PN3). 5'-flanking region of glut3-luciferase reporter transient transfection in HT22 hippocampal neurons demonstrated that (m)CpGs inhibit glut3 transcription. Contrary to this biological function, glut3 expression rises synchronously with (m)CpGs in PN14 vs PN3 neurons. Chromatin immunoprecipitation (IP) revealed that methyl-CpG binding protein 2 (Mecp2) bound the glut3-(m)CpGs. Depending on association with specific coregulators, Mecp2, a dual regulator of gene transcription, may repress or activate a downstream gene. Sequential chromatin IP uncovered the glut3-(m)CpGs to bind Mecp2 exponentially upon recruitment of Creb1 rather than histone deacetylase 1. Co-IP and coimmunolocalization confirmed that Creb1 associated with Mecp2 and cotransfection with glut3-(m)CpG in HT22 cells enhanced glut3 transcription. Separate 5-aza-2'-deoxycytidine pretreatment or in combination with trichostatin A reduced (m)CpG and specific small interference RNAs targeting Mecp2 and Creb1 separately or together depleting Mecp2 and/or Creb1 binding of glut3-(m)CpGs reduced glut3 expression in HT22 cells. We conclude that Glut3 is a methylation-sensitive neuronal gene that recruits Mecp2. Recruitment of Creb1-Mecp2 by glut3-(m)CpG contributes towards transactivation, formulating an escape from (m)CpG-induced gene suppression, and thereby promoting developmental neuronal glut3 gene transcription and expression. 23561185 Modulating β-carotene bioaccessibility by controlling oil composition and concentration in edible nanoemulsions. Diets rich in carotenoids have been correlated with a reduced risk of developing certain types of chronic diseases, but these bioactive components have low intestinal absorption due to their hydrophobic nature. The aim of this work was to study the effect of carrier oil composition (medium-chain triglyceride (MCT) to long-chain triglyceride (LCT) ratio) and total carrier oil concentration (1% or 4% w/w) on the physical stability, lipid digestibility and bioaccessibility of β-carotene-loaded nanoemulsions, using a simulated digestion process. Lipolysis led to an appreciable increase in the size and negative charge on the particles in the system. The total fraction of triacylglycerols converted to free fatty acids decreased as the percentage of LCT within the lipid phase increased, particularly for the nanoemulsions with higher fat contents. There was an increase in β-carotene bioaccessibility as the LCT within the lipid phase increased for low fat nanoemulsions, which was attributed to the increased solubilisation capacity of mixed micelles formed by LCT. β-carotene bioaccessibility showed a complex relationship on LCT content for high fat nanoemulsions, due to the opposing effects of lipid digestion and micelle solubilisation. These results may facilitate the optimisation of delivery systems for lipophilic bioactive compounds for food or pharmaceutical applications. 23584636 Long single ZnO nanowire for logic and memory circuits: NOT, NAND, NOR gate, and SRAM. We demonstrate logic and static random access memory (SRAM) circuits using a 100 μm long and 100 nm thin single ZnO nanowire (NW), which acts as a channel of field-effect transistors (FETs) with Al2O3 dielectrics. NW FETs are thus arrayed in one dimension to consist of NOT, NAND, and NOR gate logic, and SRAM circuits. Two respective top-gate NW FETs with Au and indium-tin-oxide (ITO) were connected to form an inverter, the basic NOT gate component, since the former gate leads to an enhanced mode FET while the latter to depletion mode due to their work function difference. Our inverters showed a high voltage gain of 22 under a 5 V operational voltage, resulting in successful operation of all other devices. We thus conclude that our long single NW approach is quite promising to extend the field of nano-electronics. 23506741 A novel benzo[d]imidazole derivate prevents the development of dextran sulfate sodium-induced murine experimental colitis via inhibition of NLRP3 inflammasome. NLRP3 inflammasome has been reported to be associated with various kinds of immunological diseases including colitis. However, there are few drug candidates targeting inflammasomes for the treatment of colitis. In the present study, we aimed at examining the effect of 1-ethyl-5-methyl-2-phenyl-1H-benzo[d]imidazole, a synthetic small molecular compound also named Fc11a-2, for the treatment of dextran sulfate sodium (DSS)-induced experimental colitis in mice via targeting NLRP3 inflammasome. Treatment with Fc11a-2 dose-dependently attenuated the loss of body weight and shortening of colon length induced by DSS. In addition, the disease activity index, histopathologic scores and myeloperoxidase activity were also significantly reduced by Fc11a-2 treatment. Moreover, protein and mRNA levels of DSS-induced proinflammatory cytokines in colon, including TNF-α, IL-1β, IL-18, IL-17A and IFN-γ, were markedly suppressed by Fc11a-2. Furthermore, a decreased CD11c(+) macrophage infiltration in colons and inactivation of caspase-1 in peritoneal macrophages were detected in Fc11a-2-treated mice. The mechanism of action of Fc11a-2 was related to the inhibition of the cleavage of pro-caspase-1, pro-IL-1β and pro-IL-18 which in turn suppressed the activation of NLRP3 inflammasome. Taken together, our results demonstrate the ability of Fc11a-2 to inhibit NLRP3 inflammasome activation and its potential use in the treatment of inflammatory bowel diseases. 23601396 A review of composition studies of Cameroon traditional dishes: Macronutrients and minerals. This paper reviews published data that contributes to the knowledge of the ingredients and nutrients of Cameroon traditional dishes. Macronutrient (energy, carbohydrates, protein, total fat, fibre and ash) and mineral (iron, zinc, magnesium, calcium, phosphorus, copper, manganese, potassium, sodium and selenium) data are presented for 117 commonly consumed dishes from three eco-regions. Tables providing an overview of the main ingredients and nutrient values (range of means per 100g edible portion) are presented. Considerable variability in nutrient values has been reported among dishes. Water contents range from 29.8 to 95.9g/100g edible portion while energy values range from 12 to 403kcal/100g. Energy yielding-constituents are the major nutrients recorded in published data, followed by iron, zinc and magnesium. 22559719 Variation in the volatile oil composition of Eucalyptus citriodora produced by hydrodistillation and supercritical fluid extraction techniques. This work reports variations in the yields and quality of volatiles produced from Eucalyptus citriodora leaves by different hydrodistillation (HD) and supercritical carbon dioxide extraction (SCE) techniques. HD techniques (1.5%) produced higher yields compared to SCE (0.7%). Citronellal, the major component, was maximum in the extract produced by SCE (79%) followed by oil produced by water-steam distillation (WSD) (72.6%) and water distillation (WD) (62.4%) techniques. Chemical composition of glycoside-bound volatiles produced by acid hydrolysis during HD was found to be very different from free volatiles, although in a minor quantity. The extent of artefact formation and release of aglycones was more profound in the bound volatile oil produced by WD than WSD. Highest oxygenated monoterpenes were found in SCE and WSD (93% each) followed by WD (91.4%). Although the SCE produced lower yields than the HD techniques, its extract is superior in quality in terms of higher concentration of citronellal. 23265491 Evaluation of biological activities of a groundnut (Apios americana Medik) extract containing a novel isoflavone. Groundnut (Apios americana Medik) contains a novel isoflavone, genistein-7-O-gentiobioside. In the present study, we examined the biological activities of an alcohol extract of groundnut containing genistein-7-O-gentiobioside as the main component. Although the groundnut extract by itself did not show antioxidative activity, it drove the antioxidative system in cells. Pretreatment of human breast carcinoma MCF-7 cells for 24 h with the groundnut extract and soybean isoflavone increased gene expression of heme oxygenase-1 (HO-1), a major antioxidative stress enzyme. These groundnut extract-treated cells showed antioxidative activity against free radicals derived from a radical initiator. Pretreatment of cells with 100 μg/mL groundnut extract prevented the depletion of glutathione by the radical initiator; however, treatment with 100 μg/mL of soybean isoflavone injured the cell membrane, indicating that glutathione might be released to the extracellular environment. These results suggest that the groundnut extract had isoflavone-like activity. Like soybean, groundnuts are a good source of isoflavones. 23495001 Raphanus sativus L. var niger as a source of Phytochemicals for the Prevention of Cholesterol Gallstones. Raphanus sativus L. var niger (black radish) is a plant of the cruciferous family with important ethnobotanical uses for the treatment of gallstones in Mexican traditional medicine. It has been established that the juice of black radish decreases cholesterol levels in plasma and dissolves gallstones in mice. Glucosinolates, the main secondary metabolites of black radish, can hydrolyze into its respective isothiocyanates and have already demonstrated antioxidant properties as well as their ability to diminish hepatic cholesterol levels; such therapeutic effects can prevent the formation of cholesterol gallstones. This disease is considered a current problem of public health. In the present review, we analyze and discuss the therapeutic effects of the main glucosinolates of black radish, as well as the effects that this plant has on cholesterol gallstones disease. Copyright © 2013 John Wiley & Sons, Ltd. 23205778 Transferable potentials for phase equilibria. 10. Explicit-hydrogen description of substituted benzenes and polycyclic aromatic compounds. The explicit-hydrogen version of the transferable potentials for phase equilibria (TraPPE-EH) force field is extended to various substituted benzenes through the parametrization of the exocyclic groups -F, -Cl, -Br, -C≡N, and -OH and to polycyclic aromatic hydrocarbons through the parametrization of the aromatic linker carbon atom for multiple rings. The linker carbon together with the TraPPE-EH parameters for aromatic heterocycles constitutes a force field for fused-ring heterocycles. Configurational-bias Monte Carlo simulations in the Gibbs ensemble were carried out to compute vapor-liquid coexistence curves for fluorobenzene; chlorobenzene; bromobenzene; di-, tri-, and hexachlorobenzene isomers; 2-chlorofuran; 2-chlorothiophene; benzonitrile; phenol; dihydroxybenzene isomers; 1,4-benzoquinone; naphthalene; naphthalene-2-carbonitrile; naphthalen-2-ol; quinoline; benzo[b]thiophene; benzo[c]thiophene; benzoxazole; benzisoxazole; benzimidazole; benzothiazole; indole; isoindole; indazole; purine; anthracene; and phenanthrene. The agreement with the limited experimental data is very satisfactory, with saturated liquid densities and vapor pressures reproduced to within 1.5% and 15%, respectively. The mean unsigned percentage errors in the normal boiling points, critical temperatures, and critical densities are 0.9%, 1.2%, and 1.4%, respectively. Additional simulations were carried out for binary systems of benzene/benzonitrile, benzene/phenol, and naphthalene/methanol to illustrate the transferability of the developed potentials to binary systems containing compounds of different polarity and hydrogen-bonding ability. A detailed analysis of the liquid-phase structures is provided for selected neat systems and binary mixtures. 23159732 The specific interaction of the photosensitizer methylene blue with acetylcholinesterase provides a model system for studying the molecular consequences of photodynamic therapy. The photosensitizer, methylene blue (MB), generates singlet oxygen ((1)O2) that irreversibly inhibits Torpedo californica acetylcholinesterase (TcAChE). In the dark MB inhibits reversibly, binding being accompanied by a bathochromic shift that can be used to show its displacement by other reversible inhibitors binding to the catalytic 'anionic' subsite (CAS), the peripheral 'anionic' subsite (PAS), or bridging them. Data concerning both reversible and irreversible inhibition are here reviewed. MB protects TcAChE from thermal denaturation, and differential scanning calorimetry reveals a ∼8°C increase in the denaturation temperature. The crystal structure of the MB/TcAChE complex reveals a single MB stacked against W279 in the PAS, pointing down the gorge towards the CAS. The intrinsic fluorescence of the irreversibly inhibited enzyme displays new emission bands that can be ascribed to N'-formylkynurenine (NFK); this was indeed confirmed using anti-NFK antibodies. Mass spectroscopy revealed that two Trp residues, Trp84 in the CAS, and Trp279 in the PAS, were the only Trp residues, out of a total of 14, significantly modified by photo-oxidation, both being converted to NFK. In the presence of competitive inhibitors that displace MB from the gorge, their modification is completely prevented. Thus, photo-oxidative damage caused by MB involves targeted release of (1)O2 by the bound photosensitizer within the aqueous milieu of the active-site gorge. 23261820 The effect of triclosan on the uterotrophic response to extended doses of ethinyl estradiol in the weanling rat. Triclosan (TCS), an antibacterial, has been shown to be an endocrine disruptor in the rat. We reported previously that TCS potentiated the estrogenic effect of ethinyl estradiol (EE) on uterine growth in rats exposed to EE and TCS in the uterotrophic assay, whereas TCS alone had no effect. To further characterize this potentiation, we evaluated the effect of co-exposure with lower doses of EE that are comparable to the concentrations in hormone replacement regimens and began to assess the mechanisms by which this potentiation occurs. Changes in uterine weight, epithelial cell growth, and estrogen-sensitive gene expression were assessed. TCS expectedly enhanced the uterotrophic response to EE, however at significantly lower doses of EE. Similarly, TCS increased the EE-induced stimulation of epithelial cell height following cotreatment. Cotreatment also enhanced the estrogen-induced change in gene expression, which was reversed with an ER antagonist. Furthermore, the TCS-induced potentiation was independent of ER activation, as no effects were observed in the ER TA assay. 23601391 Progress with a global branded food composition database. Excess energy, saturated fat, sugar and salt from processed and fast foods are a major cause of chronic disease worldwide. In 2010 The Food Monitoring Group established a global branded food composition database to track the nutritional content of foods and make comparisons between countries, food companies and over time. A protocol for the project was agreed and published in 2011 with 24 collaborating countries. Standardised tools and a website have been developed to facilitate data collection and entry. In 2010 data were obtained from nine countries, in 2011 from 12 and in 2012 data are anticipated from 10 additional countries. This collaborative approach to the collation of food composition data offers potential for cross-border collaboration and support in developed and developing countries. The project should contribute significantly to tracking progress of the food industry and governments towards commitments made at the recent UN high level meeting on chronic disease. 22732443 Hippocampal long-term depression mediates spatial reversal learning in the Morris water maze. Synaptic plasticity at hippocampal excitatory synapses has been proposed as the cellular mechanism underlying spatial learning and memory. However, most previous studies have focused on the role of long-term potentiation (LTP) in learning and memory, and much less is known about the role of long-term depression (LTD). Here, we report that hippocampal-dependent spatial learning in the Morris water maze facilitated hippocampal CA1 LTD induction in vivo. The LTD can be blocked by systemic application of the selective GluN2B antagonist Ro25-6981 (6 mg/kg, i.p.) or a synthetic peptide Tat-GluA2(3Y) (3 μmol/kg, i.p.) that interferes with the endocytosis of AMPA receptors. In addition, systemic or intrahippocampal administration of these two mechanistically and structurally distinct inhibitors impaired spatial reversal learning of a novel target location, when the hidden platform was moved to the quadrant opposite the initial target location. Notably, acute elevated-platform stress, which facilitates hippocampal LTD induction, enhanced both acquisition and retrieval of spatial reversal memory. The present study demonstrates that reversal learning is impaired by blocking hippocampal LTD, and enhanced by facilitating hippocampal LTD, suggesting that hippocampal LTD may be necessary and sufficient to mediate new information processing. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23592846 Using partial least squares regression to analyze cellular response data. This Teaching Resource provides lecture notes, slides, and a problem set for a lecture introducing the mathematical concepts and interpretation of partial least squares regression (PLSR) that were part of a course entitled "Systems Biology: Mammalian Signaling Networks." PLSR is a multivariate regression technique commonly applied to analyze relationships between signaling or transcriptional data and cellular behavior. 23178339 New approach to improve encapsulation and antitumor activity of doxorubicin loaded in solid lipid nanoparticles. This work aimed to develop solid lipid nanoparticles (SLNs) loaded with doxorubicin evaluating the influence of docosahexaenoic acid (DHA), a polyunsaturated fatty acid that enhances the activity of anticancer drugs, on drug encapsulation efficiency (EE). The SLN were characterized for size, zeta potential, entrapment efficiency (EE) and drug release. Studies of in vitro antitumor activity and cellular uptake were also conducted. The reduction in particle size (from 127 ± 14 to 94 ± 1 nm) and negative charges were obtained for SLN loaded with DHA and triethanolamine (TEA), amine used to increase the solubility of doxorubicin in melted lipid. The EE was significantly improved from 36 ± 4% to 99 ± 2% for SLN without and with DHA at 0.4%, respectively. The doxorubicin release in a slightly acid medium (pH 5.0) was higher than that observed at physiological pH. The in vitro studies clearly showed the higher cytotoxicity of doxorubicin-DHA-loaded SLN than free doxorubicin+DHA on human lung tumor cell line (A549) and the improved cellular uptake achieved with the drug encapsulation can be an explanation. These findings suggest that DHA-doxorubicin-loaded SLN is a promising alternative for the treatment of cancer. 22991330 Can peripheral blood γδ T cells predict osteonecrosis of the jaw? An immunological perspective on the adverse drug effects of aminobisphosphonate therapy. Nitrogen-bisphosphonates (n-BP), often referred to as aminobisphosphonates, are the most commonly prescribed drugs for the treatment of disorders of bone fragility. However, long-term continuous treatment predisposes certain individuals to serious rare side effects, such as bisphosphonate-associated osteonecrosis of the jaw (BAONJ). n-BP use is known to unintentionally activate a subset of innate T cells called Vγ9Vδ2 T cells, but the consequence of this chronic immune stimulation has remained unexplored. The primary objectives of this study were to 1) determine the fate of Vγ9Vδ2 T cells in osteoporotic patients on n-BP therapy as a function of time and type of therapy; 2) evaluate the proportion of Vγ9Vδ2 T cells in patients who had recently experienced n-BP-associated ONJ. We found there is a notable loss of Vγ9Vδ2 T cells over time in osteoporotic patients on n-BP therapy, particularly those on intravenous (iv) therapy (Spearman r = -0.55, p < 0.0001 iv; r = -0.3, p < 0.03 oral) (n = 68); no difference was observed in total T cells, monocytes, or granulocytes. Importantly, the observed negative effect on Vγ9Vδ2 T cells coincides with the reported route of administration and timing of the rare occurrence of BAONJ. Patients (n = 6) who had experienced BAONJ were all found to be significantly deficient in Vγ9Vδ2 T cells (median = 0.07%) in comparison to age- and sex-matched treatment-naïve controls (N = 11; median = 2.40%), U = 0, p = 0.001; this was the only consistent difference in the leukocytes assessed. All BAONJ cases had an underlying condition that further contributed to impaired immunity. We propose Vγ9Vδ2 T cells show a strong potential to serve as harbingers of possible adverse immune effects of n-BP therapy, particularly in those patients already having a compromised immune system as they may be most vulnerable to the development of conditions such as BAONJ. 23570914 Suppression of nuclear factor erythroid 2-related factor 2 via extracellular signal-regulated kinase contributes to bleomycin-induced oxidative stress and fibrogenesis. Pulmonary fibrosis is a serious and irreversible lung injury with obscure etiologic mechanisms and no effective treatment to date. This study explored a crucial link between oxidative stress and pulmonary fibrogenesis, focusing on nuclear factor erythroid 2-related factor 2 (Nrf2), a core transcription factor in antioxidative regulation systems. Treatment of C57 BL/6 mice with bleomycin increased fibroblast viability and collagen production and significantly downregulated Nrf2. In addition, prominent oxidative stress was indicated by changes in superoxide dismutase, catalase activity, and glutathione and thiobarbituric acid-reactive substance levels. In a cell-based model, bleomycin suppressed Nrf2 activation via extracellular signal-related kinase phosphorylation, enhancing intracellular reactive oxygen species in lung fibroblasts and stimulating abnormal cell proliferation and collagen secretion. To confirm this novel mechanism of bleomycin-induced fibrogenesis, we attempted to upregulate Nrf2 and related antioxidant proteins in bleomycin-treated fibroblasts using a putative Nrf2 activator, caffeic acid phenethyl ester, and the results showed that bleomycin-induced fibroblast proliferation and collagen content were attenuated through improved redox balance. Collectively, these results disclose a potential regulatory mechanism in pulmonary fibrosis that will aid the development of new therapies. 23517008 Surface topography effects in protein adsorption on nanostructured carbon allotropes. We report a molecular dynamics (MD) simulation study of protein adsorption on the surface of nanosized carbon allotropes, namely single-walled carbon nanotubes (SWNT) considering both the convex outer surface and the concave inner surface, together with a graphene sheet for comparison. These systems are chosen to investigate the effect of the surface curvature on protein adsorption at the same surface chemistry, given by sp(2) carbon atoms in all cases. The simulations show that proteins do favorably interact with these hydrophobic surfaces, as previously found on graphite which has the same chemical nature. However, the main finding of the present study is that the adsorption strength does depend on the surface topography: in particular, it is slightly weaker on the outer convex surfaces of SWNT and is conversely enhanced on the inner concave SWNT surface, being therefore intermediate for flat graphene. We additionally find that oligopeptides may enter the cavity of common SWNT, provided their size is small enough and the tube diameter is large enough for both entropic and energetic reasons. Therefore, we suggest that proteins can effectively be used to solubilize in water single-walled (and by analogy also multiwalled) carbon nanotubes through adsorption on the outer surface, as indeed experimentally found, and to functionalize them after insertion of oligopeptides within the cavity of nanotubes of appropriate size. 23315005 Epigenetic and small RNA regulation of senescence. Leaf senescence is regulated through a complex regulatory network triggered by internal and external signals for the reprogramming of gene expression. In plants, the major developmental phase transitions and stress responses are under epigenetic control. In this review, the underlying molecular mechanisms are briefly discussed and evidence is shown that epigenetic processes are also involved in the regulation of leaf senescence. Changes in the chromatin structure during senescence, differential histone modifications determining active and inactive sites at senescence-associated genes and DNA methylation are addressed. In addition, the role of small RNAs in senescence regulation is discussed. 23511783 It is important research, but why is it necessary? The findings regarding cardiovascular actions of dietary supplements labeled as "ephedra free" reported by Foster et al. in the March issue reaffirm decades of research that began in the 1920s with K.K. Chen's study of naturally occurring adrenergic chemicals. Although the study by Foster et al. provides scientifically sound data needed by the US Food and Drug Administration (FDA) as it evaluates the safety of these products, we should ask, "Why was it necessary that these chemicals be studied again for their cardiovascular actions in humans?" 23628605 Steroid hormone synthesis in mitochondria. Mitochondria are essential sites for steroid hormone biosynthesis. Mitochondria in the steroidogenic cells of the adrenal, gonad, placenta and brain contain the cholesterol side-chain cleavage enzyme, P450scc, and its two electron-transfer partners, ferredoxin reductase and ferredoxin. This enzyme system converts cholesterol to pregnenolone and determines net steroidogenic capacity, so that it serves as the chronic regulator of steroidogenesis. Several other steroidogenic enzymes, including 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase and aldosterone synthase also reside in mitochondria. Similarly, the mitochondria of renal tubular cells contain two key enzymes participating in the activation and degradation of vitamin D. The access of cholesterol to the mitochondria is regulated by the steroidogenic acute regulatory protein, StAR, serving as the acute regulator of steroidogenesis. StAR action requires a complex multi-component molecular machine on the outer mitochondrial membrane (OMM). Components of this machine include the 18kDa translocator protein (TSPO), the voltage-dependent anion chanel (VDAC-1), TSPO-associated protein 7 (PAP7, ACBD3), and protein kinase A regulatory subunit 1α (PKAR1A). The precise fashion in which these proteins interact and move cholesterol from the OMM to P450scc, and the means by which cholesterol is loaded into the OMM, remain unclear. Human deficiency diseases have been described for StAR and for all the mitochondrial steroidogenic enzymes, but not for the electron transfer proteins or for the components of the cholesterol import machine. 23424028 Bioavailability-based chronic toxicity measurements of permethrin to Chironomus dilutus. Compared with acute toxicity, chronic exposures to low levels of contaminants are more environmentally relevant, but fewer data are available. In the present study, sediment toxicity of the pyrethoid permethrin to Chironomus dilutus was determined. The whole-life-cycle toxicity testing was conducted with the endpoints covering survival, growth, emergence, and reproduction. Permethrin caused 50% lethality in C. dilutus at 1.83 ± 1.13 µg/g organic carbon (OC) and 1.20 ± 0.55 µg/g OC after exposures of 20 d (before pupation) and 58 d (the end of the testing), respectively. The 5% and median effect concentrations (EC5 and EC50) represented the marginal and toxic levels of the sublethal effects, respectively, and effect data were all normalized to the controls before Probit analysis. The EC5s for growth, emergence, and reproduction were 0.034 ± 0.006 µg/g OC, 0.016 ± 0.008 µg/g OC, and 0.009 ± 0.008 µg/g OC, respectively; the respective EC50s were 1.09 ± 0.56 µg/g OC, 0.838 ± 0.077 µg/g OC, and 0.039 ± 0.105 µg/g OC. In addition, a 24-h Tenax extraction was employed to better assess permethrin bioavailability. Ultimately, response spectra with a series of endpoints were developed for permethrin using either OC-normalized bulk sediment concentrations or bioavailability-based Tenax extractable concentrations as the dose metric. The development of bioavailability-based chronic toxicity endpoints for sediment-associated permethrin would provide valuable benchmarks for evaluating ecological risk of this contaminant and contributing to improve sediment management policies. Environ Toxicol Chem 2013;32:1403-1411. © 2013 SETAC. 23219725 Budding yeast Wapl controls sister chromatid cohesion maintenance and chromosome condensation. The establishment of stable sister chromatid cohesion during DNA replication requires acetylation of the chromosomal cohesin complex by the replication fork-associated acetyltransferase Eco1. Cohesin acetylation is thought to facilitate replication fork progression by counteracting an as yet ill-defined cohesion "antiestablishment" activity imposed by the Wapl protein. Here, using budding yeast, we find no evidence that cohesin acetylation must overcome Wapl during replication fork progression. Instead, Wapl emerges as a negative regulator of cohesion maintenance in G2, a function that it likely exerts through its role as destabilizer of unacetylated, chromosome-bound cohesin. Our results suggest that acetylation renders cohesin Wapl-resistant from S phase onward until mitosis. In the absence of Wapl, sister chromatid cohesion functions well, suggesting that Wapl partakes in a cohesin function outside of sister chromatid cohesion. We find that Wapl is not required for cohesin's known role in transcriptional regulation. Rather, cells lacking Wapl display increased chromosome condensation in both interphase and mitosis. Thus, as a conserved regulator of cohesin dynamics on chromosomes, Wapl controls cohesion maintenance after its establishment in S phase and adjusts the chromosome condensation status. 23565585 In vitro evaluation of the effects of various additives and polymers on nerve growth factor microspheres. Abstract Objective: To evaluate the effects of various additives or polymers on the in vitro characteristics of nerve growth factor (NGF) microspheres. Materials and methods: NGF microspheres were fabricated using polyethylene glycol (PEG), ovalbumin (OVA), bovine serum albumin (BSA) or glucose as protein protectors, and poly(lactide-co-glycolide) (PLGA) or poly(lactic acid) (PLA)/PLGA blends as encapsulation materials. Results: Encapsulation efficiencies of the NGF microspheres with various additives or polymers were not more than 30%. A comparative study revealed that OVA was somewhat superior over others, and was thus chosen as the protective additive in subsequent experiments. Polymer analysis showed that NGF release from 1:1 PLA (η = 0.8):PLGA (75/25, η = 0.45) microspheres lasted for 90 d with a burst release rate of 12.7%. About 40% of the original bioactivity was retained on the 28th day, while 10% was left on the 90th day. Discussion and conclusion: The combination of OVA as an additive and the PLA/PLGA blend as the coating matrix is suitable for encapsulation of NGF in microspheres for extended release. 23643745 Pharmacological and genetic evidence for pre- and postsynaptic D2 receptor involvement in motor responses to nociceptin/orphanin FQ receptor ligands. A combined pharmacological and genetic approach was undertaken to investigate the contribution of endogenous dopamine to the motor actions of nociceptin/orphanin FQ (N/OFQ) receptor (NOP receptor) ligands. Motor activity was evaluated by a battery of behavioural tests in mice. The involvement of the various DA receptor subtypes in the motor effects of N/OFQ and NOP receptor antagonists was evaluated pharmacologically, using D1/D5 (SCH23390), D2/D3 (raclopride, amisulpride) and D3 (S33084) receptor antagonists, and by using D2 receptor knockout mice. Low doses of N/OFQ and NOP receptor antagonists promoted movement whereas higher doses inhibited it. Motor facilitation was selectively prevented by raclopride while motor inhibition was prevented by amisulpride. Amisulpride also attenuated the hypolocomotion induced by the D2/D3 receptor agonist pramipexole and dopamine precursor L-3,4-dihydroxyphenylalanine, whereas raclopride (and S33084) worsened it. To dissect out the contribution of pre- and postsynaptic D2 receptors, mice lacking the D2 receptor (D2R(-/-)) or its long isoform (D2L(-/-)) were used. Motor facilitation induced by N/OFQ and NOP receptor antagonists was lost in D2R(-/-) and D2L(-/-) mice whereas motor inhibition induced by NOP receptor antagonists (and pramipexole) was lost in D2R(-/-) but preserved in D2L(-/-) mice. N/OFQ-induced hypolocomotion was observed in both genotypes. We demonstrate that motor actions of NOP receptor ligands rely on the modulation of endogenous dopamine. Motor facilitation induced by NOP receptor antagonists as well as low dose N/OFQ is mediated through D2L postsynaptic receptors whereas motor inhibition observed with higher doses of N/OFQ occurs by direct inhibition of mesencephalic DA neurons. Motor inhibition seen with high doses of NOP receptor antagonists appears to be mediated through the D2 presynaptic autoreceptors. These data confirm that endogenous N/OFQ is a powerful modulator of dopamine transmission in vivo and that the effects of NOP receptor antagonists on motor function reflect the blockade of this endogenous N/OFQ tone. 23333834 RANKL targeted peptides inhibit osteoclastogenesis and attenuate adjuvant induced arthritis by inhibiting NF-κB activation and down regulating inflammatory cytokines. Peptides designed from osteoprotegerin (OPG) have previously been shown to inhibit receptor activator of NF-κB ligand (RANKL) and prevent bone loss without significantly inhibiting inflammation. The objective of this study was to develop a novel peptide with dual inhibitory activity against bone loss and inflammation using site-directed mutagenesis. Out of the three putative sites (i.e., Tyr70-Asp78, Tyr82-Glu96, and Leu113-Arg122) available on OPG for RANKL binding, Leu113-Arg122 was used as a template for peptide synthesis. Peptide mutants of the template sequence (112YLEIEFCLKHR122) were synthesized and initially screened for their inhibitory effect on RANK-RANKL binding by competitive ELISA. The most active peptide was further evaluated in vitro for RANKL induced osteoclastogenesis in mouse macrophage cells, and in vivo for Freund's complete adjuvant induced arthritis (AIA) in Lewis rats. The efficacy of the candidate peptide was compared with that of the standard drug celecoxib. The peptide YR-11 (YLEIEFSLKHR), obtained by direct substitution of cysteine with a serine residue in the template sequence, significantly (p<0.05) inhibited RANK-RANKL binding, and RANKL induced TRAP activity and formation of multinucleated osteoclasts without any cytotoxicity. Administration of YR-11 peptide at the dose of 30mg/kg (i.p.) ameliorated both bone loss and inflammation in AIA rats. To elucidate the mechanism for inhibition of inflammation in arthritic rats, serum and tissue cytokines (TNF-α, IL-1β, and IL-6) were analyzed by ELISA and RT-PCR methods. Results confirmed that YR-11 peptide inhibited pro-inflammatory cytokines in the sera and hind paw tissues of AIA rats through its suppressive effect on RANKL induced nuclear translocation of NF-κB. The results obtained in this study substantiate the therapeutic benefit of this novel peptide in the prevention of bone loss and inflammation in rheumatoid arthritis with reduced side effects. 23542652 The effects of 17-α-ethinylestradiol (EE2) on molecular signaling cascades in mummichog (Fundulus heteroclitus). Exposures to ≤10ng/L of 17-α-ethinylestradiol (EE2) will reduce or shut down egg production in freshwater fish models, while mummichog (Fundulus heteroclitus), an estuarine species, are able to produce eggs at EE2 concentrations >3000ng/L. The objective of this study was to gain mechanistic insight into how mummichog are able to produce eggs during exposures to high EE2. Mummichog were exposed to 0, 50 or 250ng/L of EE2 for 14d. There were no changes in gonadosomatic index, liversomatic index, gonad development, or plasma estradiol levels after exposure to EE2. However, testosterone significantly decreased with EE2 exposures (50, 250ng/L). Microarray analysis in the liver revealed that cell processes associated with lipids were affected by EE2 at the transcriptome level. Based on the transcriptomics data, we hypothesize that mummichog are able to maintain lipid transport and uptake into the ovary and this may be associated with apolipoproteins, facilitating normal oocyte development. Novel gene regulatory networks for protein modification targets were also constructed to learn more about the potential roles of estrogens in the teleost liver. Although post-translational modifications (PTMs) are important regulatory mechanisms, the roles of PTMs in protein regulation in fish and the susceptibility of PTMs to aquatic pollutants are largely unexplored and may offer novel insight into mechanisms of endocrine disruption. 23609770 Acquisition of responding with a remifentanil-associated conditioned reinforcer in the rat. RATIONALE: Drug-associated environmental stimuli may serve as conditioned reinforcers to enhance drug self-administration behaviors in humans and laboratory animals. However, it can be difficult to distinguish experimentally the conditioned reinforcing effects of a stimulus from other behavioral processes that can change rates of responding. OBJECTIVES: To characterize the conditioned reinforcing effects of a stimulus paired with the μ-opioid agonist, remifentanil, using a new-response acquisition procedure in the rat. METHODS: First, in Pavlovian conditioning (PAV) sessions, rats received response-independent IV injections of remifentanil and presentations of a light-noise compound stimulus. In paired PAV groups, injections and stimulus presentations always co-occurred. In random PAV control groups, injections and stimulus presentations occurred with no consistent relationship. Second, in instrumental acquisition (ACQ) sessions, all animals could respond in an active nose-poke that produced the stimulus alone or in an inactive nose-poke that had no scheduled consequences. RESULTS: During ACQ, rats made significantly more active nose-pokes than inactive nose-pokes after paired PAV, but not after random PAV. Between groups, rats also made more active nose-pokes after paired PAV than after random PAV. After paired PAV, increased active responding was obtained under different schedules of reinforcement, persisted across multiple ACQ sessions, and depended on the number of PAV sessions conducted. CONCLUSIONS: The remifentanil-paired stimulus served as a conditioned reinforcer for nose-poking: responding depended on both the contingency between the stimulus and remifentanil and the contingency between the nose-poke and the stimulus. Generally, new-response acquisition procedures may provide valid, flexible models for studying opioid-based conditioned reinforcement. 23325530 Diclofenac: New data on chronic toxicity and bioconcentration in fish. Diclofenac (DCF) is a widely used nonsteroidal anti-inflammatory drug that is regularly detected in surface waters. To support a robust aquatic risk assessment, two early life stage (ELS) tests, compliant with the Organisation for Economic Co-operation and Development (OECD) test guideline 210, were conducted in rainbow trout and in zebrafish. Population relevant endpoints, such as hatching, growth, and survival, and in the trout study, histopathological effects in potential target organs, were examined. The bioconcentration of DCF in rainbow trout was measured in a separate study according to OECD test guideline 305. The bioconcentration factor (BCF) in rainbow trout remained below 10, demonstrating no relevant bioconcentration of DCF in fish. In the rainbow trout ELS test, the no observed effect concentration (NOEC) including histopathology was 320 µg/L. The effect of DCF on zebrafish growth was less clear, and the NOEC can be interpreted as 10 µg/L. However, for a number of reasons, the authors consider the moderately reduced growth of zebrafish exposed to concentrations of up to 320 µg/L not a repeatable, treatment-related effect of DCF. This leads us to a conclusion that DCF has, with high probability, no adverse effect on both fish species up to 320 µg/L. This NOEC indicates a sufficient safety margin for fish populations, because concentrations of DCF in European rivers are in the range of ng/L to low µg/L. 22712621 Bearberry identification by a multidisciplinary study on commercial raw materials. Herbal species different from the official bearberry, Arctostaphylos uva-ursi, are sold through conventional markets and also through non-controlled Internet websites, putting consumer safety at risk owing to the lack of quality control. Recently, Arctostaphylos pungens has become one of the most used species as a raw material for herbal medicines and dietary supplements in the place of official bearberry, a plant used for the treatment of various urinary disorders. A fingerprint identification based on an integrated application of different analytical techniques (HPTLC, NMR, HPLC-DAD and LC-ESI-MS) is here described to distinguish A. uva-ursi from A. pungens. The HPTLC and HPLC-DAD fingerprints resulted the simplest methods to differentiate the two species, whereas LC-ESI-MS was more useful to quantify arbutin, the main component of bearberry, and to evaluate its different content in the two species. This multidisciplinary study showed for the first time a specific phytochemical fingerprint of the new species A. pungens. 23561176 Effect of flavonoid structure on the fluidity of model lipid membranes. We investigated how the structural properties of (+)-catechin, (-)-epicatechin, (-)-epigallocatechin (EGC) and (-)-epigallocatechin-3-gallate (EGCG) and butylated hydroxytoluene (BHT) correlate with structural changes of phosphatidylcholine plus sphingomyelin (2.4:1) model lipid membranes. Changes were measured by fluorescence anisotropy, electron paramagnetic resonance, and differential scanning calorimetry. Two fluorophores and two spin probes were used to monitor membrane characteristics close to water-lipid interface and in the middle of the bilayer. The data obtained were correlated to the amount of bounded compounds, the number of H-bonds, and the topological polar surface area (TPSA) of the compounds. These correlations reflect the behaviours of (+)-catechin, (-)-epicatechin, EGC, EGCG and BHT. Our results confirm that phenolics studied here are bounded to a membrane surface predominantly via hydrogen bonds, while BTH is inserted into the lipid bilayer. 23539511 Cardiac natriuretic Peptide gene expression and plasma concentrations during the first 72 hours of life in piglets. Plasma measurement of cardiac natriuretic peptides constitutes promising markers of congenital heart disease. However, concentrations change rapidly and dramatically during the first days after delivery even in healthy neonates, which complicates clinical interpretation. It is unknown whether these changes in plasma concentrations are explained by corresponding changes in the cardiac gene expression. We quantified the chamber-specific mRNA levels of ANP (A-type natriuretic peptide) and BNP (B-type natriuretic peptide) and plasma pro-ANP and BNP-32 concentrations in healthy piglets during the first 72 hours of life (from 2 litters, n = 44). Chamber-specific ANP and BNP mRNA levels reflected hemodynamic neonate changes at birth but did not correlate with circulating natriuretic peptide concentrations. However, plasma pro-ANP and creatinine concentrations were closely correlated (P < .0001; r = 0.73). Plasma pro-ANP levels were highest on the day of delivery (5580 pmol/L [4320-6786] decreasing to 2484 pmol/L [1602-2898] after 72 hours, P < .0001). During the 72 hours, gel chromatography suggested that the translational products in circulation and in atrial tissue were immature, ie, unprocessed pro-ANP. In contrast to pro-ANP, BNP-32 plasma concentrations were low at delivery and peaked after 48 hours (12 [10.5-20.6] vs. 88.8 [71.7-101.4] pmol/L, P < .0001). To conclude, ANP and BNP gene expression differs considerably between cardiac chambers in the first 72 hours of life in healthy piglets, resembling the transition from fetal to neonate circulation. However, the cardiac gene expression does not explain plasma concentrations. 23122118 CODEX-compliant eleven organophosphorus pesticides screening in multiple commodities using headspace-solid phase microextraction-gas chromatography-mass spectrometry. A headspace-solid phase microextraction-gas chromatography-mass spectrometric (HS-SPME-GC-MS, hereafter abbreviated as "SPME") method was developed for dedicated organophosphorus (OP) pesticides assessment in multiple vegetable and fruit commodities. Specific extraction variables were optimised to achieve harmonised extraction performance of eleven OPs in a great span of seven characteristic commodities cataloged in Codex Alimentarius Commission. Comprehensive validation study confirmed analytical robustness of the SPME treatment in turnip, green cabbage, French beans, eggplant, apple, nectarine and grapes. Based on range-specific evaluation, extraction of individual OPs was characterised by sub-ppb level sensitivity and a wide 0.01-2.5 mg L(-1) dynamic range. Effective sample clean-up afforded precise quantification (0.5-10.9% R.S.D.) within a 70-120% recovery range at the MRL levels specified for individual commodities. Compared to conventional methods currently used, the SPME treatment developed here is quick, accurate, and relatively environmental friendly; it represents an attractive, practical way to deliver international standards in OP screening routines. 23567242 Bisphenol A: Update on newly developed data and how they address NTP's 2008 finding of "Some Concern" Bisphenol A (BPA) is a component of polycarbonate plastics and epoxy resins used in many commercial products including coatings and liners of food containers. Low levels of BPA can be detected in over 90% of human urine samples in the US, indicating that exposure to BPA is widespread. In 2008, the US National Toxicology Program's Center for the Evaluation of Risks to Human Reproduction (NTP-CERHR) expressed concerns regarding BPA's potential health effects, and suggested improved study designs and methodologies that they believed would address those concerns. This paper discusses some of the controversial issues surrounding BPA, summarizes the current regulatory status of BPA, reviews recent pharmacokinetic studies, and describes ongoing and planned research on the effects of BPA. In addition, we evaluate two papers studying BPA neurobehavioral effects, identified by the European Food Safety Authority and the German Federal Institute for Risk Assessment as being valid for use in risk assessment, to determine whether they address the NTP-CERHR methodological concerns. The data from these studies would likely be sufficient for NTP to lower its concern level for neurobehavioral effects of BPA. At this time, many regulatory agencies from around the world support the use of BPA in food contact materials. 23249244 Multifaceted ultrafast intramolecular charge transfer dynamics of 4-(dimethylamino)benzonitrile (DMABN). Intramolecular charge transfer (ICT) of DMABN has been the subject of extensive investigations. Through the measurements of highly time-resolved fluorescence spectra (TRFS) over the whole emission region, we have examined the ICT dynamics of DMABN in acetonitrile free from the solvation dynamics and vibronic relaxation. The ICT dynamics was found to be characterized by a broad range of time scales; nearly instantaneous (<30 fs), 160 fs, and 3.3 ps. TRFS revealed that an ICT state with partially twisted geometry, ICT(P), is formed within a few hundred femtoseconds either directly from the initial photoexcited state or via the locally excited (LE) state. The ICT(P) state undergoes further relaxation along the intramolecular nuclear coordinate to reach the twisted ICT (TICT) state with the time constant of 4.8 ps. A conformational diversity along the rotation of the dimethylamino group was speculated to account for the observed diffusive dynamics. 23578968 Evaluation of a predictive in vitro Leydig cell assay for anti-androgenicity of phthalate esters in the rat. An in vitro assay using the rat Leydig cell line R2C was evaluated for its ability to quantitatively predict inhibition of testosterone synthesis. Results obtained for endocrine active phthalates (MEHP, MBP), and inactive phthalates (MMP and MEP) were highly consistent with in vivo results based on tissue and media concentrations. Statistically significant inhibition of testosterone synthesis (p<0.05, 1-way ANOVA) was observed at 1μM MBP and 3μM MEHP, while MEP and MMP did not affect inhibition of testosterone synthesis until much higher concentrations (≫100μM). Concentrations causing 50% inhibition of testosterone synthesis for MBP and MEHP (3 and 6μM respectively), were similar to in vivo values (3 and 7μM). The R2C assay was used to determine the relative potency of 14 structurally diverse monoesters and oxidative metabolites of MEHP. Monoesters with alkyl chains 4-5 carbons in length had the highest potency for testosterone inhibition, while 0-2 carbon alkyl chains were least potent. Phase I metabolism did not completely inactivate MEHP, underscoring the need for metabolism data when interpreting in vitro pharmacodynamic data. This steroid inhibition assay provides a predictive in vitro alternative to expensive and timeconsuming developmental rat studies for phthalate-induced antiandrogenicity. 22360797 Chemical constituents of the hemiparasitic plant Phoradendron brachystachyum DC Nutt (Viscaceae). Phoradendron brachystachyum is a hemiparasitic plant widely distributed in México that belongs to the Viscaceae family. It has been commonly used in folk medicine as a substitute for the European mistletoe. In this chemical study, morolic acid was isolated as the major component (47.54% of the total composition of acetone extract) of this plant. In addition, 19 known compounds were identified: β-sitosteryl and stigmasteryl linoleates, β-sitosterol, stigmasterol, triacontanol, squalene, α- and β-amyrin, lupeol, lupenone, betulin aldehyde, betulon aldehyde, oleanolic aldehyde, betulinic acid, betulonic acid, moronic acid, morolic acid, oleanolic acid, flavonoids acacetin and acacetin 7-methyl ether. There have been no previous reports in the literature on the chemical composition of this potential natural source of hypoglycaemic and antihypertensive compounds. 23643725 The use of antioxidant enzymes in freshwater biofilms: Temporal variability vs. toxicological responses. This study aims to investigate the potential of antioxidant enzyme activities (AEA) as biomarkers of oxidative stress in freshwater biofilms. Therefore, biofilms were grown in channels for 38 days and then exposed to different concentrations (0-150μgL(-1)) of the herbicide oxyfluorfen for 5 more weeks. Under control conditions, the AEA of biofilms were found to change throughout time with a significant increase in ascorbate peroxidase (APX) activity during the exponential growth and a more important role of catalase (CAT) and glutathione reductase (GR) activities during the slow growth phase. Chronic exposure to oxyfluorfen led to slight variations in AEA, however, the ranges of variability of AEA in controls and exposed communities were similar, highlighting the difficulty of a direct interpretation of AEA values. After 5 weeks of exposure to oxyfluorfen, no clear effects were observed on chl-a concentration or on the composition of other pigments suggesting that algal group composition was not affected. Eukaryotic communities were structured clearly by toxicant concentration and both eukaryotic and bacterial richness were reduced in communities exposed to the highest concentration. In addition, during acute exposure tests performed at the end of the chronic exposure, biofilms chronically exposed to 75 and 150μgL(-1) oxyfluorfen showed a higher CAT activity than controls. Chronic exposure to oxyfluorfen provoked then structural changes but also functional changes in the capacity of biofilm CAT activity to respond to a sudden increase in concentration, suggesting a selection of species with higher antioxidant capacity. This study highlighted the difficulty of interpretation of AEA values due to their temporal variation and to the absence of absolute threshold value indicative of oxidative stress induced by contaminants. Nevertheless, the determination of AEA pattern throughout acute exposure test is of high interest to compare oxidative stress levels undergone by different biofilm communities and thus determine their antioxidant capacity. 23455593 Neural substrates of acupuncture in the modulation of cravings induced by smoking-related visual cues: an FMRI study. RATIONALE: Cue reactivity is a key factor in modulating motivational and goal-directed behaviors associated with compulsive drug intake and relapse. Smoking-associated cues produce smoking urges and cravings and are accompanied by the activation of brain regions involved in attention, motivation, and reward. OBJECTIVES: We investigated whether acupuncture ameliorates cravings induced by smoking-related visual cues, and we explored the neural mechanisms underlying the effects of acupuncture on modulating smoking urges. METHODS: After 36 h of smoking abstinence, 25 right-handed male smokers underwent fMRI, during which smoking-related and neutral visual cues were presented. Twelve subjects were treated with real acupuncture (RA) at HT7 and 13 subjects received sham acupuncture (SA). During the scanning sessions, craving scores to smoking-related visual cues were assessed before and after RA or SA treatment. The differences in brain responses to smoking vs. neutral cues after treatment between the RA and SA groups were detected using three-way ANOVAs (Cue × Session × Group). RESULTS: After treatment, the craving scores were significantly decreased in the RA group, as compared to the SA group. When we explored the neural substrates of acupuncture on the modulation of cravings induced by smoking cues, significant differences were found in the medial prefrontal cortex, the premotor cortex, the amygdala, the hippocampus, and the thalamus. CONCLUSIONS: These findings suggest that acupuncture alleviates cue-induced cravings through the regulation of activity in brain regions involved in attention, motivation, and reward relative to craving scores in the initial abstinence phase. 23493317 PDE3 and PDE4 isozyme selective inhibitors are both required for synergistic activation of brown adipose tissue. Brown adipose tissue (BAT) is a highly thermogenic organ that converts lipids and glucose into heat. Many of the metabolic and gene transcriptional hallmarks of BAT activation, namely increased lipolysis, uncoupling protein-1 (UCP1) mRNA, and glucose uptake are regulated by the adrenergic second messenger, adenosine-3',5'-cyclic monophosphate (cAMP). Cyclic nucleotide phosphodiesterases (PDEs) catalyze the breakdown of cAMP, thereby regulating the magnitude and duration of this signaling molecule. In the absence of adrenergic stimulus, we found that it required a combination of a PDE3 and a PDE4 inhibitor to fully induce UCP1 mRNA and lipolysis in brown adipocytes, whereas neither PDE inhibitor alone had any substantial effect under basal conditions. Under submaximal β-adrenoceptor stimulation of brown adipocytes, a PDE3 inhibitor alone could potentiate induction of UCP1 mRNA, while a PDE4 inhibitor alone could augment lipolysis, indicating differential roles for each of these two PDEs. Neither induction of UCP1 nor lipolysis was altered by inhibition of PDE1, PDE2 or PDE8A. Finally, when injected into mice, the combination of PDE3 and PDE4 inhibitors stimulated glucose uptake in BAT under thermoneutral and fasted conditions, a response that was further potentiated by the global ablation of PDE8A. Taken together, these data illustrate that multiple PDEs work in concert to regulate three of the important pathways leading to BAT activation, a finding that may provide an improved conceptual basis for the development of therapies for obesity-related diseases. 23541948 Signaling pathways mediating the effects of insulin-like growth factor-I in bovine muscle satellite cells. The objective of this study was to identify the signaling pathways mediating the effects of IGF-I on muscle cell proliferation, protein synthesis, and protein degradation in a physiologically more relevant muscle cell model. We isolated muscle satellite cells from adult cattle and expanded them as myoblasts or induced them to form myotubes in culture. We determined the effects of IGF-I on proliferation of myoblasts and protein synthesis and degradation in myotubes in the presence or absence of specific signaling inhibitors. Our data suggest that both the MEK/ERK and PI3K/AKT pathways mediate the stimulatory effect of IGF-I on myoblast proliferation and that the PI3K/AKT pathway mediates this effect through cyclin D2. Our data also suggest that both the MEK/ERK and PI3K/AKT pathways mediate the stimulatory effect of IGF-I on protein synthesis through p70S6K and that the PI3K/AKT pathway mediates the inhibitory effect of IGF-I on protein degradation through FoxO3a. 23561139 Chemical profile and sensory properties of different foods cooked by a new radiofrequency oven. Radio frequency (RF) heating has been used for numerous applications in the food industry such as baking, thawing or pasteurisation. It reduces cooking time, and it helps to retain acceptable food colour and texture. In this paper, chemical and sensory data obtained from broccoli, potatoes, salmon and cocoa cakes cooked using an innovative RF oven were reported. The oven has an algorithm able to monitor the energy feedback from the cavity and to adjust the energy output accordingly. The different foods were cooked to the same end point and the concentration of phytochemicals, vitamins and acrylamide were assessed. Results demonstrated that RF oven preserved ascorbic acid and increased glucosinolates concentration in broccoli and it decreased the formation of acrylamide in roasted potatoes more than 50%. The total amount of vitamins B was 30% and 50% higher in RF cooked salmon than conventionally cooked salmon prepared at 55 and 75°C, respectively. 23320931 Reversible recruitment and emission of DO3A-derived lanthanide complexes at ligating molecular films on gold. The recruitment of DO3A-derived lanthanide complexes by ligation to isophthalic acid and catechol-modified gold surfaces, and their resulting sensitization, is reported herein. Predictably pH-dependent surface recruitment is associated with the expected fingerprint europium and terbium emission characteristics. The intensity of the lanthanide luminescence scales exponentially with spacer length, indicating a strong quenching interaction between the lanthanide and the gold surface. The switchable catechol oxidation state provides a means of electrochemically triggering the release of prior ligated complexes. 23164931 The perirhinal cortex of rats: an intricate area for microinfusion of anticonvulsants against soman-induced seizures. Microinfusion of anticonvulsants into the perirhinal cortex through 1 guide cannula in each hemisphere only invades a small area of this seizure controlling site in rats exposed to soman. The purpose of the present study was to examine whether infusions made through 2 cannulas in each perirhinal cortex may produce more efficacious anticonvulsant action against soman intoxication than the use of 1 cannula only in rats infused with the ionotropic antagonists procyclidine and caramiphen or the metabotropic glutamate modulators DCG-IV and MPEP. The results showed that the mere presence of indwelling double cannulas caused proconvulsant effect in response to subsequent systemic administration of soman. Both the control and caramiphen groups with double cannulas had significantly shorter latencies to seizure onset than the corresponding groups with single cannula. Procyclidine resulted in anticonvulsant efficacy, even in rats with double cannulas. In rats that received twin infusions of DCG-IV or MPEP, the anticonvulsant impact was very high, inasmuch as a majority of the rats in each group was protected against seizure activity. Drugs possessing powerful anticonvulsant potency can apparently counteract the proconvulsant effect of double cannulas, and some can even gain enhanced anticonvulsant capacity when invading a larger area of the perirhinal cortex. Perirhinal EEG recordings (electrodes in indwelling cannulas) in a separate set of rats not exposed to soman or drugs showed no differences in basal electrical activity (total power 0.5-25Hz or the theta band 4-12Hz) between groups with single or double cannulas. The intrinsic excitability and synaptic connectivity of the perirhinal cortex may be associated with the proconvulsant impact observed in rats with double cannulas when exposed to soman. 23271737 Molecular mechanism by which a potent hepatitis C virus NS3-NS4A protease inhibitor overcomes emergence of resistance. Although optimizing the resistance profile of an inhibitor can be challenging, it is potentially important for improving the long term effectiveness of antiviral therapy. This work describes our rational approach toward the identification of a macrocyclic acylsulfonamide that is a potent inhibitor of the NS3-NS4A proteases of all hepatitis C virus genotypes and of a panel of genotype 1-resistant variants. The enhanced potency of this compound versus variants D168V and R155K facilitated x-ray determination of the inhibitor-variant complexes. In turn, these structural studies revealed a complex molecular basis of resistance and rationalized how such compounds are able to circumvent these mechanisms. 23486635 Two Dimensional Window Exchange Umbrella Sampling for Transmembrane Helix Assembly. The method of window exchange umbrella sampling molecular dynamics (WEUSMD) with a pre-optimized parameter set was recently used to obtain the most probable conformations and the energetics of transmembrane (TM) helix assembly of a generic TM sequence. When applied to glycophorin A TM domain (GpA-TM) using the restraint potentials along the helix-helix distance, however, tight interfacial packing of GpA-TM resulted in insufficient conformational sampling at short helix-helix separation. This sampling issue is addressed by extending the WEUSMD into two dimensions with the restraint potentials along the helix-helix distance and crossing angle. The two-dimensional WEUSMD results demonstrate that the incomplete sampling in the one-dimensional WEUSMD arises from high barriers along the crossing angle between the GpA-TM helices. Together with the faster convergence in both the assembled conformations and the potential of mean force, the 2D-WEUSMD can be a general and efficient approach in computational studies of TM helix assembly. 23526919 Phospholipid/Carbocyanine Dye-Shelled Microbubbles as Ultrasound-Modulated Fluorescent Contrast Agents. Fluorescent microbubbles have been fabricated with the capacity to have their emission modulated by ultrasound. These contrast agent particles could potentially be used in the future to extract fluorescence modulation from a strong light background to increase imaging depth and resolution in scattering media. Fluorescence intensity modulation was demonstrated at the ultrasound driving frequency. 23425273 Clinical development of biosimilars: an evolving landscape. Biosimilars, or similar biological medicinal products, can provide a meaningful option for patients and physicians provided they deliver the therapeutic value of a reference product at a more modest cost. Unlike generic small-molecule drugs that require primarily the demonstration of pharmaceutical equivalence, the complex nature of protein therapeutics warrants a rigorous evaluation of both pharmaceutical and therapeutic equivalence to the reference product in an abbreviated clinical program. Furthermore, the lack of comprehensive structure-activity relationship data increases the burden on appropriately designed human clinical studies with predefined acceptance criteria to demonstrate the absence of clinically meaningful differences between the biosimilar and reference product. Although a number of biosimilar proteins have been approved, especially in Europe, issues on substitutability, extrapolation to other disease indications, and selection of reference standards and comparators, remains to be standardized at a global level. 23462666 Significant Coronary Stenosis in Asymptomatic Chinese With Different Glycemic Status. OBJECTIVE To evaluate coronary artery stenosis in early diabetes or prediabetes asymptomatic of myocardial ischemia in community-dwelling Chinese adults.RESEARCH DESIGN AND METHODS Age- and sex-matched participants with normal glucose regulation (NGR), prediabetes, or diabetes diagnosed within 5 years, asymptomatic of coronary artery disease (CAD), were randomly selected from a community-dwelling Chinese population aged 40-60 years. Dual-source computed tomography coronary angiography was used to evaluate the existence and extent of coronary stenosis, which was considered significant if >50% narrowing of vessel lumen was detected.RESULTS After excluding uninterpretable segments attributable to motion artifacts, a total of 135 participants with NGR, 132 with prediabetes, and 134 with diabetes participated in data analysis. Significant coronary stenosis was detected in 10 (7.4%), 10 (7.6%), and 22 (16.4%) individuals with NGR, prediabetes, and diabetes, respectively (P for trend = 0.029). Diabetes, rather than prediabetes, was associated with a significant 2.34-fold elevated risk [odds ratio (OR) 2.34 (95% CI 1.01-5.43); P = 0.047] of significant coronary stenosis as compared with that associated with NGR. Levels of glucose evaluation were independently and significantly associated with risks of significant coronary stenosis in diabetes. Each 1-SD increase in fasting plasma glucose, 2-h postload plasma glucose, and HbA1c conveyed 2.11-fold, 1.73-fold, and 1.81-fold higher risks of significant coronary stenosis, respectively, after adjustment for other conventional cardiovascular risk factors.CONCLUSIONSUsing a noninvasive CAD diagnostic modality such as dual-source computed tomography coronary angiography, we detected a markedly elevated risk of significant coronary stenosis with early diabetes in asymptomatic Chinese adults. 22849656 NT, NPY and PGP 9.5 presence in myomeytrium and in fibroid pseudocapsule and their possible impact on muscular physiology. The uterine myoma pseudocapsule is a neurovascular bundle surrounding fibroid, containing neuropeptides, probably involved in uterine scar healing. We studied neurotensin (NT), neuropeptide tyrosine (NPY), and protein gene product 9.5 (PGP 9.5) nerve fibres in the pseudocapsule neurovascular bundle of intramural uterine fibroids on 67 no pregnant women by intracapsular myomectomy sparing the neurovascular bundle, sampling full thickness specimens of the pseudocapsule of uterine fibroids (PUF) and normal myometrium (NM) obtained from the fundus uteri (FU) and the uterine body (UB). The samples were sent for histological and immunofluorescent analyses and compared by morphometrical quantification. The Conventional Unit (C.U.) difference of NT, NPY, and PGP 9.5 nerve fibres was statistically analyzed. Our results showed that NT, NPY, and PGP 9.5 neurofibers are almost equally present in PUF as in NM of a no pregnant uterus. As all of these neuropeptides are present in the uterine muscle and can affect muscle contractility, uterine peristalsis and muscular healing. A myomectomy respecting the pseudocapsule neurofibers should facilitate smooth muscle scarring and promote restoration of normal uterine peristalsis with a possible positive influence on fertility. 23462281 The Beneficial Role of Thiamine in Parkinson Disease. Parkinson disease (PD) is the second most common form of neurodegeneration among elderly individuals. PD is clinically characterized by tremors, rigidity, slowness of movement, and postural imbalance. In this paper, we review the evidence for an association between PD and thiamine. Interestingly, a significant association has been demonstrated between PD and low levels of serum thiamine, and thiamine supplements appear to have beneficial clinical effects against PD. Multiple studies have evaluated the connection between thiamine and PD pathology, and candidate pathways involve the transcription factor Sp1, p53, Bcl-2, caspase-3, tyrosine hydroxylase, glycogen synthase kinase-3β, vascular endothelial growth factor, advanced glycation end products, nuclear factor kappa B, mitogen-activated protein kinase, and the reduced form of nicotinamide adenine dinucleotide phosphate. Thus, a review of the literature suggests that thiamine plays a role in PD, although further investigation into the effects of thiamine in PD is needed. 23639992 Microfluidics on liquid handling stations (μF-on-LHS): an industry compatible chip interface between microfluidics and automated liquid handling stations. We describe a generic microfluidic interface design that allows the connection of microfluidic chips to established industrial liquid handling stations (LHS). A molding tool has been designed that allows fabrication of low-cost disposable polydimethylsiloxane (PDMS) chips with interfaces that provide convenient and reversible connection of the microfluidic chip to industrial LHS. The concept allows complete freedom of design for the microfluidic chip itself. In this setup all peripheral fluidic components (such as valves and pumps) usually required for microfluidic experiments are provided by the LHS. Experiments (including readout) can be carried out fully automated using the hardware and software provided by LHS manufacturer. Our approach uses a chip interface that is compatible with widely used and industrially established LHS which is a significant advancement towards near-industrial experimental design in microfluidics and will greatly facilitate the acceptance and translation of microfluidics technology in industry. 23410170 Rationally Designed Multitarget Anti-HIV Agents. Multitarget-directed ligands (MTDLs), an emerging and appealing drug discovery strategy, utilizing a single chemical entity to inhibit multitargets, was confirmed to be effective in reducing the likelihood of drug resistance, diminishing problems of dosing complexity, drug-drug interactions and toxicities, as well as improving patient compliance. The exploration of MTDL strategy should be valuable in anti-HIV drug discovery. In this article, current knowledge and strategies for the rational design of the multitarget and selective anti-HIV agents are described and a number of illustrative examples are given. Moreover, the challenges, limitations and outlook of such novel drug design strategies are also presented, with a goal to highlight the representative paradigms in the rational design of MTDLs, and to help medicinal chemists discover the next generation of multitarget anti-HIV agents. 23400270 Self-templating synthesis of hollow mesoporous silica and their applications in catalysis and drug delivery. Hollow mesoporous silica materials have been intensively pursued because of their unique properties for various applications. Yolk/shell structured hollow mesoporous silica with functional cores inside their hollow interior can further broaden the applications of hollow mesoporous silica. The self-templating strategy has been developed as one of the most important strategies to effectively fabricate hollow mesoporous silicas and their yolk/shell counterparts. In this feature article, we provide an overview of advances in the self-templating synthesis of hollow mesoporous silica based on the following three strategies: surface-protected etching, structural difference-based selective etching, and cationic surfactant assisted self-templating. We then discuss some important applications of these self-templating strategy-derived hollow mesoporous silicas, such as nanoreactors for confined catalysis and multifunctional platforms for combined therapy. Finally, some perspectives for the future development of this active research field are provided. 23248173 TGFβ receptor signaling is essential for inflammation-induced but not β-cell workload-induced β-cell proliferation. Protection and restoration of a functional β-cell mass are fundamental strategies for prevention and treatment of diabetes. Consequently, knowledge of signals that determine the functional β-cell mass is of immense clinical relevance. Transforming growth factor β (TGFβ) superfamily signaling pathways play a critical role in development and tissue specification. Nevertheless, the role of these pathways in adult β-cell homeostasis is not well defined. Here, we ablated TGFβ receptor I and II genes in mice undergoing two surgical β-cell replication models (partial pancreatectomy or partial duct ligation), representing two triggers for β-cell proliferation, increased β-cell workload and local inflammation, respectively. Our data suggest that TGFβ receptor signaling is necessary for baseline β-cell proliferation. By either provision of excess glucose or treatment with exogenous insulin, we further demonstrated that inflammation and increased β-cell workload are both stimulants for β-cell proliferation but are TGFβ receptor signaling dependent and independent, respectively. Collectively, by using a pancreas-specific TGFβ receptor-deleted mouse model, we have identified two distinct pathways that regulate adult β-cell proliferation. Our study thus provides important information for understanding β-cell proliferation during normal growth and in pancreatic diseases. 23418362 The sorting of proglucagon to secretory granules is mediated by carboxypeptidase E and intrinsic sorting signals. Proglucagon is expressed in pancreatic alpha cells, intestinal L cells and brainstem neurons. Tissue-specific processing of proglucagon yields the peptide hormones glucagon in the alpha cell and glucagon-like peptide (GLP)-1 and GLP-2 in L cells. Both glucagon and GLP-1 are secreted in response to nutritional status and are critical for regulating glycaemia. The sorting of proglucagon to the dense-core secretory granules of the regulated secretory pathway is essential for the appropriate secretion of glucagon and GLP-1. We examined the roles of carboxypeptidase E (CPE), a prohormone sorting receptor, the processing enzymes PC1/3 and PC2 and putative intrinsic sorting signals in proglucagon sorting. In Neuro 2a cells that lacked CPE, PC1/3 and PC2, proglucagon co-localised with the Golgi marker p115 as determined by quantitative immunofluorescence microscopy. Expression of CPE, but not of PC1/3 or PC2, enhanced proglucagon sorting to granules. siRNA-mediated knockdown of CPE disrupted regulated secretion of glucagon from pancreatic-derived alphaTC1-6 cells, but not of GLP-1 from intestinal cell-derived GLUTag cells. Mutation of the PC cleavage site K70R71, the dibasic R17R18 site within glucagon or the alpha-helix of glucagon, all significantly affected the sub-cellular localisation of proglucagon. Protein modelling revealed that alpha helices corresponding to glucagon, GLP-1 and GLP-2, are arranged within a disordered structure, suggesting some flexibility in the sorting mechanism. We conclude that there are multiple mechanisms for sorting proglucagon to the regulated secretory pathway, including a role for CPE in pancreatic alpha cells, initial cleavage at K70R71 and multiple sorting signals. 23138333 The effect of copper on different phototrophic microorganisms determined in vivo and at cellular level by confocal laser microscopy. Microbial mats are coastal ecosystems that consist mainly of cyanobacteria, primary producers in these habitats that play an important role in stabilising delta sediments. However, these ecosystems are subject to various kinds of pollution, including metal contamination, placing their survival at risk. Among heavy metals, copper is an essential metal at low doses and toxic at high doses. This metal is present in different pesticides used in rice production, a thriving agro-industry in the Ebro Delta (Spain). For several years, our group has been studying the Ebro Delta microbial mats and has developed a method for determining the effect that metals cause on cyanobacteria populations. This method is based on confocal laser microscopy coupled to a spectrofluorometer, which rapidly provides simultaneous three-dimensional information on photosynthetic microorganisms and their fluorescence spectra profiles. The current study determines the copper effect on different photosynthetic microorganisms from culture collection (Chroococcus sp. PCC 9106 and Spirulina sp. PCC 6313) and isolated from the environment (Microcoleus-like and the microalga DE2009). Comparing all results obtained it can be observed that the minimum dose of Cu that is capable of significantly altering chlorophyll a (chl a) fluorescence intensity were 1 × 10(-7) M in Chroococcus sp. PCC 9106; 1 × 10(-7) M in Spirulina sp. PCC 6313; 3 × 10(-7) M in Microcoleus and 5 × 10(-6) M in the microalga DE2009. Moreover, the sensitivity of the technique used was 1 × 10(-7) M. 23587647 Role of BDNF epigenetics in activity-dependent neuronal plasticity. Brain-derived neurotrophic factor (BDNF) is a key mediator of the activity-dependent processes in the brain that have a major impact on neuronal development and plasticity. Impaired control of neuronal activity-induced BDNF expression mediates the pathogenesis of various neurological and psychiatric disorders. Different environmental stimuli, such as the use of pharmacological compounds, physical and learning exercises or stress exposure, lead to activation of specific neuronal networks. These processes entail tight temporal and spatial transcriptional control of numerous BDNF splice variants through epigenetic mechanisms. The present review highlights recent findings on the dynamic and long-term epigenetic programming of BDNF gene expression by the DNA methylation, histone-modifying and microRNA machineries. The review also summarizes the current knowledge on the activity-dependent BDNF mRNA trafficking critical for rapid local regulation of BDNF levels and synaptic plasticity. Current data open novel directions for discovery of new promising therapeutic targets for treatment of neuropsychiatric disorders. This article is part of a Special Issue entitled 'BDNF'. 23383723 Interactions between Pluronics (F127 and F68) and bile salts (NaTDC) in the aqueous phase and the interface of oil-in-water emulsions. Pluronics are being introduced in food research in order to delay lipid digestion, with the length of hydrophilic and hydrophobic chains playing an important role in the rate of such a process. Since bile salts play a crucial role in the lipid digestion process, the aim of this work is to analyze the interactions between Pluronic F127 or F68 and the bile salt NaTDC when the latter is added at physiological concentrations. These interactions are studied at the Pluronic-covered oil-water interface and in the aqueous phase of Pluronic-stabilized emulsions. This work has been carried out with techniques such as differential scanning calorimetry, interfacial tension, dilatational rheology, and scanning electron microscopy. As a result, Pluronic F127 was shown to be more resistant to displacement by bile salt than F68 at the oil-water interface due to the larger steric hindrance and interfacial coverage provided. In addition, Pluronics have the ability to compete for the oil-water interface and interact in the bulk with the bile salt. Concretely, Pluronic F127 seems to interact with more molecules of bile salt in the bulk, thus hindering their adsorption onto the oil-water interface. As a conclusion, Pluronic F127 affects to a larger extent the ability of bile salt to promote the further cascade of lipolysis in the presence of lipase owing to a combination of interfacial and bulk events. 23315791 N-Boc-protected 1,2-diphenylethylenediamine-based dendritic organogels with multiple-stimulus-responsive properties. A new class of poly(benzyl ether) dendrimers, decorated in their cores with N-Boc-protected 1,2-diphenylethylenediamine groups, were synthesized and fully characterized. It was found that the gelation capability of these dendrimers was highly dependent on dendrimer generation, and the second-generation dendrimer (R,R)-G(2)DPENBoc proved to be a highly efficient organogelator. A number of experiments (SEM, TEM, FTIR spectroscopy, (1)H NMR spectroscopy, rheological measurements, UV/Vis absorption spectroscopy, CD, and XRD) revealed that these dendritic molecules self-assembled into elastically interpenetrating one-dimensional nanostructures in organogels. The hydrogen bonding, π-π, and solvophobic interactions were found to be the main driving forces for formation of the gels. Most interestingly, these dendritic organogels exhibited smart multiple-stimulus-responsive behavior upon exposure to environmental stimuli such as temperature, anions, and mechanical stress. 23514599 GC-Targeted C8-Linked Pyrrolobenzodiazepine-Biaryl Conjugates with Femtomolar in Vitro Cytotoxicity and in Vivo Antitumor Activity in Mouse Models. DNA binding 4-(1-methyl-1H-pyrrol-3-yl)benzenamine (MPB) building blocks have been developed that span two DNA base pairs with a strong preference for GC-rich DNA. They have been conjugated to a pyrrolo[2,1-c][1,4]benzodiazepine (PBD) molecule to produce C8-linked PBD-MPB hybrids that can stabilize GC-rich DNA by up to 13-fold compared to AT-rich DNA. Some have subpicomolar IC50 values in human tumor cell lines and in primary chronic lymphocytic leukemia cells, while being up to 6 orders less cytotoxic in the non-tumor cell line WI38, suggesting that key DNA sequences may be relevant targets in these ultrasensitive cancer cell lines. One conjugate, 7h (KMR-28-39), which has femtomolar activity in the breast cancer cell line MDA-MB-231, has significant dose-dependent antitumor activity in MDA-MB-231 (breast) and MIA PaCa-2 (pancreatic) human tumor xenograft mouse models with insignificant toxicity at therapeutic doses. Preliminary studies suggest that 7h may sterically inhibit interaction of the transcription factor NF-κB with its cognate DNA binding sequence. 23612720 Control of one-dimensional magnetism in graphene via spontaneous hydrogenation of the grain boundary. We propose that control of one-dimensional (1D) magnetism in graphene could be made easier by spontaneous hydrogenation of chemically reactive grain boundaries (GBs) in polycrystalline graphenes. Unlike pristine graphene, where hydrogen adsorption favors the formation of zero-dimensional (0D) clusters, the defect cores (pentagon, heptagon and octagon) at the GBs in polycrystalline graphene promote hydrogenation along the GBs. The hydrogenation in polycrystalline graphene starts at the GBs, proceeds gradually towards the grain interior (GI) and results in smooth 1D graphane-graphene interfaces. Our calculations show that the type (ferro- or antiferro-magnetism) and strength of the magnetism can be controlled by controlling the orientation of GBs. Since GBs in single-layer graphenes can be fabricated in a controllable way in experiments, the hydrogenation of GBs could be a unique method to realize large-area magnetic graphenes for future spintronic applications. 22303963 Determination of three steroidal saponins from Ophiopogon japonicus (Liliaceae) via high-performance liquid chromatography with mass spectrometry. A simple and accurate analytical method was developed for simultaneous quantification of three steroidal saponins in the roots of Ophiopogon japonicus via high-performance liquid chromatography (HPLC) with mass spectrometry (MS) in this study. Separation was performed on a Tigerkin C(18) column and detection was performed by mass spectrometry. A mobile phase consisted of 0.02% formic acid in water (v/v) and 0.02% formic acid in acetonitrile (v/v) was used with a flow rate of 0.5 mL min(-1). The quantitative HPLC-MS method was validated for linearity, precision, repeatability, stability, recovery, limits of detection and quantification. This developed method provides good linearity (r >0.9993), intra- and inter-day precisions (RSD <4.18%), repeatability (RSD <5.05%), stability (RSD <2.08%) and recovery (93.82-102.84%) for three steroidal saponins. It could be considered as a suitable quality control method for O. japonicus. 23542440 Sensitization of restraint-induced corticosterone secretion after chronic restraint in rats: Involvement of 5-HT7 receptors. Serotonin (5-HT) modulates the hypothalamic-pituitary-adrenal (HPA) axis response to stress. We examined the effect of chronic restraint stress (CRS; 20 min/day) as compared to control (CTRL) conditions for 14 days, on: 1) restraint-induced ACTH and corticosterone (CORT) secretion in rats pretreated with vehicle or SB-656104 (a 5-HT7 receptor antagonist); 2) 5-HT7 receptor-like immunoreactivity (5-HT7-LI) and protein in the hypothalamic paraventricular nucleus (PVN) and adrenal glands (AG); 3) baseline levels of 5-HT and 5-hydroxyindolacetic acid (5-HIAA), and 5-HIAA/5-HT ratio in PVN and AG; and 4) 5-HT-like immunoreactivity (5-HT-LI) in AG and tryptophan hydroxylase (TPH) protein in PVN and AG. On day 15, animals were subdivided into Treatment and No treatment groups. Treatment animals received an i.p. injection of vehicle or SB-656104; No Treatment animals received no injection. Sixty min later, Treatment animals were either decapitated with no further stress (0 min) or submitted to acute restraint (10, 30, 60 or 120 min); hormone serum levels were measured. No Treatment animals were employed for the rest of measurements. CRS decreased body weight gain and increased adrenal weight. In CTRL animals, acute restraint increased ACTH and CORT secretion in a time of restraint-dependent manner; both responses were inhibited by SB-656104. Exposure to CRS abolished ACTH but magnified CORT responses to restraint as compared to CTRL conditions; SB-656104 had no effect on ACTH levels but significantly inhibited sensitized CORT responses. In CTRL animals, 5-HT7-LI was detected in magnocellular and parvocellular subdivisions of PVN and sparsely in adrenal cortex. Exposure to CRS decreased 5-HT7-LI and protein in the PVN, but increased 5-HT7-LI in the adrenal cortex and protein in whole AG. Higher 5-HT and 5-HIAA levels were detected in PVN and AG from CRS animals but 5-HIAA/5-HT ratio increased in AG only. Finally, whereas 5-HT-LI was sparsely observed in the adrenal cortex of CTRL animals, it strongly increased in the adrenal cortex of CRS animals. No TPH protein was detected in AG from both animal groups. Results suggest that CRS promotes endocrine disruption involving decreased ACTH and sensitized CORT responses to acute restraint. This phenomenon may be associated with increased function and expression of 5-HT7 receptors as well as 5-HT turnover in AG. 23395957 Cellular Mechanisms of Nociceptin/Orphanin FQ (N/OFQ) Peptide (NOP) Receptor Regulation and Heterologous Regulation by N/OFQ. The nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor is the fourth and most recently discovered member of the opioid receptor superfamily that also includes μ, δ, and κ opioid receptor subtypes (MOR, DOR, and KOR, respectively). The widespread anatomic distribution of the NOP receptor enables the modulation of several physiologic processes by its endogenous agonist, N/OFQ. Accordingly, the NOP receptor has gained a lot of attention as a potential target for the development of ligands with therapeutic use in several pathophysiological states. NOP receptor activation frequently results in effects opposing classic opioid receptor action; therefore, regulation of the NOP receptor and conditions affecting its modulatory tone are important to understand. Mounting evidence reveals a heterologous interaction of the NOP receptor with other G protein-coupled receptors, including MOR, DOR, and KOR, which may subsequently influence their function. Our focus in this review is to summarize and discuss the findings that delineate the cellular mechanisms of NOP receptor signaling and regulation and the regulation of other receptors by N/OFQ and the NOP receptor. 23604719 Simultaneous determination of five flavonoids during the growth of Fructus Sophorae by capillary electrophoresis. A method of simultaneous determination of five flavonoids during the growth of Fructus Sophorae by β-cyclodextrin (β-CD-) modified capillary zone electrophoresis was developed. The effects of various parameters such as buffer concentration, pH, applied voltage, and β-CD concentrations were investigated. After a series of optimization processes, the determination of five flavonoids in Fructus Sophorae was successfully achieved in 20 mmol/L borax buffer (pH 9.5), 25 kV applied voltage, and 8 mmol/L β-CD. The linearity, detection limits, repeatability, and recovery were satisfactory. Thus, the proposed β-CD-modified capillary zone electrophoresis method was satisfactorily used to analyze Fructus Sophorae samples. The results can be useful for the quality control and medicinal resource development of Fructus Sophorae. 23339480 Dendrimer and cancer: a patent review (2006-present). INTRODUCTION: Dendrimers were widely used in cancer diagnosis and therapy during the past decade. The surface functionalities allow bioactive molecules such as imaging probes, therapeutic compounds, targeting ligands to be present on dendrimer surface in a multivalent fashion. In addition, the interior pockets as well as the charged surface of dendrimer can be encapsulated/bound with anti-cancer drugs or therapeutic DNAs/siRNAs. AREAS COVERED: The combination of dendrimer chemistry and new cancer therapy techniques such as radiotherapy, photodynamic therapy, neuron capture therapy, and photothermal therapy provides promising strategies in future cancer therapy. Here, we focused on recent advances on this topic in the patents (2006 - present) and discussed the advantages of dendrimer technology in these inventions. EXPERT OPINION: The challenges and perspectives of dendrimer-based theranostics for cancer diagnosis and therapy are discussed. Future efforts in this area should be focused on designing materials to solve problems such as cancer metastasis, multidrug resistance (MDR) in cancer cells, and early-stage cancer diagnosis. 23221633 Novel Smad proteins localize to IR-induced double-strand breaks: interplay between TGFβ and ATM pathways. Cellular damage from ionizing radiation (IR) is in part due to DNA damage and reactive oxygen species, which activate DNA damage response (DDR) and cytokine signaling pathways, including the ataxia telangiectasia mutated (ATM) and transforming growth factor (TGF)β/Smad pathways. Using classic double-strand breaks (DSBs) markers, we studied the roles of Smad proteins in DDR and the crosstalk between TGFβ and ATM pathways. We observed co-localization of phospho-Smad2 (pSmad2) and Smad7 with DSB repair proteins following low and high linear energy transfer (LET) radiation in human fibroblasts and epithelial cells. The decays of both foci were similar to that of γH2AX foci. Irradiation with high LET particles induced pSmad2 and Smad7 foci tracks indicating the particle trajectory through cells. pSmad2 foci were absent in S phase cells, while Smad7 foci were present in all phases of cell cycle. pSmad2 (but not Smad7) foci were completely abolished when ATM was depleted or inactivated. In contrast, a TGFβ receptor 1 (TGFβR1) inhibitor abrogated Smad7, but not pSmad2 foci at DSBs sites. In summary, we suggest that Smad2 and Smad7 contribute to IR-induced DSB signaling in an ATM or TGFβR1-dependent manner, respectively. 23364615 Adsorption and Self-Assembly of Large Polycyclic Molecules on the Surfaces of TiO2 Single Crystals. Titanium dioxide is one of the most frequently studied metal oxides, and its (110) rutile surface serves as a prototypical model for the surface science of such materials. Recent studies have also shown that the (011) surface is relatively easy for preparation in ultra-high vacuum (UHV) and that both the (110) and (011) surfaces could be precisely characterized using scanning tunneling microscopy (STM). The supramolecular self-assembly of organic molecules on the surfaces of titanium dioxide plays an important role in nanofabrication, and it can control the formation and properties of nanostructures, leading to wide range of applications covering the fields of catalysis, coatings and fabrication of sensors and extends to the optoelectronic industry and medical usage. Although the majority of experiments and theoretical calculations are focused on the adsorption of relatively small organic species, in recent years, there has been increasing interest in the properties of larger molecules that have several aromatic rings in which functional units could also be observed. The purpose of this review is to summarize the achievements in the study of single polycyclic molecules and thin layers adsorbed onto the surfaces of single crystalline titanium dioxide over the past decade. 23471029 Controlled formation of mono- and dihydroxy-resolvins from EPA and DHA using soybean 15-lipoxygenase. Resolvins and protectins are important anti-inflammatory and pro-resolution compounds derived from the enzymatic oxidation of omega-3 fatty acids all-cis-5,8,11,14,17-eicosapentaenoic acid (EPA) and all-cis-4,7,10,13,16,19-docosahexaenoic acid (DHA). We have developed a simple, controlled method to synthesize an array of resolvin and protectin analogs from fatty acid starting materials using soybean 15-lipoxygenase. The conditions were optimized for the production of both mono- and dihydroxy derivatives, with enzyme concentration and pH found to have a significant effect on the reaction products. The methods were applied to five biologically important omega-3 and omega-6 fatty acid substrates. Mono- and dihydroxy compounds were successfully synthesized from all substrates and the products were characterized by normal phase (NP) HPLC, GC-MS, TOF-MS, UV-visible (UV-vis) spectroscopy, and NMR spectroscopy. The methods could be further applied to any polyunsaturated fatty acids containing the cis-1,4,7,10-undecatetraene moiety to produce a range of novel compounds with potential biological activity. 23103282 Social networks, web-based tools and diseases: implications for biomedical research. Advances in information technology have improved our ability to gather, collect and analyze information from individuals online. Social networks can be seen as a nonlinear superposition of a multitude of complex connections between people where the nodes represent individuals and the links between them capture a variety of different social interactions. The emergence of different types of social networks has fostered connections between individuals, thus facilitating data exchange in a variety of fields. Therefore, the question posed now is "can these same tools be applied to life sciences in order to improve scientific and medical research?" In this article, I will review how social networks and other web-based tools are changing the way we approach and track diseases in biomedical research. 23377115 Evaluation of genotoxic effects of five flavour enhancers (glutamates) on the root meristem cells of Allium cepa. The effects of different treatments with flavour enhancers monosodium glutamate, monopotassium glutamate, calcium diglutamate, monoammonium glutamate, and magnesium diglutamate on the cytology, DNA content, and interphase nuclear volume (INV) of A. cepa were investigated. Three concentrations of these additives - 20, 40, and 60 ppm - were applied for 6, 12, and 24 h. All the concentrations of these chemicals showed an inhibitory effect on cell division in root tips of A. cepa and caused a decrease in mitotic index values. Additionally, all the treatments changed the frequency of mitotic phases when compared with the control groups. These compounds increased chromosome abnormalities, among them are micronuclei, c-mitosis, anaphase bridges, stickiness, binucleus, laggards, and breaks. The nuclear DNA content and INV decreased when compared with control groups. 23111885 Low cytotoxic elastic niosomes loaded with salmon calcitonin on human skin fibroblasts. A low cytotoxic elastic niosomal formulation loaded with salmon calcitonin was developed. The elastic niosomes were prepared from Tween 61 mixed with cholesterol at various concentrations of the edge activators (sodium cholate (NaC) and sodium deoxycholate (NaDC); 0.25, 0.5, 2.5, 5 and 10% mole) or ethanol (10-30% v/v). The effects of the niosomal concentrations (5, 10 and 20 mM) and phosphate buffer at pH 7.0 (5, 10, 20 and 30 mM) on the physical characteristics of niosomes were investigated. The 5 mM elastic niosomes in 5 mM phosphate buffer containing calcitonin 0.22 mg/mL gave the highest elasticity (deformability index (DI)) at 6.79 ± 2.03 determined by the extrusion method. The blank elastic niosomes comprised 2.5% mole NaDC, 5% mole NaC or 20% v/v ethanol showed the highest elasticity. The 5% mole NaC elastic niosomes loaded with calcitonin gave the highest DI (21.59 ± 0.91) and percentages of calcitonin entrapment efficiency (60.11 ± 4.98). This study has demonstrated that this NaC elastic niosome did not only reduce the cytotoxicity of the loaded calcitonin but also gave superior cell viability to the ethanolic elastic niosome as well. 23545002 Ultralow friction induced by tribochemical reactions: a novel mechanism of lubrication on steel surfaces. The tribological properties of two steel surfaces rubbing against each other are measured while they are in contact with 1,3-diketones of varying structure. Such systems show after a short running-in period ultralow friction properties with a coefficient of friction of as low as μ = 0.005. It is suggested that the extremely favorable friction properties are caused by a tribochemical reaction between the 1,3-diketones and the steel surfaces, leading to formation of a chelated iron-diketo complex. The influence of temperature and the molecular structure of the 1,3 diketo-lubricants onto the friction properties of the system is elucidated under both static and dynamic conditions. With progression of the tribochemical reaction, the sliding surfaces become very conformal and smooth, so that the pressure is greatly reduced and further wear is strongly reduced. All iron particles potentially generated by wear during the initial running-in period are completely dissolved through complex formation. It is proposed that the tribochemical polishing reaction causes a transition from boundary lubrication to fluid lubrication. 22992330 Genetic correlate of cognitive training response in schizophrenia. Intensive computerized auditory training results in improved cognition for schizophrenia patients, but participants show variation in their cognitive gains and the biological factors that affect the response to training are unknown. Single nucleotide polymorphisms (SNPs) in the catechol-O-methyltransferase (COMT) gene have been related to cognitive function. Here we asked if functional variation in this gene has an impact on the response of schizophrenia patients to cognitive training. We genotyped 48 schizophrenia patients who completed 50 h of computerized cognitive training and analyzed the association between DNA variants in the COMT gene and the improvement in global cognition. Although conventional analyses did not reveal any significant associations, a set-based analysis examining the aggregate effect of common variation in the COMT gene (42 SNPs) suggested association with improvement in global cognition. Eight SNPs, mostly located in the 3' end of the COMT gene, were nominally associated with improvement in cognition. These data suggest that genotype influences the response to intensive cognitive training in schizophrenia, and may indicate that cognitive training regimens need to be personalized to the underlying biosignatures of each individual patient. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23608241 The effect of mitragynine on cAMP formation and mRNA expression of mu-opioid receptors mediated by chronic morphine treatment in SK-N-SH neuroblastoma cell. ETHOPHARMACOLOGICAL RELEVANCE: Mitragynine is an indole alkaloid compound of Mitragyna speciosa (M. speciosa) Korth. (Rubiaceae). This plant is native to the southern regions of Thailand and northern regions of Malaysia and is frequently used to manage the withdrawal symptoms in both countries. AIM OF STUDY: To investigate the effect of mitragynine after chronic morphine treatment on cyclic AMP (cAMP) level and mRNA expression of mu-opioid receptor (MOR) in human neuroblastoma SK-N-SH cell. METHOD AND MATERIALS: Mitragynine was isolated from the Mitragyna speciosa plant using the acid-base extraction method. The cAMP level upon forskolin stimulation in the cells was determined using the Calbiochem(®) Direct Immunoassay Kit. The mRNA expression of the MOR was carried out using quantitative RT-PCR. RESULT: Cotreatment and pretreatment of morphine and mitragynine significantly reduced the production of cAMP level at a lower concentration of nitrogen while the higher concentration of this compound could lead to the development of tolerance and dependence as shown by the increase of the cAMP level production in foskolin stimulation. In MOR mRNA expression study, cotreatment of morphine with mitragynine significantly reduced the down-regulation of MOR mRNA expression as compared to morphine treatment only. CONCLUSION: These finding suggest that mitragynine could possibly avoid the tolerance and dependence on chronic morphine treatment by reducing the up-regulation of cAMP level as well as reducing the down-regulation of MOR at a lower concentration of mitragynine. 23323677 Synthesis, characterization, and cure chemistry of renewable bis(cyanate) esters derived from 2-methoxy-4-methylphenol. A series of renewable bis(cyanate) esters have been prepared from bisphenols synthesized by condensation of 2-methoxy-4-methylphenol (creosol) with formaldehyde, acetaldehyde, and propionaldehyde. The cyanate esters have been fully characterized by infrared spectroscopy, (1)H and (13)C NMR spectroscopy, and single crystal X-ray diffraction. These compounds melt from 88 to 143 °C, while cured resins have glass transition temperatures from 219 to 248 °C, water uptake (96 h, 85 °C immersion) in the range of 2.05-3.21%, and wet glass transition temperatures from 174 to 193 °C. These properties suggest that creosol-derived cyanate esters may be useful for a wide variety of military and commercial applications. The cure chemistry of the cyanate esters has been studied with FTIR spectroscopy and differential scanning calorimetry. The results show that cyanate esters with more sterically demanding bridging groups cure more slowly, but also more completely than those with a bridging methylene group. In addition to the structural differences, the purity of the cyanate esters has a significant effect on both the cure chemistry and final Tg of the materials. In some cases, post-cure of the resins at 350 °C resulted in significant decomposition and off-gassing, but cure protocols that terminated at 250-300 °C generated void-free resin pucks without degradation. Thermogravimetric analysis revealed that cured resins were stable up to 400 °C and then rapidly degraded. TGA/FTIR and mass spectrometry results showed that the resins decomposed to phenols, isocyanic acid, and secondary decomposition products, including CO2. Char yields of cured resins under N2 ranged from 27 to 35%, while char yields in air ranged from 8 to 11%. These data suggest that resins of this type may potentially be recycled to parent phenols, creosol, and other alkylated creosols by pyrolysis in the presence of excess water vapor. The ability to synthesize these high temperature resins from a phenol (creosol) that can be derived from lignin, coupled with the potential to recycle the composites, provides a possible route to the production of sustainable, high-performance, thermosetting resins with reduced environmental impact. 23562075 Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Mitochondrial fusion, fission, and mitophagy form an essential axis of mitochondrial quality control. However, quality control might not be the only task carried out by mitochondrial dynamics. Recent studies link mitochondrial dynamics to the balance between energy demand and nutrient supply, suggesting changes in mitochondrial architecture as a mechanism for bioenergetic adaptation to metabolic demands. By favoring either connected or fragmented architectures, mitochondrial dynamics regulates bioenergetic efficiency and energy expenditure. Placement of bioenergetic adaptation and quality control as competing tasks of mitochondrial dynamics might provide a new mechanism, linking excess nutrient environment to progressive mitochondrial dysfunction, common to age-related diseases. 23360619 The relative protein abundance of UGT1A alternative splice variants as a key determinant of glucuronidation activity in vitro. Alternative splicing (AS) is one of the most significant components of the functional complexity of human UDP-glucuronosyltransferase enzymes (UGTs), particularly for the UGT1A gene, which represents one of the best examples of a drug-metabolizing gene regulated by AS. Shorter UGT1A isoforms [isoform 2 (i2)] are deficient in glucuronic acid transferase activity but function as negative regulators of enzyme activity through protein-protein interaction. Their abundance, relative to active UGT1A enzymes, is expected to be a determinant of the global transferase activity of cells and tissues. Here we tested whether i2-mediated inhibition increases with greater abundance of the i2 protein relative to the isoform 1 (i1) enzyme, using the extrahepatic UGT1A7 as a model and a series of 23 human embryonic kidney 293 clonal cell lines expressing variable contents of i1 and i2 proteins. Upon normalization for i1, a significant reduction of 7-ethyl-10-hydroxycamptothecin glucuronide formation was observed for i1+i2 clones (mean of 53%) compared with the reference i1 cell line. In these clones, the i2 protein content varied greatly (38-263% relative to i1) and revealed two groups: 17 clones with i2 < i1 (60% ± 3%) and 6 clones with i2 ≥ i1 (153% ± 24%). The inhibition induced by i2 was more substantial for clones displaying i2 ≥ i1 (74.5%; P = 0.001) compared with those with i2 < i1 (45.5%). Coimmunoprecipitation supports a more substantial i1-i2 complex formation when i2 exceeds i1. We conclude that the relative abundance of regulatory i2 proteins has the potential to drastically alter the local drug metabolism in the cells, particularly when i2 surpasses the protein content of i1. 23403080 Synthesis and anti-Candida activity of novel 2-hydrazino-1,3-thiazole derivatives. Eighteen new hydrazino-1,3-thiazole derivatives were evaluated against 8 strains of multi-resistant Candida spp. Introduction of an indolyl moiety linked to the hydrazone function enhanced the in vitro anti-Candida activity, with an activity spectrum towards Candida albicans strains. Introduction of a (S)-2-aminoethyl chain on the thiazole nucleus largely enhanced the in vitro antifungal activity, with a selectivity oriented towards non-C. albicans species. 23577749 In vitro antimicrobial activity of 20 selected climber species from the Bignoniaceae family. Hydroalcoholic and aqueous extracts of some climber species from the Bignoniaceae family that grow in the north of Argentina were evaluated for in vitro antibacterial activity against Gram-positive and Gram-negative strains. By means of bioautography and disc diffusion methods, it could be determined that all infusions were not active, whereas the hydroalcoholic extracts of seven species were able to inhibit bacterial growth. The minimum inhibitory concentration and minimum bactericidal concentration observed were between 62.5 and 1000 μg gallic acid equivalent (GAE)/mL and between 125 and 1000 μg GAE/mL, respectively. The tested extracts were more active against Gram-positive microorganisms. Time-kill experiments indicated that all extracts have bacteriostatic activity. Phytochemical screening showed the presence of terpenoids, phenols and flavonoids. The amount of phenolic compounds and flavonoids was higher in tinctures when compared with infusions. These results suggest the presence of antibacterial substances in the hydroalcoholic extracts, which could be used for the treatment of infections. 22961200 A convective replica-exchange method for sampling new energy basins. Replica-exchange is a powerful simulation method for sampling the basins of a rugged energy landscape. The replica-exchange method's sampling is efficient because it allows replicas to perform round trips in temperature space, thereby visiting both low and high temperatures in the same simulation. However, replicas have a diffusive walk in temperature space, and the round trip rate decreases significantly with the system size. These drawbacks make convergence of the simulation even more difficult than it already is when bigger systems are tackled. Here, we present a simple modification of the exchange method. In this method, one of the replicas steadily raises or lowers its temperature. We tested the convective replica-exchange method on three systems of varying complexity: the alanine dipeptide in implicit solvent, the GB1 β-hairpin in explicit solvent and the Aβ(25-35) homotrimer in a coarse grained representation. For the highly frustrated Aβ(25-35) homotrimer, the proposed "convective" replica-exchange method is twice as fast as the standard method. It discovered 24 out of 27 free-energy basins in less than 500 ns. It also prevented the formation of groups of replicas that usually form on either side of an exchange bottleneck, leading to a more efficient sampling of new energy basins than in the standard method. 23249338 Light-harvesting and ultrafast energy migration in porphyrin-based metal-organic frameworks. Given that energy (exciton) migration in natural photosynthesis primarily occurs in highly ordered porphyrin-like pigments (chlorophylls), equally highly ordered porphyrin-based metal-organic frameworks (MOFs) might be expected to exhibit similar behavior, thereby facilitating antenna-like light-harvesting and positioning such materials for use in solar energy conversion schemes. Herein, we report the first example of directional, long-distance energy migration within a MOF. Two MOFs, namely F-MOF and DA-MOF that are composed of two Zn(II) porphyrin struts [5,15-dipyridyl-10,20-bis(pentafluorophenyl)porphinato]zinc(II) and [5,15-bis[4-(pyridyl)ethynyl]-10,20-diphenylporphinato]zinc(II), respectively, were investigated. From fluorescence quenching experiments and theoretical calculations, we find that the photogenerated exciton migrates over a net distance of up to ~45 porphyrin struts within its lifetime in DA-MOF (but only ~3 in F-MOF), with a high anisotropy along a specific direction. The remarkably efficient exciton migration in DA-MOF is attributed to enhanced π-conjugation through the addition of two acetylene moieties in the porphyrin molecule, which leads to greater Q-band absorption intensity and much faster exciton-hopping (energy transfer between adjacent porphyrin struts). The long distance and directional energy migration in DA-MOF suggests promising applications of this compound or related compounds in solar energy conversion schemes as an efficient light-harvesting and energy-transport component. 23464618 Photoexcitation dynamics of coupled semiconducting carbon nanotube thin films. Carbon nanotubes are a promising means of capturing photons for use in solar cell devices. We time-resolved the photoexcitation dynamics of coupled, bandgap-selected, semiconducting carbon nanotubes in thin films tailored for photovoltaics. Using transient absorption spectroscopy and anisotropy measurements, we found that the photoexcitation evolves by two mechanisms with a fast and long-range component followed by a slow and short-range component. Within 300 fs of optical excitation, 20% of nanotubes transfer their photoexcitation over 5-10 nm into nearby nanotube fibers. After 3 ps, 70% of the photoexcitation resides on the smallest bandgap nanotubes. After this ultrafast process, the photoexcitation continues to transfer on a ∼10 ps time scale but to predominantly aligned tubes. Ultimately the photoexcitation hops twice on average between fibers. These results are important for understanding the flow of energy and charge in coupled nanotube materials and light-harvesting devices. 23544698 Theoretical Strategy to Build Structural Models of Microhydrated Inorganic Systems for the Knowledge of Their Vibrational Properties: The Case of the Hydrated Nitrate Aerosols. This study provides theoretical anharmonic calculations for microhydrated NaNO3-labeled (NaNO3, nH2O)x with a water-to-solute ratio (n) ranging from 1 to 3. A representative geometrical model of these forms was first investigated by simulating the molecular clusters as (NaNO3,1H2O)x with x = 1 to 4. The comparison between the calculated time independent anharmonic frequencies using the B3LYP-D/6-311+G(d,p) method and their experimental counterparts led to the choice of a supercluster model. The most probable structures of (NaNO3,nH2O)3 molecular system were investigated by using our global search algorithm we developed recently (GSAM code) both at the B3LYP/6-311+G(d,p) and the B3LYP-D/6-311+G(d,p) levels of theory. The quality of the structural model is illustrated by comparing the B3LYP/6-311+G(d,p) and B3LYP-D/6-311+G(d,p) anharmonic vibrational signatures with those obtained from IR experiments. While an average deviation of 16 cm(-1) is observed in the case of the B3LYP computations, the deviation is reduced to 7 cm(-1) for the B3LYP-D computations. 23380520 Early steps of double-strand break repair in Bacillus subtilis. All organisms rely on integrated networks to repair DNA double-strand breaks (DSBs) in order to preserve the integrity of the genetic information, to re-establish replication, and to ensure proper chromosomal segregation. Genetic, cytological, biochemical and structural approaches have been used to analyze how Bacillus subtilis senses DNA damage and responds to DSBs. RecN, which is among the first responders to DNA DSBs, promotes the ordered recruitment of repair proteins to the site of a lesion. Cells have evolved different mechanisms for efficient end processing to create a 3'-tailed duplex DNA, the substrate for RecA binding, in the repair of one- and two-ended DSBs. Strand continuity is re-established via homologous recombination (HR), utilizing an intact homologous DNA molecule as a template. In the absence of transient diploidy or of HR, however, two-ended DSBs can be directly re-ligated via error-prone non-homologous end-joining. Here we review recent findings that shed light on the early stages of DSB repair in Firmicutes. 23245512 Synthesis of acylated glycoconjugates as templates to investigate in vitro biopharmaceutical properties. A series of novel glycopyranosyl azides were synthesised wherein the carbohydrate moiety was peracylated with four acetyl, propionyl, butanoyl, pentanoyl (valeryl) or 3-methylbutanoyl (isovaleryl) ester linked groups. A panel of glycoconjugates was synthesised from these glycopyranosyl azides using copper-catalysed azide-alkyne cycloaddition. The in vitro metabolic stability, plasma stability and plasma protein binding was then measured to establish the impact of the different acyl group when presented on a common scaffold. The acetyl, propionyl and butanoyl esters exhibited metabolism consistent with esterase processing, and various mono-, di- and tri-acylated hydrolysis products as well as the fully hydrolysed compound were detected. In contrast, the pentanoyl and 3-methylbutanoyl esters were stable. 23446230 CYP2J2 overexpression increases EETs and protects against angiotensin II-induced abdominal aortic aneurysm in mice. Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acids to form epoxyeicosatrienoic acids (EETs), which possess various beneficial effects on the cardiovascular system. However, whether increasing EETs production by CYP2J2 overexpression in vivo could prevent abdominal aortic aneurysm (AAA) remains unknown. Here we investigated the effects of recombinant adeno-associated virus (rAAV)-mediated CYP2J2 overexpression on angiotensin (Ang) II-induced AAA in apoE-deficient mice. rAAV-CYP2J2 delivery led to an abundant aortic CYP2J2 expression and increased EETs generation. It was shown that CYP2J2 overexpression attenuated matrix metalloproteinase expression and activity, elastin degradation, and AAA formation, which was associated with reduced aortic inflammation and macrophage infiltration. In cultured vascular smooth muscle cells (VSMCs), rAAV-mediated CYP2J2 overexpression and EETs markedly suppressed Ang II-induced inflammatory cytokine expression. Moreover, overexpressed CYP2J2 and EETs inhibited Ang II-induced macrophage migration in a VSMC-macrophage coculture system. We further indicated that these protective effects were mediated by peroxisome proliferator-activated receptor (PPAR)γ activation. Taken together, these results provide evidence that rAAV-mediated CYP2J2 overexpression prevents AAA development which is likely via PPARγ activation and anti-inflammatory action, suggesting that increasing EETs levels could be considered as a potential strategy to prevent and treat AAA. 23561140 Changes in polyphenol content during production of grape juice concentrate. The production of grape juice concentrate on an industrial scale was evaluated and samples from the main steps of processing have been collected and analyzed. The sampling steps included the selection and washing of grapes (Nevsehir Patlak variety), pressing in order to obtain the juice separate from the seed and the skin fraction, pasteurization, clarification, filtration, evaporation, and filling-packing at 27°C with a Brix of 45°. Samples from each of the processing steps were analyzed by a number of spectrophotometric analyses. A series of anthocyanin compounds was identified using HPLC-MS, and the fate of anthocyanins, quercetin rutinoside and procyanidins was followed using HPLC. The results indicate that the removal of seed and fruit skin removes most of the procyanidins and anthocyanins, while subsequent clarification and filtration treatments further reduce the anthocyanin content. 23201331 Protective effects of sweroside on human MG-63 cells and rat osteoblasts. Herbal Fructus Corni is a folk medicine with a long history of safe use for treating osteoporosis in postmenopausal women or elderly men in Asia. Sweroside is a bioactive herbal ingredient isolated from Fructus Corni, which has been widely used for the treatment of osteoporosis in traditional Chinese medicine (TCM). Unfortunately, the working mechanisms of this compound are difficult to determine and thus remain unclear. The aim of the study was performed to determine the potential molecular mechanism of the anti-osteoporotic effect of sweroside on the human MG-63 cells and rat osteoblasts. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test was used to observe the effect of sweroside on cell proliferation. The activity of alkaline phosphatase (ALP) and the amount of osteocalcin were also assayed the cell differentiation. Sweroside significantly increased the proliferation of human MG-63 cells and rat osteoblasts (P<0.01). It increased the activity of ALP, and osteocalcin was also elevated in response to sweroside (P<0.05). Of note, flowcytometer assay showed that sweroside can attenuate and inhibit apoptosis. Sweroside has a direct osteogenic effect on the proliferation and differentiation of cultured human MG-63 cells and rat osteoblasts in vitro. These data will help in understanding the molecular mechanisms of therapeutic efficacy of sweroside, and highlight insights into drug discovery. In the current study, sweroside has been suggested to be a promising osteoporosis therapeutic natural product. 23058997 Non-enzymatic proteins from snake venoms: a gold mine of pharmacological tools and drug leads. Non-enzymatic proteins from snake venoms play important roles in the immobilization of prey, and include some large and well-recognized families of toxins. The study of such proteins has expanded not only our understanding of venom toxicity, but also the knowledge of normal and disease states in human physiology. In many cases their characterization has led to the development of powerful research tools, diagnostic techniques, and pharmaceutical drugs. They have further yielded basic understanding of protein structure-function relationships. Therefore a number of studies on these non-enzymatic proteins had major impact on several life science and medical fields. They have led to life-saving therapeutics, the Nobel prize, and development of molecular scalpels for elucidation of ion channel function, vasoconstriction, complement system activity, platelet aggregation, blood coagulation, signal transduction, and blood pressure regulation. Here, we identify research papers that have had significant impact on the life sciences. We discuss how these findings have changed the course of science, and have also included the personal recollections of the original authors of these studies. We expect that this review will provide impetus for even further exciting research on novel toxins yet to be discovered. 23639192 Puerarin stimulates proliferation and differentiation and protects against cell death in human osteoblastic MG-63 cells via ER-dependent MEK/ERK and PI3K/Akt activation. Puerarin, the main isoflavone glycoside found in the Chinese herb radix of Pueraria lobata (Willd.) Ohwi, has received increasing attention because of its possible role in the prevention of osteoporosis. Previously, we showed that puerarin could inhibit the bone absorption of osteoclasts and promote long bone growth in fetal mouse in vitro. Further study confirmed that puerarin stimulated proliferation and differentiation of osteoblasts in rat. However, the mechanisms underlying its actions on human bone cells have not been well defined. Here we show that puerarin increases proliferation and differentiation and opposes cisplatin-induced apoptosis in human osteoblastic MG-63 cells containing two estrogen receptor (ER) isoforms. Puerarin promotes proliferation by altering cell cycle distribution whereas puerarin-mediated survival may be associated with up-regulation of Bcl-xL expression. Treatment with the ER antagonist ICI 182,780 abolishes the above actions of puerarin on osteoblast-derived cells. Using small interfering double-stranded RNA technology, we further demonstrate that the effects of puerarin on proliferation, differentiation and survival are mediated by both ERα and ERβ. Moreover, we also demonstrate that puerarin functions at least partially through activation of MEK/ERK and PI3K/Akt signaling. This agent also shows much weaker effect on breast epithelial cell growth than that of estrogen. Therefore, puerarin will be a promising agent that prevents or retards osteoporosis. 23529894 Biomimetic Synthesis and Studies Toward Enantioselective Synthesis of Flindersial Alkaloids. A strategy allowing both stereocontrol and control over structural isomer formation has been defined for the antimalarial flindersial alkaloids. The recently reported flinderoles were demonstrated to be derived from the natural product borrerine. The structural isomers of flinderoles, the borreverines, were also produced in vitro along with the flinderoles through the dimerization of borrerine in acidic conditions. This result is thought to replicate the biosynthesis of these compounds. Flinderoles A, B, and C, desmethylflinderole C, isoborreverine, and dimethylisoborreverine can each be synthesized in three steps from tryptamine. Furthermore, progress toward a concise enantioselective synthesis of flinderoles A, B, and C is described. This work includes enantioselective conjugate addition to an unprotected indole-appended enone. Chirality 00:000-000, 2013. © 2013 Wiley Periodicals, Inc. 23435910 Effect of sinapic acid against dimethylnitrosamine-induced hepatic fibrosis in rats. Sinapic acid is a member of the phenylpropanoid family and is abundant in cereals, nuts, oil seeds, and berries. It exhibits a wide range of pharmacological properties. In this study, we investigated the hepatoprotective and antifibrotic effects of sinapic acid on dimethylnitrosamine (DMN)-induced chronic liver injury in rats. Sinapic acid remarkably prevented DMN-induced loss of body weight. This was accompanied by a significant increase in levels of serum alanine transaminase, aspartate transaminase, and liver malondialdehyde content. Furthermore, sinapic acid reduced hepatic hydroxyproline content, which correlated with a reduction in the expression of type I collagen mRNA and histological analysis of collagen in liver tissue. Additionally, the expression of hepatic fibrosis-related factors such as α-smooth muscle actin and transforming growth factor-β1 (TGF-β1), were reduced in rats treated with sinapic acid. Sinapic acid exhibited strong scavenging activity. In conclusion, we find that sinapic acid exhibits hepatoprotective and antifibrotic effects against DMN-induced liver injury, most likely due to its antioxidant activities of scavenging radicals, its capacity to suppress TGF-β1 and its ability to attenuate activation of hepatic stellate cells. This suggests that sinapic acid is a potentially useful agent for the protection against liver fibrosis and cirrhosis. 23104244 Cytochrome P450-mediated herb-drug interaction potential of Galgeun-tang. We evaluated the herb-drug interaction potential of Galgeun-tang (GGT) extracts, mediated by cytochrome P450 (CYP) inhibition/induction. Further, the effects of fermentation on the CYP-mediated herb-drug interaction potential of GGT extracts were determined. As measured by LC-ESI/MS/MS, GGT extracts (0-300μg/mL) showed no inhibitory activity toward eight CYP isoforms (1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4) in pooled human liver microsomes, suggesting that GGT may have low potential for herb-drug interactions mediated by CYP inhibition. Hepatic CYP expression and activity in rats treated with GGT extracts twice per day for 1week was examined. Among the tested CYP isoforms (1A1, 1A2, 1B1, 2B1, 2C11, 2E1, 3A1, 3A2, and 4A1), CYP1B1 and 4A1 were increased by GGT extracts. Hepatic activities of 7-ethoxyresorufin-O-deethylase, 7-pentoxyresorufin-O-depentylase, and chlorzoxazone 6-hydroxylase, but not midazolam hydroxylase were also elevated. These results raise the possibility that GGT extracts may increase the toxicity of environmental toxicants through the elevating CYP-dependent metabolic activation. Interestingly, the increases in CYP1B1 and CYP4A1 levels, and 7-ethoxyresorufin-O-deethylase, 7-pentoxyresorufin-O-depentylase, and chlorzoxazone 6-hydroxylase activities were attenuated by fermentation of GGT extract using Lactobacillus plantarum KFRI 402, but not 144. Further studies are needed to identify the CYP regulatory component(s) from GGT and determination its metabolism. 23266719 Immunomodulatory properties of multi-walled carbon nanotubes in peripheral blood mononuclear cells from healthy subjects and allergic patients. In the present study, we investigated the immunomodulatory activity of multi-walled carbon nanotubes (MWCNTs) in peripheral blood mononuclear cells (PBMCs) from healthy donors and mite-allergic subjects. Freshly prepared PBMCs, stimulated or not with Toll-like receptor (TLR)1-9 agonists, a T cell mitogen (phytohemagglutinin A) or mite allergen extract were cultured in the presence or absence of MWCNTs. Secretion of TNF-α, IL-2, IL-5, IL-6, IL-12/23p40 or IFN-γ was quantified in the culture supernatants by ELISA. Basal secretion of all the cytokines was not altered by MWCNTs in PBMCs from both healthy donors and allergic subjects. In PBMCs from healthy donors, TNF-α, IL-6 and IL-12/23p40 secretion in response to the TLR4 agonist, lipopolysaccharide was however increased in a dose-dependent manner by MWCNTs. Significant increases in the release of these cytokines were also observed in PBMCs stimulated with a TLR2 or TLR3 agonist. MWCNTs also increased the release of IL-2 and IFN-γ by PBMCs stimulated with a T cell mitogen. In contrast, MWCNTs inhibited allergen-induced IL-5 secretion by PBMCs from mite-allergic subjects. As well, MWCNTs altered the capacity of PBMC-derived monocytes to differentiate into functional dendritic cells. All together, our data suggest that according to its immune cell target, MWCNTs may either promote or suppress immune responses in humans. Further investigations are necessary to fully understand the complexity behind interactions of engineered nanoparticles with the immune system. 23628154 Novel pharmacokinetic studies of the Chinese formula Huang-Lian-Jie-Du-Tang in MCAO rats. Our previous studies showed that after oral administration of an Huang-Lian-Jie-Du-Tang (HLJDT) decoction, there is a higher concentration of the pure components, berberine, baicalin and gardenoside in the plasma of Middle cerebral artery occlusion (MCAO) rats than in sham-operated rats, The aim of the present study was to determine whether these components could be reliably measured in MCAO rat tissues. First, the plasma concentration-time profiles of berberine, palmatine, baicalin, baicalein and gardenoside were characterised in MCAO rats after oral administration of the aqueous extract of HLJDT. Subsequently, liver, lung and kidney tissues were obtained from sudden death MCAO rats in the absorption phase (0.25h), the distribution phase (1.0h) and the elimination phase (8.0h) after administration of the HLJDT aqueous extract. An HPLC method was developed and validated for the determination of the distribution characteristics of berberine, palmatine, baicalin, baicalein and gardenoside simultaneously from the above-mentioned rat tissues. The results indicated that berberine, palmatine, baicalin and baicalein distributed rapidly and accumulated at high levels in the lung, while gardenoside distributed widely in the lung and the kidney. To the best of our knowledge, this is the first report to describe the distribution of the active ingredients derived from HLJDT in MCAO rat tissues. The tissue distribution results provide a biopharmaceutical basis for the design of the clinic application of HLJDT in cerebrovascular disease. 22827894 Structural requirements for effective oximes - Evaluation of kinetic in vitro data with phosphylated human AChE and structurally different oximes. Treatment of poisoning by various organophosphorus (OP) nerve agents with established acetylcholinesterase (AChE) reactivators (oximes) is insufficient. In consequence, extensive research programs have been undertaken in various countries in the past decades to identify more effective oximes. The efficacy of new compounds has been investigated with different in vitro and in vivo models which hamper the comparison of results from different laboratories. The crucial mechanism of action of oximes is the reactivation of phosphylated AChE. The kinetic properties of these compounds can be quantified in vitro with isolated AChE from different origin. It was tempting to evaluate the reactivation kinetics of a series of oximes with various OP inhibitors performed under identical experimental conditions in order to get insight into structural requirements for adequate affinity and reactivity towards inhibited AChE. The determination of reactivation rate constants with bispyridinium oximes having different linkers, bearing oxime group(s) at different positions and having in part additional substituents revealed that (a) the reactivating potency was dependent on the position of the oxime groups and of additional substituents, (b) small modifications of the oxime structure had an in part marked effect on the kinetic properties and (c) no single oxime had an adequate reactivating potency with AChE inhibited by structurally different OP. These and previous studies underline the necessity to investigate in detail the kinetic properties of novel oximes and that the identification of a single oxime being effective against a broad range of structurally different OP will remain a major challenge. 23199992 Discrimination of cabbage (Brassica rapa ssp. pekinensis) cultivars grown in different geographical areas using ¹H NMR-based metabolomics. Cabbage (Brassica rapa ssp. pekinensis) is one of the most popular foods in Asia and is widely cultivated in many countries for the production of lightly fermented vegetables. In this study, metabolomic analysis was performed to distinguish two cultivars of cabbage grown in different geographical areas, Korea and China, using ¹H NMR spectroscopy coupled with multivariate statistical analysis. Principal component analysis (PCA) showed clear discrimination between extracts of cabbage grown in Korea and China for two different cultivars (Chunmyeong and Chunjung). The major biochemicals (metabolites) that contributed to discrimination between cabbages grown in the two regions were 4-aminobutyrate (GABA), acetate, asparagine, leucine, isoleucine, O-phosphocholine, phenylacetate, phenylalanine, succinate, sucrose, tyrosine, and valine. These results suggest that the levels of the major metabolites that differ significantly between cabbages grown in these two areas were influenced by environmental factors such as climate and geology. Our study demonstrates that ¹H NMR based on metabolomics, coupled with multivariate statistics, can be applied to identify the regions of cultivation of various cabbage cultivars. 23164674 Early life exposure to air pollution: how bad is it? Increasing concentrations of air pollution have been shown to contribute to an enormity of adverse health outcomes worldwide, which have been observed in clinical, epidemiological, and animal studies as well as in vitro investigations. Recently, studies have shown that air pollution can affect the developing fetus via maternal exposure, resulting in preterm birth, low birth weight, growth restriction, and potentially adverse cardiovascular and respiratory outcomes. This review will provide a summary of the harmful effects of air pollution exposure on the developing fetus and infant, and suggest potential mechanisms to limit the exposure of pregnant mothers and infants to air pollution. 23340332 Individual and combined effects of copper and parasitism on osmoregulation in the European eel Anguilla anguilla. The European eel (Anguilla anguilla), a catadromous species, breeds in the sea and migrates to estuarine, lagoon or freshwater habitats for growth and development. Yellow eels, exposed to low or fluctuating salinities, are also exposed to multiple other stressors as pollution, over-fishing and parasitism, which contribute to the dramatic decrease of eel populations in several European countries. The objective of this study was to evaluate the single and combined effects of waterborne copper and experimental infestation of eels with the nematode Anguillicoloides crassus after a salinity challenge from nearly isotonic (18ppt) to hypo- (5ppt) and hypertonic (29ppt) conditions, in order to investigate the osmoregulatory capacity of eels exposed to these stressors. In a nearly isotonic condition (18ppt), blood osmolality remained constant over the 6 weeks contamination to Cu(2+) and Anguillicoloides crassus. In fish exposed to a salinity challenge of 29ppt for 2 weeks, no significant effect was recorded in blood osmolality, Na(+)/K(+)-ATPase (NKA) activity, Na(+) and Cl(-) concentrations. After 2 weeks at 5ppt however, a significant blood osmolality decrease was detected in fish exposed to Anguillicoloides crassus infestation with or without Cu(2+) addition. This decrease may originate from lower Cl(-) levels measured in eels exposed to both stressors. Blood Na(+) levels remained relatively stable in all tested animals, but gill NKA activities were lower in eels exposed to combined stress. No apparent branchial lesions were detected following the different treatments and immunolocalization of NKA revealed well-differentiated ionocytes. Thus, the 5ppt challenge in eels exposed to copper and Anguillicoloides crassus seems to clearly enhance iono/osmoregulatory disturbances. Funded by ANR CES/CIEL 2008-12. 23344820 Biochemical modulation of cell energy by 2-deoxyglucose and malonate in 7,12-dimethylbenz(a)anthracene-induced carcinogenesis in rats. The goal of this study was to explore the impact of 2-deoxglucose or malonate individually or in combination on the level of cell energy (adenosine-5'-triphosphate) and oxidative stress in 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary proliferation in rats. A total of 60 adult female Sprague Dawley rats were randomly divided into five groups (12 rats each): group I serves as the control group. Rats in groups (II-V) were administrated intragastrically a single dose of 50 mg/kg body weight (bw) of DMBA. A day after DMBA administration, rats in group III were injected intraperitoneally (ip) with 100 mg 2-deoxyglucose (2-DG)/kg bw daily. Rats in group IV were injected ip with 10 mg sodium malonate/kg bw daily. Rats in group V were injected ip with 100 mg 2-DG/kg bw and 10 mg sodium malonate/kg bw (treatment for 90 days). The results obtained showed that DMBA induced oxidative stress by decreasing the activities of glutathione reductase (GRase) and superoxide dismutase (SOD), glutathione peroxidase (GPx) and elevating the levels of malondialdehyde (MDA) and nitric oxide (NO) in mammary tissues when compared with control. The combined treatment protected against the previous deleterious changes by a significant elevation in the activities of GRase and SOD, GPx and lowering the levels of MDA and NO more potentially when compared with individual treatment. Apoptosis, as indicated by a significant release of cytochrome c from mitochondria into the cytosol, observed in DMBA-injected rats was positively significantly correlated with the elevation of the level of NO. These data explained the possible additive effect of 2-DG and malonate by depleting the cell energy by their protective effects against the earlier stages of carcinogenesis. 23445125 Vectorization efforts to increase gram-negative intracellular drug concentration: a case study on HldE-K inhibitors. In this paper, we present different strategies to vectorize HldE kinase inhibitors with the goal to improve their gram-negative intracellular concentration. Syntheses and biological effects of siderophoric, aminoglycosidic, amphoteric, and polycationic vectors are discussed. While siderophoric and amphoteric vectorization efforts proved to be disappointing in this series, aminoglycosidic and polycationic vectors were able for the first time to achieve synergistic effects of our inhibitors with erythromycin. Although these effects proved to be nonspecific, this study provides information about the required stereoelectronic arrangement of the polycationic amines and their basicity requirements to fulfill outer membrane destabilization resulting in better erythromycin synergies. 23472886 Design, synthesis, and biological evaluation of indenoisoquinoline rexinoids with chemopreventive potential. Nuclear receptors, such as the retinoid X receptor (RXR), are proteins that regulate a myriad of cellular processes. Molecules that function as RXR agonists are of special interest for the prevention and control of carcinogenesis. The majority of these ligands possess an acidic moiety that is believed to be key for RXR activation. This communication presents the design, synthesis, and biological evaluation of both acidic and nonacidic indenoisoquinolines as new RXR ligands. In addition, a comprehensive structure-activity relationship study is presented that identifies the important features of the indenoisoquinoline rexinoids. The ease of modification of the indenoisoquinoline core and the lack of the necessity of a carboxyl group for activity make them an attractive and unusual family of RXR agonists. This work establishes a structural foundation for the design of new and novel rexinoid cancer chemopreventive agents. 23470105 Light reflection control in biogenic micro-mirror by diamagnetic orientation. As has become known, most materials, such as proteins and DNA, show orientation under strong magnetic fields. However, the critical threshold for the magnetic field of the magnetomechanical phenomena is still unknown. We demonstrate that a thin micro-mirror from a fish scale with high reflectivity exhibits a distinct magnetic response at 100 mT. A dramatic event under a magnetic field is the decrease of light scattering from guanine crystals as well as rapid rotation against the applied magnetic field. Enhancement of light scattering intensity is also observed when the three vectors of light incidence, magnetic field, and observation are orthogonally directed. The results indicate that biogenic guanine crystals have a large diamagnetic anisotropy along the surface parallel and normal directions. The micrometer to submicrometer scale of thin biogenic plates can act as a noninvasively, magnetically controlled micro-mirror for light irradiation control in the micrometer-scale region. 23562765 Bisphenol A affects androgen receptor function via multiple mechanisms. Bisphenol A (BPA), is a well-known endocrine disruptor compound (EDC) that affects the normal development and function of the female and male reproductive system, however the mechanisms of action remain unclear. To investigate the molecular mechanisms of how BPA may affect ten different nuclear receptors, stable cell lines containing individual nuclear receptor ligand binding domain (LBD)-linked to the β-Gal reporter were examined by a quantitative high throughput screening (qHTS) format in the Tox21 Screening Program of the NIH. The results showed that two receptors, estrogen receptor alpha (ERα) and androgen receptor (AR), are affected by BPA in opposite direction. To confirm the observed effects of BPA on ERα and AR, we performed transient transfection experiments with full-length receptors and their corresponding response elements linked to luciferase reporters. We also included in this study two BPA analogs, bisphenol AF (BPAF) and bisphenol S (BPS). As seen in African green monkey kidney CV1 cells, the present study confirmed that BPA and BPAF act as ERα agonists (half maximal effective concentration EC50 of 10-100nM) and as AR antagonists (half maximal inhibitory concentration IC50 of 1-2μM). Both BPA and BPAF antagonized AR function via competitive inhibition of the action of synthetic androgen R1881. BPS with lower estrogenic activity (EC50 of 2.2μM), did not compete with R1881 for AR binding, when tested at 30μM. Finally, the effects of BPA were also evaluated in a nuclear translocation assays using EGPF-tagged receptors. Similar to 17β-estradiol (E2) which was used as control, BPA was able to enhance ERα nuclear foci formation but at a 100-fold higher concentration. Although BPA was able to bind AR, the nuclear translocation was reduced. Furthermore, BPA was unable to induce functional foci in the nuclei and is consistent with the transient transfection study that BPA is unable to activate AR. 22580035 The high affinity IgE receptor (FcεRI) expression and function in airway smooth muscle. The airway smooth muscle (ASM) is no longer considered as merely a contractile apparatus and passive recipient of growth factors, neurotransmitters and inflammatory mediators signal but a critical player in the perpetuation and modulation of airway inflammation and remodeling. In recent years, a molecular link between ASM and IgE has been established through Fc epsilon receptors (FcεRs) in modulating the phenotype and function of these cells. Particularly, the expression of high affinity IgE receptor (FcεRI) has been noted in primary human ASM cells in vitro and in vivo within bronchial biopsies of allergic asthmatic subjects. The activation of FcεRI on ASM cells suggests a critical yet almost completely ignored network which may modulate ASM cell function in allergic asthma. This review is intended to provide a historical perspective of IgE effects on ASM and highlights the recent updates in the expression and function of FcεRI, and to present future perspectives of activation of this pathway in ASM cells. 23227887 Central nervous system disposition and metabolism of Fosdevirine (GSK2248761), a non-nucleoside reverse transcriptase inhibitor: an LC-MS and Matrix-assisted laser desorption/ionization imaging MS investigation into central nervous system toxicity. The CNS disposition and metabolism of Fosdevirine (FDV), an HIV non-nucleoside reverse transcriptase inhibitor, was investigated in four patients who unexpectedly experienced seizures after at least 4 weeks of treatment in a Phase IIb, HIV-1 treatment experienced study. In addition, the CNS disposition and metabolism of FDV was examined in samples from rabbit, minipig, and monkey studies. LC-MS was used to characterize and estimate the concentrations of FDV and its metabolites in cerebral spinal fluid (seizure patients, rabbit, and monkey) and brain homogenate (rabbit, minipig, and monkey). The application of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) provided the spatial distribution of FDV and its metabolites in brain tissue (rabbit, minipig, and monkey). A cysteine conjugate metabolite resulting from an initial glutathione (GSH) Michael addition to the trans-phenyl acrylonitrile moiety of FDV was the predominant drug-related component in the samples from seizure patients, rabbits, and minipigs. This metabolite persisted in the CNS for an extended period of time after the last dose in both seizure patients and minipigs. Furthermore, the localization of this metabolite was found to be highly associated with the white matter in rabbit and minipig brain sections by MALDI IMS. In contrast, the predominant component in monkey CNS was FDV, which was shown to be highly associated with the gray matter. On the basis of these data, several hypothesizes are considered, which might provide insights into species differences in CNS toxicity/seizures observed after FDV dosing. 22841391 Methylselenol, a selenium metabolite, modulates p53 pathway and inhibits the growth of colon cancer xenografts in Balb/c mice. It is has been hypothesized that methylselenol is a critical selenium metabolite for anticancer activity in vivo. In this study, we used a protein array which contained 112 different antibodies known to be involved in the p53 pathway to investigate the molecular targets of methylselenol in human HCT116 colon cancer cells. The array analysis indicated that methylselenol exposure changed the expression of 11 protein targets related to the regulation of cell cycle and apoptosis. Subsequently, we confirmed these proteins with the Western blotting approach, and found that methylselenol increased the expression of GADD 153 and p21 but reduced the level of c-Myc, E2F1 and Phos p38 MAP kinase. Similar to our previous report on human HCT116 colon cancer cells, methylselenol also inhibited cell growth and led to an increase in G1 and G2 fractions with a concomitant drop in S-phase in mouse colon cancer MC26 cells. When the MC26 cells were transplanted to their immune-competent Balb/c mice, methylselenol-treated MC26 cells had significantly less tumor growth potential than that of untreated MC26 cells. Taken together, our data suggest that methylselenol modulates the expression of key genes related to cell cycle and apoptosis and inhibits colon cancer cell proliferation and tumor growth. 23241831 Information hierarchies optimize patient-centered solutions. Enabling science and information technologies has catalyzed a surge of biological, clinical, demographic, health services, and comparative-effectiveness data. While accelerating the deconvolution of complex pathophysiological, medical, social, and environmental networks and systems, these platforms have produced informational quanta devoid of contextualization. Therapeutic innovation is thus now challenged with moving beyond knowledge generation and curation to integrated solution-seeking paradigms that organize functionally related information, producing system-level insights into health and disease for optimized patient-centered outcomes. This annual issue on therapeutics innovations highlights emerging considerations for the generation and hierarchical organization of scientific and clinical information and its translation to advancing next-generation disease management. 23330971 Highly transparent low resistance ZnO/Ag nanowire/ZnO composite electrode for thin film solar cells. We present an indium-free transparent conducting composite electrode composed of silver nanowires (AgNWs) and ZnO bilayers. The AgNWs form a random percolating network embedded between the ZnO layers. The unique structural features of our ZnO/AgNW/ZnO multilayered composite allow for a novel transparent conducting electrode with unprecedented excellent thermal stability (∼375 °C), adhesiveness, and flexibility as well as high electrical conductivity (∼8.0 Ω/sq) and good optical transparency (>91% at 550 nm). Cu(In,Ga)(S,Se)₂ (CIGSSe) thin film solar cells incorporating this composite electrode exhibited a 20% increase of the power conversion efficiency compared to a conventional sputtered indium tin oxide-based CIGSSe solar cell. The ZnO/AgNW/ZnO composite structure enables effective light transmission and current collection as well as a reduced leakage current, all of which lead to better cell performance. 23411079 Steroidal constituents from the leaves of Hosta longipes and their inhibitory effects on nitric oxide production. Hosta longipes (FR. et SAV.) MATSUMURA (Liliaceae) is an edible vegetable in Korea. This study was conducted with the aim of evaluating the potential of H. longipes as a functional food for the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In this respect, the study resulted in the identification of three new steroidal compounds, longipenane (1), longipenane 26-O-β-d-glucopyranoside (2) and neogitogenin 3-O-α-l-rhamnopyranosyl-(1→2)-O-[β-d-glucopyranosyl-(1→4)]-β-d-galactopyranoside (3), along with two known steroidal saponins (4 and 5). The identification and structural elucidation of these compounds were based on 1D and 2D NMR measurements, high-resolution FAB mass spectroscopy (HR-FAB-MS), and chemical methods. A proinflammatory mediator, nitric oxide (NO), in murine microglial BV-2 cells was used to assess the anti-neuroinflammatory effect of the isolated compounds from H. longipes. Among them, compounds 4 and 5 showed strong inhibitory effects on NO production without high cell toxicity in lipopolysaccharide-activated BV-2 cells (IC50=17.66 and 13.16μM, respectively). 23361101 Multiple dosing of ephedra-free dietary supplements: hemodynamic, electrocardiographic, and bacterial contamination effects. Four popular ephedra-free dietary supplements were evaluated for their effects on heart rate (HR), blood pressure (BP), and electrocardiographic (ECG) parameters. Twelve healthy men participated in a study randomized for product sequence, with a 21-day washout period between supplement-administration phases. Throughout the study, Holter monitors were used to assess ECG and HR activity. BP was assessed automatically on multiple occasions. The supplements were ingested three times daily for 3 days. Caffeine content, microbial load, and serum caffeine concentrations were determined. Mean systolic (SBP) and diastolic BP (DBP) readings showed significant increases relative to baseline (10.8 ± 2.5 and 5.3 ± 3.1 mm Hg, respectively; P < 0.05). All supplements significantly increased HR and decreased bradycardia runs; abnormal atrial/ventricular events were frequently noted. Gastrointestinal and sympathomimetic symptoms were also common. Two supplements were heavily contaminated with Bacillus species. In light of these findings, the use of ephedra-free dietary supplements should be discouraged in individuals with hypertension, diabetes, or other cardiovascular diseases. 22939943 Osteocyte control of osteoclastogenesis. Multiple lines of evidence support the idea that osteocytes act as mechanosensors in bone and that they control bone formation, in part, by expressing the Wnt antagonist sclerostin. However, the role of osteocytes in the control of bone resorption has been less clear. Recent studies have demonstrated that osteocytes are the major source of the cytokine RANKL involved in osteoclast formation in cancellous bone. The goal of this review is to discuss these and other studies that reveal mechanisms whereby osteocytes control osteoclast formation and thus bone resorption. This article is part of a Special Issue entitled "The Osteocyte". 23223639 Patterned polymer nanowire arrays as an effective protein immobilizer for biosensing and HIV detection. We report an array of polymeric nanowires for effectively immobilizing biomolecules on biochips owing to the large surface area. The nanowires were fabricated in predesigned patterns using an inductively coupled plasma (ICP) etching process. Microfluidic biochips integrated using the substrates with arrays of nanowires and polydimethylsiloxane channels have been demonstrated to be effective for detecting antigens, and a detection limit of antigens at 0.2 μg mL(-1) has been achieved, which is improved by a factor of 50 compared to that based on flat substrates without the nanowires. In addition, the high sensitivity for clinical detection of human immunodeficiency virus (HIV) antibody has also been demonstrated, showing a 20 times enhancement in fluorescent signal intensity between the samples with positive and negative HIV. 23588681 Emodin-6-O-β-D-glucoside down-regulates endothelial protein C receptor shedding. Endothelial protein C receptor (EPCR) plays an important role in the protein C anticoagulation pathway and in the cytoprotective pathway. Previously, EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-α converting enzyme (TACE). Soluble EPCR levels are increased in patients with systemic inflammatory diseases. Recently, we reported that a new active compound, emodin-6-O-β-D-glucoside (EG) from Reynoutria japonica, has anti-inflammatory activities. However, little is known of the effects of EG on EPCR shedding. Here, we investigated this issue by monitoring the effects of EG on the phorbol-12-myristate 13-acetate (PMA) or the cecal ligation and puncture (CLP)-mediated EPCR shedding and its underlying mechanisms. Data showed that EG potently inhibited the PMA and CLP-induced EPCR shedding by suppressing TACE expression. Given these results, EG could be used as a candidate therapeutic for the treatment of vascular inflammatory diseases. 23557487 New Analysis of the ν3 and ν4 Bands of HNO3 in the 7.6 μm Region. A new line position analysis of the nu3 and nu4 bands of nitric acid (HNO3) at 1326.186 and 1303.072 cm-1 together with its associated interacting bands is presented. The 3^1 and 4^1 energy levels were obtained from an extended analysis of high resolution Fourier transform spectra recorded at Giessen in the 7.6 µm region. The energy levels of 3^1 and 4^1 upper states of nitric acid are strongly interacting with those of the 9^3, 6^2, 5^19^1 and 7^18^1 dark states centered at 1288.899, 1289.46, 1341.05 and 1343.78 cm-1, respectively. Informations on these perturbing dark states were achieved through previous partial investigations of hot bands in high resolution Fourier transform spectra recorded at 22 µm in Giessen (for 3nu9-2nu9 and 3nu9-nu5), at 12 µm in Denver (for 3nu9-nu9), and at 11 µm in Orsay (for nu5+nu9-nu9). The energy levels calculation accounts for the various Fermi, anharmonic, A-type, B-type and C-type Coriolis resonances which couple together the {6^2,9^3,4^1,3^1,5^19^1,7^18^1} interacting energy levels. For nitric acid the nu9 mode (OH torsion relative to the -NO2 moiety) is a large amplitude motion. The theoretical model used in this work accounts also for large amplitude effects in the 93 dark state which lead to a splitting of the 93 energy levels of about 0.060 cm-1. In this way the existence of "torsional" splittings for several nu4 perturbed lines was explained by the occurrence of local A-type and B-type Coriolis resonances coupling the 4^1 energy levels with those of 93. Because four dark bands had to be accounted for in the model, the results of the energy levels calculations are reasonable, although not perfect. However a very significant improvement was achieved in term of understanding the 7.6 µm absorbing bands of nitric acid as compared to the analysis of the nu3 and nu4 bands performed several years ago [Perrin, A.; Lado-Bordowski, O.; Valentin, A. Mol. Phys. 1989, 67, 249-267]. Finally the present analysis also features, for the first time, the nu3+nu9-nu9 hot band located at 1331.09 cm-1. 23245514 Synthesis of perylene bisimide-centered glycodendrimer and its interactions with concanavalin A. A novel glycodendrimer based on 18 peripheral α-D-mannoses functionalized perylene bisimide derivative PBI-18-Man was synthesized and its selectively binding interactions for Con A were investigated by CD spectra and turbidity assay, which exhibited strong binding affinity for Con A with the binding constant of 1.3×10(8) M(-1) (7.2×10(6) M(-1) for monomeric mannose, valency corrected), 3 orders of magnitude higher affinity than the monovalent mannose ligand. Furthermore, the inhibitory activity for Con A was studied by ELLA experiment, showed 2 times inhibitor activity than the reference compound (α-MMP). 23377100 Chemically differentiating ascorbate-mediated dissolution of quantum dots in cell culture media. To investigate the dynamic dissolution of quantum dots (QDs) in cell culture media, in this study we constructed an online automatic analytical system comprising a sequential in-tube solid phase extraction (SPE) device and an inductively coupled plasma (ICP) mass spectrometer. By means of selectively extracting QDs and cadmium ions (Cd(2+)) onto the interior surface of the polytetrafluoroethylene (PTFE) tube, this novel SPE device could be used to determine the degree of QD dissolution through a simple adjustment of sample acidity. To the best of our knowledge, this study is the first to exploit PTFE tubing as a selective SPE adsorbent for the online chemical differentiation of QDs and Cd(2+) ions with the goal of monitoring the phenomenon of QD dissolution in complicated biological matrices. We confirmed the analytical reliability of this system through comparison of the measured Cd-to-QD ratios to the expected values. When analyzing QDs and Cd(2+) ions at picomolar levels, a temporal resolution of 8 min was required to load sufficient amounts of the analytes to meet the sensitivity requirements of the ICP mass spectrometer. To demonstrate the practicability of this developed method, we measured the dynamic variations in the Cd-to-QD705 ratio in the presence of ascorbate as a physiological stimulant to generate reactive oxygen species in cell culture media and trigger the dissolution of QDs; our results suggest that the ascorbate-induced QD dissolution was dependent on the time, treatment concentration, and nature of the biomolecule. 23588093 Artemisia copa aqueous extract as vasorelaxant and hypotensive agent. ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia copa Phil. (Asteraceae) is a medicinal plant commonly used in traditional medicine in Argentina. AIM OF THE STUDY: The vasorelaxant and hypotensive activities of the aqueous extract of Artemisia copa have been investigated. MATERIALS AND METHODS: The in vitro effect of the extract and isolated compounds from Artemisia copa was investigated using isolated rat aortic rings. The acute effect caused by the intravenous (i.v.) infusion (0.1-300mg/kg) on blood pressure and heart rate was evaluated in spontaneous hypertensive rats. In addition, a phytochemical analysis of the extract was performed by HPLC. RESULTS: Artemisia copa had a relaxant effect in endothelium-intact aortic rings that had been pre-contracted with 10(-7)M phenylephrine (Emax=96.7±1.3%, EC50=1.1mg/ml), 10(-5)M 5-hydroxytriptamine (Emax=96.7±3.5%, EC50=1.5mg/ml) and 80mM KCl (Emax=97.9± 4.4%, EC50=1.6mg/ml). In denuded aortic rings contracted by phenylephrine, a similar pattern was observed (Emax=92.7±6.5%, EC50=1.8mg/ml). l-NAME, indomethacin, tetraethylammonium and glibenclamide were not able to block the relaxation induced by the extract. Nevertheless, the pre-treatment with Artemisia copa attenuated the CaCl2-induced contraction in a concentration-dependent manner (Emax: 86% of inhibition for 3mg/ml and 52% de-inhibition for 1mg/ml). This pre-treatment also induced a significant attenuation of the norepinephrine-induced contraction in a concentration-dependent manner (Emax: 72.7% of inhibition for 3mg/ml and 27% de inhibition for 1mg/ml) in a Ca(2+) free medium. Upon analyzing the composition of the extract, the presence of p-coumaric acid, isovitexin, luteolin and chrysoeriol were found. Luteolin (CE50: 1.5μg/ml), chrysoeriol (CE50: 13.2μg/ml) and p-coumaric acid (CE50: 95.2μg/ml), isolated from the aqueous extract, caused dilatation of thoracic aortic rings pre-contracted with phenylephrine. Artemisia copa administered i.v. also induced a decrease in the mean arterial pressure but did not affect the heart rate in hypertensive rats. CONCLUSIONS: The aqueous extract of Artemisia copa proved to have vasorelaxing and hypotensive effects through the inhibition of Ca(2+) influx via membranous calcium channels and intracellular stores. The presence of luteolin, chrysoeriol and p-coumaric acid found in this plant could be involved in this effect. 23011663 Comparative analysis of the protective effects of caffeic acid phenethyl ester (CAPE) on pulmonary contusion lung oxidative stress and serum copper and zinc levels in experimental rat model. The aim of this study was to investigate the effects of caffeic acid phenethyl ester (CAPE) in the lungs by biochemical and histopathological analyses in an experimental isolated lung contusion model. Eighty-one male Sprague-Dawley rats were used. The animals were divided randomly into four groups: group 1 (n = 9) was defined as without contusion and without CAPE injection. Group 2 (n = 9) was defined as CAPE 10 μmol/kg injection without lung contusion. Group 3 (n = 36) was defined as contusion without CAPE-administrated group which consisted of four subgroups that were created according to analysis between days 0, 1, 2, and 3. Group 4 (n = 27) was defined as CAPE 10 μmol/kg administrated after contusion group divided into three subgroups according to analysis on days 1, 2, and 3. CAPE 10 μmol/kg was injected intraperitoneally 30 min after trauma and on days 1 and 2. Blood samples were obtained to measure catalase (CAT) and superoxide dismutase (SOD) activities and level of malondialdehyde (MDA) and for blood gas analysis. Trace elements such as zinc and copper were measured in serum. The lung tissue was also removed for histopathological examination. Isolated lung contusion increased serum and tissue SOD and CAT activities and MDA levels (p < 0.05). Both serum and tissue SOD, MDA, and CAT levels on day 3 were lower in group 4 compared to group 3 (p < 0.05). Further, the levels of SOD, MDA, and CAT in group 4 were similar compared to group 1 (p > 0.05). CAPE also had a significant beneficial effect on blood gases (p < 0.05). Both serum zinc and copper levels were (p < 0.05) influenced by the administration of CAPE. Histopathological examination revealed lower scores in group 4 compared to group 3 (p < 0.05) and no significant differences compared to group 1 (p > 0.05). CAPE appears to be effective in protecting against severe oxidative stress and tissue damage caused by pulmonary contusion in an experimental setting. Therefore, we conclude that administration of CAPE may be used for a variety of conditions associated with pulmonary contusion. Clinical use of CAPE may have the advantage of prevention of pulmonary contusion. 23315938 Research resource: tissue- and pathway-specific metabolomic profiles of the steroid receptor coactivator (SRC) family. The rapidly growing family of transcriptional coregulators includes coactivators that promote transcription and corepressors that harbor the opposing function. In recent years, coregulators have emerged as important regulators of metabolic homeostasis, including the p160 steroid receptor coactivator (SRC) family. Members of the SRC family have been ascribed important roles in control of gluconeogenesis, fat absorption and storage in the liver, and fatty acid oxidation in skeletal muscle. To provide a deeper and more granular understanding of the metabolic impact of the SRC family members, we performed targeted metabolomic analyses of key metabolic byproducts of glucose, fatty acid, and amino acid metabolism in mice with global knockouts (KOs) of SRC-1, SRC-2, or SRC-3. We measured amino acids, acyl carnitines, and organic acids in five tissues with key metabolic functions (liver, heart, skeletal muscle, brain, plasma) isolated from SRC-1, -2, or -3 KO mice and their wild-type littermates under fed and fasted conditions, thereby unveiling unique metabolic functions of each SRC. Specifically, SRC-1 ablation revealed the most significant impact on hepatic metabolism, whereas SRC-2 appeared to impact cardiac metabolism. Conversely, ablation of SRC-3 primarily affected brain and skeletal muscle metabolism. Surprisingly, we identified very few metabolites that changed universally across the three SRC KO models. The findings of this Research Resource demonstrate that coactivator function has very limited metabolic redundancy even within the homologous SRC family. Furthermore, this work also demonstrates the use of metabolomics as a means for identifying novel metabolic regulatory functions of transcriptional coregulators. 23282017 X-ray absorption near edge structure spectroscopy to resolve the in vivo chemistry of the redox-active indazolium trans-[Tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019). Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (1, KP1019) and its analogue sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (2, KP1339) are promising redox-active anticancer drug candidates that were investigated with X-ray absorption near edge structure spectroscopy. The analysis was based on the concept of the coordination charge and ruthenium model compounds representing possible coordinations and oxidation states in vivo. 1 was investigated in citrate saline buffer (pH 3.5) and in carbonate buffer (pH 7.4) at 37 °C for different time intervals. Interaction studies on 1 with glutathione in saline buffer and apo-transferrin in carbonate buffer were undertaken, and the coordination of 1 and 2 in tumor tissues was studied too. The most likely coordinations and oxidation states of the compound under the above mentioned conditions were assigned. Microprobe X-ray fluorescence of tumor thin sections showed the strong penetration of ruthenium into the tumor tissue, with the highest concentrations near blood vessels and in the edge regions of the tissue samples. 23644201 Synthesis, characterization and in vitro pharmacological evaluation of new water soluble Ni(II) complexes of 4N-substituted thiosemicarbazones of 2-oxo-1,2-dihydroquinoline-3-carbaldehyde. Four new Ni(II) complexes of general formula [Ni(H2-Qtsc-R)2](NO3)2 (H2-Qtsc-R = 4N-substituted thiosemicarbazones of 2-oxo-1,2-dihydroquinoline-3-carbaldehyde, where R = H (1), Me (2), Et (3), or Ph (4)) have been synthesized and characterized. The geometry of the complexes was confirmed by single crystal X-ray crystallography for one of the complexes (3). The binding affinity of the complexes with DNA and protein have been studied which indicate that they could interact with calf thymus DNA and bovine serum albumin protein. Investigations of antioxidative properties showed that all the complexes have strong radical scavenging properties. Cytotoxic studies showed that the complexes exhibited effective cytotoxic activity against a panel of human cancer cells without affecting the normal cells much. 23086038 PAQR3 modulates insulin signaling by shunting phosphoinositide 3-kinase p110α to the Golgi apparatus. Phosphoinositide 3-kinase (PI3K) mediates insulin actions by relaying signals from insulin receptors (IRs) to downstream targets. The p110α catalytic subunit of class IA PI3K is the primary insulin-responsive PI3K implicated in insulin signaling. We demonstrate here a new mode of spatial regulation for the p110α subunit of PI3K by PAQR3 that is exclusively localized in the Golgi apparatus. PAQR3 interacts with p110α, and the intracellular targeting of p110α to the Golgi apparatus is reduced by PAQR3 downregulation and increased by PAQR3 overexpression. Insulin-stimulated PI3K activity and phosphoinositide (3,4,5)-triphosphate production are enhanced by Paqr3 deletion and reduced by PAQR3 overexpression in hepatocytes. Deletion of Paqr3 enhances insulin-stimulated phosphorylation of AKT and glycogen synthase kinase 3β, but not phosphorylation of IR and IR substrate-1 (IRS-1), in hepatocytes, mouse liver, and skeletal muscle. Insulin-stimulated GLUT4 translocation to the plasma membrane and glucose uptake are enhanced by Paqr3 ablation. Furthermore, PAQR3 interacts with the domain of p110α involved in its binding with p85, the regulatory subunit of PI3K. Overexpression of PAQR3 dose-dependently reduces the interaction of p85α with p110α. Thus, PAQR3 negatively regulates insulin signaling by shunting cytosolic p110α to the Golgi apparatus while competing with p85 subunit in forming a PI3K complex with p110α. 23270527 Recyclable thermoresponsive polymer-cellulase bioconjugates for biomass depolymerization. Here we report the construction and characterization of a recoverable, thermoresponsive polymer-endoglucanase bioconjugate that matches the activity of unmodified enzymes on insoluble cellulose substrates. Two copolymers exhibiting a thermoresponsive lower critical solution temperature (LCST) were created through the copolymerization of an aminooxy-bearing methacrylamide with N-isopropylacrylamide (NIPAm) or N-isopropylmethacrylamide (NIPMa). The aminooxy group provided a handle through which the LCST was adjusted through small-molecule quenching. This allowed materials with LCSTs ranging from 20.9 to 60.5 °C to be readily obtained after polymerization. The thermostable endoglucanase EGPh from the hypothermophilic Pyrococcus horikoshii was transaminated with pyridoxal-5'-phosphate to produce a ketone-bearing protein, which was then site-selectively modified through oxime linkage with benzylalkoxyamine or 5 kDa-poly(ethylene glycol)-alkoxyamine. These modified proteins showed activity comparable to the controls when assayed on an insoluble cellulosic substrate. Two polymer bioconjugates were then constructed using transaminated EGPh and the aminooxy-bearing copolymers. After 12 h, both bioconjugates produced an equivalent amount of free reducing sugars as the unmodified control using insoluble cellulose as a substrate. The recycling ability of the NIPAm copolymer-EGPh conjugate was determined through three rounds of activity, maintaining over 60% activity after two cycles of reuse and affording significantly more soluble carbohydrates than unmodified enzyme alone. When assayed on acid-pretreated Miscanthus, this bioconjugate increased the amount of reducing sugars by 2.8-fold over three rounds of activity. The synthetic strategy of this bioconjugate allows the LCST of the material to be changed readily from a common stock of copolymer and the method of attachment is applicable to a variety of proteins, enabling the same approach to be amenable to thermophile-derived cellulases or to the separation of multiple species using polymers with different recovery temperatures. 23430368 The metabolic effects of growth hormone in adipose tissue. There is a general consensus that a reduction in growth hormone (GH) secretion results in obesity. However, the pathophysiologic role of GH in the metabolism of lipids is yet to be fully understood. The major somatic targets of GH are bones and muscles, but GH stimulates lipolysis and seems to regulate lipid deposition in adipose tissue. Patients with isolated GH deficiency (GHD) have enlarged fat depots due to higher fat cell volume, but their fat cell numbers are lower than those of matched controls. The treatment of patients with GH results in a relative loss of body fat and shifts both fat cell number and fat cell volume toward normal, indicating an adipogenic effect of GH. Adults with GHD are characterized by perturbations in body composition, lipid metabolism, cardiovascular risk profile, and bone mineral density. It is well established that GHD is usually accompanied by an increase in fat accumulation; GH replacement in GHD results in the reduction of fat mass, particularly abdominal fat mass. In addition, abdominal obesity results in a secondary reduction in GH secretion that is reversible with weight loss. However, whereas GH replacement in patients with GHD leads to specific depletion of intra-abdominal fat, administering GH to obese individuals does not seem to result in a consistent reduction or redistribution of body fat. Although administering GH to obese non-GHD subjects has only led to equivocal results, more recent studies indicate that GH still remains a plausible metabolic candidate. 23561192 Modifications of Kyoho grape berry quality under long-term NaCl treatment. Different concentrations of a sodium chloride spray were applied to the grapevine cultivar Kyoho to determine the effects of salinity on berry quality. The fruit's fresh weight, relative water content, hardness and titratable acid were gradually enhanced with increased salt concentrations. Anthocyanin and soluble solids increased after treatment with moderate salinity (20 and 60mM); however, the results were reversed under high salinity (100 and 150mM). The soluble sugars glucose, fructose and sucrose increased after treatment with moderate salinity, whereas glucose and fructose declined under high salinity. For the six organic acids tested, their total levels were elevated by salinity, which increased the production of tartaric and malic acids. The aroma of the berry was extremely sensitive to salinity and showed a considerable decline in abundance and variety at 20mM NaCl. In summary, moderate salinity enhanced the overall berry quality, but decreased the aroma quality, whereas high salinity decreased the berry quality. 23294699 Pentacyclic hemiacetal sterol with antifouling and cytotoxic activities from the soft coral Nephthea sp. A novel unusual pentacyclic hemiacetal sterol nephthoacetal (1), was isolated from soft coral Nephthea sp. The structure of this sterol was inferred from its two acetyl derivatives (2) and (3), by means of spectroscopic methods, and quantum chemical calculations. Anti-fouling activity of compounds 1-3 against Bugula neritina larvae was evaluated, sterol (1) exhibited significant inhibitory effect with EC(50) value of 2.5 μg/mL, while having low toxicity with LC(50)>25.0 μg/mL. The in vitro cytotoxic activity of compounds 1-3 against HeLa cells was also evaluated, all of them exhibited moderate cytotoxicity with IC(50) values of 12.3 (1), 10.1 (2), and 19.6 μg/mL (3), respectively. 23594310 Signatures of Fano Interferences in the Electron Energy Loss Spectroscopy and Cathodoluminescence of Symmetry-Broken Nanorod Dimers. Through numerical simulation, we predict the existence of the Fano interference effect in the electron energy loss spectroscopy (EELS) and cathodoluminescence (CL) of symmetry-broken nanorod dimers that are heterogeneous in material composition and asymmetric in length. The differing selection rules of the electron probe in comparison to the photon of a plane wave allow for the simultaneous excitation of both optically bright and dark plasmons of each monomer unit, suggesting that Fano resonances will not arise in EELS and CL. Yet, interferences are manifested in the dimer's scattered near- and far-fields and are evident in EELS and CL due to the rapid π-phase offset in the polarizations between super-radiant and subradiant hybridized plasmon modes of the dimer as a function of the energy loss suffered by the impinging electron. Depending upon the location of the electron beam, we demonstrate the conditions under which Fano interferences will be present in both optical and electron spectroscopies (EELS and CL) as well as a new class of Fano interferences that are uniquely electron-driven and are absent in the optical response. Among other things, the knowledge gained from this work bears impact upon the design of some of the world's most sensitive sensors, which are currently based upon Fano resonances. 23439649 E6AP/UBE3A Ubiquitin Ligase Harbors Two E2~ubiquitin Binding Sites. By exploiting (125)I-polyubiquitin chain formation as a functional readout of enzyme activity, we have quantitatively examined the mechanism of human E6AP/UBE3A for the first time. Initial rate studies identify UbcH7 as the cognate E2 carrier protein for E6AP, although related Ubc5 isoforms and the ISG15-specific UbcH8 paralog also support E6AP with reduced efficacy due to impaired binding and catalytic competence. Initial rates of polyubiquitin chain formation displayed hyperbolic kinetics with respect to UbcH7 concentration (Km = 57.6 ± 5.7 nm and kcat = 0.032 ± 0.001 s(-1)) and substrate inhibition above 2 μm. Competitive inhibition by an isosteric UbcH7C86S-ubiquitin oxyester substrate analog (Ki = 64 ± 18 nm) demonstrates that Km reflects intrinsic substrate affinity. In contrast, noncompetitive inhibition by a UbcH7C86A product analog (Ki = 7 ± 0.7 μm) and substrate inhibition at high concentrations require two functionally distinct E2∼ubiquitin substrate binding sites. The kinetics of polyubiquitin chain formation reflect binding at a cryptic Site 1 not previously recognized that catalyzes E6AP∼ubiquitin thioester formation. Subsequent binding of E2∼ubiquitin at the canonical Site 2 present in the extant crystal structure is responsible for polyubiquitin chain elongation. Other rate studies show that the conserved -4 Phe(849) residue is required for polyubiquitin chain formation rather than target protein conjugation as originally suggested. The present studies unambiguously preclude earlier models for the mechanism of Hect domain-catalyzed conjugation through the canonical binding site suggested by the crystal structure and define a novel two-step mechanism for formation of the polyubiquitin degradation signal. 23282999 Zinc sulphate and vitamin E alleviate reproductive toxicity caused by aluminium sulphate in male albino rats. This study was designed to investigate the reproductive toxicity of aluminium sulphate and the therapeutic effects of administration of zinc sulphate and vitamin E individually or in combination against the toxic effect caused by aluminium (Al) in male albino rats. The animals were divided into five groups: group 1 received distilled water and served as control; group 2 received only aluminium sulphate (50 mg/kg body weight (b.w.)); group 3 received aluminium sulphate (50 mg/kg b.w.) plus zinc sulphate (50 mg/kg b.w.); group 4 received aluminium sulphate (50 mg/kg b.w.) and vitamin E (15 mg/kg b.w.); group 5 received aluminium sulphate plus a combination of zinc sulphate and vitamin E in similar doses as above. Doses were administered orally once daily for 45 consecutive days. The results revealed that aluminium sulphate induced significant decrease in body weight gain and testis weight and significant increase in Al level in both serum and testes of male rats. Biochemical analysis showed significant decrease in serum total protein and phospholipids levels, while serum total lipid was significantly elevated post Al treatment. In addition, significant decrease in total protein, phospholipids and cholesterol levels in the testes of Al-treated rats was recorded. The data also showed significant decrease in the levels of serum testosterone, leutinizing hormone and follicle stimulating hormone and significant increase in the level of serum prolactin in Al-intoxicated rats. Moreover, histological examination showed that aluminium sulphate caused apparent alterations in the testicular structure of the treated animals. Treatment with zinc sulphate and vitamin E individually or in combination ameliorated the harmful effects of Al, which was proved histopathologically by the noticeable improvement in the testicular tissues. We can conclude that the tested dose of aluminium sulphate induced toxic effect on the reproductive system of male albino rats and the treatment with zinc sulphate and/or vitamin E alleviated these toxic effects. In some cases, vitamin E exerted a more potent effect, while in other cases, the more potent effect is related to zinc sulphate and the combination of both at most of the recorded data. 23634786 Lanostane Triterpenoids from the Mushroom Naematoloma fasciculare. In our continuing search for structurally interesting and bioactive metabolites from Korean wild mushrooms, bioassay-guided fractionation and a chemical investigation of the MeOH extracts of the fruiting bodies of the mushroom Naematoloma fasciculare resulted in the isolation of four new lanostane triterpenoids (1-4), together with 11 known compounds (5-15). The structures of 1-5 were determined by a combination of 1D and 2D NMR and HRMS. The absolute configuration of the 3-hydroxy-3-methylglutaryl group as a side chain in 1 and 2 was determined by the alkaline methanolysis method. The full NMR data assignment of the known compound fasciculol G (5) is reported for the first time. Compounds 1-15 were tested for their antiproliferative activities against four human cancer cell lines (A549, SK-OV-3, SK-MEL-2, and HCT-15) and evaluated for their inhibitory effects on nitric oxide production in a lipopolysaccharide-activated murine microglial cell line. 23289646 Living unimodal growth of polyion complex vesicles via two-dimensional supramolecular polymerization. Understanding the dynamic behavior of molecular self-assemblies with higher-dimensional structures remains a key challenge to obtaining well-controlled and monodispersed structures. Nonetheless, there exist few systems capable of realizing the mechanism of supramolecular polymerization at higher dimensions. Herein, we report the unique self-assembling behavior of polyion complexes (PICs) consisting of poly(ethylene glycol)-polyelectrolyte block copolymer as an example of two-dimensional supramolecular living polymerization. Monodispersed and submicrometer unilamellar PIC vesicles (nano-PICsomes) displayed time-dependent growth while maintaining a narrow size distribution and a unilamellar structure. Detailed analysis of the system revealed that vesicle growth proceeded through the consumption of unit PICs (uPICs) composed of a single polycation/polyanion pair and was able to restart upon the further addition of isolated uPICs. Interestingly, the resulting vesicles underwent dissociation into uPICs in response to mechanical stress. These results clearly frame the growth as a two-dimensional supramolecular living polymerization of uPICs. 23009741 Ocular perfusion pressure and ocular blood flow in glaucoma. Glaucoma is a progressive optic neuropathy of unknown origin. It has been hypothesized that a vascular component is involved in glaucoma pathophysiology. This hypothesis has gained support from studies showing that reduced ocular perfusion pressure is a risk factor for the disease. The exact nature of the involvement is, however, still a matter of debate. Based on recent evidence we propose a model including primary and secondary insults in glaucoma. The primary insult appears to happen at the optic nerve head. Increased intraocular pressure and ischemia at the post-laminar optic nerve head affects retinal ganglion cell axons. Modulating factors are the biomechanical properties of the tissues and cerebrospinal fluid pressure. After this primary insult retinal ganglion cells function at a reduced energy level and are sensitive to secondary insults. These secondary insults may happen if ocular perfusion pressure falls below the lower limit of autoregulation or if neurovascular coupling fails. Evidence for both faulty autoregulation and reduced hyperemic response to neuronal stimulation has been provided in glaucoma patients. The mechanisms appear to involve vascular endothelial dysfunction and impaired astrocyte-vessel signaling. A more detailed understanding of these pathways is required to direct neuroprotective strategies via the neurovascular pathway. 23421758 Colloidal nanoplasmonics: from building blocks to sensing devices. Nanoplasmonics is a rapidly developing field of research and technology that is based on the ability of small metal particles to interact strongly with light of wavelength significantly larger than their size. The development of nanoplasmonics has been closely associated with the application of colloid science to the controlled growth of metal nanocrystals in solution and to directing the self-assembly of such nanocrystals into organized arrays with enhanced collective properties. Engineering the morphology and the assembly of metal nanoparticles is a key step toward the fabrication of devices with great potential in detection and diagnosis as well as in a wide variety of other fields. In this Feature Article, we provide an overview of the recent work in our laboratory, which in our view somehow reflects the evolution of the field itself and provides guidelines for future research. 23614379 Glycosides from the bark of Machilus robusta. Six new glycosidic constituents (1-6), together with 10 known analogs, have been isolated from the bark of Machilus robusta. Structures of the new compounds, including the absolute configurations, were determined by spectroscopic and chemical methods as ( - )-nectandrin B-β-d-glucopyranoside (1), ( - )-(7R,7'R,8S,8'R)-4,4'-dihydroxy-3,3'-dimethoxy-7,7'-epoxylignan-4-O-β-d-glucopyranoside (2), ( - )-(7R,7'R,8S,8'R)-4,4'-dihydroxy-3,3'-dimethoxy-7,7'-epoxylignan-4'-O-β-d-glucopyranoside (3), ( - )-(8S,8'R)-4,4'-dihydroxy-3,3',5'-trimethoxylignan-4'-O-β-d-glucopyranoside (4), ( - )-(7R,8R)-syringylglycerol-8-O-β-d-glucopyranoside (5), and ( - )-3-hydroxy-2-methyl-4-pyrone-3-O-β-d-xylopyranosyl-(1 → 6)-O-β-d-glucopyranoside (6), respectively. 23627438 Sciadopitysin: active component from Taxus chinensis for anti-Alzheimer's disease. Five taxane diterpenoids derived from the 95% ethanol extract of Taxus chinensis were tested for the inhibitory activities on amyloid-beta (Aβ) peptide aggregation. Using thioflavin-T fluorescence assay, sciadopitysin was found to exhibit the most potency against Aβ aggregation and the formation of fibrils. Further cellular assay indicated that sciadopitysin increased the cell viability of SH-SY5Y cell and demonstrated neuroprotection against Aβ protein-induced insult in primary cortical neurons. According to the authors' best knowledge, this is the first report that sciadopitysin can inhibit the Aβ aggregation and reduce Aβ-induced toxicity in the primary cortical neurons. 22648529 An in vitro Study on the DNA Damaging Effects of Phytochemicals Partially Isolated from an Extract of Glinus lotoides. An extract of Glinus lotoides, a medicinal plant used in Africa and Asia for various therapeutic purposes, was recently shown to cause DNA damage in vitro. To further explore the potential genotoxicity of this plant, fractionation of the crude extract was performed using reverse phase solid-phase extraction and a stepwise gradient elution of methanol in water. Four fractions were collected and subsequently analysed for their DNA damaging effects in mouse lymphoma cells using an alkaline version of the comet assay. To identify potential genotoxic and non-genotoxic principles, each fraction was then subjected to liquid chromatography coupled to mass spectrometry, LC-MS/MS. 1D and 2D nuclear magnetic resonance analyses were used to confirm the identity of some saponins. Although fractions containing a mixture of flavonoids and oleanane-type saponins or oleanane-type saponins alone produced no DNA damage, those containing hopane-type saponins exhibited a pronounced DNA damaging effect without affecting the viability of the cells. To conclude, even if this study presents evidence that hopane-type of saponins are endowed with a DNA damaging ability, further studies are needed before individual saponins can be cited as a culprit for the previously reported genotoxicity of the crude extract of G. lotoides. Copyright © 2012 John Wiley & Sons, Ltd. 23395914 Site dependent intestinal absorption of darunavir and its interaction with ketoconazole. The expression of P-gp increases from proximal to distal parts of the small intestine, whereas for P450 enzymes the expression is reported to be highest in duodenum and jejunum, decreasing to more distal sites. To evaluate to what extent the regional differences in expression of P-gp and P450 enzymes affect the absorption of a dual substrate, we investigated the transport of darunavir across different small intestinal segments (duodenum, proximal jejunum and ileum). Moreover, the effect of ketoconazole on the intestinal absorption of darunavir was explored, since these drugs are commonly co-administered. Performing the rat in situ intestinal perfusion technique with mesenteric blood sampling, we found no significant differences in the transport of darunavir at the different intestinal segments. The involvement of P-gp in the absorption of darunavir was clearly shown by coperfusion of darunavir with the P-gp inhibitor zosuquidar. In presence of zosuquidar, a 2.2-, 4.2- and 5.7-fold increase in Papp values were measured for duodenum, proximal jejunum and ileum, respectively. Involvement of P450 mediated metabolism in the absorption of darunavir could not be demonstrated in this rat model. Upon studying the drug-drug interaction of darunavir with ketoconazole, data were indicative for an inhibitory effect of ketoconazole on P-gp as the main mechanism for the increased transport of darunavir across the small intestine. 23293000 Conformational dynamics of the human propeller telomeric DNA quadruplex on a microsecond time scale. The human telomeric DNA sequence with four repeats can fold into a parallel-stranded propeller-type topology. NMR structures solved under molecular crowding experiments correlate with the crystal structures found with crystal-packing interactions that are effectively equivalent to molecular crowding. This topology has been used for rationalization of ligand design and occurs experimentally in a number of complexes with a diversity of ligands, at least in the crystalline state. Although G-quartet stems have been well characterized, the interactions of the TTA loop with the G-quartets are much less defined. To better understand the conformational variability and structural dynamics of the propeller-type topology, we performed molecular dynamics simulations in explicit solvent up to 1.5 μs. The analysis provides a detailed atomistic account of the dynamic nature of the TTA loops highlighting their interactions with the G-quartets including formation of an A:A base pair, triad, pentad and hexad. The results present a threshold in quadruplex simulations, with regards to understanding the flexible nature of the sugar-phosphate backbone in formation of unusual architecture within the topology. Furthermore, this study stresses the importance of simulation time in sampling conformational space for this topology. 23578625 LC/MS analysis of proteolytic peptides in wheat extracts for determining the content of the allergen amylase/trypsin inhibitor CM3: Influence of growing area and variety. Food allergy from wheat is triggered by several protein classes, such as LTPs, ω5-gliadins and α-amylase/trypsin inhibitors. The latter proteins, belonging to the prolamin superfamily, are mostly involved in baker's asthma, a form of occupational allergy in which the sensitization occurs through the respiratory tract. α-Amylase/trypsin inhibitors were also found to be involved in wheat-related atopic dermatitis. In this work, the allergen Tri a 30 (the CM3 α-amylase/trypsin inhibitor) was quantified in durum wheat salt soluble extracts using a peptidomic approach. CM3 protein identification was confirmed by using LTQ-OrbiTrap analysis on peptides obtained from the enzymatically digested protein separated by gel electrophoresis. Then, marker peptides derived from the protein after enzymatic cleavage of the full wheat extracts were identified by LC-MS/MS. One of them was used as marker for quantitative determination on an UPLC/ESI-MS system by using its isotopically labelled analogue as internal standard, allowing to assess the protein content in the different samples. The CM3 allergenic proteins were found to greatly vary among different cultivation areas. 23106229 The velvet complex governs mycotoxin production and virulence of Fusarium oxysporum on plant and mammalian hosts. Fungal pathogens provoke devastating losses in agricultural production, contaminate food with mycotoxins and give rise to life-threatening infections in humans. The soil-borne ascomycete Fusarium oxysporum attacks over 100 different crops and can cause systemic fusariosis in immunocompromised individuals. Here we functionally characterized VeA, VelB, VelC and LaeA, four components of the velvet protein complex which regulates fungal development and secondary metabolism. Deletion of veA, velB and to a minor extent velC caused a derepression of conidiation as well as alterations in the shape and size of microconidia. VeA and LaeA were required for full virulence of F. oxysporum on tomato plants and on immunodepressed mice. A critical contribution of velvet consists in promoting chromatin accessibility and expression of the biosynthetic gene cluster for beauvericin, a depsipeptide mycotoxin that functions as a virulence determinant. These results reveal a conserved role of the velvet complex during fungal infection on plants and mammals. 23160527 Liver-specific disruption of the murine glucagon receptor produces α-cell hyperplasia: evidence for a circulating α-cell growth factor. Glucagon is a critical regulator of glucose homeostasis; however, mechanisms regulating glucagon action and α-cell function and number are incompletely understood. To elucidate the role of the hepatic glucagon receptor (Gcgr) in glucagon action, we generated mice with hepatocyte-specific deletion of the glucagon receptor. Gcgr(Hep)(-/-) mice exhibited reductions in fasting blood glucose and improvements in insulin sensitivity and glucose tolerance compared with wild-type controls, similar in magnitude to changes observed in Gcgr(-/-) mice. Despite preservation of islet Gcgr signaling, Gcgr(Hep)(-/-) mice developed hyperglucagonemia and α-cell hyperplasia. To investigate mechanisms by which signaling through the Gcgr regulates α-cell mass, wild-type islets were transplanted into Gcgr(-/-) or Gcgr(Hep)(-/-) mice. Wild-type islets beneath the renal capsule of Gcgr(-/-) or Gcgr(Hep)(-/-) mice exhibited an increased rate of α-cell proliferation and expansion of α-cell area, consistent with changes exhibited by endogenous α-cells in Gcgr(-/-) and Gcgr(Hep)(-/-) pancreata. These results suggest that a circulating factor generated after disruption of hepatic Gcgr signaling can increase α-cell proliferation independent of direct pancreatic input. Identification of novel factors regulating α-cell proliferation and mass may facilitate the generation and expansion of α-cells for transdifferentiation into β-cells and the treatment of diabetes. 23553905 An analysis of skeletal development in osteoblast- and chondrocyte-specific Runx2 knockout mice. Global gene deletion studies in mice and humans have established the pivotal role of runt related transcription factor-2 (Runx2) in both intramembranous and endochondral ossification processes during skeletogenesis. In this study, we for the first time generated mice carrying a conditional Runx2 allele with exon 4, which encodes the Runt domain, flanked by loxP sites. These mice were crossed with α1(I)-collagen-Cre or α1(II)-collagen-Cre transgenic mice to obtain osteoblast- or chondrocyte-specific Runx2 deficient mice, respectively. As seen in Runx2(-/-) mice, perinatal lethality was observed in α1(II)-Cre;Runx2(flox/flox) mice, but this was not the case in animals in which α1(I)-collagen-Cre was used to delete Runx2. When using double staining with Alizarin red for mineralized matrix and Alcian blue for cartilaginous matrix, we observed previously that mineralization was totally absent at embryonic day 15.5 throughout the body in Runx2(-/-) mice, but was found in areas undergoing intramembranous ossification such as skull and clavicles in α1(II)-Cre;Runx2(flox/flox) mice. In newborn α1(II)-Cre;Runx2(flox/flox) mice, mineralization impairment was restricted to skeletal areas undergoing endochondral ossification including long bones and vertebrae. In contrast, no apparent skeletal abnormalities were seen in mutant embryo, newborn, and 3- to 6-week old-mice in which Runx2 had been deleted with the α1(I)-collagen-Cre driver. These results suggest that Runx2 is absolutely required for endochondral ossification during embryonic and postnatal skeletogenesis, but that disrupting its expression in already committed osteoblasts as achieved here with the α1(I)-collagen-Cre driver does not affect overtly intramembranous and endochondral ossification. The Runx2 floxed allele established here is undoubtedly useful for investigating the role of Runx2 in particular cells. © 2013 American Society for Bone and Mineral Research. 23249525 Quinpirole and 8-OH-DPAT induce compulsive checking behavior in male rats by acting on different functional parts of an OCD neurocircuit. This study investigated whether the serotonin 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) can induce compulsive checking in a large open field, as does the dopamine D2/D3 receptor agonist quinpirole. To induce compulsive checking, male rats were exposed to eight injections of either 8-OH-DPAT (1 mg/kg), quinpirole (0.2 mg/kg), or saline. Subsequently, to assess cross-sensitization, rats received an acute challenge of 8-OH-DPAT or quinpirole. The results showed that treatment with 8-OH-DPAT induces compulsive checking and may have a stronger effect on this behavior compared with quinpirole. However, there was no cross-sensitization between 8-OH-DPAT and quinpirole on measures of compulsive checking and locomotion. Moreover, the spatial distribution of locomotor paths in 8-OH-DPAT animals was more confined and invariant than in quinpirole rats; their rate of locomotor sensitization was also faster than that in quinpirole animals. Thus, although 8-OH-DPAT and quinpirole can induce compulsive checking in a large open field, the results suggest that they do so differently. It is suggested that 8-OH-DPAT and quinpirole probably produce compulsive behavior by acting on different parts of a security motivation circuit underlying obsessive-compulsive disorder. Quinpirole may induce compulsive checking behavior by directly driving dopaminergic activity mediating the motivational drive to check. Conversely, 8-OH-DPAT may perpetuate the activated motivational state by inhibiting the serotonergic-negative feedback signals that normally deactivate the obsessive-compulsive disorder circuit. 23204443 Sphingosine 1-phosphate receptor 1 (S1P(1)) upregulation and amelioration of experimental autoimmune encephalomyelitis by an S1P(1) antagonist. Sphingosine 1-phosphate receptor 1 (S1P(1)) is a G protein-coupled receptor that is critical for proper lymphocyte development and recirculation. Agonists to S1P(1) are currently in use clinically for the treatment of multiple sclerosis, and these drugs may act on both S1P(1) expressed on lymphocytes and S1P(1) expressed within the central nervous system. Agonists to S1P(1) and deficiency in S1P(1) both cause lymphocyte sequestration in the lymph nodes. In the present study, we show that S1P(1) antagonism induces lymphocyte sequestration in the lymph nodes similar to that observed with S1P(1) agonists while upregulating S1P(1) on lymphocytes and endothelial cells. Additionally, we show that S1P(1) antagonism reverses experimental autoimmune encephalomyelitis in mice without acting on S1P(1) expressed within the central nervous system, demonstrating that lymphocyte sequestration via S1P(1) antagonism is sufficient to alleviate autoimmune pathology. 23570609 Design and evaluation of polyamidoamine dendrimer conjugate with PEG, α-cyclodextrin and lactose as a novel hepatocyte-selective gene carrier in vitro and in vivo. Abstract To develop a novel hepatocyte-selective gene carrier, we prepared polyamidoamine starburst dendrimer (generation 3, G3) conjugates with three functional molecules, i.e. α-cyclodextrin, polyethylene glycol (PEG, molecular weight = 2170) and lactose (PEG-LαCs), and evaluated gene delivery efficiency of these conjugates in vitro and in vivo. PEG-LαC (G3, degrees of substitution of the PEG moiety (DSP) 2.1) showed higher gene transfer activity than other PEG-LαCs (G3, DSP4.0, 6.2) in HepG2 cells, expressing asialoglycoprotein receptor, and the activity decreased in HeLa cells, non-expressing the receptor and in the presence of asialofetuin. High gene transfer activity of PEG-LαC (G3, DSP2.1) was retained even in the presence of 50% serum, although the activity of α-cyclodextrin/lactosylated dendrimer (G3) conjugate (Lac-α-CDE (G3)), which is lacking a PEG moiety, was severely decreased in the presence of 20% serum. PEG-LαC (G3, DSP2.1) provided negligible cytotoxicity up to a charge ratio of 50 (carrier/pDNA) in HepG2 cells and less acute organ toxicity. PEG-LαC (G3, DSP2.1) showed selective gene transfer activity to hepatic parenchymal cells rather than hepatic non-parenchymal cells. These results suggest that PEG-LαC (G3, DSP2.1) is useful as a hepatocyte-selective gene carrier in vitro and in vivo. 23614635 Safety concerns with the long-term management of osteoporosis. Introduction: Postmenopausal osteoporosis is a chronic disease that exerts a significant burden on both individuals and the community. Hence, there is a requirement for long-term treatment to be associated with a positive benefit-risk balance. Areas covered: In this descriptive review, the long-term safety of calcitonin, selective estrogen receptor modulators (SERMs), bisphosphonates, denosumab and strontium ranelate was reviewed based on randomized controlled trials of 3 years or longer supplemented by extension study data and data from large, observational studies. Expert opinion: Rare adverse events become apparent with all currently available treatments for osteoporosis with long-term therapy. Due to the rarity of these adverse events and to the worldwide burden of osteoporosis, the benefit-risk balance remains in favor of the beneficial effects of treatment on an outcome rather than the probability of an adverse effect. No single antiosteoporosis agent is appropriate for all patients. Treatment decisions should be made on an individual basis, taking into account the relative benefits and risks in different patient populations. 23402638 Iron(II)-catalyzed intramolecular aminohydroxylation of olefins with functionalized hydroxylamines. A diastereoselective aminohydroxylation of olefins with a functionalized hydroxylamine is catalyzed by new iron(II) complexes. This efficient intramolecular process readily affords synthetically useful amino alcohols with excellent selectivity (dr up to > 20:1). Asymmetric catalysis with chiral iron(II) complexes and preliminary mechanistic studies reveal an iron nitrenoid is a possible intermediate that can undergo either aminohydroxylation or aziridination, and the selectivity can be controlled by careful selection of counteranion/ligand combinations. 23117790 Orexin-A suppresses postischemic glucose intolerance and neuronal damage through hypothalamic brain-derived neurotrophic factor. Orexin-A (a glucose-sensing neuropeptide in the hypothalamus) and brain-derived neurotrophic factor (BDNF; a member of the neurotrophin family) play roles in many physiologic functions, including regulation of glucose metabolism. We previously showed that the development of postischemic glucose intolerance is one of the triggers of ischemic neuronal damage. The aim of this study was to determine whether there was an interaction between orexin-A and BDNF functions in the hypothalamus after cerebral ischemic stress. Male ddY mice were subjected to 2 hours of middle cerebral artery occlusion (MCAO). Neuronal damage was estimated by histologic and behavioral analyses. Expression of protein levels was analyzed by Western blot. Small interfering RNA directed BDNF, orexin-A, and SB334867 [N-(2-methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea; a specific orexin-1 receptor antagonist] were administered directly into the hypothalamus. The level of hypothalamic orexin-A, detected by immunohistochemistry, was decreased on day 1 after MCAO. Intrahypothalamic administration of orexin-A (1 or 5 pmol/mouse) significantly and dose-dependently suppressed the development of postischemic glucose intolerance on day 1 and development of neuronal damage on day 3. The MCAO-induced decrease in insulin receptor levels in the liver and skeletal muscle on day 1 was recovered to control levels by orexin-A, and this effect of orexin-A was reversed by the administration of SB334867 as well as by hypothalamic BDNF knockdown. These results suggest that suppression of postischemic glucose intolerance by orexin-A assists in the prevention of cerebral ischemic neuronal damage. In addition, hypothalamic BDNF may play an important role in this effect of orexin-A. 23149908 QT dispersion in patients with acromegaly. Acromegaly is a rare condition caused by a pituitary adenoma that secretes growth hormone. The mortality rate is 72 % higher in patients with acromegaly than in the general population according to meta-analyses. Mortality analysis has shown as many as 60 % of acromegalic patients die due to cardiovascular disease. Sudden cardiac death may occur in patients with acromegaly and malignant ventricular arrhythmia may play an important role in this fatal complication; however, the precise mechanism is not fully known. QT dispersion (dQT) is an electrophysiological factor known to be associated with a tendency for ventricular arrhythmia and sudden cardiac death. This study aimed to evaluate dQT as an early predictor of ventricular tachyarrhythmia, as sudden cardiac death commonly occurs in acromegalic patients. This cross-sectional case-control study enrolled 20 patients (10 female and 10 male) with acromegaly and 20 healthy controls (11 female and 9 male) after exclusion criteria were applied. Each participant underwent 12-lead electrocardiography, including ≥3 QRS complexes, at a speed of 25 mm/s after a 15-min rest. In each participant, the QT interval (beginning of the Q wave to the end of the T wave) was corrected (QTc) for heart rate using Bazett's formula [Formula: see text] QTc dispersion (dQTc) (QTc max - QTc min) was also calculated. There was no significant difference in median dQTc between the acromegalic patients (0.79 s) and the controls (0.45 s) (p > 0.05). Active acromegalic patients (n = 14) were estimated to have a median dQTc of 0.82 s, after excluding from the analysis six patients that were under full biochemical control, and that had randomly obtained growth hormone levels <0.4 ng/mL, GH <1 ng/mL based on oral glucose tolerance test, and normal IGF-I for age and gender. A significant difference was noted in median dQTc between the active acromegalic patients and the controls (p = 0.015). The dQT in active acromegalic patients was longer than that in the control group, which indicates that patients with active acromegaly might have an elevated risk for ventricular arrhythmia. We think that a non-invasive, simple and inexpensive marker-measurement of dQT-as part of cardiac monitoring could be valuable for screening complications in acromegalic patients. 23343474 Chemisorbed monolayers of corannulene penta-thioethers on gold. Penta(tert-butylthio)corannulene and penta(4-dimethylaminophenylthio)corannulene form highly stable monolayers on gold surfaces, as indicated by X-ray photoelectron spectroscopy (XPS). Formation of these homogeneous monolayers involves multivalent coordination of the five sulfur atoms to gold with the peripheral alkyl or aryl substituents pointing away from the surface. No dissociation of C-S bonds upon binding could be observed at room temperature. Yet, the XPS experiments reveal strong chemical bonding between the thioether groups and gold. Temperature-dependent XPS study shows that the thermal stability of the monolayers is higher than the typical stability of self-assembled monolayers (SAMs) of thiolates on gold. 23561109 Research on the preparation of antioxidant peptides derived from egg white with assisting of high-intensity pulsed electric field. Egg white protein powder, one of the main egg products, was hydrolysed by Alcalase, Trypsin, and Pepsin respectively to prepare antioxidant peptides. All hydrolysates were assayed by determination of reducing power (RP) ability. Three kinds of hydrolysates were prepared under optimal enzymatic parameters that were obtained from the preliminary one-factor-at-a-time (OFAT) and response surface methodology (RSM) experiments. The results showed that the Alcalase hydrolysates exerted the best RP ability. Thereafter, the Alcalase hydrolysates were sequentially fractionated by ultra filtration membranes in cut-off molecular weight (MW) of 30, 10, and 1kDa, and tested their antioxidant activities in terms of RP ability, DPPH radical scavenging ability, ABTS radical scavenging ability, and FRAP assay. Effects of high intensity pulsed electric field treatment were further investigated on antioxidant peptides to improve their activities. The results showed that Alcalase hydrolysates possessed the strongest antioxidant ability compared with the other two hydrolysates, particularly for the Fraction-3 with MW <1kDa. After PEF treatment, this fraction showed a significant improvement of RP ability within 5h (P<0.05). 23411175 Interaction and digestibility of phaseolin/polyphenol in the common bean. The polyphenols and phaseolin interaction in common bean varieties was studied. Raw beans of three different colours were analysed: black (BRS Supremo), brown (BRS Pontal) and white (WAF-75). Based on the phaseolin digestibility in vitro and phaseolin-polyphenol complexation obtained by SDS-PAGE on a 10% polyacrylamide gel, it was observed that the polyphenols interfere with the digestibility of beans by decreasing the hydrolysis of phaseolin, especially in the darker ones. Furthermore it was possible to verify a difference in the electrophoretic pattern of phaseolin, indicating an interaction between phaseolin and polyphenols. 23118018 Role of 5-hydroxytryptamine 1B (5-HT1B) receptors in the regulation of ethanol intake in rodents. Evidence indicates that the serotonergic system is important in mediating dependence on and craving for alcohol. Among serotonin receptors, 5-hydroxytryptamine 1B (5-HT1B) receptors have been associated with drug abuse including alcohol. In this review, the neurocircuitry involving 5-HT1B receptors in central reward brain regions related to alcohol intake are discussed in detail. Emphasis has been placed on the pharmacological manipulations of 5-HT1B receptor-mediated alcohol intake. Furthermore, 5-HT1B auto- and hetero-receptors regulate alcohol intake through the regulatory mechanism involving release of 5-HT, gamma-aminobutyric acid (GABA), dopamine, and glutamate is evaluated. Thus, interactions between 5-HT1B receptors and these neurotransmitter systems are suggested to modulate alcohol-drinking behavior. This review on the role of 5-HT1B receptors in neurotransmitter release and consequent alcohol intake provides important information about the potential therapeutic role of 5-HT1B receptors for the treatment of alcohol dependence. 23459146 Effects of sodium fluoride on reproductive function in female rats. The aim of this study was to investigate the effects of sodium fluoride (NaF) on female reproductive function and examine the morphology of the ovaries and uteri of rats exposed to NaF. Eighty female Sprague-Dawley (SD) rats were divided randomly into four groups of 20: one control group and three NaF treated groups. The three NaF treated groups received 100, 150, and 200ppm, respectively, of NaF for 6months via their drinking water, while the control group (GC) received distilled water. The levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), progesterone (P) and estradiol (E2) were measured using an enzyme-linked immunosorbent assay. Pathomorphological evaluation of the uteri and ovaries was conducted after staining with hematoxylin-eosin and immunohistochemistry. The rate of successful pregnancy in the NaF-treated groups declined in a dose-dependent manner. The concentration of reproductive hormones was significantly lower in the three NaF-treated groups, and the endometrium was damaged. The maturation of follicles was inhibited. In addition, the total number of follicles of all types was significantly lower in the NaF-treated groups. These results suggest that female reproductive function is inhibited by NaF and that exposure to NaF causes ovarian and uterine structural damage. NaF may thus significantly reduce the fertility of female rats. 23590689 High Level ab initio Calculations for ClFn(+) (n=1-6) Ions: Refining the Recoupled Pair Bonding Model. Based on detailed, high level ab initio calculations on a number of halogenated compounds of second row, late p-block elements, the SFn, ClFn, PFn, SCln, and SFnCl families, we found that a new type of bond - the recoupled pair bond - accounts for the ability of these elements to form hypervalent, or hypercoordinated, compounds. Hypervalent molecules are formed when it is energetically favorable for the electrons in a lone pair orbital to be recoupled, allowing each of the electrons to form chemical bonds with ligands. In this paper, we characterize the structures and energetics of the ground and low-lying excited states of the ClFn(+) (n=1-6) ions, using high level ab initio methods [MRCI, CCSD(T)/RCCSD(T)] with large correlation consistent basis sets. We computed a number of quantities, including ClFn(+) structures, bond dissociation energies and ClFn ionization energies, and compare our results with the available experimental data. Both the bond dissociation energies and ionization energies oscillate, variations that are readily explained using the recoupled pair bonding model. Comparisons are drawn between the ClFn(+) cations and their counterparts in the isoelectronic SFn series, which possess many similarities. We found two significant differences between the ClFn(+) and SFn series: (i) the bond dissociation energies of ClFn(+) are much weaker than those of the corresponding SFn species, and (ii) there is no stable (3)A2 state in ClF2(+) corresponding to the stable state found in SF2. Examination of the Mulliken populations at the HF/AVTZ level for ClFn(+) and SFn species predicts that the F atom in the axial (recoupled pair bonding) position is more highly charged than the F atom in the equatorial (covalent bonding) position; there is also less change transfer to the F atoms in ClFn(+) than in SFn. The positive charge on Cl(+) makes it more difficult for an F atom to attract electrons from Cl(+) than from S and correspondingly less favorable to recouple the electrons in the lone pair orbitals in the ClFn(+) species. 23587423 A small molecule inhibitor of fungal histone acetyltransferase Rtt109. The histone acetyltransferase Rtt109 is the sole enzyme responsible for acetylation of histone H3 lysine 56 (H3K56) in fungal organisms. Loss of Rtt109 renders fungal cells extremely sensitive to genotoxic agents, and prevents pathogenesis in several clinically important species. Here, via a high throughput chemical screen of >300,000 compounds, we discovered a chemical inhibitor of Rtt109 that does not inhibit other acetyltransferase enzymes. This compound inhibits Rtt109 regardless of which histone chaperone cofactor protein (Asf1 or Vps75) is present, and appears to inhibit Rtt109 via a tight-binding, uncompetitive mechanism. 23606301 Microfluidic Surface-Enhanced Raman Scattering Sensors Based on Nanopillar Forests Realized by an Oxygen-Plasma-Stripping-of-Photoresist Technique. A novel surface-enhanced Raman scattering (SERS) sensor is developed for real-time and highly repeatable detection of trace chemical and biological indicators. The sensor consists of a polydimethylsiloxane (PDMS) microchannel cap and a nanopillar forest-based open SERS-active substrate. The nanopillar forests are fabricated based on a new oxygen-plasma-stripping-of-photoresist technique. The enhancement factor (EF) of the SERS-active substrate reaches 6.06 × 10(6) , and the EF of the SERS sensor is about 4 times lower due to the influence of the PDMS cap. However, the sensor shows much higher measurement repeatability than the open substrate, and it reduces the sample preparation time from several hours to a few minutes, which makes the device more reliable and facile for trace chemical and biological analysis. 23560557 Takotsubo cardiomyopathy associated with thyrotoxicosis: A case report and review of the literature. Background: Takotsubo or stress-induced cardiomyopathy is a form of reversible cardiomyopathy, commonly associated with emotional or physical stress. Thyrotoxicosis has been identified as a rare cause of Takotsubo cardiomyopathy with only eleven cases reported in the literature. Here, we report a case of thyroid storm presenting with Takotsubo cardiomyopathy in the setting of Graves' disease. Patient Findings: A 71-year-old woman presented with abdominal pain, vomiting, confusion and history of weight loss. She was initially diagnosed and treated for diabetic ketoacidosis at another hospital and was transferred to our hospital one day after initial presentation due to concern for acute coronary syndrome. A diagnosis of Takotsubo cardiomyopathy was made on the basis of cardiac catheterization. At that time, she was diagnosed and treated for thyroid storm. Follow-up 7-weeks later, revealed improvement of her cardiac function and near-normalization of thyroid hormone levels. Summary: In this patient who presented with symptoms of congestive heart failure, acute coronary syndrome was initially considered, but the diagnosis of Takotsubo cardiomyopathy associated with thyroid storm was ultimately made based on cardiac catheterization and laboratory investigation. Conclusions: Thyrotoxicosis is associated with adverse disturbances in the cardiovascular system. Takotsubo cardiomyopathy could be a presenting manifestation of thyroid storm, perhaps related to excess catecholamine levels or sensitivity. 23122155 Antidepressant-like effects of fractions, essential oil, carnosol and betulinic acid isolated from Rosmarinus officinalis L. The aim of this study was to investigate the antidepressant-like effect of fractions from Rosmarinus officinalis L.: ethyl acetate 1 and 2 (AcOEt1 and 2), hexane (HEX), ethanolic (ET), and essential oil-free (EOF) fractions, as well as essential oil, the isolated compounds carnosol and betulinic acid in the tail suspension test, a predictive test of antidepressant activity. Swiss mice were acutely administered by oral route (p.o.) with fractions, essential oil or isolated compounds, 60 min before the tail suspension test or open-field test. All of them produced a significant antidepressant-like effect: AcOEt1, ET, EOF fractions and essential oil (0.1-100mg/kg, p.o); HEX (0.1-10mg/kg, p.o) and AcOEt2 fraction (0.1-1mg/kg, p.o), carnosol (0.01-0.1mg/kg, p.o.) isolated from the HEX fraction and betulinic acid (10mg/kg, p.o.), isolated from the AcOEt1 and AcOEt2 fractions. No psychostimulant effect was shown in the open-field test, indicating that the effects in the tail suspension test are specific. This study suggests that carnosol and betulinic acid could be responsible for the anti-immobility effect of extracts from R. officinalis. 23102508 Enzyme kinetic and molecular docking studies for the inhibitions of miltirone on major human cytochrome P450 isozymes. Previous studies have shown that major tanshinones isolated from Danshen (Salvia miltiorrhiza) inhibited human and rat CYP450 enzymes-mediated metabolism of model probe substrates, with potential in causing herb-drug interactions. Miltirone, another abietane type-diterpene quinone isolated from Danshen, has been reported for its anti-oxidative, anxiolytic and anti-cancer effects. The aim of this study was to study the effect of miltirone on the metabolism of model probe substrates of CYP1A2, 2C9, 2D6 and 3A4 in pooled human liver microsomes. Miltirone showed moderate inhibition on CYP1A2 (IC(50)=1.73 μM) and CYP2C9 (IC(50)=8.61 μM), and weak inhibition on CYP2D6 (IC(50)=30.20 μM) and CYP3A4 (IC(50)=33.88 μM). Enzyme kinetic studies showed that miltirone competitively inhibited CYP2C9 (K(i)=1.48 μM), and displayed mixed type inhibitions on CYP1A2, CYP2D6 and CYP3A4 with K(i) values of 3.17 μM, 24.25 μM and 35.09 μM, respectively. Molecular docking study further confirmed the ligand-binding conformations of miltirone in the active sites of these human CYP450 isoforms, and provided some information on structure-activity relationships for the CYPs inhibition by tanshinones. Taken together, CYPs inhibitions of miltirone were weaker than dihydrotanshinone, but stronger than cryptotanshinone, tanshinone I and tanshinone IIA. 23376439 Aspiration toxicology of hydrocarbons and lamp oils studied by in vitro technology. Medical literature regularly reports on accidental poisoning in children after aspiration of combustibles such as lamp oils which usually contain hydrocarbons or rape methyl esters (RMEs). We aimed to analyze the toxic potential of alkanes and different combustible classes in vitro with regard to biologic responses and mechanisms mediating toxicity. Two different in vitro models were used, i.e. (i) a captive bubble surfactometer (CBS) to assess direct influence of combustibles on biophysical properties of surfactant film and (ii) cell cultures (BEAS-2B and R3/1 cells, primary macrophages, re-differentiated epithelia) closely mimicking the inner lung surface. Biological endpoints included cell viability, cytotoxicity and inflammatory mediator release. CBS measurements demonstrate that combustibles affect film dynamics, i.e. the surface tension/area characteristics during compression and expansion, in a dose and molecular chain length dependent manner. Cell culture results confirm the dose dependent toxicity. Generally, cytotoxicity and cytokine release are higher in short-chained alkanes and hydrocarbon-based combustibles than in long-chained substances, e.g. highest inducible cytotoxicity in BEAS-2B was for hexane 84.6%, decane 74% and hexadecane 30.8%. Effects of RME-based combustibles differed between the cell models. Our results confirm data from animal experiments and give new insights into the mechanisms underlying the adverse health effects observed. 23562245 Quantitative protein analysis using (13)C7-labeled iodoacetanilide and d5-labeled N-ethylmaleimide by nano liquid chromatography/nanoelectrospray ionization ion trap mass spectrometry. We have developed a methodology for quantitative analysis and concurrent identification of proteins by the modification of cysteine residues with a combination of iodoacetanilide (IAA, 1) and (13)C7-labeled iodoacetanilide ((13)C7-IAA, 2), or N-ethylmaleimide (NEM, 3) and d5-labeled N-ethylmaleimide (d5-NEM, 4), followed by mass spectrometric analysis using nano liquid chromatography/nanoelectrospray ionization ion trap mass spectrometry (nano LC/nano-ESI-IT-MS). The combinations of these stable isotope-labeled and unlabeled modifiers coupled with LC separation and ESI mass spectrometric analysis allow accurate quantitative analysis and identification of proteins, and therefore are expected to be a useful tool for proteomics research. 23540754 Biocompatible Polylactide-block-Polypeptide-block-Polylactide Nanocarrier. Polypeptides are successfully incorporated into poly(l-lactide) (PLLA) chains in a ring-opening polymerization (ROP) of l-lactide by using them as initiators. The resulting ABA triblock copolymers possess molecular weights up to 11000 g·mol(-1) and polydispersities as low as 1.13, indicating the living character of the polymerization process. In a nonaqueous emulsion, peptide-initiated polymerization of l-lactide leads to well-defined nanoparticles, consisting of PLLA-block-peptide-block-PLLA copolymer. These nanoparticles are easily loaded by dye-encapsulation and transferred into aqueous media without aggregation (average diameter of 100 nm) or significant dye leakage. Finally, internalization of PLLA-block-peptide-block-PLLA nanoparticles by HeLa cells is demonstrated by a combination of coherent anti-Stokes Raman spectroscopy (CARS) and fluorescence microscopy. This demonstrates the promise of their utilization as cargo delivery vehicles. 23207166 Birth defects after exposure to misoprostol in the first trimester of pregnancy: prospective follow-up study. Misoprostol during the first trimester of pregnancy is associated with a specific malformative pattern (Moebius sequence and limb defects) whose incidence remains unknown. Data originate mostly from illegal use for abortion and are mainly retrospective. The present prospective controlled study analyses outcomes of first trimester misoprostol exposures after medical prescriptions. Malformation rate was higher among 236 pregnancies exposed before 12 gestational weeks (4%) than in 255 controls (1.8%), although not statistically significant (OR=2.2 [95% CI=0.6-7.7]). Three malformations (2%) in the exposed group were consistent with the misoprostol malformative pattern. This is the largest prospective study on first trimester misoprostol exposure and the first one relying on prescriptions. A trend toward a doubling of the overall rate of malformations was observed and for the first time an estimation of the incidence of misoprostol specific spectrum is proposed (2%). Brainstem injuries including severe trismus might be added to this specific pattern. 23265526 The antioxidant activity of teas measured by the FRAP method adapted to the FIA system: optimising the conditions using the response surface methodology. This study proposes a FRAP assay adapted to FIA system with a merging zones configuration. The FIA system conditions were optimised with the response surface methodology using the central composite rotatable design. The optimisation parameters studied were: the carrier flow rate, the lengths of the sample and reagent loops, and reactor length. The conditions selected in accordance with the results were: carrier flow rate of 1.00 ml/min, length of the loops 18.2 cm and length of the reaction coil 210.1 cm. The detection and quantification limits were, respectively, 28.6 and 86.8 μmol/l Fe(2+), and the precision was 1.27%. The proposed method had an analytical frequency of 30 samples/h and about 95% less volume of FRAP reagent was consumed. The FRAP assay adapted to the FIA system under the optimised conditions was utilised to determine the antioxidant activity of tea samples. 23378200 Effects of baicalin on airway remodeling in asthmatic mice. Airway remodeling is an important characteristic of asthma, linking inflammation with airway hyperresponsiveness. Baicalin, a major active component, was isolated from Radix Scutellariae. Many studies show that baicalin has anti-inflammatory, anti-bacterial, and anti-allergic effects. Here we investigate the influence of baicalin on asthmatic airway remodeling and the mechanism underlining the anti-remodeling effect in vivo.Asthmatic airway remodeling mice model was established by ovalbumin exposure. Seventy female BALB/c mice were randomly assigned to seven experimental groups: blank, ovalbumin, hexadecadrol, control, and baicalin (25 mg/kg, 50 mg/kg, 100 mg/kg) groups. Pulmonary function was measured using a whole-body plethysmograph in conscious and unrestrained mice. The lung pathology was observed and measured. The production of cytokines in bronchoalveolar lavage fluid and serum was measured using enzyme-labeled immunosorbent assay kits, and the expression levels of transforming growth factor-β1 and vascular endothelial growth factor were detected by immunohistochemistry. The protein expression levels of transforming growth factor-β1, vascular endothelial growth factor, extracellular signal-regulated kinase, and p21ras were measured using Western blot. The results show that ovalbumin exposure significantly increased the expression of interleukin-13 in BALF and serum, and transforming growth factor-β1, vascular endothelial growth factor, extracellular signal-regulated kinase and p21ras expressions in the lungs. Baicalin attenuated the effects of ovalbumin significantly.It can be concluded that baicalin has significant anti-remodeling effect on ovalbumin-induced asthmatic airway remodeling mice model by decreasing expression of transforming growth factor-β1, interleukin-13, and vascular endothelial growth factor and inhibiting the activation of the extracellular signal-regulated kinase pathway. 23335220 Biotinylated phosphoproteins from kinase-catalyzed biotinylation are stable to phosphatases: implications for phosphoproteomics. Kinase-catalyzed protein phosphorylation is involved in a wide variety of cellular events. Development of methods to monitor phosphorylation is critical to understand cell biology. Our lab recently discovered kinase-catalyzed biotinylation, where ATP-biotin is utilized by kinases to label phosphopeptides or phosphoproteins with a biotin tag. To exploit kinase-catalyzed biotinylation for phosphoprotein purification and identification in a cellular context, the susceptibility of the biotin tag to phosphatases was characterized. We found that the phosphorylbiotin group on peptide and protein substrates was relatively insensitive to protein phosphatases. To understand how phosphatase stability would impact phosphoproteomics research applications, kinase-catalyzed biotinylation of cell lysates was performed in the presence of kinase or phosphatase inhibitors. We found that biotinylation with ATP-biotin was sensitive to inhibitors, although with variable effects compared to ATP phosphorylation. The results suggest that kinase-catalyzed biotinylation is well suited for phosphoproteomics studies, with particular utility towards monitoring low-abundance phosphoproteins or characterizing the influence of inhibitor drugs on protein phosphorylation. 23534442 Novel analgesic/anti-inflammatory agents: 1,5-diarylpyrrole nitrooxyalkyl ethers and related compounds as cyclooxygenase-2 inhibiting nitric oxide donors. A series of 3-substituted 1,5-diarylpyrroles bearing a nitrooxyalkyl side chain linked to different spacers were designed. New classes of pyrrole-derived nitrooxyalkyl inverse esters, carbonates, and ethers (7-10) as COX-2 selective inhibitors and NO donors were synthesized and are herein reported. By taking into account the metabolic conversion of nitrooxyalkyl ethers (9, 10) into corresponding alcohols, derivatives 17 and 18 were also studied. Nitrooxy derivatives showed NO-dependent vasorelaxing properties, while most of the compounds proved to be very potent and selective COX-2 inhibitors in in vitro experimental models. Further in vivo studies on compounds 9a,c and 17a highlighted good anti-inflammatory and antinociceptive activities. Compound 9c was able to inhibit glycosaminoglycan (GAG) release induced by interleukin-1β (IL-1β), showing cartilage protective properties. Finally, molecular modeling and (1)H- and (13)C-NMR studies performed on compounds 6c,d, 9c, and 10b allowed the right conformation of nitrooxyalkyl ester and ether side chain of these molecules within the COX-2 active site to be assessed. 23409765 Impact of quaternary structure dynamics on allosteric drug discovery. The morpheein model of allosteric regulation draws attention to proteins that can exist as an equilibrium of functionally distinct assemblies where: one subunit conformation assembles into one multimer; a different subunit conformation assembles into a different multimer; and the various multimers are in a dynamic equilibrium whose position can be modulated by ligands that bind to a multimer-specific ligand binding site. The case study of porphobilinogen synthase (PBGS) illustrates how such an equilibrium holds lessons for disease mechanisms, drug discovery, understanding drug side effects, and identifying proteins wherein drug discovery efforts might focus on quaternary structure dynamics. The morpheein model of allostery has been proposed as applicable for a wide assortment of disease-associated proteins (Selwood, T., Jaffe, E., (2012) Arch. Bioch. Biophys, 519:131-143). Herein we discuss quaternary structure dynamics aspects to drug discovery for the disease-associated putative morpheeins phenylalanine hydroxylase, HIV integrase, pyruvate kinase, and tumor necrosis factor α. Also highlighted is the quaternary structure equilibrium of transthyretin and successful drug discovery efforts focused on controlling its quaternary structure dynamics. 23574984 Antinociceptive Activity of Stephanolepis hispidus Skin Aqueous Extract Depends Partly on Opioid System Activation. Stephanolepis hispidus is one of the most common filefish species in Brazil. Its skin is traditionally used as a complementary treatment for inflammatory disorders. However, there are very few studies on chemical and pharmacological properties using the skin of this fish. This study was undertaken in order to investigate the effect of aqueous crude extract of S. hispidus skin (SAE) in different nociception models. Here, we report that intraperitoneal administration of SAE inhibited the abdominal constrictions induced by acetic acid in mice. In addition to the effect seen in the abdominal constriction model, SAE was also able to inhibit the hyperalgesia induced by carrageenan and prostaglandin E2 (PGE2) in mice. This potent antinociceptive effect was observed in the hot plate model too, but not in tail-flick test. Naloxone, an opioid receptor antagonist, was able to block the antinociceptive effect of SAE in the abdominal constriction and hot plate models. In addition, SAE did not present cytotoxic or genotoxic effect in human peripheral blood cells. Our results suggest that aqueous crude extract from S. hispidus skin has antinociceptive activity in close relationship with the partial activation of opioid receptors in the nervous system. Moreover, aqueous crude extract from S. hispidus skin does not present toxicity and is therefore endowed with the potential for pharmacological control of pain. 23011759 Carboxylesterases are uniquely expressed among tissues and regulated by nuclear hormone receptors in the mouse. Carboxylesterases (CES) are a well recognized, yet incompletely characterized family of proteins that catalyze neutral lipid hydrolysis. Some CES have well-defined roles in xenobiotic clearance, pharmacologic prodrug activation, and narcotic detoxification. In addition, emerging evidence suggests other CES may have roles in lipid metabolism. Humans have six CES genes, whereas mice have 20 Ces genes grouped into five isoenzyme classes. Perhaps due to the high sequence similarity shared by the mouse Ces genes, the tissue-specific distribution of expression for these enzymes has not been fully addressed. Therefore, we performed studies to provide a comprehensive tissue distribution analysis of mouse Ces mRNAs. These data demonstrated that while the mouse Ces family 1 is highly expressed in liver and family 2 in intestine, many Ces genes have a wide and unique tissue distribution defined by relative mRNA levels. Furthermore, evaluating Ces gene expression in response to pharmacologic activation of lipid- and xenobiotic-sensing nuclear hormone receptors showed differential regulation. Finally, specific shifts in Ces gene expression were seen in peritoneal macrophages following lipopolysaccharide treatment and in a steatotic liver model induced by high-fat feeding, two model systems relevant to disease. Overall these data show that each mouse Ces gene has its own distinctive tissue expression pattern and suggest that some CES may have tissue-specific roles in lipid metabolism and xenobiotic clearance. 23220562 Attenuated expression of the tight junction proteins is involved in clopidogrel-induced gastric injury through p38 MAPK activation. Bleeding complications and delayed healing of gastric ulcer associated with use of clopidogrel is a common clinical concern; however, the underlying mechanisms remain to be determined. This study aimed to clarify whether clopidogrel could cause the damage of the human gastric epithelial cells and to further elucidate the mechanisms involved. After human gastric epithelial cell line GES-1 had been treated with clopidogrel (0.5-2.5 mM), the cell proliferation was examined by MTT assay, apoptosis was measured with DAPI staining and flow cytometry analysis, and the barrier function of the tight junctions (TJ) was evaluated by permeability measurement and transmission electron microscopy. Moreover, expression of the TJ proteins occludin and ZO-1 and the phosphorylation of the mitogen-activated protein kinases (MAPK) p38, ERK, and JNK were examined by western blot. In addition, three MAPK inhibitors specific to p38, ERK and JNK were used, respectively, to verify the signaling pathways responsible for regulating the expression of the TJ proteins being tested. Results showed that clopidogrel significantly increased dextran permeability, induced apoptosis, suppressed GES-1 cell viability, and reduced the expression of the TJ proteins (occludin and ZO-1), acting through p38 MAPK phosphorylation. Furthermore, these observed effects were partially abolished by SB-203580 (a p38 MAPK inhibitor), rather than by either U-0126 (an ERK inhibitor) or SP-600125 (a JNK inhibitor), suggesting that clopidogrel-induced disruption in the gastric epithelial cells is mediated by the p38 MAPK pathway. It is concluded that attenuated expression of the TJ proteins occludin and ZO-1 in human gastric epithelial cells could be involved in clopidogrel-induced gastric mucosal injury through activation of the p38 MAPK pathway. 23318226 ATP stimulates PGE(2)/cyclin D1-dependent VSMCs proliferation via STAT3 activation: role of PKCs-dependent NADPH oxidase/ROS generation. Vascular smooth muscle cells (VSMCs) that function as synthetic units play important roles in cardiovascular diseases. Extracellular nucleotides, such as ATP, have been shown to act via activation of P2 purinoceptors implicated in various inflammatory diseases, we hypothesized that extracellular nucleotides contribute to vascular diseases via up-regulation of inflammatory proteins, including cyclooxygenase-2 (COX-2) and cytosolic phospholipase A2 (cPLA2) in VSMCs. However, the mechanisms of ATP-induced cPLA2 and COX-2 expression and PGE2 synthesis remain largely unclear. We showed that pretreatment with the inhibitors of STAT3 (CBE), NADPH oxidase [diphenyleneiodonium chloride (DPI) or apocynin (APO)], ROS [N-acetyl-l-cysteine (NAC)], and PKC (Ro-318220, Gö6983, or Rottlerin) or transfection with siRNAs of STAT3 and p47(phox) markedly inhibited ATPγS-induced cPLA2 and COX-2 mRNA/protein expression and promoter activity and PGE2 secretion. ATPγS further stimulated PKC, p47(phox), and STAT3 translocation. Moreover, ATPγS-induced STAT3 phosphorylation and translocation was inhibited by pretreatment with the inhibitors of PKC, NADPH oxidase, and ROS. ATPγS enhanced NADPH oxidase activity and ROS generation in VSMCs, which were reduced by pretreatment with Ro-318220, Gö6983, or Rottlerin. Finally, we found that ATPγS significantly induced cyclin D1 expression and VSMCs proliferation, which were inhibited by pretreatment with NAC, APO, DPI, Ro-318220, Gö6983, Rottlerin, or CBE or transfection with siRNAs of COX-2 and cyclin D1. We also demonstrated that ATPγS induced cyclin D1 expression via a PGE2-dependent pathway. These results suggested that ATPγS-induced cPLA2/COX-2 expression and PGE2 secretion is mediated through a PKC/NADPH oxidase/ROS/STAT3-dependent pathway in VSMCs. 22733133 The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression. The tumour suppressor p53, involved in DNA repair, cell cycle arrest and apoptosis, also inhibits blood vessel formation, that is, angiogenesis, a process strongly contributing to tumour development. The p53 gene expresses 12 different proteins (isoforms), including TAp53 (p53 (or p53α), p53β and p53γ) and Δ133p53 isoforms (Δ133p53α, Δ133p53β and Δ133p53γ). The Δ133p53α isoform was shown to modulate p53 transcriptional activity and is overexpressed in various human tumours. However, its role in tumour progression is still unexplored. In the present study, we examined the involvement of Δ133p53 isoforms in tumoural angiogenesis and tumour growth in the highly angiogenic human glioblastoma U87. Our data show that conditioned media from U87 cells depleted for Δ133p53 isoforms block endothelial cell migration and tubulogenesis without affecting endothelial cell proliferation in vitro. The Δ133p53 depletion in U2OS osteosarcoma cells resulted in a similar angiogenesis blockade. Furthermore, using conditioned media from U87 cells ectopically expressing each Δ133p53 isoform, we determined that Δ133p53α and Δ133p53γ but not Δ133p53β, stimulate angiogenesis. Our in vivo data using the chicken chorio-allantoic membrane and mice xenografts establish that angiogenesis and growth of glioblastoma U87 tumours are inhibited upon depletion of Δ133p53 isoforms. By TaqMan low-density array, we show that alteration of expression ratio of Δ133p53 and TAp53 isoforms differentially regulates angiogenic gene expression with Δ133p53 isoforms inducing pro-angiogenic gene expression and repressing anti-angiogenic gene expression. 23299191 Effects of asymmetric dimethylarginine on inflammatory cytokines (TNF-α, IL-6 and IL-10) in rats. This study is intended to examine the effects of administration of asymmetric dimethylarginine (ADMA) on the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-10. A total of 30 Wistar adult albino rats were used. Group I was administrated (n = 10) with 1 mg/kg/day of ADMA, group II (n = 10) was administrated with 2 mg/kg/day of ADMA and the control group was administrated (n = 10) with 0.9% sodium chloride. ADMA was intraperitoneally administrated for 7 days. The serum levels of IL-6, TNF-α and IL-10 were measured. There was a significant decrease in the levels of TNF-α, IL-6 and IL-10 in group I compared with that of the control group (p < 0.001). There was also a significant decrease in the levels of IL-10 in group II compared with that of the control group (p < 0.05) but the increase was much more distinct in the levels of IL-6 and TNF-α (p < 0.001). When comparing the groups by the doses given, no difference between the levels of IL-6 and IL-10 in groups I and II (p > 0.05) was observed; the levels of TNF-α in group II were significantly lower than those of group I (p < 0.05). A significant decrease in the serum levels of inflammatory cytokines IL-6, TNF-α and IL-10, after administration of 1 mg/kg/day and 2 mg/kg/day of ADMA, indicates that ADMA has an effect on inflammation. Increase in ADMA levels in the rats shows that the effects of inflammatory cytokines were suppressed. 23463334 Formulation and pharmacokinetic evaluation of once-daily sustained-released system of nifedipine with solid dispersion and coating techniques. A novel sustained-release system was developed for poorly water-soluble drugs by applying solid dispersion (SD) technique to improve the solubility. The SD systems composed of polyvinyl pyrrolidone and stearic acid could not control the release of nifedipine. When the above SD granules were coated with ethylcellolulose (EC10, 45 and 100cp), the dissolution rate extended from 16 to 20 h. When the concentration of EC100cp was increased to 4-6 %, the sustained-release formulation F7 and F8 prepared with 4 % EC100cp and 6 % EC100cp, respectively, could control the drug release in a better manner, namely, they could control drug release in the initial hours with a high cumulative amount of drug at 24 h. The mechanism of drug release from F7 and F8 was diffusion coupled with erosion. When immediate-release capsules was orally administered to rabbits, its absorption was very rapid with a short elimination half-life, while a prolonged maintenance of the plasma drug level up to 24 h was obtained for F7 and F8. Furthermore, the oral bioavailability of F7 and F8 was significantly improved. The results suggested that this novel sustained-release system would be a promising system to improve the solubility and sustain the absorption of poorly water-soluble drugs. 23596972 Effect of moisture content, temperature and exposure time on the physical stability of chitosan powder and tablets. Abstract Context: Chitosan does not rank highly regarding its employment as tablet filler due to certain limitations. Undesirable properties that limit its utilization as excipient in solid dosage forms include its hydration propensity that negatively affects tablet stability, strength and disintegration. Objective: The objective of this study was to investigate the physical stability of chitosan powder, mixtures, granules and tablets under accelerated conditions such as elevated temperatures and humidity over different periods of time. Methods: Selected physico-chemical properties of pure chitosan powder, physical mixtures of chitosan with Kollidon® VA64 (BASF, Ludwigshafen, Germany), chitosan granules, as well as tablets were evaluated under conditions of elevated humidity and temperature. Results and discussion: The physical stability of chitosan tablets exhibited sensitivity towards varying exposure conditions. It was furthermore evident that the presence of moisture (sorbed water) had a marked influence on the physical stability of chitosan powder and tablets. It was evident that the presence of Kollidon® VA64 as well as the method of inclusion of this binder influenced the properties of chitosan tablets. The physical stability of chitosan powder deteriorated to a greater extent compared to that of the chitosan tablets, which were subjected to the same conditions. Conclusion: It is recommended that tablets containing chitosan should be stored at a temperature not exceeding 25 °C as well as at a relatively low humidity (<60%) to prevent deterioration of physical properties. Direct compression of chitosan granules which contained 5%w/w Kollidon® VA64 produced the best formulation in terms of physical stability at the different conditions. 23379723 Spiropyran polymeric microcapillary coatings for photodetection of solvent polarity. Fused silica microcapillaries were functionalized with spiropyran-polymer brushes using surface-initiated ring-opening metathesis polymerization. Based on the inherited spiropyran properties, the functionalized capillaries were successfully used to photoidentify solvents of different polarity when passing through the microcapillary in continuous flow. In the present study, six different solvents (toluene, tetrahydrofuran, acetone, acetonitrile, ethanol, and methanol) can be easily detected while passing through the modified microcapillary by simply irradiating a portion of it with UV light (365 nm). This converts the closed spiropyran moiety to the open merocyanine form, and as a consequence, the microcapillary gains a distinct color and spectral response depending on the polarity of the solvent. The rate of ring-opening of the spiropyran-polymer brushes coatings has been determined in situ in the presence of different solvents, showing that the coloration rate is also influenced by the solvent polarity and therefore can be used as an additional parameter for solvent sensing. 23579486 A New Strategy for Selective Targeting of Progesterone Receptor with Passive Antagonists. Currently available progesterone receptor (PR) antagonists, such as mifepristone (RU486), lack specificity and display partial agonist properties, leading to potential drawbacks in their clinical use. Recent X-ray crystallographic studies have identified key contacts involved in the binding of agonists and antagonists with PR opening the way for a new rational strategy for inactivating PR. We report here the synthesis and characterization of a novel class of PR antagonists designed from such studies. The lead molecule, the homosteroid APR19, displays in vivo endometrial antiprogesterone activity. APR19 inhibits progesterone-induced PR recruitment and transactivation from synthetic and endogenous gene promoters. Importantly, it exhibits high PR selectivity with respect to other steroid hormone receptors, and is devoid of any partial agonist activity on PR target gene transcription. Two-hybrid and immunostaining experiments reveal that APR19-bound PR is unable to interact with either transcriptional coactivators (SRC1, SCR2) or corepressors (NCoR, SMRT), in contrast to RU486-PR complexes. APR19 also inhibits agonist-induced phosphorylation of serine 294 regulating PR transcriptional activity and turnover kinetics. In-silico docking studies based on the crystal structure of the PR ligand-binding domain show that, in contrast to progesterone, APR19 does not establish stabilizing hydrogen bonds with the ligand binding cavity, resulting in an unstable ligand-receptor complex. Altogether, these properties highly distinguish APR19 from RU486 and likely its derivatives, suggesting that it belongs to a new class of pure antiprogestins which inactivate PR by a passive mechanism. These specific PR antagonists open new perspectives for long term hormonal therapy. 23532446 Transfer of highly porous nanoparticle layers to various substrates through mechanical compression. A new two-step layer transfer process is introduced that is capable of fabricating mechanically stabilized highly porous nanoparticle layers on various substrates. In a first step titanium dioxide nanoparticles were synthesized with Flame-Spray-Pyrolysis and accumulated on a filter paper in the gas phase. In a second step this highly porous filter cake is subsequently transferred to a final substrate via low pressure lamination at room temperature. This leads to mechanical restructuring and stabilization of the porous layer. Pore size analysis indicates homogenization of the layers through rearrangement of the aggregates inside the layers that increases with applied pressure. Additionally, the Young's moduli of the layers were quantified through Colloidal-Probe-Technique indentation measurements with an Atomic-Force-Microscope. The highest lamination pressure of 2.5 MPa resulted in triplication of the Young's modulus. The results show that our novel two-step layer transfer process leads to mechanically stabilized layers that preserve their high porosity. Through the decoupling of the high temperature nanoparticle synthesis and the final substrate the process also enables the possibility to apply temperature sensitive substrates such as polypropylene foil. 23274903 The suprachiasmatic nucleus controls circadian energy metabolism and hepatic insulin sensitivity. Disturbances in the circadian system are associated with the development of type 2 diabetes mellitus. Here, we studied the direct contribution of the suprachiasmatic nucleus (SCN), the central pacemaker in the circadian system, in the development of insulin resistance. Exclusive bilateral SCN lesions in male C57Bl/6J mice, as verified by immunochemistry, showed a small but significant increase in body weight (+17%), which was accounted for by an increase in fat mass. In contrast, mice with collateral damage to the ventromedial hypothalamus and paraventricular nucleus showed severe obesity and insulin resistance. Mice with exclusive SCN ablation revealed a loss of circadian rhythm in activity, oxygen consumption, and food intake. Hyperinsulinemic-euglycemic clamp analysis 8 weeks after lesioning showed that the glucose infusion rate was significantly lower in SCN lesioned mice compared with sham-operated mice (-63%). Although insulin potently inhibited endogenous glucose production (-84%), this was greatly reduced in SCN lesioned mice (-7%), indicating severe hepatic insulin resistance. Our data show that SCN malfunctioning plays an important role in the disturbance of energy balance and suggest that an absence of central clock activity, in a genetically intact animal, may lead to the development of insulin resistance. 23473804 Absence of correlation between oxysterol accumulation in lipid raft microdomains, calcium increase, and apoptosis induction on 158N murine oligodendrocytes. There is some evidence that oxidized derivatives of cholesterol, 7-ketocholesterol (7KC) and 7β-hydroxycholesterol (7βOHC), are increased in the plasma of patients with neurodegenerative diseases associated with demyelinization of the central nervous system (CNS). It was therefore of interest to investigate the effects of these oxysterols on oligodendrocytes, the myelin-forming cells in the CNS. To this end, 158N murine oligodendrocytes were treated with 7KC or 7βOHC inducing an apoptotic mode of cell death characterized by condensation/fragmentation of the nuclei, dephosphorylation of Akt and GSK3, mitochondrial depolarization involving Mcl-1, and caspase-3 activation. In contrast, under treatment with 27-hydroxycholesterol (27OHC), no cell death was observed. When the cells were stained with Fura-2, no significant Ca(2+) rise was found with the different oxysterols, whereas strong signals were detected with ionomycin used as positive control. At concentrations which induced apoptosis, 7KC but not 7βOHC accumulated in lipid rafts. Although not cytotoxic, 27OHC was mainly detected in lipid rafts. It is noteworthy that α-tocopherol (but not ellagic acid and resveratrol) was able to counteract 7KC- and 7βOHC-induced apoptosis and to decrease the accumulation of 7KC and 27OHC in lipid rafts. Thus, in 158N cells, the ability of oxysterols to trigger a mode of cell death by apoptosis involving GSK-3 and caspase-3 activation is independent of the increase in the Ca(2+) level and of their accumulation in lipid raft microdomains. 23322559 New monoterpene lactones from Actaea cimicifuga. Three new monoterpene lactones, cimicifugolides A-C (1-3), along with a known one (4), were identified from the dried rhizome of Actaea cimicifuga L. that was used as traditional Chinese medicine for thousands of years with the Chinese common name of shengma. The structures of the new isolates were established using spectroscopic methods, including NMR, mass, UV, and IR spectra. The inhibition activity of compounds 1, 2, and 4 against pancreatic lipase was evaluated. 23426609 Prescription of antiepileptics and the risk of road traffic crash. Studies assessing the impact of epilepsy and its medication on the risk of road traffic crashes have shown inconsistent results. The aim in this study was to assess this risk using French databases. Data from three French national databases were extracted and matched: the national health care insurance database, police reports, and the national police database of injurious crashes. Only antiepileptics prescribed predominantly in epilepsy were studied (phenobarbital, phenytoin, ethosuximide, valproic acid, vigabatrin, tiagabin, levitiracetam, zonisamide, and lacosamide). A case-control analysis comparing responsible and non-responsible drivers and a case-crossover analysis were performed. Drivers (72 685) involved in an injurious crash in France between July 2005 and May 2008, were included. Drivers exposed to prescribed antiepileptic medicines (n = 251) had an increased risk of being responsible for a crash (OR 1.74 [1.29-2.34]). The association was also significant for the most severe epileptic patients (n = 99; OR = 2.20 [1.31-3.69]). Case-crossover analysis found no association between crash risk and treatment prescription. Patients with prescription of antiepileptic drugs should be cautioned about their potential risk of road traffic crash. This risk is however more likely to be related to seizures than to the effect of antiepileptic medicines. 23473801 Hinokitiol inhibits platelet activation ex vivo and thrombus formation in vivo. Hinokitiol is a tropolone-related bioactive compound that has been used in hair tonics, cosmetics, and food as an antimicrobial agent. Recently, hinokitiol has attracted considerable interest because of its anticancer activities. Platelet activation plays a crucial role in atherothrombotic processes. We examined the effects of hinokitiol treatment on platelet activation using human platelets. In the present study, hinokitiol (1 and 2μM) inhibited the collagen-induced aggregation of human platelets, but did not inhibit the activation of platelets by other agonists, including thrombin, arachidonic acid, and ADP. Hinokitiol inhibited the phosphorylation of phospholipase C (PLC)γ2, protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and Akt in collagen-activated human platelets, and significantly reduced intracellular calcium mobilization and hydroxyl radical (OH) formation. Hinokitiol also reduced the PKC activation and platelet aggregation stimulated by PDBu. In addition, hinokitiol significantly prolonged thrombogenesis in mice. Hinokitiol did not influence the binding of a fluorescent triflavin probe to the αIIbβ3 integrin on platelet membrane, and neither ODQ nor SQ22536 significantly reversed the hinokitiol-mediated inhibition of platelet aggregation. In conclusion, hinokitiol may inhibit platelet activation by inhibiting the PLCγ2-PKC cascade and hydroxyl radical formation, followed by suppressing the activation of MAPKs and Akt. Our study suggests that hinokitiol may represent a potential therapeutic agent for the prevention or treatment of thromboembolic disorders. 23338537 Intracameral cefuroxime: prophylaxis of postoperative endophthalmitis after cataract surgery. Results of the landmark European Society of Cataract and Refractive Surgeons trial and additional prospective and retrospective studies support the use of intracameral cefuroxime in the prophylaxis of endophthalmitis following cataract surgery. Prophylaxis with intracameral cefuroxime at the recommended dose appears to be well tolerated in patients undergoing cataract surgery. However, off-label use of intracameral cefuroxime usually requires a two-step dilution process with the potential for dilution errors, and there are also concerns regarding the risk of contamination. Aprokam® (intracameral cefuroxime) has been approved in the EU for the prophylaxis of postoperative endophthalmitis after cataract surgery. After reconstitution of Aprokam®, no further dilution is required and each vial is only indicated for single-patient use; this has the potential to reduce the risk of both dilution errors and contamination. 23091189 Pharmacokinetic mechanism involved in the prolonged high retention of laninamivir in mouse respiratory tissues after intranasal administration of its prodrug laninamivir octanoate. Laninamivir octanoate (LO) (Inavir; Daiichi Sankyo, Japan) is an ester prodrug of the neuraminidase inhibitor laninamivir. We previously reported that a prolonged high retention of laninamivir in mouse respiratory tissues was achieved by intranasal administration of LO. In this study, we evaluated intrapulmonary pharmacokinetics both in vivo and in vitro to investigate the potential mechanism involved in such a preferable retention. After intranasal administration of LO to mice (0.5 μmol/kg), the drug was distributed from the airway space into the lungs, and laninamivir remained in the lung at 24 hours postdose (2680 pmol/g), with a higher concentration than that in the epithelial lining fluid. The laninamivir was localized mainly on the epithelial cells of airway tracts, determined by microautoradiography using (14)C-labeled LO. In mouse airway epithelial cells, the cellular uptake and hydrolysis of LO were observed over incubation time without any apparent saturation at the highest concentration tested (1000 μM). Furthermore, after additional incubation in drug-free medium, the intracellular laninamivir was released very slowly into the medium with an estimate rate constant of 0.0707 h(-1), which was regarded as a rate-limiting step in the cellular retention. These results demonstrated that the prolonged high retention of laninamivir in the respiratory tissues was attributed to a consecutive series of three steps: uptake of LO into the airway epithelial cells, hydrolysis of LO into laninamivir by intracellular esterase(s), and limited efflux of the generated laninamivir due to its poor membrane permeability. This prodrug approach could be useful for lung-targeting drug delivery. 23427007 Meal conditions affect the absorption of supplemental vitamin D(3) but not the plasma 25-hydroxyvitamin D response to supplementation. It is sometimes assumed that dietary fat is required for vitamin D absorption, although the impact of different amounts of dietary fat on vitamin D absorption is not established. This study was conducted to determine whether the presence of a meal and the fat content of the meal influences vitamin D absorption or the 25-hydroxyvitamin D (25OHD) response to supplemental vitamin D(3) . Based on earlier studies in rats we postulated that absorption would be greatest in the low-fat meal group. Sixty two healthy older men and women were randomly assigned to one of three meal groups: no meal, high-fat meal or low-fat meal; each was given a monthly 50,000 IU vitamin D(3) supplement with the test breakfast meal (or after a fast for the no-meal group) and followed for 90 days. Plasma vitamin D(3) was measured by LC/MS before and 12 hrs after the first dose; plasma 25OHD was measured by radioimmunoassay at baseline and after 30 and 90 days. The mean 12-hr increments in vitamin D(3) , after adjusting for age and sex, were 200.9 nmol/L in the no-meal group, 207.4 nmol/L in the high-fat meal group, and 241.1 nmol/L in the low-fat meal group (P = 0.038), with the increase in the low-fat group being significantly greater than the increases in the other two groups. However, increments in 25OHD levels at 30 and 90 days didn't differ significantly in the three groups. We conclude that absorption was increased when a 50,000 IU dose of vitamin D was taken with a low-fat meal, compared with a high-fat meal and no meal, but that the greater absorption didn't result in higher plasma 25OHD levels in the low-fat meal group. © 2013 American Society for Bone and Mineral Research. 23562324 Genome-wide Analysis Reveals SR Protein Cooperation and Competition in Regulated Splicing. SR proteins are well-characterized RNA binding proteins that promote exon inclusion by binding to exonic splicing enhancers (ESEs). However, it has been unclear whether regulatory rules deduced on model genes apply generally to activities of SR proteins in the cell. Here, we report global analyses of two prototypical SR proteins, SRSF1 (SF2/ASF) and SRSF2 (SC35), using splicing-sensitive arrays and CLIP-seq on mouse embryo fibroblasts (MEFs). Unexpectedly, we find that these SR proteins promote both inclusion and skipping of exons in vivo, but their binding patterns do not explain such opposite responses. Further analyses reveal that loss of one SR protein is accompanied by coordinated loss or compensatory gain in the interaction of other SR proteins at the affected exons. Therefore, specific effects on regulated splicing by one SR protein actually depend on a complex set of relationships with multiple other SR proteins in mammalian genomes. 23143036 Cadmium(Cd)-induced oxidative stress down-regulates the gene expression of DNA mismatch recognition proteins MutS homolog 2 (MSH2) and MSH6 in zebrafish (Danio rerio) embryos. DNA mismatch repair (MMR) of simple base mismatches and small insertion-deletion loops in eukaryotes is initiated by the binding of the MutS homolog 2 (MSH2)-MSH6 heterodimer to mismatched DNA. Cadmium (Cd) is a genotoxic heavy metal that has been recognized as a human carcinogen. Oxidant stress and inhibition of DNA repair have been proposed as major factors underlying Cd genotoxicity. Our previous studies indicated the ability of Cd to disturb the gene expression of MSH6 in zebrafish (Danio rerio) embryos. This study was undertaken to explore if Cd-induced oxidative stress down-regulated MSH gene activities. Following the exposure of zebrafish embryos at 1 h post fertilization (hpf) to sublethal concentrations of Cd at 3-5 μM for 4 or 9 h, a parallel down-regulation of MSH2, MSH6 and Cu/Zn superoxide dismutase (Cu/Zn-SOD) gene expression was detected by real-time RT-PCR and the expression levels were 40-50% of control after a 9-h exposure. Cd exposure also induced oxidative stress, yet no inhibition of catalase gene activity was observed. Whole mount in situ hybridization revealed a wide distribution of msh6 mRNA in the head regions of 10 hpf embryos and pretreatment of embryos with antioxidants butylhydroxytoluene (BHT), d-mannitol or N-acetylcysteine (NAC) at 1-10 μM restored Cd-suppressed msh6 expression. QPCR confirmed the protective effects of antioxidants on Cd-suppressed msh2/msh6 mRNA production. Down-regulated MSH gene activities reaching about 50% of control were also induced in embryos exposed to paraquat, a reactive oxygen species (ROS)-generating herbicide, or hydrogen peroxide at 200 μM. Hence, Cd at sublethal levels down-regulates msh2/msh6 expression primarily via ROS as signaling molecules. The transcriptional activation of human msh6 is known to be fully dependent on the specificity factor 1 (Sp1). Cd failed to inhibit the DNA binding activity of zebrafish Sp1 unless at lethal concentrations based on band shift assay, therefore excluding the involvement of Sp1 inactivation in Cd-induced MSH gene inhibition in zebrafish embryos. 23481677 Helicusin E, Isochromophilone X and Isochromophilone XI: New Chloroazaphilones Produced by the Fungus Bartalinia robillardoides Strain LF550. Microbial studies of the Mediterranean sponge Tethya aurantium led to the isolation of the fungus Bartalinia robillardoides strain LF550. The strain produced a number of secondary metabolites belonging to the chloroazaphilones. This is the first report on the isolation of chloroazaphilones of a fungal strain belonging to the genus Bartalinia. Besides some known compounds (helicusin A (1) and deacetylsclerotiorin (2)), three new chloroazaphilones (helicusin E (3); isochromophilone X (4) and isochromophilone XI (5)) and one new pentaketide (bartanolide (6)) were isolated. The structure elucidations were based on spectroscopic analyses. All isolated compounds revealed different biological activity spectra against a test panel of four bacteria: three fungi; two tumor cell lines and two enzymes. 23322709 A unique palladium catalyst for efficient and selective alkoxycarbonylation of olefins with formates. Forget about CO! Carbonylations are among the most important homogeneously catalyzed reactions in the chemical industry, but typically require carbon monoxide. Instead, straightforward and efficient alkoxycarbonylations of olefins can proceed with alkyl formates in the presence of a specific palladium catalyst. Aromatic, terminal aliphatic, and internal olefins are carbonylated to give industrially important linear esters at low catalyst loadings. 23620199 Trastuzumab Emtansine: First Global Approval. Genentech and ImmunoGen are collaborating on the development of trastuzumab emtansine, a HER2 antibody-drug conjugate that comprises Genentech's trastuzumab antibody linked to ImmunoGen's anti-mitotic agent, mertansine (a maytansine derivative; also known as DM1). The conjugate combines two strategies: the anti-HER2 activity of trastuzumab, and the targeted intracellular delivery of mertansine, a tubulin polymerisation inhibitor which interferes with mitosis and promotes apoptosis. The linker in trastuzumab emtansine is a non-reducible thioether linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC, designated MCC after conjugation). Trastuzumab emtansine (Kadcyla™) has been launched in the USA as second-line monotherapy for HER2-positive metastatic breast cancer, and has been filed for approval in the EU and Japan in this indication. Trastuzumab emtansine is in phase III development as first-line combination therapy or monotherapy for metastatic HER2-positive breast cancer, and as third-line monotherapy for metastatic HER2-positive breast cancer. Phase II development is underway for early-stage breast cancer and phase II/III development is underway in patients with HER2-positive gastric cancer. This article summarizes the milestones in the development of trastuzumab emtansine leading to this first approval for the treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. 23208609 Endocrine-disrupting effects of thioxanthone photoinitiators. Photoinitiators used in food packaging ink, such as 2-isopropylthioxanthone (2-ITX), have been shown to migrate into food and beverages. Recently, several studies indicated that 2-ITX might be an endocrine-disrupting chemical. In this work, the effects of 2-ITX, 4-isopropylthioxanthone (4-ITX), 2,4-diethylthio xanthone (2,4-diethyl-TX), 2-chlorothioxanthone (2-chloro-TX), and 1-chloro-4-propoxythioxanthone (1-chloro-4-propoxy-TX) on steroidogenesis and androgen and estrogen receptor-mediated transcription activation have been studied using human H295R adrenocarcinoma cells and yeast hormone bioassays, respectively. None of the compounds showed androgenic or estrogenic activities, but clear antiandrogenic and antiestrogenic activities were observed for 2-ITX, 4-ITX, and 2,4-diethyl-TX, whereas 2-chloro-TX showed only antiandrogenic activity. In an adapted version of the H295R steroidogenesis assay, using gas chromatography-tandem mass spectrometry analysis of H295R media, all five compounds increased levels of 17ß-estradiol and estrone. H295R cells incubated with 2-ITX also showed significantly reduced androgen and increased pregnenolone and progesterone levels. Expression of particular steroidogenic genes, including the one encoding for aromatase (CYP19A1), was significantly upregulated after incubation of H295R cells with 2-ITX, 4-ITX, and 2,4-diethyl-TX. In line with the increased CYP19A1 mRNA expression, 2-ITX increased catalytic activity of aromatase in H295R cells as measured by cognate aromatase assays. The results indicate that thioxanthone derivatives can act as potential endocrine disruptors both at the level of nuclear receptor signaling and steroid hormone production. 23470034 A new tetracyclic triterpenoid compound from Mastich. A new tetracyclic triterpenoid compound named as mastichinoic acid A (1) was isolated from Mastich. The structure was established as 3,7-dioxo-11β-hydroxy-5α-tirucalla-8,24(Z)-dien-26-oic acid by various spectroscopic techniques including MS, 1D, and 2D NMR and HRTOFMS. 23577042 Microrheology of highly crosslinked microtubule networks is dominated by force-induced crosslinker unbinding. We determine the time- and force-dependent viscoelastic responses of reconstituted networks of microtubules that have been strongly crosslinked by biotin-streptavidin bonds. To measure the microscale viscoelasticity of such networks, we use a magnetic tweezers device to apply localized forces. At short time scales, the networks respond nonlinearly to applied force, with stiffening at small forces, followed by a reduction in the stiffening response at high forces, which we attribute to the force-induced unbinding of crosslinks. At long time scales, force-induced bond unbinding leads to local network rearrangement and significant bead creep. Interestingly, the network retains its elastic modulus even under conditions of significant plastic flow, suggesting that crosslinker breakage is balanced by the formation of new bonds. To better understand this effect, we developed a finite element model of such a stiff filament network with labile crosslinkers obeying force-dependent Bell model unbinding dynamics. The coexistence of dissipation, due to bond breakage, and the elastic recovery of the network is possible because each filament has many crosslinkers. Recovery can occur as long as a sufficient number of the original crosslinkers are preserved under the loading period. When these remaining original crosslinkers are broken, plastic flow results. 23511610 Patterning of controllable surface wettability for printing techniques. Patterning of controllable surface wettability has attracted wide scientific attention due to its importance in both fundamental research and practical applications. In particular, it is crucial to form clear image areas and non-image areas in printing techniques based on wetting and dewetting. This review summarizes the recent research on and applications of patterning of controllable surface wettability for printing techniques, with a focus on the design and fabrication of the precise surface wettability patterning by enhancing the contrast of hydrophilicity and hydrophobicity, such as superhydrophilicity and superhydrophobicity. The selected topics mainly include patterned surface wettability for lithographic printing with different plate-making techniques, patterned surface wettability for microcontact printing with a patterned wetting stamp and special wettability mediated patterning microtransfer printing, patterned surface wettability for inkjet printing with controllable surface wettability of the substrate and printing head to ink, and patterned surface wettability by a combination of different printing techniques. A personal perspective on the future development and remaining challenges of this research is also briefly discussed. 23418859 Salidroside attenuates myocardial ischemia-reperfusion injury via PI3K/Akt signaling pathway. To investigate the cardioprotective effects of salidroside on myocardial ischemia-reperfusion injury (IRI) in rabbits and the underlying action mechanisms in PI3K/Akt signaling pathway, a rabbit ischemia/reperfusion model was created by ligating the left anterior descending coronary arterial branch for 30 min and by releasing the ligature to allow reperfusion for 120 min. Salidroside or salidroside+PI3K inhibitor (LY294002) was administered via intracoronary injections at the onset of reperfusion. Apoptosis of cardiomyocytes was assessed by terminal dUTP nick-end labeling assay, and the expression of apoptosis-related proteins was observed by immunohistochemistry. The expressions of total Akt and phosphorylated Akt (p-Akt) were detected by western blot analysis. The results showed that intracoronary injection of salidroside at the onset of reperfusion markedly reduced the apoptosis of cardiomyocytes, significantly increasing Bcl-2 and p-Akt proteins expressions and decreasing Bax and caspase-3 expressions in the hearts subjected to ischemia followed by 120-min reperfusion. However, the anti-apoptotic effect induced by salidroside was inhibited by LY294002, which blocked the activation of Akt. These results suggested that intracoronary administration of salidroside at the onset of reperfusion could significantly reduce the IRI-induced apoptosis of cardiomyocytes, and this protective mechanism seemed to be mediated by the PI3K-Akt signaling pathway. 23391484 In vitro toxicological characterization of perfluorinated carboxylic acids with different carbon chain lengths. Perfluorooctanoic acid (PFOA) is in use for the production of fluoropolymers (PFT). Due to its toxic properties it was proposed to replace the substance in its industrial applications by homologous compounds with shorter carbon chain length that were supposed to be less toxic compared to PFOA, however, the smaller PFOA homologs are poorly characterized so far. In this study we have conducted a comparative analysis of the toxicity of perfluorinated carboxylic acids (PFCA) with a carbon chain length ranging from four to twelve carbon atoms. By using the human hepatocarcinoma cell line HepG2 as an in vitro model for human hepatocytes we could show a positive correlation between the carbon chain length of the respective PFCA and its cytotoxicity. There was, however, no indication of an apoptotic mechanism for cytotoxicity. All PFCA under investigation were negative in two independent genotoxicity assays. As PFOA, being a well-known peroxisome proliferator, the other PFCA tested in this study were also shown to activate human peroxisome proliferator-activated receptor alpha (PPARα) with PFOA having the highest potential of PPARα activation. Moreover, the compounds showed weak potential to activate PPARγ and hardly activated PPARδ. Taken together, the in vitro study revealed that PFCA with a shorter carbon chain length seem to be less toxic than PFOA. 23599431 Induction of C-X-C Chemokine Receptor Type 7 (CXCR7) Switches Stromal Cell-Derived Factor-1 (SDF-1) Signaling and Phagocytic Activity in Macrophages Linked to Atherosclerosis. The discovery of CXCR7 as a new receptor for SDF-1 places many previously described SDF-1 functions attributed to CXCR4 in question, though whether CXCR7 acts as a signaling or decoy receptor has been in debate. It is known that CXCR7 is not expressed in normal blood leukocytes; however, the potential role of leukocyte CXCR7 in disease states has not been addressed. The aim of this study was to determine the expression and function of macrophage CXCR7 linked to atherosclerosis. Here, we show that CXCR7 was detected in macrophage-positive area of aortic atheroma of ApoE-null mice, but not in healthy aorta. During monocytes differentiation to macrophages, CXCR7 was up-regulated at mRNA and protein levels, with more expression in M1 than in M2 phenotype. In addition, CXCR7 induction was associated with a SDF-1 signaling switch from the pro-survival ERK and AKT pathways in monocytes to the pro-inflammatory JNK and p38 pathways in macrophages. The latter effect was mimicked by a CXCR7-selective agonist TC14012 and abolished by siRNA knockdown of CXCR7. Furthermore, CXCR7 activation increased macrophage phagocytic activity, which was suppressed by CXCR7 siRNA silencing or by inhibiting either the JNK or p38 pathways, but was not affected by blocking CXCR4. Finally, activation of CXCR7 by I-TAC showed a similar signaling and phagocytic activity in macrophages with no detectable CXCR3. We conclude that CXCR7 is induced during monocyte-to-macrophage differentiation, which is required for SDF-1 and I-TAC signaling to JNK and p38 pathways, leading to enhanced macrophage phagocytosis, thus possibly contributing to atherogenesis. 23297713 Topical wound-healing effects and phytochemical composition of heartwood essential oils of Juniperus virginiana L., Juniperus occidentalis Hook., and Juniperus ashei J. Buchholz. Ethnobotanical surveys indicated that in the traditional medicines worldwide, several Juniperus species are utilized as antihelmintic, diuretic, stimulant, antiseptic, carminative, stomachic, antirheumatic, antifungal, and for wound healing. In the present study, essential oils obtained from heartwood samples of Juniperus virginiana L., Juniperus occidentalis Hook. and Juniperus ashei J. Buchholz were evaluated for wound healing and anti-inflammatory activities by using in vivo experimental methods. The essential oils were obtained by the supercritical carbon dioxide extraction method. Linear incision and circular excision wound models were performed for the wound-healing activity assessment. The tissues were also evaluated for the hydroxyproline content as well as histopathologically. To evaluate the anti-inflammatory activity of the essential oils, the test used was an acetic acid-induced increase in capillary permeability. The essential oil of J. occidentalis showed the highest activity on the in vivo biological activity models. Additionaly, the oil of J. virginiana was found highly effective in the anti-inflammatory activity method. The experimental data demonstrated that essential oil of J. occidentalis displayed significant wound-healing and anti-inflammatory activities. 23517541 Comparative pharmacokinetics of N(ω)-hydroxy-nor-L-arginine, an arginase inhibitor, after single-dose intravenous, intraperitoneal and intratracheal administration to brown Norway rats. Abstract 1.  Rodent studies have documented that N(ω)-hydroxy-nor-L-arginine (nor-NOHA), an arginase inhibitor, has therapeutic potential in the treatment of cardiovascular and obstructive airway diseases. However, its bioavailability and pharmacokinetics have not been described so far. 2.  Anesthetized brown Norway rats were administered single doses of nor-NOHA (10, 30 or 90 mg/kg) intravenously (i.v.), intraperitonealy (i.p.) or via intratracheal (i.t.) instillation of aerosol. Plasma nor-NOHA was assayed using a validated HPLC method. 3.  Upon i.v. administration, the mean concentration showed a biphasic decline and its value dropped below 10% of the maximum after 20 min. The pharmacokinetics were linear with the total and inter-compartmental clearances of 33 and 17 mL/min/kg, central and peripheral volumes of distribution of 0.19 and 0.43 L/kg and terminal half-life of 30 min. 4.  The average absolute bioavailability of nor-NOHA after i.p. and i.t. delivery was 98% and 53%, respectively. The absorption from the airways was rate-limiting and its extent decreased with the dose. 5.  In conclusion, nor-NOHA is rapidly cleared from the plasma in concordance with the short time window of its in vivo inhibitory activity reported in the literature. I.t. instillation of aerosol for topical effects of nor-NOHA in the airways is characterized with significant systemic availability. 23289585 Infrared multiple photon dissociation action spectroscopy of deprotonated DNA mononucleotides: gas-phase conformations and energetics. The gas phase structures of the deprotonated 2'-deoxymononucleotides including 2'-deoxyadenosine-5'-monophosphate (dA5'p), 2'-deoxycytidine-5'-monophosphate (dC5'p), 2'-deoxyguanosine-5'-monophosphate (dG5'p), and thymidine-5'-monophosphate (T5'p) are examined via infrared multiple photon dissociation (IRMPD) action spectroscopy and theoretical electronic structure calculations. The measured IRMPD action spectra of all four deprotonated DNA mononucleotides exhibit unique spectral features in the region extending from ~600 to 1800 cm(-1) such that they can be readily differentiated from one another. The measured IRMPD action spectra are compared to the linear IR spectra calculated at the B3LYP/6-311+G(d,p) level of theory to determine the conformations of these species accessed in the experiments. On the basis of these comparisons and the computed energetic information, the most stable conformations of the deprotonated forms of dA5'p, dC5'p, and T5'p are conformers where the ribose moiety adopts a C3' endo conformation and the nucleobase is in an anti conformation. By contrast, the most stable conformations of the deprotonated form of dG5'p are conformers where the ribose adapts a C3' endo conformation and the nucleobase is in a syn conformation. In addition to the ground-state conformers, several stable low-energy excited conformers that differ slightly in the orientation of the phosphate ester moiety were also accessed in the experiments. 23327580 Pharmacogenomics as a risk mitigation strategy for chemotherapeutic cardiotoxicity. Damage to the heart can result from both traditional chemotherapeutic agents, such as doxorubicin, and newer 'targeted' therapies, such as trastuzumab. This chemotherapeutic cardiotoxicity is potentially life-threatening and necessitates limiting or discontinuing an otherwise-effective cancer treatment. Clinical strategies focus on surveillance rather than prevention, although there are no specific therapies for this highly morbid adverse effect. Current models for prospectively predicting risk of chemotherapeutic cardiotoxicity are limited. Cardiotoxicity can occur idiosyncratically in patients without obvious demographic risk factors, suggesting a genetically determined susceptibility, and candidate-gene studies have identified a limited number of variants that increase risk. In this commentary we indicate a need for more powerful means to identify risk prospectively, and suggest that broad pharmacogenomic approaches may be fruitful. 23639437 Cognitive Function During Nicotine Withdrawal: Implications for Nicotine Dependence Treatment. Nicotine withdrawal is associated with deficits in neurocognitive function including sustained attention, working memory, and response inhibition. Several convergent lines of evidence suggest that these deficits may represent a core dependence phenotype and a target for treatment development efforts. A better understanding of the mechanisms underlying withdrawal-related cognitive deficits may lead to improve nicotine dependence treatment. We begin with an overview of the neurocognitive effects of withdrawal in rodent and human models, followed by discussion of the neurobehavioral mechanisms that are thought to underlie these effects. We then review individual differences in withdrawal-related neurocognitive effects including genetics, gender, and psychiatric comorbidity. We conclude with a discussion of the implications of this research for developing improved therapies, both pharmacotherapy and behavioral treatments, that target cognitive symptoms of nicotine withdrawal. 23562636 Cavitation-enhanced delivery of a replicating oncolytic adenovirus to tumors using focused ultrasound. Oncolytic viruses (OV) and ultrasound-enhanced drug delivery are powerful novel technologies. OV selectively self-amplify and kill cancer cells but their clinical use has been restricted by limited delivery from the bloodstream into the tumor. Ultrasound has been previously exploited for targeted release of OV in vivo, but its use to induce cavitation, microbubble oscillations, for enhanced OV tumor extravasation and delivery has not been previously reported. By identifying and optimizing the underlying physical mechanism, this work demonstrates that focused ultrasound significantly enhances the delivery and biodistribution of systemically administered OV co-injected with microbubbles. Up to a fiftyfold increase in tumor transgene expression was achieved, without any observable tissue damage. Ultrasound exposure parameters were optimized as a function of tumor reperfusion time to sustain inertial cavitation, a type of microbubble activity, throughout the exposure. Passive detection of acoustic emissions during treatment confirmed inertial cavitation as the mechanism responsible for enhanced delivery and enabled real-time monitoring of successful viral delivery. 23097024 Simulated microgravity exposure modulates the phenotype of cultured vascular smooth muscle cells. Evidence from ground-based animal studies using tail-suspended hindlimb unloaded rats model has clearly demonstrated that simulated microgravity-induced smooth muscle cell phenotype conversion, a characteristic vascular structural and functional remodeling, may be one of the key contributors to postspaceflight orthostatic intolerance. However, the rats model involves multiple collective effects of microgravity including cephalic fluid shift and postural muscle unloading on smooth muscle cells (SMCs). It cannot isolate a single factor from the collective ones and therefore is not ideal to study the effects of gravitational vector alteration alone on SMCs. To test the hypothesis that gravitational vector alteration per se might affect smooth muscle cell phenotype, a roller culture apparatus was employed to expose cultured rat aortic smooth muscle cells (RASMCs) to simulated microgravity. Cell proliferation, cell cycle distribution, apoptosis, migration, and nitric oxide production rates were measured and compared between the control and the simulated microgravity groups. Cell cytoskeleton reorganization induced by simulated microgravity was observed by confocal microscopy. Specific contractile and synthetic Gene expression at the mRNA level was quantified by reverse transcriptional polymerase chain reaction. It was observed that simulated microgravity suppressed RASMC proliferation and migration, enhanced cell apoptosis, stimulated NO release, and destroyed the original well-organized cytoskeleton. Moreover, at the mRNA level, long-time exposure (≥72 h) to simulated microgravity induced a contractile phenotype tendency by up-regulating smMHC expression. All these findings suggest that the phenotype modulation of vascular smooth muscle cells may be gravity dependent. 23624706 Enhanced lithium storage in Fe2O3-SnO2-C nanocomposite anode with a breathable structure. A novel nanocomposite architecture of a Fe2O3-SnO2-C anode, based on clusters of Fe2O3 and SnO2 nanoparticles dispersed along the conductive chains of Super P Li™ carbon black (Timcal Ltd.), is presented as a breathable structure in this paper for lithium-ion batteries. The synthesis of the nanocomposite is achieved by combining a molten salt precipitation process and a ball milling method for the first time. The crystalline structure, morphology, and electrochemical characterization of the synthesised product are investigated systematically. Electrochemical results demonstrate that the reversible capacity of the composite anode is 1110 mA h g(-1) at a current rate of 158 mA g(-1) with only 31% of initial irreversible capacity in the first cycle. A high reversible capacity of 502 mA h g(-1) (higher than the theoretical capacity of graphite, ∼372 mA h g(-1)) can be obtained at a high current rate of 3950 mA g(-1). The electrochemical performance is compared favourably with those of Fe2O3-SnO2 and Fe2O3-SnO2-C composite anodes for lithium-ion batteries reported in the literature. This work reports a promising method for the design and preparation of nanocomposite electrodes for lithium-ion batteries. 23609782 Drugs in Development for Relapsing Multiple Sclerosis. Drug development for multiple sclerosis (MS), as with any other neurological disease, faces numerous challenges, with many drugs failing at various stages of development. The disease-modifying therapies (DMTs) first introduced for MS are only moderately effective, but given the lack of competition, they have been widely accepted in clinical practice. Although safety and efficacy continue to be the two main metrics by which drugs will be judged, the newer agents in the market also face challenges of a more comparative nature-are they more efficacious than the currently available drugs on the market? Are they safer or better tolerated? Do they offer any practical advantages over current treatments? Fingolimod represented a milestone following its approval as an oral drug for MS in 2010, offering patients a far more convenient administration route. However, association with cardiovascular complications has led to a more cautious approach in its initial prescribing, now requiring cardiac monitoring for the first 6 h as well as subsequent monitoring of blood pressure and for macular oedema. Natalizumab, amongst licensed drugs, represents the current benchmark for efficacy. The risk of progressive multifocal leukoencephalopathy during natalizumab treatment is now more quantifiable. Other monoclonal antibodies are in various phases of development. Marketing authorisation for alemtuzumab has been filed, and whilst trial data suggest that its efficacy outperforms both licensed drugs and others in development, there is a significant risk of secondary autoimmunity. Its once-yearly administration, however, seems particularly advantageous. Rituximab is unlikely to be developed further as its license will expire, but ocrelizumab, another monoclonal antibody directly targeting B cells, is currently in phase 2 development and looks promising. Daclizumab is also moderately efficacious but may struggle to establish itself given its monthly subcutaneous dosing. There are new oral drugs in development, and it is likely that BG-12 will be licensed this year. This has been licensed for psoriasis so there are good safety data in humans that may also hold true in MS; however, its three times daily dosage will probably impact on patient compliance. Laquinimod has lower efficacy than BG-12 but appears safe and could find a place as a first-line agent. Teriflunomide has just been licensed by the US FDA and may challenge the current injectable first-line therapies as it has a similar efficacy but the advantage of being taken orally. However, risk of teratogenicity may caution against its use in some women of child-bearing potential. This review will examine drugs that have been recently approved as well as those that are in late phase 2 or 3 development as treatment for relapsing MS, highlighting their mechanism of action as well as the clinical trial and safety data before discussing their potential for success in an increasingly florid and complex DMT armamentarium. 22394118 Carbon sources and medium pH affects the growth of Withania somnifera (L.) Dunal adventitious roots and withanolide A production. This work deals with optimisation of adventitious root suspension culture of Withania somnifera (L.) Dunal (Solanaceae) for the production of biomass and withanolide A and we investigated the effect of carbon source and the initial medium pH on growth and production of withanolide A in adventitious root cultures of Withania somnifera. A 2% sucrose concentration was found to be best for both biomass (113.58 g L(-1) fresh weight (FW) and 11.33 g L(-1) dry weight (DW)) and secondary metabolite accumulation (8.93 mg g(-1) DW) in the tested range of concentration (1-8%). The biomass of adventitious roots was optimal when the initial medium pH was 5.8 (113.26 g L(-1) FW and 11.33 g L(-1) DW) but the withanolide A production was highest at the medium pH level of 5.5 (9.09 mg g(-1) DW). 23127601 Consumption of tomato products is associated with lower blood mercury levels in Inuit preschool children. Some evidence suggests that various diet components and nutrients, including vegetables, fruit and food-derived antioxidants, could mitigate contaminant exposure and/or adverse health effects of contaminants. To examine the effect of the consumption of tomato products on blood mercury levels in Inuit preschool children, 155 Inuit children (25.0±9.1months) were recruited from 2006-2008 in Nunavik childcare centers (northern Québec, Canada). Food frequency questionnaires were completed at home and at the childcare center, and total blood mercury concentration was measured by inductively coupled plasma-mass spectrometry. Multivariate regression analysis was performed after multiple imputation. The median blood concentration of mercury was 9.5nmol/L. Age, duration of breastfeeding, annual consumption frequency of seal meat, and monthly consumption frequency of tomato products were significant predictors of blood mercury levels, whereas annual consumption frequencies of beluga muktuk, walrus, Arctic char, and caribou meat were not. Each time a participant consumed tomato products during the month before the interview was associated with a 4.6% lower blood mercury level (p=0.0005). All other significant predictors in the model were positively associated with blood mercury levels. Further studies should explore interactions between consumption of healthy store-bought foods available in Arctic regions and contaminant exposure. 23584948 Vandetanib: opening a new treatment practice in advanced medullary thyroid carcinoma. Medullary thyroid cancer (MTC) is frequently diagnosed in a locally advanced or metastatic stage, and 10-year survival rates in these cases are below 20 %. Cytotoxic chemotherapy has no significant impact on overall or progression-free survival. Vandetanib (Caprelsa(®), AstraZeneca) is a once-daily oral tyrosine kinase inhibitor that selectively inhibits signalling mediated by growth-factor receptor tyrosine kinase RET (constitutively activated in roughly 60 % of all MTCs), vascular endothelial growth-factor receptors 2 and 3, and epidermal growth-factor receptors. It is the first systemic drug with demonstrated anti-tumor benefits in advanced MTC, and it has recently been approved for locally advanced or metastatic MTC by the United States Food and Drug Administration (April 2011) and the European Medicines Agency (February 2012). This review, starting from the phases II and III efficacy and safety data that led to these approvals, explores important issues related to dosing, patient selection, and strategies for managing the substantial risk of toxicity associated with the drug (including life-threatening cardiac events that are the subject of a black-box warning in the United States). All these issues still remain to be defined. Vandetanib is becoming a standard of care for symptomatic, progressive, metastatic MTCs, to be used selectively in those patients who are likely to benefit from it. 23410152 Insight into the medicinal chemistry of the endocannabinoid hydrolase inhibitors. Endocannabinoid hydrolases are nowadays increasingly considered as potential therapeutic targets for treating several pathological states. So far, numerous classes of endocannabinoid hydrolase inhibitors have been described. We herein review the medicinal chemistry of these inhibitors with a particular emphasis on the basis of their design, chemical structure, structure-activity relationships, and inhibition mechanisms. 23406429 Novel triaryl sulfonamide derivatives as selective cannabinoid receptor 2 inverse agonists and osteoclast inhibitors: discovery, optimization, and biological evaluation. Cannabinoid receptors have gained increasing attention as drug targets for developing potential therapeutic ligands. Here, we report the discovery and optimization of triaryl sulfonamides as a novel series possessing significant CB2 receptor affinity and selectivity. Four sets of triaryl ligands were designed and synthesized for further structural modifications and led to the identification of eight compounds as potent and selective CB2 inverse agonists with high binding affinity (CB2K(i) < 10 nM). Especially, compound 57 exhibited the strongest binding affinity on the CB2 receptor (CB2K(i) of 0.5 nM) and the best selectivity over the CB1 receptor (selectivity index of 2594). Importantly, 57 also showed potent inhibitory activity on osteoclast formation, and it was confirmed by a cell viability assay that the inhibition effects were not derived from the cytotoxicity. Finally, 3D QSAR studies confirmed our SAR findings that three bulky groups play an important role for CB2 receptor binding affinity. 23224942 Molecular vibrational spectroscopy characterization of epoxy graphene oxide from density functional calculations. To further understand the structure of graphene oxide, several structures of graphene oxide were systematically investigated using density functional theory (DFT). Our models consisted of a hexagonal in-plane structure of graphene with epoxy groups, and different oxidation levels. We found that different arrangements of these units yielded a range of vibrational spectra. Raman positions of the D and G bands depend sensitively on the local atomic configurations. Both structure energy and spectra computations indicate that the oxidation functional groups are energetically favorable to aggregate together and to be close to one another on the opposite side of graphene surface. 23109279 Enantioselective toxicity and bioaccumulation of fipronil in fathead minnows (Pimephales promelas) following water and sediment exposures. Fipronil is a widely used, broad-spectrum pesticide that is applied as an equal mixture of two enantiomers. As regulations on older pesticides become more stringent, production and application of fipronil is expected to grow, leading to increased inputs into aquatic environments and complex exposures to biota. To better understand the potential exposures introduced by fipronil contamination, we conducted subchronic toxicity tests with larval fathead minnows (Pimephales promelas) and waterborne fipronil and its enantiomers and exposed juvenile fathead minnows to fipronil-spiked sediment. Enantioselective toxicity was observed in fish after the 7-d subchronic exposure, with increased toxicity of the racemate and (+) enantiomer observed compared with the (-) enantiomer. Curiously, toxicities of the racemate and (+) enantiomer were not significantly different, even though the racemate contains 50% of the (+) enantiomer and 50% of the less toxic (-) enantiomer. During the sediment exposure, racemic fipronil in sediment was transformed primarily to fipronil sulfide, while exposed fish rapidly accumulated fipronil and/or fipronil sulfide and transformed the majority to fipronil sulfone. Using the results of the sediment-exposure experiment, the authors explored a mechanism that may contribute to the interesting trends in enantioselective toxicity observed during the waterborne exposures. In tandem, the aquatic toxicity experiment and the spiked sediment exposure demonstrate the potentially complex behavior of fipronil in sediment and fish. 23314757 Forming double layer-encapsulated quantum dots for bio-imaging and cell targeting. We report a simple and effective approach for the preparation of double layer-encapsulated quantum dots (DL-Qdots) composed of alkyl-capping ligands to interdigitate with hydrophobic, protective agents on the surface of AgInS(2)/ZnS quantum dots (Qdots), which allow phase transfer of hydrophobic Qdots from the organic phase into the aqueous phase. The alkyl-capping ligands consist of a hydrophobic, aliphatic chain and different functional terminal groups (e.g., carboxyl, amine, hydroxyl, and thiol groups) that can serve as reactive sites to chemically couple with other materials. The resulting DL-Qdots bearing various functional groups retain good fluorescence properties and show excellent solubility as well as stability over a range of pH in the aqueous phase. Cytotoxicity studies of DL-Qdots bearing carboxyl groups (DL-Qdots-COOH) were carried out against human cervical (HeLa) cancer cells to elicit no apparent toxicity even at high concentrations of 300 μg mL(-1) and 24 h of incubation. To demonstrate their potential biomedical application, DL-Qdots-COOH were further conjugated with folate for staining in HeLa, human liver carcinoma (HepG2), and human breast (MCF-7) cancer cells. Confocal imaging characterization revealed that folate-conjugated DL-Qdots could target most specifically and effectively HeLa cells via folate receptor-mediated targeted delivery compared to HepG2 and MCF-7 cells. The generality and simplicity of this newly developed strategy can possibly be extended to a large variety of hydrophobic Qdots and nanocrystals whose surface protective agents have a long aliphatic chain. 23432587 Aminophosphonate metal complexes of biomedical potential. Metals and their complexes with organic ligands have an important role in biochemical systems such as enzymatic catalysis, metal ion transfer across the cell membranes, treatment of malignancy, rheumatoid arthritis, ulcer and other types of diseases. Special attention is directed to metal complexes with ligands which are important in biological systems, as their incorporation into metallo-organic compounds offers much scope for design of potential metal-based agents that provide new opportunities in the medicinal chemistry. In view of this, derivatives of aminophosphonic acids, owing to their broad spectrum of biological activities and wide range of applications in the medicinal and agrochemical fields, are very attractive metal-ligand agents that might form biomedical important metal complexes. Thus, a number of aminophosphonate complexes of platinum group metals have been found to possess remarkable antitumor activity while complexes of some other transition and rare-earth metals like technetium, rhenium, samarium and gadolinium have been used either as therapeutic and diagnostic radiopharmaceuticals or as magnetic resonance imaging (MRI) contrast agents. In addition, the high phosphonate affinity towards bone and other calcified tissues may be utilized for the drug targeting based on synthesis of metal complexes linked to bioactive carrier systems, affording better modalities of attack to the site of pathology. In this review article, aminophosphonate metal-based compounds with potential biomedical applications are described. 23561113 Anticancer activity and mediation of apoptosis in human HL-60 leukaemia cells by edible sea cucumber (Holothuria edulis) extract. Sea cucumbers have been a dietary delicacy and important ingredient in Asian traditional medicinal over many centuries. In this study, edible sea cucumber Holothuria edulis was evaluated for its in vitro anticancer potential. An aqueous fraction of the edible sea cucumber (ESC-AQ) has been shown to deliver a strong cytotoxic effect against the human HL-60 leukaemia cell line. An induction effect of apoptotic body formation in response to ESC-AQ treatment was confirmed in HL-60 cells stained with Hoechst 33342 and confirmed via flow cytometry analysis. The up regulation of Bax and caspase-3 protein expression was observed while the expression of Bcl-xL protein was down regulated in ESC-AQ treated HL-60 cells. Due to the profound anticancer activity, ESC-AQ appears to be an economically important biomass fraction that can be exploited in numerous industrial applications as a source of functional ingredients. 23506073 Novel regulatory system nemRA-gloA for electrophile reduction in Escherichia coli K-12. Electrophilic compounds such as glyoxals, which are toxic due to their reactive carbonyl group, are generated in vivo through various pathways. In this study, we obtained evidence indicating that the nemRA operon, previously reported to encode a repressor and the N-ethylmaleimide reductase, respectively, is co-transcribed with the 3'-proximal gloA gene encoding glyoxalase I. The operon is not only involved in cytosolic detoxification but is also regulated by electrophiles such as quinones and glyoxals. A gel mobility shift assay revealed that purified NemR repressor bound to DNA was dissociated upon interaction with quinones and glyoxals, while their reduced forms were ineffective. The cysteines of NemR at 21 and 116 were essential in sensing electrophiles in vivo and in vitro. Reversible intermolecular disulphide bonds were observed with a reducing agent as well as with electrophiles. DNA binding affinity reduced by glyoxal was also increased with a reducing agent. The NemA reductase, an FMN-containing enzyme, exhibited catalytic activity toward various electrophiles including quinones, while GloA played a major role in glyoxal detoxification. Therefore, we propose that cells have a cytosolic system consisting of the nemRA-gloA operon for the reduction of electrophiles, especially quinones and glyoxals, to maintain an appropriate intracellular redox balance. 23386058 Vascular endothelial growth factor induces growth of uterine cervix and immune cell recruitment in mice. Knowledge of uterine cervical epithelial biology and factors that influence its events may be critical in understanding the process of cervical remodeling (CR). Here, we examine the impact of exogenous vascular endothelial growth factor (VEGF) on uterine cervical epithelial growth in mice (nonpregnant and pregnant) treated with VEGF agents (recombinant and inhibitor) using a variety of morphological and molecular techniques. Exogenous VEGF altered various uterine cervical epithelial cellular events, including marked induction of growth, edema, increase in inter-epithelial paracellular space, and recruitment of immune cells to the outer surface of epithelial cells (cervical lumen). We conclude that VEGF induces multiple alterations in the uterine cervical epithelial tissues that may play a role in local immune surveillance and uterine cervical growth during CR. 23241030 Anharmonic motion in experimental charge density investigations. In the charge density study of 9-diphenylthiophosphinoylanthracene the thermal motion of several atoms needed an anharmonic description via Gram-Charlier coefficients even for data collected at 15 K. As several data sets at different temperatures were measured, this anharmonic model could be proved to be superior to a disorder model. Refinements against theoretical data showed the resemblance of an anharmonic model and a disorder model with two positions very close to each other (~0.2 Å), whereas these two models could be clearly distinguished if the second position is 0.5 Å apart. The refined multipole parameters were distorted when the anharmonic motion was not properly refined. Therefore, this study reveals the importance of detecting and properly handling anharmonic motion. Unrefined anharmonic motion leads to typical shashlik-like residual density patterns. Therefore, careful analysis of the residual density and the derived probability density function after the refinement of the Gram-Charlier coefficients proved to be the most useful tools to indicate the presence of anharmonic motion. 23403395 Targeted co-delivery of docetaxel, cisplatin and herceptin by vitamin E TPGS-cisplatin prodrug nanoparticles for multimodality treatment of cancer. We developed a nanocarrier system of herceptin-conjugated nanoparticles of d-alpha-tocopheryl-co-poly(ethylene glycol) 1000 succinate (TPGS)-cisplatin prodrug (HTCP NPs) for targeted co-delivery of cisplatin, docetaxel and herceptin for multimodality treatment of breast cancer of high human epidermal growth factor receptor 2 (HER2) overexpression. Co-polymers poly(lactic acid)-TPGS (PLA-TPGS) and carboxyl group-terminated TPGS (TPGS-COOH) were also added in the polymeric matrix to stabilize the prodrug nanoparticles and to facilitate herceptin conjugation. The HTCP NPs of high, moderate and low docetaxel versus cisplatin ratio were prepared by the nanoprecipitation method, which showed a pH-sensitive release for both anticancer drugs. The therapeutic effects of HTCP NPs were evaluated in vitro and compared with Taxotere® and cisplatin. The HTCP NPs of high docetaxel versus cisplatin ratio were found to have better efficacy than those of moderate and low docetaxel versus cisplatin ratio. The targeting effects of the HTCP NPs were demonstrated by a much lower IC50 value of 0.0201+0.00780+0.1629μg/mL of docetaxel+cisplatin+herceptin for SK-BR-3 cells, which are of high HER2 overexpression, than that of 0.225+0.0875+1.827μg/mL for NIH3T3 cells, which are of low HER2 overexpression, after 24h incubation. The same design of TPGS prodrug nanoparticles can also be applied for targeted co-delivery of other hydrophilic and hydrophobic drugs. 23567041 Evidence for a new mechanism behind HIFU-triggered release from liposomes. A promising approach for local drug delivery is high-intensity focused ultrasound (HIFU)-triggered release of drugs from stimuli-responsive nanoparticles such as liposomes. The aim of this study was to investigate whether another release mechanism is involved with HIFU-triggered release from liposomes beside cavitation and temperature. Furthermore, it was studied whether this new release mechanism allows the release of lipophilic compounds. Therefore, both a lipophilic (Nile red) and a hydrophilic (fluorescein) compound were loaded into thermosensitive (TSL) or non-thermosensitive liposomes (NTSL) and the liposomes were subjected both to continuous wave- (CW) and pulsed wave (PW)-HIFU. The mean liposome size varied from 97 to 139nm with a polydispersity index (PDI)≤0.06 for the different formulations. The Tm of the phospholipid bilayer of the TSL was around 42°C. Approximately 80% of fluorescein was released within 15min from TSL at temperatures≥42°C. In contrast, no fluorescein release from NTSL and NR release from both TSL and NTSL was observed at temperatures up to 60°C. CW-HIFU exposure of TSL resulted in rapid temperature elevation up to 52°C and subsequently almost quantitative fluorescein release. Fluorescein release from NTSL was also substantial (~64% after 16min at 20W). Surprisingly, CW-HIFU exposure (20W for 16min) resulted in the release of NR from TSL (~66% of the loaded amount), and this was even higher from NTSL (~78%). PW-HIFU exposure did not result in temperatures above the Tm of TSL. However, nearly 85% of fluorescein was released from TSL after 32min at 20W of PW-HIFU exposure, whereas the release from NTSL was around 27%. Interestingly, NR release from NTSL was~30% after 2min PW-HIFU exposure and increased to~70% after 32min. Furthermore, addition of microbubbles to the liposomes prior to PW-HIFU exposure did not result in more release, which suggests that cavitation can be excluded as the main mechanism responsible for the triggered release of both a hydrophilic and a lipophilic model compound from liposomes. Dynamic light scattering analysis showed that the mean size and PDI of the liposomes did not significantly change after CW- and PW-HIFU exposure. Taken together, it is therefore concluded that neither temperature elevation nor inertial cavitation is essential for the release of both hydrophilic and lipophilic compounds from liposomes. It is assumed that the release originates from radiation force-induced acoustic streaming, causing the liposomes to collide at the walls of the exposure chamber leading to shear forces which in turn results in reversible liposome destabilization and release of both hydrophilic and lipophilic compounds. 23644195 In vitro biosynthesis, isolation, and identification of predominant metabolites of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208). The structures of the two predominant metabolites (M4 and M5) of RVX-208, observed both in in vitro human and animal liver microsomal incubations, as well as in plasma from animal in vivo studies, were determined. A panel of biocatalytic systems was tested to identify biocatalysts suitable for milligram scale production of metabolite M4 from RVX-208. Rabbit liver S9 fraction was selected as the most suitable system, primarily based on pragmatic metrics such as catalyst cost and estimated yield of M4 (∼55%). Glucuronidation of RVX-208 catalyzed by rabbit liver S9 fraction was optimized to produce M4 in amounts sufficient for structural characterization. Structural studies using LC/MS/MS analysis and (1)H NMR spectroscopy showed the formation of a glycosidic bond between the primary hydroxyl group of RVX-208 and glucuronic acid. NMR results suggested that the glycosidic bond has the β-anomeric configuration. A synthetic sample of M4 confirmed the proposed structure. Metabolite M5, hypothesized to be the carboxylate of RVX-208, was prepared using human liver microsomes, purified by HPLC, and characterized by LC/MS/MS and (1)H NMR. The structure was confirmed by comparison to a synthetic sample. Both samples confirmed M5 as a product of oxidation of primary hydroxyl group of RVX-208 to carboxylic acid. 23279841 Protective action of ethanolic extract of Rosmarinus officinalis L. in gastric ulcer prevention induced by ethanol in rats. The pathology of a gastric ulcer is complex and multifactorial. Gastric ulcers affect many people around the world and its development is a result of the imbalance between aggressive and protective factors in the gastric mucosa. In this study, we evaluated the ethanolic extract of Rosmarinus officinalis L. (eeRo); this plant, more commonly known as rosemary, has attracted the interest of the scientific community due to its numerous pharmacological properties and their potential therapeutic applications. Here, we tested the preventive effects of eeRo against gastric ulcer induced by 70% ethanol in male Wistar rats. In addition, we aimed to clarify the mechanism involved in the preventive action of the eeRo in gastric ulcers. Based on the analysis of markers of oxidative damage and enzymatic antioxidant defense systems, the measurement of nitrite and nitrate levels and the assessment of the inflammatory response, the eeRo exhibited significant antioxidant, vasodilator and antiinflammatory properties. 23384967 Comparative analysis of human CYP3A4 and rat CYP3A1 induction and relevant gene expression by bisphenol A and diethylstilbestrol: implications for toxicity testing paradigms. Bisphenol A (BPA) and diethylstilbestrol (DES) are endocrine-disrupting chemicals that interact with the human pregnane X receptor (PXR). CYP3A4 enzyme is essential in the hydroxylation of steroid hormones and is regulated by PXR. In the present study, human and rat hepatoma cell lines were exposed to BPA and DES. Both BPA and DES (10-50μM) caused a significant activation of the CYP3A4 promoter via the PXR in the DPX2 human hepatoma cell line. No activation of rat PXR was seen. BPA and DES treated DPX2 cells demonstrated increased expression of CYP3A4 mRNA, and increased enzyme activity. In summary, BPA, in concentrations relevant to current safety levels of human exposure, activates the human PXR and demonstrates an increase in CYP3A4 mRNA expression and enzyme activity. BPA actions in this model system occur to a greater extent than DES. This study raises concerns regarding our current toxicity testing paradigms and species utilization. 23394480 Gate-modulated thermoelectric power factor of hole gas in Ge-Si core-shell nanowires. We experimentally studied the thermoelectric power factor of hole gas in individual Ge-Si core-shell nanowires with Ge core diameters ranging from 11 to 25 nm. The Ge cores are dopant-free, but the Fermi level in the cores is pinned by surface and defect states in the epitaxial Si shell thereby doping the cores into the degenerate regime. This doping mechanism avoids the high concentration of dopants usually encountered in bulk thermoelectric materials and provides a unique opportunity to enhance the carrier mobility with suppressed ionized impurity scattering. Moreover, the carrier concentration in small diameter nanowires has also been effectively modulated by field effect, allowing one to probe the electrical conductivity and thermopower within a wide range of carrier concentrations, which is crucial to understand the thermoelectric transport behavior. We found that the thermopower of nanowires with Ge core diameters down to 11 nm still follows the behavior of bulk Ge. As a result, the power factor is found to be closely correlated with the carrier mobility, which is higher than that of bulk Ge in one of the core-shell nanowires studied here. 23349501 Impaired local production of pro-resolving lipid mediators in obesity and 17-HDHA as a potential treatment for obesity-associated inflammation. Obesity-induced chronic low-grade inflammation originates from adipose tissue and is crucial for obesity-driven metabolic deterioration including insulin resistance and type 2 diabetes.Chronic inflammation may be a consequence of a failure to actively resolve inflammation,and could result from a lack of local specialized pro-resolving lipid mediators (SPM) such as resolvins and protectins, which derive from the n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We assessed obesity-induced changes of n-3-derived SPM in adipose tissue and effects of dietary EPA/DHA thereon.Moreover, we treated obese mice with SPM precursors and investigated effects on inflammation and metabolic dysregulation. Obesity significantly decreased DHA-derived 17-hydroxydocosahexaenoic acid (17-HDHA, resolvin D1 precursor) and protectin D1 levels in murine adipose tissue. Dietary EPA/DHA treatment restored endogenous biosynthesis of n-3 derived lipid mediators in obesity while attenuating adipose tissue inflammation and improving insulin sensitivity. Notably, 17-HDHA treatment reduced adipose tissue expression of inflammatory cytokines, increased adiponectin expression and improved glucose tolerance parallel to insulin sensitivity in obese mice. These findings indicate that impaired biosynthesis of certain SPM and SPM precursors including 17-HDHA and protectin D1 contributes to adipose tissue inflammation in obesity and suggest 17-HDHA as a novel treatment option for obesity-associated complications. 23094864 Tanshinone derivatives: a patent review (January 2006 - September 2012). INTRODUCTION: Tanshinone IIA (TSIIA), cryptotanshinone and tanshinone I are major bioactive constituents of Danshen, a Chinese herbal medicine. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of TSIIA and it is currently used for treating cardiovascular diseases in China. AREAS COVERED: The article presents a review of the anti-atherosclerosis, cardioprotective effects, neuroprotection and anti-tumor activities of TSIIA and a review of patents on tanshinone derivatives from January 2006 to September 2012. EXPERT OPINION: Mechanistic studies have discovered that TSIIA modulates ion channels, kinases, hormone receptors, apoptosis proteins, growth factors, cytokines, microRNA, tumor suppressor and many other targets, revealing an intricate biological network modulated by TSIIA. Many patents have attempted to overcome the low water solubility of TSIIA and tanshinone I by attaching a polar substituent or by a prodrug strategy. However, biological activities of these tanshinone derivatives need to be further evaluated. Given the extensive in vitro and in vivo biological activities of TSIIA, this compound is a promising candidate to be further developed as a novel therapeutics for treating atherosclerosis, cardiovascular diseases, neurodegenerative diseases and cancer. 23627443 Nanocarrier-based topical drug delivery for an antifungal drug. Abstract Objective: The conventional liposomal amphotericin B causes many unwanted side effects like blood disorder, nephrotoxicity, dose-dependent side effects, highly variable oral absorption and formulation-related instability. The objective of the present investigation was to develop cost-effective nanoemulsion as nanocarreir for enhanced and sustained delivery of amphotericin B into the skin. Methods and characterizations: Different oil-in-water nanoemulsions were developed by varying the composition of hydrophilic (Tween® 80) surfactants and co-surfactant by the spontaneous titration method. The developed formulation were characterized, optimized, evaluated and compared for the skin permeation with commercial formulation (fungisome 0.01% w/w). Optimized formulations loaded with amphotericin B were screened using varied concentrations of surfactants and co-surfactants as decided by the ternary phase diagram. Results and discussion: The maximum % transmittance obtained were 96.9 ± 1.0%, 95.9 ± 3.0% and 93.7 ± 1.2% for the optimized formulations F-I, F-III and F-VI, respectively. These optimized nanoemulsions were subjected to thermodynamic stability study to get the most stable nanoemulsions (F-I). The results of the particle size and zeta potential value were found to be 67.32 ± 0.8 nm and -3.7 ± 1.2 mV for the final optimized nanoemulsion F-I supporting transparency and stable nanoemulsion for better skin permeation. The steady state transdermal flux for the formulations was observed between 5.89 ± 2.06 and 18.02 ± 4.3 µg/cm(2)/h whereas the maximum enhancement ratio were found 1.85- and 3.0-fold higher than fungisome and drug solution, respectively, for F-I. The results of the skin deposition study suggests that 231.37 ± 3.6 µg/cm(2) drug deposited from optimized nanoemulsion F-I and 2.11-fold higher enhancement ratio as compared to fungisome. Optimized surfactants and co-surfactant combination-mediated transport of the drug through the skin was also tried and the results were shown to have facilitated drug permeation and skin perturbation (SEM). Conclusion: The combined results suggested that amphotericin B nanoemulsion could be a better option for localized topical drug delivery and have greater potential as an effective, efficient and safe approach. 23231457 Hydrogel-based scaffolds for enclosing encapsulated therapeutic cells. Cell encapsulation technology holds promise for the sustained and controlled delivery of different therapeutic proteins. Alginate-poly-L-lysine-alginate (APA) microcapsules represent one of the most widely studied alginate-polycation microcapsules. On the basis of this technology, two types of hydrogel-based scaffolds have been developed and analyzed with the aim of improving the retention and the retrieval of erythropoietin (Epo) secreting cell-loaded microcapsules in the tissue where they are implanted. Furthermore, these hydrogels may help to reduce the post-transplant inflammation and pericapsular fibrotic overgrowth typically observed around capsules. The hydrogel-based scaffolds could be administered as implantable forms (preformed scaffolds) or injectable forms (in situ formed scaffolds). The in vitro studies confirmed the correct adaptation of the enclosed cells to the scaffolds in terms of viability and protein expression. The posterior implantation of the cell-loaded capsules containing hydrogel-based scaffolds in mice revealed that the hematocrit levels were maintained up to 80% for at least 2 months. The histological analysis of the explanted microcapsules performed at that point showed that pericapsular overgrowth was reduced when cell-loaded microcapsules were enclosed in the hydrogels scaffolds. Incorporating microencapsulated cells within hydrogel-based scaffolds may help to improve their administration protocol and retention while reducing post-transplantation inflammation. 23325846 Isolation and identification of cell-specific microRNAs targeting a messenger RNA using a biotinylated anti-sense oligonucleotide capture affinity technique. MicroRNAs (miRNAs) are small non-coding RNAs that regulate expression by translational repression or messenger RNA (mRNA) degradation. Although numerous bioinformatic prediction models exist to identify miRNA-mRNA interactions, experimental validation of bona fide interactions can be difficult and laborious. Few methods can comprehensively identify miRNAs that target a single mRNA. We have developed an experimental approach to search for miRNAs targeting any mRNA using a capture affinity assay involving a biotinylated DNA anti-sense oligonucleotide. This method identifies miRNAs targeting the full length of the mRNA. The method was tested using three separate mRNA targets: alpha-1 antitrypsin (AAT) mRNA, interleukin-8 mRNA and secretory leucoprotease inhibitor mRNA. AAT mRNA-specific and total miRNAs from three different cell lines (monocytic THP-1, bronchial epithelial 16HBE14o- and liver HepG2 cells) were profiled, and validation studies revealed that AAT mRNA-specific miRNAs functionally target the AAT mRNA in a cell-specific manner, providing the first evidence of innate miRNAs selectively targeting and modulating AAT mRNA expression. Interleukin-8 and secretory leucoprotease inhibitor mRNAs and their cognate miRNAs were also successfully captured using this approach. This is a simple and an efficient method to potentially identify miRNAs targeting sequences within the full length of a given mRNA transcript. 23570394 Ultrafast Charge Transfer at Monolayer Graphene Surfaces with Varied Substrate Coupling. The charge transfer rates of a localized excited electron to graphene monolayers with variable substrate coupling have been investigated by the core hole clock method with adsorbed argon. Expressed as charge transfer times, we find strong variations between ∼3 fs (on graphene "valleys" on Ru(0001)) to ∼16 fs (quasi-free graphene on SiC, O/Ru(0001), or SiO2/Ru). The values for the "hills" on Gr/Ru and on Gr/Pt(111) are in between, with the ratio 1.7 between the charge transfer times measured on "hills" and "valleys" of Gr/Ru. We discuss the results for Gr on metals in terms of hybridized Ru-C orbitals, which change with the relative Gr-Ru alignment and distance. The charge transfer on the decoupled graphene layers must represent the intrinsic coupling to the graphene empty π* states. Its low rate may be influenced by processes retarding the spreading of charge after transfer. 23621493 Uncovering the Enzymes that Catalyze the Final Steps in Oxytetracycline Biosynthesis. Tetracyclines are a group of natural products sharing a linearly fused four-ring scaffold, which is essential for their broad-spectrum antibiotic activities. Formation of the key precursor anhydrotetracycline 3 during oxytetracycline 1 biosynthesis has been previously characterized. However, the enzymatic steps that transform 3 into 1, including the additional hydroxylation at C5 and the final C5a-C11a reduction, have remained elusive. Here we report two redox enzymes, OxyS and OxyR, are sufficient to convert 3 to 1. OxyS catalyzes two sequential hydroxylations at C6 and C5 positions of 3 with opposite stereochemistry, while OxyR catalyzes the C5a-C11a reduction using F420 as a cofactor to produce 1. The crystal structure of OxyS was obtained to provide insights into the tandem C6- and C5-hydroxylation steps. The substrate specificities of OxyS and OxyR were shown to influence the relative ratio of 1 and tetracycline 2. 23183183 Natriuretic peptides in developing medaka embryos: implications in cardiac development by loss-of-function studies. Cardiac natriuretic peptides (NPs), atrial NP (ANP) and B-type NP (BNP), and their receptor, guanylyl cyclase (GC)-A have attracted attention of many basic and clinical researchers because of their potent renal and cardiovascular actions. In this study, we used medaka, Oryzias latipes, as a model species to pursue the physiological functions of NPs because it is a suitable model for developmental analyses. Medaka has two ligands, BNP and C-type NP3 (CNP3) (but not ANP), that have greater affinity for the two O. latipes GC-A receptors (OLGC), OLGC7 and OLGC2, respectively. CNP3 is the ancestral molecule of cardiac NPs. Initially, we examined developmental expression of cardiac NP/receptor combinations, BNP/OLGC7 and CNP3/OLGC2, using quantitative real-time PCR and in situ hybridization. BNP and CNP3 mRNA increased at stages 25 (onset of ventricular formation) and 22 (appearance of heart anlage), respectively, whereas both receptor mRNAs increased at as early as stage 12. BNP/OLGC7 transcripts were found in arterial/ventricular tissues and CNP3/OLGC2 transcripts in venous/atrial tissues by in situ hybridization. Thus, BNP and CNP3 can act locally on cardiac myocytes in a paracrine/autocrine fashion. Double knockdown of BNP/OLGC7 genes impaired ventricular development by causing hypoplasia of ventricular myocytes as evidenced by reduced bromodeoxyuridine incorporation. CNP3 knockdown induced hypertrophy of atria and activated the renin-angiotensin system. Collectively, it appears that BNP is important for normal ventricular, whereas CNP3 is important for normal atrial development and performance, a role usually taken by ANP in other vertebrates. The current study provides new insights into the role of cardiac NPs in cardiac development in vertebrates. 22827445 Electrophoretic deposition of the thiophene-based copolymer and its composites with C60. Electrophoretic deposition is a useful and efficient technique to deposit conjugated polymers, if suitable suspension of the target polymer is obtained. Unfortunately, neither general theory nor universal procedure for the preparation of a suspension suitable for electrophoretic deposition has seemed to be established yet. Thus, accumulation of individual knowledge is still important in this area. Here, the preparation of suspensions of a thiophene-based polymer poly(3-octylthiophene-2,5-diyl-co-3-decyloxythiophene-2,5-diyl) (POT-co-DOT) and their application to the electrophoretic deposition have been reported. The suspensions of POT-co-DOT with various good/poor solvents ratios were easily obtained by mixing a toluene solution of the polymer and acetonitrile. The composition of the dispersion medium significantly affects the surface morphology of the film prepared by the electrophoretic deposition in the suspension. Composite films consisting of POT-co-DOT and C(60) have also been successfully prepared by electrophoretic deposition. Because the optical absorption peak at 333 nm in C(60) showed neither significant broadening nor a red shift, C(60) molecules were expected to be well-dispersed in the composite films. A photovoltaic device with a composite film prepared from a POT-co-DOT/C(60) = 2:1 suspension showed 10 times larger short-circuit current density and 5 times larger power conversion efficiency than a device with pure POT-co-DOT, although further work is required to improve the device performance. 23071294 ApoE derived from adipose tissue does not suppress atherosclerosis or correct hyperlipidemia in apoE knockout mice. The synthesis of apoE by adipocytes has profound effects on adipose tissue lipid flux and gene expression. Using adipose tissue transplantation from wild-type (WT) to apoE knockout (EKO) mice, we show that adipose tissue also contributes to circulating apoE. Different from circulating apoE produced by bone marrow transplantation (BMT), however, adipose tissue-derived apoE does not correct hyperlipidemia or suppress atherosclerosis. ApoE secreted by macrophages has a more acidic isoform distribution, and it increases binding of reconstituted VLDL particles to hepatocytes and fibroblasts more effectively than apoE secreted by adipocytes. The incremental binding can be entirely accounted for by binding to the LDL receptor. After BMT into EKO hosts, plasma cholesterol and macrophage-derived apoE are largely within IDL/LDL- and HDL-sized particles. After adipose tissue transplantation, most cholesterol and adipocyte apoE remain in VLDL. After BMT, circulating apoE no longer demonstrates predominance of acidic isoforms compared with that circulating after fat transplantation. In conclusion, fat transplantation provides circulating apoE levels similar to those provided by bone marrow transplantation, but it does not suppress hyperlipidemia or atherosclerosis. A potential mechanism contributing to this difference is differential binding to cell surface lipoprotein receptors. 23159106 Ethanol modulates the neurovascular coupling. Despite some evidence of the underlying molecular mechanisms the neuronal basis of ethanol-induced effects on the neurovascular coupling that forms the BOLD (blood oxygenation level dependent) signal is poorly understood. In a recent fMRI (functional magnetic resonance imaging) study monitoring ethanol-induced changes of the BOLD signal a reduction of the amplitude and a prolongation of the BOLD signal were observed. However, the BOLD signal is assumed to consist of a complex superposition of different underlying signals. To gain insight how ethanol influences stimulus efficacy, oxygen extraction, transit time and vessel-related parameters the fMRI time series from the sensori-motor and the visual cortex were analyzed using the balloon model. The results show a region-dependent decrease of the stimulus efficacy to trigger a post-stimulus neurovascular response as well as a prolongation of the transit time through the venous compartment. Oxygen extraction, feedback mechanisms and other vessel-related parameters were not affected. The results may be interpreted as follows: the overall mechanisms of the neurovascular coupling are still acting well at the moderate ethanol level of about 0.8‰ (in particular the vessel-related parts), but the potency to evoke a neurovascular response is already compromised most obviously in the supplementary motor area responsible for complex synchronizing and planning processes. 23199257 Ultrasensitive broadband probing of molecular vibrational modes with multifrequency optical antennas. Optical antennas represent an enabling technology for enhancing the detection of molecular vibrational signatures at low concentrations and probing the chemical composition of a sample in order to identify target molecules. However, efficiently detecting different vibrational modes to determine the presence (or the absence) of a molecular species requires a multispectral interrogation in a window of several micrometers, as many molecules present informative fingerprint spectra in the mid-infrared between 2.5 and 10 μm. As most nanoantennas exhibit a narrow-band response because of their dipolar nature, they are not suitable for such applications. Here, we propose the use of multifrequency optical antennas designed for operating with a bandwidth of several octaves. We demonstrate that surface-enhanced infrared absorption gains in the order of 10(5) can be easily obtained in a spectral window of 3 μm with attomolar concentrations of molecules, providing new opportunities for ultrasensitive broadband detection of molecular species via vibrational spectroscopy techniques. 23394469 Free energy of adsorption for a peptide at a liquid/solid interface via nonequilibrium molecular dynamics. Protein adsorption is of wide interest including in many technological applications such as tissue engineering, nanotechnology, biosensors, drug delivery, and vaccine production among others. Understanding the fundamentals of such technologies and their design would be greatly aided by an ability to efficiently predict the conformation of an adsorbed protein and its free energy of adsorption. In the study reported here, we show that this is possible when data obtained from nonequilibrium thermodynamic integration (NETI) combined with steered molecular dynamics (SMD) is subject to bootstrapping. For the met-enkephalin pentapeptide at a water-graphite interface, we were able to obtain accurate predictions for the location of the adsorbed peptide and its free energy of adsorption from around 50 and 80 SMD simulations, respectively. It was also shown that adsorption in this system is both energetically and entropically driven. The free energy of adsorption was also decomposed into that associated with formation of the cavity in the water near the graphite surface sufficient to accommodate the adsorbed peptide and that associated with insertion of the peptide into this cavity. This decomposition reveals that the former is modestly energetically and entropically unfavorable, whereas the latter is the opposite in both regards to a much greater extent. 23235158 First crystal structure of a fungal high-redox potential dye-decolorizing peroxidase: substrate interaction sites and long-range electron transfer. Dye-decolorizing peroxidases (DyPs) belong to the large group of heme peroxidases. They utilize hydrogen peroxide to catalyze oxidations of various organic compounds. AauDyPI from Auricularia auricula-judae (fungi) was crystallized, and its crystal structure was determined at 2.1 Å resolution. The mostly helical structure also shows a β-sheet motif typical for DyPs and Cld (chlorite dismutase)-related structures and includes the complete polypeptide chain. At the distal side of the heme molecule, a flexible aspartate residue (Asp-168) plays a key role in catalysis. It guides incoming hydrogen peroxide toward the heme iron and mediates proton rearrangement in the process of Compound I formation. Afterward, its side chain changes its conformation, now pointing toward the protein backbone. We propose an extended functionality of Asp-168, which acts like a gatekeeper by altering the width of the heme cavity access channel. Chemical modifications of potentially redox-active amino acids show that a tyrosine is involved in substrate interaction. Using spin-trapping experiments, a transient radical on the surface-exposed Tyr-337 was identified as the oxidation site for bulky substrates. A possible long-range electron transfer pathway from the surface of the enzyme to the redox cofactor (heme) is discussed. 23211525 Regulation of the human hydroxysteroid sulfotransferase (SULT2A1) by RORα and RORγ and its potential relevance to human liver diseases. The retinoid-related orphan receptors (RORs) were postulated to have functions in tissue development and circadian rhythm. In this study, we revealed a novel function of RORα (NR1F1) and RORγ (NR1F3) in regulating the human hydroxysteroid sulfotransferase (SULT2A1), a phase II conjugating enzyme known to sulfonate bile acids, hydroxysteroid dehydroepiandrosterone, and related androgens. A combination of promoter reporter gene assay and EMSA and chromatin immunoprecipitation (ChIP) assays showed that both RORα and RORγ transactivated the SULT2A1 gene promoter through their binding to a ROR response element found in the SULT2A1 gene promoter. Interestingly, this ROR response element overlaps with a previously reported constitutive androstane receptor response element on the same promoter. Down-regulation of RORα and/or RORγ by small interfering RNA inhibited the expression of endogenous SULT2A1. In primary human hepatocytes and human livers, we found a positive correlation between the expression of SULT2A1 and RORs, which further supported the regulation of SULT2A1 by RORs. We also found that the expression of RORα and RORγ was impaired in several liver disease conditions, such as steatosis/steatohepatitis, fibrosis, and hepatocellular carcinoma. The positive regulation of human SULT2A1 by RORs is opposite to the negative regulation of Sult2a1 by RORs in rodents. In summary, our results established SULT2A1 as a novel ROR target gene. The expression of RORs is a potential predictor for the expression of SULT2A1 as well as disease conditions. 23237482 Tuning the light emission from GaAs nanowires over 290 meV with uniaxial strain. Strain engineering has been used to increase the charge carrier mobility of complementary metal-oxide-semiconductor transistors as well as to boost and tune the performance of optoelectronic devices, enabling wavelength tuning, polarization selectivity and suppression of temperature drifts. Semiconducting nanowires benefit from enhanced mechanical properties, such as increased yield strength, that turn out to be beneficial to amplify strain effects. Here we use photoluminescence (PL) to study the effect of uniaxial stress on the electronic properties of GaAs/Al0.3Ga0.7As/GaAs core/shell nanowires. Both compressive and tensile mechanical stress were applied continuously and reversibly to the nanowire, resulting in a remarkable decrease of the bandgap of up to 296 meV at 3.5% of strain. Raman spectra were measured and analyzed to determine the axial strain in the nanowire and the Poisson ratio in the <111> direction. In both PL and Raman spectra, we observe fingerprints of symmetry breaking due to anisotropic deformation of the nanowire. The shifts observed in the PL and Raman spectra are well described by bulk deformation potentials for band structure and phonon energies. The fact that exceptionally high elastic strain can be applied to semiconducting nanowires makes them ideally suited for novel device applications that require a tuning of the band structure over a broad range. 23337523 Pharmacy benefit managers and their obligations during serious prescription drug shortages. Pharmacy benefit managers are connected to some 215 million Americans and to every prescribing physician and retail pharmacy in the United States. Many of them have their own large and sophisticated dispensing operations. These capabilities could be put to use when drug shortages threaten life. Indeed, these capabilities are such that they confer obligations on pharmacy benefit managers to address such shortages--not only on behalf of their clients but for society in general. 23553708 Impact of Sildenafil on Survival of Patients With Eisenmenger Syndrome. The favorable effects of short-term use of sildenafil on patients with Eisenmenger syndrome have been reported. We further studied the impact of long-term use of sildenafil on survival of these patients. In this study, the baseline data of patients newly diagnosed as Eisenmenger syndrome in our hospital between January 2005 and December 2009 were retrospectively collected. Patients were followed-up either by telephone contacts or during visits in our out-patient clinic. A total of 121 patients (68 patients in conventional group and 53 patients in sildenafil group) were finally included and 29 patients were re-evaluated after sildenafil therapy for 3-4 months. Compared with the baseline, a 6-minute walk distance, functional classes, plasma hemoglobin level, and hemodynamics were significantly improved after sildenafil treatment. During a median follow-up period of 35.8 months, 15 patients died (11 patients in conventional group). The 1- and 3-year survival rates in sildenafil group were 97.0% and 95.2%, significantly higher than 90.6% and 82.9% in conventional group P = .025). Multivariate analysis showed that sildenafil therapy, functional class and mean pulmonary arterial pressure were independently associated with survival. Therefore, long-term sildenafil therapy improved survival in patients with Eisenmenger syndrome. 23526144 Serum trace elements levels in preeclampsia and eclampsia: correlation with the pregnancy disorder. Preeclampsia and eclampsia are fatal medical complications of pregnancy accounting for 20-80 % of increased maternal death in developing countries. Their aetiologies are still under investigation. Serum trace elements have been suggested to be involved in the pathogenesis of preeclampsia. Aim of this study was to address the correlation of serum trace elements with preeclampsia and eclampsia. It was a comparative cross-sectional study conducted on conveniently recruited 44 preeclampsia, 33 eclampsia and 27 normotensive pregnant patients. Atomic absorption spectrometry was employed to analyse serum concentrations of Ca, Mg, Cu, Zn and Fe. Data were analysed by Student's t test, one-way analysis of variance and multinomial logistic and binary regression analyses. p < 0.05 was considered as a level of significance. In preeclampsia, the serum Ca and Mg were significantly lower than those in eclampsia, while Cu and Zn values were higher. Significant changes of Ca, Mg and Cu were noted among preeclampsia, eclampsia and pregnant control. Serum Ca and Mg indicated a positive association, and Cu gave a negative association in preeclampsia. Cu/Fe ratio was high in eclampsia. Significant correlations of Mg with Zn in eclampsia and Mg with Fe in preeclampsia and eclampsia were predicted. Significant changes in serum trace element levels were present in preeclampsia and eclampsia that may have a link with the pathogenesis of pregnancy disorder. 23643792 In vivo toxicological evaluation of polymeric nanocapsules after intradermal administration. Polymeric nanocarriers have shown great promise as delivery systems. An alternative strategy has been to explore new delivery routes, such as intradermal (i.d.) that can be used for vaccines and patch-based drug delivery. Despite their many advantages, there are few toxicity studies, especially in vivo. We report a safety assessment of biodegradable poly(-caprolactone) lipid-core nanocapsules (LNC) with a mean size of 245 ± 10 nm following single and repeated intradermal injections to Wistar rats. Suspensions were prepared by interfacial deposition of polymer. The animals (n = 6/group) received a single dose of saline solution (1.2 ml/kg) or LNC (7.2 × 10(12) LNC/kg), or repeated doses of two controls, saline solution or Tween 80 (0.9 ml/kg), or three different concentrations of LNC (1.8, 3.6, and 5.4 × 10(12) LNC/kg) for 28 consecutive days. Clinical and physiological signs and mortality were observed. Samples of urine, blood, and tissue were used to perform toxicological evaluation. There were no clinical signs of toxicity or mortality, but there was a slight decrease in the relative body weights in the Tween 80-treated group (p < 0.01) after repeated administration. No histopathological alterations were observed in tissues or significant changes in blood and urinary biomarkers for tissue damage. Mild alterations in white blood cells count with increases in granulocytes in the Tween-80 group (p < 0.05) were found. Genotoxicity was evaluated through the comet assay and no statistical difference was observed among the groups. Therefore, we conclude that, under the conditions of these experiments, biodegradable LNC did not present appreciable toxicity after 28 consecutive days of intradermal administration and is promising for its future application in vaccines and patch-based devices for enhancing the delivery of drugs. 23578690 Novel ROS-activated agents utilize a tethered amine to selectively target acute myeloid leukemia. This study explores the possible use of reactive oxygen-activated DNA modifying agents against acute myeloid leukemia (AML). A key amine on the lead agent was investigated via cytotoxicity assays and was found necessary for potency. The two best compounds were screened via the NCI-60 cell panel. These two compounds had potency between 200 and 800nM against many of the leukemia cancer cell types. Subsequent experiments explored activity against a transformed AML model that mimics the molecular signatures identified in primary AML patient samples. A lead compound had an IC50 of 760nM against this AML cell line as well as a therapeutic index of 7.7±3 between the transformed AML model cell line and non-cancerous human CD34+ blood stem/progenitor cells (UCB). The selectivity was much greater than the mainstays of AML treatment: doxorubicin and cytarabine. This manuscript demonstrates that this novel type of agent may be useful against AML. 23504247 Synthesis of new 1,3,4-benzotriazepin-5-one derivatives and their biological evaluation as antitumor agents. New derivatives of 1,3,4-benzotriazepin-5-one were designed and synthesized as structural analogues to the antitumor agents devazepide and asperlicin. An efficient and novel approach to the synthesis of 2-amino-1,3,4-benzotriazepin-5-one 2 was developed and its structure was confirmed. The newly synthesized derivatives were evaluated for their in vitro antitumor activity on 60 different cell lines. Compounds 8 and 9 displayed the most potent antitumor activity against several cell lines specifically ovarian cancer, renal cancer and prostate cancer, while compounds 5, 10 and 12 showed significant activities against UO-31 renal cancer cell line. 23139020 Determination of the dominant arachidonic acid cytochrome p450 monooxygenases in rat heart, lung, kidney, and liver: protein expression and metabolite kinetics. Cytochrome P450 (P450)-derived arachidonic acid (AA) metabolites serve pivotal physiological roles. Therefore, it is important to determine the dominant P450 AA monooxygenases in different organs. We investigated the P450 AA monooxygenases protein expression as well as regioselectivity, immunoinhibition, and kinetic profile of AA epoxygenation and hydroxylation in rat heart, lung, kidney, and liver. Thereafter, the predominant P450 epoxygenases and P450 hydroxylases in these organs were characterized. Microsomes from heart, lung, kidney, and liver were incubated with AA. The protein expression of CYP2B1/2, CYP2C11, CYP2C23, CYP2J3, CYP4A1/2/3, and CYP4Fs in the heart, lung, kidney, and liver were determined by Western blot analysis. The levels of AA metabolites were determined by liquid chromatography-electrospray ionization mass spectroscopy. This was followed by determination of regioselectivity, immunoinhibition effect, and the kinetic profile of AA metabolism. AA was metabolized to epoxyeicosatrienoic acids and 19- and 20-hydroxyeicosatetraenoic acid in the heart, lung, kidney, and liver but with varying metabolic activities and regioselectivity. Anti-P450 antibodies were found to differentially inhibit AA epoxygenation and hydroxylation in these organs. Our data suggest that the predominant epoxygenases are CYP2C11, CYP2B1, CYP2C23, and CYP2C11/CYP2C23 for the heart, lung, kidney, and liver, respectively. On the other hand, CYP4A1 is the major ω-hydroxylase in the heart and kidney; whereas CYP4A2 and/or CYP4F1/4 are probably the major hydroxlases in the lung and liver. These results provide important insights into the activities of P450 epoxygenases and P450 hydroxylases-mediated AA metabolism in different organs and their associated P450 protein levels. 23391162 Structure-Relaxivity Relationships of Serum Albumin Targeted MRI Probes Based on a Single Amino Acid Gd Complex. The Gd(III) complex of DO3A-N-α-aminopropionate, Gd(DOTAla), was used to generate a small library of putative MRI probes targeted to human serum albumin (HSA). Ten compounds were synthesized via multistep organic synthesis, and the corresponding Gd complexes were investigated for their affinity to HSA, lipophilicity, and relaxivity in the absence and presence of HSA. Negative charge and moderate lipophilicity correlate with increased HSA affinity and relaxivity. 23518599 Effects of rare-earth co-doping on the local structure of rare-earth phosphate glasses using high and low energy X-ray diffraction. Rare-earth co-doping in inorganic materials has a long-held tradition of facilitating highly desirable optoelectronic properties for their application to the laser industry. This study concentrates specifically on rare-earth phosphate glasses, (R2O3)x(R'2O3)y(P2O5)1-(x+y), where (R, R') denotes (Ce, Er) or (La, Nd) co-doping and the total rare-earth composition corresponds to a range between metaphosphate, RP3O9, and ultraphosphate, RP5O14. Thereupon, the effects of rare-earth co-doping on the local structure are assessed at the atomic level. Pair-distribution function analysis of high-energy X-ray diffraction data (Qmax = 28 Å(-1)) is employed to make this assessment. Results reveal a stark structural invariance to rare-earth co-doping which bears testament to the open-framework and rigid nature of these glasses. A range of desirable attributes of these glasses unfold from this finding; in particular, a structural simplicity that will enable facile molecular engineering of rare-earth phosphate glasses with 'dial-up' lasing properties. When considered together with other factors, this finding also demonstrates additional prospects for these co-doped rare-earth phosphate glasses in nuclear waste storage applications. This study also reveals, for the first time, the ability to distinguish between P-O and P[double bond, length as m-dash]O bonding in these rare-earth phosphate glasses from X-ray diffraction data in a fully quantitative manner. Complementary analysis of high-energy X-ray diffraction data on single rare-earth phosphate glasses of similar rare-earth composition to the co-doped materials is also presented in this context. In a technical sense, all high-energy X-ray diffraction data on these glasses are compared with analogous low-energy diffraction data; their salient differences reveal distinct advantages of high-energy X-ray diffraction data for the study of amorphous materials. 23228475 Cyprodinil as an activator of aryl hydrocarbon receptor. Cyprodinil is a pyrimidinamine fungicide, used worldwide by agriculture. It is used to protect fruit plants and vegetables from a wide range of pathogens. Benzo[a]pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are toxic environmental pollutants and are prototypes of aryl hydrocarbon receptor (AHR) ligands. Although the structure of cyprodinil distinctly differs from those of BaP and TCDD, our results show that cyprodinil induced nuclear translocation of the AHR, and induced the transcriptional activity of aryl hydrocarbon response element (AHRE). Cyprodinil induced the expression of cytochrome P450 (CYP) 1A1, a well-known AHR-targeted gene, in ovarian granulosa cells, HO23, and hepatoma cells, Hepa-1c1c7. Its induction did not appear in AHR signal-deficient cells, and was blocked by the AHR antagonist, CH-223191. Cyprodinil decreased AHR expression in HO23 cells, resulting in CYP1A1 expression decreasing after it peaked at 9h of treatment in HO23 cells. Dexamethasone is a synthetic agonist of glucocorticoids. Cyprodinil enhanced dexamethasone-induced gene expression, and conversely, its induction of CYP1A1 expression was decreased by dexamethasone in HO23 cells, indicating its induction of crosstalk between the AHR and glucocorticoid receptor and its role as a potential endocrine disrupter. In addition to BaP, TCDD, and an AHR agonist, β-NF, cyprodinil also phosphorylated extracellular signal-regulated kinase (ERK) in HO23 and Hepa-1c1c7 cells, indicating its deregulation of ERK activity. In summary, our results demonstrate that cyprodinil, similar to BaP, acts as an AHR activator, a potential endocrine disrupter, and an ERK disrupter. 22815248 Protective Effects of a Purified Saponin Mixture from Astragalus corniculatus Bieb., in vivo Hepatotoxicity Models. In this study, the in vivo effects of a purified saponin mixture (PSM), obtained from Astragalus corniculatus Bieb., were investigated using two in vivo hepatotoxicity models based on liver damage caused by paracetamol (PC) and carbon tetrachloride (CCl4 ). The effects of PSM were compared with silymarin. Male Wistar rats were challenged orally with 20% CCl4 or PC (2 g/kg) four days after being pre-treated with PSM (100 mg/kg) or silymarin (200 mg/kg). A significant decrease of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase (LDH) activities and glutathione (GSH) levels and an increase of malondialdehyde (MDA) quantity was observed after CCl4 and PC administration alone. PSM pre-treatment decreased serum transaminases and LDH activities and MDA levels and increased the levels of cell protector GSH. Biotransformation phase I enzymes were also assessed in both models. In the CCl4 hepatotoxicity model, pre-treatment with PSM or silymarin resulted in significantly increased activities of ethylmorphine-N-demethylase and aniline 4-hydroxylase activity and cytochrome P450, compared to the CCl4 only group. Neither silymarin nor PSM influenced PC biotransformation. Our results suggest that PSM, obtained from A. corniculatus, Bieb. showed in vivo hepatoprotective and antioxidant activities against CCl4 and PC-induced liver damage comparable to that of silymarin. Copyright © 2012 John Wiley & Sons, Ltd. 23010870 Nondestructive indices of mercury exposure in three species of turtles occupying different trophic niches downstream from a former chloralkali facility. Turtles are useful for studying bioaccumulative pollutants such as mercury (Hg) because they have long life spans and feed at trophic levels that result in high exposure to anthropogenic chemicals. We compared total Hg concentrations in blood and toenails of three species of turtles (Chelydra serpentina, Sternotherus odoratus, and Graptemys geographica) with different feeding ecologies from locations up- and downstream of a superfund site in Virginia, USA. Mercury concentrations in turtle tissues were low at the reference site (average ± 1SE: blood = 48 ± 6 ng g(-1); nail = 2,464 ± 339 ng g(-1) FW) but rose near the contamination source to concentrations among the highest ever reported in turtles [up to 1,800 ng g(-1) (blood) and 42,250 ng g(-1) (nail) FW]. Tissue concentrations remained elevated ~130 km downstream from the source compared to reference concentrations. Tissue Hg concentrations were higher for C. serpentina and S. odoratus than G. geographica, consistent with the feeding ecology and our stable isotope (δ(13)C and δ(15)N) analyses of these species. In addition, we suggest that toenails were a better indication of Hg exposure than blood, probably because this keratinized tissue represents integrated exposure over time. Our results demonstrate that downstream transport of Hg from point sources can persist over vast expanses of river thereby posing potential exposure risks to turtles, but relative exposure varies with trophic level. In addition, our study identifies turtle toenails as a simple, cost-efficient, and minimally invasive tissue for conservation-minded sampling of these long-lived vertebrates. 23318729 The in vitro and in vivo genotoxicity of isotretinoin assessed by cytokinesis blocked micronucleus assay and comet assay. Isotretinoin is a retinoic acid frequently used in monotherapy or combined with narrow-band ultraviolet B (NBUVB) irradiation to treat patients with acne and psoriasis vulgaris. As both diseases need frequent and/or prolonged therapeutic interventions, the study of the genotoxicity of retinoids becomes important. Our aim was to study the genotoxic effects of isotretinoin alone or combined with NBUVB. In vitro studies were performed in the absence of S9 metabolic activation using blood from five healthy volunteers, incubated 72 h with isotretinoin (1.2-20 μM) (i.e., at concentrations usually achieved in blood with therapeutic doses as well as at higher concentrations). In vivo studies were also performed using blood from two patients with acne and three patients with psoriasis vulgaris treated with isotretinoin in monotherapy (8 or 20mg/day) or combined with NBUVB (20mg isotretinoin/day+NBUVB). The genotoxic effect was evaluated by the cytokinesis-blocked micronucleus and the comet assays. Our studies showed that isotretinoin alone was not genotoxic when tested in human lymphocytes in vitro and in vivo. There was no clear genotoxic effect in psoriatic patients treated with isotretinoin and NBUVB. The in vitro studies showed that isotretinoin induced apoptosis and necrosis in human lymphocytes at higher doses. 23355493 Occupational exposure to anaesthetic gases and high-frequency audiometry. Objectives: Occupational exposure to anaestethic gases has been suggested to induce auditory damages. The aim of this study is to investigate high-frequency audiometric responses in subjects exposed to anaesthetic gases, in order to highlight the possible effects on auditory system. METHODS: The study was performed on a sample of 30 medical specialists of Messina University Anaesthesia and Intensive care. We have used tonal audiometry as well as high-frequency one. We have compared the responses with those obtained in a similar control group not exposed to anaesthetic gases. Results were compared statistically. Results: Results show a strong correlation (p = 0.000) between left and right ear responses to all the audiometric tests. The exposed and the control group run though the standard audiometry analysis plays different audiometric responses up only to higher frequencies (2000 HZ p = 0.009 and 4000 Hz p = 0.04); in high-frequency audiometry, as all other frequencies, the attention is drew to the fact that the sample groups distinguish themselves in a significantly statistic way (10,000 Hz p = 0.025, 12,000 Hz p = 0.008, 14,000 Hz p = 0.026, 16,000 Hz p = 0.08). The highest values are the ones related to exposed subjects both in standard (2000 Hz p = 0.01, 4000 Hz p = 0.02) and in high-frequency audiometry (10,000 Hz p = 0.011, 12,000 Hz p = 0.004, 14,000 Hz p = 0.012, 16,000 Hz p = 0.004). Conclusion: Results, even if preliminary and referred to a low-range sample, show an involvement of the anatomic structure responsible for the perception of high-frequency audiometric responses in subjects exposed to anaesthetic gases. 23296979 Anti-platelet Activity of Erythro-(7S,8R)-7-acetoxy-3,4,3`,5`-tetramethoxy-8-O-4`-neolignan from Myristica fragrans. Platelets play a critical role in pathogenesis of cardiovascular disorders and strokes. The inhibition of platelet function is beneficial for the treatment and prevention of these diseases. In this study, we investigated the anti-platelet activity of erythro-(7S,8R)-7-acetoxy-3,4,3`,5`-tetramethoxy-8-O-4`-neolignan (EATN), a neolignan isolated from Myristica fragrans, using human platelets. EATN preferentially inhibited thrombin- and platelet-activating factor (PAF)-induced platelet aggregation without affecting platelet damage in a concentration-dependent manner with IC(50) values of 3.2 ± 0.4 and 3.4 ± 0.3 μM, respectively. However, much higher concentrations of EATN were required to inhibit platelet aggregation induced by arachidonic acid. EATN also inhibited thrombin-induced serotonin and ATP release, and thromboxane B(2) formation in human platelets. Moreover, EATN caused an increase in cyclic AMP (cAMP) levels and attenuated intracellular Ca(2+) mobilization in thrombin-activated human platelets. Therefore, we conclude that the inhibitory mechanism of EATN on platelet aggregation may increase cAMP levels and subsequently inhibit intracellular Ca(2+) mobilization by interfering with a common signaling pathway rather than by directly inhibiting the binding of thrombin or PAF to their receptors. This is the first report of the anti-platelet activity of EATN isolated from M. fragrans. Copyright © 2013 John Wiley & Sons, Ltd. 23287728 Cloning and characterization of an antibacterial L-amino acid oxidase from Crotalus durissus cumanensis venom. An L-amino acid oxidase (LAAO) from Crotalus durissus cumanensis venom (CdcLAAO) was purified to homogeneity using a combination of size-exclusion and ion exchange chromatographies. CdcLAAO is a monomeric protein exhibiting an apparent molecular mass of 55 kDa and a calculated pI of 8. Its complete 498-amino-acid sequence was deduced through cDNA and protein sequencing. The enzyme oxidized L-Leu with K(m) and a V(Max) of 9.23 μM and 0.46 μM/min respectively, and exhibited Kcat and a Kcat/K(m) of 1.8 s(-1) and 195 mM(-1)s(-1). CdcLAAO inhibited in a dose-dependent manner the growth of Staphylococcus aureus and Acinetobacter baumannii. The inhibitory effect was more significant on S. aureus, with a Minimal Inhibitory Concentration (MIC) of 8 μg/mL and Minimal Bactericidal Concentration (MBC) of 16 μg/mL, than against A. baumannii, with a MIC of 16 μg/mL and MBC of 32 μg/mL. However, against Escherichia coli CdcLAAO did not show inhibitory capacity at the concentrations tested (2-128 μg/mL). CdcLAAO did not exhibit cytotoxic activity on the mouse myoblast cell line C(2)C(12) and on peripheral blood mononuclear cell (PBMC). 23542039 The in vitro cytotoxicity and genotoxicity of cigarette smoke particulate matter with reduced toxicant yields. Tobacco smoke contains more than 5600 constituents, of which approximately 150 are toxicants. This paper describes the activities in the Neutral Red uptake (NRU) assay, the Salmonella mutagenicity test (SAL), the mouse lymphoma mammalian cell mutation assay (MLA) and the in vitro micronucleus test (IVMNT) of Particulate Matter (PM) obtained from experimental cigarettes (ECs), designed to produce reduced levels of toxicants. The designs included tobacco substitute sheet (TSS) containing glycerol, which dilutes toxicants in smoke, or the incorporation of blend-treated (BT) tobacco to reduce the levels of nitrogenous toxicant precursors and some polyphenols. All samples were cytotoxic in the NRU, however TSS reduced PM cytotoxicity in this assay. All PMs were mutagenic in the SAL, MLA and IVMNT. Reductions in bacterial mutagenicity were observed in the SAL, for cigarettes with BT tobacco, compared with their respective controls. The quantitative changes in bacterial mutagenicity could be explained by analytical chemistry data on smoke generated from the ECs used in the study. These observations, and the absence of consistent qualitative differences in the activities of the experimental, control and reference cigarettes, suggest that reduced toxicity cigarettes, as measured by the tests described in this paper, may be developed without introducing any additional cytotoxic or genotoxic hazards, but the impact of this on human health risks remains unknown. 23212975 Poly(N-vinylpyrrolidone)-modified surfaces for biomedical applications. Poly(N-vinylpyrrolidone) (PVP), an important water soluble synthetic polymer, has many desirable properties including low toxicity, chemical stability, and good biocompatibility. Since PVP is hemocompatible and physiologically inactive, it has been used as a blood plasma substitute. Surface modification with PVP has been investigated extensively over the past few years as a means of preventing nonspecific protein adsorption. PVP may therefore be seen as a promising antifouling surface modifier comparable to poly(ethylene glycol) (PEG). In this review, various approaches for the design and preparation of PVP-modified surfaces are summarized and potential biomedical applications of these PVP-modified materials are indicated. Finally, some perspectives on future research on PVP for surface modification are discussed. 23043441 Grafting efficiency of synthetic polymers onto biomaterials: a comparative study of grafting-from versus grafting-to. In the present study, the two grafting techniques grafting-from - by activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP) - and grafting-to - by copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) - were systematically compared, employing cellulose as a substrate. In order to obtain a meaningful comparison, it is crucial that the graft lengths of the polymers that are grafted from and to the substrates are essentially identical. Herein, this was achieved by utilizing the free polymer formed in parallel to the grafting-from reaction as the polymer for the grafting-to reaction. Four graft lengths were investigated, and the molar masses of the four free polymers (21 ≤ M(n) ≤ 100 kDa; 1.07 ≤ Đ(M) ≤ 1.26), i.e. the polymers subsequently employed in the grafting-to reaction, were shown to be in the same range as the molar masses of the polymers grafted from the surface (23 ≤ M(n) ≤ 87 kDa; 1.08 ≤ Đ(M) ≤ 1.31). The molecular weights of the chains grafted from the surface were established after cleavage from the cellulose substrates via size exclusion chromatography (SEC). High-resolution Fourier transform infrared microscopy (FT-IRM) was employed as an efficient tool to study the spatial distribution of the polymer content on the grafted substrates. In addition, the functionalized substrates were analyzed by X-ray photoelectron spectroscopy (XPS), contact angle (CA) measurements, and field-emission scanning electron microscopy (FE-SEM). For cellulose substrates modified via the grafting-from approach, the content of polymer on the surfaces increased with increasing graft length, confirming the possibility to tailor not only the length of the polymer grafts but also the polymeric content on the surface. In comparison, for the grafting-to reaction, the grafted content could not be controlled by varying the length of the preformed polymer: the polymer content was essentially the same for the four graft lengths. Consequently, the obtained results, when employing cellulose as a substrate and under these conditions, suggest that the grafting-from approach is superior to the grafting-to technique with respect to controlling the distribution of the polymeric content on the surface. 23446276 Single-molecule chemical denaturation of riboswitches. To date, single-molecule RNA science has been developed almost exclusively around the effect of metal ions as folding promoters and stabilizers of the RNA structure. Here, we introduce a novel strategy that combines single-molecule Förster resonance energy transfer (FRET) and chemical denaturation to observe and manipulate RNA dynamics. We demonstrate that the competing interplay between metal ions and denaturant agents provides a platform to extract information that otherwise will remain hidden with current methods. Using the adenine-sensing riboswitch aptamer as a model, we provide strong evidence for a rate-limiting folding step of the aptamer domain being modulated through ligand binding, a feature that is important for regulation of the controlled gene. In the absence of ligand, the rate-determining step is dominated by the formation of long-range key tertiary contacts between peripheral stem-loop elements. In contrast, when the adenine ligand interacts with partially folded messenger RNAs, the aptamer requires specifically bound Mg(2+) ions, as those observed in the crystal structure, to progress further towards the native form. Moreover, despite that the ligand-free and ligand-bound states are indistinguishable by FRET, their different stability against urea-induced denaturation allowed us to discriminate them, even when they coexist within a single FRET trajectory; a feature not accessible by existing methods. 23122129 Differential sensitivity of D-galactose-binding lectins from fruits of dwarf elder (Sambucus ebulus L.) to a simulated gastric fluid. Some lectins from Sambucus spp. share amino acid sequences with the pollen Sam n1 allergen. The lectins ebulin f and SELfd from the early stages of growth were isolated and subjected to analysis by MALDI-TOF mass spectrometry, tryptic peptide fingerprinting, molecular characterization and pepsin digestibility. The molecular mass (33.214) and other structural features of the Sam n1 allergen fit best with a monomeric lectin like SELlm (Mr 34.2 kDa) found in shoots of dwarf elder. Ebulin f toxicity to mice was higher intraperitoneally than orally at the same dose (5mg/kg body weight). In contrast SELfd at the same dose lacks of apparent toxicity. Ebulin f, but not SELfd, undergoes extensive pepsin proteolysis, which could explain the differences in toxicity. The present study supports our hypothesis that the Sam n1 allergen could be a sequence-related monomeric lectin like SELlm present in shoots of Sambucus ebulus rather than ebulin. 23401602 Conjugated linoleic acid reduces adiposity and increases markers of browning and inflammation in white adipose tissue of mice. The objective of this study was to examine the mechanism by which conjugated linoleic acid (CLA) reduces body fat. Young male mice were fed three combinations of fatty acids at three doses (0.06%, 0.2%, and 0.6%, w/w) incorporated into AIN76 diets for 7 weeks. The types of fatty acids were linoleic acid (control), an equal mixture of trans-10, cis-12 (10,12) CLA plus linoleic acid, and an equal isomer mixture of 10,12 plus cis-9, trans-11 (9,11) CLA. Mice receiving the 0.2% and 0.6% dose of 10,12 CLA plus linoleic acid or the CLA isomer mixture had decreased white adipose tissue (WAT) and brown adipose tissue (BAT) mass and increased incorporation of CLA isomers in epididymal WAT and liver. Notably, in mice receiving 0.2% of both CLA treatments, the mRNA levels of genes associated with browning, including uncoupling protein 1 (UCP1), UCP1 protein levels, and cytochrome c oxidase activity, were increased in epididymal WAT. CLA-induced browning in WAT was accompanied by increases in mRNA levels of markers of inflammation. Muscle cytochrome c oxidase activity and BAT UCP1 protein levels were not affected by CLA treatment. These data suggest a linkage between decreased adiposity, browning in WAT, and low-grade inflammation due to consumption of 10,12 CLA. 23553560 Axitinib in metastatic renal cell carcinoma: results of a pharmacokinetic and pharmacodynamic analysis. Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, approved for second-line therapy for advanced renal cell carcinoma (RCC). Axitinib population pharmacokinetic and pharmacokinetic/pharmacodynamic relationships were evaluated. Using nonlinear mixed effects modeling with pooled data from 383 healthy volunteers, 181 patients with metastatic RCC, and 26 patients with other solid tumors in 17 trials, the disposition of axitinib was best described by a 2-compartment model with first-order absorption and a lag time, with estimated mean systemic clearance (CL) of 14.6 L/h and central volume of distribution (Vc ) of 47.3 L. Of 12 covariates tested, age over 60 years and Japanese ethnicity were associated with decreased CL, whereas Vc increased with body weight. However, the magnitude of predicted changes in exposure based on these covariates does not warrant dose adjustments. Multivariate Cox proportional hazard regression and logistic regression analyses showed that higher exposure and diastolic blood pressure were independently associated with longer progression-free and overall survivals and higher probability of partial response in metastatic RCC patients. These findings support axitinib dose titration to increase plasma exposure in patients who tolerate axitinib, and also demonstrate diastolic blood pressure as a potential marker of efficacy. 23609128 Dynamics and structural changes of small water clusters on ionization. Despite utmost importance in understanding water ionization process, reliable theoretical results of structural changes and molecular dynamics (MD) of water clusters on ionization have hardly been reported yet. Here, we investigate the water cations [(H2 O)n = 2-6 (+) ] with density functional theory (DFT), Möller-Plesset second-order perturbation theory (MP2), and coupled cluster theory with single, double, and perturbative triple excitations [CCSD(T)]. The complete basis set limits of interaction energies at the CCSD(T) level are reported, and the geometrical structures, electronic properties, and infrared spectra are investigated. The characteristics of structures and spectra of the water cluster cations reflect the formation of the hydronium cation moiety (H3 O(+) ) and the hydroxyl radical. Although most density functionals fail to predict reasonable energetics of the water cations, some functionals are found to be reliable, in reasonable agreement with high-level ab initio results. To understand the ionization process of water clusters, DFT- and MP2-based Born-Oppenheimer MD (BOMD) simulations are performed on ionization. On ionization, the water clusters tend to have an Eigen-like form with the hydronium cation instead of a Zundel-like form, based on reliable BOMD simulations. For the vertically ionized water hexamer, the relatively stable (H2 O)5 (+) (5sL4A) cluster tends to form with a detached water molecule (H2 O). © 2013 Wiley Periodicals, Inc. 23427850 Formation of a polymer surface with a gradient of pore size using a microfluidic chip. Here we demonstrate the generation of polymer monolithic surfaces possessing a gradient of pore and polymer globule sizes from ~0.1 to ~0.5 μm defined by the composition of two polymerization mixtures injected into a microfluidic chip. To generate the gradient, we used a PDMS microfluidic chip with a cascade micromixer with a subsequent reaction chamber for the formation of a continuous gradient film. The micromixer has zigzag channels of 400 × 680 μm(2) cross section and six cascades. The chip was used with a reversible bonding connection, realized by curing agent coating. After polymerization in the microfluidic chip the reversible bond was opened, resulting in a 450 μm thick polymer film possessing the pore size gradient. The gradient formation in the microfluidic reaction chamber was studied using microscopic laser-induced fluorescence (μLIF) and different model fluids. Formation of linear gradients was shown using the fluids of the same density by both diffusive mixing at flow rates of 0.001 mL/min and in a convective mixing regime at flow rates of 20 mL/min. By using different density fluids, formation of a two-dimensional wedge-like gradient controlled by the density difference and orientation of the microfluidic chip was observed. 23391631 The role of aryl hydrocarbon receptor signaling pathway in cardiotoxicity of acute lead intoxication in vivo and in vitro rat model. Lead (Pb(2+)) is a naturally occurring systemic toxicant heavy metal that affects several organs in the body including the kidneys, liver, and central nervous system. However, Pb(2+)-induced cardiotoxicity has never been investigated yet and the exact mechanism of Pb(2+) associated cardiotoxicity has not been studied. The current study was designed to investigate the potential effect of Pb(2+) to induce cardiotoxicity in vivo and in vitro rat model and to explore the molecular mechanisms and the role of aryl hydrocarbon receptor (AhR) and regulated gene, cytochrome P4501A1 (CYP1A1), in Pb(2+)-mediated cardiotoxicity. For these purposes, Wistar albino rats were treated with Pb(2+) (25, 50 and 100mg/kg, i.p.) for three days and the effects on physiological and histopathological parameters of cardiotoxicity were determined. At the in vitro level, rat cardiomyocyte H9c2 cell lines were incubated with increasing concentration of Pb(2+) (25, 50, and 100μM) and the expression of hypertrophic genes, α- and β-myosin heavy chain (α-MHC and β-MHC), brain Natriuretic Peptide (BNP), and CYP1A1 were determined at the mRNA and protein levels using real-time PCR and Western blot analysis, respectively. The results showed that Pb(2+) significantly induced cardiotoxicity and heart failure as evidenced by increase cardiac enzymes, lactate dehydrogenase and creatine kinase and changes in histopathology in vivo. In addition, Pb(2+) treatment induced β-MHC and BNP whereas inhibited α-MHC mRNA and protein levels in vivo in a dose-dependent manner. In contrast, at the in vitro level, Pb(2+) treatment induced both β-MHC and α-MHC mRNA levels in time- and dose-dependent manner. Importantly, these changes were accompanied with a proportional increase in the expression of CYP1A1 mRNA and protein expression levels, suggesting a role for the CYP1A1 in cardiotoxicity. The direct evidence for the involvement of CYP1A1 in the induction of cardiotoxicity by Pb(2+) was evidenced by the ability of AhR antagonist, resveratrol, to significantly inhibit the Pb(2+)-modulated effect on β-MHC and α-MHC mRNAs. It was concluded that acute lead exposure induced cardiotoxicity through AhR/CYP1A1-mediated mechanism. 23419783 Metformin and Sulfonylureas in Relation to Cancer Risk in Type II Diabetes Patients: A Meta-analysis using primary data of published studies. INTRODUCTION: Accumulating evidence suggests that patients with type 2 diabetes mellitus (T2DM) and hyperinsulinemia are at increased risk for developing malignancies. It remains to be fully elucidated whether use of metformin, an insulin sensitizer, and/or sulfonylureas, insulin secretagogues, affect cancer incidence in subjects with T2DM. MATERIAL & METHODS: We performed a meta-analysis using PubMed, of randomized control trials (RCTs), cohorts, and case-control studies published through July 2012 that assess effects of metformin and/or sulfonylurea sulfonylureas on cancer risk at any site, in subjects with T2DM. Fixed and random effects meta-analysis models were used, and the effect size was summarized as relative risk (RR) for RCTs/cohorts and as odds ratio (OR) for the case-control studies. RESULTS: Analysis of 24 metformin studies in subjects with T2DM showed that metformin use is associated with reduced risk for the development of cancer, in both cohort (RR=0.70 [95% CI=0.67-0.73]) and case-control studies (OR=0.90 [95% CI=0.84-0.98]), but this finding was not supported by RCTs (RR=1.01[95% CI=0.81-1.26]). Data from 18 sulfonylurea studies in subjects with T2DM showed that sulfonylurea use is associated with an increase in all-cancer risk, in cohort studies (RR=1.55 [95% CI=1.48 -1.63]), though data from RCTs (RR=1.17 [95% CI=0.95-1.45]) and case-control studies (OR=1.02 [95% CI=0.93-1.13]) failed to demonstrate a statistically significant effect. CONCLUSIONS: This analysis using pooled primary data demonstrates that metformin use reduces, while sulfonylurea use may be associated with an increased cancer risk in subjects with T2DM. These findings need to be confirmed in large-scale RCTs before they are translated into clinical practice. 22275383 Protective effect of honey against cigarette smoke induced-impaired sexual behavior and fertility of male rats. Cigarette smoking is associated with sexual dysfunction and impaired fertility in males. The aim of this study was to determine the potential protective effect of honey against the toxic effect of cigarette smoke (CS) on sexual behavior and fertility of male rats. Thirty-two adult Sprague-Dawley rats were randomly divided into four groups (8 rats/group) as control, honey (H), CS and H plus CS (H + CS) groups. Rats in control and CS groups received oral administration of distilled water daily while rats in H and H + CS groups received honey (1.2 g/kg body weight/day) by oral gavage. Rats in CS and H + CS groups were also exposed to CS for 8 min 3 times/day. From 10 to 13 weeks of treatment, each male rat was cohabited with 3 untreated female rats for sexual behavioral and reproductive performance studies. Honey significantly increased the percentages of rats achieving intromission and ejaculation as well as increased mating and fertility indexes of male rats exposed to CS. Thus, honey has a protective effect against CS-induced impaired sexual behavior and fertility in male rats. 23427056 Exendin-4, a GLP-1 receptor agonist, prevents osteopnia by promoting bone formation and suppressing bone resorption in aged ovariectomized rats. Osteoporosis mainly affects postmenopausal women and older men. Gastrointestinal hormones released after meal ingestion, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP)-2, have been shown to regulate bone turnover. However, whether GLP-1, another important gastrointestinal hormone, and its analogues also have anti-osteoporotic effects, especially in aged postmenopausal situation, is not confirmed yet. In the present study, we evaluated the effects of the GLP-1 receptor agonist exendin-4 on ovariectomy (OVX) induced osteoporosis in old rats. Twelve-month-old female Sprague-Dawley rats were subjected to OVX, and exendin-4 were administrated 4 weeks after the surgery and lasted for 16 weeks. Bone characters and related serum and gene biomarkers were analyzed. Sixteen weeks treatment of exendin-4 slowed down the body weight gain by decreasing fat mass and prevented the loss of bone mass in old OVX rats. Exendin-4 also enhanced the bone strength and prevented the deterioration of trabecular microarchitecture. Moreover, exendin-4 decreased urinary DPD/creatinine ratio and serum CTX-I and increased serum ALP, OC and P1NP levels, key biochemical markers of bone turnover. Interestingly, gene expression results further showed that exendin-4 not only inhibited bone resorption by increasing OPG/RANKL ratio, but also promoted bone formation by increasing the expressions of OC, Col1, Runx2, and ALP, which exhibited dual regulatory effects on bone turnover as compared with previous anti-osteoporotic agents. In conclusion, these findings demonstrated for the first time the anti-osteoporotic effects of exendin-4 in old OVX rats and that it might be a potential candidate for treatment of aged postmenopausal osteoporosis. © 2013 American Society for Bone and Mineral Research. 23474013 Intact inhibitory control processes in abstinent drug abusers (I): A functional neuroimaging study in former cocaine addicts. Neuroimaging studies in current cocaine dependent (CD) individuals consistently reveal cortical hypoactivity across regions of the response inhibition circuit (RIC). Dysregulation of this critical executive network is hypothesized to account for the lack of inhibitory control that is a hallmark of the addictive phenotype, and chronic abuse is believed to compound the issue. A crucial question is whether deficits in this circuit persist after drug cessation, and whether recovery of this system will be seen after extended periods of abstinence, a question with implications for treatment course and outcome. Utilizing functional magnetic resonance imaging (fMRI), we examined activation in nodes of the RIC in abstinent CD individuals (n = 27) and non-using controls (n = 45) while they performed a motor response inhibition task. In contrast to current users, these abstinent individuals, despite extended histories of chronic cocaine-abuse (average duration of use = 8.2 years), performed the task just as efficiently as non-users. In line with these behavioral findings, no evidence for between-group differences in activation of the RIC was found and instead, robust activations were apparent in both groups within the well-characterized nodes of the RIC. Similarly, our complementary Electroencephalography (EEG) investigation also showed an absence of behavioral and electrophysiological deficits in abstinent drug abusers. These results are consistent with an amelioration of neurobiological deficits in inhibitory circuitry following drug cessation, and could help explain how long-term abstinence is maintained. Finally, regression analyses revealed a significant association between level of activation in the right insula with inhibition success and increased abstinence duration in the CD cohort suggesting that this region may be integral to successful recovery from cocaine addiction. 23343324 Ordered nanoscale Archimedean tilings of a templated 3-miktoarm star terpolymer. The directed self-assembly of 3-miktoarm star terpolymer chains (polyisoprene-arm-polystyrene-arm-polyferrocenylethylmethylsilane (3 μ-ISF)) into 2D Archimedean tilings is described. A morphological change from (4.8(2)) to (6(3)) tiling is reported in the 3 μ-ISF thin film blended with PS homopolymer when a greater swelling of PI is achieved during the solvent annealing process. Highly oriented (4.8(2)) tilings were produced by templating the self-assembled three colored structures in blended thin films. The use of (4.8(2)) and (6(3)) tilings as nanolithographic masks to transfer square and triangular hole arrays into the substrate is also demonstrated. 23535870 Controlling potassium selectivity and proton blocking in a hybrid biological/solid-state polymer nanoporous membrane. Specific separations of protons and cations are usually performed by electromembrane processes, which require external electric energy. An easier process would be using a membrane able to separate both entities by passive diffusion. Presently, such synthetic nanoporous membranes do not exist. Here, we report the production of a robust hybrid biological/artificial solid-state membrane, which allows selective permeation of alkali metal cations without competing or concurrent permeation of protons. This membrane is simple to prepare and is based on the hydrophobic nature of the polymeric pore walls, and the confined gramicidin A molecules within. This work opens a new route for separation in the domain of nanobiofiltration, especially for tunable nanodevices based on differential ion conduction, with a fundamental understanding of the confinement mechanism. 23461650 Vibronic and Vibrational Coherences in Two-Dimensional Electronic Spectra of Supramolecular J-Aggregates. In J-aggregates of cyanine dyes, closely packed molecules form mesoscopic tubes with nanometer-diameter and micrometer-length. Their efficient energy transfer pathways make them suitable candidates for artificial light harvesting systems. This great potential calls for an in-depth spectroscopic analysis of the underlying energy deactivation network and coherence dynamics. We use two-dimensional electronic spectroscopy with sub-10 fs laser pulses in combination with two-dimensional decay-associated spectra analysis to describe the population flow within the aggregate. Based on the analysis of Fourier-transform amplitude maps, we distinguish between vibrational or vibronic coherence dynamics as the origin of pronounced oscillations in our two-dimensional electronic spectra. 23494106 Toxicological profiles of selected synthetic cannabinoids showing high binding affinities to the cannabinoid receptor subtype CB1. Products containing synthetic cannabinoids are consumed as a surrogate for marihuana due to their non-detectability with commonly used drug tests and their strong cannabimimetic effects. Because data concerning their toxicological properties are scarce, the cytotoxic, genotoxic, immunomodulatory, and hormonal activities of four naphthoylindole compounds (JWH-018, JWH-073, JWH-122 and JWH-210) and of one benzoylindole (AM-694) were studied in human cell lines and primary cells; tetrahydrocannabinol was included as the classical non-endogenous cannabinoid receptor ligand. All compounds induced damage to the cell membranes of buccal (TR146) and breast (MCF-7) derived cells at concentrations of ≥75-100 μM. No cytotoxic responses were seen in other assays which reflect mitochondrial damage, protein synthesis, and lysosomal activities. JWH-073 and JWH-122 induced DNA migration in buccal and liver cells (HepG2) in single cell gel electrophoresis assays, while JWH-210 was only in the latter cell line active. No estrogenic activities were detected in bone marrow cells (U2-OS), but all compounds caused anti-estrogenic effects at levels between 2.1 and 23.0 μM. Furthermore, no impact on cytokine release (i.e., on IL-10, IL-6, IL-12/23p40 and TNFα levels) was seen in LPS-stimulated human PBMCs, except with JWH-210 and JWH-122 which caused a decrease of TNFα and IL-12/23p40. All toxic effects were observed with concentrations higher than those expected in body fluids of users. Since genotoxic effects are in general linear over a wide concentration range and the exposure levels may be higher in epithelial cells or in serum, further experimental work is required to find out if DNA damage takes place in drug users. 23253856 Distinct functions of human RECQ helicases WRN and BLM in replication fork recovery and progression after hydroxyurea-induced stalling. Human WRN and BLM genes are members of the conserved RECQ helicase family. Mutations in these genes are associated with Werner and Bloom syndromes. WRN and BLM proteins are implicated in DNA replication, recombination, repair, telomere maintenance, and transcription. Using microfluidics-assisted display of DNA for replication track analysis (ma-RTA), we show that WRN and BLM contribute additively to normal replication fork progression, and non-additively, in a RAD51-dependent pathway, to resumption of replication after arrest by hydroxyurea (HU), a replication-stalling drug. WRN but not BLM is required to support fork progression after HU. Resumption of replication by forks may be necessary but is not sufficient for timely completion of the cell cycle after HU arrest, as depletion of WRN or BLM compromises fork recovery to a similar degree, but only BLM depletion leads to extensive delay of cell division after HU, as well as more pronounced chromatin bridging. Finally, we show that recovery from HU includes apparent removal of some of the DNA that was synthesized immediately after release from HU, a novel phenomenon that we refer to as nascent strand processing, NSP. 23519153 The early molecular processes underlying the neurological manifestations of an animal model of Wilson's disease. The Long-Evans Cinnamon (LEC) rat shows age-dependent hepatic manifestations that are similar to those of Wilson's disease (WD). The pathogenic process in the brain has, however, not been evaluated in detail due to the rarity of the neurological symptoms. However, copper accumulation is noted in LEC rat brain tissue from 24 weeks of age, which results in oxidative injuries. The current study investigated the gene expression profiles of LEC rat brains at 24 weeks of age in order to identify the important early molecular changes that underlie the development of neurological symptoms in WD. Biological ontology-based analysis revealed diverse altered expressions of the genes related to copper accumulation. Of particular interest, we found altered expression of genes connected to mitochondrial respiration (Sdhaf2 and Ndufb7), calcineurin-mediated cellular processes (Ppp3ca, Ppp3cb, and Camk2a), amyloid precursor protein (Anks1b and A2m) and alpha-synuclein (Snca). In addition to copper-related changes, compensatory upregulations of Cp and Hamp reflect iron-mediated neurotoxicity. Of note, reciprocal expression of Asmt and Bhmt is an important clue that altered S-adenosylhomocysteine metabolism underlies brain injury in WD, which is directly correlated to the decreased expression of S-adenosylhomocysteine hydrolase in hepatic tissue in LEC rats. In conclusion, our study indicates that diverse molecular changes, both variable and complex, underlie the development of neurological manifestations in WD. Copper-related injuries were found to be the principal pathogenic process, but Fe- or adenosylhomocysteine-related injuries were also implicated. Investigations using other animal models or accessible human samples will be required to confirm our observations. 23357976 Longer HSD11B2 CA-repeat in impaired glucose tolerance and type 2 diabetes. Type 2 11β-hydroxysteroid dehydrogenase encoded by the HSD11B2 gene converts cortisol to inactive cortisone, and alteration in this enzymatic activity might affect glucose homeostasis by affecting circulating levels or tissue availability of glucocorticoids. We investigated the association of HSD11B2 variant with glucose homeostasis. Subjects with normal glucose tolerance (n=585), impaired glucose tolerance (n=202) and type 2 diabetes (n=355) were genotyped for a highly polymorphic CA-repeat polymorphism in the first intron of HSD11B2. Allele and genotype frequencies differed between normal and impaired glucose tolerance (P = 0.0014 and 0.0407, respectively; 4DF) or type 2 diabetes (P = 0.0053 and 0.0078), with significant linear trends between the repeat length and the phenotype fraction. In normal subjects, total CA-repeat length was negatively correlated with fasting insulin and HOMA-β. Thus, subjects having more CA repeats are susceptible to developing abnormal glucose tolerance, whereas normal subjects carrying more CA repeats appeared to have frugal characteristics in insulin secretion. 23639741 Ultrasound-assisted extraction of Na and K from swine feed and its application in a digestibility assay: A green analytical procedure. The study is aimed to evaluate the efficiency of ultrasound-assisted extraction (UAE) as a simple strategy focused on sample preparation for metal determination in biological samples. The extraction of sodium and potassium extraction was carried out from swine feed followed by determination of the concentration of these metals by flame atomic emission spectrometry (FAES). The experiment was performed to cover the study of the variables influencing the extraction process and its optimal conditions (sample mass, particle size, acid concentration, sonication time and ultrasound power); the determination of these analytical characteristics and method validation using certified reference material; and the analysis of pre-starter diets. The optimal conditions established conditions were as follows: mass: 100mg, particle size:<60μm, acid concentration: 0.10molL(-1) HCl, sonication time: 50s and ultrasound power: 102W. The proposed method (UAE) was applied in digestibility assays of those nutrients present in different piglet pre-starter feeds and their results proved to be compatible with those obtained from mineralized samples (P<0.05). The ultrasound extraction method was demonstrated to be an excellent alternative for handless sampling and operational costs and the method also has the advantage of does not generating toxic residues that may negatively affect human health and contaminate the environment. 23583169 Beyond the Sympathetic Tone: The New Brown Fat Activators. If we could avoid the side effects associated with global sympathetic activation, activating brown adipose tissue to increase thermogenesis would be a safe way to lose weight. The discovery of adrenergic-independent brown fat activators opens the prospect of developing this alternative way to efficiently and safely induce negative energy balance. 23232941 Density functional theory study of the structure and vibrational modes of acrylonitrile adsorbed on Cu(100). We present a theoretical study of the structure and vibrations of acrylonitrile adsorbed on a Cu(100) metal surface. Simulations have been carried out by means of the density functional theory adopting periodic boundary conditions and including van der Waals dispersion forces. The two most stable structures (which are almost degenerate in energy) correspond to the molecule adsorbed parallel to the metal surface. In both geometries, the vinyl (C=C) and the cyano (C≡N) groups are the anchorage sites to the surface atoms. Low energy transition barriers allow fast isomerization between both structures. Molecular adsorption shifts some of their vibrational frequencies with respect to the gas phase, mainly the C=C and the C≡N stretching modes, in agreement with recent experimental measurements [Tornero et al., Phys. Chem. Chem. Phys., 2011, 13, 8475]. 23163430 Effective targeting of Aβ to macrophages by sonochemically prepared surface-modified protein microspheres. Imbalanced homeostasis and oligomerization of the amyloid-β (Aβ) peptide in the brain are hallmarks of Alzheimer's disease (AD). Microglia and macrophages play a critical role in the etiology of AD either by clearing Aβ from the brain or inducing inflammation. Recent evidence suggests that clearance of Aβ by microglia/macrophages via the phagocytic pathway is defective in AD, which can contribute to the accumulation of Aβ in the brain. We have recently demonstrated that protein microspheres modified at their surface with multiple copies of an Aβ-recognition motif can strongly bind Aβ, inhibit its aggregation, and directly reduce its toxicity by sequestering it from the medium. Here, we describe how microsphere-bound Aβ can stimulate microglial cells and be phagocytosed through a mechanism that is distinct from that of Aβ removal and, thus, contribute to the clearance of Aβ, even by defective microglial cells. The phagocytosis was most effective, with microspheres having a diameter of <1 μm. The introduction of polyethylene glycol to the surface of the microspheres changed the kinetics of the phagocytosis. Moreover, while aggregated Aβ induced a significant inflammatory response that was manifested by the release of TNF-α, the microsphere-bound Aβ dramatically reduced the amount of cytokine released from microglial cells. 23199984 Effects of chemical interesterification on the physicochemical, microstructural and thermal properties of palm stearin, palm kernel oil and soybean oil blends. Blends of palm stearin (PS), palm kernel oil (PKO) and soybean oil (SBO) at certain proportions were formulated using a mixture design based on simplex-lattice (Design Expert 8.0.4 Stat-Ease Inc., Minneapolis, 2010). All the 10 oil blends were subjected to chemical interesterification (CIE) using sodium methoxide as the catalyst. The solid fat content (SFC), triacylglycerol (TAG) composition, thermal properties (DSC), polymorphism and microstructural properties were studied. Palm-based trans-free table margarine containing ternary mixture of PS/PKO/SBO [49/20/31 (w/w)], was optimally formulated through analysis of multiple isosolid diagrams and was found to have quite similar SMP and SFC profile as compared to the commercial table margarine. This study has shown chemical interesterification are effective in modifying the physicochemical properties of palm stearin, palm kernel oil, soybean oil and their mixtures. 23376408 Developing advanced X-ray scattering methods combined with crystallography and computation. The extensive use of small angle X-ray scattering (SAXS) over the last few years is rapidly providing new insights into protein interactions, complex formation and conformational states in solution. This SAXS methodology allows for detailed biophysical quantification of samples of interest. Initial analyses provide a judgment of sample quality, revealing the potential presence of aggregation, the overall extent of folding or disorder, the radius of gyration, maximum particle dimensions and oligomerization state. Structural characterizations include ab initio approaches from SAXS data alone, and when combined with previously determined crystal/NMR, atomistic modeling can further enhance structural solutions and assess validity. This combination can provide definitions of architectures, spatial organizations of protein domains within a complex, including those not determined by crystallography or NMR, as well as defining key conformational states of a protein interaction. SAXS is not generally constrained by macromolecule size, and the rapid collection of data in a 96-well plate format provides methods to screen sample conditions. This includes screening for co-factors, substrates, differing protein or nucleotide partners or small molecule inhibitors, to more fully characterize the variations within assembly states and key conformational changes. Such analyses may be useful for screening constructs and conditions to determine those most likely to promote crystal growth of a complex under study. Moreover, these high throughput structural determinations can be leveraged to define how polymorphisms affect assembly formations and activities. This is in addition to potentially providing architectural characterizations of complexes and interactions for systems biology-based research, and distinctions in assemblies and interactions in comparative genomics. Thus, SAXS combined with crystallography/NMR and computation provides a unique set of tools that should be considered as being part of one's repertoire of biophysical analyses, when conducting characterizations of protein and other macromolecular interactions. 23376412 A review on indole alkaloids isolated from Uncaria rhynchophylla and their pharmacological studies. Uncaria rhynchophylla (Miq.) Jacks, Rubiaceae, is one of the original plants of the important Chinese crude drug, Gou-teng, mainly used for the treatment of convulsion, hypertension, epilepsy, eclampsia, and cerebral diseases. The pharmacological activities of this plant are related to the presence of active compounds predominantly indole alkaloids. In this article, we have reviewed some reports about the pharmacological activities of the main indole alkaloids isolated from U. rhynchophylla. This review paper will contribute to the studies on the chemistry, safety and quality control of medicinal preparations containing Uncaria species. 23146766 Physiologically based toxicokinetics of serum aflatoxin B1-lysine adduct in F344 rats. Aflatoxin B(1)-lysine adduct (AFB-Lys) is a reliable biomarker for aflatoxin exposure; however, a systematic toxicokinetic evaluation has not been reported. In this study, male F344 rats were orally exposed to single, or repeated, doses of AFB(1) and the toxicokinetics of serum AFB-Lys that followed treatments were investigated. A single-dose of AFB(1) increased serum AFB-Lys levels rapidly peaking at 4h, followed by first-order elimination, through which the half-life was estimated to be 2.31 days. A physiologically based pharmacokinetic model showed that approximately 3.00-3.90% and 1.12-1.98% of the administered AFB(1) doses were converted to serum AFB-Lys adducts at 2h and 24h post treatment, respectively. Repeated AFB(1) exposure at 5-25 μg/kg body weight linearly increased serum AFB-Lys levels for 5 weeks in animals, resulting in a 1-1.5 times higher AFB-Lys level overall. This indicates the potential of this adduct as a reliable biomarker for repeated low dose exposure. Higher dose exposure at 75 μg/kg increased the level of AFB-Lys to a maximum at 2 weeks, followed by a gradual decrease to near plateau level up to 5 weeks. In conclusion, this study systematically evaluated the toxicokinetics of serum AFB-Lys adduct in F344 rats using a physiologically based pharmacokinetic model and robust statistical modeling analysis and provided a firm and clear understanding of the toxicokinetics of this biomarker. 23561213 Diversity of (dihydro) hydroxycinnamic acid conjugates in Colombian potato tubers. In potato tuber, caffeic acid (the predominant hydroxycinnamic acid (HCA)), its conjugates (HCAcs; i.e. chlorogenic acid (ChA), crypto-ChA, and neo-ChA), and anthocyanin-linked HCAs have been extensively described in the literature. In contrast, only little information is available on the occurrence of other HCAcs and didydrohydroxycinnamic acid conjugates (DHCAcs). Fifteen Colombian potato cultivars were screened for these less commonly described conjugates by reversed-phase ultrahigh performance liquid chromatography coupled to a diode array detector and a heated electrospray ionisation mass spectrometer. A total of 62 HCAs/HCAcs/DHCAcs were found in extracts from peel and flesh. Among them, only twelve compounds were common to all cultivars in both peel and flesh. The less commonly described compounds accounted for 7.1-20.1% w/w of the total amount of HCAs/HCAcs/DHCAcs in whole tubers, highlighting their contribution to the total phenolic profile of potato tubers. Among all cultivars, the abundance (mg/100g DW whole tuber) of neo-ChA (0.8-7.4) ranged in similar quantities as the less commonly reported feruloyl octopamine (1.2-5.2), 5-O-feruloyl quinic acid (0.1-7.5), cis-ChA (1.1-2.2), caffeoyl putrescine (0.6-2.5), sinapoyl hexose (0.1-1.8), N(1),N(14)-bis-(dihydrocaffeoyl) spermine (0.2-1.7), N(1),N(10)-bis-(dihydrocaffeoyl) spermidine (1.1-2.6), and N(1),N(5),N(14)-tris-(dihydrocaffeoyl) spermine (trace - 11.1). 23396094 Polycationic nanoparticles synthesized using ARGET ATRP for drug delivery. This work provides a systemic comparison for ARGET ATRP and UV-initiated polycationic nanoparticles for drug delivery and a guide to deciding which type of polycationic nanoparticles have the best properties for specific applications. Polycationic nanoparticles were synthesized using a previously developed UV-initiated photoemulsion polymerization or a newly developed ARGET ATRP synthesis technique. The effect of the ratio of hydrophobic monomer in the feed was evaluated. Increasing the feed ratio of hydrophobic monomer was necessary to maintain biocompatibility and pH-responsive membrane disruptive characteristics when switching from the UV-initiated polymerization to ARGET ATRP. The resulting polycationic nanoparticles have utility as drug delivery carriers for hydrophobic drugs and/or nucleic acids. 22385272 Chemical composition and antibacterial activity of the essential oil from Mentha requienii Bentham. The chemical composition of essential oil obtained by hydrodistillation of the fresh aerial parts of Mentha requienii Bentham (Lamiaceae) collected on the Gennargentu Mountains (Sardinia, Italy) has been investigated by gas chromatography and gas chromatography-mass spectrometry. The main constituents that resulted were pulegone (78%), menthone (0.5%), isomenthone (18%), isopulegone (1.3%) and limonene (1.76%). In vitro antifungal activity is evaluated in order to identify new means that could be helpful in the prevention of contamination in indoor environments. 23497908 Wine bottle colour and oxidative spoilage: whole bottle light exposure experiments under controlled and uncontrolled temperature conditions. Exposure of a Chardonnay wine to light from a mercury vapour lamp under controlled temperature conditions showed that colour enhancement was dependent on bottle colour. The increase in colouration was Antique Green42 h, and less within-patient day-to-day variability in glucose-lowering effect than the long-acting insulin analogue insulin glargine. In clinical trials, insulin degludec achieved similar glycaemic control to that seen with insulin glargine in patients with type 1 or 2 diabetes, but with a lower risk of nocturnal hypoglycaemia. In addition, trials examining a flexible dosing regimen of insulin degludec in patients with type 1 or 2 diabetes show the potential for adjusting the injection time, without compromising glycaemic control or safety. A 200 U/mL formulation of insulin degludec is also available for use in patients who require large volumes of basal insulin. Insulin degludec/insulin aspart was noninferior to the long-acting insulin analogue insulin detemir in patients with type 1 diabetes and has the potential to reduce the number of daily injections. Trial results also indicate that insulin degludec/insulin aspart may be an appropriate option for initiating insulin therapy in patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs. Subcutaneous insulin degludec was generally well tolerated in patients with type 1 or 2 diabetes. In conclusion, insulin degludec and insulin degludec/insulin aspart represent a useful advance in the treatment of type 1 or 2 diabetes. 23425601 Biotransformation of ursolic acid by Syncephalastrum racemosum CGMCC 3.2500 and anti-HCV activity. Microbial transformation of ursolic acid (UA, 3β-hydroxy-urs-12-en-28-oic acid, 1) by filamentous fungus Syncephalastrum racemosum CGMCC 3.2500 was conducted. Five metabolites 3β, 7β, 21β-trihydroxy-urs-12-en-28-oic acid (2); 3β, 21β-dihydroxy-urs-11-en-28-oic acid-13-lactone (3); 1β, 3β, 21β-trihydroxy-urs-12-en-28-oic acid (4); 3β, 7β, 21β-trihydroxy-urs-1-en-28-oic acid-13-lactone (5); and 21-oxo-1β, 3β-dihydroxy-urs-12-en-28-oic acid (6) were afforded. Elucidation of the structures of these metabolites was primarily based on 1D and 2D NMR and HR-MS data. Metabolite 2 was a new compound. In addition, the anti-HCV activity of compounds 1-6 was evaluated. 23402847 Nano bioresearch approach by microtechnology. To progress in basic science and drug development, convenient methodology for detecting specific biological molecules and their interaction in living organism is in high demand. After more than 20 years of increasing research efforts, micro and nanotechnologies are now mature to propose a new class of miniature devices and principles enabling compartmentalized bioassays. Among them, this review proposes various examples that include array of electro-active microwells for highly parallel single cell analysis, cost-effective nanofluidic for DNA separation, parallel enzymatic reaction in 100pL droplet and high-throughput platform for membrane proteins assays. The micro devices are presented with relevant experiments to foresee their future contribution to translational research and drug discovery. 23343193 The dynamic nature of the kinome. Recent advances in proteomics have facilitated the analysis of the kinome 'en masse'. What these studies have revealed is a surprisingly dynamic network of kinase responses to highly selective kinase inhibitors, thereby illustrating the complex biological responses to these small molecules. Moreover these studies have identified key transcription factors, such as c-Myc and FOXO (forkhead box O), that play pivotal roles in kinome reprogramming in cancer cells. Since many kinase inhibitors fail despite a high efficacy of blocking their intended targets, elucidating kinome changes at a more global level will be essential to understanding the mechanisms of kinase inhibitor pharmacology. The development of technologies to study the kinome, as well as examples of kinome resilience and reprogramming, will be discussed in the present review. 23214979 3-Amido pyrrolopyrazine JAK kinase inhibitors: development of a JAK3 vs JAK1 selective inhibitor and evaluation in cellular and in vivo models. The Janus kinases (JAKs) are involved in multiple signaling networks relevant to inflammatory diseases, and inhibition of one or more members of this class may modulate disease activity or progression. We optimized a new inhibitor scaffold, 3-amido-5-cyclopropylpyrrolopyrazines, to a potent example with reasonable kinome selectivity, including selectivity for JAK3 versus JAK1, and good biopharmaceutical properties. Evaluation of this analogue in cellular and in vivo models confirmed functional selectivity for modulation of a JAK3/JAK1-dependent IL-2 stimulated pathway over a JAK1/JAK2/Tyk2-dependent IL-6 stimulated pathway. 23459147 Ninety-day dietary toxicity study of apple polyphenol extracts in Crl: CD (SD) rats. To examine the safety of Dietary Applephenon® (AP) in feed, Crl: CD (SD) rats of each sex were divided into four groups and given diets containing AP at 0%, 1.25%, 2.5%, or 5.0% for 90days. All rats survived and toxic changes were not observed throughout the study. Body weight and food efficiency in the 5.0% AP group of both sexes were significantly decreased compared with that in controls. These changes were considered to be caused by the physiological effects of AP (including the inhibitory effects on pancreatic lipase activity). Slight hypertrophy in acinar cells in the parotid and submandibular glands appeared in the 2.5% and 5.0% groups. These were suggested not to be toxicological but physiologic adaptive responses to oral stimuli by the lower pH of AP-containing diets. In conclusion, dietary AP in feed, up to a maximum level of 5.0% for 90days, given to rats did not induce toxicological effects. 23146694 Bisphenol A inhibits proliferation and induces apoptosis in micromass cultures of rat embryonic midbrain cells through the JNK, CREB and p53 signaling pathways. Bisphenol A (BPA) has been widely used in the manufacture of polycarbonate plastic, water bottles and food containers. Previous studies have established that BPA could cause developmental toxicity by inhibiting the proliferation and differentiation of rat embryonic midbrain (MB) cells in vitro. However, the underlying mechanisms have not been well studied yet. In the current study, we examined the proliferation and differentiation of MB cells treated with 10(-12)-10(-4)M BPA and found that only 10(-4)M BPA inhibited proliferation and differentiation. Then, we investigated the cell cycle progression and apoptosis of MB cells; 10(-4)M BPA caused an explicit S phase and G2/M phase arrest in the cell cycle and increased the percentage of apoptotic cells. Moreover, the phosphorylation of mitogen-activated protein kinase (MAPK) and cyclic-AMP response binding protein (CREB) and the expression of some apoptotic regulatory genes were investigated. BPA (10(-4)M) reduced the phosphorylation of C-Jun N-terminal kinase (JNK) and CREB, and increased the mRNA expression level of Bax and p53. Our findings demonstrated that BPA could cause developmental toxicity through anti-proliferation and pro-apoptosis in MB cells. Multiple signaling pathways, such as the JNK, CREB and p53-mitochondrial apoptosis pathways, participate in these effects. 23561188 Antibacterial activity-guided purification and identification of a novel C-20 oxygenated ent-kaurane from Rabdosia serra (MAXIM.) HARA. The objective of this work was to conduct an activity-guided isolation of antibacterial compounds from Rabdosia serra. The ethanol extracts of R. serra leaf and stem were partitioned sequentially into petroleum ether, ethyl acetate, butanol and water fractions, respectively. The ethanol extract of leaf evidenced broad-spectrum antibacterial activity against Gram-positive bacterial, including Bacillus subtilis, Bacillus cereus, Staphylococcus aureus, and Listeria monocytogenes. The ethyl acetate fractions of leaf and stem exhibited strong inhibition against Gram-positive bacteria, and were then purified further. On the basis of antibacterial assay-guided purification, three phenolic compounds (rosmarinic acid, methyl rosmarinate and pedalitin) and four C-20 oxygenated ent-kauranes (effusanin E, lasiodin, rabdosichuanin D and a new compound namely effusanin F) were obtained, whose contents were determined by HPLC analysis. The broth microdilution method confirmed the important inhibition potential of C-20 oxygenated ent-kauranes with low minimum inhibitory concentration (MIC) values. Effusanin E, lasiodin and effusanin F could be useful for the development of new antibacterial agents. 22972179 Energy depletion of bovine mammary epithelial cells activates AMPK and suppresses protein synthesis through inhibition of mTORC1 signaling. The molecular mechanisms by which cellular energy status regulates global protein synthesis in mammary epithelial cells have not been characterized. The objective of this study was to examine the effect of AMP-activated protein kinase (AMPK) activation by 2-deoxyglucose on protein synthesis and the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway in bovine mammary epithelial cells. Phosphorylation of AMPK at Thr172 increased by 1.4-fold within 5 min, and remained elevated throughout a 30-min time course, in response to 2-deoxyglucose. Global rates of protein synthesis declined by 78% of control values. The decline in protein synthesis was associated with repression of mTORC1 signaling, as indicated by reduced phosphorylation of ribosomal protein S6 kinase 1 and eIF4E binding protein-1 (4E-BP1). Phosphorylation of ER-stress marker eIF2α was also increased but only at 30 min of 2-deoxyglucose exposure. 2-Deoxyglucose increased phosphorylation of tuberous sclerosis complex 2 (TSC2) on AMPK consensus sites but did not change the amount of TSC1 bound to TSC2. Activation of AMPK did not result in changes in the amount of raptor bound to mTOR. The inhibitory effects of AMPK activation on mTORC1 signaling were associated with a marked increase in Ser792 phosphorylation on raptor. Collectively, the results suggest that activation of AMPK represses global protein synthesis in mammary epithelial cells through inhibition of mTORC1 signaling. 23111887 Two cases of acute dexmedetomidine withdrawal syndrome following prolonged infusion in the intensive care unit: Report of cases and review of the literature. Prolonged infusion of dexmedetomidine, an α(2)-adrenoreceptor agonist anesthetic used in the intensive care unit, produces a withdrawal syndrome of sympathetic over-activity, characterized by tachycardia, hypertension and agitation, but there is no recommended standard treatment for this syndrome. We describe two patients with a clinical diagnosis of acute dexmedetomidine withdrawal and its management with oral clonidine. We utilized the principle of managing acute drug withdrawal with longer acting medications. These two cases demonstrated the benefit of using oral, longer acting clonidine to manage acute withdrawal from shorter-acting, intravenous dexmedetomidine. 22820275 Atomoxetine modulates spontaneous and sensory-evoked discharge of locus coeruleus noradrenergic neurons. Atomoxetine (ATM) is a potent norepinephrine (NE) uptake inhibitor and increases both NE and dopamine synaptic levels in prefrontal cortex, where it is thought to exert its beneficial effects on attention and impulsivity. At the behavioral level, ATM has been shown to cause improvements on the measures of executive functions, such as response inhibition, working memory and attentional set shifting across different species. However, the exact mechanism of action for ATM's effects on cognition is still not clear. One possible target for the cognitive enhancing effects of ATM is the noradrenergic locus coeruleus (LC), the only source of NE to key forebrain areas such as cerebral cortex and hippocampus. Although it is known that ATM increases NE availability overall by blocking reuptake of NE, the effects of this agent on impulse activity of LC neurons have not been reported. Here, the effect of ATM (0.1-1 mg/kg, ip) on NE-LC neurons was investigated by recording extracellular activity of LC neurons in isoflurane-anesthetized rats. ATM caused a significant decrease of the tonic activity of LC single-units, although leaving intact the sensory-evoked excitatory component of LC phasic response. Moreover, the magnitude of the inhibitory component of LC response to paw stimulation was increased after 1 mg/kg of ATM and its duration was prolonged at 0.3 mg/kg. Together, these effects of ATM produced an increase in the phasic-to-tonic ratio of LC phasic response to sensory stimulation. ATM also modulated the average sensory-evoked local field potential (LFP) and spike-field coherence in LC depending on the dose tested. The lower dose (0.1 mg/kg) significantly decreased early positive and negative components of the sensory-evoked LFP response. Higher doses (0.3-1 mg/kg) initially increased and then decreased the amplitude of components of the evoked fields, whereas the spike-field coherence was enhanced by 1 mg/kg ATM across frequency bands. Finally, coherence between LC fields and EEG signals was generally increased by 1 mg/kg ATM, whereas 0.1 and 0.3 mg/kg respectively decreased and increased coherence values in specific frequency bands. Taken together these results suggest that ATM effects on LC neuronal activity are dose-dependent, with different doses affecting different aspects of LC firing. This modulation of activity of LC-NE neurons may play a role in the cognitive effects of ATM. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23328126 Omega-3 Fatty acids reduce adipose tissue macrophages in human subjects with insulin resistance. Fish oils (FOs) have anti-inflammatory effects and lower serum triglycerides. This study examined adipose and muscle inflammatory markers after treatment of humans with FOs and measured the effects of ω-3 fatty acids on adipocytes and macrophages in vitro. Insulin-resistant, nondiabetic subjects were treated with Omega-3-Acid Ethyl Esters (4 g/day) or placebo for 12 weeks. Plasma macrophage chemoattractant protein 1 (MCP-1) levels were reduced by FO, but the levels of other cytokines were unchanged. The adipose (but not muscle) of FO-treated subjects demonstrated a decrease in macrophages, a decrease in MCP-1, and an increase in capillaries, and subjects with the most macrophages demonstrated the greatest response to treatment. Adipose and muscle ω-3 fatty acid content increased after treatment; however, there was no change in insulin sensitivity or adiponectin. In vitro, M1-polarized macrophages expressed high levels of MCP-1. The addition of ω-3 fatty acids reduced MCP-1 expression with no effect on TNF-α. In addition, ω-3 fatty acids suppressed the upregulation of adipocyte MCP-1 that occurred when adipocytes were cocultured with macrophages. Thus, FO reduced adipose macrophages, increased capillaries, and reduced MCP-1 expression in insulin-resistant humans and in macrophages and adipocytes in vitro; however, there was no measureable effect on insulin sensitivity. 23473802 The insecticidal neurotoxin Aps III is an atypical knottin peptide that potently blocks insect voltage-gated sodium channels. One of the most potent insecticidal venom peptides described to date is Aps III from the venom of the trapdoor spider Apomastus schlingeri. Aps III is highly neurotoxic to lepidopteran crop pests, making it a promising candidate for bioinsecticide development. However, its disulfide-connectivity, three-dimensional structure, and mode of action have not been determined. Here we show that recombinant Aps III (rAps III) is an atypical knottin peptide; three of the disulfide bridges form a classical inhibitor cystine knot motif while the fourth disulfide acts as a molecular staple that restricts the flexibility of an unusually large β hairpin loop that often houses the pharmacophore in this class of toxins. We demonstrate that the irreversible paralysis induced in insects by rAps III results from a potent block of insect voltage-gated sodium channels. Channel block by rAps III is voltage-independent insofar as it occurs without significant alteration in the voltage-dependence of channel activation or steady-state inactivation. Thus, rAps III appears to be a pore blocker that plugs the outer vestibule of insect voltage-gated sodium channels. This mechanism of action contrasts strikingly with virtually all other sodium channel modulators isolated from spider venoms that act as gating modifiers by interacting with one or more of the four voltage-sensing domains of the channel. 23411184 Multi-class method for determination of veterinary drug residues and other contaminants in infant formula by ultra performance liquid chromatography-tandem mass spectrometry. A rapid, simple and generic analytical method which was able to simultaneously determine 220 undesirable chemical residues in infant formula had been developed. The method comprised of extraction with acetonitrile, clean-up by low temperature and water precipitation, and analysis by ultra performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC-ESI-MS-MS) using multiple reaction monitoring (MRM) mode. Most fat materials in acetonitrile extract were eliminated by low temperature clean-up. The water precipitation, providing a necessary and supplementary cleanup, could avoid losses of hydrophobic analytes (avermectins, ionophores). Average recoveries for spiked infant formula were in the range from 57% to 147% with associated RSD values between 1% and 28%. For over 80% of the analytes, the recoveries were between 70% and 120% with RSD values in the range of 1-15%. The limits of quantification (LOQs) were from 0.01 to 5 μg/kg, which were usually sufficient to verify the compliance of products with legal tolerances. Application of this method in routine monitoring programs would imply a drastic reduction of both effort and time. 23402855 Anti-inflammatory activity of edible brown alga Saccharina japonica and its constituents pheophorbide a and pheophytin a in LPS-stimulated RAW 264.7 macrophage cells. Anti-inflammatory activity of Saccharina japonica and its active components was evaluated via in vitro inhibitory activities against lipopolysaccharide (LPS)-induced nitric oxide (NO) production, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) expression in RAW 264.7 murine macrophage cells. Since the methanolic extract of S. japonica showed strong anti-inflammatory activity, it was fractionated with several solvents. Among the fractions, the ethyl acetate fraction demonstrated the highest inhibition of LPS-induced NO production (IC50=25.32μg/mL), followed by the CH2Cl2 fraction (IC50=75.86μg/mL). Considering the yield and anti-inflammatory potential together, the CH2Cl2 fraction was selected for chromatographic separation to yield two active porphyrin derivatives, pheophorbide a and pheophytin a, together with an inactive fucoxanthin. In contrast to fucoxanthin, pheophorbide a and pheophytin a showed dose-dependent inhibition against LPS-induced NO production at nontoxic concentrations in RAW 264.7 cells. Both compounds also suppressed the expression of iNOS proteins, while they did not inhibit the COX-2 expression in LPS-stimulated macrophages. These results indicate that pheophorbide a and pheophytin a are two important candidates of S. japonica as anti-inflammatory agents which can inhibit the production of NO via inhibition of iNOS protein expression. Thus, these compounds hold great promise for use in the treatment of various inflammatory diseases. 23164615 Differential modulation of retinal ganglion cell light responses by orthosteric and allosteric metabotropic glutamate receptor 8 compounds. To investigate the role of mGluR8 in modulating the synaptic responses of retinal ganglion cells, we used a recently identified positive allosteric modulator of mGluR8, AZ12216052 (AZ) and the mGluR8-specific orthosteric agonist (S)-3,4-dicarboxyphenylglycine (DCPG). These agents were applied to whole-cell voltage-clamped ganglion cells from an isolated, superfused mouse retina preparation. DCPG reduced OFF-ganglion cell excitatory currents, whereas AZ enhanced the peak excitatory currents in ON-, OFF-, and ON-OFF-ganglion cells. The effects on ganglion cell inhibitory currents were more varied. The effects of the allosteric modulator were stronger for bright stimuli than for dim stimuli, consistent with receptor stimulation by endogenous glutamate being stronger during bright light stimulation and with mGluR8 receptors mainly being localized away from glutamate release sites, immuno-labeled with VGLUT1. The differential sensitivity of ganglion cell light responses to DCPG and AZ supports multiple sites where mGluR8 modulates the light responses of ganglion cells. 23603193 Anti-epileptogenic and antioxidant effect of Lavandula officinalis aerial part extract against pentylenetetrazol-induced kindling in male mice. ETHNOPHARMACOLOGICAL RELEVANCE: Repeated application of Lavandula officinalis (L. officinalis) has been recommended for a long time in Iranian traditional medicine for some of nervous disorders like epilepsy and dementia. However, there is no available report for the effect of chronic administration of Lavandula extract in development (acquisition) of epilepsy. Therefore, this study was designed to investigate the anti-epileptogenic and antioxidant activity of repeated administration of Lavandula officinalis extract on pentylenetetrazol (PTZ) kindling seizures in mice model. MATERIALS AND METHODS: Lavandula officinalis was tested for its ability (i) to suppress the seizure intensity and lethal effects of PTZ in kindled mice (anti-epileptogenic effect), (ii) to attenuate the PTZ-induced oxidative injury in the brain tissue (antioxidant effect) when given as a pretreatment prior to each PTZ injection during kindling development. Valproate (Val), a major antiepileptic drug, was also tested for comparison. RESULTS: Val and Lavandula officinalis extract showed anti-epileptogenic properties as they reduced seizure score of kindled mice and PTZ-induced mortality. In this regard, Lavandula officinalis was more effective than Val. Both Lavandula officinalis and Val suppressed brain nitric oxide (NO) level of kindled mice in comparison with the control and PTZ group. Meanwhile, Lavandula officinalis suppressed NO level more than Val and Lavandula officinalis also decreased brain MDA level relative to PTZ group. CONCLUSION: This is the first report to demonstrate NO suppressing and anti-epileptogenic effect of chronic administration of Lavandula officinalis extract on acquisition of epilepsy in PTZ kindling mice model. In this regard, Lavandula officinalis extract was more effective than Val, possibly and in part via brain NO suppression. 23090968 A-kinase-anchoring protein-Lbc anchors IκB kinase β to support interleukin-6-mediated cardiomyocyte hypertrophy. In response to stress, the heart undergoes a pathological remodeling process associated with hypertrophy and the reexpression of a fetal gene program that ultimately causes cardiac dysfunction and heart failure. In this study, we show that A-kinase-anchoring protein (AKAP)-Lbc and the inhibitor of NF-κB kinase subunit β (IKKβ) form a transduction complex in cardiomyocytes that controls the production of proinflammatory cytokines mediating cardiomyocyte hypertrophy. In particular, we can show that activation of IKKβ within the AKAP-Lbc complex promotes NF-κB-dependent production of interleukin-6 (IL-6), which in turn enhances fetal gene expression and cardiomyocyte growth. These findings provide a new mechanistic hypothesis explaining how hypertrophic signals are coordinated and conveyed to interleukin-mediated transcriptional reprogramming events in cardiomyocytes. 23360548 Toward large-scale energy harvesting by a nanoparticle-enhanced triboelectric nanogenerator. This article describes a simple, cost-effective, and scalable approach to fabricate a triboelectric nanogenerator (NG) with ultrahigh electric output. Triggered by commonly available ambient mechanical energy such as human footfalls, a NG with size smaller than a human palm can generate maximum short-circuit current of 2 mA, delivering instantaneous power output of 1.2 W to external load. The power output corresponds to an area power density of 313 W/m(2) and a volume power density of 54,268 W/m(3) at an open-circuit voltage of ~1200 V. An energy conversion efficiency of 14.9% has been achieved. The power was capable of instantaneously lighting up as many as 600 multicolor commercial LED bulbs. The record high power output for the NG is attributed to optimized structure, proper materials selection and nanoscale surface modification. This work demonstrated the practicability of using NG to harvest large-scale mechanical energy, such as footsteps, rolling wheels, wind power, and ocean waves. 23517565 N-Methyldihydroquinazolinone Derivatives of Retro-2 with Enhanced Efficacy against Shiga Toxin. The Retro-2 molecule protects cells against Shiga toxins by specifically blocking retrograde transport from early endosomes to the trans-Golgi network. A SAR study has been carried out to identify more potent compounds. Cyclization and modifications of Retro-2 led to a compound with roughly 100-fold improvement of the EC50 against Shiga toxin cytotoxicity measured in a cell protein synthesis assay. We also demonstrated that only one enantiomer of the dihydroquinazolinone reported herein is bioactive. 23496305 Obstructed Diffusion in Silica Colloidal Crystals. The hindered diffusion in silica colloidal crystals was studied experimentally, both by fluorescence recovery after photobleaching and by measurement of ionic conductivity. Particle size was varied to include 120, 220, 470, and 1300 nm, and the porosities were determined by flow measurements. For fluorescein, the results showed that the obstruction factor, which is the ratio of the diffusion coefficients inside the media and in open solution, is equal to the porosity within experimental error. For proteins, the same conclusion is made after correction for size exclusion of the pores. The obstruction factors for these media are 2-fold lower than those measured for chromatographic media, 60% higher than theoretical predictions, and equal to what is assumed for electrophoretic sieving in random fibers. 23170954 Getting in shape: controlling peptide bioactivity and bioavailability using conformational constraints. Chemical biologists commonly seek out correlations between the physicochemical properties of molecules and their behavior in biological systems. However, a new paradigm is emerging for peptides in which conformation is recognized as the primary determinant of bioactivity and bioavailability. This review highlights an emerging body of work that directly addresses how a peptide's conformation controls its biological effects, cell penetration, and intestinal absorption. Based on this work, the dream of mimicking the potency and bioavailability of natural product peptides is getting closer to reality. 23122066 Lipid components prepared from a freshwater Clam (Corbicula fluminea) extract ameliorate hypercholesterolaemia in rats fed high-cholesterol diet. To explore the hypocholesterolaemic components in the fat fraction of freshwater clam extract (FCE), we further fractionated the fat fraction by silica gel column chromatography into nine fat subfractions. In the present study, we used exogenous hypercholesterolaemic rats induced by feeding a high-cholesterol diet; the doses of the added fat subfractions were equivalent to those in 30% FCE. Two (FF1, FF2) out of the nine fat subfractions strongly reduced serum cholesterol levels in the rats fed a high-cholesterol diet. Both FF1 and FF2 up-regulated the hepatic gene expression of cholesterol 7α-hydroxylase, a rate-limiting enzyme of bile acid biosynthesis. Thin-layer chromatography showed that FF1 primarily contained sphingolipids, while FF2 mainly contained triacylglycerols and sterol esters. These results indicate that fractions containing sphingolipids, triacylglycerols, and sterol esters are possibly responsible for the hypocholesterolaemic action in a novel manner through the up-regulation of the hepatic biosynthesis of bile acids. 23397049 A prospective open-label trial of paliperidone monotherapy for the treatment of bipolar spectrum disorders in children and adolescents. RATIONALE: Treatment studies for the management of pediatric bipolar disorder are limited. OBJECTIVES: This study evaluates the safety and efficacy of paliperidone monotherapy as an acute treatment of mania and related symptoms in youth with bipolar spectrum disorders. METHODS: An 8-week, prospective, open-label paliperidone monotherapy trial to assess effectiveness and tolerability in treating pediatric bipolar spectrum and related disorders (depression, psychosis, attention-deficit/hyperactivity disorder [ADHD]). Assessments included the Young Mania Rating Scale (YMRS), Clinical Global Impression scale (CGI), Children's Depression Rating Scale-Revised (CDRS-R), and Brief Psychiatric Rating Scale (BPRS). Adverse events were assessed through spontaneous self-reports, vital signs, weight monitoring, and laboratory analysis. RESULTS: Fifteen youth with bipolar spectrum disorders (YMRS at entry: 32.8 ± 6.1) were enrolled in the study and 11 (73 %) completed the 8-week trial. The total daily dose of paliperidone at study endpoint was 3 mg in 12 subjects and 6 mg in three subjects. Treatment with paliperidone was associated with statistically significant levels of improvement in mean YMRS scores (-18.7 ± 13.9, p < 0.001) at endpoint. Paliperidone treatment also resulted in significant improvement in the severity of ADHD and psychotic symptoms. Although treatment with paliperidone was generally well tolerated and was not associated with clinically significant change in cardiovascular or metabolic parameters, increases in body weight (4.1 ± 5.5 lb) were substantial. CONCLUSIONS: Open-label paliperidone treatment appears to be beneficial in the treatment of bipolar spectrum disorders and associated conditions in youth. Future placebo-controlled studies are warranted to confirm these findings. 23499945 Complex genomic interactions in the dynamic regulation of transcription by the glucocorticoid receptor. The glucocorticoid receptor regulates transcriptional output through complex interactions with the genome. These events require continuous remodeling of chromatin, interactions of the glucocorticoid receptor with chaperones and other accessory factors, and recycling of the receptor by the proteasome. Therefore, the cohort of factors expressed in a particular cell type can determine the physiological outcome upon treatment with glucocorticoid hormones. In addition, circadian and ultradian cycling of hormones can also affect GR response. Here we will discuss revision of the classical static model of GR binding to response elements to incorporate recent findings from single cell and genome-wide analyses of GR regulation. We will highlight how these studies have changed our views on the dynamics of GR recruitment and its modulation of gene expression. 22926048 A bioactive probe of the oxidative pentose phosphate cycle: novel strategy to reverse radioresistance in glucose deprived human colon cancer cells. The specific effects of glucose deprivation on oxidative pentose phosphate cycle (OPPC) function, thiol homeostasis, protein function and cell survival remain unclear due to lack of a glucose-sensitive chemical probe. Using p53 wild type and mutant human colon cells, we determined the effects of hydroxyethyl disulfide (HEDS) on NADPH, GSH, GSSG, total glutathione, total non-protein and protein thiol levels, the function of the DNA repair protein Ku, and the susceptibility to radiation-induced free radicals under normal glucose or glucose-deprived conditions. HEDS is rapidly detoxified in normal glucose but triggered a p53-independent metabolic stress in glucose depleted state that caused loss of NADPH, protein and non-protein thiol homeostasis and Ku function, and enhanced sensitivity of both p53 wild type and mutant cells to radiation induced oxidative stress. Additionally, high concentration of HEDS alone induced cell death in p53 wild type cells without significant effect on p53 mutant cells. HEDS offers a useful tool to gain insights into how glucose metabolism affects OPPC dependent stress-induced cellular functions and injury, including in tumor cells, where our findings imply a novel therapeutic approach to target glucose deprived tumor. Our work introduces a novel probe to address cancer metabolism and ischemic pathology. 23614643 Dimerized Glycosaminoglycan Chains Increase FGF Signaling during Zebrafish Development. Proteoglycans (PGs) modulate numerous signaling pathways during development through binding of their glycosaminoglycan (GAG) side chains to various signaling molecules, including fibroblast growth factors (FGFs). A majority of PGs possess two or more GAG side chains, suggesting that GAG multivalency is imperative for biological functions in vivo. However, only a few studies have examined the biological significance of GAG multivalency. In this report, we utilized a library of bis- and tris-xylosides that produce two and three GAG chains on the same scaffold, respectively, thus mimicking PGs, to examine the importance of GAG valency and chain type in regulating FGF/FGFR interactions in vivo in zebrafish. A number of bis- and tris-xylosides, but not mono-xylosides, caused an elongation phenotype upon their injection into embryos. In situ hybridization showed that elongated embryos have elevated expression of the FGF target gene mkp3 but unchanged expression of reporters for other pathways, indicating that FGF/FGFR signaling was specifically hyperactivated. In support of this observation, elongation can be reversed by the tyrosine kinase inhibitor SU5402, mRNA for the FGFR antagonist sprouty4, or FGF8 morpholino. Endogenous GAGs seem to be unaffected after xyloside treatment, suggesting that this is a gain-of-function phenotype. Furthermore, expression of a multivalent but not a monovalent GAG containing syndecan-1 proteoglycan recapitulates the elongation phenotype observed with the bivalent xylosides. On the basis of these in vivo findings, we propose a new model for GAG/FGF/FGFR interactions in which dimerized GAG chains can activate FGF-mediated signal transduction pathways. 23194512 Podocarpane, isopimarane, and abietane diterpenoids from Isodon lophanthoides var. graciliflorus. Four new diterpenoids including two podocarpanes, graciliflorins A (1) and B (2), an isopimarane acetal, graciliflorin C (3), and a rearranged abietane, graciliflorin D (4) were isolated from the aerial parts of Isodon lophanthoides var. graciliflorus (Lamiaceae) along with podocarpa-8,11,13-triene-3α,13-diol (5) and micranthin B (6). Their structures were elucidated based on the spectroscopic data. The in vitro cytotoxicity of compounds 1-4 and 6 against human carcinoma A549, MCF-7, and HeLa cell lines were evaluated using the MTT colourimetric assay. Micranthin B (6) showed moderate activity against all the cells with IC(50) values of 16.29, 18.20, and 22.25 μM, while compounds 1-4 were inactive (IC(50)>50 μg/ml). 23183532 Intestinal luminal nitrogen metabolism: role of the gut microbiota and consequences for the host. Alimentary and endogenous proteins are mixed in the small intestinal lumen with the microbiota. Although experimental evidences suggest that the intestinal microbiota is able to incorporate and degrade some of the available amino acids, it appears that the microbiota is also able to synthesize amino acids raising the view that amino acid exchange between the microbiota and host can proceed in both directions. Although the net result of such exchanges remains to be determined, it is likely that a significant part of the amino acids recovered from the alimentary proteins are used by the microbiota. In the large intestine, where the density of bacteria is much higher than in the small intestine and the transit time much longer, the residual undigested luminal proteins and peptides can be degraded in amino acids by the microbiota. These amino acids cannot be absorbed to a significant extent by the colonic epithelium, but are precursors for the synthesis of numerous metabolic end products in reactions made by the microbiota. Among these products, some like short-chain fatty acids and organic acids are energy substrates for the colonic mucosa and several peripheral tissues while others like sulfide and ammonia can affect the energy metabolism of colonic epithelial cells. More work is needed to clarify the overall effects of the intestinal microbiota on nitrogenous compound metabolism and consequences on gut and more generally host health. 23479194 Antibacterial substances from Albizia myriophylla wood against cariogenic Streptococcus mutans. Albizia myriophylla has been used for long by Thai traditional healers as an important ingredient herb in Thai herbal formulas for caries. In this study, three flavonoids lupinifolin (6), 8-methoxy-7,3',4'-trihydroxyflavone (7), and 7,8,3',4'-tetrahydroxyflavone (8), a triterpenoid lupeol (3) as well as four sterols β-sitosterone (1), stigmasta-5,22-dien-3-one (2), β-sitosterol (4), and stigmasterol (5) were isolated from A. myriophylla wood. The antibacterial activity of these compounds against Streptococcus mutans ATCC 25175 was performed using broth microdilution method. All compounds exhibited antibacterial activity against S. mutans with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) ranging from 1-256 and 2-256 μg/ml, respectively. Among the isolated compounds, lupinifolin (6) was found to be the most potent with MIC and MBC of 1 and 2 μg/ml, respectively. Lupinifolin (6) also showed a strong activity against ten clinical isolates of S. mutans with MIC and MBC ranging from 0.25-2 and 0.5-8 μg/ml, respectively. These results reported the bioactive ingredients of A. myriophylla which support its ethnomedical claims as well. Lupinifolin (6) may have a potential to be a natural anticariogenic agent. 22728231 Transfer of a two-tiered keratinocyte assay: IL-18 production by NCTC2544 to determine the skin sensitizing capacity and epidermal equivalent assay to determine sensitizer potency. At present, the identification of potentially sensitizing chemicals is carried out using animal models. However, it is very important from ethical, safety and economic point of view to have biological markers to discriminate allergy and irritation events, and to be able to classify sensitizers according to their potency, without the use of animals. Within the Sens-it-iv EU Frame Programme 6 funded Integrated Project (LSHB-CT-2005-018681), a number of in vitro, human cell based assays were developed which, when optimized and used in an integrated testing strategy, may be able to distinguish sensitizers from non-sensitizers. This study describes two of these assays, which when used in a tiered strategy, may be able to identify contact sensitizers and also to quantify sensitizer potency. Tier 1 is the human keratinocyte NCTC2544 IL-18 assay and tier 2 is the Epidermal Equivalent potency assay. The aim of this study is to show the transferability of the two-tiered approach with training chemicals: 3 sensitizers (DNCB, resorcinol, pPD) and 1 non sensitizer (lactic acid) in tier 1 and 2 sensitizers with different potency in tier 2 (DNCB; extreme and resorcinol; moderate). The chemicals were tested in a non-coded fashion. Here we describe the transferability to naïve laboratories, the establishment of the standard operating procedure, critical points, acceptance criteria and project management. Both assays were successfully transferred to laboratories that had not performed the assays previously. The two tiered approach may offer an unique opportunity to provide an alternative method to the Local Lymph Node Assay (LLNA). These assays are both based on the use of human keratinocytes, which have been shown over the last two decades, to play a key role in all phases of skin sensitization. 23293950 Luminescence enhancement of pyrene/dispersant nanoarrays driven by the nanoscale spatial effect on mixing. This work presents a simple method to generate ordered chromophore/dispersant nanoarrays through a pore-filling process for a nanoporous polymer template to enhance chromophore luminescence. Fluorescence results combining with the morphological evolution examined by scanning probe microscopy reveal that the enhanced luminescence intensity reaches the maximum intensity as the nanopores of the template are completely filled by the chromophore/dispersant mixture. The variation is attributed to nanoscale spatial effect on the enhanced mixing efficiency of chromophore and dispersant, that is, the alleviation of self-quenching problem, as evidenced by the results of attenuated total reflection Fourier transform IR spectroscopy combining with grazing incident wide-angle X-ray diffraction. The enhanced luminescence of the chromophore/dispersant nanoarrays driven by the nanoscale spatial effect is highly promising for use in designing luminescent nanodevices. 23640471 Free volume in ionic liquids: a connection of experimentally accessible observables from PALS and PVT experiments with the molecular structure from XRD data. In the current work, free volume concepts, primarily applied to glass formers in the literature, were transferred to ionic liquids (ILs). A series of 1-butyl-3-methylimidazolium ([C4MIM](+)) based ILs was investigated by Positron Annihilation Lifetime Spectroscopy (PALS). The phase transition and dynamic properties of the ILs [C4MIM][X] with [X](-) = [Cl](-), [BF4](-), [PF6](-), [OTf](-), [NTf2](-) and [B(hfip)4](-) were reported recently (Yu et al., Phys. Chem. Chem. Phys., 2012, 14, 6856-6868). In this subsequent work, attention was paid to the connection of the free volume from PALS (here the mean hole volume, 〈vh〉) with the molecular structure, represented by volumes derived from X-ray diffraction (XRD) data. These were the scaled molecular volume Vm,scaled and the van der Waals volume Vvdw. Linear correlations of 〈vh〉 at the "knee" temperature (〈vh〉(Tk)) with Vm,scaled and Vvdw gave good results for the [C4MIM](+) series. Further relationships between volumes from XRD data with the occupied volume Vocc determined from PALS/PVT (Pressure Volume Temperature) measurements and from Sanchez-Lacombe Equation of State (SL-EOS) fits were elaborated (Vocc(SL-EOS) ≈ 1.63 Vvdw, R(2) = 0.981 and Vocc(SL-EOS) ≈ 1.12 Vm,scaled, R(2) = 0.980). Finally, the usability of Vm,scaled was justified in terms of the Cohen-Turnbull (CT) free volume theory. Empirical CT type plots of viscosity and electrical conductivity showed a systematic increase in the critical free volume with molecular size. Such correlations allow descriptions of IL properties with the easily accessible quantity Vm,scaled within the context of the free volume. 23479390 Peltogynoids and 2-Phenoxychromones from Peltophorum pterocarpum and Evaluation of Their Estrogenic Activity. Phytochemical investigation of the dichloromethane extract of the leaves of Peltophorum pterocarpum, a tropical ornamental tree, led to the isolation of twelve compounds (1-12). One new derivative of peltogynoid ophioglonin (1) and a new 2-phenoxychromone (2) with its 3'-O-β-D-glucoside derivative (3) are described here for the first time. In addition, nine flavonoid derivatives, including peltogynoid ophioglonin (4), were isolated for the first time from this plant. The structures were determined by spectroscopic and chemical methods. Evaluation of the estrogenic activities of 1, 2, and 4 using different model cell systems revealed that 4 was estrogenic and that 2 was largely inactive. Interestingly, 1 was unable to stimulate the proliferation of breast and endometrial cancer cells but exhibited substantial estrogen receptor α-mediated activation of gene expression. This observation indicates that 1 can be further evaluated for its cancer chemopreventive potential. 23608699 Effects of 17α-ethinylestradiol (EE2) on reproductive endocrine status in mummichog (Fundulus heteroclitus) under differing salinity and temperature conditions. Exposure to 17α-ethinylestradiol (EE2), a synthetic estrogen, has previously been shown to decrease reproductive endocrine status and egg production in northern mummichog (Fundulus heteroclitus macrolepidotus). The objective of this study was to evaluate if variations in salinity or temperature conditions of EE2-exposed mummichog modify the effect on whole organism reproductive endocrine status and gonadal steroidogenesis. Mummichog were exposed in vivo for 14 days to 0, 50 and 250ng/L EE2 in 0, 16 and 32ppt salinity at 18°C and to 0 and 250ng/L EE2 at 10, 18 and 26°C at 16ppt. There was a little overall effect of salinity on measured endpoints. In the salinity exposure, 250ng/L EE2-exposed females had significantly reduced 17β-estradiol (E2) levels. Increased temperature triggered gonadal growth in both sexes and increased plasma E2 and E2 production and decreased 11-KT (11-ketotestosterone) production. EE2 counteracted the effect of temperature by depressing gonadal growth in males. In both exposures, EE2 effects on testosterone (T) production were variable. The use of steroidogenic precursors (25-OH-cholesterol, and/or pregnenolone and/or testosterone) in the in vitro gonadal incubations indicated decreased E2 production in females and 11-KT production in males were predominately due to suppression of the terminal conversion step between T and E2 or 11-KT. Ovarian aromatase A (cyp19a) gene expression at 16ppt and 18°C was not affected by 250ng/L EE2 (the only treatment combinations tested). Overall, temperature is a factor regulating northern mummichog reproduction; EE2 overrides its effects and disrupts the terminal step of steroidogenesis. Our results should be considered in designing future estuarine fish bioassays and in understanding effects of estrogenic endocrine disruptors in estuaries. 23452219 Computational design and biosensor applications of small molecule-sensing allosteric ribozymes. Here I describe accurate and time-efficient computational methods for designing small molecule-sensing allosteric ribozymes that serve as logic gates with NOT or YES Boolean logic functions. Theophylline-sensing ribozymes are engineered to have a high cleavage rate of 1.3 min(-1) under physiologically relevant conditions. They are highly specific to theophylline and do not respond to caffeine, which differs in a single methyl group. These ribozymes are designed by fusing a theophylline aptamer with an extended version of the hammerhead ribozyme by modeling secondary structures. Purine-sensing ribozymes are designed by fusing the minimal version of the hammerhead ribozyme with bacterial guanine or adenine aptamers by modeling 3D interactions. I have developed high-throughput compatible arrays based on purine RNA sensors that can be used for antibacterial drug discovery. The ribozymes can be employed as molecular sensors in various applications, including exogenous control of gene expression, high-throughput screening arrays, and molecular computing. 23305294 Anomalous high ionic conductivity of nanoporous β-Li3PS4. Lithium-ion-conducting solid electrolytes hold promise for enabling high-energy battery chemistries and circumventing safety issues of conventional lithium batteries. Achieving the combination of high ionic conductivity and a broad electrochemical window in solid electrolytes is a grand challenge for the synthesis of battery materials. Herein we show an enhancement of the room-temperature lithium-ion conductivity by 3 orders of magnitude through the creation of nanostructured Li(3)PS(4). This material has a wide electrochemical window (5 V) and superior chemical stability against lithium metal. The nanoporous structure of Li(3)PS(4) reconciles two vital effects that enhance the ionic conductivity: (1) the reduction of the dimensions to a nanometer-sized framework stabilizes the high-conduction β phase that occurs at elevated temperatures, and (2) the high surface-to-bulk ratio of nanoporous β-Li(3)PS(4) promotes surface conduction. Manipulating the ionic conductivity of solid electrolytes has far-reaching implications for materials design and synthesis in a broad range of applications, including batteries, fuel cells, sensors, photovoltaic systems, and so forth. 23422263 Investigation of the cumulative body burden of estrogen-3,4-quinone in breast cancer patients and controls using albumin adducts as biomarkers. Both 17β-estradiol-2,3-quinone (E2-2,3-Q) and 17β-estradiol-3,4-quinone (E2-3,4-Q) are reactive metabolites of estrogen. Elevation of E2-3,4-Q to E2-2,3-Q ratio is thought to be an important indicator of estrogen-induced carcinogenesis. Our current study compared the cumulative body burden of these estrogen quinones in serum samples taken from Taiwanese women with breast cancer (n=152) vs healthy controls (n=75) by using albumin (Alb) adducts as biomarkers. Results clearly demonstrated the presence of cysteinyl adducts of E2-2,3-Q-4-S-Alb and E2-3,4-Q-2-S-Alb in all study population at levels ranging from 61.7-1330 to 66.6-1,590 pmol/g, respectively. Correlation coefficient between E2-2,3-Q-4-S-Alb and E2-3,4-Q-2-S-Alb was 0.610 for controls and 0.767 for breast cancer patients (p<0.001). We also noticed that in premenopausal subjects with body mass index (BMI) less than 27, background levels of E2-3,4-Q-2-S-Alb was inversely proportional to BMI with about 25% increase in E2-3,4-Q-2-S-Alb per 5 kg/m(2) decrease in BMI (p<0.001). In addition, we confirmed that mean levels of E2-3,4-Q-2-S-Alb in breast cancer patients were ∼5-fold greater than in those of controls (p<0.001). Overall, this evidence suggests that disparity in estrogen disposition and the subsequent elevation of cumulative body burden of E2-3,4-Q may play a role in the development of breast cancer. 23499664 Levomilnacipran (F2695), a norepinephrine-preferring SNRI: Profile in vitro and in models of depression and anxiety. Levomilnacipran (LVM; F2695) is the more active enantiomer of the serotonin/norepinephrine (5-HT/NE) reuptake inhibitor (SNRI) milnacipran and is currently under development for the treatment of major depressive disorder. LVM was benchmarked against two other SNRIs, duloxetine and venlafaxine, in biochemical, neurochemical and pharmacological assays. LVM exhibited high affinity for human NE (Ki = 92.2 nM) and 5-HT (11.2 nM) transporters, and potently inhibited NE (IC50 = 10.5 nM) and 5-HT (19.0 nM) reuptake (human transporter) in vitro. LVM had 2-fold greater potency for norepinephrine relative to serotonin reuptake inhibition (i.e. NE/5-HT potency ratio: 0.6) and 17 and 27 times higher selectivity for NE reuptake inhibition compared with venlafaxine and duloxetine, respectively. LVM did not exhibit affinity for 23 off-target receptors. LVM (i.p.) increased cortical extracellular levels of 5-HT, and NE (minimal effective doses: MEDs = 20 and 10 mg/kg, respectively). In anti-depressive/anti-stress models, i.p. LVM diminished immobility time in the mouse forced swim (MED = 20 mg/kg) and tail suspension (MED = 2.5 mg/kg) tests, and reduced shock-induced ultrasonic vocalizations in rats (MED = 5 mg/kg). Duloxetine and venlafaxine were less potent (MEDs ≥ 10 mg/kg). At doses active in these three therapeutically-relevant models, LVM (i.p.) did not significantly affect spontaneous locomotor activity. In summary, LVM is a potent, selective inhibitor of NE and 5-HT transporters with preferential activity at the former. It is efficacious in models of anti-depressive/anti-stress activity, with minimal potential for locomotor side effects. 23610086 Reactive Metabolite Trapping Studies on Imidazo- and 2-Methylimidazo[2,1-b]thiazole-based Inverse Agonists of the Ghrelin Receptor. The current study examined the bioactivation potential of ghrelin receptor inverse agonists, 1-(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(imidazo[2,1-b]thiazol-6-yl)ethanone (1) and 1-(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b]thiazol-6-yl)ethanone (2), containing a fused imidazo[2,1-b]thiazole motif in the core structure. Both compounds underwent oxidative metabolism in NADPH- and glutathione-supplemented human liver microsomes to yield glutathione conjugates, which was consistent with their bioactivation to reactive species. Mass spectral fragmentation and NMR analysis indicated that the site of attachment of the glutathionyl moiety in the thiol conjugates was on the thiazole ring within the bicycle. Two glutathione conjugates were discerned with the imidazo[2,1-b]thiazole derivative 1. One adduct was derived from the Michael addition of glutathione to a putative S-oxide metabolite of 1, whereas, the second adduct was formed via the reaction of a second glutathione molecule with the initial glutathione-S-oxide adduct. In the case of the 2-methylimidazo[2,1-b]thiazole analog 2, glutathione conjugation occurred via an oxidative desulfation mechanism, possibly involving thiazole ring epoxidation as the rate-limiting step. Additional insights into the mechanism were obtained via 18O exchange and trapping studies with potassium cyanide. The mechanistic insights into the bioactivation pathways of 1 and 2 allowed the deployment of a rational chemical intervention strategy that involved replacement of the thiazole ring with a 1,2,4-thiadiazole group to yield -(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethanone (3). These structural changes not only abrogated the bioactivation liability but also retained the attractive pharmacological attributes of the prototype agents. 23111883 Toxicity of cadmium and protective effect of bee honey, vitamins C and B complex. The present work aimed to study the toxic effect of cadmium (Cd) on rabbits' blood indices, as well as the therapeutic effect of the antioxidant agents, vitamins C and B complex and bee honey on Cd intoxicated rabbits. Cadmium chloride (CdCl2) was injected subcutaneously at a dose of 3 mg/kg of body weight. The results showed a significant increase in serum glucose, triglycerides, cholesterol, total protein, albumin, globulin, urea and creatinine, compared to the control group. In addition, CdCl2 intoxication increased the levels of uric acid, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and bilirubin. Concerning haematological parameters, the more obvious changes were an increase in mean corpuscular volume and a decrease in white blood cells count, platelets, lymphocytes, heamatocrit, haemoglobin and red blood cells count. Treatment of CdCl2-intoxicated animals with vitamins C and B complex and bee honey showed a decrease in the harmful effects of Cd by restoring haematological and biochemical changes. Bee honey treatment was the most effective in providing recoveries in the altered blood parameters. 23178656 A novel recombinant fibrinogenase of Agkistrodon acutus venom protects against hyperacute rejection via degradation of complements. Hyperacute rejection (HAR) is a main barrier in xenotransplantation, which is mediated by the combination of natural antibody to the xenograft and complement activation. Current therapies have focus on the inhibition of complement by development of complement inhibitor and transgenic animal organ. Here, we investigated the effects of rFII, a recombinant fibrinogenase from Agkistrodon acutus venom, on complement and HAR. The degradation effect of rFII on complement was tested by SDS-PAGE, CH50 examination, ELISA Kit and cofocal immunofluorescence microscopy in vitro and in vivo. An ex-vivo rat-to-human perfusion model and a vivo guinea-pig-to-rat heat HAR model were used to determine the protection of rFII against HAR. Our investigation indicated that rFII could significantly degrade human C5, C6, and C9, decrease the activity of complement, and inhibit the MAC deposition on HUVECs membrane in vitro. In addition, serum levels of C1q, C3 and C4 in rat were gradually reduced after infusion of rFII. Importantly, in an ex vivo rat-to-human perfusion model, the survival of rat hearts perfused with human serum treated with rFII (83.36 ± 16.63 min) were significantly longer than that of hearts perfused with fresh human serum(15.94 ± 4.75 min). At the time of 15 minutes after perfusion, functions of hearts added with 50 ug/ml rFII sustained well with heart rates at 283 ± 65.32 beats/minute and LVDP at 13.70 ± 5.45 Kpa, while that of hearts perfused with fresh human serum were severely damaged by HAR with heart rates at 107.77 ± 40.31 beats/minute and LVDP at 1.01 ± 0.83 Kpa. We also found that rFII significantly decreased the levels of C1q, C3 and C4 in human fresh serum perfusate. In a vivo guinea-pig-to-rat heat HAR model, the survival of rat hearts treated with rFII were significantly longer than that of hearts perfused with normal saline; and relieved heart damage by complete activation. Our finding demonstrates the anti-complement property of rFII and its protection against HAR, indicating that rFII might be as a potential therapeutic agent for xenotransplantation. 23561103 Interlocking of β-carotene in beta-lactoglobulin aggregates produced under high pressure. Vitamin A deficiency is one of the major causes of mortality and morbidity in the developing World. This deficiency can be prevented by alimentary or pharmaceutical supplementation. However, both vitamin A oxidation and isomerization should be prevented, as these phenomenons result in loss of nutritional efficacy. The aim of this study was to investigate the effect of a food protein matrix, β-lactoglobulin (β-Lg) aggregates produced by high pressure (HP), on the stabilization of β-carotene during storage and gastro-duodenal digestion and therefore on its bioavailability. In vitro gastro-duodenal digestion of β-Lg aggregates entrapping β-carotene showed that up to 12% and 33% of total β-carotene was released after peptic and pancreatic digestion, respectively. Overall, our study showed that β-Lg aggregates are efficient for caging and stabilization of β-carotene during storage and digestion. Hence, it may be an interesting approach for the protection and the delivery of vitamin A. 23085266 Zymosan induces NADPH oxidase activation in human neutrophils by inducing the phosphorylation of p47phox and the activation of Rac2: involvement of protein tyrosine kinases, PI3Kinase, PKC, ERK1/2 and p38MAPkinase. Reactive oxygen species (ROS) production by the neutrophil NADPH oxidase plays a key role in host defense against pathogens, such as bacteria and fungi. Zymosan a cell-wall preparation from Saccharomyces cerevisiae is largely used to activate neutrophils in its opsonized form. In this study, we show that non-opsonized zymosan alone induced ROS production by human neutrophils. Zymosan-induced ROS production is higher than the formyl-methionyl-leucyl-phenylalanine (fMLF)- or the phorbol myristate acetate (PMA)-induced ROS production but is lower than the one induced by opsonized zymosan. Most of the zymosan-induced ROS production is intracellular. Interestingly, zymosan induced the phosphorylation of the NADPH oxidase cytosolic component p47phox on several sites which are Ser315, Ser328 and Ser345. Zymosan induced also the activation of the small G-protein Rac2. Phosphorylation of the p47phox as well as Rac2 activation were inhibited by genistein a broad range protein tyrosine kinase inhibitor and by wortmannin a PI3Kinase inhibitor. GF109203X a PKC inhibitor inhibited phosphorylation of p47phox on Ser315 and Ser328. SB203580 and UO126, inhibitors of p38MAPK and ERK1/2-pathway, respectively, inhibited phosphorylation of p47phox on Ser345. Zymosan-induced ROS production was completely inhibited by genistein and wortmannin and partially inhibited by SB203580, UO126 and GF109203X. These results show that zymosan alone is able to activate NADPH oxidase in human neutrophils via the phosphorylation of p47phox and Rac2 activation and that a protein tyrosine kinase, PI3Kinase, p38MAPK, ERK1/2 and PKC are involved in this process. These pathways could be potential pharmacological targets to treat zymosan- and S. cerevisiae-induced inflammation. 23527585 Does Dietary Copper Supplementation Enhance or Diminish PCB126 Toxicity in the Rodent Liver? Copper is essential for the function of the mitochondrial electron transport chain and several antioxidant proteins. However, in its free form copper can participate in Fenton-like reactions that produce reactive hydroxyl radicals. Aryl-hydrocarbon receptor (AhR) agonists, including the most potent polychlorinated biphenyl (PCB) congener, 3,3',4,4',5-pentachlorobiphenyl (PCB126), increase copper levels in rodent livers. This is accompanied by biochemical and toxic changes. To assess the involvement of copper in PCB toxicity, male Sprague-Dawley rats were fed an AIN-93G diet with differing dietary copper levels: low (2 ppm), adequate (6 ppm), and high (10 ppm). After three weeks, rats from each group were given a single ip injection of corn oil (control), 1, or 5 μmol/kg body weight PCB126. Two weeks following injections, biochemical and morphological markers of hepatic toxicity, trace metal status, and hepatic gene expression of metalloproteins were evaluated. Increasing dietary copper was associated with elevated tissue levels of copper and ceruloplasmin. In the livers of PCB126-treated rats, the hallmark signs of AhR activation were present, including increased cytochrome P450 and lipid levels and decreased glutathione. In addition, a doubling of hepatic copper levels was seen, and overall metal homeostasis was disturbed, resulting in decreased hepatic selenium, manganese, zinc, and iron. Expression of key metalloproteins was either decreased (cytochrome c oxidase), unchanged (ceruloplasmin and CuZnSOD), or increased (tyrosinase and metallothioneins 1 and 2) with exposure to PCB126. Increases in metallothionein may contribute/reflect the increased copper seen. Alterations in dietary copper did not amplify or abrogate the hepatic toxicity of PCB126. PCB126 toxicity, i.e., oxidative stress and steatosis, is clearly associated with disturbed metal homeostasis. Understanding the mechanisms of this disturbance may provide tools to prevent liver toxicity by other AhR agonists. 23212103 Clinical applications for microRNAs in cancer. The discovery that noncoding components of the genome, including microRNA (miRNA or miR), can contribute to the pathogenesis of cancer has led investigators to contemplate using these molecules to guide clinical decision making. Currently, miRNA signatures are being applied in human clinical trials and miRNA-directed therapy is under way, with miR-122 targeting in hepatitis C (HCV) being the most developed therapy thus far. miRNA-based targeting in cancer is not far behind, with several private companies developing therapeutics. We are recognizing the potential for miRNA biology to clarify both the molecular pathogenesis of cancer and the inherent complexities in translating its biology to clinics. An increased understanding of fundamental miRNA biology, improved bioinformatics, and directed in vivo targeting while minimizing off-target effects and toxicity will be required for successful translational application. Here, we provide an overview of miRNAs, with a focus on aspects of translating bench-based discoveries to the clinic. 23522833 Cu(OTf)2 catalyzed three component reaction: Efficient synthesis of spiro[indoline-3,4'-pyrano[3,2-b]pyran derivatives and their anticancer potency towards A549 human lung cancer cell lines. Cu(OTf)2 catalyzed efficient synthesis of spiropyrano[3,2-b]pyran-4(8H)-ones is accomplished via one-pot three component reaction between isatin, kojic acid and active methylenes. This synthetic protocol is operationally simple and affords product with good to excellent yields at a short reaction time. The synthesized compounds were evaluated for their tumor cell growth inhibitory activity against the human lung cancer cell line (A549) and found that 13 compounds exhibited moderate to good anticancer potency. Molecular docking studies were performed for all the synthesized compounds and the results showed that compound 4e showed greater affinity for anaplastic lymphoma kinase (ALK) receptor. 23458727 Design, synthesis, and biological evaluation of highly potent small molecule-peptide conjugates as new HIV-1 fusion inhibitors. The small molecule fusion inhibitors N-(4-carboxy-3-hydroxyphenyl)-2,5-dimethylpyrrole (NB-2) and N-(3-carboxy-4-hydroxyphenyl)-2,5-dimethylpyrrole (A12) target a hydrophobic pocket of HIV-1 gp41 and have moderate anti-HIV-1 activity. In this paper, we report the design, synthesis, and structure-activity relationship of a group of hybrid molecules in which the pocket-binding domain segment of the C34 peptide was replaced with NB-2 and A12 derivatives. In addition, the synergistic effect between the small molecule and peptide moieties was analyzed, and lead compounds with a novel scaffold were discovered. We found that either the nonpeptide or peptide part alone showed weak activity against HIV-1-mediated cell-cell fusion, but the conjugates properly generated a strong synergistic effect. Among them, conjugates Aoc-βAla-P26 and Noc-βAla-P26 exhibited a low nanomolar IC50 in the cell-cell fusion assay and effectively inhibited T20-sensitive and -resistant HIV-1 strains. Furthermore, the new molecules exhibited better stability against proteinase K digestion than T20 and C34. 23565753 Androgen receptor: past, present and future. Androgens and the androgen receptor have been the focus of prostate cancer research since the early 1940s, when Huggins and Hodges demonstrated that removal of androgens caused advanced prostate cancer to regress. Since that time, a large number of androgen deprivation therapies have been developed in an effort to cure this disease, but prostate cancer remains one of the leading causes of cancer death in males worldwide. This is due in part to the emergence of castration- recurrent prostate cancer in patients with advanced disease who have failed androgen deprivation therapy. The androgen receptor is still a major player in castration-recurrent disease, and though much has been discovered since the early work of Huggins and Hodges regarding how prostate cancer cells manage to avoid the effects of androgen deprivation, survival times for men with advanced prostate cancer have changed only modestly. Research is now directed toward delineating the mechanisms of action of the androgen receptor under castrate conditions, whether through amplification of the AR, mutation, expression of splice variants, use of alternate signaling pathways, aberrant expression and activation of coregulators, or intratumoral androgen biosynthesis. Genome-wide association studies are also adding to the wealth of knowledge surrounding the androgen receptor, and with this knowledge comes the ability to design new drug therapies directed toward eradication of this disease. 23488728 Gold nanoparticles on oxide-free silicon-molecule interface for single electron transport. Two different organic monolayers were prepared on silicon Si(111) and modified for attaching gold nanoparticles. The molecules are covalently bound to silicon and form very ordered monolayers sometimes improperly called self-assembled monolayers (SAM). They are designed to be electrically insulating and to have very few electrical interface states. By positioning the tip of an STM above a nanoparticle, a double barrier tunnel junction (DBTJ) is created, and Coulomb blockade is demonstrated at 40 K. This is the first time Coulomb blockade is observed with an organic monolayer on oxide-free silicon. This work focuses on the fabrication and initial electrical characterization of this double barrier tunnel junction. The organic layers were prepared by thermal hydrosilylation of two different alkene molecules with either a long carbon chain (C11) or a shorter one (C7), and both were modified to be amine-terminated. FTIR and XPS measurements confirm that the Si(111) substrate remains unoxidized during the whole chemical process. Colloidal gold nanoparticles were prepared using two methods: either with citrate molecules (Turkevich method) or with ascorbic acid as the surfactant. In both cases AFM and STM images show a well-controlled deposition on the grafted organic monolayer. I-V curves obtained by scanning tunneling spectroscopy (STS) are presented on 8 nm diameter nanoparticles and exhibit the well-known Coulomb staircases at low temperature. The curves are discussed as a function of the organic layer thickness and silicon substrate doping. 23567037 Hemolysin from Escherichia coli induces oxidative stress in blood. Hemolysin (HlyA) produced by some stains of Escherichia coli is considered to be an important virulence factor of those bacteria. On the other hand, reactive oxygen species (ROS) have been reported to be involved in the pathogenesis of different diseases via oxidative stress generation. The purpose of this study was to analyze the capacity of HlyA to induce oxidative stress in whole blood cultures (WBCs). To this end, ROS production, the damage induced in lipids and proteins, and the antioxidant defense system was evaluated in blood cultures exposed to low concentrations of HlyA. We found that HlyA increased the level of free radicals detected by chemiluminescence assay. Moreover, lipid peroxidation and protein damage was significantly increased in cultures treated with HlyA in comparation with those found in control cultures. On the other hand, a decrease in total antioxidant capacity of plasma and in the activity of superoxide dismutase (SOD) was observed in plasma from blood treated with HlyA. Collectively, our data demonstrate that low concentrations of E. coli hemolysin induced oxidative stress in WBCs with the induction of different oxidative damage biomarkers. 23427338 Surface-confined electroactive molecules for multistate charge storage information. Bi-stable molecular systems with potential for applications in binary memory devices are raising great interest for device miniaturization. Particular appealing are those systems that operate with electrical inputs since they are compatible with existing electronic technologies. The processing of higher memory densities in these devices could be accomplished by increasing the number of memory states in each cell, although this strategy has not been much explored yet. Here we highlight the recent advances devoted to the fabrication of charge-storage molecular surface-confined devices exhibiting multiple states. Mainly, this goal has been realized immobilizing a variety (or a combination) of electroactive molecules on a surface, although alternative approaches employing non-electroactive systems have also been described. Undoubtedly, the use of molecules with chemically tunable properties and nanoscale dimensions are raising great hopes for the devices of the future in which molecules can bring new perspectives such as multistability. 23159331 Perseverative behavior in rats with methamphetamine-induced neurotoxicity. Methamphetamine induces monoamine depletions thought to contribute to cognitive and behavioral dysfunctions. Previously, we reported that methamphetamine-induced neurotoxicity is associated with impaired formation of stimulus-response associations. Additionally, subjective observations suggested that behavioral flexibility might be affected. Thus, the present study examined whether methamphetamine neurotoxicity induces perseverative behavior. Rats were pretreated with (±)-methamphetamine (4 × 10 mg/kg, 2-hr intervals) or saline. Three weeks later, rats were trained to press a lever on one side of an operant chamber and then retrieve the reinforcer from a magazine on the opposite side until they reached criterion (>50 reinforcers/30-min). After four consecutive sessions performing the task at criterion, rats were sacrificed and brains removed for monoamine determinations. Methamphetamine-pretreated rats had ∼50% loss of striatal dopamine and prefrontal serotonin. Methamphetamine- and saline-pretreated rats were not different in the number of sessions required to reach criterion or in the total numbers of lever presses and/or head entries made across the four consecutive sessions at criterion-level performance. However, methamphetamine-pretreated rats earned fewer reinforcers, because they made extra lever-presses and head entries when they should have been retrieving the reinforcer or returning to the lever. Latencies for methamphetamine-pretreated rats to switch between the two behaviors also were significantly slower than latencies for controls. Interestingly, the degree of additional lever-presses negatively correlated with serotonin-transporter binding in the prefrontal cortex, even in saline-pretreated controls. These data suggest that methamphetamine-induced partial monoamine toxicity is associated with perseveration and that the degree of perseveration may depend on serotonin innervation of the frontal cortex. 23284082 Amide hydrolysis of a novel chemical series of microsomal prostaglandin E synthase-1 inhibitors induces kidney toxicity in the rat. A novel microsomal prostaglandin E synthase 1 (mPGES-1) inhibitor induced kidney injury at exposures representing less than 4 times the anticipated efficacious exposure in man during a 7-day toxicity study in rats. The findings consisted mainly of tubular lesions and the presence of crystalline material and increases in plasma urea and creatinine. In vitro and in vivo metabolic profiling generated a working hypothesis that a bis-sulfonamide metabolite (determined M1) formed by amide hydrolysis caused this toxicity. To test this hypothesis, rats were subjected to a 7-day study and were administered the suspected metabolite and two low-potency mPGES-1 inhibitor analogs, where amide hydrolysis was undetectable in rat hepatocyte experiments. The results suggested that compounds with a reduced propensity to undergo amide hydrolysis, thus having less ability to form M1, reduced the risk of inducing kidney toxicity. Rats treated with M1 alone showed no histopathologic change in the kidney, which was likely related to underexposure to M1. To circumvent rat kidney toxicity, we identified a potent mPGES-1 inhibitor with a low propensity for amide hydrolysis and superior rat pharmacokinetic properties. A subsequent 14-day rat toxicity study showed that this compound was associated with kidney toxicity at 42, but not 21, times the anticipated efficacious exposure in humans. In conclusion, by including metabolic profiling and exploratory rat toxicity studies, a new and active mPGES-1 inhibitor with improved margins to chemically induced kidney toxicity in rats has been identified. 23636303 Involvement of serotonin 5-HT3 receptors in the modulation of noradrenergic transmission by serotonin reuptake inhibitors: a microdialysis study in rat brain. RATIONALE: Selective serotonin reuptake inhibitors (SSRIs), in addition to being able to enhance serotonergic neurotransmission, are able to modulate other brain systems involved in depression. OBJECTIVES: This study evaluates the neurochemical effect of the SSRI citalopram on brain noradrenergic activity and the serotonin receptor involved in this effect. METHODS: Dual-probe microdialysis in the locus coeruleus (LC) and prefrontal cortex (PFC) was performed in freely awake rats. RESULTS: Systemic citalopram (10 mg/kg, i.p.) increased noradrenaline (NA) in the LC (E max = 141 ± 13 %) and simultaneously decreased NA in the PFC (Emax = -46 ± 7 %). In the local presence into the LC of the α2-adrenoceptor antagonist RS79948 (1 μM), systemic citalopram increased NA in the LC (Emax = 157 ± 25 %) and PFC (Emax = 175 ± 24 %). Local citalopram (0.1-100 μM) into the LC induced NA increase in the LC (Emax = 210 ± 25 %) and decrease in the PFC (Emax = -38 ± 9 %). Local LC citalopram effect was abolished by LC presence of the 5-HT3 receptor antagonist MDL72222 (1 μM) but not the 5-HT1/2 receptor antagonist methiothepin (1 μM). Systemic citalopram in the LC presence of MDL72222 did not modify NA in the LC but increased NA in the PFC (Emax = 158 ± 26 %). Local citalopram into the PFC enhanced NA (Emax = 376 ± 18 %) in the area, which was prevented by MDL72222. CONCLUSIONS: The SSRI citalopram modulates central noradrenergic neurotransmission by activation, through endogenous serotonin, of 5-HT3 receptors expressed in the somatodendritic (LC) and terminal (PFC) areas, which subsequently promote an enhancement of local NA. Therefore, 5-HT3 receptors and somatodendritic α2-adrenoceptors in the LC play an important role in the global effect of SSRIs. 23303281 Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates. Injection of adeno-associated virus (AAV) into the cerebrospinal fluid (CSF) offers a means to achieve widespread transgene delivery to the central nervous system, where the doses can be readily translated from small to large animals. In contrast to studies with other serotypes (AAV2, AAV4 and AAV5) in rodents, we report that a naturally occurring capsid (AAV9) and rationally engineered capsid (AAV2.5) are able to achieve broad transduction throughout the brain and spinal cord parenchyma following a single injection into the CSF (via cisterna magna or lumbar cistern) in non-human primates (NHP). Using either vector at a dose of ∼2 × 10(12) vector genome (vg) per 3-6 kg animal, approximately 2% of the entire brain and spinal cord was transduced, covering all regions of the central nervous system (CNS). AAV9 in particular displayed efficient transduction of spinal cord motor neurons. The peripheral organ biodistribution was highly reduced compared with intravascular delivery, and the presence of circulating anti-AAV-neutralizing antibodies up to a 1:128 titer had no inhibitory effect on CNS gene transfer. Intra-CSF delivery effectively translates from rodents to NHPs, which provides encouragement for the use of this approach in humans to treat motor neuron and lysosomal storage diseases. 23423468 An investigation of the photophysical properties of minor groove bound and intercalated DAPI through quantum-mechanical and spectroscopic tools. The fluorescent probe 4',6-diamidino-2-phenylindole (DAPI) is a dye known to interact with polynucleotides in a non-univocal manner, both intercalation and minor groove binding modes being possible, and to specifically change its photophysical properties according to the different environments. To investigate this behavior, quantum-mechanical calculations using time-dependent density functional theory (TDDFT), coupled with polarizable continuum and/or atomistic models, were performed in combination with spectroscopic measurements of the probe in the different environments, ranging from a homogeneous solution to the minor groove or intercalation pockets of double stranded nucleic acids. According to our simulation, the electronic transition involves a displacement of the electron charge towards the external amidine groups and this feature makes the absorption energies very environment-sensitive while a much smaller sensitivity is seen in the fluorescence energies. Moreover, the calculations show that the DAPI molecule, when minor groove bound to the nucleic acid, presents both a reduced geometrical flexibility because of the rigid DNA pocket and a reduced polarization due to the very "apolar" microenvironment. All these effects can be used to better understand the observed enhancement of the fluorescence, which makes it an excellent marker for DNA. 23350730 Parathyroid and calcium metabolism disorders during pregnancy. Abstract Parathyroid disorders are not common among pregnant women, but harbor a significant morbidity and mortality potential if they remain unrecognized and untreated. The symptoms caused by abnormally low or high blood free calcium level are mostly non-specific in the initial stages, thus when recognized might pose a real danger. Here we will survey the alterations in calcium metabolism induced by pregnancy, and describe the clinical manifestations, diagnosis and treatment of parathyroid and other calcium metabolism disorders during pregnancy. The current literature on the impact of calcium and vitamin D deficiency during pregnancy will also be reviewed. 23402938 Biotransformation and toxicokinetics of the insect repellent IR3535® in male and female human subjects after dermal exposure. The absorption and excretion of the insect repellent IR3535(®) was studied in human subjects (five males and five females) after dermal application of approx. 3g of a formulation containing 20% IR3535(®), i.e. the amounts of IR3535(®) applied were between 1.94 and 3.4 mmol/person (418-731 mg/person). Blood and urinary concentrations of IR3535(®) and its only metabolite, IR3535(®)-free acid, were determined over time. In plasma, concentrations of the parent compound IR3535(®) were at or below the limit of quantification (0.037 μmol/L). IR3535(®)-free acid peaked in plasma samples 2-6h after dermal application. Cmax mean values were 5.7 μmol/L in males, 3.0 μmol/L in females and 4.2 μmol/L in all volunteers. Mean AUC values were 41.6, 24.5 and 33.9 μmolL(-1)h in males, females and all subjects, respectively. In urine samples from all human subjects, both IR3535(®) and IR3535(®)-free acid were detectable, however, only very small amounts of IR3535(®) were found. Concentrations of IR3535(®)-free acid were several thousand-fold higher than the parent compound and peaked at the first two sampling points (4h and 8h after dermal application). Overall, IR3535(®) and IR3535(®)-free acid excreted with urine over 48 h representing 13.3 ± 3.05% of the dose applied. Since IR3535(®) is rapidly and extensively metabolized, and IR3535(®)-free acid has a low molecular weight and high water solubility, it is expected that urinary excretion of IR3535(®)-free acid and IR3535(®) represents the total extent of absorption of IR3535(®) in humans. Based on the results of this study, the skin penetration rate of IR3535(®) is 13.3% in humans after dermal application. 23157637 Systematic review of the influence of antipsychotics on the blood oxygenation level-dependent signal of functional magnetic resonance imaging. Functional Magnetic Resonance Imaging (FMRI) is a non-invasive technique for brain mapping and mostly performed using changes of the blood-oxygen-level-dependent (BOLD)-signal. It has been widely used to investigate patients with schizophrenia. Most of the studies examine patients treated with antipsychotic drugs, although little is known about the effects of these drugs on the BOLDsignal. Here we examined studies of patients with schizophrenia treated with different antipsychotics to address the question whether and to what extent antipsychotic drugs in themselves produce BOLD-signal changes. We performed a PubMed-search for the period from 1999 until January 2012 with the search items "schizophrenia" and "Magnetic Resonance Imaging" and "Antipsychotic Agents; or "Magnetic Resonance Imaging" and "Antipsychotic Agents"; or "schizophrenia" and "Antipsychotic Agents" and "FMRI". We extracted articles that examined at least two patient groups with different treatments, or patients examined on different medications at different times and that provided information about drug effects. No common effect of antipsychotics on BOLD-signal was found. However, based on the results for different antipsychotics (haloperidol, olanzapine, quetiapine and risperidone) we found evidence that the affinity to the dopamine (DA) D(2)-receptor may influence BOLD-signal. 23215461 Recombinant human fibrinogen that produces thick fibrin fibers with increased wound adhesion and clot density. Human fibrinogen is a biomaterial used in surgical tissue sealants, scaffolding for tissue engineering, and wound healing. Here we report on the post-translational structure and functionality of recombinant human FI (rFI) made at commodity levels in the milk of transgenic dairy cows. Relative to plasma-derived fibrinogen (pdFI), rFI predominately contained a simplified, neutral carbohydrate structure and >4-fold higher levels of the γ'-chain transcriptional variant that has been reported to bind thrombin and Factor XIII. In spite of these differences, rFI and pdFI were kinetically similar with respect to the thrombin-catalyzed formation of protofibrils and Factor XIIIa-mediated formation of cross-linked fibrin polymer. However, electron microscopy showed rFI produced fibrin with much thicker fibers with less branching than pdFI. In vivo studies in a swine liver transection model showed that, relative to pdFI, rFI made a denser, more strongly wound-adherent fibrin clot that more rapidly established hemostasis. 23568455 Potent Inhibitors of Phosphatidylinositol 3 (PI3) Kinase that have Antiproliferative Activity Only When Delivered as Prodrug Forms. Prodrugs for PI3K: A series of substituted analogues of the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002 were prepared and found to potently inhibit the isolated enzyme but not MCF7 cell proliferation. Two tetrazolyl-substituted analogues were further derivatized as prodrugs resulting in restoration of cell-based activity. These data provide a conceptual model for development of tumor-targeting prodrug forms of cell-impermeable PI3K inhibitors. 23287538 Alcohol intoxications during adolescence increase motivation for alcohol in adult rats and induce neuroadaptations in the nucleus accumbens. Adolescent alcohol binge drinking constitutes a major vulnerability factor to develop alcoholism. However, mechanisms underlying this susceptibility remain unknown. We evaluated the effect of adolescent binge-like ethanol intoxication on vulnerability to alcohol abuse in Sprague-Dawley rats. To model binge-like ethanol intoxication, every 2 days, rats received an ethanol injection (3.0 g/kg) for 2 consecutive days across 14 days either from postnatal day 30 (PND30) to 43 (early adolescence) or from PND 45 to PND 58 (late adolescence). In young adult animals, we measured free ethanol consumption in the two-bottle choice paradigm, motivation for ethanol in the operant self-administration task and both ethanol's rewarding and aversive properties in the conditioned place preference (CPP) and taste aversion (CTA) paradigms. While intermittent ethanol intoxications (IEI) during late adolescence had no effect on free-choice 10% ethanol consumption, we found that IEI during early adolescence promoted free-choice 10% ethanol consumption, enhanced motivation for ethanol in the self-administration paradigm and induced a loss of both ethanol-induced CPP and CTA in young adults. No modification in either sucrose self-administration or amphetamine-induced CPP was observed. As the nucleus accumbens (Nac) is particularly involved in addictive behavior, we analyzed IEI-induced long-term neuroadaptations in the Nac using c-Fos immunohistochemistry and an array of neurotransmission-related genes. This vulnerability to ethanol abuse was associated with a lower c-Fos immunoreactivity in the Nac and enduring alterations of the expression of Penk and Slc6a4, 2 neurotransmission-related genes that have been shown to play critical roles in the behavioral effects of ethanol and alcoholism. 23085085 Histone deacetylase 3 is required for maintenance of bone mass during aging. Histone deacetylase 3 (Hdac3) is a nuclear enzyme that removes acetyl groups from lysine residues in histones and other proteins to epigenetically regulate gene expression. Hdac3 interacts with bone-related transcription factors and co-factors such as Runx2 and Zfp521, and thus is poised to play a key role in the skeletal system. To understand the role of Hdac3 in osteoblasts and osteocytes, Hdac3 conditional knockout (CKO) mice were created with the osteocalcin (OCN) promoter driving Cre expression. Hdac3 CKO(OCN) mice were of normal size and weight, but progressively lost trabecular and cortical bone mass with age. The Hdac3 CKO(OCN) mice exhibited reduced cortical bone mineralization and material properties and suffered frequent fractures. Bone resorption was lower, not higher, in the Hdac3 CKO(OCN) mice, suggesting that primary defects in osteoblasts caused the reduced bone mass. Indeed, reductions in bone formation were observed. Osteoblasts and osteocytes from Hdac3 CKO(OCN) mice showed increased DNA damage and reduced functional activity in vivo and in vitro. Thus, Hdac3 expression in osteoblasts and osteocytes is essential for bone maintenance during aging. 23546395 Antimutagenic and genoprotective effects of Saraca asoca bark extract. Aim of the study:Traditionally herbal formulations have been used effectively for the management of disorders that are now being accepted worldwide. Saraca asoca bark extract (SAE) finds use in traditional herbal medicine. In the present study, SAE were studied for their antioxidant, antimutagenic, and antigenotoxic properties. METHODS: SAE were evaluated for antimutagenic property in Salmonella strains (TA97a, TA98, TA100, and TA102), in the presence and absence of metabolic activation (S9). The SAE was also studied for antigenotoxic property against cyclophosphamide (CP) in Swiss albino male mice in vivo. The extract was analyzed using high-performance liquid chromatography (HPLC). RESULTS: The study reveals antimutagenic property of the bark extract in Salmonella strains in the presence and absence of metabolic activation (S9). The study reports antigenotoxic property of the bark extract against CP in vivo. Thiobarbituric acid reactive species assay on the bark extract revealed antioxidant property. HPLC revealed the presence of two peaks corresponding to gallic acid and (-)-epicatechin, respectively. CONCLUSION: The study clearly reveals the antimutagenic and antigenotoxic properties of SAE. 23186624 Effect of clonidine in mice injected with Tityus discrepans scorpion venom. A study was conducted to assess the effect of clonidine (α(2)-adrenoceptor selective agonist) on glycemia, serum and urine α-amylase, blood urea nitrogen (BUN), serum creatinine, white blood cell count, kidney histology and zymogen granule content in pancreatic acini, in mice under the effect of Tityus discrepans (Td) scorpion venom. BALB/c male mice (20 ± 2 g, n = 7-11) were intraperitoneally (ip) injected with a sublethal dose (1 μg/g) of Td venom, and were treated (ip) with 0.1 μg/g of clonidine (Catapresan(®)) or 0.9% NaCl 30 min after the venom injection, and then every 2 h. Six hours later, mice were anesthetized with diethylether and urine and blood samples were withdrawn by cystocentesis and cardiocentesis, respectively. Tissue samples were obtained and fixed immediately in buffered formalin (2%, pH 7.4) and then processed for stain H&E. Td venom did not cause hyperglycemia by itself. However, clonidine induced hyperglycemia, which was synergized by Td venom. Although the venom did not produce hyperamylasemia, clonidine significantly diminished serum α-amylase activity in envenomed mice. Td venom did not significantly increase urinary α-amylase activity, which was unaffected by clonidine. Morphometric analysis using microphotographs of pancreata from mice injected with Td venom showed a reduced zymogen granule content as judged by the acidophilic bidimensional area of acini. This effect was significantly reduced by clonidine. Kidney samples showed histological changes which were partially affected by the drug. Clonidine reduced the increase in BUN and serum creatinine concentration in envenomed mice. Td venom produced neutrophilia and lymphopenia, which were clonidine-resistant at the assayed dose. These results suggest that α(2)-adrenoceptor selective agonists would be able to reduce some scorpion venom-induced renal and pancreatic disturbances, possibly through the inhibition of neurotransmitter release from presynaptic cholinergic and noradrenergic terminals, as well as from adrenal medulla. 23320940 Determination of very rapid molecular rotation by using the central electron paramagnetic resonance line. Picosecond rotational correlation times of perdeuterated tempone (PDT) are found in alkane and aromatic liquids by directly using the spectral width of the central electron paramagnetic resonance line. This is done by mathematically eliminating the nonsecular spectral density from the spectral parameter equations, thereby removing the need to assume a particular form for it. This is preferable to fitting a constant correction factor to the spectral density, because such a factor does not fit well in the low picosecond range. The electron-nuclear spin dipolar interaction between the probe and solvent is shown to be negligible for the very rapid rotation of PDT in these liquids at the temperatures of the study. The rotational correlation times obtained with the proposed method generally agree to within experimental uncertainty with those determined by using the traditional parameters. Using the middle line width offers greater precision and smoother trends. Previous work with the central line width is discussed, and past discrepancies are explained as possibly resulting from residual inhomogeneous broadening. The rotational correlation time almost forms a common curve across all of the solvents when plotted with respect to isothermal compressibility, which shows the high dependence of rotation on liquid free volume. 23219979 Bioactive cis-stilbenoids from the tubers of Scirpus yagara. Two new cis-stilbenoids, sciryagarol I (1) and II (2) were isolated from the EtOAc extract of the tubers of Scirpus yagara, together with four known compounds. The structures of all compounds were determined by comprehensive analyses of their spectroscopic data and comparison with literature information. The compounds 3, 4 and 6 were isolated for the first time from this genus. Some compounds were tested for their cytotoxicity against human tumor cell lines and antimicrobial activity. Compounds 1-4 showed significant cytotoxicity against the Hela cell lines with IC(50) values ranging from 7.21 to 61.21μM. 1 and 2 exhibited some antimicrobial activity against Staphylococcus aureus and Candida albicans with uniform MICs of 79.3μl/ml for 2, and 152μl/ml for 1, respectively. 22864622 Aurora A kinase (AURKA) in normal and pathological cell division. Temporally and spatially controlled activation of the Aurora A kinase (AURKA) regulates centrosome maturation, entry into mitosis, formation and function of the bipolar spindle, and cytokinesis. Genetic amplification and mRNA and protein overexpression of Aurora A are common in many types of solid tumor, and associated with aneuploidy, supernumerary centrosomes, defective mitotic spindles, and resistance to apoptosis. These properties have led Aurora A to be considered a high-value target for development of cancer therapeutics, with multiple agents currently in early-phase clinical trials. More recently, identification of additional, non-mitotic functions and means of activation of Aurora A during interphase neurite elongation and ciliary resorption have significantly expanded our understanding of its function, and may offer insights into the clinical performance of Aurora A inhibitors. Here we review the mitotic and non-mitotic functions of Aurora A, discuss Aurora A regulation in the context of protein structural information, and evaluate progress in understanding and inhibiting Aurora A in cancer. 23073171 Effects of conjugated linoleic acid supplementation and exercise on post-heparin lipoprotein lipase, butyrylcholinesterase, blood lipid profile and glucose metabolism in young men. This study was designed to investigate the effects of conjugated linoleic acid (CLA) supplementation and endurance exercise training-induced changes on post-heparin lipoprotein lipase (PH-LPL) and butyrylcholinesterase (BChE) activities along with leptin, insulin and lipid levels in plasma by a randomized double blind experiment. Eighteen sedentary male volunteers were randomly divided into CLA and Placebo (PLC) supplementation groups. Both groups underwent daily supplementation of either 3g CLA or 3g placebo for 30days, respectively, and performed exercise on a bicycle ergometer 3 times per week for 30-40min at 50% VO2 peak workload. For plasma glucose, insulin and leptin levels and BChE activity fasting blood was used. For PH-LPL measurements, blood was collected 15min after 50IU/kg iv heparin injection. In all groups, there is a statistically significant decrease in BChE (p=0.03, p=0.02) and leptin (p=0.002), insulin and HOMA-IR levels (p=0.02). Exercise with or without CLA supplementation decreased insulin levels and increased insulin sensitivity. PH-LPL activity was increased significantly in both groups, displaying increased fatty acid mobilization. We conclude that though CLA supplementation and exercise can affect these parameters, CLA is not more effective than exercise alone. Hence, a prolonged supplementation regime may be more effective. Taken together in our small study group, our findings display that BChE is a potential marker for synthetic function of liver, fat metabolism, an obesity marker, a function long overlooked. 23532897 Impact of the Proline Residue on Ligand Binding of Neurotensin Receptor 2 (NTS2)-Selective Peptide-Peptoid Hybrids. To investigate the binding mode and structure-activity relationships (SARs) of selective neurotensin receptor 2 (NTS2) ligands, novel peptide-peptoid hybrids that simulate the function of the endogenous ligand were developed. Starting from our recently described NTS2 ligands of type 1, structural variants of type 2 and the metabolically stable analogues 3 a,b were developed. Replacement of the proline unit by a collection of structural surrogates and evaluation of the respective molecular probes for NTS2 affinity and selectivity indicated similar SARs as described for NT(8-13) derivatives bound to the subtype NTS1. Peptide-peptoid hybrids 2 d, 3 a,b showed substantial NTS2 binding affinity (Ki =8.1-16 nM) and 2400-8600-fold selectivity over NTS1. The thiazolidine derivative 3 b showed metabolic stability over 32 h in a serum degradation assay. In an inositol phosphate accumulation assay, the neurotensin mimetics 3 a and 3 b displayed an inhibition of constitutive activity exceeding 1.7-2.0 times the activity of NT(8-13). The fluorinated derivative 3 a could afford attractive opportunities to detect NTS2 by (19) F magnetic resonance imaging. 23537599 Oxidative stress and myocardial dysfunction in young rabbits after short term anabolic steroids administration. The present study focuses on the short term effects of repeated low level administration of turinabol and methanabol on cardiac function in young rabbits (4months-old). The experimental scheme consisted of two oral administration periods, lasting 1month each, interrupted by 1-month wash-out period. Serial echocardiographic evaluation at the end of all three experimental periods was performed in all animals. Oxidative stress markers have also been monitored at the end of each administration period. Treated animals originally showed significantly increased myocardial mass and systolic cardiac output, which normalized at the end of the wash out period. Re-administration led to increased cardiac output, at the cost though of a progressive myocardial mass reduction. A dose-dependent trend towards impaired longitudinal systolic, diastolic and global myocardial function was also observed. The adverse effects were more pronounced in the methanabol group. For both anabolic steroids studied, the low dose had no significant effects on oxidative stress markers monitored, while the high dose created a hostile oxidative environment. In conclusion, anabolic administration has been found to create a possible deleterious long term effect on the growth of the immature heart and should be strongly discouraged especially in young human subjects. 23170796 Minocycline mediated mitochondrial cytoprotection: premises for therapy of cerebrovascular and neurodegenerative diseases. In the last decades, emerging molecular targets for ischemic neuroprotection and regeneration have been postulated. This fact allowed that classical drugs with well established therapeutic applications might be used in cerebrovascular diseases as well as neurodegenerative diseases. Minocycline is a commonly used antibiotic of the tetracycline family (7-dimethylamino-6-dimethyl-6-deoxytetracycline) which reveals cytoprotective capability and potential use in treatment of different diseases. Here, we discuss the literature concerning minocycline. The available data indicate that the antibiotic has multi-faceted effects on cell functions and, consequently, a number of clinical properties that are useful and/or could be useful for treatment of different diseases including bacterial infections, cancer, autoimmune disorders, ischemia as well as neurodegenerative and psychiatric diseases. Thus, application of minocycline as a therapeutic agent is the subject of clinical trials for various diseases. It is also evident that minocycline-mediated cytoprotection, including neuroprotection, is an important aspect of its clinical application. Here, we have reviewed the basis of the minocycline activity as well as different studies indicating that minocycline can be used as potential therapeutic agent in both cerebrovascular and neurodegenerative diseases in human. 23492810 Developing Predictive Approaches to Characterize Adaptive Responses of the Reproductive Endocrine Axis to Aromatase Inhibition: I. Data Generation in a Small Fish Model. Adaptive or compensatory responses to chemical exposure can significantly influence in vivo concentration-duration-response relationships. This study provided data to support development of a computational dynamic model of the hypothalamic-pituitary-gonadal axis of a model vertebrate and its response to aromatase inhibitors as a class of endocrine active chemicals. Fathead minnows (Pimephales promelas) were either exposed to the aromatase inhibitor fadrozole (0.5 or 30 μg/l) continuously for 1, 8, 12, 16, 20, 24, or 28 days or exposed for 8 days and then held in control water (no fadrozole) for an additional 4, 8, 12, 16, or 20 days. The time course of effects on ovarian steroid production, circulating 17β-estradiol (E2) and vitellogenin (VTG) concentrations, and expression of steroidogenesis-related genes in the ovary was measured. Exposure to 30 μg fadrozole/l significantly reduced plasma E2 and VTG concentrations after just 1 day and those effects persisted throughout 28 days of exposure. In contrast, ex vivo E2 production was similar to that of controls on day 8-28 of exposure, whereas transcripts coding for aromatase and follicle-stimulating hormone receptor were elevated, suggesting a compensatory response. Following cessation of fadrozole exposure, ex vivo E2 and plasma E2 concentrations exceeded and then recovered to control levels, but plasma VTG concentrations did not, even after 20 days of depuration. Collectively these data provide several new insights into the nature and time course of adaptive responses to an aromatase inhibitor that support development of a computational model (see companion article). 23546867 Ionizing radiation-inducible microRNA miR-193a-3p induces apoptosis by directly targeting Mcl-1. The functions of microRNAs (miRNAs) as either oncogenes or tumor suppressors in regulating cancer-related events have been established. We analyzed the alterations in the miRNA expression profile of the glioma cell line U-251 caused by ionizing radiation (IR) by using an miRNA array and identified several miRNAs whose expression was significantly affected by IR. Among the IR-responsive miRNAs, we further examined the function of miR-193a-3p, which exhibited the most significant growth-inhibiting effect. miR-193a-3p was observed to induce apoptosis in both U-251 and HeLa cells. We also demonstrated that miR-193a-3p induces the accumulation of intracellular reactive oxygen species (ROS) and DNA damage as determined by the level of γH2AX and by performing the comet assay. The induction of both apoptosis and DNA damage by miR-193a-3p was blocked by antioxidant treatment, indicating the crucial role of ROS in the action of miR-193a-3p. Among the putative target proteins, the expression of Mcl-1, an anti-apoptotic Bcl-2 family member, decreased because of miR-193a-3p transfection. A reporter assay using a luciferase construct containing the 3'-untranslated region of Mcl-1 confirmed that Mcl-1 is a direct target of miR-193a-3p. Down-regulation of Mcl-1 by siRNA transfection closely mimicked the outcome of miR-193a-3p transfection showing increased ROS, DNA damage, cytochrome c release, and apoptosis. Ectopic expression of Mcl-1 suppressed the pro-apoptotic action of miR-193a-3p, suggesting that Mcl-1 depletion is critical for miR-193a-3p induced apoptosis. Collectively, our results suggest a novel function for miR-193a-3p and its potential application in cancer therapy. 23395717 Xestospongin C induces monocytic differentiation of HL60 cells through activation of the ERK pathway. Xestospongin C (XC), which is a group of macrocyclic bis-1-oxaquinolizidines, is a potent inhibitor of sarcoendoplasmic reticulum calcium transport ATPase and IP3 receptor. Nevertheless, very less information is available regarding whether XC induces AML differentiation. We investigated the potential role of XC in the differentiation of human leukemia HL60 cells and mechanisms underlying XC actin. XC treatment inhibited proliferation by inducing G1-phase cell cycle arrest in the HL60 cells. In addition, XC induced differentiation of HL60 cells into the CD14(+) monocytic lineage, which was indicated by morphological changes, nitroblue tetrazolium reduction assay, and expressions of CD11b and CD14 surface antigens. Our results also showed that XC promotes phagocytic activity and granularity in HL60 cells, suggesting that the cells are functionally activated. Furthermore, XC enhanced tumor necrosis factor (TNF)-α-mediated cytotoxic effect by increasing the numbers of TNF receptors. Moreover, we showed that XC activates extracellular signal-regulated kinase (ERK) pathway in the differentiation stages. Inhibition of ERK activation using PD98059 significantly decreased NBT+HL60 cells induced by XC treatment. Taken together, the results show that XC promotes monocytic differentiation of HL60 cells via ERK pathway activation, suggesting that XC could be a candidate for use as a differentiation-inducing agent for AML treatment. 23521360 New methylated flavonol glucosides from Fumana montana Pomel. Three new methylated flavonol glucosides: 3-methoxy-7-O-β-(6″-galloylgluco-pyranoside) quercetin (1), 3,4'-dimethoxy-7-O-β-(6″-galloyl-glucopyranoside) quercetin (2) and 3-methoxy-7-O-β-(6″-galloylgluco-pyranoside) kaempferol (3), in addition to six known flavonols, were isolated from the ethyl acetate extract of Fumana montana Pomel. Their structures were assigned by spectroscopic methods. 23398290 Retinoids and glucocorticoids target common genes in hippocampal HT22 cells. Vitamin A metabolite retinoic acid (RA) plays a major role in the aging adult brain plasticity. Conversely, chronic excess of glucocorticoids (GC) elicits some deleterious effects in the hippocampus. We questioned here the involvement of RA and GC in the expression of target proteins in hippocampal neurons. We investigated proteins involved either in the signaling pathways [RA receptor β (RARβ) and glucocorticoid receptor (GR)] or in neuron differentiation and plasticity [tissue transglutaminase 2 (tTG) and brain-derived neurotrophic factor (BDNF)] in a hippocampal cell line, HT22. We applied RA and/or dexamethasone (Dex) as activators of the pathways and investigated mRNA and protein expression of their receptors and of tTG and BDNF as well as tTG activity and BDNF secretion. Our results confirm the involvement of RA- and GC-dependent pathways and their interaction in our neuronal cell model. First, both pathways regulate the transcription and expression of own and reciprocal receptors: RA and Dex increased RARβ and decreased GR expressions. Second, Dex reduces the expression of tTG when associated with RA despite stimulating its expression when used alone. Importantly, when they are combined, RA counteracts the deleterious effect of glucocorticoids on BDNF regulation and thus may improve neuronal plasticity under stress conditions. In conclusion, GC and RA both interact through regulations of the two receptors, RARβ and GR. Furthermore, they both act, synergistically or oppositely, on other target proteins critical for neuronal plasticity, tTG and BDNF. 23501109 Synthesis and antibacterial evaluation of novel pleuromutilin derivatives. A series of novel pleuromutilin derivatives possessing thioether moiety has been synthesized via acylation reaction under mild conditions. Their in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli, and Streptococcus agalactiae were tested by agar dilution method and Oxford cup assay. Among the 17 compounds screened, 14-O-[(4-methoxybenzamide-2- methylpropane-2-yl) thioacetate] mutilin 4i, 14-O-[(2-aminobenzamide-2-methylpropane-2-yl) thioacetate] mutilin 5a and 14-O-[(4-aminobenzamide-2-methylpropane-2-yl) thioacetate] mutilin 5c were resulted as most active antibacterial agents. 23246580 Effect of monospecific antibodies against baltergin in myotoxicity induced by Bothrops alternatus venom from northeast of Argentina. Role of metalloproteinases in muscle damage. Myotoxicity, one of the most relevant local manifestations in envenomation by Bothrops genus, may result from a direct action of myotoxins or be due to an indirect vascular degeneration and ischemia. Baltergin, a snake venom metalloproteinase (SVMP), isolated from Bothrops alternatus venom has been used to obtain monospecific IgG, in order to determine the relative role of toxin in myotoxicity induced by whole venom. Bothrops diporus venom, another medical relevant genus of the northeastern region of Argentina, was also studied. Anti-baltergin IgG was able to neutralize completely the hemorrhagic activity of B. alternatus venom at an antibodies:venom ratio of 30:1 (w:w). However, mice injected with B. diporus venom showed a small spot remaining even at the highest ratio of IgG:venom assayed (50:1; w:w). Specific antibodies were efficient to neutralize the myotoxicity of B. alternatus venom at ratio 30:1 (w:w) but did not neutralize the same effects in B. diporus venom. Anti-baltergin polyclonal antibodies were useful tools for revealing the central role of SVMPs in the development of myotoxicity of B. alternatus venom, as well as, helping to suggest indirectly presence of potent myotoxic phospholipases A2 (PLA2s) in B. diporus venom. 23416799 The production and characterization of anti-bothropic and anti-crotalic IgY antibodies in laying hens: a long term experiment. Ophidian accidents represent a great public health problem in developing countries. Recent studies have shown that antibodies produced in laying hens could be an alternative method for producing antivenin in mammals. In this study we analyzed the production of IgY antibodies in laying hens inoculated with snake venom from the Bothrops and Crotalus genera over a 360-day period. IgY antibodies present in the serum and egg yolks were analyzed according to avidity, antigen recognition pattern and efficiency in neutralizing the venom. The levels of anti-bothropic and anti-crotalic IgY antibodies increased significantly after the third immunization, and remained at these levels until the end of the experiment. Significantly high avidity levels were observed for anti-bothropic IgY antibodies on the 142nd day and for anti-crotalic antibodies on the 232nd day after the first immunization. Anti-bothropic IgY antibodies recognized antigens with molecular masses ranging from 25 kDa to 50 kDa, whereas anti-crotalic IgY antibodies mainly recognized antigens with molecular masses of 14 kDa and 30 kDa. An increase in the antigens recognized by the antivenins was observed during the experimental period. Samples of bothropic IgY antivenin antibodies presented an efficiency of 290 μl/3 DL50, a potency of 0.307 mg/ml and a specific activity of 0.230. Samples of anti-crotalic IgY antibodies presented an efficiency of 246 μl/4 DL50, a potency of 0.829 mg/ml and a specific activity of 0.271. These results show that the administration of successive doses of the venoms for more than 6 months results in an antivenin with higher avidity that is able to recognize a greater number of antigens present in the venoms. These characteristics indicate a more efficient and potent antivenin than what has been described in other studies. 23625272 Sequential Therapy Versus Standard Triple-Drug Therapy for Helicobacter pylori Eradication: a Systematic Review of Recent Evidence. BACKGROUND: Several alternative treatment regimens for Helicobacter pylori eradication have been proposed since the efficacy of standard triple therapy has declined over time, and sequential therapy is one of them. The purpose of this systematic review is to analyze and compare the efficacy, adverse effects and cost of sequential therapy with that of standard triple therapy for H. pylori infection. METHODS: MEDLINE, EMBASE, Google Scholar and Cochrane databases were used to retrieve all relevant articles published in the English language over the last 5 years (January 2008-October 2012). Eligibility criteria were randomized controlled trials (RCTs) comparing sequential and standard triple therapies in patients with documented H. pylori infection. Eligibility and quality of the trials were assessed independently by two reviewers, and the data regarding eradication rate, adverse effects and the cost of therapy were extracted. RESULTS: Of the 17 RCTs included in the analysis (Asia 13, Europe 3, Latin America, 1), 12 reported better eradication rates with the sequential therapy, four did not find a significant difference between the two treatment regimens, and one reported a better eradication rate with standard triple therapy. All except one RCT reported no significant difference in the incidence of adverse effects between standard triple therapy and sequential therapy. Sequential therapy was cheaper than standard triple therapy in all three RCTs where a cost analysis was performed. The limitations of the RCTs included in the systematic review were that the sequential therapy regimen and the duration of standard triple therapy were not uniform. Antibiotic susceptibility tests were performed in only three RCTs. CONCLUSIONS: While the majority of the RCTs have shown superior eradication rates with sequential therapy, the largest RCT from Latin America did not find a significant difference between the two treatment regimens. Sequential therapy has good efficacy; however, further trials other than those from Asia and Italy are required to assess its superiority over existing regimens before recommending sequential therapy as the first line of treatment for H. pylori infection. 23297023 Materiomics: an -omics approach to biomaterials research. The past fifty years have seen a surge in the use of materials for clinical application, but in order to understand and exploit their full potential, the scientific complexity at both sides of the interface--the material on the one hand and the living organism on the other hand--needs to be considered. Technologies such as combinatorial chemistry, recombinant DNA as well as computational multi-scale methods can generate libraries with a very large number of material properties whereas on the other side, the body will respond to them depending on the biological context. Typically, biological systems are investigated using both holistic and reductionist approaches such as whole genome expression profiling, systems biology and high throughput genetic or compound screening, as already seen, for example, in pharmacology and genetics. The field of biomaterials research is only beginning to develop and adopt these approaches, an effort which we refer to as "materiomics". In this review, we describe the current status of the field, and its past and future impact on the biomedical sciences. We outline how materiomics sets the stage for a transformative change in the approach to biomaterials research to enable the design of tailored and functional materials for a variety of properties in fields as diverse as tissue engineering, disease diagnosis and de novo materials design, by combining powerful computational modelling and screening with advanced experimental techniques. 23541767 The Decapping Scavenger Enzyme DCS-1 Controls MicroRNA Levels in Caenorhabditis elegans. In metazoans, microRNAs play a critical role in the posttranscriptional regulation of genes required for cell proliferation and differentiation. MicroRNAs themselves are regulated by a multitude of mechanisms influencing their transcription and posttranscriptional maturation. However, there is only sparse knowledge on pathways regulating the mature, functional form of microRNA. Here, we uncover the implication of the decapping scavenger protein DCS-1 in the control of microRNA turnover. In Caenorhabditis elegans, mutations in dcs-1 increase the levels of functional microRNAs. We demonstrate that DCS-1 interacts with the exonuclease XRN-1 to promote microRNA degradation in an independent manner from its known decapping scavenger activity, establishing two molecular functions for DCS-1. Our findings thus indicate that DCS-1 is part of a degradation complex that performs microRNA turnover in animals. 23401217 Mild oxidation of thiofunctional polymers to cytocompatible and stimuli-sensitive hydrogels and nanogels. Nanogels consist of three dimensionally cross-linked hydrophilic polymer chains and can thus be easily modified through functionalization of the polymeric building blocks, for example to yield stimuli-sensitive materials. For drug transport and intracellular release, redox-sensitive systems are especially of interest, as the intracellular space is reductive. In this study, parameters that allow preparation of nanogels with tunable size between 150 and 350 nm are systematically evaluated and identified. Most importantly, a new and mild oxidation catalyst, alloxan, is introduced for the preparation of the nanogels. This broadens the range of possible payloads to more-sensitive molecules. Particle stability, degradation in cytosolic conditions, and cytocompatibility in concentrations up to 10 mg · mL(-1) are demonstrated. 23574008 Photorheological Response of Aqueous Wormlike Micelles with Photocleavable Surfactant. Recently, we have reported a new cinnamic acid-type photocleavable surfactant, C4-C-N-PEG9 that experiences a photocleavage through UV-induced cyclization in aqueous solution, yielding a coumarin derivative (7-butoxy-2H-chromen-2-one) and an aminated polyoxyethylene compound. Here, we have studied the effects of C4-C-N-PEG9 on the photorheological behavior of viscoelastic wormlike micelles formed by aqueous mixture of nonionic surfactants, polyoxyethylene phytosterol ether (PhyEO20) and tetraoxyethylene dodecyl ether (C12EO4). The 4.9 wt % PhyEO20/H2O + 2.4 wt % C12EO4 solution forms wormlike micelles, and its viscosity is ∼10 Pa·s. We have found that the addition of C4-C-N-PEG9 into this viscous, non-Newtonian fluid system decreases the viscosity. Viscosity decreased in parallel to the C4-C-N-PEG9 concentration reaching ∼0.003 Pa·s at 2.5 wt % of C4-C-N-PEG9. However, viscosity of the C4-C-N-PEG9 incorporated system increased significantly (∼200 times at 1.5 wt % of C4-C-N-PEG9 system) upon UV irradiation. Small-Angle X-ray scattering studies have shown that addition of C4-C-N-PEG9 favors wormlike-to-sphere type transition in the micellar structure. However, UV irradiation in the C4-C-N-PEG9 incorporated system causes one-dimensional micellar growth. Since C4-C-N-PEG9 has relatively bigger headgroup size compared to the C12EO4, addition of C4-C-N-PEG9 into wormlike micelles reduces the critical packing parameter resulting in the formation of spherical aggregates. UV irradiation induced one-dimensional micellar growth is caused due to photocleavage of the C4-C-N-PEG9 into a less surface-active coumarin derivative and an aminated polyoxyethylene compound, as confirmed by UV-vis spectrometry and HPLC measurements. The hydrophobic coumarin derivative formed after cleavage of C4-C-N-PEG9 goes to the micellar core and is responsible for decreasing the viscosity. However, the hydrophilic aminated polyoxyethylene prefers to reside at the vicinity of headgroup of PhyEO20 reducing the interhead repulsion, increasing the critical packing parameter and the viscosity as well. 23194525 The nutritional supplement Active Hexose Correlated Compound (AHCC) has direct immunomodulatory actions on intestinal epithelial cells and macrophages involving TLR/MyD88 and NF-κB/MAPK activation. Active Hexose Correlated Compound (AHCC) is an immunostimulatory nutritional supplement. AHCC effects and mechanism of action on intestinal epithelial cells or monocytes are poorly described. AHCC was added to the culture medium of intestinal epithelial cells (IEC18 and HT29 cells) and monocytes (THP-1 cells) and assessed the secretion of proinflammatory cytokines by ELISA. Inhibitors of NFκB and MAPKs were used to study signal transduction pathways while TLR4 and MyD88 were silenced in IEC18 cells using shRNA. It was found that AHCC induced GROα and MCP1 secretion in IEC18 and IL-8 in HT29 cells. These effects depended on NFκB activation, and partly on MAPKs activation and on the presence of MyD88 and TLR4. In THP-1 cells AHCC evoked IL-8, IL-1β and TNF-α secretion. The induction of IL-8 depended on JNK and NFκB activation. Therefore, AHCC exerts immunostimulatory effects on intestinal epithelial cells and monocytes involving TLR4/MyD88 and NFκB/MAPK signal transduction pathways. 23297689 Chemical composition and antibacterial activities of the essential oils isolated from Juniperus thurifera L. var. Africana. This study describes the chemical composition and antibacterial activities of essential oils of Moroccan Juniperus thurifera L. var. Africana (Cupressaceae). The essential oil of dried leaves was isolated by hydrodistillation, vapohydrodistillation and microwaves. Sixty-four compounds in J. thurifera L. var. Africana oils were identified (79.9%, 92.4% and 98.4% of the oil, respectively). The most abundant compound in J. thurifera L. var. Africana oils is sabinene (38%, 36.2% and 39.4%). Antibacterial activities of J. thurifera essential oils was tested against bacteria Gram ( - ) and Gram (+). The oil is very active against all bacteria tested except Pseudomonas, which turned out to be very resistant. 23428155 Solubility-driven optimization of (pyridin-3-yl) benzoxazinyl-oxazolidinones leading to a promising antibacterial agent. The solubility-driven structural modification of (pyridin-3-yl) benzoxazinyl-oxazolidinones is described, which resulted in the development of a new series of benzoxazinyl-oxazolidinone analogues with high antibacterial activity against Gram-positive pathogens, including that against linezolid-resistant strains and low hERG inhibition. With regard to structure-activity relationship (SAR) trends among the various substituents on the pyridyl ring, relatively small and nonbasic substituents were preferable to sterically demanding or basic substituents. Oxazolidinone ring substitution on the pyridyl ring generated analogues with antibacterial activity superior to imidazolidinone ring. Solubility was enhanced by the incorporation of polar groups, especially when compounds were converted to their prodrugs. Among the prodrugs, compound 85 exhibited excellent solubility and a good pharmacokinetic profile. In a MRSA systemic infection model, compound 85 displayed an ED50 = 5.00 mg/kg, a potency that is 2-fold better than that of linezolid. 23442213 Osteogenesis of mesenchymal stem cells by nanoscale mechanotransduction. It is likely that mesenchymal stem cells will find use in many autologous regenerative therapies. However, our ability to control cell stem growth and differentiation is presently limited, and this is a major hurdle to the clinical use of these multipotent cells especially when considering the desire not to use soluble factors or complex media formulations in culture. Also, the large number of cells required to be clinically useful is currently a hurdle to using materials-based (stiffness, chemistry, nanotopography, etc.) culture substrates. Here we give a first demonstration of using nanoscale sinusoidal mechanotransductive protocols (10-14 nm displacements at 1 kHz frequency), "nanokicking", to promote osteoblastogenesis in human mesenchymal stem cell cultures. On the basis of application of the reverse piezo effect, we use interferometry to develop the optimal stem cell stimulation conditions, allowing delivery of nanoscale cues across the entire surface of the Petri dishes used. A combination of immunofluorescence, PCR, and microarray has then been used to demonstrate osteoblastogenesis, and the arrays implicate RhoA as central to osteoblastic differentiation in agreement with materials-based strategies. We validate this with pharmacological inhibition of RhoA kinase. It is easy to envisage such stimulation protocols being up-scaled to form large-scale osteoblast bioreactors as standard cell culture plates and incubators are used in the protocol. 23370795 Parallel buprenorphine phMRI responses in conscious rodents and healthy human subjects. Pharmacological magnetic resonance imaging (phMRI) is one method by which a drug's pharmacodynamic effects in the brain can be assessed. Although phMRI has been frequently used in preclinical and clinical settings, the extent to which a phMRI signature for a compound translates between rodents and humans has not been systematically examined. In the current investigation, we aimed to build on recent clinical work in which the functional response to 0.1 and 0.2 mg/70 kg i.v. buprenorphine (partial µ-opioid receptor agonist) was measured in healthy humans. Here, we measured the phMRI response to 0.04 and 0.1 mg/kg i.v. buprenorphine in conscious, naive rats to establish the parallelism of the phMRI signature of buprenorphine across species. PhMRI of 0.04 and 0.1 mg/kg i.v. buprenorphine yielded dose-dependent activation in a brain network composed of the somatosensory cortex, cingulate, insula, striatum, thalamus, periaqueductal gray, and cerebellum. Similar dose-dependent phMRI activation was observed in the human phMRI studies. These observations indicate an overall preservation of pharmacodynamic responses to buprenorphine between conscious, naive rodents and healthy human subjects, particularly in brain regions implicated in pain and analgesia. This investigation further demonstrates the usefulness of phMRI as a translational tool in neuroscience research that can provide mechanistic insight and guide dose selection in drug development. 23579182 Clinical and Subclinical Macrovascular Disease as Predictors of Cognitive Decline in Older Patients With Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study. OBJECTIVEMacrovascular disease may contribute to increased risk of accelerated cognitive decline in patients with type 2 diabetes. We aimed to determine associations of measures of macrovascular disease with cognitive change in a cognitively healthy older population with type 2 diabetes.RESEARCH DESIGN AND METHODSEight-hundred thirty-one men and women (aged 60-75 years) attended two waves of the prospective Edinburgh Type 2 Diabetes Study (ET2DS). At baseline, clinical and subclinical macrovascular disease was measured, including cardiovascular event history, carotid intima-media thickness (cIMT), ankle brachial index (ABI), and serum N-terminal probrain natriuretic peptide (NT-proBNP). Seven neuropsychological tests were administered at baseline and after 4 years; scores were combined to a standardized general ability factor (g). Adjustment of follow-up g for baseline g assessed 4-year cognitive change. Adjustment for vocabulary (estimated premorbid ability) was used to estimate lifetime cognitive change.RESULTSMeasures of cognitive decline were significantly associated with stroke, NT-proBNP, ABI, and cIMT, but not with nonstroke vascular events. The association of stroke with increased estimated lifetime cognitive decline (standardized β, -0.12) and of subclinical markers with actual 4-year decline (standardized β, -0.12, 0.12, and -0.15 for NT-proBNP, ABI, and cIMT, respectively) reached the Bonferroni-adjusted level of statistical significance (P < 0.006). Results altered only slightly on adjustment for vascular risk factors.CONCLUSIONSStroke and subclinical markers of cardiac stress and generalized atherosclerosis are associated with cognitive decline in older patients with type 2 diabetes. Further investigation into the potential use of subclinical vascular disease markers in predicting cognitive decline is warranted. 23486538 Eliciting preferences for priority setting in genetic testing: a pilot study comparing best-worst scaling and discrete-choice experiments. Given the increasing number of genetic tests available, decisions have to be made on how to allocate limited health-care resources to them. Different criteria have been proposed to guide priority setting. However, their relative importance is unclear. Discrete-choice experiments (DCEs) and best-worst scaling experiments (BWSs) are methods used to identify and weight various criteria that influence orders of priority. This study tests whether these preference eliciting techniques can be used for prioritising genetic tests and compares the empirical findings resulting from these two approaches. Pilot DCE and BWS questionnaires were developed for the same criteria: prevalence, severity, clinical utility, alternatives to genetic testing available, infrastructure for testing and care established, and urgency of care. Interview-style experiments were carried out among different genetics professionals (mainly clinical geneticists, researchers and biologists). A total of 31 respondents completed the DCE and 26 completed the BWS experiment. Weights for the levels of the six attributes were estimated by conditional logit models. Although the results derived from the DCE and BWS experiments differed in detail, we found similar valuation patterns in the DCE and BWS experiments. The respondents attached greatest value to tests with high clinical utility (defined by the availability of treatments that reduce mortality and morbidity) and to testing for highly prevalent conditions. The findings from this study exemplify how decision makers can use quantitative preference eliciting methods to measure aggregated preferences in order to prioritise alternative clinical interventions. Further research is necessary to confirm the survey results.European Journal of Human Genetics advance online publication, 13 March 2013; doi:10.1038/ejhg.2013.36. 23561141 Chemical stability of astaxanthin nanodispersions in orange juice and skimmed milk as model food systems. Solubilising astaxanthin in nanodispersion systems is a promising approach to incorporate astaxanthin into water-based food formulations. In this research, the chemical stabilities of astaxanthin nanodispersions diluted in orange juice and skimmed milk as model food systems and in deionised water as a control were evaluated. The nanodispersions displayed significantly (p<0.05) better stability in food systems compared to the control. The effects of stabilisers and dilution factor were also studied. In skimmed milk and deionised water, the type of stabiliser had a significant effect (p<0.05) on astaxanthin degradation during storage. In vitro cellular uptake of astaxanthin from diluted astaxanthin nanodispersions in selected food systems was also evaluated. The cellular uptake of astaxanthin nanodispersions in skimmed milk was significantly higher (p<0.05) than that of astaxanthin nanodispersions in orange juice and deionised water. High in vitro cellular uptake of astaxanthin from the prepared astaxanthin nanodispersions can be achieved via incorporation into protein-based foods such as milk. 23016524 Molecular mechanism aspect of ER stress in Alzheimer's disease: current approaches and future strategies. Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by progressive loss of memory and cognitive impairment. Aggregation of amyloid-β (Aβ) peptides is the crucial factor in the onset of AD. The toxic Aβ peptides Aβ40 and Aβ42 are produced from the Aβ precursor protein (APP), a transmembrane protein which is folded and modified in endoplasmic reticulum (ER). ER is the main organelle for the synthesis and processing of nearly all proteins as well as the main cellular source of Ca2+. Under stress conditions, three main ER pathways including inositol-requiring enzyme 1, protein kinase RNA-like ER kinase, and activating transcription factor 6 become activated causing the accumulation of unfolded or misfolded proteins within ER lumen. These pathways manage the stress by regulating the expression of chaperones and enzymes involved in protein folding. Several studies have reported the dysfunction of these stress-sensing pathways in pathological conditions, including neurodegenerative diseases. Recent studies have proposed that neuronal death in AD arises from dysfunction of the ER. Here, we will review recent research findings on the interaction between ER and mitochondria, and its effect on apoptotic pathways. We further provide insights into studies which suggest the role of ER in animal and/or cellular models of AD. Therapeutic strategies that modulate ER could represent a promising approach for prevention or treatment of AD. 23465612 Structure-based design of novel dihydroisoquinoline BACE-1 inhibitors that do not engage the catalytic aspartates. The structure-activity relationship of a series of dihydroisoquinoline BACE-1 inhibitors is described. Application of structure-based design to screening hit 1 yielded sub-micromolar inhibitors. Replacement of the carboxylic acid of 1 was guided by X-ray crystallography, which allowed the replacement of a key water-mediated hydrogen bond. This work culminated in compounds such as 31, which possess good BACE-1 potency, excellent permeability and a low P-gp efflux ratio. 23198810 Profluorogenic reductase substrate for rapid, selective, and sensitive visualization and detection of human cancer cells that overexpress NQO1. Achieving the vision of identifying and quantifying cancer-related events and targets for future personalized oncology is predicated on the existence of synthetically accessible and economically viable probe molecules fully able to report the presence of these events and targets in a rapid and highly selective and sensitive fashion. Delineated here are the design and evaluation of a newly synthesized turn-on probe whose intense fluorescent reporter signature is revealed only through probe activation by a specific intracellular enzyme present in tumor cells of multiple origins. Quenching of molecular probe fluorescence is achieved through unique photoinduced electron transfer between the naphthalimide dye reporter and a covalently attached, quinone-based enzyme substrate. Fluorescence of the reporter dye is turned on by rapid removal of the quinone quencher, an event that immediately occurs only after highly selective, two-electron reduction of the sterically and conformationally restricted quinone substrate by the cancer-associated human NAD(P)H:quinone oxidoreductase isozyme 1 (hNQO1). Successes of the approach include rapid differentiation of NQO1-expressing and -nonexpressing cancer cell lines via the unaided eye, flow cytometry, fluorescence imaging, and two-photon microscopy. The potential for use of the turn-on probe in longer-term cellular studies is indicated by its lack of influence on cell viability and its in vitro stability. 23473037 Identification of a SIRT1 mutation in a family with type 1 diabetes. Type 1 diabetes is caused by autoimmune-mediated β cell destruction leading to insulin deficiency. The histone deacetylase SIRT1 plays an essential role in modulating several age-related diseases. Here we describe a family carrying a mutation in the SIRT1 gene, in which all five affected members developed an autoimmune disorder: four developed type 1 diabetes, and one developed ulcerative colitis. Initially, a 26-year-old man was diagnosed with the typical features of type 1 diabetes, including lean body mass, autoantibodies, T cell reactivity to β cell antigens, and a rapid dependence on insulin. Direct and exome sequencing identified the presence of a T-to-C exchange in exon 1 of SIRT1, corresponding to a leucine-to-proline mutation at residue 107. Expression of SIRT1-L107P in insulin-producing cells resulted in overproduction of nitric oxide, cytokines, and chemokines. These observations identify a role for SIRT1 in human autoimmunity and unveil a monogenic form of type 1 diabetes. 23504923 Inhibitory Effect of Ketoconazole on the Pharmacokinetics of a Multireceptor Tyrosine Kinase Inhibitor BMS-690514 in Healthy Participants: Assessing the Mechanism of the Interaction With Physiologically-Based Pharmacokinetic Simulations. BMS-690514, a selective inhibitor of the ErbB and vascular endothelial growth factor receptors, has shown antitumor activity in early clinical development. The compound is metabolized by multiple enzymes, with CYP3A4 responsible for the largest fraction (34%) of metabolism. It is also a substrate of P-glycoprotein (P-gp) in vitro. To assess the effect of ketoconazole on BMS-690514 pharmacokinetics, 17 healthy volunteers received 200 mg BMS-690514 alone followed by 100 mg BMS-690514 with ketoconazole (400 mg once daily for 4 days). The AUC∞ of 100 mg BMS-690514 concomitantly administered with ketoconazole was similar to that of 200 mg BMS-690514 alone. The dose-normalized Cmax and AUC∞ of BMS-690514 from the 100-mg BMS-690514/400-mg ketoconazole treatment increased by 55% and 127%, respectively, relative to those from 200 mg BMS-690514 alone. Prediction of the drug-drug interaction (DDI) using a population-based simulator (Simcyp) indicated that, in addition to CYP3A4 inhibition, the inhibition of P-gp by ketoconazole in the intestine, liver, and kidneys must be invoked to fully account for the DDI observed. This finding suggests that the inhibition of P-gp by ketoconazole, along with its effect on CYP3A4, needs to be considered when designing a DDI study of ketoconazole with a victim drug that is a dual substrate. 23411194 Adhesive microbeads for the targeting delivery of anticaries agents of vegetable origin. The formulation of quinic acid, a food constituent demonstrating potential anticaries and antigingivitis properties, was investigated in an adhesive microparticulate delivery system with the goal of improving its effect by prolonging its residence time at the site of action. Alginate and chitosan were selected as mucoadhesive polymers. The microspheres were prepared by coacervation. Different types of alginates, polymers blends and crosslinking agent concentrations were considered and evaluated. The best results in terms of encapsulation efficiency, in vitro active agent release profile and in vitro adhesive properties, both to oral mucosa and to teeth surface, were obtained with a blend of Alginate Protanal LF200S: Alginate Protanal LF120LS 1:1.5 w/w, 0.1M CaCl(2), and chitosan coating, prepared by a one-step complex coacervation method. This microparticulate delivery system showed prolonged release of quinic acid, and could be used as an active component in chewing gums or mouthwashes for both caries and gingivitis prevention. 23183084 Progestin effects on expression of AKR1C1-AKR1C3, SRD5A1 and PGR in the Z-12 endometriotic epithelial cell line. Endometriosis is defined as the presence of endometrial glands and stroma outside the uterine cavity. This disease is associated with diminished protective effects of progesterone, which are usually explained by inadequate activation of progesterone receptors and also enhanced pre-receptor metabolism of progesterone. Endometriosis is often treated with progestins, which act as progesterone receptor agonists, although their exact mechanisms of action are not completely understood. The aim of the present study was to investigate how the progestins medroxyprogesterone acetate, dydrogesterone and dienogest, as well as progesterone, impact on the expression of genes of pre-receptor progesterone metabolism in Z-12 epithelial cell line, a model system of peritoneal endometriosis. Our data demonstrate that these progestins affect local pre-receptor metabolism to a different extent. The most favorable effects were seen for dydrogesterone and dienogest, where the first, dydrogesterone, significantly reduced SRD5A1, AKR1C2 and AKR1C3 expression, and additionally had a nonsignificant impact on progesterone receptor B (PR-B) protein levels. This might slow down the first step of pre-receptor metabolism, the conversion of progesterone to 5α-dihydroprogestrone by SRD5A1, and it might also affect further reduction of 3-keto and 20-keto groups catalyzed by AKR1C2 and AKR1C3. Similarly favorable effects were seen for dienogest, which promoted significant reduction of AKR1C1 and AKR1C2 expression and also showed no effect on PR-B protein levels. Different effects were seen for progesterone, which significantly decreased SRD5A1, PR-B and HSD17B2 protein levels. In contrast, treatment with medroxyprogesterone acetate resulted in increased AKR1C1 expression and decreased levels of PR-B, which might lead to enhanced progesterone metabolism and reduced signaling through progesterone receptors. Altogether, our data in this Z-12 cell model suggest that the beneficial effects of treatment with progestin observed in endometriosis patients might arise from decreased pre-receptor metabolism of the protective progesterone by the SRD5A1 and AKR1C enzymes. 22776039 GLP-1 receptor activated insulin secretion from pancreatic β-cells: mechanism and glucose dependence. The major goal in the treatment of type 2 diabetes mellitus is to control the hyperglycaemia characteristic of the disease. However, treatment with common therapies such as insulin or insulinotrophic sulphonylureas (SU), while effective in reducing hyperglycaemia, may impose a greater risk of hypoglycaemia, as neither therapy is self-regulated by ambient blood glucose concentrations. Hypoglycaemia has been associated with adverse physical and psychological outcomes and may contribute to negative cardiovascular events; hence minimization of hypoglycaemia risk is clinically advantageous. Stimulation of insulin secretion from pancreatic β-cells by glucagon-like peptide 1 receptor (GLP-1R) agonists is known to be glucose-dependent. GLP-1R agonists potentiate glucose-stimulated insulin secretion and have little or no activity on insulin secretion in the absence of elevated blood glucose concentrations. This 'glucose-regulated' activity of GLP-1R agonists makes them useful and potentially safer therapeutics for overall glucose control compared to non-regulated therapies; hyperglycaemia can be reduced with minimal hypoglycaemia. While the inherent mechanism of action of GLP-1R agonists mediates their glucose dependence, studies in rats suggest that SUs may uncouple this dependence. This hypothesis is supported by clinical studies showing that the majority of events of hypoglycaemia in patients treated with GLP-1R agonists occur in patients treated with a concomitant SU. This review aims to discuss the current understanding of the mechanisms by which GLP-1R signalling promotes insulin secretion from pancreatic β-cells via a glucose-dependent process. 23456681 Hierarchical porous surface for efficiently controlling microdroplets' self-removal. Superhydrophobic porous surfaces with hydrophilic polymers adsorbed in pores are designed to control the coalescing behavior of microdroplets as well as their quick self-removal. The combination of chemical composition and surface structure are greatly important in the design of new materials for heat exchange, antifogging, and anti-icing. 23161373 Ecological risk assessment in the context of global climate change. Changes to sources, stressors, habitats, and geographic ranges; toxicological effects; end points; and uncertainty estimation require significant changes in the implementation of ecological risk assessment (ERA). Because of the lack of analog systems and circumstances in historically studied sites, there is a likelihood of type III error. As a first step, the authors propose a decision key to aid managers and risk assessors in determining when and to what extent climate change should be incorporated. Next, when global climate change is an important factor, the authors recommend seven critical changes to ERA. First, develop conceptual cause-effect diagrams that consider relevant management decisions as well as appropriate spatial and temporal scales to include both direct and indirect effects of climate change and the stressor of management interest. Second, develop assessment end points that are expressed as ecosystem services. Third, evaluate multiple stressors and nonlinear responses-include the chemicals and the stressors related to climate change. Fourth, estimate how climate change will affect or modify management options as the impacts become manifest. Fifth, consider the direction and rate of change relative to management objectives, recognizing that both positive and negative outcomes can occur. Sixth, determine the major drivers of uncertainty, estimating and bounding stochastic uncertainty spatially, temporally, and progressively. Seventh, plan for adaptive management to account for changing environmental conditions and consequent changes to ecosystem services. Good communication is essential for making risk-related information understandable and useful for managers and stakeholders to implement a successful risk-assessment and decision-making process. 23407893 Imogolite-like nanotubes: structure, stability, electronic and mechanical properties of the phosphorous and arsenic derivatives. Imogolite is a single-walled aluminosilicate nanotube (NT) found in nature that can be easily synthesized, as well as its analogue aluminogermanate NT. Based on geometrical assumptions and pKa values, species such as H3PO4, H3PO3, H3AsO3, H3AsO4 could also be candidates to form imogolite-like structures. In the present work, we provide insights about the stability, electronic, structural and mechanical properties of possible imogolite like NTs by means of self-consistent charge density-functional tight-binding method (SCC-DFTB). Similarly to aluminogermanate, where the tetrahedral silicate groups are replaced by germanate, in this work tetrahedral silicate groups are substituted by phosphate, phosphite, arsenate and arsenite units in the imogolite structure. Detailed analysis is focused on structural properties, strain energy, band gap and Mulliken charges distribution. The calculated strain energy curves for all studied zigzag imogolite-like NTs present well-defined minima, which change as a consequence of composition variation. Moreover, the strain energy curves of armchair imogolite-like NTs also present minima, although in all cases less stable than zigzags by at least 2.2 meV per atom. The insulating NT behaviour changes after internal modification from silicate to phosphate, phosphite, arsenate and arsenite, as well as the charge distribution inside and outside the nanotubes. 23027804 Mechanisms in endocrinology. Role of emotional stress in the pathophysiology of Graves' disease. The role of stress in the pathophysiology of Graves' disease is suggested by several clinical observations, by recent advances in immunology and by better understanding of autoimmune diseases which provides new insights into potential effects of stress hormones on T helper cell imbalance involved in the pathogenesis of autoimmune diseases. Stress management should therefore be an important part of the treatment of Graves' disease, as stress reduction may improve the effect of therapy. However, this field still requires interventional data to support stress management in the treatment of Graves' disease. 23564646 ALLERGIC SKIN INFLAMMATION INDUCED BY CHEMICAL SENSITIZERS IS CONTROLLED BY THE TRANSCRIPTION FACTOR NRF2. Allergic contact dermatitis (ACD) is induced by low molecular weight electrophilic chemicals and metal ions. Chemical contact sensitizers trigger reactive oxygen species (ROS) production and provoke electrophilic stress leading to the accumulation of the transcription factor nuclear related factor 2 (Nrf2) in innate immune cell types. The objective of this work was to identify the role of Nrf2 in the regulation of ACD. We used the Local Lymph Node Assay (LLNA) and the Mouse Ear Swelling Test (MEST) to study the role of Nrf2 in both the sensitization and elicitation phase in nrf2 knock out (nrf2(-/-)) and wild type (nrf2(+/+)) mice. Five chemicals were used: two compounds known to react with cysteine residues, 2,4-dinitrochlorobenzene (DNCB) and cinnamaldehyde (CinA); one sensitizer known to exhibit mixed reactivity to cysteine and lysine residues, isophorone diisocyanate (IPDI); and one reacting specifically with lysine residues, trimellitic anhydride (TMA) and croton oil a well-known irritant. In the MEST assay, DNCB (1% and 2%) induced a significant increase in ear thickness in nrf2(-/-) as compared to nrf2(+/+) mice suggesting a role for Nrf2 in the control of the inflammatory process. When DNCB was used at 0.25% and 0.5% or when mice were treated with CinA, inflammation was found only in nrf2(-/-) mice. In the LLNA all chemical sensitizers induced an increase of lymphocyte proliferation in nrf2(-/-) compared to nrf2(+/+) mice for the same chemical concentration.These results reveal an important role for Nrf2 in controlling ACD and lymphocyte proliferation in response to sensitizers. 23316964 Matrix metalloproteinases as drug targets in preeclampsia. Preeclampsia is an important syndrome complicating pregnancy. While the pathogenesis of preeclampsia is not entirely known, poor placental perfusion leading to widespread maternal endothelial dysfunction is accepted as a major mechanism. It has been suggested that altered placental expression of matrix metalloproteinases (MMPs) may cause shallow cytotrophoblastic invasion and incomplete remodeling of the spiral arteries. MMPs are also thought to link placental ischemia to the cardiovascular alterations of preeclampsia. In fact, MMPs may promote vasoconstriction and surface receptors cleavage affecting the vasculature. Therefore, the overall goal of this review article is to provide an overview of the pathophisiology of preeclampsia, more specifically regarding the role of MMPs in the pathogenesis of preeclampsia and the potential of MMP inhibitors as therapeutic options. 23352910 Cell penetrating peptide tethered bi-ligand liposomes for delivery to brain in vivo: Biodistribution and transfection. Targeted nano-particulate systems hold extraordinary potential for delivery of therapeutics across blood brain barrier (BBB). In this work, we investigated the potential of novel bi-ligand (transferrin-poly-l-arginine) liposomal vector for delivery of desired gene to brain, in vivo. The in vivo evaluation of the delivery vectors is essential for clinical translation. We followed an innovative approach of combining transferrin receptor targeting with enhanced cell penetration to design liposomal vectors for improving the transport of molecules into brain. The biodistribution profile of 1, 1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine iodide(DiR)-labeled liposomes was evaluated in adult rats after single intravenous injection at dose of 15.2μmoles of phospholipids/kg body weight. We demonstrated that bi-ligand liposomes accumulated in rat brain at significantly (p<0.05) higher concentrations as compared to the single-ligand (transferrin) or plain liposomes. In addition, the bi-ligand liposomes resulted in increased expression of β-galactosidase(β-gal) plasmid in rat brain tissue in comparison to the single-ligand liposomes. Histological examination of the transfected tissues did not show any signs of tissue necrosis or inflammation. Hemolysis assay further authenticated the biocompatibility of bi-ligand liposomes in blood up to 600 nmoles of phospholipids/1.4×10(7) erythrocytes. The findings of this study provide important and detailed information regarding the distribution of bi-ligand liposomes in vivo and accentuate their ability to demonstrate improved brain penetration and transfection potential over single-ligand liposomes. 23475433 Electrophysiological study for comparing the effect of biological activity between type A botulinum toxins in rat gastrocnemius muscle. Background: New cosmetic applications and products based on the effects of botulinum toxin (BTX) treatment have stimulated demand for this class of natural compounds. This demand generates the need for appropriate standardized protocols to test and compare the effectiveness of new BTX preparations.Objectives: Based on the previously described electrophysiological methods, we measured and compared the inhibitory effects of two BTX type A (BTX-A) preparations on neuromuscular transmission through split-body test.Methods: The effectiveness was evaluated in terms of the compound muscle action potential (CMAP) and conduction velocity after BTX-A injection. We used a split-body method to compare two different BTX-As in the rat.Results: Based on the changes in the CMAP, the two different BTX-As induced paralytic effect on the rat tibialis anterior muscle. However, the two different BTX-A preparations did not differ significantly in effectiveness and did not induce a delay in conduction velocity.Conclusions: The new BTX-A preparation used in this electrophysiological study had similar effect compared with the previously marketed BTX-A.[AQ: Please approve the edits made to the sentence "The new BTX-A preparation…") We propose that a split-body electrophysiological protocol will be useful in establishing the comparative effectiveness of new BTX products. 23444783 Effects of insulin-like growth factor-1 on neurochemical phenotypes of cultured dorsal root ganglion neurons with excitotoxicity induced by glutamate. Insulin-like growth factor-1 (IGF-1) is a neurotrophic factor and plays an important role in promoting axonal growth from dorsal root ganglion (DRG) neurons. The neuropeptide- and neurofilament (NF)-immunoreactive (IR) neurons are two major phenotypical classes in DRG. Whether IGF-1 affects neurochemical phenotypes of DRG neurons remains unknown. In the present study, primary cultured DRG neurons were used to determine the effects of IGF-1 on neurochemical phenotypes of the neurons with excitotoxicity induced by glutamate (Glu). DRG neurons were dissociated and cultured for 48 hours and then exposed to IGF-1 (20 nmol/L), Glu (0.2 mmol/L), Glu (0.2 mmol/L) plus IGF-1 (20 nmol/L) for additional 24 hours. The DRG neurons were continuously exposed to culture media as control. After that, all above cultured DRG neurons were processed for detecting mRNA levels of calcitonin gene-related peptide (CGRP) and neurofilament-200 (NF-200) by real time-PCR analysis. CGRP and NF-200 expression in situ was determined by fluorescent labeling technique. The results showed that CGRP mRNA, but not NF-200 mRNA, increased after IGF-1 administration in the absence or presence of Glu. IGF-1 could increase the percentage of CGRP-expressing neurons, but not NF-200-expressing neurons, in the absence or presence of Glu. The ability of IGF-1 on CGRP expression may play a role in neurogenic inflammation or nociception. 23409925 Multifunctional carboxymethyl cellulose-based magnetic nanovector as a theragnostic system for folate receptor targeted chemotherapy, imaging, and hyperthermia against cancer. A multifunctional biocompatible nanovector based on magnetic nanoparticle and carboxymethyl cellulose (CMC) was developed. The nanoparticles have been characterized using TEM, SEM, DLS, FT-IR spectra, VSM, and TGA studies. We found that the synthesized carboxymethyl cellulose magnetic nanoparticles (CMC MNPs) were spherical in shape with an average size of 150 nm having low aggregation and superparamagnetic properties. We found that the folate-tagged CMC MNPs were delivered to cancer cells by a folate-receptor-mediated endocytosis mechanism. 5-FU was encapsulated as a model drug for delivering cytotoxicity, and we could demonstrate the sustained release of 5-FU. It was also observed that the FITC-labeled CMC MNPs could effectively enter cells, and the fate of nanoparticles was tracked with Lysotracker. The CMC MNPs could induce significant cell death when an alternating magnetic field was applied. These results indicate that the multifunctional CMC MNPs possess a high drug loading efficiency and high biocompatibility and with low cell cytotoxicity and can be considered to be promising candidates for CMC-based targeted drug delivery, cellular imaging, and magnetic hyperthermia (MHT). 23584545 Synthesis and in vitro antiproliferative effect of novel quinoline-based potential anticancer agents. Several derivatives with a quinoline scaffold and a flexible, semi-flexible or rigid side chains at position 8 of the quinoline ring were synthesized and assessed for their in vitro activity versus the human colon cancer cell line HT29 and the human breast cancer cell line MDA-MB231. The HT29 cell line was more refractory to the cytotoxic activity of some compounds, meanwhile all the quinoline derivatives except one displayed high to moderate activity against MDA-MB231 with IC50 values ranging between 4.6 and 48.2 μM. The most active derivative in this study against both tested cell lines was the Schiff's base 4e with IC50 of 4.7 and 4.6 μM against HT29 and MDA-MB231, respectively. 23421737 Novel microbial transformation of desacetylcinobufagin by Fusarium avenaceum AS 3.4594. In this paper, the microbial transformation of desacetylcinobufagin (1) by Fusarium avenaceum AS 3.4594 was investigated, and four metabolites were isolated and characterized as 3-keton-desacetylcinobufagin (2), 3-epi-desacetylcinobufagin (3), bufadienolide A (4), and 15β,16α-dihydroxyl-17βH-bufalin (5), respectively. Among them, 4 and 5 are new compounds. The cytotoxicities of transformed products (2-5) against Hela cells were also investigated. 23343200 Physically-motivated force fields from symmetry-adapted perturbation theory. We present a general methodology for generating accurate and transferable ab initio force fields, employing the framework of symmetry adapted perturbation theory (SAPT). The resulting force fields are "physically-motivated" in that they contain separate, explicit terms to account for the various fundamental intermolecular interactions, such as exchange, electrostatics, induction, and dispersion, with each term parametrized to a corresponding term in the SAPT energy decomposition. Crucially, the resulting force fields are largely compatible with existing, standard simulation packages, requiring only minimal modifications. We present several novel parametrization techniques that yield robust, physically meaningful atomic parameters that are transferable between molecular environments. We demonstrate the accuracy and generality of our method by validating against experimental second virial coefficients for a variety of small molecules. We then show that the resulting atomic parameters can be combined using physically motivated ansatzes to accurately predict arbitrary heteromolecular interaction energies, with example applications including prediction of gas adsorption in functionalized metal-organic framework materials. 23336368 Separation and structure elucidation of a new homoflavanol derivative from Pteridium aquilinum (L.) Kuhn. A novel homoflavanol derivative (1) with an unprecedented skeleton, as well as two known flavonoids kaempferol (2) and quercetin (3), was isolated from the plant Pteridium aquilinum (L.) Kuhn, and the structure and relative stereochemistry of the new compound (1) were elucidated on the basis of spectroscopic data. 23549673 Long-term Effects of Perinatal Androgenization on Reproductive Parameters of Male Rat Offspring Androgenization and Male Rat Reproduction. It is known that during sex differentiation, fetal androgens are critical determinants of the male phenotype. Although testosterone is necessary for normal development of male sexual behavior, perinatal androgen treatment can result in disruption of normal male sexual reproduction. Pregnant Wistar rats were administered either corn oil (vehicle) or testosterone propionate at 0.2 mg/kg from gestational day 12 until the end of lactation and the reproductive function of male offspring was evaluated at 90 (adulthood) and 270 (middle age) days of age. Perinatal androgenization in the rat provoked a reduction in sperm production and reserves in adulthood that did not affect fertility and did not persist at more advanced ages, as shown by the results at post-natal day 270. If perinatal androgenization promotes similar effects in humans of reproductive age, the results of the present work can impact male reproduction health, given the less efficient spermatogenesis and lower sperm reserves in the human epididymis, compared to rodents. 22693035 Angiotensin-Converting Enzyme Inhibitory Activity and Antioxidant Properties of Nepeta crassifolia Boiss & Buhse and Nepeta binaludensis Jamzad. This article reports phytochemical and biological studies on Nepeta binaludensis and Nepeta crassifolia. Both species were investigated for their angiotensin-converting enzyme (ACE) inhibitory activity and antioxidant properties through three in vitro models [2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) and ferric reducing antioxidant power (FRAP) assay]. Aerial parts were extracted with methanol and partitioned between water and subsequently n-hexane, ethyl acetate and n-butanol. N. binaludensis methanol extract exerted significantly higher reducing power (1.9 μM Fe(II)/g) than did the positive control butylhydroxytoluene (63.2 μM Fe(II)/g) in FRAP assay. The highest DPPH radical scavenging activity was found for N. crassifolia, with IC50 values of 9.6 and 12.1 µg/mL for ethyl acetate and n-butanol fractions, respectively. n-Butanol fraction of both species showed the highest ACE inhibitory activity, with IC50 values of 59.3 and 81.7 µg/mL for N. binaludensis and N. crassifolia, respectively. Phytochemical investigations resulted in the isolation of ursolic acid, oleanolic acid, apigenin, luteolin and ixoroside. Apigenin-7-O-glucoside, 8-hydroxycirsimaritin and cirsimaritin were furthermore identified in N. crassifolia ethyl acetate-soluble fraction. Nepetanudoside B was isolated from the n-butanol fraction of N. binaludensis. Copyright © 2012 John Wiley & Sons, Ltd. 23603059 Arsenic upregulates the expression of angiotensin II Type I receptor in mouse aortic endothelial cells. Although chronic arsenic exposure is a well-known risk for cardiovascular disease and has a strong correlation with hypertension, the molecular pathogenesis underlying arsenic exposure-induced hypertension remains poorly understood. To delineate the pathogenesis, we examined changes in the mRNA levels of 2 angiotensin II Type I receptor (AT1R) subtypes, AT1AR and AT1BR, in a mouse aortic endothelial cell line, END-D. Quantitative real-time PCR analysis revealed significant increases in the mRNA levels of 2 AT1R subtypes, AT1AR and AT1BR following sodium arsenite (SA) treatment. Flow cytometry analysis revealed that SA increases the generation of reactive oxygen species (ROS) in a dose-dependent manner. In addition, western blot analysis revealed that SA enhances the phosphorylations of c-Jun N-terminal kinases (JNK) and activated protein 1 (AP-1). These phosphorylations were inhibited by N-acetylcysteine (NAC), an anti-oxidant. Finally, SA-induced AT1R expression was found to be prevented both by NAC and specific JNK inhibitor, SP6001325, strongly indicating that AT1R upregulation is a result of the ROS-mediated activation of the JNK signaling pathway. Taken together, our results indicate that arsenic indeed upregulates the AT1R expression, thus highlighting a role of arsenic-induced aberrant AT1R signaling in the pathogenesis of hypertension. 23565574 Applicability of a Blood-Brain Barrier Specific Artificial Membrane Permeability Assay at the Early Stage of Natural Product-Based CNS Drug Discovery. While numerous natural products (NPs) possess activity on central nervous system (CNS) targets, there has been no analytical approach to effectively identify compounds with high brain penetration potential in complex mixtures at the early stage of drug discovery. To overcome this issue, the performance of an in vitro parallel artificial membrane permeability assay for the blood-brain barrier (PAMPA-BBB) for natural products and for plant extracts has been validated and characterized. It was found that the PAMPA-BBB assay preserves its predictive power in the case of natural products and provides high phytochemical selectivity, which enables its use as a unique filtering tool in terms of selecting brain-penetrable compounds from plant extracts. Moreover, the present study has demonstrated that simple modifications in the assay design allow the direct use of PAMPA-BBB filtered samples in a dereplication process, as performed by NMR and LC-MS. The applicability of this procedure was demonstrated using extracts prepared from Tanacetum parthenium, Vinca major, Salvia officinalis, and Corydalis cava, representing different types of chemical diversity and complexity. Thus, the proposed protocol represents a potentially valuable strategy in the NP-based CNS drug discovery environment with a high-throughput screening platform. 23561076 Blueberry estimated harvest from seven new cultivars: Fruit and anthocyanins. This study compares the yields, weights and anthocyanin contents of fruit from a group of seven new cultivars released from the New Zealand blueberry breeding programme and selected for the longest possible combined harvest season. The measured factors were primarily influenced by cultivar, and seasonal variations had relatively minor effects. The late-ripening cultivars 'Velluto Blue' and 'Centra Blue' had the highest fruit yields, anthocyanin contents and estimated total anthocyanin harvestable from a given area. 'Blue Moon' and 'Sky Blue' had the largest fruit sizes. The early-ripening cultivars 'Blue Bayou', 'Blue Moon' and 'Sunset Blue' had the lowest anthocyanin contents. The yield, fruit size and total anthocyanin content results obtained from any single year were highly correlated with the average of the three years, which makes pursuing the evaluation for these traits from a single year and at an early stage of plant development a practical proposition. 23563178 Myeloid cell RelA/p65 promotes lung cancer proliferation through Wnt/β-catenin signaling in murine and human tumor cells. Smoking is the most important risk factor for both lung cancer (LC) and chronic obstructive pulmonary disease. The aim of this study was to investigate the role of myeloid cell nuclear factor-κB in the regulation of tumor cell growth signaling. We subjected mice lacking myeloid RelA/p65 (rela(Δ-/-)) to a metastatic LC model. Cigarette smoke (CS) exposure significantly increased the proliferation of Lewis lung carcinoma cell tumors in wild-type mice. In CS-exposed rela(Δ-/-) mice, the tumor growth was largely inhibited. Transcriptome and pathway analysis of cancer tissue revealed a fundamental impact of myeloid cells on various growth signaling pathways, including the Wnt/β-catenin pathway. In conclusion, myeloid RelA/p65 is necessary to link smoke-induced inflammation with LC growth and has a role in the activation of Wnt/β-catenin signaling in tumor cells.Oncogene advance online publication, 8 April 2013; doi:10.1038/onc.2013.75. 23639423 Gene flow vs. pollution pressure: Genetic diversity of Mytilus galloprovincialis in eastern Adriatic. Environmental pollution may modify all the evolutionary processes involved in shaping the genetic patterns of exposed populations. In order to evaluate the pollution impact on the genetic diversity of Mediterranean mussel Mytilus galloprovincialis ten populations inhabiting differently polluted sites along the eastern Adriatic coast, from pristine bays to heavily trafficked harbours, were studied. Pollution pressure was assessed through an integrated study of biological effects and responses across different levels of biological organization. Eight microsatellite markers were analysed to assess genetic diversity of investigated populations. Both the principal component analysis (PCA) of the biomarker data set as well as the biomarker response index (BRI) confirmed substantial pollution pressure at the highly polluted sites, and very low pollution exposure at the three reference sites. Very shallow genetic differentiation was found in respect to maritime distances or pollution status, and this was attributed to a high gene flow among the populations. However, populations inhabiting polluted sites exhibited higher levels of genetic diversity and evolutionary mechanisms underlying this phenomenon are discussed. 23603380 Piperidine, pyridine alkaloid inhibition of fetal movement in a day 40 pregnant goat model. Inhibition of fetal movement is one mechanism behind the development of multiple congenital contracture-type defects in developing fetuses of humans and animals. We tested the alkaloids anabasine, lobeline, and myosmine for agonist actions, and sensitivity to alpha conotoxins EI and GI blockade at fetal muscle-type nicotinic acetylcholine receptors (nAChR) expressed by TE-671 cells. We also determined if the alkaloids decreased fetal movement in an IV dosed, day 40 pregnant goat model. In TE-671 cells, all three alkaloids elicited concentration-dependent changes in membrane potential sensing dye fluorescence. 1.0μM alpha conotoxin GI shifted the concentration-effect curves of anabasine and myosmine to the right, and decreased maximal responses. Neither of the conotoxins blocked the actions of lobeline in TE-671 cells. In the day 40 pregnant goats, 0.8mg/kg anabasine abolished fetal movement at 30 and 60min after dosing and fetal movement was reduced by lobeline and myosmine. The blockade of anabasine and myosmine actions in TE-671 cells by alpha conotoxin GI indicates that they are agonists at fetal muscle-type nAChR. All three alkaloids did significantly decrease fetal movement in the day 40 pregnant goat model suggesting a potential for these alkaloids to cause multiple congenital contracture-type defects in developing fetuses. 23612423 Gastroprotective mechanism of Bauhinia thonningii Schum. ETHNOPHARMACOLOGICAL RELEVANCE: Bauhinia thonningii Schum. (Cesalpiniaceae) is locally known as Tambarib and used to treat various diseases including gastric ulcer. AIM OF THE STUDY: The current study aims to evaluate the gastroprotecive mechanism(s) of methanolic (MEBT) and chloroform (CEBT) extracts of Bauhinia thonningii leaves on ethanol-induced gastric ulceration. MATERIALS AND METHODS: Gastric acidity, quantification and histochemistry of mucus, gross and microscopic examination, nitric oxide, lipid peroxidation, 2D gel electrophoresis, mass spectroscopy and biochemical tests were utilized to assess the mechanism(s) underlying the gastroprotective effects of MEBT and CEBT. Effect of these extracts into lipopolysaccharide/interferon-γ stimulated rodent cells were done in vitro. In vitro and in vivo toxicity studies were also conducted. Antioxidant activities of MEBT and CEBT were examined using DPPH, FRAP and ORAC assays. Phytochemical analyses of MEBT and CEBT were conducted using chemical and spectroscopic methods. RESULTS: Gross and histological features confirmed the anti-ulcerogenic properties of Bauhinia thonningii. Gastroprotective mechanism of MEBT was observed to be mediated through the modulation of PAS-reactive substances, MDA and proteomics biomarkers (creatine kinase, malate dehydrogenase, ATP synthase, actin and thioredoxin). MEBT and CEBT showed no significant in vitro and in vivo effects on nitric oxide. Methanolic extract (MEBT) showed superior gastroprotective effects, polyphenolic content and antioxidant activities compared to CEBT. The plant extracts showed no in vitro or in vivo toxicity. CONCLUSION: It could be concluded that MEBT possesses anti-ulcer activity, which could be attributed to the inhibition of ethanol-induced oxidative damage and the intervention in proteomic pathways but not the nitric oxide pathway. 23022398 NMDA receptor blockade impairs the muscarinic conversion of sub-threshold transient depression into long-lasting LTD in the hippocampus-prefrontal cortex pathway in vivo: correlation with gamma oscillations. Cholinergic fibers from the brainstem and basal forebrain innervate the medial prefrontal cortex (mPFC) modulating neuronal activity and synaptic plasticity responses to hippocampal inputs. Here, we investigated the muscarinic and glutamatergic modulation of long-term depression (LTD) in the intact projections from CA1 to mPFC in vivo. Cortical-evoked responses were recorded in urethane-anesthetized rats for 30 min during baseline and 4 h following LTD. In order to test the potentiating effects of pilocarpine (PILO), independent groups of rats received either a microinjection of PILO (40 nmol; i.c.v.) or vehicle, immediately before or 20 min after a sub-threshold LTD protocol (600 pulses, 1 Hz; LFS600). Other groups received either an infusion of the selective NMDA receptor antagonist (AP7; 10 nmol; intra-mPFC) or vehicle, 10 min prior to PILO preceding LFS600, or prior to a supra-threshold LTD protocol (900 pulses, 1 Hz; LFS900). Our results show that PILO converts a transient cortical depression induced by LFS600 into a robust LTD, stable for at least 4 h. When applied after LFS600, PILO does not change either mPFC basal neurotransmission or late LTD. Our data also indicate that NMDA receptor pre-activation is essential to the muscarinic enhancement of mPFC synaptic depression, since AP7 microinjection into the mPFC blocked the conversion of transient depression into long-lasting LTD produced by PILO. In addition, AP7 effectively blocked the long-lasting LTD induced by LFS900. Therefore, our findings suggest that the glutamatergic co-activation of prefrontal neurons is important for the effects of PILO on mPFC synaptic depression, which could play an important role in the control of executive and emotional functions. 23200778 Selective induction of glutathione S-transferases in round spermatids from the Brown-Norway rat by the chemotherapeutic regimen for testicular cancer. Chemotherapeutic drugs can affect DNA in male germ cells, thereby impacting on the integrity of the genome transmitted to offspring. Drug metabolizing enzymes can protect cells from xenobiotic insult. We analyzed the expression pattern of such enzymes in isolated round spermatids from rats exposed to drugs used to treat testicular cancer: bleomycin, etoposide, and cisplatin (BEP). The number of isozymes expressed and the overall relative expression values were highest for the glutathione S-transferases (GSTs). Moreover, BEP treatment significantly increased the expression of 8 GSTs and 3 aldehyde dehydrogenases. Increased expression of GST isozymes was confirmed by qRT-PCR and Western blot analysis. Although Gst genes can be targets for epigenetic modifications, promoter DNA methylation was not affected by BEP treatment. As GSTs are involved in drug resistance mechanisms, we hypothesize that BEP induction of GST expression may lead to the survival of damaged germ cells and the production of abnormal sperm. 23252848 Antiproliferative withanolides from Datura wrightii. A new withanolide, named withawrightolide (1), and four known withanolides (2-5) were isolated from the aerial parts of Datura wrightii. The structure of compound 1 was elucidated through 2D NMR and other spectroscopic techniques. In addition, the structure of withametelin L (2) was confirmed by X-ray crystallographic analysis. Using MTS viability assays, withanolides 1-5 showed antiproliferative activities against human glioblastoma (U251 and U87), head and neck squamous cell carcinoma (MDA-1986), and normal fetal lung fibroblast (MRC-5) cells with IC50 values in the range between 0.56 and 5.6 μM. 23537321 Spray drying method for large-scale and high-performance silicon negative electrodes in li-ion batteries. Nanostructured silicon electrodes have shown great potential as lithium ion battery anodes because they can address capacity fading mechanisms originating from large volume changes of silicon alloys while delivering extraordinarily large gravimetric capacities. Nonetheless, synthesis of well-defined silicon nanostructures in an industrially adaptable scale still remains as a challenge. Herein, we adopt an industrially established spray drying process to enable scalable synthesis of silicon-carbon composite particles in which silicon nanoparticles are embedded in porous carbon particles. The void space existing in the porous carbon accommodates the volume expansion of silicon and thus addresses the chronic fading mechanisms of silicon anodes. The composite electrodes exhibit excellent electrochemical performance, such as 1956 mAh/g at 0.05C rate and 91% capacity retention after 150 cycles. Moreover, the spray drying method requires only 2 s for the formation of each particle and allows a production capability of ∼10 g/h even with an ultrasonic-based lab-scale equipment. This investigation suggests that established industrial processes could be adaptable to the production of battery active materials that require sophisticated nanostructures as well as large quantity syntheses. 23381974 Graded doping for enhanced colloidal quantum dot photovoltaics. A novel approach to improving all-inorganic colloidal quantum dot (CQD) homojunction solar cells by engineering the doping spatial profile to produce a doping gradient within the n-type absorber is presented. The doping gradient greatly improves carrier collection and enhances the voltages attainable by the device, leading to a 1 power point power conversion efficiency (PCE) improvement over previous inorganic CQD solar cells. 23241354 Biomolecular Interactions of small-molecule inhibitors affecting the YopH protein tyrosine phosphatase. We have developed competitive and direct binding methods to examine small-molecule inhibitors of protein tyrosine phosphatase activity. Focusing on the Yersinia pestis outer protein H, a potent bacterial protein tyrosine phosphatase, we describe how an understanding of the kinetic interactions involving Yersinia pestis outer protein H, peptide substrates, and small-molecule inhibitors of protein tyrosine phosphatase activity can be beneficial for inhibitor screening, and we further translate these results into a microarray assay for high-throughput screening. 23429911 Molecular mechanism regulating 24-hour rhythm of dopamine d3 receptor expression in mouse ventral striatum. The dopamine D3 receptor (DRD3) in the ventral striatum is thought to influence motivation and motor functions. Although the expression of DRD3 in the ventral striatum has been shown to exhibit 24-hour variations, the mechanisms underlying the variation remain obscure. Here, we demonstrated that molecular components of the circadian clock act as regulators that control the 24-hour variation in the expression of DRD3. The transcription of DRD3 was enhanced by the retinoic acid-related orphan receptor α (RORα), and its activation was inhibited by the orphan receptor REV-ERBα, an endogenous antagonist of RORα. The serum or dexamethasone-induced oscillation in the expression of DRD3 in cells was abrogated by the downregulation or overexpression of REV-ERBα, suggesting that REV-ERBα functions as a regulator of DRD3 oscillations in the cellular autonomous clock. Chromatin immunoprecipitation assays of the DRD3 promoter indicated that the binding of the REV-ERBα protein to the DRD3 promoter increased in the early dark phase. DRD3 protein expression varied with higher levels during the dark phase. Moreover, the effects of the DRD3 agonist 7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT)-induced locomotor hypoactivity were significantly increased when DRD3 proteins were abundant. These results suggest that RORα and REV-ERBα consist of a reciprocating mechanism wherein RORα upregulates the expression of DRD3, whereas REV-ERBα periodically suppresses the expression at the time of day when REV-ERBα is abundant. Our present findings revealed that a molecular link between the circadian clock and the function of DRD3 in the ventral striatum acts as a modulator of the pharmacological actions of DRD3 agonists/antagonists. 23117149 The relationship between bone marrow characteristics and the clinical prognosis of antithyroid drug-induced agranulocytosis. This study is aimed to explore the relationship between bone marrow characteristics and clinical prognosis of antithyroid drug (ATD) induced agranulocytosis. A retrospective study was conducted in the first affiliated hospital of the University of South China. A total of 33 hospitalized patients diagnosed with ATD-induced agranulocytosis were analyzed. The bone marrow characteristics were classified into two types. Type I was characterized by reduction or absence of granulocytic precursors and type II was recognized as hypercellular bone marrow with dysmaturity of granulocytic cells. Bone marrow of 20 cases (61%) were characterized with type I whereas 13 cases (39%) with type II. The median duration of neutrophil recovery and high-grade fever were 4.7 ± 1.0 days and 3.6 ± 2.5 days respectively for type II, compared to 8.0 ± 2.8 days and 8.6 ± 3.1 days for type I (p < 0.01 in both compared groups). However, there was no significant difference between the two types in terms of age, median duration of drug administration before the diagnosis of agranulocytosis, the amount of neutrophil count on admission and the total administration dose of granulocyte-colony stimulating factor (G-CSF) before bone marrow examination. Two cases of type I died of complications from infection. This study showed that the bone marrow characteristics of ATD-induced agranulocytosis could be classifed into two types. Also, the clinical prognosis was closely related to the bone marrow features. Type I is the dominant type which is usually associated with worse clinical prognosis compared to type II. 23219696 Do mollusks use vertebrate sex steroids as reproductive hormones? II. Critical review of the evidence that steroids have biological effects. In assessing the evidence as to whether vertebrate sex steroids (e.g. testosterone, estradiol, progesterone) have hormonal actions in mollusks, ca. 85% of research papers report at least one biological effect; and 18 out of 21 review papers (published between 1970 and 2012) express a positive view. However, just under half of the research studies can be rejected on the grounds that they did not actually test steroids, but compounds or mixtures that were only presumed to behave as steroids (or modulators of steroids) on the basis of their effects in vertebrates (e.g. Bisphenol-A, nonylphenol and sewage treatment effluents). Of the remaining 55 papers, some can be criticized for having no statistical analysis; some for using only a single dose of steroid; others for having irregular dose-response curves; 40 out of the 55 for not replicating the treatments; and 50 out of 55 for having no within-study repetition. Furthermore, most studies had very low effect sizes in comparison to fish-based bioassays for steroids (i.e. they had a very weak 'signal-to-noise' ratio). When these facts are combined with the fact that none of the studies were conducted with rigorous randomization or 'blinding' procedures (implying the possibility of 'operator bias') one must conclude that there is no indisputable bioassay evidence that vertebrate sex steroids have endocrinological or reproductive roles in mollusks. The only observation that has been independently validated is the ability of estradiol to trigger rapid (1-5 min) lysosomal membrane breakdown in hemocytes of Mytilus spp. This is a typical 'inflammatory' response, however, and is not proof that estradiol is a hormone - especially when taken in conjunction with the evidence (discussed in a previous review) that mollusks have neither the enzymes necessary to synthesize vertebrate steroids nor nuclear receptors with which to respond to them. 23391387 Horizontal gene transfer: linking sex and cell fate. Integrative conjugative elements (ICEs) enable horizontal gene transfer among bacteria. In Pseudomonas, only a phenotypically distinct subpopulation of ICE-bearing cells can mobilize ICE DNA to new hosts. Transfer competence is a terminal state; division is limited, and many cells lyse. 23457119 [18F]FDG-PET as an Imaging Biomarker to NMDA Receptor Antagonist-Induced Neurotoxicity. Positron emission tomography (PET) is an effective tool for noninvasive examination of the body and provides a range of functional information. PET imaging with [(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG) has been used to image alterations in glucose metabolism in brain or cancer tissue in the field of clinical diagnosis but not in the field of toxicology. A single dose of N-methyl-d-aspartate (NMDA) receptor antagonist induces neuronal cell degeneration/death in the rat retrosplenial/posterior cingulate (RS/PC) cortex region. These antagonists also increase local cerebral glucose utilization. Here, we examined the potential of [(18)F]FDG-PET as an imaging biomarker of neurotoxicity induced by an NMDA receptor antagonist, MK-801. Using [(18)F]FDG-PET, we determined that increased glucose utilization involved the neurotoxicity induced by MK-801. The accumulation of [(18)F]FDG was increased in the rat RS/PC cortex region showing neuronal cell degeneration/death and detected before the onset of neuronal cell death. This effect increased at a dose level at which neuronal cell degeneration recovered 24h after MK-801 administration. Scopolamine prevented the neurotoxicity and [(18)F]FDG accumulation induced by MK-801. Furthermore, in cynomolgus monkeys that showed no neuronal cell degeneration/death when treated with MK-801, we noted no differences in [(18)F]FDG accumulation between test and control subjects in any region of the brain. These findings suggest that [(18)F]FDG-PET, which is available for clinical trials, may be useful in generating a predictive imaging biomarker for detecting neurotoxicity against NMDA receptor antagonists with the same pharmacological activity as MK-801. 23249745 Antibiotics that bind to the A site of the large ribosomal subunit can induce mRNA translocation. In the absence of elongation factor EF-G, ribosomes undergo spontaneous, thermally driven fluctuation between the pre-translocation (classical) and intermediate (hybrid) states of translocation. These fluctuations do not result in productive mRNA translocation. Extending previous findings that the antibiotic sparsomycin induces translocation, we identify additional peptidyl transferase inhibitors that trigger productive mRNA translocation. We find that antibiotics that bind the peptidyl transferase A site induce mRNA translocation, whereas those that do not occupy the A site fail to induce translocation. Using single-molecule FRET, we show that translocation-inducing antibiotics do not accelerate intersubunit rotation, but act solely by converting the intrinsic, thermally driven dynamics of the ribosome into translocation. Our results support the idea that the ribosome is a Brownian ratchet machine, whose intrinsic dynamics can be rectified into unidirectional translocation by ligand binding. 23583454 Substituted methcathinones differ in transporter and receptor interactions. The use of synthetic methcathinones, components of "bath salts," is a world-wide health concern. These compounds, structurally similar to methamphetamine (METH) and 3,4-methylendioxymethamphetamine (MDMA), cause tachycardia, hallucinations and psychosis. We hypothesized that these potentially neurotoxic and abused compounds display differences in their transporter and receptor interactions as compared to amphetamine counterparts. 3,4-Methylenedioxypyrovalerone and naphyrone had high affinity for radioligand binding sites on recombinant human dopamine (hDAT), serotonin (hSERT) and norepinephrine (hNET) transporters, potently inhibited [(3)H]neurotransmitter uptake, and, like cocaine, did not induce transporter-mediated release. Butylone was a lower affinity uptake inhibitor. In contrast, 4-fluoromethcathinone, mephedrone and methylone had higher inhibitory potency at uptake compared to binding and generally induced release of preloaded [(3)H]neurotransmitter from hDAT, hSERT and hNET (highest potency at hNET), and thus are transporter substrates, similar to METH and MDMA. At hNET, 4-fluoromethcathinone was a more efficacious releaser than METH. These substituted methcathinones had low uptake inhibitory potency and low efficacy at inducing release via human vesicular monoamine transporters (hVMAT2). These compounds were low potency (1) h5-HT1A receptor partial agonists, (2) h5-HT2A receptor antagonists, (3) weak h5-HT2C receptor antagonists. This is the first report on aspects of substituted methcathinone efficacies at serotonin (5-HT) receptors and in superfusion release assays. Additionally, the drugs had no affinity for dopamine receptors, and high-nanomolar to mid-micromolar affinity for hSigma1 receptors. Thus, direct interactions with hVMAT2 and serotonin, dopamine, and hSigma1 receptors may not explain psychoactive effects. The primary mechanisms of action may be as inhibitors or substrates of DAT, SERT and NET. 23589624 Cell-free co-production of an orthogonal transfer RNA activates efficient site-specific non-natural amino acid incorporation. We describe a new cell-free protein synthesis (CFPS) method for site-specific incorporation of non-natural amino acids (nnAAs) into proteins in which the orthogonal tRNA (o-tRNA) and the modified protein (i.e. the protein containing the nnAA) are produced simultaneously. Using this method, 0.9-1.7 mg/ml of modified soluble super-folder green fluorescent protein (sfGFP) containing either p-azido-l-phenylalanine (pAzF) or p-propargyloxy-l-phenylalanine (pPaF) accumulated in the CFPS solutions; these yields correspond to 50-88% suppression efficiency. The o-tRNA can be transcribed either from a linearized plasmid or from a crude PCR product. Comparison of two different o-tRNAs suggests that the new platform is not limited by Ef-Tu recognition of the acylated o-tRNA at sufficiently high o-tRNA template concentrations. Analysis of nnAA incorporation across 12 different sites in sfGFP suggests that modified protein yields and suppression efficiencies (i.e. the position effect) do not correlate with any of the reported trends. Sites that were ineffectively suppressed with the original o-tRNA were better suppressed with an optimized o-tRNA (o-tRNA(opt)) that was evolved to be better recognized by Ef-Tu. This new platform can also be used to screen scissile ribozymes for improved catalysis. 23092237 Pump-Probe Microscopy: Spatially Resolved Carrier Dynamics in ZnO Rods and the Influence of Optical Cavity Resonator Modes. Femtosecond pump-probe microscopy is used to investigate the charge recombination dynamics at different points within a single needle-shaped ZnO rod. Recombination in the tips of the rod occurs through an excitonic or electron-hole plasma state, taking place on a picosecond time scale. Photoexcitation in the larger diameter sections of the interior exhibit dramatically slower recombination that occurs primarily through defects sites, i.e., trap mediated recombination. Transient absorption imaging shows that the spatial variation in the dynamics is also influenced by the cavity resonances supported within the hexagonal cross section of the rod. Finite element simulations suggest that these optical resonator modes produce qualitatively different intensity patterns in the two different locations. Near the end of the rod, the intensity pattern has significant standing-wave character, which leads to the creation of photoexcited carriers in the core of the structure. The larger diameter regions, on the other hand, exhibit intensity distributions in which the whispering gallery (WG) mode character dominates. At these locations, the photoexcited carriers are produced in subsurface depletion zone, where the internal fields separate the electrons and holes and lead to a greater degree of trap recombination on longer time scales. 23265296 Block copolymer modified surfaces for conjugation of biomacromolecules with control of quantity and activity. Polymer brush layers based on block copolymers of poly(oligo(ethylene glycol) methacrylate) (POEGMA) and poly(glycidyl methacrylate) (PGMA) were formed on silicon wafers by activators generated by electron transfer atom transfer radical polymerization (AGET ATRP). Different types of biomolecule can be conjugated to these brush layers by reaction of PGMA epoxide groups with amino groups in the biomolecule, while POEGMA, which resists nonspecific protein adsorption, provides an antifouling environment. Surfaces were characterized by water contact angle, ellipsometry, and Fourier transform infrared spectroscopy (FTIR) to confirm the modification reactions. Phase segregation of the copolymer blocks in the layers was observed by AFM. The effect of surface properties on protein conjugation was investigated using radiolabeling methods. It was shown that surfaces with POEGMA layers were protein resistant, while the quantity of protein conjugated to the diblock copolymer modified surfaces increased with increasing PGMA layer thickness. The activity of lysozyme conjugated on the surface could also be controlled by varying the thickness of the copolymer layer. When biotin was conjugated to the block copolymer grafts, the surface remained resistant to nonspecific protein adsorption but showed specific binding of avidin. These properties, that is, well-controlled quantity and activity of conjugated biomolecules and specificity of interaction with target biomolecules may be exploited for the improvement of signal-to-noise ratio in sensor applications. More generally, such surfaces may be useful as biological recognition elements of high specificity for functional biomaterials. 23619613 Soluble polysialylated NCAM: a novel player of the innate immune system in the lung. Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of polysialylated NCAM (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, polySia was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased polySia levels and processing of the NCAM carrier were observed. Processing of polysialylated NCAM was reproduced in a mouse model by bleomycin administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, polySia chains of secreted NCAM neutralized the cytotoxic activity of extracellular histones as well as DNA/histone-network-containing "neutrophil extracellular traps", which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes. 22989704 Efficacy of all-trans retinoid acid in preventing nickel induced cardiotoxicity in myocardial cells of rats. Nickel, a metal commonly found in battery plants and welding factories, has potential cardiotoxicity, while all-trans retinoid acid (atRA) can promote cardiovascular repair and myocardial recovery. The purpose of this study was to investigate whether atRA could prevent cardiotoxicity induced by nickel both in vitro and in vivo. In the study, a rat myocardial cell line (H9c2) exposed to different concentrations of nickel chloride (NiCl(2)) displayed apoptotic features accompanied by reactive oxygen species generation. In addition, NiCl(2) also caused obvious apoptosis and systolic dysfunction in primary myocardial cells. Treatment with atRA efficiently attenuated the cytotoxicities triggered by NiCl(2) as it significantly mitigated ROS generation and decreased MAP kinases activity in NiCl(2)-treated cardiomyocytes. Additionally, NiCl(2) exposure caused obvious arrhythmia in Sprague-Dawley rats with the maximum tolerance dose of NiCl(2) between 2 and 3mg/kg. A combinational intragastric administration of 40mg/kg atRA can partially reverse NiCl(2)-induced arrhythmia in rats. Our results suggested that atRA might have therapeutic potential in alleviating the adverse effects of nickel on the cardiovascular system. 22993237 Inference on population histories by approximating infinite alleles diffusion. Reconstruction of the past is an important task of evolutionary biology. It takes place at different points in a hierarchy of molecular variation, including genes, individuals, populations, and species. Statistical inference about population histories has recently received considerable attention, following the development of computational tools to provide tractable approaches to this very challenging problem. Here, we introduce a likelihood-based approach which generalizes a recently developed model for random fluctuations in allele frequencies based on an approximation to the neutral Wright-Fisher diffusion. Our new framework approximates the infinite alleles Wright-Fisher model and uses an implementation with an adaptive Markov chain Monte Carlo algorithm. The method is especially well suited to data sets harboring large population samples and relatively few loci for which other likelihood-based models are currently computationally intractable. Using our model, we reconstruct the global population history of a major human pathogen, Streptococcus pneumoniae. The results illustrate the potential to reach important biological insights to an evolutionary process by a population genetics approach, which can appropriately accommodate very large population samples. 23371303 Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Avibactam (formerly NXL104, AVE1330A) is a synthetic non-β-lactam, β-lactamase inhibitor that inhibits the activities of Ambler class A and C β-lactamases and some Ambler class D enzymes. This review summarizes the existing data published for ceftazidime-avibactam, including relevant chemistry, mechanisms of action and resistance, microbiology, pharmacokinetics, pharmacodynamics, and efficacy and safety data from animal and human trials. Although not a β-lactam, the chemical structure of avibactam closely resembles portions of the cephem bicyclic ring system, and avibactam has been shown to bond covalently to β-lactamases. Very little is known about the potential for avibactam to select for resistance. The addition of avibactam greatly (4-1024-fold minimum inhibitory concentration [MIC] reduction) improves the activity of ceftazidime versus most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzyme(s). Against Pseudomonas aeruginosa, the addition of avibactam also improves the activity of ceftazidime (~fourfold MIC reduction). Limited data suggest that the addition of avibactam does not improve the activity of ceftazidime versus Acinetobacter species or most anaerobic bacteria (exceptions: Bacteroides fragilis, Clostridium perfringens, Prevotella spp. and Porphyromonas spp.). The pharmacokinetics of avibactam follow a two-compartment model and do not appear to be altered by the co-administration of ceftazidime. The maximum plasma drug concentration (C(max)) and area under the plasma concentration-time curve (AUC) of avibactam increase linearly with doses ranging from 50 mg to 2,000 mg. The mean volume of distribution and half-life of 22 L (~0.3 L/kg) and ~2 hours, respectively, are similar to ceftazidime. Like ceftazidime, avibactam is primarily renally excreted, and clearance correlates with creatinine clearance. Pharmacodynamic data suggest that ceftazidime-avibactam is rapidly bactericidal versus β-lactamase-producing Gram-negative bacilli that are not inhibited by ceftazidime alone.Clinical trials to date have reported that ceftazidime-avibactam is as effective as standard carbapenem therapy in complicated intra-abdominal infection and complicated urinary tract infection, including infection caused by cephalosporin-resistant Gram-negative isolates. The safety and tolerability of ceftazidime-avibactam has been reported in three phase I pharmacokinetic studies and two phase II clinical studies. Ceftazidime-avibactam appears to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date.In conclusion, avibactam serves to broaden the spectrum of ceftazidime versus ß-lactamase-producing Gram-negative bacilli. The exact roles for ceftazidime-avibactam will be defined by efficacy and safety data from further clinical trials. Potential future roles for ceftazidime-avibactam include the treatment of suspected or documented infections caused by resistant Gram-negative-bacilli producing extended-spectrum ß-lactamase (ESBL), Klebsiella pneumoniae carbapenemases (KPCs) and/or AmpC ß-lactamases. In addition, ceftazidime-avibactam may be used in combination (with metronidazole) for suspected polymicrobial infections. Finally, the increased activity of ceftazidime-avibactam versus P. aeruginosa may be of clinical benefit in patients with suspected or documented P. aeruginosa infections. 23327993 Thioredoxin-mimetic peptides (TXM) reverse auranofin induced apoptosis and restore insulin secretion in insulinoma cells. The thioredoxin reductase/thioredoxin system (TrxR/Trx1) plays a major role in protecting cells from oxidative stress. Disruption of the TrxR-Trx1 system keeps Trx1 in the oxidized state leading to cell death through activation of the ASK1-Trx1 apoptotic pathway. The potential mechanism and ability of tri- and tetra-oligopeptides derived from the canonical -CxxC- motif of the Trx1-active site to mimic and enhance Trx1 cellular activity was examined. The Trx mimetics peptides (TXM) protected insulinoma INS 832/13 cells from oxidative stress induced by selectively inhibiting TrxR with auranofin (AuF). TXM reversed the AuF-effects preventing apoptosis, and increasing cell-viability. The TXM peptides were effective in inhibiting AuF-induced MAPK, JNK and p38(MAPK) phosphorylation, in correlation with preventing caspase-3 cleavage and thereby PARP-1 dissociation. The ability to form a disulfide-bridge-like conformation was estimated from molecular dynamics simulations. The TXM peptides restored insulin secretion and displayed Trx1 denitrosylase activity. Their potency was 10-100-fold higher than redox reagents like NAC, AD4, or ascorbic acid. Unable to reverse ERK1/2 phosphorylation, TXM-CB3 (NAc-Cys-Pro-Cys amide) appeared to function in part, through inhibiting ASK1-Trx dissociation. These highly effective anti-apoptotic effects of Trx1 mimetic peptides exhibited in INS 832/13 cells could become valuable in treating adverse oxidative-stress related disorders such as diabetes. 23561169 Carotenoids and tocopherols in yellow and red raspberries. The composition of carotenoids, chlorophyll derivatives and tocopherols in raspberries of different varieties, including yellow and red varieties, over different ripening stages has been studied. The profile of pigments in ripening raspberries changes drastically, with a dramatic decrease of β-carotene and chlorophyll derivatives, the xanthophyll lutein has also decreased but not to the same extent. In contrast esterified lutein increased and is present in ripe raspberries esterified with saturated fatty acids with C8-C16 chains. Ripe raspberries contain considerable amounts of free lutein, esterified lutein, and tocopherols (up to 20, 49 and 366mg/kg dry weight, respectively). The different samples analysed show different contents of carotenoids and tocopherols. Whether the differences arise from the variety or other factors such as the environmental conditions needs to be ascertained but isoprenoids should not be neglected when considering raspberry antioxidant and nutraceutical composition. 23264021 Molecular diversity of class 2 integrons in antibiotic-resistant gram-negative bacteria found in wastewater environments in China. The molecular architecture of class 2 integrons among gram-negative bacteria from wastewater environments was investigated in Jinan, China. Out of the 391 antibiotic-resistant bacteria found, 38 isolates harboring class 2 integrons encoding potentially transferrable genes that could confer antibiotic resistance were found. These isolates were classified into 19 REP-PCR types. These strains were identified using 16S rRNA gene sequencing and found to be as follows: Proteus mirabilis (16), Escherichia coli (7), Providencia spp. (7), Proteus spp. (2), P. vulgaris (3), Shigella sp. (1), Citrobacter freundii (1), and Acinetobacter sp. (1). Their class 2 integron cassette arrays were amplified and then either analyzed using PCR-RFLP or sequenced. The typical array dfrA1-sat2-aadA1 was detected in 27 isolates. Six atypical arrays were observed, including three kinds of novel arrangements (linF2(∆attC1)-dfrA1(∆attC2)-aadA1-orf441 or linF2(∆attC1)-dfrA1(∆attC2)-aadA1, dfrA1-catB2-sat2-aadA1, and estX(Vr)-sat2-aadA1) and a hybrid with the 3'CS of class 1 integrons (dfrA1-sat2-aadA1-qacH), and dfrA1-sat1. Twenty-four isolates were also found to carry class 1 integrons with 10 types of gene cassette arrays. Several non-integron-associated antibiotic resistance genes were found, and their transferability was investigated. Results showed that water sources in the Jinan region harbored a diverse community of both typical and atypical class 2 integrons, raising concerns about the overuse of antibiotics and their careless disposal into the environment. 23630043 Synthesis and Characterization of 5-(1,2,4-Triazol-3-yl)tetrazoles with various energetic functionalities. In this contribution the synthesis and full structural as well as spectroscopic characterization of three 5-(1,2,4-triazol-3-yl)tetrazoles along with selected energetic moieties like nitro, nitrimino, and azido groups are presented. The main goal is a comparative study on the influence of those variable energetic moieties on structural and energetic properties. A complete characterization including IR and Raman as well as multinuclear NMR spectroscopy of all compounds is presented. Additionally, X-ray crystallographic measurements were performed and reveal insights into structural characteristics as well as inter- and intramolecular interactions. The standard enthalpies of formation were calculated for all compounds at the CBS-4M level of theory and reveal high positive heats of formation for all compounds. The calculated detonation parameters (using the EXPLO5.05 program) are in the range of 8000 m s(-1) (8097 m s(-1) (5), 8020 m s(-1) (6), 7874 m s(-1) (7)). As expected, the measured impact and friction sensitivities as well as decomposition temperatures strongly depend on the energetic moiety at the triazole ring. The CC connection of a triazole ring with its opportunity to introduce a large variety of energetic moieties and a tetrazole ring, implying a large energy content, leads to the selective synthesis of primary and secondary explosives. 23353815 Involvement of the essential metal transporter Zip14 in hepatic Cd accumulation during inflammation. Upregulation of Zip14 contributes to hepatic zinc (Zn) and non-transferrin-bound iron (Fe) uptake during infection and inflammation. We investigated whether this essential metal transporter is also involved in hepatic cadmium (Cd) uptake under these conditions. An injection of lipopolysaccharide (LPS), turpentine oil (Tur) and n-hexane (Hex) resulted in an decrease in plasma Zn and Fe concentrations to 25-50% and an increase in hepatic concentrations of both metals to 150-200% of control mice. LPS significantly increased plasma interleukin (IL)-6 levels more rapidly than Tur or Hex. Tur or Hex significantly increased hepatic Zip14 mRNA expression and decreased ferroportin 1 mRNA expression following continuous increase of IL-6 level. Hepatic Cd and Zn concentrations increased significantly after repeated injections of Cd in Tur- or Hex-treated mice fed a control diet. Treatment with Tur or Hex additionally increased hepatic Cd accumulation in Zn-deficient mice, unlike in Fe-deficient mice. These results suggest that Zn transporters, such as Zip14, may be involved in hepatic Cd uptake during inflammation. 23556448 Association of a functional FAAH polymorphism with methamphetamine-induced symptoms and dependence in a Malaysian population. Aim: FAAH is a membrane enzyme that terminates the activity of a large class of endogenous signaling lipids. Recent studies suggest that the FAAH Pro129Thr polymorphism is a common mutation in the FAAH gene that is significantly associated with drug-addictive traits. This study investigated the association of the Pro129Thr polymorphism of the FAAH gene with methamphetamine dependence, methamphetamine-induced psychosis, manic episodes and panic disorder in a Malaysian population. Materials & methods: This polymorphism was genotyped in 232 male methamphetamine-dependent subjects and in 241 male controls of four different ethnicities: Malay, Chinese, Kadazan-Dusun and Bajau. Intergroup statistical analyses were performed by using the χ(2)-square test and Fisher's exact test, where necessary. In cases of multiple comparisons, the Bonferroni correction was performed. Results: Our results indicated that the FAAH Pro129Thr polymorphism showed a significant association with risk of methamphetamine dependence in the pooled subjects (odds ratio [OR]: 2.017; p < 0.001) and in the Malay (OR: 2.829; p < 0.001) and Chinese (OR: 3.685; p < 0.001) groups. We also found an association of this polymorphism with episodes of methamphetamine-induced mania in the Malay group (OR: 2.836; p = 0.035). However, there was no association between this polymorphism and age of onset of drug use or the occurrence of methamphetamine-induced psychosis or of panic disorder. Conclusion: Our findings suggest that the FAAH Pro129Thr polymorphism may contribute to methamphetamine dependence in the Malay and Chinese ethnic groups. Original submitted 4 October 2012; Revision submitted 1 February 2013. 23604140 Exploration of the Orthosteric/Allosteric Interface in Human M1 Muscarinic Receptors by Bitopic Fluorescent Ligands. Bitopic binding properties apply to a variety of muscarinic compounds that span and simultaneously bind to both the orthosteric and allosteric receptor sites. We provide evidence that fluorescent pirenzepine derivatives, with the M1 antagonist fused to the Bodipy [558/568] fluorophore via spacers of varying lengths, exhibit orthosteric/allosteric binding properties at muscarinic M1 receptors. This behaviour was inferred from a combination of functional, radioligand and FRET binding experiments, performed under equilibrium and kinetic conditions on EGFP-fused M1 receptors. Though displaying a common orthosteric component, the fluorescent compounds inherit bitopic properties from a linker-guided positioning of their Bodipy moiety within the M1 allosteric vestibule. Depending on linker length, the fluorophore is allowed to reach neighbouring allosteric domains, overlapping or not with the classical gallamine site, but distinct from the allosteric indocarbazolole 'WIN' site. Site-directed mutagenesis, as well as molecular modeling and ligand docking studies based on recently solved muscarinic receptor structures, further support the definition of two groups of Bodipy-pirenzepine derivatives exhibiting distinct allosteric binding poses. Thus, the linker may dictate pharmacological outcomes for bitopic molecules that are hardly predictable from the properties of individual orthosteric and allosteric building blocks. Our findings also demonstrate that the fusion of a fluorophore to an orthosteric ligand is not neutral as it may confer, unless carefully controlled, unexpected properties to the resultant fluorescent tracer. Altogether, this study illustrates the importance of a 'multifacette' experimental approach to unravel and validate bitopic ligand binding mechanisms. 23639069 Parent-only vs. parent-child (family-focused) approaches for weight loss in obese and overweight children: a systematic review and meta-analysis. Families are recommended as the agents of change for weight loss in overweight and obese children; family approaches are more effective than those that focus on the child alone. However, interventions that focus on parents alone have not been summarized. The objective of this review was to assess the effectiveness of interventions that compared a parent-only (PO) condition with a parent-child (PC) condition. Four trials using a similar between-group background approaches to overweight and obese children's weight loss met the inclusion criteria, but only one trial reported sufficient data for meta-analysis. Further information was obtained from authors. Meta-analysis showed no significant difference in z-BMI from baseline to end of treatment between the conditions (three trials) or to end of follow up (two trials). The trials were at risk of bias and no single trial was at lower risk of bias than others. There is an absence of high quality evidence regarding the effect of parent-only interventions for weight loss in children compared to parent-child interventions, but current evidence suggests the need for further investigation. 23034931 Interplay between protein carbonylation and nitrosylation in plants. ROS and reactive nitrogen species (RNS) are key regulators of redox homeostasis in living organisms including plants. As control of redox homeostasis plays a central function in plant biology, redox proteomics could help in characterizing the potential roles played by ROS/RNS-induced posttranslational modification in plant cells. In this review, we focus on two posttranslational modifications: protein carbonylation (a marker of protein oxidation) and protein S-nitrosylation, both of which having recently emerged as important regulatory mechanisms during numerous fundamental biological processes. Here, we describe the recent progress in proteomic analysis of carbonylated and nitrosylated proteins and highlight the achievements made in understanding the physiological basis of these oxy/nitro modifications in plants. In addition, we document the existence of a relationship between ROS-based carbonylation and RNS-based nitrosylation thus supporting the finding that crosstalk between cellular signaling stress pathways induced by ROS and RNS could be mediated by specific protein modifications. 23508961 Agonist-induced Down-regulation of Endogenous Protein Kinase C α through an Endolysosomal Mechanism. Protein kinase C (PKC) isozymes undergo down-regulation upon sustained stimulation. Previous studies have pointed to the existence of both proteasome-dependent and -independent pathways of PKCα processing. Here we demonstrate that these down-regulation pathways are engaged in different subcellular compartments; proteasomal degradation occurs mainly at the plasma membrane, whereas non-proteasomal processing occurs in the perinuclear region. Using cholesterol depletion, pharmacological inhibitors, RNA interference, and dominant-negative mutants, we define the mechanisms involved in perinuclear accumulation of PKCα and identify the non-proteasomal mechanism mediating its degradation. We show that intracellular accumulation of PKCα involves at least two clathrin-independent, cholesterol/lipid raft-mediated pathways that do not require ubiquitination of the protein; one is dynamin-dependent and likely involves caveolae, whereas the other is dynamin- and small GTPase-independent. Internalized PKCα traffics through endosomes and is delivered to the lysosome for degradation. Supportive evidence includes (a) detection of the enzyme in EEA1-positive early endosomes, Rab7-positive late endosomes/multivesicular bodies, and LAMP1-positive lysosomes and (b) inhibition of its down-regulation by lysosome-disrupting agents and leupeptin. Only limited dephosphorylation of PKCα occurs during trafficking, with fully mature enzyme being the main target for lysosomal degradation. These studies define a novel and widespread mechanism of desensitization of PKCα signaling that involves endocytic trafficking and lysosome-mediated degradation of the mature, fully phosphorylated protein. 23220646 Design and synthesis of novel benzoheterocyclic derivatives as human acrosin inhibitors by scaffold hopping. Human acrosin is an attracting target for the development of novel male contraceptives. Scaffold hopping was used to optimize the isoxazolecarbaldehyde human acrosin inhibitors and extend their structure-activity relationships. Four kinds of scaffolds, namely benzimidazole, benzothiazole, 3H-indazole, and 5-phenyl-1H-pyrazole, were designed and synthesized. Most of the synthesized compounds showed potent human acrosin inhibitory activity and their binding modes were investigated by molecular docking. The scaffold of the compounds was found to be important for the inhibitory activity. Several compounds were more active than the positive control TLCK, suggesting that they can serve as good starting points for the discovery of novel male contraceptive agents. 22705340 Potentiation of mGlu5 receptors with the novel enhancer, VU0360172, reduces spontaneous absence seizures in WAG/Rij rats. Absence epilepsy is generated by the cortico-thalamo-cortical network, which undergoes a finely tuned regulation by metabotropic glutamate (mGlu) receptors. We have shown previously that potentiation of mGlu1 receptors reduces spontaneous occurring spike and wave discharges (SWDs) in the WAG/Rij rat model of absence epilepsy, whereas activation of mGlu2/3 and mGlu4 receptors produces the opposite effect. Here, we have extended the study to mGlu5 receptors, which are known to be highly expressed within the cortico-thalamo-cortical network. We used presymptomatic and symptomatic WAG/Rij rats and aged-matched ACI rats. WAG/Rij rats showed a reduction in the mGlu5 receptor protein levels and in the mGlu5-receptor mediated stimulation of polyphosphoinositide hydrolysis in the ventrobasal thalamus, whereas the expression of mGlu5 receptors was increased in the somatosensory cortex. Interestingly, these changes preceded the onset of the epileptic phenotype, being already visible in pre-symptomatic WAG/Rij rats. SWDs in symptomatic WAG/Rij rats were not influenced by pharmacological blockade of mGlu5 receptors with MTEP (10 or 30 mg/kg, i.p.), but were significantly decreased by mGlu5 receptor potentiation with the novel enhancer, VU0360172 (3 or 10 mg/kg, s.c.), without affecting motor behaviour. The effect of VU0360172 was prevented by co-treatment with MTEP. These findings suggest that changes in mGlu5 receptors might lie at the core of the absence-seizure prone phenotype of WAG/Rij rats, and that mGlu5 receptor enhancers are potential candidates to the treatment of absence epilepsy. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23247824 Nicotinic receptors in addiction pathways. Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that consist of pentameric combinations of α and β subunits. These receptors are widely distributed throughout the brain and are highly expressed in addiction circuitry. The role of nAChRs in regulating neuronal activity and motivated behavior is complex and varies both in and among brain regions. The rich diversity of central nAChRs has hampered the characterization of their structure and function with use of classic pharmacological techniques. However, recent molecular approaches using null mutant mice with specific regional lentiviral re-expression, in combination with neuroanatomical and electrophysiological techniques, have allowed the elucidation of the influence of different nAChR types on neuronal circuit activity and behavior. This review will address the influence of nAChRs on limbic dopamine circuitry and the medial habenula-interpeduncular nucleus complex, which are critical mediators of reinforced behavior. Characterization of the mechanisms underlying regulation of addiction pathways by endogenous cholinergic transmission and by nicotine may lead to the identification of new therapeutic targets for treating tobacco dependence and other addictions. 23168293 Bone hemodynamic responses to changes in external pressure. Adequate blood supply and circulation to the bones is required to maintain a healthy skeleton. Inadequate blood perfusion is associated with numerous bone pathologies and a decrease in bone mineral density, yet bone hemodynamics remains poorly understood. This study aims to 1) quantify bone hemodynamic responses to changes in external pressure, and 2) identify the predominant mechanisms regulating bone hemodynamic responses to pressure changes. Photoplethysmography was used to measure bone and skin perfusion in response to changes in external pressure. Single-limb pressure chamber experiments were performed over a pressure range of -50 to +50mmHg. Bone perfusion is decreased at all negative pressures, and larger decrements in perfusion are observed at the more extreme pressure differences. At positive pressures we observed an initial increase in perfusion followed by activation of intramuscular pressure receptors at +30mmHg, which overrides the initial response and results in decreased perfusion at the highest positive pressure levels. The myogenic effect is observed and is shown to be the predominant control mechanism in bone over a wide range of pressure exposures. Greater understanding of these hemodynamic mechanisms may be important in developing new drugs and therapies to treat various bone disorders. 23386704 Serum levels of 25-hydroxyvitamin D and the CYP3A biomarker 4β-hydroxycholesterol in a high-dose vitamin D supplementation study. The primary aim was to study the relationship between individual serum levels of 25-hydroxyvitamin D and 4β-hydroxycholesterol, which is an endogenous biomarker of the drug-metabolizing CYP3A enzymes. In addition, the relationship between this biomarker and inflammation, measured as C-reactive protein (CRP), was investigated. Serum samples were used from a recently performed clinical trial in patients with antibody deficiency or increased susceptibility to respiratory tract infections that were randomized to either placebo or high-dose (4000 IU/day) vitamin D for 12 months. One hundred sixteen patients were included in the final analyses, and serum samples collected 6 months after study start were analyzed. At this time point, 25-hydroxyvitamin D levels were found to range between 10 and 284 nM. Individual levels of 25-hydroxyvitamin D as well as CRP were compared with 4β-hydroxycholesterol levels. In addition, all participants were genotyped for two polymorphisms (Taq1 and Foq1) in the vitamin D receptor gene. There was no significant correlation between individual serum levels of 25-hydroxyvitamin D and 4β-hydroxycholesterol. However, a moderate, but statistically significant, negative correlation between CRP and 4β-hydroxycholesterol levels was observed. This study in patients with highly variable serum levels of 25-hydroxyvitamin D could not reveal any relationship between vitamin D and 4β-hydroxycholesterol, an endogenous biomarker of CYP3A activity. However, the negative correlation between CRP and 4β-hydroxycholesterol supports earlier experimental results that inflammation may suppress hepatic CYP3A activity, a finding of potentially high clinical relevance that warrants further exploration. 23124677 Cadmium chelation by frustulins: a novel metal tolerance mechanism in Nitzschia palea (Kützing) W. Smith. The ubiquity of diatom distribution, species richness, short generation time, and specific sensitivity to several environmental stressors such as metals, make diatoms particularly useful for scientific studies. Anthropogenic activities have increased the concentration of metals in air, soil and water. Due to their toxicity and persistent character, the effects of metals on organisms have been extensively studied. In this work, the association of cadmium to different extracellular molecules of Nitzschia palea cells was investigated. Cells were grown in the absence and presence (0.2 mg l(-1)) of cadmium in Chu no. 10 medium. Extracellular polysaccharides were extracted, and subsamples were used for polysaccharide and Cd determination. The frustules were broken mechanically under liquid nitrogen and the intracellular and frustule fractions separated. Frustulins, a protein family found on the outmost frustule layer, constituting a protection coating to environmental stress, were extracted. In each fraction proteins were quantified by the BCA method and separated by gel electrophoresis (SDS-PAGE). Cadmium associated to each fraction was quantified by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) analysis. Exposure of Nitzschia palea to cadmium decreased extracellular polysaccharides by 52.8 % and increased 6 times the amount of frustulins. Cadmium was mostly retained extracellularly: 85.4 % was bound to the frustulin fraction, and 11.1 % to polysaccharides. The ability of Nitzschia palea to increase the production of frustulins due to the presence of Cd, the extracellular location of this frustulin coating and the ability of these proteins to bind Cd, suggests a new cellular defense mechanism to metals unknown until now. 23225671 Enhanced nonenzymatic ligation of homopurine miniduplexes: support for greater base stacking in a pre-RNA world. The ancestors of RNA? There is a long-standing proposal that contemporary nucleic acids might have evolved from RNA-like polymers that utilized only purine-purine base pairs. Here we demonstrate the great advantage that increased nucleobase stacking area provides for nonenzymatic ligation. 23265544 Multi-targeted screening of botanicals in food supplements by liquid chromatography with tandem mass spectrometry. Safety, quality and composition assessments of food supplements based on botanical ingredients are of major concern, as they have usually not been through a rigorous testing process as required for the approval of therapeutic phytopreparations. Therefore, an efficient multi-targeted method was developed to screen selected botanicals of interest in herbal food supplements. Liquid chromatography coupled with a hybrid triple quadrupole linear ion trap was used for this purpose. Botanicals were characterised by means of appropriate biomarkers, which were unambiguously identified by mass spectrometry using an information dependent acquisition experiment which combined a multiple reaction monitoring survey with dependent enhanced product ion scans. During this procedure, product ion scans of targeted analytes were generated at three collision energies and compared with an in-house library of MS/MS spectra acquired from reference standards of all biomarkers. This generic method enables detection, identification and quantification of 98 biomarkers intended to characterise 79 selected plants. 23391632 The increased number of Leydig cells by di(2-ethylhexyl) phthalate comes from the differentiation of stem cells into Leydig cell lineage in the adult rat testis. The objective of the present study is to determine whether di(2-ethylhexyl) phthalate (DEHP) exposure at adulthood increases rat Leydig cell number and to investigate the possible mechanism. 90-day-old Long-Evans rats were randomly divided into 3 groups, and were gavaged with the corn oil (control) or 10 or 750mg/kg DEHP daily for 7 days, and then received an intraperitoneal injection of 75mg/kg ethane dimethanesulfonate (EDS) to eliminate Leydig cells. Serum testosterone concentrations were assessed by RIA, and the mRNA levels of Leydig cell genes were measured by qPCR. EDS eliminated all Leydig cells in the control testis on day 4 post-EDS, as judged by undetectable serum testosterone level and no 3β-hydroxysteroid dehydrogenase positive (3β-HSD(pos)) cells in the interstitium. However, in DEHP-treated groups, there were detectable serum testosterone concentrations and some oval-shaped 3β-HSD(pos) cells in the interstitium. These 3β-HSD(pos) cells were not stained by the antibody against 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), a marker for Leydig cells at a more advanced stage. The disappearance of mRNAs of Leydig cell biomarkers including Lhcgr, Cyp11a1, Cyp17a1, Insl3 and Hsd11b1 in the control testis was observed on day 4 post-EDS. However, there were detectable concentrations of Lhcgr, Cyp11a1 and Cyp17a1 mRNAs but undetectable concentrations of Insl3, Hsd17b3 and Hsd11b1 in the DEHP-treated testes, indicating that these 3β-HSD(pos) cells were newly formed progenitor Leydig cells. The mRNA level for nestin (Nes, biomarker for stem Leydig cells) was significantly increased in the control testis on day 4 post-EDS, but not in the DEHP treated testes, suggesting that these nestin positive stem cells were differentiated into progenitor Leydig cells in the DEHP-treated testes. The present study suggests that DEHP increases the differentiation of stem cells into progenitor Leydig cells. 23327112 Coumarins from roots of Clausena excavata. Two new coumarins, clauexcavatins A (1) and B (2), along with seven known ones (3-9), were isolated from the roots of Clausena excavata Burm. f. (Rutaceae). Their structures were elucidated on the basis of spectral data. 23471969 An Intracellular Domain Fragment of the p75 Neurotrophin Receptor (p75NTR) Enhances Tropomyosin Receptor Kinase A (TrkA) Receptor Function. Facilitation of nerve growth factor (NGF) signaling by the p75 neurotrophin receptor (p75(NTR)) is critical for neuronal survival and differentiation. However, the interaction between p75(NTR) and TrkA receptors required for this activity is not understood. Here, we report that a specific 29-amino acid peptide derived from the intracellular domain fragment of p75(NTR) interacts with and potentiates binding of NGF to TrkA-expressing cells, leading to increased neurite outgrowth in sympathetic neurons as a result of enhanced Erk1/2 and Akt signaling. An endogenous intracellular domain fragment of p75(NTR) (p75(ICD)) containing these 29 amino acids is produced by regulated proteolysis of the full-length receptor. We demonstrate that generation of this fragment is a requirement for p75(NTR) to facilitate TrkA signaling in neurons and propose that the juxtamembrane region of p75(ICD) acts to cause a conformational change within the extracellular domain of TrkA. This finding provides new insight into the mechanism by which p75(NTR) and TrkA interact to enhance neurotrophic signaling. 23483327 Transcriptional responses indicate attenuated oxidative stress in the springtail Folsomia candida exposed to mixtures of cadmium and phenanthrene. Since the 'omics revolution', the assessment of toxic chemical mixtures has incorporated approaches where phenotypic endpoints are connected to a mechanistic understanding of toxicity. In this study we determined the effect of binary mixtures of cadmium and phenanthrene on the reproduction of Folsomia candida and investigated the cellular mechanisms underlying this response. Mixture toxicity modeling showed an antagonistic deviation from concentration addition for reproduction effects of the mixtures. Subsequent transcriptional response analysis was done using five mixtures at the modeled 50 % effect level for reproduction. The transcription profiles of 86 high throughput RT-qPCR assays were studied by means of partial least squares regression analysis. The first and second principal components (PCs) were correlated with global responses to cadmium and phenanthrene, while correlations with the mixture treatments were found in the higher PCs. Specifically associated with the mixture treatments were a biotransformation phase II gene, four mitochondrial related genes and a gene involved in the biosynthesis of antioxidant selenoproteins. Membrane integrity related gene inductions were correlated with the single phenanthrene treatment but not with the mixtures. Immune and inflammatory response assays did not correlate with any of the mixtures. These results suggest moderated oxidative stress, a higher mitochondrial maintenance and less compromised membrane function in the mixture exposed samples compared to the separate cadmium or phenanthrene exposures. The antagonism found for inhibition of reproduction may partially originate from these differences. Mechanistic studies on mixture toxicity can ultimately aid risk assessment by defining relevant toxicity pathways in organisms exposed to real-world mixture exposures present in the field. 23473027 A new "immunological" role for adipocytes in obesity. Obesity-induced insulin resistance is associated with low-grade adipose tissue inflammation, but the mechanism driving this process remains unclear. In this issue of Cell Metabolism, a study by Deng et al. (2013) demonstrates a direct immunological role of adipocytes in instigating adipose inflammation via a MHCII-dependent process. 23377609 Preparation of novel monoclonal antibodies against chelated cadmium ions. The detection of cadmium ions using enzyme-linked immunosorbent assays (ELISA) has been reported by several research groups. Because cadmium ions are too small to stimulate the immune system, high molecular weight immunogens of cadmium are constructed using bifunctional chelators. At present, the most commonly used bifunctional chelator for the preparation of antigens for heavy metal ions is 1-(4-isothiocyanobenzyl) ethylenediamine N,N,N',N'-tetraacetic acid (ITCBE). However, the price of ITCBE is high. So we are interested in a cheaper bifunctional chelator, 1-(4-aminobenzyl) ethylenediamine N,N,N',N'-tetraacetic acid (aminobenzyl-EDTA). Here, cadmium ions were conjugated to carrier proteins using aminobenzyl-EDTA to make artificial antigens. Then, several mice were immunized with the antigen. And monoclonal antibodies (MAbs) against cadmium were produced. Spleen cells of immunized mice were fused with myeloma cells. The resulting hybridomas were screened using protein conjugates which were covalently bound to metal-free EDTA or cadmium. Three hybridoma cell lines (A3, E4 and B5) that produced MAbs with high selectivity and sensitivity were expanded for further study. Cross-reactivities with other metals were below 1 %. These antibodies were used to construct competitive ELISAs. The IC50 for A3 was 8.4 μg/l. The detection range and the lowest detection limit using the antibody A3 was 0.394-64.39 and 0.051 μg/l, respectively. Spike-recovery studies in tap water showed that the antibody A3 could be used for cadmium detection in drinking water. 23327668 Bioactive abietane and ent-kaurane diterpenoids from Isodon tenuifolius. Three new abietane diterpenoids, isoabietenins A-C (1-3), and 13 new ent-kauranoids, tenuifolins A-M (4-16), along with four known compounds (17-20), were isolated from the aerial parts of Isodon tenuifolius. The structures of the new metabolites were established on the basis of detailed spectroscopic analysis. The absolute configurations of 1, 15, and 16 were confirmed by single-crystal X-ray diffraction. Selected compounds were evaluated for their cytotoxicity against a small panel of human tumor cell lines, and some compounds showed inhibitory effects. Furthermore, several isolates exhibited inhibitory activity against nitric oxide production in LPS-activated RAW264.7 macrophages. 23609944 Fluorescent amino acids: modular building blocks for the assembly of new tools for chemical biology. Fluorescence spectroscopy is a powerful tool for probing complex biological processes. The ubiquity of peptide-protein and protein-protein interactions in these processes has made them important targets for fluorescence labeling, and to allow sensitive readout of information concerning location, interactions with other biomolecules, and macromolecular dynamics. This review describes recent advances in design, properties and applications in the area of fluorescent amino acids (FlAAs). The ability to site-selectively incorporate fluorescent amino acid building blocks into a protein or peptide of interest provides the advantage of closely retaining native function and appearance. The development of an array of fluorescent amino acids with a variety of properties, such as environment sensitivity, chelation-enhanced fluorescence, and profluorescence, has allowed researchers to gain insights into biological processes, including protein conformational changes, binding events, enzyme activities, and protein trafficking and localization. 23306171 A new spatane diterpenoid from the cultured soft coral Sinularia leptoclados. A new spatane diterpenoid, leptoclalin A (1), along with two previously reported known norcembranoid diterpenes (2 and 3), were isolated from a cultured soft coral Sinularia leptoclados. The structures were determined by extensive spectroscopic analyses and by comparison with the spectral data of related known compounds. Metabolite 1 is rarely found in spatane skeletons reported from soft corals. In addition, compound 1 exhibited weak cytotoxicity towards human tumor cell lines T-47 D and K-562. 22269904 Fish, contaminants and human health: quantifying and weighing benefits and risks. This paper describes a quantitative risk-benefit assessment of fish consumption. We compare the net health effect expressed in DALYs of two scenarios. The reference scenario is the current fish intake of the Dutch population, which is less than what is recommended by the health authorities. The alternative scenario describes the health effects if the population consumes 200g of fish per week, which is close to the recommendation. All health effects due to fish consumption for which there is convincing evidence are incorporated in the assessment. The QALIBRA software (www.qalibra.eu) is used to simulate the two scenarios. The results show there is a net benefit for the population if it consumes 200g of fish each week. 23237974 Lignans from Schisandra sphenathera Rehd. et Wils. and semisynthetic schisantherin A analogues: absolute configuration, and their estrogenic and anti-proliferative activity. A new dibenzocyclooctene-type lignan, named schisandrin A1 (1), together with nine known lignans (2-10), was isolated from the stems of Schisandra sphenathera. The structure of schisandrin A1, which contains a spirocyclic epoxy unit, was established by means of spectroscopic methods. The absolute configurations of schisandrin A1 (1) and schisantherin A (2) were determined by electronic circular dichroism (CD) and TDDFT calculations, with 2 further confirmed by X-ray crystallographic data. Ten new schisantherin A derivatives (11-20) and 6,7-secoschisantherol A (2b) were synthesized. In addition, natural lignans and semisynthetic schisantherin A derivatives showed the antiproliferative activity on four human cancer cell lines and Id1 (an inhibitor of DNA binding protein) and estrogenic potency. Compounds 5, 7, and 8 exhibited very potent estrogenic activity. 23625194 Lifestyle intervention and anti-obesity therapies in the polycystic ovary syndrome: impact on metabolism and fertility. Obesity is frequently present in patients with polycystic ovary syndrome (PCOS) and plays an important role in the pathogenesis of the metabolic, endocrine, and reproductive abnormalities associated with this syndrome. We aimed to summarize the effects of lifestyle changes and anti-obesity pharmacotherapy in patients with PCOS. We reviewed the literature regarding the effects of lifestyle changes and anti-obesity agents on the metabolic and endocrine abnormalities of PCOS. Lifestyle changes, including diet, exercise, and behavioral modification, appear to improve the metabolic and reproductive abnormalities of overweight and obese patients with PCOS. Therefore, lifestyle changes appear to represent the first-line management for all overweight and obese patients with PCOS. However, the optimal composition of diet and the optimal type of exercise in these patients are unknown. Anti-obesity agents that have been studied in PCOS include orlistat, sibutramine, and rimonabant. However, the latter two agents have been withdrawn from the market because of side effects. Long-term studies with orlistat in overweight and obese diabetic patients showed greater weight loss and metabolic and cardiovascular benefits than those achieved with lifestyle changes alone. However, there are limited data on the efficacy of orlistat in women with PCOS. In conclusion, lifestyle changes (diet, exercise and behavioral modification), particularly when combined with anti-obesity agents, exert beneficial effects on the endocrine abnormalities of obese patients with PCOS and improve metabolic parameters. 23359435 Crosslinking using rapid thermal processing for the fabrication of efficient solution-processed phosphorescent organic light-emitting diodes. Copolymers with a triscarbazole hole-transport group and an oxetane or benzocyclobutene crosslinkable group can be readily thermally crosslinked on timescales of 30 min or less, with rapid thermal processing (RTP) being highly effective for this purpose. Devices with RTP-crosslinked hole-transport layers and spin-coated emissive layers exhibit high external quantum efficiencies of up to 15%. 23178243 Evaluation of immunohistochemical markers to detect the genotoxic mode of action of fine and ultrafine dusts in rat lungs. Data on local genotoxicity after particle exposure are crucial to resolve mechanistic aspects such as the impact of chronic inflammation, types of DNA damage, and their role in lung carcinogenesis. We established immunohistochemical methods to quantify the DNA damage markers poly(ADP-ribose) (PAR), phosphorylated H2AX (γ-H2AX), 8-hydroxyguanosine (8-OH-dG), and 8-oxoguanine DNA glycosylase (OGG1) in paraffin-embedded tissue from particle-exposed rats. The study was based on lungs from a subchronic study that was part of an already published carcinogenicity study where rats had been intratracheally instilled with saline, quartz DQ12, amorphous silica (Aerosil(®) 150), or carbon black (Printex(®) 90) at monthly intervals for 3 months. Lung sections were stained immunohistochemically and markers were quantified in alveolar lining cells. Local genotoxicity was then correlated with already defined endpoints, i.e. mean inflammation score, bronchoalveolar lavage parameters, and carcinogenicity. Genotoxicity was most pronounced in quartz DQ12-treated rats, where all genotoxicity markers gave statistically significant positive results, indicating considerable genotoxic stress such as occurrence of DNA double-strand breaks (DSB), and oxidative damage with subsequent repair activity. Genotoxicity was less pronounced for Printex(®) 90, but significant increases in γ-H2AX- and 8-OH-dG-positive nuclei and OGG1-positive cytoplasm were nevertheless detected. In contrast, Aerosil(®) 150 significantly enhanced only 8-OH-dG-positive nuclei and oxidative damage-related repair activity (OGG1) in cytoplasm. In the present study, γ-H2AX was the most sensitive genotoxicity marker, differentiating best between the three types of particles. The mean number of 8-OH-dG-positive nuclei, however, correlated best with the mean inflammation score at the same time point. This methodological approach enables integration of local genotoxicity testing in subchronic inhalation studies and makes immunohistochemical detection, in particular of γ-H2AX and 8-hydroxyguanine, a very promising approach for local genotoxicity testing in lungs, with prognostic value for the long-term outcome of particle exposure. 23576355 Tirucallane Triterpenoids from the Stems of Brucea mollis. Three new tirucallane triterpenoids, brumollisols A-C (1-3, resp.), together with five known analogues, (23R,24S)-23,24,25-trihydroxytirucall-7-ene-3,6-dione (4), piscidinol A (5), 24-epipiscidinol A (6), 21α-methylmelianodiol (7), and 21β-methylmelianodiol (8), were isolated from an EtOH extract of the stems of Brucea mollis. Their structures were elucidated by means of spectroscopic methods including 1D- and 2D-NMR techniques and mass spectrometry. In the in vitro assays, compound 6 exhibited significant cytotoxic activity against A549 and BGC-823 cancer cells with IC50 values of 1.16 and 3.01 μM, respectively. At a concentration of 10 μM, compounds 1-5, 7, and 8 were found to inhibit NO production in mouse peritoneal macrophages with inhibitory ratios ranging from 39.8±7.7 to 68.2±4.5%. 23122077 Bacillus cereus AR156 induces resistance against Rhizopus rot through priming of defense responses in peach fruit. The biocontrol effects of Bacillus cereus AR156 on Rhizopus rot caused by Rhizopus stolonifer in postharvest peach fruit and the possible mechanisms were investigated. The results showed that fruit treated with B. cereus AR156 had significantly lower disease incidence and smaller lesion diameter than the control fruit did. B. cereus AR156 treatment remarkably enhanced activities of chitinase and β-1,3-glucanase, promoted accumulation of H(2)O(2), and improved total phenolic content and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity. Transcripts of four defense related genes were only significantly enhanced in fruit both treated with B. cereus AR156 and inoculated with R. stolonifer compared with those that were only treated with B. cereus AR156 or inoculated with R. stolonifer. These results suggest that B. cereus AR156 can effectively inhibit Rhizopus rot caused by R. stolonifer and enhance antioxidant activity in peach fruit through the priming of defense responses. 23123737 Involvement of the ANGPTs/Tie-2 system in ovarian hyperstimulation syndrome (OHSS). Ovarian hyperstimulation syndrome (OHSS) is a disorder associated with ovarian stimulation. OHSS features are ovarian enlargement with fluid shifting to the third space. Disturbances in the vasculature are considered the main changes that lead to OHSS. Our aim was to analyze the levels of angiopoietins 1 and 2 (ANGPT1 and 2) and their soluble and membrane receptors (s/mTie-2) in follicular fluid (FF) and in granulosa-lutein cells culture (GLCs) from women at risk of developing OHSS. We also evaluated the effect of ANGPT1 on endothelial cell migration. In ovaries from an OHSS rat model, we analyzed the protein concentration of ANGPTs, their mTie-2 receptor, and platelet-derived growth factor PDGF-B, -D and PDGFR-β. ANGPT1 levels were increased in both FF and GLCs from women at risk of OHSS. Incubation of these FF with an ANGPT1 neutralizing antibody decreased endothelial cell migration. In the ovaries of OHSS rat model, mTie-2 protein levels increased and PDGF-B and -D decreased. In summary, these results suggest that ANGPT1 could be another mediator in the development of OHSS. 23293962 Hepatocyte growth factor activator inhibitor type 2 (HAI-2) modulates hepcidin expression by inhibiting the cell surface protease matriptase-2. Matriptase-2, a recently identified cell surface protease, is the key enzyme of iron homoeostasis modulating the expression of the liver peptide hormone hepcidin. HAI (hepatocyte growth factor activator inhibitor) types 1 and 2 (HAI-1 and HAI-2 respectively) have been shown to inhibit the close homologue, i.e. matriptase. By co-expressing matriptase-2 and the inhibitor HAI-2 we have identified HAI-2 displaying high inhibitory potential against matriptase-2 at the cell surface as well as in conditioned medium. Accordingly, complex formation between matriptase-2 and HAI-2 was demonstrated by isolation of the complex via immobilizing either HAI-2 or matriptase-2 from lysates and conditioned medium of co-expressing cells. Furthermore, HAI-2 indirectly influences the expression of the hepcidin-encoding gene HAMP. The inhibitor abrogates the matriptase-2-mediated suppression of HAMP expression, presumably by inhibiting the supposed potential of matriptase-2 to cleave membrane-bound HJV (haemojuvelin). Taken together, the results of the present study have characterized HAI-2 as an inhibitor of matriptase-2 that modulates the synthesis of hepcidin and provides new insights into the regulatory mechanism of iron homoeostasis, with clinical importance for a treatment of iron overload diseases. 23643839 Activator or Inhibitor? GSK-3 as a new drug target. Glycogen synthase kinase-3 (GSK-3) is a cytoplasmic serine/threonine protein kinase that phosphorylates and inhibits glycogen synthase, thereby inhibiting glycogen synthesis from glucose. However, this serine/threonine kinase is now known to regulate numerous cellular processes through a number of signaling pathways important for cell proliferation, stem cell renewal, apoptosis and development. Because of these diverse roles, malfunction of this kinase is also known to be involved in the pathogenesis of human diseases, such as nervous system disorders, diabetes, bone formation, inflammation, cancer and heart failure. Therefore, GSK-3 is recognized as an attractive target for the development of new drugs. The present review summarizes the roles of GSK-3 in the insulin, Wnt/β-catenin and hedgehog signaling pathways including the regulation of their activities. The roles of GSK-3 in the development of human diseases within the context of its participation in various signaling pathways are also summarized. Finally, the possibility of new drug development targeting this kinase is discussed with recent information about inhibitors and activators of GSK-3. 23293094 Dietary exposure of mink (Mustela vison) to fish from the upper Hudson River, New York, USA: effects on reproduction and offspring growth and mortality. The effects of feeding farm-raised mink (Mustela vison) diets containing polychlorinated biphenyl (PCB)-contaminated fish from the upper Hudson River (New York, USA) on adult reproductive performance and kit growth and mortality were evaluated. Diets contained 2.5 to 20% Hudson River fish, providing 0.72 to 6.1 µg ∑PCBs/g feed (4.8-38 pg toxic equivalents [TEQWHO 2005 ]/g feed). The percentage of stillborn kits per litter was significantly increased by dietary concentrations of 4.5 µg ∑PCBs/g feed (28 pg TEQWHO 2005 /g feed) and greater. All offspring exposed to dietary concentrations of 4.5 and 6.1 µg ∑PCBs/g feed (28 and 38 pg TEQWHO 2005 /g feed) died by 10 weeks of age, and all offspring exposed to 1.5 and 2.8 µg ∑PCBs/g feed (10 and 18 pg TEQWHO 2005 /g feed) died by 31 weeks of age, leaving juveniles in the control and 0.72 µg ∑PCBs/g feed (0.41- and 4.8 pg TEQWHO 2005 /g feed) groups only. The dietary concentration predicted to result in 20% kit mortality (LC20) at six weeks of age was 0.34 µg ∑PCBs/g feed (2.6 pg TEQWHO 2005 /g feed). The corresponding maternal hepatic concentration was 0.80 µg ∑PCBs/g liver, wet weight (13 pg TEQWHO 2005 /g liver, wet wt). Mink residing in the upper Hudson River would be expected to consume species of fish that contain an average of 4.0 µg ∑PCBs/g tissue. Thus, a daily diet composed of less than 10% Hudson River fish could provide a dietary concentration of ∑PCBs that resulted in 20% kit mortality in the present study. 23333647 Viper venom induced inflammation with Montivipera xanthina (Gray, 1849) and the anti-snake venom activities of Artemisia absinthium L. in rat. The present study was conducted to explore the characterization of Montivipera xanthina crude venom partially by in vitro and in vivo and the anti-snake venom activities of Artemisia absinthium L. in comparison with carrageenan-induced acute inflammation model in rats. The LD50 value was estimated as 8.78 mg/kg within 24 h by different venom doses administrated intraperitoneally in mice. The IC50 value was 0.43 ± 0.18 μg/ml after 48 h treatment while the calculated value was 0.73 ± 0.10 μg/ml for the culture media totally refreshed after 2 h treatment with venom. Wistar rats were treated intraperitoneally with A. absinthium extract, 30 min before venom or carrageenan was injected subplantarly into the left hind paw. Intraperitoneal administration of 25 and 50 mg/kg extract was inhibited venom induced paw swelling at 0.5, 1, 2 and 3 h (p < 0.05) while 12.5, 25 and 50 mg/kg extract treatment was inhibited carrageenan-induced paw swelling at 2, 3, 4 and 5 h (p < 0.05). In conclusion, the in vivo toxicity and inflammatory actions and in vitro cytotoxic actions of crude M. xanthina venom were performed as a first report and inhibition of venom-induced inflammation by methanolic extract of A. absinthium was described. 23456735 Life-threatening hypoglycemia associated with intentional insulin ingestion. There are reports of insulin overdose by injection, yet little is known regarding the potential harms of intentional oral ingestion of insulin. In this report, we describe a case of massive insulin ingestion and ensuing hypoglycemia. To our knowledge, there are no previously published cases of hypoglycemia caused by intentional insulin ingestion. A 51-year-old man intentionally ingested three 10-ml vials (total of 3000 units) of various insulins: one vial each of insulin aspart, lispro, and glargine. Four symptomatic hypoglycemic episodes, with blood glucose levels of 48, 25, 34, and 40 mg/dl, occurred approximately 1, 3, 4, and 5 hours, respectively, after ingestion. The hypoglycemia could not be explained other than the ingestion of the insulins. The patient was admitted for observation, and euglycemia occurred within 24 hours without any additional hypoglycemic episodes. Hypoglycemia treatment is reviewed in this case report, and factors that may affect systemic response of orally ingested insulin, including gastrointestinal absorption and insulin sensitivity, are discussed. In addition, the findings of our case report may provide useful insight into the development of novel oral insulin products that are currently in research. Despite poor bioavailability (1%) when taken orally, insulin may produce symptomatic hypoglycemia with a massive ingestion. Vigilant blood glucose monitoring, supportive care with glucose replacement therapy, and admission to the hospital for observation may be required. 23164984 Placental concentrations of mercury, lead, cadmium, and arsenic and the risk of neural tube defects in a Chinese population. To examine whether in utero exposure to mercury (Hg), cadmium (Cd), lead (Pb) and arsenic (As) is associated with an elevated neural tube defects (NTDs) risk, placental concentrations of total Hg, Cd, Pb and As were measured with an inductively coupled plasma mass spectrometer (ICP-MS) in 36 anencephaly and 44 spina bifida cases as well as in 50 healthy controls. The median Hg concentration in the NTD cases (2.25 ng/g) was higher than that of the controls (1.16 ng/g). The odds ratio (OR) for an Hg concentration above the median was 8.80 (95% CI 3.80-20.36) for the NTD cases. NTD risks increased for the second and third high levels of the concentrations, with ORs of 2.70 (95% CI 1.13-6.43) and 18.20 (95% CI 5.45-60.73), respectively. Therefore, higher placental levels of Hg are associated with an elevated risk of NTDs. 23583437 Two new steroidal saponins from Selaginella uncinata (Desv.) Spring and their protective effect against anoxia. Four steroidal saponins were isolated from the anti-anoxic fraction of the 60% EtOH extract of Selaginella uncinata, including two new compounds, (3β, 7β, 12β, 25R)-spirost-5-ene-3, 7, 12-triol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl-(1→4)]-O-β-d-glucopyranoside (1), (2α, 3β, 12β, 25R)-spirost-5-ene-2, 3, 12-triol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl-(1→4)]-O-β-d-glucopyranoside (2) and two known compounds, (3β, 12β, 25R)-spirost-5-ene-3,12-diol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl-(1→4)]-O-β-d-glucopyranoside, (3), (1α, 3β, 25R)-spirost-5-ene-2-diol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl(1→4)]-O-β-d-glucopyranoside (4). The four compounds showed potent protective effect against anoxia in the anoxic PC12 cells assay, among which compounds 1 and 2 were the most active. To our knowledge, this is the first study to report the steroidal saponins in the plant S. uncinata and demonstrate their protective effect against anoxia in PC12 cell assay. 23419638 Pelargonidin activates the AhR and induces CYP1A1 in primary human hepatocytes and human cancer cell lines HepG2 and LS174T. We examined the effects of anthocyanidins (cyanidin, delphinidin, malvidin, peonidin, petunidin, pelargonidin) on the aryl hydrocarbon receptor (AhR)-CYP1A1 signaling pathway in human hepatocytes, hepatic HepG2 and intestinal LS174T cancer cells. AhR-dependent reporter gene expression in transfected HepG2 cells was increased by pelargonidin in a concentration-dependent manner at 24h. Similarly, pelargonidin induced the expression of CYP1A1 mRNA up to 5-fold in HepG2 and LS174T cells relative to the induction by 5 nM 2,3,7,8-tetrachlorodibenzodioxin (TCDD), the most potent activator of AhR. CYP1A1 and CYP1A2 mRNAs were also increased by pelargonidin in three primary human hepatocytes cultures (approximately 5% of TCDD potency) and the increase in CYP1A1 protein in HepG2 and LS174T cells was comparable to the increase in catalytic activity of CYP1A1 enzyme. Ligand binding analysis demonstrated that pelargonidin was a weak ligand of AhR. Enzyme kinetic analyses using human liver microsomes revealed inhibition of CYP1A1 activity by delphinidin (IC50 78 μM) and pelargonidin (IC50 33 μM). Overall, although most anthocyanidins had no effects on AhR-CYP1A1 signaling, pelargonidin can bind to and activate the AhR and AhR-dependent gene expression, and pelargonidin and delphinidin inhibit the CYP1A1 catalytic activity. 23121767 EGR1 is critical for gastrin-dependent upregulation of anion exchanger 2 in gastric cancer cells. The essential anion exchanger (AE) involved in bicarbonate secretion is AE2/SLC4A2, a membrane protein recognized to be relevant for the regulation of the intracellular pH in several cell types. Here we report that gastrin, a major gastrointestinal hormone, upregulates the expression of AE2 mRNA and protein in a cholecystokinin B receptor dependent manner in gastric cancer cells. The upregulated species of AE2 mRNA originates from the classical upstream promoter of the AE2 gene (here referred to as AE2a1) which provides the binding site for transcription factors early growth response 1 (EGR1) and SP1. EGR1 upregulated the AE2 expression that can be competitively inhibited by SP1 in co-transfection experiments. This competitive inhibition was avoided in cells because the SP1 expression was time-staggered to EGR1 in response to gastrin. Overexpression or knockdown of EGR1 consistently increased or decreased the expression of AE2. Our data linked a novel signal pathway involved in gastrin-stimulated AE2 expression. 23518155 A novel GIP-oxyntomodulin hybrid peptide acting through GIP, glucagon and GLP-1 receptors exhibits weight reducing and anti-diabetic properties. Oxyntomodulin (Oxm) is a 37-amino acid peptide linked to alleviation of obesity-diabetes through a dual mode of action mediated at both glucagon and GLP-1 receptors. GIP is the principle physiological regulator of postprandial insulin secretion. Therefore, the primary aim was to design a novel GIP-Oxm peptide incorporating the actions of GIP, GLP-1 and glucagon in a single molecule. The first 11 N-terminal residues of Oxm were substituted with the sequence of stable dA(2)GIP molecule to generate a novel GIP-Oxm peptide (dA(2)GIP-Oxm). dA(2)GIP-Oxm was resistant to DPP-IV and significantly stimulated in vitro insulin release. dA(2)GIP-Oxm stimulated cAMP production in GIP-R, glucagon-R and GLP-1-R transfected cells by up to 95%, 83% and 77% of that elicited by respective native ligands. Acute administration of dA(2)GIP-Oxm to HFF mice resulted in reduced plasma glucose (45% reduction) and increased insulin concentrations (1.7-fold increase). Furthermore, dA(2)GIP-Oxm lowered plasma glucose (42% reduction) and increased plasma insulin (1.6-fold increase) when administered to HFF mice four hours prior to a glucose load. Once-daily administration of dA(2)GIP-Oxm for 15 days in HFF mice lowered body weight (13% reduction), reduced plasma glucose (40% reduction) and increased plasma insulin (1.7-fold increase). Furthermore, glycemic responses were improved (38% reduction) and glucose-mediated plasma insulin concentrations enhanced (2-fold increase). These improvements in metabolic control were independent of changes in food intake and insulin sensitivity. dA(2)GIP-Oxm exerts positive beneficial actions on glucose homeostasis, beta-cell insulin secretion and body weight, mediated through GIP, glucagon and GLP-1 receptors. Such multiple-acting peptides may hold promise as novel therapies for obesity-diabetes. 23363335 Base-flipping propensities of unmethylated, hemimethylated, and fully methylated CpG sites. Methylation of C5 of cytosines at CpG dinucleotide sites of the DNA is one of the most important factors regulating the expression of genes. The interactions of these CpG sites with proteins are essential for recognition and catalysis and in many cases are characterized by the flipping of either of the cytosine bases out of the DNA helix. In this paper, we present results from molecular dynamics simulations indicating that methylation of CpG sites suppresses spontaneous extra-helical conformations of either of the two cytosines. Thus, cytosines in unmethylated sites flip out easier than in hemimethylated sites and the latter flip out easier than in fully methylated sites. The different propensities for base flipping is observed not only between the cytosines that differ in their methylation states but also between the cytosines on the complementary strand. From alchemical mutation calculations, we find that methylation of one of the cytosines increases the free energy of the extra-helical conformation by 10.3-16.5 kJ/mol and this increase is additive with respect to the second methylation. Potential of mean force calculations confirm these results and reveal that cytosines in unmethylated sites favor flipping via the major-groove pathway. We perform several analyses to correlate this behavior with structural changes induced by the different methylation states of the CpG site. However, we demonstrate that the driving force for these propensities is the change in the electronic distribution around the pyrimidine ring upon methylation. In particular, unmethylated cytosine interacts more favorably (primarily via electrostatic forces) with solvent water molecules than methylated cytosine. This is observed for, both, extra-helical cytosines and intra-helical cytosines in which the cytosine on the complementary strand flips out and water molecules enter the DNA double-helix and substitute the hydrogen bonds with the orphan guanine. On the basis of these results of spontaneous base flipping, we conjecture that the mechanism for base flipping observed in complexes between hemimethylated DNAs and proteins is not likely to be passive. 23183186 P21-activated protein kinase 1 (Pak1) mediates the cross talk between insulin and β-catenin on proglucagon gene expression and its ablation affects glucose homeostasis in male C57BL/6 mice. In gut endocrine L cells, the Wnt signaling pathway effector β-catenin (β-cat)/transcription factor 7-like 2 mediates the stimulatory effect of insulin on proglucagon (gcg) expression and glucagon-like peptide-1 (GLP-1) production. In several other cell lineages, insulin is able to stimulate p21-activated protein kinase 1 (Pak1). Here we determined the role of Pak1 in gcg expression and the effect of Pak1 deletion on glucose homeostasis. Insulin stimulated Pak1 activation through increasing its Thr423 phosphorylation in gut gcg-expressing cell lines, associated with increased gcg mRNA levels. This stimulation was attenuated by the Pak inhibitor 2,2'-dihydroxy-1,1'-dinaphthyldisulfide (IPA3) or dominant-negative Pak1. Both insulin and cAMP-promoting agents activated β-cat Ser675 phosphorylation, which was attenuated by IPA3 or protein kinase A inhibition, respectively. Gut gcg levels were reduced in male Pak1(-/-) mice, associated with impaired glucose tolerance after an ip or oral glucose challenge. These mice had lower circulating active GLP-1 levels after a glucose challenge as well as reduced distal ileum GLP-1 content after insulin treatment. Finally, the Pak1(-/-) mice exhibited reduced brainstem gcg level and abolished β-cat Ser675 phosphorylation in brain neurons after insulin treatment. We suggest that Pak1 mediates the cross talk between insulin and Wnt signaling pathways on gut and brain gcg expression, and its ablation impairs glucose homeostasis. 23265660 Superomniphobic surfaces for effective chemical shielding. Superomniphobic surfaces display contact angles >150° and low contact angle hysteresis with essentially all contacting liquids. In this work, we report surfaces that display superomniphobicity with a range of different non-Newtonian liquids, in addition to superomniphobicity with a wide range of Newtonian liquids. Our surfaces possess hierarchical scales of re-entrant texture that significantly reduce the solid-liquid contact area. Virtually all liquids including concentrated organic and inorganic acids, bases, and solvents, as well as viscoelastic polymer solutions, can easily roll off and bounce on our surfaces. Consequently, they serve as effective chemical shields against virtually all liquids--organic or inorganic, polar or nonpolar, Newtonian or non-Newtonian. 23644256 Ibuprofen plus Isosorbide Dinitrate treatment in the mdx mice ameliorates dystrophic heart structure. BACKGROUND: Co-administration of ibuprofen (IBU) and isosorbide dinitrate (ISDN) provides synergistic beneficial effects on dystrophic skeletal muscle. Whether this treatment has also cardioprotective effects in this disease was still unknown. Aims: to evaluate the effects of co-administration of IBU and ISDN (a) on left ventricular (LV) structure and function, and (b) on cardiac inflammatory response and fibrosis in mdx mice. METHODS: three groups of mice were studied: mdx mice treated with IBU (50mgkg(-1))+ISDN (30mgkg(-1)) administered daily in the diet, mdx mice that received standard diet without drugs and wild type aged-matched mice. Animals were analysed after 10-11 months of treatment. Structural and functional parameters were evaluated by echocardiography while histological analyses were performed to evaluate inflammatory response, collagen deposition, cardiomyocyte number and area. RESULTS: treatment for 10-11 months with IBU+ISDN preserved LV wall thickness and LV mass. Drug treatment also preserved the total number of cardiomyocytes in the LV and attenuated the increase in cardiomyocyte size, when compared to untreated mdx mice. Moreover, a trend towards a decreased number of inflammatory cells, a reduced LV myocardial interstitial fibrosis and an enhanced global LV function response to stress was observed in treated mdx mice. CONCLUSIONS: treatment for 10-11 months with IBU+ISDN is effective in preventing the alterations in LV morphology of mdx mice while not reaching statistical significance on LV function and cardiac inflammation. 23559436 Molecule-Induced Peroxide Homolysis. The homolytic cleavage of peroxide bonds, leading to the formation of free radicals, plays an important role in the (spontaneous) oxidation of a wide variety of hydrocarbons in the presence of oxygen. Such aerobic oxidations can be desired (e.g. for industrially applied autoxidations) or undesired (e.g. food deterioration). In this contribution we provide experimental and computational evidence for a molecule-induced homolytic dissociation mechanism between alkyl peroxide and compounds featuring weakly bonded H atoms such as (di)unsaturated hydrocarbons. 22906572 Chemicals inducing acute irritant contact dermatitis mobilize intracellular calcium in human keratinocytes. Intracellular Ca(2+) increase is a common feature of multiple cellular pathways associated with receptor and channel activation, mediator secretion and gene regulation. We investigated the possibility of using this Ca(2+) signal as a biomarker for a reaction to chemical irritants of normal human keratinocytes (NHK) in submerged primary cell culture. We tested 14 referenced chemical compounds classified as strong (seven), weak (four) or non- (three) irritants in acute irritant contact dermatitis. We found that the strong irritant compounds tested at 20-40 mM induced an intracellular Ca(2+) increase measurable by spectrofluorimetry in an automated test. Weak and non-irritant compounds however did not increase intracellular Ca(2+) concentration. We further investigated the mechanisms by which the amine heptylamine, classified as a R34 corrosive compound, increases intracellular Ca(2+). Heptylamine (20mM) induced an ATP release that persisted in the absence of intra- and extra-cellular Ca(2+). In addition, we found that this ATP activates NHK purinergic receptors that subsequently cause the increase in intracellular Ca(2+) from sarcoplasmic reticular stores. We conclude that measuring the intracellular Ca(2+) concentration in NHK is a suitable and easy way of determining any potential reaction to soluble chemical compounds. 23228043 Drug safety evaluation of defibrotide. INTRODUCTION: Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of chemotherapeutic conditioning used in preparation for hematopoietic stem-cell transplantation (SCT). Defibrotide (DF) has been shown in Phase II and III trials to improve complete response in patients with severe VOD (sVOD). None of the articles, to date, provide a comprehensive review of the safety of DF in VOD and/or a range of other conditions. AREAS COVERED: This article reviews current clinical findings on DF, primarily in terms of safety for use in treatment and prophylaxis of VOD, and relevant safety data for its use in other diseases. The literature review was conducted using a PubMed search with the fixed term 'defibrotide' in combination with ≥ 1 of 'safety', 'veno-occlusive disease' (with and without 'treatment', 'prevention'), 'oncology', 'myeloma', 'microangiopathy', 'anti-thrombotic' and 'peripheral vascular disorder'. Related articles from the EBMT and ASH conference websites were also included. EXPERT OPINION: DF was well tolerated in majority of the studies. The safety profile of DF is largely favourable with toxicities comparable to control populations in the setting of SCT complicated by sVOD. 23485065 Conformation Guides Molecular Efficacy in Docking Screens of Activated β-2 Adrenergic G Protein Coupled Receptor. A prospective, large library virtual screen against an activated β2-adrenergic receptor (β2AR) structure returned potent agonists to the exclusion of inverse-agonists, providing the first complement to the previous virtual screening campaigns against inverse-agonist-bound G protein coupled receptor (GPCR) structures, which predicted only inverse-agonists. In addition, two hits recapitulated the signaling profile of the co-crystal ligand with respect to the G protein and arrestin mediated signaling. This functional fidelity has important implications in drug design, as the ability to predict ligands with predefined signaling properties is highly desirable. However, the agonist-bound state provides an uncertain template for modeling the activated conformation of other GPCRs, as a dopamine D2 receptor (DRD2) activated model templated on the activated β2AR structure returned few hits of only marginal potency. 23143666 Survivin in adrenocortical tumors - pathophysiological implications and therapeutic potential. Treatment options for adrenocortical carcinoma (ACC) are very limited. In other solid tumors, small vaccination trials targeting the anti-apoptotic molecule survivin suggested immunological and clinical benefit in selected patients. Therefore, we investigated whether survivin might be a suitable target for immunotherapy in ACC. Survivin mRNA and protein expression was assessed in adrenal tissue specimens [by real-time-PCR in 29 ACC, 24 adrenocortical adenomas (ACA) and 12 normal adrenal glands; by immunohistochemistry in 167 ACCs, 15 ACA, and 5 normal adrenal glands]. Expression was correlated with clinical outcome using Kaplan-Meier and Cox regression analyses. The anti-apoptotic role of survivin was investigated in the SW13 ACC cell line using survivin siRNA. The presence of spontaneous survivin specific T-cells in peripheral blood was assessed by FACS dextramere staining in 29 ACC patients in comparison to healthy controls. Survivin mRNA in ACC was significantly overexpressed when compared with ACA or normal adrenal glands. Immunohistochemistry confirmed survivin protein expression in 97% of the ACCs. In 83% of samples, staining was moderate or high and clinical outcome in this subgroup showed a trend towards poorer prognosis [hazard ratio for death 2.28 (95% CI 0.99-5.28); p=0.053]. Survivin knockdown in SW-13 cell significantly increased the rate of apoptosis. Finally, spontaneous survivin-reactive T cells were detectable in 3 of 29 ACC patients. In conclusion, our data suggest that survivin could play an important role in the anti-apoptotic mechanisms in ACC and provide first hints that targeting survivin might be an interesting new therapeutic approach in this rare disease. 23265903 Inhibition of the β-carbonic anhydrases from Mycobacterium tuberculosis with C-cinnamoyl glycosides: identification of the first inhibitor with anti-mycobacterial activity. A small series of C-cinnamoyl glycoside containing the phenol moiety was tested for the inhibition of the three Mycobacterium tuberculosis β-carbonic anhydrases (CAs, EC 4.2.1.1) with activities in the low micromolar range detected. The compounds were also tested for the inhibition of growth of M. tuberculosis H(37)Rv strain, leading to the identification of (E)-1-(2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyl)-4-(3-hydroxyphenyl)but-3-en-2-one (1) as the first carbonic anhydrase inhibitor with anti-tubercular activity. 23177255 Design, synthesis and biological evaluation of glucose-containing scutellarein derivatives as neuroprotective agents based on metabolic mechanism of scutellarin in vivo. Based on metabolic mechanism of scutellarin in vivo that scutellarin could be hydrolyzed into scutellarein by β-glucuronide enzyme, some glucose-containing scutellarein derivatives were designed and synthesized through the introduction of glucose moiety at C-7 position of scutellarein via a glucosidic bond. Biological activity evaluation showed that these glucose-containing scutellarein derivatives exhibited potent DPPH radical scavenging activities. Furthermore, the improvement of physicochemical properties such as anticoagulant and neuroprotective activities alongside with the water solubility was achieved by introducing glucose. These findings suggest that the introduction of the glucose moiety to scutellarein wattants further development of this kind of compounds as neuroprotective agents. 23600626 Layer-by-Layer Polyelectrolyte Deposition: A Mechanism for Forming Biocomposite Materials. Complex coacervates prepared from poly(aspartic acid) (polyAsp) and poly-l-histidine (polyHis) were investigated as models of the metastable protein phases used in the formation of biological structures such as squid beak. When mixed, polyHis and polyAsp form coacervates whereas poly-l-glutamic acid (polyGlu) forms precipitates with polyHis. Layer-by-layer (LbL) structures of polyHis-polyAsp on gold substrates were compared with those of precipitate-forming polyHis-polyGlu by monitoring with iSPR and QCM-D. PolyHis-polyAsp LbL was found to be stiffer than polyHis-polyGlu LbL with most water evicted from the structure but with sufficient interfacial water remaining for molecular rearrangement to occur. This thin layer is believed to be fluid and like preformed coacervate films, capable of spreading over both hydrophilic ethylene glycol as well as hydrophobic monolayers. These results suggest that coacervate-forming polyelectrolytes deserve consideration for potential LbL applications and point to LbL as an important process by which biological materials form. 23414841 A novel concept of radiosynthesis of a (99m)Tc-labeled dimeric RGD peptide as a potential radiotracer for tumor imaging. Radiolabeled Arg-Gly-Asp (RGD) peptides are promising agents for non invasive imaging of αvβ3 expression in malignant tumors. The integrin αvβ3 binding affinity and consequent tumor uptake could be improved when a dimeric RGD peptide is used as the targeting moiety instead of a monomer. Towards this, a novel approach was envisaged to synthesize a (99m)Tc labeled dimeric RGD derivative using a RGD monomer and [(99m)TcN](+2) intermediate. The dithiocarbamate derivative of cyclic RGD peptide G3-c(RGDfK) (G3=Gly-Gly-Gly, f=Phe, K=Lys) was synthesized and radiolabeled with [(99m)TcN](+2) intermediate to form the (99m)TcN-[G3-c(RGDfK)]2 complex in high yield (∼98%). Biodistribution studies carried out in C57/BL6 mice bearing melanoma tumors showed good tumor uptake [4.61±0.04% IA/g at 30min post-injection] with fast clearance of the activity from non-target organs/tissue. Scintigraphic imaging studies showed visible accumulation of activity in the tumor with appreciable target to background ratio. 23194552 In vitro antibacterial, cytotoxicity and haemolytic activities and phytochemical analysis of seagrasses from the Gulf of Mannar, South India. It is essential to study the phytochemical constituents and toxicological properties of seagrasses when considering their food applications. Aqueous methanolic extracts of six seagrasses were evaluated for their antibacterial, cytotoxic (brine shrimp leathality assay) and haemolytic activity. Thin layer chromatography (TLC) and phytochemical analysis were used to compare the phytochemical profiles of six seagrasses. Among the six seagrasses examined, Halodule pinifolia and Cymodocea rotundata showed predominant growth inhibitory activity against all the tested human pathogens. Cytotoxicity of seagrass extracts against nauplii of Artemia salina revealed that Syringodium isoetifolium exhibited lesser toxicity with LC(50) value of 699.096 μg/ml. Of all the seagrasses tested, H. pinifolia recorded the minimum haemolytic activity of 2.07±0.63% at 1000 μg/ml concentration. Phytochemical analysis showed the presence of common plant chemical constituents which varied with respect to species. The present findings suggest the possible pharmacological applications of selected seagrasses that can be used as food ingredients. 23538843 Transcriptional Analysis of Drought-Induced Genes in the Roots of a Tolerant Genotype of the Common Bean (Phaseolus vulgaris L.). In Brazil, common bean (Phaseolus vulgaris L.) productivity is severely affected by drought stress due to low technology cultivation systems. Our purpose was to identify differentially expressed genes in roots of a genotype tolerant to water deficit (BAT 477) when submitted to an interruption of irrigation during its development. A SSH library was constructed taking as "driver" the genotype Carioca 80SH (susceptible to drought). After clustering and data mining, 1572 valid reads were obtained, resulting in 1120 ESTs (expressed sequence tags). We found sequences for transcription factors, carbohydrates metabolism, proline-rich proteins, aquaporins, chaperones and ubiquitins, all of them organized according to their biological processes. Our suppressive subtractive hybridization (SSH) library was validated through RT-qPCR experiment by assessing the expression patterns of 10 selected genes in both genotypes under stressed and control conditions. Finally, the expression patterns of 31 ESTs, putatively related to drought responses, were analyzed in a time-course experiment. Our results confirmed that such genes are more expressed in the tolerant genotype during stress; however, they are not exclusive, since different levels of these transcripts were also detected in the susceptible genotype. In addition, we observed a fluctuation in gene regulation over time for both the genotypes, which seem to adopt and adapt different strategies in order to develop tolerance against this stress. 23503927 Impact of long-range van der Waals forces on chiral recognition in a Cinchona alkaloid chiral selector system. Singly-charged complexes of (8S,9R)-tert-butylcarbamoylquinine (tBuCQN), N-3,5-dinitrobenzoyl-(S,R)-leucine (DNB-S/R-leucine), and alkali metal counter ions (Li(+), Na(+), K(+)) were investigated by density-functional theory. It is shown that the cations prefer formation of an ionic pair with the carboxylate group of DNB-Leu over the formation of a cation-π interaction. The [tBuCQN·DNB-S/R-Leu·Na](+) complex is bound by a coulombic attraction, a hydrogen bond, a π-π interaction and van der Waals forces. The tBuCQN chiral selector preferentially complexes with the DNB-S-Leu enantiomer, because the favourable stereochemistry allows the stabilization of the complex by at least one binding mode more compared to the complex containing the DNB-R-Leu molecule. Weakening of the binding modes is observed using the lithium counter ion compared to the sodium one. The weakening is more pronounced in [tBuCQN·DNB-R-Leu·Li](+) than in [tBuCQN·DNB-S-Leu·Li](+). The exact opposite effect is observed using the potassium counter ion. Hence, the lithium counter ion enhances the enantioselectivity of tBuCQN while the potassium counter ion reduces the enantioselectivity of tBuCQN. 23383750 Understanding and Controlling Morphology Formation in Langmuir-Blodgett Block Copolymer Films Using PS-P4VP and PS-P4VP/PDP. This contribution offers a comprehensive understanding of the factors that govern the morphologies of Langmuir-Blodgett (LB) monolayers of amphiphilic diblock copolymers (BCs). This is achieved by a detailed investigation of a wide range of polystyrene-poly(4-vinyl pyridine) (PS-P4VP) block copolymers, in contrast to much more limited ranges in previous studies. Parameters that are varied include the block ratios (mainly for similar total molecular weights, occasionally other total molecular weights), the presence or not of 3-n-pentadecylphenol (PDP, usually equimolar with VP, with which it hydrogen bonds), the spreading solution concentration ("low" and "high"), and the LB technique (standard vs "solvent-assisted"). Our observations are compared with previously published results on other amphiphilic diblock copolymers, which had given rise to contradictory interpretations of morphology formation. Based on the accumulated results, we re-establish early literature conclusions that three main categories of LB block copolymer morphologies are obtained depending on the block ratio, termed planar, strand, and dot regimes. The block composition boundaries in terms of mol % block content are shown to be similar for all BCs having alkyl chain substituents on the hydrophilic block (such as PS-P4VP/PDP) and are shifted to higher values for BCs with no alkyl chain substituents (such as PS-P4VP). This is attributed to the higher surface area per repeat unit of the hydrophilic block monolayer on the water surface for the former, as supported by the onset and limiting areas of the Langmuir isotherms for the BCs in the dot regime. 2D phase diagrams are discussed in terms of relative effective surface areas of the two blocks. We identify and discuss how kinetic effects on morphology formation, which have been highlighted in more recent literature, are superposed on the compositional effects. The kinetic effects are shown to depend on the morphology regime, most strongly influencing the strand and, especially, planar regimes, where they give rise to a diversity of specific structures. Besides film dewetting mechanisms, which are different when occurring in structured versus unstructured films (the latter previously discussed in the literature), kinetic influences are discussed in terms of chain association dynamics leading to depletion effects that impact on growing aggregates. These depletion effects particularly manifest themselves in more dilute spreading solutions, with higher molecular weight polymers, and in composition regimes characterized by equilibrium degrees of aggregation that are effectively infinite. It is by understanding these various kinetic influences that the diversity of structures can be classified by the three main composition-dependent regimes. 23316965 Inhibition of matrix metalloproteinases (MMPs) as a potential strategy to ameliorate hypertension-induced cardiovascular alterations. A group of proteases, the matrix metalloproteinases (MMPs) are well known for their capacity to degrade extracellular matrix (ECM) proteins. Particularly MMP-2 and MMP-9 contribute to the degradation and reorganization of the ECM components and are involved in the pathophysiology of cardiovascular remodeling. Imbalanced MMP activity promotes vascular smooth muscle cells and migration and proliferation and endothelial dysfunction, thus resulting in increased cardiovascular stiffness and hypertrophy. Furthermore, MMP-2 cleaves non-ECM protein substrates including cellular receptors and intracellular proteins, thus causing cardiac and vascular dysfunction. It is now becoming clear that increased MMP activity promotes long-lasting cardiovascular structural and functional alterations in both experimental and clinical hypertension, and this alteration may contribute to sustained hypertension and its complications. Other pathogenic mechanisms including activation of the renin-angiotensin-aldosterone system and oxidative stress activate and upregulate MMPs. Therefore, MMP inhibition may prevent the deleterious consequences of hypertension to the cardiovascular system. This review article will focus on growing evidence supporting the relevance of MMPs in hypertension and the effects of MMP inhibitors. Particularly, the effects of doxycycline used as a non selective MMP inhibitor in experimental and clinical studies will be discussed. 23123331 Seventy-two-hour release formulation of the poorly soluble drug silybin based on porous silica nanoparticles: in vitro release kinetics and in vitro/in vivo correlations in beagle dogs. The objective of this study was to prepare a 72 h-release formulation of silybin (72 h-SLB) using a combination of solid dispersion, gel matrix and porous silica nanoparticles (PSNs) and to investigate the in vitro/in vivo correlations (IVIVCs). The results of scanning electron microscopy and N(2) adsorption demonstrated that empty PSNs possessed a spherical shape, a highly porous structure, a large specific surface area (385.89 ± 1.12 m(2)/g) and a small pore size (2.74 nm on average). The in vitro dissolution profiles of both 72 h-SLB and silybin-loaded PSNs in different concentrations (0.01, 0.06 and 0.08M) of Na(2)CO(3) solutions revealed that 0.06 M Na(2)CO(3) solution was the optimal medium in which silybin could be released from 72 h-SLB with first-order release kinetics and from PSNs with Higuchi kinetics. Furthermore, the IVIVCs of 72 h-SLB and silybin-loaded PSNs in beagle dogs were also established. Using 0.06 M Na(2)CO(3) solution as the in vitro dissolution medium, a good linear relationship could be achieved for both 72 h-SLB and silybin-loaded PSNs. The findings support the fact that the 72 h-SLB (consisting of solid dispersion, regular gel matrix and PSNs) together with Na(2)CO(3) solution as an in vitro dissolution medium can be developed into a promising formulation for poorly soluble drugs, which enjoys a good IVIVC. 23267837 Anti-tumor effects of peptide analogs targeting neuropeptide hormone receptors on mouse pheochromocytoma cells. Pheochromocytoma is a rare but potentially lethal chromaffin cell tumor with currently no effective treatment. Peptide hormone receptors are frequently overexpressed on endocrine tumor cells and can be specifically targeted by various anti-tumor peptide analogs. The present study carried out on mouse pheochromocytoma cells (MPCs) and a more aggressive mouse tumor tissue-derived (MTT) cell line revealed that these cells are characterized by pronounced expression of the somatostatin receptor 2 (sst2), growth hormone-releasing hormone (GHRH) receptor and the luteinizing hormone-releasing hormone (LHRH) receptor. We further demonstrated significant anti-tumor effects mediated by cytotoxic somatostatin analogs, AN-162 and AN-238, by LHRH antagonist, Cetrorelix, by the cytotoxic LHRH analog, AN-152, and by recently developed GHRH antagonist, MIA-602, on MPC and for AN-152 and MIA-602 on MTT cells. Studies of novel anti-tumor compounds on these mouse cell lines serve as an important basis for mouse models of metastatic pheochromocytoma, which we are currently establishing. 22301818 Screening of immunomodulatory activity of total and protein extracts of some Moroccan medicinal plants. Herbal and traditional medicines are being widely used in practice in many countries for their benefits of treating different ailments. A large number of plants in Morocco were used in folk medicine to treat immune-related disorders. The objective of this study is to evaluate the immunomodulatory activity of protein extracts (PEs) of 14 Moroccan medicinal plants. This activity was tested on the proliferation of immune cells. The prepared total and PEs of the plant samples were tested using MTT (3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide) assay on the splenocytes with or without stimulation by concanavalin-A (Con-A), a mitogenic agent used as positive control. The results of this study indicated different activity spectra. Three groups of activities were observed. The first group represented by Citrullus colocynthis, Urtica dioica, Elettaria cardamomum, Capparis spinosa and Piper cubeba showed a significant immunosuppressive activity. The second group that showed a significant immunostimulatory activity was represented by Aristolochia longa, Datura stramonium, Marrubium vulgare, Sinapis nigra, Delphynium staphysagria, Lepidium sativum, Ammi visnaga and Tetraclinis articulata. The rest of the plant extracts did not alter the proliferation induced by Con-A. This result was more important for the PE than for the total extract. In conclusion, this study revealed an interesting immunomodulating action of certain PEs, which could explain their traditional use. The results of this study may also have implications in therapeutic treatment of infections, such as prophylactic and adjuvant with cancer chemotherapy. 22771462 Postsynaptic mGluR mediated excitation of neurons in midbrain periaqueductal grey. Metabotropic glutamate (mGlu) receptors modulate pain from within the midbrain periaqueductal grey (PAG). In the present study, the postsynaptic mGlu receptor mediated effects on rat PAG neurons were examined using whole-cell patch-clamp recordings in brain slices. The selective group I agonist DHPG (10 μM) produced an inward current in all PAG neurons tested which was associated with a near parallel shift in the current-voltage relationship. By contrast, the group II and III mGlu receptor agonists DCG-IV (1 μM) and l-AP4 (3 μM) produced an outward current in only 10-20% of PAG neurons tested. The DHPG induced current was concentration dependent (EC(50) = 1.4 μM), was reduced by the mGlu1 antagonist CPCCOEt (100 μM), and was further reduced by CPCCOEt in combination with the mGlu5 antagonist MPEP (10 μM). The glutamate transport blocker TBOA (30 μM) also produced an inward current, however, this was largely abolished by CNQX (10 μM) plus AP5 (25 μM). Slow EPSCs were evoked following train, but not single shock stimulation, which were enhanced by TBOA (30 μM). The TBOA enhancement of slow EPSCs was abolished by MPEP plus CPCCOEt. These findings indicate that endogenously released glutamate, under conditions in which neurotransmitter spill-over is enhanced, activates group I mGlu receptors to produce excitatory currents within PAG. Thus, postsynaptic group I mGlu receptors have the potential to directly modulate the analgesic, behavioural and autonomic functions of the PAG. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23612419 Traditional and alternative natural therapeutic products used in the treatment of respiratory tract infectious diseases in the eastern Catalan Pyrenees (Iberian Peninsula). ETHNOPHARMACOLOGICAL RELEVANCE: Respiratory tract diseases, including mild troubles, such as the common cold, and also life-threatening ones such as bacterial pneumonia and lung cancer, are very important in terms of mortality, incidence, prevalence and costs. Classical medicine has undoubtedly addressed these illnesses, but the body of knowledge generated by alternative approaches, among which folk medicine plays an important role, is not at all negligible. AIMS OF THE STUDY: In this context, we performed an ethnobotanical study in a Catalan region of the eastern Pyrenees, northeast Iberian Peninsula, in order to assess the popular knowledge on useful plants. We present here the data concerning pharmaceutical uses of plants devoted to respiratory illnesses. METHODOLOGY: A total of 160 informants (94 women and 66 men, born between 1915 and 1988) were interviewed during 102 semi-structured interviews. Voucher specimens were collected, and then processed and deposited in the herbarium BCN. RESULTS: We collected information about 99 plant taxa (94 species - some of them with subspecies - of 85 genera belonging to 50 families) popularly employed to prevent or treat respiratory troubles. The degree of reliability of uses is high, as indicated for instance by an informant consensus factor of 0.83 and by high medicinal importance indexes for many taxa. In addition, we have recorded information on 14 animal and four mineral products also used against respiratory ailments, this constituting the first ethnopharmacological work in the Catalan linguistic area to report plant, animal and mineral remedies, and one of the very few in the Iberian Peninsula involving the study of ethnozoological medicines. CONCLUSIONS: The data collected show a high degree of consistency and indicate a remarkable persistence of folk knowledge on plant uses. The anticatarrhal, antitussive and for sore throat are the most valuable uses. This research could be the starting point for further research aiming to obtain products that may generalise the alternative medical uses here raised at a local level. Phytochemical and pharmacological studies on some of the plants quoted here - of which we could provide material to potentially interested researchers - would be useful first steps in this process. 23618900 Interlaboratory evaluation of a cow's milk allergy mouse model to assess the allergenicity of hydrolysed cow's milk based infant formulas. This study describes two phases of a multi-phase project aiming to validate a mouse model for cow's milk allergy to assess the potential allergenicity of hydrolysed cow's milk based infant formulas (claim support EC-directive 2006/141/E). The transferability and the discriminatory power of this model was evaluated in 4 research centers. Mice were sensitized by oral gavage with whey or extensively hydrolysed whey (eWH) using cholera toxin as an adjuvant. Whey-specific antibodies, mMCP-1 levels, anaphylactic shock symptoms, body temperature and the acute allergic skin response were determined upon whey challenge. In phases I and II, all 4 centers detected elevated levels of whey-specific IgE/IgG1 in whey sensitized animals. Elevated levels of mMCP-1, anaphylactic symptoms, body temperature drop and acute allergic skin response were scored upon whey challenge in 3 out of 4 research centers. In contrast, none of the evaluated parameters were elevated in eWH orally exposed groups. The cow's milk allergy mouse model is capable to distinguish the sensitizing capacity of complete or hydrolysed cow's milk protein. The model uses straightforward parameters relevant to food allergic responses and can be effectively transferred between different laboratories. We propose this mouse model as a new strategy for the screening of new hypoallergenic cow's milk formulas. 23007559 Developmental immunotoxicity of ethanol in an extended one-generation reproductive toxicity study. The susceptibility of developing immune system to chemical disruption warrants the assessment of immune parameters in reproductive and developmental testing protocols. In this study, a wide range of immune endpoints was included in an extended one-generation reproduction toxicity study (EOGRTS) design to determine the relative sensitivity of immune and developmental parameters to ethanol (EtOH), a well-known developmental toxicant with immunomodulatory properties. Adult Wistar rats were exposed to EtOH via drinking water (0, 1.5, 4, 6.5, 9, 11.5 and 14 % (w/v EtOH)) during premating, mating, gestation and lactation and continuation of exposure of the F(1) from weaning until killed. Immune assessments were performed at postnatal days (PNDs) 21, 42 and 70. Keyhole limpet hemocyanin (KLH)-specific immune responses were evaluated following subcutaneous immunizations on PNDs 21 and 35. EtOH exposure affected innate as well as adaptive immune responses. The most sensitive immune parameters included white blood cell subpopulations, ConA-stimulated splenocyte proliferation, LPS-induced NO and TNF-α production by adherent splenocytes and KLH-specific immune responses. Most parameters showed recovery after cessation of EtOH exposure after weaning in the 14 % exposure group. However, effects on LPS-induced NO and TNF-α production by adherent splenocytes and KLH-specific parameters persisted until PND 70. The results demonstrate the relative sensitivity to EtOH of especially functional immune parameters and confirm the added value of immune parameters in the EOGRTS. Furthermore, this study identified an expanded KLH-specific parameter set and LPS-induced NO and TNF-α production by adherent splenocytes as valuable parameters that can provide additional information on functional immune effects. 23395665 Facile one-pot synthesis of novel dispirooxindole-pyrrolidine derivatives and their antimicrobial and anticancer activity against A549 human lung adenocarcinoma cancer cell line. Novel dispirooxindole-pyrrolidine derivatives have been synthesized through 1,3-dipolar cycloaddition of an azomethine ylide generated from isatin and sarcosine with the dipolarophile 3-(1H-indol-3-yl)-3-oxo-2-(2-oxoindolin-3-ylidene)propanenitrile, and also spiro compound of acenaphthenequinone obtained by the same optimized reaction condition. Synthesized compounds were evaluated for their antimicrobial activity and all the compounds shown significant activity. Anticancer activity was evaluated against A549 human lung adenocarcinoma cancer cell lines. Compounds 7b, 7g, 7i and 7r exhibit very good anticancer activity 62.96%, 62.03%, 67.67% and 60.22%, respectively, at the dose of 200μg/mL and compound 7i shows IC50 value in 50μg/mL. 23565607 Predicting Transition Temperatures of Elastin-Like Polypeptide Fusion Proteins. Elastin-like polypeptides (ELPs) are thermally sensitive peptide polymers that undergo thermally triggered phase separation and this behavior is imparted to soluble proteins when they are fused to an ELP. The transition temperature of the ELP fusion protein is observed to be different than that of a free ELP, indicating that the surface properties of the fused protein modulate the thermal behavior of ELPs. Understanding this effect is important for the rational design of applications that exploit the phase transition behavior of ELP fusion proteins. We had previously developed a biophysical model that explained the effect of hydrophobic proteins on depressing the transition temperature of ELP fusion proteins relative to free ELP. Here, we extend the model to elucidate the effect of hydrophilic proteins on the thermal behavior of ELP fusion proteins. A linear correlation was found between overall residue composition of accessible protein surface weighted by a characteristic transition temperature for each residue and the difference in transition temperatures between the ELP protein fusion and the corresponding free ELP. In breaking down the contribution of residues to polar, nonpolar, and charged, the model revealed that charged residues are the most important parameter in altering the transition temperature of an ELP fusion relative to the free ELP. 23528251 Cross-talk between constitutive androstane receptor and hypoxia-inducible factor in the regulation of gene expression. Hypoxia inducible factor (HIF) and 5'-AMP-activated protein kinase are often activated under similar physiological conditions. Constitutive androstane receptor (CAR) translocates into the nucleus in accordance with 5'-AMP-activated protein kinase and thus confers transactivation. The aim of the present study was to investigate a possible link between CAR and HIFα. Phenobarbital (PB), a typical CAR activator, increased the gene expression of HIF-target genes in the livers of mice, including erythropoietin, heme oxygenase-1 and vascular endothelial growth factor-a. PB induced an accumulation of nuclear HIF-1α and an increase in the HIF-responsive element-mediated transactivation in HepG2 cells. Cobalt chloride, a typical HIF activator, induced the gene expression of CAR-target genes, including cyp2b9 and cyp2b10, an accumulation of nuclear CAR and an increase in the PB-responsive enhancer module-mediated transactivation in the mouse liver. Immunoprecipitation-immunoblot and chromatin immunoprecipitation analyses suggest that CAR binds to the PB-responsive enhancer module with HIF-1α in the liver of untreated mice and that the complex dissociates upon PB treatment. Taken together these results suggest that CAR and HIF-α interact and reciprocally modulate the functions of each other. 23279886 The significance of low substrate concentration measurements for mechanistic interpretation in cholinesterases. Cholinesterases do not follow the Michaelis-Menten kinetics. In the past, many reaction schemes were suggested to explain their complex interactions during the substrate turnover. Covalent catalysis was recognized very early and therefore, double intermediate traditional reaction scheme for the hydrolysis of good substrates at low concentrations was postulated. However, at intermediate and high substrate concentrations homotropic pseudocooperative effects take place in all cholinesterases, due to the nature of their buried active center. In this study, the significance and usefulness of experimental data obtained at low substrate concentrations, where only one substrate molecule accesses the active site at a time, are to be specified for the overall mechanistic evaluations. Indeed, different interpretations are expected when data are processed with equations derived from different reaction schemes. Consequently, the scheme with two substrate binding sites which comprises the structurally evidenced fully occupied active site as ultimate cause for substantially decreased cholinesterase activity at extremely high substrate concentrations is considered here. A special emphasis is put on butyrylcholinesterase, the enzyme with the largest active site among cholinesterases, where the pseudocooperative effects appear at much higher concentrations than in acetylcholinesterases. 23238611 Dietary intake of magnesium may modulate depression. Depressive symptoms are frequent in students and may lead to countless problems. Several hypotheses associate magnesium with depression because of the presence of this mineral in several enzymes, hormones, and neurotransmitters, which may play a key role in the pathological pathways of depression. The aim of this study was to assess whether magnesium intake could modulate depressive symptoms. A cross-sectional study was conducted on a convenience sample of 402 Iranian postgraduate students studying in Malaysia to assess the relationship between magnesium intake and depressive symptoms. The mean age of the participants was 32.54 ± 6.22 years. The results of the study demonstrated an inverse relationship between magnesium intake and depressive symptoms, which persisted even after adjustments for sex, age, body mass index, monthly expenses, close friends, living on campus, smoking (current and former), education, physical activity, and marital status. 23612487 Sphingosine-1-phosphate promotes the nuclear translocation of β-catenin and thereby induces osteoprotegerin gene expression in osteoblast-like cell lines. Sphingosine-1-phosphate (S1P) is a well-known signaling sphingolipid and bioactive lipid mediator. Recently, it was reported that S1P inhibits osteoclast differentiation and bone resorption. On the other hand, S1P effects on osteoblasts and bone formation are little known. In this study, we investigated the effects of S1P on osteoblasts, using two osteoblast-like cell lines, SaOS-2 and MC3T3-E1. S1P activated phosphatidylinositol 3-kinase (PI3K)/Akt signaling, leading to the inhibition of glycogen synthase kinase-3β and the nuclear translocation of β-catenin, followed by the increase of the transcriptional activity by β-catenin/T-cell factor complex formation in both SaOS-2 cells and MC3T3-E1 cells. The inhibitors of PI3K and Akt suppressed S1P-induced nuclear localization of β-catenin. We further investigated the effects of PI3K/Akt signaling on the Wnt/β-catenin signaling pathway, since β-catenin takes a central role in this signaling pathway. Both inhibitors for PI3K and Akt suppressed the nuclear localization of β-catenin and T-cell factor transcriptional activity induced by Wnt-3a. S1P increased the amount of osteoprotegerin at both mRNA and protein levels, and increased the activity of alkaline phosphatase, leading to the mineralization. These findings suggest that S1P activates the PI3K/Akt signaling pathway leading to the promotion of nuclear translocation of β-catenin in osteoblast-like cells, resulting in the upregulation of osteoptotegerin and osteoblast differentiation markers including alkaline phosphatase, probably relating to the inhibition of osteoclast formation and the mineralization, respectively. 23561183 High performance thin layer chromatography-densitometry: A step further for quality control of cranberry extracts. A method for selective quantitation of catechin, proanthocyanidin (PAC) A2 and PAC-B1 in American cranberry (Vaccinium macrocarpon) extracts using high performance thin layer chromatography (HPTLC)-densitometry is presented. Methylene chloride/ethyl acetate/formic acid (6:10:1, v/v) as the mobile phase and 1% vanillin hydrochloric solution as staining reagent were used. In these conditions, three standards considered as quality markers, catechin, PAC-A2 and PAC-B1, were well resolved allowing simultaneous quantitation on one plate. All standards were quantified in the range of 0.7-5μg with RSD of repeatability and intermediate precision not exceeding 5%. Catechin, PAC-A2 and PAC-B1 profiles of cranberry extracts were analysed regarding global PAC amounts obtained by BL-DMAC assay. It appears clearly that HPTLC-densitometry process provides additional information which, combined with BL-DMAC results, allows qualitative and quantitative control of cranberry extracts. Particularly, densitometric assay highlighted degradation of PACs in a 7day-extract, leading to high overestimation with BL-DMAC protocol. 23621857 Synthesis and Cytotoxic Evaluation of Acylated Brefeldin A Derivatives as Potential Anticancer Agents. Brefeldin A (BFA) has attracted considerable attention because of its potential function in cancer prevention. However, its therapeutic use is limited by its poor bioavailability. The modifications on BFA were difficult because of its low stability and selectivity toward two hydroxyl groups within the same molecule. In this study, we report the selective acylation of BFA under mild conditions and the preparation of a series of monoacylated and diacylated BFA derivatives. Their cytotoxicity, antitumor activity against TE-1 cell, and molecular properties of adsorption, distribution, metabolism, and elimination were evaluated. BFA 7-O-benzoate, BFA 4,7-O-dibenzoate, and BFA 7-O-biotin carboxylate showed the most potent cytotoxic activity, with GI50 values of 0.39, 0.46, and 0.50μM respectively. Molecular docking of these analogs revealed that the derivatives were well tolerated at the interface between ARF1 and its guanine nucleotide exchange factor ARNO. Our results may serve as a basis for the development of novel potential anti-cancer agents from BFA derivatives. This article is protected by copyright. All rights reserved. 23432912 Structural and mechanistic principles of intramembrane proteolysis--lessons from rhomboids. Intramembrane proteases cleave membrane proteins in their transmembrane helices to regulate a wide range of biological processes. They catalyse hydrolytic reactions within the hydrophobic environment of lipid membranes where water is normally excluded. How? Do the different classes of intramembrane proteases share any mechanistic principles? In this review these questions will be discussed in view of the crystal structures of prokaryotic members of the three known catalytic types of intramembrane proteases published over the past 7 years. Rhomboids, the intramembrane serine proteases that are the best understood family, will be the initial area of focus, and the principles that have arisen from a number of structural and biochemical studies will be considered. The site-2 metalloprotease and GXGD-type aspartyl protease structures will then be discussed, with parallels drawn and differences highlighted between these enzymes and the rhomboids. Despite the significant advances achieved so far, to obtain a detailed understanding of the mechanism of any intramembrane protease, high-resolution structural information on the substrate-enzyme complex is required. This remains a major challenge for the field. 23497876 Application of reduced graphene oxide and carbon nanotube modified electrodes for measuring the enzymatic activity of alcohol dehydrogenase. An electrochemical method was developed to measure the enzymatic activity of alcohol dehydrogenase (ADH) by monitoring the amount of reduced nicotinamide adenine dinucleotide (NADH) generated in the catalysed oxidation of ethanol by ADH. The concentration of NADH was determined by amperometric measurements, which recorded the oxidation current of NADH versus time on reduced graphene oxide and functionalised multi-walled carbon nanotube modified electrodes. The initial reaction rates and the apparent Michaelis constants of the enzymatic reaction were obtained in the absence and presence of Al(3+) and nanometre-sized tridecameric aluminium polycationic (nano-Al(13)) species. The results showed that Al(3+) and nano-Al(13) exhibited inhibitory effect on the enzymatic activity of ADH. Fluorescence and circular dichroism spectra indicated the inhibitory effect was likely caused by the conformational changes of ADH and/or NADH induced by Al(3+) and nano-Al(13). 23444256 Emtricitabine/tenofovir disoproxil fumarate: a review of its use in HIV-1 pre-exposure prophylaxis. The fixed-dose combination of emtricitabine (FTC) 200 mg and tenofovir disoproxil fumarate (TDF) 300 mg (Truvada(®)), administered orally once daily, is widely used as part of first-line regimens for the treatment of HIV-1 infection. Recently, once-daily administration of FTC/TDF was approved in the USA for pre-exposure prophylaxis in conjunction with safer sex practices to reduce the risk of sexually acquired HIV-1 in high-risk adults who are not infected. To date, results of four large, randomized, double-blind, placebo-controlled, multicentre trials with FTC/TDF as pre-exposure prophylaxis have been published. Three studies showed statistically significant reductions in the number of individuals with emergent HIV-1 infection when FTC/TDF was compared with placebo over the ≈1- to 2-year study periods. Efficacy (i.e. risk reduction relative to placebo) was 44 % in the iPrEx trial in men who have sex with men, 75 % in the Partners PrEP study in heterosexual HIV-1-serodiscordant couples and 62 % in the TDF2 trial in heterosexual men and women. The fourth study (FEM-PrEP) in heterosexual women did not show a statistically significant difference between FTC/TDF and placebo, although low adherence rates reported in this trial may have been a factor. No unexpected adverse events were reported in the trials. However, since pre-exposure prophylaxis involves long-term administration of drugs to healthy individuals, it is important to monitor the long-term safety of FTC/TDF (e.g. renal function, bone mineral density) in this setting. Other notable considerations include adherence, cost and the potential for development of drug resistance. Interim guidelines are available for prescribing FTC/TDF as pre-exposure prophylaxis. If used appropriately in selected high-risk individuals, pre-exposure prophylaxis with FTC/TDF represents an important additional strategy to reduce the spread of HIV-1 infection, which continues to be a significant global concern. 23220291 Toxicological analysis of limonene reaction products using an in vitro exposure system. Epidemiological investigations suggest a link between exposure to indoor air chemicals and adverse health effects. Consumer products contain reactive chemicals which can form secondary pollutants which may contribute to these effects. The reaction of limonene and ozone is a well characterized example of this type of indoor air chemistry. The studies described here characterize an in vitro model using an epithelial cell line (A549) or differentiated epithelial tissue (MucilAir™). The model is used to investigate adverse effects following exposure to combinations of limonene and ozone. In A549 cells, exposure to both the parent compounds and reaction products resulted in alterations in inflammatory cytokine production. A one hour exposure to limonene+ozone resulted in decreased proliferation when compared to cells exposed to limonene alone. Repeated dose exposures of limonene or limonene+ozone were conducted on MucilAir™ tissue. No change in proliferation was observed but increases in cytokine production were observed for both the parent compounds and reaction products. Factors such as exposure duration, chemical concentration, and sampling time point were identified to influence result outcome. These findings suggest that exposure to reaction products may produce more severe effects compared to the parent compound. 23240993 Porosity of pillared clays studied by hyperpolarized 129Xe NMR spectroscopy and Xe adsorption isotherms. The influence of the layer charge on the microstructure was studied for a series of three hybrid pillared interlayered clays based on the organic dication Me(2)DABCO(2+) and charge reduced synthetic fluorohectorites. To get a detailed picture of the local arrangements within the interlayer space, multinuclear solid-state NMR spectroscopy was performed in conjunction with high-resolution (129)Xe MAS NMR, temperature-dependent wide-line 1D and 2D (129)Xe NMR, and Ar/Ar(l) and Xe/Xe(l) physisorption measurements. The resulting layer charge (x) for the three samples are 0.48, 0.44, and 0.39 per formula unit (pfu). The samples exhibit BET equivalent surfaces between 150 and 220 m(2)/g and pore volumes which increase from 0.06 to 0.11 cm(3)/g while the layer charge reduces. 1D and 2D (1)H, (13)C, (19)F, and (29)Si MAS data reveal that the postsynthetic charge reduction induces regions with higher defect concentrations within the silicate layers. Although the pillars tend to avoid these defect-rich regions, a homogeneous and regular spacing of the Me(2)DABCO(2+) pillars is established. Both the Ar/Ar(l) physisorption and (129)Xe NMR measurements reveal comparable pore dimensions. The trend of the temperature-dependent wide-line (129)Xe spectra as well as the exchange in the EXSY spectra is typical for a narrow 2D pore system. (129)Xe high-resolution experiments allow for a detailed description of the microstructure. For x = 0.48 a bimodal distribution with pore diameters between 5.9 and 6.4 Å is observed. Reducing the layer charge leads to a more homogeneous pore structure with a mean diameter of 6.6 Å (x = 0.39). The adsorption enthalpies ΔH(ads) determined from the temperature-dependent (129)Xe chemical shift data fit well to the ones derived from the Xe/Xe(l) physisorption measurements in the high-pressure limit while the magnitude of ΔH(ads) in the low-pressure limit is significantly larger. Thus, the (129)Xe data are influenced by adsorbate-adsorbent as well as adsorbate-adsorbate interactions. 23517126 Growth Inhibition of Human Colon Carcinoma Cells by Sesquiterpenoids and Tetralones of Zygogynum calothyrsum. Bioassay-guided phytochemical investigation of Zygogynum calothyrsum using the human colon carcinoma cell lines COLO205 and KM12 led to the isolation of three new drimane-type sesquiterpenoids, 1β-p-hydroxy-E-cinnamoyldrimeninol (1), 1β-p-hydroxy-E-cinnamoyl-5α-hydroxydrimeninol (2), and methyl ether of 1β-p-hydroxy-E-cinnamoyl-12α-methoxydrimeninol (3). Also isolated was the known 1β-p-coumaroyloxypolygodial (4) together with two new tetralones, 3'-deoxyisozygolone A (5) and calothyrlone A (9), three known tetralones, isozygolone A (6), zygolone A (7), and 4'-O-methylzygolone A (8), and a known cinnamolide (10). Compounds 1, 7, and 8 demonstrated higher cytotoxicity against COLO205 (GI50 18, 17, and 11 μM, respectively) and KM12 (GI50 14, 14, and 17 μM, respectively) than the other compounds. 23292752 New oral anticoagulants: comparative pharmacology with vitamin K antagonists. New oral anticoagulants (OACs) that directly inhibit Factor Xa (FXa) or thrombin have been developed for the long-term prevention of thromboembolic disorders. These novel agents provide numerous benefits over older vitamin K antagonists (VKAs) due to major pharmacological differences. VKAs are economical and very well characterized, but have important limitations that can outweigh these advantages, such as slow onset of action, narrow therapeutic window and unpredictable anticoagulant effect. VKA-associated dietary precautions, monitoring and dosing adjustments to maintain international normalized ratio (INR) within therapeutic range, and bridging therapy, are inconvenient for patients, expensive, and may result in inappropriate use of VKA therapy. This may lead to increased bleeding risk or reduced anticoagulation and increased risk of thrombotic events. The new OACs have rapid onset of action, low potential for food and drug interactions, and predictable anticoagulant effect that removes the need for routine monitoring. FXa inhibitors, e.g. rivaroxaban and apixaban, are potent, oral direct inhibitors of prothrombinase-bound, clot-associated or free FXa. Both agents have a rapid onset of action, a wide therapeutic window, little or no interaction with food and other drugs, minimal inter-patient variability, and display similar pharmacokinetics in different patient populations. Since both are substrates, co-administration of rivaroxaban and apixaban with strong cytochrome P450 (CYP) 3A4 and permeability glycoprotein (P-gp) inhibitors and inducers can result in substantial changes in plasma concentrations due to altered clearance rates; consequently, their concomitant use is contraindicated and caution is required when used concomitantly with strong CYP3A4 and P-gp inducers. Although parenteral oral direct thrombin inhibitors (DTIs), such as argatroban and bivalirudin, have been on the market for years, DTIs such as dabigatran are novel synthetic thrombin antagonists. Dabigatran etexilate is a low-molecular-weight non-active pro-drug that is administered orally and converted rapidly to its active form, dabigatran--a potent, competitive and reversible DTI. Dabigatran has an advantage over the indirect thrombin inhibitors, unfractionated heparin and low-molecular-weight heparin, in that it inhibits free and fibrin-bound thrombin. The reversible binding of dabigatran may provide safer and more predictable anticoagulant treatment than seen with irreversible, non-covalent thrombin inhibitors, e.g. hirudin. Dabigatran shows a very low potential for drug-drug interactions. However, co-administration of dabigatran etexilate with other anticoagulants and antiplatelet agents can increase the bleeding risk. Although the new agents are pharmacologically better than VKAs--particularly in terms of fixed dosing, rapid onset of action, no INR monitoring and lower risk of drug interactions--there are some differences between them: the bioavailability of dabigatran is lower than rivaroxaban and apixaban, and so the dabigatran dosage required is higher; lower protein binding of dabigatran reduces the variability related to albuminaemia. The risk of metabolic drug-drug interactions also appears to differ between OACs: VKAs > rivaroxaban > apixaban > dabigatran. The convenience of the new OACs has translated into improvements in efficacy and safety as shown in phase III randomized trials. The new anticoagulants so far offer the greatest promise and opportunity for the replacement of VKAs. 23463898 Cyclic denaturation and renaturation of double-stranded DNA by redox-state switching of DNA intercalators. Hybridization of complementary nucleic acid strands is fundamental to nearly all molecular bioanalytical methods ranging from polymerase chain reaction and DNA biosensors to next generation sequencing. For nucleic acid amplification methods, controlled DNA denaturation and renaturation is particularly essential and achieved by cycling elevated temperatures. Although this is by far the most used technique, the management of rapid temperature changes requires bulky instrumentation and intense power supply. These factors so far precluded the development of true point-of-care tests for molecular diagnostics. To overcome this limitation we explored the possibility of using electrochemical means to control reversible DNA hybridization by using the electroactive intercalator daunomycin (DM). We show that redox-state switching of DM altered its properties from DNA binding to nonbinding, under otherwise constant conditions, and thus altered the thermodynamic stability of duplex DNA. The operational principle was demonstrated using complementary synthetic 20mer and 40mer DNA oligonucleotides. Absorbance-based melting curve analysis revealed significantly higher melting temperatures for DNA in the presence of oxidized compared to chemically reduced DM. This difference was exploited to drive cyclic electrochemically controlled denaturation and renaturation. Analysis with in situ UV-vis and circular dichroism spectroelectrochemistry, as two independent techniques, indicated that up to 80% of the DNA was reversibly hybridized. This remarkable demonstration of electrochemical control of five cycles of DNA denaturation and renaturation, under otherwise constant conditions, could have wide-ranging implications for the future development of miniaturized analytical systems for molecular diagnostics and beyond. 23313712 Interaction of polyhexamethylene biguanide hydrochloride (PHMB) with phosphatidylcholine containing o/w emulsion and consequences for microbicidal efficacy and cytotoxicity. Oil-in-water (o/w) emulsions containing egg yolk phosphatidylcholine (EPC) were combined with aqueous polyhexamethylene biguanide hydrochloride (PHMB). The PHMB concentration in the aqueous phase was estimated by filtration centrifugation experiments. In parallel, PHMB concentration was assessed utilizing cytotoxicity assays (neutral red) on cultured murine fibroblasts (L929 cells) and tests of bactericidal efficacy on either Pseudomonas aeruginosa or Staphylococcus aureus. Biological tests were performed in cell culture medium. Filtration centrifugation experiments demonstrated much higher aqueous PHMB concentrations than did the assays for biologically effective PHMB. Therefore, biological test systems should preferably be used to verify effective PHMB concentrations. Tests of microbicidal efficacy in which the same 0.05% PHMB o/w emulsion was re-used 8 times revealed a drug delivery system activated by the presence of test bacteria. 23293875 Clinal variation in colony breeding structure and level of inbreeding in the subterranean termites Reticulitermes flavipes and R. grassei. Social insects exhibit remarkable variation in their colony breeding structures, both within and among species. Ecological factors are believed to be important in shaping reproductive traits of social insect colonies, yet there is little information linking specific environmental variables with differences in breeding structure. Subterranean termites (Rhinotermitidae) show exceptional variation in colony breeding structure, differing in the number of reproductives and degree of inbreeding; colonies can be simple families headed by a single pair of monogamous reproductives (king and queen) or they can be extended families headed by multiple inbreeding neotenic reproductives (wingless individuals). Using microsatellite markers, we characterized colony breeding structure and levels of inbreeding in populations over large parts of the range of the subterranean termites Reticulitermes flavipes in the USA and R. grassei in Europe. Combining these new data with previous results on populations of both species, we found that latitude had a strong effect on the proportion of extended-family colonies in R. flavipes and on levels of inbreeding in both species. We examined the effect of several environmental variables that vary latitudinally; while the degree of inbreeding was greatest in cool, moist habitats in both species, seasonality affected the species differently. Inbreeding in R. flavipes was most strongly associated with climatic variables (mean annual temperature and seasonality), whereas nonclimatic variables, including the availability of wood substrate and soil composition, were important predictors of inbreeding in R. grassei. These results are the first showing that termite breeding structure is shaped by local environmental factors and that species can vary in their responses to these factors. 23072918 In vitro and in vivo approaches to study osteocyte biology. Osteocytes, the most abundant cell population of the bone lineage, have been a major focus in the bone research field in recent years. This population of cells that resides within mineralized matrix is now thought to be the mechanosensory cell in bone and plays major roles in the regulation of bone formation and resorption. Studies of osteocytes had been impaired by their location, resulting in numerous attempts to isolate primary osteocytes and to generate cell lines representative of the osteocytic phenotype. Progress has been achieved in recent years by utilizing in vivo genetic technology and generation of osteocyte directed transgenic and gene deficiency mouse models. We will provide an overview of the current in vitro and in vivo models utilized to study osteocyte biology. We discuss generation of osteocyte-like cell lines and isolation of primary osteocytes and summarize studies that have utilized these cellular models to understand the functional role of osteocytes. Approaches that attempt to selectively identify and isolate osteocytes using fluorescent protein reporters driven by regulatory elements of genes that are highly expressed in osteocytes will be discussed. In addition, recent in vivo studies utilizing overexpression or conditional deletion of various genes using dentin matrix protein (Dmp1) directed Cre recombinase are outlined. In conclusion, evaluation of the benefits and deficiencies of currently used cell lines/genetic models in understanding osteocyte biology underlines the current progress in this field. The future efforts will be directed towards developing novel in vitro and in vivo models that would additionally facilitate in understanding the multiple roles of osteocytes. This article is part of a Special Issue entitled "The Osteocyte". 23300056 Determination of key receptor-ligand interactions of dopaminergic arylpiperazines and the dopamine D2 receptor homology model. Interest in structure-based G-protein-coupled receptor (GPCR) ligand discovery is huge, given that almost 30 % of all approved drugs belong to this category of active compounds. The GPCR family includes the dopamine receptor subtype D2 (D2DR), but unfortunately--as is true of most GPCRs--no experimental structures are available for these receptors. In this publication, we present the molecular model of D2DR based on the previously published crystal structure of the dopamine D3 receptor (D3DR). A molecular modeling study using homology modeling and docking simulation provided a rational explanation for the behavior of the arylpiperazine ligand. The observed binding modes and receptor-ligand interactions provided us with fresh clues about how to optimize selectivity for D2DR receptors. 23137957 Dietary exposure to mycotoxins and health risk assessment in the second French total diet study. Mycotoxins are produced in plants by micro-fungi species, and naturally contaminated the food chain. In the second French total diet study (TDS), mycotoxins were analyzed in 577 food samples collected in mainland France to be representative of the population diet and prepared ((as consumed)). Highest mean concentrations were found in wheat and cereal-based products (bread, breakfast cereals, pasta, pastries, pizzas and savoury pastries…). Exposure of adult and child populations was assessed by combining national consumption data with analytical results, using lowerbound (LB) and upperbound (UB) assumptions for left-censorship management. Individual exposures were compared with available health-based guidance values (HBGV). Only the exposure to deoxynivalenol (DON) and its acetylated derivatives was found to significantly exceed the HBGV in LB in adults (0.5% [0.1; 0.8]) and children (5% [4; 6]). HBGV was exceeded in UB only for T-2 and HT-2 toxins by, respectively, 0.2% [0.02; 0.05] and 4% [3; 5] of adults, and 11% [9; 12] and 35% [32; 37] of children. Although the exposures assessed were generally lower than the previous French TDS, the results indicated a health concern for trichothecenes and a need to reduce dietary exposure as well as analytical limits. 23178949 Pocketed microneedles for rapid delivery of a liquid-state botulinum toxin A formulation into human skin. Botulinum toxin A (BT) is used therapeutically for the treatment of primary focal hyperhidrosis, a chronic debilitating condition characterised by over-activity of the eccrine sweat glands. Systemic toxicity concerns require BT to be administered by local injection, which in the case of hyperhidrosis means multiple painful intradermal injections by a skilled clinician at 6-monthly intervals. This study investigates the potential of a liquid-loaded pocketed microneedle device to deliver botulinum toxin A into the human dermis with the aim of reducing patient pain, improving therapeutic targeting and simplifying the administration procedure. Initially, β-galactosidase was employed as a detectable model for BT to (i) visualise liquid loading of the microneedles, (ii) determine residence time of a liquid formulation on the device and (iii) quantify loaded doses. An array of five stainless steel pocketed microneedles was shown to possess sufficient capacity to deliver therapeutic doses of the potent BT protein. Microneedle-mediated intradermal delivery of β-galactosidase and formaldehyde-inactivated botulinum toxoid revealed effective deposition and subsequent diffusion within the dermis. This study is the first to characterise pocketed microneedle delivery of a liquid formulation into human skin and illustrates the potential of such systems for the cutaneous administration of potent proteins such as BT. A clinically appropriate microneedle delivery system for BT could have a significant impact in both the medical and cosmetic industries. 23376780 Consumer and farmer safety evaluation of application of botanical pesticides in black pepper crop protection. This study presents a consumer and farmer safety evaluation on the use of four botanical pesticides in pepper berry crop protection. The pesticides evaluated include preparations from clove, tuba root, sweet flag and pyrethrum. Their safety evaluation was based on their active ingredients being eugenol, rotenone, β-asarone and pyrethrins, respectively. Botanical pesticides from Acorus calamus are of possible concern because of the genotoxic and carcinogenic ingredient β-asarone although estimated margins of exposure (MOE) for consumers indicate a low priority for risk management. For the other three botanical pesticides the margin of safety (MOS) between established acute reference doses and/or acceptable daily intake values and intake estimates for the consumer, resulting from their use as a botanical pesticide are not of safety concern, with the exception for levels of rotenone upon use of tuba root extracts on stored berries. Used levels of clove and pyrethrum as botanical pesticides in pepper berry crop production is not of safety concern for consumers or farmers, whereas for use of tuba root and sweet flag some risk factors were defined requiring further evaluation and/or risk management. It seems prudent to look for alternatives for use of sweet flag extracts containing β-asarone. 23355488 Polycyclic peptide therapeutics. Owing to their excellent binding properties, high stability, and low off-target toxicity, polycyclic peptides are an attractive molecule format for the development of therapeutics. Currently, only a handful of polycyclic peptides are used in the clinic; examples include the antibiotic vancomycin, the anticancer drugs actinomycin D and romidepsin, and the analgesic agent ziconotide. All clinically used polycyclic peptide drugs are derived from natural sources, such as soil bacteria in the case of vancomycin, actinomycin D and romidepsin, or the venom of a fish-hunting coil snail in the case of ziconotide. Unfortunately, nature provides peptide macrocyclic ligands for only a small fraction of therapeutic targets. For the generation of ligands of targets of choice, researchers have inserted artificial binding sites into natural polycyclic peptide scaffolds, such as cystine knot proteins, using rational design or directed evolution approaches. More recently, large combinatorial libraries of genetically encoded bicyclic peptides have been generated de novo and screened by phage display. In this Minireview, the properties of existing polycyclic peptide drugs are discussed and related to their interesting molecular architectures. Furthermore, technologies that allow the development of unnatural polycyclic peptide ligands are discussed. Recent application of these technologies has generated promising results, suggesting that polycyclic peptide therapeutics could potentially be developed for a broad range of diseases. 22991192 Human apolipoprotein E isoforms differentially affect bone mass and turnover in vivo. The primary role of apolipoprotein E (apoE) is to mediate the cellular uptake of lipoproteins. However, a new role for apoE as a regulator of bone metabolism in mice has recently been established. In contrast to mice, the human APOE gene is characterized by three common isoforms APOE ε2, ε3, and ε4 that result in different metabolic properties of the apoE isoforms, but it remains controversial whether the APOE polymorphism influences bone traits in humans. To clarify this, we investigated bone phenotypes of apoE knock-in (k.i.) mice, which express one human isoform each (apoE2 k.i., apoE3 k.i., apoE4 k.i.) in place of the mouse apoE. Analysis of 12-week-old female k.i. mice revealed increased levels of biochemical bone formation and resorption markers in apoE2 k.i. animals as compared to apoE3 k.i. and apoE4 k.i., with a reduced osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) ratio in apoE2 k.i., indicating increased turnover with prevailing resorption in apoE2 k.i. Accordingly, histomorphometric and micro-computed tomography (µCT) analyses demonstrated significantly lower trabecular bone mass in apoE2 than in apoE3 and apoE4 k.i. animals, which was reflected by a significant reduction of lumbar vertebrae maximum force resistance. Unlike trabecular bone, femoral cortical thickness, and stability was not differentially affected by the apoE isoforms. To extend these observations to the human situation, plasma from middle-aged healthy men homozygous for ε2/ε2, ε3/ε3, and ε4/ε4 (n = 21, n = 80, n = 55, respectively) was analyzed with regard to bone turnover markers. In analogy to apoE2 k.i. mice, a lower OPG/RANKL ratio was observed in the serum of ε2/ε2 carriers as compared to ε3/ε3 and ε4/ε4 individuals (p = 0.02 for ε2/ε2 versus ε4/ε4). In conclusion, the current data strongly underline the general importance of apoE as a regulator of bone metabolism and identifies the APOE ε2 allele as a potential genetic risk factor for low trabecular bone mass and vertebral fractures in humans. 23623419 Facile synthesis of new imidazo[1,2-a]pyridines carrying 1,2,3-triazoles via click chemistry and their antiepileptic studies. The present article reports the synthesis and anticonvulsant studies of new 2-arylimidazo[1,2-a]pyridines carrying suitably substituted 1,2,3-triazoles as well as their intermediates. The structures of newly synthesized compounds were confirmed by various spectroscopic techniques. The anticonvulsant study was carried out by MES and scPTZ screening methods, while their toxicity study was performed following Rotarod method. The active compounds showed enhanced seizure control in scPTZ method when compared with that of MES method. Compounds 3f, 4c, 4f, 5k, 5p and 5w carrying active pharmacophores exhibited complete protection against seizure and their results were comparable with standard drug diazepam. Majority of new compounds were found to be non-toxic, while few of them showed toxicity at 100mg/kg. The clogP values of target compounds are in the range of 3.5-5.3, which confirm their lipophilic nature. 23627834 Dual Stimuli-Responsive Poly(N-isopropylacrylamide)-b-poly(l-histidine) Chimeric Materials for the Controlled Delivery of Doxorubicin into Liver Carcinoma. A series of dual stimuli responsive synthetic polymer bioconjugate chimeric materials, poly(N-isopropylacrylamide)55-block-poly(l-histidine)n [p(NIPAM)55-b-p(His)n] (n = 50, 75, 100, 125), have been synthesized by employing reversible addition-fragmentation chain transfer polymerization of NIPAM, followed by ring-opening polymerization of α-amino acid N-carboxyanhydrides. The dual stimuli responsive properties of the resulting biocompatiable and membrenolytic p(NIPAM)55-b-p(His)n polymers are investigated for their use as a stimuli responsive drug carrier for tumor targeting. Highly uniform self-assembled micelles (∼55 nm) fabricated by p(NIPAM)55-b-p(His)n polymers display sharp thermal and pH responses in aqueous media. An anticancer drug, doxorubicin (Dox), is effectively encapsulated in the micelles and the controlled Dox release is investigated in different temperature and pH conditions. Antitumor effect of the released Dox is also assessed using the HepG2 human hepatocellular carcinoma cell lines. Dox molecules released from the [p(NIPAM)55-b-p(His)n] micelles remain biologically active and have stimuli responsive capability to kill cancer cells. The self-assembling ability of these hybrid materials into uniform micelles and their efficiency to encapsulate Dox makes them a promising drug carrier to cancer cells. The new chimeric materials thus display tunable properties that can make them useful for a molecular switching device and controlled drug delivery applications needing responses to temperature and pH for the improvement of cancer chemotherapy. 23408851 Quantitative analysis of TALE-DNA interactions suggests polarity effects. Transcription activator-like effectors (TALEs) have revolutionized the field of genome engineering. We present here a systematic assessment of TALE DNA recognition, using quantitative electrophoretic mobility shift assays and reporter gene activation assays. Within TALE proteins, tandem 34-amino acid repeats recognize one base pair each and direct sequence-specific DNA binding through repeat variable di-residues (RVDs). We found that RVD choice can affect affinity by four orders of magnitude, with the relative RVD contribution in the order NG > HD ∼ NN ≫ NI > NK. The NN repeat preferred the base G over A, whereas the NK repeat bound G with 10(3)-fold lower affinity. We compared AvrBs3, a naturally occurring TALE that recognizes its target using some atypical RVD-base combinations, with a designed TALE that precisely matches 'standard' RVDs with the target bases. This comparison revealed unexpected differences in sensitivity to substitutions of the invariant 5'-T. Another surprising observation was that base mismatches at the 5' end of the target site had more disruptive effects on affinity than those at the 3' end, particularly in designed TALEs. These results provide evidence that TALE-DNA recognition exhibits a hitherto un-described polarity effect, in which the N-terminal repeats contribute more to affinity than C-terminal ones. 23558236 Design, synthesis and cytotoxicity of cell death mechanism of rotundic acid derivatives. In the present investigation, 16 new rotundic acid (RA) derivatives modified at the C-3, C-23 and C-28 positions were synthesized. The cytotoxicities of the derivatives were evaluated against HeLa, A375, HepG2, SPC-A1 and NCI-H446 human tumor cell lines by MTT assay. Among these derivatives, compounds 4-7 exhibited stronger cell growth inhibitory than RA and compound 4 was found to be the best inhibition activity on five human tumor cell lines with IC50 <10μM. The apoptosis mechanism of compound 4 in HeLa cells was investigated by western blot analysis. The results indicated that compound 4 could induce apoptosis through increasing protein expression of cleaved caspase-3 and Bax, and decreasing protein expression of Bcl-2. In summary, the present work suggests that compound 4 might serve as an effective chemotherapeutic candidate. 23294326 Density of GM1 in nanoclusters is a critical factor in the formation of a spherical assembly of amyloid β-protein on synaptic plasma membranes. The deposition of amyloid β-protein (Aβ) is a pathological hallmark of Alzheimer's disease (AD). We previously found that the ganglioside-enriched microdomains (ganglioside clusters) in presynaptic neuronal membranes play a key role in the initiation of the Aβ assembly process. However, not all ganglioside clusters accelerate Aβ assembly. In the present study, we directly observed a spherical Aβ in an atomic force microscopic study on the morphology of a reconstituted lipid bilayer composed of lipids that were extracted from a detergent-resistant membrane microdomain (DRM) fraction of synaptosomes prepared from aged mouse brain. The Aβ assembly was generated on a distinctive GM1 domain, which was characterized as the Aβ-sensitive ganglioside nanocluster (ASIGN). By using an artificial GM1 cluster-binding peptide, ASIGN was found to have a high density of GM1; therefore, there would be a critical density of GM1 in nanoclusters to induce Aβ binding and assembly. These results suggest that ganglioside-bound Aβ (GAβ), which acts as an endogenous seed for Aβ fibril formation in AD brains, is generated on ASIGN on synaptosomal membranes. 23339678 Impact of ketorolac administration around ovarian stimulation on in vivo and in vitro fertilization and subsequent embryo development. Abstract We performed this study to investigate the effect of ketorolac (a non-steroidal anti-inflammatory drug) administration around ovarian stimulation on in vivo and in vitro fertilization process. Sixty-four female mice (ICR) were injected with ketorolac (0, 7.5, 15 and 30 µg/d) for 3 d starting from the day of eCG treatment. In experiment 1, 41 mice were triggered by hCG and then mated; two-cell embryos were obtained and in vitro development up to blastocyst was observed. In experiment 2, 23 mice were triggered by hCG and mature oocytes were collected; in vitro fertilization rate and subsequent embryo development up to blastocyst was recorded. In experiment 1, the blastocyst-forming rates per in vivo fertilized two-cell embryo showed an inverse relationship with a dosage of ketorolac (97.6%, 64.2%, 35.4% and 25.9%). In experiment 2, degenerated oocytes were frequently observed in a dose-dependent manner (4.3%, 22.9%, 22.4% and 75.0%). Lower fertilization rates were noted in all the three ketorolac-treating groups; blastocyst-forming rate was significantly lower in 30-µg-treating group when compared with the control group. Administration of ketorolac around ovarian stimulation significantly affects the development of in vivo fertilized embryo in a dose-dependent manner. High-dose ketorolac could result in a poor oocyte quality and decreased embryo developmental competence. 23461969 Theoretical Characterization of Galanin Receptor Type 3 (Gal3 ) and Its Interaction with Agonist (GALANIN) and Antagonists (SNAP 37889 and SNAP 398299): An In Silico Analysis. In this study, we report on modeling of galanin receptor type 3 and its interaction with agonist and antagonists using in silico methodologies. Comparative structural modeling of galanin receptor type 3 was based on multiple templates. With the availability of reported selective galanin receptor type 3 antagonists, docking was carried out into the predicted binding site. Similarly, galanin, a reported agonist, was also modeled and then docked into the receptor's active site. CoMFA models were developed using ligand-based (q(2)  = 0.537, r(2)  = 0.961, noc = 5), and receptor-guided (docked mode 1: q(2)  = 0.574, r(2)  = 0.946, noc = 5), (docked mode 2: q(2)  = 0.499, r(2)  = 0.954, noc = 5) alignment schemes. CoMFA contour analysis revealed that bulky substitution around the meta position of the phenyl ring, as well as optimal substitution (para) of the phenyl ring, could produce molecules with improved activity. We also found that Gln79, Ile82, Asp86, Trp88, His99, Ile102, Tyr103, Glu170, Pro174, Ala175, Asp185, Arg273, His277, and Tyr281 are crucial, and mutational studies on these residues could be helpful. The results obtained from this study can further be exploited for structure-based drug design and also help the researchers to identify novel antagonists targeting galanin receptor type 3. 23267857 CYP2C19*17 gain-of-function polymorphism is associated with peptic ulcer disease. Single-nucleotide polymorphisms (SNPs) in the CYP2C gene cluster have been extensively investigated as predisposing factors for nonsteroidal anti-inflammatory drug (NSAID)-induced peptic ulcer disease (PUD) or upper gastrointestinal bleeding (UGIB). However, results have been inconclusive owing to different study designs, limited genotyping strategies, and small sample sizes. We investigated whether eight functional SNPs in the CYP2C family of genes--CYP2C8*3 (rs11572080 and rs10509681), CYP2C8*4, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, and CYP2C19*17--are associated with PUD in 1,239 Caucasian patients. Logistic regression analysis showed that only CYP2C19*17 was associated with PUD (odds ratio additive model: 1.47 (95% confidence interval (CI) 1.12 to 1.92); P = 0.005; R(2) 16%), but not UGIB, independent of NSAID use or Helicobacter pylori infection. PUD distribution varied (P = 0.024) according to CYP2C19*17 genotype: *1/*1, 490 (64.3%); *1/*17, 304 (71.7%); and *17/*17, 31 (73.8%). CYP2C19*17, a gain-of-function polymorphism, is associated with PUD irrespective of etiology. 23512754 Effect of the Potent Antiviral 1-Cinnamoyl-3,11-Dihydroxymeliacarpin on Cytokine Production by Murine Macrophages Stimulated with HSV-2. The limonoid 1-cinnamoyl-3,11-dihydroxymeliacarpin (CDM) isolated from leaf extracts of Melia azedarach L, has potent antiherpetic effect in epithelial cells. Since Meliacine, the partially purified extract source of CDM, has therapeutic effect on murine genital herpes, the potential use of CDM as microbicide against herpetic infections was studied here. To determine the cytotoxic effect of CDM, the MTT assay and acridine orange staining of living cells were performed. The antiherpetic action of CDM was measured by plaque reduction assay, and the immunomodulatory effect was determined by measuring the cytokine production using a bioassay and ELISA method. The results presented here showed that CDM inhibited Herpes Simplex Virus type 2 (HSV-2) multiplication in Vero cells but did not affect its replication in macrophages which were not permissive to HSV infection. In macrophages, levels of TNF-α, IFN-γ, NO, IL-6 and IL-10 were increased by CDM used alone or in combination with HSV-2. Besides, CDM not only synergized TNF-α production combined with IFN-γ, but also prolonged its expression in time. Results indicate that CDM inhibits HSV-2 multiplication in epithelial cells and also increases cytokine production in macrophages, both important actions to the clearance of infecting virus in the mouse vagina. Copyright © 2013 John Wiley & Sons, Ltd. 23576174 Sarmentosumols A to F, New Mono- and Dimeric Alkenylphenols from Piper sarmentosum. Two new mono- and four new dimeric alkenylphenols, namely sarmentosumols A to F (1-6), were isolated from the aerial parts of Piper sarmentosum. The structures of these compounds were determined through a detailed analysis of NMR and MS data. Their antimicrobial activity against Escherichia coli, Staphyloccocus aureus, and Candida albicans, and their cytotoxic activity against human myeloid leukemia (K562) and human lung adenocarcinoma (A549) cell lines were also evaluated. Except for sarmentosumol A (1), whose MIC on S. aureus was reported to be 7.0 µg/mL, none of the other newly discovered compounds exhibited antimicrobial property. The studied compounds did not possess any cytotoxic property. 23553632 The N- and C- termini of ZO-1 are surrounded by distinct proteins and functional protein networks. The proteins and functional protein networks of the tight junction remain incompletely defined. Among the currently known proteins are barrier forming proteins like occludin and the claudin family, scaffolding proteins like ZO-1, and some cytoskeletal, signaling and cell polarity proteins. To define a more complete list of proteins and infer their functional implications, we identified the proteins which are within molecular dimensions of ZO-1 by fusing biotin ligase to either its N- or C-terminus, expressing these fusion proteins in MDCK epithelial cells and purifying and identifying the resulting biotinylated proteins by mass spectrometry. Out of a predicted proteome of ≈ 9000 we identified more than 400 proteins tagged by biotin ligase fused to ZO-1, with both identical and distinct proteins near the N- and C- terminal ends. Those proximal to the N-terminus were enriched in transmembrane tight junction proteins and those proximal to the C-terminus were enriched in cytoskeletal proteins. We also identified many unexpected, but easily rationalized proteins. In addition, functional networks of interacting proteins were tagged, such as the basolateral but not apical polarity network. These results provide a rich inventory of proteins and potential novel insights into functions and protein networks that should catalyze further understanding of tight junction biology. Unexpectedly, the technique demonstrates high spatial resolution which could be generally applied to defining subcellular protein compartmentalization. 23370306 Eight New Diterpenoids and Two New Nor-Diterpenoids from the Stems of Croton cascarilloides. From the stems of Croton cascarilloides, eight new diterpenoids, named crotocascarins A-H (1-8), having a crotofolane skeleton were isolated along with two new nor-diterpenoids (9 and 10), named crotocascarins α and β, derived through rearrangement of the crotofolane skeleton. The structures of these compounds were elucidated by means of extensive one- and two-dimensional NMR spectroscopic analyses. The absolute structures of the diterpene moiety were determined by application of the circular dichroism (CD) rule for the γ-lactone ring. The relative structures of the two crotofolanes (1 and 2) and one rearranged compound (9) were confirmed by X-ray crystallographic analyses. Compounds 1, 2 and 9 possessed 2-methylbutyric acid in their molecules, the absolute configuration of which was found to be 2S by comparison of its HPLC behavior with that of an authentic sample. Therefore, the absolute structures of these crotocascarins (1, 2 and 9) were unambiguously determined. The absolute structures of crotofolanes are reported for the first time in this paper. 23562076 Improved Insulin Sensitivity despite Increased Visceral Adiposity in Mice Deficient for the Immune Cell Transcription Factor T-bet. Low-grade inflammation in fat is associated with insulin resistance, although the mechanisms are unclear. We report that mice deficient in the immune cell transcription factor T-bet have lower energy expenditure and increased visceral fat compared with wild-type mice, yet paradoxically are more insulin sensitive. This striking phenotype, present in young T-bet(-/-) mice, persisted with high-fat diet and increasing host age and was associated with altered immune cell numbers and cytokine secretion specifically in visceral adipose tissue. However, the favorable metabolic phenotype observed in T-bet-deficient hosts was lost in T-bet(-/-) mice also lacking adaptive immunity (T-bet(-/-)xRag2(-/-)), demonstrating that T-bet expression in the adaptive rather than the innate immune system impacts host glucose homeostasis. Indeed, adoptive transfer of T-bet-deficient, but not wild-type, CD4(+) T cells to Rag2(-/-) mice improved insulin sensitivity. Our results reveal a role for T-bet in metabolic physiology and obesity-associated insulin resistance. 23138972 Homogeneous palladium-catalyzed asymmetric hydrogenation. The transition metal catalyzed asymmetric hydrogenation of unsaturated compounds arguably presents one of the most attractive methods for the synthesis of chiral compounds. Over the last few decades, Pd has gradually grown up as a new and popular metal catalyst in homogeneous asymmetric hydrogenation the same as traditional Ru, Rh and Ir catalysts. Much progress has been successfully achieved in the asymmetric reduction of imines, enamines, olefins, ketones and heteroarenes. It was also found that palladium catalyzed asymmetric hydrogenation could be used as a key step in tandem reactions to quickly synthesize chiral compounds. This tutorial review intends to offer an overview of recent progress in homogeneous palladium catalyzed asymmetric hydrogenation and should serve as an inspiration for further advances in this area. 23282066 Evaluation of animal models for intestinal first-pass metabolism of drug candidates to be metabolized by CYP3A enzymes via in vivo and in vitro oxidation of midazolam and triazolam. Abstract 1. To search an appropriate evaluation methodology for the intestinal first-pass metabolism of new drug candidates, grapefruit juice (GFJ)- and vehicle (tap water)-pretreated mice or rats were orally administered midazolam (MDZ) or triazolam (TRZ), and blood levels of the parent compounds and their metabolites were measured by liquid chromatography/MS/MS. A significant effect of GFJ to elevate the blood levels was observed only for TRZ in mice. 2. In vitro experiments using mouse, rat and human intestinal and hepatic microsomal fractions demonstrated that GFJ suppressed the intestinal microsomal oxidation of MDZ and especially TRZ. Substrate inhibition by MDZ caused reduction in 1'-hydroxylation but not 4-hydroxylation in both intestinal and hepatic microsomal fractions. The kinetic profiles of MDZ oxidation and the substrate inhibition in mouse intestinal and hepatic microsomal fractions were very similar to those in human microsomes but were different from those in rat microsomes. Furthermore, MDZ caused mechanism-based inactivation of cytochrome P450 3A-dependent TRZ 1'-hydroxylation in mouse, rat and human intestinal microsomes with similar potencies. 3. These results are useful information in the analysis of data obtained in mouse and rat for the evaluation of first-pass effects of drug candidates to be metabolized by CYP3A enzymes. 23070981 Electric control of the giant Rashba effect in bulk GeTe. Relativistic effects, including the Rashba effect, are increasingly seen as key ingredients in spintronics. A link between Rashba physics and the field of ferroelectrics is established by predicting giant Rashba spin-splitting in bulk GeTe (see the Figure showing the band-structure as well as in-plane and out- of-plane spin polarization for a constant energy cut). 23371451 Increased human dermal microvascular endothelial cell survival induced by cysteamine. BACKGROUND: Cystinosis is an autosomal recessive disease caused by intralysosomal cystine accumulation, treated with cysteamine. Recently, new adverse effects of cysteamine were reported. Skin biopsies showed microvascular proliferation (angioendotheliomatosis). To examine the mechanism of angioendotheliomatosis associated with cysteamine toxicity, we examined the effect of cysteamine on human dermal microvascular endothelial cells (HDMVEC). METHODS: After cysteamine exposure (range 0-3.0 mM) during 24 h, cell viability was measured using water soluble tetrazolium salt-1 (WST-1) in both control HDMVEC and fibroblasts. Cell proliferation and apoptosis rate were measured in HDMVEC by bromodeoxyuridine (BrdU) incorporation and caspase 3 and caspase 7 activity, respectively. Intracellular glutathione (GSH) was measured in HDMVEC after cysteamine exposure of 0, 0.1 or 1.0 mM. Medium and cysteamine were refreshed every 6 h to mimic the in vivo situation. Next, cell viability in HDMVEC was measured after 24 h of GSH exposure (range 0-10.0 mM). RESULTS: HDMVEC viability and proliferation increased after cysteamine exposure 0.03-3.0 mM (p < 0.01) and 0.03-1.0 mM (p = 0.01) respectively; cell viability in fibroblasts was not affected by incubation with cysteamine. Apoptosis remained unaffected by incubation with 0-1.0 mM cysteamine, 3.0 mM caused increased apoptosis. Intracellular GSH was significantly increased after incubation with cysteamine 0.1 mM (p = 0.02) and 1.0 mM (p < 0.01). HDMVEC viability increased after exposure to GSH 1.0-5.0 mM (p < 0.01). CONCLUSION: Cysteamine concentrations, similar to those described in plasma of cystinosis patients, stimulate HDMVEC viability and proliferation and increase intracellular GSH content. We postulate that this mechanism might underlie angioendotheliomatosis induced by cysteamine. 23330847 Hydroxy-terminated conjugated polymer nanoparticles have near-unity bright fraction and reveal cholesterol-dependence of IGF1R nanodomains. Fluorescent nanoparticles have enabled many discoveries regarding how molecular machines function. Quantum dots have been the dominant class of fluorescent nanoparticles but suffer from blinking and from a substantial dark fraction--particles where the fluorescence is never seen--complicating any analysis of biological function. Nanoparticles composed of conjugated fluorescent polymers (Pdots) have recently been shown to have high brightness and no blinking. Here we develop a robust and efficient means to measure the dark fraction of Pdots, conjugating Atto dyes to the nanoparticles and testing fluorescence colocalization of dye and Pdot puncta. This established that the Pdots we generated had minimal dark fraction: ∼3%. The application of nanoparticles in biological environments is highly sensitive to surface functionalization. For Pdots we found that passivation with uncharged hydroxy-terminated polyethylene glycol caused a dramatic reduction in nonspecific cell binding and aggregation compared to a charged coating. Using carbonyl di-imidazole the hydroxy-Pdots were functionalized efficiently with streptavidin for high stability targeting, allowing specific labeling of mammalian cells. Type I insulin-like growth factor receptor (IGF1R) regulates cell survival and development, with roles in aging, heart disease, and cancer. We used hydroxy-Pdots to track the dynamics of IGF1R on a breast cancer cell-line, determining the diffusion characteristics and showing cholesterol-containing membrane nanodomains were important for receptor mobility at the plasma membrane. The near-unity bright fraction and low nonspecific binding of hydroxy-Pdots, combined with Pdot photostability and lack of blinking, provides many advantages for investigations at the single molecule level. 23036893 Effect of combining in vitro estrogenicity data with kinetic characteristics of estrogenic compounds on the in vivo predictive value. With the ultimate aim of increasing the utility of in vitro assays for toxicological risk assessment, a method was developed to calculate in vivo estrogenic potencies from in vitro estrogenic potencies of compounds by taking into account systemic availability. In vitro estrogenic potencies of three model compounds (bisphenol A, genistein, and 4-nonylphenol) relative to ethinylestradiol (EE2), determined with the estrogen receptor alpha (ERα) transcriptional activation assay using hER-HeLa-9903 cells, were taken from literature and used to calculate the EE2 equivalent (EE2EQ) effect doses in the predominantly ERα-dependent rat uterotrophic assay. Compound-specific differences in hepatic clearance relative to the reference compound EE2 were determined in vitro to examine whether in vivo estrogenic potencies reported in literature could be more accurately estimated. The EE2EQ doses allowed to predict in vivo uterotrophic responses within a factor of 6-25 and the inclusion of the hepatic clearance further improved the prediction with a factor 1.6-2.1 for especially genistein and bisphenol A. Yet, the model compounds still were less potent in vivo than predicted based on their EE2 equivalent estrogenic potency and hepatic clearance. For further improvement of the in vitro to in vivo predictive value of in vitro assays, the relevance of other kinetic characteristics should be studied, including binding to carrier proteins, oral bioavailability and the formation of estrogenic metabolites. 23404750 Computational studies identifying entry inhibitor scaffolds targeting the Phe43 cavity of HIV-1 gp120. Targeting protein-protein interactions, such as the HIV-1 gp120-CD4 interface, has become a cutting-edge approach in the current drug discovery scenario. Many small molecules have been developed so far as inhibitors of the interaction between CD4 and HIV-1 gp120. However, due to a variety of reasons such as solubility, drug toxicity and drug resistance, these inhibitors have failed to prove clinically useful. As such, the identification of novel compounds that bind to protein-protein interactions is still a research area of considerable interest. Here, a structure-based virtual screening approach was successfully applied with the aim of identifying novel HIV-1 entry inhibitors targeting the Phe43 pocket of HIV-1 gp120. Several compounds able to inhibit viral replication in cell culture were identified, with the best agent endowed with an EC(50) value of 0.9 μM. Inactivity of all the identified hits toward a mutant (Met475Ile) strain strongly suggests that they interact in the Phe43 cavity of gp120, as intended. Remarkably, all of these small molecules have a chemical scaffold unrelated to any known class of entry inhibitors reported thus far. Overall, our strategy led to the identification of four novel chemical scaffolds that inhibit HIV-1 replication through the destabilization of the HIV-1 gp120-CD4 interface. 22976834 Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging. mnd2 mice die prematurely as a result of neurodegeneration 30-40 days after birth due to loss of the enzymatic activity of the mitochondrial quality control protease HtrA2/Omi. Here, we show that transgenic expression of human HtrA2/Omi in the central nervous system of mnd2 mice rescues them from neurodegeneration and prevents their premature death. Interestingly, adult transgenic mnd2 mice develop accelerated aging phenotypes, such as premature weight loss, hair loss, reduced fertility, curvature of the spine, heart enlargement, increased autophagy, and death by 12-17 months of age. These mice also have elevated levels of clonally expanded mitochondrial DNA (mtDNA) deletions in their tissues. Our results provide direct genetic evidence linking mitochondrial protein quality control to mtDNA deletions and aging in mammals. 23434641 New 2-benzylsulfanyl-nicotinic acid based 1,3,4-oxadiazoles: Their synthesis and biological evaluation. A novel series of 5-(2-benzylsulfanyl-pyridin-3-yl)-2-(substituted)-sulfanyl-1,3,4-oxadiazoles 6a-j were synthesized from key intermediate 5-(2-benzylsulfanyl-pyridin-3-yl)-3H-[1,3,4]oxadiazole-2-thione 5. Nucleophilic substitution reactions with different electrophiles (E+), such as haloacetate and haloalkyl groups, were performed to get target compounds 6a-j. Compounds were characterized by NMR, mass, IR spectra and C, H, N analyses. All compounds were evaluated for their antimicrobial and antimycobacterial activities; selected analogs were screened for their anticancer activity on 60 tumor cell lines at single dose 1.00(-5) M. Unfortunately, none of the compounds showed a significant antitumor activity on 60 human tumor cell lines. However, compounds 6g and 6f with benzothiazole moiety (12.5 and 25 μg/ml) showed promising activity against Escherichia coli compared to ampicillin; compounds 6d, 6j bearing triazole and morpholine, respectively, showed promising antitubercular activity (25 μg/ml) compared to rifampicin. 23138381 New results on formaldehyde: the 2nd International Formaldehyde Science Conference (Madrid, 19-20 April 2012). The toxicology and epidemiology of formaldehyde were discussed on the 2nd International Formaldehyde Science Conference in Madrid, 19-20 April 2012. It was noted that a substantial amount of new scientific data has appeared within the last years since the 1st conference in 2007. Progress has been made in characterisation of genotoxicity, toxicokinetics, formation of exogenous and endogenous DNA adducts, controlled human studies and epidemiology. Thus, new research results are now at hand to be incorporated into existing evaluations on formaldehyde by official bodies. 23314331 Copper induced upregulation of apoptosis related genes in zebrafish (Danio rerio) gill. Copper (Cu) is an essential micronutrient that, when present in high concentrations, becomes toxic to aquatic organisms. It is known that Cu toxicity may induce apoptotic cell death. However, the precise mechanism and the pathways that are activated, in fish, are still unclear. Thus, this study aimed to assess which apoptotic pathways are triggered by Cu, in zebrafish (Danio rerio) gill, the main target of waterborne pollutants. Fish where exposed to 12.5 and 100 μg/L of Cu during 6, 12, 24 and 48 h. Fish gills were collected to TUNEL assay and mRNA expression analysis of selected genes by real time PCR. An approach to different apoptosis pathways was done selecting p53, caspase-8, caspase-9 and apoptosis inducing factor (AIF) genes. The higher incidence of TUNEL-positive cells, in gill epithelia of the exposed fish, proved that Cu induced apoptosis. The results suggest that different apoptosis pathways are triggered by Cu at different time points of the exposure period, as the increase in transcripts was sequential, instead of simultaneous. Apoptosis seems to be initiated via intrinsic pathway (caspase-9), through p53 activation; then followed by the extrinsic pathway (caspase-8) and finally by the caspase-independent pathway (AIF). A possible model for Cu-induce apoptosis pathways is proposed. 22546616 The brain GABA-benzodiazepine receptor alpha-5 subtype in autism spectrum disorder: a pilot [(11)C]Ro15-4513 positron emission tomography study. GABA (gamma-amino-butyric-acid) is the primary inhibitory neurotransmitter in the human brain. It has been proposed that the symptoms of autism spectrum disorders (ASDs) are the result of deficient GABA neurotransmission, possibly including reduced expression of GABAA receptors. However, this hypothesis has not been directly tested in living adults with ASD. In this preliminary investigation, we used Positron Emission Tomography (PET) with the benzodiazepine receptor PET ligand [(11)C]Ro15-4513 to measure α1 and α5 subtypes of the GABAA receptor levels in the brain of three adult males with well-characterized high-functioning ASD compared with three healthy matched volunteers. We found significantly lower [(11)C]Ro15-4513 binding throughout the brain of participants with ASD (p < 0.0001) compared with controls. Planned region of interest analyses also revealed significant reductions in two limbic brain regions, namely the amygdala and nucleus accumbens bilaterally. Further analysis suggested that these results were driven by lower levels of the GABAA α5 subtype. These results provide initial evidence of a GABAA α5 deficit in ASD and support further investigations of the GABA system in this disorder. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. 23600800 CASK is a new intracellular modulator of P2X3 receptors. ATP-gated P2X3 receptors of sensory ganglion neurons are important transducers of painful stimuli and are modulated by extracellular algogenic substances, via changes in the receptor phosphorylation state. The present study investigated the role of calcium/calmodulin-dependent serine protein kinase CASK in interacting and controlling P2X3 receptor expression and function in mouse trigeminal ganglia. Most ganglion neurons in situ or in culture co-expressed P2X3 and CASK. CASK was immunoprecipitated with P2X3 receptors from trigeminal ganglia and from P2X3/CASK-cotransfected HEK cells. Recombinant P2X3/CASK expression in HEK cells increased serine phosphorylation of P2X3 receptors, typically associated with receptor upregulation. CASK deletion mutants also enhanced P2X3 subunit expression. After silencing CASK, cell surface P2X3 receptor expression was decreased, which is consistent with depressed P2X3 currents. The reduction of P2X3 expression levels was reversed by the proteasomal inhibitor MG-132. Moreover, neuronal CASK/P2X3 interaction was upregulated by NGF signaling and downregulated by P2X3 agonist-induced desensitization. These data suggest a novel interaction between CASK and P2X3 receptors with positive outcome for receptor stability and function. As CASK-mediated control of P2X3 receptors was dependent on the receptor activation state, CASK represents an intracellular gateway to regulate purinergic nociceptive signaling. This article is protected by copyright. All rights reserved. 23157635 Antipsychotic drug effects in schizophrenia: a review of longitudinal FMRI investigations and neural interpretations. The evidence that antipsychotics improve brain function and reduce symptoms in schizophrenia is unmistakable, but how antipsychotics change brain function is poorly understood, especially within neuronal systems. In this review, we investigated the hypothesized normalization of the functional magnetic resonance imaging (fMRI) blood oxygen level dependent signal in the context of antipsychotic treatment. First, we conducted a systematic PubMed search to identify eight fMRI investigations that met the following inclusion criteria: case-control, longitudinal design; pre- and post-treatment contrasts with a healthy comparison group; and antipsychotic-free or antipsychotic-naive patients with schizophrenia at the start of the investigation. We hypothesized that aberrant activation patterns or connectivity between patients with schizophrenia and healthy comparisons at the first imaging assessment would no longer be apparent or "normalize" at the second imaging assessment. The included studies differed by analysis method and fMRI task but demonstrated normalization of fMRI activation or connectivity during the treatment interval. Second, we reviewed putative mechanisms from animal studies that support normalization of the BOLD signal in schizophrenia. We provided several neuronal-based interpretations of these changes of the BOLD signal that may be attributable to long-term antipsychotic administration. 23401323 Hemifluorinated maltose-neopentyl glycol (HF-MNG) amphiphiles for membrane protein stabilisation. SOAP OPERA: Fluorinated amphiphile F4-MNG confers greater stability on Rhodobacter capsulatus superassembly relative to conventional detergents and nonfluorinated MNGs. Such amphiphiles are attractive as tools for membrane science because of their ease of preparation and structure variation. 23411219 An electrospray ionisation-mass spectrometry screening of triacylglycerols in developing cultivated and wild peanut kernels (Arachis hypogaea L.). The accumulation of triacylglycerols during the development of three varieties of peanuts was monitored in two Tunisian cultivated peanut (Trabelsia (AraT) and Chounfakhi (AraC)) and one wild Tunisian peanut (Arbi (AraA)). The presence of TAGs composed of rare fatty acid residues such as hexacosanoic acid (C(23:0)) and heneicosanoic acid (C(21:0)) among the triacylglycerols C(23:0) LL, C(23:0) OO and C(21:0) LL was noted. The major molecular species of triacylglycerol detected in the three peanut varieties were dioleoyl linoleoyl (OOL), 1,2,3-trioleyl (OOO), 1,2-dioleyl-3-palmitoyl (POO), 1,2-dilinoleoyl-3-oleyl (OLL) and 1-oleoyl-2-linoleoyl-3-linolenoyl (OLLn). The TAG composition and content were significantly different among the three peanut varieties. The three major TAGs were OOL (20.6%), OOO (15.6%) and OLLn (13.2%) in AraA; OOL (21.4%), OOO (20.1%) and POO (17.5%) in AraC and finally OLL (20.7%), OOO (19.8%) and OLL (17.7%) in AraT. 23008229 Bonding and electronic transport properties of fullerene and fullerene derivatives in break-junction geometries. Fullerenes are considered anchoring groups for molecular electronics due to a large contact area and their affinity for noble metals. The conductances of fullerene-terminated molecules, however, are found to be even lower than for thiol termination. The effects of weak molecule-metal coupling and symmetry breaking are studied by transport measurements of C(60) and functionalized C(60). The results demonstrate highy efficient contacts between Au and C(60), despite of deposition from solution. 23424012 Cytotoxic triterpenoid saponins from the stems of Gordonia longicarpa. Nine new triterpenoid saponins named longicarposides A-I (1-9), together with three known saponins (10-12), were isolated from the stems of Gordonia longicarpa. The structures of the saponins were elucidated by a combination of 1D and 2D NMR techniques, mass spectrometry, and chemical methods. They were characterized to be oleanane-type saponins with sugar moieties linked to C-3 of the aglycone. Cytotoxic activities of these saponins were evaluated against five human tumor cell lines (HCT-8, Bel-7402, BGC-823, A549, and A2780) by using the MTT in vitro assay. Compounds 5, 7, 8, 10, and 11 exhibited potent cytotoxic activity with IC50 values of 1.42-8.42 µM, while 6, 9, and 12 showed selective cytotoxic activity toward the tested cell lines. 23300227 A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. The concept of ligand bias at G protein-coupled receptors broadens the possibilities for agonist activities and provides the opportunity to develop safer, more selective therapeutics. Morphine pharmacology in β-arrestin-2 knockout mice suggested that a ligand that promotes coupling of the μ-opioid receptor (MOR) to G proteins, but not β-arrestins, would result in higher analgesic efficacy, less gastrointestinal dysfunction, and less respiratory suppression than morphine. Here we report the discovery of TRV130 ([(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine), a novel MOR G protein-biased ligand. In cell-based assays, TRV130 elicits robust G protein signaling, with potency and efficacy similar to morphine, but with far less β-arrestin recruitment and receptor internalization. In mice and rats, TRV130 is potently analgesic while causing less gastrointestinal dysfunction and respiratory suppression than morphine at equianalgesic doses. TRV130 successfully translates evidence that analgesic and adverse MOR signaling pathways are distinct into a biased ligand with differentiated pharmacology. These preclinical data suggest that TRV130 may be a safer and more tolerable therapeutic for treating severe pain. 22963619 A comparative study of two novel nanosized radiolabeled analogues of methionine for SPECT tumor imaging. It has been reported that most tumor cells show an increased uptake of variety of amino acids specially methionine when compared with normal cells and amino acid transport is generally increased in malignant transformation. Based on the evidences, two novel nanosized analogues of methionine (Anionic Linear Globular Dendrimer G(2), a biodigredabale anionic linear globular-Methionin, and DTPA-Methionine(1) conjugates) were synthesized and labeled with (99m)Tc and used in tumor imaging/ therapy in vitro and in vivo. The results showed marked tumor SPECT molecular imaging liabilities for both compounds but with a better performance by administration of (99m)Tc-Dendrimer G(2)-Methionin. The results also showed a good anticancer activity for 99mTc-DTPA-Methionine. Based on the present study (99m)Tc-Dendrimer G(2)-Methionin or 99mTc-DTPA-(Methionine)(1) have potentials to be used in tumor molecular imaging as well as cancer therapy in future. 23416192 Synthesis and pharmacological evaluation of some novel 2-(5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-yl)-4-(coumarin-3-yl)thiazoles. A series of novel 2-(5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-yl)-4-(coumarin-3-yl)thiazoles (6) were synthesized by condensing 3-(2-bromoacetyl)coumarins (4) with various 5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-thiocarboxamides (5), obtained by the reaction of thiosemicarbazide with trifluoromethyl-β-diketones. All the tested compounds displayed significant to moderate in vivo anti-inflammatory activity when compared to the standard drug indomethacin, and good broad spectrum in vitro antibacterial activity against three Gram-positive and four Gram-negative bacteria when compared with cefixime. 23246436 Integration-dependent bacteriophage immunity provides insights into the evolution of genetic switches. Genetic switches are critical components of developmental circuits. Because temperate bacteriophages are vastly abundant and greatly diverse, they are rich resources for understanding the mechanisms and evolution of switches and the molecular control of genetic circuitry. Here, we describe a new class of small, compact, and simple switches that use site-specific recombination as the key decision point. The phage attachment site attP is located within the phage repressor gene such that chromosomal integration results in removal of a C-terminal tag that destabilizes the virally encoded form of the repressor. Integration thus not only confers prophage stability but also is a requirement for lysogenic establishment. The variety of these self-contained integration-dependent immunity systems in different genomic contexts suggests that these represent ancestral states in switch evolution from which more-complex switches have evolved. They also provide a powerful toolkit for building synthetic biological circuits. 22455800 Synthesis of 4-hydroxy-3,4-dialkyl-2,6-diaryl-piperidine derivatives as potent antimicrobial agent. A series of 4-hydroxy-3,4-dialkyl-2,6-diaryl-piperidine (7-12) have been synthesised by reduction of 3-alkyl-2,6-diarylpiperidin-4-one using the Grignard reagent. Structural assignments and conformational analysis of the compounds were established based on the spectral studies. All the piperdin-4-ol derivatives (7-12) were assayed for antibacterial, antifungal and anthelmintic activities and they exhibited significant results. 22683935 Dendritic cell migration assay: a potential prediction model for identification of contact allergens. This manuscript describes methodology and a prediction model for the MUTZ-LC migration assay. The assay represents the physiological change in Langerhans cell (LC) behavior after exposure to a sensitizing chemical, resulting in LC migration from the epidermis to the dermis. MUTZ-LC are derived from the commercially available MUTZ-3 cell line. Upon exposure to a sensitizer MUTZ-LC migrate preferentially towards CXCL12 whereas upon exposure to a non-sensitizer MUTZ-LC migrate towards CCL5. A CXCL12/CCL5 ratio >1.10 in 2/3 independent experiments is indicative of a sensitizer, whereas a CXCL12/CCL5 ratio ≤1.10 is indicative of a non-sensitizer. At non cytotoxic chemical concentrations 9 sensitizers (2,4-dinitrochlorobenzene, paraphenylendiamine, cinnamaldehyde, isoeugenol, nickel-sulfate, tetramethylthiuram disulfide, eugenol, cinnamic-alcohol, ammonium-hexachloroplatinate) were distinguished from 4 non sensitizers (sodium lauryl sulfate, salicylic acid, phenol, octanoic acid). Critical points in assay performance are (i) MUTZ-3 passage number after thawing (p6-p40); (ii) cell viability (>80%); (iii) standard curve to optimize correlation of fluorescence with cell number; and (iv) optimization of the concentration of rhCXCL12 and rhCCL5 in transwell. The protocol has been tested in three European laboratories and results suggest that it may provide working conditions for performing the DC migration assay which is aimed at distinguishing sensitizers from non sensitizers. 23099337 Caffeine reduces cadmium accumulation in the organism and enhances the levels of antioxidant protein expression in the epididymis. The aim of this study was to investigate the effects of caffeine (20 mg/L) intake on cadmium (15 mg/L) accumulation in the rat blood, testes, epididymis and prostate as well as cadmium-induced changes to the antioxidant defense system of the epididymis. Caffeine reduced the cadmium concentration in all tissues analyzed. Meanwhile, cadmium reduced catalase activity and increased superoxide dismutase (SOD) activity in the epididymis. Caffeine increased SOD activity, catalase and glutathione tissue expression and sustains the cadmium's effect on catalase and GSP-Px activity. No differences in the expression of metallothionein and lipid peroxidation were observed among the different treatments in the epididymis. In conclusion, low doses of cadmium alter the antioxidant enzymatic profile of the epididymis, but not induced oxidative lipid damage. Caffeine intake reduces overall cadmium accumulation in the organism and enhances the levels of antioxidant protein expression in the epididymis, thus exerting a protective effect against this metal. 23432579 RNAi in Clinical Studies. RNA interference (RNAi) is an efficient process of posttranscriptional gene silencing. In recent years it has been developed into a new technology in biopharmaceutical fields of science. RNAi products include short interference RNA (siRNA) but also short hairpin RNA (shRNA), bifunctional short hairpin RNA (bi-shRNA) and microRNA (miRNA). They combine with homologous fragments of the mRNA and cause its degradation. It results in inhibition of protein synthesis, or in mutation in the gene encoding it. RNAi has been used in analysis of genomes and creation of new animal models to test drugs. From the pharmaceutical point of view, what is the most important is its therapeutic application. So far the basic and clinical research has been focused on the following targets: macular degeneration, cancer and antiviral therapy. But there are also reports on clinical trials in asthma, hypercholesterolemia and genetic diseases such as inherited skin disorders and amyloidosis. Among over 20 therapeutics that reached clinical trials, only few are still investigated. Another few are clinical candidates. The review focuses on RNAi products under clinical evaluation and their most promising new applications. 23239639 Synthesis of maleimide-functionalyzed HPMA-copolymers and in vitro characterization of the aRAGE- and human immunoglobulin (huIgG)-polymer conjugates. Herein the synthesis of antibody-polymer conjugates, with a quite narrow dispersity based on the polymer HPMA, are reported. These conjugates are synthesized by coupling antibodies to maleimide-functionalized poly(N-(2-hydroxypropyl)-methacrylamide) (poly-HPMA) copolymers derived through reversible addition-fragmentation chain transfer (RAFT) polymerization of pentafluorophenyl methacrylate via the intermediate step of an activated ester polymer. We develop a protocol that allows the attachment of two different model antibodies, monoclonal anti-RAGE (receptor for advanced glycation end-products) antibody, and polyclonal human immunoglobulin (huIgG). Modification of the antibody and conjugation is monitored by SDS-PAGE electrophoresis. Preserved affinity is demonstrated by Western Blott and cell-uptake analysis, for example, to cells of the immune system. 23452147 Autoprocessing mechanism of severe acute respiratory syndrome coronavirus 3C-like protease (SARS-CoV 3CL(pro) ) from its polyproteins. Like many other RNA viruses, severe acute respiratory syndrome coronavirus (SARS-CoV) produces polyproteins containing several non-structural proteins, which are then processed by the viral proteases. These proteases often exist within the polyproteins, and are excised by their own proteolytic activity ('autoprocessing'). It is important to investigate the autoprocessing mechanism of these proteases from the point of view of anti-SARS-CoV drug design. In this paper, we describe a new method for investigating the autoprocessing mechanism of the main protease (M(pro) ), which is also called the 3C-like protease (3CL(pro) ). Using our method, we measured the activities, under the same conditions, of the mature form and pro-forms with the N-terminal pro-sequence, the C-terminal pro-sequence or both pro-sequences, toward the pro-form with both N- and C-terminal pro-sequences. The data indicate that the pro-forms of the enzyme have proteolytic activity, and are stimulated by the same proteolytic activity. The stimulation occurs in two steps, with approximately eightfold stimulation by N-terminal cleavage, approximately fourfold stimulation by C-terminal cleavage, and 23-fold stimulation by the cleavage of both termini, compared to the pro-form with both the N- and C-terminal pro-sequences. Such cleavage mainly occurs in a trans manner; i.e. the pro-form dimer cleaves the monomeric form. The stimulation by N-terminal pro-sequence removal is due to the cis (intra-dimer and inter-protomer) effect of formation of the new N-terminus, whereas that by C-terminal cleavage is due to removal of its trans (inter-dimer) inhibitory effect. A numerical simulation of the maturation pathway is presented. 23434931 TCF7L2 Variation and Proliferative Diabetic Retinopathy. Proliferative diabetic retinopathy (PDR) is the most severe vision-threatening complication of diabetes. To investigated genetic association between TCF7L2 and PDR in Caucasian type 2 diabetes mellitus (T2DM) and its functional consequences, 383 T2DM patients with PDR (T2DM-PDR) and 756 T2DM patients without diabetic retinopathy (T2DM-no DR) were genotyped with rs7903146 in TCF7L2. We found that risk allele (T) frequency of rs7903146 was significantly higher in T2DM-PDR patients (allelic P = 2.52E-04). In lymphoblastoid cells induced to undergo endoplasmic reticulum (ER) stress by treatment of tunicamycin, higher fold change of TCF7L2 and VEGFA mRNA levels were observed in rs7903146-TT cells than that in rs7903146-CC cells (P = 0.02 for TCF7L2; P = 0.004 for VEGFA), suggesting ER stress plays a role in PDR pathogenesis. Silencing TCF7L2 resulted in decreased mRNA levels of both TCF7L2 and VEGFA (P < 0.001). Retinas of oxygen-induced retinopathy (OIR) mice (a model for PDR) had higher TCF7L2 and VEGFA mRNA levels than controls (P = 2.9E-04 for TCF7L2; P = 1.9E-07 for VEGFA). Together, our study showed that TCF7L2-rs7903146 is associated with PDR in Caucasian T2DM and suggested TCF7L2 promoted pathological retinal neovascularization via ER stress-dependent upregulation of VEGFA. 23638658 Three-Dimensional Self-Assembly of Chalcopyrite Copper Indium Diselenide Nanocrystals into Oriented Films. CuInSe2, which is one of the highest efficiency thin-film solar cell active layer materials, has been an attractive target for nanocrystal synthesis and manipulation. Here, we report unprecedented, simultaneous control of the synthesis and self-assembly behavior of CuInSe2 nanocrystals. These nanocrystals are solution-processable, monodisperse tetragonal bipyramids that exhibit photoconductivity and self-assemble into crystallographically oriented thin films. Structural characterization indicates that these nanocrystals are tetragonal phase, as is used in high-efficiency, second-generation, thin-film solar cells. Elemental analysis indicates that approximately 1:1:2 Cu/In/Se stoichiometry can be achieved, and that the elemental composition can be adjusted from copper-rich to indium-rich with reaction time. 23270993 Kynurenic acid as an antagonist of α7 nicotinic acetylcholine receptors in the brain: facts and challenges. Kynurenic acid (KYNA), a major tryptophan metabolite, is a glutamate receptor antagonist, which is also reported to inhibit α7 nicotinic acetylcholine receptors (α7nAChRs). Due to variations in experimental approaches, controversy has arisen regarding the ability of KYNA to directly influence α7nAChR function. Here we summarize current concepts of KYNA neurobiology and review evidence pertaining to the proposed role of KYNA as an endogenous modulator of α7nAChRs and synaptic transmission. As dysfunction of α7nAChRs plays a major role in the pathophysiology of central nervous system disorders, elucidation of KYNA's action on this receptor subtype has significant therapeutic implications. 23318425 DMAP1 is an essential regulator of ATM activity and function. The hereditary autosomal recessive disease ataxia telangiectasia (A-T) is caused by mutation in the DNA damage kinase ATM. ATM's main function is to orchestrate DNA repair, thereby maintaining genomic stability. ATM activity is increased in response to several stimuli, including ionising radiation (IR) and hypotonic stress. DNMT1-associated protein 1 (DMAP1) is a member of the TIP60-p400 histone acetyl transferase (HAT) complex, which acetylates histone H4 at lysine 16 (H4K16) to affect chromatin relaxation and modulate ATM activation. Here we demonstrate that DMAP1 is required for both modes of ATM activation. Knockdown of DMAP1 impaired IR-induced ATM activation and consequently resulted in radiosensitivity and impaired the G2/M checkpoint. Moreover, DMAP1 was also required for efficient ATM signalling in response to hypotonic stress. Overexpression of DMAP1 increased IR-induced ATM substrate phosphorylation, suggesting that DMAP1 function is rate limiting for ATM signalling. DMAP1 associated with TIP60-dependent HAT activity, and depletion of DMAP1 reduced H4K16 acetylation in response to DNA damage. Treatment with histone deacetylase inhibitors rescued IR-induced ATM signalling in Dmap1-depleted cells. These results suggest that DMAP1 is a critical regulator of ATM activity and function.Oncogene advance online publication, 14 January 2013; doi:10.1038/onc.2012.597. 23000451 Plants as a source of butyrylcholinesterase variants designed for enhanced cocaine hydrolase activity. Cocaine addiction affects millions of people with disastrous personal and social consequences. Cocaine is one of the most reinforcing of all drugs of abuse, and even those who undergo rehabilitation and experience long periods of abstinence have more than 80% chance of relapse. Yet there is no FDA-approved treatment to decrease the likelihood of relapse in rehabilitated addicts. Recent studies, however, have demonstrated a promising potential treatment option with the help of the serum enzyme butyrylcholinesterase (BChE), which is capable of breaking down naturally occurring (-)-cocaine before the drug can influence the reward centers of the brain or affect other areas of the body. This activity of wild-type (WT) BChE, however, is relatively low. This prompted the design of variants of BChE which exhibit significantly improved catalytic activity against (-)-cocaine. Plants are a promising means to produce large amounts of these cocaine hydrolase variants of BChE, cheaply, safely with no concerns regarding human pathogens and functionally equivalent to enzymes derived from other sources. Here, in expressing cocaine-hydrolyzing mutants of BChE in Nicotiana benthamiana using the MagnICON virus-assisted transient expression system, and in reporting their initial biochemical analysis, we provide proof-of-principle that plants can express engineered BChE proteins with desired properties. 23383746 Fluorescence (fluidity/hydration) and calorimetric studies of interactions of bile acid-drug conjugates with model membranes. We have studied the interactions of three bile acid-tamoxifen conjugates, lithocholic acid-tamoxifen (LA-Tam(1)-Am), deoxycholic acid-tamoxifen (DCA-Tam(2)-Am), and cholic acid-tamoxifen (CA-Tam(3)-Am), possessing 1-3 tamoxifen molecules having an amine headgroup with model DPPC membranes and compared with N-desmethylated tamoxifen (TamNHMe) using DPH based fluorescence anisotropy, Prodan based hydration, and differential scanning calorimetry studies. DPH based anisotropy studies showed that bile acid-tamoxifen conjugates increase membrane fluidity, which strongly depends on the number of tamoxifen molecules conjugated to bile acid and the percentage of doping of bile acid-tamoxifen conjugates in the DPPC membranes. The order of membrane fluidity of the coliposomes from bile acid-tamoxifen conjugates and DPPC lipids in gel phase was found to be CA-Tam(3)-Am > DCA-Tam(2)-Am > LA-Tam(1)-Am > TamNHMe. Incorporation of bile acid-tamoxifen conjugates showed an unusual complex behavior of membrane hydration, as evident from Prodan based hydration studies. Temperature dependent study showed incorporation of LA-Tam(1)-Am and DCA-Tam(2)-Am conjugates decreases membrane hydration with an increase in temperature up to the phase transition temperature (T(m)). Differential scanning calorimetry studies showed a decrease in phase transition temperature (T(m)) upon an increase in the percentage of doping of TamNHMe and CA-Tam(3)-Am, whereas LA-Tam(1)-Am and DCA-Tam(2)-Am do not cause a major change in the phase transition temperature (T(m)) of DPPC liposomes. These studies showed the differential behavior of bile acid-tamoxifen conjugates regulating the membrane fluidity, hydration, and phase transition of model membranes depending upon the percentage of doping and tamoxifen conjugation to bile acids. 23566899 Prediction of dose-hepatotoxic response in humans based on toxicokinetic/toxicodynamic modeling with or without in vivo data: A case study with acetaminophen. In the present legislations, the use of methods alternative to animal testing is explicitly encouraged, to use animal testing only 'as a last resort' or to ban it. The use of alternative methods to replace kinetics or repeated dose in vivo tests is a challenging issue. We propose here a strategy based on in vitro tests and QSAR (Quantitative Structure Activity Relationship) models to calibrate a dose-response model predicting hepatotoxicity. The dose response consists in calibrating and coupling a PBPK (physiologically-based pharmacokinetic) model with a toxicodynamic model for cell viability. We applied our strategy to acetaminophen and compared three different ways to calibrate the PBPK model: only with in vitro and in silico methods, using rat data or using all available data including data on humans. Some estimates of kinetic parameters differed substantially among the three calibration processes, but, at the end, the three models were quite comparable in terms of liver toxicity predictions and close to the usual range of human overdose. For the model based on alternative methods, the good adequation with the two other models resulted from an overestimated renal elimination rate which compensated for the underestimation of the metabolism rate. Our study points out that toxicokinetics/toxicodynamics approaches, based on alternative methods and modelling only, can predict in vivo liver toxicity with accuracy comparable to in vivo methods. 23572520 S-nitrosation of glutathione transferase P1-1 is controlled by the conformation of a dynamic active-site helix. S-nitrosation is a post-translational modification of protein cysteine residues which occurs in response to cellular oxidative stress. Although it is increasingly being linked to physiologically important processes, the molecular basis for protein regulation by this modification remains poorly understood. We used transient kinetic methods to determine a minimal mechanism for spontaneous GSNO-mediated transnitrosation of human glutathione transferase (GST) P1-1, a major detoxification enzyme and key regulator of cell proliferation. C47 of GSTP1-1 is S-nitrosated in two steps, with the chemical step limited by a pre-equilibrium between the open and closed conformations of helix α2 at the active site. C101, in contrast, is S-nitrosated in a single step but is subject to negative cooperativity due to steric hindrance at the dimer interface. Despite the presence of a GSNO binding site at the active site of GSTP1-1, isothermal titration calorimetry as well as nitrosation experiments using CysNO demonstrate that GSNO binding does not precede S-nitrosation of GSTP1-1. Kinetics experiments using the cellular reductant GSH show that C101-NO is substantially more resistant to denitrosation than C47-NO, suggesting a potential role for C101-NO in long term nitric oxide storage or transfer. These results constitute the first report of the molecular mechanism of spontaneous protein transnitrosation, providing insight into the post-translational control of GSTP1-1 as well as the process of protein transnitrosation in general. 23348409 Genotoxicity of dried Hoodia parviflora aerial parts. Hoodia parviflora is being developed commercially for use in weight loss food and dietary supplement products. Its effects are ascribed to a number of glycosides that have been shown to be present in plant extracts from several Hoodia species, the best known of which is H. gordonii. H. parviflora has been identified as an alternative to H. gordonii, and, as part of the process to develop H. parviflora, in vitro genotoxicity tests, as recommended by recent European Food Safety Authority guidance, were conducted on a dried powder preparation of H. parviflora aerial parts. The preparation was tested for reverse mutation at doses up to 5,000μg/plate in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537, and in Escherichia coli WP2 uvrA TA, both in the presence and in the absence of an exogenous source of metabolic activation (rat liver S9). In addition, the dried powder was evaluated in an in vitro cytotoxicity chromosome aberration assay using human lymphocytes. Test conditions included both a 4 (up to 2500μg/mg) and 44-h exposure period (up to 1000μg/mg) and the incorporation of an exogenous source of metabolic activation (4-h exposure only). H. parviflora dried powder was non-genotoxic in both in vitro assays. 23404458 Composition and distribution of elements and ultrastructural topography of a human cardiac calculus. Trace elements (TEs) may contribute to the formation of calculi or stones or be involved in the aetiopathogenesis of stone diseases. The compositions and spatial distribution of elements from the inner nucleus to outer crust of the cardiac calculus were investigated by energy-dispersive X-ray fluorescence (EDXRF) spectrometer. The surface topograph, distribution map of elements, elemental and chemical compositions were also determined by environmental scanning electron microscope (ESEM)-energy-dispersive X-ray (EDX) analysis. Twenty-five elements were identifiable from 18 positions on the cardiac calculus by EDXRF spectrometer, in which the highest concentrations of toxic TEs (Ni, Pt, Hg, Sn, Pb, W, Au, Al, Si) and higher levels of essential TEs (Ca, Sr, Cr, P) were detected. A moderate positive Pearson's correlation between TEs concentrations of Mg, Ca or P and location differences from centre to periphery in the cardiac calculus was observed. A positive correlation was also found for Ca/Zn and Ca/Cu, indicating the gradual increase of calcium concentration from inner nucleus to outer crust of cardiac calculus. The drop-like nodules/crystals on the surface of petrous part of cardiac calculus were observed from ESEM analysis. ESEM-EDX analysis determined the calculus to be predominantly composed of calcium hydroxyapatite and cholesterol, as indicated by the petrous surface and drop-like nodules/crystals, respectively. This composition was confirmed using a portable Raman analyser. The spatial distribution analysis indicated a gradual increase in Mg, P and Ca concentrations from the inner nucleus to the outer crust of the cardiac calculus. The major chemical compositions of calcium hydroxyapatite and cholesterol were detected on this cardiac calculus. 23625160 The Acute and Chronic Effects of Monosodium L-Glutamate on Serum Iron and Total Iron-Binding Capacity in the Jugular Artery and Vein of Pigs. We analyzed the effects of acute and chronic oral administration of monosodium L-glutamate (MSG) on serum iron (Fe) levels and total iron-binding capacity (TIBC) in piglets. In the first experiment, 12 piglets were randomly assigned to two groups: one fed a standard diet (SD) and the other fed an SD containing MSG (10 g/kg). On day 30, serum, liver, kidney, and spleen samples were collected to determine the Fe levels. In the second experiment, six pigs were surgically fitted with a catheter in the jugular artery and vein to investigate the dynamic changes of serum Fe and TIBC. Blood samples were taken from each pig via the catheter every 30 min, for a period of 4 h. The results show that MSG increases Fe levels in the spleen (P < 0.05) and in serum obtained from the jugular artery (P < 0.01). In addition, TIBC in serum obtained from the jugular artery demonstrated an increasing trend in pigs fed the MSG diet; however, this trend was not observed in the jugular vein. In conclusion, MSG increases Fe retention by enhancing TIBC in serum. 23356859 Formulation and characterization of Brucea javanica oil microemulsion for improving safety. Abstract Objective: This study engaged in investigation of optimal formulation, characteristics analysis of Brucea javanica oil microemulsion (BJOM) in order to address safety concerns and make recommendations for improvements in BJOM safety during clinical use in vivo. Methods: Pseudo-ternary phase diagram techniques were used to determine the appropriate ratio of surfactant, cosurfactant and oil phases. Subsequent stability testing of BJOM was performed by dilution, centrifugation and accelerated stability testing. The results were expounded through additional assessment utilizing the classical thermostat method to establish the shelf life of the material. These results were utilized to evaluate the safety of BJOM by haemolytic, irritative and allergic testing in vitro. In addition, the cytotoxicity of BJOM was examined using the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), with particular emphasis given to potential uses in cancer treatment. Results: The most suitable method of preparation for BJOM was found to be a one to one ratio (K(m) 1:1) of Solutol HS15 surfactant matched with sorbitol cosurfactant in the ratio. The microemulsion droplets of BJOM possessed a spherical shape, uniform size and average diameter of 23.8 nm. The expiration date of BJOM was found to be 568 d. The safety study demonstrated no hemolysis activity at the experimental BJOM concentrations; however, mild hemolysis was observed at higher concentrations of Brucea javanica oil emulsion (BJOE), a common commercially available product. Irritation observed upon BJOM treatment can be primarily attributed to Brucea javanica oil (BJO) with little influence of BJOM excipients. In addition, BJOM caused no observed hypersensitivity or other visible allergic reactions in guinea pigs. The anticancer activity curves of BJOM and BJOE demonstrate that both BJOM and BJOE inhibit Hela cells, with BJOM demonstrating significantly more dramatic anticancer activity. Conclusion: An optimal formulation of BJOM superior to commercially available products and safe for medical application such as intravenous injection has been outlined along with its anticancer activity rating. 23432335 Montiporic acid D, a new polyacetylene carboxylic acid from scleractinian coral Montipora digitata. A new polyacetylene carboxylic acid named montiporic acid D (1) was isolated along with a known polyacetylene alcohol, (Z)-13,15-hexadecadien-2,4-diyn-1-ol (2) from scleractinian coral Montipora digitata. The structures of compounds were determined by analyses of NMR and MS spectra. 23220513 Methyleugenol hepatocellular cancer initiating effects in rat liver. Methyleugenol (MEG), a constituent of plants used in the human diet, is hepatocarcinogenic in rodents. In an experiment to elucidate its mode of action in rat liver, male F344 rats were administered MEG intragastrically at 3 doses per week for up to 16 weeks in an initiation phase, after which half the rats were fed 500 ppm phenobarbital (PB) in the diet to promote liver neoplasia and the other half were maintained on control diet for 24 weeks. At 8 and 16 week interim terminations, (32)P-nucleotide postlabeling assay revealed 3 adducts in livers of all MEG groups. The hepatocellular replicating fractions, measured by proliferating cell nuclear antigen immunohistochemistry, were doubled or more in all MEG groups. Hepatocellular altered foci, detected by glutathione S-transferase-placental type (π) immunohistochemistry, were present beginning with the high dose group at 8 weeks and extending to all MEG groups at 16 weeks. At the end of maintenance/promotion phase, the incidences, multiplicity and size of foci was similar between control and low dose groups, while those of mid and high dose groups were increased. Hepatocellular adenomas occurred in the mid and high dose groups, attaining higher multiplicity and size with PB. Thus, MEG had rapid initiating activity, reflecting the formation of DNA adducts and possibly cell proliferation. 23244521 Medicinal chemistry meets proteomics: fractionation of the human plasma proteome. Human plasma and its fractions/derivatives are frequently used materials in biomedicine as it contains thousands and thousands of proteins representing the majority of human proteome. Several important methods were developed in the past for the fractionation of this important biological fluid and its use for medicinal purposes. One of the greatest challenges is the very large dynamic range of plasma proteins ranging up to 10-12 orders of magnitude. Early attempts were mainly based on methods such as salting out or cold ethanol precipitation, as well as chromatography utilizing affinity, size exclusion, ion exchange and hydrophobic interaction techniques. More recently, fractionation applications started with the depletion of the high abundant plasma components, such as serum albumin and immunoglobulins, before isolating lower abundant proteins of interest. Plasma volumes were utilized from the milliliter scale for diagnostic applications to hundreds of liters for industrial scale plasma fractionation (e.g., medicinal product manufacturing). In this paper we review this important part of medicinal chemistry, highlighting the traditional methods along with some of their variations as well as the most significant recent achievements of the field. 23511125 Acetylcholinesterase inhibition reveals endogenous nicotinic modulation of glutamate inputs to CA1 stratum radiatum interneurons in hippocampal slices. The involvement of brain nicotinic acetylcholine receptors (nAChRs) in the neurotoxicological effects of soman, a potent acetylcholinesterase (AChE) inhibitor and a chemical warfare agent, is not clear. This is partly due to a poor understanding of the role of AChE in brain nAChR-mediated functions. To test the hypothesis that AChE inhibition builds sufficient acetylcholine (ACh) in the brain and facilitates nAChR-dependent glutamate transmission, we used whole-cell patch-clamp technique to record spontaneous glutamate excitatory postsynaptic currents (EPSCs) from CA1 stratum radiatum interneurons (SRI) in hippocampal slices. First, the frequency, amplitude and kinetics of EPSCs recorded from slices of control guinea pigs were compared to those recorded from slices of guinea pigs after a single injection of the irreversible AChE inhibitor soman (25.2μg/kg, s.c.). Second, EPSCs were recorded from rat hippocampal slices before and after their superfusion with the reversible AChE inhibitor donepezil (100nM). The frequency of EPSCs was significantly higher in slices taken from guinea pigs 24h but not 7 days after the soman injection than in slices from control animals. In 52% of the rat hippocampal slices tested, bath application of donepezil increased the frequency of EPSCs. Further, exposure to donepezil increased both burst-like and large-amplitude EPSCs, and increased the proportion of short (20-100ms) inter-event intervals. Donepezil's effects were suppressed significantly in presence of 10μM mecamylamine or 10nM methyllycaconitine. These results support the concept that AChE inhibition is able to recruit nAChR-dependent glutamate transmission in the hippocampus and such a mechanism can contribute to the acute neurotoxicological actions of soman. 23306790 Verrucarin A enhances TRAIL-induced apoptosis via NF-κB-mediated Fas overexpression. We investigated whether verrucarin A (VA) sensitizes HepG2 hepatoma cells to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. We found that VA alone induces little apoptosis, but when combined with TRAIL (VA/TRAIL), it triggered significant apoptosis, causing little or no toxicity in normal mouse splenocytes. VA/TRAIL-induced cell death is involved in the loss of mitochondrial transmembrane potential and the consequent activation of caspases. Because nuclear factor (NF)-κB inhibition has been known as a critical target in TRAIL-mediated apoptosis, we also investigated the role of NF-κB in VA/TRAIL treatment. We found that VA upregulated the DNA binding activity of NF-κB, but that the antioxidants glutathione and N-acetyl-l-cysteine, as well as NF-κB inhibitor MG132, and mutant-IκB (m-IκB) transfection, significantly downregulated VA/TRAIL-induced cell death by inhibiting caspase-3 and NF-κB activities. Transfection of mutant-eIF2α also resulted in a decrease in VA/TRAIL-induced cell death by inhibiting of caspase-3, but not NF-κB activity. Although VA/TRAIL treatment led to an increase of DR5 expression, transfection of m-IκB had no influence on the DR5 expressional level. Finally, we showed that NF-κB-mediated Fas expression is critical to VA/TRAIL-induced apoptosis. Taken together, these results indicate that VA/TRAIL sensitizes HepG2 cells to apoptosis via NF-κB-mediated overexpression of Fas. 23621616 Highly Confined Tunable Mid-Infrared Plasmonics in Graphene Nanoresonators. Single-layer graphene has been shown to have intriguing prospects as a plasmonic material, as modes having plasmon wavelengths ∼20 times smaller than free space (λp ∼ λ0/20) have been observed in the 2-6 THz range, and active graphene plasmonic devices operating in that regime have been explored. However there is great interest in understanding the properties of graphene plasmons across the infrared spectrum, especially at energies exceeding the graphene optical phonon energy. We use infrared microscopy to observe the modes of tunable plasmonic graphene nanoresonator arrays as small as 15 nm. We map the wavevector-dependent dispersion relations for graphene plasmons at mid-infrared energies from measurements of resonant frequency changes with nanoresonator width. By tuning resonator width and charge density, we probe graphene plasmons with λp ≤ λ0/100 and plasmon resonances as high as 310 meV (2500 cm(-1)) for 15 nm nanoresonators. Electromagnetic calculations suggest that the confined plasmonic modes have a local density of optical states more than 10(6) larger than free space and thus could strongly increase light-matter interactions at infrared energies. 23335833 Comparison of contact angle hysteresis of different probe liquids on the same solid surface. Advancing and receding contact angles of water, formamide and diiodomethane were measured on 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) layers deposited on three different solid supports-glass, mica and poly(methyl methacrylate). Up to five statistical monolayers were deposited on the surfaces by spreading DPPC solution. It was found that even on five statistical DPPC monolayers, the hysteresis of a given liquid depends on the kind of solid support. Also on the same solid support the contact angle hysteresis is different for each probe liquid used. The AFM images show that the heights of roughness of the DPPC films cannot be the primary cause of the observed hysteresis because the heights are too small to cause the observed hystereses. It is believed that the hysteresis is due to the liquid film present right behind the three-phase solid surface/liquid drop/gas (vapour) contact line and the presence of Derjaguin pressure. The value of contact angle hysteresis depends on both the solid surface and liquid properties as well as on intermolecular interactions between them. 23505146 Diverse effects of macromolecular crowding on the sequential glycan-processing pathway involved in glycoprotein quality control. Compared with in vitro conditions, the intracellular environment is highly crowded with biomolecules; this has numerous effects on protein functions, including enzymatic activity. We examined the effects of macromolecular crowding on glycan processing of N-glycoprotein in the endoplasmic reticulum as a model sequential metabolic pathway. Experiments with synthetic substrates of physiological glycan structure clearly showed that the first half of the pathway (glucose trimming) was accelerated, whereas the second (mannose trimming) was decelerated under molecular crowding conditions. Furthermore, calreticulin, a lectin-like molecular chaperone, bound more strongly to a glycan-processing intermediate under these conditions. This study demonstrates the diverse effects of molecular crowding on sequential enzymatic processing, and the importance of the effects of macromolecular crowding on in vitro assays for understanding sequential metabolic pathways. 23593923 Functional conservation and structural diversification of silk sericins in two moth species. Sericins are hydrophilic structural proteins produced by caterpillars in the middle section of silk glands and are layered over fibroin proteins secreted in the posterior section. In the process of spinning, fibroins form strong solid filaments, while sericins seal the pair of filaments into a single fiber and glue the fiber into a cocoon. Galleria mellonella and the previously examined Bombyx mori harbor three sericin genes that encode proteins containing long repetitive regions. Galleria sericin genes are similar to each other and the protein repeats are built from short and extremely serine-rich motifs, while Bombyx sericin genes are diversified and encode proteins with long and complex repeats. Developmental changes in sericin properties are controlled at the level of gene expression and splicing. In Galleria, MG-1 sericin is produced throughout larval life until the wandering stage, while the production of MG-2 and MG-3 reaches a peak during cocoon spinning. 23571415 Structure-based Identification of OATP1B1/3 Inhibitors. Several recent studies show that inhibition of the hepatic transport proteins organic-anion transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1 or 1B3-transfected CHO cells. At an equimolar substrate-inhibitor concentration of 10 μM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (min 50 % inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 μM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20 % of the dataset) with high specificity (86 %) and sensitivity (78 %). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 % and 74 % of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively. 23265501 Physical attributes and chemical composition of organic strawberry fruit (Fragaria x ananassa Duch, Cv. Albion) at six stages of ripening. Organic strawberry fruits (Cv. 'Albion') were harvested at six different ripening stages and evaluated for physical and chemical parameters. Biometrical characteristics and moisture content did not change significantly during ripening. Total soluble solids, pH and colour development increased while titratable acidity and fruit firmness decreased 14.7% and 91%, respectively. Fructose, glucose, and sucrose followed similar tendencies. Final contents of these sugars were 2323.4, 1988.5, and 1578.4 mg/100 g. Citric, malic, and ascorbic acids followed a descending, irregular, and increasing tendency during ripening, respectively. Final contents of these acids were 822.8, 245.8, and 78.1 mg/100 g. Total anthocyanins content (TAC) increased during ripening, while the opposite was observed for total phenolic content (TPC). TAC and TPC in ripe fruit were 56.4 mg/100g and 196 mg gallic acid equivalents (GAE)/100 g. Twenty eight phenolic compounds, mainly glycosides, were identified and quantified by HPLC-DAD-MS analysis. The concentration of these compounds was ripening dependent. 23259666 Dendrimer-based multivalent vancomycin nanoplatform for targeting the drug-resistant bacterial surface. Vancomycin represents the preferred ligand for bacteria-targeting nanosystems. However, it is inefficient for emerging vancomycin-resistant species because of its poor affinity to the reprogrammed cell wall structure. This study demonstrates the use of a multivalent strategy as an effective way for overcoming such an affinity limitation in bacteria targeting. We designed a series of fifth generation (G5) poly(amidoamine) (PAMAM) dendrimers tethered with vancomycin at the C-terminus at different valencies. We performed surface plasmon resonance (SPR) studies to determine their binding avidity to two cell wall models, each made with either a vancomycin-susceptible (D)-Ala-(D)-Ala or vancomycin-resistant (D)-Ala-(D)-Lac cell wall precursor. These conjugates showed remarkable enhancement in avidity in the cell wall models tested, including the vancomycin-resistant model, which had an increase in avidity of four to five orders of magnitude greater than free vancomycin. The tight adsorption of the conjugate to the model surface corresponded with its ability to bind vancomycin-susceptible Staphylococcus aureus bacterial cells in vitro as imaged by confocal fluorescent microscopy. This vancomycin platform was then used to fabricate the surface of iron oxide nanoparticles by coating them with the dendrimer conjugates, and the resulting dendrimer-covered magnetic nanoparticles were demonstrated to rapidly sequester bacterial cells. In summary, this article investigates the biophysical basis of the tight, multivalent association of dendrimer-based vancomycin conjugates to the bacterial cell wall, and proposes a potential new use of this nanoplatform in targeting Gram-positive bacteria. 23305807 Prophylactic effect of resveratrol against ethinylestradiol-induced liver cholestasis. Estrogens, and particularly glucuronides such as ethinylestradiol (EE), have been shown to cause cholestasis in animal studies, by reducing bile acid uptake by hepatocytes. The aim of the present article was to investigate anticholestatic activity of resveratrol (RES) against liver cholestasis induced by EE in adult female rats. The daily oral administration of the RES at a concentration of 25 mg/kg body weight for 15 days to rats treated with EE (100 μg/kg body weight for 5 days) resulted in a significant protection against EE-induced decrease in both serum cholesterol and bile acid levels as well as against an increase of serum bilirubin concentration. The treatment also resulted in a significant increase in hepatic superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase activities as well as hepatic protein-bound and nonprotein sulfhydryl groups. RES inhibited serum alkaline phosphatase, alanine aminotransferase, pi-glutathione-S-transferase, gamma-glutamyl transpeptidase, and alpha-glutathione-S-transferase activities, as well as reduced serum tumor necrosis factor-alpha, nitric oxide, and hepatic malondialdehyde as compared to EE-treated rats. The results clearly suggest that RES has a powerful prophylactic action in cholestasis induced by EE. Taken together, RES has potential as a preventive and therapeutic agent for cholestasis and deserves clinical trial in the near future as an adjuvant therapy in women treated with estrogen. 23334176 Antidepressant use and glycemic control. RATIONALE: Past research on the association of antidepressant medication use with glycemic control abnormalities has produced mixed results. OBJECTIVE: To examine the association of antidepressant use with glycemic control abnormalities and screen-positive diabetes in a representative population sample of US adults without a diagnosis of diabetes. METHODS: Using data from adult participants of the National Health and Nutrition Examination Survey (NHANES, 2005-2010), the association of antidepressant use with continuous measures of HbA1c, fasting blood sugar, 2-h oral glucose tolerance test, insulin sensitivity and screen-positive diabetes according to HbA1c, fasting blood sugar and 2-h oral glucose tolerance test were assessed. RESULTS: Antidepressant use was not associated with increased levels of HbA1c, fasting blood sugar, 2-h oral glucose tolerance test, reduced insulin sensitivity or increased prevalence of screen-positive diabetes. Results were mostly consistent across sociodemographic groups and across different lengths of exposure, different classes of antidepressants and levels of body mass index. CONCLUSIONS: In this representative population sample, antidepressant use was not associated with an increased risk of abnormalities in glycemic control or undetected diabetes. Positive findings from past research may be attributable to detection bias, in that individuals prescribed antidepressants may be more likely to be tested and diagnosed with diabetes. 23316966 Matrix metalloproteinases as drug targets in acute pulmonary embolism. Acute pulmonary embolism is a critical condition associated with increased mortality. Lung embolization causes acute pulmonary hypertension and right ventricle afterload. Global heart ischemia supervenes and may lead to severe shock and death. In this article, we reviewed current literature supporting the idea that abnormal matrix metalloproteinase (MMP) activity contributes to acute pulmonary embolism-induced hemodynamic changes. While low MMP levels are usually found in normal lung tissues, it is well known that inflammation and lung injury increase MMP expression and activity. This is probably due to recruitment and migration of inflammatory cells from the circulation to lung tissues. In addition, recent studies have shown increased MMP levels and activity in the right ventricle from animals with acute pulmonary embolism. Such increases in proteolytic activity were associated with increased cardiac troponin I in serum, suggesting a possible role for MMPs in cardiomyocyte injury during acute pulmonary embolism. These alterations have justified the use of doxycycline as an MMP inhibitor in acute pulmonary embolism. We review current evidence indicating that MMPs are targets in this critical condition. MMP inhibition apparently exerts antihypertensive effects and protects against cardiomyocyte injury caused by acute pulmonary embolism. 23375851 Chronic, low concentration exposure to pharmaceuticals impacts multiple organ systems in zebrafish. Pharmaceuticals are found in both receiving and drinking water due to their persistent release in waste-water effluents, raising concerns for environmental and human health. Chronic, aqueous exposure of zebrafish (Danio rerio) to environmentally relevant concentrations of acetaminophen (ACE), venlafaxaine (VEN) (10μgL(-1)), carbamazepine (CBZ) and gemfibrozil (GEM) (0.5 and 10μgL(-1)) decreased reproductive output. Atretic oocytes and altered ovarian histology were seen in female zebrafish exposed to CBZ and GEM, suggesting a direct effect on oocyte development that may account for the reduced fecundity. Apoptosis within the theca and granulosa cells was identified in exposed female zebrafish with atretic oocytes by TUNEL positive staining. The incidence of follicular apoptosis was nearly 2-fold higher in exposed females than the controls. All compounds significantly altered kidney proximal tubule morphology but there was no difference in the incidence of apoptotic cells within the kidney between control and exposed in either males or females. Liver histology was altered by ACE and GEM exposure. Parental exposure to pharmaceuticals did not increase developmental abnormalities, hatching success, or mortality in embryos. Yet, direct exposure of embryos to ACE increased developmental abnormalities and mortality; exposure to 0.5μgL(-1) of all pharmaceuticals increased mortality. CBZ decreased plasma 11-ketotestosterone concentrations in males and females. Overall, these data suggest that low concentration, chronic exposure of fish to pharmaceuticals impacts fish development as well as multiple organ systems in adult fish, leading to effects on reproduction and histology of liver and kidney. These results are significant in understanding the consequences of chronic, low concentration pharmaceutical exposure to fish and suggest that exposed populations are at risk of negative impacts to reproduction and health. 23481139 Nicotinic acid conjugates of nonsteroidal anti-inflammatory drugs (NSAID's) and their anti-inflammatory properties. A series of nicotinic acid conjugates with non-steroidal anti-inflammatory drugs (NSAID's) have been effectively synthesized using TBTU in high yield and purity. All the synthesized conjugates were evaluated for their in vitro anti-inflammatory activity. 23432064 Transient receptor potential channels and dermatological disorders. Transient receptor potential (TRP) cation channels are an emerging field of research in dermatology. Beyond their classical role in skin sensory perception, TRPs are involved in various cutaneous functions that include keratinocyte differentiation, apoptosis and melanocyte pigmentation. In addition, they have a role as pharmacological targets in many inflammatory skin diseases including psoriasis, chronic itch, hair disorders and skin cancers. Moreover, mutations in TRPs have recently been related to rare skin conditions such as Olmsted syndrome. This review will cover the role of TRPs in dermatologic conditions with special emphasis on itch and skin inflammatory diseases. 23295711 The interplay between environmental and genetic factors in Parkinson's disease susceptibility: The evidence for pesticides. Parkinson's disease (PD) is a common neurodegenerative disorder characterized by dopaminergic neuron loss in the substantia nigra. Several genetic and environmental factors have been implicated in the pathogenesis of PD. Single risk factors are likely to exert relatively minor effects, whereas their interaction may prove to be sufficient to cause PD. In the present review we summarize current knowledge from human genetic association studies regarding the interaction between gene polymorphisms and pesticide exposure in the risk of PD. A number of genetic association studies have investigated joint effects between genes and pesticides on PD risk. They have provided some evidence that genetic susceptibility either in metabolism, elimination and transport of pesticides or in the extent of mitochondrial dysfunction, oxidative stress and neuronal loss may predispose individuals to PD if they have been exposed to pesticides. These findings confirm the importance of considering pesticide-gene interactions in future studies in order to gain a better understanding of the pathogenic mechanisms of PD. 23610045 In Vitro Evaluation of Combined Sulfated Silk Fibroin Scaffolds for Vascular Cell Growth. A combined sulfated silk fibroin scaffold is fabricated by modifying a knitted silk scaffold with sulfated silk fibroin sponges. In vitro hemocompatibility evaluation reveals that the combined sulfated silk fibroin scaffolds reduce platelet adhesion and activation, and prolong the activated partial thromboplastin time (APTT), thrombin time (TT), and prothrombin time (PT). The response of porcine endothelial cells (ECs) and smooth muscle cells (SMCs) on the scaffolds is studied to evaluate the cytocompatibility of the scaffolds. Vascular cells are seeded on the scaffolds and cultured for 2 weeks. The scaffolds demonstrate enhanced EC adhesion, proliferation, and maintenance of cellular functions. Moreover, the scaffolds inhibit SMC proliferation and induce expression of contractile SMC marker genes. 23161673 Identifying protein interaction subnetworks by a bagging Markov random field-based method. Identification of differentially expressed subnetworks from protein-protein interaction (PPI) networks has become increasingly important to our global understanding of the molecular mechanisms that drive cancer. Several methods have been proposed for PPI subnetwork identification, but the dependency among network member genes is not explicitly considered, leaving many important hub genes largely unidentified. We present a new method, based on a bagging Markov random field (BMRF) framework, to improve subnetwork identification for mechanistic studies of breast cancer. The method follows a maximum a posteriori principle to form a novel network score that explicitly considers pairwise gene interactions in PPI networks, and it searches for subnetworks with maximal network scores. To improve their robustness across data sets, a bagging scheme based on bootstrapping samples is implemented to statistically select high confidence subnetworks. We first compared the BMRF-based method with existing methods on simulation data to demonstrate its improved performance. We then applied our method to breast cancer data to identify PPI subnetworks associated with breast cancer progression and/or tamoxifen resistance. The experimental results show that not only an improved prediction performance can be achieved by the BMRF approach when tested on independent data sets, but biologically meaningful subnetworks can also be revealed that are relevant to breast cancer and tamoxifen resistance. 23558646 Supramolecular H-bonded porous networks at surfaces: exploiting primary and secondary interactions in a bi-component melamine-xanthine system. The control over the formation of a bi-component porous network was attained by the self-assembly at a solid-liquid interface by exploiting both primary and secondary non-covalent interactions between melamine and N(3)-alkylated xanthine modules. 23454345 Biodiversity of small molecules - a new perspective in screening set selection. How is the 'diversity' of a compound set defined and how is the most appropriate compound subset identified for assay when screening the entire HTS deck is not an option? A common approach has so far been to cover as much of the chemical space as possible by screening a chemically diverse set of compounds. We show that, rather than chemical diversity, the biologic diversity of a compound library is an essential requirement for hit identification. We describe a simple and efficient approach for the design of a HTS library based on compound-target diversity. Biodiverse compound subsets outperform chemically diverse libraries regarding hit rate and the total number of unique chemical scaffolds present among hits. Specifically, by screening ∼19% of a HTS collection, we expect to discover ∼50-80% of all desired bioactive compounds. 23477344 Binding Preference of Carbon Nanotube Over Proline-Rich Motif Ligand on SH3-Domain: A Comparison with Different Force Fields. With the widespread applications of nanomaterials such as carbon nanotubes, there is a growing concern on the biosafety of these engineered nanoparticles, in particular their interactions with proteins. In molecular simulations of nanoparticle-protein interactions, the choice of empirical parameters (force fields) plays a decisive role, and thus is of great importance and should be examined carefully before wider applications. Here we compare three commonly used force fields, CHARMM, OPLSAA, and AMBER in study of the competitive binding of a single wall carbon nanotube (SWCNT) with a native proline-rich motif (PRM) ligand on its target protein SH3 domain, a ubiquitous protein-protein interaction mediator involved in signaling and regulatory pathways. We find that the SWCNT displays a general preference over the PRM in binding with SH3 domain in all the three force fields examined, although the degree of preference can be somewhat different, with the AMBER force field showing the highest preference. The SWCNT prevents the ligand from reaching its native binding pocket by (i) occupying the binding pocket directly, and (ii) binding with the ligand itself and then being trapped together onto some off-sites. The π-π stacking interactions between the SWCNT and aromatic residues are found to play a significant role in its binding to the SH3 domain in all the three force fields. Further analyses show that even the SWCNT-ligand binding can also be relatively more stable than the native ligand-protein binding, indicating a serious potential disruption to the protein SH3 function. 23561198 Cultivating conditions effects on kefiran production by the mixed culture of lactic acid bacteria imbedded within kefir grains. The influence of fermentation temperature, agitation rate, and additions of carbon sources, nitrogen sources, vitamins and minerals on production of kefiran by kefir grains lactic acid bacteria was studied in a series of experiments. The main aim of the work was to increase the exopolysaccharide (EPS) production where customised milk was used as fermentation medium. It was proved that the controlling of culturing conditions and the modifying of fermentation medium conditions (i.e., carbon, nitrogen, mineral sources and vitamins) can dramatically enhance the production of the EPS. The temperature and agitation rate were critical for kefiran production during the 24h cultivation of grains; our optimised conditions being 25°C and 80rpm, respectively. In addition, when optimising the effects of additional nutrition, it was found that 5% (w/v) lactose, 0.1% (w/v) thiamine, and 0.1% (w/v) FeCl3 led to the maximal production of EPS. The results indicate that nutrients can be utilised to improve the production of EPS and that good kefir grains growth does not appear to be a determining factor for a high production yield of EPS. 23629516 In ovo effects of two organophosphate flame retardants, TCPP and TDCPP, on pipping success, development, mRNA expression and thyroid hormone levels in chicken embryos. Tris(1-chloro-2-propyl) phosphate (TCPP) and tris(1,3-dichloro-2-propyl) phosphate (TDCPP) are organic flame retardants detected in the environment and biota for which toxicological data for avian species are limited. In this study, domestic chicken eggs were injected with TCPP or TDCPP (maximum dose = 51600 and 45000 ng/g egg, respectively) to determine dose-dependent effects on pipping success, development, hepatic messenger RNA (mRNA) expression levels of genes associated with xenobiotic metabolism and the thyroid hormone (TH) pathway, and TH levels following 20-22 days of incubation. Neither compound reduced pipping success; however, TCPP significantly delayed pipping at 9240 and 51600 ng/g and reduced tarsus length at 51600 ng/g. TDCPP exposure resulted in significant decreases in head plus bill length, embryo mass and gallbladder size at 45000 ng/g and reduced plasma free T4 levels at 7640 ng/g. Type I deiodinase, liver fatty-acid binding protein and cytochrome P450 (CYP) 3A37 mRNA levels were significantly induced by TCPP, while TDCPP induced CYP3A37 and CYP2H1. Chemical analysis of egg contents at incubation days 0, 5, 11, 18, and 19 revealed that >92% of the injected TCPP or TDCPP concentration was detectable up to day 5; however, <1% was detected by day 19. The observed phenotypic responses to TCPP and TDCPP exposure may be associated with disruption of the TH-axis, which is critical for normal growth and development in birds. The effects of TDCPP on the gallbladder indicate that the disturbance of lipid metabolism is a likely target in its mechanism of toxicity. 23104432 Lung inflammatory effects, tumorigenesis, and emphysema development in a long-term inhalation study with cigarette mainstream smoke in mice. Cigarette smoking is the leading cause of lung cancer and chronic obstructive pulmonary disease, yet there is little mechanistic information available in the literature. To improve this, laboratory models for cigarette mainstream smoke (MS) inhalation-induced chronic disease development are needed. The current study investigated the effects of exposing male A/J mice to MS (6h/day, 5 days/week at 150 and 300 mg total particulate matter per cubic meter) for 2.5, 5, 10, and 18 months in selected combinations with postinhalation periods of 0, 4, 8, and 13 months. Histopathological examination of step-serial sections of the lungs revealed nodular hyperplasia of the alveolar epithelium and bronchioloalveolar adenoma and adenocarcinoma. At 18 months, lung tumors were found to be enhanced concentration dependently (up to threefold beyond sham exposure), irrespective of whether MS inhalation had been performed for the complete study duration or was interrupted after 5 or 10 months and followed by postinhalation periods. Morphometric analysis revealed an increase in the extent of emphysematous changes after 5 months of MS inhalation, which did not significantly change over the following 13 months of study duration, irrespective of whether MS exposure was continued or not. These changes were found to be accompanied by a complex pattern of transient and sustained pulmonary inflammatory changes that may contribute to the observed pathogeneses. Data from this study suggest that the A/J mouse model holds considerable promise as a relevant model for investigating smoking-related emphysema and adenocarcinoma development. 23495719 Simulating adsorptive expansion of zeolites: application to biomass-derived solutions in contact with silicalite. We have constructed and applied an algorithm to simulate the behavior of zeolite frameworks during liquid adsorption. We applied this approach to compute the adsorption isotherms of furfural-water and hydroxymethyl furfural (HMF)-water mixtures adsorbing in silicalite zeolite at 300 K for comparison with experimental data. We modeled these adsorption processes under two different statistical mechanical ensembles: the grand canonical (V-Nz-μg-T or GC) ensemble keeping volume fixed, and the P-Nz-μg-T (osmotic) ensemble allowing volume to fluctuate. To optimize accuracy and efficiency, we compared pure Monte Carlo (MC) sampling to hybrid MC-molecular dynamics (MD) simulations. For the external furfural-water and HMF-water phases, we assumed the ideal solution approximation and employed a combination of tabulated data and extended ensemble simulations for computing solvation free energies. We found that MC sampling in the V-Nz-μg-T ensemble (i.e., standard GCMC) does a poor job of reproducing both the Henry's law regime and the saturation loadings of these systems. Hybrid MC-MD sampling of the V-Nz-μg-T ensemble, which includes framework vibrations at fixed total volume, provides better results in the Henry's law region, but this approach still does not reproduce experimental saturation loadings. Pure MC sampling of the osmotic ensemble was found to approach experimental saturation loadings more closely, whereas hybrid MC-MD sampling of the osmotic ensemble quantitatively reproduces such loadings because the MC-MD approach naturally allows for locally anisotropic volume changes wherein some pores expand whereas others contract. 23548149 PFKFB3 activation in cancer cells by the p38/MK2 pathway in response to stress stimuli. PFK-2/FBPase-2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) catalyses the synthesis and degradation of Fru-2,6-P2 (fructose-2,6-bisphosphate), a key modulator of glycolysis and gluconeogenesis. The PFKFB3 gene is involved in cell proliferation owing to its role in carbohydrate metabolism. Here we analyze its mechanism of regulation as an immediately early gene controlled by stress stimuli that activate p38/MK2 pathway. We report that exposure of HeLa and T98G cells to different stress stimuli (NaCl, H2O2, UV radiation and anisomycin) leads to a rapid increase (15-30 minutes) in PFKFB3 mRNA levels. The use of specific inhibitors in combination with MK2-deficient cells implicate control by MK2 protein kinase. Transient transfection of HeLa cells with deleted gene promoter constructs allowed us to identify a Serum Response Element (SRE) to which Serum Response Factor (SRF) binds and thus transactivates PFKFB3 gene transcription. Direct Binding of phospho-SRF to the SRE sequence (-918 nt) was confirmed by ChIP (chromatin immunoprecipiation) assays. Moreover, PFKFB3 isoenzyme phosphorylation at Ser461 by MK2 increases PFK-2 activity. Together, the results suggest a multimodal mechanism of stress stimuli affecting PFKFB3 transcriptional regulation and kinase activation by protein phosphorylation, resulting in an increase in Fru-2,6-P2 concentration and stimulation of glycolysis in cancer cells. 23629055 Porphyrin sensitizers with π-extended pull units for dye-sensitized solar cells. New π-extended porphyrin dyes with long alkoxyl chains at the ortho positions of the meso-phenyls, and meta di-tert-butylphenyl-substituted porphyrins , and were synthesized for dye-sensitized solar cells, and their optical, electrochemical and photovoltaic properties were investigated and compared with those of and . The absorption spectra of showed a slight red shift of Soret bands and blue shift of Q bands as compared to the meta-substituted porphyrins due to the electron-donating effects of dioctyloxy substituents at the ortho-positions of the meso-phenyl rings. Replacement of the carboxyl with a cyanoacrylic acid as the anchoring group results in significant broadening and red shifts of the absorptions, which is due to the strong electronic coupling between the pull unit and the porphyrin ring facilitated by the C[triple bond, length as m-dash]C triple bond. The electrochemical studies and quantum-chemical calculations (DFT) indicated that the ortho alkoxy-substituted sensitizers exhibit lower oxidation potential, i.e. a higher HOMO energy level, and their HOMO-LUMO gaps are comparable to the meta-substituted analogues. The photovoltaic measurements confirmed that the ortho-octyloxy groups in the two meso-phenyls of and play a significant role in preventing dye aggregation thereby enhancing the corresponding short-circuit current density and open-circuit voltage. The power conversion efficiency (η) of is 8.04%, which is 11% higher than that of , whereas the efficiency of is 6.03%, which is 135% higher than that of . On the other hand, the poor performance of and is due to the floppy structural nature and limited molecular rigidity of the cyanoacrylic acid anchor. 23411191 Increase in antioxidant and anticancer effects of ginsenoside Re-lysine mixture by Maillard reaction. Ginsenosides are the main active components of Panax ginseng. Structural changes in diol type ginsenosides along with generation of Maillard reaction products (MRPs) are strongly associated with increased free radical-scavenging activities. Ginsenoside Re, one of the major triol type ginsenosides of P. ginseng, possesses a hydrophobic four-ring steroid-like structure with hydrophilic sugar moieties at carbons-3 and -20. The aim of the present study was to identify changes in the structure, antioxidant and anticancer effects of ginsenoside Re upon Maillard reaction. Ginsenoside Re was transformed into less-polar ginsenosides, namely Rg(2), Rg(6) and F(4) by heat-processing. Free radical-scavenging activity of the ginsenoside Re-lysine mixture increased upon heat processing. This improved free radical-scavenging activity mediated by antioxidant MRPs, which were generated through Maillard reaction of a glucosyl moiety separated from carbon-20 of ginsenoside Re and lysine. The increased anticancer effect of ginsenoside Re-lysine mixture upon heat processing was mainly derived from the generation of less-polar ginsenosides through the regulation of Bcl-2 and Bax, as well as caspase-dependent apoptotic pathway. These results reported here have shed significant new lights on the mechanism of increased antioxidant and anticancer effects of P. ginseng upon heat processing. 23344429 Synthetic cascades are enabled by combining biocatalysts with artificial metalloenzymes. Enzymatic catalysis and homogeneous catalysis offer complementary means to address synthetic challenges, both in chemistry and in biology. Despite its attractiveness, the implementation of concurrent cascade reactions that combine an organometallic catalyst with an enzyme has proven challenging because of the mutual inactivation of both catalysts. To address this, we show that incorporation of a d(6)-piano stool complex within a host protein affords an artificial transfer hydrogenase (ATHase) that is fully compatible with and complementary to natural enzymes, thus enabling efficient concurrent tandem catalysis. To illustrate the generality of the approach, the ATHase was combined with various NADH-, FAD- and haem-dependent enzymes, resulting in orthogonal redox cascades. Up to three enzymes were integrated in the cascade and combined with the ATHase with a view to achieving (i) a double stereoselective amine deracemization, (ii) a horseradish peroxidase-coupled readout of the transfer hydrogenase activity towards its genetic optimization, (iii) the formation of L-pipecolic acid from L-lysine and (iv) regeneration of NADH to promote a monooxygenase-catalysed oxyfunctionalization reaction. 22963367 Oriented electrophoretic deposition of GdOCl nanoplatelets. Electrophoretic deposition has emerged as a versatile and precisely tunable approach for the rapid deposition of conformal thin films of colloidal nanocrystals. The electrophoretic deposition of phosphor particles has assumed special significance in recent years as a commercially viable means toward the fabrication of large-area, ultrathin high-resolution emissive display screens. Here, we demonstrate that the anisotropic shape of colloidal ligand-passivated GdOCl nanoplatelets enables their assembly with remarkable substrate alignment and a high packing density upon electrophoretic deposition. GdOCl nanocrystals are promising candidates for phosphor applications given their low maximum phonon cutoff energy, robust chemical stability over prolonged periods of operation, and ability to promote efficacious phonon energy transfer to dopant ions. Potentiostatic deposition of GdOCl nanoplatelets from cyclohexane dispersions allows the deposition of individual nanoplatelets with their basal planes parallel to the electrode surface. Tuning the applied voltage and solution concentration allows control of film thickness, ranging up to several tens of micrometers. The high degree of particle alignment is attributed to anisotropic charge distribution and entrainment within electroosmotic flows established in the vicinity of the electrode surface. The oriented high-particle-density GdOCl nanoplatelet thin films are possible candidates for phosphor applications, which is illustrated by the green emission from a Tb-doped GdOCl thin film on indium tin oxide (ITO)-coated glass. 22548348 Tomentomimulol and mimulone B: Two new C-geranylated flavonoids from Paulownia tomentosa fruits. Two new discovered C-geranylated flavonoids tomentomimulol (1) and mimulone B (2) were isolated from the methanol extract of Paulownia tomentosa (Thunb). Steud. (Paulowniaceae) fruits by exhaustive chromatographic separation together with one known compound tanariflavanone D (3). The identification of compounds and structure elucidation was carried out using 1D and 2D NMR experiments, as well as mass spectroscopy, ultra-violet, infra red and CD experiments. 23617462 Competitive Adsorption of Di-hydroxy and Tri-hydroxy Bile Salts with Whey Protein and Casein in Oil-in-Water Emulsions. The competitive adsorption between whey protein concentrate (WPC) or sodium caseinate (SCN) and four bile salts, sodium cholate (NaC), dexocycholate (NaDC), taurocholate (NaTC) and glycodeoxycholate (NaGDC) has been studied in protein stabilized oil-in-water emulsions. The bile salts that contain a conjugated amino acid (NaTC and NaGDC) were considerably more efficient at displacing both WPC and SCN proteins from the emulsion droplet interface, even though they are known to have a lower hydrophobicity than NaC and NaDC. This is explained in terms of a steric resistance to adsorption from the conjugated amino acids in NaTC and NaGDC. This leads to them adopting an adsorbed conformation at the oil-water interface that penetrates less into the oil phase causing greater disruption of the adsorbed layer and hence leads to greater displacement of protein from the interface. Complementary computer simulations of the adsorption of the four bile salts at the decane-water interface support the hypothesis that the NaTC and NaGDC adopt flatter conformations that stick out further in to the aqueous phase, which arises from a lower free energy of adsorption. The adsorption isotherms for the four bile salts have also been measured. These have been found to have a form that fits closely the Langmuir-Freundlich isotherm. The results for NaC suggest that it adsorbs as individual molecules and forms a saturated monolayer over much of the concentration range used in the displacement experiments, since it is below its critical micelle concentration in this range. For the other three bile salts on the other hand, the primary adsorbing species appears to be the micelle form, since the surface coverage is above that of a saturated monolayer for much of the concentration range studied. 23142020 A soluble guanylate cyclase stimulator, BAY 41-8543, preserves right ventricular function in experimental pulmonary embolism. Pulmonary embolism (PE) increases pulmonary vascular resistance, causing right ventricular (RV) dysfunction, and poor clinical outcome. Present studies test if the soluble guanylate cyclase stimulator BAY 41-8543 reduces pulmonary vascular resistance and protects RV function. Experimental PE was induced in anesthetized, male Sprague-Dawley rats by infusing 25 μm polystyrene microspheres (1.95 million/100 g body wt, right jugular vein) producing moderate PE. Pulmonary artery vascular resistance, estimated as RVPSP/CO, increased 3-fold after 5 h of PE. Treatment with BAY 41-8543 (50 μg/kg, I.V.; given at the time of PE induction) normalized this index by reducing RVPSP and markedly increasing CO, via preservation of heart rate and stroke volume. Ex vivo RV heart function showed minimal changes at 5 h of PE, but decreased significantly after 18 h of PE, including peak systolic pressure (PSP, Control 39 ± 1 mmHg vs. 19 ± 3 PE), +dP/dt (1192 ± 93 mmHg/s vs. 444 ± 64) and -dP/dt (-576 ± 60 mmHg/s vs. -278 ± 40). BAY 41-8543 significantly improved all three indices of RV heart function (PSP 35 ± 3.5, +dP/dt 1129 ± 100, -dP/dt -568 ± 87). Experimental PE produced increased PVR and RV dysfunction, which were ameliorated by treatment with BAY 41-8543. Thus, there is vasodilator reserve in this model of experimental PE that can be exploited to reduce the stress upon the heart and preserve RV contractile function. 23307587 Improper Selection of a Pre-specified Primary Dose-Response Analysis Delays Regulatory Drug Approval. Dose-response analysis is one of the accepted efficacy endpoints to establish effectiveness. The purpose of this research was to inform selection of an appropriate pre-specified primary dose-response analysis to demonstrate drug efficacy in a registration trial. The power and the type I error rate of the placebo-corrected (i.e., simply adjusting the observed treatment value by subtracting the placebo mean) and the placebo-anchored (i.e., including the placebo data as dose 0 in the regression) slope analyses were assessed based on regulatory submission data for two antihypertensive drugs and simulated data from hypothetical clinical trials. In the simulated hypothetical trials, the impact of different dosing strategies (i.e., the fixed dose versus the weight-based per kilogram dose), sample size, and scenarios governing the drug exposure-response relationship (e.g., E max, ED 50 , and SD) was also evaluated. For each scenario, a total 300 replications were simulated. The placebo-anchored slope analysis is always more powerful to demonstrate effectiveness in all plausible scenarios. The difference between the placebo-anchored and the placebo-corrected analyses was maximum when the studied doses were too high. However, the dose-response analysis is not sensitive to the dosing strategies. Furthermore, the type I error rate of these two methods was also found to be comparable. The design of dose-response studies should carefully consider these results to justify the inclusion of placebo and the analysis method. The pharmaceutical industry and the regulatory agencies are equally responsible for using the appropriate methods of primary analysis and providing justification in the protocol. 22921987 Repair efficiency and PUVA therapeutic response variation in patients with vitiligo. Vitiligo is an acquired depigmentation disorder affecting 0.1% to >8.8% in Indian population. Psoralen and ultraviolet A radiation (PUVA) is a gold standard treatment for vitiligo, however, response is still empirical. In order to investigate whether drug response variation is influenced by the repair ability of PUVA treated vitiligo subjects, single cell gel electrophoresis (SCGE) for genotoxicity and serum malonaldehyde (MDA) for cytotoxicity were performed on 107 subjects (77 cases and 30 healthy controls) in South Indian population. In vitro repair ability was assessed by considering the residual damage. A significant difference was observed between the patients and controls with regard to their mean values of DNA damage and MDA levels (p<0.05). On categorization to fast and slow responders based on the time of response, patients exhibited a significant deviation in residual DNA damage, suggestive of variation with respect to DNA repair efficiency (p<0.05). This is the first study to our knowledge with respect to PUVA drug response variation in vitiligo in relation to DNA repair. Large systematic studies on DNA repair may help in a better understanding of the mechanisms involved in the PUVA drug response variation. 23122104 Novel angiotensin I-converting enzyme inhibitory peptides derived from soya milk. Inhibitors of angiotensin I-converting enzyme (ACE) are useful in treating hypertension, and many have been derived from food products, including soybeans. Using the industrial protease PROTIN SD-NY10, we developed a processed soya milk (PSM) with enhanced ACE inhibitory activity. The ACE inhibitory activity of PSM (IC(50)=0.26 μg/ml) was greater than that of regular soya milk (IC(50)=8.75 μg/ml). Eight novel ACE inhibitory peptides were purified from PSM by reversed-phase chromatography: FFYY (IC(50),1.9 μM), WHP (4.8 μM), FVP (10.1 μM), LHPGDAQR (10.3 μM), IAV (27.0 μM), VNP (32.5 μM), LEPP (100.1 μM), and WNPR (880.0 μM). The IC(50) values of these peptides are comparable to those reported for other ACE inhibitory peptides derived from wheat, chicken, bonito, wine, etc. Due to the relatively low IC(50) values of several peptides identified in this study, they may serve as ideal base components of food supplements for patients with hypertension. 23471539 Minireview: ubiquitination-regulated G protein-coupled receptor signaling and trafficking. G protein-coupled receptors (GPCRs) are the largest and most diverse superfamily of membrane proteins and mediate most cellular responses to hormones and neurotransmitters. Posttranslational modifications are considered the main regulators of all GPCRs. In addition to phosphorylation, glycosylation, and palmitoylation, increasing evidence as reviewed here reveals that ubiquitination also regulates the magnitude and temporospatial aspects of GPCR signaling. Posttranslational protein modification by ubiquitin is a key molecular mechanism governing proteins degradation. Ubiquitination mediates the covalent conjugation of ubiquitin, a highly conserved polypeptide of 76 amino acids, to protein substrates. This process is catalyzed by 3 enzymes acting in tandem: an E1, ubiquitin-activating enzyme; an E2, ubiquitin-carrying enzyme; and an E3, ubiquitin ligase. Ubiquitination is counteracted by deubiquitinating enzymes that deconjugate ubiquitin-modified proteins and rescue the substrate from proteasomal degradation. Although ubiquitination is known to target many GPCRs for lysosomal or proteasomal degradation, emerging findings define novel roles for the basal status of ubiquitination and for rapid deubiquitination and transubiquitination controlling cell surface expression and cellular responsiveness of some GPCRs. In this review, we highlight the classical and novel roles of ubiquitin in the regulation of GPCR function, signaling, and trafficking. 23225536 Combined toxicity of polycyclic aromatic hydrocarbons and heavy metals to biochemical and antioxidant responses of free and immobilized Selenastrum capricornutum. The aquatic environment often contains different groups of contaminants, but their combined toxicity on microalgae has seldom been reported. The present study compared the toxic effects of combined mixed polycyclic aromatic hydrocarbons (PAHs) and heavy metals on growth and antioxidant responses of free and immobilized microalga, Selenastrum capricornutum. Five PAHs-phenanthrene, fluorene, fluoranthene, pyrene, and benzo[a]pyrene-and four heavy metals at different concentrations-0.05 to 0.1 µg Cd(2+) ml(-1) , 0.05 to 1 µg Cu(2+) ml(-1) , 0.05 to 1 µg Zn(2+) ml(-1) , and 0.5 to 2.5 µg Ni(2+) ml(-1) -were examined. Results showed that the chlorophyll a content of free and immobilized S. capricornutum was not affected by PAHs but was significantly inhibited by heavy metals. Conversely, the antioxidant parameters, including the content of reduced glutathione (GSH) and the activities of superoxide dismutase and peroxidase, were significantly induced by both PAHs and metals. For the combined toxic effects of PAHs and heavy metals, cell growth and antioxidant responses varied with exposure time and contaminants and differed between free and immobilized cells. The effects of cocontaminants on the GSH content in free cells were mainly synergistic but changed to antagonistic in immobilized cells. The toxic effects of cocontamination on free cells were also more obvious than those on immobilized cells. These findings suggest that immobilization offers some protection to microalgal cells against toxic contaminants causing differences in the interaction and responses to combined toxicants between free and immobilized cells. Immobilized cells might be more suitable for treating wastewater containing toxic contaminants than free cells. 23505043 A Stochastic Simulator of Birth-Death Master Equations with Application to Phylodynamics. In this article, we present a versatile new software tool for the simulation and analysis of stochastic models of population phylodynamics and chemical kinetics. Models are specified via an expressive and human-readable XML format and can be used as the basis for generating either single population histories or large ensembles of such histories. Importantly, phylogenetic trees or networks can be generated alongside the histories they correspond to, enabling investigations into the interplay between genealogies and population dynamics. Summary statistics such as means and variances can be recorded in place of the full ensemble, allowing for a reduction in the amount of memory used-an important consideration for models including large numbers of individual subpopulations or demes. In the case of population size histories, the resulting simulation output is written to disk in the flexible JSON format, which is easily read into numerical analysis environments such as R for visualization or further processing. Simulated phylogenetic trees can be recorded using the standard Newick or NEXUS formats, with extensions to these formats used for non-tree-like inheritance relationships. 23602989 Presynaptic CaMKIIα modulates dopamine D3 receptor activation in striatonigral terminals of the rat brain in a Ca(2+) dependent manner. CaMKIIα is expressed at high density in the nucleus accumbens where it binds to postsynaptic D3 receptors inhibiting their effects. In striatonigral projections, activation of presynaptic D3 receptors potentiates D1 receptor-induced stimulation of cAMP production and GABA release. In this study we examined whether the presynaptic effects of D3 receptor stimulation in the substantia nigra reticulata (SNr) are modulated by Ca(2+) activation of CaMKIIα. In SNr synaptosomes two procedures that increase cytoplasmic Ca(2+), ionomycin and K(+)-depolarization, blocked the additional stimulation of cAMP accumulation produced by coactivating D3 and D1 dopamine receptors. The selective CaMKIIα inhibitor KN-62 reversed the blockade produced by ionomycin and K(+)-depolarization. Incubation in either Ca(2) -free solutions or with the selective Ca(2+) blocker nifedipine, also reversed the blocking effects of K(+)-depolarization. Immunoblot studies showed that K(+)-depolarization increased CaMKIIα phosphorylation in a KN-62 sensitive manner and promoted CaMKIIα binding to D3 receptors. In K(+)-depolarized tissues, D3 receptors potentiated D1 receptor-induced stimulation of [(3)H]GABA release only when CaMKIIα was blocked with KN-62. In the presence of this inhibitor, the selective D3 agonist PD 128,907 reduced the ED50 for the D1 agonist SKF 38393 from 56 to 4 nM. KN-62 also enhanced the effects of dopamine on depolarization induced [(3)H]GABA release. KN-62 changed ED50 for dopamine from 584 to 56 nM. KN-62 did not affect D1 and D4 receptor responses. These experiments show that in striatonigral projections, CaMKIIα inhibits the action of D3 receptors in a Ca(2+) dependent manner blocking their modulatory effects on GABA release. These findings suggest a mechanism through which the frequency of action potential discharge in presynaptic terminals regulates dopamine effects. 23578632 Antioxidant ability of fractionated apple peel phenolics to inhibit fish oil oxidation. Polyphenols isolated from frozen and dried apple peels were studied as potential natural antioxidants to stabilize omega-3 polyunsaturated fatty acid (ω3 PUFA) enriched fish oil. The ethanolic extracts of apple peels were fractionated by reversed phase chromatography using gradient elution of 20-100% aqueous ethanol. The collected fractions were analyzed by ultra pressure liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). The total phenolic content and antioxidant capacity of each fraction were evaluated by Folin-Ciocalteu (FC), ferric reducing antioxidant power (FRAP) and 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) scavenging assays. Inhibition of fish oil oxidation was studied using the thiobarbituric acid reactive substances (TBARS) assay. Polyphenols fractionated using frozen apple peel extract had significantly higher FC, FRAP and DPPH(·) scavenging values than those of dried apple peel (p<0.05). The flavonol-rich fractions inhibited fish oil oxidation by 40-62% at a total phenolic concentration of 200μg/ml. The fractionated polyphenols from both dried and frozen apple peel showed higher inhibition of lipid oxidation compared to α-tocopherol, butylated hydroxytoluene and crude apple peel extracts. 22724545 Cytotoxic constituents from the fungus Daldinia concentrica (Xylariaceae). Phytochemical study on the methanol extract of the fruit bodies of Vietnamese fungus Daldinia concentrica has led to the isolation and structural elucidation of three cytotoxic constituents, 6,8-dihydroxy-3-methyl-3,4-dihydroisocoumarin (1), (22R)-hydroxylanosta-7,9(11),24-trien-3-one (2) and ergosterol (3). Their structures were elucidated by 2D-NMR and FT-ICR-MS. All the three compounds showed moderate cytotoxicity against four cancer cells, KB (a human epidermal carcinoma), MCF7 (human breast carcinoma), SK-LU-1 (human lung carcinoma) and HepG2 (hepatocellular carcinoma). In addition, the isocoumarin (1) inhibited the growth of Staphylococcus aureus with the IC50 value of 87.81 µg mL(-1). 23293001 ParseCNV integrative copy number variation association software with quality tracking. A number of copy number variation (CNV) calling algorithms exist; however, comprehensive software tools for CNV association studies are lacking. We describe ParseCNV, unique software that takes CNV calls and creates probe-based statistics for CNV occurrence in both case-control design and in family based studies addressing both de novo and inheritance events, which are then summarized based on CNV regions (CNVRs). CNVRs are defined in a dynamic manner to allow for a complex CNV overlap while maintaining precise association region. Using this approach, we avoid failure to converge and non-monotonic curve fitting weaknesses of programs, such as CNVtools and CNVassoc, and although Plink is easy to use, it only provides combined CNV state probe-based statistics, not state-specific CNVRs. Existing CNV association methods do not provide any quality tracking information to filter confident associations, a key issue which is fully addressed by ParseCNV. In addition, uncertainty in CNV calls underlying CNV associations is evaluated to verify significant results, including CNV overlap profiles, genomic context, number of probes supporting the CNV and single-probe intensities. When optimal quality control parameters are followed using ParseCNV, 90% of CNVs validate by polymerase chain reaction, an often problematic stage because of inadequate significant association review. ParseCNV is freely available at http://parsecnv.sourceforge.net. 22551786 Negative allosteric modulation of metabotropic glutamate receptor 5 results in broad spectrum activity relevant to treatment resistant depression. Evidence suggests that 30-50% of patients suffering from major depressive disorder (MDD) are classified as suffering from treatment resistant depression (TRD) as they have an inadequate response to standard antidepressants. A key feature of this patient population is the increased incidence of co-morbid symptoms like anxiety and pain. Recognizing that current standards of care are largely focused on monoaminergic mechanisms of action (MOAs), innovative approaches to drug discovery for TRD are targeting glutamate hyperfunction. Here we describe the in vitro and in vivo profile of GRN-529, a novel negative allosteric modulator (NAM) of metabotropic glutamate receptor 5 (mGluR5). In cell based pharmacology assays, GRN-529 is a high affinity (Ki 5.4 nM), potent (IC50 3.1 nM) and selective (>1000-fold selective vs mGluR1) mGluR5 NAM. Acute administration of GRN-529 (0.1-30 mg/kg p.o.) had dose-dependent efficacy across a therapeutically relevant battery of animal models, comprising depression (decreased immobility time in tail suspension and forced swim tests) and 2 of the co-morbid symptoms overrepresented in TRD, namely anxiety (attenuation of stress-induced hyperthermia, and increased punished crossings in the four plate test) and pain (reversal of hyperalgesia due to sciatic nerve ligation or inflammation). The potential side effect liability of GRN-529 was also assessed using preclinical models: GRN-529 had no effect on rat sexual behavior or motor co-ordination (rotarod), however it impaired cognition in mice (social odor recognition). Efficacy and side effects of GRN-529 were compared to standard of care agents (antidepressant, anxiolytic or analgesics) and the tool mGluR5 NAM, MTEP. To assess the relationship between target occupancy and efficacy, ex vivo receptor occupancy was measured in parallel with efficacy testing. This revealed a strong correlation between target engagement, exposure and efficacy across behavioral endpoints, which supports the potential translational value of PET imaging to dose selection in patients. Collectively this broad spectrum profile of efficacy of GRN-529 supports our hypothesis that negative allosteric modulation of mGluR5 could represent an innovative therapeutic approach to the treatment of TRD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 22975155 Mechanism of interaction of novel uncharged, centrally active reactivators with OP-hAChE conjugates. A library of more than 200 novel uncharged oxime reactivators was used to select and refine lead reactivators of human acetylcholinesterase (hAChE) covalently conjugated with sarin, cyclosarin, VX, paraoxon and tabun. N-substituted 2-hydroxyiminoacetamido alkylamines were identified as best reactivators and reactivation kinetics of the lead oximes, RS41A and RS194B, were analyzed in detail. Compared to reference pyridinium reactivators, 2PAM and MMB4, molecular recognition of RS41A reflected in its Kox constant was compromised by an order of magnitude on average for different OP-hAChE conjugates, without significant differences in the first order maximal phosphorylation rate constant k2. Systematic structural modifications of the RS41A lead resulted in several-fold improvement with reactivator, RS194B. Kinetic analysis indicated Kox reduction for RS194B as the main kinetic constant leading to efficient reactivation. Subtle structural modifications of RS194B were used to identify essential determinants for efficient reactivation. Computational molecular modeling of RS41A and RS194B interactions with VX inhibited hAChE, bound reversibly in Michaelis type complex and covalently in the pentacoordinate reaction intermediate suggests that the faster reactivation reaction is a consequence of a tighter RS194B interactions with hAChE peripheral site (PAS) residues, in particular with D74, resulting in lower interaction energies for formation of both the binding and reactivation states. Desirable in vitro reactivation properties of RS194B, when coupled with its in vivo pharmacokinetics and disposition in the body, reveal the potential of this oxime design as promising centrally and peripherally active antidotes for OP toxicity. 23134349 Silk fibroin/hyaluronic acid 3D matrices for cartilage tissue engineering. In spite of commercially available products, the complete and sustained repair of damaged articular cartilage still presents various challenges. Among biomaterials proposed for cartilage repair, silk fibroin (SF) has been recently proposed as a material template for porous scaffolds cultured with chondrocytes and investigated in static and dynamic conditions. In addition to fibroin-based constructs, literature has reported that the combination of hyaluronic acid (HA) with other scaffold materials can protect the chondral phenotype and the cells in vitro response to the scaffold. In this study, the effect of the addition of HA on the physical properties of SF sponges, with and without cross-linking with genipin, was investigated. Salt-leached scaffolds were characterized in terms of morphology and structural and physical properties, as well as mechanical performance. Un-cross-linked sponges resulted in the physical separation of highly hydrophilic HA from the SF, while cross-linking prevented this phenomenon, resulting in a homogeneous blend. The presence of HA also influenced fibroin crystallinity and tended to decrease the cross-linking degree of the scaffolds when compared to the pure SF material. 23434228 Synthesis and photochemical behavior of coumarin-caged cholesterol. The syntheses of three coumarin-caged cholesterols are reported that contain the 6-diethylaminocoumarin (DEACM), 6-bromo-7-hydroxycoumarin (BHC) and 6-bromo-7-methoxycoumarin (BMCM) photocleavable groups. Upon photolysis, the best caged derivative was found to be BHC-cholesterol whose quantum yield was determined to be 0.032 at 350 nm. 22995755 Crosslinked linear polyethylenimine enhances delivery of DNA to the cytoplasm. Crosslinked polyethylenimines (PEIs) have been frequently examined over the past decade since they can maintain the transfection efficiency of commercially available, 25k branched PEI, but exhibit less cytotoxicity. The argument is often made that the degradability of such polymers, generally synthesized with either disulfide or hydrolytically degradable crosslinkers, is critical to the high efficiency and low toxicity of the system. In this work, we present a crosslinked linear PEI (xLPEI) system in which either disulfide-responsive or non-degradable linkages are incorporated. As with previous systems, strong transfection efficiency in comparison with commercial standards was achieved with low cytotoxicity. However, these properties were shown to be present when either the degradable or non-degradable crosslinker was used. Uncomplexed polymer was demonstrated to be the critical factor determining transfection efficiency for these polymers, mediating efficient endosomal escape without signs of cell membrane damage. While several crosslinked PEI systems in the literature have demonstrated the effect of the disulfide moiety, this work demonstrates that disulfide-mediated unpackaging may not be as important as conventionally thought for some PEI systems. 23323854 Heterogeneous cationic liposomes modified with 3β-{N-[(N',N'-dimethylamino)ethyl]carbamoyl}cholesterol can induce partial conformational changes in messenger RNA and regulate translation in an Escherichia coli cell-free translation system. The effect of cationic liposomes (CLs) on messenger RNA(mRNA) conformation and translation was studied, focusing on membrane heterogeneity. CLs, composed of 1,2-dioleoyl-sn-glycerol-3-phosphocholine/1,2-dioleoyl-3-timethylammonium propane (DOPC/DOTAP) and DOPC/3β-{N-[(N',N'-dimethylamino)ethyl]carbamoyl}cholesterol (DOPC/DC-Ch), inhibited mRNA translation in an Escherichia coli cell-free translation system. Analysis of the membrane fluidity and polarity indicated a heterogeneous DOPC/DC-Ch (70/30) membrane, while other CLs exhibited homogeneous disordered membranes. mRNA adsorbed onto DOPC/DC-Ch liposomes showed translational activity, while DOPC/DOTAP liposomes inhibited mRNA translation in proportion to its adsorption onto membranes. Dehydration of DOPC/DOTAP (70/30) and DOPC/DC-Ch (70/30) was observed in the presence of mRNA but not in the case of zwitterionic DOPC liposomes, indicating that mRNA binds in regions between the phosphate [-PO(2)(-)-] and carbonyl [-C=O-] moieties of lipids. UV resonance Raman spectroscopy suggests that adenine, cytosine, and guanine interact with DOPC/DOTAP (70/30) and DOPC/DC-Ch (70/30) but not with DOPC. Circular dichroism indicates that DOPC/DOTAP (70/30) extensively denatured the mRNA. In contrast, heterogeneous DOPC/DC-Ch (70/30) induced partial conformational changes but maintained the translational activity of mRNA. 23317100 A Novel Marine Drug, SZ-685C, Induces Apoptosis of MMQ Pituitary Tumor Cells by Downregulating miR-200c. Objective: We found a novel marine drug, SZ-685C, that was isolated from the secondary metabolites of a mangrove endophytic fungus (No. 1403) collected from the South China Sea, which has been reported to inhibit the proliferation of certain tumor cells. However, its anticancer mechanism remains unknown. The aims of this study were to observe the effectiveness of SZ-685C on pituitary adenoma cells and determine the underlying mechanisms of action. Methods: A rat prolactinoma cell line, MMQ, was used in this study. A dose escalation of SZ-685C was performed on this cell line, and cell viability was assessed using an MTT assay. Hoechst 33342, Annexin V-FITC/PI, TUNEL staining and flow cytometry were used to evaluate the extent of apoptosis at each concentration of SZ-685C. The effect of SZ-685C on prolactin expression was also evaluated using RT-PCR and immunoblotting. Quantitative RT-PCR was used to detect the expression of miR-200c in SZ-685C-stimulated MMQ cells and pituitary adenoma tissues. This miRNA was then overexpressed in MMQ cells via transfection of a miR-200c mimic to identify the mechanism underling the anti-tumor effect of SZ-685C. Results: SZ-685C inhibited MMQ cell growth in a dose-dependent manner but showed little toxicity toward rat pituitary cells (RPCs). The IC50s of SZ-685C in MMQ cells and RPCs were 13.2 ± 1.3 mM and 49.1 ± 11.5 mM, respectively, which was statistically significant. Increasing numbers of apoptotic cells were observed in response to escalating concentrations of SZ-685C, and the expression level of prolactin (PRL) was inhibited. Nevertheless, the level of PRL mRNA was unchanged. Additionally, miR-200c was upregulated in MMQ cells compared with RPCs, and downregulation of miR- 200c was observed in SZ-685C-treated MMQ cells. Furthermore, the overexpression of miR-200c weakened the effect of SZ-685C-induced apoptosis of MMQ cells. Conclusions: Our results suggest that SZ-685C induces MMQ cell apoptosis in a miR-200c-dependent manner. Therefore, SZ-685C might be a useful alternative treatment for pituitary adenoma. 23160940 CB(1) receptor allosteric modulators display both agonist and signaling pathway specificity. We have previously identified allosteric modulators of the cannabinoid CB(1) receptor (Org 27569, PSNCBAM-1) that display a contradictory pharmacological profile: increasing the specific binding of the CB(1) receptor agonist [(3)H]CP55940 but producing a decrease in CB(1) receptor agonist efficacy. Here we investigated the effect one or both compounds in a broad range of signaling endpoints linked to CB(1) receptor activation. We assessed the effect of these compounds on CB(1) receptor agonist-induced [(35)S]GTPγS binding, inhibition, and stimulation of forskolin-stimulated cAMP production, phosphorylation of extracellular signal-regulated kinases (ERK), and β-arrestin recruitment. We also investigated the effect of these allosteric modulators on CB(1) agonist binding kinetics. Both compounds display ligand dependence, being significantly more potent as modulators of CP55940 signaling as compared with WIN55212 and having little effect on [(3)H]WIN55212 binding. Org 27569 displays biased antagonism whereby it inhibits: agonist-induced guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPγS) binding, simulation (Gα(s)-mediated), and inhibition (Gα(i)-mediated) of cAMP production and β-arrestin recruitment. In contrast, it acts as an enhancer of agonist-induced ERK phosphorylation. Alone, the compound can act also as an allosteric agonist, increasing cAMP production and ERK phosphorylation. We find that in both saturation and kinetic-binding experiments, the Org 27569 and PSNCBAM-1 appeared to influence only orthosteric ligand maximum occupancy rather than affinity. The data indicate that the allosteric modulators share a common mechanism whereby they increase available high-affinity CB(1) agonist binding sites. The receptor conformation stabilized by the allosterics appears to induce signaling and also selectively traffics orthosteric agonist signaling via the ERK phosphorylation pathway. 23608896 Three-dimensionally ordered macroporous Cu2O/Ni inverse opal electrodes for electrochemical supercapacitors. With an ordered polystyrene (PS) template-assisted electrochemical approach we synthesized three-dimensional ordered macroporous (3DOM) Cu2O/Ni inverse opals as electrodes for supercapacitors. The 3DOM Cu2O/Ni electrodes display superior kinetic performance, and satisfactory rate capability and cycling performance. 23525902 Chemical genetic analyses of quantitative changes in Cdk1 activity during the human cell cycle. Cyclin-dependent kinase 1 (Cdk1) controls cell proliferation and is inhibited by promising anticancer agents, but its mode of action and the consequences of its inhibition are incompletely understood. Cdk1 promotes S- and M-phases during the cell-cycle but also suppresses endoreduplication, which is associated with polyploidy and genome instability. The complexity of Cdk1 regulation has made it difficult to determine whether these different roles require different thresholds of kinase activity and whether the surge of activity as inhibitory phosphates are removed at mitotic onset is essential for cell proliferation. Here, we have used chemical genetics in a human cell line to address these issues. We rescued cells lethally depleted of endogenous Cdk1 with an exogenous Cdk1 conferring sensitivity to one ATP analogue inhibitor (1NMPP1) and resistance to another (RO3306). At no 1NMPP1 concentration was mitosis in rescued clones prevented without also inducing endoreduplication, suggesting that these two key roles for Cdk1 are not simply controlled by different Cdk1 activity thresholds. We also rescued RO3306-resistant clones using exogenous Cdk1 without inhibitory phosphorylation sites, indicating that the mitotic surge of Cdk1 activity is dispensable for cell proliferation. These results suggest that the basic mammalian cycle requires at least some qualitative changes in Cdk1 activity and that quantitative increases in activity need not be rapid. Furthermore, the viability of cells that are unable to undergo rapid Cdk1 activation, and the strong association between endoreduplication and impaired proliferation, may place restrictions on the therapeutic use of a Cdk1 inhibitors. 23497227 Synthesis and in vitro evaluation of N-Aryl pyrido-quinazolines derivatives as potent EGFR inhibitors. A series of pyrido-quinazolines have been synthesised, characterised and tested for their in vitro EGFR tyrosine kinase inhibitory activity. The compounds were prepared from Alkylideno/arylideno-bis-ureas. Their final structure of the compounds were elucidated on the basis of spectral studies (IR., 1H NMR, FT-IR and EI-MS). The cellular EGFR internalization response of selected compounds was evaluated using HeLa cells. Most of the synthesized compounds displayed potent EGFR-TK inhibitory activity and structurally halogenated derivatives had a pronounced effect in inhibiting EGFR internalization. © 2013 John Wiley & Sons A/S. 23218712 Discovery of a novel phenylethyl benzamide glucokinase activator for the treatment of type 2 diabetes mellitus. Novel benzamide derivatives were synthesized and tested at in vitro assay by measuring fold increase of glucokinase activity at 5.0 mM glucose concentration. Among the prepared compounds, YH-GKA was found to be an active glucokinase activator with EC(50) of 70 nM. YH-GKA showed similar glucose AUC reduction of 29.6% (50 mg/kg) in an OGTT study with C57BL/J6 mice compared to 29.9% for metformin (300 mg/kg). Acute treatment of the compound in C57BL/J6 and ob/ob mice elicited basal glucose lowering activity. In subchronic study with ob/ob mice, YH-GKA showed significant decrease in blood glucose levels and no adverse effects on serum lipids or body weight. In addition, YH-GKA exhibited high bioavailability and moderate elimination in preclinical species. 23092723 Lipophilic stinging nettle extracts possess potent anti-inflammatory activity, are not cytotoxic and may be superior to traditional tinctures for treating inflammatory disorders. Extracts of four plant portions (roots, stems, leaves and flowers) of Urtica dioica (the stinging nettle) were prepared using accelerated solvent extraction (ASE) involving water, hexanes, methanol and dichloromethane. The extracts were evaluated for their anti-inflammatory and cytotoxic activities in an NF-κB luciferase and MTT assay using macrophage immune (RAW264.7) cells. A standardized commercial ethanol extract of nettle leaves was also evaluated. The methanolic extract of the flowering portions displayed significant anti-inflammatory activity on par with a standard compound celastrol (1) but were moderately cytotoxic. Alternatively, the polar extracts (water, methanol, ethanol) of the roots, stems and leaves displayed moderate to weak anti-inflammatory activity, while the methanol and especially the water soluble extracts exhibited noticeable cytotoxicity. In contrast, the lipophilic dichloromethane extracts of the roots, stems and leaves exhibited potent anti-inflammatory effects greater than or equal to 1 with minimal cytotoxicity to RAW264.7 cells. Collectively these results suggest that using lipophilic extracts of stinging nettle may be more effective than traditional tinctures (water, methanol, ethanol) in clinical evaluations for the treatment of inflammatory disorders especially arthritis. A chemical investigation into the lipophilic extracts of stinging nettle to identify the bioactive compound(s) responsible for their observed anti-inflammatory activity is further warranted. 23325486 Binding site exploration of CCR5 using in silico methodologies: a 3D-QSAR approach. Chemokine receptor 5 (CCR5) is an important receptor used by human immunodeficiency virus type 1 (HIV-1) to gain viral entry into host cell. In this study, we used a combined approach of comparative modeling, molecular docking, and three dimensional quantitative structure activity relationship (3D-QSAR) analyses to elucidate detailed interaction of CCR5 with their inhibitors. Docking study of the most potent inhibitor from a series of compounds was done to derive the bioactive conformation. Parameters such as random selection, rational selection, different charges and grid spacing were utilized in the model development to check their performance on the model predictivity. Final comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were chosen based on the rational selection method, Gasteiger-Hückel charges and a grid spacing of 0.5 Å. Rational model for CoMFA (q(2) = 0.722, r(2) = 0.884, Q(2) = 0.669) and CoMSIA (q(2) = 0.712, r(2) = 0.825, Q(2) = 0.522) was obtained with good statistics. Mapping of contour maps onto CCR5 interface led us to better understand of the ligand-protein interaction. Docking analysis revealed that the Glu283 is crucial for interaction. Two new amino acid residues, Tyr89 and Thr167 were identified as important in ligand-protein interaction. No site directed mutagenesis studies on these residues have been reported. 22718275 Lipid biomarkers of oxidative stress in a genetic mouse model of Smith-Lemli-Opitz syndrome. 7-Dehydrocholesterol (7-DHC) accumulates in tissues and fluids of patients with Smith-Lemli-Opitz syndrome (SLOS), which is caused by mutations in the gene encoding 3β-hydroxysterol-Δ(7)-reductase (DHCR7). We recently reported that 7-DHC is the most reactive lipid molecule toward free radical oxidation (lipid peroxidation) and 14 oxysterols have been identified as products of oxidation of 7-DHC in solution. As the high oxidizability of 7-DHC may lead to systemic oxidative stress in SLOS patients, we report here lipid biomarkers of oxidative stress in a Dhcr7-KO mouse model of SLOS, including oxysterols, isoprostanes (IsoPs), and neuroprostanes (NeuroPs) that are formed from the oxidation of 7-DHC, arachidonic acid and docosahexaenoic acid, respectively. In addition to a previously described oxysterol, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), we provide evidence for the chemical structures of three new oxysterols in the brain and/or liver tissue of Dhcr7-KO mice, two of which were quantified. We find that levels of IsoPs and NeuroPs are also elevated in brain and/or liver tissues of Dhcr7-KO mice relative to matching WT mice. While IsoPs and NeuroPs have been established as a reliable measurement of lipid peroxidation and oxidative stress in vivo, we show that in this genetic SLOS mouse model, 7-DHC-derived oxysterols are present at much higher levels than IsoPs and NeuroPs and thus are better markers of lipid oxidation and related oxidative stress. 23385214 Water ice nanoparticles: size and temperature effects on the mid-infrared spectrum. Mid-infrared spectra have been measured for cubic ice (I(c)) nanoparticles (3-150 nm diameter) formed by rapid collisional cooling over a wide range of temperatures (5-209 K). Spectral diagnostics, such as the ratio of surface related dangling OH to interior H-bonded OH stretch bands, reveal the manner in which particle size depends on bath gas temperature and density, and on water molecule concentration. For particles smaller than 5 nm strained intermolecular bonds on the surface and subsurface cause the predominant OH stretch peak position to be dramatically blue shifted by up to 40 cm(-1). In the size regime of 8-200 nm the position of the OH stretch absorption band maximum is relatively unaffected by particle size and it is possible to measure the temperature dependence of the peak location without influences from the surface or scattering. The band maximum shifts in a linear fashion from 3218 cm(-1) at 30 K to 3253 cm(-1) at 209 K, which may assist with temperature profiling of ice particles in atmospheric clouds and extraterrestrial systems. Over the same temperature range the librational mode band shifts very little, from 870 to 860 cm(-1). In the water stretching and bending regions discrete spectral features associated with the surface or sub-surface layers have been detected in particles as large as 80 nm. 23479738 Multilevel regulation of 2-cys peroxiredoxin reaction cycle by s-nitrosylation. S-Nitrosothiols (SNOs), formed by nitric oxide (NO)-mediated S-nitrosylation, and hydrogen peroxide (H2O2), a prominent reactive oxygen species, are implicated in diverse physiological and pathological processes. Recent research has shown that the cellular action and metabolism of SNOs and H2O2 involve overlapping, thiol-based mechanisms, but how these reactive species may affect each other's fate and function is not well understood. In this study we investigated how NO/SNO may affect the redox cycle of mammalian peroxiredoxin-1 (Prx1), a representative of the 2-Cys Prxs, a group of thioredoxin (Trx)-dependent peroxidases. We found that, both in a cell-free system and in cells, NO/SNO donors such as S-nitrosocysteine and S-nitrosoglutathione readily induced the S-nitrosylation of Prx1, causing structural and functional alterations. In particular, nitrosylation promoted disulfide formation involving the pair of catalytic cysteines (Cys-52 and Cys-173) and disrupted the oligomeric structure of Prx1, leading to loss of peroxidase activity. A highly potent inhibition of the peroxidase catalytic reaction by NO/SNO was seen in assays employing the coupled Prx-Trx system. In this setting, S-nitrosocysteine (10 μm) effectively blocked the Trx-mediated regeneration of oxidized Prx1. This effect appeared to be due to both competition between S-nitrosocysteine and Prx1 for the Trx system and direct modulation by S-nitrosocysteine of Trx reductase activity. Our findings that NO/SNO target both Prx and Trx reductase may have implications for understanding the impact of nitrosylation on cellular redox homeostasis. 23194505 Temperature-dependent kinetics of grape seed phenolic compounds extraction: experiment and model. The kinetics of a batch solid-liquid extraction of total phenolic compounds (PC) from milled grape seed (Vitis vinifera L. cv. "Frankovka") using 50% ethanol at different extraction temperatures (25-80°C) was studied. The maximum yield of PC was 0.13 kg(GAE)/kg(db) after 200 min of extraction in agitated vessel at 80°C. A new model based on the assumptions of a first order kinetics mechanism for the solid-liquid extraction and a linear equilibrium at the solid-liquid interface was developed. The model involves the concept of broken and intact cells in order to describe two successive extraction periods: a very fast surface washing process followed by slow diffusion of phenolic compounds from grape seeds to the solvent. The proposed model is suited to fit experimental data and to simulate the extraction of phenolic compounds, which was confirmed by the correlation coefficient (r≥0.965), the root mean square error (RMSE≤0.003 kg(GAE)/kg(db)) and the mean relative deviation modulus (E≤2.149%). The temperature influenced both equilibrium partition coefficients of phenolic compounds and transport properties, which is manifested by a relatively high value of activation energy (23-24) kJ/mol and by values of effective diffusivity in seed particles. 23567045 Lactosylated gramicidin-based lipid nanoparticles (Lac-GLN) for targeted delivery of anti-miR-155 to hepatocellular carcinoma. Lactosylated gramicidin-containing lipid nanoparticles (Lac-GLN) were developed for delivery of anti-microRNA-155 (anti-miR-155) to hepatocellular carcinoma (HCC) cells. MiR-155 is an oncomiR frequently elevated in HCC. The Lac-GLN formulation contained N-lactobionyl-dioleoyl phosphatidylethanolamine (Lac-DOPE), a ligand for the asialoglycoprotein receptor (ASGR), and an antibiotic peptide gramicidin A. The nanoparticles exhibited a mean particle diameter of 73nm, zeta potential of +3.5mV, anti-miR encapsulation efficiency of 88%, and excellent colloidal stability at 4°C. Lac-GLN effectively delivered anti-miR-155 to HCC cells with a 16.1- and 4.1-fold up-regulation of miR-155 targets C/EBPβ and FOXP3 genes, respectively, and exhibited significant greater efficiency over Lipofectamine 2000. In mice, intravenous injection of Lac-GLN containing Cy3-anti-miR-155 led to preferential accumulation of the anti-miR-155 in hepatocytes. Intravenous administration of 1.5mg/kg anti-miR-155 loaded Lac-GLN resulted in up-regulation of C/EBPβ and FOXP3 by 6.9- and 2.2-fold, respectively. These results suggest potential application of Lac-GLN as a liver-specific delivery vehicle for anti-miR therapy. 23395783 γ-Oryzanol protects against acute cadmium-induced oxidative damage in mice testes. Cadmium is a non-essential heavy metal that is present at low levels mainly in food and water and also in cigar smoke. The present study evaluated the testicular damage caused by acute cadmium exposure and verified the protective role of γ-oryzanol (ORY). Mice were administrated with a single dose of 2.5mg/kg of CdCl2, and then treated with ORY (50mM in canola oil, 5mL/kg). Testes were removed after 24h and tested for lipid peroxidation (TBARS), protein carbonylation, DNA breakage, ascorbic acid, cadmium and non-proteic thiols contents, and for the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST) and δ-aminolevulic acid dehydratase (δ-ALA-D). Cadmium presented a significant alteration in all parameters, except GPx and CAT activities. Therapy reduced in a slight degree cadmium concentration in testes (around 23%). ORY restored SOD and GST activities as well as TBARS production to the control levels. Furthermore, ORY partially recovered δ-ALA-D activity inhibited by cadmium. This study provides the first evidence on the therapeutic properties of ORY in protecting against cadmium-induced testicular toxicity. 23456814 Effects of Urtica dioica on oxidative stress, proliferation and apoptosis after partial hepatectomy in rats. The present study was performed to investigate the effect of Urtica dioica (UD) on liver regeneration after partial hepatectomy (PH) in rats. A total of 24 male Sprague Dawley rats were divided into three groups: sham-operated, PH and PH + UD; each group contains eight animals. The rats in UD-treated groups were given UD oils (2 ml/kg/day) once a day orally for 7 days starting 3 days prior to hepatectomy operation. At day 7 after resection, liver samples were collected. The levels of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) were estimated in liver homogenates. Moreover, histopathological examination, mitotic index (MI), proliferating cell nuclear antigen labeling, proliferation index (PI), transferase-mediated deoxyuridine triphosphate nick end-labeling assay, apoptotic index (AI) were evaluated at day 7 after hepatectomy. As a result, UD significantly increased MI and PI, significantly decreased AI and also attenuated hepatic vacuolar degeneration and sinusoidal congestion in PH rats. UD treatment significantly decreased the elevated tissue MDA level and increased the reduced SOD activity and GSH level in the tissues. These results suggest that UD pretreatment was beneficial for rat liver regeneration after partial hepatectomy. 23080379 Patterned assembly of quantum dots onto surfaces modified with click microcontact printing. The self-assembly of CdSe quantum dots (QDs) onto a patterned silica surface generated from surface microcontact click printing is presented. The mechanically robust self-assembly process produces patterns of QDs which remain steadfast, even as subsequent reactions are performed on the substrate, demonstrating the utility and ease of this self-assembly process. 23402341 Characterization of the acyl-adenylate linked metabolite of mefenamic Acid. Mefenamic acid, (MFA), a carboxylic acid-containing nonsteroidal anti-inflammatory drug (NSAID), is metabolized into the chemically reactive conjugates MFA-1-O-acyl-glucuronide (MFA-1-O-G) and MFA-S-acyl-CoA (MFA-CoA), which are both implicated in the formation of MFA-S-acyl-glutathione (MFA-GSH) conjugates, protein-adduct formation, and thus the potential toxicity of the drug. However, current studies suggest that an additional acyl-linked metabolite may be implicated in the formation of MFA-GSH. In the present study, we investigated the ability of MFA to become bioactivated into the acyl-linked metabolite, mefenamyl-adenylate (MFA-AMP). In vitro incubations in rat hepatocytes with MFA (100 μM), followed by LC-MS/MS analyses of extracts, led to the detection of MFA-AMP. In these incubations, the initial rate of MFA-AMP formation was rapid, leveling off at a maximum concentration of 90.1 nM (20 s), while MFA-GSH formation increased linearly, reaching a concentration of 1.7 μM after 60 min of incubation. In comparison, MFA-CoA was undetectable in incubation extracts until the 4 min time point, achieving a concentration of 45.6 nM at the 60 min time point, and MFA-1-O-G formation was linear, attaining a concentration of 42.2 μM after 60 min of incubation. In vitro incubation in buffer with the model nucleophile glutathione (GSH) under physiological conditions showed MFA-AMP to be reactive toward GSH, but 11-fold less reactive than MFA-CoA, while MFA-1-O-G exhibited little reactivity. However, in the presence of glutathione-S-transferase (GST), MFA-AMP mediated formation of MFA-GSH increased 6-fold, while MFA-CoA mediated formation of MFA-GSH only increased 1.4-fold. Collectively, in addition to the MFA-1-O-G, these results demonstrate that mefenamic acid does become bioactivated by acyl-CoA synthetase enzyme(s) in vitro in rat hepatocytes into the reactive transacylating derivatives MFA-AMP and MFA-CoA, both of which contribute to the transacylation of GSH and may be involved in the formation of protein adducts and potentially elicit an idiosyncratic toxicity. 22995849 Molecular phylogeny of North American Branchiobdellida (Annelida: Clitellata). Branchiobdellidans, or crayfish worms, are ectosymbiotic clitellate annelids associated primarily with freshwater crayfishes. The main objectives of our study were to infer a molecular phylogeny for the North American Branchiobdellida, examine its congruence with morphology-based hypotheses of relationships at the subfamily and genus level, and use our dataset to assess consistency of GenBank-archived branchiobdellidan sequences. We used nucleotide sequence data from two mtDNA genes (COI and 16S rDNA) and three nuclear genes (28S rDNA, 18S rDNA, and ITS1) to estimate phylogenetic relationships among 47 described and one undescribed species of Branchiobdellida. We recovered a monophyletic branchiobdellidan clade with generally short branch lengths, suggesting that a large portion of the taxon has likely undergone a recent and rapid radiation in North America. Results from our phylogenetic analyses indicate that current taxonomic groupings are largely unsupported by the molecular data. All four subfamilies are either paraphyletic or polyphyletic, and only three of seven sampled non-monotypic genera were monophyletic. We found a high rate (49%) of inconsistency in GenBank-archived sequences, over 70% of which can be attributed to field- or laboratory-based error. 23563205 Correlation between activation of PPARγ and resistin downregulation in a mouse adipocyte cell line by a series of thiazolidinediones. The present study shows significant correlations between the EC50 for PPARγ activation in a reporter gene cell line and resistin downregulation in mouse adipocytes, and between the IC50 for resistin downregulation and the already published minimum effective dose for antihyperglycemic activity in a mouse model. These correlations indicate that PPARγ mediated downregulation of resistin might promote insulin sensitivity and that downregulation of resistin in mouse adipocytes provides an adequate and possibly more direct bioassay for screening of newly developed antihyperglycemic compounds. Because of the higher throughput of the PPARγ the resistin downregulation assays seems most suitable to be used as a second tier in a tiered screening strategy. 23379686 Self-aggregation properties of ionic liquid 1,3-didecyl-2-methylimidazolium chloride in aqueous solution: from spheres to cylinders to bilayers. The self-aggregation behavior of the double-chained ionic liquid (IL) 1,3-didecyl-2-methylimidazolium chloride ([C10C10mim]Cl) in aqueous solution has been investigated with a number of different experimental techniques. Two cmc values (cmc1 and cmc2) are obtained from conductivity measurements. The fraction of neutralized charge on the micellar surface suggests that cmc1 corresponds to the formation of spherical micelles and cmc2 to the transition from spherical to cylindrical micelles. Data obtained from fluorescence spectroscopy (using pyrene and Nile red as chemical probes), fluorescence anisotropy (using rhodamine B as probe), and chemical shift (1)H NMR (in D2O) provide a picture that is also consistent with a sphere-to-cylinder transition. This structural change is further confirmed by diffusion-ordered NMR spectroscopy (DOSY), from the self-diffusion coefficients for surfactant unimer and aggregates. Furthermore, a third evolution from cylindrical micelles to bilayer aggregates is proposed from the analysis of diffusion coefficients at high surfactant concentration ([IL] > 0.2 M). Phase scanning experiments performed with polarized light microscopy clearly demonstrate the presence of a lamellar liquid crystalline phase at very high IL concentration, thus confirming the coexistence of bilayer structures with elongated micelles, found at lower concentration. Additionally, [C10C10mim]Cl micelles are proposed as novel reaction media, as evidenced by the solvolysis reaction of 4-methoxybenzenesulfonyl chloride (MBSC). 23266451 How cationic lipids transfer nucleic acids into cells and across cellular membranes: recent advances. Cationic lipid- and polymer-based nanodevices are considered appropriate alternatives for virus-based particles for delivery of nucleic acids, including genes and siRNA, into eukaryotic cells. Because of colloidal stability concerns and toxicity issues the potential in vivo application of these so-called non-viral systems, in particular cationic lipids, was met with considerable skepticism. However, in recent years, the development of novel ionizable cationic lipid formulations in conjunction with sophisticated procedures to carefully control the size of the nanoparticles has rapidly advanced options for a successful therapeutic application. Thus it would appear that cationic lipids have taken a prominent step ahead in their potential use as nanocarriers for siRNA delivery in gene silencing of target genes in a variety of diseases. Verification and improvement of delivery efficiency as well as screening of targeting ligands justify further work in revealing underlying mechanisms that are instrumental in efficient crossing of cellular barriers by cationic lipid-based nanocarriers. In this regard, triggering entry into specific pathways or modulating trafficking along such pathways, either by targeting of nanoparticles or by affecting specific cellular signaling pathways, may represent promising tools. Such options may involve, for example, facilitating nanoparticle transport across endothelial cells by transcytotic mechanisms, or improving delivery efficiency by affecting nanoparticle trafficking that avoids lysosomal delivery. Here, recent progress in the field of lipid-based nanocarriers is discussed, with a focus on mechanisms underlying their interactions with cells in vitro. Where appropriate, we will include mechanisms for polymer-based systems in our discussion. 23512927 Fluorescent Polymeric Micelles with Aggregation-Induced Emission Properties for Monitoring the Encapsulation of Doxorubicin. A new type of fluorescent polymeric micelles is developed by self-assembly from a series of amphiphilic block copolymers, poly(ethylene glycol)-b-poly[styrene-co-(2-(1,2,3,4,5-pentaphenyl-1H-silol-1-yloxy)ethyl methacrylate)] [PEG-b-P(S-co-PPSEMA)]. Their capability of loading doxorubicin (DOX) is investigated by monitoring the loading content, encapsulation efficiency, and photophysical properties of micelles. Förster resonance energy transfer from PPSEMA to DOX is observed in DOX-loaded micelles, which can serve as an indication of successful encapsulation of DOX in these micelles. The application of this new type of fluorescent polymeric micelles as a fluorescent probe and an anticancer drug carrier simultaneously is explored by studying the intracellular uptake of DOX-loaded micelles. 23571414 Therapeutic Cleavage of Anti-Aquaporin-4 Autoantibody in Neuromyelitis Optica by an Igg-Selective Proteinase. Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system caused by binding of pathogenic IgG autoantibodies (NMO-IgG) to astrocyte water channel aquaporin-4 (AQP4). Astrocyte damage and downstream inflammation require NMO-IgG effector function to initiate complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we evaluated the potential therapeutic utility of the bacterial enzyme IdeS (IgG-degrading enzyme of Streptococcus pyogenes), which selectively cleaves IgG antibodies to yield Fc and F(ab')2 fragments. In AQP4-expressing cell cultures, IdeS treatment of monoclonal NMO-IgGs and NMO patient sera abolished CDC and ADCC, even when IdeS was added after NMO-IgG was bound to AQP4. Binding of NMO-IgG to AQP4 was similar to that of the NMO-F(ab')2 generated by IdeS cleavage. NMO-F(ab')2 competitively displaced pathogenic NMO-IgG, preventing cytotoxicity, and the Fc fragments generated by IdeS cleavage reduced CDC and ADCC. IdeS efficiently cleaved NMO-IgG in mice in vivo, and greatly reduced NMO lesions in mice administered NMO-IgG and human complement. IgG-selective cleavage by IdeS thus neutralizes NMO-IgG pathogenicity, and yields therapeutic F(ab')2 and Fc fragments. IdeS treatment, by therapeutic apheresis or direct administration, may be beneficial in NMO. 22961087 Loss of TDAG51 results in mature-onset obesity, hepatic steatosis, and insulin resistance by regulating lipogenesis. Regulation of energy metabolism is critical for the prevention of obesity, diabetes, and hepatic steatosis. Here, we report an important role for the pleckstrin homology-related domain family member, T-cell death-associated gene 51 (TDAG51), in the regulation of energy metabolism. TDAG51 expression was examined during adipocyte differentiation. Adipogenic potential of preadipocytes with knockdown or absence of TDAG51 was assessed. Weight gain, insulin sensitivity, metabolic rate, and liver lipid content were also compared between TDAG51-deficient (TDAG51(-/-)) and wild-type mice. In addition to its relatively high expression in liver, TDAG51 was also present in white adipose tissue (WAT). TDAG51 was downregulated during adipogenesis, and TDAG51(-/-) preadipocytes exhibited greater lipogenic potential. TDAG51(-/-) mice fed a chow diet exhibited greater body and WAT mass, had reduced energy expenditure, displayed mature-onset insulin resistance (IR), and were predisposed to hepatic steatosis. TDAG51(-/-) mice had increased hepatic triglycerides and SREBP-1 target gene expression. Furthermore, TDAG51 expression was inversely correlated with fatty liver in multiple mouse models of hepatic steatosis. Taken together, our findings suggest that TDAG51 is involved in energy homeostasis at least in part by regulating lipogenesis in liver and WAT, and hence, may constitute a novel therapeutic target for the treatment of obesity and IR. 23442151 Phenol formation in gamma radiolysis of aqueous benzene solution with sodium hypochlorite. Phenol formation by gamma radiolysis of an aqueous benzene solution containing sodium hypochlorite is reported. The phenol formation in a benzene solution containing sodium hypochlorite irradiated with (60)Co γ-rays is about six times higher than that without sodium hypochlorite. Ten micromolar sodium hypochlorite enhanced the formation of phenol up to a total dose of 6 Gy. Above 6 Gy in solutions containing sodium hypochlorite, the rate of phenol yield sharply decreased and was essentially the same as that without sodium hypochlorite. The yield of phenol with sodium hypochlorite is 0.89 μmol J(-1) and is larger than the sum of yield for the radicals and reactive oxygen species by water radiolysis such as •OH, e(-), H, H2, and H2O2. The formation of phenol with sodium hypochlorite was reduced by NaCl. Results suggest that the radiolytic formation of phenol in a benzene solution with sodium hypochlorite relates to the reaction process involving chlorine atoms. Sodium hypochlorite can be applied as a sensitizer for a benzene chemical dosimetry system. The lower limit of dose detection calculated from the detection limit of phenol and the G value of phenol was estimated to be 1 × 10(-3) Gy. 23194555 Adsorption kinetics, thermodynamics and isotherm of Hg(II) from aqueous solutions using buckwheat hulls from Jiaodong of China. The adsorption kinetics and adsorption isotherms of buckwheat hulls in the region of Jiaodong, China (BHJC) for Hg(II) were investigated. Results revealed that the adsorption kinetics of BHJC for Hg(II) were well described by a pseudo second-order reaction model, and the adsorption thermodynamic parameters ΔG, ΔH and ΔS were -5.83 kJ mol(-1)(35°C), 73.1, and 256 JK(-1) mol(-1), respectively. Moreover, Langmuir, Freundlich and Redlich-Peterson isotherm models were applied to analyse the experimental data and to predict the relevant isotherm parameters. The best interpretation for the experimental data was given by the Langmuir isotherm equation, and the maximum adsorption capacity for Hg(II) is 243.90 mg/g at 35°C. Furthermore, investigation of the adsorption selectivity showed that BHJC displayed strong affinity for mercury in the aqueous solutions and exhibited 100% selectivity for mercury in the presence of Zn(II) and Cd(II). 23410166 Multi-target compounds acting in the central nervous system designed from natural products. Modern medicinal chemistry has come to its bottleneck and is full of challenges, specially when facing with long-term central nervous system (CNS) disorders induced by several factors, such as Alzheimer's disease (AD) or Parkinson's disease (PD). In order to probe these challenges, multi-target directed ligands (MTDLs) design has been applied recently by medicinal scientists trying to get single compounds that can simultaneously modulate multiple targets. In addition, natural products have drawn the attention of drug developers again in recent years, as they have been used by human race for thousands of years and are full of diversity with their concomitant high potential to exhibit biological activities. We hereby review some of the research within the last few years focusing on multiple-target compounds acting in the CNS using natural products as lead resources. The target compounds obtained and described here represent bioactive hybrids either covalently connected or obtained by fusion of different bioactive moieties with at least one part derived from or representing directly natural products, along with some natural compounds themselves showing multiple pharmacological activities. We describe suitable ways to connect the drug components chemically, how to use the approach to enhance biological activity and selectivity, as well as potential drawbacks of the hybrid approach. This review will also show the rationale that these MTDLs are more than just the sum of their components but in many cases should be considered as new pharmacological entities in their own respect. 23137276 A novel matrix for the short-term storage of cells: utility in drug metabolism and drug transporter studies with rat, dog and human hepatocytes. 1. The SureTran™ matrix is a novel method facilitating short-term maintenance of fresh primary hepatocyte cellular function and offers the potential use of primary cells "as fresh" for several days post isolation. In the study presented, the maintenance of several key phase I and II drug metabolizing enzyme and drug transporter activities is demonstrated with rat and dog hepatocytes preserved for up to 7 days after cell isolation. 2. Intrinsic clearance values were determined for 60 new chemical entities using rat hepatocytes freshly isolated at AstraZeneca and rat hepatocytes prepared at the facilities of Abcellute Ltd (SureTran™ purveyors), stored and incubated 24 hours after isolation. A very good correspondence in the intrinsic clearance values underlines the utility of the cell maintenance matrix. 3. For human hepatocytes many of the enzyme activities assayed were well maintained for 7 days of storage but some declined to below 50% of initial values between day 4 and 7 of storage. Human OATP1B1 activity was only determined with one batch and declined to 51% of the initial test value by day 4 and further down to 35% by day 7. 23518321 Acetaminophen prevents oxidative burst and delays apoptosis in human neutrophils. Acetaminophen is a frequently prescribed over-the-counter drug to reduce fever and pain in the event of inflammatory process. As neutrophils are relevant cells in inflammatory processes, the putative interaction of acetaminophen with these cells, if present, would be of paramount importance. The present study was undertaken to evaluate the effect of acetaminophen in human neutrophils' oxidative burst and lifespan in vitro. The obtained results demonstrate that acetaminophen efficiently modulates neutrophils' oxidative burst in phorbol myristate acetate-activated neutrophils, in a concentration-dependent manner, at in vivo relevant concentrations. It was clearly demonstrated that acetaminophen is a strong scavenger of HOCl and H2O2, which probably contributed to the effect observed in neutrophils. Acetaminophen also induced the depletion of glutathione in stimulated neutrophils, suggesting its transformation into a reactive intermediate. Obtained results further revealed that acetaminophen affects programmed cell death of human neutrophils, resulting in a delay of previously stimulated neutrophils-mediated apoptosis. Overall, our data suggested that acetaminophen has considerable potential to be included in anti-inflammatory therapeutic strategies, by preventing biological damage induced by an excessive production of reactive species generated in activated neutrophils and by extending the lifespan of neutrophils, favoring the elimination of pathogens, thus contributing to tissue healing and resolution of inflammation. 23625912 Effects of aluminum chloride on some trace elements and erythrocyte osmotic fragility in rats. Aluminum (Al) is a nonessential, toxic element to which humans are constantly exposed as a result of an increase in industrialization and improving technology practices. The aim of the study was to investigate the effects of different durations and doses of Al exposure on serum and tissue element levels and erythrocyte osmotic fragility in rats. A total of 40 male Wistar Albino rats were divided into five groups: control, group I (3 weeks, 8 mg/kg), group II (6 weeks, 8 mg/kg), group III (3 weeks, 16 mg/kg), and group IV (6 weeks, 16 mg/kg). Al chloride (AlCl3) was injected intraperitoneally (i.p.) five times a week. At the end of the experimental period, levels of Al, iron (Fe), copper (Cu), and zinc (Zn) in serum, liver, and kidney tissues were measured using inductively coupled plasma optical emission spectrometry. Osmotic fragility was determined using a spectrophotometer. The results of the experiment indicate that Al induced a statistically significant increase in Al and Fe concentrations in liver and serum as well as in Cu in the kidney. The Fe concentration in serum and kidney tissues was significantly lower in all the groups. As a result of our study, it may be concluded that tissue Al accumulation may lead to an increase in osmotic fragility of erythrocytes and abnormal trace element levels. 23394432 Tailoring the lasing modes in semiconductor nanowire cavities using intrinsic self-absorption. Understanding the optical gain and mode-selection mechanisms in semiconductor nanowire (NW) lasers is key to the development of high-performance nanoscale oscillators, amplified semiconductor/plasmon lasers and single photon emitters, and so forth. Modification of semiconductor band structure/bandgap through electric field modulation, elemental doping, or alloying semiconductors has so far gained limited success in achieving output mode tunability of the NW laser. One stifling issue is the considerable optical losses induced in the NW cavities by these extrinsic methods that limit their applicability. Herein we demonstrate a new optical self-feedback mechanism based on the intrinsic self-absorption of the gain media to achieve low-loss, room-temperature NW lasing with a high degree of mode selectivity (over 30 nm). The cadmium sulfide (CdS) NW lasing wavelength is continuously tunable from 489 to 520 nm as the length of the NWs increases from 4 to 25 μm. Our straightforward approach is widely applicable in most semiconductor or semiconductor/plasmonic NW cavities. 22789395 Urinary excretion of parabens in pregnant Japanese women. Urinary excretion of free and total (free plus conjugated) forms of methyl, ethyl, n-propyl and n-butyl parabens (MP, EP, PP and BP, respectively) and their metabolite p-hydroxybenzoic acid were measured for 111 pregnant Japanese women. Frequent detection of parabens and their metabolite indicated that exposure takes place daily for pregnant Japanese women. The estrogenic potency of PP was 20 times higher than those of the other 3 parabens for the present subjects when both abundance in the urine and the relative estrogenic activity of each compound was considered. Detection of free parabens suggested dermal exposure, probably from their inclusion in personal care products. No statistical association was found between the anogenital index (birth weight-adjusted AGD) of male offspring and the concentrations of any parabens in the urine of the mothers suggesting that the parabens were not apparently estrogenically active at the exposure level of the present subjects. 22842550 Interaction of tumor cells with the immune system: implications for dendritic cell therapy and cancer progression. There is a continuous demand for preclinical modeling of the interaction of dendritic cells with the immune system and cancer cells. Recent progress in gene expression profiling with nucleic acid microarrays, in silico modeling and in vivo cell and animal approaches for non-clinical proof of safety and efficacy of these immunotherapies is summarized. Immunoinformatic approaches look promising to unfold this potential, although still unstable and difficult to interpret. Animal models have progressed a great deal in recent years, finally narrowing the gap from bench to bedside. However, translation to the clinic should be done with precaution. The most significant results concerning clinical benefit might come from detailed immunologic investigations made during well designed clinical trials of dendritic-cell-based therapies, which in general prove safe. 23324400 HOW GOOD IS THE LEVOTHYROXINE REPLACEMENT IN PRIMARY HYPOTHYROIDISM PATIENTS IN BRAZIL?- DATA OF A MULTICENTRE STUDY. Background : Studies done in every continent has shown that only around 50% of the patients subjected to thyroid hormone replacement have TSH in the normal range. However, until to date, there are no consistent data about Brazil. Objectives: To evaluate levothyroxine (LT4) replacement treatment in patients with primary hypothyroidism followed in referral centers in Brazil. Methods: Patients with primary hypothyroidism followed in referral centers (University Hospitals from Universidade Federal do Rio de Janeiro -UFRJ, Unicamp, Universidade Federal do Paraná - UFPR and Universidade Federal do Ceará-UFC) answered a questionnairethat inquired about clinical and biochemical conditions, social-economic status, life quality and clinicians' orientations as well as their understanding about the information given. Serum TSH was checked close to the interview. Results: 2292 consecutive patients met the inclusion criteria. Mean age 51.2 years and TSH values between 0.4 and 4.0 mUI/l were considered to be within the reference range. Among all patients taking thyroid medication, 42.7%% had an abnormal serum TSH (28.3% were undertreated and 14.4% were over treated). Approximately all patients (99%) took LT4 in the morning but less than 30 minutes before breakfast (85.4%). Regarding the clinicians´ orientations: 97.5% of the patients were instructed to take the medication daily, and 92.6% to take 30 minutes before breakfast (92.6%). However, only 52.1% were told that not to take LT4 along with other medication. Conclusions: Our study found that there was a significant number of patients taking thyroid hormones were not in the therapeutic range. Clinicians should, therefore, consider monitoring patients on thyroid replacement more frequently and being more precise on giving recommendations about the correct use of LT4. 23055453 Alternative copolymerization of a conjugated segment and a flexible segment and fabrication of a fluorescent sensing film for HCl in the vapor phase. A novel fluorescently active co-oligomer (P1) was designed and prepared by alternative co-polymerization of oligo(p-phenyleneethynylene) (OPE), possessing two cholesterol-containing side chains, and ethanediamine. A control co-oligomer (P2) possessing similar structure to P1 was also prepared, but in this case the OPE bears no side chains. P1 and P2 have been used for the fabrication of two fluorescent films, film 1 and film 2, respectively. Fluorescence studies demonstrated that the emission of film 1 is sensitive and selective to the presence of trace amounts of HCl in air. In contrast, film 2 shows no such response. The quenching has been attributed to the protonation of the imino groups within the oligomer chains, and the difference in the sensing behaviors of the two films was rationalized by supposing the existence of molecular channels in film 1. The proposed mechanism is supported by the results from additional experiments and theoretical calculations. Furthermore, the film as fabricated is robust, and thereby it is believed that film 1 has the potential to be developed into a new generation of sensitive and selective HCl sensor. 23609769 Altered visual perception in long-term ecstasy (MDMA) users. RATIONALE: The present study investigated the long-term consequences of ecstasy use on visual processes thought to reflect serotonergic functions in the occipital lobe. Evidence indicates that the main psychoactive ingredient in ecstasy (methylendioxymethamphetamine) causes long-term changes to the serotonin system in human users. Previous research has found that amphetamine-abstinent ecstasy users have disrupted visual processing in the occipital lobe which relies on serotonin, with researchers concluding that ecstasy broadens orientation tuning bandwidths. However, other processes may have accounted for these results. OBJECTIVES: The aim of the present research was to determine if amphetamine-abstinent ecstasy users have changes in occipital lobe functioning, as revealed by two studies: a masking study that directly measured the width of orientation tuning bandwidths and a contour integration task that measured the strength of long-range connections in the visual cortex of drug users compared to controls. METHOD: Participants were compared on the width of orientation tuning bandwidths (26 controls, 12 ecstasy users, 10 ecstasy + amphetamine users) and the strength of long-range connections (38 controls, 15 ecstasy user, 12 ecstasy + amphetamine users) in the occipital lobe. RESULTS: Amphetamine-abstinent ecstasy users had significantly broader orientation tuning bandwidths than controls and significantly lower contour detection thresholds (CDTs), indicating worse performance on the task, than both controls and ecstasy + amphetamine users. CONCLUSION: These results extend on previous research, which is consistent with the proposal that ecstasy may damage the serotonin system, resulting in behavioral changes on tests of visual perception processes which are thought to reflect serotonergic functions in the occipital lobe. 23161677 G4LDB: a database for discovering and studying G-quadruplex ligands. The G-quadruplex ligands database (G4LDB, http://www.g4ldb.org) provides a unique collection of reported G-quadruplex ligands to streamline ligand/drug discovery targeting G-quadruplexes. G-quadruplexes are guanine-rich nucleic acid sequences in human telomeres and gene promoter regions. There is a growing recognition for their profound roles in a wide spectrum of diseases, such as cancer, diabetes and cardiovascular disease. Ligands that affect the structure and activity of G-quadruplexes can shed light on the search for G-quadruplex-targeting drugs. Therefore, we built the G4LDB to (i) compile a data set covering various physical properties and 3D structure of G-quadruplex ligands; (ii) provide Web-based tools for G-quadruplex ligand design; and (iii) to facilitate the discovery of novel therapeutic and diagnostic agents targeting G-quadruplexes. G4LDB currently contains >800 G-quadruplex ligands with ∼4000 activity records, which, to our knowledge, is the most extensive collection of its kind. It offers a user friendly interface that can meet a variety of data inquiries from researchers. For example, ligands can be searched for by name, molecular properties, structures, ligand activities and so on. Building on the reported data, the database also provides an online ligand design module that can predict ligand binding affinity in real time. 23561134 Pesticide residues determination in Polish organic crops in 2007-2010 applying gas chromatography-tandem quadrupole mass spectrometry. A sensitive, accurate and reliable multiresidue method based on the application of gas chromatography-tandem quadrupole mass spectrometry (GC-QqQ-MS/MS) has been established for screening, identification and quantification of a large number of pesticide residues in produce. The method was accredited in compliance with PN-EN ISO/IEC 17025:2005 standard and it was operated under flexible scope as PB-11 method. The flexible scope of accreditation allowed for minor modifications and extension of the analytical scope while using the same analytical technique. During the years 2007-2010, the method was used for the purpose of verification of organic crop production by multiresidue analysis for the presence of pesticides. A total of 528 samples of differing matrices such as fruits, vegetables, cereals, plant leaves and other green parts were analysed, of which 4.4% samples contained pesticide residues above the threshold value of 0.01mg/kg. A total of 20 different pesticide residues were determined in the samples. 23525215 Two populations of glucocorticoid receptor-binding sites in the male rat hippocampal genome. In the present study, genomic binding sites of glucocorticoid receptors (GR) were identified in vivo in the rat hippocampus applying chromatin immunoprecipitation followed by next-generation sequencing. We identified 2470 significant GR-binding sites (GBS) and were able to confirm GR binding to a random selection of these GBS covering a wide range of P values. Analysis of the genomic distribution of the significant GBS revealed a high prevalence of intragenic GBS. Gene ontology clusters involved in neuronal plasticity and other essential neuronal processes were overrepresented among the genes harboring a GBS or located in the vicinity of a GBS. Male adrenalectomized rats were challenged with increasing doses of the GR agonist corticosterone (CORT) ranging from 3 to 3000 μg/kg, resulting in clear differences in the GR-binding profile to individual GBS. Two groups of GBS could be distinguished: a low-CORT group that displayed GR binding across the full range of CORT concentrations, and a second high-CORT group that displayed significant GR binding only after administering the highest concentration of CORT. All validated GBS, in both the low-CORT and high-CORT groups, displayed mineralocorticoid receptor binding, which remained relatively constant from 30 μg/kg CORT upward. Motif analysis revealed that almost all GBS contained a glucocorticoid response element resembling the consensus motif in literature. In addition, motifs corresponding with new potential GR-interacting proteins were identified, such as zinc finger and BTB domain containing 3 (Zbtb3) and CUP (CG11181 gene product from transcript CG11181-RB), which may be involved in GR-dependent transactivation and transrepression, respectively. In conclusion, our results highlight the existence of 2 populations of GBS in the rat hippocampal genome. 23220612 Profiling of oxidized lipid products of marine fish under acute oxidative stress. Free radical products including reactive oxygen species are potent to oxidize lipids and reliable measurements have been established mostly in human and rodent. To date, robust biomarkers were not used to assess the peroxidation in marine fish. The changes of oxidized lipid products from polyunsaturated fatty acids and cholesterol were assessed after exposure of H(2)O(2) to fish (medaka). Oxidized lipid products released by free radical reaction (F(2)-isoprostanes and metabolites, F(3)-isoprostanes, neuroprostanes, 7-ketocholesterol, 7β-hydroxycholesterol), by lipoxygenase enzymes (5(S)-, 8(S)-, 12(S)- and 15(S)-HETE, and resolvin D1) and by cytochrome P450 (9(S)-, 11(S)- and 20-HETE, and 27-hydroxycholestrol) were measured in fish muscle using LC/MS/MS. Arachidonate, docosahexaenoate, eicosapentaenoate and cholesterol levels, and antioxidant enzymes activity (catalase, SOD and gluthathione reductase) measurement were also determined. Activity of antioxidant enzymes especially catalase were elevated in presence of H(2)O(2) however longer exposure time suppressed the antioxidant activities. Arachidonate, docosahexaenoate, eicosapentaenoate and cholesterol levels were reduced in presence of H(2)O(2) and oxidized lipid products (isoprostanes, neuroprostanes 5(S)-HETE, 20-HETE, 7-ketocholesterol, 27-hydroxycholesterol and resolvin D1) were rapidly released in the fish muscle. This study validates oxidized lipid products, noticeably isoprostanes are measurable in marine fish muscle and should be considered when assessing oxidative stress especially due to exogenous factors. 23435948 Potent α-glucosidase and protein tyrosine phosphatase 1B inhibitors from Artemisia capillaris. As a part of our ongoing effort to identify anti-diabetic constituents from natural sources, we examined the inhibitory activity of the methanol extracts of 12 species of the genus Artemisia, against α-glucosidase and protein tyrosine phosphatase 1B (PTP1B). The methanol extracts of different species exhibited promising α-glucosidase and PTP1B inhibitory activities. Since the methanol extract of Artemisia capillaris exhibited the highest α-glucosidase inhibitory activity together with significant PTP1B inhibitory activity, it was selected for further investigation. Repeated column chromatography based on bioactivity guided fractionation yielded 10 coumarins (esculetin, esculin, scopolin, isoscopolin, daphnetin, umbelliferone, 7-methoxy coumarin, scoparone, scopoletin, 6-methoxy artemicapin C), 8 flavonoids (hyperoside, quercetin, isorhamnetin, cirsilineol, arcapillin, isorhamnetin 3-robinobioside, linarin, isorhamnetin 3-glucoiside), 6 phenolic compounds (1,5-dicaffeoylquinic acid, 3,4-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid methyl ester, 4,5-dicaffeoylquinic acid, 3-caffeoylquinic acid), and one chromone (capillarisin). Among these compounds, esculetin, scopoletin, quercetin, hyperoside, isorhamnetin, 3,5-dicaffeoylquinic acid methyl ester, 3,4-dicaffeoylquinic acid, and 1,5-dicaffeoylquinic acid exhibited potent α-glucosidase inhibitory activity when compared to the positive control acarbose. In addition, esculetin and 6-methoxy artemicapin C displayed PTP1B inhibitory activity. Interestingly, all isolated dicaffeoylquinic acids showed significant PTP1B inhibitory activity. Therefore, the results of the present study clearly demonstrate the potential of the A. capillaris extract to inhibit α-glucosidase and PTP1B. These inhibitory properties can be largely attributed to a combination of different chemical structures, including coumarins, flavonoids, and dicaffeoylquinic acids, which could be further explored to develop therapeutic or preventive agents for the treatment of diabetes. 23581295 Synthesis of diazenido-ligated vanadium nanoparticles. Metallic vanadium nanoparticles stabilized with 4-octylphenyldiazenido groups (particle size: 1.7 ± 0.2 nm) were synthesized via the reduction of VCl4 with superhydride (LiBHEt3) in the presence of 4-octylphenyldiazonium salt in an Ar-filled glovebox. The resulting particles were characterized using TEM, elemental analysis, and XPS measurements. The unusual reaction on the surface resulted in the passivation of V-N═N-Ar covalent bonds. 22983118 The neurotoxicity of hallucinogenic amphetamines in primary cultures of hippocampal neurons. 3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") and 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) are hallucinogenic amphetamines with addictive properties. The hippocampus is involved in learning and memory and seems particularly vulnerable to amphetamine's neurotoxicity. We evaluated the neurotoxicity of DOI and MDMA in primary neuronal cultures of hippocampus obtained from Wistar rat embryos (E-17 to E-19). Mature neurons after 10 days in culture were exposed for 24 or 48 h either to MDMA (100-800 μM) or DOI (10-100 μM). Both the lactate dehydrogenase (LDH) release and the tetrazolium-based (MTT) assays revealed a concentration- and time-dependent neuronal death and mitochondrial dysfunction after exposure to both drugs. Both drugs promoted a significant increase in caspase-8 and caspase-3 activities. At concentrations that produced similar levels of neuronal death, DOI promoted a higher increase in the activity of both caspases than MDMA. In the mitochondrial fraction of neurons exposed 24h to DOI or MDMA, we found a significant increase in the 67 kDa band of apoptosis inducing factor (AIF) by Western blot. Moreover, 24h exposure to DOI promoted an increase in cytochrome c in the cytoplasmatic fraction of neurons. Pre-treatment with an antibody raised against the 5-HT(2A)-receptor (an irreversible antagonist) greatly attenuated neuronal death promoted by 48 h exposure to DOI or MDMA. In conclusion, hallucinogenic amphetamines promoted programmed neuronal death involving both the mitochondria machinery and the extrinsic cell death key regulators. Death was dependent, at least in part, on the stimulation of the 5-HT(2A)-receptors. 22836659 Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta. Osteogenesis imperfecta (OI) is a genetic bone dysplasia characterized by osteopenia and easy susceptibility to fracture. Symptoms are most prominent during childhood. Although antiresorptive bisphosphonates have been widely used to treat pediatric OI, controlled trials show improved vertebral parameters but equivocal effects on long-bone fracture rates. New treatments for OI are needed to increase bone mass throughout the skeleton. Sclerostin antibody (Scl-Ab) therapy is potently anabolic in the skeleton by stimulating osteoblasts via the canonical wnt signaling pathway, and may be beneficial for treating OI. In this study, Scl-Ab therapy was investigated in mice heterozygous for a typical OI-causing Gly→Cys substitution in col1a1. Two weeks of Scl-Ab successfully stimulated osteoblast bone formation in a knock-in model for moderately severe OI (Brtl/+) and in WT mice, leading to improved bone mass and reduced long-bone fragility. Image-guided nanoindentation revealed no alteration in local tissue mineralization dynamics with Scl-Ab. These results contrast with previous findings of antiresorptive efficacy in OI both in mechanism and potency of effects on fragility. In conclusion, short-term Scl-Ab was successfully anabolic in osteoblasts harboring a typical OI-causing collagen mutation and represents a potential new therapy to improve bone mass and reduce fractures in pediatric OI. 23137833 Influence of resveratrol on rheumatoid fibroblast-like synoviocytes analysed with gene chip transcription. Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that primarily attacks joints and is therefore a common cause of chronic disability and articular destruction. The hyperplastic growth of RA-fibroblast-like synoviocytes (FLSs) and their resistance against apoptosis are considered pathological hallmarks of RA. The natural antioxidant resveratrol is known for its antiproliferative and pro-apoptotic properties. This study investigated the effect of resveratrol on RA-FLS. RA-FLS were isolated from the synovium of 10 RA patients undergoing synovectomy or joint replacement surgery. RA-FLS were first stressed by pre-incubation with interleukin 1beta (IL-1β) and then treated with 100 μM resveratrol for 24h. In order to evaluate the influence of resveratrol on the transcription of genes, a Gene Chip Human Gene 1.0 ST Array was applied. In addition, the effect of dexamethasone on proliferation and apoptosis of RA-FLS was compared with that of resveratrol. Gene array analysis showed highly significant effects of resveratrol on the expression of genes involved in mitosis, cell cycle, chromosome segregation and apoptosis. qRT-PCR, caspase-3/7 and proliferation assays confirmed the results of gene array analysis. In comparison, dexamethasone showed little to no effect on reducing cell proliferation and apoptosis. Our in vitro findings point towards resveratrol as a promising new therapeutic approach for local intra-articular application against RA, and further clinical studies will be necessary. 23301853 Benzoquinones and terphenyl compounds as phosphodiesterase-4B inhibitors from a fungus of the order Chaetothyriales (MSX 47445). Three bioactive compounds were isolated from an organic extract of an ascomycete fungus of the order Chaetothyriales (MSX 47445) using bioactivity-directed fractionation as part of a search for anticancer leads from filamentous fungi. Of these, two were benzoquinones [betulinan A (1) and betulinan C (3)], and the third was a terphenyl compound, BTH-II0204-207:A (2). The structures were elucidated using a set of spectroscopic and spectrometric techniques; the structure of the new compound (3) was confirmed via single-crystal X-ray diffraction. Compounds 1-3 were evaluated for cytotoxicity against a human cancer cell panel, for antimicrobial activity against Staphylococcus aureus and Candida albicans, and for phosphodiesterase (PDE4B2) inhibitory activities. The putative binding mode of 1-3 with PDE4B2 was examined using a validated docking protocol, and the binding and enzyme inhibitory activities were correlated. 23515497 Evaluation of estrogenic effects of polychlorinated biphenyls and organochlorinated pesticides using immature rat uterotrophic assay. In this study, we investigated the effects of polychlorinated biphenyls (PCBs) and organochlorinated pesticides on the serum levels of luteinising hormone (LH), follicle stimulating hormone (FSH) and weights and histomorphometry of uterine tissue in immature female rats using uterotrophic assay. A total of 36 rats were randomly divided into six groups (n = 6 per group) as control, oestradiol (E2, 100 μg/kg), PCB 180, Aroclor 1221, endosulfan and mirex at 10 mg/kg dosage. After 3 days of injections (subcutaneous), animals were decapitated and blood samples were collected. Uteri were dissected, weighed out and then fixed in 10% formaldehyde. They were processed for histomorphometry. The serum levels of LH and FSH were determined by enzyme immunoassay.Uterine weight was significantly increased by E2 and reduced by mirex (p < 0.001 and p < 0.05, respectively). Total volume of uterus was significantly raised by E2, Aroclor 1221 and endosulfan compared with that of the control group (p < 0.01). The ratio of epithelium was significantly increased by E2, PCBs and pesticides (p < 0.01). The uterine cavity ratio was decreased by aroclor (p < 0.01), PCB 180 and mirex (p < 0.05). The serum levels of LH did not significantly differ among the groups but the levels of FSH were decreased by PCB 180 and endosulfan (p < 0.05 and p < 0.01, respectively). These findings suggest that PCB 180, Aroclor 1221 and endosulfan may be estrogenic in immature uterotrophic assay. 22956631 PPTOX III: environmental stressors in the developmental origins of disease--evidence and mechanisms. Fetal and early postnatal development constitutes the most vulnerable time period of human life in regard to adverse effects of environmental hazards. Subtle effects during development can lead to functional deficits and increased disease risk later in life. The hypothesis stating that environmental exposures leads to altered programming and, thereby, to increased susceptibility to disease or dysfunction later in life has garnered much support from both experimental and epidemiological studies. Similar observations have been made on the long-term impact of nutritional unbalance during early development. In an effort to bridge the fields of nutritional and environmental developmental toxicity, the Society of Toxicology sponsored this work. This report summarizes novel findings in developmental toxicity as reported by select invited experts and meeting attendees. Recommendations for the application and improvement of current and future research efforts are also presented. 22543584 Endoplasmic reticulum protein 29 regulates epithelial cell integrity during the mesenchymal-epithelial transition in breast cancer cells. The epithelial-mesenchymal transition (EMT) correlates with disruption of cell-cell adhesion, loss of cell polarity and development of epithelial cell malignancy. Identifying novel molecules that inhibit EMT has profound potential for developing mechanism-based therapeutics. We previously demonstrated that the endoplasmic reticulum protein 29 (ERp29) is a novel factor that can drive mesenchymal-epithelial transition (MET) and induce cell growth arrest in MDA-MB-231 cells. Here, we show that ERp29 is an important molecule in establishing epithelial cell integrity during the MET. We demonstrate that ERp29 regulates MET in a cell context-dependent manner. ERp29 overexpression induced a complete MET in mesenchymal MDA-MB-231 cells through downregulating the expression of transcriptional repressors (for example, Slug, Snai1, ZEB2 and Twist) of E-cadherin. In contrast, overexpression of ERp29 induces incomplete MET in basal-like BT549 cells in which the expression of EMT-related markers (for example, vimentin; cytokeratin 19 (CK19) and E-cadherin) and the transcriptional repressors of E-cadherin were not altered. However, ERp29 overexpression in both cell-types resulted in loss of filamentous stress fibers, formation of cortical actin and restoration of an epithelial phenotype. Mechanistic studies revealed that overexpression of ERp29 in both cell-types upregulated the expression of TJ proteins (zonula-occludens-1 (ZO-1) and occludin) and the core apical-basal polarity proteins (Par3 and Scribble) at the membrane to enhance cell-cell contact and cell polarization. Knockdown of ERp29 in the epithelial MCF-7 cells decreased the expression of these proteins, leading to the disruption of cell-cell adhesion. Taken together, ERp29 is a novel molecule that regulates MET and epithelial cell integrity in breast cancer cells. 23157640 Prostate cancer, miRNAs, metallothioneins and resistance to cytostatic drugs. MicroRNAs (miRNAs) translationally repressing their target messenger RNAs due to their gene-regulatory functions play an important but not unexpected role in a tumour development. More surprising are the findings that levels of various miRNAs are well correlated with presence of specific tumours and formation of metastases. Moreover, these small regulatory molecules play a role in the resistance of cancer cells to commonly used anti-cancer drugs, such as cisplatin, anthracyclines, and taxanes. In that respect, miRNAs become very attractive target for potential therapeutic interventions. Improvements in the sensitivity of miRNAs detection techniques led to discovery of circulating miRNAs which became very attractive non-invasive biomarker of cancer with a substantial predictive value. In this review, the authors focus on i) oncogenic and anti-tumour acting miRNAs, ii) function of miRNAs in tumour progression, iii) possible role of miRNAs in resistance to anticancer drugs, and iv) diagnostic potential of miRNAs for identification of cancer from circulating miRNAs with special emphasis on prostate cancer. Moreover, relationship between miRNAs and expression of metallothionein is discussed as a possible explanation of resistance against platinum based drugs. 23637306 Renal and hepatotoxic alterations in adult mice on inhalation of specific mixture of organic solvents. This study was aimed at investigating alterations in renal and hepatic toxicity induced by exposing to a combination of three solvents, namely, benzene, toluene and xylene in adult mice. The mice were divided into three groups (control, low-dose-treated (450 ppm) and high-dose (675 ppm) groups) using randomization methods. The treated groups were exposed to vapours of a mixture of benzene, toluene and xylene at doses of 450 and 675 ppm, for 6 h day(-1) for a short-term of 7-day exposure period. The study revealed that the solvent exposure resulted in an increase in the weight of liver and kidney as compared to the control. Biochemical analyses indicated a significant decline in the activities of superoxide dismutase and catalase in both the treated groups, with concomitant increase in lipid peroxidation. Liver aminotransferases (alanine aminotransferase and aspartate aminotransferase) were elevated with significant alterations in the levels of protein, creatinine and cholesterol in these tissues upon solvent exposure. Correlated with these changes, serum thyroid hormones T3 and T4 were also significantly altered. This study, therefore, demonstrates that inhalation of vapours from the solvent mixture resulted in significant dose-dependent biochemical and functional changes in the vital tissues (liver and kidney) studied. The study has specific relevance since humans are increasingly being exposed to such solvents due to increased industrial use in such combinations. 22475014 Glaucogenin E, a new C21 steroid from Cynanchum stauntonii. Glaucogenin E (1), a new C(21) steroid sapogenin, along with three known ones (2-4) were isolated from the rhizomes of Cynanchum stauntonii (Decne.) Schltr. ex Levl. Their structures were established mainly by the spectroscopic analysis, including 2D NMR. All the isolated compounds were evaluated for their cytotoxicity against human cancer cell lines HeLa, Bel-7402, SGC-7901 and BGC-823. 23266732 Effects of Yerba Mate tea (Ilex paraguariensis) on vascular endothelial function and liver lipoprotein receptor gene expression in hyperlipidemic rats. Yerba Mate tea (Mate), an infusion made from the leaves of the tree Ilex paraguariensis, is a widely consumed beverage in South America. This study was performed to investigate the effect of Mate tea on vascular endothelial dysfunction and liver lipoprotein receptor gene expression in hyperlipidemic rats, with the aim of gaining insight into its known lipid-lowering protective mechanisms. Sixty male Sprague-Dawley rats were randomly divided into five groups: a normal control group (NC), a high-fat diet group (HC), and three Mate tea-treated groups. In the NC group, rats were fed with standard diet while in the other groups the rats were fed a high-fat diet for 8weeks. In the Mate tea-treated groups, the rats were fed a high-fat diet supplemented with low, moderate or high concentrations of aqueous Mate tea extract for the final 4weeks. Compared to the HC group, aqueous Mate tea extract significantly reduced endothelin (ET) and thromboxane B(2) (TXB(2)) levels and increased nitric oxide (NO) and 6-keto prostaglandin F(1α) (6-keto-PGF(1α)) levels in the blood, reduced the pathological damage of vascular endothelial cells, decreased intercellular adhesion molecule-1 (ICAM-1) protein expression in the thoracic aorta, and upregulated mRNA expression of hepatic low density lipoprotein receptor (LDLR) and scavenger receptor B1 (SR-B1). These findings indicate that Mate tea administration might have a regulatory effect on blood fat and endothelial function in hyperlipidemia rats. The mechanism may involve protecting vascular endothelial cell function and upregulating the expression of LDLR and SR-B1 genes, thereby inhibiting the occurrence of atherosclerosis. 22975406 Emerging opportunities for allosteric modulation of G-protein coupled receptors. Their ubiquitous nature, wide cellular distribution and versatile molecular recognition and signalling help make G-protein binding receptors (GPCRs) the most important class of membrane proteins in clinical medicine, accounting for ∼40% of all current therapeutics. A large percentage of current drugs target the endogenous ligand binding (orthosteric) site, which are structurally and evolutionarily conserved, particularly among members of the same GPCR subfamily. With the recent advances in GPCR X-ray crystallography, new opportunities for developing novel subtype selective drugs have emerged. Given the increasing recognition that the extracellular surface conformation changes in response to ligand binding, it is likely that all GPCRs possess an allosteric site(s) capable of regulating GPCR signalling. Allosteric sites are less structurally conserved than their corresponding orthosteric site and thus provide new opportunities for the development of more selective drugs. Constitutive oligomerisation (dimerisation) identified in many of the GPCRs investigated, adds another dimension to the structural and functional complexity of GPCRs. In this review, we compare 60 crystal structures of nine GPCR subtypes (rhodopsin, ß₂-AR, ß₁-AR, A(2a)-AR, CXCR4, D₃R, H₁R, M₂R, M₃R) across four subfamilies of Class A GPCRs, and discuss mechanisms involved in receptor activation and potential allosteric binding sites across the highly variable extracellular surface of these GPCRs. This analysis has identified a new extracellular salt bridge (ESB-2) that might be exploited in the design of allosteric modulators. 23345132 Androgen synthesis in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. A hallmark of severe congenital adrenal hyperplasia due to 21-hydroxylase deficiency is pre- and postnatal virilization. The most characteristic biochemical abnormality is the elevation of 17α-hydroxyprogesterone, which is metabolized to the most potent androgen receptor agonist dihydrotestosterone. 17α-Hydroxyprogesterone can be metabolized to dihydrotestosterone via 4-androstenedione through the classical Δ4-pathway or via 17α-hydroxypregnenolone and dehydroepiandrosterone through the classical Δ5-pathway, as well as through an alternative route, called the 'backdoor pathway', that bypasses dehydroepiandrosterone, 4-androstenedione, and testosterone as intermediates. This review article will summarize recent advances in the understanding of the activities of androgen synthesis pathways in patients with 21-hydroxylase deficiency obtained by urinary steroid metabolomics based on gas chromatography-mass spectrometry. Compared with healthy controls, the relative activities of the backdoor and Δ4-pathways increase in patients with congenital adrenal hyperplasia during neonatal age and infancy, whereas the activity of the Δ5-pathway remains unchanged. Thereafter, the activity of the Δ5-pathway dominates, whereas a decreasing 5α-reductase activity leads to a diminished role of the backdoor pathway for androgenic steroid production. Beside the backdoor pathway, the Δ4-pathway seems to be responsible for increased androgen generation in patients with 21-hydroxylase deficiency before the onset of adrenarche, whereas the Δ5-pathway might contribute to the increased androgen formation in those patients only after the onset of adrenarche. 23562633 Therapeutic targeting of chitosan-PEG-folate-complexed oncolytic adenovirus for active and systemic cancer gene therapy. Adenovirus (Ad)-based cancer therapies have shown much promise. However, until now, Ad has only been delivered directly to primary tumors because the therapeutic efficacy of systemic delivery is limited by the immune response of the host, short blood circulation times, and non-specific liver uptake of Ad. In order to circumvent the issues regarding systemic delivery and to increase the safety and efficacy of Ad therapies, the surface of oncolytic Ad was coated with cationic polymer chitosan via ionic crosslinking (Ad/chitosan), after which polyethylene glycol (PEG) and/or folic acid (FA) was chemically conjugated onto the surface of Ad/chitosan, generating Ad/chitosan-FA, Ad/chitosan-PEG, and Ad/chitosan-PEG-FA nanocomplex. The FA-coordinated Ad nanocomplexes (Ad/chitosan-FA & Ad/chitosan-PEG-FA) elicited folate receptor (FR)-selective cancer cell killing efficacy. In vivo administration of Ad/chitosan-PEG or Ad/chitosan-PEG-FA into mice demonstrated that PEGylation greatly increased blood circulation time, resulting in 9.0-fold and 48.9-fold increases at 24h after injection compared with naked Ad, respectively. In addition, generation of Ad-specific neutralizing antibodies in mice treated with Ad/chitosan-PEG-FA was markedly decreased by 75.3% compared with naked Ad. The quantitative polymerase chain reaction assay results showed a 285.0-fold increase in tumor tissues and a 378-fold reduction of Ad/chitosan-PEG-FA in liver tissues compared with naked Ad. Bioluminescence imaging study further supported the enhanced tumor-to-liver ratio of Ad/chitosan-PEG-FA. Consequently, systemic delivery of Ad/chitosan-PEG-FA significantly inhibited the growth of FR-positive tumor, decreasing 52.8% compared to the naked Ad-treated group. Importantly, PEGylated oncolytic Ad nanocomplexes showed no elevation of both alanine transaminase and aspartate transaminase levels, demonstrating that systemically delivered Ad-related hepatic damage can be completely eliminated with PEG conjugation. In sum, these results demonstrate that conjugation of chitosan-PEG-FA to oncolytic Ad significantly improves antitumor efficacy and safety profiles, suggesting that Ad/chitosan-PEG-FA has potential as a therapeutic agent to target FR-positive cancer via systemic administration. 22891663 The major indole alkaloid N,β-D-glucopyranosyl vincosamide from leaves of Psychotria leiocarpa Cham. & Schltdl. is not an antifeedant but shows broad antioxidant activity. N,β-D-glucopyranosyl vincosamide (GPV), a major alkaloid of Psychotria leiocarpa, constitutes up to 2.5% of the dry weight in leaves. Alkaloid content was not elicited by mechanical wounding or jasmonate. At concentrations found in natural conditions or 2.5 fold higher, GPV did not inhibit herbivory in two unrelated generalist models (Helix aspersa and Spodoptera frugiperda) or in a specific interaction model (Heliconius erato fed with Passiflora suberosa). In situ staining assay showed quenching activity of hydrogen peroxide by GPV. Exposure of P. leiocarpa to acute UV-B stress did not change GPV or chlorophyll content, indicating high tolerance to this stress by the species. In vitro antioxidant tests against singlet oxygen, superoxide anions and hydroxyl radicals showed efficient quenching activity of the alkaloid. GPV was not effective as antifeedant, but it may act indirectly in P. leiocarpa protection against oxidative stress generated upon wounding, UV exposure and perhaps other environmental stresses. 23231967 Selective and potent adenosine A3 receptor antagonists by methoxyaryl substitution on the N-(2,6-diarylpyrimidin-4-yl)acetamide scaffold. The influence of diverse methoxyphenyl substitution patterns on the N-(2,6-diarylpyrimidin-4-yl)acetamide scaffold is herein explored in order to modulate the A(3) adenosine receptor antagonistic profile. As a result, novel ligands exhibiting excellent potency (K(i) on A(3) AR < 20 nM) and selectivity profiles (above 100-fold within the adenosine receptors family) are reported. Moreover, our joint theoretical and experimental approach allows the identification of novel pharmacophoric elements conferring A(3)AR selectivity, first established by a robust computational model and thereafter characterizing the most salient features of the structure-activity and structure-selectivity relationships in this series. 23146690 Synergistic anti-cancer effects of resveratrol and chemotherapeutic agent clofarabine against human malignant mesothelioma MSTO-211H cells. Dietary phytochemicals as adjuvants have been suggested to play important roles in enhancing chemotherapeutic potential owing to multitargeted chemopreventive properties and lack of substantial toxicity. Here, we investigated the efficacy of the combined treatment of various phytochemicals with the anticancer drug clofarabine in malignant mesothelioma MSTO-211H cells and normal mesothelial MeT-5A cells. The combined treatment of resveratrol and clofarabine produced a synergistic antiproliferative effect in MSTO-211H cells, but not in MeT-5A cells. In MSTO-211H cells, the nuclear accumulation of Sp1 and the levels of p-Akt, Sp1, c-Met, cyclin D1, and p21 were effectively decreased by the combined treatment of them. In combination with clofarabine, the ability of resveratrol to reduce the contents of Sp1 and its target gene products was also evident in a time- and dose-dependent experiment. The inhibition of phosphoinositide 3-kinase using Ly294002 augmented a decrease in the p21 level induced by their combination, but it showed no significant effects on expression of Sp1 and cyclin D1. Taken together, the data provide evidence that the synergistic antiproliferative effect of resveratrol and clofarabine is linked to the inhibition of Akt and Sp1 activities, and suggest that this combination may have therapeutic value in treatment of malignant mesothelioma. 23640282 Characterization of surface ligands on functionalized magnetic nanoparticles using laser desorption/ionization mass spectrometry (LDI-MS). Functionalized magnetic nanoparticles (MNPs) have been characterized by laser desorption/ionization mass spectrometry (LDI-MS). Quantitative information about surface ligand composition and structure for monolayer and mixed monolayer protected Fe3O4 and FePt NPs can be obtained rapidly with very little sample consumption. 23125002 Free energy simulation of helical transitions. An umbrella sampling method for the calculation of free energies for helical transitions is presented. The method biases structures toward helices of a desired radius and pitch. Although computationally complex, the method has negligible overhead in actual applications. To illustrate the method, calculations of the helical free energy landscape of several peptides are presented for both the CHARMM and the AMBER force fields. 23347875 Acute effects of hexabromocyclododecane on Leydig cell cyclic nucleotide signaling and steroidogenesis in vitro. Hexabromocyclododecane (HBCDD), an additive brominated flame retardant routinely added to various consumer products, was reported to have toxic effects upon biota, including endocrine disruption. In this study, the potential toxicity of HBCDD was tested in peripubertal rat Leydig cells in vitro during 6h exposure. HBCDD inhibited human chorionic gonadotropin- and forskolin-supported cAMP accumulation and steroidogenesis. It also inhibited basal cAMP production, but elevated basal steroidogenesis. The expression of several cAMP-dependent genes, including steroidogenic acute regulatory protein, cholesterol side chain cleavage enzyme, and 3β-hydroxysteroid dehydrogenase, was also inhibited by HBCDD treatment. Nevertheless, this was not accompanied by a decrease in steroidogenic acute regulatory protein expression, as documented by western blot analysis, and activity of steroidogenic enzymes, as documented by unaffected steroidogenesis in the presence of permeable 22(R)-hydroxycholesterol. However, HBCDD caused significant decrease in mitochondrial membrane potential in untreated and human chorionic gonadotropin-treated cells. This indicates that HBCDD acute toxicity in Leydig cells reflects changes in mitochondrial membrane potential-dependent cAMP production and basal and cAMP-regulated cholesterol transport. This in turn facilitates basal but inhibits cAMP-dependent steroidogenesis. Acute effects of HBCDD treatment on transcription are also indicative of its sustained effects on Leydig cell function. 22983831 Ectopic acromegaly due to growth hormone releasing hormone. Acromegaly secondary to extra-pituitary tumors secreting growth hormone releasing hormone (GHRH) is rarely encountered. We review the literature on ectopic acromegaly and present the index report of ectopic acromegaly secondary to GHRH secretion from a mediastinal paraganglioma. Clinical and pathological manifestations and therapeutic management of 99 patients with ectopic acromegaly are reviewed. Acromegaly secondary to ectopic GHRH secretion is usually caused by a neuroendocrine tumor in the lung and pancreas. We report an additional cause of ectopic acromegaly from a mediastinal paraganglioma. Diagnostic criteria of ectopic GHRH syndrome include biochemical and pathologic tumoral confirmation of GHRH secretion and expression. Management of ectopic acromegaly consists of surgical resection of the primary tumor and biochemical normalization, with possible adjuvant use of somatostatin analogs. The review demonstrates that there are several tumor types, including paragangliomas which may secrete GHRH, leading to acromegaly. Clinical and laboratory manifestations of the syndrome and challenges in diagnosis and management of these rarely encountered patients require early diagnosis and appropriate treatment to prevent long-term morbidity and mortality with ectopic acromegaly. 23288091 Therapeutic drug monitoring of antiepileptic drugs by use of saliva. Blood (serum/plasma) antiepileptic drug (AED) therapeutic drug monitoring (TDM) has proven to be an invaluable surrogate marker for individualizing and optimizing the drug management of patients with epilepsy. Since 1989, there has been an exponential increase in AEDs with 23 currently licensed for clinical use, and recently, there has been renewed and extensive interest in the use of saliva as an alternative matrix for AED TDM. The advantages of saliva include the fact that for many AEDs it reflects the free (pharmacologically active) concentration in serum; it is readily sampled, can be sampled repetitively, and sampling is noninvasive; does not require the expertise of a phlebotomist; and is preferred by many patients, particularly children and the elderly. For each AED, this review summarizes the key pharmacokinetic characteristics relevant to the practice of TDM, discusses the use of other biological matrices with particular emphasis on saliva and the evidence that saliva concentration reflects those in serum. Also discussed are the indications for salivary AED TDM, the key factors to consider when saliva sampling is to be undertaken, and finally, a practical protocol is described so as to enable AED TDM to be applied optimally and effectively in the clinical setting. Overall, there is compelling evidence that salivary TDM can be usefully applied so as to optimize the treatment of epilepsy with carbamazepine, clobazam, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, primidone, topiramate, and zonisamide. Salivary TDM of valproic acid is probably not helpful, whereas for clonazepam, eslicarbazepine acetate, felbamate, pregabalin, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin, the data are sparse or nonexistent. 23018143 The role of personalized medicine in identifying appropriate candidates for menopausal estrogen therapy. Menopausal estrogen therapy has a complex balance of benefits and risks and is no longer routinely recommended for the majority of women during or after the transition to menopause. Recent findings from the Women's Health Initiative (WHI) and other studies suggest that a woman's clinical and biological characteristics may modify her health outcomes on hormone therapy (HT) and that some women may be more appropriate candidates for therapy than others. An emerging body of evidence suggests that it may be possible to identify women who are more likely to have favorable outcomes and less likely to have adverse events on HT, as well as to tailor the optimal dose, formulation, and route of delivery of treatment, by the use of individual risk stratification and a personalized approach. Several clinical characteristics that have been proposed for this purpose include a woman's age, time since menopause, symptom severity, baseline vascular health, risk for breast cancer, biomarker levels, and genetic predisposition. The underlying rationale for personalized medicine, that each person has a unique biologic profile that can help to guide the choice of therapy, applies well to HT decision making and holds promise for improved treatment efficacy and safety. This report, which focuses on vascular health, reviews the evidence on the role of such markers in tailoring the use of hormone therapy to appropriate candidates, with the ultimate goal of developing a personalized risk:benefit prediction model that takes into account clinical and genetic factors, "patient-centered" outcomes including sense of well being and quality of life, and other variables. The proposed personalized approach to HT decision making has the potential to improve the quality of health care. 23374871 Synthesis, crystal structure and antibacterial activity of new highly functionalized ionic compounds based on the imidazole nucleus. Several new highly functionalized imidazolium derivatives were synthesized, via appropriate synthetic routes, using imidazole, 1-methylimidazole and 2-phenyl-1-methylimidazole as key intermediates. The antibacterial activity of the prepared compounds was evaluated against: Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella thipymurium using disk-diffusion and MIC methods. Crystal X-ray structures are reported for six compounds. 23485450 Multifunctional pH-sensitive superparamagnetic iron-oxide nanocomposites for targeted drug delivery and MR imaging. A multifunctional pH-sensitive superparamagnetic iron-oxide (SPIO) nanocomposite system was developed for simultaneous tumor magnetic resonance imaging (MRI) and therapy. Small-size SPIO nanoparticles were chemically bonded with antitumor drug doxorubicin (DOX) and biocompatible poly(ethylene glycol) (PEG) through pH-sensitive acylhydrazone linkages, resulting in the formation of SPIO nanocomposites with magnetic targeting and pH-sensitive properties. These DOX-conjugated SPIO nanocomposites exhibited not only good stability in aqueous solution but also high saturation magnetizations. Under an acidic environment, the DOX was quickly released from the SPIO nanocomposites due to the cleavage of pH-sensitive acylhydrazone linkages. With the help of magnetic field, the DOX-conjugated SPIO nanocomposites showed high cellular uptake, indicating their magnetic targeting property. Comparing to free DOX, the DOX-conjugated SPIO nanocomposites showed better antitumor effect under magnetic field. At the same time, the relaxivity value of these SPIO nanocomposites was higher than 146s(-1)mM(-1) Fe, leading to ~4 times enhancement compared to that of free SPIO nanoparticles. As a negative contrast agent, these SPIO nanocomposites illustrated high resolution in MRI diagnosis of tumor-bearing mice. All of these results confirm that these pH-sensitive SPIO nanocomposites are promising hybrid materials for synergistic MRI diagnosis and tumor therapy. 23292797 Smoothened is a fully competent activator of the heterotrimeric G protein G(i). Smoothened (Smo) is a 7-transmembrane protein essential to the activation of Gli transcription factors (Gli) by hedgehog morphogens. The structure of Smo implies interactions with heterotrimeric G proteins, but the degree to which G proteins participate in the actions of hedgehogs remains controversial. We posit that the G(i) family of G proteins provides to hedgehogs the ability to expand well beyond the bounds of Gli. In this regard, we evaluate here the efficacy of Smo as it relates to the activation of G(i), by comparing Smo with the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor, a quintessential G(i)-coupled receptor. We find that with use of [(35)S]guanosine 5'-(3-O-thio)triphosphate, first, with forms of G(i) endogenous to human embryonic kidney (HEK)-293 cells made to express epitope-tagged receptors and, second, with individual forms of Gα(i) fused to the C terminus of each receptor, Smo is equivalent to the 5-HT(1A) receptor in the assay as it relates to capacity to activate G(i). This finding is true regardless of subtype of G(i) (e.g., G(i2), G(o), and G(z)) tested. We also find that Smo endogenous to HEK-293 cells, ostensibly through inhibition of adenylyl cyclase, decreases intracellular levels of cAMP. The results indicate that Smo is a receptor that can engage not only Gli but also other more immediate effectors. 23313797 Neuroprotective effects of resveratrol on embryonic dorsal root ganglion neurons with neurotoxicity induced by ethanol. Studies have established that ethanol (EtOH) consumption results in damage to the peripheral nervous systems. Although the pathobiological mechanism is still unclear, oxidative stress is known to play an important role in EtOH-induced neurotoxicity. Because resveratrol (Res) is attracting increased attention due to its antioxidative properties, we investigated the neuroprotective efficacy of Res in ethanol-treated embryonic dorsal root ganglion (DRG) neurons in vitro. Organotypic DRG explants and a dispersed cell culture model were used to evaluate the effects of Res on EtOH-induced neurotoxicity. Res increased the number of extended nerve fibers and neurons that migrated from the DRG explants. Hoechst 33342 staining and terminal deoxynucleotidyl-transferase-mediated dUTP nick-end-labeling analysis showed that the EtOH-induced apoptosis was inhibited by Res. The effects of Res were blocked by the 5'-adenosine monophosphate-activated protein kinase inhibitor Compound C and the sirtuin 1 inhibitor nicotinamide. The elevation of oxidative/nitrosative stress, as measured by the amount of reactive oxygen species, malondialdehyde, nitrite, glutathione and superoxide dismutase activity, was also attenuated by Res. The data from the present study indicate that Res protects DRG neurons from EtOH-induced neurotoxicity. Res and its derivative may be effective for the treatment of diseases characterized by axonopathy and neuron loss induced by EtOH. 23561194 The impact of Ca(2+) combination with organic acids on green tea infusions. The effect of Ca(2+) in brewing water on the organic acid content, turbidity, and formation of tea cream and sediment in green tea infusions was studied. When the Ca(2+) concentration of the brewing water was >40mgL(-1), the green tea infusion became more turbid. The turbidity of the tea infusion was highly negatively correlated with the contents of oxalic acid (R=-0.89, p<0.01), quinic acid (R=-0.90, p<0.01) and tartaric acid (R=-0.82, p<0.01). Oxalic acid on its own interacted with Ca(2+) at low concentrations, whereas polyphenols and protein did not. In conclusion, Ca(2+) in brewing water influences the quality of a tea infusion by inducing tea cream and sediment formation from combination of Ca(2+) and organic acids, such as oxalic acid, quinic acid and tartaric acid. Ca(2+) and oxalate are the main metal ion and anion, respectively, involved in tea cream and sediment formation on tea infusion cooling or concentrating. 23590129 Understanding the thermodynamic micro-environment inside a pan coater using a data logging device. Abstract Objective: The objective of the current study was to establish the use of PyroButton data-logging device to monitor and quantify the thermodynamic environment (temperature and humidity) of a pan coating process. Material and methods: PyroButtons were placed (fixed) at various locations in a pan coater, including exhaust plenum, spray-gun bar, baffles and were also allowed to freely move with the tablet-bed. A full factorial design of experiments (DOE) study on three process parameters, exhaust temperature, pan speed and spray rate was conducted on a 24 inch pan coater, using a coating system and a core tablet combination expected to have a narrow process operating space. Results: It was shown that the PyroButtons can provide a detailed and useful signature of the coating process. PyroButton data showed that the tablet-bed temperature was always lower than exhaust temperature and that the difference was a function of the operating conditions such as spray rate. Similarly, the tablet-bed humidity was found to always be higher than exhaust humidity. Some of the DOE batches showed coating defects (logo-bridging). It was shown that the relative humidity (RH), as measured by the freely-moving PyroButtons in the tablet-bed, correlated well with the logo-bridging events. A critical RH value (30%) was established, above which logo-bridging was observed for the selected formulation. Conclusions: This study showed that PyroButtons can provide very meaningful micro-environmental data that can be correlated to coating defects, and can aid in establishing a process design space for a given coating and tablet formulation. 23391637 The venom of the fishing spider Dolomedes sulfurous contains various neurotoxins acting on voltage-activated ion channels in rat dorsal root ganglion neurons. Dolomedes sulfurous is a venomous spider distributed in the south of China and characterized with feeding on fish. The venom exhibits great diversity and contains hundreds of peptides as revealed by off-line RP-HPLC/MALDI-TOF-MS analysis. The venom peptides followed a triple-modal distribution, with 40.7% of peptides falling in the mass range of 1000-3000 Da, 25.6% peptides in the 7000-9000 Da range and 23.5% peptides in the 3000-5000 Da range. This distribution modal is rather different from these of peptides from other spider venoms analyzed. The venom could inhibit voltage-activated Na(+), K(+) and Ca(2+) channels in rat DRG neurons as revealed by voltage-clamp analysis. Significantly, the venom exhibited inhibitory effects on TTX-R Na(+) and T-type Ca(2+) currents, suggesting that there exist both channel antagonists which might be valuable tools for investigation of both channels and drug development. Additionally, intrathoracically injection of venom could cause serve neurotoxic effects on zebrafish and death at higher concentrations. The LD50 value was calculated to be 28.8 μg/g body weight. Our results indicated that the venom of D. sulfurous contain diverse neurotoxins which serve to capture prey. Intensive studies will be necessary to investigate the structures and functions of specific peptides of the venom in the future. 23543413 A Re-evaluation of the Role of hCTR1, the Human High Affinity Cu Transporter in Pt-Drug Entry into Human Cells. Cisplatin (cDDP) is an anti-cancer drug used in a number of malignancies including testicular, ovarian, cervical, bladder, lung, head, and neck cancers. Its use is limited by the development of resistance, often rationalized via effects on cellular uptake. It has been claimed that hCTR1, the human high affinity copper transporter, is the major entry pathway for cDDP and related drugs via a mechanism that mimics copper. This is an unexpected property of hCTR1, a highly selective copper (I) transporter. We compared the uptake rates of copper with cDDP (and several analogs) into HEK293 cells over-expressing wild-type or mutant hCTR1, mouse embryonic fibroblasts (mefs) that do or do not express CTR1, and human ovarian tumor cells, sensitive or resistant to cDDP. We have also compared the effects of extracellular copper, which causes regulatory endocytosis of hCTR1, to those of cDDP. We confirm the correlation between higher hCTR1 levels and higher Pt-drug uptake in tumor cells sensitive to the drug. However, we show that hCTR1 is not the major entry route of platinum-drugs and that the copper transporter is not internalized in response to extracellular drug. Our data suggest the major entry pathway for platinum-drugs is not saturable at relevant concentrations and not protein-mediated. Clinical trials have been initiated that depend upon regulating membrane levels of hCTR1. If reduced drug uptake is a major factor in resistance, hCTR1 is unlikely to be a productive target in attempts to enhance efficacy, although the proteins involved in copper homeostasis may play a role. 23411168 Development of the simple and sensitive method for lipoxygenase assay in AOT/isooctane reversed micelles. In this study, we investigated the possibility of reversed micelles, widely used as an enzyme reactor for lipases, for the determination of lipoxygenase activity. Although it is rapid and simple, reversed micelles have some limitations, such as interference by UV-absorbing materials and surfactant. Lipoxygenase activity in the reversed micelles was determined by reading the absorbance of the lipid hydroperoxidation product (conjugated diene) at 234 nm. Among surfactants and organic media, AOT and isooctane were most effective for the dioxygenation of linoleic acid in reversed micelles. The strong absorbance of AOT in the UV region is a major obstacle for the direct application of the AOT/isooctane reversed micelles to lipoxygenase activity determination. To prevent interference by AOT, we added an AOT removal step in the procedure for lipoxygenase activity determination in reversed micelles. The lipoxygenase activity was dependent on water content, and maximum activity was obtained at an R-value of 10. 23561161 Effect of calcium on the kinetics of free fatty acid release during in vitro lipid digestion in model emulsions. The effects of different calcium salts on in vitro lipid digestion were examined by determining the free fatty acids released from various oil-in-water emulsions. The kinetics of the total and individual free fatty acids released by lipolysis were monitored by the pH-stat method and gas chromatography, respectively. The rate and the extent of free fatty acid release increased with an increase in the added calcium concentration, but the increase was dependent on the emulsifying agent. The effect of calcium was diminished when the emulsion contained phosphate. Soluble calcium salts, such as calcium gluconate, calcium acetate and CaCl2, had greater effects on the rate and extent of free fatty acid release than did insoluble salts, such as CaO and CaSO4, suggesting that the ionic state of calcium plays a critical role in lipid digestion in emulsions. The addition of calcium did not alter the profiles of the individual free fatty acids released. This study provides useful information for food formulation with respect to lipid digestion. 23568429 Profiling glycosyltransferase activities by tritium imaging of glycan microarrays. High-throughput microarray technology has been combined with ultrasensitive and high-resolution tritium autoradiography to create a new platform for the quantitative detection of glycosyltransferase activity on glycan arrays. In addition, we show full compatibility with the use of fluorescently labeled lectins to help with the stereochemical assignment of newly formed glycoside linkages. 23167566 Telomere length and dynamics predict mortality in a wild longitudinal study. Explaining variation in life expectancy between individuals of the same age is fundamental to our understanding of population ecology and life history evolution. Variation in the length and rate of loss of the protective telomere chromosome caps has been linked to cellular lifespan. Yet, the extent to which telomere length and dynamics predict organismal lifespan in nature is still contentious. Using longitudinal samples taken from a closed population of Acrocephalus sechellensis (Seychelles warblers) studied for over 20 years, we describe the first study into life-long adult telomere dynamics (1-17 years) and their relationship to mortality under natural conditions (n = 204 individuals). We show that telomeres shorten with increasing age and body mass, and that shorter telomeres and greater rates of telomere shortening predicted future mortality. Our results provide the first clear and unambiguous evidence of a relationship between telomere length and mortality in the wild, and substantiate the prediction that telomere length and shortening rate can act as an indicator of biological age further to chronological age when exploring life history questions in natural conditions. 23545161 Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2. Acetaminophen is one of the world's most commonly used drugs to treat fever and pain, yet its mechanism of action has remained unclear. Here we tested the hypothesis that acetaminophen blocks fever through inhibition of cyclooxygenase-2 (Cox-2), by monitoring lipopolysaccharide induced fever in mice with genetic manipulations of enzymes in the prostaglandin cascade. We exploited the fact that lowered levels of a specific enzyme make the system more sensitive to any further inhibition of the same enzyme. Mice were immune challenged by an intraperitoneal injection of bacterial wall lipopolysaccharide and their body temperature recorded by telemetry. We found that mice heterozygous for Cox-2, but not for microsomal prostaglandin E synthase-1 (mPGES-1), displayed attenuated fever, indicating a rate limiting role of Cox-2. We then titrated a dose of acetaminophen that did not inhibit the lipopolysaccharide-induced fever in wild-type mice. However, when the same dose of acetaminophen was given to Cox-2 heterozygous mice, the febrile response to lipopolysaccharide was strongly attenuated, resulting in an almost normalized temperature curve, whereas no difference was seen between wild-type and heterozygous mPGES-1 mice. Furthermore, the fever to intracerebrally injected prostaglandin E2 was unaffected by acetaminophen treatment. These findings reveal that acetaminophen, similar to aspirin and other non-steroidal anti-inflammatory drugs, is antipyretic by inhibiting cyclooxygenase-2, and not by inhibiting mPGES-1 or signaling cascades downstream of prostaglandin E2. 23359538 Tailor-Made Micro-Object Optical Sensor Based on Mesoporous Pellets for Visual Monitoring and Removal of Toxic Metal Ions from Aqueous Media. Methods for the continuous monitoring and removal of ultra-trace levels of toxic inorganic species (e.g., mercury, copper, and cadmium ions) from aqueous media such as drinking water and biological fluids are essential. In this paper, the design and engineering of a simple, pH-dependent, micro-object optical sensor is described based on mesoporous aluminosilica pellets with an adsorbed dressing receptor (a porphyrinic chelating ligand). This tailor-made optical sensor permits ultra-fast (≤ 60 s), specific, pH-dependent visualization and removal of Cu(2+) , Cd(2+) , and Hg(2+) at sub-picomolar concentrations (∼10(-11) mol dm(-3) ) from aqueous media, including drinking water and a suspension of red blood cells. The acidic active acid sites of the pellets consist of heteroatoms arranged around uniformly shaped pores in 3D nanoscale gyroidal mesostructures densely coated with the chelating ligand. The sensor can be used in batch mode, as well as in a flow-through system in which sampling, target ion recognition and removal, and analysis are integrated in a highly automated and efficient manner. Because the pellets exhibit long-term stability, reproducibility, and versatility over a number of analysis/regeneration cycles, they can be expected to be useful for the fabrication of inexpensive sensor devices for naked-eye detection of toxic pollutants. 23240655 High performance multilayer MoS2 transistors with scandium contacts. While there has been growing interest in two-dimensional (2-D) crystals other than graphene, evaluating their potential usefulness for electronic applications is still in its infancy due to the lack of a complete picture of their performance potential. The focus of this article is on contacts. We demonstrate that through a proper understanding and design of source/drain contacts and the right choice of number of MoS(2) layers the excellent intrinsic properties of this 2-D material can be harvested. Using scandium contacts on 10-nm-thick exfoliated MoS(2) flakes that are covered by a 15 nm Al(2)O(3) film, high effective mobilities of 700 cm(2)/(V s) are achieved at room temperature. This breakthrough is largely attributed to the fact that we succeeded in eliminating contact resistance effects that limited the device performance in the past unrecognized. In fact, the apparent linear dependence of current on drain voltage had mislead researchers to believe that a truly Ohmic contact had already been achieved, a misconception that we also elucidate in the present article. 23479407 First-Line Management of EGFR-Mutated Advanced Lung Adenocarcinoma: Recent Developments. Gefitinib and erlotinib are small-molecule reversible tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR). Objective responses have been observed frequently in patients with non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations, the most common being deletions in exon 19 and the exon 21 L858R mutation. EGFR mutations are prevalent in female patients, those who have never smoked, those of Asian ethnicity and those who have adenocarcinoma histology. Given the efficacy of EGFR TKIs in advanced NSCLC in the salvage setting, and their favourable toxicity profile compared with conventional chemotherapy, there is considerable interest in evaluating their efficacy in the first-line treatment of advanced NSCLC. To date, there have been several phase II and phase III studies that have examined the efficacy of first-line single-agent EGFR TKIs in unselected, clinically selected or molecularly selected populations. Here we review and compare the differences in these phase III trials. Most phase III trials chose progression-free survival (PFS) rather than overall survival (OS) as their primary endpoint. PFS was prolonged but OS was not. The recent development of novel irreversible EGFR TKIs, such as afatinib and dacomitinib, is also reviewed. 23453986 Mechanism-based testing strategy using in vitro approaches for identification of thyroid hormone disrupting chemicals. The thyroid hormone (TH) system is involved in several important physiological processes, including regulation of energy metabolism, growth and differentiation, development and maintenance of brain function, thermo-regulation, osmo-regulation, and axis of regulation of other endocrine systems, sexual behaviour and fertility and cardiovascular function. Therefore, concern about TH disruption (THD) has resulted in strategies being developed to identify THD chemicals (THDCs). Information on potential of chemicals causing THD is typically derived from animal studies. For the majority of chemicals, however, this information is either limited or unavailable. It is also unlikely that animal experiments will be performed for all THD relevant chemicals in the near future for ethical, financial and practical reasons. In addition, typical animal experiments often do not provide information on the mechanism of action of THDC, making it harder to extrapolate results across species. Relevant effects may not be identified in animal studies when the effects are delayed, life stage specific, not assessed by the experimental paradigm (e.g., behaviour) or only occur when an organism has to adapt to environmental factors by modulating TH levels. Therefore, in vitro and in silico alternatives to identify THDC and quantify their potency are needed. THDC have many potential mechanisms of action, including altered hormone production, transport, metabolism, receptor activation and disruption of several feed-back mechanisms. In vitro assays are available for many of these endpoints, and the application of modern '-omics' technologies, applicable for in vivo studies can help to reveal relevant and possibly new endpoints for inclusion in a targeted THDC in vitro test battery. Within the framework of the ASAT initiative (Assuring Safety without Animal Testing), an international group consisting of experts in the areas of thyroid endocrinology, toxicology of endocrine disruption, neurotoxicology, high-throughput screening, computational biology, and regulatory affairs has reviewed the state of science for (1) known mechanisms for THD plus examples of THDC; (2) in vitro THD tests currently available or under development related to these mechanisms; and (3) in silico methods for estimating the blood levels of THDC. Based on this scientific review, the panel has recommended a battery of test methods to be able to classify chemicals as of less or high concern for further hazard and risk assessment for THD. In addition, research gaps and needs are identified to be able to optimize and validate the targeted THD in vitro test battery for a mechanism-based strategy for a decision to opt out or to proceed with further testing for THD. 22616559 The first total synthesis of apigenin 7-O-β-D-cellobiosyl-4'-O-β-D-glucopyranoside isolated from Salvia uliginosa. The first total synthesis of apigenin 7-O-β-D-cellobioside (5) and apigenin 7-O-β-D-cellobiosyl-4'-O-β-D-glucopyranoside (8), which were isolated from petals of Salvia patens and Salvia uliginosa, were achieved in four and six steps and 76% and 57%, respectively, overall yield, from naringenin (1). The total synthesis contained two-glycosylation, acetylation, oxidation, selective deacetylation and deprotection steps. Although this route contained six steps, the targeted compounds were obtained with higher yields and easier purifications than other synthetic methods. 23266674 Inhibition of constitutive aryl hydrocarbon receptor (AhR) signaling attenuates androgen independent signaling and growth in (C4-2) prostate cancer cells. The aryl hydrocarbon receptor is a member of the basic-helix-loop-helix family of transcription factors. AhR mediates the biochemical and toxic effects of a number of polyaromatic hydrocarbons such as 2,3,7,8,-tetrachloro-dibenzo-p-dioxin (TCDD). AhR is widely known for regulating the transcription of drug metabolizing enzymes involved in the xenobiotic metabolism of carcinogens and therapeutic agents, such as cytochrome P450-1B1 (CYP1B1). Additionally, AhR has also been reported to interact with multiple signaling pathways during prostate development. Here we investigate the effect of sustained AhR signaling on androgen receptor function in prostate cancer cells. Immunoblot analysis shows that AhR expression is increased in androgen independent (C4-2) prostate cancer cells when compared to androgen sensitive (LNCaP) cells. RT-PCR studies revealed constitutive AhR signaling in C4-2 cells without the ligand induced activation required in LNCaP cells. A reduction of AhR activity by short RNA mediated silencing in C4-2 cells reduced expression of both AhR and androgen responsive genes. The decrease in androgen responsive genes correlates to a decrease in phosphorylated androgen receptor and androgen receptor expression in the nucleus. Furthermore, the forced decrease in AhR expression resulted in a 50% decline in the growth rate of C4-2 cells. These data indicates that AhR is required to maintain hormone independent signaling and growth by the androgen receptor in C4-2 cells. Collectively, these data provide evidence of a direct role for AhR in androgen independent signaling and provides insight into the molecular mechanisms responsible for sustained androgen receptor signaling in hormone refractory prostate cancer. 23200006 Detection of trace metal in distilled alcoholic drinks. The presence of trace metal cadmium assay was investigated with a copper immobilized on a graphite carbon electrode (GPC), the modified property of which was determined with handheld voltammetric systems. Following the determination of the analytical stripping conditions of 0.45 V amplitude, 30 Hz frequency, -1.4 V initial potential, and 4.0 mV increment potential, only a 60-s experimental accumulation time was used. Using these conditions, the analytical detection limit approached the nano range. At this condition, the analytical application was performed on distilled alcoholic drinks for food manufacturing systems. This developed technique is faster and less costly than the common voltammetric and spectrophotometric methods. 23419593 Temporal relationship between aquaporin-4 and glial fibrillary acidic protein in cerebellum of neonate and adult rats administered a BBB disrupting spider venom. Two astrocyte markers, the glial water channel aquaporin-4 (AQP4) and the glial fibrillary acidic protein (GFAP), have been implicated in several physiological and pathological conditions in the central nervous system (CNS) as well as in blood-brain barrier breakdown (BBBb). By color segmentation the immunoreactivity of both proteins, we demonstrate that the expression of AQP4 and GFAP was increased in the cerebellum of neonate (14-day-old, P14) and adult (8-week-old) rats administered Phoneutria nigriventer spider venom (PNV) known to cause perivascular edema, BBBb and convulsion. In the cerebellum's gray matter, PNV produced a major response, especially in the granular layer. Parallel increases in AQP4 and GFAP expression occurred 24 h after envenomation in the white matter of P14 and in the molecular layer of adults, as well as in the granular layer 2 h after envenomation. In the Purkinje layer there was a tendency of increased AQP4, for both, neonates (5 h), and adults (2 and 24 h). Moreover, PNV also provoked nonparallel upregulation of both markers with prevalence of upregulation of AQP 4 for P14 rats, and GFAP for adults. The major expression of both proteins was in the gray matter. The data indicates a venom effect in water/electrolyte balance in the cerebellum and the participation of AQP4 in these effects. Age-related and time-related regional differences probably reflect specificity in AQP4 distribution in different astrocytic membrane domains as well as its participation in K(+) buffering and neural activity. This study is the first to associate astrocytic AQP4 expression and reactive gliosis in a model of BBB permeability promoted by P. nigriventer venom. Our data provide compelling evidence that AQP4 expression was increased in the cerebellum of rats administered PNV. 23624289 Opioids and their receptors: Are we there yet? Opioids have an important place in pharmacology. While their clinical use as analgesics is fundamental in medicine, their use is constrained by their side-effects and abuse potential. Pharmacologists have sought analgesics lacking side-effects and the abuse liability of the current agents. The identification of the opioid receptors in 1973 marked the beginning of our understanding of the molecular mechanisms of these agents. The isolation of the opioid peptides quickly followed, along with the classification of three families of opioid receptors. Clinicians have long been aware of subtle differences among the mu opioids that were not easily reconciled with a single receptor and selective antagonists implied two subdivisions of mu receptors. However, the cloning of the mu opioid receptor MOR-1 has led to the realization of the extensive complexity of the mu opioid receptor gene and its vast array of splice variants. Many of these splice variants are truncated and do not conform to the structure of traditional G-protein coupled receptors. Yet, evidence now shows that they are quite important and may prove valuable targets in the development of potent analgesics lacking the undesirable properties of current opioids. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue' 23548974 Visual evoked potentials in children prenatally exposed to methylmercury. Prenatal exposure to methylmercury can cause both neurobehavioral deficits and neurophysiological changes. However, evidence of neurotoxic effects within the visual nervous system is inconsistent, possibly due to incomplete statistical adjustment for beneficial nutritional factors. We evaluated the effect of prenatal methylmercury exposure on visual evoked potential (VEP) latencies in Faroese children with elevated prenatal methylmercury exposure. A cohort of 182 singleton term births was assembled in the Faroe Islands during 1994-1995. At age 7 years, VEP tracings were obtained from 139 cohort subjects after exclusion of subjects with abnormal vision conditions. We used multiple regression analysis to evaluate the association of mercury concentrations in cord blood and maternal hair at parturition with VEP latencies after adjustment for potential confounders that included the cord-serum phospholipid concentration of n-3 polyunsaturated fatty acids (PUFAs) and the duration of breastfeeding. Unadjusted correlations between mercury exposure and VEP latencies were equivocal. Multiple regression models showed that increased mercury concentrations, especially in maternal hair, were associated with delayed latencies for VEP peak N145. After covariate adjustment, a delay of 2.22ms (p=0.02) was seen for each doubling of the mercury concentration in maternal hair. In agreement with neuropsychological findings, the present study suggests that prenatal methylmercury exposure may have an adverse effect on VEP findings despite the absence of clinical toxicity to the visual system. However, this association was apparent only after adjustment for n-3 PUFA status. 23536271 β-Ionone arrests cell cycle of gastric carcinoma cancer cells by a MAPK pathway. β-Ionone is an end ring analog of β-carotenoid which has been shown to possess potent anti-proliferative activity both in vitro and in vivo. To investigate the possible inhibitory effects of β-ionone, we studied cell growth characteristics, DNA synthesis, cell cycle progression, as well as mitogen-activated protein kinases (MAPKs) pathways in the human gastric adenocarcinoma cancer cell line (SGC-7901). Our results show that cell growth and DNA synthesis were inhibited, and the cell cycle was arrested at the G0/G1 phase in a dose-dependent manner in cells treated with β-ionone (25, 50, 100 and 200 μmol/L) for 24 h. We found that the β-ionone significantly decreased the extracellular signal-regulated kinase protein expression and significantly increased the levels of p38 and Jun-amino-terminal kinase protein expression (P < 0.01). β-Ionone also inhibited cell cycle-related proteins of Cdk4, Cyclin B1, D1 and increased p27 protein expression in SGC-7901 cells. These results suggested that the cell cycle arrest observed may be regulated through a MAPK pathway by transcriptional down-regulation of cell cycle proteins. These results demonstrate potent ability of β-ionone to arrest cell cycle of SGC-7901 cells and decrease proliferation. 23576297 "Raisin Bun"-Like Nanocomposites of Palladium Clusters and Porphyrin for Superior Formic Acid Oxidation. A novel "raisin bun"-like nanocomposite, where Pd clusters are embedded in porphyrin matrix, is developed as a promising electrocatalyst. Thanks to the synergy between the Pd clusters and the porphyrin matrix, this composite exhibits a low oxidation potential, high mass activity and excellent stability toward electrochemical oxidation of formic acid, which opens new routes for the design of high-performance catalysts in fuel cells. 23381951 Pharmacogenetics of Allopurinol-Making an Old Drug Safer. Allopurinol is a drug that has been used for decades to lower serum urate levels in patients with gout or chronic renal failure and in cancer patients undergoing chemotherapy at risk of tumor lysis syndrome. Patients may develop cutaneous hypersensitivity reactions, ranging from mild rashes to potentially fatal severe cutaneous adverse reactions (SCARs) namely drug hypersensitivity syndrome, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Recent studies have demonstrated the association between human leukocyte antigen (HLA) B*58:01 allele and allopurinol-induced SCARs, which might explain ethnic differences in their incidences. Genotyping is now required before starting abacavir and carbamazepine so as to identify individuals susceptible to SJS. However, no genetic screening is advocated before commencement of allopurinol. The lack of availability of a rapid and inexpensive screening test for the HLA-B*58:01 allele is one of the obstacles to such screening. Development of a test that is quick, accurate, and cost-effective is warranted. 23378608 Apelin inhibits diet-induced obesity by enhancing lymphatic and blood vessel integrity. Angiogenesis is tightly associated with the outgrowth of adipose tissue, leading to obesity, which is a risk factor for type 2 diabetes and hypertension, mainly because expanding adipose tissue requires an increased nutrient supply from blood vessels. Therefore, induction of vessel abnormality by adipokines has been well studied, whereas how altered vascular function promotes obesity is relatively unexplored. Also, surviving Prox1 heterozygous mice showed abnormal lymphatic patterning and adult-onset obesity, indicating that accumulation of adipocytes could be closely linked with lymphatic function. Here we propose a new anti-obesity strategy based on enhancement of lymphatic and blood vessel integrity with apelin. Apelin-knockout mice given a high-fat diet showed an obese phenotype associated with abnormal lymphatic and blood vessel enlargement. Fatty acids present in the high-fat diet induced hyperpermeability of endothelial cells, causing adipocyte differentiation, whereas apelin promoted vascular stabilization. Moreover, treatment of high-fat-diet-fed apelin-knockout mice with a selective cyclooxygenase-2 inhibitor, celecoxib, improved vascular function, and also attenuated obesity. Finally, apelin transgenic mice showed decreased subcutaneous adipose tissue owing to inhibition of high-fat-diet-induced hyperpermeability of vessels. These results indicate that apelin inhibits high-fat-diet-induced obesity by enhancing vessel integrity. Apelin could serve as a therapeutic target for treating obesity and related diseases. 23204325 Mitogen-inducible gene 6 triggers apoptosis and exacerbates ER stress-induced β-cell death. The increased insulin secretory burden placed on pancreatic β-cells during obesity and insulin resistance can ultimately lead to β-cell dysfunction and death and the development of type 2 diabetes. Mitogen-inducible gene 6 (Mig6) is a cellular stress-responsive protein that can negatively regulate the duration and intensity of epidermal growth factor receptor signaling and has been classically viewed as a molecular brake for proliferation. In this study, we used Mig6 heterozygous knockout mice (Mig6(+/-)) to study the role of Mig6 in regulating β-cell proliferation and survival. Surprisingly, the proliferation rate of Mig6(+/-) pancreatic islets was lower than wild-type islets despite having comparable β-cell mass and glucose tolerance. We thus speculated that Mig6 regulates cellular death. Using adenoviral vectors to overexpress or knockdown Mig6, we found that caspase 3 activation during apoptosis was dependent on the level of Mig6. Interestingly, Mig6 expression was induced during endoplasmic reticulum (ER) stress, and its protein levels were maintained throughout ER stress. Using polyribosomal profiling, we identified that Mig6 protein translation was maintained, whereas the global protein translation was inhibited during ER stress. In addition, Mig6 overexpression exacerbated ER stress-induced caspase 3 activation in vitro. In conclusion, Mig6 is transcriptionally up-regulated and resistant to global translational inhibition during stressed conditions in β-cells and mediates apoptosis in the form of caspase 3 activation. The sustained production of Mig6 protein exacerbates ER stress-induced β-cell death. Thus, preventing the induction, translation, and/or function of Mig6 is warranted for increasing β-cell survival. 23557931 Impact of longitudinal exposure to mycophenolic acid on acute rejection in renal-transplant recipients using a joint modeling approach. This study aimed to investigate the association between longitudinal exposure to mycophenolic acid (MPA) and acute rejection (AR) risk in the first year after renal transplantation, and to propose MPA exposure targets conditionally to this association. A joint model, adjusted for monitoring strategy (fixed-dose versus concentration-controlled) and recipient age, was developed; it combined a mixed-effects model to describe the whole pattern of MPA exposure (i.e. area under the concentration-time curve (AUC)) and a survival model. MPA AUC thresholds were determined using time-dependent receiver-operating characteristics (ROC) curves. Data from 490 adult renal-transplant recipients, representative of the general population of adult renal-transplant patients (i.e. including patients considered at low immunological risk-enrolled in the OPERA trial as well as second renal transplant and patients co-treated by either cyclosporine or tacrolimus), were analyzed. A significant association was found between the longitudinal exposure to MPA (MPA AUCs=f(t)) and AR (p=0.0081), and validated by bootstrapping. A significant positive correlation was observed between time post-transplantation and ROC thresholds which increased in average from 35mgh/L in the first days to 41mgh/L beyond six months post-transplantation (p<0.001). Using a new modeling approach which recognizes the repeated measures in a same patient, this study supports the association between MPA exposure and AR. 23576286 In Vitro and In Vivo Enzyme-Mediated Biomineralization of Oligo(poly(ethylene glycol) Fumarate Hydrogels. The enzyme alkaline phosphatase (ALP) is added at different concentrations (i.e., 0, 2.5, and 10 mg · ml(-1) ) to oligo(poly(ethylene glycol)fumarate) (OPF) hydrogels. The scaffolds are either incubated in 10 mM calcium glycerophosphate (Ca-GP) solution for 2 weeks or implanted in a rat subcutaneous model for 4 weeks. Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and alizarin red staining show a strong ability to form minerals exclusively in ALP-containing hydrogels in vitro. Additionally, the calcium content increases with increasing ALP concentration. Similarly, only ALP-containing hydrogels induce mineralization in vivo. Specifically, small (≈5-20 µm) mineral deposits are observed at the periphery of the hydrogels near the dermis/scaffold interface using Von Kossa and alizarin red staining. 23628621 Quality of Care of People With Type 2 Diabetes in Eight European Countries: Findings from the Guideline Adherence to Enhance Care (GUIDANCE) study. OBJECTIVESWe sought to determine levels of adherence in eight European countries to recommendations for the management of type 2 diabetes and to investigate factors associated with key intermediate outcomes.RESEARCH DESIGN AND METHODSGUIDANCE was a cross-sectional study including retrospective data extraction from the medical records of people with type 2 diabetes recruited, using a shared protocol, from primary and specialist care sites in the following eight European countries: Belgium, France, Germany, Italy, Ireland, Sweden, the Netherlands, and the United Kingdom. The dataset for analysis comprised 7,597 cases. Proportions meeting process and outcome criteria were determined, including between-country variations. Logistic regression was used to investigate potential predictors of meeting targets for HbA1c, blood pressure, and LDL cholesterol.RESULTSIn the total sample, adherence to process recommendations was high for some measures, for example, HbA1c recorded in past 12 months in 97.6% of cases. Target achievement for intermediate outcome measures was lower, with only 53.6% having HbA1c <7%. Considerable between-country variation was identified for both processes and outcomes. The following characteristics were associated with an increased likelihood of meeting targets for all three measures considered (HbA1c, blood pressure, LDL cholesterol): shorter diagnosis of diabetes; having one or more macrovascular complications; lower BMI; being prescribed lipid-lowering medication; and no current antihypertensive prescribing.CONCLUSIONSCompared with earlier reports, we have suggested some encouraging positive trends in Europe in relation to meeting targets for the management of people with type 2 diabetes, but there is still scope for further improvement and greater between-country consistency. 23122086 Sustainable production of pectin from lime peel by high hydrostatic pressure treatment. The application of high hydrostatic pressure technology for enzymatic extraction of pectin was evaluated. Cellulase and xylanase under five different combinations (cellulase/xylanase: 50/0, 50/25, 50/50, 25/50, and 0/50 U/g lime peel) at ambient pressure, 100 and 200 MPa were used to extract pectin from dried lime peel. Extraction yield, galacturonic acid (GalA) content, average molecular weight (M(w,ave)), intrinsic viscosity [η](w), and degree of esterification (DE) were compared to those parameters obtained for pectins extracted using acid and aqueous processes. Pressure level, type and concentration of enzyme significantly (p<0.05) influenced yield and DE of pectin. Enzyme and high pressure extraction resulted in yields which were significantly (p<0.05) higher than those using acid and aqueous extraction. Although pressure-induced enzymatic treatment improves pectin yield, it does not have any significant effect on M(w,ave) and [η](w) of pectin extracts indicating the potential of high pressure treatment for enzymatic pectin production as a novel and sustainable process. 23595692 Pine Oil Effects on Chemical and Thermal Injury in Mice and Cultured Mouse Dorsal Root Ganglion Neurons. A commercial resin-based pine oil (PO) derived from Pinus palustris and Pinus elliottii was the major focus of this investigation. Extracts of pine resins, needles, and bark are folk medicines commonly used to treat skin ailments, including burns. The American Burn Association estimates that 500,000 people with burn injuries receive medical treatment each year; one-half of US burn victims are children, most with scald burns. This systematic study was initiated as follow-up to personal anecdotal evidence acquired over more than 10 years by MH Bhattacharyya regarding PO's efficacy for treating burns. The results demonstrate that PO counteracted dermal inflammation in both a mouse ear model of contact irritant-induced dermal inflammation and a second degree scald burn to the mouse paw. Furthermore, PO significantly counteracted the tactile allodynia and soft tissue injury caused by the scald burn. In mouse dorsal root ganglion neuronal cultures, PO added to the medium blocked adenosine triphosphate-activated, but not capsaicin-activated, pain pathways, demonstrating specificity. These results together support the hypothesis that a pine-oil-based treatment can be developed to provide effective in-home care for second degree burns. Copyright © 2013 John Wiley & Sons, Ltd. 23320385 Inhibitory effect of anthocyanidins on hepatic glutathione S-transferase, UDP-glucuronosyltransferase and carbonyl reductase activities in rat and human. Abstract 1. Anthocyanins and their aglycone anthocyanidins represent the most abundant flavonoids in human diet and popular constituents of various dietary supplements. The aim of this study was to evaluate inhibitory effect of four anthocyanidins (delphinidin, cyanidin, malvidin and pelargonidin) on three families of important drug-metabolizing enzymes: carbonyl reductases (CBRs), glutathione S-transferases (GSTs) and UDP-glucuronosyltransferases (UGT). 2. Human or rat hepatic subcellular fractions were incubated with or without pure anthocyanidins (100 µM) and the activities of CBR, GST and UGT were assayed using menadione, 1-chloro-2,4-dinitrobenzene and p-nitrophenol as substrates, respectively. For the most potent inhibitors, half maximal inhibitory concentrations (IC(50)) were determined and the inhibition kinetics study was performed. 3. Anthocyanidins inhibited weakly the activity of GST and moderately the activities of CBR and UGT. Cyanidin was the most potent inhibitor of human UGT with IC(50) = 69 µM (at 200 µM substrate concentration) and competitive type of action. Delphinidin acted as significant non-competitive inhibitor of human CBR with IC(50) = 16 µM (at substrate concentration 500 µM). The inhibitory potency of anthocyanidins differed in rat and human samples significantly. 4. Anthocyanidins are able to inhibit CBR and UGT in vitro. Possible interference of anthocyanidins (in high-dose dietary supplements) with simultaneously administered drugs, which are UGT or CBR substrates, should be checked. 23480279 Experimental and computational study of the interaction of novel colchicinoids with a recombinant human αI/βI-tubulin heterodimer. The binding free energies on human tubulin of selected colchicine and thiocolchicine compounds were determined. Two methods were used for the determination of binding free energies. One is based on theoretical prediction simulating the dissociation of the compound from tubulin using a series of molecular dynamics simulations. The other method involved a series of experiments that measured the affinity of the compound on a synthetically expressed and purified tubulin protein using a spectrofluorometric technique. © 2013 John Wiley & Sons A/S. 23357629 Design, synthesis, characterization and anti-inflammatory evaluation of novel pyrazole amalgamated flavones. A series of novel pyrazole amalgamated flavones has been designed and synthesized from 1-methyl-5-(2,4,6-trimethoxy-phenyl)-1H-pyrazole 6. The structures of regioisomers 6 and 7 were resolved by 2D (1)H-(1)H COSY, (1)H-(13)C HSQC and (1)H-(13)C HMBC experiments. The newly synthesized compounds were tested for their in vitro COX inhibition and in vivo carrageenan induced hind paw edema in rats and acetic acid induced vascular permeability in mice. Although the compounds have inhibitory profile against both COX-1 and COX-2, some of the compounds are found to be selective against COX-2, supported by inhibition of paw edema and vascular permeability. Docking studies were also carried out to determine the structural features which sway the anti-inflammatory activity of the tested compounds. The keto and phenolic -OH are major factors that are prominently involved in interaction with COX-2 active site. 23061635 Menthol--pharmacology of an important naturally medicinal "cool". Menthol, a natural product of the peppermint plant Mentha x piperita (Lamiaceae), is a monoterpene which is widely used as a natural product in cosmetics, a flavoring agent, and as an intermediate in the production of other compounds. Various extracts from peppermint contain menthol as a major active constituent and have been used for centuries as traditional medicines for a number of ailments including infections, insomnia, and irritable bowel syndrome as well as an insect repellent. Menthol's characteristic cooling sensation is due, in part, to the activation of sensory neurons generally termed transient receptor potential (TRP) channels, in particular transient receptor potential melastatin family member 8 (TRPM8) and transient receptor potential subfamily A, member 1 (TRPA1). Menthol acts upon TRPM8 receptors by rapidly increasing intracellular calcium and mobilizing calcium flux through the channels to induce cold response signals at the application site. Aside from its cold-inducing sensation capabilities, menthol exhibits cytotoxic effects in cancer cells, induces reduction in malignant cell growth, and engages in synergistic excitation of GABA receptors and sodium ion channels resulting in analgesia. Notwithstanding its plethora of benefits, menthol's coldsensitivity response mechanism has been shown to inhibit mucosal recognition of nicotine and cigarette toxins common in mentholated cigarette brands thus potentially leading to toxic effects. Menthol may prove a valuable lead structure for the synthesis of drugs that target multiple receptors involved with a number of pharmacological effects. 22977168 CTNNA3 (α-catenin) gene variants are associated with diisocyanate asthma: a replication study in a caucasian worker population. Recently, a genome-wide association study (GWAS) conducted in Korean subjects identified four CTNNA3 (alpha-T catenin) single nucleotide polymorphisms (SNPs) (rs10762058, rs7088181, rs1786929, and rs4378283) associated with diisocyanate-induced occupational asthma (DA). The CTNNA3 gene codes for a cadherin involved in formation of stretch-resistant cell-cell adhesions. We conducted a candidate gene association study to replicate these findings in Caucasian workers. Genotyping was performed on DNA using a 5' nuclease PCR assay collected from 410 diisocyanate-exposed and predominantly Canadian workers including 132 workers with DA confirmed by a specific inhalation challenge (DA+); 131 symptomatic workers in whom DA was excluded by a negative challenge (DA-); and 147 hexamethylene diisocyanate-exposed asymptomatic workers (AWs). As in the Korean study, highly linked CTNNA3 rs7088181 and rs10762058 SNPs (but not rs4378283 and rs1786929) were significantly associated with DA+ when compared with AWs but not in comparison with DA- workers (p ≤ 0.05). After adjusting for potentially confounding variables of age, smoking status, and duration of exposure, minor allele homozygotes of rs7088181 and rs10762058 SNPs were at increased risk for DA compared with AWs (OR = 9.05 [95% CI: 1.69, 48.54] and OR = 6.82 [95% CI: 1.65, 28.24], respectively). In conclusion, we replicated results from the only reported GWAS study of DA demonstrating an association between two closely linked CTNNA3 gene SNPs and DA. These findings lend further support to the clinical relevance of these genotypes in predicting susceptibility to DA and the potential importance of catenins in the disease process. 23311754 Cucumber-like V2O5/poly(3,4-ethylenedioxythiophene)&MnO2 nanowires with enhanced electrochemical cyclability. Inspired by the cucumber-like structure, by combining the in situ chemical oxidative polymerization with facile soaking process, we designed the heterostructured nanomaterial with PEDOT as the shell and MnO(2) nanoparticles as the protuberance and synthesized the novel cucumber-like MnO(2) nanoparticles enriched vanadium pentoxide/poly(3,4-ethylenedioxythiophene) (PEDOT) coaxial nanowires. This heterostructured nanomaterial exhibits enhanced electrochemical cycling performance with the decreases of capacity fading during 200 cycles from 0.557 to 0.173% over V(2)O(5) nanowires at the current density of 100 mA/g. This method is proven to be an effective technique for improving the electrochemical cycling performance and stability of nanowire electrodes especially at low rate for application in rechargeable lithium batteries. 23436555 Weak-field, multiple-cycle carrier envelope phase effects in laser excitation. Although the absolute or carrier envelope phase (CEP) of a laser pulse is usually assumed to be effective for ultrashort and/or ultrastrong pulses only, it is demonstrated that these limitations can eventually be removed. Therefore, the excitation of a model positively charged homonuclear diatomic molecule, in which four electronic states are coupled by the laser field, is studied. In an initial step, nuclear wave packets in two dissociative states are prepared. Upon reaching the fragment channel, a weak pulse interacts with the system and prepares CEP-dependent asymmetries associated with electron density localized on one or the other fragmentation product. 23354391 Safety evaluation of daidzein in laying hens: part II. Effects on calcium-related metabolism. Daidzein, an estrogen-like product, has become increasingly popular as a dietary supplement, particularly for postpeak-estrus animals seeking a safe natural alternative to play a role of estrogen. However, there is little available safety data of it for raisers and consumers. A subchronic laying hensafety study has been conducted to examine if the high-dose daidzein could affect calcium-related metabolism (eggshell quality and bone mineralization). Seven hundred and sixty-eight 56-week-old Hyline Brown were randomly assigned to 4 groups with 8 replicates of 24 birds each (192 laying hensper group) and 3weeks later fed diets supplemented with 0(control), 10, 50 and 100mg of daidzein/kg for 12week. Eggshell thickness, eggshell percentage, eggshell strength, eggshell Ca concentration was increased linearly with increasing dietary daidzein supplementation (P=0.001, P=0.007, P=0.002 and P=0.000, respectively). Serum Ca increased linearly with increasing dietarydaidzein supplementation (P=0.042), and serum P showed a significant quadratic response to dietarydaidzein supplementation (P=0.036). Bone ash and bone Ca were significantly influenced by dietarydaidzein supplementation (P<0.05). These findings indicate that daidzein hold no observed adverse effect on calcium metabolism, but also a safe and effective food additive for calcium metabolism in animals and humans. 23402971 RP TLC data in correlation studies with in silico pharmacokinetic properties of benzimidazole and benztriazole derivatives. Reversed-phase thin-layer chromatographic (RP TLC) retention constants for a newly designed series benzimidazole/benztriazole with expected biological activity were determined as parameters of their lipophilicity and this series was recognized as congeneric. Pharmacokinetic descriptors of the compounds investigated were calculated in silico with the use of the established drug design software. The bioactivity descriptors, which are assumed to predicted drug absorption, distribution, metabolism, elimination and toxicity (ADMETox) in humans, were correlated with retention constants and good statistical parameters were obtained. Multiple regression analysis which was introduced suggested that the absorption through different epithelial membranes (intestinal, blood-brain or erythrocyte membrane) and distribution process depend on retention constants (as measure of lipophilicty) and total polar surface area and molar weight/volume of the analyte. Finally, the compounds with halogen substituent (compounds A4/A7 and A5/A8 in Table 1), were suggested as the best drug candidates, because of their predicted proper pharmacokinetics and have been proposed for further biological tests. 23511022 Photosensitized protein damage by dimethoxyphosphorus(V) tetraphenylporphyrin. For the purpose of the basic study of photodynamic therapy, the activity of the water-soluble P(V)porphyrin, dimethoxyP(V)tetraphenylporphyrin chloride (DMP(V)TPP), on photosensitized protein damage was examined. The quantum yield of singlet oxygen generation by DMP(V)TPP (0.64) was comparable with that of typical porphyrin photosensitizers. Absorption spectrum measurement demonstrated the binding interaction between DMP(V)TPP and human serum albumin, a water-soluble protein. Photo-irradiated DMP(V)TPP damaged the amino acid residue of human serum albumin, resulting in the decrease of the fluorescence intensity from the tryptophan residue of human serum albumin. A singlet oxygen quencher, sodium azide, could not completely inhibit the damage of human serum albumin, suggesting that the electron transfer mechanism contributes to protein damage as does singlet oxygen generation. The decrease of the fluorescence lifetime of DMP(V)TPP by human serum albumin supported the electron transfer mechanism. The estimated contribution of the electron transfer mechanism is 0.64. These results suggest that the activity of DMP(V)TPP can be preserved under lower oxygen concentration condition such as tumor. 23411212 Vitamin D and 25-hydroxyvitamin D determination in meats by LC-IT-MS. This paper reports a method for the rapid, sensitive and simultaneous analysis of vitamin D (Vit D) and 25-hydroxyvitamin D (25OH-Vit D) in meats. Samples were saponified and underwent solid phase extraction with analysis by normal phase liquid chromatography (LC) with ion trap mass spectroscopy (IT-MS), using positive polarity atmospheric pressure chemical ionisation (APCI). Limits of detection (LOD) and quantification (LOQ) for Vit D and 25OH-Vit D were 0.03 and 0.05 μg/100g respectively. Deuterium labelled Vit D and 25OH-Vit D internal standards were added as surrogates prior to saponification, correcting for extraction inefficiencies and potential MS matrix enhancement or suppression effects. Recoveries using internal/surrogate standard correction ranged from 80% to 100% for all vitamers. Measurement uncertainty ranged from 6% to 15% for all vitamers in this method. This process required only 7.5 g of sample per extraction and a batch of 28 extractions could be completed in six hours. 23360412 Bioactivation of the nasal toxicant 2,6-dichlorobenzonitrile: an assessment of metabolic activity in human nasal mucosa and identification of indicators of exposure and potential toxicity. The herbicide 2,6-dichlorobenzonitrile (DCBN) is a potent nasal toxicant in rodents; however, it is not known whether DCBN causes similar nasal toxicity in humans. The tissue-selective toxicity of DCBN in mouse nasal mucosa is largely dependent on target tissue bioactivation by CYP2A5. The human orthologues of CYP2A5, CYP2A6 and CYP2A13, are both expressed in nasal mucosa and are capable of activating DCBN. In this study, we directly determined the ability of human nasal mucosa to bioactivate DCBN. We also tested the suitability of a glutathione conjugate of DCBN (GS-DCBN) or its derivatives as biomarkers of DCBN exposure and nasal toxicity in mouse models. We found that human fetal nasal mucosa microsomes catalyze the formation of GS-DCBN, with a Km value comparable to that of adult mouse nasal mucosa microsomes. The activity of the human nasal mucosa microsomes was inhibited by 8-methoxypsoralen, a known CYP2A inhibitor. GS-DCBN and its metabolites were detected in the nasal mucosa and nasal-wash fluid obtained from DCBN-treated mice, in amounts that increased with escalations in DCBN dose, and they were all still detectable at 24 h after a DCBN treatment (at 10 mg/kg). Further studies in Cyp2a5-null mice indicated that GS-DCBN and its metabolites in nasal-wash fluid were generated in the nasal mucosa, rather than in other organs. Thus, our data indicate for the first time that the human nasal mucosa is capable of bioactivating DCBN and that GS-DCBN and its metabolites in nasal-wash fluid may collectively serve as indicators of DCBN exposure and potential nasal toxicity in humans. 23392606 Large-scale and highly efficient synthesis of micro- and nano-fibers with controlled fiber morphology by centrifugal jet spinning for tissue regeneration. PLLA fibrous tissue scaffolds with controlled fiber nanoscale surface roughness are fabricated with a novel centrifugal jet spinning process. The centrifugal jet spinning technique is a highly efficient synthesis method for micron- to nano-sized fibers with a production rate up to 0.5 g min(-1). During the centrifugal jet spinning process, a polymer solution jet is stretched by the centrifugal force of a rotating chamber. By engineering the rheological properties of the polymer solution, solvent evaporation rate and centrifugal force that are applied on the solution jet, polyvinylpyrrolidone (PVP) and poly(l-lactic acid) (PLLA) composite fibers with various diameters are fabricated. Viscosity measurements of polymer solutions allowed us to determine critical polymer chain entanglement limits that allow the generation of continuous fiber as opposed to beads or beaded fibers. Above a critical concentration at which polymer chains are partially or fully entangled, lower polymer concentrations and higher centrifugal forces resulted in thinner fibers. Etching of PVP from the PLLA-PVP composite fibers doped with increasing PVP concentrations yielded PLLA fibers with increasing nano-scale surface roughness and porosity, which increased the fiber hydrophilicity dramatically. Scanning electron micrographs of the etched composite fibers suggest that PVP and PLLA were co-contiguously phase separated within the composite fibers during spinning and nano-scale roughness features were created after the partial etching of PVP. To study the tissue regeneration efficacy of the engineered PLLA fiber matrix, human dermal fibroblasts are used to simulate partial skin graft. Fibers with increased PLLA surface roughness and porosity demonstrated a trend towards higher cell attachment and proliferation. 23329180 Targeting RET to induce medullary thyroid cancer cell apoptosis: an antagonistic interplay between PI3K/Akt and p38MAPK/caspase-8 pathways. Mutations in REarranged during Transfection (RET) receptor tyrosine, followed by the oncogenic activation of RET kinase is responsible for the development of medullary thyroid carcinoma (MTC) that responds poorly to conventional chemotherapy. Targeting RET, therefore, might be useful in tailoring surveillance of MTC patients. Here we showed that theaflavins, the bioactive components of black tea, successfully induced apoptosis in human MTC cell line, TT, by inversely modulating two molecular pathways: (i) stalling PI3K/Akt/Bad pathway that resulted in mitochondrial transmembrane potential (MTP) loss, cytochrome-c release and activation of the executioner caspases-9 and -3, and (ii) upholding p38MAPK/caspase-8/caspase-3 pathway via inhibition of Ras/Raf/ERK. Over-expression of either constitutively active myristoylated-Akt-cDNA (Myr-Akt-cDNA) or dominant-negative-caspase-8-cDNA (Dn-caspase-8-cDNA) partially blocked theaflavin-induced apoptosis, while co-transfection of Myr-Akt-cDNA and Dn-caspase-8-cDNA completely eradicated the effect of theaflavins thereby negating the possibility of existence of other pathways. A search for the upstream signaling revealed that theaflavin-induced disruption of lipid raft caused interference in anchorage of RET in lipid raft that in turn stalled phosphorylation of Ras and PI3Kinase. In such anti-survival cellular micro-environment, pro-apoptotic signals were triggered to culminate into programmed death of MTC cell. These findings not only unveil a hitherto unexplained mechanism underlying theaflavin-induced MTC death, but also validate RET as a promising and potential target for MTC therapy. 23335034 Mineralization of phenanthrene sorbed on multiwalled carbon nanotubes. Carbon nanotubes have attracted attention around the world because of their high sorption capacity for hydrophobic organic compounds (HOCs); however, the bioavailability of HOCs sorbed on carbon nanotubes to bacteria is not well known. In the present study, (14) C-labeled and unlabeled phenanthrene was spiked onto four kinds of multiwalled carbon nanotubes (MWCNTs) and aged for 60 d, and the mineralization of phenanthrene sorbed on MWCNTs was studied. The mineralization efficiencies of phenanthrene sorbed on the four kinds of MWCNTs were 2.38, 8.84, 23.88, and 31.47%, respectively, after incubation for 35 d, which were positively correlated with the sum of fast and slow desorption fractions of phenanthrene (p < 0.05). The authors found that the mineralization efficiencies agreed well with the MWCNT properties; the increasing specific surface area and mesopore and micropore volume of MWCNTs caused a significant decrease in the mineralization efficiency of phenanthrene (p < 0.05). After incubation for 35 d, the density of bacteria had a significant positive correlation with both the desorption and the mineralization efficiencies. The authors inferred that, although MWCNTs might have toxic effects on the bacteria, the biodegrading ability of bacteria might not decrease significantly under the influence of MWCNTs with low surface area. 23181488 Conformational landscape of diisopropyl ketone: quantum chemical calculations validated by microwave spectroscopy. We report on the gas-phase structure of the most abundant conformer of diisopropyl ketone, (CH(3))(2)HC-CO-CH(CH(3))(2), as observed by molecular beam Fourier transform microwave spectroscopy. The gas-phase structures of five conformers of diisopropyl ketone were optimized using ab initio calculations at the MP2/6-311++G(d,p) level of theory. The natures of the stationary points were verified using harmonic frequency calculations. The only conformer observed in the supersonic jet possesses C(2) symmetry and appears as an enantiomeric pair. From the microwave spectrum, a set of three highly accurate rotational constants, five centrifugal distortion constants, and three sextic centrifugal distortion constants were determined. The structure of the observed conformer was optimized again at different levels of theory using the HF, MP2, and B3LYP methods. The theoretical constants of the C(2) conformer were subsequently validated using the experimental constants. To understand the transitions of one conformer to the others, the isopropyl groups were rotated against each other. The resulting two-dimensional potential energy surface shows nicely the symmetry of the conformational landscape and also indicates the enantiomeric pairs of the conformers. The barriers to internal rotation of the methyl groups were determined to be 1052 and 905 cm(-1) at the MP2/6-311++G(d,p) and the B3LYP/6-311++G(d,p) levels, respectively. In agreement with the theoretical predictions, no internal rotation patterns could be observed in the microwave spectrum. 23323691 Bioactive carboxylic acids from Lysimachia clethroides. Six new carboxylic acids (1-6), together with 11 known ones (7-17), were isolated from the aerial parts of Lysimachia clethroides. Their structures were elucidated on the basis of spectroscopic analysis and chemical evidence. Five new carboxylic acids (1 and 3-6) were evaluated for their in vitro inhibitory activity against aldose reductase. 23296950 Chrysin and Luteolin Attenuate Diabetes-Induced Impairment in Endothelial-Dependent Relaxation: Effect on Lipid Profile, AGEs and NO Generation. Chrysin and luteolin are two important plant flavonoids. In the present study, we hypothesized that they protect against deleterious vascular effects of diabetes. Diabetes was induced in rats by streptozotocin (STZ) injection, while chrysin and luteolin were administered two weeks after STZ administration for 6 weeks. Then, blood pressure (BP) and serum levels of glucose, advanced glycation end products (AGEs), triglycerides (TGs), total cholesterol and low density lipoprotein-cholesterol (LDL-C) were determined. Concentration response curves for KCl, phenylephrine (PE), acetylcholine (ACh) and ACh-induced NO generation were obtained in isolated aorta. Compared with control, diabetes increased diastolic and systolic BP, while chrysin and luteolin attenuated diastolic BP elevation without affecting the developed hyperglycemia. Diabetes increased contractile response of aorta to KCl, PE, decreased relaxation response to ACh, while chrysin and luteolin prevented the impaired response to ACh. In addition, diabetes was accompanied by elevated levels of TGs, total and LDL cholesterol, while both chrysin and luteolin prevented this dyslipidemia. Furthermore, chrysin decreased the elevated AGEs level in serum of diabetic animals, while luteolin abrogated the impaired NO generation in diabetic aorta. Collectively, chrysin and luteolin attenuate diabetes-evoked impairment in endothelial-dependent relaxation possibly via ameliorating detrimental changes in lipid profile, AGEs and NO generation. Copyright © 2013 John Wiley & Sons, Ltd. 22887768 Microfabricated nanotopological surfaces for study of adhesion-dependent cell mechanosensitivity. Cells exhibit high sensitivity and diverse responses to the intrinsic nanotopography of the extracellular matrix through their nanoscale cellular sensing machinery. A simple microfabrication method for precise control and spatial patterning of the local nanoroughness on glass surfaces by using photolithography and reactive ion etching is reported. It is demonstrated that local nanoroughness as a biophysical cue could regulate a diverse array of NIH/3T3 fibroblast behaviors, including cell morphology, adhesion, proliferation, migration, and cytoskeleton contractility. The capability to control and further predict cellular responses to nanoroughness might suggest novel methods for developing biomaterials mimicking nanotopographic structures in vivo for functional tissue engineering. 23409716 Transient receptor potential channels - emerging novel drug targets for the treatment of pain. In mammals several members of the Transient Receptor Potential channel family (TRPs), expressed mainly in the sensory neurons and skin keratinocytes, are implicated in relevant physiological functions, including thermosensation,nociception and vision. Since the TRPV1-4, TRPA1 and TRPM8 channels from this family play a pivotal role in both the detection and possibly modulation of painful stimuli, they are regarded as a very promising target of novel analgesic drugs. A few agents acting at TRPs, such as capsaicin or menthol, have a long history of their application as analgesics,whereas others (e.g. SB705498, JTS653, JNJ17203212, AP18, A967079, Chembridge-5861528 or PBMC) are currently being evaluated both in animals and in humans. In this review we discuss pain physiology, as well as the pharmacological properties of the TRPs involved in pain detection as potential critical peripheral analgesic targets. We present one of the most relevant strategies in the search for novel analgesic drugs, namely the TRP channels and their ligands, both agonists and antagonists as potential novel therapeutics for inflammatory and neuropathic pain syndromes. The safety profile of these agents, in particular their impact on thermosensation, is also discussed below. 23497867 AKT signalling and mitochondrial pathways are involved in mushroom polysaccharide-induced apoptosis and G1 or S phase arrest in human hepatoma cells. This study describes molecular mechanisms for inhibiting tumour cell proliferation using polysaccharides from medicinal mushrooms in human hepatoma cells. The results show that regarding cell cycle-related proteins, three types of polysaccharides significantly enhance the expression of p27(Kip) in HepG2 and Bel-7404 cells, while suppressing the activity of cyclin D1/CDK4 and/or cyclin E/CDK2. Considering apoptosis-related factors, the polysaccharides suppressed AKT activity through the inhibition of AKT phosphorylation at Thr(308) and/or Ser(473). The growth of HepG2 and Bel-7404 cells was suppressed by the up-regulation of a subunit of PI3K and phospho-PTEN, which are modulators of AKT activity. The polysaccharides also activated the mitochondria-mediated apoptosis pathway by stimulating the activation of Bcl-2 family proteins to release cytochrome c and Smac and cleave caspase-9 and caspase-3 in HepG2 and Bel-7404 cells. These factors have a potent effect on cell cycle arrest in G(1) and/or S phase and induce apoptosis in HepG2 and Bel-7404 cells. 23427088 In vivo overexpression of tissue-nonspecific alkaline phosphatase increases skeletal mineralization and affects the phosphorylation status of osteopontin. Functional ablation of tissue-nonspecific alkaline phosphatase (TNAP) (Alpl(-/-) mice) leads to hypophosphatasia, characterized by rickets/osteomalacia attributable to elevated levels of extracellular inorganic pyrophosphate, a potent mineralization inhibitor. Osteopontin (OPN) is also elevated in the plasma and skeleton of Alpl(-/-) mice. Phosphorylated OPN is known to inhibit mineralization, however, the phosphorylation status of the increased OPN found in Alpl(-/-) mice is unknown. Here, we generated a transgenic mouse line expressing human TNAP under control of an osteoblast-specific Col1a1 promoter (Col1a1-Tnap). The transgene is expressed in osteoblasts, periosteum, and cortical bones, and plasma levels of TNAP in mice expressing Col1a1-Tnap are 10-20 times higher than those of wild-type mice. The Col1a1-Tnap animals are healthy and exhibit increased bone mineralization by microCT analysis. Crossbreeding of Col1a1-Tnap transgenic mice to Alpl(-/-) mice rescues the lethal hypophosphatasia phenotype characteristic of this disease model. Osteoblasts from [Col1a1-Tnap] mice mineralize better than non-transgenic controls and osteoblasts from [Col1a1-Tnap(+/-) ; Alpl(-/-) ] mice are able to mineralize to the level of Alpl(+/-) heterozygous osteoblasts, while Alpl(-/-) osteoblasts show no mineralization. We found that the increased levels of OPN in bone tissue of Alpl(-/-) mice are comprised of phosphorylated forms of OPN while WT and [Col1a1-Tnap(+/-) ; Alpl(-/-) ] mice had both phosphorylated and dephosphorylated forms of OPN. OPN from [Col1a1-Tnap] osteoblasts were more phosphorylated than non-transgenic control cells. Titanium dioxide-liquid chromatography and tandem mass spectrometry analysis revealed that OPN peptides derived from Alpl(-/-) bone and osteoblasts yielded a higher proportion of phosphorylated peptides than samples from WT mice, and at least two phosphopeptides, p(S(174) FQVS(178) DEQY(182) PDAT(186) DEDLT(191) )SHMK and FRIp(S(299) HELES(304) S(305) S(306) S(307) )EVN, with one non-localized site each, appear to be preferred sites of TNAP action on OPN. Our data suggest that the pro-mineralization role of TNAP may be related not only to its accepted pyrophosphatase activity but also to its ability to modify the phosphorylation status of OPN. © 2013 American Society for Bone and Mineral Research. 23561138 Enzyme-assisted extraction of bioactive compounds from ginger (Zingiber officinale Roscoe). Ginger (Zingiber officinale R.) is a popular spice used in various foods and beverages. 6-Gingerol is the major bioactive constituent responsible for the antiinflammatory, antitumour and antioxidant activities of ginger. The effect of application of α-amylase, viscozyme, cellulase, protease and pectinase enzymes to ginger on the oleoresin yield and 6-gingerol content has been investigated. Pre-treatment of ginger with α-amylase or viscozyme followed by extraction with acetone afforded higher yield of oleoresin (20%±0.5) and gingerol (12.2%±0.4) compared to control (15%±0.6 oleoresin, 6.4%±0.4 gingerol). Extraction of ginger pre-treated with enzymes followed by extraction with ethanol provided higher yield of gingerol (6.2-6.3%) than the control (5.5%) with comparable yields of the oleoresin (31-32%). Also, ethanol extract of cellulase pre-treated ginger had the maximum polyphenol content (37.5mg/g). Apart from 6-gingerol, 6-paradol along with 6- and 8-methyl shogaols were the other important bio-active constituents in the oleoresin from cellulase-treated ginger. 23436266 Clinical risk factors for adverse events in allopurinol users. Allopurinol, one of the most commonly used uric acid-lowering agents, can cause serious adverse events. To investigate the risk factors for allopurinol-induced adverse events, the authors enrolled 94 patients who developed allopurinol-induced adverse events and 378 controls who were randomly chosen from 1934 patients who used allopurinol but did not develop any adverse events in this retrospective case control study. Univariate analysis showed that patients who developed allopurinol-induced adverse events had more chronic kidney disease (46% vs 30%, P = .005), more hypertension (42% vs 30%, P = .036), less tumor lysis syndrome (P = .030), higher cholesterol (P = .013), and lower aspartate aminotransferase (P = .002) and alanine aminotransferase levels (P = .033) and more commonly used angiotensin receptor blockers (27% vs 15%, P = .007), colchicines (16% vs 5%, P = .010), or statins (19% vs 8%, P = .002) than those who did not. In multiple logistic regression analysis, the use of colchicines (odds ratio, 3.11; 95% confidence interval, 1.28-7.58; P = .012) and statins (2.10; 1.03-4.25; P = .041) was an independent risk factor predicting adverse events in allopurinol users. In conclusion, patients who use colchicine or statins are at significant risk for developing allopurinol-induced adverse events. 23613012 HDL Cholesterol Subfractions and the Effect of Testosterone Replacement in Hypogonadism. Metabolic disorders and cardiovascular events are increased in hypogonadism. Serum HDL composition is a better cardiovascular predictor than the HDL counts. However, there is no information about the HDL subfractions in patients with hypogonadism. We designed a prospective study to investigate the HDL subfractions in treatment naïve subjects with hypogonadism and the effects of 2 different testosterone replacement regimens on the HDL subfractions. Seventy young male patients with congenital hypogonadotropic hypogonadism (CHH) and 70 age and BMI-matched healthy males were enrolled in the present study. The patients were assigned to receive intramuscular injections of testosterone esters 250 mg every 3 weeks and transdermal testosterone applications 50 mg daily. Biochemical investigations including HDL subfractions and insulin resistance were done. Patients with CHH had higher levels of insulin, HOMA-IR, WC, triglyceride, and diastolic blood pressure. Although, the HDL cholesterol concentrations were similar in both groups, hypogonadal patients had lower HDL2 and higher HDL3 levels. The total testosterone levels were independent determinants of the HDL2 subfractions. During the follow-up, a significant increase in the BMI and WC values and a significant decrease in the levels of total cholesterol, HDL cholesterol, and HDL3 were observed. No difference was present between the 2 treatment arms. These results show that patients with hypogonadism have unfavorable HDL compositions in addition to the other dysmetabolic features. However, testosterone replacement for about six months neither improves the metabolic problems nor the HDL composition. Mechanistic studies are warranted to better understand the cardiovascular effects of unfavorable HDL compositions in hypogonadism. 23194544 Determination of acrylamide in local and commercial cultivar of potatoes from biological farm. This paper reports the results of a preliminary study on the characterization of parameters influencing formation of acrylamide in fried potatoes, from biological cultivation. The formation of acrylamide was investigated in relation to frying in biological extra virgin olive oil and commercial seed oil. Three different cultivars (Rossa di Colfiorito, Quarantina bianca genovese and Kennebec) were chosen. Asparagine, glucose, fructose and sucrose concentrations were determined in potato slice before frying, while acrylamide content was analysed by LC-ESI-MS/MS in the slices fried in seed and extra virgin olive oil. The Kennebec cultivar showed differences in its potential for acrylamide formation, which was primarily related to its relatively high asparagine and reducing sugars contents, respect the other local cultivars (particulary Quarantina). Values of acrylamide below detection limit (LOD) were found in Quarantina bianca genovese cultivar samples fried in extra virgin olive oil and peanuts seed oil and higher in peanuts seed oil fried potatoes of Kennebec cultivar. 23001627 Levothyroxine replacement therapy with vitamin E supplementation prevents oxidative stress and cognitive deficit in experimental hypothyroidism. Hypothyroidism has a variety of adverse effects on cognitive function. The treatment of levothyroxine alone cannot restore cognitive defects of hypothyroid patients. Antioxidant vitamin E supplementation could be useful in disturbances which are associated with oxidative stress and could effectively slow the progression of Alzheimer disease. Thus, the purpose of this study was to evaluate oxidative stress status of the serum and hippocampus in hypothyroidism and to examine the effects of levothyroxine replacement therapy with vitamin E supplementation on cognitive deficit. Sprague-Dawley rats were randomly divided into five groups: control group, PTU group, PTU + Vit E group, PTU + L-T4 group, and PTU + L-T4 + Vit E group. Serum and hippocampus malondialdehyde (MDA) levels were determined using the thiobarbituric-acid reactive substances method. Serum and hippocampus superoxide dismutase (SOD) levels were determined by measuring its ability to inhibit the photoreduction of nitroblue tetrazolium. Learning and memory was assessed by Morris water maze test. In the present study, we found that the rats of PTU + Vit E group spent less time to find the platform on days 2, 3, 4, and 5 than the PTU group. Moreover, the rats of PTU + L-T4 + Vit E group spent less time to find the platform on days 4 and 5 than the PTU + L-T4 group. The time spent in the target quadrants was measured in the probe test and no difference was observed in all groups. Oxidative damage has been observed in the serum and hippocampus of hypothyroidism rat. SOD levels of serum and hippocampus tissue were significantly increased and MDA levels were significantly decreased in the PTU + Vit E and PTU + L-T4 + Vit E groups than the PTU and PTU + L-T4 groups. Therefore, these findings indicate that levothyroxine replacement therapy with vitamin E supplementation may ameliorate cognitive deficit in PTU-induced hypothyroidism through the decrease of oxidative stress status. 23609963 LIVER X RECEPTORS, NERVOUS SYSTEM AND LIPID METABOLISM. Lipids in the nervous system are represented by cholesterol and phospholipids as constituents of cell membranes and, in particular, of myelin. Therefore, lipids are finely regulated to guarantee physiological functions. In the central nervous system, cholesterol is locally synthesized due to the presence of the blood brain barrier. In the peripheral nervous system cholesterol is either uptaken by lipoproteins and/or produced by de novo biosynthesis. Defects in lipid homeostasis in these tissues lead to structural and functional changes that often result in different pathological conditions depending on the affected pathways (i.e. cholesterol biosynthesis, cholesterol efflux, fatty acid biosynthesis etc.). Alterations in cholesterol metabolism in the central nervous system are linked to several disorders such as Alzheimer's disease, Huntington disease, Parkinson disease, Multiple Sclerosis, Smith-Lemli-Opitz syndrome, Niemann-Pick type C disease, and glioblastoma. In the peripheral nervous system changes in lipid metabolism are associated with the development of peripheral neuropathy that may be caused by metabolic disorders, injuries, therapeutics and autoimmune diseases. Transcription factors, such as the Liver X receptors (LXRs), regulate both cholesterol and fatty acid metabolism in several tissues including the nervous system. In the last few years several studies elucidated the biology of LXRs in nervous system due to the availability of knock-out mice and the development of synthetic ligands. Here, we review a survey of the literature focused on central and peripheral nervous system and in physiological and pathological settings with particular attention on the roles played by LXRs in both districts. 23525092 A 3D-RISM-SCF method with dual solvent boxes for a highly polarized system: application to 1,6-anhydrosugar formation reaction of phenyl α- and β-d-glucosides under basic conditions. One of the difficulties in application of the usual reference interaction site model self-consistent field (RISM-SCF) method to a highly polarized and bulky system arises from the approximate evaluation of electrostatic potential (ESP) with pure point charges. To improve this ESP evaluation, the ESP near a solute is directly calculated with a solute electronic wavefunction, that distant from a solute is approximately calculated with solute point charges, and they are connected with a switching function. To evaluate the fine solvation structure near the solute by incorporating the long-range solute-solvent Coulombic interaction with low computational cost, we introduced the dual solvent box protocol; one small box with the fine spacing is employed for the first and the second solvation shells and the other large box with the normal spacing is employed for long-range solute-solvent interaction. The levoglucosan formation from phenyl α- and β-d-glucosides under basic conditions is successfully inspected by this 3D-RISM-SCF method at the MP2 and SCS-MP2 levels, though the 1D-RISM-SCF could not be applied to this reaction due to the presence of highly polarized and bulky species. This 3D-RISM-SCF calculation reproduces the experimentally reported higher reactivity of the β-anomer. The 3D-RISM-SCF-calculated activation free energy for the β-anomer is closer to the experimental value than the PCM-calculated one. Interestingly, the solvation effect increases the difference in reactivity between these two anomers. The reason is successfully elucidated with 3D-RISM-SCF-calculated microscopic solvation structure and decomposition analysis of solute-solvent interaction. 23401066 Genetic loci that control the loss and regain of trabecular bone during unloading and reambulation. Changes in trabecular morphology during un- and re-loading are marked by large variations between individuals, implicating a strong genetic influence on the magnitude of the response. Here, we subjected more than 350 second-generation (BALBxC3H) 4mo old adult female mice to 3wk of hindlimb unloading followed by 3wk of reambulation to identify the quantitative trait loci (QTLs) that define an individual's propensity to either lose trabecular bone when weightbearing is removed or to gain trabecular bone when weightbearing is reintroduced. Longitudinal in vivo µCT scans demonstrated that individual mice lost between 15% and 71% in trabecular BV/TV in the distal femur during unloading (average: -43%). Changes in trabecular BV/TV during the 3wk reambulation period ranged from a continuation of bone loss (-18%) to large additions (56%) of tissue (average: +10%). During unloading, six QTLs accounted for 21% of the total variability in changes in BV/TV while one QTL accounted for 6% of the variability in changes in BV/TV during reambulation. QTLs were also identified for changes in trabecular architecture. Most of the QTLs defining morphologic changes during unloading or reambulation did not overlap with those QTLs identified at baseline, suggesting that these QTLs harbor genes that are specific for sensing changes in the levels of weightbearing. The lack of overlap in QTLs between unloading and reambulation also emphasizes that the genes modulating the trabecular response to unloading are distinct from those regulating tissue recovery during reloading. The identified QTLs contain the regulatory genes underlying the strong genetic regulation of trabecular bone's sensitivity to weightbearing and may help to identify individuals that are most susceptible to unloading induced bone loss and/or the least capable of recovering. © 2013 American Society for Bone and Mineral Research. 23400925 Bioaccumulation and biomagnification of mercury and selenium in the sarasota bay ecosystem. The bioaccumulation and biomagnification of Hg and Se were investigated in Sarasota Bay, Florida, USA, to characterize the Hg exposure risks to wild bottlenose dolphins in the bay. Concentrations of total mercury (THg), monomethylmercury (MMHg), and total selenium (TSe) were monitored in the bay, the latter of which might reduce Hg toxicity. The food web structure and dolphins' trophic level-specific consumption rates were evaluated using stable isotope ratios of carbon (δ(13) C) and nitrogen (δ(15) N). Regressions developed for Hg biomagnification in the food chain were log10 CTHg (nanograms per gram) = 0.27 × δ(15) N (‰) - 0.42, R(2)  = 0.87, for THg and log10 CMMHg  = 0.33 × δ(15) N (‰) - 1.0, R(2)  = 0.93, for MMHg. Unlike Hg, nearly constant TSe concentrations were observed at 248 ± 179 ng g(-1) in the food web, and the TSe-to-THg molar ratio was predicted by log10 (CTSe /CTHg ) = -0.10 × δ(15) N (‰) + 2.8, R(2)  = 0.60. The THg-uptake rates of Sarasota bottlenose dolphins are estimated to vary between 2.1 and 4.9 µg kg(-1) d(-1) ; however, the estimated TSe-uptake rates (15.1 µg kg(-1) d(-1) ) were higher than those for THg, and the Hg-exposure risks of the Sarasota Bay resident bottlenose dolphins are considered to be low. Approaches employed in the present study can be extended to other environments to characterize Hg contamination in aquatic systems and Hg exposure risks in top predators. Environ. Toxicol. Chem. 2013;32:1143-1152. © 2013 SETAC. 23609145 Inhibition of the Proton-Coupled Folate Transporter (PCFT-SLC46A1) by Bicarbonate and Other Anions. The proton-coupled folate transporter (PCFT) plays a key role in intestinal folate absorption and loss-of-function mutations in the gene encoding this transporter are the molecular basis for hereditary folate malabsorption. Using a stable transfectant with high expression of PCFT, physiological levels of bicarbonate produced potent and rapidly reversible inhibition of PCFT-mediated transport at neutral pH. Bisulfite and nitrite also inhibited PCFT function at neutral pH, whereas sulfate, nitrate and phosphate had no impact at all. At weakly acidic pH (6.5), bisulfite and nitrite exhibited much stronger inhibition of PCFT-mediated transport while sulfate and nitrate remained non-inhibitory. Inhibition by bisulfite and nitrite at pH 6.5 was associated with a marked decrease in the influx Vmax and collapse of the transmembrane proton gradient attributed to the diffusion of the protonated forms into these cells. Monocarboxylates such as pyruvate and acetate also collapsed the pH gradient and were also inhibitory, while citrate and glycine neither altered the proton gradient nor inhibited PCFT-mediated transport. These observations add another dimension to the unfavorable pH environment for PCFT function in systemic tissues, the presence of high concentrations of bicarbonate. 23411223 Geographical origin identification of Romanian wines by ICP-MS elemental analysis. Trace elemental analysis, besides its ability to determine stable isotopes ratios, represents a possible complementary tool useful to differentiate wines based on their regional origins. Wines and their provenance soils from two major wine producing areas in Southeast Romania ('Valea Calugareasca' and 'Murfatlar'), and also wine from the region of Moldova (Eastern Romania) were analyzed by inductively coupled plasma mass spectrometry (ICP-MS), and statistical data of elemental composition was used to differentiate these wines according to grape type and geographical origin. Moreover, this study gathers relevant elemental trace composition of wines produced in most important Romanian vineyards, thus offering a useful wine differentiation tool by their production district. The results show that the differentiation of Romanian wines according to their provenance is based on the following main elements: Ni, Ag, Cr, Sr, Zn, and Cu for Valea Calugareasca, Rb, Zn, and Mn for Murfatlar, and Pb, Co, and V for Moldova. 23567038 Internalization of Bacillus intermedius ribonuclease (BINASE) induces human alveolar adenocarcinoma cell death. Ribonuclease (RNase) treatment represents a novel mechanism based approach to anticancer therapy as an alternative to the DNA damaging drugs commonly used in clinical practice. Apart from their ribonucleolytic activity, cytotoxic effects have attracted a considerable attention to RNases because of their potential as selective agents for treatment of certain malignancies. Among these enzymes, Binase, an RNase from Bacillus intermedius, has shown promising results. Here, we have found that binase selectively attacked human A549 alveolar adenocarcinoma cells to trigger an apoptotic response, whereas normal lung epithelial cells LEK were not affected by the ribonuclease. The tumor transformation led to the modification of certain cellular characteristics causing cell sensitivity to binase. Although a general mode for RNases cytotoxicity includes their penetration into the cell, translocation to the cytosol and degradation of ribonucleic acid, many aspects of this process have not been fully elucidated. Our data revealed the following time-dependent changes induced by binase in A549 cells: (a) fast permanent internalization of the enzyme during the first hours of treatment; (b) temporary increase in cellular permeability for macromolecules during the 4-6 h of treatment; (c) apoptotic alterations in population after 24 h and (d) DNA fragmentation and cell death after 72 h of treatment with binase. Elucidation of these molecular strategies used by this promising toxin provides us essential information for the development of new anticancer drugs. 23019137 Reversal of dopamine D2 agonist-induced inhibition of ventral tegmental area neurons by Gq-linked neurotransmitters is dependent on protein kinase C, G protein-coupled receptor kinase, and dynamin. Dopaminergic neurons of the ventral tegmental area are important components of brain pathways related to addiction. Prolonged exposure of these neurons to moderate concentrations of dopamine (DA) decreases their sensitivity to inhibition by DA, a process called DA-inhibition reversal (DIR). DIR is mediated by phospholipase C and conventional subtype of protein kinase C (cPKC) through concurrent stimulation of D2 and D1-like DA receptors, or by D2 stimulation concurrent with activation of 5-HT(2) or neurotensin receptors. In the present study, we further characterized this phenomenon by use of extracellular recordings in brain slices to examine whether DIR is linked to G protein-coupled receptor kinase-2 (GRK2) or dynamin by assessing DIR in the presence of antagonists of these enzymes. DIR was blocked by β-ARK1 inhibitor, which inhibits GRK2, and by dynasore, which blocks dynamin. Reversal of inhibition by D2 agonist quinpirole was produced by serotonin (50 µM) and by neurotensin (5-10 nM). Serotonin-induced or neurotensin-induced reversal was blocked by β-ARK1 inhibitor, dynasore, or cPKC antagonist 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4c]carbazole-12-propanenitrile (Gö6976). This further characterization of DIR indicates that cPKC, GRK2, and dynamin play important roles in the desensitization of D2 receptors. As drugs of abuse produce persistent increases in DA concentration in the ventral tegmental area, reduction of D2 receptor sensitivity as a result of drug abuse may be a critical factor in the processes of addiction. 23220293 Brain monoamines and antidepressant-like responses in MRL/MpJ versus C57BL/6J mice. The MRL/MpJ mouse demonstrates enhanced wound healing and tissue regeneration and increased neurotrophic mobilization to chronic antidepressant drug treatments. This study compared brain monoamine systems between MRL/MpJ and C57BL/6J mice as a potential basis for strain differences after chronic antidepressant treatment. MRL/MpJ mice had significantly higher tissue levels of serotonin and dopamine in multiple brain regions. Microdialysis studies demonstrated that baseline levels of extracellular serotonin did not differ between strains. However, acute administration of the selective serotonin reuptake inhibitor citalopram produced an increase in extracellular serotonin in the ventral hippocampus of MRL/MpJ mice that was twice as large as achieved in C57BL/6J mice. The greater effects in MRL/MpJ mice on 5-HT levels were not maintained after local perfusion of citalopram, suggesting that mechanisms outside of the hippocampus were responsible for the greater effect of citalopram after systemic injection. The density of serotonin and norepinephrine transporters in the hippocampus was significantly higher in MRL/MpJ mice. In addition, the expression of 5-HT(1A) mRNA was lower in the hippocampus, 5-HT(1B) mRNA was higher in the hippocampus and brainstem and SERT mRNA was higher in the brain stem of MRL/MpJ mice. The exaggerated neurotransmitter release in MRL/MpJ mice was accompanied by reduced baseline immobility in the tail suspension test and a greater reduction of immobility produced by citalopram or the tricyclic antidepressant desipramine. These data suggest that differences in the response to acute and chronic antidepressant treatments between the two strains could be attributed to differences in serotonin or catecholamine transmission. 23432708 Ab initio MRCI+Q study on low-lying states of CS including spin-orbit coupling. Carbon monosulfide (CS), which plays an important role in a variety of research fields, has long received considerable interest. Due to its transient nature and large state density, the electronic states of CS have not been well understood, especially the interactions between different states. In this paper, we performed a detail ab initio study on the low-lying electronic states of CS by means of the internally contracted multireference configuration interaction method (including Davidson correction) with scalar relativistic correction using the Douglas-Kroll-Hess Hamiltonian. We focused on the spin-orbit coupling of the states via the state interaction method with the full Breit-Pauli Hamiltonian. The potential energy curves (PECs) of 18 Λ-S states correlated with the lowest dissociation limit of the CS molecule were calculated, as well as those of 50 Ω states generated from the Λ-S states. The spectroscopic constants of the bound states were obtained, which are in good agreement with previous available experimental and theoretical results. The state perturbations of the a(3)Π and A(1)Π states with other low-lying electronic states are discussed in detail, based on the calculated spin-orbit matrix as well as the PECs of the Ω states. Avoided crossing in the states of CS was indicated when spin-orbit coupling was taken into account. Finally, the allowed transition dipole moments as well as the lifetimes of the five lowest vibrational states of the A(1)Π1, A'(1)Σ(+)0(+) and a(3)Πi states were obtained. 23530552 Maternal adiposity as an independent risk factor for pre-eclampsia: a meta-analysis of prospective cohort studies. Studies investigating the association between maternal adiposity and risk of pre-eclampsia showed contradictory results. Therefore, we performed a meta-analysis of prospective cohort studies to estimate the effect of maternal adiposity on pre-eclampsia. We reviewed 1,286 abstracts and finally included 29 prospective cohort studies with 1,980,761 participants and 67,075 pre-eclampsia events. We pooled data with a random-effects model, and obtained risk estimates for five predetermined bodyweight groups: low, normal-weight (reference), overweight, obese and severely obese. In the cohort studies that unadjusted for pre-eclampsia risk factors, the pooled unadjusted relative risks (RR) with 95% confidence intervals (95%CI) for pre-eclampsia of overweight, obese and severely obese women were 1.58 (95% CI 1.44-1.72, P < 0.001), 2.68 (95% CI 2.39-3.01, P < 0.001) and 3.12 (95% CI 2.24-4.36, P < 0.001), respectively. In those cohorts that adjusted for pre-eclampsia risk factors, the pooled unadjusted RRs for pre-eclampsia of overweight, obese and severely obese women were 1.70 (95% CI 1.60-1.81, P < 0.001), 2.93 (95% CI 2.58-3.33, P < 0.001) and 4.14 (95% CI 3.61-4.75, P < 0.001), respectively. Sensitivity analysis showed maternal adiposity was associated with increased risk of pre-eclampsia in both nulliparous and multiparas women. In conclusion, overweight or obese pregnant women have a substantially increased risk of pre-eclampsia, and maternal adiposity is an independent risk factor of pre-eclampsia. 23642029 Semi-synthesis of radiolabeled amino acid and lipid brevetoxin metabolites and their blood elimination kinetics in C57BL/6 mice. Brevetoxin B (BTX-B), produced by dinoflagellates of the species Karenia, is a highly reactive molecule, due in part to an α,β-unsaturated aldehyde group at the terminal side chain, leading to the production of metabolites by reduction, oxidation, and conjugation. We have investigated in mice the blood elimination of three common bioactive brevetoxin metabolites found in shellfish, which have been semi-synthesized from BTX-B in radioactive forms. BTX-B was reduced at C42 to yield [3H] dihydro-BTX-B. [3H] S-desoxy-BTX-B2 (cysteine brevetoxin B) was semi-synthesized from BTX-B by conjugation of cysteine at the C50 olefinic group, then [3H] radiolabeled by C42 aldehyde reduction. [14C] N-palmitoyl-S-desoxy-BTX-B2 was prepared using S-desoxy-BTX-B2 as the starting material with addition of the [14C] radiolabeled fatty acid via the cysteine-amide linkage. The elimination of intravenously administered [3H] S-desoxy-BTX-B2, [14C] N-palmitoyl-S-desoxy-BTX-B2, or [3H] dihydro-BTX-B was measured in blood collected from C57BL/6 mice over a 48 hour period. Each brevetoxin metabolite tested exhibited biexponential elimination kinetics and fit a two-compartment model of elimination that was applied to generate toxicokinetic parameters. The rate of transfer between the central compartment (i.e., blood) and the peripheral compartment (e.g., tissue) for each brevetoxin differed substantially, with dihydro-BTX-B exchanging rapidly with the peripheral compartment, and S-desoxy-BTX-B2 eliminating rapidly from the central compartment and N-palmitoyl-S-desoxy-BTX-B2 eliminating slowly from the central compartment. Toxicokinetic parameters were analyzed in the context of the unique structure of each brevetoxin metabolite resulting from a reduction, amino acid conjugation, or fatty acid addition to BTX-B. 23401211 Inter- and intraspecific variation in mercury bioaccumulation by snakes inhabiting a contaminated river floodplain. Although mercury (Hg) is a well-studied contaminant, knowledge about Hg accumulation in snakes is limited. The authors evaluated Hg bioaccumulation within and among four snake species (northern watersnakes, Nerodia sipedon; queen snakes, Regina septemvittata; common garter snakes, Thamnophis sirtalis; and rat snakes, Elaphe obsoleta [Pantherophis alleghaniensis]) from a contaminated site on the South River (Waynesboro, VA, USA) and two nearby reference sites. Total Hg (THg) concentrations in northern watersnake tail tissue at the contaminated site ranged from 2.25 to 13.84 mg/kg dry weight (mean: 4.85 ± 0.29), or 11 to 19 times higher than reference sites. Blood THg concentrations (0.03-7.04 mg/kg wet wt; mean: 2.24 ± 0.42) were strongly correlated with tail concentrations and were the highest yet reported in a snake species. Within watersnakes, nitrogen stable isotope values indicated ontogenetic trophic shifts that correlated with THg bioaccumulation, suggesting that diet plays a substantial role in Hg exposure. Female watersnakes had higher mean THg concentrations (5.67 ± 0.46 mg/kg) than males (4.93 ± 0.49 mg/kg), but no significant differences between sexes were observed after correcting for body size. Interspecific comparisons identified differences in THg concentrations among snake species, with more aquatic species (watersnakes and queen snakes) accumulating higher mean concentrations (5.60 ± 0.40 and 4.59 ± 0.38 mg/kg in tail tissue, respectively) than the more terrestrial species, garter snakes and rat snakes (1.28 ± 0.32 and 0.26 ± 0.09 mg/kg, respectively). The results of the present study warrant further investigation of potential adverse effects and will aid in prioritizing conservation efforts. Environ. Toxicol. Chem. 2013;32:1178-1186. © 2013 SETAC. 23153512 Proposed model for in vitro interaction between fenitrothion and DNA, by using competitive fluorescence, (31)P NMR, (1)H NMR, FT-IR, CD and molecular modeling. In this work we proposed a model for in vitro interaction of fenitrothion (FEN) with calf thymus-DNA by combination of multispectroscopic and two dimensional molecular modeling (ONIOM) methods. The circular dichroism results showed that FEN changes the conformation of B-DNA and caused some changes to C-DNA form. The FT-IR results confirmed a partial intercalation between FEN and edges of all base pairs. The competitive fluorescence, using methylene blue as fluorescence probe, in the presence of increasing amounts of FEN, revealed that FEN is able to release the non-intercalated methylene blue from the DNA. The weak chemical shift and peak broadening of (1)H NMR spectrum of FEN in the presence of DNA confirmed a non-intercalation mode. The (31)P NMR showed that FEN interacts more with DNA via its -NO2 moiety. The ONIOM, based on the hybridization of QM/MM (DFT, 6.31++G (d,p)/UFF) methodology, was also performed by Gaussian 2003 package. The results revealed that the interaction is base sequence dependent, and FEN interacts more with AT base sequences. 23423972 Absorption, distribution, and biotransformation of hexahydro-1,3,5-trinitro-1,3,5-triazine in B6C3F1 mice (Mus musculus). Absorption, distribution, and biotransformation are 3 critical aspects affecting toxicant action in animals. In the present study, B6C3F1 mice (Mus musculus) were exposed for 28 d to contaminated feed that contained 1 of 5 different hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) concentrations: 0 mg/kg, 0.5 mg/kg, 5 mg/kg, 50 mg/kg, and 500 mg/kg. The authors quantified RDX and its reductive transformation products hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine (DNX), and hexahydro-1,3,5-trinitroso-1,3,5-triazine (TNX) in the stomach, intestine, plasma, liver, and brain of these mice. Average RDX concentrations followed a dose-dependent pattern for all matrices tested. No controls had concentrations above limits of detection. Average RDX concentrations in tissues of exposed mice ranged from 11.1 ng/mL to 182 ng/mL, 25.6 ng/g to 3319 ng/g, 123 ng/g to 233 ng/g, 144 ng/g to 35 900 ng/g, and 51.1 ng/g to 2697 ng/g in the plasma, brain, liver, stomach, and intestine, respectively. A considerable amount of RDX was present in the brain, especially in the highest-exposure group. This is consistent with the widely observed central nervous system effects caused by γ-aminobutyric acid inhibition associated with RDX exposure. N-nitroso metabolites of RDX were also present in tested tissues in a dose-dependent pattern. Average MNX concentrations in the stomachs of mice exposed to RDX ranged from nondetectable in control exposures to 490 ng/g in the highest-exposure groups. In the brain, MNX accumulated at a maximum average concentration of 165.1 ng/g, suggesting the potential formation of MNX from RDX within the brain. At higher exposures, DNX and TNX were present in the stomach, plasma, and brain of mice. The presence of RDX metabolites at notable amounts in different tissues suggests that RDX can transform into its N-nitroso metabolites in vivo by an undefined mechanism. Environ Toxicol Chem 2013;32:1295-1303. © 2013 SETAC. 23450151 Highly luminescent water-soluble quaternary Zn-Ag-In-S quantum dots for tumor cell-targeted imaging. Exploring the synthesis and biomedical applications of biocompatible quantum dots (QDs) is currently one of the fastest growing fields of nanotechnology. Hence, in this work, we present a facile approach to produce water-soluble (cadmium-free) quaternary Zn-Ag-In-S (ZAIS) QDs. Their efficient photoluminescence (PL) emissions can be tuned widely in the range of 525-625 nm by controlling the size and composition of the QDs with the PL quantum yields (QYs) of 15-30%. These highly luminescent ZAIS QDs are less toxic due to the absence of highly toxic cadmium, and can be versatilely modified by a DHLA-PEG-based ligand. Importantly, after being modified by tumor cell-specific targeting ligands (e.g., folate and RGD peptide), the PEGylated quaternary QDs show potential applications in tumor cell imaging as a promising alternative for Cd-based QDs. 22841916 Chronic caffeine prevents changes in inhibitory avoidance memory and hippocampal BDNF immunocontent in middle-aged rats. Beneficial effects of caffeine on memory processes have been observed in animal models relevant to neurodegenerative diseases and aging, although the underlying mechanisms remain unknown. Because brain-derived neurotrophic factor (BDNF) is associated with memory formation and BDNF's actions are modulated by adenosine receptors, the molecular targets for the psychostimulant actions of caffeine, we here compare the effects of chronic caffeine (1 mg/mL drinking solution for 30 days) on short- and long term memory and on levels of hippocampal proBDNF, mature BDNF, TrkB and CREB in young (3 month old) and middle-aged (12 month old) rats. Caffeine treatment substantially reduced i) age-related impairments in the two types of memory in an inhibitory avoidance paradigm, and ii) parallel increases in hippocampal BDNF levels. In addition, chronic caffeine increased proBDNF and CREB concentrations, and decreased TrkB levels, in hippocampus regardless of age. These data provide new evidence in favor of the hypothesis that modifications in BDNF and related proteins in the hippocampus contribute to the pro-cognitive effects of caffeine on age-associated losses in memory encoding. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23297712 Composition and evaluation of the anti-inflammatory and anticancer activities of the essential oil from Annona sylvatica A. St.-Hil. The essential oil from the leaves of Annona sylvatica (EOAS) was extracted by hydrodistillation, and the analysis was performed by gas chromatography-mass spectrometry. The main compounds identified in the EOAS were sesquiterpenes, such as hinesol, z-caryophyllene, β-maaliene, γ-gurjunene, silphiperfol-5-en-3-ol, ledol, cubecol-1-epi, and muurola-3,5-diene. Oral administration of the EOAS (20 and 200 mg/kg) and subcutaneous injection of dexamethasone (0.5 mg/kg, reference drug) significantly inhibited carrageenan- and complete Freund's adjuvant-induced mouse paw edema. The anticancer activity the EOAS showed growth inhibitory activity on all cell lines when administered in a high concentration. The EOAS inhibited the growth of human cancer cell lines with GI(50) values in the range of 36.04-45.37 μg/mL on all of the cell lines tested. This work describes for the first time the anti-inflammatory and anticancer effects of the essential oil of A. sylvatica and its composition. Considering that drugs currently available for the treatment of inflammatory and cancer conditions show undesirable side-effects, the present results may have clinical relevance and open new possibilities for the development of novel anti-inflammatory and anticancer drugs. 23253127 Putative impact of RNA editing on drug discovery. Virtually all organisms use RNA editing as a powerful post-transcriptional mechanism to recode genomic information and to increase functional protein diversity. The enzymatic editing of pre-mRNA by ADARs and CDARs is known to change the functional properties of neuronal receptors and ion channels regulating cellular excitability. However, RNA editing is also an important mechanism for genes expressed outside the brain. The fact that RNA editing breaks the 'one gene encodes one protein' hypothesis is daunting for scientists and a probable drawback for drug development, as scientists might search for drugs targeting the 'wrong' protein. This possible difficulty for drug discovery and development became more evident from recent publications, describing that RNA editing events have profound impact on the pharmacology of some common drug targets. These recent studies highlight that RNA editing can cause massive discrepancies between the in vitro and in vivo pharmacology. Here, we review the putative impact of RNA editing on drug discovery, as RNA editing has to be considered before using high-throughput screens, rational drug design or choosing the right model organism for target validation. 23122165 Occurrence and sensory perception of Z-2-(β-d-glucopyranosyloxy)-3-phenylpropenoic acid in rooibos (Aspalathus linearis). Z-2-(β-d-glucopyranosyloxy)-3-phenylpropenoic acid (PPAG), a compound postulated to contribute to the taste and mouthfeel of fermented rooibos tea (Aspalathus linearis), was isolated from unfermented rooibos plant material. Its structure was unequivocally confirmed by LC-MS, -MS(2), FT-IR and NMR of the underivatised natural product, and optical rotation measurements of the hydrolysed sugar moiety. A similar compound, postulated to be E-2-(β-d-glucopyranosyloxy)-3-phenylpropenoic acid, was also detected. Analysis of the leaves of a large number of rooibos plants (n=54), sampled at commercial plantations, showed that PPAG is not ubiquitously present in detectable quantities in the leaves of different plants. This leads to large variation in the fermented plant material, infusions and food-grade extracts. PPAG was shown to have a slightly bitter to astringent taste and a detection threshold of 0.4 mg/l in water. 23578652 Comparison of antioxidant activity of hydroethanolic fresh and aged garlic extracts and their effects on cerebral ischemia. Antioxidant properties and protective effect of aged garlic extract (AGE) and of 20% hydroethanolic fresh extracts from garlic clove (GCE) and skin (GSE) on cerebral ischemia were evaluated by administering extracts at the beginning of reperfusion in a rat model of stroke. All three extracts scavenged superoxide anion, peroxynitrite anion, and peroxyl radicals, but with different efficiencies; furthermore, GCE and GSE scavenged hydroxyl radicals and GSE scavenged singlet oxygen. These extracts significantly prevented reduction of neuronal nuclear antigen in the infarcted area, although no improvement in neurological function was observed. Importantly, GCE and GSE contained S-allylcystein, a compound associated with AGE's neuroprotective effect against damage induced by cerebral ischemia. Extracts decreased mRNA expression of NR1- and NR2B-NMDA-receptor subunits and prevented ischemia-induced reduction in mitochondrial potential and in ATP synthesis. These results indicate that antioxidants present in garlic extracts may regulate ROS concentrations during ischemia, favour pro-survival pathways, and attenuate mitochondrial dysfunction. 23179966 Serotonin-glutamate and serotonin-dopamine reciprocal interactions as putative molecular targets for novel antipsychotic treatments: from receptor heterodimers to postsynaptic scaffolding and effector proteins. The physical and functional interactions between serotonin-glutamate and serotonin-dopamine signaling have been suggested to be involved in psychosis pathophysiology and are supposed to be relevant for antipsychotic treatment. Type II metabotropic glutamate receptors (mGluRs) and serotonin 5-HT(2A) receptors have been reported to form heterodimers that modulate G-protein-mediated intracellular signaling differentially compared to mGluR2 and 5-HT(2A) homomers. Additionally, direct evidence has been provided that D(2) and 5-HT(2A) receptors form physical heterocomplexes which exert a functional cross-talk, as demonstrated by studies on hallucinogen-induced signaling. Moving from receptors to postsynaptic density (PSD) scenario, the scaffolding protein PSD-95 is known to interact with N-methyl-D-aspartate (NMDA), D(2) and 5-HT(2) receptors, regulating their activation state. Homer1a, the inducible member of the Homer family of PSD proteins that is implicated in glutamatergic signal transduction, is induced in striatum by antipsychotics with high dopamine receptor affinity and in the cortex by antipsychotics with mixed serotonergic/dopaminergic profile. Signaling molecules, such as Akt and glycogen-synthase-kinase-3 (GSK-3), could be involved in the mechanism of action of antipsychotics, targeting dopamine, serotonin, and glutamate neurotransmission. Altogether, these proteins stand at the crossroad of glutamate-dopamine-serotonin signaling pathways and may be considered as valuable molecular targets for current and new antipsychotics. The aim of this review is to provide a critical appraisal on serotonin-glutamate and serotonin-dopamine interplay to support the idea that next generation schizophrenia pharmacotherapy should not exclusively rely on receptor targeting strategies. 23154301 Sensory gating, Cannabinoids and Schizophrenia. Sensory gating, a mandatory process in early information processing, has been found to be defective in neuropsychiatric diseases such as schizophrenia. Understanding the neurobiology of sensory gating may provide insight into unravelling the neurobiology of information processing and to yet unanswered queries on the pathophysiology of disabling neuropsychiatric diseases. The endocannabinoid system has been linked to the pathophysiology of schizophrenia. Furthermore, cannabinoids disrupt sensory gating in animals and humans which supports the hypothesis that the disruption of sensory gating by alterations in the endocannabinoid system is a significant factor in the etiology of schizophrenia. Based on the above hypothesis this article reviews the sensory gating process in relation to the auditory conditioning-test paradigm with an emphasis on its association with the endocannabinoid system and schizophrenia. 23289872 Engagement of CF3 group in N-H···F-C hydrogen bond in the solution state: NMR spectroscopy and MD simulation studies. Unambiguous evidence for the engagement of CF(3) group in N-H···F-C hydrogen bond in a low polarity solvent, the first observation of its kind, is reported. The presence of such weak molecular interactions in the solution state is convincingly established by one and two-dimensional (1)H, (19)F, and natural abundant (15)N NMR spectroscopic studies. The strong and direct evidence is derived by the observation of through-space couplings, such as, (1h)J(FH), (1h)J(FN), and (2h)J(FF), where the spin polarization is transmitted through hydrogen bond. In an interesting example of a molecule containing two CF(3) groups getting simultaneously involved in hydrogen bond, where hydrogen bond mediated couplings are not reflected in the NMR spectrum, (19)F-(19)F NOESY experiment yielded confirmatory evidence. Significant deviations in the strengths of (1)J(NH), variable temperature, and the solvent induced perturbations yielded additional support. The NMR results are corroborated by both DFT calculations and MD simulations, where the quantitative information on different ways of involvement of fluorine in two and three centered hydrogen bonds, their percentage of occurrences, and geometries have been obtained. The hydrogen bond interaction energies have also been calculated. 23318905 Identification of benzofuran-3-yl(phenyl)methanones as novel SIRT1 inhibitors: binding mode, inhibitory mechanism and biological action. SIRT1 is a NAD(+)-dependent deacetylase. Here we described new SIRT1 inhibitors with the scaffold of benzofuran-3-yl(phenyl)methanone. The inhibitors were predicted to bind in C-pocket of SIRT1, forming hydrophobic interactions with Phe273, Phe312 and Ile347. Introducing hydroxyl to meta position of phenyl may form H-bond with Asn346. Indeed, (2,5-dihydroxyphenyl)(5-hydroxy-1-benzofuran-3-yl)methanone (16), an analogue with hydroxyls at ortho and meta positions, showed greater inhibition. The binding mode was validated by structural modifications and kinetic studies. Since C-pocket is the site where the nicotinamide moiety of NAD(+) binds and the hydrolysis takes place, binding of 16 in C-pocket would block the transformation of NAD(+) to productive conformation and hence inhibit the deacetylase activity. Consistently, 16 inhibited SIRT1 through up-regulating p53 acetylation on cellular level. 23316021 Gadolinium- and manganite-based contrast agents with fluorescent probes for both magnetic resonance and fluorescence imaging of pancreatic islets: a comparative study. Three magnetic resonance (MR)/fluorescence imaging probes were tested for visualization, cellular distribution, and survival of labeled pancreatic islets in vitro and following transplantation. As T(1) contrast agents (CAs), gadolinium(III) complexes linked to β-cyclodextrin (Gd-F-βCD) or bound to titanium dioxide (TiO2 @RhdGd) were tested. As a T(2) CA, perovskite manganite nanoparticles (LSMO@siF@si) were examined. Fluorescein or rhodamine was incorporated as a fluorescent marker in all probes. Islets labeled with gadolinium(III) CAs were visible as hyperintense spots on MR in vitro, but detection in vivo was inconclusive. Islets labeled with LSMO@siF@si CA were clearly visible as hypointense spots or areas on MR scans in vitro as well as in vivo. All CAs were detected inside the islet cells by fluorescence. Although the vitality and function of the labeled islets was not impaired by any of the tested CAs, results indicate that LSMO@siF@si CA is a superior marker for islet labeling, as it provides better contrast enhancement within a shorter scan time. 23617851 High-resolution transcriptional analysis of the regulatory influence of cell-to-cell signalling reveals novel genes that contribute to Xanthomonas phytopathogenesis. The bacterium Xanthomonas campestris is an economically important pathogen of many crop species and a model for the study of bacterial phytopathogenesis. In X. campestris, a regulatory system mediated by the signal molecule DSF controls virulence to plants. The synthesis and recognition of the DSF signal depends upon different Rpf proteins. DSF signal generation requires RpfF whereas signal perception and transduction depends upon a system comprising the sensor RpfC and regulator RpfG. Here we have addressed the action and role of Rpf/DSF signalling in phytopathogenesis by high-resolution transcriptional analysis coupled to functional genomics. We detected transcripts for many genes that were unidentified by previous computational analysis of the genome sequence. Novel transcribed regions included intergenic transcripts predicted as coding or non-coding as well as those that were antisense to coding sequences. In total, mutation of rpfF, rpfG and rpfC led to alteration in transcript levels (more than fourfold) of approximately 480 genes. The regulatory influence of RpfF and RpfC demonstrated considerable overlap. Contrary to expectation, the regulatory influence of RpfC and RpfG had limited overlap, indicating complexities of the Rpf signalling system. Importantly, functional analysis revealed over 160 new virulence factors within the group of Rpf-regulated genes. 23454829 Tissue Distribution and Identification of Radioactivity Components at Elimination Phase after Oral Administration of [14C]CS-1036, an α-Amylase Inhibitor, to Rats. (2R,3R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside (CS-1036) is a potent inhibitor of pancreatic and salivary α-amylase. After oral administration of [(14)C]CS-1036 to rats, the radioactivity was still detectable up to 7-14 days after administration in various tissues, and its terminal phase in plasma could be explained neither by the exposure of CS-1036 nor its major metabolite M1. The slow elimination of radioactivity in various tissues was hypothesized to be caused by covalent binding to macromolecules or use for biogenic components. To assess the use for biogenic components, amino acid analysis of plasma proteins and lipid analysis of adipose tissue were conducted after repeated oral administration of [(14)C]CS-1036 by high-performance liquid chromatography and accelerated mass spectrometry and by thin layer chromatography and liquid chromatography/mass spectrometry, respectively. In amino acid analysis, glutamic acid, aspartic acid, alanine, and proline were identified as major radioactive amino acids, and radioactive nonessential amino acids occupied 76.0% of the radioactivity. In lipid analysis, a part of the radioactive lipids were identified as the fatty acids constituting the neutral lipids by lipase-hydrolysis. The radioactive fatty acids from neutral lipids were identified as palmitic acid, oleic acid, and 8,11,14-eicosatrienoic acid. Intestinal flora were involved in CS-1036 metabolism and are indicated to be involved in the production of small molecule metabolites, which are the sources for amino acids and fatty acids, from [(14)C]CS-1036. In conclusion, radioactivity derived from [(14)C]CS-1036 was incorporated as the constituents of amino acids of plasma proteins and fatty acids of neutral lipids. 23247040 Engineering polypeptide coatings to augment gene transduction and in vivo stability of adenoviruses. We sought to modify adenoviral (Ad) particles by incorporating the advantageous characteristics of non-viral gene delivery vehicles to complement the viral vectors. α-Amino acid-N-carboxyanhydride chemistry was used to synthesize homopolypeptides and diblock copolypeptides that possess well-defined secondary structures. Using cryo-electron and fluorescence microscopy, we showed that these polypeptides can coat the surfaces of Ad particles in a non-covalent manner to modify their transduction properties. The coated Ad particles were found to bind to and be internalized by cells. In contrast to reports using covalently PEGylated Ad particles, we found that our physically coated Ad hybrid complexes facilitate gene transfer both in vitro and in vivo. We showed that our polypeptide coating was able to shield the Ad particles from the neutralizing effect of antibodies and mitigate the binding of blood coagulation factor (Factor X) in vitro. The coating also reduced the antigenicity of Ad in immunocompetent mice. The biodistribution of the systemically administered hybrid complexes mirrored the behavior of both viral and non-viral vectors, exhibiting liver tropism as well as enhanced lung transduction. These data demonstrated that our non-covalent modification was able to alter Ad's interactions with cells and organs with retention of transduction efficiency. Advantages such as facile coating of the Ad vector, design flexibility and ease of attaching ligands to the polypeptides make this system potentially useful as a platform for adding functionalities to Ad to target cancer metastasis. 23473444 Engineered iron-oxide-based nanoparticles as enhanced t1 contrast agents for efficient tumor imaging. We report the design and synthesis of small-sized zwitterion-coated gadolinium-embedded iron oxide (GdIO) nanoparticles, which exhibit a strong T1 contrast effect for tumor imaging through enhanced permeation and retention effect and the ability to clear out of the body in living subjects. The combination of spin-canting effects and the collection of gadolinium species within small-sized GdIO nanoparticles led to a significantly enhanced T1 contrast effect. For example, GdIO nanoparticles with a diameter of ∼4.8 nm exhibited a high r1 relaxivity of 7.85 mM(-1)·S(-1) and a low r2/r1 ratio of 5.24. After being coated with zwitterionic dopamine sulfonate molecules, the 4.8 nm GdIO nanoparticles showed a steady hydrodynamic diameter (∼5.2 nm) in both PBS buffer and fetal bovine serum solution, indicating a low nonspecific protein absorption. This study provides a valuable strategy for the design of highly sensitive iron-oxide-based T1 contrast agents with relatively long circulation half-lives (∼50 min), efficient tumor passive targeting (SKOV3, human ovarian cancer xenograft tumor as a model), and the possibility of rapid renal clearance after tumor imaging. 22469981 In vivo and in vitro models for the therapeutic targeting of Wnt signaling using a Tet-OΔN89β-catenin system. Although significant progress has been made in understanding the importance of Wnt signaling in the initiation of colorectal cancer, less is known about responses that accompany the reversal of oncogenic Wnt signaling. The aim of this study was to analyze in vivo and in vitro responses to an 'ideal' Wnt pathway inhibitor as a model for the therapeutic targeting of the pathway. A tetracycline-inducible transgenic mouse model expressing truncated β-catenin (ΔN89β-catenin) that exhibited a strong intestinal hyperplasia was analyzed during the removal of oncogenic β-catenin expression both in 3D 'crypt culture' and in vivo. Oncogenic Wnt signaling was rapidly and completely reversed. The strongest inhibition of Wnt target gene expression occurred within 24 h of doxycycline removal at which time the target genes Ascl2, Axin2 and C-myc were downregulated to levels below that in the control intestine. In vitro, the small molecule Wnt inhibitor CCT036477 induced a response within 4 h of treatment. By 7 days following doxycycline withdrawal, gene expression, cell proliferation and tissue morphology were undistinguishable from control animals.In conclusion, these results demonstrate that the reversal of Wnt signaling by inhibitors should ideally be studied within hours of treatment. The reversible system described, involving medium throughput in vitro approaches and rapid in vivo responses, should allow the rapid advance of early stage compounds into efficacy models that are more usually considered later in the drug discovery pipeline. 23411236 Purification and characterisation of a novel chitinase from persimmon (Diospyros kaki) with antifungal activity. A novel chitinase from the persimmon fruit was isolated, purified and characterised in this report. The Diospyros kaki chitinase (DKC) was found to be a monomer with a molecular mass of 29 kDa. It exhibited optimal activity at pH 4.5 with broad pH stability from pH 4.0-9.0. It has an optimal temperature of 60°C and thermostable up to 60°C when incubated for 30 min. The internal peptide sequences of DKC showed similarity with other reported plant chitinases. It has the ability to hydrolyse colloidal chitin into chito-oligomers such as chitotriose, chitobiose and into its monomer N-acetylglucosamine. It can be used to degrade chitin waste into useful products such as chito-oligosacchaarides. DKC exhibited antifungal activity towards pathogenic fungus Trichoderma viride. Chitinases with antifungal property can be used as biocontrol agents replacing chemical fungicides. 23319591 Methylation of histone H3 on lysine 4 by the lysine methyltransferase SET1 protein is needed for normal clock gene expression. The circadian oscillator controls time-of-day gene expression by a network of interconnected feedback loops and is reset by light. The requisite for chromatin regulation in eukaryotic transcription necessitates temporal regulation of histone-modifying and chromatin-remodeling enzymes for proper clock function. CHD1 is known to bind H3K4me3 in mammalian cells, and Neurospora CHD1 is required for proper regulation of the frequency (frq) gene. Based on this, we examined a strain lacking SET1 to determine the role of H3K4 methylation in clock- and light-mediated frq regulation. Expression of frq was altered in strains lacking set1 under both circadian- and light-regulated gene expression. There is a delay in the phasing of H3K4me3 relative to the peak in frq expression. White Collar 2 (WC-2) association with the frq promoter persists longer in Δset1, suggesting a more permissible chromatin state. Surprisingly, SET1 is required for DNA methylation in the frq promoter, indicating a dependence on H3K4me for DNA methylation. The data support a model where SET1 is needed for proper regulation by modulating chromatin at frq. 23337388 Crowd computing: using competitive dynamics to develop and refine highly predictive models. A recent application of a crowd computing platform to develop highly predictive in silico models for use in the drug discovery process is described. The platform, Kaggle™, exploits a competitive dynamic that results in model optimization as the competition unfolds. Here, this dynamic is described in detail and compared with more-conventional modeling strategies. The complete and full structure of the underlying dataset is disclosed and some thoughts as to the broader utility of such 'gamification' approaches to the field of modeling are offered. 23081947 Chlorine-enhanced surface mobility of Au(100). Motivated by experimental studies of two-dimensional Ostwald ripening on Au(100) electrodes in chlorine-containing electrolytes, we have studied diffusion processes using density functional theory. We find that chlorine has a propensity to temporary form AuCl complexes, which diffuse significantly faster than gold adatoms. With and without chlorine, the lowest activation energy is found for the exchange mechanism. Chlorine furthermore reduces the activation energy for the detachment from kink sites. Kinetic Monte Carlo simulations were performed on the basis of extensive density functional theory calculations. The island-decay rate obtained from these Monte Carlo simulations, as well as the decay rate obtained from the theoretical activation energies and frequency factors when inserted into analytical solutions for Ostwald ripening, are in agreement with experimental island-decay rates in chlorine-containing electrolytes. 23266502 Carbamate insecticide methomyl confers cytotoxicity through DNA damage induction. Carbamate insecticide methomyl could induce genotoxic effects, including micronuclei, chromosome aberrations and sister-chromatid exchanges. However, methomyl induction of cytotoxicity through DNA damage is largely unknown. Here we identify cytotoxicity and potential genotoxicity of methomyl in vitro. We have employed alkaline comet assay, γH2AX foci formation and DNA ladder assay to detected DNA damage and apoptosis of Drosophila S2, HeLa and HEK293 cells. The alkaline comet assay was used to evaluate total DNA single strand breaks (SSBs) in the target cells exposed in vitro to sublethal concentrations of methomyl. As expected, methomyl induced significant concentration-dependent increases in DNA damage of target cells compared with the negative control, as measured by increases in tail length (μm), tail DNA (percentage of the comet tail) and tail moment (arbitrary units). In agreement with the comet assay data, the percentage of γH2AX positive reaction in HeLa cells also revealed methomyl caused DNA double strand breaks (DSBs) in a time-dependent manner. Moreover, methomyl induced a significant increase of apoptosis in Drosophila S2, HeLa and HEK293 cells in a concentration- and time-dependent manner, as determined by Urea PAGE DNA fragmentation analysis. In conclusion, methomyl is a strongly genotoxic agent that induces cell DNA damage and apoptosis in vitro at these sublethal concentrations. 23199028 Synthesis, biological evaluation, and molecular modeling of glycyrrhizin derivatives as potent high-mobility group box-1 inhibitors with anti-heart-failure activity in vivo. Novel glycyrrhizin (GL) derivatives were designed and synthesized by introducing various amine or amino acid residues into the carbohydrate chain and at C-30. Their inhibitory effects on high-mobility group box 1 (HMGB1) were evaluated using a cell-based lipopolysaccharide (LPS) induced tumor necrosis factor α (TNF-α) release study. Compounds 10, 12, 18-20, 23, and 24, which had substituents introduced at C-30, demonstrated moderate HMGB1 inhibition with ED₅₀ values ranging from 337 to 141 μM, which are values comparable to that of the leading GL compound (1) (ED₅₀ = 70 μM). Compounds 23 and 24 emerged as novel and interesting HMGB1 inhibitors. These compounds were able to extend the survival of mice with chronic heart failure (CHF) and acute heart failure (AHF), respectively. In addition, molecular modeling studies were performed to support the biological data. 23464357 Three-dimensional in situ photocurrent mapping for nanowire photovoltaics. Devices based upon semiconductor nanowires provide many well-known advantages for next-generation photovoltaics, however, limited experimental techniques exist to determine essential electrical parameters within these devices. We present a novel application of a technique based upon two-photon induced photocurrent that provides a submicrometer resolution, three-dimensional reconstruction of photovoltaic parameters. This tool is used to characterize two GaAs nanowire-based devices, revealing the detail of current generation and collection, providing a path toward achieving the promise of nanowire-based photovoltaic devices. 23552482 Comparing molecular photofragmentation dynamics in the gas and liquid phases. This article explores the extent to which insights gleaned from detailed studies of molecular photodissociations in the gas phase (i.e. under isolated molecule conditions) can inform our understanding of the corresponding photofragmentation processes in solution. Systems selected for comparison include a thiophenol (p-methylthiophenol), a thioanisole (p-methylthioanisole) and phenol, in vacuum and in cyclohexane solution. UV excitation in the gas phase results in RX-Y (X = O, S; Y = H, CH3) bond fission in all cases, but over timescales that vary by ∼4 orders of magnitude - all of which behaviours can be rationalised on the basis of the relevant bound and dissociative excited state potential energy surfaces (PESs) accessed by UV photoexcitation, and of the conical intersections that facilitate radiationless transfer between these PESs. Time-resolved UV pump-broadband UV/visible probe and/or UV pump-broadband IR probe studies of the corresponding systems in cyclohexane solution reveal additional processes that are unique to the condensed phase. Thus, for example, the data clearly reveal evidence of (i) vibrational relaxation of the photoexcited molecules prior to their dissociation and of the radical fragments formed upon X-Y bond fission, and (ii) geminate recombination of the RX and Y products (leading to reformation of the ground state parent and/or isomeric adducts). Nonetheless, the data also show that, in each case, the characteristics (and the timescale) of the initial bond fission process that occurs under isolated molecule conditions are barely changed by the presence of a weakly interacting solvent like cyclohexane. These condensed phase studies are then extended to an ether analogue of phenol (allyl phenyl ether), wherein UV photo-induced RO-allyl bond fission constitutes the first step of a photo-Claisen rearrangement. 23578642 C-Phycocyanin from Oscillatoria tenuis exhibited an antioxidant and in vitro antiproliferative activity through induction of apoptosis and G0/G1 cell cycle arrest. This study was undertaken to develop an efficient single step chromatographic method for purification of C-phycocyanin (CPC) from species of Oscillatoria tenuis. Purification of CPC involves a multistep treatment of the crude extract by precipitation with ammonium sulphate, followed by gel filtration chromatography. Pure CPC was finally obtained from O. tenuis with purity ratio (A620/A280) 4.88. SDS-PAGE of pure CPC yielded two bands corresponding to α and β subunits; the molecular weight of α subunit is 17.0kDa, whereas the molecular weight of β subunit is 19.5kDa. Fluorescence and phase contrast microscopy revealed characteristic apoptotic features like cell shrinkage, membrane blebbing, nuclear condensation and DNA fragmentation. CPC exhibited antioxidant and antiproliferative activity against human cancer cells through apoptosis; nuclear apoptosis induction was accompanied by G0/G1 phase arrest and DNA fragmentation. CPC is a natural pigment with potential as an anticancer agent. 23159712 Mucoadhesive multiparticulate patch for the intrabuccal controlled delivery of lidocaine. The aim of the present study was to prepare and evaluate patches for the controlled release of lidocaine in the oral cavity. Mucoadhesive buccal patches, containing 8 mg/cm(2) lidocaine base, were formulated and developed by solvent casting method technique, using a number of different bio-adhesive and film-forming semi-synthetic and synthetic polymers (Carbopol, Poloxamer, different type Methocel) and plasticizers (PEG 400, triethyl citrate); the patches were evaluated for bioadhesion, in vitro drug release and permeation using a modified Franz diffusion cell. A lidocaine/Compritol solid dispersion in the form of microspheres, embedded inside the patch, alone or together with free lidocaine, was also examined to prolong the drug release. The effects of the composition were evaluated considering a number of technological parameters and the release of the drug. All the formulations tested offer a variety of drug release mechanisms, obtaining a quick or delayed or prolonged anesthetic local activity with simple changes of the formulation parameters. 23355616 Effects of DNA methylation on nucleosome stability. Methylation of DNA at CpG dinucleotides represents one of the most important epigenetic mechanisms involved in the control of gene expression in vertebrate cells. In this report, we conducted nucleosome reconstitution experiments in conjunction with high-throughput sequencing on 572 KB of human DNA and 668 KB of mouse DNA that was unmethylated or methylated in order to investigate the effects of this epigenetic modification on the positioning and stability of nucleosomes. The results demonstrated that a subset of nucleosomes positioned by nucleotide sequence was sensitive to methylation where the modification increased the affinity of these sequences for the histone octamer. The features that distinguished these nucleosomes from the bulk of the methylation-insensitive nucleosomes were an increase in the frequency of CpG dinucleotides and a unique rotational orientation of CpGs such that their minor grooves tended to face toward the histones in the nucleosome rather than away. These methylation-sensitive nucleosomes were preferentially associated with exons as compared to introns while unmethylated CpG islands near transcription start sites became enriched in nucleosomes upon methylation. The results of this study suggest that the effects of DNA methylation on nucleosome stability in vitro can recapitulate what has been observed in the cell and provide a direct link between DNA methylation and the structure and function of chromatin. 23607578 Fast Vortex-Assisted Self-Assembly of Carbon Nanoparticles on Air-Water Interface. In this work a new self-assembly technique is presented, allowing the fast formation of carbon black thin films. It consists in the controlled addition of a stable carbon material's dispersion over the water surface, disturbed by a vortex. The vortex, although not essential for the film formation, was found to drastically improve film homogeneity. A physical chemical study concerning how several parameters could be used to tune film properties was also conducted. The self-assembled films, which can be picked up in any hydrophilic substrate, showed a good electrical conductivity and a high optical transparency. As an application example, films about 200 nm thick were employed as supercapacitor electrodes. 23265529 Optimization of gas chromatography-single quadrupole mass spectrometry conditions for multiresidue analysis of pesticides in grapes in compliance to EU-MRLs. A single quadrupole GC-MS method was optimized for multiresidue determination of 47 pesticides in grapes with limit of quantifications of each compound in compliance with the EU-MRL requirements. Sample preparation involved extraction of 10 g sample with 10 ml ethyl acetate (+10 g sodium sulphate) by homogenization at 15,000 rpm followed by centrifugation at 3000 rpm. The supernatant was cleaned by dispersive solid phase extraction with primary secondary amine and acidified with 0.1% formic acid. Residues were estimated in selected ion monitoring mode with programmable temperature vaporizer-large volume injection (8 μl). All the GC and MS parameters were thoroughly optimized to achieve satisfactory linearity (R(2)>0.99) within 0.01-0.25 mg kg(-1) with minimum matrix interferences. Recoveries at 0.01 and 0.02 mg kg(-1) were within 67-120% with associated precision RSD below 19%. The method was successfully applied for analysis of the real world samples for incurred residues. 22982302 A chemistry wiki to facilitate and enhance compound design in drug discovery. At AstraZeneca a focus on hypothesis-driven design and the formation of drug design teams has placed a greater emphasis on collaboration in the drug discovery process. We have created a novel software tool based on the principles of wikis and social networks to facilitate collaborative working, visual planning and incorporation of predictive science to improve design capability. Monitoring the design and make process via the tool enabled the identification of bottlenecks and delays. Solutions to these problems were implemented, reducing the time taken from the initial idea stage to the generation of the synthesised compound by more than 50%. 23174517 Usage patterns of personal care products: important factors for exposure assessment. Complete information regarding the use of personal care products (PCPs) by consumers is limited, but such information is crucial for realistic consumer exposure assessment. To fill this gap, a database was created with person-oriented information regarding usage patterns and circumstances of use for 32 different PCPs. Out of 2700 potential participants from the Netherlands, 516 men and women completed a digital questionnaire. The prevalence of use varied by gender, age, level of education and skin type. A high frequency of use was observed for some products (e.g. lip care products), while toothpaste, deodorant and day cream were generally used once or twice a day. The frequency of use for other PCPs varied over a wide range. The amounts of use varied largely between and within different product groups. Body lotion, sunscreen and after sun lotion were often applied on adjacent body parts. The majority of PCPs were applied in the morning, but some products, such as night cream and after sun, were predominantly applied in the evening or night. As expected, the participants used several PCPs simultaneously. The database yields important personalized exposure factors which can be used in aggregate consumer exposure assessment for substances that are components of PCPs. 23022069 Performance of urinary and gene expression biomarkers in detecting the nephrotoxic effects of melamine and cyanuric acid following diverse scenarios of co-exposure. Although standard nephrotoxicity assessments primarily detect impaired renal function, KIM-1, clusterin, NGAL, osteopontin and TIMP-1 were recently identified biomarkers proposed to indicate earlier perturbations in renal integrity. The recent adulteration of infant and pet food with melamine (MEL) and structurally-related compounds revealed that co-ingestion of MEL and cyanuric acid (CYA) could form melamine-cyanurate crystals which obstruct renal tubules and induce acute renal failure. This study concurrently evaluated the ability of multiplexed urinary biomarker immunoassays and biomarker gene expression analysis to detect nephrotoxicity in F344 rats co-administered 60ppm each of MEL and CYA in feed or via gavage for 28days. The biomarkers were also evaluated for the ability to differentiate the effects of the compounds when co-administered using diverse dosing schedules (i.e., consecutive vs. staggered gavage) and dosing matrixes (i.e., feed vs. gavage). Our results illustrate the ability of both methods to detect and differentiate the severity of adverse effects in the staggered and consecutive gavage groups at much lower doses than previously observed in animals co-exposed to the compounds in feed. We also demonstrate that these urinary biomarkers outperform traditional diagnostic methods and represent a powerful, non-invasive indicator of chemical-induced nephrotoxicity prior to the onset of renal dysfunction. 23292988 Electron doping by charge transfer at LaFeO3/Sm2CuO4 epitaxial interfaces. Using X-ray absorption spectroscopy and electron energy loss spectroscopy with atomic-scale spatial resolution, experimental evidence for charge transfer at the interface between the Mott insulators Sm2 CuO4 and LaFeO3 is obtained. As a consequence of the charge transfer, the Sm2 CuO4 is doped with electrons and thus epitaxial Sm2 CuO4 /LaFeO3 heterostructures become metallic. 23265843 Lucidone from Lindera erythrocarpa Makino fruits suppresses adipogenesis in 3T3-L1 cells and attenuates obesity and consequent metabolic disorders in high-fat diet C57BL/6 mice. Obesity is associated with an increased risk of development of numerous diseases including type 2 diabetes, hypertension, hyperlipidemia, and cardiovascular disease. In this study, we investigated the effects of lucidone in vitro on gene expression during adipogenesis in 3T3-L1 cells and in vivo on high-fat diet induced obesity in C57BL/6 mice. Lucidone at 40 μmol/L suppressed adipogenesis in 3T3-L1 cells by reducing transcription levels of adipogenic genes, including PPARγ, C/EBPα, LXR-α, LPL, aP2, GLUT4 and adiponectin. Five-week-old male C57BL/6 mice fed a high fat diet (60% energy from fat) supplemented with lucidone at a dosage of 1250 mg/kg of diet for 12 weeks had reduced body and liver weight, reduced epididymal and perirenal adipose tissue, decreased food efficiency (percentage of weight gain divided by food intake), and lowered plasma cholesterol, triglyceride, glucose, and insulin levels. Dissection of adipose tissue from lucidone-treated mice showed a reduction in the average fat-cell size and percentage of large adipocytes. These results provide evidence that dietary intake of lucidone alleviates high fat diet-induced obesity in C57BL/6 mice and reveals the potential of lucidone as a nutraceutical to prevent obesity and consequent metabolic disorders. 23450829 Hierarchically Structured Nanotubes for Highly Efficient Dye-Sensitized Solar Cells. Hierarchical TiO2 nanotube arrays grown on Ti foil are yielded by subjecting electrochemically anodized, vertically oriented TiO2 nanotube arrays to hydrothermal processing. The resulting DSSCs exhibit a significantly enhanced power conversion efficiency of 7.24%, which is a direct consequence of the synergy of higher dye loading, superior light-scattering ability, and fast electron transport. 23281613 Two new ent-3,4-seco-labdane diterpenoids from Callicarpa nudiflora. Two new ent-3,4-seco-labdane diterpenoids, methylcallicarpate (1) and callicarpic acid (2), were isolated from the leaves of Callicarpa nudiflora Hook et Arn. Their structures and relative configurations were established by analysis of spectroscopic data. Their absolute configurations were assigned by the application of the CD technique for the first time among the ent-3,4-seco-labdane-type diterpenes. 23542008 Steric Complementarity in the Decoding Center Is Important for tRNA Selection by the Ribosome. Accurate tRNA selection by the ribosome is essential for the synthesis of functional proteins. Previous structural studies indicated that the ribosome distinguishes between cognate and near-cognate tRNAs by monitoring the geometry of the codon-anticodon helix in the decoding center using the universally conserved 16S ribosomal RNA bases G530, A1492 and A1493. These bases form hydrogen bonds with the 2'-hydroxyl groups of the codon-anticodon helix, which are expected to be disrupted with a near-cognate codon-anticodon helix. However, a recent structural study showed that G530, A1492 and A1493 form hydrogen bonds in a manner identical with that of both cognate and near-cognate codon-anticodon helices. To understand how the ribosome discriminates between cognate and near-cognate tRNAs, we made 2'-deoxynucleotide and 2'-fluoro substituted mRNAs, which disrupt the hydrogen bonds between the A site codon and G530, A1492 and A1493. Our results show that multiple 2'-deoxynucleotide substitutions in the mRNA substantially inhibit tRNA selection, whereas multiple 2'-fluoro substitutions in the mRNA have only modest effects on tRNA selection. Furthermore, the miscoding antibiotics paromomycin and streptomycin rescue the defects in tRNA selection with the multiple 2'-deoxynucleotide substituted mRNA. These results suggest that steric complementarity in the decoding center is more important than the hydrogen bonds between the A site codon and G530, A1492 and A1493 for tRNA selection. 23466488 Oral l-glutamine increases active GLP-1 (7-36) amide secretion and improves glycemic control in stretpozotocin-nicotinamide induced diabetic rats. l-glutamine is a non-essential amino acid. It decreased blood sugar, stimulated insulin secretion in type 2 diabetic patients. The objective of the present investigation was to evaluate l-glutamine increases glucagon like peptide-1 (GLP-1) (7-36) amide secretion in streptozotocin-nicotinamide (STZ-NTM) induced diabetic Sprague Dawley rats. Molecular docking study was performed to elucidate the molecular basis for GLP-1 receptor agonistic activity. Type 2 diabetes was induced in overnight fasted Sprague Dawley rats pre-treated with nicotinamide (100mg/kg, i.p.) followed by 20min after administration of streptozotocin (55mg/kg, i.p.). The rats were divided into; I - nondiabetic, II - diabetic control, III - sitagliptin (5mg/kg, p.o.), IV -l-glutamine (250mg/kg, p.o.), V -l-glutamine (500mg/kg, p.o.) and VI -l-glutamine (1000mg/kg, p.o.). The l-glutamine and sitagliptin treatment was 8week. Plasma glucose was estimated every week. Body weight, food and water intake were recorded daily. Glycosylated haemoglobin, lipid profile, plasma and colonic active (GLP-1) (7-36) amide, mRNA expression of proglucagon GLP-1, plasma and pancreatic insulin, histology of pancreata and biomarkers of oxidative stress (superoxidase dismutase, reduced glutathione, malondialdehyde, glutathione peroxidase, glutathione S transferase) were measured after 8week. In acute study, the rats were divided into I - glucose (2.5g/kg, p.o.), II - sitagliptin (5mg/kg, p.o.), III -l-glutamine (250mg/kg, p.o.), IV -l-glutamine (500mg/kg, p.o.) and V -l-glutamine (1000mg/kg, p.o.). Plasma glucose, active GLP-1 (7-36) amide concentration and insulin levels were measured after glucose loading. The docking data indicated that l-glutamine bind to the GLP-1 receptor. l-glutamine decreased plasma glucose, increased plasma and pancreatic insulin, increased plasma and colonic active GLP-1 (7-36) amide secretion as well as decreased oxidative stress in streptozotocin-nicotinamide induced diabetic rats. 22709945 Neonatal exposure to low dose corticosterone persistently modulates hippocampal mineralocorticoid receptor expression and improves locomotor/exploratory behaviour in a mouse model of Rett syndrome. Rett syndrome (RTT) is a pervasive neurodevelopmental disorder, primarily affecting girls. RTT causes a wide variety of debilitating symptoms and no cure currently exists. Mouse models bearing mutations in the Mecp2 gene recapitulate most physiological and behavioural RTT-related abnormalities. Stimulating neonatal environments (e.g. brief maternal separations or maternal low-dose corticosterone supplementation) reduce stress and fear responses at adulthood. The present study investigated whether impacting early in development the hypothalamic-pituitary-adrenal axis, by exposing Mecp2-308 mutant pups to a low dose of corticosterone (50 µg/ml, during the 1st week of life) may contrast RTT-related abnormalities in neuroendocrine regulation and behavioural adaptation at adulthood. In line with previous reports, when fully symptomatic, MeCP2-308 mice showed a reduction in the regular nocturnal hyperactivity in the home-cage and increased anxiety-like behaviours and plasma corticosterone (CORT) levels in response to restraint stress. An abnormal elevation in mRNA levels of mineralocorticoid receptors (MR) and BDNF gene was also evident in the hippocampus of fully symptomatic mutant mice. Neonatal CORT modulated MR gene expression and behavioural reactivity towards a novel object, also restoring wt-like levels of locomotor/exploratory behaviour in mutant mice. Enhanced sensitivity to the neonatal treatment (in terms of increase in GR and MR mRNA levels), was also evident in the hippocampus of MeCP2-308 mice compared to wt littermates. Present results corroborate the hypothesis that targeting the glucocorticoid system may prove valid in contrasting at least some of the RTT-related symptoms and provide evidence that pharmacological interventions during critical early time windows can persistently improve the behavioural phenotype of RTT mice. Current data also support the emerging role played by Mecp2 in mediating the epigenetic programming induced by early life events and indicate that, in the absence of functional MeCP2, programming of the central nervous system in response to early environmental stimuli is abnormally regulated. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. 23411340 Redox spectrophotometric method involving electrolytically generated manganese(III) sulphate with diphenylamine for the determination of ascorbic acid present in the samples of various fruits, commercial juices and sprouted food grains. A spectrophotometric method was developed for ascorbic acid present in various fruits, commercial fruit juices and sprouted food grains. The method involves the oxidation of ascorbic acid with excess manganese(III) following reduction of unreacted manganese(III) with diphenylamine or barium diphenylamine sulphonate forming a product λ(max) 570 nm the system 1 or 540 nm the system 2 and decrease in the colour intensity is proportional to the concentration of vitamin C with quantification range 0.3-3.0 μg ml(-1). The molar absorptivity and Sandell's sensitivity values of the system 1 and the system 2 were 1.829 × 10(4) and 1.813 × 10(4)mol(-1)cm(-1) and 0.0096 and 0.0097 μg cm(-2) respectively. The stoichiometry was 4:1 between manganese(III) and diphenylamine. The ascorbic acid contents of the same samples were determined separately following the procedures of the developed method as well as the reference method and the results were comparable. 23432058 TRP Channels as Targets for Therapeutic Intervention in Obesity: Focus on TRPV1 and TRPM5. The disease of obesity is one of the greatest healthcare challenges of our time. The increasing urgency for effective treatment is driving an intensive search for new targets for anti-obesity drug discovery. The TRP channel super family represents a class of proteins now recognized to serve many functions in physiology related to maintenance of health and the development of diseases. A few of these might offer new potential for therapeutic intervention in obesity. Among the TRP channels, TRPV1 appears most closely associated with body weight homeostasis through its influence on energy expenditure. TRPM5 has been thoroughly characterized as a critical component of taste signaling and recently has been implicated in insulin release. Because of its role in taste signaling, we argue that drugs designed to modulate TRPM5 could be useful in controlling energy consumption by impacting taste sensory signals. As drug targets for obesity, both TRPV1 and TRPM5 offer the advantage of operating in compartments that could limit drug distribution to the site of action. The potential for other TRP channels as anti-obesity drug targets also is discussed. 23323829 Design and application of anthracene derivative with aggregation-induced emission charateristics for visualization and monitoring of erythropoietin unfolding. Erythropoietin (EPO) is an attractive protein-unfolding/folding model because of its high degree of unfolding and folding reversibility and intermediate size. Due to its function for regulating red blood cell production by stimulating late erythroid precursor cells, EPO presents obvious values to biological research. A nonemissive anthracene derivative, that is 9,10-bis[4-(3-sulfonatopropoxyl)-styryl]anthracene sodium salt (BSPSA), with aggregation-induced emission (AIE) charateristics shows a novel phenomenon of AIE when EPO is added. The AIE biosensor for EPO shows the limit of detection is 1 × 10(-9) M. Utilizing the AIE feature of BSPSA, the unfolding process of EPO using guanidine hydrochloride is monitored, which indicates three steps for the folding structures of EPO to transform to random coil. Computational modeling suggests that the BSPSA luminogens prefer docking in the hydrophobic cavity in the EPO folding structures, and the assembly of BSPSA in this cavity makes the AIE available, making the monitoring of unfolding of EPO possible. 22468741 Plant proteins, minerals and trace elements of Eurycoma longifolia (Tongkat Ali). A water extraction method has been used to extract plant proteins from the roots of Eurycoma longifolia harvested from Perak and Pahang, Malaysia. On the basis of the spectroscopic Bradford assay, Tongkat Ali Perak and Pahang contained 0.3868 and 0.9573 mg mL(-1) of crude protein, respectively. The crude proteins were separated by one dimensional 15% sodium dodecyl sulphate polyacrylamide gel electrophoresis into two (49.8 and 5.5 kD) and four (49.8, 24.7, 21.1 and 5.5 kD) protein spots for Tongkat Ali Perak and Pahang, respectively. Isoleucine was present in the highest concentration significantly. Both plant samples showed differences in the mineral and trace element profiles, but the minerals calcium, magnesium and potassium were present in the highest concentration. The highly concerned toxic metals such as arsenic and lead were not detected. 23194524 Recovery and characterisation of coloured phenolic preparations from apple seeds. The aim of this study was to investigate whether complexly constituted phenolic extracts from apple seeds may be utilised for the recovery of natural coloured antioxidant preparations, which might serve as potential food or cosmetic ingredients. In a first step, the recovery of phenolic compounds was optimised by varying crucial extraction parameters. A single extraction step at 25°C using an acetone-water mixture (60:40, v/v) and a solid-to-solvent ratio of 1:8 (w/v) for 1 h was found to be appropriate to achieve both high phenolic yields and antioxidant activities. In a second step, differently produced apple seed extracts and a phloridzin model solution were enzymatically treated by mushroom polyphenol oxidase to investigate the rate of pigment synthesis. Depending on the extraction procedure applied, synthesis rates, pigment yields and colour properties significantly differed. Compared to the phloridzin model solution, extracts recovered from the seeds showed comparable and even better results, thus indicating such preparations to be a promising alternative to synthetic yellow dyes. 23325489 Identification and quantification of the sedative and anticonvulsant flavone glycoside from Chrysanthemum boreale. The flowers or leaves of Chrysanthemum boreale (Compositae) have been traditionally used as herb tea to reduce anxiety, insomnia, and stress. Sedative and anticonvulsant activities were evaluated in mice using pentobarbital-induced sleeping assay and pentylenetetrazole (PTZ)-induced convulsion assay. The flower extract exhibited more potent activities than the extracts of the leaves and stems, and chromatographic isolation yielded the five compounds acacetin, linarin, acacetin 7-O-β-D-glucopyranosyl-(1 → 2)[α-L-rhamnopyranosyl-(1 → 6)]-β-D-glucopyranoside, chlorogenic acid, and 3,5-di-O-caffeoylquinic acid. These compounds were simultaneously analyzed by HPLC, and the method was validated. The contents of linarin, which were shown to be most abundant in C. boreale, were observed in the order of leaf (11.93 mg/g) > flower (8.50 mg/g) > stem (5.60 mg/g). Linarin and its aglycone, acacetin, exhibited sedative and anticonvulsant activities in the present in vivo assays. It can be considered that linarin is one of the active compounds effective against anxiety, insomnia, and stress, with acacetin as its active moiety. 23503472 Associations of ABCB1, NFKB1, CYP3A, and NR1I2 polymorphisms with cyclosporine trough concentrations in Chinese renal transplant recipients. Aim:Cyclosporine requires close therapeutic drug monitoring because of its narrow therapeutic index and marked inter-individual pharmacokinetic variation. In this study, we investigated the associations of CYP3A4, CYP3A5, ABCB1, NFKB1, and NR1I2 polymorphisms with cyclosporine concentrations in Chinese renal transplant recipients in the early period after renal transplantation.Methods:A total of 101 renal transplant recipients receiving cyclosporine were genotyped for CYP3A4(*)1G, CYP3A5(*)3, ABCB1 C1236T, G2677T/A, C3435T, NFKB1 -94 ins/del ATTG, and NR1I2 polymorphisms. Cyclosporine whole blood levels were measured by a fluorescence polarization immunoassay. Trough concentrations of cyclosporine were determined for days 7-18 following transplantation.Results:The dose-adjusted trough concentration (C0) of cyclosporine in ABCB1 2677 TT carriers was significantly higher than that in GG carriers together with GT carriers [90.4±24.5 vs 67.8±26.8 (ng/mL)/(mg/kg), P=0.001]. ABCB1 3435 TT carriers had a significantly higher dose-adjusted C0 of cyclosporine than CC carriers together with CT carriers [92.0±24.0 vs 68.4±26.5 (ng/mL)/(mg/kg), P=0.002]. Carriers of the ABCB1 1236TT-2677TT-3435TT haplotype had a considerably higher CsA C0/D than carriers of other genotypes [97.2±21.8 vs 68.7±26.9 (ng/mL)/(mg/kg), P=0.001]. Among non-carriers of the ABCB1 2677 TT and 3435 TT genotypes, patients with the NFKB1 -94 ATTG ins/ins genotype had a significantly higher dose-adjusted C0 than those with the -94 ATTG del/del genotype [75.9±32.9 vs 55.1±15.1 (ng/mL)/(mg/kg), P=0.026].Conclusion:These results illustrate that the ABCB1 and NFKB1 genotypes are closely correlated with cyclosporine trough concentrations, suggesting that these SNPs are useful for determining the appropriate dose of cyclosporine. 23238657 Acute Macrovascular Dysfunction in Patients With Type 2 Diabetes Induced by Ingestion of Advanced Glycated β-Lactoglobulins. OBJECTIVE Recent evidence indicates that heat-enhanced food advanced glycation end products (AGEs) adversely affect vascular function. The aim of this study was to examine the acute effects of an oral load of heat-treated, AGE-modified β-lactoglobulins (AGE-BLG) compared with heat-treated, nonglycated BLG (C-BLG) on vascular function in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS In a double-blind, controlled, randomized, crossover study, 19 patients with T2DM received, on two different occasions, beverages containing either AGE-BLG or C-BLG. We measured macrovascular [brachial ultrasound of flow-mediated dilatation (FMD)] and microvascular (laser-Doppler measurements of reactive hyperemia in the hand) functions at baseline (T0), 90 (T90), and 180 (T180) min. RESULTS Following the AGE-BLG, FMD decreased at T90 by 80% from baseline and remained decreased by 42% at T180 (P < 0.05 vs. baseline, P < 0.05 vs. C-BLG at T90). By comparison, following C-BLG, FMD decreased by 27% at T90 and 51% at T180 (P < 0.05 vs. baseline at T180). A significant decrease in nitrite (T180) and nitrate (T90 and T180), as well as a significant increase in N(ε)-carboxymethyllisine, accompanied intake of AGE-BLG. There was no change in microvascular function caused by either beverage. CONCLUSIONS In patients with T2DM, acute oral administration of a single AGE-modified protein class significantly though transiently impaired macrovascular function in concert with decreased nitric oxide bioavailability. These AGE-related changes were independent of heat treatment. 23356907 Phthalocyanine-Peptide Conjugates: Receptor-Targeting Bifunctional Agents for Imaging and Photodynamic Therapy. The synthesis of a series of new zinc phthalocyanine-peptide conjugates targeting the gastrin-releasing peptide (GRP) and integrin receptors is reported. Two alternative synthetic methods based on Sonogashira cross-coupling of an iodinated zinc phthalocyanine with acetylenic bombesin or arginine-glycine-aspartic acid (RGD) derivatives, either in solution or on solid phase, are presented. The water-soluble conjugates were screened for their photodynamic efficacy against several cancer cell lines expressing different levels of GRP and integrin receptors, and their intracellular localization was evaluated via confocal fluorescence microscopy. Variations in photocytotoxicity between the conjugates correlate to differences in hydrophobicity as well as receptor-mediated cell uptake. In the case of the phthalocyanine-bombesin conjugate, competition experiments confirm the involvement of the GRP receptor in both the phototherapeutic activity as well as intracellular localization. These findings warrant further in vivo studies to evaluate the potential of this conjugate as photosensitizer for photodynamic therapy (PDT) of cancers overexpressing the GRP receptor. 23331669 Morphological, ecological and genetic aspects associated with endemism in the Fly Orchid group. The European genus Ophrys (Orchidaceae) is famous for its insect-like floral morphology, an adaptation for a pseudocopulatory pollination strategy involving Hymenoptera males. A large number of endemic Ophrys species have recently been described, especially within the Mediterranean Basin, which is one of the major species diversity hotspots. Subtle morphological variation and specific pollinator dependence are the two main perceptible criteria for describing numerous endemic taxa. However, the degree to which endemics differ genetically remains a challenging question. Additionally, knowledge regarding the factors underlying the emergence of such endemic entities is limited. To achieve new insights regarding speciation processes in Ophrys, we have investigated species boundaries in the Fly Orchid group (Ophrys insectifera sensu lato) by examining morphological, ecological and genetic evidence. Classically, authors have recognized one widespread taxon (O. insectifera) and two endemics (O. aymoninii from France and O. subinsectifera from Spain). Our research has identified clear morphological and ecological factors segregating among these taxa; however, genetic differences were more ambiguous. Insights from cpDNA sequencing and amplified fragment length polymorphisms genotyping indicated a recent diversification in the three extant Fly Orchid species, which may have been further obscured by active migration and admixture across the European continent. Our genetic results still indicate weak but noticeable phylogeographic clustering that partially correlates with the described species. Particularly, we report several isolated haplotypes and genetic clusters in central and southeastern Europe. With regard to the morphological, ecological and genetic aspects, we discuss the endemism status within the Fly Orchid group from evolutionary, taxonomical and conservation perspectives. 23198819 Bioinspired and highly oriented clay nanocomposites with a xyloglucan biopolymer matrix: extending the range of mechanical and barrier properties. The development of clay bionanocomposites requires processing routes with nanostructural control. Moreover, moisture durability is a concern with water-soluble biopolymers. Here, oriented bionanocomposite coatings with strong in-plane orientation of clay platelets are for the first time prepared by continuous water-based processing. Montmorillonite (MTM) and a "new" unmodified biological polymer (xyloglucan (XG)) are combined. The resulting nanocomposites are characterized by FE-SEM, TEM, and XRD. XG adsorption on MTM is measured by quartz crystal microbalance analysis. Mechanical and gas barrier properties are measured, also at high relative humidity. The reinforcement effects are modeled. XG dimensions in composites are estimated using atomistic simulations. The nanostructure shows highly oriented and intercalated clay platelets. The reinforcement efficiency and effects on barrier properties are remarkable and are likely to be due to highly oriented and well-dispersed MTM and strong XG-MTM interactions. Properties are well preserved in humid conditions and the reasons for this are discussed. 23493449 Development of N-Hydroxycinnamamide-Based Histone Deacetylase Inhibitors with Indole-Containing Cap Group. A novel series of histone deacetylase inhibitors combining N-hydroxycinnamamide bioactive fragment and indole bioactive fragment was designed and synthesized. Several compounds (17c, 17g, 17h, 17j and 17k) exhibited comparable even superior total HDACs inhibitory activity and in vitro antiproliferative activities relative to the approved drug SAHA. A representative compound 17a with moderate HDACs inhibition was progressed to isoform selectivity profile, western blot analysis and in vivo antitumor assay. Although HDACs isoform selectivity of 17a was similar to that of SAHA, our western blot results indicated that intracellular effects of 17a at 1 μM were class I selective. It was noteworthy that the effect on histone H4 acetylation of SAHA decreased with time while the effect on histone H4 acetylation of 17a maintained even increased. Most importantly, compound 17a exhibited promising in vivo antitumor activity in a U937 xenograft model. 23235435 Computational study of the spin-state energies and UV-Vis spectra of bis(1,4,7-triazacyclononane) complexes of some first-row transition metal cations. We report here computed spin-state energies and UV-Vis spectra for several transition metal complexes with a triazacyclononane ligand. Our results show that the spin ground-state is correctly obtained with either OPBE or SSB-D, except for the high-spin ground-state of the Co(ii) complex that was properly described only by SSB-D. The UV-Vis spectra from TD-DFT reproduce in general rather well the experimental spectra, but in cases of the Cr(iii) and Co(ii) complexes it clearly failed. Better results for the UV-Vis spectra have been obtained by using Ligand Field DFT. 23360232 Surface-modified HK:siRNA nanoplexes with enhanced pharmacokinetics and tumor growth inhibition. We characterized in this study the pharmacokinetics and antitumor efficacy of histidine-lysine (HK):siRNA nanoplexes modified with PEG and a cyclic RGD (cRGD) ligand targeting αvβ3 and αvβ5 integrins. With noninvasive imaging, systemically administered surface-modified HK:siRNA nanoplexes showed nearly 4-fold greater blood levels, 40% higher accumulation in tumor tissue, and 60% lower luciferase activity than unmodified HK:siRNA nanoplexes. We then determined whether the surface-modified HK:siRNA nanoplex carrier was more effective in reducing MDA-MB-435 tumor growth with an siRNA targeting Raf-1. Repeated systemic administration of the selected surface modified HK:siRNA nanoplexes targeting Raf-1 showed 35% greater inhibition of tumor growth than unmodified HK:siRNA nanoplexes and 60% greater inhibition of tumor growth than untreated mice. The improved blood pharmacokinetic results and tumor localization observed with the integrin-targeting surface modification of HK:siRNA nanoplexes correlated with greater tumor growth inhibition. This investigation reveals that through control of targeting ligand surface display in association with a steric PEG layer, modified HK: siRNA nanoplexes show promise to advance RNAi therapeutics in oncology and potentially other critical diseases. 23337202 Self-Assembly of Discrete Metal Complexes in Aqueous Solution via Block Copolypeptide Amphiphiles. The integration of discrete metal complexes has been attracting significant interest due to the potential of these materials for soft metal-metal interactions and supramolecular assembly. Additionally, block copolypeptide amphiphiles have been investigated concerning their capacity for self-assembly into structures such as nanoparticles, nanosheets and nanofibers. In this study, we combined these two concepts by investigating the self-assembly of discrete metal complexes in aqueous solution using block copolypeptides. Normally, discrete metal complexes such as [Au(CN)(2)]-, when molecularly dispersed in water, cannot interact with one another. Our results demonstrated, however, that the addition of block copolypeptide amphiphiles such as K(183)L(19) to [Au(CN)(2)]- solutions induced one-dimensional integration of the discrete metal complex, resulting in photoluminescence originating from multinuclear complexes with metal-metal interactions. Transmission electron microscopy (TEM) showed a fibrous nanostructure with lengths and widths of approximately 100 and 20 nm, respectively, which grew to form advanced nanoarchitectures, including those resembling the weave patterns of Waraji (traditional Japanese straw sandals). This concept of combining block copolypeptide amphiphiles with discrete coordination compounds allows the design of flexible and functional supramolecular coordination systems in water. 23644652 An associative capacitive network based on nanoscale complementary resistive switches for memory-intensive computing. We report on the implementation of an Associative Capacitive Network (ACN) based on the nondestructive capacitive readout of two Complementary Resistive Switches (2-CRSs). ACNs are capable of performing a fully parallel search for Hamming distances (i.e. similarity) between input and stored templates. Unlike conventional associative memories where charge retention is a key function and hence, they require frequent refresh cycles, in ACNs, information is retained in a nonvolatile resistive state and normal tasks are carried out through capacitive coupling between input and output nodes. Each device consists of two CRS cells and no selective element is needed, therefore, CMOS circuitry is only required in the periphery, for addressing and read-out. Highly parallel processing, nonvolatility, wide interconnectivity and low-energy consumption are significant advantages of ACNs over conventional and emerging associative memories. These characteristics make ACNs one of the promising candidates for applications in memory-intensive and cognitive computing, switches and routers as binary and ternary Content Addressable Memories (CAMs) and intelligent data processing. 23322347 Emerging mechanistic targets in lung injury induced by combustion-generated particles. The mechanism for biological effect following exposure to combustion-generated particles is incompletely defined. The identification of pathways regulating the acute toxicological effects of these particles provides specific targets for therapeutic manipulation in an attempt to impact disease following exposures. Transient receptor potential (TRP) cation channels were identified as "particle sensors" in that their activation was coupled with the initiation of protective responses limiting airway deposition and inflammatory responses, which promote degradation and clearance of the particles. TRPA1, V1, V4, and M8 have a capacity to mediate adverse effects after exposure to combustion-generated particulate matter (PM); relative contributions of each depend upon particle composition, dose, and deposition. Exposure of human bronchial epithelial cells to an organic extract of diesel exhaust particle was followed by TRPV4 mediating Ca(++) influx, increased RAS expression, mitogen-activated protein kinase signaling, and matrix metalloproteinase-1 activation. These novel pathways of biological effect can be targeted by compounds that specifically inhibit critical signaling reactions. In addition to TRPs and calcium biochemistry, humic-like substances (HLS) and cell/tissue iron equilibrium were identified as potential mechanistic targets in lung injury after particle exposure. In respiratory epithelial cells, iron sequestration by HLS in wood smoke particle (WSP) was associated with oxidant generation, cell signaling, transcription factor activation, and release of inflammatory mediators. Similar to WSP, cytotoxic insoluble nanosized spherical particles composed of HLS were isolated from cigarette smoke condensate. Therapies that promote bioelimination of HLS and prevent the disruption of iron homeostasis could function to reduce the harmful effects of combustion-generated PM exposure. 22420410 Structure elucidation of a new natural diketopiperazine from a Microbispora aerata strain isolated from Livingston Island, Antarctica. A new natural diketopiperazine (1) was obtained from the culture broth of Microbispora aerata strain imbas-11A, isolated from penguin excrements collected on the Antarctic Livingston Island. Compound 1 was purified consecutively by solvent extraction, silica gel column chromatography and preparative HPLC. The structure of the compound was elucidated by 1D and 2D NMR experiments and mass spectrometric investigations. The absolute configuration of compound 1 was determined by amino acid analysis and NOESY correlations. A low antiproliferative and cytotoxic effect of trans-cyclo-(D-tryptophanyl-L-tyrosyl) (1) was determined with L-929 mouse fibroblast cells, K-562 human leukemia cells and HeLa human cervix carcinoma. Trans-cyclo-(D-tryptophanyl-L-tyrosyl) (1) did not show antimicrobial activity at a concentration of 50 µg per disc against Bacillus subtilis, Staphylococcus aureus, Streptomyces viridochromogenes, Escherichia coli, Candida albicans and Mucor miehei. 23234855 Influence of carboxylic acid functionalities in ruthenium (II) polypyridyl complexes on DNA binding, cytotoxicity and antioxidant activity: synthesis, structure and in vitro anticancer activity. Four new Ru(II) complexes [RuHCl(bpy)(PPh(3))(CO)] (1), [RuHCl(bpy)(AsPh(3))(CO)] (2) (bpy = 2,2'-bipyridine), [RuCl(HL)(PPh(3))(2)(CO)] (3) and [RuCl(HL)(AsPh(3))(2)(CO)] (4) (HL = 2,2'-bipyridine-4,4'-dicarboxylic acid) were synthesized and characterized. X-ray diffraction was used to characterize 3 in solid state. The interactions of these complexes with DNA were explored by different techniques which revealed that the complexes could bind to CT-DNA through non-intercalation. The in vitro cytotoxic and antioxidant activities of the complexes validated against a panel of cancer cell lines and free radicals showed that 3 and 4 possess quite high anticancer and antioxidant activities over 1, 2 and standard drugs. An apparent dependence of biological activities on incorporation of COOH in bipyridine moiety was noticed: Inclusion of COOH caused significant differences in DNA binding, cytotoxicity and antioxidant activity. 23074173 The iron chelator, deferasirox, as a novel strategy for cancer treatment: oral activity against human lung tumor xenografts and molecular mechanism of action. Deferasirox is an orally effective iron (Fe) chelator currently used for the treatment of iron-overload disease and has been implemented as an alternative to the gold standard chelator, desferrioxamine (DFO). Earlier studies demonstrated that DFO exhibits anticancer activity due to its ability to deplete cancer cells of iron. In this investigation, we examined the in vitro and in vivo activity of deferasirox against cells from human solid tumors. To date, there have been no studies to investigate the effect of deferasirox on these types of tumors in vivo. Deferasirox demonstrated similar activity at inhibiting proliferation of DMS-53 lung carcinoma and SK-N-MC neuroepithelioma cell lines compared with DFO. Furthermore, deferasirox was generally similar or slightly more effective than DFO at mobilizing cellular (59)Fe and inhibiting iron uptake from human transferrin depending on the cell type. However, deferasirox potently inhibited DMS-53 xenograft growth in nude mice when given by oral gavage, with no marked alterations in normal tissue histology. To understand the antitumor activity of deferasirox, we investigated its effect on the expression of molecules that play key roles in metastasis, cell cycle control, and apoptosis. We demonstrated that deferasirox increased expression of the metastasis suppressor protein N-myc downstream-regulated gene 1 and upregulated the cyclin-dependent kinase inhibitor p21(CIP1/WAF1) while decreasing cyclin D1 levels. Moreover, this agent increased the expression of apoptosis markers, including cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase 1. Collectively, we demonstrate that deferasirox is an orally effective antitumor agent against solid tumors. 22954532 Attenuated effect of tungsten carbide nanoparticles on voltage-gated sodium current of hippocampal CA1 pyramidal neurons. Nanomaterials and relevant products are now being widely used in the world, and their safety becomes a great concern for the general public. Tungsten carbide nanoparticles (nano-WC) are widely used in metallurgy, aeronautics and astronautics, however our knowledge regarding the influence of nano-WC on neurons is still lacking. The aim of this study was to investigate the impact of nano-WC on tetrodotoxin (TTX)-sensitive voltage-activated sodium current (I(Na)) of hippocampal CA1 pyramidal neurons. Results showed that acute exposure of nano-WC attenuated the peak amplitudes of I(Na) in a concentration-dependent manner. The minimal effective concentration was 10(-5)g/ml. The exposure of nano-WC significantly decreased current amplitudes of the current-voltage curves of I(Na) from -50 to+50 mV, shifted the steady-state activation and inactivation curves of I(Na) negatively and delayed the recovery of I(Na) from inactivation state. After exposure to nano-WC, the peak amplitudes, overshoots and the V-thresholds of action potentials (APs) were markedly reduced. These results suggested that exposure of nano-WC could influence some characteristics of APs evoked from the hippocampal CA1 neurons by modifying the kinetics of voltage-gated sodium channels (VGSCs). 23246865 Lead-induced neurodegenerative events and abnormal behaviors occur via ORXRergic/GABA(A)Rergic mechanisms in a marine teleost. The hindering effects of metals and in particular lead (Pb) are representing a growing threat to aquatic organisms such as fish. This observation derives from toxic concentrations of Pb accounting for altered neurophysiological activities of some interesting teleost models like Thalassoma pavo, a fish species highly known for its host-cleaning symbiosis. In this study, the nominal PbNO(3) concentration of 1.6 mg/L was capable of reducing feeding and resting bouts as early as 24 h of exposure while hyperactive swimming episodes were also detected. Such abnormal behaviors were tightly correlated to up-regulated orexin receptor (ORXR) mRNA expression levels in some brain areas such as the lateral thalamic nucleus (+213%) and the optic tectum (+90%) with respect to controls. Interestingly, these transcriptional effects seemed to be attenuated when Pb-exposed fish received either 100 ng/g of ORX-A (-70%) or 0.1 μg/g of γ-aminobutyric acid(A) receptor (GABA(A)R) agonist muscimol (MUS; -97%) compared to fish exposed to Pb alone. Moreover, a net neurodegenerative process of the different brain areas was reported after Pb exposure as displayed by their marked amino cupric silver stained cells while these cells were devoid of any staining reaction after treatment with MUS only. Conversely, addition of the GABA(A)R antagonist bicuculline (BIC; 1 μg/g) moderately (p<0.05) enhanced Pb-dependent behavioral and neurodegenerative actions. Overall, these first indications strongly point to altered ORXR/GABA(A)R interactions during neurotoxic events of a metal that by evoking harmful neurobiological dysfunctions may endanger the survival of commercially valuable fish with eventual repercussions on human health. 23339577 Redox-active π-conjugated organometallic monolayers: pronounced Coulomb blockade characteristic at room temperature. We report the electrical transport characteristics of a series of molecular wires, fc-C≡C-C6H4-SAc (fc = ferrocenyl; Ac = acetyl) and AcS-C6H4-C≡C-(fc)n-C≡C-C6H4-SAc (n = 2, 3), consisting of multiple redox-active ferrocenyl centers. The self-assembled monolayers of these molecular wires on Au surfaces were comprehensively characterized by electrochemistry and conductive atomic force microscopy techniques. Characterization of the wires revealed that electron transport is made extremely efficient by the organometallic redox states. There is a strong electronic coupling between ferrocenyl moieties, and superior electron-transport ability exists through these semirigid molecular wires. Standard rate constants for the electron transfer between the electrode and the ferrocenyl moieties were measured for the monolayers by a potential-step chronoamperometry technique. The electron conduction through the molecular wires was estimated using the monolayers as a bridge from the Au(111) metal surface to the gold tip of a conductive atomic force microscope (CAFM). Using the CAFM, Coulomb blockade behavior arising from the capacitive charging of the multinuclear redox-active molecules was observed at room temperature. The conductance switching was mediated by the presence of various ferrocenyl redox states and each current step corresponded to a specific redox state. 23436791 A combination strategy to inhibit Pim-1: synergism between noncompetitive and ATP-competitive inhibitors. Pim-1 is a serine/threonine kinase critically involved in the initiation and progression of various types of cancer, especially leukemia, lymphomas and solid tumors such as prostate, pancreas and colon, and is considered a potential drug target against these malignancies. In an effort to discover new potent Pim-1 inhibitors, a previously identified ATP-competitive indolyl-pyrrolone scaffold was expanded to derive structure-activity relationship data. A virtual screening campaign was also performed, which led to the discovery of additional ATP-competitive inhibitors as well as a series of 2-aminothiazole derivatives, which are noncompetitive with respect to both ATP and peptide substrate. This mechanism of action, which resembles allosteric inhibition, has not previously been characterized for Pim-1. Notably, further evaluation of the 2-aminothiazoles indicated a synergistic inhibitory effect in enzymatic assays when tested in combination with ATP-competitive inhibitors. A synergistic effect in the inhibition of cell proliferation by ATP-competitive and ATP-noncompetitive compounds was also observed in prostate cancer cell lines (PC3), where all Pim-1 inhibitors tested in showed synergism with the known anticancer agent, paclitaxel. These results further establish Pim-1 as a target in cancer therapy, and highlight the potential of these agents for use as adjuvant agents in the treatment of cancer diseases in which Pim-1 is associated with chemotherapeutic resistance. 23596359 Exploring the Energy Landscapes of Cyclic Tetrapeptides with Discrete Path Sampling. Cyclic tetrapeptides are an important class of biologically active molecules that exhibit interesting conformational dynamics, with slow interconversion of several different structures. We present calculations on their energy landscapes using discrete path sampling. In acyclic peptides and large cyclic peptides, isomers containing cis-peptide groups are much less stable than the all-trans isomers and separated from them by large barriers. Strain in small cyclic peptides causes the cis and trans isomers to be closer in energy and separated by much lower barriers. If d-amino acids or proline residues are introduced, isomers containing cis-peptides become more stable than the all-trans structures. We also show that changing the polarity of the solvent has a significant effect on the energy landscapes of cyclic tetrapeptides, causing changes in the orientations of the peptide groups and in the degree of intramolecular hydrogen bonding. 23610057 Resistance to aerobic exercise training causes metabolic dysfunction and reveals novel exercise-regulated signaling networks. Low aerobic exercise capacity is a risk factor for diabetes and strong predictor of mortality; yet some individuals are "exercise resistant", and unable to improve exercise capacity through exercise training. To test the hypothesis that resistance to aerobic exercise training underlies metabolic disease-risk, we used selective breeding for 15 generation to develop rat models of low- and high-aerobic response to training. Before exercise training, rats selected as low- and high-responders had similar exercise capacities. However, after 8-wks of treadmill training low-responders failed to improve their exercise capacity, while high-responders improved by 54%. Remarkably, low-responders to aerobic training exhibited pronounced metabolic dysfunction characterized by insulin resistance and increased adiposity, demonstrating that the "exercise resistant" phenotype segregates with disease risk. Low-responders had impaired exercise-induced angiogenes0is in muscle; however, mitochondrial capacity was intact and increased normally with exercise training, demonstrating that mitochondria are not limiting for aerobic adaptation or responsible for metabolic dysfunction in low-responders. Low-responders had increased stress/inflammatory signaling and altered TGFβ signaling, characterized by hyperphosphorylation of a novel exercise-regulated phosphorylation site on SMAD2. Using this powerful biological model system we have discovered key pathways for low exercise training response that may represent novel targets for the treatment of metabolic disease. 23380243 Epigenetics and pesticides. Pesticides, a wide class of environmental contaminants, may cause both acute and delayed health effects in exposed subjects. These effects can range from simple irritation of the skin and eyes to more severe effects such as affecting the nervous system, the reproductive system and cancer. The molecular mechanisms underlying such effects are still under investigation. Epigenetics is the study of heritable changes in gene expression that occur without a change in the DNA sequence. Several epigenetic mechanisms, including DNA methylation, histone modifications and microRNA expression, can be triggered by environmental factors. We review current evidences indicating that epigenetic modifications may mediate pesticide effects on human health. In vitro, animal, and human investigations have identified several classes of pesticides that modify epigenetic marks, including endocrine disruptors, persistent organic pollutants, arsenic, several herbicides and insecticides. Several investigations have examined the effects of environmental exposures and epigenetic markers, and identified toxicants that modify epigenetic states. These modifications are similar to the ones found in pathological tissue samples. In spite of the current limitations, available evidence supports the concept that epigenetics holds substantial potential for furthering our understanding of the molecular mechanisms of pesticides health effects, as well as for predicting health-related risks due to conditions of environmental exposure and individual susceptibility. 23023136 Resveratrol attenuates hepatotoxicity of rats exposed to arsenic trioxide. Arsenic trioxide (As(2)O(3)) is an environmental pollutant and potent toxicant to humans. However, it also shows substantial anti-cancer activity in individuals with acute promyelocytic leukemia (APL). Unfortunately, As(2)O(3)-treated leukemia patients suffer hepatotoxicity. Resveratrol has been demonstrated to have efficient antioxidant and antineoplastic activities. The study that how As(2)O(3) in combination with resveratrol affects hepatotoxicity and arsenic accumulation in the liver is lacking, and the present study tackles this question. Wistar rats were injected with 3mg/kg As(2)O(3) on alternate days; resveratrol (8mg/kg) was administered 1h before As(2)O(3). Rats were killed on the 8th day to determine histological liver damage, the antioxidant enzymes in serum, the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), and arsenic accumulation in the liver. In the resveratrol+As(2)O(3) group, activities of superoxide dismutase, catalase in serum and GSH/GSSG were significantly increased, histopathological effects were reduced, and arsenic accumulation markedly decreased in the liver, compared with the As(2)O(3)-treated group. Thus, resveratrol attenuated As(2)O(3)-induced hepatotoxicity by decreasing oxidative stress and arsenic accumulation in the liver. These data suggest that use of resveratrol as post-remission therapy of APL and adjunctive therapy in patients with chronic exposure to arsenic may decrease arsenic hepatotoxicity. 23600656 Brucine-loaded liposomes composed of HSPC and DPPC at different ratios: in vitro and in vivo evaluation. Abstract Objective: The objective of this study is to test the hypothesis that the phase transition temperature (Tm), the main property of liposomes, can be easily controlled by changing the molar ratio of hydrogenated soy phosphatidylcholine (HSPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphacholine (DPPC) after drug encapsulation. Materials and methods: Brucine, an antitumor alkaloid, was encapsulated into the liposomes with different HSPC/DPPC compositions. The Tms of the brucine-loaded liposomes (BLs) were determined by differential scanning calorimetry (DSC). Then the physicochemical properties and pharmacokinetics of the BLs with different HSPC/DPPC compositions were investigated and compared. Results: The results of DSC revealed that HSPC and DPPC can combine into one phase. The findings of molecular modeling study suggested that HSPC interacts with DPPC via electrostatic interaction. The molar ratio of HSPC/DPPC influenced the sizes of BLs but had little effect on the entrapment efficiency (EE). The stability of BLs was improved with the increase of the HSPC ratios, especially with the presence of plasma. Following i.v. administration, it was found that AUC values of BLs in vivo were directly related to the HSPC/DPPC ratios of BLs, namely the Tms of BLs. Discussion: The behavior of liposomes, especially in vivo pharmacokinetic behavior, can be controlled by the modification of Tm. Conclusion: The characterization of BLs in vitro and in vivo had demonstrated that the Tm could be flexibly modified for liposomes composed of both HSPC and DPPC. Using HSPC/DPPC composition may be an efficient strategy to control the Tm, thus control the in vivo pharmacokinetic behavio, of BLs. 23462212 Anti-secretory and cyto-protective effects of chebulinic acid isolated from the fruits of Terminalia chebula on gastric ulcers. In continuation of our drug discovery program on Indian medicinal plants, the gastro protective mechanism of chebulinic acid isolated from Terminalia chebula fruit was investigated. Chebulinic acid was evaluated against cold restraint (CRU), aspirin (AS), alcohol (AL) and pyloric ligation (PL) induced gastric ulcer models in rats. Potential anti-ulcer activity of chebulinic acid was observed against CRU (62.9%), AS (55.3%), AL (80.67%) and PL (66.63%) induced ulcer models. The reference drug omeprazole (10mg/kg, p.o.) showed 77.73% protection against CRU, 58.30% against AS and 70.80% against PL model. Sucralfate, another reference drug (500mg/kg, p.o.) showed 65.67% protection in AL induced ulcer model. Chebulinic acid significantly reduced free acidity (48.82%), total acidity (38.29%) and upregulated mucin secretion by 59.75% respectively. Further, chebulinic acid significantly inhibited H(+) K(+)-ATPase activity in vitro with IC50 of 65.01μg/ml as compared to the IC50 value of omeprazole (30.24μg/ml) confirming its anti-secretory activity. 23038768 A calibrated human Y-chromosomal phylogeny based on resequencing. We have identified variants present in high-coverage complete sequences of 36 diverse human Y chromosomes from Africa, Europe, South Asia, East Asia, and the Americas, representing eight major haplogroups. After restricting our analysis to 8.97 Mb of the unique male-specific Y sequence, we identified 6662 high-confidence variants, including single-nucleotide polymorphisms (SNPs), multi-nucleotide polymorphisms (MNPs), and indels. We constructed phylogenetic trees using these variants, or subsets of them, and recapitulated the known structure of the tree. Assuming a male mutation rate of 1 × 10(-9) per base pair per year, the time depth of the tree (haplogroups A3-R) was ~101,000-115,000 yr, and the lineages found outside Africa dated to 57,000-74,000 yr, both as expected. In addition, we dated a striking Paleolithic male lineage expansion to 41,000-52,000 yr ago and the node representing the major European Y lineage, R1b, to 4000-13,000 yr ago, supporting a Neolithic origin for these modern European Y chromosomes. In all, we provide a nearly 10-fold increase in the number of Y markers with phylogenetic information, and novel historical insights derived from placing them on a calibrated phylogenetic tree. 23377617 Decreased zinc availability affects glutathione metabolism in neuronal cells and in the developing brain. A deficit in zinc (Zn) availability can increase cell oxidant production, affect the antioxidant defense system, and trigger oxidant-sensitive signals in neuronal cells. This work tested the hypothesis that a decreased Zn availability can affect glutathione (GSH) metabolism in the developing rat brain and in neuronal cells in culture, as well as the capacity of human neuroblastoma IMR-32 cells to upregulate GSH when challenged with dopamine (DA). GSH levels were low in the brain of gestation day 19 (GD19) fetuses from dams fed marginal Zn diets throughout gestation and in Zn-deficient IMR-32 cells. γ-Glutamylcysteine synthetase (GCL), the first enzyme in the GSH synthetic pathway, was altered by Zn deficiency (ZD). The protein and mRNA levels of the GCL modifier (GCLM) and catalytic (GCLC) subunits were lower in the Zn-deficient GD19 fetal brain and in IMR-32 cells compared with controls. The nuclear translocation of transcription factor nuclear factor (erythroid-derived 2)-like 2, which controls GCL transcription, was impaired by ZD. Posttranslationally, the caspase-3-dependent GCLC cleavage was high in Zn-deficient IMR-32 cells. Cells challenged with DA showed an increase in GCLM and GCLC protein and mRNA levels and a consequent increase in GSH concentration. Although Zn-deficient cells partially upregulated GCL subunits after exposure to DA, GSH content remained low. In summary, results show that a low Zn availability affects the GSH synthetic pathway in neuronal cells and fetal brain both at transcriptional and posttranslational levels. This can in part underlie the GSH depletion associated with ZD and the high sensitivity of Zn-deficient neurons to pro-oxidative stressors. 23108851 On the origin of chirality in nanoplasmonic gyroid metamaterials. Metallic single gyroids, a new class of self-assembled nanoplasmonic metamaterials, are analyzed on the basis of a tri-helical metamaterial model. The physical mechanisms underlying the chiral optical behavior of the nanoplasmonic single gyroid are identified and it is shown that the optical chirality in this metallic structure is primarily determined by structural chirality and the connectivity of helices along the main cubic axes. 23212787 Fast screening of authentic ginseng products by surface desorption atmospheric pressure chemical ionization mass spectrometry. Surface desorption atmospheric pressure chemical ionization mass spectrometry was developed as a rapid online detection technology for the chemical fingerprints of ginseng products without any sample pretreatment. More than 20 ginsenosides were detected in the ginseng tissue and identified by their tandem mass spectrometry. Data were well matched with their reference compounds. Herein, surface desorption atmospheric pressure chemical ionization mass spectrometry was first applied to study the nonvolatile compounds in ginseng. White and red ginseng have been successfully differentiated from their counterfeits using some ginsenosides as chemical markers. Ginsenoside can be used to differentiate between white ginseng, red ginseng, unboiled ginseng, and their counterfeits. Ginsenosides Ra1-3, Rb2-3, and Rc might be used to differentiate between white ginseng and boiled ginseng. Our result showed that surface desorption atmospheric pressure chemical ionization mass spectrometry not only could be used for fast screening authentic ginseng products but also might become a useful promising technique for the characterization of nonvolatile compounds in medicinal herbs to save researchers the laborious effort of sample pretreatment. 23561191 Hepatic biotransformation of alkylresorcinols is mediated via cytochrome P450 and β-oxidation: A proof of concept study. Alkylresorcinols (AR) are phenolic lipids present in the bran of some cereals. AR may serve as a biomarker for whole grain wheat and rye intake. While AR pharmacokinetics and two major metabolites have been reported, the metabolic pathways contributing to their relatively rapid elimination from the circulation remain to be speculative. In this study, we investigated if ω- and β-oxidation mediate catabolism of the AR homologue C19:0 to form 3,5-dihydroxybenzoic acid and 3-(3,5-dihydroxyphenyl)-1-propanoic acid (DHPPA), using 3 in vitro platforms, human cytochrome P450 4F2 (CYP4F2), human liver S9, and HepG2 cells. One hydroxylated C19:0 metabolite was formed by CYP4F2 and one hydroxylated and one carboxylated C19:0 were tentatively identified after incubation of AR with S9. The formation of DHPPA was quantifiable when HepG2 cells were treated with C19:0 for 48h. Our results are consistent with a metabolic pathway by which AR are degraded to phenolic acids via CYP4F2-mediated ω-oxidation and subsequent β-oxidation. 23472738 Anion-Exchange Reactions on a Robust Phosphonium Photopolymer for the Controlled Deposition of Ionic Gold Nanoclusters. UV curing (photopolymerization) is ubiquitous in many facets of industry ranging from the application of paints, pigments, and barrier coatings all the way to fiber optic cable production. To date no reports have focused on polymerizable phosphonium salts under UV irradiation, and despite this dearth of examples, they potentially offer numerous substantial advantages to traditional UV formulation components. We have generated a highly novel coating based on UV-curable trialkylacryloylphosphonium salts that allow for the fast (seconds) and straightforward preparation of ion-exchange surfaces amenable to a roll-to-roll process. We have quantified the surface charges and exploited their accessibility by employing these surfaces in an anion exchange experiment by which [Au25L18](-) (L = SCH2CH2Ph) nanocrystals can be assembled into the solid state. This unprecedented application of such surfaces offers a paradigm shift in the emerging chemistry of Au25 research where the nanocrystals remain single and intact and where the integrity of the cluster and its solution photophysical properties are resilient in the solid state. The specific loading of [Au25L18](-) on the substrates has been determined and the completely reversible loading and unloading of intact nanocrystals to and from the surface has been established. In the solid state, the assembly has an incredible mechanical resiliency, where the surface remains undamaged even when subjected to repeated Scotch tests. 23289710 Mammalian Trit1 is a tRNA([Ser]Sec)-isopentenyl transferase required for full selenoprotein expression. Selenoproteins are proteins carrying the rare amino acid Sec (selenocysteine). Full expression of selenoproteins requires modification of tRNA([Ser]Sec), including N(6)-isopentenylation of base A(37). We show that Trit1 is a dimethylallyl:tRNA([Ser]Sec) transferase. Knockdown of Trit1 reduces expression of selenoproteins. Incubation of in vitro transcribed tRNA[Ser]Sec with recombinant Trit1 transfers [(14)C]dimethylallyl pyrophosphate to tRNA([Ser]Sec). 37A>G tRNA([Ser]Sec) is resistant to isopentenylation by Trit1. 23545108 Discovery of a novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors. A novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors were derived from a fragment-based approach using information from X-ray crystallographic analysis of NS5B-inhibitor complexes and iterative rounds of parallel synthesis. Structure-based drug design strategies led to the discovery of potent sub-micromolar inhibitors 11a-c and 12a-c from a weak-binding fragment-like structure 1 as a starting point. 23430761 Design and evaluation of ondansetron liquid suppository for the treatment of emesis. The thermosensitive-mucoadhesive ondansetron liquid suppository (tmOLS) was developed to enhance patient compliance and bioavailability in high-risk patients receiving highly emetogenic therapy and having difficulty in swallowing, The thermosensitive-mucoadhesive liquid suppository bases were formulated using poloxamers (P407 and P188) and hydroxypropylmethyl cellulose (HPMC). The physicochemical properties of the liquid suppository bases were characterized by their gelation temperature, mucoadhesive force, rheological properties, and in vitro release. Rectal mucosal damage following rectal administration of tmOLS in rats was assessed using microscopy. Pharmacokinetic analyses were performed to compare tmOLS administered via the rectal route to ondansetron solution administered orally. The liquid suppository base of tmOLS contained P407, P188, and HPMC in the ratio 18:20:0.8, was in the liquid state at room temperature, underwent gelation at body temperature. Area under the curve and half-life (t(1/2)) of ondansetron were significantly higher in the tmOLS-treated group, indicating that the formulation bypassed the first-pass metabolism and that it was released slowly from the tmOLS because of the formation of mucoadhesive gel state. Furthermore, the t(1/2) of tmOLS was two-fold that of the oral solution. Thus, tmOLS could be administered to patients who have difficulty in swallowing; however, adjustments in dosing interval may be needed. 23276627 Methylation damage to RNA induced in vivo in Escherichia coli is repaired by endogenous AlkB as part of the adaptive response. Cytotoxic 1-methyladenine (1-meA) and 3-methylcytosine (3-meC) lesions induced in DNA and RNA in vitro and in pre-damaged DNA and RNA bacteriophages in vivo are repaired by the Escherichia coli (E. coli) protein AlkB and a human homolog, ALKBH3. However, it is not known whether endogenous RNA is repaired in vivo by repair proteins present at physiological concentrations. The concept of RNA repair as a biologically relevant process has therefore remained elusive. Here, we demonstrate AlkB-mediated repair of endogenous RNA in vivo by measuring differences in lesion-accumulation in two independent AlkB-proficient and deficient E. coli strains during exposure to methyl methanesulfonate (MMS). Repair was observed both in AlkB-overproducing strains and in the wild-type strains after AlkB induction. RNA repair appeared to be highest in RNA species below 200 nucleotides in size, mainly comprising tRNAs. Strikingly, at least 10-fold more lesions were repaired in RNA than in DNA. This may be a consequence of some 30-fold higher levels of aberrant methylation in RNA than in DNA after exposure to MMS. A high primary kinetic isotope effect (>10) was measured using a deuterated methylated RNA substrate, D3-1me(rA), demonstrating that it is the catalytic step, and not the search step that is rate-limiting. Our results demonstrate that RNA repair by AlkB takes place in endogenous RNA as part of an adaptive response in wild-type E. coli cells. 23470922 Water deficit and heat affect the tolerance to high illumination in hibiscus plants. This work studies the effects of water deficit and heat, as well as the involvement of chlororespiration and the ferredoxin-mediated cyclic pathway, on the tolerance of photosynthesis to high light intensity in Hibiscus rosa-sinensis plants. Drought and heat resulted in the down-regulation of photosynthetic linear electron transport in the leaves, although only a slight decrease in variable fluorescence (Fv)/maximal fluorescence (Fm) was observed, indicating that the chloroplast was protected by mechanisms that dissipate excess excitation energy to prevent damage to the photosynthetic apparatus. The incubation of leaves from unstressed plants under high light intensity resulted in an increase of the activity of electron donation by nicotinamide adenine dinucleotide phosphate (NADPH) and ferredoxin to plastoquinone, but no increase was observed in plants exposed to water deficit, suggesting that cyclic electron transport was stimulated by high light only in control plants. In contrast, the activities of the chlororespiration enzymes (NADH dehydrogenase (NDH) complex and plastid terminal oxidase (PTOX)) increased after incubation under high light intensity in leaves of the water deficit plants, but not in control plants, suggesting that chlororespiration was stimulated in stressed plants. The results indicate that the relative importance of chlororespiration and the cyclic electron pathway in the tolerance of photosynthesis to high illumination differs under stress conditions. When plants were not subjected to stress, the contribution of chlororespiration to photosynthetic electron flow regulation was not relevant, and another pathway, such as the ferredoxin-mediated cyclic pathway, was more important. However, when plants were subjected to water deficit and heat, chlororespiration was probably essential. 23307663 Fueling open-source drug discovery: 177 small-molecule leads against tuberculosis. With the aim of fuelling open-source, translational, early-stage drug discovery activities, the results of the recently completed antimycobacterial phenotypic screening campaign against Mycobacterium bovis BCG with hit confirmation in M. tuberculosis H37Rv were made publicly accessible. A set of 177 potent non-cytotoxic H37Rv hits was identified and will be made available to maximize the potential impact of the compounds toward a chemical genetics/proteomics exercise, while at the same time providing a plethora of potential starting points for new synthetic lead-generation activities. Two additional drug-discovery-relevant datasets are included: a) a drug-like property analysis reflecting the latest lead-like guidelines and b) an early lead-generation package of the most promising hits within the clusters identified. 23154582 Applications of asymmetric organocatalysis in medicinal chemistry. In the last decade, organocatalysis, the use of small chiral organic molecules as catalysts, has proven to be a valuable and attractive tool for the synthesis of enantiomerically enriched molecules. A number of organocatalysts and processes, such as one-pot, tandem, cascade or multicomponent reactions, have been reported to date. Furthermore, the many advantages of organocatalysis - robust, non-toxic, affordable, inert atmosphere, easy reaction manipulation, etc. - allow the preparation of bioactive compounds using simple and metal-free procedures, thus avoiding false positives in the biological evaluation. This mini-review focuses on medicinal chemistry programs that have synthesized biologically active compounds using one or more organocatalytic steps. In this respect, the potential of organocatalytic methods for enabling the chemical synthesis of important medicinal targets will be highlighted. 23603907 FOXO3 growth inhibition of colonic cells is dependent on intraepithelial lipid droplet density. Forkhead transcription factor FOXO3 plays a critical role in suppressing tumor growth, in part, by increasing cell cycle inhibitor p27kip1, and Foxo3 deficiency in mice results in marked colonic epithelial proliferation. Here, we show in Foxo3 deficient colonic epithelial cells a striking increase in intracytoplasmic lipid droplets (LDs), a dynamic organelle recently observed in human tumor tissue. While the regulation and function of LDs in non-adipocytes is unclear, we hypothesize that the anti-proliferative effect of FOXO3 was dependent on lowering LD density, thus decreasing fuel energy in both normal and colon cancer cells. In mouse colonic tumors, we found an increased expression of LD coat protein PLIN2 compared to normal colonic epithelial cells. Stimulation of LD density in human colon cancer cells led to PI3K dependent loss of FOXO3 and a decrease in the negative regulator of lipid metabolism Sirtuin6 (SIRT6). Foxo3 deficiency also led to a decrease in SIRT6, revealing the existence of the LD and FOXO3 feedback regulation in colonic cells. In parallel, LD dependent loss of FOXO3 led to its dissociation from the promoter and decreased expression of the cell cycle inhibitor p27kip1. Stimulation of LD density promoted proliferation in colon cancer cells, while silencing PLIN2 or overexpression of FOXO3 inhibited proliferation. Taken together, FOXO3 and LDs might serve as new targets for therapeutic intervention of colon cancer. 23590667 Few-Layer MoS2 with High Broadband Photogain and Fast Optical Switching for Use in Harsh Environments. Few-layered MoS2 as Schottky metal-semiconductor-metal photodetectors (MSM PDs) for use in harsh environments makes its debut as two-dimensional (2D) optoelectronics with high broadband gain (up to 13.3), high detectivity (up to ∼10(10) cm Hz(1/2)/W), fast photoresponse (rise time of ∼70 μs and fall time of ∼110 μs), and high thermal stability (at a working temperature of up to 200 °C). Ultrahigh responsivity (0.57 A/W) of few-layer MoS2 at 532 nm is due to the high optical absorption (∼10% despite being less than 2 nm in thickness) and a high photogain, which sets up a new record that was not achievable in 2D nanomaterials previously. This study opens avenues to develop 2D nanomaterial-based optoelectronics for harsh environments in imaging techniques and light-wave communications as well as in future memory storage and optoelectronic circuits. 23454148 Effect of protein malnutrition on the metabolism and toxicity of cisplatin, 5-fluorouracil and mitomycin C in rat stomach. This study investigated the effect of protein malnutrition on metabolism and toxicity of cisplatin (CP), 5-fluorouracil (FU) and mitomycin C (MMC) in rat stomach. Weanling male Wistar rats received a normal (24%) or low (2.5%) protein diet for 28days and were allocated into: normally-fed control, protein-malnourished control (PM), 3 normally-fed drug-treated groups and 3 protein-malnourished drug-treated groups (PM-CP, PM-FU and PM-MMC). Cisplatin and MMC were injected intraperitoneally (8mg/kg on day 26 and 1mg/kg/day for 7days, respectively). 5-Fluorouracil was given orally (50mg/kg/day for 5days). Compared with normally-fed counterparts, PM-CP rats exhibited higher glutathione S-transferase, aminopeptidase N and cysteine S-conjugate beta-lyase (CCBL) and lower gamma-glutamyltransferase activities, PM-FU rats exhibited decreased dihydropyrimidine dehydrogenase and cytochrome P450 1A1/2 activities and PM-MMC rats showed higher quinone reductase and depleted xanthine oxidase activities. Protein-malnourished drug-treated groups exhibited exacerbated gastrotoxicity, relative to normally-fed counterparts, manifested by lower mucus levels, higher permeability and histopathological deterioration, along with increased oxidative stress in PM-CP rats and exaggerated prostaglandin E2 production in PM-MMC rats. Conclusively, protein malnutrition alters CP, FU and MMC metabolism in rat stomach by enhancing CCBL pathway for CP activation, delaying FU elimination and activating two-electron reduction of MMC, potentiating their gastrotoxicity. 23639652 Synthetic chalcones and sulfonamides as new classes of Yersinia enterocolitica YopH tyrosine phosphatase inhibitors. YopH plays a relevant role in three pathogenic species of Yersinia. Due to its importance in the prevention of the inflammatory response of the host, this enzyme has become a valid target for the identification and development of new inhibitors. In this work, an in-house library of 283 synthetic compounds was assayed against recombinant YopH from Yersinia enterocolitica. From these, four chalcone derivatives and one sulfonamide were identified for the first time as competitive inhibitors of YopH with binding affinity in the low micromolar range. Molecular modeling investigations indicated that the new inhibitors showed similar binding modes, establishing polar and hydrophobic contacts with key residues of the YopH binding site. 23265542 Chemical composition, antimicrobial, cytotoxic and antioxidant activities of the essential oil of Artemisia indica Willd. Essential oil from the aerial parts of Artemisia indica was analysed by GC-FID and GC-MS. A total of 43 compounds representing 96.8% of the oil were identified and the major components were found to be artemisia ketone (42.1%), germacrene B (8.6%), borneol (6.1%) and cis-chrysanthenyl acetate (4.8%). Antimicrobial activity of the oil was evaluated against seven clinically significant bacterial and two fungal strains. The essential oil and its major constituents exhibited moderate to potent, broad-spectrum antibacterial and antifungal activities targeting both Gram-positive and Gram-negative bacteria. In vitro cytotoxicity evaluation against four human cancer cell lines THP-1 (leukemia), A-549 (lung), HEP-2 (liver) and Caco-2 (colon) showed that the essential oil exhibited concentration dependant growth inhibition in the 10-100 μg/ml dilution range, with IC(50) values of 10 μg/ml (THP-1), 25 μg/ml (A-549), 15.5 μg/ml (HEP-2) and 19.5 μg/ml (Caco-2). It was interesting to note that the essential oil also exhibited potent antioxidant activity. 23517546 All Zinc-Blende GaAs/(Ga,Mn)As Core-Shell Nanowires with Ferromagnetic Ordering. Combining self-catalyzed vapor-liquid-solid growth of GaAs nanowires and low-temperature molecular-beam epitaxy of (Ga,Mn)As, we successfully synthesized all zinc-blende (ZB) GaAs/(Ga,Mn)As core-shell nanowires on Si(111) substrates. The ZB GaAs nanowire cores are first fabricated at high temperature by utilizing the Ga droplets as the catalyst and controlling the triple phase line nucleation, then the (Ga,Mn)As shells are epitaxially grown on the side facets of the GaAs core at low temperature. The growth window for the pure phase GaAs/(Ga,Mn)As core-shell nanowires is found to be very narrow. Both high-resolution transmission electron microscopy and scanning electron microscopy observations confirm that all-ZB GaAs/(Ga,Mn)As core-shell nanowires with smooth side surface are obtained when the Mn concentration is not more than 2% and the growth temperature is 245 °C or below. Magnetic measurements with different applied field directions provide strong evidence for ferromagnetic ordering in the all-ZB GaAs/(Ga,Mn)As nanowires. The hybrid nanowires offer an attractive platform to explore spin transport and device concepts in fully epitaxial all-semiconductor nanospintronic structures. 23373613 Pulsed magnetic field improves the transport of iron oxide nanoparticles through cell barriers. Understanding how a magnetic field affects the interaction of magnetic nanoparticles (MNPs) with cells is fundamental to any potential downstream applications of MNPs as gene and drug delivery vehicles. Here, we present a quantitative analysis of how a pulsed magnetic field influences the manner in which MNPs interact with and penetrate across a cell monolayer. Relative to a constant magnetic field, the rate of MNP uptake and transport across cell monolayers was enhanced by a pulsed magnetic field. MNP transport across cells was significantly inhibited at low temperature under both constant and pulsed magnetic field conditions, consistent with an active mechanism (i.e., endocytosis) mediating MNP transport. Microscopic observations and biochemical analysis indicated that, in a constant magnetic field, transport of MNPs across the cells was inhibited due to the formation of large (>2 μm) magnetically induced MNP aggregates, which exceeded the size of endocytic vesicles. Thus, a pulsed magnetic field enhances the cellular uptake and transport of MNPs across cell barriers relative to a constant magnetic field by promoting accumulation while minimizing magnetically induced MNP aggregation at the cell surface. 23595057 Marine Nutraceuticals: Prospects and Perspectives. By Se-Kwon Kim, CRC Press, 2013; 464 Pages. Price £108.00, ISBN 978-1-4665-1351-8. The following paragraphs are reproduced from the publisher's website [1]. There is a great deal of consumer interest in natural bioactive substances due to their health benefits. Offering the potential to provide valuable nutraceuticals and functional food ingredients, marine-derived compounds are an abundant source of nutritionally and pharmacologically active agents, with both chemical diversity and complexity. Functional ingredients derived from marine algae, invertebrates, vertebrates, and microorganisms can help fill the need for novel bioactives to treat chronic conditions such as cancer, microbial infections, and inflammatory processes. 23600754 Microbiological transformation of the triterpene nigranoic acid by the freshwater fungus Dictyosporium heptasporum. The microbiological transformation of the triterpene nigranoic acid (3,4-secocycloarta-4(28),24(Z)-diene-3,26-dioic acid) (1) to 3,4-secocycloarta-4(28),17(20),24(Z)-triene-7β-hydroxy-16β,26-lactone-3-oic acid (2) and 3,4-secocycloarta-4(28),17(20)(Z),24(Z)-triene-7β-hydroxy-16β-methoxy-3,26-dioic acid (3) by the freshwater fungus Dictyosporium heptasporum YMF1.01213 has been demonstrated. The structures of the biotransformation products were determined by spectroscopic and MS analyses. Compound 2, characterized by the presence of a formed C-16/C-26 ester bridge, provided a novel nine-membered lactone ring structural skeleton for 3,4-secocycloartane triterpenoid derivatives. In addition, Compounds 1-3 exhibited weak anti-HIV activity in vitro. Compounds 2 and 3 were reported for the first time as natural product derivatives. 23122154 Characterisation of kiwifruit and asparagus enzyme extracts, and their activities toward meat proteins. Two plant enzyme extracts from kiwifruit and asparagus were evaluated for their ability to hydrolyse commercially available substrates and proteins present in both beef connective tissue and topside myofibrillar extracts. The results show significant differences in protease activity depending on the assay used. Protease assays with connective tissue and meat myofibrillar extracts provide a more realistic evaluation of the potential of the enzymes for application in meat tenderization. Overall, the kiwifruit protease extract was found to be more effective at hydrolysing myofibrillar and collagen proteins than the asparagus protease extract. The two protease extracts appeared to target meat myofibrillar and collagen proteins differently, suggesting the potential of a synergistic effect of these proteases in improving the tenderness of specific cuts of meat, based on their intrinsic protein composition. 23111753 Benchmarks for 0-0 transitions of aromatic organic molecules: DFT/B3LYP, ADC(2), CC2, SOS-CC2 and SCS-CC2 compared to high-resolution gas-phase data. In the present study a benchmark set of medium-sized and large aromatic organic molecules with 10-78 atoms is presented. For this test set 0-0 transition energies measured in supersonic jets are compared to those calculated with DFT and the B3LYP functional, ADC(2), CC2 and the spin-scaled CC2 variants SOS-CC2 and SCS-CC2. Geometries of the ground and excited states have been optimized with these methods in polarized triple zeta basis sets. Zero-point vibrational corrections have been calculated with the same methods and basis sets. In addition the energies have been corrected by single point calculations with a triple zeta basis augmented with diffuse functions, aug-cc-pVTZ. The deviations of the theoretical results from experimental electronic origins, which have all been measured in the gas phase with high-resolution techniques, were evaluated. The accuracy of SOS-CC2 is comparable to that of unscaled CC2, whereas ADC(2) has slightly larger errors. The lowest errors were found for SCS-CC2. All correlated wave function methods provide significantly better results than DFT with the B3LYP functional. The effects of the energy corrections from the augmented basis set and the method-consistent calculation of the zero-point vibrational corrections are small. With this benchmark set reliable reference data for 0-0 transition energies for larger organic chromophores are available that can be used to benchmark the accuracy of other quantum chemical methods such as new DFT functionals or semi-empirical methods for excitation energies and structures and thereby augments available benchmark sets augments present benchmark sets which include mainly smaller molecules. 22401597 9,10-seco-9,19-cyclolanostane triterpene from Salix caprea L. (goat willow). Chemical investigation of low polar solvent extract of Salix caprea through chromatographic techniques led to the isolation of new triterpene as 1α,3β,25-trihydroxy-9(11)-ene-16-one-9,10-seco-9,19-cyclolanostane (1) along with fatty alcohols. The structure of compound 1 was established by IR, HRESI/MS and NMR including 1D and 2D experiments. The compound 1 showed moderate in vitro antiplasmodial activity. 23103568 Estrogen receptor signaling as a target for novel breast cancer therapeutics. In breast cancer (BC) epithelial cells, the mitogenic action of estradiol is transduced through binding to two receptors, ERα and ERβ, which act as transcription factors. Anti-estrogens (AEs) and aromatase inhibitors (AIs) are used clinically to arrest the estrogen-dependent growth of BC. In the case of AE or AI resistance, Herceptin or lapatinib may be used to inhibit growth factors. Estrogen effects are mediated not only through nuclear ERs but also through cytoplasmic/membrane ERs and G-protein-coupled ERs. These estrogen-binding systems associate with various proteins that direct cell cycle signaling, proliferation and survival. The partners of nuclear ER include SRC1-3, HDACs and ERβ itself as well as newly identified proteins, such as E6-AP, LKB1, PELP1, PAX-2 and FOXA1. The partners of extra-nuclear ERα include PI3K and the tyrosine kinase Src. These various factors are all potential targets for therapeutic intervention. In addition, BC proliferation is enhanced by insulin and EGF, which stimulate signaling through the MAPK and PI3K/AKT pathways by activation of the IGF-1R and EGFR axes, respectively. These pathways are tightly interconnected with ER-activated signaling, and membrane ERα forms complexes with Src and PI3K. Chemokine-mediated signaling also modulates the estrogen response. Inhibiting these pathways with specific inhibitors or activating some of the pathways by gene manipulation may be therapeutically valuable for arresting BC cell cycle progression and for inducing apoptosis to antagonize hormone-resistance. Here, we review some newly identified putatively targetable ER partners and highlight the need to develop tumor-targeting drug carrier systems affecting both the tumor cells and the tumor environment. 23305110 Anomalous high mobility in LaAlO3/SrTiO3 nanowires. Nanoscale control of the metal-insulator transition at the interface between LaAlO(3) and SrTiO(3) provides a pathway for reconfigurable, oxide-based nanoelectronics. Four-terminal transport measurements of LaAlO(3)/SrTiO(3) nanowires at room temperature (T = 300 K) reveal an equivalent 2D Hall mobility greatly surpassing that of bulk SrTiO(3) and approaching that of n-type Si nanowires of comparable dimensions. This large enhancement of mobility is relevant for room-temperature device applications. 22694738 Differences in the structure of anthocyanins from the two amphibious plants, Lobelia cardinalis and Nesaea crassicaulis. The foliar anthocyanin profiles of two amphibious plants, Nesaea crassicaulis and Lobelia cardinalis were analysed for the first time. N. crassicaulis produced very simple anthocyanins, achieving the highest concentrations when grown submerged. In contrast, L. cardinalis produced leaves with a high content of very complex, acylated anthocyanins, especially when growing emergent. Anthocyanins were separated by high performance liquid chromatography. Nesaea crassicaulis anthocyanins were identified according to their fragment mass spectra and ultra-visible-violet spectral characteristics and 1D and 2D NMR spectra as -3,5-di-O-β-glucosides of delphinidin, cyanidin, petunidin, malvidin and peonidin as well as cyanidine and peonidin-3-O-β-glucoside. In L. cardinalis cyanidin-3-O-[6-O-(4-O-E-p-coumaroyl-O-α-rhamnopyranosyl)-β-glucopyrano]-5-O-β-glucopyranoside was the major anthocyanin and contributed more than 98% of total anthocyanin content. The remaining 2% was made up by cyanidin-3-O-[6-O-(4-O-E-caffeoyl-O-α-rhamnopyranosyl)-β-glucopyrano]-5-O-β-glucopyranoside and pelargonidin-3-O-[6-O-(4-O-E-p-coumaroyl-O-α-rhamnopyranosyl)-β-glucopyrano]-5-O-β-glucopyranoside. 23391442 Protective effects of protein transduction domain-metallothionein fusion proteins against hypoxia- and oxidative stress-induced apoptosis in an ischemia/reperfusion rat model. Ischemic heart diseases caused by insufficient oxygen supply to the cardiac muscle require pharmaceutical agents for the prevention of the progress and recurrence. Metallothionein (MT) has a potential as a protein therapeutic for the treatment of this disease due to its anti-oxidative effects under stressful conditions. In spite of its therapeutic potential, efficient delivery systems need to be developed to overcome limitations such as low transduction efficiency, instability and short half-life in the body. To enhance intra-cellular transduction efficiency, Tat sequence as a protein transduction domain (PTD) was fused with MT in a recombinant method. Anti-apoptotic and anti-oxidative effects of Tat-MT fusion protein were evaluated under hyperglycemia and hypoxia stress conditions in cultured H9c2 cells. Recovery of cardiac functions by anti-apoptotic and anti-fibrotic effects of Tat-MT was confirmed in an ischemia/reperfusion (I/R) rat myocardial infarction model. Tat-MT fusion protein effectively protected H9c2 cells under stressful conditions by reducing intracellular ROS production and inhibiting caspase-3 activation. Tat-MT fusion protein inhibited apoptosis, reduced fibrosis area and enhanced cardiac functions in I/R. Tat-MT fusion protein could be a promising therapeutic for the treatment of ischemic heart diseases. 23466228 [11C]olanzapine, radiosynthesis and lipophilicity of a new potential PET 5-HT2 and D2 receptor radioligand. Olanzapine and its precursor desmethyl-Olanzapine were synthesized from malononitrile, propionaldehyde, 1-fluoro-2-nitrobenzene, and substituted piperazine in 4, 4, 5, and 5 steps with 35%, 32%, 26%, and 32% overall chemical yield, respectively. [(11)C]Olanzapine was prepared from desmethyl-Olanzapine with [(11)C]CH3OTf through N-[(11)C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40-50% radiochemical yield based on [(11)C]CO2 and decay corrected to end of bombardment (EOB), with 370-740 GBq/μmol specific activity at EOB. The calculated LogP (CLogP) value of [(11)C]Olanzapine is 3.39. 23625905 Effect of chromium (VI) exposure on antioxidant defense status and trace element homeostasis in acute experiment in rat. Occupational exposure to hexavalent chromium (Cr(VI)) compounds is of concern in many Cr-related industries and their surrounding environment. Cr(VI) is a proven toxin and carcinogen. The Cr(VI) compounds are easily absorbed, can diffuse across cell membranes, and have strong oxidative potential. Despite intensive studies of Cr(VI) pro-oxidative effects, limited data exist on the influence of Cr(VI) on selenoenzymes thioredoxin reductase (TrxR) and glutathione peroxidase (GPx)-important components of antioxidant defense system. This study investigates the effect of Cr(VI) exposure on antioxidant defense status, with focus on these selenoenzymes, and on trace element homeostasis in an acute experiment in rat. Male Wistar rats (130-140g) were assigned to two groups of 8 animals: I. control; and II. Cr(VI) treated. The animals in Cr(VI) group were administered a single dose of K2Cr2O7 (20 mg /kg, intraperitoneally (ip)). The control group received saline solution. After 24 h, the animals were sacrificed and the liver and kidneys were examined for lipid peroxidation (LP; thiobarbituric acid reactive substances (TBARS) concentration), the level of reduced glutathione (GSH) and the activities of GPx-1, TrxR-1, and glutathione reductase (GR). Samples of tissues were also used to estimate Cr accumulation and alterations in zinc, copper, and iron levels. The acute Cr(VI) exposure caused an increase in both hepatic and renal LP (by 70%, p < 0.01 and by 15%, p < 0.05, respectively), increased hepatic GSH level and GPx-1 activity, and decreased renal GPx-1 activity. The activity of GR was not changed. A significant inhibitory effect of Cr(VI) was found on TrxR-1 activity in both the liver and the kidneys. The ability of Cr(VI) to cause TrxR inhibition could contribute to its cytotoxic effects. Further investigation of oxidative responses in different in vivo models may enable the development of strategies to protect against Cr(VI) oxidative damage. 23276135 Glyconanoparticles-an update. This review summarized the progress of glyconanoparticles in the aspects of types, synthesis, and applications for recent five years. A major challenge in the development of Au glyconanoparticles for the study of cellular interactions is to span the cellular membrane, which is used for the drug delivery. A majority of glyco-functionalized quantum dots have been utilized as fluorescent probes for biolabeling, imaging and biosensing. Recently, magnetic nanoparticles have been more frequently used in biomedical applications. The application of these new multivalent systems of glyconanoparticles is to mainly study carbohydrate-mediated interactions, which opens the new field in glycobiology. 23111684 Theoretical investigation of a novel high density cage compound 4,8,11,14,15-pentanitro-2,6,9,13-tetraoxa-4,8,11,14,15-pentaazaheptacyclo[5.5.1.1(3,11).1(5,9)] pentadecane. A novel polynitro cage compound 4,8,11,14,15-pentanitro-2,6,9,13-tetraoxa-4,8,11,14,15-pentaazaheptacyclo [5.5.1.1(3,11).1(5,9)]pentadecane(PNTOPAHP) has been designed and investigated at the DFT-B3LYP/6-31(d) level. Properties, such as electronic structure, IR spectrum, heat of formation, thermodynamic properties and crystal structure have been predicted. This compound is most likely to crystallize in C2/c space group, and the corresponding cell parameters are Z = 8, a = 29.78 Å, b = 6.42 Å, c = 32.69 Å, α = 90.00°, β = 151.05°, γ = 90.00° and ρ = 1.94 g/cm(3). In addition, the detonation velocity and pressure have also been calculated by the empirical Kamlet-Jacobs equation. As a result, the detonation velocity and pressure of this compound are 9.82 km/s, 44.67 GPa, respectively, a little higher than those of 4,10-dinitro-2,6,8,12-tetraoxa-4,10-diazaisowurtzitane(TEX, 9.28 km/s, 40.72 GPa). This compound has a comparable chemical stability to TEX, based on the N-NO(2) trigger bond length analysis. The bond dissociation energy ranges from 153.09 kJ mol(-1) to 186.04 kJ mol(-1), which indicates that this compound meets the thermal stability requirement as an exploitable HEDM. 23147005 Organization of the BcgI restriction-modification protein for the cleavage of eight phosphodiester bonds in DNA. Type IIB restriction-modification systems, such as BcgI, feature a single protein with both endonuclease and methyltransferase activities. Type IIB nucleases require two recognition sites and cut both strands on both sides of their unmodified sites. BcgI cuts all eight target phosphodiester bonds before dissociation. The BcgI protein contains A and B polypeptides in a 2:1 ratio: A has one catalytic centre for each activity; B recognizes the DNA. We show here that BcgI is organized as A(2)B protomers, with B at its centre, but that these protomers self-associate to assemblies containing several A(2)B units. Moreover, like the well known FokI nuclease, BcgI bound to its site has to recruit additional protomers before it can cut DNA. DNA-bound BcgI can alternatively be activated by excess A subunits, much like the activation of FokI by its catalytic domain. Eight A subunits, each with one centre for nuclease activity, are presumably needed to cut the eight bonds cleaved by BcgI. Its nuclease reaction may thus involve two A(2)B units, each bound to a recognition site, with two more A(2)B units bridging the complexes by protein-protein interactions between the nuclease domains. 23108214 Ameliorative effect of Drynaria quercifolia (L.) J. Sm., an ethnomedicinal plant, in arthritic animals. Drynaria quercifolia (L.) J. Sm., is an ethnomedicinal plant used widely in Tamil Nadu to treat arthritis. The present study was aimed to evaluate the traditional claim of D. quercifolia rhizome water extract in adjuvant induced arthritic animals. Anti-arthritic effect was studied by assessing the levels of lysosomal enzymes, protein bound carbohydrates, urinary degradative collagen and serum cytokines on control and adjuvant induced arthritis. The paw swelling and body weight were also analyzed. The levels of ROS and lysosomal enzymes in neutrophils of control and adjuvant induced animals were also estimated. D. quercifolia rhizome water extract at doses of 100 and 200mg/kg reduced the paw thickness and elevated the mean body weight of arthritic rats. The treatment with extract showed a significant reduction in the levels of plasma and liver lysosomal enzymes as well as protein bound carbohydrates and urinary degradative collagen levels. The treatment reduced the levels of ROS and lysosomal enzymes in neutrophils significantly. The significant reduction in the levels of serum pro-inflammatory cytokines (TNF-α and IL-1β) and the increment in the levels of anti-inflammatory cytokine (IL-10) were also observed by the treatment. The present study supports the traditional claim of using D. quercifolia to treat rheumatism. 23325050 Synthesis of bisindolylmethanes and their cytotoxicity properties. Polymer supported dichlorophosphate (PEG-OPOCl(2)) is an efficient green catalyst for the electrophilic substitution reaction of indole with aromatic aldehydes, in neat condition, to afford an excellent yield of bis(indolyl) methanes with short reaction time, at room temperature. The synthesized compounds and their anti-cancer activity are evaluated. 23376249 Synthesis and biological evaluation of 1,3,4-thiadiazole analogues as novel AChE and BuChE inhibitors. In this paper a series of new 1,3,4-thiadiazole derivatives has been designed, synthesized and evaluated as the acetyl- and butyrylcholinesterase inhibitors. Some analogues showed promising inhibition of both enzymes in vitro in the nM range. Generally, inhibitory potency of compounds was stronger against AChE than BuChE, and one of them was 1154-fold more active inhibiting AChE (IC50 = 0.17 μM) than BuChE. The kinetic studies showed that one of the most active analogues 8 (IC50 = 0.09 μM, AChE) acted as a non-competitive AChE inhibitor and was characterized by the high selectivity index (300). The other derivative (1) exhibited a mixed-type of AChE inhibition. Docking simulations enabled the detection of key binding interactions of the compounds with AChE and revealed that they occupied mainly the catalytic active site. The scoring function for the novel compounds was similar or higher than for the reference inhibitor. Additionally, based on Lipinski and other filters, the drug-likeness of compounds was assessed. They revealed that the compounds possess properties which can suggest the favourable pharmacokinetics in the human body after oral admission. 23415893 Targeted drug delivery to renal proximal tubule epithelial cells mediated by 2-glucosamine. In order to develop a novel kidney-targeted drug delivery system, we synthesized prednisolone carbamate-glucosamine conjugate (PCG) using 2-glucosamine as a ligand, and investigated its potential targeting efficacy. In vitro studies demonstrated that PCG could remarkably improve the uptake of drug by kidney cells. And the specific uptake of PCG could be largely reduced by the inhibitors of megalin receptor. More importantly, PCG showed an excellent kidney targeting property in vivo, and the concentration of the conjugate in the kidney was 8.1-fold higher than that of prednisolone group at 60 min after intravenous injection. Besides, PCG could significantly reverse the disease progression in renal ischemia-reperfusion (I/R) injury animal models. Furthermore, PCG presented no adverse effect on bone density while prednisolone resulted in severe osteoporosis. Thus, it indicated that 2-glucosamine could be a potential ligand for kidney-targeted delivery of prednisolone. 23517636 Testosterone exposure in childhood: discerning pathology from physiology. Introduction: Testosterone (T) drives normal male sexual development both in utero and at puberty. Aberrant T exposure manifests as virilization of a female fetus, contrasexual precocity in girls, and isosexual precocity in boys. Evidence of pathologic T exposure warrants a prompt evaluation. Areas covered: The authors introduce the topic of T exposure in children by reviewing its physiology in the fetus and during childhood and adolescence. Pathologic conditions leading to virilization of a female fetus as well as androgen-mediated gonadotropin-independent precocious puberty in both genders are then discussed. The authors finish by noting exogenous T exposure in children and adolescents, focusing specifically on secondary exposure to topical T preparations. Expert opinion: Contrasexual precocity in a girl or sexual precocity in a boy should prompt evaluation for causes of gonadotropin-independent pubertal changes. Initial biochemical evaluation includes a bone age, T, 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone sulfate (DHEA-S) and high sensitivity gonadotropin levels. The provider must query exposure to topical androgen-containing preparations as unintentional secondary exposure to topical T must be considered. Hyperandrogenism is temporally related to exposure of topical T and removal of exposure results in a marked decrease in serum T as well as resolution or stabilization of the signs and symptoms. 22983652 A DFT study on the initial stage of thermal degradation of Poly(methyl methacrylate)/carbon nanotube system. DFT calculations, with VWN exchange correlation functional and double numeric basis set, were used to evaluate the energies required for the scission reactions taking place in the initial stage of the thermal degradation of Poly(methyl methacrylate) (PMMA) in the presence of a carbon nanotube (CNT). Side group and main chain scissions were investigated. The results averaged from five configurations of pure PMMA (DP=5) were used as references and compared to the results obtained for the five same configurations of PMMA grafted on three carbon nanotubes of similar diameter (1.49 nm). The bond dissociation energies (BDE) of main chain scission evaluated for grafted PMMA was 4 % less endothermic than for pure PMMA. These results seemed independent of the tested chirality (11,11); (12,10) and (16,5) of the carbon nanotubes. Comparisons with the BDE of the weakest bonds due to intrinsic defaults (head to head and unsaturated end chain) were performed. 23301948 Spectral marker for Cα damage in beta peptides. The work in this article describes a spectral signature for the detection of a C(α) radical damaged peptide, which should enable the use of infrared spectroscopic methods to directly monitor oxidative events. Spectra for radical damaged peptides are computed with ab initio methods. The amide bands A, I, II, and III are analyzed for trends in the damage site. The spectral signature is found in a region (i.e., 1700-1620 cm(-1)) normally void of vibrational absorption bands from stable undamaged beta peptides. An analysis of the vibrational motions of the spectral signature is described. The uniqueness of the spectral signature is explored by an examination and comparison with C(α) monoradicals and polyradicals, as well as with other bioradicals that could act as spectral interferences. The identification of unique infrared spectral features for C(α) damage could have important implications in diagnostics for beta conformational peptides damaged by oxidative stress processes. 23172229 Cardiolipin-dependent reconstitution of respiratory supercomplexes from purified Saccharomyces cerevisiae complexes III and IV. Here, we report for the first time in vitro reconstitution of the respiratory supercomplexes from individual complexes III and IV. Complexes III and IV were purified from Saccharomyces cerevisiae mitochondria. Complex III contained eight molecules of cardiolipin, and complex IV contained two molecules of cardiolipin, as determined by electrospray ionization-mass spectrometry. Complex IV also contained Rcf1p. No supercomplexes were formed upon mixing of the purified complexes, and low amounts of the supercomplex trimer III(2)IV(1) were formed after reconstitution into proteoliposomes containing only phosphatidylcholine and phosphatidylethanolamine. Further addition of cardiolipin to the proteoliposome reconstitution mixture resulted in distinct formation of both the III(2)IV(1) supercomplex trimer and III(2)IV(2) supercomplex tetramer. No other anionic phospholipid was as effective as cardiolipin in supporting tetramer formation. Phospholipase treatment of complex IV prevented trimer formation in the absence of cardiolipin. Both trimer and tetramer formations were restored by cardiolipin. Analysis of the reconstituted tetramer by single particle electron microscopy confirmed native organization of individual complexes within the supercomplex. In conclusion, although some trimer formation occurred dependent only on tightly bound cardiolipin, tetramer formation required additional cardiolipin. This is consistent with the high cardiolipin content in the native tetramer. The dependence on cardiolipin for supercomplex formation suggests that changes in cardiolipin levels resulting from changes in physiological conditions may control the equilibrium between individual respiratory complexes and supercomplexes in vivo. 23523557 Antagonism of the transient receptor potential ankyrin 1 (TRPA1) attenuates hyperalgesia and urinary bladder overactivity in cyclophosphamide-induced haemorrhagic cystitis. The aim of this study was to investigate the involvement of the transient receptor potential ankyrin 1 (TRPA1) in haemorrhagic cystitis, the main side effect of cyclophosphamide-based chemotherapy. Hannover female rats received intraperitoneal (i.p.) injection of cyclophosphamide (three doses of 100mg/kg, every other day, in a total of five days). This treatment was followed by the treatment with TRPA1 antagonist HC 030031 (50mg/kg, p.o.). The threshold for hindpaw withdrawal or abdominal retraction to von Frey Hair and the locomotor activity were measured. The treatment with the TRPA1 antagonist HC 030031 significantly decreased mechanical hyperalgesia induced by cyclophosphamide without interfere with locomotor activity. Urodynamic parameters were performed by cystometry 24h after a single treatment with cyclophosphamide (200mg/kg, i.p.) in control and HC 030031 treated rats. Analyses of the urodynamic parameters showed that a single dose of cyclophosphamide was enough to significantly increase the number and amplitude of non-voiding contractions and to decrease the voided volume and voiding efficiency, without significantly altering basal, threshold or maximum pressure. The treatment with HC 030031 either before (100mg/kg, p.o.) or after (30mg/kg, i.v.) cyclophosphamide inhibited the non-voiding contractions but failed to counteract the loss in voiding efficiency. Our data demonstrates that nociceptive symptoms and urinary bladder overactivity caused by cyclophosphamide, in part, are dependent upon the activation of TRPA1. In this context, the antagonism of the receptor may be an alternative to minimise the urotoxic symptoms caused by this chemotherapeutic agent. 23588094 Characterization of volatiles and anti-ulcerogenic effect of Turkish sweetgum balsam (Styrax liquidus). ETHNOPHARMACOLOGICAL RELEVANCE: Sweetgum, Styrax liquidus (Turkish sweetgum) is a resinous exudate obtained from the wounded barks of Liquidambar orientalis Miller tree which belongs to Altingiaceae (Hamamelidaceae). The plant material has been used for the treatment of peptic ulcer symptoms in Turkish folk medicine since centuries. In order to evaluate the claimed activity, we studied the anti-ulcerogenic effect of Styrax liquidus by using an in vivo anti-ulcerogenic activity model and to determine the chemical composition of the balsam. MATERIALS AND METHODS: Anti-ulcerogenic effects of the balsam "Styrax liquidus" itself and its fractions obtained by successive solvent extractions with chloroform and n-butanol, were investigated against the ethanol-induced peptic ulcer model in rats. The chloroform extract demonstrated a statistically significant gastroprotective effect. In addition, the chemical characterization of the volatiles obtained by microdistillation technique from the balsam and the sub-extracts were analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS), respectively. RESULTS: Pharmacological experiments have clearly demonstrated that 150 and 300mg/kg doses of Styrax liquidus given orally to rats showed significant gastric protection. On GC-MS analysis of the resin, overall, 31 compounds representing 99.8% of the total oil were identified where styrene (81.9%), cinnamyl alcohol (6.9%) and α-pinene (3.5%) were identified as the major components. CONCLUSION: Present study confirmed the anti-ulcerogenic activity of the local ethnobotanical usage of Styrax liquidus in Turkey. 23558233 Systems analysis of genetic variation in MPTP neurotoxicity in mice. We analyzed genetic variation in severity of neuronal damage using the known dopaminergic neurotoxicant, MPTP, as a prototypical chemical denervation agent. Male mice from ten members of the BXD family of recombinant inbred strains received 12.5mg/kg MPTP s.c. (vs. saline) and 48h later brains were taken for multiple related biochemical analyses. Striatal dopamine (DA) and its metabolites, DOPAC and HVA, and serotonin and its metabolite, 5-HIAAA, were analyzed by HPLC. DA turnover was assessed using DOPAC/DA and HVA/DA ratios. Striatal tyrosine hydroxylase (TH), glial fibrilary acidic protein (GFAP), and iron content in ventral midbrain were quantified. All dopamine measures, as well as TH and GFAP, demonstrated wide, genotype-dependent differences in response to MPTP. Serotonin was largely unaffected. Principal components analysis (PC) on difference values, saline minus MPTP, for DA, DOPAC, HVA, and TH, yielded a dominant principal component. The PC trait residuals for each genotype were compared against complementary expression data for striatum of the same strains. Three transcripts representing Mtap2, Lancl 1, and Kansl1l were highly correlated with the PC, as was the difference score, MPTP minus saline for GFAP. This systems approach to the study of environmental neurotoxicants holds promise to define individual genetic differences that contribute to variability in susceptibility to risk factors for diseases such as Parkinson's disease. 23394218 Discovery of 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases. Wide-ranging exploration of analogues of an ATP-competitive pyrrolopyrimidine inhibitor of Akt led to the discovery of clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against the closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism and pharmacokinetics (DMPK) properties and, after oral dosing, showed pharmacodynamic knockdown of phosphorylation of Akt and downstream biomarkers in vivo, and inhibition of tumor growth in a breast cancer xenograft model. 23200747 Interactions of neuropathy inducers and potentiators/promoters with soluble esterases. Organophosphorus compounds (OPs) cause neurotoxic disorders through interactions with well-known target esterases, such as acetylcholinesterase and neuropathy target esterase (NTE). However, the OPs can potentially interact with other esterases of unknown significance. Therefore, identifying, characterizing and elucidating the nature and functional significance of the OP-sensitive pool of esterases in the central and peripheral nervous systems need to be investigated. Kinetic models have been developed and applied by considering multi-enzymatic systems, inhibition, spontaneous reactivation, the chemical hydrolysis of the inhibitor and "ongoing inhibition" (inhibition during the substrate reaction time). These models have been applied to discriminate enzymatic components among the esterases in nerve tissues of adult chicken, this being the experimental model for delayed neuropathy and to identify different modes of interactions between OPs and soluble brain esterases. The covalent interaction with the substrate catalytic site has been demonstrated by time-progressive inhibition during ongoing inhibition. The interaction of sequential exposure to an esterase inhibitor has been tested in brain soluble fraction where exposure to one inhibitor at a non inhibitory concentration has been seen to modify sensitivity to further exposure to others. The effect has been suggested to be caused by interaction with sites other than the inhibition site at the substrate catalytic site. This kind of interaction among esterase inhibitors should be considered to study the potentiation/promotion phenomenon, which is observed when some esterase inhibitors enhance the severity of the OP induced neuropathy if they are dosed after a non neuropathic low dose of a neuropathy inducer. 23517621 Nitroxide TEMPO: A genotoxic and oxidative stress inducer in cultured cells. 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) is a low molecular weight nitroxide and stable free radical. In this study, we investigated the cytotoxicity and genotoxicity of TEMPO in mammalian cells using the mouse lymphoma assay (MLA) and in vitro micronucleus assay. In the absence of metabolic activation (S9), 3mM TEMPO produced significant cytotoxicity and marginal mutagenicity in the MLA; in the presence of S9, treatment of mouse lymphoma cells with 1-2mM TEMPO resulted in dose-dependent decreases of the relative total growth and increases in mutant frequency. Treatment of TK6 human lymphoblastoid cells with 0.9-2.3mM TEMPO increased the frequency of both micronuclei (a marker for clastogenicity) and hypodiploid nuclei (a marker of aneugenicity) in a dose-dependent manner; greater responses were produced in the presence of S9. Within the dose range tested, TEMPO induced reactive oxygen species and decreased glutathione levels in mouse lymphoma cells. In addition, the majority of TEMPO-induced mutants had loss of heterozygosity at the Tk locus, with allele loss of ⩽34Mbp. These results indicate that TEMPO is mutagenic in the MLA and induces micronuclei and hypodiploid nuclei in TK6 cells. Oxidative stress may account for part of the genotoxicity induced by TEMPO in both cell lines. 23643730 Juglone, isolated from Juglans mandshurica Maxim, induces apoptosis via down-regulation of AR expression in human prostate cancer LNCaP cells. Juglone is a natural compound which has been isolated from Juglans mandshurica Maxim. Recent studies have shown that juglone had various pharmacological effects such as anti-viral, anti-bacterial and anti-cancer. However, its anti-cancer activity on human prostate cancer LNCaP cell has not been examined. Thus, the current study was designed to elucidate the molecular mechanism of apoptosis induced by juglone in androgen-sensitive prostate cancer LNCaP cells. MTT assay was performed to examine the anti-proliferative effect of juglone. Occurrence of apoptosis was detected by Hoechst 33342 staining and flow cytometry in LNCaP cells treated with juglone for 24h. The result shown that juglone inhibited the growth of LNCaP cells in a dose-dependent manner. Morphological changes of apoptotic body formation after juglone treatment were observed by Hoechst 33342 staining. This apoptotic induction was associated with loss of mitochondrial membrane potential, and caspase-3, -9 activation. Moreover, we found that juglone significantly inhibited the expression levels of androgen receptor (AR) and prostate-specific antigen (PSA) in a dose-dependent manner, as well as abrogated up-regulation of AR and PSA genes with and/or without dihydrotestosterone (DHT). Take together, our results demonstrated that juglone might induce the apoptosis in LNCaP cell via down-regulation of AR expression. Therefore, our results indicated that juglone may be a potential candidate of drug for androgen-sensitive prostate cancer. 23452857 Encoding and transducing the synaptic or extrasynaptic origin of NMDA receptor signals to the nucleus. The activation of N-methyl-D-aspartate-receptors (NMDARs) in synapses provides plasticity and cell survival signals, whereas NMDARs residing in the neuronal membrane outside synapses trigger neurodegeneration. At present, it is unclear how these opposing signals are transduced to and discriminated by the nucleus. In this study, we demonstrate that Jacob is a protein messenger that encodes the origin of synaptic versus extrasynaptic NMDAR signals and delivers them to the nucleus. Exclusively synaptic, but not extrasynaptic, NMDAR activation induces phosphorylation of Jacob at serine-180 by ERK1/2. Long-distance trafficking of Jacob from synaptic, but not extrasynaptic, sites depends on ERK activity, and association with fragments of the intermediate filament α-internexin hinders dephosphorylation of the Jacob/ERK complex during nuclear transit. In the nucleus, the phosphorylation state of Jacob determines whether it induces cell death or promotes cell survival and enhances synaptic plasticity. 23305918 The first total synthesis and biological evaluation of marine natural products ma'edamines A and B. We have developed the first total syntheses of marine natural products ma'edamines A (18) and B (20). Structurally, they contain a pyrazine-2-(1H)-one core and were screened for antiproliferative activity on several cancer cell lines. Out of the six cell lines tested, ma'edamines A and B showed significant cytotoxicity against human colon cancer line COLO 205 (IC(50) 7.9 and 10.3 μM, respectively), breast cancer cell line MCF-7 (IC(50): 6.9 and 10.5 μM, respectively) and human lung adenocarcinoma cell line A549 (IC(50): 12.2 and 15.4 μM, respectively). The apoptotic effect of ma'edamines was confirmed by comet assay. Hence ma'edamines are likely to be useful as leads for development of a new class of anti-cancer agents. 23041243 Process analytical tools for monitoring, understanding, and control of pharmaceutical fluidized bed granulation: A review. Fluidized bed granulation is a widely applied wet granulation technique in the pharmaceutical industry to produce solid dosage forms. The process involves the spraying of a binder liquid onto fluidizing powder particles. As a result, the (wetted) particles collide with each other and form larger permanent aggregates (granules). After spraying the required amount of granulation liquid, the wet granules are rapidly dried in the fluid bed granulator. Since the FDA launched its Process Analytical Technology initiative (and even before), a wide range of analytical process sensors has been used for real-time monitoring and control of fluid bed granulation processes. By applying various data analysis techniques to the multitude of data collected from the process analyzers implemented in fluid bed granulators, a deeper understanding of the process has been achieved. This review gives an overview of the process analytical technologies used during fluid bed granulation to monitor and control the process. The fundamentals of the mechanisms contributing to wet granule growth and the characteristics of fluid bed granulation processing are briefly discussed. This is followed by a detailed overview of the in-line applied process analyzers, contributing to improved fluid bed granulation understanding, modeling, control, and endpoint detection. Analysis and modeling tools enabling the extraction of the relevant information from the complex data collected during granulation and the control of the process are highlighted. 23448861 Acute respiratory distress syndrome due to exposure to high-concentration mixture of ethenone and crotonaldehyde. INTRODUCTION: Acute inhalational exposure leads to rapidly progressive acute respiratory distress syndrome (ARDS). This report is the first one to present a patient with ARDS in relation to long-standing exposure to a high-concentration mixture of ethenone and crotonaldehyde. Case report: A male worker in a chemical plant was accidentally exposed to the mixture of high-concentrated ethenone and crotonaldehyde for 5 min in an open space and worked continuously in the polluted area for approximately 12 h. On admission, he was conscious with the following vital parameters: blood pressure, 151/91 mmHg; pulse rate, 107 beats/min; respiratory rate, 30 breaths/min; temperature, 37.6°C; oxygen saturation, 92% supported by mask saturation 10 L/min; arterial blood gases showed P/F oxygen ratio of less than 200. Physical examination disclosed decreased bilateral vesicular sounds. A chest computed tomography revealed bilateral nonsegmental ground-glass opacities. The patient was mechanically ventilated and treated with corticosteroid. The patient was discharged without any symptoms. CONCLUSION: Exposure to mixtures of ethenone and crotonaldehyde can cause severe pulmonary injury leading to delayed ARDS. 23557933 One-year supplementation with a grape extract containing resveratrol modulates inflammatory-related microRNAs and cytokines expression in peripheral blood mononuclear cells of type 2 diabetes and hypertensive patients with coronary artery disease. Numerous studies have shown that resveratrol (RES) exerts anti-inflammatory effects but human trials evidencing these effects in vivo are limited. Furthermore, the molecular mechanisms triggered in humans following the oral intake of RES are not yet understood. Therefore, the purpose of this study was to investigate the molecular changes in peripheral blood mononuclear cells (PBMCs) associated to the one-year daily intake of a RES enriched (8mg) grape extract (GE-RES) in hypertensive male patients with type 2 diabetes mellitus (T2DM). We used microarrays and RT-PCR to analyze expression changes in genes and microRNAs (miRs) involved in the inflammatory response modulated by the consumption of GE-RES in comparison to a placebo and GE lacking RES. We also examined the changes in several serobiochemical variables, inflammatory and fibrinolytic markers. Our results showed that supplementation with GE or GE-RES did not affect body weight, blood pressure, glucose, HbA1c or lipids, beyond the values regulated by gold standard medication in these patients. We did not find either any significant change on serum inflammatory markers except for a significant reduction of ALP and IL-6 levels. The expression of the pro-inflammatory cytokines CCL3, IL-1β and TNF-α was significantly reduced and that of the transcriptional repressor LRRFIP-1 increased in PBMCs from patients taking the GE-RES extract. Also, a group of miRs involved in the regulation of the inflammatory response: miR-21, miR-181b, miR-663, miR-30c2, miR-155 and miR-34a were found to be highly correlated and altered in the group consuming the GE-RES for 12 months. Our results provide preliminary evidence that long-term supplementation with a grape extract containing RES downregulates the expression of key pro-inflammatory cytokines with the involvement of inflammation-related miRs in circulating immune cells of T2DM hypertensive medicated patients and support a beneficial immunomodulatory effect in these patients. 23500411 Synthesis of C17-OH-north unit of ritterazine G via "Red-Ox" modifications of hecogenin acetate. The C17-OH-north unit of ritterazine G was prepared in 13 steps from hecogenin acetate. This synthesis features a highly efficient and stereoselective introduction of the C17-OH via E-ring cleavage/F-ring formation, D-ring oxidation, and F-ring cleavage/E-ring formation. 23233456 In vitro transfection mediated by dendrigraft poly(L-lysines): the effect of structure and molecule size. Dendritic poly(L-lysines) (DGL) constitute promising nanomaterials applicable as a nonviral gene-delivery vector. In this study, we evaluate the transfection abilities of four DGL generations with special emphasis on the systematic description of the relationship of how generation (i.e., molecule size) affects the transfection efficacy. Using Hep2 cells, we demonstrated that the capability of unmodified DGL to deliver plasmid is of a magnitude lower than that of jetPEI. On the other hand, employing the Hep2 cell line stably transduced with eGFP, we observed that DGL G5 delivers the siRNA oligonucleotide with the same efficiency as Lipofectamine 2000. In further experiments, it was shown that DGL affords excellent ability to bind DNA, protect it against DNase I attack, and internalize it into cells. 23583929 Lesions of the dorsomedial striatum impair formation of attentional set in rats. Behavioural flexibility refers to the ability to rapidly adapt to novel situations and it has been suggested that the frontal lobe and basal ganglia are implicated in various components of adjusting to changes in environmental contingencies. Behavioural flexibility can be assessed using attentional set-shifting tasks, in which performance is impaired after damage to the prefrontal cortex. The present study explores the downstream contribution of the prefrontal projection zone in the dorsomedial striatum (DMS) to attentional set shifting. Rats were tested in two set-shifting tasks following quinolinic acid injections bilaterally into the DMS. When tested in a rodent version of the set-shifting task, rats with a DMS lesion displayed a greater number of errors during the reversal stages of the task than sham lesion controls but the nature of the errors did not differ between the two groups. Interestingly, when the rats were tested in a modified version of the set-shifting task, directly designed for measuring the formation of an attentional set, sham lesion controls displayed a pronounced shift-cost, evident of successful set-formation. In contrast, rats with DMS lesions failed to form an attentional set, showing no performance cost when a shift of attention was required. These results support previous reports of the importance of the DMS in behavioural flexibility but also suggest that this region is vital for the formation of set, possibly by extrapolating different perceptions into a unified representation of a dimension. 23526663 Recent Advances in Metal-Organic Framework-Based Mixed Matrix Membranes. Mixed matrix membranes (MMMs) combine easy processability and low cost of polymers with the high selectivity of nanoporous filler particles. These membranes represent an important avenue for enhancing the performance of polymeric membranes in gas separations. Recently, a new group of nanoporous materials called metal-organic frameworks (MOFs) have been used as filler particles in MMM applications, and significant improvements in gas selectivity and permeability have been reported for these MOF-based membranes. We discuss the recent developments in MOF-based MMMs by reviewing both the experimental studies and computational modeling methods that can accelerate selection of MOF/polymer combinations for high-performance gas separations. 23565822 Spatially Resolved Mapping of Oxygen Reduction/Evolution Reaction on Solid-Oxide Fuel Cell Cathodes with Sub-10 nm Resolution. Spatial localization of the oxygen reduction/evolution reactions on lanthanum strontium cobaltite (LSCO) surfaces with perovskite and layered perovskite structures is studied at the sub-10 nm level. Comparison between electrochemical strain microscopy (ESM) and structural imaging by scanning transmission electron microscopy (STEM) suggests that small-angle grain boundaries act as regions with enhanced electrochemical activity. The ESM activity is compared across a family of LSCO samples, demonstrating excellent agreement with macroscopic behaviors. This study potentially paves the way for deciphering the mechanisms of electrochemical activity of solids on the level of single extended structural defects such as grain boundaries and dislocations. 23589223 Fullerene Nanoarchitectonics: From Zero to Higher Dimensions. The strategic design of nanostructured materials, the properties of which could be controlled across different length scales and which, at the same time, could be used as building blocks for the construction of devices and functional systems into new technological platforms that are based on sustainable processes, is an important issue in bottom-up nanotechnology.Such strategic design has enabled the fabrication of materials by using convergent bottom-up and top-down strategies. Recent developments in the assembly of functional fullerene (C60 ) molecules, either in bulk or at interfaces, have allowed the production of shape-controlled nano-to-microsized objects that possess excellent optoelectronic properties, thus enabling the fabrication of optoelectronic devices. Because fullerene molecules can be regarded as an ideal zero-dimensional (0D) building units with attractive functions, the construction of higher-dimensional objects, that is, 1D, 2D, and 3D nanomaterials may realize important aspects of nanoarchitectonics. This Focus Review summarizes the recent developments in the production of nanostructured fullerenes and techniques for the elaboration of fullerene nanomaterials into hierarchic structures. 23432586 Immunophilins are Involved in the Altered Platelet Aggregation Observed in Patients with Type 2 Diabetes Mellitus. Platelet hyperaggregability might contribute to vascular complications associated with type 2 diabetes mellitus (DM2).Experimental evidence supports a direct link between altered Ca2+ entry and hyperaggregability in DM2 patients. Objectives: We aimed to investigate whether altered immunophilin expression and function are involved in the abnormal Ca2+ entry observed in platelets from DM2 patients. Results: Inhibition of immunophilins by tacrolimus (FK506) and sirolimus (rapamycin) reduced Ca2+ entry in platelets from healthy donors and DM2 patients. Similarly, immunophilin inhibitors reduced platelet degranulation in both healthy and DM2 subjects. Nevertheless, α-granule secretion reduction was greater than that observed for dense granules in platelets from DM2 patients. However, no difference was observed in the inhibition of secretion in platelets from healthy subjects. Additionally, altered expression of FK506 binding protein-52 (FKBP52) and coupling to Ca(2+) channels were found in platelets from DM2 patients compared to healthy subjects. Finally, reduction in platelet function from healthy subjects and DM2 patients in the presence of immunophilin antagonists was observed, being this dysfunction more evident in platelets from DM2 patients. Conclusions: We suggest that, among others, FKBP52 expression and function are altered in platelets from DM2 patients, contributing to the altered Ca(2+) entry and hyperaggregability in these cells. 22945693 Methylation levels of sodium-iodide symporter (NIS) promoter in benign and malignant thyroid tumors with reduced NIS expression. DNA methylation regulates gene expression. Aberrant methylation plays an important role in human tumorigenesis. We have previously detected reduced NIS mRNA expression in thyroid tumors as compared to non-tumor tissues. Thus, in this study we investigated whether the methylation of the CpG-island located in the NIS gene promoter was associated with reduced mRNA expression in thyroid tumors. Methylation levels of 30 pairs of samples from 10 benign and 20 malignant thyroid tumors (T) along with matched non-tumor (NT) areas were determined by semiquantitative methylation specific-PCR. NIS methylation was detected in all samples. Methylation levels and frequencies did not differ between the groups and were not associated with BRAF mutational status. Highest methylation levels and frequencies were detected in the 5' region of the CpG-island decreasing toward the 3' end. Intraindividual analysis (T versus NT) showed high tumor methylation levels in 40 % of the samples in the benign group and 30 % in the malignant group, associated with low NIS mRNA expression. No quantitative correlation was detected between methylation levels and mRNA expression in any the groups. The results of this study showed that methylation of NIS promoter is a very frequent event in both benign and malignant tumors as well as in their surrounding tissues, and characterized a non-homogeneous methylation pattern along the CpG island. Therefore, further investigations involving other sites that may be implicated in methylation regulation of NIS expression are warranted. 23050902 Ribavirin-induced intracellular GTP depletion activates transcription elongation in coagulation factor VII gene expression. Coagulation FVII (Factor VII) is a vitamin K-dependent glycoprotein synthesized in hepatocytes. It was reported previously that FVII gene (F7) expression was up-regulated by ribavirin treatment in hepatitis C virus-infected haemophilia patients; however, its precise mechanism is still unknown. In the present study, we investigated the molecular mechanism of ribavirin-induced up-regulation of F7 expression in HepG2 (human hepatoma cell line). We found that intracellular GTP depletion by ribavirin as well as other IMPDH (inosine-5'-monophosphate dehydrogenase) inhibitors, such as mycophenolic acid and 6-mercaptopurine, up-regulated F7 expression. FVII mRNA transcription was mainly enhanced by accelerated transcription elongation, which was mediated by the P-TEFb (positive-transcription elongation factor b) complex, rather than by promoter activation. Ribavirin unregulated ELL (eleven-nineteen lysine-rich leukaemia) 3 mRNA expression before F7 up-regulation. We observed that ribavirin enhanced ELL3 recruitment to F7, whereas knockdown of ELL3 diminished ribavirin-induced FVII mRNA up-regulation. Ribavirin also enhanced recruitment of CDK9 (cyclin-dependent kinase 9) and AFF4 to F7. These data suggest that ribavirin-induced intracellular GTP depletion recruits a super elongation complex containing P-TEFb, AFF4 and ELL3, to F7, and modulates FVII mRNA transcription elongation. Collectively, we have elucidated a basal mechanism for ribavirin-induced FVII mRNA up-regulation by acceleration of transcription elongation, which may be crucial in understanding its pleiotropic functions in vivo. 23548897 G-protein coupled receptor agonist BV8/prokineticin-2 and STAT3 form a feed-forward loop in both normal and malignant myeloid cells. An important role of Bv8 in mobilization of myeloid cells and myeloid cell-dependent angiogenesis has been established. Recently, it has also been shown that granulocyte colony stimulating factor (G-CSF)-induced Bv8 expression is Stat3 dependent in CD11b+Gr1+ myeloid cells. However, Bv8 downstream signaling pathway(s) intrinsic to myeloid cells crucial for angiogenesis, and potentially also for development of cancers of myeloid origin, remains largely unknown. Here we show that BV8 activates STAT3, which is critical for regulating genes important for both tumor cell proliferation/survival and tumor angiogenesis, in both normal and malignant myeloid cells. Further, BV8-induced STAT3 activation requires Janus activated kinase 2 (JAK2) activity as shown by both genetic and pharmacologic inhibition. Knocking down BV8 in human myeloid leukemia cells inhibits STAT3 activity and expression of STAT3-downstream angiogenic and pro-proliferation/survival genes, leading to a decrease in tumor cell viability. BV8 shRNA expressing leukemia cells exhibit reduced STAT3 activity and tumor growth in vivo. Taken together, we have delineated a signaling pathway downstream of BV8 that plays critical roles in both the tumor microenvironment and malignant myeloid cells for angiogenesis and tumor cell proliferation/survival. 23601709 Radiosynthesis and evaluation of [(11)C]EMPA as a potential PET tracer for orexin 2 receptors. EMPA is a selective antagonist of orexin 2 (OX2) receptors. Previous literature with [(3)H]-EMPA suggest that it may be used as an imaging agent for OX2 receptors; however, brain penetration is known to be modest. To evaluate the potential of EMPA as a PET radiotracer in non-human primate (as a step to imaging in man), we radiolabeled EMPA with carbon-11. Radiosynthesis of [(11)C]N-ethyl-2-(N-(6-methoxypyridin-3-yl)-2-methylphenylsulfonamido)-N-(pyridin-3-ylmethyl)acetamide ([(11)C]EMPA), and evaluation as a potential PET tracer for OX2 receptors is described. Synthesis of an appropriate non-radioactive O-desmethyl precursor was achieved from EMPA with sodium iodide and chlorotrimethylsilane. Selective O-methylation using [(11)C]CH3I in the presence of cesium carbonate in DMSO at room temp afforded [(11)C]EMPA in 1.5-2.5% yield (non-decay corrected relative to trapped [(11)C]CH3I at EOS) with ⩾95% chemical and radiochemical purities. The total synthesis time was 34-36min from EOB. Studies in rodent suggested that uptake in tissue was dominated by nonspecific binding. However, [(11)C]EMPA also showed poor uptake in both rats and baboon as measured with PET imaging. 23570992 Proteomic Analysis of Arsenic-Exposed Zebrafish (Danio rerio) Identifies Altered Expression in Proteins Involved in Fibrosis and Lipid Uptake in a Gender-Specific Manner. The zebrafish (Danio rerio) was used to investigate protein expression in the liver following arsenic exposure. Several disorders have been linked to arsenic exposure, including cancer, diabetes, and cardiovascular disease. The mechanisms of arsenic toxicity are poorly understood. Prior studies have described altered gene expression, inflammation, and mitogenic signaling in acute or chronic exposure models. A proteomic approach was employed to investigate arsenic-induced alteration in the zebrafish liver proteome following a 7-day exposure to 50 ppb sodium arsenite. Over 740 unique proteins were identified, with fewer than 2% showing differential expression. Molecular pathway analysis software identified lipid metabolism and transport as potential molecular targets. Immunoblots were used to confirm protein expression changes, whereas qPCR was employed to investigate gene expression changes. Overall, 25 proteins were differentially expressed in a gender-specific manner, 11 in males and 14 in females. Of these 25, a single protein, hydroxysteroid dehydrogenase like 2, showed decreased expression in both males and females following arsenic exposure. These findings indicate that protein expression is altered following arsenic exposure. The changes presented here seem to be most prevalent in lipid transport and metabolic pathways, suggesting a potential increase in fibrosis in males and decreased lipid accumulation and uptake in females. 23511786 Model-based drug development in oncology: what's next? Model-based estimates of tumor growth inhibition (TGI) metrics have the potential to enhance learning in early (phase II) clinical studies. They can be used as end points and biomarkers to predict treatment effect on clinical outcome measures-e.g., overall survival (OS)-and support phase II study design, end-of-phase II decisions, and phase III planning and execution. Efforts should be made to assess models in simulating independent studies with treatments of varying mechanisms of action. 23000507 Experimental tooth movement-induced osteoclast activation is regulated by sympathetic signaling. Experimental tooth movement (ETM) changes the distribution of sensory nerve fibers in periodontal ligament and the bone architecture through the stimulation of bone remodeling. As the sympathetic nervous system is involved in bone remodeling, we examined whether ETM is controlled by sympathetic signaling or not. In male mice, elastic rubber was inserted between upper left first molar (M1) and second molar (M2) for 3 or 5 days. Nerve fibers immunoreactive for not only sensory neuromarkers, such as calcitonin gene-related peptide (CGRP), but also sympathetic neuromarkers, such as tyrosine hydroxylase (TH) and neuropeptide Y (NPY) were increased in the periodontal ligament during ETM. To elucidate the effect of the sympathetic signal mediated by ETM, mice were intraperitoneally injected with a β-antagonist, propranolol (PRO: 20 μg/g/day), or a β-agonist, isoproterenol (ISO: 5 μg/g/day) from 7 days before ETM. PRO treatment suppressed the amount of tooth movement by 12.9% in 3-day ETM and by 32.2% in 5-day ETM compared with vehicle treatment. On the other hand, ISO treatment increased it. Furthermore, ETM remarkably increased the osteoclast number on the bone surface (alveolar socket) (Oc.N/BS) in all drug treatments. PRO treatment suppressed Oc.N/BS by 39.4% in 3-day ETM, while ISO treatment increased it by 32.1% in 3-day ETM compared with vehicle treatment. Chemical sympathectomy using 6-hydroxydopamine (6-OHDA: 250 μg/g) showed results similar to those for PRO treatment in terms of both the amount of tooth movement and osteoclast parameters. Our data showed that blockade of sympathetic signaling inhibited the tooth movement and osteoclast increase induced by ETM, and stimulation of sympathetic signaling accelerated these responses. These data suggest that the mechano-adaptive response induced by ETM is controlled by sympathetic signaling through osteoclast activation. 23225542 Multifunctional uniform core-shell Fe3O4@mSiO2 mesoporous nanoparticles for bimodal imaging and photothermal therapy. Multimodal imaging and simultaneous therapy is highly desirable because it can provide complementary information from each imaging modality for accurate diagnosis and, at the same time, afford an imaging-guided focused tumor therapy. In this study, indocyanine green (ICG), a near-infrared (NIR) imaging agent and perfect NIR light absorber for laser-mediated photothermal therapy, was successfully incorporated into superparamagnetic Fe(3)O(4)@mSiO(2) core-shell nanoparticles to combine the merit of NIR/magnetic resonance (MR) bimodal imaging properties with NIR photothermal therapy. The resultant nanoparticles were homogenously coated with poly(allylamine hydrochloride) (PAH) to make the surface of the composite nanoparticles positively charged, which would enhance cellular uptake driven by electrostatic interactions between the positive surface of the nanoparticles and the negative surface of the cancer cell. A high biocompatibility of the achieved nanoparticles was demonstrated by using a cell cytotoxicity assay. Moreover, confocal laser scanning microscopy (CLSM) observations indicated excellent NIR fluorescent imaging properties of the ICG-loaded nanoparticles. The relatively high r(2) value (171.6 mM(-1) s(-1)) of the nanoparticles implies its excellent capability as a contrast agent for MRI. More importantly, the ICG-loaded nanoparticles showed perfect NIR photothermal therapy properties, thus indicating their potential for simultaneous cancer diagnosis as highly effective NIR/MR bimodal imaging probes and for NIR photothermal therapy of cancerous cells. 23313448 cDNA cloning of a snake venom metalloproteinase from the eastern diamondback rattlesnake (Crotalus adamanteus), and the expression of its disintegrin domain with anti-platelet effects. A 5' truncated snake venom metalloproteinase was identified from a cDNA library constructed from venom glands of an eastern diamondback rattlesnake (Crotalus adamanteus). The 5'-rapid amplification of cDNA ends (RACE) was used to obtain the 1865 bp full-length cDNA sequence of a snake venom metalloproteinase (CamVMPII). CamVMPII encodes an open reading frame of 488 amino acids, which includes a signal peptide, a pro-domain, a metalloproteinase domain, a spacer, and an RGD-disintegrin domain. The predicted amino acid sequence of CamVMPII showed a 91%, 90%, 83%, and 82% sequence homology to the P-II class enzymes of C. adamanteus metalloproteinase 2, Crotalus atrox CaVMP-II, Gloydius halys agkistin, and Protobothrops jerdonii jerdonitin, respectively. Disintegrins are potent inhibitors of both platelet aggregation and integrin-dependent cell adhesion. Therefore, the disintegrin domain (Cam-dis) of CamVMPII was amplified by PCR, cloned into a pET-43.1a vector, and expressed in Escherichia coli BL21. Affinity purified recombinantly modified Cam-dis (r-Cam-dis) with a yield of 8.5 mg/L culture medium was cleaved from the fusion tags by enterokinase cleavage. r-Cam-dis was further purified by two-step chromatography consisting of HiTrap™ Benzamidine FF column, followed by Talon Metal affinity column with a final yield of 1 mg/L culture. r-Cam-dis was able to inhibit all three processes of platelet thrombus formation including platelet adhesion with an estimated IC(50) of 1 nM, collagen- and ADP-induced platelet aggregation with the estimated IC(50)s of 18 and 6 nM, respectively, and platelet function on clot retraction. It is a potent anti-platelet inhibitor, which should be further investigated for drug discovery to treat stroke patients or patients with thrombotic disorders. 23643851 Methods for Detection and Analysis of Apoptosis Signalling in the C. elegans Germline. This review assesses current and emerging methods for the detection, and analysis of apoptosis in the C. elegans germline. The nematode worm C. elegans is highly tractable to genetic manipulation, making it an excellent model for elucidating mechanisms of apoptosis signalling in a multicellular setting. Here we profile the most efficacious fluorescent tools to visualize and quantify germline apoptosis. We focus specifically on the application of fluorescent markers to screen by RNAi for genes and pathways that regulate germline apoptosis under normal conditions or in response to genotoxic stress. We also present the limitations of these methods, and suggest complimentary techniques in order that researchers new to the field can comprehensively assess apoptosis phenotypes in the C. elegans germline. 23237828 Cycloheximide stimulates suppressor of cytokine signaling-3 gene expression in 3T3-L1 adipocytes via the extracellular signal-regulated kinase pathway. Suppressor of cytokine signaling (SOCS)-3 can act as a regulator of energy metabolism and cytokine signaling in fat cells. It is regulated by hormones and toxicological factors. However, the action of cycloheximide on expression of adipocyte SOCS-3 gene is unknown. Using 3T3-L1 adipocytes, we found that cycloheximide up-regulated SOCS-3 mRNA expression in dose- and time-dependent manners. Treatment with actinomycin D prevented cycloheximide-stimulated SOCS-3 mRNA expression, suggesting that the effect of cycloheximide requires new mRNA synthesis. While cycloheximide was shown to increase activities of MEK1 and JNK, signaling was demonstrated to be inhibited by pretreatment with either MEK1 inhibitors U0126 and PD98059, or with the JNK inhibitor SP600125. U0126 and PD98059, respectively, reduced cycloheximide-stimulated SOCS-3 mRNA expression, but SP600125 did not antagonize cycloheximide effect. Moreover, cycloheximide was observed to up-regulate expression of other SOCS family members, such as SOCS-1, -2, -4, -5, -6, -7, and cytokine-inducible SH2-containing protein (CIS)-1 mRNAs. Such effects varied with the dosage and duration of cycloheximide treatment. These results imply the functional MEK1/ERK-mediated pathway is necessary for the cycloheximide stimulation of SOCS-3 gene expression. 23517010 Nanofiber near-field light-matter interactions for enhanced detection of molecular level displacements and dynamics. We experimentally demonstrate that plasmonic nanoparticles embedded in the evanescent field of subwavelength optical waveguides (WGs) are highly sensitive to distances normal to the propagation of light, showing an ∼10× increase in spatial resolution compared to the optical field decay of the WG. The scattering cross-section of the Au nanoparticle is increased by the plasmon-dielectric coupling interaction when the nanoparticle is placed near the dielectric surface of the WG, and the decay of the scattering signal is enhanced, showing angstrom level distance sensitivity within 10 nm from the WG. Numerical studies with the finite-difference time-domain (FDTD) method correlate well with the experimental results. To demonstrate real-time monitoring of a single molecule stretching in the evanescent field, we linked individual single-stranded DNA molecules between the WG and plasmonic nanoparticles and pushed on the nanoparticles with fluidic forces. The simple design and ease of obtaining optical feedback on molecular displacements makes our approach ideal for new in situ force sensing devices, imaging technologies, and high-throughput molecular analysis. 23589476 Wired Enzyme Electrodes-A Retroperspective Story about an Exciting Time at University of Texas at Austin and Its Impact on My Scientific Career. The present paper features an exciting time in the late 1980s when I, as a visiting scientist, had the privilege to participate in the early and very exciting development of the in vivo redox-polymer-wired glucose sensor in Professor Adam Heller's laboratory at the Department of Chemical Engineering at University of Texas at Austin. This story is followed by an overview of the research my visit initiated at Uppsala University. In collaboration with Swedish colleagues, we explored a few of the many possibilities to form new biosensors by utilizing Prof. Heller's concept of cross-linked redox-polymer/redox-enzyme electrodes. 23639627 Doxorubicin induces protein ubiquitination and inhibits proteasome activity during cardiotoxicity. Anthracycline-induced cardiotoxicity is a clinically complex syndrome that leads to substantial morbidity and mortality for cancer survivors. Despite several years of research, the underlying molecular mechanisms remain largely undefined and thus effective therapies to manage this condition are currently non-existent. This study therefore aimed to determine the contribution of the ubiquitin-proteasome pathway (UPP) and endoplasmic reticulum (ER)-stress within this context. Cardiotoxicity was induced with the use of doxorubicin (DXR) in H9C2 rat cardiomyoblasts (3μM) for 24hrs, whereas the tumour-bearing GFP-LC3 mouse model was treated with a cumulative dose of 20mg/kg. Markers for proteasome-specific protein degradation were significantly upregulated in both models following DXR treatment, however proteasome activity was lost. Moreover, ER-stress as assessed by increased ER load was considerably augmented (in vitro) with modest binding of DXR with ER. These results suggest that DXR induces intrinsic activation of the UPP and ER stress which ultimately contributes to dysfunction of the myocardium during this phenomenon. 23616190 High-Throughput Analytical Model to Evaluate Materials for Temperature Swing Adsorption Processes. In order for any material to be considered in a post-combustion carbon capture technology, it must have high working capacities of CO2 from flue gas and be regenerable using as little energy as possible. Shown here is an easy to use method to calculate both working capacities and regeneration energies and thereby predict optimal desorption conditions for any material. 23479389 [6]-gingerol: a novel AT₁ antagonist for the treatment of cardiovascular disease. Considering the prevalence of cardiovascular disease in public health and the limited validated therapeutic options, this study aimed to find novel compounds targeting the angiotensin II type 1 receptor, accepted as a therapeutic target in cardiovascular disease. A small library consisting of 89 compounds from 39 Chinese herbs was profiled using a cell-based calcium mobilization assay which was developed and characterized for high-throughput screening. [6]-Gingerol derived from Zingiber officinale Roscoe (ginger) was identified as a novel angiotensin II type 1 receptor antagonist, with an IC50 value of 8.173 µM. The hit was further tested by a specificity assay indicating that it had no antagonistic effects on other evaluated GPCRs, such as endothelin receptors. The major ingredient of ginger, [6]-gingerol, could inhibit angiotensin II type 1 receptor activation, which partially clarified the mechanism of ginger regulating blood pressure and strengthening heart in the cardiovascular system. 23252481 Total synthesis and evaluation of vinblastine analogues containing systematic deep-seated modifications in the vindoline subunit ring system: core redesign. The total synthesis of a systematic series of vinblastine analogues that contain deep-seated structural modifications to the core ring system of the lower vindoline subunit is described. Complementary to the vindoline 6,5 DE ring system, compounds with 5,5, 6,6, and the reversed 5,6 membered DE ring systems were prepared. Both the natural cis and unnatural trans 6,6-membered ring systems proved accessible, with the latter representing a surprisingly effective class for analogue design. Following Fe(III)-promoted coupling with catharanthine and in situ oxidation to provide the corresponding vinblastine analogues, their evaluation provided unanticipated insights into how the structure of the vindoline subunit contributes to activity. Two potent analogues (81 and 44) possessing two different unprecedented modifications to the vindoline subunit core architecture were discovered that matched the potency of the comparison natural products and both lack the 6,7-double bond whose removal in vinblastine leads to a 100-fold drop in activity. 23539351 Antidiabetic attributes of desert and steppic plants: a review. The rapidly increasing incidence of diabetes mellitus is becoming a serious threat to mankind's health in all parts of the world. In fact, known cases reflect only part of the problem, as many diabetics, especially with type 2 diabetes, are unaware of their disease, which initially shows no definitive symptoms. Despite the great efforts invested in diabetes research, its prevalence continues to grow, while current medications do not cover all of the symptoms and complications of the disease. The present review highlights a plethora of studies focusing on the antidiabetic properties of desert and semidesert (steppic) plants, many of them being used for centuries in traditional medicine by Bedouins living in the arid zones of the Middle East and also by ethnic groups in other arid and semiarid parts of the world. The review concludes in summarizing the work done on the subject and also in pointing to the yet existing gaps in diabetes research of desert and steppic plants, and suggests directions for future exploration. 23526814 tert-Butylcarbamate-Containing Histone Deacetylase Inhibitors: Apoptosis Induction, Cytodifferentiation, and Antiproliferative Activities in Cancer Cells. Herein we report novel pyrrole- and benzene-based hydroxamates (8, 10) and 2'-aminoanilides (9, 11) bearing the tert-butylcarbamate group at the CAP moiety as histone deacetylase (HDAC) inhibitors. Compounds 8 b and 10 c selectively inhibited HDAC6 at the nanomolar level, whereas the other hydroxamates effected an increase in acetyl-α-tubulin levels in human acute myeloid leukemia U937 cells. In the same cell line, compounds 8 b and 10 c elicited 18.4 and 21.4 % apoptosis, respectively (SAHA: 16.9 %), and the pyrrole anilide 9 c displayed the highest cytodifferentiating effect (90.9 %). In tests against a wide range of various cancer cell lines to determine its antiproliferative effects, compound 10 c exhibited growth inhibition from sub-micromolar (neuroblastoma LAN-5 and SH-SY5Y cells, chronic myeloid leukemia K562 cells) to low-micromolar (lung H1299 and A549, colon HCT116 and HT29 cancer cells) concentrations. In HT29 cells, 10 c increased histone H3 acetylation, and decreased the colony-forming potential of the cancer cells by up to 60 %. 23529905 Mimicking Nanofibrous Hybrid Bone Substitute for Mesenchymal Stem Cells Differentiation into Osteogenesis. Mimicking hybrid extracellular matrix is one of the main challenges for bone tissue engineering (BTE). Biocompatible polycaprolactone/poly(α,β)-DL-aspartic acid/collagen nanofibrous scaffolds were fabricated by electrospinning and nanohydroxyapatite (n-HA) was deposited by calcium phosphate dipping method for BTE. Human mesenchymal stem cells (hMSCs) were cultured on these hybrid scaffolds to investigate the cell proliferation, osteogenic differentiation by alkaline phosphatase activity, mineralization, double immunofluorescent staining using CD90 and expression of osteocalcin. The present study indicated that the PCL/PAA/collagen/n-HA scaffolds promoted greater osteogenic differentiation of hMSCs, proving to be a potential hybrid scaffolds for BTE. 23411173 Nutritional and antinutritional evaluation of raw and processed Australian wattle (Acacia saligna) seeds. Raw and processed (soaked, soaked/boiled, roasted) wattle, Acacia saligna subspecies (subsp.) saligna, pruinescens, stolonifera and lindleyi, seeds were analysed for nutritional and antinutritional qualities. Whole wattle seeds mainly comprised proteins (27.6-32.6%) and carbohydrates (30.2-36.4%), which had approximately 12.0-14.0% fat and 13.0-15.0% crude fibre. Palmitic (9.6%), stearic (2.0%), oleic (20.0%) and linoleic (64.3%) acids were identified by gas chromatography (GC) analysis. Phenolic (∼0.2%), oxalate (2.2-3.4%) and saponin (2.6-3.0%) contents were fairly high; phytate content was low. All untreated samples contained a high level of trypsin inhibitor (2474.3-3271.4 trypsin inhibitor units per gramme (TIU/g) of flour) and low level of α-chymotrypsin inhibitor (120.4-150.6 CIU/g). Soaking overnight following with 2-min boiling led to a significant reduction of protease inhibitor activity. Roasting at 2 min or longer was sufficient to reduce both trypsin and α-chymotrypsin inhibitors to negligible values, also to reduce phytate, oxalate and saponin contents, simultaneously enhanced the nutritional values of wattle seeds. 23589329 Arsenic inhibits autophagic flux activating the Nrf2-Keap1 pathway in a p62-dependent manner. The Nrf2-Keap1 signaling pathway is a protective mechanism promoting cell survival. Activation of the Nrf2 pathway by natural compounds has been proven to be an effective strategy for chemoprevention. Interestingly, a cancer-promoting function of Nrf2 has been recently observed in many types of tumors due to deregulation of the Nrf2-Keap1 axis, which leads to constitutive activation of Nrf2. Here, we report a novel mechanism of Nrf2 activation by arsenic that is distinct from that of chemopreventive compounds. Arsenic deregulates the autophagic pathway through blockage of autophagic flux, resulting in accumulation of autophagosomes and sequestration of p62, Keap1, and LC3. Thus, arsenic activates Nrf2 through a non-canonical mechanism (p62-dependent), leading to a chronic, sustained activation of Nrf2. In contrast, activation of Nrf2 by sulforaphane and tert-butylhydroquinone depend upon Keap1-C151 and not p62 (the canonical mechanism). More importantly, SF and tBHQ do not have any effect on autophagy. In fact, SF and tBHQ alleviate arsenic-mediated deregulation of autophagy. Collectively, these findings provide evidence that arsenic causes prolonged activation of Nrf2 through autophagy dysfunction, possibly providing a similar scenario to constitutive activation of Nrf2 found in certain human cancers. This may represent a previously unrecognized mechanism underlying arsenic toxicity and carcinogenicity in humans. 23570913 Electromagnetic-pulse-induced activation of p38 MAPK pathway and disruption of blood-retinal barrier. The blood-retinal barrier (BRB) is critical for maintaining retina homeostasis and low permeability. In this study, we evaluated the effects of electromagnetic pulse (EMP) exposure on the permeability of BRB, alterations of tight junction (TJ) proteins of BRB and if any, involvement of mitogen-activated protein kinase (MAPK) pathway. Male Sprague-Dawley (SD) rats and RF/6A cells which were pretreated with or without MAPKs inhibitors were sham exposed or exposed to EMP at 200kV/m for 200 pulses. The alteration of BRB permeability was examined through fluorescence microscope and quantitatively assessed using Evans blue (EB) and endogenous albumin as tracers. The expressions of TJ proteins and some signaling molecules of MAPK pathway were measured by Western blots. The observations were that EMP exposure resulted in increased BRB permeability concurrent with the decreased expressions of occludin and claudin-5, which were correlated with the increased expressions of phospho-p38, phospho-JNK and phospho-ERK and could be blocked when pretreated with p38 MAPK inhibitor. Thus, the results suggested that the alterations of occludin and claudin-5 may play an important role in the disruption of TJs, which may lead to the transient breakdown of BRB after EMP exposure with the involvement of p38 MAPK pathway through phosphorylation of signaling molecules. 23509039 2-aminothiazoles with improved pharmacotherapeutic properties for treatment of prion disease. Recently, we described the aminothiazole lead (4-biphenyl-4-ylthiazol-2-yl)-(6-methylpyridin-2-yl)-amine (1), which exhibits many desirable properties, including excellent stability in liver microsomes, oral bioavailability of ∼40 %, and high exposure in the brains of mice. Despite its good pharmacokinetic properties, compound 1 exhibited only modest potency in mouse neuroblastoma cells overexpressing the disease-causing prion protein PrP(Sc) . Accordingly, we sought to identify analogues of 1 with improved antiprion potency in ScN2a-cl3 cells while retaining similar or superior properties. Herein we report the discovery of improved lead compounds such as (6-methylpyridin-2-yl)-[4-(4-pyridin-3-yl-phenyl)thiazol-2-yl]amine and cyclopropanecarboxylic acid (4-biphenylthiazol-2-yl)amide, which exhibit brain exposure/EC50 ratios at least tenfold greater than that of compound 1. 23174539 Effects of early life permethrin exposure on spatial working memory and on monoamine levels in different brain areas of pre-senescent rats. Pesticide exposure during brain development could represent an important risk factor for the onset of neurodegenerative diseases. Previous studies investigated the effect of permethrin (PERM) administered at 34 mg/kg, a dose close to the no observable adverse effect level (NOAEL) from post natal day (PND) 6 to PND 21 in rats. Despite the PERM dose did not elicited overt signs of toxicity (i.e. normal body weight gain curve), it was able to induce striatal neurodegeneration (dopamine and Nurr1 reduction, and lipid peroxidation increase). The present study was designed to characterize the cognitive deficits in the current animal model. When during late adulthood PERM treated rats were tested for spatial working memory performances in a T-maze-rewarded alternation task they took longer to choose for the correct arm in comparison to age matched controls. No differences between groups were found in anxiety-like state, locomotor activity, feeding behavior and spatial orientation task. Our findings showing a selective effect of PERM treatment on the T-maze task point to an involvement of frontal cortico-striatal circuitry rather than to a role for the hippocampus. The predominant disturbances concern the dopamine (DA) depletion in the striatum and, the serotonin (5-HT) and noradrenaline (NE) unbalance together with a hypometabolic state in the medial prefrontal cortex area. In the hippocampus, an increase of NE and a decrease of DA were observed in PERM treated rats as compared to controls. The concentration of the most representative marker for pyrethroid exposure (3-phenoxybenzoic acid) measured in the urine of rodents 12 h after the last treatment was 41.50 μg/L and it was completely eliminated after 96 h. 23199999 Effect of red wines with different in vitro antioxidant activity on oxidative stress of high-fat diet rats. It is not known if there is a correlation between in vitro and in vivo antioxidant activity of wines. Thus, in the present study, rats were fed with a high-fat diet to induce inflammation and oxidative stress, and received supplementation (1.0 mL/day) containing water or three red wine samples characterised by high (41.1 mmol TE/L), medium (35.7 mmol TE/L) and low (14.4 mmol TE/L) in vitro antioxidant activity. A correlation was observed between in vitro antioxidant activity measured in the wines and in vivo antioxidant activity measured in plasma (r=+0.49, p=0.011). In liver, only the wine containing the highest in vitro antioxidant activity was able to reduce malondialdehyde concentration. Groups supplemented with wines containing lower in vitro antioxidant activity showed an increase in antioxidant enzyme activity. We concluded that the correlation between in vitro and in vivo antioxidant activity depends on the biomarker selected to evaluate the oxidative stress. 23364612 Green approach—multicomponent production of boron—containing hantzsch and biginelli esters. Multicomponent reactions are excellent methods that meet the requirements of green chemistry, by reducing the number of steps, and consequently reducing purification requirements. Accordingly, in this work, 11 novel hybrid-boron-containing molecules, namely eight 1,4-dihydropyridines and three 3,4-dihydropyrimidinones, derived from formylphenylboronic acids (ortho, meta and para), were obtained using a green approach, involving H-4CR and B-3CR practices, in the presence of ethanol, which is a green solvent, and using three comparatively different modes of activation (mantle heating, yield 3%-7% in 24 h, Infrared Radiation (IR) irradiation, yield 12%-17% in 12 h, and microwave irradiation, yield 18%-80%, requiring very low reaction times of 0.25-0.33 h). In addition, as a green-approach is offered, a convenient analysis, of the 12 green chemistry principles for the overall procedure was performed. Finally, since all the products are new, characterizations were carried out using common analytic procedures (1H, 11B, and 13C NMR, FAB+MS, HRMS, and IR). The accurate mass data of unexpected ions related to interactions between thioglycerol and the expected products, in the FAB+-mode, enabled unequivocal characterization of the target molecules. 23123188 Glaucoma therapy by extended release of timolol from nanoparticle loaded silicone-hydrogel contact lenses. Glaucoma is the second major cause of blindness in the world after cataract. Glaucoma management through eye drops that reduce the intraocular pressure (IOP) has major deficiencies including low patient compliance and low bioavailability. Extended wear contact lenses that deliver glaucoma drugs for extended periods could increase patient compliance, while also increasing the bioavailability. To develop extended wear contact lenses that can also provide extended glaucoma therapy, we disperse nanoparticles of PGT (propoxylated glyceryl triacylate) that contain a glaucoma drug timolol. The particles can also be loaded into prefabricated lenses by soaking the lenses in a solution of particles in ethanol. The particle loaded gels can release timolol in phosphate buffered saline (PBS) for about a month at room temperature. The most likely rate controlling mechanism is hydrolysis of the ester bond that links timolol to the PGT matrix, but other mechanisms such as water and drug diffusion, drug dissolution, drug-polymer chain cleavage, time-dependent drug permeability within the polymeric matrix, etc. may also be important. Nanoparticle incorporation in the silicone hydrogels results in reduction in ion and oxygen permeabilities, and an increase in modulus, and the impact on each of these properties is proportional to the particle loading. A gel with 5% particle loading can deliver timolol at therapeutic doses for about a month at room temperature, with a minimal impact on critical lens properties. Preliminary animal studies in Beagle dogs conducted with lenses in which particles are loaded by soaking the lenses in ethanol show a reduction in IOP. 23411307 Fatty acid composition of cooked chicken meat and chicken meat products as influenced by price range at retail. The primary objective was to determine fatty acid composition of skinless chicken breast and leg meat portions and chicken burgers and nuggets from the economy price range, standard price range (both conventional intensive rearing) and the organic range from four leading supermarkets. Few significant differences in the SFA, MUFA and PUFA composition of breast and leg meat portions were found among price ranges, and supermarket had no effect. No significant differences in fatty acid concentrations of economy and standard chicken burgers were found, whereas economy chicken nuggets had higher C16:1, C18:1 cis, C18:1 trans and C18:3 n-3 concentrations than had standard ones. Overall, processed chicken products had much higher fat contents and SFA than had whole meat. Long chain n-3 fatty acids had considerably lower concentrations in processed products than in whole meat. Overall there was no evidence that organic chicken breast or leg meat had a more favourable fatty acid composition than had meat from conventionally reared birds. 23023933 Development and evaluation of a mechanistic bioconcentration model for ionogenic organic chemicals in fish. A mechanistic mass balance bioconcentration model is developed and parameterized for ionogenic organic chemicals (IOCs) in fish and evaluated against a compilation of empirical bioconcentration factors (BCFs). The model is subsequently applied to a set of perfluoroalkyl acids. Key aspects of model development include revised methods to estimate the chemical absorption efficiency of IOCs at the respiratory surface (E(W) ) and the use of distribution ratios to characterize the overall sorption capacity of the organism. Membrane-water distribution ratios (D(MW) ) are used to characterize sorption to phospholipids instead of only considering the octanol-water distribution ratio (D(OW) ). Modeled BCFs are well correlated with the observations (e.g., r(2)  = 0.68 and 0.75 for organic acids and bases, respectively) and accurate to within a factor of three on average. Model prediction errors appear to be largely the result of uncertainties in the biotransformation rate constant (k(M) ) estimates and the generic approaches for estimating sorption capacity (e.g., D(MW) ). Model performance for the set of perfluoroalkyl acids considered is highly dependent on the input parameters describing hydrophobicity (i.e., log K(OW) of the neutral form). The model applications broadly support the hypothesis that phospholipids contribute substantially to the sorption capacity of fish, particularly for compounds that exhibit a high degree of ionization at biologically relevant pH. Additional empirical data on biotransformation and sorption to phospholipids and subsequent incorporation into property estimation approaches (e.g., k(M) , D(MW) ) are priorities with respect to improving model performance. 23220644 Optimization of 5-hydroxytryptamines as dual function inhibitors targeting phospholipase A2 and leukotriene A4 hydrolase. Dual function inhibitors targeting phospholipase A(2) (PLA(2)) and leukotriene A(4) hydrolase (LTA(4)H) may balance the arachidonic acid (AA) metabolic network and be used as new anti-inflammatory drugs. In previous study, we discovered multi-target drugs towards the AA metabolic network, among which a dual-target inhibitor (JMC08-4) for human nonpancreatic secretory phospholipase A(2) (hnps-PLA(2)) and human leukotriene A(4) hydrolase (LTA(4)H-h) was found. Based on the structure of compound JMC08-4, new dual-target inhibitors were designed assisted by molecular docking. In this report, a series of 5-hydroxytryptamine compounds were synthesized; and most of these title compounds showed more potent inhibitory activity than compound JMC08-4 in the in vitro bioassay against these two enzymes. The best one inhibited hnps-PLA(2) and LTA(4)H-h with IC(50) values of 9.2 ± 0.5 μM and 2.4 ± 1.4 μM, respectively. 23534827 Generalized structural description of calcium-sodium aluminosilicate hydrate gels: the cross-linked substituted tobermorite model. Structural models for the primary strength and durability-giving reaction product in modern cements, a calcium (alumino)silicate hydrate gel, have previously been based solely on non-cross-linked tobermorite structures. However, recent experimental studies of laboratory-synthesized and alkali-activated slag (AAS) binders have indicated that the calcium-sodium aluminosilicate hydrate [C-(N)-A-S-H] gel formed in these systems can be significantly cross-linked. Here, we propose a model that describes the C-(N)-A-S-H gel as a mixture of cross-linked and non-cross-linked tobermorite-based structures (the cross-linked substituted tobermorite model, CSTM), which can more appropriately describe the spectroscopic and density information available for this material. Analysis of the phase assemblage and Al coordination environments of AAS binders shows that it is not possible to fully account for the chemistry of AAS by use of the assumption that all of the tetrahedral Al is present in a tobermorite-type C-(N)-A-S-H gel, due to the structural constraints of the gel. Application of the CSTM can for the first time reconcile this information, indicating the presence of an additional activation product that contains highly connected four-coordinated silicate and aluminate species. The CSTM therefore provides a more advanced description of the chemistry and structure of calcium-sodium aluminosilicate gel structures than that previously established in the literature. 23149927 Longitudinal cystic fibrosis care. Cystic fibrosis is a complex disease entity that presents considerable lifelong challenges. Implementation of medical and surgical treatment options involves multisystem interventions to prevent and treat lung and gastrointestinal manifestations of cystic fibrosis and associated comorbidities. From birth through adulthood, cystic fibrosis care entails a longitudinal regimen aimed at achieving relief of disease symptoms and enhanced life expectancy. With increased knowledge of the molecular behavior of the cystic fibrosis transmembrane conductance regulator (CFTR) in health and disease, clinical practice has been enriched by the prospect of novel strategies, including mutation-specific drug and gene therapy targeting restoration of corrupted transepithelial ion transport. Emerging paradigms of comprehensive care increasingly enable personalized solutions to address the root cause of disease-transforming management options for individuals with cystic fibrosis. 23552830 Characterization and Expression of the Gene Encoding En-MAPK1, an Intestinal Cell Kinase (ICK)-like Kinase Activated by the Autocrine Pheromone-Signaling Loop in the Polar Ciliate, Euplotes nobilii. In the protozoan ciliate Euplotes, a transduction pathway resulting in a mitogenic cell growth response is activated by autocrine receptor binding of cell type-specific, water-borne signaling protein pheromones. In Euplotes raikovi, a marine species of temperate waters, this transduction pathway was previously shown to involve the phosphorylation of a nuclear protein kinase structurally similar to the intestinal-cell and male germ cell-associated kinases described in mammals. In E. nobilii, which is phylogenetically closely related to E. raikovi but inhabits Antarctic and Arctic waters, we have now characterized a gene encoding a structurally homologous kinase. The expression of this gene requires +1 translational frameshifting and a process of intron splicing for the production of the active protein, designated En-MAPK1, which contains amino acid substitutions of potential significance for cold-adaptation. 23583168 Mechanisms and Metabolic Implications of Regional Differences among Fat Depots. Fat distribution is closely linked to metabolic disease risk. Distribution varies with sex, genetic background, disease state, certain drugs and hormones, development, and aging. Preadipocyte replication and differentiation, developmental gene expression, susceptibility to apoptosis and cellular senescence, vascularity, inflammatory cell infiltration, and adipokine secretion vary among depots, as do fatty-acid handling and mechanisms of enlargement with positive-energy and loss with negative-energy balance. How interdepot differences in these molecular, cellular, and pathophysiological properties are related is incompletely understood. Whether fat redistribution causes metabolic disease or whether it is a marker of underlying processes that are primarily responsible is an open question. 23401262 Effects of Lepidium sativum, Nigella sativa and Trigonella foenum-graceum on Phenytoin Pharmacokinetics in Beagle Dogs. The present work was designed to evaluate the effect of some commonly used herbs viz. garden cress (Lepidium sativum), black seed (Nigella sativa) and fenugreek (Trigonella foenum-graceum) on the disposition of phenytoin after oral administration in a dog model. Phenytoin was given orally at a dose of 50 mg, and blood samples were obtained for the determination of drug's pharmacokinetic parameters. After a suitable washout period, animals were commenced on a specific herb treatment for one week. Garden cress treatment caused a modest increase in maximum observed concentration (C(max) ) and terminal half-life (T(1/2λ) ) of phenytoin with a reduction in clearance by 33%. The effect of black seed therapy was more drastic on drug elimination and to a lesser extent on its volume of distribution at steady state (V(ss) ) with a consequent reduction in systemic exposure measured by area under the curve (AUC(0-∞) ) by about 87%. The effect of fenugreek therapy resembled, albeit to a lesser extent, that of black seed with a significant reduction in AUC(0-∞) by ~72%. In addition, there was a 73% increase in V(ss) . Our findings suggest that the phenytoin disposition can be significantly altered by the concurrent consumption of tested herbal products. Copyright © 2013 John Wiley & Sons, Ltd. 23477419 Design, Synthesis, and Pharmacological Characterization of Novel Endomorphin-1 Analogues as Extremely Potent μ-Opioid Agonists. Recently we reported the synthesis and structure-activity study of endomorphin-1 (EM-1) analogues containing novel, unnatural α-methylene-β-aminopropanoic acids (Map). In the present study, we describe new EM-1 analogues containing Dmt(1), (R/S)-βPro(2), and (ph)Map(4)/(2-furyl)Map(4). All of the analogues showed a high affinity for the μ-opioid receptor (MOR) and increased stability in mouse brain homogenates. Of the new compounds, Dmt(1)-(R)-βPro(2)-Trp(3)-(2-furyl)Map(4) (analogue 12) displayed the highest affinity toward MOR, in the picomolar range (Ki(μ) = 3.72 pM). Forskolin-induced cAMP accumulation assays indicated that this analogue displayed an extremely high agonistic potency, in the subpicomolar range (EC50 = 0.0421 pM, Emax = 99.5%). This compound also displayed stronger in vivo antinociceptive activity after iv administration when compared to morphine in the tail-flick test, which indicates that this analogue was able to cross the blood-brain barrier. 22804459 Antioxidant activity of Buglossoides purpureocaerulea (L.) I.M. Johnst. extracts. Buglossoides purpureocaerulea is a little-known plant used in the folk tradition for the preparation of a decoction in Sud, Italy, where it is appreciated for its beneficial effects on liver diseases. These properties may be due to the presence of antioxidant compounds. This study presents the phenolic characterisation and the antioxidant activity (AA) of B. purpureocaerulea extracts obtained by decoction, ethanol infusion and ethanol and methanol macerations. Total phenols ranged between 69 and 100 mg g(-1 ) dry weight (DW). The main compounds were: rosmarinic acid, caffeic acid, lithospermic acid and salvianolic acid C. The extracts showed a good AA, particularly high for the decoction (142-283 µmol TE g(-1) DW; TE, Trolox equivalent) and ethanol maceration extract (214-364 µmol TE g(-1) DW) when determined by DPPH and ferric reducing antioxidant power test, respectively. 22923473 Liver glycogen loading dampens glycogen synthesis seen in response to either hyperinsulinemia or intraportal glucose infusion. The purpose of this study was to determine the effect of liver glycogen loading on net hepatic glycogen synthesis during hyperinsulinemia or hepatic portal vein glucose infusion in vivo. Liver glycogen levels were supercompensated (SCGly) in two groups (using intraportal fructose infusion) but not in two others (Gly) during hyperglycemic-normoinsulinemia. Following a 2-h control period during which fructose infusion was stopped, there was a 2-h experimental period in which the response to hyperglycemia plus either 4× basal insulin (INS) or portal vein glucose infusion (PoG) was measured. Increased hepatic glycogen reduced the percent of glucose taken up by the liver that was deposited in glycogen (74 ± 3 vs. 53 ± 5% in Gly+INS and SCGly+INS, respectively, and 72 ± 3 vs. 50 ± 6% in Gly+PoG and SCGly+PoG, respectively). The reduction in liver glycogen synthesis in SCGly+INS was accompanied by a decrease in both insulin signaling and an increase in AMPK activation, whereas only the latter was observed in SCGly+PoG. These data indicate that liver glycogen loading impairs glycogen synthesis regardless of the signal used to stimulate it. 23311296 Characterization of bundled and individual triple-walled carbon nanotubes by resonant Raman spectroscopy. The optical characterization of bundled and individual triple-walled carbon nanotubes was studied for the first time in detail by using resonant Raman spectroscopy. In our approach, the outer tube of a triple-walled carbon nanotube system protects the two inner tubes (or equivalently the inner double-walled carbon nanotube) from external environment interactions making them a partially isolated system. Following the spectral changes and line-widths of the radial breathing modes and G-band by performing laser energy dependent Raman spectroscopy, it is possible to extract important information as regards to the electronic and vibrational properties, tube diameters, wall-to-wall distances, radial breathing mode, and G-band resonance evolutions as well as high-curvature intertube interactions in isolated double- and triple-walled carbon nanotube systems. 22080034 Nanosilver effects on growth parameters in experimental aflatoxicosis in broiler chickens. Aflatoxicosis is a cause of economic losses in broiler production. In this study, the effect of one commercial nanocompound, Nanocid (Nano Nasb Pars Co., Iran) was evaluated in reduction of aflatoxin effects on the growth and performance indices in broiler chickens suffering from experimental aflatoxicosis. For this, a total of 300 one-day-old broiler chicks (Ross strain) were randomly divided into 4 groups with 3 replicates of 15 chicks in each separated pen during the 28-day experiment. Treatment groups including group A: chickens fed basal diet, group B: chickens fed 3 ppm productive aflatoxin in basal diet, group C: chickens fed basal diet plus 2500 ppm Nanocid, and group D: chickens fed 3 ppm productive aflatoxin and 2500 ppm Nanocid, in basal diet. Data on body weight, body weight gain (BWG), feed intake, and feed conversion ratio (FCR) were recorded at weekly intervals. Also cumulative data were assessed. Results showed, although supplement of Nanocid to conventional diet had no effect on performance but addition of Nanocid to diet containing 3 ppm aflatoxin increased significantly the cumulative BWG, cumulative feed consumption and decreased FCR in the last 2 weeks of experimental period. The improvement in these performance indices by supplement of Nanocid to diet containing aflatoxin showed the ability of Nanocid to diminish the inhibitory effects of aflatoxin. 23636886 Statistical optimization of a multivariate fermentation process for enhancing antibiotic activity of Streptomyces sp. CS392. Antibiotic activity against various gram positive bacteria including Staphylococcus aureus and Enterococcus was ascertained from a soil-isolated microbial strain Streptomyces sp. CS392. The antibiotic activity of the strain was maximized by using a dual-stage, multivariate statistical optimization framework based on the response surface methodology considering a lab-scale fermentation process. Multiple nutrient constituents of the fermentation broth were jointly optimized in the first stage, while the fermentation culture conditions were optimized in the subsequent stage. Based on the empirical models derived from the dual-stage statistical optimization framework, 39.79 % of cumulative enhancement in the antibiotic activity was obtained (analytically) at the concurrent optimal settings (Optimal nutrient composition for the first stage of optimization: 29.82 glucose, 7.6 peptone, 4.678 MgCl2 and 0.5005 g/l casamino acid; and optimal fermentation condition for the second stage of optimization: incubation period 47.55 h; incubation temperature 29.15 °C; and pH 8.36). The analytically depicted enhancement in the antibiotic activity was validated experimentally. 23044489 Ketamine combinations for the field treatment of soman-induced self-sustaining status epilepticus. Review of current data and perspectives. Organophosphorus nerve agents (NA), potent irreversible cholinesterase inhibitors, could induce severe seizures, status epilepticus (SE), seizure-related brain damage (SRBD) and lethality. Despite the lack of data in the case of NA, clinical evidences suggest that SE survivors could suffer from neurological/cognitive deficits and impairments such as spontaneous recurrent seizures (epilepsy) after a latent period of epileptogenesis. It is beyond doubt that an effective and quick management of the initial seizures and prevention of SRBD are critical to prevent these long-term consequences, explaining why most experimental data are focusing on the 5-40min post-exposure time frame. However, in field conditions, treatment may be delayed and with the exception of NMDA receptor antagonists, currently no drug provides protection (against lethality, seizures, SRBD and neurological consequences) when seizures are left unabated for one hour or more. Ketamine (KET) is the only NMDA antagonist licensed as an injectable drug in different countries and remains an anesthetic of choice in some difficult field conditions. In this short review paper, after a presentation of some of the key points of the pathophysiology of NA-induced SE and a quick survey of the potential therapeutic avenues in the context of delayed treatment of NA-induced SE, we will review the recent data we obtained showing that KET, in combination with atropine sulfate (AS), with or without a benzodiazepine, considerably reduces soman-induced neuroinflammation, provides neuroprotection, histologically and functionally, and also positively modify soman-induced changes in brain metabolism. Finally, we will also mention some results from safety studies including those bringing evidence that, at difference with MK-801, KET does not impair thermoregulation and even seems to reduce AS-induced heat stress. All in all, KET, in combination, appears a good candidate for the out-of-hospital treatment of severe NA-induced SE. 23296105 Inhalation of uranium nanoparticles: respiratory tract deposition and translocation to secondary target organs in rats. Uranium nanoparticles (<100 nm) can be released into the atmosphere during industrial stages of the nuclear fuel cycle and during remediation and decommissioning of nuclear facilities. Explosions and fires in nuclear reactors and the use of ammunition containing depleted uranium can also produce such aerosols. The risk of accidental inhalation of uranium nanoparticles by nuclear workers, military personnel or civilian populations must therefore be taken into account. In order to address this issue, the absorption rate of inhaled uranium nanoparticles needs to be characterised experimentally. For this purpose, rats were exposed to an aerosol containing 10⁷ particles of uranium per cm³ (CMD=38 nm) for 1h in a nose-only inhalation exposure system. Uranium concentrations deposited in the respiratory tract, blood, brain, skeleton and kidneys were determined by ICP-MS. Twenty-seven percent of the inhaled mass of uranium nanoparticles was deposited in the respiratory tract. One-fifth of UO₂ nanoparticles were rapidly cleared from lung (T(½)=2.4 h) and translocated to extrathoracic organs. However, the majority of the particles were cleared slowly (T(½)=141.5 d). Future long-term experimental studies concerning uranium nanoparticles should focus on the potential lung toxicity of the large fraction of particles cleared slowly from the respiratory tract after inhalation exposure. 23494233 Effects of nitric oxide synthase inhibition in the dorsolateral periaqueductal gray matter on ethanol withdrawal-induced anxiety-like behavior in rats. RATIONALE: Nitric oxide (NO)-mediated transmission in the dorsolateral periaqueductal gray matter (dlPAG) has been involved in the expression of anxiety-like behaviors. Ethanol withdrawal sensitizes the dlPAG and results in increased anxiety-like responses. OBJECTIVES: The objective of the study was to test the hypothesis that NO in the dlPAG is involved in the expression of ethanol withdrawal-induced anxiety. METHODS: Male Wistar rats were implanted with guide cannulae aimed at the dlPAG. The animals were forced to consume a liquid diet containing ethanol 6-8 % (v/v) for 15 days as their only source of diet. Six days after surgery and 24 h after ethanol discontinuation, the animals received microinjections of the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO), nonselective nitric oxide synthase inhibitor N (G)-nitro-L-arginine methyl ester (L-NAME), selective neuronal nitric oxide synthase inhibitor 1-(2-[trifluoromethyl]phenyl) imidazole (TRIM), or selective inducible nitric oxide synthase (iNOS) inhibitor N-([3-(aminomethyl)phenyl]methyl) ethanimidamide dihydrochloride (1400W) into the dlPAG. Ten minutes later, the animals were tested in the light/dark box. RESULTS: Carboxy-PTIO (1 nmol), L-NAME (200 nmol), TRIM (20 nmol), and 1400W (0.3 and 1 nmol) decreased the anxiogenic-like effects of ethanol withdrawal in rats in the light/dark box test. The NO precursor L-arginine reversed the effects of L-NAME. CONCLUSIONS: NO production in the dlPAG may play a role in the modulation of ethanol withdrawal-induced anxiety-like behavior in rats. Furthermore, iNOS-mediated NO synthesis in the dlPAG is predominantly involved in the behavioral expression of anxiety-like behavior during ethanol withdrawal. 23590892 Docosahexaenoic acid (DHA) ameliorates paraquat-induced pulmonary fibrosis in rats possibly through up-regulation of Smad 7 and SnoN. Paraquat (PQ) poisoning has caused a large number of human fatalities due to the progressive and irreversible pulmonary fibrosis. Docosahexaenoic acid (DHA) is well-recognized as important modulators of multiple biological pathways that affect health and disease. A line of studies have shown that DHA supplementation is associated with the alleviation of some tissue fibrosis. In the current study, pulmonary fibrosis of rats was produced by a single oral dose of 50mg/kgbw PQ treatment. Daily 500mg/kgbw DHA supplementation was provided 7days before PQ treatment and lasted for consecutive 35days. DHA was found to ameliorate the pulmonary fibrotic alterations induced by PQ, which was evidenced by significant reduction of histological changes, hydroxyproline content and level of the transforming growth factor-β1 (TGF-β1) mRNA. Furthermore, the protein levels of Smad 7 and SnoN in the DHA supplemented rats were significantly increased compared with those in the rats of the PQ group. These results suggested that DHA ameliorated pulmonary fibrosis induced by PQ might be attributed to its enhancement of Smad 7 and SnoN expression. 23541646 Glycyrrhetinic acid and its analogs: A new class of antifilarial agents. Although a number of chemicals have been isolated from Glycyrrhiza glabra, only a few have been evaluated for their biological significance. As part of our drug discovery program for antifilarial agents from Indian medicinal plants, the roots of G. glabra were chemically investigated, which resulted in the isolation and characterization of an antifilarial agent, glycyrrhetinic acid (GA, 1a) effective against microfilariae (mf) in vitro (LC100: 12.5μM; IC50: 1.20μM), but was inactive against adult worms. Further, GA (1a) was converted into six analogs (2a-7a) and their antifilarial potential was evaluated by studying in vitro motility and MTT reduction assays employing mf and adult worms of Brugia malayi. The results showed that out of six GA analogs, the benzyl amide analog (6a) killed adults and mf at 25 and 50μM concentration, respectively, and inhibited 49% MTT reduction potential of the adult parasites. The IC50 values were found to be 8.8 and 2.2μM for adults and mf, respectively. The SI of the compound was >60. On the other hand the octylamide analog (7a) required much higher concentration to adversely affect the parasites. Finally, both active amide analogs (6a and 7a) were in vivo evaluated using B. malayi-jird model, which showed that analog 6a possesses promising macrofilaricidal activity at 100mg/kg, s.c. ×5days and around 40% of the treated animals showed calcified masses of worm fragments in peritoneal cavity of the animals. To the best of our knowledge this is the first ever report on the antifilarial potential of GA analogs. Further work on optimization of the antifilarial lead is under progress. 23627605 How Graphene Slides: Measurement and Theory of Strain-Dependent Frictional Forces between Graphene and SiO2. Strain, bending rigidity, and adhesion are interwoven in determining how graphene responds when pulled across a substrate. Using Raman spectroscopy of circular, graphene-sealed microchambers under variable external pressure, we demonstrate that graphene is not firmly anchored to the substrate when pulled. Instead, as the suspended graphene is pushed into the chamber under pressure, the supported graphene outside the microchamber is stretched and slides, pulling in an annulus. Analyzing Raman G band line scans with a continuum model extended to include sliding, we extract the pressure dependent sliding friction between the SiO2 substrate and mono-, bi-, and trilayer graphene. The sliding friction for trilayer graphene is directly proportional to the applied load, but the friction for monolayer and bilayer graphene is inversely proportional to the strain in the graphene, which is in violation of Amontons' law. We attribute this behavior to the high surface conformation enabled by the low bending rigidity and strong adhesion of few layer graphene. 22972396 Luminescent neutral platinum complexes bearing an asymmetric N(^) N(^) N ligand for high-performance solution-processed OLEDs. The synthesis and full characterization of new platinum complexes bearing a bulky asymmetric dianionic tridentate ligand is reported. The hindrance of the ligand prevents detrimental intermolecular interactions yielding to highly emitting species in both crystalline state and thin-film. Such properties prompted their successful use in solution-processed OLEDs, showing remarkable external quantum efficiency up to 5.6%. 23422872 Balancing societal needs and regulatory certainty: the case study of peramivir in Japan. Regulators must balance societal and medical requirements against the need for certainty about benefit and risk for new medicines. This is described in a case study of the expedited review and approval of peramivir, a novel neuraminidase inhibitor, in Japan in the context of the emergence of new strain of influenza in 2009. The case illustrates the importance of regulatory science and transparency in supporting such decision making. 23410171 Design of multifunctional compounds for cardiovascular disease: from natural scaffolds to "classical" multitarget approach. Cardiovascular disease represents the main cause of death worldwide. Novel therapies to reduce elevated blood pressure and treat resistant hypertension, to consequently reduce the associated cardiovascular risk factors, are still required. Among the different strategies commonly used in medicinal chemistry to develop new molecules, the synthesis of multitarget/hybrid compounds combining two or more pharmacophore groups targeting simultaneously selected factors involved in cardiovascular diseases, has gained increasing interest. This review will focus on the most recent literature on multifunctional cardiovascular drugs, paying particular attention on hybrid compounds bearing natural scaffolds, considering that compounds derived from medicinal extracts are generally appealing for the medicinal chemist as they often bear the so-called "privileged structures". Moreover, taking into account many excellent reviews dealing with multitarget cardiovascular drugs published in the last few years, mainly devoted to RAAS inhibition and/or NO donors hybrid drugs, herein the most significant results obtained and the benefits and limitations of these approaches will be highlighted. 23373965 Discovery of a potential anti-inflammatory agent: 3-oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile. Fifteen novel derivatives of glycyrrhetinic acid (GA) were synthesized and evaluated for anti-inflammatory activities. It was found that the introduction of 1-en-3-one and 9(11),12-diene and 2,20-dinitrile functionalities into the scaffold of GA led to the discovery of potent compound 19 for inhibition of LPS-induced NO production. Furthermore, 19 effectively inhibited the protein and mRNA expression of inducible NO synthase (iNOS) and the mRNA expression of TNF-α, IL-6, and IL-1β in LPS-stimulated RAW 264.7 macrophages. Mechanistically, 19 exerted inhibitory effects on the activation of the three main MAPKs and phosphorylation and degradation of IκB-α, as well as the ratio of nuclear/cytosolic content of p65. Importantly, 19 significantly decreased the mortality rate in the mouse model of LPS-induced sepsis shock. It is noteworthy that inhibitory effect of 19 on NO production was not blocked by the glucocorticoid receptor antagonist mifepristone, indicating that it does not act through the glucocorticoid receptor. 23401470 From spots to beads-PTM-peptide bead arrays for the characterization of anti-histone antibodies. Antibodies that recognize PTMs of histones play a central role in epigenetic proteomic research. Modification-specific antibodies are employed in chromatin immunoprecipitation, for Western blotting and during the immunoprecipitation steps for MS-based global proteomic analyses. Knowledge about the antibodies' off-target binding is essential for the interpretation of experimental data. To address this challenge we developed a fast and cost efficient system for generating peptide bead arrays. We employed this method to establish a bead-based peptide array containing 384 peptides displaying phosphorylated, acetylated, methylated, and citrullinated N-terminal regions of histones H2A, H2B, H3 and H4 and controls. We profiled the binding of 40 PTM-specific antibodies important for epigenetic proteomic research. 23620256 Study of endothelial cell apoptosis using fluorescence resonance energy transfer (FRET) biosensor cell line with hemodynamic microfluidic chip system. To better understand how hyperglycemia induces endothelial cell dysfunction under the diabetic conditions, a hemodynamic microfluidic chip system was developed. The system combines a caspase-3-based fluorescence resonance energy transfer (FRET) biosensor cell line which can detect endothelial cell apoptosis in real-time, post-treatment effect and with a limited cell sample, by using a microfluidic chip which can mimic the physiological pulsatile flow profile in the blood vessel. The caspase-3-based FRET biosensor endothelial cell line (HUVEC-C3) can produce a FRET-based sensor protein capable of probing caspase-3 activation. When the endothelial cells undergo apoptosis, the color of the sensor cells changes from green to blue, thus sensing apoptosis. A double-labeling fluorescent technique (yo pro-1 and propidium iodide) was used to validate the findings revealed by the FRET-based caspase sensor. The results show high rates of apoptosis and necrosis of endothelial cells when high glucose concentration was applied in our hemodynamic microfluidic chip combined with an exhaustive pulsatile flow profile. The two apoptosis detection techniques (fluorescent method and FRET biosensor) are comparable; but FRET biosensor offers more advantages such as real-time observation and a convenient operating process to generate more accurate and reliable data. Furthermore, the activation of the FRET biosensor also confirms the endothelial cell apoptosis induced by the abnormal pulsatile shear stress and high glucose concentration is through caspase-3 pathway. A 12% apoptotic rate (nearly a 4-fold increase compared to the static condition) was observed when the endothelial cells were exposed to a high glucose concentration of 20 mM under 2 h exhaustive pulsatile shear stress of 30 dyne cm(-2) and followed with another 10 h normal pulsatile shear stress of 15 dyne cm(-2). Therefore, the most important finding of this study is to develop a novel endothelial cell apoptosis detection method, which combines the microfluidic chip system and FRET biosensor. This finding may provide new insight into how glucose causes endothelial cell dysfunction, which is the major cause of diabetes-derived complications. 23396223 Protein carbonylation in human endothelial cells exposed to cigarette smoke extract. Cigarette smoke is a significant independent risk factor for vascular diseases and is a leading cause of structural and functional alterations of the vascular endothelium. In this study, we show protein carbonylation in the human umbilical vein endothelial cell line (ECV-304) exposed to whole-phase cigarette smoke extract. The main carbonylated proteins, including cytoskeletal proteins, glycolytic enzymes, xenobiotic metabolizing and antioxidant enzymes, and endoplasmic reticulum proteins, were identified by means of two-dimensional electrophoresis and Matrix-Assisted Laser Desorption/Ionization-Time of Flight (MALDI-TOF) mass spectrometry (redox proteomics). Morphological analyses by fluorescence microscopy evidenced alterations in the microtubule cytoskeleton, especially at longer exposure time to cigarette smoke extract. Morphological analyses by transmission electron microscopy showed vacuolisation of the cytoplasm, alteration of mitochondria ultrastructure, and some enlargement of the perinuclear space. The possible role played by protein carbonylation caused by reactive species contained in cigarette smoke in the cigarette smoke-induced endothelial injury is discussed. 23348152 Disubstituted diaryl diselenides as potential atheroprotective compounds: Involvement of TrxR and GPx-like systems. Oxidative modifications of low-density lipoproteins (LDLs) have a determinant role in atherogenesis and the study of agents that can modulate LDL oxidation is of pharmacological and therapeutic significance. Therefore, the aim of this study was to evaluate the antioxidant effect of the disubstituted diaryl diselenides, p-methoxyl-diphenyl diselenide (p-CH(3)O-C(6)H(4)Se)(2) (DM) and p-chloro-diphenyl diselenide (p-Cl-C(6)H(4)Se)(2) (DC), on Cu(2+)-induced LDL oxidation. Both compounds caused a dose-dependent inhibition of human serum and isolated LDL oxidation evidenced by the increasing of the lag phase of lipid peroxidation and decreased the lipid oxidation rate (V(max)). The protein moieties from isolated LDL were also protected from Cu(2+)-induced oxidation. Moreover, the disubstituted diaryl diselenides efficiently decreased the oxidized LDL (ox-LDL) induced foam cell formation in J774A.1 macrophage cells. Mechanistically, we have demonstrated that the antioxidant and antiatherogenic effects of DM and DC are related to formation of their selenol intermediates (RSeH) either by a direct reaction with endogenous thiols (GPx-like activity) or via their reduction by TrxR (using NADPH as electron donor). Considering the powerful effect of DM and DC against LDL-induced toxicity, they could be considered for developing of new therapeutic approaches to preventing and treating atherosclerosis and cardiovascular diseases. 23535320 Potent naphthoquinones against antimony-sensitive and -resistant Leishmania parasites: Synthesis of novel α- and nor-α-lapachone-based 1,2,3-triazoles by copper-catalyzed azide-alkyne cycloaddition. Continuing our screening program for novel anti-parasite compounds, we synthesized seven 1,4-naphthoquinones coupled to 1,2,3-triazoles, five nor-β-lapachone-based 1,2,3-triazoles and ten α-lapachone-based 1,2,3-triazoles. These and other naphthoquinonoid compounds were evaluated for their activity against promastigote forms of antimony-sensitive and -resistant strains of Leishmania infantum (syn. Leishmania chagasi) and Leishmania amazonensis. The toxicity of these compounds to mammalian cells was also examined. The substances were more potent than an antimonial drug, with IC50 values ranging from 1.0 to 50.7 μM. Nor-α-lapachone derivatives showed the highest antileishmanial activity, with selectivity indices in the range of 10-15. These compounds emerged as important leads for further investigation as antileishmanial agents. Additionally, one of these compounds exhibited cross-resistance in Sb-resistant Leishmania and could provide a molecular tool for investigating the multidrug resistance mechanisms in Leishmania parasites. 23357628 Design and synthesis of dimethylaminomethyl-substituted curcumin derivatives/analogues: potent antitumor and antioxidant activity, improved stability and aqueous solubility compared with curcumin. A series of dimethylaminomethyl-substituted curcumin derivatives/analogues were designed and synthesized. All compounds effectively inhibited HepG2, SGC-7901, A549 and HCT-116 tumor cell lines proliferation in MTT assay. Particularly, compounds 2a and 3d showed much better activity than curcumin against all of the four tumor cell lines. Antioxidant test revealed that these compounds had higher free radical scavenging activity than curcumin towards both DPPH and galvinoxyl radicals. Furthermore, the aqueous solubility and stability of the target compounds were also significantly improved compared with curcumin. 23259985 Bioreducible polymers as a determining factor for polyplex decomplexation rate and transfection. Polyplex formation (complexation) and gene release from the polyplexes (decomplexation) are major events in polymeric gene delivery; however, the effect of the decomplexation rate on transfection has been rarely investigated. This study employed mixed polymers of poly((L)-lysine) (PLL: MW ~7.4 kDa) and reducible PLL (RPLL) (MW ~6.7 kDa) to design decomplexation rate-controllable PLL(100-x)RPLL(x)/pDNA complexes (PRL(x) polyplexes). The transfection efficiency of a model gene (luciferase) in MCF7 and HEK293 cell lines increased with increasing x (RPLL content) in the PRL(x) polyplexes until peaking at x = 2.5 and 10, respectively, after which point transfection efficiency declined rapidly. In MCF7 cells, PRL(2.5) polyplex produced 3 or 223 times higher gene expression than PLL or RPLL polyplexes, respectively. Similarly, the transfection efficiency of PRL(10) polyplex-transfected HEK293 cells was 3.8 or 67 times higher than that of PLL or RPLL polyplexes, respectively. The transfection results were not apparently related to the particle size, surface charge, complexation/compactness, cellular uptake, or cytotoxicity of the tested polyplexes. However, the decomplexation rate varied by RPLL content in the polyplexes, which in turn influenced the gene transfection. The nuclear localization of pDNA delivered by PRL(x) polyplexes showed a similar trend to their transfection efficiencies. This study suggests that an optimum decomplexation rate may result in high nuclear localization of pDNA and transfection. Understanding in decomplexation and intracellular localization of pDNA may help develop more effective polyplexes. 23603381 Ellagic acid attenuates bleomycin and cyclophosphamide-induced pulmonary toxicity in Wistar rats. Use of bleomycin (BLM) and cyclophosphamide (CP) as chemotherapeutic drugs is associated with side effects including toxicity to respiratory system. Their co-administration may enhance lung toxicity which may subsequently progress to the lung fibrosis. Natural compounds have shown mitigating effects against toxicity of anticancer drugs. Ellagic acid (EA), a polyphenolic compound present in many fruits and nuts in addition to walnut has shown promising protective effect against toxicity of drugs and chemicals. We studied the ameliorative effect of EA on lung toxicity in rats exposed to CP (150mg/kgb.w., i.p.) and BLM (10U/kgb.w., i.t.). EA (15mg/kgb.w., p.o.×14days) treatment modulated enhanced hydroxyproline level, lipid peroxidation, myeloperoxidase activity, nitric oxide production and protein carbonyl formation in lungs of rats exposed to toxic anticancer drugs. There was a marked decrease in GSH content and activities of antioxidant enzymes as a result of BLM and CP treatment. Bronchoalveolar lavage fluid showed increased level of cytotoxicity markers in drug treated animals. Treatment with EA attenuated these changes. Histopathological findings also showed protective effects of EA. In conclusion, EA emerged as a natural protectant with an ability to protect lungs from onslaught of pulmonary toxicity of anticancer drugs. 23298322 Timed-release polymer nanoparticles. Triggered-release of encapsulated therapeutics from nanoparticles without remote or environmental triggers was demonstrated in this work. Disassembly of the polymer nanoparticles to unimers at precise times allowed the controlled release of oligo DNA. The polymers used in this study consisted of a hydrophilic block for stabilization and second thermoresponsive block for self-assembly and disassembly. At temperatures below the second block's LCST (i.e., below 37 °C for in vitro assays), the diblock copolymer was fully water-soluble, and when heated to 37 °C, the polymer self-assembled into a narrow size distribution of nanoparticles with an average diameter of approximately 25 nm. The thermoresponsive nature of the second block could be manipulated in situ by the self-catalyzed degradation of cationic 2-(dimethylamino)ethyl acrylate (DMAEA) units to negatively charged acrylic acid groups and when the amount of acid groups was sufficiently high to increase the LCST of the second block above 37 °C. The disassembly of the nanoparticles could be controlled from 10 to 70 h. The use of these nanoparticles as a combined therapy, in which one or more agents can be released in a predetermined way, has the potential to improve the personal point of care treatment of patients. 23581965 Enhanced Hematite Water Electrolysis Using a 3D Antimony-Doped Tin Oxide Electrode. We present herein an example of nanocrystalline antimony-doped tin oxide (nc-ATO) disordered macroporous "inverse opal" 3D electrodes as efficient charge-collecting support structures for the electrolysis of water using a hematite surface catalyst. The 3D macroporous structures were created via templating of polystyrene spheres, followed by infiltration of the desired precursor solution and annealing at high temperature. Using cyclic voltammetry and electrochemical impedance spectroscopy, it was determined that the use of this 3D transparent conducting oxide with a hematite surface catalyst allowed for a seven-fold increase in active surface area for water splitting with respect to its 2D planar counterpart. This ratio of surface areas was evaluated based on the presence of oxidized trap states on the hematite surface, as determined from the equivalent circuit analysis of the Nyquist plots. Furthermore, the presence of nc-ATO 2D and 3D "underlayer" structures with hematite deposited on top resulted in decreased charge transfer resistances and an increase in the number of available active surface sites at the semiconductor-liquid junction when compared to hematite films lacking any nc-ATO substructures. Finally, absorption, transmission and reflectance spectra of all of the tested films were measured, suggesting the feasibility of using 3D disordered structures in photoelectrochemical reactions, due to the high absorption of photons by the surface catalyst material and trapping of light within the structure. 23275113 Toward a detailed characterization of oil adsorbates as "solid liquids". Solid lipid formulation systems are used to overcome oral bioavailability problems of poorly water-soluble drugs. One promising process is the conversion of a liquid lipid system in a free flowing powder by use of adsorbing excipients. The aim of this study was the detailed characterization of solid-liquid interactions in oil adsorbed to Fujicalin® and Neusilin® which were manufactured by means of dual asymmetric centrifugation or conventional mortar/pestle blending. The adsorption strength of the excipients was investigated by Benchtop-NMR and ESR spectroscopy revealing the highest adsorption power for the Neusilin® products. The adsorbate production methods as well as the storage of the excipients impact their adsorption properties. Environmental scanning electron microscopy (ESEM) and confocal laser scanning microscopy (CLSM) show that dual asymmetric centrifugation leads to a smoothing of the particle surface, whereas the mortar/pestle blending results in an uneven surface and particle destruction. The oil distribution at the particles is inhomogeneous for both production methods. The micropolarity of the adsorbed oil was investigated by ESR spectroscopy and multispectral fluorescence imaging. The adsorbing process on Neusilin® leads to an increased micropolarity of the oil component. The release of the oil component in aqueous media could be verified by Benchtop-NMR and multispectral fluorescence imaging. 23567318 Gene Cloning, Expression and Characterization of a Novel Xylanase from the Marine Bacterium, Glaciecola mesophila KMM241. Marine xylanases are rather less studied compared to terrestrial xylanases. In this study, a new xylanase gene, xynB, was cloned from the marine bacterium, Glaciecola mesophila KMM241, and expressed in Escherichia coli. xynB encodes a multi-domain xylanase XynB of glycoside hydrolase (GH) family 8. The recombinant XynB comprises an N-terminal domain (NTD) with unknown function and a catalytic domain, which is structurally novel among the characterized xylanases of GH family 8. XynB has the highest identity (38%) to rXyn8 among the characterized xylanases. The recombinant XynB showed maximal activity at pH 6-7 and 35 °C. It is thermolabile and salt-tolerant. XynB is an endo-xylanase that demands at least five sugar moieties for effective cleavage and to hydrolyze xylohexaose and xylopentaose into xylotetraose, xylotriose and xylobiose. NTD was expressed in Escherichia coli to analyze its function. The recombinant NTD exhibited a high binding ability to insoluble xylan and avicel and little binding ability to chitosan and chitin. Since the NTD shows no obvious homology to any known carbohydrate-binding module (CBM) sequence in public databases, XynB may contain a new type of CBM. 23230131 Pharmacogenomics of gemcitabine metabolism: functional analysis of genetic variants in cytidine deaminase and deoxycytidine kinase. Gemcitabine (dFdC, 2',2'-difluorodeoxycytidine) is metabolized by cytidine deaminase (CDA) and deoxycytidine kinase (DCK), but the contribution of genetic variation in these enzymes to the variability in systemic exposure and response observed in cancer patients is unclear. Wild-type enzymes and variants of CDA (Lys27Gln and Ala70Thr) and DCK (Ile24Val, Ala119Gly, and Pro122Ser) were expressed in and purified from Escherichia coli, and enzyme kinetic parameters were estimated for cytarabine (Ara-C), dFdC, and its metabolite 2',2'-difluorodeoxyuridine (dFdU) as substrates. All three CDA proteins showed similar K(m) and V(max) for Ara-C and dFdC deamination, except for CDA70Thr, which had a 2.5-fold lower K(m) and 6-fold lower V(max) for Ara-C deamination. All four DCK proteins yielded comparable metabolic activity for Ara-C and dFdC monophosphorylation, except for DCK24Val, which demonstrated an approximately 2-fold increase (P < 0.05) in the intrinsic clearance of dFdC monophosphorylation due to a 40% decrease in K(m) (P < 0.05). DCK did not significantly contribute to dFdU monophosphorylation. In conclusion, the Lys27Gln substitution does not significantly modulate CDA activity toward dFdC, and therefore would not contribute to interindividual variability in response to gemcitabine. The higher in vitro catalytic efficiency of DCK24Val toward dFdC monophosphorylation may be relevant to dFdC clinical response. The substrate-dependent alterations in activities of CDA70Thr and DCK24Val in vitro were observed for the first time, and demonstrate that the in vivo consequences of these genetic variations should not be extrapolated from one substrate of these enzymes to another. 23604721 Arginase II inhibitory activity of flavonoid compounds from Scutellaria indica. Arginase II has recently reported as a novel therapeutic target for the treatment of cardiovascular diseases such as atherosclerosis. In the course of screening plants used in natural medicines as arginase II inhibitory activity, a methanol extract of Scutellaria indica showed significant inhibitory effect. Further fractionation and repeated column chromatography led to the isolation of a new flavan-type (1), and seven known compounds (2-8). The chemical structures of isolated compounds were elucidated based on extensive 1D and 2D NMR spectroscopic data. The isolates 1-8 were investigated in vitro for their arginase II inhibitory activity using enzyme solution prepared from kidney of anesthetized C57BL/6 mice. Compounds 3 and 5 significantly inhibited arginase II activity with IC50 values of 25.1 and 11.6 μM, respectively, whereas the other compounds were apparently inactive. 23489135 Comparative antimalarial activities and ADME profiles of ozonides (1,2,4-trioxolanes) OZ277, OZ439, and their 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. To ascertain the structure-activity relationship of the core 1,2,4-trioxolane substructure of dispiro ozonides OZ277 and OZ439, we compared the antimalarial activities and ADME profiles of the 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. Consistent with previous data, both dioxolanes had very weak antimalarial properties. For the OZ277 series, the trioxane isostere had the best ADME profile, but its overall antimalarial efficacy was not superior to that of the trioxolane or tetraoxane isosteres. For the OZ439 series, there was a good correlation between the antimalarial efficacy and ADME profiles in the rank order trioxolane > trioxane > tetraoxane. As we have previously observed for OZ439 versus OZ277, the OZ439 series peroxides had superior exposure and efficacy in mice compared to the corresponding OZ277 series peroxides. 23142753 Dichlorodiphenyltrichloroethane (DDT), DDT metabolites and pregnancy outcomes. Organochlorine pesticides (OCPs) are persistent endocrine disruptors. OCPs cross the placenta; this prenatal exposure has been associated with adverse pregnancy outcomes. We investigated associations between prenatal exposure to OCPs and gestational age and birth weight in 600 infants born between 1960 and 1963. The primary OCP was 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (p,p'-DDT), its primary metabolite, 1,1'-dichloro-2,2'-bis(p-chlorophenyl)ethylene (p,p'-DDE) and the contaminant, 1,1,1-trichloro-2-(p-chlorophenyl)-2-(o-chlorophenyl)-ethane (o,p'-DDT). Regression analysis indicated that for each natural log unit increase in p,p'-DDT, birth weight increased by 274 g (95% CI: 122, 425) when controlling for p,p'-DDE and o,p'-DDT. At a given level of p,p'-DDT exposure, o,p'-DDT and p,p'-DDE were associated with decreased birth weight. p,p'-DDE was negatively associated with length of gestation, controlling for p,p'-DDT and o,p'-DDT. These findings suggest opposing associations between exposure to p,p'-DDT and p,p'-DDE and birth weight. We did not find evidence to support mediation by maternal thyroid hormone status nor that the association differed by sex. 23327494 Anxiogenic-like effects of Uncaria tomentosa (Willd.) DC. aqueous extract in an elevated plus maze test in mice: a preliminary study. The purpose of this study was to examine the effect of orally administered Uncaria tomentosa aqueous extracts (UTE) (Willd. ex Roem. & Schult.) DC. (Rubiaceae) during 7, 15, 30 and 90 days of treatment on the expression of anxiety, as expressed in the elevated plus maze test in male Albino Swiss mice. UTE revealed an anxiogenic effect in relation to the control group at 15 and 30 days, but it was reversed after 90 days of administration, without affecting the locomotor activity or any deleterious effects on the overall performance of the animal, either for its ambulation, or clinical status, and body weight and organ weight/body weight from liver, lung and kidney were unaffected. These biphasic effects are usually indicative of heterogeneity in sites of action due to the presence of many alkaloids (speciophylline, uncarine F and uncarine E) and flavanols (catechin and epigallocatechin) identified and isolated from UTE. 23411178 Simultaneous determination of 2-naphthol and 1-hydroxypyrene in fish and shellfish contaminated with crude oil by gas chromatography-mass spectrometry. This paper describes a gas chromatography-mass spectrometric method of l-hydroxypyrene (1-HOP) and 2-naphthol (2-NAP) in fish and shellfish. Alkali hydrolysis method in this study was chosen and optimized to the reaction condition for 90 min at 90°C in a 2.0M KOH solution. For five independent determinations at 0.2 and 1.0 μg/kg, the coefficient of variation was less than 5.1%. This method was used to assess the long-term influence of spilled crude oil on marine ecosystems and analyze fifty-two shellfish samples taken in the near of the accident region of the Hebei Spirit oil spill. 2-NAP and 1-HOP were detected in the mean concentration range of 0.09-12.42 and 0.03-0.06 μg/kg, respectively. 2-NAP was detected in a high concentration range in shellfishes gathered in 2 months after the accident and it decreased rapidly to 6 months after that. The results showed that 2-NAP might be an important biomarker in biota contaminated with crude oil. 23179765 Natures of benzene-water and pyrrole-water interactions in the forms of σ and π types: theoretical studies from clusters to liquid mixture. A combined and sequential use of quantum mechanical (QM) calculations and classical molecular dynamics (MD) simulations was made to investigate the σ and π types of hydrogen bond (HB) in benzene-water and pyrrole-water as clusters and as their liquid mixture, respectively. This paper aims at analyzing similarities and differences of these HBs resulted from QM and MD on an equal footing. Based on the optimized geometry at ωb97xD/aug-cc-pVTZ level of theory, the nature and property of σ and π types of HBs are unveiled by means of atoms in molecules (AIM), natural bond orbital (NBO) and energy decomposition analysis (EDA). In light of the above findings, MD simulation with OPLS-AA and SPC model was applied to study the liquid mixture at different temperatures. The MD results further characterize the behavior and structural properties of σ and π types HBs, which are somewhat different but reasonable for the clusters by QM. Finally, we provide a reasonable explanation for the different solubility between benzene/water and pyrrole/water. 23303191 Hyaluronan synthase 1 (HAS1) requires higher cellular UDP-GlcNAc concentration than HAS2 and HAS3. Mammals have three homologous genes encoding proteins with hyaluronan synthase activity (Has1-3), all producing an identical polymer from UDP-N-acetylglucosamine and UDP-glucuronic acid. To compare the properties of these isoenzymes, COS-1 cells, with minor endogenous hyaluronan synthesis, were transfected with human Has1-3 isoenzymes. HAS1 was almost unable to secrete hyaluronan or form a hyaluronan coat, in contrast to HAS2 and HAS3. This failure of HAS1 to synthesize hyaluronan was compensated by increasing the cellular content of UDP-N-acetyl glucosamine by ∼10-fold with 1 mm glucosamine in the growth medium. Hyaluronan synthesis driven by HAS2 was less affected by glucosamine addition, and HAS3 was not affected at all. Glucose-free medium, leading to depletion of the UDP-sugars, markedly reduced hyaluronan synthesis by all HAS isoenzymes while raising its concentration from 5 to 25 mm had a moderate stimulatory effect. The results indicate that HAS1 is almost inactive in cells with low UDP-sugar supply, HAS2 activity increases with UDP-sugars, and HAS3 produces hyaluronan at high speed even with minimum substrate content. Transfected Has2 and particularly Has3 consumed enough UDP-sugars to reduce their content in COS-1 cells. Comparison of different human cell types revealed ∼50-fold differences in the content of UDP-N-acetylhexosamines and UDP-glucuronic acid, correlating with the expression level of Has1, suggesting cellular coordination between Has1 expression and the content of UDP-sugars. 23424213 Protective effect of the roots extract of Platycodon grandiflorum on bile duct ligation-induced hepatic fibrosis in rats. The aim of the present study was to evaluate the protective effect of aqueous extract from Platycodon grandiflorum (BC703) on bile duct ligation (BDL)-induced hepatic fibrosis in rats. BDL rats were divided into three groups, which orally received distilled water or BC703 (10 or 50 mg/kg/day) for consecutive 28 days. Antifibrotic effects of BC703 on BDL-induced hepatic fibrosis in rats were estimated by assessing serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), blood urea nitrogen (BUN), transforming growth factor-beta 1 (TGF-β1) and hepatic levels of malondialdehyde (MDA), glutathione (GSH), total superoxide dismutase (SOD) and nitric oxide (NO). The biochemical observations were supplemented by histopathological examination of liver samples stained with hematoxylin and eosin and Masson's trichrome stain. ALT, AST, TBIL and BUN were elevated in the group treated with BDL alone than in the sham-operated group. These elevations were significantly decreased by BC703 treatment. Hepatic GSH and SOD levels, depressed by BDL, were also increased in the BC703 group. In addition, increases in hepatic MDA and NO levels in the BDL-induced cholestasis were attenuated by BC703 treatment. Furthermore, BC703 treatment significantly reduced the serum level of fibrogenic cytokine, TGF-β1. Histopathological studies further substantiated the protective effect of BC703 on BDL-induced hepatic fibrosis in rat. BC703 may have beneficial effects not only on hepatic fibrosis by cholestasis but also on hepatic fibrosis development in patients with chronic hepatic disease. 23451983 Efficient Pro-survival/angiogenic miRNA Delivery by an MRI-Detectable Nanomaterial. Herein, we report the use of biodegradable nanoparticles (NPs) containing perfluoro-1,5-crown ether (PFCE), a fluorine-based compound (NP170-PFCE) with the capacity to track cells in vivo by magnetic ressonance imaging (MRI) and efficiently release miRNA. NP170-PFCE complexed with miRNAs accumulate whitin the cell's endolysosomal compartment and interact with higher frequency with argonaute2 (Ago2) and GW182 proteins, which are involved in the biological action of miRNAs, than commercial complexes formed by commercial reagents and miRNA, which in turn accumulate in the cell cytoplasm. The release of miRNA132 (miR132) from the NPs increased 3-fold the survival of endothelial cells (ECs) transplanted in vivo and 3.5-fold the blood perfusion in ischemic limbs relatively to control. 23249341 Interaction of OH radicals with Arizona Test Dust: uptake and products. Kinetics and products of the interaction of OH radicals with solid films of Arizona Test Dust (ATD) were studied using a low pressure flow reactor (0.5-3 Torr) combined with a modulated molecular beam mass spectrometer for monitoring of the gaseous species involved. The reactive uptake coefficient of OH was measured from the kinetics of OH consumption on Pyrex rods coated with ATD as a function of OH concentration ((0.4-5.2) × 10(12) molecules cm(-3)), relative humidity (RH = 0.03-25.9%), temperature (T = 275-320 K), and UV irradiance intensity (J(NO(2)) = 0-0.012 s(-1)). Deactivation of ATD surface upon exposure to OH was observed. The initial uptake coefficient was found to be independent of temperature and irradiation conditions and to decrease with relative humidity: γ(0) = 0.2/(1 + RH(0.36)) (calculated using geometric surface area, with 30% estimated conservative uncertainty). H(2)O(2) and H(2)O were observed in the gas phase as products of the OH reaction with ATD surface with yields of (10 ± 3) and (98 ± 25) %, respectively. 22936177 Human β-cell killing by autoreactive preproinsulin-specific CD8 T cells is predominantly granule-mediated with the potency dependent upon T-cell receptor avidity. The end-stage immunopathology of type 1 diabetes resulting in β-cell destruction appears to be strongly dominated by cytotoxic CD8 T lymphocytes (CD8 T cells). However, the mechanism of cytotoxicity used by autoreactive CD8 T cells in the human setting remains unknown. Using type 1 diabetes patient-derived preproinsulin-specific CD8 T-cell clones recognizing either an HLA-A2 (A*0201) or HLA-A24 (A*2402)-restricted epitope (peptide of preproinsulin [PPI](15-24), ALWGPDPAAA; or PPI(3-11), LWMRLLPLL), we assessed the use of conventional mediators of cytotoxicity in the destruction of human β-cells in vitro compared with virus-specific cytotoxic CD8 T-cell clones. We show that PPI-specific CD8 T-cell clones are mainly reliant upon cytotoxic degranulation for inducing β-cell death. Furthermore, we find that in comparison with virus-specific CD8 T cells, there are differences in the killing potency of PPI-specific CD8 T cells that are not due to cell-intrinsic differences, but rather are mediated by differences in strength of signaling by peptide-HLA ligands. The study highlights the regulation of β-cell killing as a potential point for therapeutic control, including the possibility of blocking autoreactive CD8 T-cell function without impacting upon general immune competence. 23341258 Toxic effects of environment-friendly antifoulant nonivamide on Phaeodactylum tricornutum. Nonivamide, a synthetic derivate of natural capsaicin, has an effective antifouling activity. However, the poor understanding of the toxicity mechanism limits the application of nonivamide in antifouling paints. The present study investigated the inhibitory effects and toxicity mechanism of nonivamide on Phaeodactylum tricornutum. Under a 1.5 × 10(5) cells/ml of initial algal density (IAD), the effective concentration causing 50% inhibition at 4- d (4 d-EC50) value of nonivamide was 5.1 mg/L. Reactive oxygen species (ROS) level was significantly increased in nonivamide-treated algae. Algal antioxidants, including catalases (CAT), peroxidases (POD), superoxide dismutases (SOD), and glutathione (GSH), were all stimulated by the ROS burst. The excessive ROS substances led to the loss of algal photosynthetic pigments and also damage to the integrity of the lipid membrane. Furthermore, ROS-related genes, including psbA, psbD, psaB, rbcL, nad1, and cob, were found to be suppressed in the chloroplasts and mitochondria of nonivamide-treated algae, and the concentration of cytoplasmic Ca(2+) , an important regulator of chloroplast and mitochondrion, was elevated. The present study demonstrates that nonivamide could cause peroxidative damages to P. tricornutum by inducing ROS overproduction, which may be initiated by the suppression of ROS-related genes in algal chloroplasts and mitochondria. 23625787 Risk Factors for Excessive Anticoagulation Among Hospitalized Adults Receiving Warfarin Therapy Using a Pharmacist-Managed Dosing Protocol. STUDY OBJECTIVE: To identify specific risk factors for excessive anticoagulation, defined as an international normalized ratio (INR) higher than 5, in hospitalized adults receiving warfarin therapy using a pharmacist-managed dosing protocol. DESIGN: Retrospective nested case-control study. SETTING: Large academic tertiary care medical center. PATIENTS: Hospitalized nonsurgical patients 18 years or older who received at least one dose of warfarin according to the pharmacist-managed protocol from January 1, 2009, to January 31, 2012, were included. Patients who experienced an INR higher than 5 were designated as case patients; those who received warfarin for at least as many days as the case patients but who did not experience an INR more than 5 were deemed control patients. Controls were matched to cases in a 2:1 ratio by age, sex, INR goal, and type of warfarin therapy (new start or continuation). MEASUREMENTS AND MAIN RESULTS: A total of 87 case patients were matched to 174 controls. Ten different hypothesized risk factors were examined. Two variables, severity of illness score (odds ratio [OR] 4.89, p<0.001) and poor nutritional status (OR 4.27, p<0.001), demonstrated strong independent associations with risk of excessive anticoagulation. Administration of interacting drugs that highly potentiate warfarin's effect (OR 2.26, p=0.011) and concurrent diarrheal illness (OR 4.75, p<0.001) also displayed a statistically significant risk for excessive anticoagulation. CONCLUSION: Even in a highly standardized system for warfarin dosing by a pharmacist-managed protocol, higher disease severity and poor nutritional status placed hospitalized patients at greater risk of experiencing excessive anticoagulation. In addition, administration of interacting drugs that highly potentiate warfarin's effect or the occurrence of diarrheal illness may predict increased risk. 23523546 Pharmacokinetic evaluation in mice of amorphous itraconazole-based dry powder formulations for inhalation with high bioavailability and extended lung retention. Three Itraconazole (ITZ) dry powders for inhalation (DPI) were prepared by spray-drying a mannitol solution in which the ITZ was in suspension (F1) or was in solution without (F2) or with phospholipid (PL) (F3). These powders were endotracheally insufflated in vivo at a single dose of 0.5mg/kg for pharmacokinetic profile (lung and plasma concentration) determination in ICR CD-1 mice. ITZ was crystalline in F1 and assumed to be amorphous in the F2 and F3 formulations. The amorphous nature of ITZ in F2 and F3 formulations allowed the in vitro formation of an ITZ supersaturated solution with a maximum solubility of 450±124ng/ml (F2) and 498±44ng/ml (F3), in contrast to formulation F1 (<10ng/ml). As a result of these higher solubilities, absorption into the systemic compartment after endotracheal administration was faster for formulations F2 and F3 (shorter tmax) and in larger quantities compared to the F1 formulation (plasmatic AUC0-24h of 182ngh/ml, 491.5ngh/ml and 376.8ngh/ml, and tmax of 60min, 30min and 5min for F1, F2 and F3, respectively). PL increased the systemic bioavailability of ITZ (determined by the AUCplasma to AUClung ratio) as a consequence of their wetting and absorption enhancement effect. ITZ lung concentrations after pulmonary administration remained higher than the targeted dose, based on the minimal inhibitory concentrations for Aspergillus Fumigatus (2μg/gwetlung), 24h post-administration for both F1 and F2 formulations. However, this was not the case for formulation F3, which exhibited a faster elimination rate from the lung, with an elimination half-life of 4.1h vs. 6.5h and 14.7h for F1 and F2, respectively. 23122089 Introduction and nutritional evaluation of germinated soy germ. Germinated soy germ (GSG) were developed and evaluated for their nutritional value. Separated soy germ was germinated at room temperature for 24h under running water. As germination progressed, the protein and fibre content of GSG increased slightly, while the lipid and carbon to nitrogen (C/N) ratio decreased; free amino acids including GABA increased considerably while free sugars decreased. Linoleic and linolenic acid were the most abundant unsaturated fatty acids in soy germ, and slight changes were observed in GSG. The tocopherol and isoflavone contents showed a rapid increase of 32.4% and 27.9%, respectively, during germination. The abundance of GABA, isoflavones and tocopherols demonstrates the high nutritional value of GSG and suggests that GSG can be utilised as a reasonable and effective source of healthy foods. 23265483 Review: on published data and methods for selenium in mushrooms. Selected data published on selenium in several species of mushrooms are outlined and discussed in light of performance of analytical methods employed. Data was shown to be either dubious or concentrations too high to be credible and valid in some data reported by authors. Examples of methods and specifically the measurement techniques of Se as reported by authors studying mushrooms are outlined. Also examples of valid and incorrect data on Se in a given mushroom species with data by two or more analytical methods are illustrated. Excessive values reported due to selection of improper method of determination of Se in mushrooms relate largely to improper use of flame atomic absorption spectroscopy (AAS) and inductively coupled plasma - atomic emission spectroscopy (ICP-AES). The biased analytical data published gave a false picture on the composition and nutritional value of mushrooms with respect to selenium. 23225638 Non-ionic dendronized multiamphiphilic polymers as nanocarriers for biomedical applications. A new class of non-ionic dendronized multiamphiphilic polymers is prepared from a biodegradable (AB)n-type diblock polymer synthesized from 2-azido-1,3-propanediol (azido glycerol) and polyethylene glycol (PEG)-600 diethylester using Novozym-435 (Candida antarctica lipase) as a biocatalyst, following a well-established biocatalytic route. These polymers are functionalized with dendritic polyglycerols (G1 and G2) and octadecyl chains in different functionalization levels via click chemistry to generate dendronized multiamphiphilic polymers. Surface tension measurements and dynamic light scattering studies reveal that all of the multiamphiphilic polymers spontaneously self-assemble in aqueous solution. Cryogenic transmission electron microscopy further proves the formation of multiamphiphiles towards monodisperse spherical micelles of about 7-9 nm in diameter. The evidence from UV-vis and fluorescence spectroscopy suggests the effective solubilization of hydrophobic guests like pyrene and 1-anilinonaphthalene-8-sulfonic acid within the hydrophobic core of the micelles. These results demonstrate the potential of these dendronized multiamphiphilic polymers for the development of prospective drug delivery systems for the solubilization of poorly water soluble drugs. 23123248 Inhibition of human carboxylesterases hCE1 and hiCE by cholinesterase inhibitors. Carboxylesterases (CEs) are ubiquitously expressed proteins that are responsible for the detoxification of xenobiotics. They tend to be expressed in tissues likely to be exposed to such agents (e.g., lung and gut epithelia, liver) and can hydrolyze numerous agents, including many clinically used drugs. Due to the considerable structural similarity between cholinesterases (ChE) and CEs, we have assessed the ability of a series of ChE inhibitors to modulate the activity of the human liver (hCE1) and the human intestinal CE (hiCE) isoforms. We observed inhibition of hCE1 and hiCE by carbamate-containing small molecules, including those used for the treatment of Alzheimer's disease. For example, rivastigmine resulted in greater than 95% inhibition of hiCE that was irreversible under the conditions used. Hence, the administration of esterified drugs, in combination with these carbamates, may inadvertently result in decreased hydrolysis of the former, thereby limiting their efficacy. Therefore drug:drug interactions should be carefully evaluated in individuals receiving ChE inhibitors. 23356867 Solution structure, dynamics and binding studies of a family 11 carbohydrate-binding module from Clostridium thermocellum (CtCBM11). Non-catalytic cellulosomal CBMs (carbohydrate-binding modules) are responsible for increasing the catalytic efficiency of cellulosic enzymes by selectively putting the substrate (a wide range of poly- and oligo-saccharides) and enzyme into close contact. In the present study we carried out an atomistic rationalization of the molecular determinants of ligand specificity for a family 11 CBM from thermophilic Clostridium thermocellum [CtCBM11 (C. thermocellum CBM11)], based on a NMR and molecular modelling approach. We have determined the NMR solution structure of CtCBM11 at 25°C and 50°C and derived information on the residues of the protein that are involved in ligand recognition and on the influence of the length of the saccharide chain on binding. We obtained models of the CtCBM11-cellohexaose and CtCBM11-cellotetraose complexes by docking in accordance with the NMR experimental data. Specific ligand-protein CH-π and Van der Waals interactions were found to be determinant for the stability of the complexes and for defining specificity. Using the order parameters derived from backbone dynamics analysis in the presence and absence of ligand and at 25°C and 50°C, we determined that the protein's backbone conformational entropy is slightly positive. This data in combination with the negative binding entropy calculated from ITC (isothermal titration calorimetry) studies supports a selection mechanism where a rigid protein selects a defined oligosaccharide conformation. 23641685 Cavity Ringdown Spectroscopy of the Hydroxy-Methyl-Peroxy Radical. We report vibrational and electronic spectra of the hydroxyl-methyl-peroxy radical (HOCH2OO, or HMP), the primary product of the reaction of the hydroperoxy radical, HO2, and formaldehyde, HCHO. The ν1 vibrational (OH stretch) spectrum and the Ã-X electronic spectrum of HMP were detected by Infrared Cavity Ringdown Spectroscopy (IR-CRDS), and assignments were verified with density functional calculations. The HMP radical was generated in reactions of HCHO with HO2. Free radical reactions were initiated by pulsed laser photolysis (PLP) of Cl2 in the presence of HCHO and O2 in a flow reactor at 300-330 Torr and 295K. IR-CRDS spectra were measured in mid-IR and near-IR regions over the ranges 3525-3700 cm(-1) (ν1) and 7250-7800 cm(-1) (Ã-X) (respectively, at a delay time 100 µs after photolysis. The ν1 spectrum had an origin at 3622 cm(-1) and exhibited partially resolved P- and R-branch contours and a small Q branch. At these short delay times, spectral interference from HOOH and HCOOH was minimal, and could be subtracted. From B3LYP/6-31G+(d,p) calculations, we found that the anharmonic vibrational frequency and band contour predicted for the lowest energy conformer, HMP-A, The calculated anharmonic vibrational frequency and band contour computed using B3LYP/63-1G(d,p) level were in good agreement with the observed spectrum. In the near-IR, we observed four well spaced vibronic bands, each with partially resolved rotational contours. We assigned the apparent origin of the electronic spectrum of HMP at 7392 cm(-1) and two bands to the blue to a progression in ν15', the lowest torsional mode of the state (ν15'= 171 cm(-1)). The band furthest to the red was assigned as a hot band in ν15", leading to a ground state torsional frequency of (ν15"= 122 cm(-1)). We simulated the spectrum using second order vibrational perturbation theory (VPT2) with B3LYP/6-31+G(d,p) calculations at the minimum energy geometries of the HMP-A conformer on the X ̃ and A ̃ states. The predictions of the electronic origin frequency, torsional frequencies, anharmonicities and rotational band contours matched the observed spectrum. We investigated the torsional modes more explicitly by computing potential energy surfaces of HMP as a function of the two dihedral angles τOCOH and τOOCO. Wave functions and energy levels were calculated based on this potential surface; these results were used to calculate the Franck-Condon factors, which reproduced the vibronic band intensities in the observed electronic spectrum. The transitions that we observed all involved states with wave functions localized on the minimum energy conformer, HMP-A. Our calculations indicated that the observed near-IR spectrum was that of the minimum energy conformer HMP-A, but that this conformer is not the lowest energy conformer in the state, which remains unobserved. We estimated that the energy of this lowest conformer (HMP-B) of the à state to be T0 (Ã) ≈ 7200 cm(-1), based on the energy difference E0(HMP-B) - E0(HMP-A) on the à state computed at the B3LYP/6-31+G(d,p) level. 23299647 Gender differences in drug bioequivalence: time to rethink practices. Currently, bioequivalence (BE) studies are carried out exclusively in males, assuming that intrasubject variabilities are similar between the sexes. This article challenges this hypothesis on the basis of available evidence and urges that studies of BE of sufficient power be undertaken in women also for all generic drugs aimed at women. 23570514 Discovery of Thieno[3,2-d]pyrimidine-6-carboxamides as Potent Inhibitors of SIRT1, SIRT2, and SIRT3. The sirtuins SIRT1, SIRT2, and SIRT3 are NAD(+) dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic, and neurodegenerative disorders. Encoded library technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g., 11c: IC50 = 3.6, 2.7, and 4.0 nM for SIRT1, SIRT2, and SIRT3, respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogues 28 and 31. Crystallographic studies of 11c, 28, and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors, which makes them valuable tools for sirtuin research. 23042808 Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. Community-based studies suggest that cannabis products that are high in Δ⁹-tetrahydrocannabinol (THC) but low in cannabidiol (CBD) are particularly hazardous for mental health. Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form, under controlled conditions. In a between-subjects design, we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment. Healthy participants were randomised to receive oral CBD 600 mg (n=22) or placebo (n=26), 210 min ahead of intravenous (IV) THC (1.5 mg). Post-THC, there were lower PANSS positive scores in the CBD group, but this did not reach statistical significance. However, clinically significant positive psychotic symptoms (defined a priori as increases ≥ 3 points) were less likely in the CBD group compared with the placebo group, odds ratio (OR)=0.22 (χ²=4.74, p<0.05). In agreement, post-THC paranoia, as rated with the State Social Paranoia Scale (SSPS), was less in the CBD group compared with the placebo group (t=2.28, p<0.05). Episodic memory, indexed by scores on the Hopkins Verbal Learning Task-revised (HVLT-R), was poorer, relative to baseline, in the placebo pre-treated group (-10.6 ± 18.9%) compared with the CBD group (-0.4% ± 9.7 %) (t=2.39, p<0.05). These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health. 23019274 Novel assays for detection of urinary KIM-1 in mouse models of kidney injury. Kidney injury molecule-1 (KIM-1) has been qualified by the Food and Drug Administration and European Medicines Agency as a urinary biomarker to monitor preclinical nephrotoxicity in rats and on a case-by-case basis for the translation of potentially nephrotoxic drugs into first-in human studies. Although mouse models are widely employed in preclinical studies, few urinary biomarker studies have been performed in mice due to limited urine availability and lack of sensitive assays. Here, we report the development and validation of two different assays for quantitative assessment of mouse urinary KIM-1 (uKIM-1) and compare the sensitivity of KIM-1 relative to other standard markers in ischemia reperfusion and aristolochic acid (AA)-induced kidney injury in mice. A sensitive, reproducible, and quantitative microbead-based KIM-1 ELISA was established, which requires only 10 μl urine for triplicate determination with an assay range of 12.21 pg/ml to 50 ng/ml. The second assay is a laminar flow dipstick assay, which has an assay range of 195 pg/ml to 50 ng/ml and provides quantitative assessment of KIM-1 in 15 min. uKIM-1 levels increased with increasing time of ischemia or time after AA administration. After only 10-min ischemia followed by 24-h reperfusion, uKIM-1 was significantly elevated by 13-fold, whereas serum creatinine (sCr), blood urea nitrogen, N-acetyl-β-glucosaminidase (NAG), and proteinuria levels did not change. After AA administration, uKIM-1 levels were significantly upregulated by greater than threefold within 12 h, whereas sCr and NAG levels were unchanged. Mouse KIM-1 was stable for multiple freeze-thaw cycles, for up to 5 days at room temperature and up to at least an year when stored at -80°C. 23066853 Back to the future: can physical models of passive membrane permeability help reduce drug candidate attrition and move us beyond QSPR? It is widely recognized that adsorption, distribution, metabolism, excretion, and toxicology liabilities kill the majority of drug candidates that progress to clinical trials. The development of computational models to predict small molecule membrane permeability is therefore of considerable scientific and public health interest. Empirical qualitative structure permeability relationship models of permeability have been a mainstay in industrial applications, but lack a deep understanding of the underlying biologic physics. Others and we have shown that implicit solvent models to predict passive permeability for small molecules exhibit mediocre predictive performance when validated across experimental test sets. Given the vast increase in computer power, more efficient parallelization schemes, and extension of current atomistic simulation codes to general use graphical processing units, the development and application of physical models based on all-atom simulations may now be feasible. Preliminary results from rigorous free energy calculations using all-atom simulations indicate that performance relative to implicit solvent models may be improved, but many outstanding questions remain. Here, we review the current state-of-the-art physical models for passive membrane permeability prediction and present a prospective look at promising new directions for all-atom approaches. 23613312 Design, synthesis, and biological evaluation of cyclopropyl analogues of stilbene with raloxifene side chain as subtype-selective ligands for estrogen receptor. We have designed the cyclopropane analog of stilbene as subtype-selective ligands for estrogen receptor based on the bioisosterism that cyclopropane could act as alkene bioisoster. Three cyclopropane analogs were prepared efficiently starting from 4-benzyloxybenzaldehyde, and evaluated for their binding to estrogen receptors ERα and ERβ. These cyclopropane analogs were also found to be full agonists in estrogen receptor-mediated gene transcription assay. Compared to the stilbene analogs such as tamoxifen and raloxifene, the three cyclopropane analogs showed lower binding affinity for estrogen receptor, but higher subtype selectivity for ERα. The structure-activity relationship revealed from this study might provide clues for improving subtype selectivity for ERα. 23344975 Differential gene expression and bioinformatics analysis of copper resistance gene afe_1073 in Acidithiobacillus ferrooxidans. Copper resistance of acidophilic bacteria is very significant in bioleaching of copper ore since high concentration of copper are harmful to the growth of organisms. Copper resistance gene afe_1073 was putatively considered to be involved in copper homeostasis in Acidithiobacillus ferrooxidans ATCC23270. In the present study, differential expression of afe_1073 in A. ferrooxidans strain DY26 and DC was assessed with quantitative reverse transcription polymerase chain reaction. The results showed the expression of afe_1073 in two strains increased with the increment of copper concentrations. The expression of DY26 was lower than that of DC at the same copper concentration although A. ferrooxidans strain DY26 possessed higher copper resistance than strain DC. In addition, bioinformatics analysis showed AFE_1073 was a typical transmembrane protein P1b1-ATPase, which could reduce the harm of Cu(+) by pumping it out from the cell. There were two mutation sites in AFE_1073 between DY26 and DC and one may change the hydrophobicity of AFE_1073, which could enhance the ability of DY26 to pump out Cu(+). Therefore, DY26 needed less gene expression of afe_1073 for resisting copper toxicity than that of DC at the same copper stress. Our study will be beneficial to understanding the copper resistance mechanism of A. ferrooxidans. 23540796 A Coffee Ring Biosensor for Rapid Protein Detection. We introduce a new biosensing platform for rapid protein detection that combines one of the simplest methods for biomolecular concentration, coffee ring formation, with a sensitive aptamer-based optical detection scheme. In this approach, aptamer beacons are utilized for signal transduction where a fluorescence signal is emitted in the presence of the target molecule. Signal amplification is achieved by concentrating aptamer-target complexes within liquid droplets, resulting in the formation of coffee ring "spots". Surfaces with various chemical coatings were utilized to investigate the correlation between surface hydrophobicity, concentration efficiency and signal amplification. Based on our results, we found that the increase in coffee ring diameter with larger droplet volumes is independent of surface hydrophobicity. Furthermore, we show that highly hydrophobic surfaces produce enhanced particle concentration, via coffee ring formation, resulting in signal intensities 6-fold greater than those on hydrophilic surfaces. To validate this biosensing platform for the detection of clinical samples, we detected α-thrombin in human serum and 4x diluted whole blood. Based on our results, coffee ring spots produced detection signals 40x larger than samples in liquid droplets. Additionally, this biosensor exhibits a lower limit of detection of 2 ng/mL (54 pM) in serum, and 4 ng/mL (105 pM) in blood. Based on its simplicity and high performance, this platform demonstrates immense potential as an inexpensive diagnostic tool for the detection of disease biomarkers, particularly for use in developing countries that lack the resources and facilities required for conventional biodetection practices. 22502647 New furostanol saponins from the rhizomes of Tupistra chinensis. Three new furostanol saponins (1-3), including a polyhydroxyl saponin, were isolated from the rhizomes of Tupistra chinensis. The structures of these compounds were identified by NMR, MS spectral data and chemical methods. 23350945 Investigation of the interaction of γ-Al2O3 with aqueous solutions of dimethyl methylphosphonate using infrared multiple internal reflection spectroscopy. The interaction of dilute solutions of dimethyl methylphosphonate (DMMP) in H(2)O with thin porous layers of γ-Al(2)O(3) has been studied under steady-state conditions using infrared multiple-internal-reflection spectroscopy. Upon the initial introduction of the DMMP solution to a previously H(2)O-saturated surface, DMMP diffuses into the porous layer and displaces weakly hydrogen-bonded H(2)O molecules. This is accompanied by hydrolysis of the γ-Al(2)O(3) to form Al(OH)(3) and/or AlO(OH). The P═O group of DMMP interacts predominantly with H(2)O and gives no clear indication of bonding to the oxide surface itself, from which it is inferred that the displacement of weakly adsorbed H(2)O results from the interaction of acidic Al-OH sites with the methoxy O atoms of DMMP. No hydrolysis of the DMMP, either in solution or in contact with the oxide, was detectable under the present conditions. The results have practical implications in the decontamination of materials following exposure to toxic reagents related to DMMP. 23471710 Severe hypoglycemia from helicobacter pylori triple-drug therapy and insulin detemir drug interaction. Two drugs commonly used in triple-drug therapy for treatment of a Helicobacter pylori infection, clarithromycin and omeprazole, have rarely been associated with hypoglycemia when given alone. No documented interactions between H. pylori treatment with clarithromycin, amoxicillin, and omeprazole and insulin detemir have been previously reported. This case report describes an 82-year-old man with drug-controlled type 2 diabetes who experienced severe hypoglycemia during treatment for a H. pylori infection in an outpatient setting. His diabetes treatment included 32 units of insulin detemir once/day at bedtime and insulin aspart, determined by carbohydrate intake, 3 times/day with meals. After 5 days of clarithromycin 500 mg twice/day, amoxicillin 500 mg twice/day, and omeprazole 20 mg twice/day for treatment of the H. pylori infection, the patient experienced hypoglycemia and self-discontinued clarithromycin. Insulin detemir was decreased to 15 units and hypoglycemia reoccurred. Insulin detemir was further decreased to 10 units without further symptoms of hypoglycemia for the remainder of the H. pylori treatment. Once treatment was completed, the patient was instructed to resume taking 32 units of insulin detemir once/day. His blood glucose concentration returned to a baseline value, and he denied experiencing further hypoglycemic episodes. Health care practitioners should be aware of this possible drug interaction and anticipate that insulin detemir dosage adjustments may be required during treatment of H. pylori infection to avoid significant adverse events. 23584427 Transcriptomic analysis of cultured whale skin cells exposed to hexavalent chromium [Cr(VI)]. Hexavalent chromium Cr(VI) is known to produce cytotoxic effects in humans and is a highly toxic environmental contaminant. Interestingly, it has been shown that free ranging sperm whales (Phyester macrocephalus) may have exceedingly high levels of Cr in their skin. Also, it has been demonstrated that skin cells from whales appear more resistant to both cytotoxicity and clastogenicity upon Cr exposure compared to human cells. However, the molecular genetic mechanisms employed in whale skin cells that might lead to Cr tolerance are unknown. In an effort to understand the underlying mechanisms of Cr(VI) tolerance and to illuminate global gene expression patterns modulated by Cr, we exposed whale skin cells in culture to varying levels of Cr(VI) (i.e., 0.0, 0.5, 1.0 and 5.0μg/cm(2)) followed by short read (100bp) next generation RNA sequencing (RNA-seq). RNA-seq reads from all exposures (≈280 million reads) were pooled to generate a de novo reference transcriptome assembly. The resulting whale reference assembly had 11K contigs and an N50 of 2954bp. Using the reads from each dose (0.0, 0.5, 1.0 and 5.0μg/cm(2)) we performed RNA-seq based gene expression analysis that identified 35 up-regulated genes and 19 down-regulated genes. The experimental results suggest that low dose exposure to Cr (1.0μg/cm(2)) serves to induce up-regulation of oxidative stress response genes, DNA repair genes and cell cycle regulator genes. However, at higher doses (5.0μg/cm(2)) the DNA repair genes appeared down-regulated while other genes that were induced suggest the initiation of cytotoxicity. The set of genes identified that show regulatory modulation at different Cr doses provide specific candidates for further studies aimed at determination of how whales exhibit resistance to Cr toxicity and what role(s) reactive oxygen species (ROS) may play in this process. 23586812 Development of a Selective Peptide Macrocycle Inhibitor of Coagulation Factor XII toward the Generation of a Safe Antithrombotic Therapy. Inhibition of coagulation factor XII (FXII) activity represents an attractive approach for the treatment and prevention of thrombotic diseases. The few existing FXII inhibitors suffer from low selectivity. Using phage display combined to rational design, we developed a potent inhibitor of FXII with more than 100-fold selectivity over related proteases. The highly selective peptide macrocycle is a promising candidate for the control of FXII activity in antithrombotic therapy and a valuable tool in hematology research. 23401303 Comparing sorption behavior of pyrethroids between formulated and natural sediments. Formulated sediments are recommended for use in toxicity tests to achieve standardized evaluations. However, the organic matter used in formulated sediments may differ qualitatively from that in natural sediments, which may lead to different chemical partition patterns and, hence, different toxicity effects. By deriving partition coefficients for organic carbon and dissolved organic carbon (KOC and KDOC , respectively) for eight pyrethroid insecticides from three formulated and five natural sediments, the authors characterized the differences between formulated and natural sediments in pesticide sorption. For all pyrethroids, the mean values of KOC and KDOC of formulated sediments were two to three, and three to 10 times smaller than those of natural sediments, respectively. The two formulated sediments containing α-cellulose or Manitoba peat showed significantly (p < 0.0001) smaller KOC and KDOC values than natural sediments based on statistical analyses, while the difference was not significant for the formulated sediment containing New Brunswick peat. The KOC values were closely correlated (p < 0.001) with soot carbon content, while the amount of carboxylic or phenolic functional groups may have affected KDOC . Therefore, the source and quality of organic matter are likely the most important factors in formulated sediments and must be standardized to provide consistency in sediment toxicity tests. Environ. Toxicol. Chem. 2013;32:1033-1039. © 2013 SETAC. 23544771 Symptomatic Amyloid Goiters: Report of 5 Cases. Background: Massive amyloid deposition in the thyroid to the point of goiter formation is rare. Here we describe the clinical presentation and outcomes of 5 patients with amyloid goiter (radiographically confirmed goiter in the context of tissue-proven thyroid amyloidosis) encountered in the past 23 years at our institution. Methods: Mayo Clinic archives were searched between 1987 and 2010 for diagnosis "thyroid amyloidosis," "amyloid deposits," "amyloid deposition," or "liquid chromatography consistent with amyloid." Inclusion criteria were symptomatic thyromegaly; tissue confirmation of thyroid enlarged by amyloid deposits; and radiologic confirmation of thyroid enlargement. Results: Five patients were identified who met all inclusion criteria. Amyloid goiter etiology included both primary and secondary amyloidosis, and the goiters ranged from 50 to 130 g each. Diagnosis was made by fine-needle aspiration biopsy with Congo red staining and, if needed, spectrophotometry. All 5 patients had histories of persistent hoarseness for several years prior to presentation with compressive symptoms referable to their enlarging thyroids, and all had some degree of thyroid dysfunction (both hypothyroidism and hyperthyroidism) by the end of our follow-up period, which ranged from 5 months to 13 years. Two patients underwent surgical intervention(s), 2 were managed conservatively, and in 1, the goiter shrank following systemic therapy for amyloidosis. Conclusions: Our clinical observations suggest slower goiter progression and a higher prevalence of thyroid dysfunction than previously thought. 23507565 Intact inhibitory control processes in abstinent drug abusers (II): A high-density electrical mapping study in former cocaine and heroin addicts. Response inhibition deficits are well-documented in drug users, and are related to the impulsive tendencies characteristic of the addictive phenotype. Addicts also show significant motivational issues that may accentuate these inhibitory deficits. We investigated the extent to which these inhibitory deficits are present in abstinence. Salience of the task stimuli was also manipulated on the premise that emotionally-valenced inputs might impact inhibitory efficacy by overcoming the blunted responses to everyday environmental inputs characteristic of this population. Participants performed response inhibition tasks consisting of both neutral and emotionally valenced stimuli while high-density event-related potentials (ERPs) were recorded. Electrophysiological responses (N2/P3 components) to successful inhibitions in abstinent abusers (N = 20) and non-using participants (N = 21) were compared. In contrast to previous work in current users, our abstinent cohort showed no detectable behavioral or electrophysiological differences in their inhibitory responses, and no differences on self-reports of impulsivity, despite their long histories of chronic use (mean = 10.3 years). The current findings are consistent with a recovery of inhibitory control processes as a function of abstinence. Abstinent former users, however, did show a reduced modulation, relative to controls, of their ERPs to valenced input while performing successful inhibitions, although contrary to our hypothesis, the use of valenced inputs had no impact on inhibitory performance. Reduced ERP modulation to emotionally valenced inputs may have implications for relapse in emotional contexts outside the treatment center. 23554029 Clinical Study to Assess the Efficacy and Safety of a Citrus Polyphenolic Extract of Red Orange, Grapefruit, and Orange (Sinetrol-XPur) on Weight Management and Metabolic Parameters in Healthy Overweight Individuals. The present study investigated the efficacy and safety effects of Sinetrol-XPur (polyphenolic citrus dry extract) in weight management; metabolic parameters; and inflammatory, glycemic and oxidative status. In a 12-week, randomized, double-blind, placebo-controlled trial, Sinetrol-XPur was given to overweight subjects twice daily with meals in the tested group (N = 47) versus a placebo group (N = 48). Waist and hip circumference and abdominal fat were decreased in the Sinetrol-XPur group as compared with the placebo group (p < 0.0001) (-5.71% vs -1.56% for waist, -4.71% vs -1.35% for hip and -9.73% vs -3.18% for fat). Inflammatory markers were reduced (C-reactive protein: -22.87% vs +61%; fibrinogen: -19.93% vs -1.61%, p < 0.01). Oxidative stress was lowered as seen by the reduction of malondialdehyde (-14.03% vs 2.76%) and the increase in superoxide dismutase and glutathione (17.38% vs 2.19% and 4.63% vs -2.36%, respectively, p < 0.01). No adverse effects were observed. Kidney, liver, and lipid panels remained unchanged. These results indicated that Sinetrol-XPur supplementation is a viable option for reducing abdominal fat, waist and hip circumference, and body weight and for improving inflammatory, glycemic, and oxidative status in healthy overweight individuals. Copyright © 2013 John Wiley & Sons, Ltd. 23357565 Protective effect of silymarin against ethanol-induced gastritis in rats: role of sulfhydryls, nitric oxide and gastric sensory afferents. Silymarin has been known to exert antioxidant, anti-carcinogenic and anti-inflammatory effects. In this study, we examined the effect of silymarin on gastritis in rats. Oral administration of silymarin dose-dependently decreased gastric lesions in ethanol-induced gastritis model. Silymarin also significantly suppressed the development of gastric lesions in aspirin- or water immersion-restraint stress-induced gastritis models. Further study demonstrated that the gastroprotective effect of silymarin was blocked by nitric oxide (NO) synthase inhibitor l-NAME, SH blocker N-ethylmaleimide or TRPV1 antagonist capsazepine in ethanol-induced gastritis model. In addition, ex vivo analysis revealed that ethanol-induced decrease in gastric mucus and non-protein sulfhydryl (NPSH) groups was significantly reversed by silymarin treatment and lipid peroxidation was also suppressed by silymarin in ethanol-induced gastritis model. Taken together, these results suggest that silymarin exerts gastroprotective effects and the gastroprotective effects of silymarin might be related to the protection of gastric mucosal NO and NP-SH and the modulation of capsaicin-sensitive gastric sensory afferents. 23422745 NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites. ATR and ATM kinases are central to the checkpoint activation in response to DNA damage and replication stress. However, the nature of the signal, which initially activates these kinases in response to UV damage, is unclear. Here, we have shown that DDB2 and XPC, two early UV damage recognition factors, are required for the damage-specific ATR and ATM recruitment and phosphorylation. ATR and ATM physically interacted with XPC and promptly localized to the UV damage sites. ATR and ATM recruitment and their phosphorylation were negatively affected in cells defective in DDB2 or XPC functions. Consequently, the phosphorylation of ATR and ATM substrates, Chk1, Chk2, H2AX, and BRCA1 was significantly reduced or abrogated in mutant cells. Furthermore, UV exposure of cells defective in DDB2 or XPC resulted in a marked decrease in BRCA1 and Rad51 recruitment to the damage site. Conversely, ATR- and ATM-deficiency failed to affect the recruitment of DDB2 and XPC to the damage site, and therefore did not influence the NER efficiency. These findings demonstrate a novel function of DDB2 and XPC in maintaining a vital cross-talk with checkpoint proteins, and thereby coordinating subsequent repair and checkpoint activation. 23222689 Removal of valproic acid by plasmapheresis in a patient treated for multiple sclerosis. We present a case of a patient with multiple sclerosis who was treated with plasmapheresis and valproic acid. We used therapeutic drug monitoring to determine whether plasma concentrations of valproic acid were kept within the therapeutic window and to determine the amount of valproic acid that was removed by plasmapheresis. 23462213 A Chinese herb formula decreases the monocarboxylate transporter-mediated absorption of valproic acid in rats. Huang-Qin-Tang (HQT), a Chinese medicine prescription containing Scutellariae Radix (SR), Paeoniae Radix (PR), Glycyrrhizae Radix (GR) and JuJubae Fructus (JF), was used for the treatments of cold with symptoms of abdominalgia and diarrhea. Valproic acid (VPA) is an antiepileptic drug with narrow therapeutic window. This study investigated the effect of coadministration of HQT on the pharmacokinetics of VPA, a probe drug for monocarboxylate transporter (MCT). Rats were administered VPA alone (200.0mg/kg) and coadministered HQT (8.0g/kg) at 0.5h before VPA and 1.5h after VPA in crossover designs. In addition, the chronic effect of HQT was also evaluated by coadministration of the 7th dose at 0.5h before VPA. The serum concentration of VPA was determined by a fluorescence polarization immunoassay. The results showed that coadministration of HQT at 0.5h before VPA significantly decreased the AUC0-t and Cmax by 62% and 77%, respectively, whereas coadministration of HQT at 1.5h after VPA exerted no significant influence. When the 7th dose of HQT was given at 0.5h before VPA, the AUC0-t and Cmax of VPA were markedly decreased by 65% and 82%, respectively. Mechanism study revealed that the MCT-mediated uptake of fluorescein was inhibited by HQT and each component herbs. In conclusion, the MCT-mediated absorption of VPA was significantly decreased by concomitant administration of HQT. 23530019 Nicotine Kinetics in Zebra Finches in vivo and in vitro. Nicotine enhances cognitive performance, and in the zebra finch (Taeniopygia guttata), which is a well-established model of cognition, the effect of nicotine on song production has been reported. Nicotine and cotinine plasma levels were assessed in vivo after s.c. injection of 0.18 mg/kg nicotine, a dose that elicits changes in song production. The half-life of nicotine elimination was 33 min, and levels were undetectable by 4h. Average plasma nicotine over 2 hours was 32 ng/ml, similar to levels seen in human smokers and rat models of nicotine behavior. Nicotine brain levels were 30 and 14 ng/g at 1 and 2 h after treatment. To understand the potential for drug interactions and regulation of nicotine metabolism in zebra finches, we characterized in vitro nicotine metabolism and the hepatic enzyme involved. In humans, cytochrome P450 (CYP) 2A6 metabolizes nicotine to cotinine, and CYP2A-like activity and protein have been reported in some birds. Zebra finch liver microsomes metabolized nicotine and bupropion (CYP2B substrate) but not coumarin (CYP2A substrate). Nicotine was metabolized to cotinine with a Km of 96 μM and Vmax of 56 pmol/min/mg. Nicotine and bupropion metabolism were inhibited by C-8-xanthate (specific CYP2B inhibitor) but not CYP2A-specific inhibitors, and hepatic levels of CYP2B-like but not CYP2A-like proteins correlated with nicotine (r = 0.52, p = 0.04) and bupropion metabolism (r = 0.81, p < 0.001), suggesting CYP2B-mediation of nicotine metabolism as seen in rats. These results will facilitate further investigation of nicotine's effects in zebra finches. 23595419 Highly selective lithium recovery from brine using a λ-MnO2-Ag battery. The demand for lithium has greatly increased with the rapid development of rechargeable batteries. Currently, the main lithium resource is brine lakes, but the conventional lithium recovery process is time consuming, inefficient, and environmentally harmful. Rechargeable batteries have been recently used for lithium recovery, and consist of lithium iron phosphate as a cathode. These batteries feature promising selectivity between lithium and sodium, but they suffer from severe interference from coexisting magnesium ions, an essential component of brine, which has prompted further study. This study reports on a highly selective and energy-efficient lithium recovery system using a rechargeable battery that consists of a λ-MnO2 positive electrode and a chloride-capturing negative electrode. This system can be used to recover lithium from brine even in the presence of magnesium ions as well as other dissolved cations. In addition, lithium recovery from simulated brine is successfully demonstrated, consuming 1.0 W h per 1 mole of lithium recovered, using water similar to that from the artificial brine, which contains various cations (mole ratio: Na/Li ≈ 15.7, K/Li ≈ 2.2, Mg/Li ≈ 1.9). 23454011 Impact of co-administration of protonated nanostructured aluminum silicate (cholesterol absorption inhibitor) on the absorption of lipid soluble vitamins D3 and K1: An assessment of pharmacokinetic and in vitro intraluminal processing. Protonated nanostructured aluminum silicate (NSAS) is a protonated montmorillonite clay that was shown to be effective as an inhibitor of intestinal cholesterol absorption. The effect of NSAS on the intestinal absorption of nutrients is unknown. An in vitro lipolysis model was adapted to test the intraluminal processing of vitamin D3 and K1 in the presence of various amounts of NSAS. Additionally, vitamin absorption was assessed in male Sprague-Dawley rats randomized in the following treatment groups: IV administration of 0.1mg/kg vitamin D3 and 1mg/kg vitamin K1, and a single-dose gavage of 1mg/kg vitamin D3 and 5mg/kg of vitamin K1 in peanut oil with various doses of NSAS slurry, 2% NSAS-fortified diet, or 50mg/kg stigmastanol. The solubilized fraction of vitamin D3 in the lipolysis medium was reduced from 70% to 46% upon the addition of 120mg NSAS. In contrast, the solubilized fractions of vitamin K1 were not significantly affected. Although the NSAS-fortified diet did not significantly affect the absorbed fraction of both vitamins, NSAS slurry decreased the absorption of vitamin D3 as compared to the control. These results indicate that NSAS may be incorporated in diet to treat hypercholesterolemia; however, vitamin D3 monitoring may be required. 23605905 Ischemic stroke functional outcomes are independently associated with C-reactive protein concentrations and cognitive outcomes with triiodothyronine concentrations: a pilot study. Elevated concentrations of C-reactive protein (CRP) and decreased concentrations of triiodothyronine (T3) were shown to predict poor outcomes in patients with stroke. However, the prognostic value of CRP and T3 has not been studied simultaneously in relation to stroke functional and cognitive outcomes despite of close interaction between inflammatory markers and thyroid function. We evaluated the association of thyroid hormone and CRP concentrations with immediate outcomes after ischemic stroke. Eighty-eight ischemic stroke patients on admission to the stroke unit were evaluated for clinical stroke severity (Scandinavian stroke scale or SSS) and concentrations of thyroid-stimulating hormone, free thyroxin, free T3, and CRP. Functional outcome (modified Rankin scale) and cognitive outcome (Mini mental state examination) were evaluated at discharge. Greater ln CRP concentrations (r = -0.35, p = 0.001), but not thyroid hormone concentrations, correlated with score on the SSS. In univariate analyses lower free T3 concentrations and higher CRP concentrations were associated with poor functional and poor cognitive outcomes. After adjustment for clinical stroke severity, higher CRP concentrations (β = 0.18, p = 0.04) remained associated with worse functional outcome and lower free T3 concentrations with worse cognitive outcome (β = 0.23, p = 0.03). In sum, clinical stroke severity is associated with elevated CRP concentration. Higher CRP concentration is independently associated with worse functional outcomes and lower free T3 concentration with worse cognitive outcomes at discharge. T3 and CRP can be important biomarkers in patients with acute ischemic stroke. 23296902 Urinary chromium excretion in response to an insulin challenge is not a biomarker for chromium status. Over 50 years ago, chromium (Cr) was proposed to be an essential trace element; however, recent studies indicate that this status should be removed as the effects of Cr supplementation appear to be pharmacological rather than nutritional. The pharmacological basis for Cr's effects can explain the inability of investigators to discover a biomarker for Cr status. One potential biomarker has not been examined to date. Cr is known to be mobilized in the body in response to insulin (or insulin release in response to a glucose challenge), resulting in an increase in urinary Cr excretion. The magnitude of increase in urinary Cr loss as a function of dietary Cr intake was tested as a potential biomarker for Cr. Zucker lean rats housed in carefully controlled metal-free conditions were provided a series of purified diets containing variable Cr contents (from 16 μg/kg diet to 2,000 μg/kg) for 23 weeks. The 16 μg/kg diet contained less Cr than any diet examined to date. Urine samples were collected before and after insulin and glucose challenges (0, 2, 6, and 12 h postinjection). Urinary Cr levels were analyzed by the standard method of addition using graphite furnace atomic absorption. The rate of urinary Cr loss after a glucose or insulin challenge was found to not be dependent on the Cr content of the rats' diets. Blood iron levels of the rats were also measured to determine if the addition of Cr to the diet altered iron status. The Cr content of the diet was found to have no affect on blood iron levels. Overall, the study demonstrated that insulin-stimulated urinary Cr excretion cannot be used as a biomarker for Cr status. 23470280 Corticotropin releasing factor and catecholamines enhance glutamatergic neurotransmission in the lateral subdivision of the central amygdala. Glutamatergic neurotransmission in the central nucleus of the amygdala (CeA) plays an important role in many behaviors including anxiety, memory consolidation and cardiovascular responses. While these behaviors can be modulated by corticotropin releasing factor (CRF) and catecholamine signaling, the mechanism(s) by which these signals modify CeA glutamatergic neurotransmission remains unclear. Utilizing whole-cell patch-clamp electrophysiology recordings from neurons in the lateral subdivision of the CeA (CeAL), we show that CRF, dopamine (DA) and the β-adrenergic receptor agonist isoproterenol (ISO) all enhance the frequency of spontaneous excitatory postsynaptic currents (sEPSC) without altering sEPSC kinetics, suggesting they increase presynaptic glutamate release. The effect of CRF on sEPSCs was mediated by a combination of CRFR1 and CRFR2 receptors. While previous work from our lab suggests that CRFRs mediate the effect of catecholamines on excitatory transmission in other subregions of the extended amygdala, blockade of CRFRs in the CeAL failed to significantly alter effects of DA and ISO on glutamatergic transmission. These findings suggest that catecholamine and CRF enhancement of glutamatergic transmission onto CeAL neurons occurs via distinct mechanisms. While CRF increased spontaneous glutamate release in the CeAL, CRF caused no significant changes to optogenetically evoked glutamate release in this region. The dissociable effects of CRF on different types of glutamatergic neurotransmission suggest that CRF may specifically regulate spontaneous excitatory transmission. 23218716 Indoleamine 2,3-dioxygenase inhibitory activity of derivatives of marine alkaloid tsitsikammamine A. Tsitsikammamines are marine alkaloids whose structure is based on the pyrroloiminoquinone scaffold. These and related compounds have attracted attention due to various interesting biological properties, including cytotoxicity, topoisomerase inhibition, antimicrobial, antifungal and antimalarial activity. Indoleamine 2,3-dioxygenase (IDO1) is a well-established therapeutic target as an important factor in the tumor immune evasion mechanism. In this preliminary communication, we report the inhibitory activity of tsitsikammamine derivatives against IDO1. Tsitsikammamine A analogue 11b displays submicromolar potency in an enzymatic assay. A number of derivatives are also active in a cellular assay while showing little or no activity towards tryptophan 2,3-dioxygenase (TDO), a functionally related enzyme. This IDO1 inhibitory activity is rationalized by molecular modeling studies. An interest is thus established in this class of compounds as a potential source of lead compounds for the development of new pharmaceutically useful IDO1 inhibitors. 23395001 Sustained PU.1 levels balance cell-cycle regulators to prevent exhaustion of adult hematopoietic stem cells. To provide a lifelong supply of blood cells, hematopoietic stem cells (HSCs) need to carefully balance both self-renewing cell divisions and quiescence. Although several regulators that control this mechanism have been identified, we demonstrate that the transcription factor PU.1 acts upstream of these regulators. So far, attempts to uncover PU.1's role in HSC biology have failed because of the technical limitations of complete loss-of-function models. With the use of hypomorphic mice with decreased PU.1 levels specifically in phenotypic HSCs, we found reduced HSC long-term repopulation potential that could be rescued completely by restoring PU.1 levels. PU.1 prevented excessive HSC division and exhaustion by controlling the transcription of multiple cell-cycle regulators. Levels of PU.1 were sustained through autoregulatory PU.1 binding to an upstream enhancer that formed an active looped chromosome architecture in HSCs. These results establish that PU.1 mediates chromosome looping and functions as a master regulator of HSC proliferation. 23223641 Micro-mesoporous materials obtained by zeolite recrystallization: synthesis, characterization and catalytic applications. The review covers the recent developments in the field of novel micro-mesoporous materials obtained by zeolite recrystallization. The materials are classified into three distinctly different groups depending on the degree of recrystallization: (i) coated mesoporous zeolites (RZEO-1); (ii) micro-mesoporous nanocomposites (RZEO-2); and (iii) mesoporous materials with zeolitic fragments in the walls (RZEO-3). The first part of the review is focused on the analysis of the synthetic strategies leading to different types of recrystallized materials. In the second part, a comprehensive view on their structure, texture and porosity in connection with acidic and diffusion properties is given. The last part is devoted to the catalytic applications of recrystallized materials. The advantages and disadvantages with respect to pure micro- and mesoporous molecular sieves and other hierarchical zeolites are critically analyzed and the future opportunities and perspectives are discussed. 23567314 Evaluation of perfluoroalkyl acid activity using primary mouse and human hepatocytes. While perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) have been studied at length, less is known about the biological activity of other perfluoroalkyl acids (PFAAs) detected in the environment. Using a transient transfection assay developed in COS-1 cells, our group has previously evaluated a variety of PFAAs for activity associated with activation of peroxisome proliferator-activated receptor alpha (PPARα). Here we use primary heptatocytes to further assess the biological activity of a similar group of PFAAs using custom designed Taqman Low Density Arrays. Primary mouse and human hepatoyctes were cultured for 48h in the presence of varying concentrations of 12 different PFAAs or Wy14,643, a known activator of PPARα. Total RNA was collected and the expression of 48 mouse or human genes evaluated. Gene selection was based on either in-house liver microarray data (mouse) or published data using primary hepatocytes (human). Gene expression in primary mouse hepatocytes was more restricted than expected. Genes typically regulated in whole tissue by PPARα agonists were not altered in mouse cells including Acox1, Me1, Acaa1a, Hmgcs1, and Slc27a1. Cyp2b10, a gene regulated by the constitutive androstane receptor and a transcript normally up-regulated by in vivo exposure to PFAAs, was also unchanged in cultured mouse hepatocytes. Cyp4a14, Ehhadh, Pdk4, Cpt1b, and Fabp1 were regulated as expected in mouse cells. A larger group of genes were differentially expressed in human primary hepatocytes, however, little consistency was observed across compounds with respect to which genes produced a significant dose response making the determination of relative biological activity difficult. This likely reflects weaker activation of PPARα in human versus rodent cells as well as variation among individual cell donors. Unlike mouse cells, CYP2B6 was up-regulated in human hepatocytes by a number of PFAAs as was PPARδ. Rankings were conducted on the limited dataset. In mouse hepatocytes, the pattern was similar to that previously observed in the COS-1 reporter cell assay. With the exception of PFHxA, longer chain PFAA carboxylates were the most active. The pattern was similar in human hepatocytes, although PFDA and PFOS showed higher activity than previously observed while PFOA showed somewhat less activity. These data reflect inherent challenges in using primary hepatocytes to predict toxicological response. 23339036 The Inhibitory Effects of the Standardized Extracts of Ginkgo biloba on Aromatase Activity in JEG-3 Human Choriocarcinoma Cells. Breast cancer is the most common cancer in women worldwide. There are many endocrine adjuvant therapies for breast cancer patients that are categorized according to their mechanisms. Among them, aromatase inhibitors (AIs) that block the synthesis of estrogens have proven superiority compared with tamoxifen and have replaced it as a first-line hormonal therapy. However, AIs also have limitations due to their side effects - increased rate of bone loss and musculoskeletal complaints. We therefore need new candidate AIs with fewer side effects. The extracts of Ginkgo biloba (EGb), which contain phytochemicals from the tree, had biphasic effects for estrogens and osteoporosis-inhibiting activities in our previous experiments. In this study, we explored the possibility of EGb as an AI and their mechanisms. Aromatase activities were inhibited by EGb both in JEG-3 cells and in recombinant CYP19 microsomes. The results of polymerase chain reaction for aromatase from a coding sequence and specific promoter sequences (exon I.a, exon I.c) in JEG-3 cells as well as the results of reporter gene assays showed that EGb dose-dependently decreased the aromatase gene expression. The decreased protein levels were demonstrated by Western blotting. From these results, we concluded that EGb could act as an AI at both the enzyme and transcriptional levels. Copyright © 2013 John Wiley & Sons, Ltd. 23019217 Mithramycin A inhibits myeloid cell leukemia-1 to induce apoptosis in oral squamous cell carcinomas and tumor xenograft through activation of Bax and oligomerization. In several human malignancies, overexpression of myeloid cell leukemia-1 (Mcl-1) confers resistance to induction of apoptosis; however, Mcl-1-mediated inhibition of apoptosis in oral squamous cell carcinoma (OSCC) is not fully understood and has been investigated in this study. The Mcl-1 promoter activators (TPA) and epidermal growth factor (EGF) enhanced neoplastic transformation of JB6 cells and this response was accompanied by enhanced expression of Mcl-1, and knockdown of Mcl-1 by RNA interference (RNAi) decreased JB6 cell transformation. In the same cell line, we also demonstrated that mithramycin A (Mith) decreased TPA-induced JB6 cell transformation and Mcl-1 expression. Mcl-1 was overexpressed in human oral tumors compared with normal oral mucosa and also in several OSCC cell lines including HN22 and HSC-4 cells. Treatment of these cells with Mith also decreased Mcl-1 expression and neoplastic cell transformation, and this was accompanied by induction of several markers of apoptosis. Knockdown of Mcl-1 by RNAi also induced apoptotic cell death. The downregulation of Mcl-1 by Mith and RNAi increased pro-apoptotic protein Bax, resulting in the Bax translocation into mitochondria and its oligomerization. Mith also suppressed tumor growth in vivo and induced apoptosis in tumor by also regulating expression of Mcl-1 and Bax proteins. These indicate a critical role for Mcl-1 in the growth and survival of OSCC and demonstrate that Mith may be a potential anticancer drug candidate for clinical treatment of OSCC. 22349814 Potential tumor-suppressive role of monoglyceride lipase in human colorectal cancer. Human monoglyceride lipase (MGL) is a recently identified lipase and very little is known about its regulation and function in cellular regulatory processes, particularly in context to human malignancy. In this study, we investigated the regulation and function of MGL in human cancer(s) and report that MGL expression was either absent or reduced in the majority of primary colorectal cancers. Immunohistochemical studies showed that reduction of MGL expression in the colorectal tumor tissues predominantly occurred in the cancerous epithelial cells. MGL was found to reside in the core surface of a cellular organelle named 'lipid body'. Furthermore, it was found to interact selectively with a number of phospholipids, including phosphatidic acid and phosphoinositol(3,4,5)P3, phosphoinositol(3,5)P2, phosphoinositol(3,4)P2 and several other phosphoinositides, and among all phosphoinositides analyzed, its interaction with PI(3,4,5)P3 was found to be the strongest. In addition, overexpression of MGL suppressed colony formation in tumor cell lines and knockdown of MGL resulted in increased Akt phosphorylation. Taken together, our results suggest that MGL plays a negative regulatory role in phosphatidylinositol-3 kinase/Akt signaling and tumor cell growth. 23374868 1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanones as novel CCR1 antagonists. A novel series of CCR1 antagonists based on the 1-(4-phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanone scaffold was identified by screening a compound library utilizing CCR1-expressing human THP-1 cells. SAR studies led to the discovery of the highly potent and selective CCR1 antagonist 14 (CCR1 binding IC(50)=4 nM using [(125)I]-CCL3 as the chemokine ligand). Compound 14 displayed promising pharmacokinetic and toxicological profiles in preclinical species. 23085979 Aryl hydrocarbon receptor-mediated disruption of contact inhibition is associated with connexin43 downregulation and inhibition of gap junctional intercellular communication. The aryl hydrocarbon receptor (AhR) contributes to the control of cell-to-cell communication, cell adhesion, migration or proliferation. In the present study, we investigated the regulation of connexin43 (Cx43) and Cx43-mediated gap junctional intercellular communication (GJIC) during the AhR-dependent disruption of contact inhibition in non-tumorigenic liver epithelial cells. The contact inhibition of cell proliferation is a process restricting the cell division of confluent non-transformed cells, which is frequently abolished in cancer cells; however, the mechanisms contributing to its disruption are still only partially understood. Disruption of contact inhibition, which was induced by toxic AhR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or polycyclic aromatic hydrocarbons in epithelial WB-F344 cells, reduced Cx43 protein levels, possibly via enhanced proteasomal degradation, significantly decreased the amount of gap junction plaques and downregulated GJIC, in an AhR-dependent manner. Although both intracellular and membrane Cx43 pools were markedly reduced in cells released from contact inhibition by TCDD, siRNA-mediated Cx43 knock-down was not sufficient to stimulate proliferation in contact-inhibited cells. Our data suggest that downregulation of Cx43/GJIC in non-transformed epithelial cells is an inherent part of disruption of contact inhibition, which occurs at the post-transcriptional level. This process runs in parallel with alterations of other forms of cell-to-cell communication, thus suggesting that toxic AhR agonists may simultaneously abrogate contact inhibition and reduce GJIC, two essential mechanisms linked to deregulation of cell-to-cell communication during tumor promotion and progression. 23307185 Protease-activated receptor (PAR) 1 and PAR4 differentially regulate factor V expression from human platelets. With the recent interest of protease-activated receptors (PAR) 1 and PAR4 as possible targets for the treatment of thrombotic disorders, we compared the efficacy of protease-activated receptor (PAR)1 and PAR4 in the generation of procoagulant phenotypes on platelet membranes. PAR4-activating peptide (AP)-stimulated platelets promoted thrombin generation in plasma up to 5 minutes earlier than PAR1-AP-stimulated platelets. PAR4-AP-mediated factor V (FV) association with the platelet surface was 1.6-fold greater than for PAR1-AP. Moreover, PAR4 stimulation resulted in a 3-fold greater release of microparticles, compared with PAR1 stimulation. More robust FV secretion and microparticle generation with PAR4-AP was attributable to stronger and more sustained phosphorylation of myosin light chain at serine 19 and threonine 18. Inhibition of Rho-kinase reduced PAR4-AP-mediated FV secretion and microparticle generation to PAR1-AP-mediated levels. Thrombin generation assays measuring prothrombinase complex activity demonstrated 1.5-fold higher peak thrombin levels on PAR4-AP-stimulated platelets, compared with PAR1-AP-stimulated platelets. Rho-kinase inhibition reduced PAR4-AP-mediated peak thrombin generation by 25% but had no significant effect on PAR1-AP-mediated thrombin generation. In conclusion, stimulation of PAR4 on platelets leads to faster and more robust thrombin generation, compared with PAR1 stimulation. The greater procoagulant potential is related to more efficient FV release from intracellular stores and microparticle production driven by stronger and more sustained myosin light chain phosphorylation. These data have implications about the role of PAR4 during hemostasis and are clinically relevant in light of recent efforts to develop PAR antagonists to treat thrombotic disorders. 23313962 Pharmacokinetics of temoporfin-loaded liposome formulations: correlation of liposome and temoporfin blood concentration. Liposomal formulations of the highly hydrophobic photosensitizer temoporfin were developed in order to overcome solubility-related problems associated with the current therapy scheme. We have incorporated temoporfin into liposomes of varying membrane composition, cholesterol content, and vesicle size. Specifically, two phosphatidyl oligoglycerols were compared to PEG2000-DSPE with respect to the ability to prolong circulation half life of the liposomal carrier. We measured the resulting pharmacokinetic profile of the liposomal carrier and the incorporated temoporfin in a rat model employing a radioactive lipid label and (14)C-temoporfin. The data for the removal of liposomes and temoporfin were analyzed in terms of classical pharmacokinetic theory assuming a two-compartment model. This model, however, does not allow in a straightforward manner to distinguish between temoporfin eliminated together with the liposomal carrier and temoporfin that is first transferred to other blood components (e. g. plasma proteins) before being eliminated from the blood. We therefore additionally analyzed the data based on two separate one-compartment models for the liposomes and temoporfin. The model yields the ratio of the rate constant of temoporfin elimination together with the liposomal carrier and the rate constant of temoporfin elimination following the transfer to e. g. plasma proteins. Our analysis using this model demonstrates that a fraction of temoporfin is released from the liposomes prior to being eliminated from the blood. In case of unmodified liposomes this temoporfin release was observed to increase with decreasing bilayer fluidity, indicating an accelerated temoporfin transfer from gel-phase liposomes to e. g. plasma proteins. Interestingly, liposomes carrying either one of the three investigated surface-modifying agents did not adhere to the tendencies observed for unmodified liposomes. Although surface-modified liposomes exhibited improved pharmacokinetic properties with regard to the liposomal carrier, an enhanced temoporfin loss and elimination from the PEGylated-liposomes was observed. This effect was more pronounced for PEGylated liposomes than for the two oligo-glycerols. Our combined experimental-theoretical approach for in vivo plasma re-distribution of liposomal drugs may help to optimize colloidal drug carrier systems. 23301246 Dye sensitised solar cells with nickel oxide photocathodes prepared via scalable microwave sintering. Photoactive NiO electrodes for cathodic dye-sensitised solar cells (p-DSCs) have been prepared with thicknesses ranging between 0.4 and 3.0 μm by spray-depositing pre-formed NiO nanoparticles on fluorine-doped tin oxide (FTO) coated glass substrates. The larger thicknesses were obtained in sequential sintering steps using a conventional furnace (CS) and a newly developed rapid discharge sintering (RDS) method. The latter procedure is employed for the first time for the preparation of p-DSCs. In particular, RDS represents a scalable procedure that is based on microwave-assisted plasma formation that allows the production in series of mesoporous NiO electrodes with large surface areas for p-type cell photocathodes. RDS possesses the unique feature of transmitting heat from the bulk of the system towards its outer interfaces with controlled confinement of the heating zone. The use of RDS results in a drastic reduction of processing times with respect to other deposition methods that involve heating/calcination steps with associated reduced costs in terms of energy. P1-dye sensitized NiO electrodes obtained via the RDS procedure have been tested in DSC devices and their performances have been analysed and compared with those of cathodic DSCs derived from CS-deposited samples. The largest conversion efficiencies (0.12%) and incident photon-to-current conversion efficiencies, IPCEs (50%), were obtained with sintered NiO electrodes having thicknesses of ~1.5-2.0 μm. In all the devices, the photogenerated holes in NiO live significantly longer (τ(h) ~ 1 s) than have previously been reported for P1-sensitized NiO photocathodes. In addition, P1-sensitised sintered electrodes give rise to relatively high photovoltages (up to 135 mV) when the triiodide-iodide redox couple is used. 23448860 Extremely low-frequency magnetic field induces manganese accumulation in brain, kidney and liver of rats. The aim of the present study was to determine the effects of extremely low-frequency magnetic field (ELF-MF) on accumulation of manganese (Mn) in the kidney, liver and brain of rats. A total of 40 rats were randomly divided into eight groups. Four control groups received 0, 3.75, 15 and 60 mg Mn per kg body weight orally every 2 days for 45 days, respectively. The remaining four groups received same concentrations of Mn and were also exposed to ELF-MF (1.5 mT; 50 Hz) for 4 h for 5 days a week during 45 days. Following the last exposure, kidney, liver and brain were taken from all rats and they were analyzed for Mn accumulation levels using an inductively coupled plasma-optical emission spectrometer. In result of the current study, we observed that Mn levels in brain, kidney and liver were higher in Mn groups than in control groups. Mn levels in brain, kidney and liver were also higher in Mn plus ELF-MF groups than in Mn groups. In conclusion, result of the current study showed that the ELF-MF induced manganese accumulation in kidney, liver and brain of rats. 23143620 Induction of skin sensitization is augmented in Nrf2-deficient mice. Several in vitro DNA microarray studies have shown the importance of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in skin sensitization. Nevertheless, the exact in vivo role of the Nrf2-Keap1 pathway during the induction of skin sensitization remains unknown. To study the function of Nrf2, a local lymph node assay was performed in wild-type and Nrf2-deficient mice using 2,4-dinitrochlorobenzene. The Nrf2-deficient mice show a more pronounced response, indicating that Nrf2 is involved in dampening the induction of skin sensitization. 23645249 Repression of mammary adipogenesis by genistein limits mammosphere formationof human MCF-7 cells. Mammary adipose tissue may contribute to breast cancer development and progression by altering neighboring epithelial cell behavior and phenotype through paracrine signaling. Dietary exposure to soy foods is associated with lower mammary tumor risk and reduced body weight and adiposity in humans and in rodent breast cancer models. Despite the suggested linkage between obesity and breast cancer, the local influence of bioactive dietary components on mammary adiposity for anti-tumor effects remains unknown. Herein, we report that post-weaning dietary exposure to soy protein isolate and its bioactive isoflavone genistein lowered mammary adiposity and increased mammary tumor suppressor PTEN and E-cadherin expression in female mice, relative to control casein diet. To ascertain genistein's role in mammary adipose deposition that may affect underlying epithelial cell phenotype, we evaluated genistein's effects on SV40-immortalized mouse mammary stromal fibroblast-like (MSF) cells during differentiation to adipocytes. MSF cultured in differentiation medium with 40 nM genistein showed reductions in mature adipocyte numbers, triglyceride accumulation, and PPARγ and fatty acid synthase transcript levels. Genistein inhibition of adipose differentiation was accompanied by increased estrogen receptor (ER)-β gene expression and was modestly recapitulated by ERβ selective agonist 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN). Reduction of ERβ expression by siRNA targeting increased PPARγ transcript levels and stromal fibroblast differentiation into mature adipocytes; the latter was reversed by genistein but not DPN. Conditioned medium from genistein-treated adipocytes diminished anchorage-independent mammosphere formation of human MCF-7 breast cancer cells. Our results suggest a mechanistic pathway to support direct regulation by genistein of mammary adiposity for breast cancer prevention. 22745189 The response to sulpiride in social anxiety disorder: D2 receptor function. Some previous studies have suggested that patients with social anxiety disorder (SAD) have a hypoactive central dopaminergic system. Supporting this there have been reports from neuroimaging studies of reduced striatal D2 receptor binding in subjects with SAD. The aim of this study was to investigate D2 receptor sensitivity in patients with SAD compared with a group of matched, healthy controls using a neuroendocrine challenge with the selective D2 antagonist, sulpiride. D2 receptor function was assessed in 23 subjects with generalized SAD and 23 matched, healthy controls using a challenge with 400 mg of a selective D2 antagonist, sulpiride in a randomized, placebo-controlled, crossover design. Response to sulpiride was measured by the change in prolactin level and changes in self-rated measures of social anxiety, mood and the ability to experience pleasure. There was no significant difference in prolactin response to sulpiride between the two groups. Sulpiride resulted in no effect in either the SAD or healthy control group on measures of social anxiety, mood or the ability to experience pleasure. Contrary to our hypothesis, in this study we found no evidence of reduced D2 receptor function in subjects with SAD compared with healthy controls. 23064749 Evolutionary dynamism of the primate LRRC37 gene family. Core duplicons in the human genome represent ancestral duplication modules shared by the majority of intrachromosomal duplication blocks within a given chromosome. These cores are associated with the emergence of novel gene families in the hominoid lineage, but their genomic organization and gene characterization among other primates are largely unknown. Here, we investigate the genomic organization and expression of the core duplicon on chromosome 17 that led to the expansion of LRRC37 during primate evolution. A comparison of the LRRC37 gene family organization in human, orangutan, macaque, marmoset, and lemur genomes shows the presence of both orthologous and species-specific gene copies in all primate lineages. Expression profiling in mouse, macaque, and human tissues reveals that the ancestral expression of LRRC37 was restricted to the testis. In the hominid lineage, the pattern of LRRC37 became increasingly ubiquitous, with significantly higher levels of expression in the cerebellum and thymus, and showed a remarkable diversity of alternative splice forms. Transfection studies in HeLa cells indicate that the human FLAG-tagged recombinant LRRC37 protein is secreted after cleavage of a transmembrane precursor and its overexpression can induce filipodia formation. 23562369 The pathological effects of Heminecrolysin, a dermonecrotic toxin from Hemiscorpius lepturus scorpion venom are mediated through its lysophospholipase D activity. We have previously identified Heminecrolysin, a sphingomyelinase D (SMaseD), as the major protein responsible for the main pathological effects observed following Hemiscorpius (H.) lepturus scorpion envenomation. We aimed herein to further investigate the kinetics and molecular mechanisms triggered by Heminecrolysin to initiate hematological disorders and inflammatory reaction. We show that Heminecrolysin highly hydrolyzes lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA) and choline, with a Vmax = 1481 ± 51 μmol/min/mg and a Km = 97 ± 16.78 μM, at a much lesser extend sphingomyelin but not phosphatidylcholine substrates. Its lysophospholipase D (lysoPLD) catalytic efficiency, up to three orders of magnitude higher, comparatively to spider's SMaseDs (newly referred as phospholipases D; PLDs), could explain its strong hemolytic capacity. Chelating agents such as EDTA, EGTA, and 1, 10-phenantroline blocked Heminecrolysin-induced LPC hydrolysis at 98, 48, and 70% respectively. Hemolysis blockade occurs only when the toxin is added to erythrocytes in the presence of serum, source of LPC and complement, indicating that the production of LPA and the presence of complement are mandatory for hemolysis. Moreover, we show that Heminecrolysin efficiently binds to erythrocyte's membrane and provokes phosphatidylserine (PS) translocation without cleavage of glycophorin A, suggesting that, unlike spider's PLDs, complement was activated only via the classical pathway. Interestingly, Heminecrolysin was found to induce PS exposure on human nucleated Jurkat T cells, to stimulate secretion of the pro-inflammatory (TNF-α, IL-6), and anti-inflammatory (IL-10) cytokines by human monocytes, and to provoke a disseminated intravascular coagulation on chick embryo chorioallantoic membrane model system. Taken together, our results indicate that Heminecrolysin evokes the major characteristic clinical features of H. lepturus envenomation by using mainly its lysoPLD, rather than its SMaseD's, activity. 23291118 Syntheses and evaluation of the antioxidant activity of novel methoxypsoralen derivatives. A series of 5- and 8-methoxypsoralen (MOP) analogs, suitable for structure-antioxidative/anti-inflammatory activity relationship studies, were synthesized using as key-reactions the selective monobromination of MOPs with N-bromosaccharin and either a Heck reaction or a Suzuki coupling or a Suzuki coupling followed by a Wittig reaction to install side-chains of the acrylate- or benzoate- or cinnamate-type, respectively. The 8-MOP analogs 19 and 24, incorporating at position 5 of the psoralen nucleus a butyl acrylate or a tert-butyl cinnamate moiety, were the most powerful inhibitors of soybean LOX and inhibited effectively lipid peroxidation. Analog 19 was a more potent anti-inflammatory agent than the reference compound indomethacin and of comparable cytocompatibility to 8-MOP whereas analog 24 was a weaker inhibitor of inflammation than indomethacin and significantly more cytotoxic than 8-MOP. The results of the biological tests are discussed in terms of structural characteristics. 23580652 A lipoprotein receptor cluster IV mutant preferentially binds amyloid-β and regulates its clearance from the mouse brain. Soluble low-density lipoprotein receptor-related protein-1 (sLRP1) binds ~ 70% of amyloid β-peptide (Aβ) in human plasma. In Alzheimer's disease (AD) and individuals with mild cognitive impairment converting to AD, plasma sLRP1 levels are reduced and sLRP1 is oxidized which results in diminished Aβ peripheral binding and higher levels of free Aβ in plasma. Experimental studies have shown that free circulating Aβ re-enters the brain and that sLRP1 and/or its recombinant wild-type cluster IV (WT-LRPIV) prevent Aβ from entering the brain. Treatment of Alzheimer's APPsw+/0 mice with WT-LRPIV has been shown to reduce brain Aβ pathology. In addition to Aβ, LRPIV binds multiple ligands. To enhance LRPIV binding for Aβ relative to other LRP1 ligands, we generated a library of LRPIV-derived fragments and full-length LRPIV variants with glycine (G) replacing aspartic acid (D) residues 3394, 3556 and 3674 in the calcium binding sites. Compared to WT-LRPIV, a lead LRPIV-D3674G mutant had 1.6-fold and 2.7-fold higher binding affinity for Aβ40 and Aβ42 in vitro, respectively, and a lower binding affinity for other LRP1 ligands, e.g., apoliporotein E2, E3 and E4 (1.3-1.8-fold), tissue plasminogen activator (2.7-fold), matrix metalloproteinase-9 (4.1-fold) and Factor Xa (3.8-fold). LRPIV-D3674G cleared mouse endogenous brain Aβ40 and Aβ42 25-27% better than WT-LRPIV. A 3-month subcutaneous treatment of APPsw+/0 mice with LRPIV-D3674G (40 μg/kg/day) reduced Aβ40 and Aβ42 levels in the hippocampus, cortex and cerebrospinal fluid by 60-80%, and improved cerebral blood flow responses and hippocampal function at 9 months of age. Thus, LRPIV-D3674G is an efficient new Aβ clearance therapy. 23115086 Effects of hypothermia on the disposition of morphine, midazolam, fentanyl, and propofol in intensive care unit patients. Therapeutic hypothermia (TH) may induce pharmacokinetic changes that may affect the level of sedation. We have compared the disposition of morphine, midazolam, fentanyl, and propofol in TH with normothermia in man. Fourteen patients treated with TH following cardiac arrest (33-34°C) were compared with eight matched critically ill patients (36-38°C). Continuous infusions of morphine and midazolam were stopped and replaced with infusions of fentanyl and propofol to describe elimination and start of infusion pharmacokinetics, respectively. Serial serum and urine samples were collected for 6-8 hours for validated quantification and subsequent pharmacokinetic analysis. During TH, morphine elimination half-life (t(1/2)) was significantly higher, while total clearance (CL(tot)) was significantly lower (median [semi-interquartile range (s-iqr)]): t(1/2), 266 (43) versus 168 (11) minutes, P < 0.01; CL(tot), 1201 (283) versus 1687 (200) ml/min, P < 0.01. No significant differences were seen for midazolam. CL(tot) of fentanyl and propofol was significantly lower in hypothermic patients [median (s-iqr)]: fentanyl, 726 (230) versus 1331 (678) ml/min, P < 0.05; propofol, 2046 (305) versus 2665 (223) ml/min, P < 0.05. Compared with the matched, normothermic intensive care unit patients, t(1/2) of morphine was significantly higher during TH. CL(tot) was lower during TH for morphine, fentanyl, and propofol but not for midazolam. Reducing the infusion rates of morphine, fentanyl, and propofol during TH is encouraged. 23394393 Pharmacogenetics and pharmacogenomics: a bridge to individualized cancer therapy. In the past decade, advances in pharmacogenetics and pharmacogenomics (PGx) have gradually unveiled the genetic basis of interindividual differences in drug responses. A large portion of these advances have been made in the field of anticancer therapy. Currently, the US FDA has updated the package inserts of approximately 30 anticancer agents to include PGx information. Given the complexity of this genetic information (e.g., tumor mutation and gene overexpression, chromosomal translocation and germline variations), as well as the variable level of scientific evidence, the FDA recommendation and potential action needed varies among drugs. In this review, we have highlighted some of these PGx discoveries for their scientific values and utility in improving therapeutic efficacy and reducing side effects. Furthermore, examples are also provided for the role of PGx in new anticancer drug development by revealing novel druggable targets. 23621358 GALACTOSYLATED MICELLES FOR A RIBAVIRIN PRODRUG TARGETING TO HEPATOCYTES. Polymeric micelles potentially able to carry to hepatocytes a ribavirin (RBV) prodrug, exploiting the presence of carbohydrate receptors, i.e., ASGPR, were prepared starting from a galactosylated polylactide-polyaminoacid conjugate. This latter was obtained by chemical reaction of alpha,beta-poly(N-2-hydroxyethyl) (2-aminoethylcarbamate)-DL-aspartamide (PHEA-EDA) with polylactic acid (PLA), and subsequent reaction with lactose, obtaining PHEA-EDA-PLA-GAL copolymer. To enhance the entrapment into obtained nanostructures, a hydrophobic RBV prodrug, i.e. RBV tripalmitate, was synthesized and its capability to release RBV in the presence of an adequate enzymatic activity was demonstrated. Liver-targeted RBV tripalmitate-loaded micelles were obtained in aqueous media at low PHEA-EDA-PLA-GAL copolymer concentration value with nanometric size. By in vitro experiments, the specificity of RBV tripalmitate-loaded PHEA-EDA-PLA-GAL micelles toward HepG2 was demonstrated by using a competitive inhibition assay in the presence of free GAL. This finding raises hope in terms of future micelles-based liver-targeted drug delivery strategy for the hepatitis C treatment. 23347683 A novel class of 3-(phenoxy-phenyl-methyl)-pyrrolidines as potent and balanced norepinephrine and serotonin reuptake inhibitors: synthesis and structure-activity relationships. A series of 3-(phenoxy-phenyl-methyl)-pyrrolidine analogues were discovered to be potent and balanced norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors. Several of these compounds were identified to have suitable in vitro pharmacokinetic properties for an orally dosed and CNS-targeted drug. Compound 39b, in particular, was identified as a potent NET and SERT reuptake inhibitor (NSRI) with minimal off-target activity and demonstrated robust efficacy in the spinal nerve ligation model of pain behavior. 23432582 Bisacylimidoselenocarbamates Cause G2/M Arrest Associated with the Modulation of CDK1 and Chk2 in Human Breast Cancer MCF-7 Cells. Bisacylimidoselenocarbamate derivatives (BSC) are potent anticancer agents with a strong cytotoxic activity against different types of tumour cells. Based in phosphatidylserine exposure on the cell membranes we show that BSC treatment resulted in enhanced cell death in leukaemia CCRF-CEM cells. DNA fragmentation detection in breast adenocarcinoma MCF-7 cells showed that BSC triggered cell death is concentration and time dependent. We also show that two of these compounds, BSC 3g and 3n, cause cell-cycle arrest in the late G2/M in MCF-7 cells. Consistent with this, a reduction in CDK1 and CDK2 expression with no change in cyclin A an B1 was observed in this cell line. Activation of caspase-2 was also detected. However, the involvement of the caspase-dependent pathway in the process of cell death induced by either BSC 3g or 3n is discarded since cell death could not be prevented by pretreatment with the pancaspase inhibitor z-VAD-fmk. Moreover, since reduced levels of p21CIP1 and Chk2 proteins but no change in p53 levels could be detected in MCF-7 cells after BSC 3g or 3n treatment our results suggest that BSC treated cells die from lethal mitosis. 23455312 Cerebrovascular Dilation via Selective Targeting of the Cholane Steroid-Recognition Site in the BK Channel β1-Subunit by a Novel Nonsteroidal Agent. The Ca(2+)/voltage-gated K(+) large conductance (BK) channel β1 subunit is particularly abundant in vascular smooth muscle. By determining their phenotype, BK β1 allows the BK channels to reduce myogenic tone, facilitating vasodilation. The endogenous steroid lithocholic acid (LCA) dilates cerebral arteries via BK channel activation, which requires recognition by a BK β1 site that includes Thr169. Whether exogenous nonsteroidal agents can access this site to selectively activate β1-containing BK channels and evoke vasodilation remain unknown. We performed a chemical structure database similarity search using LCA as a template, along with a two-step reaction to generate sodium 3-hydroxyolean-12-en-30-oate (HENA). HENA activated the BK (cbv1 + β1) channels cloned from rat cerebral artery myocytes with a potency (EC50 = 53 μM) similar to and an efficacy (×2.5 potentiation) significantly greater than that of LCA. This HENA action was replicated on native channels in rat cerebral artery myocytes. HENA failed to activate the channels made of cbv1 + β2, β3, β4, or β1T169A, indicating that this drug selectively targets β1-containing BK channels via the BK β1 steroid-sensing site. HENA (3-45 μM) dilated the rat and C57BL/6 mouse pressurized cerebral arteries. Consistent with the electrophysiologic results, this effect was larger than that of LCA. HENA failed to dilate the arteries from the KCNMB1 knockout mouse, underscoring BK β1's role in HENA action. Finally, carotid artery-infusion of HENA (45 μM) dilated the pial cerebral arterioles via selective BK-channel targeting. In conclusion, we have identified for the first time a nonsteroidal agent that selectively activates β1-containing BK channels by targeting the steroid-sensing site in BK β1, rendering vasodilation. 23579487 Cellular insulin resistance disrupts leptin-mediated control of neuronal signaling and transcription. Central resistance to the actions of insulin and leptin is associated with the onset of obesity and type 2 diabetes mellitus (T2DM), whereas leptin and insulin signaling is essential for both glucose and energy homeostasis. Although it is known that leptin resistance can lead to attenuated insulin signaling, whether insulin resistance can lead to or exacerbate leptin resistance is unknown. To investigate the molecular events underlying crosstalk between these signaling pathways, immortalized hypothalamic neuronal models, rHypoE-19 and mHypoA-2/10, were utilized. Prolonged insulin exposure was used to induce cellular insulin resistance, and thereafter leptin-mediated regulation of signal transduction and gene expression was assessed. Leptin directly repressed agouti-related peptide (AgRP) mRNA levels, but induced urocortin-2 (UCN2), insulin receptor substrate-1 (IRS1), IRS2, and IR transcription, through leptin-mediated phosphatidylinositol-3-kinase (PI3K)/Akt activation. Neuronal insulin resistance, as assessed by attenuated Akt phosphorylation, blocked leptin-mediated signal transduction, and AgRP, UCN2, IRS1, IRS2 and IR synthesis. Insulin resistance caused a substantial decrease in IR protein levels, forkhead box protein 1 (FoxO1) phosphorylation, and an increase in suppressor of cytokine signaling 3 (SOCS3) protein levels. Cellular insulin resistance may cause or exacerbate neuronal leptin resistance, and by extension, obesity. It is essential to unravel the effects of neuronal insulin resistance given that both peripheral, as well as the less widely studied central insulin resistance, may contribute to the development of metabolic, reproductive and cardiovascular disorders. This study provides an improved understanding of the complex cellular crosstalk between insulin-leptin signal transduction that is disrupted during neuronal insulin resistance. 23564329 A large gap opening of graphene induced by the adsorption of CO on the Al-doped site. We investigated CO adsorption on the pristine, Stone-Wales (SW) defected, Al- and Si- doped graphenes by using density functional calculations in terms of geometric, energetic and electronic properties. It was found that CO molecule is weakly adsorbed on the pristine and SW defected graphenes and their electronic properties were slightly changed. The Al- and Si- doped graphenes show high reactivity toward CO, so calculated adoption energies are about -11.40 and -13.75 kcal mol(-1) in the most favorable states. It was found that, among all the structures, the electronic properties of Al-doped graphene are strongly sensitive to the presence of CO molecule. We demonstrate the existence of a large Eg opening of 0.87 eV in graphene which is induced by Al-doping and CO adsorption. 23089896 ATP binding cassette transporters in two distinct compartments of the skin contribute to transdermal absorption of a typical substrate. The role of two ATP binding cassette transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), in transdermal absorption of a typical common substrate was examined in vivo. Skin and plasma concentrations of rhodamine123 (Rho123) after dermal application were reduced in P-gp knockout (mdr1a/1b⁻/⁻) mice and were below the detection limit in P-gp and BCRP triple-knockout (mdr1a/1b/bcrp⁻/⁻) mice. Lower epidermal-to-hypodermal permeation of Rho123 in mdr1a/1b/bcrp⁻/⁻ mouse skin compared to the wild-type mouse skin was confirmed in an Ussing-type chamber experiment. The reduction in skin concentration after dermal application in mdr1a/1b/bcrp⁻/⁻ mice was greater in the dermis than in the epidermis, suggesting functional expressions of these transporters in two distinct skin compartments. Coadministration of the inhibitor itraconazole reduced the skin and plasma concentrations of Rho123 in the wild-type mice, but not in mdr1a/1b/bcrp⁻/⁻ mice, and a marked decrease of Rho123 concentration was seen in the dermis, demonstrating that the functional activities of these transporters can be modulated in vivo. On the other hand, the distribution of Rho123 after intravenous infusion was higher in mdr1a/1b/bcrp⁻/⁻ mice than in the wild-type mice. This supports the occurrence of vectorial transport from the skin into systemic circulation, and is consistent with the immunohistochemical localization of P-gp and BCRP in mouse dermal endothelial cells. BCRP was immunohistochemically identified in human epidermis and dermal endothelial cells. Thus, our findings show that ABC transporters in different compartments of the skin contribute to transdermal absorption of a typical substrate in vivo and can be modulated by a specific inhibitor. These findings have implications for transdermal drug delivery. 23339974 Ubiquitin - omics reveals novel networks and associations with human disease. Human neurodegenerative and infectious diseases and tumorigenesis are associated with alterations in ubiquitin pathways. Over 10% of the genome encode for genes that either bind or manipulate ubiquitin to affect a large proportion of biological processes. This has been the basis for the development of approaches allowing the enrichment of ubiquitinated proteins for comparisons using proteomics and mass spectrometry. Tools such as tagged tandem ubiquitin binding domains, chemically derivatized ubiquitin or anti-gly-gly-lys antibodies combined with mass spectrometry have contributed to surveys of poly-ubiquitinated proteins, poly-ubiquitin linkage diversity and protein ubiquitination sites and their relation to other posttranslational modifications at a proteome wide level, providing insights in to how dynamic alterations in ubiquitination and deubiquitination steps are associated with normal physiology and pathogenesis. 23411206 Simultaneous detection of multiple adulterants in dry milk using macro-scale Raman chemical imaging. The potential of Raman chemical imaging for simultaneously detecting multiple adulterants in milk powder was investigated. Potential chemical adulterants, including ammonium sulphate, dicyandiamide, melamine, and urea, were mixed together into skim dry milk in the concentration range of 0.1-5.0% for each adulterant. Using a 785-nm laser, a Raman imaging system acquired hyperspectral images in the wavenumber range of 102-2538 cm(-1) for a 25 × 25 mm(2) area of each mixture sample, with a spatial resolution of 0.25 mm. Self-modelling mixture analysis (SMA) was used to extract pure component spectra, by which the four types of the adulterants were identified at all concentration levels based on their spectral information divergence values to the reference spectra. Raman chemical images were created using the contribution images from SMA, and their use to effectively visualise identification and spatial distribution of the multiple adulterant particles in the dry milk was demonstrated. 23583556 Variation in the dorsal gradient distribution is a source for modified scaling of germ layers in Drosophila. Specification of germ layers along the dorsoventral axis by morphogenetic gradients is an ideal model to study scaling properties of gradients and cell fate changes during evolution. Classical anatomical studies in divergent insects (e.g., flies and grasshoppers) revealed that the neuroectodermal size is conserved and originates similar numbers of neuroblasts of homologous identity [1-3]. In contrast, mesodermal domains vary significantly in closely related Drosophila species [4]. To further investigate the underlying mechanisms of scaling of germ layers across Drosophila species, we quantified the Dorsal (Dl)/NF-κB gradient, the main morphogenetic gradient that initiates separation of the mesoderm, neuroectoderm, and ectoderm [5-7]. We discovered a variable range of Toll activation across species and found that Dl activates mesodermal genes at the same threshold levels in melanogaster sibling species. We also show that the Dl gradient distribution can be modulated by nuclear size and packing densities. We propose that variation in mesodermal size occurs at a fast evolutionary rate and is an important mechanism to define the ventral boundary of the neuroectoderm. 23122064 Thermal stability of yeast hydrolysate as a novel anti-obesity material. We examined the thermal stability of yeast hydrolysates before and after ultrafiltration (UF) in vitro, and the anti-obesity activity of yeast hydrolysates before and after heat treatment in vivo. Yeast hydrolysate after UF showed significantly higher thermal stability than before UF. Yeast hydrolysates before and after UF showed 3 and 4 thermal transition peaks in their thermograms, respectively, and the total thermal denaturation enthalpies of yeast hydrolysates before and after UF were 69.5 and 36.5 J/g, respectively. For the anti-obesity activity study, yeast hydrolysates before and after heating were administered ad libitum with water to 7-week-old male SD rats. The administration of yeast hydrolysate (YH-control; no heat treatment, YH-1; heat treatment at 140°C, and YH-2; heat treatment at 160°C) significantly increased mRNA expression of cocaine- and amphetamine-regulated transcript (CART) compared with control rats (saline administration). However, there was no significant difference between the heat-treated groups and YH-control and there was no significant difference in neuropeptide Y expression between the heat-treated groups and YH-control. These results suggest that yeast hydrolysate can be use an anti-obesity material after heat treatment. 23337600 ⁹⁹mTc-(Me)FGCDEVD, a potential tracer for apoptosis detection. (Me)FGC(Bz)DEVD was radiolabeled with technetium-99m in high yield. This tracer was preferentially accumulated in apoptotic cells in the in vitro studies. Tumor uptake occurred in vivo after cisplatin injection due to the apoptosis induction, which not observed in the untreated tumors. Therefore, (99m)Tc-(Me)FGCDEVD is a potential tracer for apoptosis detection. 23561157 Characterization of Hachi (Camelus dromedarius) fat extracted from the hump. In this work, the characteristics of fat from the hump of young camels (Hachi) were evaluated. The physicochemical properties of the fat were as follows: melting point, 45°C; saponification value, 202.3mg KOH/g oil; refractive index (60°C), 1.468; unsaponifiable matter, 1.37%; free fatty acids (as the percentage of oleic acid), 0.96%; and peroxide value, 3.37mequiv. O2/kg oil. High-resolution (1)H nuclear magnetic resonance ((1)H NMR) was used for the direct determination of the iodine value of Hachi fat (62.74g/100g oil). The Hachi fat was composed primarily of oleic acid (33.35%), followed by palmitic acid (26.16%), stearic acid (10.07%), palmitelaidic acid (9.56%) and myristic acid (8.83%). The thermal properties were assessed by thermogravimetry (TG) and derivative thermogravimetry (DTG). The results of the present analytical study showed that Hachi fat could be used in food products and as an important source of biological materials. 23570451 Coalescence of Repelling Colloidal Droplets: A Route to Monodisperse Populations. Populations of droplets or particles dispersed in a liquid may evolve through Brownian collisions, aggregation, and coalescence. We have found a set of conditions under which these populations evolve spontaneously toward a narrow size distribution. The experimental system consists of poly(methyl methacrylate) (PMMA) nanodroplets dispersed in a solvent (acetone) + nonsolvent (water) mixture. These droplets carry electrical charges, located on the ionic end groups of the macromolecules. We used time-resolved small angle X-ray scattering to determine their size distribution. We find that the droplets grow through coalescence events: the average radius ⟨R⟩ increases logarithmically with elapsed time while the relative width σR/⟨R⟩ of the distribution decreases as the inverse square root of ⟨R⟩. We interpret this evolution as resulting from coalescence events that are hindered by ionic repulsions between droplets. We generalize this evolution through a simulation of the Smoluchowski kinetic equation, with a kernel that takes into account the interactions between droplets. In the case of vanishing or attractive interactions, all droplet encounters lead to coalescence. The corresponding kernel leads to the well-known "self-preserving" particle distribution of the coalescence process, where σR/⟨R⟩ increases to a plateau value. However, for droplets that interact through long-range ionic repulsions, "large + small" droplet encounters are more successful at coalescence than "large + large" encounters. We show that the corresponding kernel leads to a particular scaling of the droplet-size distribution-known as the "second-scaling law" in the theory of critical phenomena, where σR/⟨R⟩ decreases as 1/√⟨R⟩ and becomes independent of the initial distribution. We argue that this scaling explains the narrow size distributions of colloidal dispersions that have been synthesized through aggregation processes. 23010867 Influence of pH, light cycle, and temperature on ecotoxicity of four sulfonylurea herbicides towards Lemna gibba. In chemical regulation, e.g. the EU Water Framework Directive, REACH, or the Pesticide Directive, standardized ecotoxicological tests are applied to evaluate and rank the hazard of compounds and for deriving environmental quality standards (EQS). Standardized test methods prescribe fixed testing conditions e.g. specific temperature, pH, light intensity etc. However, environmental conditions under which the organisms live are rarely identical to the standard conditions. Thus, the ecotoxicity of compounds found in standard test is not only a function of the compounds inherent physico-chemical properties but is also affected by test conditions. It is therefore important to study the effect of changes in test conditions in order to get reliable input ecotoxicity data for assessing the potential risk posed by a compound. The objective of this study was to investigate the implications of changing test conditions on the toxicity of four sulfonylurea herbicides (SUs). The toxicity of the four SUs towards Lemna gibba was investigated at three pH levels (6, 7.5 and 9), at two temperatures (15 and 24 °C) and two light regimes (continuous and 12:12 h light:dark cycle) The EC50 increased twofold to tenfold for the four SUs when pH was increased from 6 to 9. Decreasing the temperature from 24 to 15 °C or introducing a dark:light cycle did not cause any trends in changes in toxicity. The results show that test conditions can have an effect on the toxicity and this should be considered when the standard test results are used for derivation of EQS. 23069627 Cathepsin K knockout mitigates high-fat diet-induced cardiac hypertrophy and contractile dysfunction. The cysteine protease cathepsin K has been implicated in pathogenesis of cardiovascular disease. We hypothesized that ablation of cathepsin K protects against obesity-associated cardiac dysfunction. Wild-type mice fed a high-fat diet exhibited elevated heart weight, enlarged cardiomyocytes, increased left ventricular wall thickness, and decreased fractional shortening. All these changes were reconciled in cathepsin K knockout mice. Cathepsin K knockout partly reversed the impaired cardiomyocyte contractility and dysregulated calcium handling associated with high-fat diet. Additionally, cathepsin K knockout alleviated whole-body glucose intolerance and improved insulin-stimulated Akt phosphorylation in high-fat diet-fed mice. High-fat feeding increased the expression of cardiac hypertrophic proteins and apoptotic markers, which were inhibited by cathepsin K knockout. Furthermore, high-fat feeding resulted in cathepsin K release from lysosomes into the cytoplasm. In H9c2 myoblasts, silencing of cathepsin K inhibited palmitic acid-induced release of cytochrome c from mitochondria and expression of proapoptotic signaling molecules. Collectively, our data indicate that cathepsin K contributes to the development of obesity-associated cardiac hypertrophy and may represent a potential target for the treatment to obesity-associated cardiac anomalies. 23605046 Computational identification of functional introns: high positional conservation of introns that harbor RNA genes. An appreciable fraction of introns is thought to have some function, but there is no obvious way to predict which specific intron is likely to be functional. We hypothesize that functional introns experience a different selection regime than non-functional ones and will therefore show distinct evolutionary histories. In particular, we expect functional introns to be more resistant to loss, and that this would be reflected in high conservation of their position with respect to the coding sequence. To test this hypothesis, we focused on introns whose function comes about from microRNAs and snoRNAs that are embedded within their sequence. We built a data set of orthologous genes across 28 eukaryotic species, reconstructed the evolutionary histories of their introns and compared functional introns with the rest of the introns. We found that, indeed, the position of microRNA- and snoRNA-bearing introns is significantly more conserved. In addition, we found that both families of RNA genes settled within introns early during metazoan evolution. We identified several easily computable intronic properties that can be used to detect functional introns in general, thereby suggesting a new strategy to pinpoint non-coding cellular functions. 23142558 The 17-β-oestradiol inhibits osteoclast activity by increasing the cannabinoid CB2 receptor expression. Bone is a highly metabolically active tissue and its formation and resorption is at the base of bone remodelling. The critical importance of a balanced bone remodelling is demonstrated by human diseases, i.e. osteoporosis, in which a net increase in bone resorption is responsible of skeleton weakening and fracture risk. Oestrogens display anti-resorptive properties on bone metabolism. Indeed, the so-called post-menopausal osteoporosis occurs after interruption of gonad function and benefits from hormonal replacement treatment. Recently, an important role for the endocannabinoid system in the regulation of skeletal remodelling in human has also been shown. In particular, we showed that CB2 stimulation is able to reduce the number of human OCs in vitro. Here, we provide unprecedented evidence that 17-β-oestradiol administration inhibits activity and formation of human OCs in vitro, demonstrating that oestrogens are able to induce an increase of CB2 expression probably through the recruitment of a putative oestrogens responsive element in the CB2 encoding for gene. 23540585 Heart failure therapy in patients with coronary artery disease. Heart failure and coronary artery disease share many risk factors. Coronary artery disease often pre-dates the development of heart failure with reduced ejection fraction. A diagnosis of heart failure should be considered in any patient with a history of coronary artery disease who presents with breathlessness, ankle oedema or fatigue. Several therapies, such as renin-angiotensin antagonists and B blockers, have been proven to improve survival in patients with heart failure with reduced ejection fraction but evidence for effectiveness in heart failure with preserved ejection fraction is lacking. The management of heart failure and coronary artery disease overlaps considerably but can also be conflicting. Optimal risk factor management is key to preventing progression to heart failure in patients with coronary artery disease. 23197771 Upregulation of Mer receptor tyrosine kinase signaling attenuated lipopolysaccharide-induced lung inflammation. Mer receptor tyrosine kinase (Mer) signaling plays a central role in the intrinsic inhibition of the inflammatory response to Toll-like receptor activation. Previously, we found that lung Mer protein expression decreased after lipopolysaccharide (LPS) treatment due to enhanced Mer cleavage. The purpose of the present study was to examine whether pharmacologically restored membrane-bound Mer expression upregulates the Mer signaling pathways and suppresses lung inflammatory responses. Pretreatment with the ADAM17 (a disintegrin and metalloproteinase-17) inhibitor TAPI-0 (tumor necrosis factor alpha protease inhibitor-0) reduced LPS-induced production of soluble Mer protein in bronchoalveolar lavage (BAL) fluid, restored membrane-bound Mer expression, and increased Mer activation in alveolar macrophages and lungs after LPS treatment. TAPI-0 also enhanced Mer downstream signaling, including phosphorylation of protein kinase b, focal adhesion kinase, and signal transducer and activator of transcription 1. As expected from enhanced Mer signaling, TAPI-0 also augmented suppressor of cytokine signaling-1 and -3 mRNA and protein levels and inhibited nuclear factor κB activation at 4 and 24 hours after LPS treatment. TAPI-0 suppressed LPS-induced inflammatory cell accumulation, total protein level elevation in BAL fluid, and production of inflammatory mediators, including tumor necrosis factor-α, interleukin-1β, and macrophage inflammatory protein-2. Additionally, the effects of TAPI-0 on the activation of Mer signaling and the production of inflammatory responses could be reversed by cotreatment with specific Mer-neutralizing antibody. Restored Mer protein expression by treatment with TAPI-0 efficiently prevents the inflammatory cascade during acute lung injury. 23580027 Female sexual dysfunction in women with thyroid disorders. Background. Few data exist on the prevalence of FSD in thyroid disorders. Aim. We evaluated FSD in women with thyroid diseases and in control age matched healthy women to investigate the relationship between sexual function, and thyroid hormones. Methods. One hundred and four women with thyroid diseases and 53 controls participated in the study. Eighteen with hyperthyroidism (Group1), 22 hypothyroidism (Group2), 45 Hashimoto's thyroiditis (Group3), 19 nodular goiter (Group4) underwent thyroid function evaluation and sonography. The Female Sexual Function Index (FSFI) assessed sexual function. Results. The prevalence of FSD was 46.1% in thyroid diseases and 20.7% in controls. Only in Group4, the prevalence (68.4 %) was significantly higher than in controls (P < 0.005). The mean total FSFI score were 20.1±7.1 in women with thyroid diseases and 25.6±4.7 in the controls (P<0.001). Compared with controls, there was a significant decrease of desire in Group2; desire, arousal and lubrication in Group3; desire, arousal, lubrication, orgasm and satisfaction in Group4. In thyroid diseases the prevalence of FSD was 53% and 42%, while in the controls was 55% and 20%, in menopausal and pre-menopausal groups, respectively. We found a significant inverse correlation between TSH and FSFI (r =-0.7, P= 0.01) in Group 4, which showed the lowest FSFI score (17.8±5.7) and the highest BMI (28.4±7.1 Kg/m2).Conclusions: Women with thyroid diseases present a higher prevalence of FSD than controls. Although our findings suggest a higher impairment of sexual function in Group4 and a role for TSH in FSD, further researches are needed. 23434322 Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Tet proteins oxidize 5-methylcytosine (mC) to generate 5-hydroxymethyl (hmC), 5-formyl (fC), and 5-carboxylcytosine (caC). The exact function of these oxidative cytosine bases remains elusive. We applied quantitative mass-spectrometry-based proteomics to identify readers for mC and hmC in mouse embryonic stem cells (mESC), neuronal progenitor cells (NPC), and adult mouse brain tissue. Readers for these modifications are only partially overlapping, and some readers, such as Rfx proteins, display strong specificity. Interactions are dynamic during differentiation, as for example evidenced by the mESC-specific binding of Klf4 to mC and the NPC-specific binding of Uhrf2 to hmC, suggesting specific biological roles for mC and hmC. Oxidized derivatives of mC recruit distinct transcription regulators as well as a large number of DNA repair proteins in mouse ES cells, implicating the DNA damage response as a major player in active DNA demethylation. 23588560 Population pharmacokinetic analysis of tacrolimus in the first year after pediatric liver transplantation. PURPOSES: Tacrolimus (TAC) is the most widely used immunosuppressant for the prevention of acute rejection after solid organ transplantation. Its pharmacokinetics (PK) show considerable variability, making TAC a good candidate for therapeutic drug monitoring (TDM). The principal aim of the study was to describe the PK of TAC in pediatric patients during the first year after transplantation. METHODS: Routine TDM trough levels of TAC were obtained from 42 pediatric liver allograft recipients during the first year after transplantation. A population PK model was developed using nonlinear mixed-effects modeling to describe TAC PK during this period and to explain the observed variability by means of patients' demographics, biochemical test results and physiological characteristics. RESULTS: The PK of TAC were best described by a two-compartment model with first-order elimination. Apparent volumes of the central compartment, intercomparmental clearance and maximum blood clearance estimates were 253 L, 115 L/day and 314 L/day, respectively. The absorption first-order rate and volume of peripheral compartment were fixed to 4.5 h(-1) and 100 L, respectively. While hematocrit levels, time after transplantation and bodyweight influenced TAC clearance, bodyweight was the only covariate retained on volume of distribution. CONCLUSIONS: We developed a TAC population PK model in pediatrics covering the first year after liver transplantation that may serve as a tool for TAC dose individualization as part of TDM. 23159729 Immunotoxic effects of oil sands-derived naphthenic acids to rainbow trout. Naphthenic acids are the major organic constituents in waters impacted by oil sands. To investigate their immunotoxicity, rainbow trout (Oncorhynchus mykiss) were injected with naphthenic acids extracted from aged oil sands tailings water. In two experiments, rainbow trout were injected intraperitoneally with 0, 10, or 100 mg/kg of naphthenic acids, and sampled after 5 or 21 d. Half of the fish from the 21 d exposure were co-exposed to inactivated Aeromonas salmonicida (A.s.) to induce an immune response. A positive control experiment was conducted using an intraperitoneal injection of 100 mg/kg of benzo[a]pyrene, a known immune suppressing compound. T-lymphocytes, B-lymphocytes, thrombocytes, and myeloid cells were counted in blood and lymphatic tissue using flow cytometry. In the 5d exposure, there was a reduction in blood leucocytes and spleen thrombocytes at the 100 mg/kg dose. However, at 21 d, leucocyte populations showed no effects of exposure with the exception that spleen thrombocyte populations increase at the 100 mg/kg dose. In the 21 d exposure, B- and T-lymphocytes in blood showed a significant Dose × A.s. interaction, indicating stimulated blood cell proliferation due to naphthenic acids alone as well as due to A.s. Naphthenic acid injections did not result in elevated bile fluorescent metabolites or elevated hepatic EROD activity. In contrast to naphthenic acids exposures, as similar dose of benzo[a]pyrene caused a significant decrease in B- and T-lymphocyte absolute counts in blood and relative B-lymphocyte counts in spleen. Results suggest that the naphthenic acids may act via a generally toxic mechanism rather than by specific toxic effects on immune cells. 23247010 Regulation of human carbonyl reductase 1 (CBR1, SDR21C1) gene by transcription factor Nrf2. Monomeric carbonyl reductase 1 (CBR1, SDR21C1) is a member of the short-chain dehydrogenase/reductase superfamily and is involved in the metabolism of anthracycline anti-cancer drugs, prostaglandins, and isatin, which is an endogenous inhibitor of monoamine oxidases. Additionally, cancer progression may be partly regulated by CBR1. In the present study, we screened more than 10 drugs for the induction of the human CBR1 gene to investigate its regulation. Of the drugs, butylated hydroxyanisole (BHA) was found to be an inducer. BHA induced the mRNA and protein expression of CBR1 in hepatoma HepG2 cells. In a luciferase reporter gene assay, the promoter region between -2062 bp and the transcription start site of CBR1 was also activated by BHA. The transcription factor Nrf2 is known to be activated by BHA. There are 2 anti-oxidant responsive elements (ARE) that are bound by Nrf2 in this region. Mutation analyses revealed that one of the AREs participates in the gene regulation of CBR1 by Nrf2. Electrophoretic mobility shift assay revealed that Nrf2 binds the site. Moreover, to determine whether the functional ARE of CBR1 is conserved with the promoter region of homologues in other species, the nucleotide sequences of the functional AREs of the Chcr1 and Chcr2 genes, which are the Chinese hamster homologues of CBR1, were determined. The region has 2 AREs, and these genes were also induced by the forced expression of Nrf2 (cotransfection of pNrf2) in the luciferase reporter gene assay. In conclusion, Nrf2 is a novel transcriptional regulator of CBR1 genes in humans and the Chinese hamster. Because the regulation of CBR1 appears to be important for diseases, the induction of CBR1 by Nrf2 may be a therapeutic target. 23201124 Substrates of IAP ubiquitin ligases identified with a designed orthogonal E3 ligase, the NEDDylator. Inhibitors of Apoptosis Protein (IAPs) are guardian ubiquitin ligases that keep classic proapoptotic proteins in check. Systematic identification of additional IAP substrates is challenged by the heterogeneity and sheer number of ubiquitinated proteins (>5,000). Here we report a powerful catalytic tagging tool, the NEDDylator, which fuses a NEDD8 E2-conjugating enzyme, Ubc12, to the ubiquitin ligase, XIAP or cIAP1. This permits transfer of the rare ubiquitin homolog NEDD8 to the ubiquitin E3 substrates, allowing them to be efficiently purified for LC-MS/MS identification. We have identified >50 potential IAP substrates of both cytosolic and mitochondrial origin that bear hallmark N-terminal IAP binding motifs. These substrates include the recently discovered protein phosphatase PGAM5, which we show is proteolytically processed, accumulates in cytosol during apoptosis, and sensitizes cells to death. These studies reveal mechanisms and antagonistic partners for specific IAPs, and provide a powerful technology for labeling binding partners in transient protein-protein complexes. 23484546 Influence of gas phase equilibria on the chemical vapor deposition of graphene. We have investigated the influence of gas phase chemistry on the chemical vapor deposition of graphene in a hot wall reactor. A new extended parameter space for graphene growth was defined through literature review and experimentation at low pressures (≥0.001 mbar). The deposited films were characterized by scanning electron microscopy, Raman spectroscopy, and dark field optical microscopy, with the latter showing promise as a rapid and nondestructive characterization technique for graphene films. The equilibrium gas compositions have been calculated across this parameter space. Correlations between the graphene films grown and prevalent species in the equilibrium gas phase revealed that deposition conditions associated with a high acetylene equilibrium concentration lead to good quality graphene deposition, and conditions that stabilize large hydrocarbon molecules in the gas phase result in films with multiple defects. The transition between lobed and hexagonal graphene islands was found to be linked to the concentration of the monatomic hydrogen radical, with low concentrations associated with hexagonal islands. 23456038 Unraveling a phosphorylation event in a folded protein by NMR spectroscopy: phosphorylation of the Pin1 WW domain by PKA. The Pin1 protein plays a critical role in the functional regulation of the hyperphosphorylated neuronal Tau protein in Alzheimer's disease and is by itself regulated by phosphorylation. We have used Nuclear Magnetic Resonance (NMR) spectroscopy to both identify the PKA phosphorylation site in the Pin1 WW domain and investigate the functional consequences of this phosphorylation. Detection and identification of phosphorylation on serine/threonine residues in a globular protein, while mostly occurring in solvent-exposed flexible loops, does not lead to chemical shift changes as obvious as in disordered proteins and hence does not necessarily shift the resonances outside the spectrum of the folded protein. Other complications were encountered to characterize the extent of the phosphorylation, as part of the (1)H,(15)N amide resonances around the phosphorylation site are specifically broadened in the unphosphorylated state. Despite these obstacles, NMR spectroscopy was an efficient tool to confirm phosphorylation on S16 of the WW domain and to quantify the level of phosphorylation. Based on this analytical characterization, we show that WW phosphorylation on S16 abolishes its binding capacity to a phosphorylated Tau peptide. A reduced conformational heterogeneity and flexibility of the phospho-binding loop upon S16 phosphorylation could account for part of the decreased affinity for its phosphorylated partner. Additionally, a structural model of the phospho-WW obtained by molecular dynamics simulation and energy minimization suggests that the phosphate moiety of phospho-S16 could compete with the phospho-substrate. 23585770 Glassy Interfacial Dynamics of Ni Nanoparticles: Part II Discrete Breathers as an Explanation of Two-Level Energy Fluctuations. Recent studies of the dynamics of diverse condensed amorphous materials have indicated significant heterogeneity in the local mobility and a progressive increase in collective particle motion upon cooling that takes the form of string-like particle rearrangements. In a previous paper (Part I), we examined the possibility that fluctuations in potential energy E and particle mobility μ associated with this 'dynamic heterogeneity' might offer information about the scale of collective motion in glassy materials based on molecular dynamics simulations of the glassy interfacial region of Ni nanoparticles (NPs) at elevated temperatures. We found that the noise exponent associated with fluctuations in the Debye-Waller factor, a mobility related quantity, was directly proportional to the scale of collective motion L under a broad range of conditions, but the noise exponent associated with E(t) fluctuations was seemingly unrelated to L. In the present work, we focus on this unanticipated difference between potential energy and mobility fluctuations by examining these quantities at an atomic scale. We find that the string atoms exhibit a jump-like motion between two well-separated bands of energy states and the rate at which these jumps occur seems to be consistent with the phenomenology of the 'slow-beta' relaxation process of glass-forming liquids. Concurrently with these local E(t) jumps, we also find 'quake-like' particle displacements having a power-law distribution in magnitude so that particle displacement fluctuations within the strings are strikingly different from local E(t) fluctuations. An analysis of these E(t) fluctuations suggests that we are dealing with 'discrete breather' excitations in which large energy fluctuations develop in arrays of non-linear oscillators by virtue of large anharmonicity in the interparticle interactions and discreteness effects associated with particle packing. We quantify string collective motions on a fast caging times scale (picoseconds) and explore the significance of these collective motions for understanding the Boson peak of glass-forming materials. 23439660 Induction of xenobiotic receptors, transporters, and drug metabolizing enzymes by oxycodone. Perturbations of the expression of transporters and drug-metabolizing enzymes (DMEs) by opioids can be the locus of deleterious drug-drug interactions (DDIs). Many transporters and DMEs are regulated by xenobiotic receptors [XRs; e.g., pregnane X receptor (PXR), constitutive androstane receptor (CAR), and Aryl hydrocarbon receptor (AhR)]; however, there is a paucity of information regarding the influence of opioids on XRs. The objective of this study was to determine the influence of oxycodone administration (15 mg/kg intraperitoneally twice daily for 8 days) on liver expression of XRs, transporters, and DMEs in rats. Microarray, quantitative real-time polymerase chain reaction and immunoblotting analyses were used to identify significantly regulated genes. Three XRs (e.g., PXR, CAR, and AhR), 27 transporters (e.g., ABCB1 and SLC22A8), and 19 DMEs (e.g., CYP2B2 and CYP3A1) were regulated (P < 0.05) with fold changes ranging from -46.3 to 17.1. Using MetaCore (computational platform), we identified a unique gene-network of transporters and DMEs assembled around PXR, CAR, and AhR. Therefore, a series of transactivation/translocation assays were conducted to determine whether the observed changes of transporters/DMEs are mediated by direct activation of PXR, CAR, or AhR by oxycodone or its major metabolites (noroxycodone and oxymorphone). Neither oxycodone nor its metabolites activated PXR, CAR, or AhR. Taken together, these findings identify a signature hepatic gene-network associated with repeated oxycodone administration in rats and demonstrate that oxycodone alters the expression of many transporters and DMEs (without direct activation of PXR, CAR, and AhR), which could lead to undesirable DDIs after coadministration of substrates of these transporters/DMEs with oxycodone. 23201055 Optimization of encapsulation of a synthetic long peptide in PLGA nanoparticles: low-burst release is crucial for efficient CD8(+) T cell activation. Overlapping synthetic long peptides (SLPs) hold great promise for immunotherapy of cancer. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) are being developed as delivery systems to improve the potency of peptide-based therapeutic cancer vaccines. Our aim was to optimize PLGA NP for SLP delivery with respect to encapsulation and release, using OVA24, a 24-residue long synthetic antigenic peptide covering a CTL epitope of ovalbumin (SIINFEKL), as a model antigen. Peptide-loaded PLGA NPs were prepared by a double emulsion/solvent evaporation technique. Using standard conditions (acidic inner aqueous phase), we observed that either encapsulation was very low (1-30%), or burst release extremely high (>70%) upon resuspension of NP in physiological buffers. By adjusting formulation and process parameters, we uncovered that the pH of the first emulsion was critical to efficient encapsulation and controlled release. In particular, an alkaline inner aqueous phase resulted in circa 330 nm sized NP with approximately 40% encapsulation efficiency and low (<10%) burst release. These NP showed enhanced MHC class I restricted T cell activation in vitro when compared to high-burst releasing NP and soluble OVA24, proving that efficient entrapment of the antigen is crucial to induce a potent cellular immune response. 23422033 Resveratrol enhances exercise training responses in rats selectively bred for high running performance. High Capacity Runner (HCR) rats have been developed by divergent artificial selection for treadmill endurance running capacity to explore an aerobic biology-disease connection. The beneficial effects of resveratrol supplementation have been demonstrated in endurance running and the antioxidant capacity of resveratrol is also demonstrated. In this study we examine whether 12weeks of treadmill exercise training and/or resveratrol can enhance performance in HCR. Indeed, resveratrol increased aerobic performance and strength of upper limbs of these rats. Moreover, we have found that resveratrol activated the AMP-activated protein kinase, SIRT1, and mitochondrial transcription factor A (p<0.05). The changes in mitochondrial fission/fusion and Lon protease/HSP78 levels suggest that exercise training does not significantly induce damage of proteins. Moreover, neither exercise training nor resveratrol supplementation altered the content of protein carbonyls. Changes in the levels of forkhead transcription factor 1 and SIRT4 could suggest increased fat utilization and improved insulin sensitivity. These data indicate, that resveratrol supplementation enhances aerobic performance due to the activation of the AMPK-SIRT1-PGC-1α pathway. 23606318 Reversal of Oral Anticoagulation. Although the use of dabigatran and rivaroxaban are increasing, data on the reversal of their effects are limited. The lack of reliable monitoring methods and specific reversal agents renders treatment strategies empirical, and as a result, treatment consists mainly of supportive measures. Therefore, we performed a systematic search of the PubMed database to find studies and reviews pertaining to oral anticoagulation reversal strategies. This review discusses current anticoagulation reversal recommendations for the oral anticoagulants warfarin, dabigatran, and rivaroxaban for patients at a heightened risk of bleeding, actively bleeding, or those in need of preprocedural anticoagulation reversal. We highlight the literature that shaped these recommendations and provide directions for future research to address knowledge gaps. Although reliable recommendations are available for anticoagulation reversal in patients treated with warfarin, guidance on the reversal of dabigatran and rivaroxaban is varied and equivocal. Given the increasing use of the newer agents, focused research is needed to identify effective reversal strategies and develop and implement an accurate method (assay) to guide reversal of the newer agents. Determining patient-specific factors that influence the effectiveness of reversal treatments and comparing the effectiveness of various treatment strategies are pertinent areas for future anticoagulation reversal research. 23458895 Increased vulnerability to β-cell destruction and diabetes in mice lacking NAD(P)H:quinone oxidoreductase 1. NAD(P)H:quinone oxidoreductase 1 (NQO1) has been known to protect cells against stressors, including the diabetogenic reagent streptozotocin (STZ). The present study demonstrated that NQO1 deficiency resulted in increased pancreatic β-cell death induced by multiple low dose of STZ (MLDS) injections. NQO1 knockout (KO) mice showed hyperglycemia, body weight loss, impaired glucose clearance rate and a lower plasma insulin level after MLDS treatment. Moreover, β-cell mass and pancreatic insulin content were significantly lower in KO mice than in wild-type (WT) mice after MLDS treatment. Five days after the first STZ treatment, the islets of KO mice had substantially more TUNEL-positive β-cells than those of WT mice, but there was no difference in the regeneration of β-cells between KO mice and WT mice. At the same time, MLDS-treated KO mice showed significantly increased apoptotic markers in β-cells, including cleaved caspase 3, Smac/DIABLO and AIF (apoptosis inducing factor) in the cytoplasm. These results suggest that mice deficient in NQO1 are vulnerable to MLDS-induced β-cell destruction and diabetes, caused by increase of β-cell apoptosis in pancreas. 23609238 Prospective observational study of physical functioning, physical activity and time outdoors and the risk of hip fracture: A population based cohort study of 158 057 older adults in the 45 and Up Study. Low levels of physical activity or sun exposure and limitations to physical functioning (or disability) have been identified as possible risk factors for hip fracture. However, these factors are closely related and data on their independent and joint association with risk of hip fracture are limited. A total of 158 057 individuals aged ≥45 years sampled from the general population of New South Wales, Australia, from the prospective 45 and Up Study completed a baseline postal questionnaire in 2006-9 including data on physical activity (Active Australia questionnaire); sun exposure (usual time outdoors); and physical functioning (Medical Outcomes Score-Physical Functioning; scored 0-100). Incident first hip fractures were ascertained by linkage to administrative hospital data (n = 293; average follow-up 2.3 years). The Relative Risk (RR) of hip fracture was estimated using Cox proportional hazards. Poorer physical functioning, lower physical activity and less time outdoors were positively related to each other at baseline and individually associated with significantly increased hip fracture risk. However, physical activity and time outdoors were not significantly related to hip fracture risk after adjustment for baseline physical functioning or when analysis was restricted to those with no or mild baseline physical limitation. In contrast, physical functioning remained strongly related to hip fracture risk after adjustment for the other two factors; compared with the group without limitation (100) the RR of hip fracture among those with mild (75-95), moderate (50-70), severe (25-45) and greatest (0-20) level of physical limitation were 1.38 (95%CI 0.88-2.14), 2.14 (1.29-3.53), 3.87 (2.31-6.44), and 5.61 (3.33-9.42), respectively. The findings suggest that limitation in physical functioning, but not physical activity or time outdoors, is strongly related to hip fracture risk. The apparent increased risk of hip fracture previously described for low physical activity or sun exposure may be, at least in part, due to uncontrolled confounding. 23247298 Chirality recognition of the protonated serine dimer and octamer by infrared multiphoton dissociation spectroscopy. Infrared multiphoton dissociation (IRMPD) spectroscopy has been used to record IR signatures of chirality recognition in the protonated serine dimer and octamer in the 3200-3800 cm(-1) region. This is the first IRMPD study to investigate the heterochiral biomolecular system by utilizing the isotope-labelled species. Noticeable differences in the homo- versus heterochiral IRMPD spectra have been obtained experimentally for both the dimer and octamer. Different dissociation patterns have been noted not only between the homo- and heterochiral octamers, but also between the two -OH stretching vibrational bands of the same chirality species. Systematic theoretical searches have been carried out to identify the most stable conformers of both the homo- and heterochiral protonated serine dimer and octamer. The final geometry optimization and harmonic vibrational calculations have been performed at the MP2/6-311++G(d,p) level for the homo- and heterochiral protonated serine dimer and at the B3LYP/6-31G(d) level for the homo- and heterochiral protonated serine octamer. For the homo- and heterochiral dimer, good agreement between the experimental and theoretical spectra has been achieved and the major conformers have been identified. For the homo- and heterochiral octamer, the main IR features observed have been satisfactorily reproduced theoretically and the dominant conformers identified. More than one main conformer has been identified for the homochiral octamer. This conclusion has been further supported by the analysis of the wavelength specific dissociation products. 22906800 The AChE membrane-binding tail PRiMA is down-regulated in muscle and nerve of mice with muscular dystrophy by merosin deficiency. Since Duchenne muscular dystrophy was attributed to mutations in the dystrophin gene, more than 30 genes have been found to be causally related with muscular dystrophies, about half of them encoding proteins of the dystrophin-glycoprotein complex (DGC). Through laminin-2, the DGC bridges the muscle cytoskeleton and the extracellular matrix. Decreased levels of PRiMA-linked acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) have been observed in dystrophic muscle and nerve of dystrophin-deficient (mdx) and laminin-2 deficient (Lama2dy) mice. To help explain these observations, the relative content of AChE, BuChE and PRiMA mRNAs were compared in normal and Lama2dy mouse muscle and sciatic nerve. The 17-fold lower level of PRiMA mRNA in Lama2dy muscle explained the deficit in PRiMA-linked ChEs. This would increase acetylcholine availability and, eventually, the desensitization of nicotinic receptors. Abnormal development of the Schwann cells led to peripheral neuropathy in the Lama2dy mouse. Compared with normal nerve, dystrophic nerve displayed 4-fold less AChE-T mRNA, 3-fold more BuChE mRNA and 2.5-fold less PRiMA mRNA, which agreed with the lower AChE activity in dystrophic nerve, its increased BuChE activity and the specific drop in PRiMA-linked BuChE. The widely accepted role of glial cells as the source of BuChE, the observed dysmyelination of Lama2dy nerve and its increased BuChE activity support the idea that BuChE up-regulation is related with the aberrant differentiation of the Schwann cells. 23420697 Protein-specific force field derived from the fragment molecular orbital method can improve protein-ligand binding interactions. Accurate computational estimate of the protein-ligand binding affinity is of central importance in rational drug design. To improve accuracy of the molecular mechanics (MM) force field (FF) for protein-ligand simulations, we use a protein-specific FF derived by the fragment molecular orbital (FMO) method and by the restrained electrostatic potential (RESP) method. Applying this FMO-RESP method to two proteins, dodecin, and lysozyme, we found that protein-specific partial charges tend to differ more significantly from the standard AMBER charges for isolated charged atoms. We did not see the dependence of partial charges on the secondary structure. Computing the binding affinities of dodecin with five ligands by MM PBSA protocol with the FMO-RESP charge set as well as with the standard AMBER charges, we found that the former gives better correlation with experimental affinities than the latter. While, for lysozyme with five ligands, both charge sets gave similar and relatively accurate estimates of binding affinities. © 2013 Wiley Periodicals, Inc. 23371032 Resistance to conventional insecticides in Pakistani populations of Musca domestica L. (Diptera: Muscidae): a potential ectoparasite of dairy animals. The house fly, Musca domestica L., is an important hygienic pest of humans and dairy animals with the potential to develop resistance to most chemical classes of insecticides. Six adult house fly strains from dairy farms in Punjab, Pakistan were evaluated for resistance to selected insecticides from organochlorine, organophosphate, carbamate and pyrethroid classes. For a chlorocyclodiene and two organophosphates tested, the resistance ratios (RR) at LC50 were in the range of 5.60-22.02 fold for endosulfan, 7.66-23.24 fold for profenofos and 2.47-7.44 fold for chlorpyrifos. For two pyrethroids and one carbamate, the RR values at LC50 were 30.22-70.02 for cypermethrin, 5.73-18.31 for deltamethrin, and 4.39-15.50 for methomyl. This is the first report of resistance to different classes of insecticides in Pakistani dairy populations of house flies. Regular insecticide resistance monitoring programs on dairy farms are needed to prevent field control failures. Moreover, integrated approaches including the judicious use of insecticides are needed to delay the development of insecticide resistance in house flies. 23383710 Conjugation with betaine: a facile and effective approach to significant improvement of gene delivery properties of PEI. Herein, we developed a new gene delivery vector by grafting a betaine monomer (N,N-dimethyl(acrylamidopropyl)ammonium propane sulfonate, DMAAPS) onto 25 KDa polyethylenimine (PEI 25K) via the Michael addition reaction. The graft ratio for betaine on PEI polymer could be readily controlled, and in this study three PEI-betaine conjugates PEI-DMAAPS23%, PEI-DMAAPS55%, and PEI-DMAAPS95% were prepared with their graft ratios of 23, 55, and 95%, respectively. The PEI-betaine conjugates exhibited much lower protein adsorption and cytotoxicities compared with PEI 25K, and they also showed little or no hemolytic effect. Moreover, the PEI-betaine conjugates display satisfactory DNA condensation capability; and in the absence and presence of serum, PEI-DMAAPS23%/pEGFP and PEI-DMAAPS55%/pEGFP complexes exhibited remarkable gene transfection efficiencies determined by flow cytometry, which are in general several times higher than that of PEI 25K. With these favorable properties, the PEI-betaine conjugates hold great potential for use as efficient gene delivery vectors. This study suggests that the betaine monomer may serve as a biocompatible modifying agent and this facile strategy may provide a facile and effective way for constructing some other biocompatible materials. 23486187 Modeling distinct osteosarcoma subtypes in vivo using Cre:lox and lineage-restricted transgenic shRNA. Osteosarcoma is the most common primary cancer of bone and one that predominantly affects children and adolescents. Osteoblastic osteosarcoma represents the major subtype of this tumor, with approximately equal representation of fibroblastic and chondroblastic subtypes. We and others have previously described murine models of osteosarcoma based on osteoblast-restricted Cre:lox deletion of Trp53 (p53) and Rb1 (Rb), resulting in a phenotype most similar to fibroblastic osteosarcoma in humans. We now report a model of the most prevalent form of human osteosarcoma, the osteoblastic subtype. In contrast to other osteosarcoma models that have used Cre:lox mediated gene deletion, this model was generated through shRNA-based knockdown of p53. As is the case with the human disease the shRNA tumors most frequently present in the long bones and preferentially disseminate to the lungs; feature less consistently modeled using Cre:lox approaches. Our approach allowed direct comparison of the in vivo consequences of targeting the same genetic drivers using two different technologies, Cre:lox and shRNA. This demonstrated that the effects of Cre:lox and shRNA mediated knock-down are qualitatively different, at least in the context of osteosarcoma, and yielded distinct subtypes of osteosarcoma. Through the use of complementary genetic modification strategies we have established a model of the most common clinical subtype of osteosarcoma that was not previously represented and more fully recapitulated the clinical spectrum of this cancer. 23462505 Cooperative activation of gene expression by agonists and antagonists mediated by estrogen receptor heteroligand dimer complexes. Estrogen receptor (ER) antagonists are generally thought to inhibit estrogen action through competitive inhibition, resulting in receptor binding to antagonist rather than agonist. However, microarray analyses reveal a group of genes for which ER agonist and antagonist cooperatively regulate expression, suggesting additional models of combined agonist/antagonist action must exist. In conjunction with a chimeric reporter gene and two modified ERs, one [ERα(GSCKV)] with a mutation in the DNA-binding domain and the other (ERα-G521R) with a ligand-binding specificity mutation, we herein demonstrate that ER agonist and antagonist cooperatively activate gene expression through an ER heteroligand dimer complex (ER-HLD) consisting of one subunit of the receptor dimer bound to agonist and another occupied by antagonist. Coimmunoprecipitation experiments confirmed interaction between the agonist-bound and antagonist-bound receptors. This cooperative activation of gene expression was enhanced by steroid receptor coactivator 3 coactivator, and required each ligand-bound subunit of the dimer to bind to DNA, as well as both activation function 1 domains for maximal transcriptional activity. Ligand combinations able to induce ER-HLD transcriptional activity include the agonists 17β-estradiol or conjugated estrogens with the antagonists tamoxifen, raloxifene, bazedoxifene, or fulvestrant. Moreover, ER-HLD can activate transcription in the context of a natural promoter. Taken together, these findings broaden our understanding of the complex relationship between ER agonist and antagonist, and suggest a novel model by which cell and tissue selective effects of antiestrogens may be achieved. 23523142 Ginkgetin induces apoptosis via activation of caspase and inhibition of survival genes in PC-3 prostate cancer cells. Ginkgetin is a natural biflavonoid isolated from leaves of Ginkgo biloba L. Though it was known to have anti-inflammatory, anti-influenza virus, anti-fungal activity, osteoblast differentiation stimulating activity and neuro-protective effects, the underlying antitumor mechanism of ginkgetin still remains unclear. Thus, in the present study, anti-cancer mechanism of ginkgetin was elucidated in human prostate cancer PC-3 cells. Ginkgetin suppressed the viability of PC-3 cells in a concentration-dependent manner and also significantly increased the sub-G1 DNA contents of cell cycle in PC-3 cells. Ginkgetin activated caspase-3 and attenuated the expression of survival genes such as Bcl-2, Bcl-xL, survivin and Cyclin D1 at protein and mRNA levels. Consistently, pan-caspase inhibitor Z-DEVD-fmk blocked sub G1 accumulation and cleavages of PRAP and caspase 3 induced by ginkgetin in PC-3 cells. Overall, these findings suggest that ginkgetin induces apoptosis in PC-3 cells via activation of caspase 3 and inhibition of survival genes as a potent chemotherapeutic agent for prostate cancer treatment. 23601397 The Slovenian food composition database. The preliminary Slovenian food composition database was created in 2003, through the application of the Data management and Alimenta nutritional software. In the subsequent projects, data on the composition of meat and meat products of Slovenian origin were gathered from analyses, and low-quality data of the preliminary database were discarded. The first volume of the Slovenian food composition database was published in 2006, in both electronic and paper versions. When Slovenia joined the EuroFIR NoE, the LanguaL indexing system was adopted. The Optijed nutritional software was developed, and later upgraded to the OPEN platform. This platform serves as an electronic database that currently comprises 620 foods, and as the Slovenian node in the EuroFIR virtual information platform. With the assimilation of the data on the compositions of foods of plant origin obtained within the latest project, the Slovenian database provides a good source for food compositional values of consistent and compatible quality. 23261715 Modulation of activity and inhibitor sensitivity of rabbit aldose reductase-like protein (AKR1B19) by oxidized glutathione and SH-reagents. Rabbit aldo-keto reductase (AKR) 1B19 is an ortholog of human aldose reductase-like protein (ARLP), AKR1B10, showing 86% amino acid sequence identity. AKR1B19 exhibits the highest catalytic efficiency for 4-oxo-2-nonenal, a major product of lipid peroxidation, compared to known reductases of this aldehyde. In this study, we found that the reductase activity of AKR1B19 was activated to about 5-fold immediately after the addition of 10 μM SH-reagents (p-chloromercuriphenylsulfonic acid and p-chloromercuribenzoic acid) in the absence or presence of NADPH. In addition, a maximum of 3-fold activation of AKR1B19 was induced by incubation with glutathione disulfide (GSSG) for 1h. The activated enzyme was converted into the native enzyme by further incubation with dithiothreitol and glutathione. The activation was abolished by the C299S mutation of AKR1B19, and the glutathionylated Cys299 was identified by mass spectrometry analysis. The Cys299-modified enzyme displayed different kinetic alterations depending on substrates and inhibitors. In the reduction of 4-oxo-2-nonenal, the catalytic efficiency was increased. Thus, AKR1B10 may be modulated by cellular ratio of GSSG/glutathione and more efficiently act as a detoxifying enzyme for the cytotoxic aldehyde under oxidatively stressed conditions. Furthermore, such an activity alteration by GSSG was not detected in AKR1B10 and rat ARLPs, suggesting the presence of a GSSG-binding site near Cys299 in AKR1B19. 23404062 Synergistic effects between CA1 mu opioid and dopamine D1-like receptors in impaired passive avoidance performance induced by hepatic encephalopathy in mice. BACKGROUND AND AIM: Numerous investigations have indicated that hepatic encephalopathy (HE) alters the levels of various neurotransmitters. However, comprehensive data regarding the effects of CA1 opioidergic and dopaminergic (DAergic) systems on HE-induced amnesia are still lacking. METHODS: Following intra-dorsal hippocampal (CA1) injection of mu opioid and dopamine D1- and D2-like receptors antagonists in male mice, one-trial step-down and hole-board paradigms were used to assess memory and exploratory behaviors, respectively. RESULTS: Our data demonstrated that HE impairs memory 24 days after bile duct ligation (BDL). Furthermore, while the higher dose of DA D1-like receptor antagonist (SCH23390, 0.5 μg/mouse) induced amnesia and anxiogenic-like behaviors, mu receptor antagonist (naloxone: 0.0125, 0.025 and 0.05 μg/mouse) and DA D2-like receptor antagonist (sulpiride: 0.0625, 0.125 and 0.25 μg/mouse) by themselves, could not exert an effect on memory performance in passive avoidance task. On the other hand, pre-test injection of all drugs reversed the HE-induced amnesia 24 days after BDL, while having no effect on exploratory behaviors. Pre-test co-administration of the subthreshold dose SCH23390 (0.25 μg/mouse) and sulpiride (0.0625 μg/mouse) or naloxone (0.0125 μg/mouse) could likewise reverse the BDL-induced amnesia. However, when the subthreshold sulpiride plus naloxone were co-administered, BDL-induced amnesia was not blocked. CONCLUSIONS: Memory performance is impaired 24 days post BDL and CA1 mu opioid and DA D1-like receptors antagonist synergistic effects are likely involved in this phenomenon. 23306172 Antibacterial polyketides from the marine alga-derived endophitic Streptomyces sundarbansensis: a study on hydroxypyrone tautomerism. Polyketide 13 [=2-hydroxy-5-((6-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-2- propylchroman-4-one] and three related known compounds 7, 9 and 11 were obtained and structurally characterized from Streptomyces sundarbansensis strain, an endophytic actinomycete isolated from the Algerian marine brown algae Fucus sp. Compound 13 was obtained as the major metabolite from optimized culture conditions, by using Agar state fermentation. Due to tautomeric equilibrium, 13 in CD(3)OD solution was able to incorporate five deuterium atoms, as deduced by NMR and ESI-MS/MS analysis. The 2-hydroxy-γ-pyrone form was established for these metabolites based on the comparison of their experimental IR spectra with the DFT calculated ones, for both the corresponding 4-hydroxy-α-pyrone and 2-hydroxy-γ-pyrone forms. During antibacterial evaluation, compound 13 stood out as the most active of the series, showing a selective activity against the gram positive pathogenic methicillin-resistant S. aureus (MRSA, MIC = 6 μΜ), with a bacteriostatic effect. 22885793 Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update. Heat shock proteins (HSP) are a subset of the molecular chaperones, best known for their rapid and abundant induction by stress. HSP genes are activated at the transcriptional level by heat shock transcription factor 1 (HSF1). During the progression of many types of cancer, this heat shock transcriptional regulon becomes co-opted by mechanisms that are currently unclear, although evidently triggered in the emerging tumor cell. Concerted activation of HSF1 and the accumulation of HSPs then participate in many of the traits that permit the malignant phenotype. Thus, cancers of many histologies exhibit activated HSF1 and increased HSP levels that may help to deter tumor suppression and evade therapy in the clinic. We review here the extensive work that has been carried out and is still in progress aimed at (1) understanding the oncogenic mechanisms by which HSP genes are switched on, (2) determining the roles of HSF1/HSP in malignant transformation and (3) discovering approaches to therapy based on disrupting the influence of the HSF1-controlled transcriptome in cancer. 23514247 Nonviral Gene Delivery to Neural Stem Cells with Minicircles by Microporation. The main purpose of this work was to evaluate the transfection of novel DNA vectors, minicircles (mC), on embryonic stem cell-derived neural stem cells (NSC). We demonstrated that by combining microporation with mC, 75% of NSC expressing a transgene is achieved without compromising cell survival, morphology, and differentiation potential. When comparing mC with their plasmid DNA (pDNA) counterparts, both gave rise to similar transfection levels but cells harboring mC showed 10% higher cell viability, maintaining 90% of survival at least for 10 days. Long-term analysis showed that NSC harbor a higher number of mC copies and consequently exhibit higher transgene expression when compared to their pDNA counterpart. Taken together, our results offer the first insights on the use of mC as a novel and safe strategy to genetically engineer NSC envisaging their use as biopharmaceuticals in clinical settings for the treatment of neurodegenerative or neurological diseases. 23522564 Addition of artificial salt bridge by Ile646Lys mutation in gp41 coiled-coil domain regulates 6-helical bundle formation. HIV entry is mediated by the envelope glycoproteins gp120 and gp41. The gp41 subunit contains several functional domains: the N-terminal heptad repeat (NHR) domains fold a triple stranded coiled-coil forming a meta-stable prefusion intermediate. C-terminal heptad repeat (CHR) subsequently folds onto the hydrophobic grooves of the NHR coiled-coil to form a stable 6-helix bundle, which juxtaposes the viral and cellular membranes for fusion. The C34 which has 34 amino acid residues is known as the core structure in CHR. A highly anti-HIV peptide inhibitor derived from C34 was designed. An artificial salt bridge was added in the 6-helical bundle by substitution of lysine for Ile646. With a cholesterol modification at C-terminal, the inhibitor containing I646K mutation represented higher anti-viral activity than C34-cholesterol combination without mutation. 23351096 Stimuli-Responsive Magnetic Nanomicelles as Multifunctional Heat and Cargo Delivery Vehicles. Hybrid nanoarchitectures are among the most promising nanotechnology-enabled materials for biomedical applications. Interfacing of nanoparticles with active materials gives rise to the structures with unique multiple functionality. Superparamagnetic iron oxide nanoparticles particles SPION are widely employed in the biology and in developing of advanced medical technologies. Polymeric micelles offer the advantage of multifunctional carriers which can serve as delivery vehicles carrying nanoparticles, hydrophobic chemotherapeutics and other functional materials and molecules. Stimuli-responsive polymers are especially attractive since their properties can be modulated in a controlled manner. Here we report on multifunctional thermo-responsive poly(N-isopropylacrylamide-co-acrylamide)-block-poly(ε-caprolactone) random block copolymer micelles as magnetic hyperthermia-mediated payload release and imaging agents. The combination of copolymers, nanoparticles and doxorubicin drug was tailored the way that the loaded micelles were cable to respond to magnetic heating at physiologically-relevant temperatures. A surface functionalization of the micelles with the integrin β4 antibody and consequent interfacing of the resulting nanobio hybrid with squamous head and neck carcinoma cells which is known to specifically over-express the A9 antigen resulted in concentration of the micelles on the surface of cells. No inherent cytotoxicity was detected for the magnetic micelles without external stimuli application. Furthermore, SPION-loaded micelles demonstrate significant MRI contrast enhancement abilities. 23423695 Type 2 Diabetes With Partial Lipodystrophy of the Limbs: A new lipodystrophy phenotype. OBJECIVELipodystrophies are categorized by the extent of fat loss (generalized vs. partial) and by inheritance (congenital vs. acquired). We examined whether a group of patients with partial lipodystrophy of the limbs (PLL), type 2 diabetes mellitus (T2DM), and an absence of a family history of lipodystrophy constitute a new clinical subtype.RESEARCH AND DESIGN METHODSTen women with T2DM and PLL were identified in academic diabetes clinics and were matched by age, sex, BMI, ethnicity, and diabetes status with 10 women with control T2DM without lipodystrophy. All patients were characterized by clinical evaluation and hyperinsulinemic clamp.RESULTSPatients with T2DM and PLL exhibited symmetrical loss of subcutaneous fat in forearms, or forearms plus calves, and acanthosis nigricans. Maximally stimulated glucose disposal rates were markedly reduced by 56% in the T2DM with PLL group compared with the control T2DM patients, whether normalized by body weight or surface area. Most PLL patients exhibited little or no insulin-mediated glucose uptake after subtraction of non-insulin-mediated glucose uptake. The T2DM with PLL group also had greater elevations in hepatic transaminases and triglycerides and earlier onset of diabetes compared with control T2DM.CONCLUSIONST2DM with PLL represents a previously unrecognized phenotype of lipodystrophy and of T2DM. These T2DM patients exhibit symmetrical lipodystrophy of the distal limbs, acanthosis nigricans, marked insulin resistance with little insulin-mediated glucose uptake, hypertriglyceridemia, and hepatic transaminase elevations, which are greater in severity than observed in patients with common T2DM. 23595055 Brominated Skeletal Components of the Marine Demosponges, Aplysina cavernicola and Ianthella basta: Analytical and Biochemical Investigations. Demosponges possess a skeleton made of a composite material with various organic constituents and/or siliceous spicules. Chitin is an integral part of the skeleton of different sponges of the order Verongida. Moreover, sponges of the order Verongida, such as Aplysina cavernicola or Ianthella basta, are well-known for the biosynthesis of brominated tyrosine derivates, characteristic bioactive natural products. It has been unknown so far whether these compounds are exclusively present in the cellular matrix or whether they may also be incorporated into the chitin-based skeletons. In the present study, we therefore examined the skeletons of A. cavernicola and I. basta with respect to the presence of bromotyrosine metabolites. The chitin-based-skeletons isolated from these sponges indeed contain significant amounts of brominated compounds, which are not easily extractable from the skeletons by common solvents, such as MeOH, as shown by HPLC analyses in combination with NMR and IR spectroscopic measurements. Quantitative potentiometric analyses confirm that the skeleton-associated bromine mainly withstands the MeOH-based extraction. This observation suggests that the respective, but yet unidentified, brominated compounds are strongly bound to the sponge skeletons, possibly by covalent bonding. Moreover, gene fragments of halogenases suggested to be responsible for the incorporation of bromine into organic molecules could be amplified from DNA isolated from sponge samples enriched for sponge-associated bacteria. 23578584 Significance of the transient receptor potential canonical 2 (TRPC2) channel in the regulation of rat thyroid FRTL-5 cell proliferation, migration, adhesion and invasion. Mammalian transient receptor potential (TRP) channels are involved in many physiologically important processes. Here, we have studied the significance of the TRPC2 channel in the regulation of rat thyroid FRTL-5 cell proliferation, migration, adhesion and invasion, using stable TRPC2 (shTRPC2) knock-down cells. In the shTRPC2 cells, proliferation was decreased due to a prolonged G1/S cell cycle phase. The tumor suppressor p53 and the cyclin-dependant kinase inhibitors p27 and p21 were upregulated. Cell invasion, adhesion and migration were also attenuated in shTRPC2 cells, probably due to decreased activity of both Rac and calpain, and a decreased secretion and activity of matrix metalloproteinase 2. The attenuated proliferation, migration, invasion and ATP-evoked calcium entry was mimicked by overexpressing a non-conducting, truncated TRPC2 (TRPC2-DN) in wild type cells, and was reversed by overexpression of TRPC2-GFP in shTRPC2 cells. In conclusion, TRPC2 is an important regulator of rat thyroid cell function. 23603636 Is autologous chondrocyte implantation (ACI) an adequate treatment option for repair of cartilage defects in paediatric patients? Cartilage lesions in the knee of juvenile patients require an effective repair to regain life-long functional activity of the joint. Autologous chondrocyte implantation (ACI) is discussed to be advantageous over other methods for cartilage repair regarding long-term outcome. ACI has successfully been applied in juvenile patients, although currently recommended for patients ≥18 years of age. Only few controlled clinical trials present evidence of efficacy and safety of ACI in adolescent patients. ACI products have to undergo the process of a marketing authorisation application, including the submission of a paediatric investigation plan (PIP). Data from prospective clinical studies or retrospective collection of long-term data in paediatric patients should be submitted for risk-benefit evaluation by the Paediatric Committee (PDCO). 23147416 Decreased pain responses of C-C chemokine receptor 5 knockout mice to chemical or inflammatory stimuli. Chemokines are small chemotactic cytokines that elicit many physiological and pathological effects through binding to their corresponding receptors. Recent studies have suggested that C-C chemokine receptor (CCR) 5 interacts with μ-opioid receptor and modifies a nociceptive reaction. We examined effects of CCR5 deficiency on pain responses by employing CCR5 knockout (KO) mice. We found that pain responses of CCR5 KO mice to chemical or inflammation stimuli were milder than those of CCR5 wild type (WT) mice. However, there was no remarkable change in thermal nociception. To prove the involvement of CCR5 deletion in lowered nociception, we examined pain reactions with CCR5 WT mice following treatment of a CCR5 antagonist (D-Ala(1)-peptide T-NH(2,) DAPTA). Chemical or inflammatory pain behavior was significantly relieved by intracerebroventricular infusion of the inhibitor. When we assessed expression level of μ-opioid receptor (MOR) in the periaqueductal gray where the receptors are critical for analgesic effects, immunoreactivity of MOR was significantly higher in CCR5 KO mice than WT mice without change in phosphorylation level of the receptor. Reduced nociceptive responses in CCR5 KO mice were moderated by administration of naloxone and d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), MOR antagonists. Our data indicate that CCR5 deficiency is related to up-regulation of MOR without an increase in the receptor desensitization which might result in increased analgesic effects against chemical or inflammatory stimuli. Alternatively, higher amount of opioid ligands in CCR5 mice might be linked to these results. Therefore, CCR5 appears to be a therapeutic target for treatment of pain related diseases such as inflammatory hyperalgesia. 23597099 2-Methoxyjuglone Induces Apoptosis in HepG2 Human Hepatocellular Carcinoma Cells and Exhibits in Vivo Antitumor Activity in a H22 Mouse Hepatocellular Carcinoma Model. In order to discover anticancer agents from natural sources, an ethanol-soluble extract of the root bark of Juglans cathayensis was investigated and showed cytotoxic effects against various human cancer cell lines. A subsequent phytochemical study on the EtOAc-soluble fraction determined 2-methoxyjuglone (1) as one of the main active constituents. Compound 1 was shown to be cytotoxic against HepG2 cells. Morphological features of apoptosis were observed in 1-treated HepG2 cells, including cell shrinkage, membrane blebbing, nuclear condensation, and apoptotic body formation. Cell cycle analysis with propidium iodide staining showed that 1 induced cell cycle arrest at the S phase in HepG2 cells. Flow cytometric analysis with annexin V and propidium iodide staining demonstrated that 1 induced HepG2 cell apoptotic events in a dose-dependent manner (0-8 μg/mL). Western blot analysis of apoptosis-related proteins revealed that 1 induces HepG2 cell apoptosis through mitochondrial cytochrome c-dependent activation of the caspase-9 and caspase-3 cascade pathway (intrinsic pathway). An in vivo experiment using tumor-bearing mice showed that treatment with 1 at 0.5 and 1.0 mg/kg per day decreased the tumor mass by 56% and 67%, respectively. 23627254 Thermostated Hamiltonian Dynamics with Log-Oscillators. With this work we present two new methods for the generation of thermostated, manifestly Hamiltonian dynamics and provide corresponding illustrations. The basis for this new class of thermostats are the peculiar thermodynamics as exhibited by logarithmic oscillators. These two schemes are best suited when applied to systems with a small number of degrees of freedom. 23055393 Enhanced light focusing in self-assembled optoplasmonic clusters with subwavelength dimensions. Compact metallo-dielectric hybrid clusters with subwavelength dimensions are fabricated by template guided self-assembly. Elastic and inelastic scattering spectroscopy and electromagnetic simulations reveal that hybrid clusters comprising TiO(2) nanoparticles on top of a cluster of strongly coupled gold nanoparticles harness synergistic electromagnetic interactions between the building blocks. This results in a boost of the peak electric field intensity and a redistribution of the field in the ambient medium. The complex phase landscape in the clusters features optical vortices that enhance the magnetic field. 23454133 Co-encapsulating nanostructured lipid carriers for transdermal application: From experimental design to the molecular detail. Co-encapsulation of drugs directed at commonly associated diseases provides a convenient means for administration, especially if transdermally delivered. In this work, a comprehensive study for the co-encapsulation of drugs with a differential lipophilicity, olanzapine and simvastatin, and their transdermal delivery in a formulation containing nanostructured lipid carriers (NLC) is presented. Focus is given to the evaluation of a strategy in which NLC and chemical permeation enhancers are combined. It comprises in vitro, in silico and cellular viability approaches. The optimization and rationalization of the systems are carried out using a two-step factorial design. It is shown that the external medium in the NLC dispersion strongly influences permeation. It is also seen that the use of NLC determines a synergistic effect with selected permeation enhancers, thus promoting marked flux enhancement ratios (48 and 21, respectively for olanzapine and simvastatin) relative to the drugs in solution. The developed formulations can be considered non-irritant. A correlation between enhancer positioning in a lipid bilayer, partially governed by a H-bonding phenomenon, and enhancement effect is suggested from molecular dynamics studies and experimental observations. 23255073 Low percentage of KRAS mutations revealed by locked nucleic acid polymerase chain reaction: implications for treatment of metastatic colorectal cancer. Metastatic colorectal cancer (mCRC) is frequently characterized by the presence of mutations of the KRAS oncogene, which are generally associated with a poor response to treatment with anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies. With the methods currently used, a case is classified as KRAS-mutated when approximately 20% of the cells bear an activating KRAS mutation. These considerations raise the question of whether cells with a mutated KRAS can be found in mCRC cases classified as KRAS wild-type when more sensitive methods are used. In addition, the issue arises of whether these mCRC cases with low proportion of KRAS-mutated cells could account at least in part for the therapeutic failure of anti-EGFR therapies that occur in 40-60% of cases classified as KRAS wild type. In this study, we compared the classical assays with a very sensitive test, a locked nucleic acid (LNA) polymerase chain reaction (PCR), capable of detecting KRAS-mutated alleles at extremely low frequency (detection sensitivity limit 0.25% mutated DNA/wild-type DNA). By analyzing a cohort of 213 mCRC patients for KRAS mutations, we found a 20.6% discordance between the sequencing/TheraScreen methods and the LNA-PCR. Indeed, 44 mCRC patients initially considered KRAS wild type were reclassified as KRAS mutated by using the LNA-PCR test. These patients were more numerous among individuals displaying a clinical failure to anti-EGFR therapies. Failure to respond to these biological treatments occurred even in the absence of mutations in other EGFR pathway components such as BRAF. 23581492 The stabilization effect of dielectric constant and acidic amino acids on arginine-arginine (arg-arg) pairings: database survey and computational studies. Database survey in this study revealed that about one-third of the protein structures deposited in the Protein Data Bank (PDB) contain arginine-arginine (Arg-Arg) pairing with a carbon···carbon (CZ···CZ) interaction distance less than 5 Å. All the Arg-Arg pairings were found to bury in a polar environment composed of acidic residues, water molecules, and strong polarizable or negatively charged moieties from binding site or bound ligand. Most of the Arg-Arg pairings are solvent exposed and 68.3% Arg-Arg pairings are stabilized by acidic residues, forming Arg-Arg-Asp/Glu clusters. Density functional theory (DFT) was then employed to study the effect of environment on the pairing structures. It was revealed that Arg-Arg pairings become thermodynamically stable (about -1 kcal/mol) as the dielectric constant increases to 46.8 (DMSO), in good agreement with the results of the PDB survey. DFT calculations also demonstrated that perpendicular Arg-Arg pairing structures are favorable in low dielectric constant environment, while in high dielectric constant environment parallel structures are favorable. Additionally, the acidic residues can stabilize the Arg-Arg pairing structures to a large degree. Energy decomposition analysis of Arg-Arg pairings and Arg-Arg-Asp/Glu clusters showed that both solvation and electrostatic energies contribute significantly to their stability. The results reported herein should be very helpful for understanding Arg-Arg pairing and its application in drug design. 23351139 Drug-induced nanocarrier assembly as a strategy for the cellular delivery of nucleotides and nucleotide analogues. The natural nucleotide adenosine triphosphate (ATP) and nucleotide analogues such as azidothymidine triphosphate (AZT-TP) display important pharmacological activities for the treatment of ischemia and HIV infections, respectively. Their clinical use is, however, limited mostly due to their hydrophilicity, which highly restricts their diffusion into the target cells. Few nanocarriers have been proposed to address the challenge of ATP/AZT-TP cellular delivery, but the loading efficiency, preparation complexity, and efficient cellular delivery remain important barriers to their development. In this study, we propose an original, straightforward and versatile design of nucleotide and nucleotide analogue nanocarriers based on the natural polysaccharide chitosan (CS). We show that the drugs ATP and AZT-TP can induce ionotropic gelation of CS, leading to CS/ATP and CS/AZT-TP nanoparticles with high drug entrapment efficiency and loading rate-up to 44%. Such nanocarriers release ATP and AZT-TP in physiological media and allow an efficient in vitro cellular delivery of these molecules down to the cell cytoplasm. 23602442 Discovery of diarylurea P2Y1 antagonists with improved aqueous solubility. Preclinical data suggests that P2Y1 antagonists, such as diarylurea compound 1, may provide antithrombotic efficacy similar to P2Y12 antagonists and may have the potential of providing reduced bleeding liabilities. This manuscript describes a series of diarylureas bearing solublizing amine side chains as potent P2Y1 antagonists. Among them, compounds 2l and 3h had improved aqueous solubility and maintained antiplatelet activity compared with compound 1. Compound 2l was moderately efficacious in both rat and rabbit thrombosis models and had a moderate prolongation of bleeding time in rats similar to that of compound 1. 23142212 Microbiota of male genital tract: impact on the health of man and his partner. This manuscript describes the male genital tract microbiota and the significance of it on the host's and his partner's health. Microbiota exists in male lower genital tract, mostly in urethra and coronal sulcus while high inter-subject variability exists. Differences appear between sexually transmitted disease positive and negative men as well as circumcised and uncircumcised men. Upper genital tract is generally germ-free, except in case of infections. Prostatitis patients have frequently abundant polymicrobial communities in their semen, expressed prostatic secretion and/or post-massage urine. Coryneform bacteria have ambivalent role in male urogenital tract being frequently commensals but sometimes associated with prostatitis and urethritis. Interactions between male and female genital tract microbiota are highly likely yet there are very scarce studies on the couples' genital tract microbiota. Increase of bacterial vaginosis-type microbiota and coliforms are the most typical findings in men while the adverse effect of male genital tract bacteria on in vitro fertilization and pregnancy outcome has also been indicated. 23321054 Further evidence for the sleep-promoting effects of 5-HT2A receptor antagonists and demonstration of synergistic effects with the hypnotic, zolpidem in rats. 5-Hydroxytryptamine (5-HT)2A antagonists are promising therapeutic agents for the treatment of sleep maintenance insomnias, but unlike hypnotics, they have limited effects on sleep initiation. This study evaluated the effects of several 5-HT2A antagonists (eplivanserin, volinanserin and AVE8488) alone and/or in combination with the short-acting hypnotic, zolpidem, on the rat sleep profile. A repeated-measures design was used in which rats were treated with eplivanserin (3 and 10 mg/kg, i.p. or p.o.), volinanserin (0.3-3 mg/kg, i.p.), AVE8488 (0.1-3 mg/kg, i.p.) and zolpidem (3 and 10 mg/kg, p.o.). In addition, animals received a combination of eplivanserin (3 mg/kg, p.o.) and zolpidem (3 mg/kg, p.o.). Electroencephalogram was analyzed for 6 h after administration. Eplivanserin did not modify wakefulness and non-rapid eye movement sleep (NREMS), while zolpidem (10 mg/kg po) induced a marked increase in NREMS duration. Volinanserin (1 and 3 mg/kg) and AVE8488 (0.3 mg/kg) similarly increased NREMS, while reducing wakefulness. Moreover, the 5-HT2A antagonists and, to a lesser extent, zolpidem, increased duration of NREMS episodes, while decreasing their frequency. When eplivanserin was co-administered with zolpidem, a synergistic effect was observed as the combination produced an increase in NREMS time and bouts duration. These findings confirm further that 5-HT2A antagonists promote the maintenance of sleep, and suggest that combining a 5-HT2A antagonist with a short-acting hypnotic may be a useful strategy for the treatment of insomnia. 23625969 MYCN and HDAC2 cooperate to repress miR-183 signaling in neuroblastoma. MYCN is a master regulator controlling many processes necessary for tumor cell survival. Here, we unravel a microRNA network that causes tumor suppressive effects in MYCN-amplified neuroblastoma cells. In profiling studies, histone deacetylase (HDAC) inhibitor treatment most strongly induced miR-183. Enforced miR-183 expression triggered apoptosis, and inhibited anchorage-independent colony formation in vitro and xenograft growth in mice. Furthermore, the mechanism of miR-183 induction was found to contribute to the cell death phenotype induced by HDAC inhibitors. Experiments to identify the HDAC(s) involved in miR-183 transcriptional regulation showed that HDAC2 depletion induced miR-183. HDAC2 overexpression reduced miR-183 levels and counteracted the induction caused by HDAC2 depletion or HDAC inhibitor treatment. MYCN was found to recruit HDAC2 in the same complexes to the miR-183 promoter, and HDAC2 depletion enhanced promoter-associated histone H4 pan-acetylation, suggesting epigenetic changes preceded transcriptional activation. These data reveal miR-183 tumor suppressive properties in neuroblastoma that are jointly repressed by MYCN and HDAC2, and suggest a novel way to bypass MYCN function. 23435942 A review on cholinesterase inhibitors for Alzheimer's disease. Alzheimer's disease (AD), a progressive neurodegenerative disorder, is characterized by the deficits in the cholinergic system and deposition of beta amyloid (Aβ) in the form of neurofibrillary tangles and amyloid plaques. Since the cholinergic system plays an important role in the regulation of learning and memory processes, it has been targetted for the design of anti-Alzheimer's drugs. Cholinesterase inhibitors enhance cholinergic transmission directly by inhibiting the enzyme acetylcholinesterase (AChE) which hydrolyses acetylcholine. Furthermore, it has been also demonstrated that both acetylcholinesterase and butrylcholinesterase (BuChE) play an important role in Aβ-aggregation during the early stages of senile plaque formation. Therefore, AChE and BuChE inhibition have been documented as critical targets for the effective management of AD by an increase in the availability of acetylcholine in the brain regions and decrease in the Aβ deposition. This review discusses the different classes of cholinesterase inhibitors including tacrine, donepezil, rivastigmine, galantamine, xanthostigmine, para-aminobenzoic acid, coumarin, flavonoid, and pyrrolo-isoxazole analogues developed for the treatment of AD. 23281101 Butyltin(IV) benzoates: inhibition of thioredoxin reductase, tumor cell growth inhibition, and interactions with proteins. Thioredoxin reductase (TrxR) is overexpressed in cancer cells and is therefore a putative cancer target. Inhibition of this enzyme is considered an important strategy for the development of new chemotherapeutic agents with a specific mechanism of action. Organotin compounds have been described as experimental antitumor agents, yet their mechanism of action remains largely unknown. Based on the outcome of a virtual screening study, various di- and tri-n-butyltin(IV) carboxylates were synthesized, and their biological properties were evaluated. All synthesized compounds were able to inhibit TrxR selectively within the micromolar range and showed potent antitumor activity against HT-29 and MCF-7 cancer cell lines. Moreover, tin(IV) organometallics were found to strongly induce apoptosis in the BJAB lymphoma cell line. Mass spectrometry and atomic absorption spectroscopy experiments revealed metal binding to proteins, and efficient cellular uptake was observed using a di-n-butyltin(IV) complex as an example. 23497894 High pressure homogenization increases antioxidant capacity and short-chain fatty acid yield of polysaccharide from seeds of Plantago asiatica L. Physiological properties of homogenized and non-homogenized polysaccharide from the seeds of Plantago asiatica L., including antioxidant capacity and short-chain fatty acid (SCFA) production, were compared in this study. High pressure homogenization decreased particle size of the polysaccharide, and changed the surface topography from large flake-like structure to smaller porous chips. FT-IR showed that high pressure homogenization did not alter the primary structure of the polysaccharide. However, high pressure homogenization increased antioxidant capacity of the polysaccharide, evaluated by 4 antioxidant capacity assays (hydroxyl radical-scavenging, superoxide radical-scavenging, 1,1-diphenyl-2-picryl-hydrazyl radical (DPPH)-scavenging and lipid peroxidation inhibition). Additionally, the production of total SCFA, propionic acid and n-butyric acid in ceca and colons of mice significantly increased after dieting supplementation with homogenized polysaccharide. These results showed that high pressure homogenization treatment could be a promising approach for the production of value-added polysaccharides in the food industry. 23546600 A 5' flanking region of Gonadotropin Regulated Testicular RNA Helicase (GRTH/DDX25) gene directs its cell specific androgen regulated gene expression in testicular germ cells. Gonadotropin Regulated Testicular RNA Helicase (GRTH/Ddx25) is a post-transcriptional regulator of genes that are essential for spermatid elongation and completion of spermatogenesis. It also prevents Leydig cells (LC) from gonadotropin overstimulation of androgen production. In transgenic (Tg) mice carrying deletions of the GRTH 5' flanking regions we previously demonstrated that the -1085 bp to ATG contains the elements for basal and androgen-induced LC specific expression. No expression in germ cells (GC) was found with sequences extended up to -3.6 Kb. To define regulatory regions of GRTH required for expression in GC, Tg mice were generated with 5' flanking sequence 6.4 Kb (6.4 Kb-Tg) and/or deletion using GFP as reporter gene in the present study. GFP was expressed in all lines. Immuno-histochemistry analysis showed that 6.4Kb-Tg directed GFP expression in both GC and LC. Deletion of the sequence -205 bp to -3.6 Kb (6.4Kb/del-Tg) directs GFP expression only in meiotic and haploid GCs. This indicated that the distal region -6.4 Kb/-3.6 Kb is required for GRTH cell specific expression in GC. Also, it inhibits the expression of GRTH in LC directed by the 205 bp promoter, an effect that is neutralized by the -3.6Kb/-205bp sequence. Flutamide treatment prevents GFP/GRTH expression in Tg lines demonstrating in vivo direct and indirect effects of endogenous androgen on GC and LC, respectively. Our studies have generated and characterized transgenic lines that can be utilized to define requirements for cell specific expression of the GRTH gene and to further advance our knowledge on the regulation of GRTH by androgen in germ cells. 23122092 Chemical and sensory effects of the freezing process on the aroma profile of black truffles (Tuber melanosporum). The aim of this work was to evaluate the effect of freezing black truffles (Tuber melanosporum) on their aroma both in sensory and chemical terms. The truffles were frozen at temperatures of -20 to -80°C. Descriptive and discriminative sensory and chemical analyses, based on headspace solid phase microextraction followed by gas chromatography-mass spectrometry analysis (HS-SPME-GC-MS), were carried out after 1, 20, 40 and 60 days. Fifteen compounds with high aromatic potential in truffles were determined. Their selective ion peak areas were calculated, summed and expressed as percentage of active odour compound, in order to monitor changes in odour profile. The aroma of frozen truffles differed significantly from the aroma of fresh truffles. Volatile composition data revealed that T. melanosporum aromatic profile is deeply modified as a consequence of a freezing process. These aromatic changes could explain the loss of freshness observed in all frozen truffles. Methional and some phenols were suggested as markers of freezing time. Interestingly, 1-octen-3-one appeared as a general marker of freezing process. 23512181 Extending the range of FRET-the Monte Carlo study of the antenna effect. The problem of extending the utilizable range of Förster resonance energy transfer (FRET) is of great current interest, due to the demand of conformation studies of larger biological structures at distances exceeding typical limiting distance of 100 Å. One of the ways to address this issue is the use of so-called antenna effect. In the present work, the influence of the antenna effect on the FRET efficiency is investigated by the Monte Carlo analysis. The previously published results Bojarski et al. (J Phys Chem B 115:10120-10125, 2011) indicate that using a simple model of donor linked with a protein labeled with multiple acceptors, significantly increases the transfer efficiency in comparison with donor-single acceptor system. The effect is stronger if the transition moments of acceptors are mutually parallel. In this work, to extend the scope of possible biological systems to be analyzed, different distributions of donor-acceptors distance are analyzed, as well as the size and shape of the attached molecule. 23411314 Valuable compounds in macroalgae extracts. Bioactive compounds present in ethanolic extracts from 18 macroalgae of the Portuguese coast were analysed by gas chromatography-mass spectrometry (GC-MS), leading to the characterization of 14 compounds: proline, phloroglucinol, mannitol, 8 fatty acids and 3 sterols. A dose-dependent response against enzymes with biological significance (α-glucosidase, acetylcholinesterase and butyrylcholinesterase) and free radicals (DPPH, nitric oxide, superoxide and hydroxyl) was found, Phaeophyta being the most promising group. A PCA analysis was performed and allowed the establishment of a correlation between the algae chemical composition and the biological activity. Cystoseira tamariscifolia (Hudson) Papenfuss, Cystoseira nodicaulis (Withering) M. Roberts, Cystoseira usneoides (Linnaeus) M. Roberts and Fucus spiralis Linnaeus are among the most active species, which is in accordance with their higher contents in phloroglucinol, mannitol, oleic, arachidonic and eicosapentaenoic acids, and fucosterol. The results point to the potential interest of the use of Phaeophyta species as food additives, due to their potent antiradical activities, and especially highlights the importance of F. spiralis in the food chain of Mediterranean countries. Moreover, the incorporation of the extracts of these species in food products, nutraceutical and pharmaceutical preparations for human health should also be instigated, since they can suppress hyperglycemia and inhibit cholinesterases. 23159666 Transferrin conjugation does not increase the efficiency of liposomal Foscan during in vitro photodynamic therapy of oesophageal cancer. Photodynamic therapy (PDT) is based on the delivery of photocytotoxic agents to a target tissue, followed by irradiation. In order to increase the efficiency of PDT in oesophageal cancer therapy, polyethylene glycol (PEG)-grafted, transferrin (Tf)-conjugated liposome formulations of 5,10,15,20-tetra(m-hydroxyphenyl)chlorin (Foscan), a second-generation photosensitiser, were prepared. Expression of transferrin receptors (CD71) in the oesophageal cancer cell line, OE21, was confirmed by immunoblot and confocal laser scanning microscopy. The anti-proliferative effect of Foscan liposomes was evaluated and compared with plain formulations (i.e., without Tf) as well as with free drug. In addition, the intracellular accumulation was studied using high content analysis. Surprisingly, delivering Foscan by transferrin-conjugated PEG-liposomes to oesophageal cancer cells did not improve the photocytotoxicity or the intracellular accumulation of Foscan when compared to unmodified liposomes or indeed free photosensitiser. Tf-targeted drugs and drug delivery systems have shown improved the therapy of many cancers. Our study, however, did not corroborate these findings. If this is due to the tumour type, the choice of in vitro model or the delivery systems remains to be confirmed. 23368705 Anti-Müllerian hormone trend after laparoscopic surgery in women with ovarian endometrioma. Abstract Operative laparoscopy is the gold standard in the treatment of endometriotic ovarian cysts. Excisional surgery is the best technique to prevent recurrences and improve symptoms but it may result in ovarian reserve damage due to the removal of healthy ovarian cortex. The aim of this study was to investigate the extent of the ovarian reserve damage after stripping technique of unilateral endometriomas, by dosing the Anti-Müllerian Hormone (AMH). This prospective study was conducted at the Center of Minimally Invasive Pelvic Surgery of the Department of Health of Woman and Child, University of Padua, from October 2010 to June 2012. Twenty-five women underwent excision of monolateral endometriosis ovarian cyst by stripping without accessing a bipolar coagulation and performing an intracortical suture. The AMH serum levels were estimated in the early proliferative phase of the cycle, before surgery (time 0), 24 h after surgery (time 1), the first menstrual cycle after surgery (time 2) and the third menstrual cycle after surgery (time 3). We found a nonstatistically significant decreases in serum AMH levels after surgical excision of the cysts. Our results suggest that an appropriate surgical technique, without the use of the bipolar coagulation of ovarian border, does not determine a significant reduction of ovarian reserve. 23436544 Vemurafenib-associated pancreatitis: case report. Vemurafenib is a novel BRAF kinase inhibitor indicated in metastatic melanoma patients with V600E mutation. We report the first case of vemurafenib-associated pancreatitis. Two weeks after initiation of vemurafenib, a patient presented to the emergency department with severe epigastric pain and a serum lipase of 1544 units/L. Drug-induced pancreatitis was diagnosed on exclusion of all other potential causes. Vemurafenib was rechallenged at half the daily dose and the patient subsequently developed exacerbated symptoms of pancreatitis after two doses. The strong temporal relationship between drug exposure and toxicity, along with the positive results from a rechallenge study, strongly support a conclusion of causality. To our knowledge, this is the first report of vemurafenib-induced pancreatitis. 23591044 Melatonin and ethanol intake exert opposite effects on circulating estradiol and progesterone and differentially regulate sex steroid receptors in the ovaries, oviducts, and uteri of adult rats. Chronic ethanol intake is associated with sex hormone disturbances, and it is well known that melatonin plays a key role in regulating several reproductive processes. We report the effects of ethanol intake and melatonin treatment (at doses of 100μg/100gBW/day) on sex hormones and steroid receptors in the ovaries, oviducts and uteri of ethanol-preferring rats. After 150 days of treatment, animals were euthanized, and tissue samples were harvested to evaluate androgen, estrogen, progesterone and melatonin receptor subunits (AR, ER-α and ER-β, PRA, PRB and MT1R, respectively). Melatonin decreased estradiol (E2) and increased progesterone (P4) and 6-sulfatoxymelatonin (6-STM), while an ethanol-melatonin combination reduced both P4 and E2. Ovarian AR was not influenced by either treatment, and oviduct AR was reduced after ethanol-melatonin combination. Oviduct ER-α, ER-β and uterine ER-β were down-regulated by either ethanol or melatonin. Conversely, ovarian PRA and PRB were positively regulated by ethanol and ethanol-melatonin combination, whereas PRA was down-regulated in the uterus and oviduct after ethanol consumption. MT1R was increased in ovaries and uteri of melatonin-treated rats. Ethanol and melatonin exert opposite effects on E2 and P4, and they differentially regulate the expression of sex steroid receptors in female reproductive tissues. 23170794 Global cerebral ischemia: synaptic and cognitive dysfunction. Cardiopulmonary arrest is one of the leading causes of death and disability, primarily occurring in the aged population. Numerous global cerebral ischemia animal models induce neuronal damage similar to cardiac arrest. These global cerebral ischemia models range from vessel occlusion to total cessation of cardiac function, both of which have allowed for the investigation of this multifaceted disease and detection of numerous agents that are neuroprotective. Synapses endure a variety of alterations after global cerebral ischemia from the resulting excitotoxicity and have been a major target for neuroprotection; however, neuroprotective agents have proven unsuccessful in clinical trials, as neurological outcomes have not displayed significant improvements in patients. A majority of these neuroprotective agents have specific neuronal targets, where the success of future neuroprotective agents may depend on non-specific targets and numerous cognitive improvements. This review focuses on the different models of global cerebral ischemia, neuronal synaptic alterations, synaptic neuroprotection and behavioral tests that can be used to determine deficits in cognitive function after global cerebral ischemia. 23043137 Regulation of a viral proteinase by a peptide and DNA in one-dimensional space: II. adenovirus proteinase is activated in an unusual one-dimensional biochemical reaction. Late in an adenovirus infection, the viral proteinase (AVP) becomes activated to process virion precursor proteins used in virus assembly. AVP is activated by two cofactors, the viral DNA and pVIc, an 11-amino acid peptide originating from the C terminus of the precursor protein pVI. There is a conundrum in the activation of AVP in that AVP and pVI are sequence-independent DNA-binding proteins with nm equilibrium dissociation constants such that in the virus particle, they are predicted to be essentially irreversibly bound to the viral DNA. Here, we resolve that conundrum by showing that activation of AVP takes place on the one-dimensional contour of DNA. In vitro, pVI, a substrate, slides on DNA via one-dimensional diffusion, D(1) = 1.45 × 10(6) bp(2)/s, until it binds to AVP also on the same DNA molecule. AVP, partially activated by being bound to DNA, excises pVIc, which binds to the AVP molecule that cut it out. pVIc then forms a disulfide bond with AVP forming the fully active AVP-pVIc complex bound to DNA. In vivo, in heat-disrupted immature virus, AVP was also activated by pVI in DNA-dependent reactions. This activation mechanism illustrates a new paradigm for virion maturation and a new way, by sliding on DNA, for bimolecular complexes to form among proteins not involved in DNA metabolism. 23160092 Effects of the extracts and an active compound curcumenone isolated from Curcuma zedoaria rhizomes on alcohol-induced drunkenness in mice. The Curcuma zedoaria rhizome has been used traditionally to treat gastrointestinal diseases as an aromatic stomachic drug, and this is currently used to treat alcohol-induced loss of appetite and nausea in Japan. We examined the effects of various fractions and isolated compounds on alcohol-induced drunkenness and blood alcohol concentrations in mice. The 30% ethanol-extract (1000mg/kg) of C. zedoaria rhizome prevented drunkenness 60 and 120min after 40% alcohol administration. The n-hexane-soluble fraction (300mg/kg) and an isolated compound (3, 10 or 30mg/kg) prevented drunkenness at 30, 60 or 120min. The extract, n-hexane-soluble fraction and isolated compound reduced the elevation in blood alcohol concentrations 30 and 60min after 40% alcohol administration. The isolated compound (10 and 30mg/kg) enhanced liver ADH activity 30 and 60min after 40% alcohol administration. The compound was identified as curcumenone by a direct comparison of (1)H- and (13)C-NMR spectral data. In conclusion, the protective effect of the C. zedoaria extract on drunkenness might be due to an active substance, curcumenone, and decreases in the elevation of blood alcohol concentrations through increased liver alcohol dehydrogenase activity. 23231439 Discovery, synthesis, and structure-based optimization of a series of N-(tert-butyl)-2-(N-arylamido)-2-(pyridin-3-yl) acetamides (ML188) as potent noncovalent small molecule inhibitors of the severe acute respiratory syndrome coronavirus (SARS-CoV) 3CL protease. A high-throughput screen of the NIH molecular libraries sample collection and subsequent optimization of a lead dipeptide-like series of severe acute respiratory syndrome (SARS) main protease (3CLpro) inhibitors led to the identification of probe compound ML188 (16-(R), (R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide, Pubchem CID: 46897844). Unlike the majority of reported coronavirus 3CLpro inhibitors that act via covalent modification of the enzyme, 16-(R) is a noncovalent SARS-CoV 3CLpro inhibitor with moderate MW and good enzyme and antiviral inhibitory activity. A multicomponent Ugi reaction was utilized to rapidly explore structure-activity relationships within S(1'), S(1), and S(2) enzyme binding pockets. The X-ray structure of SARS-CoV 3CLpro bound with 16-(R) was instrumental in guiding subsequent rounds of chemistry optimization. 16-(R) provides an excellent starting point for the further design and refinement of 3CLpro inhibitors that act by a noncovalent mechanism of action. 23599433 HSP90 functions to stabilize and activate the testis-specific serine/threonine kinases, a family of kinases essential for male fertility. Spermiogenesis is characterized by a profound morphological differentiation of the haploid spermatid into spermatozoa. The testis-specific serine/threonine kinases (TSSKs) comprise a family of post-meiotic kinases expressed in spermatids, are critical to spermiogenesis and are required for male fertility in mammals. To explore the role of HSP90 in regulation of TSSKs, the stability and catalytic activity of epitope-tagged murine TSSKs were assessed in 293T and COS-7 cells. TSSK1, 2, 4, and 6 (SSTK) were all found to associate with HSP90 and pharmacological inhibition of HSP90 function using the highly specific drugs 17-AAG, SNX-5422, or NVP-AUY922 reduced TSSK protein levels in cells. The attenuation of HSP90 function abolished the catalytic activities of TSSK4 and 6, but did not significantly alter the specific activities of TSSK1 and 2. Inhibition of HSP90 resulted in increased TSSK ubiquitination and proteasomal degradation indicating that HSP90 acts to control ubiquitin-mediated catabolism of the TSSKs. To study HSP90 and TSSKs in germ cells a mouse primary spermatid culture model was developed and characterized. Using specific antibodies against murine TSSK2 and 6, it was demonstrated that HSP90 inhibition resulted in a marked decrease of the endogenous kinases in spermatids. Together, our findings demonstrate that HSP90 plays a broad and critical role in stabilization and activation of the TSSK family of protein kinases. 23059626 The effect of CCL3 and CCR1 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Bone remodeling is affected by mechanical loading and inflammatory mediators, including chemokines. The chemokine (C-C motif) ligand 3 (CCL3) is involved in bone remodeling by binding to C-C chemokine receptors 1 and 5 (CCR1 and CCR5) expressed on osteoclasts and osteoblasts. Our group has previously demonstrated that CCR5 down-regulates mechanical loading-induced bone resorption. Thus, the present study aimed to investigate the role of CCR1 and CCL3 in bone remodeling induced by mechanical loading during orthodontic tooth movement in mice. Our results showed that bone remodeling was significantly decreased in CCL3(-/-) and CCR1(-/-) mice and in animals treated with Met-RANTES (an antagonist of CCR5 and CCR1). mRNA levels of receptor activator of nuclear factor kappa-B (RANK), its ligand RANKL, tumor necrosis factor alpha (TNF-α) and RANKL/osteoprotegerin (OPG) ratio were diminished in the periodontium of CCL3(-/-) mice and in the group treated with Met-RANTES. Met-RANTES treatment also reduced the levels of cathepsin K and metalloproteinase 13 (MMP13). The expression of the osteoblast markers runt-related transcription factor 2 (RUNX2) and periostin was decreased, while osteocalcin (OCN) was augmented in CCL3(-/-) and Met-RANTES-treated mice. Altogether, these findings show that CCR1 is pivotal for bone remodeling induced by mechanical loading during orthodontic tooth movement and these actions depend, at least in part, on CCL3. 23480348 Polyallylamine functionalized palladium icosahedra: one-pot water-based synthesis and their superior electrocatalytic activity and ethanol tolerant ability in alkaline media. Polyallylamine (PAH) functionalized Pd icosahedra are synthesized through a simple, one-pot, seedless and hydrothermal growth method. Herein, PAH is used efficiently as a complex-forming agent, capping agent, and facet-selective agent. The strong interaction between PAH and Pd atom sharply changes the electronic structure of Pd atom in the Pd icosahedra. The protective function of PAH layers and enhanced antietching capability of Pd atom are responsible for the formation of the Pd icosahedra. Very importantly, the as-prepared PAH functionalized Pd icosahedra exhibit superior electrocatalytic activity and ethanol tolerant ability toward the oxygen reduction reaction (ORR) compared to the commercially available Pt black in alkaline media. At 0.95 V (vs RHE), the ORR specific kinetic current density at the Pd icosahedra is 4.48 times higher than that at commercial Pt black. The fact demonstrates the appropriate surface modification of the Pd nanoparticles by nonmetallic molecules can be regarded as an effective way to enhance the electrocatalytic activity toward the ORR. 23110522 Large-scale production of edge-selectively functionalized graphene nanoplatelets via ball milling and their use as metal-free electrocatalysts for oxygen reduction reaction. Edge-selectively functionalized graphene nanoplatelets (EFGnPs) with different functional groups were efficiently prepared simply by dry ball milling graphite in the presence of hydrogen, carbon dioxide, sulfur trioxide, or carbon dioxide/sulfur trioxide mixture. Upon exposure to air moisture, the resultant hydrogen- (HGnP), carboxylic acid- (CGnP), sulfonic acid- (SGnP), and carboxylic acid/sulfonic acid- (CSGnP) functionalized GnPs readily dispersed into various polar solvents, including neutral water. The resultant EFGnPs were then used as electrocatalysts for oxygen reduction reaction (ORR) in an alkaline electrolyte. It was found that the edge polar nature of the newly prepared EFGnPs without heteroatom doping into their basal plane played an important role in regulating the ORR efficiency with the electrocatalytic activity in the order of SGnP > CSGnP > CGnP > HGnP > pristine graphite. More importantly, the sulfur-containing SGnP and CSGnP were found to have a superior ORR performance to commercially available platinum-based electrocatalyst. 23322508 Copper tolerance and genetic diversity of Porcellionides sexfasciatus (ISOPODA) in a highly contaminated mine habitat. Organisms inhabiting metal-contaminated areas may develop metal tolerance, with either phenotypic adjustments or genetic changes (adaptation) or with both. In the present study, three populations of the terrestrial isopod Porcellionides sexfasciatus, collected at an abandoned mine area, were compared to assess the effects of metal contamination on tolerance to lethal and sublethal levels of copper, through comparison of survival, avoidance, and feeding. The effects of metal contamination on genetic diversity were considered using random amplified polymorphic DNA (RAPD) markers. No evidence of increased metal tolerance of the population inhabiting the contaminated site was found. There was no correlation between metal exposure and within-population genetic variance, but the three populations were clearly separated from each other. In conclusion, the populations of P. sexfasciatus in the mine landscape live rather isolated from each other and show no differential tolerance to Cu or indications of genetic erosion. Their phenotypic plasticity provides a means to survive despite exposure to extremely high metal concentrations in the soil. 23402211 Measuring in situ primary and competitive DNA hybridization activity on microspheres. Microspheres serve as convenient substrates for studying DNA activity on surfaces. Here, in addition to employing conventional sample preparation involving multiple wash and resuspension steps prior to flow cytometry measurements, we also directly sampled the reaction volume to acquire in situ measurements of primary and competitive hybridization events. Even in the absence of post hybridization wash steps, nonspecific binding events were negligible and thus allowed for direct, quantitative assessment of hybridization events as they occurred on colloidal surfaces. The in situ results indicate that primary duplex formation between immobilized probes and soluble targets on microsphere surfaces is less favorable than predicted by solution models. The kinetics of competitive displacement of primary hybridization partners by secondary targets measured in situ or post washing also deviate from expectations based on theoretical solution thermodynamics, but are consistent with predicted kinetic trends stemming from differences in either the toehold base length or branch migration. 23411252 A simple HPLC method for the comprehensive analysis of cis/trans (Z/E) geometrical isomers of carotenoids for nutritional studies. Geometrical isomers of carotenoids behave differently in aspects like stability towards oxidants, bioavailability, vitamin A activity and specificity for enzymes. The availability of HPLC methods for their detailed profiling is therefore advisable to expand our knowledge on their metabolism and biological role. In this paper the development of a methodology to determine the highest number of geometrical isomers of major carotenoids in humans (phytoene, phytofluene, lutein, zeaxanthin, β-cryptoxanthin, α-carotene, β-carotene and lycopene) is described. To assess its usefulness with biological samples both postprandial human plasma and lung samples from ferrets were analysed. Up to 48 isomers of the main human carotenoids were separated in 62 min. This is to the best of our knowledge the report of the highest number of carotenoid geometrical isomers separated with a HPLC method. Twenty-six different carotenoid isomers were readily detected in the biological samples. 22669363 Enzyme replacement therapy for mucopolysaccharidosis VI: long-term cardiac effects of galsulfase (Naglazyme®) therapy. Characteristic cardiac valve abnormalities and left ventricular hypertrophy are present in untreated patients with mucopolysaccharidosis type VI (MPS VI). Cardiac ultrasound was performed to investigate these findings in subjects during long-term enzyme replacement therapy (ERT) with recombinant human arylsulfatase B (rhASB, rhN-acetylgalactosamine 4-sulfatase, galsulfase, Naglazyme®). Studies were conducted in 54 subjects before ERT was begun and at specific intervals for up to 96 weeks of weekly infusions of rhASB at 1 mg/kg during phase 1/2, phase 2, and phase 3 trials of rhASB. At baseline, mitral and aortic valve obstruction was present and was significantly greater in those ≥12 years of age. Mild mitral and trace aortic regurgitation were present, the former being significantly greater in those <12 years. Left ventricular hypertrophy, with averaged z-scores ranging from 1.6-1.9 SD greater than normal, was present for ages both <12 and ≥12 years. After 96 weeks of ERT, ventricular septal hypertrophy regressed in those <12 years. For those ≥12 years, septal hypertrophy was unchanged, and aortic regurgitation increased statistically but not physiologically. Obstructive gradients across mitral and aortic valves remained unchanged. The results suggest that long-term ERT is effective in reducing intraventricular septal hypertrophy and preventing progression of cardiac valve abnormalities when administered to those <12 years of age. 23185990 Aminoacyl-tRNA Substrate and Enzyme Backbone Atoms Contribute to Translational Quality Control by YbaK. Amino acids are covalently attached to their corresponding transfer RNAs (tRNAs) by aminoacyl-tRNA synthetases. Proofreading mechanisms exist to ensure that high fidelity is maintained in this key step in protein synthesis. Prolyl-tRNA synthetase (ProRS) can misacylate cognate tRNA(Pro) with Ala and Cys. The cis-editing domain of ProRS (INS) hydrolyzes Ala-tRNA(Pro), whereas Cys-tRNA(Pro) is hydrolyzed by a single domain editing protein, YbaK, in trans. Previous studies have proposed a model of substrate-binding by bacterial YbaK and elucidated a substrate-assisted mechanism of catalysis. However, the microscopic steps in this mechanism have not been investigated. In this work, we carried out biochemical experiments together with a detailed hybrid quantum mechanics/molecular mechanics study to investigate the mechanism of catalysis by Escherichia coli YbaK. The results support a mechanism wherein cyclization of the substrate Cys results in cleavage of the Cys-tRNA ester bond. Protein side chains do not play a significant role in YbaK catalysis. Instead, protein backbone atoms play crucial roles in stabilizing the transition state, while the product is stabilized by the 2'-OH of the tRNA. 23464859 Utilizing the Unique Properties of Nanowire MOSFETs for RF Applications. Nanostructures have attracted a great deal of attention because of their potential usefulness for high density applications. More importantly, they offer excellent avenues for improved scaling beyond conventional approaches. Less attention has been paid to their intrinsic potential for distinct circuit applications. Here we discuss how a combination of 1-D transport, operation in the quantum capacitance limit, and ballistic transport can be utilized for certain RF applications. In particular this work explores how the above transport properties can provide a high degree of transconductance linearity at the device level. The article also discusses how device characteristics can be interpreted and analyzed in terms of device linearity if the above conditions are not ideally fulfilled. Using aggressively scaled silicon nanowire field-effect transistors as an example device in this work provides new insights toward the proper choice of channel material to improve linearity through the above-mentioned transport conditions. According to this study, a high degree of linearity occurs feasible while operating at low supply voltages making low-dimensional systems, and here in particular nanowires, an interesting candidate for portable RF applications. 23400748 An algorithm to detect adverse drug reactions in the neonatal intensive care unit. Critically ill newborns in neonatal intensive care units (NICUs) are at greater risk of developing adverse drug reactions (ADRs). Differentiation of ADRs from reactions associated with organ dysfunction/immaturity is difficult. Current ADR algorithm scoring was established arbitrarily without validation in infants. The study objective was to develop a valid and reliable algorithm to identify ADRs in the NICU. Algorithm development began with a 24-item questionnaire for data collection on 100 previously suspected ADRs. Five pediatric pharmacologists independently rated cases as definite, probable, possible, and unlikely ADRs. Consensus "gold standard" was reached via teleconference. Logistic regression and iterative C programs were used to derive the scoring system. For validation, 50 prospectively collected ADR cases were assessed by 3 clinicians using the new algorithm and the Naranjo algorithm. Weighted kappa and intraclass correlation coefficient (ICC) were used to compare validity and reliability of algorithms. The new algorithm consists of 13 items. Kappa and ICC of the new algorithm were 0.76 and 0.62 versus 0.31 and 0.43 for the Naranjo algorithm. The new algorithm developed using actual patient data is more valid and reliable than the Naranjo algorithm for identifying ADRs in the NICU population. Because of the relatively small and nonrandom samples, further refinement and additional testing are needed. 23526571 Discovery of a Series of Thiazole Derivatives as Novel Inhibitors of Metastatic Cancer Cell Migration and Invasion. Effective inhibitors of cancer cell migration and invasion can potentially lead to clinical applications as therapy to block tumor metastasis, the primary cause of death in cancer patients. To this end we have designed and synthesized a series of thiazole derivatives that showed potent efficacy against cell migration and invasion in metastatic cancer cells. The most effective compound, 5k, was found to have an IC50 value of 176 nM in the dose-dependent transwell migration assays in MDA-MB-231cells. At the dose of 10 μM, 5k also blocked about 80% of migration in HeLa and A549 cells and 60% of invasion of MDA-MB-231 cells. Importantly, the majority of the derivatives exhibited no apparent cytotoxicity in the clonogenic assays. The low to negligible inhibition of cell proliferation is a desirable property of these anti-migration derivatives because they hold promise of low toxicity to healthy cells as potential therapeutic agents. Mechanistic studies analyzing the actin cytoskeleton by microscopy demonstrate that compound 5k substantially reduced cellular f-actin, and prevented localization of fascin to actin-rich membrane protrusions. These results suggest that the anti-migration activity may result from impaired actin structures in protrusions that are necessary to drive migration. 23354072 Isolation and identification of β-hematin inhibitors from Flacourtia indica as promising antiplasmodial agents. An ethanolic extract (A001) of the leaves and twigs of Flacourtia indica (Burm.f.) Merr., was purified to give a new phenolic glycoside, 2-(2-benzoyl-β-D-glucopyranosyloxy)-7-(1α,2α,6α-trihydroxy-3-oxocyclohex-4-enoyl)-5-hydroxybenzyl alcohol (1) together with poliothrysoside (2), catechin-[5,6-e]-4β-(3,4-dihydroxyphenyl)dihydro-2(3H)-pyranone (3), 2-(6-benzoyl-β-D-glucopyranosyloxy)-7-(1α,2α,6α-trihydroxy-3-oxocyclohex-4-enoyl)-5-hydroxybenzyl alcohol (4), chrysoeriol-7-O-β-D-glucopyranoside (5), and mururin A (6). Compound 6 significantly inhibited the in vitro growth of both a chloroquine-sensitive (3D7) and a chloroquine-resistant (K1) strain of Plasmodium falciparum. It forms a complex with hematin and inhibits β-hematin formation, suggesting that this compound act on a heme polymerization target. 23202880 Observation of rates and products in the reaction of NO3 with submicron squalane and squalene aerosol. The reactive uptake coefficients γ, for nitrate radical, NO(3), on ∼100 nm diameter squalane and squalene aerosol were measured (1 atm pressure of N(2) and 293 K). For squalane, a branched alkane, γ(NO(3)) of 2.8 × 10(-3) was estimated. For squalene which contains 6 double bonds, γ(NO(3)) was found to be a function of degree of oxidation with an initial value of 0.18 ± 0.03 on fresh particles increasing to 0.82 ± 0.11 on average of over 3 NO(3) reactions per squalene molecule in the aerosol. Synchrotron VUV-ionization aerosol mass spectrometry was used to detect the particle phase oxidation products that include as many as 3 NO(3) subunits added to the squalene backbone. The fraction of squalene remaining in the aerosol follows first order kinetics under oxidation, even at very high oxidation equivalents, which suggests that the matrix remains a liquid upon oxidation. Our calculation indicates a much shorter chemical lifetime for squalene-like particle with respect to NO(3) than its atmospheric lifetime to deposition or wet removal. 23565754 Improved therapeutic targeting of the androgen receptor: rational drug design improves survival in castration-resistant prostate cancer. The growth and dependence of Prostate Cancer (PCa) on androgen stimulation led to the use of castration to reduce circulating levels of androgens and anti-androgens to directly target the androgen receptor (AR) ligand-binding domain (LBD). However, castration-resistant prostate cancer (CRPC) resistant to anti-androgens invariably develops and can be associated with AR genomic aberrations (mutations, amplification) and/or an increase in AR mRNA expression. Efforts to more effectively target the AR in CRPC led to the rational design of CYP17A1 inhibitors and more potent antiandrogens. The front-runner 2nd generation rationally-designed therapeutics targeting the AR, abiraterone and enzalutamide have been shown to improve survival and clinical outcome for CRPC patients. Several other CYP17A1 inhibitors and anti-androgens are in clinical and preclinical development. However, patients ultimately progress and current evidence suggests that this can occur through reactivation of AR signaling. Several ongoing programs aim to develop LBD independent therapeutic strategies that for example target the N terminus domain (NTD) of the AR or chaperone proteins. Rationally-designed approaches combining different strategies for targeting the AR or associated pathways also warrant clinical evaluation. 23628509 Cyclopenta[c]phenanthrenes - Chemistry and biological activity. Despite cyclopenta-fused polycyclic aromatic hydrocarbons (CP-PAHs) having been detected in the environment, the ability of these compounds to induce cellular and tissue responses remains poorly characterized. In this review, we look at the chemistry and biological activity of the cyclopenta[c]phenanthrenes (CP[c]Ph) as potential chemicals of concern in the process of risk assessment. The first part of the review deals with the environmental occurrence and chemistry of CP-PAHs, focusing on available methods of CP[c]Ph chemical synthesis. The most interesting structural feature of the CP[c]Ph is the presence of a pseudo fjord-region constructed by the cyclopentane ring. This compound can be treated either as a structurally similar one to B[c]Ph, or as a phenanthrene skeleton with an electrodonating alkyl substituent in the bay-region of the molecule. The second thread, providing available data on the adverse effects of CP[c]Ph compounds on cells and tissues of living organisms, mainly fish, improves our understanding of these possible environmental hazards. The data show that CP[c]Ph is less potent at inducing CYP1A gene expression in rainbow trout than benzo[a]pyrene (B[a]P), a well-known Ah-receptor agonist. Interestingly, the CP[c]Ph dependent up-regulation of CYP1A mRNA is positively correlated with the incidences of clastogenic changes in rainbow trout erythrocytes. CP[c]Ph has, comparably to B[a]P, a potential to repress expression of tumor suppressor p53, in the head kidney of rainbow trout. Furthermore, estrogen responsive genes in fish liver, ERα and VTG, are not induced by CP[c]Ph, suggesting that the compound has no endocrine disrupting potential. However, some CP[c]Phs show mutagenic activity when investigated in the Ames test, and exhibit genotoxic properties in in vitro micronucleus assay. The above characteristics suggest that CP-PAHs are chemicals of concern for which potential pathways of exposure should be further identified. 23317497 Recent progress in biological activities and synthetic methodologies of pyrroloquinoxalines. Pyrroloquinoxalines have proved to be a very attractive scaffold for medicinal chemist in the recent past. These compounds were extensively studied as bioactive compounds and many of them are known to be biologically and medicinally useful molecules, such as anti-HIV agents, antimalarial agents, antagonist agents, anticancer agents, and PARP-1 inhibitors. Additionally, pyrroloquinoxalines are also important intermediates for the construction of 5-HT3 receptor agonists. In this review the developments in biological activities and synthetic methodologies of pyrroloquinoxalines are discussed. 23400262 The importance of the TiO2/quantum dots interface in the recombination processes of quantum dot sensitized solar cells. Quantum dot sensitized solar cells (QDSSCs) present a promising technology for next generation photovoltaic cells, having exhibited a considerable leap in performance over the last few years. However, recombination processes occurring in parallel at the TiO(2)-QDs-electrolyte triple junction constitute one of the major limitations for further improvement of QDSSCs. Reaching higher conversion efficiencies necessitates gaining a better understanding of the mechanisms of charge recombination in these kinds of cells; this will essentially lead to the development of new solutions for inhibiting the described losses. In this study we have systematically examined the contribution of each interface formed at the triple junction to the recombination of the solar cell. We show that the recombination of electrons at the TiO(2)/QDs interface is as important as the recombination from TiO(2) and QDs to the electrolyte. By applying conformal MgO coating both above and below the QD surface, recombination rates were significantly reduced, and an improvement of more than 20% in cell efficiency was recorded. 23195329 Brain tumor immunotherapy: seeing the brain in the body. Brain tumor immunotherapy is often interpreted in terms of immune privilege and the blood-brain barrier (BBB), but a broader view is warranted. The delicate regulatory balance of the immune system is relevant at any site, as are the heterogeneity and plasticity of tumor growth. Criteria for tumor antigens, and often the antigens themselves, cut across tumor types. Here, this broader view, complemented by current understanding of privilege and the BBB, provides the context for review. Future success is likely to exploit simplified methods, used in combination; and similarities - more than differences - between the brain and other sites. 23631490 Green Tea Polyphenols Improve Bone Microarchitecture in High-Fat-Diet-Induced Obese Female Rats Through Suppressing Bone Formation and Erosion. Abstract This study evaluates the effects of green tea polyphenols (GTPs) on bone microarchitecture in high-fat-diet (HFD)-induced obese female rats. Thirty-six 3-month-old female rats were fed either a control diet or a HFD for 4 months. Animals in the control group continued on the control diet for another 4 months. Animals in the HFD group were divided into two groups, with 0.5 g/100 mL GTP (the HFD+GTP group) or without GTP (the HFD group) in drinking water, in addition to the HFD for another 4 months. Compared to the control group, the HFD group increased bone formation and erosion rates at the tibia, decreased trabecular volume and thickness, but had no impact on bone mineral density (BMD), trabecular number (Tb.N), and separation. Compared to the control group, the HFD+GTP group demonstrates a greater Tb.N at the proximal tibia, and a greater trabecular thickness at the femur and the lumbar vertebrae, but a smaller trabecular separation (Tb.Sp) and mineralizing surface at the proximal tibia, and a reduced endocortical mineral apposition rate (MAR) at the tibia shaft. Relative to the HFD group, the HFD+GTP group demonstrates (1) a higher BMD at the femur, a greater trabecular volume, thickness, and number at the proximal tibia, a larger cortical area and thickness at the tibial shaft, and a greater trabecular volume and thickness at the femur and the lumbar vertebrae, (2) a smaller Tb.Sp, MAR, bone formation rate, and eroded surface at the tibia. We concluded that GTP supplementation in drinking water improves bone microarchitecture in the HFD-induced obese female rats, possibly through suppressing bone turnover, resulting in a larger net bone volume. 23631499 Possible Therapeutic Uses of Salvia triloba and Piper nigrum in Alzheimer's Disease-Induced Rats. Abstract This study aimed to investigate the role of Salvia triloba L. and Piper nigrum extracts in ameliorating neuroinflammatory insults characteristic of Alzheimer's disease (AD) in an experimentally induced rat model. Adult male Sprague-Dawley rats were classified into Group 1 (n=10): normal healthy animals serving as the negative control group; Group 2 (n=60): the AD-induced group. After AD induction, animals in the AD-induced group were divided randomly and equally into 6 subgroups. The first subgroup served as AD control; the second one, which served as positive control, was treated orally with the conventional therapy for AD (rivastigmine) at a dose of 0.3 mg/kg body weight (b.w.) daily for 3 months. The third and fourth subgroups were, respectively, treated orally with the S. triloba extract at a dose of 750 and 375 mg/kg b.w. daily for 3 months. The fifth and sixth subgroups were, respectively, treated orally with the P. nigrum extract at a dose of 187.5 and 93.75 mg/kg b.w. daily for 3 months. Levels of brain acetylcholine (Ach), serum and brain acetylcholinesterase (AchE) activity, C-reactive protein (CRP), total nuclear factor kappa-B (NF-κB), and monocyte chemoattractant protein-1 (MCP-1) were estimated. The results showed that administration of AlCl3 resulted in a significant elevation in the levels of AchE activity, CRP, NF-κB, and MCP-1 accompanied with a significant depletion in the Ach level. Treatment of AD rats with each of the selected medicinal plant extracts caused marked improvement in the measured biochemical parameters. In conclusion, S. triloba and P. nigrum methanolic extracts have potent anti-inflammatory effects against neuroinflammation characterizing AD. 23093603 The Online Protein Processing Resource (TOPPR): a database and analysis platform for protein processing events. We here present The Online Protein Processing Resource (TOPPR; http://iomics.ugent.be/toppr/), an online database that contains thousands of published proteolytically processed sites in human and mouse proteins. These cleavage events were identified with COmbinded FRActional DIagonal Chromatography proteomics technologies, and the resulting database is provided with full data provenance. Indeed, TOPPR provides an interactive visual display of the actual fragmentation mass spectrum that led to each identification of a reported processed site, complete with fragment ion annotations and search engine scores. Apart from warehousing and disseminating these data in an intuitive manner, TOPPR also provides an online analysis platform, including methods to analyze protease specificity and substrate-centric analyses. Concretely, TOPPR supports three ways to retrieve data: (i) the retrieval of all substrates for one or more cellular stimuli or assays; (ii) a substrate search by UniProtKB/Swiss-Prot accession number, entry name or description; and (iii) a motif search that retrieves substrates matching a user-defined protease specificity profile. The analysis of the substrates is supported through the presence of a variety of annotations, including predicted secondary structure, known domains and experimentally obtained 3D structure where available. Across substrates, substrate orthologs and conserved sequence stretches can also be shown, with iceLogo visualization provided for the latter. 23109233 Modeling toxicity of binary metal mixtures (Cu(2+) -Ag(+) , Cu(2+) -Zn(2+) ) to lettuce, Lactuca sativa, with the biotic ligand model. The biotic ligand model (BLM) was applied to predict metal toxicity to lettuce, Lactuca sativa. Cu(2+) had the lowest median effective activity (EA50(M) ), compared with Ag(+) and Zn(2+) (EA50(Cu)  = 2.60 × 10(-8) M, EA50(Ag) = 1.34 × 10(-7)  M, EA50(Zn) = 1.06 × 10(-4)  M). At the 50% response level, the fraction of the total number of biotic ligands occupied by ions (f50(M) ) was lowest for Ag(+) among the metals (f50(Ag) = 0.22, f50(Cu) = 0.36, f50(Zn) = 0.42). Cu(2+) had the highest affinity for biotic ligands compared with Ag(+) and Zn(2+) , as shown by stability constants of the cation-biotic ligand binding, expressed as log K(MBL) (log K(CuBL) = 7.40, log K(AgBL) = 6.39, log K(ZnBL) = 4.00). Furthermore, the BLM was combined with the toxic equivalency factor approach in predicting toxicity of mixtures of Cu(2+) -Zn(2+) and Cu(2+) -Ag(+) . The fraction of biotic ligands occupied by ions was used to determine the relative toxic potency of metals and the toxic equivalency quotient (TEQ) of mixtures. This approach allowed for including interactions in estimating mixture toxicity and showed good predictive power (r(2) = 0.64-0.84). The TEQ at the 50% response level (TEQ50, Cu(2+) equivalents) for Cu(2+) -Zn(2+) mixtures was significantly lower than the value for Cu(2+) -Ag(+) mixtures. Joint toxicity depended on both TEQ and specific composition of the mixture. The present study supports the use of the accumulation of metal ions at the biotic ligands as a predictor of toxicity of single metals and mixtures. 23041228 Pim kinases in cancer: diagnostic, prognostic and treatment opportunities. PIM proteins belong to a family of ser/thr kinases composed of 3 members, PIM1, PIM2 and PIM3, with greatly overlapping functions. PIM kinases are mainly responsible for cell cycle regulation, antiapoptotic activity and the homing and migration of receptor tyrosine kinases mediated via the JAK/STAT pathway. PIM kinases have been found to be upregulated in many hematological malignancies and solid tumors. Although these kinases have been described as weak oncogenes, they are heavily targeted for anticancer drug discovery. The present review summarizes the discoveries made to date regarding PIM kinases as driving oncogenes in the process of tumorigenesis and their validation as drug targets. 23479193 Synthesis and in-silico studies of some diaryltriazole derivatives as potential cyclooxygenase inhibitors. The synthesis of several 4-phenyl-5-pyridin-4-yl-2,3-dihydro-3H-1,2,4-triazole-3-thiones possessing N-2 Mannich bases or S-alkyl substituents, is reported. Several of them exhibited a low nanomolar COX enzyme inhibition activity. Most of the compounds showed inhibition of edema was similar to that evoked by celocoxib in animal model. Molecular docking studies of the compounds into the binding sites of COX-1 and COX-2 allowed us to shed light on the binding mode of these novel COX inhibitors. 23373648 Recent advancements in small molecule inhibitors of insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase as anticancer agents. Advancements in understanding of the genetics, genomics, biochemistry and the pharmacology of cancer inhuman, have driven the current cancer chemotherapy to intently focus on development of target-based approaches rather than conventional approaches. From among the various targets identified, validated and inhibited at different hallmarks of cancer, protein tyrosine kinases (PTKs) have been exploited the most. Insulin receptors (IRs), insulin like growth factor receptors (IGF-1R) and their hybrid receptors belong to tyrosine kinase receptor (TKR) family, constitute a structural homology among them and generate a growth promoting IGF system on binding with either insulin, IGF-1 or IGF-2. The system induces the mitogenic effects through a torrent of cell signals produced as a result of cross talk with other growth promoting peptides and steroidal hormones, ultimately resulting in hijacking apoptosis and increasing cell proliferation and cell survival in cancer cells. Various strategies such as anti-IGF-1R antibodies, IGF-1 mimetic peptides, antisense strategies, IGF-1R specific peptide aptamers, targeted degradation of IGF-1R and expression of dominant negative IGF-1R mutants have been explored to inhibit the IGF-1R signaling. However, targeting IGF-1R with small molecules has gained considerable attention in last few years due to their ease of synthesis, ease of optimization of absorption,distribution, metabolism, excretion and toxicity (ADMET) parameters, oral route of administration, lesser side effects and cost effectiveness. The present review provides a broad overview and discusses the highlights on discoveries, SAR studies and binding interactions of small molecules with either IGF-1R active or allosteric sites reported till date. 23260352 Novel in vivo active anti-malarials based on a hydroxy-ethyl-amine scaffold. A novel series of anti-malarials, based on a hydroxy-ethyl-amine scaffold, initially identified as peptidomimetic protease inhibitors is described. Combination of the hydroxy-ethyl-amine anti-malarial phramacophore with the known Mannich base pharmacophore of amodiaquine (57) resulted in promising in vivo active novel derivatives. 23151612 A review of anti-inflammatory agents for symptoms of schizophrenia. Schizophrenia is a chronic debilitating mental disorder that affects about 1% of the US population. The pathophysiology and etiology remain unknown, thus new treatment targets have been challenging and few novel treatments with new mechanisms of action have come to market in the past few decades. Increasing attention has been paid to the role of inflammation in schizophrenia and new data suggests that decreasing inflammation and inflammatory biomarkers may play some role in schizophrenia treatment. This review summarizes the clinical trial literature regarding medications that possess anti-inflammatory properties that have been tested for schizophrenia symptoms and covers such medications as non-steroidal anti-inflammatory agents, such as the cyclo-oxygenase-2 (COX-2) inhibitors and aspirin, omega-3 fatty acids, neurosteroids and minocycline. Overall, there is accumulating evidence, albeit mostly adjunctive treatments, that agents working on inflammatory pathways have some benefits in people with schizophrenia. In the next few years the field will begin to see data on many treatments with anti-inflammatory properties that are currently under study. Hopefully advancements in understanding inflammation and effective treatments having anti-inflammatory properties may help revolutionize our understanding and provide new targets for prevention and treatment in schizophrenia. 23334979 Characterization of osteoblastic and osteolytic proteins in prostate cancer bone metastases. BACKGROUND: Approximately 90% of patients who die of Prostate Cancer (PCa) have bone metastases, which promote a spectrum of osteoblastic, osteolytic or mixed bone responses. Numerous secreted proteins have been reported to promote osteoblastic or osteolytic bone responses. We determined whether previously identified and/or novel proteins were associated with the osteoblastic or osteolytic response in clinical specimens of PCa bone metastases. METHODS: Gene expression was analyzed on 14 PCa metastases from 11 patients by microarray profiling and qRT-PCR, and protein expression was analyzed on 33 PCa metastases from 30 patients by immunohistochemistry on highly osteoblastic and highly osteolytic bone specimens. RESULTS: Transcript and protein levels of BMP-2, BMP-7, DKK-1, ET-1, and Sclerostin were not significantly different between osteoblastic and osteolytic metastases. However, levels of OPG, PGK1, and Substance P proteins were increased in osteoblastic samples. In addition, Emu1, MMP-12, and sFRP-1 were proteins identified with a novel role of being associated with either the osteoblastic or osteolytic bone response. CONCLUSIONS: This is the first detailed analysis of bone remodeling proteins in human specimens of PCa bone metastases. Three proteins not previously shown to be involved may have a role in the PCa bone response. Furthermore, our data suggests that the relative expression of numerous, rather than a single, bone remodeling proteins determine the bone response in PCa bone metastases. Prostate © 2013 Wiley Periodicals, Inc. 23523781 Pharmacokinetic, neurochemical, stereological and neuropathological studies on the potential effects of paraquat in the substantia nigra pars compacta and striatum of male C57BL/6J mice. The pharmacokinetics and neurotoxicity of paraquat dichloride (PQ) were assessed following once weekly administration to C57BL/6J male mice by intraperitoneal injection for 1, 2 or 3 weeks at doses of 10, 15 or 25mg/kg/week. Approximately 0.3% of the administered dose was taken up by the brain and was slowly eliminated, with a half-life of approximately 3 weeks. PQ did not alter the concentration of dopamine (DA), homovanillic acid (HVA) or 3,4-dihydroxyphenylacetic acid (DOPAC), or increase dopamine turnover in the striatum. There was inconsistent stereological evidence of a loss of DA neurons, as identified by chromogenic or fluorescent-tagged antibodies to tyrosine hydroxylase in the substantia nigra pars compacta (SNpc). There was no evidence that PQ induced neuronal degeneration in the SNpc or degenerating neuronal processes in the striatum, as indicated by the absence of uptake of silver stain or reduced immunolabeling of tyrosine-hydroxylase-positive (TH(+)) neurons. There was no evidence of apoptotic cell death, which was evaluated using TUNEL or caspase 3 assays. Microglia (IBA-1 immunoreactivity) and astrocytes (GFAP immunoreactivity) were not activated in PQ-treated mice 4, 8, 16, 24, 48, 96 or 168h after 1, 2 or 3 doses of PQ. In contrast, mice dosed with the positive control substance, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 10mg/kg/dose×4 doses, 2h apart), displayed significantly reduced DA and DOPAC concentrations and increased DA turnover in the striatum 7 days after dosing. The number of TH(+) neurons in the SNpc was reduced, and there were increased numbers of degenerating neurons and neuronal processes in the SNpc and striatum. MPTP-mediated cell death was not attributed to apoptosis. MPTP activated microglia and astrocytes within 4h of the last dose, reaching a peak within 48h. The microglial response ended by 96h in the SNpc, but the astrocytic response continued through 168h in the striatum. These results bring into question previous published stereological studies that report loss of TH(+) neurons in the SNpc of PQ-treated mice. This study also suggests that even if the reduction in TH(+) neurons reported by others occurs in PQ-treated mice, this apparent phenotypic change is unaccompanied by neuronal cell death or by modification of dopamine levels in the striatum. 23205571 Design, synthesis and structure-activity relationship of new arginine vasopressin analogues containing proline derivatives in position 2. In this study, we present the synthesis and pharmacological properties of new analogues of arginine vasopressin modified in the N-terminal part of the molecule with proline derivatives: indoline-2-carboxylic acid (Ica) and (2S,4R)-4-(naphthalene-2-ylmethyl)pyrrolidine-2-carboxylic acid. All the peptides were tested for pressor, antidiuretic and in vitro uterotonic activities. We also determined their binding affinity to the human oxytocin receptor. The Ica(2) substitution resulted in two moderately potent and selective antioxytocic agents: [Mpa(1), Ica(2), D-Arg(8)]VP and [Mpa(1),Ica(2),Val(4),D-Arg(8)]VP (pA(2) = 7.09 and 7.50, respectively). On the other hand, peptides modified with (2S,4R)-4-(naphthalene-2-ylmethyl)pyrrolidine-2-carboxylic acid, apart from their moderate antioxytocic activity, turned out to be weak antagonists of the pressor response to arginine vasopressin. The results of this study provide useful information about the structure-activity relationship of arginine vasopressin analogues and can help to design compounds with desired biological properties. 23360392 Elucidation of the Molecular Interaction between Cisplatin and Flavonol(s) and their Effect on DNA Binding. Combination therapy of cisplatin with flavonols is a promising treatment for increasing the efficacy of cisplatin when combating cancer. However, little is known about the molecular interactions between cisplatin and flavonols. The data herein helps to elucidate this interaction. Spectrophotometric data in the UV-visible range indicates that hydroxyl groups on the B-ring of flavonols are essential for reactivity with cisplatin. The use of a quartz crystal microbalance with dissipation monitoring approach clearly supports the critical role played by B-ring hydroxyls in their interactions with a cisplatin-bound double-stranded DNA surface; an increase in the number of hydroxyl groups on the B-ring of flavonols parallels the increase in their reaction rates with cisplatin and correlates well with their reported effects on leukemia cell apoptosis efficacy. This study underscores the importance of B-ring hydroxyls in cisplatin's toxicity and may be used to better understand and improve combination therapies of flavonols with cisplatin. 23544667 Self-Assembling Behavior of Cellulose Nanoparticles during Freeze-Drying: Effect of Suspension Concentration, Particle Size, Crystal Structure, and Surface Charge. Cellulose nanocrystals and cellulose nanofibers with I and II crystalline allomorphs (designated as CNC I, CNC II, CNF I, and CNF II) were isolated from bleached wood fibers by alkaline pretreatment and acid hydrolysis. The effects of concentration, particle size, surface charge, and crystal structure on the lyophilization-induced self-assembly of cellulose particles in aqueous suspensions were studied. Within the concentration range of 0.5 to 1.0 wt %, cellulose particles self-organized into lamellar structured foam composed of aligned membrane layers with widths between 0.5 and 3 μm. At 0.05 wt %, CNC I, CNF I, CNC II, and CNF II self-assembled into oriented ultrafine fibers with mean diameters of 0.57, 1.02, 1.50, and 1.00 μm, respectively. The size of self-assembled fibers became larger when more hydroxyl groups and fewer sulfates (weaker electrostatic repulsion) were on cellulose surfaces. Possible formation mechanism was inferred from ice growth and interaction between cellulose nanoparticles in liquid-crystalline suspensions. 23357434 Genetic risk factors for glucocorticoid-induced osteonecrosis: a meta-analysis. Glucocorticoid-induced osteonecrosis is a common and severe adverse event. We conducted a meta-analysis to investigate whether polymorphisms in target genes were associated with the risk of corticosteroid-induced osteonecrosis. Published literature from PubMed and EMBASE were searched for eligible publications. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a fixed- or random-effects model. There were 23 articles with 35 genes described the relationship between polymorphisms and glucocorticoid-induced osteonecrosis. Meta-analyses were carried out for those SNPs with three or more eligible studies, which included four SNPs located in three genes (PAI-1, MTHFR, ABCB1). The meta-analysis revealed that the PAI-1 4G allele was associated with an increased risk of osteonecrosis compared with the 5G allele (combined studies: OR=1.932, 95% CI=1.145-3.261). The OR for the 4G/4G vs. 5G/5G genotype of PAI-1 was 3.217 (95% CI 1.667-6.209 with combined studies), The relative risk of osteonecrosis was increased in the 4G allele vs. 5G/5G and 4G/4G genotype vs. 5G allele, with odds ratios of 2.304 (95% CI=1.235-4.299) and 2.307 (95% CI=1.527-3.485) in combined studies, respectively. The ABCB1 C3435T genotype distributions available confirmed that the C allele increased osteonecrosis risk compared with the T allele (OR 1.668, 95% CI=1.214-2.293) and TT genotype (OR 2.946, 95% CI=1.422-6.101). There was no evidence for significant association between MTHFR C677T and ABCB1 G2677T/A polymorphisms and risk of osteonecrosis. Results of this meta-analysis indicate that the PAI-1 4G/5G and ABCB1 C3435T polymorphisms may be risk factors for osteonecrosis. 23411306 Determination of seven synthetic dyes in animal feeds and meat by high performance liquid chromatography with diode array and tandem mass detectors. An efficient method was developed for the simultaneous determination of seven commonly used synthetic sulfonate dyes (Ponceau 4RC, Sunset yellow, Allura red, Azophloxine, Ponceau xylidine, Erythrosine and Orange II) in animal feed and meat using high performance liquid chromatography (HPLC-DAD) and tandem mass spectrometry (HPLC-MS/MS). Ethanol-ammonia-water (80:1:19, V/V/V) solution was used as extract solution, which can extract target species while reducing interference from the sample matrices. The recoveries of these 7 dyes in animal feed and chicken meat were between 71% and 97% with relative standard deviations less than 14.8%. HPLC-MS/MS was employed as a further means of confirmation to assure accuracy of the results. Limits of detection for these dyes were in the range of 0.02-21.83 ng mL(-1). The proposed method can be applied to confirmative screening of seven commonly used food colorants in feed and meat samples. 23287710 Dose dependent molecular effects of acrylamide and glycidamide in human cancer cell lines and human primary hepatocytes. Recently published studies suggest a weak positive correlation between increased dietary acrylamide intake and the increased risk of endometrial and ovarian cancer. However, risk assessment of acrylamide remains difficult because the carcinogenic mechanisms are still unknown and in particular the molecular effects of low level acrylamide exposure as seen by dietary intake are not well understood. Therefore, we analyzed in ovarian and endometrial cancer cell lines as well as in primary hepatocytes the expression of genes involved in cancer development and xenobiotic metabolism after high and low dose exposure (1-0.001mM) of acrylamide and its metabolite glycidamide. In conclusion our in vitro results demonstrate that exposure to high doses of glycidamide/acrylamide - exceeding the dietary exposure of the general population by far - can induce genes with growth promoting potential like the oncogene cMYC and genes involved in the MAPK pathway. However, low-dose exposure seems to activate primarily genes involved in the elimination of the toxicant. 23297755 Isolation and anti-HIV-1 activity of a new sesquiterpene lactone from Calocephalus brownii F. Muell. As part of our ongoing collaborative effort to discover potential anti-HIV-1 agents from plants, the CH(2)Cl(2) extract of Calocephalus brownii F. Muell. was phytochemically investigated, which resulted in the isolation of two sesquiterpene lactones of the cis-fused guaianolides type, one new identified as 1α-hydroxy-3βH-3α,4α-epoxy-4,10-dimethyl-5αH,7αH,8βH,10αH-guai-11(13)-ene-7,8-olide (1) and one known identified 1αH-4α-hydroxy-4,10-dimethyl-5αH,7αH,8βH,10αH-guai-11(13)-ene-7,8-olide (2). Their structures were elucidated on the bases of IR, UV, 1D-NMR, 2D-NMR, DIFNOE and high-resolution ESI-TOF-MS. The anti-HIV-1 activity was evaluated and revealed that STLs (1 and 2) caused a reduction for the viability of mock-infected MT-4 cells by CC(50) = 29.1 and 0.5 μg/mL, respectively, and caused 50% protection of MT-4 cells against HIV-1 induced cytopathogeneticy by EC(50) = 29.1 and 0.5 μg/mL, respectively, as compared with Efavirenz (EFV) as positive control that showed a CC(50) = 11.6 and EC(50) = 0.0006 μg/mL, using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide method. 23135548 Dioxin inhibits zebrafish epicardium and proepicardium development. Embryonic exposure to the environmental contaminant and aryl hydrocarbon receptor agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin), disrupts cardiac development and function in fish, birds, and mammals. In zebrafish, the temporal window of sensitivity to the cardiotoxic effects of TCDD coincides with epicardium formation. We hypothesized that this TCDD-induced heart failure results from disruption of epicardial development. To determine whether embryonic TCDD exposure inhibits epicardium and proepicardium (PE) development in zebrafish, we used histology and fluorescence immunocytochemistry to examine the epicardium formation in fish exposed to TCDD. TCDD exposure prevented epicardium formation. Using live imaging and in situ hybridization, we found that TCDD exposure blocked the formation of the PE cluster. In situ hybridization experiments showed that TCDD exposure also prevented the expression of the PE marker tcf21 at the site where the PE normally forms. TCDD also inhibited expansion of the epicardial layer across the developing heart: Exposure after PE formation was completed prevented further expansion of the epicardium. However, TCDD exposure did not affect epicardial cells already present. Because TCDD blocks epicardium formation, but is not directly toxic to the epicardium once complete, we propose that inhibition of epicardium formation can account for the window of sensitivity to TCDD cardiotoxicity in developing zebrafish. Epicardium development is crucial to heart development. Loss of this layer during development may account for most if not all of the TCDD-induced cardiotoxicity in zebrafish. 23256510 Morphology-dependent trap formation in bulk heterojunction photodiodes. We show that local structural variation affects the rate of aging in nanostructured polymer solar cells by comparing time-resolved electrostatic force microscopy (trEFM) and conventional device measurements on model polymer blends. Specifically, we study photovoltaic devices made from 1:1 blends of the polyfluorene copolymers poly(9,9'-dioctylfluorene-co-bis-N,N'-(4-butylphenyl)-bis-N,N'-phenyl-1,4-phenylene-diamine) (PFB) and poly(9,9'-dioctylfluorene-co-benzothiadiazole) (F8BT). We photooxidize these films in situ using 365, 405, and 455 nm illumination under ambient conditions, with the wavelengths chosen to preferentially excite the different components. During photooxidation, we observe a faster loss of photocurrent generation from F8BT-rich domains, leaving the PFB-rich phases to show higher photoresponse even at wavelengths absorbed predominantly by F8BT. We propose that this effect is due to the more rapid degradation of PFB hole-transport pathways in the F8BT-rich regions, resulting in a loss of percolation pathways for hole transport in the F8BT-rich phase. 23594299 Automated actuation of nasal spray products: effect of hand-related variability on the in vitro performance of Flonase nasal spray. Abstract Objective: To determine if patient-related variability for adults and children recorded during hand spraying of Flonase with an instrumented nasal spray results in significant differences in spray weight, droplet size or spray pattern. Methods: Settings derived from adult and pediatric participants hand-spraying nasal sprays were implemented into force and velocity-controlled automated actuators. Spray weight, droplet size distribution and spray pattern tests were performed using iterations of actuation force (AF) and force rise, hold and fall times. Travel, actuation velocity and release velocity settings were also investigated. Results: The variability measured in adult-derived actuator settings did not result in any differences in spray weight, but pediatric participants spraying with low AF and/or compression velocity (CV) were predicted to receive a partial dose or no dose at all under some circumstances. Droplet size characteristics were sensitive to the hand-based variability, with actuation force, force rise time and CV hand-related settings all resulting in significant differences in the droplet size. Conclusions: This study demonstrated how variability in hand spraying by adults and pediatric patients could result in differences in nasal spray characteristics, thus demonstrating the importance of monitoring how the prospective patient groups are likely to use a nasal spray. 23401106 Modeling environmental and human health risks of veterinary medicinal products applied in pond aquaculture. A model called ERA-AQUA was developed to assess the risks posed by the use of veterinary medicinal products (VMPs) applied in aquaculture ponds for the targeted produce, surrounding aquatic ecosystems, consumers, and trade of the aquaculture produce. The model calculates risks by following a risk quotient approach, calculating predicted exposure concentrations (exposure assessment) and predicted no-effect concentrations (effect assessment) for the endpoint under study. The exposure assessment is performed by combining information on the environmental characteristics of the aquaculture pond, characteristics of the cultured species, aquaculture management practices, and physicochemical properties of the compound under study. The model predicts concentrations of VMPs in the pond water, pond sediment, cultured species, and watercourse receiving pond effluent discharges by mass balance equations. The effect assessment is performed by combining (eco)toxicological information and food safety threshold concentrations for the studied compound. In the present study, the scientific background, strengths, and limitations of the ERA-AQUA model are presented together with a sensitivity analysis and an example showing its potential applications. Environ. Toxicol. Chem. 2013;32:1196-1207. © 2013 SETAC. 23614368 Intestinal bacterial transformation - a nonnegligible part of Chinese medicine research. Intestinal bacteria play an essential part in the metabolism of the constituents of herbal drugs, and a lot of investigations have been done to unveil their functions and mechanisms in modification of these constituents and their effect. This review provides a progressive description of intestinal bacterial transformation with respect to properties, reactions, correlation with the effect of herbal drugs, research interests, and methodology. In addition, the problems encountered during the investigation are addressed and perspectives are proposed. 23111884 Estimation of BDNF gene polymorphism and predisposition to dependence development for selected psychoactive compounds: genetic aspects of addiction with the selected drugs, amphetamine, tetrahydrocannabinol and opiates. The etiology of drug addiction, a central nervous system (CNS) disease, is not fully known. This complex problem is believed to be connected with concurrently affecting genetic, psychological and environmental factors. The development of addiction is connected with CNS reinforcement system and dopaminergic neurotransmission. Molecular processes are postulated to be of universal character and allow to presume a similar mechanism of dependence for both ethanol and other substances. Therefore, elements of dopaminergic transmission become excellent candidates for the examination of genetic influence on the development of addiction. A relationship between alcoholic disease and the presence of TaqIA1 and DRD2 alleles permits to initiate another investigation of gene-coding DRD2 dopamine receptor. The latest results indicate the importance of brain-derived neurotrophic factor (BDNF) in the regulation of dopaminergic route. The purpose of this research was to reveal the relationship between the Val66Met BDNF gene polymorphism and dependence of psychoactive agent. The examinations were performed with the Local Research Ethics Committee approval and patient's consent. The study group consisted of 100 patients (88 men and 12 women) aged 18-52 years, qualified for research program according to the International Classification of Diseases, Tenth Revision (ICD-10) requirements, medical examination and detailed questionnaire. 23525330 State-Dependent Etomidate Occupancy of its Allosteric Agonist Sites Measured in a Cysteine-Substituted GABAA Receptor. A central axiom of ligand-receptor theory is that agonists bind more tightly to active than to inactive receptors. However, measuring agonist affinity in inactive receptors is confounded by concomitant activation. We identified a cysteine substituted mutant GABAA receptor with unique characteristics allowing determination of allosteric agonist site occupancy in both inactive and active receptors. Etomidate, the allosteric agonist, is an anesthetic that activates/modulates α1β2γ2L GABAA receptors via transmembrane sites near β2M286 residues in M3 domains. Voltage-clamp electrophysiology studies of α1β2M286Cγ2L receptors show that GABA is an efficacious agonist, and etomidate modulates GABA-activated activity, but direct etomidate agonism is absent. Quantitative analysis of mutant activity using an established Monod-Wyman-Changeux (MWC) allosteric model indicates that the intrinsic efficacy of etomidate, defined as its relative affinity for active vs. inactive receptors, is lower than in wild-type receptors. Para-chloromercuribenzene sulfonate (pCMBS) covalently modifies β2M286C sidechain sulfhydryls, irreversibly altering GABA-induced currents. Etomidate concentration-dependently reduces the apparent rate of β2M286C-pCMBS bond formation, tracked electrophysiologically. High etomidate concentrations completely protect the β2M286C suflhydryl from covalent modification, suggesting close steric interactions. The 50% protective etomidate concentration (PC50) is 14 μM in inactive receptors and 1.1 to 2.2 μM during GABA-activation, experimentally demonstrating that activated receptors bind etomidate more avidly than inactive receptors. The experimental PC50 values are remarkably close to, and therefore validate MWC model predictions for etomidate dissociation constants in both inactive and active receptors. Our results support MWC models as valid frameworks for understanding agonism, co-agonism, and modulation of ligand-gated ion channels. 22760156 Anion binding in water at lanthanide centres: from structure and selectivity to signalling and sensing. Reversible anion binding at lanthanide centres in aqueous media has emerged as an effective means of signalling and sensing the presence of selected anions. The constitution and configuration of a wide range of anion adducts has been defined by X-ray analyses and NMR methods, and both chelating and monodentate binding modes characterised. Variation of the lanthanide ion modulates charge density, and ligand modification allows alteration of both the peripheral electrostatic gradient and the local steric demand at the metal centre. Thus, selectivity for a target anion can be engineered, and the affinity constant modulated to target the desired concentration range. Changes in anion concentration can be monitored rapidly, accurately and with high spatial resolution using optical emission spectroscopy and microscopy, facilitating the measurement of anions such as bicarbonate, lactate, citrate and urate in a variety of bio-fluids. 23393209 Determinants of Maternal Triglycerides in Women With Gestational Diabetes Mellitus in the Metformin in Gestational Diabetes (MiG) Study. OBJECTIVEFactors associated with increasing maternal triglyceride concentrations in late pregnancy include gestational age, obesity, preeclampsia, and altered glucose metabolism. In a subgroup of women in the Metformin in Gestational Diabetes (MiG) trial, maternal plasma triglycerides increased more between enrollment (30 weeks) and 36 weeks in those treated with metformin compared with insulin. The aim of this study was to explain this finding by examining factors potentially related to triglycerides in these women.RESEARCH DESIGN AND METHODSOf the 733 women randomized to metformin or insulin in the MiG trial, 432 (219 metformin and 213 insulin) had fasting plasma triglycerides measured at enrollment and at 36 weeks. Factors associated with maternal triglycerides were assessed using general linear modeling.RESULTSMean plasma triglyceride concentrations were 2.43 (95% CI 2.35-2.51) mmol/L at enrollment. Triglycerides were higher at 36 weeks in women randomized to metformin (2.94 [2.80-3.08] mmol/L; +23.13% [18.72-27.53%]) than insulin (2.65 [2.54-2.77] mmol/L, P = 0.002; +14.36% [10.91-17.82%], P = 0.002). At 36 weeks, triglycerides were associated with HbA1c (P = 0.03), ethnicity (P = 0.001), and treatment allocation (P = 0.005). In insulin-treated women, 36-week triglycerides were associated with 36-week HbA1c (P = 0.02), and in metformin-treated women, they were related to ethnicity.CONCLUSIONSAt 36 weeks, maternal triglycerides were related to glucose control in women treated with insulin and ethnicity in women treated with metformin. Whether there are ethnicity-related dietary changes or differences in metformin response that alter the relationship between glucose control and triglycerides requires further study. 23500115 Characterization and skin permeation of ketoprofen loaded vesicular systems. PURPOSE: To determine the effect of elasticity on the skin permeation of ketoprofen from surfactant-based vesicular formulations and elastic liposomes. METHODS: Ketoprofen loaded surfactant-based vesicles and elastic liposomes were prepared by sonication. Citric buffer (at pH 3.0) was used as rehydration buffer. Characterization studies of the prepared liposomal formulations were performed by dynamic light scattering, extrusion, and (1)H and (31)P-nuclear magnetic resonance (NMR) spectroscopy. Ketoprofen transport studies across human skin were performed for all formulations. RESULTS: Stable ketoprofen loaded formulations were prepared. Addition of an edge activator, in the absence of the drug, increased the elasticity of the vesicles and liposomes. Ketoprofen loading reduced the elasticity of the liposomes and surfactant-based-vesicles. However, at saturation the elasticity was still higher than that in the absence of the edge activator and ketoprofen, except for ketoprofen loaded liposomes with Span 80. NMR studies revealed that the ketoprofen molecules were entrapped in a vesicle bilayer in all vesicular formulations, and that the ketoprofen molecules affected the phosphate mobility in the liposomal formulations. Ketoprofen transport studies across human skin clearly showed that the surfactant-based vesicular formulations were superior to the elastic liposomal formulations. CONCLUSION: Surfactant-based vesicles enhance ketoprofen transport across human skin, while no enhancement of ketoprofen was observed when loaded in elastic liposomes. 23424212 Resveratrol ameliorates methotrexate-induced hepatotoxicity in rats via inhibition of lipid peroxidation. Hepatotoxicity is one of the major complications of methotrexate (MTX) therapy. This study was carried out to evaluate the possible protective effect of resveratrol (trans-3,5,4'-trihydroxystilbene, RVT) against MTX-induced hepatotoxicity. Rats were randomly divided into four groups as control, MTX treated (7 mg/kg/day, intraperitoneally (i.p.), once daily for 3 consecutive days), MTX + RVT treated (20 mg/kg/day, i.p.), and RVT treated. First dose of RVT was administrated 3 days before the MTX injection and continued for 3 days. Histopathology of liver was evaluated by light microscopy. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) were used as biochemical markers of MTX-induced hepatic injury. The levels of thiobarbituric acid reactive substances (TBARS, a marker of lipid peroxidation) and activities of hepatic antioxidant enzymes such as catalase (CAT) and glutathione-S-transferase (GST) were used to analyze the oxidative stress-mediated lipid peroxidation in liver sections. Our results showed that MTX administration significantly increased ALT, ASP, and ALP levels. TBARS, CAT, and GST levels were also markedly increased in liver after MTX administration. RVT treatment significantly prevented MTX-induced hepatotoxicity, as indicated by AST, ALT, and ALP levels and liver histopathology. Moreover, administration of RVT significantly decreased the elevated levels of TBARS and activities of CAT and GST in the liver compared to MTX-treated group. These results revealed that RVT may have a protective effect against MTX-induced hepatotoxicity by inhibiting oxidative stress-mediated lipid peroxidation. Consequently, RVT treatment might be a promising strategy against MTX-induced hepatotoxicity. 23576378 Design, Synthesis, and Antibacterial Activity of Demethylvancomycin Analogues against Drug-Resistant Bacteria. Five novel N-substituted demethylvancomycin derivatives were rationally designed and synthesized by using a structure-based approach. The in vitro antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA), gentamicin-resistant Enterococcus faecalis (GRE), methicillin-resistant Streptococcus pneumoniae (MRS), and vancomycin-resistant Enterococcus faecalis (VRE) were evaluated. One of the compounds, N-(6-phenylheptyl)demethylvancomycin (12 a), was found to exhibit more potent antibacterial activity than vancomycin and demethylvancomycin. Compound 12 a was also found to be ~18-fold more efficacious than vancomycin against MRSA; however, the two compounds were found to have similar efficacy against MRS. Furthermore, compound 12 a exhibited a favorable pharmacokinetic profile with a half-life of 5.11±0.52 h, which is longer than that of vancomycin (4.3±1.9 h). These results suggest that 12 a is a promising antibacterial drug candidate for further preclinical evaluation. 23261644 A comparative performance test of standard, medium- and high-throughput comet assays. A serious limitation of the conventional comet assay (single cell gel electrophoresis) is the restriction on the number of samples that can be processed in one experiment, imposed by the size of the electrophoresis platform. One approach to increasing throughput is to reduce the size of gels. We here compare the conventional system of two large gels on a microscope slide, with two recent developments, namely 12 minigels per slide, and a format with 96 minigels on GelBond® film. We used cells treated with X-rays or methylmethanesulphonate (MMS). The level of damage detected (% tail DNA) in X-irradiated or MMS-treated cells was not affected by the format used. Parallel experiments, using all three formats, were performed with MMS-treated cells in two independent laboratories; the difference in results between the two laboratories was of borderline significance. The potential problem of anomalous comets seen at the border of the gel, the so-called 'edge effects', has been addressed. A reliable, high throughput comet assay has applications in genotoxicity testing (particularly for in vivo studies with samples from different organs) as well as ecogenotoxicology and human biomonitoring, where the numbers of samples collected can be considerable. 23627806 Superparamagnetic Hollow Hybrid Nanogels as a Potential Guidable Vehicle System of Stimuli-Mediated MR Imaging and Multiple Cancer Therapeutics. Hollow hybrid nanogels were prepared first by co-assembly of the citric acid-coated superparamagnetic iron oxide nanoparticles (SPIONs) (44 wt%) with the graft copolymer (56 wt%) comprising acrylic acid and 2-methacryloylethyl acrylate units as the backbone and poly(ethylene glycol) and poly(N-isopropylacrylamide) as the grafts in aqueous phase of pH 3.0 into the hybrid vesicle structure, followed by in situ covalent stabilization via the photo-initiated polymerization of MEA residues within vesicles. The resultant hollow nanogels, though slightly swollen, satisfactorily retain the structural integrity while the medium pH being adjusted to 7.4. Confining SPION clusters to such a high level (44 wt%) within the pH-responsive thin gel layer remarkably enhances the transverse relaxivity (r2) and renders the MR imaging highly pH-tunable. For example, with the pH being adjusted from 4.0 to 7.4, the r2 value can be dramatically increased from 138.5 to 265.5 mM-1 s-1. The DOX-loaded hybrid nanogels also exhibit accelerated drug release in response to both pH reduction and temperature increase due to the substantial disruption of the interactions between drug molecules and copolymer components. With magnetic transport guidance toward the target and subsequent exposure to alternating magnetic field, this DOX-loaded nanogel system possessing combined capabilities of hyperthermia and stimuli-triggered drug release showed superior in vitro cytotoxicity against HeLa cells as compared to the case with only free drug or hyperthermia alone. This work demonstrates that the hollow inorganic/organic hybrid nanogels show great potential to serve as a multimodal theranostic vehicle functionalized with such desirable features as guidable delivery of stimuli-mediated diagnostic imaging and hyperthermia/chemotherapies. 23582779 Discovery of novel orally bioavailable GPR40 agonists. The GPR40 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. A series of novel orally bioavailable GPR40 agonists was discovered. SAR study and structural optimization led to identification of compounds 28a and 30a as potent GPR40 agonists with superior physiochemical properties and robust in vivo efficacy in rhesus monkeys. 23379369 Synthesis, microwave spectrum, and conformational properties of 2-fluoroethyl azide (FCH2CH2N3). A novel synthesis producing neat 2-fluoroethyl azide (FCH2CH2N3) is described. A conformational analysis using microwave spectroscopy augmented by quantum chemical calculations at the CCSD(T)/cc-pVTZ, B3LYP/aug-cc-pVTZ, and B3LYP/cc-pVTZ levels of theory has been performed for this compound. The spectra of the ground vibrational state and two vibrationally excited states of one rotameric form were assigned. A large number of transitions was assigned, and very accurate values were obtained for the rotational and quartic centrifugal distortion constants. The identified conformer has synclinal orientations for the F-C-C-N and C-C-N-N chains of atoms bringing the fluorine atom and the azido group into close proximity. It is concluded from consideration of absolute intensities that this conformer is indeed the preferred form of the molecule in accord with the theoretical calculations. The experimental and CCSD(T) rotational constants are in very good agreement, whereas much larger discrepancies were seen for the experimental and B3LYP quartic centrifugal distortion constants. 23411220 Film forming ability of gelatins from splendid squid (Loligo formosana) skin bleached with hydrogen peroxide. Properties of gelatin films from splendid squid (Loligo formosana) skin bleached with hydrogen peroxide (H(2)O(2)) at various concentrations (0-8% w/v) were investigated. Tensile strength (TS) and water vapour permeability (WVP) of films decreased, but elongation at break (EAB) increased (p<0.05) as the concentration of H(2)O(2) increased. Among all films, that prepared from gelatin with 2% H(2)O(2) bleaching showed the lowest ΔE(∗)-value (total colour difference), which was concomitant with the highest L(∗)-value (lightness). Generally, higher concentration of H(2)O(2) resulted in increased b(∗)-value (yellowness) of resulting films. Electrophoretic study revealed that α-chains of gelatin in films became lowered with increasing H(2)O(2) concentrations used for bleaching. Thermogravimetric analysis indicated that heat susceptibility and weight loss of different films varied with H(2)O(2) concentrations. Rougher surface was obtained in gelatin films prepared from skin bleached with H(2)O(2) concentrations above 4%. Thus, the concentrations of H(2)O(2) used for bleaching of squid skin prior to gelatin extraction directly affected the properties of corresponding gelatin films. 23478800 Cucurbitacin I inhibits rac1 activation in breast cancer cells by a reactive oxygen species-mediated mechanism and independently of janus tyrosine kinase 2 and p-rex1. The small GTPase Rac1 has been widely implicated in mammary tumorigenesis and metastasis. Previous studies established that stimulation of ErbB receptors in breast cancer cells activates Rac1 and enhances motility via the Rac-guanine nucleotide exchange factor P-Rex1. As the Janus tyrosine kinase 2 (Jak2)/signal transducer and activator of transcription 3 (Stat3) pathway has been shown to be functionally associated with ErbB receptors, we asked if this pathway could mediate P-Rex1/Rac1 activation in response to ErbB ligands. Here we found that the anticancer agent cucurbitacin I, a Jak2 inhibitor, reduced the activation of Rac1 and motility in response to the ErbB3 ligand heregulin in breast cancer cells. However, Rac1 activation was not affected by Jak2 or Stat3 RNA interference, suggesting that the effect of cucurbitacin I occurs through a Jak2-independent mechanism. Cucurbitacin I also failed to affect the activation of P-Rex1 by heregulin. Subsequent analysis revealed that cucurbitacin I strongly activates RhoA and the Rho effector Rho kinase (ROCK) in breast cancer cells and induces the formation of stress fibers. Interestingly, disruption of the RhoA-ROCK pathway prevented the inhibitory effect of cucurbitacin I on Rac1 activation by heregulin. Lastly, we found that RhoA activation by cucurbitacin I is mediated by reactive oxygen species (ROS). The ROS scavenger N-acetyl l-cysteine and the mitochondrial antioxidant Mito-TEMPO rescued the inhibitory effect of cucurbitacin I on Rac1 activation. In conclusion, these results indicate that ErbB-driven Rac1 activation in breast cancer cells proceeds independently of the Jak2 pathway. Moreover, they established that the inhibitory effect of cucurbitacin I on Rac1 activity involves the alteration of the balance between Rho and Rac. 23340858 Bandgap broadly tunable GaZnSeAs alloy nanowires. Composition-tunable semiconductor alloy nanowires are emerging as an important class of materials for the realization of high-performance laterally-arranged multiple bandgap (LAMB) solar cells. Here we report the first growth of GaZnSeAs quaternary alloy nanowires with composed elements between two different groups using a temperature/space-selective CVD route. Under laser excitation, these special quaternary alloy nanowires exhibit composition-related characteristic emissions, with peak wavelengths gradually tunable from 470 nm (2.64 eV) to 832 nm (1.49 eV), covering almost the entire visible spectrum. Surface photovoltage measurements further reveal that these alloy nanowires have tunable bandgaps along the length of the substrate, making them promising candidates for developing high-efficiency LAMB solar cells. These quaternary alloy nanowires represent a new advancement in material synthesis and would have potential applications in a variety of function-tunable and broadband-response optoelectronic devices. 23356964 Flavone tetraglycosides and benzyl alcohol glycosides from the Mongolian medicinal plant Dracocephalum ruyschiana. From an extract of the aerial parts of Dracocephalum ruyschiana, five new flavone tetraglycosides, five new benzyl alcohol glycosides, and 19 known compounds were isolated. The tetraglycosides contain a 7-O-β-d-glucopyranosyl-(1→2)-β-d-glucopyranosyl-(1→2)-[α-l-rhamnopyranosyl-(1→6)]-β-d-glucopyranosyl moiety. The benzyl alcohol glycosides had acyl groups on their glycosyl or aglycone moieties. The compounds were tested for antioxidant activity using DPPH. Although the new compounds were not active, phenylpropanoylquinic acid derivatives were revealed as radical scavengers in D. ruyschiana. 23396441 Control of human adenovirus type 5 gene expression by cellular Daxx/ATRX chromatin-associated complexes. Death domain-associated protein (Daxx) cooperates with X-linked α-thalassaemia retardation syndrome protein (ATRX), a putative member of the sucrose non-fermentable 2 family of ATP-dependent chromatin-remodelling proteins, acting as the core ATPase subunit in this complex, whereas Daxx is the targeting factor, leading to histone deacetylase recruitment, H3.3 deposition and transcriptional repression of cellular promoters. Despite recent findings on the fundamental importance of chromatin modification in host-cell gene regulation, it remains unclear whether adenovirus type 5 (Ad5) transcription is regulated by cellular chromatin remodelling to allow efficient virus gene expression. Here, we focus on the repressive role of the Daxx/ATRX complex during Ad5 replication, which depends on intact protein-protein interaction, as negative regulation could be relieved with a Daxx mutant that is unable to interact with ATRX. To ensure efficient viral replication, Ad5 E1B-55K protein inhibits Daxx and targets ATRX for proteasomal degradation in cooperation with early region 4 open reading frame protein 6 and cellular components of a cullin-dependent E3-ubiquitin ligase. Our studies illustrate the importance and diversity of viral factors antagonizing Daxx/ATRX-mediated repression of viral gene expression and shed new light on the modulation of cellular chromatin remodelling factors by Ad5. We show for the first time that cellular Daxx/ATRX chromatin remodelling complexes play essential roles in Ad gene expression and illustrate the importance of early viral proteins to counteract cellular chromatin remodelling. 23122135 Identification, characterisation, and quantification of phenolic compounds in the antioxidant activity-containing fraction from the seeds of Korean perilla (Perilla frutescens) cultivars. The present research was the first to investigate phenolic compound profiles and antioxidant properties in the seeds of various perilla (Perilla frutescens) cultivars. The 80% methanol extract (50 μg/ml) of this species showed potent antioxidant activities against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radicals. Phenolic compounds were characterised by nuclear magnetic resonance (NMR) spectroscopy, and ultra performance liquid chromatography with photodiode array detector and electrospray ionisation/mass (UPLC-PDA-ESI/MS) analysis. Nine compounds were elucidated as caffeic acid-3-O-glucoside (1), caffeic acid (2), luteolin-7-O-glucoside (3), apigenin-7-O-glucoside (4), rosmarinic acid-3-O-glucoside (5), rosmarinic acid (6), luteolin (7), apigenin (8), and chrysoeriol (9). The individual and total phenolic contents were remarkably different, especially rosmarinic acid-3-O-glucoside (5) and rosmarinic acid (6) which were the predominant compounds (>95%) in all perilla cultivars. Additionally, Yeupsil cultivar exhibited the highest phenolic content (5029.0 μg/g) and antioxidant activity, whereas the lowest was shown by Dasil (2138.7 μg/g). Therefore, these results suggest that antioxidant effects of perilla seeds are correlated with phenolic contents. 23508304 Multiple functional polymorphisms in the G6PC2 gene contribute to the association with higher fasting plasma glucose levels. AIMS/HYPOTHESIS: We previously identified the G6PC2 locus as a strong determinant of fasting plasma glucose (FPG) and showed that a common G6PC2 intronic single nucleotide polymorphism (SNP) (rs560887) and two common G6PC2 promoter SNPs (rs573225 and rs13431652) are highly associated with FPG. However, these promoter SNPs have complex effects on G6PC2 fusion gene expression, and our data suggested that only rs13431652 is a potentially causative SNP. Here we examine the effect of rs560887 on G6PC2 pre-mRNA splicing and the contribution of an additional common G6PC2 promoter SNP, rs2232316, to the association signal. METHODS: Minigene analyses were used to characterise the effect of rs560887 on G6PC2 pre-mRNA splicing. Fusion gene and gel retardation analyses characterised the effect of rs2232316 on G6PC2 promoter activity and transcription factor binding. The genetic association of rs2232316 with FPG variation was assessed using regression adjusted for age, sex and BMI in 4,220 Europeans with normal FPG. RESULTS: The rs560887-G allele was shown to enhance G6PC2 pre-mRNA splicing, whereas the rs2232316-A allele enhanced G6PC2 transcription by promoting Foxa2 binding. Genetic analyses provide evidence for association of the rs2232316-A allele with increased FPG (β = 0.04 mmol/l; p = 4.3 × 10(-3)) as part of the same signal as rs560887, rs573225 and rs13431652. CONCLUSIONS/INTERPRETATION: As with rs13431652, the in situ functional data with rs560887 and rs2232316 are in accord with the putative function of G6PC2 in pancreatic islets, and suggest that all three are potentially causative SNPs that contribute to the association between G6PC2 and FPG. 23617430 N3-substituted thymidine bioconjugates for cancer therapy and imaging. The compound class of 3-carboranyl thymidine analogues (3CTAs) are boron delivery agents for boron neutron capture therapy (BNCT), a binary treatment modality for cancer. Presumably, these compounds accumulate selectively in tumor cells via intracellular trapping, which is mediated by hTK1. Favorable in vivo biodistribution profiles of 3CTAs led to promising results in preclinical BNCT of rats with intracerebral brain tumors. This review presents an overview on the design, synthesis, and biological evaluation of first- and second-generation 3CTAs. Boronated nucleosides developed prior to 3CTAs for BNCT and non-boronated N3-substituted thymidine conjugates for other areas of cancer therapy and imaging are also described. In addition, basic features of carborane clusters, which are used as boron moieties in the design and synthesis of 3CTAs, and the biological and structural features of TK1-like enzymes, which are the molecular targets of 3CTAs, are discussed. 23542513 5-Hydroxy-3,6,7,8,3'4'-hexamethoxyflavone inhibits nitric oxide production in lipopolysaccharide-stimulated BV2 microglia via NF-κB suppression and Nrf-2-dependent heme oxygenase-1 induction. In this study, we found that 5-hydroxy-3,6,7,8,3'4'-hexamethoxyflavone (5HHMF) from Hizikia fusiforme considerably inhibits lipopolysaccharide (LPS)-stimulated NO production by suppressing the expression of inducible NO synthase (iNOS) in BV2 microglia. In addition, 5HHMF blocked LPS-induced phosphorylation of IκB, resulting in suppression of the nuclear translocation of nuclear factor-κB (NF-κB) subunits, namely p65 and p50, which are important molecules involved in the regulation of iNOS expression. Pyrrolidine dithiocarbamate (PDTC), a specific NF-κB inhibitor, along with 20S proteasome inhibitor (PSI) significantly inhibited LPS-induced iNOS expression, which indirectly suggested that 5HHMF downregulated iNOS expression by suppressing NF-κB activity. Thus, we found that 5HHMF enhances heme oxygenase-1 (HO-1) expression via nuclear factor-erythroid 2-related factor 2 (Nrf2) activation. In addition, cobalt protoporphyrin (CoPP), a specific HO-1 inducer, predominantly suppressed LPS-induced NO production. In contrast, zinc protoporphyrin (ZnPP), a specific HO-1 inhibitor, showed a partial suppressive effect of 5HHMF on LPS-induced NO production. Further, 5HHMF increased specific DNA-binding activity of Nrf2, and transient knockdown with Nrf2 siRNA subsequently reversed 5HHMF-induced NO inhibition, which was followed by suppression of HO-1 activity. Taken together, our findings indicate that 5HHMF suppresses NO production through modulation of iNOS, consequently suppressing NF-κB activity and induction of Nrf2-dependent HO-1 activity. 23567954 Polysulfones of new structural types as perspective antioxidant agents. A series of polysulfones of new structural types on the basis of azanorbornenes, 2,2-diallyl-1,1,3,3-tetraethylguanidiniumchloride and tris(diethylamino)diallylaminophosphonium salts were obtained by free radical polymerization reaction. Their antioxidant properties in lipid peroxidation induced by iron/ascorbate and in erythrocyte hemolysis by H2O2 were evaluated. The polysulfone of 2,2-diallyl-1,1,3,3-tetraethylguanidinium chloride showed protection of erythrocytes against hydrogen peroxide and thermal shock, protected epithelial cells against UV irradiation, was not toxic for erythrocytes, epithelial cells SPEV and 3T3 fibroblasts. The polysulfone of N-benzyl-2-azanorbornene-5 inhibited lipid peroxidation in liver homogenate, did not exhibit cytotoxicity in SPEV and 3T3 cells, protected these against UV irradiation. Both compounds had low bioavailability and may be recommended for further investigations as excipients to be externally applied. 23561131 Isolation of new monoterpene coumarins from Micromelum minutum leaves and their cytotoxic activity against Leishmania major and cancer cells. On the basis of a leishmanicidal assay-guided isolation, two new monoterpene coumarins, minutin A and minutin B, were purified from Micromelum minutum leaves together with four known coumarins, 8,4″-dihydroxy-3″,4″-dihydrocapnolactone-2',3'-diol, 8-hydroxyisocapnolactone-2',3'-diol, 8-hydroxy-3″,4″-dihydrocapnolactone-2',3'-diol, and clauslactone E. Among these compounds, minutin A, minutin B, 8-hydroxyisocapnolactone-2',3'-diol and clauslactone E showed a significant cytotoxic activity against Leishmania major with IC50 values of 26.2, 20.2, 12.1, and 9.8μM, respectively, while 8,4″-dihydroxy-3″4″-dihydrocapnolactone-2',3'-diol and 8-hydroxy-3″,4″-dihydrocapnolactone-2',3'-diol were not active. However, all these compounds exhibited some inhibitory activity against one or more lung adenocarcinoma (SBC3 and A549) and leukaemia (K562, and K562/ADM) cell lines. Amongst these, clauslactone E, minutin B and 8-hydroxyisocapnolactone-2',3'-diol possessed the strongest cytotoxic activity against SBC3, A549, K562, and K562/ADM cell lines, with IC50 values of 3.7, 10.4, 12.1, and 10.8μM for clauslactone E; 9.6, 17.5, 8.7 and 6.7μM for minutin B; 8.8, 10.1, 16.9, and 10.1μM for 8-hydroxyisocapnolactone-2',3'-diol, respectively. 23262279 High-throughput identification and characterization of novel, species-selective GPR35 agonists. Drugs targeting the orphan receptor GPR35 have potential therapeutic application in a number of disease areas, including inflammation, metabolic disorders, nociception, and cardiovascular disease. Currently available surrogate GPR35 agonists identified from pharmacologically relevant compound libraries have limited utility due to the likelihood of off-target effects in vitro and in vivo and the variable potency that such ligands exhibit across species. We sought to identify and characterize novel GPR35 agonists to facilitate studies aimed at defining the physiologic role of GPR35. PathHunter β-arrestin recruitment technology was validated as a human GPR35 screening assay, and a high-throughput screen of 100,000 diverse low molecular weight compounds was conducted. Confirmed GPR35 agonists from five distinct chemotypes were selected for detailed characterization using both β-arrestin recruitment and G protein-dependent assays and each of the human, mouse, and rat GPR35 orthologs. These studies identified 4-{(Z)-[(2Z)-2-(2-fluorobenzylidene)-4-oxo-1,3-thiazolidin-5-ylidene]methyl}benzoic acid (compound 1) as the highest potency full agonist of human GPR35 yet described. As with certain other GPR35 agonists, compound 1 was markedly selective for human GPR35, but displayed elements of signal bias between β-arrestin-2 and G protein-dependent assays. Compound 1 also displayed competitive behavior when assessed against the human GPR35 antagonist, ML-145 (2-hydroxy-4-[4-(5Z)-5-[(E)-2-methyl-3-phenylprop-2-enylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]butanoylamino]benzoic acid). Of the other chemotypes studied, compounds 2 and 3 were selective for the human receptor, but compounds 4 and 5 demonstrated similar activity at human, rat, and mouse GPR35 orthologs. Further characterization of these compounds and related analogs is likely to facilitate a better understanding of GPR35 in health and disease. 22968133 Public support and consent preference for biomedical research and biobanking in Jordan. The success of any biobank depends on a number of factors including public's view of research and the extent to which it is willing to participate in research. As a prototype of surrounding countries, public interest in research and biobanking in addition to the influence and type of informed consent for biobanking were investigated in Jordan. Data were collected as part of a national survey of 3196 individuals representing the Jordanian population. The majority of respondents (88.6%) had a positive perception of the level of research in Jordan and they overwhelmingly (98.2%) agreed to the concept of investing as a country in research. When respondents were asked if the presence of an informed consent would influence their decision to participate in biobanking, more individuals (19.8%) considered having an informed consent mechanism as a positive factor than those who considered it to have negative connotations (13.1%). However, a substantial portion (65%) did not feel it affected their decision. The majority of survey participants (64%) expressed willingness to participate in biobanking and over 90% of them preferred an opt-in consent form whether general (75.2%) or specific for disease or treatment (16.9%). These results indicate a promising ground for research and biobanking in Jordan. Educational programs or mass awareness campaigns to promote participation in biobanking and increase awareness about informed consent and individual rights in research will benefit both the scientific community as well as the public. 23402860 A comparative study of the modulatory effects of (-)-cubebin on the mutagenicity/recombinogenicity induced by different chemical agents. (-)-Cubebin (CUB) is a lignan isolated from dry seeds of Piper cubeba. We aimed to assess its genotoxic potential and influence on chromosomal damage (frequency of micronuclei - MN) induced by doxorubicin (DXR) in V79 cells and by urethane (URE) in somatic Drosophila melanogaster cells. Our findings indicate an absence of a CUB-mediated genotoxic effect at the concentrations tested. The results also revealed that CUB significantly reduced the frequency of MN induced by DXR, with a mean reduction of 63.88%. In a previous study, our research group demonstrated an absence of CUB-mediated mutagenic effects through the wing Somatic Mutation and Recombination Test (SMART) in Drosophila. In the present study, we used the standard and high bioactivation versions of the SMART to estimate the antigenotoxic effects of CUB associated with URE. At lower concentrations, the recombination level decreased, but at the highest concentration, the recombination level increased. Our data and previous studies suggest that CUB may act as a free radical scavenger at low concentrations, a pro-oxidant at higher concentrations when it interacts with the enzymatic system that catalyzes the metabolic detoxification of DXR or URE, and/or an inducer of recombinational DNA repair. 23382013 Using conditional inference trees and random forests to predict the bioaccumulation potential of organic chemicals. The present study presents a data-oriented, tiered approach to assessing the bioaccumulation potential of chemicals according to the European chemicals regulation on Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH). The authors compiled data for eight physicochemical descriptors (partition coefficients, degradation half-lives, polarity, and so forth) for a set of 713 organic chemicals for which experimental values of the bioconcentration factor (BCF) are available. The authors employed supervised machine learning methods (conditional inference trees and random forests) to derive relationships between the physicochemical descriptors and the BCF values. In a first tier, the authors established rules for classifying a chemical as bioaccumulative (B) or nonbioaccumulative (non-B). In a second tier, the authors developed a new tool for estimating numerical BCF values. For both cases the optimal set of relevant descriptors was determined; these are biotransformation half-life and octanol-water distribution coefficient (log D) for the classification rules and log D, biotransformation half-life, and topological polar surface area for the BCF estimation tool. The uncertainty of the BCF estimates obtained with the new estimation tool was quantified by comparing the estimated and experimental BCF values of the 713 chemicals. Comparison with existing BCF estimation methods indicates that the performance of this new BCF estimation tool is at least as high as that of existing methods. The authors recommend the present study's classification rules and BCF estimation tool for a consensus application in combination with existing BCF estimation methods. Environ Toxicol Chem 2013;32:1187-1195. © 2013 SETAC. 23361062 Understanding photosynthetic light-harvesting: a bottom up theoretical approach. We discuss a bottom up approach for modeling photosynthetic light-harvesting. Methods are reviewed for a full structure-based parameterization of the Hamiltonian of pigment-protein complexes (PPCs). These parameters comprise (i) the local transition energies of the pigments in their binding sites in the protein, the site energies; (ii) the couplings between optical transitions of the pigments, the excitonic couplings; and (iii) the spectral density characterizing the dynamic modulation of pigment transition energies and excitonic couplings by protein vibrations. Starting with quantum mechanics perturbation theory, we provide a microscopic foundation for the standard PPC Hamiltonian and relate the expressions obtained for its matrix elements to quantities that can be calculated with classical molecular mechanics/electrostatics approaches including the whole PPC in atomic detail and using charge and transition densities obtained with quantum chemical calculations on the isolated building blocks of the PPC. In the second part of this perspective, the Hamiltonian is utilized to describe the quantum dynamics of excitons. Situations are discussed that differ in the relative strength of excitonic and exciton-vibrational coupling. The predictive power of the approaches is demonstrated in application to different PPCs, and challenges for future work are outlined. 23474217 New plant sources of the anti-cancer alkaloid, camptothecine from the Icacinaceae taxa, India. In this study, the production of camptothecine and its derivatives, in thirteen species of the family Icacinaceae, namely, Apodytes dimidiata, Codiocarpus andamanicus, Gomphandra comosa, Gomphandra coriacea, Gomphandra polymorpha, Gomphandra tetrandra, Iodes cirrhosa, Iodes hookeriana, Miquelia dentata, Miquelia kleinii, Natsiatum herpeticum, Pyrenacantha volubilis and Sarcostigma kleinii is reported. Seeds of M. dentata were found to produce the highest content of camptothecine (1.0-1.4% by dry weight of seeds). Full scan LC-MS and ESI-MS/MS analysis of M. dentata revealed, besides camptothecine, a number of other derivatives, namely, 10-hydroxycamptothecine, 9-methoxycamptothecine, 20-deoxycamptothecine. Crude extract preparations of the seeds of M. dentata were effective against a breast cancer cell line (IC50=3.82μg/ml for MDA MB273 cell lines) and two ovarian cancer cell lines (IC50=2.8μg/ml for NCI/ADR-RES and 4.5μg/ml for SKOV). These results are the first reports of camptothecine and its derivatives in these species and offer rich alternative plant sources for the anticancer compound, camptothecine. 23142538 Effect of developmental dioxin exposure on methylation and expression of specific imprinted genes in mice. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an endocrine disruptor affecting the reproductive system in humans. The aim of this study was to evaluate the effects of TCDD administered to pregnant mice at two different doses (2-10 ng/kg/day), on imprinted genes in the male offspring. The degree of methylation and the mRNA expression of Snrpn, Peg3 and Igf2r were analyzed in the sperm, skeletal muscle and liver. TCDD administration (10 ng/kg/day) decreased the sperm count in the male offspring. It did not affect methylation but increased mRNA expression of Snrpn, Peg3, Igf2r and Air ncRNA. In muscle and liver, TCDD (10 ng/kg/day) induced increases in methylation and decreases in mRNA expression of Igf2r. These results show that the robust effects of TCDD on the mRNA expression of Snrpn, Peg3 and Igf2r genes in the sperm and of Igf2r in the muscle and liver are unrelated to changes in methylation in their respective genes. 22546615 The metabotropic glutamate receptor 8 agonist (S)-3,4-DCPG reverses motor deficits in prolonged but not acute models of Parkinson's disease. Metabotropic glutamate receptors (mGlus) are 7 Transmembrane Spanning Receptors (7TMs) that are differentially expressed throughout the brain and modulate synaptic transmission at both excitatory and inhibitory synapses. Recently, mGlus have been implicated as therapeutic targets for many disorders of the central nervous system, including Parkinson's disease (PD). Previous studies have shown that nonselective agonists of group III mGlus have antiparkinsonian effects in several animal models of PD, suggesting that these receptors represent promising targets for treating the motor symptoms of PD. However, the relative contributions of different group III mGlu subtypes to these effects have not been fully elucidated. Here we report that intracerebroventricular (icv) administration of the mGlu(8)-selective agonist (S)-3,4-dicarboxyphenylglycine (DCPG [ 2.5, 10, or 30 nmol]) does not alleviate motor deficits caused by acute (2 h) treatment with haloperidol or reserpine. However, following prolonged pretreatment with haloperidol (three doses evenly spaced over 18-20 h) or reserpine (18-20 h), DCPG robustly reverses haloperidol-induced catalepsy and reserpine-induced akinesia. Furthermore, DCPG (10 nmol, icv) reverses the long-lasting catalepsy induced by 20 h pretreatment with the decanoate salt of haloperidol. Finally, icv administration of DCPG ameliorates forelimb use asymmetry caused by unilateral 6-hydroxydopamine lesion of substantia nigra dopamine neurons. These findings suggest that mGlu(8) may partially mediate the antiparkinsonian effects of group III mGlu agonists in animal models of PD in which dopamine depletion or blockade of D(2)-like dopamine receptors is prolonged and indicate that selective activation of mGlu(8) may represent a novel therapeutic strategy for alleviating the motor symptoms of PD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23495769 Photoelectric energy conversion of plasmon-generated hot carriers in metal-insulator-semiconductor structures. Plasmonic excitation in metals has received great attention for light localization and control of light-matter interactions at the nanoscale with a plethora of applications in absorption enhancement, surface-enhanced Raman scattering, or biosensing. Electrically active plasmonic devices, which had remained underexplored, have recently become a growing field of interest. In this report we introduce a metal-insulator-semiconductor heterostructure for plasmo-electric energy conversion, a novel architecture to harvest hot-electrons derived from plasmonic excitations. We demonstrate external quantum efficiency (EQE) of 4% at 460 nm using a Ag nanostructured electrode and EQE of 1.3% at 550 nm employing a Au nanostructured electrode. The insulator interfacial layer has been found to play a crucial role in interface passivation, a requisite in photovoltaic applications to achieving both high open-circuit voltages (0.5 V) and fill-factors (0.5), but its introduction simultaneously modifies hot-electron injection and transport. We investigate the influence passivation has on these processes for different material configurations, and characterize different types of transport depending on the initial plasmon energy band, reporting power conversion efficiencies of 0.03% for nanopatterned silver electrodes. 23624419 Evaluation of the positive effects on insulin-resistance and β-cell measurements of vildagliptin in addition to metformin in type 2 diabetic patients. We evaluated the positive effects of vildagliptin in addition to metformin on glycemic control and β-cell function in type 2 diabetic patients. One hundred and seventy-one type 2 diabetic patients were instructed to add vildaglipin 50mg twice a day or placebo to metformin for 12 months. Body mass index (BMI), glycemic control, fasting plasma insulin (FPI), HOMA-IR, HOMA-β, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, vaspin, visfatin, and omentin-1 were evaluated. Before, and after 12 months since the addition of vildagliptin, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation. Vildagliptin+metformin were more effective than placebo+metformin in reducing body weight and BMI, glycemic control, HOMA-IR, glucagon and insulin resistance measurements. Vildagliptin+metformin gave also a better increase of HOMA-β, and of all β-cell parameters after the clamp. We also recorded a significant correlation between M value increase and the decrease of vaspin, visfatin, and omentin-1 obtained with vildagliptin+metformin. Vildagliptin, in addition to metformin, proved to be effective in improving β-cell function and in reducing insulin resistance measurements. 23147376 Influence of experimental type 1 diabetes on the pulmonary effects of diesel exhaust particles in mice. Epidemiologically, exposure to particulate air pollution is associated with increases in morbidity and mortality, and diabetics are especially vulnerable to effects of particles. This study was carried out to determine the respiratory effect of diesel exhaust particles (DEP; 0.4mg/kg) on mice rendered diabetic by the injection of streptozotocin or vehicle (control). Four weeks following induction of diabetes, the animals were intratracheally instilled (i.t.) with DEP (0.4mg/kg) or saline. 24h later, the measurement of airway reactivity to methacholine in vivo by a forced oscillation technique showed a significant and dose-dependent increase in airway resistance in non-diabetic mice exposed to DEP versus non-diabetic mice exposed to saline. Similarly, the airway resistance was significantly increased in diabetic mice exposed to DEP versus diabetic mice exposed to saline. Nevertheless, there was no difference in the airway resistance between diabetic and non-diabetic mice after i.t. administration of DEP. Following DEP administration there were neutrophil polymorphs infiltration of pulmonary interalveolar septae and the alveolar spaces with many macrophages containing DEP in both diabetic and non-diabetic mice. Interestingly, apoptotic cells were only found in the examined lung sections from diabetic mice exposed to DEP. Total proteins and albumin concentrations in bronchoalveolar lavage (BAL) fluid, markers for increase of epithelial permeability, were significantly increased in diabetic mice exposed to DEP compared to saline-treated diabetic and DEP-treated non diabetic mice. Superoxide dismutase activity and reduced glutathione concentration in BAL were significantly decreased in diabetic mice exposed to DEP compared to saline-treated diabetic and DEP-treated non diabetic mice. Moreover, tumor necrosis factor α (TNFα) concentrations were significantly increased in diabetic mice exposed to DEP compared to saline-treated diabetic and DEP-treated non diabetic mice. We conclude that, at the dose and time point investigated, DEP equally increased airway resistance and caused infiltration of inflammatory cells in the lung of both diabetic and non-diabetic mice. However, the occurrence of oxidative stress, the presence lung apoptotic cells and the increase of total proteins, albumin and TNFα in BAL fluid were only seen in DEP-exposed diabetic mice suggesting an increased respiratory susceptibility to particulate air pollution. 23534412 Antithrombotic activity of a newly synthesized coumarin derivative 3-(5-hydroxy-2,2-dimethyl-chroman-6-yl)-N-{2-[3-(5-hydroxy-2,2-dimethyl-chroman-6-yl)-propionylamino]-ethyl}-propionamide. Anti-platelet therapy is a useful strategy to prevent acute thromboembolic artery occlusions. This study was designed to assess the efficacy of seselin derivatives against murine pulmonary thromboembolism, bleeding time, platelet activation and thrombosis. Administration of C3 (16 mg/kg) offered 70% protection against collagen- and epinephrine-induced pulmonary thromboembolism and 30% protection against arachidonic acid-induced death in mice, without adversely affecting bleeding time. No significant difference was observed by C3 in ferric chloride-induced arterial thrombosis in rats. Significant reduction in thrombus weight was observed in arteriovenous shunt model. In rat PRP, C3 reduced ADP and collagen-induced platelet aggregation. In chronic hamster model of dyslipidemia, administration of C3 (16 mg/kg p.o. for 90 days) had no effect on plasma lipids, vasoreactivity and platelet adhesion. C3 fed hamsters showed reduced whole-blood aggregation response to ADP and collagen compared to HC-fed hamsters. In addition, C3 augmented thrombin time; however, time to occlusion was not increased. These results convincingly demonstrated that C3 is a novel molecule that reduces the risk of thrombosis and alleviates prothrombotic state associated with hyperlipidemia without any adverse effect on bleeding time. The high benefit/risk ratio of this compound makes it a suitable candidate for future valid studies. 23500335 Sex specific impact of perinatal bisphenol A (BPA) exposure over a range of orally administered doses on rat hypothalamic sexual differentiation. Bisphenol A (BPA) is a high volume production chemical used in polycarbonate plastics, epoxy resins, thermal paper receipts, and other household products. The neural effects of early life BPA exposure, particularly to low doses administered orally, remain unclear. Thus, to better characterize the dose range over which BPA alters sex specific neuroanatomy, we examined the impact of perinatal BPA exposure on two sexually dimorphic regions in the anterior hypothalamus, the sexually dimorphic nucleus of the preoptic area (SDN-POA) and the anterioventral periventricular (AVPV) nucleus. Both are sexually differentiated by estradiol and play a role in sex specific reproductive physiology and behavior. Long Evans rats were prenatally exposed to 10, 100, 1000, 10,000μg/kg bw/day BPA through daily, non-invasive oral administration of dosed-cookies to the dams. Offspring were reared to adulthood. Their brains were collected and immunolabeled for tyrosine hydroxylase (TH) in the AVPV and calbindin (CALB) in the SDN-POA. We observed decreased TH-ir cell numbers in the female AVPV across all exposure groups, an effect indicative of masculinization. In males, AVPV TH-ir cell numbers were significantly reduced in only the BPA 10 and BPA 10,000 groups. SDN-POA endpoints were unaltered in females but in males SDN-POA volume was significantly lower in all BPA exposure groups. CALB-ir was significantly lower in all but the BPA 1000 group. These effects are consistent with demasculinization. Collectively these data demonstrate that early life oral exposure to BPA at levels well below the current No Observed Adverse Effect Level (NOAEL) of 50mg/kg/day can alter sex specific hypothalamic morphology in the rat. 22583008 Fatty acid composition of the edible sea cucumber Athyonidium chilensis. The edible sea cucumber Athyonidium chilensis is a fishery resource of high commercial value in Chile, but no information on its lipid and fatty acid composition has been previously reported. Phospholipids were the major lipid contents of the ethanolic extracts of tubules, internal organs and body wall of A. chilensis. Saturated fatty acids predominated in tubule phospholipids (40.69%), while in internal organs and body wall phospholipids, the monounsaturated fatty acids were in higher amounts (41.99% and 37.94%, respectively). The main polyunsaturated fatty acids in phospholipids were C20 : 2ω-6, arachidonic (C20 : 4ω-6) and eicosapentaenoic (C20 : 5ω-3) acids. These results demonstrate for the first time that A. chilensis is a valuable food for human consumption in terms of fatty acids. 23566174 Conformational Plasticity of Hydrogen Bonded Bis-urea Supramolecular Polymers. We report a detailed structural investigation of supramolecular polymers formed by hydrogen bonded self-assembly of bis-urea monomers. The careful exploration of the energy landscape by molecular mechanics/molecular dynamics (MM/MD) simulations has allowed us to identify three distinct self-assembled structures of similar stabilities. These structures have been compared to X-ray crystal data. We observe that a slight change in the molecular structure can favor a particular structure over the others. Detailed analysis shows that hydrogen bonds stabilize all three structures to a similar extent. Therefore, it is the interactions among the lateral substituents, and with the filament environment, that are the decisive factors in the competition between the possible self-assembled structures. This study constitutes a clear reminder that the conformation of a supramolecular polymer is a sensitive function of the molecular structure and may significantly differ from the solid-state conformation of a model compound. 22991412 The role of adipokines in β-cell failure of type 2 diabetes. β-Cell failure coupled with insulin resistance is a key factor in the development of type 2 diabetes. Changes in circulating levels of adipokines, factors released from adipose tissue, form a significant link between excessive adiposity in obesity and both aforementioned factors. In this review, we consider the published evidence for the role of individual adipokines on the function, proliferation, death and failure of β-cells, focusing on those reported to have the most significant effects (leptin, adiponectin, tumour necrosis factor α, resistin, visfatin, dipeptidyl peptidase IV and apelin). It is apparent that some adipokines have beneficial effects whereas others have detrimental properties; the overall contribution to β-cell failure of changed concentrations of adipokines in the blood of obese pre-diabetic subjects will be highly dependent on the balance between these effects and the interactions between the adipokines, which act on the β-cell via a number of intersecting intracellular signalling pathways. We emphasise the importance, and comparative dearth, of studies into the combined effects of adipokines on β-cells. 23470418 Bioactivation of bisphenol A and its analogs (BPF, BPAF, BPZ and DMBPA) in human liver microsomes. Bisphenol A analogs are a class of chemicals known as diphenylmethanes, which contain two benzene rings separated by one central carbon atom, usually with a para-hydroxy group on both benzene rings. Bisphenol A (BPA) can induce an uterotrophic response in immature CD-1 mice and elicits estrogenic responses in many other experimental systems. Besides highlighting endocrine effects, a number of metabolic studies provide strong support for the idea that reactive species of BPA are formed in vitro and in vivo that can form covalent adducts with nucleophilic macromolecules and/or produce oxidative stress. We used a liquid chromatography with a triple quadrupole tandem mass spectrometry (LC-MS/MS) for the detection of metabolites and glutathione conjugates of BPA and its analogs (BPF, BPAF, BPZ and DMBPA) in human liver microsomes (HLM) or with recombinant CYP isozymes in the presence of NADPH and GSH as a trapping agent. We have confirmed that BPA and its structural analogs form hydroxylated metabolites and electrophilic species during bioactivation in HLM and CYP isozymes. These results provided important mechanistic insight into the metabolic fate of BPA structural analogs in vitro. 23500550 Current perspectives on parathyroid hormone (PTH) and PTH-related protein (PTHrP) as bone anabolic therapies. Osteoporosis is characterized by low bone mineral density and/or poor bone microarchitecture leading to an increased risk of fractures. The skeletal alterations in osteoporosis are a consequence of a relative deficit of bone formation compared to bone resorption. Osteoporosis therapies have mostly relied on antiresorptive drugs. An alternative therapeutic approach for osteoporosis is currently available, based on the intermittent administration of parathyroid hormone (PTH). Bone anabolism caused by PTH therapy is mainly accounted for by the ability of PTH to increase osteoblastogenesis and osteoblast survival. PTH and PTH-related protein (PTHrP)-an abundant local factor in bone- interact with the common PTH type 1 receptor with similar affinities in osteoblasts. Studies mainly in osteoporosis rodent models and limited data in postmenopausal women suggest that N-terminal PTHrP peptides might be considered a promising bone anabolic therapy. In addition, putative osteogenic actions of PTHrP might be ascribed not only to its N-terminal domain but also to its PTH-unrelated C-terminal region. In this review, we discuss the underlying cellular and molecular mechanisms of the anabolic actions of PTH and the similar potential of PTH-related protein (PTHrP) to increase bone mass and improve bone regeneration. 23639738 Enzyme-responsive surface erosion of poly(ethylene carbonate) for controlled drug release. Cholesterol esterase (CE) induced surface erosion of poly(ethylene carbonate) (PEC) and drug release from PEC under mild physiological environment was investigated. The degradation process was monitored by changes of mass and molecular weight (MW) and surface morphology of polymer films. During the whole period of degradation, MW of PEC was unchanged. Water uptake of the polymer was only 2.8 and 0.2% for PEC with the MW of 200 kDa (PEC200) and PEC with the MW of 41 kDa (PEC41), respectively. Degradation of less hydrophilic PEC41 with higher density was slower than that of PEC200. By this mechanism, CE-responsive drug in vitro release from PEC in situ forming depots (ISFD) was conducted successfully. As expected, less bovine serum albumin (BSA) was released from PEC41 compared with that of PEC200 in the same time period. In conclusion, this work enabled the in vitro drug release evaluation of existing PEC devices and implied a new candidate for the development of enzyme-responsive systems. 23578657 A calibrator plasmid for quantitative analysis of insect resistant maize (Yieldgard MON 810). Real-time PCR (RT-PCR) is the preferred method for the quantification of genetically modified organisms (GMOs) and implementation of labeling regulations. The precision, sensitivity, and reproducibility of RT-PCR data depend on the use of external calibrators. In this investigation, a dual target plasmid designated pRSETMON-02 comprising of MON 810 maize event specific and endogenous zein gene sequences in 1:1 ratio in tandem was constructed and validated. Commutability of plasmid DNA (pDNA) and genomic DNA (gDNA) calibrators for the quantification of MON 810 maize was assessed by employing a TaqMan RT-PCR targeting the P-35S and zein gene. Higher PCR efficiencies, good linearity and lower relative standard deviation (RSD) values were associated with pRSETMON-02 as opposed to gDNA calibrants. pDNA calibrants exhibited better performance characteristic in terms of closeness to the expected value of unknown samples than their genomic counterparts. Short term stability study of the pRSETMON-02 plasmid stored at different temperatures showed that pDNA is stable for 45days at -20, and 4°C. The results demonstrated that the developed dual target plasmid pRSETMON-02 is fit for the intended use of quantifying MON 810 maize and is a better alternative to conventional seed powder calibrants. 23411192 Effects of twin-screw extrusion on soluble dietary fibre and physicochemical properties of soybean residue. Extrusion cooking technology was applied for soluble dietary fibre extraction from soybean residue. Response surface methodology (RSM) was used to optimise the effects of extrusion parameters, namely extrusion temperature (90-130°C), feed moisture (25-35%) and screw speed (160-200 rpm) on the content of soluble dietary fibre. According to the regression coefficients significance of the quadratic polynomial model, the optimum extrusion parameters were as follows: extrusion temperature, 115°C; feed moisture, 31%; and screw speed, 180 rpm. Under these conditions, the soluble dietary fibre content of soybean residue could reach to 12.65% which increased 10.60% compared with the unextruded soybean residue. In addition, the dietary fibre in extrude soybean residue had higher water retention capacity, oil retention capacity and swelling capacity than those of dietary fibre in unextruded soybean residue. 23139351 The neuropathic diabetic foot ulcer microbiome is associated with clinical factors. Nonhealing diabetic foot ulcers (DFUs) are a common and costly complication of diabetes. Microbial burden, or "bioburden," is believed to underlie delayed healing, although little is known of those clinical factors that may influence microbial load, diversity, and/or pathogenicity. We profiled the microbiomes of neuropathic nonischemic DFUs without clinical evidence of infection in 52 individuals using high-throughput sequencing of the bacterial 16S ribosomal RNA gene. Comparatively, wound cultures, the standard diagnostic in the clinic, vastly underrepresent microbial load, microbial diversity, and the presence of potential pathogens. DFU microbiomes were heterogeneous, even in our tightly restricted study population, but partitioned into three clusters distinguished primarily by dominant bacteria and diversity. Ulcer depth was associated with ulcer cluster, positively correlated with abundance of anaerobic bacteria, and negatively correlated with abundance of Staphylococcus. Ulcer duration was positively correlated with bacterial diversity, species richness, and relative abundance of Proteobacteria, but was negatively correlated with relative abundance of Staphylococcus. Finally, poor glycemic control was associated with ulcer cluster, with poorest median glycemic control concentrating to Staphylococcus-rich and Streptococcus-rich ulcer clusters. Analyses of microbial community membership and structure may provide the most useful metrics in prospective studies to delineate problematic bioburden from benign colonization that can then be used to drive clinical treatment. 23511018 Evaluation of anti-HCV activity and SAR study of (+)-lycoricidine through targeting of host heat-stress cognate 70 (Hsc70). The anti hepatitis C virus (HCV) activity of (+)-lycoricidine (1) was evaluated for the first time in this letter, yielding an EC50 value of 0.55nmol/mL and an selection index (SI) value of 12.72. Further studies indicated that 1 induced this effect by down-regulating host heat-stress cognate 70 (Hsc70) expression. In addition, 20 derivatives were designed and synthesised to investigate the basic structure-activity relationship (SAR) of the title compound. Several of these derivatives exhibit a good inhibition of HCV, such as compound 3 (EC50=0.68nmol/mL, SI=33.86), compound 2d (EC50=15nmol/mL, SI=12) and compound 5 (EC50=33nmol/mL, SI >10.91). Meanwhile, the experimental data suggest that the modification of certain groups of (+)-lycoricidine can reduce the cytotoxicity of the compounds. 23371489 Mephedrone and methylenedioxypyrovalerone (MDPV), major constituents of "bath salts," produce opposite effects at the human dopamine transporter. RATIONALE: Psychoactive "bath salts" represent a relatively new drug of abuse combination that was placed in Schedule I in October 2011. Two common ingredients of bath salts include the cathinone analogs: mephedrone and methylenedioxypyrovalerone (MDPV). The mechanism of action of these synthetic cathinone analogs has not been well investigated. MATERIALS AND METHODS: Because cathinone and methcathinone are known to act as releasing agents at the human dopamine transporter (hDAT), mephedrone and MDPV were investigated at hDAT expressed in Xenopus oocytes. RESULTS: Whereas mephedrone was found to have the signature of a dopamine-releasing agent similar to methamphetamine or methcathinone, MDPV behaved as a cocaine-like reuptake inhibitor of dopamine. CONCLUSIONS: Mephedrone and MDPV produce opposite electrophysiological signatures through hDAT expressed in oocytes. Implications are that the combination (as found in bath salts) might produce effects similar to a combination of methamphetamine and cocaine. 23369537 Syntheses of lipophilic chalcones and their conformationally restricted analogues as antitubercular agents. Lipophilic chalcones and their conformationally restricted analogues were synthesized and evaluated for their antitubercular efficacy against Mycobacterium tuberculosis H37Rv strain. Compounds 16, 24, 25a and 25c were found to be active MIC at 60, 30, 3.5 and 7.5 μg-mL(-1). In vitro cytotoxicity of compounds 16, 24, 25a, 25c and 26 in non-cancerous human epithelial kidney cell line (HEK-293) showed that most active compound 25a was approximately 2.85 times selective towards tubercular versus healthy cells whereas compound 24 was found to be 16 times selective. 23275111 Drug release kinetics, cell uptake, and tumor toxicity of hybrid VVVVVVKK peptide-assembled polylactide nanoparticles. An exciting approach to tumor delivery is encapsulation of the drug in self-assembled polymer-peptide nanoparticles. The objective of this work was to synthesize a conjugate of low molecular weight polylactide (LMW PLA) and V6K2 peptide and investigate self-assembly, drug release kinetics, cell uptake and toxicity, drug pharmacokinetics, and tumor cell invasion with Doxorubicin (DOX) or paclitaxel (PTX). The results for PLA-V6K2 self-assembled NPs were compared with those of polyethylene glycol stabilized PLA (PLA-EG) NPs. The size of PLA-V6K2 and PLA-EG NPs was 100±20 and 130±50nm, respectively, with polydispersity index of 1.04 and 1.14. The encapsulation efficiency of DOX in PLA-V6K2 and PLA-EG NPs was 44±9% and 55±5%, respectively, and that of PTX was >90 for both NP types. The release of DOX and PTX from PLA-V6K2 was slower than that of PLA-EG, and the release rate was relatively constant with time. Based on molecular dynamic simulation, the less hydrophobic DOX was distributed in the lactide core as well as the peptide shell, while the hydrophobic PTX was localized mainly to the lactide core. PLA-V6K2 NPs had significantly higher cell uptake by 4T1 mouse breast carcinoma cells compared to PLA-EG NPs, which was attributed to the electrostatic interactions between the peptide and negatively charged moieties on the cell membrane. PLA-V6K2 NPs showed no toxicity to marrow stromal cells. DOX-loaded PLA-V6K2 NPs showed higher toxicity to 4T1 cells and the DNA damage response, and apoptosis was delayed compared to the free DOX. DOX or PTX encapsulated in PLA-V6K2 NPs significantly reduced invasion of 4T1 cells compared to those cells treated with the drug in PLA-EG NPs. Invasion of 4T1 cells treated with DOX in PLA-V6K2 and PLA-EG NPs was 5±1% and 30±5%, respectively, and that of PTX was 11±2% and 40±7%. The AUC of DOX in PLA-V6K2 NPs was 67% and 21% higher than those of free DOX and PLA-EG NPs, respectively. DOX-loaded PLA-V6K2 NPs injected in C3HeB/FeJ mice inoculated with MTCL syngeneic breast cancer cells displayed higher tumor toxicity than PLA-EG NPs and lower host toxicity than the free DOX. Cationic PLA-V6K2 NPs with higher tumor toxicity than the PLA-EG NPs are potentially useful in chemotherapy. 23046872 A cross-linked polymeric micellar delivery system for cisplatin(IV) complex. A polymeric cisplatin(IV) prodrug in the form of cross-linked micelles (M(Pt(IV)) was prepared by first constructing MPEG-b-PCL-b-PLL micelles and then attaching a cisplatin(IV) complex with two axial succinic moieties to the lysine residues of the carrier polymer in aqueous medium. The micelles obtained were characterized by TEM, DLS, and zeta potential measurement. Their in vitro release experiments were carried out at pH 7.4 and 5.0 or in the presence of 5mM sodium ascorbate (NaAsc). Results showed that the micelles were sensitive to both acidic hydrolysis and mild reducing agents; in the presence of 5mM NaAsc, cisplatin(II) was directly released and the released cisplatin(II) could chelate with nucleobases; the micelles displayed comparable cytotoxicities to cisplatin; and the micelles were much more efficiently internalized by the cells than cisplatin(II) and cisplatin(IV) counterparts. Moreover, in vivo study showed accumulation of more Pt species in the tumor site and lower systematic toxicity compared to free cisplatin(II) and cisplatin(IV). This polymeric prodrug of cisplatin is expected to be used more for future study and applications. 23594687 POST-SURGICAL THYROID ABLATION WITH LOW OR HIGH RADIOIODINE ACTIVITIES RESULTS IN SIMILAR OUTCOMES IN INTERMEDIATE RISK DIFFERENTIATED THYROID CANCER PATIENTS. BACKGROUND: In differentiated thyroid cancer (DTC) patients at intermediate risk of recurrences, no evidences are provided regarding the optimal radioactive iodine (RAI) activity to be administered for post-surgical thyroid ablation. METHODS: This study aimed to evaluate the impact of RAI activities on the outcome of 225 DTC patients classified as intermediate risk, treated with low (1110-1850 MBq) or high RAI activities (≥3700 MBq). RESULTS: Six-eighteen months after ablation remission was observed in 60.0% of patients treated with low and in 60% of those treated with high RAI activities, biochemical disease was found in 18.8% of patients treated with low and in 14.3% of patients treated with high RAI activities, metastatic disease was found in 21.2% of patients treated with low and in 25.7% of patients treated with high RAI activities (p=0.56). At the last follow-up (low activities, median 4.2 years: high activities median 6.9 years) remission was observed in 76.5% of patients treated with low and in 72.1% of patients treated with high RAI activities, persistent disease was observed in 18.8% of patients treated with low and in 23.5% of patients treated with high RAI activities, recurrent disease was 2.4% in patients treated with low and 2.1% in patients treated with high RAI activities, deaths occurred in 2.4% of patients treated with low and in 2.1% of patients treated with high RAI activities (p=0.87). CONCLUSION: our study provides the first evidence that in DTC patients at intermediate risk, high RAI activities at ablation have no major advantage over low activities. 23584886 Optimization of DDI Study Design: Comparison of Minimal PBPK Models on Prediction of CYP3A Inhibition by Ketoconazole. Ketoconazole is a potent CYP3A inhibitor used to assess the contribution of CYP3A to drug clearance and quantify the increase in drug exposure due to a strong inhibitor. Physiologically based pharmacokinetic (PBPK) models have been employed to evaluate dosing regimens resulting in maximal CYP3A inhibition by ketoconazole but have reached different conclusions. We compare two PBPK models of the ketoconazole-midazolam interaction, Model 1 (Chien et al., 2006) and Model 2 implemented in Simcyp (version 11) to predict 16 published dosing regimens. Using Model 2, 41% of the study point estimates of AUC ratio and 71% of the 90% confidence intervals were predicted within 1.5-fold of the observed but these increased to 82% and 100% respectively with Model 1. For midazolam, Model 2 predicted a maximal midazolam AUC ratio of 8 and a hepatic fraction metabolized by CYP3A of 0.97 whereas Model 1 predicted 17 and 0.90 respectively, which are more consistent with observed data. Based on Model 1, ketoconazole 400mg QD for at least 3 days and substrate administration within 2 hours is required for maximal CYP3A inhibition. Ketoconazole dosing regimens that employ 200 mg BID underestimate the systemic fraction metabolized by CYP3A (0.86 vs. 0.90) for midazolam. The systematic underprediction also applies to CYP3A substrates with high bioavailability and long half-lives. The superior predictive performance of Model 1 reflects the need for accumulation of ketoconazole at enzyme site and protracted inhibition. Model 2 is not recommended for inferring optimal study design and estimation of fraction metabolized by CYP3A. 23587660 Effect of Korean pear (Pyruspyrifolia cv. Shingo) juice on hangover severity following alcohol consumption. Korean pear has been used as a traditional prophylactic agent for alcohol hangover. However, its mechanism was not investigated in human yet. Therefore, we performed a randomized single blind crossover trial with 14 healthy young men to examine effects of Korean pear juice on alcohol hangover. All subjects consumed 540ml of spirits (alcohol conc. 20.1v/v%) after 30min from the intervention, i.e. placebo or Korean pear juice treatment. Blood and urine specimens were collected in time-courses (9 time-points for 15h after alcohol consumption). The total and average of hangover severity were alleviated to 16% and 21% by Korean pear juice at 15h after the alcohol consumption (ps<0.05). Particularly, 'trouble concentrating' was significantly improved by the pear juice treatment (p<0.05). Impaired memory, sensitivity to light and sound, and mean of hangover severity were significantly improved by Korean pear juice among the subjects with ALDH2*1/*1 or ALDH2*1/*2 genotypes (ps<0.05) but not in the subjects with ALDH2*2/*2 genotype. In addition, the pear juice treatment lowered levels of blood alcohol (p<0.01). Therefore, Korean pear juice may alleviate alcohol-hangover and its detoxification of alcohol seems to be modified by the genetic variation of ALDH2. 23295157 Anti-human VWF monoclonal antibody SZ-123 prevents arterial thrombus formation by inhibiting VWF-collagen and VWF-platelet interactions in Rhesus monkeys. The interactions between collagen, von Willebrand factor (VWF), and glycoprotein Ib (GPIb) are crucial for hemostasis and thrombosis. This axis represents a promising target for the development of new antithrombotic agents. In this study, we investigate the in vivo antithrombotic efficacy of an anti-VWF monoclonal antibody SZ-123 and its potential underlying mechanisms. Cyclic flow reductions (CFRs), an indicator of arterial thrombosis, were measured in the femoral artery of anesthetized Rhesus monkeys before and after intravenous administration of SZ-123. Ex vivo VWF binding to collagen, platelet agglutination, platelet count, and template bleeding time were used as measurements of antithrombotic activity. In addition, plasma VWF and SZ-123 levels, and VWF occupancy were measured by ELISA. Administration of 0.1, 0.3, and 0.6 mg/kg SZ-123 resulted in 45.3%, 78.2%, and 100% reductions in CFRs, respectively. When 0.3 and 0.6 mg/kg SZ-123 were administered, 100% of VWF was occupied by the antibody. Moreover, 100% ex vivo inhibition of VWF-collagen binding and 60-95% inhibition of platelet agglutination were observed from 15 min to 1 h. None of the doses resulted in significant prolongation of bleeding time. In vitro experiments revealed that SZ-123 not only blocks the collagen-VWF A3 interaction but also indirectly inhibits VWF A1 binding to GPIbα induced by ristocetin. Thus, we demonstrate that SZ-123 prevents in vivo arterial thrombus formation under high shear conditions by inhibiting VWF A3-collagen and VWF A1-platelet interactions and does not significantly prolong bleeding time. 23356946 Chemical synthesis and characterization of epicatechin glucuronides and sulfates: bioanalytical standards for epicatechin metabolite identification. The monoglucuronides and sulfates of epicatechin, 3'-O-methylepicatechin, and 4'-O-methylepicatechin, respectively, were synthesized as authentic bioanalytical standards. Reversed-phase HPLC methods capable of baseline separation of the glucuronides and sulfates have been developed. Both the epicatechin glucuronides and sulfates were stable in the solid state when stored under ambient conditions and in aqueous solution when stored refrigerated. These results should prove invaluable to the research community as analytical standards as well as in future studies of the biological and pharmacological effects of epicatechin in humans. 23174213 Osteopetrosis, osteopetrorickets and hypophosphatemic rickets differentially affect dentin and enamel mineralization. Osteopetrosis (OP) is an inherited disorder of defective bone resorption, which can be accompanied by impaired skeletal mineralization, a phenotype termed osteopetrorickets (OPR). Since individuals with dysfunctional osteoclasts often develop osteomyelitis of the jaw, we have analyzed, if dentin and enamel mineralization are differentially affected in OP and OPR. Therefore, we have applied non-decalcified histology and quantitative backscattered electron imaging (qBEI) to compare the dental phenotypes of Src(-/-), oc/oc and Hyp(-/0) mice, which serve as models for OP, OPR and hypophosphatemic rickets, respectively. While both, Src(-/-) and oc/oc mice, were characterized by defects of molar root formation, only oc/oc mice displayed a severe defect of dentin mineralization, similar to Hyp(-/0) mice. Most importantly, while enamel thickness was not affected in either mouse model, the calcium content within the enamel phase was significantly reduced in oc/oc, but not in Src(-/-) or Hyp(-/0) mice. Taken together, these data demonstrate that dentin and enamel mineralization are differentially affected in Src(-/-) and oc/oc mice. Moreover, since defects of dental mineralization may trigger premature tooth decay and thereby osteomyelitis of the jaw, they further underscore the importance of discriminating between OP and OPR in the respective individuals. 23424087 Air-plant exchange of brominated flame retardants at a rural site: Influencing factor, interspecies difference, and forest scavenging. Brominated flame retardants (BFRs) in eucalyptus leaves and pine needles from a rural site in southern China were measured to investigate the air-plant exchange. Mean concentrations of BFRs were higher in pine needles (79.8 ng/g dry wt) than in eucalyptus leaves (74.5 ng/g), whereas an inverse result was found for the leaf surface particles, with mean concentrations of 3490 ng/g and 5718 ng/g, respectively. For most of the BFRs, the correlations between their concentrations in plants and those in the vapor phase, atmospheric particles, leaf surface particles, and the environmental variables (temperature, wind speed, and relative humidity) at this site were in contrast to the results the authors observed at an electronic waste site previously, indicating that ambient air level plays a vital role in the relationships. The interspecies difference in the BFR profiles and the correlations above implied that pine needles likely have more advantages for uptake of BFRs from gaseous deposition than eucalyptus leaves, for which particle-bound deposition is more important. Like the electronic waste site, the leaf scavenging ratios of BFRs were also controlled by their octanol-air partition coefficient. It was estimated that approximately 154 kg of BFRs in the atmosphere are scavenged annually by forest in this region, which was 1.7 times larger than that via atmospheric deposition to nonforest ground. Environ Toxicol Chem 2013;32:1248-1253. © 2013 SETAC. 23159359 Challenges and recommendations for obtaining chemical structures of industry-provided repurposing candidates. There is an expanding amount of interest directed at the repurposing and repositioning of drugs, as well as how in silico methods can assist these endeavors. Recent repurposing project tendering calls by the National Center for Advancing Translational Sciences (USA) and the Medical Research Council (UK) have included compound information and pharmacological data. However, none of the internal company development code names were assigned to chemical structures in the official documentation. This not only abrogates in silico analysis to support repurposing but consequently necessitates data gathering and curation to assign structures. Here, we describe the approaches, results and major challenges associated with this. 23531533 Transgenerational, dynamic methylation of stomata genes in response to low relative humidity. Transgenerational inheritance of abiotic stress-induced epigenetic modifications in plants has potential adaptive significance and might condition the offspring to improve the response to the same stress, but this is at least partly dependent on the potency, penetrance and persistence of the transmitted epigenetic marks. We examined transgenerational inheritance of low Relative Humidity-induced DNA methylation for two gene loci in the stomatal developmental pathway in Arabidopsis thaliana and the abundance of associated short-interfering RNAs (siRNAs). Heritability of low humidity-induced methylation was more predictable and penetrative at one locus (SPEECHLESS, entropy ≤ 0.02; χ2 < 0.001) than the other (FAMA, entropy ≤ 0.17; χ2 ns). Methylation at SPEECHLESS correlated positively with the continued presence of local siRNAs (r2 = 0.87; p = 0.013) which, however, could be disrupted globally in the progeny under repeated stress. Transgenerational methylation and a parental low humidity-induced stomatal phenotype were heritable, but this was reversed in the progeny under repeated treatment in a previously unsuspected manner. 23259865 Synthesis and biological evaluation of indenoisoquinolines that inhibit both tyrosyl-DNA phosphodiesterase I (Tdp1) and topoisomerase I (Top1). Tyrosyl-DNA phosphodiesterase I (Tdp1) plays a key role in the repair of damaged DNA resulting from the topoisomerase I (Top1) inhibitor camptothecin and a variety of other DNA-damaging anticancer agents. This report documents the design, synthesis, and evaluation of new indenoisoquinolines that are dual inhibitors of both Tdp1 and Top1. Enzyme inhibitory data and cytotoxicity data from human cancer cell cultures were used to establish structure-activity relationships. The potencies of the indenoisoquinolines against Tdp1 ranged from 5 μM to 111 μM, which places the more active compounds among the most potent known inhibitors of this target. The cytotoxicity mean graph midpoints ranged from 0.02 to 2.34 μM. Dual Tdp1-Top1 inhibitors are of interest because the Top1 and Tdp1 inhibitory activities could theoretically work synergistically to create more effective anticancer agents. 23265546 Pattern recognition of peach cultivars (Prunus persica L.) from their volatile components. The volatile compounds of four peach cultivars (Prunus persica L.) were studied: Sudanell, San Lorenzo, Miraflores and Calanda (two clones, Calante and Jesca). 17-23 Samples of each cultivar with the same maturity level were analyzed, measuring color, firmness, and soluble solids content. The pulp was crushed and mixed with water prior to HS-SPME analysis, and GC-MS was used to determine the volatile compounds. Sixty-five compounds were identified using spectral library matching, Kovat's indices and, when available, pure standards. The main components were lactones and C6 compounds. From the distribution of these compounds, Principal Component Analysis led to the clustering of the samples according to their different cultivars. Finally, Canonical Component Analysis was used to create a classification function that identifies the origin of an unknown sample from its volatile composition. The results obtained will help to avoid fraud and protect the European Designation of Origin 'Melocotón de Calanda'. 23132751 Mechanical activation of CaO-based adsorbents for CO(2) capture. The reversible cycling of CaO adsorbents to CaCO(3) for high-temperature CO(2) capture is substantially improved by mechanical treatment. The mechanical milling intensity and conditions of grinding (e.g., wet vs. dry, planetary vs. vibratory milling) were determined to be the main factors that control the effectiveness of the mechanochemical synthesis to enhance the recycling stability of the sorbents prepared. In addition, MgO was used as an example of an inert binder to help mitigate CaCO(3) sintering. Wet planetary milling of MgO into CaCO(3) allowed efficient particle size reduction and the effective dispersion of MgO throughout the particles. Wet planetary milling yielded the most stable sorbents during 50 cycles of carbonation-calcination. 23379784 (Quasi-) 2D aggregation of polystyrene-b-dextran at the air-water interface. Polystyrene-b-dextran (PS-b-Dextran) copolymers can be used to prepare dextran brushes at solid surfaces, applying Langmuir-Blodgett deposition. When recording the interfacial pressure versus area isotherms of a PS-b-Dextran monolayer, time-dependent hysteresis was observed upon compression and expansion. We argue that this is due to (quasi-) 2D aggregation of the copolymer at the air-water surface, with three contributions. First, at large area per molecule, a zero surface pressure is measured; we ascribe this to self-assembly of block copolymers into surface micelles. At intermediate area we identify a second regime ("desorption regime") where aggregation into large patches occurs due to van der Waals attraction between PS blocks. At high surface pressure ("brush regime") we observe hysteretic behavior attributed to H-bonding between dextran chains. When compared to hysteresis of other amphiphilic diblock copolymers (also containing PS, e.g., polystyrene-b-poly(ethylene oxide)) a general criterion can be formulated concerning the extent of hysteresis: when the hydrophobic (PS) block is of equal size as (or bigger than) the hydrophilic block, the hysteresis is maximal. The (quasi-) 2D aggregation of PS-b-Dextran has significant implications for the preparation of dextran brushes at solid surfaces using Langmuir-Blodgett deposition. For each grafting density the monolayer needs to relax, up to several hours, prior to transfer. 23178279 Glucocorticoid receptor concentration and the ability to dimerize influence nuclear translocation and distribution. Glucocorticoid receptor (GR) concentrations and the ability of the GR to dimerize are factors which influence sensitivity to glucocorticoids. Upon glucocorticoid binding, the GR is actively transported into the nucleus, a crucial step in determining GR function. We examined the effects of GR concentration and the ability to dimerize on GR nuclear import, export and nuclear distribution using both live cell microscopy of GFP-tagged GR and immunofluorescence of untagged GR, with both wild type GR (GRwt) and dimerization deficient GR (GRdim). We found that the observed rate of GR nuclear import increases significantly at higher GR concentrations, at saturating concentrations of dexamethasone (10(-6) M) using GFP-tagged GR, while with untagged GR it is only discernable at sub-saturating ligand concentrations (10(-10)-10(-9) M). Loss of dimerization results in a slower observed rate of nuclear import (2.5- to 3.3-fold decrease for GFP-GRdim) as well as a decreased extent of GR nuclear localization (18-27% decrease for untagged GRdim). These results were linked to an increased rate of GR export at low GR concentrations (1.4- to 1.6-fold increase for untagged GR) and where GR dimerization is abrogated (1.5- to 1.7-fold increase for GFP-GRdim). Furthermore, GR dimerization was shown to be required for the appearance of discrete GC-dependent GR nuclear foci, the loss of which may explain the increased rate of GR export for the GRdim. The reduction in the observed rate of nuclear import and increased rate of nuclear export displayed at low GR concentrations and by the GRdim could explain the lowered glucocorticoid response under these conditions. 23607866 Π- Π Stacking Increases the Stability and Loading Capacity of Thermosensitive Polymeric Micelles for Chemotherapeutic Drugs. Thermosensitive amphiphilic block copolymers self-assemble into micelles above their lower critical solution temperature in water, however the micelles generally display mediocre physical stability. To stabilize such micelles and increase their loading capacity for chemotherapeutic drugs, block copolymers with novel aromatic monomers were synthesized by free radical polymerization of N-(2-benzoyloxypropyl methacrylamide (HPMAm-Bz) or the corresponding naphthoyl analogue (HPMAm-Nt), with N-(2-hydroxypropyl) methacrylamide monolactate, using a polyethylene glycol based macroinitiator. The critical micelle temperatures and critical micelle concentrations decreased with increasing the HPMAm-Bz/Nt content. The micelles of 30 to 50 nm were prepared by heating the polymer aqueous solutions from 0 to 50 oC and were colloidally stable for at least 48 h at pH 7.4 and 37 oC. Paclitaxel and docetaxel encapsulation was performed by mixing drug solutions in ethanol with polymer aqueous solutions and heating from 0 to 50 oC. The micelles had a drug loading capacity up to 34 weight % for docetaxel, which is amongst the highest loadings reported for polymeric micelles, with loaded micelle sizes ranging from 60 to 80 nm. The micelles without aromatic groups almost completely released loaded paclitaxel in 10 days, whereas the HPMAm-Bz/Nt containing micelles released 50% of the paclitaxel at the same time, which showed a better retention for the drug of the latter micelles. 1H solid-state NMR spectroscopy data are compatible with π-π stacking between aromatic groups. The empty micelles demonstrated good cytocompatibility, and paclitaxel loaded micelles showed high cytotoxicity to tumor cells. In conclusion, the π-π stacking effect introduced by aromatic groups increases the stability and loading capacity of polymeric micelles. 23143852 High-sensitivity real-time analysis of nanoparticle toxicity in green fluorescent protein-expressing zebrafish. Gold nanoparticles (AuNP) show great potential for diagnostic and therapeutic application in humans. A great number of studies have tested the cytotoxicity of AuNP using cell culture. There is, however, an urgent need to test AuNP in vertebrate animal models that interrogate biodistribution and complex biological traits like organ development, whole body metabolism, and cognitive function. The sheer number of different compounds precludes the use of small rodent model for initial screening. The extended fish embryo test (FET) is used here to bridge the gap between cell culture and small animal models. A study on the toxicity of ultrasmall AuNP in wild type and transgenic zebrafish is presented. FET faithfully reproduce all important findings of a previous study in HeLa cells and add new important information on teratogenicity and hepatotoxicity that could not be gained from studying cultured cells. 23341248 Silver nanoparticle toxicity effect on growth and cellular viability of the aquatic plant Lemna gibba. The toxicity effect of silver nanoparticles (AgNPs) on growth and cellular viability was investigated on the aquatic plant Lemna gibba exposed over 7 d to 0, 0.01, 0.1, 1, and 10 mg/L of AgNPs. Growth inhibition was demonstrated by a significant decrease of frond numbers dependent on AgNP concentration. Under these conditions, reduction in plant cellular viability was detected for 0.1, 1, and 10 mg/L of AgNPs within 7 d of AgNPs treatment. This effect was highly correlated with the production of intracellular reactive oxygen species (ROS). A significant increase of intracellular ROS formation was triggered by 1 and 10 mg/L of AgNP exposure. The induced oxidative stress was related to Ag accumulation within L. gibba plant cells and with the increasing concentration of AgNP exposure in the medium. The authors' results clearly suggested that AgNP suspension represented a potential source of toxicity for L. gibba plant cells. Due to the low release capacity of free soluble Ag from AgNP dissolution in the medium, it is most likely that the intracellular uptake of Ag was directly from AgNPs, triggering cellular oxidative stress that may be due to the release of free Ag inside plant cells. Therefore, the present study demonstrated that AgNP accumulation in an aquatic environment may represent a potential source of toxicity and a risk for the viability of duckweeds. 22258629 Toxic effects of chromium on tannery workers at Sialkot (Pakistan). Chromium is widely used in the leather industry, and tannery workers are under constant threat of adverse health effects due to its excessive exposure. Our objective was to find out the toxic effects of chromium on tannery workers at Sialkot, Pakistan. A total of 240 males consisting of 120 workers from tanneries at Sialkot and equal number of controls were included. Blood complete counts, high-sensitive C-reactive protein, malondialdehyde and routine biochemical tests were carried out by routine procedures. Chromium levels in blood (BCr) and urine were analyzed using graphite furnace atomic absorption spectrophotometer Perkin Elmer analyst-200. Results revealed that all the workers were male with average age of 33 years and 15 (13%) had skin rashes, 14 (12%) had chronic bronchitis, 10 (8%) had gastritis and 4 (3%) conjunctivitis. The tannery workers had significantly raised median (interquartile range) of BCr 569 (377-726) nmol/L as compared to 318 (245-397) nmol/L in the control (p < 0.001). Sixty-five (54%) workers had BCr levels above the upper limit set by Agency for Toxic Substance and Drug Registry. The urinary chromium excretion was significantly high in workers 131 (46-312) nmol/L as compared to 13 (3-26) nmol/L in controls (p < 0.01). The workers had hematological, hepatic and renal function impairment because of oxidative stress on body systems. It is concluded that about half of the workers had excessive exposure to chromium in the tanneries at Sialkot. They had significantly raised chromium levels in their biological fluids and adverse health effects due to enhanced oxidative stress and inflammatory changes. 23563922 Incidentally discovered thyroid nodules: frequency in an adult population during Doppler ultrasonographic evaluation of cervical vessels. In this study, the frequency of thyroid nodules was searched in a population of consecutive patients undergoing routine cervical Doppler evaluation with the use of high-end color Doppler ultrasound units equipped with new technologies that increase nodule conspicuity. Three hundred and fifteen subjects, who had been referred for Doppler ultrasonography of cervical vessel examination, were enrolled in the study. During the examinations, the presence or absence of thyroid nodules, if present, their number (as "single" or "multiple"), the longest diameter, and internal echo pattern of the largest nodule were noted. As a result, one hundred and sixty-one subjects (51 %) were shown to have at least one thyroid nodule. In this subgroup, 54 cases had single and 107 cases had multiple nodules. Incidental thyroid nodules were detected in similar ratios in both men and women (p = 0.34). The results of the study led to the conclusion that half of the elder adult population had at least one thyroid nodule. Use of ultrasound technologies with increasing resolution seems to help significantly in detecting and also evaluating smaller and previously unknown nodules. 22824787 Could maternal exposure to the antidepressants fluoxetine and St. John's Wort induce long-term reproductive effects on male rats? Based on the limited number of studies that have investigated the adverse effects of maternal treatment with antidepressants on the development of male descendents, this study was carried out in rat in order to evaluate if maternal exposure to fluoxetine (FLX) or St. John's Wort (SJW) could disrupt the development of male offspring. The dams were treated daily, by gavage, with 7.5 mg/kg of FLX or 100 mg/kg SJW during pregnancy and lactation. The reproductive and behavior parameters were analyzed in male pups. Results showed decreases in the weight of the full seminal vesicle and in the number of spermatozoa. Moreover, FLX-exposed pups presented reduced seminiferous epithelium height and diameter of seminiferous tubules. The present study shows that maternal exposure to FLX, but not SJW could interfere on reproductive parameters in adult male rats. 23570552 Retention and Release of Cinnamaldehyde from Wheat Protein Matrices. Cinnamaldehyde treatment of gliadin films provided a means of decreasing their solubility, increasing their molecular weight profile, and reducing their overall migration into food simulants as a consequence of the high degree of polymerization achieved. Despite losses incurred in the film manufacturing process, and the amount that remained covalently bonded with protein because of cross-linking, the addition of 1.5, 3, and 5% of cinnamaldehyde (g/100 g protein) to gliadins at pH 2 rendered 1.8, 4.8, and 11.0 mg cinnamaldehyde/g film, respectively, available to be released, and therefore to exert antimicrobial activity. Cinnamaldehyde diffusivity was largely dependent on environmental conditions, increasing from 0.49 × 10(-15) m(2)/s at 30% relative humidity (RH) to 13.1 × 10(-15) m(2)/s at 90% RH and 23 °C. This water sensitivity of films provides a mechanism with a noteworthy potential to retain the compound before its use, to trigger its release when needed, and to modulate the release rate according to the product humidity. 23194566 Comparison of sample preparation methods, validation of an UPLC-MS/MS procedure for the quantification of tetrodotoxin present in marine gastropods and analysis of pufferfish. Tetrodotoxin (TTX) is one of the most potent marine neurotoxins reported. The global distribution of this toxin is spreading with the European Atlantic coastline now being affected. Climate change and increasing pollution have been suggested as underlying causes for this. In the present study, two different sample preparation techniques were used to extract TTX from Trumpet shells and pufferfish samples. Both extraction procedures (accelerated solvent extraction (ASE) and a simple solvent extraction) were shown to provide good recoveries (80-92%). A UPLC-MS/MS method was developed for the analysis of TTX and validated following the guidelines contained in the Commission Decision 2002/657/EC for chemical contaminant analysis. The performance of this procedure was demonstrated to be fit for purpose. This study is the first report on the use of ASE as a mean for TTX extraction, the use of UPLC-MS/MS for TTX analysis, and the validation of this method for TTX in gastropods. 23506138 Interfacial rheology of asphaltenes at oil-water interfaces and interpretation of the equation of state. In an earlier study, (1) oil-water interfacial tension was measured by the pendant drop technique for a range of oil-phase asphaltene concentrations and viscosities. The interfacial tension was found to be related to the relative surface coverage during droplet expansion. The relationship was independent of aging time and bulk asphaltenes concentration, suggesting that cross-linking did not occur at the interface and that only asphaltene monomers were adsorbed. The present study extends this work to measurements of interfacial rheology with the same fluids. Dilatation moduli have been measured using the pulsating droplet technique at different frequencies, different concentrations (below and above CNAC), and different aging times. Care was taken to apply the technique in conditions where viscous and inertial effects are small. The elastic modulus increases with frequency and then plateaus to an asymptotic value. The asymptotic or instantaneous elasticity has been plotted against the interfacial tension, indicating the existence of a unique relationship, between them, independent of adsorption conditions. The relationship between interfacial tension and surface coverage is analyzed with a Langmuir equation of state. The equation of state also enabled the prediction of the observed relationship between the instantaneous elasticity and interfacial tension. The fit by a simple Langmuir equation of state (EOS) suggests minimal effects of aging and of nanoaggregates or gel formation at the interface. Only one parameter is involved in the fit, which is the surface excess coverage Γ∞ = 3.2 molecules/nm(2) (31.25 Å(2)/molecule). This value appears to agree with flat-on adsorption (2) of monomeric asphaltene structures consisting of aromatic cores composed of an average of six fused rings and supports the hypothesis that nanoaggregates do not adsorb on the interface. The observed interfacial effects of the adsorbed asphaltenes, correlated by the Langmuir EOS, are consistent with the asphaltene aggregation behavior in the bulk fluid expected from the Yen-Mullins model. (3, 4). 23435615 The (R)-omeprazole hydroxylation index reflects CYP2C19 activity in healthy Japanese volunteers. PURPOSE: Omeprazole has (R)- and (S)-enantiomers, which exhibit different pharmacokinetics (PK) among patients with cytochrome P450 (CYP) 2C19 genotype groups. The aim of this study was to investigate whether the 1-point, 4-h postdose (R)-omeprazole hydroxylation index (HI) of racemic omeprazole reflects the three CYP2C19 genotype groups in Japanese individuals. METHODS: Ninety healthy Japanese individuals were enrolled and classified into the three different CYP2C19 genotype groups: homozygous extensive metabolizers (hmEMs; n = 34), heterozygous EMs (htEMs; n = 44), and poor metabolizers (PMs; n = 12). Blood samples were drawn 4 h after the intake of an oral dose of omeprazole 40 mg, and plasma levels of omeprazole and its metabolites were analyzed by high-performance liquid chromatography (HPLC) using a chiral column. RESULTS: Mean plasma concentrations of (R)- and (S)-omeprazole in PMs were significantly higher than those in hmEMs and htEMs, and similar results were obtained in the case of omeprazole sulfone. Additionally, there was a significant difference in plasma concentrations of (R)-5-hydroxyomeprazole among CYP2C19 genotype groups, whereas no significant differences were observed in that of (S)-5-hydroxyomeprazole. Similarly, (R)-omeprazole HI in hmEMs, htEMs, and PMs were 5.6, 3.1, and 0.3, respectively, which were significantly different, but no significant difference was present in the (S)-omeprazole HI. CONCLUSION: Our findings demonstrate that (R)-omeprazole HI correlated better with CYP2C19 genotype groups than racemic-omeprazole HI, and these results may be useful for classification among patients in CYP2C19 genotype groups prior to omeprazole treatment. 23295224 Biocatalytic production of alpha-hydroxy ketones and vicinal diols by yeast and human aldo-keto reductases. The α-hydroxy ketones are used as building blocks for compounds of pharmaceutical interest (such as antidepressants, HIV-protease inhibitors and antitumorals). They can be obtained by the action of enzymes or whole cells on selected substrates, such as diketones. We have studied the enantiospecificities of several fungal (AKR3C1, AKR5F and AKR5G) and human (AKR1B1 and AKR1B10) aldo-keto reductases in the production of α-hydroxy ketones and diols from vicinal diketones. The reactions have been carried out with pure enzymes and with an NADPH-regenerating system consisting of glucose-6-phosphate and glucose-6-phosphate dehydrogenase. To ascertain the regio and stereoselectivity of the reduction reactions catalyzed by the AKRs, we have separated and characterized the reaction products by means of a gas chromatograph equipped with a chiral column and coupled to a mass spectrometer as a detector. According to the regioselectivity and stereoselectivity, the AKRs studied can be divided in two groups: one of them showed preference for the reduction of the proximal keto group, resulting in the S-enantiomer of the corresponding α-hydroxy ketones. The other group favored the reduction of the distal keto group and yielded the corresponding R-enantiomer. Three of the AKRs used (AKR1B1, AKR1B10 and AKR3C1) could produce 2,3-butanediol from acetoin. We have explored the structure/function relationships in the reactivity between several yeast and human AKRs and various diketones and acetoin. In addition, we have demonstrated the utility of these AKRs in the synthesis of selected α-hydroxy ketones and diols. 23494732 Ascorbigen Induces Dermal Papilla Cell Proliferation in Vitro, but Fails to Modulate Chemotherapy-Induced Alopecia in Vivo. Ascorbigen (ABG) is the predominant indole-derived compound from Brassica vegetables. In this study, we attempted to evaluate the effects of ABG on hair growth. To this end, we examined the proliferation of isolated human dermal papilla (DP) cells and keratinocytes after incubation in various concentrations (0-1.25 mM) of ABG. Furthermore, hair shaft regrowth was monitored in a mouse model of chemotherapy-induced alopecia (CIA), and hematoxylin and eosin staining was performed for histological analyses. We found that 1.25 mM ABG induced a 1.2-fold increase in the growth of DP cells, but not keratinocytes. However, ABG did not exert significant protective effects against CIA in the mouse model. These findings suggest that ABG may not be able to counteract CIA and that further investigation of the therapeutic potential of ABG in disease models is required. Copyright © 2013 John Wiley & Sons, Ltd. 22967722 Anti-obesity effects of glabridin-rich supercritical carbon dioxide extract of licorice in high-fat-fed obese mice. Licorice (Glycyrrhiza glabra Linne) is a well-known medicinal plant and glabridin is an isoflavan isolated from licorice. In this study, we investigated the anti-obesity effect of glabridin and glabridin-rich supercritical fluid extract of licorice (LSC). Glabridin effectively inhibited adipogenesis in 3T3-L1 cells. Moreover, LSC showed inhibitory effect on adipogenesis in a dose-dependent manner. The inhibitory effect of LSC resulted from inhibiting the induction of the transcriptional factors CCAAT enhancer binding protein alpha and peroxisome proliferator-activated receptor gamma. Then we fed mice with high-fat diet containing none, 0.1% and 0.25% LSC for 8weeks to explore the anti-obesity effect of LSC in vivo. LSC significantly reduced weight gain by high-fat diet in a dose-dependent manner. The reductions of the hypertrophy of white adipose tissue and of fat cell size were also observed. In the liver, LSC supplementation effectively inhibited high-fat diet-induced hepatic steatosis through downregulation of gluconeogenesis related phosphoenolpyruvate carboxykinase and glucose 6-phosphatase and upregulation of the β-oxidation related carnitine palmitoyltransferase 1. Taken together, our results suggest that glabridin and glabridin-rich licorice extract would be effective anti-obesity agents. 22798246 The influence of the genetic and non-genetic factors on bone mineral density and osteoporotic fractures in Chinese women. To investigate the effects of genetic and non-genetic factors on bone mineral densities (BMDs) and osteoporotic fractures. This was a cross-sectional study to investigate the relationships between 18 SNPs and non-genetic factors with BMDs and osteoporotic fractures in 1012 Chinese Han women. Five SNPs in genes GPR177, CTNNB1, MEF2C, SOX6, and TNFRSF11B were associated with L1-4 or total hip BMDs. rs11898505 in SPTBN1 gene was associated with osteoporotic fractures. Subjects carrying the largest number of risk alleles (highest 10 %) not only had lower BMD values as compared to those carrying the least number of risk alleles (lowest 10 %), they also had a higher risk of fracture [P = 0.002, OR = 2.252, 95 %CI (1.136, 4.463)]. Results from multivariate stepwise regression analysis revealed that age [P < 0.001, OR = 1.038, 95 % CI (1.018, 1.058)], number of falls in a year [P < 0.001, OR = 2.347, 95 % CI (1.459, 3.774)], the G risk allele in rs11898505 [P = 0.023, OR = 1.559, 95 % CI (1.062, 2.290)], and the L1-4 BMD [P = 0.017, OR = 0.286, 95 % CI (0.102, 0.798)] were associated with the occurrence of osteoporotic fractures. Genetic (rs11898505) and non-genetic factors (age, number of falls in a year and L1-4 BMD) could work in concert to contribute to the risk of osteoporotic fractures. 23474267 Continuous IV Crotalidae Polyvalent Immune Fab (Ovine) (FabAV) for selected North American Rattlesnake bite patients. BACKGROUND: In patients bitten by North American rattlesnakes and treated with Crotalidae Polyvalent Immune Fab (Ovine) (FabAV), late hematologic abnormalities-persistent, recurrent, or late, new onset of hypofibrinogenemia, prolonged PT/INR, prolonged PTT, and/or thrombocytopenia beyond 48 h post-envenomation-are common, difficult to manage, and may result in morbidity and mortality are common, difficult to manage, and may result in morbidity and mortality. The optimal management of late hematologic abnormalities, particularly the use of further treatment with antivenom, has not been well defined. The current FabAV treatment regimen is to give antivenom as a bolus dose over a one-hour period. We describe our experience using a continuous intravenous infusion of FabAV for late hematologic effects and/or associated bleeding complications in rattlesnake envenomation. METHODS: This is a retrospective, observational case series of patients envenomated by North American rattlesnakes at three medical centers managed with a continuous intravenous infusion of FabAV for late hematologic abnormalities and/or associated bleeding complications. Indications, dilution and infusion protocols, and duration of therapy were individualized. RESULTS: Five cases were identified between July 2010 and September 2011. All patients had profound late hematologic abnormalities and/or were associated with bleeding complications. Several patients had received repeat bolus infusions of FabAV, with or without human blood products, with either inadequate or only transient beneficial response. All patients were then managed with a continuous intravenous infusion of FabAV and all appeared to respond to the continuous intravenous infusion of FabAV, titrated to effect, with cessation of progression and, in most cases, improvement in hematologic abnormalities. Rates of infusion varied from 2 to 4 vials per 24 h (mean = 3.1 ± 0.4 vials/day). The termination of FabAV infusion was between day 6 and day 14 from the time of envenomation (mean = 10 ± 3 days), after which hematologic values were normalized or were normalizing in all patients and continued to do so. DISCUSSION: The use of FabAV as a continuous intravenous infusion, particularly after the acute phase of envenomation has passed, provides a continuous source of circulating antibodies to neutralize venom components reaching circulation from tissue stores and allows natural replenishment of hematologic factors such as platelets and/or fibrinogen. This method is an efficient use of FabAV, avoiding the wasteful excess of a bolus dose, may be more effective, eliminating the potential for destruction of hematologic factors when protective antivenom levels are lost between bolus FabAV doses, and appears to be safe. Further assessments of the stability and sterility of the product during infusion are needed. The need to continue hospitalization is the major drawback, but continued observation and inpatient care may be needed for other indications (e.g. bleeding) in this subset of patients. CONCLUSIONS: A continuous intravenous infusion of FabAV between 2 and 4 vials per day, titrated to effect, and continued for 6-14 days post-envenomation appeared to be associated with reversal of late hematologic effects of rattlesnake envenomation and, when combined with indicated human blood products, control of significant bleeding. Continuous intravenous infusion of FabAV may be safer, more efficacious, and more cost-effective than observation without FabAV treatment or as-needed bolus dosing in selected patients with late hematologic abnormalities. 23194504 Antioxidant activity and effective compounds of immature calamondin peel. The antioxidant activity and the flavonoids of mature and immature calamondin (Citrus mitis Blanco) peel were investigated. The hot water extract of immature calamondin peel exhibited the highest oxygen radical absorbance capacity (ORAC), reducing power, and superoxide scavenging effect. 3',5'-Di-C-β-glucopyranosylphloretin, naringin, hesperidin, nobiletin, and tangeretin are the five major flavonoids found in hot water extract with the levels of 6888±522, 2333±157, 1350±94, 165±13, and 8±4 mg/100 g dry basis, respectively. The contents of nobiletin and tangeretin increased after ripening. The hot water extract of immature calamondin peel was fractionated using a semi-preparative HPLC. Fraction VI showed the highest ORAC value (28.02±2.73 mmol Trolox equivalents (TE)/g fraction) and two compounds, naringin and hesperidin, were identified as the major active components attributed to the antioxidant activity. Fraction V contained 3',5'-di-C-β-glucopyranosylphloretin, which revealed low ORAC value with 7.43 mmol TE/g fraction. However, it might also contribute to antioxidant activity in immature calamondin peel due to its greatest quantity. 23329125 Differential sensitivity to pro-oxidant exposure in two populations of killifish (Fundulus heteroclitus). New Bedford Harbor (MA, U.S.A.; NBH) is a Superfund site inhabited by Atlantic killifish (Fundulus heteroclitus) with altered aryl hydrocarbon receptor (Ahr) signaling, leading to resistance to effects of polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The Ahr is a transcription factor that regulates gene expression of many Phase I and II detoxifying enzymes and interacts with Nrf2, a transcription factor that regulates the response to oxidative stress. This study tested the hypothesis that PCB-resistant killifish exhibit altered sensitivity to oxidative stress. Killifish F(1) embryos from NBH and a clean reference site (Scorton Creek, MA, U.S.A.; SC) were exposed to model pro-oxidant and Nrf2-activator, tert-butylhydroquinone (tBHQ). Embryos were exposed at specific embryonic developmental stages (5, 7, and 9 days post fertilization) and toxicity was assessed, using a deformity score, survival, heart rate, and gene expression to compare sensitivity between PCB -resistant and -sensitive (reference) populations. Acute exposure to tBHQ resulted in transient reduction in heart rate in NBH and SC F(1) embryos. However, embryos from NBH were more sensitive to tBHQ, with more frequent and severe deformities, including pericardial edema, tail deformities, small body size, and reduced pigment and erythrocytes. NBH embryos had lower basal expression of antioxidant genes catalase and glutathione-S-transferase alpha (gsta), and upon exposure to tBHQ, exhibited lower levels of expression of catalase, gsta, and superoxide dismutase compared to controls. This result suggests that adaptation to tolerate PCBs has altered the sensitivity of NBH fish to oxidative stress during embryonic development, demonstrating a cost of the PCB resistance adaptation. 23098805 Effects of menstrual cycle phase on cocaine self-administration in rhesus macaques. Epidemiological findings suggest that men and women vary in their pattern of cocaine use resulting in differences in cocaine dependence and relapse rates. Preclinical laboratory studies have demonstrated that female rodents are indeed more sensitive to cocaine's reinforcing effects than males, with estrous cycle stage as a key determinant of this effect. The current study sought to extend these findings to normally cycling female rhesus macaques, a species that shares a nearly identical menstrual cycle to humans. Dose-dependent intravenous cocaine self-administration (0.0125, 0.0250, and 0.0500 mg/kg/infusion) using a progressive-ratio schedule of reinforcement was determined across the menstrual cycle. The menstrual cycle was divided into 5 discrete phases - menses, follicular, periovulatory, luteal, and late luteal phases - verified by the onset of menses and plasma levels of estradiol and progesterone. Dependent variables including number of infusions self-administered per session, progressive ratio breakpoint, and cocaine intake were analyzed according to cocaine dose and menstrual cycle phase. Analysis of plasma hormone levels verified phase-dependent fluctuations of estradiol and progesterone, with estrogen levels peaking during the periovulatory phase, and progesterone peaking during the luteal phase. Progressive ratio breakpoint, infusions self-administered, and cocaine intake did not consistently vary based on menstrual cycle phase. These findings demonstrate that under the current experimental parameters, the reinforcing effects of cocaine did not vary across the menstrual cycle in a systematic fashion in normally cycling rhesus macaques. 23471156 Biomimetic metal oxides for the extraction of nanoparticles from water. Contamination of nanomaterials in the environment will pose significant health risks in the future. A viable purification method is necessary to address this problem. Here we report the synthesis and application of a series of metal oxides prepared using a biological template for the removal of nanoparticles from the aqueous environment. A simple synthesis of metal oxides such as ZnO, NiO, CuO, Co3O4 and CeO2 employing eggshell membrane (ESM) as a biotemplate is reported. The morphology of the metal oxide powders was characterized using electron microscopes and the lattice structure was established using X-ray diffraction methods. Extraction of nanoparticles from water was carried out to compare the efficiency of metal oxides. NiO showed good extraction efficiency in removing gold and silver nanoparticles from spiked water samples within an hour. Easy access and enhanced stability of metal oxides makes them interesting candidates for applications in industrial effluent treatments and water purifications. 23628455 High salt intake does not produce additional impairment in the coronary artery relaxation of spontaneously hypertensive aged rats. The effect of a salt-based diet on the coronary responsiveness in aged hypertensive rats (SHR) still unclear. We investigated the effects of high salt intake on the relaxation properties of coronary arteries of aged SHRs. Male SHR (32week-old) received drink water (SHR) or 1% NaCl solution (SHR-Salt) for 8weeks. Isolated coronary segments were subjected to concentration-response curves to acetylcholine (ACh) in the presence or absence of L-NAME (100μmol), enalaprilate (10μM), losartan (10μM), and spironolactone (100μM). Salt intake did not increase blood pressure in old SHRs, but caused ventricular hypertrophy. The endothelium-dependent relaxation in SHRs was lower than in Wistar rats. However, salt intake did not add further impairment. Both enalaprilate and losartan reduced the vasodilator response in coronary arteries from Wistar, but did not affect SHR-salt rats. Conversely, losartan attenuated the impaired ACh relaxation observed in SHR. Spironolactone reduced the relaxation induced by ACh in coronary arteries from Wistar rats but not in SHR. The renin-angiotensin-aldosterone system participates in the impaired coronary relaxation in aged SHR, but does not participate in deleterious effects under increased salt intake, indicating that age could differentiate the effects of high sodium intake in coronary arteries of SHR. 23435428 Activation of β-catenin/TCF targets following loss of the tumor suppressor SNF5. The SWI/SNF chromatin remodeling complex is a master regulator of developmental cell-fate decisions, although the key target pathways are poorly characterized. Here, we interrogated the contribution of the SWI/SNF subunit and tumor suppressor SNF5 to the regulation of developmental pathways using conditional mouse and cell culture models. We find that loss of SNF5 phenocopies β-catenin hyperactivation and that SNF5 is essential for regulating Wnt/β-catenin pathway target expression. These data provide insight into chromatin-based mechanisms that underlie developmental regulation and elucidate the emerging theme that mutation of this tumor suppressor complex can activate developmental pathways by uncoupling them from upstream control.Oncogene advance online publication, 25 February 2013; doi:10.1038/onc.2013.37. 23376997 Arylsulfonamide inhibitors of aggrecanases as potential therapeutic agents for osteoarthritis: Synthesis and biological evaluation. Aggrecanases, in particular aggrecanase-2 (ADAMTS-5), are considered the principal proteases responsible for aggrecan degradation in osteoarthritis. For this reason, considerable effort has been put on the discovery and development of aggrecanase inhibitors able to slow down or halt the progression of osteoarthritis. We report herein the synthesis and biological evaluation of a series of arylsulfonamido-based hydroxamates as aggrecanase inhibitors. Compound 18 was found to have a nanomolar activity for ADAMTS-5, ADAMTS-4 and MMP-13 and high selectivity over MMP-1 and MMP-14. Furthermore, this compound proved to be effective in blocking ex vivo cartilage degradation without having effect on cell cytotoxicity. 23463609 Transparent stretchable single-walled carbon nanotube-polymer composite films with near-infrared fluorescence. We report transparent stretchable single-walled carbon nanotube-polymer composite films that emit pronounced Raman and near-infrared fluorescence with a fine spatial resolution. The independent modulation in Raman and fluorescence spectra is demonstrated in response to touch and temperature. The optical signal transduction of transparent stretchable optoelectronic films may enable a paradigm shift in touch-sensing devices eliminating electrical interconnects. 23400943 Neurogenetic disorders and treatment of associated seizures. Seizures are a frequent complication associated with several neurogenetic disorders. Antiepileptic medications remain the mainstay of treatment in these patients. We summarized the available data associated with various antiepileptic therapies used to treat patients with neurogenetic disorders who experienced recurrent seizures. A MEDLINE search was conducted to identify articles and abstracts describing the use of antiepileptic therapy for the treatment of various neurogenetic syndromes. Of all the neurogenetic syndromes, only autism spectrum disorders, Angelman syndrome, Rett syndrome, Dravet syndrome, and tuberous sclerosis complex were identified as having sufficient published information to evaluate therapy. Some efficacy trends were identified, including frequent successes with valproic acid with clonazepam for epilepsy with Angelman syndrome; valproic acid, stiripentol, and clobazam (triple combination therapy) for epilepsy with Dravet syndrome; and vigabatrin for infantile spasms associated with tuberous sclerosis complex. Due to a paucity of information regarding the mechanisms by which seizures are generated in the various disorders, approach to seizure control is primarily based on clinical experience and a limited amount of study data exploring patient outcomes. Although exposure of the developing brain to antiepileptic medications is of some concern, the control of epileptic activity is an important undertaking in these individuals, as the severity of eventual developmental delay often appears to correlate with the severity of seizures. As such, early aggressive therapy is warranted. 23122169 Abietane diterpenoids from Isodon lophanthoides var. graciliflorus and their cytotoxicity. Seven new (1-7) and three known (8-10) abietane diterpenoids were isolated from the methanolic extract of the aerial parts of Isodon lophanthoides var. graciliflorus (Lamiaceae), a folk Chinese medicine and an herb for functional beverages. They were identified as 16-acetoxylsugiol (1), graciliflorin E (2), graciliflorin F (3), 15-O-methylgraciliflorin F (4), 15-hydroxy-20-deoxocarnosol (5), 3β-hydroxysempervirol (6), 15-hydroxy-1-oxosalvibretol (7), abieta-8,11,13-triene-14,19-diol (8), 6,12,15-trihydroxy-5,8,11,13-abietatetraen-7-one (9), and 3α-hinokiol (10) based on the spectroscopic data including COSY (correlated spectroscopy), HMBC (heteronuclear multiple bond correlation), and HR-ESI-MS (high-resolution electrospray ionization mass spectrometry). All the compounds except 10 were obtained from I. lophanthoides for the first time. Compounds 1, 2, 5, 6, 8, and 9 exhibited in vitro cytotoxicity against A549 (human lung adenocarcinoma), MCF-7 (human breast adenocarcinoma), and HeLa (human cervical carcinoma) cell lines with the IC(50) values of 1.79-52.67 μM. 23353698 ABT-737 resistance in B-cells isolated from chronic lymphocytic leukemia patients and leukemia cell lines is overcome by the pleiotropic kinase inhibitor quercetin through Mcl-1 down-regulation. Chronic lymphocytic leukemia (CLL) is the most frequent form of leukemia in adult population and despite numerous studies, it is considered an incurable disease. Since CLL is characterized by overexpression of pro-survival Bcl-2 family members, treatments with their antagonists, such as ABT-737, represent a promising new therapeutic strategy. ABT-737 is a BH3 mimetic agent which binds Bcl-2, Bcl-XL and Bcl-w with high affinity, while weakly interacts with Mcl-1 and Bfl-1. Previous studies demonstrated that quercetin, a flavonoid naturally present in food and beverages, was able to sensitize B-cells isolated from CLL patients to apoptosis when associated with death ligands or fludarabine, through a mechanism involving Mcl-1 down-regulation. Here, we report that the association between ABT-737 and quercetin synergistically induces apoptosis in B-cells and in five leukemic cell lines (Combination Index <1). Peripheral blood mononuclear cell from healthy donors were not affected by quercetin treatment. The molecular pathways triggered by quercetin have been investigated in HPB-ALL cells, characterized by the highest resistance to both ABT-737 and quercetin when applied as single molecules, but highly sensitivity to the co-treatment. In this cell line, quercetin down-regulated Mcl-1 through the inhibition of PI3K/Akt signaling pathway, leading to Mcl-1 instability. The same mechanism was confirmed in B-cells. These results may open new clinical perspectives based on a translational approach in CLL therapy. 23209189 Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21. Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes-associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10⁻⁹). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10⁻¹²) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D. 23292343 The evolution of RuBisCO stability at the thermal limit of photoautotrophy. A long-standing question in evolutionary biology is how organisms adapt to novel environments. In North American hot springs, diversification of a clade of the cyanobacterium Synechococcus into hotter environments has resulted in the unique innovation of a light-driven ecosystem at temperatures up to 74°C, and temperature adaptation of photosynthetic carbon fixation with the Calvin cycle contributed to this process. Here, we investigated the evolution of thermostability of the Calvin cycle enzyme ribulose-1, 5-bisphosphate carboxylase/oxygenase (RuBisCO) during Synechococcus divergence. Circular dichroism thermal scans revealed that the RuBisCO of the most thermotolerant Synechococcus lineage is more stable than those of other lineages or of resurrected ancestral enzymes. Using site-directed mutagenesis, we next identified four amino acid substitutions that together increased stability and activity of this enzyme at higher temperatures. These are clustered near critical subunit interfaces distant from the active site. Each of the four amino acids is also observed in a less thermostable Synechococcus RuBisCO, and the impact on stability of three of these appears to be epistatic. Recombination analyses that allow for recurrent mutation as well as patterns of synonymous variation surrounding these sites suggest that the evolution of a more thermostable RuBisCO may have involved homologous recombination. Our results provide insights on the molecular evolutionary processes that shape niche differentiation and ecosystem function. 23596325 In vivo hepatic lipid quantification using MRS at 7T in a mouse model of glycogen storage disease type 1a. The assessment of liver lipid content and composition is needed in preclinical research to investigate steatosis and steatosis-related disorders. The purpose of this study was to quantify in vivo hepatic fatty acid content and composition using a method based on short echo-time proton magnetic resonance spectroscopy at 7T. Mouse model of glycogen storage disease type 1a with inducible liver-specific deletion of the glucose-6-phosphatase gene (L-G6pc-/-) and control mice were fed a standard diet or a high fat/high sucrose diet (HF/HS) during 9 months. In control mice, hepatic lipid content was found significantly higher with HF/HS diet than with standard diet. As expected, hepatic lipid content was already elevated in L-G6pc-/- mice fed a standard diet compared to control mice. L-G6pc-/- mice rapidly developed steatosis which was not modified by HF/HS diet. On standard diet, estimated amplitudes from olefinic protons were found significantly higher in L-G6pc/- mice compared to that in control mice. L-G6pc-/- mice showed no noticeable polyunsaturation from diallylic protons. Total unsaturated fatty acid indexes measured by gas chromatography were in agreement with MRS measurements. These results showed the great potential of high magnetic field MRS to follow the diet impact and lipid alterations in mouse liver. 22740094 A pathogenetic link between non-alcoholic fatty liver disease and celiac disease. Non-alcoholic fatty liver disease (NAFLD) has recently been recognized as the leading cause of the abnormalities in the liver function tests in the Western countries. Celiac disease (CD) is a permanent immunological intolerance to gluten proteins in genetically predisposed individuals. CD has been reported in 4-13 % of the cases with steatohepatitis, although the pathogenesis of the liver steatosis in CD patients is unclear. Based on the literature data, it can be concluded that the inclusion of serological markers of CD should be a part of the general workup in the patients with steatosis when other causes of the liver disease are excluded and in the patients with NAFLD when metabolic risk factors are not evident. 23611508 Cross-Sectional Tracking of Particle Motion in Evaporating Drops: Flow Fields and Interfacial Accumulation. The lack of an effective technique for three-dimensional flow visualization has limited the experimental exploration of the "coffee ring effect" to the two dimensional, top-down viewpoint. In this report, high-speed, cross-sectional imaging of the flow fields was obtained by using optical coherence tomography to track particle motion in an evaporating colloidal water drop. This approach enables z-dimensional mapping of primary and secondary flow fields and changes in these fields over time. These sectional images show that 1μm diameter polystyrene particles have a highly non-uniform vertical distribution with particles accumulating at both the air-water interface and water-glass interface during drop evaporation. Particle density and relative humidity are shown to influence interfacial entrapment, which suggests that both sedimentation rate and evaporation rate affect the dynamic changes in the cross-sectional distribution of particles. Furthermore, entrapment at the air-water interface delays the time at which particles reach the ring structure. These results suggest that the organization of the ring structure can be controlled based on the ratio of different density particles in a colloidal solution. 23618624 Structure-activity relationships in aminosterol antibiotics: The effect of stereochemistry at the 7-OH group. Squalamine and three aminosterol analogs have been shown to inhibit bacterial cell growth and induce lysis of large unilamellar phospholipid vesicles. The analogs differ in the identity of the polyamine attached at C3 of the sterol, and the stereochemistry of a hydroxyl substituent at C7. Analogs with a tetraammonium spermine polyamine are somewhat more active than analogs with a shorter trisammonium spermidine polyamine, and analogs with an axial (α) hydroxyl substituent at C7 are more active than analogs with the corresponding equatorial (β) hydroxyl group. There is some variability noted; the 7β-OH spermine analog is the most active compound against Escherichia coli, but the least effective against Pseudomonas aeruginosa. Lytic activity correlates well with antimicrobial activity of the compounds, but the lytic activity varies with the phospholipid composition of the vesicles. 23351961 Inhibitory effects of curcumin on gastric cancer cells: A proteomic study of molecular targets. Curcumin, a natural anticancer agent, has been shown to inhibit cell growth in a number of tumor cell lines and animal models. We examined the inhibition of curcumin on cell viability and its induction of apoptosis using different gastric cancer cell lines (BGC-823, MKN-45 and SCG-7901). 3-(4,5-dimethyl-thiazol-2-yl)-2-5-diphenyltetrazolium-bromide (MTT) assay showed that curcumin inhibited cell growth in a dose- (1, 5, 10 and 30μM) and time- (24, 48, 72 and 96h) dependent manner; analysis of Annexin V binding showed that curcumin induced apoptosis at the dose of 10 and 30μM when the cells were treated for 24 and 48h. As cancers are caused by dysregulation of various proteins, we investigated target proteins associated with curcumin by two-dimensional gel electrophoresis (2-DE) and MALDI-TOF-TOF mass spectrometer. BGC-823cells were treated with 30μM curcumin for 24h and total protein was extracted for the 2-DE. In the first dimension of the 2-DE, protein samples (800μg) were applied to immobilized pH gradient (IPG) strips (24cm, pH 3-10, NL) and the isoelectric focusing (IEF) was performed using a step-wise voltage ramp; the second dimension was performed using 12.5% SDS-PAGE gel at 1W constant power per gel. In total, 75 proteins showed significant changes over 1.5-fold in curcumin-treated cells compared to control cells (Student's t-test, p<0.05). Among them, 33 proteins were upregulated and 42 proteins downregulated by curcumin as determined by spot densitometry. 52 proteins with significant mascot scores were identified and implicated in cancer development and progression. Their biological function included cell proliferation, cycle and apoptosis (20%), metabolism (16%), nucleic acid processing (15%), cytoskeleton organization and movement (11%), signal transduction (11%), protein folding, proteolysis and translation (20%), and immune response (2%). Furthermore, protein-protein interacting analysis demonstrated the interaction networks affected by curcumin in gastric cancer cells. These data provide some clues for explaining the anticancer mechanisms of curcumin and explore more potent molecular targets of the drug expected to be helpful for the development of new drugs. 23512337 Self-Assembled PAA-Based Nanoparticles as Potential Gene and Protein Delivery Systems. A series of nanoparticles is prepared via layer-by-layer assembly of oppositely charged, synthetic biocompatible polyamidoamine polymers as potential carriers. Particle size, surface charge and internal chain mobility are quantified as a function of the polymer type and number of layers. The effect of addition of surfactant is examined to simulate the effects of nanoparticle dissolution. The cyctotoxicity of these particles (in epithelia and murine cell lines) are orders of magnitude lower than polyethyleneimine controls. Stable nanoparticles may be prepared from mixtures of strongly, oppositely charged polymers, but less successfully from weakly charged polymers, and, given their acceptable toxicity characteristics, such modularly designed constructs show promise for drug and gene delivery. 22404642 Chemical constituents of Euphorbia hyberna L. (Euphorbiaceae). Chemical investigation of the aerial part and the roots of Euphorbia hyberna L. subs. hyberna. resulted in the isolation and identification of four triterpenoids (3β-O-octadecanoyllupeol (1), glut-5-en-3β-ol (2), 24-methylenecicloartan-3β-ol (3) and cicloart-23-ene-3β,25-diol (6)) along with the phenolic compounds ellagic acid (4) and 3,3'-di-O-methylellagic acid (7). Although these are all known compounds, this is the first report of their isolation from this plant. Their structures were elucidated on the basis of spectral methods, including 2D NMR experiences, and confirmed by comparing with the literature data. 23265892 Structure activity relationship studies of tricyclic bispyran sulfone γ-secretase inhibitors. An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (-)-1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer's disease. Specifically, 4-CF(3) and 4-Br substituted arylsulfone analogs, (-)-1b and (-)-1c, are equipotent to compound (-)-1a. On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated. 23442005 Density Functional Study of Organocatalytic Cross-Aldol Reactions between Two Aliphatic Aldehydes: Insight into Their Functional Differentiation and Origins of Chemo- and Stereoselectivities. The chemo-, diastereo-, and enantioselectivities in proline and axially chiral amino sulfonamide-catalyzed direct aldol reactions between two enolizable aldehydes with different electronic nature have been studied with the aid of density functional theory (DFT) method. The potential energy profiles for the enamine formation between each aliphatic aldehyde and the catalyst confirm that two subject catalysts can successfully differentiate between 3-methylbutanal as an enamine component and α-chloroaldehydes as a carbonyl component. Transition states associated with the stereochemistry-determining C-C bond-forming step with the enamine intermediate addition to the aldehyde acceptor for proline and chiral amino sulfonamide-promoted aldol reactions are reported. DFT calculations not only provide a good explanation for the formation of the sole cross-aldol product between two aliphatic aldehydes both bearing α-methylene protons but also well reproduce the opposite syn vs anti diastereoselectivities in the chiral amino sulfonamide and proline-catalyzed aldol reactions. 23047024 The cholinergic and non-cholinergic effects of organophosphates and oximes in cultured human myoblasts. Organophosphorus compounds (OPs) and oximes may interfere with other molecules than AChE in the living systems, affecting in this way various cellular processes and underlying mechanisms. These non-cholinergic effects may contribute to the clinical status in OP poisoning and therefore deserve equal scientific attention. Here, we investigated the effects of tabun and oxime K048 on the processes known to be involved in muscle response to the environmental factors, like IL-6 release and the regulation of the heat shock proteins (HSPs). While IL-6 stimulates muscle regeneration, which follows well known OP-induced myopathy, HSPs have cytoprotective effect against various stress factors including xenobiotics. All our experiments were carried out on cultured human myoblasts, as the precursors of muscle regeneration. We found unchanged AChE mRNA level after tabun/K048 treatment meaning that tabun and K048 did not interfere with the transcription or stability of this mRNA in the time period tested, even if AChE catalytic activity was significantly affected. On the other hand, after myoblast exposure to tabun, we observed significant changes in the protein levels of HSP 27 and in the secretion of IL-6. Namely, secretion of IL-6 decreased to 53% and the level of HSP 27 increased by 34% compared to the control level. Both effects were attenuated if myoblasts were pretreated with oxime K048, but not if they were treated with K048 after exposure to tabun. The molecular mechanism underlying these effects remains to be elucidated. However, it seems that these effects could be associated with OPs and oximes as a specific group of compounds rather than as a specific compound itself. Overall, the effects of OPs and oximes demonstrated here might play an important role in muscle regeneration which importantly determines the final outcome of OP myotoxicity. 23281069 Synthesis and biological evaluation of diaryl-substituted carboranes as inhibitors of hypoxia inducible factor (HIF)-1 transcriptional activity. Diaromatic-substituted ortho- and meta-carboranes were synthesized as mimics of manassantin A. Among the carboranes synthesized, compounds 1 and 2 showed significant inhibition of hypoxia-induced HIF-1 transcriptional activity, with IC(50) values of 3.2 and 2.2 μM, respectively. Compounds 1 and 2 similarly suppressed hypoxia-induced HIF-1α accumulation in a concentration-dependent manner without affecting the expression level of HIF-1α mRNA. The hypoxia-induced accumulation and translocation of HIF-1α into nuclei were not observed in HeLa cells treated with compounds 1 and 2 by immunofluorescence analysis, revealing that the inhibition of hypoxia-induced HIF-1 transcriptional activity is induced by compounds 1 and 2 through a degradation pathway of the HIF-1α protein under hypoxic conditions. 23323987 Two new diterpenoids from Excoecaria acerifolia. A new tigliane diterpenoid, acerifolin A (1), and a new isopimarane diterpenoid, acerifolin B (2), together with two known compounds, were isolated from Excoecaria acerifolia. Their structures were elucidated on the basis of their spectroscopic methods, including 1D and 2D NMR techniques. All of the compounds were evaluated for cytotoxicity against five human cancer cell lines with cisplantin as a positive control. 23497862 Morphology and structural properties of high-amylose rice starch residues hydrolysed by amyloglucosidase. High-amylose starches are attracting considerable attention because of their potential health benefits and industrial uses. Enzyme hydrolysis of starch is involved in many biological and industrial processes. In this paper, starches were isolated from high-amylose transgenic rice (TRS) and its wild type rice, Te-qing (TQ). The morphological and structural changes of starch residues following Aspergillus niger amyloglucosidase (AAG) hydrolysis were investigated. AAG hydrolysed TQ starch from the granule surface, and TRS starch from the granule interior. During AAG hydrolysis, the content of amorphous structure increased, the contents of ordered structure and single helix decreased, and gelatinisation enthalpy decreased in TQ and TRS starch residues. The A-type polymorph of TRS C-type starch was hydrolysed faster than the B-type polymorph. The short-range ordered structure and B-type polymorph in the peripheral region of the subgranule and the surrounding band of TRS starch increased the resistance of TRS starch to AAG hydrolysis. 23370776 Silencing of RB1 but not of RB2/P130 induces cellular senescence and impairs the differentiation potential of human mesenchymal stem cells. Stem cell senescence is considered deleterious because it may impair tissue renewal and function. On the other hand, senescence may arrest the uncontrolled growth of transformed stem cells and protect organisms from cancer. This double function of senescence is strictly linked to the activity of genes that the control cell cycle such as the retinoblastoma proteins RB1, RB2/P130, and P107. We took advantage of the RNA interference technique to analyze the role of these proteins in the biology of mesenchymal stem cells (MSC). Cells lacking RB1 were prone to DNA damage. They showed elevated levels of p53 and p21(cip1) and increased regulation of RB2/P130 and P107 expression. These cells gradually adopted a senescent phenotype with impairment of self-renewal properties. No significant modification of cell growth was observed as it occurs in other cell types or systems. In cells with silenced RB2/P130, we detected a reduction of DNA damage along with a higher proliferation rate, an increase in clonogenic ability, and the diminution of apoptosis and senescence. Cells with silenced RB2/P130 were cultivated for extended periods of time without adopting a transformed phenotype. Of note, acute lowering of P107 did not induce relevant changes in the in vitro behavior of MSC. We also analyzed cell commitment and the osteo-chondro-adipogenic differentiation process of clones derived by MSC cultures. In all clones obtained from cells with silenced retinoblastoma genes, we observed a reduction in the ability to differentiate compared with the control clones. In summary, our data show evidence that the silencing of the expression of RB1 or RB2/P130 is not compensated by other gene family members, and this profoundly affects MSC functions. 23440956 Graphene-Bonded and -Encapsulated Si Nanoparticles for Lithium Ion Battery Anodes. Silicon (Si) has been considered a very promising anode material for lithium ion batteries due to its high theoretical capacity. However, high-capacity Si nanoparticles usually suffer from low electronic conductivity, large volume change, and severe aggregation problems during lithiation and delithiation. In this paper, a unique nanostructured anode with Si nanoparticles bonded and wrapped by graphene is synthesized by a one-step aerosol spraying of surface-modified Si nanoparticles and graphene oxide suspension. The functional groups on the surface of Si nanoparticles (50-100 nm) not only react with graphene oxide and bind Si nanoparticles to the graphene oxide shell, but also prevent Si nanoparticles from aggregation, thus contributing to a uniform Si suspension. A homogeneous graphene-encapsulated Si nanoparticle morphology forms during the aerosol spraying process. The open-ended graphene shell with defects allows fast electrochemical lithiation/delithiation, and the void space inside the graphene shell accompanied by its strong mechanical strength can effectively accommodate the volume expansion of Si upon lithiation. The graphene shell provides good electronic conductivity for Si nanoparticles and prevents them from aggregating during charge/discharge cycles. The functionalized Si encapsulated by graphene sample exhibits a capacity of 2250 mAh g(-1) (based on the total mass of graphene and Si) at 0.1C and 1000 mAh g(-1) at 10C, and retains 85% of its initial capacity even after 120 charge/discharge cycles. The exceptional performance of graphene-encapsulated Si anodes combined with the scalable and one-step aerosol synthesis technique makes this material very promising for lithium ion batteries. 23071106 Potentiation of sulfonylurea action by an EPAC-selective cAMP analog in INS-1 cells: comparison of tolbutamide and gliclazide and a potential role for EPAC activation of a 2-APB-sensitive Ca2+ influx. Tolbutamide and gliclazide block the K(ATP) channel K(ir)6.2/Sur1, causing membrane depolarization and stimulating insulin secretion in pancreatic beta cells. We examined the ability of the EPAC-selective cAMP analog 8-pCPT-2'-O-Me-cAMP-AM to potentiate the action of these drugs and the mechanism that might account for it. Insulin secretion stimulated by both 200 μM tolbutamide and 20 μM gliclazide, concentrations that had equivalent effects on membrane potential, was inhibited by thapsigargin (1 μM) or the L-type Ca(2+) channel blocker nicardipine (2 μM) and was potentiated by 8-pCPT-2'-O-Me-cAMP-AM at concentrations ≥2 μM in INS-1 cells. Ca(2+) transients stimulated by either tolbutamide or gliclazide were inhibited by thapsigargin or nicardipine and were significantly potentiated by 8-pCPT-2'-O-Me-cAMP-AM at 5 μM but not 1 μM. Both tolbutamide and gliclazide stimulated phospholipase C activity; however, only gliclazide did so independently of its activity at K(ATP) channels, and this activity was partially inhibited by pertussis toxin. 8-pCPT-2'-O-Me-cAMP-AM alone (5 μM) did not stimulate insulin secretion, but did increase intracellular Ca(2+) concentration significantly, and this activity was inhibited by 25 μM 2-aminoethoxydiphenylborate (2-APB) or the removal of extracellular Ca(2+). 8-pCPT-2'-O-Me-cAMP-AM potentiation of insulin secretion stimulated by tolbutamide was markedly inhibited by 2-APB (25 μM) and enhanced by the PKC inhibitor bisindolylmaleimide I (1 μM). Our data demonstrate that the actions of both tolbutamide and gliclazide are strongly potentiated by 8-pCPT-2'-O-Me-cAMP-AM, that gliclazide can stimulate phospholipase C activity via a partially pertussis toxin-sensitive mechanism, and that 8-pCPT-2'-O-Me-cAMP-AM potentiation of tolbutamide action may involve activation of a 2-APB-sensitive Ca(2+) influx. 23422034 Antimicrobial, antiviral and antioxidant activities of "água-mel" from Portugal. "Água-mel" is a honey-based product produced in Portugal for ancient times. Several attributes have been reported to "água-mel" particularly in the alleviation of simple symptoms of upper respiratory tract. Samples of "água-mel" from diverse beekeepers from different regions of Portugal were studied in what concerns antimicrobial, antioxidant and antiviral properties. The amounts of phenol and brown pigment were also evaluated and correlated with the antioxidant activities. A great variability on the levels of these compounds was found among samples which were responsible for the variability detected also on the antioxidant activities, independent on the method used. Generally, antioxidant activity correlated better with brown pigments' amount than with phenols' content. The antimicrobial activity found for "água-mel" samples confirm the virtues reported by popular findings. In addition, this work also reveals the antiviral properties of "água-mel" evidenced by a decrease on the infectivity of the Qβ bacteriophage. 23519059 Tuning the electronic and photophysical properties of heteroleptic iridium(iii) phosphorescent emitters through ancillary ligand substitution: a theoretical perspective. The development and application of phosphorescent emitters in organic light-emitting diodes (OLEDs) have played a critical role in the push to commercialization of OLED-based display and lighting technologies. Here, we use density functional theory methods to study how modifying the ancillary ligand influences the electronic and photophysical properties of heteroleptic bis(4,6-difluorophenyl) pyridinato-N,C [dfppy] iridium(iii) complexes. We examine three families of bidentate ancillary ligands based on acetylacetonate, picolinate, and pyridylpyrazolate. It is found that the frontier molecular orbitals of the heteroleptic complexes can be substantially modulated both as a function of the bidentate ligand family and of the substitution patterns within a family. As a consequence, considerable control over the first absorption and phosphorescence emission transitions, both of which are dominated by one-electron transitions between the HOMO and LUMO, is obtained. Tuning the nature of the ancillary ligand, therefore, can be used to readily modulate the photophysical properties of the emitters, providing a powerful tool in the design of the emitter architecture. 22867274 Metabolic profiling of TRPV1 antagonists of the benzothiazole amide series: implications for in vitro genotoxicity assessment. In vitro metabolic profiling and in vitro genotoxicity assessment are important aspects of the drug discovery program as they eliminate harmful compounds from further development. In standard in vitro genotoxicity testing, induced rat liver S9 is used as an exogenous bio-activation system for detecting promutagens. In this study we show that rat liver S9 is an insufficient system regarding the conversion of TRPV1 antagonists of the benzothiazole amide series into relevant in vivo metabolites. Human and rat hepatocyte experiments demonstrated generation of an aryl amine metabolite that was subsequently N-acetylated. The hydrolyzed metabolites as well as the parent compound were also metabolized into glutathione (GSH) conjugates. Rat liver S9 exhibited a very low amide hydrolysis capacity and no formation of GSH conjugates when supplemented with NADPH and GSH. The discrepancy in metabolic capability between hepatocytes and rat liver S9 led to confounding results in in vitro genotoxicity assessment for this chemical class as judged by the results of Ames test, mouse lymphoma assay, SOS/umu test and Comet assay in rat hepatocytes. This study highlights the pivotal role that understanding the mechanism of metabolite formation has in interpreting as well as designing reliable and relevant in vitro genotoxicity experiments. 23538871 Sponge-Derived Kocuria and Micrococcus spp. as Sources of the New Thiazolyl Peptide Antibiotic Kocurin. Forty four marine actinomycetes of the family Microccocaceae isolated from sponges collected primarily in Florida Keys (USA) were selected from our strain collection to be studied as new sources for the production of bioactive natural products. A 16S rRNA gene based phylogenetic analysis showed that the strains are members of the genera Kocuria and Micrococcus. To assess their biosynthetic potential, the strains were PCR screened for the presence of secondary metabolite genes encoding nonribosomal synthetase (NRPS) and polyketide synthases (PKS). A small extract collection of 528 crude extracts generated from nutritional microfermentation arrays was tested for the production of bioactive secondary metabolites against clinically relevant strains (Bacillus subtilis, methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii and Candida albicans). Three independent isolates were shown to produce a new anti-MRSA bioactive compound that was identified as kocurin, a new member of the thiazolyl peptide family of antibiotics emphasizing the role of this family as a prolific resource for novel drugs. 23353026 Oxidative stress involvement in manganese-induced alpha-synuclein oligomerization in organotypic brain slice cultures. Overexposure to manganese (Mn) has been known to induce neuronal damage. However, little is known of the role that reactive oxygen species (ROS) play in protein aggregation resulting from Mn exposure. The current study investigated whether oxidative stress is involved in manganese-induced alpha-synuclein oligomerization in organotypic brain slices. After application of Mn (0-400μM) for 24h, there was a dose-dependent increase in average percentage of propidium iodide positive (PI(+)) nuclei in slices and levels of lactate dehydrogenase (LDH) in the culture medium. Moreover, the treatment with Mn resulted in a dose-dependent increase in neurocyte apoptosis, ROS level, and decrease in superoxide dismutase (SOD) activity. Mn also caused oxidative damage in cell lipid and protein. At the same time, the exposure of Mn leaded to significantly increase in the expression of alpha-synuclein mRNA and protein. Alpha-synuclein oligomerization occurred in Mn-treated slices, especially on membrane-bound form. It indicated that alpha-synuclein oligomers were more likely to combination cell membranes and resulting in membrane damage. Mn-induced neurocyte damage and alpha-synuclein oligomerization were also partially alleviated by the pretreatment with GSH and aggravated by H2O2 pretreatment. The findings revealed Mn might exert its neurotoxic effects by oxidative stress-mediated alpha-synuclein oligomerization in organotypic brain slices. 23359587 In vivo biological responses to silk proteins functionalized with bone sialoprotein. Recombinant 6mer + BSP protein, combining six repeats of the consensus sequence for Nephila clavipes dragline (6mer) and bone sialoprotein sequence (BSP), shows good support for cell viability and induces the nucleation of hydroxyapatite and tricalcium phosphate during osteoblast in vitro culture. The present study is conducted to characterize this bioengineered protein-based biomaterial further for in vivo behavior related to biocompatibility. 6mer + BSP protein films are implanted in subcutaneous pouches in the back of mice and responses are evaluated by flow cytometry and histology. The results show no major differences between the inflammatory responses induced by 6mer + BSP films and the responses observed for the controls. Thus, this new chimeric protein could represent an alternative for bone regeneration applications. 23455229 Capping-agent-free synthesis of substrate-supported porous icosahedral gold nanoparticles. We report a new capping-agent-free strategy for the synthesis of substrate-supported porous icosahedral Au nanoparticles (NPs) with rough naked surfaces, based on the crystallization from substrate-supported thin solution layers followed by solid-phase thermolysis. The plasmonic properties of icosahedral Au NPs have been studied using single particle dark-field scattering microscopy and spectroscopy. The two distinct localized surface plasmon resonance (LSPR) bands observed in the single particle dark-field spectra can be ascribed to the quadrupole resonance at ca. 425 nm and the size-dependent dipole resonance in the red region (645-708 nm). The unique rough naked surface, the facile synthesis, together with the ability to control the nanoparticle size and to vary the LSPR frequency in the red region, would make the substrate-supported porous icosahedral Au NPs promising on multiple levels in the applications of catalysis, ultrasensitive biosensors, and in surface-enhanced Raman scattering (SERS). 23376162 Sesquiterpenes from the rhizomes of Alpinia japonica and their inhibitory effects on nitric oxide production. A novel norsesquiterpene (1), three new bisabolenes sesquiterpenes (2-4), along with 7 known compounds (5-11), were isolated from the rhizomes of Alpinia japonica. The structures of the new compounds were elucidated by analysis of spectroscopic data. The absolute configuration of C-1 in 3 was deduced via the circular dichroism data of the in situ formed [Rh2(OCOCF3)4] complexes. Inhibitory effects of the isolates on nitric oxide production in lipopolysaccaride-activated RAW264.7 macrophages were evaluated. Compound 6 showed significant inhibitory activity with IC50 value of 5.3μΜ, and compounds 1, 3, 5 and 7-10 exhibited moderate inhibitory activities with IC50 values between 24.5 and 46.3μM. 23352430 Identification of early replicating fragile sites that contribute to genome instability. DNA double-strand breaks (DSBs) in B lymphocytes arise stochastically during replication or as a result of targeted DNA damage by activation-induced cytidine deaminase (AID). Here we identify recurrent, early replicating, and AID-independent DNA lesions, termed early replication fragile sites (ERFSs), by genome-wide localization of DNA repair proteins in B cells subjected to replication stress. ERFSs colocalize with highly expressed gene clusters and are enriched for repetitive elements and CpG dinucleotides. Although distinct from late-replicating common fragile sites (CFS), the stability of ERFSs and CFSs is similarly dependent on the replication-stress response kinase ATR. ERFSs break spontaneously during replication, but their fragility is increased by hydroxyurea, ATR inhibition, or deregulated c-Myc expression. Moreover, greater than 50% of recurrent amplifications/deletions in human diffuse large B cell lymphoma map to ERFSs. In summary, we have identified a source of spontaneous DNA lesions that drives instability at preferred genomic sites. 23470076 Cystatin C: an emerging biomarker in cardiovascular disease. Cystatin C (cys-C) is a small protein molecule (120 amino acid peptide chain, approximately 13kDa) produced by virtually all nucleated cells in the human body. It belongs to the family of papain-like cysteine proteases and its main biological role is the extracellular inhibition of cathepsins. It's near constant production rate, the fact that it is freely filtered from the glomerular membrane and then completely reabsorbed without being secreted from the proximal tubular cells, made it an almost perfect candidate for estimating renal function. The strong correlation between chronic kidney disease (CKD) and cardiovascular disease (CVD) along with the growing understanding of the role of cysteinyl cathepsins in the pathophysiology of CVD inspired researchers to explore the potential association of cys-C with CVD. Throughout the spectrum of CVD (peripheral arterial disease, stroke, abdominal aortic aneurysm, heart failure, coronary artery disease) adverse outcomes and risk stratification have been associated with high plasma levels of cys-C. The exact mechanisms behind the observed correlations have not been comprehensively clarified. Plausible links between high cys-C levels and poor cardiovascular outcome could be impaired renal function, atherogenesis and inflammatory mediators, remodeling of myocardial tissue and others (genetic factors, aging and social habits). The scope of the present article is to systematically review the current knowledge about cys-C biochemistry, metabolism, methods of detection and quantification and pathophysiological associations with different aspects of CVD. 23471218 Exendin-4 protects hypoxic islets from oxidative stress and improves islet transplantation outcome. Oxidative stress produced during pancreatic islet isolation leads to significant β-cell damage. Homeostatic cytokines secreted subsequently to islet transplantation damage β-cells by generating oxygen free radicals. In this study, exendin-4, a glucagon-like peptide-1 analog improved islet transplantation outcome by increasing the survival of diabetic recipient mice from 58% to 100%. We hypothesized that this beneficial effect was due to the ability of exendin-4 to reduce oxidative stress. Further experiments showed that it significantly reduced the apoptotic rate of cultured β-cells subjected to hypoxia or to IL-1β. Reduction of apoptotic events was confirmed in pancreatic islet grafts of exendin-4-treated mice. Exendin-4 enhanced Akt phosphorylation of β-cells and insulin released from them. It even augmented insulin secretion from islets cultivated at hypoxic conditions. Exposure to hypoxia led to a decrease in the activation of Akt, which was reversed when β-cells were pretreated with exendin-4. Moreover, exendin-4 increased the activity of redox enzymes in a hypoxia-treated β-cell line and reduced reactive oxygen species production in isolated pancreatic islets. Recovery from diabetes in mice transplanted with hypoxic islets was more efficient when they received exendin-4. In conclusion, exendin-4 rescued islets from oxidative stress caused by hypoxia or due to cytokine exposure. It improved the outcome of syngenic and xenogenic islet transplantation. 23274917 Determination of genotoxicity by the Comet assay applied to murine precision-cut lung slices. Precision-cut lung slices (PCLSs) are an organotypic lung model that is widely used in pharmacological, physiological, and toxicological studies. Genotoxicity testing, as a pivotal part of early risk assessment, is currently established in vivo in various organs including lung, brain, or liver, and in vitro in cell lines or primary cells. The aim of the present study was to provide the three-dimensional organ culture PCLS as a new ex vivo model for determination of genotoxicity using the Comet assay. Murine PCLS were exposed to increasing concentrations of ethyl methane sulfonate 'EMS' (0.03-0.4%) and formalin (0.5-5mM). Tissue was subsequently dissociated, and DNA single-strand breaks were quantified using the Comet assay. Number of viable dissociated lung cells was between 4×10(5) and 6.7×10(5)cells/slice. Even treatment with EMS did not induce toxicity compared to untreated tissue control. As expected, DNA single-strand breaks were increased dose-dependently and significantly after exposure to EMS. Here, tail length rose from 24μm to 75μm. In contrast, formalin resulted in a significant induction of DNA cross-links. The effects induced by EMS and formalin demonstrate the usefulness of PCLS as a new ex vivo lung model for genotoxicity testing in the early risk assessment of airborne substances in the future. 23541768 Two antagonistic clock-regulated histidine kinases time the activation of circadian gene expression. The cyanobacterial circadian pacemaker consists of a three-protein clock-KaiA, KaiB, and KaiC-that generates oscillations in the phosphorylation state of KaiC. Here we investigate how temporal information encoded in KaiC phosphorylation is transduced to RpaA, a transcription factor required for circadian gene expression. We show that phosphorylation of RpaA is regulated by two antagonistic histidine kinases, SasA and CikA, which are sequentially activated at distinct times by the Kai clock complex. SasA acts as a kinase toward RpaA, whereas CikA, previously implicated in clock input, acts as a phosphatase that dephosphorylates RpaA. CikA and SasA cooperate to generate an oscillation of RpaA activity that is distinct from that generated by either enzyme alone and offset from the rhythm of KaiC phosphorylation. Our observations reveal how circadian clocks can precisely control the timing of output pathways via the concerted action of two oppositely acting enzymes. 23530036 Discoidin Domain Receptor 1 is a novel modulator of megakaryocyte-collagen interactions. Growing evidence demonstrates that extracellular matrices (ECMs) regulate many aspects of megakaryocyte (MK) development; however, among the different ECM receptors, integrin alpha2beta1 and GPVI are the only collagen receptors studied in platelets and MKs. In this study, we demonstrate the expression of the novel collagen receptor Discoidin Domain Receptor 1 (DDR1) by human MKs at both mRNA and protein levels and provide evidence of DDR1 involvement in the regulation of MK motility on type I collagen through a mechanism based on the activity of SHP1 phosphatase and Syk tyrosine kinase. Specifically, we demonstrated that inhibition of DDR1 binding to type I collagen, preserving the engagement of the other collagen receptors, GPVI, alpha2beta1 and LAIR-1 determines a decrease in MK migration due to the reduction in SHP1 phosphatase activity and consequent increase in the phosphorylation level of its main substrate Syk. Consistently, inhibition of Syk activity restored MK migration on type I collagen. In conclusion, we report the expression and function of a novel collagen receptor on human MKs and we point out that increasing level of complexity is necessary to better understand MK-collagen interactions in the bone marrow environment. 23474320 Effects of metal burden and food avoidance on the transfer of metals from naturally contaminated prey to a marine predator Nassarius siquijorensis. Nassarid snails are important opportunistic scavengers widely found in marine intertidal shores and trophic transfer is a predominant source of metal accumulation in these species, thus there is a significant need to understand the controls of metal trophic transfer. In the present study, we took advantage of a severely contaminated estuary and collected two prey organisms (oysters Crassostrea angulata and barnacles Fistulobalanus albicostatus) with different contamination histories. These naturally contaminated prey were fed to a marine neogastropod Nassarius siquijorensis for a period of up to 7 weeks. We then investigated the influences of prey type, metal burden, and subcellular distribution in the prey on the metal accumulation, trophic transfer, and potential toxicity on N. siquijorensis. We demonstrated an obvious negative relationship between the trophic transfer and the metal concentration in prey or the metal dosage. N. siquijorensis exhibited food avoidance behavior to the Cu contaminated food, which effectively reduced the metal ingestion and resulted in a decrease of trophic transfer, as well as a potential toxic effect from dietary exposure. On the other hand, our results also implied the metal-specific impact of subcellular metal distribution in prey on the trophic transfer to N. siquijorensis. Our study suggested that metal burden and feeding avoidance should be considered in studying the trophic transfer of metals in marine benthic food chain. 23406166 A new O-prenylated flavonol from the roots of Sophora interrupta. A new O-prenylated flavonol, 3',4'-dimethoxy-7-(γ,γ-dimethylallyloxy)flavonol (1), together with three known compounds, 2'-hydroxy-3,4-dimethoxychalcone (2), biochanin A (3) and kaempferol-3-O-β-d-glucopyranoside (4), were isolated from the roots of Sophora interrupta Bedd. The structure of compound 1 was elucidated by extensive 1D and 2D NMR spectral studies. 23602986 Neuroactive effects of cotinine on the hippocampus: Behavioral and biochemical parameters. The present work evaluated the effects of nicotine (NIC), cotinine (COT), mecamylamine (MEC), methyllycaconitine (MLA) and dihydro-beta-eritroidine (DHβE) on memory extinction and the following biochemical parameters of the hippocampus: lipid peroxidation (LPO), antioxidant capacity (AC) and the phosphorylation of Extracellular-Signal-Regulated Kinase (ERK 1/2). Young male rats that were implanted bilaterally with cannulae were submitted to memory extinction tests sessions, and their hippocampi were dissected for biochemical assays. The extinction of fear memory was significantly improved by both nicotine and its metabolite. Cotinine significantly increased LPO, while nicotine significantly decreased it. Antioxidant capacity was increased by all treatments. Our results showed that cotinine, unlike nicotine, may increase oxidative stress in the hippocampus, but this increase depends upon the dose used and happens without causing corresponding impairments in cognitive function. Cotinine also increased the phosphorylation of ERK 1/2 in a similar fashion as nicotine. Considering these results, it is plausible to wonder to what extent nicotine-attributed effects are really due to the actions of this alkaloid and whether they could be due instead to cotinine or to cotinine-nicotine interactions within the brain. 23348499 Differential activation and modulation of the glucagon-like peptide-1 receptor by small molecule ligands. The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target for the treatment of type 2 diabetes due to its role in glucose homeostasis. Despite the availability of peptide-based GLP-1R drugs for treatment of this disease, there is great interest in developing small molecules that can be administered orally. The GLP-1R system is complex, with multiple endogenous and clinically used peptide ligands that exhibit different signaling biases at this receptor. This study revealed that small molecule ligands acting at this receptor are differentially biased to peptide ligands and also from each other with respect to the signaling pathways that they activate. Furthermore, allosteric small molecule ligands were also able to induce bias in signaling mediated by orthosteric ligands. This was dependent on both the orthosteric and allosteric ligand as no two allosteric-orthosteric ligand pairs could induce the same signaling profile. We highlight the need to profile compounds across multiple signaling pathways and in combination with multiple orthosteric ligands in systems such as the GLP-1R where more than one endogenous ligand exists. In the context of pleiotropical coupling of receptors and the interplay of multiple pathways leading to physiologic responses, profiling of small molecules in this manner may lead to a better understanding of the physiologic consequences of biased signaling at this receptor. This could enable the design and development of improved therapeutics that have the ability to fine-tune receptor signaling, leading to beneficial therapeutic outcomes while reducing side effect profiles. 23592429 Minireview: androgen metabolism in castration-resistant prostate cancer. The decades-old terminology of androgen independence has been replaced in recent years with castration-resistant prostate cancer. Biological and clinical evidence have together conspired to support the use of this revised terminology by demonstrating that in the vast majority of cases tumors are neither truly depleted of androgens, nor are they free of the requirement for androgens to sustain growth and progression. Abiraterone acetate, an androgen synthesis inhibitor, and enzalutamide, a potent androgen receptor antagonist, both exploit the continued requirement for androgens. A central question, given the therapeutic gains enabled by further suppression of the androgen axis with these newer agents, is whether there may be additional clinical benefit gained by moving the goal posts of androgen suppression even further. The answer lies in part with the mechanisms utilized by tumors that enable resistance to these therapies. The aims of this review were to give a broad outline of steroidogenesis in prostate cancer and to highlight recent developments in understanding resistance to hormonal therapies. 22736593 The Inhibitory Effect of 20(S)-Protopanaxatriol (ppt) Towards UGT1A1 and UGT2B7. Ginseng, a commonly used natural product, has been frequently reported to induce herb-drug interaction with many clinical drugs. The intestinal bacterial metabolites of ginsenosides have been widely regarded as the substance basis for ginseng-drug interactions. To date, little is known about the inhibitory effect of intestinal bacterial metabolites of ginsenosides towards UDP-glucuronosyltransferases (UGTs). In vitro investigation of the inhibition of 20(S)-protopanaxatriol (ppt) towards UGT1A1 and UGT2B7 was carried out. The results showed that ppt exhibited strong noncompetitive inhibition towards UGT1A1 and competitive inhibition towards UGT2B7. The inhibition kinetic parameters (Ki ) were calculated to be 8.8 and 2.2 μM for UGT1A1 and UGT2B7, respectively. Using the maximum plasma concentration of ppt, the alteration of area under the concentration-time curve was calculated to be 20% and 70% respectively for UGT1A1-mediated and UGT2B7-mediated metabolism. However, given that the varied contribution of these two UGT isoforms towards drug metabolism and the influence of herb complexity and individual difference, the explanation of these results should be paid more caution. Copyright © 2012 John Wiley & Sons, Ltd. 23454310 Light induced toxicity reduction of silver nanoparticles to Tetrahymena Pyriformis: Effect of particle size. As a result of the extensive application of silver nanoparticles (AgNPs), their potential hazards, once they are released into the natural environment, are of great concern to people. Since silver is very sensitive to light, the toxicity of AgNPs released into the natural environment will be inevitably affected by light. The aim of this study was to investigate the relationship between light, toxicity, and particle size of AgNPs and deduce the possible mechanism of any interaction. Our study revealed that there was negative correlation between the particle size and the toxicity: small AgNPs (5-10nm) had higher toxicity than large AgNPs (15-25nm) to Tetrahymena pyriformis (T. pyriformis) under dark condition. Comparing the size dependent AgNPs toxicity under dark and light conditions, the effect of light to size dependent AgNPs toxicity was ascertained. The results indicated that AgNPs toxicity was decreased by light and the most important discovery was that the change of size dependent AgNPs toxicity had significant difference under light irradiation. The decrease of small AgNPs toxicity induced by light was more notable than large AgNPs. The decreased level of cell toxicity for small AgNPs was 32±0.7%, whereas it was only 10.6±5.2% for large AgNPs kept 24h under light irradiation. The further investigation indicated that the above changes induced by light can be attributed to the decrease of released silver ions, particle growth and aggregation of AgNPs under light irradiation. The obtained results showed that the light irradiation can promote the rapid growth of small AgNPs and result in the obvious increase of particle size and serious aggregation. These phenomena would induce the decrease of silver ions released from small AgNPs, which is responsible for the remarkable decrease of toxicity for small AgNPs. 23270704 Apocynin and raisanberine alleviate intermittent hypoxia induced abnormal StAR and 3β-HSD and low testosterone by suppressing endoplasmic reticulum stress and activated p66Shc in rat testes. We hypothesized that hypoxia induced testicular damage is mediated by an activated NADPH oxidase (NOX), therefore, APO (apocynin) an inhibitor of NOX and raisanberine (RS), a calcium influx inhibitor were tested if they could attenuate hypoxic toxicity to the testis. Male Sprague-Dawley rats were exposed to hypoxia (10±0.5% O2) for 17d and intervened with APO and RS in the last 6d. Histological changes and expression of pro-inflammation factors were evaluated in vivo. Biomarkers in isolated Leydig cells incubated with H2O2 were also assayed in vitro. Hypoxic rats displayed lower serum testosterone and higher LH and FSH. Upregulation of p22/p47(phox), NOX2, MMP9, PERK and p66Shc was associated with downregulation of StAR, 3β-HSD and Cx43 in the hypoxia testis, revealed by Western blot and immunohistochemical assay, respectively. APO and RS at least partially normalize hypoxia caused male hypogonadism by suppressing ER stress, and p66Shc in testes. 23517028 Biophysical Fragment Screening of the β1-Adrenergic Receptor: Identification of High Affinity Arylpiperazine Leads Using Structure-Based Drug Design. Biophysical fragment screening of a thermostabilized β1-adrenergic receptor (β1AR) using surface plasmon resonance (SPR) enabled the identification of moderate affinity, high ligand efficiency (LE) arylpiperazine hits 7 and 8. Subsequent hit to lead follow-up confirmed the activity of the chemotype, and a structure-based design approach using protein-ligand crystal structures of the β1AR resulted in the identification of several fragments that bound with higher affinity, including indole 19 and quinoline 20. In the first example of GPCR crystallography with ligands derived from fragment screening, structures of the stabilized β1AR complexed with 19 and 20 were determined at resolutions of 2.8 and 2.7 Å, respectively. 23362105 Glycan sequence-dependent Nod2 activation investigated by using a chemically synthesized bacterial peptidoglycan fragment library. Nucleotide oligomerization domain-containing protein 2 (Nod2), an innate immune receptor, recognizes bacterial cell-wall peptidoglycan (PGN), the minimum ligand of which is muramyl dipeptide (MDP). Enzymatic digestion of PGN appears to be important for Nod2 recognition. PGN is degraded by muramidase or glucosamidase through a process that produces two types of glycan sequence; glycans containing GlcNAcβ(1→4)MurNAc or MurNAcβ(1→4)GlcNAc. In this report, a range of disaccharide or tetrasaccharide fragments of each sequence were chemically synthesized, and their activities in stimulating human Nod2 (hNod2) were investigated. The results reveal that hNod2 recognitions is dependent on the glycan sequence, as demonstrated by comparing the activities of glycans with the same peptide moieties. (MurNAcβ(1→4)GlcNAc)(2) -containing structures exhibited stronger activity than those containing (GlcNAcβ(1→4)MurNAc)(2) . The results suggest that differences in the enzymatic degradation process affect the host's immunomodulation process. 23180826 Versican 3'-untranslated region (3'-UTR) functions as a ceRNA in inducing the development of hepatocellular carcinoma by regulating miRNA activity. This study was designed to explore the role of versican in the development of hepatocellular carcinoma (HCC). Ectopic expression of the versican 3'-untranslated region (3'-UTR) was studied as a competitive endogenous RNA for regulating miRNA functions. We used this approach to modulate the expression of versican and its related proteins in 3'-UTR transgenic mice and in the liver cancer cell line HepG2, stably transfected with the 3'-UTR or a control vector. We demonstrated that transgenic mice expressing the versican 3'-UTR developed HCC and increased expression of versican isoforms V0 and V1. HepG2 cells transfected with versican 3'-UTR displayed increased proliferation, survival, migration, invasion, colony formation, and enhanced endothelial cell growth, but decreased apoptosis. We found that versican 3'-UTR could bind to miRNAs miR-133a, miR-199a*, miR-144, and miR-431 and also interacted with CD34 and fibronectin. As a consequence, expression of versican, CD34, and fibronectin was up-regulated by ectopic transfection of the versican 3'-UTR, which was confirmed in HepG2 cells and in transgenic mice as compared with wild-type controls. Transfection with siRNAs targeting the versican 3'-UTR abolished the effects of the 3'-UTR. Taken together, these results demonstrate that versican V0 and V1 isoforms play important roles in HCC development and that versican mRNAs compete with endogenous RNAs in regulating miRNA functions. 23614815 Recycling factors for ribosome disassembly in the apicoplast and mitochondrion of Plasmodium falciparum. The reduced genomes of the apicoplast and mitochondrion of the malaria parasite Plasmodium falciparum are actively translated and antibiotic-mediated translation inhibition is detrimental to parasite survival. In order to understand recycling of organellar ribosomes, a critical step in protein translation, we identified ribosome recycling factors (RRF) encoded by the parasite nuclear genome. Targeting of PfRRF1 and PfRRF2 to the apicoplast and mitochondrion respectively was established by localization of leader sequence-GFP fusions. Unlike any RRF characterized thus far, PfRRF2 formed dimers with disulphide interaction(s) and additionally localized in the cytoplasm, thus suggesting adjunct functions for the factor. PfRRF1 carries a large 108-amino-acid insertion in the functionally critical hinge region between the head and tail domains of the protein, yet complemented Escherichia coli RRF in the LJ14frr(ts) mutant and disassembled surrogate E. coli 70S ribosomes in the presence of apicoplast-targeted EF-G. Recombinant PfRRF2 bound E. coli ribosomes and could split monosomes in the presence of the relevant mitochondrial EF-G but failed to complement the LJ14frr(ts) mutant. Although proteins comprising subunits of P. falciparum organellar ribosomes are predicted to differ from bacterial and mitoribosomal counterparts, our results indicate that the essential interactions required for recycling are conserved in parasite organelles. 23343595 Weight change by baseline BMI from three-year observational data: findings from the Worldwide Schizophrenia Outpatient Health Outcomes Database. The aim was to explore weight and body mass index (BMI) changes by baseline BMI in patients completing three years of monotherapy with various first- and second-generation antipsychotics in a large cohort in a post hoc analysis of three-year observational data. Data were analyzed by antipsychotic and three baseline BMI bands: underweight/normal weight (BMI <25 kg/m(2)), overweight (25-30 kg/m(2)) and obese (>30 kg/m(2)). Baseline BMI was associated with subsequent weight change irrespective of the antipsychotic given. Specifically, a smaller proportion of patients gained ≥7% baseline bodyweight, and a greater proportion of patients lost ≥7% baseline bodyweight with increasing baseline BMI. For olanzapine (the antipsychotic associated with highest mean weight gain in the total drug cohort), the percentage of patients gaining ≥7% baseline weight was 45% (95% CI: 43-48) in the underweight/normal weight BMI cohort and 20% (95% CI: 15-27) in the obese BMI cohort; 7% (95% CI: 6-8) of the underweight/normal cohort and 19% (95% CI: 13-27) of the obese cohort lost ≥7% baseline weight. BMI has an association with the likelihood of weight gain or loss and should be considered in analyses of antipsychotic weight change. 23639075 Two new cytotoxic iridoid esters from the rhizomes and roots of Patrinia heterophylla Bunge. Two new iridoid esters, named patriheterdoid B, C, have been isolated from the rhizomes and roots of Patrinia heterophylla Bunge. Their structures were elucidated by extensive spectroscopic technologies. Together with patriheterdoid B, C, two known analogues have been isolated and identified by means of mass spectrometry and (1)H and (13)C NMR spectrometry. These compounds showed cytotoxic activity against SGC-7901, PC3 cell lines. 23147475 First-principles simulation of the absorption bands of fluorenone in zeolite L. The absorption spectrum of fluorenone in zeolite L is calculated from first-principles simulations. The broadening of each band is obtained from the explicit treatment of the interactions between the chromophore and its environment in the statistical ensemble. The comparison between the simulated and measured spectra reveals the main factors affecting the spectrum of the chromophore in hydrated zeolite L. Whereas each distinguishable band is found to originate from a single electronic transition, the bandwidth is determined by the statistical nature of the environment of the fluorenone molecule. The K(+)···O=C motif is retained in all conformations. Although the interactions between K(+) and the fluorenone carbonyl group result in an average lengthening of the C[double bond, length as m-dash]O bond and in a redshift of the lowest energy absorption band compared to gas phase or non-polar solvents, the magnitude of this shift is noticeably smaller than the total shift. An important factor affecting the shape of the band is fluorenone's orientation, which is strongly affected by the presence of water. The effect of direct interactions between fluorenone and water is, however, negligible. 23362253 Physical interaction between MYCN oncogene and polycomb repressive complex 2 (PRC2) in neuroblastoma: functional and therapeutic implications. CLU (clusterin) is a tumor suppressor gene that we have previously shown to be negatively modulated by the MYCN proto-oncogene, but the mechanism of repression was unclear. Here, we show that MYCN inhibits the expression of CLU by direct interaction with the non-canonical E box sequence CACGCG in the 5'-flanking region. Binding of MYCN to the CLU gene induces bivalent epigenetic marks and recruitment of repressive proteins such as histone deacetylases and Polycomb members. MYCN physically binds in vitro and in vivo to EZH2, a component of the Polycomb repressive complex 2, required to repress CLU. Notably, EZH2 interacts with the Myc box domain 3, a segment of MYC known to be essential for its transforming effects. The expression of CLU can be restored in MYCN-amplified cells by epigenetic drugs with therapeutic results. Importantly, the anticancer effects of the drugs are ablated if CLU expression is blunted by RNA interference. Our study implies that MYC tumorigenesis can be effectively antagonized by epigenetic drugs that interfere with the recruitment of chromatin modifiers at repressive E boxes of tumor suppressor genes such as CLU. 23409952 Rotational dynamics of metal azide ion pairs in dimethylsulfoxide solutions. Azide ion is an excellent vibrational probe for studying ion-ion and ion-dipole interactions in solutions because its frequency is sensitively dependent on its local environments. When azide ion forms contact ion pairs with cations in dimethylsulfoxide (DMSO), free azide ion and contact ion pairs are spectrally well distinguished in FTIR spectra. Here, we investigated vibrational population relaxation, P(t), and orientational relaxation dynamics, r(t), of free azide ion and contact ion pairs (LiN3, NaN3, NH4N3, MgN3(+), and CaN3(+)) in DMSO by IR pump-probe spectroscopy. For metal azide ion pairs, the metal ion slowed down the vibrational relaxation of azide ion by acting like a thermal insulator. Biexponential behavior of r(t) was analyzed in the wobbling-in-a-cone model. The long time component of r(t) of free azide ion was found to be viscosity-dependent. The wobbling motion of azide ion within the frame of metal azide ion pairs was weakly dependent on the countercation. When the overall orientational relaxation of metal azide ion pairs was analyzed by the extended Debye-Stokes-Einstein equation, it was well described under stick or superstick boundary conditions due to a strong interaction between the metal ion and DMSO molecules. Our experimental results provide important insight in understanding the rotational dynamics of small ionic species in polar solvents when the size of the ionic species is smaller than or comparable to that of the solvent molecule. 23425604 Biomarkers of Exposure and Effect in Human Lymphoblastoid TK6 Cells Following [13C2]-Acetaldehyde Exposure. The dose-response relationship for biomarkers of exposure (N(2)-ethylidene-dG adducts) and effect (cell survival and micronucleus formation) was determined across 4.5 orders of magnitude (50nM-2mM) using [(13)C2]-acetaldehyde exposures to human lymphoblastoid TK6 cells for 12h. There was a clear increase in exogenous N (2)-ethylidene-dG formation at exposure concentrations ≥ 1µM, whereas the endogenous adducts remained nearly constant across all exposure concentrations, with an average of 3.0 adducts/10(7) dG. Exogenous adducts were lower than endogenous adducts at concentrations ≤ 10µM and were greater than endogenous adducts at concentrations ≥ 250µM. When the endogenous and exogenous adducts were summed together, statistically significant increases in total adduct formation over the endogenous background occurred at 50µM. Cell survival and micronucleus formation were monitored across the exposure range and statistically significant decreases in cell survival and increases in micronucleus formation occurred at ≥ 1000µM. This research supports the hypothesis that endogenously produced reactive species, including acetaldehyde, are always present and constitute the majority of the observed biological effects following very low exposures to exogenous acetaldehyde. These data can replace default assumptions of linear extrapolation to very low doses of exogenous acetaldehyde for risk prediction. 23539641 Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies. Full, persistent blockade of central neurokinin-1 (NK1) receptors may be a potential antidepressant mechanism. The selective NK1 antagonist orvepitant (GW823296) was used to test this hypothesis. A preliminary positron emission tomography study in eight male volunteers drove dose selection for two randomized six week studies in patients with major depressive disorder (MDD). Displacement of central [(11)C]GR205171 binding indicated that oral orvepitant doses of 30-60 mg/day provided >99% receptor occupancy for ≥24 h. Studies 733 and 833 randomized patients with MDD and 17-item Hamilton Depression Rating Scale (HAM-D)≥22 to double-blind treatment with orvepitant 30 mg/day, orvepitant 60 mg/day or placebo (1:1:1). Primary outcome measure was change from baseline in 17-item HAM-D total score at Week 6 analyzed using mixed models repeated measures. Study 733 (n=328) demonstrated efficacy on the primary endpoint (estimated drug-placebo differences of 30 mg: -2.41, 95% confidence interval (CI) (-4.50 to -0.31) p=0.0245; 60 mg: -2.86, 95% CI (-4.97 to -0.75) p=0.0082). Study 833 (n=345) did not show significance (estimated drug-placebo differences of 30 mg: -1.67, 95% CI (-3.73 to 0.39) p=0.1122; 60 mg: -0.76, 95% CI (-2.85 to 1.32) p=0.4713). The results support the hypothesis that full, long lasting blockade of central NK1 receptors may be an efficacious mechanism for the treatment of MDD. 23265533 Phase behaviour of oat β-glucan/sodium caseinate mixtures varying in molecular weight. The isothermal phase behaviour at 5 °C of mixtures of sodium caseinate and oat β-glucan isolates varying in molecular weight (MW) was investigated by means of phase diagram construction, rheometry, fluorescence microscopy and electrophoresis. Phase diagrams indicated that the compatibility of the β-glucan/sodium caseinate system increases as β-glucan MW decreases. Images of mixtures taken at various biopolymer concentrations revealed phase separated domains. Results also revealed that at the state of thermodynamic equilibrium, lower MW samples yielded considerable viscosity in the mixture. At equivalent hydrodynamic volume of β-glucan in the mixtures, samples varying in molecular weight exhibited similar flow behaviour. A deviation dependent on the protein concentration was observed for the high MW sample in the concentrated regime due to the size of β-glucan aggregates formed. Results demonstrate that by controlling the structural features of β-glucan in mixtures with sodium caseinate, informed manipulation of rheological properties in these systems can be achieved. 22841917 Cognitive enhancement by omega-3 fatty acids from child-hood to old age: findings from animal and clinical studies. Omega-(n)-3 polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are major components of neuronal membranes and have a wide range of functions, from modulating synaptic plasticity and neurochemistry, to neuroimmune-modulation and neuroprotection. Thus, it is not surprising that n-3 PUFA are widely acknowledged to have cognitive-enhancing effects. Although clinical evidence is somewhat conflicting, probably in large part due to methodological issues, animal studies have consistently demonstrated that n-3 PUFA are indispensable for proper brain development, may enhance cognitive function in healthy, adult individuals and attenuate cognitive impairment in aging and age-related disorders, such as dementia. This review discusses and integrates up to date evidence from clinical and animal studies investigating the cognitive-enhancing effects of n-3 PUFA during development, child- and adult-hood, as well as old-age with associated neurodegenerative diseases, such as Alzheimer's disease. Furthermore, we cover the major underlying biochemical and neurophysiological mechanisms by which n-3 PUFA mediate these effects on cognition. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23535326 Novel and highly potent histamine H3 receptor ligands. Part 3: An alcohol function to improve the pharmacokinetic profile. Synthesis and biological evaluation of potent histamine H3 receptor antagonists incorporating a hydroxyl function are described. Compounds in this series exhibited nanomolar binding affinities for human receptor, illustrating a new possible component for the H3 pharmacophore. As demonstrated with compound BP1.4160 (cyclohexanol 19), the introduction of an alcohol function counter-intuitively allowed to reach high in vivo efficiency and favorable pharmacokinetic profile with reduced half-life. 23220588 Acrolein and chloroacetaldehyde: an examination of the cell and cell-free biomarkers of toxicity. Cyclophosphamide and ifosfamide are two commonly used DNA-alkylating agents in cancer chemotherapy that undergo biotransformation to several toxic and non-toxic metabolites, including acrolein and chloroacetaldehyde (CAA). Acrolein and CAA toxicities occur by several different mechanisms, including ROS formation and protein damage (oxidation), however, these pathways of toxicity and protecting agents used to prevent them have yet to be compared and ranked in a single study. This research focused on the molecular targets of acrolein and CAA toxicities and strategies to decrease toxicities. Hepatocyte viability (cytotoxicity) was assessed using Trypan blue uptake; formation of reactive oxygen species (ROS) and endogenous H2O2 were also assessed in the hepatocyte model. In cell-free models (bovine serum albumin and hepatic microsomes), protein carbonylation was the measurement of toxicity. The present study demonstrated that acrolein was a more potent toxin than CAA for freshly isolated rat hepatocytes, bovine serum albumin and rat hepatic microsomes. Acrolein protein carbonylation was dependent on its concentration; as acrolein concentration increased, protein carbonylation increased in a linear trend, whereas, CAA deviated from the trend and did not cause protein carbonylation at lower concentrations (<400 μM). Aldehyde dehydrogenase (ALDH) is a major pathway for detoxifying pathway for CAA in hepatocytes, as a 3-fold increase in cytotoxicity occurred when cells were incubated with cyanamide, an ALDH inhibitor. Inhibiting ALDH or depleting GSH in hepatocytes increased cytotoxicity by about 3-fold in acrolein-treated hepatocytes. The overall effectiveness of protecting agents to prevent or suppress acrolein or CAA toxicities in cell and cell-free models were ranked in order of most effective to least effective: reducing agents (sodium borohydride, sodium bisulfite)>thiol-containing compounds (N-acetylcysteine, cysteine, glutathione, 2-mercaptoethane sulfonate [MESNA], penicillamine)>carbonyl scavengers/amines (aminoguanidine, hydralazine, hydroxylamine)>antioxidants/ROS scavengers (ascorbic acid, Trolox; only utilized in hepatocyte system). An understanding of acrolein and CAA toxicities and the ability of protecting agents to protect against toxicities may help to establish or improve existing therapeutic interventions against the side effects associated with acrolein or CAA in cyclophosphamide or ifosfamide treatment. 23425339 Structure of iron ions in some acetone based electrolytes. X-ray absorption, Mössbauer, and Raman spectroscopy were combined to determine the local environment of iron ions in acetone based solutions of FeCl2. It is shown that part of the Fe(II) ions change their oxidation state, accompanied by symmetry change from octahedral Fe(H2O)6(2+) to tetrahedral [FeCl4](-) at large acetone concentrations. The ratio of Fe(II)/Fe(III) determined by Mössbauer spectroscopy agrees well with that determined by the X-ray absorption studies. Raman measurements confirm quantitative estimations of [FeCl4](-) species in acetone rich solutions. 23324437 Improved Postprandial Ghrelin Response by Nateglinide or Acarbose Therapy Contributes to Glucose Stability in Type 2 Diabetic Patients. Background: Recent studies highlight an important role of ghrelin in glucose homeostasis, while the association between ghrelin regulation and glucose fluctuation is unclear. Aim: We compared the effects of two postprandial hypoglycemic agents on ghrelin response and determined the contribution of ghrelin response to glucose stability in type 2 diabetic (T2DM) patients. Subjects and Methods: Forty newly-diagnosed T2DM patients were randomly allocated to receive Nateglinide or Acarbose for 4 weeks, with twenty BMI-matched normoglycemic subjects as controls. Mean glucose values and daily average glucose excursion were assessed using continuous glucose monitoring system. Serum ghrelin levels were determined by ELISA. Results: T2DM patients had similar fasting ghrelin levels (P = 0.546), while their postprandial ghrelin suppressions at 30 min and 120 min were reduced as compared to BMI-matched normoglycemic controls (P < 0.01). Both Nateglinide and Acarbose increased postprandial ghrelin suppression at 120 min and reduced ghrelin area under the curve (AUCGHRL) (P < 0.05), while only Nateglinide increased postprandial ghrelin suppression at 30 min (P < 0.01), which was positively correlated with the increased early-phase insulin secretion by 4 weeks of Nateglinide therapy (r = 0.48, P = 0.05). The decrease in AUCGHRL was positively correlated with the decrease in daily average glucose excursion and mean glucose values either by 4 weeks of Nateglinide or Acarbose therapy (P < 0.05). Conclusions: Both Natelinide and Acarbose increase postprandial ghrelin suppression. Improved ghrelin regulation is most likely to play a role in glucose stability in T2DM patients with Natelinide or Acarbose therapy. 23232333 Energetic constraints and parental care: is corticosterone indicative of energetic costs of incubation in a precocial bird? Suppression of the adrenocortical response (e.g., corticosterone release) to an acute stressor is a physiological adjustment thought to decrease the likelihood of avian parents abandoning their nests. However, some periods of parental care, like incubation, are energetically costly, thus corticosterone could increase during these stages to allow incubating parents to utilize energy reserves. Wood ducks (Aix sponsa) have ~30 day incubation periods and only the female incubates the eggs. We hypothesized that corticosterone would be important in regulating energy availability during incubation in this species. Because resources invested in reproduction increase with clutch size, we also hypothesized that clutch size would influence plasma corticosterone during incubation. We measured baseline and stress-induced corticosterone in incubating females during early and late stages of incubation. At both stages of incubation all hens had low baseline corticosterone levels. However, we found that stress-induced corticosterone was 105% greater late in incubation than early in incubation. We also detected a significant negative correlation between female body mass and stress-induced corticosterone late in incubation, but not during the early stages of incubation. Furthermore, we found a significant positive relationship between stress-induced corticosterone and clutch size. These lines of evidence support the hypothesis that incubation in wood ducks is energetically costly and corticosterone is important in supporting the energetic demands of incubating hens. Our findings suggest that corticosterone's role in supporting parental care behaviors are dynamic and are influenced by several factors and that there is a greater physiological cost associated with incubating larger clutches. 23296156 Role of immunoglobulin G fragment C receptor polymorphism-mediated antibody-dependant cellular cytotoxicity in colorectal cancer treated with cetuximab therapy. Antibody-dependent cellular cytotoxicity (ADCC), which is activated by effector cells via immunoglobulin G (IgG) fragment C receptors (FcRs), was proposed as a mechanism of cetuximab efficacy. Peripheral blood mononuclear cells (PBMCs) from 23 healthy donors and 13 patients with metastatic colorectal cancer (mCRC) treated with cetuximab were tested for FcγR polymorphisms and cetuximab-mediated ADCC. ADCC was measured by chromium-51 release on a epidermal growth factor receptor (EGFR)-positive human colon cancer cell line. Overall, 86 mCRC patients were genotyped for study purposes. PBMCs harbouring the FcγRIIIa 158 V/V genotype had a significantly higher cetuximab-mediated ADCC. No correlation was found between FcγR polymorphisms and response rate or time to progression after cetuximab-based therapy. Despite the in vitro analysis showing that the FcγRIIIa 158 V/V genotype is associated with higher ADCC, clinical data do not support a predictive role of FcγRIIIa polymorphisms in mCRC treated with cetuximab.The Pharmacogenomics Journal advance online publication, 8 January 2013; doi:10.1038/tpj.2012.54. 22963554 Development of New Drugs for COPD. Chronic obstructive pulmonary disease (COPD) is an increasing global health problem and cause of death. COPD is a chronic inflammatory disease predominantly affecting small airways and lung parenchyma that leads to progressive airway obstruction. However, current therapies fail to prevent either disease progression or mortality. The mainstay of current drug therapy is long-acting bronchodilators. Several once daily inhaled β2-agonists and muscarinic antagonists (and combinations) are now in development. No treatments effectively suppress chronic inflammation in COPD lungs. With better understanding of the inflammatory and destructive process in the pathophysiology of COPD, several new therapeutic targets have been identified. Several mediator antagonists or inhibitors tested in COPD have so far been disappointing, but CXCR2 antagonists that block pulmonary neutrophil and monocyte recruitment are more promising. Broad spectrum anti-inflammatory drugs may be more effective, and include inhibitors of the proinflammatory enzymes phosphodiesterase-4, p38 mitogen-activated protein kinase, Janus kinases, NF-κB kinase and PI3 kinase-γ and -δ, but side effects after oral administration are a major limitation so that in future inhaled delivery may be necessary. A new promising approach is reversal of corticosteroid resistance through increasing histone deacetylase-2 (HDAC2) activity. This might be achieved by existing treatments such as theophylline, nortriptyline and macrolides, or more selectively by PI3 kinase-δ inhibitors. Thus although there have been major advances in the development of long-acting bronchodilators for COPD, it has proved difficult to find anti-inflammatory treatments that are safe and effective. 23370180 Nonhuman primate models of polycystic ovary syndrome. With close genomic and phenotypic similarity to humans, nonhuman primate models provide comprehensive epigenetic mimics of polycystic ovary syndrome (PCOS), suggesting early life targeting for prevention. Fetal exposure to testosterone (T), of all nonhuman primate emulations, provides the closest PCOS-like phenotypes, with early-to-mid gestation T-exposed female rhesus monkeys exhibiting adult reproductive, endocrinological and metabolic dysfunctional traits that are co-pathologies of PCOS. Late gestational T exposure, while inducing adult ovarian hyperandrogenism and menstrual abnormalities, has less dysfunctional metabolic accompaniment. Fetal exposures to dihydrotestosterone (DHT) or diethylstilbestrol (DES) suggest androgenic and estrogenic aspects of fetal programming. Neonatal exposure to T produces no PCOS-like outcome, while continuous T treatment of juvenile females causes precocious weight gain and early menarche (high T), or high LH and weight gain (moderate T). Acute T exposure of adult females generates polyfollicular ovaries, while chronic T exposure induces subtle menstrual irregularities without metabolic dysfunction. 23541436 Anti-inflammatory effect of essential oil and its constituents from fingered citron (Citrus medica L. var. sarcodactylis) through blocking JNK, ERK and NF-κB signaling pathways in LPS-activated RAW 264.7 cells. We investigated the composition of essential oil from fingered citron (Citrus medica L. var. sarcodactylis) (FCEO) peels by GC-MS and its anti-inflammatory effects on lipopolysaccharide (LPS) - stimulated mouse macrophage (RAW 264.7) cells. Fifteen compounds, representing 98.97% of the essential oil, were tentatively identified; the main constituents were limonene (52.44%) and γ-terpinene (28.41%). FCEO significantly inhibited nitric oxide (NO) and prostaglandin E2 (PGE2) by suppressing the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, respectively. Additionally, FCEO suppressed the production of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6. FCEO attenuated LPS-induced nuclear factor-κB (NF-κB) activation via inhibition of inhibitor κB-α phosphorylation. Furthermore, FCEO blocked activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) but not that of p38 mitogen-activated protein kinase. These results indicate that FCEO inhibits LPS-stimulated inflammation by blocking the NF-κB, JNK, and ERK pathways in macrophages, and demonstrate that FCEO possesses anti-inflammatory properties. 23314045 Inhibition of protein glycation by urea and thiourea derivatives of glycine/proline conjugated benzisoxazole analogue - synthesis and structure-activity studies. Synthesis of a new series of urea/thiourea derivatives of Gly/Pro conjugated benzisoxazole has been reported. Structure of the compounds was characterized by physical and spectroscopical data and has been screened for their in vitro antiglycation activity. Several compounds showed promising activity with IC(50) < 5 μM compared to standard rutin (IC(50) = 41.9 μM). Further, it was found that compounds containing methoxy and bromine substituents have exerted highly potent activity. Thus, the title compounds represent novel class of potent antiglycating agents. 23413101 Population-based efficacy modeling of omalizumab in patients with severe allergic asthma inadequately controlled with standard therapy. Omalizumab, a recombinant humanized monoclonal antibody, is the first approved anti-immunoglobulin E (IgE) agent for the treatment of subjects with moderate to severe persistent allergic asthma that are inadequately controlled by the standard of care. The objective of this study was to quantitatively characterize relationships between serum free IgE and pulmonary function (as measured by forced expiratory volume in 1 s [FEV1]) as well as serum free IgE and airway inflammation (as measured by fractional exhaled nitric oxide [FeNO]) using population-based efficacy models. Data were collected from patients in the EXTRA trial who received omalizumab or placebo 150 to 375 mg subcutaneously every 2 or 4 weeks from week 0 to 48 with constant standard of care as background therapy. None of the covariates evaluated, including demographics, disease status, and baseline pharmacodynamic biomarkers, were significant in explaining the variability in the FEV1 or FeNO response to omalizumab. Results from the efficacy models further confirmed the current omalizumab dosing rationale based on the mean target free IgE level of 25 ng/ml and quantified the variability for the target. In addition, the resulting population models could be used to predict population FEV1 or FeNO response for omalizumab and/or other anti-IgE therapeutics for which PK-IgE models are constructed. 23344825 Heavy metals accumulation in crab and shrimps from Pulicat lake, north Chennai coastal region, southeast coast of India. The accumulation of heavy metals such as lead (Pb), iron (Fe), zinc (Zn), cadmium (Cd), and chromium (Cr) was examined in crab (Scylla serrata) and shrimps (Penaeus semisulcatus, Penaeus indicus, and Penaeus monodon) collected from Pulicat lake that receives effluents from industries located in north Chennai, southeast coast of India. The results showed limited difference between crab and prawns as well as significant variations between the organs. Pb is the highly accumulated metal in both crab and shrimps, except P. monodon. The highest metal concentration was mostly found in the liver followed by other organs. The concentration of metals in edible parts (muscle) was within the permissible level and safe for consumption. However, the results of the study clearly indicate the biomagnification of metals in Pulicat lake. 23202250 Nanoparticle toxicity in Daphnia magna reproduction studies: the importance of test design. The increasing use of titanium dioxide nanoparticles (nTiO(2)) inevitably results in their release into the environment, raising concerns about potential adverse effects in wildlife. By following standard test protocols, several studies investigated the ecotoxicity of nTiO(2) among others to Daphnia magna. These studies indicated a large variability - several orders of magnitude - in the response variables. However, other factors, like nanoparticle characteristics and test design, potentially triggering these differences, were largely ignored. Therefore, the present study assessed the chronic ecotoxicity of two nTiO(2) products with varying crystalline structure (A-100; P25) to D. magna. A semi-static and a flow-through exposure scenario were compared, ensuring that both contained environmentally relevant concentrations of dissolved organic carbon. Utilizing the semi-static test design, a concentration as low as 0.06 mg/L A-100 (∼330 nm) significantly reduced the reproduction of daphnia indicating environmental risk. In contrast, no implication in the number of released offspring was observed during the flow-through experiment with A-100 (∼140 nm). Likewise, P25 (∼130 nm) did not adversely affect reproduction irrespective of the test design utilized. Given the present study's results, the particle size, the product composition, i.e. the crystalline structure, and the accumulation of nTiO(2) at the bottom of the test vessel - the latter is relevant for a semi-static test design - may be suggested as factors potentially triggering differences in nTiO(2) toxicity to D. magna. Hence, these factors should be considered to improve environmental risk assessment of nanoparticles. 22750079 Predictors and mediators of add-on mirtazapine-induced cognitive enhancement in schizophrenia--a path model investigation. We aimed to evaluate predictors and mediators of enhancing effect of adjunctive mirtazapine on cognition in schizophrenia. Patients with difficult-to-treat schizophrenia received either mirtazapine (n = 19) or placebo (n = 18) in a double-blind fashion for six weeks. Mirtazapine outperformed placebo on the Block Design and Stroop Dots. In the present subsidiary study, factors underlying this difference were explored with Path Analysis. Add-on mirtazapine had an independent enhancing effect on the Block Design-measured visuo-spatial functioning. Further, this effect was mediated via changes in positive, depressive and parkinsonism symptoms, but not in negative symptoms. This effect was predicted by higher doses of FGAs, longer duration of illness and lower initial Block Design scores. Path Analysis model fit was good. Mirtazapine may have direct and indirect favorable effects on visuo-spatial functioning, but further research is needed. Path analysis may be a feasible statistical method for further research of neurocognition in psychopharmacological interventions in schizophrenia. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23383871 Robust array-based coregulator binding assay predicting ERα-agonist potency and generating binding profiles reflecting ligand structure. Testing chemicals for their endocrine-disrupting potential, including interference with estrogen receptor (ER) signaling, is an important aspect of chemical safety testing. Because of the practical drawbacks of animal testing, the development of in vitro alternatives for the uterotrophic assay and other in vivo (anti)estrogenicity tests has high priority. It was previously demonstrated that an in vitro assay that profiles ligand-induced binding of ERα to a microarray of coregulator-derived peptides might be a valuable candidate for a panel of in vitro assays aiming at an ultimate replacement of the uterotrophic assay. In the present study, the reproducibility and robustness of this coregulator binding assay was determined by measuring the binding profiles of 14 model compounds that are recommended by the Office of Prevention, Pesticides and Toxic Substances for testing laboratory proficiency in estrogen receptor transactivation assays. With a median coefficient of variation of 5.0% and excellent correlation (R(2) = 0.993) between duplicate measurements, the reproducibility of the ERα-coregulator binding assay was better than the reproducibility of other commonly used in vitro ER functional assays. In addition, the coregulator binding assay is correctly predicting the estrogenicity for 13 out of 14 compounds tested. When the potency of the ER-agonists to induce ERα-coregulator binding was compared to their ER binding affinity, their ranking was similar, and the correlation between the EC50 values was excellent (R(2) = 0.96), as was the correlation with their potency in a transactivation assay (R(2) = 0.94). Moreover, when the ERα-coregulator binding profiles were hierarchically clustered using Euclidian cluster distance, the structurally related compounds were found to cluster together, whereas the steroid test compounds having an aromatic A-ring were separated from those with a cyclohexene A-ring. We concluded that this assay is capable of distinguishing ERα agonists and antagonists and that it even reflects the structural similarity of ERα agonists, indicating a potential to achieve identification and classification of ERα endocrine disruptors with high fidelity. 23510192 Mechanism of One-Way Traffic of Hexameric Phi29 DNA Packaging Motor with Four Electropositive Relaying Layers Facilitating Antiparallel Revolution. The importance of nanomotors in nanotechnology is akin to that of mechanical engines to daily life. The AAA+ superfamily is a class of nanomotors performing various functions. Their hexagonal arrangement facilitates bottom-up assembly for stable structures. The bacteriophage phi29 DNA translocation motor contains three coaxial rings: a dodecamer channel, a hexameric ATPase ring, and a hexameric pRNA ring. The viral DNA packaging motor has been believed to be a rotational machine. However, we discovered a revolution mechanism without rotation. By analogy, the earth revolves around the sun while rotating on its own axis. One-way traffic of dsDNA translocation is facilitated by five factors: (1) ATPase changes its conformation to revolve dsDNA within a hexameric channel in one direction; (2) the 30° tilt of the channel subunits causes an antiparallel arrangement between two helices of dsDNA and channel wall to advance one-way translocation; (3) unidirectional flow property of the internal channel loops serves as a ratchet valve to prevent reversal; (4) 5'-3' single-direction movement of one DNA strand along the channel wall ensures single direction; and (5) four electropositive layers interact with one strand of the electronegative dsDNA phosphate backbone, resulting in four relaying transitional pauses during translocation. The discovery of a riding system along one strand provides a motion nanosystem for cargo transportation and a tool for studying force generation without coiling, friction, and torque. The revolution of dsDNA among 12 subunits offers a series of recognition sites on the DNA backbone to provide additional spatial variables for nucleotide discrimination for sensing applications. 23538839 Genetic diversity revealed by single nucleotide polymorphism markers in a worldwide germplasm collection of durum wheat. Evaluation of genetic diversity and genetic structure in crops has important implications for plant breeding programs and the conservation of genetic resources. Newly developed single nucleotide polymorphism (SNP) markers are effective in detecting genetic diversity. In the present study, a worldwide durum wheat collection consisting of 150 accessions was used. Genetic diversity and genetic structure were investigated using 946 polymorphic SNP markers covering the whole genome of tetraploid wheat. Genetic structure was greatly impacted by multiple factors, such as environmental conditions, breeding methods reflected by release periods of varieties, and gene flows via human activities. A loss of genetic diversity was observed from landraces and old cultivars to the modern cultivars released during periods of the Early Green Revolution, but an increase in cultivars released during the Post Green Revolution. Furthermore, a comparative analysis of genetic diversity among the 10 mega ecogeographical regions indicated that South America, North America, and Europe possessed the richest genetic variability, while the Middle East showed moderate levels of genetic diversity. 23115325 Hydrogen sulfide as an allosteric modulator of ATP-sensitive potassium channels in colonic inflammation. The ATP-sensitive potassium channel (K(ATP)) in mouse colonic smooth muscle cell is a complex containing a pore-forming subunit (Kir6.1) and a sulfonylurea receptor subunit (SUR2B). These channels contribute to the cellular excitability of smooth muscle cells and hence regulate the motility patterns in the colon. Whole-cell voltage-clamp techniques were used to study the alterations in K(ATP) channels in smooth muscle cells in experimental colitis. Colonic inflammation was induced in BALB/C mice after intracolonic administration of trinitrobenzene sulfonic acid. K(ATP) currents were measured at a holding potential of -60 mV in high K(+) external solution. The concentration response to levcromakalim (LEVC), a K(ATP) channel opener, was significantly shifted to the left in the inflamed smooth-muscle cells. Both the potency and maximal currents induced by LEVC were enhanced in inflammation. The EC(50) values in control were 6259 nM (n = 10) and 422 nM (n = 8) in inflamed colon, and the maximal currents were 9.9 ± 0.71 pA/pF (60 μM) in control and 39.7 ± 8.8 pA/pF (3 μM) after inflammation. As was seen with LEVC, the potency and efficacy of sodium hydrogen sulfide (NaHS) (10-1000 μM) on K(ATP) currents were significantly greater in inflamed colon compared with controls. In control cells, pretreatment with 100 µM NaHS shifted the EC(50) for LEV-induced currents from 2838 (n = 6) to 154 (n = 8) nM. Sulfhydration of sulfonylurea receptor 2B (SUR2B) was induced by NaHS and colonic inflammation. These data suggest that sulfhydration of SUR2B induces allosteric modulation of K(ATP) currents in colonic inflammation. 23363072 Homopolar dihydrogen bonding in alkali metal amidoboranes: crystal engineering of low-dimensional molecular materials. Hydrogen bonding is a predominant interaction in supramolecular chemistry. The absence of a conventional hydrogen bond donor in LiNMe(2)BH(3) and KNMe(2)BH(3) results in the formation of elaborate M···H-B polymeric arrays supported by heteropolar and homopolar H···H bonding, in a unique synergistic combination of unconventional intermolecular interactions. 23550656 Molecular Dynamics Simulations of CO2 Formation in Interstellar Ices. CO2 ice is one of the most abundant components in ice-coated interstellar ices besides H2O and CO, but the most favorable path to CO2 ice is still unclear. Molecular dynamics calculations on the ultraviolet photodissociation of different kinds of CO-H2O ice systems have been performed at 10 K in order to demonstrate that the reaction between CO and an OH molecule resulting from H2O photodissociation through the first excited state is a possible route to form CO2 ice. However, our calculations, which take into account different ice surface models, suggest that there is another product with a higher formation probability ((3.00 ± 0.07) × 10(-2)), which is the HOCO complex, whereas the formation of CO2 has a probability of only (3.6 ± 0.7) × 10(-4). The initial location of the CO is key to obtain reaction and form CO2: the CO needs to be located deep into the ice. The HOCO complex becomes trapped in the cold ice surface in the trans-HOCO minimum because it quickly loses its internal energy to the surrounding ice, preventing further reaction to H + CO2. Several laboratory experiments have been carried out recently, and they confirm that CO2 can also be formed through other, different routes. Here we compare our theoretical results with the data available from experiments studying the formation of CO2 through a similar pathway as ours, even though the initial conditions were not exactly the same. Our results also show that the HCO van der Waals complex can be formed through the interaction of CO with the H atom that is formed as a product of H2O photodissociation. Thus, the reaction of the H atom photofragment following H2O photodissociation with CO can be a possible route to form HCO ice. 23578636 Garnacha Tintorera-based sweet wines: Chromatic properties and global phenolic composition by means of UV-Vis spectrophotometry. Valdeorras (the N.W. corner of Spain) wants to promote the production and marketing of new sweet wines. The present work represents the first study on sweet wines manufactured with red grapes Vitis vinifera L. Garnacha Tintorera, a teinturier cultivar. Two different red sweet wines were elaborated: the first one was made with dried grapes; Vitis vinifera L. Garnacha Tintorera has excellent potential to produce wines from raisined grapes; the second one, a fortified sweet wine aged in oak barrels. Different red Garnacha Tintorera-based wines (a dry base wine, GBW; a naturally sweet wine, GNSW; and a fortified sweet wine, GFSW) were characterized. Chromatic characteristics and phenolic compounds were established by spectrophotometric methods in order to assess the technology of Garnacha Tintorera-based sweet wines. High molecular weight brown polymers, produced during the grape drying process and isolated from sweet wines by the dialysis process, were responsible for the brown colour of sweet wines. As a consequence, yellowness of sweet wines was also higher which was confirmed by colorimetric indexes. With respect to phenolic content, GFSW presented the lowest content because the maceration-alcoholic fermentation was stopped through the addition of alcohol before the diffusion of red pigments from skins to must was complete. GNSW presented the highest phenolic content due to the concentration effect resulting from evaporation of water from the grapes. Anthocyanins of sweet wines were polymerised in great extent. The percentage of polymerised tannins was sufficient to guarantee the aging process of sweet wines. 23127826 Structure-based design of flavone derivatives as c-myc oncogene down-regulators. Based on molecular docking analysis of complexes between flavone and the c-myc G-quadruplex, we designed and screened 30 flavone derivatives containing various side chains that could potentially form interactions with the G-quadruplex grooves. As a proof-of-concept, the highest-scoring flavone derivatives containing cationic pyridinium side chains were synthesized and their interactions with the c-myc G-quadruplex were examined using a PCR-stop assay. The stabilizing effects of the flavone derivatives were found to be selective towards the c-myc G-quadruplex over other biologically relevant G-quadruplex structures, such as the human telomeric sequence (HTS). The interaction between the most potent compound of the series and the c-myc G-quadruplex was examined in depth using UV-Vis titration, molecular modeling and CD spectroscopy. Our results suggest that in addition to stabilizing the c-myc G-quadruplex, the flavone derivatives were capable of inducing the formation of the G-quadruplex structure even in the absence of monovalent cations. The flavone derivatives were found to be potent inhibitors of c-myc promoters within the cellular environment and displayed promising cytotoxic behavior against human cancer cell lines. 22563917 Development of self-microemulsifying drug delivery system for oral bioavailability enhancement of berberine hydrochloride. The purpose of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) to improve the oral bioavailability of Berberine hydrochloride (BBH), an important bioactive compound from Chinese Medicines with poor water solubility. Pseudoternary phase diagrams were constructed using oil, surfactant and co-surfactant types to identify the efficient self-microemulsification region. SMEDDS was characterized by morphological observation, droplet size, zeta-potential determination, stability, in vitro release and in vivo bioavailability study. The optimal formulation with the best self-microemulsifying and solubilization ability consisted of 40% (w/w) of ethyl linoleate and oleic acid (2:1), 35% (w/w) Tween-80 and 25% (w/w) glycerol. The SMEDDS of BBH could exhibit good stability. In vitro release test showed a complete release of BBH from SMEDDS was in 5 h. In vivo results indicated that the peak plasma concentration (C(max)) and the area under the curve (AUC(0→12 h)) of SMEDDS of BBH were higher than the commercial tablet by 163.4% and 154.2%, respectively. The relative bioavailability of SMEDDS of BBH was enhanced about 2.42-fold compared with the commercial tablet in rats. The study confirmed that the SMEDDS formulation could be used as a possible alternative to traditional oral formulations of BBH to improve its bioavailability. 23584530 The histone demethylase Jmjd3 sequentially associates with the transcription factors Tbx3 and Eomes to drive endoderm differentiation. Stem cell differentiation depends on transcriptional activation driven by lineage-specific regulators as well as changes in chromatin organization. However, the coordination of these events is poorly understood. Here, we show that T-box proteins team up with chromatin modifying enzymes to drive the expression of the key lineage regulator, Eomes during endodermal differentiation of embryonic stem (ES) cells. The Eomes locus is maintained in a transcriptionally poised configuration in ES cells. During early differentiation steps, the ES cell factor Tbx3 associates with the histone demethylase Jmjd3 at the enhancer element of the Eomes locus to allow enhancer-promoter interactions. This spatial reorganization of the chromatin primes the cells to respond to Activin signalling, which promotes the binding of Jmjd3 and Eomes to its own bivalent promoter region to further stimulate Eomes expression in a positive feedback loop. In addition, Eomes activates a transcriptional network of core regulators of endodermal differentiation. Our results demonstrate that Jmjd3 sequentially associates with two T-box factors, Tbx3 and Eomes to drive stem cell differentiation towards the definitive endoderm lineage. 23261645 The effects of jaspamide on human cardiomyocyte function and cardiac ion channel activity. Jaspamide (jasplakinolide; NSC-613009) is a cyclodepsipeptide that has antitumor activity. A narrow margin of safety was observed between doses required for efficacy in mouse tumor models and doses that caused severe acute toxicity in rats and dogs. We explored the hypothesis that the observed toxicity was due to cardiotoxicity. Jaspamide was tested in a patch clamp assay to determine its effect on selected cardiac ion channels. Jaspamide (10 μM) inhibited Kv1.5 activity by 98.5%. Jaspamide also inhibited other channels including Cav1.2, Cav3.2, and HCN2; however, the Kv11.1 (hERG) channel was minimally affected. Using spontaneously contracting human cardiomyocytes derived from induced pluripotent stem cells, effects on cardiomyocyte contraction and viability were also examined. Jaspamide (30 nM to 30 μM) decreased cardiomyocyte cell indices and beat amplitude, putative measurements of cell viability and cardiac contractility, respectively. Concentration-dependent increases in rhythmic beating rate were noted at ≤ 6 h of treatment, followed by dose-dependent decreases after 6 and 72 h exposure. The toxic effects of jaspamide were compared with that of the known cardiotoxicant mitoxantrone, and confirmed by multiparameter fluorescence imaging analysis. These results support the hypothesis that the toxicity observed in rats and dogs is due to toxic effects of jaspamide on cardiomyocytes. 23352141 A bacterial source for mollusk pyrone polyketides. In the oceans, secondary metabolites often protect otherwise poorly defended invertebrates, such as shell-less mollusks, from predation. The origins of these metabolites are largely unknown, but many of them are thought to be made by symbiotic bacteria. In contrast, mollusks with thick shells and toxic venoms are thought to lack these secondary metabolites because of reduced defensive needs. Here, we show that heavily defended cone snails also occasionally contain abundant secondary metabolites, γ-pyrones known as nocapyrones, which are synthesized by symbiotic bacteria. The bacteria, Nocardiopsis alba CR167, are related to widespread actinomycetes that we propose to be casual symbionts of invertebrates on land and in the sea. The natural roles of nocapyrones are unknown, but they are active in neurological assays, revealing that mollusks with external shells are an overlooked source of secondary metabolite diversity. 23627597 Gold-Catalyzed Cycloisomerization of 1,6-Diyne Carbonates and Esters to 2,4a-Dihydro-1H-fluorenes. A synthetic method to prepare 2,4a-dihydro-1H-fluorenes efficiently from gold(I)-catalyzed 1,2-acyloxy migration/cyclopropenation/Nazarov cyclization of 1,6-diyne carbonates and esters is described. The suggested reaction pathway provides rare examples of [2,3]-sigmatropic rearrangement in this class of compounds as well as the involvement of an in situ formed cyclopropene intermediate in gold catalysis. Experimental and ONIOM(QM:QM') (our own n-layered integrated molecular orbital and molecular mechanics(quantum mechanics:quantum mechanics')) computational studies based on the proposed Au carbenoid species provide insight into this unique selectivity. 23160419 Nitrogen dioxide at the air-water interface: trapping, absorption, and solvation in the bulk and at the surface. The interaction of NO(2) with water surfaces in the troposphere is of major interest in atmospheric chemistry. We examined an initial step in this process, the uptake of NO(2) by water through the use of molecular dynamics simulations. An NO(2)-H(2)O intermolecular potential was obtained by fitting to high-level ab initio calculations. We determined the binding of NO(2)-H(2)O to be about two times stronger than that previously calculated. From scattering simulations of an NO(2) molecule interacting with a water slab we observed that the majority of the scattering events resulted in outcomes in which the NO(2) molecule became trapped at the surface or in the interior of the water slab. Typical surface-trapped/adsorbed and bulk-solvated/absorbed trajectories were analyzed to obtain radial distribution functions and the orientational propensity of NO(2) with respect to the water surface. We observed an affinity of the nitrogen atom for the oxygen in water, rather than hydrogen-bonding which was rare. The water solvation shell was less tight for the bulk-absorbed NO(2) than for the surface-adsorbed NO(2). Adsorbed NO(2) demonstrated a marked orientational preference, with the oxygens pointing into the vacuum. Such behavior is expected for a mildly hydrophobic and surfactant molecule like NO(2). Estimates based on our results suggest that at high NO(2) concentrations encountered, for example, in some sampling systems, adsorption and reaction of NO(2) at the surface may contribute to the formation of gas-phase HONO. 23620487 Inhibition of CYP2C19 and CYP3A4 by Omeprazole Metabolites and their Contribution to Drug-Drug Interactions. The aim of this study was to evaluate the contribution of metabolites to drug-drug interactions (DDI) using the inhibition of CYP2C19 and CYP3A4 by omeprazole and its metabolites as a model. Of the metabolites identified in vivo, 5-hydroxyomeprazole, 5'-O-desmethylomeprazole, omeprazole sulfone and carboxyomeprazole had an AUCm/AUCp ≥ 0.25 when either total or unbound concentrations were measured following a single 20 mg dose of omeprazole in a cocktail. All of the metabolites inhibited CYP2C19 and CYP3A4 reversibly. In addition omeprazole, omeprazole sulfone and 5'-O-desmethylomeprazole were mechanism-based inhibitors (MBI) of CYP2C19 while omeprazole and 5'-O-desmethylomeprazole were found to be MBIs of CYP3A4. Reversible [I]/Ki ratios and irreversible λ/kdeg ratios were used to evaluate whether characterization of the metabolites affected DDI risk assessment. Identifying omeprazole as an MBI of both CYP2C19 and CYP3A4 was the most important factor in DDI risk assessment. Consideration of reversible inhibition by omeprazole and its metabolites would not identify DDI risk with CYP3A4, and with CYP2C19 reversible inhibition values would only identify DDI risk if the metabolites are included in the assessment. Based on inactivation data, CYP2C19 and CYP3A4 inactivation by omeprazole would be sufficient to identify risk, but metabolites were predicted to contribute 30-63% to the in vivo hepatic interactions. Hence, consideration of metabolites may be important in quantitative predictions of in vivo DDIs. The results of this study show that while metabolites contribute to in vivo DDIs their relative abundance in circulation or logP values do not predict their contribution to in vivo DDI risk. 23430408 A toxicokinetic model for thiamethoxam in rats: implications for higher-tier risk assessment. Risk assessment for mammals is currently based on external exposure measurements, but effects of toxicants are better correlated with the systemically available dose than with the external administered dose. So for risk assessment of pesticides, toxicokinetics should be interpreted in the context of potential exposure in the field taking account of the timescale of exposure and individual patterns of feeding. Internal concentration is the net result of absorption, distribution, metabolism and excretion (ADME). We present a case study for thiamethoxam to show how data from ADME study on rats can be used to parameterize a body burden model which predicts body residue levels after exposures to LD50 dose either as a bolus or eaten at different feeding rates. Kinetic parameters were determined in male and female rats after an intravenous and oral administration of (14)C labelled by fitting one-compartment models to measured pesticide concentrations in blood for each individual separately. The concentration of thiamethoxam in blood over time correlated closely with concentrations in other tissues and so was considered representative of pesticide concentration in the whole body. Body burden model simulations showed that maximum body weight-normalized doses of thiamethoxam were lower if the same external dose was ingested normally than if it was force fed in a single bolus dose. This indicates lower risk to rats through dietary exposure than would be estimated from the bolus LD50. The importance of key questions that should be answered before using the body burden approach in risk assessment, data requirements and assumptions made in this study are discussed in detail. 23608613 Evaluation and modification of commercial dry powder inhalers for the aerosolization of a submicrometer excipient enhanced growth (EEG) formulation. The aim of this study was to evaluate and modify commercial dry powder inhalers (DPIs) for the aerosolization of a submicrometer excipient enhanced growth (EEG) formulation. The optimized device and formulation was then tested in a realistic in vitro mouth-throat - tracheobronchial (MT-TB) model. An optimized EEG submicrometer powder formulation, consisting of albuterol sulfate (drug), mannitol (hygroscopic excipient), l-leucine (dispersion enhancer) and poloxamer 188 (surfactant) in a ratio of 30:48:20:2 was prepared using a Büchi Nano spray dryer. The aerosolization performance of the EEG formulation was evaluated with five conventional DPIs: Aerolizer, Novolizer, HandiHaler, Exubera and Spiros. To improve powder dispersion, the HandiHaler was modified with novel mouth piece (MP) designs. The aerosol performance of each device was assessed using a next generation impactor (NGI) at airflow rates generating a pressure drop of 4kPa across the DPI. In silico and in vitro deposition and hygroscopic growth of formulations was studied using a MT-TB airway geometry model. Both HandiHaler and Aerolizer produced high emitted doses (EDs) together with a significant submicrometer aerosol fraction. A modified HandiHaler with a MP including a three-dimensional (3D) array of rods (HH-3D) produced a submicrometer particle fraction of 38.8% with a conventional fine particle fraction (%<5μm) of 97.3%. The mass median diameter (MMD) of the aerosol was reduced below 1μm using this HH-3D DPI. The aerosol generated from the modified HandiHaler increased to micrometer size (2.8μm) suitable for pulmonary deposition, when exposed to simulated respiratory conditions, with negligible mouth-throat (MT) deposition (2.6%). 23332762 Inactivation of BAD by IKK inhibits TNFα-induced apoptosis independently of NF-κB activation. The IκB kinase complex (IKK) is a key regulator of immune responses, inflammation, cell survival, and tumorigenesis. The prosurvival function of IKK centers on activation of the transcription factor NF-κB, whose target gene products inhibit caspases and prevent prolonged JNK activation. Here, we report that inactivation of the BH3-only protein BAD by IKK independently of NF-κB activation suppresses TNFα-induced apoptosis. TNFα-treated Ikkβ(-/-) mouse embryonic fibroblasts (MEFs) undergo apoptosis significantly faster than MEFs deficient in both RelA and cRel due to lack of inhibition of BAD by IKK. IKK phosphorylates BAD at serine-26 (Ser26) and primes it for inactivation. Elimination of Ser26 phosphorylation promotes BAD proapoptotic activity, thereby accelerating TNFα-induced apoptosis in cultured cells and increasing mortality in animals. Our results reveal that IKK inhibits TNFα-induced apoptosis through two distinct but cooperative mechanisms: activation of the survival factor NF-κB and inactivation of the proapoptotic BH3-only BAD protein. 23402647 Ionic liquid mediated synthesis and surface modification of multifunctional mesoporous Eu:GdF3 nanoparticles for biomedical applications. A procedure for the synthesis of multifunctional europium(III)-doped gadolinium(III) fluoride (Eu:GdF3) nanoparticles (~85 nm) with quasispherical shape by precipitation at 120 °C from diethylene glycol solutions containing lanthanide chlorides and an ionic liquid (1-Butyl, 2-methylimidazolium tetrafluoroborate) as fluoride source has been developed. These nanoparticles were polycrystalline and crystallized into a hexagonal structure, which is unusual for GdF3. They were also mesoporous (pore size = 3.5 Å), having a rather high BET surface area (75 m(2) g(-1)). The luminescent and magnetic (relaxivity) properties of the Eu:GdF3 nanoparticles have been also evaluated in order to assess their potentiality as "in vitro" optical biolabels and contrast agent for magnetic resonance imaging. Finally, a procedure for their functionalization with aspartic-dextran polymers is also reported. The functionalized Eu:GdF3 nanoparticles presented negligible toxicity for Vero cells, which make them suitable for biotecnological applications. 23591701 New testing procedures of a capacitive deionization reactor. Currently, according to conventional charge-discharge profiles, energy consumed in charging Capacitive Deionization (CDI) systems is always a function of different parameters (current used for charging, capacitance and current employed for discharging) making it difficult to separate the effect of these parameters on CDI performance and energy efficiency. Thus, energy efficiencies are strongly influenced by the current in the preceding charge or discharge stage of the process. We find consistently that this phenomenon, which to our knowledge has not been addressed in previous CDI communications, is much more intense when different currents are applied for each of the charging and discharging cycles. The investigation reported here provides a mechanistic analysis of the operational aspects of CDI and develops a new procedure that allows for a precise evaluation of performance and energy efficiency. Furthermore, the model developed here allows one to separate charge and discharge cycles, and therefore contributes to the possibility of defining an operational mode for real-world devices in which effective separation of deionization and regeneration steps needs to be implemented. This method of analysis could be useful not only for CDI but also for other electrochemical systems such as in secondary batteries and supercapacitors where charge and discharge are typically employed. 23494802 Curcuminoids Modulate Pro-Oxidant-Antioxidant Balance but not the Immune Response to Heat Shock Protein 27 and Oxidized LDL in Obese Individuals. Curcuminoids have potentially important functional qualities including anti-inflammatory and antioxidant properties. In this randomized double-blind placebo-controlled cross-over trial, the effects of a curcuminoid supplement on serum pro-oxidant-antioxidant balance (PAB) and antibody titres to Hsp27 (anti-Hsp27) and oxLDL (anti-oxLDL) were investigated. Thirty obese individuals were randomized to receive either curcuminoids (1 g/day) or placebo for a period of 30 days. After a wash-out period of 2 weeks, subjects were crossed over to the alternate regimen for another 30 days. Serum PAB along with anti-Hsp27 and anti-oxLDL titres was measured at the beginning and at the end of each study period. There was no significant carry-over effect for any of the assessed parameters. Curcuminoid supplementation was associated with a significant decrease in PAB (p = 0.044). However, no significant change was observed in serum concentrations of anti-Hsp27 or anti-oxLDL (p > 0.05). These findings suggest that oral curcuminoids supplementation (1g/day) is effective in reducing oxidative stress burden, though this needs to be validated in larger study populations. Copyright © 2013 John Wiley & Sons, Ltd. 23333908 Hibiscus sabdariffa L. in the treatment of hypertension and hyperlipidemia: a comprehensive review of animal and human studies. The effectiveness of Hibiscus sabdariffa L. (HS) in the treatment of risk factors associated with cardiovascular disease is assessed in this review by taking a comprehensive approach to interpreting the randomized clinical trial (RCT) results in the context of the available ethnomedical, phytochemical, pharmacological, and safety and toxicity information. HS decoctions and infusions of calyxes, and on occasion leaves, are used in at least 10 countries worldwide in the treatment of hypertension and hyperlipidemia with no reported adverse events or side effects. HS extracts have a low degree of toxicity with a LD50 ranging from 2,000 to over 5,000mg/kg/day. There is no evidence of hepatic or renal toxicity as the result of HS extract consumption, except for possible adverse hepatic effects at high doses. There is evidence that HS acts as a diuretic, however in most cases the extract did not significantly influence electrolyte levels. Animal studies have consistently shown that consumption of HS extract reduces blood pressure in a dose dependent manner. In RCTs, the daily consumption of a tea or extract produced from HS calyxes significantly lowered systolic blood pressure (SBP) and diastolic blood pressure (DBP) in adults with pre to moderate essential hypertension and type 2 diabetes. In addition, HS tea was as effective at lowering blood pressure as the commonly used blood pressure medication Captropril, but less effective than Lisinopril. Total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides were lowered in the majority of normolipidemic, hyperlipidemic, and diabetic animal models, whereas high-density lipoprotein cholesterol (HDL-C) was generally not affected by the consumption of HS extract. Over half of the RCTs showed that daily consumption of HS tea or extracts had favorable influence on lipid profiles including reduced total cholesterol, LDL-C, triglycerides, as well as increased HDL-C. Anthocyanins found in abundance in HS calyxes are generally considered the phytochemicals responsible for the antihypertensive and hypocholesterolemic effects, however evidence has also been provided for the role of polyphenols and hibiscus acid. A number of potential mechanisms have been proposed to explain the hypotensive and anticholesterol effects, but the most common explanation is the antioxidant effects of the anthocyanins inhibition of LDL-C oxidation, which impedes atherosclerosis, an important cardiovascular risk factor. This comprehensive body of evidence suggests that extracts of HS are promising as a treatment of hypertension and hyperlipidemia, however more high quality animal and human studies informed by actual therapeutic practices are needed to provide recommendations for use that have the potential for widespread public health benefit. 23531107 Preventing Interfacial Recombination in Colloidal Quantum Dot Solar Cells by Doping the Metal Oxide. Recent research has pushed the efficiency of colloidal quantum dot solar cells toward a level that spurs commercial interest. Quantum dot/metal oxide bilayers form the most efficient colloidal quantum dot solar cells, and most studies have advanced the understanding of the quantum dot component. We study the interfacial recombination process in depleted heterojunction colloidal quantum dot (QD) solar cells formed with ZnO as the oxide by varying (i) the carrier concentration of the ZnO layer and (ii) the density of intragap recombination sites in the QD layer. We find that the open-circuit voltage and efficiency of PbS QD/ZnO devices can be improved by 50% upon doping of the ZnO with nitrogen to reduce its carrier concentration. In contrast, doping the ZnO did not change the performance of PbSe QD/ZnO solar cells. We use X-ray photoemission spectroscopy, ultraviolet photoemission spectroscopy, transient photovoltage decay measurements, transient absorption spectroscopy, and intensity-dependent photocurrent measurements to investigate the origin of this effect. We find a significant density of intragap states within the band gap of the PbS quantum dots. These states facilitate recombination at the PbS/ZnO interface, which can be suppressed by reducing the density of occupied states in the ZnO. For the PbSe QD/ZnO solar cells, where fewer intragap states are observed in the quantum dots, the interfacial recombination channel does not limit device performance. Our study sheds light on the mechanisms of interfacial recombination in colloidal quantum dot solar cells and emphasizes the influence of quantum dot intragap states and metal oxide properties on this loss pathway. 23000450 -116A and K BCHE gene variants associated with obesity and hypertriglyceridemia in adolescents from Southern Brazil. Butyrylcholinesterase (BChE) has been associated to body mass index (BMI), weight, cholesterol and triglyceride levels. -116A (rs1126680) and K (A539T, 1615A, rs1803274) BCHE gene variants had previously been associated to BChE activity, weight and BMI variance in adults. The present study examined -116A and K variants, BChE activity, anthropometric and biochemical variables associated with obesity in adolescents (120 obese and 150 non-obese from Curitiba, Brazil). Both -116A and K variants were found with significantly lower frequencies (p<0.05) in obese adolescents when compared with non-obese adolescents and with the general population. Mean BChE activity (KU/L) was significantly higher in obese adolescents when compared with non-obese adolescents and with the general population. Analyzing only the obese adolescents, it was found that carriers of the -116A variant showed lower BChE activity and higher triglyceride levels than homozygotes for the usual allele. Indeed, obese carriers of the -116A variant had triglyceride levels considered high according to reference values for serum triglycerides in Brazilian adolescents. These results show: (1) a protective effect of -116A and K variants on juvenile obesity risk, suggesting a role for the BCHE gene on juvenile onset obesity different from that observed on adult onset obesity and (2) an association of the -116A variant with hypertriglyceridemia in obese adolescents probably because of its effect on lowering BChE activity and consequently diminishing the enzyme capability of maintaining homeostasis on lipid metabolism during the metabolic stress caused by obesity. 23406277 Interactions of binuclear ruthenium(II) complexes with oligonucleotides in hydrogel matrix: enantioselective threading intercalation into GC context. A stretched poly(vinyl alcohol) (PVA) film provides a unique matrix that enables also short DNA oligonucleotide duplex to be oriented and studied by linear dichroism (LD). This matrix further allows controlling DNA secondary structure by proper hydration (A or B form), and such humid films could potentially also mimic the molecular crowding in cellular contexts. However, early attempts to study intercalators and groove binders for probing DNA in PVA failed due to competitive matrix binding. Here we report the successful orientation in PVA of DNA oligonucleotide duplex hairpins with thread-intercalated binuclear complex [μ-(11,11'-bidppz)(phen)4Ru2](4+), and how LD depends on oligonucleotide sequence and metal center chirality. Opposite enantiomers of the ruthenium complex, ΔΔ and ΛΛ, were investigated with respect to enantioselectivity toward GC stretches as long as 22 bp. LD, supported by emission kinetics, reveals that threading intercalation occurs only with ΔΔ whereas ΛΛ remains externally bound, probably in either or both of the grooves of the GC-DNA. Enantioselective binding properties of sterically rigid DNA probes such as the ruthenium complexes could find applications for targeting nucleic acids, e.g., to inhibit transcription in therapeutic context such as treatment of malaria or cancer. 23255284 Formation of RNA phosphodiester bond by histidine-containing dipeptides. A new scenario for prebiotic formation of nucleic acid oligomers is presented. Peptide catalysis is applied to achieve condensation of activated RNA monomers into short RNA chains. As catalysts, L-dipeptides containing a histidine residue, primarily Ser-His, were used. Reactions were carried out in self-organised environment, a water-ice eutectic phase, with low concentrations of reactants. Incubation periods up to 30 days resulted in the formation of short oligomers of RNA. During the oligomerisation, an active intermediate (dipeptide-mononucleotide) is produced, which is the reactive species. Details of the mechanism and kinetics, which were elucidated with a set of control experiments, further establish that the imidazole side chain of a histidine at the carboxyl end of the dipeptide plays a crucial role in the catalysis. These results suggest that this oligomerisation catalysis occurs by a transamination mechanism. Because peptides are much more likely products of spontaneous condensation than nucleotide chains, their potential as catalysts for the formation of RNA is interesting from the origin-of-life perspective. Finally, the formation of the dipeptide-mononucleotide intermediate and its significance for catalysis might also be viewed as the tell-tale signs of a new example of organocatalysis. 23471488 A randomised trial of enteric-coated nutrient pellets to stimulate gastrointestinal peptide release and lower glycaemia in type 2 diabetes. AIMS/HYPOTHESES: Glucagon-like peptide-1 (GLP-1), an important mediator of postprandial glycaemia, could potentially be stimulated by delivering small quantities of nutrient to a long length of distal gut. We aimed to determine whether enteric-coated pellets, releasing small amounts of lauric acid throughout the ileum and colon, could reduce glycaemic responses to meals in type 2 diabetes, associated with stimulation of GLP-1. METHODS: Eligible patients, who had type 2 diabetes controlled by diet or metformin, were each studied on two occasions in a hospital setting. After an overnight fast, patients consumed 5 g active pellets (47% lauric acid by weight) or placebo with breakfast (T = 0 min) and lunch (T = 240 min), in a crossover design with order randomised by the hospital pharmacy and allocation concealed by numbered containers. Patients and investigators making measurements were blinded to the intervention. Blood was sampled frequently for blood glucose (the primary outcome) and hormone assays. RESULTS: Eight patients were randomised (four to receive either intervention first), and all completed the study without adverse effects. Blood glucose was lower after breakfast (T = 0-240 min, area under the curve (AUC) 2,075 ± 368 vs 2,216 ± 163 mmol/l × min) and lunch (T = 240-480 min, AUC 1,916 ± 115 vs 2,088 ± 151 mmol/l × min) (p = 0.02 for each) after active pellets than after placebo. Plasma GLP-1 concentrations were higher after breakfast (p = 0.08) and lunch (p = 0.04) for active pellets. While there were no differences in insulin or glucose-dependent insulinotropic polypeptide concentrations, glucagon concentrations were higher after breakfast and lunch (p = 0.002 for each) for active pellets. CONCLUSIONS/INTERPRETATION: Delivering small amounts of nutrient to the ileum and colon can stimulate substantial endogenous GLP-1 release and attenuate postprandial glycaemia. This novel approach has therapeutic potential in type 2 diabetes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000600842. FUNDING: The study was funded by Meyer Nutriceuticals. 23261588 Short and long-term exposure of CNS cell lines to BPA-f a radiosensitizer for Boron Neutron Capture Therapy: safety dose evaluation by a battery of cytotoxicity tests. Despite the current clinical use of boronophenylalanine-fructose (BPA-f), as radiosensitizer, in BNCT application for brain tumors, still remains to be determined the safety dose of this agent. We evaluated the potential risk of primary BPA-f toxicity before neutronic irradiation at different concentrations (0-100μgBeq/ml) after short- and long-term exposure (4-48h and 7-10 days), using a battery of tests (i.e. MTT assay, calcein-AM/Propidium Iodide staining, clonogenic test) in CNS cell models (D384 and SH-SY5Y), and non-neuronal primary human fibroblasts (F26). MTT data showed: (i) no cytotoxic effects after short-term exposure (4h) to any of BPA-f concentrations tested in all cell models; (ii) dose- and time-dependent mitochondrial activity impairment in D384 and SH-SY5Y cells only (with 60% and 40% cell death in D384 and SH-SY5Y, respectively, after 48h exposure to BPA-f 100μgBeq/ml). By Calcein-AM/PI staining, BPA-f treatment was specific toward SH-SY5Y cells only: a dose-dependent cell density reduction was observed, with a more pronounced effect after 48h exposure (15-40% at doses ranging 20-100μgBeq/ml). Clonogenic data revealed dose-dependent decrease of cell proliferative capacity in all cell lines, still the SH-SY5Y cells were the most sensitive ones: the lowest dose (20μgBeq/ml) produced 90% cell decrease. These results indicate dose- and time-dependent cytotoxic effects of BPA-f, with CNS cells showing a lower tolerance compared to fibroblasts. Long-term exposure to BPA-f compromised the proliferative capacity regardless of cell model type (cell sensitivity being SH-SY5Y>D384>F26). In short-time exposure, BPA-f exhibits a safe dosage up to 40μgBeq/ml for the viability of CNS cell lines. 23172121 Elastic CNT-polyurethane nanocomposite: synthesis, performance and assessment of fragments released during use. Intended for use in high performance applications where electrical conductivity is required, we developed a CNT-TPU composite. Such a composite can be prepared by melt processing (extrusion) on an industrial scale. Due to the known hazard upon inhalation of CNTs, we assessed three degradation scenarios that may lead to the release of CNTs from the composite: normal use, machining and outdoor weathering. Unexpectedly, we find that the relative softness of the material actually enhances the embedding of CNTs also in its degradation fragments. A release of free CNTs was not detected under any condition using several detection methods. However, since machining may induce a high acute dose of human exposure, we assessed the cytotoxicity potential of released fragments in the in vitro model of precision-cut lung slices, and found no additional toxicity due to the presence of CNTs. At very low rates over years, weathering degrades the polymer matrix as expected for polyurethanes, thus exposing a network of entangled CNTs. In a preliminary risk assessment, we conclude that this material is safe for humans in professional and consumer use. 23153029 The progesterone positive feedback effect in women after ovariectomy. Various ovarian substances regulate the secretion of gonadotrophins during the menstrual cycle, but there are still several unclarified issues. The aim of this study was to investigate the positive feedback effect of progesterone during the immediate period following ovariectomy. Experiments were performed in 12 normally cycling women (aged 39-49 years). Following abdominal hysterectomy plus bilateral ovariectomy performed on cycle day 3 (day 0), the women received either estradiol via skin patches (days 0-7, n = 6, group 1) or estradiol as above plus vaginal progesterone (days 1-7, n = 6, group 2). Serum estradiol values increased similarly in the two groups. After the operation, serum progesterone levels decreased significantly in group 1, while in group 2 they remained stable becoming higher than in group 1 (p < 0.05). An LH and an FSH surge occurred in group 2 with the values after the peak returning to the pre-surge baseline. In contrast, in group 1 LH and FSH levels following an initial decrease, increased gradually until the end of the experiment. These results demonstrate that, despite a variable response to estrogens, the positive feedback effect of progesterone remained intact immediately after ovariectomy in women. It is suggested that it is the combining action of estradiol and progesterone that can ensure the expression of a positive feedback mechanism in women. 23400782 F1-ATPase of Escherichia coli: the ε- inhibited state forms after ATP hydrolysis, is distinct from the ADP-inhibited state, and responds dynamically to catalytic site ligands. F1-ATPase is the catalytic complex of rotary nanomotor ATP synthases. Bacterial ATP synthases can be autoinhibited by the C-terminal domain of subunit ε, which partially inserts into the enzyme's central rotor cavity to block functional subunit rotation. Using a kinetic, optical assay of F1·ε binding and dissociation, we show that formation of the extended, inhibitory conformation of ε (εX) initiates after ATP hydrolysis at the catalytic dwell step. Prehydrolysis conditions prevent formation of the εX state, and post-hydrolysis conditions stabilize it. We also show that ε inhibition and ADP inhibition are distinct, competing processes that can follow the catalytic dwell. We show that the N-terminal domain of ε is responsible for initial binding to F1 and provides most of the binding energy. Without the C-terminal domain, partial inhibition by the ε N-terminal domain is due to enhanced ADP inhibition. The rapid effects of catalytic site ligands on conformational changes of F1-bound ε suggest dynamic conformational and rotational mobility in F1 that is paused near the catalytic dwell position. 23288052 Molecular mechanisms of fibrosis-associated promotion of liver carcinogenesis. Hepatocellular carcinoma (HCC) mostly develops in patients with advanced fibrosis; however, the mechanisms of interaction between a genotoxic insult and fibrogenesis are not well understood. This study tested a hypothesis that fibrosis promotes HCC via a mechanism that involves activation of liver stem cells. First, B6C3F1 mice were administered diethylnitrosamine (DEN; single ip injection of 1mg/kg at 14 days of age). Second, carbon tetrachloride (CCl(4); 0.2ml/kg, 2/week ip starting at 8 weeks of age) was administered for 9 or 14 weeks to develop advanced liver fibrosis. In animals treated with DEN as neonates, presence of liver fibrosis led to more than doubling (to 100%) of the liver tumor incidence as early as 5 months of age. This effect was associated with activation of cells with progenitor features in noncancerous liver tissue, including markers of replicative senescence (p16), oncofetal transformation (Afp, H19, and Bex1), and increased "stemness" (Prom1 and Epcam). In contrast, the dose of DEN used did not modify the extent of liver inflammation, fibrogenesis, oxidative stress, proliferation, or apoptosis induced by subchronic CCl(4) administration. This study demonstrates the potential role of liver stem-like cells in the mechanisms of chemical-induced, fibrosis-promoted HCC. We posit that the combination of genotoxic and fibrogenic insults is a sensible approach to model liver carcinogenesis in experimental animals. These results may contribute to identification of cirrhotic patients predisposed to HCC by analyzing the expression of hepatic progenitor cell markers in the noncancerous liver tissue. 23337599 N-1, C-3 substituted indoles as 5-LOX inhibitors--in vitro enzyme immunoaasay, mass spectral and molecular docking investigations. Based upon the structures of some known 5-LOX inhibitors, a set of five compounds carrying appropriate substituents at N-1 and C-3 of indole were synthesized and investigated for 5-LOX inhibitory activities. Fifty percent inhibitory concn (IC(50)) of these compounds ranges from 0.6 to 5 μM and found to be comparable to that of clinically used 5-LOX inhibitor, zileuton. The compounds under present investigations exhibited appreciable interactions with 5-LOX as apparent from their association constants calculated from the mass spectral data. Compound 5a with a tosyl group at N-1 and pyrolidinyl-1,2-dione substituent at C-3 of indole, exhibiting IC(50) 0.6 μM and stoichiometry of 1:7 in the enzyme-compound complex was identified as highly potent 5-LOX inhibitor and seems to be suitable for further investigations. 23163508 Diversity patterns of uncultured Haptophytes unravelled by pyrosequencing in Naples Bay. Haptophytes are a key phylum of marine protists, including ~300 described morphospecies and 80 morphogenera. We used 454 pyrosequencing on large subunit ribosomal DNA (LSU rDNA) fragments to assess the diversity from size-fractioned plankton samples collected in the Bay of Naples. One group-specific primer set targeting the LSU rDNA D1/D2 region was designed to amplify Haptophyte sequences from nucleic acid extracts (total DNA or RNA) of two size fractions (0.8-3 or 3-20 μm) and two sampling depths [subsurface, at 1 m, or deep chlorophyll maximum (DCM) at 23 m]. 454 reads were identified using a database covering the entire Haptophyta diversity currently sequenced. Our data set revealed several hundreds of Haptophyte clusters. However, most of these clusters could not be linked to taxonomically known sequences: considering OTUs(97%) (clusters build at a sequence identity level of 97%) on our global data set, less than 1% of the reads clustered with sequences from cultures, and less than 12% clustered with reference sequences obtained previously from cloning and Sanger sequencing of environmental samples. Thus, we highlighted a large uncharacterized environmental genetic diversity, which clearly shows that currently cultivated species poorly reflect the actual diversity present in the natural environment. Haptophyte community appeared to be significantly structured according to the depth. The highest diversity and evenness were obtained in samples from the DCM, and samples from the large size fraction (3-20 μm) taken at the DCM shared a lower proportion of common OTUs(97%) with the other samples. Reads from the species Chrysoculter romboideus were notably found at the DCM, while they could be detected at the subsurface. The highest proportion of totally unknown OTUs(97%) was collected at the DCM in the smallest size fraction (0.8-3 μm). Overall, this study emphasized several technical and theoretical barriers inherent to the exploration of the large and largely unknown diversity of unicellular eukaryotes. 23428325 Plant development: brassinosteroids go out of bounds. Patterning in plants requires defining boundary domains that separate and organize the development of the neighboring organs. Two papers now show how the interplay between brassinosteroid phytohormones and frontier genes contributes to boundary formation in plants. 23527551 Using Supramolecular Binding Motifs To Provide Precise Control over the Ratio and Distribution of Species in Multiple Component Films Grafted on Surfaces: Demonstration Using Electrochemical Assembly from Aryl Diazonium Salts. Supramolecular interactions between two surface modification species are explored to control the ratio and distribution of these species on the resultant surface. A binary mixture of aryl diazonium salts bearing oppositely charged para-substituents (either -SO3(-) or -N(+)(Me)3), which also reduce at different potentials, has been examined on glassy carbon surfaces using cyclic voltammetry and X-ray photoelectron spectroscopy (XPS). Striking features were observed: (1) the two aryl diazonium salts in the mixed solution undergo reductive adsorption at the same potential which is distinctively less negative than the potential required for the reduction of either of the two aryl diazonium salts alone; (2) the surface ratio of the two phenyl derivatives is consistently 1:1 regardless of the ratio of the two aryl diazonium salts in the modification solutions. Homogeneous distribution of the two oppositely charged phenyl species on the modified surface has also been suggested by XPS survey spectra. Diffusion coefficient measurements by DOSY NMR and DFT based computation have indicated the association of the two aryl diazonium species in the solution, which has led to changes in the molecular orbital energies of the two species. This study highlights the potential of using intermolecular interactions to control the assembly of multicomponent thin layers. 23458385 Counterion condensation on heparin oligomers. The electropherogram of native heparin shows a broad distribution of mobilities μ, which truncates abruptly at a notably high μ = 4.7 × 10(-4) cm(2) V(-1) s(-1). This highly skewed mobility distribution is also found for the 20-saccharide chain, which shows from mass spectrometry a more uniform (symmetrical) with respect to sulfation level. Since a partially degraded heparin exhibits oligomer peaks with μ> 5 × 10(-4) cm(2) V(-1) s(-1) (appearing to escape the limitation of the mobility value for native heparin), we examined the electrophoretic behavior of chain-length monodisperse heparin oligomers. Their mobilities varied inversely with the logarithm of the contour length, L, for L from 3 to 10 nm and reached an asymptotic limit for L > 20 nm. The generality of this effect was indicated by similar behavior for oligomers of poly(styrene sulfonate). A recent theory of polyelectrolyte end effects (Manning, G. S. Macromolecules2008, 41, 6217-6227), in which chain termini exhibit reduced counterion condensation was found to quantitatively account for these results. A qualitative explanation for the anomalously high value of μ of native heparin, 10-20% higher than those seen for synthetic polyelectrolytes of higher linear charge density, is suggested on the basis of similar junction effects (Manning, G. S. Macromolecules2008, 41, 6217-6227), which reduce counterion condensation at the interfaces of regions of high and low sulfation. We suggest that these effects should be considered in models for the biofunctionality of the regulated high and low sulfation (NS/NA) domains of heparan sulfate. 23466444 Pro-inflammatory properties and neutrophil activation by Helicobacter pylori urease. The gastric pathogen Helicobacter pylori produces large amounts of urease, whose enzyme activity enables the bacterium to survive in the stomach. We have previously shown that ureases display enzyme-independent effects in mammalian models, most through lipoxygenases-mediated pathways. Here, we evaluated potential pro-inflammatory properties of H. pylori urease (HPU). Mouse paw edema and activation of human neutrophils were tested using a purified, cell-free, recombinant HPU. rHPU induced paw edema with intense neutrophil infiltration. In vitro 100 nM rHPU was chemotactic to human neutrophils, inducing production of reactive oxygen species. rHPU-activated neutrophils showed increased lifespan, with inhibition of apoptosis accompanied by alterations of Bcl-XL and Bad contents. These effects of rHPU persisted in the absence of enzyme activity. rHPU-induced paw edema, neutrophil chemotaxis and apoptosis inhibition reverted in the presence of the lipoxygenase inhibitors esculetin or AA861. Neutrophils exposed to rHPU showed increased content of lipoxygenase(s) and no alteration of cyclooxygenase(s). Altogether, our data indicate that HPU, besides allowing the bacterial survival in the stomach, could play an important role in the pathogenesis of the gastrointestinal inflammatory disease caused by H. pylori. 23643744 Repeated potentiation of the metabotropic glutamate receptor 5 and the alpha 7 nicotinic acetylcholine receptor modulates behavioural and GABAergic deficits induced by early postnatal phencyclidine (PCP) treatment. The underlying mechanism of the GABAergic deficits observed in schizophrenia has been proposed to involve NMDA receptor hypofunction. An emerging treatment strategy therefore aims at enhancing GABAergic signalling by increasing the excitatory transmission onto interneurons. We wanted to determine whether behavioural and GABAergic functional deficits induced by the NMDA receptor channel blocker, phencyclidine (PCP), could be reversed by repeated administration of two drugs known to enhance GABAergic transmission: the positive allosteric modulator (PAM) of the metabotropic glutamate receptor 5 (mGluR5), ADX47273, and the partial agonist of the α7 nicotinic acetylcholine receptor (α7 nAChR), SSR180711. Adolescent rats (4-5 weeks) subjected to PCP treatment during the second postnatal week displayed a consistent deficit in prepulse inhibition (PPI), which was reversed by a one week treatment with ADX47273 or SSR180711. We examined GABAergic transmission by whole cell patch-clamp recordings of miniature inhibitory postsynaptic currents (mIPSC) in pyramidal neurons in layer II/III of prefrontal cortex (PFC) and by activation of extrasynaptic δ-containing GABAA receptors by THIP. Following PCP treatment, pyramidal neurons displayed a reduced mIPSC frequency and up-regulation of extrasynaptic THIP-induced current. ADX47273 treatment restored this up-regulation of THIP-induced current. Finally, we showed that repeated treatment with ADX47273 and SSR180711 decreased the induction of spontaneous inhibitory current caused by acute and direct agonism of mGluR5s and α7 nAChRs in slices. These results show that repeated administration of ADX47273 or SSR180711 reverses certain behavioural and functional deficits induced by PCP, likely through down-regulation or desensitisation of mGluR5s and α7 nAChRs, respectively. 23537942 Anticancer activity of novel hybrid molecules containing 5-benzylidene thiazolidine-2,4-dione. Hybridization of two different bioactive molecules with different mechanism of action is one of the methods that are being adopted to treat cancer. Molecules bearing a thiazolidine-2,4-dione scaffold have been recognized as antineoplastic agents with a broad spectrum of activity against many cancer cell lines. In this manuscript we have described the synthesis and biological evaluation of two series of N-3-substituted-5-arylidene thiazolidine-2,4-diones, bearing the α-bromoacryloylamido moiety at the para- or meta-position on the phenyl of the arylidene portion. We have observed that selected compounds 5a, 5c and 5g suppress proliferation of human myeloid leukaemia HL-60 and U937 cells by triggering morphological changes and internucleosomal DNA fragmentation, which are well-known features of apoptosis. Finally, our results indicated that the investigated compounds induced apoptotic cell death through a mechanism that involved activation of multiple caspases and was also associated with the release of cytochrome c from the mitochondria. 23239601 Gold nanoparticles produced in situ mediate bioelectricity and hydrogen production in a microbial fuel cell by quantized capacitance charging. Oppan quantized style: By adding a gold precursor at its cathode, a microbial fuel cell (MFC) is demonstrated to form gold nanoparticles that can be used to simultaneously produce bioelectricity and hydrogen. By exploiting the quantized capacitance charging effect, the gold nanoparticles mediate the production of hydrogen without requiring an external power supply, while the MFC produces a stable power density. 23416409 Quantitative proteomic analysis reveals the mode-of-action for chronic mercury hepatotoxicity to marine medaka (Oryzias melastigma). Mercury (Hg) is a widespread persistent pollutant in aquatic ecosystems. We investigated the protein profiles of medaka (Oryzias melastigma) liver chronically exposed to different mercuric chloride (HgCl2) concentrations (1 or 10 μg/L) for 60 d using two-dimensional difference gel electrophoresis (2D-DIGE), as well as cell ultrastructure and Hg content analysis of the hepatic tissue. The results showed that Hg exposure significantly increased metal accumulation in the liver, and subsequently damaged liver ultrastructure. Comparison of the 2D-DIGE protein profiles of the exposed and control groups revealed that the abundance of 45 protein spots was remarkably altered in response to Hg treatment. The altered spots were subjected to matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry analysis, with the resultant identification of 33 spots. These proteins were mainly involved in cytoskeleton assembly, oxidative stress, and energy production. Among them, several proteins related to mitochondrial function (e.g. respiratory metabolism) were significantly altered in the treated hepatocytes, implying that this organelle might be the primary target for Hg attack in the cells. This study provided new insights into the molecular mechanisms and/or toxic pathways by which chronic Hg hepatotoxicity affects aquatic organisms, and also provided basic information for screening potential biomarkers for aquatic Hg monitoring. 23618921 Concurrent Regulation of the Transcription Factors Nrf2 and ATF4 Mediates the Enhancement of Glutathione Levels by the Flavonoid Fisetin. Glutathione (GSH) and GSH-associated metabolism provide the major line of defense for the protection of cells from various forms of toxic stress. GSH also plays a key role in regulating the intracellular redox environment. Thus, maintenance of GSH levels is developing into an important therapeutic objective for the treatment of a variety of diseases. Among the transcription factors that play critical roles in GSH metabolism are NF-E2-related factor 2 (Nrf2) and activating transcription factor 4 (ATF4). Thus, compounds that can upregulate these transcription factors may be particularly useful as treatment options through their effects on GSH metabolism. We previously showed that the flavonoid fisetin not only increases basal levels of GSH but also maintains GSH levels under oxidative stress conditions. However, the mechanisms underlying these effects have remained unknown until now. Here we show that fisetin rapidly increases the levels of both Nrf2 and ATF4 as well as Nrf2- and ATF4-dependent gene transcription via distinct mechanisms. Although fisetin greatly increases the stability of both Nrf2 and ATF4, only the effect on ATF4 is dependent on protein kinase activity. Using siRNA we found that ATF4, but not Nrf2, is important for fisetin's ability to increase GSH levels under basal conditions whereas both ATF4 and Nrf2 appear to cooperate to increase GSH levels under oxidative stress conditions. Based upon these results, we hypothesize that compounds able to increase GSH levels via multiple mechanisms, such as fisetin, will be particularly effective for maintaining GSH levels under a variety of different stresses. 23401355 Formation of nanostructured MnO/Co/solid-electrolyte interphase ternary composites as a durable anode material for lithium-ion batteries. Nanoporous MnO frameworks with highly dispersed Co nanoparticles were produced from MnCO3 precursors prepared in a gel matrix. The MnO frameworks that contain 20 mol% Co exhibited excellent cycle performance as an anode material for Li-ion batteries. The solid-electrolyte interphase (SEI) formed in the frameworks through the electrochemical reaction mediates the active materials, such as MnO, Mn, and Li2O, during the conversion reaction in the charge-discharge cycle. The Co nanoparticles and SEI provide the electron and Li-ion conductive networks, respectively. The ternary nanocomposites of the MnO framework, metallic Co nanoparticles, and embedded SEI are categorized as durable anode materials for Li-ion batteries. 22480291 RP-HPLC method for the simultaneous quantitation of boeravinone E and boeravinone B in Boerhaavia diffusa extract and its formulation. A high-performance liquid chromatography method was developed and validated for the simultaneous quantitation of two major rotenoids, boeravinone E and boeravinone B, in Boerhaavia diffusa extract and its formulation. Chromatographic separation was carried out on an Inertsil ODS-3 column by using gradient mobile phase containing 0.1% v/v orthophosphoric acid in water and acetonitrile. The detection was carried out at 276 nm. The method was validated for specificity, precision, accuracy and robustness. The linearity (r (2) = 0.9989 and 0.9991) was found to be in the range of 7.26-35.75 µg mL(-1) and 2.20-11.00 µg mL(-1) for boeravinone E and B, respectively. The percent recovery observed from the extract sample was 95.22-95.83. 23220295 Effects of adolescent social defeat on adult amphetamine-induced locomotion and corticoaccumbal dopamine release in male rats. Maturation of mesocorticolimbic dopamine systems occurs during adolescence, and exposure to social stress during this period results in behavioral dysfunction including substance abuse disorders. Adult male rats exposed to repeated social defeat in adolescence exhibit reduced basal dopamine tissue content in the medial prefrontal cortex, altered dopamine tissue content in corticoaccumbal dopamine regions following acute amphetamine, and increased amphetamine conditioned place preference following repeated amphetamine treatment. Such changes may reflect altered amphetamine-induced extracellular dopamine release in the corticoaccumbal regions. Therefore, we used in vivo microdialysis to measure extracellular dopamine simultaneously within the medial prefrontal cortex and nucleus accumbens core of previously defeated rats and controls, in response to either acute or repeated (7 daily injections) of amphetamine (1.0 mg/kg). Locomotion responses to acute/repeated amphetamine were also assessed the day prior to taking dopamine measurements. Adolescent defeat potentiated adult locomotion responses to acute amphetamine, which was negatively correlated with attenuated amphetamine-induced dopamine release in the medial prefrontal cortex, but there was no difference in amphetamine-induced accumbal dopamine release. However, both locomotion and corticoaccumbal dopamine responses to repeated amphetamine were equivalent between previously defeated rats and controls. These data suggest adolescent defeat enhances behavioral responses to initial amphetamine exposure as a function of diminished prefrontal cortex dopamine activity, which may be sufficient to promote subsequently enhanced seeking of drug-associated cues. Interestingly, repeated amphetamine treatment appears to normalize amphetamine-elicited locomotion and cortical dopamine responses observed in adult rats exposed to adolescent social defeat, providing implications for treating stress-induced dopamine dysfunction. 23215148 Lipid reassembly in asymmetric Langmuir-Blodgett/Langmuir-Schaeffer bilayers. Molecular-reorganization-induced morphology alteration in asymmetric substrate-supported lipid bilayers (SLBs) was directly visualized by means of atomic force microscopy (AFM) and total internal reflection fluorescence (TIRF) microscopy. SLB samples were fabricated on mica-on-glass and glass substrates by Langmuir-Blodgett (LB)/Langmuir-Schaeffer (LS) using binary lipid mixtures, namely, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)/1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and ternary mixtures DOPC/DPPC/1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS), labeled with 0.2 mol % Texas Red 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine triethylammonium salt (TR-DHPE) dye. Phase segregations were characterized by TIRF imaging, and DPPC-enriched domain structures were also observed. Interestingly for ∼40% (n = 6) of the samples with binary mixtures in the LB leaflet and a single component in the LS leaflet, that is, (DOPC/DPPC)(LB)+DOPC(LS), the contrast of the DPPC domains changed from the original dark (without dye) to bright (more TR dye partitioning) on TIRF images, returning to dark again. This contrast reverse was also correlated to AFM height images, where a DPPC-DPPC gel phase was spotted after the TIRF image contrast returned to dark. The rupture force mapping results measured on these binary mixture samples also confirmed unambiguously the formation of DPPC-DPPC gel domain components during the contrast change. The samples were tracked over 48 h to investigate the lipid molecule movements in both the DPPC domains and the DOPC fluid phase. The fluorescence contrast changes from bright to dark in SLBs indicate that the movement of dye molecules was independent of the movement of lipid molecules. In addition, correlated multimodal imaging using AFM, force mapping, and fluorescence provides a novel route to uncover the reorganization of lipid molecules at the solid-liquid interface, suggesting that the dynamics of dye molecules is highly structure dependent. 23436129 Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open-label study in youth with fragile X syndrome. RATIONALE: Fragile X syndrome (FXS) is an inherited form of developmental disability and a single gene cause of autism. As a disorder with increasingly understood pathophysiology, FXS is a model form of developmental disability for targeted drug development efforts. Preclinical animal model findings have focused targeted drug treatment development in FXS on an imbalance between excessive glutamate and deficient gamma-aminobutyric acid (GABA) neurotransmission. METHODS: We conducted a prospective open-label 10-week trial of acamprosate in 12 youth aged 6-17 years (mean age: 11.9 years) with FXS. RESULTS: Acamprosate use (mean dose: 1,054 ± 422 mg/day) was associated with treatment response (defined by a Clinical Global Impressions Improvement (CGI-I) scale score of "very much improved" or "much improved") in nine of 12 (75 %) subjects. Improvement was noted in social behavior and inattention/hyperactivity using multiple standard behavioral outcome measures. No significant adverse effects or changes in vital signs, including weight or laboratory measures, occurred during treatment with acamprosate. Additionally, pre- and post-treatment blood biomarker analyses looking at brain-derived neurotrophic factor (BDNF) levels found a significant increase in BDNF with treatment. In our pilot sample, treatment response did not correlate with change in BDNF with treatment. CONCLUSIONS: Acamprosate was generally safe and well tolerated and was associated with a significant improvement in social behavior and a reduction in inattention/hyperactivity. The increase in BDNF that occurred with treatment may be a useful pharmacodynamic marker in future acamprosate studies. Given these findings, a double-blind, placebo-controlled study of acamprosate in youth with FXS is warranted. 22585450 Effects of Crataegus microphylla on vascular dysfunction in streptozotocin-induced diabetic rats. Vascular dysfunction plays a key role in the pathogenesis of diabetic vascular disease. In this study, we aimed to investigate whether chronic in vivo treatment of Crataegus microphylla (CM) extract in diabetic rats induced with streptozotocin (STZ, intraperitoneal, 65 mg/kg) preserves vascular function and to evaluate whether the reduction of inducible nitric oxide synthase (iNOS), proinflammatory cytokines, and lipid peroxidation mediates its mechanisms of action. Starting at 4 weeks of diabetes, CM extract (100 mg/kg) was administrated to diabetic rats for 4 weeks. In aortic rings, relaxation to acetylcholine and vasoreactivity to noradrenaline were impaired, whereas aortic iNOS expression and plasma tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), total nitrite-nitrate, and malondialdehite levels were increased in diabetic rats compared with controls. Chronic CM treatment significantly corrected all the above abnormalities in diabetic rats. In comparison, pretreatment of the aorta of diabetic rats with N-[3(aminomethyl) benzyl]-acetamidine, dihydrochloride (10(-5)  M), a selective inhibitor of iNOS, produced a similar recovery in vascular reactivity. These results suggest that chronic in vivo treatment of CM preserves endothelium-dependent relaxation and vascular contraction in STZ-induced diabetes, possibly by reducing iNOS expression in the aorta and by decreasing plasma levels of TNF-α and IL-6 and by preventing lipid peroxidation. Copyright © 2012 John Wiley & Sons, Ltd. 22489960 Screening of ecotoxicological, qualitative and reproductive variables in male European sea bass Dicentrarchus labrax (L.) reared in three different fish farms: Facility location and typology. The aim of this study was to investigate the influence of both facility location and typology of fish farm on some ecotoxicological, qualitative and reproductive variables in European sea bass Dicentrarchus labrax L. Several variables were investigated: gonado-somatic index (GSI), liver-somatic index (LSI); 7-ethoxyresorufin-O-deethylase (EROD), benzo(a)pyrene monooxygenase and acetylcholinesterase activities; glutathione (GSH), testosterone, 17β-estradiol, total lipid, phospholipid (PL) and triglyceride contents. In addition, the histological sections of gonads were examined. Results suggest that LSI, EROD activity, GSI, GSH, PL, hormone levels and gonad morphology were influenced by different facility locations and typologies of fish farm. 23475901 Generation and characterization of fully human monoclonal antibodies against human orai1 for autoimmune disease. Calcium entry into T cells following antigen stimulation is crucial for nuclear factor of activated T cells (NFAT)-mediated T cell activation. The movement of calcium is mediated by calcium release-activated calcium (CRAC) channels. There are two key components of this channel: Orai1 is the pore-forming subunit located in the plasma membrane, and stromal interaction molecule 1 (STIM1) functions as a Ca(2+) sensor in the endoplasmic reticulum. A subset of human patients carry mutations in either STIM1 or Orai1 that affect protein function or expression, resulting in defective store-operated Ca(2+) influx and CRAC channel function, and impaired T cell activation. These patients suffer from a hereditary form of severe combined immune deficiency syndrome, highlighting the importance of the CRAC channel for T lymphocyte function in humans. Since autoreactive T cells play an important role in the development of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and organ transplantation, Orai1 becomes an attractive therapeutic target for ameliorating autoimmune disease. We developed a novel approach to inhibiting CRAC function by generating high-affinity fully human monoclonal antibodies to human Orai1. These antibodies inhibited ICRAC current, store-operated Ca(2+) influx, NFAT transcription, and cytokine release. These fully human antibodies to human Orai1 may represent a novel therapeutic approach for the treatment of autoimmunity. 22765022 Flavonoid constituents and biological screening of Astragalus bombycinus Boiss. Two new flavonoid compounds were isolated from Astragalus bombycinus Boiss. and identified as quercetin-3,7-di-O-β-glucopyranoside 4'-O-α-rhamnopyranoside and 5,2',4'-trihydroxy-flavone-8-C-α-arabinopyranoside-7-O-β-glucopyranoside. In addition, apigenin, apigenin-7-O-β-glucopyranoside, apigenin 7-O-gentobioside, luteolin, luteolin-7-O-β-glucopyranoside, quercetin-3,7-di-O-β-glucopyranoside, quercetin-3-O-β-glucopyranoside-7-O-α-rhamnopyranoside and daidzein were also isolated and identified. The structure elucidation of the isolated compounds was performed by chromatographic, chemical and spectroscopic methods. Antioxidant and cytotoxic activities were also determined for the four consecutive extracts of the plant. 23624358 Recent advances in delivery of drug-nucleic acid combinations for cancer treatment. Cancer treatment that uses a combination of approaches with the ability to affect multiple disease pathways has been proven highly effective in the treatment of many cancers. Combination therapy can include multiple chemotherapeutics or combinations of chemotherapeutics with other treatment modalities like surgery or radiation. However, despite the widespread clinical use of combination therapies, relatively little attention has been given to the potential of modern nanocarrier delivery methods, like liposomes, micelles, and nanoparticles, to enhance the efficacy of combination treatments. This lack of knowledge is particularly notable in the limited success of vectors for the delivery of combinations of nucleic acids with traditional small molecule drugs. The delivery of drug-nucleic acid combinations is particularly challenging due to differences in the physicochemical properties of the two types of agents. This review discusses recent advances in the development of delivery methods using combinations of small molecule drugs and nucleic acid therapeutics to treat cancer. This review primarily focuses on the rationale used for selecting appropriate drug-nucleic acid combinations as well as progress in the development of nanocarriers suitable for simultaneous delivery of drug-nucleic acid combinations. 23265488 Rhubarb inhibits hepatocellular carcinoma cell metastasis via GSK-3-β activation to enhance protein degradation and attenuate nuclear translocation of β-catenin. The aim of our study was to investigate the mechanisms by which rhubarb regulates β-catenin as well as metastasis of hepatocellular carcinomas. Our results revealed that rhubarb extract inhibited HA22T cell migration ability in wound healing, migration and invasion assays in a dose-dependent manner. Rhubarb also reduced β-catenin protein level, downregulated its downstream proteins, cyclin D, Tbx3 and c-Myc, and attenuated the expression of MMP9 and contactin-1 metastatic factors. Additionally, rhubarb inhibited β-catenin nuclear accumulation and induced its degradation via proteasome-mediated pathway. Furthermore, we found that rhubarb suppressed the p-ser(9) GSK-3-β protein level to inactivate Wnt signalling and reduce β-catenin protein level. Taken together; we found that rhubarb blocked the metastatic process of HA22T hepatocellular carcinoma cells mediated through GSK-3-β activation, and enhancement of protein degradation as well as reduction of the nuclear accumulation of β-catenin. 23303486 Synthetic strategies for the biotinylation of bioactive small molecules. Biotinylation, the functional appendage of a biotin moiety to a bioactive compound (including small molecules and biological macromolecules), represents a common technique for identification of the intracellular binding partners that underlie the foundation of observed biological activity. Introduction of an attachment tether to the framework of a compound of interest must be planned at an early stage of development, and many considerations apply: 1) region of attachment, so as not to impede the pharmacophore; 2) stability of the parent molecular architecture to biotinylation conditions; 3) regioselectivity for the chosen tethering location over other reactive functionalities; 4) toxicity of reagents if biotinylation is to be performed in vitro; and 5) overall ease of synthesis. This review is intended to serve as a guide for the selection of appropriate tethering modalities. Examples of the common techniques used to affix biotin, including amide bond formation, [3+2] cycloadditions through "click" chemistry, Staudinger ligation, and thioether formation will be discussed, along with analysis of the wider applications of synthetic methodology that have been applied toward the biotinylation of small molecules. 23464667 Liquiritigenin prevents Staphylococcus aureus-mediated lung cell injury via inhibiting the production of α-hemolysin. Staphylococcus aureus is a significant Gram-positive bacterium that is associated with a broad spectrum of diseases ranging from minor skin infections to lethal pneumonia, endocarditis, and toxinoses. α-Hemolysin is one of the most important exotoxins that contribute to the pathogenesis of S. aureus infections. Liquiritigenin is one of the most significant active components in licorice. In this study, hemolysis, western blot, and real-time reverse transcription-PCR assays were performed to investigate the impact of liquiritigenin on the production of S. aureus α-hemolysin. The results showed that low concentrations of liquiritigenin remarkably decreased S. aureus α-hemolysin production in a dose-dependent manner. Using live/dead cell staining and lactate dehydrogenase assays, we found that liquiritigenin could protect human lung cells (A549) from α-hemolysin-mediated injury. The data indicated that this compound could potentially be useful in developing drugs aiming at staphylococcal α-hemolysin. 23000251 Bioconversion of quercetin and rutin and the cytotoxicity activities of the transformed products. Quercetin and rutin are well-know flavonoids. In spite of this, the comprehension of their metabolism is still incomplete. In this work, the cytotoxic activity of quercetin and rutin and its metabolites produced by metabolism of filamentous fungi was investigated. Flavonoids metabolism was monitored by HPLC and LC-MS. Both flavonoids were extensively metabolized. Quercetin was converted into metabolite methylquercetin (2) and quercetin glucuronide (3) and rutin into metabolite rutin sulphate (5), methylrutin (6) and rutin glucuronide (7). Cytotoxic effects of rutin, quercetin and its metabolites were measured by MTT tetrazolium reduction test and the trypan blue exclusion assay on HL-60 leukemic cells. The results showed similar concentration-dependent cytotoxic effect for rutin and rutin sulphate (5), while no cytotoxic effect was detected with the metabolites 6 and 7. In relation to the quercetin and its metabolites the results showed that all compounds have a similar concentration-dependent inhibitory effect on HL-60 cells. These findings corroborate the literature, showing that bioconversion is a useful strategy for production of biological active metabolites. 23247504 Sophorolipids-functionalized iron oxide nanoparticles. Functional iron oxide nanoparticles (NP) have been synthesized in a one and a two-step method using a natural functional glycolipid belonging to the family of sophorolipids (SL). These compounds, whose open acidic form is highly suitable for nanoparticle stabilization, are readily obtained by a fermentation process of the yeast Candida bombicola (polymorph Starmerella bombicola) in large amounts. The final carbohydrate coated iron oxide nanoparticles represent interesting potentially biocompatible materials for biomedical applications. According to the synthesis strategy, magnetic properties can eventually be tuned, thus putting in evidence the direct effect of the glycolipid on the final material's structure (maghemite and ferrihydrite have been obtained here). A combination of FT-IR, Dynamic Light Scattering (DLS) and UV-Vis experiments shows that SL complex the nanoparticle surface via their accessible COOH group thus forming stable colloids, whose hydrodynamic diameter mostly varies between 10 nm and 30 nm, both in water and in KCl-containing (0.01 M and 2 M) solutions. The materials can stand multiple filtration steps (up to 10) at different extents, where the largest recorded average aggregate size is 100 nm. In general, materials synthesized at T = 80 °C display better stability and smaller size distribution than those obtained at room temperature. 22638814 Learning to forget: manipulating extinction and reconsolidation processes to treat addiction. Finding effective long-lasting treatments for drug addiction has been an elusive goal. Consequently, researchers are beginning to investigate novel treatment strategies including manipulations of drug-associated memories. When environmental stimuli (cues) become associated with drug use, they become powerful motivators of continued drug use and relapse after abstinence. Reducing the strength of these cue-drug memories could decrease the number of factors that induce craving and relapse to aid in the treatment of addiction. Enhancing the consolidation of extinction learning and/or disrupting cue-drug memory reconsolidation are two strategies that have been proposed to reduce the strength of cues in motivating drug-seeking and drug-taking behavior. Here, we review the latest basic and clinical research elucidating the mechanisms underlying consolidation of extinction and reconsolidation of cue-drug memories in the hopes of developing pharmacological tools that exploit these signaling systems to treat addiction. 23336729 Biomimetic polymer brushes containing tethered acetylcholine analogs for protein and hippocampal neuronal cell patterning. This paper describes a method to control neuronal cell adhesion and differentiation with both chemical and topographic cues by using a spatially defined polymer brush pattern. First, biomimetic methacrylate polymer brushes containing tethered neurotransmitter acetylcholine functionalities in the form of dimethylaminoethyl methacrylate or free hydroxyl-terminated poly(ethylene glycol) units were prepared using the "grown from" method through surface-initiated atom transfer radical polymerization reactions. The surface properties of the resulting brushes were thoroughly characterized with various techniques and hippocampal neuronal cell culture on the brush surfaces exhibit cell viability and differentiation comparable to, or even better than, those on commonly used poly-l-lysine coated glass coverslips. The polymer brushes were then patterned via UV photolithography techniques to provide specially designed surface features with different sizes (varying from 2 to 200 μm) and orientations (horizontal and vertical). Protein absorption experiments and hippocampal neuronal cell culture tests on the brush patterns showed that both protein and neurons can adhere to the patterns and therefore be guided by such patterns. These results also demonstrate that, because of their unique chemical composition and well-defined nature, the developed polymer brushes may find many potential applications in cell-material interactions studies and neural tissue engineering. 22619070 Tea tree oil-induced transcriptional alterations in Staphylococcus aureus. Tea tree oil (TTO) is a steam distillate of Melaleuca alternifolia that demonstrates broad-spectrum antibacterial activity. This study was designed to document how TTO challenge influences the Staphylococcus aureus transcriptome. Overall, bioinformatic analyses (S. aureus microarray meta-database) revealed that both ethanol and TTO induce related transcriptional alterations. TTO challenge led to the down-regulation of genes involved with energy-intensive transcription and translation, and altered the regulation of genes involved with heat shock (e.g. clpC, clpL, ctsR, dnaK, groES, groEL, grpE and hrcA) and cell wall metabolism (e.g. cwrA, isaA, sle1, vraSR and vraX). Inactivation of the heat shock gene dnaK or vraSR which encodes a two-component regulatory system that responds to peptidoglycan biosynthesis inhibition led to an increase in TTO susceptibility which demonstrates a protective role for these genes in the S. aureus TTO response. A gene (mmpL) encoding a putative resistance, nodulation and cell division efflux pump was also highly induced by TTO. The principal antimicrobial TTO terpene, terpinen-4-ol, altered ten genes in a transcriptional direction analogous to TTO. Collectively, this study provides additional insight into the response of a bacterial pathogen to the antimicrobial terpene mixture TTO. Copyright © 2012 John Wiley & Sons, Ltd. 23481281 Aphanamgrandiol A, a new triterpenoid with a unique carbon skeleton from Aphanamixis grandifolia. Aphanamgrandiol A (1), a novel triterpenoid with a bicyclo[3,2,1]octane ring skeleton produced by 2,3-ring opening and 2,6-ring closure, was isolated from the stems of Aphanamixis grandifolia. The structures were established on the basis of extensive spectroscopic methods, including 1D and 2D NMR techniques, and determined unambiguously by X-ray crystal diffraction. Aphanamgrandiol A showed moderate cytotoxicities against MCG-803, SKOV-3, HCT116 and HepG2 cell lines. 23480446 Self-Assembling Multidomain Peptide Fibers with Aromatic Cores. Self-assembling multidomain peptides have been shown to have desirable properties, such as the ability to form hydrogels that rapidly recover following shear-thinning and the potential to be tailored by amino acid selection to vary their elasticity and encapsulate and deliver proteins and cells. Here we describe the effects of substitution of aliphatic hydrophobic amino acids in the central domain of the peptide for the aromatic amino acids phenylalanine, tyrosine, and tryptophan. While the basic nanofibrous morphology is retained in all cases, selection of the particular core residues results in switching from antiparallel hydrogen bonding to parallel hydrogen bonding in addition to changes in nanofiber morphology and in hydrogel rheological properties. Peptide nanofiber assemblies are investigated by circular dichroism polarimetry, infrared spectroscopy, atomic force microscopy, transmission and scanning electron microscopy, oscillatory rheology, and molecular dynamics simulations. Results from this study will aid in designing next generation cell scaffolding materials. 23313176 Injectable nanomaterials for drug delivery: Carriers, targeting moieties, and therapeutics. Therapeutics such as nucleic acids, proteins/peptides, vaccines, anti-cancer, and other drugs have disadvantages of low bio-availability, rapid clearance, and high toxicity. Thus, there is a significant need for the development of efficient delivery methods and carriers. Injectable nanocarriers have received much attention due to their vast range of structures and ability to contain multiple functional groups, both within the bulk material and on the surface of the particles. Nanocarriers may be tailored to control drug release and/or increase selective cell targeting, cellular uptake, drug solubility, and circulation time, all of which lead to a more efficacious delivery and action of therapeutics. The focus of this review is injectable, targeted nanoparticle drug delivery carriers highlighting the diversity of nanoparticle materials and structures as well as highlighting current therapeutics and targeting moieties. Structures and materials discussed include liposomes, polymersomes, dendrimers, cyclodextrin-containing polymers (CDPs), carbon nanotubes (CNTs), and gold nanoparticles. Additionally, current clinical trial information and details such as trial phase, treatment, active drug, carrier sponsor, and clinical trial identifier for different materials and structures are presented and discussed. 23259773 Freeze fracture approach to directly visualize wetting transitions on nanopatterned superhydrophobic silicon surfaces: more than a proof of principle. Freeze fracturing is applied to make the wetting behavior of artificially nanopatterned Si surfaces directly visible. For this purpose, almost hexagonally arranged nanopillars of fixed areal density (127 μm(-2)) and diameters (35 nm) but varying heights (40-150 nm) were fabricated on silicon. Measurement of contact angles (CAs) including hysteresis allowed to distinguish between the Wenzel (W) and the Cassie-Baxter (CB) states with droplets completely wetting the pillars or residing on top of them, respectively. Providing additional depth contrast by evaporating the ice replica with thin carbon and (typically 3 nm) platinum layers under 45° allowed resolving 3D features of 5 nm within the ice replica. In this way, laterally sharp transitions from CB- to W-states could be revealed, indicating the formation of zero-curvature water surfaces even on the nanoscale. 23556453 Pharmacogenetics of opiates in clinical practice: the visible tip of the iceberg. Opioids are the cornerstone of analgesic therapy and are used as a substitution therapy for opiate addiction. Interindividual variability in response to opioids is a significant challenge in the management of pain and substitution. Therefore, treatment with opioids requires a careful individualization of dosage to achieve an appropriate balance of efficacy and adverse effects and, consequently, avoid toxicity, particularly respiratory depression, sedation and for some, cardiac ventricular fibrillations. Many studies have investigated the association between genetic factors and the variability of response to opioids. Variants in genes encoding proteins implied in opioid pharmacokinetics (absorption, distribution, metabolism, excretion and toxicity), together with those implied in opioids direct and indirect pharmacodynamics (genes of opioid receptors and monoaminergic systems), are the most studied. Many association studies have not been replicated. The purpose of this article is to summarize pharmacogenetic data associated with some opioids frequently encountered in managed care settings. 23286736 Delayed frost growth on jumping-drop superhydrophobic surfaces. Self-propelled jumping drops are continuously removed from a condensing superhydrophobic surface to enable a micrometric steady-state drop size. Here, we report that subcooled condensate on a chilled superhydrophobic surface are able to repeatedly jump off the surface before heterogeneous ice nucleation occurs. Frost still forms on the superhydrophobic surface due to ice nucleation at neighboring edge defects, which eventually spreads over the entire surface via an interdrop frost wave. The growth of this interdrop frost front is shown to be up to 3 times slower on the superhydrophobic surface compared to a control hydrophobic surface, due to the jumping-drop effect dynamically minimizing the average drop size and surface coverage of the condensate. A simple scaling model is developed to relate the success and speed of interdrop ice bridging to the drop size distribution. While other reports of condensation frosting on superhydrophobic surfaces have focused exclusively on liquid-solid ice nucleation for isolated drops, these findings reveal that the growth of frost is an interdrop phenomenon that is strongly coupled to the wettability and drop size distribution of the surface. A jumping-drop superhydrophobic condenser minimized frost formation relative to a conventional dropwise condenser in two respects: preventing heterogeneous ice nucleation by continuously removing subcooled condensate, and delaying frost growth by limiting the success of interdrop ice bridge formation. 23303710 The marine polyketide myriaporone 3/4 stalls translation by targeting the elongation phase. Myriaporone 3/4, a cytotoxic polyketide, has been reported as an inhibitor of eukaryotic protein synthesis. However, the mechanism by which it inhibits translation was unknown. Here we show that myriaporone 3/4 stalls protein synthesis in the elongation phase by inducing phosphorylation of eukaryotic elongation factor 2. The phosphorylation results from direct binding of myriaporone 3/4 to eukaryotic elongation factor 2 kinase. Our study also shows that myriaporone 3/4 in the nanomolar range inhibits in vitro tube formation by endothelial cells without being cytotoxic. In general, myriaporone 3/4 was at least 300 times less toxic to primary cells than to tumor cells. 23261676 (-) Epicatechin attenuates mitochondrial damage by enhancing mitochondrial multi-marker enzymes, adenosine triphosphate and lowering calcium in isoproterenol induced myocardial infarcted rats. Cardiac mitochondrial damage plays an important role in the pathology of myocardial infarction. The protective effects of (-) epicatechin on cardiac mitochondrial damage in isoproterenol induced myocardial infarction were evaluated in rats. Rats were pretreated with (-) epicatechin (20 mg/kg body weight) daily for a period of 21 days. After the pretreatment period, isoproterenol (100 mg/kg body weight) was injected subcutaneously into rats twice at an interval of 24 h to induce myocardial infarction. Isoproterenol induced myocardial infarcted rats showed a significant increase in the levels of cardiac diagnostic markers, heart mitochondrial lipid peroxidation, calcium, and a significant decrease in the activities/levels of heart mitochondrial glutathione peroxidase, glutathione reductase, reduced glutathione, isocitrate, succinate, malate, α-ketoglutarate and NADH-dehydrogenases, cytochrome-C-oxidase and adenosine triphosphate. (-) Epicatechin pretreatment showed significant protective effects on all the biochemical parameters evaluated. The in vitro study revealed the superoxide and hydroxyl radical scavenging activity of (-) epicatechin. The possible mechanisms for the beneficial effects of (-) epicatechin on cardiac mitochondria could be attributed to scavenging of free radicals, decreasing calcium, increasing multi-enzymes (antioxidant, tricarboxylic acid cycle and respiratory chain enzymes), reduced glutathione and adenosine triphosphate. Thus, (-) epicatechin attenuated mitochondrial damage in isoproterenol induced myocardial infarcted rats. 23619817 In Vitro Neo-cartilage Formation on a Three-Dimensional Composite Polymeric Cryogel Matrix. Limited blood supply and the avascular nature of articular cartilage restricts its self repair capacity, frequently leading to osteoarthritis. This work focuses on scaffolds for tissue repair from natural polymers, for example gelatin, chitosan, and agarose in the form of composite. A novel way of fabrication, known as cryogelation, is presented, in which matrices are synthesized at sub-zero temperature. Cell seeded scaffolds incubated under appropriate conditions result in the accumulation of matrix components on the surface of the gel in the form of neo-cartilage. Neo-cartilage exhibits similarity to native cartilage with respect to its physical, mechanical and biochemical properties. Based on the similarities of neo-cartilage to the native cartilage, it can provide a new approach for the treatment of localised joint injuries. 23644192 (99m)Tc-labeled dibenzylideneacetone derivatives as potential SPECT probes for in vivo imaging of β-amyloid plaque. Four (99m)Tc-labeled dibenzylideneacetone derivatives and corresponding rhenium complexes were successfully synthesized and biologically evaluated as potential imaging probes for Aβ plaques using SPECT. All rhenium complexes (5a-d) showed affinity for Aβ(1-42) aggregates (Ki = 13.6-120.9 nM), and selectively stained the Aβ plaques on brain sections of transgenic mice. Biodistribution in normal mice revealed that [(99m)Tc]5a-d exhibited moderate initial uptake (0.31%-0.49% ID/g at 2 min) and reasonable brain washout at 60 min post-injection. Although additional optimizations are still needed to facilitate it's penetration through BBB, the present results indicate that [(99m)Tc]5a may be a potential SPECT probe for imaging Aβ plaques in Alzheimer's brains. 23514378 The role of platelet/lymphocyte serotonin transporter in depression and beyond. A large amount of the data gathered in the last 50 years support the hypothesis that alterations of the serotonin (5-HT) neurotransmission play a crucial role in the pathophysiology of not only major depression (MD), but also of different neuropsychiatric disorders. Research in this field has been substantially promoted by the evidence that the reuptake protein (SERT), present in presynaptic neurons, is a key element in terminating the activity of the neurotransmitter in the synaptic cleft. For this reason, it was specifically targeted for the development of second-generation antidepressants, in particular of selective 5-HT reuptake inhibitors (SSRIs), with the aim of increasing the intrasynaptic 5-HT concentrations. Moreover, since a lot of studies showed that circulating platelets and, more recently, lymphocytes possess functional SERT proteins, they have been widely used as peripheral mirrors of the same structures located in the central nervous system. The presence of functional SERT in blood cells suggests strict relationships between the nervous and the immune system that need to be better clarified in MD, as well as the possibility of reciprocal modulation of the two systems by different drugs. This paper aims to review briefly the literature on the 5-HT hypothesis of depression with a major focus on the possible role of SERT in this disorder, while highlighting how recent data are more oriented on dimensional rather than nosological involvement of this structure in different conditions spanning from normality to pathology. 23623556 Octameric CENP-A Nucleosomes Are Present at Human Centromeres throughout the Cell Cycle. The presence of a single centromere on each chromosome that signals formation of a mitotic kinetochore is central to accurate chromosome segregation [1]. The histone H3 variant centromere protein-A (CENP-A) is critical for centromere identity and function; CENP-A chromatin acts as an epigenetic mark to direct both centromere and kinetochore assembly [2-4]. Interpreting the centromere epigenetic mark ensures propagation of a single centromere per chromosome to maintain ploidy. Thus, understanding the nature of CENP-A chromatin is crucial for all cell divisions. However, there are ongoing debates over the fundamental composition of centromeric chromatin. Here we show that natively assembled human CENP-A nucleosomes are octameric throughout the cell cycle. Using total internal reflection fluorescence (TIRF)-coupled photobleaching-assisted copy-number counting of single nucleosomes obtained from cultured cells, we find that the majority of CENP-A nucleosomes contain CENP-A dimers. In addition, we detect the presence of H2B and H4 in these nucleosomes. Surprisingly, CENP-A associated with the chaperone HJURP can exist as either monomer or dimer, indicating possible assembly intermediates. Thus, our findings indicate that octameric CENP-A nucleosomes mark the centromeric region to ensure proper epigenetic inheritance and kinetochore assembly. 23186623 Maturation-associated changes in the internal distribution of tetrodotoxin in the female goby Yongeichthys criniger. Maturation-associated changes in the internal distribution of tetrodotoxin (TTX) in the goby Yongeichthys criniger were investigated in 29 and 40 female specimens collected from Okinawa, Japan, from August 2008 to June 2009 (Group I), and from November 2009 to August 2010 (Group II), respectively. In Group I, based on changes in the gonadosomatic index (GSI) and histologic observation of the ovary, the period from October 2008 through January 2009 was estimated to be the 'previtelline-forming period', February through March 2009 the 'vitelline-forming period', April through June 2009 the 'spawning period', and August 2008 the 'end of spawning period' of the preceding year. The TTX content (mouse unit [MU] per gram tissue) of each Y. criniger tissue (skin, muscle, liver, and ovary) quantified by liquid chromatography/mass spectrometry (LC/MS) was generally high during the spawning period and continued to rise until the end of spawning period, especially in the ovary. Total TTX per individual increased considerably during the spawning period, most of which located in the ovary, indicating that Y. criniger obtains a high amount of TTX during the spawning period, and accumulates most of it in the ovary. In contrast, the TTX content of the skin was highest at the end of spawning period, and most of the total TTX located in the skin during this period as well as during the previtelline-forming period. In Group II, the maturation stage of the ovaries of all specimens was determined, and the specimens were grouped accordingly. In the perinucleolus stage, yolk vesicle stage, and yolk globule stage I, most of the TTX was localized in the skin, but the TTX in the ovary greatly increased as the maturation stage advanced from yolk globule stage I to yolk globule stage III. 23528109 Nanopore-spanning lipid bilayers on silicon nitride membranes that seal and selectively transport ions. We report the formation of POPC lipid bilayers that span 130 nm pores in a freestanding silicon nitride film supported on a silicon substrate. These solvent-free lipid membranes self-assemble on organosilane-treated Si3N4 via the fusion of 200 nm unilamellar vesicles. Membrane fluidity is verified by fluorescence recovery after photobleaching (FRAP), and membrane resistance in excess of 1 GΩ is demonstrated using electrical impedance spectroscopy (EIS). An array of 40 000 membranes maintained high impedance over 72 h, followed by rupture of most of the membranes by 82 h. Membrane incorporation of gramicidin, a model ion channel, resulted in increased membrane conductance. This membrane conductance was diminished when the gramicidin channels were blocked with CaCl2, indicating that the change in membrane conductance results from gramicidin-mediated ion transport. These very stable, biologically functional pore-spanning membranes open many possibilities for silicon-based ion-channel devices for applications such as biosensors and high-throughput drug screening. 23183669 Interactions of the intact FsrC membrane histidine kinase with the tricyclic peptide inhibitor siamycin I revealed through synchrotron radiation circular dichroism. The suitability of synchrotron radiation circular dichroism spectroscopy (SRCD) for studying interactions between the tricyclic peptide inhibitor siamycin I and the intact FsrC membrane sensor kinase in detergent micelles has been established. In the present study, tertiary structural changes demonstrate that inhibitor binding occurs at a different, non-overlapping site to the native ligand, GBAP. 23142699 Proto-oncogene PIM-1 is a novel estrogen receptor target associating with high grade breast tumors. We searched ERα cistromes of MCF-7 breast cancer cells for previously unrecognized ERα targets and identified proto-oncogene PIM-1 as a novel potential target gene. We show that the expression of PIM-1 is induced in response to estradiol in MCF-7 cells and that the induction is mediated by ERα-regulated enhancers located distally upstream from the gene. In keeping with the growth-promoting role of the PIM-1, depletion of the PIM-1 attenuated the proliferation of the MCF-7 cells, which was paralleled with up-regulation of cyclin-dependent protein kinase inhibitor CDKN1A and CDKN2B expression. Analysis of PIM-1 expression between invasive breast tumors and benign breast tissue samples showed that elevated PIM-1 expression is associated with malignancy and a higher tumor grade. In sum, identification of PIM-1 as an ERα target gene adds a novel potential mechanism by which estrogens can contribute to breast cancer cell proliferation and carcinogenesis. 23561079 Changes in selected parameters related to proteolysis during ageing of dry-cured pork loins inoculated with probiotics. The effect of inoculation with a probiotic strain, Lactobacillus casei ŁOCK 0900, on selected parameters related to proteolysis of dry-cured pork loins during ageing was studied. Moisture content decreased significantly (p<0.05) throughout ageing, accompanied by a progressive reduction in water activity. The total nitrogen (TN) content increased during ageing with no effect (p<0.05) of inoculation with L. casei on its level. The greatest increase in non-protein nitrogen (NPN) content during ageing occurred in an inoculated sample, corresponding with the more pronounced decrease in pH. The intensity of proteolysis, as assessed by proteolysis index (PI), remained statistically significantly (p<0.05) unchanged during examined ageing periods. Inoculation with a probiotic strain does not significantly affect the degree of proteolysis in examined meat products after 21 and 28days of ageing. 23369033 Left, right, or both? On the configuration of the phenanthroindolizidine alkaloid tylophorine from Tylophora indica. The alkaloid (-)-tylophorine was isolated from a sample of Tylophora indica, and the crude extract was analyzed by HPLC/MS(n) and chiral HPLC/MS. While the literature states that the naturally occurring form of this alkaloid is the R-enantiomer and that its S-antipode is usually not found in nature, we confirmed the hypothesis of Govindachari and Nagarajan that natural levorotatory tylophorine is indeed a nearly racemic mixture with a slight excess of the R-enantiomer. 23523906 Berberine attenuates bleomycin induced pulmonary toxicity and fibrosis via suppressing NF-κB dependant TGF-β activation: A biphasic experimental study. Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating and fatal lung disorder with high mortality rate. Unfortunately, to date the treatment for IPF remains unsatisfying and in severe cases lung transplantations are performed as a therapeutic measure. Thus, it becomes great interest to find novel agents to treat IPF. Berberine, a plant alkaloid known for its broad pharmacological activities remains a remedy against multiple diseases. This study was hypothesized to investigate the antifibrotic potential of berberine against bleomycin-induced lung injury and fibrosis, a tentative animal model. Male wistar rats were subjected to single intratracheal instillation of 2.5U/kg of bleomycin on day 0. Berberine treatments were either provided in preventive or therapeutic mode respectively. Berberine administration significantly ameliorated the bleomycin mediated histological alterations and reduced the inflammatory cell infiltrate in BALF. Berberine significantly blocked collagen accumulations with parallel reduction in the hydroxyproline level. The immunological sign of bleomycin stimulated mast cell deposition and histamine release were considerably reduced by berberine. Berberine enhanced the antioxidant status, through upregulating the redox sensing transcription factor nuclear factor E2-related factor 2 (Nrf2). Berberine inhibited the bleomycin mediated activation of inflammatory mediator nuclear factor kappa B (NF-κB) and suppressed its downstream target inducible nitric oxide synthase (iNOS). Strikingly, berberine exhibited target attenuation of tumor necrosis factor alpha (TNF-α) and key pro-fibrotic mediator, transforming growth factor beta 1 (TGF-β1). Taken together, this study reveals the beneficial effects of berberine against bleomycin mediated fibrotic challenge through activating Nrf2 and suppressing NF-κB dependent inflammatory and TGF-β1 mediated fibrotic events. 23441816 Ca(2+) -calmodulin interacts with DdCAD-1 and promotes DdCAD-1 transport by contractile vacuoles in Dictyostelium cells. The Ca(2+) -dependent cell-cell adhesion molecule DdCAD-1, encoded by the cadA gene of Dictyostelium discoideum, is synthesized at the onset of development as a soluble protein and then transported to the plasma membrane by contractile vacuoles. Calmodulin associates with contractile vacuoles in a Ca(2+) -dependent manner, and co-localizes with DdCAD-1 on the surface of contractile vacuoles. Bioinformatics analysis revealed multiple calmodulin-binding motifs in DdCAD-1. Co-immunoprecipitation and pull-down studies showed that only Ca(2+) -bound calmodulin was able to bind DdCAD-1. Structural integrity of DdCAD-1, but not the native conformation, was required for its interaction with calmodulin. To investigate the role of calmodulin in the import of DdCAD-1 into contractile vacuoles, an in vitro import assay consisting of contractile vacuoles derived from cadA(-) cells and recombinant proteins was employed. Prior stripping of the bound calmodulin from contractile vacuoles by EGTA impaired import of DdCAD-1, which was restored by addition of exogenous calmodulin. The calmodulin antagonists W-7 and compound 48/80 blocked the binding of calmodulin onto stripped contractile vacuoles, and inhibited the import of DdCAD-1. Together, the data show that calmodulin forms a complex with DdCAD-1 and promotes the docking and import of DdCAD-1 into contractile vacuoles. STRUCTURED DIGITAL ABSTRACT: CaM physically interacts with DdCAD-1 by pull down (View Interaction: 1, 2) DdCAD-1 binds to CaM by far western blotting (View interaction) DdCAD-1 physically interacts with CaM by anti bait coimmunoprecipitation (View interaction). 23416001 Spirocyclic replacements for the isatin in the highly selective, muscarinic M1 PAM ML137: the continued optimization of an MLPCN probe molecule. This Letter describes the further optimization of an MLPCN probe molecule (ML137) through the introduction of 5- and 6-membered spirocycles in place of the isatin ketone. Interestingly divergent structure-activity relationships, when compared to earlier M1 PAMs, are presented. These novel spirocycles possess improved efficacy relative to ML137, while also maintaining high selectivity for the human and rat muscarinic M1 receptor subtype. 23414433 Glial reactivity in resistance to methamphetamine-induced neurotoxicity. Neurotoxic regimens of methamphetamine (METH) result in reactive microglia and astrocytes in striatum. Prior data indicate that rats with partial dopamine (DA) loss resulting from prior exposure to METH are resistant to further decreases in striatal DA when re-exposed to METH 30 days later. Such resistant animals also do not show an activated microglia phenotype, suggesting a relation between microglial activation and METH-induced neurotoxicity. To date, the astrocyte response in such resistance has not been examined. Thus, this study examined glial-fibrillary acidic protein (GFAP) and CD11b protein expression in striata of animals administered saline or a neurotoxic regimen of METH on post-natal days 60 and/or 90 (Saline:Saline, Saline:METH, METH:Saline, METH:METH). Consistent with previous work, animals experiencing acute toxicity (Saline:METH) showed both activated microglia and astocytes, whereas those resistant to the acute toxicity (METH:METH) did not show activated microglia. Interestingly, GFAP expression remained elevated in rats exposed to METH at PND60 (METH:Saline), and was not elevated further in resistant rats treated for the second time with METH (METH:METH). These data suggest that astrocytes remain reactive up to 30 days post-METH exposure. In addition, these data indicate that astrocyte reactivity does not reflect acute, METH-induced DA terminal toxicity, whereas microglial reactivity does. 23127899 Epidemiology and clinical effects of hump-nosed pit viper (Genus: Hypnale) envenoming in Sri Lanka. Hump-nosed pit vipers of Genus Hypnale are the commonest cause of snake bite in Sri Lanka. Although there are many reports of local effects, coagulopathy and acute kidney injury, it remains unclear how frequent these clinical effects are and therefore the medical importance of this snake genus. The genus has been recently revised to include Hypnale hypnale from Sri Lanka and Western Ghats of Southern India, and the two endemic species to Sri Lanka, Hypnale zara and Hypnale nepa. This was a prospective hospital-based clinical study of definite Hypnale spp. bites from July 2008 to July 2010 in six Sri Lankan hospitals. There were 114 patients included and all snakes were correctly identified by hospital staff as Hypnale spp. Of these, 93 snakes were identified as H. hypnale by an expert, 16 as H. zara and five as H. nepa. Most bites occurred on the lower limbs in the daytime. There was no difference in the clinical effects between the three species. Pain and fang marks were present in all patients, 101 had local swelling and only 16 (14%) developed extensive local swelling that spread proximally and involved more than half of the bitten limb. Systemic symptoms occurred in 18 patients; four patients had an abnormal 20 min whole blood clotting test and one patient developed an acute kidney injury that required haemodialysis. All patients were discharged alive with a median length of stay of 2 days. This study confirms that hump-nosed viper bites cause only minor effects in most cases. Future studies need to undertake formal coagulation studies and identify important early indicators of renal impairment. 22607769 MicroRNA regulation of lipid metabolism. MicroRNAs are structural components of an epigenetic mechanism of post-transcriptional regulation of messenger RNA translation. Recently, there is significant interest in the application of microRNA as a blood-based biomarker of underlying physiologic conditions, and the therapeutic administration of microRNA inhibitors and mimics. The purpose of this review is to describe the current body of knowledge on microRNA regulation of genes involved in lipid metabolism, and to introduce the role of microRNA in development and progression of atherosclerosis. 23312946 Specific chlorination of isoquinolines by a fungal flavin-dependent halogenase. Rdc2 is the first flavin-dependent halogenase identified from fungi. Based on the reported structure of the bacterial halogenase CmlS, we have built a homology model for Rdc2. The model suggests an open substrate binding site that is capable of binding the natural substrate, monocillin II, and possibly other molecules such as 4-hydroxyisoquinoline (1) and 6-hydroxyisoquinoline (2). In vitro and in vivo halogenation experiments confirmed that 1 and 2 can be halogenated at the position ortho to the hydroxyl group, leading to the synthesis of the chlorinated isoquinolines 1a and 2a, respectively, which further expands the spectrum of identified substrates of Rdc2. This work revealed that Rdc2 is a useful biocatalyst for the synthesis of various halogenated compounds. 23038668 Simple photosystem II water oxidation centre analogues in visible light oxygen and H+ generation. Calcium manganese oxide nanoparticles for application in water oxidation are synthesized by combination with a carboxylated biopolymer stabilizing agent to form very simple but effective analogues of the photosynthetic PSII oxygen evolving complex. The relative efficiency of these materials for production of O(2) and protons under visible light-promoted reactions is evaluated and prolonged reaction lifetimes are observed. 23624810 Antiaggressive activity of central oxytocin in male rats. RATIONALE: A substantial body of research suggests that the neuropeptide oxytocin promotes social affiliative behaviors in a wide range of animals including humans. However, its antiaggressive action has not been unequivocally demonstrated in male laboratory rodents. OBJECTIVE: Our primary goal was to examine the putative serenic effect of oxytocin in a feral strain (wild type Groningen, WTG) of rats that generally show a much broader variation and higher levels of intermale aggression than commonly used laboratory strains of rats. METHODS: Resident animals were intracerebroventricularly (icv) administered with different doses of synthetic oxytocin and oxytocin receptor antagonist, alone and in combination, in order to manipulate brain oxytocin functioning and to assess their behavioral response to an intruder. RESULTS: Our data clearly demonstrate that acute icv administered oxytocin produces dose-dependent and receptor-selective changes in social behavior, reducing aggression and potentiating social exploration. These antiaggressive effects are stronger in the more offensive rats. On the other hand, administration of an oxytocin receptor antagonist tends to increase (nonsignificantly) aggression only in low-medium aggressive animals. CONCLUSIONS: These results suggest that transiently enhancing brain oxytocin function has potent antiaggressive effects, whereas its attenuation tends to enhance aggressiveness. In addition, a possible inverse relationship between trait aggression and endogenous oxytocinergic signaling is revealed. Overall, this study emphasizes the importance of brain oxytocinergic signaling for regulating intermale offensive aggression. This study supports the suggestion that oxytocin receptor agonists could clinically be useful for curbing heightened aggression seen in a range of neuropsychiatric disorders like antisocial personality disorder, autism, and addiction. 23451823 Cryptocapsinepoxide-Type Carotenoids from Red Mamey, Pouteria sapota. New carotenoids, cryptocapsin-5,6-epoxide, 3'-deoxycapsanthin-5,6-epoxide, and cryptocapsin-5,8-epoxides, have been isolated from the ripe fruits of red mamey (Pouteria sapota). Cryptocapsin-5,6-epoxide was prepared by partial synthesis via epoxidation of cryptocapsin, and the (5R,6S)- and (5S,6R)-stereoisomers were identified by HPLC-ECD analysis. Spectroscopic data of the natural (anti) and semisynthetic (syn) derivatives obtained by acid-catalyzed rearrangement of cryptocapsin-5,8-epoxide stereoisomers were compared for structural elucidation. Chiral HPLC separation of natural and semisynthetic samples of cryptocapsin-5,8-epoxides was performed, and HPLC-ECD analysis allowed configurational assignment of the separated stereoisomers. 23472709 H-H and Si-H Bond Addition to Fe≡NNR2 Intermediates Derived from N2. The synthesis and characterization of Fe-diphosphineborane complexes are described in the context of N2 functionalization chemistry. Iron aminoimides can be generated at room temperature under 1 atm N2 and are shown to react with E-H bonds from PhSiH3 and H2. The resulting products derive from delivery of the E fragment to Nα and the H atom to B. The flexibility and lability of the Fe-BPh interactions in these complexes engender this reactivity. 23332347 Therapy of obese patients with cardiovascular disease. Obesity has reached epidemic proportions and is a significant public health concern. Obesity is associated with increased diabetes, cardiovascular and kidney disease, and associated morbidity and mortality. Despite the increasing public health problem of obesity, there is a dearth of effective treatment options. Following the FDA mandated withdrawal of sibutramine, the treatment options for obesity were limited to orlistat as the only pharmacological treatment option for long-term management of obesity. Recently two new medications (Belviq and Qsymia) were approved by FDA for long-term management of obesity. Many other antiobesity drugs are under development. Bariatric surgery has been shown to be effective in the treatment of obesity and its comorbidities. The available data suggest that even modest weight loss improves diabetes and cardiovascular disease (CVD) risk factors. We summarize the treatment options for obesity and the efficacy of these options in ameliorating cardiovascular risk factors. We also focus on the recently approved antiobesity drugs. 23444773 Fanconi anemia pathway--the way of DNA interstrand cross-link repair. The study of rare genetic diseases usually inspires the research of cancer biology. Fanconi anemia (FA), is a rare cancer susceptibility syndrome with an incidence of only 1 per 350,000 births. FA is an autosomal recessive disease with three main features: chromosome instability, hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC), cisplatin and so on, and susceptible to a number of cancer types, mainly leukemia and squamous cell carcinomas of the head and neck or gynecologic system. DNA crosslinking agents may led to DNA cross-linking lesion, and Fanconi anemia pathway plays a key role in repairing its cross-linking. However, FA pathway is closely linked with carcinogenesis and tumor drug resistance. This paper mainly focuses on the FA pathway and its progress in cancer research. 23399639 Chemically diverse microtubule stabilizing agents initiate distinct mitotic defects and dysregulated expression of key mitotic kinases. Microtubule stabilizers are some of the most successful drugs used in the treatment of adult solid tumors and yet the molecular events responsible for their antimitotic actions are not well defined. The mitotic events initiated by three structurally and biologically diverse microtubule stabilizers; taccalonolide AJ, laulimalide/fijianolide B and paclitaxel were studied. These microtubule stabilizers cause the formation of aberrant, but structurally distinct mitotic spindles leading to the hypothesis that they differentially affect mitotic signaling. Each microtubule stabilizer initiated different patterns of expression of key mitotic signaling proteins. Taccalonolide AJ causes centrosome separation and disjunction failure to a much greater extent than paclitaxel or laulimalide, which is consistent with the distinct defects in expression and activation of Plk1 and Eg5 caused by each stabilizer. Localization studies revealed that TPX2 and Aurora A are associated with each spindle aster formed by each stabilizer. This suggests a common mechanism of aster formation. However, taccalonolide AJ also causes pericentrin accumulation on every spindle aster. The presence of pericentrin at every spindle aster initiated by taccalonolide AJ might facilitate the maintenance and stability of the highly focused asters formed by this stabilizer. Laulimalide and paclitaxel cause completely different patterns of expression and activation of these proteins, as well as phenotypically different spindle phenotypes. Delineating how diverse microtubule stabilizers affect mitotic signaling pathways could identify key proteins involved in modulating sensitivity and resistance to the antimitotic actions of these compounds. 23353658 In vitro permeability analysis, pharmacokinetic and brain distribution study in mice of imperatorin, isoimperatorin and cnidilin in Radix Angelicae Dahuricae. Coumarins are important constituents of Radix Angelicae Dahuricae, a well-known traditional Chinese medicine possess several known bioactivities with potentials in the treatment of central nervous system diseases. By using an HPLC-MS/MS method, we analyzed the in vivo plasma and brain pharmacokinetics of three ingredients of coumarins, including imperatorin, isoimperatorin and cnidilin in mice after oral administration of Dahuricae extract at doses of 800mg/kg. The biosamples were prepared using acetonitrile precipitation and the separation was achieved on an XDB-C18 column by gradient elution. The BBB permeability and P-gp-mediated efflux were further examined in Madin Canine kidney cells transfected with full length cDNA for human multidrug resistance gene1 (MDCKII-MDR1). Our results demonstrate that the method has excellent and satisfactory selectivity, sensitivity, linearity, precision, and accuracy for simultaneous determination of imperatorin, isoimperatorin and cnidilin. The pharmacokinetics parameters were determined by using noncompartmental analyses, including the AUC(0-t) in plasma (1695.22, 1326.45 and 636.98mg*h/L), the AUC(0-t) in brain (1812.35, 2125.17 and 1145.83ng*h/g) as well as the T1/2 in plasma (0.66, 0.82, 0.97h) and brain (0.96, 1.1, 0.99h) for imperatorin, isoimperatorin and cnidilin, respectively, suggesting that the three coumarins could easily pass through the BBB in vivo. In the in vitro model we observed high permeability of imperatorin and isoimperatorin with the P-gp-mediated efflux ratios of 0.53 and 0.06, as well as medium permeability of cnidilin with 0.82. All data suggest that these three coumarins have high BBB permeability and have pharmacokinetic potentials for the treatment of central nervous system diseases. 23456248 OsSNDP1, a Sec14-nodulin domain-containing protein, plays a critical role in root hair elongation in rice. Rice is cultivated in water-logged paddy lands. Thus, rice root hairs on the epidermal layers are exposed to a different redox status of nitrogen species, organic acids, and metal ions than root hairs growing in drained soil. To identify genes that play an important role in root hair growth, a forward genetics approach was used to screen for short-root-hair mutants. A short-root-hair mutant was identified and isolated by using map-based cloning and sequencing. The mutation arose from a single amino acid substitution of OsSNDP1 (Oryza sativa Sec14-nodulin domain protein), which shows high sequence homology with Arabidopsis COW1/AtSFH1 and encodes a phosphatidylinositol transfer protein (PITP). By performing complementation assays with Atsfh1 mutants, we demonstrated that OsSNDP1 is involved in growth of root hairs. Cryo-scanning electron microscopy was utilized to further characterize the effect of the Ossndp1 mutation on root hair morphology. Aberrant morphogenesis was detected in root hair elongation and maturation zones. Many root hairs were branched and showed irregular shapes due to bulged nodes. Many epidermal cells also produced dome-shaped root hairs, which indicated that root hair elongation ceased at an early stage. These studies showed that PITP-mediated phospholipid signaling and metabolism is critical for root hair elongation in rice. 23074035 Temperature controlled water/oil wettability of a surface fabricated by a block copolymer: application as a dual water/oil on-off switch. A temperature controlled dual water/oil on-off switch is achieved by using a PMMA-b-PNIPAAm block-copolymer coated mesh, determined by the conformational change of the PNIPAAm chain around the lower critical solution temperature (LCST) and also the cooperation between PNIPAAm and PMMA. Water can permeate through the BCP-coated mesh, and oil cannot below the LCST, whereas oil can and water cannot above the LCST. 23444782 Effects of a new sustained-release microsphere formulation of exenatide, DA-3091, on obese and non-alcoholic fatty liver disease mice. The aim of this study was to examine the effects of a new sustained-release (SR) microsphere formulation of exenatide, DA-3091, on body weight gain and hepatic injury in high fat diet (HFD)-induced obese mice and high sucrose diet (HSD)-induced non-alcoholic fatty liver disease (NAFLD) mice. Then, we determined whether DA-3091 has the potency as a drug for the treatment of metabolic disease. In obese mice, after 8-week treatment, the body weight gain was significantly more suppressed by both 1 mg/kg and 2 mg/kg of DA-3091, monthly subcutaneous administered, than by 10 mg/kg/day of sibutramin, a drug against obesity. In NAFLD mice, a significant reduction in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, representative markers of hepatic injury, was observed after biweekly subcutaneous administration of 1 mg/kg and 2 mg/kg of DA-3091 for 8 weeks. A significant reduction in hepatic lipid accumulation was observed in DA-3091 treated groups as well. Based on these results, it is demonstrated that DA-3091 has the potency as a drug for the treatment of metabolic disease. 23291264 Urinary chemokine (C-C motif) ligand 2 (monocyte chemotactic protein-1) as a tubular injury marker for early detection of cisplatin-induced nephrotoxicity. Because of the difficulty in detecting segment-specific response in the kidney, we investigated the molecular events underlying acute kidney injury in the proximal tubules of rats with cisplatin (cis-diamminedichloroplatinum II)-induced nephrotoxicity. Microarray analysis revealed that mRNA levels of several cytokines and chemokines, such as interleukin-1beta, chemokine (C-C motif) ligand (CCL) 2, CCL20, chemokine (C-X-C motif) ligand (CXCL) 1, and CXCL10 were significantly increased after cisplatin treatment in both isolated proximal tubules and whole kidney. Interestingly, tubular CCL2 mRNA levels increased soon after cisplatin administration, whereas CCL2 mRNA levels in whole kidney first decreased and then increased. Levels of both CCL2 and kidney injury molecule-1 (KIM-1) in the whole kidney increased after cisplatin administration. Immunofluorescence analysis revealed CCL2 changes in the proximal tubular cells initially and then in the medullary interstitium. Urinary CCL2 excretion significantly increased approximately 3-fold compared with controls the day after cisplatin administration (5mg/kg), when no changes were observed plasma creatinine and blood urea nitrogen levels. Urinary levels of KIM-1 also increased 3-fold after cisplatin administration. In addition, urinary CCL2 rather than KIM-1 increased in chronic renal failure rats after administration of low-dose cisplatin (2mg/kg), suggesting that urinary CCL2 was selective for cisplatin-induced nephrotoxicity in renal impairment. These results indicated that the increase in cytokine and chemokine expression in renal epithelial cells might be responsible for kidney deterioration in cisplatin-induced nephrotoxicity, and that urinary CCL2 is associated with tubular injury and serves as a sensitive and noninvasive marker for the early detection of cisplatin-induced tubular injury. 23617439 Praziquantel Derivatives with Anti-Schistosomal Activity: Aromatic ring Modification. A series of aromatic ring modified praziquantel (PZQ) derivatives were prepared and evaluated against juvenile and adult stage of Schistosoma japonicumin. Several analogues comparable in activity to the drug PZQ have been identified based on in vitro and in vivo japonuicum schistosomes worm viability assay. Structure and activity relationship of these PZQ aromatic ring modified compounds was revealed. Specifically, a compound in which a bromine has been introduced in the aromatic ring of praziquantel demonstrated close antischistosomal activity to praziquentel in vivo. This article is protected by copyright. All rights reserved. 23297817 CO oxidation on colloidal Au(0.80)Pd(0.20)-Fe(x)O(y) dumbbell nanocrystals. We report a colloidal synthesis of Au(0.80)Pd(0.20)-Fe(x)O(y) dumbbell nanocrystals (NCs) derived from Au(0.75)Pd(0.25) NCs by metal oxide overgrowth. We compared the catalytic activity of the two types of NCs in the CO oxidation reaction (CO + 1/2O(2) → CO(2)), after they had been dispersed on an alumina nanopowder support. In both cases, the surface active sites were identified by means of in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). The enhanced catalytic performance of the dumbbell NCs (Au(0.80)Pd(0.20)-Fe(x)O(y)) catalyst over that of the initial Au(0.75)Pd(0.25) NCs could be correlated to the presence of the epitaxial connection between the Fe(x)O(y) and the Au(0.80)Pd(0.20) domains (as the main factor). Such connection should result in an electron flow from the metal oxide (Fe(x)O(y)) domain to the noble metal (Au(0.80)Pd(0.20)) domain and appears to influence favorably the nature and composition of the catalytically active surface sites of the dumbbells. Our experiments indicate indeed that, when the metal alloy domain is attached to the metal oxide domain (that is, in the dumbbell), surface Pd species are more active than in the case of the initial Au(0.75)Pd(0.25) NCs and also Au(δ-) sites are formed that were not present on the initial Au(0.75)Pd(0.25) NCs. 23583735 (1)H NMR-based metabonomics study on the toxicity alleviation effect of other traditional Chinese medicines in Niuhuang Jiedu tablet to realgar (As2S2). ETHNOPHARMACOLOGICAL RELEVANCE: Niuhuang Jiedu Tablet (NJT) is an effective prescription of traditional Chinese medicine (TCM) used in treating acute tonsillitis, pharyngitis, periodontitis and mouth ulcer. NJT is prepared from Xionghuang (Realgar, As2S2), Rengong Niuhuang (Bovis Calculus Artificialis), Bingpian (Borneolum Synthcticum), Shigao (Gypsum Fibrosum), Dahuang (Rhei Radix et Rhizoma), Huangqin (Scutellariae Radix), Jiegeng (Platycodonis Radix) and Gancao (Glycyrrhizae Radix et Rhizoma). In the prescription, significant level of realgar (As2S2) as a potentially toxic element is contained. AIM OF THE STUDY: In this study, (1)H NMR-based metabonomics approach has been used to investigate the toxicity of realgar (As2S2) after being counterbalanced by other TCMs in NJT. MATERIALS AND METHODS: Male Wistar rats were divided into five groups: control, group I (treated with Realgar), group II (treated with Realgar, Bovis Calculus Artificialis, Borneolum Synthcticum, Gypsum Fibrosum, Rhei Radix et Rhizoma, Scutellariae Radix, Platycodonis Radix and Glycyrrhizae Radix et Rhizoma), group III (treated with Realgar, Bovis Calculus Artificialis, Borneolum Synthcticum and Gypsum Fibrosum) and group IV (treated with Realgar, Rhei Radix et Rhizoma, Scutellariae Radix, Platycodonis Radix and Glycyrrhizae Radix et Rhizoma). Based on (1)H-NMR spectra of urine and serum from rats, PCA and PLS-DA were performed to identify different metabolic profiles. Liver and kidney histopathology examinations and serum clinical chemistry analysis were also performed. RESULTS: PLS-DA scores plots demonstrated that the cluster of group I was separated from that of control rats, while group II was located close to control rats, indicating that metabolic profiles of group II were restored toward those of control rats. The metabolic profiles of group III were similar to those of group I, while the metabolic profiles of group II were almost in line with those of group II. Statistics results were confirmed by the histopathological examination and biochemical assay. CONCLUSION: Our results indicated that it was more secure and much less toxic for counterbalanced realgar (As2S2) in NJT. The effective material bases of toxicity alleviation to realgar (As2S2) were Dahuang (Rhei Radix et Rhizoma), Huangqin (Scutellariae Radix), Jiegeng (Platycodonis Radix) and Gancao (Glycyrrhizae Radix et Rhizoma), which regulated energy metabolism, choline metabolism, amino acid metabolism and gut flora disorder affected by realgar (As2S2) exposure. 23389738 Hepatotumorigenicity of ethyl tertiary-butyl ether with 2-year inhalation exposure in F344 rats. Carcinogenicity of ethyl tertiary-butyl ether (ETBE) was examined with inhalation exposure using F344/DuCrlCrlj rats. Groups of 50 male and 50 female rats, 6 week old at commencement, were exposed to ETBE at 0, 500, 1,500 or 5,000 ppm (v/v) in whole-body inhalation chambers for 6 h/day, 5 days/week for 104 weeks. A significant increase in the incidence of hepatocellular adenomas was indicated in males exposed at 5,000 ppm, but not in females at any concentration. In addition, significantly increased incidences of eosinophilic and basophilic cell foci were observed in male rats at 5,000 ppm. Regarding non-neoplastic lesions, rat-specific changes were observed in kidney, with an increase in the severity of chronic progressive nephropathy in both sexes at 5,000 ppm. Increased incidences of urothelial hyperplasia of the pelvis were observed at 1,500 ppm and above, and mineral deposition was apparent in the renal papilla at 5,000 ppm in males. There were no treatment-related histopathological changes observed in any other organs or tissues in either sex. The present 2-year inhalation study demonstrated hepatotumorigenicity of ETBE in male, but not in female rats. 23225770 Biocompatible fibrous networks of cellulose nanofibres and collagen crosslinked using genipin: potential as artificial ligament/tendons. Bio-based fibrous nanocomposites of cellulose nanofibres and non-crosslinked/crosslinked collagen were prepared by in situ pH-induced fibrillation of collagen phase and sterilized using gamma rays at 25 KGy. Collagen phase is crosslinked using genipin, a bio-based crosslinker that introduces flexible crosslinks. Microscopy studies of the prepared materials showed nanostructured fibrous collagen and cellulose dispersed in collagen matrix. Mechanical performance of the sterilized nanocomposites was close to that of natural ligament and tendon, in simulated body conditions. Cytocompatibility studies indicated that these nanocomposites allowed human ligament cell and human endothelial cell adhesion, growth, and differentiation; which is eminently favourable to ligament tissue engineering. 23570269 Modular stitching to image single-molecule DNA transport. For study of time-dependent conformation, all previous single-molecule imaging studies of polymer transport involve fluorescence labeling uniformly along the chain, which suffers from limited resolution due to the diffraction limit. Here we demonstrate the concept of submolecular single-molecule imaging with DNA chains assembled from DNA fragments such that a chain is labeled at designated spots with covalently attached fluorescent dyes and the chain backbone with dyes of different color. High density of dyes ensures good signal-to-noise ratio to localize the designated spots in real time with nanometer precision and prevents significant photobleaching for long-time tracking purposes. To demonstrate usefulness of this approach, we image electrophoretic transport of λ-DNA through agarose gels. The unexpected pattern is observed that one end of each molecule tends to stretch out in the electric field while the other end remains quiescent for some time before it snaps forward and the stretch-recoil cycle repeats. These features are neither predicted by prevailing theories of electrophoresis mechanism nor detectable by conventional whole-chain labeling methods, which demonstrate pragmatically the usefulness of modular stitching to reveal internal chain dynamics of single molecules. 23511973 The rough endoplasmatic reticulum is a central nucleation site of siRNA-mediated RNA silencing. Despite progress in mechanistic understanding of the RNA interference (RNAi) pathways, the subcellular sites of RNA silencing remain under debate. Here we show that loading of lipid-transfected siRNAs and endogenous microRNAs (miRNA) into RISC (RNA-induced silencing complexes), encounter of the target mRNA, and Ago2-mediated mRNA slicing in mammalian cells are nucleated at the rough endoplasmic reticulum (rER). Although the major RNAi pathway proteins are found in most subcellular compartments, the miRNA- and siRNA-loaded Ago2 populations co-sediment almost exclusively with the rER membranes, together with the RISC loading complex (RLC) factors Dicer, TAR RNA binding protein (TRBP) and protein activator of the interferon-induced protein kinase (PACT). Fractionation and membrane co-immune precipitations further confirm that siRNA-loaded Ago2 physically associates with the cytosolic side of the rER membrane. Additionally, RLC-associated double-stranded siRNA, diagnostic of RISC loading, and RISC-mediated mRNA cleavage products exclusively co-sediment with rER. Finally, we identify TRBP and PACT as key factors anchoring RISC to ER membranes in an RNA-independent manner. Together, our findings demonstrate that the outer rER membrane is a central nucleation site of siRNA-mediated RNA silencing. 23553655 Treatment-, Patient-, and Disease-Related Factors and the Emergence of Adverse Events with Tyrosine Kinase Inhibitors for the Treatment of Chronic Myeloid Leukemia. Four breakpoint cluster region (BCR)-ABL1 tyrosine kinase inhibitors (TKIs) are currently available for the treatment of chronic myeloid leukemia (CML): imatinib, nilotinib, dasatinib, and bosutinib. Choosing the most appropriate TKI requires clinicians to consider a host of patient-, disease-, and treatment-related factors, not the least of which include the safety profiles of the agents. This review discusses the potential impact of treatment-, patient-, and disease-related characteristics on the emergence of adverse events during TKI therapy, with a focus on the underlying mechanisms believed to be responsible for a number of important adverse events associated with these agents and what implications they may have for treatment choice, particularly in the setting of first-line treatment. A literature search of the PubMed database was conducted to identify articles that described the molecular mechanisms of BCR-ABL1-mediated leukemic transformation, the efficacy and safety of imatinib, nilotinib, dasatinib, and bosutinib in patients with CML, the kinase-binding spectrum of each TKI, and evidence suggesting a link between the TKI-binding profile and adverse events. The pattern of adverse events associated with each agent is important when selecting treatment with a TKI. Clinical studies suggest that imatinib, nilotinib, dasatinib, and bosutinib have differing safety profiles, which are in part attributable to the specificity and selectivity of each agent. Although much basic research must be conducted to further illuminate the mechanisms responsible for TKI-related adverse events, on- and off-target effects are believed to be at least partly responsible for cardiovascular toxicity, myelosuppression, fluid retention, gastrointestinal toxicity, and dermatologic toxicity. Increased understanding of the factors that affect TKI-associated adverse events and long-term safety data will enable a more informed approach to the selection of therapy best suited to the individual needs of patients with CML. 23401244 EFFECT OF C60 FULLERENES ON THE ACCUMULATION OF WEATHERED p,p'-DDE BY PLANT AND EARTHWORM SPECIES UNDER SINGLE AND MULTISPECIES CONDITIONS. The use of engineered nanomaterials has increased dramatically in recent years, but an understanding of nanomaterial fate and effects in the environment is lacking. In particular, the interaction of nanomaterials with coexisting organic contaminants and the subsequent implications for sensitive biota is almost completely unknown. Here, the effect of C60 fullerenes on the accumulation of weathered dichlorodiphenyldichloroethylene (p,p'-DDE; DDT metabolite) by Cucurbita pepo (pumpkin) and Eisenia fetida (earthworm) was determined under single and multispecies conditions. The plants, in the presence or absence of earthworms, were grown in soil containing weathered DDE (200 ng/g) and 0 or 1,670 mg/kg C60 fullerenes. Plants and earthworms were added either simultaneously or sequentially (earthworms after plants). Neither DDE nor C60 had an impact on survival or biomass of plants and earthworms, although fullerenes significantly decreased (29.6-39.0%) the relative root mass. Under single or multispecies conditions, C60 had little impact on DDE bioaccumulation by either species. The DDE concentrations in non-fullerene-exposed shoots, roots, and earthworms were 181, 7,400, and 8,230 ng/g, respectively. On fullerene exposure, the DDE content was nonsignificantly lower at 163, 7280, and 7540 ng/g, respectively. In the presence of the earthworms, C60 significantly decreased the shoot DDE content (28.6%), but no impact on root concentrations was observed. Root DDE content was unaffected by the presence of fullerenes and decreased by 21.6 to 37.5% during coexposure with earthworms. Earthworm DDE content was decreased by plant presence. Earthworms added to soils after plant harvest accumulated more DDE but were unaffected by the C60 exposure. Additional work is necessary, but these findings suggest that fullerenes may have minimal impact on the bioaccumulation of weathered cocontaminants in soil. Environ. Toxicol. Chem. 2013;32:1117-1123. © 2013 SETAC. 22813628 Dose response analysis of monophthalates in the murine embryonic stem cell test assessed by cardiomyocyte differentiation and gene expression. The embryonic stem cell test (EST) is based on compound-induced inhibition of cardiomyocyte differentiation of pluripotent stem cells. We examined the use of transcriptomics to assess concentration-effect relationships and performed potency ranking within a chemical class. Three embryotoxic phthalate monoesters, monobutyl phthalate (MBuP), monobenzyl phthalate (MBzP) and mono-(2-ethylhexyl) phthalate (MEHP) and the non-embryotoxic monomethyl phthalate (MMP) were studied for their effects on gene expression. Effects on gene expression were observed at concentrations that did not inhibit cardiomyocyte differentiation or induce cytotoxicity. The embryotoxic phthalate monoesters altered the expression of 668 commonly expressed genes in a concentration-dependent fashion. The same potency ranking was observed for morphology and gene expression (MEHP>MBzP>MBuP>MMP). These results indicate that integrating transcriptomics provides a sensitive method to measure the dose-dependent effects of phthalate monoester exposure and enables potency ranking based on a common mode of action within a class of compounds. Transcriptomic approaches may improve the applicability of the EST, in terms of sensitivity and specificity. 23315496 Effect of the purinergic inhibitor oxidized ATP in a model of islet allograft rejection. The lymphocytic ionotropic purinergic P2X receptors (P2X1R-P2X7R, or P2XRs) sense ATP released during cell damage-activation, thus regulating T-cell activation. We aim to define the role of P2XRs during islet allograft rejection and to establish a novel anti-P2XRs strategy to achieve long-term islet allograft function. Our data demonstrate that P2X1R and P2X7R are induced in islet allograft-infiltrating cells, that only P2X7R is increasingly expressed during alloimmune response, and that P2X1R is augmented in both allogeneic and syngeneic transplantation. In vivo short-term P2X7R targeting (using periodate-oxidized ATP [oATP]) delays islet allograft rejection, reduces the frequency of Th1/Th17 cells, and induces hyporesponsiveness toward donor antigens. oATP-treated mice displayed preserved islet grafts with reduced Th1 transcripts. P2X7R targeting and rapamycin synergized in inducing long-term islet function in 80% of transplanted mice and resulted in reshaping of the recipient immune system. In vitro P2X7R targeting using oATP reduced T-cell activation and diminished Th1/Th17 cytokine production. Peripheral blood mononuclear cells obtained from long-term islet-transplanted patients showed an increased percentage of P2X7R(+)CD4(+) T cells compared with controls. The beneficial effects of oATP treatment revealed a role for the purinergic system in islet allograft rejection, and the targeting of P2X7R is a novel strategy to induce long-term islet allograft function. 23633219 Structure-Based DNA-Targeting Strategies with Small Molecule Ligands for Drug Discovery. Nucleic acids are the molecular targets of many clinical anticancer drugs. However, compared with proteins, nucleic acids have traditionally attracted much less attention as drug targets in structure-based drug design, partially because limited structural information of nucleic acids complexed with potential drugs is available. Over the past several years, enormous progresses in nucleic acid crystallization, heavy-atom derivatization, phasing, and structural biology have been made. Many complicated nucleic acid structures have been determined, providing new insights into the molecular functions and interactions of nucleic acids, especially DNAs complexed with small molecule ligands. Thus, opportunities have been created to further discover nucleic acid-targeting drugs for disease treatments. This review focuses on the structure studies of DNAs complexed with small molecule ligands for discovering lead compounds, drug candidates, and/or therapeutics. 23042730 Tumor necrosis factor-alpha potentiates the cytotoxicity of amiodarone in Hepa1c1c7 cells: roles of caspase activation and oxidative stress. Amiodarone (AMD), a class III antiarrhythmic drug, causes idiosyncratic hepatotoxicity in human patients. We demonstrated previously that tumor necrosis factor-alpha (TNF-α) plays an important role in a rat model of AMD-induced hepatotoxicity under inflammatory stress. In this study, we developed a model in vitro to study the roles of caspase activation and oxidative stress in TNF potentiation of AMD cytotoxicity. AMD caused cell death in Hepa1c1c7 cells, and TNF cotreatment potentiated its toxicity. Activation of caspases 9 and 3/7 was observed in AMD/TNF-cotreated cells, and caspase inhibitors provided minor protection from cytotoxicity. Intracellular reactive oxygen species (ROS) generation and lipid peroxidation were observed after treatment with AMD and were further elevated by TNF cotreatment. Adding water-soluble antioxidants (trolox, N-acetylcysteine, glutathione, or ascorbate) produced only minor attenuation of AMD/TNF-induced cytotoxicity and did not influence the effect of AMD alone. On the other hand, α-tocopherol (TOCO), which reduced lipid peroxidation and ROS generation, prevented AMD toxicity and caused pronounced reduction in cytotoxicity from AMD/TNF cotreatment. α-TOCO plus a pancaspase inhibitor completely abolished AMD/TNF-induced cytotoxicity. In summary, activation of caspases and oxidative stress were observed after AMD/TNF cotreatment, and caspase inhibitors and a lipid-soluble free-radical scavenger attenuated AMD/TNF-induced cytotoxicity. 23577701 New dipyranocoumarin from the leaves of Calophyllum apetalum Willd. A new dipyranocoumarin, α-hydroxytomentolide A (1) was isolated from the leaves of Calophyllum apetalum together with the known compounds friedelin (2), apetalactone (3), inophyllum C (4) and canophyllol (5). The structure of the new compound was established by spectroscopic studies which include (1)H NMR, (13)C NMR, NOESY, HetCOSY, COLOC experiments and single crystal X-ray diffraction analysis. 23606243 Hydrothermal Growth of TiO2 Nanorod Arrays and In Situ Conversion to Nanotube Arrays for Highly Efficient Quantum Dot-Sensitized Solar Cells. TiO2 nanorod (NR) and nanotube (NT) arrays grown on transparent conductive substrates are attractive electrode for solar cells. In this paper, TiO2 NR arrays are hydrothermally grown on FTO substrate, and are in situ converted into NT arrays by hydrothermally etching. The TiO2 NR arrays are reported as single crystalline, but the TiO2 NR arrays are demonstrated to be polycrystalline with a bundle of 2-5 nm single crystalline nanocolumns grown along [001] throughout the whole NR from bottom to top. TiO2 NRs can be converted to NTs by hydrothermal selective etching of the (001) core and remaining the inert sidewall of (110) face. A growth mechanism of the NR and NT arrays is proposed. Quantum dot-sensitized solar cells (QDSCs) are fabricated by coating CdSe QDs on to the TiO2 arrays. After conversion from NRs to NTs, more QDs can be filled in the NTs and the energy conversion efficiency of the QDSCs almost double. 23617279 Carbon Xerogel Microspheres and Monoliths from Resorcinol-Formaldehyde Mixtures with Varying Dilution Ratios: Preparation, Surface Characteristics, and Electrochemical Double-Layer Capacitances. Carbon xerogels in the form of microspheres and monoliths were obtained from the sol-gel polymerization of resorcinol and formaldehyde in the presence of potassium carbonate as catalyst, using water as solvent and two different molar dilution ratios. The objectives of this study were as follows: to investigate the effect of the dilution ratio, polymerization reaction time, and temperature on the rheological properties of the sols used to prepare the carbon xerogel microspheres and monoliths; and to determine the influence of their preparation methods and shapes on their surface characteristics and electrochemical double-layer (EDL) capacitance. An increase in the molar dilution ratio produced a decrease in the apparent activation energy of the sol-gel transition. Carbon xerogel microspheres were steam-activated at different burnoff percentages. The morphology, surface area, porosity, and surface chemistry of samples were determined. The main difference between the carbon xerogel microspheres and monoliths was that the latter are largely mesoporous. Better electrochemical behavior was shown by carbon xerogels in monolith than in microsphere form, but higher gravimetric and volumetric capacitances were found in activated carbon xerogel microspheres than in carbon xerogel monoliths. 23443408 In vivo evaluation of the interaction between titanium dioxide nanoparticle and rat liver DNA. Titanium dioxide nanoparticles (TiO2 NPs) are massively produced and widely used in daily life, which may pose potential risk to human health via uncharacterized interaction between DNAs. This research aims to examine the interaction between DNA and three types of TiO2 NPs of different sizes and crystallines. The interaction between TiO2 NPs and liver DNA molecules obtained from Sprague-Dawley rats was systematically evaluated in vivo using atomic force microscopy, transmission electron microscopy, various spectroscopic techniques and gel electrophoresis. We found that TiO2 NPs (diameter <25 nm and <100 nm) in anatase crystalline can covalently interact with liver DNA by either inserting itself in between DNA base pairs or binding to DNA nucleotide via P-O-Ti-O bond. Such interaction may not be NP size-dependent but may be crystalline phase-dependent, because such interaction did not occur in rutile crystal phase, in which the DNA damage was potentially caused by reactive oxygen species. 23480697 Predicting ligand binding modes from neural networks trained on protein-ligand interaction fingerprints. We herewith present a novel approach to predict protein-ligand binding modes from the single two-dimensional structure of the ligand. Known protein-ligand X-ray structures were converted into binary bit strings encoding protein-ligand interactions. An artificial neural network was then set up to first learn and then predict protein-ligand interaction fingerprints from simple ligand descriptors. Specific models were constructed for three targets (CDK2, p38-α, HSP90-α) and 146 ligands for which protein-ligand X-ray structures are available. These models were able to predict protein-ligand interaction fingerprints and to discriminate important features from minor interactions. Predicted interaction fingerprints were successfully used as descriptors to discriminate true ligands from decoys by virtual screening. In some but not all cases, the predicted interaction fingerprints furthermore enable to efficiently rerank cross-docking poses and prioritize the best possible docking solutions. 23459233 Comparative Analysis of the Symbiotic Efficiency of Medicago truncatula and Medicago sativa under Phosphorus Deficiency. Phosphorus (P)-deficiency is a major abiotic stress that limits legume growth in many types of soils. The relationship between Medicago and Sinorhizobium, is known to be affected by different environmental conditions. Recent reports have shown that, in combination with S. meliloti 2011, Medicago truncatula had a lower symbiotic efficiency than Medicago sativa. However, little is known about how Medicago-Sinorhizobium is affected by P-deficiency at the whole-plant level. The objective of the present study was to compare and characterize the symbiotic efficiency of N2 fixation of M. truncatula and M. sativa grown in sand under P-limitation. Under this condition, M. truncatula exhibited a significantly higher rate of N2 fixation. The specific activity of the nodules was much higher in M. truncatula in comparison to M. sativa, partially as a result of an increase in electron allocation to N2 versus H+. Although the main organic acid, succinate, exhibited a strong tendency to decrease under P-deficiency, the more efficient symbiotic ability observed in M. truncatula coincided with an apparent increase in the content of malate in its nodules. Our results indicate that the higher efficiency of the M. truncatula symbiotic system is related to the ability to increase malate content under limited P-conditions. 23497878 The influence of Goishi tea on adipocytokines in obese mice. This study investigated the influence of Goishi-tea on visceral fat weight in induced obese mice. Mice were divided into two main groups, normal and obesity. In obesity group, mice were fed with high-fat diet. Goishi-tea including its fractions (ethyl-acetate layer and water layer) was administrated in normal and obesity three sub-groups. Results showed no influence of Goishi-tea in normal group. However, visceral fat weight, size of adipose cell and cholesterol level were significantly decreased in obesity group fed Goishi-tea compared to control group. Moreover, adiponectin levels tended to increase and adipocytokines has significant values lower in obesity group fed Goishi-tea compared to control group. Interestingly, Goishi tea involved in the high-fat diet induced-obese mice can inhibit fat accumulation and maintain adiponectins without increasing tumor necrosis factor-alpha and interleukin-6. It would be beneficial for the prevention of metabolic syndrome and obesity-related disorder. 23545806 In Vitro Metabolism and Kinetics Studies on Methylone. Abuse of the stimulant designer drug methylone (methylenedioxymethcathinone) has been documented in most parts of the world. As with many of the new designer drugs that continuously appear in the illicit drug market, little is known about the pharmacokinetics of methylone. Using in vitro studies, CYP2D6 was determined to be the primary enzyme that metabolizes methylone, with minor contributions from CYP1A2, CYP2B6, and CYP2C19. The major metabolite was identified as dihydroxymethcathinone, and the minor metabolites were N-hydroxy-methylone, nor-methylone, and dihydro-methylone. Measuring the formation of the major metabolite, biphasic Michaelis-Menten kinetic parameters were determined: Vmax,1 = 0.046 ± 0.005 (S.E.) nmol/min/mg protein, Km,1 = 19.0 ± 4.2 μM, Vmax,2 = 0.22 ± 0.04 nmol/min/mg protein, and Km,2 = 1953 ± 761 μM; the low-capacity and high-affinity contribution was assigned to the activity of CYP2D6. Additionally, a time-dependent loss of CYP2D6 activity was observed when the enzyme was preincubated with methylone, reaching a maximum rate of inactivation at high methylone concentrations, indicating that methylone is a mechanism-based inhibitor of CYP2D6. The inactivation parameters were determined to be KI = 15.1 ± 3.4 (S.E) μM and kinact = 0.075 ± 0.005 min(-1). 23063002 Biomarkers in marine mussels, Mytilus galloprovincialis, exposed to environmentally relevant levels of the pesticides, chlorpyrifos and penoxsulam. The present study examines the influence of environmentally relevant concentrations of two pesticides, chlorpyrifos and penoxsulam on mussel physiological status. For this reason, lysosomal membrane stability (LMS), reactive oxygen species (ROS), DNA damage, protein carbonylation (PCC) and antioxidant capacity (TAC) in hemaolymph and hemocytes of the mussels was measured. Mussels were exposed to a range of concentrations of the pesticides chlorpyrifos and penoxsulam and the response of animals to the destabilization of lysosomal membrane in hemocytes (LMS) was studied. Subsequently, the half maximal effective concentration (EC50) for both pesticides was calculated. The animals were subsequently exposed for 0, 1, 3, 5, 7, 15 and 30 days to 10 times less concentration than EC50 of each pesticide (0.05 μg/l) and changes in LMS, ROS, DNA damage, protein carbonylation and antioxidant capacity of mussels was evaluated. Our results showed a significant change in the response of mussels for all parameters tested after 30 days exposure, in relation to the controls. The pesticides at the environmental concentrations used induced changes to the animal physiology through causing oxidative stress and lysosomal abnormalities and their usage in the agriculture demands great care. In addition, the results show that ROS, DNA damage, protein carbonylation and antioxidant capacity could constitute, after further investigation, reliable biomarkers for the evaluation of pollution or other environmental stressors. 23612708 Noncanonical NF-κB Activation by the Oncoprotein Tio Occurs Through a Nonconserved TRAF3-Binding Motif. Members of the nuclear factor κB (NF-κB) family of transcription factors regulate many cellular functions. Activation of NF-κB signaling is commonly classified as occurring through canonical or noncanonical pathways. Most NF-κB-inducing stimuli, including the viral oncoprotein Tio, lead to a concerted activation of both NF-κB pathways; however, extensive crosstalk at multiple levels between these signaling cascades restricts the ability to discriminate between the canonical and the noncanonical effects. We showed that noncanonical NF-κB activation by Tio depends on a distinct sequence motif that directly recruits tumor necrosis factor receptor-associated factor 3 (TRAF3). Through its TRAF3-binding motif, Tio triggered a ubiquitin-independent depletion of TRAF3 from the cytosol, which prevented TRAF3 from inhibiting signaling through the noncanonical NF-κB cascade. Furthermore, the Tio-TRAF3 interaction did not affect components of the canonical NF-κB signaling pathway or the expression of target genes; thus, Tio induced noncanonical NF-κB independently of crosstalk with the canonical pathway. Together, these data identify a distinct molecular mechanism of noncanonical NF-κB activation that should enable studies into the particular functions of this pathway. 23410168 Rationally designed multitarget anticancer agents. Balanced modulation of multiple targets is an attractive therapeutic strategy in treating complex diseases including cancer. Comparing with drugs combination, single molecule modulating desirable multiple targets has advantages in pharmacokinetic and pharmacodynamics. Different from previous reviews, we provided an overview of reported multitarget antitumor agents from the viewpoint of pharmacophores. These multitarget antitumor agents were designed by combination of pharmacophores or by high-throughput screening plus structural modification, which were exemplified by the privileged pharmacophore quinazoline and several other popular pharmacophores, including phenylaminopyrimidine, anthracycline and naphthalimide. Previous research demonstrated the importance of in-depth validation against multiple targets not only in cell-free system, but also in cancer cells. Furthermore, the multitarget compounds were also effective for resistance cell lines which highlighted their antitumor potency in the era of increasing drug resistance in cancer patients. 23210788 Green factories for biopharmaceuticals. Plants and plant cells have been used to produce many diverse and valuable recombinant proteins, including subunit vaccines, antibodies and antibody fragments, hormones, blood products, cytokines and enzymes. Different plant species and platforms have been explored as production hosts, each with unique properties in terms of production timescales, environmental containment, scalability, downstream processing strategy and overall costs. Whole plants are suitable for the economical and safe production of recombinant proteins on a large scale, providing unique advantages for pharmaceutical proteins that are required in large amounts and normally too expensive for conventional manufacturing processes. Seed-based systems have additional advantages because they exploit the natural storage properties of seeds to facilitate batch processing and distribution. The stabilizing effect of seeds after harvest allows recombinant subunit vaccines and antibodies to be delivered via the mucosal route as they are better able to withstand the harsh microenvironment when protected by the plant matrix. Although the differences between plant and human N-glycans were initially thought to limit the therapeutic potential of plant-derived glycoproteins, several such products have now been tested in the clinic and in some cases the presence of plant glycans has been turned into an advantage because they improve the performance of the protein or confer unique characteristics. In this review we discuss recent case studies of recombinant pharmaceuticals produced in plants to demonstrate the versatility and unique advantages of molecular farming and the bottlenecks that remain to be addressed. 23414252 Evidence of dynamical constraints imposed by water organization around a bio-hydrophobic interface. Molecular dynamics simulations and elastic neutron scattering experiments have been used to highlight how the structural organization of hydration water is able in some cases to locally constrain atomic movements at biologic interfaces. Using fully hydrated small peptides as models of protein interfaces, we show that the length of the side chains and the hydrophilic backbone have specific signatures. The dynamics of the side chain, which is part of biomolecules, have not only a crucial role in the whole flexibility as compared to the backbone, but also modify the values of transition temperatures. The analysis of the activation energies of methyl group dynamics suggests that the interaction between hydrophobic side chain and surrounding water plays an important role in the whole flexibility as well. We suggest that the progressive water cluster organization, around hydrophobic interfaces increases the activation energy and that a plateau regime is reached only when an extended hydrogen-bond network is established. The cluster size corresponds to a single layer of water molecules. 23373444 Metal-enzyme frameworks: role of metal ions in promoting enzyme self-assembly on α-zirconium(IV) phosphate nanoplates. Previously, an ion-coupled protein binding (ICPB) model was proposed to explain the thermodynamics of protein binding to negatively charged α-Zr(IV) phosphate (α-ZrP). This model is tested here using glucose oxidase (GO) and met-hemoglobin (Hb) and several cations (Zr(IV), Cr(III), Au(III), Al(III), Ca(II), Mg(II), Zn(II), Ni(II), Na(I), and H(I)). The binding constant of GO with α-ZrP was increased ∼380-fold by the addition of either 1 mM Zr(IV) or 1 mM Ca(II), and affinities followed the trend Zr(IV) ≃ Ca(II) > Cr(III) > Mg(II) ≫ H(I) > Na(I). Binding studies could not be conducted with Au(III), Al(III), Zn(II), Cu(II), and Ni(II), as these precipitated both proteins. Zr(IV) increased Hb binding constant to α-ZrP by 43-fold, and affinity enhancements followed the trend Zr(IV) > H(I) > Mg(II) > Na(I) > Ca(II) > Cr(III). Zeta potential studies clearly showed metal ion binding to α-ZrP and affinities followed the trend, Zr(IV) ≫ Cr(III) > Zn(II) > Ni(II) > Mg(II) > Ca(II) > Au(III) > Na(I) > H(I). Electron microscopy showed highly ordered structures of protein/metal/α-ZrP intercalates on micrometer length scales, and protein intercalation was also confirmed by powder X-ray diffraction. Specific activities of GO/Zr(IV)/α-ZrP and Hb/Zr(IV)/α-ZrP ternary complexes were 2.0 × 10(-3) and 6.5 × 10(-4) M(-1) s(-1), respectively. While activities of all GO/cation/α-ZrP samples were comparable, those of Hb/cation/α-ZrP followed the trend Mg(II) > Na(I) > H(I) > Cr(III) > Ca(II) ≃ Zr(IV). Metal ions enhanced protein binding by orders of magnitude, as predicted by the ICPB model, and binding enhancements depended on charge as well as the phosphophilicity/oxophilicity of the cation. 23535167 Methionine salvage and S-adenosylmethionine: essential links between sulfur, ethylene and polyamine biosynthesis. Both Met (methionine) and SAM (S-adenosylmethionine), the activated form of Met, participate in a number of essential metabolic pathways in plants. The subcellular compartmentalization of Met fluxes will be discussed in the present review with respect to regulation and communication with the sulfur assimilation pathway, the network of the aspartate-derived amino acids and the demand for production of SAM. SAM enters the ethylene, nicotianamine and polyamine biosynthetic pathways and provides the methyl group for the majority of methylation reactions required for plant growth and development. The multiple essential roles of SAM require regulation of its synthesis, recycling and distribution to sustain these different pathways. A particular focus of the present review will be on the function of recently identified genes of the Met salvage cycle or Yang cycle and the importance of the Met salvage cycle in the metabolism of MTA (5'-methylthioadenosine). MTA has the potential for product inhibition of ethylene, nicotianamine and polyamine biosynthesis which provides an additional link between these pathways. Interestingly, regulation of Met cycle genes was found to differ between plant species as shown for Arabidopsis thaliana and Oryza sativa. 23525118 Single-molecule surface-enhanced Raman spectroscopy: a perspective on the current status. This perspective presents an overview of single-molecule surface-enhanced Raman scattering (sm-SERS). Our overview is organized as a brief theoretical background, discussion of the factors that enhance SERS, various experimental preparations for inserting a single molecule in a hot spot, recent sm-SERS experiments, and a perspective. Although, there have been numerous review papers on sm-SERS, we mainly concentrated on the logical development of sm-SERS on the basis of the fundamental concepts and their physical significance, so that readers outside this field can understand the motivation and the underlying physics when describing current sm-SERS measurements. Indeed, understanding such current sm-SERS experiments conducted by representative groups would be very helpful for readers to answer for themselves the fundamental and practical questions surrounding sm-SERS: (1) what information can sm-SERS provide? (2) Which factors based on the SERS mechanism should be considered to significantly amplify the SERS signal? (3) What kinds of related microscopy techniques could be combined with sm-SERS to attain more meaningful results? (4) Which statistical approaches can be used and how they can be applied to properly analyze sm-SERS data? We hope that this review article can help readers answer these questions. 23620060 Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding. AIMS/HYPOTHESIS: While it is well known that diet-induced obesity causes insulin resistance, the precise mechanisms underpinning the initiation of insulin resistance are unclear. To determine factors that may cause insulin resistance, we have performed a detailed time-course study in mice fed a high-fat diet (HFD). METHODS: C57Bl/6 mice were fed chow or an HFD from 3 days to 16 weeks and glucose tolerance and tissue-specific insulin action were determined. Tissue lipid profiles were analysed by mass spectrometry and inflammatory markers were measured in adipose tissue, liver and skeletal muscle. RESULTS: Glucose intolerance developed within 3 days of the HFD and did not deteriorate further in the period to 12 weeks. Whole-body insulin resistance, measured by hyperinsulinaemic-euglycaemic clamp, was detected after 1 week of HFD and was due to hepatic insulin resistance. Adipose tissue was insulin resistant after 1 week, while skeletal muscle displayed insulin resistance at 3 weeks, coinciding with a defect in glucose disposal. Interestingly, no further deterioration in insulin sensitivity was observed in any tissue after this initial defect. Diacylglycerol content was increased in liver and muscle when insulin resistance first developed, while the onset of insulin resistance in adipose tissue was associated with increases in ceramide and sphingomyelin. Adipose tissue inflammation was only detected at 16 weeks of HFD and did not correlate with the induction of insulin resistance. CONCLUSIONS/INTERPRETATION: HFD-induced whole-body insulin resistance is initiated by impaired hepatic insulin action and exacerbated by skeletal muscle insulin resistance and is associated with the accumulation of specific bioactive lipid species. 23588796 Fluctuation analysis of an organic semiconductor-insulator interface. The space-charge region of an organic semiconductor (OS)-insulator interface is probed by analyzing the spontaneous, thermally driven drain current fluctuations of a field-effect transistor in which the OS forms the gate electrode. This so called "excess drain current noise" is the outcome of local fluctuations of the Fermi level, resulting from stochastic exchange of electrons between traps near the Fermi level. The power spectral density of this noise is characteristic of a Lorentzian process with a distribution of time constants, which is attributed to the disorder in the OS film. Furthermore, this disorder leads to local inhomogeneity of the work function in the film and a finite correlation length of the work function fluctuations. The measurement of work function noise is only possible within a correlation length of the OS-insulator interface. Through systematic variation of gate voltage, primary doping and secondary doping levels, the correlation length, disorder, and the trapping/de-trapping time constant are examined on polyaniline as a representative OS. A model is proposed for local work function variations and spontaneous charge-carrier fluctuations within polyaniline films with consequences for organic electronics using organic semiconductors. 23561093 Influence of air-drying temperature on drying kinetics, colour, firmness and biochemical characteristics of Atlantic salmon (Salmo salar L.) fillets. In this work the drying kinetics of Atlantic salmon (Salmo salar L.) fillets and the influence of air drying temperature on colour, firmness and biochemical characteristics were studied. Experiments were conducted at 40, 50 and 60°C. Effective moisture diffusivity increased with temperature from 1.08×10(-10) to 1.90×10(-10)m(2)s(-1). The colour difference, determined as ΔE values (from 9.3 to 19.3), as well as firmness (from 25 to 75Nmm(-1)) of dried samples increased with dehydration temperature. The lightness value L(∗) and yellowness value b(∗) indicated formation of browning products at higher drying temperatures, while redness value a(∗) showed dependence on astaxanthin value. Compared with fresh fish samples, palmitic acid and tocopherol content decreased in a 20% and 40%, respectively, with temperature. While eicosapentaenoic acid (EPA) content remained unchanged and docosahexaenoic acid (DHA) content changed slightly. Anisidine and thiobarbituric acid values indicated the formation of secondary lipid oxidation products, which is more relevant for longer drying time than for higher drying temperatures. 23229511 Aryl hydrocarbon receptor is a target of 17-Allylamino-17-demethoxygeldanamycin and enhances its anticancer activity in lung adenocarcinoma cells. We have demonstrated that aryl hydrocarbon receptor (AhR) is overexpressed in lung adenocarcinoma (AD). AhR is usually associated with heat shock protein 90 (Hsp90) in the cytoplasm. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor, is currently under evaluation for its anticancer activity in clinical trials. Here we investigated whether AhR plays a role in 17-AAG-mediated anticancer activity by functioning as a downstream target or by modulating its anticancer efficacy. AhR expression in lung AD cells was modulated by siRNA interference or overexpression. Tumor growth was determined with colony formation in vitro or in vivo. Anticancer activity of 17-AAG was determined by measuring cell viability, cell cycle distribution, and expression of cell cycle regulators. Proteins and mRNA levels were examined by immunoblotting and the real-time reverse transcription-polymerase chain reaction, respectively. In this study, AhR overexpression positively modulated growth of lung AD cells, at least partially, via RelA-dependent mechanisms. Although treatment with 17-AAG reduced AhR levels and AhR-regulated gene expression in lung AD cells, AhR expression increased anticancer activity of 17-AAG. In addition, 17-AAG treatment reduced cell viability, CDK2, CDK4, cyclin E, cyclin D1, and phosphorylated Rb levels in AhR-expressing lung AD cells. NAD(P)H:quinone oxidoreductase (NQO1), which is regulated by AhR, was shown to increase anticancer activity of 17-AAG in cells. Knockdown of NQO1 expression attenuated the reduction of cell cycle regulators by 17-AAG treatment in AhR overexpressed cells. We demonstrated that AhR protein not only functions as a downstream target of 17-AAG, but also enhances anticancer activity of 17-AAG in lung AD cells. 23462194 In vitro evaluation of the therapeutic potential of nevirapine in treatment of human thyroid anaplastic carcinoma. Anaplastic thyroid carcinoma (ATC) is a severe thyroid malignancy with poor prognosis, due to its early metastasis and unresponsiveness to both radiation and chemotherapy. Nevirapine, a non-nucleoside reverse transcriptase inhibitor, has been used as a re-differentiation agent to treat cancers in several human cancer models. So far, the effects of nevirapine on human thyroid anaplastic carcinoma cells have not been documented. The aim of this study was to evaluate the therapeutic potential of nevirapine in treatment of human thyroid anaplastic carcinoma. Cell proliferation was determined by methly thiazolyl tetrazolium (MTT) assay. Cell apoptosis was analyzed by Hoechst 33258 staining. The mRNA expression of NIS and TSHR was determined by real-time quantitative reverse transcription-polymerase chain reaction (real time RT-PCR). Iodine uptake was determined by (125)I radioactivity assay. At all doses (100, 200, 350, 500μmol/L) tested, nevirapine significantly inhibited cell proliferation after 48h treatment. At high dose (500μmol/L), nevirapine significantly increased the percentage of apoptotic cells compared with control (P<0.01). At lower doses (200μmol/L and 350μmol/L), nevirapine did not induce cell apoptosis, but up-regulated NIS and THSR mRNA expression in a dose-dependent manner. In FRO cells pre-treated with nevirapine, the increase in NIS expression had no obvious effect on iodine uptake. These findings indicate that nevirapine has an anti-proliferative effect on FRO cells, which correlates with an induction of cell differentiation. 22310169 Seasonal variation in biomarkers in blue mussel (Mytilus edulis), Icelandic scallop (Chlamys islandica) and Atlantic cod (Gadus morhua): implications for environmental monitoring in the Barents Sea. In the Barents Sea, the limited data on biological relevant indicators and their responses to various anthropogenic stressors have hindered the development of a consistent scientific basis for selecting indicator species and developing practical procedures for environmental monitoring. Accordingly, the main aim of the present study was to develop a common set of baseline values for contaminants and biomarkers in three species, and to identify their strengths and limitations in monitoring of the Barents Sea. Blue mussel (Mytilus edulis), Icelandic scallop (Chlamys islandica) and Atlantic cod (Gadus morhua) were sampled from a north Norwegian fjord in March, June, September and December 2010. Digestive glands from the bivalve species and liver from Atlantic cod were analysed for biomarkers of oxidative stress (catalase [CAT], glutathione peroxidase [GPX], glutathione-S-transferase activities [GST], lipid peroxidation as thiobarbituric reactive substances [TBARS] and total oxyradical scavenging capacity [TOSC]), biotransformation (ethoxyresorufine-O-deethylase activity [EROD]) and general stress (lysosomal membrane stability [LMS]). Concentrations of polycyclic aromatic hydrocarbons (PAHs) and metals in the bivalves and PAH metabolites in fish bile were quantified. Finally, energy reserves (total lipids, proteins and carbohydrates) and electron transport system (ETS) activity in the digestive gland of the bivalves and liver of Atlantic cod provided background information for reproductive cycle and general physiological status of the organisms. Blue mussel and Icelandic scallop showed very similar trends in biological cycle, biomarker expression and seasonality. Biomarker baselines in Atlantic cod showed weaker seasonal variability. However, important biological events may have been undetected due to the large time intervals between sampling occasions. Physiological biomarkers such as energy reserves and ETS activity were recommended as complementary parameters to the commonly used stress biomarkers, as they provided valuable information on the physiological status of the studied organisms. Interpretation of the seasonality in oxidative stress biomarkers was in general difficult but TOSC and lipid peroxidation were preferred over the antioxidant enzyme activities. This study is the first reporting seasonal baseline in these three species in a sub-Arctic location. Overall, the Icelandic scallop was considered the most adequate organism for environmental monitoring in the Barents Sea due to the interpretability of the biomarker data as well as its abundance, ease to handle and wide distribution from the southern Barents Sea to Svalbard. 23416930 Autophagy in ageing and ageing-associated diseases. Autophagy is a cell self-digestion process via lysosomes that clears "cellular waste", including aberrantly modified proteins or protein aggregates and damaged organelles. Therefore, autophagy is considered a protein and organelle quality control mechanism that maintains normal cellular homeostasis. Dysfunctional autophagy has been observed in ageing tissues and several ageing-associated diseases. Lifespan of model organisms such as yeast, worms, flies, and mice can be extended through promoting autophagy, either by genetic manipulations such as over-expression of Sirtuin 1, or by administrations of rapamycin, resveratrol or spermidine. The evidence supports that autophagy may play an important role in delaying ageing or extending lifespan. In this review, we summarize the current knowledge about autophagy and its regulation, outline recent developments ie the genetic and pharmacological manipulations of autophagy that affects the lifespan, and discuss the role of autophagy in the ageing-related diseases. 23199983 Production of 1-lactulose and lactulose using commercial β-galactosidase from Kluyveromyces lactis in the presence of fructose. Production of 1-lactulose and lactulose using commercial β-galactosidase DSM Maxilact® 5000 in the presence of fructose was investigated. Experiments were performed at 40 °C and pH 7.5. Lactose starting concentration was constantly 250 g/l. A novel transgalactosylation product 1-lactulose was detected besides lactulose. Effects of fructose concentration, reaction time and enzyme concentration on transgalactosylation reactions were discussed. In all reactions, the yield ratio 1-lactulose:lactulose was close to 3:1 due to the regioselectivity of β-galactosidase. The maximum production of 1-lactulose and lactulose was approximately 22 and 8 g/l, respectively, when fructose concentration was increased to 100 g/l. Lactose hydrolysis was significantly retarded since fructose strongly attracted water molecules. Higher enzyme concentration can accelerate transgalactosylation reactions without affecting the maximum production of transgalactosylation products. Fructose was a more preferred galactosyl acceptor than lactose, since the synthesis of galactooligosacchairdes was found to be absolutely inhibited in the presence of fructose. 23523372 A Mammalian Pre-mRNA 5' End Capping Quality Control Mechanism and an Unexpected Link of Capping to Pre-mRNA Processing. Recently, we reported that two homologous yeast proteins, Rai1 and Dxo1, function in a quality control mechanism to clear cells of incompletely 5' end-capped messenger RNAs (mRNAs). Here, we report that their mammalian homolog, Dom3Z (referred to as DXO), possesses pyrophosphohydrolase, decapping, and 5'-to-3' exoribonuclease activities. Surprisingly, we found that DXO preferentially degrades defectively capped pre-mRNAs in cells. Additional studies show that incompletely capped pre-mRNAs are inefficiently spliced at all introns, a fact that contrasts with current understanding, and are also poorly cleaved for polyadenylation. Crystal structures of DXO in complex with substrate mimic and products at a resolution of up to 1.5Å provide elegant insights into the catalytic mechanism and molecular basis for their three apparently distinct activities. Our data reveal a pre-mRNA 5' end capping quality control mechanism in mammalian cells, indicating DXO as the central player for this mechanism, and demonstrate an unexpected intimate link between proper 5' end capping and subsequent pre-mRNA processing. 23335515 Scaffold effects on osteogenic differentiation of equine mesenchymal stem cells: an in vitro comparative study. The in vitro viability, osteogenic differentiation, and mineralization of four different equine mesenchymal stem cells (MSCs) from bone marrow, periosteum, muscle, and adipose tissue are compared, when they are cultured with different collagen-based scaffolds or with fibrin glue. The results indicate that bone marrow cells are the best source of MSCs for osteogenic differentiation, and that an electrochemically aggregated collagen gives the highest cell viability and best osteogenic differentiation among the four kinds of scaffolds studied. 22958332 Increased responses to the actions of fibroblast growth factor 21 on energy balance and body weight in a seasonal model of adiposity. The present study aimed to investigate the actions of fibroblast growth factor 21 (FGF21) on energy balance in a natural model of relative fatness, the Siberian hamster. Hamsters were studied under long days (LD) to promote weight gain, or short days to induce weight loss, and treated with rhFGF21 (3 mg/kg/day) via s.c. minipumps for 14 days. On days 7-9, detailed assessments of ingestive behaviour, metabolic gas exchange and locomotor activity were made. FGF21 caused substantial (P < 0.0001) weight loss in the fat LD state but not in the lean SD state: at the end of the study, FGF21-treated hamsters in LD lost 18% of body weight compared to vehicle controls, which is comparable to the natural body weight loss observed in SD. Epididymal fat pads, a correlate of total carcass fat content, were reduced by 19% in FGF21 treated hamsters in LD, whereas no difference was found in SD. Body weight loss in LD was associated with a reduction in food intake (P < 0.001) and a decreased respiratory exchange ratio (P < 0.001), indicating increased fat oxidation. Treatment with FGF21 maintained the normal nocturnal increase in oxygen consumption and carbon dioxide production into the early light phase in hamsters in LD, indicating increased energy expenditure, although locomotor activity was unaffected. These data suggest a greater efficacy of FGF21 in hamsters in LD compared to those in SD, which is consistent with both the peripheral and possibly central actions of FGF21 with respect to promoting a lean phenotype. The observed differences in FGF21 sensitivity may relate to day length-induced changes in adipose tissue mass. 23561158 A method for determining regioisomer abundances of polyunsaturated triacylglycerols in omega-3 enriched fish oils using reversed-phase liquid chromatography and triple-stage mass spectrometry. Reversed-phase high performance liquid chromatography (RP-HPLC), followed by post-column addition of lithium salts and electrospray ionisation triple-stage mass spectrometry (ESI-MS(3)) of lithiated TAG adducts, is shown to provide a useful method for the positional analysis of triacylglycerols (TAGs) in fish oils containing eicosapentaenoic (EPA, 20:5) and docosahexaenoic acids (DHA, 22:6). One prominent fragmentation pathway in the ESI-MS(3) of these adduct ions involves the loss of a fatty acid from the sn-1/3 position in the first step followed by the loss of an α,β-unsaturated fatty acid from the sn-2 position in the second. Regioisomeric TAGs of the type ABA and AAB produced abundant product ions - [ABA+Li-RACOOH-R'BCHCHCOOH](+) and [AAB+Li-RACOOH-R'ACHCHCOOH](+) - the relative intensities of which were dependent on the position of acyl substituents. Standard solutions of TAGs containing different ratios of the regioisomeric pairs MME/MEM, PPE/PEP, PPD/PDP, EEP/EPE and DDP/DPD (M=14:0, P=16:0, E=20:5, D=22:6) were analysed by ESI-MS(3) with a quadrupole linear ion trap instrument. Methodology developed on the standards was applied to quantifying the relative isomeric abundances of EPA and DHA in several fish oil samples. DHA was preferentially located at the sn-2 position in both DHA-containing TAGs studied, while EPA was either observed at near equal levels in all positions, or predominantly at the sn-1 and -3 positions in some cases. The analysis protocol allows for quantification of the designated regioisomers in one simple, rapid chromatographic procedure using a single column and has the advantage of specificity over other methods for the positional analysis of TAGs, since it eliminates interferences associated with co-eluting TAGs of the same molecular weight that yield isobaric diacylglycerol-like product ions. 23154127 Modulation of the cellular redox status by the Alternaria toxins alternariol and alternariol monomethyl ether. The mycotoxin alternariol (AOH) has been reported to possess genotoxic properties, inducing enhanced levels of DNA damage after only 1 h of incubation. In the present study we addressed the question whether the induction of oxidative stress might contribute to the genotoxic effects of AOH or its naturally occurring monomethylether (AME). In the dichlorofluorescein (DCF) assay, treatment of HT29 cells for 1 h enhanced the formation of dichlorofluorescein, indicative for ROS formation. The total glutathione (tGSH) was transiently decreased. In accordance with the results of the DCF assay, AOH and AME enhanced the proportion of the transcription factor Nrf2 in the nucleus. Concomitantly, the Nrf2/ARE-dependent genes γ-glutamylcysteine ligase (γ-GCL) and glutathione-S-transferase (GSTA1/2) showed enhanced transcript levels. After 24 h of incubation this effect was also reflected on the protein level by an increase of GST activity. However, in spite of the positive DCF assay and the activation of the redox-sensitive Nrf2/ARE-pathway, the level of oxidative DNA damage, measured in the comet assay by the addition of formamidopyrimidine-DNA-glycosylase (fpg) remained unaffected. Of note, after 3 h of incubation no significant DNA damaging potential of AOH and AME was detectable, indicating either inactivation of the compounds or enhanced DNA repair. In summary, the mycotoxins AOH and AME were found to modulate the redox balance of HT29 cells but without apparent negative effect on DNA integrity. 23603635 Non-peptidyl insulin mimetics as a potential antidiabetic agent. Insulin has an important role in the maintenance of blood sugar. It is the only available therapeutic agent for the treatment of type 1 diabetes mellitus and there is a dire need for an oral substitute. Different categories of compounds including mono and di substituted benzoquinones, vanadium based compounds and natural products have been reported to cause insulin-like effects either by increasing phosphorylation of insulin receptor (IR) or inhibiting the protein tyrosine phosphatases. This review summarizes the development of various insulin mimetics with special emphasis on their structure-activity relationships and various biological actions they produce. 23625745 Effectiveness of a Pharmacy Care Management Program for Veterans with Dyslipidemia. OBJECTIVE: To evaluate the effectiveness of a care management program provided by clinical pharmacists for veterans with dyslipidemia. DESIGN: Retrospective cohort design. SETTING: Two primary care clinics at a Veterans Affairs Medical Center. PATIENTS: An intervention (IT) cohort of 213 patients referred for management of dyslipidemia by clinical pharmacists and a control cohort of 219 patients with dyslipidemia receiving usual care (UC). METHODS: Data were obtained from electronic medical records regarding drug therapy, lipid levels, and patient characteristics. Using multivariable regression models to adjust for baseline characteristics, the primary analyses compared mean final measured values of low-density lipoprotein (LDL) cholesterol, total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and triglycerides (TGs) among the IT and UC cohorts at the final follow-up visits. Secondary analyses compared the proportion of patients achieving National Cholesterol Education Program/Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP/ATPIII) concordant LDL goals and the time to achieve LDL goals between the two groups. RESULTS: Compared with the UC cohort, the adjusted difference in the mean final measured LDL for the IT cohort was -10.4 mg/dl (95% confidence interval [CI] -16.1 to -4.6, p < 0.001) and TC was -12.7 (95% CI -21.3 to -4.1, p=0.004). There were no significant differences in the adjusted mean final measured HDL or TGs between the two groups. The NCEP/ATPIII goal LDL was met in 80.3% of patients in the IT cohort and 65.3% of patients in the UC cohort (odds ratio [OR], 2.6; 95% CI 1.6-4.3, p<0.001). Time to achieve goal LDL was significantly shorter for the IT cohort compared with the UC cohort (risk ratio, 1.8; 95% CI 1.2-2.8, log-rank p=0.002). CONCLUSION: Veterans referred to a clinical pharmacist for treatment of dyslipidemia achieved significant reductions in TC and LDL. A greater proportion of patients achieved NCEP/ATPIII goal LDL, and the time to attainment of LDL goals was shorter in the pharmacist-managed cohort, supporting a continued role for pharmacy care management in the treatment of patients with dyslipidemia. 23068419 Methylparaben protects 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells and improved behavioral impairments in mouse model of Parkinson's disease. Parkinson's disease (PD) is a progressive neurodegenerative disorder of unknown etiology. Considerable evidence suggests that free radical formation and oxidative stress might play an important role in the pathogenesis of PD. In the present investigation we evaluated the therapeutic potential of methylparaben (MP) a well known pharmaceutical preservative against 6-hydroxydopamine (6-OHDA) neurotoxicity in SH-SY5Y cells and in a mouse model of PD. At nanomolar concentrations MP (0.01, 0.1 and 1 nM) significantly attenuated the 6-OHDA- and hydrogen peroxide-induced cytotoxicity in SH-SY5Y cells. The reactive oxygen species generated by 6-OHDA in SH-SY5Y cells was also inhibited by MP in a concentration dependent fashion. Further, intranigral damage induced by stereotaxically injecting 6-OHDA in mouse brain was significantly attenuated by MP treatment. MP (1, 10 or 50 μg/kg, i.p.) prevented apomorphine-induced rotational behavior and significantly improved motor deficits in 6-OHDA-lesioned mice. The cognitive impairments as evaluated by passive avoidance and Y-maze task in mice were also attenuated by MP concentration dependently. Immunohistochemical analysis of substantia nigra in MP treated mice showed significantly higher number of surviving tyrosine hydroxylase positive cells. Furthermore, MP also suppressed the lipid peroxidation products in 6-OHDA-lesioned mouse brain tissues. Considering the results obtained, the marked neuroprotection exhibited by MP might be attributed to its potent antioxidant property. In conclusion, this study reports the neuroprotective properties of MP in experimental models of PD for the first time and can be developed as a potential therapeutic agent. 23256445 Trigonelline ameliorates oxidative stress in type 2 diabetic Goto-Kakizaki rats. Previously, we showed that trigonelline (TRG) exerts antidiabetic effects in type 2 diabetic Goto-Kakizaki (GK) rats and also lowers blood and liver thiobarbituric acid reactive substances and urinary 8-hydroxydeoxyguanosine when compared with those levels in GK control rats without TRG. These results suggested that TRG also mitigates oxidative stress, which accelerates diabetes. In this study, the mechanisms of TRG prevention of oxidative stress were determined by measuring erythrocyte and liver antioxidant enzyme activities, and expressions of genes associated with reactive oxygen species production, and carbohydrate and lipid metabolisms by DNA microarray. Erythrocyte and liver glutathione peroxidase, and liver catalase activities in the GK rats fed with TRG were significantly lower than those of the GK control rats. TRG downregulated the gene expressions involved with NADPH oxidase and mitochondrial electron transfer system when compared with those of the GK control group. These results suggested that mitigation of diabetes by TRG is mediated by its ameliorating effects on oxidative stress. 23590882 Interacting Glutamate Receptor-Like Proteins in Phloem Regulate Lateral Root Initiation in Arabidopsis. Molecular, genetic, and electrophysiological evidence indicates that at least one of the plant Glu receptor-like molecules, GLR3.4, functions as an amino acid-gated Ca(2+) channel at the plasma membrane. The aspect of plant physiology, growth, or development to which GLR3.4 contributes is an open question. Protein localization studies performed here provide important information. In roots, GLR3.4 and the related GLR3.2 protein were present primarily in the phloem, especially in the vicinity of the sieve plates. GLR3.3 was expressed in most cells of the growing primary root but was not enriched in the phloem, including the sieve plate area. GLR3.2 and GLR3.4 physically interacted with each other better than with themselves as evidenced by a biophotonic assay performed in human embryonic kidney cells and Nicotiana benthamiana leaf cells. GLR3.3 interacted poorly with itself or the other two GLRs. Mutations in GLR3.2, GLR3.4, or GLR3.2 and GLR3.4 caused the same and equally severe phenotype, namely, a large overproduction and aberrant placement of lateral root primordia. Loss of GLR3.3 did not affect lateral root primordia. These results support the hypothesis that apoplastic amino acids acting through heteromeric GLR3.2/GLR3.4 channels affect lateral root development via Ca(2+) signaling in the phloem. 23208666 Poly(2-oxazoline)-derived contact biocides: contributions to the understanding of antimicrobial activity. A set of poly(2-oxazoline)-derived (co-)polymers was prepared by microwave-assisted polymerizations and acid-mediated hydrolysis and tested for antimicrobial activity in 50 × 50 × 2 mm PP compound plates containing 5 wt% of the polymers. Antimicrobial activity against gram-negative E. coli and P. aeruginosa as well as C. albicans depended only on the degree of hydrolysis, while antimicrobial activity against gram-positive S. aureus was only observed for hydrolyzed poly(2-nonyl-2-oxazoline)s. The surface energies of the compound plates compared to pure PP were hardly altered, and the compounds can be considered as alternatives for PP. The presence of the biocide additives at the surface of the PP compound plates could be shown by combined ATR-IR, zeta potential, and SEM-EDX measurements. Antimicrobial activity was maintained during double incubation as well as for lowered amounts of the biocide additive of 1% in PP compound plates. 23298810 Synthesis and biological evaluation of substituted benzoxazoles as inhibitors of mPGES-1: use of a conformation-based hypothesis to facilitate compound design. Microsomal prostaglandin E(2) synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain. In the preceding letter, we detailed the discovery of clinical candidate PF-04693627, a potent mPGES-1 inhibitor possessing a novel benzoxazole structure. While PF-04693627 was undergoing further preclinical profiling, we sought to identify a back-up mPGES-1 inhibitor that differentiated itself from PF-04693627. The design, synthesis, mPGES-1 activity and in vivo PK of a novel set of substituted benzoxazoles are described herein. Also described is a conformation-based hypothesis for mPGES-1 activity based on the preferred conformation of the cyclohexane ring within this class of inhibitors. 23640867 Facile Fluorescence-Based Detection of PAD4-Mediated Citrullination. The post-translational modifications of histone proteins are highly diverse and dynamic processes. It is becoming increasingly evident that modifying histone proteins can have a direct influence on both cellular homeostasis and disease states. Protein arginine deiminase 4 (PAD4) is an enzyme that converts peptidyl-arginine to citrulline. The overexpression of PAD4 has been found in numerous types of human cancer and autoimmune diseases. We report a new, facile, fluorescence-based assay for the detection of PAD4 activity that exploits the substrate specificity of trypsin to monitor the citrullination reaction carried out by PAD4 based on the fact that, upon citrullination, the positively charged arginine side chain is converted to the neutral citrulline. We show that the assay can be performed rapidly with readily available reagents and that it responds accordingly to a known PAD4 inhibitor. 23249747 Circular RNAs are abundant, conserved, and associated with ALU repeats. Circular RNAs composed of exonic sequence have been described in a small number of genes. Thought to result from splicing errors, circular RNA species possess no known function. To delineate the universe of endogenous circular RNAs, we performed high-throughput sequencing (RNA-seq) of libraries prepared from ribosome-depleted RNA with or without digestion with the RNA exonuclease, RNase R. We identified >25,000 distinct RNA species in human fibroblasts that contained non-colinear exons (a "backsplice") and were reproducibly enriched by exonuclease degradation of linear RNA. These RNAs were validated as circular RNA (ecircRNA), rather than linear RNA, and were more stable than associated linear mRNAs in vivo. In some cases, the abundance of circular molecules exceeded that of associated linear mRNA by >10-fold. By conservative estimate, we identified ecircRNAs from 14.4% of actively transcribed genes in human fibroblasts. Application of this method to murine testis RNA identified 69 ecircRNAs in precisely orthologous locations to human circular RNAs. Of note, paralogous kinases HIPK2 and HIPK3 produce abundant ecircRNA from their second exon in both humans and mice. Though HIPK3 circular RNAs contain an AUG translation start, it and other ecircRNAs were not bound to ribosomes. Circular RNAs could be degraded by siRNAs and, therefore, may act as competing endogenous RNAs. Bioinformatic analysis revealed shared features of circularized exons, including long bordering introns that contained complementary ALU repeats. These data show that ecircRNAs are abundant, stable, conserved and nonrandom products of RNA splicing that could be involved in control of gene expression. 23494763 Assessment of Cytotoxic Properties of Safranal and Nanoliposomal Safranal in Various Cancer Cell Lines. Saffron (Crocus sativus) is a widely used food additive used for its color and taste. It has been reported that saffron possesses significant in vivo and in vitro anti-tumor activity. In the present study, anti-tumor effects of safranal, the major aromatic compound in saffron, and its liposomal form were investigated. The role of apoptosis has also been explored in this toxicity. HeLa, MCF7 and L929 cell lines were cultured and exposed to safranal (0.01-3 mM) or liposomal safranal (0.04-0.32 mM). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) assay was performed to assess cytotoxicity. Apoptosis was evaluated by staining cells with propidium iodide and quantifying sub-Gl peak by flow cytometry. MTT assay revealed a significant and concentration-dependent cytotoxic effect of safranal on HeLa and MCF7 cell lines. Liposomal safranal showed enhanced effect compared to the safranal solution, as compared by their IC50 concentrations. Flow cytometry results revealed induction of apoptosis by safranal. It might be concluded that safranal could be involved in saffron-induced cell death in HeLa and MCF7 cells. Liposome encapsulation improved anti-tumor effect of safranal. Safranal and particularly its liposomal form could be investigated as promising chemotherapeutic agents in cancer treatment. Copyright © 2013 John Wiley & Sons, Ltd. 23287389 Adult dose-dependent behavioral and cognitive disturbances after a single neonatal PFHxS dose. Perfluoroalkyl acids, including perfluorohexane sulfonate (PFHxS), are fluorinated organic compounds used as surfactants and water and stain repellents in carpets, paper, and textiles, with characteristics to bioaccumulate and biomagnify in the food chain. PFHxS is found in umbilical cord blood, human milk and child serum from all over the world. We have recently reported that neonatal exposure to certain perfluoroalkyl acids, PFOS and PFOA, can induce persistent aberrations in spontaneous behavior and also affect learning and memory functions in the adult animal. The present study indicates that a single exposure to PFHxS on postnatal day 10, during a vulnerable period of brain development can alter adult spontaneous behavior and cognitive function in both male and female mice, effects that are both dose-response related and long-lasting/irreversible. PFHxS affected the cholinergic system, manifested as altered nicotine-induced behavior in adult animals. This is also in agreement with earlier studies on neonatal exposure to PFOS and PFOA. The present findings show that PFHxS, a member of the perfluoroalkyl acid group, can act as a developmental neurotoxicant and affect the cholinergic system and cognitive function and the effects show similarities with effects earlier reported after neonatal exposure to other POPs, such as bisphenol A, PBDEs and PCBs. 22931186 Clinical pharmacology of etoposide in children undergoing autologous stem cell transplantation for various solid tumours. 1. The population pharmacokinetics of high-dose etoposide was studied in a group of young children and adolescents. 2. Twenty-six children and adolescent were administered high-dose etoposide as a continuous infusion over 24 h. Etoposide plasma concentration-time data was modelled using NONMEM® 7. The effect of age, weight, serum creatinine (SCr), and gender on pharmacokinetic parameters (CL and V(d)) were determined by a nonlinear mixed effect model. 3. The pharmacokinetics of etoposide based on BSA dosing was best described with a 1-compartment structural model which was parameterised in terms of clearance (CL) and volume of distribution (V(d)). An exponential error model was used to explain intersubject variability and a proportional error model was used to describe residual or intrapatient variability. The final model parameter estimates for the typical (normalised to 70 kg) values of CL and V(d) were 2.31 L/hr and 17.5 L, respectively. The CL and V(d) allometrically increased with weight with the power of 3/4 and 1, respectively. After accounting for weight dependence using the allometric scaling, age, serum creatinine, and gender did not have any influence on model parameters. 4. The results of this children and adolescent population pharmacokinetic study indicates that etoposide pharmacokinetics were influenced by body weight on an allometric basis. The pharmacokinetic parameters CL and V(d) increased with increasing weight similar to BSA. 23341175 A refined aquatic ecological risk assessment for a pyrethroid insecticide used for adult mosquito management. The use of pyrethroid insecticides has increased substantially throughout the world over the past few decades as the use of organophorous, carbamate, and organochlorine insecticides is being phased out. Pyrethroids are the most common class of insecticides for ultralow-volume (ULV) aerosol applications used to manage high densities of adult mosquitoes. Pyrethroids are highly toxic to nontarget organisms such as certain aquatic organisms, and there have been concerns about the effect of applications of ULV insecticides on these organisms. To address the uncertainties associated with the risks of ULV applications and the contradictory findings of other ecological risk assessments, the authors performed a probabilistic aquatic ecological risk assessment for permethrin using actual environmental deposition on surfaces to estimate permethrin concentrations in water. The present study is the first ecological risk assessment for pyrethroids to quantitatively integrate the reduction in bioavailability resulting from the presence of dissolved organic matter. As part of the risk assessment, the authors incorporated a species sensitivity distribution to take into account the differences in toxicity for different species. The 95th percentile estimated concentration would result in less than 0.0001% of the potentially affected fraction of species reaching the lethal concentration that kills 50% of a population. The results of the present study are supported by the weight of evidence that pyrethroids applied by ground-based ULV equipment will not result in deleterious effects on aquatic organisms. 23643737 1,4-Substituted 4-(1H)-pyridylene-hydrazone-type inhibitors of AChE, BuChE, and amyloid-β aggregation crossing the blood-brain barrier. Given the fundamentally multifactorial character of Alzheimer's disease (AD), addressing more than one target for disease modification or therapy is expected to be highly advantageous. Here, following the cholinergic hypothesis, we aimed to inhibit both acetyl- and butyrylcholinesterase (AChE and BuChE) in order to increase the concentration of acetylcholine in the synaptic cleft. In addition, the formation of the amyloid fibrils should be inhibited and already preformed fibrils should be destroyed. Based on a recently identified AChE inhibitor with a 1,4-substituted 4-(1H)-pyridylene-hydrazone skeleton, a substance library has been generated and tested for inhibition of AChE, BuChE, and fibril formation. Blood-brain barrier mobility was ensured by a transwell assay. Whereas the p-nitrosubstituted compound 18C shows an anti-AChE activity in the nanomolar range of concentration (IC50 = 90 nM), the bisnaphthyl substituted compound 20L was found to be the best overall inhibitor of AChE/BuChE and enhances the fibril destruction. 23481236 Modulation of cellular insulin signaling and PTP1B effects by lipid metabolites in skeletal muscle cells. Normal glucose regulation is achieved by having adequate insulin secretion and effective glucose uptake/disposal. Excess lipids in peripheral tissues - skeletal muscle, liver and adipose tissue - may attenuate insulin signaling through the protein kinase B (AKt) pathway and up-regulate protein tyrosine phosphatase 1B (PTP1B), a negative regulator of insulin signaling. We studied accumulation of lipid metabolites [triglycerides (TAGs), diglycerides (DAGs)] and ceramides in relation to insulin signaling and expression and phosphorylation of PTP1B by preincubating rat skeletal muscle cells (L6 myotubes) with three saturated and three unsaturated free fatty acids (FFAs) (200 μM). Cells were also evaluated in the presence of wortmannin, an inhibitor of phosphatidylinositol 3-kinases and thus AKt (0-100 nM). Unsaturated FFAs increased DAGs, TAGs and PTP1B expression significantly, but cells remained insulin sensitive as assessed by robust AKt and PTP1B phosphorylation at serine (Ser) 50, Ser 398 and tyrosine 152. Saturated palmitic and stearic acids increased ceramides, up-regulated PTP1B, and had AKt and PTP1B phosphorylation at Ser 50 impaired. We show a significant correlation between phosphorylation levels of AKt and of PTP1B at Ser 50 (R(2)=0.84, P<.05). The same was observed with increasing wortmannin dose (R(2)=0.73, P<.05). Only FFAs that increased ceramides caused impairment of AKt and PTP1B phosphorylation at Ser 50. PTP1B overexpression in the presence of excess lipids may not directly cause insulin resistance unless it is accompanied by decreased PTP1B phosphorylation. A clear relationship between PTP1B phosphorylation levels at Ser 50 and its negative effect on insulin signaling is shown. 23267855 The effect of novel promoter variants in MATE1 and MATE2 on the pharmacokinetics and pharmacodynamics of metformin. Interindividual variation in response to metformin, first-line therapy for type 2 diabetes, is substantial. Given that transporters are determinants of metformin pharmacokinetics, we examined the effects of promoter variants in both multidrug and toxin extrusion protein 1 (MATE1) (g.-66T → C, rs2252281) and MATE2 (g.-130G → A, rs12943590) on variation in metformin disposition and response. The pharmacokinetics and glucose-lowering effects of metformin were assessed in healthy volunteers (n = 57) receiving metformin. The renal and secretory clearances of metformin were higher (22% and 26%, respectively) in carriers of variant MATE2 who were also MATE1 reference (P < 0.05). Both MATE genotypes were associated with altered post-metformin glucose tolerance, with variant carriers of MATE1 and MATE2 having an enhanced (P < 0.01) and reduced (P < 0.05) response, respectively. Consistent with these results, patients with diabetes (n = 145) carrying the MATE1 variant showed enhanced metformin response. These findings suggest that promoter variants of MATE1 and MATE2 are important determinants of metformin disposition and response in healthy volunteers and diabetic patients. 23450806 Biological Design for Simultaneous Optical Transparency and Mechanical Robustness in the Shell of Placuna placenta. The flat circular-shaped shells from Placenta placenta demonstrate high optical transparency in the visible light range while still maintaining mechanical robustness. The optical and mechanical design of this mineralized material system in correlation to its multiscale structural and crystallographical features are discussed in detail through both experimental and theoretical approaches. 23248236 Inhibition of bacterial thioredoxin reductase: an antibiotic mechanism targeting bacteria lacking glutathione. Increasing antibiotic resistance makes the identification of new antibacterial principles an urgent task. The thioredoxin system including thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH plays critical roles in cellular DNA synthesis and defense against oxidative stress. Notably, TrxR is very different in structure and mechanism in mammals and bacteria. Ebselen [2-phenyl-1,2 benzisoselenazol-3(2H)-one], a well-known antioxidant and a substrate for mammalian TrxR and Trx, is rapidly bacteriocidal for methicillin-resistant Staphylococcus aureus by an unknown mechanism. We have discovered that ebselen is a competitive inhibitor of Escherichia coli TrxR with a Ki of 0.52 ± 0.13 μM, through reaction with the active site dithiol of the enzyme. Bacteria lacking glutathione (GSH) and glutaredoxin, in which TrxR and Trx are essential for DNA synthesis, were particularly sensitive to ebselen. In growth-inhibited E. coli strains, Trx1 and Trx2 were oxidized, demonstrating that electron transfer via thioredoxin was blocked. Ebselen and its sulfur analog ebsulfur were bactericidal for GSH-negative pathogens. Ebsulfur inhibited a clinically isolated Helicobacter pylori strain with a minimum inhibitory concentration value as low as 0.39 μg/ml. These results demonstrate that bacterial Trx and TrxR are viable antibacterial drug targets using benzisoselenazol and benzisothiazol derivates.-Lu, J., Vlamis-Gardikas, A., Kandasamy, K., Zhao, R., Gustafsson, T. N., Engstrand, L., Hoffner, S., Engman, L., Holmgren, A. Inhibition of bacterial thioredoxin reductase: an antibiotic mechanism targeting bacteria lacking glutathione. 23474441 Transcriptional cooperation between p53 and NF-κB p65 regulates microRNA-224 transcription in mouse ovarian granulosa cells. MicroRNAs (miRNAs) have been indicated to play key roles in ovarian follicular development. However, little is known about how the miRNA gene expression itself is regulated in the mammalian ovary. We previously reported that miR-224 is involved in TGF-β1-mediated follicular granulosa cell (GC) growth and estradiol (E2) production by targeting Smad4. Here, the transcriptional regulation of miR-224 expression in GCs was further investigated. Our results showed that both the tumor suppressor gene p53 and NF-κB p65 subunit suppressed the TGF-β1-induced increase in pri-miR-224 expression in GCs. ChIP assays demonstrated that TGF-β1 enhanced the binding of p53 and p65 to the proximal promoter region of GABAA receptor ε subunit (miR-224 host gene). p53 and p65 transcriptionally cooperated to inactivate the GABAA receptor ε subunit promoter. In addition, p53/p65 could up-regulate Smad4 expression by inhibiting its target miR-224 in GCs which contributed, at least partially, to the effects of miR-224 and Smad4 on GC proliferation and E2 release. Our results provide new data about the interplay between transcription factors involved in GC proliferation and function by cooperatively regulating miRNA expression. 23429231 Endothelial cell response to (co)polymer nanoparticles depending on the inflammatory environment and comonomer ratio. Endothelial cells lining the lumen of blood vessels serve as a physiological barrier controlling nanoparticle movement from the vasculature into the tissue. For exploring the effect of polymer hydrophilicity on nanoparticle interactions with human umbilical vein endothelial cells (HUVECs) in vitro, a series of monomodal poly[acrylonitrile-co-(N-vinylpyrrolidone)] model nanoparticles with increasing hydrophilicity as related to their increasing content (0-30mol.%) of N-vinylpyrrolidone (NVP) were synthesized by miniemulsion polymerization. Nanoparticles with a low NVP content were rapidly endocytized into all cells independent from the particle dose with toxic effects only observed at high particle concentrations, while only 10-30% of the cells incorporated particles with ⩾20mol.% NVP. Since pathologies are often related to inflammation, an inflammatory HUVEC culture condition with IL-1β stimulation has been introduced and suggested to be widely applied for studying nanocarriers, since cellular uptake in this assay was clearly increased for NVP contents ⩾20mol.%. Importantly, the secretion of functional biological mediators by HUVEC was not relevantly influenced by the nanoparticles for both homeostatic and inflammatory conditions. These findings may motivate concepts for nanocarriers specifically targeted to pathologic regions. Additionally, rapidly endocytized RhodaminB loaded particles with low NVP content may be explored for cell labeling and tracking. 23601393 Nutritional composition of minor indigenous fruits: Cheapest nutritional source for the rural people of Bangladesh. In line of the development of a food composition database for Bangladesh, 10 minor indigenous fruits were analysed for their nutrient composition comprising ascorbic acid, carotenoids and mineral values. Nutrient data obtained have been compared with published data reported in different literatures, book and United States Department of Agriculture-National Nutrient Database for Standard Reference. Ascorbic acid was highest in Wood apple and lowest in Roselle. Monkey jack contained the highest amount of carotenoids, zinc and copper. Content of calcium, magnesium and phosphorous were found highest in Antidesma velutinum. Potassium was the highest in Wood apple followed by in Moneky jack. It was noted that most of the minor fruits have much higher amount of ascorbic acid than the national fruit - Jack fruit ripe, the king fruit - Mango ripe of Bangladesh and exotic fruits - Apple and Grapes. The nutrient values of these minor fruits would make awareness among the people for their mass consumption for healthy life and to grow more minor fruit trees from extinction in order to maintain biodiversity. 23466231 Pregna-5,17(20)-dien-21-oyl amides affecting sterol and triglyceride biosynthesis in Hep G2 cells. Synthesis of series [17(20)Z]- and [17(20)E]-pregna-5,17(20)-dien-21-oyl amides, containing polar substituents in amide moiety, based on rearrangement of 17α-bromo-21-iodo-3β-acetoxypregn-5-en-20-one caused by amines, is presented. The titled compounds were evaluated for their potency to regulate sterol and triglyceride biosynthesis in human hepatoma Hep G2 cells in comparison with 25-hydroxycholesterol. Three [17(20)E]-pregna-5,17(20)-dien-21-oyl amides at a concentrations of 5 μM inhibited sterol biosynthesis and stimulated triglyceride biosynthesis; their regulatory potency was dependent on the structure of amide moiety; the isomeric [17(20)Z]-pregna-5,17(20)-dien-21-oyl amides were inactive. 23449223 A far-upstream (-70 kb) enhancer mediates Sox9 auto-regulation in somatic tissues during development and adult regeneration. SOX9 encodes a transcription factor that presides over the specification and differentiation of numerous progenitor and differentiated cell types, and although SOX9 haploinsufficiency and overexpression cause severe diseases in humans, including campomelic dysplasia, sex reversal and cancer, the mechanisms underlying SOX9 transcription remain largely unsolved. We identify here an evolutionarily conserved enhancer located 70-kb upstream of mouse Sox9 and call it SOM because it specifically activates a Sox9 promoter reporter in most Sox9-expressing somatic tissues in transgenic mice. Moreover, SOM-null fetuses and pups reduce Sox9 expression by 18-37% in the pancreas, lung, kidney, salivary gland, gut and liver. Weanlings exhibit half-size pancreatic islets and underproduce insulin and glucagon, and adults slowly recover from acute pancreatitis due to a 2-fold impairment in Sox9 upregulation. Molecular and genetic experiments reveal that Sox9 protein dimers bind to multiple recognition sites in the SOM sequence and are thereby both necessary and sufficient for enhancer activity. These findings thus uncover that Sox9 directly enhances its functions in somatic tissue development and adult regeneration through SOM-mediated positive auto-regulation. They provide thereby novel insights on molecular mechanisms controlling developmental and disease processes and suggest new strategies to improve disease treatments. 23485440 Effect of iontophoresis on the in vitro trans-scleral transport of three single stranded oligonucleotides. Oligonucleotides represent a subject of clinical interest due to their potential ability to treat several diseases, including those affecting the posterior segment of the eye. Unfortunately, therapeutic oligonucleotides are currently administered by means of highly invasive approaches, such as intravitreal injections. The aim of the present work was to study in vitro, across isolated bovine sclera, the effect of iontophoresis on the transport of three single stranded oligonucleotides (ssDNA), 12-, 24- and 36-mer, selected as reference compounds in view of a non-invasive drug delivery to the back of the eye. All the three sequences were able to cross bovine sclera in vitro without iontophoresis. When anodal iontophoresis was applied, no change in flux was observed, while in the presence of cathodal iontophoresis the permeability coefficients increased four-fold compared to passive conditions. This behavior can be ascribed to the electrorepulsive mechanism, due to the negative charge of the nucleic acid backbone. It was also observed that the molecular weights of the three sequences did not affect trans-scleral transport, neither in passive, nor in current assisted permeation. Furthermore, increasing the current intensity from 1.75mA to 3mA, no effect on the trans-scleral transport of the 24-mer was noticed. Although preliminary, the results demonstrate that cathodal iontophoresis enhances trans-scleral transport of single stranded oligonucleotides and suggest its use as a novel non-invasive approach for the treatment of diseases affecting the posterior segment of the eye. 23595510 Nuclear magnetic resonance study of ion adsorption on microporous carbide-derived carbon. A detailed understanding of ion adsorption within porous carbon is key to the design and improvement of electric double-layer capacitors, more commonly known as supercapacitors. In this work nuclear magnetic resonance (NMR) spectroscopy is used to study ion adsorption in porous carbide-derived carbons. These predominantly microporous materials have a tuneable pore size which enables a systematic study of the effect of pore size on ion adsorption. Multinuclear NMR experiments performed on the electrolyte anions and cations reveal two main environments inside the carbon. In-pore ions (observed at low frequencies) are adsorbed inside the pores, whilst ex-pore ions (observed at higher frequencies) are not adsorbed and are in large reservoirs of electrolyte between carbon particles. All our experiments were carried out in the absence of an applied electrical potential in order to assess the mechanisms related to ion adsorption without the contribution of electrosorption. Our results indicate similar adsorption behaviour for anions and cations. Furthermore, we probe the effect of sample orientation, which is shown to have a marked effect on the NMR spectra. Finally, we show that a (13)C →(1)H cross polarisation experiment enables magnetisation transfer from the carbon architecture to the adsorbed species, allowing selective observation of the adsorbed ions and confirming our spectral assignments. 22968089 Effects of metabotropic glutamate receptor ligands on male sexual behavior in rats. Metabotropic glutamate receptors (mGluRs), particularly mGluR2/3, mGluR5 and mGluR7, have received much attention in medication development for the treatment of drug addiction and other neuropsychiatric diseases. However, little is known as to whether mGluR ligands also alter natural sexual behavior, a possible unwanted effect when used in humans. In the present study, we used classical copulatory behaviors to evaluate the effects of LY379268 (a selective mGluR2/3 agonist), MPEP (a selective mGluR5 antagonist) and AMN082 (a selective mGluR7 agonist), on male sexual performance in rats. We found that systemic administration of LY379268 (1, 3 mg/kg, i.p.) had no effect, while MPEP (20 mg/kg, but not 10 mg/kg, i.p.) and AMN082 (10, 20 mg/kg, but not 3 mg/kg) produced a significant and dose-dependent reduction in both sex-seeking and sex-performance behaviors, manifested as an increase in mount or intromission latency and time required for ejaculation, and a reduction in mount or intromission frequency. This inhibition lasted for about 30-60 min. These findings suggest that compounds that target mGluR5 or mGluR7, but not mGluR2/3, may have short-term inhibitory effects on male sexual performance. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23540698 The Arabidopsis Nucleosome Remodeler DDM1 Allows DNA Methyltransferases to Access H1-Containing Heterochromatin. Nucleosome remodelers of the DDM1/Lsh family are required for DNA methylation of transposable elements, but the reason for this is unknown. How DDM1 interacts with other methylation pathways, such as small-RNA-directed DNA methylation (RdDM), which is thought to mediate plant asymmetric methylation through DRM enzymes, is also unclear. Here, we show that most asymmetric methylation is facilitated by DDM1 and mediated by the methyltransferase CMT2 separately from RdDM. We find that heterochromatic sequences preferentially require DDM1 for DNA methylation and that this preference depends on linker histone H1. RdDM is instead inhibited by heterochromatin and absolutely requires the nucleosome remodeler DRD1. Together, DDM1 and RdDM mediate nearly all transposon methylation and collaborate to repress transposition and regulate the methylation and expression of genes. Our results indicate that DDM1 provides DNA methyltransferases access to H1-containing heterochromatin to allow stable silencing of transposable elements in cooperation with the RdDM pathway. 23593960 Is Diacetyl a Respiratory Sensitizer? A Reconsideration Using QSAR, QMM, and Competition Experiments. Concerns have been raised that diacetyl (DA) might be a respiratory sensitizer based on its LUMO energy similar to that of the respiratory allergen toluene-2,4-diisocyanate (TDI) and results of a local lymph node assay (LLNA) that reported an EC3 of 1.9%. To better understand the concerns, we performed a systematic literature review and experimental competition reactions between DA and TDI. The experimental evidence demonstrates that DA is at least 400-fold less reactive than TDI. The literature review finds evidence that the EC3 for DA is actually >11%. We conclude that DA is unlikely to have significant respiratory sensitization potential. 23562074 The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Endocannabinoids and cannabinoid CB1 receptors are known to play a generalized role in energy homeostasis. However, clinical trials with the first generation of CB1 blockers, now discontinued due to psychiatric side effects, were originally designed to reduce food intake and body weight rather than the metabolic risk factors associated with obesity. In this review, we discuss how, in addition to promoting energy intake, endocannabinoids control lipid and glucose metabolism in several peripheral organs, particularly the liver and adipose tissue. Direct actions in skeletal muscle and pancreas are also emerging. This knowledge may help in the design of future therapies for the metabolic syndrome. 23032515 8-Hydroxycalamenene isolated from the rhizomes of Reynoutria elliptica exerts neuroprotective effects both in vitro and in vivo. Retinal ganglion cells (RGCs) death caused by oxidative stress is a common risk factor for glaucoma. In the present study, 8-hydroxycalamenene was isolated from the hexane fraction of Reynoutria elliptica. We showed that 8-hydroxycalamenene attenuated the cell death of transformed RGC-5 cells. This compound also produced a dose-dependent decrease in the expression of apoptotic proteins (cleaved PARP and caspase-3) induced by l-buthionine-(S,R)-sulfoximine (BSO) plus glutamate and stimulated glutathione and glutathione S-transferase activity. Moreover, the addition of 8-hydroxycalamenene to cell cultures restored the reduced mitochondrial membrane potential resulting from glutamate/BSO treatment. The presence of N-methyl-d-aspartate in the retina of rats affected the thickness of the inner plexiform layer (IPL) and increased the number of TUNEL-positive RGCs. However, 8-hydroxycalamenene protected against thinning of the IPL and reduced TUNEL-positive cells in the ganglion cell layer. Thus, 8-hydroxycalamenene isolated from R. elliptica exerts neuroprotective effects both in vitro and in vivo. 23030346 Direct measurement of coherency limits for strain relaxation in heteroepitaxial core/shell nanowires. The growth of heteroepitaxially strained semiconductors at the nanoscale enables tailoring of material properties for enhanced device performance. For core/shell nanowires (NWs), theoretical predictions of the coherency limits and the implications they carry remain uncertain without proper identification of the mechanisms by which strains relax. We present here for the Ge/Si core/shell NW system the first experimental measurement of critical shell thickness for strain relaxation in a semiconductor NW heterostructure and the identification of the relaxation mechanisms. Axial and tangential strain relief is initiated by the formation of periodic a/2 ⟨110⟩ perfect dislocations via nucleation and glide on {111} slip-planes. Glide of dislocation segments is directly confirmed by real-time in situ transmission electron microscope observations and by dislocation dynamics simulations. Further shell growth leads to roughening and grain formation which provides additional strain relief. As a consequence of core/shell strain sharing in NWs, a 16 nm radius Ge NW with a 3 nm Si shell is shown to accommodate 3% coherent strain at equilibrium, a factor of 3 increase over the 1 nm equilibrium critical thickness for planar Si/Ge heteroepitaxial growth. 23232150 Analysis and characterization of eight estradiol inducible genes and a strong promoter from the steroid degrading marine bacterial strain S19-1. Buttiauxella strain S19-1 is a new marine bacterium, isolated from the Baltic Sea, which can degrade steroids. In this report, a meta-genomic approach was used to isolate estradiol inducible genes from S19-1. SalI-fragments from the chromosomal DNA of S19-1 were ligated into plasmid pKEGFP2 bearing an EGFP gene as the reporter system. All resulting plasmids harboring SalI-fragments were transformed into Escherichia coli HB101 to measure the relative fluorescent units (RFU). E. coli cells showing higher RFU after estradiol induction than those without estradiol induction, were selected and the respective plasmids were sequenced. Sequences of 8 positive plasmids were analyzed and aligned by BLAST. Among the predicted genes we found similarities to the major facilitator superfamily, glycerol dehydratase activator, formate acetyltransferase activating enzyme, histidinol-phosphate/aromatic aminotransferase, ABC-transporter, transcriptional regulator nadR, lipoate-protein ligase A, and alcohol phosphatidyl-transferase. Interestingly, one of the E. coli cell clones (containing plasmid p302) showed up in green color by normal light microscopy, which indicated that a strong promoter was present in this plasmid. Sequencing and deletion-mutagenesis revealed that the putative promoter comprises a 108 bp DNA fragment within p302, from which the putative -10 and -35 regions are TTTGAT and TTGGTT, respectively. The promoter might be used to construct S19-1 mutants in which steroid degradation occurs at high levels. 23546879 Site-specific O-glycosylation on the MUC2 mucin inhibits cleavage by the Porphyromonas gingivalis secreted cysteine protease (RgpB). The colonic epithelial surface is protected by an inner mucus layer which the commensal microflora cannot penetrate. We previously demonstrated that Entamoeba histolytica (E.h.) secretes a protease capable of dissolving this layer that is required for parasite penetration. Here, we asked if there are bacteria that can secrete similar proteases. We screened bacterial culture supernatants for such activity using recombinant fragments of the MUC2 mucin, the major structural component and the only gel-forming mucin in the colonic mucus. MUC2 has two central heavily O-glycosylated mucin domains that are protease-resistant and has cysteine rich N- and C-termini responsible for polymerization. Culture supernatants of Porphyromonas gingivalis (P.g.), a bacterium that secretes proteases responsible for periodontitis, cleaved the MUC2-C terminal region, whereas the N-terminal region was unaffected. The active enzyme was isolated and identified as Arg-gingipain B (RgpB). Two cleavage sites were localized to IR↓TT and NR↓QA. IR↓TT cleavage will disrupt the MUC2 polymers. As this site has two potential O-glycosylation sites we tested whether recombinant GalNAc-transferases (GalNAc-Ts) could glycosylate a synthetic peptide covering the IRTT sequence. Only GalNAc-T3 was able to glycosylate the second Thr in IRTT, rendering the sequence resistant to cleavage by RgpB. Furthermore, when GalNAc-T3 was expressed in CHO-cells expressing the MUC2 C-terminal, the second threonine was glycosylated and the protein became resistant to RgpB cleavage. These findings suggest that bacteria can produce proteases capable of dissolving the inner protective mucus layer by specific cleavages in the MUC2 mucin and that this cleavage can be modulated by site-specific O-glycosylation. 23600865 Hydrodynamic Interactions between Two Equally Sized Spheres in Viscoelastic Fluids in Shear Flow. The effect of using a viscoelastic suspending medium on the in-plane hydrodynamic interaction between two equally sized spheres in shear flow is studied experimentally to understand flow-induced assembly behavior (i.e., string formation). A counterrotating device equipped with a Couette geometry is used together with quantitative videomicroscopy. To evaluate the effects of differences in rheological properties of the suspending media, fluids have been selected that highlight specific constitutive features. These include a reference Newtonian fluid (N), a constant-viscosity, high-elasticity Boger fluid (BF), a wormlike micellar surfactant solution with a single dominant relaxation time (WMS), and a broad spectrum shear-thinning elastic polymer solution (ST). As expected, the trajectories are symmetric in the Newtonian fluid. In the BF, the midpoints of the spheres are observed to remain in the same plane before and after the interaction, as in the Newtonian fluid, although the path lines are in this case no longer symmetric. Interactions in the ST and WMS are highly asymmetric. Two fundamentally different kinds of path lines are observed in the WMS and ST: reversing and open trajectories. The type of trajectory depends on the initial configuration of the spheres with respect to each other and on the shear rate. On the basis of the obtained results, shear-thinning of the viscosity seems to be the key rheological parameter that determines the overall nature of the interactions, rather than the relative magnitude of the normal stress differences. 23169614 How do the electrical properties of graphene change with its functionalization? Functionalization of graphene is essential to interface it with other moieties to expand the scope of its electrical/electronic applications. However, chemical functionalization and/or molecular interactions on graphene sensitively modulate its electrical properties. To evaluate and take advantage of the properties of functionalized graphene, it is important to understand how its electrical attributes (such as carrier scattering, carrier concentration, charge polarity, quantum-capacitance enhanced doping, energy levels, transport mechanisms, and orbital hybridization of energy-bands) are influenced by a change in carbon's structural conformation, hybridization state, chemical potential, local energy levels, and dopant/interface coupling induced via functionalization or molecular interactions. Here, a detailed and integrated model describes factors influencing these electrical characteristics of functionalized graphene (covalent bonds, adsorption, π-π bonds, and lattice incorporation). The electrical properties are governed via three mechanisms: (a) conversion of carbon's hybridized state, (b) dipole interactions enhanced via quantum capacitance, and (c) orbital hybridization with an interfacing molecule. A few graphenic materials are also identified where further studies are essential to understand the effect of their functionalization. 23260347 Synthesis and evaluation of diphenylphosphinic amides and diphenylphosphine oxides as inhibitors of Kv1.5. Diphenylphosphinic amides and diphenylphosphine oxides have been synthesized and tested as inhibitors of the Kv1.5 potassium ion channel as a possible treatment for atrial fibrillation. In vitro structure-activity relationships are discussed and several compounds with Kv1.5 IC(50) values of <0.5 μM were discovered. Selectivity over the ventricular IKs current was monitored and selective compounds were found. Results from a rabbit PD-model are included. 23540587 Interleukin-23: a promising therapeutic target in seronegative spondyloarthropathy. Particular therapeutic challenges are raised by the spondyloarthropathies which represent a key area of unmet medical need. Recent investigations have shown that these conditions are characterised both by altered responsiveness to interleukin(IL)-23 and expansion of IL-23 responsive cells as well as increased production of IL-23. The gut in particular has emerged as a key site of IL-23 production, and gut inflammation is known to be strongly clinically associated with these conditions. Moreover, HLA-B27, which is strongly associated with spondyloarthropathy, has also been shown to stimulate IL-23 production. The view is thus emerging that dysregulation of IL-23 biology is a unifying feature of spondyloarthropathy, suggesting that treatments targeting this cytokine are likely to be highly efficacious. 23319584 Comparison of orientation and rotational motion of skeletal muscle cross-bridges containing phosphorylated and dephosphorylated myosin regulatory light chain. Calcium binding to thin filaments is a major element controlling active force generation in striated muscles. Recent evidence suggests that processes other than Ca(2+) binding, such as phosphorylation of myosin regulatory light chain (RLC) also controls contraction of vertebrate striated muscle (Cooke, R. (2011) Biophys. Rev. 3, 33-45). Electron paramagnetic resonance (EPR) studies using nucleotide analog spin label probes showed that dephosphorylated myosin heads are highly ordered in the relaxed fibers and have very low ATPase activity. This ordered structure of myosin cross-bridges disappears with the phosphorylation of RLC (Stewart, M. (2010) Proc. Natl. Acad. Sci. U.S.A. 107, 430-435). The slower ATPase activity in the dephosporylated moiety has been defined as a new super-relaxed state (SRX). It can be observed in both skeletal and cardiac muscle fibers (Hooijman, P., Stewart, M. A., and Cooke, R. (2011) Biophys. J. 100, 1969-1976). Given the importance of the finding that suggests a novel pathway of regulation of skeletal muscle, we aim to examine the effects of phosphorylation on cross-bridge orientation and rotational motion. We find that: (i) relaxed cross-bridges, but not active ones, are statistically better ordered in muscle where the RLC is dephosporylated compared with phosphorylated RLC; (ii) relaxed phosphorylated and dephosphorylated cross-bridges rotate equally slowly; and (iii) active phosphorylated cross-bridges rotate considerably faster than dephosphorylated ones during isometric contraction but the duty cycle remained the same, suggesting that both phosphorylated and dephosphorylated muscles develop the same isometric tension at full Ca(2+) saturation. A simple theory was developed to account for this fact. 23122097 GC/MS analysis of volatiles obtained by headspace solid-phase microextraction and simultaneous-distillation extraction from Rabdosia serra (MAXIM.) HARA leaf and stem. Volatiles in Rabdosia serra were investigated by headspace solid phase microextraction (HS-SPME) and simultaneous-distillation extraction (SDE). The HS-SPME technique was previously evaluated to optimise sampling conditions. A total of 56 and 48 compounds including alcohols, aldehydes, hydrocarbons, ketones, carboxylic acid, ester, and aromatics were identified in leaf and stem by optimised HS-SPME method (CAR/PDMS fibre; incubation time, 10 min; extraction temperature, 50°C; extraction time, 40 min), respectively. 1-Octen-3-ol and (2E)-hexenal had significant contribution to R. serra aroma. Cluster analysis indicated that leaf and stem exhibited different volatile diversity. Air drying was favourable for the retention of the volatiles, while freeze- and sun-drying led to the loss of volatiles. SDE method preferred to the analysis of compounds with low volatility including fatty acids and esters. HS-SPME was a useful technique for the analysis of readily volatile components for the characteristics of R. serra aroma. 23442197 Analysis and refactoring of the A-74528 biosynthetic pathway. A-74528 is a C30 polyketide natural product that functions as an inhibitor of 2',5'-oligoadenylate phosphodiesterase (2'-PDE), a key regulatory enzyme of the interferon pathway. Modulation of 2'-PDE represents a unique therapeutic approach for regulating viral infections. The gene cluster responsible for biosynthesis of A-74528 yields minute amounts of this natural product together with considerably larger quantities of a structurally dissimilar C30 cytotoxic agent, fredericamycin. Through construction and analysis of a series of knockout mutants, we identified the genes necessary for A-74528 biosynthesis. Remarkably, the formation of six stereocenters and the regiospecific formation of six rings in A-74528 appear to be catalyzed by only two tailoring enzymes, a cyclase and an oxygenase, in addition to the core polyketide synthase. The inferred pathway was genetically refactored in a heterologous host, Streptomyces coelicolor CH999, to produce 3 mg/L A-74528 in the absence of fredericamycin. 23553961 In Situ Study of CO Oxidation on HOPG-Supported Pt Nanoparticles. Catalyzed CO oxidation: A newly designed high-pressure flow cell is utilized to study CO oxidation on Pt nanoparticles in situ by simultaneous quadrupole mass spectrometry and high-pressure X-ray photoelectron spectroscopy. The spectroscopy data show that the active catalyst consists of metallic Pt with both chemisorbed O and patches/shell of surface oxides. 22956629 Differential mouse pulmonary dose and time course responses to titanium dioxide nanospheres and nanobelts. Three anatase titanium dioxide (TiO(2)) nanoparticles (NPs) were prepared; nanospheres (NSs), short nanobelts (NB1), and long nanobelts (NB2). These NPs were used to investigate the effect of NP shape and length on lung toxicity. Mice were exposed (0-30 µg per mouse) by pharyngeal aspiration and pulmonary toxicity was assessed over a 112-day time course. Whole lung lavage data indicated that NB1- and NB2-exposed mice, but not NS-exposed mice, had significant dose- and time-dependent pulmonary inflammation and damage. Histopathological analyses at 112 days postexposure determined no interstitial fibrosis in any NS-exposed mice, an increased incidence in 30 µg NB1-exposed mice, and significant interstitial fibrosis in 30 µg NB2-exposed mice. At 112 days postexposure, lung burden of NS was decreased by 96.4% and NB2 by 80.5% from initial deposition levels. At 112 days postexposure, enhanced dark field microscopy determined that alveolar macro- phages were the dominant deposition site, but a fraction of NB1 and NB2 was observed in the alveolar interstitial spaces. For the 30 µg exposure groups at 112 days postexposure, confocal micro- scopy and immunofluorescent staining demonstrated that retained NB2 but not NS were present in the interstitium subjacent to the terminal bronchiole near the normal location of the smallest lymphatic capillaries in the lung. These lymphatic capillaries play a critical role in particle clearance, and the accumulation of NB2, but not NS, suggests possible impaired lymphatic clearance by the high aspect ratio particles. In summary, our data indicate that TiO(2) NP shape alters pulmonary responses, with severity of responses being ranked as NS < NB1 < NB2. 23596084 Influence of the Molecular Structure of Surface-Attached Poly(N-alkyl Acrylamide) Coatings on the Interaction of Surfaces with Proteins, Cells and Blood Platelets. Blood protein adsorption and blood platelet adhesion onto surface-attached poly(alkylacrylamide) networks that exhibit small and systematic variations in chemical composition are investigated. The polymer coatings are generated by depositing a thin layer of benzophenone-group-containing copolymer onto a solid substrate, followed by photo crosslinking and simultaneous surface-attachment. The correlation of the swelling of the obtained surface-attached networks with the adsorption of blood proteins and cellular adhesion is studied. The swollen surface-attached layers are inert to blood proteins and platelet cells. These results suggest that the hydrogel-coated materials are promising candidates for the generation of hemocompatible surfaces. 23419139 In vivo drug interactions of the teratogen thalidomide with midazolam: heterotropic cooperativity of human cytochrome P450 in humanized TK-NOG mice. In vivo drug interactions of the teratogen thalidomide with the model cytochrome P450 (P450) 3A substrate midazolam were investigated in mice with humanized livers. The clearance of midazolam (administered intravenously, 10 mg kg(-1)) in chimeric mice was enhanced by orally co-administered thalidomide (100 mg kg(-1)). A larger area under the curve of the major metabolite 1'-hydroxymidazolam (1.7-fold) was obtained with thalidomide because of the heterotropic cooperativity of human P450 3A enzymes. A larger area under the curve of the minor metabolite 4-hydroxymidazolam (3.5-fold) was seen with daily pretreatment with thalidomide for 3 days, presumably because of human P450 3A induction. These results demonstrate that livers of humanized mice mediate drug interactions of thalidomide and suggest interactions of therapeutic agents during therapies with thalidomide. 23376119 p63 involvement in poly(ADP-ribose) polymerase 1 signaling of topoisomerase I-dependent DNA damage in carcinoma cells. Poly(ADP-ribose)polymerase 1 (PARP-1) inhibitors are thought as breakthrough for cancer treatment in solid tumors such as breast cancer through their effects on PARP's enzymatic activity. Our previous findings showed that the hydrophilic PARP inhibitor PJ34 enhances the sensitivity of p53 proficient MCF7 breast carcinoma cells to topotecan, a DNA Topoisomerase I (TOP 1) inhibitor. In the present study, we combine the classical TOP 1 poison camptothecin or its water-soluble derivative topotecan with PJ34 to investigate the potentiation of chemotherapeutic efficiency in MCF7 (p53(WT)), MDA-MB231 (p53(mut)) breast carcinoma cells and SCC022 (p53(null)) squamous carcinoma cells. We show that, following TPT-PJ34 combined treatment, MCF7 cells exhibit apoptotic death while MDA-MB231 and SCC022 cells are more resistant to these agents. Specifically, in MCF7, (i) PJ34 in combination with TPT causes a G2/M cell cycle arrest followed by massive apoptosis; (ii) PJ34 addition reverts TPT-dependent PARP-1 automodification and triggers caspase-dependent PARP-1 proteolysis; (iii) TPT, used as a single agent, stimulates p53 expression while in combination with PJ34 increases p53, TAp63α and TAp63γ protein levels with a concomitant reduction of MDM2 protein. The identification of p63 proteins as new players involved in the cancer cell response to TPT-PJ34 is relevant for a better understanding of the PARP1-dependent signaling of DNA damage. Furthermore, our data indicate that, in response to TPT-PJ34 combined chemotherapy, a functional cooperation between p53 and TAp63 proteins may occur and be essential to trigger apoptotic cell death. 23547584 Biological Active Analogues of the Opioid Peptide Biphalin: Mixed α/β(3)-Peptides. Natural residues of the dimeric opioid peptide Biphalin were replaced by the corresponding homo-β(3) amino acids. The derivative 1 containing hβ(3) Phe in place of Phe showed good μ- and δ-receptor affinities (Ki(δ) = 0.72 nM; Ki(μ) = 1.1 nM) and antinociceptive activity in vivo together with an increased enzymatic stability in human plasma. 23639717 Application of COSMO-RS as an Excipient Ranking Tool in Early Formulation Development. The low amounts of drug available in early discovery often results in limited information on the physico-chemical (solubility etc.) properties of a compound being obtained. As a result, predictive tools and miniaturised screens have been investigated to aid formulation development in early discovery. This study looks at the potential application of the quantum chemistry program, Conductor Screening Model for Real Solvents (COSMO-RS) to help with the selection of excipients for formulation development in early discovery. The excipient solubility predictions obtained from COSMO-RS were compared to experimentally obtained solubilities. The results showed that in general, COSMO-RS was able to help formulators with the selection of the most appropriate excipients to solubilise the model compound. 23627396 Antifungal Agents from Pseudallescheria boydii SNB-CN73 Isolated from a Nasutitermes sp. Termite. Defense mutualisms between social insects and microorganisms have been described in the literature. The present article describes the discovery of a Pseudallescheria boydii strain isolated from Nasutitermes sp. The microbial symbiont produces two antifungal metabolites: tyroscherin and N-methyltyroscherin, a compound not previously described in the literature. Methylation of tyroscherin has confirmed the structure of N-methyltyroscherin. Both compounds are effective antifungal agents with favorable selectivity indices for Candida albicans and Trichophyton rubrum. 23334322 Effects of vitamin B6 metabolism on oncogenesis, tumor progression and therapeutic responses. Pyridoxal-5'-phosphate (PLP), the bioactive form of vitamin B6, reportedly functions as a prosthetic group for >4% of classified enzymatic activities of the cell. It is therefore not surprising that alterations of vitamin B6 metabolism have been associated with multiple human diseases. As a striking example, mutations in the gene coding for antiquitin, an evolutionary old aldehyde dehydrogenase, result in pyridoxine-dependent seizures, owing to the accumulation of a metabolic intermediate that inactivates PLP. In addition, PLP is required for the catabolism of homocysteine by transsulfuration. Hence, reduced circulating levels of B6 vitamers (including PLP as well as its major precursor pyridoxine) are frequently paralleled by hyperhomocysteinemia, a condition that has been associated with an increased risk for multiple cardiovascular diseases. During the past 30 years, an intense wave of clinical investigation has attempted to dissect the putative links between vitamin B6 and cancer. Thus, high circulating levels of vitamin B6, as such or as they reflected reduced amounts of circulating homocysteine, have been associated with improved disease outcome in patients bearing a wide range of hematological and solid neoplasms. More recently, the proficiency of vitamin B6 metabolism has been shown to modulate the adaptive response of tumor cells to a plethora of physical and chemical stress conditions. Moreover, elevated levels of pyridoxal kinase (PDXK), the enzyme that converts pyridoxine and other vitamin B6 precursors into PLP, have been shown to constitute a good, therapy-independent prognostic marker in patients affected by non-small cell lung carcinoma (NSCLC). Here, we will discuss the clinical relevance of vitamin B6 metabolism as a prognostic factor in cancer patients.Oncogene advance online publication, 21 January 2013; doi:10.1038/onc.2012.623. 23289624 Distribution and seasonal variation in hypothalamic RF-amide peptides in a semi-desert rodent, the jerboa. The jerboa is a semi-desert rodent, in which reproductive activity depends on the seasons, being sexually active in the spring-summer. The present study aimed to determine whether the expression of two RF-amide peptides recently described to regulate gonadotrophin-releasing hormone neurone activity, kisspeptin (Kp) and RF-amide-related peptide (RFRP)-3, displays seasonal variation in jerboa. Kp and/or RFRP-3 immunoreactivity was investigated in the hypothalamus of jerboas captured in the field of the Middle Atlas mountain (Morocco), either in the spring or autumn. As in other rodents, the Kp-immunoreactive (-IR) neurones were found in the anteroventro-periventricular and arcuate nuclei. RFRP-3 neurones were noted within the dorso/ventromedial hypothalamus. A marked sexual dimorphism in the expression of Kp (but not RFRP-3) was observed. The number of Kp-IR neurones was nine-fold higher, and the density of Kp-IR fibres and terminal-like elements in the median eminence was two-fold higher in females than in males. Furthermore, a significant seasonal variation in peptide expression was obtained with an increase in both Kp- and RFRP-3-IR cell bodies in sexually active male jerboas captured in the spring compared to sexually inactive autumn animals. In the arcuate nucleus, the level of Kp-IR cells and fibres was significant higher during the sexually active period in the spring than during the autumnal sexual quiescence. Similarly, the number of RFRP-3-IR neurones in the ventro/dorsomedial hypothalamus was approximately three-fold higher in sexually active jerboa captured in the spring compared to sexually inactive autumn animals. Altogether, the present study reports the distribution of Kp and RFRP-3 neurones in the hypothalamus of a desert species and reveals a seasonal difference in their expression that correlates with sexual activity. These findings suggest that these two RF-amide peptides may act in concert to synchronise the gonadotrophic activity of jerboas with the seasons. 23432061 Possible Involvement of TRP Channels in Cardiac Hypertrophy and Arrhythmia. Over the past 20 years, studies of transient receptor potential (TRP) channels have significantly extended our knowledge regarding the molecular basis of Ca2+ signals in cardiac myocytes. The functional significance of cardiac TRP channels is likely connected to the alteration of membrane potential or Ca2+ entry into a noncontractile compartment, where gene expression responsible for various cardiac diseases is induced. This review highlights some aspects of TRP channels with anticipated roles in cardiac disease. Evidence suggests that (a) increased activities of TRPC1, TRPC3, or TRPC6 are involved in the development of cardiac hypertrophy, where these TRPC channels act as unique sensors for a wide range of hypertrophic stimuli, and (b) mutations in TRPM4 are now recognized as causes of human cardiac conduction disorders. Ultimately, TRP channels may become novel pharmacological targets in the treatment of human cardiac disease. 23306791 Polyethylene glycol-g-polyvinyl alcohol grafted copolymer: Reproductive toxicity study in Wistar rats. Polyethylene glycol-g-polyvinyl alcohol (PEG-PVA) grafted copolymer was administered by gavage to groups of 25 male and 25 female young Wistar rats at doses of 0 (vehicle control), 100, 300, or 1000mg/kg bw/day for one generation (F0). The study followed the treated F0 generation through mating, gestation, lactation, and weaning of the F1 generation. F1 animals were mated and followed to gestation day (GD) 15-17 at which time F2 implants were evaluated. There were no indications from the various clinical and gross pathological examinations that the oral administration of PEG-PVA grafted copolymer to the F0-parental rats produced any signs of general, reproductive, or developmental toxicity in the F0 or F1 animals or F2 implants. Based on the lack of any dose-related or biologically relevant effects on fertility, reproduction, development, and overall health of rats gavaged with PEG-PVA grafted copolymer and their progeny, the no-observed-adverse effect level (NOAEL) was determined to be the highest dose tested of 1000mg/kg bw/day. 23627717 Modeling of multiple equilibria in the self-aggregation of di-n-decyldimethylammonium chloride/octaethylene glycol monododecyl ether/cyclodextrin ternary systems. The surface tension equations of binary surfactant mixtures (di-n-decyldimethylammonium chloride and octaethylene glycol monododecyl ether) are established by combining the Szyszkowski equation of surfactant solutions, the ideal or nonideal mixing theory and the phase separation model. For surfactant mixtures, the surface tension at the air-water interface is calculated using nonideal theory due to synergism between the two adsorbed surfactant types. The incorporation of cyclodextrin complexation model to the surface tension equations gives a robust model for the description of the surface tension isotherms of binary, ternary and more complex systems involving numerous inclusion complexes. The surface tension data obtained experimentally shows excellent agreement with the theoretical model below and above the formation of micelles. The strong synergistic effect observed between the two surfactants is disrupted by the presence of CDs, leading to ideal behavior of ternary systems. Indeed, depending on the nature of the cyclodextrin (i.e. ,  or ) which allows a tuning of the cavity size, the binding constants with the surfactants are modified as well as the surface properties due to strong modification of equilibria involved in the ternary mixture. 23579962 VERY HIGH PREVALENCE OF ULTRASOUND THYROID SCAN ABNORMALITIES IN HEALTHY VOLUNTEERS IN MODENA, ITALY. Background: Italy is characterized by high prevalence of goiter. To date, only limited data about the prevalence of goiter in the Italian adult population are available. Aim. To investigate the prevalence of thyroid ultrasound abnormalities in adults unaware of any thyroid disease and evaluate the rate of differentiated thyroid cancer (DTC) obtained by this intervention. Methods. US thyroid scan was performed in adult volunteers recruited by advertisement in Modena, Italy. 135 women and 66 men (n= 201), unaware of any thyroid disease (mean age of 46 ± 10.7 years) underwent their first thyroid US scan. Results. US thyroid abnormalities were found in 101 subjects (50.3%): 91 nodular goiters (45.2%) and 13 US-thyroiditis (6.5%) associated with positive auto-antibodies in 11 of them. 17 subjects (18%) with nodules underwent US-FNAB with the following cytological class (C) outcome: 14 patients C2 (82 %), 1 patient C3 (6 %), 2 patients had C4 (12%), the latter received histological confirmation. Conclusions. The prevalence of thyroid abnormalities, is very high in subjects unaware of any thyroid disease. DTC was found in 1% of subjects and in 2% of those affected by nodular goiter. Compared to the detection rate of the well-established screening programs for breast (0.45%) and colorectal (0.27%) cancer, the prevalence of DTC seems to be much higher. Thyroid US screening could allow the detection of DTC in asymptomatic subjects and this diagnosis often includes DTC at an advanced stage. Thus, US screening not necessarily results in the over-diagnosis of clinically not relevant thyroid diseases. 23220617 Chemotherapy modulates the biological activity of breast cancer patients plasma: the protective properties of black chokeberry extract. In breast cancer patients (before and during anti-cancer therapy) oxidative/nitrative damage to various molecules is observed. Furthermore, anti-cancer treatments may also influence the hemostatic properties of blood platelets and plasma. The aim of our study was to assess the effect of oxidative/nitrative stress (estimated by measurements of the levels of carbonyl groups and 3-nitrotyrosine in proteins--ELISA and C-ELISA methods, respectively; lipid peroxidation and total antioxidant level--TAS) on the selected parameters of hemostatic activity of plasma (the process of fibrin polymerization and lysis) collected from breast cancer patients after surgery and after various phases of chemotherapy (doxorubicin and cyclophosphamide). Subsequently, we also evaluated the level of oxidative/nitrative stress and hemostatic activity in plasma from these patients in the presence of the commercial extract of Aronia melanocarpa (Aronox®) in vitro. Patients were hospitalized in Department of Oncological Surgery and Department of Chemotherapy in Medical University of Lodz, Poland. We observed increased levels of biomarkers of oxidative/nitrative stress in plasma from patients with breast cancer (before or after surgery and after various phases of chemotherapy) in comparison to healthy group. Our further experiments demonstrated the hemostatic activity of plasma from the investigated patients differs from hemostatic properties of plasma obtained from healthy volunteers. We also recognize the existence of a relationship between oxidative stress (measured by the level of carbonyl groups) and changes of hemostasis in breast cancer patients after I and IV phases of chemotherapy. Moreover, the obtained results showed that the commercial extract from A. melanocarpa berries significantly reduced, in in vitro system, the oxidative/nitrative stress and hemostasis changes in plasma from breast cancer patients, after surgery and different phases of chemotherapy. Considering the data presented in this study, we suggest that the oxidative/nitrative stress in plasma obtained from breast cancer patients (not only before or after the surgery, but also after various phases of doxorubicin and cyclophosphamide chemotherapy) may induce changes of hemostatic activity, which may contribute to thrombosis in these patients. Our results also suggest that the commercial extract of A. melanocarpa may be regarded as a promising new source of bioactive antioxidant natural compounds for breast cancer patients. 23379362 Petroacetylene, a new polyacetylene from the marine sponge Petrosia solida that inhibits blastulation of starfish embryos. A new C(30) linear polyacetylene compound designated petroacetylene (1) has been isolated from the marine sponge Petrosia solida Hoshino 1981, collected off the coast of Amami-Oshima, Kagoshima Prefecture, Japan. The structure was elucidated on the basis of spectroscopic data and chemical means. Petroacetylene (1) inhibited blastulation of starfish embryos at a concentration of 3.1 μg mL(- 1) or greater. 23500772 Activation of ALDH2 with ethanol attenuates diabetes induced myocardial injury in rats. This study assessed changes in myocardial ALDH2 expression in the diabetic rat, in particular the diabetic rat pretreated with ALDH2 activator ethanol (EtOH). The rats were divided into six groups: control, EtOH control, diabetic rat at 4th week (DM4W), 8th week (DM8W), 12th week (DM12W) and EtOH+DM8W groups. Compared with control group, fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c) levels were increased in DM groups. HbA1c level in DM12W group was higher than in DM4W group, HbA1c level in EtOH+DM8W group was lower than in DM8W group. Compared with control group, there were no changes of LVDP, HR and ±dp/dtmax in DM4W group, but there were decreased in DM8W and DM12W groups, and increased in the EtOH+DM8W group. In DM groups, SOD activity, ALDH2 mRNA and protein levels were reduced, MDA content was increased compared with control group; which decreased further as diabetes progressed. Compared with DM8W group, SOD and ALDH2 in EtOH+DM8W group was increased, MDA was decreased. Our results indicated with the development of diabetes, myocardial ALDH2 expression was further decreased accompanying decreased ventricular function. However, activation of ALDH2 can decrease diabetes induced myocardial injury. ALDH2 may be one key endogenous cardiac protective factor in diabetic individuals. 23066821 Two new alkaloids from marine sponge Callyspongia sp. Two new alkaloids, callylactam A (1) and callyimine A (4), along with three known ones (2, 3 and 5), were isolated from the marine sponge Callyspongia sp. The structures were determined on the basis of NMR and MS analysis. 23027517 Light induced nanowire assembly: the electrostatic alignment of semiconductor nanowires into functional macroscopic yarns. The electrostatic alignment and directed assembly of semiconductor nanowires into macroscopic, centimeter-long yarns is demonstrated. Different morphologies can be produced, including longitudinally segmented/graded yarns or mixed composition fibers. Nanowire yarns display long range photoconductivities and open up exciting opportunities for potential use in future nanowire-based textiles or in solar photovoltaics. 23160934 Comparison of the structural characteristics of Cu(2+)-bound and unbound α-syn12 peptide obtained in simulations using different force fields. The effects of Cu(2+) binding and the utilization of different force fields when modeling the structural characteristics of α-syn12 peptide were investigated. To this end, we performed extensive temperature replica exchange molecular dynamics (T-REMD) simulations on Cu(2+)-bound and unbound α-syn12 peptide using the GROMOS 43A1, OPLS-AA, and AMBER03 force fields. Each replica was run for 300 ns. The structural characteristics of α-syn12 peptide were studied based on backbone dihedral angle distributions, free-energy surfaces obtained with different reaction coordinates, favored conformations, the formation of different Turn structures, and the solvent exposure of the hydrophobic residues. The findings show that AMBER03 prefers to sample helical structures for the unbound α-syn12 peptide and does not sample any β-hairpin structure for the Cu(2+)-bound α-syn12 peptide. In contrast, the central structure of the major conformational clusters for the Cu(2+)-bound and unbound α-syn12 peptide according to simulations performed using the GROMOS 43A1 and OPLS-AA force fields is a β-hairpin with Turn(9-6). Cu(2+) can also promote the formation of the β-hairpin and increase the solvent exposure of hydrophobic residues, which promotes the aggregation of α-syn12 peptide. This study can help us to understand the mechanisms through which Cu(2+) participates in the fibrillation of α-syn12 peptide at the atomic level, which in turn represents a step towards elucidating the nosogenesis of Parkinson's disease. 23624380 Inhibition of TGF-β1/Smad signal pathway is involved in the effect of Cordyceps sinensis against renal fibrosis in 5/6 nephrectomy rats. The present study aimed to investigate the effects of Cordyceps sinensis on renal fibrosis and its possible mechanisms. Sprague-Dawley rats were randomly divided into three groups: sham operation (SHAM) group, 5/6 subtotal nephrectomy (SNx) untreated group, and 5/6 subtotal nephrectomy treated with C. sinensis (2.0g/kgd) (CS) group. Rats were studied 12weeks after the surgery, and the CS group presented with significantly lower proteinuria, and better renal function compared with the SNx group (p<0.05). Pathological study showed that the glomerulosclerosis tubulointerstitial injury score was significantly reduced in the CS group compared with the SNx group. Furthermore, the mRNA expression of TGF-β1, Smad2 and Smad3 and the protein expression of TGF-β1, TβRI, TβRII and p-Smad2/3 were attenuated by the C. sinensis treatment. In constrast, the mRNA and protein expression of Smad7 was upregulated. Furthermore, the expression of α-SMA and FSP1 was also significantly attenuated, accompanied by the increasing expression of E-cadherin, suggesting the inhibition of the epithelial-mesenchymal transition (EMT). In conclusion: C. sinensis exerted its antifibrotic effect on the SNx rats through the inhibition of the TGF-β1/Smad pathway. 23261705 Stimulatory effect of insulin on theca-interstitial cell proliferation and cell cycle regulatory proteins through MTORC1 dependent pathway. The present study examined the effect of insulin-mediated activation of the mammalian target of rapamycin complex 1 (MTORC1) signaling network on the proliferation of primary culture of theca-interstitial (T-I) cells. Our results show that insulin treatment increased proliferation of the T-I cells through the MTORC1-dependent signaling pathway by increasing cell cycle regulatory proteins. Inhibition of ERK1/2 signaling caused partial reduction of insulin-induced phosphorylation of RPS6KB1 and RPS6 whereas inhibition of PI3-kinase signaling completely blocked the insulin response. Pharmacological inhibition of MTORC1 with rapamycin abrogated the insulin-induced phosphorylation of EIF4EBP1, RPS6KB1 and its downstream effector, RPS6. These results were further confirmed by demonstrating that knockdown of Mtor using siRNA reduced the insulin-stimulated MTORC1 signaling. Furthermore, insulin-stimulated T-I cell proliferation and the expression of cell cycle regulatory proteins CDK4, CCND3 and PCNA were also blocked by rapamycin. Taken together, the present studies show that insulin stimulates cell proliferation and cell cycle regulatory proteins in T-I cells via activation of the MTORC1 signaling pathway. 23178221 Highly regioselective glycosylation of xylosyl-containing taxanes by Enterobacter cloaceae. Three new diglycoside taxanes (4-6) containing an additional α-d-glucose unit were obtained via Enterobacter cloaceae-mediated, highly regioselective glycosylations at OH-4 of the xylosyl moieties in 7-xylosyl taxanes (1-3). Their structures were determined on the basis of extensive spectroscopic analysis and chemical reactivity. This is the first report of an enzymatic elongation of the saccharide chain in taxanes, and the glycosylation reaction is the first described example of a transformation effected by E. cloaceae. 23633563 LXR Mediates Enhanced Hepatic Gluconeogenic Gene Expression in Adult Male Rat MPR Offspring. Epidemiological studies demonstrate that the link between impaired fetal development and glucose intolerance in later life is exacerbated by postnatal catch-up growth. Maternal protein restriction (MPR) during pregnancy and lactation in the rat has been previously demonstrated to lead to impaired glucose tolerance in adulthood, however the effects of protein restoration during weaning on glucose homeostasis are largely unknown. Recent in vitro studies have identified that the Liver X Receptor-α (LXRα) maintains glucose homeostasis by inhibiting critical genes involved in gluconeogenesis including G6Pase, 11β-HSD1 and PEPCK. Therefore, we hypothesized MPR with postnatal catch-up growth would impair LXRα in vivo, which in turn would lead to augmented gluconeogenic LXRα-target gene expression and glucose intolerance. To examine this hypothesis, pregnant Wistar rats were fed a control (20%) protein diet (C) or a low (8%) protein diet during pregnancy and switched to a control diet at birth (LP). At four months, the LP offspring had impaired glucose tolerance. In additional, LP offspring had decreased LXRα expression, while hepatic expression of 11β-HSD1 and G6Pase were significantly higher. This was concomitant with decreased binding of LXRα to the putative LXRE on 11β-HSD1 and G6Pase. Finally, we demonstrated that the acetylation of Histone H3 [K9,14] surrounding the transcriptional start site of hepatic LXRα was decreased in LP offspring, suggesting MPR-induced epigenetic silencing of the LXRα promoter. In summary, our study demonstrates for the first time the important role of LXRα in mediating enhanced hepatic gluconeogenic gene expression and consequent glucose intolerance in adult MPR offspring. 23159894 Combining multiple autosomal introns for studying shallow phylogeny and taxonomy of Laurasiatherian mammals: Application to the tribe Bovini (Cetartiodactyla, Bovidae). Mitochondrial sequences are widely used for species identification and for studying phylogenetic relationships among closely related species or populations of the same species. However, many studies of mammals have shown that the maternal history of the mitochondrial genome can be discordant with the true evolutionary history of the taxa. In such cases, the analyses of multiple nuclear genes can be more powerful for deciphering interspecific relationships. Here, we designed primers for amplifying 13 new exon-primed intron-crossing (EPIC) autosomal loci for studying shallow phylogeny and taxonomy of Laurasiatherian mammals. Three criteria were used for the selection of the markers: gene orthology, a PCR product length between 600 and 1200 nucleotides, and different chromosomal locations in the bovine genome. Positive PCRs were obtained from different species representing the orders Carnivora, Cetartiodactyla, Chiroptera, Perissodactyla and Pholidota. The newly developed markers were analyzed in a phylogenetic study of the tribe Bovini (the group containing domestic and wild cattle, bison, yak, African buffalo, Asian buffalo, and saola) based on 17 taxa and 18 nuclear genes, representing a total alignment of 13,095 nucleotides. The phylogenetic results were compared to those obtained from analyses of the complete mitochondrial genome and Y chromosomal genes. Our analyses support a basal divergence of the saola (Pseudoryx) and a sister-group relationship between yak and bison. These results contrast with recent molecular studies but are in better agreement with morphology. The comparison of pairwise nucleotide distances shows that our nuDNA dataset provides a good signal for identifying taxonomic levels, such as species, genera, subtribes, tribes and subfamilies, whereas the mtDNA genome fails because of mtDNA introgression and higher levels of homoplasy. Accordingly, we conclude that the genus Bison should be regarded as a synonym of Bos, with the European bison relegated to a subspecies rank within Bos bison. We compared our molecular dating estimates to the fossil record in order to propose a biogeographic scenario for the evolution of Bovini during the Neogene. 23147715 Gamma-radiation induced formation of chromium oxide nanoparticles from dissolved dichromate. The formation of chromium oxide nanoparticles by gamma radiolysis of Cr(VI) (CrO(4)(2-) or Cr(2)O(7)(2-)) solutions was investigated as a function of pH and initial Cr(VI) concentration by measuring [Cr(VI)], the particle concentration ([Cr(III)(col)]) and [H(2)], and by characterizing the particles using TEM, Raman, FTIR and XPS. The results show that Cr(VI) is easily reduced to Cr(III) by a homogeneous aqueous reaction with ˙e(aq)(-), but, due to the stability of Cr(III) colloids, the growth of the Cr(OH)(3) particles is very slow. As the particles grow the interior of the particle dehydrates to form Cr(2)O(3) while the outer layer remains hydrated. When most of the Cr(VI) that is initially present in the solution is converted to Cr(OH)(3) further redox reactions of chromium species occur on the particle surfaces. The redox system reaches a pseudo-equilibrium state due to cyclic reactions of Cr(III) with ˙OH and H(2)O(2), and reactions of Cr(VI) with ˙e(aq)(-) and H(2)O(2). The size distribution of the particles that are formed is controlled by these solution-solid interface reactions. 22317823 Lethality, accumulation and toxicokinetics of aluminum in some tissues of male albino rats. In the present work, the lethality percentiles including median lethal doses (LD50), accumulation, distribution and toxicokinetics of aluminum in the liver, kidney, intestine, brain and serum of male albino rats, following a single oral administration were studied throughout 1, 3, 7, 14 and 28 days. The estimated LD50 at 24 h was 3.45 g Al/kg body weight (b.wt.). The utilized dose of Al was 1/50 LD50 (0.07 g Al/kg b.wt.). Aluminum residues, in Al-treated rats, were significantly decreased in response to the experimental periods and were negatively correlated with time. In addition, the hepatic, renal, intestinal, brain and serum Al contents were significantly higher than the corresponding controls at all experimental periods, except the brain that showed significant depletion when compared with its corresponding control after 28 days. Kinetically, the highest average of Al area under concentration - time curves (AUCtotal, μg/g day) and area under moment concentration - time curves (AUMCtotal, µg/g day(2)) recorded in the brain followed by kidney, serum, intestine and liver. The longest elimination half-life time (t 1/2, day) and the mean residence time (MRT, day) were recorded in the brain followed by the liver, kidney, serum and intestine. On the other hand, the slowest clearance rates (Cls, L/day) of Al, in order, were recorded in brain, kidney, serum, intestine and the liver. The elimination rate constant (Lz, day(-) (1)) of Al from the brain was less than that in the intestine and serum was less than that in the liver and kidney. The computed maximum concentrations (C max) of Al in the intestine > kidney > serum > brain > liver were recorded after 3, 3.8, 2.2, 5.4 and 3.8 days, respectively. The computed starting concentration (C 0, μg) of Al in serum was higher than its level in the intestine followed by the brain, kidney and liver. 23598904 Suppression of ZIP8 expression is a common feature of cadmium-resistant and manganese-resistant RBL-2H3 cells. Rat basophilic leukemia RBL-2H3 cells show markedly high sensitivity to both CdCl2 and MnCl2 compared with other rat cell lines, due to efficient accumulation of cadmium and manganese. To clarify the roles of metal transporters in hyperaccumulation of cadmium and manganese in RBL-2H3 cells, Cd-resistant and Mn-resistant cells were developed from RBL-2H3 cells by continuous exposure to CdCl2 and MnCl2, respectively. The established Cd-resistant (RBL-Cdr) and Mn-resistant (RBL-Mnr) cells exhibited about 20 times higher LC50 values of CdCl2 and MnCl2, respectively, than parental RBL-2H3 cells, and showed cross-resistance to each metal. The resistance to cadmium and manganese was primarily conferred by a marked decrease in the uptake of both metals. RBL-Cdr cells also showed cross-resistance to HgCl2 and AgNO3 probably due to enhanced expression of metallothionein. Among the possible transporters involved in the uptake of Cd(2+) and Mn(2+), the expression of ZIP8 (Zrt-, Irt-related protein 8), encoded by Slc39a8, showed a marked suppression in both RBL-Cdr and RBL-Mnr cells. These results suggest that ZIP8 plays a pivotal role in the transport and toxicity of Cd(2+) and Mn(2+) in RBL-2H3 cells. 23517093 Genomics-Guided Discovery of Thailanstatins A, B, and C As Pre-mRNA Splicing Inhibitors and Antiproliferative Agents from Burkholderia thailandensis MSMB43. Mining the genome sequence of Burkholderia thailandensis MSMB43 revealed a cryptic biosynthetic gene cluster resembling that of FR901464 (4), a prototype spliceosome inhibitor produced by Pseudomonas sp. No. 2663. Transcriptional analysis revealed a cultivation condition in which a regulatory gene of the cryptic gene cluster is adequately expressed. Consequently, three new compounds, named thailanstatins A (1), B (2), and C (3), were isolated from the fermentation broth of B. thailandensis MSMB43. Thailanstatins are proposed to be biosynthesized by a hybrid polyketide synthase-nonribosomal peptide synthetase pathway. They differ from 4 by lacking an unstable hydroxyl group and by having an extra carboxyl moiety; those differences endow thailanstatins with a significantly greater stability than 4 as tested in phosphate buffer at pH 7.4. In vitro assays showed that thailanstatins inhibit pre-mRNA splicing as potently as 4, with half-maximal inhibitory concentrations in the single to sub-μM range. Cell culture assays indicated that thailanstatins also possess potent antiproliferative activities in representative human cancer cell lines, with half-maximal growth inhibitory concentrations in the single nM range. This work provides new chemical entities for research and development and new structure-activity information for chemical optimization of related spliceosome inhibitors. 23561135 4-Methyl-7-hydroxycoumarin antifungal and antioxidant activity enhancement by substitution with thiosemicarbazide and thiazolidinone moieties. According to literature data, thiosemicarbazide and thiazolidinone moieties should enhance biological properties of coumarin. Antioxidant, metal-chelating and antifungal activities of all compounds were investigated and compared to the activity of the starting material, 7-hydroxy-4-methylcoumarin, and were proven to possess potent antioxidant and antifungal activity. In general, thiosemicarbazides showed higher scavenging activity towards DPPH and galvinoxyl radicals than did 4-thiazolidinones and some of them had the same or even better activity than had ascorbic acid itself, depending on the free radical used. In antifungal activity tests towards four foodborne mycotoxigenic fungi, Aspergillus flavus, Aspergillus ochraceus. Fusarium graminearum and Fusarium verticillioides, coumarin derivatives were proven to possess a very high activity in terms of growth inhibition, depending on the fungi investigated. In general, 4-thiazolidinones showed better antifungal activity than did thiosemicarbazides. F. graminearum was the most susceptible to the compounds investigated and F. verticillioides was proven to be the most resistant. Two compounds, both coumarinyl thiosemicarbazides, were found to possess both antifungal and antioxidant activity which could be useful for applications in medicine, food industry and agriculture. 23301701 Effects of water concentration on the structural and diffusion properties of imidazolium-based ionic liquid-water mixtures. We have used molecular dynamics simulations to study the properties of three ionic liquid (IL)-water systems: 1-butyl-3-methylimidazolium chloride ([bmim]Cl), 1-ethyl-3-methylimidazolium acetate ([emim][Ac]), and 1,3-dimethylimidazolium dimethylphosphate ([dmim][DMP]). We observe the transition of those mixtures from pure IL to aqueous solution by analyzing the changes in important bulk properties (density) and structural and bonding properties (radial distribution functions, water clustering, hydrogen bonding, and cationic stacking) as well as dynamical properties (diffusion coefficients) at 12 different concentration samplings of each mixture, ranging from 0.0 to 99.95 mol % water. Our simulations revealed across all of the different structural, bonding, and dynamical properties major structural changes consistent with a transition from IL-water mixture to aqueous solution in all three ILs at water concentrations around 75 mol %. Among the structural changes observed were rapid increase in the frequency of hydrogen bonds, both water-water and water-anion. Similarly, at these critical concentrations, the water clusters formed begin to span the entire simulation box, rather than existing as isolated networks of molecules. At the same time, there is a sudden decrease in cationic stacking at the transition point, followed by a rapid increase near 90 mol % water. Finally, the diffusion coefficients of individual cations and anions show a rapid transition from rates consistent with diffusion in IL's to rates consistent with diffusion in water beginning at 75 mol % water. The location of this transition is consistent, for [bmim]Cl and [dmim][DMP], with the water concentration limit above which the ILs are unable to dissolve cellulose. 23180692 Mitigating with macrophytes: submersed plants reduce the toxicity of pesticide-contaminated water to zooplankton. In ecotoxicology, appreciation is growing for the influence that ecological interactions have on the toxicity of contaminants, such as insecticides, to sensitive species. Most previous studies, however, have focused on factors that exacerbate insecticide effects on species, while factors that may mitigate these effects have been relatively ignored. In aquatic habitats, a small number of studies have shown that submersed macrophytes can remove some insecticides from the water column via sorption. Although examining sorption dynamics is important for understanding the environmental fate of insecticides, whether and to what extent macrophytes actually mitigate insecticide effects on aquatic species remains unknown. In the present study, the authors examined how much and how quickly several realistic densities of the macrophyte Elodea canadensis decreased the toxicity of the insecticide malathion to Daphnia magna, a keystone aquatic herbivore. To do this, the authors quantified Daphnia survival in outdoor test systems (0.95 L) exposed to a factorial combination of five Elodea densities crossed with five malathion concentrations. The authors discovered that malathion's lethality to Daphnia decreased with increasing Elodea density. Furthermore, the rate at which Elodea reduced malathion's toxicity in the water column increased with macrophyte density. These results provide strong evidence that submersed macrophytes can mitigate the ecological impacts of a popular insecticide and further support that ecological interactions can strongly influence contaminant environmental effects. 23305465 Meroterpenoid pigments from the basidiomycete Albatrellus ovinus. Eight grifolin derivatives, involving three new monomers, albatrelins A-C (1-3), three novel dimers (meroterpenoid pigments), albatrelins D-F (4-6), and two known ones, 6a,7,8,9,10,10a-hexahydro-3,6,9-trimethyl-6-(4-methyl-3-penten-1-yl)-1,9-epoxy-6H-dibenzo[b,d]pyran (7) and confluentin (8), were isolated from Albatrellus ovinus. Their structures were established by extensive spectroscopic analysis. The absolute configurations of compounds 2-4 were determined as 9R by comparing their optical rotations with data reported in the literature. Albatrelin F (6) was isolated as a pair of C-2' tautomers with a ratio of 1.3:1. Confluentin (8) showed weak cytotoxicity against four human tumor cell lines, HL-60, SMMC-7712, A-549, and MCF-7, in vitro. 22712581 Isolation, characterisation and biological evaluation of a phenoxazine, a natural dyestuff isolated from leaves of Peristrophe bivalvis. Peristrophe bivalvis (L.) Merr. (Acanthaceae) is a wild growing and cultivated plant used for dyeing of foods by the ethnic minorities of Vietnam. The major component of the colour aqueous extract (CAE) of its leaves was identified as peristrophine by spectral analysis, especially the 2D NMR spectra (HSQC, HMBC and NOESY). Considering the widespread utilisation of the decoction of this plant for food dyeing, we evaluated the acute oral toxicity of the CAE. Based on the results in an acute toxicity study in mice, the LD50 value of the CAE was determined as 9100 ± 290 mg kg(-1) body weight. Additionally, in vitro cytotoxic assay showed an inhibition of peristrophine against Hepatocellular carcinoma (HepG2, IC503.90 µg mL(-1)). CAE and peristrophine (1) have also been tested for their ability to affect the cell number of the OCI acute myeloid leukaemia cell line. CAE and peristrophine significantly decreased the OCI cell number at different concentrations and times of treatment. 23411185 Comparative analysis of nutritional compositions of transgenic high iron rice with its non-transgenic counterpart. Iron is an essential micronutrient for human nutrition and polished rice contains very low amount of iron. Rice with high iron content in seed endosperm has been developed by insertion of soybean ferritin gene under the control of the endosperm specific glutelin promoter into the genome of indica rice line IR68144. The nutritional composition of the brown and milled rice grain has been compared with that of the non-transgenic rice of the same variety. In this study, the nutritional components, as well as the anti-nutrient levels, were measured. Our studies established that apart from the increased level of iron and zinc in transgenic seeds, the nutritional quality of both the brown and milled rice grains from the transgenic line was substantially equivalent to that of the non-transgenic rice plants. The result clearly shows that the measured amounts of the nutritional components are well within the range of values reported for other commercial lines. 23528300 Design and synthesis of 2-substituted benzoxazoles as novel PTP1B inhibitors. A series of benzoxazole compounds containing oxamic acid were synthesized and screened for the PTP1B inhibition. Compound 31d showed best biochemical potency (Ki) of 6.7μM. Structure-activity relationship were explained with the help of molecular modeling approach. 23155201 The scintigraphic evaluation and genetic correlation of joint involvements in pediatric patients with familial Mediterranean fever. Purpose: We aimed to evaluate the articular involvements in pediatric patients with familial Mediterranean fever (FMF) with joint symptoms by bone scintigraphy and to correlate the involved joints with the gene mutations. Materials and methods: A total of 41 newly diagnosed patients in pediatric age group (28 girls and 13 boys; mean age 9.14 ± 2.91 years) with joint involvement symptoms were included in this study. Scintigraphic images were obtained at 5th min (blood pool or early phase) and starting at 3 h (late phase) after (after tracer injection) intravenous administration of technetium-99m (99mTc)-methylendiphosphonate (MDP). Genomic DNA was isolated from leukocytes using standard salting out procedure. The sequencing data were analyzed. Results: Of the 41 patients, arthritis was found in 21 (51.2%) patients. Of the 21 patients, there was single joint involvement in 15 (71.4%) patients and multiple joint involvement in six (28.6%) patients. The mean age of patients with joint involvement (8 ± 2.3 years) were considerably lower than the patients without joint involvement (10.35 ± 3.04 years), and this was statistically significant (p = 0.008). The most commonly involved joints were ankles and knees. Multiple joint involvements were most frequently observed in the M694V and M694I gene mutations (16.7%). Conclusions: We use and recommend the bone scintigraphy in patients with FMF to determine the presence and distribution of arthritis, since bone scintigraphy is inexpensive, noninvasive, easy-to-use, and also is more sensitive in the diagnosis and distribution of arthritis than conventional radiological methods and clinical examination. 23063593 Herbacetin induces apoptosis in HepG2 cells: Involvements of ROS and PI3K/Akt pathway. Herbacetin (HER) is a natural flavonoid compound that can be extracted from Ramose Scouring Rush Herb, and its biological and pharmacological activities lack of corresponding attention. In this study, the apoptotic effect of HER against the human hepatoma cell line (HepG2) was investigated. The results showed that HepG2 cells apoptosis occurred in a dose-dependent manner within 48h incubated with HER, which was confirmed by DNA fragmentation, nuclear shrinkage, and poly (ADP-ribose) polymerase (PARP) cleavage. HER at 25-100μM induced a mitochondria-dependent apoptotic pathway associated with Bcl-2/Bax ratio decrease, mitochondrial membrane potential (ΔΨ) collapse, cytochrome c release, and caspase-3 activation. Increasing expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) was also observed in HER-treated cells. Furthermore, the addition of a ROS inhibitor (N-Acetyl-l-cysteine, NAC) significantly attenuated the apoptosis induced by HER and also blocked the expression of PGC-1α protein. Additionally, HER effectively inhibited the phosphorylation of Akt and the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002 increased the inhibition effect of HER on Akt phosphorylation. These findings provide evidences that HER induces HepG2 apoptosis in a ROS-mediated mitochondria-dependent manner that correlate with the inactivation of the PI3K/Akt pathway. 22975146 Alpha-asarone from Acorus gramineus alleviates epilepsy by modulating A-type GABA receptors. Alpha (α)-asarone is a major effective compound isolated from the Chinese medicinal herb Acorus gramineus, which is widely used in clinical practice as an antiepileptic drug; however, its mechanism of action remains unclear. In this study, we have characterized the action of α-asarone on the excitability of rat hippocampal neurons in culture and on the epileptic activity induced by pentylenetetrazole or kainate injection in vivo. Under cell-attached configuration, the firing rate of spontaneous spiking was inhibited by application of α-asarone, which was maintained in the Mg(2+)-free solution. Under whole-cell configuration, α-asarone induced inward currents in a concentration-dependent manner with an EC(50) of 248 ± 33 μM, which was inhibited by a GABA(A) receptor blocker picotoxin and a competitive GABA(A) receptor antagonist bicuculline but not a specific glycine receptor inhibitor strychnine. Measurement of tonic GABA currents and miniature spontaneous inhibitory postsynaptic currents indicated that α-asarone enhanced tonic GABAergic inhibition while left phasic GABAergic inhibition unaffected. In both pentylenetetrazole and kainate seizure models, α-asarone suppressed epileptic activity of mice by prolonging the latency to clonic and tonic seizures and reducing the mortality as well as the susceptibility to seizure in vivo presumably dependent on the activation of GABA(A) receptors. In summary, our results suggest that α-asarone inhibits the activity of hippocampal neurons and produces antiepileptic effect in central nervous system through enhancing tonic GABAergic inhibition. 23280101 Initiation of autophagy and apoptosis by sonodynamic therapy in murine leukemia L1210 cells. Sonodynamic therapy (SDT) has shown great potential in target cancer therapy, but it induced cell death modes has not been fully investigated. This study was to examine autophagic and apoptotic responses to protoporphyrin IX (PpIX) mediated SDT in murine leukemia L1210 cells. After SDT, the occurrence of autophagy was identified by morphological observation and biochemical analysis. Meanwhile, the mitochondria dependent apoptosis pathway was examined to participate in SDT induced cell death. The relationship between autophagy and apoptosis was further investigated by applying pharmacological inhibition studies, which indicated that impairment of autophagy enhanced the anti-tumor effect of SDT through induction of apoptosis and necrosis, while caspase inhibition did not affect autophagic vacuoles formation or protect SDT induced cytotoxicity. The findings supported that autophagic vacuoles formed upstream and independently from caspase-dependent cell death. Additionally, the possible mechanism of SDT-induced autophagy was evaluated by measurement of ROS (reactive oxygen species) formation. Result suggested ROS play important role in initiating autophagy, possibly through the sono-damaged mitochondria being enclosed by autophagic vacuoles. All together, these data indicate that autophagy may be cytoprotective in our experimental system, and point to an important insight into how autophagy inhibitors, in combination with SDT may contribute a regimen for cancer therapy. 23567999 Identification, structural and pharmacological characterization of τ-CnVA, a conopeptide that selectively interacts with somatostatin sst3 receptor. Conopeptides are a diverse array of small linear and reticulated peptides that interact with high potency and selectivity with a large diversity of receptors and ion channels. They are used by cone snails for prey capture or defense. Recent advances in venom gland transcriptomic and venom peptidomic/proteomic technologies combined with bioactivity screening approaches lead to the identification of new toxins with original pharmacological profiles. Here, from transcriptomic/proteomic analyses of the Conus consors cone snail, we identified a new conopeptide called τ-CnVA, which displays the typical cysteine framework V of the T1-conotoxin superfamily. This peptide was chemically synthesized and its three-dimensional structure was solved by NMR analysis and compared to that of TxVA belonging to the same family, revealing very few common structural features apart a common orientation of the intercysteine loop. Because of the lack of a clear biological function associated with the T-conotoxin family, τ-CnVA was screened against more than fifty different ion channels and receptors, highlighting its capacity to interact selectively with the somatostatine sst3 receptor. Pharmacological and functional studies show that τ-CnVA displays a micromolar (Ki of 1.5μM) antagonist property for the sst3 receptor, being currently the only known toxin to interact with this GPCR subfamily. 23580375 Solvent-induced delamination of a multifunctional two dimensional coordination polymer (adv. Mater. 15/2013). Unprecedented full delamination of a multifunctional 2D metal-organic framework (MOF) assisted only by solvent interaction is carried out on page 2141 by Félix Zamora, Salome Delgado, and co-workers. This observation is a direct consequence of the structure of the starting material, characterized by interlayer cavities that can be filled by the solvent molecules, producing delamination in a simple and reproducible way. 23345125 Conjugated oligoelectrolytes increase power generation in E. coli microbial fuel cells. A series of conjugated oligoelectrolytes with structural variations is used to stain E. coli. By taking advantage of a high-throughput screening platform that incorporates gold anodes, it is found that MFCs with COE-modified E. coli generate significantly higher power densities, relative to unmodified E. coli. These findings highlight the potential of using water-soluble molecules inspired by the work on organic semiconductors to improve electrode/microbe interfaces. 23219590 Mechanism of maprotiline-induced apoptosis: role of [Ca2+](i), ERK, JNK and caspase-3 signaling pathways. Antidepressants are generally used for treatment of various mood and anxiety disorders. Several studies have shown the anti-tumor and cytotoxic activities of some antidepressants, but the underlying mechanisms were unclear. Maprotiline is a tetracyclic antidepressant and possesses a highly selective norepinephrine reuptake ability. We found that maprotiline decreased cell viability in a concentration- and time-dependent manner in Neuro-2a cells. Maprotiline induced apoptosis and increased caspase-3 activation. The activation of caspase-3 by maprotiline appears to depend on the activation of JNK and the inactivation of ERK. Maprotiline also induced [Ca(2+)](i) increases which involved the mobilization of intracellular Ca(2+) stored in the endoplasmic reticulum. Pretreatment with BAPTA/AM, a Ca(2+) chelator, suppressed maprotiline-induced ERK phosphorylation, enhanced caspase-3 activation and increased maprotiline-induced apoptosis. In conclusion, maprotiline induced apoptosis in Neuro-2a cells through activation of JNK-associated caspase-3 pathways. Maprotiline also evoked an anti-apoptotic response that was both Ca(2+)- and ERK-dependent. 23639248 Bone Morphogenetic Protein-7 inhibits silica-induced pulmonary fibrosis in rats. Bone morphogenetic protein-7 (BMP-7) has been shown to inhibit liver and renal fibrosis in in vivo and in vitro studies. There is no study to investigate BMP-7's role in the development of pulmonary fibrosis induced by silica. In the current study, we used the rat model to explore the potential antifibrotic role of BMP-7 and its underlying mechanism in silica-induced pulmonary fibrosis. Sixty Wistar rats were randomly assigned into three groups. Control group received saline, silica group received silica and BMP-7 treated group received silica and BMP-7. BMP-7 was administered to silica-treated rats intraperitoneally at a dose of 300μg/kg/injection from day 8 to day 30 every other day. After the animals were sacrificed on day 15 and 30, hydroxyproline levels, the protein expressions of BMP/Smad and TGF-β/Smad signaling, and histopathology in lung tissues were analyzed. The hydroxyproline contents in BMP-7 treated groups were significantly lower than the silica groups (P<0.05). Histopathological results showed BMP-7 could reduce the progression of silica induced fibrosis. Furthermore, the expression of p-Smad1/5/8, a marker of BMP/Smad signaling, was significantly up-regulated in BMP-7 treated groups (P<0.05) compared with the silica groups. On the contrary, the expression of p-Smad2/3, a marker for TGF-β/Smad signaling, reduced significantly in BMP-7-treated groups compared with silica groups (P<0.05). In conclusion, the pulmonary fibrosis induced by silica in rats was significantly reduced with the therapeutic treatment of BMP-7. The antifibrotic effect of BMP-7 could be related to the activation of BMP/Smad signaling and inhibition of TGF-β/Smad pathways. 23506497 The heart in sepsis: from basic mechanisms to clinical management. Septic shock is characterized by circulatory compromise, microcirculatory alterations and mitochondrial damage, which all reduce cellular energy production. In order to reduce the risk of major cell death and a diminished likelihood of recovery, adaptive changes appear to be activated. As a result, cells and organs may survive in a non-functioning hibernation-like condition. Sepsis-induced cardiac dysfunction may represent an example of such functional shutdown. Sepsis-induced myocardial dysfunction is common, corresponds to the severity of sepsis, and is reversible in survivors. Its mechanisms include the attenuation of the adrenergic response at the cardiomyocyte level, alterations of intracellular calcium trafficking and blunted calcium sensitivity of contractile proteins. All these changes are mediated by cytokines. Treatment includes preload optimization with sufficient fluids. However, excessive volume loading is harmful. The first line vasopressor recommended at present is norepinephrine, while vasopressin can be started as a salvage therapy for those not responding to catecholamines. During early sepsis, cardiac output can be increased by dobutamine. While early administration of catecholamines might be necessary to restore adequate organ perfusion, prolonged administration might be harmful. Novel therapies for sepsis-induced cardiac dysfunction are discussed in this article. Cardiac inotropy can be increased by levosimendan, istaroxime or omecamtiv mecarbil without greatly increasing cellular oxygen demands. Heart rate reduction with ivabradine reduces myocardial oxygen expenditure and ameliorates diastolic filling. Beta-blockers additionally reduce local and systemic inflammation. Advances may also come from metabolic interventions such as pyruvate, succinate or high dose insulin substitutions. All these potentially advantageous concepts require rigorous testing before implementation in routine clinical practice. 23384387 Novel acylethanolamide derivatives that modulate body weight through enhancement of hypothalamic pro-opiomelanocortin (POMC) and/or decreased neuropeptide Y (NPY). Newly synthesized acylethanolamide derivatives oleoyl-L-valinolamide (1), oleoyl-D-valinolamide (2), elaidoyl-L-valinolamide (3), elaidoyl-D-valinolamide (4) stearoyl-L-valinolamide (5), and palmitoyl-L-valinolamide (6) were investigated in mice as antiobesity compounds. Compounds 1, 2, 5, 6 significantly decreased body weight by 6.57% following eight injections of 1 mg/kg i.p. during 39 days, while 3 and 4 showed no such activity. Receptor binding indicated that no compound activated CB1, CB2, PPARα, or TRPV1 receptors. Hypothalamic RT-PCR showed that mRNA expression of the anorexigenic genes POMC and CART was up-regulated by 1, 2, 5 and 1, 2, respectively, while that of the orexigenic genes NPY and CaMKK2 was down-regulated by the respective compounds 1, 5, 6 and 1, 2, 5. Oleoyl-L-valinolamide enhances anorectic pathways and lead to decreased glucose levels, enhanced locomotor activity, and improved cognition. Effects of oleoyl-L-valinolamide on weight were dose-dependent, and it could be given orally. 1, 2, 4, 5 down-regulated FAAH mRNA expression. 23552852 Effects of mixtures of azole fungicides in postimplantation rat whole-embryo cultures. The effect of mixtures of azole fungicides on development of postimplantation rat whole-embryos cultured in vitro has been tested. On the basis of bench mark dose (BMD) modeling of the in vitro effect in rat embryo, the potency of 7 azoles was determined and compared. Then, relative potency factors have been derived based on either the NOAEL or on the BMD curve. Alternatively, each compound was used as index compound (IC), and IC-equivalent concentrations have been calculated for each mixture. Expected effects of such IC-equivalent concentrations of the mixture were derived from the appropriate BMD curve. Test mixture includes the agrochemicals triadimefon and imazalil (MIX2) or triadimefon, imazalil, and the clinically used fluconazole (MIX3) at their previously determined no-effect concentration, corresponding to approximately a benchmark response of 5-10 %. Subsequently, we tested the effect of a mixture of the agrochemicals triadimefon, imazalil, triadimenol, cyproconazole, tebuconazole, and flusilazole (MIX6) at concentration levels derived from their established human acceptable daily intake. MIX6 was also added with fluconazole at concentration levels indicated as the minimum therapeutically effective plasmatic concentration (MIX7A) or ten times this level (MIX7B). Generally, the experimental response was higher than the estimated one, by a factor of 2-6. Our data suggest that it is in principle correct to assume that azoles act as teratogens via a common mode of action and therefore should be grouped together for risk assessment. The synergistic effect needs to be confirmed with more combinations of concentrations/compounds in vitro and with specific in vivo experiments. 23180158 Pocket-based drug design: exploring pocket space. The identification and application of druggable pockets of targets play a key role in in silico drug design, which is a fundamental step in structure-based drug design. Herein, some recent progresses and developments of the computational analysis of pockets have been covered. Also, the pockets at the protein-protein interfaces (PPI) have been considered to further explore the pocket space for drug discovery. We have presented two case studies targeting the kinetic pockets generated by normal mode analysis and molecular dynamics method, respectively, in which we focus upon incorporating the pocket flexibility into the two-dimensional virtual screening with both affinity and specificity. We applied the specificity and affinity (SPA) score to quantitatively estimate affinity and evaluate specificity using the intrinsic specificity ratio (ISR) as a quantitative criterion. In one of two cases, we also included some applications of pockets located at the dimer interfaces to emphasize the role of PPI in drug discovery. This review will attempt to summarize the current status of this pocket issue and will present some prospective avenues of further inquiry. 23178179 Inhibition of the thyroid hormone pathway in Xenopus laevis by 2-mercaptobenzothiazole. Determining the effects of chemicals on the thyroid system is an important aspect of evaluating chemical safety from an endocrine disrupter perspective. Since there are numerous chemicals to test and limited resources, prioritizing chemicals for subsequent in vivo testing is critical. 2-Mercaptobenzothiazole (MBT), a high production volume chemical, was tested and shown to inhibit thyroid peroxidase (TPO) enzyme activity in vitro, a key enzyme necessary for the synthesis of thyroid hormone. To determine the thyroid disrupting activity of MBT in vivo, Xenopus laevis larvae were exposed using 7- and 21-day protocols. The 7-day protocol used 18-357 μg/L MBT concentrations and evaluated: metamorphic development, thyroid histology, circulating T4, circulating thyroid stimulating hormone, thyroidal sodium-iodide symporter gene expression, and thyroidal T4, T3, and related iodo-amino acids. The 21-day protocol used 23-435 μg/L MBT concentrations and evaluated metamorphic development and thyroid histology. Both protocols demonstrated that MBT is a thyroid disrupting chemical at the lowest concentrations tested. These studies complement the in vitro study used to identify MBT as a high priority for in vivo testing, supporting the utility/predictive potential of a tiered approach to testing chemicals for TPO activity inhibition. The 7-day study, with more comprehensive, sensitive, and diagnostic endpoints, provides information at intermediate biological levels that enables linking various endpoints in a robust and integrated pathway for thyroid hormone disruption associated with TPO inhibition. 23395719 Identification of polyphenols and their metabolites in human urine after cranberry-syrup consumption. As the beneficial effects of American cranberry (Vaccinium macrocarpon) can be partly attributed to its phenolic composition, the evaluation of the physiological behaviour of this fraction is crucial. A rapid and sensitive method by ultra-performance liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS) has been used to identify phenolic metabolites in human urine after a single dose of cranberry syrup. Prior to the analysis, metabolites were extracted using an optimised solid-phase extraction procedure. All possible metabolites were investigated based on retention time, accurate mass data and isotope and fragmentation patterns. Free coumaroyl hexose (isomer 1 and 2), dihydroxybenzoic acid, caffeoyl glucose, dihydroferulic acid 4-O-β-d-glucuronide, methoxyquercetin 3-O-galactoside, scopoletin, myricetin and quercetin, together with other 23 phase-I and phase-II metabolites, including various isomers, could be tentatively identified in the urine. Afterwards, the metabolites were simultaneously screened in the urine of different subjects at 0, 2, 4, and 6h after the ingestion of cranberry syrup by Target Analysis(TM) software. 23160089 Two new chromone glycosides from Drynaria fortunei. Two new chromone glycosides, drynachromoside A (1), drynachromoside B (2), along with three known flavanones, 5,7,3',5'-tetrahydroxy-flavanone (3), 5,7,3',5'-tetrahydroxy-flavanone-7-O-β-d-glucopyranoside (4), and 5,7,3',5'-tetrahydroxy-flavanone-7-O-neohesperidoside (5), were isolated from the dry rhizomes of Drynaria fortunei by means of bio-active screening. The two former compounds were elucidated on the basis of physico-chemical property and spectroscopic data. The osteoblastic proliferation activities of these flavonoids were evaluated by the method of MTT. The results showed that compound 1 exhibited the biochemical effects on the proliferation of MC3T3-E1 cells, while Compound 2 showed inhibitory effects against MC3T3-E1 cells. 23373530 Investigation of the conformational changes of a conducting polymer in gas sensor active layers by means of polarization-modulation infrared reflection absorption spectroscopy (PM-IRRAS). Polarization-Modulation Infrared Reflection Absorption Spectroscopy (PM-IRRAS) was employed to observe the changes in the molecular conformation of poly(2-phenyl-1,4-xylylene) (PPPX) films that occurred after exposure to organic solvent vapors. The PPPX films were supported on solid matrixes by casting, spin-coating, and Langmuir-Blodgett (LB) techniques. The results show that the polymer is sensitive to the solvent vapors, which affect some of the vibration dipole moments, as detected by PM-IRRAS. The sensitivity depends on the method employed to immobilize the polymer, with more significant changes in films formed using techniques that result in a less systematically organized conformation. This feature enables the use of surface vibration spectroscopy to detect organic solvent vapors and may be applied in an artificial nose. 23296102 Acrolein induces Alzheimer's disease-like pathologies in vitro and in vivo. The pathologic mechanisms of Alzheimer's disease (AD) have not been fully uncovered. Acrolein, a ubiquitous dietary pollutant and by-product of oxidative stress, can induce cytotoxicity in neurons, which might play an important role in the etiology of AD. Here, we examined the effects of Acrolein on the AD pathologies in vitro and in vivo. We found Acrolein induced HT22 cells death in concentration- and time-dependent manners. Interestingly, Acrolein increased proteins' levels of amyloid precursor protein (APP), β-secretase (BACE-1) and the amyloid β-peptide transporter receptor for advanced glycation end products, and decreased A-disintegrin and metalloprotease (ADAM) 10 levels. In vivo, chronic oral exposure to Acrolein (2.5 mg/kg/day by intragastric gavage for 8 weeks) induced mild cognitive declination and pyknosis/atrophy of hippocampal neurons. The activity of superoxide dismutase was down-regulated while the level of malondialdehyde was up-regulated in rat brain. Moreover, Acrolein resulted in activation of astrocytes, up-regulation of BACE-1 in cortex and down-regulation of ADAM-10 in hippocampus and cortex. Taken together, our findings suggest that exposure to Acrolein induces AD-like pathology in vitro and in vivo. Scavenging Acrolein might be beneficial for the therapy of AD. 23211364 AT1 receptor antagonism is proangiogenic in the brain: BDNF a novel mediator. Candesartan is an angiotensin II type 1 receptor blocker (ARB) that has been to shown to limit ischemic stroke and improve stroke outcome. In experimental stroke, candesartan induces a proangiogenic effect that is partly attributable to vascular endothelial growth factor. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family that has been reported to have angiogenic effects and play an important role in recovery after stroke. The purpose of this investigation was to determine the role of BDNF in the proangiogenic effect of candesartan in the brain under hypertensive conditions. Accordingly, spontaneously hypertensive rats were treated with candesartan, and brain tissue samples were collected for quantification of BDNF expression. In addition, human cerebromicrovascular endothelial cells were treated with either low-dose (1 ƒM) or high-dose (1 µM) angiotensin II alone or in combination with candesartan (0.16 µM) to assess the effect of candesartan treatment and BDNF involvement in the behavior of endothelial cells. Candesartan significantly increased the expression of BDNF in the SHR (P < 0.05). In addition, candesartan reversed the antiangiogenic effect of the 1-µM dose of AngII (P = 0.0001). The observed effects of candesartan were ablated by neutralizing the effects of BDNF. Treatment with the AT2 antagonist PD-123319 significantly reduced tube-like formation in endothelial cells. AT2 stimulation induced the BDNF expression and migration (P < 0.05). In conclusion, candesartan exerts a proangiogenic effect on brain microvascular endothelial cells treated with angiotensin II. This response is attributable to increased BDNF expression and is mediated through stimulation of the AT2 receptor. 23177784 Rigid 5'-6-locked phenanthroline-derived nucleosides chelated to ruthenium and europium ions. We describe complexes of ruthenium and europium with rigid, 5'-6-locked 1,10-phenanthroline-containing nucleosides. Both nucleosides were synthesized from condensation of 5-amino-2'-deoxycytidine with the corresponding diketone. The ruthenium nucleoside displayed fluorescence characteristic of polypyridine ruthenium complexes with a maximum at 616 nm and a quantum yield of 0.011. Binding of europium to the 1,10-phenanthroline-2,9-diacid moiety of the lanthanide binding nucleoside showed formation of a 1:1 complex with emission at 570-630 nm, whose emission was enhanced by addition of two phenanthroline ligands. The lanthanide-binding nucleoside was incorporated into DNA oligonucleotides and shown to selectively bind one equivalent of europium ions. 22996932 Dual imaging and photoactivated nanoprobe for controlled cell tracking. A photoactivated nanoprobe for cell labeling and tracking is demonstrated. The nanoprobe enables all targeted cells to be imaged (at 680 nm) as well as specific cells to be photoactivated using 405 nm light. Photoactivated cells can then be tracked (at 525 nm) spatiotemporally in a separate channel over prolonged periods. 23583203 Hsp70 silencing with siRNA in nanocarriers enhances cancer cell death induced by the inhibitor of Hsp90. Inducers of heat shock protein 70 (Hsp70) commonly promote cancer cell viability whereas inhibitors of Hsp90 reduce it. The anticancer agent celastrol, interferes with signal transduction pathways involving these heat shock proteins. The objective of this in vitro study was to silence inducible Hsp70 and to promote celastrol-induced tumor cell death. Hsp70 siRNA loaded chitosan-TPP carriers were prepared by ionic gelation and characterized by photon correlation spectroscopy and asymmetric flow field-flow fractionation combined with dynamic light scattering. Viability of human leukemia and glioblastoma cells and Hsp70 silencing was determined following treatment with chitosan-TPP-Hsp70 siRNA particles. The results showed that silencing of Hsp70 by chitosan-TPP-Hsp70 siRNA treatment significantly reduced cell viability, and enhanced antiproliferative effects of celastrol in leukemia and glioblastoma cells. In glioblastoma spheroids, higher concentrations of celastrol and Hsp70 siRNA in chitosan-TPP nanocarriers were necessary to induce cell death. 23429184 Biochemical properties and comparative pharmacology of a coagulant from Deinagkistrodon acutus snake venom. A number of snake venom thrombin-like enzymes (TLEs) have already been characterized. Some TLEs play significant roles in vessel injury hemostasis. A novel TLE (Agacutase) was purified from Deinagkistrodon acutus snake venom by the means of Sephadex G-75, DEAE-Sepharose FF, and Sephadex G-25 column chromatography. Structural analysis indicated that Agacutase is a single-chain glycoprotein with a molecular mass of 31,084Da, isoelectric point of 4.38, optimal activity at 37°C and pH 6.6, sugar content of 7.6%. Its N-terminal 44 amino acid sequence was determined to be VIGGNECDTNEHRFLAAFFTSRPWIFQCAGTLIHEEWVLAAAHC, showing maximum identity of 80% with that of Dav-X protease. The Agacutase-induced clotting activity was not influenced by heparin, hirudin, or Dextran 40, but activated by Ca(2+) and inhibited by PMSF or lactose, which suggests that Agacutase is a serine protease and the coagulation activity is independent of Thrombin. Agacutase with arginine esterase activity specifically cleaves the α-chain of fibrinogen. Agacutase iv (0.03-0.12U/kg) shortened 16-68% of the rabbit blood clotting time. No significant influence was indicated on platelet, Factor II and XIII, or fibrinolytic system. It converts fibrinogen into the soluble fibrin that accelerates hemostasis at wound. Pharmacological comparison showed the hemostatic effect of Agacutase lasted 24h while Reptilase did 8h. Its maximum tolerated, abnormal toxicity, allergic, and hemorrhagin doses were 80U/kg, 1U, 2U, and 50U, respectively, whereas those of Reptilase or Agacutin were 35U/kg, 0.25U, 0.25U, and 0.2U, respectively. The results indicated that Agacutase may be a predominant coagulant. 23349500 β-Cell-Specific Protein Kinase A Activation Enhances the Efficiency of Glucose Control by Increasing Acute-Phase Insulin Secretion. Acute insulin secretion determines the efficiency of glucose clearance. Moreover, impaired acute insulin release is characteristic of reduced glucose control in the prediabetic state. Incretin hormones, which increase β-cell cAMP, restore acute-phase insulin secretion and improve glucose control. To determine the physiological role of the cAMP-dependent protein kinase (PKA), a mouse model was developed to increase PKA activity specifically in the pancreatic β-cells. In response to sustained hyperglycemia, PKA activity potentiated both acute and sustained insulin release. In contrast, a glucose bolus enhanced acute-phase insulin secretion alone. Acute-phase insulin secretion was increased 3.5-fold, reducing circulating glucose to 58% of levels in controls. Exendin-4 increased acute-phase insulin release to a similar degree as PKA activation. However, incretins did not augment the effects of PKA on acute-phase insulin secretion, consistent with incretins acting primarily via PKA to potentiate acute-phase insulin secretion. Intracellular calcium signaling was unaffected by PKA activation, suggesting that the effects of PKA on acute-phase insulin secretion are mediated by the phosphorylation of proteins involved in β-cell exocytosis. Thus, β-cell PKA activity transduces the cAMP signal to dramatically increase acute-phase insulin secretion, thereby enhancing the efficiency of insulin to control circulating glucose. 23246428 UPLC-Q-TOF/HSMS/MS(E)-based metabonomics for adenine-induced changes in metabolic profiles of rat faeces and intervention effects of ergosta-4,6,8(14),22-tetraen-3-one. Ergosta-4,6,8(14),22-tetraen-3-one (ergone), isolated from the medicinal fungus Polyporus umbellatus, has been proven to prevent the progression of renal injury and the subsequent renal fibrosis. Ultra performance liquid chromatography coupled with quadrupole time-of-flight high-sensitivity mass spectrometry and a novel mass spectrometry(Elevated Energy) (MS(E)) data collection technique was employed to investigate metabonomic characters of chronic renal failure (CRF) induced adenine and the protective effects of ergosta-4,6,8(14),22-tetraen-3-one (ergone). Coupled with blood biochemistry and kidney histopathology results, the significant difference in metabolic profiling between adenine-induced CRF group and ergone-treated CRF group by using pattern recognition analysis indicated that changes in global faecal metabolites were occurred. Seven endogenous metabolites were identified by using metabonomic method combined with multivariate data analysis, the accurate mass, isotopic pattern, MS(E) fragments information and MassLynx i-FIT algorithm. These biochemical changes in faecal metabolites are related to the perturbations of bile acid metabolism and phospholipid metabolism, which may be helpful to further understand the CRF and therapeutic mechanisms of ergone. This research proved that MS(E) can simultaneous acquire precursor ion information and fragment ion data at high and low collision energy in one analytical run, which facilitated the fast structural characterization of metabolites. 23640722 Structure-Activity Relationships of Quinoxaline-Based 5-HT3 A and 5-HT3 AB Receptor-Selective Ligands. Until recently, discriminating between homomeric 5-HT3 A and heteromeric 5-HT3 AB receptors was only possible with ligands that bind in the receptor pore. This study describes the first series of ligands that can discriminate between these receptor types at the level of the orthosteric binding site. During a recent fragment screen, 2-chloro-3-(4-methylpiperazin-1-yl)quinoxaline (VUF10166) was identified as a ligand that displays an 83-fold difference in [(3) H]granisetron binding affinity between 5-HT3 A and 5-HT3 AB receptors. Fragment hit exploration, initiated from VUF10166 and 3-(4-methylpiperazin-1-yl)quinoxalin-2-ol, resulted in a series of compounds with higher affinity at either 5-HT3 A or 5-HT3 AB receptors. These ligands reveal that a single atom is sufficient to change the selectivity profile of a compound. At the extremes of the new compounds were 2-amino-3-(4-methylpiperazin-1-yl)quinoxaline, which showed 11-fold selectivity for the 5-HT3 A receptor, and 2-(4-methylpiperazin-1-yl)quinoxaline, which showed an 8.3-fold selectivity for the 5-HT3 AB receptor. These compounds represent novel molecular tools for studying 5-HT3 receptor subtypes and could help elucidate their physiological roles. 23396116 Change in the transfer profile of orally administered tetrodotoxin to non-toxic cultured pufferfish Takifugu rubripes depending of its development stage. To investigate the effects of growth (organ development) on tetrodotoxin (TTX) dynamics in the pufferfish body, TTX-containing feed homogenate was administered to 6- and 15-month old non-toxic cultured specimens of the pufferfish Takifugu rubripes at a dose of 40 mouse units (MU) (8.8 μg)/20 g body weight by oral gavage. After 24 h, the specimens were killed and the skin tissues (dorsal and ventral), muscle, liver, digestive tract, and gonads were separated. TTX content (μg/g) in each tissue, determined by liquid chromatography/mass spectrometry, revealed that the TTX distribution profile, particularly the TTX content of the liver, greatly differed between the two ages; the TTX score of 15-month old fish (3.3 μg/g) was nearly 5-fold that of 6-month old fish (0.68 μg/g). The total remaining TTX amount per individual (relative amount to the given dose) was 31% in 6-month old fish, of which 71% was in the skin, and 84% in 15-month old fish, of which 83% was in the liver. The gonadosomatic index (GSI) and hepatosomatic index (HSI) scores, and histologic observations of the gonads and liver suggest that although there is little difference in maturation stage between these two ages, there are clear distinctions in the developmental stage of the liver. The results suggest that the TTX dynamics in T. rubripes are linked to the development of the liver, i.e., the TTX taken up into the pufferfish body via food organisms is eliminated or transferred mainly to the skin in young fish with an undeveloped liver, but as the fish grow and the liver continues to develop, most of the TTX is transferred to and accumulated in the liver. 23400795 Imposex effects on the veined rapa whelk (Rapana venosa) in Bohai Bay, China. Environmentally relevant concentrations of organotin compounds (OTs) may trigger sex changes in marine invertebrates and pose a threat to the marine ecosystem. In this study, we investigated organotin levels and the biological responses of wild veined rapa whelk (Rapana venosa) from Lüjuhe district (LJH), Dashentang district (DST), and Nanpaihe district (NPH) in Bohai Bay, China. We found that 11.11 and 22.95 % of the veined rapa whelks from DST and NPH exhibited imposex characteristics with a relative penis size index (RPSI) of 12.50 and 12.31, respectively. The RNA/DNA ratio was significantly lower in females from DST than those from LJH (p < 0.05), and a slight increase in DNA damage was observed in females and imposex individuals compared to males. Moreover, less genetic distance occurred between LJH and NPH (0.016) than between LJH and DST (0.028), although they belonged to the same regional population. OTs analysis showed that triphenyltin chloride concentrations (41.45 ng/g dried weight) were significantly higher than tributyltin concentrations (9.51 ng/g dried weight) in tissues (p < 0.05), but no significant differences were observed in sediments (p > 0.05). In conclusion, the occurrence of imposex individuals and biological responses of the wild veined rapa whelk from Bohai Bay suggest that the marine ecosystem might be at risk. 23373590 Stabilization of iron oxide nanoparticles in high sodium and calcium brine at high temperatures with adsorbed sulfonated copolymers. A series of sulfonated random and block copolymers were adsorbed on the surface of ~100 nm iron oxide (IO) nanoparticles (NPs) to provide colloidal stability in extremely concentrated brine composed of 8% wt NaCl + 2% wt CaCl2 (API brine; 1.4 M NaCl + 0.2 M CaCl2) at 90 °C. A combinatorial materials chemistry approach, which employed Ca(2+)-mediated adsorption of anionic acrylic acid-containing sulfonated polymers to preformed citrate-stabilized IO nanoclusters, enabled the investigation of a large number of polymer coatings. Initially a series of poly(2-methyl-2-acrylamidopropanesulfonate-co-acrylic acid) (poly(AMPS-co-AA)) (1:8 to 1:1 mol:mol), poly(styrenesulfonate-block-acrylic acid) (2.4:1 mol:mol), and poly(styrenesulfonate-alt-maleic acid) (3:1 mol:mol) copolymers were screened for solubility in API brine at 90 °C. The ratio of AMPS to AA groups was varied to balance the requirement of colloid dispersibility at high salinity (provided by AMPS) against the need for anchoring of the polymers to the iron oxide surface (via the AA). Steric stabilization of IO NPs coated with poly(AMPS-co-AA) (1:1 mol:mol) provided colloidal stability in API brine at room temperature and 90 °C for up to 1 month. The particles were characterized before and after coating at ambient and elevated temperatures by a variety of techniques including colloidal stability experiments, dynamic light scattering, zeta potential, and thermogravimetric analysis. 23085495 Changes in women's feelings about their romantic relationships across the ovulatory cycle. According to the dual mating hypothesis, women possess two overlapping suites of mate-choice mechanisms: one leading to preferences for sexually desirable men who have high-fitness genes and one leading to preferences for men who are able to invest in a woman and her children. Evidence increasingly demonstrates that women's preference for sexual desirability (but not investment attractiveness) increases when women are most fertile within the ovulatory cycle. Little is known, however, about the implications of these preference shifts for women's relationships with their long-term partners. Using luteinizing hormone tests to verify ovulation, across two studies (Samples 1 and 2), we found that women whose partners were relatively low in sexual desirability felt less close to their partner (Samples 1 and 2) and were more critical of their partner's faults (Sample 2) on high-fertility days of the cycle just prior to ovulation compared with low-fertility days of the cycle. Women whose partners were relatively high in sexual desirability felt closer to their partner (Sample 1) and more satisfied with their relationship (Sample 2) on high- than low-fertility days of the cycle. There were no such shifts in women's commitment to their relationship. Therefore, partner sexual desirability predicts women's high-fertility assessments of relationship quality but not their intentions to stay in their relationship, consistent with the dual mating hypothesis. These findings suggest that variations across the ovulation cycle in women's reproductive hormones play an important role in relationship dynamics. 23266737 Triterpenoid saponins from Clematis tangutica and their cardioprotective activities. Phytochemical investigation of the whole plants of Clematis tangutica led to the isolation of three new triterpenoid saponins (1-3), together with four known saponins (4-7). Their structures were determined by extensive spectral analysis and chemical evidences. Compounds 1-7 were evaluated for their cardioprotective activities in cardiomyocytes anoxia/reoxygenation (A/R) model. The results showed that those saponins exhibited cardioprotective effects by decreasing the levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH). 23203920 Identification of LasR ligands through a virtual screening approach. With the widespread occurrence of bacterial resistance to antibiotics, the development of new strategies beyond conventional treatments is a pursuit taken by public health institutions worldwide. LasR, a transcription factor that controls quorum sensing in Pseudomonas aeruginosa, has emerged as an attractive therapeutic target for the next generation of antimicrobial agents. In the present study, a virtual screening workflow combining pharmacophore- and structure-based approaches was used to identify new LasR ligands. Five novel inducers and three inhibitors of LasR activity were validated experimentally by use of a cell-based assay. Interestingly, these compounds are molecularly distinct from the native signal molecule, N-3-oxododecanoyl-L-homoserine lactone (OHN), and may serve as lead structures for the design of new drugs. The binding modes of these compounds to the OHN binding site in LasR were predicted and used to identify the key interactions that contribute to the induction and inhibition of LasR activity. 23279844 Protection of the flavonoid fraction from Rosa laevigata Michx fruit against carbon tetrachloride-induced acute liver injury in mice. Protective effect of the total flavonoids (TFs) from Rosa laevigata Michx fruit against carbon tetrachloride (CCl4)-induced hepatotoxicity in mice was investigated. Pretreatment with TFs significantly decreased CCl4-induced elevation of serum aspartate transaminase (AST) and alanine transaminase (ALT) activities as well as the relative liver weight. Histopathological observation also revealed that TFs reduced the incidence of liver lesions and improved hepatocyte abnormality. Moreover, oral administration of TFs significantly enhanced antioxidant enzyme activities (superoxide dismutase, catalase and glutathione peroxidase), increased the content of glutathione and decreased the content of malondialdehyde. Further research indicated that TFs prevented the DNA fragmentation and mitochondrial ultrastructural alterations caused by CCl4 based on TUNEL and transmission electron microscopy (TEM) assays. Moreover, pretreatment with TFs down-regulated the protein expressions of CYP2E1, iNOS, NF-κB, Bak and Caspase-3. Quantitative Real-time PCR assay suggested that TFs markedly decreased the levels of TNF-α, Fas/FasL and Bax gene expressions, and increased the level of Bcl-2. This is the first time to report the significant hepatoprotective effect of TFs from R. laevigata Michx fruit against CCl4-induced liver injury in mice and the action should be through reducing oxidative stress and suppressing inflammation and apoptosis. 23190030 Phenolic compounds: the role of redox regulation in neurodegenerative disease and cancer. Much work has been carried out in the last two decades on the role of oxidative stress and antioxidants deficiency in the pathophysiology of civilization diseases. A considerable amount of chemical, biochemical, epidemiological and clinical evidence indicates that (poly)phenolic compounds widely distributed in the plant kingdom, exhibit a wide range effects on biomolecules. The beneficial effects on human health, many of phenolics have been described to their reactive oxygen (ROS) and nitrogen species (RNS) scavenging and antioxidant capacity. The consumption of vegetables, fruits and flavonoid-rich beverages has been reported to prevent against neurodegenerative diseases, cancer, and ageing. This paper reviews the recent data on (1) the role oxidative stress in the pathology of civilization diseases; (2) the protection against oxidative damage due to the toxicity of ROS/RNS; (3) the cellular and molecular interactions of the (poly)phenolic compounds relevant to the prevention of neurodegenerative diseases and cancer, and (4) the methods for assessing antioxidant capacity. 23611809 Human UGT2B10 in Drug N-glucuronidations: Substrate Screening and Comparison with UGT1A3 and UGT1A4. Recent observations revealed that human UDP-glucuronosyltransferase (UGT) 2B10 catalyzes N-glucuronidation of amine-containing compounds. Knowledge of the substrate specificity and clinical significance of UGT2B10 is still limited. The purpose of this study was to expand the knowledge of UGT2B10 substrates and to evaluate its significance in drug clearance. Using recombinant UGT2B10, we found that it catalyzes the N-glucuronidation of amitriptyline, imipramine, ketotifen, pizotifen, olanzapine, diphenhydramine, tamoxifen, ketoconazole and midazolam. These are drugs that were previously reported to be substrates for UGT1A4 or UGT1A3 and that contain in their structure either tertiary aliphatic amines, cyclic amines, or an imidazole group. UGT2B10 was inactive in the glucuronidation of desipramine, nortriptyline, carbamazepine and afloqualone. This group of drugs contains secondary or primary amines, and these results suggest that UGT2B10 preferably conjugates tertiary amines. This preference is partial because UGT2B10 did not conjugate the tertiary cyclic amine in trifluoperazine. Kinetic analyses revealed that the affinity and clearance of UGT2B10 for amitriptyline, imipramine, and diphenhydramine are significantly higher than the corresponding values of UGT1A4 and UGT1A3, although the Vmax values of UGT1A4 toward these drugs are considerably higher. These findings suggest that UGT2B10 plays a major role in the N-glucuronidation of these drugs at therapeutic concentrations. These results are also supported by inhibition studies with nicotine and hecogenin. In conclusion, this study expands the understanding of the substrate specificity of UGT2B10, highlighting its preference for tertiary amines with higher affinities and clearance values than those of UGT1A4 and UGT1A3. 23643748 Prosocial effects of oxytocin in two mouse models of autism spectrum disorders. Clinical evidence suggests that oxytocin treatment improves social deficits and repetitive behavior in autism spectrum disorders (ASDs). However, the neuropeptide has a short plasma half-life and poor ability to penetrate the blood-brain barrier. In order to facilitate the development of more bioavailable oxytocinergic compounds as therapeutics to treat core ASD symptoms, small animal models must be validated for preclinical screens. This study examined the preclinical utility of two inbred mouse strains, BALB/cByJ and C58/J, that exhibit phenotypes relevant to core ASD symptoms. Mice from both strains were intraperitoneally administered oxytocin, using either acute or sub-chronic regimens. Acute oxytocin did not increase sociability in BALB/cByJ; however, sub-chronic oxytocin had significant prosocial effects in both BALB/cByJ and C58/J. Increased sociability was observed 24 hours following the final oxytocin dose in BALB/cByJ, while prosocial effects of oxytocin emerged 1-2 weeks post-treatment in C58/J. Furthermore, acute oxytocin decreased motor stereotypy in C58/J and did not induce hypoactivity or anxiolytic-like effects in an open field test. This study demonstrates that oxytocin administration can attenuate social deficits and repetitive behavior in mouse models of ASD, dependent on dose regimen and genotype. These findings provide validation of the BALB/cByJ and C58/J models as useful platforms for screening novel drugs for intervention in ASDs and for elucidating the mechanisms contributing to the prosocial effects of oxytocin. 22951947 In vitro models for assessing the potential cardiovascular disease risk associated with cigarette smoking. Atherosclerotic cardiovascular disease is a prevalent human disorder and a significant cause of human morbidity and mortality. A number of risk factors may predispose an individual to developing atherosclerosis, and of these factors, cigarette smoking is strongly associated with the development of cardiovascular disease. Current thinking suggests that exposure to toxicants found in cigarette smoke may be responsible for this elevated disease likelihood, and this gives rise to the idea that reductions in the levels of some smoke toxicants may reduce the harm associated with cigarette smoking. To assess the disease risk of individuals who smoke cigarettes with altered toxicant levels, a weight-of-evidence approach is required examining both exposure and disease-related endpoints. A key element of such an assessment framework are data derived from the use of in vitro models of cardiovascular disease, which when considered alongside other forms of data (e.g. from clinical studies) may support evidence of potential reduced risk. Importantly, such models may also be used to provide mechanistic insight into the effects of smoking and of smoke toxicant exposure in cardiovascular disease development. In this review the use of in vitro models of cardiovascular disease and one of the contributory factors, oxidative stress, is discussed in the context of assessing the risk potential of both conventional and modified cigarettes. Practical issues concerning the use of these models for cardiovascular disease understanding and risk assessment are highlighted and areas of development necessary to enhance the power and predictive capacity of in vitro disease models in risk assessment are discussed. 23561072 Intake of mulberry 1-deoxynojirimycin prevents diet-induced obesity through increases in adiponectin in mice. In this study, the anti-obesity effect of 1-deoxynojirimycin (DNJ) was examined in the diet-induced obese mouse model. Mulberry DNJ was administered to the obese mice for 12weeks. As a result, DNJ decreased both the visceral fat weight and adipocyte size. To determine the influence of DNJ on lipid metabolism, lipid parameters of the plasma and the liver and the activities of several molecules related to lipid metabolism in the liver were measured. DNJ activated the β-oxidation system, suppressed lipid accumulation in the liver and reduced plasma triacylglycerol. Since it was thought that the factor activated in the β-oxidation system was adiponectin, plasma adiponectin levels were measured and it was shown that plasma adiponectin was increased with DNJ. Therefore, it was suggested that DNJ promoted an increase in plasma adiponectin and activated the β-oxidation system. Overall, it was shown that DNJ prevents diet-induced obesity through an increase in adiponectin. 23353733 A flexible approach to 1,4-di-substituted 2-aminoimidazoles that inhibit and disperse biofilms and potentiate the effects of β-lactams against multi-drug resistant bacteria. The pyrrole-imidazole alkaloids are a 2-aminoimidazoles containing family of natural products that possess anti-biofilm activity. A library of 1,4-di-substituted 2-aminoimidazole/triazoles (2-AITs) was synthesized, and its anti-biofilm activity as well as oxacillin resensitization efficacy toward methicillin resistant Staphylococcus aureus (MRSA) was investigated. These 2-AITs were found to inhibit biofilm formation by MRSA with low micromolar IC50 values. Additionally, the most active compound acted synergistically with oxacillin against MRSA lowering the minimum inhibitory concentration (MIC) 4-fold. 23385875 Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options. Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, and TYMP) or mtDNA replication (POLG and C10orf2). MDS are phenotypically heterogeneous and usually classified as myopathic, encephalomyopathic, hepatocerebral or neurogastrointestinal. Myopathic MDS, caused by mutations in TK2, usually present before the age of 2 years with hypotonia and muscle weakness. Encephalomyopathic MDS, caused by mutations in SUCLA2, SUCLG1, or RRM2B, typically present during infancy with hypotonia and pronounced neurological features. Hepatocerebral MDS, caused by mutations in DGUOK, MPV17, POLG, or C10orf2, commonly have an early-onset liver dysfunction and neurological involvement. Finally, TYMP mutations have been associated with mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease that typically presents before the age of 20 years with progressive gastrointestinal dysmotility and peripheral neuropathy. Overall, MDS are severe disorders with poor prognosis in the majority of affected individuals. No efficacious therapy is available for any of these disorders. Affected individuals should have a comprehensive evaluation to assess the degree of involvement of different systems. Treatment is directed mainly toward providing symptomatic management. Nutritional modulation and cofactor supplementation may be beneficial. Liver transplantation remains controversial. Finally, stem cell transplantation in MNGIE disease shows promising results. 23231350 Embryonic stem cell-based screen for small molecules: cluster analysis reveals four response patterns in developing neural cells. Neural differentiation of embryonic stem cells (ESC) is considered a promising model to perform in vitro testing for neuroactive and neurotoxic compounds. We studied the potential of a dual reporter murine ESC line to identify bioactive and/or toxic compounds. This line expressed firefly luciferase under the control of the neural cell-specific tubulin alpha promoter (TUBA1A), and renilla luciferase under the control of the ubiquitous translation elongation factor 1-alpha-1 (EEF1A1) promoter. During neural differentiation, TUBA1A activity increased, while EEF1A1 activity decreased. We first validated our test system using the known neurotoxin methyl mercury. This compound altered expression of both reporter genes, with ESC-derived neural precursors being affected at markedly lower concentrations than undifferentiated ESCs. Analysis of a library of 1040 bioactive compounds picked up 127 compounds with altered EEF1A1 and/or TUBA1A promoter activity, which were classified in 4 clusters. Cluster 1 (low EEF1A1 and TUBA1A) was the largest cluster, containing many cytostatic drugs, as well as known neurodevelopmental toxicants, psychotropic drugs and endocrine disruptors. Cluster 2 (high EEF1A1, stable TUBA1A) was limited to three sulfonamides. Cluster 3 (high EEF1A1 and TUBA1A) was small, but markedly enriched in neuroactive and neurotoxic compounds. Cluster 4 (stable EEF1A1, high TUBA1A) was heterogeneous, containing endocrine disruptors, neurotoxic and cytostatic drugs. The dual reporter gene assay described here might be a useful addition to in vitro drug testing panels. Our two-dimensional testing strategy provides information on complex response patterns, which could not be achieved by a single marker approach. 23041725 Sexually dimorphic transcriptomic responses in the teleostean hypothalamus: a case study with the organochlorine pesticide dieldrin. Organochlorine pesticides (OCPs) such as dieldrin are a persistent class of aquatic pollutants that cause adverse neurological and reproductive effects in vertebrates. In this study, female and male largemouth bass (Micropterus salmoides) (LMB) were exposed to 3mg dieldrin/kg feed in a 2 month feeding exposure (August-October) to (1) determine if the hypothalamic transcript responses to dieldrin were conserved between the sexes; (2) characterize cell signaling cascades underlying dieldrin neurotoxicity; and (3) determine whether or not co-feeding with 17β-estradiol (E(2)), a hormone with neuroprotective roles, mitigates responses in males to dieldrin. Despite also being a weak estrogen, dieldrin treatments did not elicit changes in reproductive endpoints (e.g. gonadosomatic index, vitellogenin, or plasma E(2)). Sub-network (SNEA) and gene set enrichment analysis (GSEA) revealed that neuro-hormone networks, neurotransmitter and nuclear receptor signaling, and the activin signaling network were altered by dieldrin exposure. Most striking was that the majority of cell pathways identified by the gene set enrichment were significantly increased in females while the majority of cell pathways were significantly decreased in males fed dieldrin. These data suggest that (1) there are sexually dimorphic responses in the teleost hypothalamus; (2) neurotransmitter systems are a target of dieldrin at the transcriptomics level; and (3) males co-fed dieldrin and E(2) had the fewest numbers of genes and cell pathways altered in the hypothalamus, suggesting that E(2) may mitigate the effects of dieldrin in the central nervous system. 23017393 Proteomic evaluation of myofibrillar carbonylation in chilled fish mince and its inhibition by catechin. The present study investigates the susceptibility of individual myofibrillar proteins from mackerel (Scomber scombrus) mince to undergo carbonylation reactions during chilled storage, and the antioxidant capacity of (+)-catechin to prevent oxidative processes of proteins. The carbonylation of each particular protein was quantified by combining the labelling of protein carbonyls by fluorescein-5-thiosemicarbazide (FTSC) with 1-D or 2-D gel electrophoresis. Alpha skeletal actin, glycogen phosphorylase, unnamed protein product (UNP) similar to enolase, pyruvate kinase, isoforms of creatine kinase, aldolase A and an isoform of glyceraldehyde 3-phosphate dehydrogenase (G3PDH) showed elevated oxidation in chilled non-supplemented mince. Myosin heavy chain (MHC) was not carbonylated in chilled muscle, but an extensive MHC degradation was observed in those samples. The supplementation of catechin reduced protein oxidation and lipid oxidation in a concentration-dependent manner: control>25>100≈200ppm. Therefore, the highest catechin concentrations (100 and 200ppm) exhibited the strongest antioxidant activity. Catechin (200ppm) reduced significantly carbonylation of protein spots identified as glycogen phosphorylase, pyruvate kinase muscle isozyme, isoforms of creatine kinase. Conversely, catechin was ineffective to inhibit the oxidation of actin and UNP similar to enolase. These results draw attention to the inefficiency of catechin to prevent actin oxidation, in contrast to the extremely high efficiency of catechin in inhibiting oxidation of lipids and other proteins. 23402636 Health benefits of blue-green algae: prevention of cardiovascular disease and nonalcoholic fatty liver disease. Blue-green algae (BGA) are among the most primitive life forms on earth and have been consumed as food or medicine by humans for centuries. BGA contain various bioactive components, such as phycocyanin, carotenoids, γ-linolenic acid, fibers, and plant sterols, which can promote optimal health in humans. Studies have demonstrated that several BGA species or their active components have plasma total cholesterol and triglyceride-lowering properties due to their modulation of intestinal cholesterol absorption and hepatic lipogenic gene expression. BGA can also reduce inflammation by inhibiting the nuclear factor κ B activity, consequently reducing the production of proinflammatory cytokines. Furthermore, BGA inhibit lipid peroxidation and have free radical scavenging activity, which can be beneficial for the protection against oxidative stress. The aforementioned effects of BGA can contribute to the prevention of metabolic and inflammatory diseases. This review provides an overview of the current knowledge of the health-promoting functions of BGA against cardiovascular disease and nonalcoholic fatty liver disease, which are major health threats in the developed countries. 23386468 Synthesis and biological evaluation of purine 2'-fluoro-2'-deoxyriboside ProTides as anti-influenza virus agents. 2'-Fluoro-2'-deoxyguanosine has been reported to have potent anti-influenza virus activity in vitro and in vivo. Herein we describe the synthesis and biological evaluation of 6-modified 2'-fluoro-2'-deoxyguanosine analogues and their corresponding phosphoramidate ProTides as potential anti-influenza virus agents. Whereas the parent nucleosides were devoid of antiviral activity in two different cellular assays, the 5'-O-naphthyl(methoxy-L-alaninyl) ProTide derivatives of 6-O-methyl-2'-fluoro-2'-deoxyguanosine, 6-O-ethyl-2'-fluoro-2'-deoxyguanosine, and 2'-deoxy-2'-fluoro-6-chloroguanosine, and the 5'-O-naphthyl(ethoxy-L-alaninyl) ProTide of 6-O-ethyl-2'-fluoro-2'-deoxyguanosine displayed antiviral EC(99) values of ~12 μM. The antiviral results are supported by metabolism studies. Rapid conversion into the L-alaninyl metabolite and then 6-modified 2'-fluoro-2'-deoxyguanosine 5'-monophosphate was observed in enzymatic assays with yeast carboxypeptidase Y or crude cell lysate. Evidence for efficient removal of the 6-substituent on the guanine part was provided by enzymatic studies with adenosine deaminase, and by molecular modeling of the nucleoside 5'-monophosphates in the catalytic site of a model of ADAL1, thus indicating the utility of the double prodrug concept. 23419814 The transdermal delivery of fentanyl. The fentanyl patch is one of the great commercial successes in transdermal drug delivery. The suitability of this molecule for delivery through skin had been identified in the 1970s, and subsequently, a number of transdermal formulations became available on the market. This article reviews the development of fentanyl patch technology with particular emphasis on the pharmacokinetics and disposition of the drug when delivered through the skin. The various patch designs are considered as well as the bioequivalence of the different designs. The influence of heat on fentanyl permeation is highlighted. Post-mortem redistribution of fentanyl is discussed in light of the reported discrepancies in serum levels reported in patients after death compared with therapeutic levels in living subjects. Finally, alternatives to patch technology are considered, and recent novel transdermal formulations are highlighted. 23386780 Apoptotic cell death in rat epididymis following epichlorohydrin treatment. Epichlorohydrin (ECH) is an antifertility agent that acts both as an epididymal toxicant and an agent capable of directly affecting sperm motility. This study identified the time course of apoptotic cell death in rat epididymides after ECH treatment. Rats were administrated with a single oral dose of ECH (50 mg/kg). ECH-induced apoptotic changes were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and its related mechanism was confirmed by Western blot analysis and colorimetric assay. The TUNEL assay showed that the number of apoptotic cells increased at 8 h, reached a maximum level at 12 h, and then decreased progressively. The Western blot analysis demonstrated no significant changes in proapoptotic Bcl-2-associated X (Bax) and anti-apoptotic Bcl-2 expression during the time course of the study. However, phospho-p38 mitogen-activated protein kinase (p-p38 MAPK) and phospho-c-Jun amino-terminal kinase (p-JNK) expression increased at 8-24 h. Caspase-3 and caspase-8 activities also increased at 8-48 h and 12-48 h, respectively, in the same manner as p-p38 MAPK and p-JNK expression. These results indicate that ECH induced apoptotic changes in rat epididymides and that the apoptotic cell death may be related more to the MAPK pathway than to the mitochondrial pathway. 23314277 Biochemical and metabolic effects of a short-term exposure to nanoparticles of titanium silicate in tadpoles of Pelophylax perezi (Seoane). This study aimed to evaluate sublethal effects of a short-term exposure (96 h) to titanium silicate nanoparticles (TiSiO(4)-NP) on Pelophylax perezi tadpoles. Tadpoles were exposed to five concentrations of TiSiO(4)-NP (8.2, 10.2, 12.8, 16 and 20 mg/L) plus a control. Effect criteria were: mortality, cholinesterases, glutathione S-transferases, lactate dehydrogenase, and catalase activities, and alanine and lactate contents. Light scattering was used for physical characterization of TiSiO(4)-NP suspensions, revealing a high aggregation state of the NP, consistent with low z-potential values (<30 mV). Mortality among TiSiO(4)-NP treatments was <11%. Significant differences relatively to the control were observed at the biochemical level (for CAT and LDH) and in lactate and alanine contents, which may end-up in increased oxidative stress. Overall, some of the monitored endpoints suggest metabolic alterations in TiSiO(4)-NP exposed tadpoles, highlighting the potential of TiSiO(4)-NP long-term effects on these organisms. 23620266 Enantiomeric fraction determination of 2-arylpropionic acids in a package plant membrane bioreactor. Enantiomeric compositions of three 2-arylpropionic acid (2-APA) drugs, ibuprofen, naproxen, and ketoprofen, were monitored in a membrane bioreactor (MBR) treating municipal effluent in a small rural town in Australia. Specific enantiomers were determined as amide diastereomers using the chiral derivatizing reagent, (R)-1-phenylethylamine (PEA), followed by gas chromatography-tandem mass spectrometry (GC-MS/MS). The six individual enantiomers were quantified by isotope dilution and the enantiomeric fractions (EFs) were determined. Over four separate sampling events, ibuprofen EF ranged from 0.88 to 0.94 (median 0.93) in the influent and 0.38 to 0.40 (median 0.39) in the effluent. However, no significant change in ketoprofen EF was observed, with influent EFs of 0.56-0.60 (median 0.58) and effluent EFs 0.54-0.68 (median 0.56). This is the first report of enantiospecific analysis of ketoprofen in municipal wastewater and it is not yet clear why such different behavior was observed compared to ibuprofen. Naproxen EF was consistently measured at 0.99 in the influent and ranged from 0.86 to 0.94 (median 0.91) in the effluent. This study demonstrates that EF is a relatively stable parameter and does not fluctuate according to concentration or other short-term variables introduced by sampling limitations. The enantiospecific analysis of chiral chemicals presents a promising approach to elucidate a more thorough understanding of biological treatment processes and a potential tool for monitoring the performance of key biological pathways. Chirality 25:301-307, 2013. © 2013 Wiley Periodicals, Inc. 22678994 Mild Mitochondrial Depolarization is Involved in a Neuroprotective Mechanism of Citrus sunki Peel Extract. Mitochondrial membrane potential (∆Ψm ) contributes to determining a driving force for calcium to enter the mitochondria. It has been demonstrated that even a small mitochondrial depolarization is sufficient to prevent mitochondrial calcium overload and the subsequent apoptosis. Therefore, mild mitochondrial depolarization has been recently evaluated as a novel mechanism of neuroprotection via inhibiting neurotoxic mitochondrial calcium overload during neuronal insults. In the present study, using both real-time recording and flow cytometric analyses of ∆Ψm , we demonstrated that ethanolic peel extract of Citrus sunki Hort. ex Tanaka (CPE) and its active compounds are capable of inducing a mild mitochondrial depolarization. Polymethoxylated flavones such as nobiletin and tangeretin were found as the active compounds responsible for CPE effects on ∆Ψm . Neuronal viability was significantly increased in a dose-dependent manner by CPE treatment in H2 O2 -stimulated HT-22 cells as an in vitro neuronal insult model. CPE treatment significantly inhibited H2 O2 -induced apoptotic processes such as chromatin condensation, caspase 3 activation and anti-poly (ADP-ribose) polymerase (PARP) cleavage. CPE treatment significantly blocked mitochondrial calcium overload in H2 O2 -stimulated HT-22 neurons as indicated by rhod-2 acetoxymethyl ester. Taken together, our findings suggest that CPE and its active compounds may be considered as promising neuroprotective agents via inducing a mild mitochondrial depolarization. Copyright © 2012 John Wiley & Sons, Ltd. 23352650 Point-to-point ligand-receptor interactions across the subunit interface modulate the induction and stabilization of conformational states of alpha7 nAChR by benzylidene anabaseines. The homomeric α7 nicotinic acetylcholine receptor is a well-studied therapeutic target, though its characteristically rapid desensitization complicates the development of drugs with specific agonist effects. Moreover, some experimental compounds such as GTS-21 (2,4diMeOBA), a derivative of the α7-selective partial agonist benzylidene anabaseine (BA), produce a prolonged residual desensitization (RD) in which the receptor remains non-activatable long after the drug has been removed from extracellular solution. In contrast, the desensitization caused by GTS-21's dihydroxy metabolite (2,4diOHBA) is relatively short-lived. RD is hypothetically due to stable binding of the ligand to the receptor in its desensitized state. We can attribute the reduction in RD to a single BA hydroxyl group on the 4' benzylidene position. Computational prediction derived from homology modeling showed the serine36 (S36) residue of α7 as a reasonable candidate for point-to-point interaction between BA compounds and the receptor. Through evaluating the activity of BA and simple derivatives on wild-type and mutant α7 receptors, it was observed that the drug-receptor pairs which were capable of hydrogen bonding at residue 36 exhibited significantly less stable desensitization. Further experiments involving the type II positive allosteric modulator (PAM) PNU-120596 showed that the various BA compounds' preference to induce either a PAM-sensitive (D(s)) or PAM-insensitive (D(i)) desensitized state is concentration dependent and suggested that both states are destabilized by S36 H-bonding. These results indicate that the fine-tuning of agonists for specific interaction with S36 can facilitate the development of therapeutics with targeted effects on ion channel desensitization properties and conformational state stability. 23618528 Lactobacillus rhamnosus GG reduces hepatic TNFα production and inflammation in chronic alcohol-induced liver injury. The therapeutic effects of probiotic treatment in alcoholic liver disease (ALD) have been studied in both patients and experimental animal models. Although the precise mechanisms of the pathogenesis of ALD are not fully understood, gut-derived endotoxin has been postulated to play a crucial role in hepatic inflammation. Previous studies have demonstrated that probiotic therapy reduces circulating endotoxin derived from intestinal gram-negative bacteria in ALD. In this study, we investigated the effects of probiotics on hepatic tumor necrosis factor-α (TNFα) production and inflammation in response to chronic alcohol ingestion. Mice were fed Lieber DeCarli liquid diet containing 5% alcohol for 8weeks, and Lactobacillus rhamnosus GG (LGG) was supplemented in the last 2 weeks. Eight-week alcohol feeding caused a significant increase in hepatic inflammation as shown by histological assessment and hepatic tissue myeloperoxidase activity assay. Two weeks of LGG supplementation reduced hepatic inflammation and liver injury and markedly reduced TNFα expression. Alcohol feeding increased hepatic mRNA expression of Toll-like receptors (TLRs) and CYP2E1 and decreased nuclear factor erythroid 2-related factor 2 expression. LGG supplementation attenuated these changes. Using human peripheral blood monocytes-derived macrophages, we also demonstrated that incubation with ethanol primes both lipopolysaccharide- and flagellin-induced TNFα production, and LGG culture supernatant reduced this induction in a dose-dependent manner. In addition, LGG treatment also significantly decreased alcohol-induced phosphorylation of p38 MAP kinase. In conclusion, probiotic LGG treatment reduced alcohol-induced hepatic inflammation by attenuation of TNFα production via inhibition of TLR4- and TLR5-mediated endotoxin activation. 23600486 A Singlet Biradicaloid Zinc Compound and Its Nonradical Counterpart. Metal ions with radical centers in their coordination sphere are key participants in biological and catalytic processes. In the present study, we describe the synthesis of the cAAC:ZnCl2 adduct (1) using a cyclic alkylaminocarbene (cAAC) as donor ligand. Compound 1 was treated with 2 equiv of KC8 and LiB(sec-Bu)3H to yield a deep blue-colored dicarbene zinc compound (cAAC)2Zn (2) and the colorless hydrogenated zinc compound (cAACH)2Zn (3), respectively. Compounds 2 and 3 were well characterized by spectroscopic methods and single-crystal X-ray structural analysis. Density functional theory calculations were performed for 2 which indicate that this molecule possesses a singlet biradicaloid character. Moreover, we show the application of 2 in CO2 activation, which yields a zwitterionic cAAC·CO2 adduct. 22931212 Elucidation of the mechanism of ribose conjugation in a pyrazole-containing compound in rodent liver. 1. Here we report on the mechanism of ribose conjugation, through NADH as a cofactor, of a pyrazole-containing compound (PT). Incubation of PT in rat liver microsomes supplemented with NADP⁺/H, NAD⁺/H, and β-nicotinamide mononucleotide (NMN) resulted in complete conjugation to the adenine dinucleotide phosphate conjugate (ADP-C), adenine dinucleotide conjugate (AD-C), and 5-phosphoribose conjugate (Rib-C1), respectively. In hepatocytes, PT predominantly formed three ribose conjugates: Rib-C1, the ribose conjugate (Rib-C2), and the carboxylic acid of Rib-C2 (Rib-C3). 2. Phosphatase inhibitors were added to hepatocyte incubations. AD-C was detected in this reaction, which suggests that one of the major pathways for the formation of the ribose conjugates is through NAD⁺/H. When AD-C was incubated with phosphatase, Rib-C1 and Rib-C2 formed. 3. To understand the in vivo relevance of this metabolic pathway, rats were dosed with PT and Rib-C2 was found in the urine. 4. Structure-activity relationship shows that replacement of the distal thiazole group in the PT to a phenyl group abolishes this conjugation. Three amino acid residues in the active site preferentially interact with the sulfur atom in the thiazole of PT. 5. In summary, PT forms direct AD-C in hepatocytes, which is further hydrolyzed by phosphatase to give ribose conjugates. 23586441 Tuning the Emission Properties of Fluorescent Ligands by Changing pH: The Unusual Case of an Acridine-Containing Polyamine Macrocycle. Synthesis and characterization of a new macrocyclic compound, composed by a triethylentetraamine chain linking the 4 and 5 positions of an acridine moiety, are reported. The molecule, devised as a fluorescent chemosensor for anions, has revealed an intriguing pH-dependent spectroscopic behavior, whose features are the specific object of this article. Ligand protonation in aqueous solution has been analyzed by means of potentiometric, (1)H NMR, UV-vis, and fluorescence emission measurements. The molecule binds up to four protons in the pH range 2-11. Protonation takes place on the aliphatic tetraamine chain, while the acridine nitrogen does not participate to proton binding even at very low pH. Differently from acridine, the UV-vis spectra are almost unaffected by the pH. On the opposite, the emission spectra are strongly pH-dependent. In fact, at low pH values, the spectra show a blue-shifted emission, resembling that of unprotonated acridine, while at slightly acidic and alkaline pH the fluorescence features a red-shifted band similar to that of acridinium cation. This unusual behavior occurs in the mono-, bi-, and triprotonated forms of the compound and is interpreted as due to an excited state proton transfer from an aliphatic ammonium group adjacent to the acridine moiety to the acridine nitrogen. In the fully protonated state, this process is prevented owing to unfavorable molecular arrangements mainly determined by electrostatic repulsions. This interpretation is supported by quantum mechanical calculations as well as molecular dynamics simulations. 23057615 A new approach to counteract bacteria resistance: a comparative study between moxifloxacin and a new moxifloxacin derivative in different model systems of bacterial membrane. New drug design has been one of the major challenges to combat bacterial resistance over the past decade. Conventional antibiotics act by destroying bacterial cell wall or by blocking biosynthetic pathways necessary for its survival. Unfortunately, there has been a fast increase in multiresistance, to several conventional antibiotics, in clinical bacterial strains. Previous studies have shown that metalloantibiotics, ternary complexes of antibiotic-metal-phenanthroline, present an increased potential as antimicrobial agents. In this work moxifloxacin, a fourth-generation quinolone, with a broad spectrum of action, and its copper ternary complex (metalloantibiotic) have been study by fluorescence spectroscopy. Partition coefficients were determined and showed that while free moxifloxacin exhibits the same behaviour independently of the lipidic system tested, the metalloantibiotic presents higher partition to liposomes, in a lipid composition-dependent way. These significant differences in the interaction of the metalloantibiotic with model bacteria membranes point out for a putative change in its uptake mechanism with increased drug-lipid interaction potentiating metalloantibiotic influx. 23454054 Characteristics of indomethacin-saccharin (IMC-SAC) co-crystals prepared by an anti-solvent crystallization process. The creation of co-crystals of various insoluble drug substances has been extensively investigated as a promising approach to improve their pharmaceutical performance. In this study, co-crystal powders of indomethacin and saccharin (IMC-SAC) were prepared by an anti-solvent (water) addition and compared with co-crystals by evaporation method. No successful synthesis of a pharmaceutical co-crystal powder via an anti-solvent approach has been reported. Among solvents examined, methanol was practically the only one that resulted in the formation of highly pure IMC-SAC co-crystal powders by anti-solvent approach. The mechanism of a preferential formation of IMC-SAC co-crystal to IMC was explained with two aspects: phase solubility diagram and solution complexation concept. Accordingly, the anti-solvent approach can be considered as a competitive route for producing pharmaceutical co-crystal powders with acceptable properties. 23474645 Inverted CdSe/CdS/ZnS quantum dot light emitting devices with titanium dioxide as an electron-injection contact. We demonstrated the fabrication of inverted CdSe/CdS/ZnS quantum dot light emitting devices (QD-LEDs) using titanium dioxide (TiO2) as an electron-injection layer and investigated the operating mechanism by utilizing different hole-transport materials, 4,4-N,N-dicarbazole-biphenyl (CBP) and 4,4',4''-tris(carbazol-9-yl)-triphenylamine (TCTA). A more efficient device with CBP as the hole-transport layer (HTL) was obtained compared with the TCTA based device. The peak efficiency of 6.70 cd A(-1) for the CBP based device was found to be about 74.5% higher than the TCTA based device (3.84 cd A(-1)). The studies on the time-resolved photoluminescence spectra of the QD-HTL composite structures showed that the energy transfer (ET) efficiencies from the two HTLs to the QD layer were similar and the charge separation between QDs and HTLs could be neglected. The enhancement in the performance of the CBP based device was attributed to the more efficient hole-injection from CBP to QDs. 23532854 Structural and Functional Aspects of Hetero-oligomers Formed by the Small Heat-Shock Proteins αB crystallin and HSP27. Small heat shock proteins (sHSPs) exist as large polydisperse species in which there is constant dynamic subunit exchange between oligomeric and dissociated forms. Their primary role in vivo is to bind destabilized proteins and prevent their misfolding and aggregating. αB Crystallin (αB) and HSP27 are the two most widely distributed and most studied sHSPs in the human body. They are co-expressed in different tissues where they are known to associate with each other and form hetero-oligomeric complexes. This study aimed to determine how these two sHSPs interact to form hetero-oligomers in vitro and whether, by doing so, there is an increase in their chaperone activity and stability compared to their homo-oligomeric forms. Results demonstrate that HSP27 and αB form polydisperse hetero-oligomers in vitro which have an average molecular mass higher than each of the homo-oligomers and are more thermostable than αB, but less so than HSP27. The hetero-oligomer chaperone function was found to be equivalent to that of αB, with each being significantly better at preventing the amorphous aggregation of α-lactalbumin and the amyloid fibril formation of α-synuclein in comparison to HSP27. Using mass spectrometry to monitor subunit exchange over time it was found that HSP27 and αB exchange subunits 23% faster than the reported rate for HSP27/αA, and almost twice that of αA/αB. This represents the first quantitative evaluation of HSP27/αB subunit exchange and the results are discussed in the broader context of regulation of function and cellular proteostasis. 23153322 Salivary gland function 5 years after radioactive iodine ablation in patients with differentiated thyroid cancer: direct comparison of pre- and postablation scintigraphies and their relation to xerostomia symptoms. Background: Chronic sialadenitis is one of the most frequent chronic complications after radioactive iodine (RAI) therapy for thyroid cancer. To evaluate the long-term effects of RAI ablation on salivary gland function, we investigated scintigraphic changes in salivary glands by direct comparison of two salivary gland scintigraphies (SGSs) taken before and at 5 years after an RAI ablation. Methods: SGS was performed just before RAI ablation (pre-SGS) and ∼5 years after RAI ablation (F/U SGS) in 213 subjects who underwent thyroidectomy for thyroid cancer. The uptake score (U score) was graded, and the ejection fraction (EF) was quantified for the parotid and submandibular glands at pre-SGS and F/U SGS. Changes in salivary gland function were graded as mild, moderate, or severe according to the differences in U score and EF between the two SGSs. Xerostomia was assessed and compared with the SGS findings. Results: Worsening of the U score was observed in 182 of 852 salivary glands (total: 21.3%; mild: 4.2%, moderate: 7.4%, severe: 9.7%), and 47.4% of the patients had a worsening U score for at least one of four salivary glands. A decrease in EF was observed in 173 of 852 salivary glands (total: 20.3%; mild: 5.4%, moderate: 6.8%, severe: 8.1%), and 43.7% of the patients experienced a decrease in the EF of at least one of the four salivary glands. Bilateral parotid gland dysfunction was the most commonly observed condition. Thirty-five (16.4%) patients complained of xerostomia at 5 years after RAI ablation. Scintigraphic changes in salivary gland function and xerostomia were more common in patients receiving 5.55 GBq, compared with 3.7 GBq. Xerostomia was more common in patients with submandibular gland dysfunction than those with parotid gland dysfunction (68.8% vs. 33.3%, p<0.05). The number of dysfunctional salivary glands was correlated with xerostomia (p<0.01). Conclusion: About 20% of the salivary glands were dysfunctional on SGS 5 years after a single RAI ablation, especially in patients who received higher doses of RAI. While parotid glands are more susceptible to (131)I-related damage, xerostomia was more associated with submandibular gland dysfunction and the prevalence of dysfunctional salivary glands. 23170798 Neuroprotection & mechanism of ethanol in stroke and traumatic brain injury therapy: new prospects for an ancient drug. Effective efforts to screen for agents that protect against the devastating effects of stroke have not produced viable results thus far. As a result this article reviews the possible role of ethanol as a neuroprotective agent in stroke and traumatic brain injury (TBI). Previous studies have associated ethanol consumption with a decreased risk of ischemic stroke, suggesting a neuroprotective mechanism. The translation of this clinical knowledge into basic science research with the goal of new therapy for acute stroke patients remains in its initial stages. In a recent study involving rats, we have shown that ethanol administration, in the correct dose after stroke onset, protects against ischemia-induced brain injury. The purpose of this paper is to discuss ethanol's neuroprotective properties in stroke when consumed as a preconditioning agent, in TBI with a positive blood alcohol content, and finally in stroke treatment, with the goal of using post-ischemia ethanol (PIE) therapy to ameliorate brain damage in the future. 23603192 Reproductive toxicity of Campomanesia xanthocarpa (Berg.) in female Wistar rats. ETHNOPHARMACOLOGICAL RELEVANCE: There is no evidence in the literature that substantiates the safety of Campomanesia xanthocarpa (Berg.) use during pregnancy. MATERIALS AND METHODS: Thirty three female rats were randomly assigned to three groups. One group of animals received the Campomanesia xanthocarpa extract via gavage at a dose of 26.3mg/kg/day from 6 to 15 days of pregnancy (organogenic period, T1) and another group received the same extract throughout the gestational period (from the 1st to the 20th day of pregnancy, T2). Control groups received distilled water. Euthanasia was done on 20th day, when the liver, kidney, spleen ovaries, fetuses and their respective placentas were removed. Implantations, reabsorptions, live and dead fetuses were recorded. RESULTS AND CONCLUSIONS: Campomanesia xanthocarpa, in these experimental conditions, did not disturb the reproductive function of female rats and did not interrupt the progress of the embryofetal development. Moreover, our results provide further evidence that the Campomanesia xanthocarpa treatment reduces reabsorption sites, increases placenta weight and the number of live fetuses and may therefore have therapeutic applications. 23076840 Contamination, parasitism and condition of Anguilla anguilla in three Italian stocks. In conjunction with habitat loss and overfishing, pollution and parasitism are believed to be relevant causes of collapse of Anguilla, as these can affect eel swimming ability and the development of gonads and embryos. The present study investigated Persistent Organic Pollutant (POP) concentrations, infection levels of Anguillicoloides crassus, lipid content and gonad abnormalities in eels sampled in 2007-2008 in three Italian water bodies (Caprolace Lake, Lesina Lagoon and Tevere River) that vary in salinity, trophic condition, contamination level and fishing pressure. Our analysis revealed that low-to-moderate levels of contamination and parasitism were not associated with gonad abnormalities in Caprolace Lake and Lesina Lagoon. On the contrary, POP concentrations and abundances of swim bladder nematodes were remarkably high in eels from the heavily urbanized Tevere River and were associated with significant gonad and swim bladder alterations. Contamination and infestation levels were so high to potentially impair spawner successful migration and reproduction. POP concentrations in Tevere eels also exceeded levels considered safe for food consumption. Though marginally contaminated, eels from the oligotrophic Caprolace Lake were in critical health condition: their lipid reserve was so low as to be considered insufficient to sustain the energetic costs of the transoceanic migration. Lesina eel stock was the only one displaying relatively good quality but here spawner abundance is likely limited by overfishing. Our results suggest that multiple stressors may potentially affect eel reproductive success. More definitive studies are needed to assess whether health effects caused by these multiple stressors are additive, compensatory or synergistic. 22370645 Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells. The hypothesis of cancer stem cells has been proposed to explain the therapeutic failure in a variety of cancers including lung cancers. Previously, we demonstrated acquisition of epithelial-mesenchymal transition, a feature highly reminiscent of cancer stem-like cells, in gefitinib-resistant A549 cells (A549/GR). Here, we show that A549/GR cells contain a high proportion of CXCR4+ cells that are responsible for having high potential of self-renewal activity in vitro and tumorigenicity in vivo. A549/GR cells exhibited strong sphere-forming activity and high CXCR4 expression and SDF-1α secretion compared with parent cells. Pharmacological inhibition (AMD3100) and/or siRNA transfection targeting CXCR4 significantly suppressed sphere-forming activity in A549 and A549/GR cells, and in various non-small cell lung cancer (NSCLC) cell lines. A549/GR cells showed enhanced Akt, mTOR and STAT3 (Y705) phosphorylation. Pharmacological inhibition of phosphatidyl inositol 3-kinase or transfection with wild-type PTEN suppressed phosphorylation of Akt, mTOR and STAT3 (Y705), sphere formation, and CXCR4 expression in A549/GR cells, whereas mutant PTEN enhanced these events. Inhibition of STAT3 by WP1066 or siSTAT3 significantly suppressed the sphere formation, but not CXCR4 expression, indicating that STAT3 is a downstream effector of CXCR4-mediated signaling. FACS-sorted CXCR4+ A549/GR cells formed many large spheres, had self-renewal capacity, demonstrated radiation resistance in vitro and exhibited stronger tumorigenic potential in vivo than CXCR4- cells. Lentiviral-transduction of CXCR4 enhanced sphere formation and tumorigenicity in H460 and A549 cells, whereas introduction of siCXCR4 suppressed these activities in A549/GR cells. Our data indicate that CXCR4+ NSCLC cells are strong candidates for tumorigenic stem-like cancer cells that maintain stemness through a CXCR4-medated STAT3 pathway and provide a potential therapeutic target for eliminating these malignant cells in NSCLC. 23347422 Surface functionalization of a polymeric lipid bilayer for coupling a model biological membrane with molecules, cells, and microstructures. We describe a stable and functional model biological membrane based on a polymerized lipid bilayer with a chemically modified surface. A polymerized lipid bilayer was formed from a mixture of two diacetylene-containing phospholipids, 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine (DiynePC) and 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphoethanolamine (DiynePE). DiynePC formed a stable bilayer structure, whereas the ethanolamine headgroup of DiynePE enabled functional molecules to be grafted onto the membrane surface. Copolymerization of DiynePC and DiynePE resulted in a robust bilayer. Functionalization of the polymeric bilayer provided a route to a robust and biomimetic surface that can be linked with biomolecules, cells, and three-dimensional (3D) microstructures. Biotin and peptides were grafted onto the polymeric bilayer for attaching streptavidin and cultured mammalian cells by molecular recognition, respectively. Nonspecific adsorption of proteins and cells on polymeric bilayers was minimum. DiynePE was also used to attach a microstructure made of an elastomer (polydimethylsiloxan: PDMS) onto the membrane, forming a confined aqueous solution between the two surfaces. The microcompartment enabled us to assay the activity of a membrane-bound enzyme (cyochrome P450). Natural (fluid) lipid bilayers were incorporated together with membrane-bound proteins by lithographically polymerizing DiynePC/DiynePE bilayers. The hybrid membrane of functionalized polymeric bilayers and fluid bilayers offers a novel platform for a wide range of biomedical applications including biosensor, bioassay, cell culture, and cell-based assay. 23265904 Discovery of liver-targeted inhibitors of stearoyl-CoA desaturase (SCD1). Inhibitors based on a benzo-fused spirocyclic oxazepine scaffold were discovered for stearoyl-coenzyme A (CoA) desaturase 1 (SCD1) and subsequently optimized to potent compounds with favorable pharmacokinetic profiles and in vivo efficacy in reducing the desaturation index in a mouse model. Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerant and allowed for tuning of potency and PK properties. After preparation and testing of a range of functional groups on the piperidine nitrogen, three classes of analogs were identified with single digit nanomolar potency: glycine amides, heterocycle-linked amides, and thiazoles. Responding to concerns about target localization and potential mechanism-based side effects, an initial effort was also made to improve liver concentration in an available rat PK model. An advanced compound 17m with a 5-carboxy-2-thiazole substructure appended to the spirocyclic piperidine scaffold was developed which satisfied the in vitro and in vivo requirements for more detailed studies. 23281578 Glycofullerenes inhibit viral infection. Water-soluble glycofullerenes based on a hexakis-adduct of [60]fullerene with an octahedral addition pattern are very attractive compounds providing a spherical presentation of carbohydrates. These tools have been recently described and they have been used to interact with lectins in a multivalent manner. Here, we present the use of these glycofullerenes, including new members with 36 mannoses, as compounds able to inhibit a DC-SIGN-dependent cell infection by pseudotyped viral particles. The results obtained in these experiments demonstrate for the first time that these glycoconjugates are adequate to inhibit efficiently an infection process, and therefore, they can be considered as very promising and interesting tools to interfere in biological events where lectins such as DC-SIGN are involved. 23414802 Discovery of novel 2-hydroxydiarylamide derivatives as TMPRSS4 inhibitors. TMPRSS4 is a novel type II transmembrane serine protease that has been implicated in the invasion and metastasis of colon cancer cells. In this study, a novel series of 2-hydroxydiarylamide derivatives were synthesized and evaluated for inhibiting TMPRSS4 serine protease activity and suppressing cancer cell invasion. These derivatives demonstrated good inhibitory activity against TMPRSS4 serine protease, which correlated with the promising anti-invasive activity of colon cancer cells overexpressing TMPRSS4. 23313639 Design and synthesis of biaryl aryl stilbenes/ethylenes as antimicrotubule agents. Two new series of compounds E-2,3,4-trimethoxy-6-styrylbiphenyls and 2,3,4-trimethoxy-6-(1-phenylvinyl)biphenyls were designed, synthesized and evaluated for antitubulin activity. A common intermediate 4,5,6-trimethoxybiphenyl-2-carbaldehydes was employed to generate the two scaffolds. Majority of the analogs inhibited cell proliferation and those functionalized with 3,4-(1,3-dioxolane) and 3,4-difluoro groups were identified as effective inhibitors in both the series. Treatments with 19b, 19c, 22b and 22c arrested cells at G2/M phase, disrupted microtubule network, accumulated tubulin in the soluble fraction and manifested an increased expression of the G2/M marker, Cyclin B1. Molecular docking analysis demonstrated the interaction of these compounds at the colchicine binding site of tubulin. 23349494 Disruption of the cerebral white matter network is related to slowing of information processing speed in patients with type 2 diabetes. Patients with type 2 diabetes often show slowing of information processing. Disruptions in the brain white matter network, possibly secondary to vascular damage, may underlie these cognitive disturbances. The present study reconstructed the white matter network of 55 nondemented individuals with type 2 diabetes (mean age 71±4y) and 50 age-, sex- and education-matched controls using diffusion MRI based fiber tractography. Graph theoretical analysis was then applied to quantify the efficiency of these networks. Patients with type 2 diabetes showed alterations in local and global network properties compared to controls (p<0.05). These structural network abnormalities were related to slowing of information processing speed in patients. This relation was partly independent of cerebrovascular lesion load. This study shows that the approach of characterizing the brain as a network using diffusion MRI and graph theory can provide new insights into how abnormalities in the white matter affect cognitive function in patients with diabetes. 23583513 Optimization of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of HIV capsid assembly inhibitors 1: Addressing configurational instability through scaffold modification. The optimization of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly that possess a labile stereocenter at C3 is described. Quaternization of the C3 position of compound 1 in order to prevent racemization gave compound 2, which was inactive in our capsid disassembly assay. A likely explanation for this finding was revealed by in silico analysis predicting a dramatic increase in energy of the bioactive conformation upon quaternization of the C3 position. Replacement of the C3 of the diazepine ring with a nitrogen atom to give the 1,5-dihydro-benzo[f][1,3,5]triazepine-2,4-dione analog 4 was well tolerated. Introduction of a rigid spirocyclic system at the C3 position gave configurationally stable 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione analog 5, which was able to access the bioactive conformation without a severe energetic penalty and inhibit capsid assembly. Preliminary structure-activity relationships (SAR) and X-ray crystallographic data show that knowledge from the 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly can be transferred to these new scaffolds. 23356207 Quantitative purity-activity relationships of natural products: the case of anti-tuberculosis active triterpenes from Oplopanax horridus. The present study provides an extension of the previously developed concept of purity-activity relationships (PARs) and enables the quantitative evaluation of the effects of multiple minor components on the bioactivity of residually complex natural products. The anti-tuberculosis active triterpenes from the Alaskan ethnobotanical Oplopanax horridus were selected as a case for the development of the quantitative PAR (QPAR) concept. The residual complexity of the purified triterpenes was initially evaluated by 1D- and 2D-NMR and identified as a combination of structurally related and unrelated impurities. Using a biochemometric approach, the qHNMR purity and anti-TB activity of successive chromatographic fractions of O. horridus triterpenes were correlated by linear regression analysis to generate a mathematical QPAR model. The results demonstrate that impurities, such as widely occurring monoglycerides, can have a profound impact on the observed antimycobacterial activity of triterpene-enriched fractions. The QPAR concept is shown to be capable of providing a quantitative assessment in situations where residually complex constitution contributes toward the biological activity of natural products. 23159396 High resolution fluorescence microscopy evidence on the transport of immunoglobulins. Differences between mammalian IgG, F(ab')2 and avian IgY. We describe the subcellular localization of horse F(ab')(2) and IgG, and ostrich IgY labeled with fluorescein isothiocyanate (FITC) administered IV to mice. We used wide field high sensitivity fluorescence microscopy deblurred by 3-dimensional blind deconvolution of kidney, liver, lungs and brain sections. Sections were obtained from mice sacrificed 15 min, 1 or 5 h after receiving FITC-immunoproteins, counter-stained with DAPI (4',6'-diamidino-2-phenylindole) and Evans blue. FITC-IgG and its fractions are rapidly taken up and extravasated by vascular endothelium. FITC-IgG and FITC-F(ab')(2) appear to be quickly secreted by glomeruli endothelium and to be reabsorbed along all nephron segments. FITC-IgG and FITC-F(ab')(2) appeared 15 min after IV injection within bronchial, alveolar and bile duct epithelium. Hepatocytes were loaded with fluorescence after 15 min of administration. Fluorescence was absent from brain slices, except for the endothelium of some vessels in brain ventricles which appeared intensely fluorescent. Fluorescence appeared in intracellular vesicles which conferred the tissues a glowing foamy aspect for up to 5 h after inoculation. Arterial elastic layers were intensely green after horse FITC-Ig inoculation. Ostrich FITC-IgY behaved completely differently to horse Ig's; only 1 h after injection it was possible to observe small brightly green scarce vesicles in vascular endothelium of arteries, interstitial kidney capillaries between nephron tubules and were also scarce in glomeruli endothelium; FITC-IgY appeared only in hepatic sinusoids in the liver. No IgY was seen in bronchial and alveolar endothelium, in bile ducts or in hepatocytes. 23300338 The Akt DUBbed InAktive. Akt is a central node in the phosphoinositide-3 kinase-Akt-mammalian target of rapamycin pathway and is activated by a multistep process in response to growth factor stimulation. An additional layer of posttranslational modification has emerged as a new paradigm in the regulation of Akt. The identification of an E3 ligase for Lys(63)-linked ubiquitination of Akt has now been complemented with the discovery of the tumor suppressor cylindromatosis as a deubiquitinating enzyme (DUB) for Akt. Thus, like phosphorylation and dephosphorylation, cycles of ubiquitination and deubiquitination provide additional on-off switches that keep Akt activity in balance, and disturbances in this balance have pathological consequences. 23265282 Streamlined expressed protein ligation using split inteins. Chemically modified proteins are invaluable tools for studying the molecular details of biological processes, and they also hold great potential as new therapeutic agents. Several methods have been developed for the site-specific modification of proteins, one of the most widely used being expressed protein ligation (EPL) in which a recombinant α-thioester is ligated to an N-terminal Cys-containing peptide. Despite the widespread use of EPL, the generation and isolation of the required recombinant protein α-thioesters remain challenging. We describe here a new method for the preparation and purification of recombinant protein α-thioesters using engineered versions of naturally split DnaE inteins. This family of autoprocessing enzymes is closely related to the inteins currently used for protein α-thioester generation, but they feature faster kinetics and are split into two inactive polypeptides that need to associate to become active. Taking advantage of the strong affinity between the two split intein fragments, we devised a streamlined procedure for the purification and generation of protein α-thioesters from cell lysates and applied this strategy for the semisynthesis of a variety of proteins including an acetylated histone and a site-specifically modified monoclonal antibody. 23362239 Ca²⁺-dependent phosphorylation of Ca²⁺ cycling proteins generates robust rhythmic local Ca²⁺ releases in cardiac pacemaker cells. The spontaneous beating of the heart is governed by spontaneous firing of sinoatrial node cells, which generate action potentials due to spontaneous depolarization of the membrane potential, or diastolic depolarization. The spontaneous diastolic depolarization rate is determined by spontaneous local submembrane Ca²⁺ releases through ryanodine receptors (RyRs). We sought to identify specific mechanisms of intrinsic Ca²⁺ cycling by which sinoatrial node cells, but not ventricular myocytes, generate robust, rhythmic local Ca²⁺ releases. At similar physiological intracellular Ca²⁺ concentrations, local Ca²⁺ releases were large and rhythmic in permeabilized sinoatrial node cells but small and random in permeabilized ventricular myocytes. Furthermore, sinoatrial node cells spontaneously released more Ca²⁺ from the sarcoplasmic reticulum than did ventricular myocytes, despite comparable sarcoplasmic reticulum Ca²⁺ content in both cell types. This ability of sinoatrial node cells to generate larger and rhythmic local Ca²⁺ releases was associated with increased abundance of sarcoplasmic reticulum Ca²⁺-ATPase (SERCA), reduced abundance of the SERCA inhibitor phospholamban, and increased Ca²⁺-dependent phosphorylation of phospholamban and RyR. The increased phosphorylation of RyR in sinoatrial node cells may facilitate Ca²⁺ release from the sarcoplasmic reticulum, whereas Ca²⁺-dependent increase in phosphorylation of phospholamban relieves its inhibition of SERCA, augmenting the pumping rate of Ca²⁺ required to support robust, rhythmic local Ca²⁺ releases. The differences in Ca²⁺ cycling between sinoatrial node cells and ventricular myocytes provide insights into the regulation of intracellular Ca²⁺ cycling that drives the automaticity of sinoatrial node cells. 23219946 Progressive post-yield behavior of human cortical bone in shear. Bone fragility depends on its post-yield behavior since most energy dissipation in bone occurs during the post-yield deformation. Previous studies have investigated the progressive changes in the post-yield behavior of human cortical bone in tension and compression using a novel progressive loading scheme. However, little is known regarding the progressive changes in the post-yield behavior of bone in shear. The objective of this short study was to address this issue by testing bone specimens in an inclined double notch shear configuration using the progressive loading protocol. The results of this study indicated that the shear modulus of bone decreased with respect to the applied strain, but the rate of degradation was about 50% less than those previously observed in compression and tension tests. In addition, a quasi-linear relationship between the plastic and applied strains was observed in shear mode, which is similar to those previously reported in tension and compression tests. However, the viscous responses of bone (i.e. relaxation time constants and stress magnitude) demonstrated slight differences in shear compared with those observed in tension and compression tests. Nonetheless, the results of this study suggest that the intrinsic mechanism of plastic deformation of human cortical bone may be independent of loading modes. 23235742 Particle shape optimization by changing from an isotropic to an anisotropic nanostructure: preparation of highly active and stable supported Pt catalysts in microemulsions. We recently introduced a new method to synthesize an active and stable Pt catalyst, namely thermo-destabilization of microemulsions (see R. Y. Parapat, V. Parwoto, M. Schwarze, B. Zhang, D. S. Su and R. Schomäcker, J. Mater. Chem., 2012, 22 (23), 11605-11614). We are able to produce Pt nanocrystals with a small size (2.5 nm) of an isotropic structure i.e. truncated octahedral and deposit them well on support materials. Although we have obtained good results, the performance of the catalyst still needed to be improved and optimized. We followed the strategy to retain the small size but change the shape to an anisotropic structure of Pt nanocrystals which produces more active sites by means of a weaker reducing agent. We found that our catalysts are more active than those we reported before and even show the potential to be applied in a challenging reaction such as hydrogenation of levulinic acid. 22372916 Role of excipients in successful development of self-emulsifying/microemulsifying drug delivery system (SEDDS/SMEDDS). The oral delivery of hydrophobic drug presents a major challenge because of the low aqueous solubility of such compounds. Self-emulsifying/microemulsifying drug delivery system (SEDDS/SMEDDS), which are isotropic mixtures of oils, surfactants, solvents and co-solvents/surfactants, can be used for the design of formulations in order to improve the oral absorption of highly lipophilic drug compounds. The efficiency of oral absorption of said drug from such type of formulation depends on many formulation-related parameters, such as surfactant concentration, oil/surfactant ratio, polarity of the emulsion, droplet size and charge, all of which in essence determine the self-emulsification ability. Thus, only very specific pharmaceutical excipient combinations will lead to efficient self-emulsifying systems. With the growing interest in this field, there is an increasing need for guidelines in excipient selection to obtain effective delivery system with improved bioavailability. The aim of this review is to present the recent approaches in selecting the most appropriate lipid system(s); methods for its characterization and role of various excipients for improved delivery of dosage form. 23219325 Novel cinnoline-based inhibitors of LRRK2 kinase activity. Leucine rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson's disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of cinnoline-3-carboxamides that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays. These compounds are also shown to be potent inhibitors in a cellular assay and to have good to excellent CNS penetration. 23552843 Intracellular cleavable poly(2-dimethylaminoethyl methacrylate) functionalized mesoporous silica nanoparticles for efficient siRNA delivery in vitro and in vivo. A low cytotoxicity and high efficiency delivery system with the advantages of low cost and facile fabrication is needed for the application of small interfering RNA (siRNA) delivery both in vitro and in vivo. For these prerequisites, cationic polymer-mesoporous silica nanoparticles (ssCP-MSNs) were prepared by surface functionalized mesoporous silica nanoparticles with disulfide bond cross-linked poly(2-dimethylaminoethyl methacrylate) (PDMAEMA). In vitro and in vivo evaluations were performed. The synthesized ssCP-MSNs are 100-150 nm in diameter with a pore size of 10 nm and a positively charged surface with a high zeta potential of 27 mV. Consequently, the ssCP-MSNs showed an excellent binding capacity for siRNA, and an enhancement in the cell uptake and cytosolic availability of siRNA. Furthermore, the intracellular reducing cleavage of the disulfide bonds cross-linking the PDMAEMA segments led to intracellular cleavage of PDMAEMA from ssCP-MSNs, which facilitated the intracellular triggered release of siRNA. Therefore, promoted RNA interference was observed in HeLa-Luc cells, which was equal to that of Lipofectamine 2000. Significantly, compared to Lipofectamine 2000, the ssCP-MSNs were more biocompatible, with low cytotoxicity (even non-cytotoxicity) and promotion of cell proliferation to HeLa-Luc cells. The in vivo systemic distribution studies certified that ssCP-MSNs/siRNA could prolong the duration of siRNA in vivo, and that they accumulated in the adrenal gland, liver, lung, spleen, kidney, heart and thymus after intravenous injection. Encouragingly, with the ability to deliver siRNA to a tumor, ssCP-MSNs/siRNA showed a tumor suppression effect in the HeLa-Luc xenograft murine model after intravenous injection. Therefore, the ssCP-MSNs cationic polymer-mesoporous silica nanoparticles with low cytotoxicity are promising for siRNA delivery. 23280766 Comparing the effectiveness of chronic water column tests with the crustaceans Hyalella azteca (order: Amphipoda) and Ceriodaphnia dubia (order: Cladocera) in detecting toxicity of current-use insecticides. Standard U.S. Environmental Protection Agency laboratory tests are used to monitor water column toxicity in U.S. surface waters. The water flea Ceriodaphnia dubia is among the most sensitive test species for detecting insecticide toxicity in freshwater environments.Its usefulness is limited, however, when water conductivity exceeds 2,000 µS/cm (approximately 1 ppt salinity) and test effectiveness is insufficient. Water column toxicity tests using the euryhaline amphipod Hyalella azteca could complement C. dubia tests; however, standard chronic protocols do not exist. The present study compares the effectiveness of two water column toxicity tests in detecting the toxicity of two organophosphate (OP) and two pyrethroid insecticides: the short-term chronic C. dubia test, which measures mortality and fecundity, and a 10-d H. azteca test, which measures mortality and growth. Sensitivity was evaluated by comparing effect data, and end point variability was evaluated by comparing minimum significant differences. Tests were performed in synthetic water and filtered ambient water to quantify the influence of water matrix on effect concentrations. The H. azteca test detected pyrethroid toxicity far more effectively, while the C. dubia test was more sensitive to OPs. Among endpoints, H. azteca mortality was most robust. The results demonstrate that the H. azteca test is preferable when conductivity of water samples is 2,000 to 10,000 µS/cm or if contaminants of concern include pyrethroid insecticides. 23594789 Restoration of cardiac tissue thyroid hormone status in experimental hypothyroidism: a dose-response study in female rats. Thyroid hormones (THs) play a pivotal role in regulating cardiovascular homeostasis. To provide a better understanding of the coordinated processes that govern cardiac TH bioavailability, this study investigated the influence of serum and cardiac TH status on the expression of TH transporters and cytosolic binding proteins in the myocardium. In addition, we sought to determine if administration of T3 (instead of T4) improves the relationship between THs in serum and cardiac tissue, and cardiac function over a short-term treatment period. Adult female SD rats were made hypothyroid by seven weeks treatment with the anti-thyroid drug PTU (6-n-propyl-2-thiouracil). After establishing hypothyroidism, rats were assigned to one of five graded T3 (triiodothyronine) dosages plus PTU for a two week dose-response experiment. Untreated, age matched rats served as euthyroid controls. PTU was associated with depressed serum and cardiac tissue T3 and T4 levels, arteriolar atrophy, altered TH transporter and cytosolic TH binding protein expression, fetal gene re-expression, and cardiac dysfunction. Short-term administration of T3 led to a mismatch between serum and cardiac tissue TH levels. Normalization of serum T3 levels was not associated with restoration of cardiac tissue T3 levels or cardiac function. In fact, a 3 fold higher T3 dosage was necessary to normalize cardiac tissue T3 levels and cardiac function. Importantly, this study provides the first comprehensive data on the relationship between altered TH status (serum and cardiac tissue), cardiac function, and the coordinated in vivo changes in cardiac TH membrane transporters and cytosolic TH binding proteins in altered TH states. 23331178 Effect of headgroup on the physicochemical properties of phospholipid bilayers in electric fields: size matters. The effect of molecular structure on ensemble structure of phospholipid films has been investigated. Bilayers of dimyristoyl phosphatidylethanolamine (DMPE) were prepared on Au(111) electrodes using Langmuir-Blodgett and Langmuir-Schaeffer deposition. Capacitance and charge density measurements were used to investigate the adsorption behavior and barrier properties of the lipid bilayers. In situ polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS) was employed to investigate the organization of the molecules within the bilayer. DMPE bilayers exhibit lower capacitance than bilayers formed from the related lipid, dimyristoyl phosphatidylcholine (DMPC). The infrared data show that these results can be explained by structural differences between the bilayers formed from each molecule. DMPE organizes into bilayers with hydrocarbon chains tilted at a smaller angle to the surface normal, which results in a thicker film. The hydrocarbon chains contain few conformational defects. Spectra in the carbonyl and phosphate stretching mode regions indicate low solvent content of DMPE films. Both of these effects combine to produce films with lower capacitance and enhanced barrier properties. The results are explained in terms of the differences in structure between the constituent molecules. 23535321 Heterocyclic bismuth carboxylates based on a diphenyl sulfone scaffold: Synthesis and antifungal activity against Saccharomycescerevisiae. A series of heterocyclic organobismuth(III) carboxylates 4 and 5 [RCO2Bi(C6H4-2-SO2C6H4-1'-)] derived from diphenyl sulfone was synthesized to determine the influence of the carboxylate ligand structure on the lipophilicity and antifungal activity against the yeast Saccharomyces cerevisiae. In contrast to the clear structure-activity relationship between the size of the inhibition zone and the value of ClogP for specific substitution on diphenyl sulfone scaffold 1 [ClBi(5-RC6H3-2-SO2C6H4-1'-)], scaffolds 4 and 5 showed similar inhibition activities irrespective of the ClogP value. This suggests that these molecules function inside the yeast cell by separating into the cationic heterocyclic bismuth scaffold and the anionic carboxylate moiety, and that the bismuth scaffold plays an important role in the inhibition activity. 23086035 PGC-1α improves glucose homeostasis in skeletal muscle in an activity-dependent manner. Metabolic disorders are a major burden for public health systems globally. Regular exercise improves metabolic health. Pharmacological targeting of exercise mediators might facilitate physical activity or amplify the effects of exercise. The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) largely mediates musculoskeletal adaptations to exercise, including lipid refueling, and thus constitutes such a putative target. Paradoxically, forced expression of PGC-1α in muscle promotes diet-induced insulin resistance in sedentary animals. We show that elevated PGC-1α in combination with exercise preferentially improves glucose homeostasis, increases Krebs cycle activity, and reduces the levels of acylcarnitines and sphingosine. Moreover, patterns of lipid partitioning are altered in favor of enhanced insulin sensitivity in response to combined PGC-1α and exercise. Our findings reveal how physical activity improves glucose homeostasis. Furthermore, our data suggest that the combination of elevated muscle PGC-1α and exercise constitutes a promising approach for the treatment of metabolic disorders. 23497879 Physicochemical characterisation of dietary fibre components and their ability to bind some process-induced mutagenic heterocyclic amines, Trp-P-1, Trp-P-2, AαC and MeAαC. The physicochemical properties of potato fibre, wheat bran and oat samples were investigated, along with their binding capability to heterocyclic amines (HCAs). Potato fibre displayed highest total dietary fibre content (71.8/100g dry weight basis, dwb), followed by wheat bran (57.2/100 g dwb) and oat sample 2 (53.0/100 g dwb). Oat samples 1, 3 and 4 displayed considerably lower dietary fibre content (20.5-28.8/100g, dwb). Oat samples 3 and 4 displayed highest soluble fibre content (70-83%), and oat sample 3 also displayed highest swelling and water retention capacity (WRC). Dietary fibre samples, except samples 3 and 4, displayed improved binding to HCAs as sample weight increased. The behaviour of wheat bran and potato fibre was similar to oat samples 1 and 2. Binding of MeAαC was comparatively greater than that of other HCAs. Dietary fibre fractions with high insoluble fibre and functional groups of HCAs may significantly contribute to the binding capacity. 23411283 Biguanide related compounds in traditional antidiabetic functional foods. Biguanides such as metformin are widely used worldwide for the treatment of type-2 diabetes. The identification of guanidine and related compounds in French lilac plant (Galega officinalis L.) led to the development of biguanides. Despite of their plant origin, biguanides have not been reported in plants. The objective of this study was to quantify biguanide related compounds (BRCs) in experimentally or clinically substantiated antidiabetic functional plant foods and potatoes. The corrected results of the Voges-Proskauer (V-P) assay suggest that the highest amounts of BRCs are present in green curry leaves (Murraya koenigii (L.) Sprengel) followed by fenugreek seeds (Trigonella foenum-graecum L.), green bitter gourd (Momordica charantia Descourt.), and potato (Solanum tuberosum L.). Whereas, garlic (Allium sativum L.), and sweet potato (Ipomea batatas (L.) Lam.) contain negligible amounts of BRCs. In addition, the possible biosynthetic routes of biguanide in these plant foods are discussed. 23619019 Cardioprotective effects of the YiQiFuMai injection and isolated compounds on attenuating chronic heart failure via NF-κB inactivation and cytokine suppression. ETHNOPHARMACOLOGICAL RELEVANCE: The YiQiFuMai injection (YQFM) is a traditional Chinese medicine for the treatment of chronic heart failure (CHF). The present study not only evaluated the cardioprotective effect and anti-inflammatory mechanism of the YQFM injection in an experimental model of CHF but also investigated its bioactive constituents in vitro. MATERIALS AND METHODS: The left anterior descending coronary artery (LAD) in rats was ligated to make an animal model of CHF. From this, electrocardiographic parameters and exterior signs of rat hearts were recorded. Additionally, the histopathology of heart tissues was examined, and parameters of inflammatory stress were measured. Experiments were performed over two months in LAD-ligation rats treated with YQFM or vehicle. Treatment with Captopril was used as a positive control, which has previously been shown to prevent CHF, and rats without LAD-ligation were used as a negative control. Furthermore, we screened and identified potential anti-inflammatory constituents by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS) combined with NF-κB activity luciferase reporter assay systems. Further cytokine detection confirmed the anti-inflammatory effects of the potential NF-κB inhibitors from YQFM. RESULTS: The administration of YQFM significantly improved cardiac function and ameliorated the activity level of inflammatory mediators (such as tumor necrosis factor-alpha, interleukin-6, and interleukin-1β) in CHF rats. Eight potential anti-inflammatory ingredients, ginsenosides Rb1, Rg1, Rf, Rh1, Rc, Rb2, Ro, and Rg3, were characterized and confirmed. Among these compounds, ginsenoside Ro was revealed as a new NF-κB inhibitor. CONCLUSION: The results suggested that NF-κB inactivation and cytokine suppression might be one of the main mechanisms of YQFM that caused ameliorative effects in CHF rats, and the major constituents of ginsenosides were identified playing a key role in the treatment of CHF. 23151381 Effect of Australian elapid venoms on blood coagulation: Australian Snakebite Project (ASP-17). Snake venoms contain toxins that activate the coagulation network and cause venom-induced consumption coagulopathy. A previously developed mathematical model of the coagulation network was refined and used to describe and predict the time course of changes in the coagulation factors following envenomation by Brown snake (Pseudonaja spp.), Tiger snake (Notechis scutatus), Rough-scaled snake (Tropidechis carinatus) and Hoplocephalus spp. (Stephens banded, Pale headed and Broad headed). Simulations of the time course of the change in coagulation factors were compared to data obtained from a large prospective study of Australian snake bites - the Australian Snakebite Project. The model predictions were also compared against data for partial and complete VICC obtained from the same study. The model simulations were used to understand the differences in consumption and recovery of clotting factors in partial versus complete VICC as well as among bites from different snake types. The model suggested that the venoms were absorbed almost instantaneously and provided a reasonable prediction of the observed concentration of clotting factors over time in patients bitten by Australian elapid snakes. The model predictions suggested a higher consumption of factors (fibrinogen, II and IX in particular) in patients with complete VICC compared to those with partial VICC. The model also predicted that snakes with "Xa-like" venoms may produce a less severe VICC than snakes with "Xa:Va-like" venoms. 23423353 Translational repression of thymidylate synthase by targeting its mRNA. Resistance to drugs targeting human thymidylate synthase (TS) poses a major challenge in the field of anti-cancer therapeutics. Overexpression of the TS protein has been implicated as one of the factors leading to the development of resistance. Therefore, repressing translation by targeting the TS mRNA could help to overcome this problem. In this study, we report that the compound Hoechst 33258 (HT) can reduce cellular TS protein levels without altering TS mRNA levels, suggesting that it modulates TS expression at the translation level. We have combined nuclear magnetic resonance, UV-visible and fluorescence spectroscopy methods with docking and molecular dynamics simulations to study the interaction of HT with a region in the TS mRNA. The interaction predominantly involves intercalation of HT at a CC mismatch in the region near the translational initiation site. Our results support the use of HT-like compounds to guide the design of therapeutic agents targeting TS mRNA. 23150491 Maternal and fetal exposure to bisphenol a is associated with alterations of thyroid function in pregnant ewes and their newborn lambs. The putative thyroid-disrupting properties of bisphenol A (BPA) highlight the need for an evaluation of fetal exposure and its consequence on the mother/newborn thyroid functions in models relevant to human. The goals of this study were to characterize in sheep a relevant model for human pregnancy and thyroid physiology, the internal exposures of the fetuses and their mothers to BPA and its main metabolite BPA-glucuronide (Gluc), and to determine to what extent it might be associated with thyroid disruption. Ewes were treated with BPA [5 mg/(kg · d) sc] or vehicle from d 28 until the end of pregnancy. Unconjugated BPA did not appear to accumulate in pregnant ewes, and its concentration was similar in the newborns and their mothers (0.13 ± 0.02 and 0.18 ± 0.03 nmol/ml in cord and maternal blood, respectively). In amniotic fluid and cord blood, BPA-Gluc concentrations were about 1300-fold higher than those of BPA. Total T(4) concentrations were decreased in BPA-treated pregnant ewes and in the cord and the jugular blood of their newborns (30% decrease). A similar difference was observed for free T(4) plasma concentrations in the jugular blood of the newborns. Our results show in a long-gestation species with a similar regulatory scheme of thyroid function as humans that BPA in utero exposure can be associated with hypothyroidism in the newborns. If such an effect were to be confirmed for a more relevant exposure scheme to BPA, this would constitute a major issue for BPA risk assessment. 23151000 Molecular modeling and simulation of membrane lipid-mediated effects on GPCRs. Functioning of G protein-coupled receptors (GPCRs) is tightly linked to the membrane environment, but a molecular level understanding of the modulation of GPCR by membrane lipids is not available. However, specific receptor-lipid interactions as well as unspecific effects mediated by the bulk properties of the membrane (thickness, curvature, etc.) have been proposed to be key regulators of GPCR modulation. In this review, we examine computational efforts made towards modeling and simulation of (i) the complex behavior of membrane lipids, (ii) membrane lipid-GPCR interactions as well as membrane lipid-mediated effects on GPCRs and (iii) GPCR oligomerization in a native-like membrane environment. We propose that, from the perspective of computational modeling, all three of these components need to be addressed in order to achieve a deeper understanding of GPCR functioning. Presently, we are able to simulate numerous lipid properties applying advanced computational techniques, although some barriers, such as the time-length of these simulations, need to be overcome. Implementing three-dimensional structures of GPCRs in such validated membrane systems can give novel insights in membrane-dependent receptor modulation and formation of higher order receptor complexes. Finally, more realistic GPCR-membrane models would provide a very useful tool in studying receptor behavior and its modulation by small drug-like ligands, a relevant issue for drug discovery. 23092877 GH improves spatial memory and reverses certain anabolic androgenic steroid-induced effects in intact rats. GH has previously been shown to promote cognitive functions in GH-deficient rodents. In this study we report the effects of GH on learning and memory in intact rats pretreated with the anabolic androgenic steroid nandrolone. Male Wistar rats received nandrolone decanoate (15 mg/kg) or peanut oil every third day for 3 weeks and were subsequently treated with recombinant human GH (1.0 IU/kg) or saline for 10 consecutive days. During the GH/saline treatment spatial learning and memory were tested in the Morris water maze (MWM). Also, plasma levels of IGF1 were assessed and the gene expression of the GH receptors (Ghr), Igf1 and Igf2, in hippocampus and frontal cortex was analyzed. The results demonstrated a significant positive effect of GH on memory functions and increased gene expression of Igf1 in the hippocampus was found in the animals treated with GH. In addition, GH was demonstrated to increase the body weight gain and was able to attenuate the reduced body weight seen in nandrolone-treated animals. In general, the rats treated with nandrolone alone did not exhibit any pronounced alteration in memory compared with controls in the MWM, and in many cases GH did not induce any alteration. Regarding target zone crossings, considered to be associated with spatial memory, the difference between GH- and steroid-treated animals was significant and administration of GH improved this parameter in the latter group. In conclusion, GH improves spatial memory in intact rats and can reverse certain effects induced by anabolic androgenic steroid. 23561199 A Rapid tool for the stability assessment of natural food colours. Natural food colours lack stability under a number of conditions such as pH variation, oxidation, hydration, heat treatment and, most importantly, exposure to daylight. Stability tests to assess shelf life of natural colours under light irradiation can be time consuming. Thus, an accelerated test carried out under high light intensity irradiation that can be related to normal daylight irradiation conditions is highly desirable. Samples of various natural colouring solutions were prepared in aqueous model matrices at a range of pH values to mimic the majority of food matrices, pasteurised and irradiated under normal D65 light (0.2W/m(2)) at 25°C, and in parallel under high light intensity irradiation (30W/m(2)) at 3 different temperatures (25, 35 and 45°C). Similarly to the already known Q10 parameters for temperature, acceleration factors QL for irradiation, were determined and used for the first time to obtain a link between colour degradation under normal and accelerated conditions. It was possible, using these acceleration factors, to greatly reduce the time required to predict and compare the shelf life stability for a series of natural colours in aqueous model systems. 23541637 Aldosterone-induced ENaC and basal Na(+)/K(+)-ATPase trafficking via protein kinase D1-phosphatidylinositol 4-kinaseIIIβ trans Golgi signalling in M1 cortical collecting duct cells. Aldosterone regulates Na(+) transport in the distal nephron through multiple mechanisms that include the transcriptional control of epithelial sodium channel (ENaC) and Na(+)/K(+)-ATPase subunits. Aldosterone also induces the rapid phosphorylation of Protein Kinase D1 (PKD1). PKD isoforms regulate protein trafficking, by the control of vesicle fission from the trans Golgi network (TGN) through activation of phosphatidylinositol 4-kinaseIIIβ (PI4KIIIβ). We report rapid ENaCγ translocation to the plasma membrane after 30min aldosterone treatment in polarized M1 cortical collecting duct cells, which was significantly impaired in PKD1 shRNA-mediated knockdown cells. In PKD1-deficient cells, the ouabain-sensitive current was significantly reduced and Na(+)/K(+)-ATPase α and β subunits showed aberrant localization. PKD1 and PI4KIIIβ localize to the TGN, and aldosterone induced an interaction between PKD1 and PI4KIIIβ following aldosterone treatment. This study reveals a novel mechanism for rapid regulation of ENaC and the Na(+)/K(+)-ATPase, via directed trafficking through PKD1-PI4KIIIβ signalling at the level of the TGN. 23472745 Bioactivity of tomato hybrid powder: antioxidant compounds and their biological activities. Abstract The antioxidant and cytotoxic activities and the polyphenolic and anthocyanin contents of tomato hybrid powders were studied. Tomato powders were obtained, starting from the fresh fruits that had undergone an industrial process of drying and pulverization at two different temperatures. Antioxidant activities were evaluated in different extracts by using spectrophotometric assays: 2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid and N,N-dimethyl-p-phenylenediamine dihydrochloride cation radical inhibition for lipophilic and hydrophilic extracts, respectively, and 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay for polyphenolic extracts. Moreover, polyphenolic and anthocyanin contents were also carried out to detect the presence of these bioactive compounds. The effect of cytotoxic activity in vitro of tomato hybrid powder extracts on T47D (human breast carcinoma) cells was also evaluated. Results showed good antioxidant activities in lipophilic, polyphenolic, and hydrophilic extracts of samples that were obtained at a lower temperature. Extracts of the sample obtained at a higher temperature presented moderate antioxidant activity, lower than the extracts of other samples, which was probably due to the loss of labile antioxidant compounds during the industrial process. Very interesting was the presence of anthocyanins in both samples, even if in traces, and also a moderate cytotoxicity of a lipophilic extract on T47D cells. Therefore, tomato hybrid powders, on the basis of their multifunctional properties, could have a biotechnological application in agri-food or cosmetic industries as an additive for improving nutritional and/or bioactive qualities of commercial products used in daily nutrition and cosmetics. 23420115 Psychopharmacology of theobromine in healthy volunteers. BACKGROUND: Theobromine, a methylxanthine related to caffeine and present in high levels in cocoa, may contribute to the appeal of chocolate. However, current evidence for this is limited. OBJECTIVES: We conducted a within-subjects placebo-controlled study of a wide range of oral theobromine doses (250, 500, and 1,000 mg) using an active control dose of caffeine (200 mg) in 80 healthy participants. RESULTS: Caffeine had the expected effects on mood including feelings of alertness and cardiovascular parameters. Theobromine responses differed according to dose; it showed limited subjective effects at 250 mg and negative mood effects at higher doses. It also dose-dependently increased heart rate. In secondary analyses, we also examined individual differences in the drug's effects in relation to genes related to their target receptors, but few associations were detected. CONCLUSIONS: This study represents the highest dose of theobromine studied in humans. We conclude that theobromine at normal intake ranges may contribute to the positive effects of chocolate, but at higher intakes, effects become negative. 23477623 Comparison of the inhibitory effect against copper ion-induced oxidation in rat plasma after oral administration of salvianolic acid B and its decocted solutions. The effects of salvianolic acid B (Sal B) decoction on antioxidative activities were evaluated. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity, Fe(2+)-chelating activity, reducing power, and total phenolic content of the Sal B-decocted solutions did not change significantly after decoction in an aqueous solution. However, the formation of cholesteryl ester hydroperoxide (CE-OOH) in rat blood plasma containing the Sal B-decocted solutions was more effectively inhibited than that of plasma containing the Sal B solution, regardless of the decoction time. In addition, the accumulation of CE-OOH in rat plasma after oral administration of the Sal B-decocted solutions was more effectively suppressed than when the Sal B solution was administered, considering the lag time. It is likely that the decoction was partly responsible for the increased antioxidant activity in blood plasma. Therefore, the Sal B-decocted solution may contribute more to antioxidant defense in blood than a Sal B solution that is not decocted. 23315216 Transaldolase deficiency: report of 12 new cases and further delineation of the phenotype. PURPOSE: Transaldolase deficiency is a recently described inborn error of pentose phosphate pathway. We conducted this study to further delineate the associated phenotype. METHODS AND RESULTS: We report on 12 new cases representing six families with this metabolic defect that were observed over an 8 year span. None of these cases received the correct diagnosis initially because of significant overlap in the presenting symptoms (growth retardation, dysmorphic features, cutis laxa, congenital heart disease, hepatosplenomegaly, pancytopenia, and bleeding tendency) with a wide range of genetic disorders. However, the consanguineous nature of these families allowed us to pursue autozygome analysis, which highlighted TALDO as the likely candidate gene and sequencing confirmed segregation of a novel homozygous mutation with the disease in all the studied families. Biochemical analysis was also consistent with transaldolase deficiency. CONCLUSION: This study expands the clinical definition of transaldolase deficiency, and adds to its allelic heterogeneity. In addition, we emphasize the diagnostic challenge posed by this rare and pleiotropic metabolic disorder. 23448682 Synthetically tractable click hydrogels for three-dimensional cell culture formed using tetrazine-norbornene chemistry. The implementation of bio-orthogonal click chemistries is a topic of growing importance in the field of biomaterials, as it is enabling the development of increasingly complex hydrogel materials capable of providing dynamic, cell-instructive microenvironments. Here, we introduce the tetrazine-norbornene inverse electron demand Diels-Alder reaction as a new cross-linking chemistry for the formation of cell laden hydrogels. The fast reaction rate and irreversible nature of this click reaction allowed for hydrogel formation within minutes when a multifunctional PEG-tetrazine macromer was reacted with a dinorbornene peptide. In addition, the cytocompatibility of the polymerization led to high postencapsulation viability of human mesenchymal stem cells, and the specificity of the tetrazine-norbornene reaction was exploited for sequential modification of the network via thiol-ene photochemistry. These advantages, combined with the synthetic accessibility of the tetrazine molecule compared to other bio-orthogonal click reagents, make this cross-linking chemistry an interesting and powerful new tool for the development of cell-instructive hydrogels for tissue engineering applications. 23570328 Chemoselective metal-free aerobic alcohol oxidation in lignin. An efficient organocatalytic method for chemoselective aerobic oxidation of secondary benzylic alcohols within lignin model compounds has been identified. Extension to selective oxidation in natural lignins has also been demonstrated. The optimal catalyst system consists of 4-acetamido-TEMPO (5 mol %; TEMPO = 2,2,6,6-tetramethylpiperidine-N-oxyl) in combination with HNO3 and HCl (10 mol % each). Preliminary studies highlight the prospect of combining this method with a subsequent oxidation step to achieve C-C bond cleavage. 22674653 Formulas used by tibetan doctors at men-tsee-khang in India for the treatment of neuropsychiatric disorders and their correlation with pharmacological data. The aim of the present study was to identify formulas used at Men-Tsee-Khang (Tibetan Medical and Astrological Institute), India, for the treatment of neuropsychiatric disorders and to compare the Tibetan usage of particular ingredients with pharmacological data from the scientific database. Using ethnographic methods, five doctors were selected and interviewed. A correlation was observed between central nervous system disorders and rLung, one of the three humors in Tibetan medicine, which imbalance is the source of mental disorders, and ten multi-ingredient formulas used to treat the imbalance of this particular humor were identified. These formulas utilize 61 ingredients; among them were 48 plant species. Each formula treats several symptoms related to rLung imbalance, so the plants may have therapeutic uses distinct from those of the formulas in which they are included. Myristica fragrans, nutmeg, is contained in 100% of the formulas, and its seeds exhibit stimulant and depressant actions affecting the central nervous system. Preclinical and clinical data from the scientific literature indicate that all of the formulas include ingredients with neuropsychiatric action and corroborate the therapeutic use of 75.6% of the plants. These findings indicate a level of congruence between the therapeutic uses of particular plant species in Tibetan and Western medicines. Copyright © 2012 John Wiley & Sons, Ltd. 23577589 Flexibly timed once-daily dosing with degludec: a new ultra-long-acting basal insulin. Insulin treatment in type 1 and type 2 diabetes (T1D and T2D) is highly efficacious, but in practice, non-adherence and ineffective dose titration limit its effectiveness. Barriers to more effective insulin treatment are numerous, including hypoglycaemia, fear of hypoglycaemia and concern about weight gain. The regular treatment timing needed with conventional basal insulins [neutral protamine Hagedorn (NPH) insulin and the first-generation analogues glargine and detemir] may also make adherence to these treatments problematic for many patients. Indeed, surveys indicate that the rigidity of this schedule induces some patients with T1D and T2D to omit insulin doses. Degludec is a novel, ultra-long-acting basal insulin analogue that is as effective as insulin glargine, but significantly reduces patients' risk of nocturnal hypoglycaemia. Because of its peakless, extended and highly predictable glucose-lowering effect, once-daily dosing on a flexible schedule may be feasible with degludec. Studies testing this possibility suggest that degludec tolerates day-to-day variation in dose timing while maintaining full efficacy and low risk of nocturnal hypoglycaemia. Degludec would appear to be an appropriate choice for patients being considered for a basal analogue, and it may be particularly well suited to patients with unpredictable social or work schedules, those who travel frequently and those who find rigid scheduling of their insulin injections a burden or barrier to regular treatment. 23614571 Development of 2'-substituted (2S,1'R,2'S)-2-(carboxycyclopropyl)glycine analogues as potent N-methyl-D-aspartic acid receptor ligands. A series of 2'-substituted analogues of the selective NMDA receptor ligand (2S,1'R,2'S)-2-(carboxycyclopropyl)glycine ((S)-CCG-IV) have been designed, synthesized and pharmacologically characterized. The design was based on a docking study hypothesizing that substituents in the 2'-position would protrude into a region where differences among the NMDA receptors GluN2 subunits exist. Various synthetic routes were explored, and two different routes provided a series of alkyl-substituted analogues. Pharmacological characterization disclosed that these compounds are NMDA receptor agonists and that potency decreases with increasing size of the alkyl groups. Variations in agonist activity are observed at recombinant NMDA receptor subtypes with increasing size of the alkyl-substituents and are developing differently depending on the GluN2 subunit. This study demonstrates that it is possible to introduce substituents in the 2'-position of (S)-CCG-IV while maintaining agonist activity and that variation among NMDA receptor subtypes may be achieved by probing this region of the receptor. 23567861 Evaluation of 7-O-galloyl-d-sedoheptulose, isolated from Corni Fructus, in the adipose tissue of type 2 diabetic db/db mice. The aim of the present study was to evaluate the beneficial effects of 7-O-galloyl-d-sedoheptulose (GS), isolated from Corni Fructus, using type 2 diabetic mice. GS was orally administered to db/db mice at doses of 20 and 100mg/kg body weight per day for 6weeks, and the effects of GS on biochemical factors in serum and adipose tissue were investigated. To define the underlying mechanism of these effects, protein expressions related to lipid metabolism, inflammation, fibrosis, and apoptosis, were measured. The results showed that levels of glucose, leptin, insulin, C-peptide, resistin, tumor necrosis factor-α, interleukin-6, triglycerides, total cholesterol, non-esterified fatty acids, high-density lipoprotein cholesterol, very low-density lipoprotein cholesterol/low-density lipoprotein cholesterol, reactive oxygen species (ROS), and thiobarbituric acid-reactive substance (TBARS) in serum were down-regulated, while adiponectin was augmented by GS treatment. In addition, the elevated lipid, ROS, and TBARS contents in adipose tissue as well as serum levels in db/db mice were significantly decreased by the oral administration of GS. From protein analysis, the decreased expressions of peroxisome proliferator activated receptor (PPAR)α, PPARγ, and B-cell lymphoma 2 were up-regulated in the adipose tissue of db/db mice. The administration of GS significantly decreased sterol regulatory element binding protein-1, nuclear factor-kappa ?>Bp65, cyclooxygenase-2, inducible nitric oxide synthase, monocyte chemotactic protein-1, intracellular adhesion molecule-1, phosphor c-Jun N-terminal kinase, activator protein-1, transforming growth factor-β1, Bax, cytochrome c, and caspase-3 expressions. These results suggest that GS acts as a regulator of oxidative stress, inflammation, fibrosis, and apoptosis in the adipose tissue of db/db mice. 23578623 Volatile release and structural stability of β-lactoglobulin primary and multilayer emulsions under simulated oral conditions. The relationship between emulsion structure and the release of volatile organic compounds (VOCs) was investigated using a model mouth system under oral conditions (tongue mastication, artificial saliva, pH and salt). The VOCs were monitored on-line by proton transfer reaction mass spectrometry (PTR-MS). Two types of emulsion system were compared: primary and multilayer oil-in-water (P-O/W, M-O/W) emulsions consisting of soy oil coated by β-lactoglobulin and pectin layers. The P-O/W emulsions showed intensive flocculation at pH 5 and above 200mM NaCl where the electrostatic repulsive charge was at a minimum. Bridging and depletion flocculation were mostly observed for P-O/W emulsions containing artificial saliva with 1wt% mucin. The VOC release was found to increase when the emulsion droplets flocculated, thus changing the oil volume phase distribution. The adsorbed pectin layer stabilised the emulsion structure under conditions of short-time oral processing, and hindered the release of hydrophobic VOCs. 23351082 Contribution of lipids in honeybee (Apis mellifera) royal jelly to health. Honeybee (Apis mellifera) royal jelly (RJ) has a long history in human medicine because of its health-protecting properties. To develop a fundamental and comprehensive understanding of lipids in RJ, this article reviews the available literature on lipid compounds identified from RJ extracts and in vitro pharmacological effects of 10-hydroxy-2-decenoic acid in RJ and other closely related compounds, some of which are also identified as lipid compounds in RJ. Overall, the lipids in RJ are composed of mostly (aliphatic) fatty acids, almost all of which are present as free fatty acids and scarcely any as esters. Most fatty acids in RJ are medium-chain fatty acids, whether hydroxylated in terminal and/or internal positions, terminated with mono- or dicarboxylic acid groups, and saturated or monounsaturated at the 2-position. Besides these fatty acids, lipids in RJ contain sterols in minor amounts. Lipids in RJ are useful as preventive and supportive medicines with functionalities that include potential inhibitors of cancer growth, immune system modulators, alternative therapies for menopause, skin-aging protectors, neurogenesis inducers, and more. Taken together, the evidence suggests that health-protecting properties of RJ can be, in part, ascribed to actions of lipids in RJ. 23203870 EENdb: a database and knowledge base of ZFNs and TALENs for endonuclease engineering. We report here the construction of engineered endonuclease database (EENdb) (http://eendb.zfgenetics.org/), a searchable database and knowledge base for customizable engineered endonucleases (EENs), including zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs). EENs are artificial nucleases designed to target and cleave specific DNA sequences. EENs have been shown to be a very useful genetic tool for targeted genome modification and have shown great potentials in the applications in basic research, clinical therapies and agricultural utilities, and they are specifically essential for reverse genetics research in species where no other gene targeting techniques are available. EENdb contains over 700 records of all the reported ZFNs and TALENs and related information, such as their target sequences, the peptide components [zinc finger protein-/transcription activator-like effector (TALE)-binding domains, FokI variants and linker peptide/framework], the efficiency and specificity of their activities. The database also lists EEN engineering tools and resources as well as information about forms and types of EENs, EEN screening and construction methods, detection methods for targeting efficiency and many other utilities. The aim of EENdb is to represent a central hub for EEN information and an integrated solution for EEN engineering. These studies may help to extract in-depth properties and common rules regarding ZFN or TALEN efficiency through comparison of the known ZFNs or TALENs. 23192981 The role of prolactin receptor in GH signaling in breast cancer cells. GH and prolactin (PRL) are structurally related hormones that exert important effects in disparate target tissues. Their receptors (GHR and PRLR) reside in the cytokine receptor superfamily and share signaling pathways. In humans, GH binds both GHR and PRLR, whereas PRL binds only PRLR. Both hormones and their receptors may be relevant in certain human and rodent cancers, including breast cancer. GH and PRL promote signaling in human T47D breast cancer cells that express both GHR and PRLR. Furthermore, GHR and PRLR associate in a fashion augmented acutely by GH, even though GH primarily activates PRLR, rather than GHR, in these cells. To better understand PRLR's impact, we examined the effects of PRLR knockdown on GHR availability and GH sensitivity in T47D cells. T47D-ShPRLR cells, in which PRLR expression was reduced by stable short hairpin RNA (shRNA) expression, were compared with T47D-SCR control cells. PRLR knockdown decreased the rate of GHR proteolytic turnover, yielding GHR protein increase and ensuing sensitization of these cells to GHR signaling events including phosphorylation of GHR, Janus kinase 2, and signal transducer and activator of transcription 5 (STAT5). Unlike in T47D-SCR cells, acute GH signaling in T47D-ShPRLR cells was not blocked by the PRLR antagonist G129R but was inhibited by the GHR-specific antagonist, anti-GHR(ext-mAb). Thus, GH's use of GHR rather than PRLR was manifested when PRLR was reduced. In contrast to acute effects, GH incubation for 2 h or longer yielded diminished STAT5 phosphorylation in T47D-ShPRLR cells compared with T47D-SCR, a finding perhaps explained by markedly greater GH-induced GHR down-regulation in cells with diminished PRLR. However, when stimulated with repeated 1-h pulses of GH separated by 3-h washout periods to more faithfully mimic physiological GH pulsatility, T47D-ShPRLR cells exhibited greater transactivation of a STAT5-responsive luciferase reporter than did T47D-SCR cells. Our data suggest that PRLR's presence meaningfully affects GHR use in breast cancer cells. 23200887 Resveratrol affects differently rat liver and brain mitochondrial bioenergetics and oxidative stress in vitro: investigation of the role of gender. Resveratrol (3,5,4'-trihydroxy-trans stilbene) is commonly recognized by its antioxidant properties. Despite its beneficial qualities, the toxic effects of this natural compound are still unknown. Since mitochondria are essential to support the energy-dependent regulation of several cell functions, the objective of this study was to evaluate resveratrol effects on rat brain and liver mitochondrial fractions from male and females regarding oxidative stress and bioenergetics. No basal differences were observed between mitochondrial fractions from males and females, except in liver mitochondria, the generation of H(2)O(2) by the respiratory chain is lower for female preparations. Resveratrol inhibited lipid peroxidation in preparations from both genders and organs. Furthermore, brain mitochondria in both gender groups appeared susceptible to resveratrol as seen by a decrease in state 3 respiration and alterations in mitochondrial membrane potential fluctuations during ADP phosphorylation. As opposed, liver mitochondria were less affected by resveratrol. Our data also demonstrates that resveratrol inhibits complex I activity in all mitochondrial preparations. The results suggest that brain mitochondria appear to be more susceptible to resveratrol effects, and gender appears to play a minor role. It remains to be determined if resveratrol effects on brain mitochondria contribute to deterioration of mitochondrial function or instead to mediate hormesis-mediated events. 22469988 miR-143 regulates hexokinase 2 expression in cancer cells. Tumor cells activate pathways that facilitate and stimulate glycolysis even in the presence of adequate levels of oxygen in order to satisfy their continuous need of molecules, such as nucleotides, ATP and fatty acids, necessary to support their rapid proliferation. Accordingly, a variety of human tumors are characterized by elevated expression levels of the hexokinase 2 isoform (HK2). Although different molecular mechanisms, including genetic and epigenetic mechanisms, have been suggested to account for the altered expression of HK2 in tumors, the potential role of microRNAs (miRNAs) in the regulation of HK2 expression has not been evaluated. Here, we report that miR-143 inhibits HK2 expression via a conserved miR-143 recognition motif located in the 3'-untranslated region (3'UTR) of HK2 mRNA. We demonstrate that miR143 inhibits HK2 expression both in primary keratinocytes and in head and neck squamous cell carcinoma (HNSCC)-derived cell lines. Importantly, we found that miR-143 inversely correlates with HK2 expression in HNSCC-derived cell lines and in primary tumors. We also report that the miRNA-dependent regulation of hexokinase expression is not limited to HK2 as miR-138 targets HK1 via a specific recognition motif located in its 3'UTR. All these data unveil a new miRNA-dependent mechanism of regulation of hexokinase expression potentially important in the regulation of glucose metabolism of cancer cells. 23121934 Synthesis and evaluation of a series of 3,4,5-trimethoxycinnamic acid derivatives as potential antinarcotic agents. A series of 3,4,5-trimethoxycinnamic acid derivatives was prepared and evaluated for antinarcotic effects on morphine dependence in mice and binding affinities on serotonergic receptors. The key synthetic strategies involve generation of ketones 6-7, esters 9-12 through condensation reaction, and amides 13-19 via coupling reaction using 1-hydroxybenzotriazole/ethyl(dimethylaminopropryl)carbodiimide system in high yield. We found that the naloxone-induced morphine withdrawal syndrome was significantly suppressed by new synthetic 3,4,5-trimethoxycinnamic acid derivatives (20 mg/kg/day). Most of 3,4,5-trimethoxycinnamic acid derivatives were found to have high affinity to 5-HT(1A) receptor. The naloxone-induced morphine withdrawal syndrome was attenuated by (+)8-OH-DPAT (0.1 mg/kg/day, i.p.), a 5-HT(1A) receptor agonist. In cortical neuronal cells, (+)8-OH-DPAT (1 μM) produced an elevation of the pERK 1/2 expression, and the elevated pERK levels were inhibited by WAY 100635, a 5-HT(1A) receptor-specific antagonist. Interestingly, the pERK levels were increased by the 3,4,5-trimethoxycinnamic acid derivatives and the derivatives-mediated changes in pERK levels were blocked by the WAY 100635. These results suggested that new synthetic 3,4,5-trimethoxycinnamic acid derivatives have a potential antinarcotic effect through acting as a 5-HT(1A) receptor agonist in mice. 23220004 Aldo-keto reductases in retinoid metabolism: search for substrate specificity and inhibitor selectivity. Biological activity of natural retinoids requires the oxidation of retinol to retinoic acid (RA) and its binding to specific nuclear receptors in target tissues. The first step of this pathway, the reversible oxidoreduction of retinol to retinaldehyde, is essential to control RA levels. The enzymes of retinol oxidation are NAD-dependent dehydrogenases of the cytosolic medium-chain (MDR) and the membrane-bound short-chain (SDR) dehydrogenases/reductases. Retinaldehyde reduction can be performed by SDR and aldo-keto reductases (AKR), while its oxidation to RA is carried out by aldehyde dehydrogenases (ALDH). In contrast to SDR, AKR and ALDH are cytosolic. A common property of these enzymes is that they only use free retinoid, but not retinoid bound to cellular retinol binding protein (CRBP). The relative contribution of each enzyme type in retinoid metabolism is discussed in terms of the different subcellular localization, topology of membrane-bound enzymes, kinetic constants, binding affinity of CRBP for retinol and retinaldehyde, and partition of retinoid pools between membranes and cytoplasm. The development of selective inhibitors for AKR enzymes 1B1 and 1B10, of clinical relevance in diabetes and cancer, granted the investigation of some structure-activity relationships. Kinetics with the 4-methyl derivatives of retinaldehyde isomers was performed to identify structural features for substrate specificity. Hydrophilic derivatives were better substrates than the more hydrophobic compounds. We also explored the inhibitory properties of some synthetic retinoids, known for binding to retinoic acid receptors (RAR) and retinoid X receptors (RXR). Consistent with its substrate specificity towards retinaldehyde, AKR1B10 was more effectively inhibited by synthetic retinoids than AKR1B1. A RARβ/γ agonist (UVI2008) inhibited AKR1B10 with the highest potency and selectivity, and docking simulations predicted that its carboxyl group binds to the anion-binding pocket. 23562634 Novel iontophoretic administration method for local therapy of breast cancer. Ductal drug therapy is a novel therapeutic approach for primary breast cancers, particularly those involving ductal carcinoma in situ lesions. Total or partial mastectomy with or without radiotherapy is the standard local therapy for primary breast cancer. Here, we propose a novel drug administration method for ductal drug therapy based on a drug delivery system (DDS) for primary breast cancer. This DDS was designed to deliver miproxifen phosphate (TAT-59), an antiestrogen drug, to ductal lesions via the milk duct, where carcinomas originate, more efficiently than systemic administration, using an iontophoretic technique applied to the nipple (IP administration). Autoradiography imaging confirmed that TAT-59 was directly delivered to the milk duct using IP administration. The plasma concentrations of TAT-59 and its active metabolite DP-TAT-59 were quite low with IP administration. The area under the curve value of DP-TAT-59 in the mammary tissue was approximately 3 times higher with IP administration than with oral administration, at a 6-fold lower dose, indicating higher availability of the drug delivered via DDS than via systemic administration. The low plasma concentrations would limit adverse effects to minor ones. These characteristics show that this DDS is suitable for the delivery of active DP-TAT-59 to ductal lesions. 23642965 Synthesis of 7-oxabicyclo[2.2.1]hept-5-en-2-yl derivatives and their screening for antimicrobial and antioxidant properties. Novel 7-oxabicyclo[2.2.1]hept-5-en-2-yl derivatives have been synthesized using boron trifluoride diethyl etherate catalyzed Diels-Alder reaction. This method presents considerable synthetic advantages in terms of high atom economy, mild reaction condition and good yields. The synthesized compounds have been screened for their antibacterial and antioxidant activities. 23250811 Curcumin improves TNBS-induced colitis in rats by inhibiting IL-27 expression via the TLR4/NF-κB signaling pathway. Curcumin is a widely used spice with anti-inflammatory and anticancer properties. It has been reported to have beneficial effects in experimental colitis. This study explored whether curcumin improves colonic inflammation in a rat colitis model through inhibition of the TLR4/NF-κB signaling pathway and IL-27 expression. After induction of colitis with 2,4,6-trinitrobenzene sulfonic acid, rats were intragastrically administered with curcumin or sulfasalazine daily for one week. Rat intestinal mucosa was collected for evaluation of the disease activity index, colonic mucosa damage index, and histological score. Myeloperoxidase activity was detected by immunohistochemistry, and mRNA and protein expression levels of TLR4, NF-κB, and IL-27 in colonic mucosa were detected by RT-PCR and Western blot. Compared with the untreated colitis group, the curcumin-treated group showed significant decreases in the disease activity index, colonic mucosa damage index, histological score, myeloperoxidase activity, and expressions of NF-κB mRNA, IL-27 mRNA, TLR4 protein, NF-κB p65 protein, and IL-27 p28 protein (p < 0.05). TLR4 mRNA expression did not differ between groups. Disease activity index decreased more rapidly in the curcumin-treated group than in the sulfasalazine-treated group (p < 0.05). There was no significant difference in TLR4, NF-κB, and IL-27 mRNA and proteins between curcumin-treated and sulfasalazine-treated groups. Curcumin shows significant therapeutic effects on 2,4,6-trinitrobenzene sulfonic acid-induced colitis that are comparable to sulfasalazine. The anti-inflammatory actions of curcumin on colitis may involve inhibition of the TLR4/NF-κB signaling pathway and of IL-27 expression. 23558686 Disruption of Ttll5/Stamp gene (Tubulin tyrosine ligase-like protein 5/SRC-1 and TIF2 associated modulatory protein gene) in male mice causes sperm malformation and infertility. Tubulin tyrosine ligase-like family member 5 (TTLL5/STAMP) has multiple activities in cells. TTLL5 is one of 13 TTLLs, has polyglutamylation activity, augments the activity of p160 coactivators (SRC-1 and TIF2) in glucocorticoid receptor-regulated gene induction and repression, and displays steroid-independent growth activity with several cell types. To examine TTLL5/STAMP functions in whole animals, mice were prepared with an internal deletion that eliminated several activities of the Stamp gene. This mutation causes both reduced levels of STAMP mRNA and C-terminal truncation of STAMP protein. Homozygous targeted mutant (Stamptm/tm) mice appear normal except for marked decreases in male fertility associated with defects in progressive sperm motility. Abnormal axonemal structures with loss of tubulin doublets occur in most Stamptm/tm sperm tails in conjunction with substantial reduction in α-tubulin polyglutamylation, which closely correlates with the reduction in mutant STAMP mRNA. The axonemes in other structures appear unaffected. There is no obvious change in the organs for sperm development of wt vs. Stamptm/tm males despite the levels of wt STAMP mRNA in testes being 20-fold higher than in any other organ examined. This defect in male fertility is unrelated to other Ttll genes or 24 genes previously identified as important for sperm function. Thus, STAMP appears to participate in a unique, tissue-selective TTLL-mediated pathway for α-tubulin polyglutamylation that is required for sperm maturation and motility and may be relevant for male fertility. 23522182 Dose-ranging study with the glucokinase activator AZD1656 as monotherapy in Japanese patients with type 2 diabetes mellitus. AIM: To assess the glucose-lowering effects of monotherapy with the glucokinase activator AZD1656 in Japanese patients with type 2 diabetes mellitus. METHODS: This was a randomized, double-blind, placebo-controlled study performed in Japan (NCT01152385). Patients (n = 224) were randomized to AZD1656 (40-200, 20-140 or 10-80 mg titrated doses) or placebo. The primary variable was the placebo-corrected change from baseline to 4 months in glycated haemoglobin (HbA1c). Effects on fasting plasma glucose (FPG) and safety were also assessed. RESULTS: HbA1c was reduced numerically from baseline by 0.3-0.8% with AZD1656 and by 0.1% with placebo over the first 2 months of treatment, after which effects of AZD1656 started to decline. The changes from baseline to 4 months in HbA1c were not significant for the AZD1656 40-200 mg group versus placebo [mean (95% CI) placebo-corrected change: -0.22 (-0.65, 0.20)%; p = 0.30]. Formal significance testing was not carried out for the other two AZD1656 dose groups. A higher percentage of patients on AZD1656 achieved HbA1c ≤ 7% after 4 months versus placebo, but responder rates were low. Results for FPG reflected those for HbA1c. Cases of hypoglycaemia were rare with AZD1656 (one patient) and no safety concerns were raised. CONCLUSIONS: Although initially favourable plasma glucose reductions were observed, there was a loss of effect over time with sustained AZD1656 treatment. The study design did not allow an evaluation of the reasons for this lack of long-term efficacy. 23256446 Metabolic effects of honey in type 1 diabetes mellitus: a randomized crossover pilot study. The aim of this study was to evaluate the metabolic effects of 12-week honey consumption on patients suffering from type 1 diabetes mellitus (DM). This was a randomized crossover clinical trial done in the National Institute for Diabetes and Endocrinology, Cairo, Egypt. Twenty patients of both sexes aged 4-18 years with type 1 DM and HbA1C<10% participated in the study. They were randomized into two equal groups (intervention to control and control to intervention). The dietary intervention was 12-week honey consumption in a dose of 0.5 mL/kg body weight per day. The main outcome measures were serum glucose, lipids, and C-peptide, and anthropometric measurements. None of participants were lost in follow-up. The intervention resulted in significant decreases in subscapular skin fold thickness (SSFT; P=.002), fasting serum glucose (FSG; P=.001), total cholesterol (P=.0001), serum triglycerides (TG; P=.0001), and low-density lipoprotein (P=.0009), and significant increases in fasting C-peptide (FCP; P=.0004) and 2-h postprandial C-peptide (PCP; P=.002). As possible long-term effects of honey after its withdrawal, statistically significant reductions in midarm circumference (P=.000), triceps skin fold thickness (P=.006), SSFT (P=.003), FSG (P=.005), 2-h postprandial serum glucose (P=.000), TG (P=.003), and HbA1C (P=.043), and significant increases in FCP (P=.002) and PCP (P=.003) were observed. This small clinical trial suggests that long-term consumption of honey might have positive effects on the metabolic derangements of type 1 DM. 23523544 Lipidic spherulites: Formulation optimisation by paired optical and cryoelectron microscopy. Objective of this study was to assess the various steps leading to spherulite obtention by means of optical and cryoelectron microscopy. The formulation, resting and hydration steps were optimised. Green-based process and organic-based process were compared. It was found that spherulites could be obtained only when two key steps were followed: a prior resting phase of excipients and the shearing stress of the hydrated excipients. Moreover, the new formulation under study formed spherulites in the 100-200nm range, which is smaller than previously reported spherulites. Such laboratory scale optimised process led the integration of spherulites in a larger number of prospective studies. Indeed, we finally showed that the encapsulated payload of a hydrophobic compound, such as the anti-angiogenic agent fisetin, was increased to a much higher degree than with a liposomal encapsulation. 23410169 Recent developments in rationally designed multitarget antiprotozoan agents. Protozoan infections are the leading cause of morbidity and mortality among parasitic infections of humans, accounting for approximately 800 thousand mortalities and a loss of more than 30 million disability-adjusted life years annually. The major protozoan infections of humans, namely malaria, Chagas disease, human African trypanosomiasis, and leishmaniasis, are primarily centered in the tropics, with a reach into some subtropical regions of the world. Though globally massive in their impact, these diseases mostly afflict the least economically endowed and geographically marginalized populations in low-income countries. As such, there is no sufficient market incentive for industrial businessdriven antiprotozoal drug discovery due to poor marketing prospects and low returns on investment. Consequently, the pharmacopoeia for majority of these diseases, composed mainly of agents with poor efficacy and unsatisfactory safety profiles, has essentially remained unchanged for decades, creating a compelling need for more efficacious and better tolerated medicines. The policy makers and the scientific community are seeking effective ways to meet this need. So far, two approaches have emerged promising in this regard: combination chemotherapy and drug repositioning. Molecular hybridization has been cited as a potential third approach that could be used to deliver new antiprotozoal chemical entities. In this review article, recent applications of this novel strategy in antimalarial, antichagasic, antitrypanosomal, and antileishmanial drug discovery research and development over the last five years will be presented and discussed. 23576341 Synthesis and evaluation of biphenyl compounds as Kinesin spindle protein inhibitors. Kinesin spindle protein (KSP), an ATP-dependent motor protein, plays an essential role in bipolar spindle formation during the mitotic phase (M phase) of the normal cell cycle. KSP has emerged as a novel target for antimitotic anticancer drug development. In this work, we synthesized a range of new biphenyl compounds and investigated their properties in vitro as potential antimitotic agents targeting KSP expression. Antiproliferation (MTT (=3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide)) assays, combined with fluorescence-assisted cell sorting (FACS) and Western blot studies analyzing cell-cycle arrest confirmed the mechanism and potency of these biphenyl compounds in a range of human cancer cell lines. Structural variants revealed that functionalization of biphenyl compounds with bulky aliphatic or aromatic groups led to a loss of activity. However, replacement of the urea group with a thiourea led to an increase in antiproliferative activity in selected cell lines. Further studies using confocal fluorescence microscopy confirmed that the most potent biphenyl derivative identified thus far, compound 7, exerts its pharmacologic effect specifically in the M phase and induces monoaster formation. These studies confirm that chemical scope remains for improving the potency and treatment efficacy of antimitotic KSP inhibition in this class of biphenyl compounds. 23223405 Four-Year Change in Cardiorespiratory Fitness and Influence on Glycemic Control in Adults With Type 2 Diabetes in a Randomized Trial: The Look AHEAD Trial. OBJECTIVE To examine an intensive lifestyle intervention (ILI) compared with diabetes support and education (DSE) on 4-year change in fitness and physical activity (PA), and to examine the effect of change in fitness and PA, adjusting for potential confounders, on glycemic control in the Look AHEAD Trial. RESEARCH DESIGN AND METHODS Subjects were overweight/obese adults with type 2 diabetes mellitus (T2DM) with available fitness data at 4 years (n = 3,942).This clinical trial randomized subjects to DSE or ILI. DSE subjects received standard care plus information related to diet, PA, and social support three times per year. ILI subjects received weekly intervention contact for 6 months, which was reduced over the 4-year period, and were prescribed diet and PA. Measures included weight, fitness, PA, and HbA1c. RESULTS The difference in percent fitness change between ILI and DSE at 4 years was significant after adjustment for baseline fitness and change in weight (3.70 vs. 0.94%; P < 0.01). At 4 years, PA increased by 348 (1,562) kcal/week in ILI vs. 105 (1,309) kcal/week in DSE (P < 0.01). Fitness change at 4 years was inversely related to change in HbA1c after adjustment for clinical site, treatment, baseline HbA1c, prescribed diabetes medication, baseline fitness, and weight change (P < 0.01). Change in PA was not related to change in HbA1c. CONCLUSIONS A 4-year ILI increased fitness and PA in overweight/obese individuals with T2DM. Change in fitness was associated with improvements in glycemic control, which provides support for interventions to improve fitness in adults with T2DM. 23353699 c-Src-dependent MAPKs/AP-1 activation is involved in TNF-α-induced matrix metalloproteinase-9 expression in rat heart-derived H9c2 cells. TNF-α plays a critical mediator in the pathogenesis of chronic heart failure contributing to cardiac remodeling and peripheral vascular disturbances. The implication of TNF-α in inflammatory responses has been shown to be mediated through up-regulation of inflammatory genes, including matrix metalloproteinase-9 (MMP-9). However, the detailed mechanisms of TNF-α-induced MMP-9 expression are largely unclear in the heart cells. Here, we demonstrated that in rat embryonic-heart derived H9c2 cells, TNF-α could induce MMP-9 mRNA expression associated with an increase in the secretion of MMP-9, determined by real-time PCR, zymography, and promoter activity assays. TNF-α-mediated responses were attenuated by pretreatment with the inhibitor of c-Src (PP1), EGFR (AG1478), PDGFR (AG1296), PI3K (LY294002), Akt (SH-5), MEK1/2 (U0126), p38 MAPK (SB202190), JNK1/2 (SP600125), or AP-1 (Tanshinone IIA) and transfection with siRNA of c-Src, EGFR, PDGFR, p110, Akt, or c-Jun. TNF-α stimulated c-Src, PDGFR, and EGFR phosphorylation, which were reduced by PP1. In addition, TNF-α-stimulated Akt phosphorylation was inhibited by PP1, AG1478, AG1296, or LY294002. We further demonstrated that TNF-α markedly stimulated p38 MAPK, p42/p44 MAPK, and JNK1/2 phosphorylation via a c-Src/EGFR, PDGFR/PI3K/Akt pathway. Finally, we showed that, in H9c2 cells, TNF-α-stimulated AP-1 promoter activity, c-Jun mRNA expression, and c-Jun phosphorylation were attenuated by PP1, AG1478, AG1296, LY294002, SB202190, SP600125, or U0126. These results suggested that TNF-α-induced MMP-9 expression is mediated through a c-Src/EGFR, PDGFR/PI3K/Akt/MAPKs/AP-1 cascade in H9c2 cells. Consequently, MMP-9 induction may contribute to cell migration and cardiovascular inflammation. 23026700 Cassia tora (Leguminosae) seed extract alleviates high-fat diet-induced nonalcoholic fatty liver. The aim of this study was to examine the effects of Cassia tora seeds on high-fat diet (HFD)-induced hepatic steatosis, and elucidate the molecular mechanisms behind its effects. After being fed a HFD for two weeks, rats were orally dosed with Cassia seed ethanol extract (CSEE) (100, 200, or 300mg/kg) once daily for 8weeks. CSEE induced dose-dependent reductions in plasma lipid levels, as well as decreased the over hepatic lipid accumulation. Furthermore, CSEE treatment improved HFD-induced hepatic histological lesions. CSEE enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and its primary downstream targeting enzyme, acetyl-CoA carboxylase, up-regulated the gene expression of carnitine palmitoyl transferase 1, and down-regulated sterol regulatory element binding protein 1 and fatty acid synthase protein levels in the livers of HFD-fed rats. AMPK inhibition by compound C retarded CSEE-induced reduction in triglyceride accumulation in HepG2 cells stimulated by insulin. Our findings suggest that CSEE may regulate hepatic lipid homeostasis related with an AMPK-dependent signaling pathway. Targeting AMPK activation with CSEE may represent a promising approach for the prevention and treatment of obesity-related non-alcoholic fatty liver disease. 23380917 Perinatal phencyclidine administration decreases the density of cortical interneurons and increases the expression of neuregulin-1. RATIONALE: Perinatal phencyclidine (PCP) administration in rat blocks the N-methyl D-aspartate receptor (NMDAR) and causes symptoms reminiscent of schizophrenia in human. A growing body of evidence suggests that alterations in γ-aminobutyric acid (GABA) interneuron neurotransmission may be associated with schizophrenia. Neuregulin-1 (NRG-1) is a trophic factor important for neurodevelopment, synaptic plasticity, and wiring of GABA circuits. OBJECTIVES: The aim of this study was to determine the long-term effects of perinatal PCP administration on the projection and local circuit neurons and NRG-1 expression in the cortex and hippocampus. METHODS: Rats were treated on postnatal day 2 (P2), P6, P9, and P12 with either PCP (10 mg/kg) or saline. Morphological studies and determination of NRG-1 expression were performed at P70. RESULTS: We demonstrate reduced densities of principal neurons in the CA3 and dentate gyrus (DG) subregions of the hippocampus and a reduction of major interneuronal populations in all cortical and hippocampal regions studied in PCP-treated rats compared with controls. For the first time, we show the reduced density of reelin- and somatostatin-positive cells in the cortex and hippocampus of animals perinatally treated with PCP. Furthermore, an increase in the numbers of perisomatic inhibitory terminals around the principal cells was observed in the motor cortex and DG. We also show that perinatal PCP administration leads to an increased NRG-1 expression in the cortex and hippocampus. CONCLUSION: Taken together, our findings demonstrate that perinatal PCP administration increases NRG-1 expression and reduces the number of projecting and local circuit neurons, revealing complex consequences of NMDAR blockade. 23493571 Cytoplasmic-Nuclear Trafficking of G1/S Cell Cycle Molecules and Adult Human Beta Cell Replication: A Revised Model of Human Beta Cell G1/S Control. Harnessing control of human beta cell proliferation has proven frustratingly difficult. Most G1/S control molecules, generally presumed to be nuclear proteins in the human beta cell, are in fact constrained to the cytoplasm. Here, we asked whether G1/S molecules might traffic into and out of the cytoplasmic compartment in association with activation of cell cycle progression. Cdk6 and cyclin D3 were used to drive human beta cell proliferation, and promptly translocated into the nucleus in association with proliferation. In contrast, the cell cycle inhibitors p15, p18 and p19 did not alter their location, remaining cytoplasmic. Conversely, p16, p21, p27 all increased their nuclear frequency. In contrast once again, p57 decreased its nuclear frequency. While proliferating beta cells contained nuclear cyclin D3 and cdk6, proliferation generally did not occur in beta cells that contained nuclear cell cycle inhibitors, except p21. Dynamic cytoplasmic-nuclear trafficking of cdk6 was confirmed using GFP-tagged cdk6 and live-cell imaging. Thus, we provide novel working models describing the control of cell cycle progression in the human beta cell. In addition to known obstacles to beta cell proliferation, cytoplasmic-to-nuclear trafficking of G1/S molecules may represent both an obstacle, as well as a therapeutic opportunity, for human beta cell expansion. 22840229 A new cyclonerol derivative from a marine-derived fungus Ascotricha sp. ZJ-M-5. A new sesquiterpene, ascotrichic acid (1), was isolated from a marine-derived fungus Ascotricha sp., together with the other two known analogues, cyclonerodiol (2) and 10(Z)-cyclonerotriol (3). Its structure was established by spectroscopic methods (1D and 2D NMR, HR-ESI-MS). 23219778 Tartary buckwheat improves cognition and memory function in an in vivo amyloid-β-induced Alzheimer model. Protective effects of Tartary buckwheat (TB) and common buckwheat (CB) on amyloid beta (Aβ)-induced impairment of cognition and memory function were investigated in vivo in order to identify potential therapeutic agents against Alzheimer's disease (AD) and its associated progressive memory deficits, cognitive impairment, and personality changes. An in vivo mouse model of AD was created by injecting the brains of ICR mice with Aβ(25-35), a fragment of the full-length Aβ protein. Damage of mice recognition ability through following Aβ(25-35) brain injections was confirmed using the T-maze test, the object recognition test, and the Morris water maze test. Results of behavior tests in AD model showed that oral administration of the methanol (MeOH) extracts of TB and CB improved cognition and memory function following Aβ(25-35) injections. Furthermore, in groups receiving the MeOH extracts of TB and CB, lipid peroxidation was significantly inhibited, and nitric oxide levels in tissue, which are elevated by injection of Aβ(25-35), were also decrease. In particular, the MeOH extract of TB exerted a stronger protective activity than CB against Aβ(25-35)-induced memory and cognition impairment. The results indicate that TB may play a promising role in preventing or reversing memory and cognition loss associated with Aβ(25-35)-induced AD. 23220003 Glyoxal and methylglyoxal: autoxidation from dihydroxyacetone and polyphenol cytoprotective antioxidant mechanisms. Previously, this laboratory had shown that fructose and its downstream metabolites can be enzymatically metabolized to form glyoxal and methylglyoxal. Fructose metabolites, glycoaldehyde, glyceraldehyde and hydroxypyruvate have also been shown to be autoxidizable. In this study, however, fructose did not cause protein carbonylation itself and instead protected against apparent carbonylation by Fenton's reagent; fructose did not form significant levels of dicarbonyl compounds over a period of 6 days under standard conditions (37°C, pH 7.4). In contrast, dihydroxyacetone, a fructose metabolite, caused protein carbonylation and autoxidized to form dicarbonyls, which effects were further potentiated under oxidative stress conditions (Fenton's reaction). Natural polyphenols were tested for their ability to protect against glyoxal- and methylglyoxal-induced cytotoxicity, reactive oxygen species formation and improved mitochondrial membrane potential maintenance. The polyphenols investigated were gallic acid, methyl gallate, ethyl gallate, propyl gallate, rutin and curcumin. The polyphenols were assayed using primary and GSH-depleted hepatocytes. The polyphenols were also investigated for their rescuing ability and were found to provide greater hepatoprotection when toxins were pre-incubated for 30 min before adding the polyphenols. However, rutin was less protective when rescuing hepatocytes, perhaps, because rutin metabolites may scavenge reactive oxygen species more effectively than rutin itself. The longer the alkyl group attached to the gallate compound, the more cytoprotective the polyphenol was. However, the gallates with longer alkyl groups were less able to scavenge reactive oxygen species, and to maintain the mitochondrial membrane potential. 23536584 Efficacy and Safety of Lixisenatide Once-Daily Morning or Evening Injections in Type 2 Diabetes Inadequately Controlled on Metformin (GetGoal-M). OBJECTIVEExamine the efficacy and safety of lixisenatide (20 μg once daily, administered before the morning or evening meal) as add-on therapy in type 2 diabetes patients insufficiently controlled with metformin alone.RESEARCH DESIGN AND METHODSA 24-week, randomized, double-blind, placebo-controlled study in 680 patients with inadequately controlled type 2 diabetes (HbA1c 7-10% [53-86 mmol/mol]). Patients were randomized to lixisenatide morning (n = 255), lixisenatide evening (n = 255), placebo morning (n = 85), or placebo evening (n = 85) injections.RESULTSLixisenatide morning injection significantly reduced mean HbA1c versus combined placebo (mean change -0.9% [9.8 mmol/mol] vs. -0.4% [4.4 mmol/mol]; least squares [LS] mean difference vs. placebo -0.5% [5.5 mmol/mol], P < 0.0001). HbA1c was significantly reduced by lixisenatide evening injection (mean change -0.8% [8.7 mmol/mol] vs. -0.4% [4.4 mmol/mol]; LS mean difference -0.4% [4.4 mmol/mol], P < 0.0001). Lixisenatide morning injection significantly reduced 2-h postprandial glucose versus morning placebo (mean change -5.9 vs. -1.4 mmol/L; LS mean difference -4.5 mmol/L, P < 0.0001). LS mean difference in fasting plasma glucose was significant in both morning (-0.9 mmol/L, P < 0.0001) and evening (-0.6 mmol/L, P = 0.0046) groups versus placebo. Mean body weight decreased to a similar extent in all groups. Rates of adverse events were 69.4% in both lixisenatide groups and 60.0% in the placebo group. Rates for nausea and vomiting were 22.7 and 9.4% for lixisenatide morning and 21.2 and 13.3% for lixisenatide evening versus 7.6 and 2.9% for placebo, respectively. Symptomatic hypoglycemia occurred in 6, 13, and 1 patient for lixisenatide morning, evening, and placebo, respectively, with no severe episodes.CONCLUSIONSIn patients with type 2 diabetes inadequately controlled on metformin, lixisenatide 20 μg once daily administered in the morning or evening significantly improved glycemic control, with a pronounced postprandial effect, and was well tolerated. 23588477 Genome-Based Bacterial Vaccines: Current State and Future Outlook. Genome-based reverse vaccinology (RV) is a multi-step experimental strategy which starts from in silico analysis of whole genome sequences, from which vaccine candidates can be selected by using bioinformatic algorithms to identify putative protective antigens. In this review, we examine the current state of genome-based RV-engineered vaccines and future applications. The first product of genome-based RV is Bexsero(®), a vaccine developed for preventing Neisseria meningitidis serogroup B infection, and the strategy is currently being used for the development of new vaccines for other obdurate and emerging bacterial diseases. Improved sequencing technologies and the ongoing whole-genome sequence analyses of helminths, protozoa, and ectoparasites also currently serve as a basis for an RV strategy to produce new potential vaccines against eukaryotic pathogens. We also highlight an emerging approach-structure-based vaccinology-that exploits the information derived from the determined three-dimensional structures of vaccine candidates. Regardless, genome-based RV and other vaccine discovery platforms still depend on empirical experimental science to glean, from the hundreds of identified antigens from any one pathogen, those that should be combined to produce an effective vaccine. 23454648 Generation of intracellular reactive oxygen species and genotoxicity effect to exposure of nanosized polyamidoamine (PAMAM) dendrimers in PLHC-1 cells in vitro. Polyamidoamine (PAMAM) dendrimers have previously been demonstrated to elicit systematically variable cyto- and eco-toxic responses, promising as the basis for structure-activity relationships governing nanotoxicological responses. In this study, increased production of intracellular reactive oxygen species (ROS), genotoxicity and apoptosis due to in vitro exposure of fish hepatocellular carcinoma cells to dendrimer generations G4, G5 and G6 is demonstrated. A PAMAM dendrimer generation dependent increase in ROS and genotoxicity was observed, consistent with our previous studies. The toxicological responses correlate well with the nanoparticle surface chemistry, specifically, the number of surface amino groups per generation. Although ROS production initially increases approximately linearly, it saturates at higher doses. Notably, normalized to the molar dose of surface amino groups, the dose-dependent ROS production for different generations overlap exactly, indicating that the response is due to these functional units. The genotoxicity response is also well correlated to the number of surface amino groups and therefore generation of PAMAM dendrimers. The observed genotoxicity, related to DNA damage, is related to the generation and dose dependent production of intracellular ROS, at low levels. At the higher ROS levels, increased DNA damage is associated with the onset of necrosis. 23147377 Iron oxide particles modulate the ovalbumin-induced Th2 immune response in mice. This study was designed to investigate the modulatory effects of submicron and nanosized iron oxide (Fe(2)O(3)) particles on the ovalbumin (OVA)-induced immune Th2 response in BALB/c mice. Particles were intratracheally administered four times to mice before and during the OVA sensitization period. For each particle type, three different doses, namely 4×100, 4×250 or 4×500 μg/mouse, were used and for each dose, four groups of mice, i.e. group saline solution (1), OVA (2), particles (3), and OVA plus particles (4), were constituted. Mice exposed to OVA alone exhibited an allergic Th2-dominated response with a consistent increase in inflammatory scores, eosinophil numbers, specific IgE levels and IL-4 production. When the mice were exposed to OVA and to high and intermediate doses of iron oxide submicron- or nanoparticles, the OVA-induced allergic response was significantly inhibited, as evidenced by the decrease in eosinophil cell influx and specific IgE levels. However, the low dose (4×100 μg) of submicron particles had no significant effect on the OVA allergic response while the same dose of nanoparticles had an adjuvant effect on the Th2 response to OVA. In conclusion, these data demonstrate that the pulmonary immune response to OVA is a sensitive target for intratracheally instilled particles. Depending on the particle dose and size, the allergic response was suppressed or enhanced. 23542608 Pulmonary DWCNT exposure causes sustained local and low-level systemic inflammatory changes in mice. Carbon nanotubes (CNTs) represent promising vectors to facilitate cellular drug delivery and to overcome biological barriers, but some types may also elicit persistent pulmonary inflammation based on their fibre characteristics. Here, we show the pulmonary response to aqueous suspensions of block copolymer dispersed, double-walled carbon nanotubes (DWCNT, length 1-10μm) in mice by bronchoalveolar lavage (BAL) analysis, and BAL and blood cytokine and lung antioxidant profiling. The intratracheally instilled dose of 50μg DWCNT caused significant pulmonary inflammation that was not resolved during a 7-day observation period. Light microscopy investigation of the uptake of DWCNT agglomerates revealed no particle ingestion for granulocytes, but only for macrophages. Accumulating macrophage, multinucleated macrophage and lymphocyte numbers in the alveolar region further indicated ineffective resolution with chronification of the inflammation. The local inflammatory impairment of the lung was accompanied by pulmonary antioxidant depletion and haematological signs of systemic inflammation. While the observed inflammation during its acute phase was dominated by neutrophils and neutrophil recruiting cytokines, the contribution of macrophages and lymphocytes with related cytokines became more significant after day 3 of exposure. This study confirms that acute pulmonary toxicity can occur on exposure of high doses of DWCNT agglomerates and offers further insight for improved nanotube design parameters to avoid potential long-term toxicity. 23200005 Composition and distribution of the main active components in selenium-enriched fruit bodies of Cordyceps militaris link. Selenium-enriched Cordyceps militaris fruit bodies are industrially cultivated as functional food or medicinal food in China and southeast Asia. However, composition of selenium compounds and distribution of the main bioactive components are still unknown. In the selenium-enriched fruit bodies, the main soluble selenium compounds of low molecular weight were identified as SeMet (selenomethionine), and the main selenium compounds bound in proteins were identified as SeMet and SeCys (methylselenocysteine). Trace minerals as Se (selenium), Zn (zinc), Fe (iron) and the main active components as adenosine, cordycepin and carotenoids were mostly distributed in the terminal of fruit bodies, while P (phosphorus) and K (potassium) were evenly distributed in the fruit bodies. The results indicated that terminal of the fruit bodies should be the better materials for production of advanced functional food. So cultivation of relatively short and thick fruit bodies with bigger terminals deserves further research. 23460383 Thermoplastic Polyurethanes From Undecylenic Acid-Based Soft Segments: Structural Features and Release Properties. A set of thermoplastic polyurethanes is synthesized, combining undecylenic acid-derived telechelic diols as soft segments and 1,4-butanediol/4,4'-methylenebis(phenylisocyanate) as a hard segment (HS). These polymers are fully chemically and physically characterized by means of NMR and Fourier transform IR (FTIR) spectroscopy, size-exclusion chromatography (SEC), DSC, thermogravimetric analysis (TGA), tensile testing, and contact angle measurements. The obtained results reveal that both the molecular weight of the diol and the HS content greatly influence the physical and mechanical properties of these polymers. In addition, given the potential use of these materials for biomedical applications, hydrolytic degradation, their biocompatibility using a human fibroblast cell line, and performance as drug delivery carriers are evaluated. 23376354 Ion channel remodeling in vascular smooth muscle during hypertension: Implications for novel therapeutic approaches. Ion channels are multimeric, transmembrane proteins that selectively mediate ion flux across the plasma membrane in a variety of cells including vascular smooth muscle cells (VSMCs). The dynamic interplay of Ca(2+) and K(+) channels on the plasma membrane of VSMCs plays a pivotal role in modulating the vascular tone of small arteries and arterioles. The abnormally-elevated arterial tone observed in hypertension thus points to an aberrant expression and function of Ca(2+) and K(+) channels in the VSMCs. In this short review, we focus on the three well-studied ion channels in VSMCs, namely the L-type Ca(2+) (CaV1.2) channels, the voltage-gated K(+) (KV) channels, and the large-conductance Ca(2+)-activated K(+) (BK) channels. First, we provide a brief overview on the physiological role of vascular CaV1.2, KV and BK channels in regulating arterial tone. Second, we discuss the current understanding of the expression changes and regulation of CaV1.2, KV and BK channels in the vasculature during hypertension. Third, based on available proof-of-concept studies, we describe the potential therapeutic approaches targeting these vascular ion channels in order to restore blood pressure to normotensive levels. 23455995 Impacts of spinosad and λ-cyhalothrin on spider communities in cabbage fields in south Texas. Spiders are a principal arthropod group that preys on numerous pests of vegetables and other crops. In this study, we determined the effects of the two most commonly used insecticides, spinosad and λ-cyhalothrin, on diversity of spiders on cabbage in south Texas. In two seasons (fall 2008 and spring 2009), we collected a total of 588 spiders belonging to 53 species in 11 families from spinosad and λ-cyhalothrin-treated cabbages and the untreated control plants. A great majority of spiders were collected from the pitfall traps (554) where only a few (34) were collected from the blower/vacuum sampling. In the insecticide-treated plots, there were significantly fewer spider individuals, species and families than in untreated fields. Spinosad had significantly less effect on spiders in total individuals, number of species and families than λ-cyhalothrin. The effects of the two insecticides were further demonstrated by the Shannon-Weiner index (H') and the hierarchical richness index (HRI). Spider diversity in the spinosad-treated plots were not significantly different from that in the untreated fields but were greater than those in λ-cyhalothrin-treated plots in both seasons when measured by H' values. In contrast, the H' values of spider's diversity in the λ-cyhalothrin-treated plots were significantly lower than spinosad-treated and untreated plots. High values of HRI for spider richness in the spinosad-treated plots suggested that spinosad had less effect on spiders than λ-cyhalothrin. We concluded that spinosad was more compatible with spiders on cabbage compared to λ-cyhalothrin and that this information should be used when developing insecticide resistance management strategies. 23419007 Incorporation of rapid thermodynamic data in fragment-based drug discovery. Fragment-based drug discovery (FBDD) has enjoyed increasing popularity in recent years. We introduce SITE (single-injection thermal extinction), a novel thermodynamic methodology that selects high-quality hits early in FBDD. SITE is a fast calorimetric competitive assay suitable for automation that captures the essence of isothermal titration calorimetry but using significantly fewer resources. We describe the principles of SITE and identify a novel family of fragment inhibitors of the enzyme ketosteroid isomerase displaying high values of enthalpic efficiency. 23328252 Benzophenone-1 stimulated the growth of BG-1 ovarian cancer cells by cell cycle regulation via an estrogen receptor alpha-mediated signaling pathway in cellular and xenograft mouse models. 2,4-Dihydroxybenzophenone (benzophenone-1; BP-1) is an UV stabilizer primarily used to prevent polymer degradation and deterioration in quality due to UV irradiation. Recently, BP-1 has been reported to bioaccumulate in human bodies by absorption through the skin and has the potential to induce health problems including endocrine disruption. In the present study, we examined the xenoestrogenic effect of BP-1 on BG-1 human ovarian cancer cells expressing estrogen receptors (ERs) and relevant xenografted animal models in comparison with 17-β estradiol (E2). In in vitro cell viability assay, BP-1 (10(-8)-10(-5)M) significantly increased BG-1 cell growth the way E2 did. The mechanism underlying the BG-1 cell proliferation was proved to be related with the up-regulation of cyclin D1, a cell cycle progressor, by E2 or BP-1. Both BP-1 and E2 induced cell growth and up-regulation of cyclin D1 were reversed by co-treatment with ICI 182,780, an ER antagonist, suggesting that BP-1 may mediate the cancer cell proliferation via an ER-dependent pathway like E2. On the other hand, the expression of p21, a regulator of cell cycle progression at G1 phase, was not altered by BP-1 though it was down-regulated by E2. In xenograft mouse models transplanted with BG-1 cells, BP-1 or E2 treatment significantly increased the tumor mass formation compared to a vehicle (corn oil) within 8 weeks. In histopathological analysis, the tumor sections of E2 or BP-1 group displayed extensive cell formations with high density and disordered arrangement, which were supported by the increased number of BrdUrd positive nuclei and the over-expression of cyclin D1 protein. Taken together, these results suggest that BP-1 is an endocrine disrupting chemical (EDC) that exerts xenoestrogenic effects by stimulating the proliferation of BG-1 ovarian cancer via ER signaling pathway associated with cell cycle as did E2. 23266722 Non-melanoma skin cancer in mouse and man. As a frontier organ, skin is exposed to different environmental and/or occupational chemicals which cause cutaneous cancers in experimental animals. In mice, 7,12-dimethylbenz[a]anthrancene (DMBA) and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) are frequently used as skin model tumor initiator and promoter, respectively. The sequential administration of DMBA and TPA leads to the appearance of a large number of benign papillomas, of which some convert later into invasive squamous cell carcinomas (SCC). At the molecular level, initiation of carcinogenesis in mouse skin consists in the mutational activation of the Ha-ras oncoprotein. HA-RAS mutations are rare in human SCC, but HA-RAS-mutated tumors appear in melanoma patients treated with B-raf inhibitors, indicating that initiated, HA-RAS-mutated stem cells also reside in human skin. Similarly, UV-induced human SCC show footprint mutations in the tumor suppressor gene TP53 which are also observed in UV-induced mouse SCC. Strong species differences exist with respect to phorbol ester-mediated tumor promotion. While certain mouse strains are very susceptible, other rodent species are much less sensitive. Likewise, humans appear to be much more resistant to phorbol ester-mediated skin toxicity. Papilloma formation as a result of a chemical insult is uncommon in men, questioning the relevance of this preneoplastic lesion for humans. However, skin tumorigenesis in the experimental situation and in humans appears to follow common molecular mechanisms, even though there are species differences in the morphological correlates to the preneoplastic state. Therefore, we recommend not simply labeling them as irrelevant for human risk assessment. 22799569 Flavonoids and antioxidant activity of flowers of Mexican Crataegus spp. Flavonoids and antioxidant activity of extracts of flowers from some Mexican accessions of Crataegus were studied using six accessions with the purpose of contributing to the knowledge of the nutraceutical properties of the accessions of the Germplasm Bank of the Universidad Autonoma Chapingo. Flavonoids were identified by HPLC-MS. Among the flavonoids, the quercetin 3-O-glucoside (3), quercetin 3-O-rhamnoside (4), quercetin 3-O-rhamnosyl-(1 → 6)-glucoside (2) and quercetin 3-O-rhamnosyl-(1 → 2)-[rhamnosyl-(1 → 6)]-glucoside (1) were assigned. Flavonoid content and radical scavenging activity explain some of the medicinal properties attributed to flowers of Mexican hawthorns. 23628674 Effects of Traditional Chinese Medicine Wuzhi Capsule on Pharmacokinetics of Tacrolimus in Rats. Wuzhi capsule (WZC) is a preparation of an ethanol herbal extract of Schisandra sphenanthera(Nan-Wuweizi), with its main active ingredients including schisandrin, schisandrol B, schisantherin A, schisanhenol and deoxyshisandrin. WZC and tacrolimus are often co-administered for the treatment of drug-induced hepatitis in organ transplant recipients in China. Recently, it was reported that WZC could significantly increase the blood concentration of tacrolimus. The purpose of this study was to investigate whether and how WZC affects the pharmacokinetics of tacrolimus in rats. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to determine the plasma concentration of tacrolimus. The results showed that WZC increased the mean plasma concentration of tacrolimus. Compared with administration of tacrolimus alone (Cmax, 18.87±10.29 ng/mL; AUC0&→t, 40.98±37.07), a single intragastric administered dose of WZC increased, the pharmacokinetic parameters of tacrolimus (Cmax, 59.42±30.32 ng/mL; AUC0→t, 239.71±28.86) by five folds in rat plasma. After pretreatment with WZC for 12 days, there were still significant increases in AUC0→t (from 40.98±37.07 to 89.21±26.39 h ng/mL; p < 0.05) and Cmax (from 18.87±10.29 to 43.16±10.61 ng/mL; p < 0.05) of tacrolimus compared with oral of tacrolimus alone, suggesting that WZC increased the exposure of tacrolimus by one or more mechanisms. The increase in tacolimus Cmax by WZC was dose dependent. The effect of WZC on Tacrolimus AUC0→t also increased with dose with a maximal effect observed at 450 mg/kg (825.34 ng h/mL). No further increases in tacolimus AUC0→t were observed at WZC dose above 450 mg/kg. It is suggested that due to the effect of WZC on the pharmacokinetics of tacrolimus, the herb-drug interaction between WZC and tacrolimus should be taken into considered in clinical practice. 23214714 Mechanism of homogeneous reduction of CO2 by pyridine: proton relay in aqueous solvent and aromatic stabilization. We employ quantum chemical calculations to investigate the mechanism of homogeneous CO(2) reduction by pyridine (Py) in the Py/p-GaP system. We find that CO(2) reduction by Py commences with PyCOOH(0) formation where: (a) protonated Py (PyH(+)) is reduced to PyH(0), (b) PyH(0) then reduces CO(2) by one electron transfer (ET) via nucleophilic attack by its N lone pair on the C of CO(2), and finally (c) proton transfer (PT) from PyH(0) to CO(2) produces PyCOOH(0). The predicted enthalpic barrier for this proton-coupled ET (PCET) reaction is 45.7 kcal/mol for direct PT from PyH(0) to CO(2). However, when PT is mediated by one to three water molecules acting as a proton relay, the barrier decreases to 29.5, 20.4, and 18.5 kcal/mol, respectively. The water proton relay reduces strain in the transition state (TS) and facilitates more complete ET. For PT mediated by a three water molecule proton relay, adding water molecules to explicitly solvate the core reaction system reduces the barrier to 13.6-16.5 kcal/mol, depending on the number and configuration of the solvating waters. This agrees with the experimentally determined barrier of 16.5 ± 2.4 kcal/mol. We calculate a pK(a) for PyH(0) of 31 indicating that PT preceding ET is highly unfavorable. Moreover, we demonstrate that ET precedes PT in PyCOOH(0) formation, confirming PyH(0)'s pK(a) as irrelevant for predicting PT from PyH(0) to CO(2). Furthermore, we calculate adiabatic electron affinities in aqueous solvent for CO(2), Py, and Py·CO(2) of 47.4, 37.9, and 66.3 kcal/mol respectively, indicating that the anionic complex PyCOO(-) stabilizes the anionic radicals CO(2)(-) and Py(-) to facilitate low barrier ET. As the reduction of CO(2) proceeds through ET and then PT, the pyridine ring becomes aromatic, and thus Py catalyzes CO(2) reduction by stabilizing the PCET TS and the PyCOOH(0) product through aromatic resonance stabilization. Our results suggest that Py catalyzes the homogeneous reductions of formic acid and formaldehyde en route to formation of CH(3)OH through a series of one-electron reductions analogous to the PCET reduction of CO(2) examined here, where the electrode only acts to reduce PyH(+) to PyH(0). 23157442 Micro/nanostructured hyaluronic acid matrices with tuned swelling and drug release properties. Hyaluronic acid (HA) hydrogels were structured in the form of porous monoliths by means of the ice-segregation-induced self-assembly (ISISA) method coupled with freeze-drying. Physical and chemical parameters were explored in order to fine-tune the microstructure and the incidence on both swelling and dissolution behavior in aqueous media. Gentamicin-loaded HA matrices with tuned drug release properties were also prepared; their inherent properties and behavior in solution are discussed in the framework of thermal analysis and scanning electron microscopy inspection. 22640571 Syntheses and antibacterial activity of Schiff bases from 16-isopropyl-5, 9-dimethyltetracyclo [10.2.2.0(1, 10).0(4, 9)] hexadec-15-ene-5, 14-dicarboxylic acid. 16-Isopropyl-5, 9-dimethyltetracyclo [10.2.2.0(1, 10).0(4, 9)] hexadec-15-ene-5, 14-dicarboxylic acid (1b) was prepared from rosin through a Diels-Alder addition reaction. Then, a group of Schiff bases derived from 1b was synthesised. Their structures were characterised by IR,(1)H-NMR, MS and elemental analysis. The antibacterial activities of these newly synthesised Schiff bases were also investigated. The results show that these compounds possess antibacterial activities against Staphylococcus aureus and Escherichia coli. Among them, compounds 5a, 5b and 5c, exhibit remarkable antibacterial activity against E. coli. 23288103 A new hematite photoanode doping strategy for solar water splitting: oxygen vacancy generation. The enhancement of the electrical conductivity by doping is important in hematite (α-Fe(2)O(3)) photoanodes for efficient solar water oxidation. However, in spite of many successful demonstrations using extrinsic dopants, such as Sn, Ti, and Si, the achieved photocurrent is still lower than the practical requirement. There is still lack of our understanding of how intrinsic oxygen defects can change the photocurrent and interact with the extrinsic dopants. In this study, we systematically investigate the interplay of oxygen vacancies and extrinsic Sn dopants in the context of photoanodic properties. As a result, we demonstrate that the controlled generation of oxygen vacancies can activate the photoactivity of pure hematite remarkably and further enhance the Sn doping effects synergistically. Furthermore, the correlated behavior of oxygen vacancies and Sn dopants is closely linked to the variation of electrical conductance and results in the optimum concentration region to show the high photocurrent and low onset voltage. 23117208 Impact of Charcot neuroarthropathy on metatarsal bone mineral density and geometric strength indices. Charcot neuroarthropathy (CN), an inflammatory condition characterized by rapid and progressive destruction of pedal bones and joints, often leads to deformity and ulceration in individuals with diabetes mellitus (DM) and peripheral neuropathy (PN). Repetitive, unperceived joint trauma may trigger initial CN damage, causing a proinflammatory cascade that can result in osteolysis and contribute to subsequent neuropathic fracture. We aimed to characterize osteolytic changes related to development and progression of CN by measuring bone mineral density (BMD) and geometric strength indices using volumetric quantitative computed tomography. Twenty individuals with DM+PN were compared to twenty age-, sex-, and race-matched individuals with DM+PN and acute CN. We hypothesized that individuals with acute CN would have decreased BMD and decreased total area, cortical area, minimum section modulus, and cortical thickness in the diaphysis of the second and fifth metatarsals. Results showed BMD was lower in both involved and uninvolved feet of CN participants compared to DM+PN participants, with greater reductions in involved CN feet compared to uninvolved CN feet. There was a non-significant increase in total area and cortical area in the CN metatarsals, which helps explain the finding of similar minimum section modulus in DM+PN and CN subjects despite the CN group's significantly lower BMD. Larger cortical area and section modulus are typically considered signs of greater bone strength due to higher resistance to compressive and bending loads, respectively. In CN metatarsals, however, these findings may reflect periosteal woven bone apposition, i.e., a hypertrophic response to injury rather than increased fracture resistance. Future research using these techniques will aid further understanding of the inflammation-mediated bony changes associated with development and progression of CN and other diseases. 23010363 Proteins with an alpha/beta hydrolase fold: Relationships between subfamilies in an ever-growing superfamily. Alpha/beta hydrolases function as hydrolases, lyases, transferases, hormone precursors or transporters, chaperones or routers of other proteins. The amount of structural and functional available data related to this protein superfamily expands exponentially, as does the number of proteins classified as alpha/beta hydrolases despite poor sequence similarity and lack of experimental data. However the superfamily can be rationally divided according to sequence or structural homologies, leading to subfamilies of proteins with potentially similar functions. Since the discovery of proteins homologous to cholinesterases but devoid of enzymatic activity (e.g., the neuroligins), divergent functions have been ascribed to members of other subfamilies (e.g., lipases, dipeptidylaminopeptidase IV, etc.). To study the potentially moonlighting properties of alpha/beta hydrolases, the ESTHER database (for ESTerase and alpha/beta Hydrolase Enzymes and Relatives; http://bioweb.ensam.inra.fr/esther), which collects, organizes and disseminates structural and functional information related to alpha/beta hydrolases, has been updated with new tools and the web server interface has been upgraded. A new Overall Table along with a new Tree based on HMM models has been included to tentatively group subfamilies. These tools provide starting points for phylogenetic studies aimed at pinpointing the origin of duplications leading to paralogous genes (e.g., acetylcholinesterase versus butyrylcholinesterase, or neuroligin versus carboxylesterase). Another of our goals is to implement new tools to distinguish catalytically active enzymes from non-catalytic proteins in poorly studied or annotated subfamilies. 23523780 Differential responses to ω-agatoxin IVA in murine frontal cortex and spinal cord derived neuronal networks. ω-Agatoxin-IVA is a well known P/Q-type Ca(2+) channel blocker and has been shown to affect presynaptic Ca(2+) currents as well postsynaptic potentials. P/Q-type voltage gated Ca(2+) channels play a vital role in presynaptic neurotransmitter release and thus play a role in action potential generation. Monitoring spontaneous activity of neuronal networks on microelectrode arrays (MEAs) provides an important tool for examining this neurotoxin. Changes in extracellular action potentials are readily observed and are dependent on synaptic function. Given the efficacy of murine frontal cortex and spinal cord networks to detect neuroactive substances, we investigated the effects of ω-agatoxin on spontaneous action potential firing within these networks. We found that networks derived from spinal cord are more sensitive to the toxin than those from frontal cortex; a concentration of only 10nM produced statistically significant effects on activity from spinal cord networks whereas 50nM was required to alter activity in frontal cortex networks. Furthermore, the effects of the toxin on frontal cortex are more complex as unit specific responses were observed. These manifested as either a decrease or increase in action potential firing rate which could be statistically separated as unique clusters. Administration of bicuculline, a GABAA inhibitor, isolated a single response to ω-agatoxin, which was characterized by a reduction in network activity. These data support the notion that the two clusters detected with ω-agatoxin exposure represent differential responses from excitatory and inhibitory neuronal populations. 22993196 Hepatic ATGL knockdown uncouples glucose intolerance from liver TAG accumulation. Adipose triglyceride lipase (ATGL) is the predominant triacylglycerol (TAG) hydrolase in mammals; however, the tissue-specific effects of ATGL outside of adipose tissue have not been well characterized. Hence, we tested the contribution of hepatic ATGL on mediating glucose tolerance and insulin action. Glucose or insulin tolerance tests and insulin signaling were performed in C57BL/6 mice administered control (nongene specific shRNA) or Atgl shRNA adenoviruses. Glucose and lipid metabolism assays were conducted in primary hepatocytes isolated from mice transduced with control or Atgl shRNA adenoviruses. Knocking down hepatic ATGL completely abrogated the increase in serum insulin following either 1 or 12 wk of feeding a high-fat (HF) diet despite higher hepatic TAG content. Glucose tolerance tests demonstrated that ATGL knockdown normalized glucose tolerance in HF-diet-fed mice. The observed improvements in glucose tolerance were present despite unaltered hepatic insulin signaling and increased liver TAG. Mice with suppressed hepatic ATGL had reduced hepatic glucose production in vivo, and hepatocytes isolated from Atgl shRNA-treated mice displayed a 26% decrease in glucose production and a 38% increase in glucose oxidation compared to control cells. Taken together, these data suggest that hepatic ATGL knockdown enhances glucose tolerance by increasing hepatic glucose utilization and uncouples impairments in insulin action from hepatic TAG accumulation. 23614492 Terpenoids from the Chinese liverwort Plagiochila pulcherrima and their cytotoxic effects. Three new pimarane-type diterpenoids, 7β,11α-dihydroxypimara-8(14),15-diene (1), 1β,11α-dihydroxypimara-8(14),15-diene (2), and 11α-hydroxypimara-8(14),15-diene (3), five 2,3-secoaromadendrane-type sesquiterpenoids, including a new one, ethyoxyplagiochiline A2 (4), and three known fusicoccane-type diterpenoids were isolated from the Chinese liverwort Plagiochila pulcherrima. Their structures were established on the basis of extensive spectroscopic analysis. Compounds 6 and 7 exhibited moderate inhibitory activity on the proliferation of human cancer cell lines Hela, A172, and H460. Moreover, the cytotoxicity of compound 6 to Hela cells was related to apoptotis as confirmed by DAPI nuclear staining and flow cytometry. 23463333 Determination of robenidine residues in chicken muscle by high performance liquid chromatography with ultraviolet detection. A simple, robust and reliable method for the determination of residual robenidine in chicken muscle using high performance liquid chromatography with ultraviolet (UV) detection was developed and validated according to the Codex Alimentarius Commission guidelines. Chicken muscle was extracted by acetonitrile/formic acid (98:2, v/v) and defatted with hexane. Analytes were isocratically separated on a Luna C18 column (4.6 × 150 mm, 5 μm) using 70 % methanol in water containing 0.1 % trifluoroacetic acid at a flow rate of 1.0 mL/min at 30 °C. UV detection was performed at 312 nm. The method was validated by assessing performance parameters including selectivity, linearity, limit of quantification (LOQ), precision, accuracy, recovery, stability and robustness. A calibration curve that was constructed over 0.05-0.5 μg/g showed correlation coefficients of more than 0.999. The intra- and inter-day precisions (as coefficient of variation) were 1.45-3.32 and 2.63-4.99 %, respectively. The intra- and inter-day accuracies were 99.4-105.3 and 98.3-101.6 %, respectively. The recoveries were in the range of 76.6-81.8 % and the LOQ was 0.05 μg/g. The developed method showed suitable performance for the determination of robenidine residues in chicken muscle. 23600887 Two novel furostanol saponins from the tubers of Ophiopogon japonicus. Phytochemical investigation of the fresh tubers of Ophiopogon japonicus led to the isolation of two new furostanol saponins (1 and 2) together with two known steroidal saponins (3 and 4). Comprehensive spectroscopic analysis allowed the chemical structures of two new compounds to be elucidated as (25R)-26-O-[β-d-glucopyranosyl-(1 → 2)-β-d-glucopyranosyl]-5-ene-furost-1β,3β,22α,26-tetraol-3-O-α-l-rhamnopyranosyl-(1 → 2)-[β-d-xylopyranosyl-(1 → 4)]-β-d-glucopyranoside (1, ophiopogonin P) and (25R)-26-O-[β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranosyl]-5-ene-furost-1β,3β,22α,26-tetraol-3-O-α-l-rhamnopyranosyl-(1 → 2)-[β-d-xylopyranosyl-(1 → 4)]-β-d-glucopyranoside (2, ophiopogonin Q). Furostanol saponins with the disaccharide chain linked at C-26 hydroxy group of the aglycone have been rarely reported from natural sources. 23421743 Dorsamin-A's, Glycerolipids Carrying a Dehydrophenylalanine Ester Moiety from the Seed-Eating Larvae of the Bruchid Beetle Bruchidius dorsalis. Using a TLC autographic assay for radical-scavenging activity with the ABTS radical, the presence of lipophilic antioxidants in the larvae of the wild bruchid seed beetle Bruchidius dorsalis was detected. Assay-guided fractionation of the CHCl(3)-soluble fraction of the larvae resulted in the isolation of new glycerolipids, designated dorsamin-A763, -A737, -A765, -A739, and -A767, comprising 1,2-diacyl-sn-glycero-3-dehydrophenylalanine ester structural units. The ABTS radical scavenging activity of the dorsamin-A's was comparable with or stronger than that of Trolox. 23572409 Pomalidomide: first global approval. Pomalidomide (Pomalyst(®)) is a small molecule analogue of thalidomide under development with Celgene Corporation for the oral treatment of haematological and connective tissue diseases. Pomalidomide has been approved in the USA and is awaiting approval in the EU for use with low-dose dexamethasone for the treatment of relapsed and refractory multiple myeloma that has progressed following at least two prior therapies, including lenalidomide and bortezomib. The efficacy and safety of pomalidomide as monotherapy in patients with relapsed and refractory multiple myeloma has also been evaluated in a phase III trial. The agent is in phase III clinical development for the treatment of myelofibrosis and in phase II development for systemic sclerosis. Pomalidomide is also being investigated in patients with amyloidosis, prostate cancer, small cell lung cancer, pancreatic cancer, graft-versus-host disease, and Waldenstrom's macroglobulinaemia. This article summarizes the milestones in the development of pomalidomide leading to this first global approval for relapsed and refractory multiple myeloma. 23131208 Is poor research the cause of the declining productivity of the pharmaceutical industry? An industry in need of a paradigm shift. For the past 20 years target-based drug discovery has been the main research paradigm used by the pharmaceutical industry and billions of dollars have been invested into this approach. However, recent industry data strongly indicate that the target-based approach is not an effective drug discovery paradigm and is likely to be the cause of the productivity crisis the industry is experiencing. However, from a theoretical and scientific perspective the target-based approach appears sound, so why is it not more successful? The purpose of this paper is first to analyse the real-life implementation of the target-based approach to identify possible reasons for the high failure rate and second to suggest changes to the drug discovery approach, which can improve productivity. 23503588 The exoribonuclease Dis3L2 defines a novel eukaryotic RNA degradation pathway. The final step of cytoplasmic mRNA degradation proceeds in either a 5'-3' direction catalysed by Xrn1 or in a 3'-5' direction catalysed by the exosome. Dis3/Rrp44, an RNase II family protein, is the catalytic subunit of the exosome. In humans, there are three paralogues of this enzyme: DIS3, DIS3L, and DIS3L2. In this work, we identified a novel Schizosaccharomyces pombe exonuclease belonging to the conserved family of human DIS3L2 and plant SOV. Dis3L2 does not interact with the exosome components and localizes in the cytoplasm and in cytoplasmic foci, which are docked to P-bodies. Deletion of dis3l2(+) is synthetically lethal with xrn1Δ, while deletion of dis3l2(+) in an lsm1Δ background results in the accumulation of transcripts and slower mRNA degradation rates. Accumulated transcripts show enhanced uridylation and in vitro Dis3L2 displays a preference for uridylated substrates. Altogether, our results suggest that in S. pombe, and possibly in most other eukaryotes, Dis3L2 is an important factor in mRNA degradation. Therefore, this novel 3'-5' RNA decay pathway represents an alternative to degradation by Xrn1 and the exosome. 23214415 Design of mixed PEO/PAA brushes with switchable properties toward protein adsorption. Adsorption of proteins at interfaces is an ubiquitous phenomenon of prime importance. Layers of poly(ethylene oxide) (PEO) are widely used to repel proteins. Conversely, proteins were shown to adsorb deeply into brushes of poly(acrylic acid) (PAA), and their subsequent partial release could be triggered by a change of pH and/or ionic strength (I). Mixed brushes of these polymers are thus promising candidates to tune protein adsorption onto new smart surfaces. In this work, the synthesis of such mixed brushes was performed based on a "grafting to" approach, the two polymers being either grafted sequentially or simultaneously. Detailed characterization of the obtained brushes using static water contact angle measurements, X-ray photoelectron spectroscopy, electrochemical impedance spectroscopy, and polarization-modulation reflection-absorption infrared spectroscopy is presented. While sequential grafting of the two polymers for different reactions times did not give rise to a broad range of composition of mixed brushes, simultaneous grafting of the polymers from solutions with different compositions allows for the synthesis of a range of mixed brushes (mass fraction of PEO in the mixed brushes from 0.35 to 0.65). A key example is then chosen to illustrate the switchable behavior of a selected mixed PEO/PAA brush toward albumin adsorption. The adsorption behavior was monitored with a quartz crystal microbalance. The mixed brush could adsorb high amounts of albumin, but 86% of the adsorbed protein could then be desorbed upon pH and I change. The obtained properties are thus a combination of the ones of PEO and PAA, and a highly switchable behavior is observed toward protein adsorption. 23380477 Autophagy takes place in mutated p53 neuroblastoma cells in response to hypoxia mimetic CoCl(2). Solid tumors like neuroblastoma exhibit hypoxic areas, which can lead both to cell death or aggressiveness increase. Hypoxia is a known stress able to induce stabilization of p53, implicated in cell fate regulation. Recently, p53 appeared to be involved in autophagy in an opposite manner, depending on its location: when nuclear, it enhanced transcription of pro-autophagic genes whereas when cytoplasmic, it inhibited the autophagic process. Today, we used cobalt chloride, a hypoxia mimetic that inhibits proteasomal HIF-1 degradation and generates reactive oxygen species (ROS). We focused on CoCl2-induced cell death in a DNA-binding mutated p53 neuroblastoma cell line (SKNBE(2c)). An autophagic signaling was evidenced by an increase of Beclin-1, ATG 5-12, and LC3-II expression whereas the p53(mut) presence decreased with CoCl2 time exposure. Activation of the pathway seemed to protect cells from ROS production and, at least in part, from death. The autophagic inhibitors activated the apoptotic signaling and the death was enhanced. To delineate the eventual implication of the p53(mut) in the autophagic process in response to hypoxia, we monitored signaling in p53(WT)SHSY5Y cells, after either shRNA-p53 down-regulation or transcriptional activity inhibition by pifithrin alpha. We did not detect autophagy neither with p53(wt) nor when p53 was lacking whereas such a response was effective with a mutated or inactivated p53. To conclude, mutated p53 in neuroblastoma cells could be linked with the switch between apoptotic response and cell death by autophagy in response to hypoxic mimetic stress. 23488987 Enzymatic Conversion of 6-Nitroquinoline to the Fluorophore 6-Aminoquinoline Selectively under Hypoxic Conditions. There is substantial interest in small molecules that can be used to detect or kill the hypoxic (low oxygen) cells found in solid tumors. Nitroaryl moieties are useful components in the design of hypoxia-selective imaging agents and prodrugs because one-electron reductases can convert the nitroaryl group to nitroso, hydroxylamino, and amino metabolites selectively under low oxygen conditions. Here, we describe the in vitro, cell free metabolism of a pro-fluorescent substrate, 6-nitroquinoline (1) under both aerobic and hypoxic conditions. Both LC-MS and fluorescence spectroscopic analyses provided evidence that the one-electron reducing enzyme system, xanthine/xanthine oxidase, converted the nonfluorescent parent compound 1 to the known fluorophore 6-aminoquinoline (2) selectively under hypoxic conditions. The presumed intermediate in this reduction process, 6-hydroxylaminoquinoline (6), is fluorescent and can be efficiently converted by xanthine/xanthine oxidase to 2 only under hypoxic conditions. This finding provides evidence for multiple oxygen-sensitive steps in the enzymatic conversion of nitroaryl compounds to the corresponding amino derivatives. In a side reaction that is separate from the bioreductive metabolism of 1, xanthine oxidase converted 1 to 6-nitroquinolin-2(1H)-one (5). These studies may enable the use of 1 as a fluorescent substrate for the detection and profiling of one-electron reductases in cell culture or biopsy samples. In addition, the compound may find use as a fluorogenic probe for the detection of hypoxia in tumor models. The occurrence of side products such as 5 in the enzymatic bioreduction of 1 underscores the importance of metabolite identification in the characterization of hypoxia-selective probes and drugs that employ nitroaryl units as oxygen sensors. 23394318 Antidepressant abietane diterpenoids from Chinese eaglewood. Ten new abietane diterpenoids, aquilarabietic acids A-J (1-10), and a new podocarpane diterpenoid, aquilarabietic acid K (11), were isolated from the petroleum ether and ethanol extracts of Chinese eaglewood. Among them, 3, 9, and 10 are artifacts. Their structures were established on the basis of data from extensive spectroscopic and X-ray diffraction analyses. Bioassay results indicated that 1 at 10 μM demonstrated remarkable antidepressant activity in vitro by inhibiting norepinephrine reuptake in rat brain synaptosomes by 81.4% and with an IC(50) value of 9.1 × 10(-7) M. 23055539 Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents. Angiotensin IV (AngIV: VYIHPF)-related peptides have long been recognized as procognitive agents with potential as antidementia therapeutics. Their development as useful therapeutics, however, has been limited by physiochemical properties that make them susceptible to metabolic degradation and impermeable to gut and blood-brain barriers. A previous study demonstrated that the core structural information required to impart the procognitive activity of the AngIV analog, norleucine(1)-angiotensin IV, resides in its three N-terminal amino acids, Nle-Tyr-Ile. The goal of this project was to chemically modify this tripeptide in such a way to enhance its metabolic stability and barrier permeability to produce a drug candidate with potential clinical utility. Initial results demonstrated that several N- and C-terminal modifications lead to dramatically improved stability while maintaining the capability to reverse scopolamine-induced deficits in Morris water maze performance and augment hippocampal synaptogenesis. Subsequent chemical modifications, which were designed to increase hydrophobicity and decrease hydrogen bonding, yielded an orally active, blood-barrier permeant, metabolically stabilized analog, N-hexanoic-Tyr-Ile-(6) aminohexanoic amide (dihexa), that exhibits excellent antidementia activity in the scopolamine and aged rat models and marked synaptogenic activity. These data suggest that dihexa may have therapeutic potential as a treatment of disorders, such as Alzheimer's disease, where augmented synaptic connectivity may be beneficial. 23265498 Development and validation of a real-time PCR method for the simultaneous detection of black mustard (Brassica nigra) and brown mustard (Brassica juncea) in food. The paper presents a real-time PCR method allowing the simultaneous detection of traces of black mustard (Brassica nigra) and brown mustard (Brassica juncea) in food. The primers and the probe target the B. nigra partial RT gene for reverse transcriptase from gypsy-like retroelement 13G42-26. The real-time PCR method does not show any cross-reactivity with other Brassicaceae species with the exception of white mustard. Low cross-reactivities with cinnamon, cumin, fenugreek, ginger, rye and turmeric can be ignored because in common mustard containing foodstuffs these biological species are present in very low amounts. By analysing serially diluted DNA extracts from black and brown mustard, the DNA of both mustard species could be detected down to 0.1 pg. With 10 ng DNA per PCR tube the real-time PCR method allows the detection of 5 ppm black and brown mustard in brewed sausages. 23325046 Stable Isolation of Phycocyanin from Spirulina platensis Associated with High-Pressure Extraction Process. A method for stably purifying a functional dye, phycocyanin from Spirulina platensis was developed by a hexane extraction process combined with high pressure. This was necessary because this dye is known to be very unstable during normal extraction processes. The purification yield of this method was estimated as 10.2%, whose value is 3%-5% higher than is the case from another conventional separation method using phosphate buffer. The isolated phycocyanin from this process also showed the highest purity of 0.909 based on absorbance of 2.104 at 280 nm and 1.912 at 620 nm. Two subunits of phycocyanin namely α-phycocyanin (18.4 kDa) and β-phycocyanin (21.3 kDa) were found to remain from the original mixtures after being extracted, based on SDS-PAGE analysis, clearly demonstrating that this process can stably extract phycocyanin and is not affected by extraction solvent, temperature, etc. The stability of the extracted phycocyanin was also confirmed by comparing its DPPH (α,α-diphenyl-β-picrylhydrazyl) scavenging activity, showing 83% removal of oxygen free radicals. This activity was about 15% higher than that of commercially available standard phycocyanin, which implies that the combined extraction method can yield relatively intact chromoprotein through absence of degradation. The results were achieved because the low temperature and high pressure extraction effectively disrupted the cell membrane of Spirulina platensis and degraded less the polypeptide subunits of phycocyanin (which is a temperature/pH-sensitive chromoprotein) as well as increasing the extraction yield. 23461617 Mechanisms Underlying the Varied Mammary Carcinogenicity of the Environmental Pollutant 6-Nitrochrysene and Its Metabolites (-)-[R,R]- and (+)-[S,S]-1,2-Dihydroxy-1,2-dihydro-6-nitrochrysene in the Rat. The mechanisms that can account for the remarkable mammary carcinogenicity of the environmental pollutant 6-nitrochrysene (6-NC) in the rat remain elusive. In our previous studies, we identified several 6-NC-derived DNA adducts in the rat mammary gland; one major adduct was derived from (±)-trans-1,2-dihydroxy-1,2-dihydro-6-nitrochrysene (1,2-DHD-6-NC). In the present study, we resolved the racemic (±)-1,2-DHD-6-NC into (-)-[R,R]- and (+)-[S,S]-1,2-DHD-6-NC and compared their in vivo mutagenicity and carcinogenicity in the mammary glands of female transgenic (BigBlue F344 × Sprague-Dawley)F1 rats harboring lacI/cII and Sprague-Dawley rats, respectively. Both [R,R]- and [S,S]-isomers exerted similar mutagenicity and carcinogenicity but were less potent than 6-NC. Additional in vivo and in vitro studies were then performed to explore possible mechanisms that can explain the higher potency of 6-NC than 1,2-DHD-6-NC. Using ELISA, we found that neither 6-NC nor 1,2-DHD-6-NC increased the levels of several inflammatory cytokines in plasma obtained from rats 24 h after treatment. In MCF-7 cells, as determined by immunoblotting, the effects of 6-NC and 1,2-DHD-6-NC on protein expression (p53, Akt, p38, JNK, c-myc, bcl-2, PCNA, and ERβ) were comparable; however, the expressions of AhR and ERα proteins were decreased by 6-NC but not 1,2-DHD-6-NC. The expression of both receptors was decreased in mammary tissues of rats treated with 6-NC. Our findings suggest that the differential effects of 6-NC and 1,2-DHD-6-NC on AhR and ERα could potentially account for the higher carcinogenicity of 6-NC in the rat mammary gland. 23256474 Fit-for-purpose bioanalytical cross-validation for LC-MS/MS assays in clinical studies. The paradigm shift of globalized research and conducting clinical studies at different geographic locations worldwide to access broader patient populations has resulted in increased need of correlating bioanalytical results generated in multiple laboratories, often across national borders. Cross-validations of bioanalytical methods are often implemented to assure the equivalency of the bioanalytical results is demonstrated. Regulatory agencies, such as the US FDA and European Medicines Agency, have included the requirement of cross-validations in their respective bioanalytical validation guidance and guidelines. While those documents provide high-level expectations, the detailed implementation is at the discretion of each individual organization. At Bristol-Myers Squibb, we practice a fit-for-purpose approach for conducting cross-validations for small-molecule bioanalytical methods using LC-MS/MS. A step-by-step proposal on the overall strategy, procedures and technical details for conducting a successful cross-validation is presented herein. A case study utilizing the proposed cross-validation approach to rule out method variability as the potential cause for high variance observed in PK studies is also presented. 22981668 Orphan drugs: the regulatory environment. The definition of a rare disease is not universal and depends on the legislation and policies adopted by each region or country. The main objective of this article is to describe and discuss the legal framework and the regulatory environment of orphan drugs worldwide. Some reflections and discussions on the need for specific orphan drug legislation or policies are described at length. Furthermore, some aspects of the history of each region in respect of the orphan drug legislation evolution are outlined. This article describes and compares the orphan drug legislation or policies of the following countries or regions: United Sates of America (US), European Union (EU), Japan, Australia, Singapore, Taiwan and Canada. The incentives described in the orphan drug legislations or policies, the criteria for designation of orphan status and the authorisation process of an orphan drug are also described and compared. The legislations and policies are to some extent similar but not the same. It is important to understand the main differences among all available legislative systems to improve the international collaboration in the field of orphan drugs and rare diseases. 23640872 The Distorted Tropane of Scopoline. The structural isomerization of scopine into scopoline (oscine) has been observed in a supersonic jet expansion using microwave spectroscopy. The rotational spectrum evidences a single structure in the gas phase, providing a first description of the (three-ring) structurally distorted tropane in scopoline. The absence of rotational signatures of any scopine conformation suggests a practically quantitative isomerization at the vaporization temperatures of the experiment (ca. 90 °C). The determined rotational parameters of scopoline reveal the structural consequences of the intramolecular cyclation of scopine, which breaks the original epoxy group and creates a new ether bridge and a 7β-hydroxytropane configuration. The hydroxy group further stabilizes the molecule by an OH⋅⋅⋅N intramolecular hydrogen bond, which, in turn, forces the N-methyl group to the less stable axial form. Supporting ab initio (MP2) and DFT (B3LYP, M06-2X) calculations are included. 23394309 Parameterization of Reactive Force Field: Dynamics of the [Nb6O19Hx]((8-x)-) Lindqvist Polyoxoanion in Bulk Water. We present results on parameterization of reactive force field [van Duin, A. C. T.; Dasgupta, S.; Lorant, F.; Goddard, W. A. ReaxFF: A Reactive Force Field for Hydrocarbons. J. Phys. Chem. A2001, 105, 9396-9409] for investigating the properties of the [Nb6O19Hx]((8-x)-) Lindqvist polyoxoanion, x = 0-8, in water. Force-field parameters were fitted to an extensive data set consisting of structures and energetics obtained at the Perdew-Burke-Ernzerhof density functional level of theory. These parameters can reasonably describe pure water structure as well as water with an excess of H(+) and OH(-) ions. Molecular dynamics simulations were performed on [Nb6O19Hx]((8-x)-), x = 0-8, submerged in bulk water at 298 K. Analysis of the MD trajectories showed facile H atom transfer between the protonated polyoxoanion core and bulk water. The number of oxygen sites labeled with an H atom was found to vary depending on the pH of the solution. Detailed analysis shows that the total number of protons at bridging (terminal), η-O (μ2-O), sites ranges from 3(1) at pH 7, to 2(0) at pH 11, to 1(0) at pH 15. These findings closely reflect available experimental measurements. 23597793 Discovery, synthesis and in combo studies of a tetrazole analogue of clofibric acid as a potent hypoglycemic agent. A tetrazole isosteric analogue of clofibric acid (1) was prepared using a short synthetic route and was characterized by elemental analysis, NMR ((1)H, (13)C) spectroscopy, and single-crystal X-ray diffraction. The in vitro inhibitory activity of 1 against 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) was evaluated, showing a moderate inhibitory enzyme activity (51.17% of inhibition at 10μM), being more active than clofibrate and clofibric acid. The antidiabetic activity of compound 1 was determined at 50mg/Kg single dose using a non insulin dependent diabetes mellitus rat model. The results indicated a significant decrease of plasma glucose levels, during the 7h post-administration. Additionally, we performed a molecular docking of 1 into the ligand binding pocket of one subunit of human 11β-HSD1. In this model, compound 1 binds into the catalytic site of 11β-HSD1 in two different orientations. Both of them, show important short contacts with the catalytic residues Ser 170, Tyr 183, Asp 259 and also with the nicotinamide ring of NADP(+). 23281937 Structural studies of mixed glass former 0.35Na2O + 0.65[xB2O3 + (1 - x)P2O5] glasses by Raman and 11B and 31P magic angle spinning nuclear magnetic resonance spectroscopies. The mixed glass former (MGF) effect (MGFE) is defined as a nonlinear and nonadditive change in the ionic conductivity with changing glass former composition at constant modifier composition. In this study, sodium borophosphate 0.35Na(2)O + 0.65[xB(2)O(3) + (1 - x)P(2)O(5)], 0 ≤ x ≤ 1, glasses which have been shown to exhibit a positive MGFE have been prepared and examined using Raman and (11)B and (31)P magic angle spinning nuclear magnetic resonance (MAS NMR) spectroscopies. Through examination of the short-range order (SRO) structures found in the ternary glasses, it was determined that the minority glass former, B for 0.1 ≤ x ≤ 0.7 and P for 0.7 ≤ x ≤ 0.9, is "overmodified" and contains more Na(+) ions than would be expected from simple linear mixing of the binary sodium borate, x = 1, and sodium phosphate, x = 0, glasses, respectively. Changes in the intermediate range order (IRO) structures were suggested by changes in the NMR spectral chemical shifts and Raman spectra wavenumber shifts over the full composition range x in the Raman and MAS NMR spectra. The changes observed in the chemical shifts of (31)P MAS NMR spectra with x are found to be too large to be caused solely by changing sodium modification of the phosphate SRO structural groups, and this indicates that internetwork bonding between phosphorus and boron through bridging oxygens (BOs), P-O-B, must be a major contributor to the IRO structure of these glasses. While not fully developed, a first-order thermodynamic analysis based upon the Gibbs free energies of formation of the various SRO structural units in this system has been developed and can be used to account for the preferential formation of tetrahedral boron groups, B(4), by the reaction of B(3) with P(2) groups to form B(4) and P(3) groups, respectively, where the superscript denotes the number of BOs on these units, in these glasses. This preference for B(4) units appears to be a predominate cause of the changing modifier to glass former ratio with composition x in these ternary MGF glasses and appears to be associated with the large negative value of the Gibbs free energy of formation of this group. 23286240 Antiproliferative and antiplasmodial dimeric phloroglucinols from Mallotus oppositifolius from the Madagascar Dry Forest (1). Bioassay-guided fractionation of an ethanol extract of the leaves and inflorescence of Mallotus oppositifolius collected in Madagascar led to the isolation of the two new bioactive dimeric phloroglucinols mallotojaponins B (1) and C (2), together with the known mallotophenone (3). The structures of the new compounds were determined on the basis of spectroscopic evidence, including their 1D- and 2D-NMR spectra, mass spectrometry, and an X-ray crystal structure. Compounds 1 and 2 showed potent antimalarial activity against chloroquine-resistant Plasmodium falciparum, with IC50 values of 0.75 ± 0.30 and 0.14 ± 0.04 μM, while 3 was inactive in this assay. Compounds 1-3 also displayed strong antiproliferative activity against the A2780 human ovarian cancer cell line (IC50 1.10 ± 0.05, 1.3 ± 0.1 and 6.3 ± 0.4 μM, respectively). 23243660 Gas-phase dissociative electron attachment to flavonoids and possible similarities to their metabolic pathways. The gas-phase empty-level structures and formation of anion states via resonance attachment of low-energy electrons to the flavonoids naringenin (III), quercetin (IV) and myricetin (V) and the smaller reference molecules chromone (I) and flavone (II) are investigated experimentally for the first time. Dissociative electron attachment spectroscopy (DEAS) is used to measure the fragment anion currents generated through dissociative decay channels of the molecular anions of compounds I–V, detected with a mass filter as a function of the incident electron energy in the 0–14 eV energy range. Due to the insufficient volatility of flavonoids III–V, the energies of vertical electron attachment associated with temporary occupation of the lower-lying virtual orbitals are measured with electron transmission spectroscopy (ETS) only in the smaller reference molecules I and II. The experimental findings are interpreted with the support of appropriate density functional theory calculations with the B3LYP functional. The experimental vertical electron attachment energies measured in the ET spectra of I and II are compared with the orbital energies of the neutral molecules scaled using an empirically calibrated linear equation. The vertical and adiabatic electron affinities are evaluated at the B3LYP/6-31+G(d) level as the anion/neutral total energy difference. The latter theoretical method is also used for evaluation of the most stable conformers of the neutral molecules, O–H bond dissociation energies and thermodynamic energy thresholds for production of the anion fragments observed in the DEA spectra. A possible role played by loss of an H(2) molecule from the parent molecular anion in vivo in the mitochondrial respiratory chain is briefly discussed. 23246701 The protective role of curcumin on perfluorooctane sulfonate-induced genotoxicity: single cell gel electrophoresis and micronucleus test. Perfluorooctane sulfonate (PFOS) is a man-made fluorosurfactant and global pollutant. PFOS a persistent and bioaccumulative compound, is widely distributed in humans and wildlife. Therefore, it was added to Annex B of the Stockholm Convention on Persistent Organic Pollutants in May 2009. Curcumin is a natural polyphenolic compound abundant in the rhizome of the perennial herb turmeric. It is commonly used as a dietary spice and coloring agent in cooking and anecdotally as an herb in traditional Asian medicine. In this study, male rats were treated with three different PFOS doses (0.6, 1.25 and 2.5 mg/kg) and one dose of curcumin, from Curcuma longa (80 mg/kg) and combined three doses of PFOS with 80 mg/kg dose of curcumin by gavage for 30 days at 48 h intervals. Here, we evaluated the DNA damage via single cell gel electrophoresis or comet assay and micronucleus test in bone marrow in vivo. PFOS induced micronucleus frequency and decreased the ratio of polychromatic erythrocyte to normochromatic erythrocyte in bone marrow. Using the alkaline comet assay, we showed that all doses of the PFOS strongly induced DNA damage in rat bone marrow and curcumin prevented the formation of DNA damage induced by PFOS. 23356985 Inactivation of Lrp5 in osteocytes reduces young's modulus and responsiveness to the mechanical loading. Low-density-lipoprotein receptor-related protein 5 (Lrp5) is a co-receptor in Wnt signaling, which plays a critical role in development and maintenance of bone. Osteoporosis-pseudoglioma syndrome, for instance, arises from loss-of-function mutations in Lrp5, and global deletion of Lrp5 in mice results in significantly lower bone mineral density. Since osteocytes are proposed to act as a mechanosensor in the bone, we addressed a question whether a conditional loss-of-function mutation of Lrp5 selective to osteocytes (Dmp1-Cre;Lrp5(f/f)) would alter responses to ulna loading. Loading was applied to the right ulna for 3 min (360 cycles at 2Hz) at a peak force of 2.65 N for 3 consecutive days, and the contralateral ulna was used as a non-loaded control. Young's modulus was determined using a midshaft section of the femur. The results showed that compared to age-matched littermate controls, mice lacking Lrp5 in osteocytes exhibited smaller skeletal size with reduced bone mineral density and content. Compared to controls, Lrp5 deletion in osteocytes also led to a 4.6-fold reduction in Young's modulus. In response to ulna loading, mineralizing surface, mineral apposition rate, and bone formation rate were diminished in mice lacking Lrp5 in osteocytes by 52%, 85%, and 69%, respectively. Collectively, the results support the notion that the loss-of-function mutation of Lrp5 in osteocytes causes suppression of mechanoresponsiveness and reduces bone mass and Young's modulus. In summary, Lrp5-mediated Wnt signaling significantly contributes to maintenance of mechanical properties and bone mass. 23409719 Photoactive analogs of farnesyl diphosphate and related isoprenoids: design and applications in studies of medicinally important isoprenoid- utilizing enzymes. Farnesyl diphosphate (FPP) is an important metabolic intermediate in the biosynthesis of a variety of molecules including sesquiterpenes and the side chains of a number of cofactors. FPP is also the source of isoprenoid side chains found attached to proteins. Enzymes that employ FPP as a substrate are of interest because they are involved in the semisynthesis of drugs as well as targets for drug design. Photoactive analogs of FPP have been useful for identifying enzymes that use this molecule as a substrate. A variety of photocrosslinking groups have been employed to prepare FPP analogs for use in such experiments including aryl azides, diazotrifluoropropionates and benzophenones. In this review, the design of these probes is described along with an examination of how they have been used in crosslinking experiments. 23453831 Induction of apoptosis in human pancreatic MiaPaCa-2 cells through the loss of mitochondrial membrane potential (ΔΨm) by Gentiana kurroo root extract. The objective of the current study was to evaluate the methanolic root extract of Gentiana kurroo for antioxidant and antiproliferative activities as well as to study the effect of the extract on the induction of apoptosis in human pancreatic cancer cell line (Miapaca-2). The extract exerted significant antioxidant activity as verified by DPPH, hydroxyl radical, lipid peroxidation and protective oxidative DNA damage assays. The results were comparable to standard antioxidants like α-tocopherol, catechin and BHT used in such experiments. Antioxidant potential of G. kurroo may be attributed to the presence of high phenolic and flavonoid content (73±1.02 and 46±2.05mg/g extract respectively). The anti-proliferative property of Gentiana kurroo root extract was determined by sulphorhodamine B (SRB) assay against Human colon cancer cell line (HCT-116), Lung carcinoma cell line (A-549), Pancreatic cancer cell line (Miapaca-2), Lung cancer cell line (HOP-62) and acute monocytic leukaemia cell line (THP-1). G. kurroo root extract inhibited cancer cell growth depending upon the cell line used and in a dose dependent manner. The extract induced cell cycle arrest in Miapaca-2 cells at G0/G1 phase of the cell cycle. The population of apoptotic cells increased from 11.4% in case of control to 49.6% at 100μg/ml of G. kurroo root extract. The extract also induced a remarkable decrease in mitochondrial membrane potential (ΔΨm) leading to apoptosis of cancer cells used. The main chemical constituents identified by the liquid chromatography-tandem mass spectrometry (LC-ESI-MSMS) were found to be iridoid glucosides (iridoids and secoiridoids), xanthones and flavonoids. Iridoid glucosides are the bitter principles of Gentiana species. Loganic acid, Sweroside, Swertiamarin, Gentiopicroside, Gentisin, Isogentisin, Gentioside, Norswertianolin, Swertianolin, 4″-O-β-d-glucosyl-6'-O-(4-O-β-d-glucosylcaffeoyl)-linearoside and Swertisin were the principal compounds present in the methanol root extract of G. kurroo. 23427063 Nanoscale poling of polymer films. Spots of second harmonic generation (SHG) are produced from nanopatterned sub-micrometer areas of nonlinear polymer media. Information is written by using a biased-AFM tip, a highly nonlinear polymer (poly(methyl metha-acrylate)-co-Disperse Red 1), and a novel "floating-tip nanolithography" (FTN) technique. Dipoles are oriented and aligned at the nanoscale under the biased-AFM tip, resulting in SHG production. The information is storable over weeks. 23641017 Associations of TSH within the reference range with future blood pressure and lipid concentrations. 11-year follow-up of the HUNT Study. Objective In cross-sectional studies, TSH levels within the reference range have been positively associated with blood pressure and adverse serum lipid levels. In a prospective study, we aimed to find out if differences in TSH within the reference range are associated with future levels of blood pressure and lipids.Design Prospective population-based study.Methods Among 9709 women and 4644 men without previous thyroid disease who had a baseline TSH of 0.45-4.5 mU/l, we studied the associations of baseline TSH with blood pressure and lipid levels at follow-up 11 years later.Results Higher TSH at baseline was associated with higher systolic (P=0.002 in women) and diastolic (P=0.03 in women) blood pressure, non-HDL cholesterol (P=0.01 in men), and triglycerides (P=0.008 in men), and lower HDL cholesterol (P<0.001 in women and men) at follow-up, but the associations were very modest and not consistent between sexes. Among people who remained free of thyroid disease, changes in TSH during follow-up were associated with concomitant changes in systolic and diastolic blood pressure, non-HDL cholesterol, and triglyceride levels (all P<0.001), with similar results for women and men. Thus, blood pressure and lipid levels increased among people with increase in TSH, and decreased among people with a decrease in TSH, compared to people with no change in TSH.Conclusions High TSH levels within the reference range may be associated with modestly higher future levels of blood pressure and adverse serum lipids. TSH may co-vary with blood pressure and lipid levels among people with apparently normal thyroid function. 22468693 Phytochemical analysis of Gymnema sylvestre and evaluation of its antimicrobial activity. Gymnema sylvestre (CS 149), known to be a rich source of saponins and other valuable phytochemicals, has been analysed for antimicrobial activity. The chloroform extracts of aerial and root parts of G. sylvestre exhibited higher antimicrobial activity as compared to diethyl ether and acetone. The root extracts of chloroform have shown competitive minimum inhibitory concentration and minimum bactericidal concentration values in the range of 0.04-1.28 mg mL(-1) and 0.08-2.56 mg/mL, respectively, towards the pathogens. The GC-MS analysis of chloroform extracts has shown the presence of compounds like eicosane, oleic acid, stigmasterol and vitamin E. 23327686 Long-loop G-quadruplexes are misfolded population minorities with fast transition kinetics in human telomeric sequences. Single-stranded guanine (G)-rich sequences at the 3' end of human telomeres provide ample opportunities for physiologically relevant structures, such as G-quadruplexes, to form and interconvert. Population equilibrium in this long sequence is expected to be intricate and beyond the resolution of ensemble-average techniques, such as circular dichroism, NMR, or X-ray crystallography. By combining a force-jump method at the single-molecular level and a statistical population deconvolution at the sub-nanometer resolution, we reveal a complex population network with unprecedented transition dynamics in human telomeric sequences that contain four to eight TTAGGG repeats. Our kinetic data firmly establish that G-triplexes are intermediates to G-quadruplexes while long-loop G-quadruplexes are misfolded population minorities whose formation and disassembly are faster than G-triplexes or regular G-quadruplexes. The existence of misfolded DNA supports the emerging view that structural and kinetic complexities of DNA can rival those of RNA or proteins. While G-quadruplexes are the most prevalent species in all the sequences studied, the abundance of a misfolded G-quadruplex in a particular telomeric sequence decreases with an increase in the loop length or the number of long-loops in the structure. These population patterns support the prediction that in the full-length 3' overhang of human telomeres, G-quadruplexes with shortest TTA loops would be the most dominant species, which justifies the modeling role of regular G-quadruplexes in the investigation of telomeric structures. 23455513 Glycosylation of conotoxins. Conotoxins are small peptides present in the venom of cone snails. The snail uses this venom to paralyze and capture prey. The constituent conopeptides display a high level of chemical diversity and are of particular interest for scientists as tools employed in neurological studies and for drug development, because they target with exquisite specificity membrane receptors, transporters, and various ion channels in the nervous system. However, these peptides are known to contain a high frequency and variability of post-translational modifications-including sometimes O-glycosylation-which are of importance for biological activity. The potential application of specific conotoxins as neuropharmalogical agents and chemical probes requires a full characterization of the relevant peptides, including the structure of the carbohydrate part. In this review, the currently existing knowledge of O-glycosylation of conotoxins is described. 23234537 Hybrid carbon nanotube networks as efficient hole extraction layers for organic photovoltaics. Transparent, highly percolated networks of regioregular poly(3-hexylthiophene) (rr-P3HT)-wrapped semiconducting single-walled carbon nanotubes (s-SWNTs) are deposited, and the charge transfer processes of these nanohybrids are studied using spectroscopic and electrical measurements. The data disclose hole doping of s-SWNTs by the polymer, challenging the prevalent electron-doping hypothesis. Through controlled fabrication, high- to low-density nanohybrid networks are achieved, with low-density hybrid carbon nanotube networks tested as hole transport layers (HTLs) for bulk heterojunction (BHJ) organic photovoltaics (OPV). OPVs incorporating these rr-P3HT/s-SWNT networks as the HTL demonstrate the best large area (70 mm(2)) carbon nanotube incorporated organic solar cells to date with a power conversion efficiency of 7.6%. This signifies the strong capability of nanohybrids as an efficient hole extraction layer, and we believe that dense nanohybrid networks have the potential to replace expensive and material scarce inorganic transparent electrodes in large area electronics toward the realization of low-cost flexible electronics. 23313621 Vasorelaxant effects of 1-nitro-2-phenylethane, the main constituent of the essential oil of Aniba canelilla, in superior mesenteric arteries from spontaneously hypertensive rats. The present study investigated the mechanisms underlying the vasorelaxant effects of the essential oil of Aniba canelilla (EOAC) and its main constituent 1-nitro-2-phenylethane (NP) in isolated superior mesenteric artery from spontaneously hypertensive rats (SHRs). At 0.1-1000 μg/mL, EOAC and NP relaxed SMA preparations pre-contracted with 75 mMKCl with IC(50) (geometric mean [95% confidence interval]) values of 294.19 [158.20-94.64] and 501.27 [378.60-624.00] μg/mL, respectively); or with phenylephrine (PHE) (IC(50)s=11.07 [6.40-15.68] and 7.91 [4.08-11.74) μg/mL, respectively). All these effects were reversible and remained unaltered by vascular endothelium removal. In preparations maintained under Ca(2+)-free conditions, EOAC and NP (both at 600 μg/mL) reduced the PHE-, but not the caffeine-induced contraction. In Ca(2+)-free and high K(+) (75 mM) medium, the contractions produced by CaCl(2) or BaCl(2) were reduced or even abolished by EOAC and NP at 100 and 600 μg/mL, respectively. EOAC and NP (both at 10-1000 μg/mL) also relaxed the contraction evoked by phorbol dibutyrate (IC(50)=52.66 [10.82-94.64] and 39.13 [31.55-46.72] μg/mL, respectively). It is concluded that NP has a myogenic endothelium-independent vasorelaxant effects and appears to be the active principle of the EOAC. Vasorelaxant effect induced by both EOAC and NP is preferential to receptor-activated pathways and it appears to occur intracellularly more than a superficial action restricted to the membrane environment such as a simple blocking activity on a given receptor or ion channel. 23250541 Comparison of tissue metal concentrations in Zucker lean, Zucker obese, and Zucker diabetic fatty rats and the effects of chromium supplementation on tissue metal concentrations. Diabetes results in several metabolic changes, including alterations in the transport, distribution, excretion, and accumulation of metals. While changes have been examined in several rat models of insulin resistance and diabetes, the metal ion concentrations in the tissues of Zucker lean, Zucker obese (an insulin resistance and early stage diabetes model), and Zucker diabetic fatty (ZDF, a type 2 diabetes model) have not previously been examined in detail. The concentration of Cu, Zn, Fe, Mg, and Ca were examined in the liver, kidney, heart and spleen, and Cr concentration in the liver and kidney of these rats were examined. Zucker obese rats have a reduction in the concentration of Cu, Zn, Fe, Mg in the liver compared to ZDF and/or lean Zucker rats, presumably as a result of the increased fat content of the liver of the obese rats. ZDF rats have increased concentrations of kidney Cu compared to the lean rats, while kidney Ca concentrations are increased in the Zucker obese rats. Spleen Fe concentrations are decreased in Zucker obese rats compared to the lean rats. No effects on metal concentrations in the heart were observed between the lean, obese, and ZDF rats, and no effects on Cr concentrations were identified. Cr(III) complexes have previously been shown to have beneficial effects on the signs of insulin resistance in Zucker obese and ZDF rats. The effects of daily gavage administration of chromium picolinate ([Cr(pic)(3)]) (1 mg Cr/kg body mass), CrCl(3) (1 mg Cr/kg body mass), and Cr3 ([Cr(3)O(propionate)(6)(H(2)O)(3)](+)) (33 μg and 1 mg Cr/kg body mass) on metal concentrations in these tissues were examined. Treatment with CrCl(3) and Cr3, but not [Cr(pic)(3)], at 1 mg Cr/kg resulted in a statistically significant accumulation of Cr in the kidney of lean and obese but not ZDF rats but resulted in lowering the elevated levels of kidney Cu in ZDF rats, suggesting a beneficial effect on this symptom of type 2 diabetes. 23330613 Polyamine production is downstream and upstream of oncogenic PI3K signalling and contributes to tumour cell growth. PI3K (phosphoinositide 3-kinase) signalling pathways regulate a large array of cell biological functions in normal and cancer cells. In the present study we investigated the involvement of PI3K in modulating small molecule metabolism. A LC (liquid chromatography)-MS screen in colorectal cancer cell lines isogenic for oncogenic PIK3CA mutations revealed an association between PI3K activation and the levels of polyamine pathway metabolites, including 5-methylthioadenosine, putrescine and spermidine. Pharmacological inhibition confirmed that the PI3K pathway controls polyamine production. Despite inducing a decrease in PKB (protein kinase B)/Akt phosphorylation, spermidine promoted cell survival and opposed the anti-proliferative effects of PI3K inhibitors. Conversely, polyamine depletion by an ornithine decarboxylase inhibitor enhanced PKB/Akt phosphorylation, but suppressed cell survival. These results suggest that spermidine mediates cell proliferation and survival downstream of PI3K/Akt and indicate that these two biochemical pathways control each other's activities, highlighting a mechanism by which small molecule metabolism feeds back to regulate kinase signalling. Consistent with this feedback loop having a functional role in these cell models, pharmacological inhibitors of PI3K and ornithine decarboxylase potentiated each other in inhibiting tumour growth in a xenograft model. The results of the present study support the notion that the modulation of spermidine concentrations may be a previously unrecognized mechanism by which PI3K sustains chronic proliferation of cancer cells. 23353626 MRI-detectable pH nanosensors incorporated into hydrogels for in vivo sensing of transplanted-cell viability. Biocompatible nanomaterials and hydrogels have become an important tool for improving cell-based therapies by promoting cell survival and protecting cell transplants from immune rejection. Although their potential benefit has been widely evaluated, at present it is not possible to determine, in vivo, if and how long cells remain viable following their administration without the use of a reporter gene. Here, we report a pH-nanosensor-based magnetic resonance imaging (MRI) technique that can monitor cell death in vivo non-invasively. We demonstrate that specific MRI parameters that change on cell death of microencapsulated hepatocytes are associated with the measured bioluminescence imaging radiance. Moreover, the readout from this pH-sensitive nanosensor can be directly co-registered with high-resolution anatomical images. All of the components of these nanosensors are clinical grade and hence this approach should be a translatable and universal modification of hydrogels. 23279943 Potential prevention and treatment of maifanite for Alzheimer's disease based on behavior test, oxidative stress assay, and trace element analysis in hippocampus of Aβ(₂₅₋₃₅)-induced AD rats. This study aimed to assess whether maifanite can improve the learning and memory, and antioxidant abilities of Alzheimer's disease (AD) rats. The 70 rats were divided into seven groups: [A] normal control group, [B] AD model group, [C] sham group, [D] positive control group (donepezil), [E] low-dose maifanite group, [F] middle-dose maifanite group, [G] high-dose maifanite group. For [B], [D], [E], [F], and [G] groups, Aβ(25-35) ventricle injection was carried out, then respective medicine were administered once a day for 60 consecutive days. The step-down and step-through test were used to measure learning and memory ability. The hippocampus levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) were assayed. The hippocampus contents of Al, Fe, Cu, Zn, Se, and Mn were analyzed by inductively coupled plasma-atomic emission spectrometer. Maifanite decreased the acquisition errors and the retention errors while prolonging the step-down latency, and decreased the number of electric shocks while prolonging the first latency of AD rats. Aβ(25-35) ventricle injection initiated the decrease of SOD and GSH-Px activities and the increase of MDA content, and triggered the rise of Al, Fe, and Cu levels and the decline of Mn, Zn, and Se levels. The SOD and GSH-Px activities were enhanced followed by reduced MDA level, and the levels of Mn, Zn, and Se increased accompanied by Al, Fe, and Cu decreased in the maifanite treat groups. Maifanite could improve the learning and memory, and the antioxidant abilities of AD rats. Maifanite had the potential prevention and treatment for AD. 23500061 Anti-apoptotic cardioprotective effects of SHP-1 gene silencing against ischemia-reperfusion injury: Use of deoxycholic acid-modified low molecular weight polyethyleneimine as a cardiac siRNA-carrier. The cardiomyocyte apoptosis plays a critical role in the development of myocardial injury after ischemia and reperfusion. Thus, alteration of the major apoptosis-regulatory factors during myocardial ischemia-reperfusion is expected to have favorable cardioprotective effects. Herein, we report ischemic-reperfused myocardial infarction (MI) repair with siRNA against Src homology region 2 domain-containing tyrosine phosphatase-1 (SHP-1), which is known as a key factor involved in regulating the progress of apoptosis in many cell types. A low molecular weight polyethyleneimine modified with deoxycholic acid (PEI1.8-DA)-based delivery strategy was suggested for the cardiac application of SHP-1 siRNA to overcome the poor gene delivery efficiency to myocardium due to the highly charged structures of the compact cardiac muscles. The PEI1.8-DA conjugates formed stable nanocomplexes with SHP-1 siRNA via electrostatic and hydrophobic interactions. The PEI1.8-DA/SHP-1 siRNA polyplexes effectively silenced SHP-1 gene expression in cardiomyocytes, leading to a significant inhibition of cardiomyocyte apoptosis under hypoxia. In comparison to conventional gene carriers, relatively large amounts of siRNA molecules remained after treatment with the PEI1.8-DA/SHP-1 siRNA polyplexes. Cardiac administration of the PEI1.8-DA/SHP-1 siRNA polyplexes resulted in substantial improvement in SHP-1 gene silencing, which can be explained by the enhancement of cardiac delivery efficiency of the PEI1.8-DA conjugates. In addition, in vivo treatment with the PEI1.8-DA/SHP-1 siRNA polyplexes induced a highly significant reduction in myocardial apoptosis and infarct size in rat MI models. These results demonstrate that the PEI1.8-DA/SHP-1 siRNA polyplex formulation is a useful system for efficient gene delivery into the compact myocardium that provides a fundamental advantage in treating ischemic-reperfused MI. 23466461 Occurrence of fumonisins in organic and conventional cereal-based products commercialized in France, Germany and Spain. A fast and effective method for quantitative determination of fumonisins B1 and B2 (FB1 and FB2) in different cereal-based products was developed. Fumonisins were extracted combining a solid liquid extraction (SLE) pre-treatment and immunoaffinity columns (IACs), which were applied for an effective clean-up. Consecutively, high pressure liquid chromatography (HPLC) coupled to hybrid triple quadrupole-linear ion trap mass spectrometer (QTrap®) was used for the separation, detection and quantification of targeted mycotoxins. The analytical method showed acceptable recoveries ranged from 89.7% to 99.1%, as well as a relative standard deviation (%, RSD) lower than 12%. A total of 1250 samples from France, Germany and Spain were analysed. The incidence of fumonisin B1 and B2 in organic samples were 11.4% and 11.3%, respectively. By contrast, the occurrence of conventional samples was 3.6% of FB1 and 3.5% of FB2. The highest values were obtained in Spanish samples of flour, as an example toasted corn, called gofio that was contaminated with 1201.7 and 1010.5μgkg(-1) of FB1 and FB2, respectively. 23583882 Prior oral exposure to environmental immunosuppressive chemicals methoxychlor, parathion, or piperonyl butoxide aggravates allergic airway inflammation in NC/Nga mice. BACKGROUND: Immunosuppressive environmental chemicals may increase the potency of allergens and thereby play a role in the development of respiratory tract allergies, such as allergic rhinitis and asthma. OBJECTIVES: We investigated the association between environmental immunosuppressive chemicals and the allergic airway inflammation development. METHODS: We used a mouse model of ovalbumin (OVA)-induced allergic airway inflammation. NC/Nga mice were exposed orally to pesticides parathion (an organophosphate compound) or methoxychlor (an organochlorine compound), or to an insecticide synergist piperonyl butoxide, prior to OVA intraperitoneal sensitization and inhalation challenge. We assessed serum IgE levels, B-cell counts, cytokine production, IgE production in hilar lymph nodes, eosinophil counts, chemokine levels in bronchoalveolar lavage fluid, and cytokine gene expression in the lung. RESULTS: Exposure to environmental immunosuppressive chemicals markedly increased serum IgE - IgE-positive B-cells, IgE and cytokines in lymph nodes - eosinophils and chemokines in BALF - IL-10a and IL-17 in the lung. CONCLUSIONS: Allergic airway inflammation can be aggravated by prior exposure to immunosuppressive environmental chemicals. 23427074 Dechlorane plus monoadducts in a lake ontario (Canada) food web and biotransformation by lake trout (Salvelinus namaycush) liver microsomes. Compounds related to the high-production-volume flame retardant Dechlorane Plus (DP) were measured in a Lake Ontario food web located downstream of a DP manufacturing plant. These compounds, 1,3- and 1,5-DP-monoadducts (DPMA), are positional isomers and are thought to arise from the incomplete reaction of DP or impurities in the DP starting material during its manufacture. The 1,3-DPMA isomer was measured (0.12-199 ng g(-1) lipid wt) in all trophic levels, whereas 1,5-DPMA was measured only sporadically in the food web and was not detectable in the apex predator, lake trout (Salvelinus namaycush). Concentrations of DPMA isomers when detected in Lake Ontario biota were greater than that of total DP for all trophic levels. The prevalence of 1,3-DPMA in the food web, and especially in lake trout, may be due to obstruction of the existing carbon double bond to enzyme attack, rendering it less readily metabolized. To examine this hypothesis, biotransformation kinetic experiments using in vitro lake trout liver microsomal exposures were performed. Zero-order depletion rate constants for 1,3- and 1,5-DPMA were 92.2 and 134.6 pmole h(-1) , respectively, with corresponding half-lives of 2.03 ± 0.14 h (1,3-DPMA) and 1.39 ± 0.09 h (1,5-DPMA). Furthermore, the 1,5-isomer was depleted to a greater extent than 1,3-DPMA. Specific biotransformation products were not identified. These data support the hypothesis that 1,5-DPMA is more readily metabolized than 1,3-DPMA by lake trout. The present study also shows that the concentrations of these isomers, which the authors speculate might be unintended impurities or byproducts in some technical DP formulations, exceed that of the intended product in biota. Environ Toxicol Chem 2013;32:1376-1381. © 2013 SETAC. 23142804 Longitudinal in vivo imaging of bone formation and resorption using fluorescence molecular tomography. Bone research often focuses on anatomical imaging of the bone microstructure, but in order to gain better understanding in how bone remodeling is modulated through interventions also bone formation and resorption processes should be investigated. With this in mind, the purpose of this study was to establish a longitudinal in vivo imaging approach of bone formation and resorption using fluorescence molecular tomography (FMT). In this study the reproducibility, accuracy and sensitivity of FMT for bone imaging were assessed by performing longitudinal measurements with FMT and comparing it to in vivo micro-computed tomography on a set of control mice, and mice in which load-adaptation was induced in the sixth caudal vertebra. The precision error for FMT measurements, expressed as coefficient of variation, was smaller than 16%, indicating acceptable reproducibility. A correlation was found between bone resorption measured with FMT and bone resorption rate measured with in vivo micro-computed tomography only over the first 14days (R=0.81, p<0.01), but not between bone formation measured with FMT and bone formation rate measured with in vivo micro-CT. Bone formation measured by FMT was 89-109% greater (p<0.05) for mice subjected to mechanical loading than control mice. Bone resorption was 5-8% lower, but did not reach a significant difference between groups, indicating moderate sensitivity for FMT. In conclusion, in vivo FMT in mouse tail bones is feasible but needs to be optimized for monitoring load adaptation in living mice. 23274768 Effects of zinc on epithelial barrier properties and viability in a human and a porcine intestinal cell culture model. Zinc is an essential trace element with a variety of physiological and biochemical functions. Piglets are commonly supplemented, during the weaning period, with doses of zinc above dietary requirements with positive effects on health and performance that might be attributed to anti-secretory and barrier-enhancing effects in the intestine. For a better understanding of these observations increasing zinc sulfate (ZnSO4; 0-200μM) concentrations were used in an in vitro culture model of porcine (IPEC-J2) and human (Caco-2) intestinal epithelial cells and effects on barrier function, viability, and the mRNA expression of one selected heat shock protein (Hsp) were assessed. When treated apically with zinc sulfate, the transepithelial electrical resistance (TEER) did not change significantly. In contrast, cell viability measured by lactate dehydrogenase (LDH) leakage, by ATP and by WST-1 conversion in postconfluent IPEC-J2 monolayers was affected after a 24-h treatment with 200μM ZnSO4. Caco-2 cells were more resistant to Zn. ZnSO4 did not induce any effect on viability, except when it was used at the highest concentration (200μM), and only in preconfluent cells. Furthermore, ZnSO4 induced Hsp70 mRNA expression at 200μM and was more pronounced in preconfluent cells. The observed dose-related effects of zinc are cell-line specific and depended on the differentiation status of the cells. The IPEC-J2 cell line appears to be a suitable in vitro model to characterize specific effects on porcine intestinal cells. 23340334 A new bioassay for the ecotoxicological testing of VOCs on groundwater invertebrates and the effects of toluene on Niphargus inopinatus. A protocol was developed for testing the ecotoxicological effects of volatile organic compounds (VOCs) on groundwater invertebrates. Test substance volatility was addressed in a "closed from start to analysis"-design. Since manifestation of toxic effects may be delayed in 'slower metabolizing' organisms such as groundwater fauna, a time-independent (TI-) approach was adopted. Toluene was used as a model substance and its toxicity to the groundwater amphipod Niphargus inopinatus was assessed as an example. The method evaluation process considered various methodological issues such as partitioning of the toxicant between the water and the gas phase (Henry equilibrium), the possible depletion of oxygen in closed test vials, as well as microbial biodegradation of the test substance. For N. inopinatus, an LC50,14 days of 46.6mgL(-1) toluene was obtained. The ultimate LC50 value was estimated at 23.3mgL(-1) toluene. No oxygen depletion occurred in the test vials and Henry equilibrium was found to be established after 6h. The new test system proposed now awaits broad practical application. 23299834 Spatial modeling for refining and predicting surface potential mapping with enhanced resolution. Quantitatively mapping surface properties with nanometer or even subnanometer resolutions is critical for advanced scanning probe microscopy (SPM) characterization. However, the characterization performance often suffers from noises and artifacts due to instrumentation or environmental limitations. In this paper, we proposed a novel statistical approach with bivariate spatial modeling to efficiently refine and predict surface property mapping. Scanning Kelvin probe microscopy (SKPM) was selected as a representative example to test our proposed method on lateral nanowire assemblies. We revealed that the proposed method can effectively retrieve the artifact-free surface potential distribution by automatically identifying topological artifacts from surface potential maps. Furthermore, the statistical model built upon low spatial resolution was successfully used to predict the potential values from higher-resolution topography data. Compared to conventional regression model, our model is able to predict the surface potential distribution from less raw data but yields much higher accuracy. Through this means, the spatial resolution of SKPM surface potential maps can be significantly improved. This statistics-enabled predictive method opens a new route toward high-precision and high-resolution SPM characterizations without the enhancement of instrumentation capabilities. 23225366 Cytotoxic cycloartane triterpenes of the traditional Chinese medicine "shengma" (Cimicifuga dahurica). Twelve new 9,19-cycloartane triterpenes (1-12), together with fourteen known compounds (13-26), were isolated from the roots of Cimicifuga dahurica. Their structures were determined by application of spectroscopic analyses and chemical methods. Biological evaluation of the compounds against human HL-60, SMMC-7721, A549, MCF-7, and SW-480 cell lines indicated that cimigenol-type glycosides (1-3, 19, and 20) showed broad-spectrum and moderate cytotoxicities, with IC50 values ranging from 4.2 to 14.5 µM. Meanwhile, cimigenol-type aglycones (6-8, 15, 16, and 18) exhibited broad-spectrum and week cytotoxicities, having IC50 values around 20 µM. In addition, the key points of the structure-activity relationships of aglycones with a cimigenol skeleton were discussed. 23401084 Desired professional development pathways for clinical pharmacists. The 2012 American College of Clinical Pharmacy (ACCP) Certification Affairs Committee was charged with developing guidelines for the desired professional development pathways for clinical pharmacists. This document summarizes recommendations for postgraduate education and training for graduates of U.S. schools and colleges of pharmacy and describes the preferred pathways for achieving, demonstrating, and maintaining competence as clinical pharmacists. After initial licensure within the state or jurisdiction in which the pharmacist intends to practice, completion of an accredited PGY1 pharmacy residency is recommended to further develop the knowledge and skills needed to optimize medication therapy outcomes. An accredited PGY2 pharmacy residency should be completed if a pharmacist wishes to seek employment in a specific therapeutic area or practice setting, if such a residency exists. Clinical pharmacists intending to conduct advanced research that is competitive for federal funding are encouraged to complete a fellowship or graduate education. Initial certification by the Board of Pharmacy Specialties (BPS) or other appropriate sponsoring organizations should be completed in the desired primary therapeutic area or practice setting within 2 years after accepting a position within the desired specific therapeutic area or practice setting. Clinical pharmacists subsequently will need to meet the requirements to maintain pharmacist licensure and board certification. Traineeships, practice-based activities, and certificate programs can be used to obtain additional knowledge and skills that support professional growth. Pharmacists are strongly encouraged to adopt a lifelong, systematic process for professional development and work with ACCP and other professional organizations to facilitate the development and implementation of innovative strategies to assess core practice competencies. 23417717 Estimating population-level HC5 for copper using a species sensitivity distribution approach. Estimation of population-level benchmark concentrations for protecting aquatic organisms from chemicals is important for value-relevant ecological risk assessments. By employing a species sensitivity distribution (SSD) approach, the authors aimed to derive the population-level hazardous concentration for 5% of species (PHC5) for copper. Based on available information on copper toxicity and population models, the authors estimated population threshold concentrations at which the population size is stable (that is, 0 net population growth) for 13 freshwater species (3 algal, 6 invertebrate, and 4 fish species). The PHC5 for copper was then estimated (6.8 µg/L; 95% confidence interval [CI], 1.8-13.6 µg/L), by fitting a log-normal distribution to the population threshold concentrations obtained. The close overlap between the present study's estimate of the PHC5 and a field-derived threshold concentration suggests that the population-level SSD approach provides a reasonable level of protection for species richness in the natural environment. By contrast, and counterintuitively, the authors' estimate was comparable with the individual-level HC5 reported in the European Union risk assessment. Although the present study cannot determine the underlying reasons for the similar figures, the result provides an indication that the margin between individual-level and population-level benchmarks derived from SSD approaches can be very small. The results therefore suggest that attention is needed to achieve population-level protection using an individual-level SSD approach. Environ Toxicol Chem 2013;32:1396-1402. © 2013 SETAC. 23132843 Synthesis and evaluation of 3,4-dihydropyrimidin-2(1H)-ones as sodium iodide symporter inhibitors. The sodium iodide symporter (NIS) is responsible for the accumulation of iodide in the thyroid gland. This transport process is involved in numerous thyroid dysfunctions and is the basis for human contamination in the case of exposure to radioactive iodine species. 4-Aryl-3,4-dihydropyrimidin-2(1H)-ones were recently discovered by high-throughput screening as the first NIS inhibitors. Described herein are the synthesis and evaluation of 115 derivatives with structural modifications at five key positions on the pyrimidone core. This study provides extensive structure-activity relationships for this new class of inhibitors that will serve as a basis for further development of compounds with in vivo efficacy and adequate pharmacokinetic properties. In addition, the SAR investigation provided a more potent compound, which exhibits an IC(50) value of 3.2 nM in a rat thyroid cell line (FRTL5). 23202585 The ATPase domain of ISWI is an autonomous nucleosome remodeling machine. ISWI slides nucleosomes along DNA, enabling the structural changes of chromatin required for the regulated use of eukaryotic genomes. Prominent mechanistic models imply cooperation of the ISWI ATPase domain with a C-terminal DNA-binding function residing in the HAND-SANT-SLIDE (HSS) domain. Contrary to these models, we show by quantitative biochemical means that all fundamental aspects of nucleosome remodeling are contained within the compact ATPase module of Drosophila ISWI. This domain can independently associate with DNA and nucleosomes, which in turn activate ATP turnover by inducing a conformational change in the enzyme, and it can autonomously reposition nucleosomes. The role of the HSS domain is to increase the affinity and specificity for nucleosomes. Nucleosome-remodeling enzymes may thus have evolved directly from ancestral helicase-type motors, and peripheral domains have furnished regulatory capabilities that bias the remodeling reaction toward different structural outcomes. 23353816 Differential toxicity and gene expression in Caco-2 cells exposed to arsenic species. Inorganic arsenic [As(V)+As(III)] and its metabolites, especially the trivalent forms [monomethylarsonous acid, MMA(III), and dimethylarsinous acid, DMA(III)], are considered the forms of arsenic with the highest degree of toxicity, linked to certain types of cancer and other pathologies. The gastrointestinal mucosa is exposed to these forms of arsenic, but it is not known what toxic effect these species may have on it. The aim of the present work was to evaluate the toxicity and some mechanisms of action of inorganic arsenic and its metabolites [monomethylarsonic acid, MMA(V), dimethylarsinic acid, DMA(V), MMA(III) and DMA(III)] in intestinal epithelial cells, using the Caco-2 human cell line as a model. The results show that the pentavalent forms do not produce toxic effects on the intestinal monolayer, but the trivalent species have a different degree of toxicity. As(III) induces death mainly by necrosis, whereas only apoptotic cells are detected after exposure to MMA(III), and for DMA(III) the percentages of apoptosis and necrosis are similar. The three forms produce reactive oxygen species, accompanied by a reduction in intracellular GSH and lipid peroxidation, the latter being especially notable in the dimethylated form. They also alter the enzyme activity of glutathione peroxidase and catalase and induce expression of stress proteins and metallothioneins. The results indicate that the trivalent forms of arsenic can affect cell viability of intestinal cells by mechanisms related to the induction of oxidative stress. Further studies are needed to evaluate how the effects observed in this study affect the structure and functionality of the intestinal epithelium. 23274352 Growth inhibition in early life-stage tests predicts full life-cycle toxicity effects of lead in the freshwater pulmonate snail, Lymnaea stagnalis. The freshwater pulmonate snail, Lymnaea stagnalis, is the most sensitive freshwater organism tested to date for several metals (Co, Cu, Pb, Ni) based on 28 d early life-stage (ELS) tests in which growth was the most sensitive endpoint. The United States Environmental Protection Agency (USEPA) has expressed concern that growth in 28 d ELS tests with mollusks may overpredict toxicity because of the potential for recovery in a full life-cycle (LC) test. Consequently, the USEPA only accepts the survival endpoint for these tests in establishing water quality criteria (WQC). To address this concern, the current study aimed to test the sensitivity of L. stagnalis to Pb in a 56 d full LC test evaluating survival, growth, reproductive and embryonic growth endpoints and compare the estimated effect levels to those established using the 28 d ELS test design. The most sensitive endpoints in this study were 28 d growth and 56 d egg mass production, both with a NOEC of <1.0 μg L(-1) and a LOEC of 1.0 μg L(-1), showing that the ELS growth endpoint is predictive of the 56 d reproduction endpoint. Snails exposed to 1.0 and 2.7 μg L(-1) Pb showed full and partial recovery from growth inhibition between 28 and 56 d. While this recovery supports the USEPA's concern about the 28 d growth endpoint; considering the reproductive lifespan of L. stagnalis and the recovery dose-response, we conclude that the 28 d growth endpoint will be within a factor of 3 of full LC endpoints. This is consistent with the level of precision previously determined for fish ELS tests, which the USEPA accepts for WQC derivation, and suggests that tests using 28 d ELS growth endpoint for L. stagnalis may be acceptable for inclusion in WQC derivation. 23355467 Role of fat body lipogenesis in protection against the effects of caloric overload in Drosophila. The Drosophila fat body is a liver- and adipose-like tissue that stores fat and serves as a detoxifying and immune responsive organ. We have previously shown that a high sugar diet leads to elevated hemolymph glucose and systemic insulin resistance in developing larvae and adults. Here, we used stable isotope tracer feeding to demonstrate that rearing larvae on high sugar diets impaired the synthesis of esterified fatty acids from dietary glucose. Fat body lipid profiling revealed changes in both carbon chain length and degree of unsaturation of fatty acid substituents, particularly in stored triglycerides. We tested the role of the fat body in larval tolerance of caloric excess. Our experiments demonstrated that lipogenesis was necessary for animals to tolerate high sugar feeding as tissue-specific loss of orthologs of carbohydrate response element-binding protein or stearoyl-CoA desaturase 1 resulted in lethality on high sugar diets. By contrast, increasing the fat content of the fat body by knockdown of king-tubby was associated with reduced hyperglycemia and improved growth and tolerance of high sugar diets. Our work supports a critical role for the fat body and the Drosophila carbohydrate response element-binding protein ortholog in metabolic homeostasis in Drosophila. 23110976 The conjoint influence of home enriched environment and lead exposure on children's cognition and behaviour in a Mexican lead smelter community. A range of studies has been conducted on the detrimental effects of lead in mining and smelting communities. The neurocognitive and behavioural health effects of lead on children are well known. This research characterized the conjoint influence of lead exposure and home enriched environment on neurocognitive function and behaviour for first-grade children living in a Mexican lead smelter community. Structural equation models were used for this analysis with latent outcome variables, Cognition and Behaviour, constructed based on a battery of assessments administered to the first-grade children, their parents, and teachers. Structural equation modelling was used to describe complex relationships of exposure and health outcomes in a manner that permitted partition of both direct and indirect effects of the factors being measured. Home Environment (a latent variable constructed from information on mother's education and support of school work and extracurricular activities), and child blood lead concentration each had a main significant effect on cognition and behaviour. However, there were no statistically significant moderation relationships between lead and Home Environment on these latent outcomes. Home Environment had a significant indirect mediation effect between lead and both Cognition and Behaviour (p-value<0.001). The mediation model had a good fit with Root Mean Square Error of Approximation <0.0001 and a Weighted Root Mean Square Residual of 0.895. These results were highly significant and suggest that Home Environment has a moderate mediation effect with respect to lead effects on Behaviour (β=0.305) and a lower mediation effect on Cognition (β=0.184). The extent of home enrichment in this study was most highly related to the mother's support of schoolwork and slightly less by the mother's support of extracurricular activities or mother's education. Further research may be able to develop approaches to support families to make changes within their home and child rearing practices, or advocate for different approaches to support their child's behaviour to reduce the impact of lead exposure on children's cognitive and behavioural outcomes. 23427137 A liquid crystalline phase with uniform tilt, local polar order and capability of symmetry breaking. A new liquid crystalline (LC) phase with uniform tilt, local polar order and capability of symmetry breaking is found for a bent-core mesogen combining a 4-cyanoresorcinol unit with two azobenzene wings. The combination of local polar order and long range synclinic tilt in this SmCs PR phase leads, under special conditions, to macroscopic domains with opposite chirality, though the molecules themselves are achiral. 23524228 Cosmetics Europe multi-laboratory pre-validation of the SkinEthic™ reconstituted human corneal epithelium test method for the prediction of eye irritation. Cosmetics Europe, The Personal Care Association, known as Colipa before 2012, conducted a program of technology transfer and assessment of Within/Between Laboratory (WLV/BLV) reproducibility of the SkinEthic™ Reconstituted Human Corneal Epithelium (HCE) as one of two human reconstructed tissue eye irritation test methods. The SkinEthic™ HCE test method involves two exposure time treatment procedures - one for short time exposure (10min - SE) and the other for long time exposure (60min - LE) of tissues to test substance. This paper describes pre-validation studies of the SkinEthic™ HCE test method (SE and LE protocols) as well as the Eye Peptide Reactivity Assay (EPRA). In the SE WLV study, 30 substances were evaluated. A consistent outcome with respect to viability measurement across all runs was observed with all substances showing an SD of less than 18%. In the LE WLV study, 44 out of 45 substances were consistently classified. These data demonstrated a high level of reproducibility within laboratory for both the SE and LE treatment procedures. For the LE BLV, 19 out of 20 substances were consistently classified between the three laboratories, again demonstrating a high level of reproducibility between laboratories. The results for EPRA WLV and BLV studies demonstrated that all substances analysed were categorised similarly and that the method is reproducible. The SkinEthic™ HCE test method entered into the experimental phase of a formal ECVAM validation program in 2010. 23604819 Synthesis, cytotoxicity and QSAR study of N-tosyl-1,2,3,4-tetrahydroisoquinoline derivatives. 1-Substituted-N-tosyl-1,2,3,4-tetrahydroisoquinoline analogs (4a-4l) were synthesized using the modified Pictet-Spengler reaction and evaluated for cytotoxicity. All tetrahydroisoquinolines displayed cytotoxicity against MOLT-3 cell lines, except for p-methoxy analog 4d. Interestingly, the o-hydroxy derivative 4k was shown to be the most potent cytotoxic against HuCCA-1, A-549 and MOLT-3 cell lines. The lowest IC50 value of 1.23 μM was observed for MOLT-3 cells. Trimethoxy analog 4f exerted the most potent activity against HepG2 with an IC50 of 22.70 μM, which is lower than the reference drug, etoposide. QSAR studies showed that total symmetry index (Gu), 3D-MoRSE (Mor31v and Mor32u) and 3D Petitjean index (PJI3) were the most important descriptors accounting for the observed cytotoxicities. The most potent cytotoxic compound (4k) against MOLT-3 had the highest Gu value, correspondingly the inactive p-methoxy analog (4d) had the lowest Gu value. On the other hand, the highest molecular mass compound (4f) was shown to be the most potent cytotoxic against HepG2 cells. The studies disclose that tetrahydroisoquinolines 4f and 4k are potentially interesting lead pharmacophores that should be further explored. The QSAR models provided insights into the physicochemical properties of the investigated compounds. 23580257 Anti-asthmatic Effects of Baicalin in a Mouse Model of Allergic Asthma. The aim of the study was to investigate the anti-asthmatic effects of baicalin (BA) and the possible mechanisms. Asthma model was established by ovalbumin (OVA) intraperitoneal injection. A total of 60 mice were randomly assigned to six experimental groups: control, model, dexamethasone (2 mg/kg), and BA (10 mg/kg, 20 mg/kg, 40 mg/kg). Airway resistance (RI) and lung compliance (Cdyn) were measured, histological studies were evaluated by the hematoxylin and eosin staining, Th1/Th2, OVA-specific serum, and BALF IgE levels and Th17 cytokines were evaluated by enzyme-linked immunosorbent assay, and Th17 cells was evaluated by flow cytometry (FCM). Our study demonstrated that BA inhibited OVA-induced increases in RI and eosinophil count; interleukin (IL)-4, IL-17A levels, and Cdyn were recovered and increased IFN-γ level in bronchoalveolar lavage fluid. Histological studies demonstrated that BA substantially inhibited OVA-induced eosinophilia in lung tissue and airway tissue. FCM studies demonstrated that BA substantially inhibited Th17 cells. These findings suggest that BA may effectively ameliorate the progression of asthma and could be used as a therapy for patients with allergic asthma. Copyright © 2013 John Wiley & Sons, Ltd. 23256609 First-principles prediction of the effects of temperature and solvent selection on the dimerization of benzoic acid. We introduce a procedure of quantum chemical calculations (B3P86/6-31G**) to study carboxylic acid dimerization and its correlation with temperature and properties of the solvent. Benzoic acid is chosen as a model system for studying dimerization via hydrogen bonding. Organic solvents are simulated using the self-consistent reaction field (SCRF) method with the polarized continuum model (PCM). The cyclic dimer is the most stable structure both in gas phase and solution. Dimer mono- and dihydrates could be found in the gas phase if acid molecules are in contact with water vapor. However, the formation of these hydrated conformers is very limited and cyclic dimer is the principal conformer to coexist with monomer acid in solution. Solvation of the cyclic dimer is more favorable compared to other complexes, partially due to the diminishing of hydrogen bonding capability and annihilation of dipole moments. Solvents have a strong effect on inducing dimer dissociation and this dependence is more pronounced at low dielectric constants. By accounting for selected terms in the total free energy of solvation, the solvation entropy could be incorporated to predict the dimer behavior at elevated temperatures. The temperature dependence of benzoic acid dimerization obtained by this technique is in good agreement with available experimental measurements, in which a tendency of dimer to dissociate is observed with increased temperatures. In addition, dimer breakup is more sensitive to temperature in low dielectric environments rather than in solvents with a higher dielectric constant. 23376110 Synthesis of novel 16-spiro steroids: Spiro-7'-(aryl)tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazolo-trans-androsterone hybrid heterocycles. The 1,3-dipolar cycloaddition of azomethine ylide derived in situ from the reaction of acenaphthylene-1,2-dione and 1,3-thiazolane-4-carboxylic acid to various exocyclic dipolarophiles synthesized from trans-androsterone and trans-dehydroandrosterone afforded a library of novel spiro[5'.2″]acenaphthylene-1″-one-spiro[16.6']-(7'-aryl)-tetrahydro-1H-pyrrolo [1,2-c][1,3]thiazolo-trans-androsterone/dehydroandrosterone hybrid heterocycles respectively. These reactions proceeded stereo-specifically affording a single isomer of the 16-spiro steroids in excellent yields. 23434226 Identification and characterization of small molecule inhibitors of signal transducer and activator of transcription 3 (STAT3) signaling pathway by virtual screening. Inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling pathway has been considered a novel therapeutic strategy to treat human cancers that harbor aberrantly-active STAT3. In this study, a series of small molecules were identified as novel inhibitors of STAT3 signaling pathway through virtual screening. A tricyclic scaffold containing compound, 6, was identified as an inhibitor of IL-6/STAT3 signaling with an IC50 of 26.68 μM. In addition, this compound inhibited Tyr705 phosphorylation of STAT3 and had no obvious effect on upstream tyrosine kinases. Thus, compound 6 is a potential lead structure and valuable for further drug development. 23623843 Protective effects of Keemun black tea polysaccharides on acute carbon tetrachloride-caused oxidative hepatotoxicity in mice. This study was designed to investigate chemical characterization of the water-soluble polysaccharides extracted from Keemun black tea (KBTP), and their antioxidant and hepatoprotective effects against CCl4-induced oxidative damage in mice. HPLC analysis revealed that KBTP is the typical acidic heteropolysaccharides and consisted of nine monosaccharides. Furthermore, KBTP showed highly ferric-reducing antioxidant power and scavenging effects against DPPH, OH and O2(-) in vitro. Administration of KBTP (200, 400 and 800mg/kgbw) in mice ahead of CCl4 injection could observably antagonize the CCl4-induced increases in serum ALT, AST, TG and TC, and the hepatic MDA and 8-iso-PGF2a levels, respectively. Mice with KBTP pretreatment displayed a better profile of hepatosomatic index and the improved GSH and SOD activities in comparison with CCl4-intoxicated mice. These biochemical results were further supported with liver histopathological assessment, revealing that KBTP has an observable prevention of liver damage induced by CCl4 in mice. 23454052 The effect of formulation on the penetration of coated and uncoated zinc oxide nanoparticles into the viable epidermis of human skin in vivo. The use of nanoparticulate zinc oxide (ZnO-NP) in sunscreens and other cosmetic products has raised public health concerns. The two key issues are the extent of exposure to ZnO-NP and the likely hazard after the application of ZnO-NP in sunscreen and cosmetic products to humans in vivo. Our aims were to assess exposure by the extent of ZnO-NP penetration into the viable epidermis and hazard by changes in the viable epidermal redox state for a number of topical products. Of particular interest is the role of the particle coating, formulation used, and the presence of any enhancers. Multiphoton tomography with fluorescence lifetime imaging microscopy (MPT-FLIM) was used to simultaneously observe ZnO-NP penetration and potential metabolic changes within the viable epidermis of human volunteers after topical application of various ZnO-NP products. Coated and uncoated ZnO-NP remained in the superficial layers of the SC and in the skin furrows. We observed limited penetration of coated ZnO-NP dispersed in a water-in-oil emulsion formulation, which was predominantly localized adjacent to the skin furrow. However, the presence of ZnO-NP in the viable epidermis did not alter the metabolic state or morphology of the cells. In summary, our data suggest that some limited penetration of coated and uncoated ZnO-NP may occur into viable stratum granulosum epidermis adjacent to furrows, but that the extent is not sufficient to affect the redox state of those viable cells. 23378820 Electrochemical Removal Of Selenate From Aqueous Solutions. Removal of selenate from solution is investigated in batch electrochemical systems using reactive iron anodes and copper plate cathode in a bicarbonate medium. Iron anodes produce ferrous hydroxide, which is a major factor in the removal of selenate from solution. Iron anodes also generate a significant decrease in the oxidation-reduction potential (ORP) of the solution because it prevents generation of oxygen gas at the anode by electrolysis. The removal rates varied from 45.1 to 97.4%, depending on current density and selenate concentration. The transformation of selenate by the process is modeled based on a heterogeneous reaction coupled with electrochemical generation of ferrous and hydroxide. The rates are optimized at lower initial concentrations, higher electrical currents, and the presence of anions. Presence of dissolved oxygen does not cause any significant effects the removal of selenate. 23195954 Serine protease activity of calnuc: regulation by Zn2+ and G proteins. The functions of calnuc, a novel Ca(2+)-binding protein with multiple structural domains and diverse interacting partners, are yet unknown. We demonstrate unknown facets of calnuc, which is a serine protease in which Ser-378 of GXSXG motif, Asp-328 of DTG motif, and His-339 form the "catalytic triad," locating the enzyme active site in the C-terminal region. Analogous to the active site of Zn(2+) carboxypeptidases, calnuc has two high affinity (K(d) ∼ 20 nm), well conserved Zn(2+)-binding sites near its N terminus, although it is inactive as a peptidase. Zn(2+) binding allosterically and negatively regulates the serine protease activity of calnuc, inhibition being caused by an "open to close" change in its conformation not seen upon Ca(2+) binding. Most strikingly, interaction with G protein α subunit completely inhibits the enzymatic activity of calnuc. We thus illustrate that G proteins and Zn(2+) act as two "keys" that control enzymatic activity of calnuc, arresting it in "locked" state. Calnuc, therefore, exists dynamically in two different forms, (i) as a Ca(2+)-binding protein in Zn(2+)-bound form and (ii) as a protease in Zn(2+)-free form, commissioning it to perform multiple functions. 23545348 Species differences in the neuromuscular activity of post-synaptic neurotoxins from two Australian black snakes (Pseudechis porphyriacus and Pseudechis colletti). Bites by Australian black snakes (Pseudechis spp.) do not cause neurotoxicity in human envenoming. This is unusual as in vitro neurotoxicity has been reported for all Pseudechis spp. venoms. The present study aimed to identify, isolate and characterise neurotoxins from the venoms of Pseudechis porphyriacus and Pseudechis colletti to elucidate the reason for the lack of neurotoxicity in humans. α-Elapitoxin-Ppr1 and α-elapitoxin-Pc1 were isolated from P. porphyriacus and P. colletti, respectively, using reverse-phase high performance liquid chromatography. Each toxin consisted of 62 amino acids with molecular weights of 6746.5Da and 6759.6Da, respectively. α-Elapitoxin-Ppr1 and α-elapitoxin-Pc1 caused concentration-dependent (0.1-0.3μM) inhibition of indirect twitches in the chick biventer cervicis nerve-muscle preparation. Both toxins inhibited contractile responses to exogenous ACh and CCh, but not KCl, suggesting a post-synaptic mode of action at the nicotinic acetylcholine receptor (nAChR). CCh concentration-response curves obtained in the presence or absence of α-elapitoxin-Ppr1 or α-elapitoxin-Pc1 indicated pA2 values of 6.97±0.03 and 7.04±0.07, respectively. Neither α-elapitoxin-Ppr1 (0.1μM) nor α-elapitoxin-Pc1 (0.1μM) had a significant effect on the electrically-induced twitches of the rat isolated phrenic nerve-diaphragm preparation. When the venom with the toxin removed (10μg/ml) was added to both the rat and chick preparations, the inhibition was significantly less than that caused by the intact whole venoms (10μg/ml). The current study shows that α-elapitoxin-Ppr1 and α-elapitoxin-Pc1 act as pseudo-irreversible antagonists at the nAChR of the skeletal neuromuscular junction and that the avian preparation is more sensitive to the neurotoxic effects of these toxins than the mammalian preparation. 23474357 Assessing vehicle effects on skin absorption using artificial membrane assays. A vast number of variations in drug/vehicle combinations may come into contact with skin. Evaluating the effect of potential drug, vehicle and skin interactions for all possible combinations is a daunting task. A practical solution is a rapid screening technique amenable to high throughput approaches (e.g. 96-well plates). In this study, three artificial membranes (isopropyl myristate (IPM), certramides and Strat-M™) were evaluated for their ability to predict the skin permeability of caffeine, cortisone, diclofenac sodium, mannitol, salicylic acid and testosterone applied in propylene glycol, water and ethanol as unsaturated and saturated concentrations. Resultant absorption data was compared to porcine skin diffusion cell data. The correlations (r(2)) between membrane and diffusion cell data from saturated and unsaturated concentrations were 0.38, 0.47 and 0.56 for the Strat-M™, certramide and IPM membranes, respectively. This relationship improved when only saturated concentrations were evaluated (r(2)=0.60, 0.63 and 0.66 for the Strat-M™, certramide and IPM membranes, respectively). A correlation between membrane retention and the amount remaining in skin had r(2) values of 0.73 (Strat-M™), 0.67 (certramides), and 0.67 (IPM). Quantitative structure-permeability relationship models for each membrane identified different physicochemical factors influencing the absorption process. Although further investigations exploring complex topical formulations are required, these results suggest potential use as an initial screening approach to assist in narrowing the selection of formulations to be evaluated with a more biologically intact model, thereby assisting in the development of new topical formulations. 23554215 The electronic origin of unusually large (n) JFN coupling constants in some fluoroximes. SOPPA(CCSD) calculations show that the FC term is the most important contribution to the through-space transmission of JFN coupling constants for the fluoroximes studied in this work. Because of the well-known behavior of FC term, a new rationalization for the experimental (TS) JFN SSCC is presented. It is mainly based on the overlap matrix (Sij ) between fluorine and nitrogen lone pairs obtained from NBO analyses. An expression is proposed to take into account the influence of the electronic density (Dij ) between coupled nuclei as well as the s% character at the site of the coupling nuclei of bonds and non-bonding electron pairs involved in Dij . In using this approach, a linear correlation between (TS) JFN versus Dij is obtained. The most important aspect of this rationalization is related to the facility for understanding the behavior of some unusual experimental coupling constants. It is shown that, at least in this case, the electronic origin of the so-called through-space coupling is transmitted through to the overlap of orbitals on the coupled atoms, suggesting that, at least for these compounds, instead of through-space coupling, it should better be dubbed as 'through overlapping orbital coupling'. Copyright © 2013 John Wiley & Sons, Ltd. 23526674 Acute Kidney Injury During Vancomycin Therapy in Critically Ill Children. STUDY OBJECTIVE: To determine the rate, risk factors, and outcome of vancomycin-associated acute kidney injury (AKI) in critically ill children. DESIGN: Retrospective cohort study. SETTING: Tertiary care children's hospital. PATIENTS: We reviewed the charts of children admitted to the pediatric intensive care unit during a 2-year period who were treated with vancomycin. Courses of vancomycin interrupted by 3 days or more were counted separately. Patients were excluded if they received vancomycin treatment for fewer than 3 days, had preexisting renal failure, or had incomplete serum creatinine (Scr ) data. MEASUREMENTS AND MAIN RESULTS: Demographic and laboratory data; vancomycin dose, duration, and concentrations; and concurrent use of nephrotoxic drugs were recorded. Acute kidney injury was defined as a decrease in estimated glomerular filtration rate of 50% or more from the beginning of vancomycin therapy. Descriptive statistics, step-wise logistic regression, and repeated measures ANOVA were used to analyze the data. A total of 284 patients were included, for a total of 391 courses of vancomycin (272 children and 119 infants). The mean duration of vancomycin therapy was 6.9 ± 4.5 days. Forty nine (17.2%) patients developed AKI during 61 (15.6%) courses. Elevated Scr concentrations returned to baseline after stopping vancomycin in 53 (87%) courses. Mortality was higher in children who developed AKI (p<0.001; Fisher's exact test). Administration of nephrotoxic drugs (odds ratio 2.23, Confidence Interval 1.27-3.93) and presence of high blood urea nitrogen (BUN):Scr ratio before vancomycin therapy (p<0.05) were associated with AKI. The BUN and Scr concentrations significantly increased during vancomycin therapy and decreased after vancomycin was discontinued (p<0.05). CONCLUSIONS: In critically ill children, the development of reversible AKI during vancomycin therapy is associated with administration of nephrotoxic drugs and an elevated BUN: Scr ratio. 23010362 Functional and structural interaction of (-)-reboxetine with the human α4β2 nicotinic acetylcholine receptor. The interaction of the selective norepinephrine reuptake inhibitor (-)-reboxetine with the human α4β2 nicotinic acetylcholine receptor (nAChR) in different conformational states was studied by several functional and structural approaches. Patch-clamp and Ca(2+)-influx results indicate that (-)-reboxetine does not activate hα4β2 nAChRs via interaction with the orthosteric sites, but inhibits agonist-induced hα4β2 activation by a noncompetitive mechanism. Consistently, the results from the electrophysiology-based functional approach suggest that (-)-reboxetine may act via open channel block; therefore, it is capable of producing a use-dependent type of inhibition of the hα4β2 nAChR function. We tested whether (-)-reboxetine binds to the luminal [(3)H]imipramine site. The results indicate that, although (-)-reboxetine binds with low affinity to this site, it discriminates between the resting and desensitized hα4β2 nAChR ion channels. Patch-clamp results also indicate that (-)-reboxetine progressively inhibits the hα4β2 nAChR with two-fold higher potency at the end of one-second application of agonist, compared with the peak current. The molecular docking studies show that (-)-reboxetine blocks the ion channel at the level of the imipramine locus, between M2 rings 6' and 14'. In addition, we found a (-)-reboxetine conformer that docks in the helix bundle of the α4 subunit, near the middle region. According to molecular dynamics simulations, (-)-reboxetine binding is stable for both sites, albeit less stable than imipramine. The interaction of these drugs with the helix bundle might alter allostericaly the functionality of the channel. In conclusion, the clinical action of (-)-reboxetine may be produced (at least partially) by its inhibitory action on hα4β2 nAChRs. 22533550 Microwave-assisted synthesis of N-isobutyl-4,5-epoxy-2(E)-decenamide. A new and efficient synthesis of a naturally occurring amide alkaloid, N-isobutyl-4,5-epoxy-2(E)-decenamide isolated from the roots of Piper nigrum has been described involving a total of nine steps. Octanal and 2-bromoacetic acid have been used as the starting materials. 23063069 Parental exposure to natural mixtures of POPs reduced embryo production and altered gene transcription in zebrafish embryos. Determination of toxicity of complex mixtures has been proposed to be one of the most important challenges for modern toxicology. In this study we performed genome wide transcriptome profiling to assess potential toxicant induced changes in gene regulation in zebrafish embryos following parental exposure to two natural mixtures of persistent organic pollutants (POPs). The mixtures used were extracted from burbot (Lota lota) liver originating from two lakes (Lake Mjøsa and Lake Losna) belonging to the same freshwater system in Norway. The dominating groups of contaminants were polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane metabolites (DDTs). Because both mixtures used in the present study induced similar effects, it is likely that the same toxicants are involved. The Mjøsa mixture contains high levels of PBDEs while this group of pollutants is low in the Losna mixture. However, both mixtures contain substantial concentrations of PCB and DDT suggesting these contaminants as the predominant contributors to the toxicity observed. The observed effects included phenotypic traits, like embryo production and survival, and gene transcription changes corresponding with disease and biological functions such as cancer, reproductive system disease, cardiovascular disease, lipid and protein metabolism, small molecule biochemistry and cell cycle. The changes in gene transcription included genes regulated by HNF4A, insulin, LH, FSH and NF-κB which are known to be central regulators of endocrine signaling, metabolism, metabolic homeostasis, immune functions, cancer development and reproduction. The results suggest that relative low concentrations of the natural mixtures of POPs used in the present study might pose a threat to wild freshwater fish living in the lakes from which the POPs mixtures originated. 23131797 Large, chemically diverse dataset of logP measurements for benchmarking studies. Lipophilicity is a crucial parameter in drug development since it impacts both ADME properties and target affinity of drug candidates. In early drug discovery stage, accurate tools for logP prediction are highly desired. Many calculation methods were developed to aid pharmaceutical scientists in drug research; however almost all suffer from insufficient accuracy and variation of performance in several regions of the chemical space associated with new chemical entities. The low predictive power of existing software packages can be explained by limited availability and/or variable quality of experimental logP values associated with training set used, which stem from various protocols and poorly cover chemical space. In this study, a dataset of 1000 diverse test compounds out of 4.5 million was generated; logP values of 759 purchasable compounds (46% non-ionizable, 30% basic, 17% acidic, 0.5% zwitterionic and 6.5% ampholytes) from this selected set were experimentally determined by UHPLC followed by UV detection or MS detection when necessary. Finally, a data collection of 707 validated logP values ranging from 0.30 to 7.50 is now available for benchmarking of existing and development of new approaches to predict octanol/water partition coefficients of chemical compounds. 23237590 Slip flow through colloidal crystals of varying particle diameter. Slip flow of water through silica colloidal crystals was investigated experimentally for eight different particle diameters, which have hydraulic channel radii ranging from 15 to 800 nm. The particle surfaces were silylated to be low in energy, with a water contact angle of 83°, as determined for a silylated flat surface. Flow rates through centimeter lengths of colloidal crystal were measured using a commercial liquid chromatograph for accurate comparisons of water and toluene flow rates using pressure gradients as high as 10(10) Pa/m. Toluene exhibited no-slip Hagen-Poiseuille flow for all hydraulic channel radii. For water, the slip flow enhancement as a function of hydraulic channel radius was described well by the expected slip flow correction for Hagen-Poiseuille flow, and the data revealed a constant slip length of 63 ± 3 nm. A flow enhancement of 20 ± 2 was observed for the smallest hydraulic channel radius of 15 nm. The amount of slip flow was found to be independent of shear rate over a range of fluid velocities from 0.7 to 5.8 mm/s. The results support the applicability of the slip flow correction for channel radii as small as 15 nm. The work demonstrates that packed beds of submicrometer particles enable slip flow to be employed for high-volume flow rates. 23299194 Protective effect of Lygodium flexuosum (family: Lygodiaceae) against excision, incision and dead space wounds models in experimental rats. Ethnopharmacological relevance: Lygodium flexuosum (Linn) Sw. is a climbing fern, and it is the sole genus in the family Lygodiaceae. It commonly grows epiphytically on moss covered tree trunks and branches as lithophytes on shady boulders along with moss. It has been reported as a traditional folkloric medicine for a variety of ailments particularly useful for carbuncles, inflammation, ulcer, various respiratory diseases, general disorders, muscle sprains and acts as panacea for wounds. However, there are no scientific reports on wound healing activity of the plant L. flexuosum (Linn) Sw.Aim of the study: To explore the protective effect of L. flexuosum against excision, incision and dead space wounds models in experimental rats. METHODS: Wistar albino rats of either sex weighing between 180 and 220 g were topically treated with extract formulated in ointment using simple ointment BP as base. Ointments, 4% and 5% (w/w), were applied once daily in excision wound model. L. flexuosum ethanolic extract was given orally at a dose of 100, 200 and 400 mg/kg in incision and dead space wound healing models. Rats of standard groups were treated with 0.2% nitrofurazone ointment topically. The percentage wound contraction, epithelization time in excision wound model; breaking strength in incision wound model and wet and dry granulation weight, hydroxyproline content were measured. RESULTS: Topical application of L. flexuosum in excision wound model increased the percentage of wound contraction, and the epithelization time was decreased. In the incision wound model, the breaking strength of wounds increased and in dead space model the weight of dry and wet granuloma of wounds and hydroxyproline was increased. Conclusively, the data of present study indicated that the leaf extract of L. flexuosum accelerated wound healing in rats and thus supports its traditional use. 23219469 Direct transmembrane interaction between actin and the pore-competent, cholesterol-dependent cytolysin pneumolysin. The eukaryotic actin cytoskeleton is an evolutionarily well-established pathogen target, as a large number of bacterial factors disturb its dynamics to alter the function of the host cells. These pathogenic factors modulate or mimic actin effector proteins or they modify actin directly, leading to an imbalance of the precisely regulated actin turnover. Here, we show that the pore-forming, cholesterol-dependent cytolysin pneumolysin (PLY), a major neurotoxin of Streptococcus pneumoniae, has the capacity to bind actin directly and to enhance actin polymerisation in vitro. In cells, the toxin co-localised with F-actin shortly after exposure, and this direct interaction was verified by Förster resonance energy transfer. PLY was capable of exerting its effect on actin through the lipid bilayer of giant unilamellar vesicles, but only when its pore competence was preserved. The dissociation constant of G-actin binding to PLY in a biochemical environment was 170-190 nM, which is indicative of a high-affinity interaction, comparable to the affinity of other intracellular actin-binding factors. Our results demonstrate the first example of a direct interaction of a pore-forming toxin with cytoskeletal components, suggesting that the cross talk between pore-forming cytolysins and cells is more complex than previously thought. 23518924 An Essential Role for Insulin and IGF1 Receptors in Regulating Sertoli Cell Proliferation, Testis Size, and FSH Action in Mice. Testis size and sperm production are directly correlated to the total number of adult Sertoli cells (SCs). Although the establishment of an adequate number of SCs is crucial for future male fertility, the identification and characterization of the factors regulating SC survival, proliferation, and maturation remain incomplete. To investigate whether the IGF system is required for germ cell (GC) and SC development and function, we inactivated the insulin receptor (Insr), the IGF1 receptor (Igf1r), or both receptors specifically in the GC lineage or in SCs. Whereas ablation of insulin/IGF signaling appears dispensable for GCs and spermatogenesis, adult testes of mice lacking both Insr and Igf1r in SCs (SC-Insr;Igf1r) displayed a 75% reduction in testis size and daily sperm production as a result of a reduced proliferation rate of immature SCs during the late fetal and early neonatal testicular period. In addition, in vivo analyses revealed that FSH requires the insulin/IGF signaling pathway to mediate its proliferative effects on immature SCs. Collectively, these results emphasize the essential role played by growth factors of the insulin family in regulating the final number of SCs, testis size, and daily sperm output. They also indicate that the insulin/IGF signaling pathway is required for FSH-mediated SC proliferation. 22561337 Sex, stroke, and inflammation: the potential for estrogen-mediated immunoprotection in stroke. Stroke is the third leading cause of death and the primary cause of disability in the developed world. Experimental and clinical data indicate that stroke is a sexually dimorphic disease, with males demonstrating an enhanced intrinsic sensitivity to ischemic damage throughout most of their lifespan. The neuroprotective role of estrogen in the female brain is well established, however, estrogen exposure can also be deleterious, especially in older women. The mechanisms for this remain unclear. Our current understanding is based on studies examining estrogen as it relates to neuronal injury, yet cerebral ischemia also induces a robust sterile inflammatory response involving local and systemic immune cells. Despite the potent anti-inflammatory effects of estrogen, few studies have investigated the contribution of estrogen to sex differences in the inflammatory response to stroke. This review examines the potential role for estrogen-mediated immunoprotection in ischemic injury. 23543460 Radioiodide induces apoptosis in human thyroid tissue in culture. Radioiodide ((131)I) is routinely used for the treatment of toxic adenoma, Graves' disease, and for ablation of thyroid remnant after thyroidectomy in patients with thyroid cancer. The toxic effects of ionizing radiations on living cells can be mediated by a necrotic and/or apoptotic process. The involvement of apoptosis in radiation-induced cell death in the thyrocytes has been questioned. The knowledge of the mechanisms that underlie the thyrocyte death in response to radiations can help to achieve a successful treatment with the lowest (131)I dose. We developed a method to study the effects of (131)I in human thyroid tissue in culture, by which we demonstrated that (131)I induces thyroid cell apoptosis. Human thyroid tissues of about 1 mm(3) were cultured in vitro and cell viability was determined up to 3 weeks by the MTT assay. Radioiodide added to the culture medium was actively taken up by the tissues. The occurrence of apoptosis in the thyrocytes was assessed by measuring the production of a caspase-cleavage fragment of cytokeratin 18 (M30) by an enzyme-linked immunoassay. Neither variation of cell number nor spontaneous apoptosis was revealed after 1 week of culture. (131)I added to the culture medium induced a dose-dependent and a time-dependent generation of M30 fragment. The apoptotic process was confirmed by the generation of caspase-3 and PARP cleavage products. These results demonstrate that (131)I induces apoptosis in human thyrocytes. Human thyroid tissue cultures may be useful to investigate the cell death pathways induced by (131)I. 22732441 What should we do about student use of cognitive enhancers? An analysis of current evidence. This article reviews current data on the use of cognition enhancers as study aids in the student population. It identifies gaps and uncertainties in the knowledge required to make a balanced assessment of the need for some form of regulation. The review highlights the weak evidence on the prevalence of use of such drugs, especially outside the US, and the ambiguous evidence for their efficacy in a healthy population. Risks are well documented for the commonly used drugs, but poorly appreciated by users. These include not only the side-effects of the drugs themselves, but risks associated with on-line purchase, which offers no guarantees of authenticity and which for some drugs is illegal. The case for urgent action to regulate use is often linked to the belief that new and more effective drugs are likely to appear in the near future. The evidence for this is weak. However, drugs are not the only possible route to neuroenhancement and action is needed to collect more data on the impact of existing drugs, as well as new technologies, in order to guide society in making a proportionate response to the issue. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23220002 Neuropathy target esterase (NTE): overview and future. Neuropathy target esterase (NTE) was discovered by M.K. Johnson in his quest for the entity responsible for the striking and mysterious paralysis brought about by certain organophosphorus (OP) esters. His pioneering work on OP neuropathy led to the view that the biochemical lesion consisted of NTE that had undergone OP inhibition and aging. Indeed, nonaging NTE inhibitors failed to produce disease but protected against neuropathy from subsequently administered aging inhibitors. Thus, inhibition of NTE activity was not the culprit; rather, formation of an abnormal protein was the agent of the disorder. More recently, however, Paul Glynn and colleagues showed that whereas conventional knockout of the NTE gene was embryonic lethal, conditional knockout of central nervous system NTE produced neurodegeneration, suggesting to these authors that the absence of NTE rather than its presence in some altered form caused disease. We now know that NTE is the 6th member of a 9-protein family called patatin-like phospholipase domain-containing proteins, PNPLA1-9. Mutations in the catalytic domain of NTE (PNPLA6) are associated with a slowly developing disease akin to OP neuropathy and hereditary spastic paraplegia called NTE-related motor neuron disorder (NTE-MND). Furthermore, the NTE protein from affected individuals has altered enzymological characteristics. Moreover, closely related PNPLA7 is regulated by insulin and glucose. These seemingly disparate findings are not necessarily mutually exclusive, but we need to reconcile recent genetic findings with the historical body of toxicological data indicating that inhibition and aging of NTE are both necessary in order to produce neuropathy from exposure to certain OP compounds. Solving this mystery will be satisfying in itself, but it is also an enterprise likely to pay dividends by enhancing our understanding of the physiological and pathogenic roles of the PNPLA family of proteins in neurological health and disease, including a potential role for NTE in diabetic neuropathy. 23318445 Evidence of mitochondrial dysfunction and impaired ROS detoxifying machinery in Fanconi Anemia cells. Fanconi Anemia (FA) is a rare genetic disorder associated with a bone-marrow failure, cancer predisposition and hypersensitivity to DNA crosslinking agents. Majority of the 15 FA genes and encoded proteins characterized so far are integrated into DNA repair pathways, however, other important functions cannot be excluded. FA cells are sensitive to oxidants, and accumulation of oxidized proteins has been characterized for several FA subgroups. Clinical phenotypes of both FA and other closely related diseases suggest altered functions of mitochondria, organelles responsible for cellular energetic metabolism, and also serving as an important producer and the most susceptible target from reactive oxidative species (ROS). In this study, we have shown that elevated level of mitochondrial ROS in FA cells is in parallel with the decrease of mitochondrial membrane potential, the decrease of ATP production, impaired oxygen uptake and pathological changes in the morphology of mitochondria. This is accompanied by inactivation of enzymes that are essential for the energy production (F1F0ATPase and cytochrome C oxidase) and detoxification of ROS (superoxide dismutase, SOD1). In turn, overexpression of SOD1 could rescue oxygen consumption rate in FA-deficient cells. Importantly, the depletion of mitochondria improved survival rate of mitomycin C treated FA cells suggesting that hypersensitivity of FA cells to chemotherapeutic drugs could be in part due to the mitochondria-mediated oxidative stress. On the basis of our results, we propose that deficiency in FA genes lead to disabling mitochondrial ROS-scavenging machinery further affecting mitochondrial functions and suppressing cell respiration.Oncogene advance online publication, 14 January 2013; doi:10.1038/onc.2012.583. 23452855 Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm. Period determination in the mammalian circadian clock involves the turnover rate of the repressors CRY and PER. We show that CRY ubiquitination engages two competing E3 ligase complexes that either lengthen or shorten circadian period in mice. Cloning of a short-period circadian mutant, Past-time, revealed a glycine to glutamate missense mutation in Fbxl21, an F-box protein gene that is a paralog of Fbxl3 that targets the CRY proteins for degradation. While loss of function of FBXL3 leads to period lengthening, mutation of Fbxl21 causes period shortening. FBXL21 forms an SCF E3 ligase complex that slowly degrades CRY in the cytoplasm but antagonizes the stronger E3 ligase activity of FBXL3 in the nucleus. FBXL21 plays a dual role: protecting CRY from FBXL3 degradation in the nucleus and promoting CRY degradation within the cytoplasm. Thus, the balance and cellular compartmentalization of competing E3 ligases for CRY determine circadian period of the clock in mammals. 23085435 Nitrogen-containing bisphosphonates induce apoptosis of hematopoietic tumor cells via inhibition of Ras signaling pathways and Bim-mediated activation of the intrinsic apoptotic pathway. Nitrogen-containing bisphosphonates (N-BPs) induce apoptosis in tumor cells by inhibiting the prenylation of small G-proteins. However, the details of the apoptosis-inducing mechanism remain obscure. The present study showed that the induction of apoptosis by N-BPs in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of geranylgeranyl pyrophosphate (GGPP) biosynthesis. Furthermore, N-BPs decreased the levels of phosphorylated extracellular signal-regulated kinase (ERK) and mTOR via suppression of Ras prenylation and enhanced Bim expression. The present results indicated that N-BPs induce apoptosis by decreasing the mitochondrial transmembrane potential, increasing the activation of caspase-9 and caspase-3, and enhancing Bim expression through inhibition of the Ras/MEK/ERK and Ras/mTOR pathways. The accumulation of N-BPs in bones suggests that they may act more effectively on tumors that have spread to bones or on Ras-variable tumors. This is the first study to show that the specific molecular pathways of N-BP-induced apoptosis. 23432009 Chemistry and theranostic applications of radiolabeled nanoparticles for cardiovascular, oncological, and pulmonary research. Labeling nanoparticles with radionuclides has been widely used to form multifunctional and multivalency agents for various biomedical applications. A variety of nanostructures including inorganic, organic and lipid nanoparticles have been labeled with positron or gamma emitting radioisotopes through versatile radiochemistry in a number of disease models to track their in vivo fate, image biomarkers, and monitor treatment response. This review briefly summarizes the recent applications of nanoparticles labeled with radionuclides for oncological, cardiovascular, and pulmonary theranostics. 23615074 Tea and human health: The dark shadows. Tea is one of the most popularly consumed beverage. Depending on the manufacturing process, different varieties of tea can be produced. The antioxidative and antimutagenic potential of tea in cardiovascular diseases, cancer and obesity have long been studied. These therapeutic and nutritional benefits of tea can be attributed to the presence of flavanoids. However, these flavanoids also have certain detrimental effects on human health when their consumption exceeds certain limits. The toxicity of these flavanoids can be attributed to the formation of reactive oxygen species in the body which causes damage to the DNA, lipid membranes etc. The aim of this review is to summarize briefly, the less studied evidences of various forms of toxicity associated with tea and its harmful effects on human health. 23584418 The influence of thermal degradation on the electrodeposition of aluminium from an air- and water-stable ionic liquid. Aluminium electrodeposition is demonstrated from a thermally degraded ionic liquid solution. NMR and voltammetric analyses established that Al(3+) reduction was remarkably similar to that in non-degraded IL solutions suggesting that the electroactive metal-containing species was unaffected by heat treatment. Electron microscopy revealed a significant grain refinement of the deposited metal. 23627685 Understanding Morphology-Controlled Synthesis of Zinc Nanoparticles and Their Characteristics of Hydrolysis Reaction. Two-step thermochemical water-splitting cycle based on a Zn/ZnO redox pair is considered as a potential route for carbon-free production of hydrogen because the first hydrolysis step of the cycle highly depends on the method of preparation and the resultant particle characteristics, such as size, morphology, surface state, and initial oxide content. Here, employing a conventional evaporation and condensation method, we successfully produce three types of Zn nanoparticles ranging from nanorods, mesoporous nanorods with nanospheres on their surfaces, and fully sintered nanocrystals. The achievement in morphology control is realized simply by changing the injection position of the quenching gas. We found that the resultant hydrolysis kinetics is highly dependent on the morphology and porosity of the Zn nanoparticles. Finally, a series of simple mathematical modeling is made in an effort to understand the formation mechanism of Zn nanoparticles. 23235151 Mast cells produce novel shorter forms of perlecan that contain functional endorepellin: a role in angiogenesis and wound healing. Mast cells are derived from hematopoietic progenitors that are known to migrate to and reside within connective and mucosal tissues, where they differentiate and respond to various stimuli by releasing pro-inflammatory mediators, including histamine, growth factors, and proteases. This study demonstrated that primary human mast cells as well as the rat and human mast cell lines, RBL-2H3 and HMC-1, produce the heparan sulfate proteoglycan, perlecan, with a molecular mass of 640 kDa as well as smaller molecular mass species of 300 and 130 kDa. Utilizing domain-specific antibodies coupled with N-terminal sequencing, it was confirmed that both forms contained the C-terminal module of the protein core known as endorepellin, which were generated by mast cell-derived proteases. Domain-specific RT-PCR experiments demonstrated that transcripts corresponding to domains I and V, including endorepellin, were present; however, mRNA transcripts corresponding to regions of domain III were not present, suggesting that these cells were capable of producing spliced forms of the protein core. Fractions from mast cell cultures that were enriched for these fragments were shown to bind endothelial cells via the α(2)β(1) integrin and stimulate the migration of cells in "scratch assays," both activities of which were inhibited by incubation with either anti-endorepellin or anti-perlecan antibodies. This study shows for the first time that mast cells secrete and process the extracellular proteoglycan perlecan into fragments containing the endorepellin C-terminal region that regulate angiogenesis and matrix turnover, which are both key events in wound healing. 23608129 Multiple origins for Hound's tongues (Cynoglossum L.) and Navel seeds (Omphalodes Mill.) - The phylogeny of the borage family (Boraginaceae s.str.). Recent studies all indicated that both the affinities and subdivision of Boraginaceae s.str. are unsatisfactorily resolved. Major open issues are the placement and affinities of Boraginaceae s.str. in Boraginales and the major clades of the family, with especially the large tribes Cynoglosseae and Eritrichieae repeatedly retrieved as non-monophyletic groups, and the doubtful monophyly of several larger genera, especially Cynoglossum and Omphalodes. The present study addresses and solves these questions using two plastid markers (trnL-trnF, rps16) on the basis of a sampling including 16 outgroup taxa and 172 ingroup species from 65 genera. The phylogeny shows high statistical support for most nodes on the backbone and on the individual clades. Boraginaceae s.str. are sister to African Wellstediaceae, Wellstediaceae-Boraginaceae s.str. is sister to African Codonaceae. Echiochileae are retrieved as sister to the remainder of Boraginaceae s.str., which, in turn, fall into two major clades, the Boragineae-Lithospermeae (in a well-supported sister relationship) and the Cynoglosseae s.l. (including Eritrichieae). Cynoglosseae s.l. is highly resolved, with Trichodesmeae (incl. Microcaryum, Lasiocaryum) as sister to the remainder of the group. Eritrichieae s.str. (Eritrichium, Hackelia, Lappula) are resolved on a poorly supported polytomy together with the Omphalodes-clade (incl. Myosotidium, Cynoglossum p.p.), and the Mertensia-clade (incl. O. scorpioides, Asperugo). The Myosotideae (Myosotis, Trigonotis, Pseudomertensia) are retrieved in a well-supported sister-relationship to the core-Cynoglosseae, the latter comprising all other genera sampled. Cynoglossum is retrieved as highly para- and polyphyletic, with a large range of generic segregates embedded in Cynoglossum, but other species of Cynoglossum are sister to Microula or to the American "Eritrichieae" (Cryptantha and allied genera). Representatives of the genus Cynoglossum in its current definition are segregated onto six independent lineages, members of Omphalodes onto three independent lineages. At least 11 of the genera here sampled are deeply nested in other genera. The data show that individual details of nutlet morphology (e.g., winged margins, glochidia) are highly homoplasious. Conversely, a complex of nutlet characters (e.g., characters of the gynobase and cicatrix together with nutlet orientation and sculpturing) tends to circumscribe natural units. Geographical distribution of major clades suggests that the family originated in Africa and western Asia and radiated to eastern Eurasia, with several independent dispersal events into Australia and the New World. 23161424 Topoisomerase I inhibitor evodiamine acts as an antibacterial agent against drug-resistant Klebsiella pneumoniae. Topoisomerase inhibitors have been developed in a variety of clinical applications. We investigated the inhibitory effect of evodiamine on E. coli topoisomerase I, which may lead to an anti-bacterial effect. Evodiamine inhibits the supercoiled plasmid DNA relaxation that is catalyzed by E. coli topoisomerase I, and computer-aided docking has shown that the Arg161 and Asp551 residues of topoisomerase I interact with evodiamine. We investigated the bactericidal effect of evodiamine against multidrug-resistant Klebsiella pneumoniae. Evodiamine showed a significantly lower minimal inhibitory concentration value (MIC 128 µg/mL) compared with antibiotics (>512 µg/mL) against the clinical isolate of K. pneumoniae. The results suggested that evodiamine is a potential agent against drug-resistant bacteria. 23288049 Toxicity of the flame-retardant BDE-49 on brain mitochondria and neuronal progenitor striatal cells enhanced by a PTEN-deficient background. Polybrominated diphenyl ethers (PBDEs) represent an important group of flame retardants extensively used, tonnage of which in the environment has been steadily increasing over the past 25 years. PBDEs or metabolites can induce neurotoxicity and mitochondrial dysfunction (MD) through a variety of mechanisms. Recently, PBDEs with < 5 Br substitutions (i.e., 2,2',4,4'-tetrabromodiphenyl ether [BDE-47] and 2,2',4,5'-tetrabromodiphenyl ether [BDE-49]) have gained interest because of their high bioaccumulation. In particular, congeners such as BDE-49 arise as one of the most biologically active, with concentrations typically lower than those observed for BDE-47 in biological tissues; however, its potential to cause MD at biologically relevant concentrations is unknown. To this end, the effect of BDE-49 was studied in brain mitochondria and neuronal progenitor striatal cells (NPC). BDE-49 uncoupled mitochondria at concentrations < 0.1 nM, whereas at > 1 nM, it inhibited the electron transport at Complex V (mixed type inhibition; IC(50) = 6 nM) and Complex IV (noncompetitive inhibition; IC(50) = 40 nM). These concentrations are easily achieved in plasma concentrations considering that BDE-49 (this study, 400-fold) and other PBDEs accumulate 1-3 orders of magnitude in the cells, particularly in mitochondria and microsomes. Similar effects were observed in NPC and exacerbated with PTEN (negative modulator of the PI3K/Akt pathway) deficiency, background associated with autism-like behavior, schizophrenia, and epilepsy. PBDE-mediated MD per se or enhanced by a background that confers susceptibility to this exposure may have profound implications in the energy balance of brain. 23238425 Possible presence of hydrophilic SO3H nanoclusters on the surface of dry ultrathin Nafion® films: a positron annihilation study. Solutions of Nafion® with an ion exchange capacity (IEC) of 0.91 meq g(-1), which are on the verge of the formation of SO(3)H nanoclusters, were spin coated on silicon (Si), glassy carbon (GC) and platinum/silicon (Pt/Si) substrates to form films of up to 256 nm thickness. Nanostructure of the films was studied using Doppler broadening of annihilation radiation (DBAR), positron annihilation lifetime (PAL), X-ray photoelectron spectroscopy (XPS), an atomic force microscope (AFM) and contact angle measurements. Contact angles as low as 10 degrees indicate that the surface of dry ultrathin Nafion® films on Si is highly hydrophilic. XPS data of 10 nm thick, ultrathin film on Si show that oxygen concentration is enhanced and the SO(3)H group concentration, in other words, IEC on the surface is much higher than other films. The S parameter measured by DBAR of an ultrathin Nafion® film on Si is much higher than that of the films on the other substrates. We consider that a large number of hydrophilic, reversed micelle like SO(3)H groups are on the surface of the ultrathin Nafion® film on Si but not on the surface of other films. Positrons implanted into the film are trapped by the SO(3)H clusters, annihilating with the electrons of oxygen and exhibit the high S parameter. The SO(3)H concentration on the surface of thin Nafion® films on GC and Pt/Si substrates may not be so high as the threshold for the formation of a large number of SO(3)H clusters. Positrons implanted into the films annihilate mostly with fluorine atoms, resulting in a low S parameter. The film-substrate interaction plays an essential role in nanostructuring of Nafion® thin films, which may also be the case for Nafion® on the catalysts of polymer electrolyte fuel cells. 23541949 The effects of RFRP-3, the mammalian ortholog of GnIH, on the female pig reproductive axis in vitro. RFamide-related peptide-3 (RFRP-3) has been proposed as a key inhibitory regulator of mammalian reproduction. To further determine the potential mechanisms and sites of action of RFRP-3, we systematically investigated the direct effect of RFRP-3 on the female pig reproductive axis in vitro. Initially, we confirmed that G protein-coupled receptor 147 (GPR147) was distributed in isolated hypothalamic, anterior pituitary and ovarian granulosa cells, suggesting that RFRP-3 could act on these cells in vitro. Subsequently, the direct effects of RFRP-3 on hormone and steroid secretion, the synthesis of subunit genes and the expression of proteins related to proliferation in the hypothalamus, pituitary and ovary were evaluated. Our results demonstrate that different doses of RFRP-3 inhibited the release and synthesis of gonadotrophin releasing hormone, gonadotrophin and steroid hormones and impacted the relative gene expression of KISS1 and GnRHR and the protein expression of cyclin B1, PCNA and ERK 1/2. 23578643 Effect of 5-hydroxymethylfurfural derived from processed Cornus officinalis on the prevention of high glucose-induced oxidative stress in human umbilical vein endothelial cells and its mechanism. The aim of this study was to investigate the protective effect of 5-HMF on human umbilical vein endothelial cells (HUVECs) injured by high glucose in vitro, and the mechanism underlying this process. Our results demonstrated that high glucose-induced oxidative stress in HUVECs was mainly mediated through activation of reactive oxygen species (ROS), Jun N-kinase 2/3 (JNK2/3) and plasma interleukin-8 (IL-8), and inactivation of phosphorylated protein kinase B (P-Akt). Treatment of HUVECs with media containing high glucose (4.5%) in the presence of 5-HMF (100, 200 and 400μM) resulted in significant inhibition of high glucose-induced oxidative stress and expression of JNK1 and JNK2/3. Furthermore, 5-HMF rapidly inhibited high glucose-induced activation of IL-8, a downstream activator of P-Akt. Diabetes mellitus can cause a wide variety of vascular complications and high glucose can induce vascular endothelial cell apoptosis. Free radicals are formed disproportionately in diabetes by glucose oxidation. The finding of this study highlights the pharmacological application of 5-HMF for preventing cardiovascular and diabetes mellitus diseases, and provides the theoretical basis for further development of a Cornus officinalis agent for diabetes-associated vascular diseases. 22751286 Dietary flaxseed oil supplementation ameliorates the effect of cisplatin on brush border membrane enzymes and antioxidant system in rat intestine. Cisplatin (CP; cis-diamminedichloroplatinum II) is a drug widely used against different types of solid tumors. Patients receiving CP, however, experience very profound and long lasting gastrointestinal symptoms. Recently, ω-3 polyunsaturated fatty acid-enriched flaxseed/flaxseed oil (FXO) has shown numerous health benefits. The present study was undertaken to investigate whether FXO can prevent CP-induced adverse biochemical changes in the small intestine of rats. A single intraperitoneal dose of CP (6 mg/kg body weight) was administered to male Wistar rats fed with control diet (CP group) and FXO diet (CPFXO group). Administration of CP led to a significant decline in the specific activities of brush border membrane enzymes both in the mucosal homogenates and in the isolated membrane vesicles. Lipid peroxidation and total sulfhydryl groups were altered upon CP treatment, indicating the generation of oxidative stress. The activities of SOD, catalase and glutathione peroxidase also decreased in CP-treated rats. In contrast, dietary supplementation of FXO prior to and following CP treatment significantly attenuated the CP-induced changes in all these parameters. FXO feeding markedly enhanced resistance to CP-elicited adverse gastrointestinal effects. The results suggest that FXO owing to its intrinsic biochemical/antioxidant properties is an effective agent in reducing the adverse effects of CP on intestine. 23424207 Rutin- and Selenium-attenuated cadmium-induced testicular pathophysiology in rats. Cadmium (Cd) is known to cause oxidative damage in the testes of rats. The aim of this study was to investigate the protective role of rutin (RUT, 30 mg/kg) and selenium (Se, 0.15 ppm) alone or in combination against Cd (200 ppm)-induced lipid peroxidation, steroidogenesis and changes in antioxidant defence system in the rat testes. The obtained results showed that Cd increased lipid peroxidation and abnormal sperm count and decreased plasma testosterone, lactate dehydrogenase, acid phosphatase, alkaline phosphatase and testicular steroidogenic enzymes: 3β-hydroxysteroid dehydrogenase (HSD), 17β-HSD activities as well as epididymal sperm counts and motility, while RUT and Se treatment reversed this change to control values. Acute intoxication with Cd was also followed by significantly decreased activity of the antioxidant defence system (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GR), glutathione (GSH), and glutathione-S-transferase (GST)). Treatment with RUT and Se reversed Cd-induced alterations of antioxidant defence system and significantly prevented Cd-induced testes damage and depletion of plasma and testicular Se levels. RUT and Se appear not to have more profound effects than their separate effects against Cd-induced testicular toxicity, although Se was more potent than RUT in the recovery of testosterone levels. These results suggest that both RUT and Se do not have synergistic role against Cd-induced testicular injury. 23122060 A novel mechanism for the promotion of quercetin glycoside absorption by megalo α-1,6-glucosaccharide in the rat small intestine. The presence of an α-1,6-glucosaccharide enhances absorption of water-soluble quercetin glycosides, a mixture of quercetin-3-O-β-d-glucoside (Q3G, 31.8%), mono (23.3%), di (20.3%) and more d-glucose adducts with α-1,4-linkage to a d-glucose moiety of Q3G, in a ligated small intestinal loop of anesthetized rats. We prepared α-1,6-glucosaccharides with different degrees of polymerization (DP) enzymatically and separated them into a megalo-isomaltosaccharide-containing fraction (M-IM, average DP=11.0) and an oligo-isomaltosaccharide-containing fraction (O-IM, average DP=3.6). Luminal injection of either saccharide fraction promoted the absorption of total quercetin-derivatives from the small intestinal segment and this effect was greater for M-IM than O-IM addition. M-IM also increased Q3G, but not the quercetin aglycone, concentration in the water-phase of the luminal contents more strongly than O-IM. The enhancement of Q3G solubilization in the luminal contents may be responsible for the increases in the quercetin glucoside absorption promoted by α-1,6-glucosaccharides, especially that by M-IM. These results suggest that the ingestion of α-1,6-glucosaccharides promotes Q3G bioavailability. 22998180 SiC-CNT composite prepared by electrophoretic codeposition and the polymer infiltration and pyrolysis process. The paper reports on the successful anodic codeposition of submicrometer SiC powder and multiwalled carbon nanotubes from aqueous suspensions to form SiC-CNT composites. On the basis of the comprehensive analysis of the aqueous suspensions with different pHs, solids contents, and CNT contents, optimal conditions for deposition were determined. Besides having the necessary high absolute value of the ζ-potential, the suspensions that resulted in firm deposits were characterized by limited conductivity (<1 mS/cm). Lowering of suspension conductivity was achieved either by dilution of the suspension or by dialysis of the as-received CNT suspension with high intrinsic conductivity. Selected SiC-CNT deposits were further densified by use of the polymer infiltration and pyrolysis process. 23357312 Paeonol suppresses oxidized low-density lipoprotein induced endothelial cell apoptosis via activation of LOX-1/p38MAPK/NF-κB pathway. Paeonol is an active compound isolated from traditional Chinese medicine, and has been shown to have anti-atherosclerosis, anti-inflammatory, antioxidant effects. The present investigation was undertaken to determine the suppression effects of paeonol on oxidized low-density lipoprotein (ox-LDL) induced endothelial cell line HUVEC apoptosis and to uncover some of the underlying mechanisms of these effects. Cell viability and lactate dehydrogenase (LDH) were measured to evaluate the cell injuries. Apoptosis was evaluated by Hoechst 33342 staining and flow cytometry. Intracellular reactive oxygen species (ROS) generation was detected by 2',7'-dichlorofluorescein diacetate (DCFH-DA). Real-time PCR was used to confirm the expression of LOX-1 mRNA. Western blotting was used to evaluate the protein expression of LOX-1 and Bcl-2, as well as caspase-3 cleavage, p38-mitogen-activated protein kinase (p38MAPK) phosphorylation. NF-κB nuclear translocation was detected by Western blotting and immunofluorescence. Caspase-3 activity was measured using a colorimetric protease assay kit. The results showed that ox-LDL significantly decreased cell viability and increased the LDH release, as well as the apoptotic rate (P<0.01). Pre-treatment of paeonol resulted in remarkable increase of cell viability, decrease of LDH release and cell apoptosis in a concentration-dependent manner. Besides, ox-LDL caused the up-regulation of LOX-1, the down-regulation of Bcl-2, the phosphorylation of p38MAPK, the translocation of NF-κB and the activation of caspase-3. Paeonol pre-treatment reversed these effects introduced by ox-LDL. Moreover, paeonol also showed its inhibition effects on ox-LDL induced ROS overproduction. These results indicate the preventive effects of paeonol on ox-LDL induced endothelial cell apoptosis. The effects might, at least partly, be obtained via inhibition of LOX-1-ROS- p38MAPK-NF-κB signaling pathway. 23511383 Effectiveness of in-patient rehabilitation in obesity-related orthopedic conditions. Background: The aim of the present paper is to provide initial evidence that in-patient multidisciplinary rehabilitation is effective in minimizing the obesity-related disability and enhancing functional capacities in obese patients with motor disability. Subjects: 464 obese patients with orthopedic conditions admitted to our Rehabilitation Unit for multidisciplinary rehabilitation were enrolled in this study. Methods: At admission and discharge (after 4 weeks), the following outcome measures were computed: body weight (BW; Kg), body mass index (BMI; Kg/m2), Functional Independence Measure (FIM) motor and cognitive, Obesity-related disability test (TSD-OC), Visual Analogue Score (VAS) for functioning, Timed-Up-Go (TUG). Intensive rehabilitation addressed to obese patients with orthopedic conditions and motor difficulties consisted of a 4-week and 3-hour daily multidisciplinary program covering nutritional, motor and psychological aspects. Results: All of the outcomes measured, except the FIM cognitive score, improved significantly after in-patient rehabilitation. The obesity-specific disability scale appears sensitive to changes among groups with different grades of disability and the percentage of change does not differ among groups. Younger obese individuals generally showed to benefit more from rehabilitation interventions than the older ones. Conclusions: In-patient rehabilitation interventions appear effective in reducing both mild and severe disabilities related to obesity with orthopedic co-morbidities. This paper provides initial evidence that in-patient multidisciplinary intensive rehabilitation is effective in minimizing the obesity-related disability and initial support to the indications of the Italian Ministry of Health for such rehabilitation pathway. The disability grading could help the decision making of allocating patients to appropriate rehabilitation settings. 23237546 Light-triggered biocatalysis using thermophilic enzyme-gold nanoparticle complexes. The use of plasmonic nanoparticle complexes for biomedical applications such as imaging, gene therapy, and cancer treatment is a rapidly emerging field expected to significantly improve conventional medical practices. In contrast, the use of these types of nanoparticles to noninvasively trigger biochemical pathways has been largely unexplored. Here we report the light-induced activation of the thermophilic enzyme Aeropyrum pernix glucokinase, a key enzyme for the decomposition of glucose via the glycolysis pathway, increasing its rate of reaction 60% with light by conjugating the enzyme onto Au nanorods. The observed increase in enzyme activity corresponded to a local temperature increase within a calcium alginate encapsulate of ~20 °C when compared to the bulk medium maintained at standard, nonthermophilic temperatures. The encapsulated nanocomplexes were reusable and stable for several days, making them potentially useful in industrial applications. This approach could significantly improve how biochemical pathways are controlled for in vitro and, quite possibly, in vivo use. 23378626 Absorption, elimination, and metabolism of CS-1036, a novel α-amylase inhibitor in rats and monkeys, and the relationship between gastrointestinal distribution and suppression of glucose absorption. The absorption, metabolism, and excretion of (2R,3R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-deoxy-β-d-glucopyranosyl)-α-d-glucopyranoside (CS-1036), a novel and potent pancreatic and salivary α-amylase inhibitor, were evaluated in F344/DuCrlCrlj rats and cynomolgus monkeys. The total body clearance and volume of distribution of CS-1036 were low (2.67-3.44 ml/min/kg and 0.218-0.237 l/kg for rats and 2.25-2.84 ml/min/kg and 0.217-0.271 l/kg for monkeys). After intravenous administration of [(14)C]CS-1036 to rats and monkeys, radioactivity was mainly excreted into urine (77.2% for rats and 81.1% for monkeys). After oral administration, most of the radioactivity was recovered from feces (80.28% for rats and 88.13% for monkeys) with a low oral bioavailability (1.73-2.44% for rats and 0.983-1.20% for monkeys). In rats, intestinal secretion is suggested to be involved in the fecal excretion as a minor component because fecal excretion after intravenous administration was observed (15.66%) and biliary excretion was almost negligible. Although intestinal flora was involved in CS-1036 metabolism, CS-1036 was the main component in feces (70.3% for rats and 48.7% for monkeys) and in the intestinal contents (33-68% for rats up to 2 hours after the dose) after oral administration. In Zucker diabetic fatty rats, CS-1036 showed a suppressive effect on plasma glucose elevation after starch loading with a 50% effective dose at 0.015 mg/kg. In summary, CS-1036 showed optimal pharmacokinetic profiles: low oral absorption and favorable stability in gastrointestinal lumen, resulting in suppression of postprandial hyperglycemia by α-amylase inhibition. 23316913 Improved quantum efficiency of highly efficient perovskite BaSnO₃-based dye-sensitized solar cells. Ternary oxides are potential candidates as an electron-transporting material that can replace TiO₂ in dye-sensitized solar cells (DSSCs), as their electronic/optical properties can be easily controlled by manipulating the composition and/or by doping. Here, we report a new highly efficient DSSC using perovskite BaSnO₃ (BSO) nanoparticles. In addition, the effects of a TiCl₄ treatment on the physical, chemical, and photovoltaic properties of the BSO-based DSSCs are investigated. The TiCl₄ treatment was found to form an ultrathin TiO₂ layer on the BSO surface, the thickness of which increases with the treatment time. The formation of the TiO₂ shell layer improved the charge-collection efficiency by enhancing the charge transport and suppressing the charge recombination. It was also found that the TiCl₄ treatment significantly reduces the amount of surface OH species, resulting in reduced dye adsorption and reduced light-harvesting efficiency. The trade-off effect between the charge-collection and light-harvesting efficiencies resulted in the highest quantum efficiency (i.e., short-circuit photocurrent density), leading to the highest conversion efficiency of 5.5% after a TiCl₄ treatment of 3 min (cf. 4.5% for bare BSO). The conversion efficiency could be increased further to 6.2% by increasing the thickness of the BSO film, which is one of the highest efficiencies from non-TiO₂-based DSSCs. 23280620 Evidence of impaired health in yellow perch (Perca flavescens) from a biological mercury hotspot in northeastern North America. Few studies have investigated the effects of mercury (Hg) on wild fish from remote areas, even though these fish can have high total Hg concentrations. In Kejimkujik National Park and National Historic Site (KNPNHS), Nova Scotia, Canada, concentrations of total Hg in many yellow perch (Perca flavescens) currently exceed the estimated threshold level for adverse effects in fish (0.2 µg Hg g(-1) (wet wt), whole body). To determine whether Hg exposure is adversely affecting the general health of these fish, the authors collected male and female perch in the fall of 2009 and 2010 from 12 lakes within KNPNHS. The health endpoints condition, liver somatic index (LSI), and macrophage aggregates (MAs; indicators of oxidative stress and tissue damage) in the liver, kidney, and spleen were examined, and in female perch were compared between lakes and related to Hg concentrations measured in the muscle and liver tissue. No negative relationships between fish condition or LSI and Hg were found. However, within the liver, kidney, and spleen tissues of females, the relative area occupied by MAs was positively related to both muscle and liver Hg concentrations, indicating the health of these perch was adversely affected at the cellular level. These findings raise concerns for the health of these perch as well as for other wild fish populations known to have similarly elevated Hg concentrations. 23438500 Quantitative analysis of the coverage density of Br- ions on Pd{100} facets and its role in controlling the shape of Pd nanocrystals. We report an approach based on a combination of inductively coupled plasma mass spectrometry and X-ray photoelectron spectroscopy for quantitative analysis of the role played by Br(-) ions in the synthesis of Pd nanocrystals. The Br(-) ions were found to adsorb onto Pd{100} facets selectively with a coverage density of ca. 0.8 ion per surface Pd atom. The chemisorbed Br(-) ions could be removed via desorption at an elevated temperature under reductive conditions. They could also be gradually released from the surface when Pd cubic seeds grew into cuboctahedrons and then octahedrons. On the basis of the coverage density information, we were able to estimate the minimum concentration of Br(-) ions needed for the formation of Pd nanocubes with a specific size. If the concentration of Br(-) ions was below this minimum value, not all of the {100} facets could be stabilized by the capping agent, leading to the formation of nanocubes with truncated corners. The quantitative analysis developed in this study is potentially extendable to other systems involving chemisorbed capping agents. 23371760 Resin acid conversion with CYP105A1: an enzyme with potential for the production of pharmaceutically relevant diterpenoids. Cytochrome P450s are very versatile enzymes with great potential for biotechnological applications because of their ability to oxidize unactivated CH bonds. CYP105A1 from Streptomyces griseolus was first described as a herbicide-inducible sulfonylurea hydroxylase, but it is also able to convert other substrates such as vitamin D(3) . To extend the substrate pool of this interesting enzyme further, we screened a small diterpenoid compound library and were able to show the conversion of several resin acids. Binding of abietic acid, dehydroabietic acid, and isopimaric acid to the active site was assayed, and V(max) and K(m) values were calculated. The products were analyzed by NMR spectroscopy and identified as 15-hydroxyabietic acid, 15-hydroxydehydroabietic acid, and 15,16-epoxyisopimaric acid. As the observed products are difficult to obtain by chemical synthesis, CYP105A1 has proved to be a promising candidate for biotechnological applications that combine bioconversion and chemical synthesis to obtain functionalized resin acids. 23194526 Garlic oil attenuates the cardiac apoptosis in hamster-fed with hypercholesterol diet. Hypercholesterolemia is a well established risk factor for cardiac cell apoptosis. The purpose of this study is to evaluate the effects of garlic oil on cardiac apoptosis induced by a hypercholesterol diet. Twenty-four male Golden-Syrian hamsters at 3 months of age were randomly divided into three groups, control, cholesterol and garlic oil groups received a chow diet, chow diet with 2% cholesterol, and chow diet with 2% cholesterol and 1% garlic oil for 8 weeks, respectively. The TUNEL-positive apoptotic cells, and several apoptotic proteins were significantly induced in the excised left ventricle in cholesterol group, whereas significant reduction was observed in cholesterol plus garlic oil group. The IGFI receptor dependent survival pathway was inhibited in cholesterol group whereas it was obviously reversed in cholesterol plus garlic oil group. Our results suggest that administration of garlic oil shows protective effects on cardiac apoptosis in rats with high cholesterol intake. 23461821 Facile synthesis of silver nanoparticles stabilized by cationic polynorbornenes and their catalytic activity in 4-nitrophenol reduction. We report the facile one-pot single-phase syntheses of silver nanoparticles stabilized by norbornene type cationic polymers. Silver nanoparticles (AgNPs) stabilized by polyguanidino oxanorbornenes (PG) at 5 and 25 kDa and polyamino oxanorbornenes (PA) at 3 and 15 kDa have been synthesized by the reduction of silver ions with NaBH4 in aqueous solutions at ambient temperature. The four different silver nanoparticles have been characterized by UV-vis spectroscopy, Fourier transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), and transmission electron microscopy (TEM) for their particle size distributions. Interestingly, PG stabilizes the silver nanoparticles better than PA as evident from our spectroscopic data. Furthermore, the AgNP-PG-5K (5K = 5 kDa) was found to serve as an effective catalyst for the reduction of 4-nitrophenol to 4-aminophenol in the presence of NaBH4. The reduction has a pseudo-first-order rate constant of 5.50 × 10(-3) s(-1) and an activity parameter of 1375 s(-1) g(-1), which is significantly higher than other systems reported in the literature. 23485417 Hieranoid: Hierarchical Orthology Inference. An accurate inference of orthologs is essential in many research fields such as comparative genomics, molecular evolution, and genome annotation. Existing methods for genome-scale orthology inference are mostly based on all-versus-all similarity searches that scale quadratically with the number of species. This limits their application to the increasing number of available large-scale datasets. Here, we present Hieranoid, a new orthology inference method using a hierarchical approach. Hieranoid performs pairwise orthology analysis using InParanoid at each node in a guide tree as it progresses from its leaves to the root. This concept reduces the total runtime complexity from a quadratic to a linear function of the number of species. The tree hierarchy provides a natural structure in multi-species ortholog groups, and the aggregation of multiple sequences allows for multiple alignment similarity searching techniques, which can yield more accurate ortholog groups. Using the recently published orthobench benchmark, Hieranoid showed the overall best performance. Our progressive approach presents a new way to infer orthologs that combines efficient graph-based methodology with aspects of compute-intensive tree-based methods. The linear scaling with the number of species is a major advantage for large-scale applications and makes Hieranoid well suited to cope with vast amounts of sequenced genomes in the future. Hieranoid is an open source and can be downloaded at Hieranoid.sbc.su.se. 23343117 Mechanism for different fluorescence response of a coumarin-amide-dipicolylamine linkage to Zn(II) and Cd(II) in water. A coumarin-amide-dipicolylamine linkage (L) was synthesized and used as a fluorescent receptor for metal cations in water. The receptor dissolved in water with neutral pH shows almost no fluorescence due to the photoinduced electron transfer (PET) from the amide and amine nitrogens to the excited state coumarin moiety. Coordination of Zn(2+) or Cd(2+) with L creates strong fluorescence at 437 or 386 nm, respectively, due to the suppression of PET. In contrast, other metal cations scarcely show fluorescence enhancement. IR, NMR, and potentiometric analysis revealed that both Zn(2+) and Cd(2+) are coordinated with two pyridine N, amine N, and amide O; however, the Zn(2+) center is also coordinated with a hydroxide anion (OH(-)). The structure difference for Zn and Cd complexes results in longer- and shorter-wavelength fluorescence. Ab initio calculations revealed that π electrons on the excited state Cd complex are delocalized over the molecules and the Cd complex shows shorter-wavelength emission. In contrast, π electrons of OH(-)-coordinated Zn complex are localized on the coumarin moiety. This increases the electron density of coumarin moiety and shows longer-wavelength fluorescence. 23580402 Age-Related Macular Degeneration. Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, and the prevalence of the disease increases exponentially with every decade after age 50 years. It is a multifactorial disease involving a complex interplay of genetic, environmental, metabolic, and functional factors. Besides smoking, hypertension, obesity, and certain dietary habits, a growing body of evidence indicates that inflammation and the immune system may play a key role in the development of the disease. AMD may progress from the early form to the intermediate form and then to the advanced form, where two subtypes exist: the nonneovascular (dry) type and the neovascular (wet) type. The results from the Age-Related Eye Disease Study have shown that for the nonneovascular type of AMD, supplementation with high-dose antioxidants (vitamin C, vitamin E, and β-carotene) and zinc is recommended for those with the intermediate form of AMD in one or both eyes or with advanced AMD or vision loss due to AMD in one eye. As for the neovascular type of the advanced AMD, the current standard of therapy is intravitreal injections of vascular endothelial growth factor inhibitors. In addition, lifestyle and dietary modifications including improved physical activity, reduced daily sodium intake, and reduced intake of solid fats, added sugars, cholesterol, and refined grain foods are recommended. To date, no study has demonstrated that AMD can be cured or effectively prevented. Clearly, more research is needed to fully understand the pathophysiology as well as to develop prevention and treatment strategies for this devastating disease. 23245516 Overcoming acquired resistance to kinase inhibition: the cases of EGFR, ALK and BRAF. In the past decade, several kinase inhibitors have been approved based on their clinical benefit for cancer patients. Unfortunately, in many cases, patients develop resistance to these agents via secondary mutations and alternative mechanisms. This review will focus on the cases of acquired resistance to EGFR and ALK inhibitors for non-small cell lung cancer patients and BRAF inhibitors for melanoma patients. I will overview the main causes of acquired resistance, and explore the chemical scaffolds as well as combination of drugs, used to tackle these major causes of resistance. 23368777 Eukaryotic initiation factor 5A dephosphorylation is required for translational arrest in stationary phase cells. The protein known as eIF5A (eukaryotic initiation factor 5A) has an elusive role in translation. It has a unique and essential hypusine modification at a conserved lysine residue in most eukaryotes. In addition, this protein is modified by phosphorylation with unknown functions. In the present study we show that a phosphorylated state of eIF5A predominates in exponentially growing Trypanosoma cruzi cells, and extensive dephosphorylation occurs in cells in stationary phase. Phosphorylation occurs mainly at Ser(2), as shown in yeast eIF5A. In addition, a novel phosphorylation site was identified at Tyr(21). In exponential cells, T. cruzi eIF5A is partially associated with polysomes, compatible with a proposed function as an elongation factor, and becomes relatively enriched in polysomal fractions in stationary phase. Overexpression of the wild-type eIF5A, or eIF5A with Ser(2) replaced by an aspartate residue, but not by alanine, increases the rate of cell proliferation and protein synthesis. However, the presence of an aspartate residue instead of Ser(2) is toxic for cells reaching the stationary phase, which show a less-pronounced protein synthesis arrest and a decreased amount of eIF5A in dense fractions of sucrose gradients. We conclude that eIF5A phosphorylation and dephosphorylation cycles regulate translation according to the growth conditions. 23632032 Species tree reconstruction of a poorly resolved clade of salamanders (Ambystomatidae) using multiple nuclear loci. The analysis of diverse data sets can yield different phylogenetic estimates that challenge systematists to explain the source of discordance. The mole salamanders (family Ambystomatidae) are a classic example of this phylogenetic conflict. Previous attempts to resolve the ambystomatid species tree using allozymic, morphological, and mitochondrial sequence data have yielded different estimates, making it unclear which data source best approximates ambystomatid phylogeny and which ones yield phylogenetically inaccurate reconstructions. To shed light on this conflict, we present the first multi-locus DNA sequence-based phylogenetic study of the Ambystomatidae. We utilized a range of analyses, including coalescent-based methods of species-tree estimation that account for incomplete lineage sorting within a locus and concordance-based methods that estimate the number of sampled loci that support a particular clade. We repeated these analyses with the removal of individual loci to determine if any a locus has a disproportionate effect on our phylogenetic results. Collectively, these results robustly resolved many deep and relatively shallow clades within Ambystoma, including the placement of A. gracile and A. talpoideum as the sister clade to a clade containing all remaining ambystomatids, and the placement of A. maculatum as the sister lineage to all remaining ambystomatids excluding A. gracile and A. talpoideum. Both Bayesian coalescent and concordance methods produced similar results, highlighting strongly supported branches in the species tree. Furthermore, coalescent-based analyses that excluded loci produced overlapping species-tree posterior distributions, suggesting that no particular locus - including mtDNA - disproportionately contributed to our species-tree estimates. Overall, our phylogenetic estimates have greater similarity with previous allozyme and mitochondrial sequence-based phylogenetic estimates. However, intermediate depths of divergence in the ambystomatid species tree remain unresolved, potentially highlighting a region of rapid species radiation or a hard polytomy, and which limits our ability to comment on previous morphologically-based taxonomic groups. 23585274 Accurate detection of differential RNA processing. Deep transcriptome sequencing (RNA-Seq) has become a vital tool for studying the state of cells in the context of varying environments, genotypes and other factors. RNA-Seq profiling data enable identification of novel isoforms, quantification of known isoforms and detection of changes in transcriptional or RNA-processing activity. Existing approaches to detect differential isoform abundance between samples either require a complete isoform annotation or fall short in providing statistically robust and calibrated significance estimates. Here, we propose a suite of statistical tests to address these open needs: a parametric test that uses known isoform annotations to detect changes in relative isoform abundance and a non-parametric test that detects differential read coverages and can be applied when isoform annotations are not available. Both methods account for the discrete nature of read counts and the inherent biological variability. We demonstrate that these tests compare favorably to previous methods, both in terms of accuracy and statistical calibrations. We use these techniques to analyze RNA-Seq libraries from Arabidopsis thaliana and Drosophila melanogaster. The identified differential RNA processing events were consistent with RT-qPCR measurements and previous studies. The proposed toolkit is available from http://bioweb.me/rdiff and enables in-depth analyses of transcriptomes, with or without available isoform annotation. 23601389 Development of a regional food composition table for West Africa. Knowledge of the nutrient content of foods is fundamental for virtually all nutrition-related projects, programmes and policies. Low quality compositional data may lead to inappropriate policies and funds spent unnecessarily. Existing food composition tables (FCT) for most West African countries date back to 1960 and 1970 and contain in general few foods and components without documentation. As a result of the recommendations by the Economic Community of West African States (ECOWAS) Nutrition forum and other high level meetings, FAO/INFOODS, WAHO/ECOWAS and Bioversity International developed the West African FCT. It contains 472 foods and 28 components. Emphasis was given to include data on food biodiversity by incorporating cultivars/varieties and underutilized foods. The West African FCT enables users to address diet-related health problems, strengthen local development, enhance trade and promote biodiversity. In addition it contributes to poverty alleviation in both rural and urban areas. The FCT needs to be updated regularly and it is the most recent example of INFOODS for regional food composition activities. 23387865 NMR solution structure study of the representative component hydroxysafflor yellow A and other quinochalcone C-glycosides from Carthamus tinctorius. Hydroxysafflor yellow A (HSYA), a representative component of Carthamus tinctorius, has attracted much attention because of its remarkable cardiovascular activities. Its structure was originally reported in 1993 and has been widely cited to date. In our experiments, its solution structure was studied using NMR techniques in different solvents, including DMSO-d(6), pyridine-d(5), and CD(3)OH. The results indicate that the structure of HSYA is different than the previously described 1b, with 3-enol-1,7-diketo form. The structure has two keto-enol tautomers (2a and 2b), and 2a, with the 1-enol-3,7-diketo form, is the preferred tautomer. On the basis of this finding, other published quinochalcone C-glycoside structures were revised. Furthermore, a trend in the (13)C NMR data of the (E)-olefinic carbons of quinochalcone C-glycosides is summarized, and a hypothesis is proposed for the relationship between the features of the molecular structure and the preferred keto-enol tautomer. 23353058 Occurrence of copper acclimation in the least killifish Heterandria formosa, and associated biochemical and physiological mechanisms. We investigated the occurrence of copper acclimation in the least killifish, Heterandria formosa using both lethal and sublethal endpoints. We also investigated potential mechanisms underlying the observed acclimation. To assess the occurrence of acclimation, fish were exposed to either a background Cu level or to 15 μg/L Cu for seven days and subsequently exposed to a lethal Cu level (150 μg/L Cu). During the latter exposure, fish were monitored for survival till all fish had died, and (during the first 8h of this exposure) for changes in whole-body Na levels and lipid peroxidation (LPO). During the high-level Cu exposure, fish pre-exposed to copper had a significantly longer time-to-death than did the control fish. Similarly, neither whole-body Na nor LPO changed in the Cu-pre-exposed fish during the 8h of the exposure to 150 μg/L Cu - while both decreased significantly in the control fish. Thus, acclimation was evident for both time-to-death and the sublethal endpoints. These results also indicate that Cu toxicity may involve both Na loss and LPO, and that Cu-acclimation may be brought about by prevention of these effects. Our follow-up study on potential mechanisms underlying this copper acclimation used a similar pre-exposure/exposure design. Fish were subsampled at the end of the 7-day acclimation period - just before the commencement of high-level Cu exposure (T), after 4h of this Cu exposure (T), and again after 8h of this Cu exposure (T). Whole-body Cu accumulation, Na/K-ATPase activity, metallothionein levels, and catalase activity were quantified for these time points. While Cu levels were higher in the Cu-pre-exposed fish than in the control fish at T, net Cu accumulation was faster in the control fish than in the Cu-pre-exposed fish during the subsequent high-level Cu exposure. Consequently, changes in Cu accumulation dynamics may play a role in the resistance. Metallothionein induction may also play a role in the observed acclimation, as Cu-acclimated fish had a significantly higher metallothionein concentration compared to the control fish. There was no evidence of involvement of Na/K-ATPase in the acclimation, as the activity of this enzyme remained lower in the pre-exposed fish than in the control fish throughout both Cu exposure periods. There was limited evidence that a reduced loss of catalase activity plays a role in the acclimation; catalase activity did not differ after the pre-exposure period but was significantly higher in Cu-acclimated fish than in the control fish at T. 23265429 Electrodeposition of crystalline GaAs on liquid gallium electrodes in aqueous electrolytes. Crystalline GaAs (c-GaAs) has been prepared directly through electroreduction of As(2)O(3) dissolved in an alkaline aqueous solution at a liquid gallium (Ga(l)) electrode at modest temperatures (T ≥ 80 °C). Ga(l) pool electrodes yielded consistent electrochemical behavior, affording repetitive measurements that illustrated the interdependences of applied potential, concentration of dissolved As(2)O(3), and electrodeposition temperature on the quality of the resultant c-GaAs(s). Raman spectra indicated the composition of the resultant film was strongly dependent on both the electrodeposition temperature and dissolved concentration of As(2)O(3) but not to the applied bias. For electrodepositions performed either at room temperature or with high (≥0.01 M) concentrations of dissolved As(2)O(3), Raman spectra of the electrodeposited films were consistent with amorphous As(s). X-ray diffractograms of As(s) films collected after thermal annealing indicated metallurgical alloying occurred only at temperatures in excess of 200 °C. Optical images and Raman spectra separately showed the composition of the as-electrodeposited film in dilute (≤0.001 M) solutions of dissolved As(2)O(3)(aq) was pure c-GaAs(s) at much lower temperatures than 200 °C. Diffractograms and transmission electron microscopy performed on as-prepared films confirmed the identity of c-GaAs(s). The collective results thus provide the first clear demonstration of an electrochemical liquid-liquid-solid (ec-LLS) process involving a liquid metal that serves simultaneously as an electrode, a solvent/medium for crystal growth, and a coreactant for the synthesis of a polycrystalline semiconductor. The presented data serve as impetus for the further development of the ec-LLS process as a controllable, simple, and direct route for technologically important optoelectronic materials such as c-GaAs(s). 23219161 DNA polymerase POLQ and cellular defense against DNA damage. In mammalian cells, POLQ (pol θ) is an unusual specialized DNA polymerase whose in vivo function is under active investigation. POLQ has been implicated by different experiments to play a role in resistance to ionizing radiation and defense against genomic instability, in base excision repair, and in immunological diversification. The protein is formed by an N-terminal helicase-like domain, a C-terminal DNA polymerase domain, and a large central domain that spans between the two. This arrangement is also found in the Drosophila Mus308 protein, which functions in resistance to DNA interstrand crosslinking agents. Homologs of POLQ and Mus308 are found in multicellular eukaryotes, including plants, but a comparison of phenotypes suggests that not all of these genes are functional orthologs. Flies defective in Mus308 are sensitive to DNA interstrand crosslinking agents, while mammalian cells defective in POLQ are primarily sensitive to DNA double-strand breaking agents. Cells from Polq(-/-) mice are hypersensitive to radiation and peripheral blood cells display increased spontaneous and ionizing radiation-induced levels of micronuclei (a hallmark of gross chromosomal aberrations), though mice apparently develop normally. Loss of POLQ in human and mouse cells causes sensitivity to ionizing radiation and other double strand breaking agents and increased DNA damage signaling. Retrospective studies of clinical samples show that higher levels of POLQ gene expression in breast and colorectal cancer are correlated with poorer outcomes for patients. A clear understanding of the mechanism of action and physiologic function of POLQ in the cell is likely to bear clinical relevance. 23122145 Comparison of the affinity and selectivity of insoluble fibres and commercial proteins for wine proanthocyanidins. The fining action of commercial proteins and insoluble fibres for wine proanthocyanidin (PA) were compared. Fibres were prepared from fresh apple and grape sources, and their corresponding pomaces. PA removal by fibre was via adsorption, and required a higher dose to achieve a fining effect comparable with proteins. A principal component analysis data model revealed that PA molecular mass was significant in defining the fining response, and reflected changes in the proportion of the dominant terminal PA subunits catechin and epicatechin, but not epicatechin-3-O-gallate. For PA extension subunits, changes in epigallocatechin were inversely correlated with epicatechin and epicatechin-3-O-gallate. Generally, the application of proteins and fibres reduced PA molecular mass. Selectivity for PAs by subunit composition was variable between treatments, but differences were minor. This work demonstrates the potential use of fibres as an alternative to proteins in winemaking. Benefits, and possible limitations of such an approach are discussed. 22430207 Minor cell-death defects but reduced tumor latency in mice lacking the BH3-only proteins Bad and Bmf. Proapoptotic Bcl-2 family members of the Bcl-2 homology (BH)3-only subgroup are critical for the establishment and maintenance of tissue homeostasis and can mediate apoptotic cell death in response to developmental cues or exogenously induced forms of cell stress. On the basis of the biochemical experiments as well as genetic studies in mice, the BH3-only proteins Bad and Bmf have been implicated in different proapoptotic events such as those triggered by glucose- or trophic factor-deprivation, glucocorticoids, or histone deacetylase inhibition, as well as suppression of B-cell lymphomagenesis upon aberrant expression of c-Myc. To address possible redundancies in cell death regulation and tumor suppression, we generated compound mutant mice lacking both genes. Our studies revealed lack of redundancy in most paradigms of lymphocyte apoptosis tested in tissue culture. Only spontaneous cell death of thymocytes kept in low glucose or that of pre-B cells deprived of cytokines was significantly delayed when both genes were lacking. Of note, despite these minor apoptosis defects we observed compromised lymphocyte homeostasis in vivo that affected mainly the B-cell lineage. Long-term follow-up revealed significantly reduced latency to spontaneous tumor formation in aged mice when both genes were lacking. Together our study suggests that Bad and Bmf co-regulate lymphocyte homeostasis and limit spontaneous transformation by mechanisms that may not exclusively be linked to the induction of lymphocyte apoptosis. 23535186 Scoparone attenuates d-galactosamine/lipopolysaccharide-induced fulminant hepatic failure through inhibition of toll-like receptor 4 signaling in mice. The purpose of this study was to investigate the protective effects and molecular mechanisms of scoparone on d-galactosamine (d-GalN)/lipopolysaccharide (LPS)-induced fulminant hepatic failure (FHF) in mice. FHF was induced in mice by intraperitoneal injection of d-GalN (800mg/kg)/LPS (40μg/kg). Mice were treated intraperitoneally with scoparone 1h before d-GalN/LPS treatment. Treatment with d-GalN/LPS markedly increased mortality, serum aminotransferase activity, and tolllike receptor 4 (TLR4) protein expression, and these increases were attenuated by scoparone. Treatment with d-GalN/LPS markedly increased myeloid differentiation primary response gene 88 protein expression, phosphorylation of p38, extracellular signal-regulated kinase and c-Jun N-terminal kinase, nuclear protein expression of nuclear factor κB and phosphorylated c-Jun, and levels of serum tumor necrosis factor-α and interleukin-6 and these increases were attenuated by scoparone. In addition, increased levels of toll-receptor-associated activator of interferon protein expression, phosphorylation of interferon (IFN) regulatory factor 3, and serum IFN-β level in d-GalN/LPS-treated mice were attenuated by scoparone. Our results suggest that scoparone attenuates d-GalN/LPSinduced liver damage by inhibition of the TLR-mediated inflammatory pathway. 23464789 Selective Reduction of PHA Biopolyesters and Their Synthetic Analogues to Corresponding PHA Oligodiols Proved by Structural Studies. A highly selective method is described for controlling the degradation of polyhydroxyalkanoates, PHA, via a reduction reaction that uses lithium borohydride. Using this method, oligo(hydroxyalkanoate)diols derived from a poly(3-hydroxybutyrate-co-4-hydroxybutyrate) biopolyester [poly(3HB-co-4HB)] and from synthetic atactic poly[(R,S)-3-hydroxybutyrate] (a-PHB) were obtained. The structural characterization of the oligo(hydroxyalkanoate)diols was conducted using NMR and ESI-mass spectrometry analyses, which confirmed that oligomers that were terminated by two hydroxyl end groups were formed. The reduction of the ester groups occurred in a statistical way regardless of the chemical structure of the comonomer units or of the microstructure of the polyester chain. The presented method can be used to synthesize various PHA oligodiols that are potentially useful in the further synthesis of tailor-made biodegradable materials. 23579427 Acute alcohol effects on subtypes of impulsivity and the role of alcohol-outcome expectancies. RATIONALE: It is well established that alcohol acutely impairs the ability to inhibit a pre-potent response (motor impulsivity), but its effects on cognitive impulsivity, including temporal (delayed gratification) and reflection (decision making) impulsivity, are not clear. An important factor contributing to the effects of alcohol is cognitive expectancies of alcohol-related outcomes. OBJECTIVES: The current study investigated the effect of alcohol, and alcohol outcome expectancies, on subtypes of impulsivity. METHODS: Impulsivity was tested using the Stop Signal, the Single Key Impulsivity and the Information Sampling Task for motor, temporal and reflection impulsivity, respectively. Participants (n = 48) received placebo, a low (0.4 g/kg) or high dose (0.8 g/kg) of alcohol, before completing the impulsivity measures. RESULTS: Motor impulsivity was affected by alcohol dose; participants receiving a high dose displayed reduced inhibitory control. Reflection impulsivity was affected by cognitive alcohol expectancies, but not by alcohol condition; participants expecting greater cognitive and behavioural impairment by alcohol exhibited low impulsivity. Temporal impulsivity was not affected by either alcohol dose or outcome expectancies. CONCLUSIONS: These data suggest that the effects of alcohol on the subtypes of impulsivity are dissociable. Motor impulsivity is sensitive to the pharmacological effects of alcohol, whereas the reflection subtype is affected by cognitive alcohol expectancies. The findings have implications for the understanding of impulsive behaviour under the influence of alcohol. 23499614 Phylogeny and phylogeography of Mantophryne (Anura: Microhylidae) reveals cryptic diversity in New Guinea. New Guinea is one of five high biodiversity wilderness areas, and frog diversity is exceptionally large, with more than 400 species described to date. The microhylid frog genus Mantophryne is endemic to New Guinea and consists of four species, three of which have narrow geographic distributions and a fourth, M. lateralis, with a broad range that spans the eastern half of the island. Here, we sequence 104 Mantophryne samples for three mitochondrial and three nuclear loci to reconstruct the first phylogeny of the genus and to examine spatial patterns of diversity within M. lateralis. Results indicate that the wide-ranging M. lateralis is composed of at least nine geographically separated and well-supported lineages that represent putative species. Biogeographic analysis suggests that Mantophryne evolved on the eastern Papuan peninsula with subsequent dispersal westward, as well as overwater dispersal events to the Louisiade and D'Entrecasteaux archipelagos. 23368510 Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin. AIM: Assess the pharmacodynamics of lixisenatide once daily (QD) versus liraglutide QD in type 2 diabetes insufficiently controlled on metformin. METHODS: In this 28-day, randomized, open-label, parallel-group, multicentre study (NCT01175473), patients (mean HbA1c 7.3%) received subcutaneous lixisenatide QD (10 µg weeks 1-2, then 20 µg; n = 77) or liraglutide QD (0.6 mg week 1, 1.2 mg week 2, then 1.8 mg; n = 71) 30 min before breakfast. Primary endpoint was change in postprandial plasma glucose (PPG) exposure from baseline to day 28 during a breakfast test meal. RESULTS: Lixisenatide reduced PPG significantly more than liraglutide [mean change in AUC(0) (:30-4:30h) : -12.6 vs. -4.0 h/mmol/l, respectively; p < 0.0001 (0:30 h = start of meal)]. Change in maximum PPG excursion was -3.9 mmol/l vs. -1.4 mmol/l, respectively (p < 0.0001). More lixisenatide-treated patients achieved 2-h PPG <7.8 mmol/l (69% vs. 29%). Changes in fasting plasma glucose were greater with liraglutide (-0.3 vs. -1.3 mmol/l, p < 0.0001). Lixisenatide provided greater decreases in postprandial glucagon (p < 0.05), insulin (p < 0.0001) and C-peptide (p < 0.0001). Mean HbA1c decreased in both treatment groups (from 7.2% to 6.9% with lixisenatide vs. 7.4% to 6.9% with liraglutide) as did body weight (-1.6 kg vs. -2.4 kg, respectively). Overall incidence of adverse events was lower with lixisenatide (55%) versus liraglutide (65%), with no serious events or hypoglycaemia reported. CONCLUSIONS: Once daily prebreakfast lixisenatide provided a significantly greater reduction in PPG (AUC) during a morning test meal versus prebreakfast liraglutide. Lixisenatide provided significant decreases in postprandial insulin, C-peptide (vs. an increase with liraglutide) and glucagon, and better gastrointestinal tolerability than liraglutide. 23576306 Carboxylate-Assisted Formation of Alkylcarbonate Species from CO2 and Tetramethylammonium Salts with a β-Amino Acid Anion. Tetramethylammonium-based molten salts bearing a β-amino acid anion (TMAAs) are synthesized through Michael addition reactions of amines with methyl acrylate followed by hydrolysis and subsequent neutralization by using aqueous tetramethylammonium hydroxide. The CO2 capture performances of the TMAAs are evaluated and are shown to interact with CO2 in a 1:1 mode in both water and alcohol. FTIR and (13) C NMR spectroscopic studies on the interactions of TMAAs with CO2 indicate that the type of CO2 adduct varies with the solvent used. When water is used as the solvent, a bicarbonate species is produced, whereas hydroxyethylcarbonate and methylcarbonate species are generated in ethylene glycol and methanol, respectively. Computational calculations show that the carboxylate groups of TMAAs contribute towards the formation and stabilization of 1:1 CO2 adducts through hydrogen bonding interactions with the hydrogen atoms of the amino groups. 23052192 Hard-metal (WC-Co) particles trigger a signaling cascade involving p38 MAPK, HIF-1α, HMOX1, and p53 activation in human PBMC. Hard-metals are made of tungsten carbide (WC) and metallic cobalt (Co) particles and are important industrial materials produced for their extreme hardness and high wear resistance properties. While occupational exposure to metallic Co alone is apparently not associated with an increased risk of cancer, the WC-Co particle mixture was shown to increase the risk of lung cancer in exposed workers. We have previously shown that WC-Co specifically induces a burst of reactive oxygen species (ROS) and in vitro mutagenic/apoptogenic effects in human peripheral blood mononucleated cells (PBMC) used as a validated experimental model. In the present study, PBMCs were treated during a short period (15 min) to focus on the very rapid ROS burst induced by WC-Co. We investigated by microarray the response to WC-Co versus Co(2+) ions (CoCl(2)) after 15 min exposure and found that the oxidative stress response HMOX1 gene was highly expressed in WC-Co-treated samples. This result was confirmed by qRT-PCR, and western blotting was carried out to analyze translational and post-translational regulation of genes belonging to the HMOX1 pathway. We show here that WC-Co, and metallic Co particles although with slower kinetics, but not CoCl(2) or WC alone, induced a temporally ordered cascade of events. This cascade implies p38/MAP kinase activation, HIF-1α stabilization, HMOX1 transcriptional activation, and ATM-independent p53 stabilization. These events, and in particular HIF-1α stabilization, could contribute to the carcinogenic activity of WC-Co dusts. 23495151 A cellular automata model of proton hopping down a channel. Proton hopping is the process where a H-atom on a hydronium ion forms a H-bond with the O-atom of a neighboring H(2)O molecule. There is then an exchange of bonding forces when that covalent bond of the H-atom in the hydronium ion changes to a H-bond, and the previous H-bond changes to a covalent bond with the neighboring O-atom. The neighboring molecule now becomes a hydronium (H(3)O(+)) ion. This process repeats itself very rapidly among neighboring hydronium and H(2)O molecules. There is a flow of protonic character through bulk H(2)O, referred to as proton hopping. This process carries information through living systems where H(2)O is present. A cellular automata model of proton hopping down a channel has been created and studied. Variations in the rate of proton entry into the channel and the effects of the polar character of the channel walls was studied using the model. The behavior of the models corresponds to experimental results. 23455592 Caloric restriction increases the sensitivity to the hyperphagic effect of nociceptin/orphanin FQ limiting its ability to reduce binge eating in female rats. RATIONALE: Nociceptin/orphanin FQ (N/OFQ) is a functional antagonist of corticotrophin-releasing factor, the main mediator of the stress response. Stress represents a key determinant of binge eating (BE) for highly palatable food (HPF). OBJECTIVES: In relation to the antistress properties of N/OFQ, we evaluated its effect on BE. After the observation that episodes of food restriction increase the sensitivity to its hyperphagic effects, the function of NOP receptor and N/OFQ was investigated after cycles of food restrictions. MATERIALS AND METHODS: In BE experiments, four groups were used: rats fed normally and not stressed or stressed, rats exposed to cycles of restriction/refeeding and then stressed, or not stressed. In the other experiments, two groups were used: rats exposed or not to food restriction. RESULTS: Only restricted and stressed rats exhibited BE for HPF (containing chocolate cream). Intracerebroventricular injections of N/OFQ of 0.5 nmol/rat significantly reduced BE. N/OFQ 1 nmol/rat did not reduce BE but significantly increased HPF intake following food restrictions. Cycles of food restriction increased animals' sensitivity to the hyperphagic effect of N/OFQ for HPF. In situ hybridization studies following food restrictions showed decreased ppN/OFQ mRNA expression in the bed nucleus of the stria terminalis and increased expression of ppN/OFQ and NOP receptor mRNA in the ventral tegmental area and in the ventromedial hypothalamus, respectively. CONCLUSIONS: These findings indicate that N/OFQ slightly reduces BE at low doses, while higher doses increase HPF intake, due to increased sensitivity to its hyperphagic effect following a history of caloric restrictions. 23376245 Inhibition of protein tyrosine phosphatases in spinal dorsal horn attenuated inflammatory pain by repressing Src signaling. Tyrosine phosphorylation of N-methyl-d-aspartate (NMDA) subtype glutamate receptors by Src-family protein tyrosine kinases (SFKs) plays a critical role in spinal sensitization. Besides SFKs, the tyrosine phosphorylation levels of proteins are also determined by protein tyrosine phosphatases (PTPs). However, whether PTPs are involved in spinal nociceptive processing is largely unknown. The present study found that intrathecal application of broad-spectrum PTPs inhibitors orthovanadate or Bpv (phen) generated little effects on the paw withdrawal thresholds of intact rats to Von Frey filament stimuli. Although the basal nociceptive responses didn't require the involvement of PTPs, the mechanical allodynia evoked by intrathecal injection of NMDA was greatly attenuated by orthovanadate and Bpv (phen), suggesting that PTPs activity, once stimulated by NMDA receptors, became essential for spinal sensitization. Biochemical analysis demonstrated that PTPs functioned to activate SFKs member Src and promote Src interaction with NR2B subunit-containing NMDA receptors (NR2B receptors). As a result, PTPs inhibition largely suppressed Src-mediated NR2B phosphorylation at Tyr1472 and reduced the synaptic concentration of NR2B receptors in spinal dorsal horn of NMDA-treated rats. Importantly, intraplantar injection of Complete Freund's Adjuvant (CFA) naturally activated spinal PTPs to initiate Src signaling, because PTPs inhibition significantly repressed Src activity, reduced Src phosphorylation of NR2B, decreased NR2B synaptic accumulation and eventually ameliorated inflammatory pain. These data indicated an important role played by spinal PTPs in inducing Src-dependent NR2B receptor hyperfunction and suggested that PTPs inhibition might represent an effective strategy for the treatment of inflammatory pain. 23123254 Assessing protection against OP pesticides and nerve agents provided by wild-type HuPON1 purified from Trichoplusia ni larvae or induced via adenoviral infection. Human paraoxonase-1 (HuPON1) has been proposed as a catalytic bioscavenger of organophosphorus (OP) pesticides and nerve agents. We assessed the potential of this enzyme to protect against OP poisoning using two different paradigms. First, recombinant HuPON1 purified from cabbage loopers (iPON1; Trichoplusia ni) was administered to guinea pigs, followed by exposure to at least 2times the median lethal dose (LD50) of the OP nerve agents tabun (GA), sarin (GB), soman (GD), and cyclosarin (GF), or chlorpyrifos oxon, the toxic metabolite of the OP pesticide chlorpyrifos. In the second model, mice were infected with an adenovirus that induced expression of HuPON1 and then exposed to sequential doses of GD, VX, or (as reported previously) diazoxon, the toxic metabolite of the OP pesticide diazinon. In both animal models, the exogenously added HuPON1 protected animals against otherwise lethal doses of the OP pesticides but not against the nerve agents. Together, the results support prior modeling and in vitro activity data which suggest that wild-type HuPON1 does not have sufficient catalytic activity to provide in vivo protection against nerve agents. 23473681 Degradation of MAC13243 and studies of the interaction of resulting thiourea compounds with the lipoprotein targeting chaperone LolA. The discovery of novel small molecules that function as antibacterial agents or cellular probes of biology is hindered by our limited understanding of bacterial physiology and our ability to assign mechanism of action. We previously employed a chemical genomic strategy to identify a novel small molecule, MAC13243, as a likely inhibitor of the bacterial lipoprotein targeting chaperone, LolA. Here, we report on the degradation of MAC13243 into the active species, S-(4-chlorobenzyl)isothiourea. Analogs of this compound (e.g., A22) have previously been characterized as inhibitors of the bacterial actin-like protein, MreB. Herein, we demonstrate that the antibacterial activity of MAC13243 and the thiourea compounds are similar; these activities are suppressed or sensitized in response to increases or decreases of LolA copy number, respectively. We provide STD NMR data which confirms a physical interaction between LolA and the thiourea degradation product of MAC13243, with a Kd of ~150 μM. Taken together, we conclude that the thiourea series of compounds share a similar cellular mechanism that includes interaction with LolA in addition to the well-characterized target MreB. 23139413 Long range effect of mutations on specific conformational changes in the extracellular loop 2 of angiotensin II type 1 receptor. The topology of the second extracellular loop (ECL2) and its interaction with ligands is unique in each G protein-coupled receptor. When the orthosteric ligand pocket located in the transmembrane (TM) domain is occupied, ligand-specific conformational changes occur in the ECL2. In more than 90% of G protein-coupled receptors, ECL2 is tethered to the third TM helix via a disulfide bond. Therefore, understanding the extent to which the TM domain and ECL2 conformations are coupled is useful. To investigate this, we examined conformational changes in ECL2 of the angiotensin II type 1 receptor (AT1R) by introducing mutations in distant sites that alter the activation state equilibrium of the AT1R. Differential accessibility of reporter cysteines introduced at four conformation-sensitive sites in ECL2 of these mutants was measured. Binding of the agonist angiotensin II (AngII) and inverse agonist losartan in wild-type AT1R changed the accessibility of reporter cysteines, and the pattern was consistent with ligand-specific "lid" conformations of ECL2. Without agonist stimulation, the ECL2 in the gain of function mutant N111G assumed a lid conformation similar to AngII-bound wild-type AT1R. In the presence of inverse agonists, the conformation of ECL2 in the N111G mutant was similar to the inactive state of wild-type AT1R. In contrast, AngII did not induce a lid conformation in ECL2 in the loss of function D281A mutant, which is consistent with the reduced AngII binding affinity in this mutant. However, a lid conformation was induced by [Sar(1),Gln(2),Ile(8)] AngII, a specific analog that binds to the D281A mutant with better affinity than AngII. These results provide evidence for the emerging paradigm of domain coupling facilitated by long range interactions at distant sites on the same receptor. 23546525 Azidoacetylene - interpretation of gas phase infrared spectra based on high-level vibrational configuration interaction calculations. Azidoacetylene is a highly explosive substance, which has been synthesized and characterized for the first time quite recently [Banert et al., Angew. Chem., Int. Ed., 2012, 51, 7515]. As outlined in this work, the vibrational spectrum of azidoacetylene is dominated by strong couplings. For that reason, we have studied the vibrational spectrum of the title compound by gas phase measurements and high-level vibrational structure calculations beyond the harmonic approximation. Based on the interplay of theory and experiment, we were able to identify all fundamentals, strong Fermi resonances and intense overtones, which contribute to the spectrum. 23591777 Hepatoprotective effect of methylsulfonylmethane against carbon tetrachloride-induced acute liver injury in rats. This study evaluated the effect of methylsulfonylmethane (MSM) on carbon tetrachloride (CCl4)-induced acute liver injury in rats. A single injection of CCl4 (2 ml/kg, i.p.) increased serum aminotransferases (ALT and AST) activities. In addition, CCl4 treatment led to elevation of hepatic malondialdehyde (MDA) content as well as decrease in superoxide dismutase (SOD) and catalase (CAT) activities. Furthermore, cytochrome P450 2E1 (CYP2E1) content was suppressed while proinflammatory cytokines tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels increased in liver tissue after CCl4 administration. We showed that acute CCl4-induced damage was accompanied by a rise in Bax/Bcl2 ratio indicating apoptosis. Pre-treatment with MSM (400 mg/kg) inhibited the increases of serum ALT and AST activities, decreased hepatic MDA, TNF-α, IL-6 and Bax/Bcl2 ratio compared to CCl4 treated group. On the other hand, MSM raised SOD and CAT activities as well as CYP2E1 level in liver tissues. The present study shows that MSM possesses a hepatoprotective effect against CCl4-induced liver injury in rats. This protective effect might be through its antioxidant, anti-inflammatory and antiapoptotic properties. 23012257 DCPIB, the proposed selective blocker of volume-regulated anion channels, inhibits several glutamate transport pathways in glial cells. 4-(2-Butyl-6,7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid (DCPIB) was identified as the selective blocker of volume-regulated anion channels (VRAC). VRAC are permeable to small inorganic and organic anions, including the excitatory neurotransmitter glutamate. In recent years DCPIB has been increasingly used for probing the physiologic and pathologic roles of VRAC and was found to potently suppress pathologic glutamate release in cerebral ischemia. Because ischemic glutamate release can be mediated by a plethora of mechanisms, in this study we explored the selectivity of DCPIB toward the majority of previously identified glutamate transporters and permeability pathways. l-[(3)H]glutamate, d-[(3)H]aspartate, and l-[(14)C]cystine were used to trace amino acid release and uptake. We found that in addition to its well-characterized effect on VRAC, DCPIB potently inhibited glutamate release via connexin hemichannels and glutamate uptake via the glutamate transporter GLT-1 in rat glial cells. In contrast, DCPIB had no direct effect on vesicular glutamate release from rat brain synaptosomes or the cystine/glutamate exchange in astrocytes. The compound did not affect the astrocytic glutamate transporter GLAST, nor did it block glutamate release via the P2X(7)/pannexin permeability pathway. The ability of DCPIB to directly block connexin hemichannels was confirmed using a gene-specific siRNA knockdown approach. Overall, our data demonstrate that DCPIB influences several glutamate transport pathways and that its effects on VRAC in vivo should be verified using additional pharmacological controls. 23477451 Isocoumarin Derivatives and Benzofurans from a Sponge-Derived Penicillium sp. Fungus. Ten new fungal metabolites, including three hydroisocoumarins, penicimarins A-C (1-3), three isocoumarins, penicimarins D-F (6-8), and four benzofurans, penicifurans A-D (11-14), together with four known isocoumarin derivatives (4, 5, 9, 10), were obtained from the sponge-derived fungus Penicillium sp. MWZ14-4, collected from the South China Sea. Their planar structures and relative configurations were elucidated by detailed analysis of spectroscopic data and by comparison with related known compounds. The absolute configurations of 1-4 were assigned by the modified Mosher's method and TDDFT ECD calculations together with comparison of their CD spectra. Compound 1 represents a rare naturally occurring isocoumarin derivative with 4-substitution, but no substituent at the 3-position. These compounds were evaluated for antibacterial activities and cytotoxic activities in vitro. Among them, penicifuran A (11) exhibited inhibitory activity against Staphylococcus albus with an MIC value of 3.13 μM. 23386599 The role of human carboxylesterases in drug metabolism: have we overlooked their importance? Carboxylesterases are a multigene family of mammalian enzymes widely distributed throughout the body that catalyze the hydrolysis of esters, amides, thioesters, and carbamates. In humans, two carboxylesterases, hCE1 and hCE2, are important mediators of drug metabolism. Both are expressed in the liver, but hCE1 greatly exceeds hCE2. In the intestine, only hCE2 is present and highly expressed. The most common drug substrates of these enzymes are ester prodrugs specifically designed to enhance oral bioavailability by hydrolysis to the active carboxylic acid after absorption from the gastrointestinal tract. Carboxylesterases also play an important role in the hydrolysis of some drugs to inactive metabolites. It has been widely believed that drugs undergoing hydrolysis by hCE1 and hCE2 are not subject to clinically significant alterations in their disposition, but evidence exists that genetic polymorphisms, drug-drug interactions, drug-disease interactions and other factors are important determinants of the variability in the therapeutic response to carboxylesterase-substrate drugs. The implications for drug therapy are far-reaching, as substrate drugs include numerous examples from widely prescribed therapeutic classes. Representative drugs include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antiplatelet drugs, statins, antivirals, and central nervous system agents. As research interest increases in the carboxylesterases, evidence is accumulating of their important role in drug metabolism and, therefore, the outcomes of pharmacotherapy. 23411189 Determination of ethylenediaminetetraacetic acid in foods by reversed-phase high-performance liquid chromatography. A convenient HPLC method for the quantitative determination of EDTA in foods was developed. EDTA in food samples was easily extracted with water by ultrasonication. After converting to Fe(III) complex in the presence of Fe(III) ions, EDTA was separated on a reversed-phase C30 column and detected with ultraviolet detection (260 nm). Citrate and malate, which are present in many foods, also formed Fe(III) complexes but they did not interfere the chromatographic detection of EDTA. The method allowed determination of EDTA in foods at concentrations as low as 0.01 mmol/kg. Good recoveries (95.2-101%) were obtained by the standard addition method on four samples with high repeatability (RSD, 0.8-3.4%). The method was successfully applied to the analysis of EDTA in carbonated drinks, jellies, canned beans, canned corn and food supplements. 23411239 Development of apple certified reference material for quantification of organophosphorus and pyrethroid pesticides. An apple certified reference material for the analysis of pesticide residues was issued by the National Metrology Institute of Japan. Organophosphorus and pyrethroid pesticides were sprayed on apples, and these were used as raw materials of certified reference material. The harvested apples were cut into small pieces, freeze-dried, pulverized, sieved, placed into 200 brown glass bottles (3g each), and sterilized by γ-irradiation. Stability and homogeneity assessment was performed, and the relative uncertainties due to instability (for an expiry date of 32 months) and inhomogeneity were 10.3-25.0% and 4.0-6.8%, respectively. The characterization was carried out using multiple analytical methods to ensure the reliability of analytical results; the values of target pesticides were obtained by isotope dilution mass spectrometry. Certified values were 2.28 ± 0.82 mg/kg for diazinon, 3.14 ± 0.79 mg/kg for fenitrothion, 1.55 ± 0.81 mg/kg for cypermethrin, and 2.81 ± 0.70 mg/kg for permethrin. 23583775 Unraveling Hidden Regulatory Sites in Structurally Homologous Metalloproteases. Monitoring enzymatic activity in vivo of individual homologous enzymes such as the matrix metalloproteinases (MMPs) by antagonist molecules is highly desired for defining physiological and pathophysiological pathways. However, the rational design of antagonists targeting enzyme catalytic moieties specific to one of the homologous enzymes often appears to be an extremely difficult task. This is mainly due to the high structural homology at the enzyme active sites shared by members of the protein family. Accordingly, controlling enzymatic activity via alternative allosteric sites has become an attractive proposition for drug design targeting individual homologous enzymes. Yet, the challenge remains to identify such regulatory alternative sites that are often hidden and scattered over different locations on the protein's surface. We have designed branched amphiphilic molecules exhibiting specific inhibitory activity towards individual members of the MMP family. These amphiphilic isomers share the same chemical nature, providing versatile nonspecific binding reactivity that allows to probe hidden regulatory residues on a given protein surface. Using the advantage provided by amphiphilic ligands, here we explore a new approach for determining hidden regulatory sites. This approach includes diverse experimental analysis, such as structural spectroscopic analyses, NMR, and protein crystallography combined with computational prediction of effector binding sites. We demonstrate how our approach works by analyzing members of the MMP family that possess a unique set of such sites. Our work provides a proof of principle for using ligand effectors to unravel hidden regulatory sites specific to members of the structurally homologous MMP family. This approach may be exploited for the design of novel molecular effectors and therapeutic agents affecting protein catalytic function via interactions with structure-specific regulatory sites. 23322164 Carnitine palmitoyltransferase 2 and carnitine/acylcarnitine translocase are involved in the mitochondrial synthesis and export of acylcarnitines. Acylcarnitines are commonly used in the diagnosis of mitochondrial fatty acid β-oxidation disorders (mFAODs). It is generally assumed that this plasma acylcarnitine profile reflects the mitochondrial accumulation of acyl-CoAs. The identity of the enzymes and the mitochondrial and plasmalemmal transporters involved in the synthesis and export of these metabolites have remained undefined. We used lentiviral shRNA to knock down the expression of medium-chain acyl-CoA dehydrogenase (MCAD) in control and carnitine palmitoyltransferase 2 (CPT2)-, carnitine/acylcarnitine translocase (CACT)-, and plasmalemmal carnitine transporter (OCTN2)-deficient human fibroblasts. These cell lines, including mock-transduced controls, were loaded with decanoic acid and carnitine, followed by the measurement of the acylcarnitine profile in the extracellular medium. In control fibroblasts, MCAD knockdown markedly increased the production of octanoylcarnitine (3-fold, P<0.01). OCTN2-deficient cell lines also showed extracellular accumulation of octanoylcarnitine (2.8-fold, P<0.01), suggesting that the cellular export of acylcarnitines does not depend on OCTN2. In contrast, in CPT2- and CACT-deficient cells, the accumulation of octanoylcarnitine in the medium did not significantly increase in the MCAD knockdown. Similar results were obtained using pharmacological inhibition of CPT2 in fibroblasts from MCAD-deficient individuals. This shows that CPT2 and CACT are crucial for mitochondrial acylcarnitine formation and export to the extracellular fluids in mFAOD.-Violante, S., IJlst, L., te Brinke, H., Tavares de Almeida, I., Wanders, R. J. A., Ventura, F. V., Houten, S. M. Carnitine palmitoyltransferase 2 and carnitine/acylcarnitine translocase are involved in the mitochondrial synthesis and export of acylcarnitines. 23266501 In vitro anti-inflammatory effect of apigenin in the Helicobacter pylori-infected gastric adenocarcinoma cells. Infection with Helicobacter pylori causes extensive gastric epithelial cell inflammation which may progress to atrophic gastritis, intestinal metaplasia, and even gastric adenocarcinoma. Apigenin (4',5,7-trihydroxyflavone) is widely distributed in fruits and vegetables, and is a well-known antiinflammatory supplement with low cytotoxicity. In this study, we investigated the anti-inflammatory effects of apigenin in H. pylori-infected MKN45 cells, for which IκBα, cyclooxygenase-2 (COX-2), intercellular adhesion molecule-1 (ICAM-1), reactive oxygen species (ROS), interleukin-8 (IL-8), IL-6, IL-1β, and mucin-2 (MUC-2) expressions were examined. Apigenin treatments (9.3-74 μM) significantly increased the IκBα expression, and thus inhibited nuclear factor kappa B (NF-κB) activation, and the inflammatory factor (COX-2, ICAM-1, ROS, IL-6, and IL-8) expressions decreased. The ROS levels decreased partially based on the intrinsic scavenging property of apigenin. In summary, apigenin treatments effectively inhibited NF-κB activation and the related inflammatory factor expressions, as well as increased MUC-2 expression in the H. pylori-infected MKN45 cells. The compound shows great potential as a candidate agent for the inhibition of H. pylori-induced extensive gastric epithelial cell inflammation. 23489301 Cardiovascular safety of the dipetidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus(†) AIM: As there have been concerns that some classes or agents for the treatment of type 2 diabetes may increase CV risk, we evaluated the cardiovascular profile of the dipeptidyl peptidase-4 inhibitor alogliptin. METHODS: We evaluated the incidence of CV events in patients treated with alogliptin, placebo or comparator antihyperglycaemic drugs in the clinical trial database for alogliptin using the composite major adverse cardiovascular event (MACE) endpoints of CV death, non-fatal myocardial infarction and non-fatal stroke. RESULTS: The pooled analysis included 4168 patients exposed to alogliptin 12.5 and 25 mg daily for 2023 patient-years compared to 691 patients treated with placebo for 263 patient-years and 1169 patients treated with other antidiabetic agents (metformin, sulfonylureas and thiazolidinediones) for 703 patient-years. CV events were adjudicated by an expert endpoint committee blinded to treatment allocation. The incidence rates of the combined MACE were not significantly different between patients treated with alogliptin and comparator therapies (hazard ratio=0.635, 95% confidence interval, 0.0, 1.41). Additionally, other types of serious CV events were not significantly different between patients treated with alogliptin and comparator therapies. CONCLUSION: These analyses have not shown a signal of increased CV risk with alogliptin in patients with type 2 diabetes. Future results from the adequately powered EXAMINE trial will definitively assess the CV safety profile of aloglipin in patients with type 2 diabetes mellitus. 23410105 Toward a physically based quantitative modeling of impact sensitivities. Among the subsequent steps leading from impact to explosive decomposition in nitro compounds, the ability of early exothermic reactions to trigger the decomposition of neighboring molecules before the released energy has dissipated away is assumed to be critical. The rate of this process is roughly estimated using as inputs the energy content and the dissociation energy of the weakest X-NO2 bonds. While the sensitivity index thus obtained was previously shown to exhibit striking correlations with gap test pressures, its correlation with drop weight impact test data is poorer. Nevertheless, considering four different subsets of molecules depending on the environment of the most labile nitro groups, straightforward regressions against this sensitivity index yield a practical method to estimate impact sensitivity, whose combination of fair performance and generality is provided by no alternative approach, except purely empirical models based on extensive parametrization. 23135892 Protein-size molecularly imprinted polymer nanogels as synthetic antibodies, by localized polymerization with multi-initiators. A new approach is proposed for the synthesis of molecularly imprinted polymers (MIPs) (synthetic antibodies) as soluble nanogels with sizes close to the size of real antibodies. To imprint a molecular memory in particles consisting of only a few polymer chains, an initiator carrying multiple iniferter moieties is used. This allows for the simultaneous initiation of several polymer chains, and yields molecularly imprinted nanogels (17 nm, molecular weight (MW) = 97 kDa) with good affinity and selectivity for the target. 23343325 Effective optical Faraday rotations of semiconductor EuS nanocrystals with paramagnetic transition-metal ions. Novel EuS nanocrystals containing paramagnetic Mn(II), Co(II), or Fe(II) ions have been reported as advanced semiconductor materials with effective optical rotation under a magnetic field, Faraday rotation. EuS nanocrystals with transition-metal ions, EuS:M nanocrystals, were prepared by the reduction of the Eu(III) dithiocarbamate complex tetraphenylphosphonium tetrakis(diethyldithiocarbamate)europium(III) with transition-metal complexes at 300 °C. The EuS:M nanocrystals thus prepared were characterized using X-ray diffraction (XRD), transmission electron microscopy (TEM), inductively coupled plasma atomic emission spectroanalysis (ICP-AES), and a superconducting quantum interference device (SQUID) magnetometer. Enhanced Faraday rotations of the EuS:M nanocrystals were observed around 550 nm, and their enhanced spin polarization was estimated using electron paramagnetic resonance (EPR) measurements. In this report, the magneto-optical relationship between the Faraday rotation efficiency and spin polarization is discussed. 23597047 2012 Philip S. Portoghese Medicinal Chemistry Lectureship: Structure-Based Approaches to Ligands for G Protein-Coupled Adenosine and P2Y Receptors, From Small Molecules to Nanoconjugates. Adenosine receptor (ARs) and P2Y receptors (P2YRs) that respond to extracellular nucleosides/tides are associated with new directions for therapeutics. The X-ray structures of the A2AAR complexes with agonists and antagonists are examined in relationship to the G protein-coupled receptor (GPCR) superfamily and applied to drug discovery. Much of the data on AR ligand structure from early SAR studies, now is explainable from the A2AAR X-ray crystallography. The ligand-receptor interactions in related GPCR complexes can be identified by means of modeling approaches, e.g. molecular docking. Thus, molecular recognition in binding and activation processes has been studied effectively using homology modeling and applied to ligand design. Virtual screening has yielded new nonnucleoside AR antagonists, and existing ligands have been improved with knowledge of the receptor interactions. New agonists are being explored for CNS and peripheral therapeutics based on in vivo activity, such as chronic neuropathic pain. Ligands for receptors more distantly related to the X-ray template, i.e. P2YRs, have been introduced and are mainly used as pharmacological tools for elucidating the physiological role of extracellular nucleotides. Other ligand tools for drug discovery include fluorescent probes, radioactive probes, multivalent probes, and functionalized nanoparticles. 23505344 A computational study of water and CO migration sites and channels inside myoglobin. Pathways are computed for transport of H2O and CO in myoglobin (Mb), using the single sweep and zero-temperature string methods in a fully atomistic, explicitly solvated model system. Our predictions of sites and barriers in the pathways for CO transport agree with previous studies. For H2O, we predict a binding site in the distal pocket (DP), in agreement with crystallographic observations, and another one close to Leu 29 which explains the importance of this residue in controlling the pocket's hydrophobicity, as well as disordered minima in the largely apolar xenon cavities. In particular, H2O can occupy and transition among the xenon cavities, Xe4, Xe2, and Xe3. Our results support the hypothesis that the thermodynamically most favorable entry/exit portal for H2O is the so-called histidine gate (HG), the same as for CO. This result, along with the observation of water occupation of both DP and apolar Xe cavities, suggest that water and small gas molecules like CO compete for access to the protein interior, and therefore models of gas molecule transport within proteins should also explicitly consider water transport. 23474688 Nitrogen doped holey graphene as an efficient metal-free multifunctional electrochemical catalyst for hydrazine oxidation and oxygen reduction. Electrocatalysts for anode or cathode reactions are at the heart of electrochemical energy conversion and storage devices. Molecular design of carbon based nanomaterials may create the next generation electrochemical catalysts for broad applications. Herein, we present the synthesis of a three-dimensional (3D) nanostructure with a large surface area (784 m(2) g(-1)) composed of nitrogen doped (up to 8.6 at.%) holey graphene. The holey structure of graphene sheets (~25% of surface area is attributed to pores) engenders more exposed catalytic active edge sites. Nitrogen doping further improves catalytic activity, while the formation of the 3D porous nanostructure significantly reduces graphene nanosheet stacking and facilitates the diffusion of reactants/electrolytes. The three factors work together, leading to superb electrochemical catalytic activities for both hydrazine oxidation (its current generation ability is comparable to that of 10 wt% Pt-C catalyst) and oxygen reduction (its limiting current is comparable to that of 20 wt% Pt-C catalyst) with four-electron transfer processes and excellent durability. 23078542 Cell loss and autophagy in the extra-adrenal chromaffin organ of Zuckerkandl are regulated by glucocorticoid signalling. Neuroendocrine chromaffin cells exist in both intra- and extra-adrenal locations; the organ of Zuckerkandl (OZ) constitutes the largest accumulation of extra-adrenal chromaffin tissue in mammals. The OZ disappears postnatally by modes that are still enigmatic but can be maintained by treatment with glucocorticoids (GC). Whether the response to GC reflects a pharmacological or a physiological role of GC has not been clarified. Using mice with a conditional deletion of the GC-receptor (GR) gene restricted to cells expressing the dopamine β-hydroxylase (DBH) gene [GR(fl/fl) ; DBHCre abbreviated (GR(DBHCre) )], we now present the first evidence for a physiological role of GC signalling in the postnatal maintenance of the OZ: postnatal losses of OZ chromaffin cells in GR(DBHCre) mice are doubled compared to wild-type littermates. We find that postnatal cell loss in the OZ starts at birth and is accompanied by autophagy. Electron microscopy reveals autophagic vacuoles and autophagolysosomes in chromaffin cells. Autophagy in OZ extra-adrenal chromaffin cells is confirmed by showing accumulation of p62 protein, which occurs, when autophagy is blocked by deleting the Atg5 gene (Atg5(DBHCre) mice). Cathepsin-D, a lysosomal marker, is expressed in cells that surround chromaffin cells and are positive for the macrophage marker BM8. Macrophages are relatively more abundant in mice lacking the GR, indicating more robust elimination of degenerating chromaffin cells in GR(DBHCre) mice than in wild-type littermates. In summary, our results indicate that extra-adrenal chromaffin cells in the OZ show signs of autophagy, which accompany their postnatal numerical decline, a process that is controlled by GR signalling. 23042954 Efficacy of the GluK1/AMPA receptor antagonist LY293558 against seizures and neuropathology in a soman-exposure model without pretreatment and its pharmacokinetics after intramuscular administration. Control of brain seizures after exposure to nerve agents is imperative for the prevention of brain damage and death. Animal models of nerve agent exposure make use of pretreatments, or medication administered within 1 minute after exposure, in order to prevent rapid death from peripheral toxic effects and respiratory failure, which then allows the testing of anticonvulsant compounds. However, in a real-case scenario of an unexpected attack with nerve agents, pretreatment would not be possible, and medical assistance may not be available immediately. To determine if control of seizures and survival are still possible without pretreatment or immediate pharmacologic intervention, we studied the anticonvulsant efficacy of the GluK1 (GluR5)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid (LY293558) in rats that did not receive any treatment until 20 minutes after exposure to the nerve agent soman. We injected LY293558 intramuscularly, as this would be the most likely route of administration to humans. LY293558 (15 mg/kg), injected along with atropine and the oxime HI-6 at 20 minutes after soman exposure, stopped seizures and increased survival rate from 64% to 100%. LY293558 also prevented neuronal loss in the amygdala and hippocampus, and reduced neurodegeneration in a number of brain regions studied 7 days after soman exposure. Analysis of the LY293558 pharmacokinetics after intramuscular administration showed that this compound readily crosses the blood-brain barrier. There was good correspondence between the time course of seizure suppression by LY293558 and the brain levels of the compound. 23277104 Identification and expression of multiple CYP1-like and CYP3-like genes in the bivalve mollusk Mytilus edulis. Various sequencing projects over the last several years have aided the discovery of previously uncharacterized invertebrate sequences, including new cytochrome P450 genes (CYPs). Here we present data on the identification and characterization of two CYP1-like and three CYP3-like genes from the bivalve mollusk Mytilus edulis, and assess their potential as biomarkers based on their responses to several known vertebrate aryl hydrocarbon receptor (AHR) agonists. Quantitative real-time PCR was used to measure CYP transcript levels in digestive gland, labial palps, adductor muscle, gill, foot, and different regions of the mantle. Levels of both CYP1-like genes were highest in digestive gland, whereas labial palps had the highest expression levels of the three CYP3-like genes followed by digestive gland and outer margin of the mantle. Mussels were exposed by injection to the AHR agonists, β-naphthoflavone (BNF; 25 μg g(-1)), 3,3',4,4',5-polychlorinated biphenyl (PCB126; 2 μg g(-1)), or 6-formylindolo[3,2-b]carbazole (FICZ; 0.1 μg g(-1)), or to Aroclor 1254 (a mixture of PCBs; 50 μg g(-1)) for 24 h, followed by CYP expression analysis. There was no statistically significant change in expression of either of the CYP1-like genes after exposure to the various AHR agonists. The CYP3-like-1 gene was significantly up-regulated by BNF in gill tissues and the CYP3-like-2 gene was up-regulated in digestive gland by PCB126 and in gill tissue by BNF. These results suggest that distinct mechanisms of CYP gene activation could be present in M. edulis, although the importance of the CYP1-like and CYP3-like genes for xenobiotic and endogenous lipids biotransformation requires additional investigation. 23387851 Sigma receptor modulators: a patent review. Introduction: Sigma receptors are involved in several central nervous system (CNS) disorders, including mood disorders (depression and anxiety), psychosis, schizophrenia, movement disorders (i.e., Parkinson's disease) and memory deficits (i.e., Alzheimer's disease). Recently, the involvement of sigma receptors in neuropathic pain and cancer has also been observed. Areas covered: This review aims at highlighting the research advancements published in the patent literature between 1986 and 2012, dividing patents according to both their time frame and applicants. The review especially focuses on the development of sigma receptor modulators and their application over the years with respect to CNS diseases, neuropathic pain and neurodegenerative pathologies. The literature was sought through Espacenet, Orbit, ISI Web and PubMed databases. Expert opinion: In recent years, considerable progress in the knowledge of the biology and pharmacology of sigma receptors has encouraged research on the potential benefits of sigma modulators in a wide range of pathologies. So far, only few potent agonists and antagonists of sigma receptors are in clinical trial for acute and chronic neurodegenerative diseases (SA4503 and ANAVEX 2-73) or neuropathic pain (E-52862). 23602516 Cisplatin-induced cell death in Saccharomyces cerevisiae is programmed and rescued by proteasome inhibition. Cisplatin is a highly effective chemotherapeutic drug used in the treatment of several tumors. It is a DNA-damaging agent that induces apoptosis of rapidly proliferating cells, an important factor underlying its therapeutic efficacy. Unfortunately, cellular resistance occurs often. A large fraction of tumor cells harbor mutations in p53, contributing to defects in apoptotic pathways and drug resistance. However, cisplatin-induced apoptosis can also occur in p53 deficient cells; thus, elucidation of the molecular mechanism involved will potentially yield new strategies to eliminate tumors that have defects in the p53 pathway. Most of the studies in this field have been conducted in cultured mammalian cells, not amenable to systematic genetic manipulation. Therefore, we aimed to establish a simplified model devoid of a p53 ortholog to study cisplatin-induced programmed cell death (PCD), using the yeast Saccharomyces cerevisiae. Our results indicate cisplatin induces an active form of cell death in yeast, as this process was partially dependent on de novo protein synthesis and did not lead to loss of membrane integrity. Cisplatin also increased DNA condensation and fragmentation/degradation, but no significant mitochondrial dysfunction other than partial fragmentation. Co-incubation with the proteasome inhibitor MG132 increased resistance to cisplatin and, accordingly, yeast strains deficient in proteasome activity were more resistant to cisplatin than wild-type strains. Proteasome inhibitors can sensitize tumor cells to cisplatin, but protect others from cisplatin-induced cell death. Our results indicate inhibition of the proteasome protects budding yeast from cisplatin-induced cell death and validate yeast as a model to study the role of the proteasome in cisplatin-induced PCD. Elucidation of this mechanism will aid in the development of new strategies to increase the efficacy of chemotherapy. 23317163 Cellular signaling crosstalk between multiple receptors for investigation of pathophysiology in multifactorial diseases--what is clinically-relevant crosstalk? Recently, genomics and proteomics have been utilized as advanced tools for investigation of cellular signaling pathways and molecular interactions, and elucidated promiscuous networks composed of numerous interactions among pathways. However, some of these interactions are considered to be simply contributing to background 'noise' and others are as 'crosstalk' biologically-relevant to cellular physiology, leading to synergy effects more than additive responses in an entire organism. Effort is now required to determine which interactions truly contribute to final physiological output. A receptor is the prime example of connectors among the networks. It functions, not simply as a signaling gateway, but also as an active trader by forming inter-receptor dimers. Furthermore, various receptors can modulate the function of the other receptors by input to common intracellular signaling pathways, establishing functional crosstalk among networks. Our findings by combined analyses of gene polymorphisms of two separate genes present evidences that such is the case with human body in a clinical setting: 1) an integrated effect of epidermal growth factor receptor (EGFR) and protease activated receptor-1 (PAR-1) on susceptibility to airway hyperresponsiveness (AHR), and 2) a crosstalk effect between muscarinic acetylcholine receptor (mAChRs) and β(2) adrenoceptor (β(2)AR) on bronchodilatory response to anticholinergic agents in patients with COPD. These results indicate that these interactions are unlikely to be 'noise' but functionally-relevant 'crosstalk' in a human body. This review attempts to highlight the clinically-relevant 'crosstalk' paradigm in a human body which provides us a novel insight necessary to investigate pathophysiology in common multifactorial diseases and to develop new drugs. 23422733 Co-extrusion as manufacturing technique for multilayer mini-matrices with dual drug release. The aim of this work was to develop by means of co-extrusion a multilayered dosage form characterized by a dual release profile of the same drug. Co-extrudates consisted of two concentric polymer matrices: a core having a lipophilic character and a coat with a hydrophilic character. Diclofenac sodium (DS) was incorporated as model drug in both layers. Several polymers were screened on the basis of their processability via hot melt extrusion (HME) and in vitro drug release. Polymer combinations with suitable properties (i.e., similar extrusion temperature, appropriate drug release profile) were processed via co-extrusion. (Co-) extruded samples were characterized in terms of solid state (XRD, SEM), in vitro drug release, core/coat adhesion, and bioavailability. Based on the polymer screening, two polymer combinations were selected for co-extrusion: ethylcellulose (core) combined with Soluplus® (coat) and polycaprolactone (core) with PEO (coat). These combinations were successfully co-extruded. XRD revealed that DS remained crystalline during extrusion in ethylcellulose, Soluplus®, polycaprolactone, and PEO. The polycaprolactone/PEO combination could be processed at a lower temperature (70°C), vs. 140°C for ethylcellulose/Soluplus®. The maximum drug load in core and coat depended on the extrusion temperature and the die dimensions, while adhesion between core and coat was mainly determined by the drug load and by the extrusion temperature. In vitro drug release from the co-extruded formulations was reflected in the in vivo behavior: formulations with a higher DS content in the coat (i.e., faster drug release) resulted in higher Cmax and higher AUC values. Co-extrusion is a viable method to produce in a single step a multilayer dosage form with dual drug release. 22288603 Allelopathic activity studies of Mikania scandens. Preliminary investigation of a number of plant extracts for allelopathic activity using seed germination inhibition bioassay showed a promising activity of the water extract of the aerial parts of Mikania scandens. Activity-guided fractionation of the M. scandens extract led to the isolation of the highly allelopathic active compound mikanolide, with minimum inhibitory concentration of 0.083 µM mL(-1). As M. scandens is a highly abundant invasive plant in Sri Lanka and other South Asian countries, this plant could be developed as an environment friendly natural herbicide, either in crude form as shredded plant material or as pure mikanolide, which is the major constituent (∼0.02%) in the plant. 23592568 Design, Synthesis and Biological Evaluation of Trimethine Cyanine Dyes as Fluorescent Probes for the Detection of Tau Fibrils in Alzheimer's Disease Brain and Olfactory Epithelium. Shedding light on grey matter: Fluorescent trimethine cyanines were evaluated as imaging probes for neurofibrillary tangles in post-mortem brain sections of Alzheimer's disease patients. These probes bind to neurofibrillary tangles with high contrast and selectivity over amyloid β plaques. 23017388 SB365, Pulsatilla saponin D suppresses the proliferation of human colon cancer cells and induces apoptosis by modulating the AKT/mTOR signalling pathway. Pulsatilla koreana has been used as a traditional medicine for the treatment of several diseases. The purpose of this study was to determine if SB365, Pulsatilla saponin D isolated from the root of P. koreana inhibits the progression of colon cancer. We found that SB365 strongly suppressed the growth and proliferation of colon cancer cells and induced their apoptosis. Also, SB365 showed anti-angiogenic activity by decreasing the expression of HIF-1α and VEGF. These results were confirmed by an in vivo study showing that SB365 significantly inhibited tumor growth by the induction of apoptosis and inhibition of angiogenesis with stronger anticancer activity than 5-FU. When further examined for its anticancer mechanism, SB365 effectively suppressed the AKT/mTOR pathway both in vitro and in vivo. Taken together, our study demonstrated that SB365 inhibits the AKT/mTOR pathway, leading to the suppression of tumor growth and angiogenesis together with induction of apoptosis. Therefore, SB365 is a good candidate as a natural product for use in the treatment of colon cancer. 23371763 Anisotropically Luminescent Hydrogels Containing Magnetically-Aligned MWCNTs-Eu(III) Hybrids. The anisotropic emission properties of an Eu(III)-MWCNTs-based nanocomposite PNIPAAm hydrogel is induced upon application of a 10 T magnetic field, the latter dictating the alignment of the carbon nanotubes. This structuration creates directional highways for light to be preferentially absorbed, giving rise to orientation-dependent light emission intensity. Thermal control of the transparency of the aqueous matrix also allowed a stimulus-induced switching of the materials' emission properties. 23568508 Rhenium Complexes with Visible-Light-Induced Anticancer Activity. Shedding light on the matter: Rhenium(I) indolato complexes with highly potent visible-light-triggered antiproliferative activity (complex 1: EC50 light=0.1 μM vs EC50 dark=100 μM) in 2D- and 3D-organized cancer cells are reported and can be traced back to an efficient generation of singlet oxygen, causing rapid morphological changes and an induction of apoptosis. 23597071 Fabrication of Quantum Dot Microarrays Using Electron Beam Lithography for Applications in Analyte Sensing and Cellular Dynamics. Quantum dot (QD) based micro-/nanopatterned arrays are of broad interest in applications ranging from electronics, photonics, to sensor devices for biomedical purposes. Here, we report on a rapid, physico-chemically mild approach to generate high fidelity micropattern arrays of prefunctionalized water-soluble quantum dots using electron beam lithography. We show that such patterns retain their fluorescence and bioaffinity upon electron beam lithography and, based on the streptavidin-biotin interaction, allow for detection of proteins, colloidal gold nanoparticles and magnetic microparticles. Furthermore, we demonstrate the applicability of QD based microarray patterns differing in their shape (circles, squares, grid-like), size (from 1 to 10 μm) and pitch distance to study the adhesion, spreading and migration of human blood derived neutrophils. Using live cell confocal fluorescence microscopy, we show that pattern geometry and pitch distance influence the adhesion, spreading and migratory behavior of neutrophils. Research reported in this work paves the way for producing QD microarrays with multiplexed functionalities relevant for applications in analyte sensing and cellular dynamics. 23098818 The catalytic competence of cytochrome P450 in the synthesis of serotonin from 5-methoxytryptamine in the brain: an in vitro study. Brain serotonin has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs. The aim of present study was to identify rat cytochrome P450 (CYP) isoforms which can catalyze the O-demethylation of 5-methoxytryptamine to serotonin, and to find out whether that alternative pathway of serotonin synthesis may take place in the brain. The study was conducted on cDNA-expressed CYPs (rat CYP1A1/2, 2A1/2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6), on rat brain and liver microsomes and on human liver microsomes (the wild-type CYP2D6 or the allelic variant 2D6*4*4). Of the rat CYP isoforms studied, CYP2D isoforms were the most efficient in catalyzing the O-demethylation of 5-methoxytryptamine to serotonin, but they were less effective than the human isoform CYP2D6. Microsomes from different brain regions were capable of metabolizing 5-methoxytryptamine to serotonin. The reaction was inhibited by the specific CYP2D inhibitors quinine and fluoxetine. Human liver microsomes of the wild-type CYP2D6 metabolized 5-methoxytryptamine to serotonin more effectively than did the defective CYP2D6*4*4 ones. The obtained results indicate that rat brain CYP2D isoforms catalyze the formation of serotonin from 5-methoxytryptamine, and that the deficit or genetic defect of CYP2D may affect serotonin metabolism in the brain. The results are discussed in the context of their possible physiological and pharmacological significance in vivo. 23531217 Study on medicinal chemistry of k203 in wistar rats and beagle dogs. K203 is an experimental bis-pyridinium mono-aldoxime type cholinesterase reactivator of potential use in organophosphate/ organophosphonate poisoning. Pharmacokinetics of K203 were examined in Wistar rats and beagle dogs using ion-pair HPLC. Serum and cerebrospinal fluid concentrations of K203 were determined using ion-pair reversedphase chromatography on octadecyl silica column. HPLC with ultraviolet detection was used for determination of serum concentration of K203 higher than 0.1 μg/mL while its low concentrations in cerebrospinal fluid required electrochemical detection (0.015 through 4 μg/mL range). In rats the serum levels of K203 followed zero order pharmacokinetics from 15 to 120 minutes post administration. Zero order pharmacokinetics was also observed in beagle dogs after low dose (15 μmol/kg) of K203 administration. High dose administration (250 μmol/kg) led to subsequent hindered elimination from both cerebrospinal fluid and serum. 23601387 The influence of latitude on the concentration of vitamin D3 and 25-hydroxy-vitamin D3 in Australian red meat. There is little information on the vitamin D content of Australian red meat or on the possible influence of latitude on this content. To determine the content of vitamin D3 and 25-hydroxy-vitamin D3 (25OHD3), lamb and beef were analysed from 34° S with LC-IT-MS. To investigate the possible influence of latitude on vitamin D in meat, the lean meat and fat from five cuts of beef were analysed from 17° S and 41° S. Lamb contained 0.10μg vitamin D3/100g and 0.20μg 25OHD3/100g lean meat, while beef contained 0.12μg vitamin D3 and 0.27μg 25OHD3/100g (lean meat). Latitude had no effect on the vitamin D3 (P=0.21) or 25OHD3 (P=0.29) content of lean beef, but fat from cattle in the 17° S latitude group contained significantly higher (P<0.01) concentrations of vitamin D3 than fat from the 41° S group of cattle. 23140132 The effects of green tea consumption and resistance training on body composition and resting metabolic rate in overweight or obese women. Green tea has been shown to have thermogenic and antiobesity properties. Therefore, it is important to investigate its effect on weight loss in humans, especially in women. We investigated the effects of green tea consumption combined with resistance training on the body composition and the resting metabolic rate (RMR) in women who were overweight or obese (grade I). After 4 weeks on an adaptive diet, 36 women were divided into four groups (group 1 green tea; group 2 placebo; group 3 green tea plus resistance training; group 4 placebo plus resistance training). The study was double-blinded and placebo-controlled. The RMR and body composition were ascertained for each volunteer, blood tests were performed, and subjects in groups 3 and 4 were tested for their one repetition maximum. Each subject followed the protocol and continued the diet for eight additional weeks, and periodic evaluations were administered. The mean RMR of group 1 decreased significantly and was accompanied by weight loss, maintenance of lean body mass, and decreases in both waist circumference and body mass index. Group 2 showed no variations in anthropometric or blood variables and significantly decreased their mean RMR. Group 3 showed significant increases in RMR, lean body mass, and muscle strength, and significant decreases in body fat, triglycerides, and waist circumference as compared to group 4. Green tea combined with resistance training its potential is increased with decreasing body fat, waist circumference, and triacylglyceride levels and by increasing lean body mass and muscle strength. 22592975 Investigation into the genotoxicity of water extracts from hypoxis species and a commercially available hypoxis preparation. We performed an in vitro evaluation of the genotoxic potential of water extracts from four Hypoxis species (Hypoxis hemerocallidea, H. colchicifolia, H. rigidula, H. acuminata) and a commercial preparation thereof using the neutral red uptake (NRU) assay, the alkaline comet assay and the cytome assay in human hepatoma HepG2 cells. The relative cytotoxicity of these samples was established by determining their NI50 values (50% inhibition of NRU), and these results were used for dose-finding in genotoxicity tests. None of the tested extracts were identified as genotoxic in both the alkaline comet assay and cytome assay. Copyright © 2012 John Wiley & Sons, Ltd. 23264615 Cortisol and interferon tau regulation of endometrial function and conceptus development in female sheep. During early pregnancy in sheep, the elongating conceptus secretes interferon-τ (IFNT) and the conceptus as well as endometrial epithelia produce prostaglandins (PG) via PG synthase 2 (PTGS2) and cortisol via hydroxysteroid (11-β) dehydrogenase 1 (HSD11B1). Ovarian progesterone induces and PG and IFNT stimulates endometrial HSD11B1 expression and keto-reductase activity as well as many epithelial genes that govern trophectoderm proliferation, migration, and attachment during elongation. The primary aim of these studies was to test the hypothesis that HSD11B1-derived cortisol has a biological role in endometrial function and conceptus development during early pregnancy in sheep. In study 1, cyclic ewes received vehicle, cortisol, PF 915275 (PF; a selective inhibitor of HSD11B1), cortisol and PF, meloxicam (a selective inhibitor of PTGS2), cortisol and meloxicam, recombinant ovine IFNT, or IFNT and PF into the uterus from day 10 to day14 after estrus. Cortisol and IFNT stimulated endometrial HSD11B1 expression and activity, increased endometrial PTGS2 activity and the amount of PG in the uterine lumen, and up-regulated many conceptus elongation-related genes in the endometrium. Some effects of cortisol and IFNT were mediated by PTGS2-derived PG. In study 2, bred ewes received PF 915275 or recombinant ovine IFNT and into the uterus from day 10 to day 14 after mating. Inhibition of HSD11B1 activity in utero prevented conceptus elongation, whereas IFNT rescued conceptus elongation in PF-infused ewes. These results suggest that HSD11B1-derived cortisol mediates, in part, actions of ovarian progesterone and the conceptus on endometrial function and support the hypothesis that IFNT, PG, and cortisol coordinately regulate endometrial functions important for conceptus elongation and implantation during early pregnancy in sheep. 23323746 Chemistry, chemoecology, and bioactivity of the South China Sea opisthobranch molluscs and their dietary organisms. Opisthobranchs are slow-moving, brightly colored, and shell-less slug. Interestingly, these naked molluscs appear to be free of predation causing great interests to biologists, chemists, and pharmacologists as well. It is well documented that their ability to escape predation is realized by utilizing chemical substances as defensive allomones. Due to their extraordinary capacity to produce a variety of chemical defensive molecules and in particular, some of which exhibited promising pharmacological activities, opisthobranch molluscs became the hotspot of research subject in the recent years. The authors and co-workers have systematically investigated the possible diet relationship between the South China Sea opisthobranch molluscs and their related prey organisms, including sponges, corals, and algae in the last decade. A series of interesting results have been obtained concerning the chemistry and chemoecology of the studied marine organisms. The present review focuses on recent development dealing with chemistry, chemoecology, and bioactivity of the South China Sea opisthobranch molluscs and their dietary organisms. Some selected representative examples are described in detail. 23085330 Solid dispersions for preparation of phototoxic supersaturated solutions for antimicrobial photodynamic therapy (aPDT): Studies on curcumin and curcuminoides L. Curcumin is under investigation as a potential photosensitizer (PS) in antimicrobial photodynamic therapy (aPDT). The therapeutic potential of curcumin as a PS is limited by its low aqueous solubility, susceptibility to hydrolytic and photolytic degradation, and limited phototoxicity toward Gram negative (G-) bacteria. Supersaturated solutions of curcumin have demonstrated high phototoxicity toward several species of Gram positive (G+) bacteria as well as the G-Escherichia (E) coli. Thus, solid dispersions that can form supersaturated solutions of curcumin upon hydration may be beneficial in aPDT. In the present study, solid dispersions of curcumin have been prepared through lyophilization of concentrated solutions obtained from dissolution of hydroxypropyl-β-cyclodextrin (HPβCD)-curcumin co-precipitates. Hydroxypropyl methylcellulose (HPMC) was added to curcumin solutions prior to lyophilization. The resulting lyophilizates were porous, amorphous and hydrated and dissolved rapidly in contact with a model physiological salt solution. The detected drug load of the lyophilizates was in the range 0.5-1.0% (w/w) and was dependent on the selected ratio between HPβCD and curcumin in the co-precipitate. The lyophilizate with the highest drug load could easily be dissolved in aqueous medium to form curcumin solutions of relevant concentrations for aPDT (i.e., 10μM). Selected solutions of the curcumin solid dispersions showed a pronounced decrease in curcumin concentration up to 90% after storage for 168h, which indicated that supersaturated curcumin solutions were initially formed upon dissolution of the lyophilizates. Both freshly prepared and 2days old solutions of one selected curcumin lyophilizate induced significant inactivation of E. coli (∼1% bacterial survival) after exposure to a light dose of only 5J/cm(2). 23453039 Involvement of regucalcin in lipid metabolism and diabetes. Regucalcin (RGN/SMP30) was originally discovered in 1978 as a unique calcium-binding protein that does not contain the EF-hand motif of calcium-binding domain. The regucalcin gene (rgn) is localized on the X chromosome and is identified in over 15 species consisting the regucalcin family. Regucalcin has been shown to play a multifunctional role in cell regulation; maintaining of intracellular calcium homeostasis and suppressing of signal transduction, translational protein synthesis, nuclear deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis, proliferation, and apoptosis in many cell types. Moreover, regucalcin may play a pathophysiological role in metabolic disorder. The expression of regucalcin is stimulated through the action of insulin in liver cells in vitro and in vivo and it is decreased in the liver of rats with type I diabetes induced by streptozotocin administration in vivo. Overexpression of endogenous regucalcin stimulates glucose utilization and lipid production in liver cells with glucose supplementation in vitro. Regucalcin reveals insulin resistance in liver cells. Deficiency of regucalcin induces an impairment of glucose tolerance and lipid accumulation in the liver of mice in vivo. Overexpression of endogenous regucalcin has been shown to decrease triglyceride, total cholesterol and glycogen contents in the liver of rats, inducing hyperlipidemia. Leptin and adiponectin mRNA expressions in the liver tissues are decreased in regucalcin transgenic rats. Decrease in hepatic regucalcin is associated with the development and progression of nonalcoholic fatty liver disease and fibrosis in human patients. Regucalcin may be a key molecule in lipid metabolic disorder and diabetes. 23453068 Discovery of 4-alkylamino-7-aryl-3-cyanoquinoline LRRK2 kinase inhibitors. Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial Parkinson's disease (PD). The kinase activity of this complex protein is increased by pathogenic mutations. Inhibition of LRRK2 kinase activity has therefore emerged as a promising approach for the treatment of PD. Herein we report our findings on a series of 4-alkylamino-7-aryl-3-cyanoquinolines that exhibit kinase inhibitory activity against both wild type and G2019S mutant LRRK2. Activity was determined in both biochemical and cellular assays. Compound 14 was further evaluated in an in vivo pharmacodynamic study and found to significantly inhibit Ser935 phosphorylation after oral dosing. 23435356 Tryptophan hydroxylase-2: An emerging therapeutic target for stress disorders. Serotonin (5-HT) has been long recognized to modulate the stress response, and dysfunction of 5-HT has been implicated in numerous stress disorders. Accordingly, the 5-HT system has been targeted for the treatment of stress disorders. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT synthesis, and the recent identification of a second, neuron-specific TPH isoform (TPH2) opened up a new area of research. With a decade of extensive investigation, it is now recognized that: (1) TPH2 exhibits a highly flexible gene expression that is modulated by an increasing number of internal and external environmental factors including the biological clock, stressors, endogenous hormones, and antidepressant therapies; and (2) genetically determined TPH2 activity is linked to a growing body of stress-related neuronal correlates and behavioral traits. These findings reveal an active role of TPH2 in the stress response and provide new insights into the long recognized but not yet fully understood 5-HT-stress interaction. As a major modulator of 5-HT neurotransmission and the stress response, TPH2 is of both pathophysiological and pharmacological significance, and is emerging as a new therapeutic target for the treatment of stress disorders. Given that numerous antidepressant therapies influence TPH2 gene expression, TPH2 is already inadvertently targeted for the treatment of stress disorders. With increased understanding of the regulation of TPH2 activity we can now purposely utilize TPH2 as a target to develop new or optimize current therapies, which are expected to greatly improve the prevention and treatment of a wide variety of stress disorders. 23212970 Bio-based biodegradable and biocompatible hyperbranched polyurethane: a scaffold for tissue engineering. Hyperbranched polyurethanes are synthesized using TDI, PCL diol, butanediol, and pentaerythritol (1-5 wt%) as the B(4) reactant with and without the monoglyceride of sunflower oil. The biodegradation, physico-mechanical, and thermal properties are found to be tailored by varying the percentage weight of the branching unit. An MTT/hemolytic assay and subcutaneous implantation in Wistar rats followed by cytokine/ALP assay and histopathology studies confirm a better biocompatibility of HBPU with MG than without MG. HBPU supports the proliferation of dermatocytes with no toxic effect in major organs, in addition the in vitro degraded products are non-toxic. Cell adherence and proliferation endorse the bio-based HBPU as a prospective scaffold material in the niche of tissue engineering. 23443957 Microfluidic oxygen imaging using integrated optical sensor layers and a color camera. In this work we present a high resolution oxygen imaging approach, which can be used to study 2D oxygen distribution inside microfluidic environments. The presented setup comprises a fabrication process of microfluidic chips with integrated luminescent sensing films combined with referenced oxygen imaging applying a color CCD-camera. Enhancement of the sensor performance was achieved by applying the principle of light harvesting. This principle enabled ratiometric imaging employing the red and the green channel of a color CCD-camera. The oxygen sensitive emission of platinum(ii)-5,10,15,20-tetrakis-(2,3,4,5,6-pentafluorphenyl)-porphyrin (PtTFPP) was detected by the red channel, while the emission of a reference dye was detected by the green channel. This measurement setup allowed for accurate real-time 2D oxygen imaging with superior quality compared to intensity imaging. The sensor films were subsequently used to measure the respiratory activity of human cell cultures (HeLa carcinoma cells and normal human dermal fibroblasts) in a microfluidic system. The sensor setup is well suited for different applications from spatially and temporally resolving oxygen concentration inside microfluidic channels to parallelization of oxygen measurements and paves the way to novel cell based assays, e.g. in tissue engineering, tumor biology and hypoxia reperfusion phenomena. 23312281 Vascular complications of diabetes: mechanisms of injury and protective factors. In patients with diabetes, atherosclerosis is the main reason for impaired life expectancy, and diabetic nephropathy and retinopathy are the largest contributors to end-stage renal disease and blindness, respectively. An improved therapeutic approach to combat diabetic vascular complications might include blocking mechanisms of injury as well as promoting protective or regenerating factors, for example by enhancing the action of insulin-regulated genes in endothelial cells, promoting gene programs leading to induction of antioxidant or anti-inflammatory factors, or improving the sensitivity to vascular cell survival factors. Such strategies could help prevent complications despite suboptimal metabolic control. 23559221 Glucose and memory: The influence of drink, expectancy, and beliefs. RATIONALE: An increasing number of studies suggest that glucose can enhance aspects of memory and the central methodology is the use of the glucose-placebo design. One critical issue therefore is separating the pharmacological effects of glucose from the expectancies created by consuming a drink that might contain glucose. OBJECTIVE: A modified balanced placebo design examined the role that expectancy and belief about the drink consumed has on the pharmacological changes observed following glucose consumption. METHOD: Ninety-three participants, allocated according to a drink (glucose, placebo) × message (told glucose, told nothing, told placebo) unrelated design, were administered tasks assessing immediate and delayed verbal free recall, spatial recognition and semantic verification. Each task has some evidence for hippocampus involvement, and variations in task difficulty were used to assess the idea that glucose effects are sensitive to task difficulty. RESULTS: While the messages biased drink judgements in the expected direction, judgements of drink content were at chance and glucose only enhanced delayed free recall. The subtle effects of the messages did not modify the glucose enhancement. However, believing glucose had been consumed showed an independent improvement in delayed free recall. There was no evidence that task complexity enhanced the glucose effect. CONCLUSIONS: The findings indicate that expectancy effects are unlikely to be confused with glucose enhancements, but beliefs about consuming glucose can augment performance on delayed free recall. The discussion considers the hippocampus and complexity hypotheses of glucose's mode of action and proposes the routine collection of drink beliefs in future studies. 23155004 Inferring population histories using genome-wide allele frequency data. The recent development of high-throughput genotyping technologies has revolutionized the collection of data in a wide range of both model and nonmodel species. These data generally contain huge amounts of information about the demographic history of populations. In this study, we introduce a new method to estimate divergence times on a diffusion time scale from large single-nucleotide polymorphism (SNP) data sets, conditionally on a population history that is represented as a tree. We further assume that all the observed polymorphisms originate from the most ancestral (root) population; that is, we neglect mutations that occur after the split of the most ancestral population. This method relies on a hierarchical Bayesian model, based on Kimura's time-dependent diffusion approximation of genetic drift. We implemented a Metropolis-Hastings within Gibbs sampler to estimate the posterior distribution of the parameters of interest in this model, which we refer to as the Kimura model. Evaluating the Kimura model on simulated population histories, we found that it provides accurate estimates of divergence time. Assessing model fit using the deviance information criterion (DIC) proved efficient for retrieving the correct tree topology among a set of competing histories. We show that this procedure is robust to low-to-moderate gene flow, as well as to ascertainment bias, providing that the most distantly related populations are represented in the discovery panel. As an illustrative example, we finally analyzed published human data consisting in genotypes for 452,198 SNPs from individuals belonging to four populations worldwide. Our results suggest that the Kimura model may be helpful to characterize the demographic history of differentiated populations, using genome-wide allele frequency data. 23122108 Maple polyphenols, ginnalins A-C, induce S- and G2/M-cell cycle arrest in colon and breast cancer cells mediated by decreasing cyclins A and D1 levels. Polyphenols are bioactive compounds found in plant foods. Ginnalins A-C are polyphenols present in the sap and other parts of the sugar and red maple species which are used to produce maple syrup. Here we evaluated the antiproliferative effects of ginnalins A-C on colon (HCT-116) and breast (MCF-7) tumourigenic and non-tumourigenic colon (CCD-18Co) cells and investigated whether these effects were mediated through cell cycle arrest and/or apoptosis. Ginnalins A-C were twofold more effective against the tumourigenic than non-tumourigenic cells. Among the polyphenols, ginnalin A (84%, HCT-116; 49%, MCF-7) was more effective than ginnalins B and C (50%, HCT-116; 30%, MCF-7) at 50 μM concentrations. Ginnalin A did not induce apoptosis of the cancer cells but arrested cell cycle (in the S- and G(2)/M-phases) and decreased cyclins A and D1 protein levels. These results suggest that maple polyphenols may have potential cancer chemopreventive effects mediated through cell cycle arrest. 23472803 Directing cluster formation of au nanoparticles from colloidal solution. Discrete clusters of closely spaced Au nanoparticles can be utilized in devices from photovoltaics to molecular sensors because of the formation of strong local electromagnetic field enhancements when illuminated near their plasmon resonance. In this study, scalable, chemical self-organization methods are shown to produce Au nanoparticle clusters with uniform nanometer interparticle spacing. The performance of two different methods, namely electrophoresis and diffusion, for driving the attachment of Au nanoparticles using a chemical cross-linker on chemically patterned domains of polystyrene-block-poly(methyl methacrylate) (PS-b-PMMA) thin films are evaluated. Significantly, electrophoresis is found to produce similar surface coverage as diffusion in 1/6th of the processing time with an ∼2-fold increase in the number of Au nanoparticles forming clusters. Furthermore, average interparticle spacing within Au nanoparticle clusters was found to decrease from 2-7 nm for diffusion deposition to approximately 1-2 nm for electrophoresis deposition, and the latter method exhibited better uniformity with most clusters appearing to have about 1 nm spacing between nanoparticles. The advantage of such fabrication capability is supported by calculations of local electric field enhancements using electromagnetic full-wave simulations from which we can estimate surface-enhanced Raman scattering (SERS) enhancements. In particular, full-wave results show that the maximum SERS enhancement, as estimated here as the fourth power of the local electric field, increases by a factor of 100 when the gap goes from 2 to 1 nm, reaching values as large as 10(10), strengthening the usage of electrophoresis versus diffusion for the development of molecular sensors. 23526157 Blood Flow of the Acral Finger Arterioles in Patients With Type 2 Diabetes by Quality Doppler Profiles. Patients with diabetes mellitus exhibit peripheral arterioles lesions that is associated with reduced blood flow. Here, we intended to assess the acral arterioles lesion in patients with type 2 diabetes based on the rate of blood flow by multigate spectral Doppler ultrasonography. Fifty-two patients with type 2 DM were divided into two groups. Group 1 included 13 men and 12 women with an average age of 60.60 ± 14.03 years and a duration of type 2 diabetes for 2.44 ± 1.50 years. Group 2 included 17 men and 11 women with an average age of 64.25 ± 10.84 years and type 2 diabetes for 12.57 ± 6.26 years. Age-matched control subjects (n = 52) were recruited (30 men and 22 woman, mean age of 61.19 ± 10.38 years). A multigate spectral Doppler algorithm was applied to the acral finger of the thumb of the right hand to test the arteriole diameter and hemodynamic parameters, including diameter of the acral finger arterioles (D), area of the blood flow profile of the acral finger arterioles (A max) and hemodynamic parameters. Patients with diabetes exhibited a significant reduction in the arteriole diameter (1.63 ± 0.18 and 1.57 ± 0.22 mm, respectively, P < 0.001 for both) compared to control subjects (2.09 ± 0.17 mm). A max were significantly reduced in patients with diabetes (61.35 ± 10.66 mm(2)/s for group 1 and 46.50 ± 6.59 mm(2)/s for group 2, P < 0.001 for both) compared to that in control subjects (77.93 ± 12.37 mm(2)/s). Furthermore, a significant difference in Amax was found between group 1 and group 2 (P < 0.001). The vascular resistance index (RI) was significantly higher in both patient groups 0.58 ± 0.06 for group 1 (P < 0.001) and 0.64 ± 0.07 for group 2 (P < 0.001) than that in control subjects (0.48 ± 0.04). The RI value of the acral finger arterioles differed significantly between group 1 and group 2 (P < 0.01). Diabetic patients exhibited a weak blood flow in the acral finger arterioles. The multigate spectral Doppler technology can be used to test blood flow in the acral finger arterioles and provide hemodynamic data for systematic analyses of the peripheral arteriole lesions in diabetes. 23256442 Dandelion leaf extract protects against liver injury induced by methionine- and choline-deficient diet in mice. We investigated the hepatoprotective effects of the extract of dandelion leaves (EDL) on a murine model of methionine- and choline-deficient (MCD) diet-induced nonalcoholic steatohepatitis (NASH). C57BL/6 mice were fed for 4 weeks with one of the following diets: control diet (Cont), MCD diet (MCD), MCD diet supplemented with EDL at 200 mg/kg body weight·daily (MCD+D200), and MCD diet supplemented with EDL at 500 mg/kg body weight·daily (MCD+D500). Hepatic function was assessed by evaluating the following parameters: liver histology; plasma levels of alanine aminotransferase (ALT), triglyceride (TG), malondialdehyde (MDA), and reduced glutathione (GSH); expression levels of TNF-α and IL-6; and levels of caspase-3 and pJNK/JNK protein. Histopathological evaluations revealed that addition of EDL to the MCD diet dampens the severity of the clinical signs of NASH. Moreover, EDL led to a significant decrease in the serum levels of ALT, hepatic TG, and MDA, and in the expression levels of TNF-α, and IL-6; on the contrary, the levels of reduced GSH increased. At the post-transcriptional level, EDL significantly decreased the activation of procaspase-3 to active caspase-3, and the phosphorylation of JNK. These results suggest that the beneficial effects of EDL on NASH are mainly due to its antioxidant and anti-inflammatory activities. 23535516 Modulation of the JAK/ERK/STAT signaling in melanocortin-induced inhibition of local and systemic responses to myocardial ischemia/reperfusion. The janus kinases (JAK), extracellular signal-regulated kinases (ERK) and signal transducers and activators of transcription (STAT) pathways have been shown to play a cardioprotective role. We previously gave evidence that melanocortins afford cardioprotection in conditions of myocardial ischemia/reperfusion. Here we aimed to investigate the influence of melanocortins on the JAK/ERK/STAT signaling in cardiac and systemic responses to prolonged myocardial ischemia/reperfusion. Ischemia was produced in rats by ligature of the left anterior descending coronary artery for 30min. At the end of the 2-h reperfusion, western blot analysis of the cardioprotective transcription factors pJAK2, pERK1/2, pTyr-STAT3 and pSer-STAT3, the inflammatory mediator tumor necrosis factor-α (TNF-α), the pro-apoptotic factors BAX and c-jun N-terminal kinases (pJNK), the anti-apoptotic protein Bcl-XL, as well as of the cardioprotective enzyme heme oxygenase-1 (HO-1), was performed in the left ventricle and spleen. Intravenous treatment, during coronary artery occlusion, with the melanocortin analogs [Nle(4), D-Phe(7)]α-melanocyte-stimulating hormone (NDP-α-MSH) and adrenocorticotropic hormone 1-24 [ACTH-(1-24)], induced a left ventricle up-regulation of pJAK2, pERK1/2 and pTyr-STAT3 (JAK-dependent), and a reduction in pJNK and TNF-α levels; these effects of NDP-α-MSH and ACTH-(1-24) were associated with over-expression of the pro-survival proteins HO-1 and Bcl-XL, and marked decrease of the myocardial infarct size. Melanocortin treatment did not affect left ventricle pSer-STAT3 (ERK1/2-dependent) and BAX levels. In the spleen, NDP-α-MSH and ACTH-(1-24) induced similar effects on the expression of the above transcription factors/proteins, except for pERK1/2 (down-regulated) and HO-1 (unaffected). Blockade of JAK and ERK pathways with AG490 and U0126, respectively, abrogated the myocardial infarct size reduction by NDP-α-MSH. These results indicate that melanocortins inhibit local and systemic inflammatory and apoptotic cascades triggered by prolonged myocardial ischemia/reperfusion, with consequent reduction in myocardium infarct size, seemingly via activation of the JAK/STAT signaling and with modulation of an ERK (STAT unrelated) signaling pathway. 22911509 Superhydrophobic graphene foams. The static and dynamic wetting properties of a 3D graphene foam network are reported. The foam is synthesized using template-directed chemical vapor deposition and contains pores several hundred micrometers in dimension while the walls of the foam comprise few-layer graphene sheets that are coated with Teflon. Water contact angle measurements reveal that the foam is superhydrophobic with an advancing contact angle of ∼163 degrees while the receding contact angle is ∼143 degrees. The extremely water repellent nature of the foam is also confirmed when impacting water droplets are able to completely rebound from the surface. Such superhydrophobic graphene foams show potential in a variety of applications ranging from anti-sticking and self-cleaning to anti-corrosion and low-friction coatings. 23562707 CYP-450 isoenzymes catalyze the generation of hazardous aromatic amines after reaction with the azo dye Sudan III. This work describes the mutagenic response of Sudan III, an adulterant food dye, using Salmonella typhimurium assay and the generation of hazardous aromatic amines after different oxidation methods of this azo dye. For that, we used metabolic activation by S9, catalytic oxidation by ironporphyrin and electrochemistry oxidation in order to simulate endogenous oxidation conditions. The oxidation reactions promoted discoloration from 65% to 95% of Sudan III at 1×10(-4)molL(-1) and generation of 7.6×10(-7)molL(-1) to 0.31×10(-4)molL(-1) of aniline, o-anisidine, 2-methoxi-5-methylaniline, 4-aminobiphenyl, 4,4'-oxydianiline; 4,4'-diaminodiphenylmethane and 2,6-dimethylaniline. The results were confirmed by LC-MS-MS experiments. We also correlate the mutagenic effects of Sudan III using S. typhimurium with the strain TA1535 in the presence of exogenous metabolic activation (S9) with the metabolization products of this compound. Our findings clearly indicate that aromatic amines are formed due to oxidative reactions that can be promoted by hepatic cells, after the ingestion of Sudan III. Considering that, the use of azo compounds as food dyestuffs should be carefully controlled. 23614831 Influence of different polymers on crystallization tendency and dissolution behavior of cilnidipine in solid dispersions. Abstract Context: Cilnidipine (CN) is a novel dihydropyridine calcium antagonist that is practically insoluble in aqueous media and exhibits a low oral bioavailability or limited clinical efficacy. Objective: This study investigated the effects of three commercial and chemically diverse polymers - PVP, PVP/VA and Soluplus - on crystallization tendency and in vitro dissolution profiles of CN in order to determine an optimum carrier for composing the preferred solid dispersion (SD) of CN. Methods: All these co-evaporated systems were characterized up to 3 months by thermoanalytical (DSC), crystallographic (POM, PXRD), microscopic (SEM) and spectroscopic (FTIR) techniques. Results: The results showed that the polymers could be sorted by their effects of inhibiting CN crystallization in the ascending order: Soluplus, PVP/VA, PVP. The sequence was in accordance with that of the strength of drug-polymer hydrogen bonds revealed by FTIR spectra. It could be ascribed to relative hydrogen-bonding acceptor strengths of N-vinylpyrrolidone moiety in the polymer molecules. On the other hand, all the SDs showed enhanced dissolution profiles compared to pure CN alone. On their effects of enhancing CN dissolution, the polymers could be sorted in the descending order: Soluplus, PVP, PVP/VA. Conclusions: It implied that the dissolution behavior of CN could bear a close relationship to both hydration capacity and hydrogen-bonding interaction tendency of moieties of the polymers. It might suggest an optimal formulation for CN comprising both PVP and Soluplus. 23389039 Differential mRNA expression levels of human histone-modifying enzymes in normal karyotype B cell pediatric acute lymphoblastic leukemia. Histone modification enzymes regulate gene expression by altering the accessibility of promoters to transcription factors. We sought to determine whether the genes encoding histone modification enzymes are dysregulated in pediatric acute lymphoblastic leukemia (ALL). A real-time PCR array was designed, tested and used to profile the expression of 85 genes encoding histone modification enzymes in bone marrow mononuclear cells from 30 pediatric ALL patients and 20 normal controls. The expression profile of histone-modifying genes was significantly different between normal karyotype B cell pediatric ALL and normal controls. Eleven genes were upregulated in pediatric ALL, including the histone deacetylases HDAC2 and PAK1, and seven genes were downregulated, including PRMT2 and the putative tumor suppressor EP300. Future studies will seek to determine whether these genes serve as biomarkers of pediatric ALL. Ingenuity Pathway Analysis revealed that Gene Expression and Organ Morphology was the highest rated network, with 13 focus molecules (significance score = 35). Ingenuity Pathway Analysis also indicated that curcumin and miR-34 are upstream regulators of histone-modifying enzymes; future studies will seek to validate these results and examine the role of curcumin and miR-34 in leukemia. This study provides new clues into the molecular mechanisms of pediatric ALL. 23515582 Acute escitalopram treatment inhibits REM sleep rebound and activation of MCH-expressing neurons in the lateral hypothalamus after long term selective REM sleep deprivation. RATIONALE: Selective rapid eye movement sleep (REMS) deprivation using the platform-on-water ("flower pot") method causes sleep rebound with increased REMS, decreased REMS latency, and activation of the melanin-concentrating hormone (MCH) expressing neurons in the hypothalamus. MCH is implicated in the pathomechanism of depression regarding its influence on mood, feeding behavior, and REMS. OBJECTIVES: We investigated the effects of the most selective serotonin reuptake inhibitor escitalopram on sleep rebound following REMS deprivation and, in parallel, on the activation of MCH-containing neurons. METHODS: Escitalopram or vehicle (10 mg/kg, intraperitoneally) was administered to REMS-deprived (72 h) or home cage male Wistar rats. During the 3-h-long "rebound sleep", electroencephalography was recorded, followed by an MCH/Fos double immunohistochemistry. RESULTS: During REMS rebound, the time spent in REMS and the number of MCH/Fos double-labeled neurons in the lateral hypothalamus increased markedly, and REMS latency showed a significant decrease. All these effects of REMS deprivation were significantly attenuated by escitalopram treatment. Besides the REMS-suppressing effects, escitalopram caused an increase in amount of and decrease in latency of slow wave sleep during the rebound. CONCLUSIONS: These results show that despite the high REMS pressure caused by REMS deprivation procedure, escitalopram has the ability to suppress REMS rebound, as well as to diminish the activation of MCH-containing neurons, in parallel. Escitalopram caused a shift from REMS to slow wave sleep during the rebound. Furthermore, these data point to the potential connection between the serotonergic system and MCH in sleep regulation, which can be relevant in depression and in other mood disorders. 23531119 Low-temperature NMR studies on the geometry of base pairs involving 5-substituted uracil derivatives. Uridine (U) imino proton chemical shifts, measured in the slow hydrogen-bond exchange regime at low temperatures in a freonic solution, show that electron-withdrawing 5-bromo and 5-fluoro substituents on the uracil base strengthen NHN hydrogen bonds in (X)U·A base pairs formed by the free nucleosides. Whereas the halogens do not alter the preferential formation of Watson-Crick geometries, self-associates of the halouracils point to a more favorable engagement of the 2-carbonyl as proton acceptor in the cyclic hydrogen bonds, suggesting increased formation of reverse geometries and wobble base pairs with guanine when compared to the thymine base. Employing (15)N-labeled 5-bromouridine, no noticeable population of minor enol tautomers is found in the freonic mixture at 113 K. 23303198 Antihypertensive and metabolic effects of high-dose olmesartan and telmisartan in type 2 diabetes patients with hypertension. We performed a crossover study in hypertensive patients with type 2 diabetes to compare olmesartan (40 mg/day) with telmisartan (80 mg/day) in terms of their antihypertensive and metabolic effects. The subjects were 36 patients (20 men and 16 women) with type 2 diabetes who did not achieve a blood pressure <130/80 mmHg following treatment with olmesartan at 40 mg/day or telmisartan at 80 mg/day for 8 weeks or more. The primary endpoint was the blood pressure reduction rate, while the secondary endpoints were BMI, parameters of glucose metabolism, HMW-adiponectin, hs-CRP and lipids metabolism. All parameters were measured in Weeks 0, 12, and 24. Treatments were switched in Week 0, and Week 12 and the following results were obtained. There were 1) no significant differences in baseline characteristics; 2) no significant difference of the blood pressure reduction rate; 3) significant reductions of HbA1c (NGSP), FPG and HOMA-IR in olmesartan group; 4) a significant increase of HDL-C in olmesartan group; 5) a decrease of hs-CRP and a increase of HMW-adiponectin in olmesartan group; and 6) a positive correlation between the percent changes of HOMA-IR and hs-CRP in olmesartan group. In conclusion, there was no difference of the blood pressure reduction achieved at the highest dose in olmesartan group and telmisartan group. But improvement of glycemic control and insulin resistance was only observed in olmesartan group. Because there was a correlation between the percent changes of HOMA-IR and hs-CRP, these effects of olmesartan might be mediated by an anti-inflammatory action. 23017417 Pre-bottling use of dehydrated waste grape skins to improve colour, phenolic and aroma composition of red wines. Different dehydrated waste grape skins from the juice industry were added into aged and young red wines as an innovative way of compensating for colour loss before bottling. After addition of grape skins, colour intensity of wines increased a mean 11% and a maximum of 31% with predominance of the red component. Total polyphenols mean increase was 10% with a maximum value of 20%. Analysis of low molecular weight phenolic compounds by HPLC-DAD showed a significant (p<0.05) content increase of the bioactive compounds gallic acid, (+)-catechin, (-)-epicatechin, and (E)-resveratrol. Anthocyanins content also increased at an average of 50mg/l. The volatile profile of wines analysed by SBSE-GC-MS was only moderately influenced by the treatments. Mixtures of dehydrated waste grape skins were useful to improve the colour and polyphenol profile of red wines, considering them a useful tool for correcting colour loss before bottling. 23544715 Abdominal adiposity through adipocyte secretion products, a risk factor for endometrial cancer. Abstract Background and aim: The adipose cell has been considered an inert cell from a secretory point of view. Studies over the past years have confirmed the capacity of the adipocyte to synthesize many substances including: adiponectin, leptin, which integrate multiple metabolic and endocrine signals. In the context of endometrial cancer, abdominal obesity as a risk factor is associated with a chronic inflammatory process, confirmed by the increase of inflammatory markers. The study aimed to identify a correlation between abdominal obesity, plasma adipokine levels and endometrial cancer. Material and method: Two groups of patients were included in the study: group I - 44 patients diagnosed with endometrial cancer, group II - 44 patients without gynecological pathology or inflammatory disorders. After the performance of clinical examination and anthropometric measurements, abdominal fat was determined by dual X-ray absorptiometry and plasma adiponectin and leptin levels were measured. Results: A significantly higher abdominal fat and leptin value was found in the group of patients in with endometrial cancer (p < 0.0001), while the plasma adiponectin level was significantly lower, compared to the control group (p < 0.0001). Abdominal fat was in a negative linear correlation with the plasma adiponectin level and in a positive linear correlation with the plasma leptin level. Conclusions: The measurement of adiponectin and leptin levels associated with the determination of abdominal adipose tissue can be a useful predictor factor for endometrial cancer. 23407410 Visualizing RNA base-pairing probabilities with RNAbow diagrams. There are many effective ways to represent a minimum free energy RNA secondary structure that make it easy to locate its helices and loops. It is a greater challenge to visualize the thermal average probabilities of all folds in a partition function sum; dot plot representations are often puzzling. Therefore, we introduce the RNAbows visualization tool for RNA base pair probabilities. RNAbows represent base pair probabilities with line thickness and shading, yielding intuitive diagrams. RNAbows aid in disentangling incompatible structures, allow comparisons between clusters of folds, highlight differences between wild-type and mutant folds, and are also rather beautiful. 23161731 Laminar silk scaffolds for aligned tissue fabrication. 3D-biomaterial scaffolds with aligned architecture are of vital importance in tissue regeneration. A generic method is demonstrated to produce aligned biomaterial scaffolds using the physics of directional ice freezing. Homogeneously aligned 3D silk scaffolds with high porosity and alignment are prepared. The method can be adapted to a wide range of polymers and is devoid of any chemical reactions, thus avoiding potential complications associated with by-products. Mechanical properties and cellular responses with chondrocytes and bone-marrow-derived hMSCs are studied, assessing survival, proliferation, and differentiation. In vivo tests suggest biocompatibility of the matrices for future tissue engineering applications, specifically in areas where high cellular alignment is needed. 23228469 From a cytotoxic agent to the discovery of a novel antimalarial agent. A novel cytotoxin 3,5-bis(4-chlorobenzylidene)-1-[4-{2-(4-morpholinyl)ethoxy}phenyl-carbonyl]-4-piperidone hydrochloride 2 demonstrated potent antimalarial properties with IC(50) values of 0.60 and 1.97 μM against the drug sensitive D6 strain and the C235 drug-resistant strain of Plasmodium falciparum. This compound concentrates in red blood cells, lowers glutathione concentrations in erythrocytes and permeates across CACO-2 cells. These data reveal 2 to be a promising lead compound in the quest for novel antimalarial agents. 23392568 Maternal exposure to mercury chloride during pregnancy and lactation affects the immunity and social behavior of offspring. Developmental HgCl2 exposures of F1 offspring (H-2(q/s)) from unsociable SJL/J (H-2(s)) dams with high susceptibility to Hg-induced autoimmunity (SFvF1) and from highly sociable FVB/NJ (FVB; H-2(q)) dams with lower susceptibility to Hg-induced autoimmunity (FvSF1) were investigated. Hg exposure increased the serum IgG levels of all offspring at postnatal day 21 (pnd21) and of SJL/J dams but not of FVB dams. Serum IgG anti-brain antibody (Ab) levels of pnd21 SFvF1 offspring and SJL dams were higher than those of the FvSF1 offspring and FVB dams, but Hg only increased the titers of the FVB dams and their offspring. Hg significantly elevated the presence of IgG in all brain regions of the pnd21 SFvF1 offspring, and the SFvF1 offspring had greater amounts of IgG in the brain than the FvSF1 offspring, which had Hg-induced increases in only two brain regions. Cytokine levels were elevated in the brain regions of Hg-treated pnd21 SFvF1 but not of FvSF1 offspring, and SFvF1 females had more brain regions expressing cytokines than the males. At pnd70, the serum IgG, serum antibrain Abs, amounts of brain IgG, and brain cytokine levels of all of the Hg-treated offspring were equivalent to those of their appropriate controls, suggesting that developmental Hg exposure did not induce chronic immunological effects. However, the social behaviors of Hg-exposed SFvF1 offspring at pnd70 were significantly impaired, and SFvF1 females displayed greater decline in social behaviors than males, suggesting that the higher neuroinflammation of SFvF1 females earlier in life is associated with the altered behavior. Thus, developmental Hg exposure induces long-lasting effects on social behavior of offspring, which is dependent on sex and genetics and the induction of neuroinflammation. 23317450 Mechanism of copper(I)/TEMPO-catalyzed aerobic alcohol oxidation. Homogeneous Cu/TEMPO catalyst systems (TEMPO = 2,2,6,6-tetramethylpiperidine-N-oxyl) have emerged as some of the most versatile and practical catalysts for aerobic alcohol oxidation. Recently, we disclosed a (bpy)Cu(I)/TEMPO/NMI catalyst system (NMI = N-methylimidazole) that exhibits fast rates and high selectivities, even with unactivated aliphatic alcohols. Here, we present a mechanistic investigation of this catalyst system, in which we compare the reactivity of benzylic and aliphatic alcohols. This work includes analysis of catalytic rates by gas-uptake and in situ IR kinetic methods and characterization of the catalyst speciation during the reaction by EPR and UV-visible spectroscopic methods. The data support a two-stage catalytic mechanism consisting of (1) "catalyst oxidation" in which Cu(I) and TEMPO-H are oxidized by O(2) via a binuclear Cu(2)O(2) intermediate and (2) "substrate oxidation" mediated by Cu(II) and the nitroxyl radical of TEMPO via a Cu(II)-alkoxide intermediate. Catalytic rate laws, kinetic isotope effects, and spectroscopic data show that reactions of benzylic and aliphatic alcohols have different turnover-limiting steps. Catalyst oxidation by O(2) is turnover limiting with benzylic alcohols, while numerous steps contribute to the turnover rate in the oxidation of aliphatic alcohols. 23584090 Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Colon cancer is a clinically diverse disease. This heterogeneity makes it difficult to determine which patients will benefit most from adjuvant therapy and impedes the development of new targeted agents. More insight into the biological diversity of colon cancers, especially in relation to clinical features, is therefore needed. We demonstrate, using an unsupervised classification strategy involving over 1,100 individuals with colon cancer, that three main molecularly distinct subtypes can be recognized. Two subtypes have been previously identified and are well characterized (chromosomal-instable and microsatellite-instable cancers). The third subtype is largely microsatellite stable and contains relatively more CpG island methylator phenotype-positive carcinomas but cannot be identified on the basis of characteristic mutations. We provide evidence that this subtype relates to sessile-serrated adenomas, which show highly similar gene expression profiles, including upregulation of genes involved in matrix remodeling and epithelial-mesenchymal transition. The identification of this subtype is crucial, as it has a very unfavorable prognosis and, moreover, is refractory to epidermal growth factor receptor-targeted therapy. 23529793 RANKL subcellular trafficking and regulatory mechanisms in osteocytes. The receptor activator of the NF-κB ligand (RANKL) is the central player in the regulation of osteoclastogenesis and the quantity of RANKL presented to osteoclast precursors is an important factor determining the magnitude of osteoclast formation. Since osteoblastic cells are thought to be a major source of RANKL, the regulatory mechanisms of RANKL subcellular trafficking have been studied in osteoblastic cells. However, recent reports showed that osteocytes are a major source of RANKL presentation to osteoclast precursors, prompting a need to reinvestigate RANKL subcellular trafficking in osteocytes. Investigation of molecular mechanisms in detail needs well-designed in vitro experimental systems. Thus, we developed a novel co-culture system of osteoclast precursors and osteocytes embedded in collagen gel. Experiments using this model revealed that osteocytic RANKL is provided as a membrane-bound form to osteoclast precursors through osteocyte dendritic processes and that the contribution of soluble RANKL to the osteoclastogenesis supported by osteocytes is minor. Moreover, the regulation of RANKL subcellular trafficking, such as OPG-mediated transport of newly synthesized RANKL molecules to lysosomal storage compartments, and the release of RANKL to the cell surface upon stimulation with RANK, are confirmed to be functional in osteocytes. These results provide a novel understanding of the regulation of osteoclastogenesis. © 2013 American Society for Bone and Mineral Research. 23205763 Magnetic nanoclusters exhibiting protein-activated near-infrared fluorescence. Composite nanoclusters with chemical, magnetic, and biofunctionality offer broad opportunities for targeted cellular imaging. A key challenge is to load a high degree of targeting, imaging, and therapeutic functionality onto stable metal-oxide nanoparticles. Here we report a route for producing magnetic nanoclusters (MNCs) with alkyne surface functionality that can be utilized as multimodal imaging probes. We form MNCs composed of magnetic Fe(3)O(4) nanoparticles and poly(acrylic acid-co-propargyl acrylate) by the co-precipitation of iron salts in the presence of copolymer stabilizers. The MNCs were surface-modified with near-infrared (NIR) emitting fluorophore used in photodynamic therapy, an azide-modified indocyanine green. The fluorophores engaged and complexed with bovine serum albumin, forming an extended coverage of serum proteins on the MNCs. These proteins isolated indocyanine green fluorophores from the aqueous environment and induced an effective "turn-on" of NIR emission. 23454297 Caffeic acid treatment alters the extracellular adenine nucleotide hydrolysis in platelets and lymphocytes of adult rats. This study evaluated the effects of caffeic acid on ectonucleotidase activities such as NTPDase (nucleoside triphosphate diphosphohydrolase), Ecto-NPP (nucleotide pyrophosphatase/phosphodiesterase), 5'-nucleotidase and adenosine deaminase (ADA) in platelets and lymphocytes of rats, as well as in the profile of platelet aggregation. Animals were divided into five groups: I (control); II (oil); III (caffeic acid 10mg/kg); IV (caffeic acid 50mg/kg); and V (caffeic acid 100mg/kg). Animals were treated with caffeic acid diluted in oil for 30days. In platelets, caffeic acid decreased the ATP hydrolysis and increased ADP hydrolysis in groups III, IV and V when compared to control (P<0.05). The 5'-nucleotidase activity was decreased, while E-NPP and ADA activities were increased in platelets of rats of groups III, IV and V (P<0.05). Caffeic acid reduced significantly the platelet aggregation in the animals of groups III, IV and V in relation to group I (P<0.05). In lymphocytes, the NTPDase and ADA activities were increased in all groups treated with caffeic acid when compared to control (P<0.05). These findings demonstrated that the enzymes were altered in tissues by caffeic acid and this compound decreased the platelet aggregation suggesting that caffeic acid should be considered a potentially therapeutic agent in disorders related to the purinergic system. 23614827 Two new compounds from Schisandra glaucescens. One new lignan (7S,8R,7'R,8'R)-7-(3,4-methylenedioxyphenyl)-8,8'-dimethyl-8'-hydroxyl-7'-methoxyl-7'-(3',4'-methylenedioxyphenyl)-tetrahydrofuran (1), one new sesquiterpene 2-hydroxy-11,12-dehydrocalamenene (2), one new natural product erythro-1-(3,4-dimethoxyphenyl)-4-(3,4-methylenedioxyphenyl)-2,3-dimethyl-butane (3), and two known lignans (+)-anwulignan(erythro-1-(4-hydroxy-3-methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-2,3-dimethyl-butane) (4) and ( - )-zuonin-A (5) were isolated from the stems of Schisandra glaucescens Diels. Their structures were elucidated by spectroscopic methods. The cytotoxicity of compounds 1 and 2 was assayed. 23132743 Ligand-dependent actions of the vitamin D receptor are required for activation of TGF-β signaling during the inflammatory response to cutaneous injury. The vitamin D receptor (VDR) has both 1,25-dihydroxyvitamin D-dependent and -independent actions in the epidermis. Ligand-dependent actions of the VDR have been shown to promote keratinocyte differentiation and to regulate formation of the epidermal barrier. In contrast, the actions of the VDR that regulate postmorphogenic hair cycling do not require 1,25-dihydroxyvitamin D. The VDR also has immunomodulatory actions that are dependent on its ligand, 1,25-dihydroxyvitamin D. To determine whether the ligand-dependent or -independent actions of the VDR regulate the inflammatory response to cutaneous injury, studies were performed in control, VDR knockout, and vitamin D-deficient mice. These investigations demonstrate that absence of receptor or ligand impairs the dermal response to cutaneous injury. Although neutrophil recruitment is not affected, the absence of VDR signaling leads to defects in macrophage recruitment and granulation tissue formation. Studies performed to identify the molecular basis for this phenotype demonstrate that absence of the VDR, or its ligand, impairs TGF-β signaling in the dermis, characterized by decreased expression of monocyte chemotactic protein-1 and reduced phosphorylation of phosphorylated Smad-3 as well as attenuated phosphorylated Smad-3 phosphorylation in response to TGF-β in primary dermal fibroblasts lacking the VDR. Thus, these data demonstrate that the liganded VDR interacts with the TGF-β signaling pathway to promote the normal inflammatory response to cutaneous injury. 23639537 Design, synthesis and biological evaluation of indeno[1,2-d]thiazole derivatives as potent histone deacetylase inhibitors. Novel indeno[1,2-d]thiazole hydroxamic acids were designed, synthesized, and evaluated for histone deacetylases (HDACs) inhibition and antiproliferative activities on tumor cell lines. Most of the tested compounds exhibited HDAC inhibition and antiproliferative activity against both MCF7 and HCT116 cells with GI50 values in the sub-micromolar range. Among them, compound 6o showed good inhibitory activity against pan-HDAC with IC50 value of 0.14μM and significant growth inhibition on MCF7 and HCT116 cells with GI50 values of 0.869 and 0.535μM, respectively. 23449205 Lasiodiplodin analogues from the endophytic fungus Sarocladium kiliense. A new 12-membered ring lactone, (3S),(6R)-6-hydroxylasiodiplodin (1), with two known analogues, (3R)-lasiodiplodin (2), and (3R),(5S)-5-hydroxylasiodiplodin (3) were isolated from the EtOH extracts of normal Apriona germari (Hope)-associated fungus Sarocladium kiliense grown in rice medium. The structures of compounds 1-3 were elucidated by a combination of spectroscopic data interpretation, single-crystal X-ray diffraction analysis, and modified Mosher's method. 23325373 Can you enhance executive control without glucose? The effects of fructose on problem solving. The consumption of glucose can enhance executive control by increasing blood glucose and providing energy for brain processes. However, a glucose mouth rinse also positively affects executive control in the absence of an effect on blood glucose. This observation suggests that glucose can enhance executive control via another mechanism, perhaps by increasing cortical activation in motivational reward pathways. This hypothesis was examined in the current study by having participants consume fructose, glucose or a placebo 10 minutes before solving word anagrams. Fructose was used because it does not affect blood glucose levels, inhibits cortical responding, and cannot entrain a taste preference post-ingestion. The latter evidences that fructose differs from glucose in its ability to elicit activation in motivational reward pathways. It was observed that consuming fructose and glucose resulted in the resolution of more anagrams than the placebo. These results suggest that at least some of the effects of glucose and fructose on problem solving operate through a common peripheral mechanism that is independent of motivational reward pathways. 23387796 Isolation and characterization of unusual hydrazides from Streptomyces sp. impact of the cultivation support and extraction procedure. Three novel hydrazides, geralcins C-E (1-3), were isolated from Streptomyces sp. LMA-545, together with MH-031 and geralcins A and B. This unusual family of compounds was isolated from liquid-state and agar-supported fermentation using Amberlite XAD-16 solid-phase extraction during the cultivation step. The use of such neutral resin during the cultivation step allowed the specific adsorption of microbial secondary metabolites, avoiding any contamination of the crude extracts by the constituents of the culture medium. The trapped compounds were eluted from the resin with methanol, and their structures elucidated using (1)H, (13)C, and (15)N NMR spectroscopic analysis and high-resolution mass spectrometry. Molecular modeling calculations were applied in order to support structural attributions. No antimicrobial, cytotoxic, or DnaG-inhibition activities were detected for geralcins D and E. Geralcin C has no antimicrobial activity but exhibited an IC(50) of 0.8 μM against KB and HCT116 cancer cell lines. Furthermore, geralcin C inhibited the E. coli DnaG primase, a Gram-negative antimicrobial target, with an IC(50) of 0.7 mM. 23562910 Loss of FMR2 further emphasizes the link between deregulation of immediate early response genes FOS and JUN and intellectual disability. Loss of FMR2 causes Fragile X E (FRAXE) site-associated intellectual disability (ID). FMR2 regulates transcription, promotes alternative splicing with preference for G-quartet structure harbouring exons and is localized to the nuclear speckles. In primary skin fibroblasts from FRAXE patients (n = 8), we found a significant reduction in the number, but a significant increase in the size, of nuclear speckles, when compared with the controls (n = 4). Since nuclear speckles are enriched with factors involved in pre-mRNA processing, we explored the consequence of these defects and the loss of FMR2 on the transcriptome. We performed whole genome expression profiling using total RNA extracted from these cell lines and found 27 genes significantly deregulated by at least 2-fold at P < 0.05 in the patients. Among these genes, FOS was significantly upregulated and was further investigated due to its established role in neuronal cell function. We showed that (i) 30% depletion of Fmr2 in mouse primary cortical neurons led to a 2-fold increase in Fos expression, (ii) overexpression of FMR2 significantly decreased FOS promoter activity in luciferase assays, and (iii) as FOS promoter contains a serum response element, we found that not FOS, but JUN, which encodes for a protein that forms a transcriptional activator complex with FOS, was significantly upregulated in the patients' cell lines upon mitogen stimulation. These results suggest that FMR2 is an upstream regulator of FOS and JUN, and further link deregulation of the immediate early response genes to the pathology of ID- and FRAXE-associated ID in particular. 23525167 NMR characterisation of dynamics in solvates and desolvates of formoterol fumarate. Solid-state NMR is used to characterise dynamics in the ethanol solvate of the pharmaceutical material formoterol fumarate and its associated desolvate. Jump rates and activation barriers for dynamic processes such as phenyl ring rotation and methyl group rotational diffusion are derived from 1D-EXSY and (13)C spin-lattice relaxation times respectively. (2)H and (13)C spin-lattice relaxation times measured under magic-angle spinning conditions are used to show that the fumarate ion in the desolvate is undergoing small-amplitude motion on a frequency scale of 100s of MHz at ambient temperature with an activation parameter of about 32 kJ mol(-1). Exact calculations of relaxation times under MAS provide a simple and robust means to test motional models in cases where relaxation rate maxima are observed, including for systems where the crystal structure of the material is unknown. 23329065 Effects of dopamine D2 agonist quinpirole on neuronal activity of anterior cingulate cortex and striatum in rats. RATIONALE: The influence of acute D2 agonist quinpirole on locomotor activity has been effectively characterized. However, few studies have addressed the dynamic changes in neuronal activity of the anterior cingulate cortex (ACC) and striatum (STR), two crucial regions for cognitive and motor functions, after quinpirole administration. OBJECTIVE: This study was conducted in order to acquire detailed information on the evoked activity of the neurons in the ACC and STR after acute quinpirole administration. METHODS: Multichannel electrophysiological recording was used for tracking neuronal activity in the ACC and STR of urethane-anesthetized rats after administration of saline or 0.05 or 0.5 mg/kg quinpirole. RESULTS: In contrast to the responses to saline, quinpirole dose-dependently increased the ratio of neurons, the activity of which was inhibited in the ACC and STR. By examining the ensemble neuronal activities of inhibition-responded neurons, there was no significant activity difference among the "treatments" (saline and low- and high-dose quinpirole), the "periods" (the duration of 0-15 and 16-45 min after i.v. injection), and the interaction between "treatments" and "periods." Regarding activation-responded neurons, however, there was a significant "periods" difference in both ACC and STR, and the activity of 16-45 min was significantly higher than the activity of 0-15 min after high-dose quinpirole administration in ACC (p < 0.05) and STR (p < 0.001). CONCLUSION: Dose-dependent ACC and STR neuronal responses to quinpirole may offer a possible mechanism for understanding the locomotor responses to quinpirole in behaving rats. The late excitatory effect of high-dose quinpirole in the STR further suggests that this region would be critical for the activation of locomotor activity. 23632086 The Prevalence, Maintenance and Relevance of GPCR Oligomerization. Over the past decade ideas and experimental support for the hypothesis that G protein-coupled receptors may exist as dimeric or oligomeric complexes moved initially from heresy to orthodoxy, to the current situation in which the capacity of such receptors to interact is generally accepted but the prevalence, maintenance and relevance of such interactions to both pharmacology and function remain unclear. A vast body of data obtained following transfection of cultured cells is still to be translated to native systems and, even where this has been attempted, results often remain controversial and contradictory. This review will consider approaches that are currently being applied, why these might be challenging to interpret and suggest means to overcome these limitations. 23636446 A glucocorticoid education group meeting: an effective strategy for improving self-management to prevent adrenal crisis. OBJECTIVE: To assess self-management in patients receiving glucocorticoid replacement therapy for primary or secondary adrenal failure before and 6 months after a glucocorticoid education group meeting. METHODS: All patients with primary or secondary adrenal insufficiency, treated at the department of Medicine, Division of Endocrinology were invited by their endocrinologist to participate in a three-hour glucocorticoid education group meeting, consisting of a lecture about the disease and glucocorticoid doses adjustments in case of stress , followed by an instruction how to inject hydrocortisone intramusculary. Finally, all participants could practice the intramuscular injection and discuss their experience with (imminent) adrenal crises with other patients and the health care providers. Two weeks before the meeting and 6 months after the meeting, patients were asked to fill out a questionnaire about how they would act in 6 different conditions (e.g. febrile illness or vomiting). RESULTS: Of the 405 patients who were invited, 246 patients (61%) participated. At baseline the response by the participants on the questionnaire was 100% (N=246) and at follow-up 74% (N=183). At follow-up, significantly more participants (p=<0.005) gave the correct answers how to act in the different situations (e.g. self administration of a glucocorticoid injection and phone contact in case of vomiting/diarrhoea without fever). Moreover, the use of self-management tools, such as having a 'medicine passport (travel document with information about disease and medication) (p=0.007) or SOS medallion (p=0.0007)' increased. CONCLUSION: A glucocorticoid education group meeting for patients with adrenal failure seems helpful to improve self-management and proper use of stress-related glucocorticoid dose adjustment. 23453303 Protective effects of propolis on female rats' histopathological, biochemical and genotoxic changes during LPS induced endotoxemia. In recent years, propolis has been the object of extensive research for its antibacterial, antioxidant, anti-inflammatory, and antitumoral activities. This study aims to determine the hepatoprotective efficiency of propolis on experimental endotoxemia in rats. In the current study, fifty adult Sprague Dawley rats (weighing 200-300g) were randomly divided into five groups of ten rats each. Normal saline solution was administered to the rats in the control group, while in the second group LPS (30mg/kg), in the third group propolis (250mg/kg), in the fourth group first propolis and then LPS (30mg/kg), and in the fifth group, first LPS (30mg/kg) and then propolis were given. Six hours after the application, biochemical (MDA levels) and histopathological changes as well as global DNA methylation analysis in the liver tissue samples were determined, while in the blood tissue samples Genomic Template Stability (GTS, %) was evaluated using RAPD-PCR profiles. The results demonstrated that the administration of propolis could have a protective effect against changes of both genomic stability values and methylation profiles, and it minimized the increase in MDA and tissue damage caused by LPS. In conclusion, the application of propolis prior to LPS-induced endotoxemia has shown to reduce hepatic damage. 23237939 Inhibition of homologous recombination by hyperthermia shunts early double strand break repair to non-homologous end-joining. In S and G2 phase mammalian cells DNA double strand breaks (DSBs) can potentially be repaired by homologous recombination (HR) or non-homologous end-joining (NHEJ). Results of several studies suggest that these two mechanistically distinct repair pathways can compete for DNA ends. Because HR and NHEJ differ with respect to error susceptibility, generation of chromosome rearrangements, which are potentially carcinogenic products of DSB repair, may depend on the pathway choice. To investigate this hypothesis, the influence of HR and NHEJ inhibition on the frequencies of chromosome aberrations in G2 phase cells was investigated. SW-1573 and RKO cells were treated with mild (41 °C) hyperthermia in order to disable HR and/or NU7441/cisplatin to inactivate NHEJ and frequencies of chromosomal fragments (resulting from unrepaired DSBs) and translocations (products of erroneous DSB rejoining) were studied using premature chromosome condensation (PCC) combined with fluorescence in situ hybridization (FISH). It is shown here that temporary inhibition of HR by hyperthermia results in increased frequency of ionizing-radiation (IR)-induced chromosomal translocations and that this effect is abrogated by NU7441- or cisplatin-mediated inhibition of NHEJ. The results suggest that in the absence of HR, DSB repair is shifted to the error-prone NHEJ pathway resulting in increased frequencies of chromosomal rearrangements. These results might be of consequence for clinical cancer treatment approaches that aim at inhibition of one or more DSB repair pathways. 23537575 Design of pH responsive clickable prodrugs applied to histone deacetylase inhibitors: A new strategy for anticancer therapy. The aim of this study was to develop clickable prodrugs bearing a tunable pH responsive linker designed for acidic pH-mediated release of histone deacetylase inhibitors. HDACi are an important class of molecules belonging to the epigenetic modulators used for innovative cancer strategies. The behavior of these prodrugs was determined by a bioluminescence resonance energy transfer assay in living tumor cells. This work demonstrated that this innovative type of clickable prodrugs entered cancer cells and showed restored anti proliferative properties attributed to the effective release of the HDAC inhibitors. A correlation between kinetic studies, dose responses, and biological activities was obtained, making such clickable prodrugs good candidates for new strategies in epigenetic-oriented anticancer therapies. 23161664 Hypoxia-response element (HRE)-directed transcriptional regulation of the rat lysyl oxidase gene in response to cobalt and cadmium. Lysyl oxidase (LO) catalyzes crosslink of collagen, elastin, and histone H1, stabilizing the extracellular matrix and cell nucleus. This enzyme displays dual functions for tumorigenesis, i.e., as a tumor suppressor inactivating the ras oncogene and as a tumor promoter enhancing malignant cell metastasis. To elucidate LO transcriptional regulation, we have cloned the 804 base pair region upstream of the translation start site (ATG) of the rat LO gene with the maximal promoter activity. Computer analysis indicated that at least four hypoxia-response element (HRE) consensuses (5'-ACGTG-3') exist in the cloned LO promoter. Treatment of rat lung fibroblasts (RFL6) with CoCl2 (Co, 10-100 μM), a chemical hypoxia reagent, enhanced LO mRNA expression and promoter activities. Overexpression of LO was associated with upregulation of hypoxia-inducible factor (HIF)-1α at mRNA levels in cobalt (Co)-treated cells. Thus, LO is a hypoxia-responsive gene. Dominant negative-HIF-1α inhibited LO promoter activities stimulated by Co. Electrophoretic mobility shift, oligonucleotide competition, and in vitro translated HIF-1α binding assays indicated that only one HRE mapped at -387/-383 relative to ATG was functionally active among four consensuses. Site-directed mutation of this HRE significantly diminished the Co-induced and LO promoter-directed expression of the reporter gene. Cadmium (Cd), an inducer of reactive oxygen species, inhibited HIF-1α mRNA expression and HIF-1α binding to the LO gene in Co-treated cells as revealed by RT-PCR and ChIP assays, respectively. Thus, modulation of the HRE activity by Co and Cd plays a critical role in LO gene transactivation. 23612242 Transcriptional and catalytic responses of antioxidant and biotransformation pathways in mussels, Mytilus galloprovincialis, exposed to chemical mixtures. Antioxidant and biotransformation pathways are widely studied in marine organisms exposed to environmental stressors. However, mechanisms of responses and links between different intracellular levels are not always easy to elucidate and conflicting results are frequently observed between molecular and enzymatic data. In this study, transcriptional and catalytic responses of antioxidant and biotransformation parameters were analyzed after a 4-week exposure of a marine invertebrate, Mytilus galloprovincialis, to chemical mixtures from low polluted and highly polluted sediments. A significant, dose-dependent bioaccumulation was observed for polycyclic aromatic hydrocarbons, especially low molecular weight compounds. Among antioxidant defences, catalase and glutathione peroxidases did not exhibit variations in enzymatic activity, while the corresponding gene transcriptions were up- and down-regulated, respectively; unchanged mRNA levels of superoxide dismutase confirmed the non-synchronous pathways of variations for such antioxidants. Biotransformation responses also revealed inconsistent trends between transcriptional and catalytic variations of glutathione S-transferases, and a significant increase in mRNA levels for cytochrome P450 3A1. The overall results indicated that transcriptional responses might be sensitive but do not necessarily correspond to functional changes, being more useful as "exposure" rather than "effect" biomarkers. Data on gene transcription and catalytic activities should be carefully interpreted when assessing the impact of chemical pollutants and additional studies are needed on modulation of post-transcriptional mechanisms by environmental stressors. 23545999 Isolation of Five New Flavonoids from Melicope triphylla. Five new flavonoids, 5,8-dihydroxy-3,7-dimethoxy-3',4'-methylenedioxyflavone (1), 7-hydroxy-3,5-dimethoxy-3',4'-methylenedioxyflavone (2), 7-(2,3-dihydroxy-3-methylbutoxy)-3,5-dimethoxy-3',4'-methylenedioxyflavone (3), 7-(2,3-dihydroxy-3-methylbutoxy)-3,3',4',5-tetramethoxyflavone (4), and 7-(2,3-dihydroxy-3-methylbutoxy)-3,3',4',5,8-pentamethoxyflavone (5), were isolated from the leaves of Melicope triphylla. In addition, six known flavonoids were detected: 3,4',5-trihydroxy-3',7,8-trimethoxyflavone (6), 5,7-dihydroxy-3-methoxy-3',4'-methylenedioxyflavone (7), 4',5,7-trihydroxy-3,3'-dimethoxyflavone (8), 4',7-dihydroxy-3,3',5,8-tetramethoxyflavone (9), 4',7-dihydroxy-3,3',5-trimethoxyflavone (10), and 4',5,7-trihydroxy-3,3',8-trimethoxyflavone (11). The new compound structures were determined by spectroscopic methods. Compounds 1-5 did not exhibit any ichthyotoxic activity against Japanese killifish (medaka in Japanese) (Oryzias latipes var.) at 10 ppm. 23474899 Synthesis, in vitro antitumor evaluation and DNA-binding study of novel tetrahydroquinolines and some derived tricyclic and tetracyclic ring systems. The synthesis of some new tetrahydroquinolines, tetrahydropyrimido[4,5-b]quinolines, and tetrahydropentaazacyclopenta[a]anthracenes structurally related to some DNA intercalators is described. Fifteen compounds were evaluated for their antitumor activity by the National Cancer Institute (NCI), in vitro disease oriented antitumor screening. The most active tricyclic pyrimido[4,5-b]quinolines 3b, 6b, 7b and 8b were further subjected to DNA-binding investigation in an attempt to rationalize their activity. Compound 8b proved to be the most active member in this study as evidenced from its remarkable growth inhibitory potential against some individual cell lines, and its broad spectrum of antitumor activity (GI50, TGI and LC50 values 46.9, 85.3 and 97.4, respectively), together with a good DNA-binding affinity. 23268656 On-chip thin film Zernike phase plate for in-focus transmission electron microscopy imaging of organic materials. Transmission electron microscopy (TEM) is a powerful tool for imaging nanostructures, yet its capability is limited with respect to the imaging of organic materials because of the intrinsic low contrast problem. TEM phase plates have been in development for decades, yet a reliable phase plate technique has not been available because the performance of TEM phase plates deteriorates too quickly. Such an obstacle prohibits in-focus TEM phase imaging to be routinely achievable, thus limiting the technique being used in practical applications. Here we present an on-chip thin film Zernike phase plate which can effectively release charging and allow reliable in-focus TEM images of organic materials with enhanced contrast to be routinely obtained. With this stable system, we were able to characterize many polymer solar cell specimens and consequently identified and verified the existence of an unexpected nanoparticle phase. Furthermore, we were also able to observe the fine structures of an Escherichia coli specimen, without staining, using this on-chip thin film phase plate. Our system, which can be installed on a commercial TEM, opens up exciting possibilities for TEM to characterize organic materials. 22903169 Human and cattle ergotism since 1900: Symptoms, outbreaks, and regulations. Ergotism in humans and cattle are caused by several species of Claviceps that infect rye and other cereal grains. Symptoms in humans vary greatly and are generally classified as convulsive, gangrenous, or gastrointestinal (enteric). Cattle are particularly susceptible to both gangrenous and hyperthermic ergotism (also called summer syndrome). The prevalence of ergotism has decreased as knowledge of the fungus has increased, mainly through implementation of regulations and advances in milling procedures. However, outbreaks in humans have recently occurred in lower socioeconomic populations of Ethiopia (1977 and 2001) and India (1975) with devastating results. Prominent outbreaks in cattle have occurred in Australia (1987), the United States (1996), South Africa (1996-1997), and Brazil (1999) and, as opposed to human cases, they do not appear to be bound by economic development. This review provides a detailed summary of all major ergot epidemics since 1900 in both humans and cattle. Special attention is devoted to the ergotism symptoms and to the regulations surrounding the control of ergot in the food supply. 23574534 A Facile Integration of Zero- (I-III-VI Quantum Dots) and One- (Single SnO2 Nanowire) Dimensional Nanomaterials: Fabrication of a Nanocomposite Photodetector with Ultrahigh Gain and Wide Spectral Response. Via the integration of nanocomposites comprising I-III-VI semiconductor quantum dots (QDs) decorated onto a single SnO2 nanowire (NW), we successfully fabricate an ultrahigh-sensitivity and wide spectral-response photodetector. Under the illumination of He-Cd laser (325 nm) with the photon energy larger than the band gap of SnO2 nanowire, remarkably, an ultrahigh photocurrent gain up to 2.5 × 10(5) has been achieved, and an enhancement factor can reach up to 700% (cf. bare SnO2 NW) as light illumination onto the wire with an excitation intensity of 15 W/m(2). Also, a high gain value up to 1.3 × 10(5) is attained with the excited photon energy (488 nm) smaller than the band gap of SnO2 nanowire. Several key factors contribute to ultrahigh photocurrent gain and wide spectral response. First, the decorated quantum dot processes an inherent nature of a large absorption coefficient above its band gap. Furthermore, the single SnO2 nanowire provides an excellent conduction path for the photogenerated carriers as well as bears a large surface-to-volume ratio so that the coupling strength with quantum dots can be greatly enhanced. Most importantly, the spatial separation of photogenerated electrons and holes can be easily achieved due to the charge transfer arising from a type II band alignment between QDs and SnO2 NW. This work thus demonstrates a new approach in which by selectively decorating suitable QDs the photocurrent gain of SnO2 NWs can be greatly enhanced and extended to a wide spectral range of photoresponse previously inaccessible, providing a very useful guideline to create cheap, nontoxic, and highly efficient photodetectors. 23151250 Stabilizing the pro-apoptotic BimBH3 helix (BimSAHB) does not necessarily enhance affinity or biological activity. An attractive approach for developing therapeutic peptides is to enhance binding to their targets by stabilizing their α-helical conformation, for example, stabilized BimBH3 peptides (BimSAHB) designed to induce apoptosis. Unexpectedly, we found that such modified peptides have reduced affinity for their targets, the pro-survival Bcl-2 proteins. We attribute this loss in affinity to disruption of a network of stabilizing intramolecular interactions present in the bound state of the native peptide. Altering this network may compromise binding affinity, as in the case of the BimBH3 stapled peptide studied here. Moreover, cells exposed to these peptides do not readily undergo apoptosis, strongly indicating that BimSAHB is not inherently cell permeable. 23193260 Clone DB: an integrated NCBI resource for clone-associated data. The National Center for Biotechnology Information (NCBI) Clone DB (http://www.ncbi.nlm.nih.gov/clone/) is an integrated resource providing information about and facilitating access to clones, which serve as valuable research reagents in many fields, including genome sequencing and variation analysis. Clone DB represents an expansion and replacement of the former NCBI Clone Registry and has records for genomic and cell-based libraries and clones representing more than 100 different eukaryotic taxa. Records provide details of library construction, associated sequences, map positions and information about resource distribution. Clone DB is indexed in the NCBI Entrez system and can be queried by fields that include organism, clone name, gene name and sequence identifier. Whenever possible, genomic clones are mapped to reference assemblies and their map positions provided in clone records. Clones mapping to specific genomic regions can also be searched for using the NCBI Clone Finder tool, which accepts queries based on sequence coordinates or features such as gene or transcript names. Clone DB makes reports of library, clone and placement data on its FTP site available for download. With Clone DB, users now have available to them a centralized resource that provides them with the tools they will need to make use of these important research reagents. 23164613 The serotonin receptor 7 promotes neurite outgrowth via ERK and Cdk5 signaling pathways. Serotonergic neurotransmission is mediated by at least 14 subtypes of 5-HT receptors. Among these, the CNS serotonin receptor 7 (5-HTR7) is involved in diverse physiological processes. Here we show that treatment of murine striatal and cortical neuronal cultures with 5-HTR7 agonists (8-OH-DPAT and LP-211) significantly enhances neurite outgrowth. This effect is abolished by the selective 5-HTR7 antagonist SB-269970, by the ERK inhibitor U0126, by the cyclin-dependent kinase 5 (Cdk5) inhibitor roscovitine, as well as by cycloheximide, an inhibitor of protein synthesis. These data indicate that 5-HTR7 activation stimulates extensive neurite elongation in CNS primary cultures, subserved by ERK and Cdk5 activation, and de novo protein synthesis. Two-dimensional (2D) gel electrophoresis coupled to Western blot analyses reveals both qualitative and quantitative expression changes in selected cytoskeletal proteins, following treatment of striatal primary cultures with LP-211. In particular, the 34 kDa isoform of MAP1B is selectively expressed in stimulated cultures, consistent with a role of this protein in tubulin polymerization and neurite elongation. In summary, our results show that agonist-dependent activation of the endogenous 5-HTR7 in CNS neuronal primary cultures stimulates ERK- and Cdk5-dependent neurite outgrowth, sustained by modifications of cytoskeletal proteins. These data support the hypothesis that the 5-HTR7 might play a crucial role in shaping neuronal morphology and behaviorally relevant neuronal networks, paving the way to new approaches able to modulate CNS connectivity. 23411213 Simultaneous determination of aflatoxin B(1) and ochratoxin A in licorice roots and fritillary bulbs by solid-phase extraction coupled with high-performance liquid chromatography-tandem mass spectrometry. An effective method was developed for screening licorice roots and fritillary bulbs for contamination by aflatoxin B(1) and ochratoxin A using high-performance liquid chromatography connected to tandem mass spectrometry (HPLC-MS/MS). The samples were pre-concentrated and purified using solid-phase extraction, which provided satisfactory results. The separation was performed on a Waters Xbridge(TM) C18 column with a linear gradient of acetonitrile - water containing 5mM ammonium acetate. The MS spectrum was acquired in positive mode with both single quadrupole (Q1) and multiple reaction monitoring (MRM). The optimised method offered a good linear correlation (r(2)>0.9967), excellent precision (RSD<2.83%) and acceptable recovery (from 92.78 to 105.37%). The limits of detection (LOD) and the limits of quantification (LOQ) were less than 0.024 μg/kg and 0.095 μg/kg, respectively. The validated method was successfully applied to the rapid screening for AFB(1) and OTA in licorice roots and fritillary bulbs. 22918066 An unusual cause of factitious arthritis. Septic arthritis and toxic synovitis are clinical conditions that can develop in association with various causes and involve symptoms such as pain, swelling, redness, sensitivity and restricted movement in the joint. A 42-year-old male presented to the emergency department with severe joint pain and nausea after injecting a 1-cc mixture of turpentine oil, eucalyptus oil, mint oil and thyme oil, which he purchased from an alternative medicine store, into his right knee with a syringe because of chronic knee pain. Ballottement and sensitivity were present at physical examination. Knee puncture yielded 60 cc of cloudy fluid. There was no growth in the material obtained. Improvement was observed following subsequent arthroscopic washing of the joint space and IV antibiotherapy, and the patient was discharged on day 21 of hospitalization with oral antibiotic and analgesic therapy. Intra-articular injection of foreign bodies into the knee joint space for therapeutic purposes, as in this case report, is a very rare occurrence, but may lead to potentially complicated arthritis. 23411199 Quantification by UHPLC of total individual polyphenols in fruit juices. The present work proposes a new UHPLC-PDA-fluorescence method able to identify and quantify the main polyphenols present in commercial fruit juices in a 28-min chromatogram. The proposed method improve the IFU method No. 71 used to evaluate anthocyanins profiles of fruit juices. Fruit juices of strawberry, American cranberry, bilberry, sour cherry, black grape, orange, and apple, were analysed identifying 70 of their main polyphenols (23 anthocyanins, 15 flavonols, 6 hydroxybenzoic acids, 14 hydroxycinnamic acids, 4 flavanones, 2 dihydrochalcones, 4 flavan-3-ols and 2 stilbenes). One standard polyphenol of each group was used to calculate individual polyphenol concentration presents in a juice. Total amount of polyphenols in a fruit juice was estimated as total individual polyphenols (TIP). A good correlation (r(2)=0.966) was observed between calculated TIP, and total polyphenols (TP) determined by the well-known colorimetric Folin-Ciocalteu method. In this work, the higher TIP value corresponded to bilberry juice (607.324 mg/100mL fruit juice) and the lower to orange juice (32.638 mg/100mL fruit juice). This method is useful for authentication analyses and for labelling total polyphenols contents of commercial fruit juices. 22917637 Catalytic activities of a cocaine hydrolase engineered from human butyrylcholinesterase against (+)- and (-)-cocaine. It can be argued that an ideal anti-cocaine medication would be one that accelerates cocaine metabolism producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway, i.e., hydrolysis catalyzed by butyrylcholinesterase (BChE) in plasma. However, wild-type BChE has a low catalytic efficiency against naturally occurring (-)-cocaine. Interestingly, wild-type BChE has a much higher catalytic activity against unnatural (+)-cocaine. According to available positron emission tomography (PET) imaging analysis using [(11)C](-)-cocaine and [(11)C](+)-cocaine tracers in human subjects, only [(11)C](-)-cocaine was observed in the brain, whereas no significant [(11)C](+)-cocaine signal was observed in the brain. The available PET data imply that an effective therapeutic enzyme for treatment of cocaine abuse could be an exogenous cocaine-metabolizing enzyme with a catalytic activity against (-)-cocaine comparable to that of wild-type BChE against (+)-cocaine. Our recently designed A199S/F227A/S287G/A328 W/Y332G mutant of human BChE has a considerably improved catalytic efficiency against (-)-cocaine and has been proven active in vivo. In the present study, we have characterized the catalytic activities of wild-type BChE and the A199S/F227A/S287G/A328 W/Y332G mutant against both (+)- and (-)-cocaine at the same time under the same experimental conditions. Based on the obtained kinetic data, the A199S/F227A/S287G/A328 W/Y332G mutant has a similarly high catalytic efficiency (kcat/KM) against (+)- and (-)-cocaine, and indeed has a catalytic efficiency (kcat/KM=1.84×10(9)M(-1)min(-1)) against (-)-cocaine comparable to that (kcat/KM=1.37×10(9)M(-1)min(-1)) of wild-type BChE against (+)-cocaine. Thus, the mutant may be used to effectively prevent (-)-cocaine from entering brain and producing physiological effects in the enzyme-based treatment of cocaine abuse. 23371055 In obese postmenopausal women, bone microarchitecture and strength are not commensurate to greater body weight. The OFELY study. Obesity is associated with higher areal bone density (aBMD) but its protective effect on the risk of fracture is controversial. We aimed to analyse bone microarchitecture and biomechanical properties in obese (OB) postmenopausal French women compared with normal weight (NW) women. A matched case-control study from the OFELY cohort was conducted in 63 OB women (BMI>30, mean age69±8 years) age-matched with 126 NW women (19DON>ZEA>FB1. At cytotoxic doses of individual mycotoxins, all mixtures gave reduced cell viability compared to control. At noncytotoxic concentrations of individual mycotoxins, all mixtures were cytotoxic with DON-NIV, DON-ZEA, DON-NIV-FB1, DON-ZEA-FB1, NIV-ZEA-FB1 and all four mixed causing the greatest loss of cell viability. The latter observation in particular raises concerns over safety margins based on single toxin species, and suggests that the effects of multiple complex mixtures need to be better understood to assess health risks. 23623795 The effect of freeze-drying parameters and formulation composition on IgG stability during drying. The objective of this study was to explore the effects of freeze-drying parameters and formulation composition on polyclonal IgG stability during processing. Samples were freeze-dried with different primary drying pressures and secondary drying heating rates. After drying, changes in IgG in vitro binding activity, monomer recovery, average particle size, and polydispersity were studied from the rehydrated lyophilizates. Significant trends were not observed in binding activities or monomer recoveries, but increases in particle size and polydispersity were observed when using lower primary drying pressure. This effect could no longer be observed when sodium phosphate buffer was removed from the formulation. Altering the secondary drying heating rates did not result in any measurable changes in protein stability. 23570470 Disclosure of individual pharmacogenomic results in research projects: when and what kind of information to return to research participants. In the growing field of genomics, the utility of returning certain research results to participants has become a highly debated issue. Existing guidelines are not explicit as to the kind of genomic information that should be returned to research participants. Moreover, very few current recommendations and articles in the literature address the return of pharmacogenomic results. Although genetics and pharmacogenomics have many similarities, the circumstances in which disclosure could have a benefit for the participants are different. This review aims to describe the conditions in which disclosure of pharmacogenomic results is appropriate. 23151610 One hundred years of helicene chemistry. Part 2: stereoselective syntheses and chiral separations of carbohelicenes. Carbohelicenes generally incorporate a helical, distorted, conjugated, polyaromatic system with ortho-fused benzenoid rings, which is a fundamental molecular characteristic of this class of compounds. They have been described as "molecules in distress" due to their distortion. The generation of a chiral helicity in helicenes was observed because of a severe intramolecular steric strain. Helicity is a molecular necessity in the higher series of carbohelicenes, when at some point, a helical pitch occurs when a second coil is formed. The most interesting properties resulting from such molecular distortion are the very high chiroptical and circular dichroism values. For instance, the resolution of some helicene racemates by "hand picking" of a few homochiral single enantiomeric crystals allowed for a measurement of their optical rotation. Due to that intrinsic chirality spanned over a large polyaromatic template, preliminary results clearly established the efficiency of carbohelicenes to induce asymmetry and chirality in organic synthesis and in supramolecular chemistry. Additionally, they have some potential uses in several fields: materials science, nanoscience, chemical biology and supramolecular chemistry. It has encouraged many attempts to develop new asymmetric syntheses of carbohelicenes, as well as some chiral separations of enantiomers and diastereoisomers. This review is thus dedicated to carbohelicene chirality. It gathered a substantial collection of data, and a comprehensive review on the preparations of enantioenriched helicenes, either from an asymmetric synthesis or from a chiral separation. Utilizations of non-racemic helicenes and their applications will be treated in the following review (Part 3), and will not be the subject of this manuscript. 23311695 Time-resolved single molecule fluorescence spectroscopy of an α-chymotrypsin catalyzed reaction. Single molecule fluorescence spectroscopy offers great potential for studying enzyme kinetics. A number of fluorescence reporter systems allow for monitoring the sequence of individual reaction events with a confocal microscope. When using a time-correlated single photon counting (TCSPC) detection scheme, additional information about the fluorescence lifetimes of the fluorophores can be obtained. We have applied a TCSPC detection scheme for studying the kinetics of α-chymotrypsin hydrolyzing a double-substituted rhodamine 110-based fluorogenic substrate in a two-step reaction. On the basis of the lifetime information, it was possible to discriminate the intermediate and the final product. At the high substrate concentration used, only the formation of the intermediate was observed. No rebinding of the intermediate followed by rhodamine 110 formation occurred at these high concentrations. We have further found no alterations in the fluorescence lifetime of this intermediate that would indicate changes in the local environment of the fluorophore originating from strong interactions with the enzyme. Our results clearly show the power of using lifetime-resolved measurements for investigating enzymatic reactions at the single molecule level. 23547706 Oxadiazole-isopropylamides as potent and non-covalent proteasome inhibitors. Abstract Screening of the 50,000 ChemBridge compound library led to the identification of the oxadiazole-isopropylamide 1 (PI-1833) which inhibited CT-L activity (IC50 0.60 μM) with little effects on the other 2 major proteasome proteolytic activities, T-L and PGPH-L. LC/MS-MS and dialysis show that 1 is a non-covalent and rapidly reversible CT-L inhibitor. Focused library synthesis provided 11ad (PI-1840) with CT-L activity (IC50 27 nM). Detailed SAR studies indicate that the amide moiety and the 2 phenyl rings are sensitive toward modifications. Hydrophobic residues, such as propyl or butyl, in the para-position (not ortho or meta) of the A-ring and a meta-pyridyl group as B-ring significantly improve activity. Compound 11ad (IC50 0.37 µM) is more potent than 1 (IC50 3.5 µM) at inhibiting CT-L activity in intact MDA-MB-468 human breast cancer cells and inhibiting their survival. The activity of 11ad warrants further pre-clinical investigation of this class as non-covalent proteasome inhibitors. 23602891 Pregnancy Outcome following in utero Exposure to Hydroxychloroquine: A prospective comparative observational study. OBJECTIVE: To evaluate pregnancy safety of hydroxychloroquine (HCQ) for rheumatologic diseases. DESIGN: Prospective comparative observational study done at the Israeli teratology information service between 1998 and 2006. RESULTS: 114 HCQ-exposed pregnancies (98.2% in the first trimester, T1) were followed-up and compared with 455 pregnancies of women counseled for non-teratogenic exposure. The difference in the rate of congenital anomalies was not statistically significant [7/97 (7.2%) vs. 15/440 (3.4%), p=0.094]. The analysis was repeated among those exposed in T1 excluding genetic or cytogenetic anomalies or congenital infections [5/95 (5.3%) vs. 14/440 (3.2%), p=0.355]. There were no cases of neonatal lupus erythematosus. The gestational age at delivery was earlier, rate of preterm delivery higher, and birth weight lower, in the HCQ group. CONCLUSION: The present study suggests that HCQ treatment in pregnancy is not a major human teratogen. The earlier gestational age and lower birth weight might be associated with maternal disease. 23103426 Mitochondrial electron transfer chain complexes inhibition by different organochalcogens. Mitochondrial dysfunction plays a pivotal role in the cell toxicology and death decision. The aim of the present study was to investigate the effect of three organocompounds (ebselen [Ebs], diphenyl diselenide [(PhSe)(2)] and diphenyl ditelluride [(PhTe)(2)]) on mitochondrial complexes (I, II, I-III, II-III and IV) activity from rat liver and kidney to determine their potential role as molecular targets of organochalcogens. All studied organochalcogens caused a statistically significant inhibition of the mitochondrial complex I activity. Ebs and (PhTe)(2) caused a statistically significant inhibition of the mitochondrial complex II activity in both hepatic and renal membranes. Hepatic mitochondrial complex II activity was practically unchanged by (PhSe)(2), whereas it significantly inhibited renal complex II activity. Mitochondrial complex IV activity was practically unchanged by the organochalcogens. Furthermore, organochalcogens inhibited the mitochondrial respiration supported by complex I or complex II substrates. The inhibitory effect of Ebs, (PhSe)(2) and (PhTe)(2) on mitochondrial complex I was prevented by NADH, but it was not prevented by catalase (CAT) and/or superoxide dismutase (SOD). Additionally, the organochalcogens-induced inhibition of complex I and II was completely reversed by reduced glutathione (GSH). In conclusion, Ebs, (PhSe)(2) and (PhTe)(2) were more effective inhibitors of renal and hepatic mitochondrial complex I than complex II, whereas complexes III and IV were little modified by these compounds. Taking into account the presented results, we suggest that organochalcogen-induced mitochondrial complexes I and II inhibition can be mediated by their thiol oxidation activity, i.e., Ebs, (PhSe)(2) and (PhTe)(2) can oxidize critical thiol groups from mitochondrial complexes I and II. So, mitochondrial dysfunction can be considered an important factor in the toxicity of Ebs, (PhSe)(2) and (PhTe)(2). 22548364 A new cyclododeca[d]oxazole derivative from Streptomyces spp. CIBYL1. A novel secondary metabolite, N-trans-cinnamoyl 2-amino-3a,4,5,6,7,8,9,10,11,12,13,13a-dodecahydrocyclododeca[d]oxazole (1), was isolated from Streptomyces spp. CIBYL1, along with five known compounds, pimprinine (2), (3R,4S,5R,6R)-3,4,5,6-tetrahydro-4-hydroxy-3,5,6-trimethyl-2H-pyran-2-one (3), indolyl-3-carboxylic acid (4), 2-phenylacetamide (5) and di(1H-pyrrol-2-yl)methanone (6). The structures of these metabolites were elucidated on the basis of extensive analysis of spectroscopic data, including OR, IR, HRMS, 1D and 2D NMR data and chemical derivation. 23416650 Single and 90-day repeated oral dose toxicity studies of fermented Rhus verniciflua stem bark extract in Sprague-Dawley rats. Fermented Rhus verniciflua stem bark (FRVSB) extract, an urushiol-free extract of Rhus verniciflua Stokes (RVS) fermented with Fomitella fraxinea, has various biological activities. The present study was carried out to investigate the potential toxicity of the FRVSB extract following single and repeated oral administration to Sprague-Dawley rats. In the single dose toxicity study, the FRVSB extract was administered orally to male and female rats at single doses of 0, 2500, 5000, and 10,000mg/kg. No animals died and no toxic changes were observed in clinical signs, body weight, and necropsy findings during the 15-day period following administration. In the repeated dose toxicity study, the FRVSB extract was administered orally to male and female rats for 90days at doses of 0, 556, 1667, and 5000mg/kg/day. There were no treatment-related adverse effects in clinical signs, body weight, food and water consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology at any dose tested. The approximate lethal dose of the FRVSB extract was >10,000mg/kg in both genders, the oral no-observed-adverse-effect level of the FRVSB extract was >5000mg/kg/day in both genders, and no target organs were identified. 23401472 Epigenetic Regulation Is a Crucial Factor in the Repression of UGT1A1 Expression in the Human Kidney. Human UDP-glucuronosyltransferase (UGT) 1A1 catalyzes the metabolism of numerous clinically and pharmacologically important compounds such as bilirubin and SN-38. UGT1A1 is predominantly expressed in the liver and intestine, but not in the kidney. The purpose of this study was to uncover the mechanism of the tissue-specific expression of UGT1A1, focusing on its epigenetic regulation. Bisulfite sequence analysis revealed that the CpG-rich region near the UGT1A1 promoter (-85 to +40) was hypermethylated (83%) in the kidney, whereas it was hypomethylated (37%) in the liver. A chromatin immunoprecipitation assay demonstrated that histone H3 near the promoter was hypoacetylated in the kidney but was hyperacetylated in the liver; this hyperacetylation was accompanied by the recruitment of HNF1α to the promoter. The UGT1A1 promoter in human kidney-derived HK-2 cells that do not express UGT1A1 was fully methylated, but was relatively unmethylated in human liver-derived HuH-7 cells that express UGT1A1. Treatment with 5-aza-2'-deoxycytidine (5-Aza-dC), an inhibitor of DNA methylation, resulted in an increase of UGT1A1 mRNA expression in both cell types, but the increase was much larger in HK-2 cells than in HuH-7 cells. The transfection of an HNF1α expression plasmid into the HK-2 cells resulted in an increase of UGT1A1 mRNA only in the presence of 5-Aza-dC. In summary, we found that DNA hypermethylation along with histone hypoacetylation interferes with the binding of HNF1α, resulting in the defective expression of UGT1A1 in the human kidney. Thus, epigenetic regulation is a crucial determinant of tissue-specific expression of UGT1A1. 23214423 Anisotropy of chemical bonding in semifluorinated graphite C2F revealed with angle-resolved X-ray absorption spectroscopy. Highly oriented pyrolytic graphite characterized by a low misorientation of crystallites is fluorinated using a gaseous mixture of BrF(3) with Br(2) at room temperature. The golden-colored product, easily delaminating into micrometer-size transparent flakes, is an intercalation compound where Br(2) molecules are hosted between fluorinated graphene layers of approximate C(2)F composition. To unravel the chemical bonding in semifluorinated graphite, we apply angle-resolved near-edge X-ray absorption fine structure (NEXAFS) spectroscopy and quantum-chemical modeling. The strong angular dependence of the CK and FK edge NEXAFS spectra on the incident radiation indicates that room-temperature-produced graphite fluoride is a highly anisotropic material, where half of the carbon atoms are covalently bonded with fluorine, while the rest of the carbon atoms preserve π electrons. Comparison of the experimental CK edge spectrum with theoretical spectra plotted for C(2)F models reveals that fluorine atoms are more likely to form chains. This conclusion agrees with the atomic force microscopy observation of a chain-like pattern on the surface of graphite fluoride layers. 23553595 Aerosol particle size does not predict pharmacokinetic determined lung dose in children. In vitro measures of aerosol particles size, such as the fine particle mass, play a pivotal role for approval of inhaled anti-asthmatic drugs. However, the validity as a measure of dose to the lungs in children lacks evidence. In this study we investigated for the first time the association between an in vivo estimate of lung dose of inhaled drug in children and the corresponding particle size segments assessed ex vivo. Lung dose of fluticasone propionate after inhalation from a dry powder inhaler (Diskus®) was studied in 23 children aged 4-7 and 12-15 years with mild asthma. Six-hour pharmacokinetics was assessed after single inhalation. The corresponding emitted mass of drug in segments of aerosol particle size was assessed ex vivo by replicating the inhalation flows recorded by transducers built into the Diskus® inhaler and re-playing them in a breathing simulator. There was no correlation between any inhaled particle size segment and lung dose assessed by pharmacokinetics and adjusted for age and body size. Measures of particles size segments were not related to lung dose in children. Until further evidence is provided it may be warranted to emphasize pharmacokinetic or pharmacodynamic assessments of drug delivery to the lung. 23411334 Redox properties of catechins and enriched green tea extracts effectively preserve L-5-methyltetrahydrofolate: assessment using cyclic voltammetry analysis. A cyclic voltammetry (CV) study was performed in pH 5.5 Britton-Robinson buffer at room temperature to study the stability of 1mM l-5-methyltetrahydrofolate (l-5-MTHF) in combination with epigallocatechin-gallate-enriched extract (EGCGe) and epigallocatechin-enriched extract (EGCe). The combination of l-5-MTHF with enriched catechin extracts provided enhanced stability of l-5-MTHF over a period of 12h under ambient air conditions at pH 5.5. CV experiments showed that increasing the concentrations of EGCGe or EGCe extracts from 80 to 400mg/L produced a decrease in the second oxidation peak of l-5-MTHF. Thus, we calculated that l-5-MTHF remained at nearly 90% when in the presence of enriched tea extracts, compared to 74% without the tea antioxidants. The catechins responsible for this preservation were EGCG and C, confirmed by LC-MS. Compared to covalent link only low interaction (hydrogen bonds) between the different catechins present in the tea extract would stabilise l-5-MTHF. Rather, it was hypothesised that EGCGe and EGCe were effective agents to preserve l-5-MTHF, through a mechanism that also involved the redox potential of catechins to maintain l-5-MTHF in its reduced form. 23422226 Lanostane-type triterpenoid and steroid from the stem bark of Klainedoxa gabonensis. A new lanostane triterpenoid, 2-hydroxy-24-methylenelanostan-1,8-dien-3-one named klainedoxalanostenone (1) with one new steroid, 6-O-acyl-β-d-glucosyl-β-sitosterol named klainedoxasterol (2) together with ten known compounds including six triterpenoids (3-8), two steroids (9, 10) and two tanins (11, 12) were isolated from the stem bark of Klainedoxa gabonensis. To the best of our knowledge, this is the first report of lanostane-type triterpenoids from this genus. Their structures were determined by extensive analysis of spectroscopic data (1D and 2D NMR, MS) and by comparison with literature data. The xanthine oxidase inhibitory activity of nine compounds (1-6, 8, 10 and 11) were evaluated. Compound 5 showed a good xanthine oxidase inhibitory activity; the other tested compounds were moderately active. 23391485 Effect of low dose Bisphenol A on the early differentiation of human embryonic stem cells into mammary epithelial cells. It has been previously reported that Bisphenol A (BPA) can disturb the development of mammary structure and increase the risk of breast cancer in experimental animals. In this study, an in vitro model of human embryonic stem cell (hESC) differentiation into mammary epithelial cells was applied to investigate the effect of low dose BPA on the early stages of mammogenesis. A newly established hESC line was directionally differentiated into mammary epithelial cells by a well-established three-dimensional (3D) culture system. The differentiated mammary epithelial cells were characterized by immunofluorescence and western blotting assay, and were called induced differentiated mammary epithelial cells (iDMECs) based on these data. The hESCs were treated with low doses of BPA range 10(-9)-10(-6)M during the differentiation process, with DMSO as the solvent control and 17-β-estrodiol (E2) as the estrogen-positive control. Our results showed that low dose BPA and E2 could influence the mammosphere area of iDMECs and upregulate the expression level of Oct4 and Nanog proteins, while only BPA could downregulate the expression of E-cadherin protein. Taken together, this study provides some insights into the effects of low dose BPA on the early differentiation stage of mammary epithelial cells and suggests an easier canceration status of iDMECs under the effect of low dose BPA during its early differentiation stage. 23411082 Complexation of Hypocrellin A with Al3+ in water solution and the photodynamic therapy study. The complex of Hypocrellin A with Al(3+) is prepared in water solution by a facile method. The water-solubility and stability of complexes are improved. Irradiation of Al(3+)-HA complex results in higher efficient generation of singlet oxygen ((1)O2) and photocleavage ability to CT DNA than HA. In vitro studies have illustrated that the Al(3+)-HA complex has anti-cancer activity. 22080035 The influence of the intensity of smoking and years of work in the metallurgy on pro-oxidant/antioxidant balance in the blood of smelters. The aim of this study was to investigate the effect of cigarette smoking and occupational exposure to heavy metals on the degree of pro-oxidant/antioxidant imbalance in smelters. The investigations were performed on the blood and urine of 400 subjects: 300 male copper smelters and 100 nonexposed male subjects. Biological material was divided into three groups: nonsmokers, those who smoked less than 20 cigarettes a day and those who smoked more than 20 cigarettes a day. The results showed a significant increase in the concentration of lead, cadmium and arsenic in the blood and urine of smelters, while smoking more than 20 cigarettes a day caused a further increase in the concentration of these metals. The level of malondialdehyde was approximately twofold higher in the plasma of the smelters compared to the control group. We have observed a disturbance in the level of antioxidants in erythrocyte lysate manifested by an increase in metallothionein and glutathione concentrations as well as superoxide dismutase and glutathione peroxidase activities and the decrease in glutathione S-transferase activity. Cigarette smoking, years of work in metallurgy and age of smelters were additional factors significantly affecting the pro-oxidant/antioxidant balance. 23298612 Advancements in the field of intravaginal siRNA delivery. The vaginal tract is a suitable site for the administration of both local and systemic acting drugs. There are numerous vaginal products on the market such as those approved for contraception, treatment of yeast infection, hormonal replacement therapy, and feminine hygiene. Despite the potential in drug delivery, the vagina is a complex and dynamic organ that requires greater understanding. The recent discovery that injections of double stranded RNA (dsRNA) in Caenorhabditis elegans (C. elegans) results in potent gene specific silencing, was a major scientific revolution. This phenomenon known as RNA interference (RNAi), is believed to protect host genome against invasion by mobile genetic elements such as transposons and viruses. Gene silencing or RNAi has opened new potential opportunities to study the function of a gene in an organism. Furthermore, its therapeutic potential is being investigated in the field of sexually transmitted infections such as human immunodeficiency virus (HIV) and other diseases such as age-related macular degeneration (AMD), diabetes, hypercholesterolemia, respiratory disease, and cancer. This review will focus on the therapeutic potential of siRNA for the treatment and/or prevention of infectious diseases such as HIV, HPV, and HSV within the vaginal tract. Specifically, formulation design parameters to improve siRNA stability and therapeutic efficacy in the vaginal tract will be discussed along with challenges, advancements, and future directions of the field. 23535288 Aberrant activation of M phase proteins by cell proliferation-evoking carcinogens after 28-day administration in rats. We have previously reported that hepatocarcinogens increase liver cells expressing p21(Cip1), a G1 checkpoint protein and M phase proteins after 28-day treatment in rats. This study aimed to identify early prediction markers of carcinogens available in many target organs after 28-day treatment in rats. Immunohistochemical analysis was performed on Ki-67, p21(Cip1) and M phase proteins [nuclear Cdc2, phospho-Histone H3 (p-Histone H3), Aurora B and heterochromatin protein 1α (HP1α)] with carcinogens targeting different organs. Carcinogens targeting thyroid (sulfadimethoxine; SDM), urinary bladder (phenylethyl isothiocyanate), forestomach (butylated hydroxyanisole; BHA), glandular stomach (catechol; CC), and colon (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and chenodeoxycholic acid) were examined using a non-carcinogenic toxicant (caprolactam) and carcinogens targeting other organs as negative controls. All carcinogens increased Ki-67(+), nuclear Cdc2(+), p-Histone H3(+) or Aurora B(+) carcinogenic target cells, except for both colon carcinogens, which did not increase cell proliferation. On the other hand, p21(Cip1+) cells increased with SDM and CC. HP1α responded only to BHA. Results revealed carcinogens evoking cell proliferation concurrently induced cell cycle arrest at M phase or showing chromosomal instability reflecting aberration in cell cycle regulation, irrespective of target organs, after 28-day treatment. Therefore, M phase proteins may be early prediction markers of carcinogens evoking cell proliferation in many target organs. 23261528 Inhibition of Th1/Th17 responses via suppression of STAT1 and STAT3 activation contributes to the amelioration of murine experimental colitis by a natural flavonoid glucoside icariin. Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in the intestine which involves overproduction of pro-inflammatory cytokines and excessive functions of inflammatory cells. However, current treatments for IBD may have potential adverse effects including steroid dependence, infections and lymphoma. Therefore new therapies or drug candidates for the treatment of IBD are desperately needed. In the present study we found that icariin, a major bioactive compound from plants in Epimedium family, exerted protective effect on intestinal inflammation in mice induced by dextran sulfate sodium. Oral administration of icariin significantly attenuated the disease progression and alleviated the pathological changes of colitis. It also inhibited the production of pro-inflammatory cytokines and expression of p-p65, p-STAT1 and p-STAT3 in colon tissues. Further study showed that icariin dose-dependently inhibited the proliferation and activation of T lymphocytes, and suppressed pro-inflammatory cytokine levels of activated T cells. Moreover, icariin treatment inhibited the phosphorylations of STAT1 and STAT3 in CD4(+) T cells, which were the crucial transcription factors for Th1 and Th17 respectively. Taken together, these results indicate that icariin is a potential therapeutic agent for IBD. 23628508 Aspidin BB, a phloroglucinol derivative, induces cell cycle arrest and apoptosis in human ovarian HO-8910 cells. Aspidin BB, an effective phloroglucinol derivative from Dryopteris fragrans (L.) Schott, has been previously reported to exert high biological activities. In this study, we analyzed the underlying mechanisms of aspidin BB on human ovarian cancer cell line, HO-8910. Aspidin BB significantly inhibited HO-8910 cell proliferation in a dose- and time-dependent manner. The IC50 values were 15.02, 25.79 and 68.81μM after 72, 48 and 24h treatment, respectively. Meanwhile, aspidin BB markedly induced apoptosis evidenced by characteristic apoptotic morphological changes, nuclear DNA fragmentation, annexin V-FITC/propidium iodide (PI) double staining and S peak. Western blot analysis showed that aspidin BB suppressed Bcl-2 expression and enhanced Bax expression to desintegrate the outer mitochondrial membrane, then caused cytochrome c release which led to the activation of effector caspase-3, and further cleaved the poly ADP-ribose polymerase (PARP) in the nucleus, finally induced cell apoptosis. Furthermore, aspidin BB provoked S phase arrest in HO-8910 cells with up-regulation of pRb, E2F1, CDK2, cyclin E and cyclin A proteins. Taken together, these findings support the conclusion that aspidin BB exhibits cytotoxicity towards human ovarian cancer HO-8910 cells through induction of apoptosis via mitochondrial pathway and arresting cell cycle progression in S phase. 23255471 Tungsten carbide nanoparticles as efficient cocatalysts for photocatalytic overall water splitting. Tungsten carbide exhibits platinum-like behavior, which makes it an interesting potential substitute for noble metals in catalytic applications. Tungsten carbide nanocrystals (≈5 nm) are directly synthesized through the reaction of tungsten precursors with mesoporous graphitic C(3)N(4) (mpg-C(3)N(4)) as the reactive template in a flow of inert gas at high temperatures. Systematic experiments that vary the precursor compositions and temperatures used in the synthesis selectively generate different compositions and structures for the final nanocarbide (W(2)C or WC) products. Electrochemical measurements demonstrate that the WC phase with a high surface area exhibits both high activity and stability in hydrogen evolution over a wide pH range. The WC sample also shows excellent hydrogen oxidation activity, whereas its activity in oxygen reduction is poor. These tungsten carbides are successful cocatalysts for overall water splitting and give H(2) and O(2) in a stoichiometric ratio from H(2)O decomposition when supported on a Na-doped SrTiO(3) photocatalyst. Herein, we present tungsten carbide (on a small scale) as a promising and durable catalyst substitute for platinum and other scarce noble-metal catalysts in catalytic reaction systems used for renewable energy generation. 23418960 Preparation and characterization of progesterone dispersions using supercritical carbon dioxide. Abstract Context: Supercritical fluid methods offer an alternative to conventional mixing methods, particularly for heat sensitive drugs and where an organic solvent is undesirable. Objective: To design, develop and construct a unit for the particles from a gas-saturated suspension/solution (PGSS) method and form endogenous progesterone (PGN) dispersion systems using SC-CO(2). Materials and methods: The PGN dispersions were manufactured using three selected excipients: polyethylene glycol (PEG) 400/4000 (50:50), Gelucire 44/14 and D-α-tocopheryl PEG 1000 succinate (TPGS). Semisolid dispersions of PGN prepared by PGSS method were compared to the conventional methods; comelting (CM), cosolvent (CS) and physical mixing (PM). The dispersion systems made were characterized by Raman and Fourier transform infrared (FTIR) spectroscopies, X-ray powder diffraction (XRPD), scanning electron microscopy (SEM), PGN recovery, uniformity and in vitro dissolution, analyzed by high-performance liquid chromatography (HPLC). Results: Raman spectra revealed no changes in the crystalline structure of PGN treated with SC-CO(2) compared to that of untreated PGN. XRPD and FTIR showed the presence of peaks and bands for PGN confirming that PGN has been incorporated well with each individual excipient. All PGN dispersions prepared by the PGSS method resulted in the improvement of PGN dissolution rates compared to that prepared by the conventional methods and untreated PGN after 60 min (p value < 0.05). Conclusion: The novel PGN dispersions prepared by the PGSS method offer the great potential to enhance PGN dissolution rate, reduce preparation time and form stable crystalline dispersion systems over those prepared by conventional methods. 23537315 Hydrocarbon-soluble nanocatalysts with no bulk phase: coplanar, two-coordinate arrays of the base metals. A structurally unique class of hydrocarbon-soluble, ancillary-ligand-free, tetrametallic Co(I) and Ni(I) clusters is reported. The highly unsaturated complexes are supported by simple, sterically bulky phosphoranimide ligands, one per metal. The electron-rich nitrogen centers are strongly bridging but sterically limited to bimetallic interactions. The hydrocarbon-soluble clusters consist of four coplanar metal centers, mutually bridged by single nitrogen atoms. Each metal center is monovalent, rigorously linear, and two-coordinate. The clusters are in essence two-dimensional atomic-scale "molecular squares," a structural motif adapted from supramolecular chemistry. Both clusters exhibit high solution-phase magnetic susceptibility at room temperature, suggesting the potential for applications in molecular electronics. Designed to be catalyst precursors, both clusters exhibit high activity for catalytic hydrogenation of unsaturated hydrocarbons at low pressure and temperature. 23386600 Recommendations for meeting the pediatric patient's need for a clinical pharmacist: a joint opinion of the Pediatrics Practice and Research Network of the American College of Clinical Pharmacy and the Pediatric Pharmacy Advocacy Group. Children warrant access to care from clinical pharmacists trained in pediatrics. The American College of Clinical Pharmacy Pediatrics Practice and Research Network (ACCP Pediatrics PRN) released an opinion paper in 2005 with recommendations for improving the quality and quantity of pediatric pharmacy education in colleges of pharmacy, residency programs, and fellowships. Although progress has been made in increasing the availability of pediatric residencies, there is still much to be done to meet the direct care needs of pediatric patients. The purpose of this joint opinion paper is to outline strategies and recommendations for expanding the quality and capacity of pediatric clinical pharmacy practitioners by elevating the minimum expectations for pharmacists entering pediatric practice, standardizing pediatric pharmacy education, expanding the current number of pediatric clinical pharmacists, and creating an infrastructure for development of pediatric clinical pharmacists and clinical scientists. These recommendations may be used to provide both a conceptual framework and action items for schools of pharmacy, health care systems, and policymakers to work together to increase the quality and quantity of pediatric training, practice, and research initiatives. 23432095 Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer. Castrate-resistant prostate cancer (CRPC) is a fatal, metastatic form of prostate cancer. CRPC is characterized by reactivation of the androgen axis due to changes in androgen receptor signaling and/or adaptive intratumoral androgen biosynthesis. AKR1C3 is upregulated in CRPC where it catalyzes the formation of potent androgens. This makes AKR1C3 a target for the treatment of CRPC. AKR1C3 inhibitors should not inhibit AKR1C1/AKR1C2, which inactivate 5α-dihydrotestosterone. Indomethacin, used to inhibit cyclooxygenase, also inhibits AKR1C3 and displays selectivity over AKR1C1/AKR1C2. Parallel synthetic strategies were used to generate libraries of indomethacin analogues, which exhibit reduced cyclooxygenase inhibitory activity but retain AKR1C3 inhibitory potency and selectivity. The lead compounds inhibited AKR1C3 with nanomolar potency, displayed >100-fold selectivity over AKR1C1/AKR1C2, and blocked testosterone formation in LNCaP-AKR1C3 cells. The AKR1C3·NADP(+)·2'-des-methyl-indomethacin crystal structure was determined, and it revealed a unique inhibitor binding mode. The compounds reported are promising agents for the development of therapeutics for CRPC. 23201439 New modified β-cyclodextrin derivatives as detoxifying agents of chemical warfare agents (I). Synthesis and preliminary screening: evaluation of the detoxification using a half-quantitative enzymatic assay. Current treatments of organophosphorus nerve agents poisoning are imperfect, and more efficient medical countermeasures need to be developed. Chemical scavengers based on β-cyclodextrin displayed promising results, but further investigations have to be performed to evaluate the possibility of application of substituted cyclodextrins as potential detoxification agents. Herein, five new cyclodextrins scavengers were synthesized. New optimal conditions for regioselectively monosubstitution of β-cyclodextrin at O-2 position were then studied to access to key intermediates. After these optimizations, a new series of three permethylated derivatives was developed, and two compounds bearing an α-nucleophilic group via a three carbon atoms linker were prepared. The ability of these five scavengers to detoxify nerve agents (cyclosarin, soman, tabun and VX) was evaluated by a semi-quantitative biological assay. All the modified cyclodextrins significantly decreased the inhibitory effect of chemical warfare G agents on acetylcholinesterase activity. For this purpose, we showed that the specific interactions between the organophosphorus compound and the oligosaccharidic moiety of the scavenger played a pivotal role in the detoxification process. 23474319 In vitro interceptive and reparative effects of myo-inositol against copper-induced oxidative damage and antioxidant system disturbance in primary cultured fish enterocytes. Copper (Cu) is essential for normal cellular processes in most eukaryotic organisms but is toxic in excess. Our previous study reported that a nutrient antioxidant, myo-inositol (MI), can protect fish from Cu-induced oxidative injury; however, the mechanisms involved are not fully understood. Therefore, the present study aimed to analyze potential pathways. First, to investigate the hypothesis that MI protects enterocytes against Cu toxicity via the intercept pathway, enterocytes were treated with different concentrations of MI (0-75mg/L medium) in the presence of 6mg/L of Cu for 24h (Experiment 1). Next, we investigated the potential reparative role of MI after a Cu challenge (Experiment 2). The results of Experiment 1 indicated that cells exposed to Cu alone for 24h exhibited increases in lactate dehydrogenase release (LDH), malondialdehyde (MDA) formation and protein oxidation (P<0.05). Notably, a dose-dependent inhibitory effect on LDH release was observed with all doses of MI. Moreover, co-treatment with MI completely inhibited Cu-induced protein carbonyl (PC) formation. However, Cu-induced lipid peroxidation was not altered by MI co-treatment. Additionally, Cu exposure suppressed total-superoxide dismutase (T-SOD), CuZnSOD and catalase (CAT) activities, and these changes were completely blocked by co-treatment with sufficient MI concentrations. In contrast, cells exposed to Cu exhibited adaptive increases in reduced glutathione (GSH) content and the activities of anti-hydroxyl radical (AHR), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and glutathione reductase (GR). Interestingly, the Cu-stimulated increases in these antioxidants were blocked by co-treatment with sufficient MI concentrations. The results of Experiment 2 indicated that cell injury (LDH release), lipid peroxidation (MDA formation) and protein oxidation induced by Cu were reversed by subsequent MI treatment. Meanwhile, Cu-induced decreases in alkaline phosphatase (AKP), anti-superoxide anion (ASA), T-SOD and CuZnSOD activities were completely restored by subsequent MI treatment, while the reduced CAT activity was partially restored. However, MI rescues partially restored the adaptive increase in GPx activity induced by Cu, whereas the adaptive increase in reduced GSH content was completely reversed by 75mg/L of MI. However, subsequent MI treatments did not alter the induction of GST activity by Cu. In conclusion, we demonstrated for the first time that MI not only protected enterocytes from Cu-induced oxidative damage but also increased the repair activity in primary enterocytes after challenge with Cu. Moreover, MI-mediated increases in antioxidant enzyme activities contributed to lipid and protein oxidant repair. 23146838 Influence of ovarian and non-ovarian estrogens on weight gain in response to disruption of sweet taste--calorie relations in female rats. Regulation of energy balance in female rats is known to differ along a number of dimensions compared to male rats. Previous work from our lab has demonstrated that in female rats fed dietary supplements containing high-intensity sweeteners that may disrupt a predictive relation between sweet tastes and calories, excess weight gain is demonstrated only when females are also fed a diet high in fat and sugar, and is evidenced primarily in animals already prone to gain excess weight. In contrast, male rats show excess weight gain when fed saccharin-sweetened yogurt supplements when fed both standard chow diets and diets high in fat and sugar, and regardless of their proneness to excess weight gain. The goal of the present experiments was to determine whether ovarian, or other sources of estrogens, contributes to the resistance to excess weight gain in female rats fed standard chow diets along with dietary supplements sweetened with yogurt. Results of the first experiment indicated that when the ovaries were removed surgically in adult female rats, patterns of weight gain were similar in animals fed saccharin-sweetened compared to glucose-sweetened yogurt supplements. In the second experiment, when the ovaries were surgically removed in adult female rats, and local production of estrogens was suppressed with the aromatase inhibitor anastrozole, females fed the saccharin-sweetened yogurt consumed more energy and gained more weight than females fed the glucose-sweetened yogurt. However, when the ovaries were surgically removed prior to the onset of puberty (at 24-25 days of age), females given saccharin-sweetened yogurt along with vehicle gained excess weight. In contrast, weight gain was similar in those given saccharin-sweetened and glucose-sweetened yogurt along with anastrozole. The results suggest that behavioral differences between males and females in response to disruption of sweet→calorie relations may result from differences in patterns of local estrogen production. These differences may be established developmentally during the pubertal period in females. 22997060 Comparison of emetic potencies of the 8-ketotrichothecenes deoxynivalenol, 15-acetyldeoxynivalenol, 3-acetyldeoxynivalenol, fusarenon X, and nivalenol. Although the acute toxic effects of trichothecene mycotoxin deoxynivalenol (DON or vomitoxin), a known cause of human food poisoning, have been well characterized in several animal species, much less is known about closely related 8-ketotrichothecenes that similarly occur in cereal grains colonized by toxigenic fusaria. To address this, we compared potencies of DON, 15-acetyldeoxynivalenol (15-ADON), 3-acetyldeoxynivalenol (3-ADON), fusarenon X (FX), and nivalenol (NIV) in the mink emesis model following intraperitoneal (ip) and oral administration. All five congeners dose-dependently induced emesis by both administration methods. With increasing doses, there were marked decreases in latency to emesis with corresponding increases in emesis duration and number of emetic events. The effective doses resulting in emetic events in 50% of the animals for ip exposure to DON, 15-ADON, 3-ADON, FX, and NIV were 80, 170, 180, 70, and 60 µg/kg bw, respectively, and for oral exposure, they were 30, 40, 290, 30, and 250 µg/kg bw, respectively. The emetic potency of DON determined here was comparable to that reported in analogous studies conducted in pigs and dogs, suggesting that the mink is a suitable small animal model for investigating acute trichothecene toxicity. The use of a mouse pica model, based on the consumption of kaolin, was also evaluated as a possible surrogate for studying emesis but was found unsuitable. From a public health perspective, comparative emetic potency data derived from small animal models such as the mink should be useful for establishing toxic equivalency factors for DON and other trichothecenes. 23574014 Dual-Purpose Polymer Labels for Fluorescent and Mass Cytometric Affinity Bioassays. We describe the synthesis and characterization of a family of poly(N-alkylacrylamide) polymers carrying 2-6 fluorescent dye molecules, ∼70 pendant DTPA (diethylenetriaminepentaacetic acid) groups, and an orthogonal maleimide end-group for covalent attachment to an antibody (Ab). These dual-purpose labels were designed for use in multiplexed immunoassays based on both mass cytometry and fluorescent flow cytometry. A challenge in the polymer synthesis was finding conditions for attaching a sufficient number of dye molecules to each polymer chain. Although attachment of a terminal maleimide to the polymers was not as efficient as anticipated, the end-functional polymers were still effective in labeling Abs. Secondary goat antimouse IgG was labeled with the four dual-label polymers as well as a control polymer, and while the resultant antibody-polymer conjugates showed positive performance in mass cytometric and fluorescent assays, some trials showed problems such as low signal and nonspecific adsorption. Four primary antibody conjugates were prepared and used to stain cells in 4-plex assays. The results of both primary assays are bittersweet in that the CD3-FITC and CD45-DyLight 649 conjugates performed well, while the CD13-DyLight 405 and the CD38-DyLight 549 conjugates did not. 23391254 A continuous network of lipid nanotubes fabricated from the gliding motility of kinesin powered microtubule filaments. Synthetic interconnected lipid nanotube networks were fabricated on the millimeter scale based on the simple, cooperative interaction between phospholipid vesicles and kinesin-microtubule (MT) transport systems. More specifically, taxol-stabilized MTs, in constant 2D motion via surface absorbed kinesin, extracted and extended lipid nanotube networks from large Lα phase multilamellar liposomes (5-25 μm). Based on the properties of the inverted motility geometry, the total size of these nanofluidic networks was limited by MT surface density, molecular motor energy source (ATP), and total amount and physical properties of lipid source material. Interactions between MTs and extended lipid nanotubes resulted in bifurcation of the nanotubes and ultimately the generation of highly branched networks of fluidically connected nanotubes. The network bifurcation was easily tuned by changing the density of microtubules on the surface to increase or decrease the frequency of branching. The ability of these networks to capture nanomaterials at the membrane surface with high fidelity was subsequently demonstrated using quantum dots as a model system. The diffusive transport of quantum dots was also characterized with respect to using these nanotube networks for mass transport applications. 23629675 Improved Nutritive Quality and Salt Resistance in Transgenic Maize by Simultaneously Overexpression of a Natural Lysine-Rich Protein Gene, SBgLR, and an ERF Transcription Factor Gene, TSRF1. Maize (Zea mays L.), as one of the most important crops in the world, is deficient in lysine and tryptophan. Environmental conditions greatly impact plant growth, development and productivity. In this study, we used particle bombardment mediated co-transformation to obtain marker-free transgenic maize inbred X178 lines harboring a lysine-rich protein gene SBgLR from potato and an ethylene responsive factor (ERF) transcription factor gene, TSRF1, from tomato. Both of the target genes were successfully expressed and showed various expression levels in different transgenic lines. Analysis showed that the protein and lysine content in T1 transgenic maize seeds increased significantly. Compared to non-transformed maize, the protein and lysine content increased by 7.7% to 24.38% and 8.70% to 30.43%, respectively. Moreover, transgenic maize exhibited more tolerance to salt stress. When treated with 200 mM NaCl for 48 h, both non-transformed and transgenic plant leaves displayed wilting and losing green symptoms and dramatic increase of the free proline contents. However, the degree of control seedlings was much more serious than that of transgenic lines and much more increases of the free proline contents in the transgenic lines than that in the control seedlings were observed. Meanwhile, lower extent decreases of the chlorophyll contents were detected in the transgenic seedlings. Quantitative RT-PCR was performed to analyze the expression of ten stress-related genes, including stress responsive transcription factor genes, ZmMYB59 and ZmMYC1, proline synthesis related genes, ZmP5CS1 and ZmP5CS2, photosynthesis-related genes, ZmELIP, ZmPSI-N, ZmOEE, Zmrbcs and ZmPLAS, and one ABA biosynthesis related gene, ZmSDR. The results showed that with the exception of ZmP5CS1 and ZmP5CS2 in line 9-10 and 19-11, ZmMYC1 in line 19-11 and ZmSDR in line 19-11, the expression of other stress-related genes were inhibited in transgenic lines under normal conditions. After salt treatment, the expressions of the ten stress-related genes were significantly induced in both wild-type (WT) and transgenic lines. However, compared to WT, the increases of ZmP5CS1 in all these three transgenic lines and ZmP5CS2 in line 9-10 were less than WT plants. This study provides an effective approach of maize genetic engineering for improved nutritive quality and salt tolerance. 23347151 Effects of hydrogen bonding on internal conversion of GFP-like chromophores. I. The para-amino systems. To understand the effects of solvent-solute hydrogen bonding (SSHB) on the excited-state dynamics of two GFP-like chromophores, p-ABDI and p-CFABDI, we have determined the quantum yields for fluorescence (Φf) and the isomerization Z → E (ΦZE) and the femtosecond fluorescence and transient infrared absorption in selected solvents. The behavior that ΦZE ≅ 0.50 in aprotic solvents, such as CH3CN, indicates that the E-Z photoisomerization adopts a one-bond-flip mechanism through the torsion of the exocyclic C═C bond (the τ torsion) to form a perpendicular species (τ ∼90°) in the singlet excited state followed by internal conversion (IC) to the ground state and partition to form the E and Z isomers with equal probabilities. The observed ΦZE decreased from 0.50 to 0.15-0.28 when CH3CN was replaced with the protic solvents CH3OH and CF3CH2OH. In conjunction with the solvent-independent rapid (<1 ps) kinetics for the fluorescence decay and the solvent-dependent slow (7-20 ps) kinetics for the ground-state recovery, we conclude that the SSHB modifies the potential energy surface for the τ torsion in a way that the IC occurs also for the twisted intermediates with a τ-torsion angle smaller than 90°, which favors the formation of the Z isomers. The possibility of IC induced by torsion of the exocyclic C-C bond (the φ torsion) is also considered but excluded. 23193276 KEGG OC: a large-scale automatic construction of taxonomy-based ortholog clusters. The identification of orthologous genes in an increasing number of fully sequenced genomes is a challenging issue in recent genome science. Here we present KEGG OC (http://www.genome.jp/tools/oc/), a novel database of ortholog clusters (OCs). The current version of KEGG OC contains 1 176 030 OCs, obtained by clustering 8 357 175 genes in 2112 complete genomes (153 eukaryotes, 1830 bacteria and 129 archaea). The OCs were constructed by applying the quasi-clique-based clustering method to all possible protein coding genes in all complete genomes, based on their amino acid sequence similarities. It is computationally efficient to calculate OCs, which enables to regularly update the contents. KEGG OC has the following two features: (i) It consists of all complete genomes of a wide variety of organisms from three domains of life, and the number of organisms is the largest among the existing databases; and (ii) It is compatible with the KEGG database by sharing the same sets of genes and identifiers, which leads to seamless integration of OCs with useful components in KEGG such as biological pathways, pathway modules, functional hierarchy, diseases and drugs. The KEGG OC resources are accessible via OC Viewer that provides an interactive visualization of OCs at different taxonomic levels. 23570561 Synthesis and Biological Evaluation of Urea Derivatives as Highly Potent and Selective Rho Kinase Inhibitors. RhoA and its downstream effector ROCK mediate stress fiber formation and cell contraction through their effects on the phosphorylation of myosin light chain (MLC). Inhibition of the RhoA/ROCK pathway has proven to be a promising strategy for several indications such as cardiovascular disease, glaucoma, and inflammatory disease. In 2010, our group reported urea-based ROCK inhibitors as potential antiglaucoma agents. These compounds showed potent IC50 values in enzymatic and cell-based assays and significant intraocular pressure (IOP)-lowering effects in rats (∼7 mmHg). (22) To develop more advanced ROCK inhibitors targeting various potential applications (such as myocardial infarction, erectile dysfunction, multiple sclerosis, etc.) in addition to glaucoma, a thorough SAR for this urea-based scaffold was studied. The detailed optimization process, counter-screening, and in vitro and in vivo DMPK studies are discussed. Potent and selective ROCK inhibitors with various in vivo pharmacokinetic properties were discovered. 23330549 A molecular platinum cluster junction: a single-molecule switch. We present a theoretical study of electron transport through single-molecule junctions incorporating a Pt(6) metal cluster bound within an organic framework. The insertion of this molecule between a pair of electrodes leads to a fully atomically engineered nanometallic device with high conductance at the Fermi level and two sequential high on/off switching states. The origin of this property can be traced back to the existence of a degenerate HOMO consisting of two asymmetric orbitals with energies close to the Fermi level of the metal leads. The degeneracy is broken when the molecule is contacted to the leads, giving rise to two resonances that become pinned to the Fermi level and display destructive interference. 23418017 Cytophilic/Cytophobic Design of Nanomaterials at Biointerfaces. To control interactions between cells and nanomaterials has been a great challenge because numerous nanomaterials have been intensively explored in the fields of biology and medicine. However, current surface modification of nanomaterials is mainly carried out in an empirical way. Herein, a general strategy to tune the surface chemistry of nanomaterials is proposed based on cell affinity, that is, cytophilic or cytophobic. The cell affinity of nanomaterials directly affects cellular response to materials at the very early stage of cell-material interactions before other events, such as endocytosis, cell spreading, and cell differentiation, occur. In this Concept, it is suggested that there is a developing library of cytophilic and cytophobic moieties, and how the cell affinity of nanomaterials functions at biointerfaces is discussed by exemplifying several applications, namely therapy, tissue engineering, and biosensors. It is believed that control of the cytophilic/cytophobic property will be helpful in guiding the design of functional nanomaterials for their biomedical applications. 23188714 Pyrimidine salvage in Trypanosoma brucei bloodstream forms and the trypanocidal action of halogenated pyrimidines. African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host. However, uptake of pyrimidines in bloodstream form trypanosomes has not been investigated, making it difficult to judge the relative importance of salvage and synthesis or to design a pyrimidine-based chemotherapy. Detailed characterization of pyrimidine transport activities in bloodstream form Trypanosoma brucei brucei found that these cells express a high-affinity uracil transporter (designated TbU3) that is clearly distinct from the procyclic pyrimidine transporters. This transporter had low affinity for uridine and 2'deoxyuridine and was the sole pyrimidine transporter expressed in these cells. In addition, thymidine was taken up inefficiently through a P1-type nucleoside transporter. Of importance, the anticancer drug 5-fluorouracil was an excellent substrate for TbU3, and several 5-fluoropyrimidine analogs were investigated for uptake and trypanocidal activity; 5F-orotic acid, 5F-2'deoxyuridine displayed activity in the low micromolar range. The metabolism and mode of action of these analogs was determined using metabolomic assessments of T. brucei clonal lines adapted to high levels of these pyrimidine analogs, and of the sensitive parental strains. The analysis showed that 5-fluorouracil is incorporated into a large number of metabolites but likely exerts toxicity through incorporation into RNA. 5F-2'dUrd and 5F-2'dCtd are not incorporated into nucleic acids but act as prodrugs by inhibiting thymidylate synthase as 5F-dUMP. We present the most complete model of pyrimidine salvage in T. brucei to date, supported by genome-wide profiling of the predicted pyrimidine biosynthesis and conversion enzymes. 23192895 Synthesis and thermal decomposition behaviors of magnesium borohydride ammoniates with controllable composition as hydrogen storage materials. An ammonia-redistribution strategy for synthesizing metal borohydride ammoniates with controllable coordination number of NH(3) was proposed, and a series of magnesium borohydride ammoniates were easily synthesized by a mechanochemical reaction between Mg(BH(4))(2) and its hexaammoniate. A strong dependence of the dehydrogenation temperature and purity of the released hydrogen upon heating on the coordination number of NH(3) was elaborated for Mg(BH(4))(2)·xNH(3) owing to the change in the molar ratio of H(δ+) and H(δ-), the charge distribution on H(δ+) and H(δ-), and the strength of the coordinate bond N:→Mg(2+). The monoammoniate of magnesium borohydride (Mg(BH(4))(2)·NH(3)) was obtained for the first time. It can release 6.5% pure hydrogen within 50 minutes at 180 °C. 23225365 In vitro antileishmanial activity of resveratrol originates from its cytotoxic potential against host cells. In addition to a range of beneficial pharmacological activities, resveratrol is recently reported to have potential antileishmanial activities in vitro. The present study was conducted to evaluate the effect of resveratrol on promastigotes and amastigotes of transgenic Leishmania major expressing green fluorescent protein in comparison with its direct cytotoxic effects on host cells (bone marrow-derived and J774-G8 macrophages, respectively). As assessed by FACS analysis, resveratrol showed moderate antipromastigote activity at <35 µg/mL (153.2 µM) and promising effects at higher sample concentrations. In contrast, the green fluorescent protein signal as a measure of the intracellular parasites' viability was reduced in a concentration-dependent manner. Resveratrol strongly inhibited NO production, but did not display direct NO-scavenging activity in sodium nitroprusside solution. Western blotting indicated that resveratrol reduced recombinant interferon-γ/LPS-induced expression of iNOS protein. Microscopic studies, MTT evaluation, and FACS analysis showed significant cytotoxic effects on host cells in a concentration-dependent manner. This finding suggests that the in vitro antileishmanial activity of resveratrol is due to cytotoxic effects on host cells rather than attributable to a specific antiparasitic potential. 23210779 Natural cures for type 1 diabetes: a review of phytochemicals, biological actions, and clinical potential. Autoimmune diseases are the third largest category of illness in the industrialized world, following cardiovascular diseases and cancers. Among them, type 1 diabetes, also named autoimmune diabetes, afflicts 10 million people worldwide. This disease is caused by autoimmunity-mediated destruction of pancreatic β-cells, leading to insulin deficiency, hyperglycemia and complications. Currently, there is no cure for type 1 diabetes. Insulin injection is the only medication; however, it accompanies serious medical complications. Current strategies to cure type 1 diabetes include immunotherapy, replacement therapy, and combination therapy. Despite recent advances in anti-diabetic strategies, no strategy is clinically successful. How to cure type 1 diabetes without undesirable side effects still remains a formidable challenge in drug research and development. Plants provide an extraordinary source of natural medicines for different diseases. Moreover, secondary metabolites of plant origin serve as an invaluable chemical library for drug discovery and current medicinal chemistry in the pharmaceutical industry. Over the past 25 years, 50% of prescription drugs have been developed from natural products and their derivatives. In this article, we review more than 20 plant compounds and extracts reported in the literature to prevent and treat type-1 diabetes. Emphasis is placed on their chemistry and biology in terms of regulation of immune cells and pancreatic β-cells. We summarize recent progress in understanding the biological actions, mechanisms and therapeutic potential of the compounds and extracts of plant origin in type 1 diabetes. New views on phytocompound-based strategies for prevention and treatment of type 1 diabetes are also discussed. 23194502 An isoquinoline alkaloid from the Chinese herbal plant Corydalis yanhusuo W.T. Wang inhibits P-glycoprotein and multidrug resistance-associate protein 1. Overexpression of P-glycoprotein (P-gp) and multidrug resistance-associate protein 1 (MRP1) is a major mechanism leading to multidrug resistance (MDR) of cancer cells. These transporters expel anti-cancer drugs and greatly impair therapeutic efficacy of chemotherapy. A Chinese herbal plant Yanhusuo (Corydalis yanhusuo W.T. Wang, YHS) is frequently used in functional food and traditional Chinese medicine to improve the efficacy of chemotherapy. The objective of this work was to study effects of glaucine, an alkaloid component of YHS, on P-gp and MRP1 in resistant cancer cells. The resistant cancer cell line, MCF-7/ADR and corresponding parental sensitive cells were employed to determine reversal properties of glaucine. Glaucine inhibits P-gp and MRP1-mediated efflux and activates ATPase activities of the transporters, indicating that it is a substrate and inhibits P-gp and MRP1 competitively. Furthermore, glaucine suppresses expression of ABC transporter genes. It reverses the resistance of MCF-7/ADR to adriamycin and mitoxantrone effectively. 23163395 Does catch and release affect the mating system and individual reproductive success of wild Atlantic salmon (Salmo salar L.)? In this study, we documented the breeding system of a wild population of Atlantic salmon (Salmo salar L.) by genetically sampling every returning adult and assessed the determinants of individual fitness. We then quantified the impacts of catch and release (C&R) on mating and reproductive success. Both sexes showed high variance in individual reproductive success, and the estimated standardized variance was higher for males (2.86) than for females (0.73). We found a weak positive relationship between body size and fitness and observed that fitness was positively correlated with the number of mates, especially in males. Mature male parr sired 44% of the analysed offspring. The impact of C&R on the number of offspring was size dependent, as the reproductive success of larger fish was more impaired than smaller ones. Also, there was an interactive negative effect of water temperature and air exposure time on reproductive success of C&R salmon. This study improves our understanding of the complex reproductive biology of the Atlantic salmon and is the first to investigate the impact of C&R on reproductive success. Our study expands the management toolbox of appropriate C&R practices that promote conservation of salmon populations and limit negative impacts on mating and reproductive success. 23313376 Pterostilbene exerts antitumor activity against human osteosarcoma cells by inhibiting the JAK2/STAT3 signaling pathway. Osteosarcoma is a high-grade malignant bone tumor. Pterostilbene (PTE) is a natural, dimethylated analog of resveratrol with higher bioavailability. While PTE has been shown to have potent antitumor activity against various types of cancer, the molecular mechanisms underlying the effects of PTE remain largely unknown. The Janus kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) signaling pathway plays a crucial role in tumorigenesis and immune development. In this study, we assessed the antitumor activity of PTE against human osteosarcoma cells and explored the role of JAK2/STAT3 and apoptosis-related signaling pathways on the activity of PTE. PTE treatment resulted in a dose- and time-dependent inhibition of osteosarcoma cell viability. Additionally, PTE exhibited strong antitumor activity, as evidenced not only by reductions in tumor cell adhesion, migration and mitochondrial membrane potential (MMP) but also by increases in the apoptotic index, reactive oxygen species (ROS) and several biochemical parameters. Furthermore, PTE treatment directly inhibited the phosphorylation of JAK2 at Tyr 1007 and the downstream activation of STAT3. PTE also down-regulated the expression of STAT3 target genes, including the anti-apoptotic proteins Bcl-xL and Mcl-1, leading to the up-regulation of mitochondrial apoptosis pathway-related proteins (Bax, Bak, cytosolic Cytochrome c, and cleaved Caspase3) and cyclin-dependent kinase inhibitors such as p21 and p27. PTE, used in combination with a known JAK2/STAT3 inhibitor, AG490, further decreased the viability of osteosarcoma cells. Taken together, PTE is a potent inhibitor of osteosarcoma cell growth that targets the JAK2/STAT3 signaling pathway. These data suggest that inhibition of JAK2/STAT3 signaling is a novel mechanism of action for PTE during therapeutic intervention in osteosarcoma cancers. 23566514 Discovery and synthesis of novel 4-aminopyrrolopyrimidine Tie-2 kinase inhibitors for the treatment of solid tumors. The synthesis and biological evaluation of novel Tie-2 kinase inhibitors are presented. Based on the pyrrolopyrimidine chemotype, several new series are described, including the benzimidazole series by linking a benzimidazole to the C5-position of the 4-amino-pyrrolopyrimidine core and the ketophenyl series synthesized by incorporating a ketophenyl group to the C5-position. Medicinal chemistry efforts led to potent Tie-2 inhibitors. Compound 15, a ketophenyl pyrrolopyrimidine urea analog with improved physicochemical properties, demonstrated favorable in vitro attributes as well as dose responsive and robust oral tumor growth inhibition in animal models. 23562995 Optical modulation of ZnO microwire optical resonators with a parallelogram cross-section. A novel ZnO microwire optical resonator with a parallelogram cross-section is fabricated, which can effectively control the light field in two dimensions. Wave-guided Fabry-Pérot modes with different polarizations are directly observed and further investigated systematically. Such a ZnO optical resonator offers another building block for the development of optoelectronic devices. 23578651 Development and validation of ethylenethiourea determination in foods using methanol-based extraction, solid-phase extraction cleanup and LC-MS/MS. To response to the need for a rapid, cost-effective, eco-friendly and efficient extraction process, a sensitive method for the determination of ethylenethiourea (ETU) in food matrices by high-performance liquid chromatography-mass spectrometry (HPLC-LC/MS) was developed and validated. ETU was extracted from food commodities with methanol, cleaned up by alumina-SPE column, and then determined by HPLC-MS/MS. The MS detection was operated in positive ionization mode. For confirmation of target compound, two precursor ion>product ion transitions were selected by multi-reaction monitoring mode (MRM). The method showed good linearity with correlation coefficient higher than 0.9950. Recoveries at three spiked levels (10, 50, 100ng/g) in random selected food matrices were in range of 71-121% with RSDs not larger than 25%. The limit of quantitation for the analyte was estimated at 5ng/g. 23525674 Cavitation during tensile deformation of isothermally crystallized polypropylene and high-density polyethylene. The cavitation phenomenon was studied in isothermally and non-isothermally crystallized polypropylene and high-density polyethylene. It was found that nano-voids were not present in the crystallized samples, but were formed during their tensile deformation. The process of cavitation was initiated before reaching the yield point. The ellipsoidal voids were initially elongated perpendicularly to the deformation direction, but if the polymer (i.e., high-density polyethylene) was able to deform beyond the yield, then the reorientation of voids into the deformation direction was observed at local strains of 100-200 %. This behavior was similar to that observed previously in the samples crystallized without an exact control of solidification conditions. The calculations of Guinier's radius showed that voids in deformed polypropylene samples were characterized by the gyration radii of 28-50 nm. Smaller voids were observed in polyethylene. The scale of cavitation during deformation, studied on the example of polyethylene, depended on the preceding crystallization process and was most intensive for the specimens crystallized at the highest temperature of 125 °C. 23200253 Further exploration of M₁ allosteric agonists: subtle structural changes abolish M₁ allosteric agonism and result in pan-mAChR orthosteric antagonism. This letter describes the further exploration of two series of M(1) allosteric agonists, TBPB and VU0357017, previously reported from our lab. Within the TPBP scaffold, either electronic or steric perturbations to the central piperidine ring led to a loss of selective M(1) allosteric agonism and afforded pan-mAChR antagonism, which was demonstrated to be mediated via the orthosteric site. Additional SAR around a related M(1) allosteric agonist family (VU0357017) identified similar, subtle 'molecular switches' that modulated modes of pharmacology from allosteric agonism to pan-mAChR orthosteric antagonism. Therefore, all of these ligands are best classified as bi-topic ligands that possess high affinity binding at an allosteric site to engender selective M(1) activation, but all bind, at higher concentrations, to the orthosteric ACh site, leading to non-selective orthosteric site binding and mAChR antagonism. 23399323 Inhibition of ghrelin O-acyltransferase attenuates food deprivation-induced increases in ingestive behavior. Ghrelin is an orexigenic hormone produced by the stomach in direct proportion to the time since the last meal and has therefore been called a 'hunger signal'. The octanoylation of ghrelin is critical for its orexigenic functions and is dependent upon ghrelin O-acyltransferase (GOAT) catalyzation. The GOAT inhibitor, GO-CoA-Tat, decreases the circulating concentrations of octanoylated ghrelin and attenuates weight gain on a high fat diet in mice. Unlike rats and mice, Siberian hamsters and humans do not increase food intake after food deprivation, but increase food hoarding after food deprivation. In Siberian hamsters, exogenous ghrelin increases ingestive behaviors similarly to 48-56h food deprivation. Therefore, we tested the necessity of increased ghrelin in food-deprived Siberian hamsters to stimulate ingestive behaviors. To do so we used our simulated natural housing system that allows hamsters to forage for and hoard food. Animals were given an injection of GO-CoA-Tat (i.p., 11μmol/kg) every 6h because that is the duration of its effective inhibition of octanoylated ghrelin concentrations during a 48h food deprivation. We found that GO-CoA-Tat attenuated food foraging (0-1h), food intake (0-1 and 2-4h), and food hoarding (0-1h and 2 and 3days) post-refeeding compared with saline treated animals. This suggests that increased octanoylated ghrelin concentrations play a role in the food deprivation-induced increases in ingestive behavior. Therefore, ghrelin is a critical aspect of the multi-faceted mechanisms that stimulate ingestive behaviors, and might be a critical point for a successful clinical intervention scheme in humans. 23080539 Pluripotent stem cells escape from senescence-associated DNA methylation changes. Pluripotent stem cells evade replicative senescence, whereas other primary cells lose their proliferation and differentiation potential after a limited number of cell divisions, and this is accompanied by specific senescence-associated DNA methylation (SA-DNAm) changes. Here, we investigate SA-DNAm changes in mesenchymal stromal cells (MSC) upon long-term culture, irradiation-induced senescence, immortalization, and reprogramming into induced pluripotent stem cells (iPSC) using high-density HumanMethylation450 BeadChips. SA-DNAm changes are highly reproducible and they are enriched in intergenic and nonpromoter regions of developmental genes. Furthermore, SA-hypomethylation in particular appears to be associated with H3K9me3, H3K27me3, and Polycomb-group 2 target genes. We demonstrate that ionizing irradiation, although associated with a senescence phenotype, does not affect SA-DNAm. Furthermore, overexpression of the catalytic subunit of the human telomerase (TERT) or conditional immortalization with a doxycycline-inducible system (TERT and SV40-TAg) result in telomere extension, but do not prevent SA-DNAm. In contrast, we demonstrate that reprogramming into iPSC prevents almost the entire set of SA-DNAm changes. Our results indicate that long-term culture is associated with an epigenetically controlled process that stalls cells in a particular functional state, whereas irradiation-induced senescence and immortalization are not causally related to this process. Absence of SA-DNAm in pluripotent cells may play a central role for their escape from cellular senescence. 23354070 Evidence for a new binding mode to GSK-3: allosteric regulation by the marine compound palinurin. Glycogen synthase kinase 3β (GSK-3β) is widely recognised as a relevant player in the pathogenesis of several highly prevalent disorders such as Alzheimer's disease, mood disorders, diabetes and cancer. Therefore, this enzyme constitutes a highly attractive therapeutic target for the development of selective inhibitors as new promising drugs for the treatment of these pathologies. We describe here the isolation and biochemical characterization of the marine natural sesquiterpene palinurin as a GSK-3β inhibitor. Experimental studies performed for characterizing the inhibitory mechanism indicate that GSK-3β inhibition by palinurin cannot be competed out by ATP nor peptide substrate. Molecular modelling techniques have enabled us to propose an unconventional binding mode to GSK-3β. Moreover, molecular dynamics simulations have identified an allosteric mechanism by which binding of palinurin leads to GSK-3β inhibition. The inhibitory activities determined for a series of structurally related analogues support the proposed binding mode of palinurin, which is the first compound described to target this allosteric site. The results offer new opportunities for designing and developing selective inhibitors with novel mechanisms of action. 23074088 Resolving sub-molecular binding and electrical switching mechanisms of single proteins at electroactive conducting polymers. Polymer-based electrodes for interfacing biological tissues are becoming increasingly sophisticated. Their many functions place them at the cross-roads of electromaterials, biomaterials, and drug-delivery systems. For conducting polymers, the mechanism of conductivity requires doping with anionic molecules such as extracellular matrix molecules, a process that distinguishes them as biomaterials and provides a means to control interactions at the cellular-electrode interface. However, due to their complex structure, directly observing the selective binding of target molecules or proteins has so far eluded researchers. This situation is compounded by the polymer's ability to adopt different electronic states that alter the polymer-dopant interactions. Here, the ability to resolve sub-molecular binding specificity between sulfate and carboxyl groups of dopants and heparin binding domains of human plasma fibronectin is demonstrated. The interaction exploits a form of biological 'charge complementarity' to enable specificity. When an electrical signal is applied to the polymer, the specific interaction is switched to a non-specific, high-affinity binding state that can be reversibly controlled using electrochemical processes. Both the specific and non-specific interactions are integral for controlling protein conformation and dynamics. These details, which represent the first direct measurement of biomolecular recognition between a single protein and any type of organic conductor, give new molecular insight into controlling cellular interactions on these polymer surfaces. 23408434 Neuronatin-mediated aberrant calcium signaling and endoplasmic reticulum stress underlie neuropathology in Lafora disease. Lafora disease (LD) is a teenage-onset inherited progressive myoclonus epilepsy characterized by the accumulations of intracellular inclusions called Lafora bodies and caused by mutations in protein phosphatase laforin or ubiquitin ligase malin. But how the loss of function of either laforin or malin causes disease pathogenesis is poorly understood. Recently, neuronatin was identified as a novel substrate of malin that regulates glycogen synthesis. Here we demonstrate that the level of neuronatin is significantly up-regulated in the skin biopsy sample of LD patients having mutations in both malin and laforin. Neuronatin is highly expressed in human fetal brain with gradual decrease in expression in developing and adult brain. However, in adult brain, neuronatin is predominantly expressed in parvalbumin-positive GABAergic interneurons and localized in their processes. The level of neuronatin is increased and accumulated as insoluble aggregates in the cortical area of LD brain biopsy samples, and there is also a dramatic loss of parvalbumin-positive GABAergic interneurons. Ectopic expression of neuronatin in cultured neuronal cells results in increased intracellular Ca(2+), endoplasmic reticulum stress, proteasomal dysfunction, and cell death that can be partially rescued by malin. These findings suggest that the neuronatin-induced aberrant Ca(2+) signaling and endoplasmic reticulum stress might underlie LD pathogenesis. 23340333 Hepatic transcriptome profiling indicates differential mRNA expression of apoptosis and immune related genes in eelpout (Zoarces viviparus) caught at Göteborg harbor, Sweden. The physiology and reproductive performance of eelpout (Zoarces viviparus) have been monitored along the Swedish coast for more than three decades. In this study, transcriptomic profiling was applied for the first time as an exploratory tool to search for new potential candidate biomarkers and to investigate possible stress responses in fish collected from a chronically polluted area. An oligonucleotide microarray with more than 15,000 sequences was used to assess differentially expressed hepatic mRNA levels in female eelpout collected from the contaminated area at Göteborg harbor compared to fish from a national reference site, Fjällbacka. Genes involved in apoptosis and DNA damage (e.g., SMAC/diablo homolog and DDIT4/DNA-damage-inducible protein transcript 4) had higher mRNA expression levels in eelpout from the harbor compared to the reference site, whereas mRNA expression of genes involved in the innate immune system (e.g., complement components and hepcidin) and protein transport/folding (e.g., signal recognition particle and protein disulfide-isomerase) were expressed at lower levels. Gene Ontology enrichment analysis revealed that genes involved biological processes associated with protein folding, immune responses and complement activation were differentially expressed in the harbor eelpout compared to the reference site. The differential mRNA expression of selected genes involved in apoptosis/DNA damage and in the innate immune system was verified by quantitative PCR, using the same fish in addition to eelpout captured four years later. Thus, our approach has identified new potential biomarkers of pollutant exposure and has generated hypotheses on disturbed physiological processes in eelpout. Despite a higher mRNA expression of genes related to apoptosis (e.g., diablo homolog) in eelpout captured in the harbor there were no significant differences in the number of TUNEL-positive apoptotic cells between sites. The mRNA level of genes involved in apoptosis/DNA damage and the status of the innate immune system in fish species captured in polluted environments should be studied in more detail to lay the groundwork for future biomonitoring studies. 23183413 Mortality, bioaccumulation and physiological responses in juvenile freshwater mussels (Lampsilis siliquoidea) chronically exposed to copper. Several studies have indicated that the early life stages of freshwater mussels are among the most sensitive aquatic organisms to inorganic chemicals, including copper. However, little is known about the toxic mode of action and sub-lethal effects of copper exposure in this group of imperiled animals. In this study, the physiological effects of long-term copper exposure (survival, growth, copper bioaccumulation, whole-body ion content, oxygen consumption, filtration rate, ATPase activities, and biomarkers of oxidative stress) were evaluated in juvenile (6 month old) mussels (Lampsilis siliquoidea). The mussels' recovery capacity and their ability to withstand further acute copper challenge were also evaluated in secondary experiments following the 28 day exposure by assessing survival, copper bioaccumulation and whole-body ion content. Mussels chronically exposed to 2 and 12 μg Cu/L showed significantly higher mortality than those held under control conditions (mortality 20.9, 69.9 and 12.5%, respectively), indicating that juvenile L. siliquoidea is underprotected by the U.S. Environmental Protection Agency (USEPA) biotic ligand model (BLM)-derived chronic water quality criteria (WQC) (2.18 μg Cu/L) and the hardness-derived USEPA WQC (12.16 μg Cu/L). Soft tissue copper burden increased equally for both copper exposures, suggesting that chronic toxicity is not associated with copper bioaccumulation. Several physiological disturbances were also observed during chronic copper exposure. Most relevant was a decrease in whole-body sodium content paralleled by an inhibition of Na(+) K(+)-ATPase activity, indicating a metal-induced ionoregulatory disturbance. Filtration and oxygen consumption rates were also affected. Redox parameters (reactive oxygen production, antioxidant capacity against peroxyl radicals, glutathione-S-transferase (GST) activity, and glutathione (GSH) concentration) did not show clear responses, but membrane damage as lipid peroxidation (LPO) was observed in both copper exposures. Mussels previously held in control conditions or pre-exposed to 2 μg dissolved Cu/L were able to maintain their ionic homeostasis and did not experience mortality after the 4-d recovery period. In contrast, those previously exposed to 12 μg dissolved Cu/L exhibited 50% mortality indicating that they had already reached a 'point of no return'. Pre-exposure to copper did not influence mussel response to the copper challenge test. As observed for the chronic exposure, mortality of mussels held in the absence of copper and submitted to the challenge test was also associated with an ionoregulatory disturbance. These results indicate that ionoregulatory disruption in freshwater mussels chronically exposed to copper is the main mechanism of toxicity and that redox parameters do not appear to be useful as indicators of sub-lethal copper toxicity in these animals. 23307790 Calorie-restricted weight loss reverses high-fat diet-induced ghrelin resistance, which contributes to rebound weight gain in a ghrelin-dependent manner. Twelve weeks of high-fat diet feeding causes ghrelin resistance in arcuate neuropeptide Y (NPY)/agouti-related protein (AgRP) neurons. In the current study, we investigated whether diet-induced weight loss could restore NPY/AgRP neuronal responsiveness to ghrelin and whether ghrelin mediates rebound weight gain after calorie-restricted (CR) weight loss. Diet-induced obese (DIO) mice were allocated to one of two dietary interventions until they reached the weight of age-matched lean controls. DIO mice received chow diet ad libitum or chow diet with 40% CR. Chow-fed and high-fat-fed mice served as controls. Both dietary interventions normalized body weight, glucose tolerance, and plasma insulin. We show that diet-induced weight loss with CR increases total plasma ghrelin, restores ghrelin sensitivity, and increases hypothalamic NPY and AgRP mRNA expression. We propose that long-term DIO creates a higher body weight set-point and that weight loss induced by CR, as seen in the high-fat CR group, provokes the brain to protect the new higher set-point. This adaptation to weight loss likely contributes to rebound weight gain by increasing peripheral ghrelin concentrations and restoring the function of ghrelin-responsive neuronal populations in the hypothalamic arcuate nucleus. Indeed, we also show that DIO ghrelin-knockout mice exhibit reduced body weight regain after CR weight loss compared with ghrelin wild-type mice, suggesting ghrelin mediates rebound weight gain after CR weight loss. 23339547 Comparative single-dose pharmacokinetics of rasagiline in minipigs after oral dosing or transdermal administration via a newly developed patch. Abstract 1. A rasagiline transdermal patch was developed for the treatment of early and advanced Parkinson's disease. Relevant pharmacokinetic parameters of rasagiline obtained after transdermal administration to minipigs were compared with those of rasagiline after oral administration. 2. A total of 18 minipigs were randomly divided into three groups (six animals for each group). A single dose of 1 mg rasagiline tablet was orally administrated to one group. Meanwhile, single dose of 1.25 and 2.5 mg (2 and 4 cm(2)) rasagiline patches were given (at the postauricular skin) to the other two groups, respectively. The pharmacokinetic parameters such as plasma half-life (t(1/2)), time to peak plasma-concentration (T(max)), mean residence time (MRT), area under the curve (AUC((0-)(t)())) were significantly (p < 0.05) different between transdermal and oral administrations. 3. The plasma half-life (t(1/2)) of rasagiline (1.25 mg patch: 11.8 ± 6.5 h, 2.5 mg patch: 12.5 ± 4.7 h) in minipig following transdermal administration was significantly prolonged as compared with that following the oral administration (1 mg tablet: 4.7 ± 2.5 h). The dose-normalized relative bioavailability of rasagiline patch in minipig were 178.5% and 156.4%, respectively, for 1.25 and 2.5 mg patches compared with 1 mg rasagiline tablet. The prolonged t(1/2) and increased bioavailability of rasagiline patch suggested a possible longer dosing interval compared with oral tablet. 23611120 D - Glucose hydrogenation over Ru Nanoparticles Embedded in Mesoporous Hypercrosslinked Polystyrene. The kinetics of D-glucose hydrogenation on the catalyst containing Ru nanoparticles in the matrix of hypercrosslinked polystyrene was studied. Two routes of the hydrogenation reaction were revealed, their rates differ by several digits. The first route includes the interaction of D-glucose with the spilled-over hydrogen supplied by the catalyst; the second one includes classical interaction of the sorbed substrate with incident hydrogen from the reaction medium. Mathematical description of D-glucose conversion and the change of the catalyst activity by the fist way of D-glucose hydrogenation were obtained. The most probable scheme of the process flow was suggested. The main kinetic parameters were calculated. The role of hydrogen spillover phenomenon in the kinetics of the processes is discussed. 23566299 Determination of the α-Conotoxin Vc1.1 Binding Site on the α9α10 Nicotinic Acetylcholine Receptor. α-Conotoxin Vc1.1 specifically and potently inhibits the nicotinic acetylcholine receptor subtype α9α10 (α9α10 nAChR) and is a potential novel treatment for neuropathic pain. Here, we used a combination of computational modeling and electrophysiology experiments to determine the Vc1.1 binding site on the α9α10 nAChR. Interactions of Vc1.1 with two probable binding sites, α9α10 and α10α9, were modeled. Mutational energies calculated by assuming specific interactions in the α10α9 binding site correlated better with electrophysiological recordings than those assuming interactions with the α9α10 binding site. Two novel Vc1.1 analogues, [N9F]Vc1.1 and [N9W]Vc1.1, were predicted to have large differences in affinity between the two binding sites. Data from functional studies were consistent with computational predictions that assumed preferred binding of Vc1.1 to the α10α9 pocket. Moreover, our modeling study suggested that a single hydrogen bond formed between Vc1.1 and position 59 of the α10α9 pocket confers specificity to rat versus human α9α10 nAChRs. 23441829 Double C-H bond activation of hydrocarbons by a gas phase neutral oxide cluster: the importance of spin state. The neutral cluster V2O5 is generated and detected in the gas phase. Its reactivity toward butane is studied both experimentally and theoretically. Experimental results show clearly that neutral V2O5 can react with n-butane (C4H10) to generate V2O5H2, indicating double hydrogen atom transfer from C4H10 to V2O5 to produce C4H8. Further experimental evidence indicates that V2O5 is only partially reacted even at very high concentrations of C4H10. Density functional theory (DFT) studies show that the lowest energy triplet state of V2O5 is reactive toward C4H10, whereas the ground state singlet V2O5 is inert. Calculated results are in agreement with experimental findings, and a detailed reaction mechanism is provided. Reactions of V2O5H2 with several oxidants are also studied theoretically to find a path to regenerate V2O5. Neutral (3)V2O5 can also react with C2H6 to form V2O5H2 and C2H4, but only as a minor reaction channel; the major product is the adsorption product V2O5(C2H6). 23349486 Reduced Adipose Tissue Macrophage Content Is Associated With Improved Insulin Sensitivity in Thiazolidinedione-Treated Diabetic Humans. Obesity is associated with increased adipose tissue macrophage (ATM) infiltration, and rodent studies suggest that inflammatory factors produced by ATMs contribute to insulin resistance and type 2 diabetes. However, a relationship between ATM content and insulin resistance has not been clearly established in humans. Since thiazolidinediones attenuate adipose tissue inflammation and improve insulin sensitivity, we examined the temporal relationship of the effects of pioglitazone on these two parameters. The effect of 10 and 21 days of pioglitazone treatment on insulin sensitivity in 26 diabetic subjects was assessed by hyperinsulinemic-euglycemic clamp studies. Because chemoattractant factors, cytokines, and immune cells have been implicated in regulating the recruitment of ATMs, we studied their temporal relationship to changes in ATM content. Improved hepatic and peripheral insulin sensitivity was seen after 21 days of pioglitazone. We found early reductions in macrophage chemoattractant factors after only 10 days of pioglitazone, followed by a 69% reduction in ATM content at 21 days and reduced ATM activation at both time points. Although markers for dendritic cells and neutrophils were reduced at both time points, there were no significant changes in regulatory T cells. These results are consistent with an association between adipose macrophage content and systemic insulin resistance in humans. 23404198 TRIM16 overexpression induces apoptosis through activation of caspase-2 in cancer cells. TRIM16 exhibits tumour suppressor functions by interacting with cytoplasmic vimentin and nuclear E2F1 proteins in neuroblastoma and squamous cell carcinoma cells, reducing cell migration and replication. Reduced TRIM16 expression in a range of human primary malignant tissues correlates with increased malignant potential. TRIM16 also induces apoptosis in breast and lung cancer cells, by unknown mechanisms. Here we show that overexpression of TRIM16 induces apoptosis in human breast cancer (MCF7) and neuroblastoma (BE(2)-C) cells, but not in non-malignant HEK293 cells. TRIM16 increased procaspase-2 protein levels in MCF7 and induced caspase-2 activity in both MCF7 and BE(2)-C cells. We show that TRIM16 and caspase-2 proteins directly interact in both MCF7 and BE(2)-C cells and co-localise in MCF7 cells. Most importantly, the induction of caspase-2 activity is required for TRIM16 to initiate apoptosis. Our data suggest a novel mechanism by which TRIM16 can promote apoptosis by directly modulating caspase-2 activity. 23327491 Surfactant-mediated control of colloid pattern assembly and attachment strength in evaporating droplets. This study demonstrates that the pattern assembly and attachment strength of colloids in an evaporating sessile droplet resting on a smooth substrate can be controlled by adding nonionic solutes (surfactant) to the solution. As expected, increasing the surfactant concentration leads to a decrease in initial surface tension of the drop, σ(0). For the range of initial surface tensions investigated (39-72 mN m(-1)), three distinct deposition patterns were produced: amorphous stains (σ(0) = 63-72 mN m(-1)), coffee-ring stains (σ(0) = 48-53 mN m(-1)), and concentric rings (σ(0) = 39-45 mN m(-1)). A flow-displacement system was used to measure the attachment strength of the dried colloids. Characteristic drying regimes associated with the three unique pattern formations are attributed to abrupt transitions of contact line dynamics during evaporation. The first transition from slipping- to pinned-contact line was found to be a direct result of the competition between mechanical instability of the droplet and the friction generated by pinned colloids at the contact line. The second transition from pinned- to recurrent-stick-rip-slip-contact line was caused by repeated liquid film rupturing from evaporation-intensified surfactant concentration. Data from flow-displacement tests indicate that attachment strength of dried particles is strongest for amorphous stains (lowest surfactant concentration) and weakest for concentric rings (highest surfactant concentration). The mechanism behind these observations was ascribed to the formation and adsorption of micelles onto colloid and substrate surfaces as the droplet solution evaporates. The range of attachment forces observed between the colloids and the solid substrate were well captured by extended-DLVO interactions accounting for van der Waals attraction, electric double layer repulsion, and micelle-protrusion repulsion. Both empirical and theoretical results suggest that an increasingly dense layer of adsorbed micellar-protrusions on colloid and substrate surfaces acts as a physical barrier that hinders strong van der Waals attractive interactions at close proximity. Thereby, colloid stains dried at higher surfactant concentrations are more easily detached from the substrate when dislodging forces are applied than stains dried at lower surfactant concentrations. 23600807 Secondary metabolites from the endophytic fungi Penicillium polonicum and Aspergillus fumigatus. Two new compounds, rhodostegone (1) from endophytic fungus Penicillium polonicum and cyclo-(l-Val-l-Leu) (2) from Aspergillus fumigatus, together with six known diketopiperazines (3-8), were isolated. The structures of these compounds were characterized through a combination of extensive IR, MS, NMR, and CD analysis. 23443628 A population-based study of dosing and persistence with anti-dementia medications. PURPOSE: Cholinesterase inhibitors and memantine are the mainstay of pharmacological intervention for the cognitive symptoms of Alzheimer's disease (AD). This study assessed the adequacy of dosing and persistence with AD medications and the predictors of these variables in the 'real world' (outside the clinical trial setting). METHODS: The Health Service Executive-Primary Care Reimbursement Services prescription claims database in the Republic of Ireland contains prescription information for 1.6 million people. Patients aged >70 years who received at least two prescriptions for donepezil, rivastigmine, galantamine and memantine between January 2006 and December 2010 were included in the study. Rates of dose-maximisation were recorded by examining the initiation dose of each AD drug commenced during the study period and any subsequent dose titrations. Non-persistence was defined by a gap in prescribing of more than 63 consecutive days. Predictors of dose-maximisation and non-persistence were also analysed. RESULTS: Between January 2006 and December 2010, 20,729 patients aged >70 years received a prescription for an AD medication. Despite most patients on donepezil and memantine receiving a prescription for the maximum drug dose, this dose was maintained for 2 consecutive months in only two-thirds of patients. Patients were significantly more likely to have their doses of donepezil and memantine maximised if prescribed in more recent years (2010 vs. 2007). Rates of non-persistence were 30.1 % at 6 months and 43.8 % at 12 months. Older age [75+ vs. <75 years; hazards ratio (HR) 1.16, 95 % confidence interval (CI) 1.06-1.27] and drug type (rivastigmine vs. donepezil; HR 1.15, 95 % CI 1.03-1.27) increased the risk of non-persistence. Non-persistence was lower for those commencing therapy in more recent years (2010 vs. 2007; HR 0.81, 95 % CI 0.73-0.89, p < 0.001) and for those on multiple anti-dementia medications (HR 0.59, 95 % CI 0.54-0.65, p < 0.001). Persistence was significantly higher when memantine was co-prescribed with donepezil (p < 0.0001). CONCLUSION: Future studies should explore the reasons underlying non-persistence and failure to maintain dose-maximisation in patients on AD medications. There may be scope to improve the dosing and persistence with these medications in the community. 23225241 Ovariectomy Stimulates Hepatic Fat and Cholesterol Accumulation in High-fat Diet-fed Rats. This study was designed to determine how estrogens withdrawal during a high-fat (HF) diet regimen affects liver triacylglycerol (TAG) and cholesterol accumulation. Female Sprague-Dawley rats were submitted to a HF (42% energy as fat) or a standard (SD) diet for 6 weeks before being either ovariectomized (Ovx) or sham operated (Sham). Thereafter, Ovx and Sham rats were kept on the same diet for another 6 weeks leading to euthanasia. Liver TAG content was increased (p<0.01) in Ovx rats but not by the HF diet alone. However, the combination of HF diet and Ovx resulted in a greater liver TAG accumulation (p<0.06) than that observed in Ovx-SD/SD. Measurement of molecular markers of liver lipid metabolism revealed an increase in transcripts of markers of lipid oxidation (CPT-1 and PGC1; p<0.05) in rats fed the HF diet. This increase was, however, substantially less if HF fed rats were Ovx. Liver total cholesterol levels were increased (p<0.01) only in the Ovx-HF/HF rats while plasma cholesterol levels were increased in Ovx-SD/SD and in SHAM-HF/HF and Ovx-HF/HF rats. Transcripts of molecular markers of cholesterol metabolism suggest that biliary acids synthesis (CYP7a-1) was reduced in Ovx-SD/SD and Sham-HF/HF rats and even more so in Ovx-HF/HF rats. It is concluded that the effects of a HF diet on liver TAG accumulation are especially observed in Ovx rats possibly through a reduction in hepatic lipid oxidation. The combination of Ovx and HF diet also acts synergistically to favor liver cholesterol accumulation. 23135547 Mechanisms of hepatocellular toxicity associated with dronedarone--a comparison to amiodarone. Dronedarone is a new antiarrhythmic drug with an amiodarone-like benzofuran structure. Shortly after its introduction, dronedarone became implicated in causing severe liver injury. Amiodarone is a well-known mitochondrial toxicant. The aim of our study was to investigate mechanisms of hepatotoxicity of dronedarone in vitro and to compare them with amiodarone. We used isolated rat liver mitochondria, primary human hepatocytes, and the human hepatoma cell line HepG2, which were exposed acutely or up to 24h. After exposure of primary hepatocytes or HepG2 cells for 24h, dronedarone and amiodarone caused cytotoxicity and apoptosis starting at 20 and 50 µM, respectively. The cellular ATP content started to decrease at 20 µM for both drugs, suggesting mitochondrial toxicity. Inhibition of the respiratory chain required concentrations of ~10 µM and was caused by an impairment of complexes I and II for both drugs. In parallel, mitochondrial accumulation of reactive oxygen species (ROS) was observed. In isolated rat liver mitochondria, acute treatment with dronedarone decreased the mitochondrial membrane potential, inhibited complex I, and uncoupled the respiratory chain. Furthermore, in acutely treated rat liver mitochondria and in HepG2 cells exposed for 24h, dronedarone started to inhibit mitochondrial β-oxidation at 10 µM and amiodarone at 20 µM. Similar to amiodarone, dronedarone is an uncoupler and an inhibitor of the mitochondrial respiratory chain and of β-oxidation both acutely and after exposure for 24h. Inhibition of mitochondrial function leads to accumulation of ROS and fatty acids, eventually leading to apoptosis and/or necrosis of hepatocytes. Mitochondrial toxicity may be an explanation for hepatotoxicity of dronedarone in vivo. 23497896 Inhibition of citral degradation in an acidic aqueous environment by polyoxyethylene alkylether surfactants. Citral is a flavour component widely used in food and cosmetic industries, but is chemically unstable and degrades over time in aqueous solutions due to acid-catalysed and oxidative reactions leading to loss of desirable flavour. The present study reveals the effect of non-ionic micellar solutions of Brij30 and Brij35 on the extent of solubilisation and stabilisation of citral. The rate of chemical degradation of citral in acidic aqueous solutions was found to be highest, which was subsequently reduced significantly within these studied surfactant systems, suggesting protection of citral from an acidic environment once it is incorporated into the micelles. The work concludes that polyoxyethylene alkylether surfactants with lower HLB value, less dense hydrophilic corona and more hydrophobic core volume are efficient in solubilising and stabilising citral against an acidic environment. 23229539 Surgical trauma induces iron accumulation and oxidative stress in a rodent model of postoperative cognitive dysfunction. Postoperative cognitive dysfunction (POCD) is recognized as a complication after surgery in the elderly. The exact pathogenic mechanisms of POCD are still unknown. In this study, we investigated the role of iron accumulation within the central nervous system in the development of cognitive dysfunction in rats following splenectomy. Cognitive function was assessed using a Morris water maze on postoperative days 1, 3, and 7. Impaired cognitive function was observed on days 1 and 3 after splenectomy, while an anesthesia-alone group showed no significant difference from the control. Serum iron levels decreased and brain iron content increased on days 1 and 3 after surgery, which was in parallel with the impairment of cognitive function. Furthermore, the levels of proteins involved in the maintenance of brain iron homeostasis, including ferritin, transferrin receptor 1, and iron regulatory protein 2, were significantly different at postoperative days 1 and 3 in the hippocampus of splenectomized animals when compared with those of the control. The alterations in iron homeostasis were accompanied by intensified oxidative stress as measured by increases in the lipid peroxidation product, malondialdehyde, and a decrease in the levels of superoxide dismutase activity. Overall, these findings suggest that the impaired cognitive function was primarily due to surgical trauma rather than anesthesia. Increased iron accumulation and oxidative stress in the brain, especially in the hippocampus, may be involved in the pathogenesis of POCD. 23389045 Self-assembly of pyridine-modified lipoic Acid derivatives on gold and their interaction with thyroxine (t4). Pyridyl derivatives of lipoic acid were prepared as ligands for the study of the interaction with thyroxine (T4). Thin self-assembled films of the ligands were prepared in 70% ethanol on gold and their interaction with T4 was studied by titration experiments in an aqueous buffer solution using Surface Plasmon Resonance (SPR). The thickness and refractive index of the ligand layers were calculated from SPR spectra recorded in two media, also allowing for surface coverage and the density of the layers to be estimated. Two ligands, a 4-pyridyl and a bis(2-hydroxyethyl) derivative of lipoic acid, were selected to investigate the feasibility for producing molecularly imprinted self-assembled layers on gold for T4. The methodology was to co-assemble T4 and the ligand onto the gold surface, elute the T4 from the layer under alkaline conditions, and study the rebinding of T4 to the layer. Multiple elution/rebinding cycles were conducted in different buffer solutions, and rebinding of T4 could be observed, with a moderate binding affinity that depended greatly on the solvent used. More optimal binding was observed in HBS buffer, and the affinity of the interaction could be slightly increased when the 4-pyridyl and bis(2-hydroxy-ethyl) derivatives of lipoic acid were combined in the imprinted layer. 23591995 Selective kinin receptor agonists as cardioprotective agents in myocardial ischemia and diabetes. Cardiac ischemia is a leading cause of death, especially in diabetic patients. The diabetic ischemic heart is resistant experimentally to established cardioprotective treatments. New pharmacological approaches to cardiac protection are warranted. The kallikrein-kinin system is involved in myocardial protection in ischemia. Respective role of B1 (B1R) and B2 (B2R) receptors remains controversial. We tested whether pharmacological activation of kinin receptors may have therapeutic effect in cardiac ischemia-reperfusion in non diabetic (NDiab) and diabetic (Diab) mice. We assessed effect on infarct size (IS) and signaling pathways involved in myocardial protection of potent selective pharmacological agonists of B1R or B2R given at reperfusion. In NDiab mice, a B2R agonist reduced significantly IS by 47%, similarly to ramiprilat or ischemic postconditioning, via activation of PI3K/Akt pathway leading to inhibition of GSK3β. B1R agonist has no effect on IS. In contrast, in Diab mice, the B2R agonist, ramiprilat or ischemic postconditioning failed to reduce IS but a B1R agonist significantly reduced IS by 44% via activation of PI3K/Akt and ERK1/2, both leading to GSK3β inhibition. Differential effect of B2R or B1R agonists in NDiab and Diab mice can be linked to inactivation of B2R signaling and induction of B1R in heart of Diab mice. Thus, a pharmacological B2R agonist is cardioprotective in acute ischemia in non diabetic animals. B1R agonist overcomes resistance of diabetic heart to cardioprotective treatments. Pharmacological activation of B1R and B2R may become treatment for diabetic and non diabetic patients respectively in acute coronary syndromes. 23601710 Optimization of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of HIV capsid assembly inhibitors 2: Structure-activity relationships (SAR) of the C3-phenyl moiety. Detailed structure-activity relationships of the C3-phenyl moiety that allow for the optimization of antiviral potency of a series of 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione inhibitors of HIV capsid (CA) assembly are described. Combination of favorable substitutions gave additive SAR and allowed for the identification of the most potent compound in the series, analog 27. Productive SAR also transferred to the benzotriazepine and spirobenzodiazepine scaffolds, providing a solution to the labile stereocenter at the C3 position. The molecular basis of how compound 27 inhibits mature CA assembly is rationalized using high-resolution structural information. Our understanding of how compound 27 may inhibit immature Gag assembly is also discussed. 23620283 Homeodomain-interacting protein kinase 2-dependent repression of myogenic differentiation is relieved by its caspase-mediated cleavage. Differentiation of skeletal muscle cells is accompanied by drastic changes in gene expression programs that depend on activation and repression of genes at defined time points. Here we identify the serine/threonine kinase homeodomain-interacting protein kinase 2 (HIPK2) as a corepressor that inhibits myocyte enhancer factor 2 (MEF2)-dependent gene expression in undifferentiated myoblasts. Downregulation of HIPK2 expression by shRNAs results in elevated expression of muscle-specific genes, whereas overexpression of the kinase dampens transcription of these genes. HIPK2 is constitutively associated with a multi-protein complex containing histone deacetylase (HDAC)3 and HDAC4 that serves to silence MEF2C-dependent transcription in undifferentiated myoblasts. HIPK2 interferes with gene expression on phosphorylation and HDAC3-dependent deacetylation of MEF2C. Ongoing muscle differentiation is accompanied by elevated caspase activity, which results in caspase-mediated cleavage of HIPK2 following aspartic acids 916 and 977 and the generation of a C-terminally truncated HIPK2 protein. The short form of the kinase loses its affinity to the repressive multi-protein complex and its ability to bind HDAC3 and HDAC4, thus alleviating its repressive function for expression of muscle genes. This study identifies HIPK2 as a further protein that determines the threshold and kinetics of gene expression in proliferating myoblasts and during the initial steps of myogenesis. 23376697 Developmental abnormalities and changes in cholinesterase activity in sea urchin embryos and larvae from sperm exposed to engineered nanoparticles. The objective of this study is to examine the toxicity of engineered nanoparticles (NPs) that are dispersed in sea water by using an in vivo model. Because many products of nanotechnology contain NPs and are commonly used and well-established in the market, the accidental release of NPs into the air and water is quite possible. Indeed, at the end of their life cycle, some NPs are inevitably released into waste water and can reach marine ecosystem and affect the organisms there. Although there are few data on the presence of NPs in the marine environment, our awareness of their potential impact on environmental and organismal health is growing. Shallow-water benthonic organisms such as sea urchins provide planktonic larvae as a trophic base for finfish juveniles and are exposed to water from estuaries and precipitation. Such organisms can therefore be directly affected by NPs that are dispersed into those media. We evaluated the effects of exposure to different concentrations of nanosilver, titanium oxide and cobalt NPs on the sperm of the sea urchin Paracentrotus lividus by analyzing the functionality and the morphology and biochemistry of the first developmental stages of the sea urchin. Sperm were exposed to sea water containing suspensions of NPs ranging from 0.0001 mg/L to 1 mg/L. Fertilization ability was not affected, but developmental anomalies were identified in embryos from the gastrula to pluteus stages, including morphological alterations of the skeletal rods. In addition, the enzymatic activity (cholinesterase, ChE) of the larvae was measured. Acetylcholinesterase (AChE) and propionylcholinesterase activity (PrChE) was affected in all of the exposed samples. The results did not vary consistently with the concentration of NP, but controls were significantly different from exposed samples. Exposure of sea urchin to these NPs may cause neurotoxic damage, and the altered ChE activity may be involved in skeletogenic aberrations. In conclusion, the sea urchin represents a suitable and sensitive model for testing the toxicity and effects of engineered NPs that are dispersed in sea water. 23421714 (M)- and (P)-Bicelaphanol A, Dimeric Trinorditerpenes with Promising Neuroprotective Activity from Celastrus orbiculatus. (M)-Bicelaphanol A (1) and (P)-bicelaphanol A (2), two unprecedented dimeric trinorditerpenes existing as atropisomers, together with their monomer celaphanol A (3), were isolated from the root bark of Celastrus orbiculatus. The structures and absolute configurations of 1 and 2 were determined by spectroscopic and single-crystal X-ray diffraction analyses. Compound 1 exhibited a significant in vitro neuroprotective effect against a hydrogen peroxide-induced cell viability decrease in PC12 cells at 1 μM, while compounds 2 and 3 showed such effects at 10 μM. 23218717 Synthesis and insecticidal evaluation of novel N-pyridylpyrazolecarboxamides containing cyano substituent in the ortho-position. In an attempt to search for potent insecticides targeting the ryanodine receptor (RyR), a series of novel N-pyridylpyrazolecarboxamides containing cyano substituent in the ortho-position were designed and synthesized. Their insecticidal activities of target compounds against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella) indicated that most of the compounds showed moderate to high activities at the tested concentrations. In particular, compound 6l and 6o showed 86% larvicidal activities against Plutella xylostella at the concentration of 0.1mg/L, while the activity of compound 6h against Mythimna separate was 80% at 1mg/L. The calcium imaging technique was applied to investigate the effects of some title compounds on the intracellular calcium ion concentration ([Ca(2+)](i)), experimental results demonstrated that compound 6h stimulates a transient elevation in [Ca(2+)](i) in the absence of external calcium after the central neurons dye loading with fluo-3 AM. However, when the central neurons were dyed with fluo-5N and incubated with 2-APB, [Ca(2+)]i decreased transiently by treated of compound 6h. All of the calcium imaging technique experiments demonstrated that these novel compounds deliver calcium from endoplasmic reticulum to cytoplasm, which proved that the title compounds were the possible activators of insect RyR. 23220413 Exposure of zebrafish embryos/larvae to TDCPP alters concentrations of thyroid hormones and transcriptions of genes involved in the hypothalamic-pituitary-thyroid axis. Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) has been frequently detected in the environment and in various biota, including fish, and has been implicated in disruption of the thyroid endocrine system. In the present study, zebrafish (Danio rerio) embryos were exposed to different concentrations of TDCPP (10, 50, 100, 300 and 600 μg/L) from 2 h post-fertilization (hpf) to 144 hpf. Developmental endpoints, and whole-body concentrations of thyroid hormones and transcriptional profiles of genes involved in the hypothalamic-pituitary-thyroid (HPT) axis were examined. Exposure to TDCPP caused a dose-dependent developmental toxicity, including decreased body weight, reduced hatching, survival and heartbeat rates, and increased malformation (spinal curvature). Treatment with the positive control chemical 3,3',5-triiodo-l-thyronine (T3) significantly decreased whole-body thyroxin (T4) concentrations, increased whole-body T3 concentrations, and upregulated mRNA expression involved in the HPT axis as a compensatory mechanism. These results suggested that the HPT axis in 144-hpf zebrafish larvae was responsive to chemical exposure and could be used to evaluate the effects of chemicals on the thyroid endocrine system. TDCPP exposure significantly decreased whole-body T4 concentrations and increased whole-body T3 concentrations, indicating thyroid endocrine disruption. The upregulation of genes related to thyroid hormone metabolism (dio1 and ugt1ab) might be responsible for decreased T4 concentrations. Treatment with TDCPP also significantly increased transcription of genes involved in thyroid hormone synthesis (tshβ, slc5a5 and tg) and thyroid development (hhex, nkx2.1 and pax8) as a compensatory mechanism for decreased T4 concentrations. Taken together, these results suggest that TDCPP alters the transcription of genes involved in the HPT axis and changes whole-body concentrations of thyroid hormones in zebrafish embryos/larvae, thus causing an endocrine disruption of the thyroid system. 23546605 Ovarian Expression of Insulin-Like Peptide 3 (INSL3) and Its Receptor (RXFP2) During Development of Bovine Antral Follicles and Corpora Lutea and Measurement of Circulating INSL3 Levels During Synchronized Estrous Cycles. Insulin-like peptide 3 (INSL3), a major product of testicular Leydig cells, is also expressed by the ovary, but its functional role remains poorly understood. Here, we quantified expression of INSL3 and its receptor RXFP2 in theca interna cell (TIC) and granulosa cell compartments of developing bovine antral follicles and in corpora lutea (CL). INSL3 and RXFP2 mRNA levels were much higher in TIC than granulosa cell and increased progressively during follicle maturation with INSL3 peaking in large (11-18 mm) estrogen-active follicles and RXFP2 peaking in 9- to 10-mm follicles before declining in larger (11-18 mm) follicles. Expression of both INSL3 and RXFP2 in CL was much lower than in TIC. In situ hybridization and immunohistochemistry confirmed abundant expression of INSL3 mRNA and protein in TIC. These observations indicate follicular TIC rather than CL as the primary site of both INSL3 production and action, implying a predominantly autocrine/paracrine role in TIC. To corroborate the above findings, we showed that in vitro exposure of TIC to a luteinizing concentration of LH greatly attenuated expression of both INSL3 and its receptor while increasing progesterone secretion and expression of STAR and CYP11A1. Moreover, in vivo, a significant cyclic variation in plasma INSL3 was observed during synchronized estrous cycles. INSL3 and estradiol-17β followed a similar pattern, both increasing after luteolysis, before falling sharply after the LH surge. Thus, theca-derived INSL3, likely from the dominant preovulatory follicle, is detectable in peripheral blood of cattle, and expression is down-regulated during luteinization induced by the preovulatory LH surge. Collectively, these findings underscore the likely role of INSL3 as an important intrafollicular modulator of TIC function/steroidogenesis, while raising doubts about its potential contribution to CL function. 23625909 Optimization of conventional water treatment plant using dynamic programming. In this research, the mathematical models, indicating the capability of various units, such as rapid mixing, coagulation and flocculation, sedimentation, and the rapid sand filtration are used. Moreover, cost functions were used for the formulation of conventional water and wastewater treatment plant by applying Clark's formula (Clark, 1982). Also, by applying dynamic programming algorithm, it is easy to design a conventional treatment system with minimal cost. The application of the model for a case reduced the annual cost. This reduction was approximately in the range of 4.5-9.5% considering variable limitations. Sensitivity analysis and prediction of system's feedbacks were performed for different alterations in proportion from parameters optimized amounts. The results indicated (1) that the objective function is more sensitive to design flow rate (Q), (2) the variations in the alum dosage (A), and (3) the sand filter head loss (H). Increasing the inflow by 20%, the total annual cost would increase to about 12.6%, while 20% reduction in inflow leads to 15.2% decrease in the total annual cost. Similarly, 20% increase in alum dosage causes 7.1% increase in the total annual cost, while 20% decrease results in 7.9% decrease in the total annual cost. Furthermore, the pressure decrease causes 2.95 and 3.39% increase and decrease in total annual cost of treatment plants. 23315996 The pH Taxis of an Intelligent Catalytic Microbot. A Pd nanoparticle-containing polymer microsphere moves with increasing speed across a pH gradient, following differential catalytic decomposition of aqueous hydrogen peroxide. The directional motion is akin to the pH taxis of living microorganisms. The artificial pH taxis exhibits random walk, translation, vertical, hopping, and pulsed motion, when the size of the motor and the imposed pH gradient are modulated. 23092395 Chemical profile and biological activities of Deguelia duckeana A.M.G. Azevedo (Fabaceae). Deguelia duckeana is popularly known as timbó and used by indigenous people as ictiotoxic. On account of there being no literature pertaining to the chemical profile or biological activity of this plant, the hexane, methanol and aqueous crude extracts from leaves, stems and roots were assayed that presented very high cytotoxic potential against Artemia salina, achieving 100% mortality in up to 5.0 µg mL(-1) concentration, but lower antioxidant potential on 2,2-diphenyl-1-picryl-hydrazyl and Fe(3+)/Phenanthroline assays. The phytochemical analysis of crude extracts showed the presence of flavonoids and related compounds as major constituents as well as steroids in all of them, and tannins in polar extracts. All the extracts were assayed for antibacterial activity but only the hexane extract of stems showed moderate activity on Staphylococcus aureus, which was fractionated and yielded a mixture of 3,5,4'-trimethoxy-4-prenylstilbene, lonchocarpine, 4-hydroxylonchocarpine and derricidine, reported for the first time in D. duckeana and other fraction with β-sitosterol and stigmasterol mixture. 23470080 Copeptin as a biomarker in cardiac disease. The introduction of biochemical biomarkers in the evaluation of patients with cardiovascular disease has led to practice-changing advancements in the way these patients are diagnosed and managed. Measurements of cardiac troponins or brain-type natriuretic peptide (BNP) and its precursor, N-terminal brain-type natriuretic peptide (NT-proBNP), have become indispensable in the evaluation of patients with acute coronary syndromes and heart failure, respectively, constituting an integral part of the diagnostic algorithm and risk stratification of these conditions. Copeptin, a glycopeptide, part of the prehormone molecule of the antidiuretic hormone - or arginine-vasopressin - has shown considerable promise in this field. There is evidence that copeptin might be useful as a diagnostic or prognostic biomarker and risk-stratifier in a range of cardiovascular disease conditions. The main clinical scenarios where copeptin has been studied as a biomarker are: early rule-out of myocardial infarction in patients with acute chest pain, diagnosis of heart failure in patients with acute dyspnea and determining the prognosis of destabilized or chronic stable heart failure. The present review is aimed at providing concise information about the molecular structure and biosynthesis of copeptin, the available medical chemistry methods of quantification, and the potential clinical uses of this molecule in patients with heart disease. 23293970 Tobacco smoke modulates ozone-induced toxicity in rat lungs and central nervous system. Adult Sprague-Dawley (SD) male rats were exposed for a single 3 h period to air, ozone (O₃) or O₃) followed by tobacco smoke (O₃/TS). For pulmonary effects, bronchoalveolar lavage (BAL) cells and fluid were analyzed. Data revealed a significant increase in polymorphonuclear leukocytes (PMN), total protein and albumin concentrations in the O₃ group, reflecting inflammatory and toxic responses. A subsequent exposure to TS attenuated PMN infiltration into the airspaces and their recovery in the BAL. A similar reduction was observed for BAL protein and albumin in the O₃/TS group, but it was not statistically significant. We also observed a significant increase in BAL total antioxidant capacity following O₃ exposure, suggesting development of protective mechanisms for oxidative stress damage from O₃. Exposure to TS attenuated the levels of total antioxidant capacity. Lung tissue protein analysis showed a significant reduction of extracellular superoxide dismutase (EC-SOD) in the O₃ or O₃/TS group and catalase in the O₃/TS group. TS further altered O₃-induced EC-SOD and catalase protein expression, but the reductions were not significant. For effects in the central nervous system (CNS), we measured striatal dopamine levels by HPLC with electrochemical detection. O₃ exposure produced a nonsignificant decrease in the striatal dopamine content. The effect was partially reversed in the O₃/TS group. Overall, the results show that the toxicity of O₃ in the lung is modulated by TS exposure, and the attenuating trend, though nonsignificant in many cases, is contrary to the synergistic toxicity predicted for TS and O₃, suggesting limited cross-tolerance following such exposures. 23564642 A Microscale Neuron and Schwann Cell Coculture Model for Increasing Detection Sensitivity of Botulinum Neurotoxin Type A. Botulinum neurotoxin (BoNT) is a potent and specific biomolecule that is both implicated as a potential threat in bioterrorism and used in therapeutics. Highly sensitive and robust assays that measure BoNT activity are needed to manage outbreak or controlled distribution of BoNT. Current in vivo and in vitro assays have limitations, including high costs and variability for mouse bioassays, extensive preparations for primary and stem cell-derived neurons, and inherent low sensitivity for cell lines. Sensitivity of cell lines can be increased by direct differentiation and with their physiological relevance (compared with cell-free strategies) and robustness (compared with primary cell strategies); adopting cell lines is an attractive alternative to in vivo assays. Here, we present two distinct strategies that improved sensitivity of a cell line to BoNT serotype A (BoNT/A) without direct differentiation. We developed a cell-based BoNT assay using microscale culture and coculture of neuronal and Schwann cell lines, NG108-15 and S16, respectively, to improve both sensitivity and physiological relevance. Results showed that NG108-15 and S16 coculture decreased EC50 from 12.5 to 0.8ng/µl (p < 0.001) in macroscale and from 2.6 to 1.1ng/µl (p = 0.006) in microscale. In addition, NG108-15 monoculture at microscale decreased EC50 from 12.5 to 2.6ng/µl (p < 0.001) compared with macroscale. Finally, controlling the spatial arrangement of microscale coculture revealed that S16-derived soluble factors can increase sensitivity. Thus, our study demonstrates two distinct strategies for increasing the sensitivity of a cell line to BoNT using coculture and microscale culture, thereby advancing assay technology for BoNT detection. 23525786 Combinatorial Design of Hydrolytically Degradable, Bone-like Biocomposites Based on PHEMA and Hydroxyapatite. With advantages such as design flexibility in modifying degradation, surface chemistry, and topography, synthetic bone-graft substitutes are increasingly demanded in orthopedic tissue engineering to meet various requirements in the growing numbers of cases of skeletal impairment worldwide. Using a combinatorial approach, we developed a series of biocompatible, hydrolytically degradable, elastomeric, bone-like biocomposites, comprising 60 wt% poly(2-hydroxyethyl methacrylate-co-methacrylic acid), poly(HEMA-co-MA), and 40 wt% bioceramic hydroxyapatite (HA). Hydrolytic degradation of the biocomposites is rendered by a degradable macromer/crosslinker, dimethacrylated poly(lactide-b-ethylene glycol-b-lactide), which first degrades to break up 3-D hydrogel networks, followed by dissolution of linear pHEMA macromolecules and bioceramic particles. Swelling and degradation were examined at Hank's balanced salt solution at 37 °C in a 12-week period of time. The degradation is strongly modulated by altering the concentration of the co-monomer of methacrylic acid and of the macromer, and chain length/molecular weight of the macromer. 95% weight loss in mass is achieved after degradation for 12 weeks in a composition consisting of HEMA/MA/Macromer = 0/60/40, while 90% weight loss is seen after degradation only for 4 weeks in a composition composed of HEMA/MA/Macromer = 27/13/60 using a longer chain macromer. For compositions without a co-monomer, only about 14% is achieved in weight loss after 12-week degradation. These novel biomaterials offer numerous possibilities as drug delivery carriers and bone grafts particularly for low and medium load-bearing applications. 23281917 Design and development of multiple emulsion for enhancement of oral bioavailability of acyclovir. The objective of this investigation was to design and develop water-in-oil-in-water type multiple emulsions (w/o/w emulsions) entrapping acyclovir for improving its oral bioavailability. Multiple emulsions (MEs) were prepared and optimized using Span-80 and Span-83 as lipophilic surfactant and Brij-35 as hydrophilic surfactant. The physio-chemical properties of the w/o/w emulsions - particle size, viscosity, phase separation (centrifugation test) and entrapment efficiency were measured and evaluated along with macroscopic and microscopic observations to confirm multiple nature, homogeneity and globule size. Stability study, in vitro and ex vivo release studies were performed followed by in vivo studies in rats. Stable w/o/w emulsions with a particle size of 33.098 ± 2.985 µm and 85.25 ± 4.865% entrapment efficiency were obtained. Stability studies showed that the concentration of lipophilic surfactant was very important for stability of MEs. Drug release from the prepared formulations showed initial rapid release followed by a much slower release. In vivo studies in rats indicated prolonged release and better oral bioavailability as compared to drug solution. The overall results of this study show the potential of the w/o/w emulsions as promising drug delivery systems for acyclovir. 23643664 Sustained resistance to acute MPTP toxicity by hypothalamic dopamine neurons following chronic neurotoxicant exposure is associated with sustained up-regulation of parkin protein. Hypothalamic tuberoinfundibular dopamine (TIDA) neurons remain unaffected in Parkinson disease (PD) while there is significant degeneration of midbrain nigrostriatal dopamine (NSDA) neurons. A similar pattern of susceptibility is observed following acute exposure to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and the resistance of TIDA neurons to MPTP is associated with increased expression of parkin and ubiquitin carboxy-terminal hydrolase L-1 (UCHL- 1). In the present study, the response of TIDA and NSDA neurons to acute MPTP administration following chronic MPTP exposure was examined. Mice were treated with ten injections of either MPTP (20 mg/kg; s.c.; every 3.5 days) or saline vehicle (10 ml/kg; s.c.; every 3.5 days). Following a 21 day recovery period, chronic saline- and MPTP-treated mice received an additional injection of either saline (10 ml/kg; s.c.) or MPTP (20 mg/kg; s.c.) and were sacrificed 24 h later. NSDA neurons displayed significant axon terminal degeneration (as indexed by decreases in DA, tyrosine hydroxylase (TH) and DA transporter concentrations in the striatum) as well as loss of TH-immunoreactive (IR) neurons in the substantia nigra (SN) following MPTP, whereas TIDA neurons revealed no overt axon terminal pathology or loss of TH-IR cell bodies. NSDA neuronal pathology was associated with transient decreases in concentrations of parkin and UCHL-1 protein in the SN, which returned to normal levels by 21 days following cessation of chronic neurotoxicant exposure. Resistance of TIDA neurons to MPTP toxicity was correlated with a transient increase in UCHL-1 and a sustained elevation in parkin in the arcuate nucleus. TIDA neurons represent a DA neuron population with a unique and inherent ability to adapt to acute and chronic toxicant administration with a sustained elevation of the neuroprotective protein parkin. The correlation between the ability to increase parkin and UCHL-1 expression and the resistance of DA neurons to neurotoxicant exposure is consistent with a functional link between these features and an underlying differential susceptibility to toxicant-associated neurodegeneration. 23613080 Hierarchical NiO microflake films with high coloration efficiency, cyclic stability and low power consumption for applications in a complementary electrochromic device. We have demonstrated that thin films of hierarchical NiO microflakes assembled from nanoleaves can be grown directly on FTO-coated glass substrates using a facile and template-free hydrothermal technique. This hierarchical structure holds the advantages of both nanometre-sized building blocks and microsized assemblies. Thus, the films exhibit highly enhanced electrochromic performances and cyclic stability due to their high surface area and good electrochemical stability. Moreover, a complementary electrochromic device combining the hierarchical NiO microflake film with a self-weaving WO3 nanoflake film is fabricated to further improve the electrochromic performance. As a result, the complementary electrochromic device shows a high optical modulation (73.2% at 550 nm), large coloration efficiency (146.9 cm(2) C(-1) at 550 nm by applying a low coloration voltage of -1.0 V) and fast switching responses with a coloring time of 1.8 s and a bleaching time of 3.2 s. It is also observed that there is no significant degradation of the electrochromic properties after 2000 continuous coloration/bleaching cycles, making it attractive for practical applications. 23539547 Use of human in vitro skin models for accurate and ethical risk assessment: metabolic considerations. Several human skin models employing primary cells and immortalised cell lines, used as monocultures or combined to produce reconstituted 3D skin constructs, have been developed. Furthermore, these models have been included in European genotoxicity and sensitization/irritation assay validation projects. In order to help interpret data, Cosmetics Europe (formerly COLIPA) facilitated research projects that measured a variety of defined phase 1 and 2 enzyme activities and created a complete proteomic profile of xenobiotic metabolising enzymes (XMEs) in native human skin and compared them with data obtained from a number of in vitro models of human skin. Here, we have summarised our findings on the current knowledge of the metabolic capacity of native human skin and in vitro models, and make an overall assessment of the metabolic capacity from gene expression, proteomic expression and substrate metabolism data. The known low expression and function of phase 1 enzymes in native whole skin was reflected in the in vitro models. Some XMEs in whole skin were not detected in in vitro models and vice versa, and some major hepatic XMEs such as cytochrome P450-monooxygenases were absent or measured only at very low levels in the skin. Conversely, despite varying mRNA and protein levels of phase 2 enzymes, functional activity of glutathione S-transferases, N-acetyltransferase 1, and UDP-glucuronosyltransferases were all readily measurable in whole skin and in vitro skin models at activity levels similar to those measured in the liver. These projects have enabled a better understanding of the contribution of XMEs to toxicity endpoints. 23570839 New dimeric and trimeric coumarin glucosides from Daphne retusa Hemsl. New dimeric and a trimeric coumarin glucosides namely Daphneretusin A (1) Daphneretusin B (2) along with three known oligomers (3-5) were obtained as a result of bioassay guided fractionation of Daphne retusa Hemsl. Fractions (n-hexane, CHCl3, AcOEt, CH3OH and water) exhibited potent radical scavenging activity in relevant non-physiological bioassays. The structures of isolated compounds were elucidated by UV, IR, EIMS, FAB-MS, 1D, and 2D NMR spectroscopic analysis. 23382448 Dicer1 is required to repress neuronal fate during endocrine cell maturation. MicroRNAs (miRNAs) are important regulators of gene expression programs in the pancreas; however, little is known about the role of miRNA pathways during endocrine cell specification and maturation during neonatal life. In this study, we deleted Dicer1, an essential RNase for active miRNAs biogenesis, specifically from NGN3+ endocrine progenitor cells. We found that deletion of Dicer1 in endocrine progenitors did not affect the specification of hormone-expressing endocrine cells. However, the islets in the mutant mice in the neonatal period exhibited morphological defects in organization and loss of hormone expression, and the mutant mice subsequently developed diabetes. Dicer1-deficient β-cells lost insulin expression while maintaining the expression of β-cell transcription factors such as Pdx1 and Nkx6.1 early in the postnatal period. Surprisingly, transcriptional profiling showed that that the Dicer1-deficient endocrine cells expressed neuronal genes before the onset of diabetes. The derepression of neuronal genes was associated with a loss in binding of the neuronal transcriptional repressor RE-1-silencing transcription factor to its targets in Dicer1-deficient β-cells. These studies suggest that miRNAs play a critical role in suppressing neuronal genes during the maturation of endocrine cells. 23103297 (-)-Carvone: antispasmodic effect and mode of action. (-)-Carvone is a monoterpene ketone found in spearmint (Mentha spicata var. crispa) essential oil that is widely used as an odor and flavor additive. An intestinal antispasmodic effect was recently reported for (-)-carvone, and it has been shown to be more potent than its (+)-antipode. The mechanism of (-)-carvone action in the intestines has not been investigated. To gain a better understanding of the (-)-carvone antispasmodic effect, we investigated its pharmacological effects in the guinea pig ileum. Terminal portions of the ileum were mounted for isotonic contraction recordings. The effect of (-)-carvone was compared with that of the classical calcium channel blocker (CCB) verapamil. In isolated ileal smooth muscle, (-)-carvone did not produce direct contractile or relaxation responses and did not modify electrically elicited contractions or low K(+)-evoked contractions. The submaximal contractions induced by histamine (p<0.001), BaCl2 (p<0.05), and carbachol (p<0.01) were significantly reduced by (-)-carvone. The contractile response elicited by high concentrations of carbachol was reduced but not abolished by (-)-carvone. No additive action was detected with co-incubation of (-)-carvone and verapamil on carbachol-induced contraction. (-)-Carvone reduced the contraction induced by high K(+) and was almost 100 times more potent than verapamil. Thus, (-)-carvone showed a typical and potent CCB-like action. Many effects described for both (-)-carvone and spearmint oil can be explained as a CCB-like mode of action. 23131177 Characterization of substituted phenylpropylamides as highly selective agonists at the melatonin MT2 receptor. Melatonin is a widely distributed hormone that regulates several major physiological processes, including the circadian rhythm and seasonal adaptation. The two subtypes of mammalian G protein-coupled melatonin receptors are primarily responsible for mediating the actions of melatonin. Because synthetic melatonin agonists have considerable therapeutic potentials in modulating insomnia and circadian- related sleep disorders, it is highly desirable to develop subtype-selective melatoninergic compounds. The pharmacological potencies of a series of substituted N-[3-(3-methoxyphenyl)propyl] amides towards human melatonin MT(1) and MT(2) receptors were evaluated by the FLIPR high-throughput screening assay, whilst their subtype-selectivity was subsequently verified with ERK phosphorylation and cAMP assays. Structure-activity relationship analysis of highly potent subtype-selective ligands (MT(2) EC(50) 10-90 pM) revealed that a benzyloxyl substituent incorporated at C6 position of the 3-methoxyphenyl ring dramatically enhanced the MT(2) potency and at the same time decreased MT(1) potency. Incorporation of structural moieties conferring the subtype selectivity produced several extremely potent MT(2)-selective ligands. The most potent subtype-selective ligand, 2q had a substantially higher potency for MT(2) receptor than melatonin for elevation of [Ca(2+)]i and inhibition of forskolin-elevated cAMP. Representative MT(2)-selective ligands also induced ERK phosphorylation in both recombinant and native cell lines, and no cross-reactivity to 17 other GPCRs could be detected. These ligands represent invaluable tools for delineating the functional roles of distinct melatonin receptor subtypes and are viable candidates for drug development. 22889721 Microcrack density and nanomechanical properties in the subchondral region of the immature piglet femoral head following ischemic osteonecrosis. Development of a subchondral fracture is one of the earliest signs of structural failure of the immature femoral head following ischemic osteonecrosis, and this eventually leads to a flattening deformity of the femoral head. The mechanical and mineralization changes in the femoral head preceding subchondral fracture have not been elucidated. We hypothesized that ischemic osteonecrosis leads to early material and mechanical alterations in the bone of the subchondral region. The purpose of this investigation was to assess the bone of the subchondral region for changes in the histology of bone cells, microcrack density, mineral content, and nanoindentation properties at an early stage of ischemic osteonecrosis in a piglet model. This large animal model has been shown to develop a subchondral fracture and femoral head deformity resembling juvenile femoral head osteonecrosis. The unoperated, left femoral head of each piglet (n=8) was used as a normal control, while the right side had a surgical ischemia induced by disrupting the femoral neck vessels with a ligature. Hematoxylin and eosin (H&E) staining and TUNEL assay were performed on femoral heads from 3 piglets. Quantitative backscattered electron imaging, nanoindentation, and microcrack assessments were performed on the subchondral region of both control and ischemic femoral heads from 5 piglets. H&E staining and TUNEL assay showed extensive cell death and an absence of osteoblasts in the ischemic side compared to the normal control. Microcrack density in the ischemic side (3.2±0.79 cracks/mm(2)) was significantly higher compared to the normal side (0.27±0.27 cracks/mm(2)) in the subchondral region (p<0.05). The weighted mean of the weight percent distribution of calcium (CaMean) also was significantly higher in the ischemic subchondral region (p<0.05). Furthermore, the nanoindentation modulus within localized areas of subchondral bone was significantly increased in the ischemic side (16.8±2.7GPa) compared to the normal control (13.3±3.2GPa) (p<0.05). Taken together, these results support the hypothesis that the nanoindentation modulus of the subchondral trabecular bone is increased in the early stage of ischemic osteonecrosis of the immature femoral head and makes it more susceptible to microcrack formation. We postulate that continued loading of the hip joint when there is a lack of bone cells to repair the microcracks due to ischemic osteonecrosis leads to microcrack accumulation and subsequent subchondral fracture. 23627902 Structural Characterization and Molecular Order of Rodlike Mesogens with Three- and Four-Ring Core by XRD and (13)C NMR Spectroscopy. Structural characterizations using XRD and (13)C NMR spectroscopy of two rodlike mesogens consisting of (i) three phenyl ring core with a polar cyano terminal and (ii) four phenyl ring core with flexible dodecyl terminal chain are presented. The three-ring-core mesogen with cyano terminal exhibits enantiotropic smectic A phase while the four-ring mesogen reveals polymesomorphism and shows enantiotropic nematic, smectic C, and tilted hexatic phases. The molecular organization in the three-ring mesogen is found to be partial bilayer smectic Ad type, and the interdigitation of the molecules in the neighboring layers is attributed to the presence of the polar terminal group. For the four-ring mesogen, the XRD results confirm the existence of the smectic C and the tilted hexatic mesophases. A thermal variation of the layer spacing across the smectic C phase followed by a discrete jump at the transition to the tilted hexatic phase is also observed. The tilt angles have been estimated to be about 45° in the smectic C phase and about 40° in tilted hexatic phase. (13)C NMR results indicate that in the mesophase the molecules are aligned parallel to the magnetic field. From the (13)C-(1)H dipolar couplings determined from the 2D experiments, the overall order parameter for the three-ring mesogen in its smectic A phase has been estimated to be 0.72 while values ranging from 0.88 to 0.44 have been obtained for the four-ring mesogen as it passes from the tilted hexatic to the nematic phase. The orientations of the different rings of the core unit with respect to each other and also with respect to the long axis of the molecule have also been obtained. 23511088 Derivatives of Dictyostelium discoideum differentiation-inducing factor-3 suppress the activities of Trypanosoma cruzi in vitro and in vivo. Chagas disease (human American trypanosomiasis), which is caused by the protozoan parasite Trypanosoma cruzi, is responsible for numerous deaths each year; however, established treatments for the disease are limited. Differentiation-inducing factor-1 (DIF-1) and DIF-3 are chlorinated alkylphenones originally found in the cellular slime mold Dictyostelium discoideum that have been shown to possess pharmacological activities. Here, we investigated the effects of DIF-3 derivatives on the infection rate and growth of T. cruzi by using an in vitro assay system utilizing host human fibrosarcoma HT1080 cells. Certain DIF-3 derivatives, such as butoxy-DIF-3 (Bu-DIF-3), at micro-molar levels strongly suppressed both the infection rate and growth of T. cruzi in HT1080 cells and exhibited little toxicity for HT1080 cells. For example, the IC50 of DIF-3 and Bu-DIF-3 versus the growth of T. cruzi in HT1080 cells were 3.95 and 0.72μM, respectively, and the LD50 of the two compounds versus HT1080 cells were both greater than 100μM. We also examined the effects of DIF-3 and Bu-DIF-3 on T. cruzi activity in C57BL/6 mice. Intraperitoneally administered Bu-DIF-3 (50mg/kg) significantly suppressed the number of trypomastigotes in blood with no apparent adverse effects. These results strongly suggest that DIF-3 derivatives could be new lead compounds in the development of anti-trypanosomiasis drugs. 23527619 Novel Cellulose Polyampholyte-Gold Nanoparticle-Based Colorimetric Competition Assay for the Detection of Cysteine and Mercury(II). We provide a highly sensitive and selective assay to detect cysteine (Cys) and Hg(2+) in aqueous solutions using Au nanoparticles (NPs) stabilized by carboxylethyl quaternized cellulose (CEQC). This method is based on the thiophilicity of Hg(2+) and Au NPs as well as the unique optical properties of CEQC-stabilized Au NPs. CEQC chains are good stabilizing agents for Au NPs even in a high-salt solution. The addition of Cys results in the aggregation of CEQC-stabilized Au NPs, which induces the visible color change and obvious redshift in UV-visible absorption spectra. On the other hand, Hg(2+) is more apt to interact with thiols than Au NPs; thus, it can remove the Cys and trigger Au NP aggregate redispersion again. By taking advantage of this mechanism, a novel off-on colorimetric sensor has been established for Cys and Hg(2+) detection. This new assay could selectively detect Cys and Hg(2+) with the detection limits as low as 20 and 40 nM in aqueous solutions, respectively. 23561124 Comparison of biogenic amine and polyphenol profiles of grape berries and wines obtained following conventional, organic and biodynamic agricultural and oenological practices. The bio-active compounds present in food and beverages have a high potential influence on the future health of humans. The levels of biogenic amines, anthocyanins, polyphenols and antioxidant activity were measured in white (Pignoletto) and red (Sangiovese) grape berries and wines from the Emilia-Romagna region (Italy) obtained following conventional, organic and biodynamic agricultural and oenological practices. No significant difference was shown among the samples coming from different agricultural and winemaking practices. Principal Component Analysis was also performed. Biogenic amine amounts were higher in red than in white berries, while in the wines an opposite trend was observed, with histamine, tyramine and putrescine being the most abundant in Pignoletto wines. Red grapes and wines were richer in anthocyanins and showed higher antioxidant activity than white ones. The total level of polyphenols was similar in red and white berries, but with different metabolite profiles depending on the grape variety. 22985735 Comparative cytological responses of lung epithelial and pleural mesothelial cells following in vitro exposure to nanoscale SiO2. Due to unique surface chemistries and the ability to easily functionalize their surface, amorphous silica nanoparticles are being assimilated into medicinal and consumer products at an increasing rate. Subsequently, there is an emergent need to understand the interactions of these particulates with biological systems in an attempt to mitigate toxicity. The identification of susceptible or resistant cell types of the pulmonary system remains a critical step in the development of toxicity assessments for nanoparticle-based platforms. Specific to this study, the cellular responses of A549 lung epithelial and MeT-5A pleural mesothelial cell lines as a means of detecting nanoparticle-induced oxidative stress were examined. Basal expression and cellular antioxidant activity, including SOD, CAT, and GSH, were examined prior to H(2)O(2) and ~30 nm SiO(2) (0.01-100mg/L) exposures. Dose-response observations were made regarding oxidant production, cytotoxicity, GSH depletion and NRF2 transcription factor activation. Results indicated that, while both cell types exhibited susceptibility to H(2)O(2) and SiO(2)-induced oxidative stress and damage, the A549 cell line was relatively more resilient. 23280951 The impact of structure on oxidatively generated DNA damage products resulting from the C3'-thymidinyl radical. What's the damage? Trapping the C3'-thymidinyl radical in biologically significant architectures delivers both the repaired oligomer and 1-(2'-deoxy-β-D-threo-pentofuranosyl)thymidine-containing substrates. The stereoselectivity of the reduction was found to be dependent upon the DNA structure. 23122068 Separation and purification of sulforaphene from radish seeds using macroporous resin and preparative high-performance liquid chromatography. This present study described a rapid and cost-effective method for the separation and purification of natural sulforaphene from radish seeds by SP-700 macroporous resin and preparative high-performance liquid chromatography (HPLC). Sulforaphene with high purity and recovery was obtained by preparative HPLC with a C18 column and 30% methanol in ultra-pure water as the mobile phase. 12.5 kg of radish seeds, which contained 87.5 g of sulforaphene, produced 117.5 g of sulforaphene-rich extract of 65.8% sulforaphene after primary separation by SP-700 macroporous resin. 5.9 g of 96.5% sulforaphene was obtained from 9.5 g of the sulforaphene-rich extract after purification by preparative HPLC. The purified compound was assessed by analytical HPLC and characterised by ESI/MS, (1)H NMR and (13)C NMR. Standard curve was developed using the purified sulforaphene to allow quantification of sulforaphene in the extracts of radish seeds by analytical HPLC. 23469924 Identification of a RhoA- and SRF-Dependent Mechanism of Androgen Action that is Associated with Prostate Cancer Progression. Androgen receptor (AR) action is critical for prostate cancer (CaP) progression, but is not inhibited fully by available androgen deprivation therapy (ADT). One of the limitations to current ADT is that it targets all androgen action in CaP, and other, cells irrespective of clinical relevance. The resulting off-target effects are responsible for ADT associated side effects that affect negatively a patient's quality of life. Isolation of the AR-dependent events that drive CaP progression may lead to novel forms of ADT that are at least as effective but more selective. Here, an approach is described that starts from insights in the basic mechanism(s) by which AR regulates target gene expression to identify novel drugable targets downstream of AR. Exploration of the molecular events that underlie androgen regulation of the ARassociated coregulator FHL2 led to the isolation of a novel indirect mechanism of androgen action that is mediated by the secondary transcription factor Serum Response Factor (SRF). Using a combination of oligoarray and in silico analyses, an SRF-dependent fraction of AR action was identified that is enriched in CaP tissues, is able to discriminate between benign and malignant prostate, and correlates with aggressive disease and biochemical failure. The RhoA signaling axis, a well known upstream stimulator of SRF action that harbors drugable targets, conveyed androgen-responsiveness to SRF, and was activated in CaP where it correlates with increased CaP aggressiveness and poor outcome after surgery. 22954283 Can first-trimester screening program detect women at high risk for gestational diabetes mellitus? This study was designed to compare first-trimester maternal serum biochemical markers of aneuploidy and fetal nuchal translucency in pregnancies complicated by gestational diabetes mellitus and those of a control group. The study included 60 gestational diabetic and 60 control women who attended the first-trimester combined screening program for Down syndrome between 11 and 14 gestational weeks with complete follow-up data and delivered in our institution. Maternal serum free β-human chorionic gonadotropin, pregnancy-associated plasma protein-A and fetal nuchal translucency were investigated. The combined risks, double test risks and age risks were calculated by PRISCA software version 4.0. Comparison of the results between the two groups yielded no significant differences in serum levels of free β-human chorionic gonadotropin and fetal nuchal translucency. However, women who developed gestational diabetes mellitus had significantly lower pregnancy-associated plasma protein-A. And also, the combined risks and double test risks calculated by PRISCA software were statistically higher in gestational diabetic women than normal pregnant women. These results suggest that differences can be seen between diabetic and healthy pregnant women in first-trimester maternal serum biochemical markers of aneuploidy. 23410038 The metalloproteases meprin α and meprin β: unique enzymes in inflammation, neurodegeneration, cancer and fibrosis. The metalloproteases meprin α and meprin β exhibit structural and functional features that are unique among all extracellular proteases. Although meprins were discovered more than 30 years ago, their precise substrates and physiological roles have been elusive. Both enzymes were originally found to be highly expressed in kidney and intestine, which focused research on these particular tissues and associated pathologies. Only recently it has become evident that meprins exhibit a much broader expression pattern, implicating functions in angiogenesis, cancer, inflammation, fibrosis and neurodegenerative diseases. Different animal models, as well as proteomics approaches for the identification of protease substrates, have helped to reveal more precise molecular signalling events mediated by meprin activity, such as activation and release of pro-inflammatory cytokines. APP (amyloid precursor protein) is cleaved by meprin β in vivo, reminiscent of the β-secretase BACE1 (β-site APP-cleaving enzyme 1). The subsequent release of Aβ (amyloid β) peptides is thought to be the major cause of the neurodegenerative Alzheimer's disease. On the other hand, ADAM10 (a disintegrin and metalloprotease domain 10), which is the constitutive α-secretase, was shown to be activated by meprin β, which is itself shed from the cell surface by ADAM10. In skin, both meprins are overexpressed in fibrotic tumours, characterized by massive accumulation of fibrillar collagens. Indeed, procollagen III is processed to its mature form by meprin α and meprin β, an essential step in collagen fibril assembly. The recently solved crystal structure of meprin β and the unique cleavage specificity of these proteases identified by proteomics will help to generate specific inhibitors that could be used as therapeutics to target meprins under certain pathological conditions. 23127598 Absorption of triphenylmethane dyes Brilliant Blue and Patent Blue through intact skin, shaven skin and lingual mucosa from daily life products. Currently, there is evidence of health risks of triphenylmethane dyes after systemic absorption. This paper investigates the fate of Brilliant Blue (BB) and Patent Blue (PB) after 24-h in vitro diffusion, firstly through intact and secondly through shaven pig-ear skin (stored by freezing) from four leave-on cosmetics under in-use conditions. Both dyes showed no measurable permeation through intact skin but significant permeation was found through shaven skin. From 250 ng/cm(2) of dye in one applied dose there were found 52 ng/cm(2) of BB and 91 ng/cm(2) of PB from ethanol-based after-shave, 39 ng/cm(2) of BB and 86 ng/cm(2) of PB from ethanol-free facial-cleanser, 35 ng/cm(2) of BB and 43 ng/cm(2) of PB from O/W emulsion, and no amount from W/O emulsion, as available to become systemically absorbed. Thirdly, the paper focuses on lingual mucosa after licking lollipops. Ex vivo porcine tongue dorsum was exposed to human saliva with 15,000 ng/cm(2) of dye for 20 min. 24-h diffusion resulted in 34 ng/cm(2) of BB and 86 ng/cm(2) of PB which can be directly absorbed into the blood system. Findings are troubling, particularly with regard to the frequent use of after-shave products by the male population and repeated lollipops licking by children. 23380305 Selective brain region activation by histamine H3 receptor antagonist/inverse agonist ABT-239 enhances acetylcholine and histamine release and increases c-Fos expression. Histamine axons originate solely from the tuberomamillary nucleus (TMN) to innervate almost all brain regions. This feature is consistent with a function for histamine over a host of physiological processes, including regulation of appetite, body temperature, cognitive processes, pain perception and sleep-wake cycle. An important question is whether these diverse physiological roles are served by different histamine neuronal subpopulations. Here we report that systemic administration of the non-imidazole histamine H3 receptor antagonist 4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile (ABT-239, 3 mg/kg) increased c-Fos expression dose-dependently in rat cortex and nucleus basalis magnocellularis (NBM) but not in the nucleus accumbens (NAcc) nor striatum, and augmented acetylcholine and histamine release from rat prefrontal cortex. To further understand functional histaminergic pathways in the brain, dual-probe microdialysis was used to pharmacologically block H3 receptors in the TMN. Perfusion of the TMN with ABT-239 (10 μM) increased histamine release from the TMN, NBM, and cortex, but not from the striatum or NAcc. When administered locally, ABT-239 increased histamine release from the NBM, but not from the NAcc. Systemic as well as intra-TMN administration of ABT-239 increased c-Fos expression in the NBM, and cortex, but not in the striatum or NAcc. Thus, as defined by their sensitivity to ABT-239, histaminergic neurons establish distinct pathways according to their terminal projections, and can differentially modulate neurotransmitter release in a brain region-specific manner. This implies independent functions of subsets of histamine neurons according to their terminal projections, with relevant consequences for the development of specific compounds that affect only subsets of histamine neurones, thus increasing target specificity. 23352929 Suppressive effects of Indigofera suffruticosa Mill extracts on lipopolysaccharide-induced inflammatory responses in murine RAW 264.7 macrophages. Indigofera suffruticosa Mill is used as an herbal medicine for the treatment of inflammation. The aim of this study is to assess the anti-inflammatory potency of I. suffruticosa and its likely molecular mechanisms of action in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Both water and ethanolic extracts of I. suffruticosa significantly decreased LPS-induced nitric oxide (NO) as well as the expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α, and pro-interleukin-1β. Moreover, LPS-induced inhibitory factor-κB-α phosphorylation, nuclear factor-κB (NF-κB) nuclear protein-DNA binding affinity, and NF-κB reporter gene activity were dramatically inhibited by I. suffruticosa extracts. Exogenous addition of I. suffruticosa significantly induced heme oxygenase-1 (HO-1) expression, and the presence of HO-1 small interfering RNA partly reversed the inhibitory effects of I. suffruticosa on LPS-induced NO production and iNOS expression. Furthermore, I. suffruticosa induced HO-1 expression may be through activation of the ERK/nuclear factor E2-related factor 2 pathway. Eight phenolic compounds were found in the I. suffruticosa extracts, but salicylic acid was the only one detected in the plasma of mice fed with I. suffruticosa extracts. In summary, I. suffruticosa have a strong anti-inflammatory property that diminishes pro-inflammatory mediator expressions by lessening LPS-induced NF-κB activation and inducing HO-1 expression in macrophages. 23393163 Vesnarinone Suppresses TNFα mRNA Expression by Inhibiting Valosin-Containing Protein. Vesnarinone is a synthetic quinolinone derivative used in the treatment of cardiac failure and cancer. It is also known to cause agranulocytosis as a side effect, which restricts its use, although the mechanism underlying agranulocytosis is not well understood. Here, we show that vesnarinone binds to valosin-containing protein (VCP), which interacts with polyubiquitinated proteins and is essential for the degradation of IκBα to activate nuclear factor (NF)κB. We show that vesnarinone impairs the degradation of IκBα, and that the impairment of the degradation of IκBα is the result of the inhibition of the interaction between VCP and the 26S proteasome by vesnarinone. These results suggest that vesnarinone suppresses NFκB activation by inhibiting the VCP-dependent degradation of polyubiquitinated IκBα, resulting in the suppression of tumor necrosis factor-α mRNA expression. 23584277 Kinetics and mechanism of oxygen reduction in a protic ionic liquid. The oxygen reduction reaction (ORR) has been studied at Pt surfaces in the protic ionic liquid diethylmethylammonium trifluoromethanesulfonate. Water content measurements suggested that the ORR proceeded in the ionic liquid predominantly via a 4-electron reduction to water. A mechanistic analysis using rotating ring-disk electrode (RRDE) voltammetry confirmed that negligible amounts of hydrogen peroxide were formed during the ORR. A kinetic analysis of the ORR was performed using rotating disk electrode (RDE) voltammetry and the importance of correcting for ohmic (iR) drop prior to performing kinetic measurements in the ionic liquid is demonstrated. A Tafel analysis of the RDE voltammetry data revealed a change in the ORR Tafel slope from 70 mV per decade at low ORR overpotentials to 117 mV per decade at high overpotentials, and the reason for this change is discussed. The change in the Tafel slope for the ORR with increasing overpotential meant that the exchange current density for the ORR varied from 0.007 nA cm(-2) to 10 nA cm(-2), depending on the applied potential. Finally, the implications of these results for the development of protic ionic liquid fuel cells are discussed. 23206861 Tetrahydro-β-carboline derivatives targeting fatty acid amide hydrolase (FAAH) and transient receptor potential (TRP) channels. A series of twenty-five derivatives of tetrahydro-β-carbolines 1-3 was synthesized and assayed on FAAH and TRPV1 and TRPA1 channels. Four carbamates, that is, 5a,c,e, and 9b inhibited FAAH with significant potency and interacted also effectively with TRPV1 and TRPA1 nociceptive receptors, while ureas 7b,d,f, and 8a,b were endowed with specific submicromolar TRPV1 modulating activities. 23301495 Cyanide antidotes for mass casualties: water-soluble salts of the dithiane (sulfanegen) from 3-mercaptopyruvate for intramuscular administration. Current cyanide antidotes are administered by IV infusion, which is suboptimal for mass casualties. Therefore, in a cyanide disaster, intramuscular (IM) injectable antidotes would be more appropriate. We report the discovery of the highly water-soluble sulfanegen triethanolamine as a promising lead for development as an IM injectable cyanide antidote. 23177256 Pharmacophore identification of c-Myc inhibitor 10074-G5. A structure-activity relationship (SAR) study of the c-Myc (Myc) inhibitor 10074-G5 (N-([1,1'-biphenyl]-2-yl)-7-nitrobenzo[c][1,2,5]oxadiazol-4-amine, 1) - which targets a hydrophobic domain of the Myc oncoprotein that is flanked by arginine residues - was executed in order to determine its pharmacophore. Whilst the 7-nitrobenzofurazan was found to be critical for inhibitory activity, the ortho-biphenyl could be replaced with a para-carboxyphenyl group to furnish the new inhibitor JY-3-094 (3q). Around five times as potent as the lead with an IC(50) of 33 μM for disruption of the Myc-Max heterodimer, JY-3-094 demonstrated excellent selectivity over Max-Max homodimers, with no apparent effect at 100 μM. Importantly, the carboxylic acid of JY-3-094 improves the physicochemical properties of the lead compound, which will facilitate the incorporation of additional hydrophobicity that might enhance Myc inhibitory activity further still. 23550722 Thermal Stability of Peroxy Acyl Nitrates Formed in the Oxidation of CxF2x+1CH2C(O)H (x = 1,6) in the Presence of NO2. The formation of CxF2x+1CH2C(O)OONO2 (x = 1,6) from the photooxidation of CxF2x+1CH2C(O)H (x = 1,6) in the presence of NO2 was investigated. The infrared spectrum of C6F13CH2C(O)OONO2 is reported for the first time, and thermal stability for both peroxynitrates at 295 K and 9.0 mbar is informed. Kinetic parameters (activation energy and pre-exponential factor) for CF3CH2C(O)OONO2 at 9.0 and 1000 mbar are: 108 ± 2 kJ/mol, 1.5 × 10(15) and 114 ± 2 kJ/mol, 2.4 × 10(16), respectively. A comparison is made between fluoro and hydrogenated peroxy acyl nitrates. 23408116 The UDP-Glucuronosyltransferase (UGT) 1A Polymorphism c.2042C>G (rs8330) Is Associated with Increased Human Liver Acetaminophen Glucuronidation, Increased UGT1A Exon 5a/5b Splice Variant mRNA Ratio, and Decreased Risk of Unintentional Acetaminophen-Induced Acute Liver Failure. Acetaminophen is cleared primarily by hepatic glucuronidation. Polymorphisms in genes encoding the acetaminophen UDP-glucuronosyltransferase (UGT) enzymes could explain interindividual variability in acetaminophen glucuronidation and variable risk for liver injury after acetaminophen overdose. In this study, human liver bank samples were phenotyped for acetaminophen glucuronidation activity and genotyped for the major acetaminophen-glucuronidating enzymes (UGTs 1A1, 1A6, 1A9, and 2B15). Of these, only three linked single nucleotide polymorphisms (SNPs) located in the shared UGT1A-3'UTR region (rs10929303, rs1042640, rs8330) were associated with acetaminophen glucuronidation activity, with rs8330 consistently showing higher acetaminophen glucuronidation at all the tested concentrations of acetaminophen. Mechanistic studies using luciferase-UGT1A-3'UTR reporters indicated that these SNPs do not alter mRNA stability or translation efficiency. However, there was evidence for allelic imbalance and a gene-dose proportional increase in the amount of exon 5a versus exon 5b containing UGT1A mRNA spliced transcripts in livers with the rs8330 variant allele. Cotransfection studies demonstrated an inhibitory effect of exon 5b containing cDNAs on acetaminophen glucuronidation by UGT1A1 and UGT1A6 cDNAs containing exon 5a. In silico analysis predicted that rs8330 creates an exon splice enhancer site that could favor exon 5a (over exon 5b) utilization during splicing. Finally, the prevalence of rs8330 was significantly lower (P = 0.027, χ(2) test) in patients who had acute liver failure from unintentional acetaminophen overdose compared with patients with acute liver failure from other causes or a race- or ethnicity-matched population. Together, these findings suggest that rs8330 is an important determinant of acetaminophen glucuronidation and could affect an individual's risk for acetaminophen-induced liver injury. 23383423 International Union of Pharmacology. LXXXVII. Complement peptide C5a, C4a, and C3a receptors. The activation of the complement cascade, a cornerstone of the innate immune response, produces a number of small (74-77 amino acid) fragments, originally termed anaphylatoxins, that are potent chemoattractants and secretagogues that act on a wide variety of cell types. These fragments, C5a, C4a, and C3a, participate at all levels of the immune response and are also involved in other processes such as neural development and organ regeneration. Their primary function, however, is in inflammation, so they are important targets for the development of antiinflammatory therapies. Only three receptors for complement peptides have been found, but there are no satisfactory antagonists as yet, despite intensive investigation. In humans, there is a single receptor for C3a (C3a receptor), no known receptor for C4a, and two receptors for C5a (C5a₁ receptor and C5a₂ receptor). The most recently characterized receptor, the C5a₂ receptor (previously known as C5L2 or GPR77), has been regarded as a passive binding protein, but signaling activities are now ascribed to it, so we propose that it be formally identified as a receptor and be given a name to reflect this. Here, we describe the complex biology of the complement peptides, introduce a new suggested nomenclature, and review our current knowledge of receptor pharmacology. 23580421 Large Areal Mass, Flexible and Free-Standing Reduced Graphene Oxide/Manganese Dioxide Paper for Asymmetric Supercapacitor Device. Well-separated RGO sheets decorated with MnO2 nanoparticles facilitate easy access of the electrolyte ions to the high surface area of the paper electrode, enabling fabrication of thicker electrode with heavier areal mass and higher areal capacitance (up to 897 mF cm(-2) ). Electrochemical performance of the bent asymmetric device with total active mass of 15 mg remains similar to the one in the flat configuration, demonstrating good mechanical robustness of the device. 23511718 PEG as a spacer arm markedly increases the immunogenicity of meningococcal group Y polysaccharide conjugate vaccine. Neisseria meningitidis is a life-threatening pathogen that causes meningitis and other clinical manifestations. As a key virulence determinant, meningococcal capsular polysaccharide (PS) can be used to prevent meningococcal diseases. Conjugation of PS to carrier protein can significantly improve the immunogenicity of PS and induce memory response in infants and young children. However, the conjugate vaccine may suffer from steric shielding of antigenic PS epitopes by carrier protein. Here, a heterobifunctional polyethylene glycol (PEG) was used as a spacer arm to conjugate meningococcal group Y capsular PS with tetanus toxoid (TT). PEG can avoid self-crosslink of PS and increase the PS/TT ratio of the vaccine. Significant structural change in TT and PS was not observed upon conjugation. As compared to the vaccine without PEG, immunization with the vaccine using PEG as the spacer arm led to 3.0-fold increase in the PS-specific IgG titers and a prolonged immune persistence. Paradoxically, PEG, a non-immunogenic hydrophilic polymer has been widely used to couple therapeutic protein for increasing its circulatory time and decreasing its immunogenicity. Presumably, PEG can fully decrease the steric shielding effect of TT on antigenic epitopes of PS and suppress the immunogenicity of TT. In addition, PEG can prolong the immune persistence of the conjugate vaccine and improve its ability to elicit cellular immunity. Thus, PEG can be used as a spacer arm to develop more effective PS conjugate vaccine for prevention of bacterial infection. 23617807 The Differences in the Sublimation Energy of Benzene and Hexahalogenbenzenes Are Caused by Dispersion Energy. The crystals of benzene and hexahalogenbenzenes have been studied by means of the density-functional theory augmented by an empirical dispersion correction term as well as by the symmetry-adapted perturbation theory. In order to elucidate the nature of noncovalent binding, pairwise interactions have been investigated. It has been demonstrated that the structures of dimers with the highest stabilization energy differ notably along the crystals. It has been shown that the differences in the experimental sublimation energies might be attributed to the dispersion interaction. To our surprise, the dihalogen bonding observed in the hexachloro- and hexabromobenzenes plays a rather minor role in energy stabilization, because they are energetically comparable with the other binding motifs. However, the dihalogen bond is by far the most frequent binding motif in hexachloro- and hexabromobenzenes. 22874922 Novel non-canonical TGF-β signaling networks: emerging roles in airway smooth muscle phenotype and function. The airway smooth muscle (ASM) plays an important role in the pathophysiology of asthma and chronic obstructive pulmonary disease (COPD). ASM cells express a wide range of receptors involved in contraction, growth, matrix protein production and the secretion of cytokines and chemokines. Transforming growth factor beta (TGF-β) is one of the major players in determining the structural and functional abnormalities of the ASM in asthma and COPD. It is increasingly evident that TGF-β functions as a master switch, controlling a network of intracellular and autocrine signaling loops that effect ASM phenotype and function. In this review, the various elements that participate in non-canonical TGF-β signaling, including MAPK, PI3K, WNT/β-catenin, and Ca(2+), are discussed, focusing on their effect on ASM phenotype and function. In addition, new aspects of ASM biology and their possible association with non-canonical TGF-β signaling will be discussed. 23116144 Multivalent agents: a novel concept and preliminary practice in Anti-HIV drug discovery. The term multivalency (polyvalency) in the biological science is defined as the simultaneous binding of multiple ligands to one receptor (or multiple receptors to one ligand). The possibility of gaining potency and selectivity was significantly increased through the use of multivalent ligand as a homo- or hetero-dimer, thus multivalent ligands provided a more attractive strategy to design novel anti-HIV agents with therapeutic applications. Moreover, similar to phenomenon of multivalency, an alternative strategy is called the "mixed sites inhibitor", viz. a single molecule that possesses enough chemical space to maximize interactions with its complementary binding pocket, or to bind simultaneously in more than one regions in a target. Actually, the addition of a third heterocyclic nucleus to the parent compound resulted in "mixed sites" anti-HIV agents with broad spectrum of activities against the mutant HIV-1 strains. Based on current representative examples, the present article provided a brief review on the rationale for the design of different classes of multivalency anti-HIV agents and also discussed the advantages over their monomeric counterparts, providing a novel paradigm to facilitate the development of anti-HIV/AIDS therapeutic agents in treatment of HIV infected community. 23312279 Damned if you do, damned if you don't: the conundrum of adipose tissue vascularization. The plasticity of adipose tissue requires highly regulated changes in accompanying blood vessels. In obesity, adipose tissue angiogenesis plays a complex role to support tissue growth and promote metabolic disease. Emerging research (Sung et al., 2013) indicates that exploiting the mediators of adipose tissue angiogenesis may offer the possibility for therapeutic interventions. 23180796 Animal QTLdb: an improved database tool for livestock animal QTL/association data dissemination in the post-genome era. The Animal QTL database (QTLdb; http://www.animalgenome.org/QTLdb) is designed to house all publicly available QTL and single-nucleotide polymorphism/gene association data on livestock animal species. An earlier version was published in the Nucleic Acids Research Database issue in 2007. Since then, we have continued our efforts to develop new and improved database tools to allow more data types, parameters and functions. Our efforts have transformed the Animal QTLdb into a tool that actively serves the research community as a quality data repository and more importantly, a provider of easily accessible tools and functions to disseminate QTL and gene association information. The QTLdb has been heavily used by the livestock genomics community since its first public release in 2004. To date, there are 5920 cattle, 3442 chicken, 7451 pigs, 753 sheep and 88 rainbow trout data points in the database, and at least 290 publications that cite use of the database. The rapid advancement in genomic studies of cattle, chicken, pigs, sheep and other livestock animals has presented us with challenges, as well as opportunities for the QTLdb to meet the evolving needs of the research community. Here, we report our progress over the recent years and highlight new functions and services available to the general public. 23600432 5-Lipoxygenase inhibitors: a review of recent patents (2010 - 2012). Introduction: 5-Lipoxygenase (5-LO) is a crucial enzyme of the arachidonic acid (AA) cascade and catalyzes the formation of bioactive leukotrienes (LTs) with the help of FLAP, the 5-LO-activating protein. LTs are inflammatory mediators playing a pathophysiological role in different diseases like asthma, allergic rhinitis as well as cardiovascular diseases and certain types of cancer. With the rising number of indications for anti-LT therapy, 5-LO inhibitor drug development becomes increasingly important. Areas covered: Here, both recent findings regarding the pathophysiological role of 5-LO and the patents claimed for 5-LO inhibitors are discussed. Focusing on direct inhibitors, several patents disclosing FLAP antagonists are also subject of this review. Novel compounds include 1,5-diarylpyrazoles, indolizines and indoles and several natural product extracts. Expert opinion: Evaluation of the patent activities revealed only quite moderate action. Nevertheless, several auspicious drug-like molecules were disclosed. It seems that in the near future, FLAP inhibitors can be expected to enter the market for the treatment of asthma. With the resolved structure of 5-LO, structure-based drug design is now applicable. Together with the identification of downstream enzyme inhibitors and dual-targeting drugs within the AA cascade, several tools are at hand to cope with 5-LOs increasing pathophysiological roles. 23245696 Exonuclease 1 preferentially repairs mismatches generated by DNA polymerase α. The Saccharomyces cerevisiae EXO1 gene encodes a 5' exonuclease that participates in mismatch repair (MMR) of DNA replication errors. Deleting EXO1 was previously shown to increase mutation rates to a greater extent when combined with a mutator variant (pol3-L612M) of the lagging strand replicase, DNA polymerase δ (Pol δ), than when combined with a mutator variant (pol2-M644G) of the leading strand replicase, DNA polymerase ɛ (Pol ɛ). Here we confirm that result, and extend the approach to examine the effect of deleting EXO1 in a mutator variant (pol1-L868M) of Pol α, the proofreading-deficient and least accurate of the three nuclear replicases that is responsible for initiating Okazaki fragment synthesis. We find that deleting EXO1 increases the mutation rate in the Pol α mutator strain to a significantly greater extent than in the Pol δ or Pol ɛ mutator strains, thereby preferentially reducing the efficiency of MMR of replication errors generated by Pol α. Because these mismatches are closer to the 5' ends of Okazaki fragments than are mismatches made by Pol δ or Pol ɛ, the results not only support the previous suggestion that Exo1 preferentially excises lagging strand replication errors during mismatch repair, they further imply that the 5' ends serve as entry points for 5' excision of replication errors made by Pol α, and possibly as strand discrimination signals for MMR. Nonetheless, mutation rates in the Pol α mutator strain are 5- to 25-fold lower in an exo1Δ strain as compared to an msh2Δ strain completely lacking MMR, indicating that in the absence of Exo1, most replication errors made by Pol α can still be removed in an Msh2-dependent manner by other nucleases and/or by strand displacement. 23331770 Food-related impulsivity in obesity and Binge Eating Disorder - a systematic review. Impulsivity towards food has been recognized as a potential factor leading to increased food intake in obesity. Patients suffering from binge eating disorder (BED) form a specific subgroup of obese people that might be characterized by increased impulsivity. These assumptions, although, have yet to be verified. Therefore, this review evaluates evidence for food-related impulsivity in obese people with and without BED and examines possible differences between both populations. More precisely, evidence for the two components of impulsivity is analyzed separately: evidence for reward sensitivity, specifically, the urge for appetitive stimuli and evidence for rash-spontaneous behaviour such as acting disinhibited with no regard for the consequences. Our search resulted in 51 articles demonstrating generally increased food-related impulsivity. We found particular emphasis on increased reward sensitivity in obese people, which appeared to be more pronounced in people with BED. There was little and conflicting evidence, however, concerning increased rash-spontaneous behaviour in obese people without BED, but consistent evidence of an increase in obese people with BED. All in all, the evidence supports the view that BED represents a specific phenotype of obesity with increased food-related impulsivity. Taking these specific deficits into account can enhance the effectiveness of weight reduction programmes and psychotherapy. 23357626 Apoptosis-inducing activity of the actin-depolymerizing agent aplyronine A and its side-chain derivatives. Aplyronine A (1) and mycalolide B (2), which are cytotoxic actin-depolymerizing marine macrolides, were revealed to induce apoptosis in human leukemia HL60 cells and human epithelial carcinoma HeLa S(3) cells. Based on these results, actin-depolymerizing compounds were expected to exhibit apoptosis-inducing activity in cancer cells. Compounds 3-6, which were synthesized based on the side-chain structure of aplyronine A, were evaluated for their actin-depolymerizing activities in vitro and cytotoxicities against HL60 cells. The growth-inhibitory activities of 3-6 were well correlated with their actin-depolymerizing activities, and derivative 6 was shown to induce the disruption of actin filaments and apoptosis in HL60 cells. These results suggested that actin-depolymerizing agents 1, 2, and 6-induced apoptosis in HL60 cells may have been due to their actin-depolymerizing activity. 23410745 Association of nephrolithiasis with metabolic syndrome and its components. OBJECTIVE: Both metabolic syndrome (MetS) and nephrolithiasis (NL) are common and clinically important disorders. Therefore, we conducted this study to assess the association of MetS and NL. MATERIALS/METHODS: Data were obtained from 116,536 individuals who underwent health screening tests between January 2010 and December 2010 at a health promotion center in Seoul, Korea. All subjects were asked to respond to a questionnaire including medical history of each subject. Anthropometric and biochemical measurements were applied to each subject. Presence of NL was evaluated by an abdominal ultrasonography. The subjects were classified into MetS and non-MetS group according to the criteria for MetS (National Cholesterol Education Program Adult Treatment Panel III). Compared to the non-MetS group, we estimated the Odds Ratios (ORs) and 95% Confidence Intervals (CIs) of the presence of NL in the MetS group adjusting for age, serum levels of creatinine and uric acid, and past medical history of NL based on the multivariate logistic regression analysis. RESULTS: The prevalence of MetS was 15.9% (N=1129/7107) in the NL group, and 11.2% (N=12,287/109,429) in the non-NL group, respectively. After adjusting for the potential confounding factors, male MetS patients had a higher presence of NL than non-MetS subjects (OR 1.11; 95% CI 1.02-1.20; p=0.01). Of MetS components, only high blood pressure (BP) was a significantly related factor to the presence of NL (male; OR 1.08; 95% CI 1.01-1.15; p=0.043, female; OR 1.24; 95% CI 1.08-1.42; p=0.002). As the number MetS components increased, the presence of NL was significantly higher in male subjects (P for trend<0.001), but not in female subjects (P for trend=0.961). CONCLUSIONS: We found that NL was associated with MetS and high BP. 23528611 Epidermal growth factor receptor inhibitor PKI-166 governs cardiovascular protection without beneficial effects on the kidney in hypertensive 5/6 nephrectomised rats. Transactivation of epidermal growth factor receptor (EGFR) signaling by G-protein-coupled receptors has been implicated in several cardiovascular (CV) conditions, including hypertension, heart failure, cardiac and vascular hypertrophy. However, the therapeutic potential of EGFR inhibition in these conditions is currently unknown. Main objective of the present study was to investigate cardiac, vascular and renal effects of EGFR inhibition by PKI-166 in the hypertensive chronic kidney disease (CKD) model. Rats underwent 5/6 nephrectomy (5/6Nx) and were treated with PKI-166 or lisinopril or vehicle from week 6 after disease induction until week 12. Sham animals received either PKI-166 or vehicle. Treatment with PKI-166 did not affect the development of the characteristic renal features in 5/6Nx including proteinuria, diminished creatinine clearance and increased glomerulosclerosis, whereas these were attenuated by lisinopril. Despite absence of effects on progressive renal damage, PKI-166 attenuated the progression of hypertension and maintained cardiac function (LVEDP) to a similar extent as lisinopril. Also, PKI-166 attenuated the increase in phosphorylated EGFR in heart as induced by 5/6Nx. Moreover, PKI-166 and lisinopril restored the impaired contraction of isolated thoracic aortic rings to phenylephrine and angiotensin II and impaired myogenic constriction of small mesenteric arteries in 5/6Nx rats. Blockade of the EGFR displays a CV benefit independently of limiting the progression of renal injury. Our findings extend the evidence on EGFR signaling as a target in CV disorders. 23437926 Evidence for the Involvement of Descending Pain-Inhibitory Mechanisms in the Antinociceptive Effect of Hecogenin Acetate. Hecogenin is a sapogenin present in the leaves of species from the Agave genus, with a wide spectrum of reported pharmacological activities. The present study was undertaken to evaluate whether hecogenin acetate (1) has antinociceptive properties and to determine its mechanism of action. The nociceptive threshold was evaluated using the tail flick test in mice. Mice motor performance was evaluated in a Rotarod test. By using Fos expression as a marker of neural activation, the involvement of the periaqueductal gray in 1-induced antinociception was evaluated. Intraperitoneal administration of 1 (5-40 mg/kg) produced a dose-dependent increase in the tail flick latency time compared to vehicle-treated group (p < 0.01). Mice treated with 1 (40 mg/kg) did not show motor performance alterations. The antinociception of 1 (40 mg/kg) was prevented by naloxone (nonselective opioid receptor antagonist; 5 mg/kg), CTOP (μ-opioid receptor antagonist; 1 mg/kg), nor-BNI (κ-opioid receptor antagonist; 0.5 mg/kg), naltrindole (δ-opioid receptor antagonist; 3 mg/kg), or glibenclamide (ATP-sensitive K(+) channel blocker; 2 mg/kg). Systemic administration of 1 (5-40 mg/kg) increased the number of Fos positive cells in the periaqueductal gray. The present study has demonstrated for the first time that 1 produces consistent antinociception mediated by opioid receptors and endogenous analgesic mechanisms. 23563356 No mutations in the serotonin related TPH1 and HTR1B genes in patients with monogenic sclerosing bone disorders. Since the identification of LRP5 as the causative gene for the osteoporosis pseudoglioma syndrome (OPPG) as well as the high bone mass (HBM) phenotype, LRP5 and the Wnt/β-catenin signaling have been extensively studied for their role in the differentiation and proliferation of osteoblasts, in the apoptosis of osteoblasts and osteocytes and in the response of bone to mechanical loading. However, more recently the direct effect of LRP5 on osteoblasts and bone formation has been questioned. Gene expression studies showed that mice lacking lrp5 have increased expression of tph1, the rate limiting enzyme for the production of serotonin in the gut. Furthermore mice lacking either tph1 or htr1B, the receptor for serotonin on the osteoblasts, were reported to have an increased bone mass due to increased bone formation. This led to the still controversial hypothesis that LRP5 influences bone formation indirectly by regulating the expression of thp1 and as a consequence influencing the production of serotonin in the gut. Based on these data we decided to evaluate the role of TPH1 and HTR1B in the development of craniotubular hyperostoses, a group of monogenic sclerosing bone dysplasias. We screened the coding regions of both genes in 53 patients lacking a mutation in the known causative genes LRP5, LRP4 and SOST. We could not find disease-causing coding variants in neither of the tested genes and therefore, we cannot provide support for an important function of TPH1 and HTR1B in the pathogenesis of sclerosing bone dysplasias in our tested patient cohort. 23063590 Artemisinic acid inhibits melanogenesis through downregulation of C/EBP α-dependent expression of HMG-CoA reductase gene. Cholesterol is associated with the regulation of melanogenesis which is the major physiological defense against solar irradiation. The present study was designed to determine the effects of artemisinic acid on melanogenesis and its mechanisms of action in human epidermal melanocytes. In this study, we found that artemisinic acid inhibited melanin content. The mRNA levels of microphthalmia-associated transcription factor (MITF) and its downstream genes tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2 were reduced by artemisinic acid treatment. Additionally, the mRNA levels of melanogenesis-related genes (c-KIT, stem cell factor (SCF), and macrophage migration inhibitory factor (MIF)) were down-regulated by artemisinic acid. Furthermore, cAMP production and protein kinase A (PKA) activity were suppressed by artemisinic acid. Moreover, attempts to elucidate a possible mechanism underlying the artemisinic acid-mediated effects revealed that artemisinic acid regulated melanogenesis by inhibiting cholesterol synthesis through downregulation of the hydroxymethylglutaryl CoA (HMG CoA) reductase gene, which was mediated through reduced expression of the CCAAT/enhancer-binding protein (C/EBP) α gene. Taken together, these findings indicate that the inhibition of melanogenesis by artemisinic acid occurs through reduced expression of the HMG CoA reductase gene, which is mediated by C/EBP α inhibition and suggest that artemisinic acid may be useful as a hyperpigmentation inhibitor. 23335450 TGF-β1 Conjugated to Gold Nanoparticles Results in Protein Conformational Changes and Attenuates the Biological Function. Gold nanoparticles (AuNPs) are widely used as carriers or therapeutic agents due to their great biocompatibility and unique physical properties. Transforming growth factor-beta 1 (TGF-β1), a member of the cysteine-knot structural superfamily, plays a pivotal role in many diseases and is known as an immunosuppressive agent that attenuates immune response resulting in tumor growth. The results reported herein reflect strong interactions between TGF-β1 and the surface of AuNPs when incubated with serum-containing medium, and demonstrate a time- and dose-dependent pattern. Compared with other serum proteins that can also bind to the AuNP surface, AuNP-TGFβ1 conjugate is a thermodynamically favored compound. Epithelial cells undergo epithelial-mesenchymal transition (EMT) upon treatment with TGF-β1; however, treatment with AuNPs reverses this effect, as detected by cell morphology and expression levels of EMT markers. TGF-β1 is found to bind to AuNPs through S-Au bonds by X-ray photoelectron spectroscopy. Fourier transform infrared spectroscopy is employed to analyze the conformational changes of TGF-β1 on the surface of AuNPs. The results indicate that TGF-β1 undergoes significant conformational changes at both secondary and tertiary structural levels after conjugation to the AuNP surface, which results in the deactivation of TGF-β1 protein. An in vivo experiment also shows that addition of AuNPs attenuates the growth of TGF-β1-secreting murine bladder tumor 2 cells in syngeneic C3H/HeN mice, but not in immunocompromised NOD-SCID mice, and this is associated with an increase in the number of tumor-infiltrating CD4(+) and CD8(+) T lymphocytes and a decrease in the number of intrasplenic Foxp3(+) lymphocytes. The findings demonstrate that AuNPs may be a promising agent for modulating tumor immunity through inhibiting immunosuppressive TGF-β1 signaling. 23395652 Structural analogs of huperzine A improve survival in guinea pigs exposed to soman. Chemical warfare nerve agents such as soman exert their toxic effects through an irreversible inhibition of acetylcholinesterase (AChE) and subsequently glutamatergic function, leading to uncontrolled seizures. The natural alkaloid (-)-huperzine A is a potent inhibitor of AChE and has been demonstrated to exert neuroprotection at an appropriate dose. It is hypothesized that analogs of both (+)- and (-)-huperzine A with an improved ability to interact with NMDA receptors together with reduced AChE inhibition will exhibit more effective neuroprotection against nerve agents. In this manuscript, the tested huperzine A analogs 2 and 3 were demonstrated to improve survival of guinea pigs exposed to soman at either 1.2 or 2×LD(50). 23585358 Bottom-up Synthesis of Nanoscale Conjugation-Interrupted Frameworks and Their Electrical Properties. Soluble covalent organic nanoframeworks up to generation 2.5 (G2.5) are synthesized with self-similar H-shaped conformations by using a bottom-up approach including iterative C-H bond functionalization. The electrical characteristics of nanoscale thin-film semiconductors of the conjugation-interrupted frameworks can be tuned by post-modification with diazonium salt. 23224775 DFT and TDDFT study on the electronic structure and photoelectrochemical properties of dyes derived from cochineal and lac insects as photosensitizer for dye-sensitized solar cells. Essential parameters related to the photoelectrochemical properties, such as ground state geometries, electronic structures, oxidation potential and electron driving force, of cochineal insect dyes were investigated by DFT and TDDFT at the B3LYP/6-31+G(d,p) level of the theory. The results show that the major charge flow dynamic for all dyes is the HOMO→LUMO transition. The bi-coordinated binding mode, in which the dye uses one carboxyl- and hydroxyl oxygen bound to Ti(IV), is found for all dye-TiO(2) systems. Additionally, the doubly bi-coordinated binding mode in which the dye used both carboxyl groups bound to two Ti(IV) is also possible due to high energy distribution occupied at anchoring groups. This study highlights that most of these insect dyes can be good photosensitizers in dye-sensitized solar cells based on their strong binding to the TiO(2) surface, good computed excited state oxidation potential and thermodynamically favored electron driving force. 23225075 Metal concentrations in cerebrospinal fluid and blood plasma from patients with amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis (ALS) is a progressive and fatal degenerative disorder of motor neurons. The cause of this degeneration is unknown, and different causal hypotheses include genetic, viral, traumatic and environmental mechanisms. In this study, we have analyzed metal concentrations in cerebrospinal fluid (CSF) and blood plasma in a well-defined cohort (n = 17) of ALS patients diagnosed with quantitative electromyography. Metal analyses were performed with high-resolution inductively coupled plasma mass spectrometry. Statistically significant higher concentrations of manganese, aluminium, cadmium, cobalt, copper, zinc, lead, vanadium and uranium were found in ALS CSF compared to control CSF. We also report higher concentrations of these metals in ALS CSF than in ALS blood plasma, which indicate mechanisms of accumulation, e.g. inward directed transport. A pattern of multiple toxic metals is seen in ALS CSF. The results support the hypothesis that metals with neurotoxic effects are involved in the pathogenesis of ALS. 23632081 Identification of an Allosteric Modulator of Serotonin Transporter with Novel Mechanism of Action. Serotonin transporters (SERT) play an essential role in the termination and regulation of serotonin signaling in the brain. SERT is also the target of antidepressants and psychostimulants. Molecules with novel activities and modes of interaction with regard to SERT function are of great scientific and clinical interest. We explored structural regions outside the putative serotonin translocation pathway to identify potential binding sites for allosteric transporter modulators (ATMs). Mutational studies revealed a pocket of amino acids outside the orthosteric substrate binding sites located in the interface between extracellular loops 1 and 3 that when mutated affect transporter function. Using the structure of the bacterial transporter homologue leucine transporter as a template, we developed a structural model of SERT. We performed molecular dynamics simulations to further characterize the allosteric pocket that was identified by site-directed mutagenesis studies and employed this pocket in a virtual screen for small-molecule modulators of SERT function. In functional transport assays, we found that one of the identified molecules, ATM7, increased the reuptake of serotonin, possibly by facilitating the interaction of serotonin with transport-ready conformations of SERT when concentrations of serotonin were low and rate limiting. In addition, ATM7 potentiates 3,4-methylenedioxy-N-methylamphetamine (MDMA, "Ecstasy")-induced reversed transport by SERT. Taking advantage of a conformationally sensitive residue in transmembrane domain 6, we demonstrate that ATM7 mechanistically stabilizes an outward-facing conformation of SERT. Taken together these observations demonstrate that ATM7 acts through a novel mechanism that involves allosteric modulation of SERT function. 23628829 Improved group contribution parameter set for the application of solubility parameters to melt extrusion. Hot-melt extrusion is gaining importance for the production of amorphous solid solutions; in parallel, predictive tools for estimating drug solubility in polymers are increasingly demanded. The Hansen solubility parameter (SP) approach is well acknowledged for its predictive power of the miscibility of liquids as well as the solubility of some amorphous solids in liquid solvents. By solely using the molecular structure, group contribution (GC) methods allow the calculation of Hansen SPs. The GC parameter sets available were derived from liquids and polymers which conflicts with the object of prediction, the solubility of solid drugs. The present study takes a step from the liquid based SPs toward their application to solid solutes. On the basis of published experimental Hansen SPs of solid drugs and excipients only, a new GC parameter set was developed. In comparison with established parameter sets by van Krevelen/Hoftyzer, Beerbower/Hansen, Breitkreutz and Stefanis/Panayiotou, the new GC parameter set provides the highest overall predictive power for solubility experiments (correlation coefficient r=-0.87 to -0.91) as well as for literature data on melt extrudates and casted films (r=-0.78 to -0.96). 23579044 Effects of chronic methylphenidate on cocaine self-administration under a progressive-ratio schedule of reinforcement in rhesus monkeys. It has been hypothesized that drugs that serve as substrates for dopamine (DA) and norepinephrine (NE) transporters may be more suitable medications for cocaine dependence than drugs that inhibit DA and NE uptake by binding to transporters. Previous studies have shown that the DA/NE releaser d-amphetamine can decrease cocaine self-administration in preclinical and clinical studies. The present study examined the effects of methylphenidate (MPD), a DA uptake inhibitor, for its ability to decrease cocaine self-administration under conditions designed to reflect clinically relevant regimens of cocaine exposure and pharmacotherapy. Each morning, rhesus monkeys pressed a lever to receive food pellets under a fixed-ratio 50 schedule of reinforcement; cocaine was self-administered under a progressiveratio schedule of reinforcement in the evening. After cocaine (0.003-0.56 mg/kg per injection, i.v.) dose-response curves were determined, self-administration sessions were suspended and MPD (0.003-0.0056 mg/kg per hr, i.v. or 1.0-9.0 mg/kg p.o., b.i.d.) was administered for several weeks. A cocaine self-administration session was conducted every 7 days. When a MPD dose was reached that either persistently decreased cocaine self-administration or produced disruptive effects, the cocaine dose-effect curve was re-determined. In most cases, MPD treatment either produced behaviorally disruptive effects or increased cocaine selfadministration; it took several weeks for these effects to dissipate. These data are consistent with the largely negative results of clinical trials with MPD. In contrast to the positive effects with the monoamine releaser d-amphetamine under identical conditions, these results do not support use of monoamine uptake inhibitors like MPD as a medication for cocaine dependence. 23233454 Determining and reporting purity of organic molecules: why qNMR. Although NMR has been routinely used to determine/estimate relative number of protons for structure elucidation, it has been rarely used to determine and report the purity of organic compounds. Through this paper, we want to emphasize on routine use of quantitative NMR (qNMR) for this purpose. The results of qNMR can be routinely considered as documentation of purity much like other established methods (HPLC, elemental analysis and differential scanning calorimetry). qNMR is a fast, easy, accurate and non-destructive alternate to speed up the whole analytical process and serves the purpose of both identification and purity determination of compounds using single technique. 23588682 Oromucosal delivery of venlafaxine by linseed mucilage based gel: in vitro and in vivo evaluation in rabbits. Linseed is the crop that is used as a foodstuff in European and Asian countries. The objective of the present work was to extract mucilage from linseed, utilize it as mucoadhesive gelling agent along with synthetic polymers and administration of venlafaxine by buccal route in the gel form. Buccal administration of venlafaxine will avoid first pass metabolism, which will increase the bioavailability of the drug. Linseed mucilage based buccal mucoadhesive gel preparations in combination with chitosan, carbopol 934P, carboxy methylcellulose and polyvinyl pyrrolidone were formulated and the viscosity, gel strength, percentage mucoadhesion and in vitro diffusion of the formulation was evaluated. Formulation (F2) was subjected to in vivo analysis in rabbits. Formulation F2, which contained linseed mucilage (2 %) and chitosan (0.5 %), showed the highest percentage of mucoadhesion, gel strength and sustained drug diffusion. The bioavailability by the oral route and buccal route were compared with that of the intravenous route. The bioavailability of venlafaxine in the formulation F2 was 63.08 ± 1.28 % by buccal route, which was higher than by the oral route (39.21 ± 6.18 %). Based on these results, the combination of linseed mucilage and chitosan can be used to form a buccal mucoadhesive gel and increase the bioavailability of venlafaxine. 23442025 On the generation of the hydrated electron during the sonolysis of aqueous solutions. The formation of the hydrated electron through the secondary reaction, H + OH(–) → H(2)O + e(aq), has been examined in the sonolysis of argon-saturated aqueous solutions at an ultrasound frequency of 355 kHz. The detection of the hydrated electron was achieved by measuring its reaction with the one-electron acceptors Fe(CN)(6)(3–) and methyl viologen. The results obtained indicate that hydrated electrons are produced predominately at the bubble/aqueous solution interface at comparatively high local concentrations, estimated to be >1.5 × 10(–3) M. The half life of the hydrated electron under such conditions is estimated to be <60 ns. 23024176 In vitro perturbations of targets in cancer hallmark processes predict rodent chemical carcinogenesis. Thousands of untested chemicals in the environment require efficient characterization of carcinogenic potential in humans. A proposed solution is rapid testing of chemicals using in vitro high-throughput screening (HTS) assays for targets in pathways linked to disease processes to build models for priority setting and further testing. We describe a model for predicting rodent carcinogenicity based on HTS data from 292 chemicals tested in 672 assays mapping to 455 genes. All data come from the EPA ToxCast project. The model was trained on a subset of 232 chemicals with in vivo rodent carcinogenicity data in the Toxicity Reference Database (ToxRefDB). Individual HTS assays strongly associated with rodent cancers in ToxRefDB were linked to genes, pathways, and hallmark processes documented to be involved in tumor biology and cancer progression. Rodent liver cancer endpoints were linked to well-documented pathways such as peroxisome proliferator-activated receptor signaling and TP53 and novel targets such as PDE5A and PLAUR. Cancer hallmark genes associated with rodent thyroid tumors were found to be linked to human thyroid tumors and autoimmune thyroid disease. A model was developed in which these genes/pathways function as hypothetical enhancers or promoters of rat thyroid tumors, acting secondary to the key initiating event of thyroid hormone disruption. A simple scoring function was generated to identify chemicals with significant in vitro evidence that was predictive of in vivo carcinogenicity in different rat tissues and organs. This scoring function was applied to an external test set of 33 compounds with carcinogenicity classifications from the EPA's Office of Pesticide Programs and successfully (p = 0.024) differentiated between chemicals classified as "possible"/"probable"/"likely" carcinogens and those designated as "not likely" or with "evidence of noncarcinogenicity." This model represents a chemical carcinogenicity prioritization tool supporting targeted testing and functional validation of cancer pathways. 23274353 Changes in physiological responses of an Antarctic fish, the emerald rock cod (Trematomus bernacchii), following exposure to polybrominated diphenyl ethers (PBDEs). Although polybrominated diphenyl ethers (PBDEs) have the ability to undergo long-range atmospheric transport to remote ecosystems like Antarctica, a recent study found evidence for a local source within the Antarctic. PBDEs from sewage treatment outfalls of McMurdo Station and Scott Base on Ross Island have been attributed to the high concentrations measured in emerald rock cod (Trematomus bernacchii). The potential impact of PBDEs on Antarctic fish physiology is unknown and therefore, the aim of this study was to obtain a greater understanding of physiological responses of emerald rock cod for assessing changes in ecosystem quality. A PBDE mixture (ΣPBDE 8 congeners) was administered fortnightly over 42 days and physiological changes were observed throughout this period and for a further 14 days thereafter. Changes in liver composition, molecular level changes and enzyme activities of selected detoxification-mediated and antioxidant defence markers were measured. Changes in total lipid, lipid peroxide and protein carbonyl concentrations in emerald rock cod liver were consistent with increases in nucleus surface area in the PBDE-treated groups, suggesting alterations in cellular function. Changes in the activities of selected antioxidant enzymes indirectly indicated oxidative stress, possibly resulting in the changes in liver composition. Additionally, glutathione-S-transferase (GST) activity reached its peak faster than that of ethoxyresorufin-O-deethylase (EROD), suggesting that during the early response to PBDE exposures there could be a greater involvement of GST-mediated detoxification. Thus, for at least the species examined here, protein carbonyl and lipid peroxides were useful and informative biomarkers for cellular level responses following PBDE-related exposure. Furthermore, our findings suggest that emerald rock cod exposed to PBDEs develop oxidative stress - a condition with potential consequences for fish growth, health and reproduction. 23412396 Repeated Low Dose Administration of the Monoacylglycerol Lipase Inhibitor JZL184 Retains CB1 Receptor Mediated Antinociceptive and Gastroprotective Effects. The monoacylglycerol lipase (MAGL) inhibitor JZL184 produces antinociceptive and anti-inflammatory effects. However, repeated administration of high dose JZL184 (40 mg/kg) causes dependence, antinociceptive tolerance, cross-tolerance to the pharmacological effects of cannabinoid receptor agonists, and CB(1) receptor downregulation and desensitization. This functional CB(1) receptor tolerance poses a hurdle in the development of MAGL inhibitors for therapeutic use. Consequently, the present study tested whether repeated administration of low dose JZL184 maintains its antinociceptive actions in the chronic constrictive injury (CCI) of the sciatic nerve neuropathic pain model and protective effects in a model of NSAlD-induced gastric hemorrhages. Mice given daily injections of high dose JZL184 (≥16 mg/kg) for six days displayed decreased CB(1) receptor density and function in brain, as assessed in [(3)H]SR141716A binding and CP55,940-stimulated [(35)S]GTPγS binding assays, respectively. In contrast, normal CB(1) receptor expression and function were maintained following repeated administration of low dose JZL184 (≤8 mg/kg). Likewise, the antinociceptive and gastroprotective effects of high dose JZL184 underwent tolerance following repeated administration, but these effects were maintained following repeated low dose JZL184 treatment. Consistent with these observations, repeated high dose JZL184, but not repeated low dose JZL184, elicited cross-tolerance to the common pharmacological effects of Δ(9)-tetrahydrocannabinol (THC). This same pattern of effects was found in a rimonabant-precipitated withdrawal model of cannabinoid dependence. Taken together, these results indicate that prolonged, partial MAGL inhibition maintains potentially beneficial antinociceptive and anti-inflammatory effects, without producing functional CB(1) receptor tachyphylaxsis/tolerance or cannabinoid dependence. 22906573 Comparison of two in vitro systems to assess cellular effects of nanoparticles-containing aerosols. Inhalation treatment with nanoparticle containing aerosols appears a promising new therapeutic option but new formulations have to be assessed for efficacy and toxicity. We evaluated the utility of a VITROCELL®6 PT-CF+PARI LC SPRINT® Baby Nebulizer (PARI BOY) system compared with a conventional MicroSprayer. A549 cells were cultured in the air-liquid interface, exposed to nanoparticle aerosols and characterized by measurement of transepithelial electrical resistance and staining for tight junction proteins. Deposition and distribution rates of polystyrene particles and of carbon nanotubes on the cells were assessed. In addition, cytotoxicity of aerosols containing polystyrene particles was compared with cytotoxicity of polystyrene particles in suspension tested in submersed cultures. Exposure by itself in both exposure systems did not damage the cells. Deposition rates of aerosolized polystyrene particles were about 700 times and that of carbon nanotubes about 4 times higher in the MicroSprayer than in the VITROCELL®6 PT-CF system. Cytotoxicity of amine-functionalized polystyrene nanoparticles was significantly higher when applied as an aerosol on cell cultured in air-liquid interface culture compared with nanoparticle suspensions tested in submersed culture. The higher cytotoxicity of aerosolized nanoparticles underscores the importance of relevant exposure systems. 23495911 Chromium supplementation in overweight and obesity: a systematic review and meta-analysis of randomized clinical trials. The increased prevalence of obesity has made the use of dietary supplements as weight reducing agents highly popular, but their efficacy has not been proven. One such supplement is chromium. The purpose of this review was to evaluate the evidence for or against the efficacy of chromium supplementation in overweight and obese individuals. Electronic searches were conducted in Medline, Embase, Amed and The Cochrane Library. The bibliographies of located articles were also searched. No age, gender or language restrictions were imposed. The reporting quality of identified randomized clinical trials (RCTs) was assessed using a methodological checklist adapted from the Consolidated Standard of Reporting Trials Statement and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Thirty-nine trials were identified and 20 were included. There were variations in reporting quality of included studies. A meta-analysis of 11 studies showed a statistically significant difference in weight loss favouring chromium over placebo (mean difference (MD): -0.50 kg; 95% confidence interval (CI): -0.97, -0.03). There was a high statistical heterogeneity. Adverse events included watery stools, vertigo, headaches and urticaria. The evidence from available RCTs shows that chromium supplementation generates statistically significant reductions in body weight. The magnitude of the effect is small, and the clinical relevance is uncertain. Future trials should last at least 16 weeks and greater uniformity in the measuring and assessment tools for body composition is recommended. 23536582 Fasting Plasma Glucose at 24-28 Weeks to Screen for Gestational Diabetes Mellitus: New evidence from China. OBJECTIVETo evaluate the usefulness of a fasting plasma glucose (FPG) at 24-28 weeks' gestation to screen for gestational diabetes mellitus (GDM).RESEARCH DESIGN AND METHODSThe medical records and results of a 75-g 2-h oral glucose tolerance test (OGTT) of 24,854 pregnant women without known pre-GDM attending prenatal clinics in 15 hospitals in China were examined.RESULTSFPG cutoff value of 5.1 mmol/L identified 3,149 (12.1%) pregnant women with GDM. FPG cutoff value of 4.4 mmol/L ruled out GDM in 15,369 (38.2%) women. With use of this cutoff point, 12.2% of patients with mild GDM will be missed. The positive predictive value is 0.322, and the negative predictive value is 0.928.CONCLUSIONSFPG at 24-28 weeks' gestation could be used as a screening test to identify GDM patients in low-resource regions. Women with an FPG between ≥4.4 and ≤5.0 mmol/L would require a 75-g OGTT to diagnose GDM. This would help to avoid approximately one-half (50.3%) of the formal 75-g OGTTs in China. 23353741 Synthesis and biological evaluation of some novel resveratrol amide derivatives as potential anti-tumor agents. Three series of novel resveratrol amide derivatives (1a-q, 2a-h, 3a-l) were synthesized and evaluated for their biological activities. All compounds were characterized by (1)H NMR, (13)C NMR, MS and elemental analysis. Furthermore, compound 3e was also characterized by X-ray crystallography. All the compounds were evaluated for their anti-tumor activity against MCF-7, A549 and B16-F10 tumor cell lines as well as cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) inhibitory activity of murine macrophage RAW 264.7 cell line. Among them, compounds 1c, 1g and 3e displayed the most potent COX-2 inhibitory activity with the IC50 values of 1.02, 1.27 and 1.98 μM, respectively. Molecular docking studies were performed to position compounds 1c and 3e into the active site of COX-2 to determine the probable binding modes. 23373772 Catalytic hydrotrifluoromethylation of unactivated alkenes. A visible-light-mediated hydrotrifluoromethylation of unactivated alkenes that uses the Umemoto reagent as the CF(3) source and MeOH as the reductant is disclosed. This effective transformation operates at room temperature in the presence of 5 mol % Ru(bpy)(3)Cl(2); the process is characterized by its operational simplicity and functional group tolerance. 23281636 Paeoniflorin acts as a liver X receptor agonist. Paeoniflorin is one of the active ingredients of Paeonia lactiflora Pall., a novel traditional herbal medicine exerting pharmacological effects including antihyperlipidemic, neuroprotective, and anti-hepatofibrosis effects. Liver X receptor (LXR) acts as a ligand-activated transcription factor to exhibit antihyperlipidemic and neuroprotective effects. In this study, the activity of paeoniflorin against LXR was evaluated by the mammalian one-hybrid and transient transfection reporter assays. The results showed that paeoniflorin transactivated GAL4, rat cholesterol 7 α-hydroxylase, phospholipid transfer protein, and ATP-binding cassette A1 gene promoters in dose-dependent manner. Furthermore, the docking study demonstrated that paeoniflorin resided in the LXR ligand-binding pocket in the similar manner as GSK 3987, a novel LXR agonist. These results indicated that paeoniflorin might exert pharmacological effects through LXR pathway. 23221006 Role of organic cation/carnitine transporter 1 in uptake of phenformin and inhibitory effect on complex I respiration in mitochondria. Phenformin causes lactic acidosis in clinical situations due to inhibition of mitochondrial respiratory chain complex I. It is reportedly taken up by hepatocytes and exhibits mitochondrial toxicity in the liver. In this study, uptake of phenformin and [(14)C]tetraethylammonium (TEA) and complex I inhibition by phenformin were examined in isolated liver and heart mitochondria. Uptake of phenformin into isolated rat liver mitochondria was higher than that into heart mitochondria. It was inhibited by several cat ionic compounds, which suggests the involvement of multispecific transport system(s). Similar characteristics were also observed for uptake of TEA; however, uptake of phenformin into mitochondria of organic cation/carnitine transporter 1 (OCTN1) knockout mice was lower than that in wild-type mice, whereas uptake of TEA was comparable between the two strains, suggesting the involvement of distinct transport mechanisms for these two cations in mitochondria. Inhibition by phenformin of oxygen consumption via complex I respiration in isolated rat liver mitochondria was greater than that in heart mitochondria, whereas inhibitory effect of phenformin on complex I respiration was similar in inside-out structured submitochondrial particles prepared from rat livers and hearts. Lactic acidosis provoked by iv infusion of phenformin was weaker in octn1(-/-) mice than that in wild-type mice. These observations suggest that uptake of phenformin into liver mitochondria is at least partly mediated by OCTN1 and functionally relevant to its inhibition potential of complex I respiration. This study was, thus, the first to demonstrate OCTN1-mediated mitochondrial transport and toxicity of biguanide in vivo in rodents. 23625887 5'-Trityl-Substituted Thymidine Derivatives as a Novel Class of Antileishmanial Agents: Leishmania infantum EndoG as a Potential Target. Two series of 5'-triphenylmethyl (trityl)-substituted thymidine derivatives were synthesized and tested against Leishmania infantum axenic promastigotes and amastigotes. Several of these compounds show significant antileishmanial activity, with IC50 values in the low micromolar range. Among these, 3'-O-(isoleucylisoleucyl)-5'-O-(3,3,3-triphenylpropanoyl)thymidine displays particularly good activity against intracellular amastigotes. Assays performed to characterize the nature of parasite cell death in the presence of the tritylthymidines indicated significant alterations in mitochondrial transmembrane potential, an increase in superoxide concentrations, and also significant decreases in DNA degradation during the cell death process. Results point to the mitochondrial nuclease LiEndoG as a target for the action of this family of compounds. 23643739 Glycerol and urea can be used to increase skin permeability in reduced hydration conditions. The natural moisturizing factor (NMF) is a group of hygroscopic molecules that is naturally present in skin and protects from severe drying. Glycerol and urea are two examples of NMF components that are also used in skin care applications. In the present study, we investigate the influence of glycerol and urea on the permeability of a model drug (metronidazole, Mz) across excised pig skin membranes at different hydrating conditions. The degree of skin hydration is regulated by the gradient in water activity across the membrane, which in turn depends on the water activity of the formulation in contact with the skin membrane. Here, we determine the water activity of all formulations employed using an isothermal calorimetric method. Thus, the gradient in water activity is controlled by a novel experimental set-up with well-defined boundary conditions on both sides of the skin membrane. The results demonstrate that glycerol and urea can retain high steady state flux of Mz across skin membranes at dehydrating conditions, which otherwise would decrease the permeability due to dehydration. X-ray diffraction measurements are performed to give insight into the effects of glycerol and urea on SC molecular organization. The novel steady state flux results can be related to the observation that water, glycerol, and urea all affect the structural features of the SC molecular components in a similar manner. 22765159 Bioactive alkaloids produced by Pseudomonas brassicacearum subsp. Neoaurantiaca, an endophytic bacterium from Salvia miltiorrhiza. Eleven compounds were isolated from the culture of an endophytic bacterium Pseudomonas brassicacearum subsp. Neoaurantiaca in Salvia miltiorrhiza Bunge. Their structures were elucidated by spectroscopic methods as cyclo-(Gly-L-Ala) (1), cyclo-(L-Ala-L-Ala) (2), cyclo-(L-Pro-Gly) (3), cyclo-(L-Pro-L-Ser) (4), cyclo-(L-Ala-trans-4-hydroxy-L-Pro) (5), cyclo-(L-Val-L-Pro) (6), cyclo-(Gly-L-Tyr) (7), cyclo-(L-Ala-L-Tyr) (8), cyclo-(L-Tyr-trans-4-hydroxy-L-Pro) (9), 3-methylhydantoin (10) and 2-piperidinone (11). All these compounds were isolated from this bacterium for the first time. The brine shrimp lethality, antifungal and antibacterial activities of these compounds were evaluated. The results indicated that some cyclodipeptides may play an important role in plant-bacteria interactions. 23444389 Increased glucagon-like peptide-1 secretion may be involved in antidiabetic effects of ginsenosides. Panax ginseng is one of the most popular herbal remedies. Ginsenosides, major bioactive constituents in P. ginseng, have shown good antidiabetic action, but the precise mechanism was not fully understood. Glucagon-like peptide-1 (GLP1) is considered to be an important incretin that can regulate glucose homeostasis in the gastrointestinal tract after meals. The aim of this study was to investigate whether ginseng total saponins (GTS) exerts its antidiabetic effects via modulating GLP1 release. Ginsenoside Rb1 (Rb1), the most abundant constituent in GTS, was selected to further explore the underlying mechanisms in cultured NCI-H716 cells. Diabetic rats were developed by a combination of high-fat diet and low-dose streptozotocin injection. The diabetic rats orally received GTS (150 or 300 mg/kg) daily for 4 weeks. It was found that GTS treatment significantly ameliorated hyperglycemia and dyslipidemia, accompanied by a significant increase in glucose-induced GLP1 secretion and upregulation of proglucagon gene expression. Data from NCI-H716 cells showed that both GTS and Rb1 promoted GLP1 secretion. It was observed that Rb1 increased the ratio of intracellular ATP to ADP concentration and intracellular Ca(2)(+) concentration. The metabolic inhibitor azide (3 mM), the KATP channel opener diazoxide (340 μM), and the Ca(2)(+) channel blocker nifedipine (20 μM) significantly reversed Rb1-mediated GLP1 secretion. All these results drew a conclusion that ginsenosides stimulated GLP1 secretion both in vivo and in vitro. The antidiabetic effects of ginsenosides may be a result of enhanced GLP1 secretion. 23223445 The chemical synthesis of DNA/RNA: our gift to science. It is a great privilege to contribute to the Reflections essays. In my particular case, this essay has allowed me to weave some of my major scientific contributions into a tapestry held together by what I have learned from three colleagues (Robert Letsinger, Gobind Khorana, and George Rathmann) who molded my career at every important junction. To these individuals, I remain eternally grateful, as they always led by example and showed many of us how to break new ground in both science and biotechnology. Relative to my scientific career, I have focused primarily on two related areas. The first is methodologies we developed for chemically synthesizing DNA and RNA. Synthetic DNA and RNA continue to be an essential research tool for biologists, biochemists, and molecular biologists. The second is developing new approaches for solving important biological problems using synthetic DNA, RNA, and their analogs. 23624383 Venom toxins in the exploration of molecular, physiological and pathophysiological functions of Acid-Sensing Ion Channels. Acid-sensing ion channels (ASICs) are voltage-independent proton-gated cation channels that are largely expressed in the nervous system as well as in some non-neuronal tissues. In rodents, six different isoforms (ASIC1a, 1b, 2a, 2b, 3 and 4) can associate into homo- or hetero-trimers to form a functional channel. Specific polypeptide toxins targeting ASIC channels have been isolated from the venoms of spider (PcTx1), sea anemone (APETx2) and snakes (MitTx and mambalgins). They exhibit different and sometimes partially overlapping pharmacological profiles and are usually blockers of ASIC channels, except for MitTx which is a potent activator. This review focuses on the use of these toxins to explore the structure-function relationships, the physiological and the pathophysiological roles of ASIC channels, illustrating at the same time the therapeutic potential of some of these natural compounds. 23353743 Design and synthesis of novel 1,2,3-triazole-dithiocarbamate hybrids as potential anticancer agents. A series of novel 1,2,3-triazole-dithiocarbamate hybrids were designed, synthesized and evaluated for anticancer activity against four selected human tumor cell lines (MGC-803, MCF-7, PC-3, EC-109). Majority of the synthesized compounds exhibited moderate to potent activity against MGC-803 and MCF-7. Among them, compounds 3a and 3c showed excellent broad spectrum anticancer activity with IC50 values ranging from 0.73 to 11.61 μM and 0.49-12.45 μM, respectively. Particularly, compound 3a was more potent than 5-fluorouracil against all tested human cancer cell lines. Flow cytometry analysis demonstrated that treatment of MGC-803 with 3c led to cell cycle arrest at G2/M phase accompanied by an increase in apoptotic cell death after 12 h. 23561152 Probing the binding between norbixin and dairy proteins by spectroscopy methods. Annatto (norbixin) has been used to color cheeses for centuries, but there is very little knowledge about interactions between the pigment and dairy proteins. In this study, binding of norbixin with whey protein isolate (WPI), sodium caseinate (NaCN), and 6 individual dairy proteins was investigated by using fluorescence spectroscopy, Fourier transform infrared spectroscopy (FTIR), circular dichroism (CD) and differential scanning calorimetry (DSC). Norbixin was observed to effectively quench the fluorescence of WPI and NaCN by forming complexes. The binding affinity between NaCN and norbixin was higher than that of WPI-norbixin. For individual proteins, bovine serum albumin had higher binding affinity with norbixin than β-lactoglobulin and α-lactalbumin, while κ-casein bound with norbixin better than α- and β-caseins. Binding changed the conformation of WPI and NaCN, but the extent and trend varied for individual proteins. 23256621 Universal concept for the implementation of a single cleavable unit at tunable position in functional poly(ethylene glycol)s. Poly(ethylene glycol) (PEG) with acid-sensitive moieties gained attention particularly for various biomedical applications, such as the covalent attachment of PEG (PEGylation) to protein therapeutics, the synthesis of stealth liposomes, and polymeric carriers for low-molecular-weight drugs. Cleavable PEGs are favored over their inert analogues because of superior pharmacodynamic and/or pharmacokinetic properties of their formulations. However, synthetic routes to acetal-containing PEGs published up to date either require enormous efforts or result in ill-defined materials with a lack of control over the molecular weight. Herein, we describe a novel methodology to implement a single acetaldehyde acetal in well-defined (hetero)functional poly(ethylene glycol)s with total control over its position. To underline its general applicability, a diverse set of initiators for the anionic polymerization of ethylene oxide (cholesterol, dibenzylamino ethanol, and poly(ethylene glycol) monomethyl ether (mPEG)) was modified and used to synthesize the analogous labile PEGs. The polyether bearing the cleavable lipid had a degree of polymerization of 46, was amphiphilic and exhibited a critical micelle concentration of 4.20 mg·L(-1). From dibenzylamino ethanol, three heterofunctional PEGs with different molecular weights and labile amino termini were generated. The transformation of the amino functionality into the corresponding squaric acid ester amide demonstrated the accessibility of the cleavable functional group and activated the PEG for protein PEGylation, which was exemplarily shown by the attachment to bovine serum albumin (BSA). Furthermore, turning mPEG into a macroinitiator with a cleavable hydroxyl group granted access to a well-defined poly(ethylene glycol) derivative bearing a single cleavable moiety within its backbone. All the acetal-containing PEGs and PEG/protein conjugates were proven to degrade upon acidic treatment. 23180652 Stability of pharmaceuticals and other polar organic compounds stored on polar organic chemical integrative samplers and solid-phase extraction cartridges. The stability of 24 chemicals, including pharmaceuticals and personal care products, and some agrochemicals on extraction media was evaluated by preloading them onto Oasis hydrophilic lipophilic balanced solid-phase extraction (SPE) cartridges and polar organic chemical integrative samplers (POCIS) followed by storage at -20°C over time. After 20 months, the average loss was 11% on POCIS, with only 2,4-dichlorophenoxyacetic acid, atrazine, chlorpyrifos, and gemfibrozil showing a statistically significant decline compared with initial concentrations. Losses on SPE cartridges were below 19%, with an average loss of 9%. In addition to laboratory spiked samples, multiple POCIS deployed in wastewater-impacted surface waters and SPE extracts of these waters were stored in their original coextracted matrix for nearly two years with minimal observed losses. Errors from typical sampling, handling, and concentration estimates from POCIS sampling rates were typically ± 15 to 30% relative standard deviation, so observed storage losses are minimal for most POCIS applications. While losses during storage on SPE cartridges for 20 months were small but statistically significant for many compounds, addition of labeled internal standards prior to freezing should correct for such losses. Thus, storage of processed water samples for analysis of polar organic pollutants is viable for archival purposes or studies for which samples cannot be analyzed in the short term. 23030706 Use of precision-cut renal cortical slices in nephrotoxicity studies. 1.Unlike cell lines and primary cells in culture, precision-cut tissue slices remain metabolically differentiated for at least 24-48 h and allow to study the effect of xenobiotics during short-term and long-term incubations. 2.In this article, we illustrate the use of such an experimental model to study the nephrotoxic effects of (i) chloroacetaldehyde, a metabolite of the anticancer drug ifosfamide, (ii) of cobalt chloride, a potential leakage product of the cobalt-containing nanoparticles, and (iii) of valproate, a widely used antiepileptic drug. 3.Since all the latter test compounds, like many toxic compounds, negatively interact with cellular metabolic pathways, we also illustrate our biochemical toxicology approach in which we used not only enzymatic but also carbon 13 NMR measurements and mathematical modelling of metabolic pathways. 4.This original approach, which can be applied to any tissue, allows to predict the nephrotoxic effects of milligram amounts of test compounds very early during the research and development processes of drugs and chemicals. This approach, combined with the use of cells that retain their in vivo metabolic properties and, therefore, are predictive, reduces the risk, the time and cost of such processes. 23632309 Investigation of in vivo metabolic profile of Abelmoschus Manihot based on pattern recognition analysis. ETHNOPHARMACOLOGICAL RELEVANCE:: Abelmoschus manihot (L.) Medik. var. manihot is one of the most commonly used Chinese medicines and has played an important role in treating chronic glomerulonephritis and diabetic nephropathy. AIM OF THE STUDY:: Metabolites identification of traditional Chinese medicine (TCM) is a complex and time-consuming process due to the complicity of TCM and subsequent large number of detected ions. In this paper, UPLC-MS combined with pattern recognition analysis approach were used to simplify and quicken the identification of the metabolites of Abelmoschus Manihot. MATERIALS AND METHODS:: Rat urine samples were collected before (as control sample) and after Abelmoschus Manihot administration. Pattern recognition analysis method was used to differentiate components between Abelmoschus Manihot-treated group and its controlled comparison. These components could be considered as Abelmoschus Manihot-related metabolites in vivo. RESULTS:: LC-MS based metabolomics could be an advanced tool to help us find metabolites with regards to its capacity of processing large datasets, differentiating and classifying of sample groups, as well as its indiscriminative nature of biomarker and metabolite identification. Using this method, seven metabolites were identified, which are flavonoid aglycone glucuronidation, sulfatation, and methylation metabolites. CONCLUSION:: Our results showed that UPLC-MS based- pattern recognition analysis approach can be used to quickly identify Abelmoschus Manihot related metabolites in biological fluids. Furthermore, this work demonstrates the potential application of combining the UPLC-MS approach with the metabolomics approach in identifying the metabolites of TCM. 23265507 2012: no trans fatty acids in Spanish bakery products. Trans fatty acids (TFA) are strongly correlated with an increased risk of cardiovascular and other chronic diseases. Current dietary recommendations exclude bakery products from frequent consumption basically due to their traditionally high content of TFA. The aim of this work was to analyse the lipid profile of different bakery products currently commercialised in Spain and with a conventionally high fat and TFA content. Premium and store brands for each product were included in the study. No significant amounts of TFA were found in any of the analysed products, regardless the brand. TFA content ranged between 0.17 g and 0.22 g/100 g product (mean=0.19 g/100 g product). Expressed on percentage of fatty acids, the maximum value was 0.87 g/100 g fatty acids and the mean value was 0.68%. These data are significantly lower than those observed in previously published papers for these types of products, and highlighted the importance of updating food composition databases in order to accurately estimate the real and current intake of TFA. 23325492 Stability of citrate-capped silver nanoparticles in exposure media and their effects on the development of embryonic zebrafish (Danio rerio). The stability of citrate-capped silver nanoparticles (AgNPs) and the embryonic developmental toxicity were evaluated in the fish test water. Serious aggregation of AgNPs was observed in undiluted fish water (DM-100) in which high concentration of ionic salts exist. However, AgNPs were found to be stable for 7 days in DM-10, prepared by diluting the original fish water (DM-100) with deionized water to 10 %. The normal physiology of zebrafish embryos were evaluated in DM-10 to see if DM-10 can be used as a control vehicle for the embryonic fish toxicity test. As results, DM-10 without AgNPs did not induce any significant adverse effects on embryonic development of zebrafish determined by mortality, hatching, malformations and heart rate. When embryonic toxicity of AgNPs was tested in both DM-10 and in DM-100, AgNPs showed higher toxicity in DM-10 than in DM-100. This means that the big-sized aggregates of AgNPs were low toxic compared to the nano-sized AgNPs. AgNPs induced delayed hatching, decreased heart rate, pericardial edema, and embryo death. Accumulation of AgNPs in the embryo bodies was also observed. Based on this study, citrate-capped AgNPs are not aggregated in DM-10 and it can be used as a control vehicle in the toxicity test of fish embryonic development. 23473024 Nanoparticle film assemblies as platforms for electrochemical biosensing-factors affecting the amperometric signal enhancement of hydrogen peroxide. Factors affecting the enhanced amperometric signal observed at electrodes modified with polyelectrolyte-gold nanoparticle (Au-NP) composite films, which are potential interfaces for first-generation biosensors, were systematically investigated and optimized for hydrogen peroxide (H2O2) detection. Polyelectrolyte multilayer films embedded with citrate-stabilized gold nanoparticles exhibited high sensitivity toward the oxidation of H2O2. From this Au-NP film assembly, the importance of Au-NP ligand protection, film permeability, the density of Au-NPs within the film, and electronic coupling between Au-NPs (interparticle) and between the film and the electrode (interfacial) were evaluated. Using alternative Au-NPs, including those stabilized with thiols, polymers, and bulky ligands, suggests that the amperometric enhancement of H2O2 is optimized at poly-l-lysine-linked film assemblies embedded with Au-NPs possessing small, charged, and conductive (conjugated) peripheral ligands. As a potential application of these Au-NP film assemblies, an enhanced amperometric signal for H2O2 oxidation was shown for modified "needle" electrodes. The overall aim of this research is to gain a greater understanding of designing electrochemical sensing strategies that incorporate Au-NPs and target specific analytes. 23339604 Supramolecular organization and magnetic properties of mesogen-hybridized mixed-valent manganese single molecule magnets [Mn(III)8Mn(IV)4O12(L(x,y,z-CB))16(H2O)4]. Single molecule magnets (SMM) may be considered for the construction of future integrated nanodevices, provided however that some degree of ordering is imparted to these molecules (surfaces nanostructuration). Combining such nanoobjects with liquid-crystalline orderings to control their assembly and to potentially address them individually therefore appears as one promising strategy. Four mesomorphic, mixed-valent [Mn(III)(8)Mn(IV)(4)O(12)(L(x,y,z-CB))(16)(H(2)O)(4)] SMM, differing in the number of liquid-crystalline promoters, (L(x,y,z-CB)), were synthesized, and their self-organizing and magnetic properties were investigated. The influence of the peripheral modifications, and precisely how supramolecular ordering and magnetic properties may be affected by the evolution of the proto-mesogenic cyanobiphenyl-based ligands substitution pattern, was explored. Small-angle X-ray scattering studies revealed that all of the hybridized clusters self-organize into room-temperature bilayer smectic phases, mandated by the specific mesogenic functionalization and that the polymetallic cores are further organized according to a short-range pseudo-2D lattice with hexagonal and/or square symmetry. All mesomorphous hybridized dodecamanganese complexes still behave as SMM: they exhibit blocking of the magnetization at about 2.6 K as evidenced by the occurrence of frequency-dependent out-of-phase ac susceptibility signals as well as an opening of the hysteresis cycle with coercive fields varying between 0.13 and 0.6 T, depending on the surface ligands topology. Comparison of the magnetic properties within this series reveals intricate correlations between the structural features of the mesomorphous molecule magnet (i.e., symmetry of the ligands substitution patterns, molecular conformation, average intercluster distances, and respective inclination) with respect to the relative proportion of slow- and fast-relaxing species and the absolute values of the coercive fields. 23281330 Production of hybrid diesel fuel precursors from carbohydrates and petrochemicals using formic acid as a reactive solvent. We report the one-pot alkylation of mesitylene with carbohydrate-derived 5-(hydroxymethyl)furfural (HMF) as a step toward diesel-range liquids. Using FeCl(3) as a catalyst, HMF is shown to alkylate toluene, xylene, and mesitylene in high yields in CH(2)Cl(2) and MeNO(2) solvents. Efforts to extend this reaction to greener or safer solvents showed that most ether-based solvents are unsatisfactory. Acid catalysts (e.g, p-TsOH) also proved to be ineffective. Using formic acid as a reactive solvent, mesitylene could be alkylated to give mesitylmethylfurfural (MMF) starting from fructose with yields up to approximately 70 %. The reaction of fructose with formic acid in the absence of mesitylene gave rise to low yields of the formate ester of HMF, which indicates the stabilizing effect of replacing the hydroxyl substituent with mesityl. The arene also serves as a second phase into which the product is extracted. Even by using formic acid, the mesitylation of less expensive precursors such as glucose and cellulose proceeded only in modest yields (ca. 20 %). These simpler substrates were found to undergo mesitylation by using hydrogen chloride/formic acid via the intermediate chloromethylfurfural. 23245697 Ribonucleotide incorporation, proofreading and bypass by human DNA polymerase δ. In both budding and fission yeast, a large number of ribonucleotides are incorporated into DNA during replication by the major replicative polymerases (Pols α, δ and ɛ). They are subsequently removed by RNase H2-dependent repair, which if defective leads to replication stress and genome instability. To extend these studies to humans, where an RNase H2 defect results in an autoimmune disease, here we compare the ability of human and yeast Pol δ to incorporate, proofread, and bypass ribonucleotides during DNA synthesis. In reactions containing nucleotide concentrations estimated to be present in mammalian cells, human Pol δ stably incorporates one rNTP for approximately 2000 dNTPs, a ratio similar to that for yeast Pol δ. This result predicts that human Pol δ may introduce more than a million ribonucleotides into the nuclear genome per replication cycle, an amount recently reported to be present in the genome of RNase H2-defective mouse cells. Consistent with such abundant stable incorporation, we show that the 3'-exonuclease activity of yeast and human Pol δ largely fails to edit ribonucleotides during polymerization. We also show that, like yeast Pol δ, human Pol δ pauses as it bypasses ribonucleotides in DNA templates, with four consecutive ribonucleotides in a DNA template being more problematic than single ribonucleotides. In conjunction with recent studies in yeast and mice, this ribonucleotide incorporation may be relevant to impaired development and disease when RNase H2 is defective in mammals. As one tool to investigate ribonucleotide incorporation by Pol δ in human cells, we show that human Pol δ containing a Leu606Met substitution in the polymerase active site incorporates 7-fold more ribonucleotides into DNA than does wild type Pol δ. 23115324 BET bromodomain proteins mediate downstream signaling events following growth factor stimulation in human lung fibroblasts and are involved in bleomycin-induced pulmonary fibrosis. Epigenetic alterations, such as histone acetylation, regulate the signaling outcomes and phenotypic responses of fibroblasts after growth factor stimulation. The bromodomain and extra-terminal domain-containing proteins (Brd) bind to acetylated histone residues, resulting in recruitment of components of the transcriptional machinery and subsequent gene transcription. Given the central importance of fibroblasts in tissue fibrosis, this study sought to determine the role of Brd proteins in human lung fibroblasts (LFs) after growth factor stimulation and in the murine bleomycin model of lung fibrosis. Using small interfering RNA against human Brd2 and Brd4 and pharmacologic Brd inhibitors, this study found that Brd2 and Brd4 are essential in mediating the phenotypic responses of LFs downstream of multiple growth factor pathways. Growth factor stimulation of LFs causes increased histone acetylation, association of Brd4 with growth factor-responsive genes, and enhanced transcription of these genes that could be attenuated with pharmacologic Brd inhibitors. Of note, lung fibrosis induced after intratracheal bleomycin challenge in mice could be prevented by pretreatment of animals with pharmacologic inhibitors of Brd proteins. This study is the first demonstration of a role for Brd2 and Brd4 proteins in mediating the responses of LFs after growth factor stimulation and in driving the induction of lung fibrosis in mice in response to bleomycin challenge. 22872607 AKRs expression in peripheral blood lymphocytes from smokers: The role of body mass index. Aldo-keto reductases (AKRs) metabolize a wide range of substrates, including polycyclic aromatic hydrocarbons (PAHs), generating metabolites (o-quinones) and reactive oxygen species (ROS), which are capable of initiating and promoting carcinogenesis. Exposure to PAHs, their metabolites, and ROS further increase AKRs isoform expression that may amplify oxidative damage. Human AKR enzymes are highly polymorphic, and allelic variants may contribute to different AKRs expression in individuals. Despite the importance of AKRs in PAHs metabolism, there are no studies that evaluate, in general human populations, the effect of PAHs on AKRs expression in peripheral blood lymphocytes (PBLs). The aim of this study was to determine the effect of tobacco smoke exposure, and AKR1A1*2 and AKR1C3*2 polymorphisms, on AKR1A1 and AKR1C1-AKR1C3 messenger RNA (mRNA) levels in PBLs from smokers. In the smoker group, there is a statistically significant positive association between AKR1A1, AKR1C1, and AKR1C3 mRNA induction and urine cotinine levels in individuals with a body mass index (BMI) less than 25. However, AKR1A1*2 and AKR1C3*2 alleles did not influence AKR1A1 and AKR1C1-AKR1C3 mRNA levels. These results suggest that AKRs induction by PAHs in smokers' PBLs is associated with BMI; therefore, the role of adipose tissue accumulation in PAHs' effects needs further investigation. 23379962 High-yield dispersions of large-diameter semiconducting single-walled carbon nanotubes with tunable narrow chirality distributions. Here, we report a thorough study on the ability of fluorene-based semiconducting polymers to disperse large-diameter (average diameter ⟨d⟩ ≈ 1.3 nm) laser vaporization (LV) single-walled carbon nanotubes (SWCNTs). We demonstrate the ability to select purely semiconducting species using poly[(9,9-dioctylfluorenyl-2,7-diyl)-alt-co-(6,6'-{2,2'-bipyridine})] (PFO-BPy) and poly[(9,9-dihexylfluorenyl-2,7-diyl)-co-(9,10-anthracene)] (PFH-A), producing samples with narrow and bright excitonic emission relative to comparable aqueous dispersions. Rapid processing and high yields offer the ability to easily incorporate these semiconducting SWCNTs into commercially scalable applications, as demonstrated by large-area thin films prepared by ultrasonic spraying. By modifying the growth temperature of the LV synthesis, we demonstrate the ability to tune the range of diameters and chiralities within dispersions by exerting synthetic control over the composition of the starting material. This synthetic control allows us to show that PFH-A preferentially disperses near-armchair semiconducting SWCNTs over a large range of diameters (0.8 nm < d < 1.4 nm) and induces unique solvatochromic shifts for the excitonic transitions of nanotubes with particular chiral indices. 23419813 Dextran-pegylated microparticles for enhanced cellular uptake of hydrophobic drugs. Polyethylene glycol monosubstituted with a polymerizable acrylic moiety was linked to 6-carboxy free position on dextran side chains and then subjected to radical polymerization with a comonomer in order to obtain microspheres for the oral controlled release of ketoconazole, a hydrophobic model drug. Microparticles were submitted to studies on their ability to absorb and retain water. Cell uptake studies, in the presence and absence of mucus, across two different monolayers, respectively, HT29-MTX-E12 and Caco-2, were done. Cytotoxicity studies were carried out to calculate the IC50 value. The ability of microspheres to open monolayers tight junctions was tested by measuring their TEER values. Images of cell uptake were visualized by CLSM. In HT29-MTX-E12 cells, more mucoadhesion and drug internalization is seen thanks to the presence of PEG and dextran chains. 22955948 IKK-β mediates hydrogen peroxide induced cell death through p85 S6K1. The IκB kinase (IKK)/NF-κB pathway has been shown to be a major regulator in cell survival. However, the mechanisms through which IKK mediates cell death are not clear. In this study, we showed that IKK-β contributed to hydrogen peroxide (H(2)O(2))-induced cell death independent of the NF-κB pathway. Our results demonstrated that the pro-death function of IKK-β under oxidative stress was mediated by p85 S6K1 (S6 kinase 1), but not p70 S6K1 through a rapamycin-insensitive and mammalian target of rapamycin complex 1 kinase-independent mechanism. We found that IKK-β associated with p85, but not p70 S6K1, which was required for H(2)O(2)-induced activation of p85 S6K1. IKK-β and p85 S6K1 contributed to H(2)O(2)-induced phosphorylation of Mdm2 (S166) and p53 accumulation. p85 S6K1 is critical for IKK-β-mediated cell death. Thus, these findings established a novel oxidative stress-responsive pathway that involves IKK-β, p85 S6K1 and Mdm2, which is response for H(2)O(2)-induced cell death. Our results have important implications for IKK-β and p85 S6K1 as potential targets for the prevention of diseases involved in oxidative stress-induced aberrant cell death. 23288360 A popular engagement at the ends. Three recent studies converged on a specific protein-protein interface between TPP1 and telomerase as being crucial for the regulation of both telomerase recruitment and processivity in mammalian cells. An equivalent interaction appears to exist in budding yeast, making this a nearly universal means of telomerase regulation. 23602733 Evaluation of reproductive and developmental toxicities of Pu-erh black tea (Camellia sinensis var. assamica) extract in Sprague Dawley rats. ETHNOPHARMACOLOGICAL RELEVANCE: Pu-erh black tea, which is obtained by first parching crude green tea leaves and followed by secondary fermentation with microorganisms, has been believed to be beneficial beverages for health in PR China. But its potential toxicity when administered at a high dose as concentrated extract has not been completely investigated. AIM OF THE STUDY: The present study was aimed at evaluating potential reproductive and developmental toxicities of Pu-erh black tea extract (BTE) in Sprague Dawley rats. MATERIALS AND METHODS: Growing rats were given BTE by gavage at levels of 0, 200, 700 and 2500mg/kg/day as the F0 generation in reproductive toxicity study. Additionally, BTE was administered to mate female rats from gestation day 0.5 through 19.5 at the doses of 0, 200, 700 and 2500mg/kg/day to evaluate the developmental toxicity. RESULTS: In the reproductive toxicity study, only 2500mg/kg/day BTE reduced the body weight gain and altered the relative organ weights including testes, prostata and ovary both for F0 parents and F1 offspring compared to the controls. High dose of BTE (2500mg/kg/day) administration caused developmental disturbances in embryo-to-foetus period including resorbed embryos, decreased embryo size and skeletal anomalies. CONCLUSION: In conclusion, the no-observed-adverse-effect level of BTE is 700mg/kg/day both for reproductive toxicity and developmental toxicities. 23391133 Hydrolytic activities of crystalline cellulose nanofibers. Cellulose is commonly believed to be inactive to organic substances; this inertness is an essential requirement for raw materials in industrial products. Here we demonstrate the contradictory but promising properties, which are the hydrolytic activities of crystalline cellulose nanofibers for the ester, monophosphate, and even amide bonds of small organic substrates under extremely mild conditions (neutral pH, moderate temperature, and atmospheric pressure). The hydrolytic activities were significantly extended to decompose the coat proteins of model viruses, followed by a drastic decrease in their infection capabilities to the host cells. 23462193 Identification of nuclear factor-κB sites in the Slc2a4 gene promoter. Glucose transporter GLUT4 protein, codified by Slc2a4 gene plays a key role in glycemic homeostasis. Insulin resistance, as in obesity, has been associated to inflammatory state, in which decreased GLUT4 is a feature. Inflammatory NF-κB transcriptional factor has been proposed as a repressor of Slc2a4; although, the binding site(s) in Slc2a4 promoter and the direct repressor effect have never been reported yet. A motif-based sequence analysis of mouse Slc2a4 promoter revealed two putative κB sites located inside -83/-62 and -134/-113bp. Eletrophoretic mobility assay showed that p50 and p65 NF-κB subunits bind to both putative κB sites. Chromatin immunoprecipitation assay using genomic DNA from adipocytes confirmed p50- and p65-binding to Slc2a4 promoter. Moreover, transfection experiments revealed that NF-κB binds to the -134/-113bp region of the mouse Slc2a4 gene promoter, inhibiting the Slc2a4 gene transcription. The current findings demonstrate the existence of two κB sites in Slc2a4 gene promote, and that NF-κB has a direct repressor effect upon the Slc2a4 gene, providing an important link between insulin resistance and inflammation. 23600612 Chemical constituents from Solidago canadensis with hypolipidemic effects in HFD-fed hamsters. Two new compounds, 8-dehydroxymethylvisanol (1) and 9-O-[3-O-acetyl-β-d-glucopyranosyl]-4-hydroxy-cinnamic acid (4), together with two known lignans, visanol (2) and 9-aldehydevibsanol (3), were isolated from the 80% EtOH extract of Solidago canadensis. The structures of the two new compounds were elucidated on the basis of 1D, 2D NMR, and mass spectral analysis. All the lignans exhibited moderate hypolipidemic activity in high-fat diet-fed hamsters. 23331263 On the origin of thermal untwisting of DNA. In aqueous solutions, the helical twist of DNA decreases with temperature. This phenomenon was noticed and studied experimentally several decades ago, but its physical origin remains elusive. The present paper shows that the thermal untwisting can be predicted from the specific properties of the torsional elasticity of the double helix revealed in recent computational studies. The temperature coefficient of untwisting estimated using coarse-grained models fitted to all-atom MD data accounts for the experimental results nearly quantitatively. The agreement is further improved with the computed torsional rigidity scaled to remove the discrepancy from experiment. The results confirm that the torsional rigidity of DNA is strongly anharmonic. They indicate that for random DNA, its value grows with small twisting and decreases with untwisting. 23465865 Changes in hypothalamic-pituitary-adrenal stress responsiveness before and after puberty in rats. This article is part of a Special Issue "Puberty and Adolescence". Many endocrine changes are associated with pubertal and adolescent development. One such change is the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to physical and/or psychological stressors. Recent human and non-human animal studies have shown that hormonal stress reactivity increases significantly throughout puberty and adolescence. Specifically, exposure to various stressors results in greater adrenocorticotropic hormone (ACTH) and glucocorticoid responses in peripubertal compared to adult animals. This review will focus on how stress reactivity changes throughout puberty and adolescence, as well as potential mechanisms that mediate these changes in stress responsiveness. Though the implications of these pubertal shifts in stress responsiveness are not fully understood, the significant increase in stress-related mental and physical dysfunctions during this stage of development highlights the importance of studying pubertal and adolescent maturation of HPA function and its reactivity to stress. 23487486 Effects of progesterone and medroxyprogesterone on actin remodeling and neuronal spine formation. Sex steroids are important regulators of neuronal cell morphology, and this is critical for gender differences in brain function and dysfunction. Neuronal morphology is controlled by multiprotein complexes including moesin (a member of the ezrin/radixin/moesin family), focal adhesion kinase (FAK), or the Wiskott-Aldrich syndrome protein-family verprolin homologous (WAVE1) protein, controlling dynamic remodeling of the cytoskeleton and cell membrane. We investigated the actions of natural progesterone (P) and of the synthetic progestin medroxyprogesterone acetate (MPA) on actin remodeling, focal adhesion complex formation, and actin branching in rat cortical neurons. Treatment with P and, to a lesser extent, MPA, increases the number and density of dendritic spines. P increases the phosphorylation of moesin, FAK, and WAVE1, and their redistribution toward cell membrane sites where spines are formed. Signaling to moesin is achieved by PR via a Gα/Gβ-dependent signaling to the small GTPase Ras homolog gene family, member A and its related kinase, Rho-associated kinase-2. In parallel, WAVE1 recruitment is triggered by a Gαi/Gβ-dependent signaling of PR to c-Src, FAK, and Rac1 GTPase. Rac1 recruits cyclin-dependent kinase-5, which phosphorylates WAVE1. Silencing of moesin, FAK, or WAVE1 abrogates the increase in dendritic spines induced by progesterone. In all applications, MPA is found to act similar to P, albeit with a lower efficacy. In conclusion, our findings indicate that the control of actin polymerization and branching and focal adhesion complex formation via moesin, FAK, and WAVE1 is a key function of progesterone receptor in neurons, which may be relevant for the regulation of dendritic spine turnover and neuronal plasticity. 23376242 Liposomes modified with P-aminophenyl-α-d-mannopyranoside: A carrier for targeting cerebral functional regions in mice. Targeting of intracerebral functional regions has been limited by the inability to transport drugs across the blood-brain barrier (BBB) and by poor accumulation in these regions. To overcome these hurdles, liposomes modified with P-aminophenyl-α-d-mannopyranoside (MAN) were used as a fluorescent dye carrier through the BBB and used the specific distribution of liposomes (LIP) modified with MAN (MAN-LIP) to target various functional regions of the brain. An in vitro BBB model was established to evaluate the transendothelial ability of MAN-LIP, and liposomes uptake by C6 glioma cells was analyzed by flow cytometry and live cell imaging. Liposome targeting was evaluated using in vivo and ex vivo imaging. After MAN-LIP administration, the transendothelial ability and the delivery of fluorescent dye to the brain significantly increased. MAN-LIP concentrated in the cortex at 4h, shifting distribution to the cerebellum and brainstem at 12h. The fluorescence intensity in the hippocampus and pontine nuclei remained high and stable over a period of 12h. The results demonstrate that MAN-LIP is able to enhance cellular uptake in vitro and also promotes penetration through the BBB and accumulation in the brain with a distinct spatio-temporal pattern. 23551856 Effect of pioglitazone on body composition and bone density in subjects with prediabetes in the ACT NOW trial. AIMS: This study examined the effects of pioglitazone on body weight and bone mineral density (BMD) prospectively in patients with impaired glucose tolerance as pioglitazone (TZD) increases body weight and body fat in diabetic patients and increases the risk of bone fractures. METHODS: A total of 71 men and 163 women aged 49.3 (10.7) years [mean (s.d.)]; body mass index (BMI), 34.5 (5.9) kg/m(2) were recruited at five sites for measurements of body composition by dual energy X-ray absorptiometry at baseline and at conversion to diabetes or study end, if they had not converted. RESULTS: Mean follow-up was 33.6 months in the pioglitazone group and 32.1 months in the placebo group. Body weight increased 4.63 ± 0.60 (m ± s.e.) kg in the pioglitazone group compared to 0.98 ± 0.62 kg in the PIO group (p < 0.0001). Body fat rose 4.89 ± 0.42 kg in the pioglitazone group compared to 1.41 ± 0.44 kg, (p < 0.0001) in placebo-treated subjects. The increase in fat was greater in legs and trunk than in the arms. BMD was higher in all regions in men and significantly so in most. PIO decreased BMD significantly in the pelvis in men and women, decreased BMD in the thoracic spine and ribs of women and the lumbar spine and legs of men. Bone mineral content also decreased significantly in arms, legs, trunk and in the total body. CONCLUSIONS: Pioglitazone increased peripheral fat more than truncal fat and decreased BMD in several regions of the body. 23256769 Effects of formation conditions on the physicochemical properties, aggregation, and phase transformation of iron oxide nanoparticles. In this work, hematite transformation from a precursor 6-line ferrihydrite phase was investigated by systematically altering the forced hydrolysis hematite synthesis. Specifically, we used a combination of in situ and ex situ characterization techniques to examine the effects of varying the Fe(III) injection rates and cooling methods on the hematite and 6-line ferrihydrite nanoparticle size, isoelectric point, mineral phase, and aggregation. Finally, As(V) adsorption experiments were performed to determine how the two iron oxide phases existed in the reaction system. Nanoparticle synthesis thermodynamics and kinetics were found to control the extent of distinct 6-line ferrihydrite phases in the iron oxide nanoparticle solutions, as well as the particle size and isoelectric point. Conversion of 6-line ferrihydrite to hematite was greatly influenced by the degree of aggregation (determined by synthesis conditions) during drying. As(V) adsorption experiments revealed that 6-line ferrihydrite and hematite exist as a linear combination of two separate phases. These results provide unique information regarding how in situ iron oxide nanoparticle properties can direct their ex situ behavior. 23415714 Androgen/androgen receptor pathway regulates expression of the genes for cyclooxygenase-2 and amphiregulin in periovulatory granulosa cells. It is well known that the androgen/androgen receptor (AR) pathway is involved in both male and female fertility in mammals. AR knockout female mice are reported to exhibit various abnormalities in follicle development, and a subfertile phenotype. In exogenous gonadotropin-induced superovulation, serum androgen levels were robustly elevated in female mice at the periovulatory stage after human chorionic gonadotropin (hCG) treatment. At this stage, ovarian AR proteins were strongly expressed in cumulus cells. Because these results suggested that the androgen/AR pathway is involved in ovulation, we investigated the expression of ovulation-related genes in the mouse ovary treated with the nonaromatizable androgen, 5α-dihydrotestosterone (DHT). DHT treatment induced the expression of the genes for cyclooxyganase-2 (Cox-2 or prostaglandin endoperoxidase synthase 2) and the epidermal growth factor-like factor, amphiregulin (Areg), in the ovary, whereas their hCG-induced expression was suppressed by the AR antagonist flutamide. These genes were also induced by DHT in AR-expressing primary granulosa and granulosa tumor-derived cells. Reporter assays, electrophoretic shift mobility assays and chromatin immunoprecipitation assays demonstrated that androgen response sequence(s) existing upstream of each gene were responsible for androgen responsiveness and were occupied by the AR in periovulatory granulosa cells. Our results suggest that the androgen/AR pathway is involved in the ovulatory process via expression of the Cox-2 and Areg genes in periovulatory granulosa cells. 23252610 Analysis of 4-Hydroxy-1-(3-pyridyl)-1-butanone (HPB)-Releasing DNA Adducts in Human Exfoliated Oral Mucosa Cells by Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry. Quantitation of DNA adducts could provide critical information on the relationship between exposure to tobacco smoke and cancer risk in smokers. In this study, we developed a robust and sensitive liquid chromatography-tandem mass spectrometry method for the analysis of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing DNA adducts in human oral cells, a noninvasive source of DNA for biomarker studies. Isolated DNA undergoes acid hydrolysis, after which samples are purified by solid-phase extraction and analyzed by LC-ESI-MS/MS. The developed method was applied to the analysis of samples obtained via collection with a commercial mouthwash from 30 smokers and 15 nonsmokers. In smokers, the levels of HPB-releasing DNA adducts averaged 12.0 pmol HPB/mg DNA (detected in 20 out of 28 samples with quantifiable DNA yield), and in nonsmokers, the levels of adducts averaged 0.23 pmol/mg DNA (detected in 3 out of 15 samples). For the 30 smoking subjects, matching buccal brushings were also analyzed, and HPB-releasing DNA adducts were detected in 24 out of 27 samples with quantifiable DNA yield, averaging 44.7 pmol HPB/mg DNA. The levels of adducts in buccal brushings correlated with those in mouthwash samples of smokers (R = 0.73, p < 0.0001). Potentially, the method can be applied in studies of individual susceptibility to tobacco-induced cancers in humans. 22872141 The impact of FANCD2 deficiency on formaldehyde-induced toxicity in human lymphoblastoid cell lines. Formaldehyde (FA), a major industrial chemical and ubiquitous environmental pollutant, has recently been classified by the International Agency for Research on Cancer as a human leukemogen. The major mode of action of FA is thought to be the formation of DNA-protein cross-links (DPCs). Repair of DPCs may be mediated by the Fanconi anemia pathway; however, data supporting the involvement of this pathway are limited, particularly in human hematopoietic cells. Therefore, we assessed the role of FANCD2, a critical component of the Fanconi anemia pathway, in FA-induced toxicity in human lymphoblast cell models of FANCD2 deficiency (PD20 cells) and FANCD2 sufficiency (PD20-D2 cells). After treatment of the cells with 0-150 μM FA for 24 h, DPCs were increased in a dose-dependent manner in both cell lines, with greater increases in FANCD2-deficient PD20 cells. FA also induced cytotoxicity, micronuclei, chromosome aberrations, and apoptosis in a dose-dependent manner in both cell lines, with greater increases in cytotoxicity and apoptosis in PD20 cells. Increased levels of γ-ATR and γ-H2AX in both cell lines suggested the recognition of FA-induced DNA damage; however, the induction of BRCA2 was compromised in FANCD2-deficient PD20 cells, potentially reducing the capacity to repair DPCs. Together, these findings suggest that FANCD2 protein and the Fanconi anemia pathway are essential to protect human lymphoblastoid cells against FA toxicity. Future studies are needed to delineate the role of this pathway in mitigating FA-induced toxicity, particularly in hematopoietic stem cells, the target cells in leukemia. 23601605 Empirical evidence does not support an association between less ambitious pre-treatment goals and better treatment outcomes: a meta-analysis. Setting realistic weight loss goals may play a role in weight loss. We abstracted data from randomized controlled trials and observational studies conducted between 1998 and 2012 concerning the association of weight loss goals with weight loss. Studies included those that (i) were conducted in humans; (ii) delivered a weight loss intervention; (iii) lasted ≥6 weeks; (iv) assessed baseline weight loss goals; (vi) assessed pre- and post-weight either in the form of body mass index or some other measure that could be converted to weight loss based on information included in the original study or later provided by the author(s); and (vii) assessed the correlation between weight loss goals and final weight loss or provided data to calculate the correlation. Studies that included interventions to modify weight loss goals were excluded. Eleven studies met inclusion criteria. The overall correlation between goal weight and weight at intervention completion was small and statistically insignificant ( ρ ̂ = 0.0 5 ; P = 0.20). The current evidence does not demonstrate that setting realistic goals leads to more favourable weight loss outcomes. Thus, our field may wish to reconsider the value of setting realistic goals in successful weight loss. 23254196 Phytoestrogen genistein protects against endothelial barrier dysfunction in vascular endothelial cells through PKA-mediated suppression of RhoA signaling. The soy-derived phytoestrogen genistein has received attention for its potential to improve vascular function, but its mechanism remains unclear. Here, we report that genistein at physiologically relevant concentrations (0.1-10 μM) significantly inhibited thrombin-induced increase in endothelial monolayer permeability. Genistein also reduced the formation of stress fibers by thrombin and suppressed thrombin-induced phosphorylation of myosin light chain (MLC) on Ser(19)/Thr(18) in endothelial cells (ECs). Genistein had no effect on resting intracellular [Ca(2+)] or thrombin-induced increase in Ca(2+) mobilization. Addition of the inhibitors of endothelial nitric oxide synthase or estrogen receptor did not alter the protective effect of genistein. RhoA is a small GTPase that plays an important role in actin-myosin contraction and endothelial barrier dysfunction. RhoA inhibitor blocked the protective effect of genistein on endothelial permeability and also ablated thrombin-induced MLC-phosphorylation in ECs. Inhibition of PKA significantly attenuated the effect of genistein on thrombin-induced EC permeability, MLC phosphorylation, and RhoA membrane translocation in ECs. Furthermore, thrombin diminished cAMP production in ECs, which were prevented by treatment with genistein. These findings demonstrated that genistein improves thrombin-induced endothelial barrier dysfunction in ECs through PKA-mediated suppression of RhoA signaling. 23168241 Merit of quinacrine in the decrease of ingested sulfite-induced toxic action in rat brain. We aimed at investigating the effects of sulfite-induced lipid peroxidation and apoptosis mediated by secretory phospholipase A2 (sPLA2) on somatosensory evoked potentials (SEP) alterations in rats. Thirty male albino Wistar rats were randomized into three experimental groups as follows; control (C), sodium metabisulfite treated (S), sodium metabisulfite+quinacrine treated (SQ). Sodium metabisulfite (100 mg/kg/day) was given by gastric gavage for 5 weeks and 10 mg/kg/day quinacrine was applied as a single dose of intraperitoneal injection for the same period. The latencies of SEP components were significantly prolonged in the S group and returned to control levels following quinacrine administration. Plasma-S-sulfonate level was increased in S and SQ groups. TBARS levels in the S group were significantly higher than those detected in controls. Quinacrine significantly decreased brain TBARS levels in the SQ group compared with the S group. Quinacrine treatment did not have an effect on the increased sPLA2 level of the sulfite administered group. Immunohistochemistry showed that sulfite caused an increase in caspase-3 and TUNEL positive cells, restored to control levels via quinacrine administration. This study showed that sPLA2 might play a role in ingested sulfite-induced SEP alterations, oxidative stress, apoptotic cell death and DNA damage in the brain. 23347052 Self-healing mussel-inspired multi-pH-responsive hydrogels. Self-healing hydrogels can be made using either reversible covalent cross-links or coordination chemistry bonds. Here we present a multi-pH-responsive system inspired by the chemistry of blue mussel adhesive proteins. By attaching DOPA to an amine-functionalized polymer, a multiresponsive system is formed upon reaction with iron. The degree of polymer cross-linking is pH controlled through the pH-dependent DOPA/iron coordination chemistry. This leads to the formation of rapidly self-healing high-strength hydrogels when pH is raised from acidic toward basic values. Close to the pK(a) value, or more precisely the pI value, of the polymer, the gel collapses due to reduced repulsion between polymer chains. Thereby a bistable gel-system is obtained. The present polymer system more closely resembles mussel adhesive proteins than those previously reported and thus also serves as a model system for mussel adhesive chemistry. 23321916 Assessment of permethylated transition-metal sandwich complexes as internal reference redox systems in ionic liquids. This work reports the voltammetric behaviour of decamethylcobaltocenium, DmCc(+), in different ionic liquids for the first time. Its redox potential was studied relative to that of decamethylferrocene, DmFc, and it is shown that the difference in the mid-point potential between these two permethylated transition-metal sandwich complexes is independent of the ionic liquid composition. A variable difference in mid-point potential, in contrast, was observed for ferrocene and cobaltocenium relative to that of DmFc in similar ionic liquids. In addition, different limitations in the application of DmFc(0/+) and DmCc(+/0) couples as internal reference redox systems in ILs are discussed. From these, the observed spontaneous reaction between DmFc and oxygen leads to important implications toward the establishment of particular conditions for DmFc applications. 23440404 Conformation-dependent conductance through a molecular break junction. Ab initio molecular dynamics simulations have been performed of a gold-1,4-benzenedithiol (BDT)-gold nanojunction under mechanical stress. For three different pulling rates between 10 and 40 m s(-1), it is found that the nanowire always ruptures between the second and third Au atom from the thiol sulfur. Larger rupture forces and longer extensions are required at higher pulling rates and vice versa. The electrical conductance was calculated along a pulling trajectory using the DFT-NEGF method to study the effect of thermal and stress-induced structural changes on the electrical transport properties. While the mechanically induced stretching of the junction is seen to lower the time-averaged conductance, thermal conformational changes are capable of altering the conductance by one order of magnitude. No single geometric quantity could be identified as the main contributor to the conductance fluctuations. Small modulations, however, can be explained in terms of C=C double bond vibrations in the BDT molecule. The dependence of the conductance on different geometric variables has further been investigated systematically by performing constrained geometry optimizations along a number of angle and dihedral coordinates. The largest changes in the conductance are observed when the Au-S-C angle and the Au-S-C-C dihedral are simultaneously constrained. 23590473 Hair as an alternative matrix in bioanalysis. Alternative matrices are steadily gaining recognition as biological samples for toxicological analyses. Hair presents many advantages over traditional matrices, such as urine and blood, since it provides retrospective information regarding drug exposure, can distinguish between chronic and acute or recent drug use by segmental analysis, is easy to obtain, and has considerable stability for long periods of time. For this reason, it has been employed in a wide variety of contexts, namely to evaluate workplace drug exposure, drug-facilitated sexual assault, pre-natal drug exposure, anti-doping control, pharmacological monitoring and alcohol abuse. In this article, issues concerning hair structure, collection, storage and analysis are reviewed. The mechanisms of drug incorporation into hair are briefly discussed. Analytical techniques for simultaneous drug quantification in hair are addressed. Finally, representative examples of drug quantification using hair are summarized, emphasizing its potentialities and limitations as an alternative biological matrix for toxicological analyses. 23451803 Digitized charge transfer magnitude determined by metal-organic coordination number. Well-ordered metal-organic nanostructures of Fe-PTCDA (perylene-3,4,9,10-tetracarboxylic-3,4,9,10-dianhydride) chains and networks are grown on a Au(111) surface. These structures are investigated by high-resolution scanning tunneling microscopy. Digitized frontier orbital shifts are followed in scanning tunneling spectroscopy. By comparing the frontier energies with the molecular coordination environments, we conclude that the specific coordination affects the magnitude of charge transfer onto each PTCDA in the Fe-PTCDA hybridization system. A basic model is derived, which captures the essential underlying physics and correlates the observed energetic shift of the frontier orbital with the charge transfer. 23094599 Silicon surface functionalization targeting Si-N linkages. Silicon substrates have been a fascinating topic of fundamental and applied research for well over 50 years. They have attracted even more attention over the last couple of decades with advances in chemical functionalization that made oxide-free silicon surfaces a reality. Fundamentally new electronic properties and chemical reactivity became available, and the focus of chemical research turned more toward targeting specific chemical bonds and functionalities on silicon. Although thermodynamics clearly drives most processes under ambient conditions toward the formation of an oxide layer, kinetic control of the oxidation processes and thermodynamic tricks based on gaining stability of surface monolayers with high-density assembly have allowed for the formation of stable Si-C bonds and Si-O-C linkages on oxide-free silicon crystals. This feature article targets recent advances in making Si-N linkages on the same oxide-free single crystals. It covers the range of chemical approaches to achieving this goal and offers possible chemistry that can take advantage of the systems produced. The present status of the field and the future directions of its development will be considered. 23418087 Lifelong exposure to bisphenol a alters cardiac structure/function, protein expression, and DNA methylation in adult mice. Bisphenol A (BPA) is an estrogenizing endocrine disruptor compound of concern. Our objective was to test whether lifelong BPA would impact cardiac structure/function, calcium homeostasis protein expression, and the DNA methylation of cardiac genes. We delivered 0.5 and 5.0 µg/kg/day BPA lifelong from gestation day 11 or 200 µg/kg/day from gestation day 11 to postnatal day 21 via the drinking water to C57bl/6n mice. BPA 5.0 males and females had increased body weight, body mass index, body surface area, and adiposity. Echocardiography identified concentric remodeling in all BPA-treated males. Systolic and diastolic cardiac functions were essentially similar, but lifelong BPA enhanced male and reduced female sex-specific differences in velocity of circumferential shortening and ascending aorta velocity time integral. Diastolic blood pressure was increased in all BPA females. The calcium homeostasis proteins sarcoendoplasmic reticulum ATPase 2a (SERCA2a), sodium calcium exchanger-1, phospholamban (PLB), phospho-PLB, and calsequestrin 2 are important for contraction and relaxation. Changes in their expression suggest increased calcium mobility in males and reduced calcium mobility in females supporting the cardiac function changes. DNA methyltransferase 3a expression was increased in all BPA males and BPA 0.5 females and reduced in BPA 200 females. Global DNA methylation was increased in BPA 0.5 males and reduced in BPA 0.5 females. BPA induced sex-specific altered DNA methylation in specific CpG pairs in the calsequestrin 2 CpG island. These results suggest that continual exposure to BPA impacts cardiac structure/function, protein expression, and epigenetic DNA methylation marks in males and females. 23432007 (89)Zr-PET Radiochemistry in the Development and Application of Therapeutic Monoclonal Antibodies and Other Biologicals. Positron emission tomography with (89)Zr can be used to follow the behaviour of therapeutic monoclonal antibodies (mAbs) and other biologicals in vivo. The favourable radiophysical characteristics of (89)Zr allow multiple days PET scanning after injection. For the coupling of (89)Zr to proteins six desferrioxamine (DFO)-based bifunctional chelators have been described, five of which forming stable complexes in vivo. Of the methods that give stable complexes three are based on random lysine modification of mAbs and two on site-specific engineering. Up to now only two methods, random lysine modification with N-suc-DFO or DFO-Bz-NCS, have been used in clinical studies. In this review firstly aspects of the physicochemical properties and production of (89)Zr are emphasized as well as important items that have to be taken into account for current good manufacturing practice (cGMP) compliant production of (89)Zr-labeled proteins. Next, the different DFO-based conjugation strategies will be discussed with respect to synthesis, and their (pre)clinical evaluation particularly in the field of oncology. 23333261 Contribution of single-minded 2 to hyperglycaemia-induced neurotoxicity. Diabetes mellitus is associated to central nervous system damage, which results in impairment of brain functions and cognitive deficits and decline in memory. However, the mechanisms mediating the actions of glucose on the neurons remained elusive. Single-minded 2 (Sim2), a basic helix-loop-helix (bHLH)-PAS transcriptional repressor, is thought to be involved in some symptoms of Down syndrome. We hypothesized that Sim2 mediated hyperglycaemia-induced neuronal injury and impairment of learning and memory. It was found that expression of Sim2 protein in cortical neurons was increased in streptozotocin-induced diabetes mellitus rat model. Drebrin, down-regulated by Sim2, was subsequently decreased as detected by confocal laser scanning microscopy and Western blot analysis. The expression pattern of Sim2 and Drebrin correspond to 50mmol/L glucose (hyperglycaemia) was also found in primary cultured neurons. Curcumin, one neuroprotective agent, inhibited hyperglycaemia-induced neurotoxicity. Moreover, curcumin alleviated Sim2 expression, and reversely raised Drebrin expression in neurons treated with hyperglycaemia. Finally, we found that silencing Sim2 expression decreased hyperglycaemia-induced neuronal injury. In conclusion, Sim2 may mediate neurotoxicity during hyperglycaemia and thereby play a critical role in the development of hyperglycaemia-induced cognitive deficits. 23234812 Strontium Ranelate affects signaling from mechanically-stimulated osteocytes towards osteoclasts and osteoblasts. Strontium Ranelate (SrRan) is used to decrease the risk of bone fractures. Any factor that alters the release of paracrine signals by osteocytes in response to mechanical stimuli potentially affects bone mass and structure, and thus fracture resistance. We hypothesized that SrRan affects paracrine signaling from mechanically-stimulated osteocytes towards osteoclast-precursors and osteoblasts. MLO-Y4 osteocytes were cultured for 24h with SrRan (0.1-3mM) and either or not mechanically stimulated by pulsating fluid flow (PFF; 0.7 ± 0.3 Pa, 5 Hz) for 60 min. Nitric oxide (NO) and prostaglandin E(2) (PGE(2)) release, and expression of mechanoresponsive genes were quantified. Conditioned medium (CM) from osteocytes was added to mouse bone marrow cells for 7 days to assess osteoclastogenesis, or MC3T3-E1 osteoblasts for 4-16 days to measure osteogenic gene expression. SrRan (3mM) enhanced NO and PGE(2) release to the same extent in static osteocytes (NO: 1.6-fold; PGE(2): 2.8-fold) and PFF-stimulated osteocytes (NO: 1.3-fold; PGE(2): 2.6-fold). CM from PFF-treated osteocytes without SrRan enhanced Ki67 expression but reduced Runx2 and Ocn expression in osteoblasts. This effect on gene expression was not observed with CM obtained from osteocytes treated with the combination of PFF and 3mM SrRan. CM from PFF-treated osteocytes inhibited osteoclastogenesis by 1.9-fold. The combination of PFF and 3mM SrRan reduced osteocyte-stimulated osteoclastogenesis even more strongly (4.3-fold). In conclusion, SrRan affects paracrine signaling between mechanically-stimulated MLO-Y4 osteocytes and both osteoblasts and osteoclast precursors. The positive effects of SrRan on bone fracture resistance may thus be partly explained by altered paracrine signaling by osteocytes. 23411195 Odour quality of spray-dried hens' egg powders: the influence of composition, processing and storage conditions. This study aimed to determine whether compositional or processing parameters have an influence on the odour quality of egg powders. The parameters tested were: whole egg vs. egg yolk, polyunsaturated fatty acid (PUFA) enrichment, spray-drying temperature (160°C vs. 180°C), production scale (industrial vs. pilot plant), storage temperature (15°C vs. 30°C) and time (1, 2, 4 and 8 months). The quality of egg powders was evaluated by sensory analysis using free sorting, and by gas chromatography coupled to mass spectrometry and olfactometry. PUFA enrichment and spray-drying temperature do not affect the odour of egg yolk powders. There are significant differences between the odour of whole-egg and egg-yolk powders as well as between powders produced on an industrial scale or in a pilot plant. An increase in the odour intensity of egg powders was observed during storage, while unpleasant odours were perceived when the egg powders were stored at 30°C. 23421617 Impact of model perfume molecules on the self-assembly of anionic surfactant sodium dodecyl 6-benzene sulfonate. The impact of two model perfumes with differing degrees of hydrophobicity/hydrophilicity, linalool (LL) and phenylethanol (PE), on the solution structure of anionic surfactant sodium dodecyl 6-benzene sulfonate, LAS-6, has been studied by small angle neutron scattering, SANS. For both types of perfume molecules, complex phase behavior is observed. The phase behavior depends upon the concentration, surfactant/perfume composition, and type of perfume. The more hydrophilic perfume PE promotes the formation of more highly curved structures. At relatively low surfactant concentrations, small globular micelles, L1, are formed. These become perfume droplets, L(sm), stabilized by the surfactant at much higher perfume solution compositions. At higher surfactant concentrations, the tendency of LAS-6 to form more planar structures is evident. The more hydrophobic linalool promotes the formation of more planar structures. Combined with the greater tendency of LAS-6 to form planar structures, this results in the planar structures dominating the phase behavior for the LAS-6/linalool mixtures. For the LAS-6/linalool mixture, the self-assembly is in the form of micelles only at the lowest surfactant and perfume concentrations. Over most of the concentration-composition space explored, the structures are predominantly lamellar, L(α), or vesicle, L(v), or in the form of a lamellar/micellar coexistence. At low and intermediate amounts of LL, a significantly different structure is observed, and the aggregates are in the form of small, relatively monodisperse vesicles (i.e., nanovesicles), L(sv). 22840199 Pelargonium graveolens L'Her. and Artemisia arborescens L. essential oils: Chemical composition, antifungal activity against Rhizoctonia solani and insecticidal activity against Rhysopertha dominica. The chemical composition of the Pelargonium graveolens essential oil allowed the identification of 15 compounds (93.86% of the total essential oil). The major fractions were citronellol (35%) and geraniol (28.8%). The chemical composition of the Artemisia arborescens essential oil revealed twenty-one compounds representing 93.57% of the total essential oil. The main compounds were chamazulene (31.9%) and camphor (25.8%). The insecticidal effects were tested towards the insect Rhysopertha dominica. Results revealed that these two essential oils were highly effective against R. dominica at the dose of 50 µL on Petri dish of 8.5 cm of diameter. The antifungal activity was evaluated against Rhizoctonia solani and results showed that both of the essential oils were highly active at a dose of 12.5 µL/20 mL of PDA. Moreover, the inhibitory effect of P. graveolens essential oil was evidenced as stronger than that of the A. arborescens oil for all the tested doses. 23624376 Polyglycerol coatings of glass vials for protein resistance. Proteins are surface active molecules which undergo non-specific adsorption when getting in contact with surfaces such as the primary packaging material. This process is critical as it may cause a loss of protein content or protein aggregation. To prevent unspecific adsorption, protein repellent coatings are of high interest. We describe the coating of industrial relevant borosilicate glass vials with linear methoxylated polyglycerol, hyperbranched polyglycerol, and hyperbranched methoxylated polyglycerol. All coatings provide excellent protein repellent effects. The hyperbranched, non-methoxylated coating performed best. The protein repellent properties were maintained also after applying industrial relevant sterilization methods (⩾200°C). Marginal differences in antibody stability between formulations stored in bare glass vials and coated vials were detected after 3months storage; the protein repellent effect remained largely stable. Here, we describe a new material suitable for the coating of primary packaging material of proteins which significantly reduces the protein adsorption and thus could present an interesting new possibility for biomedical applications. 23122114 Hair mercury levels and food consumption in residents from the Pearl River Delta: South China. The Pearl River Delta (PRD) is located in the Southern part of China and is the main region for fish culture in Guangdong Province. In order to assess the potential health risks associated with dietary consumption of mercury, hair samples from 91 urban, town and fishing village residents, 37 species of fish, cereal, vegetables, and meat samples were collected. The average total mercury (THg) and methylmercury (MeHg) concentrations in hair were 1.08 ± 0.94 and 0.58 ± 0.59 μg/g, respectively. Daily Hg intake via fish consumption is significantly correlated with THg and MeHg accumulated in human hair (r=0.48, p<0.01; r=0.43, p<0.01). The estimated daily intake of Hg via different food types showed that both fish and cereal consumption were the two main routes of Hg exposure for residents in the sampling areas. Besides food intake, smoking was also an important source for daily THg intake in the smoke group, contributing 11-18% to EDI of THg. 23411284 Thermal protection of β-carotene in re-assembled casein micelles during different processing technologies applied in food industry. β-Carotene is a carotenoid usually applied in the food industry as a precursor of vitamin A or as a colourant. β-Carotene is a labile compound easily degraded by light, heat and oxygen. Casein micelles were used as nanostructures to encapsulate, stabilise and protect β-carotene from degradation during processing in the food industry. Self-assembly method was applied to re-assemble nanomicelles containing β-carotene. The protective effect of the nanostructures against degradation during the most common industrial treatments (sterilisation, pasteurisation, high hydrostatic pressure and baking) was proven. Casein micelles protected β-carotene from degradation during heat stabilisation, high pressure processing and the processes most commonly used in the food industry including baking. This opens new possibilities for introducing thermolabile ingredients in bakery products. 23583765 Systematic characterization of structure-activity relationships and ADMET compliance: a case study. Traditionally, activity landscape modeling has been focused on analyzing SAR, despite the fact that lead optimization in drug discovery involves concurrent enhancements of activity and ADMET properties of leads. As a case study, we discuss the systematic analysis of activity landscapes, incorporating ADMET considerations, using a dataset of 166 compounds screened for kappa-opioid receptor activity. Pairwise MACCS/Tanimoto structure similarities, property similarities utilizing 33 ADMET descriptors and a 35-dimensional 'violation bit vector' representing drug-likeness are analyzed. We address the question about the range of ADMET property violations that arise from structural changes, subtle and significant. Pairs of compounds are identified bearing identical, comparable and significantly different drug-likeness in the three informative regions of structure-activity landscapes. 23456097 Combining NMR and small angle X-ray and neutron scattering in the structural analysis of a ternary protein-RNA complex. Many processes in the regulation of gene expression and signaling involve the formation of protein complexes involving multi-domain proteins. Individual domains that mediate protein-protein and protein-nucleic acid interactions are typically connected by flexible linkers, which contribute to conformational dynamics and enable the formation of complexes with distinct binding partners. Solution techniques are therefore required for structural analysis and to characterize potential conformational dynamics. Nuclear magnetic resonance spectroscopy (NMR) provides such information but often only sparse data are obtained with increasing molecular weight of the complexes. It is therefore beneficial to combine NMR data with additional structural restraints from complementary solution techniques. Small angle X-ray/neutron scattering (SAXS/SANS) data can be efficiently combined with NMR-derived information, either for validation or by providing additional restraints for structural analysis. Here, we show that the combination of SAXS and SANS data can help to refine structural models obtained from data-driven docking using HADDOCK based on sparse NMR data. The approach is demonstrated with the ternary protein-protein-RNA complex involving two RNA recognition motif (RRM) domains of Sex-lethal, the N-terminal cold shock domain of Upstream-to-N-Ras, and msl-2 mRNA. Based on chemical shift perturbations we have mapped protein-protein and protein-RNA interfaces and complemented this NMR-derived information with SAXS data, as well as SANS measurements on subunit-selectively deuterated samples of the ternary complex. Our results show that, while the use of SAXS data is beneficial, the additional combination with contrast variation in SANS data resolves remaining ambiguities and improves the docking based on chemical shift perturbations of the ternary protein-RNA complex. 23266453 Targeted adenovirus mediated inhibition of NF-κB-dependent inflammatory gene expression in endothelial cells in vitro and in vivo. In chronic inflammatory diseases the endothelium expresses mediators responsible for harmful leukocyte infiltration. We investigated whether targeted delivery of a therapeutic transgene that inhibits nuclear factor κB signal transduction could silence the proinflammatory activation status of endothelial cells. For this, an adenovirus encoding dominant-negative IκB (dnIκB) as a therapeutic transgene was employed. Selectivity for the endothelial cells was achieved by introduction of antibodies specific for inflammatory endothelial adhesion molecules E-selectin or VCAM-1 chemically linked to the virus via polyethylene glycol. In vitro, the retargeted adenoviruses selectively infected cytokine-activated endothelial cells to express functional transgene. The comparison of transductional capacity of both retargeted viruses revealed that E-selectin based transgene delivery exerted superior pharmacological effects. Targeted delivery mediated dnIκB transgene expression in endothelial cells inhibited the induced expression of several inflammatory genes, including adhesion molecules, cytokines, and chemokines. In vivo, in mice suffering from glomerulonephritis, E-selectin-retargeted adenovirus selectively homed in the kidney to microvascular glomerular endothelium. Subsequent downregulation of endothelial adhesion molecule expression 2 days after induction of inflammation demonstrated the pharmacological potential of this gene therapy approach. The data justify further studies towards therapeutic virus design and optimization of treatment schedules to investigate their capacity to interfere with inflammatory disease progression. 23623493 Synthesis, characterization and cytotoxic activity on breast cancer cells of new half-titanocene derivatives. A series of novel titanocene-complexes has been prepared and evaluated for their growth regulatory effects in MCF7 and SkBr3 breast cancer cells. The capability of some of these compound to elicit relevant repressive effects on cancer cell growth could be taken into account towards novel pharmacological approaches in cancer therapy. 23207252 Effects of the herbal medicine composition "Saiko-ka-ryukotsu-borei-To" on the function of endothelial progenitor cells in hypertensive rats. Endothelial progenitor cells (EPCs) are known to repair vascular injuries. Recent studies suggest that Saiko-ka-ryukotsu-borei-To (SKRBT), a traditional herbal medicine that has been used to treat stress-related neuropsychiatric disorders, has protective effects on cardiovascular diseases such as hypertension and arteriosclerosis. Spontaneously hypertensive rats (SHRs) were fed diets containing lyophilized SKRBT extract for 6 weeks. Peripheral blood mononuclear cells (MNCs) were isolated and cultured to assay EPC colony formation. Oxidative stress in MNCs was evaluated by thiobarbituric acid reactive substance (TBARS) assay and flowcytometric analyses. Treatment with SKRBT increased EPC colony numbers significantly (p<0.05) with decrease in oxidative stress and without affecting blood pressure in SHRs. Treatment with SKRBT did not reduce the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits in cardiovascular organs. Serum IL-6 level was significantly reduced. SKRBT is a feasible herbal medicine that protects against cardiovascular diseases through an increase in EPC function along with anti-oxidative effects, and may affect the link between chronic inflammation and cardiovascular disease. 23224291 Proteomic and metabolomic responses to connexin43 silencing in primary hepatocyte cultures. Freshly established cultures of primary hepatocytes progressively adopt a foetal-like phenotype and display increased production of connexin43. The latter is a multifaceted cellular entity with variable subcellular locations, including the mitochondrial compartment. Cx43 forms hemichannels and gap junctions that are involved in a plethora of physiological and pathological processes, such as apoptosis. The present study was conducted with the goal of shedding more light onto the role of connexin43 in primary hepatocyte cultures. Connexin43 expression was suppressed by means of RNA interference technology, and the overall outcome of this treatment on the hepatocellular proteome and metabolome was investigated using tandem mass tag-based differential protein profiling and (1)H NMR spectroscopy, respectively. Global protein profiling revealed a number of targets of the connexin43 knock-down procedure, including mitochondrial proteins (heat shock protein 60, glucose-regulated protein 75, thiosulphate sulphurtransferase and adenosine triphosphate synthase) and detoxifying enzymes (glutathione S-transferase μ 2 and cytochrome P450 2C70). At the metabolomic level, connexin43 silencing caused no overt changes, though there was some evidence for a subtle increase in intracellular glycine quantities. Collectively, these data could further substantiate the established existence of a mitochondrial connexin pool and could be reconciled with the previously reported involvement of connexin43 signalling in spontaneously occurring apoptosis in primary hepatocyte cultures. 23376696 Tissue distributions of fluoride and its toxicity in the gills of a freshwater teleost, Cyprinus carpio. Fish take up fluoride directly from water and are susceptible to fluoride contamination of their environment. In this study, we examined the tissue distributions of fluoride and its toxicity in the gills of the common carp (Cyprinus carpio) chronically exposed to fluoride. Carp were exposed to a range of aqueous fluoride (35-124 mg/L) and sampled at 30, 60 and 90 days. The accumulation of fluoride in the tissues increased with the level and duration of exposure. Steady state was not achieved under the experimental conditions. The gills accumulated the highest levels of fluoride followed by the liver>brain>kidney>muscle>intestine. A dose-dependent inhibition was observed for the enzyme activities of Na(+)-K(+)-ATPase and Ca(2+)-ATPase in the gills after the fish were exposed for 90 days. Also, accumulation of fluoride was associated with the inhibition of superoxide dismutase (SOD) activities and a dose-dependent stimulation of malondialdehyde (MDA) levels in the gill tissues, suggesting that fluoride promoted oxidative stress in the fish. Microscopic examinations revealed injuries to gill tissues and chloride cells, with the severity of injury increasing with exposure concentration. These results suggest that chronic exposure to elevated concentrations of fluoride may induce toxicity in the common carp. 22914985 Effects of mycophenolic acid alone and in combination with its metabolite mycophenolic acid glucuronide on rat embryos in vitro. Mycophenolic acid (MPA) is an immunosuppressive agent that acts as a selective, non-reversible inhibitor of the enzyme inosine-5'-monophosphate dehydrogenase (IMPDH). Malformations have been described in children after maternal exposure to mycophenolate. However, the causal link is unclear in most cases because women had been treated with a combination of drugs and birth defects may have other causes. Therefore, it is important to study the action of this drug and its main metabolite on embryonic tissue. We studied the teratogenic potential of MPA and its major metabolite, the mycophenolic acid glucuronide (MPAG) in the rat whole-embryo culture. A total of 147 day 9.5 embryos were cultivated for 48 h in the standard medium containing 85 % serum. We tested MPA at concentrations of 0.1; 0.25; 0.5; 0.75 mg/l (0.31; 0.78; 1.56; 2.34 μM) and MPA glucuronide at concentrations of 3; 10; 30; 100 mg/l (6.04; 20.14; 60.43; 201.43 μM). Both substances are highly protein bound, and MPA glucuronide might displace MPA from protein binding. Therefore, we examined whether the effects of MPA can be enhanced when studied in combination with the glucuronide. Furthermore, the focus was on additional endpoints to the standard evaluation of cultivated embryos, such as development of cranial nerves [trigeminal nerve (V), facial nerve (VII), glossopharyngeal nerve (IX), vagus nerve (X)] after staining with an antibody against 2H3 neurofilament. Ultrastructural changes were evaluated by electron microscopy. At a concentration of 0.75 mg MPA/l medium, all embryos showed dysmorphic changes. Embryos exposed to 0.25 mg MPA/l medium showed impaired development of nerves, and at 0.1 mg/l, no effects were detectable. Concentration-dependent ultrastructural changes, such as signs of apoptosis, were found by electron microscopy. The examination of the metabolite in this assay showed that at a concentration of 100 mg MPAG/l, the embryos exhibited distinct malformations. This is probably caused by MPA, which was detectable at 0.6 % in the material used for our experiments. The combination of the parent compound (0.03; 0.1; 0.25 mg/l) with its metabolite MPAG (3 mg/l) did not cause enhanced toxicity under our experimental conditions. IMPDH, the target enzyme of MPA, could be detected in rat embryos on day 9.5 of embryonic development as well as at the end of the culture period 48 h later. In summary, MPA impairs embryonic development at low, therapeutically relevant concentrations, but the glucuronide does not exhibit such a potential. Activity of MPA is not enhanced by MPAG. 23276633 Testosterone metabolites mediate its effects on myocardial damage induced by ischemia/reperfusion in male Wistar rats. The role of testosterone in cardiovascular (CV) homeostasis is in controversy, and the exact effects of testosterone on the cardiovascular system remain poorly understood. Testosterone is metabolized by aromatase into 17β-estradiol and by 5α-reductase into dihydrotestosterone (DHT). Thus, identification of these metabolites in the heart may help to explain the controversy regarding the cardiovascular effects of testosterone. We analyzed the expression patterns of these testosterone-metabolizing enzymes and assessed the effect of its enzymatic activity inhibition on ischemia (40 min)/reperfusion (4h, I/R) via the left anterior descendent coronary artery in intact and gonadectomized male rats. Myocardial damage was measured as percentage of infarcted area vs. area at risk. Aromatase and 5α-reductase protein expression was found in the left ventricle of intact and orchidectomized rats. Exogenous testosterone had no effect on I/R induced myocardial damage in intact male rats, meanwhile exogenous testosterone protects against I/R injury in orchidectomized rats. However, enzymatic inhibition of aromatase increased myocardial damage in the presence of testosterone, while enzymatic inhibition of 5α-reductase significantly decreased the level of myocardial damage. Our results also showed that sub-chronic inhibition of 5α-reductase resulted in myocardial protection in both groups. Furthermore, in orchidectomized and intact male rats IV treatment with DHT induces a significant increase in the myocardial damage induced by I/R. Thus, the effect of testosterone on cardiovascular pathophysiology could be related, at least in part to changes in the balance of testosterone 5α-reduction and aromatization. 23339654 Type I collagen self-assembly: the roles of substrate and concentration. Collagen molecules, self-assembled into macroscopic hierarchical tissue networks, are the main organic building block of many biological tissues. A particularly common and important form of this self-assembly consists of type I collagen fibrils, which exhibit a nanoscopic signature, D-periodic gap/overlap spacing, with a distribution of values centered at approximately 67 nm. In order to better understand the relationship between type I collagen self-assembly and D-spacing distribution, we investigated surface-mediated collagen self-assembly as a function of substrate and incubation concentration. Collagen fibril assembly on phlogopite and muscovite mica as well as fibrillar gel coextrusion in glass capillary tubes all exhibited D-spacing distributions similar to those commonly observed in biological tissues. The observation of D-spacing distribution by self-assembly of type I collagen alone is significant as it eliminates the necessity to invoke other preassembly or postassembly hypotheses, such as variation in the content of collagen types, enzymatic cross-linking, or other post-translational modifications, as mechanistic origins of D-spacing distribution. The D-spacing distribution on phlogopite mica is independent of type I collagen concentration, but on muscovite mica D-spacing distributions showed increased negative skewness at 20 μg/mL and higher concentrations. Tilted D-spacing angles were found to correlate with decreased D-spacing measurements, an effect that can be removed with a tilt angle correction, resulting in no concentration dependence of D-spacing distribution on muscovite mica. We then demonstrated that tilted D-spacing is uncommon in biological tissues and it does not explain previous observations of low D-spacing values in ovariectomized dermis and bone. 23281179 Correct Spectral Conversion between Surface-Enhanced Raman and Plasmon Resonance Scattering from Nanoparticle Dimers for Single-Molecule Detection. Simultaneous measurement of surface-enhanced Raman scattering (SERS) and localized surface plasmon resonance (LSPR) in nanoparticle dimers presents outstanding opportunities in molecular identification and in the elucidation of physical properties, such as the size, distance, and deformation of target species. SERS-LSPR instrumentation exists and has been used under limited conditions, but the extraction of SERS and LSPR readouts from a single measurement is still a challenge. Herein, the extraction of LSPR spectra from SERS signals is reported and a tool for measuring the interparticle distance from Raman enhancement data by the standardization of the SERS signal is proposed. The SERS nanoruler mechanism incorporates two important aspects (the LSPR scattering peak shift and the Raman shift for measuring interparticle distance), and signifies their exact one-to-one correspondence after spectral correction. The developed methodology is applied to calculate the interparticle distance between nanoparticle dimers from SERS signals, to detect and quantify DNA at the single-molecule level in a base-pair-specific manner. It is also shown that the SERS nanoruler concept can be used in structural analysis for the specific detection of the interaction of immunoglobulin G (IgG) with its target from bianalyte Raman signals with identical shaping at single-molecule resolution. The SERS profile shaping approach not only offers a new detection mechanism for single molecules, but also has excellent potential for studying protein interactions and the intracellular detection of mRNA. 23462104 Effects of seaweed-restructured pork diets enriched or not with cholesterol on rat cholesterolaemia and liver damage. Seaweed enriched-restructured pork (RP) is a potential functional food. However, indications of adverse effects associated with herbal medications, which include among others liver failure, toxic hepatitis, and death have been reported. Cholesterol feeding produces hepatomegalia and fat liver infiltration. The effect of seaweed-RP diet, cholesterol-enriched or not, on plasma cholesterol, liver damage markers, structure, and cytochrome CYP4A-1 were evaluated after 5wk. Eight rat groups were fed a mix of 85% AIN-93M rodent-diet plus 15% RP. The Cholesterol-control (CC), Cholesterol-Wakame (CW), Cholesterol-Nori (CN) and Cholesterol-Sea Spaghetti (CS) groups respectively consumed similar diets to control (C), Wakame (W), Nori (N), and Sea Spaghetti (S) but as part of hypercholesterolaemic diets. CN and CS significantly blocked the hypercholesterolaemic effect observed in CC group. After 5-wk, N and S diets increased the CYP4A-1 expression. However, seaweed-RPs were unable to reduce the histological liver alterations observed in CC group. Larger and more abundant hepatocellular alterations were found in CS and CN rats suggesting that the hypocholesterolaemic effects of these seaweed-RPs seem to be a two-edged sword as they increased liver damage. Future studies are needed to understand the involved mechanisms. 23063411 Characterisation of the roles of ABCB1, ABCC1, ABCC2 and ABCG2 in the transport and pharmacokinetics of actinomycin D in vitro and in vivo. Actinomycin D plays a key role in the successful treatment of Wilms tumour. However, associated liver toxicities remain a drawback to potentially curative treatment. We have used MDCKII cells over-expressing ABCB1, ABCC1, ABCC2 and ABCG2, alongside knockout mouse models to characterise actinomycin D transport and its impact on pharmacokinetics. Growth inhibition, intracellular accumulation and cellular efflux assays were utilised. A 59-fold difference in GI(50) was observed between MDCKII-WT and MDCKII-ABCB1 cells (12.7 nM vs. 745 nM, p<0.0001). Reduced sensitivity was also seen in MDCKII-ABCC1 and ABCC2 cells (GI(50) 25.7 and 40.4 nM respectively, p<0.0001). Lower intracellular accumulation of actinomycin D was observed in MDCKII-ABCB1 cells as compared to MDCKII-WT (0.98 nM vs. 0.1 nM, p<0.0001), which was reversed upon ABCB1 inhibition. Lower accumulation was also seen in MDCKII-ABCC1 and ABCC2 cells. Actinomycin D efflux over 2 h was most pronounced in MDCKII-ABCB1 cells, with 5.5-fold lower intracellular levels compared to WT. In vivo studies showed that actinomycin D plasma concentrations were significantly higher in Abcb1a/1b(-/-) as compared to WT mice following administration of 0.5 mg/kg actinomycin D (AUC(0-6 h) 242 vs. 152 μg/Lh respectively). While comparable actinomycin D concentrations were observed in the kidneys and livers of Abcb1a/1b(-/-) and Abcc2(-/-) mice, concentrations in the brain were significantly higher at 6h following drug administration in Abcb1a/1b(-/-) mice compared to WT. Results confirm actinomycin D as a substrate for ABCB1, ABCC1 and ABCC2, and indicate that Abcb1a/1b and Abcc2 can influence the in vivo disposition of actinomycin D. These data have implications for ongoing clinical pharmacology trials involving children treated with actinomycin D. 23567034 Antibacterial, cytotoxic activities and chemical composition of fruits of two Cameroonian Zanthoxylum species. ETHNOPHARMACOLOGICAL RELEVANCE: Zanthoxylum leprieurii (Syn. Fagara leprieurii) is a plant extensively used by traditional healers in Cameroon for the treatment of stomach disorders, gonorrhea, intestinal parasites and sterility. The infusion from the fruit is taken in Cameroon for the treatment of sickle cell anemia, as well. Similarly, the roots of Zanthoxylum zanthoxyloides (Syn. Fagara zanthoxyloides) are also used for wound dressing, sickle cell anemia and as pain reliever, in addition to the uses mentioned for Zanthoxylum leprieurii. AIM OF THE STUDY: To scientifically validate their traditional use, the in vitro antimicrobial and anticancer assays were performed. In addition, chemical compositions of their fruit extracts and essential oils were also studied. MATERIAL AND METHODS: The chemical compositions of their essential oils and methanol extracts were studied. GC and GC-MS were used for analyzing the essential oils while various chromatographic methods were used to isolate the pure compounds from methanol extracts. MTT assay was used for the cytotoxic studies of methanol extracts, their fractions and some pure compounds. Antimicrobial activity of methanol extracts, some isolated compounds as well as essential oils was tested against a panel of human pathogenic bacteria by diffusion and dilution methods. RESULTS: The principal constituents of the essential oil of Zanthoxylum zanthoxyloides were identified as citronellol and geraniol whereas Zanthoxylum leprieurii was rich in E-β-ocimene. Furthermore, we report for the first time, the presence of 7,8-dimethoxycoumarin and sinapic acid in the methanol extract of Zanthoxylum leprieurii. In vitro bioassays reveal that the methanol extracts, essential oil and some of the isolated compounds from fruits of both the plants exhibit moderate anticancer and antimicrobial activities. CONCLUSION: Altogether, the present findings justify the traditional use of Zanthoxylum zanthoxyloides and Zanthoxylum leprieurii in the treatment of stomach disorders and cancer disease. The antimicrobial properties in the essential oil of Zanthoxylum zanthoxyloides are of additional significance. 23515282 Functional Diversity of HDL Cargo. For decades high-density lipoproteins (HDL) and HDL-cholesterol (HDL-C) levels were viewed as synonymous and modulation of HDL-C levels by drug therapy held great promise for the prevention and treatment of cardiovascular disease. Nevertheless, recent failures of drugs that raise HDL-C to reduce cardiovascular risk and the now greater understanding of the complexity of HDL composition and biology have prompted researchers in the field to redefine HDL. As such, the focus of HDL has now started to shift away from a cholesterol centric view towards HDL particle number, subclasses, and other alternative metrics of HDL. Many of the recently discovered functions of HDL are, in fact, not strictly conferred by its ability to promote cholesterol flux, but by the other molecules it transports, including a diverse set of proteins, small RNAs, hormones, carotenoids, vitamins, and bioactive lipids. Based on the ability of HDL to interact with almost all cells and transport and deliver fat-soluble cargo, HDL has the remarkable capacity to affect a wide-variety of endocrine-like systems. Here in this review, we characterize the unique cargo on HDL and address the functional relevance and consequences of HDL transport and delivery of non-cholesterol molecules to recipient cells and tissues. 23537747 Nobiletin attenuates metastasis via both ERK and PI3K/Akt pathways in HGF-treated liver cancer HepG2 cells. Hepatocyte growth factor (HGF), and its receptor, c-Met activation has recently been shown to play important roles in cancer invasion and metastasis in a wide variety of tumor cells. We use HGF as an invasive inducer of human HepG2 cells to investigate the effect of four flavones including apigenin, tricetin, tangeretin, and nobiletin on HGF/c-Met-mediated tumor invasion and metastasis. Among them, nobiletin markedly inhibited HGF-induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and transwell-chamber invasion/migration assay under non-cytotoxic concentrations. Data also showed nobiletin inhibited HGF-induced cell scattering and cytoskeleton changed such as filopodia and lamellipodia. Furthermore, nobiletin could inhibit HGF-induced the membrane localization of phosphorylated c-Met, ERK2, and Akt, but not phosphorylated JNK1/2 and p38. Next, nobiletin significantly decreased the levels of phospho-ERK2 and phospho-Akt in ERK2 or Akt siRNA-transfected cells concomitantly with a marked reduction on cell invasion and migration. In conclusion, nobiletin attenuates HGF-induced HepG2 cells metastasis involving both ERK and PI3K/Akt pathways and are potentially useful as anti-metastatic agents for the treatment of hepatoma. 23639188 Antiangiogenetic effects of anthranoids from Alternaria sp., an endophytic fungus in a Thai medicinal plant Erythrina variegata. Endophytic fungi are known as a prolific source for the discovery of structurally interesting and biologically active secondary metabolites, some of which are promising candidates for drug development. In the present study, three anthranoids were isolated from an Alternaria sp. endophytic fungus and evaluated for their antiangiogenic activity in a rat aortic sprouting assay, an ex vivo model of angiogenesis. Of these three compounds, altersolanol (2) was further characterized and found to show a promising activity in ex vivo, in vitro and in vivo angiogenesis asssays. Using human umbilical vein endothelial cells as an in vitro model, the angiogenic effect of 2 was found to occur via suppression of all three main functions of endothelial cells, namely proliferation, tube formation and migration. 23485991 A Rice Immunophilin Gene, OsFKBP16-3, Confers Tolerance to Environmental Stress in Arabidopsis and Rice. The putative thylakoid lumen immunophilin, FKBP16-3, has not yet been characterized, although this protein is known to be regulated by thioredoxin and possesses a well-conserved CxxxC motif in photosynthetic organisms. Here, we characterized rice OsFKBP16-3 and examined the role of this gene in the regulation of abiotic stress in plants. FKBP16-3s are well conserved in eukaryotic photosynthetic organisms, including the presence of a unique disulfide-forming CxxxC motif in their N-terminal regions. OsFKBP16-3 was mainly expressed in rice leaf tissues and was upregulated by various abiotic stresses, including salt, drought, high light, hydrogen peroxide, heat and methyl viologen. The chloroplast localization of OsFKBP16-3-GFP was confirmed through the transient expression of OsFKBP16-3 in Nicotiana benthamiana leaves. Transgenic Arabidopsis and transgenic rice plants that constitutively expressed OsFKBP16-3 exhibited increased tolerance to salinity, drought and oxidative stresses, but showed no change in growth or phenotype, compared with vector control plants, when grown under non-stressed conditions. This is the first report to demonstrate the potential role of FKBP16-3 in the environmental stress response, which may be regulated by a redox relay process in the thylakoid lumen, suggesting that artificial regulation of FKBP16-3 expression is a candidate for stress-tolerant crop breeding. 22876956 Nitrogen, oxygen or sulfur containing heterocyclic compounds as analgesic drugs used as modulators of the nitroxidative stress. Numerous lines of evidence suggest that heterocyclic compounds used as analgesic, anti-inflammatory and anti-migraine agents can be potent regulators of the nitroxidative stress and targeting free nitrogen and oxygen radicals is a very promising strategy for future pain management. Both classical analgesics (nonsteroidal anti-inflammatory drugs, opioid drugs) and many analgesic adjuvants, including desipramine, duloxetine, fluoxetine, paroxetine, escitalopram, phenytoin or carbamazepine and α-lipoic acid can modulate the balance between pro-oxidant and antioxidant processes in the mammalian tissues and these properties of drugs such as indomethacin, meloxicam, tenoxicam, valdecoxib or some metabolites of analgesic drugs formed by the activity of tissue peroxidases may contribute to their clinical efficacy and drug-related toxic effects, including gastrointestinal ulcers, hepatic failure, agranulocytosis, aplastic anemia, neutropenia, opiate-induced hyperalgesia and tolerance. The antioxidant capacities of novel heterocyclic compounds, including the compounds acting either by prevention of formation or catalyzed decomposition of peroxynitrite anion (ONOO-), namely the peroxynitrite decomposition catalysts or as superoxide (O2 •-)-scavengers which are the functional mimetics of superoxide dismutase (SOD) enzymes (SODm), as well as the derivatives of 6-nitro-3,4-methylenedioxyphenyl-Nacylhydrazone (LASSBio-881) or γ-butyrolactone (LPP1, BM113, BM113A, BM138 and BM138A) are also discussed as potent and promising future heterocyclic analgesics. 23298140 Honey as a source of dietary antioxidants: structures, bioavailability and evidence of protective effects against human chronic diseases. In the long human tradition honey has been used not only as a nutrient but also as a medicine. Its composition is rather variable and depends on the floral source and on external factors, such as seasonal, environmental conditions and processing. In this review, specific attention is focused on absorption, metabolism, and beneficial biological activities of honey compounds in human. Honey is a supersaturated solution of sugars, mainly composed of fructose (38%) and glucose (31%), containing also minerals, proteins, free amino acids, enzymes, vitamins and polyphenols. Among polyphenols, flavonoids are the most abundant and are closely related to its biological functions. Honey positively affects risk factors for cardiovascular diseases by inhibiting inflammation, improving endothelial function, as well as the plasma lipid profile, and increasing low-density lipoprotein resistance to oxidation. Honey also displays an important antitumoral capacity, where polyphenols again are considered responsible for its complementary and overlapping mechanisms of chemopreventive activity in multistage carcinogenesis, by inhibiting mutagenesis or inducing apoptosis. Moreover, honey positively modulates the glycemic response by reducing blood glucose, serum fructosamine or glycosylated hemoglobin concentrations and exerts antibacterial properties caused by its consistent amount of hydrogen peroxide and non-peroxide factors as flavonoids, methylglyoxal and defensin-1 peptide. In conclusion, the evidence of the biological actions of honey can be ascribed to its polyphenolic contents which, in turn, are usually associated to its antioxidant and anti-inflammatory actions, as well as to its cardiovascular, antiproliferative and antimicrobial benefits. 23060096 A sensitive H2O2 assay based on dumbbell-like PtPd-Fe3O4 nanoparticles. Dumbbell-like Pt(48)Pd(52)-Fe(3)O(4) nanoparticles are synthesized and functionalized with oleylamine-polyethyleneglycol to serve as an efficient catalyst for H(2)O(2) reduction and tetramethylbenzidine (TMB) oxidation in biological solutions. The Pt(48)Pd(52)-Fe(3)O(4)/TMB kit is even more active than the natural enzyme for H(2)O(2) detection with a detection limit reaching 2 μM, and is successfully used to quantitatively monitor the extracellular H(2)O(2) generated by neutrophils. 23340981 Effects of acute and sub-chronic nicotine on impulsive choice in rats in a probabilistic delay-discounting task. RATIONALE: Cigarette smokers typically display impulsivity by preferring immediate rewards over larger, delayed rewards at shorter delays than do non-smokers. Suggesting causality, nicotine injections in rats increase the choice for an immediate reward over a larger, delayed reward. OBJECTIVES: To examine the generality of this latter effect, the present study employed a delay-discounting task to determine if acute and sub-chronic nicotine will also increase impulsive choice when subjective reward value is manipulated by changes in the probability, rather than magnitude, of reward. MATERIALS AND METHODS: Rats were presented with two levers, one of which delivered an immediate water reward on half of the trials, while the other lever delivered the same reward on every trial, but only after one of five increasing delays. RESULTS: Acute injections of 1.2 mg/kg, but not 0.8 mg/kg, of nicotine increased the preference for the immediate (but less certain) reward lever at intermediate delays. Moreover, twice-daily injections of 0.8 mg/kg of nicotine for 6 days progressively increased the preference for the immediate reward. Latency to make the first response on each trial was not affected by nicotine. CONCLUSIONS: The similar increases in impulsive choice produced by both acute and sub-chronic nicotine in delay-discounting paradigms whether subjective reward value is manipulated by changes in reward magnitude or probability suggests that nicotine may be increasing what is common to these paradigms, namely delay discounting. Whatever the mechanism, these data indicate that both acute and sub-chronic nicotine may help develop and maintain an addiction by increasing impulsivity. 22809021 Live-birth rates after HP-hMG stimulation in the long GnRH agonist protocol: association with mid-follicular hCG and progesterone concentrations, but not with LH concentrations. The aim of this retrospective study was to investigate the impact of endogenous and exogenous luteinizing hormone (LH) activity on treatment outcome, when taking into consideration potential confounding variables. Data were derived from IVF patients (n = 358) stimulated with highly purified menotrophin (HP-hMG) in a long gonadotrophin-releasing hormone (GnRH) agonist protocol. Simple retrospective logistic regression analysis showed that the mid-follicular exogenous concentrations of human chorionic gonadotrophin (hCG) (p = 0.027), provided by the HP-hMG preparation, and female age (p = 0.009) were significantly associated with live-birth rate, while the mid-follicular progesterone concentration (p = 0.075), the estradiol concentration on last stimulation day (p = 0.075) and number of embryos transferred (p = 0.071) were borderline significant. Endogenous LH was not associated with live-birth rate; neither at start of stimulation (p = 0.123), nor in the mid-follicular phase (p = 0.933) or on the last day of stimulation (p = 0.589). In the multiple regression analysis of life birth, mid-follicular hCG (p = 0.016) was identified as a positive predictor, and age (p = 0.004) and mid-follicular progesterone (p = 0.029) as negative predictors. In conclusion, mid-follicular concentrations of exogenous hCG and progesterone, but not endogenous LH, are associated with live-birth rate in IVF patients treated with HP-hMG in a long GnRH agonist cycle. 23404443 Effects of induced hyperinsulinaemia with and without hyperglycaemia on measures of cardiac vagal control. AIMS/HYPOTHESIS: We examined the effects of serum insulin levels on vagal control over the heart and tested the hypothesis that higher fasting insulin levels are associated with lower vagal control. We also examined whether experimentally induced increases in insulin by beta cell secretagogues, including glucagon-like peptide-1 (GLP-1), will decrease vagal control. METHODS: Respiration and ECGs were recorded for 130 healthy participants undergoing clamps. Three variables of cardiac vagal effects (the root mean square of successive differences [rMSSD] in the interbeat interval of the heart rate [IBI], heart-rate variability [HRV] caused by peak-valley respiratory sinus arrhythmia [pvRSA], and high-frequency power [HF]) and heart rate (HR) were obtained at seven time points during the clamps, characterised by increasing levels of insulin (achieved by administering insulin plus glucose, glucose only, glucose and GLP-1, and glucose and GLP-1 combined with arginine). RESULTS: Serum insulin level was positively associated with HR at all time points during the clamps except the first-phase hyperglycaemic clamp. Insulin levels were negatively correlated with variables of vagal control, reaching significance for rMSSD and log(10)HF, but not for pvRSA, during the last four phases of the hyperglycaemic clamp (hyperglycaemic second phase, GLP-1 first and second phases, and arginine). These associations disappeared when adjusted for age, BMI and insulin sensitivity. Administration of the beta cell secretagogues GLP-1 and arginine led to a significant increase in HR, but this was not paired with a significant reduction in HRV measures. CONCLUSION/INTERPRETATION: Experimentally induced hyperinsulinaemia is not correlated with cardiac vagal control or HR when adjusting for age, BMI and insulin sensitivity index. Our findings suggest that exposure to a GLP-1 during hyperglycaemia leads to a small acute increase in HR but not to an acute decrease in cardiac vagal control. 23280997 Electrophoretic deposition of CdSe/ZnS quantum dots for light-emitting devices. The electrophoretic deposition of thin films of colloidal quantum dots is an alternative to spin-casting and printing for large-area, high-throughput processing of quantum-dot (QD) optoelectronics. In this study, QD light-emitting diodes (QD-LEDs) fabricated with electrophoretically deposited films of CdSe/ZnS core/shell QDs are demonstrated for the first time. 23097351 Antiulcerogenic activities of the extracts and isolated flavonoids of Euphorbia cuneata Vahl. The total alcohol extracts of Euphorbia cuneata Vahl.(Euphorbiaceae) were screened for antiulcerogenic activity using an ethanol-induced ulcer model at doses of 125, 250 and 500 mg/kg. The extracts possessed antiulcerogenic activity in a dose-dependent manner. Four flavonoidal compounds were isolated and identified as naringenin, aromadendrin, apigenin and 4'-O-methoxy-luteolin-7-O-rhamnoglucoside, each demonstrating antiulcerogenic activity with curative ratios ranging from 75.78% to 88.23%. In addition, the alcohol extracts and isolated compounds were shown to scavenge the 1,1-diphenyl,2-picrylhydrazyl radical by different ratio, with the most effective being 4'-O-methoxy-luteolin-7-O-rhamnoglucoside (91.14%). The antioxidant activity of the alcohol extracts and the isolated compounds may explain the antiulcerogenic properties. No side effects were observed on either liver or kidney functions. 23520132 Effects of Prior Intensive versus Conventional Therapy and History of Glycemia on Cardiac Function in Type 1 Diabetes in the DCCT/EDIC. Intensive diabetes therapy reduces the prevalence of coronary calcification and progression of atherosclerosis, and the risk of cardiovascular disease events in the DCCT/EDIC study. The effects of intensive therapy on measures of cardiac function and structure and their association with glycemia have not been explored in type 1 diabetes (T1DM). We assess whether intensive treatment compared to conventional treatment during the DCCT led to differences in these parameters during EDIC. After 6.5 years of intensive versus conventional therapy in the DCCT, and 15 years additional follow-up in EDIC, left ventricular indices were measured by cardiac magnetic resonance (CMR) imaging in 1017 of the 1371 members of the DCCT cohort. There were no differences between the DCCT intensive versus conventional treatment in end diastolic volume, end systolic volume, stroke volume, cardiac output, left ventricular mass, ejection fraction, LV mass/EDV, nor aortic distensibility. Mean DCCT/EDIC HbA1c over time was associated with EDV, SV, CO, LVmass, LVmass/EDV, and AD. These associations persisted after adjustment for CVD risk factors. Cardiac function and remodeling in T1DM assessed by CMR in the EDIC cohort was associated with prior glycemic exposure, but there was no effect of intensive versus conventional treatment during the DCCT on cardiac parameters. 23255384 Structural and stereochemical studies of hydroxyanthraquinone derivatives from the endophytic fungus Coniothyrium sp. Four known hydroxyanthraquinones (1-4) together with four new derivatives having a tetralone moiety, namely coniothyrinones A-D (5-8), were isolated from the culture of Coniothyrium sp., an endophytic fungus isolated from Salsola oppostifolia from Gomera in the Canary Islands. The structures of the new compounds were elucidated by detailed spectroscopic analysis and comparison with reported data. The absolute configurations of coniothyrinones A (5), B (6), and D (8) were determined by TDDFT calculations of CD spectra, allowing the determination of the absolute configuration of coniothyrinone C (7) as well. Coniothyrinones A (5), B (6), and D (8) could be used as ECD reference compounds in the determination of absolute configuration for related tetralone derivatives. This is the first report of anthraquinones and derivatives from an isolate of the genus Coniothyrium sp. These compounds showed inhibitory effects against the fungus Microbotryum violaceum, the alga Chlorella fusca, and the bacteria Escherichia coli and Bacillus megaterium. 23333639 Exposure to 1800 MHz radiofrequency electromagnetic radiation induces oxidative DNA base damage in a mouse spermatocyte-derived cell line. Whether exposure to radiofrequency electromagnetic radiation (RF-EMR) emitted from mobile phones can induce DNA damage in male germ cells remains unclear. In this study, we conducted a 24h intermittent exposure (5 min on and 10 min off) of a mouse spermatocyte-derived GC-2 cell line to 1800 MHz Global System for Mobile Communication (GSM) signals in GSM-Talk mode at specific absorption rates (SAR) of 1 W/kg, 2 W/kg or 4 W/kg. Subsequently, through the use of formamidopyrimidine DNA glycosylase (FPG) in a modified comet assay, we determined that the extent of DNA migration was significantly increased at a SAR of 4 W/kg. Flow cytometry analysis demonstrated that levels of the DNA adduct 8-oxoguanine (8-oxoG) were also increased at a SAR of 4 W/kg. These increases were concomitant with similar increases in the generation of reactive oxygen species (ROS); these phenomena were mitigated by co-treatment with the antioxidant α-tocopherol. However, no detectable DNA strand breakage was observed by the alkaline comet assay. Taking together, these findings may imply the novel possibility that RF-EMR with insufficient energy for the direct induction of DNA strand breaks may produce genotoxicity through oxidative DNA base damage in male germ cells. 23313245 Novel diaryl ureas with efficacy in a mouse model of malaria. Exploration of triclosan analogs has led to novel diaryl ureas with significant potency against in vitro cultures of drug-resistant and drug-sensitive strains of the human malaria parasite Plasmodium falciparum. Compound 18 demonstrated EC(50) values of 37 and 55 nM versus in vitro cultured parasite strains and promising in vivo efficacy in a Plasmodium berghei antimalarial mouse model, with >50% survival at day 31 post-treatment when administered subcutaneously at 256 mg/kg. This series of compounds provides a chemical scaffold of novel architecture, as validated by cheminformatics analysis, to pursue antimalarial drug discovery efforts. 23575765 Solution processed zinc oxide nanopyramid/silver nanowire transparent network films with highly tunable light scattering properties. Metal nanowire transparent networks are promising replacements to indium tin oxide (ITO) transparent electrodes for optoelectronic devices. While the transparency and sheet resistance are key metrics for transparent electrode performance, independent control of the film light scattering properties is important to developing multifunctional electrodes for improved photovoltaic absorption. Here we show that controlled incorporation of ZnO nanopyramids into a metal nanowire network film affords independent, highly tunable control of the scattering properties (haze) with minimal effects on the transparency and sheet resistance. Varying the zinc oxide/silver nanostructure ratios prior to spray deposition results in sheet resistances, transmission (600 nm), and haze (600 nm) of 6-30 Ω □(-1), 68-86%, and 34-66%, respectively. Incorporation of zinc oxide nanopyramid scattering agents into the conducting nanowire mesh has a negligible effect on mesh connectivity, providing a straightforward method of controlling electrode scattering properties. The decoupling of the film scattering power and electrical characteristics makes these films promising candidates for highly scattering transparent electrodes in optoelectronic devices and can be generalized to other metal nanowire films as well as carbon nanotube transparent electrodes. 22935104 In silico drug repositioning: what we need to know. Drug repositioning, exemplified by sildenafil and thalidomide, is a promising way to explore alternative indications for existing drugs. Recent research has shown that bioinformatics-based approaches have the potential to offer systematic insights into the complex relationships among drugs, targets and diseases necessary for successful repositioning. In this article, we propose the key bioinformatics steps essential for discovering valuable repositioning methods. The proposed steps (repurposing with a purpose, repurposing with a strategy and repurposing with confidence) are aimed at providing a repurposing pipeline, with particular focus on the proposed Drugs of New Indications (DNI) database, which can be used alongside currently available resources to improve in silico drug repositioning. 23086197 NADPH-cytochrome P450 oxidoreductase: roles in physiology, pharmacology, and toxicology. This is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 2012 meeting in San Diego, California, on April 25, 2012. The symposium speakers summarized and critically evaluated our current understanding of the physiologic, pharmacological, and toxicological roles of NADPH-cytochrome P450 oxidoreductase (POR), a flavoprotein involved in electron transfer to microsomal cytochromes P450 (P450), cytochrome b(5), squalene mono-oxygenase, and heme oxygenase. Considerable insight has been derived from the development and characterization of mouse models with conditional Por deletion in particular tissues or partial suppression of POR expression in all tissues. Additional mouse models with global or conditional hepatic deletion of cytochrome b(5) are helping to clarify the P450 isoform- and substrate-specific influences of cytochrome b(5) on P450 electron transfer and catalytic function. This symposium also considered studies using siRNA to suppress POR expression in a hepatoma cell-culture model to explore the basis of the hepatic lipidosis phenotype observed in mice with conditional deletion of Por in liver. The symposium concluded with a strong translational perspective, relating the basic science of human POR structure and function to the impacts of POR genetic variation on human drug and steroid metabolism. 23153456 IFNα converts IL-22 into a cytokine efficiently activating STAT1 and its downstream targets. Besides their antiviral activity, type I Interferons (IFN) display context-specific immunomodulation. In contrast to long-known IFNα/β, Interleukin (IL)-22 is an anti-bacterial, largely tissue protective cytokine that recently gained attention. Herein, cellular IFNα/IL-22 interactions are investigated. We report that pre-conditioning of epithelial cells with IFNα initiated dramatic changes in IL-22 signaling normally dominated by signal transducer and activator of transcription (STAT)-3. Specifically, by using human DLD1 colon epithelial/carcinoma cells we demonstrate that, upon IFNα, IL-22 converts into a cytokine robustly activating STAT1 and its downstream pro-inflammatory targets CXCL9, CXCL10, and inducible nitric oxide synthase (iNOS). Accordingly, only after IFNα pre-incubation was IL-22-induced STAT1 binding to the CXCL10 promoter detectable. Using the viral mimic polyinosinic:polycytidylic acid and the IFNα/β antagonist B18R we furthermore demonstrate the capability of endogenous IFN to promote IL-22-induced STAT1 activation and expression of CXCL10. IL-22-induced STAT1 activation subsequent to IFNα priming became likewise apparent in human Caco2 colon epithelial/carcinoma cells, HepG2 hepatoma cells, and primary keratinocytes. Current observations may relate to characteristics of IFNα/β in clinical therapy and expose margins of tissue protection by IL-22 application. 23169387 Excited-state proton coupled charge transfer modulated by molecular structure and media polarization. Charge and proton transfer reactions in the excited states of organic dyes can be coupled in many different ways. Despite the complementarity of charges, they can occur on different time scales and in different directions of the molecular framework. In certain cases, excited-state equilibrium can be established between the charge-transfer and proton-transfer species. The interplay of these reactions can be modulated and even reversed by variations in dye molecular structures and changes of the surrounding media. With knowledge of the mechanisms of these processes, desired rates and directions can be achieved, and thus the multiple emission spectral features can be harnessed. These features have found versatile applications in a number of cutting-edge technological areas, particularly in fluorescence sensing and imaging. 23406469 Cell type determines the light-induced endosomal escape kinetics of multifunctional mesoporous silica nanoparticles. We investigated uptake and individual endosome lysis events in fibroblast, normal, and carcinoma cell lines using a colloidal mesoporous silica (CMS) nanoparticle (NP)-based reporter system with a covalently attached photosensitizer. Endosome lysis was induced through the activation of protoporphyrin IX (PpIX). Surprisingly, this release-on-demand system resulted in more broadly distributed lysis times than expected, particularly for Renca, a renal carcinoma cell line. An analysis of the NP load per endosome, endosome size, and uptake characteristics indicate that Renca cells not only take up a lower amount of NPs in comparison with the fibroblast cells but also have larger endosomes and a lower NP load per endosome. We then created a stochastic model detailing steps downstream of uptake to understand how much factors that cannot be directly measured, such as variations in the PpIX load per NP, affect the lysis time distributions. Model results indicate that the distributions are primarily determined by the endosome properties, rather than variations across NPs. 23268927 Association between beta cell function and future glycemic control in patients with type 2 diabetes. The aim of this study was to clarify the association between C-peptide immunoreactivity (CPR), a marker of beta cell function, and future glycemic control in patients with type 2 diabetes. We conducted a retrospective analysis of 513 consecutive patients with type 2 diabetes who were admitted to our hospital between 2000 and 2007 and followed up for 2 years. Serum and urinary CPR levels were measured during admission, and CPR index was calculated as the ratio of CPR to plasma glucose. The associations between these markers at baseline and glycemic control after 2 years were assessed by means of logistic regression models. After 2 years, 167 patients (32.6%) showed good glycemic control (HbA1c <6.9%). Baseline serum and urinary CPR indices were significantly associated with good glycemic control after 2 years, and the postprandial CPR to plasma glucose ratio (postprandial CPR index) showed the strongest association (odds ratio (OR) 1.29, 95% confidence interval (CI) 1.12-1.50, P = 0.001) among CPR indices. Multivariate analyses showed consistent results (OR 1.23, 95%CI 1.03-1.48, P = 0.021). In conclusion, preserved beta cell function at baseline was associated with better glycemic control thereafter in patients with type 2 diabetes. 23259536 Photonic modulation of electron transfer with switchable phase inversion. Photochromes may be reversibly photoisomerized between two metastable states and their properties can influence, and be influenced by, other chromophores in the same molecule through energy or electron transfer. In the photochemically active molecular tetrad described here, a porphyrin has been covalently linked to a fullerene electron acceptor, a quinoline-derived dihydroindolizine photochrome, and a dithienylethene photochrome. The porphyrin first excited singlet state undergoes photoinduced electron transfer to the fullerene to generate a charge-separated state. The quantum yield of charge separation is modulated by the two photochromes: one isomer of each quenches the porphyrin excited state, reducing the quantum yield of electron transfer to near zero. Interestingly, when the molecule is illuminated with white light, the quantum yield decreases as the white light intensity is increased, generating an out-of-phase response of the quantum yield to white light. However, when the same experiment is performed in the presence of additional, steady-state UV illumination, a phase inversion occurs. The quantum yield of electron transfer now increases with increasing white light intensity. Such effects illustrate emergent complexity in a relatively simple system and could find applications in molecular logic, photochemical labeling and drug delivery, and photoprotection for artificial photosynthetic molecules. The photochemistry leading to this behavior is discussed. 23411183 Quality enhancement in refrigerated red drum (Sciaenops ocellatus) fillets using chitosan coatings containing natural preservatives. The present work was undertaken to examine the influence of grape seed extract (GS) and tea polyphenols (TP), as natural preservatives, combined with chitosan (Ch), on the quality of red drum (Sciaenops ocellatus) fillets during refrigerated storage. Two different treatments (Ch+GS and Ch+TP) and a control were prepared. The samples were stored (4 ± 1°C) for 20 days and the sampling was done at 0, 4, 8, 12, 16, 20 days. Microbiological, physicochemical and sensory attributes were periodically assessed. The results indicated that the two pretreatments could more effectively maintain quality and could extend the shelf life by 6-8 days compared with the control group during refrigerated storage. 23609109 Application of Medicinal Plants in Maternal Healthcare and Infertility: A South African Perspective. Plants have played significant roles as medicine during pregnancy, birth, and postpartum care in many rural areas of the world. In addition to this, plants have been used for centuries to treat infertility and related reproduction problems. The aim of this paper was to review the current status of plant species used in maternal healthcare, including infertility, in South Africa, in terms of scientific evaluation for efficacy and safety. In addition to this, the role of medicinal plants as a tool in achieving the MDG5 of reducing maternal mortality by 2015 was evaluated. A search was done with the aid of Google Scholar, PubMed, Science Direct, peer-reviewed papers, and books, using keywords such as child birth, labour pain, maternal health, maternal mortality, menstrual pains, and postpartum. The plants listed in the different research articles were classified according to their use and the target effect of a plant extract or compound on reproductive function. Eighty-four plant species were found to be used to treat infertility and related problems. Twenty plant species are used during pregnancy, while 26 plant species are used to ease childbirth. For postpartum healing and any problems after childbirth, nine plant species were recorded. Unhealthy pregnancy and birth complications are among the factors that contribute to the loss of cognitive potential in the developing world's children, condemning them to impoverished lives. The best way to keep a country poor is to rob its children of their full developmental potential. In this respect, medicinal plants play a significant role in reducing maternal mortality and ensuring the birth of healthy children. 23369344 Endothelium-dependent vasodilatation effects of the essential oil from Fructus alpiniae zerumbet (EOFAZ) on rat thoracic aortic rings in vitro. Fructus Alpiniae Zerumbet (FAZ) is an herb widely used to treat vascular disorders in Guizhou province, China, the essential oil has been identified as one of it vasodilation effect active components, and especial, the composition was significantly difference from the leaves. Vasodilation effects and mechanism of essential oil from FAZ (EOFAZ) were investigated. The EOFAZ showed significant vasodilation effect on endothelium-with rat thoracic aortic rings preincubated with norepinephrine (NE, 1.0μM) or KCl (60mM) in a concentration-dependent manner (1.14-72.96μg/ml). The non-selective nitric oxide synthase inhibitor l-NAME, as well as the soluble guanylate cyclase inhibitor MB, attenuated the relaxation of EOFAZ in endothelium-intact rat thoracic aortic rings. However, there were not significantly affected the vasodilation effects pretreated with cyclooxygenase inhibition by indomethacin (Indo) or β-noradrenergic inhibition by propranolol (Prop). The present results first demonstrated that vasodilation effect of EOFAZ depending upon the endothelium and concentration, and the mechanism involvement of NOS-cGMP system. In contrast, prostacyclin and β-adrenoceptor may not be associated with EOFAZ-induced vasorelaxation. 23458617 MDM2 Non-Genotoxic Inhibitors as Innovative Therapeutic Approaches for the Treatment of Pediatric Malignancies. Since the discovery of p53 as "guardian of the genome" , a large number of efforts have been put in place in order to find molecular strategies aiming to restore p53 wild-type functions, particularly in the light of the fact that its pathway results ineffective in most tumors even though they have non-mutated p53. In this context, pediatric cancers, that are mostly p53 wild-type at the time of diagnosis, represent an ideal target for such therapeutic approach. Within the several mechanisms and proteins ruling p53 activity, the murine double minute 2 (MDM2) is its crucial negative regulator, frequently found overexpressed in p53-wild-type tumors. The development of new technologies such as nuclear magnetic resonance structure analyses, computational structure-based design studies, and library peptides screening have recently led to the discovery and characterization of a large number of compounds belonging to different chemical families that are able to target the interaction p53-MDM2, rescuing the p53 wild-type pathway with an overall pro-apoptotic and anticancer activity. Within the preclinical assessment of these molecules, the cis-imidazoline analogue Nutlin-3 has definitely attracted great interest for its in vitro and in vivo antitumor activity in several pediatric cancer models, either as single agent on in combination with standard chemotherapy. In this light, the aim of this review is to summarize the main preclinical evidences of the potential of MDM2 inhibitors for the treatment of childhood cancers and the key suggestions coming from their assessment in the treatment of adult cancers as proof of concept for future pediatric clinical studies. 23243659 Sponge-like Ni(OH)2-NiF2 composite film with excellent electrochemical performance. Sponge-like porous Ni(OH)(2)-NiF(2) composite (PNC) film was successfully synthesized by the anodization of nickel in a NH(4)F and H(3)PO(4) containing electrolyte. Thanks to the good conductivity and the highly porous architecture, PNC exhibited not only a high specific capacitance, but also a superior rate capability and a good cyclability (2090 F g(-1) at 10 mV s(-1), capacitance >1200 F g(-1) at 100 A g(-1) after 2000 cycles). Anodization of nickel is proven to be fast and facile and can be easily scaled up. The method described here is promising for the fabrication of supercapacitor electrodes with excellent performance. 23313638 Total synthesis of bicyclic depsipeptides spiruchostatins C and D and investigation of their histone deacetylase inhibitory and antiproliferative activities. The bicyclic depsipeptide histone deacetylase (HDAC) inhibitors spiruchostatins C and D were synthesized for the first time in a highly convergent and unified manner. The method features the amide coupling of a D-leucine-D-cysteine- or D-valine-D-cysteine-containing segment with a D-alanine- or D-valine-containing segment to directly assemble the corresponding seco-acids, key precursors of macrolactonization. The HDAC inhibitory assay and cell-growth inhibition analysis of the synthesized depsipeptides determined the order of potency of spiruchostatins A-D in comparison with the clinically approved depsipeptide FK228 (romidepsin). Novel aspects of structure-activity relationships (SAR) were revealed. 23426982 Theoretical Study on the Photodegradation Mechanism of Nona-BDEs in Methanol. Polybrominated diphenyl ethers (PBDEs) have received special environmental concern due to their potential toxicity to humans and wildlife worldwide, however, it is difficult to reveal their dominant photochemical degradation pathways by experiment. We explored the reaction mechanisms of photochemical degradation-debromination of three nona-BDEs in methanol using theoretical calculations, in which time-dependent density functional theory (TDDFT) combined with the polarizable continuum (PCM) model is applied. The selectivity of debromination was studied, and the major octa-BDE products photochemically debrominated from nona-BDEs were identified. We find that the debromination reaction results from the electronic transitions from π to σ* orbitals when nona-BDEs are exposed to UV-light in the sunlight region, at which point the two low-lying excited states for each nona-BDE are πσ*(5Br) and πσ*(4Br), which correlate to the σ* orbitals located on the penta-Br and tetra-Br substituted phenyls, respectively. Our calculations indicate that each nona-BDE may degrade to form three kinds of octa-BDE products via the πσ*(5Br) state, whereas only one kind of octa-BDEs can be formed via the πσ*(4Br) state. Our calculations can interpret the recent experiments successfully. 23209192 Cotinine in human placenta predicts induction of gene expression in fetal tissues. Maternal cigarette smoking during pregnancy is associated with increased risk of perinatal morbidity and mortality. However, the mechanisms underlying adverse birth outcomes following prenatal exposure to cigarette smoke remain unknown due, in part, to the absence or unreliability of information regarding maternal cigarette smoke exposure during pregnancy. Our goal was to determine if placental cotinine could be a reliable biomarker of fetal cigarette smoke exposure during pregnancy. Cotinine levels were determined in placentas from 47 women who reported smoking during pregnancy and from 10 women who denied cigarette smoke exposure. Cotinine levels were significantly higher in placentas from women reporting cigarette smoking (median = 27.2 ng/g) versus women who reported no smoke exposure (2.3 ng/g, P < 0.001). Receiver operating characteristic curve analysis identified an optimal cut point of 7.5 ng/g (sensitivity = 78.7%, specificity = 100%) to classify placenta samples from mothers who smoked versus those from mothers who did not. Among 415 placentas for which maternal cigarette smoking status was unavailable, 167 had cotinine levels > 7.5 ng/g and would be considered positive for cigarette smoke exposure. Data from quantitative reverse-transcription polymerase chain reaction analyses demonstrated that in utero cigarette smoke exposure predicted by cotinine in placenta is associated with changes in the expression of xenobiotic-metabolizing enzymes in fetal tissues. CYP1A1 mRNA in fetal lung and liver tissue and CYP1B1 mRNA in fetal lung tissue were significantly induced when cotinine was detected in placenta. These findings indicate that cotinine in placenta is a reliable biomarker for fetal exposure and response to maternal cigarette smoking during pregnancy. 23384446 The effect of inorganic arsenic on endothelium-dependent relaxation: Role of NADPH oxidase and hydrogen peroxide. Chronic arsenic ingestion predisposes to vascular disease, but underlying mechanisms are poorly understood. In the present study we have analyzed the effects of short-term arsenite exposure on vascular function and endothelium-dependent relaxation. Endothelium-dependent relaxations, nitric oxide (NO) and endothelium derived hyperpolarizing factor (EDHF)-type, were studied in rabbit iliac artery and aortic rings using the G protein-coupled receptor agonist acetylcholine (ACh) and by cyclopiazonic acid (CPA), which promotes store-operated Ca(2+) entry by inhibiting the endothelial SERCA pump. Production of reactive oxygen species (ROS) in the endothelium of rabbit aortic valve leaflets and endothelium-denuded RIA and aortic rings was assessed by imaging of dihydroethidium. In the iliac artery, exposure to 100μM arsenite for 30min potentiated EDHF-type relaxations evoked by both CPA and ACh. Potentiation was prevented by catalase, the catalase/superoxide dismutase mimetic manganese porphyrin and the NADPH oxidase inhibitor apocynin. By contrast in aortic rings, that exhibited negligible EDHF-type responses, endothelium-dependent NO-mediated relaxations evoked by CPA and ACh were unaffected by arsenite. Arsenite induced apocynin-sensitive increases in ROS production in the aortic valve endothelium, but not in the media and adventitia of the iliac artery and aorta. Our results suggest that arsenite can potentiate EDHF-type relaxations via a mechanism that is dependent on hydrogen peroxide, thus demonstrating that dismutation of the superoxide anion generated by NADPH oxidase can potentially offset loss of NO bioavailability under conditions of reduced eNOS activity. By contrast, selective increases in endothelial ROS production following exposure to arsenite failed to modify relaxations mediated by endogenous NO. 23122116 Quantitative analysis of fungicide azoxystrobin in agricultural samples with rapid, simple and reliable monoclonal immunoassay. This work presents analytical performance of a kit-based direct competitive enzyme-linked immunosorbent assay (dc-ELISA) for azoxystrobin detection in agricultural products. The dc-ELISA was sufficiently sensitive for analysis of residue levels close to the maximum residue limits. The dc-ELISA did not show cross-reactivity to other strobilurin analogues. Absorbance decreased with the increase of methanol concentration in sample solution from 2% to 40%, while the standard curve became most linear when the sample solution contained 10% methanol. Agricultural samples were extracted with methanol, and the extracts were diluted with water to 10% methanol adequate. No significant matrix interference was observed. Satisfying recovery was found for all of spiked samples and the results were well agreed with the analysis with liquid chromatography. These results clearly indicate that the kit-based dc-ELISA is suitable for the rapid, simple, quantitative and reliable determination of the fungicide. 23495161 Two novel potent α-amylase inhibitors from the family of acarviostatins isolated from the culture of Streptomyces coelicoflavus ZG0656. Two novel aminooligosaccharides were separated from the culture filtrate of Streptomyces coelicoflavus ZG0656. Their chemical structures were determined by acidic hydrolysis, electrospray-ionization tandem mass spectrometry (ESI-MS/MS), and NMR spectroscopy. The compounds were named acarviostatins III0(-1) and III23 according to the nomenclature of this group of metabolites. The two novel acarviostatins were both mixed noncompetitive inhibitors of porcine pancreatic α-amylase (PPA). The inhibition constants (K(i)) for acarviostatins III0(-1) and III23 were 0.009 and 0.026 μM, respectively, 151 and 52 times more potent than acarbose. 23266731 Wound-healing plants from TCM: in vitro investigations on selected TCM plants and their influence on human dermal fibroblasts and keratinocytes. Wound-healing plants from Traditional Chinese Medicine and described for wound healing in the Pharmacopoeia of People's Republic of China (2005 ed.) were investigated by in vitro bioassay on human skin cells. Therefore water and EtOH-water extracts (6:4, v/v) from 12 plants were tested on human primary dermal fibroblasts (pNHDF) and human HaCaT keratinocyte cell line by quantification of cell viability (MTT assay) and cellular proliferation (BrdU incorporation ELISA). No functional activity was found for extracts from Achyranthis bidentatae rhizoma, Cimicifugae rhizoma, Corydalis rhizoma, Gardeniae fructus, Houttuyniae herba, Lonicerae japonicae caulis, Paeoniae rubrae radix and Rehmanniae radix. Extracts from Notoginseng radix et rhizoma, Angelicae sinensis radix and Lonicerae japonicae flos showed moderate activity, while extracts from Moutan cortex (the root bark of Paeonia suffruticosa Andr., Ranunculaceae) increased cell viability of HaCaT keratinocytes and pNHDF in a dose-dependent manner significantly. Bioassay-guided fractionation yielded paeonol 1, the flavan-3-ols catechin 2 and epicatechin-3-O-gallate 3, the dimeric proanthocyanidin epicatechin-(4β→8)-catechin 4, a mixture of trigalloyl-glucoses 5 and 1,2,3,4,6-penta-O-galloyl-β-d-glucose (PGG) 6. The proanthocyanidin-containing fractions as well as PGG-containing fractions contributed substantially to the stimulating effects. Especially PGG-containing fractions enhanced cell viability and cellular proliferation of HaCaT keratinocytes at concentration of 100nM. From these data we conclude that indication claims for TCM herbal materials must be carefully investigated in order to establish evidence-driven use of such plants. In case of Moutan cortex skin cell stimulating effects have clearly been proven. These effects can be related to the polyphenol fractions of condensed and hydrolysable tannins. 23380082 Use of the Combination Index to determine interactions between plant-derived phenolic acids on hepatotoxicity endpoints in human and rat hepatoma cells. The beneficial or adverse effects of isolated phytochemicals are not always concordant with effects of the botanical dietary supplements from which they were derived. This disparity could be due to interactions between the various phytochemicals present in the whole plant. The phenolic acids, rosmarinic acid (RA), caffeic acid (CA) and ferulic acid (FA) are widely present in foods and dietary supplements, and they are assumed to exert various beneficial biological effects. However, there is little data on the potential biological interactions of these three phenolic acids which commonly occur together and are linked metabolically. In the present study, liver toxicity of the three phenolic acids was assessed on the three compounds singly and in various binary and one ternary combinations. A series of in vitro endpoints relevant to liver toxicity were evaluated in both a human (HepG2/C3A) and rat (MH1C1) hepatocyte cell line. The Combination Index (CI) was calculated for each endpoint from both the concentration responses of the single compounds and the responses of the various binary and ternary mixtures. Both synergistic and antagonistic interactions were observed for some endpoints and some combinations of test agents. Interactions were most prevalent in measures of oxidative stress and cytochrome P450 activities in both cell types. There was only a 53% concordance between the rat and human cells which may be suggestive of species differences. The data suggest an approach for better characterizing the beneficial or adverse effects of complex botanical products through evaluation of interactions between individual phytochemical components. 23266452 N-acetylgalactosamine functionalized mixed micellar nanoparticles for targeted delivery of siRNA to liver. Due to its efficient and specific gene silencing ability, RNA interference has shown great potential in the treatment of liver diseases. However, achieving in vivo delivery of siRNA to critical liver cells remains the biggest obstacle for this technique to be a real clinic therapeutic modality. Here, we describe a promising liver targeting siRNA delivery system based on N-acetylgalactosamine functionalized mixed micellar nanoparticles (Gal-MNP), which can efficiently deliver siRNA to hepatocytes and silence the target gene expression after systemic administration. The Gal-MNP were assembled in aqueous solution from mixed N-acetylgalactosamine functionalized poly(ethylene glycol)-b-poly(ε-caprolactone) and cationic poly(ε-caprolactone)-b-poly(2-aminoethyl ethylene phosphate) (PCL-b-PPEEA); the properties of nanoparticles, including particle size, zeta potential and the density of poly(ethylene glycol) could be easily regulated. The hepatocyte-targeting effect of Gal-MNP was demonstrated by significant enriching of fluorescent siRNA in primary hepatocytes in vitro and in vivo. Successful down-regulation of liver-specific apolipoprotein B (apoB) expression was achieved in mouse liver, at both the transcriptional and protein level, following intravenous injection of Gal-MNP/siapoB to BALB/c mice. Systemic delivery of Gal-MNP/siRNA did not induce the innate immune response or positive hepatotoxicity. The results of this study suggested therapeutic potential for the Gal-MNP/siRNA system in liver disease. 23282101 Catalytic enantioselective cyclization and C3-fluorination of polyenes. (Xylyl-phanephos)Pt(2+) in combination with XeF(2) mediates the consecutive diastereoselective cation-olefin cyclization/fluorination of polyene substrates. Isolated yields were typically in the 60-69% range while enantioselectivities reached as high as 87%. The data are consistent with a stereoretentive fluorination of a P(2)Pt-alkyl cation intermediate. 23287056 Synthesis and biological evaluation of new N-alkylcarbazole derivatives as STAT3 inhibitors: preliminary study. The signalling pathway of Janus tyrosine Kinases-Signal Transducers and Activators of Transcription (JAK-STAT) is activated by a number of cytokines, hormones (GH, erythropoietin and prolactin), and growth factors. JAK-STAT signalling is involved in regulation of cell proliferation, differentiation and apoptosis. These activities are due to different members of JAK-STAT family consisting of: JAK1, JAK2, JAK3, Tyk2 and STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6. Recent studies suggest a key role for STAT family proteins, in particular for STAT3, in selectively inducing and maintaining a pro-carcinogenic inflammatory microenvironment, that promote tumour cells transformation. Moreover, a striking correlation between cancer development/progression and STAT3 persistent activation exists, probably due to STAT3 promoting of the pro-oncogenic inflammatory pathways, like NF-kB, IL-6 and JAK family kinases. Recent study demonstrated that carbazoles can inhibit STAT3 mediated transcription. From these evidences, STAT3 represents a therapeutic target, so we have synthesized a new set of N-alkylcarbazole derivatives substituted in positions 2, 4 and 6, to evaluate their activity on STAT3. Some of these compounds showed an interesting activity as STAT3 selective inhibitors; in particular, compounds 9a 9b and 9c revealed to inhibit the STAT3 activation for the 50%, 90% and 95%, respectively. 23343172 Size-matching effect on inorganic nanosheets: control of distance, alignment, and orientation of molecular adsorption as a bottom-up methodology for nanomaterials. We have been investigating complexes composed of nanolayered materials with anionic charges such as clay nanosheets and dye molecules such as cationic porphyrins. It was found that the structure of dye assembly on the layered materials can be effectively controlled by the use of electrostatic host-guest interaction. The intermolecular distance, the molecular orientation angle, the segregation/integration behavior, and the immobilization strength of the dyes can be controlled in the clay-dye complexes. The mechanism to control these structural factors has been discussed and was established as a size-matching effect. Unique photochemical reactions such as energy transfer through the use of this methodology have been examined. Almost 100% efficiency of the energy-transfer reaction was achieved in the clay-porphyrin complexes as a typical example for an artificial light-harvesting system. Control of the molecular orientation angle is found to be useful in regulating the energy-transfer efficiency and in preparing photofunctional materials exhibiting solvatochromic behavior. Through our study, clay minerals turned out to serve as protein-like media to control the molecular position, modify the properties of the molecule, and provide a unique environment for chemical reactions. 23330542 PXR antagonists and implication in drug metabolism. Adopted orphan nuclear receptor (NR), pregnane X receptor (PXR), plays a central role in the regulation of xeno- and endobiotic metabolism. Since the discovery of the functional role of PXR in 1998, there is evolving evidence for the role of PXR agonists in abrogating metabolic pathophysiology (e.g., cholestasis, hypercholesterolemia, and inflammation). However, more recently, it is clear that PXR is also an important mediator of adverse xeno- (e.g., enhances acetaminophen toxicity) and endobiotic (e.g., hepatic steatosis) metabolic phenotypes. Moreover, in cancer therapeutics, PXR activation can induce drug resistance, and there is growing evidence for tissue-specific enhancement of the malignant phenotype. Thus, in these instances, there may be a role for PXR antagonists. However, as opposed to the discovery efforts for PXR agonists, there are only a few antagonists described. The mode of action of these antagonists (e.g., sulforaphane) remains less clear. Our laboratory efforts have focused on this question. Since the original discovery of azoles analogs as PXR antagonists, we have preliminarily defined an important PXR antagonist pharmacophore and developed less-toxic PXR antagonists. In this review, we describe our published and unpublished findings on recent structure-function studies involving the azole chemical scaffold. Further work in the future is needed to fully define potent, more-selective PXR antagonists that may be useful in clinical application. 23562270 Social information signaling by neurons in primate striatum. Social decisions depend on reliable information about others. Consequently, social primates are motivated to acquire information about the identity, social status, and reproductive quality of others [1]. Neurophysiological [2] and neuroimaging [3, 4] studies implicate the striatum in the motivational control of behavior. Neuroimaging studies specifically implicate the ventromedial striatum in signaling motivational aspects of social interaction [5]. Despite this evidence, precisely how striatal neurons encode social information remains unknown. Therefore, we probed the activity of single striatal neurons in monkeys choosing between visual social information at the potential expense of fluid reward. We show for the first time that a population of neurons located primarily in medial striatum selectively signals social information. Surprisingly, representation of social information was unrelated to simultaneously expressed social preferences. A largely nonoverlapping population of neurons that was not restricted to the medial striatum signaled information about fluid reward. Our findings demonstrate that information about social context and nutritive reward are maintained largely independently in striatum, even when both influence decisions to execute a single action. 22834411 The alignment of barium ferrite nanoparticles from their suspensions in electric and magnetic fields. The alignment of plate-like barium ferrite nanoparticles, with diameters of 10-350 nm and thicknesses of 3-10 nm, in electric and/or magnetic fields was studied. Stable suspensions were prepared in 1-butanol with dodecylbenzenesulphonic acid as a surfactant. The deposits were produced from the suspensions with classic electrophoretic deposition, electrophoretic deposition in a magnetic field, and with drying in a magnetic field. The experiments, supported by theoretical calculations, show that the alignment of the nanoplates in the deposits was determined by the interplay between the hydrodynamic, electric, and magnetic forces. The preferential alignment of the nanoplates in plane with the substrate coincided with their magnetic orientation, and it increased with the shape anisotropy of the particles. The deposits were sintered at 1150 °C for 5 h to obtain ceramic films, which showed a magnetic orientation up to 90%. 23443405 Low temperature solution-processed high performance photodiode based on Si-ZnO core-shell structure. Radial heterojunction photodiodes based on a silicon nanowire arrays (SiNWs)-zinc oxide (ZnO) core-shell structure is demonstrated in this report. The heterojunction can be constructed by spin-coating ZnO nanoparticles onto SiNWs and a low temperature post-annealing process (<270 °C). The photodiode displays typical diode rectifying characteristics with an ideality factor of as low as 1.28, and shows an excellent photoresponse in both visible and near infrared regions in which a peak value of 0.54 A/W at zero bias was attained. The sensitivity is superior to that of previously reported devices fabricated with vacuum-deposition methods. In contrast, the planar silicon-ZnO junction only displays the peak photoresponsivity of 0.34 A/W. The superior performance of radial junction is ascribed to the highlight-harvesting capability, large interfacial area and efficient charge carrier collection arising from the core (SiNWs)-shell (ZnO) structure. Here, high temperature processes are dispensable by using facile solution-processed techniques, which avoid thermal minority lifetime degradation of silicon and simplify the fabrication process of the photodiodes. 23200004 Determination of mercury in rice by MSFIA and cold vapour atomic fluorescence spectrometry. In the present paper the use of a MSFIA system for determination of mercury in rice by cold vapour atomic fluorescence spectrometry (CV AFS) is proposed. The sample digestion is performed in a microwave oven using nitric acid and hydrogen peroxide. The experimental conditions for vapour generation were determined using a full two-level factorial design involving the following factors: nitric acid and tin chloride concentrations and sample flow rate. Employing the conditions optimised, the method allows the determination of mercury using the external calibration technique with aqueous standards. The reached limits of detection and quantification were 0.48 and 1.61 ng g⁻¹ respectively, and the precision (as relative standard deviation) was 3.28% and 1.56% for rice samples with a mercury content of 3.63 and 5.81 ng g⁻¹, respectively. The method accuracy was confirmed analysing a certified reference material of rice flour furnished by National Institute of Standard and Technology. The interference of nitrous acid and nitrous oxides are removed using potassium dichromate. The method was applied to mercury determination in twelve rice samples acquired in Palma de Mallorca (Spain) between the months of January and April of 2012. The mercury content found varied from 2.15 to 7.25 ng g⁻¹. These results agree with those reported by others authors. 23256723 Effect of rehabilitative exercise training on peripheral muscle remodelling in patients with COPD: targeting beyond the lungs. Locomotor muscle dysfunction and weakness are frequently observed in patients with Chronic Obstructive Pulmonary Disease (COPD). In addition to intolerable sensations of dyspnoea which importantly contribute to exercise limitation, intrinsic muscle abnormalities have also been implicated in inducing leg muscle fatigue/discomfort during exercise in these patients. It is, however, uncertain whether these intrinsic muscle abnormalities are linked to a specific 'myopathy' or they constitute a consequence of the disease. Besides muscle disuse, other factors which may contribute to peripheral muscle dysfunction include systemic inflammation, oxidative and nitrosative stress, chronic hypoxia, corticosteroid use and malnutrition. There is clear evidence that rehabilitative exercise training induces significant skeletal muscle fibre remodelling and improvements in functionality in the absence of changes in lung function. The ultimate purpose of this review is to identify and summarize the results of studies implementing diverse types of exercise training on peripheral muscle fibre phenotypic and genotypic modifications in patients with COPD. 23010164 The long road of research on snake venom serine proteinases. It has long been recognized that snake venom serine proteinases (SVSPs) affect various physiological functions including blood coagulation, fibrinolysis, blood pressure and platelet aggregation. Therefore, SVSPs have been used as refined tools to study molecular mechanisms involved in the activation of key factors that control hemostasis and as therapeutic agents in various thrombotic and hemostatic conditions. The aim of this review is to highlight the state of our knowledge on the advances made in SVSP research since the 18th century. It includes the personal accounts of some distinguished scientists that addressed specific problems and contributed to advance the field. 23237533 Magnetic assembly and patterning of general nanoscale materials through nonmagnetic templates. Applied magnetic field represents an effective tool to rapidly assemble micro- and nanoscale magnetic objects into defined structures. Ordered assembly is typically achieved by using magnetic micropatterns, for which the downside is that they require advanced microfabrication techniques to produce. In addition, most conventional magnetic assembly strategies are restricted to target objects that possess magnetic properties. Herein we present a general strategy that allows convenient magnetically driven assembly of nonmagnetic objects in defined locations with high spatial resolution. The process involves immersing a polymer relief pattern in a uniformly magnetized ferrofluid, which modulates the local magnetic fields around the pattern. Nonmagnetic target objects dispersed in the same ferrofluid can then be magnetically assembled at positions defined by the polymer pattern. As the nonmagnetic polymer patterns can be conveniently fabricated at low cost through photolithography and soft-lithography processes, our method provides a general yet very effective means to assemble a wide range of nonmagnetic objects with controlled spatial distribution, paving the way toward patterning functional microstructures. 23333716 Antibacterial activity of Veronica montana L. extract and of protocatechuic acid incorporated in a food system. This study was designed to evaluate the antibacterial activity of the Veronica montana L. water extract and its main phenolic compound, protocatechuic acid. The antibacterial activity was determined by microdilution assay against six strains of Gram-positive and Gram-negative bacteria. Listeria monocytogenes was the most sensitive of the tested bacterial species. Antibacterial preserving properties of protocatechuic acid were also evaluated after its incorporation in cream cheese, using L. monocytogenes as commonly cheese contaminant. The compound successfully inhibited L. monocytogenes development in cream cheese, at room temperature and in refrigerator (25°C and 4°C, respectively), after 3days of inoculation. Sensory evaluation was carried out in order to validate the mentioned food system. A possible mode of action of the tested compound towards bacterial cells was assessed and appears to be direct lysis of pathogenic cytoplasmic membrane. Prediction of pharmacokinetic properties was also performed using computational analyzes. The obtained results can serve as an important platform for the development of effective natural preservatives. 23602732 In vitro and in vivo safety evaluation of Acer tegmentosum. ETHNOPHARMACOLOGICAL RELEVANCE: Acer tegmentosum, which contains salidroside and tyrosol, has been used for the treatment of hepatic disorders in eastern Asia. However, little is known about its safety. AIM OF THE STUDY: To determine the safety of Acer tegmentosum, we evaluated its acute oral toxicity and genotoxicity profiles. MATERIALS AND METHODS: Salidroside and tyrosol present in Acer tegmentosum were quantified using high-performance liquid chromatography. Acute oral toxicity testing of Acer tegmentosum was performed in rats. Genotoxicity of Acer tegmentosum was assessed by bacterial reverse mutation, chromosomal aberration, and bone marrow micronucleus tests. All the tests were conducted in accordance with the good laboratory practices. RESULTS: The amounts of salidroside and tyrosol in Acer tegmentosum were found to be 85.01±1.21mg/g and 3.12±0.04mg/g, respectively. In the bacterial reverse mutation test, Acer tegmentosum increased the number of revertant Salmonella typhimurium TA98 colonies, regardless of metabolic activation by S9 mixture. In contrast, Acer tegmentosum application did not significantly increase the number of chromosomal aberrations in Chinese hamster ovary (CHO)-K1 cells and micronucleated polychromatic erythrocytes in mice. In the acute oral toxicity test, the median lethal dose (LD50) of Acer tegmentosum was found to be >2000mg/kg in rats. CONCLUSION: Take together, Acer tegmentosum exhibits mutagenicity, which was evident from the bacterial reverse mutation test. Further studies are needed to identify the components responsible for such an effect and the underlying mechanisms. 23526745 The Mechanisms of Radical SAM/Cobalamin Methylations: An Evolving Working Hypothesis. All about Me: Pierre and co-workers have revealed mechanistic details of a tryptophan methyltransferase (TsrM) involved in the biosynthesis of the thiopeptide antibiotic, thiostrepton. Utilising cobalamin and a [4Fe-4S] cluster to generate 2-methyltryptophan from tryptophan, a key difference between this enzyme and other radical SAM methyltransferases is that the reaction is not initiated by a single-electron reduction of SAM to generate 5'-dA⋅. 23585380 Dual Growth Factor Delivery Using Biocompatible Core-Shell Microcapsules for Angiogenesis. An optimized electrodropping system produces homogeneous core-shell microcapsules (C-S MCs) by using poly(L-lactic-co-glycolic acid) (PLGA) and alginate. Fluorescence imaging clearly shows the C-S domain in the MC. For release control, the use of high-molecular-weight PLGA (HMW 270 000) restrains the initial burst release of protein compared to that of low-MW PLGA (LMW 40 000). Layer-by-layer (LBL) assembly of chitosan and alginate on MCs is also useful in controlling the release profile of biomolecules. LBL (7-layer) treatment is effective in suppressing the initial burst release of protein compared to no LBL (0-layer). The difference of cumulative albumin release between HMW (7-layer LBL) and LMW (0-layer LBL) PLGA is determined to be more than 40% on day 5. When dual angiogenic growth factors (GFs), such as platelet-derived GF (PDGF) and vascular endothelial GF (VEGF), are encapsulated separately in the core and shell domains, respectively, the VEGF release rate is much greater than that of PDGF, and the difference of the cumulative release percentage between the two GFs is about 30% on day 7 with LMW core PLGA and more than 45% with HMW core PLGA. As for the angiogenic potential of MC GFs with human umbilical vein endothelial cells (HUVECs), the fluorescence signal of CD31+ suggests that the angiogenic sprout of ECs is more active in MC-mediated GF delivery than conventional GF delivery, and this difference is significant, based on the number of capillary branches in the unit area. This study demonstrates that the fabrication of biocompatible C-S MCs is possible, and that the release control of biomolecules is adjustable. Furthermore, MC-mediated GFs remain in an active form and can upregulate the angiogenic activity of ECs. 23560844 Metal-dependent protein phosphatase 1A functions as an extracellular signal-regulated kinase phosphatase. Protein phosphorylation is an important post-translational modification that regulates almost every aspect of signal transduction in cells. Activation of the mitogen-activated protein kinase (MAPK) family kinase extracellular signal-regulated kinase (ERK) is a point of convergence for many cellular activities in response to external stimulation. With stimuli, ERK activity is significantly increased by the phosphorylation of Thr202 and Tyr204 at its activation loop. Downregulation of ERK phosphorylation at these two sites by several phosphatases, such as protein phosphatase 2A, HePTP and MAPK phosphatase 3, is essential for maintaining appropriate ERK function in different cellular processes. However, it is unknown whether metal-dependent protein phosphatase (PPM) family phosphatases directly dephosphorylate ERK. In this study, we found that PPM1A negatively regulated ERK by directly dephosphorylating its pThr202 position early in EGF stimulation. Additional kinetic studies revealed that key residues participated in phospho-ERK recognition by PPM1A. Importantly, PPM1A preferred the phospho-ERK peptide sequence over a panel of other phosphopeptides through the interactions of basic residues in the active site of PPM1A with the pThr-Glu-pTyr motif of ERK. Whereas Lys165 and Arg33 were required for efficient catalysis or phosphosubstrate binding of PPM1A, Gln185 and Arg186 were determinants of PPM1A substrate specificity. The interaction between Arg186 of PPM1A and Glu203 and pTyr204 of phospho-ERK was identified as a hot-spot for phospho-ERK-PPM1A interaction. STRUCTURED DIGITAL ABSTRACT: PPM1A physically interacts with ERK2 by pull down (View interaction) PPM1A dephosphorylates p38 by phosphatase assay (View Interaction: 1, 2) PPM1A binds to ERK2 by pull down (View interaction) PPM1A dephosphorylates ERK2 by phosphatase assay (View Interaction: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20). 23396041 Dissolved azaspiracids are absorbed and metabolized by blue mussels (Mytilus edulis). The relationship between azaspiracid shellfish poisoning and a small dinoflagellate, Azadinium spinosum, has been shown recently. The organism produces AZA1 and -2, while AZA3 and other analogues are metabolic products formed in shellfish. We evaluated whether mussels were capable of accumulating dissolved AZA1 and -2, and compared the toxin profiles of these mussels at 24 h with profiles of those exposed to live or lysed A. spinosum. We also assessed the possibility of preparative production of AZA metabolites by exposing mussels to semi-purified AZA1. We exposed mussels to similar concentration of AZAs: dissolved AZA1 + 2 (crude extract) at 7.5 and 0.75 μg L(-1), dissolved AZA1+2 (7.5 μg L(-1)) in combination with Isochrysis affinis galbana, and lysed and live A. spinosum cells at 1 × 10(5) and 1 × 10(4) cell mL(-1) (containing equivalent amounts of AZA1 + 2). Subsequently, we dissected and analysed digestive glands, gills and remaining flesh. Mussels (whole flesh) accumulated AZAs to levels above the regulatory limit, except at the lower levels of dissolved AZAs. The toxin profile of the mussels varied significantly with treatment. The gills contained 42-46% and the digestive glands 23-24% of the total toxin load using dissolved AZAs, compared to 3-12% and 75-90%, respectively, in mussels exposed to live A. spinosum. Exposure of mussels to semi-purified AZA1 produced the metabolites AZA17 (16.5%) and AZA3 (1.7%) after 4 days of exposure, but the conversion efficiency was too low to justify using this procedure for preparative isolation. 23612421 Urinary metabonomic study of the surface layer of poria cocos as an effective treatment for chronic renal injury in rats. ETHNOPHARMACOLOGICAL RELEVANCE: Poria cocos Wolf (Polyporaceae) is a well-known medicinal fungus. the epidermis of the sclerotia ("Fu-Ling-Pi" in Chinese) is used as a diuretic and traditionally used for promoting urination and reduce edema. AIM OF THE STUDY: Traditional Chinese medicines (TCM) treat many diseases through multi-components, multi-ways and multi-targets. However, the molecular mechanisms of TCM are not yet well understood. In the present work, ultra performance liquid chromatography-based metabonomics analysis was applied to investigate the urinary metabolite profiling of the renoprotective effect of FLP on adenine-induced chronic kidney disease (CKD) rat model and involved possible mechanism. MATERIAL AND METHODS: A metabonomic approach based on ultra performance liquid chromatography coupled with quadrupole time-of-flight high-sensitivity mass spectrometry and a novel mass spectrometry(Elevated Energy) data collection technique was developed. The resulting dataset was analyzed by principal component analysis and partial least squares discriminant analysis. The identification of all potential biomarkers was performed using reference standard by comparing their mass spectra, MS(E) fragments information, isotopic pattern and MassLynx i-FIT algorithm. RESULTS: By partial least squares-discriminate analysis analyses, 15 biomarkers in rat urine were identified and 11 of them were related to the pathway of adenine metabolism and amino acid metabolism. Among these biomarkers, eight biomarkers like adenine, L-acetylcarnitine, 8-hydroxyadenine, hypoxanthine, creatine, methionine, phytosphingosine and phenylalanine were reversed to the control level in FLP-treated groups and six biomarkers like 2,8-dihydroxyadenine, indole-3-carboxylic acid, 3-methyldioxyindole, ethyl-N2-acetyl-L-argininate, 3-O-methyldopa and xanthurenic acid were reversed to high normal group by FLP, which indicates that the urinary metabolic pattern significantly changed after FLP treatment. CONCLUSIONS: Our study indicates that FLP treatment can ameliorate CKD by intervening in some dominating metabolic pathways, such as adenine metabolism and amino acid metabolism. The metabonomic results not only supplied a systematic view of the development and progression of CKD and mechanism studies of FLP but also provided the theoretical basis for the prevention or treatment of CKD. 23369933 Mercuric chloride-induced testicular toxicity in rats and the protective role of sodium selenite and vitamin E. Mercury has been recognized as an environmental pollutant that adversely affects male reproductive systems of animals. This study examined the effects of mercuric chloride on the antioxidant system and histopathological changes and also evaluated the ameliorating effects of sodium selenite and/or vitamin E in the rat testis tissues. Sexually mature male Wistar rats (weighing 300-320g and each group six animals) were given mercuric chloride (1mg/kg bw) and/or sodium selenite (0.25mg/kg bw)+vitamin E (100mg/kg) daily via gavage for 4weeks. In the present study, mercuric chloride exposure resulted in an increase in the TBARS level and a decrease in the SOD, CAT, GPx activities, with respect to the control. Further, light microscopic investigation revealed that mercury exposure induced histopathological alterations in the testis tissues. Supplementation of sodium selenite and/or vitamin E to mercury-induced groups declined lipid peroxidation, increased SOD, CAT, GPx activities. While some histopathological changes were detected in mercuric chloride treated group, milder histopathological changes were observed in animal co-treated with sodium selenite and/or vitamin E supplementation to mercuric chloride-treated rats. As a result, mercuric chloride induced testicular toxicity is reduced by sodium selenite and/or vitamin E, but not ameliorate completely. 23418011 Structural insights into the recovery of aldolase activity in N-acetylneuraminic acid lyase by replacement of the catalytically active lysine with γ-thialysine by using a chemical mutagenesis strategy. Chemical modification has been used to introduce the unnatural amino acid γ-thialysine in place of the catalytically important Lys165 in the enzyme N-acetylneuraminic acid lyase (NAL). The Staphylococcus aureus nanA gene, encoding NAL, was cloned and expressed in E. coli. The protein, purified in high yield, has all the properties expected of a class I NAL. The S. aureus NAL which contains no natural cysteine residues was subjected to site-directed mutagenesis to introduce a cysteine in place of Lys165 in the enzyme active site. Subsequently chemical mutagenesis completely converted the cysteine into γ-thialysine through dehydroalanine (Dha) as demonstrated by ESI-MS. Initial kinetic characterisation showed that the protein containing γ-thialysine regained 17 % of the wild-type activity. To understand the reason for this lower activity, we solved X-ray crystal structures of the wild-type S. aureus NAL, both in the absence of, and in complex with, pyruvate. We also report the structures of the K165C variant, and the K165-γ-thialysine enzyme in the presence, or absence, of pyruvate. These structures reveal that γ-thialysine in NAL is an excellent structural mimic of lysine. Measurement of the pH-activity profile of the thialysine modified enzyme revealed that its pH optimum is shifted from 7.4 to 6.8. At its optimum pH, the thialysine-containing enzyme showed almost 30 % of the activity of the wild-type enzyme at its pH optimum. The lowered activity and altered pH profile of the unnatural amino acid-containing enzyme can be rationalised by imbalances of the ionisation states of residues within the active site when the pK(a) of the residue at position 165 is perturbed by replacement with γ-thialysine. The results reveal the utility of chemical mutagenesis for the modification of enzyme active sites and the exquisite sensitivity of catalysis to the local structural and electrostatic environment in NAL. 23416115 Anti-diabetic and anti-lipidemic effects of chlorogenic acid are mediated by ampk activation. Chlorogenic acid (CGA) has been shown to stimulate glucose uptake in skeletal muscle through the activation of AMPK. However, its effect on other metabolic pathways and likewise its effects after long-term consumption have yet to be understood. We investigated the effects of CGA on glucose tolerance, insulin sensitivity, hepatic gluconeogenesis, lipid metabolism and skeletal muscle glucose uptake in Lepr(db/db) mice. Hepatoma HepG2 was used to investigate CGA's effect on hepatic glucose production and fatty acid synthesis. Subsequently, we attempted to evaluate whether these effects of CGA are associated with the activation of AMPK. In Lepr(db/db) mice, acute treatment with CGA lowered AUCglucose in an OGTT. Chronic administration of CGA inhibited hepatic G6Pase expression and activity, attenuated hepatic steatosis, improved lipid profiles and skeletal muscle glucose uptake, which in turn improved fasting glucose level, glucose tolerance, insulin sensitivity and dyslipidemia in Lepr(db/db) mice. CGA activated AMPK, leading to subsequent beneficial metabolic outcomes, such as suppression of hepatic glucose production and fatty acid synthesis. Inhibition and knockdown of AMPK abrogated these metabolic alterations. In conclusion, CGA improved glucose and lipid metabolism, via the activation of AMPK. 23535351 Management of schizophrenia: clinical experience with asenapine. Schizophrenia is a chronic brain disorder comprising a range of clinical features, including positive and negative symptoms, cognitive dysfunction and mood symptoms (particularly depression and anxiety). The management of schizophrenia requires effective short- and long-term treatment with antipsychotic medication that is effective across these symptom domains, while being well tolerated over the long term. Asenapine is the first tetracyclic atypical antipsychotic to be licensed in the USA and several other countries outside Europe for the acute and maintenance treatment of schizophrenia in adults. It has a unique receptor-binding profile and a broad range of therapeutic effects. Since clinical trials are conducted under strict conditions in tightly defined patient populations, evidence of an agent's efficacy and tolerability under 'real-world' clinical practice conditions is also required. As in clinical trials, real-life case reports demonstrate that asenapine is effective in treating the positive symptoms of schizophrenia, both in the acute setting and for relapse prevention. It is also effective in treating negative symptoms and shows promise in the treatment of depressive symptoms associated with schizophrenia. Asenapine has a favourable tolerability profile, having a minimal impact on weight and metabolic parameters. As such, asenapine is valuable option for the treatment of schizophrenia in adults. 23512824 Recruiting the Host's Immune System to Target Helicobacter pylori's Surface Glycans. Due to the increased prevalence of bacterial strains that are resistant to existing antibiotics, there is an urgent need for new antibacterial strategies. Bacterial glycans are an attractive target for new treatments, as they are frequently linked to pathogenesis and contain distinctive structures that are absent in humans. We set out to develop a novel targeting strategy based on surface glycans present on the gastric pathogen Helicobacter pylori (Hp). In this study, metabolic labeling of bacterial glycans with an azide-containing sugar allowed selective delivery of immune stimulants to azide-covered Hp. We established that Hp's surface glycans are labeled by treatment with the metabolic substrate peracetylated N-azidoacetylglucosamine (Ac4 GlcNAz). By contrast, mammalian cells treated with Ac4 GlcNAz exhibited no incorporation of the chemical label within extracellular glycans. We further demonstrated that the Staudinger ligation between azides and phosphines proceeds under acidic conditions with only a small loss of efficiency. We then targeted azide-covered Hp with phosphines conjugated to the immune stimulant 2,4-dinitrophenyl (DNP), a compound capable of directing a host immune response against these cells. Finally, we report that immune effector cells catalyze selective damage in vitro to DNP-covered Hp in the presence of anti-DNP antibodies. The technology reported herein represents a novel strategy to target Hp based on its glycans. 23171045 New 2-(aryloxy)-3-phenylpropanoic acids as peroxisome proliferator-activated receptor α/γ dual agonists able to upregulate mitochondrial carnitine shuttle system gene expression. The preparation of a series of 2-(aryloxy)-3-phenylpropanoic acids, resulting from the introduction of different substituents into the biphenyl system of the previously reported peroxisome proliferator-activated receptor α/γ (PPARα/γ) dual agonist 1, allowed the identification of new ligands with higher potency on PPARα and fine-tuned moderate PPARγ activity. For the most promising stereoisomer (S)-16, X-ray and calorimetric studies in PPARγ revealed, at high ligand concentration, the presence of two molecules simultaneously bound to the receptor. On the basis of these results and docking experiments in both receptor subtypes, a molecular explanation was provided for its different behavior as a full and partial agonist of PPARα and PPARγ, respectively. The effects of (S)-16 on mitochondrial acylcarnitine carrier and carnitine-palmitoyl-transferase 1 gene expression, two key components of the carnitine shuttle system, were also investigated, allowing the hypothesis of a more beneficial pharmacological profile of this compound compared to the less potent PPARα agonist fibrates currently used in therapy. 22451355 Antiproliferative and antiangiogenic properties of horse chestnut extract. This study was designed to examine the in vitro antiproliferative effect of the horse chestnut extract (HCE) on cancer cell lines. Furthermore, we have investigated the in vitro effect of HCE on some angiogenic events by using human umbilical vein endothelial cells. The cell proliferation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and anchorage-independent growth by colony-forming assay. To understand the growth inhibitory effects, carcinoma cell lines (Jurkat, CEM, HeLa, and MCF-7) were treated with various concentrations of HCE. Incubation of Jurkat, CEM, HeLa, and MCF-7 cancer cells with HCE at 125 µg/mL for 72 h caused 93.7%, 32.3%, 20.4% and 40.4% reduction in cell survival. Colony-forming assay also confirmed growth-inhibitory effects of the compound studied. In HeLa HCE-treated cells, we found a significant increase in cells having sub-G(0) /G(1) DNA content which is considered to be a marker of apoptotic cell death. Apoptosis was also further confirmed by DNA fragmentation analysis.Furthermore, HCE inhibited migration of human umbilical vein endothelial cells as well as decreased secretion of matrix metalloproteinase and vascular endothelial growth factor.In conclusion, the present study has assessed the in vitro antiproliferative/antiangiogenic potential of HCE. These results generate a rationale for in vivo efficacy studies with horse chestnut in preclinical cancer models. 22849972 Increased expression of transthyretin in leptin-deficient ob/ob mice is not causative for their major phenotypic abnormalities. The hormone leptin is a critical regulator of adipogenesis and energy metabolism. Similarly, leptin-deficient ob/ob mice display various metabolic abnormalities, including not only obesity and insulin resistance, but also hypogonadism and high bone mass. By genome-wide expression analysis using hypothalamus RNA from wild-type and ob/ob mice, we observed the increased expression of the gene for transthyretin (Ttr) in the latter, as confirmed by quantitative real-time-polymerase chain reaction. Because Ttr encodes a carrier protein for retinol transport, and because we further found increased retinol levels in the serum of ob/ob mice, we investigated whether the additional absence of Ttr would influence the ob/ob phenotype. It was found that Ttr-deficient ob/ob mice were indistinguishable from ob/ob littermates in terms of body weight, as well as serum glucose, insulin and cholesterol levels. Although all of these parameters were identical to wild-type controls in Ttr-deficient mice, we found that the sole deletion of Ttr caused a significant increase of trabecular bone mass, bone marrow adiposity and mean adipocyte area in white adipose tissue. Interestingly, all these latter parameters were highest in Ttr-deficient ob/ob mice, and only in these mice did we observe a full penetrance of liver steatosis at 24 weeks of age. Taken together, our data demonstrate that the increased expression of Ttr in ob/ob mice does not cause (but rather attenuates) their phenotypic abnormalities. 22982773 A common mechanism for resistance to oxime reactivation of acetylcholinesterase inhibited by organophosphorus compounds. Administration of oxime therapy is currently the standard approach used to reverse the acute toxicity of organophosphorus (OP) compounds, which is usually attributed to OP inhibition of acetylcholinesterase (AChE). Rate constants for reactivation of OP-inhibited AChE by even the best oximes, such as HI-6 and obidoxime, can vary >100-fold between OP-AChE conjugates that are easily reactivated and those that are difficult to reactivate. To gain a better understanding of this oxime specificity problem for future design of improved reactivators, we conducted a QSAR analysis for oxime reactivation of AChE inhibited by OP agents and their analogues. Our objective was to identify common mechanism(s) among OP-AChE conjugates of phosphates, phosphonates and phosphoramidates that result in resistance to oxime reactivation. Our evaluation of oxime reactivation of AChE inhibited by a sarin analogue, O-methyl isopropylphosphonofluoridate, or a cyclosarin analogue, O-methyl cyclohexylphosphonofluoridate, indicated that AChE inhibited by these analogues was at least 70-fold more difficult to reactivate than AChE inhibited by sarin or cyclosarin. In addition, AChE inhibited by an analogue of tabun (i.e., O-ethyl isopropylphosphonofluoridate) was nearly as resistant to reactivation as tabun-inhibited AChE. QSAR analysis of oxime reactivation of AChE inhibited by these OP compounds and others suggested that the presence of both a large substituent (i.e., ⩾the size of dimethylamine) and an alkoxy substituent in the structure of OP compounds is the common feature that results in resistance to oxime reactivation of OP-AChE conjugates whether the OP is a phosphate, phosphonate or phosphoramidate. 23280958 Spectroscopic fingerprints of toroidal nuclear quantum delocalization via ab initio path integral simulations. We investigate the quantum-mechanical delocalization of hydrogen in rotational symmetric molecular systems. To this purpose, we perform ab initio path integral molecular dynamics simulations of a methanol molecule to characterize the quantum properties of hydrogen atoms in a representative system by means of their real-space and momentum-space densities. In particular, we compute the spherically averaged momentum distribution n(k) and the pseudoangular momentum distribution n(kθ). We interpret our results by comparing them to path integral samplings of a bare proton in an ideal torus potential. We find that the hydroxyl hydrogen exhibits a toroidal delocalization, which leads to characteristic fingerprints in the line shapes of the momentum distributions. We can describe these specific spectroscopic patterns quantitatively and compute their onset as a function of temperature and potential energy landscape. The delocalization patterns in the projected momentum distribution provide a promising computational tool to address the intriguing phenomenon of quantum delocalization in condensed matter and its spectroscopic characterization. As the momentum distribution n(k) is also accessible through Nuclear Compton Scattering experiments, our results will help to interpret and understand future measurements more thoroughly. 23252823 Pyrenyl-linker-glucono gelators. Correlations of gel properties with gelator structures and characterization of solvent effects. A series of glucono-appended 1-pyrenesulfonyl derivatives containing α,ω-diaminoalkane spacers (Pn, where n, the number of methylene units separating the amino groups, is 2, 3, 4, 6, 7, and 8) have been prepared. Careful analyses of correlations between the structures of these molecules and their gels have provided important insights into the factors responsible for one-dimensional aggregation of small molecules containing both lipophilic and hydrophilic parts. The gelation behavior has been examined in 30 liquids of diverse structure and polarity, and the properties of their gels and the gelation mechanisms have been investigated using a variety of techniques. Possible reasons are discussed regarding why the Pn are better gelators than the corresponding naphthyl analogues (Nn) which had been investigated previously. P2 and P3 are ambidextrous gelators (i.e., they gelate both water and some organic liquids), and P4-P8 gelate some organic liquids which are protic and aprotic, but not water. In at least one of the liquids examined, P3, P4, P6, P7, and P8 form gels at less than 1 w/v % concentrations, and some of the gels in 1-decanol are thixotropic. Analyses of the gelation abilities using Hansen solubility parameters yield both qualitative and quantitative insights into the role of liquid-gelator interactions. For example, the critical gelation concentrations increase generally with increasing polar and hydrogen bonding interactions between the gelators and their liquid components. As revealed by FT-IR, (1)H NMR, UV-vis, and fluorescence spectra, hydrogen-bonding between glucono units and π-π stacking between pyrenyl groups are important in the formation and maintenance of the gel networks. The results from this study, especially those relating the aggregation modes and liquid properties, offer insights for the design of new surfactant-containing low-molecular-mass gelators with predefined gelating abilities. 23201451 Application of OECD Guideline 423 in assessing the acute oral toxicity of moniliformin. Moniliformin is a Fusarium mycotoxin highly prevalent in grains and grain-based products worldwide. In this study, the acute oral toxicity of moniliformin was assessed in Sprague-Dawley male rats according to OECD Guideline 423 with a single-dose exposure. Clinical observations and histopathological changes were recorded together with the excretion of moniliformin via urine and feces, utilizing a novel liquid chromatography-mass spectrometry method. According to our study, moniliformin is acutely toxic to rats with a rather narrow range of toxicity. Moniliformin can be classified into category 2 (LD(50) cut-off value 25 mg/kg b.w.), according to the Globally Harmonized System for the classification of chemicals. The clinical observations included muscular weakness, respiratory distress and heart muscle damage. Pathological findings confirmed that heart is the main target tissue of acute moniliformin toxicity. A significant proportion (about 38%) of the administered moniliformin was rapidly excreted in urine in less than 6 h. However, the toxicokinetics of the majority of the administered dose still requires clarification, as the total excretion was only close to 42%. Considering the worldwide occurrence of moniliformin together with its high acute toxicity, research into the subchronic toxicity is of vital importance to identify the possible risk in human/animal health. 23501108 Synthesis and anticancer activity of novel 2-pyridyl hexahyrocyclooctathieno[2,3-d]pyrimidine derivatives. A series of new 2-pyridyl hexahydrocycloocta [4,5]thieno[2,3-d]pyrimidines with different substituents as C-4 position was synthesized. The anticancer activity of the newly synthesized compounds was tested in vitro using a two-stage process utilizing 60 different human tumor cell lines representing leukemia, melanoma and cancers of lung, colon, central nervous system, ovary, kidney, prostate as well as breast. Compounds 4a, 6a, 7a, 7d and 7g showed potent anticancer activity at low concentrations against most of the used human tumor cell lines comparable with doxorubicin as standard potent anticancer drug (average log10 GI50 over all cell lines = -6.85). Also, compound 4b was selective against SNB-75 (CNS cancer) log10 GI50 = -5.57. Interestingly, compound 7e exhibited promising selectivity against 13 tumor cell lines showing growth inhibition percentages between 54.05 and 89.23. 23436742 Thermal and Electrical Conduction in Ultrathin Metallic Films: 7 nm down to Sub-Nanometer Thickness. For ultrathin metallic films (e.g., less than 5 nm), no knowledge is yet available on how electron scattering at surface and grain boundaries reduces the electrical and thermal transport. The thermal and electrical conduction of metallic films is characterized down to 0.6 nm average thickness. The electrical and thermal conductivities of 0.6 nm Ir film are reduced by 82% and 50% from the respective bulk values. The Lorenz number is measured as 7.08 × 10(-8) W Ω K(-2) , almost a twofold increase of the bulk value. The Mayadas-Shatzkes model is used to interpret the experimental results and reveals very strong electron reflection (>90%) at grain boundaries. 23485151 Postsynthesis modification of a porous coordination polymer by LiCl To enhance H+ transport. A Ca(2+) porous coordination polymer with 1D channels was functionalized by the postsynthesis addition of LiCl to enhance the H(+) conductivity. The compound showed over 10(-2) S cm(-1) at 25 °C and 20% relative humidity. Pulse-field gradient NMR elucidated that the fast H(+) conductivity was achieved by the support of Li(+) ion movements in the channel. 23619611 Novel oral anticoagulants: clinical pharmacology, indications and practical considerations. BACKGROUND: Novel oral anticoagulants are approved in several indications: rivaroxaban, apixaban, and dabigatran for the prevention of venous thromboembolism after elective hip or knee replacement surgery, and edoxaban for hip or knee replacement surgery and hip fracture surgery (in Japan only); rivaroxaban for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE; and rivaroxaban, apixaban, and dabigatran for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. These agents overcome some limitations of traditional anticoagulants, are suggested to have no requirement for routine coagulation monitoring, and are administered orally. Rivaroxaban, apixaban, and dabigatran have different pharmacological characteristics, and guidance is needed on optimum doses and dosing intervals and the effects of renal or hepatic impairment, age, food, and other drugs. Dabigatran has stricter prescribing advice than rivaroxaban or apixaban for patients with moderate-to-severe renal impairment. All three drugs have restrictions on use in patients with hepatic impairment. Apixaban requires twice-daily dosing in all indications, whereas rivaroxaban and dabigatran are dosed once- or twice-daily depending on indication. Although head-to-head comparisons are lacking, the novel oral anticoagulants may show favorable cost-benefit relations compared with traditional vitamin K antagonists or no therapy. AIM: This review summarizes the pharmacology of rivaroxaban, apixaban, edoxaban, and dabigatran, and the indications for which they are approved. Issues regarding the optimization of the use of these anticoagulants for the management of thromboembolic disorders will also be discussed. 23462665 Exenatide-Induced Reduction in Energy Intake Is Associated With Increase in Hypothalamic Connectivity. OBJECTIVEGlucagon-like peptide-1 receptor agonists like exenatide are known to influence neural activity in the hypothalamus of animals and to reduce energy intake. In humans, however, significant weight loss has been observed in only a subgroup of patients. Why only some individuals respond with weight loss and others do not remains unclear. In this functional magnetic resonance imaging (fMRI) study, we investigated differences in hypothalamic connectivity between "responders" (reduction in energy intake after exenatide infusion) and "nonresponders."RESEARCH DESIGN AND METHODSWe performed a randomized, double-blinded, placebo-controlled, cross-over fMRI study with intravenous administration of exenatide in obese male volunteers. During brain scanning with continuous exenatide or placebo administration, participants rated food and nonfood images. After each scanning session, energy intake was measured using an ad libitum buffet. Functional hypothalamic connectivity was assessed by eigenvector centrality mapping, a measure of connectedness throughout the brain.RESULTSResponders showed significantly higher connectedness of the hypothalamus, which was specific for the food pictures condition, in the exenatide condition compared with placebo. Nonresponders did not show any significant exenatide-induced changes in hypothalamic connectedness.CONCLUSIONSOur results demonstrate a central hypothalamic effect of peripherally administered exenatide that occurred only in the group that showed an exenatide-dependent anorexigenic effect. These findings indicate that the hypothalamic response seems to be the crucial factor for the effect of exenatide on energy intake. 23411232 Quantification of vitamin D3 and its hydroxylated metabolites in waxy leaf nightshade (Solanum glaucophyllum Desf.), tomato (Solanum lycopersicum L.) and bell pepper (Capsicum annuum L.). Changes in vitamin D(3) and its metabolites were investigated following UVB- and heat-treatment in the leaves of Solanum glaucophyllum Desf., Solanum lycopersicum L. and Capsicum annuum L. The analytical method used was a sensitive and selective liquid chromatography electrospray ionisation tandem mass spectrometry (LC-ESI-MS/MS) method including Diels-Alder derivatisation. Vitamin D(3) and 25-hydroxy vitamin D(3) were found in the leaves of all plants after UVB-treatment. S. glaucophyllum had the highest content, 200 ng vitamin D(3)/g dry weight and 31 ng 25-hydroxy vitamin D(3)/g dry weight, and was the only plant that also contained 1,25 dihydroxy vitamin D(3) in both free (32 ng/g dry weight) and glycosylated form (17 ng/g dry weight). 23597507 Phα1β toxin prevents capsaicin-induced nociceptive behavior and mechanical hypersensitivity without acting on TRPV1 channels. Phα1β toxin is a peptide purified from the venom of the armed spider Phoneutria nigriventer, with markedly antinociceptive action in models of acute and persistent pain in rats. Similarly to ziconotide, its analgesic action is related to inhibition of high voltage activated calcium channels with more selectivity for N-type. In this study we evaluated the effect of Phα1β when injected peripherally or intrathecally in a rat model of spontaneous pain induced by capsaicin. We also investigated the effect of Phα1β on Ca(2+) transients in cultured dorsal root ganglia (DRG) neurons and HEK293 cells expressing the TRPV1 receptor. Intraplantar or intrathecal administered Phα1β reduced both nocifensive behavior and mechanical hypersensitivity induced by capsaicin similarly to that observed with SB366791, a specific TRPV1 antagonist. Peripheral nifedipine and mibefradil did also decrease nociceptive behavior induced by intraplantar capsaicin. In contrast, ω-conotoxin MVIIA (a selective N-type Ca(2+) channel blocker) was effective only when administered intrathecally. Phα1β, MVIIA and SB366791 inhibited, with similar potency, the capsaicin-induced Ca(2+) transients in DRG neurons. The simultaneous administration of Phα1β and SB366791 inhibited the capsaicin-induced Ca(2+) transients that were additive suggesting that they act through different targets. Moreover, Phα1β did not inhibit capsaicin-activated currents in patch-clamp recordings of HEK293 cells that expressed TRPV1 receptors. Our results show that Phα1β may be effective as a therapeutic strategy for pain and this effect is not related to the inhibition of TRPV1 receptors. 23444387 Significance of reductive metabolism in human intestine and quantitative prediction of intestinal first-pass metabolism by cytosolic reductive enzymes. The number of new drug candidates that are cleared via non-cytochrome P450 (P450) enzymes has increased. However, unlike oxidation by P450, the roles of reductive enzymes are less understood. The metabolism in intestine is especially not well known. The purposes of this study were to investigate the significance of reductive metabolism in human intestine, and to establish a quantitative prediction method of intestinal first-pass metabolism by cytosolic reductive enzymes, using haloperidol, mebendazole, and ziprasidone. First, we estimated the metabolic activities for these compounds in intestine and liver using subcellular fractions. Metabolic activities were detected in human intestinal cytosol (HIC) for all three compounds, and the intrinsic clearance values were higher than those in human liver cytosol for haloperidol and mebendazole. These metabolic activities in HIC were NADPH- and/or NADH-dependent. Furthermore, the metabolic activities for all three compounds in HIC were largely inhibited by menadione, which has been used as a carbonyl reductase (CBR)-selective chemical inhibitor. Therefore, considering subcellular location, cofactor requirement, and chemical inhibition, these compounds might be metabolized by CBRs in human intestine. Subsequently, we tried to quantitatively predict intestinal availability (Fg) for these compounds using human intestinal S9 (HIS9). Our prediction model using apparent permeability of parallel artificial membrane permeability assay and metabolic activities in HIS9 could predict Fg in humans for the three compounds well. In conclusion, CBRs might have higher metabolic activities in human intestine than in human liver. Furthermore, our prediction method of human Fg using HIS9 is applicable to substrates of cytosolic reductive enzymes. 23632007 Development of a method for extraction and assay of human erythrocyte acetylcholinesterase and pesticide inhibition. A method of extracting membranes from red blood cells (RBCs) is described, which were in turn used to assay acetylcholinesterase (AChE) activity. The evidence for the enzyme activity was established by selective inhibition using 1,5-bis(4-allyldimethylammoniumphenyl) pentan-3-one dibromide, tetraisopropyl pyrophosphoramide and neostigmine. Blood samples were exposed to three organophosphorus (dichlorvos, chlorpyrifos and diazinon) and two carbamate (carbaryl and carbofuran) pesticides. Afterwards AChE activities in RBC membranes were determined. The concentrations capable to inhibit the enzyme activity by 50% (IC50) for the pesticides were 10.66 µM (dichlorvos), 21.42 µM (chlorpyrifos), 109.98 µM (carbaryl) and 5.44 µM (carbofuran). The results related to 20% enzyme inhibition (level used in the estimation of threshold limits for anticholinesterase compounds) were below those acceptable daily intake values enacted by relevant national and international regulations. These results suggest that the proposed AChE extraction from RBC and assay could be a suitable method for monitoring occupational exposure to pesticides. 23489623 Synthesis of (R)-norbgugaine and its potential as quorum sensing inhibitor against Pseudomonas aeruginosa. (R)-Bgugaine is a natural pyrrolidine alkaloid from Arisarum vulgare, which shows antifungal and antibacterial activity. In this Letter, we have accomplished the simple synthesis of norbgugaine (demethylated form of natural bgugaine) employing Wittig olefination and cat. hydrogenation as the key steps and its biological studies are reported for the first time. The synthesized norbgugaine was evaluated for inhibition of quorum sensing mediated virulence factors (motility, biofilm formation, pyocyanin pigmentation, rhamnolipid production and LasA protease) in Pseudomonas aeruginosa wherein swarming motility is reduced by 95%, and biofilm formation by 83%. 23007555 Effect of ifenprodil on GluN1/GluN2B N-methyl-D-aspartate receptor gating. Ifenprodil is an allosteric inhibitor of GluN1/GluN2B N-methyl-D-aspartate receptors. Despite its widespread use as a prototype for drug development and a subtype-selective tool for physiologic experiments, its precise effect on GluN1/GluN2B gating is yet to be fully understood. Interestingly, recent crystallographic evidence identified that ifenprodil, unlike zinc, binds at the interface of the GluN1/GluN2B amino terminal domain dimer by an induced-fit mechanism. To delineate the effect of this unique binding on GluN1/GluN2B receptor gating, we recorded steady-state currents from cell-attached and outside-out patches. At pH 7.9 in cell-attached patches, ifenprodil increased the occupancy of the long-lived shut conformations, thereby reducing the open probability of the receptor with no change in the mean open time. In addition, ifenprodil selectively affected the area of shut time constants, but not the time constants themselves. Kinetic analyses suggested that ifenprodil prevents the transition of the receptor to an open state and increases its dwell time in an intrinsically occurring closed conformation or desensitized state. We found distinct differences in the action of ifenprodil at GluN1/GluN2B in comparison with previous studies on the effect of zinc on GluN1/GluN2A gating, which may arise due to their unique binding sites. Our data also uncover the potential pH-dependent action of ifenprodil on gating. At a low pH (pH 7.4), but not pH 7.9, ifenprodil reduces the mean open time of GluN1/GluN2B receptors, which may be responsible for its usefulness as a context-dependent inhibitor in conditions like ischemia and stroke, when the pH of the extracellular milieu becomes acidic. 22960471 Differential cell-specific cytotoxic responses of oral cavity cells to tobacco preparations. To examine the effects of standardized (reference) tobacco preparations on human oral cavity cells, two oral squamous cell carcinoma cell lines (101A, 101B) and normal human gingival epithelial cells (HGEC) were treated with cigarette smoke total particulate matter (TPM), smokeless tobacco extracted with complete artificial saliva (ST/CAS), or whole-smoke conditioned media (WS-CM). EC-50 values, as determined by sulforhodamine B assays, varied among the cell types and agents. When normalized to nicotine content, cytotoxicity for WS-CM and TPM was higher compared to that observed with ST/CAS. Nicotine alone had no or only minimal cytotoxicity for all cell types in the applied range. Activation of pro-apoptotic caspase-3 was examined in all cell types at their respective EC-50 doses for the three agents. TPM, but not ST/CAS or WS-CM significantly activated caspase-3 in all three cell types. Fluorescence-activated cell sorting (FACS) for expression of the early apoptosis marker Annexin V and for nuclear staining by 7-aminoactinomycin (7-AAD) revealed different extents of apoptosis versus non-apoptotic cell death for the three agents. These data characterize differential responses of normal and malignant oral cells after exposure to TPM, ST/CAS, or WS-CM. They assist in understanding differential effects of combustible versus non-combustible tobacco products, and in identifying novel biomarkers for tobacco smoke exposure and effect in the oral cavity. 23524188 Mild hyperthermia triggered doxorubicin release from optimized stealth thermosensitive liposomes improves intratumoral drug delivery and efficacy. Liposome mediated anticancer drug delivery has the advantage of reducing cytotoxicity in healthy tissues. However, undesired slow drug release impedes the therapeutic efficacy of clinically applied PEG-liposomal doxorubicin (Dox). The aim of this study is to combine stealth thermosensitive liposomes (TSL) and local mild hyperthermia (HT) to increase bioavailable Dox levels in tumors. Dox was encapsulated in stealth TSL (~80nm) with optimized PEG concentration in the membrane, and compared with lysolipid-based Dox-LTSL for in vitro stability, release kinetics, and in vivo tumor growth control. In vitro cytotoxicity of Dox-TSL against murine BFS-1 sarcoma and, human BLM melanoma cell lines and Human Umbilical Vein Endothelial Cells (HUVEC) under normothermia (37°C) and HT (42°C) was compared with non-encapsulated Dox. In vitro Dox uptake in nuclei was imaged in BLM and HUVEC. In vivo intravascular Dox release from TSL in BFS-1 tumors under local mild HT in dorsal skin flap window chamber models was captured by intravital confocal microscopy. Intravascular Dox-TSL release kinetics, penetration depth and interstitial Dox density were subjected to quantitative image analysis. Systemic Dox-TSL administration in combination with local mild HT on subcutaneous tumor growth control was compared to Dox-LTSL plus local mild HT. Dox-TSL was stable at 37°C, while released over 95% Dox within 1min in 90% serum at 42°C. Dox-TSL demonstrated efficient in vivo intratumoral Dox release under local mild HT, followed by significant Dox uptake by tumor and tumor vascular endothelial cells. Dox-TSL plus mild HT showed improved tumor growth control over Dox-LTSL plus mild HT. Survival after a single treatment of Dox-TSL plus mild HT was 67%, while survival after Dox-LTSL plus mild HT was 22%. This combination of Dox-TSL and local mild HT offers promising clinical opportunities to improve liposomal Dox delivery to solid tumors. 23552268 Potential anticancer activity of carvone in N2a neuroblastoma cell line. Carvone (CVN) is a monocyclic monoterpene found in the essential oils of Mentha spicata var. crispa (Lamiaceae) and Carum carvi L. (Apiaceae) plants and has been reported to have antioxidant, antimicrobial, anticonvulsant, and antitumor activities. The beneficial health properties of CVN have encouraged us to look into its anticancer activity. To the best of our knowledge, reports are not available on the anticancer activity of CVN in cultured primary rat neuron and N2a neuroblastoma (NB) cells. Therefore, the present study is an attempt toward exploring the potential anticancer activity of CVN, if any, in cultured primary rat neuron and N2a NB cells. Our results indicated that CVN (only at 25 mg/L) treatment led to an increase in the total antioxidant capacity levels in cultured primary rat neuron cells compared with control cells. Also, CVN (at concentrations higher than 100 mg/L) treatment led to an increase in the total oxidative stress levels in both cell types. The mean values of the total scores of cells showing DNA damage (for comet assay) were not found to be significantly different from the control values in both cells (p > 0.05). On the other hand, after 24 h treatment with CVN, 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay showed that CVN application significantly reduced the cell viability rates in both cell types at concentrations higher than 100 mg/L. Summarizing, our data suggest that CVN represents little potential for promising anticancer agent to improve brain tumors therapy. 23307927 Loss and gain of Drosophila TDP-43 impair synaptic efficacy and motor control leading to age-related neurodegeneration by loss-of-function phenotypes. Cytoplasmic accumulation and nuclear clearance of TDP-43 characterize familial and sporadic forms of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, suggesting that either loss or gain of TDP-43 function, or both, cause disease formation. Here we have systematically compared loss- and gain-of-function of Drosophila TDP-43, TAR DNA Binding Protein Homolog (TBPH), in synaptic function and morphology, motor control, and age-related neuronal survival. Both loss and gain of TBPH severely affect development and result in premature lethality. TBPH dysfunction caused impaired synaptic transmission at the larval neuromuscular junction (NMJ) and in the adult. Tissue-specific knockdown together with electrophysiological recordings at the larval NMJ also revealed that alterations of TBPH function predominantly affect pre-synaptic efficacy, suggesting that impaired pre-synaptic transmission is one of the earliest events in TDP-43-related pathogenesis. Prolonged loss and gain of TBPH in adults resulted in synaptic defects and age-related, progressive degeneration of neurons involved in motor control. Toxic gain of TBPH did not downregulate or mislocalize its own expression, indicating that a dominant-negative effect leads to progressive neurodegeneration also seen with mutational inactivation of TBPH. Together these data suggest that dysfunction of Drosophila TDP-43 triggers a cascade of events leading to loss-of-function phenotypes whereby impaired synaptic transmission results in defective motor behavior and progressive deconstruction of neuronal connections, ultimately causing age-related neurodegeneration. 23197649 Allosteric modulation of a chemogenetically modified G protein-coupled receptor. Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetically modified muscarinic acetylcholine receptors (mAChRs) that have minimal responsiveness to acetylcholine (ACh) but are potently and efficaciously activated by an otherwise inert synthetic ligand, clozapine-N-oxide (CNO). DREADDs have been used as tools for selectively modulating signal transduction pathways in vitro and in vivo. Recent comprehensive studies have validated how the pharmacology of a CNO-bound DREADD mirrors that of an ACh-bound wild-type (WT) mAChR. However, nothing is known about whether this equivalence extends to the allosteric modulation of DREADDs by small molecules. To address this, we investigated the actions at an M(1) DREADD of benzyl quinolone carboxylic acid (BQCA), a positive allosteric modulator of ACh binding and function that is known to behave according to a simple two-state mechanism at the WT receptor. We found that allosteric modulation of the CNO-bound DREADD receptor is not equivalent to the corresponding modulation of the ACh-bound WT receptor. We also found that BQCA engenders stimulus bias at the M(1) DREADD, having differential types of cooperativity depending on the signaling pathway. Furthermore, the modulation of ACh itself by BQCA at the DREADD is not compatible with the two-state model that we previously applied to the M(1) WT receptor. 23481650 N-substituted azaindoles as potent inhibitors of Cdc7 kinase. Cdc7 kinase is responsible for the initiation and regulation of DNA replication and has been proposed as a target for cancer therapy. We have identified a class of Cdc7 inhibitors based on a substituted indole core. Synthesis of focused indole and azaindole analogs yielded potent and selective 5-azaindole Cdc7 inhibitors with improved intrinsic metabolic stability (ie 36). In parallel, quantum mechanical conformational analysis helped to rationalize SAR observations, led to a proposal of the preferred binding conformation in the absence of co-crystallography data, and allowed the design of 7-azaindole 37 as a second lead in this series. 23361587 Anti-aging molecule, Sirt1: a novel therapeutic target for diabetic nephropathy. Caloric restriction prolongs the lifespan of many species. Therefore, investigators have researched the usefulness of caloric restriction for healthy lifespan extension. Sirt1, an NAD(+)-dependent deacetylase, was identified as a molecule necessary for caloric restriction-related anti-aging strategies. Sirt1 functions as an intracellular energy sensor to detect the concentration of NAD(+), and controls in vivo metabolic changes under caloric restriction and starvation through its deacetylase activity to many targets including histones, nuclear transcriptional factors, and enzymes. During the past decade, investigators have reported the relationship between disturbance of Sirt1 activation and the onset of aging- and obesity-associated diseases such as diabetes, cardiovascular disease and neurodegenerative disorders. Consequently, a calorie restriction-mimetic action of Sirt1 is now expected as a new therapy for these diseases. In addition, recent studies have gradually clarified the role of Sirt1 in the onset of kidney disease. Its activation may also become a new target of treatment in the patients with chronic kidney disease including diabetic nephropathy. In this article, we would like to review the role of Sirt1 in the onset of kidney disease based on previous studies, and discuss its possibility as the target of treatment in diabetic nephropathy. 23420703 Systematic and efficient side chain optimization for molecular docking using a cheapest-path procedure. Molecular docking of small-molecules is an important procedure for computer-aided drug design. Modeling receptor side chain flexibility is often important or even crucial, as it allows the receptor to adopt new conformations as induced by ligand binding. However, the accurate and efficient incorporation of receptor side chain flexibility has proven to be a challenge due to the huge computational complexity required to adequately address this problem. Here we describe a new docking approach with a very fast, graph-based optimization algorithm for assignment of the near-optimal set of residue rotamers. We extensively validate our approach using the 40 DUD target benchmarks commonly used to assess virtual screening performance and demonstrate a large improvement using the developed side chain optimization over rigid receptor docking (average ROC AUC of 0.693 vs. 0.623). Compared to numerous benchmarks, the overall performance is better than nearly all other commonly used procedures. Furthermore, we provide a detailed analysis of the level of receptor flexibility observed in docking results for different classes of residues and elucidate potential avenues for further improvement. © 2013 Wiley Periodicals, Inc. 23160529 HLA-A*24 is an independent predictor of 5-year progression to diabetes in autoantibody-positive first-degree relatives of type 1 diabetic patients. We investigated whether HLA-A*24 typing complements screening for HLA-DQ and for antibodies (Abs) against insulin, GAD, IA-2 (IA-2A), and zinc transporter-8 (ZnT8A) for prediction of rapid progression to type 1 diabetes (T1D). Persistently Ab(+) siblings/offspring (n = 288; aged 0-39 years) of T1D patients were genotyped for HLA-DQA1-DQB1 and HLA-A*24 and monitored for development of diabetes within 5 years of first Ab(+). HLA-A*24 (P = 0.009), HLA-DQ2/DQ8 (P = 0.001), and positivity for IA-2A ± ZnT8A (P < 0.001) were associated with development of T1D in multivariate analysis. The 5-year risk increased with the number of the above three markers present (n = 0: 6%; n = 1: 18%; n = 2: 46%; n = 3: 100%). Positivity for one or more markers identified a subgroup of 171 (59%) containing 88% of rapid progressors. The combined presence of HLA-A*24 and IA-2A(+) ± ZnT8A(+) defined a subgroup of 18 (6%) with an 82% diabetes risk. Among IA-2A(+) ± ZnT8A(+) relatives, identification of HLA-A*24 carriers in addition to HLA-DQ2/DQ8 carriers increased screening sensitivity for relatives at high Ab- and HLA-inferred risk (64% progression; P = 0.002). In conclusion, HLA-A*24 independently predicts rapid progression to T1D in Ab(+) relatives and complements IA-2A, ZnT8A, and HLA-DQ2/DQ8 for identifying participants in immunointervention trials. 23402972 Exploring food effects on indinavir absorption with human intestinal fluids in the mouse intestine. Food can have a significant impact on the pharmacokinetics of orally administered drugs, as it may affect drug solubility as well as permeability. Since fed state conditions cannot easily be implemented in the presently available permeability tools, including the frequently used Caco-2 system, exploring food effects during drug development can be quite challenging. In this study, we investigated the effect of fasted and fed state conditions on the intestinal absorption of the HIV protease inhibitor indinavir using simulated and human intestinal fluids in the in situ intestinal perfusion technique in mice. Although the solubility of indinavir was 6-fold higher in fed state human intestinal fluids (FeHIF) as compared to fasted state HIF (FaHIF), the intestinal permeation of indinavir was 22-fold lower in FeHIF as compared to FaHIF. Dialysis experiments showed that only a small fraction of indinavir is accessible for absorption in FeHIF due to micellar entrapment, possibly explaining its low intestinal permeation. The presence of ritonavir, a known P-gp inhibitor, increased the intestinal permeation of indinavir by 2-fold in FaHIF, while there was no increase when using FeHIF. These data confirm that drug-food interactions form a complex interplay between solubility and permeability effects. The use of HIF in in situ intestinal perfusions holds great promise for biorelevant absorption evaluation as it allows to directly explore this complex solubility/permeability interplay on drug absorption. 23238662 Acute-Phase Serum Amyloid A Protein and Its Implication in the Development of Type 2 Diabetes in the KORA S4/F4 Study. OBJECTIVE We sought to investigate whether elevated levels of acute-phase serum amyloid A (A-SAA) protein precede the onset of type 2 diabetes independently of other risk factors, including parameters of glucose metabolism. RESEARCH DESIGN AND METHODS Within the population-based Cooperative Health Research in the Region of Augsburg (KORA) S4 study, we measured A-SAA concentrations in 836 initially nondiabetic subjects (55-74 years of age) without clinically overt inflammation who participated in a 7-year follow-up examination including an oral glucose tolerance test. RESULTS A-SAA concentrations were significantly associated with incident type 2 diabetes (odds ratio [OR] for a one-SD increase of A-SAA adjusted for age and sex = 1.28 [95% CI 1.08-1.53], P = 0.005), particularly in younger subjects (P value for interaction = 0.047). The association attenuated when adjusting for parameters of glucose metabolism (fasting glucose, fasting insulin, HbA1c, and 2-h glucose; OR 1.16 [0.95-1.42], P = 0.15). Similar analyses for high-sensitive C-reactive protein (hs-CRP) yielded the following ORs: 1.39 (1.10-1.68, P = 0.0006) and 1.13 (0.88-1.45, P = 0.34), respectively. In contrast, A-SAA concentrations were significantly associated with 2-h glucose levels at follow-up even after adjustment for parameters of glucose metabolism (P = 0.008, n = 803). CONCLUSIONS Our findings indicate similarly strong prospective associations with type 2 diabetes for A-SAA and hs-CRP and suggest a potential causal link via postchallenge hyperglycemia. 23115119 STAAR: statistical analysis of aromatic rings. The statistical analysis of aromatic rings program allows for an automated search for anion-π interactions between phenylalanine residues and carboxylic acid moieties of neighboring aspartic acid or glutamic acid residues in protein data bank (PDB) structures. The program is written in C++ and is available both as a standalone code and through a web implementation that allows users to upload and analyze biomolecular structures in PDB format. The program outputs lists of Phe/Glu or Phe/Asp pairs involved in potential anion-π interactions, together with geometrical (distance and angle between the Phe's center of mass and Glu or Asp's center of charge) and energetic (quantum mechanical Kitaura-Morokuma interaction energy between the residues) descriptions of each anion-π interaction. Application of the program on the latest content of the PDB shows that anion-π interactions are present in thousands of protein structures and can possess strong energies, as low as -8.72 kcal/mol. 23600717 Three new Lycopodium alkaloids from Lycopodium obscurum. Chemical investigation on the crude alkaloid portion of Lycopodium obscurum led to isolation of three new fawcettimine-type Lycopodium alkaloids, lycobscurines A-C (1-3), together with three known compounds. Their structures were determined by spectroscopic methods including HR-ESI-MS and NMR techniques. All compounds were tested in an assay for acetylcholinesterase inhibitory activity. 22889561 The human Aurora kinase inhibitor danusertib is a lead compound for anti-trypanosomal drug discovery via target repurposing. New drugs for neglected tropical diseases such as human African trypanosomiasis (HAT) are needed, yet drug discovery efforts are not often focused on this area due to cost. Target repurposing, achieved by the matching of essential parasite enzymes to those human enzymes that have been successfully inhibited by small molecule drugs, provides an attractive means by which new drug optimization programs can be pragmatically initiated. In this report we describe our results in repurposing an established class of human Aurora kinase inhibitors, typified by danusertib (1), which we have observed to be an inhibitor of trypanosomal Aurora kinase 1 (TbAUK1) and effective in parasite killing in vitro. Informed by homology modeling and docking, a series of analogs of 1 were prepared that explored the scope of the chemotype and provided a nearly 25-fold improvement in cellular selectivity for parasite cells over human cells. 23315585 Low-level domoic acid protects mouse cerebellar granule neurons from acute neurotoxicity: role of glutathione. Domoic acid (DomA) is a potent marine neurotoxin. By activating α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid/kainate receptors, DomA induces oxidative stress-mediated apoptotic cell death in neurons. The effect of prolonged (10 days) exposure to a low, nontoxic concentration (5nM) of DomA on acute (intermediate concentration) neurotoxicity of this toxin was investigated in cerebellar granule neurons (CGNs) from wild-type mice and mice lacking the glutamate cysteine ligase (GCL) modifier subunit (Gclm (/)). CGNs from Gclm (/) mice have very low glutathione (GSH) levels and are very sensitive to DomA toxicity. In CGNs from wild-type mice, prolonged exposure to 5nM DomA did not cause any overt toxicity but reduced oxidative stress-mediated apoptotic cell death induced by exposure to an intermediate concentration (100nM for 24h) of DomA. This protection was not observed in CGNs from Gclm (/) mice. Prolonged DomA exposure increased GSH levels in CGNs of wild-type but not Gclm (/) mice. Levels of GCLC (the catalytic subunit of GCL) protein and mRNA were increased in CGNs of both mouse strains, whereas levels of GCLM protein and mRNA, activity of GCL, and levels of GCL holoenzyme were only increased in CGNs of wild-type mice. Chronic DomA exposure also protected wild-type CGNs from acute toxicity of other oxidants. The results indicate that CGNs from Gclm (/) mice, which are already more sensitive to DomA toxicity, are unable to upregulate their GSH levels. As Gclm (/) mice may represent a model for a common human polymorphism in GCLM, such individuals may be at particular risk for DomA-induced neurotoxicity. 22972178 GH and cortisol responses following an acute session of respiratory muscle endurance training in severely obese patients. It is well established that obese patients are hypo-responsive to classical GH-releasing stimuli, including aerobic exercise. Recently, we have demonstrated that whole body vibration was able to markedly stimulate GH secretion in obese patients, thus suggesting that this refractoriness is not absolute but dependent on the GH-releasing stimulus. Furthermore, we have shown the ability of a respiratory muscle endurance training (RMET) to stimulate GH and cortisol secretion in healthy subjects. The objective of this study was to evaluate the effects of RMET on GH and cortisol responses in severely obese patients. Eight severely obese patients (4 M/4 F, mean age±SEM: 22.8±1.6 years, body mass index, BMI: 39.9±1.1 kg/m2) underwent an incremental progressive RMET protocol of 11 daily sessions, obtained through the use of a specifically designed respiratory device (Spiro Tiger®). The 12th session of RMET (15 min duration: 1 min at a respiration rate of 28 acts/min, 5 min at 32 acts/min, 5 min at 34 acts/min, 4 min at 36 acts/min) was associated with blood samplings for determination of GH, cortisol, and lactate (LA) levels. An age- and sex-matched normal-weighted control group (n=7, 4 M/3 F, age: 26.1±3.1 years, BMI: 22.4±0.6 kg/m2) was also recruited. In both normal-weighted subjects and obese patients, GH secretion significantly increased after a 15-min RMET session. Although serum GH levels at 30 min were higher in normal-weighted subjects than in obese patients, there was no statistically significant difference in either GH peaks or net GH areas under the curve between the 2 groups. RMET significantly increased serum cortisol levels in normal-weighted subjects, but was associated to a progressive cortisol decline in obese patients. RMET stimulated LA production, with no significant differences in normal-weighted subjects and in obese patients. A 15-min RMET session was capable to induce a GH response in severely obese patients, which was comparable to that recorded in normal-weighted subjects. A progressive decline in serum cortisol levels occurred in obese patients after RMET, while an opposite pattern (i. e., a significant cortisol increase) was found in normal-weighted subjects. Optimization of long-term RMET protocols could represent a valid strategy to (physiologically) stimulate GH/IGF-I system in those GH hyposecretory states such as obesity. 23276161 Thermodynamically consistent force fields for the assembly of inorganic, organic, and biological nanostructures: the INTERFACE force field. The complexity of the molecular recognition and assembly of biotic-abiotic interfaces on a scale of 1 to 1000 nm can be understood more effectively using simulation tools along with laboratory instrumentation. We discuss the current capabilities and limitations of atomistic force fields and explain a strategy to obtain dependable parameters for inorganic compounds that has been developed and tested over the past decade. Parameter developments include several silicates, aluminates, metals, oxides, sulfates, and apatites that are summarized in what we call the INTERFACE force field. The INTERFACE force field operates as an extension of common harmonic force fields (PCFF, COMPASS, CHARMM, AMBER, GROMACS, and OPLS-AA) by employing the same functional form and combination rules to enable simulations of inorganic-organic and inorganic-biomolecular interfaces. The parametrization builds on an in-depth understanding of physical-chemical properties on the atomic scale to assign each parameter, especially atomic charges and van der Waals constants, as well as on the validation of macroscale physical-chemical properties for each compound in comparison to measurements. The approach eliminates large discrepancies between computed and measured bulk and surface properties of up to 2 orders of magnitude using other parametrization protocols and increases the transferability of the parameters by introducing thermodynamic consistency. As a result, a wide range of properties can be computed in quantitative agreement with experiment, including densities, surface energies, solid-water interface tensions, anisotropies of interfacial energies of different crystal facets, adsorption energies of biomolecules, and thermal and mechanical properties. Applications include insight into the assembly of inorganic-organic multiphase materials, the recognition of inorganic facets by biomolecules, growth and shape preferences of nanocrystals and nanoparticles, as well as thermal transitions and nanomechanics. Limitations and opportunities for further development are also described. 23534440 Bioinformatics and Molecular Dynamics Simulation Study of L1 Stalk Non-Canonical rRNA Elements: Kink-Turns, Loops, and Tetraloops. The L1 stalk is a prominent mobile element of the large ribosomal subunit. We explore the structure and dynamics of its non-canonical rRNA elements, which include two kink-turns, an internal loop, and a tetraloop. We use bioinformatics to identify the L1 stalk RNA conservation patterns and carry out over 11.5 μs of MD simulations for a set of systems ranging from isolated RNA building blocks up to complexes of L1 stalk rRNA with the L1 protein and tRNA fragment. We show that the L1 stalk tetraloop has an unusual GNNA or UNNG conservation pattern deviating from major GNRA and YNMG RNA tetraloop families. We suggest that this deviation is related to a highly conserved tertiary contact within the L1 stalk. The available X-ray structures contain only UCCG tetraloops which in addition differ in orientation (anti vs syn) of the guanine. Our analysis suggests that the anti orientation might be a mis-refinement, although even the anti interaction would be compatible with the sequence pattern and observed tertiary interaction. Alternatively, the anti conformation may be a real substate whose population could be pH-dependent, since the guanine syn orientation requires protonation of cytosine in the tertiary contact. In absence of structural data, we use molecular modeling to explore the GCCA tetraloop that is dominant in bacteria and suggest that the GCCA tetraloop is structurally similar to the YNMG tetraloop. Kink-turn Kt-77 is unusual due to its 11-nucleotide bulge. The simulations indicate that the long bulge is a stalk-specific eight-nucleotide insertion into consensual kink-turn only subtly modifying its structural dynamics. We discuss a possible evolutionary role of helix H78 and a mechanism of L1 stalk interaction with tRNA. We also assess the simulation methodology. The simulations provide a good description of the studied systems with the latest bsc0χOL3 force field showing improved performance. Still, even bsc0χOL3 is unable to fully stabilize an essential sugar-edge H-bond between the bulge and non-canonical stem of the kink-turn. Inclusion of Mg(2+) ions may deteriorate the simulations. On the other hand, monovalent ions can in simulations readily occupy experimental Mg(2+) binding sites. 23220514 Effect of linalool as a component of Humulus lupulus on doxorubicin-induced antitumor activity. As malignant neoplasm is a major public health problem, there is a need for the development of a novel modulator that enhances antitumor activity and reduces adverse reactions to antitumor agents. In this study, the effects of some volatile oil components in Humulus lupulus on doxorubicin (DOX) permeability in tumor cells and DOX-induced antitumor activity were examined. In vitro, DOX levels in tumor cells by combined linalool as its component significantly increased in the DOX influx system, and the increased effect by linalool on DOX cytotoxicity was shown. In vivo, the combination of DOX with linalool significantly decreased tumor weight compared with that of DOX alone treated group. The promotion of DOX influx level by combined linalool did not depend on energy, whereas it was suppressed by the absence of Na(+). This promoting effect was suppressed by the presence of S-(4-nitrobenzyl)-6-thioinosine and inhibited dependently on phlorizin concentration. It is considered that linalool promoted DOX influx in tumor cells because of its action on DOX transport through concentrative Na(+)-dependent nucleoside transporter 3, which increased DOX concentration in tumor cells and thus enhanced the antitumor activity of DOX. Therefore, linalool as a food component is anticipated to be an effective DOX modulator. 23456816 A novel model approach for esophageal burns in rats: A comparison of three methods. BACKGROUND: Corrosive esophageal injury causes serious clinical problems. We aimed to create a new experimental esophageal burn model using a single catheter without a surgical procedure. Materials and methods: We conducted the study with two groups of 12 male rats that fasted for 12 h before application. A modified Foley balloon catheter was inserted into the esophageal lumen. The control group was given 0.9% sodium chloride, while the experimental group was given 37.5% sodium hydroxide with the other part of the catheter. After 60s, esophagus was washed with distilled water. The killed rats were examined using histopathological methods after 28 days. RESULTS: In comparison with the histopathological changes experienced by the study groups, the control groups were observed to have no pathological changes. Basal cell degeneration, dermal edema, and a slight increase in the keratin layer and collagen density of submucosa due to stenosis were all observed in the group subjected to esophageal corrosion. CONCLUSION: A new burn model can thus, we believe, be created without the involvement of invasive laparoscopic surgery and general anesthesia. The burn in our experiment was formed in both the distal and proximal esophagus, as in other models; it can also be formed optionally in the entire esophagus. 23497887 Kinetics of protein physicochemical changes induced by heating in meat using mimetic models: (2) effects of fibre type, peroxides and antioxidants. Heating-induced changes in meat proteins were investigated using models made of aqueous suspensions of myofibrils according to muscle fibre types and cellular compounds (oxidants and antioxidants). These changes were evaluated by measurements of carbonyl groups and protein surface hydrophobicity. Model results were compared to trial results obtained on pork meat (M. Longissimus dorsi) heated under the same conditions (45 and 75°C, from 5 to 120 min). Myofibrillar proteins from α-white fibres were more sensitive to oxidation and thermal denaturation than those from β-red fibres. At 45°C, there were negligible differences due to peroxide or antioxidant types. At 75°C, organic peroxides (ROOH) were less oxidative than hydrogen peroxide (H2O2), and antioxidant enzymes were less efficient than vitamin E and carnosine at protecting proteins against oxidation. Protein oxidation observed in meat is lower than in the mimetic models and the increase in hydrophobicity remained limited in meat. 23017414 Soymilk phenolic compounds, isoflavones and antioxidant activity as affected by in vitro gastrointestinal digestion. The aim of this research was to evaluate changes in the phenolic compounds, isoflavones and antioxidant activity of soymilk following in vitro gastrointestinal digestion (including dialysis). Gastric digestion significantly influenced the release of bioactive substances from the soymilk matrix, increasing the concentration of total phenolic components (35% as the sum of individuals and 14% by Folin-Ciocalteu [F-C] method), total isoflavone content (22%) and total antioxidant activity (76%). The concentration of all those compounds was reduced significantly in the duodenal fraction in comparison to gastric digestion and their lowest concentration was observed in the dialysed fraction, where phenolic acids were not detected. The bioaccessibility of soymilk phenolic compounds was 15% as the sum of individuals and 20% by F-C assay; isoflavones 36% and constituents with antioxidant activity 27%. Results suggest that most of these compounds were sufficiently available to be absorbed and could contribute health benefits. 23184251 Substrate ambiguity among the nudix hydrolases: biologically significant, evolutionary remnant, or both? Many members of the nudix hydrolase family exhibit considerable substrate multispecificity and ambiguity, which raises significant issues when assessing their functions in vivo and gives rise to errors in database annotation. Several display low antimutator activity when expressed in bacterial tester strains as well as some degree of activity in vitro towards mutagenic, oxidized nucleotides such as 8-oxo-dGTP. However, many of these show greater activity towards other nucleotides such as ADP-ribose or diadenosine tetraphosphate (Ap(4)A). The antimutator activities have tended to gain prominence in the literature, whereas they may in fact represent the residual activity of an ancestral antimutator enzyme that has become secondary to the more recently evolved major activity after gene duplication. Whether any meaningful antimutagenic function has also been retained in vivo requires very careful assessment. Then again, other examples of substrate ambiguity may indicate as yet unexplored regulatory systems. For example, bacterial Ap(4)A hydrolases also efficiently remove pyrophosphate from the 5' termini of mRNAs, suggesting a potential role for Ap(4)A in the control of bacterial mRNA turnover, while the ability of some eukaryotic mRNA decapping enzymes to degrade IDP and dIDP or diphosphoinositol polyphosphates (DIPs) may also be indicative of new regulatory networks in RNA metabolism. DIP phosphohydrolases also degrade diadenosine polyphosphates and inorganic polyphosphates, suggesting further avenues for investigation. This article uses these and other examples to highlight the need for a greater awareness of the possible significance of substrate ambiguity among the nudix hydrolases as well as the need to exert caution when interpreting incomplete analyses. 23516024 Multifocal motor neuropathy: current therapies and novel strategies. Multifocal motor neuropathy (MMN) is a purely motor mononeuritis multiplex characterized by the presence of conduction block on motor but not on sensory nerves and by the presence of high titers of anti-GM1 antibodies. Several data point to a pathogenetic role of the immune system in this neuropathy, although this has not yet been proved. Several uncontrolled studies and randomized controlled trials have demonstrated the efficacy of therapy with high-dose intravenous immunoglobulin (IVIg) in MMN. However, this therapy has a short-lasting effect that needs to be maintained with periodic infusions. This can be partly overcome by the use of subcutaneous immunoglobulin (SCIg) at the same dose. The high cost and need for repeated infusions have led to the search for other immune therapies, the efficacy of which have not yet been confirmed in randomized trials. In addition, some therapies, including corticosteroids and plasma exchange, are not only ineffective but have been associated with clinical worsening. More recently, a number of novel therapies have been investigated in MMN, including interferon-β1a, the anti-CD20 monoclonal antibody rituximab and the complement inhibitor eculizumab. Preliminary data from open-label uncontrolled studies show that some patients improve after these therapies; however, randomized controlled trials are needed to confirm efficacy. Until then, IVIg (and SCIg) remains the mainstay of treatment in MMN, and the use of other immune therapies should only be considered for patients not responding to, or becoming resistant to, IVIg. 23376437 In vitro biokinetics of chlorpromazine and the influence of different dose metrics on effect concentrations for cytotoxicity in Balb/c 3T3, Caco-2 and HepaRG cell cultures. The extrapolation of in vitro to in vivo toxicity data is a challenge. Differences in sensitivity between cell systems may be due to intrinsic properties of the cell but also because of differences in exposure. In this study, the cytotoxicity and biokinetics of the antipsychotic chlorpromazine (CPZ) were studied in in vitro assays using different cell types and exposure conditions. Different dose metrics were assessed to express the sensitivity to CPZ. The biokinetics of CPZ were measured in cell cultures of Balb/c 3T3, Caco-2 and HepaRG cells. Cytotoxicity was measured by Alamar Blue and expressed using different dose metrics, including the nominal, measured total and measured free CPZ medium concentrations. CPZ was taken up by the cells; the highest amounts in the cell compartments were found in the Caco-2 and HepaRG cells. CPZ was highly protein-bound in the Caco-2 cell medium containing 10% fetal bovine serum, resulting in lower bioavailable exposure concentrations. Moreover, also uptake into the cells strongly influenced the concentration in the medium. The Balb/c 3T3 cells were the most sensitive to the toxic effect of CPZ. The use of different dose metrics influenced the cytotoxicity results found in the three cell types. The data show that in comparing the sensitivity of the tested cell systems, the freely dissolved concentration is a more appropriate dose metric than total concentration in the medium. The ranking in sensitivity of the three cell types for CPZ was dependent on the dose metric used. 23439033 Orthogonal patterning of multiple biomolecules using an organic fluorinated resist and imprint lithography. The ability to spatially deposit multiple biomolecules onto a single surface with high-resolution while retaining biomolecule stability and integrity is critical to the development of micro- and nanoscale biodevices. While conventional lithographic patterning methods are attractive for this application, they typically require the use of UV exposure and/or harsh solvents and imaging materials, which may be damaging to fragile biomolecules. Here, we report the development of a new patterning process based on a fluorinated patterning material that is soluble in hydrofluoroether solvents, which we show to be benign to biomolecules, including proteins and DNA. We demonstrate the implementation of these materials into an orthogonal processing system for patterning multibiomolecule arrays by imprint lithography at room temperature. We further showcase this method's capacity for fabricating patterns of receptor-specific ligands for fundamental cell studies. 23534413 Virtual and in vitro bioassay screening of phytochemical inhibitors from flavonoids and isoflavones against xanthine oxidase and cyclooxygenase-2 for gout treatment. Synthetic drugs such as allopurinol and benzbromarone are commonly used to treat the complex pathogenesis of gout, a metabolic disease that results from an inflammation of the joints caused by precipitation of uric acid. We seek to discover novel phytochemicals that could treat gout, by targeting the xanthine oxidase and cyclooxygenase-2 enzymes. In this study, we report the screening of nine compounds of flavonoids from the ZINC and PubChem databases (containing 2092 flavonoids) using the IGEMDOCK software tool against the xanthine oxidase and cyclooxygenase-2 3D protein structures. Each compound was also evaluated by an in vitro bioassay testing the inhibition of xanthine oxidase and cyclooxygenase-2. Myricetin and luteolin were found to be the potential dual inhibitors of xanthine oxidase and cyclooxygenase-2 as demonstrated by IC(50): 62.7 and 3.29 μg/mL (xanthine oxidase)/70.8 and 16.38 μg/mL (cyclooxygenase-2), respectively. In addition, structure-activity relationships and other important factors of the flavonoids binding to the active site of xanthine oxidase and cyclooxygenase-2 were discussed, which is expected for further rational drug design. 23307290 Natalizumab therapy for multiple sclerosis. The treatment of relapsing remitting multiple sclerosis has witnessed major progress since the first effective disease modifying treatment, ß-interferon, became available in 1993. One of the most remarkable new treatments has been natalizumab. This review describes the evolution of this humanized anti-α4ß1 monoclonal antibody, from preclinical experimental research through proof-of-concept (phase 1/2) and pivotal (phase 3) clinical trials to the now extensive experience of its use in clinical practice. The future potential and challenges of natalizumab and oral therapies with a similar mechanism of action are also discussed. 23066090 A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion. Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within the research field. Herein, we report the identification and characterization of 3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile (ESI-09), a novel noncyclic nucleotide EPAC antagonist that is capable of specifically blocking intracellular EPAC-mediated Rap1 activation and Akt phosphorylation, as well as EPAC-mediated insulin secretion in pancreatic β cells. Using this novel EPAC-specific inhibitor, we have probed the functional roles of overexpression of EPAC1 in pancreatic cancer cells. Our studies show that EPAC1 plays an important role in pancreatic cancer cell migration and invasion, and thus represents a potential target for developing novel therapeutic strategies for pancreatic cancer. 23273412 Synthesis and antioxidant activity of thymol and carvacrol based Schiff bases. Thymol and carvacrol are well known antioxidants found in the extract of the plants of thyme species. The Schiff bases of 2-iso-propyl-5-methyl-phenol (thymol/1a), 2-tert-butyl-5-methyl-phenol (1b) and 5-iso-propyl-2-methyl-phenol (carvacrol/1c) exhibited much better antioxidant activity than thymol and carvacrol in DPPH assay. Ten compounds (4k, 4l, 4r, 5k, 5l, 5q, 5r, 6k, 6l and 6r) showed better or similar activity as compared to the reference compound ascorbic acid. Twenty-four most active compounds were also screened by ABTS method and showed 60-90% inhibition at 5 μg/mL concentration. 23635005 An Antioxidative Carbohydrate Polymer from Enhydra fluctuans and Its Interaction with Bovine Serum Albumin. Enhydra fluctuans leaves are traditionally sold on Indian markets for various health benefits. However no phytochemical study on its high molecular weight compound has so far been performed. Chemical, chromatographic, ESI-TOF-MS and NMR analyses of the water extracted carbohydrate polymer (CP) of E. fluctuans leaves showed the presence of a 24 kDa arabinogalactan having a (1,3)-linked β-D-Galp main chain, substituted at O-6 by (1,6)-linked β-D-Galp side chains. The latter residues were substituted at O-3 by (1,3)-, (1,5)- and (1,3,5)-linked α-L-Araf chains, and nonreducing end-units of α-L-Araf and β-D-Galp. This polymer contained esterified phenolic acids. Biochemical analysis revealed similarity in antioxidative potential between the identified carbohydrate polymer and known standard antioxidants. The highly branched side chains and the phenolic acid residues of the arabinogalactan might be the functional sites. Fluorimetric and ultraviolet spectrometric analyses showed that the studied carbohydrate polymer can form complex with bovine serum albumin having binding constant K=2.42×10(6)/M and changes its microenvironment. Thus, traditional aqueous extraction method provides a carbohydrate polymer, which stimulates a fair biological response: this could represent an interesting approach in phytotherapeutic treatments. 23441753 Loading and distribution of a model small molecule drug in poly(N-isopropylacrylamide) brushes: a neutron reflectometry and AFM study. The structure of a hydrated poly(N-isopropylacrylamide) brush loaded with 5 vol % Isoniazid is studied as a function of temperature using neutron reflectometry (NR) and atomic force microscopy (AFM). NR measurements show that Isoniazid increases the thickness of the brush before, during and after the polymer collapse, and it is retained inside the brush at all measured temperatures. The Isoniazid concentration in the expanded brush is ~14% higher than in the bulk solution, and the concentration nearly doubles in the collapsed polymer, suggesting stronger binding between Isoniazid and the polymer compared to water, even at temperatures below the lower critical solution temperature (LCST) where the polymer is hydrophilic. Typically, additives that bind strongly to the polymer backbone and increase the hydrophilicity of the polymer will delay the onset of the LCST, which is suggested by AFM and NR measurements. The extent of small-molecule loading and distribution throughout a thermo-responsive polymer brush, such as pNIPAAm, will have important consequences for applications such as drug delivery and gating. 23116113 In vivo DNA electrotransfer for immunotherapy of cancer and neurodegenerative diseases. Electroporation is the process commonly referred to the transient increase in the permeability of cell membranes on submission to electric field pulses. Electroporation has become an increasingly extensive method to enhance in vivo DNA delivery for both gene therapy applications as well as for delivery of DNA vaccines, mostly against cancer. In vivo gene electrotransfer is of special interest since it is the most efficient non-viral strategy for gene delivery and it is worthy of low manufacturing costs, ease of realization and favorable safety profile. No adverse findings observed in toxicology and biodistribution/integration studies have been warranted for the evaluation of this approach in humans. Therefore, gene delivery followed by electroporation is currently being investigated in several clinical trials. The positive outcomes of early studies suggest that the efficacy of gene delivery and immunogenicity has greatly improved by electroporation. This review briefly summarizes salient features and recent findings that have contributed to the rapid progress of electroimmunotherapy as well as an overview of advanced clinical studies in oncology. Translation of in vivo DNA electrovaccination for neurodegenerative diseases as well as future expectations are also discussed. 23323680 In situ TEM of two-phase lithiation of amorphous silicon nanospheres. To utilize high-capacity Si anodes in next-generation Li-ion batteries, the physical and chemical transformations during the Li-Si reaction must be better understood. Here, in situ transmission electron microscopy is used to observe the lithiation/delithiation of amorphous Si nanospheres; amorphous Si is an important anode material that has been less studied than crystalline Si. Unexpectedly, the experiments reveal that the first lithiation occurs via a two-phase mechanism, which is contrary to previous understanding and has important consequences for mechanical stress evolution during lithiation. On the basis of kinetics measurements, this behavior is suggested to be due to the rate-limiting effect of Si-Si bond breaking. In addition, the results show that amorphous Si has more favorable kinetics and fracture behavior when reacting with Li than does crystalline Si, making it advantageous to use in battery electrodes. Amorphous spheres up to 870 nm in diameter do not fracture upon lithiation; this is much larger than the 150 nm critical fracture diameter previously identified for crystalline Si spheres. CHEMDNER_CORPUS_BIOCREATIVE_4/CHEMDNER_TRAIN/cdi_ann_training_13-07-31.txt0000644002344200234200000125644612176242610026063 0ustar mkrallingerBioinfoUnix21826085 haloperidol 22080034 aflatoxin 22080035 S 22080035 arsenic 22080035 cadmium 22080035 copper 22080035 glutathione 22080035 malondialdehyde 22080035 superoxide 22080037 Mercury 22080037 mercury 22080037 nitric oxide 22258629 Chromium 22258629 chromium 22258629 graphite 22258629 malondialdehyde 22288603 mikanolide 22294443 PCAHs 22294443 Polycyclic aromatic hydrocarbons 22294443 benzo(a)anthracene 22294443 benzo(a)pyrene 22294443 benzo(e)pyrene 22294443 benzoflouroanthene 22294443 cyclohexane 22294443 fluoranthene 22294443 methanolic potassium hydroxide 22294443 polycyclic aromatic hydrocarbons 22294443 pyrene 22301816 Thiovit 22301816 captafol 22301816 captan 22301818 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide 22301818 MTT 22303963 acetonitrile 22303963 formic acid 22303963 steroidal saponins 22304302 (25S)-1β,3β,4β-trihydroxyspirostan-5β-yl-O-β-D-glucopyranoside 22304302 MTT 22304302 furostanol 22304302 kitigenin-5β-O-β-D-glucopyranoside 22304302 reinocarnoside A (1), B (2) and C (3) 22304302 spirostanols 22304302 steroidal glycosides 22310169 O 22310169 PAH 22310169 PAHs 22310169 S 22310169 ethoxyresorufine 22310169 glutathione 22310169 polycyclic aromatic hydrocarbons 22310169 thiobarbituric 22310170 TCS 22310170 phosphate 22310170 triclosan 22312034 4aα,7β,7aα-nepetalactone 22312034 SDS 22312034 elemol 22312034 germacrene 22312034 polyacrylamide 22312034 sodium dodecyl sulphate 22317823 Al 22317823 Aluminum 22317823 aluminum 22349814 PI(3,4,5)P3 22349814 monoglyceride 22349814 phosphatidic acid 22349814 phosphatidylinositol 22349814 phosphoinositides 22349814 phosphoinositol(3,4)P2 22349814 phosphoinositol(3,4,5)P3 22349814 phosphoinositol(3,5)P2 22360797 acacetin 22360797 acacetin 7-methyl ether 22360797 acetone 22360797 betulin aldehyde 22360797 betulinic acid 22360797 betulon aldehyde 22360797 betulonic acid 22360797 flavonoids 22360797 lupenone 22360797 lupeol 22360797 morolic acid 22360797 moronic acid 22360797 oleanolic acid 22360797 oleanolic aldehyde 22360797 squalene, α- and β-amyrin 22360797 stigmasterol 22360797 triacontanol 22360797 β-sitosterol 22360797 β-sitosteryl and stigmasteryl linoleates 22370634 RAP 22370634 Rapamycin 22370634 rapamycin 22370645 WP1066 22370645 gefitinib 22370645 phosphatidyl inositol 22385272 isomenthone 22385272 isopulegone 22385272 limonene 22385272 menthone 22385272 pulegone 22394118 Carbon 22394118 carbon 22394118 sucrose 22394118 withanolide A 22397600 nimesulide 22397675 2-pyrrolidone 22397675 IVM 22397675 Ivermectin 22397675 N-methyl-2-pyrrolidone 22397675 NMP 22397675 PLA 22397675 benzyl benzoate 22397675 ivermectin 22397675 poly(D,L-lactide) 22397675 triacetine 22401597 1α,3β,25-trihydroxy-9(11)-ene-16-one-9,10-seco-9,19-cyclolanostane 22401597 9,10-seco-9,19-cyclolanostane 22401597 fatty alcohols 22401597 triterpene 22404642 24-methylenecicloartan-3β-ol 22404642 3,3'-di-O-methylellagic acid 22404642 3β-O-octadecanoyllupeol 22404642 cicloart-23-ene-3β,25-diol 22404642 ellagic acid 22404642 glut-5-en-3β-ol 22404642 triterpenoids 22420410 Trans-cyclo-(D-tryptophanyl-L-tyrosyl) 22420410 amino acid 22420410 diketopiperazine 22420410 trans-cyclo-(D-tryptophanyl-L-tyrosyl) 22424088 DPPH 22424088 eugenol 22424088 superoxide 22424117 8-O-cafeoyl massenoside 22424117 8-O-trans-cinnamoyl caryoptoside 22424117 8-O-trans-cinnamoyl mussaenoside 22424117 8-O-trans-cinnamoyl shanzhiside methylester 22424117 acetyl 22424117 ethylacetate 22424117 iridoid glucosides 22424117 iridoids 22430207 glucose 22445601 Glutamate 22445601 LY541850 22445601 amphetamine 22445601 glutamate 22445601 phencyclidine 22451355 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide 22455800 3-alkyl-2,6-diarylpiperidin-4-one 22455800 4-hydroxy-3,4-dialkyl-2,6-diaryl-piperidine 22455800 Grignard reagent 22455800 piperdin-4-ol 22468693 acetone 22468693 chloroform 22468693 diethyl ether 22468693 eicosane 22468693 oleic acid 22468693 saponins 22468693 stigmasterol 22468693 vitamin E 22468741 Isoleucine 22468741 arsenic 22468741 calcium 22468741 magnesium 22468741 potassium 22468741 sodium dodecyl sulphate polyacrylamide 22469981 doxycycline 22469981 tetracycline 22469988 ATP 22469988 fatty acids 22469988 glucose 22469988 oxygen 22475014 C(21) 22475014 C21 22475014 Glaucogenin E 22475014 steroid 22480291 acetonitrile 22480291 boeravinone B 22480291 boeravinone E 22480291 boeravinone E and B 22480291 orthophosphoric acid 22480291 rotenoids 22489960 17β-estradiol 22489960 7-ethoxyresorufin 22489960 GSH 22489960 O 22489960 benzo(a)pyrene 22489960 glutathione 22489960 testosterone 22489960 triglyceride 22497567 18F 22497567 18F-IMC 22497567 F-IMC 22497567 IMC 22497567 fluoro-indomethacin 22497567 indomethacin 22502647 furostanol 22502647 polyhydroxyl 22502647 saponin 22502647 saponins 22507666 (R,S)-3,5-dihydroxyphenylglycine 22507666 2-methyl-6-(phenylethynyl)pyridine hydrochloride 22507666 AMPA 22507666 DHPG 22507666 Glutamate 22507666 MPEP 22507666 Ser 22507666 adenosine 22507666 cAMP 22507666 dopamine 22507666 glutamate 22510064 NaOH 22510064 Poloxamer 407 22510064 poloxamer 407 22510064 rebamipide 22510064 sodium hydroxide 22512590 Nikkomycin Z 22512590 nikkomycin 22512590 polyoxin 22516666 CO(2) 22516666 Venlafaxine 22516666 benzodiazepines 22516666 carbon dioxide 22516666 lorazepam 22516666 paroxetine 22516666 pregabalin 22516666 venlafaxine 22533550 2-bromoacetic acid 22533550 N-isobutyl-4,5-epoxy-2(E)-decenamide 22533550 Octanal 22533550 amide 22546615 (S)-3,4-DCPG 22546615 (S)-3,4-dicarboxyphenylglycine 22546615 6-hydroxydopamine 22546615 DCPG 22546615 Glutamate 22546615 decanoate salt 22546615 dopamine 22546615 glutamate 22546615 haloperidol 22546615 reserpine 22546616 GABA 22546616 [(11)C]Ro15-4513 22546616 benzodiazepine 22546616 gamma-amino-butyric-acid 22548348 C-geranylated flavonoids 22548348 Tomentomimulol 22548348 methanol 22548348 mimulone B 22548348 tanariflavanone D 22548348 tomentomimulol 22548364 (3R,4S,5R,6R)-3,4,5,6-tetrahydro-4-hydroxy-3,5,6-trimethyl-2H-pyran-2-one 22548364 2-phenylacetamide 22548364 N-trans-cinnamoyl 2-amino-3a,4,5,6,7,8,9,10,11,12,13,13a-dodecahydrocyclododeca[d]oxazole 22548364 cyclododeca[d]oxazole 22548364 di(1H-pyrrol-2-yl)methanone 22548364 indolyl-3-carboxylic acid 22548364 pimprinine 22551786 GRN-529 22551786 MTEP 22551786 glutamate 22559719 Citronellal 22559719 carbon dioxide 22559719 citronellal 22559719 oxygenated monoterpenes 22561337 estrogen 22563917 BBH 22563917 Berberine hydrochloride 22563917 Tween-80 22563917 berberine hydrochloride 22563917 ethyl linoleate 22563917 glycerol 22563917 oleic acid 22579656 GABA 22579656 THDOC 22579656 allopregnanolone 22579656 allotetrahydrodeoxycorticosterone 22579656 estrogens 22579656 progesterone 22583008 Fatty acid 22583008 Saturated fatty acids 22583008 arachidonic (C20 : 4ω-6) and eicosapentaenoic (C20 : 5ω-3) acids 22583008 fatty acid 22583008 fatty acids 22583008 monounsaturated fatty acids 22583008 polyunsaturated fatty acids 22585425 APC 22585425 Allylpyrocatechol 22585425 GSH 22585425 acetate 22585425 allylpyrocatechol 22585425 myristate 22585425 oxygen 22585425 phorbol 22585425 sodium ascorbate 22585425 superoxide 22585450 N-[3(aminomethyl) benzyl]-acetamidine 22585450 STZ 22585450 acetylcholine 22585450 dihydrochloride 22585450 malondialdehite 22585450 nitrate 22585450 nitric oxide 22585450 nitrite 22585450 noradrenaline 22585450 streptozotocin 22594605 1,3-dimethylpyrimidine-2,4(1H,3H)-dione 22594605 9-acetyl-1,3,7-trimethyl-pyrimidinedione 22594605 caffeine 22594605 pyrimidinedione 22610853 Curcumin 22610853 cholesterol 22610853 curcumin 22610853 curcuminoids 22610853 triglycerides 22616559 apigenin 7-O-β-D-cellobioside 22616559 apigenin 7-O-β-D-cellobiosyl-4'-O-β-D-glucopyranoside 22616559 naringenin 22616577 24-hydroxytormentic acid 22616577 3-O-β-D-glucopyranosylsitosterol 22616577 Arjunolic acid 22616577 C-C 22616577 NaIO4 22616577 SiO2 22616577 THF 22616577 acetal triterpenes 22616577 bicyclotriacetal of β-sitosterol 22616577 hydroxyl 22616577 lactol pentacyclic triterpenes 22616577 silica gel 22616577 sodium periodate 22616577 vicinal diol 22619070 terpene 22619070 terpinen-4-ol 22623520 Methiocarb 22623520 carbamate 22623520 glutathione 22623520 malondialdehyde 22623520 methiocarb 22623520 superoxide 22623520 taurine 22623520 vitamin E 22625411 sulfonamide 22625411 sulfonamides 22625416 omega-3 fatty acids 22625416 sterols 22625416 terpenes 22625416 terpenoid 22625416 tocochromanols 22628017 H2 O2 22628017 Succinate 22628017 anthocyanin 22628017 anthocyanins 22628017 cyanidin-3-galactoside 22628017 malate 22628017 malvidin-3-galactoside 22628017 malvidin-3-glucoside 22628017 pyruvate 22628265 4-O-methylhonokiol 22628265 Ethanol 22628265 ethanol 22628265 honokiol 22628265 magnolol 22628265 neolignan 22628265 nitric oxide 22628265 obovatol 22634360 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 22634360 6-hydroxydopamine 22634360 Glutamate 22634360 L-AP4 22634360 MPTP 22634360 VU0155041 22634360 glutamate 22640571 (1)H 22640571 16-Isopropyl-5, 9-dimethyltetracyclo [10.2.2.0(1, 10).0(4, 9)] hexadec-15-ene-5, 14-dicarboxylic acid 22640571 16-isopropyl-5, 9-dimethyltetracyclo [10.2.2.0(1, 10).0(4, 9)] hexadec-15-ene-5, 14-dicarboxylic acid 22640571 Schiff bases 22641218 Celastrol 22644836 cholesterol 22644836 glucose 22644836 triglycerides 22648529 flavonoids 22648529 hopane 22648529 methanol 22648529 oleanane 22648529 saponins 22658648 Myo-inositol 22658648 glucose 22658648 inositol 22658648 myo-inositol 22659473 Glutamate 22659473 glutamate 22660443 Azole 22660443 azoles 22660443 corticosteroids 22661401 Cu(2+) 22661401 Mn(2+) 22661401 Ni(2+) 22661401 Zn(2+) 22669363 N-acetylgalactosamine 22670797 (E)-2-(4-tert-butylbenzylidene) hydrazinecarbothioamide 22670797 4-tert-butylphenylthiourea 22670797 QNT3-18 22670797 QNT3-20 22670797 octanol 22677475 TBBPA 22677475 Tetrabromobisphenol A 22677475 tetrabrombisphenol A 22678994 H2 O2 22678994 Polymethoxylated flavones 22678994 acetoxymethyl ester 22678994 calcium 22678994 nobiletin 22678994 poly (ADP-ribose) 22678994 tangeretin 22683935 2,4-dinitrochlorobenzene 22683935 ammonium-hexachloroplatinate 22683935 cinnamaldehyde 22683935 cinnamic-alcohol 22683935 eugenol 22683935 isoeugenol 22683935 nickel-sulfate 22683935 octanoic acid 22683935 paraphenylendiamine 22683935 phenol 22683935 salicylic acid 22683935 sodium lauryl sulfate 22683935 tetramethylthiuram disulfide 22693035 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) 22693035 2,2-diphenyl-1-picrylhydrazyl 22693035 8-hydroxycirsimaritin 22693035 ABTS 22693035 Apigenin-7-O-glucoside 22693035 DPPH 22693035 Fe(II) 22693035 Nepetanudoside B 22693035 apigenin 22693035 butylhydroxytoluene 22693035 cirsimaritin 22693035 ethyl acetate 22693035 ixoroside 22693035 luteolin 22693035 methanol 22693035 n-Butanol 22693035 n-butanol 22693035 n-hexane 22693035 oleanolic acid 22693035 ursolic acid 22694738 -3,5-di-O-β-glucosides of delphinidin 22694738 Anthocyanins 22694738 acylated anthocyanins 22694738 anthocyanin 22694738 anthocyanins 22694738 cyanidin 22694738 cyanidin-3-O-[6-O-(4-O-E-caffeoyl-O-α-rhamnopyranosyl)-β-glucopyrano]-5-O-β-glucopyranoside 22694738 cyanidin-3-O-[6-O-(4-O-E-p-coumaroyl-O-α-rhamnopyranosyl)-β-glucopyrano]-5-O-β-glucopyranoside 22694738 cyanidine 22694738 malvidin 22694738 pelargonidin-3-O-[6-O-(4-O-E-p-coumaroyl-O-α-rhamnopyranosyl)-β-glucopyrano]-5-O-β-glucopyranoside 22694738 peonidin 22694738 peonidin-3-O-β-glucoside 22694738 petunidin 22705340 Glutamate 22705340 MTEP 22705340 VU0360172 22705340 polyphosphoinositide 22709945 CORT 22709945 corticosterone 22712581 peristrophine 22712581 phenoxazine 22712621 arbutin 22718275 3β,5α-dihydroxycholest-7-en-6-one 22718275 3β-hydroxysterol 22718275 7-DHC 22718275 7-Dehydrocholesterol 22718275 DHCEO 22718275 IsoPs 22718275 NeuroPs 22718275 arachidonic acid 22718275 docosahexaenoic acid 22718275 isoprostanes 22718275 neuroprostanes 22718275 oxysterol 22718275 oxysterols 22724545 (22R)-hydroxylanosta-7,9(11),24-trien-3-one 22724545 6,8-dihydroxy-3-methyl-3,4-dihydroisocoumarin 22724545 ergosterol 22724545 isocoumarin 22724545 methanol 22728231 DNCB 22728231 lactic acid 22728231 pPD 22728231 resorcinol 22728761 D-Serine 22728761 D-serine 22728761 cocaine 22732443 AMPA 22732443 Ro25-6981 22736593 20(S)-Protopanaxatriol 22736593 20(S)-protopanaxatriol 22736593 UDP 22736593 ginsenosides 22736593 ppt 22743159 Glutamate 22743159 glutamate 22745189 Sulpiride 22745189 sulpiride 22750050 ATP 22750050 adenosine monophosphate 22750050 adenosine triphosphate 22750050 fatty acid 22750050 glucose 22750050 serine 22750050 threonine 22750079 Mirtazapine 22750079 mirtazapine 22751286 Cisplatin 22751286 cis-diamminedichloroplatinum II 22751286 cisplatin 22751286 glutathione 22751286 sulfhydryl 22751286 ω-3 polyunsaturated fatty acid 22760156 bicarbonate 22760156 citrate 22760156 lactate 22760156 lanthanide 22760156 urate 22765022 5,2',4'-trihydroxy-flavone-8-C-α-arabinopyranoside-7-O-β-glucopyranoside 22765022 Flavonoid 22765022 apigenin 22765022 apigenin 7-O-gentobioside 22765022 apigenin-7-O-β-glucopyranoside 22765022 daidzein 22765022 flavonoid 22765022 luteolin 22765022 luteolin-7-O-β-glucopyranoside 22765022 quercetin-3,7-di-O-β-glucopyranoside 22765022 quercetin-3,7-di-O-β-glucopyranoside 4'-O-α-rhamnopyranoside 22765022 quercetin-3-O-β-glucopyranoside-7-O-α-rhamnopyranoside 22765159 2-piperidinone 22765159 3-methylhydantoin 22765159 cyclo-(Gly-L-Ala) 22765159 cyclo-(Gly-L-Tyr) 22765159 cyclo-(L-Ala-L-Ala) 22765159 cyclo-(L-Ala-L-Tyr) 22765159 cyclo-(L-Ala-trans-4-hydroxy-L-Pro) 22765159 cyclo-(L-Pro-Gly) 22765159 cyclo-(L-Pro-L-Ser) 22765159 cyclo-(L-Tyr-trans-4-hydroxy-L-Pro) 22765159 cyclodipeptides 22765159 yclo-(L-Val-L-Pro) 22766173 KI 22766173 iodide 22766173 terephthalic acid 22766394 Modafinil 22766394 modafinil 22771462 AP5 22771462 CNQX 22771462 CPCCOEt 22771462 DHPG 22771462 Glutamate 22771462 MPEP 22771462 TBOA 22771462 antagonist MPEP 22771462 glutamate 22776039 glucose 22780426 (+)-2-heptadecyl-4-hydroxy-3,4,7,8-tetrahydro-2H-chromen-5(6H)-one 22780426 (-)-(4S)-2-[(Z)-1'-(6″,7″-dihydroxyphenethyl-amino)octadec-11'-enylidene]-4-hydroxycyclohexane-1,3-dione 22780426 2-(1,3-dihydroxyphenyl)-octacosan-1'-one 22780426 Dindygulerione C 22780426 acylresorcinol 22780426 dindyguleranone 22780426 dindygulerione C 22780426 dindygulerione D 22780426 octaketide 22780426 polyketide 22780563 Ca (CH(3)COO)(2) 22780563 Calcium acetate 22780563 H(3)PO(4) 22780563 Hydroxyapatite 22780563 Ti 22780563 carbon 22780563 hydroxyapatite 22780563 n-butanol 22780563 phosphoric acid 22788542 flavonoids 22788542 quercetin 22788542 rutin 22788700 CaA 22788700 Polyphenol 22788700 caffeic 22788700 chlorogenic 22788700 ferulic acids 22788700 polyphenol 22788700 polyphenols 22788700 rutin 22788743 folate 22788743 phenolic 22788743 vitamin C 22789395 methyl, ethyl, n-propyl and n-butyl parabens 22789395 p-hydroxybenzoic acid 22789395 parabens 22799569 Flavonoid 22799569 Flavonoids 22799569 flavonoids 22799569 quercetin 3-O-glucoside 22799569 quercetin 3-O-rhamnoside 22799569 quercetin 3-O-rhamnosyl-(1 → 2)-[rhamnosyl-(1 → 6)]-glucoside 22799569 quercetin 3-O-rhamnosyl-(1 → 6)-glucoside 22804459 DPPH 22804459 Trolox 22804459 caffeic acid 22804459 ethanol 22804459 ferric 22804459 lithospermic acid 22804459 methanol 22804459 rosmarinic acid 22804459 salvianolic acid C 22809021 estradiol 22809021 progesterone 22809387 Li 22809387 LiFePO(4) 22809387 LiPF(6) 22809387 PEI 22809387 polyethyleneimine 22813628 MBuP 22813628 MBzP 22813628 MEHP 22813628 MMP 22813628 mono-(2-ethylhexyl) phthalate 22813628 monobenzyl phthalate 22813628 monobutyl phthalate 22813628 monomethyl phthalate 22813628 monophthalates 22813628 phthalate monoester 22813628 phthalate monoesters 22815230 1,1-diphenyl-2-picryl hydrazyl 22815230 DPPH 22815230 FeSO4 22815230 acetone 22815230 ferric 22815230 ferrous 22815230 methanol 22815230 trypan blue 22815248 CCl4 22815248 GSH 22815248 MDA 22815248 N 22815248 Saponin 22815248 alanine 22815248 aniline 22815248 aspartate 22815248 carbon tetrachloride 22815248 ethylmorphine 22815248 glutathione 22815248 lactate 22815248 malondialdehyde 22815248 paracetamol 22815248 saponin 22815248 silymarin 22818587 tryptophan 22820275 ATM 22820275 Atomoxetine 22820275 isoflurane 22820275 norepinephrine 22824787 FLX 22824787 fluoxetine 22824788 cadmium 22827445 C(60) 22827445 C60 22827445 POT-co-DOT 22827445 acetonitrile 22827445 poly(3-octylthiophene-2,5-diyl-co-3-decyloxythiophene-2,5-diyl) 22827445 thiophene 22827445 toluene 22827894 bispyridinium oximes 22827894 organophosphorus 22827894 oxime 22827894 oximes 22830982 1-OH-midazolam 22830982 Fluorescein diacetate 22830982 acetaminophen 22830982 caffeine 22830982 dextromethorpahn 22830982 dextromethorphan 22830982 dextrorphan 22830982 hydroxy-omeprazole 22830982 hydroxyl-repaglinide 22830982 midazolam 22830982 omeprazole 22830982 omeprazole sulfone 22830982 paraxanthine 22830982 repaglinide 22830982 tolbutamide 22832075 Vitamin A 22832075 all-trans-retinoic acid 22832075 retinoic acid 22832075 retinoids 22832075 retinol 22832075 vitamin A 22832075 vitamin-A 22834411 1-butanol 22834411 barium ferrite 22834411 dodecylbenzenesulphonic acid 22836659 Cys 22836659 Gly 22836881 aspirin 22836881 nitrates 22838394 (1)H 22838394 (13)C 22838394 2,3-demethoxy-secoisolintetralin diacetate 22838394 2,3-demethoxy-secoisolintetralin monoacetate 22838394 9-acetyl-9'-pentadecanoil-dihydroclusin 22838394 diarylbutane lignans 22838394 dihydroclusin diacetate 22838394 dihydroclusin monoacetate 22840199 camphor 22840199 chamazulene 22840199 citronellol 22840199 geraniol 22840229 10(Z)-cyclonerotriol 22840229 cyclonerodiol 22840229 cyclonerol 22840229 sesquiterpene 22841391 Methylselenol 22841391 methylselenol 22841391 selenium 22841397 Biotin 22841397 acetyl-CoA 22841397 biotin 22841397 glucose 22841916 Caffeine 22841916 adenosine 22841916 caffeine 22841917 DHA 22841917 EPA 22841917 Omega-(n)-3 polyunsaturated fatty acids 22841917 PUFA 22841917 PUFAs 22841917 docosahexaenoic acid 22841917 eicosapentaenoic acid 22841917 omega-3 fatty acids 22846225 Chelerythrine 22846225 ZIP 22846225 chelerythrine 22846225 myristoylated ζ-pseudosubstrate peptide 22846225 staurosporine 22849656 neurotensin 22849656 tyrosine 22849972 cholesterol 22849972 glucose 22859660 Ach 22859660 ISO 22859660 SNP 22859660 acetylcholine 22859660 fenofibrate 22859660 glycerol 22859660 isoproterenol 22859660 phenylepherine 22859660 sodium nitroprusside 22862926 glucose 22865292 H(+) 22865292 chloroquine 22867274 GSH 22867274 N 22867274 NADPH 22867274 amide 22867274 aryl amine 22867274 benzothiazole amide 22867274 glutathione 22872141 Formaldehyde 22872141 formaldehyde 22872607 Aldo-keto 22872607 PAHs 22872607 cotinine 22872607 o-quinones 22872607 oxygen 22872607 polycyclic aromatic hydrocarbons 22874922 Ca(2+) 22876956 6-nitro-3,4-methylenedioxyphenyl-Nacylhydrazone 22876956 LASSBio-881 22876956 Nitrogen 22876956 O2 •- 22876956 ONOO- 22876956 carbamazepine 22876956 desipramine 22876956 duloxetine 22876956 escitalopram 22876956 fluoxetine 22876956 indomethacin 22876956 meloxicam 22876956 nitrogen 22876956 oxygen 22876956 paroxetine 22876956 peroxynitrite 22876956 phenytoin 22876956 sulfur 22876956 superoxide 22876956 tenoxicam 22876956 valdecoxib 22876956 α-lipoic acid 22876956 γ-butyrolactone 22889561 danusertib 22889612 BaP 22889612 RVT 22889612 benzo(a)pyrene 22889612 resveratrol 22889721 Hematoxylin 22889721 calcium 22889721 eosin 22891663 GPV 22891663 N,β-D-glucopyranosyl vincosamide 22891663 chlorophyll 22891663 hydrogen peroxide 22891663 hydroxyl 22891663 indole alkaloid 22891663 oxygen 22891663 superoxide 22898132 boric acid 22898132 caffeine 22898132 glucose 22898132 hydroxyurea 22898132 methoxyacetic acid 22898132 paraoxon-methyl 22898132 retinoic acid 22898132 sodium salicylate 22898132 valproic acid 22898132 valproic and methoxyacetic acid 22903180 silver 22906569 bilirubin 22906569 biliverdin 22906572 ATP 22906572 Ca(2+) 22906572 Heptylamine 22906572 amine 22906572 calcium 22906572 heptylamine 22906573 amine 22906573 carbon 22906573 polystyrene 22911509 Teflon 22911509 graphene 22914985 MPA 22914985 MPA glucuronide 22914985 MPAG 22914985 Mycophenolic acid 22914985 inosine-5'-monophosphate 22914985 mycophenolate 22914985 mycophenolic acid 22914985 mycophenolic acid glucuronide 22917637 (+)- and (-)-cocaine 22917637 (+)-cocaine 22917637 (-)-cocaine 22917637 [(11)C](+)-cocaine 22917637 [(11)C](-)-cocaine 22917637 cocaine 22921987 MDA 22921987 Psoralen 22921987 malonaldehyde 22923473 fructose 22923473 glucose 22926048 GSH 22926048 GSSG 22926048 HEDS 22926048 NADPH 22926048 glucose 22926048 glutathione 22926048 hydroxyethyl disulfide 22926048 pentose phosphate 22926048 thiol 22931186 Etoposide 22931186 creatinine 22931186 etoposide 22931212 5-phosphoribose 22931212 ADP 22931212 H 22931212 NAD 22931212 NADH 22931212 NADP 22931212 NMN 22931212 Rib 22931212 adenine 22931212 adenine dinucleotide phosphate 22931212 amino acid 22931212 carboxylic acid 22931212 phenyl 22931212 pyrazole 22931212 ribose 22931212 sulfur 22931212 thiazole 22931212 β-nicotinamide mononucleotide 22935104 sildenafil 22935104 thalidomide 22940283 thiocholine esters 22940855 4-amino-5-(2-hydroxyphenyl)-2H-1,2,4-triazole-3(4H)-thione 22940855 H 22940855 H2 22940855 H3B 22940855 N2 22940855 N3 22940855 O1 22940855 S1 22940855 chloroform 22940855 hydrogen 22940855 methanol 22940855 thiol dimer 22940855 thione 22940855 thione and thiol dimers 22940855 thione dimer 22940855 thione-thiol 22940855 triazole 22945693 CpG 22945693 sodium-iodide 22949511 hydroxylates 22949511 lysines 22949511 lysyl 22949511 prolyl 22954532 Na 22954532 TTX 22954532 Tungsten carbide 22954532 WC 22954532 sodium 22954532 tetrodotoxin 22954532 tungsten carbide 22955948 H(2)O(2) 22955948 hydrogen peroxide 22955948 rapamycin 22956629 TiO(2) 22956629 titanium dioxide 22956630 4-hydroxybenzoic acid 22956630 OH 22956630 Paraben esters and their salts 22956630 Parabens 22956630 alkyl esters 22956630 benzoic acid 22956630 benzylparaben 22956630 butyl- and benzylparaben 22956630 butylparaben 22956630 ethyl 22956630 ethylparaben 22956630 methyl 22956630 methylparaben 22956630 p-hydroxybenzoic acid 22956630 parabens 22956630 propyl 22956630 propylparaben 22958332 carbon dioxide 22958332 oxygen 22960471 7-AAD 22960471 7-aminoactinomycin 22960471 Nicotine 22960471 nicotine 22960471 sulforhodamine B 22961087 triglycerides 22961200 alanine dipeptide 22963367 GdOCl 22963367 ITO 22963367 Tb-doped GdOCl 22963367 cyclohexane 22963367 indium tin oxide 22963553 Ipratropium bromide 22963553 Oxitropium bromide 22963553 Tiotropium bromide 22963553 aclidinium bromide 22963553 glycopyrrolate bromide 22963553 ipratropium bromide 22963553 oxitropium bromide 22963553 tiotropium 22963553 tiotropium bromide 22963554 corticosteroid 22963554 macrolides 22963554 nortriptyline 22963554 theophylline 22963619 (99m)Tc 22963619 99mTc 22963619 DTPA 22963619 Methionin 22963619 Methionine 22963619 amino acid 22963619 amino acids 22963619 methionine 22966070 O(2) 22966070 glucose 22966070 tyr 22966070 tyrosine 22967722 Glabridin 22967722 carbon dioxide 22967722 carnitine 22967722 glabridin 22967722 glucose 22967722 isoflavan 22967722 phosphoenolpyruvate 22968089 AMN082 22968089 LY379268 22968089 MPEP 22968089 glutamate 22972178 cortisol 22972178 lactate 22972179 2-Deoxyglucose 22972179 2-deoxyglucose 22972179 Ser 22972179 Thr 22972179 rapamycin 22972222 glucose 22972222 vildagliptin 22972396 platinum 22975146 (α)-asarone 22975146 Alpha-asarone 22975146 GABA 22975146 Mg(2+) 22975146 bicuculline 22975146 glycine 22975146 kainate 22975146 pentylenetetrazole 22975146 picotoxin 22975146 strychnine 22975146 α-asarone 22975155 2PAM 22975155 MMB4 22975155 N-substituted 2-hydroxyiminoacetamido alkylamines 22975155 RS194B 22975155 RS41A 22975155 cyclosarin 22975155 oxime 22975155 oximes 22975155 paraoxon 22975155 pyridinium 22975155 sarin 22975155 tabun 22977168 diisocyanate 22977168 hexamethylene diisocyanate 22981737 C 22981737 acetylcholine 22981737 tyrosine 22982206 Verrucarin A 22982206 oxygen 22982206 salubrinal 22982206 verrucarin A 22982773 HI-6 22982773 O-ethyl isopropylphosphonofluoridate 22982773 O-methyl cyclohexylphosphonofluoridate 22982773 O-methyl isopropylphosphonofluoridate 22982773 alkoxy 22982773 cyclosarin 22982773 dimethylamine 22982773 obidoxime 22982773 organophosphorus 22982773 oxime 22982773 phosphate 22982773 phosphates 22982773 phosphonate 22982773 phosphonates 22982773 phosphoramidate 22982773 phosphoramidates 22982773 sarin 22982773 tabun 22983118 2,5-dimethoxy-4-iodoamphetamine hydrochloride 22983118 3,4-Methylenedioxymethamphetamine 22983118 5-HT 22983118 DOI 22983118 Ecstasy 22983118 MDMA 22983118 MTT 22983118 amphetamine 22983118 amphetamines 22983118 lactate 22983118 tetrazolium 22983652 PMMA 22983652 Poly(methyl methacrylate) 22983652 carbon 22985735 GSH 22985735 H(2)O(2) 22985735 SiO(2) 22985735 SiO2 22985735 silica 22985953 MMT 22985953 Na(+) 22985953 Na+ 22985953 carbohydrates 22985953 glycerol 22985953 hydroxyl 22985953 montmorillonite 22985953 sugar alcohol 22985953 sugar alcohols 22985953 xylitol 22986217 fatty acids 22986217 glucose 22986217 isoflavones 22986456 cholesterol 22986456 glucose 22986456 triglyceride 22989703 8-OHdG 22989703 H(2)O(2) 22989703 H2O2 22989703 apo-10'-lycopenoic acid 22989703 apo-14'-lycopenoic acid 22989703 apo-lycopenoic acids 22989703 lycopene 22989704 NiCl(2) 22989704 Nickel 22989704 all-trans retinoid acid 22989704 atRA 22989704 nickel 22989704 nickel chloride 22989704 oxygen 22989705 BADGE 22989705 Bisphenol A diglycidyl ether 22989705 Cisplatin 22989705 GSH 22989705 MDA 22989705 Pioglitazone 22989705 cisplatin 22989705 glutathione 22989705 malondialdehyde 22989705 pioglitazone 22991234 Calcium 22991234 calcium 22991234 calcium citrate 22991330 Nitrogen-bisphosphonates 22991330 aminobisphosphonate 22991330 aminobisphosphonates 22991330 bisphosphonate 22991330 n-BP 22992330 O 22992330 catechol 22993196 Glucose 22993196 TAG 22993196 glucose 22993196 triacylglycerol 22993196 triglyceride 22995755 PEI 22995755 PEIs 22995755 disulfide 22995755 polyethylenimine 22995755 polyethylenimines 22995849 nucleotide 22996261 DACA 22996261 N-[(2-dimethylamino)ethyl]acridine-4-carboxamide 22996261 Raloxifene 22996261 aldehyde 22996261 phthalazine 22996261 raloxifene 22997060 15-ADON 22997060 15-acetyldeoxynivalenol 22997060 3-ADON 22997060 3-acetyldeoxynivalenol 22997060 8-ketotrichothecenes 22997060 8-ketotrichothecenes deoxynivalenol 22997060 DON 22997060 NIV 22997060 deoxynivalenol 22997060 fusarenon X 22997060 kaolin 22997060 nivalenol 22997060 trichothecene 22997060 trichothecenes 22997060 vomitoxin 22998180 SiC 22998180 carbon 23000250 Amino acid 23000250 acetylcholine 23000251 Flavonoids 23000251 MTT 23000251 Quercetin 23000251 flavonoids 23000251 methylquercetin 23000251 methylrutin 23000251 quercetin 23000251 quercetin glucuronide 23000251 rutin 23000251 rutin glucuronide 23000251 rutin sulphate 23000251 tetrazolium 23000251 trypan blue 23000442 Mollugin 23000442 O 23000442 mollugin 23000442 phenacetin 23000447 glyphosate 23000449 carbamate 23000449 organophosphate 23000449 organophosphates 23000450 cholesterol 23000450 triglyceride 23000450 triglycerides 23000451 (-)-cocaine 23000451 Cocaine 23000451 cocaine 23000507 6-OHDA 23000507 6-hydroxydopamine 23000507 ISO 23000507 PRO 23000507 isoproterenol 23000507 propranolol 23000507 tyrosine 23001627 L-T4 23001627 Levothyroxine 23001627 MDA 23001627 PTU 23001627 Vit E 23001627 levothyroxine 23001627 malondialdehyde 23001627 nitroblue tetrazolium 23001627 superoxide 23001627 thiobarbituric-acid 23001627 vitamin E 23002087 statins 23007555 Ifenprodil 23007555 N-methyl-D-aspartate 23007555 amino 23007555 ifenprodil 23007555 ifenprodil, 23007555 zinc 23007559 EtOH 23007559 NO 23007559 ethanol 23008099 (1R)-Normetanephrine 23008099 (1R)-normetanephrine 23008099 (1S)-normetanephrine 23008099 3'-phosphoadenosine-5'-phosphosulfate 23008099 adrenergic amines 23008099 normetanephrine 23008229 Au 23008229 C(60) 23008229 Fullerenes 23008229 fullerene 23008229 thiol 23010164 serine 23010165 l-amino acid 23010362 (-)-reboxetine 23010362 Ca(2+) 23010362 [(3)H]imipramine 23010362 acetylcholine 23010362 imipramine 23010362 norepinephrine 23010695 (R)-2-pentyl-4-pentynoic acid 23010695 (S)-2-pentyl-4-pentynoic acid 23010695 VPA 23010695 valproic acid 23010867 sulfonylurea 23010870 (13)C 23010870 (15)N 23010870 Hg 23010870 Mercury 23010870 mercury 23011663 CAPE 23011663 MDA 23011663 caffeic acid phenethyl ester 23011663 copper 23011663 malondialdehyde 23011663 superoxide 23011663 zinc 23012257 4-(2-Butyl-6,7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid 23012257 DCPIB 23012257 amino acid 23012257 cystine 23012257 d-[(3)H]aspartate 23012257 glutamate 23012257 l-[(14)C]cystine 23012257 l-[(3)H]glutamate 23016524 Ca2+ 23016524 inositol 23017385 Rosmarinic acid 23017385 caffeic acid 23017385 flavonoid 23017385 luteolin-3'-O-glucuronide 23017388 5-FU 23017388 Pulsatilla saponin D 23017388 SB365 23017389 (1)H 23017389 (13)C 23017389 DPPH 23017389 Fe(2+) 23017389 Fe(3+) 23017389 chrysoeriol 23017389 chrysoeriol-7-O-[2″-O-E-feruloyl]-β-d-glucoside 23017389 ethyl acetate 23017389 ferric 23017389 ferric thiocyanate 23017389 ferrous 23017389 flavones 23017389 flavonoids 23017389 isorhamnetin-3-β-d-glucoside 23017389 methanol 23017389 silica gel 23017393 (+)-catechin 23017393 Catechin 23017393 FTSC 23017393 catechin 23017393 creatine 23017393 fluorescein-5-thiosemicarbazide 23017393 glyceraldehyde 23017393 pyruvate 23017401 Genistein 23017401 dicarboximide 23017401 genistein 23017401 genistin 23017401 genistin, its β-glycosylated 23017401 iprodione 23017401 procymidone 23017401 vinclozolin 23017404 Sugar 23017404 fructose 23017404 glucose 23017404 hexose 23017404 hexoses 23017404 sucrose 23017404 sugar 23017406 GABA 23017406 Glu 23017406 polyamine 23017406 polyamines 23017406 γ-aminobutyric acid 23017414 isoflavone 23017414 isoflavones 23017414 phenolic 23017414 phenolic acids 23017417 (+)-catechin 23017417 (-)-epicatechin 23017417 (E)-resveratrol 23017417 Anthocyanins 23017417 gallic acid 23017417 polyphenol 23017417 polyphenols 23017423 DHA 23017423 dehydroascorbic acid 23017423 glucose 23017423 l-ascorbic acid 23017423 sucrose 23017423 sugar 23018143 estrogen 23019137 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4c]carbazole-12-propanenitrile 23019137 5-HT 23019137 Gö6976 23019137 Serotonin 23019137 dopamine 23019137 neurotensin 23019137 quinpirole 23019137 serotonin 23019217 Mith 23019217 Mithramycin A 23019217 mithramycin A 23019274 N-acetyl 23019274 aristolochic acid 23019274 creatinine 23019274 nitrogen 23019274 urea 23022069 CYA 23022069 MEL 23022069 cyanurate 23022069 cyanuric acid 23022069 melamine 23022398 AP7 23022398 NMDA 23022398 PILO 23022398 pilocarpine 23022398 urethane 23023024 BAs 23023024 MDA 23023024 Malondialdehyde 23023024 bile acids 23023024 superoxide 23023024 α-tocopherol 23023136 Arsenic trioxide 23023136 As(2)O(3) 23023136 GSH 23023136 GSSG 23023136 Resveratrol 23023136 arsenic 23023136 arsenic trioxide 23023136 oxidized glutathione 23023136 reduced glutathione 23023136 resveratrol 23023136 superoxide 23023933 octanol 23023933 perfluoroalkyl acids 23026700 AMP 23026700 acetyl-CoA 23026700 carnitine palmitoyl 23026700 ethanol 23026700 fatty acid 23026700 sterol 23026700 triglyceride 23028140 N-desmethylimatinib 23028140 imatinib 23030346 Ge 23030346 Si 23030680 5-hydroxyelzasonan 23030680 N 23030680 elzasonan 23030680 elzasonan N-oxide 23030680 iminium 23030680 indole 23030706 carbon 13 23030706 chloroacetaldehyde 23030706 cobalt 23030706 cobalt chloride 23030706 ifosfamide 23030706 valproate 23030766 amino acid 23032515 8-Hydroxycalamenene 23032515 8-hydroxycalamenene 23032515 BSO 23032515 N-methyl-d-aspartate 23032515 S 23032515 glutamate 23032515 glutathione 23032515 hexane 23032515 l-buthionine-(S,R)-sulfoximine 23033256 Bisulfite 23034931 S 23034931 nitro 23034931 nitrogen 23034931 oxy 23036893 4-nonylphenol 23036893 EE2 23036893 bisphenol A 23036893 estrogen 23036893 ethinylestradiol 23036893 genistein 23038668 Calcium manganese oxide 23038668 H+ 23038668 O(2) 23038668 oxygen 23041228 ser 23041228 thr 23041228 tyrosine 23041510 1α,25 (OH) 2D3 23041510 2β-hydroxypropyloxy 23041510 ALF 23041510 ALN 23041510 Alendronate 23041510 ELD 23041510 Eldecalcitol 23041510 alendronate 23041510 alfacalcidol 23041510 bisphosphonate 23041510 eldecalcitol 23041538 NASPM 23041538 SCH 58261 23041538 adenosine 23041538 calcium 23041538 glucose 23041538 oxygen 23041538 spermine 23041661 ATP 23041661 Arg 23041661 Glu 23041661 adenosine-5'-triphosphate 23041661 disulfide 23041661 γ-phosphate oxygen 23041725 17β-estradiol 23041725 Organochlorine 23041725 dieldrin 23041725 estrogen 23041725 organochlorine 23042728 VPA 23042728 VPD 23042728 Valpromide 23042728 amide 23042728 valproic acid 23042730 AMD 23042730 Amiodarone 23042730 N-acetylcysteine 23042730 TOCO 23042730 amiodarone 23042730 ascorbate 23042730 glutathione 23042730 oxygen 23042730 trolox 23042730 α-TOCO 23042730 α-tocopherol 23042808 CBD 23042808 Cannabidiol 23042808 THC 23042808 cannabidiol 23042808 Δ⁹-tetrahydrocannabinol 23042953 amino acids 23042953 cholesterol 23042953 triglycerides 23042954 (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid 23042954 AMPA 23042954 HI-6 23042954 LY293558 23042954 oxime 23042954 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 23043137 C 23043137 amino acid 23043137 disulfide 23043137 pVIc 23043441 azide-alkyne 23043441 copper(I) 23044047 phalloidin 23044489 KET 23044489 Ketamine 23044489 MK-801 23044489 NMDA 23044489 Organophosphorus 23044489 atropine sulfate 23044489 benzodiazepine 23044489 soman 23046872 NaAsc 23046872 Pt(IV) 23046872 cisplatin 23046872 cisplatin(II) 23046872 cisplatin(IV) 23046872 nucleobases 23046872 sodium ascorbate 23047001 ATP 23047001 BTZ 23047001 BTZs 23047001 benzothiazepinones 23047024 K048 23047024 Organophosphorus 23047024 organophosphates 23047024 oxime 23047024 oximes 23047024 tabun 23047287 5(6)-carboxyfluorescein 23047287 Arg-Gly-Asp 23047287 adamantine 23047287 amantadine 23047287 cyclic RGD 23047287 graphene 23047287 β-CD 23047287 β-cyclodextrin 23047912 (14)C 23047912 L-BMAA 23047912 oxygen 23047912 vitamin E 23047912 β-N-methylamino-L-alanine 23050902 6-mercaptopurine 23050902 GTP 23050902 Ribavirin 23050902 inosine-5'-monophosphate 23050902 lysine 23050902 mycophenolic acid 23050902 ribavirin 23050902 vitamin K 23052192 Co 23052192 Co(2+) 23052192 CoCl(2) 23052192 WC 23052192 cobalt 23052192 oxygen 23052192 tungsten carbide 23052195 PPA 23052195 c-AMP 23052195 glutathione 23052195 phenylpropanolamine 23055393 TiO(2) 23055453 HCl 23055453 OPE 23055453 cholesterol 23055453 ethanediamine 23055453 imino 23055453 oligo(p-phenyleneethynylene) 23055539 AngIV 23055539 Angiotensin IV 23055539 C 23055539 N 23055539 N-hexanoic-Tyr-Ile-(6) aminohexanoic amide 23055539 Nle-Tyr-Ile 23055539 amino acids 23055539 angiotensin IV 23055539 dihexa 23055539 hydrogen 23055539 norleucine 23055539 scopolamine 23055539 tripeptide 23057615 copper 23057615 moxifloxacin 23057615 phenanthroline 23057615 quinolone 23057692 ciclopirox 23059626 Met 23060096 H(2)O(2) 23060096 H2O2 23060096 Pt(48)Pd(52)-Fe(3)O(4) 23060096 PtPd-Fe3O4 23060096 TMB 23060096 oleylamine 23060096 polyethyleneglycol 23060096 tetramethylbenzidine 23061607 Organosilicon 23061607 organosilicon 23061607 silicon 23061635 GABA 23061635 Menthol 23061635 calcium 23061635 menthol 23061635 monoterpene 23061635 nicotine 23061635 sodium 23063002 chlorpyrifos 23063002 oxygen 23063002 penoxsulam 23063066 esfenvalerate 23063069 DDT 23063069 PBDEs 23063069 PCB 23063069 PCBs 23063069 dichlorodiphenyltrichloroethane 23063069 polybrominated diphenyl ethers 23063069 polychlorinated biphenyls 23063411 Actinomycin D 23063411 actinomycin D 23063590 Artemisinic acid 23063590 Cholesterol 23063590 HMG CoA 23063590 HMG-CoA 23063590 artemisinic acid 23063590 cAMP 23063590 cholesterol 23063590 hydroxymethylglutaryl CoA 23063593 HER 23063593 Herbacetin 23063593 LY294002 23063593 N-Acetyl-l-cysteine 23063593 NAC 23063593 flavonoid 23063593 phosphatidylinositol 23063593 poly (ADP-ribose) 23065696 (13) C 23065696 carbon 23066090 3-(5-tert-butyl-isoxazol-3-yl)-2-[(3-chloro-phenyl)-hydrazono]-3-oxo-propionitrile 23066090 ESI-09 23066090 cAMP 23066090 nucleotide 23066821 callyimine A 23066821 callylactam A 23066949 2-acetamino 23066949 Asp 23066949 GlcNAcstatin 23066949 aspartate 23066949 imidazole 23066949 nitrogen 23068419 6-OHDA 23068419 6-hydroxydopamine 23068419 Methylparaben 23068419 apomorphine 23068419 hydrogen peroxide 23068419 methylparaben 23068419 oxygen 23068419 tyrosine 23069619 ibuprofen 23069627 calcium 23069627 glucose 23069627 palmitic acid 23070981 GeTe 23071106 2-APB 23071106 2-aminoethoxydiphenylborate 23071106 8-pCPT-2'-O-Me-cAMP-AM 23071106 ATP 23071106 Ca(2+) 23071106 K 23071106 Tolbutamide 23071106 bisindolylmaleimide I 23071106 cAMP 23071106 gliclazide 23071106 nicardipine 23071106 sulfonylurea 23071106 thapsigargin 23071106 tolbutamide 23071294 cholesterol 23073171 CLA 23073171 glucose 23073171 linoleic acid 23074021 MEG 23074021 Methyleugenol 23074021 S 23074021 glutathione 23074021 methyleugenol 23074035 PMMA 23074035 PMMA-b-PNIPAAm 23074035 PNIPAAm 23074088 carboxyl 23074173 (59)Fe 23074173 DFO 23074173 Deferasirox 23074173 Fe 23074173 deferasirox 23074173 desferrioxamine 23074173 iron 23074173 poly(ADP-ribose) 23076553 CH3 23076553 Cl 23076553 F 23076553 Lewis acid 23076553 Lewis base 23076553 Lewis bases 23076553 N 23076553 N(CH3)3 23076553 NF3 23076553 NHn(X3-n) 23076553 halogen 23077105 7α,17β-[9-[(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol 23077105 ICI182/780 23077105 actinomycin D 23077105 bile salts 23077105 estrogen 23077105 ethynylestradiol 23077105 glutathione 23078542 dopamine 23079231 (3)H-thymidine 23079231 Curcumin 23079231 curcumin 23079231 sirolimus 23080539 doxycycline 23081912 2,3,7,8-tetrachlorodibenzo-p-dioxin 23081912 Hoechst H33342 23081912 Ko143 23081912 TCDD 23081912 aryl hydrocarbon 23081912 arylhydrocarbon 23081912 dioxin 23081912 imidazole 23081912 prochloraz 23081912 salicyl amide 23081947 Au 23081947 AuCl 23081947 Chlorine 23081947 chlorine 23085085 acetyl 23085085 lysine 23085266 GF109203X 23085266 NADPH 23085266 PMA 23085266 SB203580 23085266 Ser 23085266 UO126 23085266 fMLF 23085266 formyl-methionyl-leucyl-phenylalanine 23085266 genistein 23085266 oxygen 23085266 phorbol myristate acetate 23085266 tyrosine 23085266 wortmannin 23085330 Curcumin 23085330 HPβCD 23085330 Hydroxypropyl 23085330 curcumin 23085330 hydroxypropyl-β-cyclodextrin 23085435 BPs 23085435 GGPP 23085435 N 23085435 Nitrogen 23085435 bisphosphonates 23085435 geranylgeranyl pyrophosphate 23085979 2,3,7,8-tetrachlorodibenzo-p-dioxin 23085979 Aryl hydrocarbon 23085979 TCDD 23085979 aryl hydrocarbon 23085979 polycyclic aromatic hydrocarbons 23086035 acylcarnitines 23086035 glucose 23086035 sphingosine 23086038 glucose 23086038 phosphoinositide (3,4,5)-triphosphate 23086197 NADPH 23086197 heme 23086197 squalene 23086197 steroid 23086198 1-OH-pyrene 23086198 1-hydroxy-(OH)-pyrene 23086198 1-naphthol 23086198 PAH 23086198 PAHs 23086198 UDP 23086198 diols 23086198 heterocyclic amines 23086198 hydroxylated benzo(a)pyrene 23086198 monohydroxylated PAH 23086198 nitrosamines 23086198 polycyclic aromatic hydrocarbons 23086703 1,1,3,3-tetramethyl-2-propylguanidine 23086703 1,4-phenylenedimethanamine 23086703 1-naphthylmethyl 23086703 1-propylguanidine 23086703 2-pyridylmethyl 23086703 FC131 23086703 [1,1'-biphenyl]-4,4'-diyldimethanamine 23086703 bis(pyridin-2-ylmethyl)amine 23086703 cyclic pentapeptide 23086703 dipicolylamine 23086703 naphthalene-2,6-diyldimethanamine 23086703 zinc(II) 23087261 Lys 23087261 Lysine 23087261 lysine 23089896 ATP 23089896 Rho123 23089896 itraconazole 23089896 rhodamine123 23091169 androstane 23091169 glutamine 23091169 phenobarbital 23091189 (14)C 23091189 Inavir 23091189 Laninamivir octanoate 23091189 ester 23091189 laninamivir 23091189 laninamivir octanoate 23092136 hydrogen 23092237 ZnO 23092395 2,2-diphenyl-1-picryl-hydrazyl 23092395 3,5,4'-trimethoxy-4-prenylstilbene 23092395 4-hydroxylonchocarpine 23092395 Fe(3+) 23092395 Phenanthroline 23092395 derricidine 23092395 flavonoids 23092395 hexane 23092395 lonchocarpine 23092395 methanol 23092395 steroids 23092395 stigmasterol 23092395 tannins 23092395 β-sitosterol 23092723 MTT 23092723 celastrol 23092723 dichloromethane 23092723 ethanol 23092723 hexanes 23092723 methanol 23092877 nandrolone 23092877 nandrolone decanoate 23092877 steroid 23092894 Glutamate 23092894 glutamate 23094599 Si-C 23094599 Si-N 23094599 Si-O-C 23094599 Silicon 23094599 silicon 23094864 STS 23094864 Sodium tanshinone IIA sulfonate 23094864 TSIIA 23094864 Tanshinone 23094864 Tanshinone IIA 23094864 cryptotanshinone 23094864 tanshinone 23094864 tanshinone I 23095167 Kainate 23095167 glutamate 23095167 kainate 23095244 Ecstasy 23095244 ecstasy 23097024 NO 23097024 nitric oxide 23097351 1,1-diphenyl,2-picrylhydrazyl 23097351 4'-O-methoxy-luteolin-7-O-rhamnoglucoside 23097351 alcohol 23097351 apigenin 23097351 aromadendrin 23097351 ethanol 23097351 flavonoidal 23097351 flavonoids 23097351 naringenin 23098805 cocaine 23098805 estradiol 23098805 estrogen 23098805 progesterone 23098818 5-methoxytryptamine 23098818 O 23098818 fluoxetine 23098818 quinine 23098818 serotonin 23098879 1α, 6α-epoxy-9-oxo-10β-hydroxyl-furanoeremophilane 23098879 9-oxo-1α, 6β, 10β-trihydroxy-furanoeremophilane 23098879 C1-C6 23098879 furanoeremophilane 23098879 furanoeremophilanes 23098879 oxygen 23098993 HC 030031 23098993 capsaicin 23099337 Caffeine 23099337 cadmium 23099337 caffeine 23099337 glutathione 23099337 superoxide 23099339 folic acid 23099339 glucose 23099339 hydroxybutyrate 23099339 resazurin 23099339 vitamin C 23099645 5-Aza-2'-deoxycytidine 23099645 trichostatin A 23099811 (13)C 23099811 (15)N 23099811 Hg 23099811 MeHg 23099811 N 23099811 carbon 23099811 mercury 23099811 methylmercury 23099811 nitrogen 23102508 Miltirone 23102508 abietane 23102508 cryptotanshinone 23102508 dihydrotanshinone 23102508 diterpene quinone 23102508 miltirone 23102508 tanshinone I 23102508 tanshinone IIA 23102508 tanshinones 23103297 (-)-Carvone 23103297 (-)-carvone 23103297 BaCl2 23103297 K(+) 23103297 calcium 23103297 carbachol 23103297 histamine 23103297 monoterpene ketone 23103297 verapamil 23103426 (PhSe)(2) 23103426 (PhTe)(2) 23103426 GSH 23103426 NADH 23103426 diphenyl diselenide 23103426 diphenyl ditelluride 23103426 organochalcogen 23103426 organochalcogens 23103426 reduced glutathione 23103426 superoxide 23103426 thiol 23103568 Estrogen 23103568 estradiol 23103568 estrogen 23103568 estrogens 23103568 lapatinib 23103568 tyrosine 23104244 7-ethoxyresorufin 23104244 7-pentoxyresorufin 23104244 O 23104244 chlorzoxazone 23104244 midazolam 23104245 1,4-BD 23104245 1,4-butanediol 23104245 GBL 23104245 GHB 23104245 Gamma-hydroxybutyrate 23104245 gamma-butyrolactone 23104245 gamma-hydroxybutyrate 23104419 Androgen 23104419 androgen 23104419 creatine 23104419 estradiol 23104419 lactate 23104419 methimazole 23104419 testosterone 23104982 Ala-Pro-7-amido-4-trifluoromethylcoumarin 23104982 serine 23106229 beauvericin 23106229 depsipeptide 23106482 (2R*,3S*,5S*)-N,2-dimethyl-3-hydroxy-5-(10-phenyldecyl)pyrrolidine 23106482 (S)-1-(1'-hydroxyethyl)-β-carboline 23106482 1-(β-carboline-1-yl)-3,4,5-trihydroxy-1-pentanone 23106482 1-methoxycarbonyl-β-carboline 23106482 3-O-β-d-galactopyranosyl-hederagenin 28-O-β-d-xylopyranosyl(1 → 6)-β-d-galactopyranosyl ester 23106482 4-hydroxycinnamic acid methyl ester 23106482 N-methyl 23106482 bergenin 23106482 caffeic acid 23106482 coniferin 23106482 emodin 23106482 gagaminine 23106482 indolo[2,3-α]carbazole 23106482 methyl 4-[2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-1-(hydroxymethyl)ethyl] ferulate 23106482 methylconiferin 23106482 nobiletin 23106482 perlolyrine 23106482 pyrrolidine alkaloid 23106482 qingyangshengenin 23106482 syringaresinol 4'-O-β-d-glucopyranoside 23108214 carbohydrates 23109233 Ag 23109233 Ag(+) 23109233 Cu 23109233 Cu(2+) 23109233 Cu(2+) -Ag(+) 23109233 Cu(2+) -Zn(2+) 23109233 Zn 23109233 Zn(2+) 23109279 Fipronil 23109279 fipronil 23109279 fipronil sulfide 23109279 fipronil sulfone 23110522 carbon dioxide 23110522 carboxylic acid 23110522 graphene 23110522 graphite 23110522 hydrogen 23110522 oxygen 23110522 platinum 23110522 sulfonic acid 23110522 sulfur 23110522 sulfur trioxide 23111282 cholesterol 23111282 fatty acid 23111374 2-PAM 23111374 2-Pralidoxime 23111374 HI-6 23111374 Obidoxime 23111374 Organophosphorus 23111374 P-O 23111374 obidoxime 23111374 organophosphorus 23111374 oxime 23111374 oximes 23111374 pyridinium and bis-pyridinium aldoximes 23111374 serine 23111374 tabun 23111684 4,10-dinitro-2,6,8,12-tetraoxa-4,10-diazaisowurtzitane 23111684 4,8,11,14,15-pentanitro-2,6,9,13-tetraoxa-4,8,11,14,15-pentaazaheptacyclo [5.5.1.1(3,11).1(5,9)]pentadecane 23111684 4,8,11,14,15-pentanitro-2,6,9,13-tetraoxa-4,8,11,14,15-pentaazaheptacyclo[5.5.1.1(3,11).1(5,9)] pentadecane 23111684 N-NO(2) 23111684 PNTOPAHP 23111684 TEX 23111879 Fe 23111879 FeCl3 23111879 FeCl3 • 6H2O 23111879 Ferric chloride 23111879 HCl 23111879 Iron 23111879 bromide 23111879 ferric chloride 23111883 Cadmium chloride 23111883 Cd 23111883 CdCl2 23111883 alanine 23111883 aspartate 23111883 bilirubin 23111883 cadmium 23111883 cholesterol 23111883 creatinine 23111883 glucose 23111883 triglycerides 23111883 urea 23111883 uric acid 23111883 vitamins C and B 23111884 amphetamine 23111884 ethanol 23111884 tetrahydrocannabinol 23111885 NaC 23111885 NaDC 23111885 Tween 61 23111885 cholesterol 23111885 ethanol 23111885 phosphate 23111885 sodium cholate 23111885 sodium deoxycholate 23111887 clonidine 23111887 dexmedetomidine 23115086 fentanyl 23115086 midazolam 23115086 morphine 23115086 propofol 23115119 Asp 23115119 Glu 23115119 Phe 23115119 aspartic acid 23115119 carboxylic acid 23115119 glutamic acid 23115119 phenylalanine 23115324 bleomycin 23115325 ATP 23115325 Hydrogen sulfide 23115325 K 23115325 K(+) 23115325 LEVC 23115325 NaHS 23115325 levcromakalim 23115325 potassium 23115325 sodium hydrogen sulfide 23115325 sulfonylurea 23115325 trinitrobenzene sulfonic acid 23116643 3-NT 23116643 3-nitrotyrosine 23116643 CCl(4) 23116643 Cu 23116643 Rosmarinic acid 23116643 Zn 23116643 carbon tetrachloride 23116643 rosmarinic acid 23116643 superoxide 23116643 thiobarbituric acid 23117790 N-(2-methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea 23117790 SB334867 23117790 glucose 23118018 5-HT 23118018 5-hydroxytryptamine 23118018 GABA 23118018 alcohol 23118018 dopamine 23118018 ethanol 23118018 gamma-aminobutyric acid 23118018 glutamate 23118018 serotonin 23118019 5'-(2-aminomethyl) naltrindole 23118019 5'-AMN 23118019 5'-MABN 23118019 N-((Naltrindol-5-yl) methyl) pentanimidamide 23118019 U50,488 23118019 [(3)H]-diprenorphine 23118019 [(35)S]-GTPγS 23118019 guanosine-5'-O-(3-[35S]-thio) triphosphate 23118019 naltrindole 23121767 bicarbonate 23121934 (+)8-OH-DPAT 23121934 1-hydroxybenzotriazole 23121934 3,4,5-trimethoxycinnamic acid 23121934 WAY 100635 23121934 amides 23121934 esters 23121934 ethyl(dimethylaminopropryl)carbodiimide 23121934 ketones 23121934 morphine 23121934 naloxone 23122060 Q3G 23122060 d-glucose 23122060 quercetin 23122060 quercetin glucoside 23122060 quercetin glycoside 23122060 quercetin glycosides 23122060 quercetin-3-O-β-d-glucoside 23122060 saccharide 23122061 (1)H 23122061 (13)C 23122061 ethanol 23122061 glucoalkaloid 23122061 harmanyl β-d-glucopyranoside 23122061 β-carboline 23122064 amphetamine 23122064 cocaine 23122066 bile acid 23122066 cholesterol 23122066 silica gel 23122066 sphingolipids 23122066 sterol esters 23122066 triacylglycerols 23122068 (1)H 23122068 (13)C 23122068 Sulforaphene 23122068 methanol 23122068 sulforaphene 23122077 2,2-diphenyl-1-picrylhydrazyl 23122077 DPPH 23122077 H(2)O(2) 23122085 diacylglycerol ether 23122085 diacylglycerol ethers 23122085 ethanol 23122085 fatty acid ethyl esters 23122085 monoacylglycerol ethers 23122085 squalene 23122085 triacylglycerol 23122085 triacylglycerols 23122086 GalA 23122086 galacturonic acid 23122089 C 23122089 GABA 23122089 Linoleic and linolenic acid 23122089 N 23122089 amino acids 23122089 carbon 23122089 isoflavone 23122089 isoflavones 23122089 nitrogen 23122089 sugars 23122089 tocopherol 23122089 tocopherols 23122089 unsaturated fatty acids 23122092 1-octen-3-one 23122092 Methional 23122092 phenols 23122097 (2E)-hexenal 23122097 1-Octen-3-ol 23122097 alcohols 23122097 aldehydes 23122097 carboxylic acid 23122097 ester 23122097 esters 23122097 fatty acids 23122097 hydrocarbons 23122097 ketones 23122105 Allura Red AC 23122105 aromatic amine or amide 23122105 ascorbic acid 23122105 citric acid 23122105 sucrose 23122108 Ginnalin A 23122108 Ginnalins A-C 23122108 Polyphenols 23122108 ginnalin A 23122108 ginnalins A-C 23122108 ginnalins B and C 23122108 polyphenols 23122108 sugar 23122114 Hg 23122114 MeHg 23122114 mercury 23122114 methylmercury 23122116 azoxystrobin 23122116 methanol 23122116 strobilurin 23122118 organophosphorus 23122129 D-galactose 23122129 amino acid 23122135 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) 23122135 2,2-diphenyl-1-picrylhydrazyl 23122135 ABTS 23122135 DPPH 23122135 apigenin 23122135 apigenin-7-O-glucoside 23122135 caffeic acid 23122135 caffeic acid-3-O-glucoside 23122135 chrysoeriol 23122135 luteolin 23122135 luteolin-7-O-glucoside 23122135 methanol 23122135 rosmarinic acid 23122135 rosmarinic acid-3-O-glucoside 23122136 anthocyanins 23122137 Vescalagin 23122137 cholesterol 23122137 fatty acid 23122137 fructosamine 23122137 fructose 23122137 glucose 23122137 triglyceride 23122137 vescalagin 23122140 DPPH 23122140 H(2)O(2) 23122141 behenic acid 23122141 fatty acids 23122141 triacylglycerols 23122145 catechin 23122145 epicatechin 23122145 epicatechin-3-O-gallate 23122145 epigallocatechin 23122145 proanthocyanidin 23122145 proanthocyanidins 23122152 phenol 23122152 secoiridoid aglycones 23122155 AcOEt 23122155 HEX 23122155 betulinic acid 23122155 carnosol 23122155 ethyl acetate 23122155 hexane 23122160 MNG 23122160 acetonitrile and salts 23122160 ammonium bicarbonate 23122160 dinotefuran 23122160 primary secondary amine 23122165 E-2-(β-d-glucopyranosyloxy)-3-phenylpropenoic acid 23122165 PPAG 23122165 Z-2-(β-d-glucopyranosyloxy)-3-phenylpropenoic acid 23122165 sugar 23122167 Schisarisanlactone A 23122167 Schisarisanlactones A and B 23122167 nortriterpenoids 23122167 schisarisanlactones A (1) and B 23122169 15-O-methylgraciliflorin F 23122169 15-hydroxy-1-oxosalvibretol 23122169 15-hydroxy-20-deoxocarnosol 23122169 16-acetoxylsugiol 23122169 3α-hinokiol 23122169 3β-hydroxysempervirol 23122169 6,12,15-trihydroxy-5,8,11,13-abietatetraen-7-one 23122169 Abietane 23122169 abieta-8,11,13-triene-14,19-diol 23122169 abietane 23122169 diterpenoids 23122169 graciliflorin E 23122169 graciliflorin F 23123188 PGT 23123188 ethanol 23123188 oxygen 23123188 phosphate 23123188 propoxylated glyceryl triacylate 23123188 timolol 23123248 carbamate 23123248 carbamates 23123248 rivastigmine 23123254 chlorpyrifos 23123254 chlorpyrifos oxon 23123254 cyclosarin 23123254 diazinon 23123254 diazoxon 23123254 organophosphorus 23123254 sarin 23123254 soman 23123254 tabun 23123331 Na(2)CO(3) 23123331 SLB 23123331 silica 23123331 silybin 23123737 lutein 23123743 17β-Estradiol 23123743 DPN 23123743 Estrogen 23123743 G-15 23123743 ICI 182,780 23123743 PP2 23123743 PPT 23123743 [³H]-inositol phosphate 23123743 estrogen 23123743 inositol phosphate 23123743 tyrosine 23123945 ATR 23123945 Atrazine 23123945 DOPAC 23123945 HVA 23123945 Mn 23123945 amphetamine 23123945 atrazine 23123945 dopamine 23123945 monoamine 23124677 Cadmium 23124677 Cd 23124677 cadmium 23124677 nitrogen 23124905 1,2-sn- dicaprin 23124905 1,2-sn-dicaprin 23124905 1,3-sn-dicaprin 23124905 2,3-sn-dicaprin 23124905 dicaprin 23124905 diglyceride 23124905 ester 23124950 silicon 23124950 silver 23125070 Testosterone 23125070 androstenedione 23125070 testosterone 23127598 Brilliant Blue 23127598 Patent Blue 23127598 ethanol 23127598 triphenylmethane 23127599 Res 23127599 fatty acid 23127599 resveratrol 23127599 sucrose 23127601 mercury 23127826 flavone 23127826 pyridinium 23128829 cocaine 23131177 3-methoxyphenyl 23131177 Ca(2+) 23131177 Melatonin 23131177 N-[3-(3-methoxyphenyl)propyl] amides 23131177 benzyloxyl 23131177 cAMP 23131177 melatonin 23131177 phenylpropylamides 23131797 octanol 23131798 1,3,5-triazine 23131798 2,4,6-trisubstituted 1,3,5-triazines 23131798 2,4,6-trisubstituted-1,3,5-triazines 23131798 N-cyclopentyl-4-ethoxy-6-(4-methylpiperidin-1-yl)-1,3,5-triazin-2-amine 23132334 DTG 23132334 Dolutegravir 23132334 S/GSK1349572 23132334 UDP 23132334 creatinine 23132334 dolutegravir 23132743 1,25-dihydroxyvitamin D 23132743 vitamin D 23132751 CO(2) 23132751 CaCO(3) 23132751 CaO 23132751 MgO 23132843 3,4-dihydropyrimidin-2(1H)-ones 23132843 4-Aryl-3,4-dihydropyrimidin-2(1H)-ones 23132843 iodide 23132843 iodine 23132843 pyrimidone 23132843 sodium iodide 23135547 ATP 23135547 Amiodarone 23135547 Dronedarone 23135547 amiodarone 23135547 benzofuran 23135547 dronedarone 23135547 fatty acids 23135547 oxygen 23135548 2,3,7,8-tetrachlorodibenzo-p-dioxin 23135548 Dioxin 23135548 TCDD 23135548 aryl hydrocarbon 23135548 dioxin 23137833 dexamethasone 23137833 resveratrol 23137957 DON 23137957 deoxynivalenol 23137957 trichothecenes 23138333 Cu 23138333 chl a 23138333 chlorophyll a 23138333 copper 23138381 Formaldehyde 23138381 formaldehyde 23138972 Ir 23138972 Pd 23138972 Rh 23138972 Ru 23138972 enamines 23138972 heteroarenes 23138972 imines 23138972 ketones 23138972 olefins 23138972 palladium 23139020 19- and 20-hydroxyeicosatetraenoic acid 23139020 arachidonic acid 23139020 epoxyeicosatrienoic acids 23139378 gemfibrozil 23139378 gemfibrozil and its glucuronide 23139378 gemfibrozil glucuronide 23139378 itraconazole 23139378 repaglinide 23139413 Gln 23139413 Ile 23139413 Sar 23139413 cysteines 23139413 losartan 23140132 triacylglyceride 23140132 triglycerides 23141425 EGCG 23141425 Epigallocatechin-3-gallate 23141425 polyphenol 23142020 BAY 41-8543 23142020 polystyrene 23142538 2,3,7,8-Tetrachlorodibenzo-p-dioxin 23142538 TCDD 23142538 dioxin 23142558 17-β-oestradiol 23142558 Oestrogens 23142558 oestrogens 23142699 estradiol 23142699 estrogen 23142699 estrogens 23142753 1,1'-dichloro-2,2'-bis(p-chlorophenyl)ethylene 23142753 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane 23142753 1,1,1-trichloro-2-(p-chlorophenyl)-2-(o-chlorophenyl)-ethane 23142753 DDT 23142753 Dichlorodiphenyltrichloroethane 23142753 Organochlorine 23142753 o,p'-DDT 23142753 p,p'-DDE 23142753 p,p'-DDT 23143036 BHT 23143036 Cadmium 23143036 Cd 23143036 Cu 23143036 N-acetylcysteine 23143036 NAC 23143036 Zn 23143036 butylhydroxytoluene 23143036 d-mannitol 23143036 hydrogen peroxide 23143036 oxygen 23143036 paraquat 23143036 superoxide 23143039 Cadmium 23143039 cadmium 23143039 carbonyl 23143039 gluconate 23143039 glucose 23143039 glutathione 23143039 malondialdehyde 23143620 2,4-dinitrochlorobenzene 23143674 clemizole 23144001 perylene 23146662 Bryostatin 1 23146662 Merle 23 23146662 bryostatin 23146662 bryostatin 1 23146662 bryostatins 23146662 phorbol ester 23146662 phorbol esters 23146690 Ly294002 23146690 clofarabine 23146690 phosphoinositide 23146690 resveratrol 23146692 1,1-diphenyl-2-picrylhydrazyl 23146692 2,2-azobis-(2-amidino-propane) dihydrochloride 23146692 AAPH 23146692 CAAP 23146692 Cys-Ala-Ala-Pro 23146692 DPPH 23146692 VCSV 23146692 Val-Cys-Ser-Val 23146692 amino acid 23146692 oxygen 23146694 BPA 23146694 Bisphenol A 23146694 N 23146694 polycarbonate 23146765 (1)H 23146765 1H 23146765 B12 23146765 CCl(4) 23146765 carbon tetrachloride 23146765 choline 23146765 folate 23146765 formate 23146765 glucose 23146765 lactate 23146766 AFB 23146766 AFB(1) 23146766 Aflatoxin B(1) 23146766 Lys 23146766 aflatoxin 23146766 aflatoxin B1 23146766 lysine 23146838 anastrozole 23146838 estrogen 23146838 estrogens 23146838 glucose 23146838 saccharin 23146838 sugar 23146871 Alexa green 23146871 Fe 23146871 Fe(3+) 23146871 Manganese 23146871 Mn 23146871 Mn(2+) 23146871 Mn(3+) 23146871 iron 23146871 manganese 23147005 phosphodiester 23147376 Superoxide 23147376 methacholine 23147376 streptozotocin 23147377 Fe(2)O(3) 23147377 Iron oxide 23147377 iron oxide 23147415 BW284c51 23147415 bambuterol 23147415 choline 23147415 donepezil 23147415 glucose 23147415 physostigmine 23147416 CTAP 23147416 D-Ala(1)-peptide T-NH(2,) 23147416 DAPTA 23147416 d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2 23147416 naloxone 23147475 C 23147475 K(+) 23147475 O 23147475 O=C 23147475 fluorenone 23147475 fluorenone carbonyl 23147475 zeolite L 23147567 PAH 23147567 PAHs 23147567 anthracene 23147567 naphthalene 23147567 phenanthrene 23147567 poly(dimethylsiloxane) 23147567 polycyclic aromatic hydrocarbons 23147567 pyrene 23147567 silicone 23147715 Cr(2)O(3 23147715 Cr(2)O(7)(2-) 23147715 Cr(III) 23147715 Cr(OH)(3) 23147715 Cr(VI) 23147715 CrO(4)(2-) 23147715 H(2) 23147715 H(2)O(2) 23147715 OH 23147715 chromium 23147715 chromium oxide 23147715 dichromate 23147750 Ca(+) 23147750 Ca(2+) 23147750 HCO 3(-) 23147750 Mg(+) 23147750 Mg(2+) 23147750 SO 4(-) 23147750 SO 4(2-) 23147750 coal 23147837 BDE-47 23147837 BDE-99 23147837 PBDE 23147837 PBDEs 23147837 Polybrominated diphenyl ethers 23147837 polybrominated diphenyl ethers 23149337 adenosine 23149337 histamine 23149908 glucose 23150491 BPA 23150491 BPA-Gluc 23150491 BPA-glucuronide 23150491 bisphenol A 23150491 bisphenol a 23151003 Purine 23151003 adenosine 23151003 nucleoside tri- and di-phosphates 23151003 nucleotides 23151003 pyrimidine 23151610 Carbohelicenes 23151610 benzenoid 23151610 carbohelicene 23151610 carbohelicenes 23151610 helicene 23151610 helicenes 23151611 5-HIAA 23151611 5-HT 23151611 5-hydroxyindoleacetic acid 23151611 dopamine 23151611 norepinephrine 23151611 oleanolic acid 23151611 serotonin 23151612 aspirin 23151612 minocycline 23151612 neurosteroids 23151612 omega-3 fatty acids 23151612 steroidal 23152186 Arsenic 23152186 As(III) 23152186 arsenic 23152186 dexamethasone 23152186 glucose 23152186 sphingosine-1-phosphate 23153029 estradiol 23153029 estrogens 23153029 progesterone 23153054 alprazolam 23153054 clonazepam 23153054 dexamethasone 23153054 diltiazem 23153054 midazolam 23153054 nifedipine 23153054 quinidine 23153054 tacrolimus 23153054 verapamil 23153057 bupropion 23153057 diclofenac 23153057 midazolam 23153057 phenacetin 23153057 phenobarbital 23153057 rifampicin 23153057 salicylamide 23153057 β-naphthoflavone 23153322 RAI 23153322 radioactive iodine 23153456 nitric oxide 23153456 polyinosinic:polycytidylic acid 23153512 (1)H 23153512 (31)P 23153512 FEN 23153512 NO2 23153512 fenitrothion 23153512 methylene blue 23154127 AME 23154127 AOH 23154127 DCF 23154127 S 23154127 alternariol 23154127 alternariol monomethyl ether 23154127 dichlorofluorescein 23154127 formamidopyrimidine 23154127 glutathione 23154127 monomethylether 23154127 γ-glutamylcysteine 23154304 ADP 23154304 adenosine diphosphate 23154304 arachidonic acid 23154304 hydrazone 23154304 indole hydrazone 23154304 indomethacin 23154865 BH3 23155201 99mTc 23155201 MDP 23155201 methylendiphosphonate 23155201 technetium-99m 23157442 Gentamicin 23157635 oxygen 23157637 dopamine 23157637 haloperidol 23157637 olanzapine 23157637 oxygen 23157637 quetiapine 23157637 risperidone 23157640 anthracyclines 23157640 cisplatin 23157640 platinum 23157640 taxanes 23159106 Ethanol 23159106 Oxygen 23159106 ethanol 23159106 oxygen 23159331 (±)-methamphetamine 23159331 Methamphetamine 23159331 dopamine 23159331 methamphetamine 23159331 serotonin 23159396 4',6'-diamidino-2-phenylindole 23159396 DAPI 23159396 Evans blue 23159396 FITC 23159396 fluorescein isothiocyanate 23159397 CaNa(2)EDTA 23159397 calcium disodium ethylenediaminetetraacetic acid 23159479 Oxytocin 23159479 oxytocin 23159529 14C 23159529 17864 23159529 Glutaraldehyde 23159529 PEG 23159529 methionine 23159529 platinum 23159529 polyethylene glycol 23159529 sunitinib 23159662 Venlafaxine 23159662 venlafaxine 23159666 5,10,15,20-tetra(m-hydroxyphenyl)chlorin 23159666 Foscan 23159666 PEG 23159666 polyethylene glycol 23159667 8-Chloro-adenosine 23159667 8-chloro-adenosine 23159667 8-chloro-adenosine-5'-O-stearate 23159667 8CA 23159667 8CAS 23159667 MTT 23159667 PEG-DSPE 23159667 cholesterol 23159667 distearoyl phosphatidylethanolamine 23159667 octadecanoyl 23159667 phosphatidylcholine 23159667 poly (ethylene glycol) 23159712 Carbopol 23159712 Compritol 23159712 PEG 400 23159712 Poloxamer 23159712 lidocaine 23159712 triethyl citrate 23159729 Naphthenic acid 23159729 Naphthenic acids 23159729 benzo[a]pyrene 23159729 naphthenic acids 23159732 N'-formylkynurenine 23159732 NFK 23159732 O2 23159732 Trp 23159732 methylene blue 23159732 oxygen 23159790 Gly 23159790 Ser 23159790 amino acid 23159790 amino acids 23159790 nucleotide 23159790 proline 23159888 Alcohol 23159888 S 23159888 alcohol 23159888 glutathione 23160003 bicyclic phenols 23160003 dienone-phenol 23160003 phenol 23160003 polycyclic cyclohexadienones 23160089 5,7,3',5'-tetrahydroxy-flavanone 23160089 5,7,3',5'-tetrahydroxy-flavanone-7-O-neohesperidoside 23160089 5,7,3',5'-tetrahydroxy-flavanone-7-O-β-d-glucopyranoside 23160089 MTT 23160089 chromone glycosides 23160089 drynachromoside A 23160089 drynachromoside B 23160089 flavanones 23160089 flavonoids 23160092 (1)H 23160092 (13)C 23160092 alcohol 23160092 curcumenone 23160092 ethanol 23160092 n-hexane 23160419 H(2)O 23160419 HONO 23160419 NO(2) 23160419 Nitrogen dioxide 23160419 hydrogen 23160419 nitrogen 23160419 oxygen 23160419 oxygens 23160527 glucose 23160529 zinc 23160934 Cu(2+) 23160934 α-syn12 peptide 23160940 CP55940 23160940 Org 27569 23160940 PSNCBAM-1 23160940 WIN55212 23160940 [(3)H]CP55940 23160940 [(3)H]WIN55212 23160940 [(35)S]GTPγS 23160940 cAMP 23160940 forskolin 23160940 guanosine 5'-O-(3-[(35)S]thio)triphosphate 23160961 Ser 23160961 acyl 23160961 fatty acids 23160961 triacylglyceride 23160964 1,25-Dihydroxyvitamin D3 23160964 1,25-dihydroxyvitamin D 23160964 RO-27-5646 23160964 Vitamin D 23160964 vitamin D 23161217 5-bromo-2'-deoxyuridine 23161217 BrdU 23161217 Suramin 23161217 alanine 23161217 bilirubin 23161217 ethanol 23161217 phospho 23161217 polysulfonated naphthylurea 23161217 suramin 23161424 Arg 23161424 Asp 23161424 Evodiamine 23161424 evodiamine 23161648 Cl(-) 23161648 HCO (3)- 23161648 SO (4)2- 23161648 coal 23161664 Cadmium 23161664 Cd 23161664 Co 23161664 CoCl2 23161664 Lysyl 23161664 cadmium 23161664 cobalt 23161664 lysyl 23161664 oxygen 23161673 tamoxifen 23161677 guanine 23161677 nucleic acid 23161804 (18-Crown-6)-2,3,11,12-tetracarboxylic acid 23161804 (18-crown-6)-2,3,11,12-tetracarboxylic acid 23161804 Isoxazoline 23161804 amine 23161804 crown ether 23161804 hydrochloride 23161804 hydrogen 23161804 isoxazoline 23161804 methanol 23161804 oxygen 23161804 β-amino acid 23163430 polyethylene glycol 23163508 chlorophyll 23163696 H-89 23163696 U-73122 23163696 benzodiazepine 23163696 cyclo(1-8) [DLeu(5) ]OP 23163696 flumazenil 23163696 inositol 1,4,5-trisphosphate 23164613 5-HT 23164613 8-OH-DPAT 23164613 LP-211 23164613 SB-269970 23164613 U0126 23164613 cycloheximide 23164613 roscovitine 23164613 serotonin 23164615 (S)-3,4-dicarboxyphenylglycine 23164615 AZ12216052 23164615 DCPG 23164615 glutamate 23164711 ZINC 23164711 monosulfated benzofurans 23164711 sulfate 23164711 sulfated benzofurans 23164931 DCG-IV 23164931 MPEP 23164931 Procyclidine 23164931 caramiphen 23164931 glutamate 23164931 procyclidine 23164984 As 23164984 Cd 23164984 Hg 23164984 Pb 23164984 arsenic 23164984 cadmium 23164984 mercury 23168241 Quinacrine 23168241 S 23168241 Sodium metabisulfite 23168241 quinacrine 23168241 sodium metabisulfite 23168241 sulfite 23168241 sulfonate 23168915 H(2) 23168915 NiO 23168915 nickel oxide 23169614 carbon 23169614 graphene 23170796 7-dimethylamino-6-dimethyl-6-deoxytetracycline 23170796 Minocycline 23170796 minocycline 23170796 tetracycline 23170798 ethanol 23171045 2-(aryloxy)-3-phenylpropanoic acids 23171045 acylcarnitine 23171045 biphenyl 23171045 carnitine 23171045 palmitoyl 23172038 titanium dioxide 23172121 polyurethane 23172121 polyurethanes 23172229 Cardiolipin 23172229 cardiolipin 23172229 phosphatidylcholine 23172229 phosphatidylethanolamine 23174213 calcium 23174457 Cd(2+) 23174457 Mn(2+) 23174457 cadmium 23174457 paraoxon 23174539 3-phenoxybenzoic acid 23174539 5-HT 23174539 PERM 23174539 dopamine 23174539 monoamine 23174539 noradrenaline 23174539 permethrin 23174539 pyrethroid 23174539 serotonin 23174746 Ritalin 23174746 amphetamine 23174746 methylphenidate 23177255 DPPH 23177255 glucose 23177255 scutellarein 23177255 scutellarin 23177256 10074-G5 23177256 7-nitrobenzofurazan 23177256 JY-3-094 23177256 N-([1,1'-biphenyl]-2-yl)-7-nitrobenzo[c][1,2,5]oxadiazol-4-amine 23177256 arginine 23177256 ortho-biphenyl 23177256 para-carboxyphenyl 23177784 1,10-phenanthroline 23177784 1,10-phenanthroline-2,9-diacid 23177784 5-amino-2'-deoxycytidine 23177784 diketone 23177784 europium 23177784 lanthanide 23177784 nucleoside 23177784 nucleosides 23177784 phenanthroline 23177784 polypyridine ruthenium 23177784 ruthenium 23178170 C 23178170 Ca(2+) 23178170 calcium 23178170 potassium 23178178 Na(+)K(+) 23178178 Ti 23178178 TiO(2) 23178178 Titanium dioxide 23178178 glutathione 23178178 lactate 23178178 titanium dioxide 23178179 2-Mercaptobenzothiazole 23178179 2-mercaptobenzothiazole 23178179 MBT 23178179 iodo-amino acids 23178179 sodium-iodide 23178182 MK-801 23178182 N-Methyl-d-aspartate 23178182 NMDA 23178182 NO 23178182 UCCB01-125 23178182 nitric oxide 23178221 7-xylosyl taxanes 23178221 OH 23178221 diglycoside taxanes 23178221 xylosyl 23178221 xylosyl-containing taxanes 23178221 α-d-glucose 23178243 8-OH-dG 23178243 8-hydroxyguanine 23178243 8-hydroxyguanosine 23178243 8-oxoguanine 23178243 Aerosil 23178243 PAR 23178243 Printex 23178243 carbon black 23178243 paraffin 23178243 poly(ADP-ribose) 23178243 silica 23178279 dexamethasone 23178339 DHA 23178339 TEA 23178339 amine 23178339 docosahexaenoic acid 23178339 doxorubicin 23178339 polyunsaturated fatty acid 23178339 triethanolamine 23178949 formaldehyde 23179351 nickel chloride 23179765 benzene 23179765 hydrogen 23179765 pyrrole 23179966 5-HT 23179966 N-methyl-D-aspartate 23179966 NMDA 23179966 Serotonin 23179966 dopamine 23179966 glutamate 23179966 serotonin 23180370 NaCl 23180370 SO4 23180370 sulphate 23180382 graphene 23180382 graphenes 23180652 2,4-dichlorophenoxyacetic acid 23180652 atrazine 23180652 chlorpyrifos 23180652 gemfibrozil 23180692 malathion 23180762 magnesium 23180762 tartrate 23181488 (CH(3))(2)HC-CO-CH(CH(3))(2) 23181488 diisopropyl ketone 23181488 isopropyl 23181488 methyl 23183084 20-keto 23183084 3-keto 23183084 5α-dihydroprogestrone 23183084 Progestin 23183084 dienogest 23183084 dydrogesterone 23183084 medroxyprogesterone acetate 23183084 progesterone 23183084 progestin 23183084 progestins 23183186 2,2'-dihydroxy-1,1'-dinaphthyldisulfide 23183186 IPA3 23183186 Ser 23183186 Thr 23183186 cAMP 23183186 glucose 23183413 Cu 23183413 GSH 23183413 K(+) 23183413 Na(+) 23183413 S 23183413 copper 23183413 glutathione 23183413 oxygen 23183413 peroxyl 23183413 sodium 23183532 amino acid 23183532 amino acids 23183532 ammonia 23183532 fatty acids 23183532 nitrogen 23183532 sulfide 23184251 8-oxo-dGTP 23184251 ADP 23184251 Ap(4)A 23184251 DIP 23184251 DIPs 23184251 IDP 23184251 dIDP 23184251 diadenosine polyphosphates 23184251 diadenosine tetraphosphate 23184251 diphosphoinositol polyphosphates 23184251 nucleotides 23184251 oxidized nucleotides 23184251 polyphosphates 23184251 pyrophosphate 23184251 ribose 23184951 ATP 23185990 2'-OH 23185990 Ala 23185990 Amino acids 23185990 Aminoacyl 23185990 Cys 23185990 Pro 23185990 Prolyl 23185990 aminoacyl 23185990 ester 23186623 TTX 23186623 tetrodotoxin 23186624 Catapresan 23186624 Clonidine 23186624 NaCl 23186624 clonidine 23186624 creatinine 23186624 diethylether 23186624 formalin 23186624 nitrogen 23186624 urea 23188714 2'deoxyuridine 23188714 5-fluoropyrimidine 23188714 5-fluorouracil 23188714 5F-2'dCtd 23188714 5F-2'dUrd 23188714 5F-2'deoxyuridine 23188714 5F-dUMP 23188714 5F-orotic acid 23188714 Pyrimidine 23188714 halogenated pyrimidines 23188714 nucleoside 23188714 pyrimidine 23188714 pyrimidines 23188714 thymidine 23188714 uracil 23188714 uridine 23189968 iron 23190030 (poly)phenolic 23190030 Phenolic 23190030 flavonoid 23190030 nitrogen 23190030 oxygen 23190172 17β-Oestradiol 23190172 17β-oestradiol 23190172 H(2) O(2) 23190172 oestrogen 23192895 H(δ+) 23192895 H(δ-) 23192895 Mg(BH(4))(2) 23192895 Mg(BH(4))(2)·NH(3) 23192895 Mg(BH(4))(2)·xNH(3) 23192895 N:→Mg(2+) 23192895 NH(3) 23192895 ammonia 23192895 hexaammoniate 23192895 hydrogen 23192895 magnesium borohydride 23192895 magnesium borohydride ammoniates 23192895 metal borohydride ammoniates 23192982 17β-estradiol 23192982 cholesterol 23192982 estrogen 23193276 amino acid 23194502 Glaucine 23194502 adriamycin 23194502 glaucine 23194502 isoquinoline alkaloid 23194502 mitoxantrone 23194504 3',5'-Di-C-β-glucopyranosylphloretin 23194504 3',5'-di-C-β-glucopyranosylphloretin 23194504 Trolox 23194504 flavonoids 23194504 hesperidin 23194504 naringin 23194504 nobiletin 23194504 oxygen 23194504 superoxide 23194504 tangeretin 23194505 ethanol 23194507 cis-isomers of lycopene and β-carotene 23194507 lutein 23194507 lycopene 23194507 zeaxanthin 23194507 β-carotene 23194510 4(5)-methylimidazole 23194510 4-MI 23194510 D-glucose 23194510 NH(3) 23194510 Sulphite 23194510 pyrazine 23194510 sulphite 23194512 MTT 23194512 Micranthin B 23194512 Podocarpane 23194512 abietane 23194512 diterpenoids 23194512 graciliflorin C 23194512 graciliflorin D 23194512 graciliflorins A (1) and B 23194512 isopimarane 23194512 isopimarane acetal 23194512 micranthin B 23194512 podocarpa-8,11,13-triene-3α,13-diol 23194512 podocarpanes 23194517 amino acid 23194517 amino acids 23194517 astaxanthin 23194517 carbonyl 23194517 fatty acid 23194517 sulfhydryl 23194517 tocopherol 23194522 ABTS 23194522 phenolic acids 23194522 polyphenol 23194522 polyphenols 23194524 acetone 23194524 phloridzin 23194524 polyphenol 23194525 Hexose 23194526 cholesterol 23194528 1-propanol 23194528 2-furaldehyde 23194528 2-methyl-1-butanol 23194528 2-methyl-1-propanol 23194528 3-methyl-1-butanol 23194528 5-(Hydroxymethyl)-2-furaldehyde 23194528 5-(hydroxymethyl)-2-furaldehyde 23194528 ethyl acetate 23194528 furan 23194528 silver 23194531 anthocyanin 23194531 anthocyanins 23194531 ethanol 23194533 Fatty acids 23194533 fatty acids 23194533 lauric acid 23194533 saturated fatty acids 23194540 boscalid 23194543 sodium 23194544 Asparagine 23194544 acrylamide 23194544 asparagine 23194544 fructose 23194544 glucose 23194544 sucrose 23194544 sugars 23194555 Cd(II) 23194555 Hg(II) 23194555 Zn(II) 23194555 mercury 23194566 TTX 23194566 Tetrodotoxin 23194566 tetrodotoxin 23194750 10-DEBC 23194750 GW9662 23194750 KCl 23194750 LNNA 23194750 LY294002 23194750 N(G)-nitro-L-arginine 23194750 NO 23194750 Thiazolidinediones 23194750 glitazones 23194750 phenylephrine 23194750 pioglitazone 23194750 rosiglitazone 23194750 ser 23194750 thiazolidinedione 23194750 thiazolidinediones 23194750 troglitazone 23194825 12-O-tetradecanoyl-phorbol-13-acetate 23194825 3,4-methylenedioxymethamphetamine 23194825 BSO 23194825 Ecstasy 23194825 GBR 12909 23194825 GSH 23194825 MDMA 23194825 N-Me-α-MeDA 23194825 N-acetylcysteine 23194825 N-methyl-α-methyldopamine 23194825 NAC 23194825 buthionine sulfoximine 23194825 catechol 23194825 dopamine 23194825 ecstasy 23194825 glutathione 23194825 retinoic acid 23194825 superoxide 23194825 α-MeDA 23194825 α-methyldopamine 23194825 γ-glutamylcysteine 23195954 Asp 23195954 C 23195954 Ca(2+) 23195954 His 23195954 N 23195954 Ser 23195954 Serine 23195954 Zn(2+) 23195954 Zn2+ 23195954 serine 23195960 K 23195960 Na 23195960 Na(+) 23195960 ouabain 23196320 Ag 23196320 AuAg 23197649 ACh 23197649 BQCA 23197649 CNO 23197649 acetylcholine 23197649 benzyl quinolone carboxylic acid 23197649 clozapine-N-oxide 23197771 TAPI-0 23197771 tyrosine 23198810 naphthalimide 23198810 quinone 23198819 MTM 23198819 Montmorillonite 23198819 quartz 23198831 H(+) 23198831 H(2) 23198831 Hydrogen 23198831 Pt 23198831 Ru 23198831 hydrogen 23198958 GaAs 23198958 In(Ga)As 23199028 amine 23199028 amino acid 23199028 carbohydrate 23199028 glycyrrhizin 23199983 1-lactulose 23199983 Fructose 23199983 Lactose 23199983 fructose 23199983 galactosyl 23199983 lactose 23199983 lactulose 23199984 TAG 23199984 sodium methoxide 23199984 stearin 23199984 triacylglycerol 23199992 4-aminobutyrate 23199992 GABA 23199992 O-phosphocholine 23199992 acetate 23199992 asparagine 23199992 isoleucine 23199992 leucine 23199992 phenylacetate 23199992 phenylalanine 23199992 succinate 23199992 sucrose 23199992 tyrosine 23199992 valine 23199992 ¹H 23199999 malondialdehyde 23200004 hydrogen peroxide 23200004 mercury 23200004 nitric acid 23200004 nitrous acid 23200004 nitrous oxides 23200004 potassium dichromate 23200004 tin chloride 23200005 Fe 23200005 K 23200005 P 23200005 Se 23200005 SeCys 23200005 SeMet 23200005 Selenium 23200005 Zn 23200005 adenosine 23200005 cordycepin 23200005 iron 23200005 methylselenocysteine 23200005 phosphorus 23200005 potassium 23200005 selenium 23200005 selenomethionine 23200005 zinc 23200006 alcoholic 23200006 cadmium 23200006 carbon 23200006 copper 23200006 graphite 23200246 12-hydroxy-scabrolide A 23200246 13-epi-scabrolide C 23200246 norditerpenoids 23200253 TBPB 23200253 TPBP 23200253 VU0357017 23200253 piperidine 23200747 Organophosphorus 23200778 BEP 23200778 S 23200778 aldehyde 23200778 bleomycin 23200778 cisplatin 23200778 etoposide 23200778 glutathione 23200887 3,5,4'-trihydroxy-trans stilbene 23200887 ADP 23200887 H(2)O(2) 23200887 Resveratrol 23200887 resveratrol 23200901 Aconitum alkaloids 23200901 BAC 23200901 BHA 23200901 BMA 23200901 Ko143 23200901 MK571 23200901 aconine 23200901 aconitine 23200901 benzoylaconine 23200901 benzoylhypaconine 23200901 benzoylmesaconine 23200901 cyclosporine A 23200901 hypaconitine 23200901 mesaconine 23200901 mesaconitine 23200901 verapamil 23201003 1,25(OH)(2)D(3) 23201003 1α,25-dihydroxyvitamin D(3) 23201003 1α,25-dihydroxyvitamin D₃ 23201003 JBP485 23201055 PLGA 23201055 Poly(lactic-co-glycolic acid) 23201124 N 23201309 3'-hydroxyl 23201309 3-phosphoglycerate 23201309 ADP 23201309 Nucleoside 23201309 creatine 23201309 nucleoside diphosphate 23201309 nucleotide 23201309 pyruvate 23201309 tenofovir 23201309 tenofovir mono- or diphosphate 23201309 tenofovir monophosphate 23201331 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide 23201331 MTT 23201331 Sweroside 23201331 sweroside 23201370 alanine 23201370 amino 23201370 aspartate 23201370 cholesterol 23201370 triglycerides 23201439 carbon 23201439 cyclosarin 23201439 organophosphorus 23201439 β-cyclodextrin 23201442 Estrogen 23201442 Fatty acids 23201442 H₂O₂ 23201442 NADH 23201442 NAD⁺ 23201442 Raloxifene 23201442 acetoacetate 23201442 estrogen 23201442 fatty acid 23201442 fatty acids 23201442 oxygen 23201442 phenoxyl 23201442 raloxifene 23201442 ¹⁴CO₂ 23201442 β-hydroxybutyrate 23201451 Moniliformin 23201451 moniliformin 23202250 TiO(2) 23202250 carbon 23202250 titanium dioxide 23202585 ATP 23202585 C 23202880 N(2) 23202880 NO(3) 23202880 NO3 23202880 branched alkane 23202880 nitrate 23202880 squalane 23202880 squalene 23203454 CHDA 23203454 DINCH 23203454 DINP 23203454 Hexamoll 23203454 MINCH 23203454 OH 23203454 carboxy 23203454 cyclohexane-1,2-dicarboxylic acid 23203454 di-iso-nonylphthalate 23203454 diisononyl-cyclohexane-1,2-dicarboxylate 23203454 mono-isononyl-cyclohexane-1,2-dicarboxylate 23203454 monoester 23203454 monoesters 23203454 oxo 23203454 phthalate 23203870 zinc 23203920 N-3-oxododecanoyl-L-homoserine lactone 23203920 OHN 23204325 glucose 23204443 Sphingosine 1-phosphate 23205571 (2S,4R)-4-(naphthalene-2-ylmethyl)pyrrolidine-2-carboxylic acid 23205571 Ica 23205571 N 23205571 [Mpa(1), Ica(2), D-Arg(8)]VP 23205571 [Mpa(1),Ica(2),Val(4),D-Arg(8)]VP 23205571 arginine vasopressin 23205571 indoline-2-carboxylic acid 23205571 oxytocin 23205571 proline 23205763 alkyne 23205763 azide 23205763 indocyanine green 23205763 metal-oxide 23205778 1,4-benzoquinone 23205778 2-chlorofuran 23205778 2-chlorothiophene 23205778 Br 23205778 Cl 23205778 C≡N 23205778 F 23205778 OH 23205778 anthracene 23205778 aromatic heterocycles 23205778 benzene 23205778 benzenes 23205778 benzimidazole 23205778 benzisoxazole 23205778 benzo[b]thiophene 23205778 benzo[c]thiophene 23205778 benzonitrile 23205778 benzothiazole 23205778 benzoxazole 23205778 bromobenzene 23205778 carbon 23205778 chlorobenzene 23205778 di-, tri-, and hexachlorobenzene 23205778 dihydroxybenzene 23205778 fluorobenzene 23205778 fused-ring heterocycles 23205778 hydrogen 23205778 indazole 23205778 indole 23205778 isoindole 23205778 methanol 23205778 naphthalen-2-ol 23205778 naphthalene 23205778 naphthalene-2-carbonitrile 23205778 phenanthrene 23205778 phenol 23205778 polycyclic aromatic 23205778 polycyclic aromatic hydrocarbons 23205778 purine 23205778 quinoline 23206503 2-AG 23206503 2-arachidonoylglycerol 23206503 AEA 23206503 GW6471 23206503 N-palmitoylethanolamine 23206503 PEA 23206503 SR141716 23206503 anandamide 23206503 cannabinoids 23206503 fatty acid ethanolamide 23206861 Tetrahydro-β-carboline 23206861 carbamates 23206861 fatty acid amide 23206861 tetrahydro-β-carbolines 23206990 Estrogen 23207166 Misoprostol 23207166 misoprostol 23207252 NADPH 23207252 nicotinamide adenine dinucleotide phosphate 23207252 thiobarbituric acid 23207328 AZT 23207328 PPG-5-CETETH-20 23207328 oleic acid 23207328 zidovudine 23207477 Co 23207477 Cobalt 23207477 cobalt 23208007 sialic acid 23208609 1-chloro-4-propoxy-TX 23208609 1-chloro-4-propoxythioxanthone 23208609 17ß-estradiol 23208609 2,4-diethyl-TX 23208609 2,4-diethylthio xanthone 23208609 2-ITX 23208609 2-chloro-TX 23208609 2-chlorothioxanthone 23208609 2-isopropylthioxanthone 23208609 4-ITX 23208609 4-isopropylthioxanthone 23208609 androgen 23208609 estrogen 23208609 estrone 23208609 pregnenolone 23208609 progesterone 23208609 steroid 23208609 thioxanthone 23208666 Poly(2-oxazoline) 23208666 poly(2-nonyl-2-oxazoline)s 23208666 poly(2-oxazoline) 23209192 Cotinine 23209192 cotinine 23210481 6,6'-bis-O-(3-nonyldodecanoyl)-α,α'-trehalose 23210481 TDCM 23210481 Vizantin 23210481 trehalose 6,6'-dicorynomycolate 23210481 trehalose-6,6'-dicorynomycolate 23210481 vizantin 23210547 carbon 23210662 PAMAM 23210662 doxorubicin 23210662 ethynyl 23210851 ATP 23211364 Candesartan 23211364 PD-123319 23211364 candesartan 23211525 androgens 23211525 dehydroepiandrosterone 23211525 hydroxysteroid 23211525 retinoid 23211525 sulfonate bile acids 23212787 Ginsenoside 23212787 Ginsenosides Ra1-3, Rb2-3, and Rc 23212787 ginsenosides 23212970 MTT 23212970 PCL diol 23212970 TDI 23212970 butanediol 23212970 monoglyceride 23212970 pentaerythritol 23212970 polyurethane 23212970 polyurethanes 23212975 PEG 23212975 PVP 23212975 Poly(N-vinylpyrrolidone) 23212975 poly(ethylene glycol) 23214415 PAA 23214415 PEO 23214415 poly(acrylic acid) 23214415 poly(ethylene oxide) 23214423 Br(2) 23214423 BrF(3) 23214423 C(2)F 23214423 C2F 23214423 carbon 23214423 fluorine 23214423 graphene 23214423 graphite 23214423 graphite fluoride 23214430 Au 23214430 silica 23214714 C 23214714 CH(3)OH 23214714 CO(2) 23214714 CO(2)(-) 23214714 CO2 23214714 N 23214714 Py(-) 23214714 PyCOO(-) 23214714 PyCOOH(0) 23214714 PyH(+) 23214714 PyH(0) 23214714 Py·CO(2) 23214714 formaldehyde 23214714 formic acid 23214714 pyridine 23214926 ADP 23214926 AMF-26 23214926 Δ¹,²-octalin 23214979 3-Amido pyrrolopyrazine 23214979 3-amido-5-cyclopropylpyrrolopyrazines 23214990 poly(N-isopropyl acrylamide) 23215007 1,3,5,6-tetramethyluracil 23215007 1,3,5-trimethyluracil 23215007 5,6-dimethyl-, 1,3,5-trimethyl-, and 1,3,5,6-tetramethyl 23215007 5,6-dimethyl-, 1,3,5-trimethyl-, and 1,3,5,6-tetramethyluracils 23215007 5,6-dimethyluracil 23215007 N(2) 23215007 methylated uracils 23215007 uracils 23215148 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine triethylammonium 23215148 1,2-dioleoyl-sn-glycero-3-phospho-L-serine 23215148 1,2-dioleoyl-sn-glycero-3-phosphocholine 23215148 1,2-dipalmitoyl-sn-glycero-3-phosphocholine 23215148 DOPC 23215148 DOPS 23215148 DPPC 23215148 TR-DHPE 23215148 Texas Red 23215238 EDTA 23215238 calcium carbonate 23215461 carbohydrate 23216335 androgens 23217961 Am80 23217961 Cinnamic acid 23217961 benzoic acid 23217961 carboxyl 23217961 carboxylic acid 23217961 diphenylamine 23217961 methyl 23217961 phenylpropionic acid 23217961 retinoid 23217961 retinoids 23218712 YH-GKA 23218712 benzamide 23218712 glucose 23218712 phenylethyl benzamide 23218713 bisulfite 23218713 cysteine 23218713 dipeptidyl aldehydes 23218713 serine 23218713 α-ketoamides 23218713 α-ketoesters 23218713 α-ketoheterocycles 23218716 Indoleamine 23218716 Tsitsikammamine A 23218716 Tsitsikammamines 23218716 pyrroloiminoquinone 23218716 tryptophan 23218716 tsitsikammamine 23218716 tsitsikammamine A 23218717 2-APB 23218717 Ca(2+) 23218717 N-pyridylpyrazolecarboxamides 23218717 calcium 23218717 cyano 23218717 fluo-3 AM 23218717 ryanodine 23219161 C 23219161 N 23219325 Leucine 23219325 cinnoline 23219325 cinnoline-3-carboxamides 23219339 N-methyl-D-aspartate 23219339 NMDA 23219339 OMT 23219339 Oxymatrine 23219339 calcium 23219339 oxymatrine 23219469 cholesterol 23219525 ambrisentan 23219525 bosentan 23219525 pregnane 23219525 sildenafil 23219525 tadalafil 23219590 BAPTA 23219590 Ca(2+) 23219590 Ca2+ 23219590 Maprotiline 23219590 maprotiline 23219590 norepinephrine 23219658 N-methyl-d-Aspartate 23219658 N-methyl-d-aspartate 23219658 NMDA 23219658 glutamate 23219696 Bisphenol-A 23219696 estradiol 23219696 nonylphenol 23219696 progesterone 23219696 steroid 23219696 steroids 23219696 testosterone 23219778 MeOH 23219778 methanol 23219778 nitric oxide 23219979 EtOAc 23219979 cis-stilbenoids 23219979 sciryagarol I (1) and II 23220002 esters 23220002 glucose 23220002 organophosphorus 23220003 Fructose 23220003 GSH 23220003 Glyoxal 23220003 alkyl 23220003 curcumin 23220003 dicarbonyl 23220003 dicarbonyls 23220003 dihydroxyacetone 23220003 ethyl gallate 23220003 fructose 23220003 gallate 23220003 gallates 23220003 gallic acid 23220003 glyceraldehyde 23220003 glycoaldehyde 23220003 glyoxal 23220003 hydroxypyruvate 23220003 methyl gallate 23220003 methylglyoxal 23220003 oxygen 23220003 polyphenol 23220003 polyphenols 23220003 propyl gallate 23220003 rutin 23220004 4-methyl 23220004 NAD 23220004 Retinaldehyde 23220004 UVI2008 23220004 aldehyde 23220004 carboxyl 23220004 retinaldehyde 23220004 retinoic acid 23220004 retinoid 23220004 retinoids 23220004 retinol 23220291 limonene 23220291 ozone 23220293 5-HT 23220293 catecholamine 23220293 citalopram 23220293 desipramine 23220293 dopamine 23220293 monoamine 23220293 monoamines 23220293 norepinephrine 23220293 serotonin 23220295 amphetamine 23220295 dopamine 23220412 Metolachlor 23220412 chloroacetanilide 23220412 chlorophyll a 23220412 chlorophyll a, b or c 23220412 glutathione 23220412 metolachlor 23220413 3,3',5-triiodo-l-thyronine 23220413 TDCPP 23220413 Tris(1,3-dichloro-2-propyl) phosphate 23220413 thyroxin (T4) 23220513 (32)P 23220513 MEG 23220513 Methyleugenol 23220513 S 23220513 glutathione 23220513 phenobarbital 23220514 DOX 23220514 Na(+) 23220514 S-(4-nitrobenzyl)-6-thioinosine 23220514 doxorubicin 23220514 linalool 23220514 nucleoside 23220514 phlorizin 23220560 MeHg 23220560 methylmercury 23220562 DAPI 23220562 MTT 23220562 SB-203580 23220562 SP-600125 23220562 U-0126 23220562 clopidogrel 23220586 PEG 23220586 organophosphorus 23220586 polyethylene glycol 23220586 soman 23220588 2-mercaptoethane sulfonate 23220588 Acrolein 23220588 Aldehyde 23220588 CAA 23220588 Cyclophosphamide 23220588 H2O2 23220588 MESNA 23220588 N-acetylcysteine 23220588 Trolox 23220588 Trypan blue 23220588 acrolein 23220588 amines 23220588 aminoguanidine 23220588 ascorbic acid 23220588 carbonyl 23220588 chloroacetaldehyde 23220588 cyanamide 23220588 cyclophosphamide 23220588 cysteine 23220588 glutathione 23220588 hydralazine 23220588 hydroxylamine 23220588 ifosfamide 23220588 oxygen 23220588 penicillamine 23220588 sodium bisulfite 23220588 sodium borohydride 23220588 thiol 23220589 2-PAM 23220589 BT-03 23220589 BT-05 23220589 BT-07-4M 23220589 BT-08 23220589 HI-6 23220589 Organophosphorus 23220589 TMB-4 23220589 Toxidin 23220589 dichlorvos 23220589 obidoxime 23220589 oximes 23220589 paraoxon 23220589 tabun 23220612 20-HETE 23220612 27-hydroxycholesterol 23220612 27-hydroxycholestrol 23220612 5(S)-, 8(S)-, 12(S)- and 15(S)-HETE 23220612 5(S)-HETE 23220612 7-ketocholesterol 23220612 7β-hydroxycholesterol 23220612 9(S)-, 11(S)- and 20-HETE 23220612 Arachidonate 23220612 H(2)O(2) 23220612 cholesterol 23220612 docosahexaenoate 23220612 eicosapentaenoate 23220612 gluthathione 23220612 isoprostanes 23220612 neuroprostanes 23220612 oxygen 23220612 polyunsaturated fatty acids 23220612 resolvin D1 23220617 3-nitrotyrosine 23220617 carbonyl 23220617 cyclophosphamide 23220617 doxorubicin 23220635 aryl hydrocarbon 23220644 5-hydroxytryptamine 23220644 5-hydroxytryptamines 23220644 JMC08-4 23220644 arachidonic acid 23220646 3H-indazole 23220646 5-phenyl-1H-pyrazole 23220646 TLCK 23220646 benzimidazole 23220646 benzoheterocyclic 23220646 benzothiazole 23220646 isoxazolecarbaldehyde 23221006 Phenformin 23221006 TEA 23221006 [(14)C]tetraethylammonium 23221006 carnitine 23221006 oxygen 23221006 phenformin 23221633 oxygen 23221633 phospho 23222689 valproic acid 23223023 fatty acids 23223023 oleic and stearic acid 23223023 palmitic acid 23223234 6-azauracil 23223234 nucleotide 23223345 CARB 23223345 Carbohydrate 23223345 carbohydrate 23223345 glucose 23223551 C-H 23223551 CuO(+) 23223551 CuOH(+) 23223551 copper hydroxide 23223551 copper oxide 23223551 hydrocarbons 23223551 methane 23223551 oxygen 23223551 transition metal 23223639 polydimethylsiloxane 23223641 zeolite 23223641 zeolites 23223708 Nafion 23223708 PVDF 23223708 Polyvinylidene fluoride 23223708 vanadium 23223801 Lanthanide 23223801 Ln(3+) 23223801 Trivalent lanthanide 23223857 Carbon 23223857 carbon 23224291 (1)H 23224291 S 23224291 adenosine triphosphate 23224291 glucose 23224291 glutathione 23224291 glycine 23224291 thiosulphate 23224775 Ti(IV) 23224775 TiO(2) 23224775 carboxyl 23224775 carboxyl- and hydroxyl oxygen 23224942 epoxy 23224942 epoxy graphene oxide 23224942 graphene 23224942 graphene oxide 23225075 aluminium 23225075 cadmium 23225075 cobalt 23225075 copper 23225075 manganese 23225075 uranium 23225075 vanadium 23225075 zinc 23225241 Cholesterol 23225241 TAG 23225241 biliary acids 23225241 cholesterol 23225241 estrogens 23225241 triacylglycerol 23225365 MTT 23225365 NO 23225365 Resveratrol 23225365 resveratrol 23225365 sodium nitroprusside 23225366 9,19-cycloartane 23225366 cimigenol 23225366 cycloartane 23225366 triterpenes 23225536 Cd(2+) 23225536 Cu(2+) 23225536 GSH 23225536 Ni(2+) 23225536 PAHs 23225536 Zn(2+) 23225536 benzo[a]pyrene 23225536 chlorophyll a 23225536 fluoranthene 23225536 fluorene 23225536 glutathione 23225536 phenanthrene 23225536 polycyclic aromatic hydrocarbons 23225536 pyrene 23225536 superoxide 23225542 Fe(3)O(4) 23225542 Fe3O4 23225542 ICG 23225542 PAH 23225542 indocyanine green 23225542 poly(allylamine hydrochloride) 23225638 1-anilinonaphthalene-8-sulfonic acid 23225638 2-azido-1,3-propanediol 23225638 PEG 23225638 azido glycerol 23225638 diethylester 23225638 octadecyl 23225638 polyethylene glycol 23225638 polyglycerols 23225638 pyrene 23225671 nucleic acids 23225671 purine 23225764 L-lysines 23225764 poly(methacrylate)s 23225770 genipin 23225780 N-Cyano sulfoximines 23225780 N-cyano sulfoximines 23227887 FDV 23227887 Fosdevirine 23227887 GSH 23227887 GSK2248761 23227887 cysteine 23227887 glutathione 23227887 nucleoside 23227887 trans-phenyl acrylonitrile 23228028 Al 23228028 Ga 23228028 In(2)O(3) 23228028 In2O3 23228028 Mg 23228193 denbinobin B 23228193 phenanthrenequinone 23228193 phenanthrenes 23228469 3,5-bis(4-chlorobenzylidene)-1-[4-{2-(4-morpholinyl)ethoxy}phenyl-carbonyl]-4-piperidone hydrochloride 23228469 glutathione 23228471 2-(3,5-diphenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-phenylthiazoles 23228471 EtOH 23228471 HCl 23228471 chalcones 23228471 phenacyl bromide 23228471 thiazolyl-pyrazoline 23228471 thiosemicarbazide 23228475 2,3,7,8-tetrachlorodibenzo-p-dioxin 23228475 BaP 23228475 Benzo[a]pyrene 23228475 Cyprodinil 23228475 Dexamethasone 23228475 TCDD 23228475 aryl hydrocarbon 23228475 cyprodinil 23228475 dexamethasone 23228475 pyrimidinamine 23228696 Metformin 23228696 SB202190 23228696 Taxol 23228696 metformin 23228696 paclitaxel 23228696 platinum 23228697 Orlistat 23228697 PPD 23228697 doxazolidine 23228697 irinotecan 23228697 orlistat 23228697 p-aminobenzyl carbamate 23228697 pentyl carbamate 23229055 (1)H 23229055 (13)C 23229055 2H-indazol-3-ol 23229055 6-carbethoxy-2-cyclohexen-1-one 23229055 Cyclohexenone 23229055 Indazole 23229055 chalcone 23229055 chalcones 23229511 17-AAG 23229511 17-Allylamino-17-demethoxygeldanamycin 23229511 Aryl hydrocarbon 23229511 NAD(P)H 23229511 aryl hydrocarbon 23229511 quinone 23229539 iron 23229539 malondialdehyde 23229539 superoxide 23230131 2',2'-difluorodeoxycytidine 23230131 2',2'-difluorodeoxyuridine 23230131 Ara-C 23230131 Gemcitabine 23230131 cytarabine 23230131 cytidine 23230131 dFdC 23230131 dFdU 23230131 deoxycytidine 23230131 gemcitabine 23230274 arsenite 23230274 oxygen 23230281 peroxynitrite 23231350 methyl mercury 23231350 sulfonamides 23231439 (R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide 23231439 CID: 46897844 23231439 ML188 23231439 N-(tert-butyl)-2-(N-arylamido)-2-(pyridin-3-yl) acetamides 23231439 dipeptide 23231457 poly-L-lysine 23231809 Dopamine 23231809 dopamine 23231967 N-(2,6-diarylpyrimidin-4-yl)acetamide 23231967 adenosine 23231967 methoxyaryl 23231967 methoxyphenyl 23232056 amides 23232056 diphenylpropanamide 23232059 Cynaropicrin 23232059 cynaropicrin 23232059 sesquiterpene lactone 23232150 alcohol 23232150 estradiol 23232150 formate 23232150 glycerol 23232150 histidinol-phosphate 23232150 steroid 23232150 steroids 23232333 corticosterone 23232461 K 23232461 Na 23232461 Organotin 23232461 organotin 23232461 organotins 23232866 Fluo-4 23232866 PDMS 23232866 calcium 23232866 poly(dimethylsiloxane) 23232941 C=C 23232941 Cu(100) 23232941 C≡N 23232941 acrylonitrile 23232941 cyano 23232941 vinyl 23233034 citrate 23233034 silver 23233456 DGL 23233456 Dendritic poly(L-lysines) 23233456 jetPEI 23233456 poly(L-lysines) 23234246 (99m)Tc 23234246 (99m)Tc(CO)(3) 23234246 (99m)Tc(CO)(3)}(+) 23234246 99mTc 23234246 M(CO)(3) 23234246 Re 23234246 benzenesulfonamide 23234246 benzenesulfonamide rhenium 23234246 technetium tricarbonyl 23234246 {(99m)Tc(CO)(3)}(+) 23234313 poly(propylene imine) 23234313 poly(propylene-imine) 23234537 P3HT 23234537 carbon 23234537 poly(3-hexylthiophene) 23234607 2-oxoglutarate 23234607 2OG 23234812 NO 23234812 Nitric oxide 23234812 PGE(2) 23234812 SrRan 23234812 Strontium Ranelate 23234812 prostaglandin E(2) 23234855 2,2'-bipyridine 23234855 2,2'-bipyridine-4,4'-dicarboxylic acid 23234855 COOH 23234855 Ru(II) 23234855 [RuCl(HL)(AsPh(3))(2)(CO)] 23234855 [RuCl(HL)(PPh(3))(2)(CO)] 23234855 [RuHCl(bpy)(AsPh(3))(CO)] 23234855 [RuHCl(bpy)(PPh(3))(CO)] 23234855 bipyridine 23234855 bpy 23234855 carboxylic acid 23234855 ruthenium (II) polypyridyl complexes 23235151 C 23235151 N 23235151 histamine 23235151 sulfate 23235158 Asp 23235158 Tyr 23235158 amino acids 23235158 aspartate 23235158 chlorite 23235158 heme 23235158 hydrogen peroxide 23235158 iron 23235158 tyrosine 23235435 Co(ii) 23235435 Cr(iii) 23235435 bis(1,4,7-triazacyclononane) 23235435 transition metal 23235435 triazacyclononane 23235742 Pt 23235742 levulinic acid 23237482 As 23237482 GaAs 23237546 Au 23237546 calcium 23237546 glucose 23237590 silica 23237828 Cycloheximide 23237828 PD98059 23237828 SP600125 23237828 U0126 23237828 actinomycin D 23237828 cycloheximide 23237939 NU7441 23237939 cisplatin 23237974 6,7-secoschisantherol A 23237974 Lignans 23237974 dibenzocyclooctene 23237974 epoxy 23237974 lignan 23237974 lignans 23237974 schisandrin A1 23237974 schisantherin A 23238233 chikusetsusaponin FK2 23238233 chikusetsusaponin FK6 23238233 chikusetsusaponin FK7 23238233 chikusetsusaponin FT1 23238233 chikusetsusaponin IVa 23238233 chikusetsusaponin L10 23238233 chikusetsusaponin L5 23238233 chikusetsusaponin L9a 23238233 chikusetsusaponin L9bc 23238233 chikusetsusaponin LM1 23238233 chikusetsusaponin LM2 23238233 chikusetsusaponin LM3 23238233 chikusetsusaponin LM4 23238233 chikusetsusaponin LM5 23238233 chikusetsusaponin LM6 23238233 chikusetsusaponin V 23238233 chikusetsusaponins 23238233 dammarane 23238233 ginsenoside F3 23238233 ginsenoside F5 23238233 ginsenoside F6 23238233 ginsenoside Rb3 23238233 ginsenoside Rc 23238233 ginsenoside Rd 23238233 ginsenoside Re 23238233 ginsenoside Rg1 23238233 triterpenoid saponins 23238235 4-HHE 23238235 4-ONE 23238235 4-hydroxy-hexenal 23238235 4-oxo-2-nonenal 23238235 acrolein 23238235 crotonaldehyde 23238236 DPPH(·) 23238236 Sterols 23238236 fatty acids 23238236 nitric oxide 23238236 superoxide 23238236 triterpenes 23238352 H(2)O 23238352 H(2)S 23238352 Zinc oxide 23238352 ZnO 23238352 ZnS 23238352 oxygen 23238352 wurtzite 23238352 zinc 23238425 Nafion 23238425 Pt 23238425 SO(3)H 23238425 SO3H 23238425 Si 23238425 fluorine 23238425 glassy carbon 23238425 oxygen 23238425 platinum 23238425 silicon 23238611 magnesium 23238657 N(ε)-carboxymethyllisine 23238657 nitrate 23238657 nitric oxide 23238657 nitrite 23238662 glucose 23238783 Wellbutrin SR 23238783 bupropion 23238783 hydroxybupropion 23238991 CFSE 23238991 MTT 23238991 silica 23239015 Graphene Oxide 23239015 Octacationic 23239015 Pc(8+) 23239015 Poly-Ortho-Functionalizable Tetraarylporphycene 23239015 graphene oxide 23239015 poly-ortho-substituted tetraarylporphycene 23239601 hydrogen 23239639 HPMA 23239639 SDS 23239639 ester 23239639 maleimide 23239639 pentafluorophenyl methacrylate 23239639 poly(N-(2-hydroxypropyl)-methacrylamide) 23239639 poly-HPMA 23239825 carboxyl 23239825 serine 23239825 threonine 23240655 Al(2)O(3) 23240655 MoS(2) 23240655 MoS2 23240655 graphene 23240655 scandium 23240993 (1)H 23240993 (129)Xe 23240993 (13)C 23240993 (19)F 23240993 (29)Si 23240993 129Xe 23240993 Ar 23240993 Ar(l) 23240993 Me(2)DABCO(2+) 23240993 Xe 23240993 Xe(l) 23241030 9-diphenylthiophosphinoylanthracene 23241354 tyrosine 23243659 H(3)PO(4) 23243659 NH(4)F 23243659 Ni(OH)(2) 23243659 Ni(OH)2 23243659 NiF(2) 23243659 NiF2 23243659 nickel 23243660 H(2) 23243660 O–H 23243660 chromone 23243660 flavone 23243660 flavonoids 23243660 myricetin 23243660 naringenin 23243660 quercetin 23244178 aluminum oxide 23244178 amine 23244178 amines 23244178 aryl azide 23244178 aryl azides 23244178 aryl thiol 23244178 azides 23244178 diazirine 23244178 oligo(ethylene glycol) 23244178 phosphonic acids 23244178 primary amine 23244178 primary amines 23244178 thiols 23244521 ethanol 23245188 (Si-H)(2) 23245188 H 23245188 H(2)O(2) 23245188 O 23245188 OPD 23245188 Si 23245188 Silicon 23245188 o-phenylenediamine 23245188 oxygen 23245188 silicon 23245512 3-methylbutanoyl 23245512 acetyl 23245512 acetyl, propionyl and butanoyl esters 23245512 acyl 23245512 alkyne 23245512 azide 23245512 butanoyl 23245512 carbohydrate 23245512 copper 23245512 ester 23245512 glycopyranosyl azides 23245512 isovaleryl 23245512 mono-, di- and tri-acylated 23245512 pentanoyl 23245512 pentanoyl and 3-methylbutanoyl esters 23245512 propionyl 23245512 valeryl 23245514 PBI-18-Man 23245514 mannose 23245514 perylene 23245514 perylene bisimide 23245514 α-D-mannoses 23245697 Ribonucleotide 23245697 dNTPs 23245697 nucleotide 23245697 rNTP 23245697 ribonucleotide 23245697 ribonucleotides 23246428 Ergosta-4,6,8(14),22-tetraen-3-one 23246428 adenine 23246428 bile acid 23246428 ergone 23246428 ergosta-4,6,8(14),22-tetraen-3-one 23246436 C 23246531 KNT-127 23246531 SNC80 23246531 benzodiazepine 23246531 benzodiazepines 23246531 diazepam 23246531 ethanol 23246531 naltrindole 23246700 DEHA 23246700 DEHP 23246700 DiBP 23246700 DnBP 23246700 Phthalate 23246700 Phthalates 23246700 di-(2-ethylhexyl) adipate 23246700 di-2-ethylhexyl phthalate 23246700 di-isobutyl phthalate 23246700 di-isononyl phthalate 23246700 di-n-butyl phthalate 23246700 phthalate 23246700 phthalates 23246701 Curcumin 23246701 PFOS 23246701 Perfluorooctane sulfonate 23246701 curcumin 23246701 perfluorooctane sulfonate 23246701 polyphenolic 23246865 BIC 23246865 GABA 23246865 MUS 23246865 Pb 23246865 PbNO(3) 23246865 amino cupric silver 23246865 bicuculline 23246865 muscimol 23246865 γ-aminobutyric acid 23246867 IPA3 23246867 ML-141 23246867 PD0325901 23246867 glucose 23247009 Aldose 23247009 BGG 23247009 Beta-glucogallin 23247009 alcohol 23247009 aldehydes 23247009 aldose 23247009 sorbitol 23247010 BHA 23247010 anthracycline 23247010 butylated hydroxyanisole 23247010 carbonyl 23247010 isatin 23247010 monoamine 23247010 nucleotide 23247010 prostaglandins 23247040 α-Amino acid-N-carboxyanhydride 23247298 OH 23247298 serine 23247504 COOH 23247504 KCl 23247504 carbohydrate 23247504 ferrihydrite 23247504 iron oxide 23247504 maghemite 23247824 acetylcholine 23247824 dopamine 23247824 nicotine 23248173 glucose 23248196 Statin 23248196 Statins 23248196 atorvastatin 23248196 simvastatin 23248196 statin 23248196 statins 23248236 2-phenyl-1,2 benzisoselenazol-3(2H)-one 23248236 Ebselen 23248236 Ebsulfur 23248236 GSH 23248236 NADPH 23248236 benzisoselenazol 23248236 benzisothiazol 23248236 dithiol 23248236 ebselen 23248236 ebsulfur 23248236 glutathione 23248236 methicillin 23248236 sulfur 23249244 4-(dimethylamino)benzonitrile 23249244 DMABN 23249244 acetonitrile 23249244 dimethylamino 23249338 Zn(II) 23249338 [5,15-bis[4-(pyridyl)ethynyl]-10,20-diphenylporphinato]zinc(II) 23249338 [5,15-dipyridyl-10,20-bis(pentafluorophenyl)porphinato]zinc(II) 23249338 acetylene 23249338 chlorophylls 23249338 porphyrin 23249341 H(2)O 23249341 H(2)O(2) 23249341 NO(2) 23249341 OH 23249525 8-OH-DPAT 23249525 8-hydroxy-2-(di-n-propylamino) tetralin 23249525 Quinpirole 23249525 dopamine 23249525 quinpirole 23249525 serotonin 23249745 sparsomycin 23250357 Colesevelam 23250357 bile acid 23250357 glucose 23250357 metformin 23250541 Ca 23250541 Cr 23250541 Cr(III) 23250541 Cr3 23250541 Cr3 ([Cr(3)O(propionate)(6)(H(2)O)(3)](+)) 23250541 CrCl(3) 23250541 Cu 23250541 Fe 23250541 Mg 23250541 Zn 23250541 [Cr(pic)(3)] 23250541 chromium 23250541 chromium picolinate 23250541 fatty rats 23250811 2,4,6-trinitrobenzene sulfonic acid 23250811 Curcumin 23250811 curcumin 23250811 sulfasalazine 23252421 octylamine 23252481 Fe(III) 23252481 catharanthine 23252481 vinblastine 23252481 vindoline 23252610 4-Hydroxy-1-(3-pyridyl)-1-butanone 23252610 4-hydroxy-1-(3-pyridyl)-1-butanone 23252610 HPB 23252823 (1)H 23252823 1-decanol 23252823 1-pyrenesulfonyl 23252823 Pyrenyl 23252823 amino 23252823 glucono 23252823 hydrogen 23252823 methylene 23252823 naphthyl 23252823 pyrenyl 23252823 α,ω-diaminoalkane 23252848 MTS 23252848 withametelin L 23252848 withanolide 23252848 withanolides 23252848 withanolides 1-5 23252848 withawrightolide 23253441 oxadiazepines 23253441 oxadiazine 23253856 hydroxyurea 23254196 Ca(2+) 23254196 Genistein 23254196 Ser 23254196 Thr 23254196 cAMP 23254196 estrogen 23254196 genistein 23254196 nitric oxide 23255050 Fe 23255050 Gd 23255050 Iron oxide 23255050 acetylcholine 23255050 gadolinium 23255050 glutathione 23255050 iron 23255050 iron oxide 23255050 polyvinylpyrrolidone 23255284 L-dipeptides 23255284 Ser-His 23255284 carboxyl 23255284 dipeptide 23255284 dipeptide-mononucleotide 23255284 dipeptides 23255284 histidine 23255284 imidazole 23255284 nucleotide 23255284 phosphodiester 23255384 Coniothyrinones A (5), B (6), and D 23255384 anthraquinones 23255384 coniothyrinone C 23255384 coniothyrinones A (5), B (6), and D 23255384 coniothyrinones A-D 23255384 hydroxyanthraquinone 23255384 hydroxyanthraquinones 23255384 tetralone 23255471 C(3)N(4) 23255471 H(2) 23255471 H(2)O 23255471 Na 23255471 O(2) 23255471 SrTiO(3) 23255471 Tungsten carbide 23255471 W(2)C 23255471 WC 23255471 hydrogen 23255471 oxygen 23255471 platinum 23255471 tungsten 23255471 tungsten carbide 23255471 tungsten carbides 23256442 GSH 23256442 MDA 23256442 alanine 23256442 choline 23256442 malondialdehyde 23256442 methionine 23256442 reduced GSH 23256442 reduced glutathione 23256442 triglyceride 23256445 8-hydroxydeoxyguanosine 23256445 NADPH 23256445 TRG 23256445 Trigonelline 23256445 carbohydrate 23256445 glutathione 23256445 oxygen 23256445 thiobarbituric acid 23256445 trigonelline 23256446 cholesterol 23256446 glucose 23256446 triglycerides 23256510 F8BT 23256510 PFB 23256510 poly(9,9'-dioctylfluorene-co-benzothiadiazole 23256510 poly(9,9'-dioctylfluorene-co-bis-N,N'-(4-butylphenyl)-bis-N,N'-phenyl-1,4-phenylene-diamine 23256510 polyfluorene 23256609 Benzoic acid 23256609 benzoic acid 23256609 carboxylic acid 23256609 hydrogen 23256609 mono- and dihydrates 23256621 (hetero)functional poly(ethylene glycol)s 23256621 PEG 23256621 PEGs 23256621 Poly(ethylene glycol) 23256621 acetal 23256621 acetaldehyde acetal 23256621 amino 23256621 cholesterol 23256621 dibenzylamino ethanol 23256621 ethylene oxide 23256621 hydroxyl 23256621 mPEG 23256621 poly(ethylene glycol) 23256621 poly(ethylene glycol) monomethyl ether 23256621 poly(ethylene glycol)s 23256621 polyether 23256621 squaric acid ester amide 23256643 Mn 23256643 Mn(II) 23256643 acetyl acetonate 23256643 m-PyNO 23256643 manganese(II) diacetylacetonate and dihexafluoroacetylacetonate 23256643 pyridine 23256643 pyridine nitrogen 23256719 N-acetyl-L-cysteine 23256719 NAC 23256719 NO 23256719 Thiol 23256719 carbocysteine 23256719 corticosteroids 23256719 erdosteine 23256719 fudosteine 23256719 glutathione 23256719 superoxide 23256724 CO2 23256724 Clonazepam 23256724 clonazepam 23256724 serotonin 23256769 As(V) 23256769 Fe(III) 23256769 ferrihydrite 23256769 hematite 23256769 iron oxide 23256816 calcium 23256816 pentamidine 23256819 ((13)C)methyldodecanesulfonate 23256819 Amino Acids 23256819 amino 23256819 amino acids 23256819 cysteine 23256819 histidine 23256819 lysine 23256819 methionine 23258537 Magnesium 23258537 ferrous 23258537 potassium 23258537 ribonucleotides 23258671 W 23258671 beta-tungsten 23258671 nitrogen 23258671 tungsten 23258742 2,2',4,4',5-pentabromodiphenyl ether 23258742 BDE-99 23258742 DMSO 23258742 PBDE 23258742 PBDE-99 23258742 PBDEs 23258742 dimethylsulfoxide 23258742 polybrominated diphenyl ethers 23258773 Aroclors 1016 and 1254 23258773 PCB 23258773 PCBs 23258773 polychlorinated biphenyls 23258773 polyethylene 23259536 dihydroindolizine 23259536 dithienylethene 23259536 fullerene 23259536 porphyrin 23259536 quinoline 23259666 (D)-Ala-(D)-Ala 23259666 (D)-Ala-(D)-Lac 23259666 C 23259666 PAMAM 23259666 Vancomycin 23259666 iron oxide 23259666 poly(amidoamine) 23259666 vancomycin 23259742 ZrO(2) 23259742 carbon 23259742 oxygen 23259773 Si 23259773 carbon 23259773 platinum 23259773 silicon 23259865 camptothecin 23259865 indenoisoquinolines 23259866 PCHD 23259866 poly(1,3-cyclohexadiene) 23259866 poly(cyclohexadiene) 23259866 polybutadiene 23259866 polyisoprene 23259866 polystyrene 23259985 PLL 23259985 Polyplex 23259985 poly((L)-lysine) 23259985 polyplex 23259985 polyplexes 23260032 Asparagine 23260032 Bismuth 23260032 asparagine 23260032 bismuth 23260347 Diphenylphosphinic amides 23260347 diphenylphosphine oxides 23260347 diphenylphosphinic amides 23260347 potassium 23260352 Mannich base 23260352 amodiaquine 23260352 hydroxy-ethyl-amine 23261524 nutlin-3 23261527 prostaglandins 23261528 flavonoid 23261528 icariin 23261528 sodium 23261528 steroid 23261528 sulfate 23261588 BPA-f 23261588 Boron 23261588 Calcein-AM 23261588 MTT 23261588 Propidium Iodide 23261588 boronophenylalanine 23261588 calcein-AM 23261588 fructose 23261590 Neoechinulin A 23261590 PGE2 23261590 indole 23261590 neoechinulin A 23261590 nitric oxide 23261590 nitrogen 23261590 oxygen 23261590 prostaglandin E2 23261644 MMS 23261644 methylmethanesulphonate 23261645 Jaspamide 23261645 NSC-613009 23261645 cyclodepsipeptide 23261645 jaspamide 23261645 jasplakinolide 23261645 mitoxantrone 23261667 copper 23261676 (-) Epicatechin 23261676 (-) epicatechin 23261676 Isoproterenol 23261676 NADH 23261676 adenosine triphosphate 23261676 calcium 23261676 glutathione 23261676 hydroxyl 23261676 isocitrate 23261676 isoproterenol 23261676 malate 23261676 reduced glutathione 23261676 succinate 23261676 superoxide 23261676 tricarboxylic acid 23261676 α-ketoglutarate 23261705 rapamycin 23261715 4-oxo-2-nonenal 23261715 Cys 23261715 GSSG 23261715 NADPH 23261715 SH 23261715 aldehyde 23261715 aldose 23261715 amino acid 23261715 dithiothreitol 23261715 glutathione 23261715 glutathione disulfide 23261715 oxidized glutathione 23261715 p-chloromercuribenzoic acid 23261715 p-chloromercuriphenylsulfonic acid 23261820 TCS 23261820 Triclosan 23261820 estrogen 23261820 ethinyl estradiol 23261820 triclosan 23262162 DPPH 23262162 Resveratrol 23262162 Vitamin E 23262162 ethanol 23262162 polyamide 23262162 resveratrol 23262162 trolox 23262203 Gadolinium 23262203 HPMA 23262203 N-(2-hydroxypropyl)methacrylamide 23262279 2-hydroxy-4-[4-(5Z)-5-[(E)-2-methyl-3-phenylprop-2-enylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]butanoylamino]benzoic acid 23262279 4-{(Z)-[(2Z)-2-(2-fluorobenzylidene)-4-oxo-1,3-thiazolidin-5-ylidene]methyl}benzoic acid 23262279 ML-145 23262390 Manganese 23262390 Mn 23262390 manganese 23263987 cAMP 23263987 cyclic AMP 23263987 glucose 23264030 Fluoxetine 23264030 fluoxetine 23264030 hydrochloride 23264030 serotonin 23264615 Cortisol 23264615 PF 915275 23264615 cortisol 23264615 hydroxysteroid 23264615 keto 23264615 meloxicam 23264615 progesterone 23264615 prostaglandins 23265282 Cys 23265282 N 23265282 α-thioester 23265282 α-thioesters 23265296 PGMA 23265296 POEGMA 23265296 amino 23265296 biotin 23265296 epoxide 23265296 poly(glycidyl methacrylate) 23265296 poly(oligo(ethylene glycol) methacrylate) 23265296 silicon 23265429 As 23265429 As(2)O(3) 23265429 Ga(l) 23265429 GaAs 23265429 as 23265429 gallium 23265452 Polyphenolic 23265452 apigenin 23265452 chrysin 23265452 flavonoid 23265452 flavonoids 23265452 galangin 23265452 gallic acid 23265452 p-Coumaric acid 23265452 phenolic acids 23265452 pinocembrin 23265456 polyphenols 23265458 ABTS(+) 23265458 ADP 23265462 6-O-caffeoylsophorose 23265462 Benzoic acid 23265462 caffeic acid 23265462 monocarboxylic acid 23265462 phloretin 23265462 quercetin 23265462 sophorose 23265462 sugar 23265467 As(V) 23265467 HCl 23265467 HFO 23265467 NaOH 23265467 arsenic 23265467 carboxyl 23265467 hydrated ferric oxide 23265467 hydrous ferric oxide 23265467 hydroxyl 23265469 CO(2) 23265469 fructosyl nystose 23265469 kestose 23265469 n-butane 23265469 nystose 23265469 propane 23265469 sucrose 23265483 Se 23265483 selenium 23265488 ser 23265491 alcohol 23265491 genistein-7-O-gentiobioside 23265491 glutathione 23265491 isoflavone 23265491 isoflavones 23265492 DEAE 23265492 arabinose 23265492 mannose 23265492 sulphate 23265501 Citric, malic, and ascorbic acids 23265501 Fructose 23265501 anthocyanins 23265501 gallic acid 23265501 glucose 23265501 sucrose 23265501 sugars 23265502 Ascorbic acid 23265502 Nitrate 23265502 ascorbic acid 23265502 nitrate 23265502 nitrite 23265502 vitamin C 23265504 DPPH 23265504 catechin 23265504 citric acid 23265504 fructose 23265504 malic acid 23265504 phenols 23265504 quercetin 23265504 sinapic acid 23265504 succinic acid 23265504 sucrose 23265504 sugar 23265504 β-carotene 23265504 ρ-coumaric acid 23265504 ρ-hydroxybenzoic acid 23265506 DPPH(·) 23265506 DPPH· 23265506 acetylcysteine 23265506 ascorbic acid 23265506 caffeic acid 23265506 catechin 23265506 chlorogenic acid 23265506 quercetin 23265507 TFA 23265507 Trans fatty acids 23265507 fatty acids 23265507 trans fatty acids 23265517 glutathione 23265517 malondialdehyde 23265517 streptozotocin 23265517 superoxide 23265526 Fe(2+) 23265529 ethyl acetate 23265529 formic acid 23265529 primary secondary amine 23265529 sodium sulphate 23265533 sodium 23265542 artemisia ketone 23265542 borneol 23265542 cis-chrysanthenyl acetate 23265542 germacrene B 23265546 lactones 23265843 Lucidone 23265843 cholesterol 23265843 glucose 23265843 lucidone 23265843 triglyceride 23265880 (123)I 23265880 (2-((2-((dimethylamino)methyl)-4-iodophenyl)thio)phenyl)methanol 23265880 FLIP-IDAM 23265880 [(125)I]-IDAM 23265880 [(125)I]Flip-IDAM 23265880 biphenylthiol 23265880 serotonin 23265892 4-Br 23265892 4-CF(3) 23265892 SCH 900229 23265892 arylsulfone 23265892 sulfone 23265892 tricyclic bispyran sulfone 23265896 5- and 6-methoxybenzimidazole-1,3,5-triazines 23265896 5- and 6-methoxysubstituted benzimidazole 23265896 5-methoxy 23265896 6-methoxy 23265896 ZSTK474 23265896 benzimidazole 23265899 C5-Ethynylbenzenesulfonamide-modified nucleotide 23265899 C5-ethynylbenzenesulfonamide-modified nucleotides 23265899 EBNA 23265899 nucleotide 23265899 nucleotides 23265901 8-oxoadenine 23265901 8-oxoadenines 23265901 DSR-6434 23265901 N 23265901 adenine 23265901 amino 23265901 tertiary amines 23265902 9-fluoro 23265902 SCH 900229 23265902 Selectfluor 23265902 difluoroquinone 23265902 quinone 23265902 sulfone 23265903 (E)-1-(2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyl)-4-(3-hydroxyphenyl)but-3-en-2-one 23265903 C-cinnamoyl glycoside 23265903 C-cinnamoyl glycosides 23265903 phenol 23265904 5-carboxy-2-thiazole 23265904 CoA 23265904 amides 23265904 benzo-fused spirocyclic oxazepine 23265904 benzylic 23265904 glycine amides 23265904 nitrogen 23265904 oxazepine 23265904 piperidine 23265904 spirocyclic piperidine 23265904 stearoyl-CoA 23265904 stearoyl-coenzyme A 23265904 thiazoles 23266447 rhodamine 23266452 N-acetylgalactosamine 23266452 PCL-b-PPEEA 23266452 poly(ethylene glycol) 23266452 poly(ethylene glycol)-b-poly(ε-caprolactone) 23266452 poly(ε-caprolactone)-b-poly(2-aminoethyl ethylene phosphate) 23266453 polyethylene glycol 23266501 4',5,7-trihydroxyflavone 23266501 Apigenin 23266501 apigenin 23266501 oxygen 23266502 Carbamate 23266502 Urea 23266502 methomyl 23266674 2,3,7,8,-tetrachloro-dibenzo-p-dioxin 23266674 TCDD 23266674 androgen 23266674 aryl hydrocarbon 23266674 polyaromatic hydrocarbons 23266719 carbon 23266722 12-O-tetradecanoylphorbol-13-acetate 23266722 7,12-dimethylbenz[a]anthrancene 23266722 DMBA 23266722 TPA 23266722 phorbol ester 23266731 1,2,3,4,6-penta-O-galloyl-β-d-glucose 23266731 EtOH 23266731 MTT 23266731 PGG 23266731 catechin 23266731 epicatechin-(4β→8)-catechin 23266731 epicatechin-3-O-gallate 23266731 flavan-3-ols 23266731 paeonol 23266731 polyphenol 23266731 proanthocyanidin 23266731 trigalloyl-glucoses 23266732 6-keto prostaglandin F(1α) 23266732 6-keto-PGF(1α) 23266732 NO 23266732 TXB(2) 23266732 nitric oxide 23266732 thromboxane B(2) 23266737 Triterpenoid saponins 23266737 creatine 23266737 lactate 23266737 saponins 23266737 triterpenoid saponins 23267837 Cetrorelix 23267837 somatostatin 23267855 glucose 23267855 metformin 23267862 Ca(2+) 23267862 Mg(2+) 23268927 glucose 23270527 N-isopropylacrylamide 23270527 N-isopropylmethacrylamide 23270527 NIPAm 23270527 NIPMa 23270527 alkoxyamine 23270527 aminooxy 23270527 benzylalkoxyamine 23270527 carbohydrates 23270527 ketone 23270527 methacrylamide 23270527 oxime 23270527 poly(ethylene glycol) 23270527 pyridoxal-5'-phosphate 23270527 sugars 23270704 APO 23270704 Apocynin 23270704 H2O2 23270704 NADPH 23270704 apocynin 23270704 calcium 23270704 raisanberine 23270704 testosterone 23270993 KYNA 23270993 Kynurenic acid 23270993 acetylcholine 23270993 glutamate 23270993 tryptophan 23271737 acylsulfonamide 23271742 Arsenic 23271742 arsenic 23271742 arsenic trioxide 23273150 C=O 23273150 CH 23273150 CO 23273150 H 23273150 N-methylacetamide 23273150 NH 23273150 NMA 23273150 O 23273150 O H 23273150 amide 23273150 carbonyl 23273225 Porphyrin 23273225 porphyrin 23273225 tetrakis(3,5-di-t-butyl-4-hydroxyphenyl)porphyrin 23273225 tetrakis(4-pyridyl)porphyrin 23273412 2-iso-propyl-5-methyl-phenol 23273412 2-tert-butyl-5-methyl-phenol 23273412 5-iso-propyl-2-methyl-phenol 23273412 ABTS 23273412 DPPH 23273412 Schiff bases 23273412 Thymol 23273412 ascorbic acid 23273412 carvacrol 23273412 thymol 23274352 Co 23274352 Cu 23274352 Ni 23274352 Pb 23274353 O 23274353 PBDE 23274353 PBDEs 23274353 S 23274353 carbonyl 23274353 ethoxyresorufin 23274353 glutathione 23274353 peroxide 23274353 polybrominated diphenyl ethers 23274746 chlorogenic acids 23274746 flavonoids 23274768 ATP 23274768 Zinc 23274768 Zn 23274768 ZnSO4 23274768 lactate 23274768 zinc 23274768 zinc sulfate 23274903 glucose 23274903 oxygen 23274917 EMS 23274917 ethyl methane sulfonate 23274917 formalin 23275110 PHEA-IB-p(MANa(+)) 23275110 PHEA-graft-polymethacrylate 23275110 calcium 23275110 β-poly(N-2-hydroxyethyl)-graft-{N-2-ethylene[2-poly(methacrylic acid sodium salt)isobutyrate]}-d,l-aspartamide 23275111 DOX 23275111 Doxorubicin 23275111 PLA 23275111 PTX 23275111 lactide 23275111 paclitaxel 23275111 polyethylene glycol 23275111 polylactide 23275113 Fujicalin 23275113 Neusilin 23276135 Au 23276135 carbohydrate 23276161 aluminates 23276161 apatites 23276161 oxides 23276161 silicates 23276161 sulfates 23276627 1-meA 23276627 1-methyladenine 23276627 3-meC 23276627 3-methylcytosine 23276627 MMS 23276627 methyl methanesulfonate 23276627 nucleotides 23276633 17β-estradiol 23276633 DHT 23276633 Testosterone 23276633 dihydrotestosterone 23276633 testosterone 23277104 3,3',4,4',5-polychlorinated biphenyl 23277104 6-formylindolo[3,2-b]carbazole 23277104 Aroclor 1254 23277104 BNF 23277104 FICZ 23277104 PCB126 23277104 PCBs 23277104 aryl hydrocarbon 23277104 β-naphthoflavone 23277230 ABTS 23277230 DPPH 23277230 Fisetin 23277230 NO 23277230 STZ 23277230 bioflavonoid 23277230 fisetin 23277230 glucose 23277230 nitric oxide 23277230 streptozotocin 23278398 Cu 23278398 Trp 23278398 Zn 23278398 catecholamines 23278398 quinazoline 23278398 superoxide 23278633 H 23278633 N(3)-Substituted Xanthines 23278633 graphite 23278633 nucleobases 23278633 xanthine 23278633 xanthines 23279802 4-aminoquinazoline 23279841 ethanol 23279841 nitrate 23279841 nitrite 23279844 CCl4 23279844 alanine 23279844 aspartate 23279844 carbon tetrachloride 23279844 flavonoid 23279844 flavonoids 23279844 glutathione 23279844 malondialdehyde 23279844 superoxide 23279943 Al 23279943 Cu 23279943 Fe 23279943 GSH 23279943 MDA 23279943 Mn 23279943 Se 23279943 Zn 23279943 donepezil 23279943 glutathione 23279943 malondialdehyde 23279943 superoxide 23280101 PpIX 23280101 oxygen 23280101 protoporphyrin IX 23280620 Hg 23280620 mercury 23280766 organophosphate 23280766 pyrethroid 23280951 1-(2'-deoxy-β-D-threo-pentofuranosyl)thymidine 23280951 C3'-thymidinyl 23280958 hydrogen 23280958 hydroxyl hydrogen 23280958 methanol 23280997 CdSe 23280997 ZnS 23281069 Diaromatic-substituted ortho- and meta-carboranes 23281069 carboranes 23281069 diaryl-substituted carboranes 23281069 manassantin A 23281101 Butyltin(IV) benzoates 23281101 Organotin 23281101 di- and tri-n-butyltin(IV) carboxylates 23281101 di-n-butyltin(IV) 23281101 tin(IV) 23281242 Pt 23281242 Ru 23281242 pt 23281242 ru 23281242 silica 23281330 5-(hydroxymethyl)furfural 23281330 CH(2)Cl(2) 23281330 FeCl(3) 23281330 HMF 23281330 MMF 23281330 MeNO(2) 23281330 arene 23281330 carbohydrate 23281330 carbohydrates 23281330 chloromethylfurfural 23281330 ether 23281330 formate ester 23281330 formic acid 23281330 fructose 23281330 glucose 23281330 hydrogen chloride 23281330 hydroxyl 23281330 mesityl 23281330 mesitylene 23281330 mesitylmethylfurfural 23281330 p-TsOH 23281330 toluene 23281330 xylene 23281578 Glycofullerenes 23281578 carbohydrates 23281578 glycofullerenes 23281578 hexakis-adduct of [60]fullerene 23281578 mannoses 23281613 callicarpic acid 23281613 diterpenes 23281613 ent-3,4-seco-labdane 23281613 ent-3,4-seco-labdane diterpenoids 23281613 methylcallicarpate 23281636 ATP 23281636 GSK 3987 23281636 Paeoniflorin 23281636 cholesterol 23281636 paeoniflorin 23281847 hydrogen 23281917 Brij-35 23281917 Span-80 23281917 Span-83 23281917 acyclovir 23281937 (11)B 23281937 (31)P 23281937 11B 23281937 31P 23281937 B 23281937 Na(+) 23281937 Na(2)O 23281937 Na2O 23281937 P 23281937 P-O-B 23281937 [xB(2)O(3) + (1 - x)P(2)O(5)] 23281937 [xB2O3 + (1 - x)P2O5] 23281937 boron 23281937 oxygens 23281937 phosphorus 23281937 sodium 23281937 sodium borate 23281937 sodium borophosphate 23281937 sodium phosphate 23282017 Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] 23282017 KP1019 23282017 KP1339 23282017 carbonate 23282017 citrate 23282017 glutathione 23282017 indazolium trans-[Tetrachlorobis(1H-indazole)ruthenate(III)] 23282017 ruthenium 23282017 sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] 23282066 MDZ 23282066 TRZ 23282066 midazolam 23282066 triazolam 23282101 (Xylyl-phanephos)Pt(2+) 23282101 P(2)Pt-alkyl 23282101 XeF(2) 23282101 olefin 23282101 polyene 23282101 polyenes 23282576 metal-oxide 23282999 Al 23282999 Zinc sulphate 23282999 aluminium 23282999 aluminium sulphate 23282999 cholesterol 23282999 testosterone 23282999 vitamin E 23282999 zinc sulphate 23284002 DPI 23284002 GSH 23284002 H(2)O(2) 23284002 N-acetyl-cysteine 23284002 NAC 23284002 NAD(P)H 23284002 TSA 23284002 Trichostatin A 23284002 diphenyleneiodonium 23284002 glutathione 23284002 oxygen 23284002 sulforaphane 23284082 Amide 23284082 amide 23284082 bis-sulfonamide 23284082 creatinine 23284082 prostaglandin E 23284082 urea 23286198 CTAB 23286198 NaOL 23286198 hexadecyltrimethylammonium bromide 23286198 sodium oleate 23286240 chloroquine 23286240 dimeric phloroglucinols 23286240 ethanol 23286240 mallotojaponins B (1) and C (2) 23286240 mallotophenone 23287045 Copper 23287045 Cu 23287045 Cu salts 23287045 CuO 23287045 CuSO4 23287045 copper (II) oxide 23287045 copper salts 23287045 copper sulfate 23287045 oxygen 23287045 transition metal 23287056 N-alkylcarbazole 23287056 carbazoles 23287056 tyrosine 23287389 PBDEs 23287389 PCBs 23287389 PFHxS 23287389 PFOA 23287389 PFOS 23287389 Perfluoroalkyl acids 23287389 bisphenol A 23287389 nicotine 23287389 perfluoroalkyl acid 23287389 perfluoroalkyl acids 23287389 perfluorohexane sulfonate 23287538 amphetamine 23287538 ethanol 23287538 sucrose 23287700 AM4054 23287700 AM4113 23287700 Cannabinoid 23287700 SR141716A 23287700 rimonabant 23287700 Δ(9)-tetrahydrocannabinol 23287710 acrylamide 23287710 glycidamide 23287728 L-Leu 23287728 L-amino acid 23287728 amino-acid 23288049 2,2',4,4'-tetrabromodiphenyl ether 23288049 2,2',4,5'-tetrabromodiphenyl ether 23288049 BDE-47 23288049 BDE-49 23288049 Br 23288049 PBDE 23288049 PBDEs 23288049 Polybrominated diphenyl ethers 23288052 CCl(4) 23288052 DEN 23288052 carbon tetrachloride 23288052 diethylnitrosamine 23288091 carbamazepine 23288091 clobazam 23288091 clonazepam 23288091 eslicarbazepine acetate 23288091 ethosuximide 23288091 felbamate 23288091 gabapentin 23288091 lacosamide 23288091 lamotrigine 23288091 levetiracetam 23288091 oxcarbazepine 23288091 phenobarbital 23288091 phenytoin 23288091 pregabalin 23288091 primidone 23288091 retigabine 23288091 rufinamide 23288091 stiripentol 23288091 tiagabine 23288091 topiramate 23288091 valproic acid 23288091 vigabatrin 23288091 zonisamide 23288103 Si 23288103 Sn 23288103 Ti 23288103 hematite 23288103 oxygen 23288103 α-Fe(2)O(3) 23288866 aminobenzotriazole 23288866 loperamide 23289403 PLL 23289403 poly(l-lysine) 23289403 vinylbenzyl 23289412 1H-1,2,3-, 2H-1,2,3-, 1H-1,2,4- and 4H-1,2,4-triazole 23289412 carbon 23289412 nitrogen 23289412 triazoles 23289585 2'-deoxyadenosine-5'-monophosphate 23289585 2'-deoxycytidine-5'-monophosphate 23289585 2'-deoxyguanosine-5'-monophosphate 23289585 2'-deoxymononucleotides 23289585 T5'p 23289585 dA5'p 23289585 dC5'p 23289585 dG5'p 23289585 mononucleotides 23289585 nucleobase 23289585 phosphate ester 23289585 ribose 23289585 thymidine-5'-monophosphate 23289615 2-propanol 23289615 alcohol 23289624 amide 23289646 poly(ethylene glycol) 23289710 Sec 23289710 Ser 23289710 [(14)C]dimethylallyl pyrophosphate 23289710 amino acid 23289710 dimethylallyl 23289710 isopentenyl 23289710 selenocysteine 23289872 (1)H 23289872 (15)N 23289872 (19)F 23289872 CF(3) 23289872 CF3 23289872 F-C 23289872 FF 23289872 FH 23289872 FN 23289872 N-H 23289872 NH 23289872 fluorine 23289872 hydrogen 23290050 (1)H 23290050 (13)C 23290050 indole 23290050 indoxyl red 23290050 silica 23290262 Alkyladenine 23290262 MMS 23290262 methyl methanesulfonate 23290724 C 23290724 N 23290724 Zinc 23290724 Zn²⁺ 23290724 copper 23290724 zinc 23291118 5- and 8-methoxypsoralen 23291118 8-MOP 23291118 MOP 23291118 MOPs 23291118 N-bromosaccharin 23291118 acrylate 23291118 benzoate 23291118 butyl acrylate 23291118 cinnamate 23291118 indomethacin 23291118 methoxypsoralen 23291118 psoralen 23291118 tert-butyl cinnamate 23291264 cis-diamminedichloroplatinum II 23291264 cisplatin 23291264 creatinine 23291264 nitrogen 23291264 urea 23292343 amino acid 23292343 amino acids 23292343 ribulose-1, 5-bisphosphate 23292752 Dabigatran 23292752 Dabigatran etexilate 23292752 apixaban 23292752 argatroban 23292752 dabigatran 23292752 dabigatran etexilate 23292752 rivaroxaban 23292752 vitamin K 23292753 Sugar 23292753 alkyne 23292753 azide 23292753 cyclopropene 23292753 mannosamine 23292753 mannosamines 23292753 methylcyclopropenes 23292753 sugars 23292753 tetrazine 23292768 C 23292768 C-OH 23292768 CD 23292768 CH2OH 23292768 C≡C-H 23292768 D 23292768 H-O 23292768 O-H 23292768 OD 23292768 OH 23292768 methanol 23292768 propargyl alcohol 23292797 5-HT 23292797 5-hydroxytryptamine 23292797 [(35)S]guanosine 5'-(3-O-thio)triphosphate 23292797 adenylyl 23292797 cAMP 23292881 aluminum 23292881 zeolite 23292881 zeolites 23292988 LaFeO3 23292988 Sm2 CuO4 23292988 Sm2CuO4 23293000 phosphate 23293000 sugar 23293094 PCB 23293094 polychlorinated biphenyl 23293950 pyrene 23293962 iron 23293966 graphene 23293966 peroxide 23293966 quarteranthene 23293970 O₃ 23293970 dopamine 23293970 ozone 23293970 superoxide 23293971 NiO 23293971 nickel oxide 23294326 ganglioside 23294566 Androgen 23294566 Androgens 23294566 androgen 23294566 androgens 23294566 oestradiol 23294566 oestrogen 23294566 oestrogens 23294699 Pentacyclic hemiacetal sterol 23294699 acetyl 23294699 nephthoacetal 23294699 pentacyclic hemiacetal sterol 23294699 sterol 23294895 Aspirin 23294895 aspirin 23295156 L-Carnitine 23295156 NADPH 23295156 fatty acids 23295156 l-Carnitine 23295156 l-NAME 23295223 3,17β-Hydroxysteroid 23295223 3,17β-hydroxysteroid 23295223 carbon 23295223 cholesterol 23295223 estradiol 23295223 polycyclic aromatic hydrocarbons 23295223 steroid 23295223 steroids 23295223 testosterone 23295224 2,3-butanediol 23295224 NADPH 23295224 acetoin 23295224 alpha-hydroxy ketones 23295224 diketones 23295224 diols 23295224 glucose-6-phosphate 23295224 keto 23295224 vicinal diketones 23295224 vicinal diols 23295224 α-hydroxy ketones 23295229 Aldehyde 23295229 Mg(2+) 23295229 NAD(+) 23295229 NADH 23295229 aldehyde 23295229 aldehydes 23295229 butyraldehyde 23295229 carboxylic acids 23295229 magnesium 23295582 HCl 23295582 TBF 23295582 Terbinafine 23295582 Terbinafine hydrochloride 23295582 poloxamer gel 23295739 Methylprednisolone 23295739 corticosterone 23295739 methylprednisolone 23295740 TAM 23295740 Tamoxifen 23295740 estrogen 23295740 tamoxifen 23295740 zinc 23296019 GDP 23296019 GTP 23296100 GSH 23296100 Manganese 23296100 Mn 23296100 Mn(2+) 23296100 N-acetylcysteine 23296100 NAC 23296100 glutathione 23296100 propidium iodide 23296100 thymine 23296102 Acrolein 23296102 malondialdehyde 23296102 superoxide 23296105 UO₂ 23296105 Uranium 23296105 uranium 23296122 magnesium 23296122 magnesium and zinc porphyrins 23296122 metalloporphyrins 23296122 zinc 23296156 chromium-51 23296368 3-MGA 23296368 3-methylglutaconic 23296368 3-methylglutaconic aci 23296368 3-methylglutaconic acid 23296368 3-methylglutaconyl-CoA 23296368 leucine 23296837 EHT 23296837 MPP(+) 23296837 MPTP 23296837 dopamine 23296837 eicosanoyl-5-hydroxytryptamide 23296837 nitric oxide 23296837 tyrosine 23296902 Cr 23296902 chromium 23296902 glucose 23296902 graphite 23296902 iron 23296950 ACh 23296950 Chrysin 23296950 KCl 23296950 Luteolin 23296950 NO 23296950 STZ 23296950 TGs 23296950 acetylcholine 23296950 cholesterol 23296950 chrysin 23296950 flavonoids 23296950 glucose 23296950 luteolin 23296950 phenylephrine 23296950 streptozotocin 23296950 triglycerides 23296979 ATP 23296979 Ca(2+) 23296979 EATN 23296979 Erythro-(7S,8R)-7-acetoxy-3,4,3`,5`-tetramethoxy-8-O-4`-neolignan 23296979 arachidonic acid 23296979 cAMP 23296979 cyclic AMP 23296979 erythro-(7S,8R)-7-acetoxy-3,4,3`,5`-tetramethoxy-8-O-4`-neolignan 23296979 neolignan 23296979 serotonin 23296979 thromboxane B(2) 23297346 3-mercaptopyruvate 23297346 H(2)S 23297346 Hydrogen sulfide 23297346 carbon monoxide 23297346 cystathionine 23297346 nitric oxide 23297689 sabinene 23297712 cubecol-1-epi 23297712 dexamethasone 23297712 hinesol 23297712 ledol 23297712 muurola-3,5-diene 23297712 sesquiterpenes 23297712 silphiperfol-5-en-3-ol 23297712 z-caryophyllene 23297712 β-maaliene 23297712 γ-gurjunene 23297713 acetic acid 23297713 carbon dioxide 23297713 hydroxyproline 23297755 1α-hydroxy-3βH-3α,4α-epoxy-4,10-dimethyl-5αH,7αH,8βH,10αH-guai-11(13)-ene-7,8-olide 23297755 1αH-4α-hydroxy-4,10-dimethyl-5αH,7αH,8βH,10αH-guai-11(13)-ene-7,8-olide 23297755 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide 23297755 CH(2)Cl(2) 23297755 EFV 23297755 Efavirenz 23297755 cis-fused guaianolides 23297755 sesquiterpene lactone 23297755 sesquiterpene lactones 23297817 1/2O(2) 23297817 Au 23297817 Au(0.75)Pd(0.25) 23297817 Au(0.80)Pd(0.20) 23297817 Au(0.80)Pd(0.20)-Fe(x)O(y) 23297817 CO 23297817 CO(2) 23297817 Fe(x)O(y) 23297817 Pd 23297817 alumina 23297817 metal oxide 23298140 flavonoids 23298140 free amino acids 23298140 fructosamine 23298140 fructose 23298140 glucose 23298140 hydrogen peroxide 23298140 methylglyoxal 23298140 peroxide 23298140 polyphenols 23298140 sugars 23298158 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane 23298158 Alumina 23298158 F4-TCNQ 23298158 F4-TNCQ 23298158 Fluorinated Tetracyanoquinodimethane 23298158 P3HT 23298158 Poly(3-hexylthiophene) 23298158 aluminum oxide 23298158 poly(3-hexylthiophene) 23298322 2-(dimethylamino)ethyl acrylate 23298322 DMAEA 23298322 acrylic acid 23298810 PF-04693627 23298810 benzoxazole 23298810 benzoxazoles 23298810 cyclohexane 23298810 prostaglandin E(2) 23299191 dimethylarginine 23299191 sodium chloride 23299194 hydroxyproline 23299194 nitrofurazone 23299909 N 23300000 Ce(3+) 23300000 La(3+) 23300000 Nd(3+) 23300000 ammonia 23300000 flavonoid 23300000 phenylalanine 23300000 superoxide 23300056 arylpiperazine 23300056 arylpiperazines 23300056 dopamine 23300227 Morphine 23300227 TRV130 23300227 [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine 23300227 morphine 23300338 Lys 23300338 rapamycin 23301246 FTO 23301246 NiO 23301246 fluorine 23301246 iodide 23301246 nickel oxide 23301246 tin oxide 23301246 triiodide 23301495 3-mercaptopyruvate 23301495 Cyanide 23301495 cyanide 23301495 dithiane 23301495 sulfanegen 23301495 triethanolamine 23301701 1,3-dimethylimidazolium dimethylphosphate 23301701 1-butyl-3-methylimidazolium chloride 23301701 1-ethyl-3-methylimidazolium acetate 23301701 [bmim]Cl 23301701 [dmim][DMP] 23301701 [emim][Ac] 23301701 hydrogen 23301701 imidazolium 23301853 BTH-II0204-207:A 23301853 Benzoquinones 23301853 benzoquinones 23301853 betulinan A 23301853 betulinan C 23301853 terphenyl 23301948 amide 23302583 7-mercaptocoumarin 23302583 phenylpiperazine 23302583 prazosin 23302594 4-pyridone 23302594 Himeic acids E-G 23302594 himeic acid A 23302594 himeic acids E-G 23303191 GlcNAc 23303191 Glucose 23303191 N-acetyl glucosamine 23303191 N-acetylglucosamine 23303191 N-acetylhexosamines 23303191 UDP 23303191 glucosamine 23303191 glucuronic acid 23303191 sugar 23303191 sugars 23303198 glucose 23303198 olmesartan 23303198 telmisartan 23303441 ATP 23303441 Paroxetine 23303441 [(3)H]paroxetine 23303441 paroxetine 23303441 sulfate 23303486 amide 23303486 biotin 23303486 thioether 23303710 Myriaporone 3/4 23303710 myriaporone 3/4 23305110 LaAlO(3) 23305110 LaAlO3 23305110 Si 23305110 SrTiO(3) 23305110 SrTiO3 23305294 Li(3)PS(4) 23305294 Lithium 23305294 lithium 23305444 6-Hydroxy-benzofuran-5-carboxylic acid 23305444 benzofuran salicylic acid 23305444 salicylic acid 23305444 tyrosine 23305465 6a,7,8,9,10,10a-hexahydro-3,6,9-trimethyl-6-(4-methyl-3-penten-1-yl)-1,9-epoxy-6H-dibenzo[b,d]pyran 23305465 Albatrelin F 23305465 Confluentin 23305465 Meroterpenoid 23305465 albatrelins A-C 23305465 albatrelins D-F 23305465 confluentin 23305465 grifolin 23305465 meroterpenoid 23305777 3'-methoxymiliumollin 23305777 4'-O-methylmiliumollin 23305777 7-methoxymiliumollin 23305777 8-O-4' neolignan 23305777 Miliumollin 23305777 Miliumollinone 23305777 Neolignans 23305777 dihydrobenzofuran neolignans 23305777 miliumollin 23305777 miliumollinone 23305777 miliusamollin 23305807 Estrogens 23305807 RES 23305807 S 23305807 alanine 23305807 bile acid 23305807 bilirubin 23305807 estrogen 23305807 ethinylestradiol 23305807 glutamyl 23305807 glutathione 23305807 malondialdehyde 23305807 nitric oxide 23305807 resveratrol 23305807 sulfhydryl 23305807 superoxide 23305918 ma'edamines 23305918 ma'edamines A (18) and B 23305918 ma'edamines A and B 23305918 pyrazine-2-(1H)-one 23305993 (5Z)-5-[(5-bromo-1H-indol-3-yl)methylene]-3-(4-chlorobenzyl)-thiazolidine-2,4-dione 23305993 GW9962 23305993 LYSO-07 23305993 LYSO-7 23305993 NO 23305993 nitric oxide 23306171 diterpenes 23306171 diterpenoid 23306171 leptoclalin A 23306171 norcembranoid 23306171 spatane 23306172 2-hydroxy-5-((6-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-2- propylchroman-4-one 23306172 2-hydroxy-γ-pyrone 23306172 4-hydroxy-α-pyrone 23306172 CD(3)OD 23306172 deuterium 23306172 hydroxypyrone 23306172 methicillin 23306790 MG132 23306790 N-acetyl-l-cysteine 23306790 Verrucarin A 23306790 glutathione 23306790 verrucarin A 23306791 PEG-PVA 23306791 Polyethylene glycol 23306791 polyvinyl alcohol 23307185 serine 23307185 threonine 23307790 glucose 23311296 carbon 23311700 RAI 23311718 (1)H 23311718 [C(2)mim][TF(2)N] 23311718 [C(4)mim][AOT] 23311718 [C(4)mim][BF(4)] 23311718 [C(4)mim][PF(6)] 23311718 [C(4)mim][TF(2)N] 23311718 [C(6)mim][TF(2)N] 23311718 benzene 23311754 MnO(2) 23311754 MnO2 23311754 PEDOT 23311754 V(2)O(5) 23311754 V2O5 23311754 lithium 23311754 poly(3,4-ethylenedioxythiophene) 23311754 vanadium pentoxide 23312946 4-hydroxyisoquinoline 23312946 6-hydroxyisoquinoline 23312946 flavin 23312946 hydroxyl 23312946 isoquinolines 23312946 monocillin II 23313176 carbon 23313176 dendrimers 23313245 diaryl ureas 23313376 AG490 23313376 PTE 23313376 Pterostilbene 23313376 Tyr 23313376 oxygen 23313376 resveratrol 23313448 ADP 23313448 amino acids 23313621 1-nitro-2-phenylethane 23313621 BaCl(2) 23313621 Ca(2+) 23313621 CaCl(2) 23313621 K(+) 23313621 KCl 23313621 PHE 23313621 caffeine 23313621 phenylephrine 23313621 phorbol dibutyrate 23313638 D-alanine 23313638 D-leucine-D-cysteine 23313638 D-valine 23313638 D-valine-D-cysteine 23313638 FK228 23313638 amide 23313638 romidepsin 23313638 spiruchostatins A-D 23313638 spiruchostatins C and D 23313639 2,3,4-trimethoxy-6-(1-phenylvinyl)biphenyls 23313639 3,4-(1,3-dioxolane) 23313639 3,4-difluoro 23313639 4,5,6-trimethoxybiphenyl-2-carbaldehydes 23313639 E-2,3,4-trimethoxy-6-styrylbiphenyls 23313639 biaryl aryl stilbenes 23313639 colchicine 23313639 ethylenes 23313712 PHMB 23313712 neutral red 23313712 phosphatidylcholine 23313712 polyhexamethylene biguanide hydrochloride 23313797 5'-adenosine monophosphate 23313797 EtOH 23313797 Hoechst 33342 23313797 Res 23313797 dUTP 23313797 ethanol 23313797 glutathione 23313797 malondialdehyde 23313797 nicotinamide 23313797 nitrite 23313797 oxygen 23313797 resveratrol 23313797 superoxide 23313961 PCL 23313961 PEG 23313961 Triamcinolone acetonide 23313961 benzyl alcohol 23313961 folate 23313961 poly(ethylene glycol) 23313961 polycaprolactone 23313961 triamcinolone 23313962 (14)C-temoporfin 23313962 PEG2000-DSPE 23313962 cholesterol 23313962 glycerols 23313962 temoporfin 23314045 Gly 23314045 Pro 23314045 benzisoxazole 23314045 bromine 23314045 glycine 23314045 methoxy 23314045 proline 23314045 rutin 23314045 thiourea 23314045 urea 23314276 17β-trenbolone 23314276 androgen 23314276 androgens 23314277 S 23314277 TiSiO(4) 23314277 alanine 23314277 glutathione 23314277 lactate 23314277 titanium silicate 23314331 Copper 23314331 Cu 23314757 AgInS(2) 23314757 COOH 23314757 ZnS 23314757 amine 23314757 carboxyl 23314757 folate 23314757 hydroxyl 23314757 thiol 23315090 cholesterol 23315090 triglyceride 23315216 pentose phosphate 23315496 ATP 23315496 oATP 23315496 rapamycin 23315585 DomA 23315585 Domoic acid 23315585 GSH 23315585 cysteine 23315585 domoic acid 23315585 glutamate 23315585 glutathione 23315585 kainate 23315585 α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid 23315601 Glucose 23315601 glucose 23315683 C60 23315683 ICBA 23315683 InP 23315683 N 23315683 P3HT 23315683 bisadduct 23315683 carbon 23315683 indene 23315683 poly(3-hexylthiophene) 23315791 (1)H 23315791 (R,R)-G(2)DPENBoc 23315791 N-Boc-protected 1,2-diphenylethylenediamine 23315791 hydrogen 23315791 poly(benzyl ether) 23315938 acyl carnitines 23315938 amino acid 23315938 amino acids 23315938 fatty acid 23315938 glucose 23315938 steroid 23315996 Pd 23315996 hydrogen peroxide 23316021 Fluorescein 23316021 Gadolinium 23316021 Gd-F-βCD 23316021 TiO2 23316021 gadolinium(III) 23316021 rhodamine 23316021 titanium dioxide 23316021 β-cyclodextrin 23316913 BSO 23316913 BaSnO₃ 23316913 OH 23316913 TiCl₄ 23316913 TiO₂ 23316913 oxides 23316913 perovskite 23316965 doxycycline 23316966 doxycycline 23317100 FITC 23317100 MTT 23317100 SZ-685C 23317159 ATP 23317159 CEP701 23317159 LY2784544 23317159 Ruxolitinib 23317159 SAR302503 23317159 SB1518 23317159 TG101348 23317159 tasocitinib 23317159 tyrosine 23317163 acetylcholine 23317450 2,2,6,6-tetramethylpiperidine-N-oxyl 23317450 Cu 23317450 Cu(2)O(2) 23317450 Cu(I) 23317450 Cu(II) 23317450 H 23317450 N-methylimidazole 23317450 NMI 23317450 O(2) 23317450 TEMPO 23317450 alcohol 23317450 alcohols 23317450 aliphatic alcohols 23317450 alkoxide 23317450 benzylic alcohols 23317450 benzylic and aliphatic alcohols 23317450 copper(I) 23317450 nitroxyl 23317497 Pyrroloquinoxalines 23317497 pyrroloquinoxalines 23317498 nucleoside 23317498 nucleosides 23317572 isoflavonoid rotenone 23317572 rotenoisins A 23317572 rotenone 23318226 APO 23318226 ATP 23318226 DPI 23318226 Gö6983 23318226 N-acetyl-l-cysteine 23318226 NAC 23318226 NADPH 23318226 PGE(2) 23318226 PGE2 23318226 Ro-318220 23318226 Rottlerin 23318226 apocynin 23318226 diphenyleneiodonium chloride 23318226 nucleotides 23318425 acetyl 23318425 lysine 23318445 oxygen 23318445 superoxide 23318645 iodine 23318729 Isotretinoin 23318729 isotretinoin 23318729 retinoic acid 23318729 retinoids 23318730 Platinum folate 23318730 folic acid 23318730 platinum 23318730 platinum folate 23318905 (2,5-dihydroxyphenyl)(5-hydroxy-1-benzofuran-3-yl)methanone 23318905 Asn 23318905 H 23318905 Ile 23318905 NAD(+) 23318905 Phe 23318905 benzofuran-3-yl(phenyl)methanone 23318905 benzofuran-3-yl(phenyl)methanones 23318905 hydroxyl 23318905 hydroxyls 23318905 nicotinamide 23318905 phenyl 23319584 Ca(2+) 23319584 Calcium 23319584 nucleotide 23319591 lysine 23320385 1-chloro-2,4-dinitrobenzene 23320385 Anthocyanidins 23320385 Anthocyanins 23320385 Cyanidin 23320385 Delphinidin 23320385 S 23320385 UDP 23320385 anthocyanidins 23320385 carbonyl 23320385 cyanidin 23320385 delphinidin 23320385 flavonoids 23320385 glutathione 23320385 malvidin 23320385 menadione 23320385 p-nitrophenol 23320385 pelargonidin 23320412 sulfate 23320521 Dideoxy bicyclic pyrimidine nucleoside 23320521 cidofovir 23320521 ddBCNAs 23320521 ether 23320521 l-dideoxy bicyclic nucleoside 23320521 n-C(9)H(18)-O-n-C(5)H(11) 23320931 catechol 23320931 europium 23320931 isophthalic acid 23320931 lanthanide 23320931 terbium 23320940 PDT 23320940 perdeuterated tempone 23321054 5-HT 23321054 5-Hydroxytryptamine 23321054 AVE8488 23321054 Eplivanserin 23321054 Volinanserin 23321054 eplivanserin 23321054 volinanserin 23321054 zolpidem 23321916 DmCc(+) 23321916 DmCc(+/0) 23321916 DmFc 23321916 DmFc(0/+) 23321916 cobaltocenium 23321916 decamethylcobaltocenium 23321916 decamethylferrocene 23321916 ferrocene 23321916 permethylated transition-metal 23322164 Acylcarnitines 23322164 Carnitine 23322164 acyl-CoA 23322164 acyl-CoAs 23322164 acylcarnitine 23322164 acylcarnitines 23322164 carnitine 23322164 decanoic acid 23322164 fatty acid 23322164 octanoylcarnitine 23322347 Ca(++) 23322347 calcium 23322347 iron 23322508 Copper 23322508 copper 23322559 cimicifugolides A-C 23322559 monoterpene lactones 23322648 1-O-Hexadecyl-2-O-methyl-3-O-(2'-amino-2'-deoxy-α-D-glucopyranosyl)-sn-glycerol 23322648 1-O-hexadecyl-2-O-methyl-3-O-(2'-amino-2'-deoxy-β-D-glucopyranosyl)-sn-glycerol 23322648 O 23322648 amino 23322648 azide 23322648 glucosamine 23322648 glycero 23322648 guanidino 23322648 thioglycosidic 23322709 CO 23322709 alkyl formates 23322709 carbon monoxide 23322709 esters 23322709 formates 23322709 olefins 23322709 palladium 23323677 (1)H 23323677 (13)C 23323677 2-methoxy-4-methylphenol 23323677 CO2 23323677 N2 23323677 acetaldehyde 23323677 alkylated creosols 23323677 bis(cyanate) esters 23323677 bisphenols 23323677 creosol 23323677 cyanate esters 23323677 formaldehyde 23323677 isocyanic acid 23323677 methylene 23323677 phenol 23323677 phenols 23323677 propionaldehyde 23323680 Li 23323680 Li-Si 23323680 Si 23323680 Si-Si 23323680 silicon 23323691 aldose 23323691 carboxylic acids 23323763 9α-epi-tuberospironine 23323763 pyrrolo[1,2-α]azepine 23323763 tuberostemonoxirine 23323829 9,10-bis[4-(3-sulfonatopropoxyl)-styryl]anthracene sodium salt 23323829 BSPSA 23323829 anthracene 23323829 guanidine hydrochloride 23323854 1,2-dioleoyl-3-timethylammonium propane 23323854 1,2-dioleoyl-sn-glycerol-3-phosphocholine 23323854 3β-{N-[(N',N'-dimethylamino)ethyl]carbamoyl}cholesterol 23323854 C=O 23323854 DC-Ch 23323854 DOPC 23323854 DOTAP 23323854 PO(2)(-) 23323854 adenine 23323854 carbonyl 23323854 cytosine 23323854 guanine 23323854 phosphate 23323987 acerifolin A 23323987 acerifolin B 23323987 cisplantin 23323987 diterpenoid 23323987 diterpenoids 23323987 isopimarane 23323987 tigliane 23324400 LEVOTHYROXINE 23324400 LT4 23324400 levothyroxine 23324437 Acarbose 23324437 Glucose 23324437 Nateglinide 23324437 Natelinide 23324437 glucose 23325046 DPPH 23325046 hexane 23325046 oxygen 23325046 α,α-diphenyl-β-picrylhydrazyl 23325050 PEG-OPOCl(2) 23325050 aromatic aldehydes 23325050 bis(indolyl) methanes 23325050 bisindolylmethanes 23325050 dichlorophosphate 23325050 indole 23325373 Fructose 23325373 fructose 23325373 glucose 23325486 Glu 23325486 Thr 23325486 Tyr 23325486 amino acid 23325489 3,5-di-O-caffeoylquinic acid 23325489 Linarin 23325489 PTZ 23325489 acacetin 23325489 acacetin 7-O-β-D-glucopyranosyl-(1 → 2)[α-L-rhamnopyranosyl-(1 → 6)]-β-D-glucopyranoside 23325489 chlorogenic acid 23325489 flavone glycoside 23325489 linarin 23325489 pentobarbital 23325489 pentylenetetrazole 23325492 citrate 23325492 silver 23325530 DCF 23325530 Diclofenac 23325631 3-nitrophenylacetic acid 23325631 CO(2) 23325631 bicarbonate 23327112 Coumarins 23327112 clauexcavatins A (1) and B (2) 23327112 coumarins 23327360 TiO(2) 23327360 amino acid 23327360 amino acids 23327360 phosphoryl 23327360 quartz 23327360 titanium dioxide 23327494 catechin 23327494 epigallocatechin 23327494 flavanols 23327494 speciophylline 23327494 uncarine E 23327494 uncarine F 23327532 4-nitrophenol 23327532 4-vinylphenol 23327532 Styrene 23327532 Styrene glycol 23327532 Styrene oxide 23327532 styrene 23327534 germacrene B 23327534 globulol 23327534 viridiflorene 23327534 α-cadinol 23327534 τ-cadinol 23327557 (-)-epicatechin 23327557 Procyanidins 23327557 galacturonic acid 23327557 procyanidin 23327557 procyanidins 23327580 doxorubicin 23327668 abietane 23327668 diterpenoids 23327668 ent-kaurane 23327668 ent-kauranoids 23327668 isoabietenins A-C 23327668 nitric oxide 23327668 tenuifolins A-M 23327794 7'-(3',4'-dihydroxyphenyl)-N-[4-methoxyphenyl)ethyl]propenamide 23327794 acetylcholine 23327794 chloroform 23327794 liriodenine 23327794 microcosamine A 23327794 microgrewiapine A 23327794 microgrewiapine A 3-acetate 23327794 microgrewiapines A-C 23327794 piperidine alkaloids 23327993 AD4 23327993 AuF 23327993 NAC 23327993 NAc-Cys-Pro-Cys amide 23327993 ascorbic acid 23327993 auranofin 23327993 disulfide 23328072 1,25(OH)₂D3 23328072 1,25(OH)₂D₃ 23328072 1,25-dihydroxyvitamin D₃ 23328072 vitamin D 23328072 vitamin D₃ 23328126 Omega-3 Fatty acids 23328126 Omega-3-Acid Ethyl Esters 23328126 ω-3 fatty acid 23328126 ω-3 fatty acids 23328252 17-β estradiol 23328252 2,4-Dihydroxybenzophenone 23328252 BP-1 23328252 Benzophenone-1 23328252 ICI 182,780 23328252 benzophenone-1 23328252 estrogen 23329065 dopamine 23329065 quinpirole 23329065 urethane 23329125 2,3,7,8-tetrachlorodibenzo-p-dioxin 23329125 PCB 23329125 PCBs 23329125 S 23329125 TCDD 23329125 aryl hydrocarbon 23329125 glutathione 23329125 polychlorinated biphenyls 23329125 superoxide 23329125 tBHQ 23329125 tert-butylhydroquinone 23329180 theaflavin 23329180 theaflavins 23329180 tyrosine 23330542 acetaminophen 23330542 azole 23330542 azoles 23330542 pregnane 23330542 sulforaphane 23330549 Pt(6) 23330549 platinum 23330613 5-methylthioadenosine 23330613 Polyamine 23330613 ornithine 23330613 phosphoinositide 23330613 polyamine 23330613 putrescine 23330613 spermidine 23330789 silanes 23330847 Hydroxy 23330847 carbonyl di-imidazole 23330847 cholesterol 23330847 hydroxy 23330847 polyethylene glycol 23330848 C2H3OH 23330848 H 23330848 choline 23330848 coumarin 23330848 galanthamine 23330848 tacrine 23330908 C 23330908 zanamivir 23330971 Ag 23330971 CIGSSe 23330971 Cu(In,Ga)(S,Se)₂ 23330971 ZnO 23330971 indium 23330971 oxide 23330971 silver 23331178 Au(111) 23331178 DMPC 23331178 DMPE 23331178 carbonyl 23331178 dimyristoyl phosphatidylcholine 23331178 dimyristoyl phosphatidylethanolamine 23331178 hydrocarbon 23331178 phosphate 23331539 hydrogen 23331539 quinazolinon 23331618 4-Aminoquinoline-Triazine 23331618 4-amino-7-chloroquinolines 23331618 7-chloro-4-aminoquinoline-triazine 23331618 chloroquine 23331618 triazine 23332347 Belviq 23332347 Qsymia 23332347 orlistat 23332347 sibutramine 23332762 Ser 23332762 serine 23333093 catechin 23333093 cholesterol 23333261 Curcumin 23333261 curcumin 23333261 glucose 23333261 streptozotocin 23333575 APAP 23333575 GSH 23333575 Genistein 23333575 UDP 23333575 acetaminophen 23333575 alanine 23333575 genistein 23333575 glucuronide 23333575 glutathione 23333575 lactate 23333575 malondialdehyde 23333575 uridine diphosphate 23333639 8-oxoG 23333639 8-oxoguanine 23333639 formamidopyrimidine 23333639 oxygen 23333639 α-tocopherol 23333641 11β-hydroxysteroid 23333641 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane 23333641 2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane 23333641 HPTE 23333641 MXC 23333641 Methoxychlor 23333641 methoxychlor 23333716 phenolic 23333716 protocatechuic acid 23333834 Arg 23333834 Asp 23333834 Glu 23333834 Leu 23333834 Tyr 23333834 YR-11 23333834 celecoxib 23333834 cysteine 23333834 serine 23333899 DOXIL 23333899 Dox 23333899 Doxorubicin 23333899 Lipodox 23333899 PEG-DOPE 23333899 R8-PEG-PE 23333899 doxorubicin 23333899 octa-arginine 23333899 polyethylene glycol-dioleoyl phosphatidylethanolamine 23333900 CBZ 23333900 Soluplus 23333900 carbamazepine 23333900 polyethyleneglycol 23333900 polyvinyl acetate 23333900 polyvinyl caprolactam 23333908 Anthocyanins 23333908 Captropril 23333908 Lisinopril 23333908 anthocyanins 23333908 cholesterol 23333908 hibiscus acid 23333908 polyphenols 23333908 triglycerides 23334176 glucose 23334176 sugar 23334322 B6 23334322 PLP 23334322 Pyridoxal-5'-phosphate 23334322 aldehyde 23334322 homocysteine 23334322 pyridoxal 23334322 pyridoxine 23334322 vitamin B6 23334583 Ca(+2) 23335034 (14) C 23335034 Carbon 23335034 carbon 23335034 phenanthrene 23335220 ATP 23335220 biotin 23335220 phosphorylbiotin 23335243 sesquiterpene 23335243 sesquiterpenes 23335243 terpenes 23335320 N 23335320 N-heterocyclic carbene 23335320 Pd 23335320 amino acid 23335320 carbene 23335320 palladacycles 23335320 pyridine 23335320 α-carbon 23335450 S-Au 23335450 cysteine 23335565 5-azacytidine 23335565 oxygen 23335565 phytic Acid 23335565 phytic acid 23335833 1,2-dipalmitoyl-sn-glycero-3-phosphocholine 23335833 DPPC 23335833 diiodomethane 23335833 formamide 23335833 poly(methyl methacrylate) 23336337 diterpenes 23336337 ester 23336337 jolkinol D 23336337 lathyrane diterpene 23336337 octanol 23336368 flavonoids 23336368 homoflavanol 23336368 kaempferol 23336368 quercetin 23336729 acetylcholine 23336729 dimethylaminoethyl methacrylate 23336729 hydroxyl 23336729 methacrylate 23336729 poly(ethylene glycol) 23336729 poly-l-lysine 23337202 [Au(CN)(2)]- 23337397 MTT 23337397 Trypan blue 23337599 indole 23337599 indoles 23337599 pyrolidinyl-1,2-dione 23337599 tosyl 23337599 zileuton 23337600 (99m)Tc-(Me)FGCDEVD 23337600 (Me)FGC(Bz)DEVD 23337600 cisplatin 23337600 technetium-99m 23337600 ⁹⁹mTc-(Me)FGCDEVD 23337925 acetylene 23337941 QQT(CN)4 23337941 quinoidal oligothiophene 23337941 quinoidal quaterthiophene 23338525 Ir 23338525 IrO(2) 23338525 Nafion 23338525 O(2) 23338525 O2 23338525 Sn 23338525 SnO(2) 23338525 bi-metal oxides 23338525 hydrogen 23338525 oxygen 23338537 Aprokam 23338537 cefuroxime 23339036 estrogens 23339036 tamoxifen 23339547 rasagiline 23339572 (2E)-1-phenyl-3-[4-(trifluoromethyl)-phenyl]prop-2-en-1-one 23339572 (2E)-1-phenyl-3-pyrimidin-2-ylprop-2-en-1-one 23339572 1,3-diphenylprop-2-yn-1-one 23339572 4-[(1E)-3-oxo-3-phenylprop-1-en-1-yl]benzonitrile 23339572 4-hydroxynonenal 23339572 5,5'-dithiobis-(2-nitrobenzoic acid) 23339572 BAP 23339572 Chalcones 23339572 N-acetylcysteine 23339572 benzalacetophenone 23339572 chalcone 23339572 chalcones 23339572 dimethylfumarate 23339572 sulforaphane 23339572 thiol 23339572 thiols 23339572 α,β-unsaturated carbonyl 23339577 AcS-C6H4-C≡C-(fc)n-C≡C-C6H4-SAc 23339577 Au 23339577 Au(111) 23339577 acetyl 23339577 fc-C≡C-C6H4-SAc 23339577 ferrocenyl 23339577 organometallic 23339604 Mn(III)(8)Mn(IV)(4)O(12)(L(x,y,z-CB))(16)(H(2)O)(4) 23339604 Mn(III)8Mn(IV)4O12(L(x,y,z-CB))16(H2O)4 23339604 dodecamanganese 23339604 manganese 23339678 ketorolac 23339974 gly-gly-lys 23340331 HCl 23340331 Pb 23340331 Pb(2+) 23340331 carbon dioxide 23340331 carbonate 23340331 hydroxide 23340332 Cl(-) 23340332 Cu(2+) 23340332 K(+) 23340332 Na(+) 23340332 copper 23340333 disulfide 23340334 Toluene 23340334 oxygen 23340334 toluene 23340646 Fe(3)O(4) 23340646 Fe3O4 23340646 Li(4)Ti(5)O(12) 23340646 graphite 23340646 lithium 23340646 sodium 23340858 GaZnSeAs 23340977 Fe 23340977 Mn 23340977 NH3 23340977 ammonia 23340981 nicotine 23341175 Pyrethroids 23341175 carbamate 23341175 organochlorine 23341175 organophorous 23341175 permethrin 23341175 pyrethroid 23341175 pyrethroids 23341248 Ag 23341248 Silver 23341248 oxygen 23341248 silver 23341258 Ca(2+) 23341258 GSH 23341258 Nonivamide 23341258 capsaicin 23341258 glutathione 23341258 nonivamide 23341258 oxygen 23341258 superoxide 23343117 Cd 23343117 Cd(2+) 23343117 Cd(II) 23343117 N 23343117 O 23343117 OH(-) 23343117 Zn 23343117 Zn(2+) 23343117 Zn(II) 23343117 amide 23343117 amide and amine nitrogens 23343117 amine 23343117 coumarin 23343117 dipicolylamine 23343117 hydroxide 23343117 pyridine 23343172 porphyrin 23343172 porphyrins 23343324 3 μ-ISF 23343324 polyferrocenylethylmethylsilane 23343324 polyisoprene 23343324 polystyrene 23343325 Co(II) 23343325 Eu(III) 23343325 EuS 23343325 Fe(II) 23343325 Mn(II) 23343325 dithiocarbamate 23343325 tetraphenylphosphonium tetrakis(diethyldithiocarbamate)europium(III) 23343325 transition-metal 23343474 C-S 23343474 Penta(tert-butylthio)corannulene 23343474 corannulene penta-thioethers 23343474 penta(4-dimethylaminophenylthio)corannulene 23343474 sulfur 23343474 thioether 23343474 thiolates 23343595 olanzapine 23344429 FAD 23344429 L-lysine 23344429 L-pipecolic acid 23344429 NADH 23344429 amine 23344429 haem 23344820 2-DG 23344820 2-deoxglucose 23344820 2-deoxyglucose 23344820 7,12-dimethylbenz(a)anthracene 23344820 DMBA 23344820 MDA 23344820 NO 23344820 adenosine-5'-triphosphate 23344820 glutathione 23344820 malonate 23344820 malondialdehyde 23344820 nitric oxide 23344820 sodium malonate 23344820 superoxide 23344824 saponins 23344824 tannins 23344824 terpenoids 23344825 Cd 23344825 Cr 23344825 Fe 23344825 Pb 23344825 Zn 23344825 cadmium 23344825 chromium 23344825 iron 23344825 zinc 23344975 Copper 23344975 Cu(+) 23344975 copper 23345132 17α-Hydroxyprogesterone 23345132 17α-hydroxypregnenolone 23345132 17α-hydroxyprogesterone 23345132 4-androstenedione 23345132 Androgen 23345132 androgen 23345132 dehydroepiandrosterone 23345132 dihydrotestosterone 23345132 steroid 23345132 testosterone 23346898 Ni(II) 23346898 [Ni(Me(6)tren)Br](Br) 23346898 [Ni(Me(6)tren)Cl](ClO(4)) 23346898 trigonal bipyramidal Ni(II) 23347052 DOPA 23347052 amine 23347052 iron 23347151 C-C 23347151 CF3CH2OH 23347151 CH3CN 23347151 CH3OH 23347151 C═C 23347151 hydrogen 23347151 para-amino 23347422 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine 23347422 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphoethanolamine 23347422 DiynePC 23347422 DiynePE 23347422 PDMS 23347422 diacetylene 23347422 ethanolamine 23347422 polydimethylsiloxan 23347547 Quercetin 23347547 acetic acid 23347547 flavonoid 23347547 quercetin 23347683 3-(phenoxy-phenyl-methyl)-pyrrolidine 23347683 3-(phenoxy-phenyl-methyl)-pyrrolidines 23347683 5-HT 23347683 5-hydroxytryptamine 23347683 norepinephrine 23347683 serotonin 23347684 1-azabicyclo[2.2.1]heptanes 23347684 2-(4-Chloro-2-cyano-2-phenylbutyl)aziridines 23347684 2-(4-chloro-2-cyano-2-phenylbutyl)aziridines 23347684 2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes 23347684 LiAlH(4) 23347684 LiAlH₄ 23347684 azaheterobicyclic 23347684 endo- and exo-2-aminomethyl-4-phenyl-1-azabicyclo[2.2.1]heptanes 23347875 22(R)-hydroxycholesterol 23347875 3β-hydroxysteroid 23347875 HBCDD 23347875 Hexabromocyclododecane 23347875 cAMP 23347875 cholesterol 23347875 forskolin 23347875 hexabromocyclododecane 23347875 nucleotide 23348152 (p-CH(3)O-C(6)H(4)Se)(2) 23348152 (p-Cl-C(6)H(4)Se)(2) 23348152 Cu(2+) 23348152 NADPH 23348152 RSeH 23348152 diaryl diselenides 23348152 p-chloro-diphenyl diselenide 23348152 p-methoxyl-diphenyl diselenide 23348152 selenol 23348152 thiols 23348499 glucose 23348501 2,5-dimethylfuran-3-thiol 23348501 2-oxoclopidogrel 23348501 3-nitropyridine-2-thiol 23348501 6-chloropyridazine-3-thiol 23348501 CPT 23348501 GSH 23348501 NPT 23348501 clopidogrel 23348501 disulfide 23348501 glutathione 23348501 thiol 23348501 thiols 23348514 Metformin 23348514 alanine 23348514 fatty acid 23348514 glucose 23348514 metformin 23348754 3,4-methylenedioxymethamphetamine 23348754 Ecstasy 23348754 MDMA 23348754 Oxytocin 23348754 cocaine 23348754 methamphetamine 23348754 oxytocin 23349486 Thiazolidinedione 23349486 pioglitazone 23349486 thiazolidinediones 23349498 glucose 23349500 Glucose 23349500 cAMP 23349500 calcium 23349500 glucose 23349501 17-HDHA 23349501 17-hydroxydocosahexaenoic acid 23349501 DHA 23349501 EPA 23349501 docosahexaenoic acid 23349501 eicosapentaenoic acid 23349501 glucose 23349501 polyunsaturated fatty acids 23349501 protectin D1 23349501 resolvin D1 23349501 resolvins 23350730 calcium 23350730 vitamin D 23350797 7-Chloro-4-quinolinyl Hydrazones 23350797 7-chloro-4-quinolinyl hydrazone 23350797 nitric oxide 23350945 Al(2)O(3) 23350945 Al(OH)(3) 23350945 Al-OH 23350945 Al2O3 23350945 AlO(OH) 23350945 DMMP 23350945 H(2)O 23350945 O 23350945 P═O 23350945 dimethyl methylphosphonate 23350945 hydrogen 23350945 methoxy 23350945 oxide 23351082 10-hydroxy-2-decenoic acid 23351082 esters 23351082 fatty acids 23351082 medium-chain fatty acids 23351082 mono- or dicarboxylic acid 23351096 doxorubicin 23351096 iron oxide 23351096 poly(N-isopropylacrylamide-co-acrylamide)-block-poly(ε-caprolactone) 23351139 ATP 23351139 AZT-TP 23351139 adenosine triphosphate 23351139 azidothymidine triphosphate 23351139 nucleotide 23351139 nucleotides 23351961 3-(4,5-dimethyl-thiazol-2-yl)-2-5-diphenyltetrazolium-bromide 23351961 Curcumin 23351961 MTT 23351961 SDS 23351961 curcumin 23352141 nocapyrones 23352141 pyrone polyketides 23352141 γ-pyrones 23352430 CpG 23352430 cytidine 23352430 dinucleotides 23352430 hydroxyurea 23352650 2,4diMeOBA 23352650 2,4diOHBA 23352650 GTS-21 23352650 H 23352650 PNU-120596 23352650 acetylcholine 23352650 benzylidene 23352650 benzylidene anabaseine 23352650 benzylidene anabaseines 23352650 dihydroxy 23352650 hydrogen 23352650 hydroxyl 23352650 serine 23352910 1, 1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine iodide 23352910 DiR 23352910 poly-l-arginine 23352929 NO 23352929 nitric oxide 23352929 phenolic 23352929 salicylic acid 23353026 GSH 23353026 H2O2 23353026 Mn 23353026 lactate 23353026 manganese 23353026 oxygen 23353026 propidium iodide 23353026 superoxide 23353027 DMAG 23353027 GSH 23353027 GSSG 23353027 H2O2 23353027 S 23353027 arsenic 23353027 arsenite 23353027 dimethylarsinic glutathione 23353027 nitrogen 23353027 oxygen 23353027 thio-DMA 23353027 thio-dimethylarsinic acid 23353058 Cu 23353058 K 23353058 Na 23353058 copper 23353658 Coumarins 23353658 acetonitrile 23353658 cnidilin 23353658 coumarins 23353658 imperatorin 23353658 isoimperatorin 23353659 MTT 23353659 Phenolic glycosides 23353659 chlorophenolic glucosides 23353659 curculigine E 23353659 curculigine F 23353659 curculigine G 23353659 curculigine H 23353659 curculigine I 23353659 orcinoside H 23353659 phenolic glycoside 23353659 phenolic glycosides 23353698 ABT-737 23353698 flavonoid 23353698 quercetin 23353699 AG1296 23353699 AG1478 23353699 LY294002 23353699 PP1 23353699 SB202190 23353699 SH-5 23353699 SP600125 23353699 Tanshinone IIA 23353699 U0126 23353733 1,4-di-substituted 2-aminoimidazole 23353733 1,4-di-substituted 2-aminoimidazoles 23353733 2-AITs 23353733 2-aminoimidazoles 23353733 pyrrole-imidazole alkaloids 23353733 triazoles 23353733 β-lactams 23353741 (1)H 23353741 (13)C 23353741 PGE2 23353741 prostaglandin E2 23353741 resveratrol amide 23353743 1,2,3-triazole-dithiocarbamate 23353743 5-fluorouracil 23353815 Cd 23353815 Fe 23353815 Hex 23353815 Zn 23353815 cadmium 23353815 iron 23353815 n-hexane 23353815 zinc 23353816 As(III) 23353816 As(V) 23353816 DMA(III) 23353816 DMA(V) 23353816 GSH 23353816 MMA(III) 23353816 MMA(V) 23353816 arsenic 23353816 dimethylarsinic acid 23353816 dimethylarsinous acid 23353816 glutathione 23353816 monomethylarsonic acid 23353816 monomethylarsonous acid 23353816 oxygen 23354070 ATP 23354070 palinurin 23354070 sesquiterpene 23354072 2-(2-benzoyl-β-D-glucopyranosyloxy)-7-(1α,2α,6α-trihydroxy-3-oxocyclohex-4-enoyl)-5-hydroxybenzyl alcohol 23354072 2-(6-benzoyl-β-D-glucopyranosyloxy)-7-(1α,2α,6α-trihydroxy-3-oxocyclohex-4-enoyl)-5-hydroxybenzyl alcohol 23354072 catechin-[5,6-e]-4β-(3,4-dihydroxyphenyl)dihydro-2(3H)-pyranone 23354072 chloroquine 23354072 chrysoeriol-7-O-β-D-glucopyranoside 23354072 hematin 23354072 heme 23354072 mururin A 23354072 phenolic glycoside 23354072 poliothrysoside 23354072 β-hematin 23354391 Ca 23354391 Daidzein 23354391 calcium 23354391 daidzein 23354391 estrogen 23354727 steroids 23354755 coal 23355287 TiO2 23355287 carbon 23355467 carbohydrate 23355467 carbon 23355467 fatty acid 23355467 fatty acids 23355467 glucose 23355467 stearoyl-CoA 23355467 sugar 23355467 triglycerides 23355488 actinomycin D 23355488 cystine 23355488 romidepsin 23355488 vancomycin 23355489 Ser 23355489 poly(ADP-ribose) 23355489 serine 23355616 CpG 23355616 CpGs 23355616 dinucleotides 23355616 nucleotide 23356207 monoglycerides 23356207 triterpene 23356207 triterpenes 23356740 Octopamine 23356740 Tyramine 23356740 adrenaline 23356740 amines 23356740 catecholamines 23356740 cyclic AMP 23356740 dopamine 23356740 noradrenaline 23356740 octopamine 23356740 phenolamines 23356740 tyramine 23356791 Formaldehyde 23356791 formaldehyde 23356791 formate 23356791 glucose 23356791 glutathione 23356791 lactate 23356859 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide 23356859 MTT 23356859 tetrazolium 23356867 carbohydrate 23356867 cellohexaose 23356867 cellotetraose 23356867 saccharide 23356907 Phthalocyanine 23356907 acetylenic bombesin 23356907 arginine 23356907 aspartic acid 23356907 bombesin 23356907 glycine 23356907 phthalocyanine 23356907 zinc phthalocyanine 23356946 3'-O-methylepicatechin 23356946 4'-O-methylepicatechin 23356946 epicatechin 23356946 epicatechin glucuronides and sulfates 23356946 glucuronides 23356946 monoglucuronides 23356946 sulfates 23356964 7-O-β-d-glucopyranosyl-(1→2)-β-d-glucopyranosyl-(1→2)-[α-l-rhamnopyranosyl-(1→6)]-β-d-glucopyranosyl 23356964 DPPH 23356964 Flavone tetraglycosides 23356964 acyl 23356964 benzyl alcohol glycosides 23356964 glycosyl 23356964 lavone tetraglycosides 23356964 phenylpropanoylquinic acid 23357308 2-(3-pyridyl)-4,5-disubstituted thiazoles 23357308 5-acetyl-4-methyl-2-(3-pyridyl)thiazole 23357308 amphotricin B 23357308 ampicillin 23357308 thiazole 23357312 2',7'-dichlorofluorescein diacetate 23357312 DCFH-DA 23357312 Hoechst 33342 23357312 Paeonol 23357312 lactate 23357312 oxygen 23357312 paeonol 23357362 Ba(2+) 23357362 Vicenin 2 23357362 acetylcholine 23357565 N-ethylmaleimide 23357565 NO 23357565 SH 23357565 Silymarin 23357565 aspirin 23357565 capsaicin 23357565 capsazepine 23357565 ethanol 23357565 l-NAME 23357565 nitric oxide 23357565 silymarin 23357565 sulfhydryl 23357565 sulfhydryls 23357626 Aplyronine A 23357626 aplyronine A 23357626 mycalolide B 23357627 Boc-Phe-Leu-Glu(P)(OC(6)H(4))(2) 23357627 Phosphonic 23357627 glutamic acid 23357627 phosphonic glutamic acid 23357628 DPPH 23357628 MTT 23357628 curcumin 23357628 dimethylaminomethyl-substituted curcumin 23357628 galvinoxyl 23357629 (1)H 23357629 (13)C 23357629 1-methyl-5-(2,4,6-trimethoxy-phenyl)-1H-pyrazole 23357629 OH 23357629 acetic acid 23357629 flavones 23357629 keto 23357629 phenolic 23357629 pyrazole 23357633 C-(3-aminomethyl-cyclohexyl)-methylamine 23357633 benzene 23357633 ethambutol 23357633 t-butyl 23357976 11β-hydroxysteroid 23357976 cortisol 23357976 cortisone 23357976 glucose 23359435 benzocyclobutene 23359435 oxetane 23359435 triscarbazole 23359520 cholesterol 23359520 glucose 23359520 triglycerides 23359538 Cd(2+) 23359538 Cu(2+) 23359538 Hg(2+) 23359538 aluminosilica 23359538 cadmium 23359538 copper 23359538 mercury 23359555 C(60) 23359555 N-alkylcarbazole 23359555 fullerene 23359587 hydroxyapatite 23359587 tricalcium phosphate 23360142 CO 23360142 carbon monoxide 23360180 Ag 23360180 Oxygen 23360180 PLGA 23360180 oxygen 23360180 silver 23360230 Au 23360230 PEG 23360232 PEG 23360232 histidine 23360232 lysine 23360361 DMAPODA 23360361 Decanoic acid 23360361 N-[3-(Dimethylamino)propyl]-Octadecanamide 23360361 N-[3-(dimethylamino)propyl]-octadecanamide 23360361 amino 23360361 behenic acid 23360361 carboxylic 23360361 fatty acid 23360361 fatty acids 23360361 myristic acid 23360361 stearic acid 23360392 Cisplatin 23360392 Flavonol 23360392 cisplatin 23360392 flavonols 23360392 hydroxyl 23360392 hydroxyls 23360392 quartz 23360412 2,6-dichlorobenzonitrile 23360412 8-methoxypsoralen 23360412 DCBN 23360412 glutathione 23360619 7-ethyl-10-hydroxycamptothecin glucuronide 23360619 UDP 23360619 glucuronic acid 23361101 Caffeine 23361101 caffeine 23361383 AmB 23361383 N-acetylcysteine 23361383 Potassium 23361383 amiloride 23361383 amphotericin B 23361383 mannitol 23361383 potassium 23361383 spironolactone 23361517 EYYTO 23361517 Er(3+) 23361517 Er3+ 23361517 Y(2)Ti(2)O(7) 23361517 Y2Ti2O7 23361517 YTO 23361517 Yb(3+) 23361517 Yb3+ 23361587 NAD(+) 23361914 (S)-argininamide 23361914 [(3)H]UR-PLN196 23361914 [2,3-(3)H]propionyl 23361914 guanidine 23362105 GlcNAcβ(1→4)MurNAc 23362105 MDP 23362105 MurNAcβ(1→4)GlcNAc 23362105 Nucleotide 23362105 disaccharide 23362105 muramyl dipeptide 23362105 tetrasaccharide 23362239 Ca²⁺ 23362239 ryanodine 23362923 Amino Acids 23362923 amino acids 23362923 cyclic pentapeptides 23362942 (1)H 23362942 amino acid 23362942 amino acids 23362942 pillar[n]arene (n = 5, 6) 23362960 biotins 23363072 H 23363072 H-B 23363072 Hydrogen 23363072 KNMe(2)BH(3) 23363072 LiNMe(2)BH(3) 23363072 alkali metal amidoboranes 23363072 dihydrogen 23363072 hydrogen 23363335 CpG 23363335 CpG dinucleotide 23363335 cytosine 23363335 cytosines 23363335 guanine 23363335 hydrogen 23363335 pyrimidine 23363407 6-mercaptohexanol 23363407 oxygen 23363407 silica 23363425 (2S,4R)hydroxyproline 23363425 (poly-)amines 23363425 C 23363425 Hyp 23363425 Pro-Hyp-Gly 23363425 Silica 23363425 phosphate 23363425 silica 23363425 silicic acid 23363574 2',5'-ADP-sepharose-4B 23363574 d-glucose 6-phosphate 23363574 Ag(+) 23363574 As(5+) 23363574 Co(2+) 23363574 Glucose 6-phosphate 23363574 NADP(+) 23363574 TI(+) 23363574 Tl(+) 23363574 arsenic (V) oxide 23363574 cobalt (II) nitrate 23363574 glucose 6-phosphate 23363574 pentose phosphate 23363574 polyacrylamide 23363574 silver nitrate 23363574 sodium dodecyl sulfate 23363574 thallium sulphate 23363576 EtOH 23363576 alanine 23363576 aspartate 23363576 ethanol 23363576 glutathione 23363576 hydrogen peroxide 23363576 malondialdehyde 23363576 superoxide 23363577 Se 23363577 diethylenetriaminepentaacetic acid 23363577 selenium 23364612 1,4-dihydropyridines 23364612 11B 23364612 13C 23364612 1H 23364612 3,4-dihydropyrimidinones 23364612 boron 23364612 ethanol 23364612 formylphenylboronic acids 23364612 thioglycerol 23364615 TiO2 23364615 Titanium dioxide 23364615 metal oxides 23364615 titanium dioxide 23364884 E-64 23364884 cysteine 23364884 serotonine 23368510 glucose 23368510 metformin 23368777 Ser 23368777 Tyr 23368777 alanine 23368777 aspartate 23368777 lysine 23368777 sucrose 23368884 BRD9757 23368884 Hydroxamic acids 23369033 (-)-tylophorine 23369033 levorotatory tylophorine 23369033 phenanthroindolizidine alkaloid 23369343 alloxan 23369343 bilirubin 23369343 carbonyl 23369343 d-galactose 23369343 glucose 23369343 nitric oxide 23369343 peroxide 23369343 peroxides 23369343 sulfhydryl 23369343 superoxide 23369343 α-santalol 23369344 Indo 23369344 Prop 23369344 cGMP 23369344 guanylate 23369344 indomethacin 23369344 l-NAME 23369344 nitric oxide 23369344 propranolol 23369344 prostacyclin 23369537 chalcones 23369833 N 23369833 N-sulfocarbamoyl 23369833 carbamate 23369833 carbamate and N-sulfocarbamoyl 23369933 Mercuric chloride 23369933 Mercury 23369933 mercuric chloride 23369933 mercury 23369933 sodium selenite 23369933 vitamin E 23370006 Uranium 23370006 manganese 23370006 uranium 23370006 zinc 23370180 DES 23370180 DHT 23370180 diethylstilbestrol 23370180 dihydrotestosterone 23370180 testosterone 23370306 2-methylbutyric acid 23370306 Diterpenoids 23370306 Nor-Diterpenoids 23370306 crotocascarins 23370306 crotocascarins A-H 23370306 crotofolane 23370306 crotofolanes 23370306 diterpene 23370306 diterpenoids 23370306 nor-diterpenoids 23370306 γ-lactone 23370795 buprenorphine 23371032 carbamate 23371032 chlorocyclodiene 23371032 chlorpyrifos 23371032 cypermethrin 23371032 deltamethrin 23371032 endosulfan 23371032 methomyl 23371032 organochlorine 23371032 organophosphate 23371032 organophosphates 23371032 pyrethroid 23371032 pyrethroids 23371303 AVE1330A 23371303 Avibactam 23371303 Ceftazidime 23371303 NXL104 23371303 avibactam 23371303 carbapenem 23371303 ceftazidime 23371303 cephalosporin 23371303 cephem 23371303 creatinine 23371303 metronidazole 23371303 β-lactam 23371451 BrdU 23371451 Cysteamine 23371451 GSH 23371451 bromodeoxyuridine 23371451 cysteamine 23371451 glutathione 23371451 tetrazolium salt-1 23371488 Nicotine 23371488 nicotine 23371488 polycarbonate 23371489 MDPV 23371489 Mephedrone 23371489 cathinone 23371489 cocaine 23371489 dopamine 23371489 mephedrone 23371489 methamphetamine 23371489 methcathinone 23371489 methylenedioxypyrovalerone 23371760 15,16-epoxyisopimaric acid 23371760 15-hydroxyabietic acid 23371760 15-hydroxydehydroabietic acid 23371760 CH 23371760 Resin acid 23371760 abietic acid 23371760 dehydroabietic acid 23371760 diterpenoid 23371760 diterpenoids 23371760 isopimaric acid 23371760 resin acids 23371760 sulfonylurea 23371760 vitamin D(3) 23371763 Eu(III) 23371763 carbon 23371965 Cys 23371965 GSH 23371965 PEITC 23371965 PIC 23371965 Phenethylisothiocyanate 23371965 glutathione 23371965 isothiocyanate 23371965 parathion 23371965 phenethyl isocyanate 23371965 phenethyl isothiocyanate 23371965 phenethylamine 23371965 sulfur 23373444 Al(III) 23373444 Au(III) 23373444 Ca(II) 23373444 Cr(III) 23373444 Cu(II) 23373444 H(I) 23373444 Mg(II) 23373444 Na(I) 23373444 Ni(II) 23373444 Zn(II) 23373444 Zr(IV) 23373444 glucose 23373444 α-Zr(IV) phosphate 23373444 α-ZrP 23373444 α-zirconium(IV) phosphate 23373463 cobalt 23373463 hydroxide 23373463 α- to β-cobalt hydroxide 23373463 α-Co(OH)2 23373463 β-Co(OH)2 23373530 PPPX 23373530 poly(2-phenyl-1,4-xylylene) 23373544 Deoxyschisandrin 23373544 Eudragit 23373544 lignans 23373544 poloxamer 188 23373544 schisantherin A 23373590 AMPS 23373590 Ca(2+) 23373590 CaCl2 23373590 NaCl 23373590 acrylic acid 23373590 calcium 23373590 citrate 23373590 iron oxide 23373590 poly(2-methyl-2-acrylamidopropanesulfonate-co-acrylic acid) 23373590 poly(AMPS-co-AA) 23373590 poly(styrenesulfonate-alt-maleic acid) 23373590 poly(styrenesulfonate-block-acrylic acid) 23373590 sodium 23373613 iron oxide 23373648 steroidal hormones 23373648 tyrosine 23373724 (1)H 23373724 1β-d-Arabinofuranosylcytosine 23373724 1β-d-arabinofuranosyluracil 23373724 Ara-C 23373724 Ara-U 23373724 Cytarabine 23373724 OH 23373724 PAMAM 23373724 PEG 23373724 cytidine 23373724 hydroxyl 23373772 CF(3) 23373772 MeOH 23373772 Ru(bpy)(3)Cl(2) 23373772 alkenes 23373965 1-en-3-one 23373965 2,20-dinitrile 23373965 3-oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile 23373965 9(11),12-diene 23373965 NO 23373965 glycyrrhetinic acid 23374865 Cu(I) 23374865 acetone 23374865 azide-alkyne 23374865 bile acid 23374865 cresol red sodium 23374865 pyrene 23374868 1-(4-Phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanones 23374868 1-(4-phenylpiperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanone 23374868 [(125)I]-CCL3 23374869 2-benzofuran-1(3H)-one 23374869 6-benzyloxyphthalides 23374869 Br 23374869 C 23374869 CF(3) 23374869 CH(3) 23374869 Cl 23374869 F 23374869 H 23374869 I 23374869 Phthalide 23374869 isatin 23374869 monoamine 23374869 phenyl 23374869 phthalide 23374869 phthalides 23374869 phthalimide 23374871 1-methylimidazole 23374871 2-phenyl-1-methylimidazole 23374871 imidazole 23374871 imidazolium 23374872 (11)C 23374872 (18)F 23374872 tariquidar 23375260 guanine nucleotide 23375851 11-ketotestosterone 23375851 ACE 23375851 CBZ 23375851 GEM 23375851 VEN 23375851 acetaminophen 23375851 carbamazepine 23375851 gemfibrozil 23375851 venlafaxaine 23376090 Chlordecone 23376090 chlordecone 23376090 organochlorine 23376110 1,3-thiazolane-4-carboxylic acid 23376110 16-spiro steroids 23376110 Spiro-7'-(aryl)tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazolo-trans-androsterone 23376110 acenaphthylene-1,2-dione 23376110 azomethine 23376110 dehydroandrosterone 23376110 spiro[5'.2″]acenaphthylene-1″-one-spiro[16.6']-(7'-aryl)-tetrahydro-1H-pyrrolo [1,2-c][1,3]thiazolo-trans-androsterone 23376110 trans-androsterone 23376110 trans-dehydroandrosterone 23376119 PJ34 23376119 Poly(ADP-ribose) 23376119 TPT 23376119 camptothecin 23376119 poly(ADP-ribose) 23376119 topotecan 23376162 Sesquiterpenes 23376162 [Rh2(OCOCF3)4] 23376162 bisabolenes 23376162 nitric oxide 23376162 sesquiterpenes 23376242 MAN 23376242 P-aminophenyl-α-d-mannopyranoside 23376245 Bpv (phen) 23376245 N-methyl-d-aspartate 23376245 NMDA 23376245 Tyr 23376245 Tyrosine 23376245 glutamate 23376245 orthovanadate 23376245 tyrosine 23376249 1,3,4-thiadiazole 23376249 acetyl 23376353 DOX 23376353 PLGA 23376353 VER 23376353 carboxyl 23376353 cyclo(Arg-Gly-Asp-D-Phe-Lys) 23376353 doxorubicin 23376353 verapamil 23376354 Ca(2+) 23376354 K(+) 23376412 indole alkaloids 23376437 CPZ 23376437 chlorpromazine 23376439 alkanes 23376439 decane 23376439 hexadecane 23376439 hexane 23376439 hydrocarbon 23376439 hydrocarbons 23376439 methyl esters 23376477 Ca(2+) 23376477 Ca²⁺ 23376477 K(+) 23376477 K⁺ 23376477 Nonylphenol 23376477 estrogen 23376477 nonylphenol 23376477 xenoestrogen 23376608 Apigenin 23376608 apigenin 23376696 Ca(2+) 23376696 K(+) 23376696 MDA 23376696 Na(+) 23376696 chloride 23376696 fluoride 23376696 malondialdehyde 23376696 superoxide 23376697 cobalt 23376697 titanium oxide 23376712 BHF177 23376712 Baclofen 23376712 N-([1R,2R,4S]-bicyclo[2.2.1]hept-2-yl)-2-methyl-5-(4-[trifluoromethyl]phenyl)-4-pyrimidinamine 23376712 baclofen 23376712 chlordiazepoxide 23376712 γ-Aminobutyric acid 23376780 eugenol 23376780 pyrethrins 23376780 rotenone 23376780 β-asarone 23376817 BrdU 23376817 DMA(III) 23376817 DMA(V) 23376817 arsenic 23376817 bromodeoxyuridine 23376817 dimethylarsinous acid 23376817 methylate arsenicals 23376997 Arylsulfonamide 23376997 arylsulfonamido 23376997 hydroxamates 23377100 Cd 23377100 Cd(2+) 23377100 PTFE 23377100 ascorbate 23377100 cadmium 23377100 oxygen 23377100 polytetrafluoroethylene 23377115 calcium diglutamate 23377115 glutamates 23377115 magnesium diglutamate 23377115 monoammonium glutamate 23377115 monopotassium glutamate 23377115 monosodium glutamate 23377609 1-(4-aminobenzyl) ethylenediamine N,N,N',N'-tetraacetic acid 23377609 1-(4-isothiocyanobenzyl) ethylenediamine N,N,N',N'-tetraacetic acid 23377609 EDTA 23377609 ITCBE 23377609 aminobenzyl-EDTA 23377609 cadmium 23377617 GSH 23377617 Zn 23377617 dopamine 23377617 glutathione 23377617 zinc 23377617 γ-Glutamylcysteine 23378200 Baicalin 23378200 baicalin 23378608 Fatty acids 23378608 celecoxib 23378626 (2R,3R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-deoxy-β-d-glucopyranosyl)-α-d-glucopyranoside 23378626 CS-1036 23378626 [(14)C]CS-1036 23378626 glucose 23378627 androstane 23378820 Iron 23378820 Selenate 23378820 bicarbonate 23378820 ferrous 23378820 ferrous hydroxide 23378820 hydroxide 23378820 iron 23378820 oxygen 23378820 selenate 23379362 Petroacetylene 23379362 petroacetylene 23379362 polyacetylene 23379369 2-fluoroethyl azide 23379369 C-C-N-N 23379369 F-C-C-N 23379369 FCH2CH2N3 23379369 azido 23379369 fluorine 23379686 (1)H 23379686 1,3-didecyl-2-methylimidazolium chloride 23379686 4-methoxybenzenesulfonyl chloride 23379686 D2O 23379686 MBSC 23379686 Nile red 23379686 [C10C10mim]Cl 23379686 pyrene 23379686 rhodamine B 23379723 Spiropyran 23379723 acetone 23379723 acetonitrile 23379723 ethanol 23379723 merocyanine 23379723 methanol 23379723 silica 23379723 spiropyran 23379723 tetrahydrofuran 23379723 toluene 23379784 H 23379784 Polystyrene 23379784 poly(ethylene oxide) 23379784 polystyrene 23379962 PFH-A 23379962 PFO-BPy 23379962 carbon 23379962 fluorene 23379962 poly[(9,9-dihexylfluorenyl-2,7-diyl)-co-(9,10-anthracene)] 23379962 poly[(9,9-dioctylfluorenyl-2,7-diyl)-alt-co-(6,6'-{2,2'-bipyridine})] 23380082 caffeic acid 23380082 ferulic acid 23380082 phenolic acids 23380082 rosmarinic acid 23380243 arsenic 23380305 4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile 23380305 ABT-239 23380305 Histamine 23380305 acetylcholine 23380305 histamine 23380477 CoCl(2) 23380477 CoCl2 23380477 cobalt chloride 23380477 oxygen 23380917 GABA 23380917 N-methyl D-aspartate 23380917 PCP 23380917 phencyclidine 23380917 γ-aminobutyric acid 23381681 GSH 23381681 Se 23381681 Selenium 23381681 Thyroxine 23381681 glutathione 23381681 selenium 23381681 seleno 23381681 sodium selenite 23381681 triiodothyronine 23381882 Fexofenadine 23381882 Midazolam 23381882 Pravastatin 23381882 Ritonavir 23381882 Saquinavir 23381882 fexofenadine 23381882 midazolam 23381882 pravastatin 23381882 ritonavir 23381882 saquinavir 23381951 Allopurinol 23381951 abacavir 23381951 allopurinol 23381951 carbamazepine 23382013 octanol 23382105 MMF 23382105 MPA 23382105 cyclosporine 23382105 mycophenolate mofetil 23382105 mycophenolic acid 23382105 tacrolimus 23382380 AMPA 23382380 glutamate 23383423 amino acid 23383594 CH4 23383594 CO2 23383594 carbon 23383594 carbon dioxide 23383594 methane 23383594 zeolite 23383710 DMAAPS 23383710 N,N-dimethyl(acrylamidopropyl)ammonium propane sulfonate 23383710 PEI 23383710 polyethylenimine 23383723 F68 23383723 NaTDC 23383723 Pluronic 23383723 Pluronic F127 23383723 Pluronic F127 or F68 23383723 Pluronics 23383723 Pluronics (F127 and F68) 23383723 bile salt 23383723 bile salts 23383746 CA-Tam 23383746 DCA-Tam 23383746 DPH 23383746 DPPC 23383746 LA-Tam 23383746 N-desmethylated tamoxifen 23383746 Prodan 23383746 TamNHMe 23383746 amine 23383746 bile acid 23383746 bile acids 23383746 cholic acid 23383746 deoxycholic acid 23383746 lithocholic acid 23383746 tamoxifen 23383750 3-n-pentadecylphenol 23383750 PDP 23383750 PS-P4VP 23383750 hydrogen 23383750 polystyrene-poly(4-vinyl pyridine) 23383871 cyclohexene 23383871 estrogen 23383871 steroid 23384042 CH2Cl2 23384042 perylene 23384363 nitrogen 23384387 Oleoyl-L-valinolamide 23384387 acylethanolamide 23384387 elaidoyl-D-valinolamide 23384387 elaidoyl-L-valinolamide 23384387 glucose 23384387 oleoyl-D-valinolamide 23384387 oleoyl-L-valinolamide 23384387 palmitoyl-L-valinolamide 23384387 stearoyl-L-valinolamide 23384446 ACh 23384446 Arsenite 23384446 CPA 23384446 Ca(2+) 23384446 NADPH 23384446 NO 23384446 acetylcholine 23384446 apocynin 23384446 arsenic 23384446 arsenite 23384446 cyclopiazonic acid 23384446 dihydroethidium 23384446 hydrogen peroxide 23384446 manganese porphyrin 23384446 nitric oxide 23384446 oxygen 23384446 superoxide 23384967 BPA 23384967 Bisphenol A 23384967 DES 23384967 bisphenol A 23384967 diethylstilbestrol 23384967 steroid 23384996 NH4HCO3 23384996 alanine 23384996 amino acid 23384996 amino acids 23384996 ammonia 23384996 aspartate 23384996 glutamate 23384996 glutamine 23385211 Imipramine 23385211 N 23385211 amine 23385211 desipramine 23385211 ethylene glycol 23385211 imipramine 23385211 imipramines 23385211 lithium aluminium hydride 23385211 serotonin 23385214 H 23385214 OH 23386250 Ca(2+) 23386250 FK-506 23386250 K(+) 23386250 tacrolimus 23386468 2'-Fluoro-2'-deoxyguanosine 23386468 2'-deoxy-2'-fluoro-6-chloroguanosine 23386468 2'-fluoro-2'-deoxyguanosine 23386468 2'-fluoro-2'-deoxyguanosine 5'-monophosphate 23386468 5'-O-naphthyl(ethoxy-L-alaninyl) 23386468 5'-O-naphthyl(methoxy-L-alaninyl) 23386468 6-O-ethyl-2'-fluoro-2'-deoxyguanosine 23386468 6-O-methyl-2'-fluoro-2'-deoxyguanosine 23386468 L-alaninyl 23386468 adenosine 23386468 guanine 23386468 nucleoside 5'-monophosphates 23386468 nucleosides 23386468 phosphoramidate 23386468 purine 2'-fluoro-2'-deoxyriboside 23386597 Ezogabine 23386597 ethyl N-(2-amino-4-[{fluorophenyl}methlamino]phenylcarbamate) 23386597 ezogabine 23386597 potassium 23386597 retigabine 23386599 amides 23386599 carbamates 23386599 carboxylic acid 23386599 ester 23386599 esters 23386599 statins 23386599 thioesters 23386616 NADPH 23386616 oxygen 23386704 25-hydroxyvitamin D 23386704 4β-hydroxycholesterol 23386704 vitamin D 23386780 ECH 23386780 Epichlorohydrin 23386780 amino 23386780 dUTP 23386780 epichlorohydrin 23387796 (1)H 23387796 (13)C 23387796 (15)N 23387796 Amberlite XAD-16 23387796 Geralcin C 23387796 geralcin C 23387796 geralcins A and B 23387796 geralcins C-E 23387796 geralcins D and E 23387796 hydrazides 23387796 methanol 23387851 ANAVEX 2-73 23387851 E-52862 23387851 SA4503 23387865 (13)C 23387865 (E)-olefinic carbons 23387865 1-enol-3,7-diketo 23387865 3-enol-1,7-diketo 23387865 CD(3)OH 23387865 DMSO-d(6) 23387865 HSYA 23387865 Hydroxysafflor yellow A 23387865 hydroxysafflor yellow A 23387865 keto-enol 23387865 pyridine-d(5) 23387865 quinochalcone C-glycoside 23387865 quinochalcone C-glycosides 23389039 curcumin 23389045 4-pyridyl 23389045 Pyridyl 23389045 bis(2-hydroxy-ethyl) 23389045 bis(2-hydroxyethyl) 23389045 ethanol 23389045 lipoic Acid 23389045 lipoic acid 23389045 pyridine 23389045 thyroxine (T4) 23389045 thyroxine (t4) 23389625 C 23389625 Carbon 23389625 LiFePO(4) 23389625 LiFePO4 23389625 carbon 23389625 lithium 23389625 sucrose 23389738 ETBE 23389738 ethyl tertiary-butyl ether 23389956 betamethasone 23389956 cortisol 23389956 sGC 23391096 PAMAM 23391096 Paclitaxel 23391096 Taxol 23391096 paclitaxel 23391096 polyamidoamine 23391096 tertiary amines 23391133 amide 23391133 ester 23391133 monophosphate 23391162 Amino Acid 23391162 DO3A-N-α-aminopropionate 23391162 Gd 23391162 Gd(DOTAla) 23391162 Gd(III) 23391254 ATP 23391254 taxol 23391441 Alexa Fluor 488 23391441 FITC 23391441 Texas Red 23391441 biotin 23391441 biotin-fluorescein isothiocyanate 23391441 gentamicin 23391441 phalloidin 23391442 oxygen 23391443 cAMP 23391484 PFCA 23391484 PFOA 23391484 PFT 23391484 Perfluorooctanoic acid 23391484 carbon 23391484 fluoropolymers 23391484 perfluorinated carboxylic acids 23391485 17-β-estrodiol 23391485 BPA 23391485 Bisphenol A 23391485 DMSO 23391598 As 23391598 Cd 23391598 Co 23391598 Cr 23391598 Cu 23391598 Fe 23391598 Hg 23391598 I 23391598 Mn 23391598 Mo 23391598 Ni 23391598 Pb 23391598 Se 23391598 Zn 23391631 Pb(2+) 23391631 aryl hydrocarbon 23391631 creatine 23391631 lactate 23391631 resveratrol 23391632 11β-hydroxysteroid 23391632 3β-hydroxysteroid 23391632 DEHP 23391632 EDS 23391632 di(2-ethylhexyl) phthalate 23391632 ethane dimethanesulfonate 23391632 testosterone 23391637 Ca(2+) 23391637 K(+) 23391637 Na(+) 23392568 Hg 23392568 HgCl2 23392568 mercury chloride 23392606 PLLA 23392606 PVP 23392606 poly(l-lactic acid) 23392606 polyvinylpyrrolidone 23393163 Vesnarinone 23393163 quinolinone 23393163 vesnarinone 23393209 Metformin 23393209 Triglycerides 23393209 glucose 23393209 metformin 23393209 triglyceride 23393209 triglycerides 23393216 25-OHD 23393216 25-hydroxycholecalciferol 23393216 Vitamin D 23393216 cholesterol 23393216 glucose 23393216 triglycerides 23393216 vitamin D 23393219 Repaglinide 23393219 Rifampicin 23393219 repaglinide 23393219 rifampicin 23394218 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide 23394218 AZD5363 23394309 H 23394309 H(+) 23394309 Hydrocarbons 23394309 O 23394309 OH(-) 23394309 [Nb6O19Hx]((8-x)-) 23394309 oxygen 23394318 abietane 23394318 aquilarabietic acid K 23394318 aquilarabietic acids A-J 23394318 diterpenoid 23394318 diterpenoids 23394318 ethanol 23394318 norepinephrine 23394318 petroleum ether 23394318 podocarpane 23394432 CdS 23394432 cadmium sulfide 23394469 graphite 23394469 met-enkephalin 23394469 pentapeptide 23394480 Ge 23394480 Si 23394542 (31)P 23394542 CdSe 23394542 carbon 23394542 chlorine 23395165 glutathione 23395165 purine 23395165 serine 23395652 (+)- and (-)-huperzine A 23395652 (-)-huperzine A 23395652 NMDA 23395652 huperzine A 23395656 Mitoxantrone 23395656 indazolo[4,3-gh]isoquinolinone 23395656 indazolo[4,3-gh]isoquinolinones 23395663 Lactose 23395663 [2,9(10),16(17),23(24)-tetrakis((1-(β-d-lactose-2-yl)-1H-1,2,3-triazol-4-yl)methoxyl)phthalocyaninato] zinc(II) 23395663 lactose 23395663 zinc phthalocyanine 23395665 3-(1H-indol-3-yl)-3-oxo-2-(2-oxoindolin-3-ylidene)propanenitrile 23395665 acenaphthenequinone 23395665 azomethine 23395665 dispirooxindole-pyrrolidine 23395665 isatin 23395665 sarcosine 23395689 DOPE 23395689 Gadolinium 23395689 Gd 23395689 Gd(3+) 23395689 Manganese 23395689 Mn 23395689 Mn oxide 23395689 MnO 23395689 Oleic acid 23395689 PEG-2000 23395689 cholesterol 23395689 dioleoyl-phosphatidylethanolamine 23395689 doxorubicin 23395689 manganese 23395689 phosphatidylethanolamine 23395689 polyethylene glycol 23395717 PD98059 23395717 Xestospongin C 23395717 bis-1-oxaquinolizidines 23395717 nitroblue tetrazolium 23395719 caffeoyl glucose 23395719 coumaroyl hexose 23395719 dihydroferulic acid 4-O-β-d-glucuronide 23395719 dihydroxybenzoic acid 23395719 methoxyquercetin 3-O-galactoside 23395719 myricetin 23395719 phenolic 23395719 polyphenols 23395719 quercetin 23395719 scopoletin 23395783 Cadmium 23395783 CdCl2 23395783 ORY 23395783 S 23395783 ascorbic acid 23395783 cadmium 23395783 glutathione 23395783 superoxide 23395783 thiols 23395783 γ-Oryzanol 23395783 γ-oryzanol 23395783 δ-ALA 23395783 δ-aminolevulic acid 23395914 darunavir 23395914 ketoconazole 23395914 zosuquidar 23396041 AZA 23396041 AZA1 23396041 AZA1 + 2 23396041 AZA1 and -2 23396041 AZA1+2 23396041 AZA17 23396041 AZA3 23396041 AZAs 23396041 azaspiracid 23396041 azaspiracids 23396116 TTX 23396116 tetrodotoxin 23396441 ATP 23396441 sucrose 23396442 ACN 23396442 DMSO 23396442 acetonitrile 23396442 dimethyl sulfoxide 23397032 Dexamethasone 23397032 dexamethasone 23397049 Paliperidone 23397049 paliperidone 23398290 Dex 23398290 Retinoids 23398290 Vitamin A 23398290 dexamethasone 23398290 retinoic acid 23399323 O 23399639 Laulimalide 23399639 Taccalonolide AJ 23399639 fijianolide B 23399639 laulimalide 23399639 paclitaxel 23399639 taccalonolide AJ 23399641 CB1954 23399641 PR-104A 23400262 MgO 23400262 TiO(2) 23400262 TiO2 23400270 silica 23400270 silicas 23400782 ADP 23400782 ATP 23400782 C 23400782 N 23400795 organotin 23400795 tributyltin 23400795 triphenyltin chloride 23400796 Co 23400796 Cr 23400796 Cu 23400796 Mn 23400796 Zn 23400888 acetylcholine 23400925 (13) C 23400925 (15) N 23400925 Hg 23400925 MMHg 23400925 Se 23400925 carbon 23400925 mercury 23400925 monomethylmercury 23400925 nitrogen 23400925 selenium 23400943 clobazam 23400943 clonazepam 23400943 stiripentol 23400943 valproic acid 23400943 vigabatrin 23401139 C10-C16 23401139 C16-C23 23401139 C23-C34 23401139 PHC 23401139 PHCs 23401139 Petroleum hydrocarbons 23401139 petroleum hydrocarbon 23401211 Hg 23401211 mercury 23401211 nitrogen 23401217 alloxan 23401244 C60 23401244 DDE 23401244 DDT 23401244 FULLERENES 23401244 dichlorodiphenyldichloroethylene 23401244 fullerene 23401244 fullerenes 23401244 p,p'-DDE 23401262 Phenytoin 23401262 phenytoin 23401281 Al 23401281 Cd 23401281 Cu 23401281 Fe 23401281 Mn 23401281 Pb 23401281 Zn 23401281 carbon 23401291 (E)-N-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methylene)hexadecan-1-amine 23401291 Fatty acid 23401291 Schiff base 23401291 Schiff-base 23401291 acyl 23401291 fatty acid 23401291 β-ketoacyl 23401303 carbon 23401303 carboxylic 23401303 phenolic 23401303 pyrethroid 23401303 pyrethroids 23401323 MNG 23401323 maltose-neopentyl glycol 23401324 PCBs 23401324 organochlorine 23401324 polybrominated diphenyl ethers 23401324 polychlorinated biphenyls 23401355 Co 23401355 Li 23401355 Li2O 23401355 Mn 23401355 MnCO3 23401355 MnO 23401355 lithium 23401470 N 23401472 5-Aza-dC 23401472 5-aza-2'-deoxycytidine 23401472 Bisulfite 23401472 CpG 23401472 SN-38 23401472 UDP 23401472 bilirubin 23401602 fatty acids 23401602 linoleic acid 23402270 PAEMH 23402270 poly(2-aminoethylmethacrylate hydrochloride) 23402270 polystyrene 23402341 GSH 23402341 MFA 23402341 MFA-1-O-G 23402341 MFA-1-O-acyl-glucuronide 23402341 MFA-AMP 23402341 MFA-CoA 23402341 MFA-GSH 23402341 MFA-S-acyl-CoA 23402341 MFA-S-acyl-glutathione 23402341 Mefenamic acid 23402341 S 23402341 acyl 23402341 acyl-CoA 23402341 adenylate 23402341 carboxylic acid 23402341 glutathione 23402341 mefenamic Acid 23402341 mefenamic acid 23402341 mefenamyl 23402364 (·)NO 23402364 Etoposide 23402364 H2O2 23402364 Nitric oxide 23402364 VP-16 23402364 VP-16,213 23402364 chloroform 23402364 etoposide 23402364 iminoxyl 23402364 nitric oxide 23402364 nitrogen oxide 23402364 nitroxide 23402364 o-quinone 23402364 o-quinone- and nitroso-VP-16 23402364 oxygen 23402364 phenoxy 23402423 CdTe 23402423 monothiol 23402636 cholesterol 23402636 sterols 23402636 triglyceride 23402636 γ-linolenic acid 23402638 Iron(II) 23402638 amino alcohols 23402638 hydroxylamine 23402638 hydroxylamines 23402638 iron nitrenoid 23402638 iron(II) 23402638 olefins 23402647 1-Butyl 23402647 2-methylimidazolium tetrafluoroborate 23402647 Eu 23402647 GdF3 23402647 diethylene glycol 23402647 europium(III) 23402647 fluoride 23402647 gadolinium(III) fluoride 23402647 lanthanide chlorides 23402855 CH2Cl2 23402855 NO 23402855 fucoxanthin 23402855 nitric oxide 23402855 pheophorbide a 23402855 pheophytin a 23402855 porphyrin 23402859 Chlorpyrifos 23402859 alanine 23402859 aspartate 23402859 catechin 23402859 chlorpyrifos 23402859 cholesterol 23402859 glutathione 23402859 lactate 23402859 malondialdehyde 23402859 organophosphorus 23402859 quercetin 23402859 superoxide 23402859 trigliceride 23402860 (-)-Cubebin 23402860 (-)-cubebin 23402860 CUB 23402860 DXR 23402860 URE 23402860 doxorubicin 23402860 lignan 23402860 urethane 23402938 IR3535 23402971 benzimidazole 23402971 benztriazole 23402972 indinavir 23402972 ritonavir 23403080 (S)-2-aminoethyl 23403080 2-hydrazino-1,3-thiazole 23403080 hydrazino-1,3-thiazole 23403080 hydrazone 23403080 indolyl 23403080 thiazole 23403395 COOH 23403395 PLA-TPGS 23403395 TPGS 23403395 Taxotere 23403395 carboxyl 23403395 cisplatin 23403395 d-alpha-tocopheryl-co-poly(ethylene glycol) 1000 succinate 23403395 docetaxel 23403395 poly(lactic acid)-TPGS 23403395 vitamin E 23403537 tetrapeptide 23403537 tetrapeptides 23404062 SCH23390 23404062 dopamine 23404062 naloxone 23404062 sulpiride 23404443 arginine 23404443 glucose 23404458 Al 23404458 Au 23404458 Ca 23404458 Cr 23404458 Cu 23404458 Hg 23404458 Mg 23404458 Ni 23404458 P 23404458 Pb 23404458 Pt 23404458 Si 23404458 Sn 23404458 Sr 23404458 W 23404458 Zn 23404458 calcium 23404458 calcium hydroxyapatite 23404458 cholesterol 23404739 19,20-anhydrosipholenol A 4β-4-chlorobenzoate 23404739 19,20-anhydrosipholenol A 4β-benzoate ester 23404739 Sipholenol A 23404739 Sipholenol A 4β-4-chlorobenzoate 23404739 carbamate 23404739 ester 23404739 esters 23404739 ether 23404739 oxime 23404739 sipholane triterpene 23404739 sipholane triterpenoids 23404739 sipholanes 23404739 sipholenol A 23404739 sipholenol A 4β-4-chlorobenzoate 23404739 sipholenol A succinate 23404739 sipholenols 23404739 sipholenone A 23404739 triterpene 23404739 tyrosine 23404750 Phe 23405943 1,1-diphenyl-2-picrylhydrazyl 23405943 4-aminophenol 23405943 Fe(2+) 23405943 ascorbic acid 23405943 benzoyl 23405943 paracetamol 23405943 salicylate 23405943 salicylic acid 23405943 thiobarbituric acid 23406166 2'-hydroxy-3,4-dimethoxychalcone 23406166 3',4'-dimethoxy-7-(γ,γ-dimethylallyloxy)flavonol 23406166 O-prenylated flavonol 23406166 biochanin A 23406166 kaempferol-3-O-β-d-glucopyranoside 23406277 PVA 23406277 [μ-(11,11'-bidppz)(phen)4Ru2](4+) 23406277 poly(vinyl alcohol) 23406277 ruthenium 23406277 ruthenium(II) 23406348 alkyl acrylates 23406348 ethyl (n-butyl) acrylate 23406348 ethyl acrylate 23406348 hydrogen 23406348 methyl 23406348 methyl acrylate 23406348 methyl, ethyl, and n-butyl acrylate 23406348 methylene 23406348 n-butyl acrylate 23406429 triaryl 23406429 triaryl sulfonamide 23406429 triaryl sulfonamides 23406469 PpIX 23406469 protoporphyrin IX 23406469 silica 23407893 H3AsO3 23407893 H3AsO4 23407893 H3PO3 23407893 H3PO4 23407893 Imogolite 23407893 aluminogermanate 23407893 aluminosilicate 23407893 arsenate 23407893 arsenic 23407893 arsenite 23407893 germanate 23407893 imogolite 23407893 phosphate 23407893 phosphite 23407893 phosphorous 23407893 silicate 23408116 Acetaminophen 23408116 UDP 23408116 acetaminophen 23408270 (+)-Limonene epoxide 23408270 (+)-limonene epoxide 23408270 praziquantel 23408434 Ca(2+) 23408434 calcium 23408851 C 23408851 N 23408851 amino acid 23409716 A967079 23409716 AP18 23409716 Chembridge-5861528 23409716 JNJ17203212 23409716 JTS653 23409716 SB705498 23409716 capsaicin 23409716 menthol 23409719 FPP 23409719 Farnesyl diphosphate 23409719 aryl azides 23409719 benzophenones 23409719 diazotrifluoropropionates 23409719 farnesyl diphosphate 23409719 isoprenoid 23409719 isoprenoids 23409719 sesquiterpenes 23409765 phenylalanine 23409765 porphobilinogen 23409765 pyruvate 23409842 (1)H 23409842 (13)C 23409842 (15)N 23409842 Arg 23409842 amide nitrogen 23409842 polyethylene glycol 23409925 5-FU 23409925 FITC 23409925 carboxymethyl 23409925 folate 23409952 Azide 23409952 CaN3(+) 23409952 DMSO 23409952 LiN3 23409952 MgN3(+) 23409952 NH4N3 23409952 NaN3 23409952 azide 23409952 dimethylsulfoxide 23409952 metal azide 23410078 Axistatins 1-3 23410078 agelasine F 23410078 axistatins 1 (1), 2 (2), and 3 (3) 23410078 axistatins 1-3 23410078 diterpenes 23410078 formamide 23410078 formamides 23410078 pyrimidine 23410105 X-NO2 23410105 nitro 23410168 anthracycline 23410168 naphthalimide 23410168 phenylaminopyrimidine 23410172 ARA 23410172 Arachidonic acid 23410172 eicosanoid 23410172 oxylipin 23410634 carbonyl 23410634 glutathione 23410634 hydrogen peroxide 23410634 menadione 23410634 oxygen 23410634 tert-butyl hydroperoxide 23410745 Cholesterol 23410745 creatinine 23410745 uric acid 23411075 Arylglycine 23411075 arylglycine 23411075 icilin 23411076 (99m)Tc 23411076 2-arylbenzothiazoles 23411076 2-phenylbenzothiazole 23411076 Re 23411076 Re 2-arylbenzothiazoles 23411076 rhenium 2-arylbenzothiazoles 23411079 NO 23411079 Steroidal 23411079 longipenane 23411079 longipenane 26-O-β-d-glucopyranoside 23411079 neogitogenin 3-O-α-l-rhamnopyranosyl-(1→2)-O-[β-d-glucopyranosyl-(1→4)]-β-d-galactopyranoside 23411079 nitric oxide 23411079 steroidal 23411079 steroidal saponins 23411082 (1)O2 23411082 Al(3+) 23411082 Al3+ 23411082 Hypocrellin A 23411082 oxygen 23411168 AOT 23411168 diene 23411168 isooctane 23411168 linoleic acid 23411173 Palmitic 23411173 carbohydrates 23411173 linoleic 23411173 oleic 23411173 oxalate 23411173 phytate 23411173 saponin 23411173 stearic 23411175 polyacrylamide 23411175 polyphenol 23411175 polyphenols 23411177 cholesterol oxides 23411177 eicosapentaenoic-docosahexaenoic acid 23411177 polyunsaturated fatty acids 23411177 saturated fatty acids 23411178 1-HOP 23411178 1-hydroxypyrene 23411178 2-NAP 23411178 2-naphthol 23411178 KOH 23411178 l-hydroxypyrene 23411181 1β-acetoxyfuranoeudesm-4(15)-ene 23411181 ABTS 23411181 DPPH 23411181 Isofuranodiene 23411181 MTT 23411181 furanosesquiterpenes 23411182 Ag 23411182 Cu 23411182 Ir 23411182 Ni 23411182 Pt 23411182 Rh 23411182 ascorbic acid 23411182 ascorbic, citric and malic acids 23411182 citric and malic acids 23411183 polyphenols 23411184 acetonitrile 23411184 avermectins 23411185 Iron 23411185 iron 23411185 zinc 23411189 Citrate 23411189 EDTA 23411189 Fe(III) 23411189 ethylenediaminetetraacetic acid 23411189 malate 23411191 Ginsenoside Re 23411191 Ginsenosides 23411191 carbon 23411191 carbons 23411191 diol 23411191 ginsenoside Re 23411191 ginsenosides 23411191 ginsenosides, namely Rg(2), Rg(6) and F(4) 23411191 glucosyl 23411191 lysine 23411191 sugar 23411191 triol 23411194 quinic acid 23411195 PUFA 23411195 polyunsaturated fatty acid 23411199 anthocyanins 23411199 dihydrochalcones 23411199 flavan-3-ols 23411199 flavanones 23411199 flavonols 23411199 hydroxybenzoic acids 23411199 hydroxycinnamic acids 23411199 polyphenol 23411199 polyphenols 23411199 stilbenes 23411206 ammonium sulphate 23411206 dicyandiamide 23411206 melamine 23411206 urea 23411208 doxorubicin 23411208 vitamin E 23411208 α-TOS 23411208 α-Tocopherol 23411208 α-tocopherol 23411208 α-tocopheryl succinate 23411210 6-OHDA 23411210 6-hydroxydopamine 23411210 MDA 23411210 gallic acid 23411210 glutathione 23411210 malondialdehyde 23411210 thiol 23411211 3-MA 23411211 3-methyladenine 23411211 Cannabisin B 23411211 cannabisin B 23411211 rapamycin 23411212 25-hydroxyvitamin D 23411212 25OH-Vit D 23411212 Deuterium 23411212 Vit D 23411212 Vitamin D 23411212 vitamin D 23411213 acetonitrile 23411213 aflatoxin B(1) 23411213 ammonium acetate 23411213 ochratoxin A 23411217 Ara 23411217 Araf 23411217 Gal 23411217 GalA 23411217 GlcA 23411217 Rha 23411219 1,2,3-trioleyl 23411219 1,2-dilinoleoyl-3-oleyl 23411219 1,2-dioleyl-3-palmitoyl 23411219 1-oleoyl-2-linoleoyl-3-linolenoyl 23411219 OLL 23411219 OLLn 23411219 OOL 23411219 OOO 23411219 POO 23411219 dioleoyl linoleoyl 23411219 fatty acid 23411219 heneicosanoic acid 23411219 hexacosanoic acid 23411219 triacylglycerol 23411219 triacylglycerols 23411220 H(2)O(2) 23411220 hydrogen peroxide 23411223 Ag 23411223 Co 23411223 Cr 23411223 Cu 23411223 Mn 23411223 Ni 23411223 Pb 23411223 Rb 23411223 Sr 23411223 V 23411223 Zn 23411232 1,25 dihydroxy vitamin D(3) 23411232 25-hydroxy vitamin D(3) 23411232 Vitamin D(3) 23411232 vitamin D(3) 23411232 vitamin D3 23411236 N-acetylglucosamine 23411236 chitobiose 23411236 chitotriose 23411239 Organophosphorus 23411239 cypermethrin 23411239 diazinon 23411239 fenitrothion 23411239 organophosphorus 23411239 permethrin 23411239 pyrethroid 23411248 zinc 23411250 3-hydroxy-4-nitroso-2,7-naphthalenedisulfonic acid 23411250 Fe(II) 23411250 Fe(III) 23411250 NRS 23411250 polyphenols 23411250 pyrogallic acid 23411252 lutein 23411252 lycopene 23411252 phytoene 23411252 phytofluene 23411252 vitamin A 23411252 zeaxanthin 23411252 α-carotene 23411252 β-carotene 23411252 β-cryptoxanthin 23411255 ascorbate 23411255 ascorbic acid 23411255 carbonyls 23411255 glutathione 23411255 peroxides 23411265 Phytosterols 23411265 Phytosteryl sinapates 23411265 oxygen 23411265 phenolic acids 23411265 phytosterols 23411265 phytosteryl esters of fatty acids 23411265 phytosteryl phenolates 23411265 phytosteryl sinapates 23411265 phytosteryl vanillates 23411265 sinapic or vanillic acid 23411265 vanillates 23411265 vanillic acid 23411265 vinyl vanillate 23411268 (1)H 23411268 1H 23411271 azo 23411271 caffeates 23411271 caffeic and dihydrocaffeic esters 23411271 cysteinyl thiol 23411271 methyl caffeate 23411271 methyl dihydrocaffeate 23411271 thiol 23411272 carbonyl 23411272 carbonyls 23411272 catechin 23411272 glucose 23411272 methylglyoxal 23411272 procyanidins 23411283 Biguanide 23411283 Biguanides 23411283 biguanide 23411283 biguanides 23411283 guanidine 23411283 metformin 23411284 oxygen 23411284 vitamin A 23411284 β-Carotene 23411284 β-carotene 23411306 Allura red 23411306 Azophloxine 23411306 Erythrosine 23411306 Ethanol 23411306 Orange II 23411306 Ponceau 4RC 23411306 Ponceau xylidine 23411306 Sunset yellow 23411306 ammonia 23411306 sulfonate 23411307 Fatty acid 23411307 MUFA 23411307 PUFA 23411307 SFA 23411307 fatty acid 23411307 fatty acids 23411311 C11:0 23411311 C8:0 23411311 SFA 23411311 SFAs 23411311 UFA 23411311 UFAs 23411311 caprylic acid 23411311 dienoic acid 23411311 fatty acids 23411311 p-anisidine 23411311 saturated fatty acids 23411311 sesamol 23411311 unsaturated fatty acids 23411312 5-hydroxymethylfurfural 23411312 ACs 23411312 HMF 23411312 anthocyanin 23411312 anthocyanins 23411312 polyphenols 23411312 sugars 23411314 DPPH 23411314 fatty acids 23411314 fucosterol 23411314 hydroxyl 23411314 mannitol 23411314 nitric oxide 23411314 oleic, arachidonic and eicosapentaenoic acids 23411314 phloroglucinol 23411314 proline 23411314 sterols 23411314 superoxide 23411334 EGCG 23411334 L-5-methyltetrahydrofolate 23411334 catechin 23411334 catechins 23411334 epigallocatechin-gallate 23411334 hydrogen 23411334 l-5-MTHF 23411334 l-5-methyltetrahydrofolate 23411335 ascorbic acid 23411335 natamycin 23411335 sugar 23411340 ascorbic acid 23411340 barium diphenylamine sulphonate 23411340 diphenylamine 23411340 manganese(III) 23411340 manganese(III) sulphate 23411340 vitamin C 23411342 2,2'- azobisisobutyronitrile 23411342 2-vinylpyridine 23411342 HCl 23411342 Pb(II) 23411342 Pb(NO(3))(2) 23411342 acetonitril 23411342 diphenylcarbazone 23411342 ethylene glycol dimethacrylate 23411351 carbaryl 23411351 carbohydrate 23412078 (14)C-glucose 23412078 (3)H-glucose 23412078 Canagliflozin 23412078 Glucose 23412078 acetaminophen 23412078 canagliflozin 23412078 glucose 23412078 sodium 23412396 (35)S 23412396 CP55,940 23412396 JZL184 23412396 Monoacylglycerol 23412396 THC 23412396 [(3)H]SR141716A 23412396 monoacylglycerol 23412396 rimonabant 23412396 Δ(9)-tetrahydrocannabinol 23412992 ATP 23412992 K+ 23412992 Na+ 23412992 NaK 23412992 potassium 23412992 sodium 23412992 steroid 23412992 steroids 23413033 Potassium 23413033 potassium 23413101 nitric oxide 23414252 hydrogen 23414252 methyl 23414433 METH 23414433 dopamine 23414433 methamphetamine 23414802 2-hydroxydiarylamide 23414802 serine 23414841 (99m)Tc 23414841 (99m)TcN-[G3-c(RGDfK)]2 23414841 Arg-Gly-Asp 23414841 G3-c(RGDfK) 23414841 G3=Gly-Gly-Gly 23414841 K=Lys 23414841 [(99m)TcN](+2) 23414841 dithiocarbamate 23414841 f=Phe 23415714 5α-dihydrotestosterone 23415714 Androgen 23415714 DHT 23415714 androgen 23415714 flutamide 23415714 prostaglandin 23415893 2-glucosamine 23415893 glucosamine 23415893 prednisolone 23415893 prednisolone carbamate 23416001 isatin 23416001 ketone 23416001 spirocycles 23416011 Celecoxib 23416011 budesonide 23416011 celecoxib 23416011 nitro 23416011 nitro-substituted 21-ester 23416011 nitro-substituted acylsulfonamide 23416011 nitropheny 23416011 prednisolone 23416070 fatty acid 23416070 glucose 23416115 CGA 23416115 Chlorogenic acid 23416115 chlorogenic acid 23416115 fatty acid 23416115 glucose 23416191 HJC0123 23416191 estrogen 23416192 2-(5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-yl)-4-(coumarin-3-yl)thiazoles 23416192 3-(2-bromoacetyl)coumarins 23416192 5-hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-thiocarboxamides 23416192 cefixime 23416192 indomethacin 23416192 thiosemicarbazide 23416192 trifluoromethyl-β-diketones 23416229 acetylcholine 23416262 oxygen 23416264 2,5-dimethylfuran 23416264 Formaldehyde 23416264 acetaldehyde 23416264 acrolein 23416264 aldehyde 23416264 aldehydes 23416264 formaldehyde 23416264 hydroquinone 23416264 nicotine 23416326 (32)P 23416326 PAH 23416326 PAHs 23416326 nucleotides 23416409 Hg 23416409 HgCl2 23416409 Mercury 23416409 mercuric chloride 23416409 mercury 23416650 urushiol 23416930 rapamycin 23416930 resveratrol 23416930 spermidine 23417420 5α-dihydrotestosterone 23417420 DHT 23417420 androgen 23417717 copper 23417790 Hg 23417790 mercury 23417790 methylmercury 23418006 Catechols 23418006 catechol 23418011 Dha 23418011 Lys 23418011 N-acetylneuraminic acid 23418011 amino acid 23418011 cysteine 23418011 dehydroalanine 23418011 lysine 23418011 pyruvate 23418011 thialysine 23418011 γ-thialysine 23418059 polybrominated diphenylether 23418059 polychlorinated biphenyls 23418087 BPA 23418087 Bisphenol A 23418087 CpG 23418087 bisphenol a 23418087 calcium 23418087 phospho 23418087 sodium 23418674 EtOAc 23418674 berberine 23418859 LY294002 23418859 Salidroside 23418859 dUTP 23418859 salidroside 23418880 (-)-sukhodianine-β-N-oxide 23418880 corydalmine 23418880 corynoxidine 23418880 crebanine N-oxide 23418880 dehydrocorydalmine 23418880 demethylaristofolin C 23418880 denitroaristolochic acid 23418880 methicillin 23418880 palmatine 23418960 CO(2) 23418960 D-α-tocopheryl PEG 1000 succinate 23418960 Gelucire 23418960 PEG 23418960 PGN 23418960 TPGS 23418960 carbon dioxide 23418960 polyethylene glycol 23418960 progesterone 23419007 ketosteroid 23419139 1'-hydroxymidazolam 23419139 4-hydroxymidazolam 23419139 midazolam 23419139 thalidomide 23419143 Au 23419143 Cu 23419143 Pd 23419143 Si 23419143 copper 23419593 K(+) 23419638 2,3,7,8-tetrachlorodibenzodioxin 23419638 Pelargonidin 23419638 TCDD 23419638 anthocyanidins 23419638 aryl hydrocarbon 23419638 cyanidin 23419638 delphinidin 23419638 malvidin 23419638 pelargonidin 23419638 peonidin 23419638 petunidin 23419783 Metformin 23419783 Sulfonylureas 23419783 metformin 23419783 sulfonylurea 23419783 sulfonylureas 23419813 6-carboxy 23419813 PEG 23419813 Polyethylene glycol 23419813 acrylic 23419813 ketoconazole 23419814 fentanyl 23419950 PEG 23419950 hydroxyl 23419950 mannose 23419950 mannoside 23419950 methoxy 23420115 Caffeine 23420115 Theobromine 23420115 caffeine 23420115 methylxanthine 23420115 theobromine 23420400 1,3,5,7-tetranitro-1,3,5,7-tetrazocine 23420400 C-NO(2) 23420400 HMX 23420400 N(3) 23420400 NH(2) 23420400 NHC(NO(2))(3) 23420400 NO(2) 23420400 Trinitromethyl-substituted aminotetrazoles 23420400 nitro 23420400 tetrazole 23420400 trinitromethyl-substituted aminotetrazole 23420471 P3HT 23420471 PCBM 23420471 TiO2 23421331 glucose 23421331 metformin 23421617 LAS-6 23421617 linalool 23421617 phenylethanol 23421617 sodium dodecyl 6-benzene sulfonate 23421714 (M)- and (P)-Bicelaphanol A 23421714 (M)-Bicelaphanol A 23421714 (P)-bicelaphanol A 23421714 Trinorditerpenes 23421714 celaphanol A 23421714 hydrogen peroxide 23421737 15β,16α-dihydroxyl-17βH-bufalin 23421737 3-epi-desacetylcinobufagin 23421737 3-keton-desacetylcinobufagin 23421737 bufadienolide A 23421737 desacetylcinobufagin 23421743 1,2-diacyl-sn-glycero-3-dehydrophenylalanine ester 23421743 ABTS 23421743 CHCl(3) 23421743 Dehydrophenylalanine 23421743 Dorsamin-A 23421743 Ester 23421743 Trolox 23421743 dorsamin-A 23421743 dorsamin-A763, -A737, -A765, -A739, and -A767 23421877 4(R),15-dihydroxyatractylenolide II 23421877 4(R),15-epoxy-13-hydroxyatractylenolide II 23421877 4(R),15-epoxy-1β-hydroxyatractylenolide II 23421877 4(R),15-epoxy-atractylenolide II 23421877 atractylenolide II 23421877 eudesmane 23421877 sesquiterpenoid lactones 23421877 sodium phenobarbital 23422033 AMP 23422033 Resveratrol 23422033 resveratrol 23422034 phenol 23422034 phenols 23422226 2-hydroxy-24-methylenelanostan-1,8-dien-3-one 23422226 6-O-acyl-β-d-glucosyl-β-sitosterol 23422226 Lanostane 23422226 klainedoxalanostenone 23422226 klainedoxasterol 23422226 lanostane 23422226 lanostane triterpenoid 23422226 steroid 23422226 steroids 23422226 tanins 23422226 triterpenoid 23422226 triterpenoids 23422226 xanthine 23422227 chloroform 23422227 sesquiterpenes 23422263 17β-estradiol-2,3-quinone 23422263 17β-estradiol-3,4-quinone 23422263 E2-2,3-Q 23422263 E2-3,4-Q 23422263 cysteinyl 23422263 estrogen 23422263 estrogen quinones 23422263 estrogen-3,4-quinone 23422733 Diclofenac sodium 23422733 PEO 23422733 Soluplus 23422733 polycaprolactone 23422872 peramivir 23423243 acetylsalicylic acid 23423243 warfarin 23423353 Hoechst 33258 23423468 4',6-diamidino-2-phenylindole 23423468 DAPI 23423468 amidine 23423695 glucose 23423695 triglycerides 23423710 5-Aza-2'-deoxycytidine 23423710 Aza-CdR 23423710 MTT 23423942 17β-estradiol 23423942 17β-trenbolone 23423942 estradiol 23423942 trenbolone 23423972 N-nitroso 23423972 hexahydro-1,3,5-trinitro-1,3,5-triazine 23423972 hexahydro-1,3,5-trinitroso-1,3,5-triazine 23423972 hexahydro-1,3-dinitroso-5-nitro-1,3,5-triazine 23423972 hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine 23423972 γ-aminobutyric acid 23424012 MTT 23424012 longicarposides A-I 23424012 oleanane 23424012 saponins 23424012 sugar 23424012 triterpenoid saponins 23424028 Permethrin 23424028 carbon 23424028 permethrin 23424028 pyrethoid permethrin 23424207 3β-hydroxysteroid 23424207 Cadmium 23424207 Cd 23424207 GSH 23424207 RUT 23424207 Rutin 23424207 S 23424207 Se 23424207 Selenium 23424207 cadmium 23424207 glutathione 23424207 lactate 23424207 rutin 23424207 selenium 23424207 superoxide 23424207 testosterone 23424208 3-hydroxy-3-methylglutaryl 23424208 3β-hydroxysterol 23424208 Probucol 23424208 Simvastatin 23424208 Triparanol 23424208 cholesterol 23424208 potassium 23424208 probucol 23424208 simvastatin 23424208 triparanol 23424212 Aspartate 23424212 MTX 23424212 RVT 23424212 Resveratrol 23424212 S 23424212 alanine 23424212 glutathione 23424212 methotrexate 23424212 resveratrol 23424212 thiobarbituric acid 23424212 trans-3,5,4'-trihydroxystilbene 23424213 GSH 23424213 MDA 23424213 NO 23424213 alanine 23424213 aspartate 23424213 bilirubin 23424213 eosin 23424213 glutathione 23424213 hematoxylin 23424213 malondialdehyde 23424213 nitric oxide 23424213 nitrogen 23424213 superoxide 23424213 urea 23425339 Fe(H2O)6(2+) 23425339 Fe(II) 23425339 Fe(III) 23425339 FeCl2 23425339 [FeCl4](-) 23425339 acetone 23425339 iron 23425601 1β, 3β, 21β-trihydroxy-urs-12-en-28-oic acid 23425601 21-oxo-1β, 3β-dihydroxy-urs-12-en-28-oic acid 23425601 3β, 21β-dihydroxy-urs-11-en-28-oic acid-13-lactone 23425601 3β, 7β, 21β-trihydroxy-urs-1-en-28-oic acid-13-lactone 23425601 3β, 7β, 21β-trihydroxy-urs-12-en-28-oic acid 23425601 3β-hydroxy-urs-12-en-28-oic acid 23425601 ursolic acid 23425604 N (2)-ethylidene-dG 23425604 N(2)-ethylidene-dG 23425604 [(13)C2]-acetaldehyde 23425604 [13C2]-Acetaldehyde 23425604 acetaldehyde 23425605 3-hydroxybenzylhydrazine 23425605 MeHg 23425605 calcium 23425605 catecholamine 23425605 dopamine 23425605 methylmercury 23425605 tyrosine 23425605 α-methyltyrosine 23426609 ethosuximide 23426609 lacosamide 23426609 levitiracetam 23426609 phenobarbital 23426609 phenytoin 23426609 tiagabin 23426609 valproic acid 23426609 vigabatrin 23426609 zonisamide 23426718 Paricalcitol 23426718 calcitriol 23426718 paricalcitol 23426718 vitamin D 23426954 (-)-3cis -[2-hydroxyl-4-(1,1-dimethyl-heptyl)phenyl]-trans-4-[3-hydroxyl-propyl] cyclohexan-1-ol 23426954 (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]-pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)-methanone mesylate 23426954 CP55,940 23426954 N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride 23426954 SR141716A 23426954 WIN55,212-2 23426954 alanine 23426954 aspartate 23426954 guanosine 5'-3-O-(thio)triphosphate 23426982 Br 23426982 Methanol 23426982 Nona-BDEs 23426982 PBDEs 23426982 Polybrominated diphenyl ethers 23426982 methanol 23426982 nona-BDE 23426982 nona-BDEs 23426982 octa-BDE 23426982 octa-BDEs 23426982 penta-Br 23426982 phenyls 23426982 tetra-Br 23427007 25-hydroxyvitamin D 23427007 25OHD 23427007 vitamin D 23427007 vitamin D(3) 23427056 creatinine 23427056 glucose 23427063 Disperse Red 1 23427063 poly(methyl metha-acrylate) 23427064 Cd 23427064 cadmium 23427074 1,3- and 1,5-DP 23427074 Dechlorane Plus 23427074 Dechlorane plus 23427074 carbon 23427076 Au 23427076 SiO2 23427088 Titanium dioxide 23427088 pyrophosphate 23427137 4-cyanoresorcinol 23427137 azobenzene 23427850 PDMS 23428155 (pyridin-3-yl) benzoxazinyl-oxazolidinones 23428155 Oxazolidinone 23428155 benzoxazinyl-oxazolidinone 23428155 imidazolidinone 23428155 linezolid 23428155 pyridyl 23428212 2,2,6,6-tetramethylpiperidine-1-oxyl 23428212 Carbon 23428212 TEMPO 23428212 carbon 23428212 graphene 23428212 sodium carboxyl 23428325 brassinosteroid 23428325 brassinosteroids 23428347 Bortezomib 23428347 bortezomib 23428841 Lecithin 23428841 TAM 23428841 Tamoxifen 23428841 Tamoxifen citrate 23428841 lecithin 23428841 tamoxifen 23428841 tamoxifen citrate 23429043 1,2-Benzisothiazolin-3-one 23429043 1,2-benzisothiazolin-3-one 23429043 2634-33-5 23429043 BIT 23429184 Ca(2+) 23429184 N 23429184 PMSF 23429184 lactose 23429184 serine 23429231 N-vinylpyrrolidone 23429231 NVP 23429231 RhodaminB 23429231 poly[acrylonitrile-co-(N-vinylpyrrolidone)] 23429282 avarol 23429282 avarol and its monoacetate 23429282 sesquiterpenoids 23429889 Rosuvastatin 23429889 cholesterol 23429889 rosuvastatin 23429911 7-OH-DPAT 23429911 7-hydroxy-N,N-dipropyl-2-aminotetralin 23429911 dexamethasone 23429911 dopamine 23429911 retinoic acid 23430408 (14)C 23430408 thiamethoxam 23430761 P188 23430761 P407 23430761 hydroxypropylmethyl 23430761 ondansetron 23430761 poloxamers 23432004 Gd 23432004 gadolinium 23432007 (89)Zr 23432007 DFO 23432007 DFO-Bz-NCS 23432007 N-suc-DFO 23432007 desferrioxamine 23432007 lysine 23432061 Ca2+ 23432095 17β-hydroxysteroid 23432095 2'-des-methyl-indomethacin 23432095 5α-dihydrotestosterone 23432095 Indomethacin 23432095 NADP(+) 23432095 androgen 23432095 androgens 23432095 indomethacin 23432095 testosterone 23432151 2-dodecanyl-7-β isopranyl monoscodilone 23432151 2-n-butyloxo-6-β-hydroxy-7-β-isoprenyl ankaflavin 23432151 2-n-undecanyloxo-7-β-isoprenyl ankaflavin 23432151 9H-1-isoprenyl-benzopyran-5-isopropanoic acid-6-ol-6-n-decanoate 23432151 Silica gel 23432151 acetonitrile 23432151 benzopranyl capriate 23432151 carbon tetrachloride 23432151 ethyl acetate 23432151 hordeumflavin B 23432151 n-octadec-8,11-dien-7α-ol-1-oic acid 23432151 shorghumoic acid 23432151 sorghumflavin A 23432151 vulgaredilone 23432203 N 23432203 amino acids 23432203 p-chloroamphetamine 23432203 α-amino 23432335 (Z)-13,15-hexadecadien-2,4-diyn-1-ol 23432335 Montiporic acid D 23432335 montiporic acid D 23432335 polyacetylene alcohol 23432335 polyacetylene carboxylic acid 23432582 BSC 23432582 Bisacylimidoselenocarbamate 23432582 Bisacylimidoselenocarbamates 23432582 phosphatidylserine 23432582 z-VAD-fmk 23432586 Ca(2+) 23432586 Ca2+ 23432586 FK506 23432586 rapamycin 23432586 sirolimus 23432586 tacrolimus 23432587 Aminophosphonate 23432587 aminophosphonate 23432587 aminophosphonic acids 23432587 gadolinium 23432587 phosphonate 23432587 platinum 23432587 rhenium 23432587 samarium 23432587 technetium 23432708 CS 23432708 Carbon monosulfide 23433812 ATP 23433812 arsenate 23433812 dNTP 23434226 Tyr 23434226 tyrosine 23434228 6-bromo-7-hydroxycoumarin 23434228 6-bromo-7-methoxycoumarin 23434228 6-diethylaminocoumarin 23434228 BHC 23434228 BMCM 23434228 DEACM 23434228 cholesterol 23434228 cholesterols 23434228 coumarin 23434322 5-(hydroxy)methylcytosine 23434322 5-carboxylcytosine 23434322 5-formyl 23434322 5-hydroxymethyl 23434322 5-methylcytosine 23434322 caC 23434322 cytosine 23434322 hmC 23434422 Euryspongins A-C 23434422 bicyclic furanosesquiterpene 23434422 dehydroeuryspongin A 23434422 euryspongins A-C 23434422 furan 23434422 sesquiterpenes 23434422 α,β-unsaturated-γ-lactone 23434491 17β-estradiol 23434491 7-ethoxyresorufin 23434491 E2 23434491 KTC 23434491 O 23434491 estrogen 23434491 ketoconazole 23434491 steroid 23434641 1,3,4-oxadiazoles 23434641 2-benzylsulfanyl-nicotinic acid 23434641 5-(2-benzylsulfanyl-pyridin-3-yl)-2-(substituted)-sulfanyl-1,3,4-oxadiazoles 23434641 5-(2-benzylsulfanyl-pyridin-3-yl)-3H-[1,3,4]oxadiazole-2-thione 23434641 C 23434641 H 23434641 N 23434641 ampicillin 23434641 benzothiazole 23434641 haloacetate 23434641 haloalkyl 23434641 morpholine 23434641 rifampicin 23434641 triazole 23434648 C 23434648 LPA 23434669 ATP 23434669 Rapamycin 23434669 rapamycin 23434929 Catecholamine 23434929 Corticosterone 23434929 Somatostatin 23434929 Streptozotocin 23434929 corticosterone 23434929 somatostatin 23434931 oxygen 23434931 tunicamycin 23434934 nucleotide 23435179 acetylcholine 23435179 disulfide 23435356 5-HT 23435356 Serotonin 23435356 Tryptophan 23435615 (R)- and (S)-omeprazole 23435615 (R)-5-hydroxyomeprazole 23435615 (R)-omeprazole 23435615 (S)-5-hydroxyomeprazole 23435615 (S)-omeprazole 23435615 Omeprazole 23435615 omeprazole 23435615 omeprazole sulfone 23435615 racemic omeprazole 23435615 racemic-omeprazole 23435910 DMN 23435910 Sinapic acid 23435910 alanine 23435910 aspartate 23435910 dimethylnitrosamine 23435910 hydroxyproline 23435910 malondialdehyde 23435910 phenylpropanoid 23435910 sinapic acid 23435913 Tadalafil 23435913 acebutolol 23435913 acetonitrile 23435913 formic acid 23435913 tadalafil 23435913 tert-butyl methyl ether 23435916 NO 23435916 Pristimerin 23435916 nitric oxide 23435916 pristimerin 23435916 prostaglandin E2 23435916 quinonemethide triterpenoid 23435942 acetylcholine 23435942 coumarin 23435942 donepezil 23435942 flavonoid 23435942 galantamine 23435942 para-aminobenzoic acid 23435942 pyrrolo-isoxazole 23435942 rivastigmine 23435942 tacrine 23435942 xanthostigmine 23435948 1,5-dicaffeoylquinic acid 23435948 3,4-dicaffeoylquinic acid 23435948 3,5-dicaffeoylquinic acid 23435948 3,5-dicaffeoylquinic acid methyl ester 23435948 3-caffeoylquinic acid 23435948 4,5-dicaffeoylquinic acid 23435948 6-methoxy artemicapin C 23435948 7-methoxy coumarin 23435948 acarbose 23435948 arcapillin 23435948 capillarisin 23435948 chromone 23435948 cirsilineol 23435948 coumarins 23435948 daphnetin 23435948 dicaffeoylquinic acids 23435948 esculetin 23435948 esculin 23435948 flavonoids 23435948 hyperoside 23435948 isorhamnetin 23435948 isorhamnetin 3-glucoiside 23435948 isorhamnetin 3-robinobioside 23435948 isoscopolin 23435948 linarin 23435948 methanol 23435948 phenolic 23435948 quercetin 23435948 scoparone 23435948 scopoletin 23435948 scopolin 23435948 tyrosine 23435948 umbelliferone 23436129 Acamprosate 23436129 GABA 23436129 acamprosate 23436129 gamma-aminobutyric acid 23436129 glutamate 23436266 Allopurinol 23436266 alanine 23436266 allopurinol 23436266 aspartate 23436266 cholesterol 23436266 colchicine 23436266 colchicines 23436266 statins 23436266 uric acid 23436544 Vemurafenib 23436544 vemurafenib 23436791 2-aminothiazole 23436791 2-aminothiazoles 23436791 ATP 23436791 indolyl-pyrrolone 23436791 paclitaxel 23436791 serine 23436791 threonine 23437766 4-(adamantan-1-ylaminomethyl)-benzene-1,3-diol 23437766 amantadine 23437766 benzyl 23437766 rimantadine 23437926 ATP 23437926 CTOP 23437926 Hecogenin 23437926 Hecogenin Acetate 23437926 K(+) 23437926 glibenclamide 23437926 hecogenin acetate 23437926 naloxone 23437926 naltrindole 23437926 nor-BNI 23438500 Br(-) 23438500 Br- 23438500 Pd 23438503 Atomoxetine 23438503 atomoxetine 23438503 methylphenidate 23439033 hydrofluoroether 23439131 PEG 23439131 poly(ethylene glycol) 23439223 cortisol 23439223 estradiol 23439223 steroid 23439223 testosterone 23439241 bupropion 23439241 phenacetin 23439561 NADPH 23439561 PGE2 23439561 Prostaglandin E 23439561 calcium 23439561 prostaglandin E 23439561 prostaglandin E2 23439561 thymidine 23439649 (125)I 23439649 Phe 23439649 oxyester 23439649 thioester 23439660 Aryl hydrocarbon 23439660 androstane 23439660 noroxycodone 23439660 oxycodone 23439660 oxymorphone 23440404 Au 23440404 Au-S-C 23440404 Au-S-C-C 23440404 BDT 23440404 C=C 23440404 gold-1,4-benzenedithiol 23440404 thiol sulfur 23440664 HCl 23440664 Nikkomycin Z 23440664 cGMP 23440956 Graphene 23440956 Lithium 23440956 Si 23440956 Silicon 23440956 graphene 23440956 graphene oxide 23440956 lithium 23441753 Isoniazid 23441753 hydrated poly(N-isopropylacrylamide) 23441753 pNIPAAm 23441753 poly(N-isopropylacrylamide) 23441816 Ca(2+) 23441829 C-H 23441829 C2H4 23441829 C2H6 23441829 C4H10 23441829 C4H8 23441829 V2O5 23441829 V2O5H2 23441829 hydrocarbons 23441829 hydrogen 23441829 n-butane 23441829 oxide 23441843 Bisulfite 23441843 Lig 23441843 Z-Ligustilide 23441843 Z-ligustilide 23441878 Br 23441878 C 23441878 CCl4 23441878 CHBr2 23441878 CHBr3 23441878 CHI2 23441878 CHI3 23441878 H 23441878 I 23441878 halogen 23441878 polyhalomethanes 23442005 3-methylbutanal 23442005 Aliphatic Aldehydes 23442005 C 23442005 aldehyde 23442005 aldehydes 23442005 aliphatic aldehyde 23442005 aliphatic aldehydes 23442005 amino sulfonamide 23442005 carbonyl 23442005 enamine 23442005 proline 23442005 α-chloroaldehydes 23442005 α-methylene 23442025 Fe(CN)(6)(3–) 23442025 H 23442025 H(2)O 23442025 OH(–) 23442025 argon 23442025 methyl 23442151 H 23442151 H2 23442151 H2O2 23442151 NaCl 23442151 Phenol 23442151 Sodium hypochlorite 23442151 benzene 23442151 chlorine 23442151 oxygen 23442151 phenol 23442151 sodium hypochlorite 23442151 •OH 23442197 A-74528 23442197 C30 polyketide 23442197 fredericamycin 23443405 Si 23443405 ZnO 23443405 silicon 23443405 zinc oxide 23443408 O-Ti-O 23443408 TiO2 23443408 Titanium dioxide 23443408 nucleotide 23443408 oxygen 23443408 titanium dioxide 23443628 donepezil 23443628 galantamine 23443628 memantine 23443628 rivastigmine 23443957 PtTFPP 23443957 oxygen 23443957 platinum(ii)-5,10,15,20-tetrakis-(2,3,4,5,6-pentafluorphenyl)-porphyrin 23444256 Emtricitabine 23444256 FTC 23444256 TDF 23444256 Truvada 23444256 emtricitabine 23444256 tenofovir disoproxil fumarate 23444284 nevirapine 23444335 iron 23444335 selenium 23444335 zinc 23444387 NADH 23444387 NADPH 23444387 carbonyl 23444387 haloperidol 23444387 mebendazole 23444387 menadione 23444387 ziprasidone 23444389 ADP 23444389 ATP 23444389 Ca(2)(+) 23444389 Ginsenoside Rb1 23444389 Ginsenosides 23444389 Rb1 23444389 azide 23444389 diazoxide 23444389 ginsenosides 23444389 glucose 23444389 nifedipine 23444389 saponins 23444389 streptozotocin 23444429 poly(ADP-ribose) 23444773 MMC 23444773 cisplatin 23444773 mitomycin C 23444782 alanine 23444782 aspartate 23444782 sibutramin 23444783 Glu 23444783 glutamate 23444785 MDA 23444785 Malondialdehyde 23444785 superoxide 23444833 4,8-diamino-3-hydroxyoctanoic acid 23444833 Asn 23444833 Dhb 23444833 FOHOrn 23444833 Iron 23444833 LySta 23444833 Lystabactins 23444833 Ser 23444833 amino acid 23444833 asparagine 23444833 dihydroxy benzoic acid 23444833 formylated/hydroxylated ornithines 23444833 lystabactins 23444833 lystabactins A, B, and C 23444833 nonproteinogenic amino acid 23444833 serine 23445125 amines 23445125 erythromycin 23445362 Arylazanylpyrazolone 23445362 Cu 23445362 Zn 23445362 arylazanylpyrazolone 23445362 arylazanylpyrazolones 23445362 aryloxanylpyrazolone 23445362 arylsulfanylpyrazolone 23445362 phenol 23445362 pyrazolone 23445362 superoxide 23445497 O-carboxyanhydrides 23445497 Phe-OCA 23445497 PheLA 23445497 camptothecin 23445497 docetaxel 23445497 doxorubicin 23445497 hydroxyl 23445497 paclitaxel 23445497 phenyl O-carboxyanhydride 23445497 poly(O-carboxyanhydride) 23445497 polylactide 23446230 EETs 23446230 arachidonic acids 23446230 epoxyeicosatrienoic acids 23446276 Mg(2+) 23446276 adenine 23446276 urea 23447132 cAMP 23447132 calcium 23447132 nucleotide 23447427 Cu(2+) 23447427 H2 23447427 ZnIn2 S4 23447427 copper 23447427 hydrogen 23447427 sulphide 23447538 serine 23447538 tryptic 23448196 glucose 23448202 cadmium telluride 23448384 2,3-di(2-pyridinyl)pyrazine 23448384 H2ba 23448384 H2ca 23448384 H2fa 23448384 H2xa 23448384 Hfa(-) 23448384 MeOH 23448384 [H(1.5)-dppz]2[Hba]3 23448384 [H-dppz(+)][Hfa(-)] 23448384 [H-dppz(+)][Hfa(-)]·MeOH 23448384 [H-dppz]2[Hba]2[H2ba] 23448384 [H-dppz][Hba] 23448384 [H-dppz][Hca] 23448384 [dppz][H2fa] 23448384 anilic acids 23448384 bromanilic acid 23448384 chloranilic acid 23448384 dppz 23448384 ethanol 23448384 fluoranilic acid 23448384 hydrogen 23448384 methanol 23448620 carbazochrome sodium sulfonate 23448620 tinidazole 23448682 PEG 23448682 dinorbornene 23448682 ene 23448682 norbornene 23448682 tetrazine 23448682 thiol 23448860 Mn 23448860 manganese 23448861 crotonaldehyde 23448861 ethenone 23448861 oxygen 23449201 Lactose 23449201 hydroxypropyl 23449201 hydroxypropyl methyl 23449201 lactose 23449201 polyvinylpyrrolidone 23449205 (3R),(5S)-5-hydroxylasiodiplodin 23449205 (3R)-lasiodiplodin 23449205 (3S),(6R)-6-hydroxylasiodiplodin 23449205 EtOH 23449205 Lasiodiplodin 23449205 lactone 23449220 5-fluoro-2'-deoxyuridine 23449220 FdU 23449220 FdUMP 23449220 deoxythymidine 23450151 Ag 23450151 Cd 23450151 DHLA-PEG 23450151 In 23450151 S 23450151 ZAIS 23450151 Zn 23450151 cadmium 23450151 folate 23450752 4-aryl-1,2,3,4-tetrahydropyrimidines 23450752 4-aryl-1,4-dihydropyridines 23450752 4-aryl-2-oxo-1,2,3,4-tetrahydropyrimidines 23450752 4-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidines 23450752 5,5-dimethyl 23450752 hydrogen 23450752 racemic 4-aryl-1,4-dihydropyridines 23450752 sulfur 23450752 tetraproline 23450777 C 23450777 C3 N4 23450777 Graphitic carbon nitride 23450777 N 23450777 carbon nitride 23450777 graphitic carbon nitride 23450777 hydrogen 23450829 Ti 23450829 TiO2 23451707 QAOs 23451707 sulfated quinazolin-4(3H)-ones 23451758 4-substituted imidazole 23451758 C2-D 23451758 C2-H 23451758 Cu(2+) 23451758 H 23451758 His 23451758 amino acid 23451758 deuterium 23451758 histidine 23451758 hydrogen 23451758 imidazole 23451797 Sesquiterpene Lactones 23451797 alantolides 23451797 racemosalactones A-E 23451797 sesquiterpene lactones 23451797 sesquiterpene latones 23451803 Au 23451803 Fe-PTCDA 23451803 PTCDA 23451803 perylene-3,4,9,10-tetracarboxylic-3,4,9,10-dianhydride 23451823 3'-deoxycapsanthin-5,6-epoxide 23451823 Cryptocapsin-5,6-epoxide 23451823 Cryptocapsinepoxide 23451823 cryptocapsin 23451823 cryptocapsin-5,6-epoxide 23451823 cryptocapsin-5,8-epoxide 23451823 cryptocapsin-5,8-epoxides 23451983 PFCE 23451983 fluorine 23451983 perfluoro-1,5-crown ether 23452042 N 23452042 N-hydroxyarylamine 23452042 NAD(+) 23452042 O 23452042 lysine 23452147 C 23452147 N 23452219 Purine 23452219 Theophylline 23452219 adenine 23452219 caffeine 23452219 guanine 23452219 methyl 23452219 purine 23452219 theophylline 23452254 (R, R)-[(R*PO3)2M5O15](2-) 23452254 (R, R)-[(R*PO3)2W5O15](2-) 23452254 CH3CH(NH3) 23452254 Mo 23452254 POMs 23452254 W 23452254 oxygen 23452254 polyoxometalates 23452254 transition metal 23452855 glutamate 23452855 glycine 23452857 N-methyl-D-aspartate 23452857 NMDA 23452857 serine 23453039 calcium 23453039 cholesterol 23453039 glucose 23453039 streptozotocin 23453039 triglyceride 23453067 2'-C-methyl-6-O-methyl guanosine nucleoside 23453067 2'-C-methyl-6-O-methyl- 23453067 2'-C-methyl-6-O-methylguanosine 23453067 2'-C-methylguanosine 23453067 6-O-methyl 23453067 L-Alanine ester phosphoramidates 23453067 N 23453067 guanine 23453067 guanine nucleosides 23453067 guanosine 23453067 nucleobase 23453067 nucleotide 23453068 4-alkylamino-7-aryl-3-cyanoquinoline 23453068 4-alkylamino-7-aryl-3-cyanoquinolines 23453068 Ser 23453068 leucine 23453303 MDA 23453831 4″-O-β-d-glucosyl-6'-O-(4-O-β-d-glucosylcaffeoyl)-linearoside 23453831 BHT 23453831 DPPH 23453831 Gentiopicroside 23453831 Gentioside 23453831 Gentisin 23453831 Iridoid glucosides 23453831 Isogentisin 23453831 Loganic acid 23453831 Norswertianolin 23453831 SRB 23453831 Sweroside 23453831 Swertiamarin 23453831 Swertianolin 23453831 Swertisin 23453831 catechin 23453831 flavonoid 23453831 flavonoids 23453831 hydroxyl 23453831 iridoid glucosides 23453831 iridoids 23453831 methanol 23453831 secoiridoids 23453831 sulphorhodamine B 23453831 xanthones 23453831 α-tocopherol 23454011 aluminum silicate 23454011 cholesterol 23454011 montmorillonite 23454011 stigmastanol 23454011 vitamin D3 23454011 vitamin D3 and K1 23454011 vitamin K1 23454011 vitamins 23454011 vitamins D3 and K1 23454052 ZnO 23454052 zinc oxide 23454054 IMC 23454054 SAC 23454054 indomethacin 23454054 methanol 23454054 saccharin 23454133 H 23454133 olanzapine 23454133 simvastatin 23454148 5-Fluorouracil 23454148 5-fluorouracil 23454148 Cisplatin 23454148 MMC 23454148 N 23454148 S 23454148 cisplatin 23454148 cysteine 23454148 dihydropyrimidine 23454148 glutathione 23454148 mitomycin C 23454148 prostaglandin E2 23454148 quinone 23454148 xanthine 23454208 N 23454208 bafilomycin A1 23454208 flavonoid 23454208 luteolin 23454297 ADP 23454297 ATP 23454297 Caffeic acid 23454297 adenine nucleotide 23454297 adenosine 23454297 caffeic acid 23454297 nucleoside triphosphate 23454297 nucleotide 23454308 Al(3+) 23454308 alumina 23454308 aluminium oxide 23454309 (15)N 23454309 Hg 23454309 mercury 23454309 methyl 23454310 silver 23454529 LZ-11 23454529 N-(2-(quinazolin-2-yl)phenyl)benzamide 23454529 QPB 23454529 benzofuroquinoline 23454529 hydrogen 23454529 indoloquinoline 23454529 phenyl 23454529 quinazoline 23454648 PAMAM 23454648 Polyamidoamine 23454648 amino 23454648 oxygen 23454648 polyamidoamine 23454829 (2R,3R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside 23454829 8,11,14-eicosatrienoic acid 23454829 CS-1036 23454829 [(14)C]CS-1036 23454829 [14C]CS-1036 23454829 alanine 23454829 amino acid 23454829 amino acids 23454829 aspartic acid 23454829 fatty acids 23454829 glutamic acid 23454829 oleic acid 23454829 palmitic acid 23454829 proline 23455056 amide 23455056 bis(pinacolato)diboron 23455056 boron 23455056 boronate ester 23455056 oleanane 23455056 oleanolic acid 23455056 oleanolic vinyl boronates 23455056 palladium 23455056 triterpenoids 23455056 vinyl triflates 23455057 MTT 23455057 Ru(II) 23455057 [(C6H6)Ru(L)Cl]Cl·2H2O 23455057 arene 23455057 arene ruthenium(II) 23455057 p-BrPIP 23455057 p-CF3PIP 23455057 p-COOHPIP 23455057 p-HOPIP 23455057 p-MeOPIP 23455057 p-NMe2PIP 23455057 phenanthroimidazole 23455229 Au 23455312 Ca(2+ 23455312 Cholane 23455312 HENA 23455312 K(+) 23455312 LCA 23455312 Steroid 23455312 Thr 23455312 lithocholic acid 23455312 sodium 3-hydroxyolean-12-en-30-oate 23455312 steroid 23455314 (3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone 23455314 CIQ 23455314 N-methyl-d-aspartate 23455314 NMDA 23455314 amino 23455373 C18H37 23455373 OSiMe2 23455373 POSS 23455373 Polyhedral oligomeric silsesquioxane 23455373 Q8C18 23455373 T8C18 23455373 octa-n-octadecyloctasilsesquioxane 23455373 octakis(n-octadecyldimethylsiloxy)octasilsesquioxane 23455373 polyhedral oligomeric silsesquioxanes 23455513 O 23455513 carbohydrate 23455995 Spinosad 23455995 spinosad 23455995 λ-cyhalothrin 23456038 (1)H 23456038 (15)N 23456038 amide 23456038 phosphate 23456038 phospho 23456038 serine 23456038 threonine 23456097 N 23456248 amino acid 23456248 nitrogen 23456248 phosphatidylinositol 23456735 glucose 23456814 GSH 23456814 MDA 23456814 deoxyuridine triphosphate 23456814 glutathione 23456814 malondialdehyde 23456814 superoxide 23456816 sodium chloride 23456816 sodium hydroxide 23456892 ALN 23456892 RSG 23456892 Rosiglitazone 23456892 alendronate 23456892 deoxypyridinoline 23456892 rosiglitazone 23457119 MK-801 23457119 N-methyl-d-aspartate 23457119 NMDA 23457119 Scopolamine 23457119 [(18)F]FDG 23457119 [(18)F]fluoro-2-deoxy-d-glucose 23457119 [18F]FDG 23457119 glucose 23458167 silicon 23458385 poly(styrene sulfonate) 23458385 saccharide 23458422 PNB 23458422 Poly(NIPAM-co-BMA) 23458422 poly(N-isopropylacrylamide-co-butyl methacrylate) 23458422 sulfuric acid 23458573 Cocaine 23458573 cocaine 23458575 oxygen 23458617 Nutlin-3 23458617 cis-imidazoline 23458621 silica 23458727 A12 23458727 N-(3-carboxy-4-hydroxyphenyl)-2,5-dimethylpyrrole 23458727 N-(4-carboxy-3-hydroxyphenyl)-2,5-dimethylpyrrole 23458727 NB-2 23458730 Baicalin 23458730 DXM 23458730 baicalin 23458730 dextromethorphan 23458895 NAD(P)H 23458895 STZ 23458895 glucose 23458895 quinone 23458895 streptozotocin 23459146 NaF 23459146 eosin 23459146 estradiol 23459146 hematoxylin 23459146 progesterone 23459146 sodium fluoride 23459146 testosterone 23459233 H+ 23459233 N2 23459233 P 23459233 Phosphorus 23459233 succinate 23460347 PEG-DMA 23460347 poly(ethylene glycol)-dimethacrylate 23460383 1,4-butanediol 23460383 4,4'-methylenebis(phenylisocyanate) 23460383 Polyurethanes 23460383 Undecylenic Acid 23460383 diol 23460383 polyurethanes 23460383 telechelic diols 23460383 undecylenic acid 23461617 (-)-[R,R]- and (+)-[S,S]-1,2-DHD-6-NC 23461617 (-)-[R,R]- and (+)-[S,S]-1,2-Dihydroxy-1,2-dihydro-6-nitrochrysene 23461617 (±)-1,2-DHD-6-NC 23461617 (±)-trans-1,2-dihydroxy-1,2-dihydro-6-nitrochrysene 23461617 1,2-DHD-6-NC 23461617 6-NC 23461617 6-Nitrochrysene 23461617 6-nitrochrysene 23461650 cyanine 23461784 Germanium 23461784 germanium 23461784 lithium 23461784 silicon 23461821 4-aminophenol 23461821 4-nitrophenol 23461821 NaBH4 23461821 Silver 23461821 norbornene 23461821 polyamino oxanorbornenes 23461821 polyguanidino oxanorbornenes 23461821 polynorbornenes 23461821 silver 23461841 aldosterone 23461841 fatty acid 23461841 fatty acids 23461841 glucose 23461841 magnesium oxide 23461841 spironolactone 23461969 Ala 23461969 Arg 23461969 Asp 23461969 Gln 23461969 Glu 23461969 His 23461969 Ile 23461969 Pro 23461969 Trp 23461969 Tyr 23461969 phenyl 23462104 Cholesterol 23462104 cholesterol 23462193 Glucose 23462194 (125)I 23462194 Hoechst 33258 23462194 Iodine 23462194 MTT 23462194 Nevirapine 23462194 iodine 23462194 methly thiazolyl tetrazolium 23462194 nevirapine 23462212 Chebulinic acid 23462212 H(+) 23462212 K(+) 23462212 Sucralfate 23462212 alcohol 23462212 aspirin 23462212 chebulinic acid 23462212 omeprazole 23462213 VPA 23462213 Valproic acid 23462213 fluorescein 23462213 monocarboxylate 23462213 valproic acid 23462281 Thiamine 23462281 nicotinamide adenine dinucleotide phosphate 23462281 thiamine 23462281 tyrosine 23462379 N 23462380 neostigmine 23462505 17β-estradiol 23462505 Estrogen 23462505 bazedoxifene 23462505 estrogen 23462505 fulvestrant 23462505 raloxifene 23462505 tamoxifen 23462666 glucose 23463333 acetonitrile 23463333 formic acid 23463333 hexane 23463333 methanol 23463333 robenidine 23463333 trifluoroacetic acid 23463334 nifedipine 23463334 polyvinyl pyrrolidone 23463334 stearic acid 23463336 acetic acid 23463609 carbon 23463634 graphene 23463732 PFBV 23463732 PMMA 23463732 polyfluorene-bis-vinylphenylene 23463898 daunomycin 23464618 Carbon 23464618 carbon 23464667 Liquiritigenin 23464667 lactate 23464667 liquiritigenin 23464789 PHA 23464789 PHB 23464789 ester 23464789 hydroxyl 23464789 lithium borohydride 23464789 oligo(hydroxyalkanoate)diols 23464789 poly(3-hydroxybutyrate-co-4-hydroxybutyrate) 23464789 poly(3HB-co-4HB) 23464789 poly[(R,S)-3-hydroxybutyrate] 23464789 polyester 23464789 polyhydroxyalkanoates 23464859 silicon 23464990 BDP-G 23464990 BDP-Y 23464990 BODIPY 23464990 O2 23464990 Pt(II) 23464990 PtTPBP 23464990 SiO2 23464990 tetrabenzoporphyrin 23464990 tetraphenyl 23465066 GaS 23465066 MoS2 23465066 PET 23465066 Si 23465066 SiO2 23465066 graphene 23465066 polyethylene terephthalate 23465066 silicon 23465072 A1443 23465072 GABA 23465072 Glutamate 23465072 [(3)H]A1443 23465072 [(3)H]EBOB 23465072 [(3)H]Isoxazoline 23465072 [(3)H]ethynylbicycloorthobenzoate 23465072 avermectin 23465072 chloride 23465072 glutamate 23465072 isoxazoline 23465072 phenyl 23465594 AMP 23465594 Ethanol 23465594 Ser 23465594 Thr 23465594 acetyl CoA 23465594 acyl-CoA 23465594 alanine 23465594 carbohydrate 23465594 ethanol 23465594 fatty acid 23465594 stearoyl CoA 23465594 sterol 23465594 triglycerides 23465612 aspartates 23465612 carboxylic acid 23465612 dihydroisoquinoline 23465612 hydrogen 23466228 (11)C 23466228 1-fluoro-2-nitrobenzene 23466228 N 23466228 Olanzapine 23466228 [(11)C]CH3OTf 23466228 [(11)C]CO2 23466228 [(11)C]Olanzapine 23466228 [11C]olanzapine 23466228 malononitrile 23466228 piperazine 23466228 propionaldehyde 23466231 17α-bromo-21-iodo-3β-acetoxypregn-5-en-20-one 23466231 25-hydroxycholesterol 23466231 Pregna-5,17(20)-dien-21-oyl amides 23466231 [17(20)E]-pregna-5,17(20)-dien-21-oyl amides 23466231 [17(20)Z]- and [17(20)E]-pregna-5,17(20)-dien-21-oyl amides 23466231 [17(20)Z]-pregna-5,17(20)-dien-21-oyl amides 23466231 amide 23466231 sterol 23466231 triglyceride 23466235 Asp 23466235 hydrogen 23466444 oxygen 23466459 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine 23466459 PhIP 23466459 heterocyclic amine 23466459 heterocyclic amines 23466461 FB1 23466461 FB2 23466461 Fumonisins 23466461 fumonisin B1 and B2 23466461 fumonisins 23466461 fumonisins B1 and B2 23466488 NTM 23466488 STZ 23466488 amide 23466488 amino acid 23466488 glucose 23466488 glutathione 23466488 l-glutamine 23466488 malondialdehyde 23466488 nicotinamide 23466488 sitagliptin 23466488 streptozotocin 23466488 stretpozotocin 23466488 sugar 23466874 glucose 23466874 phlorotannins 23466874 polyphenols 23466874 tyrosine 23468099 choline 23468099 glucose 23468310 5,7,4'-trihydroxy-3,6,8-trimethoxyflavone 23468310 Sarothrin 23468310 flavonoid 23468310 sarothrin 23468426 ACV 23468426 AhCV 23468426 AhCaG 23468426 AhCmC 23468426 Fe(II) 23468426 IPN 23468426 Isopenicillin N 23468426 cephalosporin 23468426 cysteinyl 23468426 iron 23468426 isopenicillin N 23468426 lactam 23468426 methylene 23468426 monocyclic hydroxy-lactam 23468426 penicillin 23468426 thioether 23468426 valinyl 23468426 δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine 23468426 δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-S-methylcysteine 23468426 δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-Xaa 23468426 δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-allylglycine 23468426 δ-(L-α-aminoadipoyl)-L-homocysteinyl-D-valine 23469688 8-(Tosylamino)quinoline 23469688 8-(tosylamino)quinoline 23469688 8-TQ 23469688 BAY 11-7082 23469688 LY294002 23469688 U0126 23469781 Imiquimod 23469781 Quinolines 23469781 quinoline 23469781 quinolines 23469781 sitamaquinine 23469924 Androgen 23469924 androgen 23470034 3,7-dioxo-11β-hydroxy-5α-tirucalla-8,24(Z)-dien-26-oic acid 23470034 mastichinoic acid A 23470034 tetracyclic triterpenoid 23470076 amino acid 23470076 cysteine 23470076 cysteinyl 23470080 N 23470080 arginine 23470104 CH 23470104 CH2OH 23470104 CH3OH 23470104 Cl 23470104 Cl2 23470104 H 23470104 HCl 23470104 Hydroxymethyl 23470104 hydroxymethyl 23470105 guanine 23470152 Au(111) 23470152 adamantane 23470152 au(111) 23470152 ferrocene 23470152 ferrocenyl 23470152 phenyleneethynylene 23470152 sulfur 23470152 trithiol 23470280 ISO 23470280 catecholamine 23470280 catecholamines 23470280 dopamine 23470280 glutamate 23470280 isoproterenol 23470359 PFAAs 23470359 carboxylates 23470359 perfluoroalkyl acids 23470359 sulfonates 23470418 BPA 23470418 BPAF 23470418 BPF 23470418 BPZ 23470418 Bisphenol A 23470418 DMBPA 23470418 GSH 23470418 NADPH 23470418 benzene 23470418 bisphenol A 23470418 diphenylmethanes 23470418 glutathione 23470418 para-hydroxy 23470922 NADH 23470922 NADPH 23470922 nicotinamide adenine dinucleotide phosphate 23470922 plastoquinone 23471029 DHA 23471029 EPA 23471029 Mono- and dihydroxy 23471029 Resolvins 23471029 all-cis-4,7,10,13,16,19-docosahexaenoic acid 23471029 all-cis-5,8,11,14,17-eicosapentaenoic acid 23471029 cis-1,4,7,10-undecatetraene 23471029 fatty acid 23471029 mono- and dihydroxy 23471029 mono- and dihydroxy-resolvins 23471029 omega-3 and omega-6 fatty acid 23471029 omega-3 fatty acids 23471029 polyunsaturated fatty acids 23471029 resolvin 23471156 CeO2 23471156 Co3O4 23471156 CuO 23471156 NiO 23471156 ZnO 23471156 metal oxide 23471156 metal oxides 23471156 silver 23471218 oxygen 23471440 propionic acid 23471440 quinolones 23471488 glucose 23471488 lauric acid 23471488 metformin 23471504 Olmesartan medoxomil 23471504 olmesartan 23471504 olmesartan medoxomil 23471539 amino acids 23471561 Anthraquinone 23471561 bis-anthraquinone 23471710 amoxicillin 23471710 carbohydrate 23471710 clarithromycin 23471710 glucose 23471710 omeprazole 23471969 amino acid 23471969 amino acids 23472709 B 23472709 E-H 23472709 Fe-BPh 23472709 Fe-diphosphineborane 23472709 Fe≡NNR2 23472709 H 23472709 H-H 23472709 H2 23472709 Iron aminoimides 23472709 N2 23472709 PhSiH3 23472709 Si-H 23472738 Au25 23472738 SCH2CH2Ph 23472738 [Au25L18](-) 23472738 trialkylacryloylphosphonium salts 23472745 2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid 23472745 2,2-diphenyl-1-picrylhydrazyl 23472745 N,N-dimethyl-p-phenylenediamine dihydrochloride 23472745 anthocyanin 23472745 anthocyanins 23472745 polyphenolic 23472803 Au 23472803 PMMA 23472803 au 23472803 poly(methyl methacrylate) 23472803 polystyrene 23472840 Pluronic F127 23472840 aspirin 23472840 erythromycin 23472840 ibuprofen 23472886 carboxyl 23472886 indenoisoquinoline 23472886 indenoisoquinoline rexinoids 23472886 indenoisoquinolines 23473024 Au 23473024 H2O2 23473024 citrate 23473024 hydrogen peroxide 23473024 poly-l-lysine 23473024 thiols 23473030 Iron 23473030 iron 23473037 leucine 23473037 nitric oxide 23473037 proline 23473444 GdIO 23473444 dopamine sulfonate 23473444 gadolinium 23473444 iron oxide 23473444 iron-oxide 23473664 glutamate 23473681 MAC13243 23473681 S-(4-chlorobenzyl)isothiourea 23473681 thiourea 23473801 ADP 23473801 Hinokitiol 23473801 ODQ 23473801 OH 23473801 SQ22536 23473801 arachidonic acid 23473801 calcium 23473801 hinokitiol 23473801 hydroxyl 23473802 cystine 23473802 disulfide 23473802 sodium 23473804 27-hydroxycholesterol 23473804 27OHC 23473804 7-ketocholesterol 23473804 7KC 23473804 7β-hydroxycholesterol 23473804 7βOHC 23473804 Ca(2+) 23473804 Fura-2 23473804 calcium 23473804 cholesterol 23473804 ellagic acid 23473804 ionomycin 23473804 oxysterol 23473804 oxysterols 23473804 resveratrol 23473804 α-tocopherol 23474013 cocaine 23474217 10-hydroxycamptothecine 23474217 20-deoxycamptothecine 23474217 9-methoxycamptothecine 23474217 camptothecine 23474319 Copper 23474319 Cu 23474319 GSH 23474319 MDA 23474319 S 23474319 carbonyl 23474319 copper 23474319 glutathione 23474319 lactate 23474319 malondialdehyde 23474319 myo-inositol 23474319 reduced GSH 23474319 reduced glutathione 23474319 superoxide 23474320 Cu 23474321 K(+) 23474321 Na(+) 23474323 cholesterol 23474323 creatinine 23474323 polyphenols 23474323 tannins 23474356 4-quinolone-3-carboxylic acid 23474356 C 23474356 Macrolones 23474356 azithromycin 23474356 clarithromycin 23474356 hydrogen 23474356 macrolide 23474356 macrolides 23474356 macrolone 23474356 macrolones 23474356 octanol 23474356 quinolone 23474356 secondary amide 23474357 IPM 23474357 caffeine 23474357 certramide 23474357 certramides 23474357 cortisone 23474357 diclofenac sodium 23474357 ethanol 23474357 isopropyl myristate 23474357 mannitol 23474357 propylene glycol 23474357 salicylic acid 23474357 testosterone 23474382 HMG-CoA 23474382 alcian blue 23474382 simvastatin 23474382 statins 23474386 5-(benzyloxy)pyridin-2(1H)-one 23474386 5-(benzyloxy)pyridin-2(1H)-ones 23474386 amides 23474386 benzoimidazoles 23474441 estradiol 23474645 4,4',4''-tris(carbazol-9-yl)-triphenylamine 23474645 4,4-N,N-dicarbazole-biphenyl 23474645 CBP 23474645 CdS 23474645 CdSe 23474645 TCTA 23474645 TiO2 23474645 ZnS 23474645 titanium dioxide 23474688 C 23474688 Nitrogen 23474688 Pt 23474688 carbon 23474688 graphene 23474688 hydrazine 23474688 nitrogen 23474688 oxygen 23474899 tetrahydropentaazacyclopenta[a]anthracenes 23474899 tetrahydropyrimido[4,5-b]quinolines 23474899 tetrahydroquinolines 23474899 tricyclic pyrimido[4,5-b]quinolines 23474972 NaCl 23474972 carbon 23474972 hydrogen 23475901 Ca(2+) 23475901 Calcium 23475901 calcium 23477344 Carbon 23477344 Proline 23477344 carbon 23477344 proline 23477419 (2-furyl)Map 23477419 (R)-βPro 23477419 (R/S)-βPro 23477419 (ph)Map 23477419 Dmt 23477419 EM-1 23477419 Endomorphin-1 23477419 Forskolin 23477419 Map 23477419 Trp 23477419 cAMP 23477419 endomorphin-1 23477419 morphine 23477419 α-methylene-β-aminopropanoic acids 23477451 Benzofurans 23477451 Isocoumarin 23477451 benzofurans 23477451 hydroisocoumarins 23477451 isocoumarin 23477451 isocoumarins 23477451 penicifuran A 23477451 penicifurans A-D 23477451 penicimarins A-C 23477451 penicimarins D-F 23477623 2,2-diphenyl-1-picrylhydrazyl 23477623 CE-OOH 23477623 DPPH 23477623 Fe(2+) 23477623 Sal B 23477623 cholesteryl ester hydroperoxide 23477623 copper 23477623 phenolic 23477623 salvianolic acid B 23478800 Cucurbitacin I 23478800 N-acetyl l-cysteine 23478800 cucurbitacin I 23478800 guanine nucleotide 23478800 oxygen 23478800 tyrosine 23479193 4-phenyl-5-pyridin-4-yl-2,3-dihydro-3H-1,2,4-triazole-3-thiones 23479193 Mannich bases 23479193 S-alkyl 23479193 celocoxib 23479193 diaryltriazole 23479194 7,8,3',4'-tetrahydroxyflavone 23479194 8-methoxy-7,3',4'-trihydroxyflavone 23479194 Lupinifolin 23479194 lupeol 23479194 lupinifolin 23479194 sterols 23479194 stigmasta-5,22-dien-3-one 23479194 stigmasterol 23479194 triterpenoid 23479194 β-sitosterol 23479194 β-sitosterone 23479318 Cd 23479318 Pb 23479318 cadmium 23479389 [6]-Gingerol 23479389 [6]-gingerol 23479390 2-Phenoxychromones 23479390 2-phenoxychromone 23479390 3'-O-β-D-glucoside 23479390 Peltogynoids 23479390 dichloromethane 23479390 estrogen 23479390 ophioglonin 23479407 Gefitinib 23479407 afatinib 23479407 dacomitinib 23479407 erlotinib 23479407 tyrosine 23479455 5-hydroxytryptamine 23479455 EMD 386088 23479455 clozapine 23479455 ketamine 23479455 serotonin 23479738 Cys 23479738 H2O2 23479738 NO 23479738 S 23479738 S-Nitrosothiols 23479738 S-nitrosocysteine 23479738 S-nitrosoglutathione 23479738 SNO 23479738 SNOs 23479738 cys 23479738 cysteines 23479738 disulfide 23479738 hydrogen peroxide 23479738 nitric oxide 23479738 oxygen 23479738 thiol 23480196 COOH 23480196 HCl 23480196 HNO(3) 23480196 Ni 23480196 carbon 23480279 colchicine 23480279 colchicinoids 23480279 thiocolchicine 23480348 PAH 23480348 Pd 23480348 Pd icosahedra 23480348 Polyallylamine 23480348 Pt black 23480348 ethanol 23480348 oxygen 23480348 palladium icosahedra 23480446 amino acid 23480446 amino acids 23480446 aromatic amino acids 23480446 hydrogen 23480446 phenylalanine 23480446 tryptophan 23480446 tyrosine 23480532 lactose 23480532 lactose monohydrate 23480597 polyamine 23480798 2F-ethanol 23480798 Cl 23480798 F 23480798 OCCF 23480798 carbon tetrachloride 23480798 cl 23480798 ethanol 23480798 f 23480798 hydrogen 23480798 o-h 23480798 phenol 23480798 trihydrate 23480848 2D 23480848 Fe(II) 23480848 Fe-NO 23480848 NO 23480848 Na2[Fe(CN)5NO]·2H2O 23480848 Nitrosyl 23480848 SNP 23480848 cyanide 23480848 deuterium oxide 23480848 dimethyl sulfoxide 23480848 ethanol 23480848 ethylene glycol 23480848 formamide 23480848 heme 23480848 methanol 23480848 nitric oxide 23480848 nitrosyl 23480848 sodium nitroprusside 23480848 trans-CN 23481139 Nicotinic acid 23481139 TBTU 23481139 nicotinic acid 23481236 DAGs 23481236 Ser 23481236 TAGs 23481236 ceramides 23481236 diglycerides 23481236 fatty acids 23481236 glucose 23481236 palmitic and stearic acids 23481236 phosphatidylinositol 23481236 serine 23481236 triglycerides 23481236 tyrosine 23481236 wortmannin 23481281 Aphanamgrandiol A 23481281 bicyclo[3,2,1]octane 23481281 carbon 23481281 triterpenoid 23481650 5-azaindole 23481650 7-azaindole 23481650 N-substituted azaindoles 23481650 azaindole 23481650 indole 23481677 Chloroazaphilones 23481677 Helicusin E 23481677 Isochromophilone X 23481677 Isochromophilone XI 23481677 bartanolide 23481677 chloroazaphilones 23481677 deacetylsclerotiorin 23481677 helicusin A 23481677 helicusin E 23481677 isochromophilone X 23481677 isochromophilone XI 23481677 pentaketide 23483327 cadmium 23483327 phenanthrene 23484490 Carbon 23484490 carbon 23484546 acetylene 23484546 graphene 23484546 hydrocarbon 23484546 hydrogen 23484622 Benzo[a]pyrene 23484622 ZnO 23484622 benzo[a]pyrene 23484622 oxygen 23484622 p-benzoquinone 23484622 zinc oxide 23484851 Asp 23484851 Phe 23484851 aspartic acid 23484851 phenylalanine 23484851 pyrene 23484974 quartz 23485065 dopamine 23485151 Ca(2+) 23485151 H(+) 23485151 H+ 23485151 Li(+) 23485151 LiCl 23485441 ADP 23485441 NAD(+) 23485441 Poly(ADP-ribose) 23485441 amino acid 23485441 ribose 23485441 ribosyl 23485450 DOX 23485450 Fe 23485450 PEG 23485450 acylhydrazone 23485450 doxorubicin 23485450 iron-oxide 23485450 poly(ethylene glycol) 23485613 Gossypol 23485613 gossypol 23485991 N 23485991 disulfide 23485991 hydrogen peroxide 23485991 methyl viologen 23486187 Trp 23487486 MPA 23487486 medroxyprogesterone 23487486 medroxyprogesterone acetate 23487486 progesterone 23487486 progestin 23487486 steroids 23488728 Si(111) 23488728 amine 23488728 ascorbic acid 23488728 carbon 23488728 citrate 23488728 oxide 23488728 silicon 23488739 H2O 23488739 diamond 23488739 dimethylsulfoxide 23488739 ethylene glycol 23488739 glycidol 23488739 hydrogen 23488739 octane 23488739 oleic acid 23488739 poly(glycidol) 23488739 toluene 23488748 hydrogen 23488987 6-Aminoquinoline 23488987 6-Nitroquinoline 23488987 6-aminoquinoline 23488987 6-hydroxylaminoquinoline 23488987 6-nitroquinolin-2(1H)-one 23488987 6-nitroquinoline 23488987 Nitroaryl 23488987 amino 23488987 hydroxylamino 23488987 nitroaryl 23488987 nitroso 23488987 oxygen 23488987 xanthine 23489135 1,2,4,5-tetraoxane 23489135 1,2,4-trioxane 23489135 1,2,4-trioxolane 23489135 1,2,4-trioxolanes 23489135 1,2-dioxolane 23489135 OZ277 23489135 OZ439 23489135 dioxolanes 23489135 dispiro ozonides 23489135 ozonides 23489135 peroxides 23489135 tetraoxane 23489135 trioxane 23489135 trioxolane 23489301 aloglipin 23489301 alogliptin 23489301 metformin 23489301 sulfonylureas 23489301 thiazolidinediones 23489623 (R)-Bgugaine 23489623 (R)-norbgugaine 23489623 bgugaine 23489623 norbgugaine 23489623 pyocyanin 23489623 pyrrolidine alkaloid 23489624 MTT 23489629 11β-hydroxysteroid 23489629 N-(Pyridin-2-yl) arylsulfonamide 23489629 N-(Pyridin-2-yl) arylsulfonamides 23489629 N-(pyridin-2-yl) arylsulfonamides 23489629 PF-915275 23489629 glutathione 23489976 Cortisol 23489976 cortisol 23490078 Haloalkane 23490078 asparagine 23490078 carbon 23490078 halide 23490078 haloalkane 23490078 halogen 23490078 hydrogen 23490078 tryptophan 23490078 tryptophans 23490078 tyrosine 23491602 5'-phosphate 23491602 Mn(2+) 23491602 amino acid 23492810 17β-estradiol 23492810 VTG 23492810 fadrozole 23492810 vitellogenin 23493317 adenosine-3',5'-cyclic monophosphate 23493317 cAMP 23493317 glucose 23493317 nucleotide 23493374 (m)CpG 23493374 (m)CpGs 23493374 5-aza-2'-deoxycytidine 23493374 CpG 23493374 bisulfite 23493374 glucose 23493374 methyl 23493374 trichostatin A 23493449 Indole 23493449 N-Hydroxycinnamamide 23493449 N-hydroxycinnamamide 23493449 SAHA 23493449 indole 23494106 AM-694 23494106 JWH-018 23494106 JWH-073 23494106 JWH-122 23494106 JWH-210 23494106 benzoylindole 23494106 cannabinoid 23494106 cannabinoids 23494106 naphthoylindole 23494106 tetrahydrocannabinol 23494232 AMPA 23494232 Ketamine 23494232 SCH23390 23494232 alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 23494232 dopamine 23494232 ketamine 23494233 1-(2-[trifluoromethyl]phenyl) imidazole 23494233 1400W 23494233 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide 23494233 Carboxy-PTIO 23494233 Ethanol 23494233 L-NAME 23494233 L-arginine 23494233 N (G)-nitro-L-arginine methyl ester 23494233 N-([3-(aminomethyl)phenyl]methyl) ethanimidamide dihydrochloride 23494233 NO 23494233 Nitric oxide 23494233 TRIM 23494233 carboxy-PTIO 23494233 ethanol 23494233 nitric oxide 23494732 ABG 23494732 Ascorbigen 23494732 eosin 23494732 hematoxylin 23494732 indole 23494763 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium 23494763 MTT 23494763 Safranal 23494763 propidium iodide 23494763 safranal 23494802 Curcuminoid 23494802 Curcuminoids 23494802 curcuminoid 23494802 curcuminoids 23494810 (R)- and (S)-nicotine 23494810 (S)-nicotine 23494810 (S)-nornicotine 23494810 N 23494810 Nicotine 23494810 Nornicotine 23494810 nicotine 23494810 pyridyl 23494810 pyrrolidyl 23494831 2-hydroperoxycoelenterazine 23494831 C2(-) 23494831 Ca(2+) 23494831 Coelenterazine 23494831 His 23494831 N7 23494831 Oxygen 23494831 coelenterazine 23494831 oxygen 23494831 peroxy 23494834 Graphene 23494834 graphene 23495001 Cholesterol 23495001 Glucosinolates 23495001 cholesterol 23495001 glucosinolates 23495001 isothiocyanates 23495151 H 23495151 H(2)O 23495151 H(3)O(+) 23495151 O 23495151 hydronium 23495161 acarviostatins 23495161 acarviostatins III0(-1) and III23 23495163 C 23495163 carbon 23495163 hexane 23495163 n-alkanes 23495163 nonacosan-10-ol 23495190 Artemisinin 23495190 Artemisinins 23495190 artemisinin 23495190 polypyrrole 23495719 HMF 23495719 furfural 23495719 hydroxymethyl furfural 23495769 Ag 23495769 Au 23495769 silver 23495911 Chromium 23495911 chromium 23496305 fluorescein 23496349 W3 23496349 W3(-) 23496349 W3(2-) 23496349 W3O 23496349 W3O(-) 23496349 W3O2 23496349 W3O2(-) 23496349 W3Ox(-) 23496349 W3Ox(-/0) 23496349 oxygen 23496349 tritungsten 23496349 tritungsten oxide 23496412 Calcium Carbonate 23496412 Kaolinite 23496412 calcium carbonate 23496412 kaolinite 23496412 metal oxide 23497227 1H 23497227 Alkylideno/arylideno-bis-ureas 23497227 N-Aryl pyrido-quinazolines 23497227 pyrido-quinazolines 23497227 tyrosine 23497860 astaxanthin 23497860 canthaxanthin 23497860 lutein 23497860 β-carotene 23497864 (8R)-piperitone-4-en-9-O-β-d-glucopyranoside 23497864 1-O-β-d-(4-hydroxybenzoyl)glucose 23497864 6'-O-β-glucopyranosylalbiflorin 23497864 albiflorin 23497864 formic acid 23497864 methanol 23497864 monoterpene glycosides 23497864 oxypaeoniflorin 23497864 paeoniflorin 23497864 phenolic and monoterpene glycosides 23497864 phenolic glycoside 23497864 pyridylpaeoniflorin 23497864 β-gentiobiosylpaeoniflorin 23497866 ethanol 23497866 flavonoids 23497866 isorhamnetin 23497866 kaempferol 23497866 quercetin 23497867 Ser 23497867 Thr 23497875 DPPH 23497875 Fe 23497875 FeEDTA 23497875 ascorbate 23497875 iron 23497875 nitrate 23497876 Al(13) 23497876 Al(3+) 23497876 NADH 23497876 alcohol 23497876 carbon 23497876 ethanol 23497876 graphene oxide 23497876 reduced nicotinamide adenine dinucleotide 23497876 tridecameric aluminium 23497878 cholesterol 23497878 ethyl-acetate 23497879 AαC 23497879 HCAs 23497879 MeAαC 23497879 Trp-P-1 23497879 Trp-P-2 23497881 alcohols 23497881 esters 23497881 l-malic acid 23497882 DEAE 23497882 Trolox 23497882 galactose 23497882 glucose 23497882 mannose 23497882 oxygen 23497887 H2O2 23497887 ROOH 23497887 carbonyl 23497887 carnosine 23497887 hydrogen peroxide 23497887 organic peroxides 23497887 peroxide 23497887 peroxides 23497887 vitamin E 23497894 1,1-diphenyl-2-picryl-hydrazyl 23497894 SCFA 23497894 hydroxyl 23497894 n-butyric acid 23497894 propionic acid 23497894 short-chain fatty acid 23497894 superoxide 23497896 Citral 23497896 citral 23497896 polyoxyethylene alkylether 23497898 phosphatidylcholine 23497908 mercury 23499236 enoyl 23499236 rhodanine 23499237 UDP 23499237 UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine 23499237 amino acid 23499237 hydroxamate 23499237 zinc 23499237 α-amino acid 23499664 5-HT 23499664 Duloxetine 23499664 F2695 23499664 LVM 23499664 Levomilnacipran 23499664 duloxetine 23499664 milnacipran 23499664 norepinephrine 23499664 serotonin 23499664 venlafaxine 23499758 Raloxifene 23499758 UDP 23499758 amino acid 23499758 mycophenolic acid 23499758 raloxifene 23499823 (4'R)- and (4'S)- 2'-{[(E)-3β-hydroxyandrost-5-en-17-ylidene]-methyl} oxazolines 23499823 (4'R)- and (4'S)- 4'-substituted 2'-{[(E)-androst-5-en-17-ylidene]-methyl}oxazolines 23499823 (D)-serine methyl ester 23499823 (L)-serine methyl ester 23499823 17α-bromo-21-iodo-3β-acetoxypregn-5-en-20-one 23499823 4'-hydroxymethyl 23499823 4'-methoxycarbonyl 23499823 amides 23499823 methyl 2'-{[(E)-3β-acetoxyandrost-5-en-17-ylidene]methyl}-(4'R)-4',5'-dihydro-1',3'-oxazole-4'-carboxylate 23499823 methyl 2'-{[(E)-3β-acetoxyandrost-5-en-17-ylidene]methyl}-(4'S)-4',5'-dihydro-1',3'-oxazole-4'-carboxylate 23499823 methyl N-[3β-acetoxy-21-oxopregna-5,17(20)-dien-21-yl]-(D)-serinate 23499823 methyl N-[3β-acetoxy-21-oxopregna-5,17(20)-dien-21-yl]-(L)-serinate 23499925 N 23500061 deoxycholic acid 23500061 polyethyleneimine 23500061 tyrosine 23500065 Lys 23500065 proanthocyanidin 23500115 (1)H 23500115 (31)P 23500115 Ketoprofen 23500115 ketoprofen 23500115 phosphate 23500335 BPA 23500335 Bisphenol A 23500335 bisphenol A 23500335 epoxy 23500335 estradiol 23500335 polycarbonate 23500335 tyrosine 23500411 OH 23500411 hecogenin acetate 23500411 ritterazine G 23500537 BHT 23500537 EDTA 23500537 Oxyphytosterol 23500537 Trolox 23500537 butylated hydroxytoluene 23500537 campesterol 23500537 copper 23500537 iron 23500537 oxycampesterol 23500537 oxyphytosterol 23500537 oxyphytosterols 23500537 oxysitosterol 23500537 sitosterol 23500537 stanol 23500537 stanol ester 23500537 sterol 23500537 sterol esters 23500537 α-tocopherol 23500547 cholesterol 23500550 C 23500550 N 23500768 Astaxanthin 23500768 astaxanthin 23500768 bleomycin 23500768 hydroxyproline 23500770 DON 23500770 deoxynivalenol 23500772 EtOH 23500772 MDA 23500772 ethanol 23500772 glucose 23500778 BSO 23500778 Hirsutenone 23500778 MTT 23500778 N-methyl-d-aspartate 23500778 NMDA 23500778 SNP 23500778 dUTP 23500778 glutamate 23500778 hirsutenone 23500778 l-buthionine-(S,R)-sulfoximine 23500778 propidium iodide 23500778 sodium nitroprusside 23501108 2-pyridyl hexahydrocycloocta [4,5]thieno[2,3-d]pyrimidines 23501108 2-pyridyl hexahyrocyclooctathieno[2,3-d]pyrimidine 23501108 doxorubicin 23501109 14-O-[(2-aminobenzamide-2-methylpropane-2-yl) thioacetate] mutilin 23501109 14-O-[(4-aminobenzamide-2-methylpropane-2-yl) thioacetate] mutilin 23501109 14-O-[(4-methoxybenzamide-2- methylpropane-2-yl) thioacetate] mutilin 23501109 methicillin 23501109 pleuromutilin 23503472 Cyclosporine 23503472 cyclosporine 23503923 PAA 23503923 PLGA 23503923 poly(acrylic acid) 23503923 poly(lactide-co-glycolide) 23503927 (8S,9R)-tert-butylcarbamoylquinine 23503927 DNB 23503927 K(+) 23503927 Leu 23503927 Li(+) 23503927 N-3,5-dinitrobenzoyl-(S,R)-leucine 23503927 Na(+) 23503927 R-Leu 23503927 S-Leu 23503927 S/R-leucine 23503927 [tBuCQN·DNB-R-Leu·Li](+) 23503927 [tBuCQN·DNB-S-Leu·Li](+) 23503927 [tBuCQN·DNB-S/R-Leu·Na](+) 23503927 carboxylate 23503927 lithium 23503927 potassium 23503927 sodium 23503927 tBuCQN 23504247 1,3,4-benzotriazepin-5-one 23504247 2-amino-1,3,4-benzotriazepin-5-one 23504247 asperlicin 23504247 devazepide 23504356 fenfluramine 23504356 oxytocin 23504645 SO2 23504645 benzene 23504923 BMS-690514 23504923 Ketoconazole 23504923 Tyrosine 23504923 ketoconazole 23505091 oxygen 23505146 N 23505146 glucose 23505146 mannose 23505344 CO 23505344 H2O 23505344 Leu 23505344 Xe 23505344 Xe2 23505344 Xe3 23505344 Xe4 23505344 histidine 23505344 xenon 23506052 (2,2,6,6-tetramethylpiperidin-1-yl)oxyl 23506052 1,2-dioleoyl-sn-glycero-3-phosphocholine 23506052 1,2-dipalmitoyl-sn-glycero-3-phosphocholine 23506052 1,6-diphenyl-1,3,5-hexatriene 23506052 6-lauroyl-2-dimethylamino naphthalene 23506052 DOPC 23506052 DPH 23506052 DPPC 23506052 Laurdan 23506052 TEMPO 23506052 cholesterol 23506073 FMN 23506073 N-ethylmaleimide 23506073 carbonyl 23506073 disulphide 23506073 glyoxal 23506073 glyoxals 23506073 quinones 23506497 calcium 23506497 catecholamines 23506497 dobutamine 23506497 istaroxime 23506497 ivabradine 23506497 levosimendan 23506497 norepinephrine 23506497 omecamtiv mecarbil 23506497 oxygen 23506497 pyruvate 23506497 succinate 23506741 1-ethyl-5-methyl-2-phenyl-1H-benzo[d]imidazole 23506741 Fc11a 23506741 Fc11a-2 23506741 benzo[d]imidazole 23506741 sodium 23506741 sulfate 23507565 cocaine 23507565 heroin 23507573 tyrosine 23508304 glucose 23508887 5-hydroxymethylcytosine 23508887 5-methylcytosine 23508961 cholesterol 23508961 leupeptin 23509039 (4-biphenyl-4-ylthiazol-2-yl)-(6-methylpyridin-2-yl)-amine 23509039 (6-methylpyridin-2-yl)-[4-(4-pyridin-3-yl-phenyl)thiazol-2-yl]amine 23509039 2-aminothiazoles 23509039 aminothiazole 23509039 cyclopropanecarboxylic acid (4-biphenylthiazol-2-yl)amide 23509853 CF3COO(-) 23509853 CF3COOH 23509853 Copper(II) 23509853 Cu(I) 23509853 Cu(II) 23509853 Dioxygen 23509853 H2O2 23509853 Hydrogen Peroxide 23509853 O2 23509853 PV-tmpa 23509853 [(PV-tmpa)Cu(II)](ClO4)2 23509853 [(tmpa)Cu(II)](ClO4)2 23509853 acetone 23509853 bis(pyrid-2-ylmethyl){[6-(pivalamido)pyrid-2-yl]methyl}amine 23509853 copper 23509853 decamethylferrocene 23509853 decamethylferrocenium 23509853 pivalamido 23509853 tmpa 23509853 trifluoroacetic acid 23509853 tris(2-pyridylmethyl)amine 23509904 aspartyl 23510192 nucleotide 23510192 phosphate 23510479 poly(1,2-butadiene) 23511016 DOTA 23511016 Gd 23511016 Gd(3+) 23511016 pantoprazole 23511018 (+)-lycoricidine 23511022 DMP(V)TPP 23511022 P(V)porphyrin 23511022 amino acid 23511022 dimethoxyP(V)tetraphenylporphyrin chloride 23511022 dimethoxyphosphorus(V) tetraphenylporphyrin 23511022 oxygen 23511022 porphyrin 23511022 sodium azide 23511022 tryptophan 23511088 alkylphenones 23511088 butoxy 23511125 Donepezil 23511125 acetylcholine 23511125 donepezil 23511125 glutamate 23511125 mecamylamine 23511125 methyllycaconitine 23511311 glucose 23511711 Ketoconazole 23511711 Midazolam 23511711 ketoconazole 23511711 midazolam 23511718 PEG 23511718 polyethylene glycol 23512337 PAA 23512337 polyamidoamine 23512337 polyethyleneimine 23512409 Polythiophene 23512409 polythiophene 23512438 alphamethrin 23512438 citric and acetic acids 23512438 endosulfan 23512438 gluconic acid 23512438 imidacloprid 23512438 monocrotophos 23512438 phosphate 23512438 phosphorus 23512754 1-Cinnamoyl-3,11-Dihydroxymeliacarpin 23512754 1-cinnamoyl-3,11-dihydroxymeliacarpin 23512754 CDM 23512754 MTT 23512824 2,4-dinitrophenyl 23512824 Ac4 GlcNAz 23512824 DNP 23512824 azide 23512824 azides 23512824 peracetylated N-azidoacetylglucosamine 23512824 phosphines 23512927 DOX 23512927 Doxorubicin 23512927 PEG-b-P(S-co-PPSEMA) 23512927 PPSEMA 23512927 doxorubicin 23512927 poly(ethylene glycol)-b-poly[styrene-co-(2-(1,2,3,4,5-pentaphenyl-1H-silol-1-yloxy)ethyl methacrylate)] 23514378 5-HT 23514378 serotonin 23514599 4-(1-methyl-1H-pyrrol-3-yl)benzenamine 23514599 Biaryl 23514599 KMR-28-39 23514599 MPB 23514599 PBD 23514599 PBD-MPB 23514599 Pyrrolobenzodiazepine 23514599 pyrrolo[2,1-c][1,4]benzodiazepine 23515282 cholesterol 23515497 Aroclor 1221 23515497 PCB 180 23515497 PCBs 23515497 endosulfan 23515497 formaldehyde 23515497 mirex 23515497 oestradiol 23515497 organochlorinated 23515497 polychlorinated biphenyls 23515582 Escitalopram 23515582 escitalopram 23515582 serotonin 23515934 5-HT 23515934 Oleanolic acid 23515934 acetic acid 23515934 formalin 23515934 glutamate 23515934 methysergide 23515934 naloxone 23515934 oleanolic acid 23515934 yohimbine 23517008 carbon 23517008 graphene 23517008 graphite 23517010 Au 23517028 Arylpiperazine 23517028 arylpiperazine 23517028 indole 23517028 quinoline 23517093 FR901464 23517093 Thailanstatins 23517093 Thailanstatins A, B, and C 23517093 carboxyl 23517093 hydroxyl 23517093 phosphate 23517093 thailanstatins 23517126 1β-p-coumaroyloxypolygodial 23517126 1β-p-hydroxy-E-cinnamoyl-5α-hydroxydrimeninol 23517126 1β-p-hydroxy-E-cinnamoyldrimeninol 23517126 3'-deoxyisozygolone A 23517126 4'-O-methylzygolone A 23517126 Sesquiterpenoids 23517126 Tetralones 23517126 calothyrlone A 23517126 cinnamolide 23517126 isozygolone A 23517126 methyl ether of 1β-p-hydroxy-E-cinnamoyl-12α-methoxydrimeninol 23517126 sesquiterpenoids 23517126 tetralones 23517126 zygolone A 23517145 11α-hydroxy-3,7-dioxolanost-8,24(E)-dien-26- oic acid 23517145 15-O-acetylganolucidate A 23517145 3,11,15,23-tetraoxo-27ξ-lanosta-8,16-dien-26-oic acid 23517145 3,7,11-trioxo-5α-lanosta-8,24(E)-dien-26-oic acid 23517145 3-(4-methoxy-2-oxo-2H-pyran-6-yl)propanoic acid 23517145 5-hydroxy-5-(methoxymethyl)-4-methylfuran-2(5H)-one 23517145 Lactone 23517145 Lanostanoids 23517145 NO 23517145 ethyl 3,7,11,12,15,23-hexaoxo-5α-lanost-8-en-26-oate 23517145 ethyl lucidenate A 23517145 ethyl lucidenate F 23517145 lactone 23517145 lanostanoids 23517145 methyl 3,7,11,12,15,23-hexaoxo-5α-lanost-8-en-26-oate 23517379 2,5-dialkoxy-phenylene-thienylene 23517379 graphene 23517379 thiophene 23517470 Ca(2+) 23517474 Amides 23517474 Ca(2+) 23517474 K(+) 23517474 Li(+) 23517474 Mg(2+) 23517474 Na(+) 23517474 amide 23517474 amide carbonyl oxygen 23517474 amides 23517474 butyramide 23517474 chloride 23517541 N(ω)-hydroxy-nor-L-arginine 23517541 nor-NOHA 23517546 (Ga,Mn)As 23517546 Ga 23517546 GaAs 23517546 Mn 23517546 Si 23517546 Zinc-Blende 23517546 zinc-blende 23517565 N-Methyldihydroquinazolinone 23517565 dihydroquinazolinone 23517621 2,2,6,6-Tetramethylpiperidine-1-oxyl 23517621 Nitroxide 23517621 TEMPO 23517621 glutathione 23517621 oxygen 23517636 17-hydroxyprogesterone 23517636 DHEA-S 23517636 Testosterone 23517636 androgen 23517636 androstenedione 23517636 dehydroepiandrosterone sulfate 23517729 2,7,12-tris(α-pyridinio-p-tolyl)-17-(p-(methoxymethyl)phenyl) porphycene 23517729 Py3MeO-TBPo 23517729 oxygen 23517729 porphycene 23517729 sodium azide 23518155 N 23518155 cAMP 23518155 glucose 23518321 Acetaminophen 23518321 H2O2 23518321 HOCl 23518321 acetaminophen 23518321 glutathione 23518321 phorbol myristate acetate 23518599 (R2O3)x(R'2O3)y(P2O5)1-(x+y) 23518599 Ce 23518599 Er 23518599 La 23518599 Nd 23518599 O 23518599 P 23518599 P-O 23518599 RP3O9 23518599 RP5O14 23518599 Rare-earth 23518599 metaphosphate 23518599 rare-earth 23518599 rare-earth phosphate 23518599 ultraphosphate 23518857 C-HF 23518857 CH2F2H2CO 23518857 CH2O 23518857 FCF 23518857 difluoromethane 23518857 formaldehyde 23518857 hydrogen 23519059 acetylacetonate 23519059 bis(4,6-difluorophenyl) pyridinato-N,C [dfppy] iridium(iii) 23519059 iridium(iii) 23519059 picolinate 23519059 pyridylpyrazolate 23519153 Copper 23519153 Fe 23519153 S-adenosylhomocysteine 23519153 adenosylhomocysteine 23519153 copper 23519153 iron 23520074 (125) I 23520074 C 23520074 N 23520074 amino 23520074 phospho 23520074 serine 23521014 Carbon 23521014 carbon 23521318 α-terpineol 23521360 3,4'-dimethoxy-7-O-β-(6″-galloyl-glucopyranoside) quercetin 23521360 3-methoxy-7-O-β-(6″-galloylgluco-pyranoside) kaempferol 23521360 3-methoxy-7-O-β-(6″-galloylgluco-pyranoside) quercetin 23521360 ethyl acetate 23521360 flavonols 23521360 methylated flavonol glucosides 23521567 1,2-dipalmitoyl-sn-glycero-3-phosphocholine 23521567 DPPC 23522182 AZD1656 23522182 glucose 23522564 C 23522564 Ile 23522564 N 23522564 amino acid 23522564 cholesterol 23522564 lysine 23522833 Cu(OTf)2 23522833 isatin 23522833 kojic acid 23522833 methylenes 23522833 spiro[indoline-3,4'-pyrano[3,2-b]pyran 23522833 spiropyrano[3,2-b]pyran-4(8H)-ones 23523142 Ginkgetin 23523142 Z-DEVD-fmk 23523142 biflavonoid 23523142 ginkgetin 23523258 1'-hydroxy midazolam 23523258 Sch B 23523258 Schisandrin B 23523258 ketoconazole 23523258 midazolam 23523546 ITZ 23523546 Itraconazole 23523546 itraconazole 23523546 mannitol 23523557 HC 030031 23523557 cyclophosphamide 23523780 Ca(2+) 23523780 bicuculline 23523781 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 23523781 3,4-dihydroxyphenylacetic acid 23523781 DOPAC 23523781 HVA 23523781 MPTP 23523781 dopamine 23523781 homovanillic acid 23523781 paraquat 23523781 paraquat dichloride 23523781 silver 23523781 tyrosine 23523906 Berberine 23523906 berberine 23523906 bleomycin 23523906 histamine 23523906 hydroxyproline 23523906 nitric oxide 23523949 Creatine 23523949 Crocin 23523949 DZN 23523949 GSH 23523949 MDA 23523949 crocin 23523949 diazinon 23523949 glutathione 23523949 malondealdehyde 23523949 vitamin E 23523991 FNA 23523991 creatinine 23523991 morphine 23523991 naloxone 23523991 nitrogen 23523991 tyrosine 23523991 urea 23523991 β-funaltrexamine 23524160 (1)H 23524160 (13)C 23524160 3-(1H-indol-3-yl)pyrrolidine-2,5-dione 23524160 pyrrolidine-2,5-dione 23524160 serotonin 23524188 Dox 23524188 PEG 23524188 doxorubicin 23524189 TPPS 23524189 meso-tetrakis (4-sulfonatophenyl) porphyrin 23524189 oxygen 23524189 porphyrin 23524254 (1)H 23524254 (13)C 23524254 (15)N 23524254 PVP 23524254 PVP-K30 23524254 hydrogen 23524254 vincamine 23524305 oxygen 23524983 TFMO 23524983 hydroxamate 23524983 hydroxamates 23524983 trifluoromethyloxadiazole 23524983 zinc 23525092 1,6-anhydrosugar 23525092 levoglucosan 23525092 phenyl α- and β-d-glucosides 23525112 4α-PDD 23525112 4α-phorbol 12, 13-didecanoate 23525112 Ca(2+) 23525112 Gö6976 23525112 H2O2 23525112 Oxygen 23525112 PMA 23525112 oxygen 23525112 phorbol 12-myristate 13-acetate 23525112 trichostatin A 23525167 (13)C 23525167 (2)H 23525167 ethanol 23525167 formoterol fumarate 23525167 fumarate 23525167 methyl 23525167 phenyl 23525215 CORT 23525215 corticosterone 23525215 zinc 23525330 Cysteine 23525330 Etomidate 23525330 GABA 23525330 Para-chloromercuribenzene sulfonate 23525330 cysteine 23525330 etomidate 23525330 pCMBS 23525330 suflhydryl 23525330 sulfhydryls 23525662 steroid 23525674 polyethylene 23525674 polypropylene 23525786 HEMA 23525786 Hydroxyapatite 23525786 PHEMA 23525786 dimethacrylated poly(lactide-b-ethylene glycol-b-lactide) 23525786 hydroxyapatite 23525786 methacrylic acid 23525786 pHEMA 23525786 poly(2-hydroxyethyl methacrylate-co-methacrylic acid) 23525786 poly(HEMA-co-MA) 23525902 1NMPP1 23525902 ATP 23525902 RO3306 23525902 phosphates 23526144 Ca 23526144 Cu 23526144 Fe 23526144 Mg 23526144 Zn 23526231 (+)-10-O-methylhernovine N-oxide 23526231 (+)-3-hydroxy-anhydrolycorine N-oxide 23526231 (+)-N-methoxycarbonyl-lindcarpine 23526231 (+)-N-methoxylcarbonyl-nandigerine 23526231 (1)H 23526231 ethanol 23526571 Thiazole 23526571 thiazole 23526674 Vancomycin 23526674 creatinine 23526674 nitrogen 23526674 urea 23526674 vancomycin 23526745 2-methyltryptophan 23526745 4Fe-4S 23526745 Cobalamin 23526745 cobalamin 23526745 thiostrepton 23526745 tryptophan 23526814 2'-aminoanilides 23526814 SAHA 23526814 benzene 23526814 hydroxamates 23526814 pyrrole 23526814 pyrrole anilide 23526814 tert-Butylcarbamate 23526814 tert-butylcarbamate 23526919 Carbocyanine 23527317 N 23527317 N-1,2(R)-dihydroxypropyl 23527317 [(3)H]dihydrotetrabenazine 23527317 [(3)H]dopamine 23527317 lobelane 23527317 methamphetamine 23527317 monoamine 23527317 nor-lobelane 23527551 Aryl Diazonium 23527551 N(+)(Me)3 23527551 SO3(-) 23527551 aryl diazonium 23527551 glassy carbon 23527551 phenyl 23527585 3,3',4,4',5-pentachlorobiphenyl 23527585 Aryl-hydrocarbon 23527585 Copper 23527585 PCB 23527585 PCB126 23527585 copper 23527585 glutathione 23527585 hydroxyl 23527585 iron 23527585 manganese 23527585 polychlorinated biphenyl 23527585 selenium 23527585 zinc 23527619 Au 23527619 Cys 23527619 Cysteine 23527619 Hg(2+) 23527619 Mercury(II) 23527619 carboxylethyl 23527619 cysteine 23527619 thiols 23528109 CaCl2 23528109 POPC 23528109 Si3N4 23528109 organosilane 23528109 silicon 23528109 silicon nitride 23528251 5'-AMP 23528251 Cobalt chloride 23528251 Phenobarbital 23528251 androstane 23528252 BPA 23528252 androgen 23528252 bisphenol A 23528252 testosterone 23528300 2-substituted benzoxazoles 23528300 benzoxazole 23528300 oxamic acid 23528390 Quinolones 23528390 oxygen 23528390 quinolone 23528390 quinolones 23528611 PKI-166 23528611 creatinine 23528611 lisinopril 23528611 phenylephrine 23529571 carbon 23529571 graphene 23529671 glucose 23529894 Flinderoles A, B, and C 23529894 borrerine 23529894 borreverines 23529894 dimethylisoborreverine 23529894 enone 23529894 flinderoles 23529894 flinderoles A, B, and C 23529894 indole 23529894 isoborreverine 23529894 tryptamine 23529898 PHB 23529898 Poly(3-Hydroxybutyrate) 23529898 TiO2 23529898 poly(3-hydroxybutyrate) 23529905 PAA 23529905 PCL 23529905 poly(α,β)-DL-aspartic acid 23529905 polycaprolactone 23530011 Carbohydrate 23530011 carbohydrates 23530011 cholesterol 23530011 fatty acids 23530011 glucose 23530011 triglycerides 23530018 ATP 23530018 CGP 23530018 CGPs 23530018 Chalcogenopyrylium 23530018 E217βG 23530018 Se 23530018 Te 23530018 [(3)H]E217βG 23530018 [(3)H]estradiol glucuronide 23530018 calcein 23530018 chalcogen 23530018 chalcogenopyrylium 23530018 methine 23530018 pyrylium 23530018 trimethine 23530019 C-8-xanthate 23530019 Nicotine 23530019 bupropion 23530019 cotinine 23530019 coumarin 23530019 nicotine 23530020 2,6-xylidine 23530020 4- and 6-hydroxy-o-toluidine 23530020 4-hydroxy-2,6-xylidine 23530020 Lidocaine 23530020 Prilocaine 23530020 amide 23530020 bis-(4-nitrophenyl) phosphate 23530020 diisopropyl fluorophosphate 23530020 lidocaine 23530020 o-Toluidine 23530020 o-toluidine 23530020 prilocaine 23530036 tyrosine 23530765 Bis(l-histidinato)cadmium Dihydrate 23530765 Copper 23530765 Cu(II) 23530765 bis(l-histidinato)cadmium dihydrate 23530765 copper 23530765 histidine 23531107 Metal Oxide 23531107 PbS 23531107 PbSe 23531107 ZnO 23531107 metal oxide 23531107 nitrogen 23531107 oxide 23531119 (15)N 23531119 2-carbonyl 23531119 5-bromo 23531119 5-bromouridine 23531119 5-fluoro 23531119 5-substituted uracil 23531119 NHN 23531119 Uridine 23531119 enol 23531119 guanine 23531119 halogens 23531119 halouracils 23531119 hydrogen 23531119 nucleosides 23531119 thymine 23531119 uracil 23531160 5-HT 23531160 TRP 23531160 indoleamine 23531160 monoamine 23531160 monoamines 23531160 serotonin 23531160 tryptophan 23531217 bis-pyridinium mono-aldoxime 23531217 octadecyl silica 23531217 organophosphate 23531217 organophosphonate 23532446 polypropylene 23532446 titanium dioxide 23532897 Proline 23532897 inositol phosphate 23532897 proline 23532897 thiazolidine 23533220 17β-estradiol 23533220 cAMP 23533220 catecholamine 23533220 dopamine 23533220 testosterone 23534412 3-(5-hydroxy-2,2-dimethyl-chroman-6-yl)-N-{2-[3-(5-hydroxy-2,2-dimethyl-chroman-6-yl)-propionylamino]-ethyl}-propionamide 23534412 ADP 23534412 arachidonic acid 23534412 coumarin 23534412 epinephrine 23534412 ferric chloride 23534412 seselin 23534413 Myricetin 23534413 allopurinol 23534413 benzbromarone 23534413 flavonoids 23534413 isoflavones 23534413 luteolin 23534413 uric acid 23534413 xanthine 23534440 H 23534440 Mg(2+) 23534440 cytosine 23534440 guanine 23534440 nucleotide 23534440 sugar 23534442 (1)H 23534442 (13)C 23534442 1,5-diarylpyrrole nitrooxyalkyl ethers 23534442 3-substituted 1,5-diarylpyrroles 23534442 NO 23534442 Nitrooxy 23534442 alcohols 23534442 carbonates 23534442 esters 23534442 ethers 23534442 nitric oxide 23534442 nitrooxyalkyl 23534442 nitrooxyalkyl ester and ether 23534442 nitrooxyalkyl ethers 23534442 pyrrole 23534827 C-(N)-A-S-H 23534827 aluminate 23534827 calcium (alumino)silicate 23534827 calcium-sodium aluminosilicate 23534827 calcium-sodium aluminosilicate hydrate 23534827 silicate 23534827 tobermorite 23535167 5'-methylthioadenosine 23535167 MTA 23535167 Met 23535167 Methionine 23535167 S-adenosylmethionine 23535167 SAM 23535167 amino acids 23535167 aspartate 23535167 ethylene 23535167 methionine 23535167 methyl 23535167 nicotianamine 23535167 sulfur 23535185 Galangin 23535185 N 23535185 calcium 23535185 cromolyn 23535185 galangin 23535185 histamine 23535185 phorbol 12-mystate 13-acetate 23535186 N 23535186 Scoparone 23535186 d-GalN 23535186 d-galactosamine 23535186 scoparone 23535288 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine 23535288 BHA 23535288 SDM 23535288 butylated hydroxyanisole 23535288 caprolactam 23535288 catechol 23535288 chenodeoxycholic acid 23535288 phenylethyl isothiocyanate 23535288 sulfadimethoxine 23535320 1,2,3-triazoles 23535320 1,4-naphthoquinones 23535320 Nor-α-lapachone 23535320 alkyne 23535320 azide 23535320 copper 23535320 naphthoquinones 23535320 nor-β-lapachone 23535320 α- and nor-α-lapachone 23535320 α-lapachone 23535321 ClBi(5-RC6H3-2-SO2C6H4-1'-) 23535321 Heterocyclic bismuth carboxylates 23535321 RCO2Bi(C6H4-2-SO2C6H4-1'-) 23535321 bismuth 23535321 carboxylate 23535321 diphenyl sulfone 23535321 heterocyclic organobismuth(III) carboxylates 23535326 BP1.4160 23535326 alcohol 23535326 cyclohexanol 23535326 histamine 23535326 hydroxyl 23535334 hydroxycinnamates 23535334 p-coumaryl, coniferyl and sinapyl alcohols 23535351 Asenapine 23535351 asenapine 23535360 Amino Acids 23535360 amino acids 23535360 cysteine 23535360 lysine 23535394 Saxitoxin 23535394 calcium 23535394 potassium 23535394 saxitoxin 23535394 sodium 23535516 AG490 23535516 D-Phe 23535516 N 23535516 Nle 23535516 U0126 23535870 potassium 23535915 atrazine 23536271 amino 23536271 β-Ionone 23536271 β-ionone 23536315 ASA 23536315 BAY 11-7082 23536315 BAY-11-7082 23536315 Ro 106-9920 23536315 acetylsalicylic acid 23536315 dexamethasone 23536582 Glucose 23536582 glucose 23536584 Metformin 23536584 glucose 23536584 metformin 23536728 Pregnane 23537133 Ag 23537133 AgCl 23537133 C 23537133 RSiMe3 23537133 TMS(+) 23537133 acetonitrile 23537133 allyl 23537133 benzyl 23537133 carbon 23537133 carbons 23537133 fullerene 23537133 glassy carbon 23537133 graphite 23537133 tetraalkyammonium 23537133 trimethylsilanes 23537133 trimethylsilyl 23537315 Co(I) 23537315 Hydrocarbon 23537315 Ni(I) 23537315 hydrocarbon 23537315 nitrogen 23537315 phosphoranimide 23537315 unsaturated hydrocarbons 23537321 carbon 23537321 li 23537321 lithium 23537321 silicon 23537339 3-substitued 3-azidooxindoles 23537339 Fe 23537339 Iron 23537339 Oxindoles 23537339 oxindoles 23537339 α-azido-β-keto esters 23537339 β-Keto Esters 23537339 β-keto esters 23537597 CaLac 23537597 FeSO4 23537597 ZnSO4 23537597 calcium lactate 23537597 ferrous sulfate 23537597 protoporphyrins 23537597 vitamin C 23537597 zinc sulfate 23537597 δ-aminolevulinic acid 23537599 methanabol 23537599 turinabol 23537661 PC-dibenzodioxins 23537661 PC-dibenzofurans 23537661 PCBs 23537661 hydrocarbon 23537661 methylmercury 23537661 non-ortho PCB 23537661 organochlorine 23537661 polychlorinated biphenyls 23537700 7 beta-hydroxycholesterol 23537700 7b-HC 23537700 7β-hydroxycholesterol 23537700 Oxysterols 23537700 glutamine 23537700 phosphoenol pyruvate 23537700 pyruvate 23537747 Nobiletin 23537747 apigenin 23537747 nobiletin 23537747 phospho 23537747 tangeretin 23537747 tricetin 23537748 AMP 23537748 CCM 23537748 CIP 23537748 Curcumin 23537748 Methicillin 23537748 NOR 23537748 OXI 23537748 ampicillin 23537748 ciprofloxacin 23537748 curcumin 23537748 methicillin 23537748 norfloxacin 23537748 oxacillin 23537748 polyphenolic flavonoid 23537942 5-benzylidene thiazolidine-2,4-dione 23537942 N-3-substituted-5-arylidene thiazolidine-2,4-diones 23537942 arylidene 23537942 phenyl 23537942 thiazolidine-2,4-dione 23537942 α-bromoacryloylamido 23538843 carbohydrates 23538843 proline 23538868 (3Z,6E)-1-N-methyl-3-benzy lidene-6-(2S-methyl-3-hydroxypropylidene)piperazine-2,5-dione 23538868 (3Z,6E)-1-N-methyl-3-benzylidene-6-(2R-methyl-3-hydroxypropylidene)piperazine-2,5-dione 23538868 (3Z,6S)-3-benzylidene-6-(2S-but-2-yl)piperazine-2,5-dione 23538868 (3Z,6S)-3-benzylidene-6-isobutylpiperazine-2,5-dione 23538868 (3Z,6Z)-3- (4-hydroxybenzylidene)-6-isobutylidenepiperazine-2,5-dione 23538868 (3Z,6Z)-3-((1H-imidazol-5-yl)-methylene)-6-isobutylidenepiperazine-2,5-dione 23538868 13C 23538868 Diketopiperazine 23538868 diketopiperazine 23538871 Kocurin 23538871 Thiazolyl 23538871 kocurin 23538871 methicillin 23538871 thiazolyl 23539511 creatinine 23539547 N 23539547 S 23539547 UDP 23539547 glutathione 23539641 GW823296 23539641 [(11)C]GR205171 23539641 orvepitant 23540754 PLLA 23540754 Polylactide 23540754 l-lactide 23540754 poly(l-lactide) 23541399 Androgen 23541399 androgen 23541399 testosterone 23541436 NO 23541436 PGE2 23541436 limonene 23541436 nitric oxide 23541436 prostaglandin E2 23541436 γ-terpinene 23541637 Aldosterone 23541637 K(+) 23541637 Na(+) 23541637 aldosterone 23541637 ouabain 23541637 phosphatidylinositol 23541646 Glycyrrhetinic acid 23541646 MTT 23541646 amide 23541646 benzyl amide 23541646 glycyrrhetinic acid 23541646 octylamide 23541670 5H-pyrrolo[2,3-b]pyrazine 23541670 5H-pyrrolo[2,3-b]pyrazine-2-phenyl ethers 23541670 ATP 23541768 histidine 23541949 RFRP-3 23541949 RFamide-related peptide-3 23541949 steroid 23541950 dehydroepiandrosterone sulfate 23541950 steroid 23541950 testosterone 23542008 2'-fluoro 23542008 2'-hydroxyl 23542008 hydrogen 23542039 Neutral Red 23542039 glycerol 23542039 polyphenols 23542041 NO 23542041 O2(-) 23542041 nitric oxide 23542126 GSH 23542126 Thiobarbituric-acid 23542126 carbonyls 23542126 glutathione 23542239 PEG 23542239 iron oxide 23542239 poly(amino acid)s 23542239 poly(ethylene glycol) 23542440 5-HIAA 23542440 5-HT 23542440 5-hydroxyindolacetic acid 23542440 CORT 23542440 SB-656104 23542440 Serotonin 23542440 corticosterone 23542440 tryptophan 23542513 5-Hydroxy-3,6,7,8,3'4'-hexamethoxyflavone 23542513 5-hydroxy-3,6,7,8,3'4'-hexamethoxyflavone 23542513 5HHMF 23542513 CoPP 23542513 NO 23542513 PDTC 23542513 Pyrrolidine dithiocarbamate 23542513 ZnPP 23542513 cobalt protoporphyrin 23542513 nitric oxide 23542513 zinc protoporphyrin 23542608 Carbon 23542608 carbon 23542652 17-α-ethinylestradiol 23542652 EE2 23542652 estradiol 23542652 estrogens 23543321 Polyamines 23543321 S-adenosylmethionine 23543321 polyamine 23543321 polyamines 23543413 Cisplatin 23543413 Cu 23543413 Pt 23543413 cDDP 23543413 copper 23543413 platinum 23543460 (131)I 23543460 MTT 23543460 Radioiodide 23544667 hydroxyl 23544667 sulfates 23544698 (NaNO3, nH2O)x 23544698 (NaNO3,1H2O)x 23544698 (NaNO3,nH2O)3 23544698 Hydrated Nitrate 23544698 NaNO3 23545002 1,3 diketo 23545002 1,3-diketones 23545002 diketo 23545002 iron 23545002 steel 23545108 nucleoside 23545161 Acetaminophen 23545161 acetaminophen 23545161 aspirin 23545161 prostaglandin 23545161 prostaglandin E 23545161 prostaglandin E2 23545348 ACh 23545348 KCl 23545348 acetylcholine 23545458 saponins 23545806 Methylone 23545806 N-hydroxy-methylone 23545806 dihydro-methylone 23545806 dihydroxymethcathinone 23545806 methylenedioxymethcathinone 23545806 methylone 23545999 3,4',5-trihydroxy-3',7,8-trimethoxyflavone 23545999 4',5,7-trihydroxy-3,3',8-trimethoxyflavone 23545999 4',5,7-trihydroxy-3,3'-dimethoxyflavone 23545999 4',7-dihydroxy-3,3',5,8-tetramethoxyflavone 23545999 4',7-dihydroxy-3,3',5-trimethoxyflavone 23545999 5,7-dihydroxy-3-methoxy-3',4'-methylenedioxyflavone 23545999 5,8-dihydroxy-3,7-dimethoxy-3',4'-methylenedioxyflavone 23545999 7-(2,3-dihydroxy-3-methylbutoxy)-3,3',4',5,8-pentamethoxyflavone 23545999 7-(2,3-dihydroxy-3-methylbutoxy)-3,3',4',5-tetramethoxyflavone 23545999 7-(2,3-dihydroxy-3-methylbutoxy)-3,5-dimethoxy-3',4'-methylenedioxyflavone 23545999 7-hydroxy-3,5-dimethoxy-3',4'-methylenedioxyflavone 23545999 Flavonoids 23545999 flavonoids 23546003 2,3-Bis(halomethyl)quinoxaline 23546003 Quinoxaline 23546003 bis(chloromethyl) 23546003 bis(fluoromethyl) 23546003 bis(iodomethyl) 23546003 halomethyl 23546003 quinoxaline 23546004 Acylated Sucroses 23546004 Acylated quinic acid 23546004 acylated sucroses 23546004 aldose 23546004 mumeic acid-A 23546004 mumeoses F-J 23546395 (-)-epicatechin 23546395 Thiobarbituric acid 23546395 cyclophosphamide 23546395 gallic acid 23546525 Azidoacetylene 23546525 azidoacetylene 23546600 androgen 23546601 Estrogen 23546601 Tamoxifen 23546601 estrogen 23546601 tamoxifen 23546605 estradiol-17β 23546605 estrogen 23546605 progesterone 23546867 oxygen 23546879 C 23546879 GalNAc 23546879 N 23546879 O 23546879 cysteine 23546879 threonine 23547584 Biphalin 23547584 Phe 23547584 homo-β(3) amino acids 23547584 hβ(3) Phe 23547652 3-HPT 23547652 3-Hydroxypyridin-2-thione 23547652 3-hydroxypyridin-2-thione 23547652 3HPT 23547652 Zinc 23547652 hydroxamic acid 23547652 zinc 23547706 Oxadiazole-isopropylamides 23547706 PI-1833 23547706 PI-1840 23547706 amide 23547706 butyl 23547706 meta-pyridyl 23547706 oxadiazole-isopropylamide 23547706 phenyl 23547706 propyl 23547757 Belactosin A 23547757 Cis-Cyclopropane 23547757 belactosin A 23547757 cis-cyclopropane 23547757 threonine 23547757 trans-cyclopropane 23547757 β-lactone 23547776 LDN-212854 23547786 DTP 23547786 PGS 23547786 dodecyl triphenyl phosphonium bromide 23547786 palygorskite 23547786 quaternary phosphonium salt 23548149 Fru-2,6-P2 23548149 H2O2 23548149 NaCl 23548149 Ser 23548149 anisomycin 23548149 carbohydrate 23548149 fructose-2,6-bisphosphate 23548896 C 23548896 amino acids 23548896 phosphotyrosine 23548896 tyrosine 23548974 PUFA 23548974 PUFAs 23548974 mercury 23548974 methylmercury 23548974 polyunsaturated fatty acids 23549285 Spongiatriol 23549285 furanoditerpenoid 23549672 11β-hydroxysteroid 23549672 cortisol 23549672 cortisone 23549673 androgen 23549673 androgens 23549673 testosterone 23549673 testosterone propionate 23550066 Ketamine 23550066 ThioTEPA 23550066 ketamine 23550066 norketamine 23550066 troleandomycin 23550656 CO 23550656 CO2 23550656 H 23550656 H2O 23550656 HCO 23550656 HOCO 23550656 OH 23550656 trans-HOCO 23550722 C6F13CH2C(O)OONO2 23550722 CF3CH2C(O)OONO2 23550722 CxF2x+1CH2C(O)H 23550722 CxF2x+1CH2C(O)OONO2 23550722 NO2 23550722 Peroxy Acyl Nitrates 23550722 peroxy acyl nitrates 23551856 Pioglitazone 23551856 TZD 23551856 glucose 23551856 pioglitazone 23552101 PI(4)P 23552101 PI(4,5)P2 23552101 glucose 23552101 phosphatidylinositol 4-phosphate 23552101 phosphatidylinositol-4,5-bisphosphate 23552264 carbon 23552268 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide 23552268 CVN 23552268 Carvone 23552268 carvone 23552268 monocyclic monoterpene 23552398 C 23552398 C-O 23552398 CO 23552398 CO2 23552398 COH 23552398 COOH 23552398 H2O 23552398 Pt(111) 23552398 hydrogen 23552398 oxygen 23552482 CH3 23552482 H 23552482 O 23552482 RO 23552482 RX 23552482 RX-Y 23552482 S 23552482 allyl 23552482 allyl phenyl ether 23552482 cyclohexane 23552482 ether 23552482 p-methylthioanisole 23552482 p-methylthiophenol 23552482 phenol 23552482 thioanisole 23552482 thiophenol 23552830 amino acid 23552843 PDMAEMA 23552843 disulfide 23552843 poly(2-dimethylaminoethyl methacrylate) 23552843 silica 23552852 azole 23552852 azoles 23552852 cyproconazole 23552852 fluconazole 23552852 flusilazole 23552852 imazalil 23552852 tebuconazole 23552852 triadimefon 23552852 triadimenol 23552899 ZnO 23552899 graphene 23552899 metal oxide 23552908 Au(111) 23552908 DFA 23552908 acetylene 23552908 benzene 23552908 cyclopentadienyl 23552908 diferrocenylacetylene 23552908 ferrocene 23552908 ferrocenes 23553560 Axitinib 23553560 axitinib 23553595 Diskus 23553595 fluticasone propionate 23553632 C 23553632 N 23553632 biotin 23553655 Tyrosine 23553655 bosutinib 23553655 dasatinib 23553655 imatinib 23553655 nilotinib 23553655 tyrosine 23553677 Silver 23553677 silver 23553679 Gabapentin 23553679 gabapentin 23553708 Sildenafil 23553708 sildenafil 23553811 Vernakalant 23553811 alcohol 23553811 aldosterone 23553811 apixaban 23553811 aspirin 23553811 clopidogrel 23553811 dabigatran 23553811 dronedarone 23553811 polyunsaturated fatty acids 23553811 rivaroxaban 23553811 statins 23553811 warfarin 23553905 Alcian blue 23553905 Alizarin red 23553961 CO 23553961 O 23553961 Pt 23553961 oxides 23554029 glutathione 23554029 malondialdehyde 23554029 superoxide 23554215 fluorine 23554215 fluoroximes 23554215 nitrogen 23554335 2,4-dinitroaniline 23554335 2,4-dinitrophenyl 23554335 CH 23554335 Pt 23554335 dodecanethiol 23556445 hydroxyurea 23556446 ATP 23556448 methamphetamine 23557487 HNO3 23557487 NO2 23557487 OH 23557487 nitric acid 23557931 MPA 23557931 cyclosporine 23557931 mycophenolic acid 23557931 tacrolimus 23557933 RES 23557933 glucose 23557933 resveratrol 23558233 5-HIAAA 23558233 DOPAC 23558233 HVA 23558233 MPTP 23558233 Serotonin 23558233 dopamine 23558233 iron 23558233 serotonin 23558233 tyrosine 23558236 MTT 23558236 rotundic acid 23558446 tyrosine 23558646 H 23558646 N(3)-alkylated xanthine 23558646 melamine 23558646 xanthine 23558682 N 23558682 arginine 23558682 carbonyl 23558682 cysteine 23558682 histidine 23558682 hydrogen 23558682 sugar 23558686 C 23558747 N 23558747 methyl 23559221 Glucose 23559221 glucose 23559436 (di)unsaturated hydrocarbons 23559436 H 23559436 Peroxide 23559436 alkyl peroxide 23559436 hydrocarbons 23559436 oxygen 23559436 peroxide 23560557 catecholamine 23560844 Arg 23560844 Gln 23560844 Glu 23560844 Lys 23560844 Thr 23560844 Tyr 23560844 pThr-Glu-pTyr 23560844 phospho 23560989 2-(dimethylamino)ethyl methacrylate 23560989 DMAEMA 23560989 EGDMA 23560989 PEG 23560989 Poly(ethylene glycol) 23560989 ethylene glycol dimethacrylate 23561072 1-deoxynojirimycin 23561072 DNJ 23561072 triacylglycerol 23561075 (epi)afzelechin 23561075 Catechin 23561075 Proanthocyanidin 23561075 catechin-7-O-glucoside 23561075 catechin-O-glucoside 23561075 flavan-3-ol 23561075 flavan-3-ols 23561076 anthocyanin 23561076 anthocyanins 23561079 nitrogen 23561089 Gallic acid 23561089 ethanol 23561089 methanol 23561089 phenolic 23561089 polyphenolic 23561089 trolox 23561091 (2S)-3',4'-methylenedioxy-5-methoxy-7-hydroxyflavan 23561091 Flavonoids 23561091 MTT 23561091 eriocaulin A 23561091 eriocaulosides A-C 23561091 flavan 23561091 flavone acyl glucosides 23561091 flavones 23561091 flavonoids 23561091 hispidulin 7-O-β-d-(6-O-cinnamoyl)glucopyranoside 23561091 isoflavones 23561091 jaceosidin 7-O-β-d-(6-O-p-coumaroyl)glucopyranoside 23561091 jaceosidin 7-O-β-d-(6-O-p-hydroxybenzoyl)glucopyranoside 23561093 Anisidine 23561093 DHA 23561093 EPA 23561093 astaxanthin 23561093 docosahexaenoic acid 23561093 eicosapentaenoic acid 23561093 palmitic acid 23561093 thiobarbituric acid 23561093 tocopherol 23561103 Vitamin A 23561103 vitamin A 23561103 β-carotene 23561109 ABTS 23561109 DPPH 23561113 Hoechst 33342 23561120 FAD 23561120 IPTG 23561120 NADH 23561120 Phenol 23561120 hydroxytyrosol 23561120 isopropyl-β-d-thiogalactopyranoside 23561120 monophenols 23561120 phenol 23561120 tyrosol 23561124 amine 23561124 amines 23561124 anthocyanins 23561124 histamine 23561124 polyphenol 23561124 polyphenols 23561124 putrescine 23561124 tyramine 23561128 nitrite 23561128 sodium nitrite 23561128 sulfur 23561131 8,4″-dihydroxy-3″,4″-dihydrocapnolactone-2',3'-diol 23561131 8,4″-dihydroxy-3″4″-dihydrocapnolactone-2',3'-diol 23561131 8-hydroxy-3″,4″-dihydrocapnolactone-2',3'-diol 23561131 8-hydroxyisocapnolactone-2',3'-diol 23561131 clauslactone E 23561131 coumarins 23561131 minutin A 23561131 minutin B 23561131 monoterpene coumarins 23561135 4-Methyl-7-hydroxycoumarin 23561135 4-thiazolidinones 23561135 7-hydroxy-4-methylcoumarin 23561135 DPPH 23561135 ascorbic acid 23561135 coumarin 23561135 coumarinyl thiosemicarbazides 23561135 galvinoxyl 23561135 thiazolidinone 23561135 thiosemicarbazide 23561135 thiosemicarbazides 23561137 3β-hydroxy-8,24-dien-21-al 23561137 NO 23561137 ergosterol 23561137 ergosterol peroxide 23561137 ethyl acetate 23561137 inotodiol 23561137 lanosterol 23561137 petroleum ether 23561137 trametenolic acid 23561138 6- and 8-methyl shogaols 23561138 6-Gingerol 23561138 6-gingerol 23561138 6-paradol 23561138 acetone 23561138 ethanol 23561138 gingerol 23561138 polyphenol 23561139 acrylamide 23561139 ascorbic acid 23561139 glucosinolates 23561139 vitamins 23561139 vitamins B 23561140 anthocyanin 23561140 anthocyanins 23561140 polyphenol 23561140 procyanidins 23561140 quercetin rutinoside 23561141 astaxanthin 23561147 FAs 23561147 Fatty acid 23561147 fatty acids 23561152 Annatto 23561152 Norbixin 23561152 norbixin 23561152 sodium 23561157 (1)H 23561157 KOH 23561157 O2 23561157 fatty acids 23561157 iodine 23561157 myristic acid 23561157 oleic acid 23561157 palmitelaidic acid 23561157 palmitic acid 23561157 peroxide 23561157 stearic acid 23561158 DHA 23561158 EPA 23561158 Li-RACOOH 23561158 R'ACHCHCOOH 23561158 R'BCHCHCOOH 23561158 TAGs 23561158 acyl 23561158 diacylglycerol 23561158 docosahexaenoic acids 23561158 eicosapentaenoic 23561158 fatty acid 23561158 lithiated TAG 23561158 polyunsaturated triacylglycerols 23561158 triacylglycerols 23561158 α,β-unsaturated fatty acid 23561161 CaCl2 23561161 CaO 23561161 CaSO4 23561161 calcium 23561161 calcium acetate 23561161 calcium gluconate 23561161 fatty acid 23561161 fatty acids 23561161 phosphate 23561165 carbonyl 23561165 sulphydryl 23561169 C8-C16 23561169 chlorophyll 23561169 fatty acids 23561169 isoprenoids 23561169 lutein 23561169 tocopherols 23561169 xanthophyll 23561169 β-carotene 23561171 H 23561171 Na 23561171 OH 23561171 acyl 23561171 di-malonyl 23561171 ginsenosides 23561171 malonyl 23561171 protopanaxadiol 23561171 protopanaxatriol 23561171 saponins 23561171 sugar 23561176 (+)-catechin 23561176 (-)-epicatechin 23561176 (-)-epigallocatechin 23561176 (-)-epigallocatechin-3-gallate 23561176 BHT 23561176 BTH 23561176 EGC 23561176 EGCG 23561176 H 23561176 butylated hydroxytoluene 23561176 flavonoid 23561176 hydrogen 23561176 phosphatidylcholine 23561176 sphingomyelin 23561177 Folates 23561177 folate 23561177 folates 23561178 amino acids 23561178 hydroperoxide 23561178 linoleic acid 23561178 linolenic acid 23561183 Catechin 23561183 Methylene chloride 23561183 PAC 23561183 PAC-A2 23561183 PAC-B1 23561183 catechin 23561183 ethyl acetate 23561183 formic acid 23561183 proanthocyanidin 23561183 vanillin hydrochloric 23561185 fatty acids 23561185 triacylglycerols 23561185 triglyceride 23561185 β-carotene 23561188 C-20 oxygenated ent-kaurane 23561188 C-20 oxygenated ent-kauranes 23561188 Effusanin E 23561188 butanol 23561188 effusanin E 23561188 effusanin F 23561188 ethanol 23561188 ethyl acetate 23561188 lasiodin 23561188 methyl rosmarinate 23561188 pedalitin 23561188 petroleum ether 23561188 rabdosichuanin D 23561188 rosmarinic acid 23561190 (1)H 23561190 (13)C 23561190 24-mCAF 23561190 24-methylene cycloartanyl ferulate 23561190 CAF 23561190 acetonitrile 23561190 cycloartenyl ferulate 23561190 n-hexane 23561190 triterpene alcohol 23561191 3,5-dihydroxybenzoic acid 23561191 3-(3,5-dihydroxyphenyl)-1-propanoic acid 23561191 Alkylresorcinols 23561191 DHPPA 23561191 alkylresorcinols 23561191 phenolic 23561192 Anthocyanin 23561192 NaCl 23561192 fructose 23561192 glucose 23561192 sodium chloride 23561192 sucrose 23561192 sugars 23561192 tartaric and malic acids 23561194 Ca(2+) 23561194 Oxalic acid 23561194 oxalate 23561194 oxalic acid 23561194 polyphenols 23561194 quinic acid 23561194 tartaric acid 23561197 Fe3O4 23561197 ascorbic acid 23561197 sucrose 23561197 urea 23561197 xanthine 23561198 FeCl3 23561198 carbon 23561198 lactic acid 23561198 lactose 23561198 nitrogen 23561198 thiamine 23561203 Pyronine B 23561203 SDS 23561203 Se(IV) 23561203 selenium 23561203 sodium dodecyl sulphate 23561208 Vanillin 23561208 anthocyanins 23561208 furfuryl alcohol 23561208 proanthocyanidins 23561208 syringaldehyde 23561213 (dihydro) hydroxycinnamic acid 23561213 5-O-feruloyl quinic acid 23561213 ChA 23561213 HCA 23561213 HCAs 23561213 N(1),N(10)-bis-(dihydrocaffeoyl) spermidine 23561213 N(1),N(14)-bis-(dihydrocaffeoyl) spermine 23561213 N(1),N(5),N(14)-tris-(dihydrocaffeoyl) spermine 23561213 anthocyanin 23561213 caffeic acid 23561213 caffeoyl putrescine 23561213 chlorogenic acid 23561213 cis-ChA 23561213 crypto-ChA 23561213 didydrohydroxycinnamic acid 23561213 feruloyl octopamine 23561213 hydroxycinnamic acid 23561213 neo-ChA 23561213 sinapoyl hexose 23561222 CAPE 23561222 Caffeic acid phenethyl ester 23561222 caffeic acid 23561222 caffeic acid phenethyl ester 23562076 glucose 23562245 (13)C7 23562245 IAA 23562245 N-ethylmaleimide 23562245 NEM 23562245 cysteine 23562245 d5 23562245 iodoacetanilide 23562369 1, 10-phenantroline 23562369 EDTA 23562369 EGTA 23562369 LPA 23562369 LPC 23562369 choline 23562369 lysophosphatidic acid 23562369 lysophosphatidylcholine 23562369 phosphatidylcholine 23562369 phosphatidylserine 23562369 sphingomyelin 23562597 19-cyclopropyl acetate 23562597 19-hydroxy 23562597 4',19-Diacetate 23562597 4'-esters 23562597 Ilicicolin H 23562597 N 23562597 O 23562597 ilicicolin H 23562633 PEG 23562633 PEG-FA 23562633 alanine 23562633 aspartate 23562633 folate 23562633 folic acid 23562633 polyethylene glycol 23562634 DP-TAT-59 23562634 TAT-59 23562634 miproxifen phosphate 23562706 DON 23562706 FB1 23562706 MTT 23562706 NIV 23562706 ZEA 23562706 deoxynivalenol 23562706 fumonisin B1 23562706 fumonisins B1 23562706 nivalenol 23562706 zearalenone 23562707 2,6-dimethylaniline 23562707 2-methoxi-5-methylaniline 23562707 4,4'-diaminodiphenylmethane 23562707 4,4'-oxydianiline 23562707 4-aminobiphenyl 23562707 Sudan III 23562707 aniline 23562707 aromatic amines 23562707 azo 23562707 ironporphyrin 23562707 o-anisidine 23562765 17β-estradiol 23562765 BPA 23562765 BPAF 23562765 BPS 23562765 Bisphenol A 23562765 R1881 23562765 androgen 23562765 bisphenol AF 23562765 bisphenol S 23562765 estrogen 23562995 ZnO 23563049 Ketoprofen 23563049 ketoprofen 23563049 prostaglandin 23563055 2,2-diphenyl-1-picrylhydrazyl 23563205 thiazolidinediones 23563356 serotonin 23564211 cetirizine 23564211 oxygen 23564211 verapamil 23564329 Al 23564329 CO 23564329 Si 23564329 graphene 23564329 graphenes 23564643 6-OH-PBDE-47 23564643 PBDE 23564643 PBDE-47 23564643 PBDEs 23564643 Polybrominated diphenyl ethers 23564643 organobromine 23564646 2,4-dinitrochlorobenzene 23564646 CinA 23564646 DNCB 23564646 IPDI 23564646 TMA 23564646 cinnamaldehyde 23564646 cysteine 23564646 isophorone diisocyanate 23564646 lysine 23564646 oxygen 23564646 trimellitic anhydride 23564918 NH2 23565585 PEG 23565585 PLA 23565585 PLGA 23565585 glucose 23565585 poly(lactic acid) 23565585 poly(lactide-co-glycolide) 23565585 polyethylene glycol 23565749 Ag 23565749 AgCl 23565749 AgNO3 23565749 NaCl 23565749 Silver 23565749 Silver Chloride 23565749 ethylene glycol 23565749 halide 23565749 polyol 23565749 silver 23565753 Androgen 23565753 Androgens 23565753 androgen 23565753 androgens 23565754 N 23565754 androgen 23565754 androgens 23565776 Amino Acid 23565776 amino Acid 23565776 amino acid 23565776 amino acids 23565776 aminoacid 23565776 nucleotide 23565776 phenylalanine 23565776 phenylanaline 23565776 saturated or unsaturated diacyl glycerol 23565776 thymidine 23565822 LSCO 23565822 Oxygen 23565822 lanthanum strontium cobaltite 23565822 oxygen 23565822 perovskite 23566174 Bis-urea 23566174 Hydrogen 23566174 bis-urea 23566174 hydrogen 23566269 3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one 23566269 3-hydroxy-pyridine-2(1H)-one 23566269 4-Hydroxypyridazin-3(2H)-one 23566269 4-hydroxypyridazin-3(2H)-one 23566269 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one 23566269 MK-801 23566269 N-methyl-d-aspartate 23566269 Tyr 23566269 d-Amino Acid 23566269 d-Amino acid 23566269 d-amino acids 23566269 d-serine 23566299 Acetylcholine 23566299 acetylcholine 23566299 hydrogen 23566514 4-amino-pyrrolopyrimidine 23566514 4-aminopyrrolopyrimidine 23566514 benzimidazole 23566514 ketophenyl 23566514 ketophenyl pyrrolopyrimidine urea 23566514 pyrrolopyrimidine 23566899 acetaminophen 23567034 7,8-dimethoxycoumarin 23567034 E-β-ocimene 23567034 MTT 23567034 citronellol 23567034 geraniol 23567034 methanol 23567034 sinapic acid 23567037 oxygen 23567037 superoxide 23567041 Fluorescein 23567041 Nile red 23567041 fluorescein 23567045 Lac-DOPE 23567045 N-lactobionyl-dioleoyl phosphatidylethanolamine 23567046 Au 23567046 DOX 23567046 doxorubicin 23567046 iron oxide 23567242 BPA 23567242 Bisphenol A 23567242 epoxy 23567242 polycarbonate 23567269 oxygen 23567314 PFAA 23567314 PFAAs 23567314 PFDA 23567314 PFOA 23567314 PFOS 23567314 Wy14,643 23567314 androstane 23567314 carboxylates 23567314 perfluoroalkyl acid 23567314 perfluoroalkyl acids 23567314 perfluorooctane sulfonate 23567314 perfluorooctanoic acid 23567318 N 23567318 carbohydrate 23567318 xylobiose 23567318 xylohexaose 23567318 xylopentaose 23567318 xylotetraose 23567318 xylotriose 23567486 HES-HEMA 23567486 HES-MA 23567486 HES-P(EG)6MA 23567486 PEG 23567486 hydroxyethyl 23567486 hydroxyethyl methacrylate 23567486 methacrylate 23567486 polyethylene glycol 23567486 polyethylene glycol methacrylate 23567861 7-O-galloyl-d-sedoheptulose 23567861 N 23567861 cholesterol 23567861 fatty acids 23567861 glucose 23567861 nitric oxide 23567861 oxygen 23567861 sterol 23567861 thiobarbituric acid 23567861 triglycerides 23567954 2,2-diallyl-1,1,3,3-tetraethylguanidinium chloride 23567954 2,2-diallyl-1,1,3,3-tetraethylguanidiniumchloride and tris(diethylamino)diallylaminophosphonium salts 23567954 H2O2 23567954 N-benzyl-2-azanorbornene-5 23567954 Polysulfones 23567954 ascorbate 23567954 azanorbornenes 23567954 hydrogen peroxide 23567954 iron 23567954 polysulfone 23567954 polysulfones 23567959 (1)H 23567959 (13)C 23567959 1,3,5-substituted-2,3-dihydro-2-imino-benzimidazoles 23567959 5-substituted-2-aminobenzimidazoles 23567959 5-substituted-2-iminobenzimidazole 23567959 acetate 23567959 hydrazone 23567999 cysteine 23567999 τ-CnVA 23568274 tyrosine 23568429 tritium 23568455 LY294002 23568455 Phosphatidylinositol 23568455 phosphatidylinositol 23568455 tetrazolyl 23568508 Rhenium 23568508 Rhenium(I) indolato complexes 23568508 oxygen 23568512 AA-GSH 23568512 AAMA 23568512 Acrylamide 23568512 GAMA 23568512 GSH 23568512 N-acetyl-S-(2-carbamoylethyl)cysteine 23568512 N-acetyl-S-(2-hydroxy-2-carbamoylethyl)cysteine 23568512 N7-(2-carbamoyl-2-hydroxyethyl)guanine 23568512 N7-GA-Gua 23568512 acrylamide 23568512 asparagine 23568512 carbohydrates 23568512 glutathione 23568512 glycidamide 23568512 mercapturic acids 23568578 GABA 23568578 alanine 23568578 amino acid 23568578 amino acids 23568578 glutamate 23568578 glutamine 23568578 threonine 23568578 γ-aminobutyric acid 23568579 cocaine 23570266 silica 23570328 2,2,6,6-tetramethylpiperidine-N-oxyl 23570328 4-acetamido-TEMPO 23570328 C-C 23570328 HCl 23570328 HNO3 23570328 TEMPO 23570328 benzylic alcohols 23570394 C 23570394 Graphene 23570394 O 23570394 Pt(111) 23570394 Ru 23570394 SiC 23570394 SiO2 23570394 graphene 23570451 PMMA 23570451 acetone 23570451 poly(methyl methacrylate) 23570500 (1)H 23570500 DOX 23570500 FITC 23570500 PEO45 23570500 PtNEA 23570500 doxorubicin 23570500 fluorescein isothiocyanate 23570500 poly(ethylene oxide) 23570500 tNEA 23570500 trans-N-(2-ethoxy-1,3-dioxan-5-yl) acrylamide 23570514 NAD(+) 23570514 Thieno[3,2-d]pyrimidine-6-carboxamides 23570514 carboxamide 23570514 nicotinamide 23570533 HB-C12 23570533 Quartz 23570533 dodecyl 3,4,5-trihydroxybenzoate 23570533 lignin 23570552 Cinnamaldehyde 23570552 cinnamaldehyde 23570561 Urea 23570561 urea 23570609 Lac-α-CDE 23570609 PEG 23570609 PEG-LαC 23570609 PEG-LαCs 23570609 lactose 23570609 polyamidoamine 23570609 polyethylene glycol 23570609 α-cyclodextrin 23570839 AcOEt 23570839 CH3OH 23570839 CHCl3 23570839 Daphneretusin A 23570839 Daphneretusin B 23570839 coumarin 23570839 n-hexane 23570840 Goniolandrene A and B 23570840 Goniothalamin 23570840 butanol 23570840 chloroform 23570840 goniolandrene B 23570840 goniolandrene-A (1), -B (2) 23570840 methanol 23570840 n-hexane 23570914 bleomycin 23570914 caffeic acid phenethyl ester 23570914 glutathione 23570914 oxygen 23570914 superoxide 23570914 thiobarbituric acid 23570992 Arsenic 23570992 arsenic 23570992 hydroxysteroid 23570992 sodium arsenite 23570993 Carbon 23570993 carbon 23570998 Quercetin 23570998 flavonoids 23570998 quercetin 23570998 rutin 23571415 sodium fluorescein 23572409 Pomalidomide 23572409 Pomalyst 23572409 bortezomib 23572409 dexamethasone 23572409 lenalidomide 23572409 pomalidomide 23572409 thalidomide 23572520 CysNO 23572520 GSH 23572520 NO 23572520 S 23572520 cysteine 23572520 glutathione 23572520 nitric oxide 23573957 E-stilbene 23573957 prolinamide 23573957 prolinamides 23573990 PEO 23573990 helium 23573990 nitrogen 23573990 polyethylene oxide 23573990 sPS 23573990 syndiotactic polystyrene 23573990 tetrahydrofuran 23574008 7-butoxy-2H-chromen-2-one 23574008 C12EO4 23574008 C4-C-N-PEG9 23574008 H2O 23574008 PhyEO20 23574008 cinnamic acid 23574008 coumarin 23574008 polyoxyethylene 23574008 polyoxyethylene phytosterol ether 23574008 tetraoxyethylene dodecyl ether 23574014 DTPA 23574014 diethylenetriaminepentaacetic acid 23574014 maleimide 23574014 poly(N-alkylacrylamide) 23574534 Cd 23574534 He 23574534 SnO2 23574984 Naloxone 23574984 PGE2 23574984 acetic acid 23574984 prostaglandin E2 23575765 ITO 23575765 ZnO 23575765 carbon 23575765 indium tin oxide 23575765 silver 23575765 zinc oxide 23576174 Mono- and Dimeric Alkenylphenols 23576174 Sarmentosumols A to F 23576174 dimeric alkenylphenols 23576174 sarmentosumol A 23576174 sarmentosumols A to F 23576286 Ca-GP 23576286 OPF 23576286 Oligo(poly(ethylene glycol) Fumarate 23576286 alizarin red 23576286 calcium 23576286 calcium glycerophosphate 23576286 oligo(poly(ethylene glycol)fumarate) 23576297 Formic Acid 23576297 Palladium 23576297 Pd 23576297 Porphyrin 23576297 formic acid 23576297 porphyrin 23576306 (13) C 23576306 Alkylcarbonate 23576306 CO2 23576306 Carboxylate 23576306 Tetramethylammonium 23576306 alcohol 23576306 amines 23576306 amino 23576306 bicarbonate 23576306 carboxylate 23576306 ethylene glycol 23576306 hydrogen 23576306 hydroxyethylcarbonate 23576306 methanol 23576306 methyl acrylate 23576306 methylcarbonate 23576306 tetramethylammonium hydroxide 23576306 β-Amino Acid 23576306 β-amino acid 23576341 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide 23576341 ATP 23576341 MTT 23576341 biphenyl 23576341 urea 23576355 (23R,24S)-23,24,25-trihydroxytirucall-7-ene-3,6-dione 23576355 21α-methylmelianodiol 23576355 21β-methylmelianodiol 23576355 24-epipiscidinol A 23576355 EtOH 23576355 NO 23576355 Tirucallane 23576355 Triterpenoids 23576355 brumollisols A-C 23576355 piscidinol A 23576355 tirucallane 23576355 triterpenoids 23576378 Demethylvancomycin 23576378 N-(6-phenylheptyl)demethylvancomycin 23576378 demethylvancomycin 23576378 gentamicin 23576378 methicillin 23576378 vancomycin 23577042 biotin 23577589 glucose 23577701 (1)H 23577701 (13)C 23577701 apetalactone 23577701 canophyllol 23577701 dipyranocoumarin 23577701 friedelin 23577701 inophyllum C 23577701 α-hydroxytomentolide A 23577749 flavonoids 23577749 gallic acid 23577749 phenolic 23577749 phenols 23577749 terpenoids 23578584 ATP 23578584 calcium 23578610 baicalein 23578623 NaCl 23578627 2″-hydroxyoleuropein 23578627 3,4-Dihydroxyphenylglycol 23578627 DHPG 23578627 isoverbascoside 23578627 phenol 3,4-dihydroxyphenylglycol 23578627 phenolic 23578627 verbascoside 23578627 β-hydroxy 23578627 β-hydroxyacteoside 23578627 β-hydroxyisoacteoside 23578632 1,1-diphenyl-2-picrylhydrazyl 23578632 DPPH 23578632 DPPH(·) 23578632 Polyphenols 23578632 butylated hydroxytoluene 23578632 ethanol 23578632 ferric 23578632 omega-3 polyunsaturated fatty acid 23578632 polyphenols 23578632 thiobarbituric acid 23578632 α-tocopherol 23578632 ω3 PUFA 23578633 PFOA 23578633 PFOS 23578633 perfluorooctane sulfonate 23578633 perfluorooctane sulfonic acid 23578633 perfluorooctanoic acid 23578634 Ca-propionate 23578634 FeNa-EDTA 23578634 FeNa-ethylenediaminetetraacetic acid 23578634 KCl 23578634 NaCl 23578636 Anthocyanins 23578636 alcohol 23578636 alcoholic 23578636 phenolic 23578636 tannins 23578642 ammonium sulphate 23578643 5-HMF 23578643 5-hydroxymethylfurfural 23578643 glucose 23578643 oxygen 23578651 ETU 23578651 alumina 23578651 ethylenethiourea 23578651 methanol 23578652 ATP 23578652 NMDA 23578652 S-allylcystein 23578652 hydroethanolic 23578652 hydroxyl 23578652 oxygen 23578652 peroxyl 23578652 peroxynitrite 23578652 superoxide 23578690 amine 23578690 cytarabine 23578690 doxorubicin 23578690 oxygen 23578690 tethered amine 23578763 prednisone 23578968 MBP 23578968 MEHP 23578968 MEP 23578968 MMP 23578968 Monoesters 23578968 carbon 23578968 carbons 23578968 monoesters 23578968 phthalate 23578968 phthalate esters 23578968 phthalates 23578968 steroid 23578968 testosterone 23579044 MPD 23579044 cocaine 23579044 d-amphetamine 23579044 dopamine 23579044 methylphenidate 23579044 monoamine 23579044 norepinephrine 23579182 N 23579333 Co 23579333 Co(iii) 23579333 Ni 23579333 hydroxide 23579333 hydroxides 23579333 iodine 23579333 oxygen 23579333 potassium phosphate 23579427 alcohol 23579486 APR19 23579486 Progesterone 23579486 RU486 23579486 homosteroid 23579486 hydrogen 23579486 mifepristone 23579486 progesterone 23579486 serine 23579486 steroid 23579487 glucose 23579487 phosphatidylinositol 23580169 (Ca,Eu)2SiS4 23580169 Ca 23580169 Ca2SiS4 23580169 Eu 23580169 europium 23580169 monoclinic Eu2SiS4 23580169 thiosilicate 23580257 Baicalin 23580257 baicalin 23580257 dexamethasone 23580257 eosin 23580257 hematoxylin 23580402 cholesterol 23580402 sodium 23580402 sugars 23580402 vitamin C 23580402 vitamin E 23580402 zinc 23580402 β-carotene 23580404 PbS 23580421 Graphene Oxide 23580421 Manganese Dioxide 23580421 MnO2 23580652 aspartic acid 23580652 calcium 23580652 glycine 23581295 4-octylphenyldiazenido 23581295 4-octylphenyldiazonium 23581295 LiBHEt3 23581295 V-N═N-Ar 23581295 VCl4 23581295 diazenido 23581295 superhydride 23581295 vanadium 23581492 Arg-Arg 23581492 Arg-Arg-Asp 23581492 Glu 23581492 acidic amino acids 23581492 arginine 23581492 carbon 23581965 ATO 23581965 Antimony-Doped Tin Oxide 23581965 Hematite 23581965 antimony-doped tin oxide 23581965 hematite 23581965 oxide 23581965 polystyrene 23581993 ATP 23581993 carbon 23582235 Poly(ADP-ribose) 23582235 Zinc 23582235 zinc 23582235 zinc chloride 23582330 Glucose 23582330 Sugar 23582330 glucose 23582330 haloacid 23582330 phosphosugars 23582330 sugar 23582779 glucose 23583168 fatty-acid 23583203 TPP 23583203 celastrol 23583437 (1α, 3β, 25R)-spirost-5-ene-2-diol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl(1→4)]-O-β-d-glucopyranoside 23583437 (2α, 3β, 12β, 25R)-spirost-5-ene-2, 3, 12-triol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl-(1→4)]-O-β-d-glucopyranoside 23583437 (3β, 12β, 25R)-spirost-5-ene-3,12-diol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl-(1→4)]-O-β-d-glucopyranoside 23583437 (3β, 7β, 12β, 25R)-spirost-5-ene-3, 7, 12-triol-3-O-α-L-rhamnopyranosyl-(1→2)-O-[α-L-rhamnopyranosyl-(1→4)]-O-β-d-glucopyranoside 23583437 EtOH 23583437 steroidal saponins 23583454 3,4-Methylenedioxypyrovalerone 23583454 3,4-methylendioxymethamphetamine 23583454 4-fluoromethcathinone 23583454 5-HT 23583454 Butylone 23583454 MDMA 23583454 METH 23583454 [(3)H] 23583454 amphetamine 23583454 cocaine 23583454 dopamine 23583454 mephedrone 23583454 methamphetamine 23583454 methcathinone 23583454 methcathinones 23583454 methylone 23583454 monoamine 23583454 naphyrone 23583454 norepinephrine 23583454 serotonin 23583513 1,5-dihydro-benzo[f][1,3,5]triazepine-2,4-dione 23583513 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione 23583513 diazepine 23583641 MTT 23583641 NO 23583641 methanol 23583641 polyurethane 23583735 (1)H 23583735 As2S2 23583735 Realgar 23583735 amino acid 23583735 choline 23583735 realgar 23583882 methoxychlor 23583882 organochlorine 23583882 organophosphate 23583882 parathion 23583882 piperonyl butoxide 23583910 2,3-oxidosqualen 23583910 Aminopropylindenes 23583910 Grundmann's ketone 23583910 N,N-dimethylaminopropyl 23583910 aminopropylindenes 23583910 cholesterol 23583910 lanosterol 23583910 oxidosqualene 23583928 JNJ 10191584 23583928 VUF 8430 23583928 diazepam 23583928 histamine 23583928 scopolamine 23583929 quinolinic acid 23584090 CpG 23584277 diethylmethylammonium trifluoromethanesulfonate 23584277 hydrogen peroxide 23584277 oxygen 23584358 8-iso-prostane 23584358 Agomelatine 23584358 N-acetylcysteine 23584358 NAC 23584358 Paracetamol 23584358 agomelatine 23584358 alanine 23584358 aspartate 23584358 glutathione 23584358 melatonin 23584358 paracetamol 23584358 superoxide 23584418 Al(3+) 23584418 Aluminium 23584418 aluminium 23584426 As(V) 23584426 Fe3O4 23584426 arsenic 23584426 arsenics 23584426 ferroferric oxide 23584427 Cr 23584427 Cr(VI) 23584427 Hexavalent chromium 23584427 hexavalent chromium 23584427 oxygen 23584541 1,2,3-triazole 23584541 3-O-propargylated betulinic acid and its 1,2,3-triazoles 23584541 3{1N(2-cyanophenyl)-1H-1,2,3-triazol-4yl}methyloxy betulinic acid 23584541 3{1N(5-hydroxy-naphth-1yl)-1H-1,2,3-triazol-4yl}methyloxy betulinic acid 23584541 C 23584541 betulinic acid 23584545 Schiff's base 23584545 quinoline 23584556 C 23584556 N 23584556 amino acid 23584556 zinc 23584636 Al2O3 23584636 Au 23584636 ITO 23584636 ZnO 23584636 indium-tin-oxide 23584857 2-deoxyglucose 23584886 Ketoconazole 23584886 ketoconazole 23584886 midazolam 23584948 Caprelsa 23584948 Vandetanib 23584948 tyrosine 23585058 APV 23585058 BAPTA-AM 23585058 Ca2+ 23585058 GABA 23585058 NMDA 23585058 UO126 23585058 calcium 23585058 γ amino-butyric acid 23585235 D 23585235 D2 23585235 H 23585235 H2 23585235 HD 23585235 Pd 23585235 Pd(111) 23585235 hydrogen 23585358 C-H 23585358 diazonium 23585380 PLGA 23585380 poly(L-lactic-co-glycolic acid) 23585383 Ag 23585383 Fe2 O3 23585383 iron oxide 23585770 Ni 23586441 (1)H 23586441 Acridine 23586441 acridine 23586441 acridinium 23586441 aliphatic ammonium 23586441 nitrogen 23586441 tetraamine 23586441 triethylentetraamine 23586519 2-propanol 23586519 P2VP 23586519 PDMS 23586519 PFS 23586519 THF 23586519 decane 23586519 poly(2-vinylpyridine 23586519 poly(ferrocenyldimethylsilane) 23586519 polydimethylsiloxane 23586638 C 23586638 CH3C(O)O(•)CHCH2OH 23586638 CH3C(O)OCH(OH)(•)CH2 23586638 CH3COOC2H3 23586638 H 23586638 NO 23586638 O2 23586638 OH 23586638 Vinyl Acetate 23586638 Vinyl acetate 23586638 acetic acid 23586638 ethylenic 23586638 formaldehyde 23586638 formic acetic anhydride 23586839 2H 23586839 C 23586839 CH 23586839 CH2 23586839 H 23586839 H2 23586839 Ir 23586839 Methane 23586839 Pt 23586839 Ta 23586839 Transition Metal 23586839 W 23586839 carbene 23586839 carbyne 23586839 hydrido-methylidyne 23586839 hydrogen 23586839 methane 23586839 transition metal 23587048 3-Hydroperoxy-N-nitrosomorpholine 23587048 3-oxapentanal 23587048 6-(2-{2-[(9H-purin-6-yl)amino]ethoxy}ethoxy)-9H-purin-2-amine 23587048 Ade 23587048 Gua 23587048 N 23587048 N-Nitrosomorpholine 23587048 Na(AcO)3BH 23587048 NaBH4 23587048 NaNCBH3 23587048 O 23587048 Purine 23587048 ascorbate 23587048 borohydride 23587048 diazonium 23587048 hydride 23587048 hydroperoxide 23587048 imine 23587048 iminium 23587048 nicotinamide 23587048 α-hydroxynitrosamine 23587423 lysine 23587426 2-amino-2-hydroxymethyl-propane-1,3-diol 23587426 4-alkyloxybenzaldehyde 23587426 aromatic amino alcohols 23587426 methicillin 23587660 alcohol 23588093 5-hydroxytriptamine 23588093 Ca(2+) 23588093 CaCl2 23588093 KCl 23588093 Luteolin 23588093 calcium 23588093 chrysoeriol 23588093 glibenclamide 23588093 indomethacin 23588093 isovitexin 23588093 l-NAME 23588093 luteolin 23588093 norepinephrine 23588093 p-coumaric acid 23588093 phenylephrine 23588093 tetraethylammonium 23588094 chloroform 23588094 cinnamyl alcohol 23588094 ethanol 23588094 n-butanol 23588094 styrene 23588094 α-pinene 23588312 5-FU 23588312 5-Fluorouracil 23588312 dihydropyrimidine 23588390 4-(N)-stearoyl 23588390 BrdU 23588390 GEM-C18 23588390 GEM-C18-PLGA 23588390 PLGA 23588390 gemcitabine 23588390 stearoyl 23588390 stearoyl gemcitabine 23588558 statin 23588560 TAC 23588560 Tacrolimus 23588560 tacrolimus 23588562 CBD 23588562 THC 23588562 cannabidiol 23588562 tetrahydrocannabinol 23588681 Emodin-6-O-β-D-glucoside 23588681 PMA 23588681 emodin-6-O-β-D-glucoside 23588681 phorbol-12-myristate 13-acetate 23588682 carboxy 23588682 polyvinyl pyrrolidone 23588682 venlafaxine 23588796 polyaniline 23588997 ZrH2 23588997 hydrogen 23588997 zirconium 23588997 zirconium hydrides 23589223 C60 23589223 Fullerene 23589223 fullerene 23589329 Arsenic 23589329 arsenic 23589329 sulforaphane 23589329 tBHQ 23589329 tert-butylhydroquinone 23589462 (1) H 23589462 (13) C 23589462 (15) N 23589462 Cu(II) 23589462 N-C 23589462 Zn(II) 23589462 amino acids 23589476 glucose 23589501 Cu 23589501 NaCl 23589501 O2 23589501 dioxygen 23589501 hydrogen 23589501 neocuproine 23589501 oxygen 23589501 pyrene 23589624 amino acid 23589624 amino acids 23589624 p-azido-l-phenylalanine 23589624 p-propargyloxy-l-phenylalanine 23589624 pAzF 23589624 pPaF 23590189 H2O2 23590189 PVO 23590189 Vanillin 23590189 acetal 23590189 hydrogen peroxide 23590189 oxygen 23590189 peroxalate ester 23590189 poly(vanillin oxalate) 23590189 vanillin 23590386 CS2 23590386 P3AT 23590386 P3ATs 23590386 P3DDT 23590386 PQT12 23590386 Poly(3-alkylthiophene)s 23590386 carbon disulfide 23590386 chloroform 23590386 dichloromethane 23590386 pBTTT12 23590386 poly(2,5-bis(3-dodecylthiophen-2-yl)thieno[3,2-b]thiophene) 23590386 poly(3,3‴-didodecyl-quaterthiophene) 23590386 poly(3-alkylthiophene)s 23590386 poly(3-dodecylthiophene) 23590386 tetrahydrofuran 23590473 alcohol 23590667 MoS2 23590689 Cl(+) 23590689 ClF2(+) 23590689 ClFn 23590689 ClFn(+) 23590689 F 23590689 HF 23590689 PFn 23590689 S 23590689 SCln 23590689 SF2 23590689 SFn 23590689 SFnCl 23590882 Ca(2+) 23590882 Glutamate 23590882 amino acid 23590882 amino acids 23590892 DHA 23590892 Docosahexaenoic acid 23590892 Paraquat 23590892 hydroxyproline 23590892 paraquat 23591044 6-STM 23591044 6-sulfatoxymelatonin 23591044 Ethanol 23591044 Melatonin 23591044 androgen 23591044 estradiol 23591044 estrogen 23591044 ethanol 23591044 melatonin 23591044 progesterone 23591044 steroid 23591111 SAHA 23591111 hydroxamic acid 23591111 vorinostat 23591111 zinc 23591111 β-cyclodextrin 23591111 βCD 23591660 C60 23591660 Ga 23591660 carbon 23591777 CCl4 23591777 MDA 23591777 MSM 23591777 carbon tetrachloride 23591777 malondialdehyde 23591777 methylsulfonylmethane 23591777 superoxide 23591995 ramiprilat 23592429 Abiraterone acetate 23592429 androgen 23592429 androgens 23592429 enzalutamide 23592516 L-amino acid 23592516 NK-252 23592516 OPZ 23592516 choline 23592516 oltipraz 23592516 thiol 23592516 urea 23592568 Trimethine Cyanine 23592568 trimethine cyanines 23592779 vitamin B12 23593923 serine 23593960 Diacetyl 23593960 TDI 23593960 diacetyl 23593960 toluene-2,4-diisocyanate 23594296 C 23594296 Cl 23594296 HP-βCD 23594296 Tween 80 23594296 chloroform 23594296 dichloromethane 23594296 ethanol 23594296 ethyl acetate 23594296 hydrogen 23594296 hydroxyl 23594296 hydroxypropyl β-cyclodextrin 23594296 methanol 23594296 octanol 23594296 phosphate 23594296 sodium citrate 23594296 taxol 23594789 6-n-propyl-2-thiouracil 23594789 PTU 23594789 Thyroid hormones 23594789 thyroid hormone 23594789 triiodothyronine 23595055 MeOH 23595055 brominated tyrosine 23595055 bromine 23595055 bromotyrosine 23595419 Ag 23595419 K 23595419 Li 23595419 Mg 23595419 MnO2 23595419 Na 23595419 chloride 23595419 lithium 23595419 lithium iron phosphate 23595419 magnesium 23595419 sodium 23595510 (1)H 23595510 (13)C 23595510 carbide 23595510 carbon 23595510 carbons 23595554 bromadiolone 23595554 difenacoum 23595692 Pine Oil 23595692 adenosine triphosphate 23595692 capsaicin 23595692 pine oil 23595692 pine-oil 23596084 Poly(N-alkyl Acrylamide) 23596084 benzophenone 23596084 poly(alkylacrylamide) 23596091 FITC 23596091 FITC-labeled mPEG-PCL 23596091 Fluorescein isothiocyanate 23596091 mPEG-PCL 23596091 monomethoxy poly(ethylene glycol)-block-poly(ε-caprolactone) 23596325 fatty acid 23596325 glucose 23596325 sucrose 23596325 unsaturated fatty acid 23596359 Cyclic Tetrapeptides 23596359 Cyclic tetrapeptides 23596359 cyclic tetrapeptides 23596359 d-amino acids 23596359 hydrogen 23596359 proline 23596972 VA64 23597047 Adenosine 23597047 nucleosides/tides 23597047 nucleotides 23597071 biotin 23597099 2-Methoxyjuglone 23597099 2-methoxyjuglone 23597099 EtOAc 23597099 ethanol 23597099 propidium iodide 23597133 CO 23597133 H 23597133 H-CO(X̃(2)A') 23597133 HCO 23597450 O-methylated isoflavone 23597450 Prunetin 23597450 nitric oxide 23597450 prostaglandin E2 23597450 prunetin 23597490 Embelin 23597490 STZ 23597490 benzoquinone 23597490 embelin 23597490 glucose 23597490 glutathione 23597490 malondialdehyde 23597490 streptozotocin 23597490 superoxide 23597507 Ca(2+) 23597507 SB366791 23597507 calcium 23597507 capsaicin 23597507 mibefradil 23597507 nifedipine 23597510 Nicotine 23597510 SAHA 23597510 Suberoylanilide hydroxamic acid 23597510 alcohol 23597510 cocaine 23597510 nicotine 23597793 (1)H 23597793 (13)C 23597793 11β-hydroxysteroid 23597793 Asp 23597793 NADP(+) 23597793 Ser 23597793 Tyr 23597793 clofibrate 23597793 clofibric acid 23597793 glucose 23597793 nicotinamide 23597793 tetrazole 23598462 graphene 23598904 AgNO3 23598904 Cd 23598904 Cd(2+) 23598904 CdCl2 23598904 HgCl2 23598904 Mn 23598904 Mn(2+) 23598904 MnCl2 23598904 cadmium 23598904 manganese 23599006 7-O-(β-D-glucopyranosyl)-galactin 23599006 alanine 23599006 aspartate 23599431 TC14012 23599433 serine 23599433 threonine 23600432 1,5-diarylpyrazoles 23600432 arachidonic acid 23600432 indoles 23600432 indolizines 23600486 (cAAC)2Zn 23600486 (cAACH)2Zn 23600486 CO2 23600486 KC8 23600486 LiB(sec-Bu)3H 23600486 Zinc 23600486 ZnCl2 23600486 cAAC 23600486 cyclic alkylaminocarbene 23600486 dicarbene zinc 23600486 zinc 23600612 8-dehydroxymethylvisanol 23600612 9-O-[3-O-acetyl-β-d-glucopyranosyl]-4-hydroxy-cinnamic acid 23600612 9-aldehydevibsanol 23600612 EtOH 23600612 lignans 23600612 visanol 23600626 PolyHis 23600626 ethylene glycol 23600626 poly(aspartic acid) 23600626 poly-l-glutamic acid 23600626 poly-l-histidine 23600626 polyAsp 23600626 polyGlu 23600626 polyHis 23600646 Fe3O4 23600646 TiO2 23600646 bisphenol A 23600646 dibutyl phthalate 23600648 (-)-4-hydroxybenzoic acid-4-O-[6'-O-(2″-methylbutyryl)-β-D-glucopyranoside] 23600648 dioxaspirocycle 23600648 quinochalcone glycoside 23600648 saffloquinoside C 23600656 1,2-dipalmitoyl-sn-glycero-3-phosphacholine 23600656 Brucine 23600656 DPPC 23600656 brucine 23600656 phosphatidylcholine 23600717 fawcettimine 23600717 lycobscurines A-C 23600735 Anthraquinones 23600735 flavonoids 23600735 terpenoids 23600754 3,4-secocycloarta-4(28),17(20)(Z),24(Z)-triene-7β-hydroxy-16β-methoxy-3,26-dioic acid 23600754 3,4-secocycloarta-4(28),17(20),24(Z)-triene-7β-hydroxy-16β,26-lactone-3-oic acid 23600754 3,4-secocycloarta-4(28),24(Z)-diene-3,26-dioic acid 23600754 3,4-secocycloartane 23600754 ester 23600754 lactone 23600754 nigranoic acid 23600800 ATP 23600800 MG-132 23600800 calcium 23600800 serine 23600807 cyclo-(l-Val-l-Leu) 23600807 diketopiperazines 23600807 rhodostegone 23600887 (25R)-26-O-[β-d-glucopyranosyl-(1 → 2)-β-d-glucopyranosyl]-5-ene-furost-1β,3β,22α,26-tetraol-3-O-α-l-rhamnopyranosyl-(1 → 2)-[β-d-xylopyranosyl-(1 → 4)]-β-d-glucopyranoside 23600887 (25R)-26-O-[β-d-glucopyranosyl-(1 → 6)-β-d-glucopyranosyl]-5-ene-furost-1β,3β,22α,26-tetraol-3-O-α-l-rhamnopyranosyl-(1 → 2)-[β-d-xylopyranosyl-(1 → 4)]-β-d-glucopyranoside 23600887 C-26 hydroxy 23600887 Furostanol 23600887 disaccharide 23600887 furostanol 23600887 ophiopogonin P 23600887 ophiopogonin Q 23600887 saponins 23600887 steroidal saponins 23600914 24(S)-hydroxycholesterol 23600914 24-OHC 23600914 TO901317 23600914 cholesterol 23600914 retinoic acid 23600925 Diaminothiazole 23600925 diaminothiazole 23600925 serine 23600925 threonine 23601387 25-hydroxy-vitamin D3 23601387 25OHD3 23601387 vitamin D 23601387 vitamin D3 23601391 sugar 23601393 Ascorbic acid 23601393 Potassium 23601393 ascorbic acid 23601393 calcium 23601393 copper 23601393 magnesium 23601393 phosphorous 23601393 zinc 23601396 calcium 23601396 carbohydrates 23601396 copper 23601396 iron 23601396 magnesium 23601396 manganese 23601396 phosphorus 23601396 potassium 23601396 selenium 23601396 sodium 23601396 zinc 23601409 Glucose 23601409 arabinose 23601409 ethanol 23601409 galactose 23601409 mannose 23601409 monosaccharide 23601409 xylose 23601709 DMSO 23601709 EMPA 23601709 O 23601709 [(11)C]CH3I 23601709 [(11)C]EMPA 23601709 [(11)C]N-ethyl-2-(N-(6-methoxypyridin-3-yl)-2-methylphenylsulfonamido)-N-(pyridin-3-ylmethyl)acetamide 23601709 [(3)H]-EMPA 23601709 carbon 23601709 cesium carbonate 23601709 chlorotrimethylsilane 23601709 sodium iodide 23601710 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione 23601710 benzotriazepine 23601710 phenyl 23601710 spirobenzodiazepine 23601711 6-bromo-8-ethoxy-3-nitro-2H-chromene 23601711 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene 23601711 BENC-511 23601711 S14161 23601711 l-proline 23601711 triethylamine 23602400 2-Phenyl-4-piperidinyl-6,7-dihydrothieno[3,4-d]pyrimidine 23602400 4-amino 23602400 4-amino-2-phenylpyrimidine 23602400 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine 23602400 N-propylacetamide 23602400 pyrimidines 23602442 amine 23602442 diarylurea 23602442 diarylureas 23602516 Cisplatin 23602516 cisplatin 23602732 Salidroside 23602732 salidroside 23602732 tyrosol 23602891 HCQ 23602891 Hydroxychloroquine 23602891 hydroxychloroquine 23602903 H2O2 23602903 Monoterpene pyridine alkaloids 23602903 Scrophularianines A-C 23602903 cyclopenta [c] pyridine 23602903 iridoids 23602903 monoterpene pyridine 23602903 monoterpene pyridine alkaloids 23602903 phenolics 23602986 COT 23602986 Cotinine 23602986 DHβE 23602986 MEC 23602986 MLA 23602986 NIC 23602986 cotinine 23602986 dihydro-beta-eritroidine 23602986 mecamylamine 23602986 methyllycaconitine 23602986 nicotine 23602989 Ca(2) 23602989 Ca(2+) 23602989 GABA 23602989 K(+) 23602989 KN-62 23602989 PD 128,907 23602989 SKF 38393 23602989 [(3)H]GABA 23602989 cAMP 23602989 dopamine 23602989 ionomycin 23602989 nifedipine 23603053 2'-OH-BDE-007 23603053 3'-OH-BDE-007 23603053 3'-OH-BDE-028 23603053 3-OH-BDE-047 23603053 4'-OH-BDE-017 23603053 4'-OH-BDE-049 23603053 5'-OH-BDE-099 23603053 6'-OH-BDE-099 23603053 6-OH-BDE-047 23603053 OH-PBDE 23603053 OH-PBDEs 23603053 PBDE 23603053 PBDEs 23603053 Polybrominated diphenyl ethers 23603053 estrogen 23603053 hydroxylated polybrominated diphenyl ethers 23603059 Arsenic 23603059 N 23603059 N-acetylcysteine 23603059 NAC 23603059 SP6001325 23603059 arsenic 23603059 oxygen 23603059 sodium arsenite 23603112 BMPCP-4P2 23603112 TMPCP 23603112 TMPCP-4P 23603112 bi-cationic meso-5,10-bis(4-N-methylpyridyl)-15,20-di-(4-carboxyphenyl)porphyrin 23603112 porphyrin 23603112 porphyrins 23603112 tetrapeptide 23603112 tetrapeptides 23603112 tri-cationic meso-tri(4-N-methylpyridyl)-mono-(4-carboxyphenyl)porphyrin 23603193 MDA 23603193 NO 23603193 PTZ 23603193 Val 23603193 Valproate 23603193 nitric oxide 23603193 pentylenetetrazol 23603293 Toluquinol 23603293 methylhydroquinone 23603293 toluquinol 23603339 3-methylcholanthrene 23603339 7-ethoxyresorufin 23603339 DHEA 23603339 Dehydroepiandrosterone 23603339 O 23603339 actinomycin D 23603339 androgen 23603339 bicalutamide 23603339 dehydroepiandrosterone 23603339 estrogen 23603339 phenacetin 23603380 Piperidine 23603380 acetylcholine 23603380 alpha conotoxin GI 23603380 anabasine 23603380 lobeline 23603380 myosmine 23603380 pyridine alkaloid 23603381 BLM 23603381 Ellagic acid 23603381 GSH 23603381 bleomycin 23603381 carbonyl 23603381 cyclophosphamide 23603381 hydroxyproline 23603381 nitric oxide 23603385 TiO2 23603385 titanium dioxide 23603635 benzoquinones 23603635 tyrosine 23603635 vanadium 23604140 Bodipy 23604140 Bodipy [558/568] 23604140 gallamine 23604140 indocarbazolole 23604140 pirenzepine 23604592 As 23604592 Cd 23604592 Pb 23604592 oxygen 23604719 flavonoids 23604719 β-CD 23604719 β-cyclodextrin 23604721 flavan 23604721 flavonoid 23604721 methanol 23604819 1-Substituted-N-tosyl-1,2,3,4-tetrahydroisoquinoline 23604819 N-tosyl-1,2,3,4-tetrahydroisoquinoline 23604819 Trimethoxy 23604819 o-hydroxy 23604819 p-methoxy 23604819 tetrahydroisoquinolines 23605905 thyroxin 23605905 triiodothyronine 23606243 CdSe 23606243 FTO 23606243 TiO2 23606278 Statins 23606278 cholesterol 23606278 statins 23606301 Oxygen 23606301 PDMS 23606301 oxygen 23606301 polydimethylsiloxane 23606318 dabigatran 23606318 rivaroxaban 23606318 warfarin 23606463 amino 23606463 carbonyl 23606629 (E)-5-(2-bromovinyl)-2'-deoxyuridine 23606629 BVDU 23606629 IDA-POM 23606629 L-alanine 23606629 Phosphoramidate 23606629 nucleoside 23606629 nucleoside monophosphates 23606629 nucleosides 23606629 nucleotide 23606629 phosphoramidate 23606629 phosphoramidate triester 23606629 phosphoramidates 23606629 pivaloyloxymethyl iminodiacetate 23606629 thymidine 23607523 C7 23607523 N 23607523 O 23607523 Pyralomicin 23607523 benzopyranopyrrole 23607523 cyclitol 23607523 glucose 23607523 phosphate 23607523 pyralomicin 23607523 sugar 23607578 Carbon 23607578 carbon 23607578 carbon black 23607669 HB(C6F5)2 23607669 amines 23607669 borane 23607669 dienes 23607669 imines 23607866 1H 23607866 N-(2-benzoyloxypropyl methacrylamide 23607866 N-(2-hydroxypropyl) methacrylamide monolactate 23607866 Paclitaxel 23607866 docetaxel 23607866 ethanol 23607866 naphthoyl 23607866 paclitaxel 23607866 polyethylene glycol 23607869 C-C 23607869 C-f 23607869 C-h 23608109 crizotinib 23608241 Mitragynine 23608241 cAMP 23608241 cyclic AMP 23608241 forskolin 23608241 foskolin 23608241 indole alkaloid 23608241 mitragynine 23608241 morphine 23608241 nitrogen 23608613 albuterol sulfate 23608613 l-leucine 23608613 mannitol 23608613 poloxamer 188 23608699 11-KT 23608699 11-ketotestosterone 23608699 17α-ethinylestradiol 23608699 17β-estradiol 23608699 25-OH-cholesterol 23608699 EE2 23608699 estrogen 23608699 pregnenolone 23608699 testosterone 23608896 Cu2O 23608896 Ni 23608896 polystyrene 23609128 (H2 O)5 (+) 23609128 (H2 O)n 23609128 H2 O 23609128 H3 O(+) 23609128 hydronium 23609128 hydroxyl 23609145 Bicarbonate 23609145 Bisulfite 23609145 Folate 23609145 Monocarboxylates 23609145 acetate 23609145 bicarbonate 23609145 bisulfite 23609145 citrate 23609145 folate 23609145 glycine 23609145 nitrate 23609145 nitrite 23609145 phosphate 23609145 pyruvate 23609145 sulfate 23609438 Ca(2+) 23609438 Calcium 23609438 Potassium 23609438 cAMP 23609438 calcium 23609438 potassium 23609606 NADPH 23609606 UDPGA 23609606 [(14)C]-fenclozic acid 23609606 acyl glucuronide 23609606 carboxylic acid 23609606 fenclozic acid 23609606 taurine 23609769 Amphetamine 23609769 MDMA 23609769 amphetamine 23609769 ecstasy 23609769 methylendioxymethamphetamine 23609769 serotonin 23609770 remifentanil 23609782 BG-12 23609782 Fingolimod 23609782 Laquinimod 23609782 Teriflunomide 23609944 amino acid 23609944 amino acids 23609963 cholesterol 23609963 fatty acid 23610077 SBA-15 23610077 Silanol 23610077 alkoxysilanes 23610077 bis-silylamine 23610077 chlorosilanes 23610077 nitrobenzene 23610077 silanol 23610077 silica 23610086 -(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)ethanone 23610086 1,2,4-thiadiazole 23610086 1-(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(2-methylimidazo[2,1-b]thiazol-6-yl)ethanone 23610086 1-(2-(2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-(imidazo[2,1-b]thiazol-6-yl)ethanone 23610086 18O 23610086 2-methylimidazo[2,1-b]thiazole 23610086 Imidazo- and 2-Methylimidazo[2,1-b]thiazole 23610086 NADPH 23610086 S-oxide 23610086 glutathione 23610086 glutathione-S-oxide 23610086 glutathionyl 23610086 imidazo[2,1-b]thiazole 23610086 potassium cyanide 23610086 thiazole 23610086 thiol 23611120 D - Glucose 23611120 D-glucose 23611120 Polystyrene 23611120 Ru 23611120 hydrogen 23611120 polystyrene 23611124 Indolecarboxamide 23611124 indole-2-carboxamide 23611338 m-MitoPhB(OH)2O•- 23611338 o-, m-, and p-MitoPhB(OH)2 23611338 o-MitoPhB(OH)2 23611338 o-MitoPhB(OH)2O•- 23611338 o-MitoPhNO2 23611338 o-MitoPhOH 23611338 ortho-MitoPhB(OH)2 23611338 p-MitoPhB(OH)2O•- 23611338 •NO2 23611338 Aromatic boronic acids 23611338 ONOO- 23611338 PhB(OH)2 23611338 PhB(OH)2O•- 23611338 TPP 23611338 arylboronate 23611338 arylboronates 23611338 peroxynitrite 23611338 phenolic 23611338 phenols 23611338 phenyl 23611338 triphenylphosphonium 23611338 triphenylphosphonium-substituted arylboronic acid 23611508 polystyrene 23611538 EGCG 23611538 Epigallocatechin-3-gallate 23611538 Schiff bases 23611538 amines 23611538 polyphenol 23611538 thioflavin T 23611809 UDP 23611809 afloqualone 23611809 amine 23611809 amitriptyline 23611809 carbamazepine 23611809 cyclic amines 23611809 desipramine 23611809 diphenhydramine 23611809 hecogenin 23611809 imidazole 23611809 imipramine 23611809 ketoconazole 23611809 ketotifen 23611809 midazolam 23611809 nicotine 23611809 nortriptyline 23611809 olanzapine 23611809 pizotifen 23611809 secondary or primary amines 23611809 tamoxifen 23611809 tertiary aliphatic amines 23611809 tertiary amines 23611809 tertiary cyclic amine 23611809 trifluoperazine 23612242 S 23612242 glutathione 23612242 polycyclic aromatic hydrocarbons 23612242 superoxide 23612421 2,8-dihydroxyadenine 23612421 3-O-methyldopa 23612421 3-methyldioxyindole, 23612421 8-hydroxyadenine 23612421 L-acetylcarnitine 23612421 adenine 23612421 amino acid 23612421 creatine 23612421 ethyl-N2-acetyl-L-argininate, 23612421 hypoxanthine 23612421 indole-3-carboxylic acid 23612421 methionine 23612421 phenylalanine 23612421 phytosphingosine 23612421 xanthurenic acid 23612423 ATP 23612423 DPPH 23612423 MDA 23612423 chloroform 23612423 creatine 23612423 ethanol 23612423 malate 23612423 nitric oxide 23612487 S1P 23612487 Sphingosine-1-phosphate 23612487 phosphatidylinositol 23612487 sphingolipid 23612709 calcium 23612720 ferro 23612720 graphane 23612720 graphene 23612720 graphenes 23612720 hydrogen 23613012 Cholesterol 23613012 Testosterone 23613012 cholesterol 23613012 testosterone 23613012 testosterone esters 23613012 triglyceride 23613080 FTO 23613080 NiO 23613080 WO3 23613312 4-benzyloxybenzaldehyde 23613312 alkene 23613312 cyclopropane 23613312 cyclopropyl 23613312 estrogen 23613312 raloxifene 23613312 stilbene 23613312 tamoxifen 23613425 DOX 23613425 Doxorubicin 23613425 PLA 23613425 doxorubicin 23613425 mPEG 23613425 methoxy 23613425 poly(D,L-lactic acid) 23613425 poly(ethylene glycol) 23614379 ( - )-(7R,7'R,8S,8'R)-4,4'-dihydroxy-3,3'-dimethoxy-7,7'-epoxylignan-4'-O-β-d-glucopyranoside 23614379 ( - )-(7R,7'R,8S,8'R)-4,4'-dihydroxy-3,3'-dimethoxy-7,7'-epoxylignan-4-O-β-d-glucopyranoside 23614379 ( - )-(7R,8R)-syringylglycerol-8-O-β-d-glucopyranoside 23614379 ( - )-(8S,8'R)-4,4'-dihydroxy-3,3',5'-trimethoxylignan-4'-O-β-d-glucopyranoside 23614379 ( - )-3-hydroxy-2-methyl-4-pyrone-3-O-β-d-xylopyranosyl-(1 → 6)-O-β-d-glucopyranoside 23614379 ( - )-nectandrin B-β-d-glucopyranoside 23614492 11α-hydroxypimara-8(14),15-diene 23614492 1β,11α-dihydroxypimara-8(14),15-diene 23614492 2,3-secoaromadendrane 23614492 7β,11α-dihydroxypimara-8(14),15-diene 23614492 Terpenoids 23614492 diterpenoids 23614492 ethyoxyplagiochiline A2 23614492 fusicoccane 23614492 pimarane 23614492 sesquiterpenoids 23614571 (2S,1'R,2'S)-2-(carboxycyclopropyl)glycine 23614571 (S)-CCG-IV 23614571 2'-substituted (2S,1'R,2'S)-2-(carboxycyclopropyl)glycine 23614571 N-methyl-D-aspartic acid 23614571 NMDA 23614635 bisphosphonates 23614635 estrogen 23614635 strontium ranelate 23614643 SU5402 23614643 bis- and tris-xylosides 23614643 mono-xylosides 23614643 xyloside 23614643 xylosides 23614652 AA-I 23614652 Aristolic Acid 23614652 Aristolochic Acid I 23614652 Aristolochic acid I 23614652 Cysteine 23614652 Glutathione 23614652 aristolic acid 23614652 cysteine 23614652 glutathione 23614652 nitro 23614728 Eosin 23614728 Haematoxylin 23614728 phosgene 23614815 amino-acid 23614815 disulphide 23614827 (+)-anwulignan(erythro-1-(4-hydroxy-3-methoxyphenyl)-4-(3,4-methylenedioxyphenyl)-2,3-dimethyl-butane) 23614827 (7S,8R,7'R,8'R)-7-(3,4-methylenedioxyphenyl)-8,8'-dimethyl-8'-hydroxyl-7'-methoxyl-7'-(3',4'-methylenedioxyphenyl)-tetrahydrofuran 23614827 ( - )-zuonin-A 23614827 2-hydroxy-11,12-dehydrocalamenene 23614827 erythro-1-(3,4-dimethoxyphenyl)-4-(3,4-methylenedioxyphenyl)-2,3-dimethyl-butane 23614827 lignans 23614831 Cilnidipine 23614831 N-vinylpyrrolidone 23614831 PVP 23614831 Soluplus 23614831 calcium 23614831 cilnidipine 23614831 dihydropyridine 23614831 hydrogen 23614904 Atorvastatin 23614904 Bile Acid 23614904 Sterol 23614904 atorvastatin 23614904 bile acid 23614904 bile acids 23614904 cholesterol 23614904 cholesterol ester 23615074 flavanoids 23615074 oxygen 23616238 Met 23616238 metformin 23616238 triacylglycerol 23616376 DPh-DNTT 23616387 azide-alkyne 23616387 copper 23616387 triazole 23616387 triazoles 23617226 2,9-dimethyl-1,10-phenanthroline 23617226 Bis(2,9-dimethyl-1,10-phenanthroline)copper(I) 23617226 Copper(I) Phenanthroline 23617226 Cu 23617226 [Cu(dmp)2]+ 23617226 acetonitrile 23617226 dichloromethane 23617226 dmp 23617279 Carbon 23617279 Formaldehyde 23617279 Resorcinol 23617279 carbon 23617279 formaldehyde 23617279 potassium carbonate 23617279 resorcinol 23617430 3-carboranyl thymidine 23617430 N3-substituted thymidine 23617430 boron 23617430 carborane 23617439 PZQ 23617439 Praziquantel 23617439 bromine 23617439 praziquantel 23617439 praziquentel 23617462 Di-hydroxy and Tri-hydroxy Bile Salts 23617462 NaC 23617462 NaDC 23617462 NaGDC 23617462 NaTC 23617462 amino acid 23617462 amino acids 23617462 bile salts 23617462 decane 23617462 dexocycholate 23617462 glycodeoxycholate 23617462 sodium 23617462 sodium cholate 23617462 taurocholate 23617753 BRD0476 23617753 naphthyl 23617753 quinoline 23617807 Benzene 23617807 Hexahalogenbenzenes 23617807 benzene 23617807 dihalogen 23617807 hexachloro- and hexabromobenzenes 23617807 hexahalogenbenzenes 23618528 ethanol 23618624 7β-OH spermine 23618624 Squalamine 23618624 aminosterol 23618624 hydroxyl 23618624 polyamine 23618624 sterol 23618624 tetraammonium spermine polyamine 23618624 trisammonium spermidine polyamine 23618921 Fisetin 23618921 Flavonoid 23618921 GSH 23618921 Glutathione 23618921 fisetin 23618921 flavonoid 23619019 Captopril 23619019 ginsenoside Ro 23619019 ginsenosides 23619019 ginsenosides Rb1, Rg1, Rf, Rh1, Rc, Rb2, Ro, and Rg3 23619611 Apixaban 23619611 Dabigatran 23619611 Rivaroxaban 23619611 apixaban 23619611 dabigatran 23619611 edoxaban 23619611 rivaroxaban 23619611 vitamin K 23619613 bleomycin 23619613 polySia 23619613 polysialic acid 23620060 Diacylglycerol 23620060 Glucose 23620060 glucose 23620060 sphingomyelin 23620162 Al(3+) 23620162 Al2O3 23620162 AlY20 23620162 Y(3+) 23620162 Y2O3 23620162 oxygen 23620199 DM1 23620199 MCC 23620199 N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate 23620199 SMCC 23620199 maytansine 23620199 mertansine 23620199 taxane 23620199 thioether 23620200 glucose 23620256 glucose 23620256 propidium iodide 23620256 yo pro-1 23620266 (R)-1-phenylethylamine 23620266 2-APA 23620266 2-arylpropionic acid 23620266 2-arylpropionic acids 23620266 Naproxen 23620266 PEA 23620266 amide 23620266 ibuprofen 23620266 ketoprofen 23620266 naproxen 23620283 C 23620283 serine 23620283 threonine 23620487 5'-O-desmethylomeprazole 23620487 5-hydroxyomeprazole 23620487 Omeprazole 23620487 carboxyomeprazole 23620487 omeprazole 23620487 omeprazole sulfone 23621358 GAL 23621358 PHEA-EDA 23621358 PHEA-EDA-PLA-GAL 23621358 PLA 23621358 RBV 23621358 RBV tripalmitate 23621358 RIBAVIRIN 23621358 alpha,beta-poly(N-2-hydroxyethyl) (2-aminoethylcarbamate)-DL-aspartamide 23621358 carbohydrate 23621358 galactosylated polylactide-polyaminoacid 23621358 lactose 23621358 polylactic acid 23621358 ribavirin 23621493 Oxytetracycline 23621493 Tetracyclines 23621493 anhydrotetracycline 23621493 oxytetracycline 23621493 tetracycline 23621616 Graphene 23621616 graphene 23621857 Acylated Brefeldin A 23621857 BFA 23621857 BFA 4,7-O-dibenzoate 23621857 BFA 7-O-benzoate 23621857 BFA 7-O-biotin carboxylate 23621857 Brefeldin A 23621857 guanine nucleotide 23621857 hydroxyl 23621857 monoacylated and diacylated BFA 23623416 Echinocandins 23623416 acyl 23623416 anidulafungin 23623416 branched chain saturated fatty acid 23623416 caspofungin 23623416 cyclohexapeptides 23623416 diphenylisoxazoloyl 23623416 echinocandins 23623416 hydroxy-glutamine 23623416 lipocyclohexapeptides 23623416 micafungin 23623416 pentyloxyl 23623416 pneumocandins 23623416 threonine 23623416 unsaturated linear fatty acid 23623419 1,2,3-triazoles 23623419 2-arylimidazo[1,2-a]pyridines 23623419 diazepam 23623419 imidazo[1,2-a]pyridines 23623493 half-titanocene 23623493 titanocene 23623743 1,3-DNB 23623743 1,3-dinitrobenzene 23623743 3-CPD 23623743 3-NPA 23623743 3-chloropropanediol 23623743 3-nitropropionic acid 23623743 TMRM 23623743 deferoxamine 23623743 polyacrylamide 23623743 tetramethyl rhodamine methyl ester 23623751 Dopamine 23623751 Methylphenidate 23623751 cocaine 23623751 dopamine 23623751 methylphenidate 23623751 norepinephrine 23623795 sodium phosphate 23623843 8-iso-PGF2a 23623843 CCl4 23623843 DPPH 23623843 GSH 23623843 MDA 23623843 O2(-) 23623843 OH 23623843 carbon tetrachloride 23623843 ferric 23623843 monosaccharides 23624029 17-hydroxyprogesterone 23624029 androgen 23624029 steroid 23624240 Co3O4 23624240 cobalt 23624240 cobalt oxide 23624376 Polyglycerol 23624376 borosilicate 23624376 hyperbranched methoxylated polyglycerol 23624376 hyperbranched polyglycerol 23624376 linear methoxylated polyglycerol 23624419 Vildagliptin 23624419 arginine 23624419 metformin 23624419 vildaglipin 23624419 vildagliptin 23624423 17β-Estradiol 23624423 4-Hydroxytamoxifen 23624423 OHT 23624423 Tamoxifen 23624423 estrogen 23624423 tamoxifen 23624706 C 23624706 Fe2O3 23624706 Li 23624706 SnO2 23624706 carbon black 23624706 lithium 23624706 molten salt 23624810 oxytocin 23624862 GDP 23624862 GTP 23625160 Fe 23625160 MSG 23625160 Monosodium L-Glutamate 23625160 iron 23625160 monosodium L-glutamate 23625194 orlistat 23625194 rimonabant 23625194 sibutramine 23625745 Cholesterol 23625745 cholesterol 23625745 triglycerides 23625750 (1-deoxy-1-6[[(3-iodophenyl) methyl]amino]-9H-purin-9-yl)-N-methyl-B-D-ribofuronamide 23625750 IB-MECA 23625750 adenosine 23625750 sodium taurocholate 23625769 Furosemide 23625769 furosemide 23625769 torsemide 23625779 Amino 23625779 MCM-41 23625779 Silica 23625779 amino 23625779 saponins 23625779 silica 23625787 Warfarin 23625787 warfarin 23625887 3'-O-(isoleucylisoleucyl)-5'-O-(3,3,3-triphenylpropanoyl)thymidine 23625887 5'-Trityl 23625887 5'-triphenylmethyl (trityl) 23625887 Thymidine 23625887 superoxide 23625887 thymidine 23625887 tritylthymidines 23625905 Cr 23625905 Cr(VI) 23625905 GSH 23625905 K2Cr2O7 23625905 chromium (VI) 23625905 copper 23625905 glutathione 23625905 hexavalent chromium 23625905 iron 23625905 thiobarbituric acid 23625905 zinc 23625909 alum 23625912 Al 23625912 Al chloride 23625912 AlCl3 23625912 Aluminum 23625912 Cu 23625912 Fe 23625912 Zn 23625912 aluminum chloride 23625912 copper 23625912 iron 23625912 zinc 23627275 2-(2-methoxyethoxy)ethyl methacrylate 23627275 MEO2MA 23627275 OEGMA 23627275 Pdop 23627275 Rh6G 23627275 SiO2 23627275 methyl orange 23627275 oligo(ethylene glycol) methacrylate 23627275 polydopamine 23627275 rhodamine 6G 23627396 N-methyltyroscherin 23627396 tyroscherin 23627438 Sciadopitysin 23627438 ethanol 23627438 sciadopitysin 23627438 taxane diterpenoids 23627438 thioflavin-T 23627443 Tween 23627443 amphotericin B 23627597 1,2-acyloxy 23627597 1,6-Diyne Carbonates and Esters 23627597 1,6-diyne carbonates and esters 23627597 2,4a-Dihydro-1H-fluorenes 23627597 2,4a-dihydro-1H-fluorenes 23627597 Au 23627597 cyclopropene 23627597 gold(I) 23627605 Graphene 23627605 SiO2 23627605 graphene 23627685 Zinc 23627685 Zn 23627685 ZnO 23627685 carbon 23627685 hydrogen 23627685 oxide 23627717 cyclodextrin (i.e. ,  or ) 23627717 di-n-decyldimethylammonium chloride 23627717 octaethylene glycol monododecyl ether 23627806 2-methacryloylethyl acrylate 23627806 MEA 23627806 acrylic acid 23627806 citric acid 23627806 iron oxide 23627806 poly(N-isopropylacrylamide) 23627806 poly(ethylene glycol) 23627834 Dox 23627834 Doxorubicin 23627834 NIPAM 23627834 Poly(N-isopropylacrylamide)-b-poly(l-histidine) 23627834 doxorubicin 23627834 p(NIPAM)55-b-p(His)n 23627834 poly(N-isopropylacrylamide)55-block-poly(l-histidine)n 23627834 α-amino acid N-carboxyanhydrides 23627902 (1)H 23627902 (13)C 23627902 cyano 23627902 dodecyl 23627902 phenyl 23628154 baicalein 23628154 baicalin 23628154 berberine 23628154 gardenoside 23628154 palmatine 23628332 1-hydroxy-6-oxo-2-cyclohexenecarboxylate 23628332 6-(oxymethyl)-2-hydroxyphenyl-O-β-d-glucopyranosyl-(1→6)-β-d-glucopyranoside 23628332 CHCl3 23628332 Idescarpin 23628332 idescarpin 23628332 methanol 23628332 n-BuOH 23628333 2-thio-6-oxo-1,6-dihydropyrimidine 23628333 2-thio-6-oxo-1,6-dihydropyrimidines 23628333 NADH 23628333 lactate 23628455 ACh 23628455 L-NAME 23628455 NaCl 23628455 Spironolactone 23628455 acetylcholine 23628455 aldosterone 23628455 enalaprilate 23628455 losartan 23628455 sodium 23628455 spironolactone 23628508 Aspidin BB 23628508 aspidin BB 23628508 phloroglucinol 23628508 poly ADP-ribose 23628508 propidium iodide 23628509 B[a]P 23628509 B[c]Ph 23628509 CP-PAHs 23628509 CP[c]Ph 23628509 CP[c]Phs 23628509 Cyclopenta[c]phenanthrenes 23628509 alkyl 23628509 benzo[a]pyrene 23628509 cyclopenta-fused polycyclic aromatic hydrocarbons 23628509 cyclopenta[c]phenanthrenes 23628509 cyclopentane 23628509 estrogen 23628509 phenanthrene 23628605 3β-hydroxysteroid 23628605 Steroid 23628605 aldosterone 23628605 cholesterol 23628605 pregnenolone 23628605 steroid 23628605 vitamin D 23628621 cholesterol 23628674 Tacrolimus 23628674 deoxyshisandrin 23628674 ethanol 23628674 schisandrin 23628674 schisandrol B 23628674 schisanhenol 23628674 schisantherin A 23628674 tacolimus 23628674 tacrolimus 23629055 C 23629055 Porphyrin 23629055 carboxyl 23629055 cyanoacrylic acid 23629055 dioctyloxy 23629055 meso-phenyl 23629055 meso-phenyls 23629055 meta di-tert-butylphenyl-substituted porphyrins 23629055 meta-substituted porphyrins 23629055 ortho-octyloxy 23629055 porphyrin 23629516 TCPP 23629516 TDCPP 23629516 Tris(1-chloro-2-propyl) phosphate 23629516 organophosphate 23629516 tris(1,3-dichloro-2-propyl) phosphate 23629675 Lysine 23629675 NaCl 23629675 ethylene 23629675 lysine 23629675 proline 23629675 tryptophan 23630043 5-(1,2,4-Triazol-3-yl)tetrazoles 23630043 5-(1,2,4-triazol-3-yl)tetrazoles 23630043 CC 23630043 azido 23630043 nitrimino 23630043 nitro 23630043 tetrazole 23630043 triazole 23631351 (1)H 23631351 (13)C 23631351 1,1-diphenyl-2-picrylhydrazyl 23631351 5,3',5″,4″'-tetrahydroxy-3″',5″'dimethoxy-biflavone (4' → 8″)-7-O-((2-rhamnoside) rhamnoside) 23631351 acetylated chalcone 23631351 acetylated chalcone glycoside 23631351 biflavonoid glycosides 23631351 ethyl acetate 23631351 methanol 23631351 trans-2',6'-dihydroxy-4'-O-(4″-acetyl-rhamnoside)-4-methoxychalcone 23631427 2-(3-chlorophenoxy)-N-(4-oxo-4H-3,1-benzothiazin-2-yl)acetamide 23631427 Adenosine 23631427 Benzothiazinones 23631427 Monoamine 23631427 N-(4-oxo-4H-3,1-benzothiazin-2-yl)-4-phenylbutanamide 23631427 adenosine 23631427 benzothiazinones 23631427 chlorobenzylpiperazinylbenzamido 23631427 cinnamoylamino 23631427 methoxy 23631427 monoamine 23631427 phenylbutyrylamino 23631427 xanthine 23631490 Polyphenols 23631490 polyphenols 23631493 Lycopene 23631493 lycopene 23631499 AlCl3 23631499 acetylcholine 23631499 rivastigmine 23631553 1H 23631553 Hydrogen 23631553 Polybenzoxazine 23631553 TEPA 23631553 acetic acid 23631553 benzoxazine 23631553 bisphenol-A 23631553 formalin 23631553 polybenzoxazine 23631553 tetraethylenepentamine 23632007 1,5-bis(4-allyldimethylammoniumphenyl) pentan-3-one dibromide 23632007 carbamate 23632007 carbaryl 23632007 carbofuran 23632007 chlorpyrifos 23632007 diazinon 23632007 dichlorvos 23632007 neostigmine 23632007 organophosphorus 23632007 tetraisopropyl pyrophosphoramide 23632081 3,4-methylenedioxy-N-methylamphetamine 23632081 MDMA 23632081 Serotonin 23632081 amino acids 23632081 leucine 23632081 serotonin 23632082 2-APB 23632082 Ba(2+) 23632082 Ca(2+) 23632082 K(+) 23632082 KB-R7943 23632082 La(3+) 23632082 ML204 23632082 Na(+) 23632082 SCH 23390 23632082 TRH 23632082 TTX 23632082 capsazepine 23632082 flufenamic acid 23632082 thyrotropin 23632158 glutamate 23632309 flavonoid 23633521 glucose 23633529 clindamycin phosphate 23633529 dexamethasone phosphate 23633529 fosphenytoin 23633529 oxymethyl 23633529 phosphate 23633529 phosphates 23633529 ritonavir oxymethyl phosphate 23633529 ritonavir phosphate 23633532 11-dehydrocorticosterone 23633532 11DHC 23633532 11β-hydroxysteroid 23633532 AMP 23633532 CORT 23633532 Dexamethasone 23633532 Ser 23633532 Thr 23633532 acetyl-CoA 23633532 corticosterone 23633532 dexamethasone 23633532 diacylglyderide 23633563 glucose 23634786 3-hydroxy-3-methylglutaryl 23634786 Lanostane Triterpenoids 23634786 MeOH 23634786 fasciculol G 23634786 lanostane triterpenoids 23634786 nitric oxide 23634899 $^{17}$OH 23634899 Hydroxyl 23634899 OH 23635005 Carbohydrate 23635005 carbohydrate 23635005 esterified phenolic acids 23635005 phenolic acid 23635005 α-L-Araf 23635005 β-D-Galp 23635023 AlGaAs 23635023 GaAs 23636303 MDL72222 23636303 RS79948 23636303 citalopram 23636303 methiothepin 23636303 noradrenaline 23636303 serotonin 23636446 hydrocortisone 23636584 biotin 23636886 MgCl2 23636886 glucose 23637306 alanine 23637306 aspartate 23637306 benzene 23637306 cholesterol 23637306 creatinine 23637306 superoxide 23637306 toluene 23637306 xylene 23638641 5-N-acetylcystenyl-[6]-shogaol 23638641 5-cysteinyl-[6]-shogaol 23638641 5-glutathionyl-[6]-shogaol 23638641 Cysteine 23638641 Shogaols 23638641 [6]-shogaol 23638641 cysteine 23638641 glutathione 23638641 mercapturic acid 23638641 thiol 23638641 thiols 23638658 Chalcopyrite 23638658 Copper Indium Diselenide 23638658 Cu 23638658 CuInSe2 23638658 In 23638658 Se 23638658 copper 23638658 indium 23638985 (1)H 23638985 3β,12β,20S,26-tetrahydroxydammar-24E-en-6α-O-β-d-glucopyranosyl-(1 → 2)-O-β-d-glucopyranoside 23638985 Ginsenjilinol 23638985 NO 23638985 dammarane 23638985 ginsenjilinol 23638985 ginsenoside Re5 23638985 ginsenoside Rf 23638985 indomethacin 23638985 nitric oxide 23638985 panajaponol A 23638985 protopanaxatriol 23638985 saponin 23638985 saponins 23638985 triterpene 23639075 (1)H 23639075 (13)C 23639075 iridoid esters 23639075 patriheterdoid B, C 23639096 Calcium 23639096 calcium 23639096 catechol 23639096 catechols 23639096 dopamine 23639188 altersolanol 23639188 anthranoids 23639192 ICI 182,780 23639192 Puerarin 23639192 cisplatin 23639192 estrogen 23639192 isoflavone glycoside 23639192 puerarin 23639248 hydroxyproline 23639248 silica 23639361 calcium 23639361 cortistatin-8 23639361 naringenin 23639361 naringin 23639430 cocaine 23639430 dopamine 23639430 quinine 23639430 saccharin 23639437 Nicotine 23639437 nicotine 23639537 indeno[1,2-d]thiazole 23639537 indeno[1,2-d]thiazole hydroxamic acids 23639543 2'-α-fluorine 23639543 2'-α-fluoro 23639543 Ribonucleoside phosphonate 23639543 adenine 23639543 cytidine 23639543 diphosphophosphonate 23639543 nucleoside phosphonates 23639543 triphosphate 23639545 (1)H 23639545 Cs(+) 23639545 K(+) 23639545 Li(+) 23639545 Na(+) 23639545 Rb(+) 23639545 acetamido 23639545 amino 23639545 bis(choloyl) 23639545 l-α-phosphatidylcholine 23639545 p-bis(aminomethyl)benzene 23639545 p-phenylenediamine 23639627 Anthracycline 23639627 DXR 23639627 Doxorubicin 23639627 doxorubicin 23639652 chalcone 23639652 chalcones 23639652 sulfonamide 23639652 sulfonamides 23639652 tyrosine 23639738 Cholesterol 23639738 PEC 23639738 poly(ethylene carbonate) 23639739 6-OHDA 23639741 HCl 23639741 K 23639741 Na 23639741 potassium 23639741 sodium 23639992 PDMS 23639992 polydimethylsiloxane 23640282 Fe3O4 23640282 FePt 23640471 1-butyl-3-methylimidazolium 23640471 C4MIM 23640471 [B(hfip)4](-) 23640471 [BF4](-) 23640471 [C4MIM](+) 23640471 [Cl](-) 23640471 [NTf2](-) 23640471 [OTf](-) 23640471 [PF6](-) 23640722 2-(4-methylpiperazin-1-yl)quinoxaline 23640722 2-amino-3-(4-methylpiperazin-1-yl)quinoxaline 23640722 2-chloro-3-(4-methylpiperazin-1-yl)quinoxaline 23640722 3-(4-methylpiperazin-1-yl)quinoxalin-2-ol 23640722 Quinoxaline 23640722 VUF10166 23640722 [(3) H]granisetron 23640867 arginine 23640867 citrulline 23640867 trypsin 23640872 7β-hydroxytropane 23640872 N 23640872 N-methyl 23640872 OH 23640872 Scopoline 23640872 Tropane 23640872 epoxy 23640872 hydrogen 23640872 hydroxy 23640872 oscine 23640872 scopine 23640872 scopoline 23640872 tropane 23640962 isoflavonoids 23640962 nitric oxide 23640962 prostaglandin E2 23640962 saponins 23641017 cholesterol 23641017 triglyceride 23641017 triglycerides 23641685 Cl2 23641685 HCHO 23641685 HCOOH 23641685 HMP 23641685 HO2 23641685 HOCH2OO 23641685 HOOH 23641685 Hydroxy-Methyl-Peroxy 23641685 O2 23641685 OCOH 23641685 OH 23641685 OOCO 23641685 formaldehyde 23641685 hydroperoxy 23641685 hydroxyl-methyl-peroxy 23641955 MK-0524 23641955 UDP 23641955 laropiprant 23641955 prostaglandin D2 23641955 uridine diphosphate 23642029 BTX-B 23642029 Brevetoxin B 23642029 N-palmitoyl-S-desoxy-BTX-B2 23642029 S-desoxy-BTX-B2 23642029 [14C] 23642029 [14C] N-palmitoyl-S-desoxy-BTX-B2 23642029 [3H] 23642029 [3H] S-desoxy-BTX-B2 23642029 [3H] dihydro-BTX-B 23642029 aldehyde 23642029 amide 23642029 amino acid 23642029 brevetoxin 23642029 cysteine 23642029 cysteine brevetoxin B 23642029 dihydro-BTX-B 23642029 fatty acid 23642029 olefinic 23642029 α,β-unsaturated aldehyde 23642965 7-oxabicyclo[2.2.1]hept-5-en-2-yl 23642965 boron trifluoride diethyl etherate 23643542 18β-GA 23643542 18β-glycyrrhetinic acid 23643542 glycyrrhizin 23643664 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 23643664 MPTP 23643664 carboxy 23643664 dopamine 23643664 tyrosine 23643700 Ascorbic acid 23643700 Vitamin C 23643700 ascorbic acid 23643700 vitamin C 23643725 ascorbate 23643725 chl-a 23643725 glutathione 23643725 oxyfluorfen 23643730 DHT 23643730 Hoechst 33342 23643730 Juglone 23643730 MTT 23643730 androgen 23643730 dihydrotestosterone 23643730 juglone 23643737 1,4-Substituted 4-(1H)-pyridylene-hydrazone 23643737 1,4-substituted 4-(1H)-pyridylene-hydrazone 23643737 acetyl 23643737 acetylcholine 23643739 Glycerol 23643739 glycerol 23643739 metronidazole 23643739 urea 23643744 ADX47273 23643744 NMDA 23643744 PCP 23643744 SSR180711 23643744 THIP 23643744 acetylcholine 23643744 glutamate 23643744 phencyclidine 23643745 Amisulpride 23643745 L-3,4-dihydroxyphenylalanine 23643745 S33084 23643745 SCH23390 23643745 amisulpride 23643745 dopamine 23643745 pramipexole 23643745 raclopride 23643748 oxytocin 23643792 Tween 80 23643792 Tween-80 23643792 poly(-caprolactone) 23643839 glucose 23643839 serine 23643839 threonine 23643933 TSA 23643933 Trichostatin A 23643933 trichostatin 23644192 (99m)Tc 23644192 (99m)Tc-labeled dibenzylideneacetone 23644192 rhenium 23644195 (1)H 23644195 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one 23644195 RVX-208 23644195 carboxylate 23644195 carboxylic acid 23644195 glucuronic acid 23644195 primary hydroxyl 23644200 disaccharide 23644200 galactose 23644200 glycosylated isomalyngamide A 23644200 isomalyngamide A 23644200 lactose 23644200 mannose 23644200 monosaccharide 23644201 2-oxo-1,2-dihydroquinoline-3-carbaldehyde 23644201 4N-substituted thiosemicarbazones 23644201 Et 23644201 H 23644201 H2-Qtsc-R 23644201 Me 23644201 Ni(II) 23644201 Ph 23644201 [Ni(H2-Qtsc-R)2](NO3)2 23644214 4-aminothieno[2,3-d]pyrimidine-6-carbonitrile 23644214 C 23644214 PCl5 23644214 POCl3 23644214 amines 23644214 ampicillin 23644214 chloro 23644214 greseofulvin 23644214 nitrile 23644214 oxothieno[2,3-d]pyrimidine-6-carboxamide 23644256 IBU 23644256 ISDN 23644256 Ibuprofen 23644256 Isosorbide Dinitrate 23644256 ibuprofen 23644256 isosorbide dinitrate 23644525 carbon 23645248 17beta-oestradiol 23645248 Oestrogen 23645248 oestrogen 23645248 sodium iodide 23645249 2,3-bis (4-hydroxyphenyl)-propionitrile 23645249 DPN 23645249 Genistein 23645249 estrogen 23645249 fatty acid 23645249 genistein 23645249 isoflavone 23645249 triglyceride CHEMDNER_CORPUS_BIOCREATIVE_4/CHEMDNER_TRAIN/chemdner_data_preparation_v17july31.pdf0000644002344200234200000172474412176225740030514 0ustar mkrallingerBioinfoUnix%PDF-1.3 % 4 0 obj << /Length 5 0 R /Filter /FlateDecode >> stream x]YsF~ǯ^8 Qf-c;{h(:[=DpI!EY(̬꿦Jf9|j7MduUU,=nܿxf|ɛr]&-8i!]'^Oߧ_4KO_;JO>>uPD#u^~j:vY<1^M?^duixtbkDqIvݤRKe 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A:63:67 23411189 A:761:765 23411189 A:92:96 23411189 T:17:48 23411191 A:0:12 23411191 A:1019:1033 23411191 A:1034:1040 23411191 A:1123:1135 23411191 A:241:255 23411191 A:274:279 23411191 A:285:297 23411191 A:387:392 23411191 A:405:412 23411191 A:533:547 23411191 A:572:586 23411191 A:619:661 23411191 A:722:736 23411191 A:737:743 23411191 A:84:88 23411191 A:913:921 23411191 A:944:950 23411191 A:94:106 23411191 A:957:971 23411191 A:976:982 23411191 T:50:64 23411191 T:65:71 23411194 A:19:30 23411194 A:917:928 23411195 A:184:210 23411195 A:212:216 23411195 A:544:548 23411199 A:101:112 23411199 A:1196:1207 23411199 A:241:253 23411199 A:426:437 23411199 A:442:454 23411199 A:459:468 23411199 A:472:492 23411199 A:497:518 23411199 A:522:532 23411199 A:536:552 23411199 A:556:568 23411199 A:575:584 23411199 A:600:610 23411199 A:658:668 23411199 A:720:731 23411199 A:783:794 23411199 A:881:892 23411199 T:44:55 23411206 A:165:182 23411206 A:184:197 23411206 A:199:207 23411206 A:213:217 23411208 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A:422:423 23434641 A:425:426 23434641 A:428:429 23434641 A:779:792 23434641 A:883:893 23434641 A:920:928 23434641 A:933:943 23434641 T:42:59 23434641 T:4:35 23434648 A:1052:1053 23434648 A:1137:1140 23434648 A:1292:1295 23434648 A:427:430 23434648 A:632:635 23434648 A:786:789 23434669 A:24:33 23434669 A:506:515 23434669 A:842:845 23434669 T:76:85 23434929 A:1097:1111 23434929 A:1215:1228 23434929 A:1354:1368 23434929 A:24:36 23434929 A:344:358 23434929 A:86:100 23434929 T:33:45 23434931 A:601:612 23434931 A:932:938 23434934 A:122:132 23435179 A:483:492 23435179 A:925:938 23435356 A:0:9 23435356 A:1008:1012 23435356 A:1057:1061 23435356 A:11:15 23435356 A:166:170 23435356 A:235:245 23435356 A:295:299 23435356 A:94:98 23435356 T:0:10 23435615 A:1008:1026 23435615 A:1105:1128 23435615 A:1220:1243 23435615 A:1256:1270 23435615 A:1422:1436 23435615 A:1483:1497 23435615 A:1553:1571 23435615 A:235:249 23435615 A:278:296 23435615 A:676:686 23435615 A:715:725 23435615 A:871:894 23435615 A:9:19 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23448384 A:1486:1498 23448384 A:213:226 23448384 A:21:33 23448384 A:231:244 23448384 A:246:250 23448384 A:253:269 23448384 A:271:275 23448384 A:278:293 23448384 A:35:39 23448384 A:406:414 23448384 A:45:72 23448384 A:598:606 23448384 A:731:735 23448384 A:740:744 23448384 A:74:78 23448384 A:816:836 23448384 A:868:889 23448384 A:910:914 23448384 A:936:952 23448384 A:954:958 23448384 A:993:997 23448384 T:101:113 23448384 T:118:145 23448384 T:58:66 23448620 A:527:557 23448620 A:690:700 23448682 A:284:293 23448682 A:294:304 23448682 A:565:568 23448682 A:569:578 23448682 A:607:619 23448682 A:786:795 23448682 A:796:806 23448682 A:877:882 23448682 A:883:886 23448682 A:970:979 23448682 T:88:97 23448682 T:98:108 23448860 A:1016:1025 23448860 A:128:137 23448860 A:139:141 23448860 A:294:296 23448860 A:421:423 23448860 A:619:621 23448860 A:758:760 23448860 A:810:812 23448860 A:844:846 23448860 A:901:903 23448860 A:931:933 23448860 T:47:56 23448861 A:1124:1132 23448861 A:1137:1151 23448861 A:248:256 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A:33:53 23451797 A:81:102 23451797 A:870:881 23451797 A:9:31 23451797 T:52:74 23451803 A:146:148 23451803 A:45:53 23451803 A:505:510 23451803 A:518:526 23451803 A:55:109 23451823 A:178:202 23451823 A:17:41 23451823 A:256:268 23451823 A:43:73 23451823 A:472:496 23451823 A:616:641 23451823 A:79:104 23451823 T:0:19 23451983 A:101:105 23451983 A:110:118 23451983 A:141:145 23451983 A:262:266 23451983 A:74:99 23452042 A:20:26 23452042 A:356:374 23452042 A:375:376 23452042 A:521:527 23452042 A:632:638 23452042 A:785:791 23452042 A:826:827 23452042 A:850:851 23452042 A:969:975 23452042 T:105:123 23452042 T:124:125 23452042 T:22:28 23452147 A:1096:1097 23452147 A:1155:1156 23452147 A:1272:1273 23452147 A:1279:1280 23452147 A:1423:1424 23452147 A:1565:1566 23452147 A:745:746 23452147 A:774:775 23452147 A:851:852 23452147 A:858:859 23452219 A:191:203 23452219 A:352:364 23452219 A:387:395 23452219 A:423:429 23452219 A:478:490 23452219 A:585:591 23452219 A:695:702 23452219 A:706:713 23452219 A:812:818 23452254 A:1020:1026 23452254 A:102:118 23452254 A:120:124 23452254 A:126:152 23452254 A:1319:1335 23452254 A:1427:1431 23452254 A:159:169 23452254 A:176:178 23452254 A:180:181 23452254 A:624:650 23452254 A:657:667 23452855 A:310:317 23452855 A:321:330 23452857 A:18:38 23452857 A:582:588 23452857 T:65:69 23453039 A:1024:1031 23453039 A:1162:1169 23453039 A:1300:1312 23453039 A:1320:1331 23453039 A:136:143 23453039 A:396:403 23453039 A:69:76 23453039 A:873:887 23453039 A:963:970 23453067 A:1009:1019 23453067 A:1066:1073 23453067 A:265:275 23453067 A:333:352 23453067 A:389:420 23453067 A:548:571 23453067 A:579:588 23453067 A:659:660 23453067 A:670:680 23453067 A:732:763 23453067 A:74:94 23453067 A:902:925 23453067 A:933:942 23453067 T:123:155 23453067 T:75:118 23453068 A:13:20 23453068 A:339:376 23453068 A:635:638 23453068 T:13:49 23453303 A:1165:1168 23453303 A:726:729 23453831 A:1604:1622 23453831 A:1624:1632 23453831 A:1637:1649 23453831 A:1652:1661 23453831 A:1666:1676 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A:222:231 23454054 A:233:236 23454054 A:237:240 23454054 A:480:488 23454054 A:564:567 23454054 A:568:571 23454054 A:662:665 23454054 A:666:669 23454054 A:684:687 23454054 T:19:31 23454054 T:32:41 23454054 T:43:46 23454054 T:47:50 23454133 A:1154:1155 23454133 A:259:269 23454133 A:274:285 23454133 A:945:955 23454133 A:960:971 23454148 A:105:119 23454148 A:1279:1295 23454148 A:129:140 23454148 A:1313:1316 23454148 A:1376:1379 23454148 A:142:145 23454148 A:1516:1519 23454148 A:436:439 23454148 A:442:451 23454148 A:456:459 23454148 A:551:565 23454148 A:677:688 23454148 A:689:690 23454148 A:719:720 23454148 A:725:733 23454148 A:734:735 23454148 A:843:860 23454148 A:89:98 23454148 A:919:922 23454148 A:942:949 23454148 A:973:981 23454148 T:65:74 23454148 T:76:90 23454148 T:95:106 23454208 A:1033:1041 23454208 A:1189:1197 23454208 A:1279:1287 23454208 A:160:168 23454208 A:319:327 23454208 A:504:505 23454208 A:583:591 23454208 A:58:66 23454208 A:617:625 23454208 A:84:93 23454208 A:857:871 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23943091 N 23532913 N 23856313 N 23746784 N 23792943 N 23939698 N 23553052 N 23244684 Y 23922901 N 23692073 N 23846829 N 23666162 N 23969886 N 23776179 N 23929523 N 23494657 N 23220104 Y 22828795 N 23836949 N 23892687 N 23314320 Y 23712835 N 23668967 N 23924705 N 23879520 N 23343596 Y 23832181 N 23159993 N 23749053 N 23917695 N 23883769 N 23716052 N 23628501 N 23855747 N 23755833 N 23837566 N 23797032 N 23701042 N 23435516 N 23726226 N 23733208 N 23924095 N 23927343 N 23922862 N 23339514 N CHEMDNER_CORPUS_BIOCREATIVE_4/CHEMDNER_TEST/chemdner_abs_test.txt0000644002344200234200016255272212236174040025202 0ustar mkrallingerBioinfoUnix23845789 Intravital microscopy technique to study parasite dynamics in the labyrinth layer of the mouse placenta. Intravital imaging techniques are the best approach to investigate in situ cellular behavior under physiological conditions. Many techniques have emerged during these last few years for this purpose. We recently described an intravital imaging technique that allows for the observation of placenta physiological responses at the labyrinth layer of this tissue. This technique will be very useful to study many placental opportunistic infections and in this article we reinforce its usefulness by analyzing placental physiological entrapment of beads and parasites. In particular, our results show that small beads (1.0μm) or Plasmodium chabaudi-GFP-infected-Red Blood Cells (Pc-GFP-iRBCs) cannot get trapped inside small or large blood vessels of popliteal lymph nodes (PLNs). Inside the placenta, clusters of beads could only be found inside the maternal blood vessels. However, Pc-GFP-iRBCs were found inside and outside the maternal blood vessels. We observed that trophoblasts can ingest infected-Red Blood Cells (iRBCs) in vitro and immunofluorescence of placenta revealed Pc-GFP-iRBCs inside and outside the maternal blood vessels. Taken together, we conclude that fast deposition of particles inside blood vessels seems to be an intrinsic characteristic of placenta blood flow, but iRBCs could be internalized by trophoblast cells. Thus these results represent one of the many possible uses of our intravital imaging technique to address important questions inside the parasitological field. 23887075 The optimum number of oocytes in IVF treatment: an analysis of 2455 cycles in China. What is the association between the number of oocytes retrieved and the live birth rate (LBR) following first IVF treatment cycles in China? In first IVF treatment cycles, the LBR after fresh transfer was maximal in the groups with 6-10 or 11-15 oocytes and reduced in the groups with 0-5 or >15 oocytes. Despite this, the cumulative LBR after including frozen embryo transfer cycles increased with an ovarian response. There is a strong association between oocyte number and IVF outcome; however, this is a comprehensive analysis conducted to investigate the relationship between oocyte number and fresh cycle as well as cumulative LBRs in first IVF treatment cycles. This is a large retrospective cohort study (n = 2455); patients were categorized into four groups according to the number of oocytes retrieved (0-5, 6-10, 11-15 and >15 oocytes). The fresh embro transfer LBR and cumulative LBR were evaluated by group. Univariate analysis was performed to identify factors that predict the chance of LBR. Multivariate logistic regression was used to assess the association between oocyte number and LBR after adjusting for confounding factors that were identified as significant in the univariate analysis. A total of 2455 women who were undergoing their first IVF treatment cycle at the Reproductive Medicine Center of Anhui Provincial Hospital, P.R. China from April 2007 to December 2011 were identified and reviewed. All patients had normal menstrual cycles and were stimulated with a long GnRH agonist protocol. Associations between oocyte number and LBR and miscarriage rate as well as the rate of moderate-severe ovarian hyperstimulation syndrome (OHSS) were analyzed. The fresh embryo LBR per started cycle increased with the number of retrieved oocytes up to Groups 2 and 3 (6-10 and 11-15 oocytes) and then decreased, because of the high number of cycles with all embryos being cryopreserved, in order to avoid moderate-severe OHSS in group 4 (>15 oocytes). However, the cumulative LBR per started cycle continued to increase with oocyte number, as did the incidence of moderate-severe OHSS. There was no significant difference in the miscarriage rates among the patient groups. As a retrospective study, our analysis depends on previously recorded data; therefore, certain variables could not be collected. Our findings may be influenced by our young and thin patient population and the inability to control for certain markers of ovarian reserve such as historical maximum serum FSH, antral follicle count and serum anti-Mullerian hormone. Our data suggest that in IVF cycles stimulated with a long protocol, the optimal number of oocytes for achieving a live birth is somewhere between 6 and 15. The balance between maximum treatment success and minimum risk of complications, especially OHSS, should be further investigated. This study was supported by the Medical Scientific Research Plan Project of Anhui Provincial Department of Health (13ZC014) and the Natural Science Foundation of Anhui Higher Education Institutions (KJ2013Z132). 23916763 Chronic inflammatory demyelinating polyneuropathy associated with primary biliary cirrhosis. We report a patient with chronic inflammatory demyelinating polyneuropathy associated with primary biliary cirrhosis (PBC). Except for minimal biochemical abnormalities, clinical symptoms of PBC were not observed, and we diagnosed our patient with asymptomatic PBC from the results of a liver biopsy. Although the patient noticed little muscle weakness, an electrophysiological study demonstrated slow conduction velocities and prolonged distal latencies, with definite conduction blocks in the median, ulnar, and tibial nerves. The disturbed sensory pattern was asymmetrical, and sensory nerve action potentials were not evoked. From these observations, we diagnosed this patient with chronic inflammatory demyelinating polyneuropathy. Neuropathy associated with PBC is very rare. We must differentiate demyelinating neuropathy with PBC in patients with asymmetrical sensory dominant neuropathy with high immunoglobulin M titers, and investigate for the presence of anti-mitochondrial antibodies to rule out a complication of asymptomatic PBC. 23964783 Charge Transfer in E. coli DNA Photolyase - Understanding Polarisation and Stabilisation Effects via QM/MM Simulations. We study fast hole transfer events in E. coli DNA photolyase, a key step in the photo-activation process, using a multi-scale computational method that combines non-adiabatic propagation schemes and linear-scaling quantum chemical methods with molecular mechanics force fields. This scheme allows us to follow the time-dependent evolution of the electron hole in an unbiased fashion, i.e. no assumptions about hole wavefunction localisation, time scale separation or adiabaticity of the process have to be made beforehand. DNA photolyase facilitates an efficient long-range charge transport between its flavin adenine dinucleotide (FAD) cofactor and the protein surface via a chain of evolutionary conserved Trp residues on the sub-nanosecond time scale despite the existence of multiple potential trap states. By including a large number of aromatic residues along the charge transfer pathway into the quantum description, we are able to identify the main pathway among alternative possible routes. The simulations show that charge transfer, which is extremely fast in this protein, occurs on the same time scale as the protein response to the electrostatic changes, i.e. time-scale separation as often presupposed in charge transfer studies seems to be inappropriate for this system. Therefore, coupled equations of motion, which propagate electrons and nuclei simultaneously, appear to be necessary. The applied computational model is shown to capture the essentials of the reaction kinetics and thermodynamics while allowing direct simulations of charge transfer events on their natural time scale. 23793158 Robust structural analysis of native biological macromolecules from multi-crystal anomalous diffraction data. Structure determinations for biological macromolecules that have no known structural antecedents typically involve the incorporation of heavier atoms than those found natively in biological molecules. Currently, selenomethionyl proteins analyzed using single- or multi-wavelength anomalous diffraction (SAD or MAD) data predominate for such de novo analyses. Naturally occurring metal ions such as zinc or iron often suffice in MAD or SAD experiments, and sulfur SAD has been an option since it was first demonstrated using crambin 30 years ago; however, SAD analyses of structures containing only light atoms (Zmax ≤ 20) have not been common. Here, robust procedures for enhancing the signal to noise in measurements of anomalous diffraction by combining data collected from several crystals at a lower than usual X-ray energy are described. This multi-crystal native SAD method was applied in five structure determinations, using between five and 13 crystals to determine substructures of between four and 52 anomalous scatterers (Z ≤ 20) and then the full structures ranging from 127 to 1200 ordered residues per asymmetric unit at resolutions from 2.3 to 2.8 Å. Tests were devised to assure that all of the crystals used were statistically equivalent. Elemental identities for Ca, Cl, S, P and Mg were proven by f'' scattering-factor refinements. The procedures are robust, indicating that truly routine structure determination of typical native macromolecules is realised. Synchrotron beamlines that are optimized for low-energy X-ray diffraction measurements will facilitate such direct structural analysis. 23208951 Microstructured, functional PVA hydrogels through bioconjugation with oligopeptides under physiological conditions. In this work, bioconjugation techniques are developed to achieve peptide functionalization of poly(vinyl alcohol), PVA, as both a polymer in solution and within microstructured physical hydrogels, in both cases under physiological conditions. PVA is unique in that it is one of very few polymers with excellent biocompatibility and safety and has FDA approval for clinical uses in humans. However, decades of development have documented only scant opportunities in bioconjugation with PVA. As such, materials derived thereof fail to answer the call for functional biomaterials for advanced cell culture and tissue engineering applications. To address these limitations, PVA is synthesized with terminal thiol groups and conjugated with thiolated peptides using PVA in solution. Further, microstructured, surface-adhered PVA physical hydrogels are assembled, the available conjugation sites within the hydrogels are quantified, and quantitative kinetic data are collected on peptide conjugation to the hydrogels. The success of bioconjugation in the gel phase is quantified through the use of a cell-adhesive peptide and visualization of cell adhesion on PVA hydrogels as cell culture substrates. Taken together, the presented data establish a novel paradigm in bioconjugation and functionalization of PVA physical hydrogels. Coupled with an excellent safety profile of PVA, these results deliver a superior biomaterial for diverse biomedical applications. 23916760 Histopathological features of the outer membrane of chronic subdural hematoma and correlation with clinical and radiological features. We compared the histopathological features of the outer membrane of a chronic subdural hematoma (CSH) with its clinico-radiological presentation in patients. One hundred and fifty-six patients undergoing surgery for CSH were prospectively included in this study. Histopathological specimens of the outer neomembrane obtained intraoperatively were studied. Histological features were classified into four types and analyzed in relation to the Glasgow Coma Scale (GCS) score at presentation and radiological features. On histopathological examination, there were no cases of type I, 42.3% cases of type II and 34.6% cases of type III and 23.1% cases of types IV CSH neomembranes. Patients presenting with a GCS <13 exclusively had type II neomembranes. Increased radiodensity and thickness of the hematoma correlated with type IV neomembranes. This study may serve as an incentive to investigate the histopathology of CSH membranes in predicting outcomes and the recurrence of subdural hemorrhage after drainage surgery. 23886572 Tamoxifen favoured the rat sensorial cortex regeneration after a penetrating brain injury. A penetrating brain injury produces a glial scar formed by astrocytes, oligodendrocytes, microglia and NG2 cells. Glial scar is a barrier preventing the extent of damage but it has deleterious effects in the regeneration of the axons. Estradiol and tamoxifen reduce gliosis and have neuroprotective effects in the hippocampus and the spinal cord. We evaluated the proliferation of glia and the electrocorticogram in the sensorial cortex in a brain injury model. At seven days post-injury, estradiol, tamoxifen and estradiol plus tamoxifen reduced the number of resident and proliferative NG2 and reactive astrocyte vimentin+ cells. Estradiol and tamoxifen effects on NG2 cells could be produced by the classical oestrogen receptors found in these cells. The glial scar was also reduced by tamoxifen. At thirty days post-injury, the amount of resident and proliferative astrocytes increased significantly, except in the estradiol plus tamoxifen group, whilst the oligodendrocytes proliferation in the glial scar was reduced in treated animals. Tamoxifen promotes the survival of FOX-3+ neurons in the injured area and a recovery in the amplitude of electrocorticogram waves. At thirty days, estradiol did not favour the suvival of neurons but produced a greater number of reactive astrocytes. In contrast, the number of oligodendrocytes was reduced. Tamoxifen could favour brain repair promoting neuron survival and adjusting glial cell number. It seems to recover adequate neural communication. 23907535 A long noncoding RNA mediates both activation and repression of immune response genes. An inducible program of inflammatory gene expression is central to antimicrobial defenses. This response is controlled by a collaboration involving signal-dependent activation of transcription factors, transcriptional co-regulators, and chromatin-modifying factors. We have identified a long noncoding RNA (lncRNA) that acts as a key regulator of this inflammatory response. Pattern recognition receptors such as the Toll-like receptors induce the expression of numerous lncRNAs. One of these, lincRNA-Cox2, mediates both the activation and repression of distinct classes of immune genes. Transcriptional repression of target genes is dependent on interactions of lincRNA-Cox2 with heterogeneous nuclear ribonucleoprotein A/B and A2/B1. Collectively, these studies unveil a central role of lincRNA-Cox2 as a broad-acting regulatory component of the circuit that controls the inflammatory response. 23323548 Cloning and functional characterization of the pig (Sus scrofa) organic anion transporting polypeptide 1a2. Abstract 1. Organic anion transporting polypeptides (OATPs) are a family of transporter proteins that have been extensively recognized as key determinants of absorption, distribution, metabolism and excretion of various drugs. Human OATP1A2 has been demonstrated to transport wide spectrum of endogenous and exogenous compounds. Study on OATP1A2 orthologues of other species, however, is still limited. 2. Here, we described the cloning and functional characterization of a member of the OATP/Oatp family member obtained from pig (Sus scrofa) liver. Sequence analysis suggested that it has a high homology with human OATP1A2 and bovine Oatp1a2. Prototypic substrates estrone-3-sulfate (E-3-S) and taurocholic acid were transported by the protein. The transport of these two substrates is pH-dependent, with lower pH showing higher uptake function. Kinetic study showed the transport of these two substrates have a K(m) of 42.5 ± 12.1 and 33.1 ± 8.7 µM, respectively. Pig Slco1a2 has the highest expression level in the liver, and to a less extend in the brain and small intestine. 3. In conclusion, an OATP member was cloned from pig liver. Sequence analysis and phylogenic study revealed it as an orthologue of human OATP1A2. Its kinetic characteristic for prototypic substrates and organ distribution are similar with that of OATP1A2. 23798429 Cell geometric constraints induce modular gene-expression patterns via redistribution of HDAC3 regulated by actomyosin contractility. Physical forces in the form of substrate rigidity or geometrical constraints have been shown to alter gene expression profile and differentiation programs. However, the underlying mechanism of gene regulation by these mechanical cues is largely unknown. In this work, we use micropatterned substrates to alter cellular geometry (shape, aspect ratio, and size) and study the nuclear mechanotransduction to regulate gene expression. Genome-wide transcriptome analysis revealed cell geometry-dependent alterations in actin-related gene expression. Increase in cell size reinforced expression of matrix-related genes, whereas reduced cell-substrate contact resulted in up-regulation of genes involved in cellular homeostasis. We also show that large-scale changes in gene-expression profile mapped onto differential modulation of nuclear morphology, actomyosin contractility and histone acetylation. Interestingly, cytoplasmic-to-nuclear redistribution of histone deacetylase 3 modulated histone acetylation in an actomyosin-dependent manner. In addition, we show that geometric constraints altered the nuclear fraction of myocardin-related transcription factor. These fractions exhibited hindered diffusion time scale within the nucleus, correlated with enhanced serum-response element promoter activity. Furthermore, nuclear accumulation of myocardin-related transcription factor also modulated NF-κB activity. Taken together, our work provides modularity in switching gene-expression patterns by cell geometric constraints via actomyosin contractility. 23966462 Hashimoto's thyroiditis: an accidental discovery of a lingual thyroid in a 7-year-old child. An ectopic thyroid located at the base of the tongue is a rare entity, resulting from early developmental defects of thyroid gland embryogenesis during its descent from the foramen caecum to its normal eutopic pretracheal site. This condition is the main cause of congenital primary hypothyroidism, even though signs and symptoms of thyroid dysfunction may also appear later in childhood. Lingual thyroid may sometimes present with symptoms of respiratory obstruction or feeding difficulties. We illustrate the case of a 7-year-old girl with subclinical hypothyroidism due to Hashimoto's thyroiditis arising in a lingual thyroid. She had never suffered from upper airway obstructive symptoms, but did refer a 3-month history of cough. Rapid normalisation of thyroid-stimulating hormone levels and termination of the cough were attained when the L-thyroxine treatment started. After 6 months a significant reduction of lingual thyroid size was also noted. The diagnostic procedures and therapeutic options in childhood are discussed. 23834992 Why are suspected cases of child maltreatment referred by educators so often unsubstantiated? School professionals have a unique vantage point for identifying child maltreatment and they are a frequent source of referral to child protective services. Disturbingly, past studies have found that maltreatment concerns reported by educators go unsubstantiated by child protective services at much higher rates than suspected maltreatment reported by other professionals. This study explores whether there are systematic differences in the characteristics of cases reported by educators as compared to other professionals and examines whether such variation might account for differences in investigation outcome. Analyses were based on 7,725 cases of suspected maltreatment referred by professionals to child protective services from the Canadian Incidence Study of Reported Child Abuse and Neglect - 2003 a national database on the characteristics of children and families investigated by child protective services. School professionals were responsible for 35.8% of professional referrals. Reports by educators were much more likely to be unsubstantiated (45.3%) than those by other professionals (28.4%) in subsequent child protective investigation. Cases reported by educators were found to contain significantly more child risk factors (e.g., child emotional and behavioural problems) and fewer caregiver and family risk factors (e.g., caregiver mental health problem, single parent family) than cases reported by other professionals. Even controlling for these differences, educator-reported concerns were still 1.84, 95% CI [1.41, 2.40] times as likely to be unsubstantiated as reports from other professionals. Contrary to the notion that educators are mostly reporting non-severe cases, suspected/substantiated cases reported by school professionals were more likely to be judged as chronic and more likely to involve families with a previous child protection history. Results are concerning for the capacity of the education and child protection systems to work together to meet their shared goal of promoting healthy child development. Additional research is needed on the way in which child risks and problems influence child protective service, particularly in the context of chronic abuse and neglect and lack of availability of child and family mental health interventions. Potential problems with credibility of school professionals as reporters of child maltreatment concerns also warrant further investigation. 23867530 Aerobic biodegradation process of petroleum and pathway of main compounds in water flooding well of Dagang oil field. Aerobic biodegradation of crude oil and its pathways were investigated via in vitro culture and GC-MS analysis in water flooding wells of Dagang oil field. The in vitro aerobic culture lasted 90days when 99.0% of n-alkanes and 43.03-99.9% of PAHs were degraded and the biomarkers and their ratios were changed. The spectra of components in the residual oil showed the similar biodegradation between aerobic process of 90days and degradation in reservoir which may last for some millions years, and the potential of serious aerobic biodegradation of petroleum in reservoir. 24 Metabolites compounds were separated and identified from aerobic culture, including fatty acid, naphthenic acid, aromatic carboxylic acid, unsaturated acid, alcohols, ketones and aldehydes. The pathways of alkanes and aromatics were proposed, which suggests that oxidation of hydrocarbon to organic acid is an important process in the aerobic biodegradation of petroleum. 23752100 Tactile interactions lead to coherent motion and enhanced chemotaxis of migrating cells. When motile cells come into contact with one another their motion is often considerably altered. In a process termed contact inhibition of locomotion (CIL) cells reshape and redirect their movement as a result of cell-cell contact. Here we describe a mathematical model that demonstrates that CIL alone is sufficient to produce coherent, collective cell migration. Our model illustrates a possible mechanism behind collective cell migration that is observed, for example, in neural crest cells during development, and in metastasizing cancer cells. We analyse the effects of varying cell density and shape on the alignment patterns produced and the transition to coherent motion. Finally, we demonstrate that this process may have important functional consequences by enhancing the accuracy and robustness of the chemotactic response, and factors such as cell shape and cell density are more significant determinants of migration accuracy than the individual capacity to detect environmental gradients. 23917724 Independent Risk Factors for Urinary Tract Infection and for Subsequent Bacteremia or Acute Cellular Rejection: A Single-Center Report of 1166 Kidney Allograft Recipients. Urinary tract infection (UTI) is a frequent, serious complication in kidney allograft recipients. We reviewed the records of 1166 kidney allograft recipients who received their allografts at our institution between January 2005 and December 2010 and determined the incidence of UTI during the first 3 months after transplantation (early UTI). We used Cox proportional hazards models to determine the risk factors for early UTI and whether early UTI was an independent risk factor for subsequent bacteremia or acute cellular rejection (ACR). UTI, defined as 10⁵ or more bacterial colony-forming units/mL urine, developed in 247 (21%) of the 1166 recipients. Independent risk factors for the first episode of UTI were female gender (hazard ratio [HR], 2.9; 95% confidence intervals [CI], 2.2-3.7; P<0.001), prolonged use of Foley catheter (HR, 3.9; 95% CI, 2.8-5.4; P <0.001), ureteral stent (HR, 1.4; 95% CI, 1.1-1.8; P=0.01), age (HR, 1.1; 95% CI, 1.0-1.2; P=0.03), and delayed graft function (HR, 1.4; 95% CI, 1.0-1.9; P=0.06). Trimethoprim/sulfamethoxazole prophylaxis was associated with a reduced risk of UTI (HR, 0.6; 95% CI, 0.3-0.9; P=0.02). UTI was an independent risk factor for subsequent bacteremia (HR, 2.4; 95% CI, 1.2-4.8; P=0.01). Untreated UTI, but not treated UTI, was associated with an increased risk of ACR (HR, 2.8; 95% CI, 1.3-6.2; P=0.01). Female gender, prolonged use of Foley catheter, ureteral stent, age, and delayed graft function are independent risk factors for early UTI. UTI is independently associated with the development of bacteremia, and untreated UTI is associated with subsequent ACR. 23959234 A semi-quantitative model of Quorum-Sensing in Staphylococcus aureus, approved by microarray meta-analyses and tested by mutation studies. Staphylococcus aureus (SA) causes infections including severe sepsis by antibiotic-resistant strains. It forms biofilms to protect itself from the host and antibiotics. Biofilm and planktonic lifestyle are regulated by a complex quorum sensing system (QS) with the central regulator agr. To study biofilm formation and QS we set up a Boolean node interaction network (94 nodes, 184 edges) that included different two component systems such as agr, sae and arl. Proteins such as sar, rot and sigB were included. Each gene node represents the resulting activity of its gene products (mRNA and protein). Network consistency was tested according to previous knowledge and the literature. Regulator mutation combinations (agr(-), sae(-), sae(-)/agr(-), sigB(+), sigB(+)/sae(-)) were tested in silico in the model and compared regarding system changes and responses to experimental gene expression data. High connectivity served as a guide to identify master regulators, and their detailed behaviour was studied both in vitro and in the model. System analysis showed two stable states, biofilm forming versus planktonic, with clearly different sub-networks turned on. Predicted node activity changes from the in silico model were in line with microarray gene expression data of different knockout strains. Additional in silico predictions about node activity and biofilm formation were compared to new in vitro experiments (northern blots and biofilm adherence assays) which confirmed these. Further experiments in silico as well as in vitro showed the sae locus as the central modulator of biofilm production. Sae knockout strains showed stronger biofilms. Wild type phenotype was rescued by sae complementation. The in silico network provides a theoretical model that agrees well with the presented experimental data on how integration of different inputs is achieved in the QS of SA. It faithfully reproduces the behaviour of QS mutants and their biofilm forming ability and allows predictions about mutations and mutation combinations for any node in the network. The model and simulations allow us to study QS and biofilm formation in SA including behaviour of MRSA strains and mutants. The in vitro and in silico evidence stresses the role of sae and agr in fine-tuning biofilm repression and/or SA dissemination. 23173962 The role of sympathetic nervous system in the progression of chronic kidney disease in the era of catheter based sympathetic renal denervation. The kidney has been shown to be critically involved as both trigger and target of sympathetic nervous system overactivity in both experimental and clinical studies. Renal injury and ischemia, activation of renin angiotensin system and dysfunction of nitric oxide system have been implicated in adrenergic activation from kidney. Conversely, several lines of evidence suggest that sympathetic overactivity, through functional and morphological alterations in renal physiology and structure, may contribute to kidney injury and chronic kidney disease progression. Pharmacologic modulation of sympathetic nervous system activity has been found to have a blood pressure independent renoprotective effect. The inadequate normalization of sympathoexcitation by pharmacologic treatment asks for novel treatment options. Catheter based renal denervation targets selectively both efferent and afferent renal nerves and functionally denervates the kidney providing blood pressure reduction in clinical trials and renoprotection in experimental models by ameliorating the effects of excessive renal sympathetic drive. This review will focus on the role of sympathetic overactivity in the pathogenesis of kidney injury and CKD progression and will speculate on the effect of renal denervation to these conditions. 22580612 MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches. Mucin 1 (MUC1) is a heterodimeric protein formed by two subunits that is aberrantly overexpressed in human breast cancer and other cancers. Historically, much of the early work on MUC1 focused on the shed mucin subunit. However, more recent studies have been directed at the transmembrane MUC1-C-terminal subunit (MUC1-C) that functions as an oncoprotein. MUC1-C interacts with EGFR (epidermal growth factor receptor), ErbB2 and other receptor tyrosine kinases at the cell membrane and contributes to activation of the PI3KAKT and mitogen-activated protein kinase kinase (MEK)extracellular signal-regulated kinase (ERK) pathways. MUC1-C also localizes to the nucleus where it activates the Wnt/β-catenin, signal transducer and activator of transcription (STAT) and NF (nuclear factor)-κB RelA pathways. These findings and the demonstration that MUC1-C is a druggable target have provided the experimental basis for designing agents that block MUC1-C function. Notably, inhibitors of the MUC1-C subunit have been developed that directly block its oncogenic function and induce death of breast cancer cells in vitro and in xenograft models. On the basis of these findings, a first-in-class MUC1-C inhibitor has entered phase I evaluation as a potential agent for the treatment of patients with breast cancers who express this oncoprotein. 23741072 Glioma grade is associated with the accumulation and activity of cells bearing m2 monocyte markers. This study is directed at identifying the cell source(s) of immunomodulatory cytokines in high-grade gliomas and establishing whether the analysis of associated markers has implications for tumor grading. Glioma specimens classified as WHO grade II-IV by histopathology were assessed by gene expression analysis and immunohistochemistry to identify the cells producing interleukin (IL)-10, which was confirmed by flow cytometry and factor secretion in culture. Finally, principal component analysis (PCA) and mixture discriminant analysis (MDA) were used to investigate associations between expressed genes and glioma grade. The principle source of glioma-associated IL-10 is a cell type that bears phenotype markers consistent with M2 monocytes but does not express all M2-associated genes. Measures of expression of the M2 cell markers CD14, CD68, CD163, and CD204, which are elevated in high-grade gliomas, and the neutrophil/myeloid-derived suppressor cell (MDSC) subset marker CD15, which is reduced, provide the best index of glioma grade. Grade II and IV astrocytomas can be clearly differentiated on the basis of the expression of certain M2 markers in tumor tissues, whereas grade III astrocytomas exhibit a range of expression between the lower and higher grade specimens. The content of CD163(+) cells distinguishes grade III astrocytoma subsets with different prognosis. Clin Cancer Res; 19(14); 3776-86. ©2013 AACR. 23670090 Evaluation of the role of chronic daily melatonin administration and pinealectomy on penicillin-induced focal epileptiform activity and spectral analysis of ECoG in rats: an in vivo electrophysiological study. In the present study, we aimed to investigate the effects of pinealectomy and chronic melatonin administration on focal epileptiform activity induced by penicillin in the rat cortex and to determine the relation between melatonin levels and electrocorticogram (ECoG) power spectrum. For this purpose, male Sprague-Dawley rats were divided into six groups: control, sham operated, ethanol, melatonin, pinealectomy and pinealectomy + melatonin group. Melatonin-treated rats was intraperitoneally injected with a daily single dose of 10 mg/kg melatonin for 14 days, but the last dose was given 30 min after local application of penicillin as a convulsant agent. Focal epileptiform activity was produced by intracortical administration of penicillin (200 units/1 Î¼l). While chronic melatonin application did not affect either the onset latency or the spike frequency of epileptiform activity, pinealectomy significantly reduced latency to onset of initial epileptiform discharges and increased cortical epileptiform activity. However, acute melatonin administration decreased the epileptiform activity. The results also indicated that exogenously applied melatonin did not change the spectral analysis of ECoG, but pinealectomy led to a reduction in the power of the fast bands (gamma) power in ECoG. We conclude that endogenous melatonin signaling seem to have a tonic inhibitory action on neuronal excitability and epileptiform activity, and also a certain concentration of melatonin required for normal cortical excitability. 23832115 Apoptosis induced by the fungal pathogen gliotoxin requires a triple phosphorylation of Bim by JNK. We previously reported that gliotoxin (GT), the major virulence factor of the mold Aspergillus fumigatus causing invasive aspergillosis (IA) in immunocompromised patients, induces apoptosis in a Bak-dependent manner. The signaling pathway leading to Bak activation and subsequent mitochondrial outer membrane permeabilization (MOMP) is elusive. Here, we show that GT and the supernatant of A. fumigatus (but not its GT-defective mutant) activate the JNK pathway and require a co-operative JNK-mediated BimEL phosphorylation at three sites (S100, T112 and S114) to induce apoptosis in mouse fibroblasts, human bronchial and mouse alveolar epithelial cells. Cells (i) treated with the JNK inhibitor SP600125, (ii) deleted or knocked down for JNK1/2 or Bim or (iii) carrying the BimEL triple phosphomutant S100A/T112A/S114A instead of wild-type BimEL are similarly resistant to GT-induced apoptosis. Triple-phosphorylated BimEL is more stable, redistributes from a cytoskeletal to a membrane fraction, better interacts with Bcl-2 and Bcl-xL and more effectively activates Bak than the unphosphorylated mutant. These data indicate that JNK-mediated BimEL phosphorylation at S100, T112 and S114 constitutes a novel regulatory mechanism to activate Bim in response to apoptotic stimuli.Cell Death and Differentiation advance online publication, 5 July 2013; doi:10.1038/cdd.2013.78. 23921351 Effect of sex ratios, spiking and extra artificial insemination on the breeding efficiency of broiler breeders. Since early fertility decline is a permanent problem of broiler breeders, the aim of this study was to test the effects of various sex ratios, spiking strategies and additional artificial inseminations (AI) on their breeding efficiency. Six breeder flocks were analysed during the whole reproduction cycle. In Flock A the sex ratio was maintained at 10% during the whole cycle (control), while in Flock B the number of males was increased to a final ratio of 16%. In Flocks C (technological control), D, E and F the ratio of males was gradually decreased from 10% to 6.5% until the end of the cycle. Moreover, at the age of 44 weeks in Flocks D and E 50 and 100% of cockerels were replaced by young ones, respectively, while in Flock F additional artificial inseminations were applied in the second half of the reproduction cycle. The increase of sperm transport was successful only in Groups B (increase in male numbers) and D (50% replacement of old cockerels with young ones); however, it was not sufficient for increasing the fertility rates in either group. Nor did additional artificial inseminations (Flock F) have an effect on fertility. As a conclusion, it can be established that increasing the sperm count in the hens' oviducts in any way could not improve fertility in the last third of the production cycle. The results also suggest that the expensive and labour-intensive spiking technique used in broiler breeder management is useless. The prime factor responsible for the shortened persistence of fertility may be the reduced ability of the female oviduct to accept and store sperm. 23414099 Potential-dependent interaction of DOPC liposomes with an octadecanol-covered Au(111) surface investigated using electrochemical methods coupled with in situ fluorescence microscopy. The potential-controlled incorporation of DOPC liposomes (100 nm diameter) into an adsorbed octadecanol layer on Au(111) was studied using electrochemical and in situ fluorescence microscopy. The adsorbed layer of octadecanol included a small amount of a lipophilic fluorophore-octadecanol modified with BODIPY-to enable fluorescence imaging. The deposited octadecanol layer was found not to allow liposomes to interact unless the potential was less than -0.4 V/SCE, which introduces defects into the adsorbed layer. Small increases in the capacitance of the adsorbed layer were measured after introducing the defects, allowing the liposomes to interact with the defects and then annealing the defects at 0 V/SCE. A change in the adsorbed layer was also signified by a more positive desorption potential for the liposome-modified adsorbed layer as compared to that for an adsorbed layer that was porated in a similar fashion but without liposomes present in the electrolyte. These subtle changes in capacitance are difficult to interpret, so an in situ spectroscopic study was performed to provide a more direct measure of the interaction. The incorporation of liposomes should result in an increase in the fluorescence measured because the fluorophore should become further separated from the gold surface, reducing the efficiency of fluorescence quenching. No significant increase in the fluorescence of the adsorbed layer was observed during the potential pulses used in the poration procedure in the absence of liposomes. In the presence of liposomes, the fluorescence intensity was found to depend on the potential and time used for poration. At 0 V/SCE, no significant change in the fluorescence was observed for defect-free adsorbed layers. Changing the poration potential to -0.4 V/SCE caused significant increases in the fluorescence and the appearance of new structural features in the adsorbed layers that were more easily observed during the desorption procedure. The extent of fluorescence changes was found to be strongly dependent on the nature of the adsorbed layer under investigation, which suggests that the poration and liposome interaction are dependent on the quality of the adsorbed layer and its ease of poration through changes in the electrode potential. 23707995 Up-regulation of GAP-43 in the chinchilla ventral cochlear nucleus after carboplatin-induced hearing loss: correlations with inner hair cell loss and outer hair cell loss. Inner ear damage leads to nerve fiber growth and synaptogenesis in the ventral cochlear nucleus (VCN). In this study, we documented the relationship between hair cell loss patterns and synaptic plasticity in the chinchilla VCN using immunolabeling of the growth associated protein-43 (GAP-43), a protein associated with axon outgrowth and modification of presynaptic endings. Unilateral round window application of carboplatin caused hair cell degeneration in which inner hair cells (IHC) were more vulnerable than outer hair cells (OHC). One month after carboplatin treatment (0.5-5 mg/ml), we observed varying patterns of cochlear hair cell loss and GAP-43 expression in VCN. Both IHC loss and OHC loss were strongly correlated with increased GAP-43 immunolabeling in the ipsilateral VCN. We speculate that two factors might promote the expression of GAP-43 in the VCN; one is the loss of afferent input through IHC or the associated type I auditory nerve fibers. The other occurs when the medial olivocochlear efferent neurons lose their cochlear targets, the OHC, and may as compensation increase their synapse numbers in the VCN. 23863549 Localized Cutaneous Argyria: Two Case Reports and Clinicopathologic Review. : We report 2 cases of patients who presented with blue macules clinically suspicious for blue nevi. One patient had no documented history of trauma or silver exposure, and the other reported exposure to silver over 30 years ago. Microscopic examination revealed a dermal population of brown-black globules predominantly adhering to collagen fibers. In both cases, no melanocytic proliferation was identified by immunohistochemistry. Analysis of the skin biopsies with scanning electron microscopy and energy dispersive x-ray spectroscopy demonstrated the presence of silver and selenium. These findings were diagnostic of localized cutaneous argyria. Our case reports highlight the importance of including localized cutaneous argyria in the differential diagnosis of pigmented lesions. 23827955 Orthopaedic triage during natural disasters and mass casualties: do scoring systems matter? Mass casualty events, either natural disasters or man-made, are associated with extremities injuries. The treating surgeon often faces a challenging decision: can the affected extremity be saved or amputated? The following article will present the author's view on the subject of triage and the use of scoring systems in the decision-making process whether to salvage or amputate an affected extremity. The author will analyse the existing scoring systems and emphasise significance of the regional factors: geographical, cultural and level of health care, as factors playing roles in this process. 23827702 Oncogenic miRNAs and the perils of losing control of a stem cell's epigenetic identity. Pathways that regulate epigenetic control of stem cell identity are critical to the molecular etiology of cancer. In back-to-back articles in Cell and Cell Stem Cell, Song et al. identify miR-22 as both a repressor of TET proteins and a powerful oncogene in the mammary epithelium and hematopoietic system. 23953183 Association of genetic variability in selected regions in visfatin (NAMPT) gene with anthropometric parameters and dietary composition in obese and non-obese Central-European population. Visfatin (NAMPT/PBEF) is a recently identified adipocytokine which harbors strong insulin-mimetic activity and was reported to be associated with obesity. However, nothing is known about whether visfatin is related to specific nutritional behavior which may result in obesity development. This is the first study focusing on genetic variability of the visfatin gene and its association with circulating visfatin, anthropometric parameters and dietary composition. We analyzed a total of 11 exons and adjacent non-coding regions of the NAMPT gene in 20 extremely obese Czech individuals (mean BMI 52.2±5.0 SD) using direct sequencing and a frequency of rs2302559 was established in the validation cohort of another 605 individuals with completed 7-day food records and complex anthropometric measurements. Serum levels of visfatin, leptin and leptin-receptor were measured in all sequenced individuals and in part of the validation cohort. Three common polymorphisms were identified, two in non-coding regions (rs78411774 A/C, rs71564769 A/C) and one synonymous SNP in exon 7 (rs2302559 A/G). The rs2302559 showed significant correlation with visfatin serum level throughout the entire study cohort (p<0.001); there was a significant tendency toward higher visfatin levels in G allele carriers with GG homozygotes having the highest visfatin serum levels. Furthermore, a negative correlation was observed between visfatin and leptin serum level (p=0.01). No association between investigated SNPs and anthropometric parameters or native dietary composition was observed. This is the first study to demonstrate that the rs2302559 polymorphism in the PBEF gene is related to circulating levels of visfatin. As the SNP is synonymous, we hypothesize it might be linked to another SNP in the PBEF gene which controls visfatin serum levels. 23411282 Microbial metabolites, but not other phenolics derived from grape seed phenolic extract, are transported through differentiated Caco-2 cell monolayers. Grape seed phenolic extract (GSE) is predicted to have health benefits, even though its bioavailability, including digestibility, permeability and ultimate metabolism, are still poorly understood. In vitro gastric and pancreatic digestion and in vitro ileal and faecal fermentation were combined with Caco-2 cell permeability studies for GSE samples. Qualitatively, there was no change in type/number of GSE compounds following gastric and pancreatic digestion and LC-MS analysis. However, the monomers were significantly (P<0.05) increased after gastric digestion, along with a significant (P<0.05) decrease in polymers. In addition, all forms of phenolic compounds decreased following pancreatic digestion. However, none of the original GSE phenolic compounds passed the Caco-2 cell monolayer, since all were recovered in the apical compartment. In contrast, the two intestinal microbiota metabolites with deprotonated molecular weights of [M-H]-165/121 and 193/175, that were found both in the ileal and faecal fermented samples, passed the Caco-2 cell monolayer. 23788665 Area deprivation across the life course and physical capability in midlife: findings from the 1946 british birth cohort. Physical capability in later life is influenced by factors occurring across the life course, yet exposures to area conditions have only been examined cross-sectionally. Data from the National Survey of Health and Development, a longitudinal study of a 1946 British birth cohort, were used to estimate associations of area deprivation (defined as percentage of employed people working in partly skilled or unskilled occupations) at ages 4, 26, and 53 years (residential addresses linked to census data in 1950, 1972, and 1999) with 3 measures of physical capability at age 53 years: grip strength, standing balance, and chair-rise time. Cross-classified multilevel models with individuals nested within areas at the 3 ages showed that models assessing a single time point underestimate total area contributions to physical capability. For balance and chair-rise performance, associations with area deprivation in midlife were robust to adjustment for individual socioeconomic position and prior area deprivation (mean change for a 1-standard-deviation increase: balance, -7.4% (95% confidence interval (CI): -12.8, -2.8); chair rise, 2.1% (95% CI: -0.1, 4.3)). In addition, area deprivation in childhood was related to balance after adjustment for childhood socioeconomic position (-5.1%, 95% CI: -8.7, -1.6). Interventions aimed at reducing midlife disparities in physical capability should target the socioeconomic environment of individuals-for standing balance, as early as childhood. 23911433 Health risk perception and betel chewing behavior - The evidence from Taiwan. In this study, we provided an empirical examination of the interaction between people's health risk perception and betel chewing. We hypothesized that a better knowledge of possible health risks would reduce both the number of individuals who currently chew betel and the likelihood of those who do not yet chew betel to begin the habit. We constructed a simultaneous equation model with Bayesian two-stage approach to control the endogeneity between betel chewing and risk perception. Using a national survey of 26,684 observations in Taiwan, our study results indicated that better health knowledge reduced the possibility that people would become betel chewers. We also found that, in general, betel chewers have a poorer health risk perception than other population. Overall, the empirical evidence suggested that health authorities could reduce the odds of people becoming betel chewers by improving their knowledge of betel-chewing's harmful effects. 23820275 A comparative study of cerebral microcirculation during pulsatile and nonpulsatile selective cerebral perfusion: assessment by synchrotron radiation microangiography. Currently, nonpulsatile selective cerebral perfusion for cerebroprotection against thoracic aortic aneurysm is used in clinical settings. We performed synchrotron radiation microangiography to determine the effects on selective cerebral perfusion modulation by pulsatile flow. We established cerebral perfusion at normothermia and severe hypothermia in anesthetized rats, during which cerebral angiography was performed. NG-nitro-L-arginine-methyl ester hydrochloride (L-NAME) was administered to determine the effect of pulsatile flow with nitric oxide synthesis. In comparison with nonpulsatile flow, the relative diameters of small internal carotid artery were 132.11 ± 5.49% and 114.96 ± 4.60% during pulsatile flow at normothermia and severe hypothermia (p < 0.05). The angiographic scores, an indicator of vessel count, for nonpulsatile and pulsatile flow at normothermia were 0.198 ± 0.013 vs. 0.258 ± 0.010 (p < 0.001) and those at severe hypothermia were 0.158 ± 0.017 vs. 0.214 ± 0.015 (p < 0.01), respectively. In comparison with nonpulsatile flow, the relative internal carotid artery diameters during pulsatile flow with and without L-NAME were 98.50 ± 1.7% vs. 114.96 ± 4.6%, respectively, during severe hypothermia. These results show that pulsatile flow is effective in increasing blood vessel diameter, number of vessels, and perfusion distribution range in the rat model and that it was more effective at normothermia during nitric oxide production. 23574406 Methamphetamine-induced neurotoxicity disrupts naturally occurring phasic dopamine signaling. Methamphetamine (METH) is a highly addictive drug that is also neurotoxic to central dopamine (DA) systems. Although striatal DA depletions induced by METH are associated with behavioral and cognitive impairments, the link between these phenomena remains poorly understood. Previous work in both METH-pretreated animals and the 6-hydroxydopamine model of Parkinson's disease suggests that a disruption of phasic DA signaling, which is important for learning and goal-directed behavior, may be such a link. However, previous studies used electrical stimulation to elicit phasic-like DA responses and were also performed under anesthesia, which alters DA neuron activity and presynaptic function. Here we investigated the consequences of METH-induced DA terminal loss on both electrically evoked phasic-like DA signals and so-called 'spontaneous' phasic DA transients measured by voltammetry in awake rats. Not ostensibly attributable to discrete stimuli, these subsecond DA changes may play a role in enhancing reward-cue associations. METH pretreatment reduced tissue DA content in the dorsomedial striatum and nucleus accumbens by ~55%. Analysis of phasic-like DA responses elicited by reinforcing stimulation revealed that METH pretreatment decreased their amplitude and underlying mechanisms for release and uptake to a similar degree as DA content in both striatal subregions. Most importantly, characteristics of DA transients were altered by METH-induced DA terminal loss, with amplitude and frequency decreased and duration increased. These results demonstrate for the first time that denervation of DA neurons alters naturally occurring DA transients and are consistent with diminished phasic DA signaling as a plausible mechanism linking METH-induced striatal DA depletions and cognitive deficits. 23831181 Older Adults Display Concurrent but not Delayed Associations between Life Stressors and Depressive Symptoms: A Microlongitudinal Study. The present study investigated the temporal association between life event stressors relevant to older adults and depressive symptoms using a micro-longitudinal design (i.e., monthly increments over a six-month period). Existing research on stress and depressive symptoms has not examined this association over shorter time periods (e.g., monthly), over multiple time increments, or within-persons. An in-person initial interview was followed by six monthly interviews conducted by telephone. Community. Data were drawn from a study of 144 community-dwelling older adults with depressive symptoms. Stressful life events were measured using the Geriatric Life Events Scale (GALES), and depressive symptoms were assessed with the Short - Geriatric Depression Scale (S-GDS). Using multilevel modeling, 31% of the S-GDS' and 39% of the GALES' overall variance was due to within-person variability. Females and persons with worse health reported more depressive symptoms. Stressful life events predicted concurrent depressive symptoms, but not depressive symptoms one month later. The lack of a time-lagged relationship suggests that older adults with depressive symptoms may recover more quickly from life stressors than previously thought, although additional research using varying time frames is needed to pinpoint the timing of this recovery as well as to identify older adults at risk of long-term effects of life stressors. 23930808 Path length entropy analysis of diastolic heart sounds. Early detection of coronary artery disease (CAD) using the acoustic approach, a noninvasive and cost-effective method, would greatly improve the outcome of CAD patients. To detect CAD, we analyze diastolic sounds for possible CAD murmurs. We observed diastolic sounds to exhibit 1/f structure and developed a new method, path length entropy (PLE) and a scaled version (SPLE), to characterize this structure to improve CAD detection. We compare SPLE results to Hurst exponent, Sample entropy and Multiscale entropy for distinguishing between normal and CAD patients. SPLE achieved a sensitivity-specificity of 80%-81%, the best of the tested methods. However, PLE and SPLE are not sufficient to prove nonlinearity, and evaluation using surrogate data suggests that our cardiovascular sound recordings do not contain significant nonlinear properties. 23955681 Thermodynamically destabilized hydride formation in "bulk" Mg-AlTi multilayers for hydrogen storage. Thermodynamic destabilization of MgH2 formation through interfacial interactions in free-standing Mg-AlTi multilayers of overall "bulk" (0.5 μm) dimensions with a hydrogen capacity of up to 5.5 wt% is demonstrated. The interfacial energies of Mg-AlTi and Mg-Ti (examined as a baseline) are calculated to be 0.81 and 0.44 J m(-2). The enhanced interfacial energy of AlTi opens the possibility of creating ultrathin alloy interlayers that provide further thermodynamic improvements in metal hydrides. 23122103 Rapid resolution liquid chromatography-electrospray ionisation tandem mass spectrometry method for identification of chemical constituents in Citri Reticulatae Pericarpium. Citri Reticulatae Pericarpium (CRP) is one of the most commonly used traditional Chinese medicines with great medicinal and dietary values. In this work, we developed an approach utilising rapid resolution liquid chromatography/electrospray ionisation tandem mass spectrometry (RRLC-ESI-MS/MS) for the identification and profiling of chemical composition in CRP. On the basis of RRLC retention times, cochromatography with available authentic standards, mass spectral fragmentation patterns and literature information, a total of 41 chemical compounds, including 4 flavone-C-glycosides, 7 flavonoid-O-glycosides and 19 polymethoxyflavones were unambiguously identified or tentatively characterised in CRP. The occurrence of 1 flavone-C-glycoside and 3 cyclic peptides in particular has not yet been described. The results indicated that the developed method could serve as a rapid, effective tool for structural characterisation of chemical constituents in CRP. 23903840 Glycoprotein B cleavage is important for murid herpesvirus 4 to infect myeloid cells. Glycoprotein B (gB) is a conserved herpesvirus virion component implicated in membrane fusion. As with many - but not all - herpesviruses, the gB of murid herpesvirus 4 (MuHV-4) is cleaved into disulfide-linked subunits, apparently by furin. Preventing gB cleavage for some herpesviruses causes minor infection deficits in vitro, but what the cleavage contributes to host colonization has been unclear. To address this we mutated the furin cleavage site (R-R-K-R) of the MuHV-4 gB. Abolishing gB cleavage did not affect its expression levels, glycosylation or antigenic conformation. In vitro, mutant viruses entered fibroblasts and epithelial cells normally, but had a significant entry deficit in myeloid cells such as macrophages and bone marrow-derived dendritic cells. The deficit in myeloid cells was not due to reduced virion binding or endocytosis, suggesting that gB cleavage promotes infection at a post-endocytic entry step, presumably viral membrane fusion. In vivo, viruses lacking gB cleavage showed reduced lytic spread in the lungs. Alveolar epithelial cell infection was normal, but alveolar macrophage infection was significantly reduced. Normal long-term latency in lymphoid tissue was established nonetheless. 23839667 The effect of an intervention on schoolchildren's susceptibility to a peer's candy intake. Background/objectives:The aim of the study was to pilot test two interventions designed to reduce children's susceptibility to peers' candy intake and to determine if interventions had different effects on boys and girls.Subjects/methods:In the standard intervention, peer modeling was explained while communicating the importance of not following other's food intake by means of photos, video clips and interactive tasks. A second animated intervention was similar but added a monkey puppet as a (cue) reminder. A social modeling component was conducted 1 day after the intervention to test whether the interventions affected the extent to which children model their peers' eating. During the modeling session, the participants' (N=141; 78% boys, mean age=7.84±0.72 years) solved a puzzle with a same-sex 'confederate' who was instructed to eat chocolate candy when he/she was covertly signaled. The monkey puppet was put in sight to test whether the monkey served as a cue reminder in the animated intervention. Candy intake was compared across control and intervention conditions.Results:The standard intervention reduced candy intake in boys but not girls. Nevertheless, children still remained susceptible to a peer's eating. There was no significant effect of the animated intervention on consumption.Conclusions:There are gender differences when children are exposed to an (over)eating peer. Although interventions are effective, social norms can be powerful. Social networks should be leveraged when possible. The study is registered at the Dutch Trial Register: NTR3459. 23843965 The distribution of fruit and seed toxicity during development for eleven neotropical trees and vines in Central Panama. Secondary compounds in fruit mediate interactions with natural enemies and seed dispersers, influencing plant survival and species distributions. The functions of secondary metabolites in plant defenses have been well-studied in green tissues, but not in reproductive structures of plants. In this study, the distribution of toxicity within plants was quantified and its influence on seed survival was determined in Central Panama. To investigate patterns of allocation to chemical defenses and shifts in allocation with fruit development, I quantified variation in toxicity between immature and mature fruit and between the seed and pericarp for eleven species. Toxicity of seed and pericarp was compared to leaf toxicity for five species. Toxicity was measured as reduced hyphal growth of two fungal pathogens, Phoma sp. and Fusarium sp., and reduced survivorship of brine shrimp, Artemia franciscana, across a range of concentrations of crude extract. I used these measures of potential toxicity against generalist natural enemies to examine the effect of fruit toxicity on reductions of fruit development and seed survival by vertebrates, invertebrates, and pathogens measured for seven species in a natural enemy removal experiment. The seed or pericarp of all vertebrate- and wind-dispersed species reduced Artemia survivorship and hyphal growth of Fusarium during the immature and mature stages. Only mature fruit of two vertebrate-dispersed species reduced hyphal growth of Phoma. Predispersal seed survival increased with toxicity of immature fruit to Artemia during germination and decreased with toxicity to fungi during fruit development. This study suggests that fruit toxicity against generalist natural enemies may be common in Central Panama. These results support the hypothesis that secondary metabolites in fruit have adaptive value and are important in the evolution of fruit-frugivore interactions. 23927535 Two-Color Laser Printing of Individual Gold Nanorods. We report on the deposition of individual gold nanorods from an optical trap using two different laser wavelengths. Laser light, not being resonant to the plasmon resonances of the nanorods, is used for stable trapping and in situ alignment of individual nanorods. Laser light, being resonant to the transversal mode of the nanorods, is used for depositing nanorods at desired locations. The power and polarization dependence of the process is investigated and discussed in terms of force balances between gradient and scattering forces, plasmonic heating, and rotational diffusion of the nanorods. This two-color approach enables faster printing than its one-color equivalent and provides control over the angular orientation (±16°) and location of the deposited nanorods at the single-nanorod level. 23883981 Variations in hospital charges for inpatient procedures. Newly available data expose striking local and national cost differences. 23868491 Hearing loss and the risk of disability pension in Norway: The Hunt Study. The purpose was to explore the possible associations between measured hearing thresholds and work related disability pension granted for other medical reasons in a Norwegian population. Method: This study included 25,537 persons from the Nord-Trøndelag Health Study (HUNT) aged 20-54 years at baseline in HUNT1 (1984-1986) who also participated in the follow-up study 11 years later, HUNT2 (1995-1997) that included a hearing examination. Logistic regression analyses of disability pension granted up to 1996 or earlier in life were conducted for men and women separately and in two age strata. Effects of low, middle and high-frequency hearing thresholds were explored, adjusting the effects of each hearing frequency for each other. Further adjustment was made for educational level, category of work (seven categories) and general health in HUNT1. Results: In all, 0.4% (16 of 4306) of the disability pensions granted up to 1996 was due to hearing related diagnoses. The risk of being granted disability pension up to 1996 with registered diagnoses not related to hearing loss increased with degree of loss of low-frequency hearing in young and middle-aged men and middle-aged women (OR 1.72, 95% CI 1.25-2.37; OR 1.16, 95% CI 1.04-1.30; OR 1.11, 95% CI 1.00-1.23). Conclusions: Hearing loss diagnoses are rarely reported as main causes in disability statistics, however, degree of hearing loss increased the risk of being granted with disability pensioning with diagnoses not related to hearing loss. 23809772 Do spectral bands of fetal heart rate variability associate with concomitant fetal scalp pH? Objective information on specific fetal heart rate (FHR) parameters would be advantageous when assessing fetal responses to hypoxia. Small, visually undetectable changes in FHR variability can be quantified by power spectral analysis of FHR variability. To investigate the effect of intrapartum hypoxia and acidemia on spectral powers of FHR variability. This is a retrospective observational clinical study with data from an EU multicenter project. We had 462 fetuses with a normal pH-value (pH>7.20; controls) in fetal scalp blood sample (FBS) and 81 fetuses with a low scalp pH-value (≤7.20; low-FBS pH-fetuses). The low-FBS pH-fetuses were further divided into two subgroups according to the degree of acidemia: fetuses with FBS pH7.11-7.20 (n=58) and fetuses with FBS pH ≤7.10 (n=23). Spectral powers of FHR variability in relation to the concomitant FBS pH-value. Fetuses with FBS pH ≤7.20 had increased spectral powers of FHR variability compared with controls (2.49AU vs. 2.23AU; p=0.038). However, the subgroup of most affected fetuses (those with FBS pH ≤7.10) had significantly lower FHR variability spectral powers when compared to fetuses with FBS pH7.11-7.20. This study shows that spectral powers of FHR variability change as a fetus becomes hypoxic, and that spectral powers decrease with deepening fetal acidemia. 23459109 Differential surface properties of commercial crystalline telmisartan samples. The aim of the present study was to investigate differences in surface chemistry of commercially available telmisartan (TMS) samples in Indian market and to correlate them to the surface molecular environment. Comprehensive characterization of material properties of four TMS samples from different sources showed that all samples exhibited same polymorphic form, but different particle shape, particle size distribution, surface energetics and surface chemistry. Wettability and surface free energy were determined using sessile drop contact angle technique. TMS samples exhibited significant variations in their wetting behavior. The role of crystal shape, particle size distribution, surface energetics and surface chemistry in controlling TMS powder wettability was collectively explored by contact angle experiments. Evaluation of work of adhesion (Wa), immersion (Wi) and spreading (Ws) indicated that samples had differential wetting behavior. The surface chemistry was elucidated by X-ray photoelectron spectroscopy (XPS). The surface polarity index was determined by XPS and expressed as (oxygen+nitrogen)-to-(carbon) atomic concentration ratio. It was found to be different for all four TMS samples. Crystal morphology of TMS polymorph A was predicted using Bravais-Friedel Donnay-Harker (BFDH) method. Molecular lipophilic surface potential (MLSP) data for TMS showed the varied surface lipophilic environment throughout the molecule. Hence it can be concluded that the differential abundance of surface elements play an important role in controlling the biopharmaceutical performance of TMS powder samples. 23385092 New pyrazole derivatives containing 1,2,4-triazoles and benzoxazoles as potent antimicrobial and analgesic agents. Azole class of compounds are well known for their excellent therapeutic properties. Present paper describes about the synthesis of three series of new 1,2,4-triazole and benzoxazole derivatives containing substituted pyrazole moiety (11a-d, 12a-d and 13a-d). The newly synthesized compounds were characterized by spectral studies and also by C, H, N analyses. All the synthesized compounds were screened for their analgesic activity by the tail flick method. The antimicrobial activity of the new derivatives was also performed by Minimum Inhibitory Concentration (MIC) by the serial dilution method. The results revealed that the compound 11c having 2,5-dichlorothiophene substituent on pyrazole moiety and a triazole ring showed significant analgesic and antimicrobial activity. 23597321 Stable isotope ratios of blood components and muscle to trace dietary changes in lambs. Multielemental stable isotope ratio (SIR) analysis was used in lamb plasma, erythrocytes and muscle to detect the switch from a pasture- to a concentrate-based diet, with the aim of verifying the possibility to trace the change of feeding in animal tissues. During 89 days of experimental feeding, lambs were subjected to four dietary treatments: pasture (P), pasture followed by concentrate in the stall for either 14 days (P-S14) or 37 days (P-S37) or concentrate in the stall (S). Pasture and concentrate diets comprised C3 plants only and had different values of 13C/12C, 18O/16O, 2H/1H and 34S/32S ratios. Muscle 13C/12C and 34S/32S and plasma 13C/12C and 18O/16O ratios in P, P-S14 and P-S37 lambs were significantly different. A multivariate analytical approach revealed that 13C/12C and 18O/16O ratios in plasma were the most powerful variables for the discrimination among the dietary treatments. 23816283 Diet-related practices and BMI are associated with diet quality in older adults. To assess the association of diet-related practices and BMI with diet quality in rural adults aged ≥74 years. Cross-sectional. Dietary quality was assessed by the twenty-five-item Dietary Screening Tool (DST). Diet-related practices were self-reported. Multivariate linear regression models were used to analyse associations of DST scores with BMI and diet-related practices after controlling for gender, age, education, smoking and self- v. proxy reporting. Geisinger Rural Aging Study (GRAS) in Pennsylvania, USA. A total of 4009 (1722 males, 2287 females; mean age 81·5 years) participants aged ≥74 years. Individuals with BMI < 18·5 kg/m2 had a significantly lower DST score (mean 55·8, 95 % CI 52·9, 58·7) than those individuals with BMI = 18·5-24·9 kg/m2 (mean 60·7, 95 % CI 60·1, 61·5; P = 0·001). Older adults with higher, more favourable DST scores were significantly more likely to be food sufficient, report eating breakfast, have no chewing difficulties and report no decline in intake in the previous 6 months. The DST may identify potential targets for improving diet quality in older adults including promotion of healthy BMI, breakfast consumption, improving dentition and identifying strategies to decrease concern about food sufficiency. 23852875 Rotavirus activity and meteorological variations in an Asian subtropical city, Hong Kong, 1995-2009. Rotavirus is a leading cause of severe infectious diarrhea in infants and young children aged <5 years. Rotavirus infections have minimal to strong seasonality depending on geographical locations. In this study, a comprehensive retrospective analysis was performed to evaluate the association between rotavirus admission and multiple key meteorological variables, including air temperature, relative humidity, atmospheric pressure, and solar radiation over a 15-year period from 1995 to 2009 in Hong Kong. Rotavirus infections were found to show a distinct cyclical pattern with an annual peak in cold season. The weekly number of cases showed the strongest correlation with average air temperature of the previous 7 days (rho = -0.69; P < 0.0001), followed by atmospheric pressure (rho = +0.67; P < 0.0001); whereas only weak correlation with relative humidity (rho = -0.252; P < 0.0001) and solar radiation (rho = -0.312; P < 0.0001) was observed. Curve fitting regression analysis suggested that the correlation was nonlinear in nature in which the effect was more profound towards lower air temperature and higher atmospheric pressure conditions. In binary logistic regression analysis, a final model that included air temperature (≤20°C) and atmospheric pressure (≥1,013 hPa) predicted correctly 85.3% and 82.6% of weeks with rotavirus activity above and below the baseline level, respectively. In multivariate Poisson model, air temperature and solar radiation were independent factors associated with the weekly number of rotavirus cases, adjusted for seasonal variation. In summary, the current study provides evidence suggesting that local seasonal activity of rotavirus correlated strongly with air temperature, followed by atmospheric pressure but only minimally with relative humidity in pre-vaccine era. J Med. Virol. 85:2026-2033, 2013. © 2013 Wiley Periodicals, Inc. 23363537 Intraindividual neuropsychological test variability in healthy individuals with high average intelligence and educational attainment. Knowledge of patterns of neuropsychological performance among normal, healthy individuals is integral to the practice of clinical neuropsychology, because clinicians may not always account for intraindividual variability (IIV) before coming to diagnostic conclusions. The IIV was assessed among a sample of 46 healthy individuals with high average intelligence and educational attainment, utilizing a battery of neuropsychological tests, including the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) and Wechsler Memory Scale, Fourth Edition (WMS-IV). The data indicated substantial variability in neurocognitive abilities. All participants were found to demonstrate scores considered impaired by at least 2 standard deviations (SDs). Despite adjusting for outliers, no participant produced a "normal" testing profile with an intraindividual maximum discrepancy (MD) of less than 1 SD in either direction. When WAIS-IV Full Scale IQ (FSIQ) was considered, participants generally demonstrated cognitive test scores ranging from 2 SDs less than to 1.5 SDs greater than their FSIQ. Furthermore, after demographic corrections, the majority (59%) of participants demonstrated at least 1 impaired cognitive test score, as defined by being 1 to 1.5 SDs below the mean. Overall, results substantiate the need for clinicians to consider FSIQ and educational attainment in interpretation of neuropsychological testing results, given the relevant commonality of "abnormal" test scores within this population. This may ultimately reduce the likelihood of making false-positive conclusions of impairment when educational attainment and intelligence are high, thus improving diagnostic accuracy. 23806667 Distribution of cytomegalovirus gN variants and associated clinical sequelae in infants. Human cytomegalovirus (HCMV) is the most widespread cause of congenital infection. The effects of various viral strains and viral loads on the infection outcome have been under debate. To determine the distribution of gN variants in HCMV strains isolated from children with congenital or postnatal infection and to establish the relationship between the viral genotype, the viral load, and the sequelae. The study population included congenitally HCMV-infected newborns and children with postnatal or unproven congenital HCMV infection. The genotyping was performed by RFLP analysis of PCR-amplified fragments, and the viral load was measured by quantitative real-time PCR. Our results demonstrated that the HCMV genotypes gN3b, gN4b, and gN4c were prevalent in the patients examined. There were no differences in the distributions of gN genotypes in the congenitally and postnatally infected children. Multiple HCMV strains were detected in both groups of children. A significant association between the HCMV gN4 genotype and the incidence of neurological disorders was observed (p=0.045). Our results suggest that the detection of the gN2 or the gN4 genotype may be indicative of serious manifestations in children. In contrast, the gN3b and the gN1 genotypes represent less pathogenic HCMV strains. The HCMV load in urine was significantly higher in children with congenital infection compared with children with postnatal infection. No correlation was found between the viral load and the genotype. Our results suggest that the gN genotype may be a virological marker of symptomatic HCMV infection in newborns. 23837580 Preparation, optimization, and in-vitro/in-vivo/ex-vivo characterization of chitosan-heparin nanoparticles: drug-induced gelation. Management of blood coagulation-related diseases is currently limited by the inability to provide an adequate drug concentration in blood circulation for a long term. As a promising way to overcome this problem, the long-acting forms of these drugs have attracted many interests in recent years. In this study, chitosan-heparin nanoparticles were prepared as a polymeric delivery system intended for the prolonged intravenous delivery of heparin where the drug was used as both the therapeutic agent and a gel-forming counter-ion. The nanoparticle preparation method was optimized using a Taguchi orthogonal array. Critical formulation variables were optimized in this study in terms of their corresponding effects on the target response of particle size. Nanoparticles were characterized by the Fourier transform infrared spectroscopy, transmission electron microscopy and zeta potential. The size, polydispersity index, zeta potential and encapsulation efficiency for the optimized formulation were found to be 61.33 ± 1.53 nm, 0.06, +15.7 mv and 74.16 ± 1.27%, respectively. The sizes of the prepared drug-loaded nanoparticles were stable at least 1 week at room temperature and 3 months in refrigerator. The ex-vivo and in-vivo tests on the heparin-chitosan nanoparticles using activated partial thromboplastin time (aPTT) as the biological index were indicative of a smoother and longer elevation in aPTT in the presence of nanoparticulate drug. 23869608 Brachial plexopathy injury due to laparoscopic rectal surgery. We read with interest the article by Codd et al, " A systematic review of peripheral nerve injury following laparoscopic colorectal surgery"[1]. The authors conducted a systematic review of Medline and Embase. This resulted in 10 cases identified with peripheral nerve injury after laparoscopic colorectal surgery. These injuries were associated with a lengthy procedure and abduction of the arm. The authors concluded that such injuries are rare but the surgeon and theatre team must be aware of the risk of peripheral nerve injury when positioning for laparoscopic colorectal procedures. This article is protected by copyright. All rights reserved. 23940116 hGAAP promotes cell adhesion and migration via the stimulation of store-operated Ca2+ entry and calpain 2. Golgi antiapoptotic proteins (GAAPs) are highly conserved Golgi membrane proteins that inhibit apoptosis and promote Ca(2+) release from intracellular stores. Given the role of Ca(2+) in controlling cell adhesion and motility, we hypothesized that human GAAP (hGAAP) might influence these events. In this paper, we present evidence that hGAAP increased cell adhesion, spreading, and migration in a manner that depended on the C-terminal domain of hGAAP. We show that hGAAP increased store-operated Ca(2+) entry and thereby the activity of calpain at newly forming protrusions. These hGAAP-dependent effects regulated focal adhesion dynamics and cell migration. Indeed, inhibition or knockdown of calpain 2 abrogated the effects of hGAAP on cell spreading and migration. Our data reveal that hGAAP is a novel regulator of focal adhesion dynamics, cell adhesion, and migration by controlling localized Ca(2+)-dependent activation of calpain. 23274771 NF-κB-associated mechanisms underlying the response of embryonic cells to Doxorubicin. The involvement of NF-κB in the regulation of teratogen-induced apoptosis has not been established yet. Therefore, we tried to assess the involvement of the p65 subunit of NF-κB in the embryonic response to the anti-cancer drug Doxorubicin (DOX). Thus, exposure of p65 knockout (p65(-/-)) or wild type (WT) mouse embryonic fibroblasts (MEFs) to DOX resulted in a decrease in cell survival, culture density and cell proliferation, which was found to be more prominent in p65(-/-) MEFs. Those phenomena were accompanied by a DOX-induced increase in the proportion of apoptotic cells, which was demonstrated only in p65(-/-) cells and a G2/M arrest, which was found to be more prominent in WT cells. Furthermore, DOX-treated WT and p65(-/-) MEFs differed in their expression of various apoptosis-associated molecules, when the former demonstrated a decrease in the percentage of p65-positive and a more prominent decrease in the percentage of p53-positive cells, while a decreased percentage of IκBα-positive and a more prominent decrease in the percentage of bcl-2-positive cells was detected among the latter. The fact that the response of the cells to the teratogen was clearly p65-dependent implicates this molecule to be involved in the response of the embryonic cells to DOX. 23774209 Extracellular RNA Liberates Tumor Necrosis Factor-α to Promote Tumor Cell Trafficking and Progression. Extracellular RNA (eRNA) released from injured cells promotes tissue permeability, thrombosis, and inflammation in vitro and in vivo, and RNase1 pretreatment can reduce all these effects. In this study, we investigated the role of the eRNA/RNase1 system in tumor progression and metastasis. Under quiescent and stimulatory conditions, tumor cells released much higher levels of endogenous extracellular RNA (eRNA) than nontumor cells. In glioblastomas, eRNA was detected at higher levels in tumors than nontumor tissue. eRNA induced tumor cells to adhere to and migrate through human cerebral microvascular endothelial cells (HCMEC/D3), in a manner requiring activation of VEGF signaling. In addition, eRNA liberated TNF-α from macrophages in a manner requiring activation of the TNF-α-converting enzyme TACE. Accordingly, supernatants derived from eRNA-treated macrophages enhanced tumor cell adhesion to HCMEC/D3. TNF-α release evoked by eRNA relied upon signaling activation of mitogen-activated protein kinases and the NF-κB pathway. In subcutaneous xenograft models of human cancer, administration of RNase1 but not DNase decreased tumor volume and weight. Taken together, these results suggest that eRNA released from tumor cells has the capacity to promote tumor cell invasion through endothelial barriers by both direct and indirect mechanisms, including through a mechanism involving TNF-α release from tumor-infiltrating monocytes/macrophages. Our findings establish a crucial role for eRNA in driving tumor progression, and they suggest applications for extracellular RNase1 as an antiinvasive regimen for cancer treatment. Cancer Res; 73(16); 5080-9. ©2013 AACR. 23916866 A simple method for quantifying biomass cell and polymer distribution in biofilms. Biofilms are ubiquitous and play an essential role in both environmental processes and hospital infections. Standard methods are not capable of quantifying biomass concentration in dilute suspensions. Furthermore, standard techniques cannot differentiate biomass composition. In this study, a user-friendly technique was developed for measuring biomass cell and polymer content in detached biofilms using a standard coulter counter. The method was demonstrated for an environmentally relevant strain of Pseudomonas aeruginosa (Schroeter) Migula grown in a bioreactor and also for a medically relevant strain of P. aeruginosa (PAO1) grown on standard growth pegs. Results were compared and validated by standard assays, including EPA method 1684 for measuring biomass, microscopic direct counts, and a crystal violet staining assay. The minimum detection limit for the coulter counter method (0.07mg-biomass L(-1)) was significantly lower than the EPA method 1684 (1.9±0.4mg/L) and the crystal violet assay (1.1±0.2mgL(-1)). However, the coulter counter method is limited to dilute biomass samples (below 204±16mgL(-1)) due to clogging of the aperture tube. While biomass measurements are useful, the major advantage of the coulter counter method is the ability to directly determine EPS, cell, and aggregate fractions after mild chemical treatment. The rapid technique (4-5min per sample) was used to measure biomass fractions in dispersed P. aeruginosa (Schroeter) and PAO1 biofilms. This technique will be critical for understanding biofilm formation/dispersal. 23818613 Structural and functional analysis of the yeast N-acetyltransferase Mpr1 involved in oxidative stress tolerance via proline metabolism. Mpr1 (sigma1278b gene for proline-analog resistance 1), which was originally isolated as N-acetyltransferase detoxifying the proline analog l-azetidine-2-carboxylate, protects yeast cells from various oxidative stresses. Mpr1 mediates the l-proline and l-arginine metabolism by acetylating l-Δ(1)-pyrroline-5-carboxylate, leading to the l-arginine-dependent production of nitric oxide, which confers oxidative stress tolerance. Mpr1 belongs to the Gcn5-related N-acetyltransferase (GNAT) superfamily, but exhibits poor sequence homology with the GNAT enzymes and unique substrate specificity. Here, we present the X-ray crystal structure of Mpr1 and its complex with the substrate cis-4-hydroxy-l-proline at 1.9 and 2.3 Å resolution, respectively. Mpr1 is folded into α/β-structure with eight-stranded mixed β-sheets and six α-helices. The substrate binds to Asn135 and the backbone amide of Asn172 and Leu173, and the predicted acetyl-CoA-binding site is located near the backbone amide of Phe138 and the side chain of Asn178. Alanine substitution of Asn178, which can interact with the sulfur of acetyl-CoA, caused a large reduction in the apparent kcat value. The replacement of Asn135 led to a remarkable increase in the apparent Km value. These results indicate that Asn178 and Asn135 play an important role in catalysis and substrate recognition, respectively. Such a catalytic mechanism has not been reported in the GNAT proteins. Importantly, the amino acid substitutions in these residues increased the l-Δ(1)-pyrroline-5-carboxylate level in yeast cells exposed to heat stress, indicating that these residues are also crucial for its physiological functions. These studies provide some benefits of Mpr1 applications, such as the breeding of industrial yeasts and the development of antifungal drugs. 23837446 Genetic background, and not ontogenetic effects, affects avian seasonal timing of reproduction. Avian seasonal timing is a life-history trait with important fitness consequences and which is currently under directional selection due to climate change. To predict micro-evolution in this trait, it is crucial to properly estimate its heritability. Heritabilities are often estimated from pedigreed wild populations. As these are observational data, it leaves the possibility that the resemblance between related individuals is not due to shared genes but to ontogenetic effects; when the environment for the offspring provided by early laying pairs differs from that by late pairs and the laying dates of these offspring when they reproduce themselves is affected by this environment, this may lead to inflated heritability estimates. Using simulation studies, we first tested whether and how much such an early environmental effect can inflate heritability estimates from animal models, and we showed that pedigree structure determines by how much early environmental effects inflate heritability estimates. We then used data from a wild population of great tits (Parus major) to compare laying dates of females born early in the season in first broods and from sisters born much later, in second broods. These birds are raised under very different environmental conditions but have the same genetic background. The laying dates of first and second brood offspring do not differ when they reproduce themselves, clearly showing that ontogenetic effects are very small and hence, family resemblance in timing is due to genes. This finding is essential for the interpretation of the heritabilities reported from wild populations and for predicting micro-evolution in response to climate change. 23542084 A highly sensitive differential pulse anodic stripping voltammetry for determination of 17β-estradiol (E2) using CdSe quantum dots based on indirect competitive immunoassay. In this study a new and fast procedure was developed to determine trace 17β-estradiol (E2) concentrations using CdSe quantum dots (QDs) conjugation with bovine serum albumin (BSA)-E2. To increase the high efficiency of the method, the immunoassay design was restricted to an indirect competitive format. The E2 antigen and bioconjugate were incubated in a microtiter plate with an anti-E2 antibody and competition for antibody binding sites was established. The in situ bismuth-coated carbon electrodes were used for detecting the cadmium ions (Cd(2+)) released during the acid dissolution step. After optimization, the well-defined sharp anodic stripping voltammograms curves of the E2 concentration ranging from 50 to 1000 pg/mL was recorded, and the lowest detection limit was 50 pg/mL with 6% reproducibility and 7% repeatability. Finally, the assay was applied to tap water and wastewater samples. The detection limits were 52.56 ± 0.125 pg/mL for tap water and 51.42 ± 0.453 pg/mL for wastewater. These results show that the assay exhibited sensitive analytical performance in E2 detection with high sensitivity and accuracy with satisfactory results. 23265543 Influence of nitrogen supply on the production of higher alcohols/esters and expression of flavour-related genes in cachaça fermentation. This study provides the first attempt to analyse the influence of ammonium supplements on sugar-cane juice fermentation and the flavour profile in a cachaça industrial process. The objective was to find a relationship between higher alcohol/ester content and the transcription levels of the main genes involved in production of these compounds under cachaça fermentation. Sugar-cane juice with a low amount of assimilable nitrogen (81 mg N/L), was further supplemented with mid-range or high concentrations of ammonium sulfate. Overall, higher alcohol production was reduced by ammonium supplementation, and this can be correlated with a general downregulation of genes encoding decarboxylases and dehydrogenases of the Ehrlich pathway. The production of acetate esters was enhanced by mid-range ammonium supplementation and the production of acyl esters by high ammonium supplementation. The acyl esters could be correlated with expression of alcohol acyl-transferase EEB1 and the acyl esterase IAH1. 23739492 Work characteristics, socioeconomic position and health: a systematic review of mediation and moderation effects in prospective studies. Social inequalities in health persist in modern societies. The contribution of adverse work and employment conditions towards their explanation is analysed by two approaches, mediation and moderation. Yet the relative significance of each approach remains unclear in respective research. We set out to study this question by conducting a systematic literature review. We included all original papers based on prospective observational studies of employed cohorts that were published between January 1980 and October 2012 meeting our search criteria, by using major databases and by observing established quality criteria. 26 reports were included after quality assessment. 17 studies examined the mediation hypothesis and nine studies tested the moderation hypothesis. Moderate support was found for the mediation hypothesis where OR or HR of health according to socioeconomic position (SEP) were reduced in a majority of analyses after introducing work characteristics in multivariate models. Evidence in favour of the moderation hypothesis was found in some studies, demonstrating stronger effects of adverse work on health among people with low SEP. Despite some support in favour of the two hypotheses future research should aim at reducing the heterogeneity in defining and measuring core variables and at applying advanced statistical analyses. Policy recommendations would benefit from a higher degree of consistency of respective research evidence. 23392953 Small ruminant lentiviruses in Jordan: evaluation of sheep and goat serological response using recombinant and peptide antigens. Small ruminant lentiviruses infect sheep and goats worldwide, causing chronic progressive diseases and relevant economic losses. Disease eradication and prevention is mostly based on serological testing. The goal of this research was to investigate the presence of the small ruminant lentiviruses (SRLVs) in Jordan and to characterize the serological response in sheep and goat populations. A panel of sera were collected from flocks located in Northern Jordan and Jordan Valley. The samples were tested using three ELISA assays: a commercially available ELISA based on p25 recombinant protein and transmembrane peptide derived from British maedi-visna virus (MVV) EV1 strain, an ELISA based on P16-P25 recombinant protein derived from two Italian strains representative of MVV- and caprine arthritis encephalitis virus (CAEV)-like SRLVs, and an ELISA based on SU5 peptide from the same two Italian isolates. The results indicate that both MVV- and CAEV-like strains are present in Jordan and that the majority of the viruses circulating among sheep and goat populations belong to the MVV-like genotype. 23953890 Dynamics of serum metabolites in patients with chronic hepatitis C receiving pegylated interferon plus ribavirin: A metabolomics analysis. Serum samples from patients with chronic hepatitis C were subjected to metabolomics analysis to clarify the pretreatment characteristics of their metabolites and also changes in specific metabolites resulting from antiviral therapy with pegylated interferon plus ribavirin (PegIFN/RBV). The serum levels of low-molecular-weight metabolites in the twenty patients before and 24weeks after completion of PegIFN/RBV therapy were analyzed using capillary electrophoresis and liquid chromatography-mass spectrometry. Ten patients showed a non-virological response (NVR) and 10 achieved a sustained virological response (SVR) with eradication of viremia. The pretreatment levels of tryptophan were significantly higher in the patients of SVR than in those of NVR (p=0.010). The area under the curve (AUC) value of tryptophan calculated from the receiver operating characteristic (ROC) curve for discriminating SVR from NVR was 0.84 (95% confidential interval, 0.66-1.02, p=0.010). The ROC curve of multiple logistic regression model incorporating the pretreatment levels of tryptophan and γ-glutamate-arginine showed that the AUC value was highly significant (AUC=0.92, 95% confidential interval, 0.79-1.05, p=0.002). Twenty four weeks after completion of treatment, the levels of γ-glutamyl dipeptides, glutamic acid, 5-oxoproline, glucosamine and methionine sulfoxide were decreased, whereas those of 5-methoxy-3-indoleacetate, glutamine, kynurenine and lysine were increased significantly (p<0.05) in both the NVR and SVR patients. The pretreatment serum levels of certain metabolites including tryptophan are associated with the response to PegIFN/RBV therapy. PegIFN/RBV therapy can ameliorate the oxidative stress responsible for glutathione metabolism. 23904253 Growth, photosynthetic efficiency, and biochemical composition of Tetraselmis suecica F&M-M33 grown with LEDs of different colors. The effect of light quality on cell size and cell cycle, growth rate, productivity, photosynthetic efficiency and biomass composition of the marine prasinophyte Tetraselmis suecica F&M-M33 grown in 2-L flat panel photobioreactors illuminated with light emitting diodes (LEDs) of different colors was investigated. Biomass productivity and photosynthetic efficiency were comparable between white and red light, while under blue and green light productivity decreased to less than half and photosynthetic efficiency to about one third. Differences in cell size and number correlated with the cell cycle phase. Under red light cells were smaller and more motile. Chlorophyll content was strongly reduced with red and enhanced with blue light, while carotenoids and gross biomass composition were not affected by light quality. The eicosapentaenoic acid content increased under red light. Red light can substitute white light without affecting productivity of T. suecica F&M-M33, leading to smaller and more motile cells and increased eicosapentaenoic acid content. Red LEDs can thus be profitably used for the production of this microalga for aquaculture. Biotechnol. Bioeng. 2013;9999: 1-9. © 2013 Wiley Periodicals, Inc. 23835074 BAHA implant: Implantation technique and complications. BAHA implants have been shown to be effective in certain forms of conductive hearing loss, but the presence of the titanium abutment is responsible for sometimes severe skin reactions. The objective of this study was to compare two operative techniques: skin flap, and full-thickness skin graft. Between January 2004 and January 2011, 72 patients were treated by BAHA implant and 32 of these patients (total of 41 implants) were included in the study. Two surgical techniques were used: full-thickness skin graft (n=21) and skin flap (n=20). Four types of skin complications were observed: necrosis, inflammation/infection, hypertrophic scar, and fixture loss due to inadequate osseointegration. Complications requiring surgical revision were observed in 20% of cases with the skin flap method and 38% of cases with the skin graft technique, with no significant difference between the two groups (P=0.31). The skin graft technique appears to be associated with a higher rate of major complications. The most common complication is hypertrophic scar. The apparently high complication rate in this series can be explained by a selection bias (exclusion of a large number of complication-free patients). 23951708 Multilevel statistical models and the analysis of experimental data. Data sets from ecological experiments can be difficult to analyze, due to lack of independence of experimental units and complex variance structures. In addition, information of interest may lie in complicated contrasts among treatments, rather than direct output from statistical tests. Here, we present a statistical framework for analyzing data sets containing non-independent experimental units and differences in variance among treatments (heteroscedasticity) and apply this framework to experimental data on interspecific competition among three tadpole species. Our framework involves three steps: (1) use a multilevel regression model to calculate coefficients of treatment effects on response variables; (2) combine coefficients to quantify the strength of competition (the target information of our experiment); and (3) use parametric bootstrapping to calculate significance of competition strengths. We repeated this framework using three multilevel regression models to analyze data at the level of individual tadpoles, at the replicate level, and at the replicate level accounting for heteroscedasticity. Comparing results shows the need to correctly specify the statistical model, with the model that accurately accounts for heteroscedasticity leading to different conclusions from the other two models. This approach gives a single, comprehensive analysis of experimental data that can be used to extract informative biological parameters in a statistically rigorous way. 23643101 Implementing clinical guidelines in stroke: A qualitative study of perceived facilitators and barriers. Clinical guidelines are frequently used as a mechanism for implementing evidence-based practice. However research indicates that health professionals vary in the extent to which they adhere to these guidelines. This study aimed to study the perceptions of stakeholders and health professionals on the facilitators and barriers to implementing national stroke guidelines in Ireland. Qualitative interviews using focus groups were conducted with stakeholders (n=3) and multidisciplinary team members from hospitals involved in stroke care (n=7). All focus group interviews were semi-structured, using open-ended questions. Data was managed and analysed using NVivo 9 software. The main themes to emerge from the focus groups with stakeholders and hospital multidisciplinary teams were very similar in terms of topics discussed. These were resources, national stroke guidelines as a tool for change, characteristics of national stroke guidelines, advocacy at local level and community stroke care challenges. Facilitators perceived by stakeholders and health professionals included having dedicated resources, user-friendly guidelines relevant at local level and having supportive advocates on the ground. Barriers were inadequate resources, poor guideline characteristics and insufficient training and education. This study highlights health professionals' perspectives regarding many key concepts which may affect the implementation of stroke care guidelines. The introduction of stroke clinical guidelines at a national level is not sufficient to improve health care quality as they should be incorporated in a quality assurance cycle with education programmes and feedback from surveys of clinical practice. 23200945 Bradykinetic alcohol dehydrogenases make yeast fitter for growth in the presence of allyl alcohol. Previous studies showed that fitter yeast (Saccharomyces cerevisiae) that can grow by fermenting glucose in the presence of allyl alcohol, which is oxidized by alcohol dehydrogenase I (ADH1) to toxic acrolein, had mutations in the ADH1 gene that led to decreased ADH activity. These yeast may grow more slowly due to slower reduction of acetaldehyde and a higher NADH/NAD(+) ratio, which should decrease the oxidation of allyl alcohol. We determined steady-state kinetic constants for three yeast ADHs with new site-directed substitutions and examined the correlation between catalytic efficiency and growth on selective media of yeast expressing six different ADHs. The H15R substitution (a test for electrostatic effects) is on the surface of ADH and has small effects on the kinetics. The H44R substitution (affecting interactions with the coenzyme pyrophosphate) was previously shown to decrease affinity for coenzymes 2-4-fold and turnover numbers (V/Et) by 4-6-fold. The W82R substitution is distant from the active site, but decreases turnover numbers by 5-6-fold, perhaps by effects on protein dynamics. The E67Q substitution near the catalytic zinc was shown previously to increase the Michaelis constant for acetaldehyde and to decrease turnover for ethanol oxidation. The W54R substitution, in the substrate binding site, increases kinetic constants (Ks, by >10-fold) while decreasing turnover numbers by 2-7-fold. Growth of yeast expressing the different ADHs on YPD plates (yeast extract, peptone and dextrose) plus antimycin to require fermentation, was positively correlated with the log of catalytic efficiency for the sequential bi reaction (V1/KiaKb=KeqV2/KpKiq, varying over 4 orders of magnitude, adjusted for different levels of ADH expression) in the order: WT≈H15R>H44R>W82R>E67Q>W54R. Growth on YPD plus 10mM allyl alcohol was inversely correlated with catalytic efficiency. The fitter yeast are "bradytrophs" (slow growing) because the ADHs have decreased catalytic efficiency. 23959231 The influence of coupling agents on mechanical property retention and long-term cytocompatibility of phosphate glass fibre reinforced PLA composites. Completely resorbable composites are an attractive alternative for metallic bone-fracture fixation devices. However, failure of their interfacial integrity within aqueous environments, which can lead to a rapid loss of overall mechanical properties, has been reported in the literature. In this study coupling agents were investigated for phosphate glass fibre reinforced poly(lactic acid) composites. Three coupling agents with varying wettability were employed to improve initial mechanical properties and their retention in vitro via improvement of the interfacial bond between polymer matrix and fibres. Coupling agents were grafted onto the glass fibres by dip-coating in coupling agent solution at optimised concentrations. Three-aminopropyltriethoxy silane and sorbitol ended PLA oligomer treatments improved the initial flexural properties (27% strength with APS and 17% modulus via SPLA treatment) of the composites and 3-aminopropyltriethoxy silane and hexamethylene diisocyanate (HDI) treatments also decreased the loss of flexural strength and modulus during degradation. HDI treated samples retained 57.2% and 64.7% of their initial strength and modulus, respectively compared to control where only 34% of initial strength and 52% of initial modulus was retained after 28 days of degradation in PBS solution. Initial improvements in flexural properties were associated with improved shear bond strength at the interface due to covalent bonding between the glass fibres and polymer matrix provided by the coupling agents. Delay in mechanical property loss with degradation was suggested to be due to the hydrophobicity at the interface, which could have hindered the interfacial integrity loss and consequently loss of mechanical integrity of the composites. All coupling agent treated and control composites were tested for cytocompatibility using a primary human osteoblast cell line. A comparable response to the control, in terms of cell adhesion, proliferation and differentiation was observed supporting the use of these agents within implantable devices. 23825183 Platelet-Rich Plasma Significantly Improves Clinical Outcomes in Patients With Chronic Tennis Elbow: A Double-Blind, Prospective, Multicenter, Controlled Trial of 230 Patients. BACKGROUND:Elbow tenderness and pain with resisted wrist extension are common manifestations of lateral epicondylar tendinopathy, also known as tennis elbow. Previous studies have suggested platelet-rich plasma (PRP) to be a safe and effective therapy for tennis elbow. PURPOSE:To evaluate the clinical value of tendon needling with PRP in patients with chronic tennis elbow compared with an active control group. STUDY DESIGN:Randomized controlled trial; Level of evidence, 1. METHODS:A total of 230 patients with chronic lateral epicondylar tendinopathy were treated at 12 centers over 5 years. All patients had at least 3 months of symptoms and had failed conventional therapy. There were no differences in patients randomized to receive PRP (n = 116) or active controls (n = 114). The PRP was prepared from venous whole blood at the point of care and contained both concentrated platelets and leukocytes. After receiving a local anesthetic, all patients had their extensor tendons needled with or without PRP. Patients and investigators remained blinded to the treatment group throughout the study. RESULTS:Patient outcomes were followed for up to 24 weeks. At 12 weeks (n = 192), the PRP-treated patients reported an improvement of 55.1% in their pain scores compared with 47.4% in the active control group (P = .094). At 24 weeks (n = 119), the PRP-treated patients reported an improvement of 71.5% in their pain scores compared with 56.1% in the control group (P = .027). The percentage of patients reporting significant elbow tenderness at 12 weeks was 37.4% in the PRP group versus 48.4% in the control group (P = .036). At 24 weeks, 29.1% of the PRP-treated patients reported significant elbow tenderness versus 54.0% in the control group (P < .001). Success rates for patients with 24 weeks of follow-up were 83.9% in the PRP group compared with 68.3% in the control group (P = .012). No significant complications occurred in either group. CONCLUSION:Treatment of chronic tennis elbow with leukocyte-enriched PRP is safe and results in clinically meaningful improvements compared with an active control group. 23611476 Stability of sulforaphane for topical formulation. Abstract Context: Sulforaphane (SFN) is a natural compound that has been investigated as a chemopreventive agent. SFN has been shown to inhibit the activator-protein-1 (AP-1) transcription factor and may be effective for inhibition of ultraviolet (UV) induced skin carcinogenesis. This study was designed to investigate the stability of SFN as a function of pH, temperature and in various solvents and formulations. Materials and methods: Stability was analyzed using high-performance liquid chromatography. A potential lead formulation was identified and evaluated in vivo. Results: SFN was determined to undergo apparent first-order degradation kinetics for the conditions explored. It was observed that SFN undergoes base catalyzed degradation. Buffer species and solvent type impacts stability as well. SFN was found to be very sensitive to temperature with degradation rate changing by a factor of nearly 3.1 for every 10 °C change in temperature (at pH 4.0). SFN completely degraded after 30 days in a conventional pharmaceutical cream formulation. Improved stability was observed in organic formulation components. Stability studies were conducted on two nonaqueous topical formulations: a polyethylene glycol (PEG) ointment base and an organic oleaginous base. Conclusion: Topically applied SFN in the PEG base formulation significantly reduced AP-1 activation after UV stimulation in the skin of a transgenic mouse model, indicating that SFN in this formulation retains efficacy in vivo. 23898949 Four Mechanisms in the Reactions of 3-Aminopyrrole with 1,3,5-Triazines: Inverse Electron Demand Diels-Alder Cycloadditions vs SNAr Reactions via Uncatalyzed and Acid-Catalyzed Pathways. Reaction of 3-aminopyrrole with seven 1,3,5-triazines was studied in a one-step reaction (in situ formation of 3-aminopyrrole) and a two-step reaction (using the tetraphenylborate salt and an amine base). An inverse-electron demand Diels-Alder reaction (IEDDA) was observed with R1 = CF3, CO2Et, and H with the formation of 5H-pyrrolo[3,2-d]pyrimidine derivatives. SNAr was observed when 2,4,6-trifluoro- or 2,4,6-trichloro-1,3,5-triazine were used-1,3,5-triazines that had leaving groups. If excess 1,3,5-triazine was present the initial SNAr product reacted further, in the presence of acid and water, with another equivalent of 1,3,5-triazine to give compounds containing three linked heterocyclic rings. No reaction was observed with R1 = C6H5 and OCH3. Four mechanisms are proposed to explain the experimental results: uncatalyzed and acid catalyzed inverse electron demand Diels-Alder cascades leading to cycloaddition, and uncatalyzed and acid-catalyzed SNAr reactions leading, respectively, to single and double substitution products. Acid catalysis was a factor when there was reduced reactivity in either reactant. 23262270 Reducing effect of an extract of Phaseolus vulgaris on food intake in mice--focus on highly palatable foods. Different lines of experimental evidence indicate that treatment with extracts from and derivatives of Phaseolus vulgaris reduces intake of food, including highly palatable foods and beverages, in rats. The present study was designed to extend to mice these lines of evidence. To this end, CD1 mice were treated acutely with a standardized extract of P. vulgaris and then exposed to unlimited access to regular food pellets (Experiment 1) or 1-hour limited access to three different palatable foods/beverages, such as butter cookies (Experiment 2), a condensed-milk beverage (Experiment 3), and a chocolate-flavored beverage (Experiment 4). Treatment with P. vulgaris extract resulted in a significant reduction in the intake of regular food pellets, that was still evident 24h later, as well as of the three palatable nourishments. Together, these results (a) extend to mice several previous findings on the capacity of P. vulgaris extracts to suppress food intake in rats, (b) suggest that P. vulgaris extracts may interfere with the central mechanisms regulating appetite, food intake, palatability, and/or the rewarding and hedonic properties of food, and (c) P. vulgaris extracts may represent a potentially effective therapy for overeating, obesity, and food craving. 23928011 Fabrication of nano-fibrous poly(l-lactic acid) scaffold reinforced by surface modified chitosan micro-fiber. To mimic the fibrillar structure of natural extracellular matrix and optimize the chemical composition of the scaffold, a nano-fibrous poly(l-lactic acid) (PLLA) scaffold reinforced by surface modified chitosan micro-fiber (MCTSF) was fabricated using the thermally induced phase separation method. The composite scaffold has a novel structure comprised of a nano-matrix with reinforcing micro-fibers, in which the nano-fibrous PLLA matrix promotes cell adhesion and proliferation, while the MCTSF provides the mechanical support and adjusts the biocompatibility. The morphology of the composite scaffold showed a nano-fibrous PLLA matrix (100-500nm fiber diameter), an interconnected microporous structure (1.0-8.0μm pore size), and high porosity (>90%). MCTSF were homogeneously distributed in the composite scaffold and had intimate interactions with PLLA matrix. As a result, the compressive modulus of PLLA/MCTSF (100:40, w/w) increased 4.7-fold compared with that of a pristine PLLA scaffold. The prepared composite scaffold also showed good properties including buffering the acidic degradation of PLLA during in vitro degradation, enhanced protein adsorption capacity, and good cytocompatibility, suggesting that the PLLA/MCTSF composite scaffolds are potential candidate materials in tissue engineering. 23871304 Effects of foot orthoses on the temporal pattern of muscular activity during walking. Several studies have described the biomechanical effects of foot orthotics, as well as their effects at the level of muscular recruitment. Although the latter effect is unlikely to be limited to muscular intensity, the temporal pattern of activity of the muscles involved in walking with orthoses is still unclear. Twelve adults with everted static rearfoot posture higher than 5° of valgus participated in the study. For all participants, the kinematic data and the muscular temporal activity of the tibialis anterior, the soleus, the gastrocnemius medialis, the gastrocnemius lateralis and the peroneus longus were measured under two experimental conditions, walking with and without custom-made orthoses. Data were recorded and analyzed using a motion analysis and a surface EMG system. The results showed that, when walking with insoles, the activity of the tibialis anterior, the soleus, the gastrocnemius medialis, the gastrocnemius lateralis and the peroneus longus is shorter than walking without orthoses. Furthermore, when walking with orthoses, the activity of the soleus and the gastrocnemius medialis is delayed. Our study corroborates that the realignment of the calcaneus with the talus decreases the range of eversion and inversion of midfoot. Moreover, it reports noticeable modifications on the start time and the duration of the muscular activity of the tibialis anterior, soleus, gastrocnemii and peroneus longus while using foot orthoses. 23852891 Knockdown of PLA2G2A sensitizes gastric cancer cells to 5-FU in vitro. Elevated expression of the PLA2G2A phospholipase in gastric cancer (GC) is associated with improved patient survival. PLA2G2A is also an important regulator of proliferation, invasion and metastasis in GC. However, no relation about PLA2G2A and chemosensitivity in GC cells was reported. 5-Fluorouracil (5-FU) is widely used for treatment of advanced gastric cancer. However, it is common for such patients to develop resistance to 5-FU, and this drug resistance becomes a critical problem for chemotherapy. The mechanisms underlying this resistance are largely unknown. In the present study, we investigated whether PLA2G2A could confer 5-FU resistance or sensitise in GC cells in vitro. The 5-FU sensitivity of GC cell lines SGC-7901, MKN-45, RF-48, N87, AGS, MKN-28, RF-1, MGC-803 were determined by MTT assays. PLA2G2A levels were determined by western blot assays. The effects of 5-FU on PLA2G2A expression were determined in vitro. PLA2G2A was inhibited by silencing of the PLA2G2A using small interfering RNA in vitro. PLA2G2A was overexpressed by transfection of full-long PLA2G2A cDNA in vitro, and the effects were evaluated on 5-FU sensitivity. The cell lines SGC-7901, MKN-45, RF-48 and N87 were sensitive, whereas AGS, MKN-28, RF-1 and MGC-803 were resistant to 5-FU. Significant correlation was observed between basal PLA2G2A and 5-FU sensitivity. Silencing of PLA2G2A increased 5-FU killing in 5-FU-treated cells, and overexpression of PLA2G2A decreased 5-FU killing in 5-FU-treated cells. PLA2G2A was correlated with sensitivity to 5-FU. Silencing of PLA2G2A was sensitive to 5-FU treatment. Thus, PLA2G2A may be a useful therapeutic target for a subset of gastric cancers. 23901898 Kernel-Based Partial Least Squares: Application to Fingerprint-Based QSAR with Model Visualization. Numerous regression-based and machine learning techniques are available for the development of linear and nonlinear QSAR models that can accurately predict biological endpoints. Such tools can be quite powerful in the hands of an experienced modeler, but too frequently a disconnect remains between the modeler and project chemist because the resulting QSAR models are effectively black boxes. As a result, learning methods that yield models that can be visualized in the context of chemical structures are in high demand. In this work, we combine direct kernel-based PLS with Canvas 2D fingerprints to arrive at predictive QSAR models that can be projected onto the atoms of a chemical structure, allowing immediate identification of favorable and unfavorable characteristics. The method is validated using binding affinities for ligands from 10 different protein targets covering 7 distinct protein families. Models with significant predictive ability (test set Q(2) > 0.5) are obtained for 6 of 10 data sets, and fingerprints are shown to consistently outperform large collections of classical physicochemical and topological descriptors. In addition, we demonstrate how a simple bootstrapping technique may be employed to obtain uncertainties that provide meaningful estimates of prediction accuracy. 23860192 The effect of involuntary motor activity on myoelectric pattern recognition: a case study with chronic stroke patients. Objective. This study investigates the effect of the involuntary motor activity of paretic-spastic muscles on the classification of surface electromyography (EMG) signals. Approach. Two data collection sessions were designed for 8 stroke subjects to voluntarily perform 11 functional movements using their affected forearm and hand at relatively slow and fast speeds. For each stroke subject, the degree of involuntary motor activity present in the voluntary surface EMG recordings was qualitatively described from such slow and fast experimental protocols. Myoelectric pattern recognition analysis was performed using different combinations of voluntary surface EMG data recorded from the slow and fast sessions. Main results. Across all tested stroke subjects, our results revealed that when involuntary surface EMG is absent or present in both the training and testing datasets, high accuracies (>96%, >98%, respectively, averaged over all the subjects) can be achieved in the classification of different movements using surface EMG signals from paretic muscles. When involuntary surface EMG was solely involved in either the training or testing datasets, the classification accuracies were dramatically reduced (<89%, <85%, respectively). However, if both the training and testing datasets contained EMG signals with the presence and absence of involuntary EMG interference, high accuracies were still achieved (>97%). Significance. The findings of this study can be used to guide the appropriate design and implementation of myoelectric pattern recognition based systems or devices toward promoting robot-aided therapy for stroke rehabilitation. 23320964 Smoking behaviour and attitudes among German nursing students. Tobacco consumption is a major public health threat. Healthcare workers can contribute to the reduction of tobacco use. The principles of intervention need to be provided already during vocational school. This research examines the smoking habits, the personal attitudes towards smoking and the professional beliefs of healthcare trainees. The aim of this study is to ascertain the necessity and the general conditions for multilevel interventions of prevention and health promotion. In 2010, a questionnaire survey was conducted in a Berlin vocational school for healthcare workers. Of 148 students (RR = 49.3%) 41.9% of the students are daily or occasional smokers. The nicotine dependency and the number of cigarettes per day are comparatively low. The majority of smoking students is willing to quit and has already undertaken several attempts. Non-smoking protection is evaluated to be very important and intervention rates in patient care range between 49% and 72%. In both questions, non-smokers and smokers differ significantly. The self-reported smoking prevalence in our population is considerably lower than in previous studies. However, the smoking rate among healthcare trainees is still higher than in the general population. The students' own smoking behaviours and its influences on the treatment of patients should be reflected during school. It is necessary to develop adequate recruitment strategies and attractive interventions for this target group. 23870142 Tandem Stem-Loops in roX RNAs Act Together to Mediate X Chromosome Dosage Compensation in Drosophila. Dosage compensation in Drosophila is an epigenetic phenomenon utilizing proteins and long noncoding RNAs (lncRNAs) for transcriptional upregulation of the male X chromosome. Here, by using UV crosslinking followed by deep sequencing, we show that two enzymes in the Male-Specific Lethal complex, MLE RNA helicase and MSL2 ubiquitin ligase, bind evolutionarily conserved domains containing tandem stem-loops in roX1 and roX2 RNAs in vivo. These domains constitute the minimal RNA unit present in multiple copies in diverse arrangements for nucleation of the MSL complex. MLE binds to these domains with distinct ATP-independent and ATP-dependent behavior. Importantly, we show that different roX RNA domains have overlapping function, since only combinatorial mutations in the tandem stem-loops result in severe loss of dosage compensation and consequently male-specific lethality. We propose that repetitive structural motifs in lncRNAs could provide plasticity during multiprotein complex assemblies to ensure efficient targeting in cis or in trans along chromosomes. 23538322 Hematological and biochemical alterations in the fish Prochilodus lineatus caused by the herbicide clomazone. The indiscriminate use of herbicides has led to the contamination of water bodies, possibly affecting the health of aquatic biota. Therefore, to evaluate the possible effects of the clomazone-based herbicide (Gamit(®) 500) on the fish Prochilodus lineatus, juveniles were exposed for 96h to three concentrations (1, 5 and 10mgL(-1)) of clomazone, and an analysis was made of their hematological parameters: hemoglobin (Hb); hematocrit (Hct); red blood cell (RBC) count; mean corpuscular volume (MCV); mean corpuscular hemoglobin (MCH); mean corpuscular hemoglobin concentration (MCHC) and biochemical parameters: glutathione S-transferase (GST); catalase (CAT); glutathione peroxidase (GPx) and acetylcholinesterase (AChE). Hct presented a significant decrease at the concentration of 10mgL(-1), while the parameters Hb, HCM and MCHC presented a significant decrease at the two higher concentrations, indicating an anemic condition. The RBC increased significantly at the lowest concentration, possibly due to the release of new red blood cells into the bloodstream in response to splenic contraction, which may occur as an adaptive response to the stressor agent. P. lineatus presented activation of the biotransformation pathway, indicated by augmented hepatic activity of the enzyme GST and hepatic activation of the antioxidant enzyme CAT at the higher concentrations. Liver GPx was significantly inhibited at the higher concentrations, which may indicate the efficient action of CAT in the elimination of H2O2 or its competition with GST for the same substrate (GSH). AChE activity in brain and muscle was inhibited at the higher concentrations, indicating the neurotoxic effects of the herbicide in the fish. The hematological and biochemical alterations led to the conclusion that the herbicide clomazone has toxic effects on the species P. lineatus, and that its presence in the environment may jeopardize the health of these animals. 23831484 Peroxides with antiplasmodial activity inhibit proliferation of Perkinsus olseni, the causative agent of Perkinsosis in bivalves. Perkinsus olseni, the causative agent of Perkinsosis, can drastically affect the survival of target marine mollusks, with dramatic economic consequences for aquaculture. P. olseni is a member of the Alveolata group, which also comprises parasites that are highly relevant for medical and veterinary sciences such as Plasmodium falciparum and Toxoplasma. P. olseni shares several unique metabolic pathways with those pathological parasites but is not toxic to humans. In this work, six antimalarially active peroxides, derived from the natural product artemisinin or synthetic trioxolanes, were synthesized and tested on P. olseni proliferation and survival. All peroxides tested revealed an inhibitory effect on P. olseni proliferation at micromolar concentrations. The relevance of the peroxide functionality on toxicity and the effect of Fe(II)-intracellular concentration on activity were also evaluated. Results demonstrated that the peroxide functionality is the toxofore and intracellular iron concentration also proved to be a crucial co-factor on the activation of peroxides in P. olseni. These data points to a mechanism of bioactivation in P. olseni sharing similarities with the one proposed in P. falciparum parasites. Preliminary studies on bioaccumulation were conducted using fluorescent-labeled peroxides. Results show that synthetic trioxolanes tend to accumulate on a vacuole while the labeled artemisinin accumulates in the cytoplasm. Preliminary experiments on differential genes expression associated to Fe(II) transport protein (Nramp) and calcium transport protein (ATP6/SERCA) were also conducted by qPCR. Results point to a fourfold increase in expression of both genes upon exposure to trioxolanes and approximately twofold upon exposure to artemisinin derivatives. Data obtained in this investigation is relevant for better understanding of the biology of Perkinsus and may also be important in the development of new strategies for Perkinsosis prevention and control. 23273551 They know their trauma by heart: An assessment of psychophysiological failure to recover in PTSD. Posttraumatic stress disorder (PTSD) develops following exposure to atraumatic event and is characterized by persistent intense reactivity to trauma related cues. Equally important, but less studied, is the failure to restore physiological homeostasis after these excessive reactions. This study investigates psychophysiological markers of sustained cardiac activity after exposure to reminders of traumatic event in PTSD patients. Participants passively listened to neutral and personal traumatic event while electrocardiogram was continuously recorded. Heart rate (HR) and heart rate variability (HRV) were analyzed in 19 PTSD patients and 16 trauma-exposed controls. Both PTSD patients and trauma exposed controls exhibited a significant increase in HR to the exposure of their personal trauma. PTSD patients sustained the increase of HR while controls recovered to basal levels. In PTSD patients, sustained HR was positively associated with re-experiencing symptoms. The PTSD group also showed a reduced HRV (a measure of parasympathetic influence on the heart) during personal trauma exposure and lack of recovery. The sample size was small and PTSD patients were under medication. Our findings provide an experimental account of the failure of PTSD patients to exhibit physiological recovery after exposure to trauma-related stimuli. PTSD patients exhibited a sustained tachycardia with attenuation of HRV that persisted even after cessation of the stressor. Re-experiencing symptoms facilitated engagement in the trauma cues, suggesting that, in their daily-life, patients most likely present repeated episodes of sustained over-reactivity, which may underpin the emotional dysregulation characteristic of PTSD. 23967311 Major Clades of Australasian Rutoideae (Rutaceae) Based on rbcL and atpB Sequences. Rutaceae subfamily Rutoideae (46 genera, c. 660 species) is diverse in both rainforests and sclerophyll vegetation of Australasia. Australia and New Caledonia are centres of endemism with a number of genera and species distributed disjunctly between the two regions. Our aim was to generate a high-level molecular phylogeny for the Australasian Rutoideae and identify major clades as a framework for assessing morphological and biogeographic patterns and taxonomy. Phylogenetic analyses were based on chloroplast genes, rbcL and atpB, for 108 samples (78 new here), including 38 of 46 Australasian genera. Results were integrated with those from other molecular studies to produce a supertree for Rutaceae worldwide, including 115 of 154 genera. Australasian clades are poorly matched with existing tribal classifications, and genera Philotheca and Boronia are not monophyletic. Major sclerophyll lineages in Australia belong to two separate clades, each with an early divergence between rainforest and sclerophyll taxa. Dehiscent fruits with seeds ejected at maturity (often associated with myrmecochory) are inferred as ancestral; derived states include woody capsules with winged seeds, samaras, fleshy drupes, and retention and display of seeds in dehisced fruits (the last two states adaptations to bird dispersal, with multiple origins among rainforest genera). Patterns of relationship and levels of sequence divergence in some taxa, mostly species, with bird-dispersed (Acronychia, Sarcomelicope, Halfordia and Melicope) or winged (Flindersia) seeds are consistent with recent long-distance dispersal between Australia and New Caledonia. Other deeper Australian/New Caledonian divergences, some involving ant-dispersed taxa (e.g., Neoschmidia), suggest older vicariance. This comprehensive molecular phylogeny of the Australasian Rutoideae gives a broad overview of the group's evolutionary and biogeographic history. Deficiencies of infrafamilial classifications of Rutoideae have long been recognised, and our results provide a basis for taxonomic revision and a necessary framework for more focused studies of genera and species. 23651543 Maternal-fetal transfer of selenium in the mouse. Selenoprotein P (Sepp1) is taken up by receptor-mediated endocytosis for its selenium. The other extracellular selenoprotein, glutathione peroxidase-3 (Gpx3), has not been shown to transport selenium. Mice with genetic alterations of Sepp1, the Sepp1 receptors apolipoprotein E receptor-2 (apoER2) and megalin, and Gpx3 were used to investigate maternal-fetal selenium transfer. Immunocytochemistry (ICC) showed receptor-independent uptake of Sepp1 and Gpx3 in the same vesicles of d-13 visceral yolk sac cells, suggesting uptake by pinocytosis. ICC also showed apoER2-mediated uptake of maternal Sepp1 in the d-18 placenta. Thus, two selenoprotein-dependent maternal-fetal selenium transfer mechanisms were identified. Selenium was quantified in d-18 fetuses with the mechanisms disrupted. Maternal Sepp1 deletion, which lowers maternal whole-body selenium, decreased fetal selenium under selenium-adequate conditions but deletion of fetal apoER2 did not. Fetal apoER2 deletion did decrease fetal selenium, by 51%, under selenium-deficient conditions, verifying function of the placental Sepp1-apoER2 mechanism. Maternal Gpx3 deletion decreased fetal selenium, by 13%, but only under selenium-deficient conditions. These findings indicate that the selenoprotein uptake mechanisms ensure selenium transfer to the fetus under selenium-deficient conditions. The failure of their disruptions (apoER2 deletion, Gpx3 deletion) to affect fetal selenium under selenium-adequate conditions indicates the existence of an additional maternal-fetal selenium transfer mechanism.-Burk, R. F., Olson, G. E., Hill, K. E., Winfrey, V. P., Motley, A. K., and Kurokawa, S. Maternal-fetal transfer of selenium in the mouse. 23884647 Clinical and Prothrombotic Profile of Hepatic Vein Outflow Tract Obstruction. To study the clinical as well as prothrombotic profile and outcome of hepatic venous outflow tract obstruction in children. This is a prospective study of a cohort of hepatic venous outflow tract obstruction (HVOTO) pediatric cases. All children and adolescents presenting with acute or chronic liver disease were screened for HVOTO with ultrasound and Doppler imaging and confirmed by multidetector computerised tomography (MDCT) with contrast enhancement. Of the 162 cases of chronic liver disease, 13 (7.4 %) were diagnosed to have HVOTO. Ascites and edema over the feet were the most prominent features. Anabolic steroids and herbal drugs were being taken by one case each. Six cases were diagnosed on Doppler and for rest 7 cases conclusive diagnosis was made on multidetector computerised tomography. Five out of 13 cases were heterogenous (CT) for mutation of the gene encoding methylene tetrahydrofolate reductase (MTHFR) and one case of these was also heterogenous for Factor Leiden V. One case was known celiac and developed HVOTO and was also found to be having hepatocellular carcinoma. Other causes were drug induced, pressure on inferior vena cava (IVC) and inferior vena cava (IVC) web. Thus the authors could find a prothrombotic cause for 10 out of 13 (76.9 %) cases. Three cases did not need any intervention. In one patient with infective thrombus of the IVC intervention was not planned. Six underwent angioplasty and 3 underwent transjugular intrahepatic portosystemic shunt. All were asymptomatic with improving growth parameters at follow up. Ascites, pedal edema, prominent abdominal veins and hepatomegaly should raise the suspicion of HVOTO in childhood liver disease. Majority of the cases would be harbouring a prothrombotic cause. MTHFR mutation was the commonest cause of HVOTO in the present study. Angioplasty and/or transjugular intrahepatic portosystemic shunt (TIPSS) can successfully treat HVOTO. 23864374 Combination of Chondroitinase ABC and AAV-NT3 promotes neural plasticity at descending spinal pathways following thoracic contusion in rats. Transmission through descending pathways to lumbar motoneurons, although important for voluntary walking in humans and rats, has not been fully understood at the cellular level in contusion models. Major descending pathways innervating lumbar motoneurons include those at corticospinal tract and ventrolateral funiculus (VLF). We examined transmission and plasticity at synaptic pathways from dorsal corticospinal tract (dCST) and VLF to individual motoneurons located in ventral horn and interneurons located in dorsomedial grey matter at lumbar segments following thoracic chronic contusion in adult anesthetized rats. To accomplish this we used intracellular electrophysiological recordings and performed acute focal spinal lesions during the recordings. We directly demonstrate that after thoracic T10 chronic contusion the disrupted dCST axons spontaneously form new synaptic contacts with individual motoneurons, extending around the contusion cavity, through spared ventrolateral white matter. These detour synaptic connections are very weak and strengthening these connections in order to improve function may be a target for therapeutic interventions following SCI. We found that degradation of scar-related chondroitin sulfate proteoglycans using the enzyme ChondroitinaseABC (ChABC) combined with adeno-associated viral (AAV) vector-mediated prolonged delivery of neurotrophin NT-3 (AAV-NT3) strengthened these spontaneously formed connections in contused spinal cord. Moreover, ChABC/AAV-NT3 treatment induced the appearance of additional detour synaptic pathways innervating dorsomedial interneurons. Improved transmission in ChABC/AAV-NT3 treated animals associated with increased immunoreactivity of 5-HT-positive fibers in lumbar dorsal and ventral horns. Improved locomotor function assessed with automated Catwalk highlights the physiological significance of these novel connections. 23877281 Local noise estimation in low-dose chest CT images. Image noise in computed tomography (CT) images may have significant local variation due to tissue properties, dose, and location of the X-ray source. We developed and tested an automated tissue-based estimator method for estimating local noise in CT images. An automated TBE method for estimating the local noise in CT image in 3 steps was developed: (1) Partition the image into homogeneous and transition regions, (2) For each pixel in the homogeneous regions, compute the standard deviation in a [Formula: see text] voxel local region using only pixels from the same homogeneous region, and (3) Interpolate the noise estimate from the homogeneous regions in the transition regions. Noise-aware fat segmentation was implemented. Experiments were conducted on the anthropomorphic phantom and in vivo low-dose chest CT scans to validate the TBE, characterize the magnitude of local noise variation, and determine the sensitivity of noise estimates to the size of the region in which noise is computed. The TBE was tested on all scans from the Early Lung Cancer Action Program public database. The TBE was evaluated quantitatively on the phantom data and qualitatively on the in vivo data. The results show that noise can vary locally by over 200 Hounsfield units on low-dose in vivo chest CT scans and that the TBE can characterize these noise variations within 5 %. The new fat segmentation algorithm successfully improved segmentation on all 50 scans tested. The TBE provides a means to estimate noise for image quality monitoring, optimization of denoising algorithms, and improvement of segmentation algorithms. The TBE was shown to accurately characterize the large local noise variations that occur due to changes in material, dose, and X-ray source location. 23587443 Sentinel lymph node imaging by a fluorescently labeled DNA tetrahedron. Sentinel lymph nodes (SLNs) are the first lymph nodes which cancer cells reach after traveling through lymphatic vessels from the primary tumor. Evaluating the nodal status is crucial in accurate staging of human cancers and accordingly determines prognosis and the most appropriate treatment. The commonly used methods for SLN identification in clinics are based on employment of a colloid of radionuclide or injection of a small dye. Although these methods have certainly contributed to improve surgical practice, new imaging materials are still required to overcome drawbacks of the techniques such as inconvenience of handling radioactive materials and short retention time of small dyes in SLNs. Here, we prepare a fluorescence-labeled DNA tetrahedron and perform SLN imaging by using the DNA nanoconstruct. With a successful identification of SLNs by the DNA nanoconstruct, we suggest that DNA tetrahedron hold great promises for clinical applications. 23748534 Platelet-derived growth factor-A and sonic hedgehog signaling direct lung fibroblast precursors during alveolar septal formation. Alveolar septal formation is required to support the respiration of growing mammals; in humans effacement of the alveolar surface and impaired gas exchange are critical features of emphysema and pulmonary fibrosis. Platelet-derived growth factor-A (PDGF-A) and its receptor PDGF-receptor-α (PDGFRα) are required for secondary septal elongation in mice during postnatal days 4 through 12 and they regulate the proliferation and septal location of interstitial fibroblasts. We examined lung fibroblasts (LF) to learn whether PDGFRα expression distinguished a population of precursor cells, with enhanced proliferative and migratory capabilities. We identified a subpopulation of LF that expresses sonic hedgehog (Shh) and stem cell antigen-1 (Sca1). PDGF-A and Shh both increased cytokinesis and chemotaxis in vitro, but through different mechanisms. In primary LF cultures, Shh signaled exclusively through a noncanonical pathway involving generation of Rac1-GTP, whereas both the canonical and noncanonical pathways were used by the Mlg neonatal mouse LF cell line. LF preferentially oriented their primary cilia toward their anterior pole during migration. Furthermore, a larger proportion of PDGFRα-expressing LF, which are more abundant at the septal tips, bore primary cilia compared with other alveolar cells. In pulmonary emphysema, destroyed alveolar septa do not regenerate, in part because cells fail to assume a configuration that allows efficient gas exchange. Better understanding how LF are positioned during alveolar development could identify signaling pathways, which promote alveolar septal regeneration. 23127543 A soy, whey and caseinate blend extends postprandial skeletal muscle protein synthesis in rats. Blends of dairy and soy protein are used in commercial sports nutrition products; however, no studies have systematically compared blends to isolated protein sources and their effects on muscle protein synthesis (MPS). Dairy whey protein (WP), soy protein isolate (SP), and two blends (Blend 1 and Blend 2) consisting of ratios of 50:25:25 and 25:50:25 for whey:caseinate:soy, respectively, were evaluated for their ability to affect MPS. Male Sprague-Dawley rats were trained to eat 3 meals/day: a 4 g meal at 0700-0720 hours followed by ad lib feeding at 1300-1400 hours and 1800-1900 hours. After ~5 days of training, fasted rats were administered their respective 4 g meal at 0700-0720 hours and an intravenous flooding dose of (2)H5-phenylalanine 10 min prior to euthanasia. Individual rats were euthanized at designated postprandial time points. Blood and gastrocnemius samples were collected and the latter was used to measure mixed muscle protein fractional synthetic rates (FSR). Plasma leucine concentrations peaked in all groups at 90 min and were still above baseline at 300 min post-meal. FSR tended to increase in all groups post-meal but initial peaks of FSR were different times (45, 90 and 135 min for WP or SP, Blend 1 and Blend 2, respectively). Blend 2 had a significantly higher FSR compared to WP alone at 135 min (P < 0.05). Single source proteins and protein blends all enhance skeletal MPS after a meal, however, Blend 2 had a delayed FSR peak which was significantly higher than whey protein at 135 min. 23537166 Temperature Dependence and Energetics of Single Ions at the Aqueous Liquid-Vapor Interface. We investigate temperature-dependence of free energetics with two single halide anions, I- and Cl-, crossing the aqueous liquid-vapor interface through molecular dynamics simulations. The result shows that I- has a modest surface stability of 0.5 kcal/mol at 300 K and the stability decreases as the temperature increases, indicating the surface adsorption process for the anion is entropically disfavored. In contrast, Cl- shows no such surface state at all temperatures. Decomposition of free energetics reveals that water-water interactions provide a favorable enthalpic contribution, while the desolvation of ion induces an increase in free energy. Calculations of surface fluctuations demonstrate that I- generates significantly greater interfacial fluctuations compared to Cl-. The fluctuation is attributed to the malleability of the solvation shells, which allows for more long-ranged perturbations and solvent density redistribution induced by I- as the anion approaches the liquid-vapor interface. The increase in temperature of the solvent enhances the inherent thermally-excited fluctuations and consequently reduces the relative contribution from anion to surface fluctuations, which is consistent with the decrease in surface-stability of I-. Our results indicate a strong correlation with induced interfacial fluctuations and anion surface stability; moreover, resulting temperature dependent behavior of induced fluctuations suggests the possibility of a critical level of induced fluctuations associated with surface stability. 23934498 Functional Identification of Rubber Oxygenase (RoxA) in Soil and Marine Myxobacteria. Rubber oxygenase RoxA of Xanthomonas sp. (RoxAXsp) is the so far only known extracellular c-type diheme cytochrome that is able to cleave poly(cis-1,4-isoprene). All other described rubber-degrading bacteria are Gram-positive and employ a non-heme protein (latex clearing protein [Lcp]) for the postulated primary attack of polyisoprene. Here, we identified RoxA orthologs in the genomes of Haliangium ochraceum, Myxococcus fulvus, Corallococcus coralloides and Chondromyces apiculatus. The roxA orthologs of H. ochraceum (RoxAHOC), C. coralloides BO35 (RoxACCO) and M. fulvus (RoxAMfu) were functionally expressed in a ΔroxA Xanthomonas sp. background. All RoxA orthologs oxidatively cleaved polyisoprene as revealed by restoration of clearing-zone formation and detection of 12-oxo-4,8-dimethyltrideca-4,8-diene-1-al (ODTD) as cleavage product. RoxAXsp, RoxAMfu and RoxACco were purified and biochemically characterized. The optimal temperature of RoxACco and RoxAMfu was between 22 and 30°C. All RoxA orthologs as isolated showed an oxidized UVvis spectrum. Chemical reduction of RoxACco and RoxAMfu indicated the presence of two slightly different heme centers with absorption maxima between 549 and 553 nm similar to RoxAXsp. Sequence analysis and modeling of the three-dimensional structures of RoxA orthologs revealed a high degree of similarity to the recently solved RoxAXsp structure and included several conserved residues, notably W302, F317 and a MauG motif around H517. Lcp-like sequences were not detected in the genomes of Xanthomonas sp., H. ochraceum, M. fulvus and C. coralloides. No RoxA orthologs were found in Gram-positive bacteria and this first description of functional RoxA in Gram-negative bacteria other than Xanthomonas proves that RoxA is more common among rubber degraders than previously assumed. 23657001 Killer Treg cells ameliorate inflammatory insulitis in non-obese diabetic mice through local and systemic immunomodulation. Treg cells endowed with enhanced killing activity through decoration with Fas-ligand (FasL) protein (killer Treg) have been effective in delay of hyperglycemia in prediabetic non-obese diabetic (NOD) mice. In this study, we assessed the therapeutic efficacy of these cells, harvested from age-matched euglycemic NOD donors, on the course of disease in new-onset diabetics. One dose of 4 × 10(6) killer Treg cells stabilized blood glucose associated with increased insulin levels in 5 of 9 mice and partially reversed the severity of islet inflammation, whereas naive Treg cells did not modulate the course of disease significantly. Killer Treg cells were shown to operate through induction of cell apoptosis within the pancreatic lymph nodes, resulting in reduced efficiency of adoptive disease transfer to NOD/SCID recipients. A second mechanism of action consisted of increased fractions of CD4(+)CD25(-)FoxP3(+) T cells in the pancreas and all lymphoid organs. Immunomodulation with FasL rather than Treg cells enhanced the expression of CD25 and FoxP3 in the thymus, suggesting a possible contribution of thymic output to prolonged stabilization of the glucose levels. Autologous Treg cells evolve as excellent vehicles for targeted delivery of FasL as an immunomodulatory protein, which delete pathogenic cells at the site of inflammation and induce systemic dominance of suppressor subsets. 23460485 Is there a difference in timing and cause of death after fractures in the elderly? Patients who sustain osteoporotic fractures have excessive mortality compared to age-matched controls, which is most pronounced within the first 6 months postfracture. However, the timing and cause of death in the first 3 months after sustaining a fracture are unclear. We therefore evaluated and compared the timing and cause of death in patients who sustained a pelvic, proximal femoral, spinal, or proximal humeral fracture 30 and 90 days after fracture. From medical records, we recorded age at time of fracture, sex, fracture site, comorbidities, date of death, and cause of death of 1630 patients with 1630 fractures admitted to our department between 2001 and 2007. The median age at the time of fracture was 83 years and 89% of the patients were women. Fifty-eight patients died within 30 days after fracture (3.6%), and 122 patients (7.5%) died within 90 days after fracture. Cardiovascular causes of death were most frequent in all fracture groups. Patients who suffered from spinal fractures died earlier within 30 days after fracture than patients who suffered from other types of fractures. This shows the severity and impact of a spinal injury compared to other typical fragility fractures. Level II, prognostic study. See Instructions for Authors for a complete description of levels of evidence. 23713696 The effects of paternal disengagement on women's sexual decision making: An experimental approach. An abundance of research demonstrates a robust association between father absence-or low-quality paternal involvement-and daughters' accelerated sexual development, promiscuity, and sexual risk taking. Although recent natural experiments provide support for fathers playing a causal role in these outcomes, these effects have not been examined using a randomized experimental design to eliminate genetic and environmental confounds inherent in previous studies. We redressed this empirical gap by experimentally testing the effects of primed paternal disengagement cues on women's sexual decision making. Across 5 experiments, reminders of paternal disengagement increased women's activation of sexual thoughts (Experiment 1), sexual permissiveness (Experiments 2-4), and negativity toward condom use (Experiment 5). Moreover, these effects were specific to women's sexual decision making, as paternal disengagement cues failed to influence women's willingness to take nonsexual risks (Experiment 4) or men's risky sexual attitudes (Experiment 5). These results provide the first true experimental evidence supporting a causal relationship between paternal disengagement and changes in women's psychology that promote risky sexual behavior. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23661293 Long-term follow-up of a phase III study comparing radiotherapy with or without weekly oxaliplatin for locoregionally advanced nasopharyngeal carcinoma. Previous results from our trial showed that adding oxaliplatin to radiotherapy (RT) increased survival in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) at 2 years. Here, we present the data of long-term efficacy and late toxic effects. Between January 2001 and January 2003, 115 Patients with nonkeratinizing/undifferentiated locoregionally advanced NPC were randomly to receive either RT alone (n = 56) or plus concurrent oxaliplatin 70 mg/m(2) weekly for six cycles (n = 59). After a median follow-up of 114 months (range 18-139 months), the 5-year overall survival (OS) and metastasis-free survival (MFS) rates in the concurrent chemoradiotherapy (CCRT) group were significantly higher than those observed in the RT-alone group (OS, 73.2% versus 60.2%, P = 0.028; MFS, 74.7% versus 63.0%, P = 0.027). However, CCRT did not improve locoregional failure-free survival significantly. Subgroup analyses showed that the superiorities of CCRT mainly existed in the T3-4N0-1 stage subgroup (OS: HR = 0.394, P = 0.034). The grade 3/4 late toxic effects were similar in the two groups. The long-term follow-up data confirms the role of CCRT as a treatment of locoregionally advanced NPC. Oxaliplatin can be considered as an alternative optional therapeutic regimen for these patients due to its high efficiency and low toxic effect. 23959212 Neuronostatin Ameliorates Sodium Taurocholate-Induced Acute Pancreatitis in Rats. Neuronostatin is encoded in the preprosomatostatin gene and exerts important physiological actions on neuronal and cardiovascular regulation and metabolism in diverse tissues. An intraperitoneal injection of neuronostatin can induce c-Jun expression in the periphery of pancreatic islets. Because of the relatively high amount of neuronostatin present in the pancreas, it is necessary to investigate the effects of neuronostatin on pancreas. Furthermore, little is known about the effect of neuronostatin on acute pancreatitis. Neuronostatin (30, 60, and 120 nmol) was injected in to the external jugular vein 30 min before retrograde infusion of 2 % sodium taurocholate into the pancreaticobiliary duct. After 6 h, histological damage of the pancreas was evaluated by pancreas weight and paraffin section. A blood sample was collected to determine the serum amylase and lipase activities. In our findings, neuronostatin groups had a reduction in interstitial edema, acinar cell vacuolization, and inflammatory infiltration of the pancreas compared with the model group. Biochemical data showed that serum amylase and lipase activities were significantly decreased in neuronostatin-pretreated groups by comparison with the model group. Histopathologic examination suggests that neuronostatin ameliorated the histological damage of sodium taurocholate-induced acute pancreatitis in rats. The biochemical analysis was consistent with that obtained from histopathologic examination, which was toward a trend of attenuating acute pancreatitis. In summary, neuronostatin might be potentially capable of ameliorating pancreatic damage in acute pancreatitis in rats. 23707478 TAL effectors: highly adaptable phytobacterial virulence factors and readily engineered DNA-targeting proteins. Transcription activator-like (TAL) effectors are transcription factors injected into plant cells by pathogenic bacteria of the genus Xanthomonas. They function as virulence factors by activating host genes important for disease, or as avirulence factors by turning on genes that provide resistance. DNA-binding specificity is encoded by polymorphic repeats in each protein that correspond one-to-one with different nucleotides. This code has facilitated target identification and opened new avenues for engineering disease resistance. It has also enabled TAL effector customization for targeted gene control, genome editing, and other applications. This article reviews the structural basis for TAL effector-DNA specificity, the impact of the TAL effector-DNA code on plant pathology and engineered resistance, and recent accomplishments and future challenges in TAL effector-based DNA targeting. 23327759 Dibenzocyclooctadiene lignans and norlignans from fruits of Schisandra wilsoniana. Seven new dibenzocyclooctadiene lignans, marlignans M-S (1-7), four new norlignans, marphenols C-F (8-11), and 21 known compounds (12-32) were isolated from the fruits of Schisandra wilsoniana. The structures of 1-11 were elucidated by spectroscopic methods including 1D- and 2D-NMR techniques and CD experiments. Compounds 1-11 were evaluated for their anti-HIV activities and showed EC(50) values in the range 2.97-6.18 μg/mL and therapeutic index values of 5.33-29.13. 23281663 In vivo biodistribution of mixed shell micelles with tunable hydrophilic/hydrophobic surface. The miserable targeting performance of nanocarriers for cancer therapy arises largely from the rapid clearance from blood circulation and the major accumulation in the organs of the reticuloendothelial system (RES), leading to inefficient enhanced permeability and retention (EPR) effect after intravenous injection (i.v.). Herein, we reported an efficient method to prolong the blood circulation of nanoparticles and decrease their deposition in liver and spleen. In this work, we fabricated a series of mixed shell micelles (MSMs) with approximately the same size, charge and core composition but with varied hydrophilic/hydrophobic ratios in the shell through spontaneously self-assembly of block copolymers poly(ethylene glycol)-block-poly(l-lysine) (PEG-b-PLys) and poly(N-isopropylacrylamide)-block-poly(aspartic acid) (PNIPAM-b-PAsp) in aqueous medium. The effect of the surface heterogeneity on the in vivo biodistribution was systematically investigated through in vivo tracking of the (125)I-labeled MSMs determined by Gamma counter. Compared with single PEGylated micelles, some MSMs were proved to be significantly efficient with more than 3 times lower accumulation in liver and spleen and about 6 times higher concentration in blood at 1 h after i.v.. The results provide us a novel strategy for future development of long-circulating nanocarriers for efficient cancer therapy. 23523368 An Ancient Transcription Factor Initiates the Burst of piRNA Production during Early Meiosis in Mouse Testes. Animal germ cells produce PIWI-interacting RNAs (piRNAs), small silencing RNAs that suppress transposons and enable gamete maturation. Mammalian transposon-silencing piRNAs accumulate early in spermatogenesis, whereas pachytene piRNAs are produced later during postnatal spermatogenesis and account for >95% of all piRNAs in the adult mouse testis. Mutants defective for pachytene piRNA pathway proteins fail to produce mature sperm, but neither the piRNA precursor transcripts nor the trigger for pachytene piRNA production is known. Here, we show that the transcription factor A-MYB initiates pachytene piRNA production. A-MYB drives transcription of both pachytene piRNA precursor RNAs and the mRNAs for core piRNA biogenesis factors including MIWI, the protein through which pachytene piRNAs function. A-MYB regulation of piRNA pathway proteins and piRNA genes creates a coherent feedforward loop that ensures the robust accumulation of pachytene piRNAs. This regulatory circuit, which can be detected in rooster testes, likely predates the divergence of birds and mammals. 23698464 PET/CT images of bilateral diffuse intraglomerular metastasis of malignant melanoma. Intraglomerular metastasis is a very rare condition with an underlying cause that is not yet well understood. We present the 18F-FDG PET/CT images of histologically proven intraglomerular metastases from newly diagnosed malignant melanoma with positive sentinel lymph node metastases. During the initial diagnostic evaluation period, the patient also had a sudden increased serum creatinine level. FDG PET/CT demonstrated diffuse glomerular FDG uptake unlike typical physiologic pelvicaliceal activity. Renal biopsy revealed diffuse crescentic lesions containing metastatic melanoma cells. 23129417 Cloning, characterization and expression of the LECT2 gene in grass carp. An expressed sequence tag of grass carp leukocyte cell-derived chemotaxin 2 (LECT2) gene was screened from an established intestinal cDNA library. Rapid amplification of cDNA ends gave rise to a full-length LECT2 cDNA (gcLECT2) with a complete open-reading frame of 474 bp, encoding 158 amino acids about 17.9 kDa. Homology search and sequence alignment showed that this deduced protein sequence shared a high identity with LECT2 from other vertebrates. Western blotting indicated immunological cross-reactivity occurs between grass carp and human LECT2 protein. This gcLECT2 genomic sequence is 1,868 bp in size, which consists of five exons and four introns. Real-time quantitative PCR analysis revealed that gcLECT2 gene is ubiquitously expressed in different tissues of healthy grass carp including brain, gut, liver, spleen, kidney, muscle and heart, while the expression levels were significantly increased in liver and spleen followed by Aeromonas salmonicida infection. 992 bp 5'-flanking region sequence was cloned and analyzed, where one CAAT box and one GC island were found. Our results showed that the LECT2 is suggested to be most possibly involved in the grass carp's immune response. 23550816 The sleeper effect of intimate partner violence exposure: long-term consequences on young children's aggressive behavior. Children who have been exposed to intimate partner violence (IPV) experience a wide variety of short-term social adjustment and emotional difficulties, including externalizing behavioral problems such as aggression. While children are affected by IPV at all ages, little is known about the long-term consequences of IPV exposure at younger ages. Because early experiences provide the foundation for later development, children exposed to IPV as an infant or toddler may experience worse negative outcomes over time than children never exposed. Using the National Survey of Child and Adolescent Well-Being (NSCAW), latent growth curve modeling was conducted to examine whether early IPV exposure occurring between birth and age three (n = 107), compared with no exposure (n = 339), affects the development of aggressive behavior over 5 years. This modeling allowed for empirical exploration of developmental trajectories, and considered whether initial social development trajectories and change over time vary according to early IPV exposure. Children who were exposed to more frequent early IPV did not have significantly different aggressive behavior problems initially than children who were never exposed. However, over time, the more frequently children were exposed between birth and 3 years, the more aggressive behavior problems were exhibited by age eight. Results indicate a long-term negative behavioral effect on children who have been exposed to IPV at an early age. An initial assessment directly following exposure to IPV may not be able to identify behavior problems in young children. Because the negative effects of early IPV exposure are delayed until the child is of school age, early intervention is necessary for reducing the risk of later aggressive behavior. 23929395 The Factor Structure of the Liebowitz Social Anxiety Scale for Children and Adolescents: Development of a Brief Version. The Liebowitz Social Anxiety Scale for Children and Adolescents (LSAS-CA-SR) is a validated instrument for the assessment of social anxiety in youth. The three main objectives of the present study were to (a) examine the factor structure of the LSAS-CA-SR; (b) to validate the factors against relevant personality measures, and (c) to create a brief and reliable version of the questionnaire. A total of 1,362 adolescents completed self-report measures of social anxiety, temperament, character and personality traits. The factor structure was examined using a combination of confirmatory and exploratory factor analysis. The analysis was conducted on both the anxiety and avoidance sub-scales, and identical items for both sub-scales were maintained. Two factors emerged: social interaction and school performance. These factors demonstrated high internal consistency and a significant correlation with relevant self-report measures. A brief version comprised of 14 items was highly correlated (0.96) with the full version. The new factor structure represents advancement over the previous efforts, and holds promise for efficient utilization of the LSAS-CA. 23861222 Inhibitions of epithelial to mesenchymal transition and cancer stem cells-like properties are involved in miR-148a-mediated anti-metastasis of hepatocellular carcinoma. The epithelial-mesenchymal transition (EMT) and acquisition of cancer stem cells (CSCs)-like properties are essential steps in the metastasis and postsurgical recurrence of hepatocellular carcinomas (HCCs). The molecular mechanisms involved, however, remain obscure. As determined by an miRNA microarray analysis, there was lower expression of miR-148a in poorly differentiated HCC tissues relative to well-differentiated HCC tissues. MHCC97H and MHCC97L (HCC cells with migratory capacity) and HCC tissues with various differentiation status were selected for further investigation. The results showed that miR-148a levels inversely correlated with the differentiation status of HCC tissues. In MHCC97H and MHCC97L cells, over-expression of miR-148a blocked the EMT process, attenuated the expression of CD90 and CD44 (biomarkers for liver cancer stem cells), and inhibited their migratory capacity. Via TargetScan and microRNA.org algorithms, miR-148a was predicted to bind to the Wnt1 mRNA 3'-UTR. Wnt1 was confirmed as a target gene of miR-148a in HCC cells, and the Wnt signal pathway was determined to be involved in the miR-148a-mediated inhibition of EMT and CSCs-like properties of MHCC97H cells. Moreover, the expression of miR-148a in nonmetastatic HCC tissues was higher than that in metastatic HCC tissues. The results suggest that miR-148a inhibits the metastasis of HCCs by blocking EMT and CSCs-like properties through effects on the Wnt signaling pathway. © 2013 Wiley Periodicals, Inc. 23903945 Improving organizational climate for excellence in patient care. Managers in health care organizations today are expected to achieve higher-quality patient care at a lower cost. Developing and maintaining a positive organizational climate can help improve motivation and foster higher employee performance. In turn, this will help the organization deliver better patient care at a lower cost. This article offers metrics for assessing organizational climate, analyzes barriers to a positive climate, and explores strategies that managers can use to build the type of climate that fosters high performance. 23821038 Zebrafish rhabdomyosarcoma reflects the developmental stage of oncogene expression during myogenesis. Rhabdomyosarcoma is a pediatric malignancy thought to arise from the uncontrolled proliferation of myogenic cells. Here, we have generated models of rhabdomyosarcoma in the zebrafish by inducing oncogenic KRAS(G12D) expression at different stages during muscle development. Several zebrafish promoters were used, including the cdh15 and rag2 promoters, which drive gene expression in early muscle progenitors, and the mylz2 promoter, which is expressed in differentiating myoblasts. The tumors that developed differed in their ability to recapitulate normal myogenesis. cdh15:KRAS(G12D) and rag2:KRAS(G12D) fish developed tumors that displayed an inability to complete muscle differentiation as determined by histological appearance and gene expression analyses. By contrast, mylz2:KRAS(G12D) tumors more closely resembled mature skeletal muscle and were most similar to well-differentiated human rhabdomyosarcoma in terms of gene expression. mylz2:KRAS(G12D) fish showed significantly improved survival compared with cdh15:KRAS(G12D) and rag2:KRAS(G12D) fish. Tumor-propagating activity was enriched in myf5-expressing cell populations within all of the tumor types. Our results demonstrate that oncogenic KRAS(G12D) expression at different stages during muscle development has profound effects on the ability of tumor cells to recapitulate normal myogenesis, altering the tumorigenic capability of these cells. 23722919 Incorporating social media into practice: a blueprint for reproductive health providers. Industries are quick to adopt online applications that consumers are using to attract attention to products or services. The adoption of social media among medical professionals, although slow, is an inexorable reality particularly in reproductive health, where patients typically use online resources to pursue their health concerns. On the basis of the literature and personal experience with social media in infertility care, we provide guidance for reproductive health practitioners on how to use social media effectively. 23632052 Guided paravertebral blocks with versus without clonidine for women undergoing breast surgery: a prospective double-blinded randomized study. Paravertebral blocks (PVBs) have been introduced as an alternative to general anesthesia for breast cancer surgeries. The addition of clonidine as an adjuvant in PVBs may enhance quality and duration of analgesia and significantly reduce the consumption of analgesics after breast surgery. In this prospective randomized double-blind study, we assessed the significance of adding clonidine to the anesthetic mixture for women undergoing mastectomy. Sixty patients were randomized equally into 2 groups, both of which received PVB block, either with or without clonidine. Analgesic consumption was noted up to 2 weeks after the operation. A visual analog scale was used to assess pain postoperatively during the hospital stay, and a numeric rating scale was used when patients were discharged. Analgesic consumption was significantly lower in the clonidine group 48 hours postoperatively with 95% confidence interval (CI) for the difference (-69.5% to -6.6%). Pain scores at rest showed significant reduction in the clonidine group during the period from 24 to 72 hours postoperatively with 95% CI for the ratios of 2 means (1.09-3.61), (2.04-9.04), and (2.54-16.55), respectively, with shoulder movement at 24, 48, and 72 hours postoperatively 95% CI for the ratio of 2 means (1.10-3.15), (1.32-6.38), and (1.33-8.42), respectively. The time needed to resume daily activity was shorter in the clonidine group compared with the control group with 95% CI for the ratio of 2 means (1.14-1.62). The addition of clonidine enhanced the analgesic efficacy of PVB up to 3 days postoperatively for patients undergoing breast surgery. 23942297 Role of stereotactic radiosurgery in gynecologic cancer. This current work offers an opinion on the evidence accumulated in humans regarding stereotactic ablative radiation (SABR) therapy, a favorable option for the treatment of persistent or recurrent metastatic gynecologic cancers. SABR precisely and accurately kills cancer cells, making durable disease control possible. This article evaluates SABR's clinical performance and the variations in the main components of SABR technology, such as target localization and radiation beam collimation coupled with respiratory motion tracking, in the context of their contribution to the banked clinical successes in gynecologic radiation oncology. In an era of patient requests for short radiotherapy courses, SABR now provides well tolerated and efficacious treatment for women with gynecologic cancers. 23914172 What Color is My Arm? Changes in Skin Color of an Embodied Virtual Arm Modulates Pain Threshold. It has been demonstrated that visual inputs can modulate pain. However, the influence of skin color on pain perception is unknown. Red skin is associated to inflamed, hot and more sensitive skin, while blue is associated to cyanotic, cold skin. We aimed to test whether the color of the skin would alter the heat pain threshold. To this end, we used an immersive virtual environment where we induced embodiment of a virtual arm that was co-located with the real one and seen from a first-person perspective. Virtual reality allowed us to dynamically modify the color of the skin of the virtual arm. In order to test pain threshold, increasing ramps of heat stimulation applied on the participants' arm were delivered concomitantly with the gradual intensification of different colors on the embodied avatar's arm. We found that a reddened arm significantly decreased the pain threshold compared with normal and bluish skin. This effect was specific when red was seen on the arm, while seeing red in a spot outside the arm did not decrease pain threshold. These results demonstrate an influence of skin color on pain perception. This top-down modulation of pain through visual input suggests a potential use of embodied virtual bodies for pain therapy. 23906706 Haematological and biochemical reference intervals of four feline breeds. Many feline breeds have been generated from a small number of ancestors. Thus, breed-specific peculiarities can be expected, which could include haematological and biochemical measurements. Despite this, there are only a few reports on breed-specific reference intervals (RI). This information is essential in routine practice where results from individual patients are usually compared with a RI. The aim was to compare haematological and biochemical data from clinically healthy Abyssinian, Holly Birman, Norwegian Forest and Siberian cats with published RIs to assess whether the published RIs are acceptable in these breeds. Comparison with established RIs using guidelines from the National Committee for Clinical Laboratory Standards and the American Society of Veterinary Clinical Pathology, revealed a number of breed-related clinicopathological differences. New RIs were established, but in most cases the new RIs overlapped the published RIs, and the use of the breed-specific data would minimally affect the clinical interpretation of laboratory results. Important differences that could result in misinterpretation of laboratory results were as follows: microcytosis and high α2-globulin concentrations in Abyssinian cats; high serum creatinine, α2-globulin and glucose concentrations in Holly Birman cats; high serum alkaline phosphatase activity and calcium and phosphate concentration in Norwegian Forest cats; low β2-globulin and γ-globulin concentrations in Norwegian Forest and Siberian cats. Breed-specific RIs should be used for these analytes. In addition, care should be taken in interpreting clinicopathological data in purebred cats for which specific RIs have not been established. 23852048 A Brønsted acid-catalyzed generation of palladium complexes: efficient head-to-tail dimerization of alkynes. A Brønsted acid Ph2P(O)OH can efficiently catalyze the reaction of a Pd(0) complex with an alkyne to produce a novel alkenyl(alkynyl)palladium complex via selective hydropalladation and ligand exchange processes. On the basis of this finding, an efficient Pd(0)/Ph2P(O)OH mediated head-to-tail dimerization of alkynes was disclosed. 23340887 Early-Adulthood Cardiovascular Disease Risk Factor Profiles Among Individuals With and Without Diabetes in the Framingham Heart Study. OBJECTIVEMany studies of diabetes have examined risk factors at the time of diabetes diagnosis instead of considering the lifetime burden of adverse risk factor levels. We examined the 30-year cardiovascular disease (CVD) risk factor burden that participants have up to the time of diabetes diagnosis.RESEARCH DESIGN AND METHODSAmong participants free of CVD, incident diabetes cases (fasting plasma glucose ≥126 mg/dL or treatment) occurring at examinations 2 through 8 (1979-2008) of the Framingham Heart Study Offspring cohort were age- and sex-matched 1:2 to controls. CVD risk factors (hypertension, high LDL cholesterol, low HDL cholesterol, high triglycerides, obesity) were measured at the time of diabetes diagnosis and at time points 10, 20, and 30 years prior. Conditional logistic regression was used to compare risk factor levels at each time point between diabetes cases and controls.RESULTSWe identified 525 participants with new-onset diabetes who were matched to 1,049 controls (mean age, 60 years; 40% women). Compared with those without diabetes, individuals who eventually developed diabetes had higher levels of hypertension (odds ratio [OR], 2.2; P = 0.003), high LDL (OR, 1.5; P = 0.04), low HDL (OR, 2.1; P = 0.0001), high triglycerides (OR, 1.7; P = 0.04), and obesity (OR, 3.3; P<0.0001) at time points 30 years before diabetes diagnosis. After further adjustment for BMI, the ORs for hypertension (OR, 1.9; P = 0.02) and low HDL (OR, 1.7; P = 0.01) remained statistically significant.CONCLUSIONSCVD risk factors are increased up to 30 years before diagnosis of diabetes. These findings highlight the importance of a life course approach to CVD risk factor identification among individuals at risk for diabetes. 23325849 An autonomous chromatin/DNA-PK mechanism for localized DNA damage signaling in mammalian cells. Rapid phosphorylation of histone variant H2AX proximal to DNA breaks is an initiating event and a hallmark of eukaryotic DNA damage responses. Three mammalian kinases are known to phosphorylate H2AX in response to DNA damage. However, the mechanism(s) for damage-localized phosphorylation remains incompletely understood. The DNA-dependent protein kinase (DNA-PK) is the most abundant H2AX-modifying kinases and uniquely activated by binding DNA termini. Here, we have developed a novel approach to examine enzyme activity and substrate properties by executing biochemical assays on intact cellular structures. We apply this approach to examine the mechanisms of localized protein modification in chromatin within fixed cells. DNA-PK retains substrate specificity and independently generates break-localized γH2AX foci in chromatin. In situ DNA-PK activity recapitulates localization and intensity of in vivo H2AX phosphorylation and requires no active cellular processes. Nuclease treatments or addition of exogenous DNA resulted in genome-wide H2AX phosphorylation, showing that DNA termini dictated the locality of H2AX phosphorylation in situ. DNA-PK also reconstituted focal phosphorylation of structural maintenance of chromatin protein 1, but not activating transcription factor 2. Allosteric regulation of DNA-PK by DNA termini protruding from chromatin constitutes an autonomous mechanism for break-localized protein phosphorylation that generates sub-nuclear foci. We discuss generalized implications of this mechanism in localizing mammalian DNA damage responses. 23916610 MicroRNA-187, down-regulated in clear cell renal cell carcinoma and associated with lower survival, inhibits cell growth and migration though targeting B7-H3. Aberrantly expressed microRNAs (miRNAs) are frequently associated with the aggressive malignant behavior of human cancers, including clear cell renal cell carcinoma (ccRCC). Based on the preliminary deep sequencing data, we hypothesized that miR-187 may play an important role in ccRCC development. In this study, we found that miR-187 was down-regulated in both tumor tissue and plasma of ccRCC patients. Lower miR-187 expression levels were associated with higher tumor grade and stage. All patients with high miR-187 expression survived 5years, while with low miR-187 expression, only 42% survived. Suppressed in vitro proliferation, inhibited in vivo tumor growth, and decreased motility were observed in cells treated with the miR-187 expression vector. Further studies showed that B7 homolog 3 (B7-H3) is a direct target of miR-187. Over-expression of miR-187 decreased B7-H3 mRNA level and repressed B7-H3-3'-UTR reporter activity. Knockdown of B7-H3 using siRNA resulted in similar phenotype changes as that observed for overexpression of miR-187. Our data suggest that miR-187 is emerging as a novel player in the disease state of ccRCC. miR-187 plays a tumor suppressor role in ccRCC. 23898973 Traditional botanical knowledge of artisanal fishers in southern Brazil. This study characterized the botanical knowledge of artisanal fishers of the Lami community, Porto Alegre, southern Brazil based on answers to the following question: Is the local botanical knowledge of the artisanal fishers of the rural-urban district of Lami still active, even since the district's insertion into the metropolitan region of Porto Alegre? This region, which contains a mosaic of urban and rural areas, hosts the Lami Biological Reserve (LBR) and a community of 13 artisanal fisher families. Semi-structured interviews were conducted with 15 fishers, complemented by participatory observation techniques and free-lists; in these interviews, the species of plants used by the community and their indicated uses were identified. A total of 111 species belonging to 50 families were identified. No significant differences between the diversities of native and exotic species were found. Seven use categories were reported: medicinal (49%), human food (23.2%), fishing (12.3%), condiments (8%), firewood (5%), mystical purposes (1.45%), and animal food (0.72%). The medicinal species with the highest level of agreement regarding their main uses (AMUs) were Aloe arborescens Mill., Plectranthus barbatus Andrews, Dodonaea viscosa Jacq., Plectranthus ornatus Codd, Eugenia uniflora L., and Foeniculum vulgare Mill. For illness and diseases, most plants were used for problems with the digestive system (20 species), followed by the respiratory system (16 species). This community possesses a wide botanical knowledge, especially of medicinal plants, comparable to observations made in other studies with fishing communities in coastal areas of the Atlantic Forest of Brazil. Ethnobotanical studies in rural-urban areas contribute to preserving local knowledge and provide information that aids in conserving the remaining ecosystems in the region. 23882012 Clinically relevant mutant DNA gyrase alters supercoiling, changes the transcriptome, and confers multidrug resistance. Bacterial DNA is maintained in a supercoiled state controlled by the action of topoisomerases. Alterations in supercoiling affect fundamental cellular processes, including transcription. Here, we show that substitution at position 87 of GyrA of Salmonella influences sensitivity to antibiotics, including nonquinolone drugs, alters global supercoiling, and results in an altered transcriptome with increased expression of stress response pathways. Decreased susceptibility to multiple antibiotics seen with a GyrA Asp87Gly mutant was not a result of increased efflux activity or reduced reactive-oxygen production. These data show that a frequently observed and clinically relevant substitution within GyrA results in altered expression of numerous genes, including those important in bacterial survival of stress, suggesting that GyrA mutants may have a selective advantage under specific conditions. Our findings help contextualize the high rate of quinolone resistance in pathogenic strains of bacteria and may partly explain why such mutant strains are evolutionarily successful. Fluoroquinolones are a powerful group of antibiotics that target bacterial enzymes involved in helping bacteria maintain the conformation of their chromosome. Mutations in the target enzymes allow bacteria to become resistant to these antibiotics, and fluoroquinolone resistance is common. We show here that these mutations also provide protection against a broad range of other antimicrobials by triggering a defensive stress response in the cell. This work suggests that fluoroquinolone resistance mutations may be beneficial under a range of conditions. 23914927 Inhibition of mammalian carbonic anhydrases I-XIV with grayanotoxin III: solution and in silico studies. Abstract Grayanotoxin III (GTX3) was investigated for inhibition of all catalytically active mammalian carbonic anhydrase (CA, EC 4.2.1.1) isoforms, i.e. CA I to CA XIV. It showed micromolar inhibition (KIs of 8.01 and 6.13 µM) for cytosolic isoforms CA I and II, respectively. GTX3 showed a submicromolar inhibition (KIs in the range of 0.51-2.15 µM) for the remaining cytosolic (CA III, VII and XIII), membrane-associated/transmembrane (CA IV, IX, XII and XIV), mitochondrial (CA VA and CA VB) and secreted (CA VI) isoforms. This inhibition profile is very different from that of the sulfonamide CA inhibitors (CAIs), which possess different clinical applications. A molecular docking study for GTX3 within the active sites of CA I and II assisted to the understanding of molecular mechanism of the ligand. The interesting inhibition profile, coupled with various possibilities of interacting with the enzyme active site make this family of natural compounds attractive leads for designing novel chemotypes acting as CAIs. 23449924 United Kingdom national experience of entirely subcutaneous implantable cardioverter-defibrillator technology: important lessons to learn. The aim of this study was to describe the early phase United Kingdom (UK) clinical experience with a novel entirely subcutaneous implantable cardioverter-defibrillator (S-ICD). A questionnaire was sent to all UK hospitals implanting S-ICDs. Nineteen of 25 (76%) hospitals responded with the details of 111 implanted patients [median 5/hospital (range 1-18)]. Mean duration of follow-up was 12.7 ± 7.1 months. Median patient age was 33 years (range 10-87 years). Underlying pathology was primary electrical disease in 43%, congenital heart disease 12%, hypertrophic cardiomyopathy 20%, ischaemic cardiomyopathy 14%, idiopathic dilated cardiomyopathy 5%, and other cardiomyopathies 7% patients. Nineteen (17%) patients required 20 re-operations, including permanent device explantation in 10 (9%). Twenty-four appropriate shocks were delivered in 13 (12%) patients, including 10 for ventricular fibrillation. One patient suffered arrhythmic death, but there were no failures to detect or terminate ventricular arrhythmias above the programmed detection rate. Fifty-one inappropriate shocks were delivered in 17 (15%) patients. Forty-one (80%) were for T-wave over-sensing and 1 (2%) for atrial flutter-wave over-sensing. The 11 patients who received inappropriate shocks due to T-wave over-sensing were significantly younger than patients who did not (24 ± 10 vs. 37 ± 19 years; P = 0.02). The S-ICD is an important innovation in ICD technology. However, these data indicate that adverse event rates are significant during early clinical adoption. Important lessons in patient selection, implant technique, and device programming can be learnt from this experience. 23624292 Trabecular bone adapts to long-term cyclic loading by increasing stiffness and normalization of dynamic morphometric rates. Bone has the ability to adapt to external loading conditions. Especially the beneficial effect of short-term cyclic loading has been investigated in a number of in vivo animal studies. The aim of this study was to assess the long-term effect (>10weeks) of cyclic mechanical loading on the bone microstructure, bone stiffness, and bone remodeling rates. Mice were subjected to cyclic mechanical loading at the sixth caudal vertebra with 8N or 0N (control) three times per week for a total period of 14weeks. Structural bone parameters were determined from in vivo micro-computed tomography (micro-CT) scans performed at week 0, 4, 6, 8, 10, 12, and 14. Mechanical parameters were derived from micro-finite element analysis. Dynamic bone morphometry was calculated using registration of serial micro-CT scans. Bone volume fraction and trabecular thickness increased significantly more for the loaded group than for the control group (p=0.006 and p=0.002 respectively). The trabecular bone microstructure adapted to the load of 8N in approximately ten weeks, indicated by the trabecular bone volume fraction, which increased from 16.7% at 0weeks to 21.6% at week 10 and only showed little change afterwards (bone volume fraction of 21.5% at 14weeks). Similarly bone stiffness - at the start of the experiment 649N/mm - reached 846N/mm at 10weeks in the loaded group and was maintained to the end of the experiment (850N/mm). At 4weeks the bone formation rate was 32% greater and the bone resorption rate 22% less for 8N compared to 0N. This difference was significantly reduced as the bone adapted to 8N, with 8N remodeling rates returning to the values of the 0N group at approximately 10weeks. Together these data suggest that once bone has adapted to a new loading state, the remodeling rates reduce gradually while maintaining bone volume fraction and stiffness. 23430161 Reduced Acute Recovery from Alcohol Impairment in Adults with ADHD. RATIONALE: Prior research has found that adults with attention-deficit/hyperactivity disorder (ADHD) show increased sensitivity to the impairing effects of alcohol (Weafer et al., Exp Clin Psychopharmacol 17: 113-121, 2009). However, these studies have focused exclusively on the ascending limb of the blood alcohol concentration (BAC) curve, and it is unclear whether these adults continue to show increased sensitivity during the later phase of the dose as BAC is declining. OBJECTIVE: This study tested the hypothesis that those with ADHD would display increased response to alcohol during the ascending limb of the BAC curve and less recovery from the impairing effects during the descending limb. METHODS: Adult social drinkers with ADHD and control adults completed measures of motor coordination, reaction time (RT), and subjective intoxication twice following 0.64 g/kg alcohol and placebo. The measures were administered during the ascending limb of the BAC curve and again during the descending limb. RESULTS: During the ascending limb, alcohol reduced motor coordination, slowed RT, and increased self-reports of subjective intoxication. Those with ADHD displayed greater impairment of motor coordination compared with controls. During the descending limb, controls reported diminished subjective intoxication and showed recovery from the impairing effects of alcohol on both their motor coordination and their RT. Those with ADHD showed reduced subjective intoxication and faster RT during this time, but they did not recover motor control. CONCLUSIONS: The protracted time course of motor impairment in adults with ADHD despite reductions in subjective intoxication may contribute to poor decision making and diminished behavioral control in this group. 23924998 Elicitation of HIV-1-neutralizing antibodies against the CD4-binding site. The HIV-1 site of binding for the CD4 receptor has long attracted attention as a potential supersite of vulnerability to antibody-mediated neutralization. We review recent findings related to effective CD4-binding site antibodies isolated from HIV-1-infected individuals and discuss implications for immunogen design. Highly effective CD4-binding site antibodies such as antibody VRC01 have the ability to neutralize over 90% of circulating HIV-1 strains. Sequence and structural analysis of these antibodies from over half a dozen HIV-1-infected donors reveals remarkable similarity in their ontogenies and their modes of recognition, all of which involve mimicry of CD4 receptor by antibody-heavy chain. Meanwhile, other effective CD4-binding site neutralizers such as antibody CH103 have been shown to utilize a different mode of recognition, with next-generation sequencing of both virus and antibody suggesting co-evolution to drive the development of antibody-neutralization breadth. The nexus of information concerning the CD4-binding site and its recognition by human antibodies capable of effective neutralization has expanded remarkably in the last few years. Although barriers are substantial, new insights from donor-serum responses, atomic-level structures of antibody-Env complexes, and next-generation sequencing of B-cell transcripts are invigorating vaccine-design efforts to elicit effective CD4-binding site antibodies. 23210781 Antimicrobial plant metabolites: structural diversity and mechanism of action. Microbial infectious diseases continue to be one of the leading causes of morbidity and mortality. It has been estimated that microbial species comprise about 60% of the Earth's biomass. This, together with the fact that their genetic, metabolic and physiological diversity is extraordinary, makes them a major threat to the health and development of populations across the world. Widespread antibiotic resistance, the emergence of new pathogens in addition to the resurgence of old ones, and the lack of effective new therapeutics exacerbate the problems. Thus, the need to discover and develop new antimicrobial agents is critical to improve mankind's future health. Plant secondary metabolites (PSMs) offer particular promise in this sense. Plant Kingdom could be considered a rich source of the most diverse structures (e.g. there are more than 12,000 known alkaloids, more than 8,000 phenolic compounds and over 25,000 different terpenoids), many of which were proven to possess strong antimicrobial properties (e.g. thymol, eurabienol, etc.). In many instances, PSMs can be easily isolated from the plant matrix, either in pure state or in the form of mixtures of chemically related compounds. What is also important is that the development of bacterial resistance toward natural plant products (that are generally regarded as eco-friendly) has been thus far documented in a very limited number of cases (e.g. for reserpine). Having all of the mentioned advantages of PSMs as potential antimicrobials in mind, a major question arises: why is it that there are still no commercially available or commonly used antibiotics of plant origin? This review tries to give a critical answer to this question by considering potential mechanisms of antimicrobial action of PSMs (inhibition of cell wall or protein synthesis, inducing leakage from the cells by tampering with the function of the membranes, interfering with intermediary metabolisms or DNA/RNA synthesis/function), as well as their physical and chemical properties (e.g. hydrophilicity/lipophilicity, chemical stability). To address the possible synergistic/antagonistic effects between PSMs and with standard antibiotics, special attention has been given to the antimicrobial activity of PSM-mixtures (e.g. essential oils, plant extracts). Moreover, possible ways of overcoming some of PSMs molecular limitations in respect to their usage as potential antibiotics were also discussed (e.g. derivatization that would enable fine tuning of certain molecular characteristics). 23332644 A three generations nation-wide population study of family load estimates in bipolar disorder with different age at onset. This nation-wide register-based study investigates how often bipolar disorder (BD) occurs in affected families compared to control families by estimating the family load as a random effect; this effect measures the degree of dependence among family members in relation to BD. Furthermore, the study addresses the impact of certain risk factors, namely, sex, age at onset of BD, degree of urbanization, year of birth, month of birth, and maternal and paternal age at birth. A total of N=1204 children and adolescent psychiatric cases born between 1950 and 1997 and registered in the Danish Central Psychiatric Register (DPCR) developed BD before the age of 58 years. N=3553 controls without any psychiatric diagnosis were matched for age, gender, and region of residence. Psychiatric diagnoses were also obtained on the relatives, e.g. parents, siblings, and offspring as a part of the Danish Three Generation Study (3GS). A family component was obtained by using different regression models. Familial factors accounted for 20% of the variation in disease outcome when controlling for year and month of birth, sex, and degree of urbanization. Only female sex was associated with an increased hazard ratio of BD. Also having a mother, father or a sibling with the disorder was proven to be a significant risk factor. Furthermore, case relatives did not develop BD earlier than control relatives. These findings based on a very large and representative dataset provide further and very solid evidence for the high family aggregation of BD. 23871247 Sodium nitroprusside (SNP) sensitizes human gastric cancer cells to TRAIL-induced apoptosis. To investigate the effects of the nitrous oxide (NO)-donor sodium nitroprusside (SNP) on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human gastric cancer cells. The MTT assay and flow cytometry were used to detect cellular proliferation and markers of apoptosis, respectively. Expression levels of caspases-8, and 9 were determined by Western blot. Changes in Nitric Oxide Synthase (NOS) activity, NO production, and caspase activation were also evaluated. We found that TRAIL induced apoptosis and cell cycle arrest in human gastric cancer cell lines, and that this effect was mediated by NO production, and activation of both the extrinsic and intrinsic signaling pathways of apoptosis. In addition, we found that the NO-donor SNP sensitizes gastric cancer cells to TRAIL-mediated apoptosis. Treatment of cells with both TRAIL and SNP resulted in increased activation of caspase-8 and caspase-9 and NO release. Inhibition of caspase-8 blocked cell TRAIL-induced apoptosis, while a selective caspase-9 inhibitor was unable to prevent apoptosis induced by either TRAIL or TRAIL plus SNP. Inhibition of NOS could block the activation of caspase-9, but had no obvious effect on cell apoptosis. SNP-sensitized gastric cancer cells to TRAIL-induced cytotoxicity by stimulating the release of NO, in turn facilitating the mitochondria-mediated signal transduction pathway. The engagement of the mitochondria signaling pathways along with the TRAIL death receptor signaling pathway synergistically increase levels of apoptosis in these cells. 23464923 Exploring the transitional process from receiving a diagnosis to living with motor neurone disease. Motor neurone disease (MND) is a rapidly progressing neurodegenerative condition that results in a marked reduction in life expectancy. Currently, little is known about the experiences of people after they have received this diagnosis and the effect of this on their sense of self and identity. In this study, interpretative phenomenological analysis was used to explore both the personal and lived experiences of people with MND. Seven people diagnosed with MND within the previous six months were recruited. The three themes constructed from the participants' accounts were 'Then they dropped the bomb shell'; Receiving a diagnosis of MND; 'Getting on with it'; Learning to live with MND; and 'A lot of normal life is lost'; Experiencing progressive loss. Participants described receiving a diagnosis as a devastating experience but most participants were able to accept their diagnosis and employ adaptive strategies to cope with increasing levels of functional decline. However, in spite of this, the participants experienced functional changes that affected their identity, social status and social relationships. 23588795 Migraine, headache, and the risk of depression: Prospective cohort study. While cross-sectional studies have shown associations between migraine and depression, few studies have been able to evaluate the association between migraine and incident depression. A prospective cohort study among 36,016 women without a history of depression enrolled in the Women's Health Study who provided information about migraine and headache at baseline. Women were classified as either having nonmigraine headache, migraine with aura, migraine without aura, past history of migraine or no history of headache. Cox proportional hazards models were used to evaluate the association between migraine and headache status and incident depression. At baseline, 5115 women reported a history of nonmigraine headache, 1805 reported migraine with aura, 2723 reported migraine without aura, and 1896 reported a past history of migraine. During 13.8 mean years of follow-up, 3833 new cases of depression occurred. The adjusted relative risks of incident depression were 1.44 (95% CI: 1.32, 1.56) for nonmigraine headache, 1.53 (95% CI: 1.35, 1.74) for migraine with aura, 1.40 (95% CI: 1.25, 1.56) for migraine without aura, and 1.56 (95% CI: 1.37, 1.77) for past history of migraine compared to no history of headache. Middle-aged women with migraine or nonmigraine headache are at increased risk of incident depression. Frequent migraine attacks (weekly or daily) were associated with the highest risk for developing depression. 23611621 Application of nanomaterials in sample preparation. Nanotechnology is one of the most important trends in material science. Due to the ultra-small size, nanomaterials possess unique physical and chemical properties. In this review, we summarized and discussed the recent applications of different nanomaterials, including metallic nanoparticles, metal organic frameworks (MOFs) materials, carbonaceous nanomaterials and siliceous nanoparticles, in sample preparation techniques. 23726180 Trends in the prevalence of hospitalization attributable to hypertensive diseases among United States adults aged 35 and older from 1980 to 2007. We aimed to examine the trend in the prevalence of hospitalization attributable to hypertensive disease and its subtypes among United States adults aged ≥35 years from 1980 to 2007. Data (n = 4,598,488,000 hospitalized cases) from the National Hospital Discharge Surveys were used to examine the trends of hospitalized patients with first (the reason for admission) and patients with any second to seventh (a co-morbid condition when admission) diagnosis of hypertensive disease (International Classification of Disease, 9th Revision, Clinical Modification: 401 to 405) by gender and geographic region. Age-adjusted rates of disease were calculated using the United States 2000 standard population. The results show that age-adjusted hospitalization rates due to first diagnosis of hypertensive disease increased from 1.74% to 2.06% in men (p <0.01), and from 2.0% to 2.09% in women (p = 0.06) from 1980 to 1981 to 2006 to 2007. Age-adjusted rates due to any second to seventh diagnosis of hypertensive disease significantly increased from 7.06% to 35.09% in men (p <0.001), and from 7.88% to 31.98% (p <0.001) in women from 1980 to 1981 to 2006 to 2007. Patients with second to seventh diagnosis of essential hypertension and hypertensive chronic kidney disease had the highest and the second highest annual percent increases. Subjects living in the Southern region of the United States had the highest prevalence of hospitalization due to any second to seventh diagnosis of hypertensive disease compared with all other regions in 2006 to 2007. In conclusion, the prevalence of hospitalization due to hypertensive disease significantly increased in the United States from 1980 to 2007. 23561153 Extraction and structural characterisation of rhamnogalacturonan I-type pectic polysaccharides from potato cell wall. Cell wall material from potato pulp by-product was used for the extraction of galactan-rich rhamnogalacturonan I (RG-I) type pectic polysaccharides using alkaline (NaOH and KOH) and enzymatic (endopolygalacturonase from Aspergillus niger) methods. The extraction yield increased as the concentration of alkaline solution was increased from 0.5M (22-24%) to 2M (53-56%). The yield of 38% obtained upon the enzymatic treatment was similar to those observed with 1M alkaline solutions. The results reveal the high debranching of arabinan side chains of RG I as compared to the galactan ones under harsh alkaline conditions. The molecular weight distribution shows that the enzymatic extraction led to the highest proportion of high-molecular weight polysaccharides (>500kDa; 62.2%). According to monosaccharide pattern, the weak acidic fractions of high alkaline (1-2M)-based polysaccharide extracts was the most enriched with galactan-rich RG I. Using milder conditions (enzyme and weak alkaline), two RG I populations with low and high linked homogalacturonan fragments were recovered in the weak and strong acidic fractions, respectively. The structure of galactan-rich RG I was confirmed by H(1) NMR spectroscopy analysis. 23858424 The ONE Step Initiative: Quality Improvement in a Pediatric Clinic for Secondhand Smoke Reduction. Although comprehensive smoking counseling to limit secondhand smoke (SHS) is widely endorsed, it is often not done. Published evaluations of brief and practical systems that improve screening and counseling to reduce SHS are limited. Our objective was to determine if a quality improvement activity around smoking counseling leads to changes in (1) medical assistant and pediatric provider assessment of smoking history and (2) smoking or other behaviors affecting children's SHS exposure. In a large urban teaching clinic we assessed the ONE Step intervention, which included the following: (1) "Ask" (medical assistant asking whether caregivers smoke); (2) "Advise" (providers advising smoking outside and quitting if ready); (3) "Refer" (providers referring to the Colorado telephone QuitLine); and (4) electronic medical record prompts and required documentation regarding smoking. Medical assistant and provider assessments of smoking were evaluated with a chart review by using a pre-/posttest design. Caregiver behavior change was evaluated with a time-series survey that included assessment at baseline and follow-up via telephone at 6 and 12 months from study entry. ONE Step was associated with a statistically significant increase in Ask, Advise, and Refer documentation. Caregiver surveys showed that 97% found discussions of SHS with providers acceptable. Six- and 12-month follow-ups, respectively, showed that 14% and 13% of smokers reported quitting and that 63% and 70% of current smokers reported reduced SHS exposure. ONE Step was feasible to deliver in a busy outpatient setting, acceptable to families, and appears to have resulted in decreased exposure to SHS in our pediatric population. 23891388 Qualitative analysis by interviews and video recordings to establish the components of a skilled rotational forceps delivery. To define the skills of a mid-cavity rotational forceps delivery to facilitate transfer of skills from expert obstetricians to trainee obstetricians. Qualitative interviews and video analysis carried out at maternity units of two university teaching hospitals (St. Michael's Hospital, Bristol, and Ninewells Hospital, Dundee). Ten obstetricians were identified as experts in conducting operative vaginal deliveries. Semi-structured interviews were carried out to identify key technical skills. The experts were also video recorded conducting mid-cavity rotational deliveries in a simulation setting. The interviews and video recordings were transcribed verbatim and analysed using thematic coding. The anonymised data were individually coded by the three researchers and then compared for consistency of interpretation. The experts reviewed the data for respondent validation. The themes that emerged following the coding were used to formulate a taxonomy of skills. Rotational forceps were preferred by eight experts and two experts preferred manual rotation followed by direct traction forceps. The final taxonomy included detailed technical skills for Kielland rotational forceps delivery and manual rotation followed by direct traction forceps delivery. This explicitly defined skills taxonomy could aid trainees' understanding of the technique of rotational forceps delivery. This is an important potential contributor to safely reducing the rate of second-stage caesarean section. 23329066 Phase II study to assess the efficacy, safety and tolerability of the mitotic spindle kinesin inhibitor AZD4877 in patients with recurrent advanced urothelial cancer. Background AZD4877 is a potent inhibitor of the mitotic spindle kinesin, Eg5. Early-phase clinical studies in a broad range of cancers showed that AZD4877 is well tolerated. This Phase II study evaluated the efficacy, safety and pharmacokinetics (Cmax) of AZD4877 in patients with previously treated advanced urothelial cancer (ClinicalTrials.gov identifier NCT00661609). Patients and methods AZD4877 25 mg was administered once-weekly for 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity or withdrawal. The primary objective was to determine the objective response rate (RECIST). Recruitment was to be halted if ≤2 of the first 20 evaluable patients achieved an objective tumor response. Cmax was assessed on days 1 and 8 of cycle 1. Results None of the first 20 patients evaluable for efficacy achieved an objective response; enrollment was therefore halted. During this initial analysis, a further 21 patients were recruited. Overall, 39 patients were evaluable for efficacy, including one with confirmed partial response (PR) and seven patients with stable disease for ≥8 weeks (including one unconfirmed PR). The most commonly reported treatment-related adverse events (TRAEs) were neutropenia (22 patients), fatigue (12), leukopenia (7) and constipation (6); the most commonly reported grade ≥3 TRAE was neutropenia (21). Four patients had serious TRAEs. On days 1 and 8, the geometric mean Cmax of AZD4877 was 138 ng/ml (CV = 75 %) and 144 ng/ml (CV = 109 %), respectively. Conclusions AZD4877 was generally tolerable in patients with advanced urothelial cancer. Given the limited clinical efficacy, further development of AZD4877 in urothelial cancer is not planned. 23836512 Ameliorative effect of grapefruit juice on amiodarone-induced cytogenetic and testicular damage in albino rats. To evaluate the ameliorative role of grapefruit juice on the cytogenetic and testicular damage induced by the antiarrythmic drug amiodarone in albino rats. Animals were divided into four groups. Group I was considered as control. Group II was given grapefruit juice at a dose level of 27 mL/kg body weight. Group III was orally administered amiodarone (18 mg/kg body weight) daily for 5 weeks. Animals were sacrificed after 5 weeks of treatment. Bone marrow was collected from the femurs for analysis of chromosomal aberrations and mitotic indices. Testes were removed and stained with H&E for histological examination. Sperms were collected from epidedymis for detection of sperm head abnormalities. Comet assay was used to detect DNA damage. Amiodarone treatment caused a significant increase in the percentage of chromosomal aberrations, decreased the mitotic index and increased DNA damage. The testis showed many histopathological alterations, inhibition of spermatogenesis and morphometric changes. The number of sperm head abnormalities was increased. Treating animals with amiodarone and grapefruit juice caused a reduction in chromosomal aberrations, mitotic index, DNA damage and testicular alterations caused by amiodarone. The results of this study indicated that grapefruit juice ameliorates the cytotoxicty and testicular alterations induced by amiodarone in albino rats and this is may be due to the potent antioxidant effects of its components. 23179911 Slaughter of Atlantic salmon (Salmo salar L.) in the presence of carbon monoxide. The different stunning methods for Atlantic salmon can still be improved with regard to animal welfare. Salmon exposed to carbon monoxide expressed no aversive reactions towards CO as such. CO exposed fish showed an earlier onset of rigour mortis and a faster decrease in muscle pH due to depletion of oxygen during the treatment. Exposure to CO did increase the level of cortisol compared to undisturbed control fish, but the increase was less than in the water only control group. Neuroglobin, a CO binding globin, was found in salmon brain and Saccus vasculosus, a richly vascularized sac connected to the fish brain. Binding of CO to neuroglobin during sedation might possibly improve animal welfare. 23503664 Double- vs. single-balloon enteroscopy: single center experience with emphasis on procedural performance. This study aims to compare double- (DBE) and single-balloon enteroscopy (SBE) in small bowel disorders with respect to procedural performance and clinical impact. This retrospective analysis at a tertial referral center included 1,052 DBEs and 515 SBEs performed in 904 patients over 7 years. Procedural and patients' characteristics were precisely analyzed. Significantly more patients with anemia and gastrointestinal bleeding were investigated by DBE (P < 0.01). Oral insertion depth and length of investigated small bowel in the combined approach were significantly higher in the DBE compared to the SBE group (245 ±â€‰65.3 vs. 218 ±â€‰62.6 and 355 ±â€‰101.9 vs. 319 ±â€‰91.2, respectively; P < 0.001, each). By analyzing only recent years of enteroscopy (2008-2011), no difference in small bowel visualization could be observed. The anal insertion depths and complete enteroscopy rates (CER) were comparable. Procedure times were significantly shorter within the SBE procedure (oral: 50 vs. 40 min; anal: 55 vs. 46 min, P < 0.001) and the usage of sedation was significantly less (propofol: P < 0.001; pethidine: P < 0.05). Diagnostic yield was significantly higher in the SBE, compared to the DBE group (61.7 vs. 48.2 %; P < 0.001). The rate of severe adverse events was close to zero. Both enteroscopy techniques are safe diagnostic tools and proved to be indispensable in the daily gastroenterological practice. The lower insertion depths, but higher diagnostic yield, of SBE may reflect the more focused selection of patients scheduled for small bowel diagnostics in recent years. 23946311 Both low and high temperature may increase the risk of stroke mortality. To examine temperature in relation to stroke mortality in a multicity time series study in China. We obtained data on daily temperature and mortality from 8 large cities in China. We used quasi-Poisson generalized additive models and distributed lag nonlinear models to estimate the accumulative effects of temperature on stroke mortality across multiple days, adjusting for long-term and seasonal trends, day of the week, air pollution, and relative humidity. We applied the Bayesian hierarchical model to pool city-specific effect estimates. Both cold and hot temperatures were associated with increased risk of stroke mortality. The potential effect of cold temperature might last more than 2 weeks. The pooled relative risks of extreme cold (first percentile of temperature) and cold (10th percentile of temperature) temperatures over lags 0-14 days were 1.39 (95% posterior intervals [PI] 1.18-1.64) and 1.11 (95% PI 1.06-1.17), compared with the 25th percentile of temperature. In contrast, the effect of hot temperature was more immediate. The relative risks of stroke mortality over lags 0-3 days were 1.06 (95% PI 1.02-1.10) for extreme hot temperature (99th percentile of temperature) and 1.14 (95% PI 1.05-1.24) for hot temperature (90th percentile of temperature), compared with the 75th percentile of temperature. This study showed that both cold and hot temperatures were associated with increased risk of stroke mortality in China. Our findings may have important implications for stroke prevention in China. 23889668 Early detection of anthracycline-mediated cardiotoxicity: the value of considering both global longitudinal left ventricular strain and twist. Anthracyclines are important anticancer drugs, but their use is limited by cardiotoxicity. Left ventricular ejection fraction (LVEF) is often inadequate to detect myocardial disease induced by chemotherapy. Tissue Doppler and bidimensional-strain imaging could detect LV myocardial dysfunction earlier than LVEF. In drug-induced cardiotoxicity, torsional and longitudinal LV deformations [LV twist (LVtw), radial strain (GRS), global longitudinal strain (GLS)] are damaged. We assessed whether a new index, GLS×LVtw, could predict future anthracycline-induced cardiomyopathy. Echocardiography, troponin, and natriuretic peptide determination were prospectively performed in 74 patients before and after 6, 12, 24, and 52 weeks of anthracycline treatment. These patients were treated for breast cancer, Hodgkin's or non-Hodgkin's lymphoma, acute lymphoblastic or myeloblastic leukaemia, or osteosarcoma. At 6 weeks after initiation of chemotherapy, isovolumic relaxation time, systolic mitral annular velocity, LVGLS, LVGRS, LV apical rotation, LVtw, and GLS×LVtw deteriorated, and troponin levels became elevated (all p < 0.05 by ANOVA) before LVEF decreased. The receiver operating characteristic curves identified early deterioration of GLS×LVtw as the best predictor of later cardiotoxicity (area under curve = 0.93), followed by GLS (0.84) and LV apical rotation (0.81) deterioration. In conclusion, early change in the GLS×LVtw index seems to be a good predictor of future development of anthracycline-induced cardiotoxicity. 23856759 Detection of aac(6')-Ib-cr in Avian Pathogenic Escherichia coli Isolates in Japan. We investigated the prevalence of plasmid-mediated quinolone resistance (PMQR) genes in avian pathogenic Escherichia coli (APEC) strains in Japan. A total of 117 APEC strains collected between 2004 and 2007 were examined for PMQR genes (qnrA, qnrB, qnrC, qnrD, qnrS, acc(6')-Ib-cr, qepA and oqxAB) by polymerase chain reaction. None of the APEC strains carried qnrA, qnrB, qnrC, qnrD, qnrS, qepA or oqxAB, but one of the isolates was identified as an AAC(6')-Ib-cr producer. Phylogenetic grouping, multi-locus sequence typing and serotyping showed that this isolate belonged to phylogenetic group A, sequence type 167 and untypeable serogroup. To our knowledge, this is the first report of the aac(6')-Ib-cr gene in bacteria from food-producing animals in Japan. 23611330 Breastfeeding intentions among pregnant adolescents and young adults and their partners. Abstract Background: Rates of breastfeeding remain disproportionately low among young mothers in the United States. Although breastfeeding behavior may be most directly related to breastfeeding intention, little is known about breastfeeding intentions among young women who are expecting a baby. Subjects and Methods: Pregnant adolescents and young adults (14-21 years old) and their male partners were recruited for participation. Females were asked if they intended to breastfeed, and their partners were asked if they wanted their partners to breastfeed; participants indicated reasons for their responses. Logistic regression modeling was used to determine the associations between breastfeeding intentions and sociodemographic characteristics, relationship characteristics, and partner's intention to breastfeed. Results: Approximately 73% of females reported intending to breastfeed, and 80% of males reported wanting his partner to breastfeed, most commonly because it is "healthier for the baby" and "a more natural way to feed the baby." Sociodemographic and relationship characteristics explained a small amount of variance of breastfeeding intention (15% and 4% among females, respectively, and 8% and 4% among males, respectively). Partner intention explained an additional 23% and 24% of the variance in individual intention for females and males, respectively. Females who had experienced intimate partner violence (IPV) from their current partner had lower odds of intending to breastfeed (odds ratio=0.37; 95% confidence interval=0.16, 0.84). Race/ethnicity modified associations among both genders. Conclusions: These findings emphasize the importance of dyadic approaches and suggest strategies for improving breastfeeding intentions and behavior among young couples expecting a baby. These results are also among the first to document the relationship between IPV and breastfeeding intentions among young women. 23868744 Small mammals as hosts of Leishmania spp. in a highly endemic area for zoonotic leishmaniasis in north-eastern Brazil. Leishmania parasites cause leishmaniasis in humans and animals worldwide. These parasites are transmitted by phlebotomine sand flies, which become infected upon feeding on an infected mammalian host. We assessed the occurrence of Leishmania infection in small mammals in an area of cutaneous and visceral leishmaniasis endemicity. A total of 180 small mammals were trapped in 2003 and 2006 in a rural area in north-eastern Brazil. Spleen and skin samples from these animals were assessed by two PCR protocols, one targeting Leishmania (Viannia) spp. and other Leishmania (Leishmania) infantum. Additionally, serum samples were tested by an immunochromatographic test with rK39 as antigen. Overall, 23.2% (38/164) of the animals were positive to L. (V.) spp. and 8.8% (14/160) to L. (L.) infantum). Five animals of four species (Didelphis albiventris, Nectomys squamipes, Rattus rattus and Holochilus sciureus) were positive by both PCR protocols, an overall co-infection rate of 2.5%. By serology, 5% (7/139) of the animals were positive, but all of them were PCR-negative. An isolate obtained from a water rat (N. squamipes) was characterized as L. (V.) braziliensis (zymodeme Z-74). This study reinforces the involvement of different small mammals (e.g., N. squamipes, R. rattus and H. scieurus) in the transmission cycles of L. (V.) braziliensis and L. (L.) infantum in north-eastern Brazil. The finding of L. (V.) braziliensis infection in black rats suggests a rapid process of adaptation of a New World Leishmania species to an Old World rodent and raises interesting questions regarding the co-evolution of these parasites and their vertebrate hosts. 23057672 In vitro-in vivo correlation study for the dermatopharmacokinetics of terbinafine hydrochloride topical cream. Background: To investigate the relationship between dermatopharmacokinetic (DPK) tape stripping from in vitro and in vivo using 1% terbinafine hydrochloride topical cream as the model formulation. Methodology: In vitro and in vivo tape strippings were conducted on separated pig ear skin used as a biological membrane for franz diffusion cell testing and the non-hairy skin area at the ventral forearms of healthy volunteers, respectively. Terbinafine (1%) topical cream was applied to the skin for 0.5, 2, and 4 h. The drug profiles of terbinafine across the stratum corneum were determined immediately (time 0 h), and at 0.5, 1, 2, and 4 h after removing the formulation. The amounts of terbinafine were analyzed by a validated high-performance liquid chromatography-ultraviolet method. The area under the curve (AUC) and the maximum amounts of terbinafine absorption (Qmax) were obtained from pharmacokinetic software. Partition coefficient (KSC/veh) and diffusion parameter (D/L(2)) were derived from the Fick's second law equation. During the schedule time of 8 h, the deviations of in vitro and in vivo data were 6.61 and 30.46% for AUC and Qmax, respectively. There was insignificant difference of the KSC/veh and the D/L(2) between excised pig ear and human skin. In addition, KSC/veh and D/L(2) at Tmax of 2 h were used to predict the AUC presented the value of 4.7481 %h whereas the true value calculated from pharmacokinetic software provided the value of 5.9311 %h differing from each other in approximate of 20%. Conclusions: In vitro tape stripping using the separated pig ear skin as a viable membrane of the franz diffusion cell testing demonstrates the potential to represent in vivo tape stripping in human for topical bioavailability/bioequivalence study of terbinafine hydrochloride 1% topical cream. 23327905 Labdane-type diterpenoids from the fruits of Vitex trifolia. Seven new labdane-type diterpenoids, vitextrifolins A-G (1-7), along with eight previously reported analogues, were isolated from the fruits of Vitex trifolia. The structures of 1-7 were elucidated by spectroscopic data interpretation. The isolates were evaluated for their cytotoxicity against four human cancer cell lines (A549, HCT116, HL-60, and ZR-75-30), but all were inactive (IC(50) < 5 μg/mL). 23914827 The effect of pelvic physiotherapy on reduction of functional constipation in children: design of a multicentre randomised controlled trial. Functional constipation is a common disorder worldwide and is found in all paediatric age groups. Functional constipation can be caused by delayed colonic transit or dysfunction of the pelvic floor muscles. Standard medical care in paediatric practice is often based on clinical experience and mainly consists of a behavioural approach and toilet training, along with the prescription of laxatives. Evidence to evaluate the effectiveness of pelvic physiotherapy for this complaint is lacking. A two-armed multicentre randomised controlled trial has been designed. We hypothesise that the combination of pelvic physiotherapy and standard medical care will be more effective than standard medical care alone for constipated children, aged 5 to 17 years. Children with functional constipation according to the Rome III will be included. Web-based baseline and follow-up measurements, scheduled at 3 and 6 months after inclusion, consist of the numeric rating scale in relation to the perceived severity of the problem, the Strength and Difficulties Questionnaire and subjective improvement post-intervention (global perceived effect). Examination of the pelvic floor muscle functions, including digital testing and biofeedback, will take place during baseline and follow-up measurements at the physiotherapist. The control group will only receive standard medical care, involving at least three contacts during five months, whereas the experimental group will receive standard medical care plus pelvic physiotherapy, with a maximum of six contacts. The physiotherapy intervention will include standard medical care, pelvic floor muscle training, attention to breathing, relaxation and awareness of body and posture. The study duration will be six months from randomisation, with a three-year recruitment period. The primary outcome is the absence of functional constipation according to the Rome III criteria. This section discusses the relevance of publishing the study design and the development of the presented physiotherapy protocol. It also addresses difficulties when interpreting the literature with regard to the effectiveness of biofeedback, potential confounding, and future research indications. To our knowledge, this article is the first to describe the design of a randomised controlled trial among children with constipation to assess the effect of pelvic physiotherapy as an add-on to standard medical care. Current Controlled Trials NL30551.068.09. 23642484 Use of infrared thermography to assess the influence of high environmental temperature on rabbits. The aim of this work was to ascertain if infrared thermography (IRT) can be used on rabbits to assess differences in surface body temperature when they are subjected to two different environmental temperatures outside the comfort zone. Rabbits housed in room A were maintained at a temperature of below 30°C and rabbits in room B at a temperature of above 32°C for a year. Faeces were collected six times during the year to assess stress by means of faecal cortisol metabolites (FCM). The assessment of IRT was carried out to assess maximum and minimum temperatures on the eyes, nose and ears. FCM concentration was higher in room B than A, to confirm that stress conditions were higher in room B. Significant differences in IRT were found between the animals housed in both rooms. It was observed that it was more difficult for animals from room B to maintain a regular heat loss. Although all the body zones used to assess temperature with IRT gave statistical differences, the correlations found between the eyes, nose and ears were moderate, suggesting that they were giving different information. In addition, differences up to 3.36°C were found in the eye temperature of rabbits housed in the same room, with a clear effect of their position in relation to extractors and heating equipments. Therefore, IRT could be a good tool to assess heat stress in animals housed on typical rabbit farm buildings, giving a measure of how the animal is perceiving a combination of humidity, temperature and ventilation. Some face areas were better for analysing images. Minimum temperature on eyes and temperatures on nose are suggested to assess heat losses and critical areas of the farm for heat stress in rabbits. 23053824 Diabetes and risk of subsequent gastric cancer: a population-based cohort study in Taiwan. Epidemiological data concerning the association between diabetes and the subsequent development of gastric cancer are controversial. This population-based retrospective cohort study investigated the subsequent risk of gastric cancer for diabetic patients. From claims data of the universal health insurance of Taiwan, we identified 19,625 persons aged ≥20 years newly diagnosed with diabetes during 2000-2005. A comparison group (n = 78,500), frequency matched by age, sex, and calendar year, was randomly selected from people without diabetes. Incidence and hazard ratios (HR) of gastric cancer were ascertained during the follow-up period until 2008. We also explored associations of antidiabetic medicines with the incidence of gastric cancer. During the follow-up period, 47 subjects in the diabetic group and 216 subjects in the comparison group suffered gastric cancer, with the incidence rates of 4.34 and 4.86 per 10,000 person-years, respectively. During the first 4 years after diabetes diagnosis, the incidence of gastric cancer was relatively low in diabetic patients [adjusted HR = 0.63; 95 % confidence interval (CI) = 0.42-0.97]. However, after that time, the diabetic group had a 76 % (95 % CI = 1.06-2.91) higher risk of developing gastric cancer than the comparison group. In diabetic patients, alpha-glucosidase inhibitors were associated with a significantly decreased risk of gastric cancer (adjusted HR = 0.38; 95 % CI = 0.15-0.96). Our findings suggested that the association between diabetes and subsequent risk of gastric cancer may vary over time. Increased risk of gastric cancer was observed in patients with longer duration of diabetes. 23468593 Hedgehog signaling acts with the temporal cascade to promote neuroblast cell cycle exit. In Drosophila postembryonic neuroblasts, transition in gene expression programs of a cascade of transcription factors (also known as the temporal series) acts together with the asymmetric division machinery to generate diverse neurons with distinct identities and regulate the end of neuroblast proliferation. However, the underlying mechanism of how this "temporal series" acts during development remains unclear. Here, we show that Hh signaling in the postembryonic brain is temporally regulated; excess (earlier onset of) Hh signaling causes premature neuroblast cell cycle exit and under-proliferation, whereas loss of Hh signaling causes delayed cell cycle exit and excess proliferation. Moreover, the Hh pathway functions downstream of Castor but upstream of Grainyhead, two components of the temporal series, to schedule neuroblast cell cycle exit. Interestingly, hh is likely a target of Castor. Hence, Hh signaling provides a link between the temporal series and the asymmetric division machinery in scheduling the end of neurogenesis. 23768365 Promising interaction between nanoencapsulated lutein with low molecular weight chitosan: characterization and bioavailability of lutein in vitro and in vivo. This study aims to develop water-soluble low molecular weight chitosan (LMWC) nanoencapsules with lutein to improve its bioavailability. Lutein-LMWC nanoencapsules were prepared, characterized and bioavailability was studied in vitro and in vivo with lutein in mixed micelles (control). The particle size ranged between 80-600 nm, which was confirmed by Atomic Force Microscope. The interaction between LMWC and lutein in nanocencapsules by (1)H and (13)C NMR showed the essentiality of water molecules to hold the lutein between LMWC chains of nanoparticle with a reversible weak bond. Bioavailability of lutein (200 μM) in vitro showed that lutein-LMWC nanoencapsules was significantly higher (27.7%) than control. Postprandial lutein level in the plasma (54.5%), liver (53.9%) and eyes (62.8%) of mice fed on nanoencapsulated lutein were higher than the control. LMWC may serve as novel carrier for enhancing the lutein bioavailability and can be suggested as the better dietary compound in food and pharmaceutical applications. 23759873 Site-specific cellular delivery of quantum dots with chemoselectively-assembled modular peptides. Modular peptides displaying both quantum dot bioconjugation motifs and specific subcellular targeting domains were constructed using a chemoselective aniline-catalyzed hydrazone coupling chemistry. Peptides were ratiometrically assembled onto quantum dots to facilitate their specific delivery to either the plasma membrane, endosomes, the cytosol or the mitochondria of target cells. 23796867 Factors influencing discordant results of the QuantiFERON-TB Gold In-tube test in patients with active TB. Indeterminate or negative results from the QuantiFERON-TB Gold In-tube test (QFT-GIT) for TB-confirmed patients indicate the lower sensitivity of this method. The aim of this study was to determine the factors associated with indeterminate and negative QFT-GIT results in active TB patients. We analyzed retrospectively the laboratory and clinical data of patients diagnosed with TB between December 2009 and April 2012 at a tertiary university hospital in Seoul, Korea. Among 1301 patients who underwent QFT-GIT, TB-PCR and TB-culture, 168 (12.9%), those with positive TB-PCR or TB-culture were diagnosed with TB. Thirty-nine (23.2%) had indeterminate or negative results by QFT-GIT assay, which did not correlate with positive results of TB-PCR or TB-culture. These patients were older, had lower lymphocyte, total protein and albumin levels, and showed significantly higher CRP levels than the positive group. Multivariate logistic regression analysis showed that the probability of indeterminate and negative QFT-GIT results increased as CRP (odd ratio, 1.069; 95% CI, 1.013-1.127; P = 0.014) or age (1.030, 1.005-1.056, 0.02) increases. When levels of markers of inflammation, such as CRP, are high or the patient is older, QFT-GIT results should be interpreted carefully and correlated with additional tests for TB. 23877933 Lateral pharyngoplasty reduces nocturnal blood pressure in patients with obstructive sleep apnea. To compare the values of 24-hour ambulatory blood pressure monitoring (ABPM) in patients with obstructive sleep apnea (OSA), before and after lateral pharyngoplasty, and to investigate the influence of pre- and post-treatment polysomnographic and anthropometric variations on changes in ABPM. Prospective study. Arterial blood pressure with 24-hour ABPM and nocturnal polysomnography were measured before and 6 months after surgery in 18 consecutively evaluated adults with OSA at a tertiary center. A total of 83.3% were normotensive patients. Nocturnal measurements showed a decrease of 5.3 mmHg in mean arterial pressure (MAP; P = .01), 7.4 mmHg in mean arterial systolic pressure (SP; P = .006), and 4.2 mmHg in mean arterial diastolic pressure (DP; P = .03), leading to significant reductions in all 24-hour measurements: 3.6 mmHg in MAP, 4.8 mmHg in SP, and 2.9 mmHg in DP. There were also significant mean reductions in the apnea-hypopnea index (AHI), from 33.5 to 20.9 (P = .02), arousal index, from 31.6 to 16.7 (P = .005), and percentage of total sleep time with oxyhemoglobin saturation < 90%, from 10.6% to 0.9% (P = .008). No correlations were noted between the measurements of arterial blood pressure and polysomnographic or anthropometric variations. In this small case series, lateral pharyngoplasty reduced the values obtained in the 24-hour ABPM due to a significant reduction of blood pressures during sleep in patients with OSA 6 months after surgery. Although the patients presented with reductions in AHI, arousals, and desaturation time, this was not correlated with the improvement in arterial blood pressure. 4 Laryngoscope, 2013. 23723125 Genetic and chemical targeting of epithelial-restricted with serine box reduces EGF receptor and potentiates the efficacy of afatinib. EGF receptor (EGFR) is elevated in more than 90% of head and neck squamous cell carcinoma (HNSCC). However, a majority of patients with HNSCC do not respond to anti-EGFR therapeutics. Insensitivity to EGFR inhibitors may be due to kinase-independent actions of EGFR and/or activation of Her2. Strategies to reduce EGFR and Her2 protein levels in concert may be an optimal approach to enhance the efficacy of current anti-EGFR molecules. In this study, knockdown of epithelial-restricted with serine box (ESX) decreased EGFR and Her2 promoter activity, expression, and levels. ESX was elevated in primary HNSCC tumors and associated with increased EGFR and Her2. Genetic ablation of ESX decreased EGFR and Her2 levels and enhanced the antiproliferative effects of EGFR/Her2 tyrosine kinase inhibitors (TKI), lapatinib and afatinib. Biphenyl isoxazolidine, a novel small-molecule ESX inhibitor, reduced EGFR and Her2 levels and potentiated the antiproliferative efficacy of afatinib. Single-agent biphenyl isoxazolidine retarded the in vivo tumorigenicity of CAL27 cells. Importantly, the combination of biphenyl isoxazolidine and afatinib was significantly superior in vivo and resulted in a 100% response rate with a 94% reduction in tumor volume. Targeting EGFR/Her2 levels with an ESX inhibitor and EGFR/Her2 kinase activity with a TKI simultaneously is a highly active therapeutic approach to manage HNSCC. Our work provides evidence to support the further development of ESX inhibitors as an adjuvant to enhance the response rate of patients with HNSCC to current anti-EGFR/Her2 therapeutics. Mol Cancer Ther; 12(8); 1515-25. ©2013 AACR. 23391491 Whole-body and microscopic autoradiography to determine tissue distribution of biopharmaceuticals - Target discoveries with receptor micro-autoradiography engendered new concepts and therapies for vitamin D. Information about the distribution of biopharmaceuticals is basic for understanding their actions. Tissue and cellular localization is a key to function. Autoradiography with radiolabeled compounds has provided valuable information with both low resolution whole-body macro-autoradiography and high resolution microscopic autoradiography (micro-autoradiography). Whole-body macro-autoradiography is a uniform and expedient single method approach, providing convenient dose- and time-related overviews with data similar to those obtained with conventional bioassays - and therefore widely used. However, whole-body macro-autoradiography, like common bioassays, has limitations. High specificity-low capacity sites of binding and deposition frequently remain unrecognized. Lack of cellular resolution can cause false negatives and provide misleading results (e.g., false blood-brain barrier). For micro-autoradiography, different methods are advertised in the literature. Most of them are, however, unsuited for drug localization because of inadequate resolution and frequent artifacts. Most drugs interact with their receptors non-covalently by weak electrostatic forces. Therefore, translocation and loss can occur during tissue preparation. This has complicated the use of micro-autoradiography. Receptor micro-autoradiography has overcome these complications and is a method of choice. It has been validated through several diffusible compounds with known localization, extensively applied. It has contributed numerous discoveries, followed by new concepts and therapies. Pictorial evidence in this review indicates that cellular information is essential, a 'sine qua non' for meaningful drug distribution studies. High resolution cellular microscopic information obtained from autoradiography requires tissue dissection and the necessary precautions for preserving pristine in vivo drug deposition. Receptor micro-autoradiography fulfils these requirements. It reveals crucial information at the subcellular level that cannot currently be obtained with any other type of autoradiography or spectrometric imaging. 23965276 High-sensitivity cardiac troponin T is an independent predictor of inhospital mortality in emergency department patients with suspected infection: a prospective observational derivation study. To assess the prognostic and discriminative accuracy of high-sensitivity cardiac troponin T (hs-cTnT) for prediction of inhospital mortality in emergency department (ED) patients with suspected infection. Prospective observational derivation study in ED patients with suspected infection. Prognostic performance of hs-cTnT (divided in four quartiles because of non-linearity) for prediction of inhospital mortality was assessed using multivariable logistic regression, correcting for predisposition, infection, response and organ failure (PIRO) score as a measure of illness severity and quality of ED treatment as quantified by the number of 'Surviving Sepsis Campaign' goals achieved. Discriminative power of hs-cTnT was assessed by receiver operator characteristics with area under the curve (AUC) analysis. Hs-cTnT (median (IQR) was 57 (25-90) ng/L (n=23) in non-survivors, significantly higher than the 15 (7-28) ng/L in survivors (n=269, p<0.001). Additionally, the lowest quartile of hs-cTnT was a perfect predictor of survival because zero death occurred. Therefore, the second quartile was used as a reference category in the multivariable logistic regression analysis showing that hs-cTnT was an independent predictor of inhospital mortality: Corrected ORs were 2.2 (95% CI 0.4 to 12.1) and 5.8 (1.2 to 27.3) for the 3rd and 4th quartile compared with the 2nd hs-cTnT quartile. The AUCs of hs-TnT was 0.81 (0.74 to 0.88), similar to the AUC of 0.78 (0.68 to 0.87) of the PIRO score (p>0.05). Overall negative predictive value of hs-cTnT was 99%. In ED patients with suspected infection, the routinely used biomarker hs-cTnT is an independent predictor of inhospital mortality with excellent discriminative performance. Future studies should focus on the additional value of hs-cTnT to existing risk stratification tools. 23868029 Follicle Measurements Using Sonography-Based Automated Volume Count Accurately Predict the Yield of Mature Oocytes in In Vitro Fertilization/Intracytoplasmic Sperm Injection Cycles. Aims: We define criteria to predict the number of mature oocytes using automated three-dimensional (3D) ultrasound follicle measurements. Methods: Fifty in vitro fertilization/intracytoplasmic sperm injection patients underwent automated 3D echographic monitoring by a single researcher following the stimulation procedure. Classic criteria for triggering oocyte maturation as defined in the literature were utilized. 3D parameters, including the follicular volume and follicle diameter calculated from the volume measurement, were related to the oocyte count, mature oocyte count and the number of observed fertilized oocytes. Results: We found that when oocyte maturation was induced, 55% of the total follicles with a diameter of at least 10 mm had a volume of at least 1.5 cm(3). The number of mature eggs that were retrieved was correlated with the number of follicles observed with a volume of at least 1 cm(3) or a calculated follicle diameter of at least 12 mm. Conclusion: Sonography-based automated volume count measurements of follicle volume and reconstructed follicle diameter can be used to reliably predict the number of mature oocytes. 23427795 Relationship between hemoglobin, serum retinol and habitual meat consumption in the elderly: a population-based study. Considering the scarcity of data on the relationship between hemoglobin, serum retinol and habitual meat consumption in the elderly, a cross-sectional population-based study was performed, which was representative of the population of a state capital in Northeastern Brazil, including 176 elderly aged between 60 and 90 years, who responded to questionnaires about habitual food consumption and socioeconomic aspects. Blood counts and serum retinol analyses were carried out. The prevalence of anemia was 9.58%, and 96% of elderly showing adequate serum retinol levels. The consumption of vitamin A and iron was adequate in 93.75% and 85%, respectively. There was no correlation between serum retinol and hemoglobin values (p=0.56), and as expected, there was a positive association between meat consumption and hemoglobin (p=0.02). Based on results obtained in this study, it was concluded that the maintenance of adequate vitamin A and meat intake in this population should be encouraged, which appears to be an effective intervention strategy to achieve appropriate serum retinol and hemoglobin values, and hence lower iron deficiency anemia rates. 23934774 Structural and mutational analyses of Aes, an inhibitor of MalT in Escherichia coli. The acyl esterase Aes effectively inhibits the transcriptional activity of MalT - the central activator of maltose and maltodextrin utilizing genes in Escherichia coli. To provide better insight into the nature of the interaction between Aes and MalT, we determined two different crystal structures of Aes - in its native form and covalently modified by a phenylmethylsulfonyl moiety at its active site serine. Both structures show distinct space groups and were refined to a resolution of 1.8 Å and 2.3 Å, respectively. The overall structure of Aes resembles a canonical α˜β-hydrolase fold, which is extended by a funnel-like cap structure that forms the substrate-binding site. The catalytic triad of Aes, comprising residues Ser165, His292, and Asp262, is located at the bottom of this funnel. Analysis of the crystal-packing contacts of the two different space groups as well as analytical size exclusion chromatography revealed a homodimeric arrangement of Aes. The Aes dimer adopts an antiparallel contact involving both the hydrolase core and the cap, with its two-fold axis perpendicular to the largest dimension of Aes. In order to identify the surface area of Aes that is responsible for the interaction with MalT, we performed a structure-based alanine-scanning mutagenesis to identify Aes residues that are significantly impaired in MalT inhibition, but still exhibit wildtype expression and enzymatic activity. These residues map to a shallow slightly concave surface patch of Aes at the opposite site of the dimerization interface and indicate the surface area that interacts with MalT. © Proteins 2013. © 2013 Wiley Periodicals, Inc. 23007560 The influence of chronic fluorosis on mitochondrial dynamics morphology and distribution in cortical neurons of the rat brain. The present study was designed to evaluate the effects of chronic fluorosis on the dynamics (including fusion and fission proteins), fragmentation, and distribution of mitochondria in the cortical neurons of the rat brain in an attempt to elucidate molecular mechanisms underlying the brain damage associated with excess accumulation of fluoride. Sixty Sprague-Dawley rats were divided randomly into three groups of 20 each, that is, the untreated control group (drinking water naturally containing <0.5 mg fluoride/l, NaF), the low-fluoride group (whose drinking water was supplemented with 10 mg fluoride/l) and the high-fluoride group (50 mg fluoride/l). After 6 months of exposure, the expression of mitofusin-1 (Mfn1), fission-1 (Fis1), and dynamin-related protein-1 (Drp1) at both the protein and mRNA levels were detected by Western blotting, immunohistochemistry, and real-time PCR, respectively. Moreover, mitochondrial morphology and distribution in neurons were observed by transmission electron or fluorescence microscopy. In the cortices of the brains of rats with chronic fluorosis, the level of Mfn1 protein was clearly reduced, whereas the levels of Fis1 and Drp1 were elevated. The alternations of expression of the mRNAs encoding all three of these proteins were almost the same as the corresponding changes at the protein levels. The mitochondria were fragmented and the redistributed away from the axons of the cortical neurons. These findings indicate that chronic fluorosis induces abnormal mitochondrial dynamics, which might in turn result in a high level of oxidative stress. 23716123 10.2% power conversion efficiency polymer tandem solar cells consisting of two identical sub-cells. Polymer tandem solar cells with 10.2% power conversion efficiency are demonstrated via stacking two PDTP-DFBT:PC71 BM bulk heterojunctions, connected by MoO3 /PEDOT:PSS/ZnO as an interconnecting layer. The tandem solar cells increase the power conversion efficiency of the PDTP-DFBT:PC71 BM system from 8.1% to 10.2%, successfully demonstrating polymer tandem solar cells with identical sub-cells of double-digit efficiency. 23918599 Did I turn off the gas? Reality monitoring of everyday actions. Failing to remember whether we performed, or merely imagined performing, an everyday action can occasionally be inconvenient, but in some circumstances it can have potentially dangerous consequences. In this fMRI study, we investigated the brain activity patterns, and objective and subjective behavioral measures, associated with recollecting such everyday actions. We used an ecologically valid "reality-monitoring" paradigm in which participants performed, or imagined performing, specified actions with real objects drawn from one of two boxes. Lateral brain areas, including prefrontal cortex, were active when participants recollected both the actions that had been associated with objects and the locations from which they had been drawn, consistent with a general role in source recollection. By contrast, medial prefrontal and motor regions made more specific contributions, with supplementary motor cortex activity being associated with recollection decisions about actions but not locations, and medial prefrontal cortex exhibiting greater activity when remembering performed rather than imagined actions. These results support a theoretical interpretation of reality monitoring that entails the fine-grained discrimination between multiple forms of internally and externally generated information. 23624320 In vitro modification of substituted cysteines as tool to study receptor functionality and structure-activity relationships. Mutagenic investigations of expressed membrane proteins are routine, but the variety of modifications is limited by the twenty canonical amino acids. We describe an easy and effective cysteine substitution mutagenesis method to modify and investigate distinct amino acids in vitro. The approach combines the substituted cysteine accessibility method (SCAM) with a functional signal transduction readout system using different thiol-specific reagents. We applied this approach to the prolactin-releasing peptide receptor (PrRPR) to facilitate biochemical structure-activity relationship studies of eight crucial positions. Especially for D(6.59)C, the treatment with the positively charged methanethiosulfonate (MTS) ethylammonium led to an induced basal activity, whereas the coupling of the negatively charged MTS ethylsulfonate nearly reconstituted full activity, obviously by mimicking the wild-type charged side chain. At E(5.26)C, W(5.28)C, Y(5.38)C, and Q(7.35)C, accessibility was observed but hindered transfer into the active receptor conformation. Accordingly, the combination of SCAM and signaling assay is feasible and can be adapted to other G-protein-coupled receptors (GPCRs). This method circumvents the laborious way of inserting non-proteinogenic amino acids to investigate activity and ligand binding, with rising numbers of MTS reagents allowing selective side chain modification. This method pinpoints to residues being accessible but also presents potential molecular positions to investigate the global conformation. 23291560 Postweaning exposure to dietary zearalenone, a mycotoxin, promotes premature onset of puberty and disrupts early pregnancy events in female mice. Zearalenone (ZEA) is a mycotoxin commonly found in contaminated livestock feed and human food with levels in the range of ppb and low ppm. It was hypothesized that ZEA, an endocrine disruptor, could affect puberty and early pregnancy. To test this hypothesis, newly weaned (3 weeks old) C57BL/6J female mice were exposed to 0, 0.002, 4, 10, and 40 ppm ZEA and 0.05 ppm diethylstilbestrol (positive control) in phytoestrogen-free AIN-93G diet. Females exposed to 10 and 40 ppm ZEA diets showed earlier onset of vaginal opening. Those treated with 40 ppm ZEA diet also had earlier first copulation plug and irregular estrous cyclicity. At 8 weeks old, all females were mated with untreated stud males on AIN-93G diet during mating. Treatment resumed upon identification of a vaginal plug on gestation day 0.5 (D0.5). Embryo implantation was assessed on D4.5. Exposure to 40 ppm ZEA diet resulted in reduced percentage of plugged mice with implantation sites, distended uterine appearance, and retained expression of progesterone receptor in D4.5 uterine epithelium. To determine the exposure timing and mechanisms of disrupted embryo implantation, four groups of females were fed with 0 or 40 ppm ZEA diets during premating (weaning to mating) and postmating (D0.5-D4.5), respectively. Premating exposure to 40 ppm ZEA diet reduced fertilization rate, whereas postmating exposure to 40 ppm ZEA diet delayed embryo transport and preimplantation embryo development, which subsequently affected embryo implantation. These data demonstrate that postweaning exposure to dietary ZEA can promote premature onset of puberty and disrupt early pregnancy events. 23845182 Correcting the optimal resampling-based error rate by estimating the error rate of wrapper algorithms. High-dimensional binary classification tasks, for example, the classification of microarray samples into normal and cancer tissues, usually involve a tuning parameter. By reporting the performance of the best tuning parameter value only, over-optimistic prediction errors are obtained. For correcting this tuning bias, we develop a new method which is based on a decomposition of the unconditional error rate involving the tuning procedure, that is, we estimate the error rate of wrapper algorithms as introduced in the context of internal cross-validation (ICV) by Varma and Simon (2006, BMC Bioinformatics 7, 91). Our subsampling-based estimator can be written as a weighted mean of the errors obtained using the different tuning parameter values, and thus can be interpreted as a smooth version of ICV, which is the standard approach for avoiding tuning bias. In contrast to ICV, our method guarantees intuitive bounds for the corrected error. Additionally, we suggest to use bias correction methods also to address the conceptually similar method selection bias that results from the optimal choice of the classification method itself when evaluating several methods successively. We demonstrate the performance of our method on microarray and simulated data and compare it to ICV. This study suggests that our approach yields competitive estimates at a much lower computational price. 23913686 Functional Modeling Identifies Paralogous Solanesyl Diphosphate Synthases that Assemble the Side Chain of Plastoquinone-9 in Plastids. It is a little-known fact that plastoquinone-9, a vital redox cofactor of photosynthesis, doubles as a precursor for the biosynthesis of a vitamin E analog called plastochromanol-8, the physiological significance of which has remained elusive. Gene network reconstruction, GFP-fusion experiments, and targeted metabolite profiling of insertion mutants indicated that Arabidopsis possesses two paralogous solanesyl diphosphate synthases -AtSPS1 (At1g78510) and AtSPS2 (At1g17050)- that assemble the side-chain of plastoquinone-9 in plastids. Similar paralogous pairs were detected throughout terrestrial plant lineages, but were not distinguished in the literature and genomic databases from mitochondrial homologs involved in the biosynthesis of ubiquinone. The leaves of the atsps2 knockout were devoid of plastochromanol-8, and displayed severe losses of both non-photoactive and photoactive plastoquinone-9, resulting in near complete photoinhibition at high light intensity. Such a photoinhibition was paralleled by significant damages to photosystem II, but not to photosystem I. In contrast, in the atsps1 knockout, a small loss of plastoquinone-9 that was restricted to the non-photoactive pool was sufficient to eliminate half of the plastochromanol-8 content of leaves. Taken together these results demonstrate that plastochromanol-8 originates from a sub-fraction of the non-photoactive pool of plastoquinone-9. In contrast to other plastochromanol-8 biosynthetic mutants, neither the single atsps knockouts nor the atsps1 atsps2 double knockout displayed any defects in tocopherols accumulation or germination. 23889452 Comment on "weak measurements with orbital-angular-momentum pointer States". A Comment on the Letter by Puentes et al., Phys. Rev. Lett. 109, 040401 (2012). The authors of the Letter offer a Reply. 23838025 Does geographic location affect incidence of ANCA-associated renal vasculitis in northern Saskatchewan, Canada? Objectives. To compare the incidence of renal ANCA-associated vasculitis (AAV) in urban vs more rural populations in northern Saskatchewan, and as a secondary objective to compare time to diagnosis between these geographic areas.Methods. Northern Saskatchewan has a population of 562 882 of which approximately 260 600 live in the major urban area. A pathology database search for renal biopsy reports suggestive of AAV between January 2007 and December 2011 and subsequent chart review yielded 33 new diagnoses of granulomatosis polyangiitis (GPA) or microscopic polyangiitis (MPA). Data extraction included demographics, residential data, serological status, recorded symptom onset and estimations of BVAS, five-factor score (FFS) and vasculitis damage index (VDI).Results. Of 33 renal AAV cases, 24.2 % (n = 8) lived within the city. The incidence rate for urban residents was 6.1 cases/million/year, and for those residing elsewhere, 16.5 cases/million/year. The odds ratio for the more rural population was 2.69 (95% CI 1.3, 7.5). Mean time to diagnosis was 1.33 (s.d. 0.94) months for urban and 3.52 (s.d. 3.83) months for more rural patients (P = 0.002, 95% CI 0.7, 3.9). Secondary analysis supported these observations with higher BVAS, VDI and FFS scores in patients living outside the urban centre.Conclusion. The incidence of renal biopsy-proven AAV was higher in patients living in northern Saskatchewan smaller communities and rural settings. A significantly longer time to diagnosis existed for patients outside the urban centre and was associated with poorer BVAS, VDI and FFS scores. 23790844 Protective effect of ligand-binding proteins against folic acid loss due to photodecomposition. The B group vitamin known as folates is essential for a variety of physiological processes and plays an important role in the prevention of neural tube defects. However, it decomposes when exposed to UV light. In this study, the response of the synthetic form of folates known as folic acid to UV irradiation in the presence of β-lactoglobulin (β-LG), bovine serum albumin (BSA) and α-lactalbumin (α-LA) was investigated using circular dichroism, absorbance and fluorescence spectroscopy. Photodecomposition of folic acid was delayed in the presence of the proteins, which ranked in the order β-LG>BSA>α-LA in terms of effectiveness. Protein unfolding or decomposition occurred at the same time, due to interaction with folic acid photodecomposition products. The results suggest potential uses of ligand-binding proteins as carriers of water-soluble active compounds for nutraceutical applications. 23963870 The cellient automated cell block system is useful in the differential diagnosis of atypical glandular cells in Papanicolaou tests. Atypical glandular cells (AGC) is a very important diagnosis in gynecological cytology. In the current study, the authors investigated the usefulness of Cellient cell blocks (CB) for characterizing AGC on Papanicolaou (Pap) tests. A total of 148 patients with an AGC diagnosis based on Pap tests by cytotechnologists and referred to cytopathologists were studied. Among these patients, there were 68 patients with CB preparations and 80 patients with Pap tests only (TP-AGC group). Follow-up results by Pap tests or biopsies were obtained in 117 of 148 patients. The median follow-up was 13 months (range, 1 month-36 months). Of the 68 patients with CBs, 31 (46%) were reclassified as negative for dysplasia or low-grade intraepithelial lesion; 30 patients (44%) retained a diagnosis of AGC (CB-AGC group); and 7 patients (10%) were given specific diagnoses of high-grade intraepithelial lesion (3 patients), endocervical adenocarcinoma in situ (1 patient), and invasive adenocarcinoma (3 patients). On follow-up, the CB-AGC group was found to have a significantly lower rate of negative/low-grade squamous intraepithelial lesion diagnoses compared with the TP-AGC group (55% vs 85%; P = .006). The CB-AGC group had a significantly higher rate of endocervical or endometrial adenocarcinoma compared with the TP-AGC group (36% vs 8%; P = .003) at the time of follow-up. The rates of high-grade squamous intraepithelial lesion were not found to be statistically different between these 2 groups (9% vs 7%; P = .66). The Cellient CB is a useful technique to further categorize a diagnosis of AGC on Pap tests. Using the Cellient CB system, the pathologist has the ability to improve the diagnostic accuracy of AGC so that unnecessary colposcopic evaluation or biopsies can be avoided. Cancer (Cancer Cytopathol) 2013. © 2013 American Cancer Society. 23848254 Genetic risk factors for Clostridium difficile infection in ulcerative colitis. Patients with inflammatory bowel disease (IBD) are at higher risk for Clostridium difficile infection (CDI). Disruption of gut microbiome and interaction with the intestinal immune system are essential mechanisms for pathogenesis of both CDI and IBD. Whether genetic polymorphisms associated with susceptibility to IBD are also associated with risk of CDI is unknown. To use a well-characterised and genotyped cohort of patients with UC to (i) identify clinical risk factors for CDI; (ii) examine if any of the IBD genetic risk loci were associated with CDI; and (iii) to compare the performance of predictive models using clinical and genetic risk factors in determining risk of CDI. We used a prospective registry of patients from a tertiary referral hospital. Medical record review was performed to identify all ulcerative colitis (UC) patients within the registry with a history of CDI. All patients were genotyped on the Immunochip. We examined the association between the 163 risk loci for IBD and risk of CDI using a dominant genetic model. Model performance was examined using receiver operating characteristics curves. The study included 319 patients of whom 29 developed CDI (9%). Female gender and pancolitis were associated with increased risk, while use of anti-TNF was protective against CDI. Six genetic polymorphisms including those at TNFRSF14 [Odds ratio (OR) 6.0, P-value 0.01] were associated with increased risk while 2 loci were inversely associated. On multivariate analysis, none of the clinical parameters retained significance after adjusting for genetics. Presence of at least one high-risk locus was associated with an increase in risk for CDI (20% vs. 1%) (P = 6 Ã— 10(-9) ). Compared to 11% for a clinical model, the genetic loci explained 28% of the variance in CDI risk and had a greater AUROC. Host genetics may influence susceptibility to Clostridium difficile infection in patients with ulcerative colitis. 23900982 APOM and high-density lipoprotein are associated with lung function and percent emphysema. Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD.We assessed the association of lung function with 2,100 genes selected for cardiovascular diseases among 20,077 European-Americans and 6,900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with percent emphysema, and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with FEV1/FVC and percent emphysema.We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10(-6)) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10(-7)). Both SNPs flank the gene for apolipoprotein M (apoM), a component of HDL. Both replicated in an independent cohort. SNPs in a second gene related to apoM and HDL, PCSK9, were associated with FEV1/FVC among African-Americans. rs707974 was associated with percent emphysema among European-Americans and African-Americans, and APOM expression was related to FEV1/FVC and percent emphysema. Higher HDL levels were associated with lower FEV1/FVC and greater percent emphysema.These findings suggest a novel role for the APOM/HDL pathway in the pathogenesis of COPD and emphysema. 23347953 Motivational properties of D2 and D3 dopamine receptors agonists and cocaine, but not with D1 dopamine receptors agonist and l-dopa, in bilateral 6-OHDA-lesioned rat. Dopamine dysregulation syndrome in Parkinson's disease (PD) has been attributed to dopamine replacement therapy (DRT). We hypothesize that DRT can induce a potential rewarding effect in an animal model of PD. Using the conditioned place preference (CPP) paradigm, we investigated the motivational effects of l-dopa, dopamine receptor agonists (DRAs), and cocaine in rat with a bilateral 6-OHDA lesion of the nigrostriatal dopaminergic pathway. In 6-OHDA animals, D1 receptors agonist (SKF81297) revealed significantly a conditioned place aversion (CPA) at 3 mg/kg and 9 mg/kg doses. D2 receptors agonist (bromocriptine) induced both CPP and CPA at 1 mg/kg and 10 mg/kg doses respectively. D3 receptors agonist (PD128907) induced a CPP only at 1 mg/kg, comparable to that of cocaine. Sham animals revealed biphasic CPP curves, with significant dose effect, for the intermediate dose of the 3 DRAs. However, l-dopa induced no significant effect while cocaine induced CPP in both lesioned and sham animals. In conclusion, this study confirms the predominant roles of D2R class, and most specifically D3R subtypes, in rewarding properties of DRT. 23812802 Efficacy and tolerability of perospirone in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. Perospirone is a second-generation antipsychotic (SGA) used only in Japan, and acts as a serotonin (5-HT)1A receptor partial agonist, 5-HT2A receptor inverse agonist, and dopamine (D)2, D4, and α1-adrenergic receptor antagonist. To our knowledge, no meta-analysis addressing the efficacy and effectiveness of perospirone in schizophrenia has been published to date. The aim of the study was to identify the characteristics of perospirone by assessing the efficacy, discontinuation rate, and side effects of perospirone versus other antipsychotics in the treatment of patients with schizophrenia. Using information obtained from the PubMed, PsycINFO, Google Scholar and Cochrane Library databases without language restrictions published up to 10 June 2013, we conducted a systematic review and meta-analysis of patient data from randomized controlled trials comparing perospirone with other antipsychotic medications. Risk ratio (RR), standardized mean difference (SMD) and 95 % confidence intervals were calculated. All studies used the Positive and Negative Syndrome Scale (PANSS) for the evaluation of the schizophrenia psychopathology. The search in PubMed, Cochrane Library databases, Google Scholar and PsycINFO yielded 69 hits. We included three studies in the current meta-analysis and excluded 66 studies based on title, abstract, and full text review. Moreover, two additional studies were identified from a review article. Across the five studies (mean duration 9.6 weeks), 562 adult patients with schizophrenia were randomized to perospirone (n = 256), olanzapine (n = 20), quetiapine (n = 28), risperidone (n = 53), aripiprazole (n = 49), haloperidol (n = 75), or mosapramine (n = 81). Perospirone was not different from other pooled antipsychotics regarding reduction in PANSS negative (SMD = 0.38, p = 0.09) and general (SMD = 0.28, p = 0.06) subscale scores, and discontinuation due to any cause (RR = 1.03, p = 0.83), inefficacy (RR = 0.99, p = 0.98) and side effects (RR = 0.72, p = 0.25). However, perospirone was inferior to other pooled antipsychotics in the reduction of PANSS total scores (SMD = 0.36, p = 0.04) and positive subscale scores (SMD = 0.34, p = 0.03). Moreover, excluding the comparison of perospirone with the first-generation antipsychotic (haloperidol), perospirone was inferior to other pooled SGAs in the reduction of PANSS total scores (SMD = 0.46, p = 0.02), positive (SMD = 0.42, p = 0.03), negative (SMD = 0.52, p = 0.02) and general subscale scores (SMD = 0.37, p = 0.03). However, perospirone was superior to haloperidol in the reduction of PANSS negative subscale scores (SMD = -0.41, p = 0.01). Perospirone also had lower scores related to extrapyramidal symptoms than other pooled antipsychotics (SMD = -0.30, p = 0.01). Our results suggest that although perospirone seems to be a well tolerated treatment, perospirone does not reduce PANSS score as much as other SGAs. 23927242 Van der Waals interactions in density functional theory by combining the quantum harmonic oscillator-model with localized Wannier functions. We present a new scheme to include the van der Waals (vdW) interactions in approximated Density Functional Theory (DFT) by combining the quantum harmonic oscillator model with the maximally localized Wannier function technique. With respect to the recently developed DFT/vdW-WF2 method, also based on Wannier Functions, the new approach is more general, being no longer restricted to the case of well separated interacting fragments. Moreover, it includes higher than pairwise energy contributions, coming from the dipole-dipole coupling among quantum oscillators. The method is successfully applied to the popular S22 molecular database, and also to extended systems, namely graphite and H2 adsorbed on the Cu(111) metal surface (in this case metal screening effects are taken into account). The results are also compared with those obtained by other vdW-corrected DFT schemes. 23702461 Fullerenol C₆₀(OH)₃₆ could associate to band 3 protein of human erythrocyte membranes. The present study was aimed at investigating the effect of fullerenol C60(OH)36 on chosen parameters of the human erythrocyte membrane and the preliminary estimation of the properties of fullerenol as a potential linking agent transferring the compounds (e.g., anticancer drugs) into the membrane of erythrocytes. The results obtained in this study confirm the impact of fullerenol on erythrocyte cytoskeletal transmembrane proteins, particularly on the band 3 protein. The presence of fullerenol in each of the concentrations used prevented degradation of the band 3 protein. The results show that changes in the morphology of red blood cells caused by high concentrations of fullerenol (up to 150mg/L) did not lead to increased red blood cell hemolysis or the leakage of potassium. Moreover, fullerenol slightly prevented hemolysis and potassium efflux. The protective effect of fullerenol at the concentration of 150mg/L was 20.3%, and similar results were obtained for the efflux of potassium. The study shows that fullerenol slightly changed the morphology of the cells and, therefore, altered the intracellular organization of erythrocytes through the association with cytoskeletal proteins. 23639843 Differential proteomic analysis of abnormal intramyoplasmic aggregates in desminopathy. Desminopathy is a subtype of myofibrillar myopathy caused by desmin mutations and characterized by protein aggregates accumulating in muscle fibers. The aim of this study was to assess the protein composition of these aggregates. Aggregates and intact myofiber sections were obtained from skeletal muscle biopsies of five desminopathy patients by laser microdissection and analyzed by a label-free spectral count-based proteomic approach. We identified 397 proteins with 22 showing significantly higher spectral indices in aggregates (ratio >1.8, p<0.05). Fifteen of these proteins not previously reported as specific aggregate components provide new insights regarding pathomechanisms of desminopathy. Results of proteomic analysis were supported by immunolocalization studies and parallel reaction monitoring. Three mutant desmin variants were detected directly on the protein level as components of the aggregates, suggesting their direct involvement in aggregate-formation and demonstrating for the first time that proteomic analysis can be used for direct identification of a disease-causing mutation in myofibrillar myopathy. Comparison of the proteomic results in desminopathy with our previous analysis of aggregate composition in filaminopathy, another myofibrillar myopathy subtype, allows to determine subtype-specific proteomic profile that facilitates identification of the specific disorder. Our proteomic analysis provides essential new insights in the composition of pathological protein aggregates in skeletal muscle fibers of desminopathy patients. The results contribute to a better understanding of pathomechanisms in myofibrillar myopathies and provide the basis for hypothesis-driven studies. The detection of specific proteomic profiles in different myofibrillar myopathy subtypes indicates that proteomic analysis may become a useful tool in differential diagnosis of protein aggregate myopathies. This article is part of a Special Issue entitled: From Genome to Proteome: Open Innovations. 23785116 Dietary intakes of red meat, poultry, and fish during high school and risk of colorectal adenomas in women. Adolescent diet may be etiologically relevant for colorectal carcinogenesis. We examined the association between meat and fish intakes during adolescence and the risk of colorectal adenomas later in life among 19,771 women participating in the Nurses' Health Study II. Subjects had completed a validated food frequency questionnaire in 1998 (when aged 34-51 years) about their diets during high school and subsequently underwent at least 1 lower-bowel endoscopy during the study period (1998-2007). During this period, 1,494 subjects were diagnosed with colorectal adenomas. Intake of red meat during adolescence was not associated with colorectal adenoma risk when comparing those in the highest versus lowest category of intake (odds ratio (OR) = 1.04, 95% confidence interval (CI): 0.81, 1.35). Similarly, intake of fish during adolescence was not associated with colorectal adenoma risk (OR = 0.96, 95% CI: 0.78, 1.17). Intake of poultry during adolescence was associated with a lower risk of total colorectal (OR = 0.80, 95% CI: 0.64, 0.99), distal (OR = 0.71, 95% CI: 0.51, 0.99), rectal (OR = 0.51, 95% CI: 0.29, 0.90), and advanced (OR = 0.60, 95% CI: 0.38, 0.93) adenomas. Replacement of 1 serving per day of red meat with 1 serving per day of poultry or fish was associated with 41% and 35% decreased risks for rectal adenomas and advanced adenomas, respectively. Our findings do not suggest an association between red meat intake during adolescence and colorectal adenomas later in life, but higher poultry intake during this time was associated with a lower risk of colorectal adenomas. 23707724 Exploring the long-term response of undisturbed Mediterranean catchments to changes in atmospheric inputs through time series analysis. The aim of this study was to gain insights on the potential hydrological and biogeochemical mechanisms controlling the response of two nested Mediterranean catchments to long-term changes in atmospheric inorganic nitrogen and sulphate deposition. One catchment was steep and fully forested (TM9, 5.9 ha) and the other one had gentler slopes and heathlands in the upper part while side slopes were steep and forested (TM0, 205 ha). Both catchments were highly responsive to the 45% decline in sulphate concentration measured in atmospheric deposition during the 1980s and 1990s, with stream concentrations decreasing by 1.4 to 3.4 μeq L(-1) y(-1). Long-term changes in inorganic nitrogen in both, atmospheric deposition and stream water were small compared to sulphate. The quick response to changes in atmospheric inputs could be explained by the small residence time of water (4-5 months) in these catchments (inferred from chloride time series variance analysis), which was attributed to steep slopes and the role of macropore flow bypassing the soil matrix during wet periods. The estimated residence time for sulphate (1.5-3 months) was substantially lower than for chloride suggesting unaccounted sources of sulphate (i.e., dry deposition, or depletion of soil adsorbed sulphate). In both catchments, inorganic nitrogen concentration in stream water was strongly damped compared to precipitation and its residence time was of the order of decades, indicating that this essential nutrient was strongly retained in these catchments. Inorganic nitrogen concentration tended to be higher at TM0 than at TM9 which was attributed to the presence of nitrogen fixing species in the heathlands. Our results indicate that these Mediterranean catchments react rapidly to environmental changes, which make them especially vulnerable to changes in atmospheric deposition. 23885091 Strong spatial genetic structure reduces reproductive success in the critically endangered plant genus pseudomisopates. Clonal growth can be a double-edged sword for endangered species, because the short-term insurance against extinction may incur a longer-term hazard of creating small inbred populations with low fecundity. In the present study, we quantify the advantages and disadvantages of clonal growth regarding the fitness of the central Iberian monotypic endangered genus Pseudomisopates. Preliminary studies showed that the species is self-incompatible and exhibits extensive clonal growth with plants flowering profusely. However, seeds at many sites seemed to be unviable, and no seedlings have been observed in the field. A fully replicated nested sampling design (n = 100) was conducted to explore genetic (using seven SSR loci) and environmental factors potentially affecting seed viability, such as: 1) clonal and genetic diversity, 2) spatial genetic structure, and 3) environmental factors (shrub cover and grazing). Generalized Linear Mixed Models were fitted relating genetic and environmental variables to reproductive variables (seed viability and flower display). Our results indicate that the relatively low genotypic diversity of the population (PD = 0.23), as quantified by SSRs, and the strong spatial genetic structure observed are congruent with intense clonal growth. This clonal growth is enhanced by unfavorable environmental conditions, such as canopy closure and grazing. Under these circumstances, both flower display and mate availability decrease, thus hindering sexual reproduction. Indeed, a mixed reproductive system (clonal and sexual) to escape environmental stochasticity is crucial for the survival of Pseudomisopates, a species inhabiting a disturbance-prone ecosystem. 23824344 Medical students' experiences and perception of support following the death of a patient in the UK, and while overseas during their elective period. To investigate medical students' experiences and perception of support following a patient's death, contrasting their experiences in the UK, and while overseas during their elective period. An anonymous online questionnaire was distributed to all final year medical students at one UK medical school in November 2009. 220 students were contacted, 60% responded. 72% (94) of medical students had been involved in end-of-life care at some point during their course; students on elective experiencing patient death across all ages. Some students saw many patients dying during their elective period. Students had mixed emotions following a patient's death. In the UK, students reported feeling shocked, upset and sad. When overseas, many students were angry or frustrated, and many reported feelings of injustice. Following a death, students found talking to people beneficial, but when overseas they turned to friends and family using email and Facebook, rather than talking to local doctors and nurses. Only 13% (16) of medical students thought their medical training had prepared them sufficiently to deal with death. Of those who did feel prepared some said they had gained this knowledge through working as a healthcare assistant. Students feel ill prepared for experiencing the death of a patient. Even though they may have 'medical knowledge' they are still lacking in emotional support and are often inadequately supported around the time of a patient's death. Medical schools should consider their curricula so that students are aware of the possible experiences and emotions which they may face when involved with the death of a patient, and students should be given advice on whom to turn to for support. 23595515 Target-specific oral anticoagulants in atrial fibrillation: results of phase III trials and comments on sub-analyses. Dabigatran, rivaroxaban, apixaban and edoxaban administered in fixed doses and without routine laboratory monitoring have been compared to warfarin for the prevention of stoke in patients with nonvalvular atrial fibrillation (AF). Phase III data is currently available for dabigatran, rivaroxaban and apixaban. It is derived from three randomized controlled trials: RE-LY, ROCKET AF and ARISTOTLE. Dabigatran and apixaban appeared to be superior to warfarin for the primary endpoint of stroke or systemic embolism, while rivaroxaban was deemed non-inferior. The risk of major bleeding was modestly decreased overall with the new agents, while the risk of intracranial hemorrhage was substantially reduced. The results of ENGAGE AF-TIMI 48 comparing edoxaban to warfarin are still pending. Large, well designed clinical trials support the use of three new target-specific oral anticoagulants for the prevention of stroke in individuals with nonvalvular AF. 23786837 A nationwide population study of trazodone use in urology patients. Erectile dysfunction (ED) has been a prevalent disease worldwide. The mainstay of treatment for ED focused on oral medications such as phosphodiesterase-5 (PDE-5) inhibitors or other medical aids with variable acceptance. Trazodone is a second-generation antidepressant approved by the U.S. Food and Drug Administration in 1981. Some evidence has suggested that trazodone may be helpful in improving ED, especially for problems dealing with male arousal. Although controversial, trazodone can sometimes be used for ED as an off-label medication for urological patients. By using a nationwide health insurance database, we attempted to estimate and thereafter analyze the existence and extent of off-label use of trazodone for ED in Taiwan. The 1/500 randomly sampled outpatient visits dataset and the 1/1 million randomly selected dataset issued in 2000 in the National Health Insurance Research Database were used to estimate the total number of visits and the urological visits involving trazodone prescriptions. The refill rate, patient age at first prescription, and the diagnoses assigned to the prescription visits were also gathered and analyzed. The prescription visits in urological clinics consisted exclusively of male patients (99.0 ± 1.3%, p < 0.001). The use of trazodone was more prevalent and regular among the elderly (p < 0.001), which happens to parallel the trend of incidence rates of ED. Starting in 1998, the prescription rate for trazodone increased rapidly, but then slowed, equalized, and topped out in 2003. One of the reasons for this marked change in prescriptions rates in Taiwan may be the increased awareness of ED as a treatable disease under the promotion and marketing of three PDE-5 inhibitors. ED-related diagnoses assigned to the prescription visits accounted for 55% of total visits, whereas anxiety/depression-associated diagnoses were the bases of less than 13%, and those attributed to insomnia accounted for 2.3% of visits. Despite the fact that trazodone was not officially approved for patients with urological conditions, this medication has been used as an ED treatment in Taiwan at least since 1997; the prescriptions of trazodone were more prevalent among the elderly, and this trend increased, then evened out, and eventually reached its maximum point in 2003, correlating with the introduction of PDE-5 inhibitors. 23017409 Ginger extract and zingerone ameliorated trinitrobenzene sulphonic acid-induced colitis in mice via modulation of nuclear factor-κB activity and interleukin-1β signalling pathway. Ginger is a commonly used spice with anti-inflammatory potential. Colitis is the common pathological lesion of inflammatory bowel diseases. In this study, we investigated the therapeutic effects of ginger and its component zingerone in mice with 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis. Ginger and zingerone ameliorated TNBS-induced colonic injury in a dose-dependent manner. Pathway analysis of ginger- and zingerone-regulated gene expression profiles showed that ginger and zingerone significantly regulated cytokine-related pathways. Network analysis showed that nuclear factor-κB (NF-κB) and interleukin-1β (IL-1β) were key molecules involved in the expression of ginger- and zingerone-affected genes. Ex vivo imaging and immunohistochemical staining further verified that ginger and zingerone suppressed TNBS-induced NF-κB activation and IL-1β protein level in the colon. In conclusion, ginger improved TNBS-induced colitis via modulation of NF-κB activity and IL-1β signalling pathway. Moreover, zingerone might be the active component of ginger responsible for the amelioration of colitis induced by TNBS. 23391259 Effects of nitrate adaptation by rumen inocula donors and substrate fiber proportion on in vitro nitrate disappearance, methanogenesis, and rumen fermentation acid. A study was conducted to evaluate the main effects of dietary nitrate adaptation by cattle and alfalfa cell wall to starch ratio in in vitro substrates on nitrate disappearance and nitrite and volatile fatty acid (VFA) concentrations, as well as hydrogen (H2) and methane (CH4) accumulations. Rumen fluid from steers fed diets containing urea or nitrate was added into in vitro incubations containing sodium nitrate as the sole nitrogen source and 20 cell wall : 80 starch or 80 cell wall : 20 starch as the carbohydrate source. The results showed that during 24 h incubation, rumen fluid inoculums from steers adapted to dietary nitrate resulted in more rapid nitrate disappearance by 6 h of incubation (P < 0.01), no significant effect on nitrite concentration and diminished CH4 accumulation (P < 0.05). Cell wall to starch ratio did not affect nitrate disappearance, CH4 accumulation and total VFA concentration. The higher cell wall ratio had the lower total gas production and H2 concentration (P < 0.05). Ammonia-N (NH3-N) concentration increased because of adaptation of donors to nitrate feeding (P < 0.05). Nitrate adaptation did not alter total VFA concentration, but increased acetate, and decreased propionate and butyrate molar proportions (P < 0.01). 23912064 New triterpene glycosides from Ziziphi Spinosae Semen. Four new dammarane-type triterpene glycosides, named jujubosides I-IV (1-4), were isolated from Ziziphi Spinosae Semen, along with seven known saponins (5-11). The structures of new compounds were established on the basis of extensive spectroscopic analysis. All compounds were evaluated for the effects on neonatal rat cardiomyocyte injury induced by hydrogen peroxide in vitro. 23500062 Raft forming system-An upcoming approach of gastroretentive drug delivery system. In recent era various technologies have been made in research and development of controlled release oral drug delivery system to overcome various physiological difficulties such as variation in gastric retention and emptying time. To overcome this drawback and to maximize the oral absorption of various drugs, novel drug delivery systems have been developed. Gastroretentive drug delivery system is facing many challenges which can be overcome by upcoming newly emerging approach i.e. raft forming system. The purpose of writing this review is to focus on recent development of stomach specific floating drug delivery system to circumvent the difficulties associated with formulation design. Various gastroretentive approaches that have been developed till now are also discussed. The present study provides valuable information & highlights advances in this raft forming system. This review attempts to discuss various factors like physiological factors, physicochemical factors and formulation factors to be considered in the development of the raft forming system. Different types of smart polymers used for their formulation have also been summarized. The review focuses on the mechanism, formulation and development of the raft forming system. This review also summarizes the studies to evaluate the performance and application of these systems. The study finally highlights advantages, disadvantages, and marketed preparation of the raft forming system. 23892540 Variants in BET1L and TNRC6B associate with increasing fibroid volume and fibroid type among European Americans. Uterine fibroids (UFs) affect 77 % of women by menopause and account for $9.4 billion in yearly healthcare costs. We recently replicated findings from the first UF genome-wide association study (GWAS), conducted in the Japanese. Here we tested these GWAS-discovered SNPs for association with UF characteristics to further assess whether risk varies by sub-phenotypes of UFs. Women were enrolled in Right from the Start (RFTS) and the BioVU DNA repository (BioVU). UF status was determined by pelvic imaging. We tested the top GWAS-associated SNPs for association with UF characteristics (RFTS: type, number, volume; BioVU: type) using covariate adjusted logistic and linear regression. We also combined association results of UF type using meta-analysis. 456 European American (EA) cases and 1,549 controls were examined. Trinucleotide repeat containing 6B (TNRC6B) rs12484776 associated with volume in RFTS (β = 0.40, 95 % CI 0.05-0.75, p = 0.024). RFTS analyses evaluating stratified quartiles of volume showed the strongest OR at rs12484776 for the largest volume (16.6-179.1 cc, odds ratio (OR) = 2.19, 95 % confidence interval (CI) 1.07-4.46, p = 0.031). Meta-analysis showed a strong association at blocked early in transport 1 homolog (BET1L) rs2280543 for intramural UFs (meta-OR = 0.51, standard error (SE) = 0.14, Q = 0.590, I = 0, p = 2.48 Ã— 10(-6)), which is stronger than the overall association with UF risk. This study is the first to evaluate these SNPs for association with UF characteristics and suggests these genes associate with increasing UF volume and protection from intramural UF in EAs. 23587424 Kappa-opioid receptor-selective dicarboxylic ester-derived salvinorin A ligands. Salvinorin A, the active ingredient of the hallucinogenic plant Salvia divinorum is the most potent known naturally occurring hallucinogen and is a selective κ-opioid receptor agonist. To better understand the ligand-receptor interactions, a series of dicarboxylic ester-type of salvinorin A derivatives were synthesized and evaluated for their binding affinity at κ-, δ- and μ-opioid receptors. Most of the analogues show high affinity to the κ-opioid receptor. Methyl malonyl derivative 4 shows the highest binding affinity (Ki=2nM), analogues 5, 7, and 14 exhibit significant affinity for the κ-receptor (Ki=21, 36 and 39nM). 23748739 Feasibility of the Cut-and-Push Method for Removing Large-Caliber Soft Percutaneous Endoscopic Gastrostomy Devices. Introduction: Percutaneous endoscopic gastrostomy (PEG) is the method of choice for long-term nutrition in patients with longstanding eating difficulties due to pathological entities that impair swallowing. The feeding catheters are designed to be removed by external traction or by endoscopy. Aim: To evaluate the feasibility of the cut-and-push method as a possible safe alternative to the pullout method for removal of soft PEG devices with a large caliber. Methods: Patients with 20 French (Fr) or larger soft PEG system were enrolled for PEG removal by the cut-and-push technique. The replacement catheters were 2 Fr larger than the original ones. Patients were observed at 24 and 72 hours via home nursing care and then weekly for 1 month for signs of intestinal obstruction, tube leakage, or blockage. Results: Seventy-nine patients (52 men; mean age 67 years) underwent the procedure: 42 due to leakage and 37 due to blockage. Mean time before tube removal was 4.8 months (range, 3-8). PEG devices were 20 Fr and 24 Fr in 57 (72.2%) and 22 (27.8%) cases, respectively. Collection of the inner component from stool was reported within 48 hours in 63 cases (80%). No cases of intestinal obstruction or other severe adverse events due to the inner component being eliminated throughout the intestine were observed in any patient during the study. Conclusions: The cut-and-push method employed for removal of a soft PEG tube with a large caliber seems to be safe and can be performed when removal by external traction may determine the occurrence of peristomal complications or jeopardize PEG replacement. 23709364 Lycopene protects against MPP(+)-induced cytotoxicity by maintaining mitochondrial function in SH-SY5Y cells. Mitochondrial dysfunction is implicated in pathogenesis of Parkinson's disease (PD). Lycopene, a member of the carotenoid family of phytochemicals, exerts its neuroprotective effects by reducing oxidative damage and improving mitochondrial function in several experimental models. In an attempt to clarify the protective effect of lycopene on toxin-insulted dopaminergic neuronal death, the present study was carried out by using a typical PD-1-methyl-4-phenylpyridinium iodide (MPP(+))-induced dopaminergic SH-SY5Y cellular model. SH-SY5Y cells were preincubated with different dose of lycopene for 2 h, followed by the challenge with 500 Î¼M MPP(+) for 24 h. It is found that lycopene attenuated MPP(+)-induced cytotoxicity, as evidenced by the improved cell viability and the decreased apoptotic rate. Additionally, lycopene suppressed the reactive oxygen species accumulation and lipid peroxidation caused by MPP(+). Lycopene also ameliorated MPP(+)-induced mitochondria-derived ROS production and mitochondrial morphological changes. Furthermore, lycopene attenuated MPP(+)-induced opening of the mitochondrial permeability transition pore and the concomitant disruption of the mitochondrial membrane potential, reversed MPP(+)-induced reduction in ATP concentration and decreases in mitochondrial DNA copy numbers and mitochondrial RNA transcript levels. Together, the protective effects of lycopene against MPP(+)-induced cytotoxicity may be attributable to its roles in improving mitochondrial function. These data suggest that lycopene may provide a valuable therapeutic strategy for the treatment of PD. 23845732 Biocide and antimicrobial susceptibility of methicillin-resistant staphylococcal isolates from horses. The aim of this study was to evaluate the biocide and antimicrobial susceptibility of methicillin-resistant staphylococcal isolates from horses. Fourteen methicillin-resistant staphylococci (MRS) were subjected to an extensive genotype characterization, including SCCmec, dru, spa, PFGE and MLST typing. Antimicrobial susceptibility testing was performed and resistance genes were detected by PCR. Minimum bactericidal concentrations (MBCs) of four biocides [chlorhexidine acetate (CHA), benzalkonium chloride (BAC), triclosan (TCL) and glutaraldehyde (GLA)] were determined following the recommendations of document NF EN 1040. The presence of qac and sh-fabI genes was investigated by PCR. Several antimicrobial resistance patterns and genes were detected. When MRS strains were exposed for a longer period of time, a lower concentration of the biocide was needed to achieve lethality. TCL had the lowest MBC values. All MBC values were lower than the recommended in-use concentrations for veterinary medicine. S. haemolyticus and S. cohnii subsp. cohnii carried plasmid-borne qacA and sh-fabI or qacB and a qacH-like genes, respectively. Biocides appear to be a reliable antiseptic option against MRS, since even in the presence of bacterial efflux mechanisms, the recommended concentration is much higher than the in vitro MBC. 23575975 Benchmark quantum-chemical calculations on a complete set of rotameric families of the DNA sugar-phosphate backbone and their comparison with modern density functional theory. The DNA sugar-phosphate backbone has a substantial influence on the DNA structural dynamics. Structural biology and bioinformatics studies revealed that the DNA backbone in experimental structures samples a wide range of distinct conformational substates, known as rotameric DNA backbone conformational families. Their correct description is essential for methods used to model nucleic acids and is known to be the Achilles heel of force field computations. In this study we report the benchmark database of MP2 calculations extrapolated to the complete basis set of atomic orbitals with aug-cc-pVTZ and aug-cc-pVQZ basis sets, MP2(T,Q), augmented by ΔCCSD(T)/aug-cc-pVDZ corrections. The calculations are performed in the gas phase as well as using a COSMO solvent model. This study includes a complete set of 18 established and biochemically most important families of DNA backbone conformations and several other salient conformations that we identified in experimental structures. We utilize an electronically sufficiently complete DNA sugar-phosphate-sugar () backbone model system truncated to prevent undesired intramolecular interactions. The calculations are then compared with other QM methods. The BLYP and TPSS functionals supplemented with Grimme's D3(BJ) dispersion term provide the best tradeoff between computational demands and accuracy and can be recommended for preliminary conformational searches as well as calculations on large model systems. Among the tested methods, the best agreement with the benchmark database has been obtained for the double-hybrid DSD-BLYP functional in combination with a quadruple-ζ basis set, which is, however, computationally very demanding. The new hybrid density functionals PW6B95-D3 and MPW1B95-D3 yield outstanding results and even slightly outperform the computationally more demanding PWPB95 double-hybrid functional. B3LYP-D3 is somewhat less accurate compared to the other hybrids. Extrapolated MP2(D,T) calculations are not as accurate as the less demanding DFT-D3 methods. Preliminary force field tests using several charge sets reveal an almost order of magnitude larger deviations from the reference QM data compared to modern DFT-D3, underlining the challenges facing force field simulations of nucleic acids. As expected, inclusion of the solvent environment approximated by a continuum approach has a large impact on the relative stabilities of different backbone substates and is important when comparing the QM data with structural bioinformatics and other experimental data. 23252554 Exploring the sequence-structure relationship for amyloid peptides. Amyloid fibril formation is associated with misfolding diseases, as well as fulfilling a functional role. The cross-β molecular architecture has been reported in increasing numbers of amyloid-like fibrillar systems. The Waltz algorithm is able to predict ordered self-assembly of amyloidogenic peptides by taking into account the residue type and position. This algorithm has expanded the amyloid sequence space, and in the present study we characterize the structures of amyloid-like fibrils formed by three peptides identified by Waltz that form fibrils but not crystals. The structural challenge is met by combining electron microscopy, linear dichroism, CD and X-ray fibre diffraction. We propose structures that reveal a cross-β conformation with 'steric-zipper' features, giving insights into the role for side chains in peptide packing and stability within fibrils. The amenity of these peptides to structural characterization makes them compelling model systems to use for understanding the relationship between sequence, self-assembly, stability and structure of amyloid fibrils. 23756216 Vertical distribution profiles and diagenetic fate of synthetic surfactants in marine and freshwater sediments. This manuscript deals with the presence and degradation of the most commonly-used surfactants, including anionic (linear alkylbenzene sulfonates, LAS, and alkyl ethoxysulfates, AES) and non-ionic (alcohol polyethoxylates, AEOs, and nonylphenol polyethoxylates, NPEOs) compounds, in sediments and pore water from several aquatic environments (Southwest, Spain). Different vertical distributions were observed according to the respective sources, uses, production volumes and physicochemical properties of each surfactant. Levels of nonionics (up to 10mgkg(-1)) were twice as high as anionics in industrial areas and harbors, whereas the opposite was found near urban wastewater discharge outlets. Sulfophenyl carboxylic acids (SPCs), LAS degradation products, were identified at anoxic depths at some sampling stations. Their presence was related to in situ anaerobic degradation of LAS in marine sediments, whereas the occurrence of these metabolites in freshwater sediments was attributed to the existence of wastewater sources nearby. No significant changes in the average length of AEO and NPEO ethoxylated chains were observed along the sediment cores, suggesting that their biodegradation was very limited in the sampling area. This may be directly related to their lower bioavailability, as their calculated sediment-pore water distribution coefficients (log Ksw), which showed that non-ionic surfactants examined in this study had greater sorption affinity than the anionic surfactants (e.g., 2.3±0.3 for NPEOs). 23929679 CONFECT: Conformations from an Expert Collection of Torsion Patterns. The generation of sets of low-energy conformations for a given molecule is a central task in drug design. Herein we present a new conformation generator called CONFECT that builds on our previously published library of torsion patterns. Conformations are generated as well as ranked by means of normalized frequency distributions derived from the Cambridge Structural Database (CSD). Following an incremental construction approach, conformations are selected from a systematic enumeration within energetic boundaries. The new tool is benchmarked in several different ways, indicating that it allows the efficient generation of high-quality conformation ensembles. These ensembles are smaller than those produced by state-of-the-art tools, yet they effectively cover conformational space. 23545134 Chronic dietary exposure to chlorpyrifos causes behavioral impairments, low activity of brain membrane-bound acetylcholinesterase, and increased brain acetylcholinesterase-R mRNA. Chlorpyrifos (CPF) is an organophosphate (OP) insecticide that is metabolically activated to the highly toxic chlorpyrifos oxon. Dietary exposure is the main route of intoxication for non-occupational exposures. However, only limited behavioral effects of chronic dietary exposure have been investigated. Therefore, male Wistar rats were fed a dose of 5mg/kg/day of CPF for thirty-one weeks. Animals were evaluated in spatial learning and impulsivity tasks after 21 weeks of CPF dietary exposure and one week after exposure ended, respectively. In addition, the degree of inhibition of brain acetylcholinesterase (AChE) was evaluated for both the soluble and particulate forms of the enzyme, as well as AChE gene expression. Also, brain acylpeptide hydrolase (APH) was investigated as an alternative target for OP-mediated effects. All variables were evaluated at various time points in response to CPF diet and after exposure ended. Results from behavioral procedures suggest cognitive and emotional disorders. Moreover, low levels of activity representing membrane-bound oligomeric forms (tetramers) were also observed. In addition, increased brain AChE-R mRNA levels were detected after four weeks of CPF dietary exposure. However, no changes in levels of brain APH were observed among groups. In conclusion, our data point to a relationship between cognitive impairments and changes in AChE forms, specifically to a high inhibition of the particulate form and a modification of alternative splicing of mRNA during CPF dietary exposure. 23782615 A Sensitive and Accurate protein domain cLassification Tool (SALT) for short reads. Protein domain classification is an important step in functional annotation for next-generation sequencing data. For RNA-Seq data of non-model organisms that lack quality or complete reference genomes, existing protein domain analysis pipelines are applied to short reads directly or to contigs that are generated using de novo sequence assembly tools. However, these strategies do not provide satisfactory performance in classifying short reads into their native domain families. We introduce SALT, a protein domain classification tool based on profile hidden Markov models and graph algorithms. SALT carefully incorporates the characteristics of reads that are sequenced from the domain regions and assembles them into contigs based on a supervised graph construction algorithm. We applied SALT to two RNA-Seq datasets of different read lengths and quantified its performance using the available protein domain annotations and the reference genomes. Compared with existing strategies, SALT showed better sensitivity and accuracy. In the third experiment, we applied SALT to a non-model organism. The experimental results demonstrated that it identified more transcribed protein domain families than other tested classifiers. The source code and supplementary data are available at https://sourceforge.net/projects/salt1/ CONTACT: yannisun@msu.edu Supplementary data are available at Bioinformatics online. 23830980 Functionalization of 3D scaffolds with protein-releasing biomaterials for intracellular delivery. Appropriate combinations of mechanical and biological stimuli are required to promote proper colonization of substrate materials in regenerative medicine. In this context, 3D scaffolds formed by compatible and biodegradable materials are under continuous development in an attempt to mimic the extracellular environment of mammalian cells. We have here explored how novel 3D porous scaffolds constructed by polylactic acid, polycaprolactone or chitosan can be decorated with bacterial inclusion bodies, submicron protein particles formed by releasable functional proteins. A simple dipping-based decoration method tested here specifically favors the penetration of the functional particles deeper than 300μm from the materials' surface. The functionalized surfaces support the intracellular delivery of biologically active proteins to up to more than 80% of the colonizing cells, a process that is slightly influenced by the chemical nature of the scaffold. The combination of 3D soft scaffolds and protein-based sustained release systems (Bioscaffolds) offers promise in the fabrication of bio-inspired hybrid matrices for multifactorial control of cell proliferation in tissue engineering under complex architectonic setting-ups. 23915360 Assessment of attitudes towards methadone maintenance treatment between heroin users at a compulsory detoxification centre and methadone maintenance clinic in Ningbo, China. In China, the Compulsory Detoxification Centres are the main response for people who use illegal drugs. Due to high relapse rates among people released from the Compulsory Detoxification Centres, it is likely that they may seek medical help, including Methadone Maintenance Treatment (MMT) services, at some point. Therefore, better understanding of the attitudes and beliefs of people in the Compulsory Detoxification Centres can help to provide more adequate response to opioid dependence. In total, 329 detained heroin users and 112 active MMT clients were recruited from a local Compulsory Detoxification Centre and MMT clinic, respectively. The survey contained specific questions relating to attitudes and beliefs regarding MMT. Participants at the Compulsory Detoxification Centre and the MMT clinic expressed different opinions, regarding positive and negative attitudes and beliefs towards MMT. In addition, participants from both sites hold certain negative attitudes and beliefs about methadone despite their acknowledgement of the positive effects of MMT. Finally, participants at the Compulsory Detoxification Centre and the MMT clinic reported distinctive treatment preferences, with the former preferring community-based treatment and the latter MMT. Developing targeted education about MMT for people at the Compulsory Detoxification Centres could help improve access to accurate and evidence-based health and treatment information. The study may also help providers understand and adjust services needed for target population in the future. 23838419 Dopaminergic modulation of memory and affective processing in Parkinson depression. Depression is common in Parkinson's disease and is associated with cognitive impairment. Dopaminergic medications are effective in treating the motor symptoms of Parkinson's disease; however, little is known regarding the effects of dopaminergic pharmacotherapy on cognitive function in depressed Parkinson patients. This study examines the neuropsychological effects of dopaminergic pharmacotherapy in Parkinsonian depression. We compared cognitive function in depressed and non-depressed Parkinson patients at two time-points: following overnight withdrawal and after the usual morning regimen of dopaminergic medications. A total of 28 non-demented, right-handed patients with mild to moderate idiopathic Parkinson's disease participated. Ten of these patients were depressed according to DSM IV criteria. Results revealed a statistically significant interaction between depression and medication status on three measures of verbal memory and a facial affect naming task. In all cases, depressed Parkinson's patients performed significantly more poorly while on dopaminergic medication than while off. The opposite pattern emerged for the non-depressed Parkinson's group. The administration of dopaminergic medication to depressed Parkinson patients may carry unintended risks. 23891167 The use of navigation to achieve soft tissue balance in total knee arthroplasty - A randomised clinical study. Achieving soft tissue balance is an operative goal in total knee arthroplasty. This randomised, prospective study compared computer navigation to conventional techniques in achieving soft tissue balance. Forty one consecutive knee arthroplasties were randomised to either a non-navigated or navigated group. In the non-navigated group, balancing was carried out using surgeon judgement. In the navigated group, balancing was carried out using navigation software. In both groups, the navigation software was used as a measuring tool. Balancing of the mediolateral extension gap was superior in the navigation group (p=0.001). No significant difference was found between the two groups in balancing the mediolateral flexion gap or in achieving equal flexion and extension gaps. Computer navigation offered little advantage over experienced surgeon judgement in achieving soft tissue balance in knee replacement. However, the method employed in the navigated group did provide a reproducible and objective assessment of flexion and extension gaps and may therefore benefit surgeons in training. Level I, RCT. 23257216 Dating an impressive Neotropical radiation: Molecular time estimates for the Sigmodontinae (Rodentia) provide insights into its historical biogeography. With about 400 living species and 82 genera, rodents of the subfamily Sigmodontinae comprise one of the most diverse and more broadly distributed Neotropical mammalian clades. There has been much debate on the origin of the lineage or the lineages of sigmodontines that entered South America, the timing of entrance and different aspects of further diversification within South America. The ages of divergence of the main lineages and the crown age of the subfamily were estimated by using sequences of the interphotoreceptor retinoid binding protein and cytochrome b genes for a dense sigmodontine and muroid sampling. Bayesian inference using three fossil calibration points and a relaxed molecular clock estimated a middle Miocene origin for Sigmodontinae (∼12Ma), with most tribes diversifying throughout the Late Miocene (6.9-9.4Ma). These estimates together results of analyses of ancestral area reconstructions suggest a distribution for the most recent common ancestor of Sigmodontinae in Central-South America and a South American distribution for the most recent common ancestor of Oryzomyalia. 23915382 Serum interleukin-22 and vascular endothelial growth factor serve as sensitive biomarkers but not as predictors of therapeutic response to biologics in patients with psoriasis. The T-helper (Th)17 cell plays a crucial role in the pathogenesis of psoriasis, and several biological therapies have shown to be highly efficient in the treatment. However, some patients respond poorly to these therapies and may even develop paradoxical adverse effects. To evaluate the significance of serum immunological factors or circulating competent cells for biomarkers or predictors to biological therapies, we retrospectively analyzed 28 patients with psoriasis (19 psoriasis vulgaris, three pustular psoriasis and six psoriasis arthropathica). The numbers of patients treated with each agents were 16 for ustekinumab, six for adalimumab and six for infliximab. Patients were classified into three types according to the responsiveness: 13 patients were high-responders showing a 75% or more reduction of Psoriasis Area and Severity Index (PASI); 10 patients were moderate-responders showing PASI reduction of less than 75%; and five patients were non-responders showing PASI elevation. During the treatments, serum levels of interleukin (IL)-22 and vascular endothelial growth factor (VEGF) were monitored. At baseline, serum IL-22 levels were significantly higher in the psoriatic patients than the normal controls. Both serum IL-22 and VEGF levels significantly correlated with PASI. After the treatment, the high-responders showed significant decreases in serum IL-22 and VEGF. On the other hand, serum IL-22 levels in the non-responders were elevated. However, the baseline levels of serum IL-22 and VEGF were not significantly different between the three groups. These results suggest that serum IL-22 and VEGF levels serve as sensitive biomarkers but not as predictors of therapeutic response to biologics in patients with psoriasis. 23523661 Baicalein attenuates bleomycin-induced pulmonary fibrosis in rats through inhibition of miR-21. Currently, there is no satisfactory treatment for pulmonary fibrosis, and effective agents urgently need to be developed. The aim of the present study was to investigate the effects of baicalein on bleomycin-induced pulmonary fibrosis, and the novel mechanisms involved in the anti-fibrosis effects. Pulmonary fibrosis was induced by a single intratracheal instillation of 5 mg/kg bleomycin. Two bleomycin-treated groups were orally administered daily with 50 and 100 mg/kg of baicalein from day 1 to 28. The results showed baicalein decreased hydroxyproline content and α-SMA levels and increased lung index. Histopathological examinations demonstrated baicalein could obviously lower the degree of alveolitis and lung fibrosis. The total antioxidant capacity in bleomycin-treated rats with baicalein was also remarkably higher than in those without baicalein. Baicalein remarkably decreased miR-21 levels and inhibited the increased expression of TGF-β1 and p-Smad-2/3 in bleomycin-treated rats. Baicalein can attenuate bleomycin-induced pulmonary fibrosis. The attenuation is partly achieved by improving antioxidant activity, alleviating inflammation, repressing miR-21, and inhibiting TGF-β/Smad signaling. 23961762 Towards Understanding the Influence of Intermolecular Interactions and Molecular Orientation on the Chemical Enhancement of SERS. Implementation of SERS as an analytical technique is limited because the factors that govern the enhancement of individual vibrational modes are not well understood. Although the chemical effect only accounts for up to two orders of magnitude enhancement, it can still have a significant impact on the consistency of chemical spectral signatures. We report on a combined theoretical and experimental study on the benzenethiol on silver and 4-mercaptophenol on silver systems. The primary and unique finding was that for the benzenethiol on silver system, inclusion of interaction between multiple benzenethiol analyte molecules was essential to account for the relative enhancements observed experimentally. An examination of the molecular orbitals showed sharing of electron density across the entire model of multiple benzenethiol molecules mediated by the metal atoms. Addition of multiple 4-mercaptophenol molecules to the theoretical model had little effect on the predicted spectra, and we attribute this to the fact a much larger model is necessary to replicate the networks of hydrogen bonds. Molecular orientation was also found to affect the predicted spectra, and it was found that an upright position improved agreement between theoretical and experimental spectra. An analysis of the vibrational frequency shifts between the normal Raman spectrum of the neat compound and the SERS spectrum also suggest both benzenethiol and 4-mercaptophenol are in an upright position. 22305633 IgM-phosphorylcholine autoantibodies and outcome in acute coronary syndromes. Antibodies against proinflammatory phosphorylcholine (anti-PC) seem to be protective and reduce morbidity. We sought to determine whether low levels of immunoglobulin-M (IgM) autoantibodies against PC add prognostic information in acute coronary syndromes (ACS). IgM anti-PC titers were measured in serum obtained within 24h of admission from 1185 ACS patients (median age 66 years, 30% women). We evaluated major acute cardiovascular events (MACE) and all-cause mortality short--(6 months), intermediate--(18 months) and long--(72 months) terms. Low anti-PC titers were associated with MACE and all-cause mortality at all follow-up times. After adjusting for clinical variables, plasma troponin-I, proBNP and CRP levels, associations remained at all times with MACE, short and intermediate terms also with all-cause mortality. With anti-PC titers below median, adjusted hazard ratios at 18months were for MACE 1.79 (95% confidence interval [CI]: 1.31 to 2.44; p=0.0002) and for all-cause mortality 2.28 (95% CI: 1.32 to 3.92; p=0.003). Anti-PC and plasma CRP were unrelated and added to risk prediction. Serum IgM anti-PC titers provide prognostic information above traditional risk factors in ACS. The ease of measurement and potential therapeutic perspective indicate that it may be a valuable novel biomarker in ACS. 23867527 Environmentally friendly pretreatment of plant biomass by planetary and attrition milling. This study evaluated the use of planetary and attrition milling as pretreatment processes for lignocellulosic biomass using rice straw. Planetary milling reduced the rice straw crystallinity from 0.48 to 0.11. Since the samples could be milled and enzymatically treated using the same media, loss of the biomass due to washing was effectively eliminated. In contrast, conventional sodium hydroxide and soaking in aqueous ammonia (SAA) processes showed a loss of 34.2% and 14.8%, respectively. Furthermore, milling produced significantly lower concentrations of soluble phenolics than the alkali treatments. Using a bioluminescent bioreporter strain that is sensitive to these phenolics, neither of the milled samples elicited a response while the sodium hydroxide and SAA samples led to a 25.8 and 4.7 -fold induction, respectively. Although planetary milling produced more reducing sugars than attrition milling before saccharification, both had similar monosaccharide yields, i.e., 0.38 and 0.34g/g-biomass, respectively, when 40g/l rice straw was treated. 23794171 Abatacept: a review of its use in the management of rheumatoid arthritis. The biological disease-modifying antirheumatic drug abatacept (Orencia) has a novel mechanism of action; its activity is mediated via the selective modulation of T cell co-stimulation. This article reviews the clinical efficacy and tolerability of intravenous and subcutaneous abatacept in patients with rheumatoid arthritis (RA) and intravenous abatacept in patients with juvenile idiopathic arthritis (JIA), as well as summarizing its pharmacological properties. In patients with RA, the beneficial effects of intravenous or subcutaneous abatacept on signs and symptoms, disease activity, the progression of structural damage, physical function and/or health-related quality of life were seen in a number of well-designed trials, including in methotrexate-naive patients with early RA and poor prognostic factors and in patients with established RA and an inadequate response to either methotrexate or anti-tumour necrosis factor therapy. Subcutaneous abatacept plus methotrexate was also noninferior to subcutaneous adalimumab plus methotrexate in patients with active RA who were naive to biological therapy and had an inadequate response to methotrexate. In paediatric patients with JIA, intravenous abatacept improved signs and symptoms and delayed the time to flare. Abatacept was generally well tolerated in RA and JIA and was associated with low rates of immunogenicity. In conclusion, abatacept is an important option for use in the treatment of RA and JIA. 23207250 Combination of phenylpropanoids with 5-fluorouracil as anti-cancer agents against human cervical cancer (HeLa) cell line. Combination therapy is the most effective treatment strategy in cancer to overcome drug toxicity and drug induced resistance. The effect of eight phenylpropanoids in combination with 5-fluorouracil against the cervical cancer cells (HeLa) is reported here. The cytotoxic activity of these phenylpropanoids against HeLa cells is in the order of eugenol>ferulic>cinnamic>caffeic>chlorogenic>p-coumaric>3,4-dimethoxycinnamic>2,4,5-trimethoxycinnamic acids. Eugenol, ferulic and caffeic acids interacted synergistically with the drug, in bringing about a reduction in the amount of the latter. Flow cytometry results indicated that the combination of eugenol and 5-fluorouracil increased the number of cells in the S and G2/M phases when compared to treatment with the individual compounds alone. This indicates that they possess different cell cycle targets and induce apoptosis in the cancer cells. In vitro hemolytic activity of phenylpropanoids on human erythrocytes showed that the compounds possessed minimum amount of hemolytic activity, indicating that they can be used as drugs without causing adverse toxicity. 3D-quantitative structure activity relationship studies indicate the importance of electrostatic region near the substitutions present in the benzene ring and near the double bond of the compounds for anticancer and hemolytic activities, respectively. The models derived had good statistical predictive capability. 23719831 Pten-Null Tumors Cohabiting the Same Lung Display Differential AKT Activation and Sensitivity to Dietary Restriction. PTEN loss is considered a biomarker for activated phosphoinositide 3-kinase (PI3K)/AKT, a pathway frequently mutated in cancer, and was recently shown to confer resistance to dietary restriction. Here, we show that Pten loss is not sufficient to drive AKT activation and resistance to dietary restriction in tumors with low growth factor receptor levels. We describe a murine Pten-null Kras-driven lung cancer model that harbors both dietary restriction-resistant, higher-grade, bronchiolar tumors with high AKT activity, and dietary restriction-sensitive, lower-grade, alveolar tumors with low AKT activity. We find that this phenotype is cell autonomous and that normal bronchiolar cells express higher levels of insulin-like growth factor-I receptor (IGF-IR) and of ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5), an endoplasmic reticulum enzyme known to modulate growth factor receptor levels. Suppression of ENTPD5 is sufficient to decrease IGF-IR levels and sensitize bronchiolar tumor cells to serum in vitro and to dietary restriction in vivo. Furthermore, we find that a significant percentage of human non-small cell lung carcinomas (NSCLC) have low AKT activity despite PTEN loss. 23359564 Functional evaluation of a novel vitreous substitute using polyethylene glycol sols injected into a foldable capsular vitreous body. Polyethylene glycol (PEG) is a short-term (41 days) potential vitreous substitute and is too short for an ideal vitreous substitute. Previously, a foldable capsular vitreous body (FCVB) was designed to mimic vitreous function. The aim of this study is to evaluate whether PEG injected into FCVB can serve as a long-term vitreous substitute. In vitro study, a concentration of 5% (w/v) PEG sols showed natural-like mechanical and optical properties in terms of pH, density, light transmittance, refractive index, interfacial tension, viscosity, rheology, and cytotoxicity. Then in vivo tests, 30 rabbits received standard pars plana vitrectomy, of which 12 eyes were implanted with PEG injected into FCVB, nine eyes were injected with PEG sols alone, and nine others were injected with balance salt solution as control. A clinical evaluation of the anterior segment, fundus, and intraocular pressure was measured pre- and postoperatively up to 180 days, which showed that FCVBs had good retina supporting function, except for a higher incidence of cataracts. Gross pathology, hematoxylin and eosin, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining analysis also showed that FCVBs had good biocompatibility, and that all quadrants of the capsular wall fitted well with the retina. This study demonstrated that PEG injected into FCVB can serve as a long-term vitreous substitute and has potential clinical use. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 101A: 2538-2547, 2013. 23843239 Structural and Functional Integrity of Spermatozoa Is Compromised as a Consequence of Acute Uropathogenic E. coli-Associated Epididymitis. Uropathogenic Escherichia coli (UPEC)-associated epididymitis is commonly diagnosed in outpatient settings. Although the infection can be successfully cleared using antimicrobial medications, forty percent of patients unexplainably show persistent impaired semen parameters even after treatment. Our aim was to investigate whether pathogenic UPEC and its associated virulence factor hemolysin (hlyA) perturb the structural and functional integrity of both the epididymis and sperm, actions which may be responsible for the observed impairment and possibly a reduction of fertilization capabilities. Semen collected from patients diagnosed with E. coli only related epididymitis showed sperm counts were low 14 days post-antimicrobial treatment regardless of hlyA status. At Day 84 following treatment, hlyA production correlated with approximately 4-fold lower sperm concentrations than in men with hlyA-negative strains. In vivo experiments with the hlyA-producing UPEC CFT073 strain in a murine epididymitis model, showed that just three days post-infection structural damage to the epididymis (epithelial damage, leukocyte infiltration and edema formation) were present. This was more severe in UPEC CFT073 compared to non-pathogenic E. coli (NPEC 470) infection. Moreover, pathogenic UPEC strains prematurely activated the acrosome in vivo and in vitro. Raman microspectroscopy revealed UPEC CFT073 undermined sperm integrity by inducing nuclear DNA damage. Consistent with these observations, the in vitro fertilization capability of hlyA-treated mouse sperm was completely abolished, although sperm were motile. These findings provide new insights into understanding the possible processes underlying clinical manifestations of acute epididymitis. 23874444 Increased baseline proinflammatory cytokine production in chronic hepatitis C patients with rapid virological response to peginterferon plus ribavirin. Chronic hepatitis C (CHC) patients achieving rapid virological response (RVR) on PEG-IFN/ribavirin (P/R) therapy have high chance of sustained virological response (SVR). To analyze host immunological factors associated with RVR, viral kinetics, phenotype distribution and Th1/Th2 cytokine production by peripheral blood mononuclear cells (PBMC) were studied prior to and during P/R therapy. TNF-α, IFN-γ, IL-2, IL-6, IL-4 and IL-10 production by PBMC were measured after Toll-like receptor 4 (TLR-4) or phorbol myristate acetate/Ionomycin stimulation in 20 healthy controls and in 50 CHC patients before receiving and during P/R therapy. RVR was achieved by 14, complete early virological response (cEVR) by 19 patients and 17 patients were null-responders (NR). Patients with RVR showed an increased baseline TNF-α and IL-6 production by TLR-4 activated monocytes and increased IFN-γ, decreased IL-4 and IL-10 production by lymphocytes compared to non-RVR patients. SVR was also associated with increased baseline TNF-α production and decreased IL-10 levels compared to patients who did not achieve SVR. Baseline IL-2 production was higher in cEVR compared to NR patients. Antiviral treatment increased TNF-α, IL-6 production by monocytes and IFN-γ secretion by lymphocytes and decreased IL-4 and IL-10 production by lymphocytes in cEVR compared to NR patients. RVR was associated with increased baseline proinflammatory cytokine production by TLR-4 stimulated monocytes and by activated lymphocytes. In null-responders and in patients who did not achieve SVR both TLR-4 sensing function and proinflammatory cytokine production were impaired, suggesting that modulation of TLR activity and controlled induction of inflammatory cytokine production may provide further therapeutic strategy for CHC patients non-responding to P/R treatment. 23786603 The effect of alternating and biphasic currents on humans' wound healing: a literature review. Although different types of currents, including bidirectional currents, have been used to promote healing, there is neither a summary about their effects nor consensus on best parameters to be used. The aim of this article is to provide an overview of current evidence on the effectiveness of bidirectional electrical stimulation on wound healing in accordance with the parameters used. Relevant articles were selected following a search of Medline, Cochrane, Embase, CINAHL, and PEDro for English, Spanish, Portuguese, Italian, or French articles published between 1980 and 2011. Ten trials and four case-series were found that deal with pressure ulcers, diabetic ulcers, venous ulcers, skin flaps, and amputation. Eight trials were of low-quality. Five of ten controlled trials found a statistically significant difference on wound healing, and another four trials found positive trends. Both of the two skin flap trials, one of two diabetic trials, and two of five pressure ulcer trials found a significant difference in bidirectional stimulated groups. Both TENS and NMES types of currents were used, but many parameters were not specified. In general, bidirectional currents appear to increase wound healing rates and reduce size of wounds, above all in skin flaps. However, there is a lack of well-designed studies on biphasic and alternating stimulation, and there is a need for improvement in description of parameters and in uniformity of nomenclature. 23907187 Intra-abdominal inverted umblical cord in gastroschisis: a unique ultrasound finding. A relatively new surgical technique allows for sutureless closure of a gastroschisis defect. Immediately after birth, a long umbilical cord stump is temporarily inverted into the abdominal cavity and later retracted and used to close the abdominal wall defect. Knowledge of this entity is important since the inverted umbilical cord simulates an intra-abdominal mass on cross-sectional imaging. While this procedure is well described in the surgical literature, the imaging features of inverted umbilical cord have yet to be reported. The case presented here highlights the sonographic imaging findings of the umbilical cord during the intestinal decompression phase of sutureless repair of gastroschisis. 23769125 Prediction of the distribution coefficients of metals in Amazonian soils. Soil pollution with metals alters ecosystem structure and function, as well as poses risks to human health. In this study the distribution coefficients (Kd) were determined for Cd, Co, Cr, Cu, Hg, Ni, Pb, and Zn in 21 soils from eastern Amazonian via Freundlich adsorption isotherm. The stepwise multiple regression models were used to estimate the Kd values through the combined effect of soil attributes. Multiple regressions showed that Kd values were strongly correlated with the soil pH, CEC and Fe oxide contents. A close association between Kd of metals and soil properties was observed using three principal components (PCA) and Pearson's correlation. In the principal components analysis showed that concentration of metals was related to pH, Fe and Mn oxides contents, which in combination explained 90 percent of the variation. This probably happens because of greater affinity of those metals to Fe and Mn oxides formed predominantly under tropical conditions. 23875942 Surface Roughness of Acrylic and Silicone-Based Soft Liners: In Vivo Study in a Rat Model. The aim of this in vivo animal study was to investigate changes in the surface roughness of soft liners over time. Forty adult Wistar rats (Rattus norvergicus albinus) were fitted with acrylic custom-made palatal plates relined by dynamic impressions and tested with the following soft liners: Dentuflex (DF), Trusoft (TS), Dentusoft (DS), and Ufi Gel P (UG). Half of the animals for each tested material had the plates fitted during the material reline procedure. Their surface roughness was read immediately (IRa group, n = 5). The other half used the palatal plates for 14 days before roughness readings were performed (FRa group, n = 5). The surface roughness (Ra) of the inner surface from the relined dentures was recorded using a Surftest SJ-401 with eight readings per specimen, and mean values were obtained. Data (μm) were analyzed by two-way ANOVA and Tukey's test (α = 0.05). IRa means (2.92 ± 0.87 μm) and FRa means (3.35 ± 0.65 μm) were significantly different (p = 0.016). UG showed a lower (p = 0.01) Ra mean (2.1 ± 0.52 μm) than DF (3.94 ± 0.81 μm), TS (4.12 ± 0.64 μm), and DS (3.27 ± 0.64 μm). Ufi Gel P showed the smoothest surface among the materials evaluated. The period of use resulted in changes in the surface roughness of the materials tested. 23876717 Fungal disease following contaminated steroid injections: exserohilum is ready for its close-up. This Commentary highlights the article by Ritter et al. that reported the pathology associated with the recent fungal outbreak associated with contaminated methylprednisolone acetate injections. 23832629 CHARMM36 all-atom additive protein force field: Validation based on comparison to NMR data. Protein structure and dynamics can be characterized on the atomistic level with both nuclear magnetic resonance (NMR) experiments and molecular dynamics (MD) simulations. Here, we quantify the ability of the recently presented CHARMM36 (C36) force field (FF) to reproduce various NMR observables using MD simulations. The studied NMR properties include backbone scalar couplings across hydrogen bonds, residual dipolar couplings (RDCs) and relaxation order parameter, as well as scalar couplings, RDCs, and order parameters for side-chain amino- and methyl-containing groups. It is shown that the C36 FF leads to better correlation with experimental data compared to the CHARMM22/CMAP FF and suggest using C36 in protein simulations. Although both CHARMM FFs contains the same nonbond parameters, our results show how the changes in the internal parameters associated with the peptide backbone via CMAP and the χ1 and χ2 dihedral parameters leads to improved treatment of the analyzed nonbond interactions. This highlights the importance of proper treatment of the internal covalent components in modeling nonbond interactions with molecular mechanics FFs. © 2013 Wiley Periodicals, Inc. 23796576 Psychrophilic anaerobic digestion of lignocellulosic biomass: A characterization study. Psychrophilic (20°C) specific methane (CH4) yield from cellulose (C), xylan (X), cellulose/xylan mixture (CX), cow feces (CF), and wheat straw (WS) achieved (Nl CH4kg(-1)VS) of 338.5±14.3 (C), 310.5±3.4 (X), 305.5±29.6 (CX mixture), and 235.3±22.7 (WS) during 56days, and 237.6±17.7 (CF) during 70days. These yields corresponded to COD recovery of 73.3±3.1% (C)=69.1±0.76% (X)=67.3±5.8% (CX mixture)>52.9±2.6% (CF)>46.5±2.7% (WS). Cellulose-fed culture had a lower and statistically different initial CH4 production rate from those calculated for cultures fed X, CX mixture, CF and WS. It seemed that the presence of hemicellulose in complex substrate such as wheat straw and cow feces supported the higher initial CH4 rate compared to cellulose. Biomethanation of the pure and complex lignocellulosic substrates tested is feasible at psychrophilic conditions given that a well-adapted inoculum is used; however, hydrolysis was the rate limiting step. 23861836 Decreasing fertility rate correlates with the chronological increase and geographical variation in incidence of kawasaki disease in Japan. Kawasaki disease (KD) is a common cause of acquired paediatric heart disease in developed countries. KD was first identified in the 1960s in Japan, and has been steadily increasing since it was first reported. The aetiology of KD has not been defined, but is assumed to be infection-related. The present study sought to identify the factor(s) that mediate the geographical variation and chronological increase of KD in Japan. Based upon data reported between 1979 and 2010 from all 47 prefectures in Japan, the incidence and mean patient age at the onset of KD were estimated. Using spatial and time-series analyses, incidence and mean age were regressed against climatic/socioeconomic variables. Both incidence and mean age of KD were inversely correlated with the total fertility rate (TFR; i.e., the number of children that would be born to one woman). The extrapolation of a time-series regressive model suggested that KD emerged in the 1960s because of a dramatic decrease in TFR in the 1940s through the 1950s. Mean patient age is an inverse surrogate for the hazard of contracting the aetiologic agent. Therefore, the observed negative correlation between mean patient age and TFR suggests that a higher TFR is associated with KD transmission. This relationship may be because a higher TFR facilitates sibling-to-sibling transmission. Additionally, the observed inverse correlation between incidence and TFR implies a paradoxical "negative" correlation between the incidence and the hazard of contracting the aetiologic agent. It was hypothesized that a decreasing TFR resulted in a reduced hazard of contracting the agent for KD, thereby increasing KD incidence. 23165754 EphB4 enhances the process of endochondral ossification and inhibits remodeling during bone fracture repair. Previous reports have identified a role for the tyrosine kinase receptor EphB4 and its ligand, ephrinB2, as potential mediators of both bone formation by osteoblasts and bone resorption by osteoclasts. In the present study, we examined the role of EphB4 during bone repair after traumatic injury. We performed femoral fractures with internal fixation in transgenic mice that overexpress EphB4 under the collagen type 1 promoter (Col1-EphB4) and investigated the bone repair process up to 12 weeks postfracture. The data indicated that Col1-EphB4 mice exhibited stiffer and stronger bones after fracture compared with wild-type mice. The fractured bones of Col1-EphB4 transgenic mice displayed significantly greater tissue and bone volume 2 weeks postfracture compared with that of wild-type mice. These findings correlated with increased chondrogenesis and mineral formation within the callus site at 2 weeks postfracture, as demonstrated by increased safranin O and von Kossa staining, respectively. Interestingly, Col1-EphB4 mice were found to possess significantly greater numbers of clonogenic mesenchymal stromal progenitor cells (CFU-F), with an increased capacity to form mineralized nodules in vitro under osteogenic conditions, when compared with those of the wild-type control mice. Furthermore, Col1-EphB4 mice had significantly lower numbers of TRAP-positive multinucleated osteoclasts within the callus site. Taken together, these observations suggest that EphB4 promotes endochondral ossification while inhibiting osteoclast development during callus formation and may represent a novel drug target for the repair of fractured bones. 23535526 Thoracic aortic aneurysm with aortic pseudocoarctation involving the left subclavian artery. A 39-year-old man with a thoracic aortic aneurysm and pseudocoarctation underwent graft replacement of the distal arch. The left subclavian artery, which rose just after the aneurysm, was also reconstructed at surgery. The aneurysmal wall was extremely thin, and the adventitia and a small amount of medial tissue were found on histologic examination. Thus, surgical treatment was recommended due to risk of rupture. Furthermore, because aneurysms involved the cervical branch, separate reconstruction was also performed. Endovascular intervention is not appropriate for this group of patients because of the complex kinking of the aorta and the extremely thin aneurysmal wall. 23562649 Asymptomatic dogs are highly competent to transmit Leishmania (Leishmania) infantum chagasi to the natural vector. We evaluated the ability of dogs naturally infected with Leishmania (Leishmania) infantum chagasi to transfer the parasite to the vector and the factors associated with transmission. Thirty-eight infected dogs were confirmed to be infected by direct observation of Leishmania in lymph node smears. Dogs were grouped according to external clinical signs and laboratory data into symptomatic (n=24) and asymptomatic (n=14) animals. All dogs were sedated and submitted to xenodiagnosis with F1-laboratory-reared Lutzomyia longipalpis. After blood digestion, sand flies were dissected and examined for the presence of promastigotes. Following canine euthanasia, fragments of skin, lymph nodes, and spleen were collected and processed using immunohistochemistry to evaluate tissue parasitism. Specific antibodies were detected using an enzyme-linked immunosorbent assay. Antibody levels were found to be higher in symptomatic dogs compared to asymptomatic dogs (p=0.0396). Both groups presented amastigotes in lymph nodes, while skin parasitism was observed in only 58.3% of symptomatic and in 35.7% of asymptomatic dogs. Parasites were visualized in the spleens of 66.7% and 71.4% of symptomatic and asymptomatic dogs, respectively. Parasite load varied from mild to intense, and was not significantly different between groups. All asymptomatic dogs except for one (93%) were competent to transmit Leishmania to the vector, including eight (61.5%) without skin parasitism. Sixteen symptomatic animals (67%) infected sand flies; six (37.5%) showed no amastigotes in the skin. Skin parasitism was not crucial for the ability to infect Lutzomyia longipalpis but the presence of Leishmania in lymph nodes was significantly related to a positive xenodiagnosis. Additionally, a higher proportion of infected vectors that fed on asymptomatic dogs was observed (p=0.0494). Clinical severity was inversely correlated with the infection rate of sand flies (p=0.027) and was directly correlated with antibody levels (p=0.0379). Age and gender did not influence the transmissibility. Our data show that asymptomatic dogs are highly infective and competent for establishing sand fly infection, indicating their role in maintaining L. (L.) infantum chagasi cycle as well as their involvement in VL spreading in endemic areas. 23595884 Glucocorticoid receptor is required for foetal heart maturation. Glucocorticoids are vital for the structural and functional maturation of foetal organs, yet excessive foetal exposure is detrimental to adult cardiovascular health. To elucidate the role of glucocorticoid signalling in late-gestation cardiovascular maturation, we have generated mice with conditional disruption of glucocorticoid receptor (GR) in cardiomyocytes and vascular smooth muscle cells using smooth muscle protein 22-driven Cre recombinase (SMGRKO mice) and compared them with mice with global deficiency in GR (GR(-/-)). Echocardiography shows impaired heart function in both SMGRKO and GR(-/-) mice at embryonic day (E)17.5, associated with generalized oedema. Cardiac ultrastructure is markedly disrupted in both SMGRKO and GR(-/-) mice at E17.5, with short, disorganized myofibrils and cardiomyocytes that fail to align in the compact myocardium. Failure to induce critical genes involved in contractile function, calcium handling and energy metabolism underpins this common phenotype. However, although hearts of GR(-/-) mice are smaller, with 22% reduced ventricular volume at E17.5, SMGRKO hearts are normally sized. Moreover, while levels of mRNA encoding atrial natriuretic peptide are reduced in E17.5 GR(-/-) hearts, they are normal in foetal SMGRKO hearts. These data demonstrate that structural, functional and biochemical maturation of the foetal heart is dependent on glucocorticoid signalling within cardiomyocytes and vascular smooth muscle, though some aspects of heart maturation (size, ANP expression) are independent of GR at these key sites. 23666953 Phototherapy device effectiveness in Nigeria: irradiance assessment and potential for improvement. This study investigated the effectiveness of simple-to-implement adjustments of phototherapy devices on irradiance levels in a cross-section of Nigerian hospitals. A total of 76 phototherapy devices were evaluated in 16 hospitals while adjustments were implemented for a subset of 25 devices for which consent was obtained. The mean irradiance level was 7.6 ± 5.9 µW/cm(2)/nm for all devices prior to adjustments. The average irradiance level improved from 9.0 µW/cm(2)/nm to 27.3 µW/cm(2)/nm for the adjusted group (n = 25) compared with 6.8 ± 5.4 µW/cm(2)/nm for the unadjusted group (n = 51). Simple, inexpensive adjustments to phototherapy devices with sub-optimal irradiance levels can significantly improve their effectiveness to acceptable international standards and should be widely promoted in resource-constrained settings. 23909496 Factors limiting organ donation in Baden-Württemberg. In the German state of Baden-Wurttemberg, the number of deceased donors from whom organs have been recovered has been decreasing over the past several years. We questioned whether changing donor age and/or cause of death (COD) were contributing to this trend. All potential donors who reported to our regional Baden-Württemberg organ procurement organization were reviewed (2006-2010, n = 1771). Changes in age distribution and COD were analyzed, factors we thought might have affected the conversion from potential to successful organ donation. Between 2006 and 2010, the annual number of reported cases with subarachnoid hemorrhage (SAH) as the COD decreased from 117 to 65, while the number of deaths from other reasons increased from 264 to 294. Conversion rates were higher in the SAH group (56%) compared with the other reasons group (37%). Mortality rates are changing in certain devastating brain injuries. This, and other factors, may contribute adversely to organ donation rates. 23564616 Determination of degree of methylation of food pectins by chromatography. In Florida, 90% of citrus is processed into juice, leaving large amounts of peel waste that could be processed into food ingredients such as pectins for other applications. Pectins of low degree of methylation (DM < 50) have important functional properties for use in foods and pharmaceuticals. Thus determination of DM is important, but DM analyses are difficult to perform and assays can have interference due to the presence of salts or neutral sugars. A chromatography method has been developed for determination of DM of food pectin using alkaline hydrolysis followed by pectin digestion with a commercial pectinase. Analysis was performed by ion exclusion chromatography (IEC) to obtain methanol (MeOH) concentrations and by anion exchange chromatography (AEC) to obtain galacturonic acid (GalA) concentrations. Data were compared with values obtained using other DM analysis procedures. For example, a 55-75 DM pectin assayed as 55.5, 59.6, 60.1 and 57.0 DM by IEC, AEC, colorimetric and conductivity detection methods respectively. The chromatography procedure described in this paper provides an alternative method for determination of DM of food pectins for accurate and efficient analysis when confronted with limited quantities or large numbers of samples. 23884840 The clinical and CT imaging features of metanephric adenoma. Patients with metanephric adenoma have a good prognosis after undergoing total nephrectomy or local resection with kidney preservation. Accurate diagnosing is important for guiding clinical treatment. Only few previous case reports have been found focusing on the imaging findings of metanephric adenoma. To evaluate the multislice computed tomography (MSCT) imaging characteristics of metanephric adenoma. The imaging findings in eight patients with metanephric adenoma were studied retrospectively. MSCT was undertaken to investigate tumor location, size, attenuation, cystic or solid appearance, calcification, capsule sign, and enhancement pattern. Tumors (mean diameter, 3.3 ± 1.0 cm) were solitary (8/8), solid (7/8) with cystic components (2/8), no calcifications (7/8), had a poorly-defined margin (8/8), were centered in the renal medulla (7/8), compressed the renal pelvis (3/8), and none had retroperitoneal lymph node metastasis. The attenuation of metanephric adenoma tumors was less or equal compared to the renal cortex or medulla on unenhanced CT (30.6 ± 2.6 vs. 36.3 ± 4.6 vs. 33.2 ± 3.9, P > 0.05), while tumor enhancement after administration of an contrast agent was lower than that of normal renal cortex and medulla during all phases (P < 0.05). Metanephric adenoma tends to be a solitary, poorly defined margin, isodense or hypodense mass arising from the renal medulla with enhancement less than the cortex and medulla during all phases. 23928544 Red Cell Distribution Width Is Independently Related to Endothelial Dysfunction in Patients With Chronic Kidney Disease. Red cell distribution width (RDW) is a measure of erythrocyte size variability and has been shown as an independent predictor of mortality. The aim of this article was to evaluate the association of RDW with endothelial dysfunction in patients with chronic kidney disease (CKD). Patients with 1 to 5 stages of CKD were included in the study. Endothelial function was assessed with flow-mediated dilatation (FMD). Estimated glomerular filtration rate (eGFR) and carotid intima media thickness (CIMT) were determined. Clinicodemographic characteristics, biochemical values, complete blood counts, ferritin, C-reactive protein (CRP) and cholesterol levels were recorded. Spearman's correlation was used to determine correlates of RDW. Multivariate linear regression model was used to assess independent associates of FMD. Overall, 367 patients with CKD 1 to 5 were included in the study. RDW showed a significant increase from stage 1 to stage 5 CKD. Median RDW was 13.5. Patients with RDW values higher than median had significantly lower hemoglobin, eGFR and FMD values and higher CIMT and CRP values compared with patients who had RDW values below median. RDW showed a significant positive correlation with the presence of diabetes mellitus, CIMT and CRP, whereas a significant negative correlation with eGFR, ferritin and FMD. Multivariate analysis showed independent predictors of FMD as RDW, presence of diabetes, hemoglobin, eGFR, CRP, and serum albumin. Multivariate regression model revealed RDW as a significant predictor of FMD independent of major confounding factors, such as diabetes, inflammation, anemia and kidney function in CKD. 23881366 Novel sheathless CE-MS interface as an original and powerful infusion platform for nanoESI study: from intact proteins to high molecular mass noncovalent complexes. Development of nano-electrospray (nanoESI) sources allowed to increase significantly the sensitivity which is often lacking when studying biological noncovalent assemblies. However, the flow rate used to infuse the sample into the mass spectrometer cannot be precisely controlled with nanoESI and the robustness of the system could represent an issue. In this study, we have used a sheathless capillary electrophoresis-mass spectrometry (CESI) prototype as a nanoESI infusion device. The hydrodynamic mobilization of the capillary content was characterized and the ability of the system to generate a stable electrospray under controlled flow rate conditions ranging from 4 up to 900 nL/min was demonstrated. The effect of the infusing flow rate on the detection of an intact model protein analyzed under native conditions was investigated. Results demonstrated a significant increase in sensitivity of 46-fold and a signal-to-noise ratio improvement of nearly 5-fold when using an infusing flow rate from 456.9 down to 13.7 nL/min. The CESI prototype was further used to detect successfully the β ring homodimer in its native conformation. Obtained results were compared with those achieved with conventional ESI. Intensity signals were increased by a factor of 5, while sample consumption decreased 80 times. β ring complexed with the P14 peptide was also studied. Finally, the CESI interface was used to observe the quaternary structure of native hemocyanins from Carcinus maenas crabs; this high molecular complex coexisting under various degrees of complexation and resulting in masses ranging from 445 kDa to 1.34 MDa. 23890368 Sub-Tenon injection of 2% lidocaine prevents intra-operative floppy iris syndrome (IFIS) in male patients taking oral α-adrenergic antagonists. Purpose:  To compare 2% sub-Tenon and 1% intra-cameral lidocaine for cataract surgery in relation to the incidence and severity of IFIS. Prospective randomized clinical study. Methods:  From 81 eligible, we included 71 men aged from 59 to 90 years (mean 76.5 ± 6.8) undergoing routine cataract surgery and taking oral α-adrenergic antagonists, for urological reasons, for more than 1 year. Following randomization 34 men, aged from 62 to 90 years (mean 77.4 ± 8.1) received sub-Tenon injection of 2.5 ml of 2% lidocaine and the remaining 37 men aged from 59 to 89 years (mean 75.2 ± 7.2) received 1% preservative free intra-cameral lidocaine. Outcome measures were the incidence of IFIS, severity of intra-operative pupillary constriction and iris prolapse. Results:  Intra-operative floppy iris syndrome (IFIS) was noted in 3 of 34 patients (8.8%) receiving sub-Tenon lidocaine and in 18 of 37 patients (48.6%) receiving intra-cameral lidocaine (p = 0.00). Severe IFIS was observed only in 3 of 37 patients (8.1%) receiving intra-cameral lidocaine. Pupil diameter at the end of surgery was 4.37 ± 1.07 mm in the sub-Tenon lidocaine group and 4.02 ± 1.06 mm in the intra-cameral lidocaine group (p = 0.00). Iris prolapse was noted in two cases in the sub-Tenon lidocaine group and in 10 cases in the intra-cameral lidocaine group (p = 0.00). Twenty-five patients were receiving tamsulosin. The incidence of IFIS in tamsulosin subgroup was 76.9% (10 of 13 patients) in the intra-cameral lidocaine group and 16.6% (2 of 12 patients) in the sub-Tenon lidocaine group (p = 0.00). Conclusion:  Sub-Tenon lidocaine reduces significantly the incidence of IFIS in patients taking oral α-adrenergic inhibitors as compared with intra-cameral lidocaine. 23895310 Activated platelets correlate with mobilization of naïve CD34(+) cells and generation of CD34(+) /KDR(+) cells in the circulation. A meta-regression analysis. Bone marrow-derived circulating CD34(+) progenitor cells participate in remodeling and repair of the vasculature. Coexpression of the kinase-insert domain-containing receptor (KDR) has been proposed to identify the regenerative capacity. Recently, we provided evidence that the major fraction of circulating CD34(+) /KDR(+) cells is not mobilized from bone marrow, but is generated at sites of vascular injury through interaction with platelets. To determine the relationship between platelet activation, the recruitment of naïve CD34(+) cells and the generation of CD34(+) /KDR(+) progenitor cells in a broad range of (patho)physiologic conditions, a detailed meta-regression analysis was conducted. Twenty-eight conditions were found in which the numbers of CD34(+) and/or CD34(+) /KDR(+) cells and the levels of soluble P-selectin, as a marker for in vivo platelet activation, were documented. To combine heterogeneous data from 214 selected articles, results were standardized to a uniform scale by calculating standardized mean differences (SMDs) obtained from patient and control cohorts. Subsequently, a random-effects meta-regression analysis was performed on pooled SMDs. Our systemic survey supports a model in which activated platelets are a determinant for mobilization of CD34(+) cells from the bone marrow and the generation of CD34(+) /KDR(+) cells in the circulation. 23921660 Efficient identification of Y chromosome sequences in the human and Drosophila genomes. Notwithstanding their biological importance Y chromosomes remain poorly known in most species. A major obstacle to their study is the identification of Y chromosome sequences: due to its high content of repetitive DNA, in most genome projects the Y chromosome sequence is fragmented into a large number of small, unmapped scaffolds. Identification of Y-linked genes among these fragments has yielded important insights about the origin and evolution of Y chromosomes, but the process is labor intensive, restricting studies to a small number of species. Apart from these fragmentary assemblies, in a few mammalian species the euchromatic sequence of the Y is essentially complete, owing to painstaking BAC mapping and sequencing. Here we use female short read sequencing and k-mer comparison to identify Y-linked sequences in two very different genomes, Drosophila virilis and human. Using this method, essentially all D. virilis scaffolds were unambiguously classified as Y-linked or not Y-linked. We found 800 new scaffolds (totaling 8.5 Mbp), and four new genes in the Y chromosome of D. virilis, including JYalpha, a gene involved in hybrid male sterility. Our results also strongly support the preponderance of gene gains over gene losses in the evolution of the Drosophila Y. In the intensively studied human genome, used here as a positive control, we recovered all previously known genes or gene families, plus a small amount (283 kb) of new, unfinished sequence. Despite some ambiguity caused by misassembled segmental duplications, the vast majority of the human sequence could be reliably identified as Y or not Y-linked. Hence this method works in large and complex genomes and can be applied to any species with sex-chromosomes. 23954561 Unfolded protein response (UPR) signaling regulates arsenic trioxide-mediated macrophage innate immune function disruption. Arsenic exposure is known to disrupt innate immune functions in humans and in experimental animals. In this study, we provide a mechanism by which arsenic trioxide (ATO) disrupts macrophage functions. ATO treatment of murine macrophage cells diminished internalization of FITC-labeled latex beads, impaired clearance of phagocytosed fluorescent bacteria and reduced secretion of pro-inflammatory cytokines. These impairments in macrophage functions are associated with ATO-induced unfolded protein response (UPR) signaling pathway characterized by the enhancement in proteins such as GRP78, p-PERK, p-eIF2α, ATF4 and CHOP. The expression of these proteins is altered both at transcriptional and translational levels. Pretreatment with chemical chaperon, 4-phenylbutyric acid (PBA) attenuated the ATO-induced activation in UPR signaling and afforded protection against ATO-induced disruption of macrophage functions. This treatment also reduced ATO-mediated reactive oxygen species (ROS) generation. Interestingly, treatment with antioxidant N-acetylcysteine (NAC) prior to ATO exposure, not only reduced ROS production and UPR signaling but also improved macrophage functions. These data demonstrate that UPR signaling and ROS generation are interdependent and are involved in the arsenic-induced pathobiology of macrophage. These data also provide a novel strategy to block the ATO-dependent impairment in innate immune responses. 23918415 N-Substituted 1,2-Dihydroquinolines as Anticancer Agents: Electronic Control of Redox Stability, Assessment of Antiproliferative Effects, and Mechanistic Insights. Redox chemotherapy: Antiproliferative activities of a series of N-substituted 1,2-dihydroquinolines capable of causing redox imbalance in cancer cells are presented. Detailed studies showed that these derivatives arrest the cell cycle in the G2 /M phase and induce apoptosis through an intrinsic pathway characterized by loss of mitochondrial membrane potential, DNA fragmentation, cytochrome c release, and activation of caspases 9 and 3. 23692396 Long-term results of intratympanic prednisolone injection in patients with idiopathic sudden sensorineural hearing loss. Abstract Conclusion: The results demonstrate the stability of the efficacy over time of the intratympanic prednisolone protocol and they suggest that the spontaneous recovery does not significantly influence the long-term evaluation of intratympanic therapy. A 10-day follow-up after 3 days of intratympanic prednisolone administration can be considered a sufficient period to evaluate the effectiveness of the undertaken therapy. Objective: To assess the stability of the efficacy over time of intratympanic steroid therapy for patients with idiopathic sudden sensorineural hearing loss. Methods: A total of 122 patients received an intratympanic steroid injection of prednisolone daily for 3 days. Audiograms were performed before therapy and at 10 days and 1 year after therapy. Successful recovery was defined as complete and partial recovery using Siegel's criteria and complete and marked recovery following Furuhashi's criteria. Results: The comparison of audiometric data at study entry, at 10 days, and at 1 year after the treatment showed a statistically significant improvement of the mean pure tone audiometry. The evaluation of the hearing outcomes demonstrated a statistically significant improvement, with similar success rates when evaluated 10 days and 1 year after the treatment. Comparing the hearing outcomes at 1 year with the results at 10 days, no significant difference was detected between these two time points. 23333897 Activation of Rac1 GTPase by nanoparticulate structures in human macrophages. Inflammatory activation of alveolar macrophages by ambient particles can be facilitated via Toll-like receptors (TLR). The action of TLR agonists and antagonists has been reported to depend on the formation of nanoparticulate structures. Aim of the present study was to identify the signaling pathways induced by nanoparticulate structures in human macrophages, which might be critical for inflammatory cell activation. METHODS: Studies were performed in primary human alveolar macrophages or in differentiated THP-1 macrophages. Silica nanoparticles were prepared by Stöber synthesis and characterized by dynamic light scattering and scanning electron microscopy. Mycobacterial DNA was isolated from Mycobacterium bovis BCG, and nanoparticle formation was assessed by atomic force microscopy and dynamic light scattering. Actin polymerization was measured by phalloidin-TRITC staining, and cell activation was determined by reverse transcription quantitative PCR analysis, L929 cytotoxicity assay (cytokine induction), and pull-down assays (Rho GTPases). RESULTS: In contrast to immune stimulatory sequence ISS 1018, BCG DNA spontaneously formed nanoparticulate structures and induced actin polymerization as did synthetic silica nanoparticles. Co-incubation with silica nanoparticles amplified the responsiveness of macrophages toward the TLR9 ligand ISS 1018. The activation of Rac1 was induced by silica nanoparticles as well as BCG DNA and is suggested as the critical signaling event inducing both cytoskeleton changes as well as inflammatory cell activation. CONCLUSION: Nanoparticles can induce signaling pathways, which amplify an inflammatory response in macrophages. 23921318 Bacteremia in patients receiving TNF-alpha antagonists - A prospective multicenter study. TNF-alpha antagonists have changed the outcome of various chronic inflammatory diseases. Their use has spread widely and many patients receive those treatments for years. Previous reports found that the use of TNF-alpha antagonists may be associated with an increased risk of serious bacterial infections. We report 47 prospective bacteremia cases from the RATIO registry. A national prospective study was conducted in France between 2004 and 2007 to collect severe bacterial infections in patients receiving TNF-alpha antagonists. All reported cases of bacteremia were validated by an expert committee. Forty-seven bacteremic episodes were reported. Staphylococcus aureus represented the most frequent causative pathogen (40%) and was mostly associated with bones and/or joints infections (68%) and with a worse outcome compared to that observed with other bacterial pathogens. Patients receiving TNF-alpha antagonists may develop bacteremia and S. aureus has to be included in the spectrum of the initial empiric antimicrobial therapy. 23584606 Factors Associated With Treatment Initiation for Psychiatric and Substance Use Disorders Among Persons With HIV. OBJECTIVE Prior studies of individuals with HIV infection have found that accessing psychiatric and substance abuse treatment when needed can improve health and prolong life, yet little is known about factors associated with treatment initiation. METHODS In a retrospective cohort design including individuals with HIV infection (≥14 years old) in an integrated health care system in Northern California, this study included 822 patients with a major psychiatric diagnosis and 1,624 with a substance use disorder diagnosis. Data were extracted from a regional HIV registry and computerized databases. RESULTS Twenty-four percent (N=198) of study patients with psychiatric diagnoses and 15% (N=245) with substance abuse or dependence received one or more specialty care visits within 12 months of diagnosis. Among patients with a psychiatric diagnosis, significant predictors of visiting a psychiatry clinic included not having an AIDS diagnosis at baseline or before the study (p=.049), having a diagnosis of major depression (p=.013), having a diagnosis of bipolar disorder (p<.001), and receiving a psychiatric diagnosis in 1996 versus later years of the study (p<.01). Among patients with a substance use disorder, significant predictors of initiating substance abuse treatment included age <30 (p=.015) and being in the HIV transmission risk group of injection drug use (p<.001). CONCLUSIONS Clinical, diagnostic, and demographic factors were associated with specialty care treatment initiation in this sample of individuals with HIV infection and substance use or psychiatric disorders. Developing strategies to enhance treatment initiation has the potential to improve outcomes for individuals with HIV infection. 23591790 Fev regulates hematopoietic stem cell development via ERK signaling. Reprogramming of somatic cells to desired cell types holds great promise in regenerative medicine. However, production of transplantable hematopoietic stem cells (HSCs) in vitro by defined factors has not yet been achieved. Therefore, it is critical to fully understand the molecular mechanisms of HSC development in vivo. Here, we show that Fev, an ETS transcription factor, is a pivotal regulator of HSC development in vertebrates. In fev-deficient zebrafish embryos, the first definitive HSC population was compromised and fewer T cells were found in the thymus. Genetic and chemical analyses support a mechanism whereby Fev regulates HSC through direct regulation of ERK signaling. Blastula transplant assay demonstrates that Fev regulation of HSC development is cell autonomous. Experiments performed with purified cord blood show that fev is expressed and functions in primitive HSCs in humans, indicating its conserved role in higher vertebrates. Our data indicate that Fev-ERK signaling is essential for hemogenic endothelium-based HSC development. 23756911 Perioperative analgesia in pediatric surgery. Poor pain management has continued to be a problem after pediatric surgery. This review examines the current situation and recent advances in the area. Nonopioids such as paracetamol and NSAIDs play an increasing role as components of multimodal analgesia in children. However, studies on the safety and efficacy of many adjuvants in pediatrics are still lacking. The use of opioids is influenced understandably by safety concerns about respiratory depression, but data on its incidence are poor. The role of regional techniques in the treatment of pain after pediatric surgery is growing in line with the developments in adults; the emphasis here is more on peripheral techniques too. The concept of multimodal analgesia including the use of regional analgesic techniques is governing the current developments and discussions in the area of pediatric postoperative analgesia. 23035930 Revisions of the Fish Invasiveness Screening Kit (FISK) for its Application in Warmer Climatic Zones, with Particular Reference to Peninsular Florida. The initial version (v1) of the Fish Invasiveness Scoring Kit (FISK) was adapted from the Weed Risk Assessment of Pheloung, Williams, and Halloy to assess the potential invasiveness of nonnative freshwater fishes in the United Kingdom. Published applications of FISK v1 have been primarily in temperate-zone countries (Belgium, Belarus, and Japan), so the specificity of this screening tool to that climatic zone was not noted until attempts were made to apply it in peninsular Florida. To remedy this shortcoming, the questions and guidance notes of FISK v1 were reviewed and revised to improve clarity and extend its applicability to broader climatic regions, resulting in changes to 36 of the 49 questions. In addition, upgrades were made to the software architecture of FISK to improve overall computational speed as well as graphical user interface flexibility and friendliness. We demonstrate the process of screening a fish species using FISK v2 in a realistic management scenario by assessing the Barcoo grunter Scortum barcoo (Terapontidae), a species whose management concerns are related to its potential use for aquaponics in Florida. The FISK v2 screening of Barcoo grunter placed the species into the lower range of medium risk (score = 5), suggesting it is a permissible species for use in Florida under current nonnative species regulations. Screening of the Barcoo grunter illustrates the usefulness of FISK v2 as a proactive tool serving to inform risk management decisions, but the low level of confidence associated with the assessment highlighted a dearth of critical information on this species. 23945188 Acceptability and impact on anthropometry of a locally developed Ready-to-use therapeutic food in pre-school children in Vietnam. In South East Asia, concerns exist about the acceptability of peanut-based Ready-to-Use-Therapeutic-Foods (RUTF) for the treatment of severe acute malnutrition (SAM). Therefore, an alternative, culturally acceptable RUTF made from locally available ingredients and complying with local food traditions and preferences was developed. The current study evaluated its acceptability and impact on anthropometry METHODS: The study was a randomized, two-arm, cross-over intervention trial to test the acceptability of the local product (bar) against a commercially available, peanut-based RUTF paste (Plumpy'nut(R)). Children (n = 67) from two kindergartens in a rural area of North Vietnam were recruited. The age of the children was between 3 and 5 years. The Vietnamese RUTF was well-accepted, although overall acceptability was less than of Plumpy'nut(R), with the latter scoring higher on palatability (P < 0.05). In contrast, reluctance to eat Plumpy'nut(R) was higher than for the Vietnamese RUTF (P < 0.05). Impact on anthropmetrical indices was similar for both RUTF. The nutritional status of the children who consumed the two RUTF over a 4 week period improved significantly, with a mean weight gain of 0.64 (SD 0.27) Kg, and increases in WHZ and HAZ z-scores of 0.48 (SD 0.30) and 0.05 (SD 0.13) respectively (P < 0.01 both). Weight gain was similar between the 2 products (0.32 kg per 2 weeks for both). Both the commercial Plumpy'nut(R) and the local produced RUTF were accepted although the harder consistency of the local product might have caused the lower overall acceptance. The promising increase in nutritional status needs to be confirmed in a controlled trial in children with SAM. 23771687 Post-translational modifications of the cardiac Na channel: contribution of CaMKII-dependent phosphorylation to acquired arrhythmias. The voltage-gated Na channel isoform 1.5 (NaV1.5) is the pore forming α-subunit of the voltage-gated cardiac Na channel, which is responsible for the initiation and propagation of cardiac action potentials. Mutations in the SCN5A gene encoding NaV1.5 have been linked to changes in the Na current leading to a variety of arrhythmogenic phenotypes, and alterations in the NaV1.5 expression level, Na current density, and/or gating have been observed in acquired cardiac disorders, including heart failure. The precise mechanisms underlying these abnormalities have not been fully elucidated. However, several recent studies have made it clear that NaV1.5 forms a macromolecular complex with a number of proteins that modulate its expression levels, localization, and gating and is the target of extensive post-translational modifications, which may also influence all these properties. We review here the molecular aspects of cardiac Na channel regulation and their functional consequences. In particular, we focus on the molecular and functional aspects of Na channel phosphorylation by the Ca/calmodulin-dependent protein kinase II, which is hyperactive in heart failure and has been causally linked to cardiac arrhythmia. Understanding the mechanisms of altered NaV1.5 expression and function is crucial for gaining insight into arrhythmogenesis and developing novel therapeutic strategies. 23572020 Sensitized photochemistry of di(4-tetrazolouracil) dinucleoside monophosphate as a route to dicytosine cyclobutane photoproduct precursors. The DNA cis-syn cyclobutane photoproduct formed between two adjacent cytosine residues is highly mutagenic and responsible for the tandem CC to TT transition. However, its instability has prevented its in vitro study, so far. With a view to prepare oligodeoxynucleotides containing the CC cyclobutane lesion, we have synthesized in good yield a ditetrazolouracil cyclobutane dinucleotide photoproduct as a stable precursor of this photoproduct. Our approach also overcomes the low photochemical reactivity of the cytosine-cytosine deoxydinucleoside monophosphate. 23881559 Congruent Validity of the Strength and Difficulties Questionnaire to Screen for Comorbidities in Children With ADHD. Objective: This study aimed to determine whether the Strengths and Difficulties Questionnaire (SDQ) is an effective screening tool for identifying comorbid mental health difficulties in children with ADHD. Method: Parents of children with ADHD (5-13 years) completed the SDQ and the Anxiety Disorders Interview Schedule for DSM-IV-Parent Version (ADIS-C/P-IV). Data from both the measures were compared to determine congruent validity. Results: Analyses revealed that significant relationships exist between the SDQ total score and the total number of comorbidities on the ADIS-C/P-IV. The SDQ emotional problem and conduct problem scales were significantly related to internalizing and externalizing comorbidities on the ADIS-C/P-IV, respectively. Conclusion: While significant relationships were found between the SDQ and ADIS-C/P-IV across various domains, this relationship was stronger for externalizing comorbidities. Additional screening questions are required to effectively screen for less common internalizing comorbidities in children with ADHD, for example, major depression and panic disorder. 23532099 Methamphetamine Alters Blood Brain Barrier Protein Expression in Mice, Facilitating Central Nervous System Infection by Neurotropic Cryptococcus neoformans. Methamphetamine (METH) is a drug of abuse that is a potent and highly addictive central nervous system (CNS) stimulant. The blood brain barrier (BBB) is a unique interface that in part functions to prevent microbial invasion of the CNS. The effects of METH on brain vasculature have not been studied extensively. We hypothesized that METH alters the BBB integrity, increasing susceptibility to CNS infection. Using a murine model of METH administration, we demonstrated that METH alters BBB integrity and modifies the expression of tight junction and adhesion molecules. Additionally, we showed that BBB disruption accelerates transmigration of the neurotropic fungus Cryptococcus neoformans into the brain parenchyma after systemic infection. Furthermore, METH-treated mice displayed increased mortality as compared to untreated animals. Our findings provide novel evidence of the impact of METH abuse on the integrity of the cells that comprise the BBB and protect the brain from infection. 23249284 Attitudes to deceased organ donation and registration as a donor among minority ethnic groups in North America and the UK: a synthesis of quantitative and qualitative research. Objectives. A systematic review and synthesis of quantitative and qualitative research were undertaken to examine attitudes to deceased donation and registration as an organ donor among ethnic minorities in the UK and North America. Design. A systematic search and assessments of relevance and quality were conducted. Parallel syntheses were then undertaken of 14 quantitative and 12 qualitative papers followed by their integration. The synthesis was organised around five barriers that emerged as key issues: (1) knowledge regarding deceased donation and registration as a donor; (2) discussion of donation/registration with family members; (3) faith and cultural beliefs; (4) bodily concerns including disfigurement and intactness; and (5) trust in doctors and the health care system. Results. In all countries, knowledge of organ donation and registration remained low despite public campaigns, with African-Americans and Black African and Black Caribbean populations in the UK often regarding organ donation as a 'white' issue. Each of the four attitudinal barriers was also more prevalent among ethnic minorities compared with the majority population. However, the significance of trust and uncertainties regarding religion/faith differed between groups, reflecting salient aspects of ethnic identity and experiences. Differences were also identified within ethnic groups associated with age and generation, although respect for the views of elders often influenced younger peoples' willingness to donate. Conclusion. There is a need for a more nuanced understanding of ethnicity and of variations in attitudes associated with country of origin, age/generation, socio-economic status and area of residence, to inform public campaigns and promote sensitive discussions with bereaved ethnic minority families. The traditional focus on knowledge and attitudes also requires to be complemented by a greater emphasis on organisational and service-related barriers and changes required to enhance ethnic minorities' access to registration as a donor and consent to deceased donation. 23872737 Biologic markers of chronic GVHD. Biologic markers of chronic GVHD may provide insight into the pathogenesis of the syndrome, identify molecular targets for novel interventions, and facilitate advances in clinical management. Despite extensive work performed to date largely focused on prediction and diagnosis of the syndrome, little synthesis of findings and validation of promising candidate markers in independent populations has been performed. Studies suggest that risk for subsequent chronic GVHD development may be associated with donor-recipient genetic polymorphism, deficiency in regulatory immune cell populations (NK, Treg, DC2), and variation in inflammatory and immunoregulatory mediators post-HCT (increased TNFα, IL-10 and BAFF, and decreased TGFβ and IL-15). Established chronic GVHD is associated with alteration in immune cell populations (increased CD3(+) T cells, Th17, CD4(+) and CD8(+) effector memory cells, monocytes, CD86 expression, BAFF/B cell ratio, and deficiency of Treg, NK cells, and naïve CD8(+) T cells). Inflammatory and immunomodulatory factors (TNFα, IL-6, IL-1β, IL-8, sIL-2R, and IL-1Ra, BAFF, anti-dsDNA, sIL-2Rα, and sCD13) are also perturbed. Little is known about biologic markers of chronic GVHD phenotype and severity, response to therapy, and prognosis.Bone Marrow Transplantation advance online publication, 22 July 2013; doi:10.1038/bmt.2013.97. 23413204 Biological exhaust air treatment systems as a potential microbial risk for farm animals assessed with a computer simulation. Livestock operations are under increasing pressure to fulfil minimum environmental requirements and avoid polluting the atmosphere. In regions with high farm animal densities, new farm buildings receive building permission only when biological exhaust air treatment systems (BEATS) are in place, such as biofilters. However, it is currently unknown whether BEATS can harbour pathogens such as zoonotic agents, which are potentially emitted via the purified gas. Because BEATS are located very close to the livestock building, it is assumed that BEATS-related microorganisms are aerially transported to farm animals via the inlet system of the ventilation system. To support this hypothesis, a computer simulation was applied to calculate the wind field around a facility consisting of a virtual livestock house and an adjacent biofilter. Under the chosen wind conditions (speed and direction), it can be shown that turbulences and eddies may occur in the near surrounding of a livestock building with an adjacent biofilter. Consequently, this might cause the entry of the released biofilter's purified gas into the barn, including possible microorganisms within this purified gas. If field investigations verify the results of the simulations, counter-measures must be taken to ensure biosecurity on farms with BEATS. © 2013 Society of Chemical Industry. 23734982 The role of Arabidopsis thaliana NAR1, a cytosolic iron-sulfur cluster assembly component, in gametophytic gene expression and oxidative stress responses in vegetative tissue. Iron-sulfur proteins have iron-sulfur clusters as a prosthetic group and are responsible for various cellular processes, including general transcriptional regulation, photosynthesis and respiration. The cytosolic iron-sulfur assembly (CIA) pathway of yeast has been shown to be responsible for regulation of iron-sulfur cluster assembly in both the cytosol and the nucleus. However, little is known about the roles of this pathway in multicellular organisms. In a forward genetic screen, we identified an Arabidopsis thaliana mutant with impaired expression of the endosperm-specific gene Flowering Wageningen (FWA). To characterize this mutant, we carried out detailed phenotypic and genetic analyses during reproductive and vegetative development. The mutation affects NAR1, which encodes a homolog of a yeast CIA pathway component. Comparison of embryo development in nar1-3 and other A. thaliana mutants affected in the CIA pathway showed that the embryos aborted at a similar stage, suggesting that this pathway potentially functions in early seed development. Transcriptome analysis of homozygous viable nar1-4 seedlings showed transcriptional repression of a subset of genes involved in 'iron ion transport' and 'response to nitrate'. nar1-4 also exhibited resistance to the herbicide paraquat. Our results indicate that A. thaliana NAR1 has various functions including transcriptional regulation in gametophytes and abiotic stress responses in vegetative tissues. 23560650 Synthesis and Biological Evaluation of a New Series of Hexahydro-2H-pyrano[3,2-c]quinolines as Novel Selective σ1 Receptor Ligands. The synthesis and pharmacological activity of a new series of hexahydro-2H-pyrano[3,2-c]quinoline derivatives as potent σ1 receptor (σ1R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other σ1R ligands, showed high selectivity over the σ2 receptor (σ2R). The activity was shown to reside in only one of the four possible diastereoisomers, which exhibited a perfect match with known σ1R pharmacophores. A hit to lead program based on a high-throughput screening hit (8a) led to the identification of compound 32c, with substantially improved activity and physicochemical properties. Compound 32c also exhibited a good ADMET (absorption, distribution, metabolism, excretion, toxicity) profile and was identified as a σ1R antagonist on the basis of its analgesic activity in the mouse capsaicin and formalin models of neurogenic pain. 23870916 Optimal extraction and fingerprint analysis of Cnidii fructus by accelerated solvent extraction and high performance liquid chromatographic analysis with photodiode array and mass spectrometry detections. A confirmatory and reliable procedure has been developed for extraction and determination of Cnidii fructus by accelerated solvent extraction (ASE) and high-performance liquid chromatography coupled with photodiode array, electrospray ionisation ion trap tandem mass spectrometry and time of flight mass spectrometry (HPLC-PDA-ESI-ITMS(n)/TOF-MS). The determination method enabled the characterisation of sixteen bioactive components in C. fructus and quantification of three major coumarins, namely osthole, imperatorin and isopimpinellin. Response surface methodology (RSM) was employed to optimise the extraction parameters yielding the optimum conditions of ASE (extraction temperature 122°C, extraction time 5min and two static cycles). And the total contents of three major coumarins extracted by ASE under the optimum conditions was significantly higher than those by reflux and ultrasonic extraction (P<0.05) with better reproducibility. At last, the proposed method coupled with pattern recognition was applied to analysis of C. fructus from eight different regions in China. 23891819 Developmental transition to bilaterally symmetric cell divisions is regulated by Pax-mediated transcription in embryos of the leech Helobdella austinensis. The leech embryo develops by spiral cleavage, and establishes the symmetry properties of its adult body plan through the bilaterally symmetric divisions of mesodermal proteloblast DM″ and ectodermal proteloblast DNOPQ‴. We here show that transcriptional inhibitors α-amanitin and actinomycin D specifically disrupt the symmetry and orientation of these two proteloblast cell divisions while having no apparent effect on the timing or geometry of other divisions. Transcriptional inhibition had a similar effect on both proteloblasts, i.e. cytokinesis was highly asymmetric and the cleavage plane roughly orthogonal to that seen during normal development. These findings suggest that zygotic gene product(s) are required, either directly or indirectly, for the correct placement of the proteloblast cleavage furrow. The same phenotypes were also observed following in vivo expression of dominant-negative Pax gene constructs. These dominant-negative phenotypes depended on protein/DNA interaction, and could be rescued by coexpression of full length Pax proteins. However, symmetric cleavage of the mesodermal proteloblast was rescued by full length constructs of either Hau-Paxβ1 or Hau-Pax2/5/8, while only Hau-Paxβ1 rescued the symmetry of ectodermal cleavage. We conclude that both proteloblasts need Pax-mediated transcription to adopt their normally symmetric cleavage patterns, but differ in terms of the specific Pax proteins required. The implication of these findings for the evolution of spiral cleavage is discussed. 23928777 FBXW7 and NOTCH1 Mutations Cooperate in T-ALL. FBXW7 missense mutations in T-ALL promote MYC stability and leukemia-initiating cell activity. 23916944 MicroRNA 23b Regulates Autophagy Associated with Radioresistance of Pancreatic Cancer Cells. Tumor resistance to radiation is a challenge to treatment of patients with pancreatic cancer. Improving our understanding of the mechanisms of radioresistance could lead to strategies to increase patients' response to therapy. We investigated the roles of microRNAs (miRNAs) involved in radioresistance of pancreatic cancer cells. We established radioresistant pancreatic cancer cell lines and used array analysis to compare levels of different miRNAs between radioresistant cell lines and the parental cell lines from which they were derived. We transfected pancreatic cancer cells with miRNA mimics or inhibitors and evaluated their effects on cell radiosensitivity using a clonogenic survival assay. The effects of miRNA on autophagy were determined by transmission electron microscopy and immunoblot analysis. We used a luciferase reporter assay to identify mRNA targets of specific miRNAs. Radioresistant pancreatic cancer cells had reduced levels of the miRNA MIR23B and increased autophagy, compared with cells that were not radioresistant. Overexpression of MIR23B inhibited radiation-induced autophagy, whereas an inhibitor of MIR23B promoted autophagy in pancreatic cancer cells. Overexpression of MIR23B sensitized pancreatic cancer cells to radiation. The target of MIR23B, ATG12, was overexpressed in radioresistant cells; levels of ATG12 protein correlated with the occurrence of autophagy. Expression of MIR23B blocked radiation-induced autophagy and sensitized pancreatic cancer cells to radiation. We observed an inverse correlation between level of MIR23B and autophagy in human pancreatic cancer tissue samples. In pancreatic cancer cells, reduced levels of the miRNA MIR23B increase levels of ATG12 and autophagy to promote radioresistance. MIR23B might be used to increase the sensitivity of pancreatic cancer cells to radiation therapy. 23835292 The level of agreement regarding patient disposition between emergency physicians and consultants in the emergency department. Consultation is a common and important aspect of emergency medicine practice. We examined the frequency of consultations, the level of agreement and factors of disagreement with regard to the disposition of patients who visited two emergency departments (EDs) of tertiary care hospitals in Japan. We analyzed 3,503 consecutive patients who visited two EDs in Japan during a 3-month period. The initial diagnosis in the ED, the presence of consultation, and the patient disposition following the ED visit were recorded. At least one consultation was requested in 34.7% of the patients (1,215/3,503), and 88% of these patients were admitted to the hospital (1,063/1,215). Consultants and emergency physicians (EPs) agreed on patient disposition 95% of the time (1,153/1,215), with κ = 0.76 (95% CI 0.70-0.82). Opinions about disposition were discordant in 5% of the patients consulted upon. In 63% of those cases, patients were not diagnosed in the ED. Consultants and EPs agreed on patient disposition in most cases. In more than half of the cases in which disagreements arose between EPs and consultants, the EPs were not able to reach an initial diagnosis. Further studies are needed to examine the association between disagreements in disposition and adverse outcomes. 23193255 H2DB: a heritability database across multiple species by annotating trait-associated genomic loci. H2DB (http://tga.nig.ac.jp/h2db/), an annotation database of genetic heritability estimates for humans and other species, has been developed as a knowledge database to connect trait-associated genomic loci. Heritability estimates have been investigated for individual species, particularly in human twin studies and plant/animal breeding studies. However, there appears to be no comprehensive heritability database for both humans and other species. Here, we introduce an annotation database for genetic heritabilities of various species that was annotated by manually curating online public resources in PUBMED abstracts and journal contents. The proposed heritability database contains attribute information for trait descriptions, experimental conditions, trait-associated genomic loci and broad- and narrow-sense heritability specifications. Annotated trait-associated genomic loci, for which most are single-nucleotide polymorphisms derived from genome-wide association studies, may be valuable resources for experimental scientists. In addition, we assigned phenotype ontologies to the annotated traits for the purposes of discussing heritability distributions based on phenotypic classifications. 23726084 Tandem sulfur chemiluminescence and flame ionization detection with planar microfluidic devices for the characterization of sulfur compounds in hydrocarbon matrices. The detection of sulfur compounds in different hydrocarbon matrices, from light hydrocarbon feedstocks to medium synthetic crude oil feeds provides meaningful information for optimization of refining processes as well as demonstration of compliance with petroleum product specifications. With the incorporation of planar microfluidic devices in a novel chromatographic configuration, sulfur compounds from hydrogen sulfide to alkyl dibenzothiophenes and heavier distributions of sulfur compounds over a wide range of matrices spanning across a boiling point range of more than 650°C can be characterized, using one single analytical configuration in less than 25min. In tandem with a sulfur chemiluminescence detector for sulfur analysis is a flame ionization detector. The flame ionization detector can be used to establish the boiling point range of the sulfur compounds in various hydrocarbon fractions for elemental specific simulated distillation analysis as well as profiling the hydrocarbon matrices for process optimization. Repeatability of less than 3% RSD (n=20) over a range of 0.5-1000 parts per million (v/v) was obtained with a limit of detection of 50 parts per billion and a linear range of 0.5-1000 parts per million with a correlation co-efficient of 0.998. 23639262 A user-study measuring the effects of lexical simplification and coherence enhancement on perceived and actual text difficulty. Low patient health literacy has been associated with cost increases in medicine because it contributes to inadequate care. Providing explanatory text is a convenient approach to distribute medical information and increase health literacy. Unfortunately, writing text that is easily understood is challenging. This work tests two text features for their impact on understanding: lexical simplification and coherence enhancement. A user study was conducted to test the features' effect on perceived and actual text difficulty. Individual sentences were used to test perceived difficulty. Using a 5-point Likert scale, participants compared eight pairs of original and simplified sentences. Abstracts were used to test actual difficulty. For each abstract, four versions were created: original, lexically simplified, coherence enhanced, and lexically simplified and coherence enhanced. Using a mixed design, one group of participants worked with the original and lexically simplified documents (no coherence enhancement) while a second group worked with the coherence enhanced versions. Actual difficulty was measured using a Cloze measure and multiple-choice questions. Using Amazon's Mechanical Turk, 200 people participated of which 187 qualified based on our data qualification tests. A paired-samples t-test for the sentence ratings showed a significant reduction in difficulty after lexical simplification (p<.001). Results for actual difficulty are based on the abstracts and associated tasks. A two-way ANOVA for the Cloze test showed no effect of coherence enhancement but a main effect for lexical simplification, with the simplification leading to worse scores (p=.004). A follow-up ANOVA showed this effect exists only for function words when coherence was not enhanced (p=.008). In contrast, a two-way ANOVA for answering multiple-choice questions showed a significant beneficial effect of coherence enhancement (p=.003) but no effect of lexical simplification. Lexical simplification reduced the perceived difficulty of texts. Coherence enhancement reduced the actual difficulty of text when measured using multiple-choice questions. However, the Cloze measure results showed that lexical simplification can negatively impact the flow of the text. 23945227 Oxygen Extraction Fraction and Stroke Risk in Patients with Carotid Stenosis or Occlusion: A Systematic Review and Meta-Analysis. BACKGROUND AND PURPOSE:Increased oxygen extraction fraction on PET has been considered a risk factor for stroke in patients with carotid stenosis or occlusion, though the strength of this association has recently been questioned. We performed a systematic review and meta-analysis to summarize the association between increased oxygen extraction fraction and ipsilateral stroke risk.MATERIALS AND METHODS:A comprehensive literature search was performed. We included studies with baseline PET oxygen extraction fraction testing, ipsilateral stroke as the primary outcome, and at least 1 year of follow-up. A meta-analysis was performed by use of a random-effects model.RESULTS:After screening 2158 studies, 7 studies with 430 total patients with mean 30-month follow-up met inclusion criteria. We found that 6 of 7 studies were amenable to meta-analysis. Although 4 of the 6 studies independently did not reach statistical significance, meta-analysis revealed a significant positive relationship between abnormal oxygen extraction fraction and future ipsilateral stroke, with a pooled OR of 6.04 (95% CI, 2.58-14.12). There was no statistically significant difference in OR in the subgroup analyses according to testing method or disease site.CONCLUSIONS:Abnormal oxygen extraction fraction remains a powerful predictor of stroke in carotid stenosis or occlusion and is a valuable reference standard to compare and validate MR imaging-based measures of brain oxygen metabolism. However, there is a need for further evaluation of oxygen extraction fraction testing in patients with high-grade but asymptomatic carotid disease. 23932318 Nonresectional Single-Suture Leaflet Remodeling for Degenerative Mitral Regurgitation Facilitates Minimally Invasive Mitral Valve Repair. Both leaflet resection and neochordal construction are effective mitral repair techniques, but they may become incrementally time-consuming when using minimally invasive approaches. We have used a single-suture leaflet-remodeling technique of inverting the prolapsed or flail segment tissue into the left ventricle. This repair is straightforward, expeditious, and facilitates a minimally invasive approach. Ninety-nine patients with degenerative mitral regurgitation (MR) underwent a minimally invasive single-suture repair of the mitral valve from May 2007 through December 2012. Preoperative and perioperative echocardiograms as well as patient outcomes were analyzed and compared with those obtained from patients undergoing minimally invasive mitral valve repair using quadrangular resection at the same institution during the same period. All 99 patients had a successful mitral repair through a sternal-sparing minimally invasive approach. Ninety-one of the 99 patients had zero MR on postoperative echocardiogram, and 8 of 99 had trace to mild MR. Patients in the nonresectional group had significantly shorter cardiopulmonary bypass and cross-clamp times compared with the quadrangular resection group (115.8 ± 41.7 minutes versus 144.9 ± 38.2 minutes; p < 0.001; 76.2 ± 28.1 minutes versus 112.6 ± 33.5 minutes; p < 0.001, respectively). The mean length of stay was 7.5 ± 3 days. All patients were discharged alive and free from clinical symptoms of MR. There have been no reoperations for recurrent MR on subsequent average follow-up of 1 year. An effective, highly efficient, and thus far durable single-suture mitral leaflet-remodeling technique facilitates minimally invasive repair of degenerative MR. 23651794 Crew and patient safety in ambulances: results of a personnel survey and experimental side impact crash test. Introduction Ambulance drivers often travel under stressful conditions at high speed while using vehicles with poor high-speed maneuverability. The occupant safety of ambulance vehicles has not yet been addressed by the automotive safety paradigm; particularly for the rear patient compartment. This study had two objectives: (1) to assess by survey the French Emergency Medical Services (EMS) to determine the layout of the vehicle most often used and the EMS personnel's behavior during transport; and (2) to conduct a crash test to analyze the injuries which may affect EMS personnel and patients in the rear patient compartment. Method Firstly, a survey was distributed to the 50 largest metropolitan French EMS programs. Secondly, a crash test was performed with a Mobile Intensive Care Unit (MICU) in conditions closest to reality. Forty-nine of the 50 biggest metropolitan French EMS programs responded to the survey. This represents 108 French MICUs. During the last three years, 12 of 49 EMS programs (24%) identified at least one accident with an MICU, and six of these 12 (50%) suffered at least one death in those accidents. A crash test using a typical French EMS MICU showed that after impact of a collision, the ambulance was moved more than five meters with major consequences for all passengers. A study-approved human cadaver placed in the position of a potential patient was partially thrown from the stretcher with a head impact. The accelerometric reaction of the anthropomorphic manikin head was measured at 48G. The crash test demonstrated a lack of safety for EMS personnel and patients in the rear compartment. It would be preferable if each piece of medical equipment were provided with a quick release system resistant to three-dimensional 10G forces. The kinetic changes undergone by the "patient" substitute on the stretcher would probably have an effect of causing injury pathology. This study highlights the need for more research and development in this area. Fournier M , Chenaitia H , Masson C , Michelet P , Behr M , Auffray JP . Crew and patient safety in ambulances: results of a personnel survey and experimental side impact crash test. Prehosp Disaster Med. 2013;28(4):1-6 . 23273052 Bistable magnetoresistance switching in exchange-coupled CoFe₂O₄--Fe₃O₄ binary nanocrystal superlattices by self-assembly and thermal annealing. Self-assembly of multicomponent nanocrystal superlattices provides a modular approach to the design of metamaterials by choosing constituent nanocrystal building blocks with desired physical properties and engineering the interparticle coupling. In this work, we report the self-assembly of binary nanocrystal superlattices composed of magnetically hard CoFe₂O₄ nanocrystals and magnetically soft Fe₃O₄ nanocrystals. Both NaZn₁₃- and MgZn₂-type CoFe₂O₄--Fe₃O₄ binary nanocrystal superlattices have been formed by the liquid-air interfacial assembly approach. Exchange coupling is achieved in both types of binary superlattices after thermal annealing under vacuum at 400 °C. The exchange-coupled CoFe₂O₄--Fe₃O₄ binary nanocrystal superlattices show single-phase magnetization switching behavior and magnetoresistance switching behavior below 200 K. The NaZn₁₃-type CoFe₂O₄--Fe₃O₄ binary nanocrystal superlattices annealed at 500 °C even exhibit bistable magnetoresistance switching behavior at room temperature constituting a simple nonvolatile memory function. 23604752 Nuclear medicine training and practice in Portugal. Nuclear medicine in Portugal has been an autonomous speciality since 1984. In order to obtain the title of Nuclear Medicine Specialist, 5 years of training are necessary. The curriculum is very similar to the one approved under the auspices of the European Union of Medical Specialists, namely concerning the minimum recommended number of diagnostic and therapeutic procedures. There is a final assessment, and during the training the resident is in an approved continuing education programme. Departments are accredited by the Medical College in order to verify their capacity to host nuclear medicine residencies. 23406956 Protective role of L-carnitine and vitamin E on the testis of atherosclerotic rats. Atherosclerosis is a condition caused by lipid build-up and inflammation in the arteries, so hyperlipidemia is the major reason for atherosclerosis. Testis was found to be negatively affected by hyperlipidemia which leads to its impaired functions. Vitamin E and l-carnitine have well-known lipid-lowering and antioxidative activities. Triton WR 1339 is a non-ionic detergent, which induces severe hyperlipidemia by inhibition of lipoprotein lipase. The present study evaluates the protective role of vitamin E and l-carnitine on the testis in atherosclerosis and detects the most effective choice for protection against atherosclerosis; vitamin E, l-carnitine or a combination of both. A total of 80 albino male rats were divided into eight groups (10 rats for each group): control (G(1)), triton (G(2)), l-carnitine (G(3)), triton + l-carnitine (G(4)), vitamin E (G(5)), triton + vitamin E (G(6)), l-carnitine + vitamin E (G(7)) and triton + l-carnitine + vitamin E (G(8)). Data showed a significant increase in the levels of total cholesterol (TC), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), 17 beta hydroxysteroid dehydrogenase (17 β HSD), testicular catalase and malondialdehyde (MDA) in G(2) when compared with G(1), whereas high-density lipoprotein cholesterol (HDL-C), serum testosterone, testicular 17 ketosteroid reductase (17 KSR), total thiol and glutathione-S-transferase (GST) data showed a significant decrease in G(2) when compared with G(1). Treatment with l-carnitine or/and vitamin E helps in improving the adverse effect of triton; also the histological changes confirm this finding. So the present study recommends all people to include l-carnitine and vitamin E in their diet to be protected against atherosclerosis. 23851561 Knowledge and understanding of urinary incontinence: Survey of family practitioners in northern Alberta. To investigate family physicians' knowledge of, attitudes toward, and understanding of urinary incontinence (UI), as well as their perceptions of barriers to continence care, as a foundation for designing interventions to improve service provision for those in northern Alberta who suffer from UI. Descriptive survey using a standardized instrument. The survey instrument was completed either by telephone interview or on paper copy faxed back to the researchers, depending on participant preference. Northern Alberta. Random sample of family physicians (N = 158). Physician knowledge of and attitudes toward UI, UI management practices, and barriers to providing UI care. Survey response rate was 10.6% (158 of 1488); 84.2% (133 of 158) of respondents practised in urban settings, 44.9% (71 of 158) had been in practice for fewer than 15 years, 24.1% (38 of 158) reported having no training in UI management since graduation, and 53.8% (85 of 158) reported that they proactively discussed UI with their patients. Overall, 70.0% of respondents felt fairly confident in managing UI. Most family physicians referred patients for specialist care, with few referrals to community services. Respondents thought that continence services were scarce, with long waiting times, and that such services were generally overstretched; they believed that although high-quality continence care was a personal priority, it was not a priority focus for their practice partnerships or networks. In terms of the highest ranked areas for improvement in UI management, increased awareness and understanding among physicians (ranked first by 28.5% of respondents), followed by dedicated incontinence clinics or nurses for referral (17.7%) and improving patient awareness and understanding (12.0%). There continues to be considerable variation in knowledge about UI management and a relative overreliance on specialist care, despite well recognized difficulties in gaining access to services. Respondents believed that increased awareness among patients and health care providers coupled with greater access to continence services were key factors in improving care delivery. 23401304 Engineering new protein-protein interactions on the β-propeller fold by yeast cell surface display. REINVENTING THE WHEEL: The β-propeller domain folds like a wheel to provide key protein-protein interactions in the cell. Here we used high-throughput yeast sorting to "invent" β-propellers of new binding specificities with cellular targets. 23454056 Mechanism of the uptake of cationic and anionic calcium phosphate nanoparticles by cells. The uptake of calcium phosphate nanoparticles (diameter 120nm) with different charge by HeLa cells was studied by flow cytometry. The amount of uptaken nanoparticles increased with increasing concentration of nanoparticles in the cell culture medium. Several inhibitors of endocytosis and macropinocytosis were applied to elucidate the uptake mechanism of nanoparticles into HeLa cells: wortmannin, LY294002, nocodazole, chlorpromazine and nystatin. Wortmannin and LY294002 strongly reduced the uptake of anionic nanoparticles, which indicates macropinocytosis as uptake mechanism. For cationic nanoparticles, the uptake was reduced to a lesser extent, indicating a different uptake mechanism. The localization of nanoparticles inside the cells was investigated by conjugating them with the pH-sensitive dye SNARF-1. The nanoparticles were localized in lysosomes after 3h of incubation. 23607394 RGD capsid modification enhances mucosal protective immunity of a non-human primate adenovirus vector expressing Pseudomonas aeruginosa OprF. Replication-deficient adenoviral (Ad) vectors of non-human serotypes can serve as Ad vaccine platforms to circumvent pre-existing anti-human Ad immunity. We found previously that, in addition to that feature, a non-human primate-based AdC7 vector expressing outer membrane protein F of P. aeruginosa (AdC7OprF) was more potent in inducing lung mucosal and protective immunity compared to a human Ad5-based vector. In this study we analysed if genetic modification of the AdC7 fibre to display an integrin-binding arginine-glycine-aspartic acid (RGD) sequence can further enhance lung mucosal immunogenicity of AdC7OprF. Intratracheal immunization of mice with either AdC7OprF.RGD or AdC7OprF induced robust serum levels of anti-OprF immunoglobulin (Ig)G up to 12 weeks that were higher compared to immunization with the human vectors Ad5OprF or Ad5OprF.RGD. OprF-specific cellular responses in lung T cells isolated from mice immunized with AdC7OprF.RGD and AdC7OprF were similar for T helper type 1 (Th1) [interferon (IFN)-γ in CD8(+) and interleukin (IL)-12 in CD4(+)], Th2 (IL-4, IL-5 and IL-13 in CD4(+)) and Th17 (IL-17 in CD4(+)). Interestingly, AdC7OprF.RGD induced more robust protective immunity against pulmonary infection with P. aeruginosa compared to AdC7OprF or the control Ad5 vectors. The enhanced protective immunity induced by AdC7OprF.RGD was maintained in the absence of alveolar macrophages (AM) or CD1d natural killer T cells. Together, the data suggest that addition of RGD to the fibre of an AdC7-based vaccine is useful to enhance its mucosal protective immunogenicity. 23597860 Clinical outcomes associated with receipt of integrated pharmacy services by hemodialysis patients: a quality improvement report. Reducing medication-related problems and improving medication adherence in hemodialysis patients may improve clinical outcomes. In 2005, a large US dialysis organization created an integrated pharmacy program for its patients. We aimed to compare the outcomes of hemodialysis patients enrolled in this program and matched control patients. Quality improvement report. Hemodialysis patients with concurrent Medicare and Medicaid eligibility who chose to receive program services and propensity score-matched controls; the propensity score was an estimated function of demographic characteristics, comorbid conditions, medication exposure, serum concentrations, and vascular access method. Program services included medication delivery, refill management, medication list reviews, telephonic medication therapy management, and prior authorization assistance. Relative rates of death and hospitalization. Survival estimates calculated with the Kaplan-Meier method; mortality hazards compared with Cox regression; hospitalization rates compared with Poisson regression. In outcome models, there were 8,864 patients receiving integrated pharmacy services and 43,013 matched controls. In intention-to-treat and as-treated analyses, mortality HRs for patients receiving integrated pharmacy services versus matched controls were 0.92 (95% CI, 0.86-0.97) and 0.79 (95% CI, 0.74-0.84), respectively. Corresponding relative rates of hospital admissions were 0.98 (95% CI, 0.95-1.01) and 0.93 (95% CI, 0.90-0.96), respectively, and of hospital days, 0.94 (95% CI, 0.90-0.98) and 0.86 (95% CI, 0.82-0.90), respectively. Cumulative incidences of disenrollment from the pharmacy program were 23.4% at 12 months and 37.0% at 24 months. Patients were not randomly assigned to receive integrated pharmacy services; as-treated analyses may be biased because of informative censoring by disenrollment from the pharmacy program; data regarding use of integrated pharmacy services were lacking. Receipt of integrated pharmacy services was associated with lower rates of death and hospitalization in hemodialysis patients with concurrent Medicare and Medicaid eligibility. Studies are needed to measure pharmacy program use and assess detailed clinical and economic outcomes. 23895930 Comparison of hybrid capture 2 High-Risk HPV results in the low positive range with cobas(®) HPV Test results from the ATHENA study. The increasing importance of high-risk human papillomavirus (hrHPV) testing in cervical cancer screening warrants evaluation of HPV DNA tests with an equivocal zone requiring retesting of samples in the low positive range. To compare the results of the digene hc2 High Risk HPV DNA Test (hc2), which has a manufacturer's recommended retesting zone with the cobas HPV Test, a real-time polymerase chain reaction amplification test without an equivocal range. A retrospective subanalysis of the ATHENA study comparing results for hc2 High Risk HPV DNA Test and the cobas HPV Test using the LINEAR ARRAY HPV Genotyping Test (LA) and Sanger sequencing as comparators was performed. The ability of each test to detect high-grade cervical disease in the equivocal range was also evaluated. 5.2% of samples fell within the equivocal zone (RLU/CO 1.0-2.5) and required retesting with the hc2 High Risk HPV DNA Test. In this low-positive range the cobas HPV Test showed better positive percent agreement (PPA) than hc2 High Risk HPV DNA Test for LA and sequencing (84.2% vs.70.9% and 92.1% vs.82.5%, respectively). hc2 High Risk HPV DNA Test and the cobas HPV Test demonstrated comparable sensitivity for detection of high-grade disease in the equivocal range. In the low cobas HPV Test range (cycle threshold [Ct] 40-35), the cobas HPV test again demonstrated a better PPA than hc2 High Risk HPV DNA Test with LA and sequencing as comparators and more high-grade disease was detected by the cobas HPV Test than hc2 High Risk HPV DNA Test. The cobas HPV Test demonstrates reliable performance in the hc2 High Risk HPV DNA Test equivocal zone, thus supporting it as an option for HPV testing that avoids the need for retesting. 23739277 Improving treadmill performance in patients with lumbar stenosis: evaluation of a custom angle load reduction device. The aim of this study was to evaluate a custom angle load reduction rolling walker to determine the relationship between flexion and load reduction on walking performance in patients with lumbar spinal stenosis.The hypothesis was that walking performance in patients with lumbar spinal stenosis would be significantly improved using the Oliver Static Measuring Apparatus device compared with unaided treadmill walking. Fifteen patients with symptomatic neurogenic intermittent claudication caused by lumbar spinal stenosis were recruited at a Veterans Affairs Medical Center. This study used a cross-sectional design with two random-order treadmill conditions: (1) spinal flexion and unloading and (2) level walking. Primary outcome measures included initiation time of first symptoms, total walking time, spinal flexion angle, and unloading force. Secondary measures included baseline pain, fatigue, and disability severity. The participants' initiation time of symptoms and total walking time were significantly greater with the use of the Oliver Static Measuring Apparatus compared with the unaided walking trial. The participants with increased baseline pain, fatigue, and disability severity had decreased walking performance for the unaided condition but not for the Oliver Static Measuring Apparatus condition. The results show that spinal flexion is important for pain reduction in lumbar spinal stenosis. The Oliver Static Measuring Apparatus device used in this study was shown to be effective and immediate in significantly increasing total walking time and prolonging the onset of neurogenic intermittent claudication symptoms while ambulating. 23898831 Reversible Switching of InP Nanowire Growth Direction by Catalyst Engineering. We demonstrate high yield vapor-liquid-solid (VLS) growth of ⟨100⟩-oriented InP nanowire arrays. The highest yield (97%) is obtained when the catalyst droplet is filled with indium prior to nanowire nucleation to the equilibrium composition during nanowire growth. Using these ⟨100⟩ wires as a template we can reversibly switch between a ⟨100⟩ and a ⟨111⟩ growth direction by varying the indium content of the droplet. Modeling VLS growth by a kinetic nucleation model indicates that the growth direction is governed by the liquid-vapor interface energy that is strongly affected by the indium concentration in the catalyst droplet. 23876808 Emetic Potentials of Newly Identified Staphylococcal Enterotoxin-like Toxins. Staphylococcal enterotoxins (SEs) are a common causative agent of food poisoning. Recently, many new SE-like (SEl) toxins have been reported, although the role of SEls in food poisoning remains unclear. In this study, the emetic potentials of SElK, SElL, SElM, SElN, SElO, SElP, and SElQ were assessed using a monkey-feeding assay. All the SEls that were tested induced emetic reactions in monkeys at a dose of 100 μg/kg, although the numbers of affected monkeys were significantly smaller than the numbers that were affected after consuming SEA or SEB. This result suggests that these new SEs may play some role in staphylococcal food poisoning. 23850829 Regulating tension in three-dimensional culture environments. The processes of development, repair, and remodeling of virtually all tissues and organs, are dependent upon mechanical signals including external loading, cell-generated tension, and tissue stiffness. Over the past few decades, much has been learned about mechanotransduction pathways in specialized two-dimensional culture systems; however, it has also become clear that cells behave very differently in two- and three-dimensional (3D) environments. Three-dimensional in vitro models bring the ability to simulate the in vivo matrix environment and the complexity of cell-matrix interactions together. In this review, we describe the role of tension in regulating cell behavior in three-dimensional collagen and fibrin matrices with a focus on the effective use of global boundary conditions to modulate the tension generated by populations of cells acting in concert. The ability to control and measure the tension in these 3D culture systems has the potential to increase our understanding of mechanobiology and facilitate development of new ways to treat diseased tissues and to direct cell fate in regenerative medicine and tissue engineering applications. 23830897 Cyclosporine A treated in vitro models induce cholestasis response through comparison of phenotype-directed gene expression analysis of in vivo Cyclosporine A-induced cholestasis. In vitro models for hepatotoxicity testing are a necessity for advancement of toxicological research. Assessing the in vitro response requires in vivo validated gene sets reflective of the hepatotoxic phenotype. Cholestasis, the impairment of bile flow, is induced in C57BL/6J mice treated with cyclosporine A (CsA) to identify phenotype reflective gene sets. CsA treatment through oral gavage for 25 days induced cholestasis, as confirmed by histopathology and serum chemistry. Over 1, 4, and 11 days of CsA exposure gradual increases in serum markers were correlated to gene expression. This phenotype-directed analysis identified gene sets specific to the onset and progression of cholestasis, such as PPAR related processes and drug metabolism, by circumventing other effects of CsA, such as immunosuppression, found in dose*time group analysis. In vivo gene sets are enriched in publicly available data sets of CsA-treated HepaRG and primary mouse hepatocytes. However, genes identified within these gene sets did not overlap between in vivo and in vitro. In vitro regulated genes represent the initial response to cholestasis, whereas in vivo genes represent the later adaptive response. We conclude that the applicability of in vitro models for hepatotoxicity testing fully depends on a solid in vivo phenotype anchored analysis. 23212110 Evolving approaches of hematopoietic stem cell-based therapies to induce tolerance to organ transplants: the long road to tolerance. The immunoregulatory properties of hematopoietic stem cells (HSCs) have been recognized for more than 60 years, beginning in 1945, when Owen reported that genetically disparate freemartin cattle sharing a common placenta were red blood cell chimeras. In 1953, Billingham, Brent, and Medawar demonstrated that murine neonatal chimeras prepared by infusion of donor-derived hematopoietic cells exhibited donor-specific tolerance to skin allografts. Various approaches using HSCs in organ transplantation have gradually brought closer to reality the dream of inducing donor-specific tolerance in organ transplant recipients. Several hurdles needed to be overcome, especially the risk of graft-versus-host disease (GVHD), the toxicity of ablative conditioning, and the need for close donor-recipient matching. For wide acceptance, HSC therapy must be safe and reproducible in mismatched donor-recipient combinations. Discoveries in other disciplines have often unexpectedly and synergistically contributed to progress in this area. This review presents a historic perspective of the quest for tolerance in organ transplantation, highlighting current clinical approaches. 23905021 Densitometric HPTLC analysis of 8-gingerol in Zingiber officinale extract and ginger-containing dietary supplements, teas and commercial creams. To develop and validate a simple, accurate HPTLC method for the analysis of 8-gingerol and to determine the quantity of 8-gingerol in Zingiber officinale extract and ginger-containing dietary supplements, teas and commercial creams. The analysis was performed on 10×20 cm aluminium-backed plates coated with 0.2 mm layers of silica gel 60 F254 (E-Merck, Germany) with n-hexane: ethyl acetate 60: 40 (v/v) as mobile phase. Camag TLC Scanner III was used for the UV densitometric scanning at 569. This system was found to give a compact spot of 8-gingerol at retention factor (Rf) value of (0.39±0.04) and linearity was found in the ranges 50-500 ng/spot (r (2)=0.9987). Limit of detection (12.76 ng/spot), limit of quantification (26.32 ng/spot), accuracy (less than 2 %) and recovery (ranging from 98.22-99.20) were found satisfactory. The HPTLC method developed for quantification of 8-gingerol was found to be simple, accurate, reproducible, sensitive and is applicable to the analysis of 8-gingerol in Zingiber officinale extract and ginger-containing dietary supplements, teas and commercial creams. 23850828 Hematopoietic-specific Rho GTPases Rac2 and RhoH and human blood disorders. The small guanosine triphosphotases (GTPases) Rho proteins are members of the Ras-like superfamily. Similar to Ras, most Rho GTPases cycle between active GTP-bound, and inactive GDP-bound conformations and act as molecular switches that control multiple cellular functions. While most Rho GTPases are expressed widely, the expression of Rac2 and RhoH are restricted to hematopoietic cells. RhoH is an atypical GTPase that lacks GTPase activity and remains in the active conformation. The generation of mouse knock-out lines has led to new understanding of the functions of both of these proteins in blood cells. The phenotype of these mice also led to the identification of mutations in human RAC2 and RHOH genes and the role of these proteins in immunodeficiency diseases. This review outlines the basic biology of Rho GTPases, focusing on Rac and RhoH and summarizes human diseases associated with mutations of these genes. 23274908 Congenital Hyperinsulinism Caused by Hexokinase I Expression or Glucokinase-Activating Mutation in a Subset of β-Cells. Congenital hyperinsulinism causes persistent hypoglycemia in neonates and infants. Most often, uncontrolled insulin secretion (IS) results from a lack of functional KATP channels in all β-cells or only in β-cells within a resectable focal lesion. In more rare cases, without KATP channel mutations, hyperfunctional islets are confined within few lobules, whereas hypofunctional islets are present throughout the pancreas. They also can be cured by selective partial pancreatectomy; however, unlike those with a KATP focal lesion, they show clinical sensitivity to diazoxide. Here, we characterized in vitro IS by fragments of pathological and adjacent normal pancreas from six such cases. Responses of normal pancreas were unremarkable. In pathological region, IS was elevated at 1 mmol/L and was further increased by 15 mmol/L glucose. Diazoxide suppressed IS and tolbutamide antagonized the inhibition. The most conspicuous anomaly was a large stimulation of IS by 1 mmol/L glucose. In five of six cases, immunohistochemistry revealed undue presence of low-Km hexokinase-I in β-cells of hyperfunctional islets only. In one case, an activating mutation of glucokinase (I211F) was found in pathological islets only. Both abnormalities, attributed to somatic genetic events, may account for inappropriate IS at low glucose levels by a subset of β-cells. They represent a novel cause of focal congenital hyperinsulinism. 23567961 Identification of novel FLT3 kinase inhibitors. FLT3 and PDGFR tyrosine kinases are important targets for therapy of different types of leukemia. Several FLT3/PDGFR inhibitors are currently under clinical investigation for combination with standard therapy for treatment of acute myeloid leukemia (AML), however these agents only induce partial remission and development of resistance has been reported. In this work we describe the identification of potent and novel dual FLT3/PDGFR inhibitors that resulted from our efforts to screen a library of 25,607 small molecules against the FLT3 dependent cell line MOLM-13 and the PDGFR dependent cell line EOL-1. This effort led to the identification of five compounds that were confirmed to be active on additional FLT3 dependent cell lines (cellular EC50 values between 35 and 700 nM), while having no significant effect on 24 other tyrosine kinases. 23890772 Planktonic ciliate community structure in shallow lakes of lowland Western Europe. Temperate shallow meso- to eutrophic lakes can exist in one of two alternative states with contrasting foodwebs, referred to as the clear-water and the turbid state. We describe the planktonic ciliate communities of such lakes based on a survey of 66 northwestern European lakes. Ciliates were enumerated and identified to species level according to the quantitative protargol staining technique. Ciliate biomass was on average twice as high in the turbid than in the clear-water lakes. The ciliate communities were dominated by oligotrichs and protostomatids, and no differences in functional composition or α-diversity could be detected between turbid and clear-water lakes, although β-diversity tended to be higher in the latter. At the species level, however, community structure strongly differed between turbid and clear-water lakes, and several indicator species could be identified for the different lake categories. Variation partitioning showed that nutrient status did not explain ciliate community structure independent of the alternative states, while lake area was identified as an additional structuring factor for the ciliate communities. These results stress the importance of the ecosystem structure in shaping ciliate communities in temperate shallow lakes and suggest that nutrient status has little direct effect on ciliate community structure in such lakes. 23916787 Circulating plasma DNA and DNA integrity in breast cancer patients undergoing neoadjuvant chemotherapy. In breast cancer patients undergoing neoadjuvant chemotherapy before surgery, biomarkers for predicting response to therapy are urgently required. In 65 patients with locally confined breast cancer who had completed the course of chemotherapy until surgery, plasma DNA biomarkers obtained before and during therapy were evaluated concerning (early) estimation of therapy response. Levels of repetitive ALU 115 and ALU 247 elements as well as DNA integrity calculated according the formulas of Umetani (1) and Wang (2) were correlated with changes in histopathological staging at surgery and compared with conventional tumor markers CEA and CA 15-3. At surgery, 13 patients presented complete remission (CR), 32 partial remission (PR) and 20 no change of disease (NC). Pretherapeutic Her2-neu status was positively correlated with therapy response (p=0.019). DNA biomarkers before onset of therapy cycles 1, 2 and 6 did not indicate outcome after therapy. However, kinetics of ALU 115 from cycle 1 to 6 showed decreases in CR patients, while in NC patients, an increase was observed (p=0.033). Similar tendencies were found for ALU 247 fragments. DNA integrity index as well as CEA and CA 15-3 were not informative for therapy outcome. Kinetics of plasma DNA (ALU 115) is associated with response to neoadjuvant chemotherapy in patients with locally confined breast cancer. 23829511 Thermal distribution of microwave antenna for atrial fibrillation catheter ablation. Abstract Purpose: The aim of this study is to investigate the effects of ablation parameters on thermal distribution during microwave atrial fibrillation catheter ablation, such as ablation time, ablation power, blood condition and antenna placement, and give proper ablative parameters to realise transmural ablation. Materials and methods: In this paper, simplified 3D antenna-myocardium-blood finite element method models were built to simulate the endocardial ablation operation. Thermal distribution was obtained based on the coupled electromagnetic-thermal analysis. Under different antenna placement conditions and different microwave power inputs within 60 s, the lesion dimensions (maximum depth, maximum width) of the ablation zones were analysed. Results: The ablation width and depth increased with the ablation time. The increase rate significantly slowed down after 10 s. The maximum temperature was located in 1 mm under the antenna tip when perpendicular to the endocardium, while 1.5 mm away from the antenna axis and 26 mm along the antenna (with antenna length about 30 mm) in the myocardium when parallel to the endocardium. The maximum temperature in the ablated area decreased and the effective ablation area (with the temperature raised to 50°C) shifted deeper into the myocardium due to the blood cooling. Conclusion: The research validated that the microwave antenna can provide continuous long and linear lesions for the treatment of atrial fibrillation. The dimensions of the created lesion widths were all larger than those of the depths. It is easy for the microwave antenna to produce transmural lesions for an atrial wall thickness of 2-6 mm by adjusting the applied power and ablation time. 23770036 Synergistic effect of hydrogen peroxide on polyploidization during the megakaryocytic differentiation of K562 leukemia cells by PMA. The human myelogenous cell line, K562 has been extensively used as a model for the study of megakaryocytic (MK) differentiation, which could be achieved by exposure to phorbol 12-myristate 13-acetate (PMA). In this study, real-time PCR analysis revealed that the expression of catalase (cat) was significantly repressed during MK differentiation of K562 cells induced by PMA. In addition, PMA increased the intracellular reactive oxygen species (ROS) concentration, suggesting that ROS was a key factor for PMA-induced differentiation. PMA-differentiated K562 cells were exposed to hydrogen peroxide (H2O2) to clarify the function of ROS during MK differentiation. Interestingly, the percentage of high-ploidy (DNA content >4N) cells with H2O2 was 34.8±2.3% at day 9, and was 70% larger than that without H2O2 (21.5±0.8%). Further, H2O2 addition during the first 3 days of PMA-induced MK differentiation had the greatest effect on polyploidization. In an effort to elucidate the mechanisms of enhanced polyploidization by H2O2, the BrdU assay clearly indicated that H2O2 suppressed the division of 4N cells into 2N cells, followed by the increased polyploidization of K562 cells. These findings suggest that the enhancement in polyploidization mediated by H2O2 is due to synergistic inhibition of cytokinesis with PMA. Although H2O2 did not increase ploidy during the MK differentiation of primary cells, we clearly observed that cat expression was repressed in both immature and mature primary MK cells, and that treatment with the antioxidant N-acetylcysteine effectively blocked and/or delayed the polyploidization of immature MK cells. Together, these findings suggest that MK cells are more sensitive to ROS levels during earlier stages of maturation. 23891572 Bioseparation of papain from Carica papaya latex by precipitation of papain-poly (vinyl sulfonate) complexes. The formation of insoluble complexes between enzymes and polyelectrolytes is a suitable technique for isolating these biomolecules from natural sources, because it is a simple and rapid technique that allows the concentration of the protein. This technique can be used in most purification protocols at the beginning of the downstream process. The aim of this investigation is to isolate papain from Carica papaya latex by precipitation of insoluble complexes between this enzyme and poly (vinyl sulfonate). The papain-poly (vinyl sulfonate) complex was insoluble at pH lower than 6, with a PVS/PAP stoichiometric ratio of 1:279. Ionic strength affected the complex formation. The presence of the polymer increased the enzymatic activity and protected the enzyme from autodegradation. The optimal conditions for the formation of insoluble papain-polyelectrolyte complex formation were applied to C. papaya latex and a high recovery was obtained (around 86%) and a purification factor around 2. This method can be applied as an isolation method of papain from C. papaya latex or as a first step in a larger purification strategy. 23913169 Inhibin-expressing clear cell neuroendocrine tumor of the ampulla: an unusual presentation of von Hippel-Lindau disease. von Hippel-Lindau (VHL) disease is a hereditary autosomal dominant disorder associated with deletions or mutations in the VHL tumor suppressor gene. Characteristically, up to 60 % of neuroendocrine tumors (NETs) associated with VHL disease display a spectrum of clear cell morphology including multivacuolated lipid-rich cell change. Unlike neurofibromatosis type 1 and multiple endocrine neoplasia type 1 syndromes, ampullary NETs have not been described in association with VHL disease. In this report, we discuss the features of an incidental ampullary clear cell NET occurring in a patient with pancreatic VHL disease including multiple pancreatic NETs. The ampullary lesion consisted of epithelial cells resembling lipoblasts or signet ring cells. In our case, all NETs showing clear cell change were positive for inhibin. While the underlying mechanism of this finding is largely unknown, it is of note that positivity for inhibin has not been observed in clear cell NETs associated with multiple endocrine neoplasia type 1 syndrome. Our case proves that NETs can develop in the ampullary region in patients with VHL; clear cell change can occur in these lesions and can mimic signet ring cell carcinoma. This issue is of clinical significance especially in small biopsy samples; thus, positivity for keratin alone should not be taken as evidence of an adenocarcinoma. Moreover, demonstration of inhibin expression in a NET with clear cell change along with other clinical stigmata should alert the diagnostician to the possibility of VHL disease. However, further larger series examining inhibin expression in both syndrome-related and sporadic clear cell NETs are needed to confirm our findings. 23821337 Calcineurin inhibition rescues early synaptic plasticity deficits in a mouse model of Alzheimer's disease. Functional and ultrastructural investigations support the concept that altered brain connectivity, exhausted neural plasticity, and synaptic loss are the strongest correlates of cognitive decline in age-related neurodegenerative dementia of Alzheimer's type. We have previously demonstrated that in transgenic mice, expressing amyloid-β precursor protein-Swedish mutation active caspase-3 accumulates in hippocampal postsynaptic compartments leading to altered postsynaptic density (PSD) composition, increased long-term depression (LTD), and dendritic spine loss. Furthermore, we found strong evidence that dendritic spine alteration is mediated by calcineurin activation, a calcium-dependent phosphatase involved in synapse signaling. In the present work, we analyzed the molecular mechanism linking alteration of synaptic plasticity to the increase of calcineurin activity. We found that acute treatment of young and plaque-free transgenic mice with the calcineurin inhibitor FK506 leads to a complete rescue of LTD and PSD composition. Our findings are in agreement with other results reporting that calcineurin inhibition improves memory function and restores dendritic spine density, confirming that calcineurin inhibition may be explored as a neuroprotective treatment to stop or slowdown synaptic alterations in Alzheimer's disease. 23142425 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism-related enzymes gene polymorphisms, NNK metabolites levels and urothelial carcinoma. Gene polymorphisms of the 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism-related enzymes-cytochrome P450 (CYP) monooxygenase 2A13 (CYP2A13) and UDP-glucuronosyltransferases (UGT)-2B7 could contribute to the levels of NNK-related metabolites in urine, thereby increasing the susceptibility to urothelial carcinoma (UC). Therefore, our study aimed to evaluate the roles of two gene polymorphisms (CYP2A13 and UGT2B7) of NNK metabolism-related enzymes in the carcinogenesis of UC in Taiwan. A hospital-based pilot case-control study was conducted. There were 121 UC cases and 121 age- and sex-matched healthy participants recruited from March 2007 to April 2009. Urine samples were analyzed for NNK-related metabolites using the liquid chromatography-tandem mass spectrometry method. Genotyping was conducted using a polymerase chain reaction-restriction fragment length polymorphism technique. ANCOVA and multivariate logistic regression were applied for data analyses. In healthy controls, former smokers had significantly higher total NNAL and higher NNAL-Gluc than never smokers or current smokers. Subjects carrying the UGT2B7 268 His/Tyr or Tyr/Tyr genotype had significantly lower total NNAL than those carrying His/His genotype. However, no association was seen between gene polymorphisms of CYP2A13 and UGT2B7 and UC risk after adjustment for age and sex. Significant dose -response associations between total NNAL, free NNAL, the ratios of free NNAL/total NNAL and NNAL-Gluc/total NNAL and UC risk were observed. In the future, large-scale studies will be required to verify the association between the single nucleotide polymorphisms of NNK metabolism-related enzymes and UC risk. 23743713 Transcriptomic and Metabolic Changes Associated with Photorespiratory Ammonium Accumulation in the Model Legume Lotus japonicus. The transcriptomic and metabolic consequences of the lack of plastidic glutamine (Gln) synthetase in the model legume Lotus japonicus were investigated. Wild-type and mutant plants lacking the plastidic isoform of Gln synthetase were grown in conditions that suppress photorespiration and then transferred for different lengths of time to photorespiratory conditions. Transcript and metabolite levels were determined at the different time points considered. Under photorespiratory active conditions, the mutant accumulated high levels of ammonium, followed by its subsequent decline. A coordinate repression of the photorespiratory genes was observed in the mutant background. This was part of a greater modulation of the transcriptome, especially in the mutant, that was paralleled by changes in the levels of several key metabolites. The data obtained for the mutant represent the first direct experimental evidence for a coordinate regulation of photorespiratory genes over time. Metabolomic analysis demonstrated that mutant plants under active photorespiratory conditions accumulated high levels of several amino acids and organic acids, including intermediates of the Krebs cycle. An increase in Gln levels was also detected in the mutant, which was paralleled by an increase in cytosolic Gln synthetase1 gene transcription and enzyme activity levels. The global panoramic of the transcripts and metabolites that changed in L. japonicus plants during the transfer from photorespiration-suppressed to photorespiration-active conditions highlighted the link between photorespiration and several other cellular processes, including central carbon metabolism, amino acid metabolism, and secondary metabolism. 23155202 Influence of coadministration of artemether and lumefantrine on selected plasma biochemical and erythrocyte oxidative stress indices in female Wistar rats. Among the artemisinin-based combination therapy (ACT) regimens, artemisinin derivative, artemether in combination with lumefantrine (artemether-lumefantrine, AL) has achieved excellent results in the fight against malarial scourge. In this study, we evaluated the toxic potential of these drugs at the therapeutic doses in female Wistar rats. Animals were randomly divided into four groups: those administered 1% Tween 80 (control), those administered artemether (4 mg/kg body weight), those administered lumefantrine (24 mg/kg body weight), and those coadministered artemether (4 mg/kg body weight) and lumefantrine (24 mg/kg body weight). The drugs were orally administered twice daily for 3 days by gastric intubation after which selected plasma biochemical indices, and erythrocytes antioxidant defence and lipid peroxidation markers were evaluated. Coadministration of artemether and lumefantrine raised liver and renal function markers and increased atherogenic index. While reduced glutathione, glucose-6-phosphate dehydrogenase (G6PD) and catalase activities were reduced, glutathione peroxidase and glutathione-s-transferase activities increased in all the treated groups compared to the control group. The drugs caused significant (p < 0.05) elevation of malondialdehyde (MDA) levels compared to the control group. These results imply that coadministration of artemether and lumefantrine may increase the risks of atherosclerosis as well as liver and renal function impairments in the users. In addition, the drugs may also promote oxidative stress in the erythrocytes. 23601404 Data collection and assessment of commonly consumed foods and recipes in six geo-political zones in Nigeria: Important for the development of a National Food Composition Database and Dietary Assessment. A cross-sectional study was undertaken to collect and assess commonly consumed foods/recipes from the six geopolitical zones in Nigeria for the production of food composition database (FCDB) for dietary assessment. Communities used were selected using a multi-stage sampling plan. Focus group discussions, interviews, recipe documentation, food preparations and literature reviews were employed. Qualitative methods were used to analyse and present data. SWOT (strengths, weaknesses, opportunities, and threats) analysis was used to evaluate the project. A total of 322 recipes were collected out of which 110 were soups. Food consumption patterns across the geographical zones were found to be changing. Variations in recipes and methods of preparation of similar foods were observed. Factors to be considered in the development of a country-specific FCDB were identified. There were challenges with the use of values reported in literature for Nigerian foods. The study justifies the need for a country-specific FCDB that will include traditional recipes. 23892841 Risk factors for coronary artery lesions in Kawasaki disease. Aim To identify the risk factors associated with the development of coronary artery lesions (CAL) in pediatric patients with Kawasaki Disease (KD). Methods A retrospective chart review of the medical records of pediatric patients diagnosed with KD who were admitted to King Abdulaziz University Hospital, Jeddah, Saudi Arabia between January 2001 and December 2011 was performed. Odd ratio (OR) with 95 % Confidence interval (CI) was measured for each risk factor for CAL. Data were presented as frequencies (percentages). A P-value less than 0.05 was considered statistically significant. Results A total of 44 patients were included in the study. Males were predominant, 27 (61.4%). The mean age of the patients was 26.7 months (range 1.5-108 months). Typical KD was recorded in 23 patients (52.3%), while coronary artery lesions were found in 26 (59.1%) patients. Coronary artery lesion was more common among patients with atypical KD, males, patients presented with history of fever more than 5 days, and intravenous immunoglobulins (IVIG) infusion after 10 days of start of fever (OR 4.2, 95% CI 1.1-15.3; p =0.01, OR 5.2, 95% CI 1.4-19.5; p =0.01, OR 5.4, 95% CI 1.5-20.1; p =0.01, OR 5.6, 95% CI 1.4-21.9; p =0.6, respectively). Conclusion Atypical Kawasaki disease should be considered in children and early administration of IVIG reduces the frequency of coronary artery lesions. 22928818 Impact of reference gene selection for type 2 cannabinoid receptor gene expression studies in human spermatozoa. Quantitative real-time polymerase chain reaction (qRT-PCR) has been employed to study the gene expression profiles in human spermatozoa, but accurate analysis is dependent upon normalisation of data against an endogenous control. β-Actin (ACTB) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) are the most commonly used reference genes for normalisation of gene expression in human spermatozoa, but the expression of these genes in many tissues has considerable variation under different physiological, pathological and experimental conditions which limits their effectiveness in normalisation. The expression stability of a panel of 12 reference genes was studied in normal and pathological human spermatozoa using geNorm and NormFinder software. Although there were some discrepancies in the ranking of reference gene stability, each software program ranked B2 M, ACTB, CYC1 and 18S RNA within the top 5 and recommended the combined use of at least two reference genes. Normalisation of qRT-PCR data for the cannabinoid receptor type 2 in spermatozoa using the different housekeeping genes demonstrated how, without validation, conflicting results are obtained. We recommend that the arbitrary use of reference genes should be avoided and the validation of reference gene stability should be undertaken prior to every study. For normalisation of CB2 expression, we would recommend using the geometric mean of B2 M and ACTB. 23830315 Hypertensive extracorporeal limb perfusion for critical limb ischemia. This article reports the early results in humans of hypertensive extracorporeal limb perfusion (HELP) technology in the prevention of major limb amputation due to ischemia. The short-term aim was to dilate pre-existing collateral channels, and the long-term aim was to stimulate remodeling and new collateral development by increasing endothelial shear stress and wall tension. This study evaluated 20 patients with critical limb ischemia who were treated with HELP. These patients had no other option but major amputation, as determined by at least two vascular surgeons. The arterial circulation to the ischemic limb was isolated from the systemic circulation by the use of an endoluminal balloon catheter in seven patients and by an implantable, inflatable, occlusive cuff in 13. The limbs were hyperperfused through the peripheral access system with an extracorporeal pump, producing a minimally pulsatile waveform at 200% to 300% of the mean arterial pressure. This was performed repeatedly in sessions of 24 to 36 hours, up to a maximum of 74 hours. The primary end point was avoidance of major amputation. The secondary end points were the clinical improvements in rest pain, ulcer healing, and claudication distance. Patients were analyzed and reviewed using infrared thermography and ultrasound imaging parameters of the limb. Given adequate arterial access, 39 of 40 connections developed flows four to eight times those supplied to the limb by the normal cardiac output. A progressive decrease was noted in peripheral resistance. All patients developed a pain-free, warm foot or hand while on the pump in the short-term. In the longer term at a mean of 22 months (range, 12-54 months), eight of 20 patients (40%) had avoided major amputation and four more had a delay in amputation of an average of 4 months. The ankle-brachial index changed from 0.04 ± 0.07 (range, 0.00-0.94) to 0.63 ± 0.39 (t-test, P < .05). Bleeding, infection, premature cessation of the treatment, and poor patient selection resulted in the failures. There were two short-term unrelated deaths that occurred at 1 and 3 months follow-up. The collateral circulation of ischemic limbs can be augmented and regulated by a connection to an extracorporeal centrifugal pump, with isolation from the systemic circulation provided by balloons and with an access system providing repeatable pump connections. Major amputation may be avoided in selected cases. 23686447 Characterization of MHC class II B polymorphism in bottlenecked New Zealand saddlebacks reveals low levels of genetic diversity. The major histocompatibility complex (MHC) is integral to the vertebrate adaptive immune system. Characterizing diversity at functional MHC genes is invaluable for elucidating patterns of adaptive variation in wild populations, and is particularly interesting in species of conservation concern, which may suffer from reduced genetic diversity and compromised disease resilience. Here, we use next generation sequencing to investigate MHC class II B (MHCIIB) diversity in two sister taxa of New Zealand birds: South Island saddleback (SIS), Philesturnus carunculatus, and North Island saddleback (NIS), Philesturnus rufusater. These two species represent a passerine family outside the more extensively studied Passerida infraorder, and both have experienced historic bottlenecks. We examined exon 2 sequence data from populations that represent the majority of genetic diversity remaining in each species. A high level of locus co-amplification was detected, with from 1 to 4 and 3 to 12 putative alleles per individual for South and North Island birds, respectively. We found strong evidence for historic balancing selection in peptide-binding regions of putative alleles, and we identified a cluster combining non-classical loci and pseudogene sequences from both species, although no sequences were shared between the species. Fewer total alleles and fewer alleles per bird in SIS may be a consequence of their more severe bottleneck history; however, overall nucleotide diversity was similar between the species. Our characterization of MHCIIB diversity in two closely related species of New Zealand saddlebacks provides an important step in understanding the mechanisms shaping MHC diversity in wild, bottlenecked populations. 23906793 Yeast growth in raffinose results in resistance to acetic-acid induced programmed cell death mostly due to the activation of the mitochondrial retrograde pathway. In order to investigate whether and how a modification of mitochondrial metabolism can affect yeast sensitivity to programmed cell death (PCD) induced by acetic acid (AA-PCD), yeast cells were grown on raffinose, as a sole carbon source, which, differently from glucose, favours mitochondrial respiration. We found that, differently from glucose-grown cells, raffinose-grown cells were mostly resistant to AA-PCD and that this was due to the activation of mitochondrial retrograde (RTG) response, which increased with time, as revealed by the up-regulation of the peroxisomal isoform of citrate synthase and isocitrate dehydrogenase isoform 1, RTG pathway target genes. Accordingly, the deletion of RTG2 and RTG3, a positive regulator and a transcription factor of the RTG pathway, resulted in AA-PCD, as shown by TUNEL assay. Neither deletion in raffinose-grown cells of HAP4, encoding the positive regulatory subunit of the Hap2,3,4,5 complex nor constitutive activation of the RTG pathway in glucose-grown cells due to deletion of MKS1, a negative regulator of RTG pathway, had effect on yeast AA-PCD. The RTG pathway was found to be activated in yeast cells containing mitochondria, in which membrane potential was measured, capable to consume oxygen in a manner stimulated by the uncoupler CCCP and inhibited by the respiratory chain inhibitor antimycin A. AA-PCD resistance in raffinose-grown cells occurs with a decrease in both ROS production and cytochrome c release as compared to glucose-grown cells en route to AA-PCD. 23897961 Bortezomib-Based Versus Nonbortezomib-Based Induction Treatment Before Autologous Stem-Cell Transplantation in Patients With Previously Untreated Multiple Myeloma: A Meta-Analysis of Phase III Randomized, Controlled Trials. To characterize efficacy and safety of bortezomib-based versus nonbortezomib-based induction regimens through an integrated analysis of data from phase III studies in transplantation-eligible patients with previously untreated myeloma. Patient-level data from the IFM 2005-01 (bortezomib-dexamethasone v vincristine-doxorubicin-dexamethasone [VAD] induction), HOVON-65/GMMG-HD4 (bortezomib-doxorubicin-dexamethasone v VAD), and PETHEMA GEM05MENOS65 (bortezomib-thalidomide-dexamethasone v thalidomide- dexamethasone) studies were pooled in an integrated analysis of efficacy and safety. Study-level data from the GIMEMA MM-BO2005 study (bortezomib-thalidomide-dexamethasone v thalidomide-dexamethasone) supplemented the integrated patient-level analysis. Key efficacy end points were post-transplantation complete plus near-complete response (CR+nCR) rate and progression-free survival (PFS). Patient-level data for 1,572 patients (bortezomib-based induction, n = 787; nonbortezomib-based induction, n = 785) were included. Post-transplantation CR+nCR rate was significantly higher following bortezomib-based versus nonbortezomib-based induction (38% v 24%; odds ratio, 2.05; P < .001); the benefit remained similar (pooled odds ratio, 1.96) when GIMEMA MM-BO2005 data were included. Median PFS was 35.9 months versus 28.6 months with bortezomib-based versus nonbortezomib-based induction, respectively (hazard ratio, 0.75; P < .001); 3-year overall survival (OS) rates were 79.7% and 74.7%, respectively (hazard ratio for OS, 0.81; P = .0402). Median duration of induction treatment was 11 weeks in both treatment groups. Rates of peripheral neuropathy during induction were 34% versus 17% (grade ≥ 3, 6% v 1%). Overall, 3% and 4% of patients died during bortezomib-based and nonbortezomib-based induction, respectively. Bortezomib-based induction results in significant improvements in response and PFS/OS compared with nonbortezomib-based induction and is generally well tolerated, with a higher rate of peripheral neuropathy but no apparent increase in risk of death during induction. 23528225 The brain's heart - therapeutic opportunities for patent foramen ovale (PFO) and neurovascular disease. Patent foramen ovale (PFO), a common congenital cardiac abnormality, is a connection between the right and left atria in the heart. As a "back door to the brain", PFO can serve as a conduit for paradoxical embolism, allowing venous thrombi to enter the arterial circulation, avoiding filtration by the lungs, and causing ischemic stroke. PFO-related strokes affect more than 150,000 people per year in the US, and PFO is present in up to 60% of migraine patients with aura, and in one out of four normal individuals. So, in such a highly prevalent condition, what are the best treatment and prevention strategies? Emerging studies show PFO-related neurovascular disease to be a multi-organ condition with varying individual risk factors that may require individualized therapeutic approaches - opening the field for new pharmacologic and therapeutic targets. The anatomy of PFO suggests that, in addition to thrombi, it can also allow harmful circulatory factors to travel directly from the venous to the arterial circulation, a concept important in finding novel therapeutic targets for PFO-related neurovascular injury. Here, we: 1) review emerging data on PFO-related injuries and clinical trials; 2) discuss potential mechanisms of PFO-related neurovascular disease in the context of multi-organ interaction and heart-brain signaling; and 3) discuss novel therapeutic targets and research frontiers. Clinical studies and molecular mapping of the circulatory landscape of this multi-organ disease will both be necessary in order to better individualize clinical treatment for a condition affecting more than a quarter of the world's population. 23862689 TLR5 stop codon polymorphism is associated with invasive aspergillosis after allogeneic stem cell transplantation. Single nucleotide polymorphisms (SNPs) have been associated with an increased incidence of invasive aspergillosis (IA) after allogeneic stem cell transplantation (allo-SCT). We analyzed 41 patients with proven/probable IA after allo-SCT for an association of SNPs, within the TLR2, TLR4, TLR5, TLR9, and NOD2/CARD15 genes, with susceptibility to IA. The control group consisted of 130 patients who had allo-SCT but did not develop IA. While no association was found for donor SNPs and the recipients' risk of IA, analysis of recipient SNPs showed a significant association between the presence of recipient TLR5-Stop SNP (1174C> T) and the incidence of IA (P = 0.004). Multivariate analysis demonstrated that the recipient TLR5-Stop SNP appeared as an independent risk factor for IA after allo-SCT. Our study suggests that TLR5 is involved in host defense against Aspergillus fumigatus, and that the recipient TLR5-Stop SNP represents a risk factor for the development of IA after allo-SCT. 23867118 Methodological considerations in use of the cortisol/DHEA(S) ratio in adolescent populations. The cortisol/DHEA(S) ratio has demonstrated utility in studies of HPA activity and psychopathology. However, use of the cortisol/DHEA(S) ratio in adolescent populations requires additional consideration of differential changes in DHEA(S) and cortisol during the course of puberty. This study examines the relationship between pubertal status and individual cortisol and DHEAS levels as well as with the cortisol/DHEAS ratio. Morning salivary cortisol and urinary DHEAS levels were obtained for 267 young adolescents at three time points, each approximately one year apart. Growth curve modeling and repeated measures ANOVA were used to assess the effect of adrenal development on individual hormone levels and on the total ratio. Pubic hair development was a significant predictor of change over time in DHEAS but not cortisol. Development was also a significant predictor of the cortisol/DHEAS ratio when raw cortisol and DHEAS values were used. Our findings indicate that, when DHEAS levels were adjusted to control for pubertal status, the ratio demonstrated stability over time. This finding is in line with the hypothesis that the ratio may tap stable individual differences in HPA functioning. 23777906 Brain edema formation is associated with the time rate of blood pressure variation in acute stroke patients. Both brain edema and increased blood pressure (BP) variability are associated with poor outcome after stroke. The aim of the present study was to evaluate a possible association between edema formation and a relatively new index of BP variability defined as time rate (TR) of BP variation. A total of 128 first-ever acute stroke patients underwent 24-h ambulatory BP monitoring within 24 h from onset of stroke. All patients were imaged with computed tomography scan on admission and after 5 days to determine the presence of brain edema. The TR of BP variation was defined as the first derivative of the BP values against time. Known risk factors and neurological severity on admission were documented. The 24-h TR of systolic BP variation was significantly higher (P<0.001) in stroke patients with brain edema (0.69±0.15 mmHg/min) compared with those without edema (0.57±0.12 mmHg/min). The multivariate logistic regression model showed that a 0.1 mmHg/min increase in the TR of 24-h systolic BP variation was associated with a 13.9% increased probability of the presence of brain edema (odds ratio=1.139, 95% confidence interval: 1.058-1.225, P<0.001), after adjusting for history of diabetes mellitus, hypercholesterolemia, type of stroke, neurological deficit, and 24-h systolic BP. Increased values of 24-h TR of systolic BP variation are associated independently with formation of edema in acute stroke patients. 23855264 Four-part choral synthesis system for investigating intonation in a cappella choral singing. Accurate tuning is an important aspect of singing in harmony in the context of a choir or vocal ensemble. Tuning and 'pitch drift' are concerning factors in performance for even the most accomplished professional choirs when singing a cappella (unaccompanied). In less experienced choirs tuning often lacks precision, typically because individual singers have not developed appropriate listening skills. In order to investigate accuracy of tuning in ensemble singing situations, a chorally appropriate reference is required against which frequency measurements can be made. Since most basic choral singing involves chords in four parts, a four-part reference template is used in which the fundamental frequencies of the notes in each chord can be accurately set. This template can now be used in experiments where three of the reference parts are tuned in any musical temperament (tuning system), in this case equal and just temperaments, and played over headphones to a singer to allow her/his tuning strategy to be investigated. This paper describes a practical implementation of a four-part choral synthesis system in Pure Data (Pd) and its use in an investigation of tuning of notes by individual singers using an exercise originally written to explore pitch drift in a cappella choral singing. 23535877 Endoscopic ultrasound-guided antegrade treatments for biliary disorders in patients with surgically altered anatomy. Endoscopic retrograde cholangiopancreatography in patients with surgically altered anatomy is challenging. Several endoscopic ultrasound (EUS)-guided biliary access techniques have been reported as effective alternatives. EUS-guided antegrade treatments (AG) have been developed more recently but have not yet been studied well. To evaluate the feasibility and safety of EUS-AG for biliary disorders in patients with surgically altered anatomies. We retrospectively identified all the patients who underwent EUS-AG. The left intrahepatic bile duct (IHBD) was initially punctured from the intestine followed by cholangiography, antegrade guidewire manipulation, and bougie dilation of the fistula. Either antegrade biliary stenting (ABS) or antegrade balloon dilation (ABD) was performed depending on the biliary disorders. In stone cases, the stones were antegradely pushed out using a balloon. After ABD, a nasobiliary drainage tube was placed to prevent possible bile leak and to keep an access route for any possible repeat procedures. EUS-AG was attempted in seven patients including choledocholithiasis in five, malignant biliary obstruction in one, and bilioenteric anastomosis stricture in one. EUS-AG was not performed in one patient because EUS-cholangiography did not indicate the presence of stones. In the remaining six patients, the IHBD was successfully punctured, followed by cholangiography, guidewire insertion, and bougie dilation. ABS and ABD were successfully performed in one and five patients, respectively. Antegrade procedures with ABD were repeated twice in one patient. Mild complications were observed in two patients. EUS-AG for biliary disorders in patients with surgically altered anatomy is feasible. Further studies are warranted. 23857028 Biomechanical evaluation of meniscal root repair: a porcine study. Meniscal root repair is commonly practised using transtibial pull-out sutures. The purpose of the study was to investigate whether these are effective in restoring contact of the root to its footprint and a normal loading pattern of the cartilage under restricted loading conditions as used post-operatively. First, a transtibial pull-out suture was simulated using porcine menisci (n = 10). It was repetitively loaded (100×; 1-10 N) and the elongation of the suture determined. In the second part of the study, porcine knees (n = 8) were subjected to repetitive low-level femoro-tibial loads (50 cycles; 100 N). A displacement sensor measured the deformation of the cartilage in the area of femoro-tibial contact. The residual deformation of the cartilage, which results from its viscoelastic behaviour, was determined as a measure of the local stress. Three scenarios were investigated: meniscal root intact, detached, and repaired. Repetitive loading caused a median suture elongation of 3.8 mm. Residual deformation of the cartilage was increased (p = 0.047) with the root detached. Root repair could not restore it to normal (n.s.). In this model, meniscus root repair was not effective in restoring the normal loading pattern of the cartilage because cyclic loading caused an elongation of the repair. In practice, this effect might impair the healing of repaired meniscal roots to the tibial bone. 23919505 rFN/Cad-11-Modified Collagen Type II Biomimetic Interface Promotes the Adhesion and Chondrogenic Differentiation of Mesenchymal Stem Cells. Properties of the cell-material interface are determining factors in the successful function of cells for cartilage tissue engineering. Currently, cell adhesion is commonly promoted through the use of polypeptides; however, due to their lack of complementary or modulatory domains, polypeptides must be modified to improve their ability to promote adhesion. In this study, we utilized the principle of matrix-based biomimetic modification and a recombinant protein, which spans fragments 7-10 of fibronectin module III (heterophilic motif ) and extracellular domains 1-2 of cadherin-11 (rFN/Cad-11) (homophilic motif ), to modify the interface of collagen type II (Col II) sponges. We showed that the designed material was able to stimulate cell proliferation and promote better chondrogenic differentiation of rabbit mesenchymal stem cells (MSCs) in vitro than both the FN modified surfaces and the negative control. Further, the Col II/rFN/Cad-11-MSCs composite stimulated cartilage formation in vivo; the chondrogenic effect of Col II alone was much less significant. These results suggested that the rFN/Cad-11-modified collagen type II biomimetic interface has dual biological functions of promoting adhesion and stimulating chondrogenic differentiation. This substance, thus, may serve as an ideal scaffold material for cartilage tissue engineering, enhancing repair of injured cartilage in vivo. 23728955 Structure guided inhibitor designing of CDK2 and discovery of potential leads against cancer. On the basis of stereo specific information obtained from crystal structures of CDK2, indole and chromene analogues were designed by suitably substituting the pharmacophores on their moiety and docked with target protein for calculating binding affinities. The binding affinities are represented in glide score. (5E)-5-[(1-methyl-1H-indol-3-yl)methylidene]-2,4,6-trioxotetrahydro-2H-pyrimidin-1-ide (I1), (5E)-5-(1H-indol-3-ylmethylidene)-2,4,6-trioxotetrahydro-2H-pyrimidin-1-ide (I2) and 2-amino-4-(4-methyl phenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (C9) were selected for synthesis and biological testing based on vital interactions. (5E)-5-(1H-indol-3-ylmethylidene)-2,4,6-trioxotetrahydro-2H-pyrimidin-1-ide(I2) and 2-amino-4-(4-methyl phenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (C9) were proved to be active against MCF-7 and HeLa cell lines. 23936190 Neuregulin Upregulates Microglial α7 Nicotinic Acetylcholine Receptor Expression in Immortalized Cell Lines: Implications for Regulating Neuroinflammation. Neuregulin, previously known as ARIA, is a signaling protein involved in cell survival, synaptic plasticity, cell communication and differentiation. Neuregulin has also been described as a potent inducer of acetylcholine receptor transcription in muscle and although both neuregulin and acetylcholine have been individually described to have neuroprotective roles, their relationship in the cholinergic anti-inflammatory pathway of the brain has not been examined. Using three cell lines, BV-2, EOC-20 and RAW 264.7, we investigated the role that neuregulin signaling through the Erb family of tyrosine kinases may play in the anti-inflammatory process mediated by the α7 nicotinic acetylcholine receptors. Here we show that ErbB4 is expressed in all of our cell lines and is phosphorylated upon treatment with neuregulin. Neuregulin treatment further increases the expression of α7 nicotinic acetylcholine receptors in the microglial lines tested. Given the central role of α7 nicotinic acetylcholine receptors in regulating system inflammation we analyzed the expression of several pro-inflammatory cytokines in our system. Using ELISAs for TNF-α and IL-6 we show that treatment with NRG can produce a nearly a 33% decrease in the levels of tumor necrosis factor-α secreted by activated microglia and a nearly 88% decrease in IL-6. Given these results we propose a neuroprotective role for neuregulin wherein it modulates the expression of TNF-α and thus inflammation in the CNS via the upregulation of α7 nicotinic acetylcholine receptor expression in microglia in vitro. We suggest that the disregulation of neuregulin expression may be pivotal in neurological disorders characterized by inflammation. 23301848 Inelastic X-ray scattering studies of the short-time collective vibrational motions in hydrated lysozyme powders and their possible relation to enzymatic function. High-resolution inelastic X-ray scattering was used to investigate the collective vibrational excitations in hydrated lysozyme powders as a function of hydration level and temperature. It is found that the samples with strong enzymatic function are "soft", in the sense that they exhibit low frequency and large amplitude intraprotein collective vibrational motions on certain length scales. This is not the case for samples with weak or no enzymatic activity. Thus, we identify a possible correlation between the short-time intraprotein collective vibrational motions and the establishment of enzymatic function in hydrated lysozyme powders, and bring new insight to notions of protein "conformational flexibility" and "softness" in terms of these motions. 23665056 Comparative assessment of dermal wound healing potentials of various Trifolium L. extracts and determination of their isoflavone contents as potential active ingredients. Trifolium species are used in Turkish folk medicine as a wound healing agent, expectorant, antiseptic, sedative and to alleviate pain in rheumatism. In the present study, the aqueous methanolic extracts (80%) of 13 Trifolium species (Trifolium ambigum, Trifolium arvense var. arvense, Trifolium campestre, Trifolium canescens, Trifolium hybridum var. anatolicum, Trifolium hybridum var. hybridum, Trifolium pannonicum, Trifolium pratense var. pratense, Trifolium purpureum var. purpureum, Trifolium repens var. repens, Trifolium resupinatum var. microcephalum, Trifolium spadiceum and Trifolium trichocephalum) collected from different regions of Anatolia were evaluated for their in vivo wound healing effects. In vivo wound healing activities of the plant aqueous methanolic extracts were evaluated by linear incision and circular excision wound models subsequent to histopathological analysis. Active constituents were determined by a validated high performance liquid chromatographic method. Precision of the method was performed by the evaluation of intra-day and inter-day variations of the each standard at limits of quantification (LOQ) levels. The aqueous methanolic extracts of Trifolium canescens and Trifolium pretense var. pratense possessed better wound healing activity compared to the other extracts and control groups. The animal groups treated with the Trifolium canescens extract demonstrated increased contraction (48.96%) on excision and a significant increase in wound tensile strength (35.6%) on incision models. The main compounds were detected as genistein and biochanin A for Trifolium canescens. The results of the present study revealed the wound healing potential of Trifolium canescens. This might be due to the combined effect of the isoflavones genistein, formononetin, daidzein, and biochanin A present in the extract. 23273038 N-cinnamoylated chloroquine analogues as dual-stage antimalarial leads. The control of malaria is challenged by drug resistance, and new antimalarial drugs are needed. New drug discovery efforts include consideration of hybrid compounds as potential multitarget antimalarials. Previous work from our group has demonstrated that hybrid structures resulting from cinnamic acid conjugation with heterocyclic moieties from well-known antimalarials present improved antimalarial activity. Now, we report the synthesis and SAR analysis of an expanded series of cinnamic acid derivatives displaying remarkably high activities against both blood- and liver-stage malaria parasites. Two compounds judged most promising, based on their in vitro activity and druglikeness according to the Lipinski rules and Veber filter, were active in vivo against blood-stage rodent malaria parasites. Therefore, the compounds reported represent a new entry as promising dual-stage antimalarial leads. 23441959 Genetic and crossbreeding parameters for incidence of recorded clinical lameness in New Zealand dairy cattle. To estimate genetic and crossbreeding parameters for the incidence of recorded clinical lameness in New Zealand dairy cattle. Herd records from 76,357 cows, collected during the 2005/06 to 2008/09 milking seasons from 155 herds in the Livestock Improvement Corporation young sire progeny test scheme, were used to estimate genetic parameters and breed effects for incidence of recorded clinical lameness in HolsteinFriesian, Jersey and crossbred dairy cattle. Recorded clinical lameness was coded "1" for cows that presented at least one event of clinical lameness at any day during the season and "0" for unaffected cows. Genetic parameters were estimated using an animal model across breeds considering all and then only first lactation records. Heritability and repeatability of recorded clinical lameness were calculated from the variance component estimates both with and without logit transformation. The mean incidence of recorded clinical lameness per herd was 6.3 (min 2, max 34)%. The incidence of recorded clinical lameness in Holstein Friesian cows (mean 6.8, SE 0.24%) was higher than the incidence of recorded clinical lameness in crossbred (mean 6.1, SE 0.19%) and Jersey cows (mean 6.0, SE 0.28%) (p=0.0002). There was no difference in incidence between crossbred and Jersey cows (p=0.96). Estimates of the heritability of recorded clinical lameness as an untransformed trait were 0.053 (SE 0.014) for first lactation records and 0.016 (SE 0.003) for all lactation records. As a transformed (logit) trait heritabilities were 0.067 (SE 0.024) and 0.044 (SE 0.016) for first and all lactation records, respectively. The repeatability estimates of recorded clinical lameness were 0.071 (SE 0.005) and 0.107 (SE 0.011) for untransformed and logit transformed lactation records, respectively. Sire estimated breeding values for recorded clinical lameness showed the lowest values in Jersey sires, and ranged between -5 and 8%. Despite the low heritability of recorded clinical lameness, this study provided evidence that there is significant exploitable animal genetic variation. Selection of specific sires across and within breeds could be an option for increasing genetic resistance to lameness in New Zealand dairy cattle. 23515443 Diaphragm and ventilatory dysfunction during cancer cachexia. Cancer cachexia is characterized by a continuous loss of locomotor skeletal muscle mass, which causes profound muscle weakness. If this atrophy and weakness also occurs in diaphragm muscle, it could lead to respiratory failure, which is a major cause of death in patients with cancer. Thus, the purpose of the current study was to determine whether colon-26 (C-26) cancer cachexia causes diaphragm muscle fiber atrophy and weakness and compromises ventilation. All diaphragm muscle fiber types were significantly atrophied in C-26 mice compared to controls, and the atrophy-related genes, atrogin-1 and MuRF1, significantly increased. Maximum isometric specific force of diaphragm strips, absolute maximal calcium activated force, and maximal specific calcium-activated force of permeabilized diaphragm fibers were all significantly decreased in C-26 mice compared to controls. Further, isotonic contractile properties of the diaphragm were affected to an even greater extent than isometric function. Ventilation measurements demonstrated that C-26 mice have a significantly lower tidal volume compared to controls under basal conditions and, unlike control mice, an inability to increase breathing frequency, tidal volume, and, thus, minute ventilation in response to a respiratory challenge. These data demonstrate that C-26 cancer cachexia causes profound respiratory muscle atrophy and weakness and ventilatory dysfunction. 22370641 WNT6 is a novel target gene of caveolin-1 promoting chemoresistance to epirubicin in human gastric cancer cells. Resistance to chemotherapy is a major obstacle for curative treatment of human gastric cancer (GC). However, the underlying molecular mechanisms are largely unknown. Wingless-type MMTV integration site family members (WNTs) are secreted glycoproteins involved in embryogenesis and, on inappropriate expression in the adult, in cancer. Here, we show expression of WNT6 in GC patient specimens, human GC cell lines and in a mouse model of GC. In human GC cells, WNT6 expression was enhanced by caveolin-1 (Cav1), a scaffold protein of plasma membrane caveolae. WNT6 knock-down and overexpression experiments demonstrated that WNT6 increased the resistance to apoptotic cell death induced by the anthracycline chemotherapeutics epirubicin (Epi) and doxorubicin (Dox). Epi increased the activity of the human WNT6 promoter through Cav1-dependent binding of β-catenin to the proximal WNT6 promoter. Epi increased both WNT6/Wnt6 and Cav1 expression in human GC cells and within the tumor area of a murine model of GC (CEA424-SV40 TAg). In GC patients, WNT6 expression was positively associated with the tumor stage and the nodal status, and inversely correlated with the response to ECF (Epi, cisplatin, 5-fluorouracil) chemotherapy. These results showed that WNT6 and Cav1 are upregulated by chemotherapeutics and enhance the resistance of GC cells to anthracycline drugs. Understanding the molecular mechanisms driving WNT6/Cav1-induced drug resistance will provide benefits in developing new therapies for GC. 23969597 Tractography-Guided Stimulation of Somatosensory Fibers for Thalamic Pain Relief. Background: The spinothalamocortical tract (STC) is seen as a neural tract responsible for or involved in the generation or transmission of thalamic pain. Either the thalamus itself or the posterior limb of the internal capsule (PLIC) are targets for deep brain stimulation (DBS) in patients with thalamic pain, but due to its low contrast, conventional MRI cannot visualize the STC directly. Objectives: To show the feasibility of integrating diffusion tensor imaging-based tractography into the stereotactic treatment planning for identification of an object-oriented lead trajectory that allows STC-DBS with multiple electrode contacts. Methods: Diffusion tensor imaging was performed in 4 patients with thalamic pain. The STC was modeled and integrated into the stereotactic treatment planning for DBS. DBS-lead implantation was done according to trajectory planning along the modeled STC at the level of the PLIC. Results: After implantation, electrode stimulation was possible over a length of more than 20 mm with a tractography-based trajectory along the PLIC part of the STC. After a follow-up of 12 months, pain relief of more than 40% was achieved in 3 of 4 patients with rating on a visual analogue scale. In 1 patient, stimulation failed to reach any long-lasting positive effects. Conclusions: Integrating tractography data into stereotactic planning of DBS in thalamic pain is technically feasible. It can be used to identify a lead trajectory that allows for multiple contact stimulation along the STC at the level of the PLIC. Due to long-lasting positive stimulation effect, tractography-guided stimulation of sensory fibers seems to be beneficial for thalamic pain relief. 23936401 Assessing Uncertainty in High-Resolution Spatial Climate Data across the US Northeast. Local and regional-scale knowledge of climate change is needed to model ecosystem responses, assess vulnerabilities and devise effective adaptation strategies. High-resolution gridded historical climate (GHC) products address this need, but come with multiple sources of uncertainty that are typically not well understood by data users. To better understand this uncertainty in a region with a complex climatology, we conducted a ground-truthing analysis of two 4 km GHC temperature products (PRISM and NRCC) for the US Northeast using 51 Cooperative Network (COOP) weather stations utilized by both GHC products. We estimated GHC prediction error for monthly temperature means and trends (1980-2009) across the US Northeast and evaluated any landscape effects (e.g., elevation, distance from coast) on those prediction errors. Results indicated that station-based prediction errors for the two GHC products were similar in magnitude, but on average, the NRCC product predicted cooler than observed temperature means and trends, while PRISM was cooler for means and warmer for trends. We found no evidence for systematic sources of uncertainty across the US Northeast, although errors were largest at high elevations. Errors in the coarse-scale (4 km) digital elevation models used by each product were correlated with temperature prediction errors, more so for NRCC than PRISM. In summary, uncertainty in spatial climate data has many sources and we recommend that data users develop an understanding of uncertainty at the appropriate scales for their purposes. To this end, we demonstrate a simple method for utilizing weather stations to assess local GHC uncertainty and inform decisions among alternative GHC products. 23896568 Cancer Metabolism: New Validated Targets for Drug Discovery. Recent studies in cancer metabolism directly implicate catabolic fibroblasts as a new rich source of i) energy and ii) biomass, for the growth and survival of anabolic cancer cells. Conversely, anabolic cancer cells upregulate oxidative mitochondrial metabolism, to take advantage of the abundant fibroblast fuel supply. This simple model of "metabolic-symbiosis" has now been independently validated in several different types of human cancers, including breast, ovarian, and prostate tumors. Biomarkers of metabolic-symbiosis are excellent predictors of tumor recurrence, metastasis, and drug resistance, as well as poor patient survival. New pre-clinical models of metabolic-symbiosis have been generated and they genetically validate that catabolic fibroblasts promote tumor growth and metastasis. Over 30 different stable lines of catabolic fibroblasts and >10 different lines of anabolic cancer cells have been created and are well-characterized. For example, catabolic fibroblasts harboring ATG16L1 increase tumor cell metastasis by >11.5-fold, despite the fact that genetically identical cancer cells were used. Taken together, these studies provide >40 novel validated targets, for new drug discovery and anti-cancer therapy. Since anabolic cancer cells amplify their capacity for oxidative mitochondrial metabolism, we should consider therapeutically targeting mitochondrial biogenesis and OXPHOS in epithelial cancer cells. As metabolic-symbiosis promotes drug-resistance and may represent the escape mechanism during anti-angiogenic therapy, new drugs targeting metabolic-symbiosis may also be effective in cancer patients with recurrent and advanced metastatic disease. 23732775 Pancreatic lipase-related protein 2 digests fats in human milk and formula in concert with gastric lipase and carboxyl ester lipase. Background:Dietary fats must be digested into fatty acids and monoacylglycerols prior to absorption. In adults, colipase-dependent pancreatic triglyceride lipase (PTL) contributes significantly to fat digestion. In newborn rodents and humans, the pancreas expresses low levels of PTL. In rodents, a homologue of PTL, pancreatic lipase-related protein 2 (PLRP2), and carboxyl ester lipase (CEL) compensate for the lack of PTL. In human newborns, the role of PLRP2 in dietary fat digestion is unclear. To clarify the potential of human PLRP2 to influence dietary fat digestion in newborns, we determined PLRP2 activity against human milk and infant formula.Methods:The activity of purified recombinant PLRP2, gastric lipase (GL), and CEL against fats in human milk and formula was measured with each lipase alone and in combination with a standard pH-stat assay.Results:Colipase added to human milk stimulated fat digestion. PLRP2 and CEL had activity against human milk and formula. Predigestion with GL increased PLRP2 activity against both substrates. Together, CEL and PLRP2 activity was additive with formula and synergistic with human milk.Conclusion:PLRP2 can digest fats in human milk and formula. PLRP2 acts in concert with CEL and GL to digest fats in human milk in vitro. 23924742 Enhancing effect of a cysteinyl thiol on the antioxidant activity of flavonoids and identification of the antioxidative thiol adducts of myricetin. The enhancing effect of a cysteinyl thiol N-benzoylcysteine methyl ester on the antioxidant activity of several flavonoids was investigated in a lipid oxidation system. Obvious enhancement was apparent for catechin, myricetin, quercetin, and taxifolin, the activity for myricetin being the most potent among them. An HPLC analysis of the products from the antioxidation reaction of myricetin in the presence of the thiol was carried out and the structures of the products were determined to clarify the enhancing effect chemically. The obtained data indicated that two thiol adducts on the B ring, and probably C-ring adducts, which were produced in the antioxidation process, exerted an enhancing effect on the antioxidant activity of myricetin. 23527545 The Arf GAP AGAP2 Interacts with βArrestin2 and Regulates β2-Adrenergic Receptor Recycling and Erk Activation. AGAP2 is a multidomain Arf GAP (ADP ribosylation factor-directed GTPase-activating protein) that was shown to promote the fast-recycling of transferrin receptors. Here, we tested the hypothesis that AGAP2 regulates trafficking of β2-adrenergic receptors. We found that AGAP2 formed a complex with βArrestin1 and βArrestin2, proteins that are known to regulate β2-adrenergic receptor signaling and trafficking. AGAP2 colocalized with βArrestin2 on the plasma membrane, and knockdown of AGAP2 expression reduced plasma membrane association of βArrestin2 upon β2-adrenergic receptor activation. AGAP2 also colocalized with internalized β2-adrenergic receptors on endosomes, and overexpression of AGAP2 slowed accumulation of β2-adrenergic receptor in the perinuclear recycling endosomes. On the contrary, knockdown of AGAP2 expression prevented recycling of β2-adrenergic receptor back to the plasma membrane. In addition, AGAP2 formed a complex with endogenous Erk and overexpression of AGAP2 potentiated Erk phosphorylation induced by β2-adrenergic receptors. Taken together, these results support the hypothesis that AGAP2 plays a role in the signaling and recycling of β2-adrenergic receptors. 23863988 Ex Vivo Dermoscopy for Biobank-Oriented Sampling of Melanoma. IMPORTANCE In the era of targeted therapy for cancer, translational research identifying molecular targets in melanoma offers novel opportunities for potential new treatments. OBJECTIVES To describe a method for sampling fresh tissue from primary melanoma and to test whether the area of maximal thickness can be identified with dermoscopy to ensure it remains available for routine histopathological diagnosis. DESIGN, SETTING, AND PARTICIPANTS Tumors clinically suspicious for melanoma with diameter exceeding 5 mm were included. Dermoscopy-guided sampling was performed using a 2-mm to 3-mm punch through not the thickest part of the tumor. In vivo and ex vivo dermoscopic images obtained were available to the diagnosing pathologist. Melanoma samples were obtained in a referral melanoma unit. MAIN OUTCOMES AND MEASURES In study 1, Breslow thickness in 10 melanomas was compared between sampled tissue and the remaining specimen to confirm that the area of maximal thickness remained available for the histopathological diagnosis. In study 2, forty-three additional melanomas were sampled for biobanking prospectively. Agreement between 2 independent observers on dermoscopic identification of the thickest part of the melanoma was studied. RESULTS In study 1, the area of maximal Breslow thickness in all 10 melanomas was not sampled and remained in the main specimen. In study 2, sampling was performed by one of the investigators. Concordance was 93% between 2 independent observers for the dermoscopic selection of the thickest portion of the melanoma. Pathologists asserted that the sampling procedure did not compromise their ability to evaluate melanoma specimens. A limitation is that this is a single-center study. Each case required joint evaluation by expert dermoscopists and dermatopathologists. CONCLUSIONS AND RELEVANCE In applying the dermoscopy-guided sampling protocol, we make the following 5 recommendations: Samples should only be obtained from areas that will not interfere with the pathologist's diagnosis and prognostic information. Sampling should not be obtained from tumors for which one suspects that the histopathological evaluation may prove difficult. Sampling should not be performed on small melanomas; we recommend a minimum diameter of 10 mm. All the dermoscopy-guided sampling should be documented with images, available to pathologists and clinicians, and reflected in the pathology report. Finally, the frozen biobank samples should be made available for routine hematoxylin-eosin histopathological evaluation until the final pathology report is produced. Ex vivo dermoscopy may serve to guide the procurement of small samples from primary melanoma for fresh tissue biobanking without compromising the histopathological evaluation. 23449200 Practical approach for measuring heat capacity of pharmaceutical crystals/glasses by modulated-temperature differential scanning calorimetry. A practical protocol to obtain accurate heat capacity values of pharmaceutical compounds using modulated-temperature differential scanning calorimetry was established. Three pharmaceutical compounds, acetaminophen, indomethacin, and tri-O-methyl-β-cyclodextrin were used as model compounds. Powder samples did not produce reproducible results, presumably due to inclusion of gas in gap of powders that influenced the measured heat capacity and thermal homogeneity in the sample. Thus, the amorphous characteristics were evaluated using quench-cooled samples. Crystalline samples were obtained by partially melting the sample to allow recrystallization using the residual crystal as a template. Optimum sample mass was about 10 mg. Use of too small sample size resulted in poor reproducibility due to localization of the sample in the pan, while too large size resulted in low heat capacity values probably because of heterogeneity of the sample temperature. The optimum modulation period was in the range of 60 s and 90 s, to which the ramp rates of 2°C/min and 1°C/min, respectively, were applied. The ramp amplitude was less significant in the evaluation. This information should help in comprehending basic characteristics of pharmaceutical compounds. 23908411 Religion and ties between adult children and their parents. Objectives. This study examined whether religious adults (measured by the frequency of attendance at religious services) report more extensive ties with their parents. Method. Using data from the National Survey of Families and Households (N = 9,002), a series of bivariate and multivariate regression models were tested. Several dimensions of adult children's relationships with their parents were considered including relationship quality, frequency of contact, providing care to parents, and providing other assistance. Adult children who attended religious services more frequently were significantly more likely to provide assistance to parents, and they reported higher quality relationships and more frequent contact with both their fathers and mothers. Results were similar for sons and daughters, and for younger and older adult children. Discussion. A better understanding of what motivates and fosters strong ties between adult children and their parents is vitally important given the "graying" of America and the consequences of such ties for the health and well-being of both generations. Religion is only one of many factors associated with adult children's ties to parents, and this association is generally modest, but it is an important factor that should be given greater attention in future research. 23950498 Caffeoyl Shikimate Esterase (CSE) Is an Enzyme in the Lignin Biosynthetic Pathway. Lignin is a major component of plant secondary cell walls. Here, we describe caffeoyl shikimate esterase (CSE) as an enzyme central to the lignin biosynthetic pathway. Arabidopsis thaliana cse mutants deposit less lignin, and the remaining lignin is enriched in H units. Phenolic metabolite profiling identified accumulation of the lignin pathway intermediate caffeoyl shikimate in cse mutants compared to wild type, suggesting this as a substrate for CSE. Accordingly, recombinant CSE hydrolyzed caffeoyl shikimate into caffeate. Associated with the changes in lignin, the conversion of cellulose to glucose of cse mutants increased up to fourfold compared to wild type upon saccharification without pretreatment. Collectively, these data necessitate revision of currently accepted models of the lignin biosynthetic pathway. 23769851 Verification of changes in the time taken to initiate chest compressions according to modified basic life support guidelines. The 2010 American Heart Association (AHA) for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science has changed the basic life support (BLS) sequence from "A-B-C" to "C-A-B." The AHA explained that this change may shorten the initiation time for chest compressions. In this study, the 2010 AHA guidelines for BLS (2010-BLS) were studied through a simulation program and practiced on a manikin. The time saved in initiating initial chest compressions was calculated, and the significance of the new guidelines was evaluated. Forty health care providers who had undergone both the BLS guidelines of 2005 (2005-BLS) and the 2010-BLS programs were targeted in this study. The following items were measured: time spent on rescue breathing, including setting up of ventilation equipment; time taken to initiate chest compressions; and time taken to initiate chest compressions without performance of rescue breathing because of the lack of ventilation equipment. The time taken to initiate chest compressions was 36.0 ± 4.1 seconds when 2005-BLS was followed and 15.4 ± 3.0 seconds when 2010-BLS was followed (P < .001). Furthermore, chest compressions were initiated earlier when 2010-BLS was followed (15.4 ± 3.0 seconds) than when 2005-BLS was followed without the performance of rescue breathing (19.8 ± 2.7 seconds; P < .001). The mean time spent on setting up ventilation equipment and performing rescue breathing was 15.9 ± 3.8 seconds, indicating considerable time variations among individuals. Chest compressions were initiated earlier by health care providers who were re-educated according to the 2010 AHA guidelines. 23807372 Asymmetric Ti-crossed Claisen condensation: application to concise asymmetric total synthesis of alternaric acid. Asymmetric Ti-crossed Claisen condensation utilizing the dioxane-2,5-dione chiral template and its successful application to total synthesis of chiral alternaric acid are described. 23175666 Intraindividual and interindividual variabilities in endogenous cortisol 6β-hydroxylation clearance as an index for in vivo CYP3A phenotyping in humans. This study was designed to evaluate the in vivo activity of cytochrome P450 3A (CYP3A) in 49 healthy Japanese subjects aged 22-58 years using endogenous cortisol 6β-hydroxylation clearance [CLm(6β)], a novel biomarker for CYP3A phenotyping. CLm(6β) in the 49 healthy subjects was 2.40 ± 0.79 ml/min with an approximately 4-fold interindividual variability of CYP3A activity. The mean clearance in the 24 women was 2.50 ± 0.89 ml/min; the value in the women was higher than in the 25 men (2.30 ± 0.69 ml/min) by approximately 9%. We also measured the change of CLm(6β) in 14 healthy subjects in the morning at 10:00-12:00 every 2 or 3 days over a period of 36-53 days and observed a 1.5-fold to 3.4-fold day-to-day intraindividual variability in the CYP3A activity. The mean value for CLm(6β) in each subject for 36-53 days was 2.54 ± 0.76 ml/min (n = 14). We also evaluated the CLm(6β) every 2 hours from 8:00-20:00 in 26 healthy subjects. The within-day intraindividual clearance variability was 1.1-fold to 2.5-fold (2.45 ± 0.91 ml/min, n = 26). No characteristic diurnal rhythms were observed in the in vivo activity of CYP3A. 23927290 Rapid estimation of hydration thermodynamics of macromolecular regions. This work describes a novel protocol to efficiently calculate the local free energy of hydration of specific regions in macromolecules. The method employs Monte Carlo simulations in the grand canonical ensemble to generate water configurations in a selected spherical region in the macromolecule. Excess energy and entropy of hydration are calculated by analyzing the water configurational distributions following the recently published grid inhomogeneous solvation theory method [C. N. Nguyen, T. K. Young, and M. K. Gilson, J. Chem. Phys. 137, 044101 (2012)]. Our method involves the approximations of treating the macromolecule and distant solvent as rigid and performing calculations on multiple such conformations to account for conformational diversity. These approximations are tested against water configurations obtained from a molecular dynamics simulation. The method is validated by predicting the number and location of water molecules in 5 pockets in the protein Interleukin-1β for which experimental water occupancy data are available. Free energy values are validated against decoupling free energy perturbation calculations. The results indicate that the approximations used in the method enable efficient prediction of free energies of water displacement. 23072214 Anatomy and Histology of the Male Reproductive Tract and Spermatogenesis Fine Structure in the Lesser Anteater (Tamandua tetradactyla, Myrmecophagidae, Xenarthra): Morphological Evidences of Reproductive Functions. The anatomy and histology of the male genital tract of the lesser anteater were studied. Fine details of spermatozoa regarding their genesis and morphology were also studied in six adult specimens. The testes lie in the pelvic cavity. The deferent duct emerges from the epididymis and opens into the ejaculatory duct, which drains into the membranous urethra. Accessory glands (prostate, seminal vesicle and bulbourethral gland) are histologically similar to those described in other mammals. The short penis presents an urethral orifice, while the corpus spongiosum becomes thinner at the end indicating the absence of a histologically defined glans. The seminiferous epithelium shows: (1) Sertoli cells with deep nuclear indentations, (2) spermatogonia with crusty-like chromatin, (3) spermatocytes at different stages of maturation and (4) three morphologically distinct stages of spermatid differentiation according to nuclear shape, acrosome development and chromatin condensation. Sperm heads appear oval. The length of the spermatozoa averages 67.33 ± 1.60 Î¼m. Two specimens with inactive spermatogenesis were azoospermic. Their testes and epididymis presented sizes smaller than those with active spermatogenesis. These studies together with others in anteaters may contribute to successful breeding in conservation programmes. 23892268 Angiotensin as stress mediator: Role of its receptor and interrelationships among other stress mediators and receptors. The involvement of renin-angiotensin system (RAS) and its active peptides, particularly angiotensin II (Ang II), has been described not only in hypertension, but also in stress-associated anxiety disorders. Ang II and its two subtypes of receptors, viz. AT1 and AT2, are localized on stress-responsive brain areas including the hypothalamus-adrenal-pituitary (HPA) axis. The different types of stressors increase the levels of Ang II and change the expression of its receptors. Transgenic animals with a centrally inactivated angiotensin system demonstrate increased anxiety-related behavior describing the anxiolytic effects of basal Ang II. However, studies showing the anxiolytic potential of AT1 receptor antagonists have described the anxiogenic effects of endogenously released Ang II. It suggests that the basal Ang II (in low amount) may attenuate anxiety, while stress-released Ang II (in high amount) may produce anxiety. By employing AT2-deficient mice, the functional role of AT2 receptors in attenuating stress-associated anxiety has been described. Moreover, AT1 receptor antagonists-induced anti-anxiety effects are associated with up-regulation of AT2 receptors in the brain suggesting that the centrally acting AT2 receptor agonists may serve as potential anxiolytic agents. The present review discusses the dual role of Ang II and its receptors in the development of stress-associated anxiety along with its interrelationship with benzodiazepines (BZD) receptors, and other stress mediators including corticotrophin releasing hormone (CRH) and serotonin (5-HT). 23836655 Vibronic origin of sulfur mass-independent isotope effect in photoexcitation of SO2 and the implications to the early earth's atmosphere. Signatures of mass-independent isotope fractionation (MIF) are found in the oxygen ((16)O,(17)O,(18)O) and sulfur ((32)S, (33)S, (34)S, (36)S) isotope systems and serve as important tracers of past and present atmospheric processes. These unique isotope signatures signify the breakdown of the traditional theory of isotope fractionation, but the physical chemistry of these isotope effects remains poorly understood. We report the production of large sulfur isotope MIF, with Δ(33)S up to 78‰ and Δ(36)S up to 110‰, from the broadband excitation of SO2 in the 250-350-nm absorption region. Acetylene is used to selectively trap the triplet-state SO2 ($$\widetilde{a}$$(3)B1), which results from intersystem crossing from the excited singlet ($$\widetilde{A}$$(1)A2/$$\widetilde{B}$$(1)B1) states. The observed MIF signature differs considerably from that predicted by isotopologue-specific absorption cross-sections of SO2 and is insensitive to the wavelength region of excitation (above or below 300 nm), suggesting that the MIF originates not from the initial excitation of SO2 to the singlet states but from an isotope selective spin-orbit interaction between the singlet ($$\widetilde{A}$$(1)A2/$$\widetilde{B}$$(1)B1) and triplet ($$\widetilde{a}$$(3)B1) manifolds. Calculations based on high-level potential energy surfaces of the multiple excited states show a considerable lifetime anomaly for (33)SO2 and (36)SO2 for the low vibrational levels of the $$\widetilde{A}$$(1)A2 state. These results demonstrate that the isotope selectivity of accidental near-resonance interactions between states is of critical importance in understanding the origin of MIF in photochemical systems. 23794180 The Schedule for Nonadaptive and Adaptive Personality for Youth (SNAP-Y): A New Measure for Assessing Adolescent Personality and Personality Pathology. The Schedule for Nonadaptive and Adaptive Personality-Youth Version (SNAP-Y) is a new, reliable self-report questionnaire that assesses 15 personality traits relevant to both normal-range personality and the alternative DSM-5 model for personality disorder. Community adolescents, 12 to 18 years old (N = 364), completed the SNAP-Y; 347 also completed the Big Five Inventory-Adolescent, 144 provided 2-week retest data, and 128 others completed the Minnesota Multiphasic Personality Inventory-Adolescent. Outpatient adolescents (N = 103) completed the SNAP-Y, and 97 also completed the Minnesota Multiphasic Personality Inventory-Adolescent. The SNAP-Y demonstrated strong psychometric properties, and structural, convergent, discriminant, and external validities. Consistent with the continuity of personality, results paralleled those in adult and college samples using the adult Schedule for Nonadaptive and Adaptive Personality-Second Edition (SNAP-2), from which the SNAP-Y derives and which has established validity in personality-trait assessment across the normal-abnormal continuum. The SNAP-Y thus provides a new, clinically useful instrument to assess personality traits and personality pathology in adolescents. 23562775 Loudness functions with air and bone conduction stimulation in normal-hearing subjects using a categorical loudness scaling procedure. In a previous study (Stenfelt and Håkansson, 2002) a loudness balance test between bone conducted (BC) sound and air conducted (AC) sound was performed at frequencies between 0.25 and 4 kHz and at levels corresponding to 30-80 dB HL. The main outcome of that study was that for maintaining equal loudness, the level increase of sound with BC stimulation was less than that of AC stimulation with a ratio between 0.8 and 0.93 dB/dB. However, because it was shown that AC and BC tone cancellation was independent of the stimulation level, the loudness level difference did not originate in differences in basilar membrane stimulation. Therefore, it was speculated that the result could be due to the loudness estimation procedure. To investigate this further, another loudness estimation method (adaptive categorical loudness scaling) was here employed in 20 normal-hearing subjects. The loudness of a low-frequency and a high-frequency noise burst was estimated using the adaptive categorical loudness scaling technique when the stimulation was bilaterally by AC or BC. The sounds where rated on an 11-point scale between inaudible and too loud. The total dynamic range for these sounds was over 80 dB when presented by AC (between inaudible and too loud) and the loudness functions were similar for the low and the high-frequency stimulation. When the stimulation was by BC the loudness functions were steeper and the ratios between the slopes of the AC and BC loudness functions were 0.88 for the low-frequency sound and 0.92 for the high-frequency sound. These results were almost equal to the previous published results using the equal loudness estimation procedure, and it was unlikely that the outcome stems from the loudness estimation procedure itself. One possible mechanism for the result was loudness integration of multi-sensory input. However, no conclusive evidence for such a mechanism could be given by the present study. This article is part of a special issue entitled "MEMRO 2012". 23339690 Functional tissue engineering in articular cartilage repair: is there a role for electromagnetic biophysical stimulation? Hyaline cartilage lesions represent an important global health problem. Several approaches have been developed in the last decades to resolve this disability cause, including tissue engineering, but to date, there is not a definitive procedure that is able to promote a repair tissue with the same mechanical and functional characteristics of native cartilage, and to obtain its integration in the subchondral bone. The need of resolutive technologies to obtain a "more effective" tissue substitutes has led Butler to propose the "Functional Tissue Engineering" (FTE) paradigm, whose principles are outlined in a so-called FTE road map. It consists of a two-phase strategy: in vitro tissue engineering and clinically surgery evaluation. The first phase, based on construct development, should take into account not only the chondrocyte biology, as their sensitivity to biochemical and physical stimuli, the risk of dedifferentiation in culture, and the ability to produce extracellular matrix, but also the features of suitable scaffolds. The in vivo phase analyzes the inflammatory microenvironment where the construct will be placed, because the cytokines released by synoviocytes and chondrocytes could affect the construct integrity, and, in particular, cause matrix degradation. The use of pulsed electromagnetic fields (PEMFs) represents an innovative therapeutic approach, because it is demonstrated that this physical stimulus increases the anabolic activity of chondrocytes and cartilage explants with consequent increase of matrix synthesis, but, at the same time, PEMFs limit the catabolic effects of inflammatory cytokines, reducing the construct degradation inside the surgical microenvironment. PEMFs mediate an up-regulation of A2A adenosine receptors and a potentiation of their anti-inflammatory effects. 23863817 A Comparison of Quality Improvement Practices at Adult and Pediatric Trauma Centers. Quality assurance practices are structured performance improvement and patient safety processes designed to continuously monitor, evaluate, and improve the performance of a trauma program. These practices are integral in the provision of quality injury care, and yet no comprehensive description of existing quality improvement practices used by pediatric trauma centers is available. Therefore, we compared the quality improvement programs used in adult and pediatric trauma centers by performing a reanalysis of our recent survey of trauma quality improvement practices in Canada, United States, Australia, and New Zealand. Prospective observational study. Pediatric and adult trauma centers in United States, Canada, and Australasia. None. None. We surveyed 184 trauma centers verified by professional trauma organizations in the United States, Canada, and Australasia regarding their quality improvement programs. Centers were classified according to population served (adult, adult and pediatric, or pediatric patients), and quality improvement programs were compared using descriptive statistics. Most of the trauma centers reported engagement in quality improvement activities. Adult centers devoted a larger percentage of their quality indicators to the measurement of safety (adult 50% vs adult and pediatric 53% vs pediatric 38%, p < 0.001), whereas pediatric centers placed a greater emphasis on the timeliness of care (20% vs 24% vs 30%, p < 0.001). Few centers used quality indicators to measure the patient-centered nature of care, long-term outcomes, or secondary injury prevention. Opportunities for the improvement of pediatric quality improvement programs exist including a need to determine the optimal structure for trauma quality improvement, develop patient-centered quality indicators of injury care, measure long-term outcomes, and create measures of secondary injury prevention. 23963121 Predictors of 30-Day Readmission After Intracerebral Hemorrhage: A Single-Center Approach for Identifying Potentially Modifiable Associations With Readmission. To determine whether patient's demographics or severity of illness predict hospital readmission within 30 days following spontaneous intracerebral hemorrhage, to identify readmission associations that may be modifiable at the single-center level, and to determine the impact of readmission on outcomes. We collected demographic, clinical, and hospital course data for consecutive patients with spontaneous intracerebral hemorrhage enrolled in an observational study. Readmission within 30 days was determined retrospectively by an automated query with manual confirmation. We identified the reason for readmission and tested for associations between readmission and functional outcomes using modified Rankin Scale (a validated functional outcome measure from 0, no symptoms, to 6, death) scores before intracerebral hemorrhage and at 14 days, 28 days, and 3 months after intracerebral hemorrhage. Neurologic ICU of a tertiary care hospital. Critically ill patients with spontaneous intracerebral hemorrhage. Patients received standard critical care management for intracerebral hemorrhage. Of 246 patients (mean age, 65 yr; 51% female), 193 patients (78%) survived to discharge. Of these, 22 patients (11%) were readmitted at a median of 9 days (interquartile range, 4-15 d). The most common readmission diagnoses were infections after discharge (n = 10) and vascular events (n = 6). Age, history of stroke and hypertension, severity of neurologic deficit at admission, Acute Physiology and Chronic Health Evaluation score, ICU and hospital length of stay, ventilator-free days, days febrile, and surgical procedures were not predictors of readmission. History of coronary artery disease was associated with readmission (p = 0.03). Readmitted patients had similar modified Rankin Scale and severity of neurologic deficit at 14 days but higher (worse) modified Rankin Scale scores at 3 months (median [interquartile range], 5 [3-6] vs 3 [1-4]; p = 0.01). Severity of illness and hospital complications were not associated with 30-day readmission. The most common indication for readmission was infection after discharge, and readmission was associated with worse functional outcomes at 3 months. Preventing readmission after intracerebral hemorrhage may depend primarily on optimizing care after discharge and may improve functional outcomes at 3 months. 23766527 Gametocyte Dynamics and the Role of Drugs in Reducing the Transmission Potential of Plasmodium vivax. Background. Designing interventions that will reduce transmission of vivax malaria requires knowledge of Plasmodium vivax gametocyte dynamics. Methods. We analyzed data from a randomized controlled trial in northwestern Thailand and 2 trials in Papua, Indonesia, to identify and compare risk factors for vivax gametocytemia at enrollment and following treatment. Results. A total of 492 patients with P. vivax infections from Thailand and 476 patients (162 with concurrent falciparum parasitemia) from Indonesia were evaluable. Also, 84.3% (415/492) and 66.6% (209/314) of patients with monoinfection were gametocytemic at enrollment, respectively. The ratio of gametocytemia to asexual parasitemia did not differ between acute and recurrent infections (P = .48 in Thailand, P = .08 in Indonesia). High asexual parasitemia was associated with an increased risk of gametocytemia during follow-up in both locations. In Thailand, the cumulative incidence of gametocytemia between day 7 and day 42 following dihydroartemisinin + piperaquine (DHA + PIP) was 6.92% vs 29.1% following chloroquine (P < .001). In Indonesia, the incidence of gametocytemia was 33.6% following artesunate + amodiaquine (AS + AQ), 7.42% following artemether + lumefantrine, and 6.80% following DHA + PIP (P < .001 for DHA + PIP vs AS + AQ). Conclusions. P. vivax gametocyte carriage mirrors asexual-stage infection. Prevention of relapses, particularly in those with high asexual parasitemia, is likely the most important strategy for interrupting P. vivax transmission. 23845289 Cancer of the external auditory canal. Cancer of the external auditory canal is a rare tumour with an annual incidence of one per one million inhabitants. The objective of this study was to evaluate the 5-year overall survival and disease-free survival rates in a series of patients with carcinoma of the external auditory canal and to compare our results concerning the clinical presentation, management and survival with those of the literature. Ten patients were included in this retrospective, single-centre study over a 20-year period. Data concerning age, symptoms, imaging, TNM stage according to the Pittsburgh classification, histology, management, sequelae, recurrences and survival were recorded. The mean age of the patients of this series was 60.7 years. Seven patients had a squamous cell carcinoma. The other histological types were undifferentiated carcinoma, adenoid cystic carcinoma and neuroendocrine carcinoma. Staging was based on the Pittsburgh classification with one stage I, one stage III and eight stage IV tumours. Five-year overall survival rates were 100%, 50% and 0%, respectively. The mean 5-year overall survival rate was 35% and the mean 5-year disease-free survival rate was 24%. Carcinoma of the external auditory canal is a difficult diagnosis when the tumour does not present as a fungating mass protruding from the external auditory canal. The Pittsburgh classification was used for TNM staging of these tumours, allowing comparison of our results with those of the literature. The clinical findings and survival rates observed in this study are comparable to those reported in the literature. These tumours are associated with a poor prognosis on the basis of our results and published data. 23566735 Does infrapatellar fat pad resection in total knee arthroplasty impair clinical outcome? A systematic review. The infrapatellar fat pad (IPFP) is often removed during total knee arthroplasty (TKA). No evidence based guidelines on changes in clinical outcome have yet been described. The aim of this review is to investigate whether regular removal of the IPFP during TKA should be performed. Seven databases were systematically searched. Clinical studies, in which TKA with IPFP resection was compared with IPFP preservation, were included. Risk of bias was assessed using the Cochrane collaboration tool. Studies reporting anterior knee pain, patellar tendon length, range of motion, patellar vascularisation or functional outcome were included. The indication for TKA varied in the different studies: osteoarthritis (OA), rheumatic arthritis (RA) and multiple indications (OA, RA and osteonecrosis). After IPFP resection: 1. For OA, no differences in function, range of motion, and anterior knee pain were found. 2. In the RA study, there was a trend towards more discomfort and a decrease in function. 3. In OA and RA patients a decrease in patellar tendon length was observed. 4. One study reported no decrease in patellar vascularisation. Limitations of this review are the high risk of bias scores of the included studies, the varying outcome measures, follow up, number and type of participants. Randomised clinical trials are required to support or refute the results, contributing to a possible future evidence based guideline on IPFP resection during TKA. 22945792 A probable clinically significant interaction between warfarin and cloxacillin: three case reports. CASES: Three patients were admitted to the Imam Hospital, Tehran, Iran with a diagnosis of bacterial endocarditis. The patients had indications for valve replacement surgery and anticoagulant therapy. The administration of cloxacillin reduced the effect of warfarin, and subsequent increases in warfarin doses were unable to overcome this effect. CONCLUSION: A decrease in warfarin anticoagulation effects was detected in our three patients following cloxacillin therapy for infective endocarditis. Penicillinase-resistant penicillins remain essential antibiotics in the treatment of severe infections caused by Staphylococcus aureus due to their bactericidal activity, safety, and cost. Thus, in situations where anticoagulants are indicated in patients with infective endocarditis, it would be better to replace warfarin with low-molecular-weight or unfractionated heparin. 23884703 Community-Wide Job Loss and Teenage Fertility: Evidence From North Carolina. Using North Carolina data for the period 1990-2010, we estimate the effects of economic downturns on the birthrates of 15- to 19-year-olds, using county-level business closings and layoffs as a plausibly exogenous source of variation in the strength of the local economy. We find little effect of job losses on the white teen birthrate. For black teens, however, job losses to 1 % of the working-age population decrease the birthrate by around 2 %. Birth declines start five months after the job loss and then last for more than one year. Linking the timing of job losses and conceptions suggests that black teen births decline because of increased terminations and perhaps also because of changes in prepregnancy behaviors. National data on risk behaviors also provide evidence that black teens reduce sexual activity and increase contraception use in response to job losses. Job losses seven to nine months after conception do not affect teen birthrates, indicating that teens do not anticipate job losses and lending confidence that job losses are "shocks" that can be viewed as quasi-experimental variation. We also find evidence that relatively advantaged black teens disproportionately abort after job losses, implying that the average child born to a black teen in the wake of job loss is relatively more disadvantaged. 23434212 Exploring National Surgical Quality Improvement Program respiratory comorbidities: developing a predictive understanding of postoperative respiratory occurrences, Clavien 4 complications, and death. For preoperative risk stratification, little is known about the implications of respiratory comorbidities in relation to postoperative complications in the diverse population of surgical patients. We hypothesized that patients with preoperative respiratory comorbidities would be at increased risk of postoperative respiratory occurrences and death. Under the data use agreement and with the approval of the Henry Ford Health System Institutional Review Board (IRB #6830), we reviewed 5 y (2005-2009) of National Surgical Quality Improvement Program participant use files. Respiratory comorbidities were defined as current smoker, chronic obstructive pulmonary disease, dyspnea, and current pneumonia. Respiratory outcomes tracked in the National Surgical Quality Improvement Program included reintubation, postoperative pneumonia, and prolonged ventilation. We defined Clavien 4 and 5 outcomes to include postoperative septic shock, postoperative dialysis, pulmonary embolism, myocardial infarction, cardiac arrest, prolonged ventilatory requirements, need for reintubation, and death. Of 971,455 patients identified, 361,412 had respiratory comorbidities. As the number of respiratory comorbidities increased, we found a statistically significant increase in the occurrence of postoperative respiratory adverse events, including Clavien 4 and 5 complications. Multivariate regression analysis showed that respiratory comorbidities and age were independent predictors of mortality. All data reported here were significant at P < 0.001. This study showed a significant association between respiratory comorbidities and postoperative adverse events, including Clavien 4 complications and death. Further prospective studies are required to explore this association. 23871059 Regulating the secondary metabolism in grape berry using exogenous 24-epibrassinolide for enhanced phenolics content and antioxidant capacity. The objective of this study is to investigate the influence of application of exogenous 24-epibrassinolide (EBR) on the antioxidant capacity, anthocyanins and phenolics content of Vitis vinifera grape berry (cvs. Yan 73 and Cabernet Sauvignon). The grapevine clusters were sprayed with 0 (control), 0.10, 0.40, or 0.80mg/l of 24-epibrassinolide during veraison, respectively. The EBR application increased the activities of phenylalanine ammonia-lyase (PAL) and UDP-glucose: flavonoid 3-O-glucosyltransferase (UFGT), the content of total phenolics, tannins, flavonoids and anthocyanins, individual anthocyanins and the antioxidant capacity of matured grape skins in both varieties. The application also increased the content of flavonoids and anthocyanins in Yan73 pulp. Compared to the other treatments, the treatment of EBR at 0.40mg/l had significantly higher level than the control in all above assays. Our results indicated that the exogenous EBR treatment can significantly promote grape ripening and enhance anthocyanins and other phenolics contents and antioxidant capacity in the grape skin. 23624148 Sciadopitysin protects osteoblast function via its antioxidant activity in MC3T3-E1 cells. Age-related osteoblast dysfunction is the main cause of age-related bone loss in both men and women. In the present study, the effect of sciadopitysin, a type of biflavonoids, on osteoblast function was investigated in osteoblastic MC3T3-E1 cells. Sciadopitysin caused a significant elevation of alkaline phosphatase activity, collagen synthesis, osteocalcin production, mineralization, and glutathione content in the cells (P<0.05). Sciadopitysin also decreased the production of tumor necrosis factor-a (TNF-α) induced by antimycin A, a mitochondrial electron transport inhibitor. We investigated the protective effects of sciadopitysin on antimycin A-induced toxicity in osteoblastic MC3T3-E1 cells. Exposure of MC3T3-E1 cells to antimycin A caused a significant reduction in osteoblast dysfunction. However, pretreatment with sciadopitysin prior to antimycin A exposure significantly reduced antimycin A-induced cell damage by preventing mitochondrial membrane potential dissipation, adenosine triphosphate (ATP) loss, reactive oxygen species (ROS) release, and nitrotyrosine increase, suggesting that sciadopitysin may be useful for protecting mitochondria against a burst of oxidative stress. Moreover, sciadopitysin increased phosphorylation of cAMP-response element-binding protein (CREB) inhibited by antimycin A. Our results demonstrate that sciadopitysin may reduce or prevent osteoblasts degeneration. 23931642 New insights into the role of aminopeptidases in the treatment for both preeclampsia and preterm labor. Introduction: Evidence elucidating the pathophysiology and pharmacology of conventional drugs, β-2 stimulants and magnesium sulfate, on safety and effectiveness for preeclampsia and preterm labor are rarely found. Both compounds pass through the placental barrier and could exert their adverse effects on the fetus. Exposure to these agents could be problematic long after the birth, and possibly result in diseases such as autism and cardiomyopathy. Since 1970 the possible roles of placental aminopeptidases, which degrade peptide hormones, in preeclampsia and preterm labor have been studied. Areas covered: Many studies reveal that the fetus secretes peptide hormones, such as angiotensin II, vasopressin, and oxytocin, under hypoxia (stress) during the course of its growth, suggesting the critical effects these hormones have during pregnancy. The roles of placental aminopeptidases, the enzymes which degrade fetal hormones without passing through the placental barrier, were clarified. A first-step production system for recombinant aminopeptidases was established, by which engineered recombinant aminopeptidases were used for further experiments testing expected efficacy on controlling the level of hormones. Expert opinion: The authors conclude that both aminopeptidase A and placental leucine aminopeptidase could be potentially safe and effective drugs for patients and their babies in the treatment of preeclampsia and preterm labor. 23965064 Rounds best way to answer concerns. Intentional rounding could help curb a 'toxic' complaints culture in some NHS hospitals, a health watchdog claims. 23873252 Reference limit of Thyrotropin (TSH) and free Thyroxine (FT4) in thyroperoxidase positive and negative subjects: a population based study. Background: Current reference values for thyroid function tests are based on data from different ethnicities and geographical areas. The aim of the present study was to determine reference intervals for thyrotropin (TSH) and freeT4 (FT4), based on the criteria of the National Academy of Clinical Biochemistry (NACB) in an Iranian population. Material and methods: This study was conducted within the framework of Tehran Thyroid Study (TTS), an ongoing prospective cohort of 5704 randomly selected individuals, age 20 ≥ years. A total of 2199 individuals (43.3%, male, 56.7% female), based on NACB criteria were included in this study. Reference limit analysis was performed for the negative thyroid peroxidase antibody (TPOAb) group. Results: After applying all exclusion criteria except TPOAb positivity (10.5%), data of 2459 participants remained for analysis. Of these 953 (43.3%) were males and 1246 (56.7%) were females; the mean ±SD age was 43.53±14.16 years. The mean ±SD and median + IQR for TSH were 1.77 mU/L ±1.24 and 1.46(0.93-2.23) mU/L, respectively. The 2.5th and 97.5th percentiles TSH were 0.32 mU/L and 5.06 mU/L respectively. The mean± SD and median (IQR) for FT4 for all negative TPOAb group were 1.19 ±0.16 and 1.18 (1.08-1.31) ng/dl respectively. Conclusion: Reference ranges for thyroid function tests need to be derived from national databases. This study determined age and sex specific TSH and FT4 reference ranges in a Tehranian population, which could eventually enable clinicians to classify patients more appropriately. 23706208 Size-controlled preparation of α-calcium sulphate hemihydrate starting from calcium sulphate dihydrate in the presence of modifiers and the dissolution rate in simulated body fluid. Different-sized α-calcium sulphate hemihydrate (α-CSH) rods were hydrothermally prepared by converting calcium sulphate dihydrate at 110-140°C in the presence of MgCl2, sodium citrate (CANa), and sodium dodecyl benzene sulfonate (SDBS) as the modifiers. The α-CSH rods with the average diameters and the average lengths in the ranges of 2.6-5.2 and 17.5-33.1 μm, respectively, were tunably prepared. The presence of the modifiers favoured the formation of small-sized α-CSH rods. The effect of the modifiers on decreasing the diameters of α-CSH rods was in an order of SDBS>CANa>MgCl2. The dissolution rates of the different-sized α-CSH rods prepared at 140°C in simulated body fluid were in an order of α-CSH (CANa)>α-CSH (MgCl2)>α-CSH (reference)>α-CSH (SDBS). The naked and small-sized α-CSH rods had high dissolution rates. The adsorption of SDBS on the surfaces of α-CSH rods decreased their dissolution rates. 23892513 A knowledge- and model-based system for automated weaning from mechanical ventilation: technical description and first clinical application. To describe the principles and the first clinical application of a novel prototype automated weaning system called Evita Weaning System (EWS). EWS allows an automated control of all ventilator settings in pressure controlled and pressure support mode with the aim of decreasing the respiratory load of mechanical ventilation. Respiratory load takes inspired fraction of oxygen, positive end-expiratory pressure, pressure amplitude and spontaneous breathing activity into account. Spontaneous breathing activity is assessed by the number of controlled breaths needed to maintain a predefined respiratory rate. EWS was implemented as a knowledge- and model-based system that autonomously and remotely controlled a mechanical ventilator (Evita 4, Dräger Medical, Lübeck, Germany). In a selected case study (n = 19 patients), ventilator settings chosen by the responsible physician were compared with the settings 10 min after the start of EWS and at the end of the study session. Neither unsafe ventilator settings nor failure of the system occurred. All patients were successfully transferred from controlled ventilation to assisted spontaneous breathing in a mean time of 37 ± 17 min (± SD). Early settings applied by the EWS did not significantly differ from the initial settings, except for the fraction of oxygen in inspired gas. During the later course, EWS significantly modified most of the ventilator settings and reduced the imposed respiratory load. A novel prototype automated weaning system was successfully developed. The first clinical application of EWS revealed that its operation was stable, safe ventilator settings were defined and the respiratory load of mechanical ventilation was decreased. 23643416 Human amnion epithelial cells modulate hyperoxia-induced neonatal lung injury in mice. Human amnion epithelial cells (hAECs) prevent pulmonary inflammation and injury in fetal sheep exposed to intrauterine lipopolysaccharide. We hypothesized that hAECs would similarly mitigate hyperoxia-induced neonatal lung injury. Newborn mouse pups were randomized to either normoxia (inspired O2 content (FiO2) = 0.21, n = 60) or hyperoxia (FiO2 = 0.85, n = 57). On postnatal days (PND) 5, 6 and 7, hAECs or sterile saline (control) was administered intraperitoneally. All animals were assessed at PND 14. Hyperoxia was associated with lung inflammation, alveolar simplification and reduced postnatal growth. Administration of hAECs to hyperoxia-exposed mice normalized body weight and significantly attenuated some aspects of hyperoxia-induced lung injury (mean linear intercept and septal crest density) and inflammation (interleukin-1α, interleukin-6, transforming growth factor-β and platelet-derived growth factor-β). However, hAECs did not significantly alter changes to alveolar airspace volume, septal tissue volume, tissue-to-airspace ratio, collagen content or leukocyte infiltration induced by hyperoxia. Intraperitoneal administration of hAECs to neonatal mice partially reduced hyperoxia-induced lung inflammation and structural lung damage. These observations suggest that hAECs may be a potential therapy for neonatal lung disease. 23334882 Aliifodinibius roseus gen. nov., sp. nov., and Aliifodinibius sediminis sp. nov., two moderately halophilic bacteria isolated from salt mine samples. Two rod-shaped, non-motile bacteria were isolated from two separate salt mines in Yunnan, south-western China. These strains, designated YIM D15(T) and YIM J21(T), were Gram-negative and moderately halophilic. The two strains required 6-10 % NaCl (w/v; optimal) for growth. The DNA G+C contents of strains YIM D15(T) and YIM J21(T) were 49.0 mol% and 48.4 mol%, respectively. The predominant isoprenoid quinone was MK-7. The polar lipid profiles of strains YIM D15(T) and YIM J21(T) were composed predominantly of diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, three unknown polar lipids and one glycolipid. Minor amounts of other lipids were also detectable. The predominant cellular fatty acids were iso-C15 : 0, anteiso-C15 : 0, iso-C17 : 1ω9c/10 methyl-C16 : 0 and C16 : 1ω7c/C16 : 1ω6c. Phylogenetic analysis based on 16S rRNA gene sequence comparisons showed that the two isolates formed a distinct clade with the genus Fodinibius (in the phylum Bacteroidetes) and were related to the species Fodinibius salinus, with sequence similarities of 91.9-92.4 %. Analyses of 16S rRNA gene sequences revealed that strains YIM D15(T) and YIM J21(T) were related to each other (97.3 % sequence similarity). The DNA-DNA hybridization relatedness between the two isolates was 34 %. On the basis of the phylogenetic analysis, DNA-DNA hybridization relatedness, phenotypic and chemotaxonomic characteristics, strains YIM D15(T) and YIM J21(T) should be classified as members of a novel genus and as two novel species, for which the names Aliifodinibius roseus gen. nov., sp. nov. (type strain YIM D15(T) = ACCC 10715(T) = KCTC 23442(T)) and Aliifodinibius sediminis sp. nov. (type strain YIM J21(T) = ACCC 10714(T) = DSM 21194(T)) are proposed. 23905514 Toward silicon anodes for next-generation lithium ion batteries: a comparative performance study of various polymer binders and silicon nanopowders. Silicon is widely regarded as one of the most promising anode materials for lithium ion and next-generation lithium batteries because of its high theoretical specific capacity. However, major issues arise from the large volume changes during alloying with lithium. In recent years, much effort has been spent on preparing nanostructured silicon and optimizing various aspects of material processing with the goal of preserving the electrode integrity upon lithiation/delithiation. The performance of silicon anodes is known to depend on a large number of parameters and, thus, the general definition of a "standard" is virtually impossible. In this work, we conduct a comparative performance study of silicon anode tapes prepared from commercially available materials while using both a well-defined electrode configuration and cycling method. Our results demonstrate that the polymer binder has a profound effect on the cell performance. Furthermore, we show that key parameters such as specific capacity, capacity retention, rate capability, and so forth can be strongly affected by the choice of silicon material, polymer binder and electrolyte system - even the formation of metastable crystalline Li15Si4 is found to depend on the electrode composition and low potential exposure time. Overall, the use of either poly(acrylic acid) with a viscosity-average molecular weight of 450.000 or poly(vinyl alcohol) Selvol 425 in combination with both silicon nanopowder containing a native oxide surface layer of ∼1 nm in diameter and with a monofluoroethylene carbonate-based electrolyte led to improved cycling stability at high loadings. 23517329 Constraint Network Analysis (CNA): A Python Software Package for Efficiently Linking Biomacromolecular Structure, Flexibility, (Thermo-)Stability, and Function. For deriving maximal advantage from information on biomacromolecular flexibility and rigidity, results from rigidity analyses must be linked to biologically relevant characteristics of a structure. Here, we describe the Python-based software package Constraint Network Analysis (CNA) developed for this task. CNA functions as a front- and backend to the graph-based rigidity analysis software FIRST. CNA goes beyond the mere identification of flexible and rigid regions in a biomacromolecule in that it (I) provides a refined modeling of thermal unfolding simulations that also considers the temperature-dependence of hydrophobic tethers, (II) allows performing rigidity analyses on ensembles of network topologies, either generated from structural ensembles or by using the concept of fuzzy noncovalent constraints, and (III) computes a set of global and local indices for quantifying biomacromolecular stability. This leads to more robust results from rigidity analyses and extends the application domain of rigidity analyses in that phase transition points ("melting points") and unfolding nuclei ("structural weak spots") are determined automatically. Furthermore, CNA robustly handles small-molecule ligands in general. Such advancements are important for applying rigidity analysis to data-driven protein engineering and for estimating the influence of ligand molecules on biomacromolecular stability. CNA maintains the efficiency of FIRST such that the analysis of a single protein structure takes a few seconds for systems of several hundred residues on a single core. These features make CNA an interesting tool for linking biomacromolecular structure, flexibility, (thermo-)stability, and function. CNA is available from http://cpclab.uni-duesseldorf.de/software for nonprofit organizations. 23007558 Cellular and molecular mechanisms of hepatocellular carcinoma: an update. Hepatocellular carcinoma (HCC) is the most common primary malignant tumor that accounts for ~80 % of all liver cancer cases worldwide. It is a multifactorial disease caused by a variety of risk factors and often develops in the background of underlying cirrhosis. A number of cellular phenomena, such as tumor microenvironment, inflammation, oxidative stress, and hypoxia act in concert with various molecular events to facilitate tumor initiation, progression, and metastasis. The emergence of microRNAs and molecular-targeted therapies adds a new dimension in our efforts to combat this deadly disease. Intense research in this multitude of areas has led to significant progress in our understanding of cellular processes and molecular mechanisms that occur during multistage events that lead to hepatocarcinogenesis. In this review, we discuss the current knowledge of HCC, focusing mainly on advances that have occurred during the past 5 years and on the development of novel therapeutics for liver cancer. 23312061 Plasma homocysteine levels increase following stress in older but not younger men. The incidence and prevalence of cardiovascular disease (CVD) increases with age. Some evidence suggests that mental stress may increase plasma homocysteine (Hcy), an amino acid relating to CVD. However, none of these studies assessed age effects on Hcy stress reactivity, nor did they control for age. The objective of this study was (a) to investigate whether Hcy reactivity to psychosocial stress differs between younger and middle-aged to older men and (b) to study whether psychosocial stress induces Hcy increases independent of age. Twenty eight younger (20-30 years) and 22 middle-aged to older (47-65 years) apparently healthy men underwent an acute standardized psychosocial stress task combining public speaking and mental arithmetic in front of an audience. Blood samples for Hcy measurements were obtained immediately before and after, as well as 10 and 20min after stress. Moreover, salivary cortisol was repeatedly measured to test the effectiveness of the stress task in triggering a neuroendocrine stress response. Hcy reactivity to stress differed between age groups (F(1.4, 60.7)=5.41, p=.014). While the older group displayed an increase in the Hcy response to stress (F(2.5, 39.8)=3.86, p=.022), Hcy levels in the younger group did not change (p=.27). Psychosocial stress per se did not change Hcy levels independent of age (p=.53). Our findings suggest that psychosocial stress does not evoke an Hcy response per se, but only in interaction with age pointing to a mechanism by which mental stress may increase CVD risk in older individuals. 23017421 Hypocholesterolemic effects of low calorie structured lipids on rats and rabbits fed on normal and atherogenic diet. The hypocholesterolemic effects of two low calorie structured lipids (SL1 and SL2) containing essential fatty acids, prepared by lipase catalysed interesterification of ethyl behenate respectively with sunflower and soybean oils were studied in rats and rabbits. The feeding experiment conducted on rats as well as rabbits, fed on normal and atherogenic diet containing 10% of SL1 and SL2 (experimental) and sunflower oil (control) indicated no adverse effects on growth and food intake. However, the structured lipids beneficially lowered serum and liver lipids, particularly cholesterol, LDL cholesterol, triglycerides and also maintains the essential fatty acid status in serum and liver. The lipid deposition observed in the arteries of rabbits fed on atherogenic diets was significantly reduced when structured lipids were included in the diet. These observations coincided with reduced levels of serum cholesterol particularly LDL cholesterol observed in experimental groups. Therefore the structured lipids, designed to have low calorific value also beneficially lower serum lipids and lipid deposition in animals fed on atherogenic diets. 23937395 NMR and Raman Spectroscopy Monitoring of Proton/Deuteron Exchange in Aqueous Solutions of Ionic Liquids Forming Hydrogen Bond: A Role of Anions, Self-Aggregation, and Mesophase Formation. The H/D exchange process in the imidazolium-based room temperature ionic liquids (RTILs) 1-decyl-3-methyl-imidazolium bromide- and chloride ([C10mim][Br] and [C10mim][Cl]) in D2O solutions of various concentrations was studied applying (1)H, (13)C NMR, and Raman spectroscopy. The time dependencies of integral intensities in NMR spectra indicate that the H/D exchange in [C10mim][Br] at very high dilution (10(-4) mole fraction of RTIL) runs only slightly faster than in [C10mim][Cl]. The kinetics of this process drastically changes above critical aggregation concentration (CAC). The time required to reach the apparent reaction saturation regime in the solutions of 0.01 mole fraction of RTIL was less 10 h for [C10mim][Br], whereas no such features were seen for [C10mim][Cl] even tens of days after the sample was prepared. The H/D exchange was not observed in the liquid crystalline gel mesophase. The role of anions, self-aggregation (micellization), and mesophase formation has been discussed. Crucial influence of Br(-) and Cl(-) anions on the H/D exchange rates above CAC could be related to the short-range ordering and molecular microdynamics, in particular that of water molecules. The concept of the conformational changes coupled with the H/D exchange in imidazolium-based ionic liquids with longer hydrocarbon chains can be rejected in the light of (13)C NMR experiment. The revealed changes in (13)C NMR spectra are caused by the secondary ((13)C) isotope effects not being the signal shifts due to the conformational trans-gauche transition. 23255045 Vitamin E management of oxidative damage-linked dysfunctions of hyperthyroid tissues. Thyroid hormones affect growth, development, and metabolism of vertebrates, and are considered the major regulators of their homeostasis. On the other hand, elevated circulating levels of thyroid hormones are associated with modifications in the whole organism (weight loss and increased metabolism and temperature) and in several body regions. Indeed, tachycardia, atrial arrhythmias, heart failure, muscle weakness and wasting, bone mass loss, and hepatobiliary complications are commonly found in hyperthyroid animals and humans. Most thyroid hormone actions result from influences on transcription of T3-responsive genes, which are mediated through nuclear receptors. However, there is significant evidence that tissue oxidative stress underlies some dysfunctions produced by hyperthyroidism. During the last decades, increasing interest has been turned to the use of antioxidants as therapeutic agents in various diseases and pathophysiological disorders believed to be mediated by oxidative stress. In particular, because elevated circulating levels of thyroid hormones are associated with tissue oxidative injury, more attention has been paid to explore the application of antioxidants as therapeutic agents in thyroid related disorders. At present, vitamin E is among the most commonly consumed dietary supplements due to the belief that it, as an antioxidant, may attenuate morbidity and mortality. This is due to the results of numerous scientific studies, which demonstrate that vitamin E has a primary function to destroy peroxyl radicals, thus protecting polyunsaturated fatty acids biological membranes from oxidative damage. However, results are also available indicating that protective vitamin E effects against oxidative damage can be obtained even through different mechanisms. 23376407 Excessive ethanol consumption under exposure to lead intensifies disorders in bone metabolism: A study in a rat model. It was investigated whether ethanol (Et) modifies the damaging impact of lead (Pb) on bone metabolism in a rat model reflecting excessive alcohol consumption by humans exposed to relatively high levels of this metal. For this purpose, markers of bone formation (osteocalcin, procollagen I, osteoprotegerin, alkaline phosphatase) and resorption (telopeptides of collagen I, soluble receptor activator of nuclear factor-κB ligand), calciotropic hormones (parathormone, calcitonin, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D) in the serum, and the femur content of mineral (including calcium - Ca and inorganic phosphorus - Pi) and organic components were estimated in the rats exposed to 500mg Pb/l (in drinking water) or/and Et (5g/kg b.wt./24h, by oral gavage) for 12weeks. Moreover, Ca and Pi in the serum and urine, alkaline phosphatase in the bone tissue and Pb in the blood and femur were determined. The exposure to Pb or/and Et decreased bone formation and increased its resorption resulting in the bone demineralization. These effects were accompanied by destroying the hormonal regulation of mineral metabolism, and Ca and Pi imbalance. The co-exposure to Pb and Et-induced disorders in bone metabolism were more advanced than those caused by Pb alone. Et co-administration increased Pb concentration in the blood and decreased its accumulation in the bone. This paper is the first report providing evidence that consumption of Et under exposure to Pb intensifies disorders in bone metabolism and that destroying of the receptor activator nuclear factor-κB (RANK)/RANK ligand/osteoprotegerin system is involved in the mechanisms of interactive action of these xenobiotics on the skeleton. The modifying impact of Et may be an effect of its independent osteotropic action and interaction with Pb. Based on the results it can be concluded that alcohol abuse by subjects excessively exposed to Pb considerably increases the risk of bone damage. 23512773 An intragastric balloon in the treatment of obese individuals with metabolic syndrome: A randomized controlled study. There are limited controlled data for intragastric balloons (IGB) in obesity treatment. This randomized, controlled study evaluated the efficacy and safety of an IGB in obese individuals with metabolic syndrome (MS). Sixty-six adults (BMI: 30-40 kg/m(2) ) were randomized to IGB for 6 months, with a 12 month behavioral modification (IGB Group; "IGBG"), or 12 month behavioral modification alone (Control Group; "CG"). The primary outcome was percentage change in body weight. Thirty-one subjects (female: 68%; mean age: 43; mean BMI: 36.0) were randomized to IGBG and 35 (66%; 48; 36.7) to CG. At 6 months, there was a significantly greater weight loss in the IGBG: -14.2 vs. -4.8; P < 0.0001. This was associated with a significantly greater reduction in waist circumference, and an improvement in quality of life, with a trend for a larger %MS remission (50% vs. 30%; n.s.). At month 12, the differences in weight loss were enduring: -9.2 vs. -5.2; P = 0.007. Gastrointestinal-related adverse events were common in the IGBG, resolving predominantly within two weeks. The IGB was removed prematurely in three subjects (one for refractory gastrointestinal symptoms). Statistically significant and clinically relevant improvements in weight loss and health outcomes were observed with the IGBG at 6 months versus behavioral modification alone. The differential weight loss was still evident 6 months after IGB removal. 23086899 Comment on real-time observation on dynamic growth/dissolution of conductive filaments in oxide-electrolyte- based ReRAM. Filament formation and dissolution in the system Ag(Cu)/ZrO(2) /Pt were observed by Liu et al. [Adv. Mater. 2012, 24, 1844]. Their explanation of the phenomena is shown here to be inappropriate. Various situations, including the "bipolar electrode" shown in the figure, are considered and the difference between the behavior in electrochemical metallization memories (ECMs) and valence change memories (VCMs) outlined. Of crucial importance for distinguishing ECM from VCM behavior, that is, the effects of cation and anion migration, is the choice of the solid materials used to transport metal cations. A possible explanation of the phenomena is proposed. 23099431 Pharmacokinetic study of Growth Hormone-Releasing Peptide 6 (GHRP-6) in nine male healthy volunteers. GHRP-6 is a growth hormone secretagogue that also enhances tissue viability in different organs. In the present work, we studied the pharmacokinetics of this short therapeutic hexapeptide (His-(D-Trp)-Ala-Trp-(D-Phe)-Lys-NH(2,) MW=872.44 Da) in nine male healthy volunteers after a single intravenous bolus administration of 100, 200 and 400 μg/kg of body weight. GHRP-6 was quantified in human plasma by a specific LC-MS method, previously developed and validated following FDA guidelines, using (13)C(3)Ala-GHRP-6 as internal standard (Gil et al., 2012, J. Pharm. Biomed. Anal. 60, 19-25). The Lower Limit of Quantification (5 ng/mL) was reached in all subjects at 12h post-administration, which was sufficient for modeling a pharmacokinetic profile including over 85% of the Area under the Curve (AUC). Disposition of GHRP-6 best fitted a bi-exponential function with R(2) higher than 0.99, according to a mathematic modeling and confirmed by an Akaike index (AIC) lower than that of the corresponding one-compartment model for all subjects. Averaging all three dose levels, the distribution and elimination half-life of GHRP-6 were 7.6 ± 1.9 min and 2.5 ± 1.1h, respectively. These values are coherent with existing data for other drugs whose disposition also fits this model. Dose dependence analysis revealed a noticeable trend for AUC to increase proportionally with administered dose. Atypical GHRP-6 concentration spikes were observed during the elimination phase in four out of the nine subjects studied. 23353012 Feasibility of spray drying bacteriophages into respirable powders to combat pulmonary bacterial infections. The use of bacterial viruses for antibacterial treatment (bacteriophage therapy) is currently being reevaluated. In this study, we analyze the potential of processing bacteriophages in a dry powder formulation, using a laboratory spray dryer. The phages were dried in the presence of lactose, trehalose or dextran 35, serving as an excipient to give the resulting powder the necessary bulk mass and offer protection to the delicate phage structure. Out of the three excipients tested, trehalose was found to be the most efficient in protecting the phages from temperature and shear stress throughout the spray drying process. A low inlet air temperature and atomizing force appeared to be the best parameter conditions for phage survival. Pseudomonas podovirus LUZ19 was remarkably stable, suffering less than 1 logarithmic unit reduction in phage titer. The phage titer of Staphyloccus phage Romulus-containing powders, a member of the Myoviridae family, showed more than 2.5 logarithmic units reduction. On the other hand, Romulus-containing powders showed more favorable characteristics for pulmonary delivery, with a high percentage of dry powder particles in the pulmonary deposition fraction (1-5μm particle diameter). Even though the parameters for spray drying all phages were not optimized, it was demonstrated that spray drying phages with this industrial relevant and scalable set up was possible. The resulting powders had desirable size ranges for pulmonary delivery of phages with dry powder inhalers (DPIs). 22776694 Passive stiffness of airway smooth muscle: the next target for improving airway distensibility and treatment for asthma? Reduced airway distensibility due to increased airway stiffness is a characteristic of asthma. Airway stiffness is determined by the property and structural organization of the various elements of the airway wall, and is often divided into active and passive components. Active stiffness is thought to be associated with activation of muscle cells in the airway wall. This component of stiffness can be inhibited when active force produced by the muscle is abolished. Passive stiffness, on the other hand, is thought to stem from non-muscle component of the airway wall, especially the collagen/elastin fibrous network of the extracellular matrix within which the muscle cells are embedded. In this brief review, the notion that passive stiffness is exclusively extracellular in origin is challenged. Recent evidence suggests that a substantial portion of the passive stiffness of an in vitro preparation of tracheal smooth muscle is calcium sensitive and is regulated by Rho-kinase, although the underlying mechanism and the details of regulation for the development of this intracellular passive stiffness are still largely unknown. To reduce airway stiffness different lines of attack must be tailored to different components of the stiffness. The regulatable passive stiffness is distinct from the relatively permanent stiffness of the extracellular matrix and the stiffness associated with active muscle contraction. To improve airway distensibility during asthma exacerbation, a comprehensive approach to reduce overall airway stiffness should therefore include a strategy for targeting the regulatable passive stiffness. 23680587 Isocyanate exposure assessment combining industrial hygiene methods with biomonitoring for end users of orthopedic casting products. Previous studies have suggested a potential risk to healthcare workers applying isocyanate-containing casts, but the authors reached their conclusions based on immunological or clinical pulmonology test results alone. We designed a study to assess potential exposure to methylene diphenyl diisocyanate (MDI) among medical personnel applying orthopedic casts using two different application methods. Air, dermal, surface, and glove permeation sampling methods were combined with urinary biomonitoring to assess the overall risk of occupational asthma to workers handling these materials. No MDI was detected in any of the personal and area air samples obtained. No glove permeation of MDI was detected. A small proportion of surface (3/45) and dermal wipe (1/60) samples were positive for MDI, but were all from inexperienced technicians. Urinary metabolites of MDI [methylenedianiline (MDA)] were detected in three of six study participants prior to both a 'dry' and 'wet' application method, five of six after the dry method, and three of six after the wet method. All MDA results were below levels noted in worker or general populations. Our conclusion is that the risk of MDI exposure is small, but unquantifiable. Because there is some potential risk of dermal exposure, medical personnel are instructed to wear a minimum of 5-mil-thick (5 mil = 0.005 inches) nitrile gloves and avoid contact to unprotected skin. This could include gauntlets, long sleeves, and/or a laboratory coat. 23871611 Beyond the silence: Bilateral somatosensory stimulation enhances skilled movement quality and neural density in intact behaving rats. It is thought that a close dialogue between the primary motor (M1) and somatosensory (S1) cortices is necessary for skilled motor learning. The extent of the relative S1 contribution in producing skilled reaching movements, however, is still unclear. Here we used anodal transcranial direct current stimulation (tDCS), which is able to alter polarity-specific excitability in the S1, to facilitate skilled movement in intact behaving rats. We hypothesized that the critical role of S1 in reaching performance can be enhanced by bilateral tDCS. Pretrained rats were assigned to control or stimulation conditions: (1) UnAno: the unilateral application of an anodal current to the side contralateral to the paw preferred for reaching; (2) BiAno1: bilateral anodal current; (3) BiAno2: a bilateral anodal current with additional 30ms of 65μA pulses every 5s. Rats received tDCS (65μA; 10min/rat) to the S1 during skilled reach training for 20 days (online-effect phase). After-effect assessment occurred for the next ten days in the absence of electrical stimulation. Quantitative and qualitative analyses of online-effects of tDCS showed that UnAno and BiAno1 somatosensory stimulation significantly improve skilled reaching performance. Bilateral BiAno1 stimulation was associated with greater qualitative functional improvement than unilateral UnAno stimulation. tDCS-induced improvements were not observed in the after-effects phase. Quantitative cytoarchitectonic analysis revealed that somatosensory tDCS bilaterally increases cortical neural density. The findings emphasize the central role of bilateral somatosensory feedback in skill acquisition through modulation of cortico-motor excitability. 23926346 Subviral dense bodies of human cytomegalovirus stimulate maturation and activation of monocyte-derived immature dendritic cells. Dendritic cells play a central role in the immune control of human cytomegalovirus (HCMV) infection. This work aimed at investigating the impact of non-infectious, subviral dense bodies of HCMV on maturation and activation of dendritic cells (DC). Treatment of immature DC with dense bodies led to the maturation of these cells and significantly increased their capacity for cytokine release and antigen presentation. Dense bodies activated DC may thereby contribute to the development of antiviral immunity. 23924635 Distinct temporal requirements for Runx1 in hematopoietic progenitors and stem cells. The transcription factor Runx1 is essential for the formation of yolk sac-derived erythroid/myeloid progenitors (EMPs) and hematopoietic stem cells (HSCs) from hemogenic endothelium during embryogenesis. However, long-term repopulating HSCs (LT-HSCs) persist when Runx1 is conditionally deleted in fetal liver cells, demonstrating that the requirement for Runx1 changes over time. To define more precisely when Runx1 transitions from an essential factor to a homeostatic regulator of EMPs and HSCs, and whether that transition requires fetal liver colonization, we performed conditional, timed deletions of Runx1 between E7.5 and E13.5. We determined that Runx1 loss reduces the formation or function of EMPs up through E10.5. The Runx1 requirement in HSCs ends later, as deletion up to E11.5 eliminates HSCs. At E11.5, there is an abrupt transition to Runx1 independence in at least a subset of HSCs that does not require fetal liver colonization. The transition to Runx1 independence in EMPs is not mediated by other core binding factors (Runx2 and/or Runx3); however, deleting the common non-DNA-binding β subunit (CBFβ) severely compromises LT-HSC function. Hence, the requirements for Runx1 in EMP and HSC formation are temporally distinct, and LT-HSC function is highly reliant on continued core binding factor activity. 23915980 Resistance of Lophelia pertusa to coverage by sediment and petroleum drill cuttings. In laboratory experiments, the cold-water coral Lophelia pertusa was exposed to settling particles. The effects of reef sediment, petroleum drill cuttings and a mix of both, on the development of anoxia at the coral surface were studied using O2, pH and H2S microsensors and by assessing coral polyp mortality. Due to the branching morphology of L. pertusa and the release of coral mucus, accumulation rates of settling material on coral branches were low. Microsensors detected H2S production in only a few samples, and sulfate reduction rates of natural reef sediment slurries were low (<0.3nmolScm(-3)d(-1)). While the exposure to sediment clearly reduced the coral's accessibility to oxygen, L. pertusa tolerated both partial low-oxygen and anoxic conditions without any visible detrimental short-term effect, such as tissue damage or death. However, complete burial of coral branches for >24h in reef sediment resulted in suffocation. 23676768 Patterns of Epistasis between Beneficial Mutations in an Antibiotic Resistance Gene. Understanding epistasis is central to biology. For instance, epistatic interactions determine the topography of the fitness landscape and affect the dynamics and determinism of adaptation. However, few empirical data are available, and comparing results is complicated by confounding variation in the system and the type of mutations used. Here, we take a systematic approach by quantifying epistasis in two sets of four beneficial mutations in the antibiotic resistance enzyme TEM-1 β-lactamase. Mutations in these sets have either large or small effects on cefotaxime resistance when present as single mutations. By quantifying the epistasis and ruggedness in both landscapes, we find two general patterns. First, resistance is maximal for combinations of two mutations in both fitness landscapes and declines when more mutations are added due to abundant sign epistasis and a pattern of diminishing returns with genotype resistance. Second, large-effect mutations interact more strongly than small-effect mutations, suggesting that the effect size of mutations may be an organizing principle in understanding patterns of epistasis. By fitting the data to simple phenotype resistance models, we show that this pattern may be explained by the nonlinear dependence of resistance on enzyme stability and an unknown phenotype when mutations have antagonistically pleiotropic effects. The comparison to a previously published set of mutations in the same gene with a joint benefit further shows that the enzyme's fitness landscape is locally rugged but does contain adaptive pathways that lead to high resistance. 23122138 One-step purification of lactoperoxidase from bovine milk by affinity chromatography. Sulphanilamide was determined to be a new inhibitor of lactoperoxidase (LPO) with an IC(50) of 0.848.10(-5)M. The K(i) for sulphanilamide was determined to be 3.57.10(-5)M and sulphanilamide showed competitive inhibition, which makes it a suitable ligand for constructing a Sepharose 4B-L-tyrosine affinity matrix. The affinity matrix was synthesised by coupling sulphanilamide as the ligand and L-tyrosine as the spacer arm to a cyanogen bromide (CNBr)-activated-Sepharose 4B matrix. Lactoperoxidase was purified 409-fold from the synthesized affinity matrix in a single step, with a yield of 62.3% and a specific activity of 40.9 EU/mg protein. The enzyme activity was measured using ABTS as a chromogenic substrate (pH 6.0). The degree of LPO purification was monitored by SDS-PAGE and its R(z) (A(412)/A(280)) value. The R(z) value for the purified LPO was found to be 0.7. Maximum binding was achieved and K(m) and V(max) values were determined. 23922970 Mutation of GDP-Mannose-4,6-Dehydratase in Colorectal Cancer Metastasis. Fucosylation is a crucial oligosaccharide modification in cancer. The known function of fucosylation in cancer is to mediate metastasis through selectin ligand-dependent processes. Previously, we found complete loss of fucosylation in the colon cancer cell line HCT116 due to a mutation in the GDP-fucose synthetic enzyme, GDP-mannose-4,6-dehydratase (GMDS). Loss of fucosylation led to escape of cancer cells from tumor immune surveillance followed by tumor progression and metastasis, suggesting a novel function of fucosylation in tumor progression pathway. In the present study, we investigated the frequency of GMDS mutation in a number of clinical colorectal cancer tissue samples: 81 samples of primary colorectal cancer tissue and 39 samples of metastatic lesion including liver and lymph node. Four types of deletion mutation in GMDS were identified in original cancer tissues as well as metastatic lesions. The frequency of GMDS mutation was slightly higher in metastatic lesions (12.8%, 5/39 samples) than in original cancer tissues (8.6%, 7/81 samples). No mutation of the GMDS gene was observed in normal colon tissues surrounding cancer tissues, suggesting that the mutation is somatic rather than in the germline. Immunohistochemical analysis revealed complete loss of fucosylation in three cases of cancer tissue. All three cases had GMDS mutation. In one of three cases, loss of fucosylation was observed in only metastatic lesion, but not its original colon cancer tissue. These data demonstrate involvement of GMDS mutation in the progression of colorectal cancer. 23508707 Comparison of respiratory-triggered 3-D fast spin-echo and single-shot fast spin-echo radial slab MR cholangiopancreatography images in children. The two most commonly performed magnetic resonance cholangiopancreatography (MRCP) sequences, 3-D fast spin-echo (3-D FSE) and single-shot fast spin-echo radial slabs (radial slabs), have not been compared in children. The purpose of this study was to compare 3-D FSE and radial slabs MRCP sequences on a 3-T scanner to determine their ability to show various segments of pancreaticobiliary tree and presence of artifacts in children. We reviewed 79 consecutive MRCPs performed in 74 children on a 3-T scanner. We noted visibility of major ducts on 3-D FSE and radial slabs. We noted the order of branching of ducts in the right and left hepatic ducts and the degree of visibility of the pancreatic duct. Statistical analysis was performed using McNemar and signed rank tests. There was no significant difference in the visibility of major bile ducts and the order of branching in the right hepatic lobe between sequences. A higher order of branching in the left lobe was seen on radial slabs than 3-D FSE (mean order of branching 2.82 versus 2.27; P-value = 0.0002). The visibility of pancreatic duct was better on radial slabs as compared to 3-D FSE (mean value of 1.53 vs. 0.90; P-value < 0.0001). 3-D FSE sequence was artifact-free in 25/79 (31.6%) MRCP exams as compared to radial slabs, which were artifact-free in 18/79 (22.8%) MRCP exams (P-value = 0.0001). There is no significant difference in the visibility of major bile ducts between 3-D FSE and radial slab MRCP sequences at 3-T in children. However, radial slab MRCP shows a higher order of branching in the left hepatic lobe and superior visibility of the pancreatic duct than 3-D FSE. 23901929 Mitochondrial genome of the Emberiza aureola (Emberizidae: Emberiza). Abstract The Emberiza aureola (yellow-breasted bunting), Vulnerable (IUCN), is a Eurasian bird with very wide geographical range. The complete mitochondrial genome of E. aureola (16,800 bp in length) contained 37 genes (13 protein-coding genes, 2 rRNA genes, and 22 tRNA genes) and a non-coding region (D-loop), which is similar to the typical mtDNA of vertebrates. All the protein-coding genes in E. aureola were distributed on the H-strand, except for the ND6 subunit gene and ten tRNA genes which were encoded on the L-strand. 23886038 Role of the Candida albicans MNN1 gene family in cell wall structure and virulence. The Candida albicans cell wall is the first point of contact with the host, and its outer surface is heavily enriched in mannoproteins modified through the addition of N- and O-mannan. Previous work, using mutants with gross defects in glycosylation, has clearly identified the importance of mannan in the host-pathogen interaction, immune recognition and virulence. Here we report the first analysis of the MNN1 gene family, which contains six members predicted to act as α-1,3 mannosyltransferases in the terminal stages of glycosylation. We generated single null mutants in all members of the C. albicans MNN1 gene family, and disruption of MNN14 led to both in vitro and in vivo defects. Null mutants in other members of the family demonstrated no phenotypic defects, suggesting that these members may display functional redundancy. The mnn14Δ null mutant displayed hypersensitivity to agents associated with cell wall and glycosylation defects, suggesting an altered cell wall structure. However, no gross changes in cell wall composition or N-glycosylation were identified in this mutant, although an extension of phosphomannan chain length was apparent. Although the cell wall defects associated with the mnn14Δ mutant were subtle, this mutant displayed a severe attenuation of virulence in a murine infection model. Mnn14 plays a distinct role from other members of the MNN1 family, demonstrating that specific N-glycan outer chain epitopes are required in the host-pathogen interaction and virulence. 23937095 Directional phytoscreening: contaminant gradients in trees for plume delineation. Tree sampling methods have been used in phytoscreening applications to delineate contaminated soil and groundwater, augmenting traditional investigative methods that are time-consuming, resource-intensive, invasive, and costly. In the past decade, contaminant concentrations in tree tissues have been shown to reflect the extent and intensity of subsurface contamination. This paper investigates a new phytoscreening tool: directional tree coring, a concept originating from field data that indicated azimuthal concentrations in tree trunks reflected the concentration gradients in the groundwater around the tree. To experimentally test this hypothesis, large diameter trees were subjected to subsurface contaminant concentration gradients in a greenhouse study. These trees were then analyzed for azimuthal concentration gradients in aboveground tree tissues, revealing contaminant centroids located on the side of the tree nearest the most contaminated groundwater. Tree coring at three field sites revealed sufficiently steep contaminant gradients in trees reflected nearby groundwater contaminant gradients. In practice, trees possessing steep contaminant gradients are indicators of steep subsurface contaminant gradients, providing compass-like information about the contaminant gradient, pointing investigators toward higher concentration regions of the plume. 23929550 Wall shear stress association with rupture status in volume matched sidewall aneurysms. Flow induced tangential wall shear stress (WSS) is thought to be involved in aneurysm formation, growth, and rupture. Low WSS was previously associated with rupture, but definitive quantitative analyses remain scant as larger aneurysms are associated with lower WSS regardless of rupture status, and ruptured aneurysms are larger than unruptured aneurysms. Here, the intra-dome WSS was evaluated on 18 internal carotid artery aneurysms, volume matched as ruptured/unruptured pairs in order to remove the confounding effect of size dependence. Computational fluid dynamic simulations were performed and WSS was evaluated at peak systole, end diastole, and as time averaged over the cardiac cycle. WSS logarithmic scaling was applied to refine value discrimination at extrema. Ruptured/unruptured lesions were statistically evaluated using pairwise t test analysis. The effect of size on WSS was evaluated in parametric models. In parametric data, there was a statistically significant negative correlation between volume and WSS values. In patient data, mean WSS was not statistically significant but low range WSS values were significantly lower for ruptured aneurysms, regardless of WSS evaluation (time averaged, peak systole, end diastole). Statistically, logarithmic WSS performed better than WSS, with minimum logarithmic WSS at end diastole being the best rupture status discriminator (p=0.001, area under the curve=0.98). Higher range and maximal WSS were not significantly significant. Aneurysm size is a confounding factor to WSS rupture discrimination, and volume matched analysis is necessary for unbiased evaluation. While these results lend support to the hypothesis that lower WSS induces wall changes which may be associated with rupture, it raises questions regarding the extent of this association, which requires further exploration. 23903478 Update on factors motivating pharmacy students to pursue residency and fellowship training. The factors motivating pharmacy students to pursue residency and fellowship training in 2011 versus 1993 were assessed. A survey replicating previous research was electronically sent to 794 residency directors and 29 fellowship program directors with a request to forward the survey to current residents and fellows. A similar survey was sent to 124 colleges of pharmacy with a request to forward the survey to the faculty member most involved with residency and fellowship promotion within their doctor of pharmacy (Pharm.D.) curriculum. Participants were asked to rank leading motivating factors and barriers to pharmacy students pursuing these programs. Additional data collected included when and the methods by which these programs are promoted. Among residents and fellows, 865 usable surveys were returned. The leading motivating reasons for residents and fellows to pursue training were "to gain knowledge and experience," "to gain confidence," and "understood as a prerequisite for certain jobs." A total of 124 U.S. pharmacy schools were surveyed, and 65 (52%) returned completed responses. "Understood as a prerequisite for certain jobs," "faculty stressing importance," and "recognition of the new and challenging roles for pharmacists in the future" were the factors most frequently cited by faculty members. Compared with previous research, a new factor motivating pharmacy students to pursue residency and fellowship training is the consideration that these opportunities are a prerequisite for certain jobs. This development may be attributable to trends in the supply and demand of pharmacists, the recognition of the value in these programs by major pharmacy organizations, and the evolving role of pharmacists in direct patient care. 23879230 Multilocus phylogeography of the European ground squirrel: cryptic interglacial refugia of continental climate in Europe. The theory of classical and cryptic Pleistocene refugia is based mainly on historical changes in temperature, and the refugia are usually defined within a latitudinal gradient. However, the gradient of oceanic-continental climate (i.e. longitudinal) was also significantly variable during glacial cycles with important biotic consequences. Range-wide phylogeography of the European ground squirrel (EGS) was used to interpret the evolutionary and palaeogeographical history of the species in Europe and to shed light on its glacial-interglacial dynamic. The EGS is a steppe-inhabiting species and the westernmost member of the genus in the Palaearctic region. We have analysed 915 specimens throughout the present natural range by employing mitochondrial DNA sequences (cytochrome b gene) and 12 nuclear microsatellite markers. The reconstructed phylogeography divides the species into two main geographical groups, with deep substructuring within both groups. Bulgaria is the centre of the ancestral area, and it also has the highest genetic diversity within the species. The northernmost group of the EGS survived in the southern part of Pannonia throughout several glacial-interglacial cycles. Animals from this population probably repeatedly colonized areas further to the north and west during the glacial periods, while in the interglacial periods, the EGS distribution contracted back to this Pannonian refugium. The EGS thus represents a species with a glacial expansion/interglacial contraction palaeogeographical dynamics, and the Pannonian and southeastern Balkanian steppes are supported as cryptic refugia of continental climate during Pleistocene interglacials. 23906236 Diabetes mellitus, metabolic syndrome and obesity are not significant risk factors for hepatocellular carcinoma in an HBV- and HCV-endemic area of Southern Taiwan. A prominent factor in hepatocellular carcinoma (HCC) is chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV). Diabetes mellitus (DM), metabolic syndrome (MetS), and obesity have also been implicated in HCC development, but these associations are not observed in all HBV- and HCV-endemic areas. We attempted to clarify the role of these factors in HCC development in an HBV- and HCV-endemic area in southern Taiwan. A community-based health examination was conducted in 2004 in Tainan County. After individuals with incomplete data and those with known HCC were excluded, there were 56,231 participants who were over 40 years of age. A further 262 HCC cases were identified from the National Cancer Registration Database records from 2005 to 2007. The hepatitis B surface antigen (HBsAg) seropositivity, anti-HCV seropositivity, platelet count, serum biochemical data, blood pressure, sociodemographic information, and anthropometric measurements were analyzed. Survival analyses were used to identify the associations between these factors and HCC. For the 262 HCC cases, male gender and age greater than 65 years were risk factors. Furthermore, a high alanine aminotransferase level, chronic HBV and/or HCV infection, and liver cirrhosis were also risk factors for HCC. However, DM, MetS and obesity were not associated with HCC development in the non-HBV-/non-HCV-infected, HBV, HCV, or dual B/C groups. In this HBV- and HCV- endemic area, DM, MetS and obesity were not risk factors for developing HCC. 23688054 Prognostic values of VEGF and IL-8 in malignant pleural effusion in patients with lung cancer. Abstract Objective: The aim of this study was to evaluate the prognostic value of VEGF and IL-8 in pleural effusion in patients with lung cancer. Materials and method: Commercially available ELISA was used to determine VEGF and IL-8 levels. Results: The level of VEGF showed significant correlations with lymph node metastasis and distant metastasis. But, IL-8 was only correlated with lymph node metastasis. Univariate and multivariate analysis revealed elevated VEGF level was an independent predictor of shorter OS and DFS. Conclusion: VEGF could be an important component that contributes to pleural effusion formation, and an important prognostic factor for lung cancer. 23746658 Correlation of staging systems to survival in patients with resected hilar cholangiocarcinoma. We aimed to identify staging parameters associated with survival in patients with hilar cholangiocarcinoma. Clinicopathologic characteristics were obtained retrospectively for all resected patients with Bismuth-Corlette III cholangiocarcinoma between 1993 and 2011. Patients were stratified by the American Joint Commission on Cancer (AJCC) (7th edition) and Memorial Sloan-Kettering Cancer Center (MSKCC) staging systems. Survival analyses tested the effects of clinicopathologic factors and staging covariates on recurrence-free and overall survival. Eighty patients (mean age 63 ± 11 years, 63% male) underwent anatomic hepatectomy with bile duct resection/reconstruction for Bismuth-Corlette IIIa (53%) and IIIb (47%) cholangiocarcinoma. The median follow-up was 26 months (interquartile range = 12 to 50 months), and the median time to recurrence was 15 months (interquartile range = 6 to 38 months). Neither AJCC nor MSKCC staging systems were associated with recurrence-free survival (all P ≥ .059). MSKCC T-stage but not the AJCC staging system was associated with overall survival (P ≤ .026). MSKCC T-stage classification but not AJCC staging is independently associated with overall survival for patients after resection of hilar cholangiocarcinoma. 23793715 Continuous hypothalamic KATP activation blunts glucose counter-regulation in vivo in rats and suppresses KATP conductance in vitro. Acute systemic delivery of the sulfonylurea receptor (SUR)-1-specific ATP-sensitive K(+) channel (KATP) opener, NN414, has been reported to amplify glucose counter-regulatory responses (CRRs) in rats exposed to hypoglycaemia. Thus, we determined whether continuous NN414 could prevent hypoglycaemia-induced defective counter-regulation. Chronically catheterised male Sprague-Dawley rats received a continuous infusion of NN414 into the third ventricle for 8 days after implantation of osmotic minipumps. Counter-regulation was examined by hyperinsulinaemic-hypoglycaemic clamp on day 8 after three episodes of insulin-induced hypoglycaemia (recurrent hypoglycaemia [RH]) on days 5, 6 and 7. In a subset of rats exposed to RH, NN414 infusion was terminated on day 7 to wash out NN414 before examination of counter-regulation on day 8. To determine whether continuous NN414 exposure altered KATP function, we used the hypothalamic glucose-sensing GT1-7 cell line, which expresses the SUR-1-containing KATP channel. Continuous exposure to NN414 in the setting of RH increased, rather than decreased, the glucose infusion rate (GIR), as exemplified by attenuated adrenaline (epinephrine) secretion. Termination of NN414 on day 7 with subsequent washout for 24 h partially diminished the GIR. The same duration of exposure of GT1-7 cells to NN414 substantially reduced KATP conductance, which was also reversed on washout of the agonist. The suppression of KATP current was not associated with reduced channel subunit mRNA or protein levels. These data indicate that continuous KATP activation results in suppressed CRRs to hypoglycaemia in vivo, which in vitro is associated with the reversible conversion of KATP into a stable inactive state. 23177918 "We never thought of a vasectomy": a qualitative study of men and women's counseling around sterilization. Sterilization is the most commonly used method of contraception in the United States; however, little is known about how providers counsel about these procedures or the information patients desire. In this study, we explore male and female experiences of sterilization counseling and their perspectives on ideal sterilization counseling. In-depth individual and group interviews were conducted with 37 heterosexual couples between the ages of 25 and 55 years. Each couple had reached their desired family size. Interviews were recorded and transcribed using NVivo software and analyzed using modified grounded theory. Men and women differed in their experiences of sterilization counseling. Women commonly received counseling on female sterilization but not vasectomy, while men rarely discussed either form of sterilization with their providers. Both men and women desired more information about sterilization. Contraceptive counseling of couples who have completed childbearing does not routinely include men or the option of vasectomy, despite the advantages of this method with respect to safety, efficacy and cost. Family planning and primary care providers have an important role in ensuring that couples are aware of all their options and can make an informed decision about their contraception. 23209282 Burial of the polymorphic residue 129 in amyloid fibrils of prion stop mutants. Misfolding of the natively α-helical prion protein into a β-sheet rich isoform is related to various human diseases such as Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker syndrome. In humans, the disease phenotype is modified by a methionine/valine polymorphism at codon 129 of the prion protein gene. Using a combination of hydrogen/deuterium exchange coupled to NMR spectroscopy, hydroxyl radical probing detected by mass spectrometry, and site-directed mutagenesis, we demonstrate that stop mutants of the human prion protein have a conserved amyloid core. The 129 residue is deeply buried in the amyloid core structure, and its mutation strongly impacts aggregation. Taken together the data support a critical role of the polymorphic residue 129 of the human prion protein in aggregation and disease. 23891289 Crystal Structures of Lgr4 and Its Complex with R-Spondin1. The leucine-rich repeat-containing G-protein-coupled receptors (Lgrs) are a large membrane protein family mediating signaling events during development and in the adult organism. Type 2 Lgrs, including Lgr4, Lgr5, and Lgr6, play crucial roles in embryonic development and in several cancers. They also regulate adult stem cell maintenance via direct association with proteins in the Wnt signaling pathways, including Lrp5/6 and frizzled receptors. The R-spondins (Rspo) were recently identified as functional ligands for type 2 Lgrs and were shown to synergize with both canonical and noncanonical Wnt signaling pathways. We determined and report the structure of the Lgr4 ectodomain alone and bound to Rspo1. The structures reveal an extended horseshoe leucine-rich repeat (LRR) receptor architecture that binds, with its concave side, the ligand furin-like repeats via an intimate interface. The molecular details of ligand/receptor recognition provide insight into receptor activation and could serve as template for stem-cell-based regenerative therapeutics development. 23941309 Association of supermarket characteristics with the body mass index of their shoppers. Research on the built food environment and weight status has mostly focused on the presence/absence of food outlets while ignoring their internal features or where residents actually shop. We explored associations of distance travelled to supermarkets and supermarket characteristics with shoppers' body mass index (BMI). Shoppers (n=555) of five supermarkets situated in different income areas in the city were surveyed for food shopping habits, demographics, home postal code, height and weight. Associations of minimum distance to a supermarket (along road network, objectively measured using ArcGIS), its size, food variety and food basket price with shoppers' BMI were investigated. The 'food basket' was defined as the mixture of several food items commonly consumed by residents and available in all supermarkets. Supermarkets ranged in total floor space (7500-135,000 square feet) and had similar varieties of fruits, vegetables and cereals. The majority of participants shopped at the surveyed supermarket more than once per week (mean range 1.2 ± 0.8 to 2.3 ± 2.1 times per week across the five supermarkets, p < 0.001), and identified it as their primary store for food (52% overall). Mean participant BMI of the five supermarkets ranged from 23.7 ± 4.3 kg/m² to 27.1 ± 4.3 kg/m² (p < 0.001). Median minimum distance from the shoppers' residence to the supermarket they shopped at ranged from 0.96 (0.57, 2.31) km to 4.30 (2.83, 5.75) km (p < 0.001). A negative association was found between food basket price and BMI. There were no associations between BMI and minimum distance to the supermarket, or other supermarket characteristics. After adjusting for age, sex, dissemination area median individual income and car ownership, BMI of individuals who shopped at Store 1 and Store 2, the supermarkets with lowest price of the 'food basket', was 3.66 kg/m² and 3.73 kg/m² higher compared to their counterparts who shopped at the supermarket where the 'food basket' price was highest (p < 0.001). The food basket price in supermarkets was inversely associated with BMI of their shoppers. Our results suggest that careful manipulation of food prices may be used as an intervention for decreasing BMI. 23932420 Interspecific introgression and changes in population structure in a flatfish species complex after the Prestige accident. Oil spills cause aggressive impacts on marine ecosystems affecting immense areas and the species inhabiting them. If wastes are not cleaned up properly, the remnants may affect local populations for a long time. This work focuses on the long-term impacts of the Prestige spillage that occurred off Galician coast (Spain) in November 2002. Model species were two sympatric flatfish, the megrims Lepidorhombus whiffiagonis and Lepidorhombus boscii. Samples obtained before and nine years after the Prestige accident from affected and unaffected areas were genotyped for six hypervariable nuclear markers and for the mitochondrial D-loop sequence. The results revealed a high proportion of post-F1 interspecific hybrids in the area affected, and also increased intraspecific population differentiation likely due to such localized introgression of foreign genes. These changes suggest the appearance of a hybrid zone following the accident and emphasize the need of paying special attention to potential evolutionary impacts of oil spills. 23899446 Targeted detection of phosphatidylserine in biomimetic membranes and in vitro cell systems using annexin V-containing cubosomes. In this work we have formulated Annexin V (ANX) decorated phosphatidylserine containing phytantriol (PSPhy) cubosomes to act as probes for the enhanced detection of apoptotic membranes in both model and in vitro cell systems. Small angle X-ray scattering (SAXS) and cryogenic-transmission electron microscopy (Cryo-TEM) indicated that ANX-containing PSPhy (ANX-PSPhy) cubosomes retain the Pn3m cubic symmetry and cubic phase nanoparticle characteristics of PSPhy cubosomes. The interaction of ANX-PSPhy cubosomes with apoptotic model and cellular membranes was also investigated using both quartz crystal microbalance with dissipation and confocal microscopy which confirmed that ANX-PSPhy cubosomes can selectively bind to apoptotic cells and model membranes. Neutron reflectometry has also been used to show strong binding of ANX-PSPhy cubosomes to a model apoptotic membrane, and in addition reveals changes in both the bilayer structure and in the internal structure of the cubosome in a region adjacent to the membrane as a result of material exchange. This material exchange between cubosome and apoptotic model bilayer was further demonstrated using Cryo-TEM. We have demonstrated that lipid bound protein, in this case Annexin V, can be used to target cubosome systems to biological surfaces in vitro. 23904153 Epigenetic Cancer Prevention Mechanisms in Skin Cancer. Epigenetics is an important emerging area for study of mechanisms of cancer prevention. In recent years, it has been realized that cancer prevention agents, derived from natural dietary sources, impact cancer cell survival by modulating epigenetic processes. In the present manuscript, we review key epigenetic regulatory mechanisms and examine the impact of sulforaphane and green tea polyphenols on these processes. We also discuss available information on the epigenetics in the context of skin cancer. These studies indicate that diet-derived chemopreventive agents modulate DNA methylation status and histone modification via multiple processes and point to additional areas for study of epigenetic mechanisms in skin cancer. 23643835 Myelodysplastic syndrome: An inability to appropriately respond to damaged DNA? Myelodysplastic syndrome (MDS) is considered a hematopoietic stem cell disease that is characterized by abnormal hematopoietic differentiation and a high propensity to develop acute myeloid leukemia. It is mostly associated with advanced age, but also with prior cancer therapy and inherited syndromes related to abnormalities in DNA repair. Recent technologic advances have led to the identification of a myriad of frequently occurring genomic perturbations associated with MDS. These observations suggest that MDS and its progression to acute myeloid leukemia is a genomic instability disorder, resulting from a stepwise accumulation of genetic abnormalities. The notion is now emerging that the underlying mechanism of this disease could be a defect in one or more pathways that are involved in responding to or repairing damaged DNA. In this review, we discuss these pathways in relationship to a large number of studies performed with MDS patient samples and MDS mouse models. Moreover, in view of our current understanding of how DNA damage response and repair pathways are affected by age in hematopoietic stem cells, we also explore how this might relate to MDS development. 23900542 Prdm1a directly activates foxd3 and tfap2a during zebrafish neural crest specification. The neural crest comprises multipotent precursor cells that are induced at the neural plate border by a series of complex signaling and genetic interactions. Several transcription factors, termed neural crest specifiers, are necessary for early neural crest development; however, the nature of their interactions and regulation is not well understood. Here, we have established that the PR/SET domain-containing transcription factor Prdm1a is co-expressed with two essential neural crest specifiers, foxd3 and tfap2a, at the neural plate border. Through rescue experiments, chromatin immunoprecipitation and reporter assays, we have determined that Prdm1a directly binds to and transcriptionally activates enhancers for foxd3 and tfap2a and that they are functional, direct targets of Prdm1a at the neural plate border. Additionally, analysis of dominant activator and dominant repressor Prdm1a constructs suggests that Prdm1a is required both as a transcriptional activator and transcriptional repressor for neural crest development in zebrafish embryos. 23791789 Allopurinol and xanthine use different translocation mechanisms and trajectories in the fungal UapA transporter. In Aspergillus nidulans UapA is a H(+)-driven transporter specific for xanthine, uric acid and several analogues. Here, genetic and physiological evidence is provided showing that allopurinol is a high-affinity, low-capacity, substrate for UapA. Surprisingly however, transport kinetic measurements showed that, uniquely among all recognized UapA substrates, allopurinol is transported by apparent facilitated diffusion and exhibits a paradoxical effect on the transport of physiological substrates. Specifically, excess xanthine or other UapA substrates inhibit allopurinol uptake, as expected, but the presence of excess allopurinol results in a concentration-dependent enhancement of xanthine binding and transport. Flexible docking approaches failed to detect allopurinol binding in the major UapA substrate binding site, which was recently identified by mutational analysis and substrate docking using all other UapA substrates. These results and genetic evidence suggest that the allopurinol translocation pathway is distinct from, but probably overlapping with, that of physiological UapA substrates. Furthermore, although the stimulating effect of allopurinol on xanthine transport could, in principle, be rationalized by a cryptic allopurinol-specific allosteric site, evidence was obtained supporting that accelerated influx of xanthine is triggered through exchange with cytoplasmically accumulated allopurinol. Our results are in line with recently accumulating evidence revealing atypical and complex mechanisms underlying transport systems. 23920054 Ribosomal and mitochondrial DNA analysis of Trichuridae nematodes of carnivores and small mammals. Several species of Trichuridae nematodes can infect dogs, cats and wild mammals. The diagnosis of these infections relies on the microscopic identification of eggs which are characterized by a similar "lemon" shape and polar plugs in all Trichuridae. Thus, morphological diagnosis to species level is challenging. The use of biomolecular diagnostic methods is desirable but very little genetic data are known from Trichuridae of carnivores and small mammals. The aim of this work was to genetically characterize several species of Trichuridae that can affect dogs, cats and wild mammals, as a basis to develop molecular diagnostic tests. Specimens (adult worms or eggs) of Eucoleus aerophilus (syn. Capillaria aerophila), Eucoleus boehmi (syn. Capillaria boehmi), Pearsonema plica (syn. Capillaria plica), Aonchotheca putorii (syn. Capillaria putorii), Calodium hepaticum (syn. Capillaria hepatica), Calodium splenaecum (syn. Capillaria splenaeca) and Trichuris vulpis were obtained from carcasses of red foxes, feces of dogs, the liver of a vole and from the spleen of Crocidura sp. Parts of the small subunit rRNA (18S rRNA) gene and of the mitochondrial cytochrome c oxidase subunit I (cox 1 mtDNA) gene were amplified from the above mentioned nematodes, yielding the first 18S rRNA gene sequences of all the capillariid nematodes and the first cox 1 mtDNA sequences of E. boehmi, P. plica, C. hepaticum, A. putorii and T. vulpis. The 18S rRNA gene is highly conserved among the different species and not suitable as a target for specific diagnostic oligonucleotides. However, these sequences contribute to a better understanding of the complex taxonomic relations among Trichuridae. Indeed, a dendrogram based on the 18S rRNA gene locus supports the latest taxonomic revision. Interspecies divergence was much higher at the cox 1 mtDNA gene locus, rendering it suitable for DNA barcoding and particularly valuable in resolving closely related species. Furthermore, the mitochondrial genetic markers defined in the present study are useful to develop Trichuridae species-specific primers. 23828170 Identification of molecular candidates and interaction networks via integrative toxicogenomic analysis in a human cell line following low-dose exposure to the carcinogenic metals cadmium and nickel. Cadmium and nickel have been classified as carcinogenic to humans by the World Health Organization's International Agency for Research on Cancer. Given their prevalence in the environment, the fact that cadmium and nickel may cause diseases including cancer even at low doses is a cause for concern. However, the exact mechanisms underlying the toxicological effects induced by low-dose exposure to cadmium and nickel remain to be elucidated. Furthermore, it has recently been recognized that integrative analysis of DNA, mRNA and proteins is required to discover biomarkers and signaling networks relevant to human toxicant exposure. In the present study, we examined the deleterious effects of chronic low-dose exposure of either cadmium or nickel on global profiling of DNA copy number variation, mRNA and proteins. Array comparative genomic hybridization, gene expression microarray and functional proteomics were conducted, and a bioinformatics tool, which predicted signaling pathways, was applied to integrate data for each heavy metal separately and together. We found distinctive signaling networks associated with subchronic low-dose exposure to cadmium and nickel, and identified pathways common to both. ACTB, HSP90AA1, HSPA5 and HSPA8, which are key mediators of pathways related to apoptosis, proliferation and neoplastic processes, were key mediators of the same pathways in low-dose nickel and cadmium exposure in particular. CASP-associated signaling pathways involving CASP3, CASP7 and CASP9 were observed in cadmium-exposed cells. We found that HSP90AA1, one of the main modulators, interacted with HIF1A, AR and BCL2 in nickel-exposed cells. Interestingly, we found that HSP90AA1 was involved in the BCL2-associated apoptotic pathway in the nickel-only data, whereas this gene interacted with several genes functioning in CASP-associated apoptotic signaling in the cadmium-only data. Additionally, JUN and FASN were main modulators in nickel-responsive signaling pathways. Our results provide valuable biomarkers and distinctive signaling networks that responded to subchronic low-dose exposure to cadmium and nickel. 23633002 Accessing local knowledge to identify where species of conservation concern occur in a tropical forest landscape. Conventional biodiversity surveys play an important role in ensuring good conservation friendly management in tropical forest regions but are demanding in terms of expertise, time, and budget. Can local people help? Here, we illustrate how local knowledge can support low cost conservation surveys. We worked in the Malinau watershed, East Kalimantan, Indonesia, an area currently at risk of extensive forest loss. We selected eight species of regional conservation interest: rafflesia (Rafflesia spp.), black orchid (Coelogyne pandurata), sun bear (Helarctos malayanus), tarsier (Tarsius bancanus), slow loris (Nycticebus coucang), proboscis monkey (Nasalis larvatus), clouded leopard (Neofelis diardi/N. nebulosa), and orang-utan (Pongo pygmaeus). We asked 52 informants in seven villages if, where and when they had observed these species. We used maps, based on both geo-referenced and sketched features, to record these observations. Verification concerns and related issues are discussed. Evaluations suggest our local information is reliable. Our study took 6 weeks and cost about USD 5000. Extensive expert based field surveys across the same region would cost one or two orders of magnitude more. The records extend the known distribution for sun bear, tarsier, slow loris, and clouded leopard. Reports of rafflesia, proboscis monkey, and orang-utan are of immediate conservation significance. While quality concerns should never be abandoned, we conclude that local people can help expand our knowledge of large areas in an effective, reliable, and low cost manner and thus contribute to improved management. 23459865 Metaphorical motion in mathematical reasoning: further evidence for pre-motor implementation of structure mapping in abstract domains. The theory of computation and category theory both employ arrow-based notations that suggest that the basic metaphor "state changes are like motions" plays a fundamental role in all mathematical reasoning involving formal manipulations. If this is correct, structure-mapping inferences implemented by the pre-motor action planning system can be expected to be involved in solving any mathematics problems not solvable by table lookups and number line manipulations alone. Available functional imaging studies of multi-digit arithmetic, algebra, geometry and calculus problem solving are consistent with this expectation. 23954331 Lipokines and oxysterols: novel adipose-derived lipid hormones linking adipose dysfunction and insulin resistance. The expansion of adipose tissue (AT) is, by definition, a hallmark of obesity. However, not all the increases of fat mass are associated with pathophysiological cues. Indeed, while a "healthy" fat mass accrual, mainly in the subcutaneous depots, preserves metabolic homeostasis explaining the occurrence of "metabolically healthy" obese phenotype, "unhealthy" AT expansion is importantly associated with insulin resistance/type 2 diabetes and the metabolic syndrome. The development of a dysfunctional adipose organ may find mechanistic explanation in a reduced ability to recruit new and functional (pre)adipocytes from undifferentiated precursor cells. Such a failure of the adipogenic process underlies the "AT expandability" paradigm. The inability of AT to expand further to store excess nutrients, rather than obesity per se, induces a "diabetogenic" milieu by promoting the overflow and the ectopic deposition of fatty acids in insulin-dependent organs (ie, lipotoxicity), the secretion of different, metabolically detrimental, adipose-derived hormones (ie, adipokines and lipokines), and the occurrence of local and systemic inflammation and oxidative stress. Hitherto, fatty acids (ie, lipokines) and the oxidation by-products of cholesterol and poly-unsaturated fatty acids, such as the non-enzymatic oxysterols and the reactive aldheyde species, respectively, emerge as key modulators of (pre)adipocyte signaling through Wnt/β-catenin and MAPK pathways, and potential regulators of glucose homeostasis. These and other mechanistic insights linking adipose dysfunction, oxidative stress and impairment of glucose homeostasis are discussed in this review article, which focuses on "adipose peroxidation" as a potential instigator of, and a putative therapeutic target for, the obesity-associated metabolic dysfunctions. 23122078 Purification and characterization of membrane-bound polyphenoloxidase (mPPO) from Snake fruit [Salacca zalacca (Gaertn.) Voss]. Membrane-bound polyphenoloxidase (mPPO) an oxidative enzyme which is responsible for the undesirable browning reaction in Snake fruit (Salacca zalacca (Gaertn.) Voss) was investigated. The enzyme was extracted using a non-ionic detergent (Triton X-114), followed by temperature-induced phase partitioning technique which resulted in two separate layers (detergent-poor phase at the upper layer and detergent-rich phase at the lower layer). The upper detergent-poor phase extract was subsequently fractionated by 40-80% ammonium sulfate and chromatographed on HiTrap Phenyl Sepharose and Superdex 200 HR 10/30. The mPPO was purified to 14.1 folds with a recovery of 12.35%. A single prominent protein band appeared on native-PAGE and SDS-PAGE implying that the mPPO is a monomeric protein with estimated molecular weight of 38kDa. Characterization study showed that mPPO from Snake fruit was optimally active at pH 6.5, temperature 30°C and active towards diphenols as substrates. The K(m) and V(max) values were calculated to be 5.46 mM and 0.98 U/ml/min, respectively, when catechol was used as substrate. Among the chemical inhibitors tested, l-cysteine showed the best inhibitory effect, with an IC(50) of 1.3 ± 0.002 mM followed by ascorbic acid (1.5 ± 0.06 mM), glutathione (1.5 ± 0.07 mM), EDTA (100 ± 0.02 mM) and citric acid (186 ± 0.16 mM). 23270991 Antivirals: past, present and future. Vaccination is possible to prevent infections with some viruses: hepatitis B virus (HBV), varicella-zoster virus (VZV), influenza A and B viruses, Yellow fever virus and poliovirus; but not for others: human immunodeficiency virus (HIV), hepatitis C virus (HCV), herpes simplex virus (HSV), cytomegalovirus (CMV), and most hemorrhagic fever viruses (HFV) (except for Yellow fever virus). Antiviral therapy is obviously needed to control those infections that are not amenable to prophylaxis by vaccination, but is also highly desirable for those infections where vaccination has not been implemented or did not fulfill its premises for complete protection. 23831547 Evening-type military veterans report worse lifetime posttraumatic stress symptoms and greater brainstem activity across wakefulness and REM sleep. Evening chronotypes exhibit increased rates of affective dyregulation and sleep disturbances (e.g., insomnia and nightmares). Such symptoms are common to military veterans with posttraumatic stress disorder (PTSD); however, the influence of chronotype on this population remains unknown. We examined behavioral, psychological, and neural correlates of chronotype in 36 combat-exposed military veterans with varying degrees of posttraumatic stress symptomatology. We employed FDG-PET to assess neural activity across wakefulness and rapid eye movement (REM) sleep. We used polysomnography and diaries to monitor sleep, and a self-report survey to measure chronotype. Eveningness was associated with greater lifetime PTSD symptoms, more disturbed sleep, and more frequent and intense nightmares. Eveningness was also associated with greater brain activity in posterior cingulate/precuneus and brainstem regions across wakefulness and REM sleep, overlapping with regions related to arousal and REM sleep generation. Chronotype may be an important correlate of neural activity in REM sleep-generating and/or arousal regulatory regions among combat-exposed veterans with PTSD symptoms. Further investigations of the role of chronotype in PTSD are warranted. 23417768 Flock-Based Microfluidics. Flock-based microfluidics are created by depositing hydrophilic microfibers on an adhesive-coated substrate using an electric field. This enables the fabrication of self-powered microfluidics from one or more different kinds of fibers that form 2D and 3D flowpaths, which can wick 40 microliters of liquid per square centimeter. With this approach, large areas of functional wicking materials can be produced at extremely low cost. 23886017 Rhodium/Chiral urea relay catalysis enables an enantioselective semipinacol rearrangement/michael addition cascade. The combined use of rhodium and cinchona-based squaramide has first been introduced for asymmetric relay catalysis, enabling a highly enantioselective semipinacol rearrangement/Michael addition cascade. 23777912 Adenoviral vector tethering to metal surfaces via hydrolyzable cross-linkers for the modulation of vector release and transduction. The use of arterial stents and other medical implants as a delivery platform for surface immobilized gene vectors allows for safe and efficient localized expression of therapeutic transgenes. In this study we investigate the use of hydrolyzable cross-linkers with distinct kinetics of hydrolysis for delivery of gene vectors from polyallylamine bisphosphonate-modified metal surfaces. Three cross-linkers with the estimated t1/2 of ester bonds hydrolysis of 5, 12 and 50 days demonstrated a cumulative 20%, 39% and 45% vector release, respectively, after 30 days exposure to physiological buffer at 37 °C. Transgene expression in endothelial and smooth muscles cells transduced with substrate immobilized adenovirus resulted in significantly different expression profiles for each individual cross-linker. Furthermore, immobilization of adenoviral vectors effectively extended their transduction effectiveness beyond the initial phase of release. Transgene expression driven by adenovirus-tethered stents in rat carotid arteries demonstrated that a faster rate of cross-linker hydrolysis resulted in higher expression levels at day 1, which declined by day 8 after stent implantation, while inversely, slower hydrolysis was associated with increased arterial expression at day 8 in comparison with day 1. In conclusion, adjustable release of transduction-competent adenoviral vectors from metallic surfaces can be achieved, both in vitro and in vivo, through surface immobilization of adenoviral vectors using hydrolyzable cross-linkers with structure-specific release kinetics. 23829659 Induction of an EMT-like transformation and MET in vitro. The epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) play pivotal roles in metastasis of epithelial cancers. The distinction between them has shed new light on the molecular mechanisms of tumor metastasis. Recently, tumor microenvironment (TM) has been identified as one of the most potent inducers of EMT and MET. TM is characterized by its complexity and flexibility. The purpose of this study was to ascertain the exact effect of each distinct TM component on the evolution hepatocellular carcinoma (HCC) metastasis. Two different cell culture models were used. The HCC cell line Bel-7402 was co-cultured with the normal liver cell line HL-7702 or with the retinal vascular endothelial cell line RF/6A in double-layer six-well plates, imitating the direct interaction between tumor-host cells and tumor cells. Bel-7402 was also cultured in the conditioned medium (CM) of the human lung fibroblast cell line MRC-5, HL-7702 or RF/6A, imitating an indirect interaction. Integrin β1, β3, β4, β7, laminin β3, E-cadherin and Snail levels were measured by quantitative RT-PCR in tumor sepecimens from 42 resected HCC. We found that Bel-7402 cells co-cultured with HL-7702 or RF/6A cells were induced to undergo MET. The expression of E-cadherin, α-catenin and β-catenin was up-regulated, accompanied with a strengthened E-cadherin/catenin complex on the membrane of co-cultured Bel-7402 cells. Consequently, the invasion and migration ability of cells was declined. Conversely, Bel-7402 cells cultured in conditioned medium from MRC-5 cells underwent an EMT-like transformation as the cells became elongated with increased invasion and migration ability. Furthermore, we demonstrated that HL-7702 cells could generally inhibit the tumorigenicity and viability of Bel-7402 cells. We also found that integrin β1 expression was negatively associated with capsular formation, and that integrin β4 expression was negatively associated with CK19 expression. Our findings highlight the strong influences exerted by TM on tumor progression through EMT and MET by impacting the expression of adhesion molecules, including the E-cadherin/catenin complex, laminins and integrins. 23552500 Eye movements during natural actions in patients with schizophrenia. Visual scanning and planning of actions are reported to be abnormal in patients with schizophrenia. Most studies that monitored eye movements in these patients were performed under free-viewing conditions and used 2- dimensional images. However, images differ from the natural world in several ways, including task demands and the dimensionality of the display. Our study was designed to assess whether abnormalities in visual exploration in patients with schizophrenia generalize to active-viewing tasks in realistic conditions of viewing and to examine whether disturbances in action sequencing in these patients are reflected in their visual scanning patterns while executing natural tasks. We monitored visual scan paths in patients with schizophrenia and healthy controls. Participants performed several tasks in which they were asked to look at a realistic scene on a table (free-viewing) and perform 2 active-viewing tasks: a familiar task (sandwich-making) and an unfamiliar task (model-building). The scenes contained both task-relevant and task-irrelevant objects. We included 15 patients and 15 controls in our analysis. Patients exhibited abnormalities in the free-viewing condition. Their patterns of exploration were similar to those of controls in the familiar task, but they showed scanning differences in the unfamiliar task. Patients were also slower than controls to accomplish both tasks. Patients with schizophrenia were taking antipsychotic medications, so the presence of medication effects cannot be excluded. People with schizophrenia present a basic psychomotor slowing and seem to establish a less efficient planning strategy in the case of more complex and unfamiliar tasks. 23939833 Acid-Catalyzed Direct Conjugate Alkenylation of α,β-Unsaturated Ketones. New tricks, old reaction: The title reaction proceeds under mild and transition-metal-free conditions (see scheme; Tf=trifluoromethanesulfonyl). Various combinations of substrates are applicable to the synthesis of γ,δ-unsaturated ketones by employing silicon substituents at the β-position of the enones. The silicon substituents play a key role in stabilization of the cationic intermediate by hyperconjugation. 23835519 A novel approach to spatially assessing instream woody habitat densities across large areas. Fish habitat restoration efforts frequently involve the reintroduction of instream woody habitat (IWH) in areas where large scale removal has taken place over time. Identifying areas of low IWH density for reintroduction requires a 'current state' spatial representation of the IWH densities that is traditionally a labour intensive and costly exercise. We present a meso-macro scale assessment procedure that incorporates a rapid on-ground field survey method with a novel analytical approach to map IWH densities. In situ IWH locations with categorical values for size and complexity were obtained along the lower Ovens River in South Eastern Australia. Despite relatively high densities of IWH and limited access, 120 km of river was able to be investigated. A bound kernel density estimate (BKDE) analysis was performed using the IWH point locations, weighted by an average volume inferred from the point size and complexity values. A fine scale map is obtained providing a continuous representation of IWH densities (m(3) m(-2)) indicating a high degree of IWH density variability along the river. The relative high resolution map is produced for habitat restoration managers to assess river sections generally less than 1 km long for IWH reintroduction. 23322517 Reduced Blood Leukocyte and Neutrophil Numbers in the Pathogenesis of Type 1 Diabetes. Very little is known about the role of the innate immune system in the course of human type 1 diabetes. Here we investigated neutrophil numbers along with other leukocyte populations in patients at diagnosis of type 1 diabetes and during prediabetes. Complete and differential blood counts were analyzed from 107 adult patients with newly diagnosed type 1 diabetes, 21 children with persistent islet autoantibodies and a family history of type 1 diabetes, and 1 238 age and gender matched control subjects, all individuals without any signs of acute infection.Adult patients with newly diagnosed type 1 diabetes had significantly lower total WBC (p<1×10 - 6), neutrophil (p<1×10 - 6), basophil (p<1×10 - 6), monocyte (p=4×10 - 6) and lymphocyte (p<1×10 - 6) counts compared to control subjects. Erythrocyte, eosinophil and platelet counts did not differ between groups. Similarly, children with persistent islet autoantibodies had decreased WBC (p=0.001), neutrophils (p=0.003), and lymphocytes (p=0.006) in comparison to control children. Our findings demonstrate a perturbation of leukocyte homeostasis at and prior to onset of type 1 diabetes suggesting a general involvement of the innate immune system in the pathogenesis of type 1 diabetes. 23942071 Microtubule-associated protein tau facilitates the targeted killing of proliferating cancer cells in vitro and in a xenograft mouse tumour model in vivo. Background:Antibody drug conjugates (ADCs) and immunotoxins (ITs) are promising anticancer immunotherapeutics. Despite their encouraging performance in clinical trials, both ADCs and ITs often suffer from disadvantages such as stoichiometrically undefined chemical linkage of the cytotoxic payload (ADCs) and the potential immunogenicity of toxins derived from bacteria and plants (ITs).Methods:Human microtubule-associated protein tau (MAP) was cloned in-frame with human EGF, expressed in E. coli and purified by standard chromatographic methods. The in vitro activity was confirmed by flow cytometry, cell viability assays and tubulin polymerisation assay. The in vivo efficacy was demonstrated using noninvasive far-red in vivo imaging.Results:The EGF-MAP selectively induced apoptosis in EGFR-overexpressing proliferating cancer cells through stabilisation of microtubules. Nonproliferating cells were not affected, demonstrating superior selectivity of EGF-MAP for cancer cells. The EGF-MAP was well tolerated at high doses in mice compared with the ETA'-based control. The in vivo efficacy of EGF-MAP was demonstrated in a tumour xenograft mouse model.Conclusion:Our data indicate the general mechanism of action for a new class of human immunotherapeutic reagents suitable for the treatment of cancer. This approach combines the binding specificity of targeting ligands with the selective cytotoxicity of MAP towards proliferating cells.British Journal of Cancer advance online publication, 13 August 2013; doi:10.1038/bjc.2013.457 www.bjcancer.com. 23937378 One-Step Synthesis of Robust Amine- and Vinyl-Capped Magnetic Iron Oxide Nanoparticles for Polymer Grafting, Dye Adsorption, and Catalysis. Magnetic iron oxide nanoparticles (MIONs) bearing amine and vinyl groups are fabricated straightforwardly using vinyl-based tertiary amine molecules as both alkaline source and ligands based on the coprecipitation of iron ions in aqueous solution. The as-prepared MIONs present amphiphilic performance that can be well-dispersed both in aqueous solution and common organic solvents (e.g., ethanol, dichloromethane and tetrahydrofuran). Transmission electron microscopy (TEM), X-ray diffraction (XRD), and vibrating sample magnetometer (VSM) measurements reveal that the MIONs are superparamagnetic Fe3O4 nanoparticles with a mean diameter below 10 nm. The presence of ligands on the surface of MIONs was confirmed by thermogravimetric analysis (TGA), Fourier transform infrared (FTIR), and X-ray photoelectron spectroscopy (XPS) characterizations. Benefiting from the surface vinyl groups, the MIONs are able to graft polyvinyl-based polymers by in situ polymerization of the corresponding vinyl monomers as confirmed by grafting poly(methyl methacrylate) (PMMA) in this paper. On the basis of their surface amine groups, the MIONs show high adsorption capacity (ca. 0.42 mmol/g) for congo red dye and excellent performance for in situ growth of Pt nanocatalyst. Moreover, the MIONs possess high stability and can be reused several times without obvious decrease of their adsorption capacity and catalytic efficiency. Considering the facile fabrication process and versatile performance of the obtained MIONs, this work may open up new opportunities for the large-scale applications of MIONs. 23711834 Remarkable anti-breast cancer activity of ferrocene tagged multi-functionalized 1,4-dihydropyrimidines. A novel series of ferrocene tagged multi-functionalized 1,4-dihydropyrimidines is synthesized by base catalyzed cyclocondensation between ferrocenyl chalcones and amidines. The structures of synthesized compounds were established on the basis of (1)H NMR, (13)C NMR, FTIR spectroscopy as well as by mass spectrometry. The compounds were evaluated for in vitro anticancer activity. The most active compounds from the series displayed GI50 value equal to doxorubicin against the strain of human breast cancer cell line MDA-MB-435. 22915288 12-Month effects of once-weekly sustained-release growth hormone treatment in adults with GH deficiency. The weekly sustained-release recombinant human GH formulation LB03002, showed beneficial effects in GH-deficient (GHD) adults in a previous 26-week double-blind study. Prior studies of long-acting GH preparations in adults have only been conducted for 6 or 8 months, so the effects of longer-term use are unknown; this is important to address, as replacement is given for many years in GHD adults. This open-label, 26-week study extension evaluated longer-term safety and efficacy of LB03002 over 52 weeks in adults with GHD who had previously been randomized to GH, and provides additional safety and efficacy data over 26 weeks in the cohort who had previously been randomized to placebo. Of 147 adults with GHD who completed a preceding study, 136 patients continued in this open-label study to receive LB03002 over an additional 26 weeks. This represented a continuation of long-acting GH for 26 weeks in the cohort who took this medication in the prior study (LB03002 Throughout group), and describes the first use of long-acting GH in the cohort that was randomized to placebo in the prior study (Switched to LB03002 group). The LB03002 dose was adjusted according to serum insulin-like growth factor-I (IGF-I) levels. LB03002 treatment demonstrated mean significant decreases from baseline in fat mass (FM) for both 26 (Switched group, P = 0.001) and 52 weeks (Throughout group, P = 0.002) of 1.11 (1.95) kg and 1.06 (3.16) kg, respectively. Prolonged GH treatment was effective in sustaining the increase in lean body mass (LBM), serum IGF-I and IGFBP-3 levels achieved during the first 26 weeks. Long-term treatment with the sustained-release weekly GH preparation over both 26 and 52 weeks in adults with GHD demonstrated a sustained reduction of FM with a favorable safety profile. This study extends prior knowledge about long-acting GH because it reports the most prolonged treatment of adults with any long-acting GH preparation, thereby confirming the value and safety of such agents for long-term GH replacement. 23611355 Evaluation of characteristics of Pediococcus spp. to be used as a vaginal probiotic. The aim of our research was to select, identify and characterize an isolate of lactic acid bacteria to be considered as a vaginal probiotic. Thirty-five isolates of Pediococcus spp. showed bacteriocinogenic activity against Listeria monocytogenes and the ability to survive in simulated vaginal fluid (SVF) at pH 4·2. One isolate of Pediococcus spp. was selected and characterized to evaluate its safety before the use as vaginal probiotic. Pediococcus pentosaceus SB83 did not show the presence of virulence factors such as the production of gelatinase, lipase and DNase, haemolytic activity, nor the presence of virulence genes (genes esp, agg, gelE, efaAfm, efaAfs, cylA, cylB and cylM). Pediococcus pentosaceus SB83 was considered sensitive to chloramphenicol, gentamicin, streptomycin, kanamycin, erythromycin and ampicillin. This strain was considered resistant to tetracycline and vancomycin. Pediococcus pentosaceus SB83 was a biofilm producer at different pH values (4·2, 5·5 and 6·5) in SVF and in de Man, Rogosa and Sharpe medium. The in vitro results provide a basis for the use of P. pentosaceus SB83 as a vaginal probiotic, to prevent colonization by L. monocytogenes in pregnant women. The application of vaginal probiotics could have the potential for preventing vaginal infections and consequently reduce abortion and neonatal infections. 23830000 Life events in bipolar patients: A comparative study with siblings and healthy controls. While many studies have focused on life events in depressive disorders, data regarding them in bipolar disorder are scant. The aim of this work was to explore the characteristics of life events in bipolar patients. Sixty bipolar patients have been included in our study. The evaluation focused on the sociodemographic and clinical characteristics with a standardized measurement of life events using Paykel's interview. The results were compared with those of siblings and healthy controls groups. The three groups were matched for age and sex. Compared to the controls, bipolar patients and their siblings had a higher global score of life events and more events in the fields of work, socio-family events and health. Bipolar patients reported more desirable events compared with their siblings and controls. The siblings reported higher scores of uncontrollable and undesirable events than patients and controls, and a higher score of controllable events than patients. The Paykel's interview has no validated Tunisian version, which could be a methodological bias in the assessment of life events. Moreover, the assessment of the life events was made during the euthymic phase of the bipolar disorder; however, there was no standardized measure of mood symptoms, to confirm this euthymia. Our findings could help in the identification of the etiopathogeny of bipolar disorder and would contribute to improve the understanding and management of these patients focusing on the psychosocial aspect which is often overlooked. 23939710 Predictive Factors of HTLV1-HIV Coinfections in French Guiana. French Guiana, the French territory most affected by human immunodeficiency virus (HIV) (1.3% of pregnant women), is also endemic for human T lymphotropic virus 1 (HTLV1). The objective of this study was to determine if the HTLV1/HIV coinfected patients had particular characteristics. All HIV-infected patients and having a computerized medical file containing an HTLV1serology were included: there were 1,333 HIV monoinfections and 76 HTLV1/VIH coinfections. The prevalence of HTLV1/HIV coinfections was 5.39%. Women (odds ratio [OR] = 1.91[1.13-3.24]), subjects > 40 years of age, and patients of Surinamese origin (OR = 2.65 [1.25-5.61]) were overrepresented among the coinfected and CD4 count at the time of diagnosis. The viral load was higher among coinfected patients. The clinical stage was not significantly different between the two groups. The number of CD4 cells was not higher among the coinfected, unlike most reports from the literature. Prevalence of HTLV1 among HIV-infected patients is high in French Guiana, and physicians seem to omit the prescription of serology for this potentially serious coinfection. 23834246 New Insights into the Carrier-Mediated Transport of Estrone-3-sulfate in the Caco-2 Cell Model. The current studies were undertaken to gain new insights into the interplay and mechanism of membrane transporters involved in the permeability of estrone-3-sulfate (E1S) in Caco-2 cells cultured either on the bottom of multiwell plastic dishes or on filter support. We demonstrate that Caco-2 cells from the "Deutsche sammlung von mikroorganismen und zellkulturen" (DSMZ) exhibit extensive and consistent carrier-mediated uptake of [(3)H]-E1S after a culture period of 11-13 days. The kinetic characterization, the inhibitory profile and the pH dependence for the initial linear uptake permeability (PUP) of [(3)H]-E1S suggest that the organic anion transporting polypeptide (OATP) 2B1 is the main transporter involved in the apical E1S PUP in Caco-2 cells from the DSMZ. Furthermore, our results indicate that the efflux transporter breast cancer resistance protein (BCRP) affects E1S PUP, even when uptake is measured at the initial linear uptake phase. Although almost identical results were obtained for cells cultured on plastic dishes and on filter supports, the OATP2B1 stimulator dexamethasone did not affect the PUP for cells grown on dishes but increased [(3)H]-E1S PUP by more than 2-fold for filter grown cells. The basolateral PUP of [(3)H]-E1S of filter grown cells was inhibited by several inhibitors of the bidirectional transporter organic solute transporter α/β (OSTα/β). Efflux studies were performed by loading the cells with either [(3)H]-E1S or [(3)H]-taurocholic acid (TCA) and subsequently measuring the efflux of radio labeled substance in the absence or presence of BCRP or OST α/β inhibitors. Similar effluxes of [(3)H]-E1S was observed across the apical and basolateral membrane, and the apical efflux was greatly decreased in the presence of the BCRP inhibitor fumitremorgin C. In contrast, efflux of [(3)H]-TCA to the basolateral compartment was clearly larger than to the apical compartment. Trans-stimulation of basolateral [(3)H]-E1S efflux was observed in the presence of taurolithocholic acid (TLC), although none of the applied OSTα/β inhibitors were able to confirm the existence of carrier-mediated efflux at the basolateral membrane, neither for [(3)H]-E1S nor for [(3)H]-TCA. These results highlight the importance of transporter interplay for E1S and drug compounds in Caco-2 cells and emphasize the importance of identifying the basolateral transporters in these cells. 23653394 A timetable organizer for the planning and implementation of screenings in manual or semi-automation mode. We have designed an Excel spreadsheet to facilitate the planning and execution of screenings performed manually or in semi-automation mode, following a sequential set of events. Many assays involve multiple steps, often including time-sensitive stages, thus complicating the proper implementation to ensure that all plates are treated equally to achieve reliable outcomes. The spreadsheet macro presented in this study analyzes and breaks down the timings for all tasks, calculates the limitation in the number of plates that suit the desired parameters, and allows for optimization based on tolerance of time delay and equal treatment of plates when possible. The generated Gantt charts allow for visual inspection of the screening process and provide timings in a tabulated form to assist the user to conduct the experiments as projected by the software. The program can be downloaded from http://sourceforge.net/projects/sams-hts/. 23863982 Efficient oxygen evolution reaction catalyzed by low-density Ni-doped Co3O4 nanomaterials derived from metal-embedded graphitic C3N4. A synthetic route to low-density porous Ni-doped Co3O4 nanomaterials that show stable and superior electrocatalytic activity for O2 evolution reaction is reported. The materials are prepared via thermal treatment of "pre-synthesized" metal ions-embedded graphitic C3N4-based polymers. 23150213 The clinical relevance of plasma protein binding changes. Controversy reigns as to how protein binding changes alter the time course of unbound drug concentrations in patients. Given that the unbound concentration is responsible for drug efficacy and potential drug toxicity, this area is of significant interest to clinicians and academics worldwide. The present uncertainty means that many questions relating to this area exist, including "How important is protein binding?", "Is protein binding always constant?", "Do pH and temperature changes alter binding?" and "How do protein binding changes affect dosing requirements?". In this paper, we seek to address these questions and consider the data associated with altered pharmacokinetics in the presence of changes in protein binding and the clinical consequences that these may have on therapy, using examples from the critical care area. The published literature consistently indicates that a change in the protein binding and unbound concentrations of some drugs are common in certain specific patient groups such as the critically ill. Changes in pharmacokinetic parameters, including clearance and apparent volume of distribution (V(d)), may be dramatic. Drugs with high protein binding, high intrinsic clearance (e.g. clearance by glomerular filtration) and where dosing is not titrated to effect are most likely to be affected in a clinical context. Drugs such as highly protein bound antibacterials with multiple half-lives within a dosing interval and that have some level of renal clearance, such as ertapenem, teicoplanin, ceftriaxone and flucloxacillin, are commonly affected. In response to these challenges, clinicians need to adapt dosing regimens rationally based on the pharmacokinetic/pharmacodynamic characteristics of the drug. We propose that further pharmacokinetic modelling-based research is required to enable the design of robust dosing regimens for drugs affected by altered protein binding. 23906127 Health-related effects of welfare-to-work policies. Non-health related policies may have consequences for health that are more important than the outcomes they were originally designed to produce. In this paper we evaluate the effects of welfare-to-work programs (WTW) on physical and mental health status and a variety of health behaviors. The paper is based on data from the minimum income program of Madrid's Government (IMI). We match the program's administrative records (39,200 households) - covering the whole history of the program from the second half of 1990 to 2001 - with a specific survey of former recipients who took part in different work-related activities conducted in 2001 (2300 households). We perform propensity score matching to find that both health status - including physical and mental health problems - and behaviors outcomes were modestly better for those individuals who had taken part in work-related activities. These results offer support for the contention that welfare-to-work policies may have positive unintended health effects. 23557842 Development of solid lipid nanoparticles based controlled release system for topical delivery of terbinafine hydrochloride. The study describes the development and evaluation of solid lipid nanoparticles (SLNs) of terbinafine hydrochloride (TH) for sustained release and skin targeting. TH-loaded SLNs were prepared by solvent-injection technique and optimized using 3(3) full-factorial design. Effect of drug:lipid ratio, surfactant concentration and volume of organic solvent were studied on % entrapment efficiency (%EE) and particle size (PS). The optimum formulation based on desirability (0.945) exhibited %EE of 73.74% and PS of 300nm. Optimized SLNs were incorporated into Carbopol gel and evaluated for drug content, pH, in vitro release, ex vivo retention, in vivo pharmacodynamic and stability studies. Drug release from SLNs dispersion followed Korsmeyer-Peppas model, indicating Fickian drug release, while that from the gel followed Higuchi model. The ex vivo studies through rat abdominal skin indicated skin retention ability of SLNs as compared to commercial product. In vivo pharmacodynamic studies showed that the SLNs based gel reduced fungal burden of Candida albicans in rats as compared to commercial product in shorter duration of time. The SLNs dispersion and gel exhibited physicochemical stability under refrigeration upto 3months. It was concluded that SLNs incorporated Carbopol gel had skin targeting ability and may serve as a promising carrier in treatment of fungal skin infections. 23852020 Upregulation of Phosphorylated HSP27, PRDX2, GRP75, GRP78 and GRP94 in Acquired Middle Ear Cholesteatoma Growth. Cholesteatoma is a destructive and expanding growth of keratinizing squamous epithelium in the middle ear or petrous apex. The molecular and cellular processes of the pathogenesis of acquired middle ear cholesteatoma have not been fully understood. In this study, comparative proteomic analysis was conducted to investigate the roles of specific proteins in the pathways regarding keratinocyte proliferation in cholesteatoma. The differential proteins were detected by comparing the two-dimension electrophoresis (2-DE) maps of the epithelial tissues of 12 attic cholesteatomas with those of retroauricular skins. There were 14 upregulated proteins in the epithelial tissues of cholesteatoma in comparison with retroauricular skin. The modulation of five crucial proteins, HSP27, PRDX2, GRP75, GRP78 and GRP94, was further determined by RT-PCR, Western blot and immunohistochemistry. Phosphorylation of HSP27 at Ser-82 was identified by mass spectroscopy. The results of this study suggested that phosphorylated HSP27 is the end expression of two potential signal-transduction pathways, and together with PRDX2, they are very likely involved in the proliferation of keratinocytes in cholesteatoma. Upregulations of GRP75, GRP78 and GRP94 in keratinocytes may be able to counter endoplasmic reticulum stress, to inhibit cell apoptosis, to prevent protein unfolding and to promote cholesteatoma growth. 23881845 DL4-mediated Notch signaling is required for the development of fetal αβ and γδ T cells. T-cell development depends upon interactions between thymocytes and thymic epithelial cells (TECs). The engagement of delta-like 4 (DL4) on TECs by Notch1 expressed by blood-borne BM-derived precursors is essential for T-cell commitment in the adult thymus. In contrast to the adult, the earliest T-cell progenitors in the embryo originate in the fetal liver and migrate to the nonvascularized fetal thymus via chemokine signals. Within the fetal thymus, some T-cell precursors undergo programmed TCRγ and TCRδ rearrangement and selection, giving rise to unique γδ T cells. Despite these fundamental differences between fetal and adult T-cell lymphopoiesis, we show here that DL4-mediated Notch signaling is essential for the development of both αβ and γδ T-cell lineages in the embryo. Deletion of the DL4 gene in fetal TECs results in an early block in αβ T-cell development and a dramatic reduction of all γδ T-cell subsets in the fetal thymus. In contrast to the adult, no dramatic deviation of T-cell precursors to alternative fates was observed in the fetal thymus in the absence of Notch signaling. Taken together, our data reveal a common requirement for DL4-mediated Notch signaling in fetal and adult thymopoiesis. 23834685 The polypill and the prevention of heart attacks and strokes. David S Wald speaks to Caroline Telfer, Assistant Commissioning Editor. David S Wald is a Consultant Cardiologist and Reader in Preventive Cardiology. He trained at Oxford University (UK) and Imperial College of Science and Technology, London (UK). His work combines interventional and preventive approaches to cardiovascular disease. He is currently leading a multicenter randomized trial assessing the value of preventive angioplasty in patients with acute myocardial infarction and a UK trial of a polypill for people over the age of 50 years for the prevention of ischemic heart disease and stroke. 23664760 The use of lung donors older than 55 years: A review of the United Network of Organ Sharing database. Current lung transplantation guidelines stipulate that the ideal donor is aged younger than 55 years, but several institutions have reported that outcomes using donors aged 55 years and older are comparable with those of younger donors. We retrospectively reviewed the United Network for Organ Sharing (UNOS) database to identify all adult lung transplants between 2000 and 2010 in the United States. Patients were stratified by donor age 18 to 34 (reference), 35 to 54, 55 to 64, and ≥ 65 years. Primary outcomes included survival at 30 days and at 1, 3, and 5 years and rates of bronchiolitis obliterans syndrome (BOS). Survival was assessed using the Kaplan-Meier method. Risk factors for mortality were identified by multivariable Cox and logistic regression. We identified 10,666 recipients with median follow-up of 3 years (range, 0-10 years). Older donors were more likely to have died of cardiovascular or cerebrovascular causes, but there were no differences in recipient diagnosis, lung allocation score, or incidence of BOS as a function of donor age. The use of donors aged 55 to 64 years was not a risk factor for mortality at 1 year (odds ratio, 1.1; p = 0.304) or 3 years (odds ratio, 0.923; p = 0.571) compared with the reference group; however, use of donors aged > 65 years was associated with increased mortality at both time points (odds ratio, 2.8 and 2.4, p < 0.02). Outcomes after lung transplantation using donors aged 55 to 64 years were similar to those observed with donors meeting conventional age criteria. Donors aged ≥ 65 years, however, were associated with decreased intermediate-term survival, although there was no increased risk of BOS for this group. 23933565 Characterization of degradation products of idarubicin through LC-UV, MS(n) and LC-MS-TOF studies. Idarubicin was subjected to forced degradation under the ICH recommended conditions of hydrolysis, oxidation, dry heat and photolysis to characterize its possible impurities and/or degradation products. The drug was found unstable to acid hydrolysis at 85°C and to alkaline hydrolysis, and oxidation at room temperature. The hydrolytic and oxidative degradation products were resolved with gradient and isocratic elution, respectively on an Inertsil RP18 (250mm×4.6mm; 5μ) column with HCOONH4 (20mM, pH 3.0) and acetonitrile. The drug degraded to two products (O-I and O-II) in oxidative condition, two products (K-I and K-II) in alkaline hydrolytic, and one product (A-I) in acidic hydrolytic conditions. The purity of each in the LC-UV chromatogram was ascertained through LC-PDA analysis. The products were characterized through +ESI-MS(n) studies on the drug and LC-MS-TOF studies on the degraded drug solutions. Based on the multistage mass fragmentation pattern of idarubicin and accurate mass analysis of the degradation products, the O-I, O-II and A-I were characterized as desacetylidarubicin hydroperoxide, desacetylidarubicin and deglucosaminylidarubicin, respectively. The products K-I and K-II were not characterized due to their low concentrations and/or extremely weak ionization. The mechanisms of degradation of idarubicin to these products were proposed and discussed. 23889229 In Situ Integration of Squaraine-Nanowire-Array-Based Schottky-Type Photodetectors with Enhanced Switching Performance. Organic nanostructure-based photodetectors are important building blocks for future high-performance, low-cost, flexible nano-optoelectronic devices. However, device integration remains a large challenge, and the structure-dependent performance of the device has been seldom studied. Here, we report the in situ integration of 2,4-bis[4-(N,N-dimethylamino)phenyl]squaraine (SQ)-nanowire (NW)-array-based photodetectors by growing the organic NW arrays on prefabricated electrodes through an evaporation-induced self-assembly process. In contrast with ohmic-contact devices, asymmetric electrode pairs of Au-Ti were utilized to achieve the construction of Schottky-type photodetectors on the basis of organic NW arrays. Significantly, the Schottky-type photodetectors exhibited a significantly enhanced performance as compared to the ohmic-type devices in terms of their higher photosensitivity and switching speed. The presence of a strong built-in electric field at the junction interface, which greatly facilitated the separation/transportation of photogenerated electron-hole pairs, was suggested to be responsible for the superior performance of the Schottky-type photodetectors. More importantly, the organic NW-array-based devices also showed a higher sensitivity and reproducibility than that of the single NW-based devices, and they were capable of low-light detection. The investigation of the photodetector circuitry also disclosed a very low pixel-to-pixel variation owing to the average effect of the NW-array-based devices. It is expected that organic NW-array-based Schottky-type photodetectors will have important applications in future organic nano-optoelectronic devices. 23163726 The structure and properties of septin 3: a possible missing link in septin filament formation. The human genome codes for 13 members of a family of filament-forming GTP-binding proteins known as septins. These have been divided into four different subgroups on the basis of sequence similarity. The differences between the subgroups are believed to control their correct assembly into heterofilaments which have specific roles in membrane remodelling events. Many different combinations of the 13 proteins are theoretically possible and it is therefore important to understand the structural basis of specific filament assembly. However, three-dimensional structures are currently available for only three of the four subgroups. In the present study we describe the crystal structure of a construct of human SEPT3 which belongs to the outstanding subgroup. This construct (SEPT3-GC), which includes the GTP-binding and C-terminal domains, purifies as a nucleotide-free monomer, allowing for its characterization in terms of GTP-binding and hydrolysis. In the crystal structure, SEPT3-GC forms foreshortened filaments which employ the same NC and G interfaces observed in the heterotrimeric complex of human septins 2, 6 and 7, reinforcing the notion of 'promiscuous' interactions described previously. In the present study we describe these two interfaces and relate the structure to its tendency to form monomers and its efficiency in the hydrolysis of GTP. The relevance of these results is emphasized by the fact that septins from the SEPT3 subgroup may be important determinants of polymerization by occupying the terminal position in octameric units which themselves form the building blocks of at least some heterofilaments. 23630454 PICK1 Deficiency Impairs Secretory Vesicle Biogenesis and Leads to Growth Retardation and Decreased Glucose Tolerance. Secretory vesicles in endocrine cells store hormones such as growth hormone (GH) and insulin before their release into the bloodstream. The molecular mechanisms governing budding of immature secretory vesicles from the trans-Golgi network (TGN) and their subsequent maturation remain unclear. Here, we identify the lipid binding BAR (Bin/amphiphysin/Rvs) domain protein PICK1 (protein interacting with C kinase 1) as a key component early in the biogenesis of secretory vesicles in GH-producing cells. Both PICK1-deficient Drosophila and mice displayed somatic growth retardation. Growth retardation was rescued in flies by reintroducing PICK1 in neurosecretory cells producing somatotropic peptides. PICK1-deficient mice were characterized by decreased body weight and length, increased fat accumulation, impaired GH secretion, and decreased storage of GH in the pituitary. Decreased GH storage was supported by electron microscopy showing prominent reduction in secretory vesicle number. Evidence was also obtained for impaired insulin secretion associated with decreased glucose tolerance. PICK1 localized in cells to immature secretory vesicles, and the PICK1 BAR domain was shown by live imaging to associate with vesicles budding from the TGN and to possess membrane-sculpting properties in vitro. In mouse pituitary, PICK1 co-localized with the BAR domain protein ICA69, and PICK1 deficiency abolished ICA69 protein expression. In the Drosophila brain, PICK1 and ICA69 co-immunoprecipitated and showed mutually dependent expression. Finally, both in a Drosophila model of type 2 diabetes and in high-fat-diet-induced obese mice, we observed up-regulation of PICK1 mRNA expression. Our findings suggest that PICK1, together with ICA69, is critical during budding of immature secretory vesicles from the TGN and thus for vesicular storage of GH and possibly other hormones. The data link two BAR domain proteins to membrane remodeling processes in the secretory pathway of peptidergic endocrine cells and support an important role of PICK1/ICA69 in maintenance of metabolic homeostasis. 23047803 Symptom distress in older adults following cancer surgery. Symptom distress remains a significant health problem among older adults with cancer following surgery. Understanding factors influencing older adults' symptom distress may lead to early identification and interventions, decreasing morbidity and improving outcomes. We conducted this study to identify factors associated with symptom distress following surgery among 326 community-residing patients 65 years or older with a diagnosis of thoracic, digestive, gynecologic, and genitourinary cancers. This secondary analysis used combined subsets of data from 5 nurse-directed intervention clinical trials targeting patients after surgery at academic cancer centers in northwest and northeastern United States. Symptom distress was assessed by the Symptom Distress Scale at baseline and at 3 and 6 months. A multivariable analysis, using generalized estimating equations, showed that symptom distress was significantly less at 3 and 6 months (3 months: P < .001, 6 months: P = .002) than at baseline while controlling for demographic, biologic, psychological, treatment, and function covariates. Thoracic cancer, comorbidities, worse mental health, and decreased function were, on average, associated with increased symptom distress (all P < .05). Participants 75 years or older reported increased symptom distress over time compared with those aged 65 to 69 years (P < .05). Age, type of cancer, comorbidities, mental health, and function may influence older adults' symptom distress following cancer surgery. Older adults generally experience decreasing symptom distress after thoracic, abdominal, or pelvic cancer surgery. Symptom management over time for those with thoracic cancer, comorbidities, those with worse mental health, those with decreased function, and those 75 years or older may prevent morbidity and improve outcomes of older adults following surgery. 23844178 Histamine-HisCl1 Receptor Axis Regulates Wake-Promoting Signals in Drosophila melanogaster. Histamine and its two receptors, histamine-gated chloride channel subunit 1 (HisCl1) and ora transientless (Ort), are known to control photoreception and temperature sensing in Drosophila. However, histamine signaling in the context of neural circuitry for sleep-wake behaviors has not yet been examined in detail. Here, we obtained mutant flies with compromised or enhanced histamine signaling and tested their baseline sleep. Hypomorphic mutations in histidine decarboxylase (HDC), an enzyme catalyzing the conversion from histidine to histamine, caused an increase in sleep duration. Interestingly, hisCl1 mutants but not ort mutants showed long-sleep phenotypes similar to those in hdc mutants. Increased sleep duration in hisCl1 mutants was rescued by overexpressing hisCl1 in circadian pacemaker neurons expressing a neuropeptide pigment dispersing factor (PDF). Consistently, RNA interference (RNAi)-mediated depletion of hisCl1 in PDF neurons was sufficient to mimic hisCl1 mutant phenotypes, suggesting that PDF neurons are crucial for sleep regulation by the histamine-HisCl1 signaling. Finally, either hisCl1 mutation or genetic ablation of PDF neurons dampened wake-promoting effects of elevated histamine signaling via direct histamine administration. Taken together, these data clearly demonstrate that the histamine-HisCl1 receptor axis can activate and maintain the wake state in Drosophila and that wake-activating signals may travel via the PDF neurons. 23712563 Color indicator for supramolecular polymer chemistry: phenolphthalein-containing thermo- and pH-sensitive N-(Isopropyl)acrylamide copolymers and β-cyclodextrin complexation. The copolymerization parameters of N-(isopropyl)acrylamide (1) and N-(2-hydroxy-5-(1-(4-hydroxyphenyl)-3-oxo-1,3-dihydroisobenzofuran-1-yl)benzyl)acrylamide (2) are determined. For both monomers, the homoaddition proceeds slightly faster than the heteroaddition step; however, the polymer formation occurs in a statistic fashion. Copolymers of different compositions are prepared and the cloud points are determined. Thereby, a significant influence of the concentration of monomer 2 and the pH value is found. For the first time, the complexation of polymer attached phenolphthalein by β-cyclodextrins is shown. Furthermore, it is possible to achieve a decomplexation by the addition of suitable guest molecules. Both procedures can be followed with the naked eye. 23833181 The FACT Histone Chaperone Guides Histone H4 into its Nucleosomal Conformation in Saccharomyces cerevisiae. The pob3-Q308K mutation alters the small subunit of the Saccharomyces cerevisiae histone/nucleosome chaperone FACT, causing defects in both transcription and DNA replication. We describe histone mutations that suppress some of these defects, providing new insight into the mechanism of FACT activity in vivo. FACT is primarily known for its ability to promote reorganization of nucleosomes into a more open form, but neither the pob3-Q308K mutation nor the compensating histone mutations affect this activity. Instead, purified mutant FACT complexes fail to release from nucleosomes efficiently, and the histone mutations correct this flaw. We confirm that pob3-T252E also suppresses pob3-Q308K, and show that combining two suppressor mutations can be detrimental, further demonstrating the importance of balance between association and dissociation for efficient FACT:nucleosome interactions. To explain our results, we propose that histone H4 can adopt multiple conformations, most of which are incompatible with nucleosome assembly. FACT guides H4 to adopt appropriate conformations, and this activity can be enhanced or diminished by mutations in Pob3 or histones. FACT can therefore destabilize nucleosomes by favoring the reorganized state, but it can also promote assembly by tethering histones and DNA together and maintaining them in conformations that promote canonical nucleosome formation. 23450708 Luminescent conjugated oligothiophenes for sensitive fluorescent assignment of protein inclusion bodies. Small hydrophobic ligands identifying intracellular protein deposits are of great interest, as protein inclusion bodies are the pathological hallmark of several degenerative diseases. Here we report that fluorescent amyloid ligands, termed luminescent conjugated oligothiophenes (LCOs), rapidly and with high sensitivity detect protein inclusion bodies in skeletal muscle tissue from patients with sporadic inclusion body myositis (s-IBM). LCOs having a conjugated backbone of at least five thiophene units emitted strong fluorescence upon binding, and showed co-localization with proteins reported to accumulate in s-IBM protein inclusion bodies. Compared with conventional amyloid ligands, LCOs identified a larger fraction of immunopositive inclusion bodies. When the conjugated thiophene backbone was extended with terminal carboxyl groups, the LCO revealed striking spectral differences between distinct protein inclusion bodies. We conclude that 1) LCOs are sensitive, rapid and powerful tools for identifying protein inclusion bodies and 2) LCOs identify a wider range of protein inclusion bodies than conventional amyloid ligands. 23892434 Regulation of TGF-β signaling, exit from the cell cycle, and cellular migration through cullin cross-regulation: SCF-FBXO11 turns off CRL4-Cdt2. Deregulation of the cell cycle and genome instability are common features of cancer cells and various mechanisms exist to preserve the integrity of the genome and guard against cancer. The cullin 4-RING ubiquitin ligase (CRL4) with the substrate receptor Cdt2 (CRL4 (Cdt2) ) promotes cell cycle progression and prevents genome instability through ubiquitylation and degradation of Cdt1, p21, and Set8 during S phase of the cell cycle and following DNA damage. Two recently published studies report the ubiquitin-dependent degradation of Cdt2 via the cullin 1-RING ubiquitin ligase (CRL1) in association with the substrate specificity factor and tumor suppressor FBXO11 (CRL1 (FBXO11) ). The newly identified pathway restrains the activity of CRL4 (Cdt2) on p21 and Set8 and regulates cellular response to TGF-β, exit from the cell cycle and cellular migration. Here, we show that the CRL1 (FBXO11) also promotes the degradation of Cdt2 during an unperturbed cell cycle to promote efficient progression through S and G 2/M phases of the cell cycle. We discuss how this new method of regulating the abundance of Cdt2 participates in various cellular activities. 23815871 Epidemiology of complementary and alternative medicine use in patients with Parkinson's disease. Parkinson's disease (PD) is a common and debilitating neurodegenerative disorder without a known neuroprotective cure. Currently, an increasing number of patients with PD resort to complementary and alternative medicine (CAM). This study aimed to determine the epidemiology of CAM use for PD worldwide. Methodological issues included the definition of CAM, running a search strategy using five databases, and citation tracking. Six studies estimated the prevalence of CAM use for PD to be between 25.7% and 76%. The response rates in these surveys varied from 81% to 100%. Frequently utilized forms of therapy were acupuncture, massage, herbs, and vitamins/health supplements, and these therapies were mainly used to improve the associated motor symptoms of PD. However, only 11% to 20% of these patients were referred to use CAM by a healthcare professional. Of the sociodemographic and disease-specific factors, CAM use was correlated with female sex, age, age at onset of PD, longer duration of PD, degree of education, higher income, rural location, comorbidity for indications, levodopa load, and severe motor symptoms. These results suggested that CAM use is widespread among patients with PD worldwide, but the largely unexamined use of CAM requires more attention. Moreover, there is a lack of communication between physicians and patients, increasing the risks associated with CAM use and the potential for adverse events. 23792352 Diversity-oriented synthesis of α-aminophosphonates: A new class of potential anticancer agents. A small library of structurally diverse α-aminophosphonates has been synthesized by reacting alkyl/aryl aldehydes, alkyl/aryl amines and alkyl/aryl phosphites in one-pot catalyzed by Amberlite-IR 120 resin (acidic). All the synthesized α-aminophosphonates were assayed for their in vitro cytotoxic activities against a panel of five human cancer cell lines including A-549, NCI-H23 (Lung), Colo 320DM (Colon), MG-63 (Bone marrow) and Jurkat (Blood T lymphocytes). Compound 4n having (R)-1-phenylethanamine was found to be the most active amongst all the synthesized α-aminophosphonates against all the five cancer cell lines, most prominent being against Jurkat cell line with an IC50 value of 4 Î¼M. Surprisingly, compound 4o having (S)-1-phenylethanamine was found to be devoid of any cytotoxicity. Our finding suggests that these chemical entities could further serve as interesting template for the design of potential anticancer agents. 23911622 A method to analyze "source-sink" structure of non-point source pollution based on remote sensing technology. With the purpose of providing scientific basis for environmental planning about non-point source pollution prevention and control, and improving the pollution regulating efficiency, this paper established the Grid Landscape Contrast Index based on Location-weighted Landscape Contrast Index according to the "source-sink" theory. The spatial distribution of non-point source pollution caused by Jiulongjiang Estuary could be worked out by utilizing high resolution remote sensing images. The results showed that, the area of "source" of nitrogen and phosphorus in Jiulongjiang Estuary was 534.42 km(2) in 2008, and the "sink" was 172.06 km(2). The "source" of non-point source pollution was distributed mainly over Xiamen island, most of Haicang, east of Jiaomei and river bank of Gangwei and Shima; and the "sink" was distributed over southwest of Xiamen island and west of Shima. Generally speaking, the intensity of "source" gets weaker along with the distance from the seas boundary increase, while "sink" gets stronger. 23935154 Cells with intense EGFR staining and a high nuclear to cytoplasmic ratio are specific for infiltrative glioma: a useful marker in neuropathological practice. BackgroundThe differential diagnosis between infiltrative glioma (IG) and benign or curable glial lesions, such as gliosis, pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor, ganglioglioma, or demyelinating disease, may be challenging for the pathologist because specific markers are lacking. Recently, we described a strong EGFR immunolabelling pattern in cells with a high nuclear to cytoplasmic ratio that enables the discrimination of low-grade IG from gliosis. The aim of this study was to extend our observation to high-grade glioma to assess whether EGFR expression pattern is of value in the discrimination of all IG from noninfiltrative glial lesions (NIG), including gliosis, benign tumors, and demyelinating disease.MethodsOne hundred one IG and 58 NIG were compared for immunohistochemical expression of EGFR with use of an antibody that recognizes an epitope in the extracellular domain of both EGFRwt and EGFRvIII. Highly EGFR-positive cells with a high nuclear to cytoplasmic ratio were isolated and further characterized.ResultsCells with intense EGFR staining and a high nuclear to cytoplasmic ratio were significantly associated with the diagnosis of IG (P < .0001). The sensitivity and specificity of this staining pattern for the diagnosis of IG were 95% and 100%, respectively. EGFR expression was independent of IDH1 mutations and EGFR amplification. Finally, we showed that these particular cells displayed the phenotype and properties of glial progenitors and coexpressed CXCR4, a marker of invasiveness.ConclusionsWe demonstrate that cells with intense EGFR staining and a high nuclear to cytoplasmic ratio are specific criteria for the diagnosis of IG, irrespective of grade, histological subtype, and progression pathway, and their identification represents a tool to discriminate IG from benign or curable glial lesions. 23911395 Identification of a novel HLA-A*24:02-restricted adenovirus serotype 11-specific CD8(+) T-cell epitope for adoptive immunotherapy. Subgroup B adenovirus serotype 11 (Ad11) occasionally causes fatal infections in immunocompromised patients. The present study describes a novel Ad11 epitope presented by HLA-A*24:02 that could be used for adoptive immunotherapy. Ten synthetic Ad11 hexon protein-derived nonamer peptides that bound to HLA-A*24:02 were selected by a computer algorithm and MHC stabilization assay. Stimulation of peripheral blood mononuclear cells from HLA-A*24:02+ donors with each of these synthetic peptides induced peptide-specific CD8(+) T-cells for three peptides. Testing the reactivity of these peptide-specific CD8(+) T-cells against various target cells confirmed that peptide TYFNLGNKF is naturally processed in Ad11-infected cells and is presented by HLA-A*24:02. Emergence of TYFNLGNKF-specific CD8(+) T-cells coincided with the clearance of adenoviruses in a patient with Ad11 disease. Importantly, TYFNLGNKF-specific CD8(+) T-cells were suggested to be not serotype cross-reactive. The novel HLA-A*24:02-restricted Ad11 epitope could be used for anti-Ad11 adoptive immunotherapy and to monitor immunity to Ad11 using MHC tetramers. 23311697 Bottom-up approach to creating three-dimensional nanoring arrays composed of Au nanoparticles. A bottom-up approach to creating 3D assemblies of Au nanorings by drying aqueous dispersions of PS colloidal particles and Au NPs is shown. The evaporation of water from the dispersion allowed for the formation of hexagonally assembled colloidal crystals and nanorings composed of Au nanoparticles among the PS colloidal particles. The size of the nanorings could be controlled on a scale of tens to hundreds of nanometers. After sintering, the Au NPs formed Au nanorings. This simple approach supplies a potentially useful path to novel plasmonic materials and unique metamaterials for the visible light region. 23127825 Precipitation of Ibuprofen Sodium using compressed carbon dioxide as antisolvent. Precipitation with compressed antisolvent (PCA) process was used to produce fine particles of Ibuprofen Sodium with the ultimate goal of obtaining controlled particle size and size distribution of this non-steroidal anti-inflammatory drug. This systematic investigation shows that particle size and size distribution of the final product can be controlled reproducibly by varying a number operating parameters such as antisolvent addition rate, temperature, concentration, and solution addition rate. The mechanisms that control particle size and particle size distribution were explained by invoking the differences in the relative weight of primary, secondary nucleation and growth kinetic phenomena. A number of techniques were used for the characterization of the generated particles. In addition to scanning electron microscope (SEM), dynamic light scattering measurements were conducted to determine the size of the particles in terms of number-weighted size distribution. The influence of process parameters on the Ibuprofen Sodium crystallinity was investigated using X-ray diffraction (XRD). Moreover, the ''in vitro'' drug performance was tested. The results showed an improvement of the PCA processed Ibuprofen Sodium ''in vitro'' drug activity. In addition, dissolution investigations demonstrated that the flow rate, in combination with the particle size distribution, substantially influence the drug "in vitro" dissolution. 23774443 Fracture healing with alendronate treatment in the Brtl/+ mouse model of osteogenesis imperfecta. Osteogenesis imperfecta (OI) is a heritable bone dysplasia characterized by increased skeletal fragility. Patients are often treated with bisphosphonates to attempt to reduce fracture risk. However, bisphosphonates reside in the skeleton for many years and long-term administration may impact bone material quality. Acutely, there is concern about risk of non-union of fractures that occur near the time of bisphosphonate administration. This study investigated the effect of alendronate, a potent aminobisphosphonate, on fracture healing. Using the Brtl/+ murine model of type IV OI, tibial fractures were generated in 8-week-old mice that were untreated, treated with alendronate before fracture, or treated before and after fracture. After 2, 3, or 5weeks of healing, tibiae were assessed using microcomputed tomography (μCT), torsion testing, quantitative histomorphometry, and Raman microspectroscopy. There were no morphologic, biomechanical or histomorphometric differences in callus between untreated mice and mice that received alendronate before fracture. Alendronate treatment before fracture did not cause a significant increase in cartilage retention in fracture callus. Both Brtl/+ and WT mice that received alendronate before and after fracture had increases in the callus volume, bone volume fraction and torque at failure after 5weeks of healing. Raman microspectroscopy results did not show any effects of alendronate in wild-type mice, but calluses from Brtl/+ mice treated with alendronate during healing had a decreased mineral-to-matrix ratio, decreased crystallinity and an increased carbonate-to-phosphate ratio. Treatment with alendronate altered the dynamics of healing by preventing callus volume decreases later in the healing process. Fracture healing in Brtl/+ untreated animals was not significantly different from animals in which alendronate was halted at the time of fracture. 23657457 Analysis of esterified and nonesterified fatty acids in serum from obese individuals after intake of breakfasts prepared with oils heated at frying temperature. In this study, levels of esterified and nonesterified fatty acids (EFAs and NEFAs, respectively) were compared in obese individuals (body mass index between 30 and 47 kg m(-2)) in basal state and after intake of four different breakfasts prepared with oils heated at frying temperature. The target oils were three sunflower oils--pure, enriched with dimethylsiloxane (400 μg mL(-1)) as lipophilic oxidation inhibitor, and enriched with phenolic compounds (400 μg mL(-1)) as hydrophilic oxidation inhibitors--and virgin olive oil with a natural content of phenolic compounds of 400 μg mL(-1). The intake of breakfasts was randomized to avoid trends associated to this variability source. EFAs and NEFAs were subjected to a sequential derivatization step for independent gas chromatography-mass spectrometry analysis of both fractions of metabolites in human serum. Derivatization was assisted by ultrasonic energy to accelerate the reaction kinetics, as required for high-throughput analysis. Statistical analysis supported on univariate (multifactor ANOVA) and multivariate approaches (principal component analysis and partial least squares-discriminant analysis) allowed identification of the main variability sources and also discriminating between individuals after intake of each breakfast. Individuals' samples after intake of breakfasts prepared with virgin olive oil were clearly separated from those who ingested the remaining breakfasts. The main compounds contributing to discrimination were omega-3 and omega-6 EFAs with special emphasis on arachidonic acid and eicosapentaenoic acid. These two polyunsaturated fatty acids are the precursors of eicosanoid metabolites, which are of vital importance as they play important roles in inflammation and in the pathogenesis of vascular and malignant diseases as cancer. 23152124 Involvement of lysosomal exocytosis in the excretion of mesoporous silica nanoparticles and enhancement of the drug delivery effect by exocytosis inhibition. The exocytosis of phosphonate modified mesoporous silica nanoparticles (P-MSNs) is demonstrated and lysosomal exocytosis is identified as the mechanism responsible for this event. Regulation of P-MSN exocytosis can be achieved by inhibiting or accelerating lysosomal exocytosis. Slowing down P-MSN exocytosis enhances the drug delivery effect of CPT-loaded P-MSNs by improving cell killing. 23624633 Reproductive and obstetric outcomes after radical abdominal trachelectomy for early-stage cervical cancer in a series of 31 pregnancies. What are the reproductive and obstetric outcomes in patients undergoing radical abdominal trachelectomy (RAT) for early-stage cervical cancer? When RAT was performed before a pregnancy achieved with fertility treatments, pregnancy rate of 36.2% was obtained and 71.4% of these women gave birth at ≥ 32 weeks of gestation. Reproductive and obstetric outcomes after radical vaginal trachelectomy (RVT) are well documented; however, these outcomes after RAT have not been well studied. This is a retrospective cohort study of patients at a single institution who underwent RAT and became pregnant. Reproductive and obstetric outcomes of 114 patients who had undergone RAT from September 2002 to December 2010 were investigated. Women of reproductive age with early-stage cervical cancer who wished to preserve their fertility were documented. Patients' median age was 33 years (25-40 years). A total of 31 pregnancies were achieved in 25 patients and 6 patients had 2 pregnancies. Eighteen of 25 patients (72.0%) had infertility problems; 17 patients conceived with IVF-embryo transfer and 1 patient with intrauterine insemination. The pregnancy rate among patients who wished to conceive was 36.2% (25/69). Among 31 pregnancies in 25 patients, 4 patients had first trimester miscarriage and 1 patient had second trimester miscarriage. Excluding the five patients who miscarried and the five ongoing pregnancies, all the 21 patients had deliveries by Cesarean section. Four patients had a preterm birth in the second trimester and 17 patients delivered in the third trimester. Of the 17 pregnancies that reached the third trimester, 2 (11.8%) were preterm births between 29 and 32 weeks, 11 (64.7%) were delivered between 32 and 37 weeks and 4 (23.5%) at ≥ 37 weeks of gestation. Because of the retrospective data collection, not all pregnancies may have been recorded. Prospective multicenter studies are needed to determine if the results shown in this retrospective cohort can be generalized to all patients with early-stage cervical cancer who wish to undergo the fertility-sparing RAT procedure. 23877720 Characterization of an insect-specific flavivirus (OCFVPT) co-isolated from Ochlerotatus caspius collected in southern Portugal along with a putative new Negev-like virus. We describe the isolation and characterization of an insect-specific flavivirus (ISF) from Ochlerotatus caspius (Pallas, 1771) mosquitoes collected in southern Portugal. The RNA genome of this virus, tentatively designated OCFVPT, for O. caspius flavivirus from Portugal, encodes a polyprotein showing all the features expected for a flavivirus. As frequently observed for ISF, the viral genomes seems to encode a putative Fairly Interesting Flavivirus ORF (FIFO)-like product, the synthesis of which would occur as a result of a -1 translation frameshift event. OCFVPT was isolated in the C6/36 Stegomyia albopicta (= Aedes albopictus) cell line where it replicates rapidly, but failed to replicate in Vero cells in common with other ISFs. Unlike some of the latter, however, the OCFVPT genome does not seem to be integrated in the mosquito cells we tested. Phylogenetic analyses based on partial ISF NS5 nucleotide sequences placed OCFVPT among recently published viral strains documented from mosquitoes collected in the Iberian Peninsula, while analyses of ORF/E/NS3/or NS5 amino acid sequences cluster OCFVPT with HANKV (Hanko virus), an ISF recently isolated from O. caspius mosquitoes collected in Finland. Taking into account the genetic relatedness with this virus, OCFVPT is not expected to be overtly cytopathic to C6/36 cells. The cytopathic effects associated with its presence in culture supernatants are postulated to be the result of the replication of a co-isolated putative new Negev-like virus. 23566829 No association of functional variant in pri-miR-218 and risk of congenital heart disease in a Chinese population. MiR-218 plays an important role in heart development in zebrafish. pri-miR-218 rs11134527 variant is associated with cervical cancer carcinogenesis. Therefore, we hypothesized that single nucleotide polymorphism (SNPs) in pri-miR-218 might influence susceptibility to sporadic congenital heart disease (CHD). We conducted a case-control study of CHD in a Chinese population to test our hypothesis by sequencing and genotyping pri-miR-218 in 1116 CHD cases and 1219 non-CHD controls. We identified one SNP rs11134527 located in pri-miR-218 sequence. Logistic regression analyses showed that there was no significant association in genotype and allele frequencies of pri-miR-218 rs11134527 A/G polymorphism between CHD cases in overall or various subtypes and the control group. However, real-time PCR analysis showed that rs11134527 allele G significantly increased mature miR-218 expression. In vitro binding assays further revealed that the rs11134527 variant affects miR-218-mediated regulation of Robo1. This is the first study to investigate the relationship between miR-218 and CHD cases. Our results demonstrate that the functional variant rs11134527 in pri-miR-218 has no major role in genetic susceptibility to sporadic CHD, at least in the population studied here. 23943400 Characteristics of individuals who report present and past weight loss behaviours: results from a Canadian university community. To characterise individuals who reported present and past weight loss behaviours on psycho-behavioural factors known to influence body weight, e.g. overeating, dietary restriction. An online questionnaire was distributed to a university community. Questions pertaining to present weight loss, previous weight loss, eating behaviour tendencies, perceived stress and sleep quality were answered by 3,069 individuals. Body weight and height were self-reported. Present and past weight loss behaviours were prevalent in the sample, with 33.3 % of the participants who reported trying to lose weight, 33.1 % who reported having previously lost weight (>10 lbs), and 18.8 % who reported repeated weight loss behaviour (i.e. present and past weight loss behaviours). Trying to lose weight and previous weight loss were both independently associated with increased risk for psycho-behavioural characteristics known to be associated with obesity, e.g. overeating tendencies, perceived stress, short sleep duration. This risk was particularly elevated among the underweight/normal-weight individuals who reported repeated weight loss behaviours. Indeed, adjusted odds ratios for reporting restrictive and overeating tendencies, perceived stress and short sleep for these individuals were significantly higher compared to their underweight/normal-weight peers who did not report repeated weight loss behaviours (adjusted odds ratios 4.7, 2.7, 1.8, and 1.8, respectively, p < 0.01 to <0.0001). Normal-weight individuals reporting weight loss behaviours are characterised by a psycho-behaviour profile which may further increase their risk of weight gain. 23851389 Identification and characterization of an oleate hydratase-encoding gene from Bifidobacterium breve. Bifidobacteria are common commensals of the mammalian gastrointestinal tract. Previous studies have suggested that a bifidobacterial myosin cross reactive antigen (MCRA) protein plays a role in bacterial stress tolerance, while this protein has also been linked to the biosynthesis of conjugated linoleic acid (CLA) in bifidobacteria. In order to increase our understanding on the role of MCRA in bifidobacteria we created and analyzed an insertion mutant of the MCRA-encoding gene of B. breve NCFB 2258. Our results demonstrate that the MCRA protein of B. breve NCFB 2258 does not appear to play a role in CLA production, yet is an oleate hydratase, which contributes to bifidobacterial solvent stress protection. 23952822 Ethics of clinical science in a public health emergency: drug discovery at the bedside. Clinical research under the usual regulatory constraints may be difficult or even impossible in a public health emergency. Regulators must seek to strike a good balance in granting as wide therapeutic access to new drugs as possible at the same time as gathering sound evidence of safety and effectiveness. To inform current policy, I reexamine the philosophical rationale for restricting new medicines to clinical trials, at any stage and for any population of patients (which resides in the precautionary principle), to show that its objective to protect public health, now or in the future, could soon be defeated in a pandemic. Providing wider therapeutic access and coordinating observations and natural experiments, including service delivery by cluster (wedged cluster trials), may provide such a balance. However, there are important questions of fairness to resolve before any such research can proceed. 23819780 Human Factors Research Applied: The Development of a Personal Touch Screen Insulin Pump and Users' Perceptions of Actual Use. Abstract Background: A brief history of the field of human factors research is covered, along with how this discipline is leveraged within medical device companies, to eliminate design flaws in products, in order to make them safe and effective for human use. The way in which human factors research was used to develop the t:slim(®) insulin delivery system (Tandem Diabetes Care(®) Inc., San Diego, CA) is also discussed. Following the development of the t:slim pump, a product evaluation study was conducted to assess users' perceptions of the t:slim pump under actual use conditions versus their current pump system. Subjects and Methods: A 30-day, within-subjects study with a total of 74 participants was conducted at four different investigator sites across the United States. Study participants used the t:slim insulin pump in their normal environment for 30 days. Participants were given the Insulin Delivery System Rating Questionnaire during their first visit to assess their current insulin pump and then at the end of the study to measure their perceptions of the t:slim pump. A paired-samples t test was completed to analyze the data. Results: The results indicated that 16 of the questionnaire variables showed statistically significant differences in scores. Conclusions: It was found that the utilization of a systematic human factors process resulted in an insulin pump that was proved to be safe and effective for human use and was cleared by the Food and Drug Administration for use in the United States. In addition, the results of the product evaluation study showed that, after use of the t:slim pump for 30 days, participants' perceptions of several variables improved. 23711781 The effect of β-sitosterol on the properties of cholesterol/phosphatidylcholine/ganglioside monolayers--the impact of monolayer fluidity. In this paper the influence of one of phytosterols, namely β-sitosterol on cholesterol (Chol)/phosphatidylcholine (PC)/ganglioside (GM3) monolayers was examined to find the correlation between the properties of model system and the effect of phytocompound. The studied monolayers differed in condensation and fluidity, which were modified by the structure of phosphatidylcholine. It was found that the incorporation of β-sitosterol into cholesterol/phosphatidylcholine/ganglioside films changes their morphology, condensation and interactions between the lipids. The substitution of cholesterol more strongly decreased the condensation and stability of the film containing PC molecules having monounsaturated chains than more densely packed monolayer composed of saturated phosphatidylcholine. However, thorough analysis of data obtained so far suggests that the magnitude of β-sitosterol effect is determined by the composition of the system rather than its fluidity itself. Moreover, the results collected herein correlate well with the findings that phytosterol more strongly inhibits the growth of cancer cells, which at a given proportion of cholesterol to phospholipids in membranes, have more unsaturated fatty acids within phospholipids molecules. 23715049 Impact of late calcineurin inhibitor withdrawal on ambulatory blood pressure and carotid intima media thickness in renal transplant recipients. Calcineurin inhibitors (CNIs) have an unfavorable cardiovascular risk profile in renal transplant recipients. The aim of this substudy was to assess the effects of late CNI or mycophenolate mofetil (MMF) withdrawal on ambulatory blood pressure monitoring and carotid intima media thickness. A total of 119 stable renal transplant recipients on triple regimen with steroids, a CNI and MMF were randomized into either the concentration-controlled CNI or MMF withdrawal groups. Patients were treated for traditional cardiovascular risk factors according to predefined targets. Ambulatory blood pressure monitoring and measurements of intima media thickness were performed at baseline and after 1, 2, and 3 years after randomization. CNI withdrawal resulted in a significant decline in both ambulatory day- and nighttime blood pressures (daytime: systolic blood pressure, -1.6 mm Hg/y, P=0.018; diastolic blood pressure, -1.3 mm Hg/y, P=0.002; nighttime systolic blood pressure: -1.9 mm Hg/y, P=0.008; diastolic blood pressure: -1.3 mm Hg/y, P=0.014), which was not observed after MMF withdrawal. There was no difference in the proportion of nocturnal nondippers (both groups, 69%, P=0.95). Despite the reduction in ambulatory blood pressure, no effect of CNI withdrawal on carotid intima media thickness was found. In stable renal transplant recipients, late CNI withdrawal from a triple drug regimen decreased blood pressure in comparison with MMF withdrawal but had no specific impact on carotid intima media thickness. Considering the high prevalence of hypertension in patients on CNI therapy, most stable renal transplant recipients may benefit from late CNI withdrawal by improved blood pressure control. 23838322 Occupational differences between Alzheimer's and aphasic dementias: implication for teachers. We aimed to determine whether there is an association between teaching and the development of progressive speech and language disorders (SLDs). Occupation was compared between 100 patients with a progressive SLD, 404 patients with Alzheimer's dementia, and the 2008 US census. In SLDs, the most common occupation was teacher (22%) versus 8% in Alzheimer's dementia. The odds ratio (OR) of being a teacher in SLDs compared to Alzheimer's dementia was 3.4 (95% confidence interval [CI] = 1.87-6.17). No differences were observed in the frequency of other occupations. The frequency of teachers was higher in SLDs compared to the US census, OR of 6.9 (95% CI = 4.3-11.1). Farming, forestry, and fishing occupations were more frequent in SLDs compared to the US census. We identified an association between progressive SLDs and the occupation of teaching. Since teaching is a communication demanding occupation, teachers may be more sensitive to the development of speech and language impairments. 23861903 When kinesthesia becomes visual: a theoretical justification for executing motor tasks in visual space. Several experimental studies in the literature have shown that even when performing purely kinesthetic tasks, such as reaching for a kinesthetically felt target with a hidden hand, the brain reconstructs a visual representation of the movement. In our previous studies, however, we did not observe any role of a visual representation of the movement in a purely kinesthetic task. This apparent contradiction could be related to a fundamental difference between the studied tasks. In our study subjects used the same hand to both feel the target and to perform the movement, whereas in most other studies, pointing to a kinesthetic target consisted of pointing with one hand to the finger of the other, or to some other body part. We hypothesize, therefore, that it is the necessity of performing inter-limb transformations that induces a visual representation of purely kinesthetic tasks. To test this hypothesis we asked subjects to perform the same purely kinesthetic task in two conditions: INTRA and INTER. In the former they used the right hand to both perceive the target and to reproduce its orientation. In the latter, subjects perceived the target with the left hand and responded with the right. To quantify the use of a visual representation of the movement we measured deviations induced by an imperceptible conflict that was generated between visual and kinesthetic reference frames. Our hypothesis was confirmed by the observed deviations of responses due to the conflict in the INTER, but not in the INTRA, condition. To reconcile these observations with recent theories of sensori-motor integration based on maximum likelihood estimation, we propose here a new model formulation that explicitly considers the effects of covariance between sensory signals that are directly available and internal representations that are 'reconstructed' from those inputs through sensori-motor transformations. 23948305 Chronic inflammation-derived nitric oxide causes conversion of human colonic adenoma cells into adenocarcinoma cells. It has been suggested that nitric oxide (NO) derived from chronically inflamed tissues is a cause of carcinogenesis. We herein demonstrated that administration of an inducible NO synthase inhibitor, aminoguanidine, significantly suppressed the tumorigenic conversion of human colonic adenoma (FPCK-1-1) cells into adenocarcinoma (FPCK/Inflam) cells accelerated by foreign body-induced chronic inflammation in nude mice. To determine whether NO directly promotes carcinogenesis, we exposed FPCK-1-1 cells continuously to chemically generated NO (FPCK/NO), and periodically examined their tumorigenicity. FPCK/NO cells formed tumors, whereas vehicle-treated cells (FPCK/NaOH) did not. We selected a tumorigenic population from FPCK/NO cells kept it in three-dimensional (3D) culture where in vivo-like multicellular spheroidal growth was expected. FPCK/Inflam cells developed large spheroids whereas FPCK/NO cells formed tiny but growing compact aggregates in 3D culture. Meanwhile, FPCK-1-1 and FPCK/NaOH cells underwent anoikis (apoptotic cell death consequential on insufficient cell-to-substrate interactions) through activation of caspase 3. The survived cells in the 3D culture (FPCK/NO/3D), which were derived from FPCK/NO cells, showed a similar tumor incidence to that of FPCK/Inflam cells. These results showed that NO was one of the causative factors for the acceleration of colon carcinogenesis, especially in the conversion from adenoma to adenocarcinoma in the chronic inflammatory environment. 23853094 Foxp3 Protein Stability Is Regulated by Cyclin-dependent Kinase 2. Foxp3 is a transcription factor required for the development of regulatory T cells (Treg). Mice and humans with a loss of Foxp3 function suffer from uncontrolled autoimmunity and inflammatory disease. Expression of Foxp3 is necessary for the anti-inflammatory capacity of Treg, but whether Foxp3 activity is further subject to regulation by extracellular signals is unclear. The primary structure of Foxp3 contains four cyclin-dependent kinase (CDK) motifs (Ser/Thr-Pro) within the N-terminal repressor domain, and we show that CDK2 can partner with cyclin E to phosphorylate Foxp3 at these sites. Consistent with our previous demonstration that CDK2 negatively regulates Treg function, we find that mutation of the serine or threonine at each CDK motif to alanine (S/T→A) results in enhanced Foxp3 protein stability in CD4(+) T cells. T cells expressing the S/T→A mutant of Foxp3 showed enhanced induction (e.g. CD25) and repression (e.g. IL2) of canonical Foxp3-responsive genes, exhibited an increased capacity to suppress conventional T cell proliferation in vitro, and were highly effective at ameliorating colitis in an in vivo model of inflammatory bowel disease. These results indicate that CDK2 negatively regulates the stability and activity of Foxp3 and implicate CDK-coupled receptor signal transduction in the control of regulatory T cell function and stability. 23643544 Herbalists and wild medicinal plants in M'Sila (North Algeria): An ethnopharmacology survey. AIM OF THE STUDY: The main aim of this study was to identify, catalogue and document the large number of wild medicinal plants used in the M'Sila region (northern Algeria) for the treatment of several human pathologies. Another more ambitious aim is to contribute to overcoming the limits of an orally transmitted pharmacopoeia, attempting to exploit the large ethnopharmacology patrimony of the region for further pharmacological purposes. MATERIALS AND METHODS: Our field study was carried out over a period of three years (2008-2010). During this period, herbalists were interviewed using semi-structured questionnaires investigating the herbalist as a holder of information (gender, age and educational level) and about wild medicinal plants (local name, uses and part used). In addition, the relative importance value of the species was determined and informant consensus factor (ICF) was calculated for the medicinal plants included in the study. RESULTS: A total of 83 herbalists were interviewed, men dominate the practice of traditional medicine in the region. About 41% of them are between 31-40 years, and about a third (34%) is illiterate. The traditional herbal knowledge is passed from generation to generation in the verbal form, being almost totally absent a writing tradition. The interviewed herbalists identified and recorded 58 plants species and 50 genera belonging to 27 plant families. Lamiaceae and Asteraceae were the most represented plant families. The aerial parts were the most commonly used plant part, while infusion and decoction were the most common method of traditional drug preparation. CONCLUSIONS: The survey provides a veritable source of information on the herbalists and wild medicinal plants. Plants which are used in different parts of the world for the treatment of similar diseases may be deemed to be effective in pharmacological terms. These medicinal plants may be incorporated into the healthcare delivery system of the country. 23952846 Chronic pain and pain medication use in chronic obstructive pulmonary disease. A cross-sectional study. Rationale: Pain is a common problem for patients with chronic obstructive pulmonary disease (COPD). However, pain is minimally discussed in COPD management guidelines. Objectives: The objective of this study was to describe chronic pain prevalence among patients with COPD compared with similar patients with other chronic diseases in a managed care population in the southwestern United States (age ≥ 40 yr). Methods: Using data for the period January 1, 2006 through December 31, 2010, patients with COPD were matched to two control subjects without COPD but with another chronic illness based on age, sex, insurance, and healthcare encounter type. Odds ratios (OR) for evidence of chronic pain were estimated using conditional logistic regression. Pulmonary function data for 200 randomly selected patients with COPD were abstracted. Measurements and Main Results: Retrospectively analyzed recurrent pain-related utilization (diagnoses and treatment) was considered evidence of chronic pain. The study sample comprised 7,952 patients with COPD (mean age, 69 yr; 42% male) and 15,904 patients with other chronic diseases (non-COPD). Patients with COPD compared with non-COPD patients had a higher percentage of chronic pain (59.8 vs. 51.7%; P < 0.001), chronic use of pain-related medications (41.2 vs. 31.5%; P < 0.001), and chronic use of short-acting (24.2 vs. 15.1%; P < 0.001) and long-acting opioids (4.4 vs. 1.9%; P < 0.001) compared with non-COPD patients. In conditional logistic regression models, adjusting for age, sex, Hispanic ethnicity, and comorbidities, patients with COPD had higher odds of chronic pain (OR, 1.56; 95% confidence interval [CI], 1.43-1.71), chronic use of pain-related medications (OR, 1.60; 95% CI, 1.46-1.74), and chronic use of short-acting or long-acting opioids (OR, 1.74; 95% CI, 1.57-1.92). Conclusions: Chronic pain and opioid use are prevalent among adults with COPD. This finding was not explained by the burden of comorbidity. 23940053 Assembly of Functional Ribonucleoprotein Complexes by AU-rich Element RNA-binding Protein 1 (AUF1) Requires Base-dependent and -independent RNA Contacts. AU-rich element RNA-binding protein 1 (AUF1) regulates the stability and/or translational efficiency of diverse mRNA targets, including many encoding products controlling the cell cycle, apoptosis, and inflammation, by associating with AU-rich elements (AREs) residing in their 3[prime]-untranslated regions. Previous biochemical studies showed that optimal AUF1 binding requires 33-34 nucleotides with a strong preference for U-rich RNA, despite observations that few AUF1-associated cellular mRNAs contain such extended U-rich domains. Using the smallest AUF1 isoform (p37AUF1) as a model, we employed fluorescence anisotropy-based approaches to define thermodynamic parameters describing AUF1 ribonucleoprotein (RNP) complex formation across a panel of RNA substrates. These data demonstrated that 15 nucleotides of AU-rich sequence were sufficient to nucleate high-affinity p37AUF1 RNP complexes within a larger RNA context. In particular, p37AUF1 binding to short ARE targets was significantly stabilized by interactions with a 3[prime]-purine residue and largely base-independent but non-ionic contacts 5[prime] of the AU-rich site. RNP stabilization by the upstream RNA domain was associated with an enhanced negative change in heat capacity consistent with conformational changes in protein and/or RNA components, and fluorescence resonance energy transfer-based assays demonstrated that these contacts were required for p37AUF1 to remodel local RNA structure. Finally, reporter mRNAs containing minimal high-affinity p37AUF1 target sequences associated with AUF1 and were destabilized in a p37AUF1-dependent manner in cells. These findings provide a mechanistic explanation for the diverse population of AUF1 target mRNAs, but also suggest how AUF1 binding could regulate protein and/or miRNA-binding events at adjacent sites. 23793148 A Medipix quantum area detector allows rotation electron diffraction data collection from submicrometre three-dimensional protein crystals. When protein crystals are submicrometre-sized, X-ray radiation damage precludes conventional diffraction data collection. For crystals that are of the order of 100 nm in size, at best only single-shot diffraction patterns can be collected and rotation data collection has not been possible, irrespective of the diffraction technique used. Here, it is shown that at a very low electron dose (at most 0.1 e(-) Å(-2)), a Medipix2 quantum area detector is sufficiently sensitive to allow the collection of a 30-frame rotation series of 200 keV electron-diffraction data from a single ∼100 nm thick protein crystal. A highly parallel 200 keV electron beam (λ = 0.025 Å) allowed observation of the curvature of the Ewald sphere at low resolution, indicating a combined mosaic spread/beam divergence of at most 0.4°. This result shows that volumes of crystal with low mosaicity can be pinpointed in electron diffraction. It is also shown that strategies and data-analysis software (MOSFLM and SCALA) from X-ray protein crystallography can be used in principle for analysing electron-diffraction data from three-dimensional nanocrystals of proteins. 23914856 Distal false lumen occlusion in aortic dissection with a homemade extra-large vascular plug: the candy-plug technique. Purpose : To report a technique to create an extra-large vascular plug for occlusion of a large distal false lumen in chronic aortic dissection. Technique : The "candy-plug" technique is demonstrated in a 58-year-old multimorbid man with a history of complicated acute type B aortic dissection and a 9-cm chronic thoracic false lumen aneurysm. The patient underwent a staged repair with a cervical debranching procedure as a first step and a thoracic endovascular aortic repair from the innominate artery to the celiac artery as a second step. To occlude the large false lumen from a distal route, a stent-graft was modified on-table with a diameter-restricting suture, giving it a wrapped candy-like shape. This plug was deployed into the false lumen, and the remaining opening was occluded with a standard vascular plug. On 3-month follow-up imaging, the thoracic false lumen aneurysm remained completely thrombosed. Conclusion : The candy-plug technique can facilitate complete occlusion of chronic thoracic false lumen aneurysm by prohibiting distal false lumen backflow. 23544604 Pyrazolines: a biological review. Pyrazoline is an important five membered nitrogen heterocycle, which has been extensively researched upon. The ring is quite stable and has inspired chemists to carry out various structural variations in the ring. This has propelled the development of distinct pyrazolines with an array of pharmacological activities viz. anti-inflammatory, analgesic, antimicrobial, anticancer, antidepressant etc. The review aims at highlighting this pharmacological diversity of pyrazolines. The review is a gist of latest work done describing the pharmacological aspects and potential of pyrazoline ring. 23870799 The major role of viruses in cellular evolution: facts and hypotheses. Viral particles are much more abundant than cells and viral genes outnumber cellular ones in the biosphere. Cellular genomes also harbour many integrated viruses whereas cellular genes are rare in viral genomes. The gene flux from virus to cell is thus overwhelming if compared with the opposite event. Novel viral genes continuously arose during replication/recombination of viral genomes in the virocell. These genes can become 'cellular genes' when viral genomes integrate into cellular ones. Together with the arm race between viruses and cells, this explains why viruses have played a major role in shaping cellular gene contents. Several documented cases show that viruses have been involved in the emergence of evolutionary innovations. This gives credit to hypotheses suggesting that viruses have played an important role in the formation of modern cells. 22948513 Evaluating the redistributive impact of public health expenditure using an insurance value approach. This article analyses the redistributive impact of public health expenditure in Spain using an insurance value approach to compute individual and household's value of health services non-cash benefit. We model the intensity of use of different health care services using a count data framework on a nationally representative health care survey and then predict probabilities on the 2006 Spanish EU-SILC sample. This allows us to extend disposable income with the expected monetary value of public health services and to compare it with strictly cash income. Since non-cash income due to public health services is associated with health needs, we use needs-adjusted equivalence scales to perform distributional analysis and poverty/inequality comparisons. The results show that public health expenditure in Spain acts progressively on income distribution, and that health in-kind benefits, once considered as part of disposable income, can be extremely effective in reducing poverty and inequality. 23820140 The importance of cystoscopy and bladder biopsy in women with refractory overactive bladder: the urogynaecologist's point of view? To assess the sensitivity, specificity, positive and negative predictive value of cystoscopy and the clinical value of bladder biopsy in women with refractory overactive bladder (OAB) symptoms. Prospective observational study carried out in a tertiary referral urogynaecology unit in London. Consecutive women with OAB resistant to pharmacotherapy who underwent cystoscopy, hydrodistention and bladder biopsy were studied. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of cystoscopy as well as histological findings for chronic cystitis were evaluated. 106 women aged 22-91 years were studied. Histopathology showed chronic cystitis in 94 women, follicular cystitis 3, acute and chronic cystitis in 2, transitional cell carcinoma in 6 and no abnormality in 1 woman. Trabeculations and increased vascularity were the most common cystoscopic findings, seen in 71% and 72% of women respectively. Haemorrhages on first filling and haemorrhages on refilling had specificities of 86.6% and 80% respectively for chronic cystitis. Their sensitivities were 9.8% and 13.1% respectively. Trabeculations and increased vascularity had sensitivities of 68.1% and 68.1% and their specificities were 11.6% and 4.5% respectively. Trabeculations, increased vascularity, haemorrhages on first filling and haemorrhages on refilling all had a PPV over 80% for chronic cystitis. More than 90% of women with refractory OAB symptoms have chronic cystitis on histopathology. Cystoscopy alone is useful, but not always adequate to diagnose chronic cystitis. Antibiotic therapy in those women might be beneficial before starting anticholinergics. Larger randomised controlled trials are mandatory to confirm our hypothesis. 23774593 Group B Streptococcus and Streptococcus suis Capsular Polysaccharides Induce Chemokine Production by Dendritic Cells via Toll-Like Receptor 2- and MyD88-Dependent and -Independent Pathways. Streptococcus agalactiae (also known as group B Streptococcus [GBS]) and Streptococcus suis are encapsulated streptococci causing severe septicemia and meningitis. Bacterial capsular polysaccharides (CPSs) are poorly immunogenic, but anti-CPS antibodies are essential to the host defense against encapsulated bacteria. The mechanisms underlying anti-CPS antibody responses are not fully elucidated, but the biochemistry of CPSs, particularly the presence of sialic acid, may have an immunosuppressive effect. We investigated the ability of highly purified S. suis and GBS native (sialylated) CPSs to activate dendritic cells (DCs), which are crucial actors in the initiation of humoral immunity. The influence of CPS biochemistry was studied using CPSs extracted from different serotypes within these two streptococcal species, as well as desialylated CPSs. No interleukin-1β (IL-1β), IL-6, IL-12p70, tumor necrosis factor alpha (TNF-α), or IL-10 production was observed in S. suis or GBS CPS-stimulated DCs. Moreover, these CPSs exerted immunosuppressive effects on DC activation, as a diminution of gamma interferon (IFN-γ)-induced B cell-activating factor of the tumor necrosis factor family (BAFF) expression was observed in CPS-pretreated cells. However, S. suis and GBS CPSs induced significant production of CCL3, via partially Toll-like receptor 2 (TLR2)- and myeloid differentiation factor 88 (MyD88)-dependent pathways, and CCL2, via TLR-independent mechanisms. No major influence of CPS biochemistry was observed on the capacity to induce chemokine production by DCs, indicating that DCs respond to these CPSs in a patterned way rather than a structure-dedicated manner. 23439661 Disposition and Metabolism of GSK2251052 in Humans: A Novel Boron-Containing Antibiotic. (S)-3-(Aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole (GSK2251052) is a novel boron-containing antibiotic that inhibits bacterial leucyl tRNA synthetase, and that has been in development for the treatment of serious Gram-negative infections. In this study, six healthy adult male subjects received a single i.v. dose of [(14)C]GSK2251052, 1500 mg infused over 1 hour. Blood, urine, and feces were collected over an extended period of 14 days, and accelerator mass spectrometry was used to quantify low levels of radioactivity in plasma at later time points to supplement the less-sensitive liquid scintillation counting technique. An excellent mass balance recovery was achieved representing a mean total of 98.2% of the dose, including 90.5% recovered in the urine. Pharmacokinetic analysis demonstrated that radioactivity was moderately associated with the blood cellular components, and together with GSK2251052, both were highly distributed into tissues. The parent compound had a much shorter half-life than total radioactivity in plasma, approximately 11.6 hours compared with 96 hours. GSK2251052 and its major metabolite M3, which resulted from oxidation of the propanol side chain to the corresponding carboxylic acid, comprised the majority of the plasma radioactivity, 37 and 53% of the area under the plasma versus time concentration curve from time zero to infinity, respectively. Additionally, M3 was eliminated renally, and was demonstrated to be responsible for the long plasma radioactivity elimination half-life. A combination of in vitro metabolism experiments and a pharmacokinetic study in monkeys with the inhibitor 4-methylpyrazole provided strong evidence that alcohol dehydrogenase, potentially in association with aldehyde dehydrogenase, is the primary enzyme involved in the formation of the M3 metabolite. 23629703 Emergence of colistin resistance in Enterobacteriaceae after the introduction of selective digestive tract decontamination in an intensive care unit. Selective decontamination of the digestive tract (SDD) selectively eradicates aerobic Gram-negative bacteria (AGNB) by the enteral administration of oral nonabsorbable antimicrobial agents, i.e., colistin and tobramycin. We retrospectively investigated the impact of SDD, applied for 5 years as part of an infection control program for the control of an outbreak with extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae in an intensive care unit (ICU), on resistance among AGNB. Colistin MICs were determined on stored ESBL-producing K. pneumoniae isolates using the Etest. The occurrence of both tobramycin resistance among pathogens intrinsically resistant to colistin (CIR) and bacteremia caused by ESBL-producing K. pneumoniae and CIR were investigated. Of the 134 retested ESBL-producing K. pneumoniae isolates, 28 were isolated before SDD was started, and all had MICs of <1.5 mg/liter. For the remaining 106 isolated after starting SDD, MICs ranged between 0.5 and 24 mg/liter. Tobramycin-resistant CIR isolates were found sporadically before the introduction of SDD, but their prevalence increased immediately afterward. Segmented regression analysis showed a highly significant relationship between SDD and resistance to tobramycin. Five patients were identified with bacteremia caused by ESBL-producing K. pneumoniae before SDD and 9 patients thereafter. No bacteremia caused by CIR was found before SDD, but its occurrence increased to 26 after the introduction of SDD. In conclusion, colistin resistance among ESBL-producing K. pneumoniae isolates emerged rapidly after SDD. In addition, both the occurrence and the proportion of tobramycin resistance among CIR increased under the use of SDD. SDD should not be applied in outbreak settings when resistant bacteria are prevalent. 23845033 Interrelationship of Circulating Matrix Metalloproteinase-9, TNF-a, and OPG/RANK/RANKL Systems in COPD Patients with Osteoporosis. Abstract Previous studies have shown that matrix metalloproteinase-9 (MMP-9) and its cognate inhibitor TIMP-1, inflammatory cytokine TNF-α, and the OPG/RANK/RANKL system may each play individual roles in the pathogenesis of osteoporosis in patients with COPD. In the present study, we investigated the interrelationships of these factors in male COPD patients with and without osteoporosis. The serum levels of MMP-9, MMP-9/TIMP-1 ratio, TNF-α, RANKL, OPG, and the RANKL/OPG ratio were higher in COPD patients with osteoporosis than in individuals with normal or low bone mineral density (BMD) (N = 30, all P < 0.05 or < 0.01). The lung function FEV1%Pre and the BMD of the lumbar spine and femoral neck were found to be negatively correlated with MMP-9 serum level (r = -0.36, P < 0.05, r = -0.58, P < 0.001, and r = -0.62, P < 0.01, respectively), RANKL serum level (r = -0.21, P < 0.05, and r = -0.25, P < 0.05, and r = -0.26, P < 0.05, respectively), and RANKL/OPG ratio (r = -0.23, P < 0.05, r = -0.33, P < 0.05, and r = -0.38, P < 0.05, respectively). However, they had no correlation with TIMP-1, TNF-α, OPG, or RANK. The MMP-9 serum level was found to be positively correlated with TNF-α level (r = 0.35, P < 0.05) and RANKL/OPG ratio (r = 0.27, P < 0.05) but not associated with RANKL. These results suggest that MMP-9, TNF-α, and the OPG/RANK/RANKL system may be closely interrelated and may play interactive roles in pathogenesis of osteoporosis in COPD. 23932231 The epigenetic landscape in the course of time: Conrad Hal Waddington's methodological impact on the life sciences. It seems that the reception of Conrad Hal Waddington's work never really gathered speed in mainstream biology. This paper, offering a transdisciplinary survey of approaches using his epigenetic landscape images, argues that (i) Waddington's legacy is much broader than is usually recognized-it is widespread across the life sciences (e.g. stem cell biology, developmental psychology and cultural anthropology). In addition, I will show that (ii) there exist as yet unrecognized heuristic roles, especially in model building and theory formation, which Waddington's images play within his work. These different methodological facets envisioned by Waddington are used as a natural framework to analyze and classify the manners of usage of epigenetic landscape images in post-Waddingtonian 'landscape approaches'. This evaluation of Waddington's pictorial legacy reveals that there are highly diverse lines of traditions in the life sciences, which are deeply rooted in Waddington's methodological work. 23868331 Evaluating hypoxia during air travel in healthy infants. Up to a third of ex-preterm infants flying near term exhibit pulse oxygen saturation (SpO2) of less than 85% during air travel. A hypoxia challenge test (HCT) is recommended to evaluate the requirement for in-flight supplemental O2. The validity of the HCT in healthy, term infants has not been reported. This study aimed to characterise the in-flight hypoxia response and the accuracy of the HCT to predict this response in healthy, term infants in the first year of life. Infants (n=24: (15 male)) underwent a HCT prior to commercial air travel during which parents monitored SpO2. Thirty-two flights were undertaken with six infants completing multiple flights. The median in-flight SpO2 nadir was 87% and significantly lower than the HCT SpO2 nadir (92%: p<0.001). Infants on seven flights recorded SpO2<85% with one infant recording a HCT with a SpO2 less than 85%. There was marked variability in the in-flight SpO2 in the six infants who undertook multiple flights, and for three of these infants, the SpO2 nadir was both above and below 85%. We report that in healthy term infants an in-flight SpO2 below 85% is common and can vary considerably between flights and that the HCT poorly predicts the risk of in-flight hypoxia (SpO2<85%). As it is common for healthy term infants to have SpO2 less than 85% during air travel further research is needed to clarify whether this is an appropriate cut-off in this age group. 23904078 Invasive candidosis: contrasting the perceptions of infectious disease physicians and intensive care physicians. Introduction We analyze how infectious disease physicians perceive and manage invasive candidosis in Brazil, in comparison to intensive care unit specialists. Methods A 38-question survey was administered to 56 participants. Questions involved clinicians' perceptions of the epidemiology, diagnosis, treatment and prophylaxis of invasive candidosis. P < 0.05 was considered statistically significant. Results The perception that candidemia not caused by Candida albicans occurs in less than 10% of patients is more commonly held by intensive care unit specialists (p=0.018). Infectious disease physicians almost always use antifungal drugs in the treatment of patients with candidemia, and antifungal drugs are not as frequently prescribed by intensive care unit specialists (p=0.006). Infectious disease physicians often do not use voriconazole when a patient's antifungal treatment has failed with fluconazole, which also differs from the behavior of intensive care unit specialists (p=0.019). Many intensive care unit specialists use fluconazole to treat candidemia in neutropenic patients previously exposed to fluconazole, in contrast to infectious disease physicians (p=0.024). Infectious disease physicians prefer echinocandins as a first choice in the treatment of unstable neutropenic patients more frequently than intensive care unit specialists (p=0.013). When candidemia is diagnosed, most infectious disease physicians perform fundoscopy (p=0.015), whereas intensive care unit specialists usually perform echocardiograms on all patients (p=0.054). Conclusions This study reveals a need to better educate physicians in Brazil regarding invasive candidosis. The appropriate management of this disease depends on more drug options being available in our country in addition to global coverage in private and public hospitals, thereby improving health care. 23591113 Electrophysiological evidence for 4-isobutyl-3-isopropylbicyclophosphorothionate as a selective blocker of insect GABA-gated chloride channels. Invertebrate γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and glutamate-gated chloride channels (GluCls), which function as inhibitory neurotransmitter receptors, are important targets of insecticides and antiparasitic agents. The antagonism of GABACls and GluCls by 4-isobutyl-3-isopropylbicyclophosphorothionate (PS-14) was examined in cultured cockroach and rat neurons using a whole-cell patch-clamp method. The results indicated that PS-14 selectively blocks cockroach GABACls relative to cockroach GluCls and rat GABACls. PS-14 represents a useful probe for the study of insect GABA receptors. 23832616 The effect of a nano-filled resin coating on the 3-year clinical performance of a conventional high-viscosity glass-ionomer cement. The main aim of the study was to compare the clinical performance of the conventional high-powder/liquid ratio glass-ionomer cement (GIC) Fuji IX GP Extra (F IX), Fuji IX GP Extra with a low-viscosity nano-filled resin coating, G-Coat Plus (F IX+GCP), and a resin composite, Solare (S), as a comparison material. Moderate-depth occlusal cavities in the first permanent molars of 91 11-12-year-old children (1-4 restorations per child) were restored with either F IX (87 restorations), F IX+GCP (84 restorations) or S (83 restorations). Direct clinical assessment, photographic assessment and assessment of stone casts of the restorations were carried out at 6 months, 1 year, 2 years and 3 years. The colour match with the tooth of the GIC restorations improved over the 3 years of the study. Marginal staining and marginal adaptation were minimal for all restorations; three restorations exhibited secondary caries at 3 years. From the assessment of the casts, at 2 years, there was significantly less wear of the F IX GP Extra+GCP restorations than the F IX GP Extra restorations (P < 0.005). At 3 years, approximately 37 % of F IX GP Extra restorations showed wear slightly more than the adjacent enamel, compared to 28 % of F IX GP Extra+GCP restorations and 21 % of Solare restorations. Although this was not statistically significant, there was a trend that GCP can protect F IX GP Extra against wear. Although both Fuji IX GP Extra and Fuji IX GP Extra with G-Coat Plus showed acceptable clinical performance in occlusal cavities in children, the application of G-Coat Plus gave some protection against wear. The application of G-Coat Plus to Fuji IX GP Extra glass-ionomer cement may be beneficial in reducing wear in occlusal cavities. 23523101 Activation of PPARγ is required for hydroxysafflor yellow A of Carthamus tinctorius to attenuate hepatic fibrosis induced by oxidative stress. Oxidative stress caused hepatic fibrosis by activating hepatic stellate cells (HSCs), which were implemented by depressing PPARγ activation. Hydroxysafflor yellow A (HSYA) as a nature active ingredient with antioxidant capacity was able to effectively attenuate oxidative stress mediated injury. So it will be very interesting to study effect of HSYA on HSCs activation and liver fibrosis, and reveal the role of PPARγ·CCl4 and H2O2 were used to mimic oxidative stress mediated hepatic injury in vitro and in vivo respectively. The anti-fibrosis effects of HSYA were evaluated and its mechanisms were disclosed by applying western blot, histopathological analysis, flow cytometry, RT-PCR and ELISA. Our results showed that HSCs activation and proliferation could be induced by oxidative stress, and the expressive levels of TGF-β1 and TIMP-1, the serum levels of ALT, AST, HA, LN, III-C and IV-C were also enhanced by oxidative stress, which is correlated with liver fibrosis (p<0.05 or p<0.01). HSYA was able to effectively inhibit oxidative stress mediated hepatic injury by increasing the activities of antioxidant enzymes, up regulating the expression of PPARγ and MMP-2, and down regulating the expression of TGF-β1 and TIMP-1, and reducing α-SMA level. The protective effect of HSYA can be significantly attenuated by GW9662 via blocking PPARγ (p<0.05 or p<0.01). Taken together, these results demonstrate that HSYA is able to significantly protect the liver from oxidative stress, which requires for HSYA to stimulate PPARγ activity, reduce cell proliferation and suppress ECM synthesis. 23908248 Molecular Imaging Reveals Rapid Reduction of Endothelial Activation in Early Atherosclerosis With Apocynin Independent of Antioxidative Properties. Antioxidative drugs continue to be developed for the treatment of atherosclerosis. Apocynin is an nicotinamide adenine dinucleotide phosphate oxidase inhibitor with anti-inflammatory properties. We used contrast-enhanced ultrasound molecular imaging to assess whether short-term apocynin therapy in atherosclerosis reduces vascular oxidative stress and endothelial activation APPROACH AND RESULTS: Genetically modified mice with early atherosclerosis were studied at baseline and after 7 days of therapy with apocynin (4 mg/kg per day IP) or saline. Contrast-enhanced ultrasound molecular imaging of the aorta was performed with microbubbles targeted to vascular cell adhesion molecule 1 (VCAM-1; MBV), to platelet glycoprotein Ibα (MBPl), and control microbubbles (MBCtr). Aortic vascular cell adhesion molecule 1 was measured using Western blot. Aortic reactive oxygen species generation was measured using a lucigenin assay. Hydroethidine oxidation was used to assess aortic superoxide generation. Baseline signal for MBV (1.3±0.3 AU) and MBPl (1.5±0.5 AU) was higher than for MBCtr (0.5±0.2 AU; P<0.01). In saline-treated animals, signal did not significantly change for any microbubble agent, whereas short-term apocynin significantly (P<0.05) reduced vascular cell adhesion molecule 1 and platelet signal (MBV: 0.3±0.1; MBPl: 0.4±0.1; MBCtr: 0.3±0.2 AU; P=0.6 between agents). Apocynin reduced aortic vascular cell adhesion molecule 1 expression by 50% (P<0.05). However, apocynin therapy did not reduce reactive oxygen species content, superoxide generation, or macrophage content. Short-term treatment with apocynin in atherosclerosis reduces endothelial cell adhesion molecule expression. This change in endothelial phenotype can be detected by molecular imaging before any measurable decrease in macrophage content and is not associated with a detectable change in oxidative burden. 23912885 Efficiency of the anaerobic digestion of amine wastes. Laboratory-scale anaerobic degradation of monoethanolamine waste (MEAw) with co-substrate organics was conducted at room temperature and organic loading rates from 0.19 to 5.03 kg COD/m(3) day for 486 days in a hybrid digester. 90 % feed COD conversion to methane was obtained at the lower loads and only 45 % at the highest MEA waste/COD ratio (MEAwr) of 0.62 due to inhibition of methanogenesis. Inhibition at comparable loads decreased with time, implying that the culture adapted to the challenging feed. Methane yield was negatively correlated to MEAwr applied and inhibition avoided at MEAwr <0.5. Acetate accumulation implies inhibition of acetoclastic methanogenesis that can be caused by ammonia, a product of MEAw degradation. Moderate total ammonia nitrogen and free ammonia nitrogen accumulation, maximum 2.2 g N/l and 90 mg N/l, respectively suggests, however, that other components of MEAw, and/or degradation products of such, also inhibit methanogenesis, disturbing the digester performance. 23792562 Reversal of an ancient sex chromosome to an autosome in Drosophila. Although transitions of sex-determination mechanisms are frequent in species with homomorphic sex chromosomes, heteromorphic sex chromosomes are thought to represent a terminal evolutionary stage owing to chromosome-specific adaptations such as dosage compensation or an accumulation of sex-specific mutations. Here we show that an autosome of Drosophila, the dot chromosome, was ancestrally a differentiated X chromosome. We analyse the whole genome of true fruitflies (Tephritidae), flesh flies (Sarcophagidae) and soldier flies (Stratiomyidae) to show that genes located on the dot chromosome of Drosophila are X-linked in outgroup species, whereas Drosophila X-linked genes are autosomal. We date this chromosomal transition to early drosophilid evolution by sequencing the genome of other Drosophilidae. Our results reveal several puzzling aspects of Drosophila dot chromosome biology to be possible remnants of its former life as a sex chromosome, such as its minor feminizing role in sex determination or its targeting by a chromosome-specific regulatory mechanism. We also show that patterns of biased gene expression of the dot chromosome during early embryogenesis, oogenesis and spermatogenesis resemble that of the current X chromosome. Thus, although sex chromosomes are not necessarily evolutionary end points and can revert back to an autosomal inheritance, the highly specialized genome architecture of this former X chromosome suggests that severe fitness costs must be overcome for such a turnover to occur. 23958344 Spinal cord injury induced changes of nuclear receptors PPARα and LXRβ and modulation with oleic acid/albumin treatment. In previous studies with animal models of spinal cord injury (SCI) pharmacological activation of peroxisome proliferator activated receptors (PPAR) and liver X receptors (LXR) were used to reduce tissue damage and promote behavioral recovery in animal models. We have studied the endogenous expression of the transcription factors PPARα and LXRβ in the chronic stage after SCI in rats. The immunohistochemical investigation revealed a long lasting increase in the level of PPARα in white matter in the vicinity of the lesion site. The source of this signal was identified in a subpopulation of astrocytes outside of the glial scar area. Intrathecal injections of oleic acid/albumin reduced the lesion-induced PPARα immunoreactivity. In addition, ependymal cells displayed a prominent PPARα signal in the non-injured spinal cord, and continued to express the receptor as they proliferated and migrated within the damaged tissue. The nuclear receptor LXRβ was detected at similar levels after SCI as in sham operated animals. We found high levels of immunoreactivity in the gray matter, while in the white matter it was present in subpopulations of astrocytes and oligodendrocytes. Macrophages that had accumulated within the center of the lesion contained LXRβ in their cell nuclei. Possible endogenous functions of PPARα and LXRβ after SCI are discussed, specifically the control of fatty acid and cholesterol metabolism and the regulation of inflammatory reactions. 23905676 Brucine suppresses colon cancer cells growth via mediating KDR signalling pathway. Angiogenesis plays an important role in colon cancer development. This study aimed to demonstrate the effect of brucine on tumour angiogenesis and its mechanism of action. The anti-angiogenic effect was evaluated on the chicken chorioallantoic membrane (CAM) model and tube formation. The mechanism was demonstrated through detecting mRNA and protein expressions of VEGFR2 (KDR), PKCα, PLCγ and Raf1 by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot (WB), as well as expressions of VEGF and PKCβ and mTOR by ELISA and WB. The results showed that brucine significantly reduced angiogenesis of CAM and tube formation, inhibited the VEGF secretion and mTOR expression in LoVo cell and down-regulated the mRNA and phosphorylation protein expressions of KDR, PKCα, PLCγ and Raf1. In addition, the effects of brucine on KDR kinase activity, viability of LoVo cell and gene knockdown cell were detected with the Lance™ assay, WST-1 assay and instantaneous siRNA. Compared to that of normal LoVo cells, the inhibition on proliferation of knockdown cells by brucine decreased significantly. These results suggest that brucine could inhibit angiogenesis and be a useful therapeutic candidate for colon cancer intervention. 23956827 Experience with robot-assisted laparoscopic radical prostatectomy at a secondary training hospital: operation time, treatment outcomes, and complications with the accumulation of experience. To investigate the learning curve and outcomes of robot-assisted laparoscopic radical prostatectomy (RALP) performed by a relatively lower volume surgeon at a secondary training hospital. The medical records and the surgery video recordings of 100 patients who underwent RALP by a single surgeon between March 2010 and January 2013 were reviewed. The first 10 cases were grouped into period 1, cases 11 to 40 into period 2, cases 41 to 70 into period 3, and cases 71 to 100 into period 4. The interval between the operations, the operative time for each step of the surgery, the total console time, and the operative outcomes were investigated. The mean interval between surgeries was 10.6±9.3 days. The console time decreased progressively after the first 10 cases and reached under 3 hours after 75 cases. The time taken to begin dissection of the dorsal vein complex, for the division of the bladder neck, for lateral dissection with neurovascular bundle preservation, and for apex dissection decreased significantly with experience, although the time for vesicourethral anastomosis did not. The margin-positive rate of stage T2 patients was 27.4% (20/73), and the transfusion rate was 50% in period 1 patients and 3.3% in period 4 patients. No major complications occurred. It is difficult to shorten the learning curve of surgeons in secondary training hospitals owing to the smaller number of cases and the irregular surgical intervals. Although the operation time was relatively longer, the surgical outcome and complication rates were comparable with those of surgeons at larger hospitals. 23846903 Injection-induced earthquakes. Earthquakes in unusual locations have become an important topic of discussion in both North America and Europe, owing to the concern that industrial activity could cause damaging earthquakes. It has long been understood that earthquakes can be induced by impoundment of reservoirs, surface and underground mining, withdrawal of fluids and gas from the subsurface, and injection of fluids into underground formations. Injection-induced earthquakes have, in particular, become a focus of discussion as the application of hydraulic fracturing to tight shale formations is enabling the production of oil and gas from previously unproductive formations. Earthquakes can be induced as part of the process to stimulate the production from tight shale formations, or by disposal of wastewater associated with stimulation and production. Here, I review recent seismic activity that may be associated with industrial activity, with a focus on the disposal of wastewater by injection in deep wells; assess the scientific understanding of induced earthquakes; and discuss the key scientific challenges to be met for assessing this hazard. 23734637 The role of histamine in neurogenic inflammation. The term 'neurogenic inflammation' has been adopted to describe the local release of inflammatory mediators, such as substance P and calcitonin gene-related peptide, from neurons. Once released, these neuropeptides induce the release of histamine from adjacent mast cells. In turn, histamine evokes the release of substance P and calcitonin gene-related peptide; thus, a bidirectional link between histamine and neuropeptides in neurogenic inflammation is established. The aim of this review is to summarize the most recent findings on the role of histamine in neurogenic inflammation, with particular regard to nociceptive pain, as well as neurogenic inflammation in the skin, airways and bladder. This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1. 23910108 Giant costal osteochondroma in a man with multiple exostoses. We report the case of a 42-year-old man who presented with kyphosis resulting from a giant symptomatic costal osteochondroma around the left fourth rib. The osteochondroma on the left side of the back was 56 cm × 47 cm × 33 cm and was painful. The size and growth of the tumor suggested a malignant transformation of a large costal osteochondroma. Multiple osteochondromas were also found on the legs. The patient's family history revealed hereditary characteristics. This patient was clinically diagnosed as a case of multiple familial osteochondromatosis. Complete removal of the tumor relieved the symptoms, and histopathologic examination confirmed malignant transformation of chondrosarcoma. There was no recurrence after 16 months of follow-up. 23922244 TEMPORAL DYNAMICS OF CLONAL EVOLUTION IN CHRONIC LYMPHOCYTIC LEUKEMIA WITH STEREOTYPED IGHV4-34/IGKV2-30 ANTIGEN RECEPTORS: LONGITUDINAL IMMUNOGENETIC EVIDENCE. Chronic lymphocytic leukemia (CLL) patients assigned to stereotyped subset #4 possess distinctive patterns of intraclonal diversification (ID) within their immunoglobulin (IG) genes. Though highly indicative of an ongoing response to antigen(s), the critical question concerning the precise timing of antigen involvement is unresolved. Hence, we conducted a large-scale longitudinal study of 8 subset #4 cases totaling 511 and 398 subcloned IG heavy and kappa sequences. Importantly, we could establish a hierarchical pattern of subclonal evolution, thus revealing which somatic hypermutations were negatively or positively selected. In addition, distinct clusters of subcloned sequences with cluster-specific mutational profiles were observed initially, however at later time-points the minor cluster had often disappeared and hence been selected against. Despite the high intensity of ID, it was remarkable that certain residues remained essentially unaltered. These novel findings strongly support a role for persistent antigen stimulation in the clonal evolution of CLL subset #4. 23916067 DNA methylation and differentiation: HOX genes in muscle cells. Tight regulation of homeobox genes is essential for vertebrate development. In a study of genome-wide differential methylation, we recently found that homeobox genes, including those in the HOX gene clusters, were highly overrepresented among the genes with hypermethylation in the skeletal muscle lineage. Methylation was analyzed by reduced representation bisulfite sequencing (RRBS) of postnatal myoblasts, myotubes and adult skeletal muscle tissue and 30 types of non-muscle-cell cultures or tissues. In this study, we found that myogenic hypermethylation was present in specific subregions of all four HOX gene clusters and was associated with various chromatin epigenetic features. Although the 3' half of the HOXD cluster was silenced and enriched in polycomb repression-associated H3 lysine 27 trimethylation in most examined cell types, including myoblasts and myotubes, myogenic samples were unusual in also displaying much DNA methylation in this region. In contrast, both HOXA and HOXC clusters displayed myogenic hypermethylation bordering a central region containing many genes preferentially expressed in myogenic progenitor cells and consisting largely of chromatin with modifications typical of promoters and enhancers in these cells. A particularly interesting example of myogenic hypermethylation was HOTAIR, a HOXC noncoding RNA gene, which can silence HOXD genes in trans via recruitment of polycomb proteins. In myogenic progenitor cells, the preferential expression of HOTAIR was associated with hypermethylation immediately downstream of the gene. Other HOX gene regions also displayed myogenic DNA hypermethylation despite being moderately expressed in myogenic cells. Analysis of representative myogenic hypermethylated sites for 5-hydroxymethylcytosine revealed little or none of this base, except for an intragenic site in HOXB5 which was specifically enriched in this base in skeletal muscle tissue, whereas myoblasts had predominantly 5-methylcytosine at the same CpG site. Our results suggest that myogenic hypermethylation of HOX genes helps fine-tune HOX sense and antisense gene expression through effects on 5' promoters, intragenic and intergenic enhancers and internal promoters. Myogenic hypermethylation might also affect the relative abundance of different RNA isoforms, facilitate transcription termination, help stop the spread of activation-associated chromatin domains and stabilize repressive chromatin structures. 23543185 Replication of genetic loci for sarcoidosis in US black women: data from the Black Women's Health Study. In the United States, incidence and mortality from sarcoidosis, a chronic, granulomatous disease, are increased in black women. In data from the Black Women's Health Study, a follow-up of US black women, we assessed two SNPs (rs2076530 and rs9268480) previously identified in the BTNL2 gene (chromosome 6p21), of which rs4424066 and rs3817963 are perfect proxies, to determine if they represent independent signals of disease risk. We also assessed whether local ancestry in four genomic regions previously identified through admixture mapping was associated with sarcoidosis. Finally, we assessed the relation of global percent African ancestry to risk. We conducted a nested case-control study of 486 sarcoidosis cases and 943 age- and geography-matched controls. Both BTNL2 SNPs were associated with risk of sarcoidosis in separate models, but in a combined analysis the increased risk was due to the A-allele of the rs3817963 SNP; each copy of the A-allele was associated with a 40 % increase in risk of sarcoidosis (p = 0.02) and was confirmed by our haplotypic analysis. Local African ancestry around the rs30533 ancestry informative marker at chromosome 5q31 was associated with a 29 % risk reduction (p = 0.01). Therefore, we adjusted our analysis of global African ancestry for number of copies of African alleles in rs30533. Subjects in the highest quintile of percent African ancestry had a 54 % increased risk of sarcoidosis. The present results from a population of African-American women support the role of the BTNL2 gene and the 5q31 locus in the etiology of sarcoidosis, and also demonstrate that percent African ancestry is associated with disease risk. 23964985 The General Relationship Between Universal Human Values and Adolescents' Problem/Pathological Gambling in Macao: A Parsimonious, Quantitative Model. This study modeled the general relationship between individual Macao adolescents' universal human values, measured by the Schwartz Values Inventory, and their problem/pathological gambling, indicated by the South Oaks Gambling Screen, using parsimonious, quantitative structural equation modeling. Data were collected through 471 questionnaires (261 females and 210 males) in 2010. Of the 10 value types in the Schwartz Values Inventory and derived value subtypes, only the human value subtype "nonfaith tradition" was found to be (negatively) related to problem/pathological gambling in the model. The corresponding factor loading was -0.07 (p = .015). This study was supported by the Education and Youth Affairs Bureau, the Government of Macao. 23052197 Benzo[a]pyrene-induced transcriptomic responses in primary hepatocytes and in vivo liver: toxicokinetics is essential for in vivo-in vitro comparisons. The traditional 2-year cancer bioassay needs replacement by more cost-effective and predictive tests. The use of toxicogenomics in an in vitro system may provide a more high-throughput method to investigate early alterations induced by carcinogens. Recently, the differential gene expression response in wild-type and cancer-prone Xpa (-/-) p53 (+/-) primary mouse hepatocytes after exposure to benzo[a]pyrene (B[a]P) revealed downregulation of cancer-related pathways in Xpa (-/-) p53 (+/-) hepatocytes only. Here, we investigated pathway regulation upon in vivo B[a]P exposure of wild-type and Xpa (-/-) p53 (+/-) mice. In vivo transcriptomics analysis revealed a limited gene expression response in mouse livers, but with a significant induction of DNA replication and apoptotic/anti-apoptotic cellular responses in Xpa (-/-) p53 (+/-) livers only. In order to be able to make a meaningful in vivo-in vitro comparison we estimated internal in vivo B[a]P concentrations using DNA adduct levels and physiologically based kinetic modeling. Based on these results, the in vitro concentration that corresponded best with the internal in vivo dose was chosen. Comparison of in vivo and in vitro data demonstrated similarities in transcriptomics response: xenobiotic metabolism, lipid metabolism and oxidative stress. However, we were unable to detect cancer-related pathways in either wild-type or Xpa (-/-) p53 (+/-) exposed livers, which were previously found to be induced by B[a]P in Xpa (-/-) p53 (+/-) primary hepatocytes. In conclusion, we showed parallels in gene expression responses between livers and primary hepatocytes upon exposure to equivalent concentrations of B[a]P. Furthermore, we recommend considering toxicokinetics when modeling a complex in vivo endpoint with in vitro models. 23777870 The genome sequence and transmission of an iflavirus from the brown planthopper, Nilaparvata lugens. A previously unknown iflavirus has been identified in a laboratory colony of the brown planthopper, Nilaparvata lugens. The iflavirus-like sequence was first identified in contig sequences obtained from transcriptome sequencing (RNA-seq) of the brown planthopper. The complete viral genome was resequenced using the Sanger method. The positive-strand RNA genome was 10,937 nucleotides excluding the 3' poly(A) tail, and contained a single large open reading frame encoding coat proteins in the 5' region and replicases in the 3' region. Conserved motifs for coat proteins, helicase, cysteine protease, and RNA-dependent RNA polymerase were identified in the deduced amino sequence, and the estimated molecular mass of the large polyprotein was 358.6kDa. RT-PCR detection of the viral genome indicated that viral shedding occurred through the honeydews of insects in the infected colony. To test transmission, the collected honeydews were used to feed insects in a non-viruliferous colony. After 7 days, the expected RT-PCR fragment was detected in the insects, indicating that the virus can be transmitted horizontally. This is the first iflavirus identified in planthoppers; thus, we propose the name of the virus as Nilaparvata lugens honeydew virus-1. 23830646 Severe meningococcal infection: a review of epidemiology, diagnosis, and management. Neisseria meningitidis, also known as meningococcus, is a relatively uncommon cause of invasive infection, but when it occurs it is frequently severe and potentially life threatening. Meningococcus should be considered and investigated promptly as a potentially etiologic pathogen in any patient with meningitis, or sepsis accompanied by a petechial rash. Suspected patients should receive early appropriate antimicrobial therapy concomitantly with confirmatory invasive diagnostic tests. Vaccines have reduced the incidence of infection with certain non-B meningococcal serogroups, and new serotype B vaccines are on the horizon. This article reviews the epidemiology, diagnosis, and management of severe meningococcal infections. 23246581 In vitro neurotoxic effects of Pseudechis spp. venoms: A comparison of avian and murine skeletal muscle preparations. Two common in vitro skeletal muscle preparations used for the study of venom neurotoxicity are the indirectly stimulated chick isolated biventer cervicis nerve-muscle preparation and the rat isolated phrenic nerve-diaphragm preparation. The aim of the current study was to compare the in vitro neurotoxicity of six Pseudechis spp. (Black snakes) venoms in both avian (chicken) and mammalian (rat) skeletal muscle preparations to determine differences in sensitivity. All Pseudechis spp. venoms significantly inhibited indirect twitches, in both preparations, indicating the presence of post synaptic neurotoxins. The inhibitory effects of all venoms were more rapid in the avian preparation, except for Pseudechis colletti venom where no significant difference was seen between the murine and avian muscles. Time taken to produce 50% reduction in stimulated twitches (i.e. t(50)) was markedly shorter in the avian preparation. We have shown that the avian in vitro preparation is more sensitive to the neurotoxic activity of Pseudechis spp. than the murine preparation. This difference is likely to be due to species differences in the interaction between the neurotoxins and the nicotinic receptor binding sites as well as differences in the 'safety factor' between the preparations. 23958914 Pharmacological and nonpharmacological prevention of fentanyl-induced cough: a meta-analysis. Fentanyl-induced cough (FIC) is often observed after intravenous bolus administration of fentanyl during anesthesia induction. This meta-analysis assessed the efficacy of pharmacological and nonpharmacological interventions to reduce the incidence of FIC. We searched for randomized controlled trials comparing pharmacological or nonpharmacological interventions with controls to prevent FIC; we included 28 studies retrieved from PubMed, Embase, and Cochrane Library. Overall incidence of FIC was approximately 31 %. Lidocaine [odds ratio (OR)  = 0.29, 95 % confidence interval (CI) 0.21-0.39], N-methyl-D-aspartate (NMDA) receptor antagonists (OR 0.09, 95 % CI 0.02-0.42), propofol (OR 0.07, 95 % CI 0.01-0.36), α2 agonists (OR 0.32, 95 % CI 0.21-0.48), β2 agonists (OR 0.10, 95 % CI 0.03-0.30), fentanyl priming (OR 0.33, 95 % CI 0.19-0.56), and slow injection of fentanyl (OR 0.25, 95 % CI 0.11-0.58)] were effective in decreasing the incidence of FIC, whereas atropine (OR 1.10, 95 % CI 0.58-2.11) and benzodiazepines (OR 2.04, 95 % CI 1.33-3.13) were not effective. This meta-analysis found that lidocaine, NMDA receptor antagonists, propofol, α2 agonists, β2 agonists, and priming dose of fentanyl were effective in preventing FIC, but atropine and benzodiazepines were not. Slow injection of fentanyl was effective in preventing FIC, but results depend on the speed of administration. 23944776 Staff must avoid word 'obese'. School nurses are sceptical about how new government guidance on ways to inform parents that their child is overweight will help them tackle the problem. 23900447 A gold nanocarrier and DNA-metal ligation-based sensing ensemble for fluorescent assay of thiol-containing amino acids and peptides. By engineering a gold nanoparticle and thymine-Hg(2+)-thymine-based hairpin DNA probe, a gold nanocarrier-based strategy for in vitro detection and live-cell imaging of thiol-containing amino acids/peptides was proposed. 23702231 Results of low-dose carperitide infusion in high-risk patients undergoing coronary artery bypass grafting. This study investigated the efficacy of human atrial natriuretic peptide (hANP, carperitide) for high-risk patients undergoing coronary artery bypass grafting (CABG). This was a randomized controlled trial of 367 high-risk patients (European System for Cardiac Operative Risk Evaluation above 6) undergoing CABG. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE). Secondary endpoints were (1) postoperative death, (2) MACCE + hemodialysis, and (3) serum creatinine and brain natriuretic peptide (BNP) levels. Logistic regression analysis was conducted to identify preoperative and perioperative factors related to early death and MACCE. There was no significant difference of survival between the hANP and placebo groups (p = 0.1651), but the MACCE-free rate was significantly higher in the hANP group than in the placebo group (p < 0.0001). No patient from the hANP group started hemodialysis after operation, but 7 patients did in the placebo group, and the dialysis rate was significantly lower in the hANP group (p = 0.0147). Serum creatinine and BNP were also significantly lower in the hANP group at 1 year postoperatively. MACCE were strongly associated with age 75 years or older, chronic kidney disease, hemodialysis, left ventricular dysfunction, and nonuse of carperitide. In the early postoperative period, carperitide has a cardiorenal protective effect that prevents postoperative MACCE and hemodialysis. Perioperative low-dose carperitide infusion may be useful in high-risk patients undergoing on-pump CABG. 23690255 Designing healthy communities. Designing Healthy Communities points out that our car-focused and pedestrian-unfriendly community design has significantly worsened the obesity epidemic and has created a pandemic of health crisis and inequities. Many health impacts resulting from our built environment disproportionately affect vulnerable groups. Along with a 4-hour DVD set, the Designing Healthy Communities companion book was recently published by Jossey-Bass (a Wiley imprint) and copublished by the American Public Health Association to document how the built environment and where we live affect our health. Dr. Jackson provides visionary discussions of how we can design healthy communities to address and prevent many of our devastating health concerns. A number of case studies illustrated how community issues were identified and ways communities were transformed into healthful physical environments. This text provides refreshing perspectives and challenges policy makers, health professionals, and citizens to work together, take charge, and be the change agent for our own communities. 23928409 MicroRNA profiles in graft preservation solution are predictive for ischemic-type biliary lesions after liver transplantation. Ischemic-type biliary lesions (ITBL) are the second most common cause of graft loss after liver transplantation. Though exact pathophysiology of ITBL is unknown, bile duct injury during graft preservation is considered to be a major cause. Here, we investigated whether the release of cholangiocyte-derived microRNAs (CDmiRs) during graft preservation is predictive for the development of ITBL after liver transplantation. Graft preservation solutions (perfusates) and paired liver biopsies collected at the end of cold ischemia were analysed by RT-qPCR for CDmiR-30e, CDmiR-222 and CDmiR-296 and hepatocyte-derived miRNAs (HDmiRs) HDmiR-122 and HDmiR-148a. MicroRNAs in perfusates were evaluated on their stability by incubation and fractionation experiments. MicroRNA profiles in perfusates from grafts that developed ITBL (n=20) and grafts without biliary strictures (n=37) were compared. MicroRNAs in perfusates were proven to be stable and protected against degradation by interacting proteins. Ratios between HDmiRs/CDmiRs were significantly higher in perfusates obtained from grafts that developed ITBL (P<0.01) and were identified as an independent risk factor by multivariate analysis (P<0.01, HR: 6.89). The discriminative power of HDmiRs/CDmiRs in perfusates was validated by analysis of separate brain death- (DBD) and cardiac death donors (DBD; P⩽0.016) and was superior to expression in liver biopsies (C=0.77 in perfusates vs. C<0.50 in biopsies). This study demonstrates that differential release of CDmiRs during graft preservation is predictive for the development of ITBL after liver transplantation. This provides new evidence for the link between graft-related bile duct injury and the risk for later development of ITBL. 23944288 Beneficial effects of Rituximab in patients with anti-MAG (myelin-associated glycoprotein) neuropathy: case reports. Abstract Anti-myelin-associated glycoprotein (MAG) neuropathy is a primary demyelinating sensorimotor polyneuropathy that can be very debilitating and is known to be resistant to treatment. There are only a few conflicting reports on the effect of Rituximab in anti-MAG neuropathy. We present three patients who improved remarkably with Rituximab infusions. Until the safety and efficacy of this drug are determined in larger controlled studies, use of Rituximab should be limited to patients with significant neurologic deficits. 23956418 Systemic Lupus Erythematosus Immune Complexes Increase the Expression of SLAM Family Members CD319 (CRACC) and CD229 (LY-9) on Plasmacytoid Dendritic Cells and CD319 on CD56dim NK Cells. Patients with systemic lupus erythematosus (SLE) display an activated type I IFN system due to unceasing IFN-α release from plasmacytoid dendritic cells (pDCs) stimulated by nucleic acid-containing immune complexes (ICs). NK cells strongly promote the IFN-α production by pDCs; therefore, we investigated surface molecules that could be involved in the pDC-NK cell cross-talk. In human PBMCs stimulated with RNA-containing ICs (RNA-ICs), the expression of the signaling lymphocyte activation molecule (SLAM) family receptors CD319 and CD229 on pDCs and CD319 on CD56(dim) NK cells was selectively increased. Upregulation of CD319 and CD229 on RNA-IC-stimulated pDCs was induced by NK cells or cytokines (e.g., GM-CSF, IL-3). IFN-α-producing pDCs displayed a higher expression of SLAM molecules compared with IFN-α(-) pDCs. With regard to signaling downstream of SLAM receptors, pDCs expressed SHIP-1, SHP-1, SHP-2, and CSK but lacked SLAM-associated protein (SAP) and Ewing's sarcoma-activated transcript 2 (EAT2), indicating that these receptors may act as inhibitory receptors on pDCs. Furthermore, pDCs from patients with SLE had decreased expression of CD319 on pDCs and CD229 on CD56(dim) NK cells, but RNA-IC stimulation increased CD319 and CD229 expression. In conclusion, this study reveals that the expression of the SLAM receptors CD319 and CD229 is regulated on pDCs and NK cells by lupus ICs and that the expression of these receptors is specifically altered in SLE. These results, together with the observed genetic association between the SLAM locus and SLE, suggest a role for CD319 and CD229 in the SLE disease process. 23873847 Preclinical Activity of the Type II CD20 Antibody GA101 (Obinutuzumab) Compared with Rituximab and Ofatumumab In Vitro and in Xenograft Models. We report the first preclinical in vitro and in vivo comparison of GA101 (obinutuzumab), a novel glycoengineered Type II CD20 monoclonal antibody, with rituximab and ofatumumab, the two currently approved Type I CD20 antibodies. The three antibodies were compared in assays measuring direct cell death (AnnexinV/PI staining and time-lapse microscopy), complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP) and internalization. The models used for the comparison of their activity in vivo were SU-DHL4 and RL xenografts. GA101 was found to be superior to rituximab and ofatumumab in the induction of direct cell death (independent of mechanical manipulation required for cell aggregate disruption formed by antibody treatment) whereas it was 10-1000 times less potent in mediating CDC. GA101 demonstrated superior activity to rituximab and ofatumumab in ADCC and whole-blood B-cell depletion assays, and was comparable to these two in ADCP. GA101 also showed slower internalization rate upon binding to CD20 than rituximab and ofatumumab. In vivo, GA101 induced a strong anti-tumor effect, including complete tumor remission in the SU-DHL4 model and overall superior efficacy compared with both rituximab and ofatumumab. When rituximab-pretreated animals were used, second-line treatment with GA101 was still able to control tumor progression whereas tumors escaped rituximab treatment. Taken together, the preclinical data demonstrate that the glyoengineered Type II, CD20 antibody GA101 is differentiated from the two approved Type I CD20 antibodies rituximab and ofatumumab by its overall preclinical activity, further supporting its clinical investigation. 23948015 A Situated Practice of Ethics for Participatory Visual and Digital Methods in Public Health Research and Practice: A Focus on Digital Storytelling. This article explores ethical considerations related to participatory visual and digital methods for public health research and practice, through the lens of an approach known as "digital storytelling." We begin by briefly describing the digital storytelling process and its applications to public health research and practice. Next, we explore 6 common challenges: fuzzy boundaries, recruitment and consent to participate, power of shaping, representation and harm, confidentiality, and release of materials. We discuss their complexities and offer some considerations for ethical practice. We hope this article serves as a catalyst for expanded dialogue about the need for high standards of integrity and a situated practice of ethics wherein researchers and practitioners reflexively consider ethical decision-making as part of the ongoing work of public health. (Am J Public Health. Published online ahead of print August 15, 2013: e1-e9. doi:10.2105/AJPH.2013.301310). 23900963 Development of a novel RP-HPLC method for the efficient separation of aripiprazole and its nine impurities. The development of an RP-HPLC method for the determination of aripiprazole and its nine impurities was performed with the use of partial least squares regression, response surface plot methodology and chromatographic response function. The HPLC retention times and computed molecular parameters of the aripiprazole and its nine impurities were further used for the quantitative structure-retention relationship (QSRR) study. The QSRR model, R(2) : 0.899, Q(2) : 0.832, root mean square error of estimation (RMSEE): 4.761, root mean square error of prediction (RMSEP): 6.614, was developed. Very good agreement between the predicted and observed retention times (tR ) for three additional aripiprazole impurities (TC1-TC3) indicated the high prediction potential of the QSRR model for tR evaluation of other aripiprazole impurities and metabolites. The developed HPLC method is the first reported method for the efficient determination of aripiprazole and its nine impurities, which could be used for the analysis of additional three aripiprazole impurities (TC1-TC3). This article is protected by copyright. All rights reserved. 23500536 Characterization of monomeric and multimeric snake neurotoxins and other bioactive proteins from the venom of the lethal Australian common copperhead (Austrelaps superbus). Envenomation by Australian copperheads results mainly in muscle paralysis largely attributed to the presence of postsynaptic α-neurotoxins. However, poorly reversible neurotoxic effects suggest that these venoms may contain snake presynaptic phospholipase A2 neurotoxins (SPANs) that irreversibly inhibit neurotransmitter release. Using size-exclusion liquid chromatography, the present study isolated the first multimeric SPAN complex from the venom of the Australian common copperhead, Austrelaps superbus. The multimeric SPAN P-elapitoxin-As1a (P-EPTX-As1a) along with two novel monomeric SPANs and a new postsynaptic α-neurotoxin were then pharmacologically characterized using the chick biventer cervicis nerve-muscle preparation. All SPANs inhibited nerve-evoked twitch contractions at the neuromuscular junction without inhibiting contractile responses to cholinergic agonists or KCl. These actions are consistent with a prejunctional action to inhibit neurotransmitter release, without direct myotoxicity. Furthermore, the multimeric P-EPTX-As1a caused tetanic 'fade' in muscle tension under high frequency nerve stimulation, and produced a triphasic alteration to neurotransmitter release. These actions have been previously noted with other multimeric SPAN complexes such as taipoxin. Moreover, the neurotoxic α-subunit of P-EPTX-As1a shows high homology to taipoxin α-chain. Several other coagulopathic and myotoxic high mass proteins including a class PIII snake venom metalloproteinase, C-type lectin, l-amino acid oxidase, acetylcholinesterase and phospholipase B were also identified that may contribute to the overall toxicity of A. superbus venom. In conclusion, clinicians should be aware that early antivenom intervention might be necessary to prevent the onset of irreversible presynaptic neurotoxicity caused by multimeric and monomeric SPANs and that A. superbus venom is potentially capable of producing coagulopathic and myotoxic effects. 22956627 Loss of A(1) adenosine receptor attenuates alpha-naphthylisothiocyanate-induced cholestatic liver injury in mice. Cholestasis has limited therapeutic options and is associated with high morbidity and mortality. The A(1) adenosine receptor (A(1)AR) was postulated to participate in the pathogenesis of hepatic fibrosis induced by experimental extrahepatic cholestasis; however, the contribution of A(1)AR to intrahepatic cholestatic liver injury remains unknown. Here, we found that mice lacking A(1)AR were resistant to alpha-naphthyl isothiocyanate (ANIT)-induced liver injury, as evidenced by lower serum liver enzyme levels and reduced extent of histological necrosis. Bile acid accumulation in liver and serum was markedly diminished in A(1)AR(-/-) mice compared with wild-type (WT) mice. However, biliary and urinary outputs of bile acids were significantly enhanced in A(1)AR(-/-) mice. In the liver, mRNA expression of genes related to bile acid transport (Bsep and Mdr2) and hydroxylation (Cyp3a11) was increased in A(1)AR(-/-) mice. In the kidney, A(1)AR deficiency prevented the decrease of glomerular filtration rate caused by ANIT. Treatment of WT mice with A(1)AR antagonist DPCPX also protected against ANIT hepatotoxicity. Our results indicated that lack of A(1)AR gene protects mice from ANIT-induced cholestasis by enhancing toxic biliary constituents efflux through biliary excretory route and renal elimination system and suggested a potential role of A(1)AR as therapeutic target for the treatment of intrahepatic cholestasis. 23957416 Preparation methods for monodispersed garlic oil microspheres in water using the microemulsion technique and their potential as antimicrobials. Garlic oil is considered as a natural broad-spectrum antibiotic because of its well-known antimicrobial activity. However, the characteristics of easy volatility and poor aqueous solubility limit the application of garlic oil in industry. The purpose of the present work is to develop and evaluate an oil-free microemulsion by loading garlic oil in microemulsion system. Microemulsions were prepared with ethoxylated hydrogenated castor (Cremophor RH40) as surfactant, n-butanol (or ethanol) as cosurfactant, oleic acid-containing garlic oil as oil phase, and ultrapure water as water phase. The effects of the ratio of surfactant to cosurfactant and different oil concentration on the area of oil-in-water (O/W) microemulsion region in pseudoternary phase diagrams were investigated. The particle size and garlic oil encapsulation efficiency of the formed microemulsions with different formulations were also investigated. In addition, the antimicrobial activity in vitro against Escherichia coli and Staphylococcus aureus was assessed. The experimental results show that a stable microemulsion region can be obtained when the mass ratio of surfactant to cosurfactant is, respectively, 1:1, 2:1, and 3:1. Especially, when the mixture surfactants of RH40/n-butanol 2/1 (w/w) is used in the microemulsion formulation, the area of O/W microemulsion region is 0.089 with the particle size 13.29 to 13.85 nm and garlic oil encapsulation efficiency 99.5%. The prepared microemulsion solution exhibits remarkable antibacterial activity against S. aureus. 23831258 Genetic and non-genetic factors affecting the visual outcome of ocular Behcet's disease. To examine the prognostic factors for visual outcome in Korean BD patients with uveitis. Seventy-seven Korean BD patients with uveitis were enrolled. HLA-B and HLA-A genotypes were determined by PCR-based method. Visual acuity was measured by Snellen chart. Vision loss was graded into visual impairment (VI) defined as VA<20/40 for more than 6months, loss of useful vision (LUV) as VA<20/200, and near total blindness (NTB) as VA of light perception or worse. VI was associated with a longer duration of uveitis, posterior uveitis, and cataract, LUV with male gender, a longer duration of uveitis, posterior uveitis, and cataract, and NTB with a longer duration of uveitis, cataract, and glaucoma. HLA-B(∗)51 and HLA-A(∗)26:01 did not show any association with VI, LUV, or NTB. However, HLA-B(∗)51 carriers had earlier onset of uveitis and HLA-A(∗)26:01 was strongly associated with posterior uveitis. In patients with posterior uveitis, VI was associated with a longer duration of uveitis and cataract, LUV with a longer duration, and NTB with HLA-B(∗)51. Longer duration of uveitis, posterior uveitis, male gender, cataract, and glaucoma were found to be associated with poor visual outcome in BD-related uveitis. HLA-B(∗)51 was associated with NTB in patients with posterior uveitis. HLA-A(∗)26:01 showed no association with VI, LUV, or NTB, however, was strongly associated with posterior uveitis. 23624261 Cytochrome bd-I in Escherichia coli is less sensitive than cytochromes bd-II or bo'' to inhibition by the carbon monoxide-releasing molecule, CORM-3: N-acetylcysteine reduces CO-RM uptake and inhibition of respiration. Background: CO-releasing molecules (CO-RMs) are potential therapeutic agents, able to deliver CO - a critical gasotransmitter - in biological environments. CO-RMs are also effective antimicrobial agents; although the mechanisms of action are poorly defined, haem-containing terminal oxidases are primary targets. Nevertheless, it is clear from several studies that the effects of CO-RMs on biological systems are frequently not adequately explained by the release of CO: CO-RMs are generally more potent inhibitors than is CO gas and other effects of the molecules are evident. Methods: Because sensitivity to CO-RMs cannot be predicted by sensitivity to CO gas, we assess the differential susceptibilities of strains, each expressing only one of the three terminal oxidases of E. coli - cytochrome bd-I, cytochrome bd-II and cytochrome bo', to inhibition by CORM-3. We present the first sensitive measurement of the oxygen affinity of cytochrome bd-II (Km 0.24μM) employing globin deoxygenation. Finally, we investigate the way(s) in which thiol compounds abolish the inhibitory effects of CORM-2 and CORM-3 on respiration, growth and viability, a phenomenon that is well documented, but poorly understood. Results: We show that a strain expressing cytochrome bd-I as the sole oxidase is least susceptible to inhibition by CORM-3 in its growth and respiration of both intact cells and membranes. Growth studies show that cytochrome bd-II has similar CORM-3 sensitivity to cytochrome bo'. Cytochromes bo' and bd-II also have considerably lower affinities for oxygen than bd-I. We show that the ability of N-acetylcysteine to abrogate the toxic effects of CO-RMs is not attributable to its antioxidant effects, or prevention of CO targeting to the oxidases, but may be largely due to the inhibition of CO-RM uptake by bacterial cells. Conclusions: A strain expressing cytochrome bd-I as the sole terminal oxidase is least susceptible to inhibition by CORM-3. N-acetylcysteine is a potent inhibitor of CO-RM uptake by E. coli. General significance: Rational design and exploitation of CO-RMs require a fundamental understanding of their activity. CO and CO-RMs have multifaceted effects on mammalian and microbial cells; here we show that the quinol oxidases of E. coli are differentially sensitive to CORM-3. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins. 23831015 Dimensions of impulsive behavior in obese, overweight, and healthy-weight adolescents. Impulsivity is a multidimensional construct that has been linked with obesity. To explore profiles of impulsive behavior potentially associated with adolescent weight status, we measured multiple dimensions of impulsivity (delay discounting, sustained attention, and behavioral disinhibition) using laboratory behavioral tasks in a sample of adolescents (N=61). For comparison purposes, we also assessed self-reported impulsive behavior with the BIS-11-A. Participants differed in body mass index: obese (n=21), overweight (n=20), and healthy-weight (n=20). Obese and overweight adolescents were more impulsive on the measure of delay discounting than healthy-weight adolescents, but no difference was found between obese and overweight adolescents on this measure. Obese adolescents also were more impulsive on the measure of inattention compared to overweight and healthy-weight adolescents, who did not differ on this measure. Behavioral disinhibition had no association with weight status, nor did the self-report measure of impulsivity. The additive pattern of these findings for certain laboratory behavioral measures indicates that obese adolescents are more impulsive than their healthy-weight counterparts on two dimensions of behavior, whereas overweight adolescents are more impulsive on only one dimension. Consequently, adolescents who are impulsive on two dimensions of behavior (i.e., delay discounting and sustained attention) may be at greater risk of becoming obese rather than overweight compared to adolescents who are impulsive on only one dimension of behavior (i.e., delay discounting). 23833275 The gut microbiome: The role of a virtual organ in the endocrinology of the host. The human microbiome contains a vast array of microbes and genes which shows greater complexity than the host's own karyome, many of these functions are beneficial and show co-evolution with the host while others are detrimental. The microbiota which colonize the gut is now being considered as a virtual organ or emergent system, with properties that need to be integrated into host biology and physiology. Unlike other organs the functions that the gut microbiota provide to the host are as yet not fully understood and can be quite easily removed by antibiotics, diet or surgery. In this review we have looked some of the best characterised functions that only the gut microbiota provide and how they interact with the host's endocrine system and we have tried to make it clear that 21st century biology cannot afford to ignore this facet of biology, if it wants to fully understand what makes us human. 23200245 Investigating the binding interactions of galantamine with β-amyloid peptide. The anti-Alzheimer's agent galantamine is known to possess anti-amyloid properties. However the exact mechanisms are not clear. We studied the binding interactions of galantamine with amyloid peptide dimer (Aβ(1-40)) through molecular docking and molecular dynamics simulations. Galantamine's binding site within the amyloid peptide dimer was identified by docking experiments and the most stable complex was analyzed by molecular dynamics simulation. These studies show that galantamine was interacting with the central region of the amyloid dimer (Lys16-Ala21) and the C-terminal region (Ile31-Val36) with minimum structural drift of Cα atom in those regions. Strikingly, a significant drift was observed at the turn region from Asp23-Gly29 (Cα atom RMSD=9.2 Å and 11.6 Å at 50 fs and 100 fs respectively). Furthermore, galantamine's binding mode disrupts the key pi-pi stacking interaction between aromatic rings of Phe19 (chain A) and Phe19 (chain B) and intermolecular hydrogen bonds seen in unbound peptide dimer. Noticeably, the azepine tertiary nitrogen of galantamine was in close proximity to backbone CO of Leu34 (distance <3.5 Å) to stabilize the dimer conformation. In summary, the results indicate that galantamine binding to amyloid peptide dimer leads to a significant conformational change at the turn region (Asp23-Gly29) that disrupts interactions between individual β-strands and promotes a nontoxic conformation of Aβ(1-40) to prevent the formation of neurotoxic oligomers. 23919215 Are medical ethics universal or culture specific. In our society and culture where family is of utmost importance, sometimes I wonder how much of a doctor's duty is to the patient and how much is to the whole family. As a medical student, I remember being told by my professors that we should treat the patient as a whole and not focus on just one problem or organ system. Similarly when practicing medicine in Pakistan, one cannot treat the patient alone and ignore the family. How much should relatives' wishes be taken into account when dealing with a patient Don't patients have a right to their medical information When, how, and by whom can that right be waived What role does culture play when debating medical ethics. 23763646 (131)I-MIBG Targeting of Neuroblastoma Cells Is Acutely Enhanced by KCl Stimulation through the Calcium/Calmodulin-Dependent Kinase Pathway. Abstract The efficacy of (131)I-metaiodobenzylguanidine (MIBG) therapy relies on norepinephrine transporter (NET) function. The ionic make-up of the extracellular fluid critically controls neuronal cell activity and can also affect substrate transport. In this study, we explored the effect of treatment with elevated KCl concentration on MIBG uptake in SK-N-SH neuroblastoma cells. KCl stimulation caused a rapid increase of (131)I-MIBG uptake in a manner that was calcium-dependent and accompanied by activation of calcium/calmodulin-dependent protein kinase (CaMK)II. The effect was completely abolished by KN93, an inhibitor of CaMKI, II, and IV. STO609, a selective inhibitor of CaMK kinase required for activation of CaMKI and IV, but not CaMKII, only modestly attenuated the response. The KCl effect was also completely abrogated by ML7, a selective inhibitor of myosin light chain kinase (MLCK). This restricted form of CaMK activates myosin, which is required for vesicle trafficking. Saturation kinetic analysis revealed KCl stimulation to increase maximal transport velocity without affecting substrate affinity. In conclusion, KCl stimulation rapidly upregulates NET function through the CaMK pathway via activation of CaMKII and MLCK. These findings allow a better understanding of how NET function is acutely modulated by the ionic environment, which in turn may ultimately help improve the efficacy of (131)I-MIBG therapy. 23741012 STAT3 mediates oncogenic addiction to TEL-AML1 in t(12;21) acute lymphoblastic leukemia. The t(12;21)(p13;q22) translocation is the most common chromosomal abnormality in pediatric leukemia. Although this rearrangement involves 2 well-characterized transcription factors, TEL and AML1, the molecular pathways affected by the result of the translocation remain largely unknown. Also in light of recent studies showing genetic and functional heterogeneities in cells responsible for cancer clone maintenance and propagation, targeting a single common deregulated pathway may be critical for the success of novel therapies. Here we describe a novel signaling pathway that is essential for oncogenic addiction in TEL-AML1 leukemia. Our data indicate a direct role for TEL-AML1, via increasing the activity of RAC1, in regulating the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which results in transcriptional induction of MYC. We demonstrate that human leukemic cell lines carrying this translocation are highly sensitive to treatment with S3I-201, a specific STAT3 inhibitor, and, more interestingly, that primary human leukemic samples are also responsive to the drug in the same concentration range. Thus, STAT3 inhibition represents a promising possible therapeutic strategy for the treatment of TEL-AML1 leukemia. 23940348 CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. A characteristic of memory T (TM) cells is their ability to mount faster and stronger responses to reinfection than naïve T (TN) cells do in response to an initial infection. However, the mechanisms that allow this rapid recall are not completely understood. We found that CD8 TM cells have more mitochondrial mass than CD8 TN cells and, that upon activation, the resulting secondary effector T (TE) cells proliferate more quickly, produce more cytokines, and maintain greater ATP levels than primary effector T cells. We also found that after activation, TM cells increase oxidative phosphorylation and aerobic glycolysis and sustain this increase to a greater extent than TN cells, suggesting that greater mitochondrial mass in TM cells not only promotes oxidative capacity, but also glycolytic capacity. We show that mitochondrial ATP is essential for the rapid induction of glycolysis in response to activation and the initiation of proliferation of both TN and TM cells. We also found that fatty acid oxidation is needed for TM cells to rapidly respond upon restimulation. Finally, we show that dissociation of the glycolysis enzyme hexokinase from mitochondria impairs proliferation and blocks the rapid induction of glycolysis upon T-cell receptor stimulation in TM cells. Our results demonstrate that greater mitochondrial mass endows TM cells with a bioenergetic advantage that underlies their ability to rapidly recall in response to reinfection. 23932164 Egg laying pattern, egg weight, body weight at hatch, and sex ratio bias relative to oviposition time of young-and mid-age broiler breeders. Two experiments were conducted to determine oviposition pattern and the effect of oviposition time on egg weight, body weight at hatch, and sex ratio of hatched chickens. In Experiment 1, eggs were collected from young and mid-age broiler flocks for 6 consecutive days at hourly intervals between 0400 and 2000h. In Experiment 2, eggs were categorized to represent eggs where oviposition occurred early, middle and late in the clutch (later in the day). These eggs were incubated to determine body weight at hatch and sex ratio of hatched chickens relative to oviposition time. Time of oviposition was affected by age. For the young flock, the percentage of ovipositions occurring before the 1100h was 79%. In contrast to the young flock, the percentage of ovipositions occurring before the 1100h in the mid-age flock was less (68%; P<0.01). Furthermore, for the mid-age flock, the percentage of ovipositions occurring from 1200 to 1700h was greater (P<0.01) at 32% in comparison to that of the younger flock at 21%. Egg weights when oviposition occurred earlier in the day were greater (P<0.01) than when oviposition occurred in the middle and later in the clutch (later in the day). Similarly, body weight at hatch of chicks from eggs where oviposition occurred earlier in the day was heavier than when oviposition occurred in the middle and later in the clutch (later in the day).With hatching of the eggs from hens when ovipositions occurred earlier in the day, there was a female sex bias. Differences in egg weights, body weight at hatch, and sex ratio due to time of oviposition suggest that oviposition time together with incubation conditions should be considered for obtaining greater uniformity and growth of chickens. 23957572 Therapeutic consequences from changing voice ideals (clear to harsh, pleasant to jarring): Summarizing report on a round-table discussion at the 5th World Voice Congress, Luxor, Egypt, 27-31 October 2012. Starting out with an attempt to define an 'ideal voice', the discussion moved on to the hazards of pop singing, followed by the topics of harsh voices (from the desired effects in modern singing expression to devastating clinical cases), phoniatric targets (aesthetics and fitness), and, finally, the phoniatricians' attitudes comprising acceptance, neglect, and rejection. Therapy should aim at a resilient and effective voice regardless of the mere sound, unless the perfection of the vocal sound is the ultimate goal. In addition, the panellists agreed that voice specialists and all friends of healthy and efficient voices are obliged permanently to engage in voice care. 23499541 Comparison of different vaccination schedules for sustaining the immune response against porcine reproductive and respiratory syndrome virus. In order to better understand how immunization against porcine reproductive and respiratory syndrome virus (PRRSV) can be improved using commercial vaccines, different strategies of immunization were applied in the field using an inactivated vaccine (INV), a modified live vaccine (MLV) or a combination of the two and the responses compared. In experiment 1 (E1), 21 piglets were distributed in three groups. Group A was vaccinated with a commercial INV at 2.5, 3.5 and 6.5months old; group B pigs received the INV at 1.5, 2.5, 5.5 and 6.5months old, while pigs in group C were kept as unvaccinated controls. At 7.5months of age all pigs were challenged with PRRSV and followed for 21days. In experiment 2 (E2), 32 piglets were distributed evenly in four groups. Groups A, B and C were vaccinated with a commercial MLV at 1.5months old, while group D pigs were kept as controls. At 4.5months old, groups A and C received the INV while B received a second MLV, 1month later group C pigs received a third INV. At 6.5months old all pigs were challenged as in E1. In both experiments, total antibodies, neutralizing antibodies (NA) and cell-mediated immunity (CMI) were evaluated, and viraemia was determined after challenge. In E1, immunization with an INV induced high interferon-γ responses after the second and subsequent vaccinations. Development of NA after challenge was faster in INV vaccinated pigs compared to unvaccinated controls. In E2, re-vaccination with INV induced NA responses similar to re-vaccination with MLV; however, a significant increase in NA titres after challenge was only detected in group C pigs. The use of combined protocols (MLV+INV) was superior to the use of MLV alone in inducing cell mediated immunity. In conclusion, the highest immune responses against PRRSV after a single shot were achieved with MLV; after that, INV re-vaccination should be considered as the best strategy to induce significant boosters. 23943331 Stable carbon isotope analysis of dissolved inorganic carbon (DIC) and dissolved organic carbon (DOC) in natural waters - Results from a worldwide proficiency test. Stable carbon isotope ratios of dissolved inorganic (DIC) and organic carbon (DOC) are of particular interest in aquatic geochemistry. The precision for this type of analysis is typically reported in the range of 0.1‰ to 0.5‰. However, there is no published attempt that compares δ(13) C measurements of DIC and DOC among different laboratories for natural water samples. Five natural water samples (lake water, seawater, two geothermal waters, and petroleum well water) were analyzed for δ(13) CDIC and δ(13) CDOC values by five laboratories with isotope ratio mass spectrometry (IRMS) in an international proficiency test. The reported δ(13) CDIC values for lake water and seawater showed fairly good agreement within a range of about 1‰, whereas geothermal and petroleum waters were characterized by much larger differences (up to 6.6‰ between laboratories). δ(13) CDOC values were only comparable for seawater and showed differences of 10 to 21‰ for other samples. This study indicates that scatter in δ(13) CDIC isotope data can be in the range of several per mil for samples from extreme environments (geothermal waters) and may not yield reliable information with respect to dissolved carbon (petroleum wells). The analyses of lake water and seawater also revealed a larger than expected difference and researchers from various disciplines should be aware of this. Evaluation of analytical procedures of the participating laboratories indicated that the differences cannot be explained by analytical errors or different data normalization procedures and must be related to specific sample characteristics or secondary effects during sample storage and handling. Our results reveal the need for further research on sources of error and on method standardization. Copyright © 2013 John Wiley & Sons, Ltd. 23588647 Characterization of culturable Paenibacillus spp. from the snow surface on the high Antarctic Plateau (DOME C) and their dissemination in the Concordia research station. Culturable psychrotolerant bacteria were isolated from the top snow on the high Antarctic Plateau surrounding the research station Concordia. A total of 80 isolates were recovered, by enrichment cultures, from two different isolation sites (a distant pristine site [75° S 123° E] and a site near the secondary runway of Concordia). All isolates were classified to the genus Paenibacillus by 16S rRNA gene phylogenetic analysis and belonged to two different species (based on threshold of 97 % similarity in 16S rRNA gene sequence). ERIC-PCR fingerprinting indicated that the isolates from the two different sites were not all clonal. All isolates grew well from 4 to 37 °C and were resistant to ampicillin and streptomycin. In addition, the isolates from the secondary runway were resistant to chromate and sensitive to chloramphenicol, contrary to those from the pristine site. The isolates were compared to 29 Paenibacillus isolates, which were previously recovered from inside the Concordia research station. One of these inside isolates showed ERIC- and REP-PCR fingerprinting profiles identical to those of the runway isolates and was the only inside isolate that was resistant to chromate and sensitive to chloramphenicol. The latter suggested that dissemination of culturable Paenibacillus strains between the harsh Antarctic environment and the inside of the Concordia research station occurred. In addition, inducible prophages, which are potentially involved in horizontal dissemination of genes, were detected in Paenibacillus isolates recovered from outside and inside the station. The highest lysogeny was observed in strains harvested from the hostile environment outside the station. 23643519 Insecticidal and repellence activity of the essential oil of Pogostemon cablin against urban ants species. Ants are highly abundant in neotropical regions, with certain species adapted to the urban environment, where they can cause damage to human health. The main method for controlling ants consists of using organosynthetic insecticides, which are potentially toxic to the environment. Essential plant oils are considered a viable alternative to the use of conventional insecticides. In this study, we analyze the bioinsecticidal activity and repellence of patchouli essential oil (Pogostemon cablin) against three species of urban ants: Camponotus melanoticus, Camponotus novograndensis, and Dorymyrmex thoracicus. The chemical composition of the essential oil was analyzed by GC-MS and GC-FID. The major compounds were patchoulol (36.6%) followed by α-bulnesene (13.95%), and α-guaiene (11.96%). Toxicity and repellency bioassays were performed using the essential oil over the ants, and mortality evaluations were performed at 4, 24, and 48 h after performing the bioassays. Mortality percentage of the ants on 7 μg/mg was on average 84%. The essential oil of P. cablin displayed toxicity against all three species of urban ants, with the lowest LD₅₀ being observed for D. thoracicus (2.02 μg oil/mg insect) after 48 h of exposure compared to C. melanoticus (2.34 μg oil/mg insect) and C. novogranadensis (2.95 μg oil/mg insect). The essential oil of P. cablin was strongly repellent to the three species of ants in all concentrations tested (0.01% and 1% v/v). Considering the potential toxicity and repellency of the P. cablin essential oil to the urban ants, future studies could investigate the practical application of this oil to control of this insects. 23899644 A proposed rationale and test methodology for establishment of acceptance criteria for vacuum integrity testing of pharmaceutical freeze dryers. A scientific rationale is proposed for the establishment of acceptance criteria for leak rates in pharmaceutical freeze dryers. A method was developed to determine the quantity of air that could leak into any lyophilizer from the outside while still maintaining Class 100/Grade A microbial conditions. A lyophilizing product is assumed most vulnerable to microbial contamination during secondary drying, when mass transfer of water vapor from product to condenser is minimal. Using the void volume of the dryer, calculated from change in internal pressure when a known volume of air is introduced, and the potential maximum bioburden of the leaked air (based on measured values), calculations can determine the allowable leaked volume of air, the flow rate required to admit that volume in a given time frame, and the pressure rise that would result from the leak over a given testing period. For the dryers in this study, using worst-case air quality conditions, it was determined that a leak resulting in a pressure rise of 0.027 mbar over a 30min period would allow the dryers to remain in secondary drying conditions for 62h before the established action level of one colony forming unit for each cubic meter of air space would be reached. 23806115 Nuchal translucency and cardiac abnormalities in euploid singleton pregnancies. Abstract Objective: To investigate different cut-off levels of nuchal translucency (NT) to predict abnormal cardiac findings (ACF) in second trimester ultrasound examination and confirmed postnatal congenital heart defects (CHD) in euploid pregnancies. Methods: A retrospective analysis was performed on singleton pregnancies examined in our ultrasound units from 2006 to 2011. Fetuses with an abnormal karyotype were excluded. Different cut-off levels of NT thickness were analyzed to evaluate its performance to detect the ACF on second trimester ultrasound (2nd US) examination and also the CHD detected in neonatal follow-up evaluation of ACF cases. Results: Of the 12 840 cases, a total number of 8541 euploid pregnancies were included in the study. Thirty-three had ACFs detected by 2nd US (3.86/1000). The mean NT thickness was found to be higher in fetuses with ACFs (p < 0.0001). Of 33 ACFs, 17 (52%, 1.99/1000) had major CHDs in neonatal follow-up. The area under the ROC curves for NT thickness to predict ACFs and CHDs were 0.67 and 0.65, respectively. Conclusions: Higher NT thickness is associated with higher risk of ACF. NT is a weak predictor of ACF and major CHD; however, fetuses with an unexplained increase in NT measurement should be referred for further cardiac investigations. 23579428 Involvement of nNOS/NO/sGC/cGMP signaling pathway in cocaine sensitization and in the associated hippocampal alterations: does phosphodiesterase 5 inhibition help to drug vulnerability? RATIONALE: Repeated cocaine administration induces behavioral sensitization in about 50 % of treated animals. Nitric oxide could be involved in the acquisition and maintenance of behavioral cocaine effects, probably by activation of neuronal nitric oxide synthase (nNOS)/NO/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) signaling pathway, since inhibition of the nNOS enzyme attenuates development of sensitization in rats. On the other hand, increased cGMP availability by phosphodiesterase 5 inhibitors has been correlated to the misuse and recreational use of these agents and also to the concomitant use with illicit drugs in humans. Hippocampus is an important brain region for conditioning to general context previously associated to drug availability, influencing drug-seeking behavior and sensitization. Moreover, cocaine and other drugs of abuse can affect the strength of glutamate synapses in this structure, lastly modifying neuronal activity in main regions of the reward circuitry. OBJECTIVE: The objective of this study is to determine whether the pharmacological manipulation of nNOS/NO/sGC/cGMP signaling pathway altered changes induced by repeated cocaine exposure. RESULTS: The present investigation showed a relationship between behavioral cocaine sensitization, reduced threshold to generate long-term potentiation (LTP) in hippocampal dentate gyrus, and increased nNOS activity in this structure. However, when nNOS or sGC were inhibited, the number of sensitized animals was reduced, and the threshold to generate LTP was increased. The opposite occurred when cGMP availability was increased. CONCLUSION: We demonstrate a key role of the nNOS activity and NO/sGC/cGMP signaling pathway in the development of cocaine sensitization and in the associated enhancement of hippocampal synaptic transmission. 23867512 Novel targeting of phosphatidylinositol 3-kinase and Mammalian target of rapamycin in renal cell carcinoma. Allosteric inhibitors of the kinase mammalian target of rapamycin (mTOR) have demonstrated significant clinical activity in patients with advanced renal cell carcinoma (RCC). Unfortunately, substantial clinical responses to these rapalogues are seen only in a subset of patients with advanced RCC. Preclinical studies have identified multiple theoretical shortcomings of the rapalogues, and numerous novel agents directed against the phosphatidylinositol 3-kinase/Akt/mTOR pathway, which address many of these shortcomings, are in active clinical development. In this review, we discuss the preclinical and clinical experience with the rapalogues in RCC, potential mechanisms of resistance to the rapalogues, and the progress in the clinical development of novel agents directed against the phosphatidylinositol 3-kinase/Akt/mTOR pathway. 23870458 Chlamydia trachomatis infection of the male genital tract: An update. Chlamydia trachomatis (CT) is the most prevalent cause of sexually transmitted diseases. Although the prevalence of chlamydial infection is similar in men and women, current research and screening are still focused on women, who develop the most severe complications, leaving the study of male genital tract (MGT) infection underrated. Herein, we reviewed the literature on genital CT infection with special focus on the MGT. Data indicate that CT certainly infects different parts of the MGT such as the urethra, seminal vesicles, prostate, epididymis and testis. However, whether or not CT infection has detrimental effects on male fertility is still controversial. The most important features of CT infection are its chronic nature and the presence of a mild inflammation that remains subclinical in most individuals. Chlamydia antigens and pathogen recognition receptors (PRR), expressed on epithelial cells and immune cells from the MGT, have been studied in the last years. Toll-like receptor (TLR) expression has been observed in the testis, epididymis, prostate and vas deferens. It has been demonstrated that recognition of chlamydial antigens is associated with TLR2, TLR4, and possibly, other PRRs. CT recognition by PRRs induces a local production of cytokines/chemokines, which, in turn, provoke chronic inflammation that might evolve in the onset of an autoimmune process in genetically susceptible individuals. Understanding local immune response along the MGT, as well as the crosstalk between resident leukocytes, epithelial, and stromal cells, would be crucial in inducing a protective immunity, thus adding to the design of new therapeutic approaches to a Chlamydia vaccine. 23928239 Updates and Revisions to the BI-RADS Magnetic Resonance Imaging Lexicon. This article summarizes the updates and revisions to the second edition of the BI-RADS MRI lexicon. A new feature in the lexicon is background parenchymal enhancement and its descriptors. Another major focus is on revised terminology for masses and non-mass enhancement. A section on breast implants and associated lexicon terms has also been added. Because diagnostic breast imaging increasingly includes multimodality evaluation, the new edition of the lexicon also contains revised recommendations for combined reporting with mammography and ultrasound if these modalities are included as comparison, and clarification on the use of final assessment categories in MR imaging. 23786736 Sleep-laughing--hypnogely. To explain relatively common phenomenon of laughing during sleep and help to better define criteria for differentiating between physiological and pathological sleep-laughing. Observational study of patients who underwent a sleep assessment in a referential tertiary health facility. A total of ten patients exhibited sleep laughing, nine of whom had episodes associated with rapid eye movement (REM) sleep. Also, in one of the patients sleep-laughing was one of the symptoms of REM sleep Behaviour Disorder, and in another patient sleep-laughing was associated with NREM sleep arousal parasomnia. The collected data and review of literature suggests that hypnogely in majority of the cases presents as a benign physiological phenomenon related to dreaming and REM sleep. Typically, these dreams are odd, bizarre or even unfunny for a person when awake. Nevertheless, they bring a sense of mirth and a genuine behavioural response. In a minority of cases, sleep-laughing appears to be a symptom of neurological disorders affecting the central nervous system. In these patients the behavioural substrate differs when compared to physiological laughing, and the sense of mirth is usually absent. 23824214 Recovery in Remitted First-Episode Psychosis at 7 Years of Follow-up of an Early Dose Reduction/Discontinuation or Maintenance Treatment Strategy: Long-term Follow-up of a 2-Year Randomized Clinical Trial. IMPORTANCE Short-term outcome studies of antipsychotic dose-reduction/discontinuation strategies in patients with remitted first-episode psychosis (FEP) showed higher relapse rates but no other disadvantages compared with maintenance treatment; however, long-term effects on recovery have not been studied before. OBJECTIVE To compare rates of recovery in patients with remitted FEP after 7 years of follow-up of a dose reduction/discontinuation (DR) vs maintenance treatment (MT) trial. DESIGN Seven-year follow-up of a 2-year open randomized clinical trial comparing MT and DR. SETTING One hundred twenty-eight patients participating in the original trial were recruited from 257 patients with FEP referred from October 2001 to December 2002 to 7 mental health care services in a 3.2 million-population catchment area. Of these, 111 patients refused to participate and 18 patients did not experience remission. PARTICIPANTS After 7 years, 103 patients (80.5%) of 128 patients who were included in the original trial were located and consented to follow-up assessment. INTERVENTION After 6 months of remission, patients were randomly assigned to DR strategy or MT for 18 months. After the trial, treatment was at the discretion of the clinician. MAIN OUTCOMES AND MEASURES Primary outcome was rate of recovery, defined as meeting the criteria of symptomatic and functional remission. Determinants of recovery were examined using logistic regression analysis; the treatment strategy (MT or DR) was controlled for baseline parameters. RESULTS The DR patients experienced twice the recovery rate of the MT patients (40.4% vs 17.6%). Logistic regression showed an odds ratio of 3.49 (P = .01). Better DR recovery rates were related to higher functional remission rates in the DR group but were not related to symptomatic remission rates. CONCLUSIONS AND RELEVANCE Dose reduction/discontinuation of antipsychotics during the early stages of remitted FEP shows superior long-term recovery rates compared with the rates achieved with MT. To our knowledge, this is the first study showing long-term gains of an early-course DR strategy in patients with remitted FEP. Additional studies are necessary before these results are incorporated into general practice. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN16228411. 23832516 Gastrointestinal Muc5ac and Muc2 mucin O-glycan pattern reveal a regio-specific distribution - 3. Studies of mucus in mouse stomach, small intestine, and colon. The mouse intestinal mucus is mainly made up by the gel-forming Muc2 mucin and the stomach surface mucus Muc5ac, both extensively O-glycosylated. The oligosaccharide diversity provides a vast library of potential recognition sites for both commensal and pathogenic organisms. The mucin glycans are thus likely very important for the selection and maintenance of a stable intestinal flora. Here we have explored the O-glycan patterns of the mouse gastrointestinal tract mucins. The mucins from the mucus of the distal and proximal colon, ileum, jejunum, duodenum and stomach of conventionally raised wild-type (C57BL/6) mice were separated by composite gel electrophoresis. The O-linked glycans were released by reductive elimination and structurally characterized by liquid chromatography-mass spectrometry. The mucins glycans were mostly core 2 type (Galβ1-3(GlcNAcβ1-6)GalNAcol), but also core 1 (Galβ1-3GalNAcol). In the stomach Muc5ac about half of the mucin O-glycans were neutral and many monosulfated, but with a low grade of sialylation and fucosylation. Mouse ileum, jejunum and duodenum had similar glycan patterns dominated by sialylated and sulfated core 2 glycans, but few fucosylated. Colon was on the other hand dominated by highly charged fucosylated glycans. The distal colon is different from the proximal colon as different biosynthetic pathways are utilized, although sialylated and sulfated glycans were highly abundant in both parts. The sulfation was higher in the distal colon, while sialic acid was more common in the proximal colon. Many fucosylated glycans were found in both the proximal and distal colon. Thus the mucin O-glycans vary along the mouse gastrointestinal tract. 23834348 Synthesis and nonvolatile memory behaviors of dioxatetraazapentacene derivatives. Two novel heteroacenes 2,3,9,10-tetra(furan-2-yl)-1,4,8,11-tetraaza-6,13-dioxapentacene (FAOP, 1) and 2,3,9,10-tetra(thiophen-2-yl)-1,4,8,11-tetraaza-6,13-dioxapentacene (TAOP, 2) was successfully synthesized through a one-step condensation reaction, which have been fully characterized by (1)H NMR (nuclear magnetic resonance), (13)C NMR, FT-IR (Fourier transform infrared spectroscopy), and HRMS (high-resolution mass spectrum). The sandwich-structure memory devices have been fabricated using FAOP (1) and TAOP (2) as active layers, showing a typical bipolar resistive switching (RS) behavior in positive and negative regions. 23895502 Cell density during differentiation can alter the phenotype of bone marrow-derived macrophages. Bone marrow-derived macrophages (BMDMs) are widely used primary cells for studying macrophage function. However, despite numerous protocols that are currently available, lack of a notable consensus on generating BMDMs may obscure the reliability in comparing findings from different studies or laboratories. In this study, we addressed the effect of cell density on the resulting macrophage population. With reference to previously published methods, bone marrow cells from wild type C57BL/6 mice were plated at either 4 x 105 cells or 5 x 106 cells per 10 cm and cultured in 20% L-cell conditioned media for 7 days, after which they were analyzed for cell surface markers, production of proinflammatory cytokines, and responsiveness to polarizing signals. Reproducibly, cells plated at lower density gave a pure population of CD11b+F4/80+ macrophages (97.28 +/- 0.52%) with majority being Ly-6C-Ly-6G- and c-Fms+, while those plated at higher density produced less CD11b+F4/80+ cells and a considerably higher proportion of CD11b+F4/80+CD11c+ (68.72 +/- 2.52%) and Ly-6C-Ly-6G+ (71.10 +/- 0.90%) cells. BMDMs derived from higher plating density also secreted less proinflammatory cytokines such as IL-6, IL-12 and TNF-alpha and were less phagocytic, and had a different pattern of expression for M1- and M2-related genes upon LPS or IL-4 stimulation. Overall, our findings indicate that altering cell density during BMDM differentiation can give rise to distinct macrophage populations that could vary the outcome of a functional study. 22585533 β-Eudesmol induces JNK-dependent apoptosis through the mitochondrial pathway in HL60 cells. β-eudesmol, a natural sesquiterpenol present in a variety of Chinese herbs, is known to inhibit the proliferation of human tumor cells. However, the molecular mechanisms of the effect of β-eudesmol on human tumor cells are unknown. In the present study, we report the cytotoxic effect of β-eudesmol on the human leukemia HL60 cells and its molecular mechanisms. The cytotoxic effect of β-eudesmol on HL60 cells was associated with apoptosis, which was characterized by the presence of DNA fragmentation. β-eudesmol-induced apoptosis was accompanied by cleavage of caspase-3, caspase-9, and poly (ADP-ribose) polymerase; downregulation of Bcl-2 expression; release of cytochrome c from mitochondria; and decrease in mitochondrial membrane potential (MMP). Activation of c-Jun N-terminal kinases (JNK) mitogen-activated protein kinases was observed in β-eudesmol-treated HL60 cells, and the inhibitor of JNK blocked the β-eudesmol-induced apoptosis, downregulation of Bcl-2, and the loss of MMP. These data suggest that β-eudesmol induces apoptosis in HL60 cells via the mitochondrial apoptotic pathway, which is controlled through JNK signaling. Copyright © 2012 John Wiley & Sons, Ltd. 23747817 Potentially toxic contamination of sediments, water and two animal species in Lake Kalimanci, FYR Macedonia: relevance to human health. The objectives of the research were: (1) to examine the concentrations of metals in Vimba melanops and Rana temporaria and (2) to evaluate the potential risks of the contaminated organisms to human health in Makedonska Kamenica region. Analyses identified high levels of Cr, Hg, Ni and Pb in studied animals, which also exceeded their permissible levels in food. In sediment and soil samples, levels of Cd, Cu, Cr, Pb, Zn and As were perceived, while Cd, Cu, Ni, Pb, Se and As were increased in water samples. Results of transfer factor revealed that the examined animals had higher bioaccumulation rate from surrounding waters than from sediments or soils. The accomplished Health Risk Index disclosed that studied animals can have considerably high health risks for inhabitants. Conclusively, they could be considered as highly contaminated with metals and can consequently harm human health, especially children in their early development stages. 23149860 Economics of the hydrolysis of cellulosic sludge to glucose. Cellulosic sludge from paper mills making bleached products can be enzymatically converted to glucose. A kinetic model that accounts for product inhibition was used to estimate the cost:benefits of the process. In the proposed scheme, the sludge is enzymatically hydrolyzed in a sequence of CSTRs, the ash separated, and the product glucose concentrated through reverse osmosis. The water recovered is mostly recycled. By far, the most important economic variable is the value of the glucose. However, even if the glucose is assumed to be of no value the avoided cost of sludge disposal approximately offsets the process costs. The approach should generate significant revenue if the glucose is valued at market. 23949016 Five-year clinical performance of a HEMA-free one-step self-etch adhesive in noncarious cervical lesions. The objective of this randomized controlled trial was to evaluate the clinical performance of a 2-hydroxyethyl methacrylate (HEMA)-free one-step adhesive. Two hundred sixty-seven cervical lesions in 52 patients were restored with the composite Gradia Direct (GC), bonded with either the one-step self-etch adhesive G-Bond (GC) or the three-step etch-and-rinse adhesive Optibond FL (Kerr) in a random order. The restorations were evaluated for retention, marginal integrity, marginal discoloration, and caries occurrence after 5 years. Specific statistics were used to account for the clustered data (multiple restorations per patient). The clinical success rate for G-Bond (87.4 %) was not significantly different from that of Optibond FL (90.9 %). Both adhesives showed progressive marginal deterioration, but G-Bond exhibited more small enamel defects and marginal discoloration, and unlike previous recalls, several restorations failed because of deep microleakage. Large sclerotic lesions were a significant risk factor for retention loss with G-Bond. Irrespective of the adhesive, almost all restorations with retention loss were located in the lower jaw. After 5 years of clinical service, restorations bonded with the HEMA-free one-step adhesive did not need repair or replacement more often than those with the three-step etch-and-rinse adhesive, and both adhesives had a high retention rate (>90 %). There were indications that G-Bond did not (self-)etch enough in some clinical situations, as G-Bond exhibited more incisal defects and marginal discolorations, and sclerotic lesions were at higher risk of retention loss. The clinical performance of the HEMA-free one-step adhesive was clinically acceptable after 5 years. 23665226 Cationized IVIg as a potential substitute to IVIg for the treatment of experimental immune thrombocytopenia. In this study, we evaluated the possibility of using cationized IVIg (cIVIg) instead of IVIg as a more effective therapy for the treatment of experimental immune thrombocytopenia in mice. The pharmacokinetics (PK) and biodistribution of cIVIg and IVIg in mice were compared. cIVIg displayed a shorter plasma half-life and an increased organ uptake in both the spleen and liver compared to IVIg, suggesting that cIVIg could be more potent than IVIg to prevent platelet clearance in a mouse model of thrombocytopenia. However, although the biodistribution of cIVIg in the spleen and liver was improved, its ability to prevent platelet clearance in mice remained similar to that of IVIg. Altogether, our data demonstrate the possibility of using chemical cationization of IVIg preparations to increase organ uptake, and also highlight the challenges of developing effective substitutes to IVIg. 23843263 Phosphinine Lipids: A Successful Marriage between Electron-Acceptor and Self-Assembly Features. A push in the right direction: An electron-accepting organophosphorus system has been combined with self-assembly features to create a strongly electron-accepting liquid-crystalline material. The stability and behavior of the self-assembled liquid crystal could be controlled by adjusting weak intermolecular forces, such as hydrogen bonding and π-π interactions. 23884110 Double recognition of dopamine based on a boronic acid functionalized poly(aniline-co-anthranilic acid)-molecularly imprinted polymer composite. In this work, we report a competitive sensor performing "double recognition" for the specific capture of dopamine (DA) with the combination of boronic acid functional groups and molecularly imprinted cavities based on poly(aniline-co-anthranilic acid) (PANANA) as the support material. This novel imprinting receptor bearing a covalent ester linkage to DA via boronic acid functional groups was prepared and applied as a recognition element in the construction of the electrochemical sensor. For the first time, aminophenylboronic acids (APBAs) and vinyl groups were both introduced onto the surface of PANANA nanomaterials. Then, selective copolymerization of acrylamide and ethylene glycol dimethacrylate (EGDMA) in the presence of the template DA was further achieved at the surface of APBA and vinyl group functionalized PANANA. The double recognition through the functional groups (boronic acids) and the shape of the cavities endowed this sensor with a specific affinity for the template DA in the presence of other interferents, such as norepinephrine (NE), epinephrine (EP), ascorbic acid (AA) and uric acid (UA). Moreover, the results obtained from a series of electrochemical experiments proved that this receptor had a good adsorption capacity and a fast mass transfer rate for DA. Thus, a novel electrochemical sensor with good selectivity and sensitivity was constructed with a linear response to the DA concentration in the range from 1.0 × 10(-8) to 1.0 × 10(-5) M and a detection limit of 3.33 × 10(-9) M (S/N = 3). Besides, this novel electrochemical sensor was successfully applied to the detection of DA in DA injected and human plasma samples. 23820070 Associations of TCF12, CTNNAL1 and WNT10B gene polymorphisms with litter size in pigs. In previous research, several WNT signaling pathway genes including transcription factor 12 (TCF12), catenin alpha-like protein 1 (CTNNAL1) and wingless-type MMTV integration site family, member 10B (WNT10B) were differentially expressed in PMSG-hCG stimulated preovulatory ovarian follicles of Large White and Chinese Taihu sows. In the present research, these three genes were selected as the candidate genes for litter size traits in pigs. Four mutations (TCF12 c.-201+65 G>A, TCF12 c.-200-300 G>A, CTNNAL1 c.1878 G>C and WNT10B c.*12 C>T) were detected in eleven pig populations, and results indicated CTNNAL1 c.1878 G and WNT10B c.*12 C were the major alleles in all tested pig populations, while TCF12 c.-201+65 A and TCF12 c.-200-300 A were the major alleles in several Chinese native pig breeds. Association analysis of four mutations with litter size in Large White and DIV pigs showed that both the signficant differences of total number born (TNB) and number born alive (NBA) among three genotypes and the significance of additive effects appeared at TCF12 c.-200-300 G>A and CTNNAL1 c.1878 G>C loci, suggesting these two mutations might be reliable markers for pig selection and breeding. 23943697 Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow-up of 1 323 275 person years. To determine whether maternal obesity during pregnancy is associated with increased mortality from cardiovascular events in adult offspring. Record linkage cohort analysis. Birth records from the Aberdeen Maternity and Neonatal databank linked to the General Register of Deaths, Scotland, and the Scottish Morbidity Record systems. 37 709 people with birth records from 1950 to present day. Death and hospital admissions for cardiovascular events up to 1 January 2012 in offspring aged 34-61. Maternal body mass index (BMI) was calculated from height and weight measured at the first antenatal visit. The effect of maternal obesity on outcomes in offspring was tested with time to event analysis with Cox proportional hazard regression to compare outcomes in offspring of mothers in underweight, overweight, or obese categories of BMI compared with offspring of women with normal BMI. All cause mortality was increased in offspring of obese mothers (BMI >30) compared with mothers with normal BMI after adjustment for maternal age at delivery, socioeconomic status, sex of offspring, current age, birth weight, gestation at delivery, and gestation at measurement of BMI (hazard ratio 1.35, 95% confidence interval 1.17 to 1.55). In adjusted models, offspring of obese mothers also had an increased risk of hospital admission for a cardiovascular event (1.29, 1.06 to 1.57) compared with offspring of mothers with normal BMI. The offspring of overweight mothers also had a higher risk of adverse outcomes. Maternal obesity is associated with an increased risk of premature death in adult offspring. As one in five women in the United Kingdom is obese at antenatal booking, strategies to optimise weight before pregnancy are urgently required. 23770930 Controlled synthesis of a catalytically active hybrid metal-oxide incorporated zeolitic imidazolate framework (MOZIF). A rare hybrid Metal-Oxide incorporated Zeolitic Imidazolate Framework, MOZIF-1, containing tetrahedral Zn(II) and Mo(VI) centres has been synthesized. MOZIF-1 can degrade methyl orange and orange II dyes under visible light. Na3[PMo12O40] is the source of Mo(VI) in MOZIF-1. 23936473 GPR88 Reveals a Discrete Function of Primary Cilia as Selective Insulators of GPCR Cross-Talk. A number of G protein-coupled receptors (GPCRs) localize to primary cilia but the functional significance of cilia to GPCR signaling remains incompletely understood. We investigated this question by focusing on the D1 dopamine receptor (D1R) and beta-2 adrenergic receptor (B2AR), closely related catecholamine receptors that signal by stimulating production of the diffusible second messenger cyclic AMP (cAMP) but differ in localization relative to cilia. D1Rs robustly concentrate on cilia of IMCD3 cells, as shown previously in other ciliated cell types, but disrupting cilia did not affect D1R surface expression or ability to mediate a concentration-dependent cAMP response. By developing a FRET-based biosensor suitable for resolving intra- from extra- ciliary cAMP changes, we found that the D1R-mediated cAMP response is not restricted to cilia and extends into the extra-ciliary cytoplasm. Conversely the B2AR, which we show here is effectively excluded from cilia, also generated a cAMP response in both ciliary and extra-ciliary compartments. We identified a distinct signaling effect of primary cilia through investigating GPR88, an orphan GPCR that is co-expressed with the D1R in brain, and which we show here is targeted to cilia similarly to the D1R. In ciliated cells, mutational activation of GPR88 strongly reduced the D1R-mediated cAMP response but did not affect the B2AR-mediated response. In marked contrast, in non-ciliated cells, GPR88 was distributed throughout the plasma membrane and inhibited the B2AR response. These results identify a discrete 'insulating' function of primary cilia in conferring selectivity on integrated catecholamine signaling through lateral segregation of receptors, and suggest a cellular activity of GPR88 that might underlie its effects on dopamine-dependent behaviors. 23954199 Structure-activity relationships for perfluoroalkane-induced in vitro interference with rat liver mitochondrial respiration. Perfluorinated alkyl acids (PFAAs) represent a broad class of commercial products designed primarily for the coatings industry. However, detection of residues globally in a variety of species led to the discontinuation of production in the U.S. Although PFAAs cause activation of the PPARα and CAR nuclear receptors, interference with mitochondrial bioenergetics has been implicated as an alternative mechanism of cytotoxicity. Although the mechanisms by which the eight carbon chain PFAAs interfere with mitochondrial bioenergetics are fairly well described, the activities of the more highly substituted or shorter chain PFAAs are far less well characterized. The current investigation was designed to explore structure-activity relationships by which PFAAs interfere with mitochondrial respiration in vitro. Freshly isolated rat liver mitochondria were incubated with one of 16 different PFAAs, including perfluorinated carboxylic, acetic, and sulfonic acids, sulfonamides and sulfamido acetates, and alcohols. The effect on mitochondrial respiration was measured at five concentrations and dose-response curves were generated to describe the effects on state 3 and 4 respiration and respiratory control. With the exception of PFOS, all PFAAs at sufficiently high concentrations (>20μM) stimulated state 4 and inhibited state 3 respiration. Stimulation of state 4 respiration was most pronounced for the carboxylic acids and the sulfonamides, which supports prior evidence that the perfluorinated carboxylic and acetic acids induce the mitochondrial permeability transition, whereas the sulfonamides are protonophoric uncouplers of oxidative phosphorylation. In both cases, potency increased with increasing carbon number, with a prominent inflection point between the six and eight carbon congeners. The results provide a foundation for classifying PFAAs according to specific modes of mitochondrial activity and, in combination with toxicokinetic considerations, establishing structure-activity-based boundaries for initial estimates of risk for noncancer endpoints for PFAAs for which minimal in vivo toxicity testing currently exists. 23956398 Molecular analysis of the Acinetobacter baumannii biofilm-associated protein. Acinetobacter baumannii is a multidrug resistant pathogen associated with hospital outbreaks of infection across the globe, particularly in the intensive care unit. The ability of A. baumannii to survive in the hospital environment for long periods is linked to antibiotic resistance and its capacity to form biofilms. Here we studied the prevalence, expression and function of the A. baumannii biofilm-associated protein (Bap) in 24 carbapenem-resistant A. baumannii ST92 strains isolated from a single institution over a 10-year period. The bap gene was highly prevalent, with 22/24 strains positive for bap by PCR. Partial sequencing of bap was performed on the index case strain MS1968 and revealed it to be a large and highly repetitive gene approximately 16 kb in size. Phylogenetic analysis employing a 1,948 amino acid region corresponding to the C-terminus of Bap showed BapMS1968 clusters with Bap sequences from clonal complex (CC) 2 strains ACICU, TCDC-AB0715 and 1656-2, and is distinct from CC1 strains. Using overlapping PCR, the bapMS1968 gene was cloned and its expression in a recombinant E. coli strain resulted in increased biofilm formation. A Bap-specific antibody was generated and western blot analysis showed the majority of A. baumannii strains expressed an ∼200 kDa Bap protein. Further analysis of three Bap-positive A. baumannii strains demonstrated Bap is expressed at the cell surface and is associated with biofilm formation. Finally, biofilm formation by these Bap-positive strains could be inhibited by affinity-purified Bap antibodies, demonstrating the direct contribution of Bap to biofilm growth by A. baumannii clinical isolates. 23644005 Fluorosurfactant-capped gold nanoparticles-based label-free colorimetric assay for Au³⁺ with tunable dynamic range via a redox strategy. Gold nanoparticles-based colorimetric assay possesses several unique advantages, and has been applied for a wide range of targets, varying from nucleic acids to different metal ions. However, due to the lack of proper coordinating ligand, gold nanoparticles-based colorimetric sensing system for Au³⁺ has not been developed so far. It is well-known that Au³⁺ could induce the oxidation transition of thiol compounds to disulfide compounds. In this article, for the first time we converted such thiol masking reaction into colorimetric sensing system for label-free detection of Au³⁺ via a target-controlled aggregation of nanoparticles strategy. In the new proposed sensing system, fluorosurfactant-capped gold nanoparticles were chosen as signal reporter units, while an Au³⁺-triggered oxidation of cysteine (Cys), which inhibited the aggregation of gold nanoparticles, acted as the recognition unit. By varying the amount of Cys, a tunable response range accompanied with different windows of color change could be obtained for Au³⁺, illustrating the universality of the sensing system for Au³⁺ samples with different sensitivity requirements. Under optimized condition, the proposed sensing system exhibits a high sensitivity towards Au³⁺ with a detection limit of 50 nM, which is lower than previously reported spectroscopic methods. It has also been applied for detection of Au³⁺ in practical water samples with satisfactory result. 23837874 Detection of muramyl dipeptide-sensing pathway defects in monocytes of patients with Crohn's disease using phospho-specific whole blood flow cytometry. Peripheral blood mononuclear cells of Crohn's disease (CD) patients with the common 1007fs mutation of the caspase recruitment domain-containing 15/nucleotide-binding oligomerization domain-containing 2 (CARD15/NOD2) gene show impaired nuclear factor kappa B (NF-κB) activation in response to muramyl dipeptide (MDP), as determined by Western blotting. We applied phospho-specific flow cytometry to examine NF-κB and p38 activation in whole blood monocytes of 16 CD patients with or without the 1007fs and previously described rare mutations of the CARD15 gene, and healthy reference subjects. Aliquots of whole blood were supplemented with MDP (0-1000 ng/mL), incubated for 10-40 min and processed for flow cytometry. Bacterial lipopolysaccharide (LPS) was used as a positive control agonist. We found that NF-κB and p38 phosphorylation induced by MDP was not detectable in monocytes of patients homozygous for the CARD15 1007fs mutation, while those induced by LPS were normal. We also determined MDP-induced NF-κB phosphorylation levels in nuclear extracts of mononuclear cells separated from blood using enzyme-linked immunosorbent assay (ELISA), and observed that the levels decreased in a 1007fs mutation-dose dependent manner. We conclude that phospho-specific whole blood flow cytometry provides a means to study phosphorylation of NF-κB and p38 in clinical samples and can be applied to screening of CD patients homozygous for the CARD15 1007fs mutation. 23931656 Barriers to mental health treatment: results from the WHO World Mental Health surveys. To examine barriers to initiation and continuation of mental health treatment among individuals with common mental disorders. Method Data were from the World Health Organization (WHO) World Mental Health (WMH) surveys. Representative household samples were interviewed face to face in 24 countries. Reasons to initiate and continue treatment were examined in a subsample (n = 636 78) and analyzed at different levels of clinical severity. Among those with a DSM-IV disorder in the past 12 months, low perceived need was the most common reason for not initiating treatment and more common among moderate and mild than severe cases. Women and younger people with disorders were more likely to recognize a need for treatment. A desire to handle the problem on one's own was the most common barrier among respondents with a disorder who perceived a need for treatment (63.8%). Attitudinal barriers were much more important than structural barriers to both initiating and continuing treatment. However, attitudinal barriers dominated for mild-moderate cases and structural barriers for severe cases. Perceived ineffectiveness of treatment was the most commonly reported reason for treatment drop-out (39.3%), followed by negative experiences with treatment providers (26.9% of respondents with severe disorders). Low perceived need and attitudinal barriers are the major barriers to seeking and staying in treatment among individuals with common mental disorders worldwide. Apart from targeting structural barriers, mainly in countries with poor resources, increasing population mental health literacy is an important endeavor worldwide. 23287887 A prospective, case-control study on the lipid profile and the cardiovascular risk of menopausal women on oestrogen plus progestogen therapy in a northern Italy province. To evaluate the effects of oestrogen plus progestogen therapy (EPT) on the lipid metabolism of menopausal patients. We conducted a prospective study on 223 patients with clinical and blood chemistry diagnosis of menopause, who were eligible for hormone therapy and a follow-up period lasting at least 5 years. We selected a control group. Patients attended annual or 6-monthly visits for the duration of the 5-year follow-up period. For each patient, total-cholesterol, HDL-cholesterol, LDL-cholesterol and triglyceride values were considered at the first visit and after 5 years. We compared these values of the above parameters in relation to time and EPT and the repercussions that the presence/absence of replacement therapy had in terms of lipid profile alteration between the groups studied. Of the 223 patients eligible for enrolment, 178 made up the study group (EPT Group) and 45 made up the control cohort (N-EPT-Group). At the first visit, median value was (EPT-Group vs. N-EPT-Group): cholesterol was 240 versus 226 mg/dL, LDL-cholesterol 169 versus 174 mg/dL, HDL-cholesterol 60 mg/dL in both groups, triglyceride 125 versus 92 mg/dL (p:n.s). Five years later, median value was (EPT-Group versus N-EPT-Group): cholesterol 225 versus 236 mg/dL (p < 0.001), LDL-cholesterol 125 versus 184 mg/dL (p < 0.001), HDL-cholesterol 64 versus 68 mg/dL (p:n.s.), triglyceride 72 versus 94 mg/dL (p:n.s.). No adverse effects of EPT were observed. Thorough risk/benefit assessment, associated with initially low doses and without rigid cutoffs, particularly when started early, EPT can be made a valid means of cardiovascular prevention, specifically because it positively alters the lipid profile of menopausal women. 23333577 Suppression of Src/ERK and GSK-3/β-catenin signaling by pinosylvin inhibits the growth of human colorectal cancer cells. Pinosylvin, a naturally occurring trans-stilbenoid mainly found in Pinus species, has exhibited a potential cancer chemopreventive activity. However, the growth inhibitory activity against cancer cells and the underlying molecular mechanisms remain to be elucidated. Therefore, the anti-proliferative activity of pinosylvin was investigated in human colorectal HCT 116 cancer cells. Pinosylvin inhibited the proliferation of HCT 116 cells by arresting transition of cell cycle from G1 to S phase along with the downregulation of cyclin D1, cyclin E, cyclin A, cyclin dependent kinase 2 (CDK2), CDK4, c-Myc, and retinoblastoma protein (pRb), and the upregulation of p21(WAF1/CIP1) and p53. Pinosylvin was also found to attenuate the activation of proteins involved in focal adhesion kinase (FAK)/c-Src/extracellular signal-regulated kinase (ERK) signaling, and phosphoinositide 3-kinase (PI3K)/Akt/ glycogen synthase kinase 3β (GSK-3β) signaling pathway. Subsequently, pinosylvin suppressed the nuclear translocation of β-catenin, one of downstream molecules of PI3K/Akt/GSK-3β signaling, and these events led to the sequential downregulation of β-catenin-mediated transcription of target genes including BMP4, ID2, survivin, cyclin D1, MMP7, and c-Myc. These findings demonstrate that the anti-proliferative activity of pinosylvin might be associated with the cell cycle arrest and downregulation of cell proliferation regulating signaling pathways in human colorectal cancer cells. 23747753 Organic anion-transporting polypeptide 1a4 (Oatp1a4) is important for secondary bile acid metabolism. Organic anion transporting polypeptides (human: OATPs; rodent: Oatps) were thought to have important functions in bile acid (BA) transport. Oatp1a1, 1a4, and 1b2 are the three major Oatp1 family members in rodent liver. Our previous studies have characterized the BA homeostasis in Oatp1a1-null and Oatp1b2-null mice. The present study investigated the physiological role of Oatp1a4 in BA homeostasis by using Oatp1a4-null mice. Oatp1a4 expression is female-predominant in livers of mice, and thereby it was expected that female Oatp1a4-null mice will have more prominent changes than males. Interestingly, the present study demonstrated that female Oatp1a4-null mice had no significant alterations in BA concentrations in serum or liver, though they had increased mRNA of hepatic BA efflux transporters (Mrp4 and Ostα/β) and ileal BA transporters (Asbt and Ostα/β). In contrast, male Oatp1a4-null mice showed significantly altered BA homeostasis, including increased concentrations of deoxycholic acid (DCA) in serum, liver and intestinal contents. After feeding a DCA-supplemented diet, male but not female Oatp1a4-null mice had higher concentrations of DCA in serum and livers than their WT controls. This suggested that Oatp1a4 is important for intestinal absorption of secondary BAs in male mice. Furthermore, loss of Oatp1a4 function did not decrease BA accumulation in serum or livers of bile-duct-ligated mice, suggesting that Oatp1a4 is not likely a BA uptake transporter. In summary, the present study for the first time demonstrates that Oatp1a4 does not appear to mediate the hepatic uptake of BAs, but plays an important male-predominant role in secondary BA metabolism in mice. 23758203 Improving Electrical Conductivity in Polycarbonate Nanocomposites Using Highly Conductive PEDOT/PSS Coated MWCNTs. We describe a strategy to design highly electrically conductive polycarbonate nanocomposites by using multiwalled carbon nanotubes (MWCNTs) coated with a thin layer of poly(3,4-ethylenedioxythiophene)/poly(styrenesulfonate), a conductive polymer. We found that this coating method improves the electrical properties of the nanocomposites in two ways. First, the coating becomes the main electrical conductive path. Second, the coating promotes the formation of a percolation network at a low filler concentration (0.3 wt %). To tailor the electrical properties of the conductive polymer coating, we used a polar solvent ethylene glycol, and we can tune the final properties of the nanocomposite by controlling the concentrations of the elementary constituents or the intrinsic properties of the conductive polymer coating. This very flexible technique allows for tailoring the properties of the final product. 23727181 Effects of taraxasterol on ovalbumin-induced allergic asthma in mice. Taraxasterol was isolated from the Chinese medicinal herb Taraxacum officinale which has been frequently used as a remedy for inflammatory diseases. In the present study, we determined the in vivo protective effect of taraxasterol on allergic asthma induced by ovalbumin (OVA) in mice. Mice were sensitized and challenged with OVA, and were orally treated daily with taraxasterol at 2.5, 5 and 10mg/kg from day 23 to 27 after sensitization. The number of inflammatory cells in bronchoalveolar lavage fluid (BALF) was determined. Th2 cytokine interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-13 (IL-13) production in BALF and OVA-specific immunoglobulin E (IgE) production in sera were measured using ELISA. Histological changes in lung tissues were examined using hematoxylin and eosin (H&E) and periodic acid-Schiff staining (PAS). Airway hyperresponsiveness (AHR) to inhaled methacholine was assessed. Taraxasterol dramatically decreased the total inflammatory cell and main inflammatory cell counts, reduced the production of Th2 cytokine IL-4, IL-5, IL-13 in BALF and OVA-specific IgE in sera, and suppressed AHR in a dose-dependent manner. Histological studies demonstrated that taraxasterol substantially suppressed OVA-induced inflammatory cells infiltration into lung tissues and goblet cell hyperplasia in airways. This finding suggests that taraxasterol protects against OVA-induced allergic asthma in mice. 23964677 Polyketides from the Littoral Plant Associated Fungus Pseudallescheria boydii. Four previously unreported chemical entities, boydone A (1), boydone B (2), botryorhodine F (3), and botryorhodine G (4), along with five known compounds, fusidilactone A (5), (R)-(-)-mevalonolactone (6), (R)-(-)-lactic acid (7), ovalicin (8), and botryorhodine C (9), were isolated from the ethyl acetate extracts of the fermented broths of the fungal strain Pseudallescheria boydii NTOU2362. The structures of 1-9 were characterized on the basis of their spectroscopic data analyses. The absolute configurations of 1 and 2 were established by comparison with the literature and the modified Mosher's method. The growth inhibitory activities of 1-9 against the A549 non-small-cell lung cancer cell line were evaluated, and 2 and 8 exhibited moderate to potent bioactivities with GI50 values of 41.3 and 4.1 μM, respectively, in comparison with fluorouracil (GI50 = 3.6 μM). 23860845 Biocatalysts for cascade reaction: porcine pancreas lipase (PPL)-catalyzed synthesis of bis(indolyl)alkanes. A cascade reaction between aldehydes and indole catalyzed by lipase from porcine pancreas Type II (PPL) in solvent mixture at 50 °C was reported for the first time. Some control experiments had been designed to demonstrate that the PPL was responsible for the cascade reaction. After the optimization of the stepwise process, a series of bis(indolyl)alkanes were prepared in moderate to excellent yields under the catalysis of PPL. 23868860 Study of the Selective Uptake Progress of Aptamer-Modified PLGA Particles by Liver Cells. It is of paramount importance to study the cellular uptake processes of particles with defined surface property, especially the uptake pathways and intracellular transportation. In this study, aptamer AS1411 molecules, which are known to specifically bind the over-expressed nucleolin on cancer cell membrane, were conjugated onto bovine serum albumin-decorated poly(D,L-lactide-co-glycolide; PLGA, Φ400 nm) particles with a density of 1-1.7 molecule/10 nm(2) . The aptamer-modified PLGA particles were preferably ingested by liver cancer cells with higher amount and faster rate. The clathrin-mediated endocytosis and macropinocytosis pathways played a more important role in uptake of the aptamer modified particles. 23944210 Temperature management of non-elective intensive care patients without neurological abnormalities: a point prevalence study of practice in Australia and New Zealand. To determine the frequency of pharmacological and physical cooling in non-elective general intensive care unit patients without neurological abnormalities in Australia and New Zealand, and to establish the indications for antipyretics, the prevalence of fever, and the methods of temperature measurement. A point prevalence study conducted on two days in 2010, in 38 ICUs in Australia and New Zealand, examining non-elective (emergency) patients admitted with sepsis and other inflammatory abnormalities but without neurological abnormalities. Of 506 general ICU patients surveyed on the study days, 311 had sepsis or other inflammatory abnormalities and no neurological abnormalities. These patients had a mean peak temperature of 37.3°C (SD, 0.8°C). In 100 patients (32.2%), the peak temperature was above 38°C. Paracetamol was the most common antipyretic used (152/311; 48.9%) and was administered for pain in 92/152 patients (60.5%), for pain and fever in 26/152 patients (17.1%), and for fever alone in 14/152 patients (9.2%). Patients who received paracetamol for fever had a mean peak recorded temperature of 38.3°C (SD, 0.8°C). Temperature measurements were mainly non-core (251/ 311; 81%) with axillary (116/311; 37%) and tympanic (110/ 311; 35%) measurements the most common. Pharmacological antipyretics are used regularly for pain management rather than fever management, with paracetamol the most common antipyretic therapy. The use of NSAIDS and physical cooling is rare. Non-core temperature measurements were common. 23642540 Small RNA populations for two unrelated viruses exhibit different biases in strand polarity and proximity to terminal sequences in the insect host Homalodisca vitripennis. Next generation sequence analyses were used to assess virus-derived small RNA (vsRNA) profiles for Homalodisca coagulata virus-1 (HoCV-1), family Dicistroviridae, and Homalodisca vitripennis reovirus (HoVRV), family Reoviridae, from virus-infected H. vitripennis, the glassy-winged sharpshooter. The vsRNA reads were mapped against the monopartite genome of HoCV-1 and all 12 genome segments of HoVRV, and 21nt vsRNAs were most common. However, strikingly contrasting patterns for the HoCV-1 and HoVRV genomic RNAs were observed. The majority of HoCV-1 vsRNAs mapped to the genomic positive-strand RNA and, although minor hotspots were observed, vsRNAs mapped across the entire genomic RNA. In contrast, HoVRV vsRNAs mapped to both positive and negative-sense strands for all genome segments, but different genomic segments showed distinct hotspots. The HoVRV vsRNAs were more common for 5' and 3' regions of HoVRV regions of all segments. These data suggest that taxonomically different viruses in the same host offer different targets for RNA-antiviral defense. 23742993 A recombinant measles vaccine expressing chikungunya virus-like particles is strongly immunogenic and protects mice from lethal challenge with chikungunya virus. Chikungunya virus (CHIKV), a mosquito-transmitted alphavirus, recently reemerged in the Indian Ocean, India and Southeast Asia, causing millions of cases of severe polyarthralgia. No specific treatment to prevent disease or vaccine to limit epidemics is currently available. Here we describe a recombinant live-attenuated measles vaccine (MV) expressing CHIKV virus-like particles comprising capsid and envelope structural proteins from the recent CHIKV strain La Reunion. Immunization of mice susceptible to measles virus induced high titers of CHIKV antibodies that neutralized several primary isolates. Specific cellular immune responses were also elicited. A single immunization with this vaccine candidate protected all mice from a lethal CHIKV challenge, and passive transfer of immune sera conferred protection to naïve mice. Measles vaccine is one of the safest and most effective human vaccines. A recombinant MV-CHIKV virus could make a safe and effective vaccine against chikungunya that deserves to be further tested in human trials. 23892559 Why do some patients prefer to leave decisions up to the doctor: lack of self-efficacy or a matter of trust? Decision-making preferences among cancer survivors during their follow-up care remains understudied and limited research examines factors that underlie these preferences. The purpose of this study was to assess cancer patients' decision-making preferences during follow-up care, the role of trust and self-efficacy, and the effect of preferences on health outcomes. Six hundred twenty-three bladder, leukemia, and colorectal cancer survivors were recruited to the Assessment of Patient Experiences of Cancer Care study between April 2003 and November 2004. Respondents were asked about their follow-up care experiences, including decision-making preferences, trust in physicians, self-efficacy, health-related quality of life (HRQOL), and health appraisal. Unadjusted mean scores of trust and self-efficacy measures by decision preference group were examined. Multinomial logistic and linear regressions were conducted to examine predictors of decision-making preferences and the impact of decision-making preferences on HRQOL and health appraisal. While the majority of patients preferred shared decision-making (61.0 %), 16.1 % preferred to control their decisions and 22.1 % preferred physician control over decisions. Compared to the other groups, patients preferring physician control had greater trust in their physician (p < 0.001), similar self-efficacy for engaging in the decision-making process, and lower self-efficacy for taking responsibility over decisions (p < 0.001). There were no notable differences between decision-making groups on outcome measures. Patients who prefer physicians to control decisions are as confident about participating in the decision-making process and experience similar health outcomes as those preferring greater decisional control. Physicians need to tailor their communication behavior to encourage participation and trust among all patients. Findings from this study provide unique insights into the decision-making preferences of cancer patients during receipt of follow-up care, which remains an understudied phase of cancer care delivery. Results underscore the need for approaches to decision-making and patient engagement to become more nuanced and to encourage patients to participate in decision-making in ways they are most comfortable. Furthermore, physicians and health care professionals should foster environments that promote trust and clear communication regardless of patient decision-making styles. 22265583 Risk of myocardial infarction in women with pelvic inflammatory disease. There is evidence that chronic inflammation may promote atherosclerotic disease. The purpose of this study was to test the hypothesis that pelvic inflammatory disease (PID) is a risk marker for myocardial infarction (MI). Using the Taiwan Longitudinal Health Insurance Database 2005 (LHID2005), this cohort study comprised patients with a recorded diagnosis of PID (N=68,668) between January 1, 2004 and December 31, 2005, with age-matched controls (1:2) (N=136,906). Each patient was followed-up using entry data until the end of 2006. Cox proportional hazard regressions were used to evaluate the up to 3-year MI-free survival rates, after adjusting for known confounding factors. We found that patients with PID were more likely to have MI than the control population after adjusting for potential confounders [adjusted hazard ratio (HR), 1.86, 95% confidence interval (CI), 1.23-2.81]. When stratified by patient's age, the adjusted HR for MI was 2.09 (95% CI, 1.24-3.52) for patients with PID aged over 55 years. However, the adjusted HR for MI occurring was not significant for patients with PID aged ≤ 55 years. PID is a risk marker for MI that is independent of traditional MI risk factors. Further research in this important area of public health is warranted. 23068768 Voluntary exercise does not ameliorate spatial learning and memory deficits induced by chronic administration of nandrolone decanoate in rats. Chronic exposure to the anabolic androgenic steroids (AAS) nandrolone decanoate (ND) in supra-physiological doses is associated with learning and memory impairments. Given the well-known beneficial effects of voluntary exercise on cognitive functions, we examined whether voluntary exercise would improve the cognitive deficits induced by chronic administration of ND. We also investigated the effects of ND and voluntary exercise on hippocampal BDNF levels. The rats were randomly distributed into 4 experimental groups: the vehicle-sedentary group, the ND-sedentary group, the vehicle-exercise group, and the ND-exercise group. The vehicle-exercise and the ND-exercise groups were allowed to freely exercise in a running wheel for 15 days. The vehicle-sedentary and the ND-sedentary groups were kept sedentary for the same period. Vehicle or ND injections were started 14 days prior to the voluntary exercise and continued throughout the 15 days of voluntary exercise. After the 15-day period, the rats were trained and tested on a water maze spatial task using four trials per day for 5 consecutive days followed by a probe trial two days later. Exercise significantly improved performance during both the training and retention of the water maze task, and enhanced hippocampal BDNF. ND impaired spatial learning and memory, and this effect was not rescued by exercise. ND also potentiated the exercise-induced increase in hippocampal BDNF levels. These results seem to indicate that voluntary exercise is unable to improve the disruption of cognitive functions by chronic ND. Moreover, increased levels of BDNF may play a role in ND-induced impairments in learning and memory. The harmful effects of ND and other AAS on learning and memory should be taken into account when athletes decide to use AAS for performance or body image improvement. 23915323 A pool of peptides extracted from wheat bud chromatin inhibits tumor cell growth by causing defective DNA synthesis. We previously reported that a pool of low molecular weight peptides can be extracted by alkali treatment of DNA preparations obtained from prokaryotic and eukaryotic cells after intensive deproteinization. This class of peptides, isolated from wheat bud chromatin, induces growth inhibition, DNA damage, G2 checkpoint activation and apoptosis in HeLa cells. In this work we studied their mechanism of action by investigating their ability to interfere with DNA synthesis. BrdUrd comet assays were used to detect DNA replication defects during S phase. DNA synthesis, cell proliferation, cell cycle progression and DNA damage response pathway activation were assessed using 3H-thymidine incorporation, DNA flow cytometry and Western blotting, respectively. BrdUrd labelling close to DNA strand discontinuities (comet tails) detects the number of active replicons. This number was significantly higher in treated cells (compared to controls) from entry until mid S phase, but markedly lower in late S phase, indicating the occurrence of defective DNA synthesis. In mid S phase the treated cells showed less 3H-thymidine incorporation with respect to the controls, which supports an early arrest of DNA synthesis. DNA damage response activation was also shown in both p53-defective HeLa cells and p53-proficient U2OS cells by the detection of the phosphorylated form of H2AX after peptide treatment. These events were accompanied in both cell lines by an increase in p21 levels and, in U2OS cells, of phospho-p53 (Ser15) levels. At 24 h of recovery after peptide treatment the cell cycle phase distribution was similar to that seen in controls and CDK1 kinase accumulation was not detected. The data reported here show that the antiproliferative effect exhibited by these chromatin peptides results from their ability to induce genomic stress during DNA synthesis. This effect seems to be S-phase specific since surviving cells are able to progress through their normal cell cycle when the peptide fraction is removed from the culture medium. It is likely that the subsequent apoptosis is a consequence of the failed attempt of the tumour cells to repair the DNA damage induced by the peptides. 23757119 How Long Should Women with Postmenopausal Osteoporosis be Treated with a Bisphosphonate? Bisphosphonates are very frequently prescribed to women suffering from postmenopausal osteoporosis with or without fragility fractures. The present review was aimed to update the available information on the most efficient treatment duration. Studies on bisphosphonate treatment duration were identified by Medline up to January 2013. Bisphosphonates are very effective in the short as well as in the medium-term. However, the optimal duration of use has not been determined yet. Therefore, this review summarizes the long-term effects of bisphosphonates on surrogate parameters of fracture prevention, bone mineral density measurements, and bone turnover markers. An initial treatment period of 3-5 years is recommended. Then, the patient has to be re-evaluated for fracture risk, which depends on fracture status as well as on other health issues. Beyond that, life style factors such as regular physical activity as well as a sufficient intake of calcium and vitamin D or, if necessary supplementation of calcium and/or vitamin D play an essential part in fracture prevention. 23724957 Thermal stability and molecular microstructure of heat-induced cereal grains, revealed with Raman molecular microspectroscopy and differential scanning calorimetry. The objectives of the present study were to use Raman molecular microspectroscopy and differential scanning calorimetry (DSC) to reveal molecular thermal stability and thermal degradation behavior of heat-induced cereal grains and reveal the molecular chemistry of the protein structures of cereal grain tissues affected by heat processing and to quantify the protein secondary structures using multicomponent peak modeling Gaussian and Lorentzian methods. Hierarchical cluster analysis (CLA) and principal components analysis (PCA) were also conducted to identify molecular differences in the Raman spectra. Three cereal grain seeds, wheat, triticale, and corn, were used as the model for feed protein in the experiment. The specimens were autoclaved (moist heating) and dry-heated (roasted) at 121 °C for 80 min, respectively. Raman spectroscopy results revealed that there are marked differences in the secondary structures of the proteins subjected to various heating treatments of different cereals. The sensitivity of cereals to moist heating was much higher than the sensitivity to dry heating. The multivariate analyses (CLA and PCA) showed that heat treatment was significantly isolated between the different Raman raw spectra. The DSC study revealed that the thermal degradation behavior of cereals was significantly changed after moist- and dry-heat treatments. The position of the major endothermic peak of dry-heated cereals shifted toward a higher temperature, from 131.7 to 134.0 °C, suggesting the high thermal stability of dry-heated cereals. In contrast, the endothermic peak position was slightly decreased to 132.1 °C in the case of moist autoclaved heating. The digestive behavior and nutritive value of rumen-undegradable protein in animals may be related to the changes of the protein secondary molecular structure and thermal stability of the cereal grain materials, which is attributed by Raman microspectroscopy and DSC endotherm profiles. 23846438 Prognostic and putative predictive biomarkers of gastric cancer for personalized medicine. We investigated various phenotypic and genotypic biomarkers of gastric cancer (GC) testing the following hypotheses: are these biomarkers suitable for the identification of GC subtypes, are they of prognostic significance, and should any of these biomarkers be considered to tailor patient treatment in the future. The study cohort consisted of 482 patients. pTNM-stage was based on surgical pathologic examination. The Laurén and mucin phenotype was assessed. Helicobacter pylori and Epstein-Barr virus infections were documented. The following biomarkers were determined: BRAF, KRAS, NRAS, and PIK3CA genotype, microsatellite instability, mucin 1, mucin 2, mucin 5, and mucin 6, CD10, E-cadherin, β-catenin, and lysozyme. The histologic phenotype correlated with 10/13 (77%) clinicopathologic patient characteristics and 6/13 (46%) immunohistochemical/molecular biological biomarkers. Inversely, immunohistochemical biomarkers (mucin phenotype, E-cadherin, β-catenin, and lysozyme) were unsuitable for subclassification of GC. It showed too much overlap between the different subtypes. Among the genotypes, only microsatellite instability correlated with tumor type being more prevalent in intestinal and unclassified GCs. Patient survival correlated significantly with 8 (62%) clinicopathologic and 5 (36%) immunohistochemical/molecular biomarkers. Interestingly, in proximal GCs, KRAS mutation was associated with worse prognosis, as was persistent H. pylori infection in unclassified GCs. Mucin 2 (all patients, proximal GCs) and PIK3CA (exon 20; intestinal type GC) prognosticated independently patient survival. The biomarkers examined herein are unsuitable to aid histologic classification of GC. However, several of them show a correlation with either phenotype and/or prognosis and may be considered to tailor patient treatment in the future, such as KRAS, PIK3CA, MSI, and H. pylori status. 23716587 Adiponectin levels and the risk of hypertension: a systematic review and meta-analysis. Animal studies and small controlled studies in humans suggest that adiponectin may regulate blood pressure via brain-mediated and endothelium-mediated mechanisms. We performed a systematic review and meta-analysis to evaluate the epidemiological evidence on plasma adiponectin levels and hypertension in free-living adult population. A systematic search of MEDLINE and EMBASE, up to February 2013, identified 43 nonprospective and 5 prospective studies that included 17 598 adults (8220 with hypertension; mean age 19-69 years; and mean body mass index 22-38 kg/m(2)). Two investigators independently extracted data on adiponectin levels by hypertension status and dose-response relationship. We used a random-effects model to compute the weighted mean difference in adiponectin levels between adults with hypertension and normotensive adults and a 2-stage generalized least-square trend methods to compute the odds ratio of hypertension per 1 µg/mL increase in adiponectin. Adults with hypertension had 1.64 µg/mL (95% confidence interval, -2.07, -1.21) lower adiponectin levels than normotensive adults. Every 1 µg/mL increase in adiponectin levels was associated with 6% reduced risk of hypertension (95% confidence interval, 0.92, 0.97). These findings were consistent across study design and characteristics, including age, sex, and body mass index (P>0.05). However, our meta-analysis was limited by unexplained large between-study heterogeneity, a small number of prospective studies, and selective reporting of dose-response data. In conclusion, epidemiological evidence suggests that plasma adiponectin level is a biomarker and possible mediator in the development of adiposity-related hypertension. The question remains as to adiponectin as a potential therapeutic target and its relationship with other adipokines in blood pressure regulation. 23522623 Clinical and ictal characteristics of infantile seizures: EEG correlation via long-term video EEG monitoring. The semiology of infantile seizures often shows different characteristics from that of adults. We performed this study to describe clinical and ictal characteristics of infantile seizures at less than two years of age. A retrospective study was done for infants with epilepsy (ages: 1-24months) who underwent long-term video electroencephalography (EEG) monitoring at Samsung medical center between November 1994 and February 2012. We analyzed the clinical and ictal characteristics of the 56 cases from 51 patients. In 69% of the patients, the seizure onset was before six months of age and the etiology was symptomatic in one third of the patients. Twelve seizure types were identified; spasms (24%), unilateral motor seizures (18%), and generalized tonic seizures (15%) were the three frequent types of seizure. All partial seizures were well correlated with the partial-onset ictal EEG, however 19.4% (7/36) of clinically generalized seizures revealed partial-onset ictal EEG. About one-thirds (4/11) of generalized tonic seizures had its ictal onset on unilateral or bilateral frontal areas and two out of seven generalized myoclonic seizures showed unilateral frontal rhythmic activities. Hypomotor seizures mainly arose from the temporal areas and hypermotor seizures from the frontal regions. Even though most of the seizure semiology of infants is well correlated with ictal EEG, some of the generalized tonic seizures or myoclonic seizures revealed partial-onset ictal EEG suggesting localized epileptic focus. Accurate definition of seizures via video EEG monitoring is necessary for proper management of seizures in infancy, especially in some clinically generalized seizures. 23801674 Characterization of Different Osteosarcoma Phenotypes by PET Imaging in Preclinical Animal Models. The aim of this study was to characterize the different phenotypes of osteosarcoma by PET, comparing the uptake of 3 tracers ((18)F-FDG, (18)F-fluoromisonidazole [(18)F-FMISO], and (18)F-fluoride) in preclinical mouse models that reflect the heterogeneity of the human disease. Mouse LM8 osteosarcoma, human 143B, and Caprin-1 stably overexpressing SaOS-2 cells were injected intratibially in C3H and severe-combined immunodeficient mice. PET imaging with (18)F-FDG, (18)F-FMISO, and (18)F-fluoride was performed in these mouse models, and a ratio between the standardized uptake value of the primary tumor and a control area of bone was calculated and compared among the models. Histology and immunohistochemistry were performed to confirm the PET findings. The pattern of tracer uptake differed among the primary tumors of the 3 models in accordance with the histology and immunohistochemistry on primary tumor sections. The osteolytic tumors in the 143B model showed the highest uptake of (18)F-FDG, an indicator of glucose metabolism, which was significantly higher (P < 0.05) than in the SaOS-2/Caprin-1 model and correlated with the percentage of Ki67-positive cells in the primary tumors. Hypoxia, indicated by (18)F-FMISO accumulation, was higher in the SaOS-2/Caprin-1 and 143B cell line-derived tumors (P < 0.01). Finally (18)F-fluoride, a marker of bone remodeling, correlated with the osteoblastic phenotype. The SaOS-2/Caprin-1 cell-derived tumors showed a significantly higher uptake than the moderately osteoblastic LM8 (P < 0.05) and the osteolytic 143B (P < 0.01) cell line-derived tumors. Differential PET imaging with tracers indicating metabolic activity, hypoxia, or bone remodeling will be helpful for the characterization of different osteosarcoma phenotypes and subsequent evaluation of more specific treatment modalities targeting the processes that are predominant in each specific tumor type or subtype. 23611022 Patent indicators: a window to pharmaceutical market success. Pharmaceutical success in the market is the best reward for pharmaceutical investors undergoing the lengthy, costly and risky process of pharmaceutical Research and Development (R&D). Drugs with high market revenues trigger fierce competition between pharmaceutical enterprises, as is demonstrated by the increasing Mergers & Acquisitions (M&A) cases focusing on seizing the best-selling products. On the other hand, patents, as the best shield for innovative drugs against generic drugs, become a powerful weapon for pharmaceutical enterprises to win the substantial returns generated by market exclusivity. Patents seem to be directly responsible for the commercial success of new medicines. In this context, it is of great significance to find out the empirical associations between pharmaceutical commercial success and patents. By comprehensively analysing 127 drugs marketed in the USA and their 621 American patents, this article identifies the evidence to link various patent indicators with pharmaceutical sales in actual market. 23929775 MHC class I molecules are preferentially ubiquitinated on endoplasmic reticulum luminal residues during HRD1 ubiquitin E3 ligase-mediated dislocation. Misfolded MHC class I heavy chains (MHC I HCs) are targeted for endoplasmic reticulum (ER)-associated degradation (ERAD) by the ubiquitin E3 ligase HRD1, and E2 ubiquitin conjugating enzyme UBE2J1, and represent one of the few known endogenous ERAD substrates. The mechanism by which misfolded proteins are dislocated across the ER membrane into the cytosol is unclear. Here, we investigate the requirements for MHC I ubiquitination and degradation and show that endogenous misfolded MHC I HCs are recognized in the ER lumen by EDEM1 in a glycan-dependent manner and targeted to the core SEL1L/HRD1/UBE2J1 complex. A soluble MHC I HC lacking its transmembrane domain and cytosolic tail uses the same ERAD components and is degraded as efficiently as wild-type MHC I. Unexpectedly, HRD1-dependent polyubiquitination is preferentially targeted to the ER luminal domain of full-length MHC I HCs, despite the presence of an exposed cytosolic C-terminal tail. MHC I luminal domain ubiquitination occurs before p97 ATPase-mediated extraction from the ER membrane and can be targeted to nonlysine, as well as lysine, residues. A subset of integral membrane proteins, therefore, requires an early dislocation event to expose part of their luminal domain to the cytosol, before HRD1-mediated polyubiquitination and dislocation. 23676716 Clinical Factors Predicting the Response of Acute Graft-versus-Host Disease to Corticosteroid Therapy: An Analysis from the GVHD Working Group of the Japan Society for Hematopoietic Cell Transplantation. Systemic corticosteroid therapy is recommended as a first-line treatment for acute graft-versus-host disease (GVHD). We performed a retrospective study to identify the factors affecting the response of grade II to IV acute GVHD to systemic corticosteroid therapy using the Japanese national registry data for patients who received first allogeneic hematopoietic cell transplantation with bone marrow (BM) (n = 1955), peripheral blood stem cells (PBSCs) (n = 642), or umbilical cord blood (UCB) (n = 839). Of 3436 patients, 2190 (63.7%) showed improvement of acute GVHD to first-line therapy with corticosteroids. Various factors were identified to predict corticosteroid response. Interestingly, UCB (versus HLA-matched related BM) transplantation was significantly associated with a higher probability of improvement, whereas HLA-matched unrelated BM and HLA-mismatched stem cell sources other than UCB were significantly associated with a lower probability of improvement. HLA-matched related PBSC transplantation was not significantly different from HLA-matched related BM transplantation. Patients without improvement from corticosteroid therapy had a 2.5-times higher nonrelapse mortality and a .6-times lower overall survival rate. The present study demonstrated, for the first time, a higher probability of improvement in grade II to IV acute GVHD with systemic corticosteroid therapy in patients after UCB transplantation than in those after BM and PBSC transplantation. A prospective study is warranted. 23433221 Risk of hypertension in patients with bipolar disorder in Taiwan: A population-based study. To examine the prevalence, incidence, and risk factors of hypertension in patients with bipolar disorder in Taiwan. The National Health Research Institute provided a database of 1,000,000 random subjects for study in Taiwan. Study subjects ≥18years or older had at least one service claim during 2005 for either outpatient or inpatient care, with a primary or secondary diagnosis of hypertension combined with antihypertensive drug treatment were identified. We also compared the incidence of hypertension in patients with bipolar disorder and the general population from 2006 through 2010. The 1-year prevalence of hypertension in patients with bipolar disorder was higher than the general population (18.13% vs. 13.22%, odds ratio, 1.43; 95% confidence interval, 1.25-1.64) in Taiwan. Compared with the general population, patients with bipolar disorder had a higher prevalence of hypertension among 18- to 39-year-olds and 40- to 59-year-olds, in both sexes, and in the group with lower socioeconomic status. The average annual incidence of hypertension in patients with bipolar disorder from 2006 to 2010 was higher than the general population (2.83% vs. 1.99%, risk ratio, 1.40; 95% confidence interval, 1.20-1.62). Patients with bipolar disorder had a higher incidence of hypertension among 18- to 39-year-olds and 40- to 59-year-olds and in both sexes compared with the general population. Patients with bipolar disorder had a higher prevalence and a higher incidence of hypertension than those in the general population. Prevention, early detection, and comprehensive treatment of hypertension are important issues for patients with bipolar disorder. 23952007 Prehospital Peripheral Intravenous Vascular Access Success Rates in Children. Abstract Objective. Achieving successful peripheral intravenous (PIV) vascular access in children can be difficult. In the prehospital setting, opportunities are rare. Obtaining access becomes vital in emergent and life-threating conditions, such as seizures, hypoglycemia, and cardiac arrest. This study examines prehospital pediatric PIV attempts, success rates, and the impact of patient age. Methods. This was a retrospective chart review of patients aged 18 years or younger receiving prehospital PIV attempts from January 1, 2003, through May 31, 2011. Included cases were identified by querying electronic patient care reports for PIV attempts within the specified age range. The documentation of PIV attempts and successes was reported by emergency medical service providers. This study was approved by an institutional review board. Results. Throughout the 101-month study period, there were 261,008 ambulance responses. PIV attempts were made in 4188 patients aged 18 years or younger. PIV placement was successful in 3699 patients (88.3%) and failed in 489 (11.7%). Age was significantly associated with success. Each 1-year increase in age was associated with an 11% increase in odds of PIV success (odds ratio, 1.11; 95% CI, 1.09-1.12; p < 0.001). Success was lowest in patients younger than 2 years old, with an overall success rate of 64.1% (141/220). Accounting for multiple attempts, success was achieved in 53.0% of attempts (141/266). Conclusions. Prehospital PIV attempts are uncommon (2% of emergent responses). Success rates are significantly associated with patient age in the pediatric population and lowest in those aged 2 years or less. Consideration of alternative forms of vascular access in this population may be beneficial. Key words: ambulance; emergency medical services; intraosseous; intravenous; pediatric. 23919512 Identification of novel key amino acids at the interface of the transmembrane domains of human BST-2 and HIV-1 Vpu. BST-2 (bone marrow stromal cell antigen 2) is an interferon-inducible protein that inhibits virus release by tethering viral particles to the cell surface. This antiviral activity of BST-2 is antagonized by HIV-1 accessory protein Vpu. Vpu physically interacts with BST-2 through their mutual transmembrane (TM) domains. In this study, we utilized the BRET assay and molecular dynamics (MD) simulation method to further characterize the interaction of BST-2 and Vpu. Amino acids I34, L37, P40 and L41 in the TM domain of BST-2, and L11, A18 and W22 in the TM domain of Vpu were identified to be critical for the interaction between BST-2 and Vpu. The residues P40 in the TM domain of BST-2 and L11 in the TM domain of Vpu were shown, for the first time, to be important for their interaction. Furthermore, triple-amino-acid substitutions, 14-16 (AII to VAA) and 26-28 (IIE to AAA) in Vpu TM, not the single-residue mutation, profoundly disrupted BST-2/Vpu interaction. The results of MD simulation revealed significant conformational changes of the BST-2/Vpu complex as a result of mutating P40 of BST-2 and L11, 14-16 (AII to VAA) and 26-28 (IIE to AAA) of Vpu. In addition, disrupting the interaction between BST-2 and Vpu rendered BST-2 resistant to Vpu antagonization. Through use of the BRET assay, we identified novel key residues P40 in the TM domain of BST-2 and L11 in the TM domain of Vpu that are important for their interaction. These results add new insights into the molecular mechanism behind BST-2 antagonization by HIV-1 Vpu. 23816958 An fMRI examination of the effects of acoustic-phonetic and lexical competition on access to the lexical-semantic network. The current study explored how factors of acoustic-phonetic and lexical competition affect access to the lexical-semantic network during spoken word recognition. An auditory semantic priming lexical decision task was presented to subjects while in the MR scanner. Prime-target pairs consisted of prime words with the initial voiceless stop consonants /p/, /t/, and /k/ followed by word and nonword targets. To examine the neural consequences of lexical and sound structure competition, primes either had voiced minimal pair competitors or they did not, and they were either acoustically modified to be poorer exemplars of the voiceless phonetic category or not. Neural activation associated with semantic priming (Unrelated-Related conditions) revealed a bilateral fronto-temporo-parietal network. Within this network, clusters in the left insula/inferior frontal gyrus (IFG), left superior temporal gyrus (STG), and left posterior middle temporal gyrus (pMTG) showed sensitivity to lexical competition. The pMTG also demonstrated sensitivity to acoustic modification, and the insula/IFG showed an interaction between lexical competition and acoustic modification. These findings suggest the posterior lexical-semantic network is modulated by both acoustic-phonetic and lexical structure, and that the resolution of these two sources of competition recruits frontal structures. 23440457 A hyperpolarization-activated ion current of amphibian oocytes. A comparative analysis of a hyperpolarization-activated ion current present in amphibian oocytes was performed using the two-electrode voltage-clamp technique in Xenopus laevis, Xenopus tropicalis, and Ambystoma mexicanum. This current appears to be driven mainly by Cl(-) ions, is independent of Ca(2+), and is made evident by applying extremely negative voltage pulses; it shows a slow activating phase and little or no desensitization. The pharmacological profile of the current is complex. The different channel blocker used for Cl(-), K(+), Na(+) and Ca(2+) conductances, exhibited various degrees of inhibition depending of the species. The profiles illustrate the intricacy of the components that give rise to this current. During X. laevis oogenesis, the hyperpolarization-activated current is present at all stages of oocytes tested (II-VI), and the amplitude of the current increases from about 50 nA in stage I to more than 1 Î¼A in stage VI; nevertheless, there was no apparent modification of the kinetics. Our results suggest that the hyperpolarization-activated current is present both in order Anura and Urodela oocytes. However, the electrophysiological and pharmacological characteristics are quite perplexing and seem to suggest a mixture of ionic conductances that includes the activation of both anionic and cationic channels, most probably transiently opened due to the extreme hyperpolarizion of the plasma membrane. As a possible mechanism for the generation of the current, a kinetic model which fits the data suggests the opening of pores in the plasma membrane whose ion selectivity is dependent on the extracellular Cl(-) concentration. The extreme voltage conditions could induce the opening of otherwise latent pores in plasma membrane proteins (i.e., carriers), resembling the ´slippage´ events already described for some carriers. These observations should be valuable for other groups trying to express cloned, voltage-dependent ion channels in oocytes of amphibian in which hyperpolarizing voltage pulses are applied to activate the channels. 23929262 Treatment of an Initial Infection with Clostridium difficile in Patients with Inflammatory Bowel Disease. : Although the incidence of Clostridium difficile-associated diarrhea in the general population has increased dramatically over the past decade, an even greater rate of infection exists in patients with inflammatory bowel disease. Susceptibility in this population is likely inherent to the pathophysiology and treatment of these diseases. C. difficile infection can cause serious complications and death. Consequently, early diagnosis and initiation of effective antibacterial therapy is imperative. This article evaluates treatment recommendations for an initial episode of C. difficile infection in patients with inflammatory bowel disease based on the current guidelines and a Cochrane systematic review. 23223191 Gamma-radiolysis-assisted cobalt oxide nanoparticle formation. The formation of Co(3)O(4) nano-scale colloid particles by gamma irradiation of CoSO(4) solutions was investigated. Solutions of 0.2-0.3 mM CoSO(4) at pH 6.0 and 10.6 (air-saturated and Ar-purged) were irradiated at an absorbed dose rate of 5.5 kGy h(-1). The resulting concentrations of H(2), H(2)O(2), Co(II) and Co(III) species in solution and the chemical composition and sizes of particles that were formed were measured as a function of irradiation time. Particle formation was observed only for initially air-saturated CoSO(4) solutions at pH 10.6. Analysis of the particle formation as a function of irradiation time shows that the particles evolve from Co(OH)(2) to CoOOH and then to Co(3)O(4). The radiolytic oxidation of Co(II) to Co(III) was completed in 100 min and the chemical composition of the final particles was identified as Co(3)O(4) by XPS, Raman and UV-Vis spectroscopy. Transmission electron microscopy (TEM) images show the final particles are approximately uniform in size, ranging from 8 to 20 nm. A mechanism is proposed to explain the particle formation. A key factor is the low solubility of Co(OH)(2) in air-saturated solutions at high pH. This mechanism for particle formation is compared with the mechanism previously reported for the radiolytic formation of γ-FeOOH nanoparticles. 23859078 Metalloprotease genes of Trichophyton mentagrophytes are important for pathogenicity. Metalloproteases (Mep) of the M36 family are important virulence factors for the host invasion by the dermatophyte Trichophyton mentagrophytes. Dermatophytes secrete keratinase to degrade human and animal keratin and invade the skin. In previous studies, primers designed from the MEP gene sequences of Aspergillus fumigatus and A. oryzae were used to amplify the MEP genes from T. mentagrophytes, and the five MEP genes (MEP1-MEP5) were expressed. Differences in the expression of these five MEP genes in different dermatophytes were observed in an in vitro protein induction study, indicating their different functions and proteolytic abilities. However, specific pathogenic functions and mechanisms of each of the metalloproteases, as well as differences in their proteolytic activities, remain uncertain. In the current study, Agrobacterium tumefaciens-mediated transformation (ATMT) was used to successfully transform five MEP genes, resulting in five MEP mutant strains. MEP3 showed strongest proteolytic activity, hair biodegradation ability, and animal pathogenicity among the mutant strains. The MEP4 and MEP5 mutants were the least pathogenic through the above tests. Therefore, we hypothesize that the MEP4 and MEP5 genes are most likely to significantly affect the pathogenicity of T. mentagrophytes. 23471741 Cobicistat: A New Boost for the Treatment of Human Immunodeficiency Virus Infection. Ritonavir is commonly used as a pharmacokinetic booster for antiretroviral regimens in the management of human immunodeficiency virus infections. Limitations to ritonavir boosting include increased pill burden, adverse effects, and a wide range of clinically significant drug-drug interactions. Cobicistat is a new pharmacokinetic booster that is a selective inhibitor of cytochrome P450 3A, the main metabolizing pathway of several antiretrovirals. Cobicistat has been studied as a booster for elvitegravir, a second-generation integrase inhibitor, and protease inhibitors. Based on successful clinical trials, a new single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir has been approved for the management of treatment-naïve patients. Additional studies are underway investigating the safety and efficacy of cobicistat-boosted protease inhibitor regimens for both treatment-naïve and treatment-experienced patients. Cobicistat is well tolerated and may become a preferred booster for antiretroviral regimens, as it can be coformulated with several agents to create simpler regimens. 23672612 Melanoma inhibitory activity promotes melanoma development through activation of YBX1. Melanoma inhibitory activity (MIA), a small soluble secreted protein, is functionally important for progression of malignant melanoma. We recently revealed that p54(nrb) acts as a mediator of MIA action. In this study, we characterize the transcriptional regulation of p54(nrb) by MIA to explain MIA's molecular action. We identified one highly conserved region in the p54(nrb) promoter that is necessary and sufficient for MIA-dependent activation. Functional promoter analysis identified the transcription factor YBX1 as the mediator of MIA activation of p54(nrb) transcription. We screened the genome for further potential MIA-regulated genes carrying the element in their promoter regions. Integrating our sequence data with expression data from human melanomas identified a list of 23 potential MIA-YBX1 targets in melanomas. In summary, we present for the first time effects of MIA on transcriptional regulation. Uncovering new potential downstream effectors working via activation of YBX1 supports the important role of MIA in melanoma. 23813195 A Multidimensional Investigation of Children's /r/ Productions: Perceptual, Ultrasound, and Acoustic Measures. This study explored relationships among perceptual, ultrasound, and acoustic measurements of children's correct and misarticulated /r/ sounds. Longitudinal data documenting changes across these parameters were collected from 2 children who acquired /r/ over a period of intervention and were compared with data from children with typical speech. Participants were 3 children with typical speech, recorded once, and 2 children with /r/ misarticulation, recorded over 7-8 months. The following data from /r/ produced in nonwords were collected: perceptually rated accuracy, ultrasound measures of tongue shape, and F3 - F2 distance. Regression models revealed significant associations among perceptual, ultrasound, and acoustic measures of /r/ accuracy. The inclusion of quantitative tongue-shape measurements improved the match between the ultrasound and perceptual/acoustic data. Perceptually incorrect /r/ productions were found to feature posteriorly located peaked tongue shapes. Of the children who were seen longitudinally, 1 developed a bunched /r/ and 1 demonstrated retroflexion. The children with typical speech also differed in their tongue shapes. Results support the validity of using qualitative and quantitative ultrasound measures to characterize the accuracy of children's /r/ sounds. Clinically, findings suggest that it is important to encourage pharyngeal constriction while allowing children to find the /r/ tongue shape that best fits their individual vocal tract. 23837177 Community-centered education improves vaccination rates in children from low-income households. We partnered with the Salvation Army to educate resource-poor families regarding childhood immunizations in an effort to improve vaccine coverage rates. Eligibility for enrollment included children of families presenting at registration for our Salvation Army holiday gift program, available to families with an annual income <150% of federal poverty guidelines. Parents completed a questionnaire, were provided each child's vaccination status as documented in the New York State Immunization Information System, and interacted with the study team to address immunization-related concerns. Missed vaccines were identified and parents were directed to their child's medical home for necessary immunizations. Vaccine coverage was ascertained via the New York State Immunization Information System every 6 to 8 weeks with telephone follow-up for children who remained delayed. The McNemar test and standard 2-proportion comparison were used to determine confidence intervals when analyzing matched or independent data, respectively. A total of 1531 children were enrolled; 416 (28%) of the 1477 children with accurate immunization records were vaccine complete. When we excluded influenza vaccine, 1034 (70%) of children had received all other recommended vaccines. Nine months later, vaccine completion rates increased from 28% to 45%, largely because of improvements in influenza vaccination rates, which increased by 17% (confidence interval [CI] 15.5-19.5), a significant improvement over county (8%, 95% CI 7.4-8.1) and statewide (5%, 95% CI 4.7-4.8) rates during the same period. Immunization rates in poor children are suboptimal. Partnering with community-based organizations to address parental concerns, provide education, and perform follow-up was effective in improving immunization rates, particularly for influenza vaccine. 23873549 Genetic parameters of natural antibody isotypes and survival analysis in beak-trimmed and non-beak-trimmed crossbred laying hens. Natural antibodies (NAb) are important humoral components of innate immunity. As the first line of defense, NAb provide protection against infection and support adaptive immunity. An earlier study indicated that serum levels of NAb isotypes IgM and IgG at a young age were predictive for survival in non-beak-trimmed purebred laying hens during the laying period. In the present study, genetic parameters of NAb isotypes were estimated and relationships between survival and NAb isotypes levels in crossbred laying hens were investigated. In total, 1,555 beak-trimmed and 1,169 non-beak-trimmed crossbred laying hens were used. Genetic parameters of IgM and IgG titers binding keyhole limpet hemocyanin at 24 wk of age were estimated with a linear animal model. The heritabilities of NAb isotypes IgG and IgM were 0.21 (SE = 0.04) and 0.26 (SE = 0.04), respectively. The genetic correlation between IgG and IgM isotypes was 0.43 (SE = 0.11). These results indicated that NAb isotype titers were heritable traits in the crossbred laying hens. Both NAb isotypes can be selected for simultaneously because the detected positive genetic correlation (0.43, SE = 0.11) between them is positive. Both row and level of the cage were indicated to be associated environmental factors for NAb isotype titers. Different from an earlier study with purebred hens, survival analysis showed no significant associations of survival with NAb isotype titers in beak-trimmed or non-beak-trimmed crossbred hens. Non-health-related causes of mortality, especially in birds with intact beaks, overruled the anticipated relationships between NAb isotype titers and survival. 23883296 "Tertius gaudens": germplasm exchange networks and agroecological knowledge among home gardeners in the Iberian Peninsula. The idea that knowledge flows through social networks is implicit in research on traditional knowledge, but researchers have paid scant attention to the role of social networks in shaping its distribution. We bridge those two bodies of research and investigate a) the structure of network of exchange of plant propagation material (germplasm) and b) the relation between a person's centrality in such network and his/her agroecological knowledge. We study 10 networks of germplasm exchange (n = 363) in mountain regions of the Iberian Peninsula. Data were collected through participant observation, semi-structured interviews, and a survey. The networks display some structural characteristics (i.e., decentralization, presence of external actors) that could enhance the flow of knowledge and germplasm but also some characteristics that do not favor such flow (i.e., low density and fragmentation). We also find that a measure that captures the number of contacts of an individual in the germplasm exchange network is associated with the person's agroecological knowledge. Our findings highlight the importance of social relations in the construction of traditional knowledge. 23933660 In vivo time-gated fluorescence imaging with biodegradable luminescent porous silicon nanoparticles. Fluorescence imaging is one of the most versatile and widely used visualization methods in biomedical research. However, tissue autofluorescence is a major obstacle confounding interpretation of in vivo fluorescence images. The unusually long emission lifetime (5-13 μs) of photoluminescent porous silicon nanoparticles can allow the time-gated imaging of tissues in vivo, completely eliminating shorter-lived (<10 ns) emission signals from organic chromophores or tissue autofluorescence. Here using a conventional animal imaging system not optimized for such long-lived excited states, we demonstrate improvement of signal to background contrast ratio by >50-fold in vitro and by >20-fold in vivo when imaging porous silicon nanoparticles. Time-gated imaging of porous silicon nanoparticles accumulated in a human ovarian cancer xenograft following intravenous injection is demonstrated in a live mouse. The potential for multiplexing of images in the time domain by using separate porous silicon nanoparticles engineered with different excited state lifetimes is discussed. 23945075 The Influence of Gene Flow on Species Tree Estimation: A Simulation Study. Gene flow among populations or species and incomplete lineage sorting (ILS) are two evolutionary processes responsible for generating gene tree discordance and therefore hindering species tree estimation. Numerous studies have evaluated the impacts of ILS on species tree inference, yet the ramifications of gene flow on species trees remain less studied. Here, we simulate and analyze multilocus sequence data generated with ILS and gene flow to quantify their impacts on species tree inference. We characterize species tree estimation errors under various models of gene flow, such as the isolation-migration model, the n-island model, and gene flow between non-sister species or involving ancestral species, and species boundaries crossed by a single gene copy (allelic introgression) or by a single migrant individual. These patterns of gene flow are explored on species trees of different sizes (4 vs. 10 species), at different time scales (shallow vs. deep), and with different migration rates. Species trees are estimated with the multispecies coalescent model using Bayesian methods (BEST and *BEAST) and with a summary statistic approach (MPEST) that facilitates phylogenomic-scale analysis. Even in cases where the topology of the species tree is estimated with high accuracy, we find that gene flow can result in overestimates of population sizes (species tree dilation) and underestimates of species divergence times (species tree compression). Signatures of migration events remain present in the distribution of coalescent times for gene trees, and with sufficient data it is possible to identify those loci that have crossed species boundaries. These results highlight the need for careful sampling design in phylogeographic and species delimitation studies as gene flow, introgression, or incorrect sample assignments can bias the estimation of the species tree topology and of parameter estimates such as population sizes and divergence times. 23800696 Postoperative external beam radiation therapy and concurrent cisplatin followed by carboplatin/paclitaxel for stage III (FIGO 2009) endometrial cancer. The optimal adjuvant therapy in advanced endometrial cancer is controversial. One regimen is concurrent external beam pelvic irradiation (RT) and cisplatin, then carboplatin/paclitaxel. This study reports an institutional experience using this approach in stage III (FIGO 2009) endometrial cancer. Patients with stage III (FIGO 2009) endometrial cancer who underwent total hysterectomy and bilateral salpingo-oophorectomy at a single institution from 01/2004 to 12/2009 were identified retrospectively. Those treated with adjuvant RT/cisplatin, followed by carboplatin/paclitaxel comprised the study population. Of the 40 eligible patients, 7 (18%) were stage IIIA and 33 (82%) IIIC. Nineteen patients (48%) were ≥60years of age. Twenty-three (58%) had ≥50% myometrial invasion, 30 (75%) lymphovascular invasion, 11 (28%) cervical stromal invasion, and 5 (12%) positive peritoneal cytology. Histology was endometrioid in 32 (80%), serous in 6 (15%), and clear cell in 2 (5%). At a median follow-up of 49months, the 5-year freedom from relapse was 79% and overall survival 85%. The 5-year rate of vaginal recurrence was 3%, non-vaginal pelvic recurrence 3%, para-aortic recurrence 11%, peritoneal recurrence 5%, and other distant recurrence 11%. Thirty-one patients (78%) were able to complete the planned RT/cisplatin and 4cycles of carboplatin/paclitaxel. Acute grade 3 toxicity occurred in 10 patients (4 neutropenia, 2 anemia, 1 fatigue, 2 diarrhea). No late toxicity was grade ≥3. These favorable outcomes corroborate those of RTOG 9708. Until prospective data that compare adjuvant therapy regimens mature, concurrent chemoradiation should be strongly considered in stage III endometrial cancer. 23644583 Motor excitability during visual perception of known and unknown spoken languages. It is possible to comprehend speech and discriminate languages by viewing a speaker's articulatory movements. Transcranial magnetic stimulation studies have shown that viewing speech enhances excitability in the articulatory motor cortex. Here, we investigated the specificity of this enhanced motor excitability in native and non-native speakers of English. Both groups were able to discriminate between speech movements related to a known (i.e., English) and unknown (i.e., Hebrew) language. The motor excitability was higher during observation of a known language than an unknown language or non-speech mouth movements, suggesting that motor resonance is enhanced specifically during observation of mouth movements that convey linguistic information. Surprisingly, however, the excitability was equally high during observation of a static face. Moreover, the motor excitability did not differ between native and non-native speakers. These findings suggest that the articulatory motor cortex processes several kinds of visual cues during speech communication. 23436571 A simple method for fabricating patterned curvilinear microstructures in poly(dimethylsiloxane) by selective wetting. The fabrication of patterned microstructures in poly(dimethylsiloxane) (PDMS) is a prerequisite for soft lithography. Herein, curvilinear surface relief microstructures in PDMS are fabricated through a simple three-stage approach combining microcontact printing (μCP), selective surface wetting/dewetting and replica molding (REM). First, using an original PDMS stamp (first-generation stamp) with linear relief features, a chemical pattern on gold substrate is generated by μCP using hexadecanethiol (HDT) as an ink. Then, by a dip-coating process, an ordered polyethylene glycol (PEG) polymer-dot array forms on the HDT-patterned gold substrate. Finally, based on a REM process, the PEG-dot array on gold substrate is used to fabricate a second-generation PDMS stamp with microcavity array, and the second-generation PDMS stamp is used to generate third-generation PDMS stamp with microbump array. These fabricated new-generation stamps are utilized in μCP and in micromolding in capillaries (MIMIC), allowing the generation of surface micropatterns which cannot be obtained using the original PDMS stamp. The method will be useful in producing new-generation PDMS stamps, especially for those who want to use soft lithography in their studies but have no access to the microfabrication facilities. 23897697 Lgr4 is a key regulator of prostate development and prostate stem cell differentiation. Mechanisms modulating prostate cell fate determination remain unexplored. The leucine-rich repeat containing G-protein coupled receptors (LGRs) have been identified as important stem cell markers in various tissues. Here, we investigated the roles of Lgr4/Gpr48 in prostate stem cells and development. Lgr4 was ubiquitously expressed during early prostate development prior to lineage specification, with adult expression restricted to a few basal cells (principally Lin(-) Sca1(+) CD49f(+) ). Lgr4(-/-) mice had compromised branching morphogenesis and delayed epithelial differentiation, leading to decreased prostate size and impaired luminal cell function. In vitro prostate sphere culture revealed that Lgr4(-/-) Lin(-) /Sca1(+) /CD49f(+) (LSC) cells failed to generate p63(low) cells, indicating a differentiation deficiency. Furthermore, Lgr4 ablation arrested prostate stem cell (PSC) differentiation of in vivo kidney capsule prostate grafts, suggesting that Lgr4 modulates prostate stem cell properties independent of hormonal and mesenchymal effects. Analysis of neonatal prostates and prostate spheres revealed a decrease in Wnt, Sonic Hedgehog, and Notch1 expression in Lgr4(-/-) cells. Lgr4 loss blocked differentiation of prostate sphere p63(hi) cells to p63(low) . Treatment with exogenous Sonic Hedgehog partially restored the differentiation of p63(hi) cells in Lgr4(-/-) spheres. Taken together, our data revealed the roles of Lgr4 in early prostate development and in stem cell differentiation through regulation of the Wnt, Notch and Sonic Hedgehog signaling pathways. Stem Cells 2013. 23678004 Parp-2 is required to maintain hematopoiesis following sublethal γ-irradiation in mice. Hematopoietic stem cells self-renew for life to guarantee the continuous supply of all blood cell lineages. Here we show that Poly(ADP-ribose) polymerase-2 (Parp-2) plays an essential role in hematopoietic stem/progenitor cells (HSPC) survival under steady-state conditions and in response to stress. Increased levels of cell death were observed in HSPC from untreated Parp-2-/- mice, but this deficit was compensated by increased rates of self-renewal, associated with impaired reconstitution of hematopoiesis upon serial bone marrow transplantation. Cell death after γ-irradiation correlated with an impaired capacity to repair DNA damage in the absence of Parp-2. Upon exposure to sublethal doses of γ-irradiation, Parp-2-/- mice exhibited bone marrow failure that correlated with reduced long-term repopulation potential of irradiated Parp-2-/- HSPC under competitive conditions. In line with a protective role of Parp-2 against irradiation-induced apoptosis, loss of p53 or the pro-apoptotic BH3-only protein Puma restored survival of irradiated Parp-2-/- mice, whereas loss of Noxa had no such effect. Our results show that Parp-2 plays essential roles in the surveillance of genome integrity of HSPC by orchestrating DNA repair and restraining p53-induced and Puma-mediated apoptosis. The data may affect the design of drugs targeting Parp proteins and the improvement of radiotherapy-based therapeutic strategies. 23657803 Increasing prevalence and diversity of ESBL/AmpC-type β-lactamase genes in Escherichia coli isolated from veal calves from 1997 to 2010. Several studies on faecal carriage of extended-spectrum β-lactamase (ESBL)/AmpC-producing Escherichia coli have been performed in cattle, but little is known about faecal carriage in veal calves. This study describes the prevalence and molecular characteristics of ESBL/AmpC genes in E. coli isolated from faecal samples of veal calves from 1997 to 2010. Pooled faecal samples were inoculated using selective enrichment broth and subsequently selective MacConkey agar. All isolates with reduced susceptibility to cefotaxime were screened by PCR and sequencing analysis for the presence of ESBL/AmpC genes. The prevalence of E. coli with reduced susceptibility to cefotaxime showed a discontinuous increasing trend, ranging from 4% in 1998 and 1999 to 39% in 2010. Promoter mutations of the chromosomal ampC gene were present in all years. In 2000, ESBL genes blaCTX-M-1, blaTEM-52 and blaTEM-20 were first observed. Before 2005 the majority of E. coli with reduced susceptibility to cefotaxime harboured ampC promoter mutations. From 2005 onwards the majority harboured blaCTX-M genes, of which blaCTX-M-1 was the most abundant, followed by blaCTX-M-14 and blaCTX-M-15. The diversity of blaCTX-M genes gradually increased from one variant in 2000 to six variants in 2010. The prevalence of blaTEM-52 was relatively low, but it was detected from 2000 onwards. blaCMY and blaSHV were found sporadically. The prevalence and molecular diversity of genes encoding cefotaxime resistance in E. coli isolated from veal calves over a 14 year period showed an increasing trend. From 2005 onwards, blaCTX-M genes were most abundant, especially blaCTX-M-1. 23928456 Declines in sugar-sweetened beverage consumption among children in los angeles county, 2007 and 2011. This study assessed changes in consumption of sugar-sweetened beverages (SSBs) among children (aged ≤17 years) in Los Angeles County. We analyzed children's data from the 2007 (n = 5,595) and 2011 (n = 5,934) Los Angeles County Health Survey. The percentage of children who consumed 1 or more SSB per day decreased from 43.3% in 2007 to 38.3% in 2011 (P < .001); this decrease was seen across most sociodemographic subgroups. Despite measurable progress in reducing SSB consumption among children in Los Angeles County, consumption remains high, highlighting the need for additional policy and programmatic interventions. 23643194 Cytokine targets in airway inflammation. Asthma is an inflammatory disease of the airway wall that leads to bronchial hyper-reactivity and airway obstruction, caused by inflammation, mucus hyper-production and airway wall remodelling. Central to pathogenesis, Th2 and Th17 lymphocytes of the adaptive immune system control many aspects of the disease by producing cytokines such as IL-4, IL-5, IL-13, and IL-17. In addition, many cells of the innate immune system such as mast cells, basophils, neutrophils, eosinophils, dendritic cells (DCs), and innate lymphoid cells (ILCs) play an important role in the initiation or maintenance of disease. Epithelial cells are ever more implicated in disease pathogenesis, as they are able to sense exposure to pathogens via pattern recognition receptors (PRRs) and can activate DCs. This review article will deal with the role of cytokines that are considered essential controllers of the inflammatory, immune and regenerative response to allergens, viruses and environmental pollutants. Emerging Th2 cytokines such as thymic stromal lymphopoietin, GM-CSF, IL-1, IL-33, IL-25 mediate the crosstalk between epithelial cells, DCs, and ILCs. Understanding the crosstalk between structural cells, innate and adaptive immune cells that is mediated by cytokines provides important mechanistic insights into how asthma develops and perpetuates itself. It could also provide the framework on which we will select new therapeutic strategies that prevent exacerbations and alter the natural course of the disease. 23500490 The C-Terminal Region of Cytoplasmic Polyadenylation Element Binding Protein Is a ZZ Domain with Potential for Protein-Protein Interactions. Cytoplasmic polyadenylation element binding protein (CPEB) provides temporal and spatial control of protein synthesis required for early development and neuronal synaptic plasticity. CPEB regulates protein expression by inhibiting polyadenylation of selected mRNA transcripts, which prevents binding of the ribosome for protein synthesis. Two RNA recognition motif domains and a C-terminal binuclear zinc-binding domain are required for mRNA binding, but the zinc-binding domain is not required for sequence-specific recognition of the targeted mRNA transcript. The structure and function of the zinc-binding domain of CPEB are unknown. The C-terminal region of CPEB may participate in assembly of the ribonucleoprotein complex that includes the scaffold protein, Symplekin, and the cleavage and polyadenylation specificity factor. Sumoylation of Symplekin is required for polyadenylation, and both cleavage and polyadenylation specificity factor and poly(A) polymerase are sumoylated. The foreshortened poly(A) tail is maintained by poly(A) ribonuclease, which associates with CPEB. While zinc-binding domains are renowned for nucleic acid recognition, binuclear zinc-binding structural motifs, such as LIM (Lin-11, Isl-1, Mec-3), RING (really interesting new gene), PHD (plant homeodomain) and ZZ (ZZ-type zinc finger) domains, participate in protein-protein interactions. Here, we report the solution structure of the C-terminal zinc-binding domain of CPEB1 (CPEB1-ZZ), which has a cross-braced zinc binding topology. The structural similarity to other ZZ domains suggests that the CPEB1-ZZ domain recruits sumoylated proteins during assembly of the ribonucleoprotein complex prior to mRNA export from the nucleus. 23933182 Does severe acute pain provoke lasting changes in attentional and emotional mechanisms of pain-related processing? A longitudinal study. Pain experiences, learning, and genetic factors have been proposed to shape attentional and emotional processes related to pain. We aimed at investigating whether a singular major pain experience also changes cognitive-emotional processing. The influence of acute postoperative pain after cosmetic surgery of the thorax was tested in 80 preoperatively pain-free male individuals. Acute pain was measured as independent variable during the first week postsurgery by pain intensity ratings and the requested analgesic boluses (patient-controlled epidural analgesia). Pain catastrophizing (Pain Catastrophizing Scale), pain anxiety (Pain Anxiety Symptom Scale), pain hypervigilance (Pain Vigilance and Awareness Questionnaire), and attentional biases to emotionally loaded stimuli (including pain) in a dot-probe task were assessed 1week, 3months, and 6months postsurgery as dependent variables. Hierarchical regression analyses were performed to test whether the 2 acute pain parameters can predict these cognitive-emotional variables. As a rigorous test, significant prediction was required in addition to the prediction of the dependent variables by themselves with lag-1. Acute pain (mainly the pain ratings) appeared to be a significant predictor for the Pain Catastrophizing Scale, Pain Anxiety Symptom Scale, and Pain Vigilance and Awareness Questionnaire 1week after surgery (deltaR(2)=[8.7% to 11.3%]). In contrast, the attentional biases in the dot-probe task could not be predicted by the pain ratings. The levels of pain catastrophizing and pain hypervigilance increased in the acute phase after surgery when influenced by acute pain and declined, along with pain anxiety, during the next 3months. In conclusion, a one-time intense pain experience, such as acute postoperative pain, appeared to produce at least short-lived changes in the attentional and emotional processing of pain. 23899223 Investigating possible ethnicity and sex bias in clinical examiners: an analysis of data from the MRCP(UK) PACES and nPACES examinations. Bias of clinical examiners against some types of candidate, based on characteristics such as sex or ethnicity, would represent a threat to the validity of an examination, since sex or ethnicity are 'construct-irrelevant' characteristics. In this paper we report a novel method for assessing sex and ethnic bias in over 2000 examiners who had taken part in the PACES and nPACES (new PACES) examinations of the MRCP(UK). PACES and nPACES are clinical skills examinations that have two examiners at each station who mark candidates independently. Differences between examiners cannot be due to differences in performance of a candidate because that is the same for the two examiners, and hence may result from bias or unreliability on the part of the examiners. By comparing each examiner against a 'basket' of all of their co-examiners, it is possible to identify examiners whose behaviour is anomalous. The method assessed hawkishness-doveishness, sex bias, ethnic bias and, as a control condition to assess the statistical method, 'even-number bias' (i.e. treating candidates with odd and even exam numbers differently). Significance levels were Bonferroni corrected because of the large number of examiners being considered. The results of 26 diets of PACES and six diets of nPACES were examined statistically to assess the extent of hawkishness, as well as sex bias and ethnicity bias in individual examiners. The control (odd-number) condition suggested that about 5% of examiners were significant at an (uncorrected) 5% level, and that the method therefore worked as expected. As in a previous study (BMC Medical Education, 2006, 6:42), some examiners were hawkish or doveish relative to their peers. No examiners showed significant sex bias, and only a single examiner showed evidence consistent with ethnic bias. A re-analysis of the data considering only one examiner per station, as would be the case for many clinical examinations, showed that analysis with a single examiner runs a serious risk of false positive identifications probably due to differences in case-mix and content-specificity. In examinations where there are two independent examiners at a station, our method can assess the extent of bias against candidates with particular characteristics. The method would be far less sensitive in examinations with only a single examiner per station as examiner variance would be confounded with candidate performance variance. The method however works well when there is more than one examiner at a station and in the case of the current MRCP(UK) clinical examination, nPACES, found possible sex bias in no examiners and possible ethnic bias in only one. 23374351 LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation. Eukaryotic cells have a layer of heterochromatin at the nuclear periphery. To investigate mechanisms regulating chromatin distribution, we analyzed heterochromatin organization in different tissues and species, including mice with mutations in the lamin B receptor (Lbr) and lamin A (Lmna) genes that encode nuclear envelope (NE) proteins. We identified LBR- and lamin-A/C-dependent mechanisms tethering heterochromatin to the NE. The two tethers are sequentially used during cellular differentiation and development: first the LBR- and then the lamin-A/C-dependent tether. The absence of both LBR and lamin A/C leads to loss of peripheral heterochromatin and an inverted architecture with heterochromatin localizing to the nuclear interior. Myoblast transcriptome analyses indicated that selective disruption of the LBR- or lamin-A-dependent heterochromatin tethers have opposite effects on muscle gene expression, either increasing or decreasing, respectively. These results show how changes in NE composition contribute to regulating heterochromatin positioning, gene expression, and cellular differentiation during development. 23900172 Methamphetamine enhances Cryptococcus neoformans pulmonary infection and dissemination to the brain. Methamphetamine (METH) is a major addictive drug of abuse in the United States and worldwide, and its use is linked to HIV acquisition. The encapsulated fungus Cryptococcus neoformans is the most common cause of fungal meningitis in patients with AIDS. In addition to functioning as a central nervous system stimulant, METH has diverse effects on host immunity. Using a systemic mouse model of infection and in vitro assays in order to critically assess the impact of METH on C. neoformans pathogenesis, we demonstrate that METH stimulates fungal adhesion, glucuronoxylomannan (GXM) release, and biofilm formation in the lungs. Interestingly, structural analysis of the capsular polysaccharide of METH-exposed cryptococci revealed that METH alters the carbohydrate composition of this virulence factor, an event of adaptation to external stimuli that can be advantageous to the fungus during pathogenesis. Additionally, we show that METH promotes C. neoformans dissemination from the respiratory tract into the brain parenchyma. Our findings provide novel evidence of the impact of METH abuse on host homeostasis and increased permissiveness to opportunistic microorganisms. Methamphetamine (METH) is a major health threat to our society, as it adversely changes people's behavior, as well as increases the risk for the acquisition of diverse infectious diseases, particularly those that enter through the respiratory tract or skin. This report investigates the effects of METH use on pulmonary infection by the AIDS-related fungus Cryptococcus neoformans. This drug of abuse stimulates colonization and biofilm formation in the lungs, followed by dissemination of the fungus to the central nervous system. Notably, C. neoformans modifies its capsular polysaccharide after METH exposure, highlighting the fungus's ability to adapt to environmental stimuli, a possible explanation for its pathogenesis. The findings may translate into new knowledge and development of therapeutic and public health strategies to deal with the devastating complications of METH abuse. 23796238 Morphine-induced cognitive impairment is attenuated by induced pain in rats. Opioid medications are frequently used in the effective treatment of intractable pain, but prolonged use of such medications can be complicated by a host of adverse effects. Among these adverse effects, tolerance and mental clouding can be especially disabling and can lead to both a reduced effectiveness of treatment and a reduced quality of life for many requiring treatment with these medications. Here we examined the relative contributions of complete Freund's adjuvant (CFA)-induced inflammatory pain and opioid medication on spatial memory for a well-learned task in male Sprague-Dawley rats. Although CFA, by itself, had little effect on spatial memory, morphine administered to pain-free animals produced profound detrimental effects on spatial memory that persisted longer than the analgesic effectiveness of the drug. However, no significant cognitive deficits were observed in animals receiving morphine in the presence of CFA-induced pain. Taken together, these results are evidence that the pain state of the organism can alter some of the negative effects of morphine. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23587402 Intracloacally passaged low-virulent Histomonas meleagridis protects turkeys from histomonosis. Histomonosis (blackhead disease or infectious enterohepatitis) caused by the extracellular protozoon parasite Histomonas meleagridis is an important disease of turkeys and a threat to the poultry industry. Due to recent legislation on drug restrictions, research to find new alternatives is an urgent matter in the battle against histomonosis. In the present study, intracloacal inoculation of a low-virulent H. meleagridis strain isolated after serial passages in turkeys clearly demonstrated a reduction of virulence and hence its effectiveness as a vaccine against histomonosis. The low-virulent isolate has been evaluated in a comparative experimental infection study. No mortality nor predominant caecal or liver lesions could be observed in the groups inoculated with 10(3), 10(4) or 10(5) histomonads per bird. Only dilated caeca with a yellow and foamy content could be noticed. Groups inoculated with similar doses of a virulent strain displayed a dose-related pathology and mortality up to 100%. The protective capacity of the strain with reduced virulence could be demonstrated as none of the birds cloacally inoculated with 10(3), 10(4) or 10(5) histomonads died upon challenge with 10(5)H. meleagridis of the virulent strain. Hereby, 71% of the challenge control group died. Interestingly, no or only very minor pathological lesions in the caeca and liver could be detected after challenge of the birds inoculated with the passaged histomonads. In conclusion, cloacal inoculation of the low-virulent strain obtained after serial backpassages was able to induce protection of turkeys against challenge with a virulent H. meleagridis strain. 23831147 Epileptic seizures and headache-migraine: A review on types of association and terminology. There are different possible temporal associations between epileptic seizures and headache attacks which have given rise to unclear or controversial terminologies. The classification of the International League Against Epilepsy does not refer to this type of disorder, while the International Classification of Headache Disorders (ICHD-2) defines three kinds of association: 1. migraine-triggered seizure ("migralepsy"), 2. hemicrania epileptica, and 3. post-ictal headache. We performed an extensive review of the literature, not including "post-ictal" and "inter-ictal" headaches. On the basis of well-documented reports, the following clinical entities may be identified: (A) "epileptic headache (EH)" or "ictal epileptic headache (IEH)": in this condition headache (with or without migrainous features) is an epileptic manifestation per se, with onset, and cessation if isolated, coinciding with the scalp or deep EEG pattern of an epileptic seizure. EH maybe followed by other epileptic manifestations (motor/sensory/autonomic); this condition should be differentiated from "pure" or "isolated" EH, in which headache/migraine is the sole epileptic manifestation (requiring differential diagnosis from other headache forms). "Hemicrania epileptica" (if confirmed) is a very rare variant of EH, characterized by ipsilateral location of headache and ictal EEG paroxysms. (B) "Pre-ictal migraine" and "pre-ictal headache": when a headache attack is followed during, or shortly after, by a typical epileptic seizure. The migraine attack may be with or without aura, and its seizure-triggering role ("migraine-triggered seizure") is still a subject of debate. A differentiation from occipital epilepsy is mandatory. The term "migralepsy" has not been used univocally, and may therefore led to misinterpretation. On the basis of this review we suggest definitions and a terminology which may become the basis of a forthcoming classification of headaches associated with epileptic seizures. 23897328 Bilateral breast reconstruction from a single hemiabdomen using angiosome-based flap design. Performing bilateral autologous breast reconstruction using the abdominal donor site usually entails harvesting one flap from each hemiabdomen. However, the overlapping vascular territories of the superior epigastric, deep inferior epigastric, superficial inferior epigastric, and superficial circumflex iliac vessels make it theoretically possible to harvest two flaps based on vessels from one hemiabdomen. This may be useful in the obese patient, where one hemiabdomen may provide adequate tissue to reconstruct two breasts. The authors describe three clinical scenarios where they have used this principle, including the first reports in the literature of metachronous and synchronous bilateral breast reconstructions using two flaps based on pedicles from a single hemiabdomen. Therapeutic, V. 23428657 Neurobiology of addiction versus drug use driven by lack of choice. Research on the neurobiology of addiction often involves nonhuman animals that are given ready access to drugs for self-administration but without other choices. Here we argue using cocaine as an example that this standard setting may no longer be sufficient and can even lead to the formulation of unrealistic views about the neurobiology of addiction. Addiction as a psychiatric disorder is defined as resulting from brain dysfunctions that affect normal choice-making, not as an expectable response to lack of alternative choices. We encourage neurobiologists involved in addiction research to increase animals' choice during drug access, preferably by supplying alternative rewarding pursuits. Only animals that continue to take and prefer drugs despite and at the expense of other available choices may be considered as having developed an addiction-like behavior in comparison to those that remain able to stop drug use for other pursuits, even after extended drug use. The systematic comparison of these two individual behaviors should reveal new insights about the neurobiology of drug choice and addiction. More generally, this research should also shed a unique light on how the brain 'chooses' among qualitatively different kinds of pursuits. 23845105 Coumestrol from the national cancer Institute's natural product library is a novel inhibitor of protein kinase CK2. Casein kinase 2 (CK2) is involved in various cellular events such as proliferation, apoptosis, and the cell cycle. CK2 overexpression is associated with multiple human cancers and may therefore be a promising target for cancer therapy. To identity novel classes of inhibitors for CK2, we screened a natural product library obtained from National Cancer Institute. The quantitative luminescent kinase assay ADP-Glo™ was used to screen CK2 inhibitors from the natural product library. The same assay was used to determine cell-free dose-dependent response of CK2 inhibitors and conduct a kinetic study. Docking was performed to predict the binding patterns of selected CK2 inhibitors. Western blot analysis was used to evaluate Akt phosphorylation specific to CK2 and apoptosis effect. The cell viability assay CellTiter-Glo(®) was used to evaluate the inhibition effects of CK2 inhibitors on cancer cells. We identified coumestrol as a novel reversible ATP competitive CK2 inhibitor with an IC(50) value of 228 nM. Coumestrol is a plant-derived compound that belongs to the class of phytoestrogens, natural compounds that mimic the biological activity of estrogens. In our study, coumestrol showed high selectivity among 13 kinases. The hydrogen bonds formed between coumestrol and the amino acids in the ATP binding site were first reviewed by a molecular docking study that suggested a possible interaction of coumestrol with the hinge region of ATP site of CK2. In addition, coumestrol inhibited cancer cell growth partially through down-regulation of CK2-specific Akt phosphorylation. Finally, coumestrol exerted strong inhibition effects on the growth of three cancer cell lines. Our study shows that coumestrol, a novel ATP competitive and cell permeable CK2 inhibitor with submicromolar IC(50), had inhibition effects on the growth of three cancer cell lines and may represent a promising class of CK2 inhibitors. 23863407 A Requirement for Fatty Acid Oxidation in the Hormone-Induced Meiotic Maturation of Mouse Oocytes. We have previously shown that fatty acid oxidation (FAO) is required for AMP-activated protein kinase (PRKA)-induced maturation in vitro. In the present study, we have further investigated the role of this metabolic pathway in hormone-induced meiotic maturation. Incorporating an assay with 3H-palmitic acid as substrate, we first examined the effect of PRKA activators on FAO levels. There was a significant stimulation of FAO in cumulus cell-enclosed oocytes (CEO) treated with AICAR and RSVA405. In denuded oocytes (DO), AICAR stimulated FAO only in the presence of carnitine, the molecule that facilitates fatty acyl CoA entry into mitochondria. The carnitine palmitoyltransferase 1 (CPT1B) activator C75 successfully stimulated FAO in CEO. All three of these activators trigger germinal vesicle breakdown. Meiotic resumption induced by follicle-stimulating hormone (FSH) or amphiregulin was completely inhibited by the FAO inhibitors etomoxir, mercaptoacetate, and malonyl CoA. Importantly, FAO was increased in CEO stimulated by FSH and epidermal growth factor (EGF), and this increase was blocked by FAO inhibitors. Moreover, compound C, a PRKA inhibitor, prevented the FSH-induced increase in FAO. Both carnitine and palmitic acid augmented hormonal induction of maturation. In a more physiological setting, etomoxir eliminated hCG-induced maturation in follicle-enclosed oocytes. In addition, CEO and DO from hCG-treated mice displayed an etomoxir-sensitive increase in FAO, indicating that this pathway was stimulated during in vivo meiotic resumption. Taken together, our data indicate that hormone-induced maturation in mice requires a PRKA-dependent increase in FAO. 23904313 Laryngotracheal rhinosporidiosis. Rhinosporidiosis is a chronic granulomatous disease caused by Rhinosporidium seeberi. It usually affects mucous membranes of the nose, nasopharynx, and ocular conjunctiva. Cutaneous, laryngeal, tracheal, genital, and bony dissemination is rare. Laryngotracheal involvement poses many diagnostic and therapeutic challenges. A 45-year-old South Indian man presented with complaints of a mass in both nostrils for 2 years, associated with progressive hoarseness of voice and difficulty in breathing for 6 months. Rhinosporidial lesions were seen bilaterally in the nasal cavity. Telescopic and fiberoptic laryngoscopic examinations showed reddish, strawberry-like masses with whitish spots on their surface involving the larynx and trachea. Computed tomography of the head and neck revealed soft-tissue mass lesions involving the bilateral nasal cavities and nasopharynx, extending to the oropharynx and involving the larynx and trachea. A preliminary tracheostomy was performed, followed by direct laryngoscopic excision of the laryngeal lesions and rigid-bronchoscopy-guided excision of the tracheal lesions. The patient was prescribed dapsone and advised to take it for 2 years. At 2 years of follow-up, there was no recurrence. 23664560 Characterization of xanthatin: anticancer properties and mechanisms of inhibited murine melanoma in vitro and in vivo. Anti-cancer investigations on Xanthatin mainly focus on in vitro experiments. We herein reported the anti-tumor effects of Xanthatin both in vitro and in vivo. MTS assay results showed that Xanthatin had a remarkable anti-proliferative effect on B16-F10 cells. Moreover, the expression of β-catenin was up-regulated both in vitro and in vivo. Animal studies further revealed that Xanthatin killed the tumor cells around the blood vessels which contributes to reduce microvascular density extremely. All these results indicate that Xanthatin inhibited murine melanoma B16-F10 cell proliferation possibly associated with activation of Wnt/β-catenin pathway and its activity against melanoma tumor might also be relevant to inhibition of angiogenesis. 23932988 Combined effects of dietary fructooligosaccharide and Bacillus licheniformis on innate immunity, antioxidant capability and disease resistance of triangular bream (Megalobrama terminalis). This study was conducted to investigate the effects of fructooligosaccharide (FOS) and Bacillus licheniformis (B. licheniformis) and their interaction on innate immunity, antioxidant capability and disease resistance of triangular bream Megalobrama terminalis (average initial weight 30.5 ± 0.5 g). Nine experimental diets were formulated to contain three FOS levels (0, 0.3% and 0.6%) and three B. licheniformis levels (0, 1 Ã— 10(7), 5 Ã— 10(7) CFU g(-1)) according to a 3 Ã— 3 factorial design. At the end of the 8-week feeding trial, fish were challenged by Aeromonas hydrophila (A. hydrophila) and survival rate was recorded for the next 7 days. The results showed that leucocyte counts, alternative complement activity as well as total serum protein and globulin contents all increased significantly (P < 0.05) as dietary B. licheniformis levels increased from 0 to 1 Ã— 10(7) CFU g(-1), while little difference (P > 0.05) was observed in these parameters in terms of dietary FOS levels. Both plasma alkaline phosphatase and phenoloxidase activities were significantly (P < 0.05) affected only by dietary FOS levels with the highest values observed in fish fed 0.6 and 0.3% FOS, respectively. Both immunoglobulin M content and liver superoxide dismutase (SOD) activity were significantly affected (P > 0.05) by both FOS and B. licheniformis. Liver catalase, glutathione peroxidase as well as plasma SOD activities of fish fed 1 Ã— 10(7) CFU g(-1)B. licheniformis were all significantly (P < 0.05) higher than that of the other groups, whereas the opposite was true for malondialdehyde content. After A. hydrophila challenge, survival rate was not affected (P > 0.05) by either FOS levels or B. licheniformis contents, whereas a significant (P < 0.05) interaction between these two substances was observed with the highest value observed in fish fed 0.3% FOS and 1 Ã— 10(7) CFU g(-1)B. licheniformis. The results of this study indicated that dietary FOS and B. licheniformis could significantly enhance the innate immunity and antioxidant capability of triangular bream, as well as improve its disease resistance. The best combination of these two prebiotics and/or probiotics was 0.3% FOS and 1 Ã— 10(7) CFU g(-1)B. licheniformis. 23851224 Another record of significant regional variation in toxicity of Tityus serrulatus venom in Brazil: A step towards understanding the possible role of sodium channel modulators. The scorpion Tityus serrulatus is responsible for the most severe accidents that have been registered in Brazil, mainly in the state of Minas Gerais (MG), being the lung edema (LE), the main cause of death in these accidents. Although an increased in the number of accidents caused to this species in Federal District (Distrito Federal - DF), it seems that this particular species is not responsible for severe scorpionism cases in this region. Given this observation, we tested the toxicity in mice and compared the ability of T. serrulatus venom from DF (Ts-DF) and Minas Gerais State (Ts-MG) to induce LE in rats. The LD50 of Ts-DF venom was 51.6 Î¼g/mouse, almost twice (1.98) higher than that obtained for Ts-MG venom. The ability of venom (0.5 mg/kg) to induce LE in rats was determined by the wet weight differences between treated and untreated lungs, by pulmonary morphological analyses and by pulmonary vascular permeability (PVP) using the Evans blue protocol. Significant differences in the wet weight of lungs and changes in PVP were found in Ts-MG venom treated rats when compared to rats treated with Ts-DF venom or untreated rats (p < 0.001), but no differences occurred when comparing rats treated with Ts-DF venom and untreated rats (p < 0.05). These results were confirmed by evaluation of pulmonary morphology. Comparison of chromatographic profiles obtained from these venoms (Ts-DF and Ts-MG) using the fractal dimension (D) analysis and the molecular mass fingerprint of the chromatographic fractions showed a higher number of components between 35 and 40% acetonitrile in Ts-MG venom than in Ts-DF venom, indicating a higher diversity of sodium channel modulators in that venom. 23910740 Assessing the quality of tests: Revision of the EFPA review model. Background: Diverse national and international organizations have been developing projects for many years to improve testing practices. The main goal of this paper is to present the revised model of the European Federation of Psychologists' Associations (EFPA) for the evaluation of the quality of tests. This model aims to provide test users with rigorous information about the theoretical, practical and psychometric characteristics of tests, in order to enhance their use. Method: For the revision of the test review model, an EFPA task force was established, consisting of six European experts from different countries, who worked on the update of the previous European model, adapting it to the recent developments in the field of psychological and educational measurement. Results: The updated EFPA model provides for the comprehensive evaluation of tests. The first part describes test characteristics exhaustively, and in the second part, a quantitative and narrative evaluation of the most relevant psychometric characteristics of tests is presented. Conclusions: A revision of the European model for the description and evaluation of psychological and educational tests is presented. The revised model is analyzed in light of recent developments in the field. 23965265 Synergistic Effects of COMT and TPH2 on Social Cognition. Whether genetic factors affect social cognition, particularly emotion management, requires elucidation. This study investigates whether social cognition varies with genetic variations of COMT and tryptophan hydroxylase-2 (TPH2), which modulate dopamine and serotonin neurotransmissions respectively, and thereby emotion regulation. NIMH-recommended "managing emotions branch and 2 subtasks" of MSCEIT and six neurocognition domains, and genotypes of COMT Val158Met and TPH2 G703T were measured in 150 Han-Chinese healthy adults. Subjects carrying the M allele (M group) of COMT exceeded Val/Val homozygotes (V group) in managing emotions branch (p = 0.032) and emotional relation subtask (p = 0.037). TPH2 T/T homozygotes (T group) excelled those with the G allele (G group) in emotional management subtask (p = 0.025). Subjects with M+T variation surpassed the other 3 groups (M+G, V+T and V+G) in managing emotion branch (p = 0.002), emotional relation subtask (p = 0.023), and emotional management subtask (p = 0.002). The findings remained after control for gender, age, education, and neurocognitive functions. Synergistically, the effect size of COMT-TPH2 combination surmounted the sum of separate effect sizes of COMT and TPH2. The findings suggest that genetic variations of COMT and TPH2 have synergistic effects on social cognition in the general population. 23907167 Relationship Between Dry Eye Symptoms and Pain Sensitivity. IMPORTANCE Dry eye disease (DED) is common, but little is known about factors contributing to symptoms of dry eye, given the poor correlation between these symptoms and objective signs at the ocular surface. OBJECTIVE To explore whether pain sensitivity plays a role in patients' experience of DED symptoms. DESIGN, SETTING, AND PARTICIPANTS A population-based cross-sectional study of 1635 female twin volunteers, aged 20 to 83 years, from the TwinsUK adult registry. MAIN OUTCOMES AND MEASURES Dry eye disease was diagnosed if participants had at least 1 of the following: (1) a diagnosis of DED by a clinician, (2) the prescription of artificial tears, and/or (3) symptoms of dry eyes for at least 3 months. A subset of 689 women completed the Ocular Surface Disease Index (OSDI) questionnaire. Quantitative sensory testing using heat stimulus on the forearm was used to assess pain sensitivity (heat pain threshold [HPT]) and pain tolerance (heat pain suprathreshold [HPST]). RESULTS Of the 1622 participants included, 438 (27.0%) were categorized as having DED. Women with DED showed a significantly lower HPT (P = .03) and HPST (P = .003)-and hence had higher pain sensitivity-than those without DED. A strong significant association between the presence of pain symptoms on the OSDI and the HPT and HPST was found (P = .008 for the HPT and P = .003 for the HPST). In addition, participants with an HPT below the median had DED pain symptoms almost twice as often as those with an HPT above the median (31.2% vs 20.5%; odds ratio, 1.76; 95% CI, 1.15-2.71; P = .01). CONCLUSIONS AND RELEVANCE High pain sensitivity and low pain tolerance are associated with symptoms of DED, adding to previous associations of the severity of tear insufficiency, cell damage, and psychological factors. Management of DED symptoms is complex, and physicians need to consider the holistic picture, rather than simply treating ocular signs. 23863840 A competitive regulatory mechanism discriminates between juxtaposed splice sites and pri-miRNA structures. We have explored the functional relationships between spliceosome and Microprocessor complex activities in a novel class of microRNAs (miRNAs), named Splice site Overlapping (SO) miRNAs, whose pri-miRNA hairpins overlap splice sites. We focused on the evolutionarily conserved SO miR-34b, and we identified two indispensable elements for recognition of its 3' splice site: a branch point located in the hairpin and a downstream purine-rich exonic splicing enhancer. In minigene systems, splicing inhibition owing to exonic splicing enhancer deletion or AG 3'ss mutation increases miR-34b levels. Moreover, small interfering-mediated silencing of Drosha and/or DGCR8 improves splicing efficiency and abolishes miR-34b production. Thus, the processing of this 3' SO miRNA is regulated in an antagonistic manner by the Microprocessor and the spliceosome owing to competition between these two machineries for the nascent transcript. We propose that this novel mechanism is commonly used to regulate the relative amount of SO miRNA and messenger RNA produced from primary transcripts. 23737123 Pucker sign in proximal humeral fractures: implications on management. Fracture of the surgical neck of humerus in young patients is a relatively rare injury. We reviewed the available material on the topic and identified puckering at the shoulder in high-energy fracture of the surgical neck as a finding which has been reported infrequently but signifies a need for open reduction. We present a review of the literature on the subject and our similar experience in two young males who had puckering and ecchymosis at the shoulder. 22940465 Fragrance chemicals lyral and lilial decrease viability of HaCat cells' by increasing free radical production and lowering intracellular ATP level: protection by antioxidants. We investigate in this study the biochemical effects on cells in culture of two commonly used fragrance chemicals: lyral and lilial. Whereas both chemicals exerted a significant effect on primary keratinocyte(s), HaCat cells, no effect was obtained with any of HepG2, Hek293, Caco2, NIH3T3, and MCF7 cells. Lyral and lilial: (a) decreased the viability of HaCat cells with a 50% cell death at 100 and 60 nM respectively; (b) decreased significantly in a dose dependant manner the intracellular ATP level following 12-h of treatment; (c) inhibited complexes I and II of electron transport chain in liver sub-mitochondrial particles; and (d) increased reactive oxygen species generation that was reversed by N-acetyl cysteine and trolox and the natural antioxidant lipoic acid, without influencing the level of free and/or oxidized glutathione. Lipoic acid protected HaCat cells against the decrease in viability induced by either compound. Dehydrogenation of lyral and lilial produce α,β-unsaturated aldehydes, that reacts with lipoic acid requiring proteins resulting in their inhibition. We propose lyral and lilial as toxic to mitochondria that have a direct effect on electron transport chain, increase ROS production, derange mitochondrial membrane potential, and decrease cellular ATP level, leading thus to cell death. 23966261 Stress Fracture of the Anterior Process of the Calcaneus: A Case Report. Stress fracture of the anterior process of the calcaneus is rare. We present a case of a 14-year-old female basketball player who suffered a stress fracture of the anterior process of the calcaneus that was not associated with a calcaneonavicular coalition. After conservative treatment failed, drilling of the fracture site was required to facilitate healing. A possible cause of this rare type of stress fracture seemed to be a long anterior process of the calcaneus.Level of Evidence: Therapeutic, Level IV: Case study. 23771918 Vertebral fractures in patients with acromegaly: a 3-year prospective study. Context: Cross-sectional studies showed an elevated prevalence of vertebral fractures in acromegaly. However, no data are available on incident vertebral fractures in this clinical setting. Objective: The objective of the study was to investigate the incidence and risk factors of vertebral fractures in patients with acromegaly. Design: This was a 3-year prospective study. Setting: The study was conducted at referral centers. Subjects: Eighty-eight patients with acromegaly (33 females, 55 males; mean age 50 years, range 21-85 years) and 106 control subjects, matched for sex and age (43 females and 63 males, mean age 55 years, range 33-79 years), attending outpatient bone clinics participated in the study. Main Measures: Patients and control subjects were evaluated for the incidence of vertebral fractures using a quantitative morphometric approach on spine x-ray, which was performed at baseline and after 3 years of follow-up. At the same time points, patients with acromegaly were also evaluated for bone mineral density with dual-energy X-ray absorptiometry at lumbar spine and femoral neck. Results: After a 3-year follow-up, 37 patients with acromegaly (42.0%) and 4 control subjects (3.8%) experienced incident vertebral fractures (P < .001). The incidence of vertebral fractures was significantly higher in patients with active disease as compared with those who had controlled/cured acromegaly at the study entry (62.5% vs 25.0%; P < .001). The risk of incident vertebral fractures was significantly associated with hypogonadism, a change in the femoral neck bone mineral density, and prevalent vertebral fractures at the study entry only in patients with controlled/cured acromegaly, whereas in patients with active disease, the fracture risk was not influenced by the above-mentioned clinical factors, but it was significantly associated with the duration of active acromegaly. Conclusions: This prospective study demonstrates a high rate of incident vertebral fractures both in patients with active and controlled acromegaly. 23951074 Short-chain fructo-oligosaccharides modulate intestinal microbiota and metabolic parameters of humanized gnotobiotic diet induced obesity mice. Prebiotic fibres like short-chain fructo-oligosaccharides (scFOS) are known to selectively modulate the composition of the intestinal microbiota and especially to stimulate Bifidobacteria. In parallel, the involvement of intestinal microbiota in host metabolic regulation has been recently highlighted. The objective of the study was to evaluate the effect of scFOS on the composition of the faecal microbiota and on metabolic parameters in an animal model of diet-induced obesity harbouring a human-type microbiota. Forty eight axenic C57BL/6J mice were inoculated with a sample of faecal human microbiota and randomly assigned to one of 3 diets for 7 weeks: a control diet, a high fat diet (HF, 60% of energy derived from fat)) or an isocaloric HF diet containing 10% of scFOS (HF-scFOS). Mice fed with the two HF gained at least 21% more weight than mice from the control group. Addition of scFOS partially abolished the deposition of fat mass but significantly increased the weight of the caecum. The analysis of the taxonomic composition of the faecal microbiota by FISH technique revealed that the addition of scFOS induced a significant increase of faecal Bifidobacteria and the Clostridium coccoides group whereas it decreased the Clostridium leptum group. In addition to modifying the composition of the faecal microbiota, scFOS most prominently affected the faecal metabolome (e.g. bile acids derivatives, hydroxyl monoenoic fatty acids) as well as urine, plasma hydrophilic and plasma lipid metabolomes. The increase in C. coccoides and the decrease in C. leptum, were highly correlated to these metabolic changes, including insulinaemia, as well as to the weight of the caecum (empty and full) but not the increase in Bifidobacteria. In conclusion scFOS induce profound metabolic changes by modulating the composition and the activity of the intestinal microbiota, that may partly explain their effect on the reduction of insulinaemia. 22969061 Advances in supramolecular electronics - from randomly self-assembled nanostructures to addressable self-organized interconnects. Supramolecular organic electronics rests on the use of bottom-up chemical self-assembly processes in order to design conducting components on the 5-100 nm scale. The challenges in this field are both the construction of 1D-nanostructures displaying optimized transport properties and their precise connections to electrodes. The present Research News highlights important advances in such materials regarding their electrical performances, from semiconductors to organic metals, but also regarding their processability. In particular, by externally controlling light-responsive supramolecular polymerization processes, and by using appropriate methods of casting with an applied electric field, it becomes possible to pre-determine the accurate positioning of organic interconnects within patterned nano-circuitry. These strategies using external stimuli to obtain addressability, thus hold promising alternatives to other conducting materials such as carbon nanotubes for further technological applications in nanosciences. 23320737 The transcription factor Fli-1 regulates monocyte, macrophage and dendritic cell development in mice. Fli-1 belongs to the Ets transcription factor family and is expressed in haematopoietic cells, including most of the cells that are active in immunity. The mononuclear phagocytes, i.e. monocytes, macrophages and dendritic cells, originate in haematopoietic stem cells and play an important role in immunity. To assess the role of Fli-1 in mononuclear phagocyte development in vivo, we generated mice that express a truncated Fli-1 protein, lacking the C-terminal transcriptional activation domain (Fli-1(Δ) (CTA) ). Fli-1(Δ) (CTA) (/Δ) (CTA) mice had significantly increased populations of haematopoietic stem cells and common dendritic cell precursors in bone marrow compared with wild-type littermates. Significantly increased classical dendritic cells, plasmacytoid dendritic cells, and macrophage populations were found in spleens from Fli-1(∆) (CTA) (/∆) (CTA) mice compared with wild-type littermates. Fli-1(Δ) (CTA) (/Δ) (CTA) mice also had increased pre-classical dendritic cell and monocyte populations in peripheral blood mononuclear cells. Furthermore, bone marrow reconstitution studies demonstrated that expression of Fli-1 in both haematopoietic cells and stromal cells affected mononuclear phagocyte development in mice. Expression of Fms-like tyrosine kinase 3 ligand (Flt3L), a haematopoietic growth factor, in multipotent progenitors was statistically significantly increased from Fli-1(∆) (CTA) (/∆) (CTA) mice compared with wild-type littermates. Fli-1 protein binds directly to the promoter region of the Flt3L gene. Hence, Fli-1 plays an important role in the mononuclear phagocyte development, and the C-terminal transcriptional activation domain of Fli-1 negatively modulates mononuclear phagocyte development. 23958822 Epiphyseal abnormalities, trabecular bone loss and articular chondrocyte hypertrophy develop in the long bones of postnatal Ext1-deficient mice. Long bones are integral components of the limb skeleton. Recent studies have indicated that embryonic long bone development is altered by mutations in Ext genes and consequent heparan sulfate (HS) deficiency, possibly due to changes in activity and distribution of HS-binding/growth plate-associated signaling proteins. Here we asked whether Ext function is continuously required after birth to sustain growth plate function and long bone growth and organization. Compound transgenic Ext1(f/f);Col2CreERT mice were injected with tamoxifen at postnatal day 5 (P5) to ablate Ext1 in cartilage and monitored over time. The Ext1-deficient mice exhibited growth retardation already by 2weeks post-injection, as did their long bones. Mutant growth plates displayed a severe disorganization of chondrocyte columnar organization, a shortened hypertrophic zone with low expression of collagen X and MMP-13, and reduced primary spongiosa accompanied, however, by increased numbers of TRAP-positive osteoclasts at the chondro-osseous border. The mutant epiphyses were abnormal as well. Formation of a secondary ossification center was significantly delayed but interestingly, hypertrophic-like chondrocytes emerged within articular cartilage, similar to those often seen in osteoarthritic joints. Indeed, the cells displayed a large size and round shape, expressed collagen X and MMP-13 and were surrounded by an abundant Perlecan-rich pericellular matrix not seen in control articular chondrocytes. In addition, ectopic cartilaginous outgrowths developed on the lateral side of mutant growth plates over time that resembled exostotic characteristic of children with Hereditary Multiple Exostoses, a syndrome caused by Ext mutations and HS deficiency. In sum, the data do show that Ext1 is continuously required for postnatal growth and organization of long bones as well as their adjacent joints. Ext1 deficiency elicits defects that can occur in human skeletal conditions including trabecular bone loss, osteoarthritis and HME. 23103347 Adolescent male rats are less sensitive than adults to the anxiogenic and serotonin-releasing effects of fenfluramine. Risk taking behavior increases during adolescence, which is also a critical period for the onset of drug abuse. The central serotonergic system matures during the adolescent period, and its immaturity during early adolescence may contribute to adolescent risk taking, as deficits in central serotonergic function have been associated with impulsivity, aggression, and risk taking. We investigated serotonergic modulation of behavior and presynaptic serotonergic function in adult (67-74 days old) and adolescent (28-34 days old) male rats. Fenfluramine (2 mg/kg, i.p.) produced greater anxiogenic effects in adult rats in both the light/dark and elevated plus maze tests for anxiety-like behavior, and stimulated greater increases in extracellular serotonin in the adult medial prefrontal cortex (mPFC) (1, 2.5, and 10 mg/kg, i.p.). Local infusion of 100 mM potassium chloride into the mPFC also stimulated greater serotonin efflux in adult rats. Adult rats had higher tissue serotonin content than adolescents in the prefrontal cortex, amygdala, and hippocampus, but the rate of serotonin synthesis was similar between age groups. Serotonin transporter (SERT) immunoreactivity and SERT radioligand binding were comparable between age groups in all three brain regions. These data suggest that lower tissue serotonin stores in adolescents limit fenfluramine-stimulated serotonin release and so contribute to the lesser anxiogenic effects of fenfluramine. 23872866 Modulation of plasma antioxidant levels, glutathione S-transferase activity and DNA damage in smokers following a single portion of broccoli: a pilot study. Broccoli is a rich source of bioactive compounds (i.e. glucosinolates, carotenoids, vitamin C and folate) that may exert an antioxidant effect and reduce oxidative damage. The objective of this pilot study was to investigate the effect of broccoli consumption on carotenoids, vitamin C and folate absorption, glutathione S-transferase (GST) activity, and oxidatively induced DNA damage in male smokers. Ten healthy subjects consumed a single portion of steamed broccoli (250 g) with cooked pasta. Blood was drawn at baseline and at 3, 6 and 24 h from consumption. Broccoli significantly (P ≤ 0.01) increased plasma level of vitamin C and folate (+35% and 70%, respectively) at 3 h, and β-carotene (+8%) at 6 h. A modulation of GST activity occurred in plasma 6 h after broccoli consumption. A significant (P ≤ 0.01) reduction of the levels of H2 O2 -induced DNA damage (-18%) was observed in blood mononuclear cells 24 h after broccoli intake in GSTM1 positive, but not in GSTM1 null subjects. One portion of broccoli increased plasma antioxidant levels, modulated plasma GST activity and improved cell resistance against H2 O2 -induced DNA damage in healthy smokers. These results support the importance of consuming fruit and vegetable regularly. © 2013 Society of Chemical Industry. 23901103 Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain. P-glycoprotein (P-gp) is one of the best-known mediators of drug efflux-based multidrug resistance in many cancers. This validated therapeutic target is a prototypic, plasma membrane resident ATP-Binding Cassette transporter that pumps xenobiotic compounds out of cells. The large, polyspecific drug-binding pocket of P-gp recognizes a variety of structurally unrelated compounds. The transport of these drugs across the membrane is coincident with changes in the size and shape of this pocket during the course of the transport cycle. Here, we present the crystal structures of three inward-facing conformations of mouse P-gp derived from two different crystal forms. One structure has a nanobody bound to the C-terminal side of the first nucleotide-binding domain. This nanobody strongly inhibits the ATP hydrolysis activity of mouse P-gp by hindering the formation of a dimeric complex between the ATP-binding domains, which is essential for nucleotide hydrolysis. Together, these inward-facing conformational snapshots of P-gp demonstrate a range of flexibility exhibited by this transporter, which is likely an essential feature for the binding and transport of large, diverse substrates. The nanobody-bound structure also reveals a unique epitope on P-gp. 23947327 Bridging the Gap Between Implementation Science and Parenting Intervention. Kaminski et al.(1) recently reported selected findings from a study evaluating two group-based parenting interventions designed to promote "more positive socioemotional, behavioral, cognitive, and health outcomes" for children in low-income families (defined as < 200% of the federal poverty line). The authors provide a laudably clear and detailed flow diagram of study enrollment and follow-up assessment rates. However, specific and meaningful information about intervention exposure, participation rates, and other fundamental implementation considerations are not provided alongside the reporting of outcomes. The omission of core implementation data brings into sharp focus two interrelated and chronic limitations in the intervention research literature, in general, and particularly in the knowledge base on parenting interventions. These gaps, described below, heavily constrain the public health impact of programming for vulnerable families and children. (Am J Public Health. Published online ahead of print August 15, 2013: e1-e2. doi:10.2105/AJPH.2013.301500). 23937398 "Psychiatry is not a science like others" - a focus group study on psychotropic prescribing in primary care. Psychotropic drug prescribing is problematic and knowledge of factors affecting the initiation and maintenance of such prescribing is incomplete. Such knowledge could provide a basis for the design of interventions to change prescribing patterns for psychotropics. The aim of this study was to explore the views of general practitioners (GPs), GP interns, and heads of primary care units on factors affecting the prescribing of psychotropic drugs in primary care. We performed four focus group discussions in Gothenburg, Sweden, with a total of 21 participants (GPs, GP interns, and heads of primary care units). The focus group discussions were transcribed verbatim and analyzed using manifest content analysis. Three different themes emerged from the focus group discussions. The first theme Seeking care for symptoms, reflects the participants' understanding of why patients approach primary care and comprised categories such as knowledge, attitudes, and society and the media. The second theme, Lacking a framework, resources, and treatment alternatives, which reflects the conditions for the physician-patient interaction, comprised categories such as economy and resources, technology, and organizational aspects. The third theme, Restricting or maintaining prescriptions, with the subthemes Individual factors and External influences, reflects the physicians' internal decision making and comprised categories such as emotions, knowledge, and pharmaceutical industry. The results of the present study indicate that a variety of factors may affect the prescribing of psychotropic medications in primary care. Many factors were related to characteristics of the patient, the physician or their interaction, rather than the patients' medical needs per se. The results may be useful for interventions to improve psychotropic prescribing in primary care. 23828577 TGF-β1 regulates cell fate during epithelial-mesenchymal transition by upregulating survivin. Members of the transforming growth factor beta (TGF-β) superfamily are multifunctional cytokines that regulate several cellular processes, including cell cycle arrest, differentiation, morphogenesis, and apoptosis. TGF-β promotes extracellular matrix production and morphological change. Morphogenetic responses to TGF-β include cell migration and epithelial-mesenchymal transition (EMT), which are critical during embryogenesis, development of fibrotic diseases, and the spreading of advanced carcinomas. The purpose of this study was to clarify how TGF-β regulates the fate of retinal pigment epithelial (RPE) cells. TGF-β1 promoted cell cycle progression and phosphorylation of retinoblastoma protein (Rb) in ARPE-19 cells. TGF-β1 induced survivin expression, which in turn stabilized tubulin and Aurora B. RT-PCR and western blot analysis revealed that survivin expression increased in ARPE-19 cells following TGF-β1 treatment. When survivin was depleted, TGF-β1 induced cell cycle arrest and apoptosis and also reduced Rb phosphorylation. In conclusion, the present study shows that induction of EMT in human RPE cells upregulates survivin, leading to survivin-dependent inhibition of cell cycle arrest and apoptosis. Whether cells undergo EMT or apoptosis in response to TGF-β1 is dependent on their cell cycle state, and TGF-β1 regulates the cell cycle via survivin. 23909755 Biological Importance and Statistical Significance. Statistical ideas behind the analysis of experiments related to crop composition and the genetic factors underlying composition are discussed. The emphasis is on concepts rather than statistical formulations. Statistical analysis and biological considerations are shown to be complementary rather than contradictory, in that the statistical analysis of a data set depends on the experimental design, that no amount of statistical sophistication can rescue a badly designed study, and that good experimental design is crucial. The traditional null hypothesis significance testing approach has severe limitations, but p values and statistical significance still often seem to be the primary objective of an analysis. Emphasis instead should be on identifying the size of effects that are biologically important and, with the involvement of the "domain" scientist, using these to help design experiments with appropriate sample sizes and statistical power. The issues discussed here are also directly applicable to other areas of research. 23770613 Combined deficiency in glutathione peroxidase 4 and vitamin e causes multiorgan thrombus formation and early death in mice. Rationale: Growing evidence indicates that oxidative stress contributes markedly to endothelial dysfunction. The selenoenzyme glutathione peroxidase 4 (Gpx4) is an intracellular antioxidant enzyme important for the protection of membranes by its unique activity to reduce complex hydroperoxides in membrane bilayers and lipoprotein particles. Yet a role of Gpx4 in endothelial cell function has remained enigmatic. Objective: To investigate the role of Gpx4 ablation and subsequent lipid peroxidation in the vascular compartment in vivo. Methods and Results: Endothelium-specific deletion of Gpx4 had no obvious impact on normal vascular homeostasis, nor did it impair tumor-derived angiogenesis in mice maintained on a normal diet. In stark contrast, aortic explants from endothelium-specific Gpx4 knockout mice showed a markedly reduced number of endothelial branches in sprouting assays. To shed light onto this apparent discrepancy between the in vivo and ex vivo results, we depleted mice of a second antioxidant, vitamin E, which is normally absent under ex vivo conditions. Therefore, mice were fed a vitamin E-depleted diet for 6 weeks before endothelial deletion of Gpx4 was induced by 4-hydroxytamoxifen. Surprisingly, ≈80% of the knockout mice died. Histopathological analysis revealed detachment of endothelial cells from the basement membrane and endothelial cell death in multiple organs, which triggered thrombus formation. Thromboembolic events were the likely cause of various clinical pathologies, including heart failure, renal and splenic microinfarctions, and paraplegia. Conclusions: Here, we show for the first time that in the absence of Gpx4, sufficient vitamin E supplementation is crucial for endothelial viability. 23360215 Exploring a new frontier in cancer treatment: targeting the ubiquitin and ubiquitin-like activating enzymes. The labeling of proteins with small ubiquitin (Ub) and ubiquitin-like (Ubl) modifiers regulates a plethora of activities within the cell, such as protein recycling, cell cycle modifications, and protein translocation. These processes are often overactive in diseased cells, leading to unregulated cell growth and disease progression. Therefore, in systems where Ub/Ubl protein labeling is dysregulated, the development of drugs to selectively and potently disrupt Ub/Ubl protein labeling offers a targeted molecular approach for sensitizing these diseased cells. This Perspective outlines the progress that has been made in the context of inhibitor development for targeting Ub/Ubl pathways. 23969537 Feeding Immaturity in Preterm Neonates: Risk Factors for Oropharyngeal Aspiration and Timing of Maturation. Oropharyngeal aspiration (OPA) is a common cause of morbidity in premature neonates. We sought to identify significant risk factors and determine the timing of feeding maturation in preterm infants with OPA. We performed a retrospective medical record review of 148 former preterm neonates referred for modified barium swallow study (MBSS) over a 3-year period. We looked at MBSS result and potential clinical and demographic risk factors and performed bivariate and multivariable logistic regression analyses to evaluate predictors of failure. We evaluated the timing of resolution of OPA based on MBSS result. Of the 148 infants comprising our study cohort, 47 (32%) passed their initial MBSS and 101 (68%) were found to aspirate thin liquids. Infants who aspirate had younger corrected gestational age (CGA) and postnatal age at the time of testing. Increasing CGA led to lower odds of failing. Infants passed a MBSS at a median CGA of 53 weeks and those who failed an initial MBSS eventually passed after a median of ∼3.4 months from the first study. Infants with BPD had lower odds of failing their MBSS (OR = .16), but those on inhaled corticosteroids and diuretics had higher odds of failing, and infants who were multiples also had higher odds of failing. We determined the median CGA for passing MBSS and identified risk factors for OPA in this population. This information can help guide providers when counseling families on timing of feeding maturity and anticipation of appropriate timing for follow-up MBSS testing. 22994904 Long-term ethanol effects on acute stress responses: modulation by dynorphin. The brain stress-response system is critically involved in the addiction process, stimulating drug consumption and the relapse to drug taking in abstinent addicts. At the same time, its functioning is affected by chronic drug exposure. Here, we have investigated the role of the endogenous opioid peptide dynorphin as a modulator of effects of long-term ethanol consumption on the brain stress-response system. Using the two-bottle choice paradigm, we demonstrate an enhanced ethanol preference in male dynorphin knockout mice. Exposure to mild foot shock increased ethanol consumption in wild-type control littermates, but not in dynorphin-deficient animals. Blood adrenocorticotropic hormone levels determined 5 minutes after the shock were not affected by the genotype. We also determined the neuronal reactivity after foot shock exposure using c-Fos immunoreactivity in limbic structures. This was strongly influenced by both genotype and chronic ethanol consumption. Long-term alcohol exposure elevated the foot shock-induced c-Fos expression in the basolateral amygdala in wild-type animals, but had the opposite effect in dynorphin-deficient mice. An altered c-Fos reactivity was also found in the periventricular nucleus, the thalamus and the hippocampus of dynorphin knockouts. Together these data suggest that dynorphin plays an important role in the modulation of the brain stress-response systems after chronic ethanol exposure. 23557703 Effects of Common Genetic Variants Associated With Type 2 Diabetes and Glycemic Traits on α- and β-Cell Function and Insulin Action in Humans. Although meta-analyses of genome-wide association studies have identified >60 single nucleotide polymorphisms (SNPs) associated with type 2 diabetes and/or glycemic traits, there is little information on whether these variants also affect α-cell function. The aim of the current study was to evaluate the effects of glycemia-associated genetic loci on islet function in vivo and in vitro. We studied 43 SNPs in 4,654 normoglycemic participants from the Finnish population-based Prevalence, Prediction, and Prevention of Diabetes-Botnia (PPP-Botnia) Study. Islet function was assessed, in vivo, by measuring insulin and glucagon concentrations during oral glucose tolerance test, and, in vitro, by measuring glucose-stimulated insulin and glucagon secretion from human pancreatic islets. Carriers of risk variants in BCL11A, HHEX, ZBED3, HNF1A, IGF1, and NOTCH2 showed elevated whereas those in CRY2, IGF2BP2, TSPAN8, and KCNJ11 showed decreased fasting and/or 2-h glucagon concentrations in vivo. Variants in BCL11A, TSPAN8, and NOTCH2 affected glucagon secretion both in vivo and in vitro. The MTNR1B variant was a clear outlier in the relationship analysis between insulin secretion and action, as well as between insulin, glucose, and glucagon. Many of the genetic variants shown to be associated with type 2 diabetes or glycemic traits also exert pleiotropic in vivo and in vitro effects on islet function. 23955300 Limitations of routine neuroimaging in predicting outcomes of preterm infants. Preterm births are increasing in number and while the rates of cerebral palsy have declined, there are increasing numbers of infants who survive with handicaps. In some studies, up to 50 % of children will have morbidity when followed up to school age. A review of current literature was conducted to determine the validity of routine cranial ultrasound scans (CUS) to predict neurodevelopmental outcomes, including motor and cognitive deficits. We also reviewed the additional benefit offered by including MRI scans in scanning protocols to enhance the reliability in predicting the neurodevelopmental sequelae of prematurity. CUS is valuable as a screening tool to determine significant brain injury when conducted regularly over the first weeks of life in preterm infants. Subtle changes on CUS are difficult to interpret and more precise information is offered by performing MRI scans. These are most often carried out at term equivalent age but earlier scans may be just as useful in predicting neurocognitive outcomes. When MRI scans are either normal or seriously abnormal, there is a very clear correlation with outcome to 2 years of age. Mild and moderate degrees of injury defined on MRI need more sophisticated scanning sequences to determine the likelihood of associated sequelae. Follow-up to school age is essential to diagnose more subtle cognitive delays. CUS provides a good screening tool to detect serious brain injury resulting in motor handicaps but MRI scans are complementary and necessary to accurately predict the outcomes of preterm infants, especially cognitive delays. 23022519 Should epidermal growth factor receptor tyrosine kinase inhibitors be considered ideal drugs for the treatment of selected advanced non-small cell lung cancer patients? An ideal target-based agent for the treatment of cancer patients should fulfil a number of requirements, including the availability of biomarkers to select the target population, superiority over existing treatments and specific advantages in terms of pharmacokinetics and/or metabolism. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, erlotinib and afatinib, have been investigated in the treatment of non-small cell lung cancer (NSCLC), and to date a large amount of clinical data are available. The activity of EGFR-TKIs was initially investigated in unselected patients leading to unsatisfactory results. However, the discovery that response to EGFR-TKIs is associated with the presence of activating EGFR mutations in NSCLC, has led to the design of clinical trials in which patients were selected on the basis of the EGFR mutational status or of clinical and pathological features that are highly associated with the presence of EGFR mutations. In this respect, several phase III randomized trials have demonstrated that first-line EGFR-TKIs, compared to chemotherapy, is associated with longer progression-free survival, higher response rate, better toxicity profile and quality of life in patients carrying EGFR mutations. Although no survival advantage was demonstrated, all the trials suffered of a high post-progression treatment cross-over, which predictably undermined the results. This review will summarize the current evidence that strongly support the hypothesis that gefitinib, erlotinib and afatinib are ideal drugs for NSCLC patients carrying EGFR mutations. 23587126 Genomic damage as an independent predictor marker of mortality in hemodialysis patients. Hemodialysis (HD) patients present an enhanced mortality. Since oxidative DNA damage can be considered a biomarker of genomic instability our aim was to evaluate the influence of this genetic biomarker in all-cause mortality in a group of HD patients followed for 4 years. 123 chronic HD patients were included. Overall genomic damage was analyzed using the Comet assay. Oxidative DNA damage was measured using the Comet assay complemented with the use of Endo-III and FPG enzymes. Follow-up was carried out from January 2007 to July 2011. Selected HD patients had a mean age of 62 ± 15 years. During the follow-up 36% of patients died (48% due to cardiovascular disease) and 23% were transplanted. Older patients, with high CRP levels, low levels of cholesterol-HDL and albumin, and higher genetic damage at the beginning of the study showed an increased risk for mortality. Multivariate analysis showed that only genomic damage, age and CRP were independently associated with mortality. Our study shows for the first time that, in HD patients, the presence of high levels of genomic damage is a strong predictor of all-cause mortality. This association remains significant after adjustment for relevant covariates. 23623577 High b-value diffusion tensor imaging of the remote white matter and white matter of obstructive unilateral cerebral arterial regions. To assess diffusion changes in the remote white matter and areas of white matter with cerebral artery obstruction without magnetic resonance imaging (MRI) evidence of brain parenchymal abnormalities using high b-value diffusion tensor imaging (DTI). A total of 34 patients with severe unilateral stenosis (≥75%) or occlusion of the middle cerebral artery (MCA) without abnormal brain parenchymal signals at MRI underwent DTI with a b value of 2200 s/mm(2) at 3 T. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (eigenvalue λ₁) and radial diffusivity (eigenvalue λ₂₃) were measured at the bilateral corona radiata, anterior and posterior limbs of the internal capsule, cerebral peduncle, and pons. The mean FA was significantly lower at the ipsilateral corona radiata and anterior and posterior limbs of the internal capsule than at the contralateral corona radiata and anterior and posterior limbs of the internal capsule (p < 0.05). The mean ADC, λ₁ and λ₂₃ were significantly higher at the ipsilateral corona radiata than at the contralateral corona radiata (p < 0.01). The mean λ₂₃ were significantly higher at the ipsilateral anterior and posterior limb of the internal capsule than at the contralateral anterior and posterior limb of the internal capsule (p < 0.05). The mean ADC, λ₁ and λ₂ ₃were not significantly different between the ipsilateral cerebral peduncle and pons. High b-value DTI could sensitively reveal diffusion changes in white matter in regions of cerebral artery obstruction without abnormal anisotropy and diffusivity of the remote white matter of patients with severe MCA stenosis or occlusion without MRI evidence of brain parenchymal abnormalities. 23278988 Prognostic significance of Ror2 and Wnt5a expression in medulloblastoma. Medulloblastoma (MB) is a clinically and biologically heterogeneous group of tumors, and currently classified into four molecular subgroups (Wnt, Shh, Group 3 and Group 4). Intracellular signaling of the Wnt pathway has been divided into two classes: the "canonical" and the "non-canonical" signaling pathway. The canonical signaling pathway is a well-established, β-catenin-dependent signaling pathway in MB. In contrast, very little research about the non-canonical WNT signaling pathway in MB exists. In order to identify the roles of Wnt-5a and Ror2, two non-canonical WNT pathway-related genes, we studied 76 cases of MB with immunohistochemistry and quantitative real-time PCR and correlated the results with clinicopathological and other molecular parameters and prognosis. Wnt5a and Ror2 were immunopositive in 20 (29.4%) and 35 (51.5%) of 68 cases, respectively. There were positive associations among protein expressions of Wnt5a, Ror2 and β-catenin. Ror2 mRNA levels were well correlated with immunoexpression. Ror2 mRNA expression was significantly associated with CTNNB1 mutation. High Ror2 mRNA expression was an independent favorable prognostic factor. In conclusion, our study demonstrates the first attempt to identify Wnt5a and Ror2 as additional mechanisms contributing to dysregulation of the non-canonical WNT signaling pathway in MB. Ror2 may play a role as an oncosuppressor in MB. 23933476 Reliable noninvasive prenatal testing by massively parallel sequencing of circulating cell-free DNA from maternal plasma processed up to 24h after venipuncture. Circulating cell-free fetal DNA (ccffDNA) in maternal plasma is an attractive source for noninvasive prenatal testing (NIPT). The amount of total cell-free DNA significantly increases 24h after venipuncture, leading to a relative decrease of the ccffDNA fraction in the blood sample. In this study, we evaluated the downstream effects of extended processing times on the reliability of aneuploidy detection by massively parallel sequencing (MPS). Whole blood from pregnant women carrying normal and trisomy 21 (T21) fetuses was collected in regular EDTA anti-coagulated tubes and processed within 6h, 24 and 48h after venipuncture. Samples of all three different time points were further analyzed by MPS using Z-score calculation and the percentage of ccffDNA based on X-chromosome reads. Both T21 samples were correctly identified as such at all time-points. However, after 48h, a higher deviation in Z-scores was noticed. Even though the percentage of ccffDNA in a plasma sample has been shown previously to significantly decrease 24h after venipuncture, the percentages based on MPS results did not show a significant decrease after 6, 24 or 48h. The quality and quantity of ccffDNA extracted from plasma samples processed up to 24h after venipuncture are sufficiently high for reliable downstream NIPT analysis by MPS. Furthermore, we show that it is important to determine the percentage of ccffDNA in the fraction of the sample that is actually used for NIPT, as downstream procedures might influence the fetal or maternal fraction. 23864300 Does fertility status influence impulsivity and risk taking in human females? Adaptive influences on intertemporal choice and risky decision making. Informed by the research on adaptive decision making in other animal species, this study investigated human females' intertemporal and risky choices across the ovulatory cycle. We tested the hypothesis that at peak fertility, women who are exposed to environments that signal availability of higher quality mates (by viewing images of attractive males), become more impulsive and risk-seeking in economic decision tasks. To test this, we collected intertemporal and risky choice measures before and after exposure to images of either attractive males or neutral landscapes both at peak and low fertility conditions. The results showed an interaction between women's fertility status and image type, such that women at peak fertility viewing images of attractive men chose the smaller, sooner monetary reward option less than women at peak fertility viewing neutral images. Neither fertility status nor image type influenced risky choice. Thus, though exposure to images of men altered intertemporal choices at peak fertility, this occurred in the opposite direction than predicted-i.e., women at peak fertility became less impulsive. Nevertheless, the results of the current study provide evidence for shifts in preferences over the ovulatory cycle and opens future research on economic decision making. 23839448 181 Percutaneous dorsal root ganglion lysis with phenol for treatment of thoracic compression fracture. Symptomatic thoracic compression fracture is 1 of the most common causes of back pain in the elderly. Vertebroplasty is widely used in patients where conservative treatment failed. We introduce an alternative percutaneous technique for treating thoracic compression pain. Patients with thoracic compression fracture undergoing percutaneous dorsal root ganglion lysis with phenol between August 1, 2010, and January 31, 2012, at Chang Gung Memorial Hospital, a tertiary care center in Chia-Yi, Taiwan. Inclusion criteria were: thoracic compression fracture on spine radiograph; back pain between 3 to 8 weeks where conservative treatment failed; visual analogue scale (VAS) score of 7 or more; T score = -1; back knocking pain on fracture level; still back pain after vertebroplasty, or severe cardiopulmonary disease, or liver cirrhosis child C, or strong patient preference. The primary outcome was pain relief and satisfied improvement at 1 day, 1 week, 1 month, and 1 year as measured by VAS score and EuroQol-5 dimensions (EQ-5D) questionnaire. Of the 28 thoracic compression fractures treated with percutaneous dorsal root ganglion lysis with phenol cases, the change in mean VAS score between baseline and 1 day was -2.0 (95% CI -1.3∼-2.7, P < .001), between baseline and 1 week was -4.1 (-3.4 to -4.8, P < .001), between baseline and 1 month was -5.5 (-4.7 to -6.3, P < .001), and between baseline and 1 year was -6.3 (-5.6 to -7.1, P < .001). Satisfied improvement was 14 % 1 day after the procedure, 46% at 1 week, 72% at 1 month, and 84% at 1 year. Complication rate was 3.6%. For thoracic compression fracture patients, percutaneous dorsal root ganglion lysis with phenol is an effective and safe alternative treatment method. Pain relief is fast and lasts for 1 year. 23929933 Fibroblast Growth Factor 23 and Cardiovascular Mortality after Kidney Transplantation. Circulating fibroblast growth factor 23 (FGF23) is associated with adverse cardiovascular outcomes in CKD. Whether FGF23 predicts cardiovascular mortality after kidney transplantation, independent of measures of mineral metabolism and cardiovascular risk factors, is unknown. The association between plasma C-terminal FGF23 and cardiovascular mortality was analyzed in a single-center prospective cohort of 593 stable kidney transplant recipients (mean age ± SD, 52±12 years; 54% male; estimated GFR, 47±16 ml/min per 1.73 m(2)), at a median of 6.1 (interquartile range, 2.7-11.7) years after transplantation. Multivariate Cox regression models were built, adjusting for measures of renal function and mineral metabolism; Framingham risk factors; the left ventricular wall strain markers midregional fragment of pro-A-type natriuretic peptide (MR-proANP) and N-terminal-pro brain natriuretic peptide (NT-proBNP); and copeptin, the stable C-terminal portion of the precursor of vasopressin. In multivariate linear regression analysis, MR-proANP (β=0.20, P<0.001), NT-proBNP (β=0.18, P<0.001), and copeptin (β=0.26, P<0.001) were independently associated with FGF23. During follow-up for 7.0 (interquartile range, 6.2-7.5) years, 128 patients (22%) died, of whom 66 (11%) died due to cardiovascular disease; 54 (9%) had graft failure. FGF23 was associated with an higher risk of cardiovascular mortality in a fully adjusted multivariate Cox regression model (hazard ratio [HR], 1.88 [95% confidence interval (CI), 1.11 to 3.19]; P=0.02). FGF23 was also independently associated with all-cause mortality (full model HR, 1.86 [95% CI, 1.27 to 2.73]; P=0.001). Net reclassification improved for both cardiovascular mortality (HR, 0.07 [95% CI, 0.01 to 0.14]; P<0.05) and all-cause mortality (HR, 0.11 [95% CI, 0.05 to 0.18]; P<0.001). Plasma FGF23 is independently associated with cardiovascular and all-cause mortality after kidney transplantation. The association remained significant after adjustment for measures of mineral metabolism and cardiovascular risk factors. 23820826 Enhancing the usefulness of cross dehydrogenative coupling reactions with a removable protecting group. A removable protecting group has been identified that allows the products of widely-used cross dehydrogenative couplings to be synthetically elaborated. The method can be used with enantiopure amines with no loss of enantiomeric excess. The methodology is exemplified by a new synthesis of enantiopure praziquantel, the drug used in the treatment of millions of people suffering from the neglected tropical disease, schistosomiasis. 23822881 Distinct mechanism of formation of the 48, XXYY karyotype. To expose the unusual nature of a coincident sex chromosomal aneuploidy in a patient and his father. Molecular mechanisms involved probably are based on the sperm chromosome of paternal origin, which determine the mode of formation. Conventional cytogenetics techniques and multiple Quantitative Fluorescent PCR of STR markers in sexual chromosomes in the patient and his parents. 48,XXYY and 47,XYY aneuploidies in the patient and his father, respectively, were identified. The additional X and Y chromosomes showed parental origin. An infrequent origin of the 48,XXYY syndrome was demonstrated. Mostly, it is thought to result from an aneuploid sperm produced through two consecutive non disjunction events in both meiosis I and II in a chromosomally normal father, but in our father's patient a 47,XYY was discovered. It is suggested that a higher incidence of 24,XY and 24,YY sperm may be possible in 47,XYY individuals andan increased risk for aneuploidy pregnancies may exist. Although 48,XXYY patients and Klinefelter syndrome are often compared, recently they are regarded as a distinct genetic and clinical entity. 23884880 Anatomic Variations in Branching Patterns of the Axillary Artery: A Multidetector-Row Computed Tomography Angiography Study. Anatomic variations in branching pattern of axillary artery (AxA) are common and typically involve subscapular artery (SsA) and posterior circumflex humeral artery (PCHA). Several skin and muscle flaps are based on the branches of AxA. Furthermore, these branches are frequently used as recipient vessels in functioning free muscle transfers for upper extremity reconstruction and in breast reconstruction. Accurate knowledge of the normal anatomy and variations in branching pattern of AxA is of significant clinical importance for the reconstructive microsurgeon. The purpose of this article is to report the variable branching pattern of AxA based on multidetector-row computed tomography angiography study of 62 upper extremities. The thoracoacromial artery consistently originated from the first or second part of AxA. The classic origin and branching patterns of SsA and PCHA were observed in 21 cases (33.9%). Anatomic variations of SsA and PCHA were observed in 41 upper extremities (66.1%). In addition to the classic pattern, five distinct variations were noted. 23877758 Clinical value of surveillance pouchoscopy in asymptomatic ileal pouch patients with underlying inflammatory bowel disease. There is no consensus on the need for and the interval of surveillance pouchoscopy in asymptomatic ileal pouch patients with underlying ulcerative colitis (UC). The purpose of this study was to evaluate the likelihood of finding dysplasia or incidental ileal pouch disorders in asymptomatic patients undergoing surveillance pouchoscopy. This study included all eligible consecutive asymptomatic UC patients undergoing surveillance pouchoscopy to our subspecialty Pouchitis Clinic from 2002 to 2011. Univariable and multivariable analyses were performed. A total of 138 patients met the inclusion criteria, with 72 (52.2 %) being male. The mean age at pouch construction was 45.4 ± 15.0 years, and the mean interval from ileostomy closure to the inception of first surveillance pouchoscopy was 89.4 ± 78.8 months. One patient was found to have indefinite for dysplasia on pouch body mucosal biopsy (0.7 %), and two patients had non-caseating granulomas, suggesting Crohn's disease (CD) of the pouch. Of the 138 patients, 69 (50 %) had abnormal endoscopic findings, 102 (73.9 %) had acute and/or chronic inflammation on histology, and 62 (44.9 %) had both abnormal endoscopy and histology. The abnormal endoscopic findings included isolated pouch ulcer (n = 29, 21 %), active pouchitis (n = 31, 22.5 %), inflammatory polyps (n = 10, 7.2 %), strictures at the anastomosis (n = 5, 3.6 %), inlet (n = 10, 7.2 %) or outlet (n = 2, 1.4 %). Thirteen patients (13/17, 76.5 %) with pouch strictures underwent endoscopic balloon dilatation therapy and nine had (9/10, 90 %) endoscopic polypectomy. Multivariable analysis showed that patients with a preoperative diagnosis of CD and concomitant extraintestinal manifestations had a higher risk for abnormal pouch endoscopic findings with odds ratios of 2.552 (95 % confidence interval [CI] 1.108-16.545, p = 0.035) and 4.281 (95 % CI 1.204-5.409, p = 0.014), respectively. Dysplasia was rare in asymptomatic patients with restorative proctocolectomy who underwent surveillance pouchoscopy in this cross-sectional study. However, "incidental" abnormal endoscopic and/or histologic findings were common, which often needed endoscopic therapeutic intervention. 23764359 14-Deoxyandrographolide targets adenylate cyclase and prevents ethanol-induced liver injury through constitutive NOS dependent reduced redox signaling in rats. Chronic alcoholism is one of the most common causes of liver diseases worldwide. Nitric oxide (NO) has been proposed to have potential for clinical application against chronic hepatocellular injuries. However, mechanisms underlying hepatoprotective functions of NO in ethanol-induced apoptosis are largely unknown. Sprauge-Dawley rats were exposed to ethanol for 8weeks. Half of the ethanol-fed animals received 14-deoxyandrographolide (14-DAG) treatment for the last 4weeks of study. Preventive effect of 14-DAG against ethanol-induced hepatotoxicity involved constitutive nitric oxide synthase (cNOS) activation followed by up-regulation of γ-glutamylcysteine synthetase activity and reduced oxidative stress. Enhanced interaction of cNOS with caveolin-1 caused down-regulation of enzyme activity and led to depletion of NO in the hepatocytes of ethanol-fed animals. 14-DAG acted as activator of adenylate cyclase and modulated cyclic AMP (cAMP) mediated expression of caveolin-1 and calmodulin. This eventually favored activation of cNOS through inhibition of cNOS-caveolin-1 interaction. Our results suggest that, protective effect of 14-DAG against ethanol-induced hepatic injury is based on its ability to reduce oxidative stress through cNOS dependent improvement of redox status. 14-DAG mediated activation of adenylate cyclase-cAMP signaling leading to up-regulation of cNOS may provide a promising approach in the prevention of liver diseases during chronic alcoholism. 23600402 Assessing the Accuracy and Performance of Implicit Solvent Models for Drug Molecules: Conformational Ensemble Approaches. The accuracy and performance of implicit solvent methods for solvation free energy calculations were assessed on a set of 20 neutral drug molecules. Molecular dynamics (MD) provided ensembles of conformations in water and water-saturated octanol. The solvation free energies were calculated by popular implicit solvent models based on quantum mechanical (QM) electronic densities (COSMO-RS, MST, SMD) as well as on molecular mechanical (MM) point-charge models (GB, PB). The performance of the implicit models was tested by a comparison with experimental water-octanol transfer free energies (ΔGow) by using single- and multiconformation approaches. MD simulations revealed difficulties in a priori estimation of the flexibility features of the solutes from simple structural descriptors, such as the number of rotatable bonds. An increasing accuracy of the calculated ΔGow was observed in the following order: GB1 ∼ PB < GB7 ≪ MST < SMD ∼ COSMO-RS with a clear distinction identified between MM- and QM-based models, although for the set excluding three largest molecules, the differences among COSMO-RS, MST, and SMD were negligible. It was shown that the single-conformation approach applied to crystal geometries provides a rather accurate estimate of ΔGow for rigid molecules yet fails completely for the flexible ones. The multiconformation approaches improved the performance, but only when the deformation contribution was ignored. It was revealed that for large-scale calculations on small molecules a recent GB model, GB7, provided a reasonable accuracy/speed ratio. In conclusion, the study contributes to the understanding of solvation free energy calculations for physical and medicinal chemistry applications. 23294854 The clinical picture of late-onset PTSD: A 20-year longitudinal study of Israeli war veterans. Delayed-onset posttraumatic stress disorder (PTSD) has been under medico-legal debate for years. Previous studies examining the prevalence and clinical characteristics of delayed-onset PTSD have yielded inconclusive findings. This study prospectively examines the prevalence and clinical picture of late-onset PTSD among Israeli war veterans. It also evaluates whether or not late-onset PTSD erupts after a completely non-symptomatic period. 675 Israeli veterans from the 1982 Lebanon War, with and without antecedent combat stress reaction (CSR), have been assessed 1, 2 and 20 years post-war. They were divided into 4 groups, according to the duration of delay in PTSD onset. Participants completed self-report questionnaires tapping psychopathology, combat exposure and socio-demographics. 16.5% of the veterans suffered from late-onset PTSD. A longer delay in PTSD onset was associated with less severe psychopathology. Also, CSR was associated with a shorter delay in PTSD onset. Finally, the vast majority of veterans already suffered from PTSD symptoms prior to late PTSD onset. Our results offer further validation for the existence of delayed-onset PTSD. Delayed-onset PTSD appears to be a unique sub-type of PTSD, with an attenuated clinical picture. In addition, delayed-onset PTSD may be the result of an incubation process, wherein symptoms already exist prior to PTSD onset. 23306390 The role of SLC2A1 in early onset and childhood absence epilepsies. Early Onset Absence Epilepsy constitutes an Idiopathic Generalized Epilepsy with absences starting before the age of four years. Mutations in SLC2A1, encoding the glucose transporter, account for approximately 10% of EOAE cases. The role of SLC2A1 mutations in absence epilepsies with a later onset has not been assessed. We found two mutation carriers in 26 EOAE patients, while no mutations were found in 124 probands affected by CAE or JAE. 23566059 The immunomodulation effect of aronia extract lacks association with its antioxidant anthocyanins. Abstract Polyphenols comprise a diverse group of molecules with antioxidative and anti-inflammatory activities. To compare the antioxidative and anti-inflammatory capacity of Aronia melanocarpa berries (chokeberries), recognized for their high content of anthocyanins, a noncytotoxic isolation method was developed to obtain high-purity anthocyanins in the extract. The antioxidative activity of the extract, the anthocyanin-rich fraction (AF) was determined by 1,1-diphenyl-2-picrylhydrazyl radical and ferric-reducing ability of plasma along with resveratrol as a reference. The immunomodulation properties were assessed in lipopolysaccharide (LPS)-stimulated human monocytes mono mac 6. The isolated AF, containing six different anthocyanins, exhibited a stronger antioxidative capacity compared to resveratrol. Resveratrol enhanced tumor necrosis factor-α and reduced interleukin-10 (IL-10) production by LPS, whereas AF only had a slight effect in reducing IL-10. These results demonstrated that there was no major relationship between the antioxidative effect and immunomodulation capacities of AF and resveratrol. The immunomodulatory activity of the extract is associated with bioactive compounds in Aronia other than its anthocyanins. 23394887 A mandatory campaign to vaccinate health care workers against pertussis. Pertussis is a highly contagious respiratory infection that has dramatically increased in recent decades and has caused outbreaks in health care facilities. Because of these trends, we implemented a mandatory pertussis (Tdap) employee vaccination program. Final vaccination compliance was 97.8% across all clinical campuses. 23674784 Digital Compared with Screen-Film Mammography: Performance Measures in Concurrent Cohorts within an Organized Breast Screening Program. Purpose: To evaluate the performance of digital direct radiography (DR) and computed radiography (CR) compared with that of screen-film mammography (SFM) in large concurrent cohorts. Materials and Methods: This study was approved by the University of Toronto Research Ethics Board and did not require informed consent. Concurrent cohorts of women aged 50-74 years screened with DR (n = 220 520), CR (n = 64 210), or SFM (n = 403 688) between 2008 and 2009 were identified and followed for 12 months. Performance was compared between cohorts, with SFM as the referent cohort. Associations were examined by using mixed-effect logistic regression. Results: The cancer detection rate was similar for DR (4.9 per 1000; 95% confidence interval [CI]: 4.7, 5.2) and SFM (4.8 per 1000; 95% CI: 4.7, 5.0); however, the rate was significantly lower for CR (3.4 per 1000; 95% CI: 3.0, 3.9) (odds ratio, 0.79; 95% CI: 0.68, 0.93). Recall rates were higher for DR (7.7%; 95% CI: 7.6%, 7.8%) and lower for CR (6.6%; 95% CI: 6.5%, 6.7%) than for SFM (7.4%; 95% CI: 7.3%, 7.5%). Positive predictive value was lower for CR (5.2%; 95% CI: 4.7%, 5.8%) than for SFM (6.6%; 95% CI: 6.4%, 6.8%); however, the adjusted odds were not significant. Conclusion: Although DR is equivalent to SFM for breast screening among women aged 50-74 years, the cancer detection rate was lower for CR. Screening programs should monitor the performance of CR separately and may consider informing women of the potentially lower cancer detection rates. © RSNA, 2013. 23909752 The cooperative roles of PHO80-like cyclins in regulating the G1/S transition and posterior cytoskeletal morphogenesis in Trypanosoma brucei. Cyclins and cyclin-dependent kinases (CDKs) represent the fundamental, crucial regulators of the cell division cycle in eukaryotes. Trypanosoma brucei expresses a large number of cyclins and Cdc2-related kinases (CRKs). However, how these cyclins and CRKs cooperate to regulate cell cycle progression remains poorly understood. Here, we carry out directional yeast two-hybrid assays to identify the interactions between the 10 cyclins and the 11 CRKs and detect a total of 26 cyclin-CRK pairs, among which 20 pairs are new. Our current efforts are focused on four PHO80-like cyclins, CYC2, CYC4, CYC5 and CYC7, and their physical and functional interactions with CRK1. Silencing of the four cyclins and CRK1 leads to the increase of G1 cells and defective DNA replication, suggesting their important roles in promoting the G1/S transition. Additionally, CYC2-, CYC7- and CRK1-deficient cells possess an elongated posterior that is filled with newly assembled microtubules. Further, we show that the four cyclins display distinct subcellular localizations and half-lives, suggesting that they likely undergo distinct regulation. Altogether, our results demonstrate the involvement of four CRK1-associated cyclins, CYC2, CYC4, CYC5 and CYC7, in promoting the G1/S transition and the requirement of CYC2 and CYC7 in maintaining posterior cytoskeletal morphogenesis during the G1/S transition. 23214511 Radiosynthesis and evaluation of [¹¹C-carbonyl]-labeled carbamates as fatty acid amide hydrolase radiotracers for positron emission tomography. Fatty acid amide hydrolase (FAAH) plays a key role in regulating the tone of the endocannabinoid system. Radiotracers are required to image and quantify FAAH activity in vivo. We have synthesized a series of potent FAAH inhibitors encompassing two classes of N-alkyl-O-arylcarbamates and radiolabeled eight of them with carbon-11. The [¹¹C-carbonyl]-radiotracers were evaluated in vitro and ex vivo in rats as potential FAAH imaging agents for positron emission tomography (PET). Both sets of [¹¹C]O-arylcarbamates showed good to excellent brain penetration and an appropriate regional distribution. Pretreatments with a FAAH inhibitor demonstrated that 80-95% of brain uptake of radioactivity constituted binding of the radiotracers to FAAH. Brain extraction measurements showed that binding to FAAH was irreversible and kinetically different for the two classes of carbamates. These promising results are discussed in terms of the requirements of a suitable radiotracer for the in vivo imaging of FAAH using PET. 23699990 Maternal smoking during pregnancy and daughters' risk of gestational diabetes and obesity. The primary aim of the study was to investigate the risk of developing gestational diabetes in women who were exposed to tobacco smoke in utero. Secondary aims were to assess the risk of obesity and non-gestational diabetes. Data were retrieved from the Medical Birth Register of Sweden for women who were born in 1982 (when smoking data were first registered) or later and who had given birth to at least one child; 80,189 pregnancies were included. The associations between in utero smoking exposure (three categories: non-smokers, 1-9 cigarettes/day [moderately exposed] and >9 cigarettes/day [heavily exposed]) and subsequent gestational diabetes (n = 291), non-gestational diabetes (n = 280) and obesity (n = 7,300) were assessed. The adjusted ORs (aORs) of gestational diabetes were increased among women who were moderately (1.62, 95% CI 1.24, 2.13) and heavily (1.52, 95% CI 1.12, 2.06) exposed. The corresponding aORs of obesity were 1.36 (95% CI 1.28, 1.44) and 1.58 (95% CI 1.48, 1.68), respectively. A reduced OR for non-gestational diabetes was seen in the offspring of heavy smokers (aOR 0.66, 95% CI 0.45, 0.96). Women exposed to smoking during fetal life were at higher risk of developing gestational diabetes and obesity. 23964993 Extended Ni(III) Oxyhalide Perovskite Derivatives: Sr2NiO3X (X = F, Cl). Extended layered oxyhalide compounds, Sr2NiO3X (X = F, Cl), with the square pyramidal coordination around the trivalent nickel ions in the low spin state (S = 1/2), are successfully synthesized by a high-pressure and high-temperature reaction. Both these compounds crystallize in the n = 1 Ruddlesden-Popper type structure, but the difference of halogen anions incorporated dictate the anion-site ordering patterns and the magnetic ground states. Sr2NiO3F adopts the tetragonal cell in the space group I4/mmm (a = b = 3.79125(2) Å and c = 13.13754(9) Å), with O/F anions being disordered at the apical sites, while the crystal structure of Sr2NiO3Cl is described in the tetragonal space group P4/nmm (a = b = 3.85566(1) Å and c = 14.43240(6) Å) with O/Cl anions being fully ordered at the apical sites. Additionally, Sr2NiO3Cl undergoes a long-range antiferromagnetic order below TN = 33 K, while the fluorine counterpart does not exhibit a long-range ordering but spin glass transition at TSG = 11 K. In light of the positive Weiss temperatures for both X = F and Cl, the unpaired electron likely occupies a d(xy) orbital. Namely, the superexchange interaction mediated by d(xy)-Opπ-d(xy) in the NiO2 basal plane is antiferromagnetic, while the direct exchange interaction between d(xy)-d(xy) along the diagonal directions is ferromagnetic. The origin of spin glass behavior observed in X = F is probably due to randomness of the direct d(xy)-d(xy) bonds caused by off-centering nickel ions and O/F site disordering. 23419432 Incident hyperglycemia, parenteral nutrition administration and adverse outcomes in patients with myeloma admitted for initial auto-SCT. Parenteral nutrition (PN) exacerbates hyperglycemia, which is associated with increased morbidity and mortality in various cancer populations. By using a retrospective design, we examined incident hyperglycemia in PN and non-PN recipients and the associations with clinical events and 5-year survival in a cohort treated for myeloma with melphalan and auto-SCT (n=112). Clinical comparisons were made at admission, and 'before' and 'after' initiating PN to discern differences and temporality. Actual infusion times were used for PN patients; time frames based on mean PN infusion days were created for the non-PN recipients. Oral intake was lower 'before' in PN vs non-PN patients (P<0.001); however, no differences in mucositis, emesis, infections or transfusions were detected 'before.' Incident hyperglycemia (7.0 mmol/L) was significant 'after' PN initiation, and PN recipients experienced delays in WBC (P<0.05) and platelet engraftment (P=0.009), and required significantly greater RBC (P=0.0014) and platelet (P=0.001) support 'after' than non-PN patients. Neutropenic fever and longer hospital stay were more frequent among PN vs non-PN recipients (P<0.001). Differences in 5-year mortality were not apparent. The findings fail to support clinical benefits of PN administration during auto-SCT for myeloma. Further study is needed to discern if hyperglycemia or feeding per se was deleterious in this patient population. 23815125 ε-Decalactone: A Thermoresilient and Toughening Comonomer to Poly(l-lactide). The renewable monomer ε-decalactone is an excellent partner to l-lactide, where their copolymers overcome inherent drawbacks of polylactide, such as low thermal stability and brittleness. ε-Decalactone is a seven-membered lactone that was successfully polymerized with Sn(Oct)2 and 1,5,7-triazabicyclo[4.4.0]dec-5-ene into both an amorphous homopolymer and copolymers with high molecular weight, low dispersity, and predicted macromolecular architecture. The thermoresilient nature of ε-decalactone is reflected in a high polymerization ceiling temperature and increased thermal stability for the prepared copolymers. The high ceiling temperature enables easy modulation of the polymerization rate via temperature while maintaining architectural control. The apparent rate constant was increased 15-fold when the temperature was increased from 110 to 150 °C. Copolymers of l-lactide and ε-decalactone, either with the latter as a central block in triblock polymers or with randomly positioned monomers, exhibited exceptionally tough material characteristics. The triblock copolymer had an elongation-at-break 250 times greater than that of pure poly(l-lactide). The toughness of the copolymers is attributed to the flexible nature of the polymer derived from the monomer ε-decalactone and to the segment immiscibility. These properties result in phase separation to soft and hard domains, which provides the basis for the elastomeric behavior. 23917546 Management of psychiatric inpatients with advanced cancer: a pilot study. The prevalence of cancer is not well established and probably underestimated in long-stay psychiatric inpatients. Psychiatric patients do not have the same access for cancer screening and care. Therapeutic decision-making is a real ethical problem. In this context, access to medical care should be provided by the establishment of guidelines and/or recommendations for this specific population. The aim of our study was to assess how cancer was managed among long term psychiatric inpatients. For this pilot study, we used a mixed methodology: a quantitative part with a retrospective chart review of cancer patients in a psychiatric institution and a qualitative part based on semi-structured interviews with psychiatrists with discourse analysis. Delay in cancer diagnosis can be explained by communication and behavior disorders, inadequate screening, and additional tests often refused by patients. Compliance and ethical issues (i.e. obtaining informed consent) are many pitfalls to optimal cancer care that should be explored in further research. 23951377 Symptomatic Versus Inapparent Outcome in Repeat Dengue Virus Infections Is Influenced by the Time Interval between Infections and Study Year. Four dengue virus serotypes (DENV1-4) circulate globally, causing more human illness than any other arthropod-borne virus. Dengue can present as a range of clinical manifestations from undifferentiated fever to Dengue Fever to severe, life-threatening syndromes. However, most DENV infections are inapparent. Yet, little is known about determinants of inapparent versus symptomatic DENV infection outcome. Here, we analyzed over 2,000 DENV infections from 2004 to 2011 in a prospective pediatric cohort study in Managua, Nicaragua. Symptomatic cases were captured at the study health center, and paired healthy annual samples were examined on a yearly basis using serological methods to identify inapparent DENV infections. Overall, inapparent and symptomatic DENV infections were equally distributed by sex. The mean age of infection was 1.2 years higher for symptomatic DENV infections as compared to inapparent infections. Although inapparent versus symptomatic outcome did not differ by infection number (first, second or third/post-second DENV infections), substantial variation in the proportion of symptomatic DENV infections among all DENV infections was observed across study years. In participants with repeat DENV infections, the time interval between a first inapparent DENV infection and a second inapparent infection was significantly shorter than the interval between a first inapparent and a second symptomatic infection. This difference was not observed in subsequent infections. This result was confirmed using two different serological techniques that measure total anti-DENV antibodies and serotype-specific neutralizing antibodies, respectively. Taken together, these findings show that, in this study, age, study year and time interval between consecutive DENV infections influence inapparent versus symptomatic infection outcome, while sex and infection number had no significant effect. Moreover, these results suggest that the window of cross-protection induced by a first infection with DENV against a second symptomatic infection is approximately 2 years. These findings are important for modeling dengue epidemics and development of vaccines. 23408338 [(68)Ga]-Albumin-PET in the Monitoring of Left Ventricular Function in Murine Models of Ischemic and Dilated Cardiomyopathy: Comparison with Cardiac MRI. The purpose of this study is to evaluate left ventricular functional parameters in healthy mice and in different murine models of cardiomyopathy with the novel blood pool (BP) positron emission tomography (PET) tracer [(68)Ga]-albumin. ECG-gated microPET examinations were obtained in healthy mice, and mice with dilative (DCM) and ischemic cardiomyopathy (ICM) using the novel BP tracer [(68)Ga]-albumin (AlbBP), as well as [(18)F]-FDG microPET. Cine-magnetic resonance imaging (MRI) examination performed on a clinical 1.5-T MRI provided the reference standard measurements. When considering the combined group of healthy controls, DCM and ICM AlbBP-PET significantly overestimated the magnitudes of EDV (AlbBP, 181 ±â€‰86 Î¼l; cine-MRI, 125 ±â€‰80 Î¼l; P < 0.001) and ESV (AlbBP, 136 ±â€‰92 Î¼l; cine-MRI, 96 ±â€‰77 Î¼l; P < 0.001), whereas the EF (AlbBP, 31 ±â€‰16 %; cine-MRI, 33 ±â€‰21 %; P = 0.910) matched closely to cine-MRI results, as did findings with [(18)F]-FDG. High correlations were found between the measured cardiac parameters (EDV: R = 0.978, ESV: R = 0.989, and LVEF: R = 0.992). Measuring left ventricular function in mice with [(68)Ga]-albumin BP PET is feasible and showed a high correlation compared to cine-MRI, which was used as a reference standard. 23583212 Predictive value of serum human epididymis protein 4 and cancer antigen 125 concentrations in endometrial carcinoma. The purpose of this study was to evaluate the performance of preoperative serum levels of human epididymis protein 4 (HE4) and cancer antigen 125 (CA125) in the prediction of the presence of metastases in endometrial carcinoma. Preoperative sera were collected from 98 women with a diagnosis of endometrial carcinoma. The concentrations of HE4 and CA125 were assessed by enzyme-linked immunosorbent assay and correlated with the results of the final histopathologic report. Fourteen patients had metastases (≥stage IIIA, International Federation of Gynecology and Obstetrics 2009 classification). The serum concentrations of HE4 and CA125 were higher in the group with metastases than in the group without metastases (median [interquartile range], 148.6 pmol/L [71.6-219.1 pmol/L] vs 77.2 pmol/L [52.9-99.3 pmol/L]; P = .001; and 20.0 U/mL [10.1-70.8 U/mL] vs 4.3 U/mL [2.9-10.4 U/mL]; P < .001, respectively). By a multivariate analysis, the combination of HE4 and CA125 (a risk score algorithm) was the only predictive factor for the presence of metastases (odds ratio, 21.562; 95% confidence interval, 5.472-84.963; P < .001), and the grade was the predictor for a deep (≥50%) myometrial invasion by the tumor (odds ratio, 2.005; 95% confidence interval, 1.123-3.581; P = .019). The sensitivity, specificity, positive predictive value, and negative predictive value for the combination of the markers to predict the presence of metastases were 71.4%, 89.5%, 55.6%, and 94.4%, respectively. A combination of preoperative HE4 and CA125 seems to be a better predictor of metastatic disease than either 1 alone in endometrial carcinoma. 23916028 Aberration-corrected transmission electron microscopy analyses of GaAs/Si interfaces in wafer-bonded multi-junction solar cells. Aberration-corrected scanning transmission electron microscopy (STEM) and electron energy loss spectroscopy (EELS) investigations have been applied to investigate the structure and composition fluctuations near interfaces in wafer-bonded multi-junction solar cells. Multi-junction solar cells are of particular interest since efficiencies well above 40% have been obtained for concentrator solar cells which are based on III-V compound semiconductors. In this methodologically oriented investigation, we explore the potential of combining aberration-corrected high-angle annular dark-field STEM imaging (HAADF-STEM) with spectroscopic techniques, such as EELS and energy-dispersive X-ray spectroscopy (EDXS), and with high-resolution transmission electron microscopy (HR-TEM), in order to analyze the effects of fast atom beam (FAB) and ion beam bombardment (IB) activation treatments on the structure and composition of bonding interfaces of wafer-bonded solar cells on Si substrates. Investigations using STEM/EELS are able to measure quantitatively and with high precision the widths and the fluctuations in element distributions within amorphous interface layers of nanometer extensions, including those of light elements. Such measurements allow the control of the activation treatments and thus support assessing electrical conductivity phenomena connected with impurity and dopant distributions near interfaces for optimized performance of the solar cells. 23185981 Exposure and risk assessment for ochratoxin A and fumonisins in Japan. The authors performed exposure and risk assessments based on surveillance studies of retail foods in Japan that were undertaken during the past six years (2004-2010). The exposure to ochratoxin A (OTA) and fumonisins (FBs) in different age groups, including toddlers and young children (1-6 years old), older children (7-14 years old), adolescents (15-19 years old) and adults (over 20 years old) was simulated, and the risk of these mycotoxins was evaluated by comparing the provisional maximum tolerated daily intake (PMTDI) for FBs and the provisional maximum tolerated weekly intake (PMTWI) for OTA established by the FAO/WHO Joint Export Committee on Food Additives. The exposure assessment for both mycotoxins in each age group in Japan indicated that the highest exposure occurred in toddlers and children, but in all cases the percentage of the PMTWI and PMTDI at the 99th percentile of exposure was less than 35% for OTA and 10% for FBs. 23952566 Impacts of a PECS Instructional Coaching Intervention on Practitioners and Children with Autism. Abstract There is a growing research literature on the potential benefits of augmentative and alternative communication (AAC) for individuals with autism; however few studies have investigated implementation of AAC within real-life contexts. Thus, the purpose of this study was to investigate the impact of training for practitioners in implementation of aided AAC, and to examine implementation of Picture Exchange Communication System (PECS) in real-life contexts. In particular, this study involved the implementation of instructional coaching to increase opportunities offered by behavioral therapists for their preschool-aged clients to use PECS to make requests. Results indicated increases in therapist implementation of AAC and client use of AAC in trained contexts, with limited generalization to untrained contexts. 23896691 KOtBu-mediated stereoselective addition of quinazolines to alkynes under mild conditions. A facile alkenylation of quinazolines with unactivated terminal alkynes has been achieved in the presence of KOtBu without the aid of any transition metal catalysts. The reaction is carried out under very mild conditions and shows a high stereoselectivity. A possible radical-based mechanism is also explored. 23936169 Women's Satisfaction with Body Image before Pregnancy and Body Mass Index 4 Years after Delivery in the Mothers of Generation XXI. Body image satisfaction (BIS) influences body weight regulation and may contribute to long-term healthier lifestyle after pregnancy. Thus, we aimed to assess the association between BIS before pregnancy and body mass index (BMI) 4 years after the index pregnancy. As part of the follow-up of a birth cohort, 3612 women with prepregnancy BMI >18.5 kg/m(2) were reevaluated 4 years after the birth of a child. BIS was defined as the difference between perceived and ideal body size before pregnancy, assessed by Stunkard Silhouettes after birth. The associations of BIS with BMI change (continuous) and BMI classes at 4 years, based on measured weight and height, were estimated using linear and multinomial regression, respectively. Among women with normal prepregnancy BMI, those who felt too small, regarding their ideal, had a 0.25 kg/m(2) smaller increase in BMI within 4 years and a lower likelihood of becoming overweight or obese [multivariate-adjusted odds ratio (OR) = 0.63; 95% confidence interval (95%CI): 0.44-0.91 and OR = 0.21; 95%CI: 0.05-0.91, respectively) than those satisfied with body image. Feeling too large was associated with a 0.41 kg/m(2) larger increase in BMI and a higher risk of becoming overweight or obese (OR = 2.12; 95%CI:1.73-2.59 and OR = 3.42; 95%CI:2.02-5.79, respectively). A similar, non-significant, trend was observed for overweight women. Obese women who felt too large had a non-significant decrease in BMI. BIS plays a role in maternal body weight after delivery. Realistic body size goals may promote the motivation to lose weight and contribute to higher success in attaining them. 23908400 Immunization of fucose-containing polysaccharides from Reishi mushroom induces antibodies to tumor-associated Globo H-series epitopes. Carbohydrate-based vaccines have shown therapeutic efficacy for infectious disease and cancer. The mushroom Ganoderma lucidum (Reishi) containing complex polysaccharides has been used as antitumor supplement, but the mechanism of immune response has rarely been studied. Here, we show that the mice immunized with a l-fucose (Fuc)-enriched Reishi polysaccharide fraction (designated as FMS) induce antibodies against murine Lewis lung carcinoma cells, with increased antibody-mediated cytotoxicity and reduced production of tumor-associated inflammatory mediators (in particular, monocyte chemoattractant protein-1). The mice showed a significant increase in the peritoneal B1 B-cell population, suggesting FMS-mediated anti-glycan IgM production. Furthermore, the glycan microarray analysis of FMS-induced antisera displayed a high specificity toward tumor-associated glycans, with the antigenic structure located in the nonreducing termini (i.e., Fucα1-2Galβ1-3GalNAc-R, where Gal, GalNAc, and R represent, respectively, D-galactose, D-N-acetyl galactosamine, and reducing end), typically found in Globo H and related tumor antigens. The composition of FMS contains mainly the backbone of 1,4-mannan and 1,6-α-galactan and through the Fucα1-2Gal, Fucα1-3/4Man, Fucα1-4Xyl, and Fucα1-2Fuc linkages (where Man and Xyl represent d-mannose and d-xylose, respectively), underlying the molecular basis of the FMS-induced IgM antibodies against tumor-specific glycans. 23800571 Clinical outcomes after zotarolimus and everolimus drug eluting stent implantation in coronary artery bifurcation lesions: insights from the RESOLUTE All Comers Trial. We investigated clinical outcomes after treatment of coronary bifurcation lesions with second generation drug eluting stents (DES). Post hoc analysis of a randomised, multicentre, non-inferiority trial. Multicentre study. All comers study with minimal exclusion criteria. Patients were treated with either zotarolimus or everolimus eluting stents. The patient population was divided according to treatment of bifurcation or non-bifurcation lesions and clinical outcomes were compared between groups. Clinical outcomes within 2-year follow-up. A total of 2265 patients were included in the present analysis. Two-year follow-up data were available in 2223 patients: 1838 patients in the non-bifurcation group and 385 patients in the bifurcation group. At 2-year follow-up the bifurcation and the non-bifurcation lesion groups showed no significant differences in terms of cardiac death (2.3 vs 2.1, p=0.273), target lesion failure (9.7% vs 13.8%, p=0.255), major adverse cardiac events (11.5% vs 15.1%, p=0.305), target lesion revascularisation (4.7% vs 6.0%, p=0.569), and definite or probable stent thrombosis (1.6% vs 1.8%, p=0.419). The use of second generation DES for the treatment of coronary bifurcation lesions was associated with similar long term mortality and clinical outcomes compared with non-bifurcation lesions. 23595833 Clinical reasoning for the infectious disease specialist: a primer to recognize cognitive biases. Infectious disease specialists are frequently consulted for diagnostic and therapeutic advice on challenging cases. When evaluating patients, the infectious disease specialist is well positioned to offer an appropriate diagnostic approach but is also at risk of not recognizing the correct diagnosis for a variety of reasons. We believe it is important to provide infectious disease specialists and trainees with a fundamental understanding of diagnostic errors, clinical reasoning, and cognitive biases. We present 2 cases demonstrating common cognitive biases leading to diagnostic errors, and we reflect on strategies that may aid in their prevention. We hope to provide knowledge and tools that may help prevent diagnostic errors in the future. 23958730 HippDB: A database of readily targeted helical protein-protein interactions. HippDB catalogues every protein-protein interaction whose structure is available in the Protein Data Bank (PDB) and which exhibits one or more helices at the interface. The website accepts queries on variables such as helix length and sequence, and it provides computational alanine scanning and change in solvent-accessible surface area (ΔSASA) values for every interfacial residue. HippDB is intended to serve as a starting-point for structure-based small molecule and peptidomimetic drug development.Availability and Implementation: HippDB is freely available on the web at http://www.nyu.edu/projects/arora/hippdb. The website is implemented in PHP, MySQL and Apache. arora@nyu.edu SUPPLEMENTARY INFORMATION: Source code freely available for download at http://code.google.com/p/helidb, implemented in Perl and supported on Linux. 23736670 The relationship between arterial carbon dioxide tension and end-tidal carbon dioxide tension in intubated adults with traumatic brain injuries who required emergency craniotomies. Anesthetic management of patients who have suffered traumatic brain injuries can be challenging. We investigated the relationship between arterial to end-tidal carbon dioxide partial pressure gradients (Pa-etCO₂) and 3 predictor variables: (1) injury severity score, (2) use of positive end-expiratory pressure, and (3) presence of rib fractures. Using a convenient sampling method, we sampled 56 patients who arrived to the operating room intubated after traumatic brain injuries between 2005 and 2011. Two groups were compared retrospectively: those with Pa-etCO₂ greater than 10 mm Hg (case group) (n = 37) and those with Pa-etCO₂ gradients of 10 mm Hg or less (control group) (n = 19). Descriptive and inferential statistics were employed to identify any differences between the groups. Stepwise regression was also performed. Cross tabulation analysis revealed that injury severity score of 30 or more was a predictor of Pa-etCO₂ gradient. Stepwise regression analysis revealed the presence of rib fracture and body mass index to be significant predictors of Pa-etCO₂ gradient (P < .011). This study identified coexisting conditions in which the patients' Pa-etCO₂ gradients were large. Results showed that injury severity score of 30 or more, the presence of rib fractures, and higher body mass index were statistically significant predictors of Pa-etCO₂ gradients greater than 10 mm Hg. These observations should be considered when evaluating PetCO₂ in conjunction with arterial blood gas analysis to determine optimal ventilation status of these patients. 23629479 Cost analysis of S1 and XELOX as adjuvant therapy for gastric cancer. Both S1 and XELOX (capecitabine+oxaliplatin) have been recommended as an adjuvant treatment for gastric cancer according to the guidelines of the National Comprehensive Cancer Network (NCCN). This study compared the two regimens in terms of monetary costs, assuming equal efficacy of both regimens. Chemotherapy cost data of 188 patients were collected from the medical records, 91 for the S1 group and 97 for XELOX. Costs were classified as direct costs (chemotherapy, hospitalization, venous access, and tests), adverse event-related treatments costs, and societal (travel and time) costs. The total direct costs of S1 and XELOX per cycle per patient were $1938±236 and $2317±315, respectively. S1 cost $27 and $9 less than XELOX on total adverse event-related costs and societal costs, respectively. The total costs of S1 and XELOX were $1994±322 versus $2410±391 per cycle per patient, respectively. The total cost of S1 was 17.3% less than that of XELOX for the average patient. All the differences were statistically significant. S1, compared with XELOX, could be a more affordable option as an adjuvant treatment for gastric cancer when all healthcare resources are taken into account in China. 23870793 Outbreak of Escherichia coli O157:H7 in a child care center in Cook County, Illinois, with prolonged shedding and household transmission. During the investigation of an outbreak of Escherichia coli O157:H7 in a child care center, illness logs were reviewed and parents interviewed to identify classroom and household exposures. Costs incurred by the center and the public health laboratory were estimated from self-administered questionnaires. We conclude that household transmission played a role in this outbreak and estimate the cost of investigation and intervention at over $6,000 per case. 23826767 Multiple internalization pathways of polyelectrolyte multilayer capsules into Mammalian cells. Polyelectrolyte multilayer (PEM) capsules are carrier vehicles with great potential for biomedical applications. With the future aim of designing biocompatible, effective therapeutic delivery systems (e.g., for cancer), the pathway of internalization (uptake and fate) of PEM capsules was investigated. In particular the following experiments were performed: (i) the study of capsule co-localization with established endocytic markers, (ii) switching-off endocytotic pathways with pharmaceutical/chemical inhibitors, and (iii) characterization and quantification of capsule uptake with confocal and electron microscopy. As result, capsules co-localized with lipid rafts and with phagolysosomes, but not with other endocytic vesicles. Chemical interference of endocytosis with chemical blockers indicated that PEM capsules enter the investigated cell lines through a mechanism slightly sensitive to electrostatic interactions, independent of clathrin and caveolae, and strongly dependent on cholesterol-rich domains and organelle acidification. Microscopic characterization of cells during capsule uptake showed the formation of phagocytic cups (vesicles) to engulf the capsules, an increased number of mitochondria, and a final localization in the perinuclear cytoplasma. Combining all these indicators we conclude that PEM capsule internalization in general occurs as a combination of different sequential mechanisms. Initially, an adsorptive mechanism due to strong electrostatic interactions governs the stabilization of the capsules at the cell surface. Membrane ruffling and filopodia extensions are responsible for capsule engulfing through the formation of a phagocytic cup. Co-localization with lipid raft domains activates the cell to initiate a lipid-raft-mediated macropinocytosis. Internalization vesicles are very acidic and co-localize only with phagolysosome markers, excluding caveolin-mediated pathways and indicating that upon phagocytosis the capsules are sorted to heterophagolysosomes. 23849810 Comparison of nutritional status assessment parameters in predicting length of hospital stay in cancer patients. Undernutrition has been associated with an increased length of hospital stay which may reflect the patient prognosis. The aim of this study was to quantify and compare the association between nutritional status and handgrip strength at hospital admission with time to discharge in cancer patients. An observational prospective study was conducted in an oncology center. Patient-Generated Subjective Global Assessment, Nutritional Risk Screening 2002 and handgrip strength were conducted in a probabilistic sample of 130 cancer patients. The association between baseline nutritional status, handgrip strength and time to discharge was evaluated using survival analysis with discharge alive as the outcome. Nutritional risk ranged from 42.3 to 53.1% depending on the tool used. According to Patient-Generated Subjective Global Assessment severe undernutrition was present in 22.3% of the sample. The association between baseline data and time to discharge was stronger in patients with low handgrip strength (adjusted hazard ratio, low handgrip strength: 0.33; 95% confidence interval: 0.19-0.55), compared to undernourished patients evaluated by the other tools; Patient-Generated Subjective Global Assessment: (adjusted hazard ratio, severe undernutrition: 0.45; 95% confidence interval: 0.27-0.75) and Nutritional Risk Screening 2002: (adjusted hazard ratio, with nutritional risk: 0.55; 95% confidence interval: 0.37-0.80). An approximate 3-fold decrease in probability of discharge alive was observed in patients with low handgrip strength. Decreasing handgrip strength tertiles allowed to discriminate between patients who will have longer hospital stay, as well as undernutrition and nutritional risk assessed by Patient-Generated Subjective Global Assessment and Nutritional Risk Screening 2002. 23605692 Using multiple targeted therapies in oncology: considerations for use, and progress to date in breast cancer. There has been significant progress in our basic understanding of drugs and targets in the management of breast cancer. Recent breast cancer clinical trials have examined whether combinations of drugs targeting transmembrane receptors or their downstream effectors involved in cell signal transduction can increase response rates and overcome acquired and/or de novo drug resistance compared to a single targeted agent with or without systemic chemotherapy. We reviewed published clinical trials and conference proceedings examining combinations of targeted therapies across different breast cancer subtypes. Improvements in pathological complete response (pCR) rates and progression free survival (PFS) in preoperatively treated and metastatic human epidermal growth factor 2 (HER2)-positive breast cancer, respectively, have been observed with combinations of anti-HER2 therapies given concomitantly. Promising results were also observed in estrogen receptor (ER)-positive, HER2-negative breast cancer using a mammalian target of rapamycin inhibitor with tamoxifen or an aromatase inhibitor (AI) in the preoperative setting and for patients with metastatic breast cancer that had previously progressed on endocrine therapy alone. A recent phase II trial reported a statistically significant improvement in PFS with the addition of an oral inhibitor of cyclin-dependent kinase 4/6 to letrozole compared to letrozole alone (26.1 versus 7.5 months). A phase III study is planned for early 2013. On the basis of preclinical data, clinical trials have examined combinations of hormonal agents such as fulvestrant with an AI. However, the results are conflicting. Early data indicated that poly (ADP-ribose) polymerase (PARP) inhibitors exploiting the concept of synthetic lethality would offer improved outcomes for patients with ER-negative, progesterone receptor (PR)-negative, HER2-negative breast cancer often referred to as triple negative breast cancer (TNBC); however, data in the phase III setting failed to confirm these findings but this may be because the drug was not a true PARP inhibitor. Chemotherapy continues to be the mainstay of treatment for TNBC until specific drugs and their associated targets are identified. As advances in medical technologies continue to identify multiple molecularly distinct breast cancer subgroups that are predicted to respond to combinations of targeted agents new challenges have arisen. In particular, how do we evaluate the safety and efficacy of these new drug combinations in relatively small subgroups of patients? Novel clinical trial designs will be required and increasingly regulatory agencies will require companion diagnostic tests that can identify the subgroups likely to respond to these therapies. The US Food and Drug Administration is assessing the role of pCR in breast cancer studies as a surrogate endpoint to predict clinical benefit in the accelerated drug approval process. 23843027 Adenosine receptor expression in an experimental animal model of myocardial infarction with preserved left ventricular ejection fraction. Adenosine, a purine nucleoside and a "retaliatory metabolite" in ischemia, is ubiquitous in the body and increases 100-fold during ischemia. Its biological actions are mediated by four adenosine receptors (ARs): A1, A2A, A2B and A3. The aim of this study was to determine possible myocardial alterations in AR expression in an experimental animal model of myocardial infarction (MI) with a preserved left ventricular (LV) ejection fraction. LV tissue was collected from sexually mature male farm pigs with MI (n = 6) induced by permanent surgical ligation of the left anterior descending coronary artery and from five healthy pigs (C). mRNA expression of A1R, A2AR, A2BR, A3R and TNF-α was determined by real-time PCR in tissue collected from border (BZ) and remote zones (RZ) of the infarcted area and from LV of C. BZ, RZ and samples of C were stained immunohistochemically to investigate A3R immunoreaction. After 4 weeks a different regulation of ARs was observed. A1R mRNA expression was significantly lower in the infarct regions than in controls (C = 0.75 ± 0.2, BZ = 0.05 ± 0.2, RZ = 0.07 ± 0.02 p = 0.0025, p = 0.0016, C vs. BZ and RZ, respectively). Conversely A3R was higher in infarct areas (C = 0.94 ± 0.2, BZ = 2.85 ± 0.5, RZ = 3.48 ± 1.0, p = 0.048 C vs. RZ). No significant differences were observed for A2AR (C = 1.58 ± 0.6, BZ = 0.42 ± 0.1, RZ = 1.37 ± 0.6) and A2BR (C = 1.66 ± 0.2, BZ = 1.54 ± 0.5, RZ = 1.25 ± 0.4). A3R expression was confirmed by immunohistochemical analysis and was principally localized in cardiomyocytes. TNF-α mRNA results were: C 0.41 ± 0.25; BZ 1.60 ± 0.19; RZ 0.17 ± 0.04. The balance between A1R and A3R as well as between A2AR and A2BR was consistent with adaptative retaliatory anti-ischemic adenosinergic changes in the infarcted heart with preserved LV function. 23927431 Harmonized guidance for DIC from the ISTH and the current status of anticoagulant therapy in Japan: a rebuttal. We are happy to respond to the important comments from Dr. Iba [1] and have an opportunity to explain further how to apply our guidance for the management of disseminated intravascular coagulation (DIC). The International Society of Thrombosis and Haemostasis (ISTH)/ Scientific and Standardization Committee (SSC) guidance [2] has been developed for physicians worldwide, while the three guidelines established by the British Committee for Standards in Haematology (BCSH) [3], the Japanese Society of Thrombosis and Hemostaisis (JSTH) [4] and the Italian Society for Thrombosis and Hemostaisis (SISET) [5] were made specifically for the physicians in each country, which have different environments and regulations. This article is protected by copyright. All rights reserved. 23665463 Further evidence of hepatitis B virus genotype I circulation in Northeast India. Hepatitis B virus (HBV) genotypes have known to show a geographical pattern in their distribution and have been used to trace the migration of populations from geographically distant regions. Novel recombinants between HBV genotypes A, G and C referred as genotype I has been recently reported from Eastern India. In our investigation to characterise antiviral resistance mutations, we identified a rare case of HBV genotype I infection in chronic hepatitis B subject. We encountered confounding results of this emerging genotype 'designated as genotype G' in three widely used HBV sequence database for genotype determination. The recombinant fragment of genotype G largely occupies the surface gene sequence of the newly identified genotype I and could hence lead to misclassification of genotype I. Additionally, recombination analysis of the generated sequences in Simplot and jpHMM model showed two different patterns of recombination events. In conclusion, the increasing recognition of genotype I in this population suggests that further studies may reveal uncommon genotypes from other geographically distant regions. Our observation of potential genotype I misclassification despite the use of public HBV sequence database and other recombination analysis tools highlights the need for updating and validating public sequence domains of diagnostic importance. 23906984 The difficult hepaticojejunostomy after pancreatic head resection: reconstruction with a T tube. After pancreatic head resection, bile leaks from a difficult hepaticojejunostomy secondary to a small or fragile common hepatic duct may be reduced by a T tube at the side of the anastomosis. A retrospective analysis of patients who underwent a difficult hepaticojejunostomy without or with a T tube was performed. In 48% (55/114) of patients, a T tube was placed at the side of the hepaticojejunostomy; 52% (59/114) did not have a T tube. Bile leaks occurred in 12% (14/114) (9% [5/55] in patients with a T tube vs 15% [9/59] without a T tube, P = .316). Bile leaks were associated with mortality, abscess formation, hemorrhage, and sepsis. Seven percent (8/114) of patients required revisional laparotomy (2% [1/55] with a T tube vs 12% [7/59] without a T tube, P = .036). Mortality was not different between the groups. Minor T-tube-associated complications occurred in 15% (8/55) without major complications. Augmentation of anastomosis with a T tube cannot prevent biliary leakage but does reduce the severity of bile leaks, resulting in less reoperations. 23901025 Early death in those previously hospitalised for mental healthcare in Scotland: a nationwide cohort study, 1986-2010. To compare the mortality in those previously hospitalised for mental disorder in Scotland to that experienced by the general population. Population-based historical cohort study using routinely available psychiatric hospital discharge and death records. All Scotland. Individuals with a first hospital admission for mental disorder between 1986 and 2009 who had died by 31 December 2010 (34 243 individuals). The main outcome measure was death from any cause, 1986-2010. Excess mortality was presented as standardised mortality ratios (SMRs) and years of life lost (YLL). Excess mortality was assessed overall and by age, sex, main psychiatric diagnosis, whether the psychiatric diagnosis was 'complicated' (ie, additional mental or physical ill-health diagnoses present), cause of death and time period of first admission. 111 504 people were included in the study, and 34 243 had died by 31 December 2010. The average reduction in life expectancy for the whole cohort was 17 years, with eating disorders (39-year reduction) and 'complicated' personality disorders (27.5-year reduction) being worst affected. 'Natural' causes of death such as cardiovascular disease showed modestly elevated relative risk (SMR1.7), but accounted for 67% of all deaths and 54% of the total burden of YLL. Non-natural deaths such as suicide showed higher relative risk (SMR5.2) and tended to occur at a younger age, but were less common overall (11% of all deaths and 22% of all YLL). Having a 'complicated' diagnosis tended to elevate the risk of early death. No worsening of the overall excess mortality experienced by individuals with previous psychiatric admission over time was observed. Early death for those hospitalised with mental disorder is common, and represents a significant inequality even in well-developed healthcare systems. Prevention of suicide and cardiovascular disease deserves particular attention in the mentally disordered. 23592020 Positive association between Toll-like receptor 4 gene +896A/G polymorphism and susceptibility to gastric carcinogenesis: a meta-analysis. Several studies have investigated the association between the Toll-like receptor 4 (TLR4) gene +896A/G polymorphism and gastric carcinogenesis, including gastric cancer and precancerous gastric lesions. However, published results are inconsistent. So, we performed a meta-analysis to assess whether the TLR4 +896A/G single-nucleotide polymorphism (SNP) is a risk factor in gastric cancer development. We searched PubMed and Embase databases for studies that reported the odds ratio (OR) and 95 % confidence interval (CI) for the association between the TLR4 +896A/G SNP and the risk of gastric cancer and/or precancerous lesions with the last update of November 2012. Data were analyzed using Review Manager (Version 5.1), and publication bias was estimated. We included 10 study populations, comprising 2,233 cases and 2,849 controls from 8 publications. The pooled OR was 2.00 (95 % CI = 1.59-2.53) for the G allelic model. Analysis stratified by different stages and anatomic sites of neoplasia resulted in a significantly increased risk associated with gastric cancer (OR = 1.87, 95 % CI = 1.44-2.44), especially the non-cardia subtype (OR = 2.03, 95 % CI = 1.51-2.72). Besides, the G allele emerged as a strong risk factor for precancerous gastric lesions (OR = 2.47, 95 % CI = 1.57-3.88). A subsequent subgroup analysis by Helicobacter pylori-positive ratio in cases (>80 %) indicated an enhancement in the association with precancerous lesions (OR = 3.43, 95 % CI = 1.92-6.13). The TLR4 +896A/G SNP is a risk factor in gastric carcinogenesis, especially in H. pylori-infected patients with precancerous lesions. 23821591 Neuroprotective effects of alpha-ketoglutarate and ethyl pyruvate against motor dysfunction and oxidative changes caused by repeated 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine exposure in mice. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin associated with drug abuse and causes permanent symptoms of Parkinson's disease (PD) by destroying dopaminergic neurons in the substantia nigra of the brain. In the present study, the neuroprotective effects of two carboxylic acid compounds, viz. alpha-ketoglutarate (A-KG), a Kreb's cycle intermediate and ethyl pyruvate (EP), a lipid-soluble analogue of pyruvate, were evaluated against MPTP intoxication in mice and compared with madopar (MD; combination of levodopa plus benserazide), a standard drug. Animals received oral treatment of A-KG (500 mg/kg), EP (100 mg/kg) or MD (5 mg/kg) daily for 5 days followed by intraperitoneal administration of MPTP (20 mg/kg) and posttreatment (+10 min) of A-KG, EP or MD daily for the remaining 5 days. MPTP caused the inhibition of complex I of electron transport chain accompanied by oxidative stress in the brain. It also caused cytotoxicity in the midbrain region as characterized by histology and immunohistochemistry. Treatments of A-KG and EP were found to resolve the loss of motor coordination, oxidative stress, diminished complex I activity and tyrosine hydroxylase-positive neurons in midbrain. A-KG and EP also regressed the histological damage in the brain and minimized the accumulation of alpha-synuclein in the midbrain region. The data suggest that A-KG and EP which are nontoxic carboxylic acid compounds could be of potential therapeutic value in the treatment of PD. 23657353 Male chronic pelvic pain syndrome and the role of interdisciplinary pain management. This paper is a team collaboration which aims to describe the multidisciplinary chronic pelvic pain (CPP) service for men in a major London teaching hospital. Evidence from the European Association for Urology Guidelines and the small pool of relevant psychological literature is reviewed as well as results from our pelvic pain programme (LINK) in association with a description of the programme. Treatment targets for men with CPP are outlined. The roles of the consultant in pain management, clinical nurse specialist, clinical psychologist and specialist physiotherapist in delivering treatment are described. This includes the journey from initial consultation through treatment options. Finally, we describe our pelvic pain programme (LINK) which aims to deliver an effective multidisciplinary intervention via single sex groups. This programme links all significant treatment dimensions as well as connecting groups of patients to reduce their sense of isolation. Evidence is presented from the formal evaluation of the programme. 23883890 A parallel-group, randomised controlled trial of a multimedia, self-directed, coping skills training intervention for patients with cancer and their partners: design and rationale. Coping skills training interventions have been found to be efficacious in helping both patients and their partners manage the physical and emotional challenges they face following a cancer diagnosis. However, many of these interventions are costly and not sustainable. To overcome these issues, a self-directed format is increasingly used. The efficacy of self-directed interventions for patients has been supported; however, no study has reported on the outcomes for their partners. This study will test the efficacy of Coping-Together-a multimedia, self-directed, coping skills training intervention for patients with cancer and their partners. The proposed three-group, parallel, randomised controlled trial will recruit patients diagnosed in the past 4 months with breast, prostate, colorectal cancer or melanoma through their treating clinician. Patients and their partners will be randomised to (1) a minimal ethical care (MEC) condition-selected Cancer Council New South Wales booklets and a brochure for the Cancer Council Helpline, (2) Coping-Together generic-MEC materials, the six Coping-Together booklets and DVD, the Cancer Council Queensland relaxation audio CD and login to the Coping-Together website or (3) Coping-Together tailored-MEC materials, the Coping-Together DVD, the login to the website and only those Coping-Together booklet sections that pertain to their direct concerns. Anxiety (primary outcome), distress, depression, dyadic adjustment, quality of life, illness or caregiving appraisal, self-efficacy and dyadic and individual coping will be assessed before receiving the study material (ie, baseline) and again at 3, 6 and 12 months postbaseline. Intention-to-treat and per protocol analysis will be conducted. This study has been approved by the relevant local area health and University ethics committees. Study findings will be disseminated not only through peer-reviewed publications and conference presentations but also through educational outreach visits, publication of lay research summaries in consumer newsletters and publications targeting clinicians. Australian New Zealand Clinical Trials Registry ACTRN12613000491763 (03/05/2013). 23298241 The dynamics of dendrimers by NMR relaxation: interpretation pitfalls. NMR is a powerful tool to study the dynamics of dendrimers. By analogy to linear polymers, shorter T(1) relaxation times have been traditionally associated to less mobile nuclei and hence, dendrimers described with reduced local motions at either the core or the periphery. Herein we report a NMR relaxation study [(1)H and (13)C T(1), T(2); (13)C{(1)H}NOE; various fields and temperatures] which reveals profound differences between the relaxation behavior of dendrimers and linear polymers. Dendrimers show slower dynamics at internal layers and on increasing generation and may display internal nuclei in the slow motional regime with larger T(1) values than the periphery. In contrast to the relaxation properties of linear polymers, these T(1) increments should not be interpreted as resulting from faster dynamics. Only the recording of T(1) data at various temperatures (alternatively, T(2) or NOE at one temperature) ensures the correct interpretation of dendrimer dynamics. 23743515 Nonimmediate hypersensitivity reactions to iodinated contrast media. To provide a detailed analysis of the latest findings on the mechanisms underlying the nonimmediate reactions to iodinated contrast media and comment on the recent advances in diagnosis, focusing on the roles of the skin test, drug provocation test (DPT), and lymphocyte transformation test (LTT). Several studies have reported new findings supporting an important role for T-lymphocytes in the nonimmediate reactions to iodinated contrast media. The LTT has been used as an in-vitro tool for diagnosis, but with variable results. However, the inclusion of autologous monocyte-derived dendritic cells as professional antigen-presenting cells has improved the sensitivity of this test. Regarding in-vivo diagnosis, although skin testing has been routine, it has now been shown that its sensitivity and negative predictive value are low. Recent studies have demonstrated that the DPT is a well tolerated and useful procedure that is necessary to confirm the diagnosis of nonimmediate hypersensitivity reactions to iodinated contrast media. Nonimmediate reactions to contrast media are usually T-cell mediated. Diagnosis is based on skin testing, although its sensitivity and negative predictive value are not optimal. Consequently, drug provocation testing is often needed to confirm the diagnosis and also to seek alternative contrast media that can be tolerated. 23949921 Effect of Race on Left Ventricular Ejection Fraction Decline After Initial Improvement with Beta Blockers in Patients with Non-Ischemic Cardiomyopathy: A Retrospective Analysis. Although beta blockers (BBs) are established therapy in heart failure, some patients whose left ventricular ejection fraction (LVEF) initially increases on BB therapy experience a subsequent LVEF decline. This study aimed to evaluate the proportion of patients with non-ischemic cardiomyopathy (NICM) whose LVEF declines while on BB therapy and determine important predictors of LVEF decline. A retrospective analysis of 238 patients receiving a BB (carvedilol, metoprolol succinate, or tartrate), with an ejection fraction of ≤40 % and NICM, whose LVEF initially rose ≥5 % after 1 year of BB therapy, was conducted. Post-response LVEF decline ≥5 % to a final LVEF of ≤35 % was evaluated within 4 years of BB initiation. In our study, we had 52 Caucasians (22 %), 78 Hispanics (33 %), and 108 African Americans (45 %). Overall, 32 patients (13.44 %) had post-response LVEF decline. The nadir LVEF of patients with post-response LVEF decline was 25 % (interquartile range 20-27). Compared with others, Hispanics had lower nadir LVEF (22 %, p < 0.001). Important predictors of LVEF decline were Hispanic race (odds ratio (OR) 6.094, p < 0.001), New York Heart Association (NYHA) class (OR 2.287, p < 0.05), baseline LVEF (OR 1.075, p < 0.05), and age (OR 0.933, p < 0.001). A significant proportion (13.44 %) of NICM patients with LVEF increase over 1 year of BB therapy experienced subsequent LVEF decline. Race, NYHA class, baseline LVEF, and age are important predictors of this decline. 23912600 DNA vaccines: A simple DNA sensing matter? Since the introduction of DNA vaccines two decades ago, this attractive strategy has been hampered by its low immunogenicity in humans. Studies conducted to improve the immunogenicity of DNA vaccines have shown that understanding the mechanism of action of DNA vaccines might be the key to successfully improving their immunogenicity. Our current understanding is that DNA vaccines induce innate and adaptive immune responses in two ways: (1) encoded protein (or polypeptide) antigen(s) by the DNA plasmid can be expressed in stromal cells (i.e., muscle cells) as well as DCs, where these antigens are processed and presented to naïve CD4 or CD8 T cells either by direct or cross presentation, respectively; and (2) the transfected DNA plasmid itself may bind to an un-identified cytosolic DNA sensor and activate the TBK1-STING pathway and the production of type I interferons (IFNs) which function as an adjuvant. Recent studies investigating double-stranded cytosolic DNA sensor(s) have highlighted new mechanisms in which cytosolic DNA may release secondary metabolites, which are in turn recognized by a novel DNA sensing machinery. Here, we discuss these new metabolites and the possibilities of translating this knowledge into improved immunogenicity for DNA vaccines. 23910690 Clinical, functional, and genetic characterization of chronic granulomatous disease in 89 Turkish patients. Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder of phagocytes resulting in impaired killing of bacteria and fungi. A mutation in one of the 4 genes encoding the components p22(phox), p47(phox), p67(phox), and p40(phox) of the leukocyte nicotinamide dinucleotide phosphate reduced (NADPH) oxidase leads to autosomal recessive (AR) CGD. A mutation in the CYBB gene encoding gp91(phox) leads to X-linked recessive CGD. The aim of this study is to show the correlation between clinical, functional, and genetic data of patients with CGD from Turkey. We report here the results of 89 patients with CGD from 73 Turkish families in a multicenter study. Most of the families (55%) have an AR genotype, and 38% have an X-linked genotype; patients from 5 families with a suspected AR genotype (7%) were not fully characterized. We compared patients with CGD according to the severity of NADPH oxidase deficiency of neutrophils. Patients with A22(0), A67(0) or X91(0) phenotypes with a stimulation index of 1.5 or less have early clinical presentation and younger age at diagnosis (mean, 3.2 years). However, in p47(phox)-deficient cases and in 5 other AR cases with high residual oxidase activity (stimulation index â‰¥ 3), later and less severe clinical presentation and older age at diagnosis (mean, 7.1 years) were found. Pulmonary involvement was the most common clinical feature, followed by lymphadenitis and abscesses. Later and less severe clinical presentation and older age at diagnosis are related to the residual NADPH oxidase activity of neutrophils and not to the mode of inheritance. CGD caused by A22(0) and A67(0) subtypes manifests as severe as the X91(0) subtype. 23848823 Temporal lobe arteriovenous malformations: anatomical subtypes, surgical strategy, and outcomes. Object Descriptions of temporal lobe arteriovenous malformations (AVMs) are inconsistent. To standardize reporting, the authors blended existing descriptions in the literature into an intuitive classification with 5 anatomical subtypes: lateral, medial, basal, sylvian, and ventricular. The authors' surgical experience with temporal lobe AVMs was reviewed according to these subtypes. Methods Eighty-eight patients with temporal lobe AVMs were treated surgically. Results Lateral temporal lobe AVMs were the most common (58 AVMs, 66%). Thirteen AVMs (15%) were medial, 9 (10%) were basal, and 5 (6%) were sylvian. Ventricular AVMs were least common (3 AVMs, 3%). A temporal craniotomy based over the ear was used in 64%. Complete AVM resection was achieved in 82 patients (93%). Four patients (5%) died in the perioperative period (6 in all were lost to follow-up); 71 (87%) of the remaining 82 patients had good outcomes (modified Rankin Scale scores 0-2); and 68 (83%) were unchanged or improved after surgery. Conclusions Categorization of temporal AVMs into subtypes can assist with surgical planning and also standardize reporting. Lateral AVMs are the easiest to expose surgically, with circumferential access to feeding arteries and draining veins at the AVM margins. Basal AVMs require a subtemporal approach, often with some transcortical dissection through the inferior temporal gyrus. Medial AVMs are exposed tangentially with an orbitozygomatic craniotomy and transsylvian dissection of anterior choroidal artery and posterior cerebral artery feeders in the medial cisterns. Medial AVMs posterior to the cerebral peduncle require transcortical approaches through the temporo-occipital gyrus. Sylvian AVMs require a wide sylvian fissure split and differentiation of normal arteries, terminal feeding arteries, and transit arteries. Ventricular AVMs require a transcortical approach through the inferior temporal gyrus that avoids the Meyer loop. Surgical results with temporal lobe AVMs are generally good, and classifying them does not offer any prediction of surgical risk. 23941877 Cyclin-dependent kinase 5 modulates STAT3 and androgen receptor activation through phosphorylation of Ser727 on STAT3 in prostate cancer cells. Cyclin-dependent kinase 5 (Cdk5) is known to regulate prostate cancer metastasis. Our previous results indicate that Cdk5 activates androgen receptor (AR) and supports prostate cancer growth. We also find that STAT3 is a target of Cdk5 in promoting thyroid cancer cell growth, while STAT3 may play a regulator to AR activation under cytokine control. This study is to investigate the regulation of Cdk5 and its activator p35 on STAT3/AR signaling in prostate cancer cells. Our results show that Cdk5 biochemically interacts with STAT3 and this interaction depends on Cdk5 activation in prostate cancer cells. The phosphorylation of STAT3 at serine-727 (p-S727-STAT3) is regulated by Cdk5 in cells and xenograft tumors. The mutant of STAT3 S727A reduces its interaction with Cdk5. We further show that the nuclear distribution of p-S727-STAT3 and the expression of STAT3-regulated genes (junB, c-fos, c-myc and survivin) are regulated by Cdk5 activation. STAT3 mutant does not further decrease cell proliferation upon Cdk5 inhibition, which implies that the role of STAT3 regulated by Cdk5 correlates to cell proliferation control. Interestingly, Cdk5 may regulate the interaction between STAT3 and AR through phosphorylation of S727-STAT3 and therefore up-regulate AR protein stability and transactivation. Correspondingly, clinical evidence shows that the level of p-S727-STAT3 is significantly correlated with Gleason score and the levels of upstream regulators (Cdk5 and p35) as well as downstream protein (AR). In conclusion, this study demonstrates that Cdk5 regulates STAT3 activation through S727 phosphorylation and further promotes AR activation by protein-protein interaction in prostate cancer cells. 23880198 Abdominal adiposity largely explains associations between insulin resistance, hyperglycemia and subclinical atherosclerosis: The NEO study. The relative importance of insulin resistance and hyperglycemia to the development of atherosclerosis remains unclear. Furthermore, adiposity may be responsible for observed associations. Our aim was to study the relative contributions of adiposity, insulin resistance and hyperglycemia to subclinical atherosclerosis. In this cross-sectional analysis of the Netherlands Epidemiology of Obesity (NEO) study, a cohort of persons of 45-65 years, BMI, waist circumference (WC), fasting glucose (FPG), HbA1c and insulin concentrations were measured and the revised HOMA-IR was calculated. The carotid Intima-Media Thickness (cIMT) was measured by ultrasound. We performed linear regression analyses between standardized values of FPG, HbA1c, HOMA-IR, BMI, WC with cIMT, and subsequently included age, sex, ethnicity, education and smoking, HOMA-IR, HbA1c and FPG, BMI and WC in the models. After exclusion of participants with glucose lowering therapy (n = 356) or missing data (n = 252), this analysis included 6065 participants, 43% men, and mean (SD) cIMT of 616 (92) μm. Differences in cIMT (95% CI) per SD were: FPG: 16 (10,21); HbA1c: 12 (7,16); HOMA-IR: 11 (6,16) μm. These associations attenuated after adjustments, and attenuated most strongly after adjustment for WC. Differences in cIMT (95% CI) per SD in the full model were: FPG: 4 (0,7); HbA1c: 2 (-1,5); HOMA-IR: 0 (-3,3); BMI 16 (13,19); WC: 18 (14,21) μm. In middle-aged individuals, we observed similar contributions of insulin resistance and hyperglycemia to subclinical atherosclerosis. These contributions were largely explained by abdominal adiposity, emphasizing the importance of weight management. 23959502 Adderall for All: A Defense of Pediatric Neuroenhancement. I argue that young patients should be able to access neuroenhancing drugs without a diagnosis of ADHD. The current framework of consent for pediatric patients can be adapted to accommodate neuroenhancement. After a brief overview of pediatric neuroenhancement, I develop three arguments in favor of greater acceptance of neuroenhancement for young patients. First, ADHD is not relevantly different from other disadvantages that could be treated with stimulant medication. Second, establishing a legitimate framework for pediatric neuroenhancement would mitigate the bad effects of diversion and improve research on neuroenhancement and ADHD. Third, some pediatric patients have rights to access neuroenhancements. I then consider several objections to pediatric neuroenhancement. I address concerns about addiction, advertising, authentic development, the parent-child relationship and equal opportunity and conclude that these concerns may inform a framework for prescribing neuroenhancement but they do not justify limits on prescribing. 23897210 Characterization of major hydrolytic enzymes secreted by Pythium myriotylum, causative agent for soft rot disease. Pythium myriotylum, an oomycetous necrotroph is the causal agent of soft rot disease affecting several crops. Successful colonization by necrotrophs depends on their secretion of a diverse array of plant cell wall degrading enzymes (CWDEs). The induction dynamics of CWDEs secreted by P. myriotylum was analysed as little information is available for this pathogen. Activities of CWDEs that included pectinase, cellulase, xylanase and protease were detected using radial diffusion assay and differential staining. In Czapek Dox minimal medium supplemented with respective substrates as carbon source, the increase in CWDE activities was observed till 8 days of incubation after which a gradual decline in enzymatic activities was observed. With sucrose as sole carbon source, all the enzymes studied showed increase in activity with fungal growth while with cell wall material derived from ginger rhizome as sole carbon source, an initial spurt in cellulase, xylanase and pectinase activities was observed 3 days post incubation while protease activity increased from three days of incubation and reached maximum at 13 days of incubation. To further evaluate the role of CWDEs in pathogenicity, UV-induced mutants (pmN14uv1) were generated wherein significant reduction in cellulase, pectinase and protease activities were observed while that of xylanase remained unchanged compared to wild type isolate (RGCBN14). Bioassays indicated changes in infection potential of pmN14uv1 thereby suggesting the crucial role played by P. myriotylum CWDEs in initiating the rotting process. Hence appropriate strategies that target the production/activity of these secretory hydrolytic enzymes will help in reducing disease incidence/pathogen virulence. 23716622 The Neuroactive Steroid Pregnenolone Sulfate Stimulates Trafficking of Functional N-Methyl D-Aspartate Receptors to the Cell Surface via a Noncanonical, G Protein, and Ca2+-Dependent Mechanism. N-methyl D-aspartate (NMDA) receptors (NMDARs) mediate fast excitatory synaptic transmission and play a critical role in synaptic plasticity associated with learning and memory. NMDAR hypoactivity has been implicated in the pathophysiology of schizophrenia, and clinical studies have revealed reduced negative symptoms of schizophrenia with a dose of pregnenolone that elevates serum levels of the neuroactive steroid pregnenolone sulfate (PregS). This report describes a novel process of delayed-onset potentiation whereby PregS approximately doubles the cell's response to NMDA via a mechanism that is pharmacologically and kinetically distinct from rapid positive allosteric modulation by PregS. The number of functional cell-surface NMDARs in cortical neurons increases 60-100% within 10 minutes of exposure to PregS, as shown by surface biotinylation and affinity purification. Delayed-onset potentiation is reversible and selective for expressed receptors containing the NMDAR subunit subtype 2A (NR2A) or NR2B, but not the NR2C or NR2D, subunits. Moreover, substitution of NR2B J/K helices and M4 domain with the corresponding region of NR2D ablates rapid allosteric potentiation of the NMDA response by PregS but not delayed-onset potentiation. This demonstrates that the initial phase of rapid positive allosteric modulation is not a first step in NMDAR upregulation. Delayed-onset potentiation by PregS occurs via a noncanonical, pertussis toxin-sensitive, G protein-coupled, and Ca(2+)-dependent mechanism that is independent of NMDAR ion channel activation. Further investigation into the sequelae for PregS-stimulated trafficking of NMDARs to the neuronal cell surface may uncover a new target for the pharmacological treatment of disorders in which NMDAR hypofunction has been implicated. 23246459 Dendritic cell activation by polysaccharide isolated from Angelica dahurica. Angelica dahurica is used in functional foods for the prevention and treatment of various diseases, such as inflammation and cancer. In the present study, we examined the effect of A. dahurica polysaccharide (ADP) on dendritic cell (DC) maturation. ADP increased the expressions of CD86 and MHC-II molecules, the production of IL-12, IL-1β, and TNF-α, and allogeneic T cell activation ability of DCs, and reduced DC endocytosis. As a mechanism of action, the knockdown of TLR4 with small interfering RNA decreased the ADP-induced production of nitric oxide and IL-12 by DCs, suggesting the membrane receptor candidate of ADP. After binding to TLR4, ADP increased the phosphorylation of ERK, JNK, and p38 MAPKs, and the nuclear translocation of NF-κB p50/p65. These results indicate that ADP activates DCs through TLR4 and downstream signalings. 23051835 Sex and dose-dependent effects of developmental exposure to bisphenol A on anxiety and spatial learning in deer mice (Peromyscus maniculatus bairdii) offspring. Bisphenol A (BPA) is a widely produced, endocrine disrupting compound that is pervasive in the environment. Data suggest that developmental exposure to BPA during sexual differentiation of the brain leads to later behavioral consequences in offspring. Outbred deer mice (Peromyscus maniculatus bairdii) are an excellent animal model for such studies as they exhibit well-defined sex- and steroid-dependent behaviors. Here, dams during gestation and lactation were fed with a phytoestrogen-free control diet, the same diet supplemented with either ethinyl estradiol (0.1 ppb), or one of the three doses of BPA (50 mg, 5 mg, 50 μg/kg feed weight). After weaning, the pups were maintained on control diet until they reached sexual maturity and then assessed for both spatial learning capabilities and anxiety-like and exploratory behaviors. Relative to controls, males exposed to the two upper but not the lowest dose of BPA demonstrated similar impairments in spatial learning, increased anxiety and reduced exploratory behaviors as ethinyl estradiol-exposed males, while females exposed to ethinyl estradiol, but not to BPA, consistently exhibited masculinized spatial abilities. We also determined whether dams maintained chronically on the upper dose of BPA contained environmentally relevant concentrations of BPA in their blood. While serum concentrations of unconjugated BPA in controls were below the minimum level of detection, those from dams on the BPA diet were comparable (5.48±2.07 ng/ml) to concentrations that have been observed in humans. Together, these studies demonstrate that developmental exposure to environmentally relevant concentrations of BPA can disrupt adult behaviors in a dose- and sex-dependent manner. 23458995 Considering the impact drug-like properties have on the chance of success. Many definitions of 'drug-like' compound properties have been published; based on the analysis of simple molecular properties of successful drugs. These are typically presented as rules that define acceptable boundaries for these properties. When a compound does not 'fit' within these boundaries then its properties differ from those of the majority of drugs, which could indicate a higher risk of poor pharmacokinetics or safety outcomes in vivo. Here, we review the strengths and weaknesses of these rules and note, in particular, that the overly rigid application of strict cut-off points can introduce artificial distinctions between similar compounds, running the risk of missing valuable opportunities. Alternatively, compounds can be ranked according to their similarity to marketed drugs using a continuous measure of drug-likeness. However, being similar to known drugs does not necessarily mean that a compound is more likely to become a drug and we demonstrate how a new approach, employing Bayesian methods, can be used to compare a set of successful drugs with a set of non-drug compounds to identify those properties that give the greatest distinction between the two sets, and hence the greatest increase in the likelihood of a compound becoming a successful drug. This analysis further illustrates that guidelines for drug-likeness might not be generally applicable across all compound and target classes or therapeutic indications. Therefore, it might be more appropriate to consider specific guidelines for drug-likeness that are project specific. 23665928 Pharmaceuticals in tap water: human health risk assessment and proposed monitoring framework in China. Pharmaceuticals are known to contaminate tap water worldwide, but the relevant human health risks have not been assessed in China. We monitored 32 pharmaceuticals in Chinese tap water and evaluated the life-long human health risks of exposure in order to provide information for future prioritization and risk management. We analyzed samples (n = 113) from 13 cities and compared detected concentrations with existing or newly-derived safety levels for assessing risk quotients (RQs) at different life stages, excluding the prenatal stage.Results: We detected 17 pharmaceuticals in 89% of samples, with most detectable concentrations (92%) at < 50 ng/L. Caffeine (median-maximum, nanograms per liter: 24.4-564), metronidazole (1.8-19.3), salicylic acid (16.6-41.2), clofibric acid (1.2-3.3), carbamazepine (1.3-6.7), and dimetridazole (6.9-14.7) were found in ≥ 20% of samples. Cities within the Yangtze River region and Guangzhou were regarded as contamination hot spots because of elevated levels and frequent positive detections. Of the 17 pharmaceuticals detected, 13 showed very low risk levels, but 4 (i.e., dimetridazole, thiamphenicol, sulfamethazine, and clarithromycin) were found to have at least one life-stage RQ ≥ 0.01, especially for the infant and child life stages, and should be considered of high priority for management. We propose an indicator-based monitoring framework for providing information for source identification, water treatment effectiveness, and water safety management in China. ConclusION: Chinese tap water is an additional route of human exposure to pharmaceuticals, particularly for dimetridazole, although the risk to human health is low based on current toxicity data. Pharmaceutical detection and application of the proposed monitoring framework can be used for water source protection and risk management in China and elsewhere. 23135544 LARGE2 generates the same xylose- and glucuronic acid-containing glycan structures as LARGE. LARGE (like-glycosyltransferase) and LARGE2 (glycosyltransferase-like 1B (GYLTL1B)) are homologous Golgi glycosyltransferases possessing two catalytic domains with homology to members of glycosyltransferase families GT8 and GT49. Mutations in human and mouse Large result in muscular dystrophy due to underglycosylation of dystroglycan. The systemic function of LARGE2 is unknown, but at a cellular level the enzyme can substitute for LARGE in glycosylating dystroglycan. Here, we show that LARGE2 catalyzes the same glycosylation reaction as LARGE. It is a bifunctional glycosyltransferase using uridine diphosphate (UDP)-xylose (Xyl) and UDP-glucuronic acid (GlcA) as donor sugars to produce a xyloglucuronan with alternating Xyl and GlcA residues. 23780346 Computational study of decomposition mechanisms and thermodynamic properties of molecular-type cracking patterns for the highly energetic molecule GZT. This study uses the Gaussian 03 program and density functional theory B3LYP with three basis set methods-[B3LYP/6-311+G(d,p), B3LYP/6-31+G(2d,p), and B3LYP/6-31G(d,p)]-to model the highly energetic ionic compound diguanidinium 5,5'-azotetrazolate (GZT) to research its decomposition mechanisms and thermodynamic properties. Molecular-type cracking patterns are proposed, which were initiated by heterocyclic ring opening, sequential cracking of the two five-membered rings of GZT, and simultaneous release of N2 molecules; whereas proton transfer, bond-breaking, and atomic rearrangements were performed subsequently. Finally, 15 reaction paths and five transition states were obtained. All possible decomposition species and transition states, including intermediates and products, were identified, and their corresponding enthalpy and Gibbs free energy values were obtained. The results revealed that (1) the maximum activation energy required is 187.8 kJ mol(-1), and the enthalpy change (ΔH) and Gibbs free-energy change (ΔG) of the net reaction are -525.1 kJ mol(-1) and -935.6 kJ mol(-1), respectively; (2) GZT can release large amounts of energy, the main contribution being from the disintegration of the 5,5'-azotetrazolate anion (ZT(2-)) skeleton (ΔH = -598.3 kJ mol(-1)); and (3) the final products contained major amounts of N2 gas, but remaining gas molecules such as HCN and NH3 were obtained, which are in agreement with experimental results. The detailed decomposition simulation results demonstrated the feasibility of this method to calculate the energies of the thermodynamic reactions for the highly energetic GZT and predict the most feasible pathways and the final products. 23169263 1H NMR spectra of ethane-1,2-diol and other vicinal diols in benzene: GIAO/DFT shift calculations. The proton NMR spectra of several 1,2-diols in benzene have been analysed so as to associate each magnetically nonequivalent proton with its chemical shift. The shifts and coupling constants of the OH and methylene protons of ethane-1,2-diol have been determined in a wide range of solvents. The conformer distribution and the proton NMR shifts of these 1,2-diols in benzene have been computed on the basis of density functional theory. The solvent is included using the integral-equation-formalism polarizable continuum model implemented in Gaussian 09. Relative Gibbs energies for all stable conformers are calculated at the Perdew, Burke and Enzerhof (PBE)0/6-311 + G(d,p) level, and shifts are calculated using the gauge-including atomic orbital method with the PBE0/6-311 + G(d,p) geometry but using the cc-pVTZ basis set. Previous calculations on ethane-1,2-diol and propane-1,2-diol have been corrected and extended. New calculations on tert-butylethane-1,2-diol, phenylethane-1,2-diol, butane-2,3-diols (dl and meso) and cyclohexane-1,2-diols (cis and trans) are presented. Overall, the computed NMR shifts are in good agreement with experimental values for the OH protons but remain systematically high for CH protons. Some results based on the Gaussian 03 solvation model are included for comparison. 23468139 Unstable expression of recombinant antibody during long-term culture of CHO cells is accompanied by histone H3 hypoacetylation. The gradual loss of recombinant protein expression in CHO cell lines during prolonged subculture is a common issue, referred to as instability, which seriously affects the industrial production processes of therapeutic proteins. Loss of recombinant gene copies, due to the genetic instability of CHO cells, and epigenetic silencing of transgene sequences, are the main reported causes of production instability. To increase our understanding on the molecular mechanisms inherent to CHO cells involved in production instability, we explored the molecular features of stable and unstable antibody producing cell lines obtained without gene amplification, to exclude the genetic instability induced by the gene amplification process. The instability of recombinant antibody production during long-term culture was caused by a 48-53% decrease in recombinant mRNA levels without significant loss of recombinant gene copies, but accompanied by a ~45% decrease in histone H3 acetylation (H3ac). Thus, our results suggest a critical role of H3ac in the stability of recombinant protein production. 23764904 Blockade of corticosteroid receptors induces anxiolytic-like effects in streptozotocin-induced diabetic mice, and synergizes with diazepam. Anxiety disorder is a psychiatric condition reported in diabetic patients. It is known that hypothalamus-pituitary-adrenal axis activity is increased in these patients and corticosteroids levels are augmented, whereas the anxiolytic actions of diazepam are reduced. The aim of this study was to evaluate the participation of glucocorticoid (GR) and mineralocorticoid (MR) receptors in anxiety in diabetic mice and whether the blockade of these receptors synergizes with diazepam in the diabetic condition, leading to a reduction of anxiety. Diabetes was induced with streptozotocin (STZ) and anxiety-like levels were evaluated on days 5, 15, and 30 after STZ. Independent groups of control and diabetic mice were treated with diazepam (0.25-2.0 mg/kg), RU-486 (12.5-100 mg/kg), spironolactone (12.5-100 mg/kg), or the combination of suboptimal doses of diazepam and MR or GR antagonists. Results showed that STZ increased anxiety-like behavior 15 days after its administration. The response to diazepam was reduced in diabetic mice, whereas GR and MR blockade induced anxiolytic-like effects in these animals. Coadministration of MR or GR antagonists synergized with diazepam to induce anxiolytic-like effects. The results suggest the participation of corticosteroid receptors in the increased anxiety-like response in diabetic mice and that the blockade of these receptors facilitates the effects of diazepam. 23907201 A case of angioleiomyoma in the buccal space. Angioleiomyoma in the buccal space is a less common benign neoplasm. To the best of our knowledge, only two cases have been described. We herein describe a new case of angioleiomyoma in the buccal space of a 45-year-old Japanese woman. No specific features were observed on clinical examination or ultrasonography. With an initial diagnosis of an ectopic lymph node or benign tumor, excision via the oral cavity was performed under local anesthesia. Healing was uneventful. Immunohistochemical examination revealed that the excised specimen was progesterone receptor-positive and estrogen receptor-negative. 23740731 PCR-Based Diagnosis of Prosthetic Joint Infection. We performed a meta-analysis to evaluate use of PCR assays for diagnosis of prosthetic joint infection (PJI). The pooled sensitivity and specificity were 0.86 (95% confidence interval [CI], 0.77 to 0.92) and 0.91 (CI, 0.81 to 0.96), respectively. Subgroup analyses showed that use of tissue samples may improve sensitivity, and quantitative PCR and sonication of prostheses fluid may improve specificity. The results showed that PCR is reliable and accurate for detection of PJI. 23849380 Concomitant lymphocyte-rich classical Hodgkin's lymphoma and Warthin's tumor. Lymphomas associated with Warthin's tumor (WT) are extremely rare. Here, we report the simultaneous occurrence of lymphocyte-rich classical Hodgkin's lymphoma (LRCHL) and WT in a 78-year-old patient whose symptoms included an enlargement of the left parotid gland. Upon parotidectomy, the tissue specimen showed a WT with extensive replacement of the lymphoid stroma by small lymphocytes and some scattered Reed-Sternberg cells; however, the oncocytic epithelium was preserved. Further investigation revealed mediastinal and abdominal lymphadenopathy, consistent with stage IVB disease. To our knowledge, this is the first case report of LRCHL associated with WT. The lymphoid stroma in WT is part of the systemic lymphoid tissue and thus may be involved in the dissemination of the lymphoma. This case serves as a reminder that a careful evaluation of the histomorphological and immunohistological features of the lymphoid tissue is required for a WT biopsy. 23874641 Comparison of Oxidative Stress/DNA Damage in Semen and Blood of Fertile and Infertile Men. Abnormal spermatozoa frequently display typical features of oxidative stress, i.e. excessive level of reactive oxygen species (ROS) and depleted antioxidant capacity. Moreover, it has been found that a high level of oxidatively damaged DNA is associated with abnormal spermatozoa and male infertility. Therefore, the aim of our study was the comparison of oxidative stress/DNA damage in semen and blood of fertile and infertile men. The broad range of parameters which describe oxidative stress and oxidatively damaged DNA and repair were analyzed in the blood plasma and seminal plasma of groups of fertile and infertile subjects. These parameters include: (i) 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanine (8-oxoGua) levels in urine; (ii) 8-oxodG level in DNA isolated from leukocytes and spermatozoa; (iii) antioxidant vitamins (A, C and E) and uric acid. Urinary excretion of 8-oxodG and 8-oxoGua and the level of oxidatively damaged DNA in leukocytes as well as the level of antioxidant vitamins were analyzed using HPLC and HPLC/GC/MS methods. The results of our study demonstrate that 8-oxodG level significantly correlated with every parameter which describe sperm quality: sperm count, motility and morphology. Moreover, the data indicate a higher level of 8-oxodG in sperm DNA compared with DNA of surrogate tissue (leukocytes) in infertile men as well as in healthy control group. For the whole study population the median values of 8-oxodG/10(6) dG were respectively 7.85 and 5.87 (p = 0.000000002). Since 8-oxodG level in sperm DNA is inversely correlated with urinary excretion rate of 8-oxoGua, which is the product of OGG1 activity, we hypothesize that integrity of spermatozoa DNA may be highly dependent on OGG1 activity. No relationship between the whole body oxidative stress and that of sperm plasma was found, which suggests that the redox status of semen may be rather independent on this characteristic for other tissues. 23507559 α-Lipoic acid-induced inhibition of proliferation and met phosphorylation in human non-small cell lung cancer cells. α-Lipoic acid (α-LA), a naturally occurring anti-oxidant and co-factor for metabolic enzymes, suppresses the growth of different types of tumor cells. The mechanisms that are responsible for these results, however, remain to be elucidated. In the present study, we investigated the effects of α-LA on the proliferation and activation status of definitive receptor tyrosine kinases, epidermal growth factor receptor (EGFR) and Met/hepatocyte growth factor (HGF) receptor, in gefitinib-sensitive human non-small cell lung cancer cells harboring EGFRs with an activating mutation. The enantiomers R-α-LA and S-α-LA suppressed cell proliferation and increased the level of reactive oxygen species in HCC-827 and PC-9 human non-small cell lung cancer cells in an indistinguishable dose-dependent fashion. A phospho-receptor tyrosine kinase array and cell cycle analysis indicated that α-LA decreased tyrosine phosphorylation levels of EGFR, ErbB2, and Met, and this was associated with an inhibition in the cell-cycle transition from the G1 phase to the S phase without inducing apoptosis. Gefitinib, an inhibitor for EGFR tyrosine kinase, inhibited EGFR tyrosine phosphorylation/activation and proliferation of the cells. Instead, the addition of HGF induced Met tyrosine phosphorylation, and this was associated with a resistance to gefitinib-induced growth inhibition, which meant a gain in proliferative ability. In the presence of gefitinib and HGF, the addition of α-LA suppressed Met tyrosine phosphorylation, and this was associated with an inhibition in cell growth. These results suggest that the suppression of tyrosine phosphorylation/activation of growth factor receptors that is critical for the proliferation of human non-small cell lung cancer cells is a mechanism by which α-LA exerts growth inhibition for cancer cells. 23924099 MacKenzie backs campaign for more nurse peers in the Lords. Practising nurses are needed in the House of Lords to strengthen the voice of the 675,000-strong profession, a nurse peer said. 23967268 Cigarette smoke modulates vascular smooth muscle phenotype: implications for carotid and cerebrovascular disease. The role of smooth muscle cell (SMC) phenotypic modulation in the cerebral circulation and pathogenesis of stroke has not been determined. Cigarette smoke is a major risk factor for atherosclerosis, but potential mechanisms are unclear, and its role in SMC phenotypic modulation has not been established. In cultured cerebral vascular SMCs, exposure to cigarette smoke extract (CSE) resulted in decreased promoter activity and mRNA expression of key SMC contractile genes (SM-α-actin, SM-22α, SM-MHC) and the transcription factor myocardin in a dose-dependent manner. CSE also induced pro-inflammatory/matrix remodeling genes (MCP-1, MMPs, TNF-α, IL-1β, NF-κB). CSE increased expression of KLF4, a known regulator of SMC differentiation, and siKLF4 inhibited CSE induced suppression of SMC contractile genes and myocardin and activation of inflammatory genes. These mechanisms were confirmed in vivo following exposure of rat carotid arteries to CSE. Chromatin immune-precipitation assays in vivo and in vitro demonstrated that CSE promotes epigenetic changes with binding of KLF4 to the promoter regions of myocardin and SMC marker genes and alterations in promoter acetylation and methylation. CSE exposure results in phenotypic modulation of cerebral SMC through myocardin and KLF4 dependent mechanisms. These results provides a mechanism by which cigarette smoke induces a pro-inflammatory/matrix remodeling phenotype in SMC and an important pathway for cigarette smoke to contribute to atherosclerosis and stroke. 23807493 Reaction of strongly electrophilic alkenylboranes with phosphanylalkynes: rare examples of intermolecular 1,1-alkenylboration reactions. Simple alkenylbis(pentafluorophenyl)boranes undergo 1,1-alkenylboration with phosphanylacetylenes to give phosphane-borane Lewis pairs with a conjugated diene backbone. 23859273 A HEURISTIC CLUSTER-BASED EM ALGORITHM FOR THE PLANTED (l, d) PROBLEM. The planted motif search problem arises from locating the transcription factor binding sites (TFBSs) which are crucial for understanding the gene regulatory relationship. Many attempts in using expectation maximization for TFBSs discovery are successful in past. However, identifying highly degenerate motifs and reducing the effect of local optima are still an arduous task. To alleviate the vulnerability of EM to local optima trapping, we present a heuristic cluster-based EM algorithm, CEM, which refines the cluster subsets in EM method to explore the best local optimal solution. Based on experiments using both synthetic and real datasets, our algorithm demonstrates significant improvements in identifying the motif instances and performs better than current widely used algorithms. CEM is a novel planted motif finding algorithm, which is able to solve the challenging instances and easy to parallel since the process of solving each cluster subset is independent. 23612253 Analysis of genetic variability and relationships among Mentha L. using the limonene synthase gene, LS. The genus Mentha comprises a group of aromatic plants with worldwide distribution. Because of frequent interspecific hybridization, the genetic relationships within the genus are not clearly understood. Limonene synthase, which catalyses the first committed step in the essential oil monoterpene biosynthetic pathway, is considered to be a possible rate limiting enzyme. With the homology-based cloning method, primers were designed according to cDNA sequence to amplify full-length DNA sequences in 13 Mentha samples from five species, using Perilla as an outgroup. Analyses of gene structure, length variation, GC-content, Ts/Tv ratio and evolutionary diversity were carried out. Consensus phylogenetic trees were obtained using maximum likelihood, neighbor-joining, and maximum parsimony, respectively, based on the full-length genomic DNA sequences, complete ORF coding sequences and predicted amino acid sequences. The results presented here based on the sequence of MhLS provide the first credibly supported genetic relationships for Mentha, which enables a basis for further mint taxonomy, cultivation and breeding. 23719143 Carbohydrates and the human gut microbiota. Due to its scale and its important role in maintaining health, the gut microbiota can be considered as a 'new organ' inside the human body. Many complex carbohydrates are degraded and fermented by the human gut microbiota in the large intestine to both yield basic energy salvage and impact gut health through produced metabolites. This review will focus on the gut microbes and microbial mechanisms responsible for polysaccharides degradation and fermentation in the large intestine. Gut microbes and bacterial metabolites impact the host at many levels, including modulation of inflammation, and glucose and lipid metabolisms. A complex relationship occurs in the intestine between the human gut microbiota, diet and the host. Research on carbohydrates and gut microbiota composition and functionality is fast developing and will open opportunities for prevention and treatment of obesity, diabetes and other related metabolic disorders through manipulation of the gut ecosystem. 23932062 Human rights to in vitro fertilization. The Inter-American Court of Human Rights (the Court) has ruled that the Supreme Court of Costa Rica's judgment in 2000 prohibiting in vitro fertilization (IVF) violated the human right to private and family life, the human right to found and raise a family, and the human right to non-discrimination on grounds of disability, financial means, or gender. The Court's conclusions of violations contrary to the American Convention on Human Rights followed from its ruling that, under the Convention, in vitro embryos are not "persons" and do not possess a right to life. Accordingly, the prohibition of IVF to protect embryos constituted a disproportionate and unjustifiable denial of infertile individuals' human rights. The Court distinguished fertilization from conception, since conception-unlike fertilization-depends on an embryo's implantation in a woman's body. Under human rights law, legal protection of an embryo "from conception" is inapplicable between its creation by fertilization and completion of its implantation in utero. 23678874 A novel HLA-A allele detected by sequence-based typing: HLA-A*24:223. Compared with A*24:02:01:01, HLA-A*24:223 shows one nucleotide difference at genomic nt 149 G>A (codon 26 GGC>GAC) in exon 2. 23394205 Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity. ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series of sulfonylmorpholinopyrimidines that show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM. Compound 6 potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in vitro and has high free exposure in mouse following moderate oral doses. At well tolerated doses 6 leads to significant growth inhibition of LoVo xenografts grown in nude mice. Compound 6 is a useful compound to explore ATR pharmacology in vivo. 22562621 Characteristics of foreign-born HIV infected individuals and differences by region of origin and gender. To compare foreign-born (FB) and US-born (USB) patients (pts) in a US HIV care program. Retrospective review. Data were collected on all FB and a random sample of 5 % of USB pts in an HIV clinic in Colorado, USA. Comparisons were made between FB pts and USB pts and among FB pts by global region of origin and sex. Among 150 FB and 59 USB pts, FB pts were younger (40 vs. 45 years), proportionately more female (39 vs. 17 %), with heterosexual sex as HIV risk factor (69 vs. 23 %) and reported substance use less (6 vs. 38 %) (All p ≤ 0.001) compared to USB pts. Age and substance differences persisted between FB and USB women. Significant differences also existed between FB and USB pts in reason for HIV test, tuberculosis and mental health diagnoses, and diagnosis of >1 co-morbidity, but not in mean CD4 cell count (502 vs. 569), antiretroviral therapy (ART) (92 vs. 90 %), or alcohol use (29 vs. 37 %). Compared to FB women, FB men were more commonly men that have sex with men, from Latin America/Caribbean, have HIV testing for illness, and have had a concomitant HIV and AIDS diagnosis while FB women were more commonly refugees, heterosexual and from Africa. Differences exist between FB and USB HIV-infected pts, and among FB pts themselves. HIV care and prevention programs must recognize and address these dissimilarities in order to maximize clinical outcomes, improve linkage to and continuity in care and optimize resource allocation. 23714170 Increased oxidative stress biomarkers in the saliva of Down syndrome patients. The DNA oxidation byproduct 8-hydroxy-2'-deoxyguanosine (8-OHdG) is a well-known biomarker used to evaluate oxidative stress. We previously reported that the generation of reactive oxygen species (ROS) is increased in cultured gingival fibroblasts (GF) from patients with Down syndrome (DS). Thus, the aim of this study was to evaluate 8-OHdG as a marker of oxidative stress in saliva of DS patients. The study group consisted of DS patients (66 patients; age range 1-62 years) and systemically healthy control subjects (71 subjects; age range 4-58 years). Periodontal status was judged based on standard measurements of probing depth (PD) and gingival index (GI). The salivary levels of 8-OHdG were determined using an enzyme-linked immunosorbent assay. The mean of PD and GI values were not significantly different between young (1-12 years) patients with DS (DS-1) and controls (C-1) or between adult (30-62 years) patients with DS (DS-2) and controls (C-2). There were statistically significant positive correlations between the salivary 8-OHdG levels and GI in the DS-1, DS-2 and C-2 groups, but not in the C-1. There were also statistically significant positive correlations between salivary 8-OHdG levels and PD in the DS-2 and C-2 groups, but not in the DS-1 or C-1 groups. The salivary levels of 8-OHdG of DS-1 and DS-2 groups were significantly higher than in the C-l and C-2 groups, respectively. These results suggest that progressive oxidative stress occurred in DS patients. Oxidative stress may contribute to the clinical features of DS, particularly to the progressive periodontitis characteristic of early ageing. 23845057 Lifestyle referral assessment in an acute cardiology setting: study protocol for a randomized controlled feasibility trial. Lifestyle and behaviour change are important factors in the prevention of cardiovascular disease and reduction of premature mortality. Public health initiatives have focused on opportunities for healthcare staff to deliver lifestyle advice routinely in primary and secondary care but there is no consistent approach to onward referrals and the rate of uptake of advice remains low. We do not know if advice is more effective in supporting behaviour change when a systematic approach is taken that includes identification of barriers to change, directing patients toward services, referral to services, and feedback on outcome. This is a single-centre, randomized, unblinded feasibility trial in an acute hospital setting which aims to assess the feasibility of a definitive trial and provide proof of concept for the systematic delivery of individualized lifestyle advice in patients managed through an acute cardiology in-patient service.Patients will be recruited before discharge and randomized to two groups. A control group will receive the usual lifestyle assessment and referral, while an intervention group will receive the usual assessment plus the new individualized lifestyle assessment and referral. The new assessment will inform assignment of each patient to one of three categories based on personal barriers to change. Patients may be referred to a formal lifestyle-change programme, through the 'Leeds Let's Change' website, or they may be guided in self-management, using goal setting, or they may be assigned to a 'deferment' category, for reassessment at follow-up. These latter patients will be given a contact card for the 'Leeds Let's Change' service. Lifestyle change is an important mechanism for improving health and wellbeing across the population but there are widely acknowledged difficulties in addressing lifestyle factors with patients and supporting behaviour change. A systematic approach to assessment would facilitate audit and provide an indicator of the quality of care. The new assessment template has been designed to be quick and easy to use in practice and could, for example, be added to a primary care consultation or form part of a nursing discharge assessment in an acute setting. Current Controlled Trials ISRCTN41781196. 23312945 Synthesis and antibacterial evaluation of a novel tricyclic oxaborole-fused fluoroquinolone. We have designed and synthesized a novel class of compounds based on fluoroquinolone antibacterial prototype. The design concept involved the replacement of the 3-carboxylic acid in ciprofloxacin with an oxaborole-fused ring as an acid-mimicking group. The synthetic method employed in this work provides a good example of incorporating boron atom in complex molecules with multiple functional groups. The antibacterial activity of the newly synthesized compounds has been evaluated. 23895334 Mechanistic Aspects Regarding the Elimination of H2O2 from C(4a)-hydroperoxyflavin. The Role of a Proton Shuttle Required for H2O2 Elimination. DFT calculations presented for C(4a)-hydroperoxyflavin (C(4a)-FLHOOH) at the B3LYP/6-311+G(d,p) level suggest a new mechanism for the elimination of H2O2. The calculated activation barrier for a concerted four-centered elimination (ΔE‡ = 32.86 kcal/mol) strongly suggests that in the absence of interactions with the local environment a spontaneous elimination is not feasible. A proton shuttle from the N5 hydrogen to the proximal oxygen of the OOH moiety involving three water molecules has an activation barrier that is reduced to 17.11 kcal/mol. Calculations that utilize CH3OH to model the role of a local Thr or Ser residue shows that an alcohol functionality hydrogen bonded to the N5 H-atom can catalyze the elimination of H2O2 with a free energy of activation of 21.5 kcal/mol. Interaction of amines and amide residues (CH3NH2 and CH3(C=O)NH2) with the N5 locus of C(4a)-hydroperoxyflavin markedly reduce the activation barrier for H2O2 elimination relative to the concerted pathway. Proton transfer from a COOH group (∆G‡ = 8.36 kcal/mol) or the NH2 group of a positively charged Arg model (∆G‡ = 9.99 kcal/mol) to the proximal oxygen of the OOH moiety of C(4a)-FLHOOH in the TS for H2O2 elimination strongly enhances elimination of H2O2. 23959887 Consequences of domain insertion on sequence-structure divergence in a superfold. Although the universe of protein structures is vast, these innumerable structures can be categorized into a finite number of folds. New functions commonly evolve by elaboration of existing scaffolds, for example, via domain insertions. Thus, understanding structural diversity of a protein fold evolving via domain insertions is a fundamental challenge. The haloalkanoic dehalogenase superfamily serves as an excellent model system wherein a variable cap domain accessorizes the ubiquitous Rossmann-fold core domain. Here, we determine the impact of the cap-domain insertion on the sequence and structure divergence of the core domain. Through quantitative analysis on a unique dataset of 154 core-domain-only and cap-domain-only structures, basic principles of their evolution have been uncovered. The relationship between sequence and structure divergence of the core domain is shown to be monotonic and independent of the corresponding type of domain insert, reflecting the robustness of the Rossmann fold to mutation. However, core domains with the same cap type share greater similarity at the sequence and structure levels, suggesting interplay between the cap and core domains. Notably, results reveal that the variance in structure maps to α-helices flanking the central β-sheet and not to the domain-domain interface. Collectively, these results hint at intramolecular coevolution where the fold diverges differentially in the context of an accessory domain, a feature that might also apply to other multidomain superfamilies. 23536586 Psychometric properties, norms, and factor structure of the diabetes eating problem survey-revised in a large sample of children and adolescents with type 1 diabetes. OBJECTIVE The purpose of this study was to examine the psychometric properties of the Diabetes Eating Problem Survey-Revised (DEPS-R) in a large sample of young patients with type 1 diabetes, to establish norms, and to validate it against the Eating Attitudes Test-12 (EAT-12). RESEARCH DESIGN AND METHODS A total of 770 children and adolescents aged 11-19 years with type 1 diabetes completed the DEPS-R and the EAT-12. In addition, age- and sex-standardized BMI and HbA1c data were obtained from the Norwegian Childhood Diabetes Registry. In addition to tests of validity, principal axis factoring was conducted to investigate the factor structure of the 16-item DEPS-R. RESULTS The DEPS-R demonstrated satisfactory Cronbach α (0.89) and was significantly correlated with the EAT-12 (0.65; P < 0.01), indicating convergent validity. The mean (SD) DEPS-R scores were 11.0 (10.7) for the total sample and 7.7 (7.4) and 14.2 (2.4) for males and females, respectively. CONCLUSIONS This study replicates and extends previous research demonstrating the psychometric properties of the abbreviated 16-item DEPS-R. Findings support the utility of this important screening tool to identify disturbed eating in young patients with type 1 diabetes. 23896686 A High-Throughput Screening Assay for Fungicidal Compounds against Cryptococcus neoformans. Cryptococcus neoformans is a pathogenic fungus that causes meningitis worldwide, particularly in human immunodeficiency virus (HIV)-infected individuals. Although amphotericin B is the "gold standard" treatment for cryptococcal meningitis, the toxicity and inconvenience of intravenous injection emphasize a need for development of new anticryptocccal drugs. Recent data from humans and animal studies suggested that a nutrient-deprived host environment may exist in cryptococcal meningitis. Thus, a screening assay for identifying fungicidal compounds under nutrient-deprived conditions may provide an alternative strategy to develop new anticryptococcal drugs for this disease. A high-throughput fungicidal assay was developed using a profluorescent dye, alamarBlue, to detect residual metabolic activity of C. neoformans under nutrient-limiting conditions. Screening the Library of Pharmacologically Active Compounds (LOPAC) with this assay identified a potential chemical scaffold, 10058-F4, that exhibited fungicidal activity in the low micromolar range. These results thus demonstrate the feasibility of this alamarBlue-based assay for high-throughput screening of fungicidal compounds under nutrient-limiting conditions for new anticryptococcal drug development. 23867732 Facial pain with localized and widespread manifestations: Separate pathways of vulnerability. Human association studies of common genetic polymorphisms have identified many loci that are associated with risk of complex diseases, although individual loci typically have small effects. However, by envisaging genetic associations in terms of cellular pathways, rather than any specific polymorphism, combined effects of many biologically relevant alleles can be detected. The effects are likely to be most apparent in investigations of phenotypically homogenous subtypes of complex diseases. We report findings from a case-control, genetic association study of relationships between 2925 single nucleotide polymorphisms (SNPs) and 2 subtypes of a commonly occurring chronic facial pain condition, temporomandibular disorder (TMD): 1) localized TMD and 2) TMD with widespread pain. When compared to healthy controls, cases with localized TMD differed in allelic frequency of SNPs that mapped to a serotonergic receptor pathway (P=0.0012), while cases of TMD with widespread pain differed in allelic frequency of SNPs that mapped to a T-cell receptor pathway (P=0.0014). A risk index representing combined effects of 6 SNPs from the serotonergic pathway was associated with greater odds of localized TMD (odds ratio 2.7, P=1.3 E-09), and the result was reproduced in a replication case-control cohort study of 639 people (odds ratio 1.6, P=0.014). A risk index representing combined effects of 8 SNPs from the T-cell receptor pathway was associated with greater odds of TMD with widespread pain (P=1.9 E-08), although the result was not significant in the replication cohort. These findings illustrate potential for clinical classification of chronic pain based on distinct molecular profiles and genetic background. 23804565 Evolutionary dynamics of bovine coronaviruses: natural selection pattern of the spike gene implies adaptive evolution of the strains. Coronaviruses demonstrate great potential for interspecies transmission, including zoonotic outbreaks. Although bovine coronavirus (BCoV) strains are frequently circulating in cattle farms worldwide, causing both enteric and respiratory disease, little is known about their genomic evolution. We sequenced and analysed the full-length spike (S) protein gene of 33 BCoV strains from dairy and feedlot farms collected during outbreaks that occurred from 2002 to 2010 in Sweden and Denmark. Amino acid identities were >97 % for the BCoV strains analysed in this work. These strains formed a clade together with Italian BCoV strains and were highly similar to human enteric coronavirus HECV-4408/US/94. A high similarity was observed between BCoV, canine respiratory coronavirus (CRCoV) and human coronavirus OC43 (HCoV-OC43). Molecular clock analysis of the S gene sequences estimated BCoV and CRCoV diverged from a common ancestor in 1951, while the time of divergence from a common ancestor of BCoV and HCoV-OC43 was estimated to be 1899. BCoV strains showed the lowest similarity to equine coronavirus, placing the date of divergence at the end of the eighteenth century. Two strongly positive selection sites were detected along the receptor-binding subunit of the S protein gene: spanning amino acid residues 109-131 and 495-527. By contrast, the fusion subunit was observed to be under negative selection. The selection pattern along the S glycoprotein implies adaptive evolution of BCoVs, suggesting a successful mechanism for BCoV to continuously circulate among cattle and other ruminants without disappearance. 23898817 Combining Attention Training with Internet-Based Cognitive-Behavioural Self-Help for Social Anxiety: A Randomised Controlled Trial. Guided Internet-based cognitive-behavioural self-help (ICBT) has been proven to be effective for social anxiety disorder (SAD) by several independent research groups. However, as the proportion of clinical significant change has room for improvement, new treatments should be developed and investigated. A novel treatment is attention bias modification (ABM). This study aimed at evaluating the combination of ABM and ICBT. We compared two groups, one group receiving ICBT and ABM targeting attentional avoidance and the other group receiving ICBT and control training. ABM and control training tasks were both based on the dot-probe paradigm. A total of 133 participants, diagnosed with SAD, were randomised to these two groups. The attention training group (N = 66) received 2 weeks of daily attention training followed by 9 weeks of ICBT. The control group (N = 67) received 2 weeks of daily control training, also followed by 9 weeks of ICBT. Social anxiety measures as well as the attention bias were assessed at pre-assessment, at week 2, and at post-treatment. Results showed no significant differences between the attention training group and the control group. Both groups improved substantially on social anxiety symptoms from pre- to post-assessment (d within = 1.39-1.41), but showed no change in attention processes (d within = 0.10-0.17). In this trial, the attention modification training failed to induce differential change in attention bias. Results demonstrate that the applied ABM procedure with its focus on the reduction of attentional avoidance was ineffective in the Internet-based setting. The results do not suggest that adding ABM targeting attentional avoidance to ICBT results in better outcomes than ICBT alone. 23948224 Accelerated azo dye removal by biocathode formation in single-chamber biocatalyzed electrolysis systems. Biocatalyzed electrolysis systems (BES) have been the topic of a great deal of research. However, the biocathodes formed in single-chamber BES without extra inocula have not previously been researched. Along with the formation of biocathodes, the polarization current increased to 1.76mA from 0.35mA of abio-cathodes at -1.2V (vs. SCE). Electrochemical impedance spectroscopy (EIS) results also indicated that the charge transfer resistance (Rct) was decreased to 148.9Ω, less than 1978Ω of the abio-cathodes cleared. The performance of the biocathodes was tested for azo dye decolorization, and the dye removal efficiency was 13.3±3.2% higher than abio-cathodes with a 0.5V direct current (DC) power supply. These aspects demonstrate that biocathode accelerates the rate of electrode reaction in BES and comparing with noble metal catalysts, biocathodes have low toxicity or non-toxic and reproducible properties, which can be widely applied in bioelectrochemical field in the future. 23951147 Trained eyes: experience promotes adaptive gaze control in dynamic and uncertain visual environments. Current eye-tracking research suggests that our eyes make anticipatory movements to a location that is relevant for a forthcoming task. Moreover, there is evidence to suggest that with more practice anticipatory gaze control can improve. However, these findings are largely limited to situations where participants are actively engaged in a task. We ask: does experience modulate anticipative gaze control while passively observing a visual scene? To tackle this we tested people with varying degrees of experience of tennis, in order to uncover potential associations between experience and eye movement behaviour while they watched tennis videos. The number, size, and accuracy of saccades (rapid eye-movements) made around 'events,' which is critical for the scene context (i.e. hit and bounce) were analysed. Overall, we found that experience improved anticipatory eye-movements while watching tennis clips. In general, those with extensive experience showed greater accuracy of saccades to upcoming event locations; this was particularly prevalent for events in the scene that carried high uncertainty (i.e. ball bounces). The results indicate that, even when passively observing, our gaze control system utilizes prior relevant knowledge in order to anticipate upcoming uncertain event locations. 23894573 Identification of hotspots in the European union for the introduction of four zoonotic arboviroses by live animal trade. Live animal trade is considered a major mode of introduction of viruses from enzootic foci into disease-free areas. Due to societal and behavioural changes, some wild animal species may nowadays be considered as pet species. The species diversity of animals involved in international trade is thus increasing. This could benefit pathogens that have a broad host range such as arboviruses. The objective of this study was to analyze the risk posed by live animal imports for the introduction, in the European Union (EU), of four arboviruses that affect human and horses: Eastern and Western equine encephalomyelitis, Venezuelan equine encephalitis and Japanese encephalitis. Importation data for a five-years period (2005-2009, extracted from the EU TRACES database), environmental data (used as a proxy for the presence of vectors) and horses and human population density data (impacting the occurrence of clinical cases) were combined to derive spatially explicit risk indicators for virus introduction and for the potential consequences of such introductions. Results showed the existence of hotspots where the introduction risk was the highest in Belgium, in the Netherlands and in the north of Italy. This risk was higher for Eastern equine encephalomyelitis (EEE) than for the three other diseases. It was mainly attributed to exotic pet species such as rodents, reptiles or cage birds, imported in small-sized containments from a wide variety of geographic origins. The increasing species and origin diversity of these animals may have in the future a strong impact on the risk of introduction of arboviruses in the EU. 23430162 Effect of chronic ethanol treatment on μ-opioid receptor function, interacting proteins and morphine-induced place preference. RATIONALE: Both the acute and chronic consumption of ethanol have been reported to modify several molecular events in the central nervous system, and the endogenous μ-opioid receptor system is involved in the reinforcing/rewarding effects of ethanol. OBJECTIVES: The present study was designed to clarify the effects of chronic ethanol treatment on cellular processes involving μ-opioid receptor and the development of morphine-induced rewarding effects. METHODS: Male C57BL/6J mice were continuously treated with a liquid diet containing 3.0 w/v ethanol. The direct involvement of μ-opioid receptor functions in the activation of G-proteins and changes in protein levels in the lower midbrain of mice after chronic treatment with ethanol were investigated by a [(35)S] GTPγS binding assay and Western blotting, respectively. The rewarding effects of morphine (5 mg/kg) under treatment with ethanol were measured by the conditioned place preference paradigm. RESULTS: The function of μ-opioid receptor was increased by treatment with ethanol in the lower midbrain using [(35)S] GTPγS binding assay. Furthermore, the GRK2 protein level was significantly increased by treatment with ethanol. Chronic treatment with ethanol enhanced the rewarding effects of morphine. On the other hand, this enhancement of the rewarding effects of morphine by ethanol treatment was significantly inhibited by the GRK2 inhibitor β-adrenergic receptor kinase 1 inhibitor. CONCLUSIONS: The present study demonstrated that chronic treatment with ethanol enhanced the rewarding effects of morphine by up-regulating functional changes in μ-opioid receptor, mediated by GRK2. 23370835 Impact of protein supplementation and care and support on body composition and CD4 count among HIV-infected women living in rural India: results from a randomized pilot clinical trial. Body composition in HIV-infected individuals is subject to many influences. We conducted a pilot 6-month randomized trial of 68 women living with AIDS (WLA) from rural India. High protein intervention combined with education and supportive care delivered by HIV-trained village women (activated social health activist [Asha] life [AL]) was compared to standard protein with usual care delivered by village community assistants (usual care [UC]). Measurements included CD4 counts, ART adherence, socio-demographics, disease characteristics (questionnaires); and anthropometry (bioimpedance analyzer). Repeated measures analysis of variance modeled associations. AL significantly gained in BMI, muscle mass, fat mass, ART adherence, and CD4 counts compared to UC, with higher weight and muscle mass gains among ART adherent (≥66%) participants who had healthier immunity (CD4 ≥450). BMI of WLA improved through high protein supplementation combined with education and supportive care. Future research is needed to determine which intervention aspect was most responsible. 23911319 Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in patterns specific to developmental stage and neuroanatomical structure. We identified de novo mutations in persons with schizophrenia and then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood. In the dorsolateral and ventrolateral prefrontal cortex during fetal development, genes harboring damaging de novo mutations in schizophrenia formed a network significantly enriched for transcriptional coexpression and protein interaction. The 50 genes in the network function in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport. These results suggest that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia. These results also support the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain. 23958729 iBMQ: a R/Bioconductor package for Integrated Bayesian Modeling of eQTL data. Recently, mapping studies of expression quantitative loci (eQTL) (where gene expression levels are viewed as quantitative traits) have provided insight into the biology of gene regulation. Bayesian methods provide natural modelling frameworks for analyzing eQTL studies, where information shared across markers and/or genes can increase the power to detect eQTLs. Bayesian approaches tend to be computationally demanding and require specialized software. As a result, most eQTL studies employ univariate methods treating each gene independently, leading to sub-optimal results. We present a powerful, computationally-optimized and free open source R package, iBMQ. Our package implements a joint hierarchical Bayesian model where all genes and SNPs are modeled concurrently. Model parameters are estimated using a Markov chain Monte Carlo algorithm. The free and widely used openMP parallel library speeds up computation. Using a mouse cardiac data set, we show that iBMQ improves the detection of large trans-eQTL hotspots compared to other state-of-the-art packages for eQTL analysis. The R-package iBMQ is available from the Bioconductor web site at http://bioconductor.org and runs on Linux, Windows and MAC OS X. It is distributed under the Artistic Licence-2.0 terms. christian.deschepper@ircm.qc.ca; rgottard@fhcrc.org SUPPLEMENTARY INFORMATION: Supplementary material is available at Bioinformatics online. 23919334 Advances in chronic obstructive pulmonary disease. Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation in the presence of identifiable risk factors. Inflammation is the central pathological feature in the pathogenesis of COPD. In addition to its pulmonary effects, COPD is associated with significant extrapulmonary manifestations, including ischaemic heart disease, osteoporosis, stroke and diabetes. Anxiety and depression are also common. Spirometry remains the gold standard diagnostic tool. Pharmacologic and non-pharmacologic therapy can improve symptoms, quality of life and exercise capacity and, through their effects on reducing exacerbations, have the potential to modify disease progression. Bronchodilators are the mainstay of pharmacotherapy, with guidelines recommending a stepwise escalating approach. Smoking cessation is paramount in managing COPD, with promotion of physical activity and pulmonary rehabilitation being other key factors in management. Comorbidities should be actively sought and managed in their own right. Given the chronicity and progressive nature of COPD, ongoing monitoring and support with timely discussion of advanced-care planning and end-of-life issues are recommended. 23910429 Race/Ethnic Disparities in Risk Factor Control and Survival in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. This study sought to evaluate the impact of race/ethnicity on cardiovascular risk factor control and on clinical outcomes in a setting of comparable access to medical care. The BARI 2D trial enrolled 1,750 participants from the United States and Canada that self-reported either White non-Hispanic (n = 1,189), Black non-Hispanic (n = 349), or Hispanic (n = 212) race/ethnicity. Participants had type 2 diabetes and coronary artery disease and were randomized to cardiac and glycemic treatment strategies. All patients received intensive target-based medical treatment for cardiac risk factors. Average follow-up was 5.3 years. Kaplan-Meier survival curves and Cox proportional hazards regression models were constructed to assess potential differences in mortality and cardiovascular outcomes across racial/ethnic groups. Long-term risk of death and death/myocardial infarction/stroke did not vary significantly by race/ethnicity (5-year death: 11.0% Whites, 13.7% Blacks, 8.7% Hispanics, p = 0.19; adjusted hazard ratio 1.18 Black versus White, 95% confidence interval 0.84 to 1.67, p = 0.33 and 0.82 Hispanic versus White, 95% confidence interval 0.51 to 1.34, p = 0.43). Among the 1,168 patients with suboptimal risk factor control at baseline, the ability to attain better risk factor control during the trial was associated with higher 5-year survival (71%, 86% and 95% for patients with 0 or 1, 2, and 3 factors in control, respectively, p <0.001); this pattern was observed within each race/ethnic group. In conclusion, significant race/ethnic differences in cardiac risk profiles that persisted during follow-up did not translate into significant differences in 5-year death or death/MI/stroke. 23254542 Strength, power, and speed qualities in english junior elite rugby league players. Kirkpatrick, J and Comfort, P. Strength, power, and speed qualities in English junior elite rugby league players. J Strength Cond Res 27(9): 2414-2419, 2013-The aim of this study was to compare strength, power, and speed characteristics of elite junior English rugby league forwards and backs. A squad of males under 20's (n = 24; age 18.70 ± 0.90 years; body mass 86.4 ± 9.93 kg; height 178.47 ± 6.97 cm) players from a Super League team performed a range of assessments, including 10-, 20-, and 40-m sprints; vertical jump; and 1 repetition maximum (1RM) bench press and 1-RM back squat. Independent t-tests revealed no significance between body mass and height (180.13 ± 7.65 cm, 176.83 ± 6.10 cm; p > 0.05) or body mass (90.08 ± 11.72 kg, 82.75 ± 6.28 kg; p > 0.05) for the forwards and backs, respectively. Backs were significantly quicker over the 10-m sprints (1.99 ± 0.60 seconds, 2.06 ± 0.10 seconds; p = 0.011), 20-m sprints (3.26 ± 0.70 seconds, 3.39 ± 0.17 seconds; p = 0.002), and 40-m sprints (5.55 ± 0.13 seconds, 5.80 ± 0.26 seconds; p = 0.0001) compared with the forwards. No significant difference (p > 0.05) was observed for the vertical jump performances between the forwards (50.58 ± 7.06 cm) and the backs (50.60 ± 5.02 cm). In addition, forwards demonstrated a higher 1RM bench press and 1RM back squat (110.00 ± 15.8 kg and 140.21 ± 26.21 kg) compared with the backs (101.67 ± 9.13 kg and 132.71 ± 9.38 kg), although this was not statistically significant (p > 0.05); when expressed relative to body mass the differences between forwards and backs was reduced further for both bench press (1.22 ± 0.10 kg/kg, 1.23 ± 0.08 kg/kg, respectively; p > 0.05) and back squat (1.61 ± 0.13 kg/kg, 1.56 ± 0.20 kg/kg, respectively; p > 0.05). In addition, relative squat strength demonstrated moderate inverse correlations between relative squat strength sprint times (r = -0.45, -0.46, and -0.44; p < 0.01) across 10, 20, and 40 m, respectively. These findings highlight the importance of maximizing squat strength in academy rugby league athletes and highlight that differences in sprint performance between positions may be attributable to the differences in relative strength levels between positions. 23553342 The evolving role of antifungal susceptibility testing. Although increasing numbers of hospital microbiology laboratories are performing antifungal susceptibility testing (AST), its routine use is uncommon. The utility of AST is founded on the belief that susceptibility (or resistance) of an agent allows some prediction of clinical outcome. This review provides an overview of the development of antifungal susceptibility testing methodology, including wild-type minimum inhibitory concentration (MIC) distributions, epidemiologic breakpoints, and Interpretive Clinical Breakpoints for antifungal agents. In addition, we examine the current clinical utility of AST and the clinical data support utilized in the development of clinical breakpoints (CBP) for common pathogens causing invasive fungal infections. In the treatment of fungal infections, identifying consistent correlations between MICs - or susceptibility category - and clinical outcomes is an ongoing challenge, and current data sets are insufficient for many drugs and pathogens to enable the development, revision, or confirmation of CBPs. Antifungal susceptibility testing is of current value, but further research in many areas is needed before MICs are independently used to guide treatment decisions. 23444913 Synergistic antitumor activity from two-stage delivery of targeted toxins and endosome-disrupting nanoparticles. Plant-derived Type I toxins are candidate anticancer therapeutics requiring cytosolic delivery into tumor cells. We tested a concept for two-stage delivery, whereby tumor cells precoated with an antibody-targeted gelonin toxin were killed by exposure to endosome-disrupting polymer nanoparticles. Co-internalization of particles and tumor cell-bound gelonin led to cytosolic delivery and >50-fold enhancement of toxin efficacy. This approach allows the extreme potency of gelonin to be focused on tumors with significantly reduced potential for off-target toxicity. 23920389 Causes of mortality after dose-escalated radiation therapy and androgen deprivation for high-risk prostate cancer. Men with high-risk prostate cancer have other competing causes of mortality; however, current risk stratification schema do not account for comorbidities. We aim to identify the causes of death and factors predictive for mortality in this population. A total of 660 patients with high-risk prostate cancer were treated with definitive high-dose external beam radiation therapy (≥74 Gy) and androgen deprivation (AD) between 1996 and 2009 at a single institution. Cox proportional hazards regression analysis was conducted to determine factors predictive of survival. The median radiation dose was 78 Gy, median duration of AD was 6 months, and median follow-up was 74 months. The 10-year overall survival (OS) was 60.6%. Prostate cancer was the leading single cause of death, with 10-year mortality of 14.1% (95% CI 10.7-17.6), compared with other cancers (8.4%, 95% CI 5.7-11.1), cardiovascular disease (7.3%, 95% CI 4.7-9.9), and all other causes (10.4%, 95% CI 7.2-13.6). On multivariate analysis, older age (HR 1.55, P=.002) and Charlson comorbidity index score (CS) ≥1 (HR 2.20, P<.0001) were significant factors predictive of OS, whereas Gleason score, T stage, prostate-specific antigen, duration of AD, radiation dose, smoking history, and body mass index were not. Men younger than 70 years of age with CS = 0 were more likely to die of prostate cancer than any other cause, whereas older men or those with CS ≥1 more commonly suffered non-prostate cancer death. The cumulative incidences of prostate cancer-specific mortality were similar regardless of age or comorbidities (P=.60). Men with high-risk prostate cancer are more likely to die of causes other than prostate cancer, except for the subgroup of men younger than 70 years of age without comorbidities. Only older age and presence of comorbidities significantly predicted for OS, whereas prostate cancer- and treatment-related factors did not. 23824835 Integrative variable selection via Bayesian model uncertainty. We are interested in developing integrative approaches for variable selection problems that incorporate external knowledge on a set of predictors of interest. In particular, we have developed an integrative Bayesian model uncertainty (iBMU) method, which formally incorporates multiple sources of data via a second-stage probit model on the probability that any predictor is associated with the outcome of interest. Using simulations, we demonstrate that iBMU leads to an increase in power to detect true marginal associations over more commonly used variable selection techniques, such as least absolute shrinkage and selection operator and elastic net. In addition, iBMU leads to a more efficient model search algorithm over the basic BMU method even when the predictor-level covariates are only modestly informative. The increase in power and efficiency of our method becomes more substantial as the predictor-level covariates become more informative. Finally, we demonstrate the power and flexibility of iBMU for integrating both gene structure and functional biomarker information into a candidate gene study investigating over 50 genes in the brain reward system and their role with smoking cessation from the Pharmacogenetics of Nicotine Addiction and Treatment Consortium. Copyright © 2013 John Wiley & Sons, Ltd. 23942641 Attention to endogenous and exogenous cues affects auditory localization. Three experiments examine attentional differences in auditory localization using either endogenous or exogenous visual cues. Participants were presented with visual cues on a computer screen and asked to localize auditory targets presented through headphones. In conditions in which the auditory and visual stimuli traveled in the same direction, participants showed illusory directional hearing (Hari in Neurosci Lett 189:29-30, 1995) in that the targets were perceived to travel through the head. In conditions in which the directions of the auditory and visual stimuli were conflicting, participants localized the auditory targets as traveling in the direction of the visual cues. These data suggest that visual capture plays a predominate role in the processes of auditory localization that occurs within the head. Additionally, endogenous response times were significantly greater than exogenous response times. We propose this is the result of additional time required to shift one's attentional window in the endogenous condition. 23933254 Visual sustained attention and numerosity sensitivity correlate with math achievement in children. In this study, we investigated in school-age children the relationship among mathematical performance, the perception of numerosity (discrimination and mapping to number line), and sustained visual attention. The results (on 68 children between 8 and 11years of age) show that attention and numerosity perception predict math scores but not reading performance. Even after controlling for several variables, including age, gender, nonverbal IQ, and reading accuracy, attention remained correlated with math skills and numerosity discrimination. These findings support previous reports showing the interrelationship between visual attention and both numerosity perception and math performance. It also suggests that attentional deficits may be implicated in disturbances such as developmental dyscalculia. 23922787 HIV Risk-Reduction Counseling and Testing on Behavior Change of MSM. HIV and AIDS incidence in China is high among men who have sex with men (MSM) and ours was one of few studies in China to evaluate the role of HIV risk reduction counseling and testing. Respondent-driven sampling (RDS) was used to recruit 430 MSM. Participants were followed up at 6, 12 and 18 months to evaluate behavioral changes after counseling to reduce risk behaviors. At baseline, HIV prevalence was 4.7%, whereas HIV incidence was 5.2 per 100 person-years. The incidence was 3.8 during six to 12 months, and 1.1 during 12 to 18 months. During the study period, the reported unprotected anal intercourse (UAI) significantly decreased from 60.9% to 42.9%. The proportion of participants who had one or no partner significantly increased from 40.9% to 48.0%. The study also found that some risk behaviors decreased between baseline and 12 months, followed by a slight increase between 12 and 18 months. Reductions in UAI can be achieved through counseling and testing, but may wane over time. Future programs should consider HIV risk-reduction counseling and testing for interventions in MSM in China. 23846268 Genome Sequence of "Candidatus Methanomassiliicoccus intestinalis" Issoire-Mx1, a Third Thermoplasmatales-Related Methanogenic Archaeon from Human Feces. "Candidatus Methanomassiliicoccus intestinalis" Issoire-Mx1 is a methanogenic archaeon found in the human gut and is a representative of the novel order of methanogens related to Thermoplasmatales. Its complete genome sequence is presented here. 23915474 Parental influence on adolescent compliance with graduated driver licensing conditions and crashes as a restricted licensed driver: New Zealand Drivers Study. To examine the influence of parental knowledge of, and support for graduated driver licensing (GDL) conditions, parental management of adolescent driving and parental driving behaviour on adolescent compliance with GDL conditions and crashes as a restricted licence driver. This research was part of the New Zealand Drivers Study (NZDS), a prospective cohort study of 3992 newly licensed car drivers. NZDS participants were recruited at the learner licence stage, with follow-up aligned with the GDL stages. At the restricted licence stage 1200 parents of NZDS adolescents, aged 15-17 years at learner licensure, were recruited and completed interviews. 895 of these adolescents progressed to their full licence and completed the full licence interview. These 895 parent-adolescent pairs were the study population in this research. Topics examined included parental knowledge of, and support for GDL conditions, management of adolescent driving (driving rules, adolescent vehicle ownership, delaying licensure), and their own driving behaviours. Outcomes examined were adolescent compliance with GDL restricted licence conditions (night-time and passenger), and crashes as a driver during the restricted licence stage. After controlling for other variables, factors independently associated with adolescent low compliance with GDL conditions were: low parental knowledge of conditions, parents' implementing few driving rules, adolescent vehicle ownership, and parent crash involvement. Factors independently associated with adolescents being a crash involved driver were: parents' actively delaying licensure, adolescent vehicle ownership, and parent crash involvement. There is increasing recognition of the importance of parental involvement in adolescent driving. The results show that parents are influential in determining adolescent compliance with GDL and risk of crash. Parents can have considerable positive influence on their adolescent's driving through ensuring compliance with the components of GDL, limiting vehicle ownership and by modelling safe driving behaviours. 23381653 Properties and mechanisms of action of naturally occurring antifungal peptides. Antimicrobial peptides are a vital component of the innate immune system of all eukaryotic organisms and many of these peptides have potent antifungal activity. They have potential application in the control of fungal pathogens that are a serious threat to both human health and food security. Development of antifungal peptides as therapeutics requires an understanding of their mechanism of action on fungal cells. To date, most research on antimicrobial peptides has focused on their activity against bacteria. Several antimicrobial peptides specifically target fungal cells and are not active against bacteria. Others with broader specificity often have different mechanisms of action against bacteria and fungi. This review focuses on the mechanism of action of naturally occurring antifungal peptides from a diverse range of sources including plants, mammals, amphibians, insects, crabs, spiders, and fungi. While antimicrobial peptides were originally proposed to act via membrane permeabilization, the mechanism of antifungal activity for these peptides is generally more complex and often involves entry of the peptide into the cell. 23829557 Studies of efficacy and liver toxicity related to adeno-associated virus-mediated RNA interference. Abstract Adeno-associated virus (AAV)-mediated RNA interference shows promise as a therapy for chronic hepatitis B virus (HBV) infection, but its low efficacy and hepatotoxicity pose major challenges. We have generated AAV vectors containing different promoters and a panel of HBV-specific short hairpin RNAs (shRNAs) to investigate factors that contribute to the efficacy and pathogenesis of AAV-mediated RNA interference. HBV transgenic mice injected with high doses of AAV vectors containing the U6 promoter produced abundant shRNAs, transiently inhibited HBV, but induced severe hepatotoxicity. Sustained HBV suppression without liver toxicity can be achieved by lowering the dose of AAV-U6 vectors. AAVs containing the weaker H1 promoter did not cause liver injury, but their therapeutic efficacy was highly dependent on the sequence of the shRNA. Mice treated with the toxic U6-promoter-driven shRNA showed little change in hepatic microRNA levels, but a dramatic increase in hepatic leukocytes and inflammatory cytokines and chemokines. Hepatotoxicity was completely absent in immunodeficient mice and significantly alleviated in wild-type mice depleted of macrophages and granulocytes, suggesting that host inflammatory responses are the major cause of liver injury induced by the overexpressed shRNAs from AAV-U6 vectors. Our results demonstrate that selection of a highly potent shRNA and control its expression level is critical to achieve sustained HBV suppression without inducing inflammatory side effects. 23503967 Maternal perinatal diet induces developmental programming of bone architecture. Maternal high-fat (HF) diet can alter offspring metabolism via perinatal developmental programming. This study tests the hypothesis that maternal HF diet also induces perinatal programming of offspring bone mass and strength. We compared skeletal acquisition in pups from C57Bl/6J mice fed HF or normal diet from preconception through lactation. Three-week-old male and female pups from HF (HF-N) and normal mothers (N-N) were weaned onto normal diet. Outcomes at 14 and 26 weeks of age included body mass, body composition, whole-body bone mineral content (WBBMC) via peripheral dual-energy X-ray absorptiometry, femoral cortical and trabecular architecture via microcomputed tomography, and glucose tolerance. Female HF-N had normal body mass and glucose tolerance, with lower body fat (%) but higher serum leptin at 14 weeks vs. N-N (P<0.05 for both). WBBMC was 12% lower at 14 weeks and 5% lower at 26 weeks, but trabecular bone volume fraction was 20% higher at 14 weeks in female HF-N vs. N-N (P<0.05 for all). Male HF-N had normal body mass and mildly impaired glucose tolerance, with lower body fat (%) at 14 weeks and lower serum leptin at 26 weeks vs. N-N (P<0.05 for both). Serum insulin was higher at 14 weeks and lower at 26 weeks in HF-N vs. N-N (P<0.05). Trabecular BV/TV was 34% higher and cortical bone area was 6% higher at 14 weeks vs. N-N (P<0.05 for both). These data suggest that maternal HF diet has complex effects on offspring bone, supporting the hypothesis that maternal diet alters postnatal skeletal homeostasis. 23464881 Templating Sub-10 nm Atomic Layer Deposited Oxide Nanostructures on Graphene via One-Dimensional Organic Self-Assembled Monolayers. Molecular-scale control over the integration of disparate materials on graphene is a critical step in the development of graphene-based electronics and sensors. Here, we report that self-assembled monolayers of 10,12-pentacosadiynoic acid (PCDA) on epitaxial graphene can be used to template the reaction and directed growth of atomic layer deposited (ALD) oxide nanostructures with sub-10 nm lateral resolution. PCDA spontaneously assembles into well-ordered domains consisting of one-dimensional molecular chains that coat the entire graphene surface in a manner consistent with the symmetry of the underlying graphene lattice. Subsequently, zinc oxide and alumina ALD precursors are shown to preferentially react with the functional moieties of PCDA, resulting in templated oxide nanostructures. The retention of the original one-dimensional molecular ordering following ALD is dependent on the chemical reaction pathway and the stability of the monolayer, which can be enhanced via ultraviolet-induced molecular cross-linking. 23456754 Between-within models for survival analysis. A popular way to control for confounding in observational studies is to identify clusters of individuals (e.g., twin pairs), such that a large set of potential confounders are constant (shared) within each cluster. By studying the exposure-outcome association within clusters, we are in effect controlling for the whole set of shared confounders. An increasingly popular analysis tool is the between-within (BW) model, which decomposes the exposure-outcome association into a 'within-cluster effect' and a 'between-cluster effect'. BW models are relatively common for nonsurvival outcomes and have been studied in the theoretical literature. Although it is straightforward to use BW models for survival outcomes, this has rarely been carried out in practice, and such models have not been studied in the theoretical literature. In this paper, we propose a gamma BW model for survival outcomes. We compare the properties of this model with the more standard stratified Cox regression model and use the proposed model to analyze data from a twin study of obesity and mortality. We find the following: (i) the gamma BW model often produces a more powerful test of the 'within-cluster effect' than stratified Cox regression; and (ii) the gamma BW model is robust against model misspecification, although there are situations where it could give biased estimates. 23831495 Dietary administration of microalgae Navicula sp. affects immune status and gene expression of gilthead seabream (Sparus aurata). Effects of silage microalgae enriched with a probiotic and lyophilized microalgae were evaluated on main immune parameters and different gene expression of gilthead seabream (Sparus aurata L.). A total of 60 seabream were grouped into 3 treatment diets which were a control diet (commercial diet) without microalgae (C), commercial diet supplemented with silage microalgae Navicula sp. plus Lactobacillus sakei 5-4 (10(6) CFU g(-1)) (SM), and commercial diet supplemented with lyophilized microalgae (LM) for 4 weeks. Generally, the results showed a significant increase in the immune parameters, principally in leucocyte peroxidase, phagocytosis and complement activities in fish fed with SM diet compared to control group. About the gene expression in head-kidney, transcript levels (Interleukin-8, Interleukin-1β and β-defensin) were upregulated in fish fed with SM after 4 weeks of treatments. However, the gene expression was upregulated in intestine from fish fed with LM with significant difference in transferrin and cyclooxygenase 2 gene at 2 weeks, and in occludin, transferrin, interleukin-8 and interleukin-1β at 4 weeks. Finally, about the digestive enzymes, LM diet caused an upregulated of α-amylase and alkaline phosphatase genes at 2 weeks; however SM diet caused an upregulated trypsin gene at 4 weeks. SM diet a higher enhancing effect on gilthead seabream immune parameters than that observed when using LM. Furthermore, dietary administration of microalgae Navicula sp. provokes upregulation of several genes in the gut that correlates with slight inflammation. Further studies are needed to know if this diatom could be useful for administering as diet supplement for farmed fish. 23644649 Accuracy of the StatStrip versus SureStep Flexx glucose meter in neonates at risk of hypoglycemia. The study was performed to evaluate the accuracy of the StatStrip (SS) and SureStep Flexx (SF) glucose meters compared to plasma glucose in infants at risk for neonatal hypoglycemia and to determine the effect of bilirubin and hematocrit on the results. A prospective cross-sectional study was conducted on 172 venous blood glucose samples from infants who had initial low point-of-care (POC) glucose tests measured simultaneously by SS and SF. Plasma glucose levels were compared to both POC instruments, and the effect of bilirubin and hematocrit levels on mean glucose differences were analysed. Mean (SD) plasma glucose was 2.12 (0.45) mmol/L; (range, 1.11-3.06 mmol/L). Mean (1.96SD) glucose differences of the SS versus SF were 0.21 (0.70) mmol/L and -0.04 (0.78) mmol/L, respectively. SS sensitivity was 94.7 % with an 86.1 % negative predictive value (NPV) at 2.8 mmol/L, while the SF had a 100 % sensitivity and NPV at the same cut-off level. No correlations were identified between mean glucose differences and either hematocrit or bilirubin levels in both glucose meters. Both the SS and SF glucose meters have limited use when compared to plasma glucose. Hence, they can only be employed as screening tools in at-risk neonates with an appropriate, predetermined cut-off level. Hematocrit and bilirubin levels did not affect the accuracy of both devices. 23441007 Solvatochromic Effect on the Photoluminescence of MoS2 Monolayers. The effect of surrounding solvents on the photoluminescence (PL) of MoS2 monolayers on Si/SiO2 substrates is studied. A redshift (up to -60 meV) is observed for MoS2 monolayers with nonhalogenated solvent surroundings. A blueshift (up to 60 meV) and intensity increase (2-50 times) are observed for monolayers with halogenated solvent surroundings. 23578616 Evolution of quality parameters during red wine dealcoholization by osmotic distillation. Osmotic distillation technique was used for the total dealcoholization of a red wine (Aglianico grape variety) up to 0.19vol.%. The dealcoholization process was performed in subsequent cycles which gave rise wine samples at different alcoholic degrees. The effect of processing on the main chemical and physical properties of Aglianico wine was evaluated. Among wine samples, no significant differences (p<0.05) of oenological parameters such as pH, total acidity were found. Similarly, the total phenolic, flavonoids and tartaric esters content and the composition of organic acids did not show significant differences (p<0.05) during the process. On the contrary, colour intensity and tonality of wine samples changed significantly when the alcohol reduction was over the 6.5vol.%. Finally, the total dealcoholized wine showed properties similar to Aglianico wine except for the volatile compounds, which decreased over 98%. Hence, flavour enrichment may be required to produce a pleasurable and delicious non alcoholic beverage from wine. 23954057 The 2010 haiti earthquake response. This article presents an overview of the mental health response to the 2010 Haiti earthquake. Discussion includes consideration of complexities that relate to emergency response, mental health and psychosocial response in disasters, long-term planning of systems of care, and the development of safe, effective, and culturally sound mental health services in the Haitian context. This information will be of value to mental health professionals and policy specialists interested in mental health in Haiti, and in the delivery of mental health services in particularly resource-limited contexts in the setting of disasters. 23612552 The role of transcription factors in laboratory medicine. Abstract Accumulating genetic and epigenetic modifications lead to alterations in gene expression, resulting in dysregulation of cellular homeostasis. The transcriptional machinery comprises many factors that cooperate to modulate gene expression. "Crosstalk" between DNA-bound transcription factors may have synergistic or antagonistic effects on the rate of transcription. The aberrant expression of several transcription regulators in the vast majority of pathological conditions including neurodegenerative diseases and various malignancies, as well as their involvement in many cancer-related processes such as cell growth regulation, angiogenesis, invasion, and metastasis, renders transcription factors very appealing as potential molecular biomarkers and as candidates for targeted therapy. In the present mini-review, we provide a brief overview of the transcriptional machinery and summarize current knowledge regarding the implication of key transcription factors such as AP-1, NF-κB, STATs, HOX proteins, and histone modifiers, in human diseases, with emphasis on cancer. 23845552 Isolation of cytotoxic compounds from the seeds of Crataegus pinnatifida. To study the chemical constituents and bioactivity of the seeds of Crataegus pinnatifida. The chemical constituents were isolated and purified by macroporous adsorptive resin D101, silica gel, and ODS column chromatography, and preparative HPLC. Their structures were elucidated on the basis of spectroscopic methods. In addition, the cytotoxic activities of compounds 1-4 were investigated on OPM2 and RPMI-8226 cells. Four compounds were obtained and their structures were identified as (7S, 8S)-4-[2-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-1-(hydroxymethyl)ethoxy]-3, 5-dimethoxybenzaldehyde (1), (+)-balanophonin (2), erythro-guaiacylglycerol-β-coniferyl aldehyde ether (3), buddlenol A (4). Compound 1 is a novel norlignan, while compounds 1-4 exhibited marginal inhibition on the proliferation of OPM2 and RPMI-8226 cells. 23946856 Molecular assembly of amino acid interlinked, topologically symmetric, π-complementary donor-acceptor-donor triads. Amino acid interlinked pyrene and naphthalenediimide (NDI) based novel donor-acceptor-donor (D-A-D) triads are designed to exploit their topological symmetry and complementary π-character for facile charge-transfer complexation. Consequently, free-floating high-aspect-ratio supercoiled nanofibres and hierarchical helical bundles of triads are realized by modulating the chemical functionality of interlinking amino acids. 23957269 Quantifying the Contribution of Long-Range Saharan Dust Transport on Particulate Matter Concentrations in Houston, Texas, using Detailed Elemental Analysis. The transatlantic transport of North African dust by summertime trade winds occasionally increases ambient particulate matter (PM) concentrations in Texas above air quality standards. Exemptions from such exceedences can be sought for episodic events that are beyond regulatory control by providing qualitative supportive information such as satellite images and back-trajectories. Herein we demonstrate that chemical mass balancing can successfully isolate, differentiate and quantify the relative contributions from local and global mineral dust sources through detailed measurements of a wide suite of elements in ambient PM. We identified a major dust storm originating in Northwest Africa in mid-July 2008 which eventually impacted air quality in Houston during July 25, 26, and 27, 2008. Daily PM2.5 and PM10 samples were collected at two sites in Houston over a 2-week period encompassing the Saharan dust episode to quantify the transported mineral dust concentrations during this peak event. Average PM concentrations more than doubled during the Saharan intrusion compared with non-Saharan. Relative concentrations of several elements often associated with anthropogenic sources were significantly diluted by crustal minerals coincident with the large-scale Saharan dust intrusion. During non-Saharan days, local mineral dust sources including cement manufacturing, and soil and road dust contributed in total 26% to PM2.5 mass and 50% to PM10 mass; during the three-day Saharan episode the total dust contribution increased to 64% for PM2.5 and 85% for PM10. Importantly, this approach was also able to determine that local emissions of crustal minerals dominated the period immediately following the Saharan dust episode: simple quantification of bulk crustal materials may have misappropriated this elevated PM to trans-Atlantic transport of Saharan dust. 23628655 Tricuspid atresia with aortopulmonary window: challenges in achieving a balanced circulation. Tricuspid atresia and aortopulmonary window are rare congenital cardiac anomalies. The occurrence of both these anomalies in the same patient is extremely rare, with only 1 case reported in the literature. We report the surgical management of one such patient and discuss the management issues with respect to Stage 1 single ventricle palliation. 23963318 On the distribution of DNA translocation times in solid-state nanopores: an analysis using Schrödinger's first-passage-time theory. In this short paper, a correction is made to the recently proposed solution of Li and Talaga to a 1D biased diffusion model for linear DNA translocation, and a new analysis will be given to their data. It was pointed out by us recently that this 1D linear translocation model is equivalent to the one that was considered by Schrödinger for the Ehrenhaft-Millikan measurements on electron charge. Here, we apply Schrödinger's first-passage-time distribution formula to the data set in Li and Talaga. It is found that Schrödinger's formula can be used to describe the time distribution of DNA translocation in solid-state nanopores. These fittings yield two useful parameters: the drift velocity of DNA translocation and the diffusion constant of DNA inside the nanopore. The results suggest two regimes of DNA translocation: (I) at low voltages, there are clear deviations from Smoluchowski's linear law of electrophoresis, which we attribute to the entropic barrier effects; (II) at high voltages, the translocation velocity is a linear function of the applied electric field. In regime II, the apparent diffusion constant exhibits a quadratic dependence on the applied electric field, suggesting a mechanism of Taylor-dispersion effect likely due the electro-osmotic flow field in the nanopore channel. This analysis yields a dispersion-free diffusion constant value of 11.2 nm(2) Î¼s(-1) for the segment of DNA inside the nanopore, which is in quantitative agreement with the Stokes-Einstein theory. The implication of Schrödinger's formula for DNA sequencing is discussed. 23831922 The prognosis of CALM-AF10 positive adult T-cell acute lymphoblastic leukemias depends on the stage of maturation arrest. CALM-AF10 (also known as PICALM-MLLT10) is the commonest fusion protein in T-cell acute lymphoblastic leukemia, but its prognostic impact remains unclear. Molecular screening at diagnosis identified CALM-AF10 in 30/431 (7%) T-cell acute lymphoblastic leukemia patients aged 16 years and over and 15/234 (6%) in those aged up to 15 years. CALM-AF10 positive patients were predominantly (72%) surface (s)CD3/T-cell receptor negative in adults, but predominantly (67%) T-cell receptor positive in children. Amongst 22 adult CALM-AF10+ patients treated according to the LALA94/GRAALL03-05 protocols, the poor prognosis for event-free survival (p=0.0017) and overall survival (p=0.0014) was restricted to the 15 T-cell receptor negative cases. Amongst CALM-AF10+ T-cell receptor negative patients, 82% demonstrated an early T-cell precursor phenotype, reported to be of poor prognosis in pediatric T-cell acute lymphoblastic leukemia. Early T-cell precursor acute lymphoblastic leukemia corresponded to 22% of adult LALA94/GRAALL03-05 T-cell acute lymphoblastic leukemias, but had no prognostic impact per se. CALM-AF10 fusion within early T-cell precursor acute lymphoblastic leukemia (21%) did, however, identify a poor prognostic group for event-free survival (p=0.04). CALM-AF10 therefore identifies a poor prognostic group within sCD3/T-cell receptor negative adult T-cell acute lymphoblastic leukemias and is over-represented within early T-cell precursor acute lymphoblastic leukemias, where it identifies those likely to fail treatment. Its prognosis and overlap with early T-cell precursor acute lymphoblastic leukemia in pediatric T-cell acute lymphoblastic leukemia merits analysis. The clinical trial GRAALL was registered at Clinical Trials.gov number NCT00327678. 23796876 Efficacy of Withania somnifera on seminal plasma metabolites of infertile males: A proton NMR study at 800MHz. Traditional Indian systems of medicine use roots of Withania somnifera for impotence, infertility treatment, stress, and the aging process. Although Withania somnifera improves semen quality by regulating reproductive hormone levels and oxidative stress, the molecular mechanism is not clear. Our study uses high-resolution Nuclear Magnetic Resonance (NMR) spectroscopy to explore the scientific basis to reveal the pre- and post-treatment efficacy of Withania somnifera on seminal plasma of infertile men-which remains unexplored to date. A total of 180 infertile male patients were administered Withania somnifera root powder at the rate of 5g/d for a 3-month period. The study included age-matched, healthy men as a control (n=50) group. Proton NMR spectroscopy was used to measure lactate, alanine, glutamate, glutamine, citrate, lysine, choline, glycerophosphocholine (GPC), glycine, tyrosine, histidine, phenylalanine, and uridine in all seminal plasma samples. To appraise infertility levels, we also measured sperm concentration, motility, lipid peroxide, and hormonal perturbation. Withania somnifera therapy repairs the disturbed concentrations of lactate, alanine, citrate, GPC, histidine, and phenylalanine in seminal plasma and recovers the quality of semen of post-treated compared to pre-treated infertile men. Serum biochemistry was also improved over post-therapy in infertile men. Our findings reveal that Withania somnifera not only reboots enzymatic activity of metabolic pathways and energy metabolism but also invigorates the harmonic balance of seminal plasma metabolites and reproductive hormones in infertile men. The results suggest that Withania somnifera may be used as an empirical therapy for clinical management and treatment of infertility. 23822946 Second look at congenital vascular malformations: current classification, diagnostic and treatment principles. Congenital vascular malformations (CVMs) are not rare disorders, with the overall incidence of 1.5%. Due to their complex embryology and various clinical presentations, there was a long lasting confusion among vascular specialists regarding the etiology, classification, basic principles of evaluation and treatment of these anomalies. The introduction of the Hamburg classification and its adoption by experts around the world made further studies of CVMs and comparison of results among different specialists possible. Precise diagnosis of the type and extent of the malformation is paramount for the choice of adequate treatment. In most instances this can be achieved with a detailed history, careful physical examination and a combination of appropriate non-invasive studies. Invasive tests should be reserved for confirmation of diagnosis and serve as a road map for treatment planning. Modern treatment of CVMs is based on a multidisciplinary team approach involving specialists in vascular surgery, interventional radiology, pediatrics, nuclear medicine, orthopedic surgery, plastic and reconstructive surgery and physical therapy. Surgical and endovascular techniques are used in conjunction to minimize morbidity and improve treatment outcomes. 23454016 Synthesis of novel 2-amino-4-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-6-aryl-4H-pyran-3-carbonitrile derivatives as antimicrobial and antioxidant agents. As a part of systematic investigation of synthesis and biological activities of indole analogues linked to various heterocyclic systems, we have synthesized new compounds viz., 2-amino-4-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-6-aryl-4H-pyran-3-carbonitriles (2a-i), 4,5-diamino-6-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-8-aryl-2-oxo-2,6-dihydrodipyrano [2,3-b:3,2-e]pyridine-3-carbonitriles (3a-i), 4-amino-5-(5'-substituted 2'-phenyl-1H-indol-3-yl)-7-aryl-1H-pyrano[2,3-d]pyrimidin-2(5H)-ones (4a-i), 4-amino-5-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-7-aryl-1H-pyrano[2,3-d]pyrimidin-2(5H)-thiones (5a-i), 4-(5'-subtituted 2'-phenyl-1H-indol-3'-yl)-6-aryl-1,4-dihydropyrano[2,3-c]pyrazol-3-amines (6a-i) and 5-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-7-aryl-3H-pyrano[2,3-d]pyrimidin-4(5H)-ones (7a-i). Antibacterial activity results revealed that, compound 6a showed promising activity versus Escherichia coli, Staphylococcus aureus and Klebsiella pneumoniae. Compound 6d exhibited good activity against S. aureus, K. pneumoniae and Pseudomonas aeruginosa. Antifungal activity results indicated that, compound 4d exhibited maximum zone of inhibition against Aspergillus oryzae and Aspergillus flavus. In case of antioxidant activity, compound 4a showed promising radical scavenging activity, ferric ions (Fe(3+)) reducing antioxidant power (FRAP) and metal chelating activity. 23917323 Population pharmacokinetics of colistin methanesulfonate in rats: achieving sustained lung concentrations of colistin for targeting respiratory infections. Colistin methanesulfonate (CMS), the inactive prodrug of colistin, is administered by inhalation for the management of respiratory infections. However, limited pharmacokinetic data is available for CMS and colistin following pulmonary delivery. This study investigates the pharmacokinetics of CMS and colistin following intravenous (IV) and intratracheal (IT) administration in rats and determines the targeting advantage after direct delivery into the lungs. In addition to plasma, bronchoalveolar lavage (BAL) fluid was collected to quantify drug concentrations in lung epithelial lining fluid (ELF). The resulting data was analyzed using a population modeling approach in S-ADAPT. A three-compartment model described the disposition of both compounds in plasma following IV administration. The estimated mean clearance from the central compartment was 0.122 L/h for CMS and 0.0657 L/h for colistin. Conversion of CMS to colistin from all three compartments was required to fit the plasma data. The fraction of the IV dose converted to colistin in the systemic circulation was 0.0255. Two BAL fluid compartments were required to reflect drug kinetics in the ELF after IT dosing. A slow conversion of CMS (mean conversion time, MCTCMS = 3.48 h) in the lungs contributed to high and sustained concentrations of colistin in ELF. The fraction of the CMS dose converted to colistin in ELF (fm,ELF = 0.226) was higher than the corresponding fractional conversion in plasma after IV administration. In conclusion, pulmonary administration of CMS achieves high and sustained exposures of colistin in lungs for targeting respiratory infections. 23966632 Phosphatase Wip1 Is Essential for the Maturation and Homeostasis of Medullary Thymic Epithelial Cells in Mice. Thymic epithelial cells (TECs) are a key cell type in the thymic microenvironment essential for T cell development. However, intrinsic molecular mechanisms controlling TEC differentiation and activities are poorly defined. In this study, we found that deficiency of p53-induced phosphatase 1 (Wip1) in mice selectively caused severe medullary TEC (mTEC) maturation defects in an intrinsic manner. Wip1 knockout (KO) mice had decreased mature epithelial cell adhesion molecule(+)Ulex europaeus agglutinin-1 (UEA-1)(+) mTECs, including UEA-1(+)MHC class II(high), UEA-1(+)CD80(+), UEA-1(+)CD40(+), and UEA-1(+)Aire(+) cells, but not decreased numbers of cortical epithelial cell adhesion molecule(+)BP-1(+) TECs, in the postnatal stage but not in the fetal stage. Wip1-deficient mTECs express fewer tissue-restricted Ags and UEA-1(+)involucrin(+) terminal-differentiated cells. Animal models, including grafting fetal Wip1-deficient thymic tissue into T cell-deficient nude mice and reconstitution of lethally irradiated Wip1KO mouse recipients with wild-type bone marrow cells, also showed the impaired mTEC components in Wip1KO thymi, indicating the intrinsic regulatory role of Wip1 in mTEC maturation. Furthermore, thymus regeneration was significantly less efficient in adult Wip1KO mice than in wild-type mice after cyclophosphamide treatment. Wip1 deficiency resulted in elevated p38 MAPK activity in mTECs. Activated p38 MAPK has the ability to suppress CD40 expression on mTECs. Wip1-deficient thymi displayed poor response to CD40L in the fetal thymus organ culture system. Thus, Wip1 positively controls mTEC maturation, homeostasis, and regeneration through limiting the p38 MAPK pathway. 23927603 Improving evidence-based primary care for chronic kidney disease: study protocol for a cluster randomized control trial for translating evidence into practice (TRANSLATE CKD). Chronic kidney disease (CKD) and end stage renal disease (ESRD) are steadily increasing in prevalence in the United States. While there is reasonable evidence that specific activities can be implemented by primary care physicians (PCPs) to delay CKD progression and reduce mortality, CKD is under-recognized and undertreated in primary care offices, and PCPs are generally not familiar with treatment guidelines. The current study addresses the question of whether the facilitated TRANSLATE model compared to computer decision support (CDS) alone will lead to improved evidence-based care for CKD in primary care offices. This protocol consists of a cluster randomized controlled trial (CRCT) followed by a process and cost analysis. Only practices providing ambulatory primary care as their principal function, located in non-hospital settings, employing at least one primary care physician, with a minimum of 2,000 patients seen in the prior year, are eligible. The intervention will occur at the cluster level and consists of providing CKD-specific CDS versus CKD-specific CDS plus practice facilitation for all elements of the TRANSLATE model. Patient-level data will be collected from each participating practice to examine adherence to guideline-concordant care, progression of CKD and all-cause mortality. Patients are considered to meet stage three CKD criteria if at least two consecutive estimated glomerular filtration rate (eGFR) measurements at least three months apart fall below 60 ml/min. The process evaluation (cluster level) will determine through qualitative methods the fidelity of the facilitated TRANSLATE program and find the challenges and enablers of the implementation process. The cost-effectiveness analysis will compare the benefit of the intervention of CDS alone against the intervention of CDS plus TRANSLATE (practice facilitation) in relationship to overall cost per quality adjusted years of life. This study has three major innovations. First, this study adapts the TRANSLATE method, proven effective in diabetes care, to CKD. Second, we are creating a generalizable CDS specific to the Kidney Disease Outcome Quality Initiative (KDOQI) guidelines for CKD. Additionally, this study will evaluate the effects of CDS versus CDS with facilitation and answer key questions regarding the cost-effectiveness of a facilitated model for improving CKD outcomes. The study is testing virtual facilitation and Academic detailing making the findings generalizable to any area of the country. Registered as NCT01767883 on clinicaltrials.gov NCT01767883. 23702607 The association of the mitochondrial DNA OriB variant (16184-16193 polycytosine tract) with type 2 diabetes in Europid populations. The association between the mitochondrial DNA 16181-16193 polycytosine variant (known as the OriB variant as it maps to the OriB origin of replication) and type 2 diabetes has not been reliably characterised, with studies reporting conflicting results. We report a systematic review of published literature in Europid populations, new data from the Norfolk Diabetes Case-Control Study and a meta-analysis to help quantify this association. We performed a systematic review identifying all the studies of the OriB variant and type 2 diabetes in Europid populations published before January 2013. We typed the OriB variant by pyrosequencing and sequencing in the Norfolk Diabetes Case-Control Study, which comprised 5,574 type 2 diabetes cases and 6,950 population-based controls. Overall, the meta-analysis included eight published studies plus the current new results, with a total of 11,794 type 2 diabetes cases and 14,465 controls. In the Norfolk Diabetes Case-Control Study, the OR for type 2 diabetes for the OriB variant was 1.09 (95% CI 0.96, 1.24). In a combined analysis, the relative risk for type 2 diabetes for the OriB variant in Europid populations was 1.10 (95% CI 1.01, 1.20; p = 0.03) CONCLUSIONS/INTERPRETATION: Results from this systematic review and meta-analysis suggest that the mitochondrial DNA OriB variant is modestly associated with an increased risk of type 2 diabetes in Europid populations, with an effect size comparable with that of recently identified variants from genome-wide association studies. 22173957 Gadolinium chloride pretreatment ameliorates acute cadmium-induced hepatotoxicity. Cadmium is a known industrial and environmental pollutant. It causes hepatotoxicity upon acute administration. Features of cadmium-induced acute hepatoxicity encompass necrosis, apoptosis, peliosis and inflammatory infiltration. Gadolinium chloride (GdCl3) may prevent cadmium-induced hepatotoxicity by suppressing Kupffer cells. The effect of GdCl3 pretreatment on a model of acute cadmium-induced liver injury was investigated. Male Wistar rats 4-5 months old were injected intraperitoneally with normal saline followed by cadmium chloride (CdCl2; 6.5 mg/kg) or GdCl3 (10 mg/kg) followed by CdCl2 (6.5 mg/kg; groups I and II, respectively). Rats of both the groups were killed at 9, 12, 16, 24, 48 and 60 h after cadmium intoxication. Liver sections were analyzed for necrosis, apoptosis, peliosis and mitoses. Liver regeneration was also evaluated by tritiated thymidine incorporation into hepatic DNA. Serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were also determined. Hepatic necrosis, hepatocyte and nonparenchymal cell apoptosis and macroscopic and microscopic types of peliosis hepatis were minimized by gadolinium pretreatment. Serum levels of AST and ALT were also greatly diminished in rats of group II. Tritiated thymidine incorporation into hepatic DNA was increased in gadolinium pretreatment rats. Kupffer cell activation was minimal in both the groups of rats. Gadolinium pretreatment attenuates acute cadmium-induced liver injury in young Wistar rats, with mechanisms other than Kupffer cell elimination. 23436039 Venovenous extracorporeal membrane oxygenation is effective against post-cardiotomy acute respiratory failure in adults. Acute respiratory failure is a serious issue that occasionally occurs after weaning from cardiopulmonary bypass (CPB) after heart surgery. This condition can be refractory to mechanical ventilation and the mortality rate is high. Venovenous extracorporeal membrane oxygenation (VV-ECMO) is applied to treat acute lung failure after CPB at our institution. This report describes the use of VV-ECMO after cardiac surgery at a single institution. We analyzed the outcomes of 11 patients who developed severe acute respiratory failure requiring VV-ECMO after undergoing heart surgery with a cardiopulmonary bypass. Four (36.4%) patients died in hospital. One patient required conversion from VV- to venoarterial (VA-) ECMO because of circulatory instability. One patient each died of respiratory failure and heart failure and two died of ischemic colitis. Lung damage secondarily developed in these four patients to other disabled organs. Seven (63.6%) patients whose lungs were primarily disabled were weaned from VV-ECMO upon recovery from respiratory failure and were ambulatory at the time of discharge from hospital. The ratio of PaO2/FIO2 (P/F) at 24 h after starting VV-ECMO did not significantly differ between survivors and non-survivors (187.9 ± 57.7 vs. 135.5 ± 20.5, p = 0.10), but tended to be higher in survivors. Non-survivors were significantly older than survivors. Patients who develop severe acute respiratory failure after undergoing heart surgery using cardiopulmonary bypass derive a survival benefit from VV-ECMO. 23925641 Single-molecule localization microscopy - near-molecular spatial resolution in light microscopy with photoswitchable fluorophores. Fluorescence imaging beyond the diffraction limit has grown into a method of choice to elucidate questions related to biological structure and organisation. Among super-resolution techniques, imaging based on the localization of individual photoswitchable fluorescent probes has become particularly popular due to its relative ease of implementation and the nature of qualitative and quantitative answers it can offer. We review the field of single-molecule localization microscopy (SMLM) by providing an overview of its underlying principles and of different categories of photoswitchable fluorophores. In addition to summarizing target-specific labelling strategies and presenting examples of successful applications of SMLM in fixed and living systems, we show how SMLM data offer unique opportunities for quantitative biomolecular counting and distribution analysis. 23515291 Insulin-Like Growth Factor Binding Protein 2 (IGFBP-2) Promotes Growth and Survival of Breast Epithelial Cells: Novel Regulation of the Estrogen Receptor. In breast tumors IGF binding protein-2 (IGFBP-2) is elevated, and the presence of IGFBP-2 has been shown to correlate with malignancy. However, how IGFBP-2 contributes to the malignant state is still unclear. Silencing IGFBP-2 blocked cell proliferation and in MCF-7 cells increased cell death, indicating that IGFBP-2 was acting in both a mitogenic and a survival capacity. Exogenous IGFBP-2 acting via integrin receptors to reduce phosphatase and tensin homolog deleted from chromosome 10 (PTEN) levels protected these cells against death induced by various chemotherapeutic agents. This was dependent on a functional estrogen receptor (ER)-α because silencing ER-α blocked the ability of IGFBP-2 to confer cell survival. Loss of IGFBP-2 increased levels of PTEN and improved chemosensitivity of the cells, confirming its role as a survival factor. Silencing IGFBP-2 had no effect on the response to IGF-II, but responses to estrogen and tamoxifen were no longer observed due to loss of ER-α, which could be prevented by the inhibition of PTEN. Conversely, exogenous IGFBP-2 increased ER-α mRNA and protein in both normal and cancer cells via its interaction with integrin receptors. These actions of IGFBP-2 on ER-α involved the IGF-I receptor and activation of phosphatidylinositol 3-kinase in the cancer cells but were independent of this in normal breast cells. The production of IGFBP-2 by breast cancer cells enhances their proliferative potential, increases their survival, and protects them against chemotherapy-induced death. IGFBP-2 not only modulates IGFs and directly regulates PTEN but also has a role in maintaining ER-α expression. 23929759 Synthesis of a Silylium Zwitterion. A zwitterionic construction has been synthesized that covalently links a trialkylsilylium cation and a weakly coordinating carborane anion in one neutral molecule (see X-ray structure; Si green, C gray, B orange, Cl red). The silylium character of this molecule is supported by DFT calculations (see LUMO), (29) Si CP/MAS NMR spectroscopy, and reactivity. 23917075 Role of CYP2A13 in the bioactivation and lung tumorigenicity of the tobacco-specific lung procarcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK): in vivo studies using a CYP2A13-humanized mouse model. The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is abundant in tobacco smoke, is a potent lung procarcinogen. The present study was aimed to prove that transgenic expression of human CYP2A13, known to be selectively expressed in the respiratory tract and be the most efficient enzyme for NNK bioactivation in vitro, will enhance NNK bioactivation and NNK-induced tumorigenesis in the mouse lung. Kinetic parameters of NNK bioactivation in vitro and incidence of NNK-induced lung tumors in vivo were determined for wild-type, Cyp2a5-null, and CYP2A13-humanized (CYP2A13-transgenic/Cyp2a5-null) mice. As expected, in both liver and lung microsomes, the loss of CYP2A5 resulted in significant increases in Km values for the formation of 4-oxo-4-(3-pyridyl)butanal, representing the reactive intermediate that can lead to the formation of O(6)-methylguanine (O(6)-mG) DNA adducts; however, the gain of CYP2A13 at a fraction of the level of mouse lung CYP2A5 led to recovery of the activity in the lung, but not in the liver. The levels of O(6)-mG, the DNA adduct highly correlated with lung tumorigenesis, were significantly higher in the lungs of CYP2A13-humanized mice, than in Cyp2a5-null mice. Moreover, incidences of lung tumorigenesis were significantly greater in CYP2A13-humanized mice, than in Cyp2a5-null mice, and the magnitude of the differences in incidence was greater at low (30 mg/kg) than at high (200 mg/kg) NNK doses. These results indicate that CYP2A13 is a low-Km enzyme in catalyzing NNK bioactivation in vivo, and support the notion that genetic polymorphisms of CYP2A13 can influence the risks of tobacco-induced lung tumorigenesis in humans. 23952498 Medical and psychological outcomes for young adults with Type 1 diabetes: no improvement despite recent advances in diabetes care. To assess medical and psychological outcomes among young people with Type 1 diabetes and to compare medical outcomes with a previous audit. An observational study in two diabetes clinics for young adults (aged 16-21 years) in Sheffield, UK. Young people (n = 96: 81.4% response rate) with Type 1 diabetes (diagnosed > 6 months) completed measures of depressive symptoms, anxiety and disordered eating and consented for their medical records to be consulted. Mean HbA1c (86 ± 23 mmol/mol; 10.0 ± 2.1%); was comparable with that reported previously and considerably higher than recommended (< 58 mmol/mol or 7.5%). Screening rates were improved and non-attendance was lower than previously reported, but levels of non-proliferative retinopathy have increased. Microvascular complications are present in 46.9% of those diagnosed more than 7 years. Elevated levels of disordered eating were reported by 35.1%. Those scoring above cut-off levels for clinical anxiety (26.6%) and depression (10.9%) are comparable with other work with young people with Type 1 diabetes. Despite technological advances and improvements to delivery of care, HbA1c remain above recommended levels in a significant proportion of young people, many of whom already have microvascular complications. We need to learn from European centres who achieve better results, improve transition from paediatric care, integrate mental health support with diabetes care provision and take into account young people's views about clinic. This article is protected by copyright. All rights reserved. 23709636 Stabilizing selection, purifying selection, and mutational bias in finite populations. Genomic traits such as codon usage and the lengths of noncoding sequences may be subject to stabilizing selection rather than purifying selection. Mutations affecting these traits are often biased in one direction. To investigate the potential role of stabilizing selection on genomic traits, the effects of mutational bias on the equilibrium value of a trait under stabilizing selection in a finite population were investigated, using two different mutational models. Numerical results were generated using a matrix method for calculating the probability distribution of variant frequencies at sites affecting the trait, as well as by Monte Carlo simulations. Analytical approximations were also derived, which provided useful insights into the numerical results. A novel conclusion is that the scaled intensity of selection acting on individual variants is nearly independent of the effective population size over a wide range of parameter space and is strongly determined by the logarithm of the mutational bias parameter. This is true even when there is a very small departure of the mean from the optimum, as is usually the case. This implies that studies of the frequency spectra of DNA sequence variants may be unable to distinguish between stabilizing and purifying selection. A similar investigation of purifying selection against deleterious mutations was also carried out. Contrary to previous suggestions, the scaled intensity of purifying selection with synergistic fitness effects is sensitive to population size, which is inconsistent with the general lack of sensitivity of codon usage to effective population size. 23821714 Assessing the relative importance of environmental effects, carry-over effects and species differences in thermal stress resistance: a comparison of Drosophilids across field and laboratory generations. There is increasing interest in comparing species of related organisms for their susceptibility to thermal extremes in order to evaluate potential vulnerability to climate change. Comparisons are typically undertaken on individuals collected from the field with or without a period of acclimation. However this approach does not allow the potential contributions of environmental and carry-over effects across generations to be separated from inherent species differences in susceptibility. To assess the importance of these different sources of variation, we here consider heat and cold resistance in Drosophilid species from tropical and temperate sites in the field and across two laboratory generations. Resistance in field-collected individuals tended to be lower when compared to F1 and F2 laboratory generations, and species differences in field flies were only weakly correlated to differences established under controlled rearing conditions, unlike in F1 - F2 comparisons. This reflected large environmental effects on resistance associated with different sites and conditions experienced within sites. For the cold recovery assay (after 8 h cold stress) there was no strong evidence of carry-over effects, whereas for the heat knockdown (heat) and cold recovery assays (after 2 h cold stress) there was some evidence for such effects. However for heat these were species-specific in direction. Variance components for inherent species differences were substantial for resistance to heat and 8 h cold stress, but small for 2 h cold stress, though this may be a reflection of the species being considered in the comparisons. These findings highlight that inherent differences among species are difficult to characterize accurately without controlling for environmental sources of variation and carry-over effects. Moreover they also emphasize the complex nature of carry-over effects that depend on the nature of stress traits and the species being evaluated. 23823077 Optical aberrations in patients with recurrent herpes simplex keratitis and apparently normal vision. To analyse high-order aberrations (HOA), modulation transfer function (MTF) and Strehl ratio in patients with a history of herpes simplex keratitis (HSK) and apparently normal vision. Fifteen patients with a history of recurrent unilateral HSK and normal Snellen visual acuity (0 logMAR) were enrolled. Eyes with HSK (HSK group) were statistically compared with normal fellow eyes (Control group). HOA, MTF and Strehl ratio were measured using the OPD-SCAN II (Nidek Co, Gamagori, Japan) aberrometer. Measures were performed at least 3 months after the last episode of herpes. Statistical significance was indicated by p<0.05. Despite apparently normal vision in both eyes (as assessed by routine visual acuity charts), significantly higher total HOA, trefoil and tetrafoil were present in the HSK group compared with the Control group. The MTF and strehl ratio were lower in the HSK group compared with the Control group. In the HSK group, eyes with corneal opacities tended to present with greater optical aberrations than eyes with a clear cornea. Using patients as their own controls, the outcomes of this study indicate that eyes with recurrent HSK with no apparent decrease in visual acuity (0 logMAR) have significantly greater optical aberrations than eyes with no past history of herpetic disease. This outcome may explain some visual complaints of HSK patients, such as a decrease in contrast quality or reduced colour perception, compared with the unaffected contralateral eye despite apparently normal vision in both eyes. 23820902 Phosphoinositide 3-kinase p110δ Mediates Estrogen- and FSH-Stimulated Ovarian Follicle Growth. In the mammalian ovary, primordial follicles are generated early in life and remain dormant for prolonged periods. Their growth resumes via primordial follicle activation and they continue to grow until the preovulatory stage under the regulation of hormones and growth factors, such as estrogen, follicle stimulating hormone (FSH), and insulin-like growth factor-I (IGF-I). Both FSH and IGF-I activate the PI3K/Akt signaling pathway in granulosa cells (GCs), yet it remains inconclusive whether the PI3K pathway is crucial for follicle growth. In this study, we investigated the p110δ-isoform (encoded by the Pik3cd gene) of PI3K catalytic subunit expression in the mouse ovary and its function in fertility. Pik3cd null females were subfertile, exhibited fewer growing follicles and more atretic antral follicles in the ovary, and responded poorly to exogenous gonadotropins compared to controls. Ovary transplantation showed that Pik3cd null ovaries responded poorly to FSH stimulation in vitro; this confirmed that the follicle growth defect was intrinsically ovarian. In addition, estradiol (E2)-stimulated follicle growth and GC proliferation in preantral follicles was impaired in Pik3cd null ovaries. FSH and E2 substantially activated the PI3K/Akt pathway in GCs of control mice, but not in those of Pik3cd null mice. However, primordial follicle activation and oocyte meiotic maturation were not affected by Pik3cd knockout. Taken together, our findings indicate that the p110δ-isoform of the PI3K catalytic subunit is a key component of the PI3K pathway for both FSH and E2-stimulated follicle growth in ovarian granulosa cells; however, it is not required for primordial follicle activation and oocyte development. 23894157 Elevated sclerostin levels are associated with vertebral fractures in patients with type 2 diabetes mellitus. Context:Patients with Type 2 diabetes (T2DM) patients are at increased risk of vertebral fractures (VFs) compared with non-T2DM individuals, because of poor bone quality. Recent studies in non-diabetic subjects have shown that elevated sclerostin levels are associated with VFs independent of bone mineral density (BMD).Objective:We aimed to investigate the association between sclerostin levels and VFs in T2DM.Research Design and Methods:We conducted a cross-sectional observational study in 146 postmenopausal women and 175 men over 50 years old. Sclerostin levels were compared in the patients with and without VFs confirmed by spinal radiographs.Results:Sclerostin levels were significantly higher in men than in women (P<0.01). Stepwise forward multiple regression analyses demonstrated that spine BMD was the strongest and independent positive determinants for sclerostin in both genders. When the participants were divided into two subgroups by the T score of spine BMD to eliminate the influence of BMD on sclerostin values, elevated sclerostin levels were associated with an increased risk of VFs in the male patients with BMD T scores ≥ -1 [odds ratio (OR) 1.85, 95% confidence interval (CI) 1.12-3.07] and female with T scores < -1[OR 3.23, 95%CI 1.42-7.34] after adjusting for multiple variables including BMD and bone metabolic markers.Conclusions:Elevated sclerostin levels were associated with an increased risk of VFs in T2DM patients independently of BMD and bone turnover in both genders, suggesting that sclerostin levels may reflect bone fragility attributed to the deterioration of bone quality under the gender-specific range of BMD T scores. 23799531 Copper and silver complexes bearing flexible hybrid scorpionate ligand. The addition of flexible scorpionate ligand, [](-) {i.e. HB(mt)2(mp), where mt = methyl-2-mercaptoimidazole and mp = 2-mercaptopyridine} to group eleven centres is reported for the first time. The coordination of this hybrid ligand to copper(i) and silver(i) centres in the presence of triphenylphosphine and trialkylphosphine co-ligands has been investigated. The trialkylphosphines coordinates to both copper and silver centres while the less basic triarylphosphine only successfully coordinates to the copper centre. Structural characterisation of [Cu{HB(mt)2(mp)}(PPh3)], [Cu{HB(mt)2(mp)}(PCy3)] and [Ag{HB(mt)2(mp)}(PCy3)] confirm κ(3)-SSH coordination modes for ligand where one of the mt 'arms' and the mp 'arm' of the scorpionate ligand are coordinated to the metal centre. The second mt 'arm' remains uncoordinated in all three complexes. A comparison has been made with the parent sulfur based scorpionate ligand, [](-) {HB(mt)3}. 23773927 Influence of pre-analytical conditions on the measurement of components of the GH/IGF axis in rats. Pre-analytical variability characterises effects which are introduced to an analysis by manipulation and storage of a biological sample after taking it ex-vivo, but before actually quantifying the respective analyte. In humans, recent studies demonstrated that pre-analytical factors can be an important confounder for immunoassay measurements of circulating hormones of the GH/IGF-system. In contrast, this topic has rarely been addressed in rodent studies. We therefore now systematically investigated if and how commonly used sample processing and pre-treatment protocols affect measured hormone concentrations of the GH/IGF system in rats. Furthermore, we explored if short term fasting, age and circadian rhythmicity have an impact upon the concentrations of IGF-I, IGFBP-2 and IGFBP-3 in rats. On average, concentrations of IGF-I were lower by 9.2% (p<0.01), while those of IGF-II and IGFBP-3 were lower by 24% (p<0.01) in EDTA plasma when compared to plain serum from the same rats. In contrast, concentrations of GH were significantly higher in plain plasma samples compared with serum (+137.8%; p<0.01). Repeated freeze/thaw cycles significantly influenced the measurements of serum IGF-II (+25.9%; p<0.01) and IGFBP-3 (+19.3%; p<0.01) when compared to native serum. Pre-treatment of EDTA plasma with protease inhibitors, or immediate storage of EDTA blood on ice, did not significantly affect the outcome of any measurement. Acidification of plasma samples with HCl led to significantly lower IGF-I in samples (-11.9%, p<0.001) and detection of GH was completely hampered in these samples. With respect to biological variability, age (12-week-old vs. 1-year-old male Wistar rats), but not fasting (up to 18h) or circadian rhythmicity affected circulating concentrations of IGF-I and IGFBP-3. Pre-analytical variability is a potentially confounding factor which also must be considered in rodent studies when analysing and comparing hormones of the GH/IGF system. If and to what extent a specific pre-analytical procedure affects immunoassay measurements in rodent studies cannot be predicted in advance but rather needs to be tested for each analyte separately. 23643944 Naked-eye detection of nucleic acids through rolling circle amplification and magnetic particle mediated aggregation. We are presenting a new method for sequence-specific and naked-eye detection of nucleic acids (NAs) through isothermal amplification and magnetic particle mediated aggregation. A padlock probe was designed to hybridize to specific sequence on target genes followed by ligation and rolling circle amplification (RCA). Magnetic particles (MPs) were then added into RCA products solution. MPs would physically combine with long linear DNA coils (such as products of RCA reaction) and form visible intertwined aggregates, while no aggregate was observed in the absence of high molecular weight NAs (>1kb). As little as 0.62amol (124fM) of target DNA molecules was detected by the naked eye. It was further applied to detect human papillomavirus type 18 gene in genomic DNA isolated from HeLa cells. This assay is sensitive and low-cost with minimal instrumentation, revealing great potential for molecular diagnostics in developing countries and regions with limited settings. 23507028 Is the foot striking pattern more important than barefoot or shod conditions in running? People have advocated barefoot running, claiming that it is better suited to human nature. Humans usually run barefoot using a forefoot strike and run shod using a heel strike. The striking pattern was thought to be a key factor that contributes to the benefit of barefoot running. The purpose of this study is to use scientific data to prove that the striking pattern is more important than barefoot or shod conditions for runners on running injuries prevention. Twelve habitually male shod runners were recruited to run under four varying conditions: barefoot running with a forefoot strike, barefoot running with a heel strike, shod running with a forefoot strike, and shod running with a heel strike. Kinetic and kinematic data and electromyography signals were recorded during the experiments. The results showed that the lower extremity can gain more compliance when running with a forefoot strike. Habitually shod runners can gain more shock absorption by changing the striking pattern to a forefoot strike when running with shoes and barefoot conditions. Habitually shod runners may be subject to injuries more easily when they run barefoot while maintaining their heel strike pattern. Higher muscle activity in the gastrocnemius was observed when running with a forefoot strike, which may imply a greater training load on the muscle and a tendency for injury. 23297254 Pesticides in urban streams and early life stages of pacific coho salmon. Pesticides are frequently detected in urban streams and are believed to be primarily the result of homeowner use. Although concentrations in most cases are low (<1 µg/L), there is concern that pesticide inputs threaten efforts to restore and enhance salmon habitat. The authors exposed early life stages of coho salmon (Oncorhynchus kisutch) to a pesticide mixture ("cocktail") representative of those pesticides most frequently reported in urban streams in western Washington State, USA. Life stages were continuously exposed to pulses of the cocktail simulating those in urban streams in fall and winter when coho salmon eggs and sac fry are present. Nominal concentrations of eight herbicides, two insecticides, a fungicide, and a breakdown product were the maximum detected. Fertilization, hatching success, survival, deformities, and growth of fry were not significantly affected. A reduction in fertilization success (19-25%) was not reproducible even when gametes were exposed to 100 times the maximum concentrations detected. Based on the end points examined in the present study, the results suggest that direct exposure to the pesticides most frequently detected in urban streams in western Washington does not impair early life stages of coho salmon and is not a major factor governing the recovery of salmon populations. The extent to which pesticide exposure would affect smoltification, outmigration, and ocean survival needs to be determined. 22790503 Update on the biochemistry of chlorophyll breakdown. In land plants, chlorophyll is broken down to colorless linear tetrapyrroles in a highly conserved multi-step pathway. The pathway is termed the 'PAO pathway', because the opening of the chlorine macrocycle present in chlorophyll catalyzed by pheophorbide a oxygenase (PAO), the key enzyme of the pathway, provides the characteristic structural basis found in all further downstream chlorophyll breakdown products. To date, most of the biochemical steps of the PAO pathway have been elucidated and genes encoding many of the chlorophyll catabolic enzymes been identified. This review summarizes the current knowledge on the biochemistry of the PAO pathway and provides insight into recent progress made in the field that indicates that the pathway is more complex than thought in the past. 23680470 Radiochemical synthesis and in vivo evaluation of [(18)F]AZ11637326: An agonist probe for the α7 nicotinic acetylcholine receptor. The alpha-7 nicotinic acetylcholine receptor (α7 nAChR) is key in brain communication and has been implicated in the pathophysiology of diseases of the central nervous system. A positron-emitting radioligand targeting the α7 nAChR would enable better understanding of a variety of neuropsychiatric illnesses, including schizophrenia and Alzheimer's disease, and could enhance the development of new drugs for these and other conditions. We describe our attempt to synthesize an α7 nAChR-selective radiotracer for positron emission tomography (PET). We prepared the high-affinity (Kd=0.2 nM) α7 nAChR agonist, 5'-(2-[(18)F]fluorophenyl)spiro[1-azabicyclo-[2.2.2]octane]-3,2'-(3'H)furo[2,3-b]pyridine, [(18)F]AZ11637326, in two steps, a nucleophilic fluorination followed by decarbonylation. We studied [(18)F]AZ11637326 in rodents, including mice lacking α7 nAChR, and in non-human primates. [(18)F]AZ11637326 was synthesized in a non-decay-corrected radiochemical yield of 3% from the end of synthesis (90min) with a radiochemical purity >90% and average specific radioactivity of 140GBq/μmol (3,781mCi/μmol). Modest rodent brain uptake was observed (2-5% injected dose per gram of tissue, depending on specific activity), with studies comparing CD-1 and α7 nAChR null mice indicating an element of target-specific binding. Blocking studies in non-human primates did not reveal specific binding within the brain. Despite the high affinity and target selectivity of AZ11637326 for α7 nAChR in vitro and encouraging rodent studies, receptor-mediated binding could not be demonstrated in non-human primates. Further structural optimization of compounds of this class will be required for them to serve as suitable radiotracers for PET. 23754528 PASylation: a biological alternative to PEGylation for extending the plasma half-life of pharmaceutically active proteins. A major limitation of biopharmaceutical proteins is their fast clearance from circulation via kidney filtration, which strongly hampers efficacy both in animal studies and in human therapy. We have developed conformationally disordered polypeptide chains with expanded hydrodynamic volume comprising the small residues Pro, Ala and Ser (PAS). PAS sequences are hydrophilic, uncharged biological polymers with biophysical properties very similar to poly-ethylene glycol (PEG), whose chemical conjugation to drugs is an established method for plasma half-life extension. In contrast, PAS polypeptides offer fusion to a therapeutic protein on the genetic level, permitting Escherichia coli production of fully active proteins and obviating in vitro coupling or modification steps. Furthermore, they are biodegradable, thus avoiding organ accumulation, while showing stability in serum and lacking toxicity or immunogenicity in mice. We demonstrate that PASylation bestows typical biologics, such as interferon, growth hormone or Fab fragments, with considerably prolonged circulation and boosts bioactivity in vivo. 23835441 Transmural healing evaluated by bowel sonography in patients with Crohn's disease on maintenance treatment with biologics. Both thiopurines and anti-tumor necrosis factor (TNF) α agents are effective for treating Crohn's disease (CD) as they can induce clinical remission (CR) and mucosal healing (MH) in most patients. Nevertheless, data on transmural healing (TH) induced by thiopurines and anti-TNF-α agents are still lacking. This study aimed to explore the rate of TH evaluated by bowel sonography in patients with CD treated with biologics and immunosuppressors and its correlation with CR and MH. We performed an observational longitudinal study evaluating TH, CR, and MH in all patients with CD attending our clinic who would complete 2 years of maintenance treatment with biologics or thiopurines. CR and MH were assessed in accordance with current literature, whereas TH was recorded using bowel sonography. All patients underwent endoscopy and bowel sonography before starting treatment and 2 years later. The study included 66 patients with CD treated with biologics and 67 patients receiving thiopurines. Finally, TH was present in 17 patients on biologics and only 3 patients treated with thiopurines (25% versus 4%; P < 0.01; odds ratio = 6.2). CR was achieved in 37 patients on biologics and in 34 patients on thiopurines (59.7% versus 53%; P = not significant), whereas MH was more frequent in patients treated with anti-TNF-α agents even though without statistical significance (38% versus 25%; P = not significant). TH can be achieved in approximately 25% of patients with CD treated with anti-TNF-α agents and significantly correlates with MH. Further studies are needed to define the potential role of TH as long-term prognostic factor. 22777683 Retail Redlining in New York City: Racialized Access to Day-to-Day Retail Resources. Racial residential segregation is associated with health inequalities in the USA, and one of the primary mechanisms is through influencing features of the neighborhood physical environment. To better understand how Black residential segregation might contribute to health risk, we examined retail redlining; the inequitable distribution of retail resources across racially distinct areas. A combination of visual and analytic methods was used to investigate whether predominantly Black census block groups in New York City had poor access to retail stores important for health. After controlling for retail demand, median household income, population density, and subway ridership, percent Black was associated with longer travel distances to various retail industries. Our findings suggest that Black neighborhoods in New York City face retail redlining. Future research is needed to determine how retail redlining may perpetuate health disparities and socioeconomic disadvantage. 23496243 The effect of rituximab on thyroid function and autoimmunity. no abstract required. 23870221 Shared and Nonshared Familial Susceptibility to Surgically Treated Inguinal Hernia, Femoral Hernia, Incisional Hernia, Epigastric Hernia, and Umbilical Hernia. The familial risk of abdominal wall hernia (AWH) is largely unknown. In addition, it is unknown whether inguinal hernia (IH), femoral hernia (FH), incisional hernia (INH), epigastric hernia (EH), and umbilical hernia (UH) share familial susceptibility. The aim of this nationwide study was to determine the familial risks of concordant AWH (same disease in proband and exposed relative) and discordant AWH (different disease in proband and exposed relative). Data from the Swedish Multigeneration Register on individuals aged 0 to 78 years were linked to the Swedish hospital discharge register and the Swedish outpatient register for the period from 1964 to 2010. Standardized incidence ratios (SIRs) and 95% CIs for surgically treated IH (n = 209,814 cases), FH (n = 4,576), INH (n = 19,494), EH (n = 8,257), and UH (n = 22,761) were calculated for siblings of individuals with hernia compared with the siblings of unaffected individuals. The procedure was repeated for spouses. All concordant and most discordant familial sibling risks were increased. Familial concordant SIRs for siblings were IH = 1.97 (95% CI, 1.94-1.99), FH = 3.40 (95% CI, 2.44-4.62), INH = 2.24 (95% CI, 2.04-2.46), EH = 5.57 (95% CI, 4.64-6.64), and UH = 3.61 (95% CI, 3.33-3.91). Concordant familial risks were higher than discordant risks. For example, when the proband sibling had IH, the discordant SIRs were FH = 1.74 (95% CI, 1.61-1.88), INH = 1.22 (95% CI, 1.16-1.28), EH = 1.30 (95% CI, 1.20-1.40), and UH = 1.35 (95% CI, 1.29-1.41). Concordant SIRs for spouses were lower: IH = 1.23 (95% CI, 1.20-1.26), FH = 0.97 (95% CI, 0.64-1.36), INH = 1.56 (95% CI, 1.41-1.71), EH = 1.70 (95% CI, 1.09-2.45), and UH = 1.31 (95% CI, 1.09-1.56). Family history of surgically treated AWH is an important risk factor for surgical treatment of AWH. The 5 forms of AWH studied share familial susceptibility, but site-specific familial factors might exist. Several spouse risks were increased, suggesting the possibility of a nongenetic contribution to familial risks. 23396446 Study of PcaV from Streptomyces coelicolor yields new insights into ligand-responsive MarR family transcription factors. MarR family proteins constitute a group of >12 000 transcriptional regulators encoded in bacterial and archaeal genomes that control gene expression in metabolism, stress responses, virulence and multi-drug resistance. There is much interest in defining the molecular mechanism by which ligand binding attenuates the DNA-binding activities of these proteins. Here, we describe how PcaV, a MarR family regulator in Streptomyces coelicolor, controls transcription of genes encoding β-ketoadipate pathway enzymes through its interaction with the pathway substrate, protocatechuate. This transcriptional repressor is the only MarR protein known to regulate this essential pathway for aromatic catabolism. In in vitro assays, protocatechuate and other phenolic compounds disrupt the PcaV-DNA complex. We show that PcaV binds protocatechuate in a 1:1 stoichiometry with the highest affinity of any MarR family member. Moreover, we report structures of PcaV in its apo form and in complex with protocatechuate. We identify an arginine residue that is critical for ligand coordination and demonstrate that it is also required for binding DNA. We propose that interaction of ligand with this arginine residue dictates conformational changes that modulate DNA binding. Our results provide new insights into the molecular mechanism by which ligands attenuate DNA binding in this large family of transcription factors. 23897919 Missing the Mark With Latina Women With Type 2 Diabetes: Implications for Educators. PurposeThe purpose of this qualitative study was to explore nutritional behaviors and attitudes among Latino women with type 2 diabetes.MethodsWomen over 18 years old and previously diagnosed with type 2 diabetes were recruited to participate in semi-structured qualitative interviews in their homes in Los Angeles, California, and Las Vegas, Nevada. Recruitment was conducted through flyers posted in local businesses. Interviews were conducted in Spanish or English. Data were transcribed and analyzed using an iterative process that involves reading interview transcripts and designating themes that arise from the data.ResultsAcquisition of nutritional knowledge and behavioral capability were positively associated with observational learning, formal nutritional education, and culturally competent meal planners. The use of traditional remedies and the consultation of naturistas reveal a tendency toward medical pluralism. In the home environment, husbands had the greatest influence on Latina women's attitudes and perceived choices.ConclusionsThe social environment, including support and reinforcement, is critical for Latinas' nutritional success. Observational learning is critical for Latinas' behavioral capability. 23948060 Degraded limonoids and quinoline alkaloids from Dictamnus angustifolius G. Don ex Sweet. and their anti-platelet aggregation activity. A new degraded limonoid, named isodictamdiol A (1), two known degraded limonoids (2, 3) and a new nature product of quinoline alkaloid (4) along with five known quinoline alkaloids (5-9) were isolated from the root bark of Dictamnus angustifolius G. Don ex Sweet.. Certain useful NMR data were generalized to determine the structures of compounds 1 and 4. The structural elucidation of Compound 4 was first reported herein. Compounds 1-9 showed significant inhibitory effects on platelet aggregation induced by ADP at 250μM, while Compound 4 showed potent anti-platelet aggregation activity. 23065920 Urinary proteome in a snapshot: normal urine and glomerulonephritis. The analysis of the urinary proteome is a potential source of information regarding the kidney's physiopathology. A clear knowledge of the protein composition of normal urine is an essential prerequisite to looking at its pathology. Technological evolution in the field of proteomics (2-dimensional [2D] electrophoresis, equalization, mass spectrometry and exosomes) has greatly expanded the power of analysis, allowing the detection of almost 2,000 spots in normal urine, only a minor part of which has been characterized as isoforms of known proteins. The identity of most spots (80%) remains to be determined. The analysis of urine composition in nephrotic syndrome (glomerulosclerosis and membranous nephropathy) and in lupus nephritis is in progress, but has not yet furnished any relevant material. The unique exception is the presence of acidic components that suggests alteration of the charge selectivity properties of the glomerular wall in cases of heavy proteinuria. In lupus nephritis, prostaglandin-H2-isomerase and hepcidin have also been identified as activity biomarkers. Several overexpressed or underexpressed proteins have also been found in urine IgA nephropathy, but their specificity needs validation. Decreased levels of aquaporin 2 and of inter-a-trypsin-inhibitor heavy chain 4 have been associated, respectively, with hypertension and with a different response to angiotensin-converting enzyme inhibition in IgA nephropathy patients. From the present stage, mainly characterized by discovery of new proteins in urine, we should now proceed to their validation as biomarkers of diseases and possibly to clinical trials. Participation by basic scientists and clinicians together in projects launched by worldwide organizations is of vital importance. 23793891 The nuclear cap-binding complex interacts with the U4/U6·U5 tri-snRNP and promotes spliceosome assembly in mammalian cells. The nuclear cap-binding complex (CBC) binds to the 7-methyl guanosine cap present on every RNA polymerase II transcript. CBC has been implicated in many aspects of RNA biogenesis; in addition to roles in miRNA biogenesis, nonsense-mediated decay, 3'-end formation, and snRNA export from the nucleus, CBC promotes pre-mRNA splicing. An unresolved question is how CBC participates in splicing. To investigate CBC's role in splicing, we used mass spectrometry to identify proteins that copurify with mammalian CBC. Numerous components of spliceosomal snRNPs were specifically detected. Among these, three U4/U6·U5 snRNP proteins (hBrr2, hPrp4, and hPrp31) copurified with CBC in an RNA-independent fashion, suggesting that a significant fraction of CBC forms a complex with the U4/U6·U5 snRNP and that the activity of CBC might be associated with snRNP recruitment to pre-mRNA. To test this possibility, CBC was depleted from HeLa cells by RNAi. Chromatin immunoprecipitation and live-cell imaging assays revealed decreased cotranscriptional accumulation of U4/U6·U5 snRNPs on active transcription units, consistent with a requirement for CBC in cotranscriptional spliceosome assembly. Surprisingly, recruitment of U1 and U2 snRNPs was also affected, indicating that RNA-mediated interactions between CBC and snRNPs contribute to splicing. On the other hand, CBC depletion did not impair snRNP biogenesis, ruling out the possibility that decreased snRNP recruitment was due to changes in nuclear snRNP concentration. Taken together, the data support a model whereby CBC promotes pre-mRNA splicing through a network of interactions with and among spliceosomal snRNPs during cotranscriptional spliceosome assembly. 23909833 Cylindroside A, a new triterpenoid saponin from Cylindrokelupha dalatensis and its cytotoxic activity. A new triterpenoid saponin, named cylindroside A (1), was isolated from the seeds of Cylindrokelupha dalatensis (Kosterm.) T.L. Wu by using chromatographic method. The structure of 1 was established by comprehensive spectroscopic analysis and chemical degradation. Compound 1 displayed significant antitumor activity in vitro against BCG and MCF-7 cancer cell lines and IC50 values were 4.17 ± 0.23 and 3.07 ± 0.66 Î¼M by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, respectively. 23806866 The root barks of Morus alba and the flavonoid constituents inhibit airway inflammation. The root barks of Morus alba have been used in traditional medicine as an anti-inflammatory drug, especially for treating lung inflammatory disorders. To find new alternative agents against airway inflammation and to establish the scientific rationale of the herbal medicine in clinical use, the root barks of Morus alba and its flavonoid constituents were examined for the first time for their pharmacological activity against lung inflammation. For in vivo evaluation, an animal model of lipopolysaccharide-induced airway inflammation in mice was used. An inhibitory action against the production of proinflammatory molecules in lung epithelial cells and lung macrophages was examined. Against lipopolysaccharide-induced airway inflammation, the ethanol extract of the root barks of Morus alba clearly inhibited bronchitis-like symptoms, as determined by TNF-α production, inflammatory cells infiltration and histological observation at 200-400mg/kg/day by oral administration. In addition, Morus alba and their major flavonoid constituents including kuwanone E, kuwanone G and norartocarpanone significantly inhibited IL-6 production in lung epithelial cells (A549) and NO production in lung macrophages (MH-S). Taken together, it is concluded that Morus alba and the major prenylated flavonoid constituents have a potential for new agents to control lung inflammation including bronchitis. 23795681 Cascading "Triclick" Functionalization of Poly(caprolactone) Thin Films Quantified via a Quartz Crystal Microbalance. A series of mono- and multifunctionalized degradable polyesters bearing various "clickable" groups, including ketone, alkyne, azide, and methyl acrylate (MA) are reported. Using this approach, we demonstrate a cascade approach to immobilize and quantitate three separate bioactive groups onto poly(caprolactone) (PCL) thin films. The materials are based on tunable copolymer compositions of ε-caprolactone and 2-oxepane-1,5-dione. A quartz crystal microbalance (QCM) was used to quantify the rate and extent of surface conjugation between RGD peptide and polymer thin films using "click" chemistry methods. The results show that alkyne-functionalized polymers have the highest conversion efficiency, followed by MA and azide polymers, while polymer films possessing keto groups are less amenable to surface functionalization. The successful conjugation was further confirmed by static contact angle measurements, with a smaller contact angle correlating directly with lower levels of surface peptide conjugation. QCM results quantify the sequential immobilization of peptides on the PCL thin films and indicate that Michael addition must occur first, followed by azide-alkyne Huisgen cycloadditions. 23321274 Development of a novel bioerodible dexamethasone implant for uveitis and postoperative cataract inflammation. Delivery of anti-inflammatory steroids concurrently to both anterior and posterior segments of the eye is a challenge. The anterior ocular structures limit topical delivery. Injection can be disproportionately and repeatedly invasive and selective for only one ocular hemisphere. We developed a novel implant that can compensate for the limited conveyance of topical medicine and reduce the repetitive invasiveness of injection from the capsular bag allowing dexamethasone (DXM) delivery to both the anterior and posterior chambers. To establish proof of concept, microparticles were prepared with PLGA [poly(d,l-lactide-co-glycolide), 50:50, MW. 7000-17000], hydroxypropyl methyl cellulose (HPMC), and DXM by oil-in-water emulsion/solvent evaporation technique. Zeatsizer Nano and SEM (scanning electron microscopy) results showed microspheres in the range of 8±1µm. The target load of DXM in the microparticles was ~20.0% with a % recovery of 99.9% (w/w). Dose related pharmacokinetics with near zero order kinetics was observed for up to 6 weeks in rabbits with intracapsular bag implants. DXM flow was bidirectional from the endocapsular space and significant concentrations were found in the anterior and posterior chambers after up to 6 weeks. Whereas, with topical drops the exposure was minimal in all the ocular tissues with greater systemic exposure. Intraocular pressure was normal in all of the study groups; slit lamp biomicroscopy examinations revealed that no cells or fibrin formation in the anterior and posterior chamber with implants but flare, cells and fibrin was present in the topical drops group. Histological examination revealed normal tissues and no signs of inflammation in all the groups. The implant did not migrate to the center of the eye or obstruct the visual axis. We believe these findings demonstrate the feasibility of drug delivery from the capsular bag to the anterior and posterior segments effectively compared to topical alternatives. 23872194 p-Terphenyl curtisian E inhibits in vitro platelet aggregation via cAMP elevation and VASP phosphorylation. Mushrooms possess untapped source of enormous natural compounds showing anti-inflammatory, antioxidant and anti-platelet activities. Paxillus curtisii, wild mushroom, is a rich source of curtisian E (CE) reported for neuroprotective effects; however, its anti-platelet effect was unknown. Here, therefore, we investigated the anti-platelet activity of CE in rat platelets. Curtisian E (12.5-200μM) attenuated collagen (2.5μg/ml), thrombin (0.1U/ml) and ADP (10μM) induced platelet aggregation in vitro. Likewise, CE diminished intracellular calcium and adenosine triphosphate (ATP) release in collagen activated platelets. Fibrinogen binding and fibronectin adhesion to platelets were also inhibited. While CE downregulated c-jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), p38, and Akt dose dependently in collagen stimulated platelets, it upregulated intraplatelet cyclic adenosine monophosphate (cAMP) and vasodilator-stimulated-phosphoprotein (VASP) phosphorylation. Protein kinase A inhibitor (H-89) markedly inhibited p-VASP(157) protein expression, suggesting that cAMP-PKA-VASP(157) pathway may mediate its anti-platelet effect and thus CE could be considered as a potential anti-thrombotic agent. 23954808 Identification of a novel alternative splicing variant of hemocyanin from shrimp Litopenaeus vannamei. Recent evidences suggest that invertebrates express families of immune molecules with high levels of sequence diversity. Hemocyanin is an important non-specific immune molecule present in the hemolymph of both mollusks and arthropods. In the present study, we characterized a novel alternative splicing variant of hemocyanin (cHE1) from Litopenaeus vannamei that produced mRNA transcript of 2580bp in length. The isoform contained two additional sequences of 296 and 268bp in the 5'- and 3'-terminus respectively, in comparison to that of wild type hemocyanin (cHE). Sequence of cHE1 shows 100% identity to that of hemocyanin genomic DNA (HE, which does not form an open reading frame), suggesting that cHE1 might be an alternative splicing variant due to intron retention. Moreover, cHE1 could be detected by RT-PCR from five tissues (heart, gill, stomach, intestine and brain), and from shrimps at stages from nauplius to mysis larva. Further, cHE1 mRNA transcripts were significantly increased in hearts after 12h of infection with Vibrio parahemolyticus or poly I: C, while no significant difference in the transcript levels of hepatopancreas cHE was detected in the pathogen-treated shrimps during the period. In summary, these studies suggested a novel splicing variant of hemocyanin in shrimp, which might be involved in shrimp resistance to pathogenic infection. 22866766 Mucoadhesive nanoliposomal formulation for vaginal delivery of an antifungal. Context: Ciclopirox olamine (CPO) is indicated in the treatment of vaginal fungal infections. The frequent and large dosing of available vaginal CPO creams gives rise to poor compliance amongst females. In such a situation a delivery system capable of providing sustained release of CPO is warranted and can be realized through incorporation of its liposomal formulation into a mucoadhesive gel base. The liposomal formulation would offer sustained release whereas mucoadhesive gel would prolong the contact with vaginal wall; thus avoiding frequent and large dosing. Objective: The present study aimed at investigating mucoadhesive liposomal CPO gel for vaginal use. Method: The study embarked on evaluating liposomal CPO and its Carbopol 974(®)P gel for stability at vaginal pH, release profile, rheological characteristics, mucoadhesive behavior and finally antifungal activity. Results: The results revealed that CPO liposomes were stable at vaginal pH; its Carbopol gel released 58.75 ± 6.4% of CPO at the end of 24 h which suggested sustained release. Rheology via viscometric, oscillatory stress sweep and oscillatory frequency sweep testing of the gel, studied at different temperatures and under different dilutions with vaginal fluid simulant testified pseudoplastic behavior of the gel. It also pointed towards the predominance of elastic behavior of the gel at all the dilutions. The gel exhibited good mucoadhesivity to sheep vaginal tissue. Furthermore, CPO entrapped in liposome too displayed antifungal activity. Conclusion: The study undertaken recommended Carbopol 974(®)P gel loaded with CPO liposomes as a potential delivery system for treatment of fungal vaginal infections. 23456649 Moderately differentiated neuroendocrine carcinoma (atypical carcinoid) of the parotid gland: report of three cases with contemporary review of salivary neuroendocrine carcinomas. Primary neuroendocrine carcinomas (NECs) of the salivary glands are rare. Most reported NECs in that region are small cell carcinomas with few cases of large cell undifferentiated carcinoma and typical carcinoid tumors. Only two moderately differentiated NECs (atypical carcinoid tumors) have been previously reported. In the current series, the authors report three additional moderately differentiated NECs (atypical carcinoid tumors) of the parotid gland; two occurred in women and one in a man. All patients were initially treated with parotidectomy, with selective lymph node excision in one, and radiation therapy in another. Follow-up was available for two cases (18 and 79 months). One patient had two local recurrences, developing lymph node and liver metastases requiring further surgery and chemotherapy. Currently, she is alive with disease, on supportive care. The second patient is alive with no signs of recurrence. Patients' work-up excluded the possibility of metastatic NECs to the salivary glands in all cases. Histologically, the tumors demonstrated infiltrating nests, cords and trabeculae of round, oval to spindle shaped cells with moderate to focally abundant eosinophilic cytoplasm, small to prominent nucleoli and chromatin stippling. Scattered rosette-like structures were prominent in one tumor. The highest mitotic counts for the three tumors ranged from 5 to 8 mitotic figures/10hpfs. Necrosis, focal but distinct, was noted in two tumors, vascular invasion in two tumors and perineural invasion in one tumor. Immunohistochemical staining was diagnostic of neuroendocrine carcinoma, showing uniform positive labeling with broad-spectrum cytokeratin (with a paranuclear punctuate pattern in one case), chromogranin and synaptophysin antibodies. CK20 was negative in two tumors and stained rare cells (<1 %) in the third. 23844983 Correlation of histopathologic and dynamic tissue perfusion measurement findings in transplanted kidneys. Cortical perfusion of the renal transplant can be non-invasively assessed by color Doppler ultrasonography. We performed the Dynamic Tissue Perfusion Measurement (DTPM) of the transplant's renal cortex using color Doppler ultrasonography (PixelFlux technique), and compared the results with the histopathological findings of transplant biopsies. Ninety-six DTPM studies of the renal transplant's cortex followed by transplant biopsies were performed in 78 patients. The cortical perfusion data were compared with the parameter of peritubular inflammatory cell accumulation (PTC 0 to 3) based on Banff-classification system. A significant decrease of cortical perfusion could be demonstrated as the inflammatory cells accumulation in peritubular capillaries increased. Increasing peritubulitis caused a perfusion loss from central to distal layers of 79% in PTC 0, of 85% in PTC 1, of 94% in PTC 2, and of 94% in PTC 3. Furthermore, the perfusion loss due to peritubular inflammation was more prominent in the distal cortical layer. The extent of perfusion decline with increasing peritubulitis (from PTC 0 to PTC 3) was 64% in proximal 20% cortical layer (p20), 63% in proximal 50% cortical layer (p50), increased to 76% in distal 50% cortical layer (d50), and peaked at 90% in the distal 20% cortical layer (d20). For those without peritubulitis (PTC 0), the increase in the the Interstitial Fibrosis/Tubular Atrophy (IF/TA) score was accompanied by a significantly increased cortical perfusion. A Polyomavirus infection was associated with an increased cortical perfusion. Our study demonstrated that the perfusion of the renal transplant is associated with certain pathological changes within the graft. DTPM showed a significant reduction of cortical perfusion in the transplant renal cortex related to peritubular capillary inflammation. 23161369 Interspecific effects of 4A-DNT (4-amino-2,6-dinitrotoluene) and RDX (1,3,5-trinitro-1,3,5-triazine) in Japanese quail, Northern bobwhite, and Zebra finch. The purpose of this study was to assess the toxicological effects of two munition compounds, 4-amino-2,6-dinitrotoluene (4A-DNT) and 1,3,5-trinitro-1,3,5-triazine (RDX), on three different bird species: two common toxicological model species-the Northern Bobwhite (Colinus virginianus) and the Japanese Quail (Coturnix japonica), and a representative passerine-the Zebra Finch (Taeniopygia guttata). Bobwhite were exposed to 4A-DNT at 0, 8, 15, 30, 60, or 150 mg/kg body weight (bw) d by oral gavage for seven days; because the high dose of 4A-DNT was lethal to bobwhite, the maximum dose was changed to 100 mg/kg bw d for Japanese quail and finches to ensure tissue could be used for future toxicogenomic work. RDX was similarly administered at 0, 0.5, 1.5, 3, 6, or 12 mg/kg bw d. Blood was drawn prior to euthanasia for blood cellularity and chemistry analyses. Finches were clearly least affected by 4A-DNT as evidenced by a lack of observable effects. Bobwhite appeared to be the most sensitive species to 4A-DNT as observed through changes in blood cellularity and plasma chemistry effects. Bobwhite appeared to be more sensitive to RDX than Japanese Quail due to increased effects on measures of plasma chemistries. Finches exhibited the greatest sensitivity to RDX through increased mortality and seizure activity. This study suggests that sensitivity among species is chemical-specific and provides data that could be used to refine current avian sensitivity models used in ecological risk assessments. 23237706 Impact of the redox-cycling herbicide diquat on transcript expression and antioxidant enzymatic activities of the freshwater snail Lymnaea stagnalis. The presence of pesticides in the environment results in potential unwanted effects on non-target species. Freshwater organisms inhabiting water bodies adjacent to agricultural areas, such as ditches, ponds and marshes, are good models to test such effects as various pesticides may reach these habitats through several ways, including aerial drift, run-off, and drainage. Diquat is a non-selective herbicide used for crop protection or for weed control in such water bodies. In this study, we investigated the effects of diquat on a widely spread aquatic invertebrate, the holarctic freshwater snail Lymnaea stagnalis. Due to the known redox-cycling properties of diquat, we studied transcript expression and enzymatic activities relative to oxidative and general stress in the haemolymph and gonado-digestive complex (GDC). As diquat is not persistent, snails were exposed for short times (5, 24, and 48 h) to ecologically relevant concentrations (22.2, 44.4, and 222.2 μg l(-1)) of diquat dibromide. RT-qPCR was used to quantify the transcription of genes encoding catalase (cat), a cytosolic superoxide dismutase (Cu/Zn-sod), a selenium-dependent glutathione peroxidase (gpx), a glutathione reductase (gred), the retinoid X receptor (rxr), two heat shock proteins (hsp40 and hsp70), cortactin (cor) and the two ribosomal genes r18S and r28s. Enzymatic activities of SOD, Gpx, Gred and glutathione S-transferase (GST) were investigated in the GDC using spectrophoto/fluorometric methods. Opposite trends were obtained in the haemolymph depending on the herbicide concentration. At the lowest concentration, effects were mainly observed after 24 h of exposure, with over-transcription of cor, hsp40, rxr, and sod, whereas higher concentrations down-regulated the expression of most of the studied transcripts, especially after 48 h of exposure. In the GDC, earlier responses were observed and the fold-change magnitude was generally much higher: transcription of all target genes increased significantly (or non-significantly for cat) after 5 h of exposure, and went back to control levels afterwards, suggesting the onset of an early response to oxidative stress associated to the unbalance of reactive oxygen species (ROS) in hepatocytes. Although increases obtained for Gred and SOD activities were globally consistent with their respective transcript expressions, up-regulation of transcription was not always correlated with increase of enzymatic activity, indicating that diquat might affect steps downstream of transcription. However, constitutive levels of enzymatic activities were at least maintained. In conclusion, diquat was shown to affect expression of the whole set of studied transcripts, reflecting their suitability as markers of early response to oxidative stress in L. stagnalis. 23527908 Preemptive treatment with voriconazole in lung transplant recipients. Invasive fungal infection (IFI) is associated with high mortality in lung transplant (LTx) recipients. Data for voriconazole use in preemptive treatment remain scant. A single-center, retrospective cohort study was conducted to investigate the efficacy and safety of voriconazole preemptive treatment for post-LTx colonization. We reviewed 62 adult LTx patients, who received their first course of voriconazole prophylaxis (i.e., as preemptive treatment) between July 2003 and June 2010. Outcomes were determined at 6 and 12 months after commencing therapy. Aspergillus fumigatus (75.8%) was the most common colonizing isolate. Median duration of voriconazole prophylaxis was 85 days. At 6 months, 1 LTx patient (1.6%) had IFI, 47 (75.8%) cleared their colonizing isolate, 3 (4.8%) had persistent colonization, 7 (11.3%) had recurrent colonization, 1 (1.6%) had new colonization, 2 (3.2%) had aspergilloma, and 1 (1.6%) was clinically unstable with no culture results. Sixteen (25.8%) had died by 12 months. Ten (16.1%) had likely drug-related hepatotoxicity. LTx patients with diabetes mellitus within 30 days before commencing prophylaxis were at higher risk of recurrent Aspergillus colonization at 6 months (P = 0.030). Chronic rejection within 30 days before prophylaxis was associated with 12-month mortality (P = 0.007). Voriconazole preemptive treatment resulted in low incidence of IFI and IFI-related mortality. 23210787 Preclinical profile of bacopasides from Bacopa monnieri (BM) as an emerging class of therapeutics for management of chronic pains. Chronic pains management costs billions of dollars in medical exchequer to the world population. Additionally, 77% of people with chronic pains also have a degree of medically treatable depression. Opioids have a narrower safety index due to their side effects associated with its tolerance, hyperalgesia and subsequent dependence. Likewise, non steroidal anti-inflammatory drugs and anticonvulsants, also have limited safety and tolerability profile in the management of chronic pains. Bacopa monnieri, a renowned ayurvedic medicine has a strong antidepressant effect and significant antinociceptive effect, which is comparable to the effect of morphine via adenosinergic, opioidergic, and adrenergic mechanisms. BM has been also reported to be effective in neuropathic pains. Additionally, it has a strong anti-inflammatory effect mediated via COX-2 inhibitory mechanism. Apart from its effect of augmenting morphine analgesia, BM also inhibits opioid-withdrawal induced hyperalgesia, and acquisition and expression of morphine tolerance. BM is reported to have a strong protective effect against toxic effects of opiates on major organs like brain, kidneys and heart. BM is well documented to be safe and well tolerated herbal therapy in multiple clinical trials including various age groups. This minireview evaluated the preclinical data that highlights potential of BM as a future candidate for clinical management of chronic pains. 23642133 The Evolution of Drosophila melanogaster as a Model for Alcohol Research. Animal models have been widely used to gain insight into the mechanisms underlying the acute and long-term effects of alcohol exposure. The fruit fly Drosophila melanogaster encounters ethanol in its natural habitat and possesses many adaptations that allow it to survive and thrive in ethanol-rich environments. Several assays to study ethanol-related behaviors in flies, ranging from acute intoxication to self-administration and reward, have been developed in the past 20 years. These assays have provided the basis for studying the physiological and behavioral effects of ethanol and for identifying genes mediating these effects. In this review we describe the ecological relationship between flies and ethanol, the effects of ethanol on fly development and behavior, the use of flies as a model for alcohol addiction, and the interaction between ethanol and social behavior. We discuss these advances in the context of their utility to help decipher the mechanisms underlying the diverse effects of ethanol, including those that mediate ethanol dependence and addiction in humans. 23870902 ESR spectroscopic properties of irradiated gum Arabic. Electron spin resonance (ESR) spectra of irradiated gum Arabic with doses between 0.5 and 5kGy were studied. A linear relationship between the absorbed dose and the intensities of the ESR spectra was observed. ESR spectra of irradiated gum Arabic showed a decay of relative concentrations of free radicals originated by radiation and the production of at least two species of free radicals with half-times: 3.3 and 125.4h. The results of spectral simulations for these radical groups were giso=2.0046; A=1.2mT and gx=gy=2.0062, gz=2.0025. Hydration and dehydration of irradiated gum Arabic returns the ESR spectrum to its initial state before irradiation. The results show that ESR can be used as simple and reliable method to detect irradiated gum Arabic up to 60days after initial radiation with doses on the order of 5kGy. 23926333 The Golgi protein ACBD3, an interactor for poliovirus protein 3A, modulates poliovirus replication. We have shown that the circulating vaccine-derived polioviruses responsible for poliomyelitis outbreaks in Madagascar have recombinant genomes composed of sequences encoding capsid proteins derived from poliovaccine Sabin, mostly type 2 (PVS2), and sequences encoding nonstructural proteins derived from other human enteroviruses. Interestingly, almost all these recombinant genomes encode a nonstructural 3A protein related to that of field coxsackievirus A17 (CV-A17) strains. Here, we investigated the repercussions of this exchange, by assessing the role of the 3A proteins of PVS2 and CV-A17 and their putative cellular partners in viral replication. We found that the Golgi protein acyl-coenzyme A binding domain-containing 3 (ACBD3), recently identified as an interactor for the 3A proteins of several picornaviruses, interacts with the 3A proteins of PVS2 and CV-A17 at viral RNA replication sites, in human neuroblastoma cells infected with either PVS2 or a PVS2 recombinant encoding a 3A protein from CV-A17 (PVS2-3A(CV-A17)). The siRNA-mediated downregulation of ACBD3 significantly increased the growth of both viruses, suggesting that ACBD3 slowed viral replication. This was confirmed with replicons. Furthermore, PVS2-3A(CV-A17) was more resistant to the replication-inhibiting effect of ACBD3 than the PVS2 strain, and the amino acid in position 12 of 3A was involved in modulating the sensitivity of viral replication to ACBD3. Overall, our results indicate that exchanges of nonstructural proteins can modify the relationships between enterovirus recombinants and cellular interactors, and may thus be one of the factors favoring their emergence. 23776229 Canonical transient receptor potential 3 channels regulate mitochondrial calcium uptake. Mitochondrial Ca(2+) homeostasis is fundamental to regulation of mitochondrial membrane potential, ATP production, and cellular Ca(2+) homeostasis. It has been known for decades that isolated mitochondria can take up Ca(2+) from the extramitochondrial solution, but the molecular identity of the Ca(2+) channels involved in this action is largely unknown. Here, we show that a fraction of canonical transient receptor potential 3 (TRPC3) channels is localized to mitochondria, a significant fraction of mitochondrial Ca(2+) uptake that relies on extramitochondrial Ca(2+) concentration is TRPC3-dependent, and the up- and down-regulation of TRPC3 expression in the cell influences the mitochondrial membrane potential. Our findings suggest that TRPC3 channels contribute to mitochondrial Ca(2+) uptake. We anticipate our observations may provide insights into the mechanisms of mitochondrial Ca(2+) uptake and advance understanding of the physiological role of TRPC3. 23890598 Ovine nematodes in wild lagomorphs in Australia and first record of Trichostrongylus rugatus in free living lagomorphs. Gastrointestinal parasites are a major problem for sheep graziers and anthelmintic resistance has been reported worldwide. Given that in experimental circumstances, sheep helminths are able to develop in rabbits and hares, and that hares are very mobile and sympatric with sheep in many regions of Australia, free-living lagomorphs were investigated regarding carriage of ovine nematode parasites under field conditions. We performed specific worm counts in the gastrointestinal tracts of 88 rabbits and 110 hares. We revealed that ruminant worms are common in hares (prevalence 79%) and that they are occasionally found in rabbits (9%). Statistical analyses showed that the ruminant worm Trichostrongylus colubriformis occurred frequently in hares whilst rabbits were commonly infected with lagomorph-specific Trichostrongylus retortaeformis. Detection of the ovine worm Trichostrongylus rugatus is reported for the first time in wild lagomorphs. The potential for cross-transmission between hares and sheep in the natural environment is much more prevalent than previously believed. 23695545 Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a prospective randomized study. Eradication rates following standard triple therapy for Helicobacter pylori infection are declining. Recent studies, conducted in a number of countries, have shown that sequential therapy for H. pylori infection yields high cure rates. To compare the efficacy and tolerability of a sequential regimen as a first-line treatment of H. pylori infection with a standard triple treatment regime in Morocco. A total of 281 naive H. pylori-infected patients, confirmed by histological examination, were assigned randomly to one of two treatment groups: standard triple therapy [omeprazole (20 mg bid) + amoxicillin (1 g bid) + clarithromycin (500 mg bid) for 7 days] or sequential therapy [omeprazole (20 mg bid) + amoxicillin (1 g bid) for 5 days, followed by omeprazole (20 mg bid) + tinidazole (500 mg bid) + clarithromycin (500 mg bid) for an additional 5 days]. H. pylori eradication was checked 4-6 weeks after treatment initiation by using a (13)C-urea breath test. Compliance and adverse events were assessed. The two groups did not differ significantly in gender, age, previous disease history, endoscopic and histological features and smoking. The intention-to-treat and per-protocol eradication rates were 65.9 and 71 % in the standard triple therapy group, and 82.8 and 89.9 % in the sequential therapy group, respectively. The eradication rate was significantly higher in the sequential therapy group than in the standard triple therapy group (p < 0.001), There was no statistically significant difference in compliance (97.5  vs. 96.3 %) and incidence of side-effects (27.5 vs. 27.9 %) between the two groups. Based on our results, we conclude that for eradication of H. pylori infection, the 10-day sequential therapy is more effective than the standard triple therapy and is equally tolerated. These results confirm those of other studies in other countries. 23842138 Altered cardiac autonomic nervous function in depression. Depression is an independent risk factor for coronary artery disease. Autonomic instability may play a mediating or moderating role in this relationship; however this is not well understood. The objective of this study was to explore cardiac autonomic function and cardiac arrhythmia in depression, the correlation between depression severity and Heart Rate Variability (HRV) related indices, and the prevalence of arrhythmia. Individuals (n = 53) with major depression as assessed by the Diagnostic and Statistical Manual of Mental Disorders, who had a Hamilton Rating Scale for Depression (HAMD) score >=20 and a Zung Self-Rating Depression Scale score > 53 were compared to 53 healthy individuals, matched for age and gender. Multichannel Electrocardiograph ECG-92C data were collected over 24 hours. Long-term changes in HRV were used to assess the following vagally mediated changes in autonomic tone, expressed as time domain indices: Standard deviation of the NN intervals (SDNN), standard deviation of 5 min averaged NN intervals (SDANN), Root Mean Square of the Successive Differences (RMSSD) and percentage of NN intervals > 50 ms different from preceding interval (pNN50). Pearson's correlations were conducted to explore the strength of the association between depression severity (using the SDS and HRV related indices, specifically SDNN and low frequency domain / high frequency domain (LF/HF)). The values of SDNN, SDANN, RMSSD, PNN50 and HF were lower in the depression group compared to the control group (P<.05). The mean value of the LF in the depression group was higher than the in control group (P<.05). Furthermore the ratio of LF/HF was higher among the depression group than the control group (P<.05). A linear relationship was shown to exist between the severity of the depression and HRV indices. In the depression group, the prevalence of arrhythmia was significantly higher than in the control group (P<.05), particularly supraventricular arrhythmias. Our findings suggest that depression is accompanied by dysfunction of the cardiac autonomic nervous system, and further, that depression severity is linked to severity of this dysfunction. Individuals with depression appear to be susceptible to premature atrial and/or ventricular disease. 23516035 Using iron-loaded sepiolite obtained by adsorption as a catalyst in the electro-Fenton oxidation of Reactive Black 5. This study explores the possibility of using iron-loaded sepiolite, obtained by recovering iron from polluted water, as a catalyst in the electro-Fenton oxidation of organic pollutants in textile effluents. The removal of iron ions from aqueous solution by adsorption on sepiolite was studied in batch tests at iron concentrations between 100 and 1,000 ppm. Electro-Fenton experiments were carried out in an electrochemical cell with a working volume of 0.15 L, an air flow of 1 L/min, and 3 g of iron-loaded sepiolite. An electric field was applied using a boron-doped diamond anode and a graphite sheet cathode connected to a direct current power supply with a constant potential drop. Reactive Black 5 (100 mg/L) was selected as the model dye. The adsorption isotherms proved the ability of the used adsorbent. The removal of the iron ion by adsorption on sepiolite was in the range of 80-100 % for the studied concentration range. The Langmuir and Freundlich isotherms were found to be applicable in terms of the relatively high regression values. Iron-loaded sepiolite could be used as an effective heterogeneous catalyst for the degradation of organic dyes in the electro-Fenton process. Successive batch processes were performed at optimal working conditions (5 V and pH 2). The results indicate the suitability of the proposed combined process, adsorption to iron remediation followed by the application of the obtained iron-loaded sepiolite to the electro-Fenton technique, to oxidize polluted effluents. 23666354 Molecular structure and vibrational spectra studies on antipyrine derivative, 4-(2,3,4-trihydroxybenzylideneamino) antipyrine. The molecular geometry, theoretical harmonic frequencies and infrared intensities of 4-(2,3,4-trihydroxybenzylideneamino) antipyrine (THBAP) were calculated using different density functional methods (LSDA, mPW1PW91, B3LYP and HCTH) with various basic sets, including 3-21G, 6-311G, LanL2DZ, and SDD. The purpose of this research is to compare the performance of different density functional theory (DFT) methods at different basis sets in predicting geometry and vibration spectrum of THBAP. The optimized geometric band lengths and bond angles obtained by using mPW1PW91 at both LanL2DZ and SDD basic sets show the best agreement with the experimental data. A comparison between the observed fundamental vibrational frequencies of THBAP and the calculated results has been made and the result indicates that the mPW1PW91/6-311G level is superior to all the remaining levels for predicting all the vibration spectra on average for THBAP. 23920327 Triple-Negative Breast Cancer and the Need for New Therapeutic Targets. Triple-negative breast cancers (TNBCs) are a diverse and heterogeneous group of tumors that by definition lack estrogen and progesterone receptors and amplification of the HER2 gene. The majority of the tumors classified as TNBCs are highly malignant, and only a subgroup responds to conventional chemotherapy with a favorable prognosis. Results from decades of research have identified important molecular characteristics that can subdivide this group of breast cancers further. High-throughput molecular analyses including sequencing, pathway analyses, and integrated analyses of alterations at the genomic and transcriptomic levels have improved our understanding of the molecular alterations involved in tumor development and progression. How this knowledge should be used for rational selection of therapy is a challenging task and the subject of numerous ongoing research programs. This review summarizes the current knowledge on the clinical characteristics and molecular alterations of TNBCs. Currently used conventional therapeutic strategies and targeted therapy studies are discussed, with references to recently published results on the molecular characterization of TNBCs. 22948317 The Cholegas Study: safety of prophylactic cholecystectomy during gastrectomy for cancer: preliminary results of a multicentric randomized clinical trial. Cholelithiasis is more frequent in patients after gastrectomy, due to dissection of vagal branches and gastrointestinal reconstruction. A randomized controlled trial was conducted from November 2008 to March 2012. Patients were randomized into two groups: prophylactic cholecystectomy (PC) and standard gastric surgery only (SS) for curable cancers. We planned three end points: evaluation of the number of patients who developed symptoms and needed further surgery for cholelithiasis after standard gastric cancer surgery, evaluation of the incidence of cholelithiasis overall after standard gastric cancer surgery and perioperative complications or costs of prophylactic cholecystectomy. The present study answers to the last end point only. After 40 months from the beginning of study, 172 patients were eligible from 9 Centers. Ten patients refused consent and 32 were excluded due to flawing of inclusion criteria (not confirmed adenocarcinomas and no R0 surgery). Therefore, final analysis included 130 patients: 65 in PC group and 65 in SS. Among PC group, 12 patients had surgical complications during the perioperative period; only 1 biliary leakage, conservatively treated, might have been caused by prophylactic cholecystectomy. 6 patients had surgical complications in SS group. One postoperative death occurred in PC group due to pulmonary embolism. Differences were not statistically significant. Similarly, no differences were significant in duration of surgery, blood loss, hospital stay. Concomitant cholecystectomy during standard surgery for gastric malignancies seemed to add no extra perioperative morbidity, mortality and costs to the sample included in the study. 23352512 Comparative properties of Aβ1-42, Aβ11-42, and [Pyr¹¹]Aβ11-42 generated from O-acyl isopeptides. The use of water-soluble O-acyl isopeptides enabled us to investigate the biochemical properties of Aβ11-42 species, by preparing highly concentrated stock solutions after a pretreatment. Aβ11-42 and [Pyr(11)]Aβ11-42 showed comparable aggregation capability and cytotoxicity, suggesting that the pyroglutamate modification at Glu(11) does not have a crucial role in these events. However, given that Aβ11-42 is converted to [Pyr(11)]Aβ11-42 by a glutamyl cyclase in vivo, the potential aggregative and cytotoxic nature of [Pyr(11)]Aβ11-42 that was observed in the present study provides valuable insights into the pathological functions of pyroglutamate-modified Aβ species in Alzheimer's disease. 23901283 Current status of bevacizumab in advanced ovarian cancer. Ovarian cancer is the most lethal gynecological cancer, mainly because of the delay in diagnosis. Recently, much effort has been put into investigating and introducing novel targeted agents into clinical practice, with the aim of improving prognosis and quality of life. Angiogenesis is a possible target. The aim of this review is to investigate the most common molecular pathways of angiogenesis, which have provided novel targets for tailored therapy in patients with ovarian cancer. These therapeutic strategies include monoclonal antibodies and tyrosine-kinase inhibitors. These drugs have as molecular targets vascular endothelial growth factor, vascular endothelial growth factor receptors, platelet-derived growth factor, fibroblast growth factor, and angiopoietin. Bevacizumab was investigated in several Phase III studies, with interesting results. Today, there is strong evidence for introducing bevacizumab in the treatment of patients with advanced and recurrent ovarian cancer. Nevertheless, further investigations and large clinical trials are needed to understand the safety and effectiveness of bevacizumab, the optimal duration and timing of treatment, and activity in association with other chemotherapeutic and targeted agents. It also is necessary to identify biologic factors predictive of efficacy to choose the most appropriate antiangiogenic agent in the integrated treatment of epithelial ovarian cancer. 23747523 Snowdrops falling slowly into place: An improved phylogeny for Galanthus (Amaryllidaceae). Snowdrops (Galanthus, 20 spp.; Amaryllidaceae) are cherished garden plants and the world's most traded wild-sourced ornamental bulb genus. Despite their popularity and economic importance, species delimitation is problematic and the infrageneric classification uncertain. We present a molecular phylogenetic study of Galanthus with the aim of resolving these issues and to better understand the evolution within the genus. Sequences of nuclear encoded nrITS, and plastid encoded matK, trnLF, ndhF, and psbK-psbI, for all currently recognised species and two naturally occurring putative hybrids, were analysed using maximum parsimony and Bayesian inference. Phylogenetic analysis of Galanthus, based on nuclear ITS sequences, provides a well-resolved topology, including seven well-supported named clades (platyphyllus, trojanus, ikariae, elwesii, nivalis, woronowii, and alpinus), and five major clades (A-E). The recovered ITS topology is in accordance with the geographical distribution of Galanthus species. The combined plastid data set provided far less resolution than that of ITS, with generally lower levels of statistical support, and one case of significant incongruence with the ITS dataset (involving G. gracilis). Phylogenetic network and hybridization analyses identified several possible hybridization events but these are more likely to be due to the result of a lack of resolution in the plastid dataset. The putative natural hybrid, G. ×valentinei nothosubsp. subplicatus, is supported by our data and analyses, whereas a hybrid origin for G. ×allenii is not. ITS and plastid data indicated that some Galanthus species are in need of taxonomic recircumscription. 23802227 Effects of propofol on damage of rat intestinal epithelial cells induced by heat stress and lipopolysaccharides. Gut-derived endotoxin and pathogenic bacteria have been proposed as important causative factors of morbidity and death during heat stroke. However, it is still unclear what kind of damage is induced by heat stress. In this study, the rat intestinal epithelial cell line (IEC-6) was treated with heat stress or a combination of heat stress and lipopolysaccharide (LPS). In addition, propofol, which plays an important role in anti-inflammation and organ protection, was applied to study its effects on cellular viability and apoptosis. Heat stress, LPS, or heat stress combined with LPS stimulation can all cause intestinal epithelial cell damage, including early apoptosis and subsequent necrosis. However, propofol can alleviate injuries caused by heat stress, LPS, or the combination of heat stress and LPS. Interestingly, propofol can only mitigate LPS-induced intestinal epithelial cell apoptosis, and has no protective role in heat-stress-induced apoptosis. This study developed a model that can mimic the intestinal heat stress environment. It demonstrates the effects on intestinal epithelial cell damage, and indicated that propofol could be used as a therapeutic drug for the treatment of heat-stress-induced intestinal injuries. 23751984 Droplet sorting in a loop of flat microfluidic channels. Motivated by recent experiments, we numerically study the droplet traffic in microfluidic channels forming an asymmetric loop with a long and a short arm. The loop is connected to an inlet and an outlet channel by two right angled T-junctions. Assuming flat channels, we employ the boundary element method (BEM) to numerically solve the two-dimensional Darcy equation that governs two phase flow in the Hele-Shaw limit. The occurrence of different sorting regimes is summarized in sorting diagrams in terms of droplet size, distance between consecutive droplets in the inlet channel, and loop asymmetry for mobility ratios of the liquid phases larger and smaller than one. For large droplet distances, the traffic is regulated by the ratio of the total hydraulic resistances of the long and short arms. At high droplet densities and below a critical droplet size, droplet-droplet collisions are observed for both mobility ratios. 23603194 Evaluation of mechanisms involved in the antinociception of the ethanol extract from the inner bark of Caesalpinia pyramidalis in mice. ETHNOPHARMACOLOGICAL RELEVANCE: Caesalpinia pyramidalis Tul. (Fabaceae) is an endemic tree of the Northeast region of Brazil, mainly in the Caatinga region. More commonly, inner bark or flowers are traditionally used to treat many painful and inflammatory processes. A common use of this plant is made by macerating a handful of its stem bark in a liter of wine or sugarcane brandy. It is drunk against stomachache, dysenteries, and diarrheas. MATERIALS AND METHODS: The ethanol extract of Caesalpinia pyramidalis inner bark was used in mice via oral route, at the doses of 10, 30, and 100mg/kg, in behavioral models of nociception and investigates some of the mechanisms underlying this effect. RESULTS: The ethanol extract (30 and 100mg/kg, P<0.001), given orally, produced dose dependent inhibition of acetic acid-induced visceral pain. The ethanol extract also caused significant and dose-dependent inhibition of capsaicin-(100mg/kg, P<0.001) and glutamate-(10, 30, and 100mg/kg, P<0.01) induced pain. The antinociception caused by the ethanol extract (30mg/kg) in the abdominal constriction test was significantly attenuated (P<0.001) by intraperitoneal treatment of mice with l-arginine (600mg/kg). CONCLUSIONS: Collectively, the present results suggest that the ethanol extract of Caesalpinia pyramidalis produced dose-related antinociception in several models of pain through mechanisms that involved both glutamatergic system and/or the l-arginine-nitric oxide pathway, supporting the folkloric usage of the plant to treat various painful processes. 23852162 Stability-Indicating Spectrofluorimetric Method for Determination of Itopride Hydrochloride in Raw Material and Pharmaceutical Formulations. A simple, sensitive and rapid spectrofluorimetric method for determination of itopride hydrochloride in raw material and tablets has been developed. The proposed method is based on the measurement of the native fluorescence of the drug in water at 363 nm after excitation at 255 nm. The relative fluorescence intensity-concentration plot was rectilinear over the range of 0.1-2 Î¼g/mL (2.5 × 10(-7)-5.06 × 10(-6) mole/L), with good correlation (r = 0.9999), limit of detection of 0.015 Î¼g/mL and a lower limit of quantification of 0.045 μg/mL. The described method was successfully applied for the determination of itopride hydrochloride in its commercial tablets with average percentage recovery of 100.11 ±â€‰0.32 without interference from common excipients. Additionally, the proposed method can be applied for determination of itopride in combined tablets with rabeprazole or pantoprazole without prior separation. The method was extended to stability study of itopride. The drug was exposed to acidic, alkaline, oxidative and photolytic degradation according to ICH guidelines. Moreover, the method was utilized to investigate the kinetics of the alkaline, acidic and oxidative degradation of the drug. A proposal for the degradation pathways was postulated. 23612789 Differential targeting of the dopamine transporter to recycling or degradative pathways during amphetamine- or PKC-regulated endocytosis in dopamine neurons. The dopamine transporter (DAT) clears the extracellular dopamine released during neurotransmission and is a major target for both therapeutic and addictive psychostimulant amphetamines. Amphetamine exposure or activation of protein kinase C (PKC) by the phorbol ester PMA has been shown to down-regulate cell surface DAT. However, in dopamine neurons, the trafficking itinerary and fate of internalized DAT has not been elucidated. By monitoring surface-labeled DAT in transfected dopamine neurons from embryonic rat mesencephalic cultures, we find distinct sorting and fates of internalized DAT after amphetamine or PMA treatment. Although both drugs promote DAT internalization above constitutive endocytosis in dopamine neurons, PMA induces ubiquitination of DAT and leads to accumulation of DAT on LAMP1-positive endosomes. In contrast, after amphetamine exposure DAT is sorted to recycling endosomes positive for Rab11 and the transferrin receptor. Furthermore, quantitative assessment of DAT recycling using an antibody-feeding assay reveals that significantly less DAT returns to the surface of dopamine neurons after internalization by PMA, compared with vehicle or amphetamine treatment. These results demonstrate that, in neurons, the DAT is sorted differentially to recycling and degradative pathways after psychostimulant exposure or PKC activation, which may allow for either the transient or sustained inhibition of DAT during dopamine neurotransmission.-Hong, W. C., Amara, S. G. Differential targeting of the dopamine transporter to recycling or degradative pathways during amphetamine- or PKC-regulated endocytosis in dopamine neurons. 23918241 Upregulation of microRNA-203 is associated with advanced tumor progression and poor prognosis in epithelial ovarian cancer. MicroRNA-203 (miR-203), possessing tumor suppressive or promotive activities, has been found to be downregulated or upregulated in different cancer types. The purpose of this study was to investigate whether the increased expression of miR-203 can be used as a noninvasive diagnostic and prognostic biomarker in epithelial ovarian cancer (EOC). Real-time quantitative PCR was performed to detect the expression levels of miR-203 in EOC tissues. The expression levels of miR-203 were significantly higher in EOC tissues compared to adjacent non-cancerous tissues (p < 0.001). High expression of miR-203 was observed in 65.38 % (102/156) of EOC. In addition, high miR-203 expression was found to be closely correlated with advanced FIGO stage (p < 0.001), higher histological grade (p = 0.02), lymph node involvement (p < 0.001), and positive recurrence (p < 0.001). Moreover, high miR-203 expression was correlated with shorter overall survival (p < 0.001) and shorter progression-free survival (p < 0.001) of EOC patients. Furthermore, multivariate analysis showed that the status of miR-203 expression was an independent predictor for both overall survival and progression-free survival in EOC. These findings provide the convincing evidence for the first time that the upregulation of miR-203 may serve as a novel molecular marker to predict the aggressive tumor progression and unfavorable prognosis of EOC patients. 23899523 Decreased expression of sirtuin 6 is associated with release of high mobility group box-1 after cerebral ischemia. Sirtuin 6 (SIRT6) belongs to the sirtuin family of NAD(+)-dependent deacetylases and has been implicated in the regulation of metabolism, inflammation, and aging. Here, we found that SIRT6 was predominantly expressed in neuronal cells throughout the entire brain. Ischemia models using transient middle cerebral artery occlusion in rats and oxygen/glucose deprivation (OGD) in SH-SY5Y neuronal cells showed that ischemia reduced SIRT6 expression and induced the release of high mobility group box-1 (HMGB1) from cell nuclei. The reduced expression of SIRT6 via treatment with SIRT6 siRNA dramatically enhanced the OGD-induced release of HMGB1 in SH-SY5Y cells. Together, our data suggest that SIRT6 may serve as a potential therapeutic target for HMGB1-mediated inflammation after cerebral ischemia. 23742259 Rapid analysis of single droplets of lanthanide-ligand solutions by electrospray ionization mass spectrometry using an induction-based fluidics source. Electrospray ionization mass spectra of lanthanide coordination complexes were measured by launching nanoliter-sized droplets directly into the aperture of an electrospray ionization mass spectrometer. Droplets ranged in size from 102 nL to 17 nL, while metal concentrations were 293 μM. The sample solution was delivered to a source capillary by a nanoliter dispenser at a rate of 21 nL/s, and droplets were ejected from the capillary by pulsing a potential onto the capillary. The end of the capillary was situated in front of the mass spectrometer and aimed directly at the aperture. The period and power of the electrical pulse was controlled by a digital energy source. The intensity of the extracted ion time profiles from the experiment showed reproducible production of lanthanide nitrato-anion complexes (Ce, Tb, and Lu). The integrated ion intensities of the complexes were reproducible, having relative standard deviations on the order 10% for anions, and 10-30% for cations. The integrated ion intensities were proportional to the droplet size, and the response was linear from about 100 to 650 pmol. However, the intercept is not zero, indicating a nonlinear response at lower analyte quantities or droplet sizes. Cation complexes were generated in separate experiments that corresponded to lanthanide nitrate ion pairs coordinated with the separations ligand octyl,phenyl,(N,N-diisobutylcarbamoyl)methylphosphine oxide (CMPO). Experiments showed a preference for formation of CMPO complexes with Ln(3+) having larger ionic radii. The relative standard deviation values of the cation abundance measurements were somewhat higher for the more highly coordinated complexes, which are also less stable. The mass spectral quality was high enough to measure the ratios of the minor isotopic ions to a high degree of accuracy. The approach suggests that the methodology has utility for analysis of solutions where the sample quantity is limited, or where the sampling efficiency of a normal ESI source is limiting on account of hazards derived from the sample solution. 23396090 Overcoming chemotherapy resistance of ovarian cancer cells by liposomal cisplatin: molecular mechanisms unveiled by gene expression profiling. Previously we reported that liposomal cisplatin (CDDP) overcomes CDDP resistance of ovarian A2780cis cancer cells (Krieger et al., Int. J. Pharm. 389, 2010, 10-17). Here we find that the cytotoxic activity of liposomal CDDP is not associated with detectable DNA platination in resistant ovarian cancer cells. This suggests that the mode of action of liposomal CDDP is different from the free drug. To gain insight into mechanisms of liposomal CDDP activity, we performed a transcriptome analysis of untreated A2780cis cells, and A2780cis cells in response to exposure with IC50 values of free or liposomal CDDP. A process network analysis of upregulated genes showed that liposomal CDDP induced a highly different gene expression profile in comparison to the free drug. p53 was identified as a key player directing transcriptional responses to free or liposomal CDDP. The free drug induced expression of essential genes of the intrinsic (mitochondrial) apoptosis pathway (BAX, BID, CASP9) most likely through p38MAPK activation. In contrast, liposomal CDDP induced expression of genes from DNA damage pathways and several genes of the extrinsic pathway of apoptosis (TNFRSF10B-DR5, CD70-TNFSF7). It thus appears that liposomal CDDP overcomes CDDP resistance by inducing DNA damage and in consequence programmed cell death by the extrinsic pathway. Predictions from gene expression data with respect to apoptosis activation were confirmed at the protein level by an apoptosis antibody array. This sheds new light on liposomal drug carrier approaches in cancer and suggests liposomal CDDP as promising strategy for the treatment of CDDP resistant ovarian carcinomas. 23572037 Exacerbation of latent lupus: is the culprit acid-fast bacilli or antitubercular therapy? Typical as well as atypical presentations of systemic lupus erythematosus are being increasingly recognized due to improved diagnostic methods. In a tuberculosis-endemic country like India, it was traditionally believed that the occurrence of tuberculosis in lupus was due to the chronic immunosuppression caused by lupus or because of the use of steroids or isoniazid-induced lupus. Increasingly several patients with no recorded predisposition to lupus with a history of treatment for tuberculosis are coming with evidence of systemic lupus erythematosus rather than a drug-limited story. Whether the development of an autoimmune state is a mere conjecture or the presence of acid-fast bacilli in the body for a prolonged duration causes complex antigenic interactions leading to an antigenic response needs to be looked into. We present a report of three such patients and review the pathogenetic interactions that could possibly explain the role of mycobacterial antigens as a putative antigen in the pathogenesis of lupus. 23734565 Responses of aquatic insects to Cu and Zn in stream microcosms: understanding differences between single species tests and field responses. Field surveys of metal-contaminated streams suggest that some aquatic insects, particularly mayflies (Ephemeroptera) and stoneflies (Plecoptera), are highly sensitive to metals. However, results of single species toxicity tests indicate these organisms are quite tolerant, with LC50 values often several orders of magnitude greater than those obtained using standard test organisms (e.g., cladocerans and fathead minnows). Reconciling these differences is a critical research need, particularly since water quality criteria for metals are based primarily on results of single species toxicity tests. In this research we provide evidence based on community-level microcosm experiments to support the hypothesis that some aquatic insects are highly sensitive to metals. We present results of three experiments that quantified effects of Cu and Zn, alone and in combination, on stream insect communities. EC50 values, defined as the metal concentration that reduced abundance of aquatic insects by 50%, were several orders of magnitude lower than previously published values obtained from single species tests. We hypothesize that the short duration of laboratory toxicity tests and the failure to evaluate effects of metals on sensitive early life stages are the primary factors responsible for unrealistically high LC50 values in the literature. We also observed that Cu alone was significantly more toxic to aquatic insects than the combination of Cu and Zn, despite the fact that exposure concentrations represented theoretically similar toxicity levels. Our results suggest that water quality criteria for Zn were protective of most aquatic insects, whereas Cu was highly toxic to some species at concentrations near water quality criteria. Because of the functional significance of aquatic insects in stream ecosystems and their well-established importance as indicators of water quality, reconciling differences between field and laboratory responses and understanding the mechanisms responsible for variation in sensitivity among metals and metal mixtures is of critical importance. 23908443 Prevalence of Anti-Peptidylarginine Deiminase Type 4 Antibodies in Rheumatoid Arthritis and Unaffected First-degree Relatives in Indigenous North American Populations. To determine whether anti-peptidylarginine deiminase type 4 (PAD4) antibodies were present in first-degree relatives (FDR) of patients with rheumatoid arthritis (RA) in 2 indigenous North American populations with high prevalence of RA. Participants were recruited from 2 indigenous populations in Canada and the United States, including patients with RA (probands), their unaffected FDR, and healthy unrelated controls. Sera were tested for the presence of anti-PAD4 antibodies, anticyclic citrullinated peptide (anti-CCP) antibodies, and rheumatoid factor (RF). HLA-DRB1 subtyping was performed and participants were classified according to number of shared-epitope alleles present. Antibodies to PAD4 were detected in 24 of 82 (29.3%) probands; 2 of 147 (1.4%) relatives; and no controls (p < 0.0001). Anti-CCP was present in 39/144 (27.1%) of the relatives, and there was no overlap between positivity for anti-CCP and PAD4 in the relatives. In RA patients, anti-PAD4 antibodies were associated with disease duration (p = 0.0082) and anti-CCP antibodies (p = 0.008), but not smoking or shared-epitope alleles. Despite a significant prevalence of anti-CCP in FDR, anti-PAD4 antibodies were almost exclusively found in established RA. The prevalence of anti-PAD4 antibodies in RA is similar to the prevalence described in other populations and these autoantibodies are associated with disease duration and anti-CCP in RA. 23687277 Mutational Analysis of the Multiple-Antibiotic Resistance Regulator MarR Reveals a Ligand Binding Pocket at the Interface between the Dimerization and DNA Binding Domains. The Escherichia coli regulator MarR represses the multiple-antibiotic resistance operon marRAB and responds to phenolic compounds, including sodium salicylate, which inhibit its activity. Crystals obtained in the presence of a high concentration of salicylate indicated two possible salicylate sites, SAL-A and SAL-B. However, it was unclear whether these sites were physiologically significant or were simply a result of the crystallization conditions. A study carried out on MarR homologue MTH313 suggested the presence of a salicylate binding site buried at the interface between the dimerization and the DNA-binding domains. Interestingly, the authors of the study indicated a similar pocket conserved in the MarR structure. Since no mutagenesis analysis had been performed to test which amino acids were essential in salicylate binding, we examined the role of residues that could potentially interact with salicylate. We demonstrated that mutations in residues shown as interacting with salicylate at SAL-A and SAL-B in the MarR-salicylate structure had no effect on salicylate binding, indicating that these sites were not the physiological regulatory sites. However, some of these residues (P57, R86, M74, and R77) were important for DNA binding. Furthermore, mutations in residues R16, D26, and K44 significantly reduced binding to both salicylate and 2,4-dinitrophenol, while a mutation in residue H19 impaired the binding to 2,4-dinitrophenol only. These findings indicate, as for MTH313, the presence of a ligand binding pocket located between the dimerization and DNA binding domains. 23583884 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced inflammatory activation is mediated by intracellular free calcium in microglial cells. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been known to induce inflammatory signaling in a number of cell types and tissues. However, the adverse effects of TCDD on the central nervous system (CNS) have not been entirely elucidated. In this study, using reverse transcriptase PCR (RT-PCR) and ELISA, we showed that TCDD up-regulated the expression and secretion of tumor necrosis factor-alpha (TNF-α) in a time-dependent manner in cultured HAPI microglial cells. TCDD also caused a fast (within 30min as judged by the increase in its mRNA level) activation of cytosolic phospholipase A2 (cPLA2). This initial action was accompanied by up-regulation of cyclooxygenase-2 (COX-2), an important inflammation marker within 1h after TCDD treatment. These pro-inflammatory responses were inhibited by two types of Ca(2+) blockers, bis-(o-aminophenoxy) ethane-N,N,N',N'-tetra-acetic acid acetoxymethyl ester (BAPTA-AM) and nifedipine, thus, indicating that the effects are triggered by initial increase in the intracellular concentration of free Ca(2+) ([Ca(2+)]i). Further, TCDD exposure could induce phosphorylation- and ubiquitination-dependent degradation of IкBα, and the translocation of NF-κB p65 from the cytosol to the nucleus in this microglial cell line. Thus, the NF-κB signaling pathway can be activated after TCDD treatment. However, Ca(2+) blockers also obviously attenuated NF-κB activation and transnuclear transport induced by TCDD. In concert with these results, we highlighted that the secretion of pro-inflammatory cytokine and NF-κB activation induced by TCDD can be mediated by elevation of [Ca(2+)]i in HAPI microglial cells. 23710895 Durability of SVR in chronic hepatitis C patients treated with peginterferon-α2a/ribavirin in combination with a direct-acting anti-viral. The introduction of direct-acting anti-virals has increased sustained virological response (SVR) rates in chronic hepatitis C genotype 1 infection. At present, data on long-term durability of viral eradication after successful triple therapy are lacking. To evaluate the long-term durability of viral eradication in patients treated with triple therapy, including direct-acting anti-virals. Patients who participated in randomised, controlled trials or an extended access programme of treatment with peginterferon-α2a/ribavirin in combination with a direct-acting anti-viral (telaprevir, danoprevir, faldaprevir, simeprevir, mericitabine, balapiravir) were followed after achieving SVR. The median follow-up after the patients was 21 (range: 7-64) months. One hundred and three patients with chronic hepatitis C genotype 1 infection [f/m: 34/69; GT-1b: 67 GT-1a: 34, GT-4: 2; mean age: 47.6 years (45.5-49.7; 95% CI)] achieving a SVR triple therapy were followed. Two cases of late relapses (2/103, 1.9%; 95% CI: 0.24-6.8) were observed. One patient was cirrhotic, both carried the genotype 1b and completed the prescribed treatment. The relapses occurred 8 and 12 months after cessation of anti-viral treatment. Cloning sequencing revealed identical sequence in both patients. Resistance analysis revealed no presence of viral resistance. Like the SVR after peginterferon-α2/ribavirin combination treatment, HCV eradication after triple therapy remains durable after long-term follow-up. 23773834 Physical characteristics and formation mechanism of denitrifying granular sludge in high-load reactor. The physical characteristics of denitrifying granular sludge and their granulation mechanism were investigated in two denitrifying reactors (R1 and R2). The results showed that the denitrifying granular sludge was streamlined in shape with the aspect ratio (AR) of 0.62±0.05, large in size with the diameter of 2.39±0.05mm, and fast in settlement with the average settling velocity (VS) of 126.36±13.32 m/h at the nitrate loading rate (NLR) of 35.14±0.38kg/(m(3)d). The dominance of denitrifying granular sludge with good settleability was attributed to the enhanced growth of granular sludge by extracellular polymers (EPS) and the shaping of granular sludge by shear force. 23834994 Analysis of arm elevation muscle activity through different movement planes and speeds during in-water and dry-land exercise. The objectives of this cross-sectional, analytical inference analysis were to compare shoulder muscle activation at arm elevations of 0° to 90° through different movement planes and speeds during in-water and dry-land exercise and to extrapolate this information to a clinical rehabilitation model. Six muscles of right-handed adult subjects (n = 16; males/females: 50%; age: 26.1 ± 4.5 years) were examined with surface electromyography during arm elevation in water and on dry land. Participants randomly performed 3 elevation movements (flexion, abduction, and scaption) through 0° to 90°. Three movement speeds were used for each movement as determined by a metronome (30°/sec, 45°/sec, and 90°/sec). Dry-land maximal voluntary contraction tests were used to determine movement normalization. Muscle activity levels were significantly lower in water compared with dry land at 30°/sec and 45°/sec but significantly higher at 90°/sec. This sequential progressive activation with increased movement speed was proportionally higher on transition from gravity-based on-land activity to water-based isokinetic resistance. The pectoralis major and latissimus dorsi muscles showed higher activity during abduction and scaption. These findings on muscle activation suggest protocols in which active flexion is introduced first at low speeds (30°/sec) in water, then at medium speeds (45°/sec) in water or on dry land, and finally at high speeds (90°/sec) on dry land before in water. Abduction requires higher stabilization, necessitating its introduction after flexion, with scaption introduced last. This model of progressive sequential movement ensures that early active motion and then stabilization are appropriately introduced. This should reduce rehabilitation time and improve therapeutic goals without compromising patient safety or introducing inappropriate muscle recruitment or movement speed. 23794388 Juvenile idiopathic arthritis, mitral valve prolapse and a familial variant involving the integrin-binding fragment of FBN1. Mutations in Fibrillin 1 (FBN1) are associated with Marfan syndrome and in some instances with the MASS phenotype (myopia, mitral valve prolapse, borderline non-progressive aortic root dilatation, skeletal features, and striae). Potential confusion over diagnosis and management in patients with borderline features has been addressed through the revised Ghent nosology, which emphasizes the importance of aortic root dilatation and ectopia lentis as features of Marfan syndrome. The overlapping and more common mitral valve prolapse syndrome is precluded by ectopia lentis or aortic dilatation. Among these clinically related conditions, there is no compelling evidence that genotype predicts phenotype, with the exception of neonatal Marfan syndrome, mutations in which cluster within FBN1 exons 24-32. Recent reports also link two very different phenotypes to changes in FBN1. Heterozygous mutations in transforming growth factor β-binding protein-like domain 5 (TB5) can cause acromicric or geleophysic dysplasias-and mutations in the TB4 domain, which contains an integrin binding RGD loop, have been found in congenital scleroderma/stiff skin syndrome. We report on a variant in an evolutionarily conserved residue that stabilizes the integrin binding fragment of FBN1, associated with juvenile idiopathic arthritis, mitral valve prolapse or apparently normal phenotype in different family members. © 2013 Wiley Periodicals, Inc. 23907014 17β-Estradiol increases expression of the oxidative stress response and DNA repair protein apurinic endonuclease (Ape1) in the cerebral cortex of female mice following hypoxia. While it is well established that 17β-estradiol (E2) protects the rodent brain from ischemia-induced damage, it has been unclear how this neuroprotective effect is mediated. Interestingly, convincing evidence has also demonstrated that maintaining or increasing the expression of the oxidative stress response and DNA repair protein apurinic endonuclease 1 (Ape1) is instrumental in reducing ischemia-induced damage in the brain. Since E2 increases expression of the oxidative stress response proteins Cu/Zn superoxide dismutase and thioredoxin in the brain, we hypothesized that E2 may also increase Ape1 expression and that this E2-induced expression of Ape1 may help to mediate the neuroprotective effects of E2 in the brain. To test this hypothesis, we utilized three model systems including primary cortical neurons, brain slice cultures, and whole animals. Although estrogen receptor α and Ape1 were expressed in primary cortical neurons, E2 did not alter Ape1 expression in these cells. However, immunofluorescent staining and quantitative Western blot analysis demonstrated that estrogen receptor α and Ape1 were expressed in the nuclei of cortical neurons in brain slice cultures and that E2 increased Ape1 expression in the cerebral cortex of these cultures. Furthermore, Ape1 expression was increased and oxidative DNA damage was decreased in the cerebral cortices of ovariectomized female C57Bl/6J mice that had been treated with E2 and exposed to hypoxia. Taken together, our studies demonstrate that the neuronal microenvironment may be required for increased Ape1 expression and that E2 enhances expression of Ape1 and reduces oxidative DNA damage, which may in turn help to reduce ischemia-induced damage in the cerebral cortex and mediate the neuroprotective effects of E2. 23685998 Measuring corneal clouding in patients suffering from mucopolysaccharidosis with the Pentacam densitometry programme. To identify a means to objectively measure corneal clouding in patients with mucopolysaccharidosis in a prospective controlled clinical trial. Corneal haze was assessed by slit lamp examination and measured using the densitometry programme of the Pentacam, a rotating Scheimpflug camera in 33 mucopolysaccharidoses (MPS) patients and 32 controls. Pentacam measurements were available in 31 right and 31 left eyes of 32 patients and in 32 left and right eyes of 32 subjects in the control group. Slit lamp findings correlated very well with corneal density measurements (Spearman correlation right eye (OD)/left eye (OS)=0.782/0.791). MPS patients had higher density units (median OD/OS=14.1/14.7) than control subjects (median OD/OS=6.7/6.9, p<0.001). In patients, the corneal centre density values (median OD/OS=13.8/14.0) did not differ from corneal periphery values (median OD/OS=14.3/14.7). The densitometry programme of the Pentacam provides objective measurement of corneal haze in mucopolysaccharidosis patients. 23970476 Staphylococcus aureus in early cystic fibrosis lung disease. Staphylococcus aureus: is a common bacterial organism infecting children with cystic fibrosis (CF). Emerging evidence suggests early lower airway infection with this organism in young children with CF results in the deterioration of lung function, poorer nutrition parameters and heightens the airway inflammatory response. Despite contributing significantly to the burden of early lung disease among this group, there are ongoing controversies in the management of S. aureus infection, and gaps in our understanding of exactly how this organism causes lung disease. To reduce the morbidity and mortality of early infection ongoing research is needed to: (i) understand the early host immune response that enables this pathogen to reside within the CF lung; (ii) determine if there are organism specific factors that are associated with CF lung disease; and (iii) clarify the utility of anti-staphylococcal antibiotic prophylaxis and/or eradication in the treatment of this patient population. Pediatr Pulmonol. © 2013 Wiley Periodicals, Inc. 23823144 Visual Manifestations in Alzheimer's disease: A Clinic-Based Study From India. Introduction: Alzheimer's disease (AD) is characterized by amnesia, though non-memory-cognitive domains like visual are also affected. We planned to study frequency of visual dysfunctions in AD and their relationship with dementia severity. Materials and Methods: This study was conducted in the Cognitive clinic of Department of Neurology, Bangur Institute of Neurosciences, Kolkata, between January 2007 and December 2010. 55 patients of AD were evaluated by neurological and neuropsychological assessments and by special tests for visual dysfunctions. Results: Common visual dysfunctions were visuo-constructional (87.3%), visuo-perceptual (63.6%), object agnosia(47.3%), prosopagnosia (45.5%), visual hallucination (27.3%) and simultanagnosia (12.7%). Symptoms of ventral visual pathway dysfunction were more common than that of dorsal pathway. MMSE score and number of visual manifestations had a good correlation. Conclusions: Visual dysfunctions are common in AD, elicitation of which helps us to understand the cause of disability so that appropriate steps can be taken. 23653120 Microlunatus cavernae sp. nov., a novel actinobacterium isolated from Alu ancient cave, Yunnan, South-West China. A Gram-positive, coccoid, non-endospore-forming actinobacterium, designated YIM C01117(T), was isolated from a soil sample collected from Alu ancient cave, Yunnan province, south-west China. Based on the 16S rRNA gene sequence analysis, strain YIM C01117(T) was shown to belong to the genus Microlunatus, with highest sequence similarity of 97.4 % to Microlunatus soli DSM 21800(T). The whole genomic DNA relatedness as shown by the DNA-DNA hybridization study between YIM C01117(T) and M. soli DSM 21800(T) had a low value (47 ± 2 %). Strain YIM C01117(T) was determined to contain LL-diaminopimelic acid with Gly, Glu and Ala amino acids (A3γ' type) in the cell wall. Whole-cell hydrolysates were found to contain glucose, galactose, mannose and ribose. The major polar lipids were determined to be phosphatidylglycerol and diphosphatidylglycerol. The predominant menaquinone system present is MK-9(H4), while the major fatty acids were identified to be anteiso-C15:0 (24.1 %), iso-C16:0 (22.3 %) and iso-C15:0 (11.4 %). The G+C content of the genomic DNA was determined to be 65.9 mol%. The chemotaxonomic and genotypic data support the affiliation of the strain YIM C01117(T) to the genus Microlunatus. The results of physiological and biochemical tests allow strain YIM C01117(T) to be differentiated phenotypically from recognized Microlunatus species. Strain YIM C01117(T) is therefore considered to represent a novel species of the genus Microlunatus, for which the name Microlunatus cavernae sp. nov. is proposed. The type strain is YIM C01117(T) (= DSM 26248(T) = JCM 18536(T)). 23581504 Prolonged inhibition of 5-HT3 receptors by palonosetron results from surface receptor inhibition rather than inducing receptor internalization. The 5-HT3 receptor antagonist palonosetron is an important treatment for emesis and nausea during cancer therapy. Its clinical efficacy may result from its unique binding and clearance characteristics and receptor down-regulation mechanisms. We investigated the mechanisms by which palonosetron exerts its long-term inhibition of 5-HT3 receptors for a better understanding of its clinical efficacy. Cell surface receptors (recombinantly expressed 5HT3 A or 5HT3 AB in COS-7 cells) were monitored using [(3) H]granisetron binding and ELISA after exposure to palonosetron. Receptor endocytosis was investigated using immunofluorescence microscopy. Chronic exposure to palonosetron reduced the number of available cell surface [(3) H]granisetron binding sites. This down-regulation was not sensitive to either low temperature or pharmacological inhibitors of endocytosis (dynasore or nystatin) suggesting that internalization did not play a role. This was corroborated by our observation that there was no change in cell surface 5-HT3 receptor levels or increase in endocytic rate. Palonosetron exhibited slow dissociation from the receptor over many hours, with a significant proportion of binding sites being occupied for at least 4 days. Furthermore, our observations suggest that chronic receptor down-regulation involved interactions with an allosteric binding site. Palonosetron acts as a pseudo-irreversible antagonist causing prolonged inhibition of 5-HT3 receptors due to its very slow dissociation. In addition, an irreversible binding mode persists for at least 4 days. Allosteric receptor interactions appear to play a role in this phenomenon. 23925947 Different types of aqueous two-phase systems for biomolecule and bioparticle extraction and purification. Upstream improvements have led to significant advances in the productivity of biomolecules and bioparticles. Today, downstream processes are the bottleneck in the production of some biopharmaceuticals, a change from previous years. Current purification platforms will reach their physical limits at some point, indicating the need for new approaches. This article reviews an alternative method to extract and purify biomolecules/bioparticles named aqueous two-phase system (ATPS). Biocompatibility and readiness to scale up are some of the ATPS characteristics. We also discuss some of ATPS applications in the biotechnology field. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 2013. 23949591 Gonococcal susceptibility to cephalosporins-hawaii, 2003 to 2011. Among gonococcal isolates examined at the Hawaii State Laboratory Division from 2003 to 2011, the prevalence of elevated cefixime minimum inhibitory concentrations (MICs; ≥0.064 μg/mL) and elevated cefpodoxime MICs (≥0.19 μg/mL) increased over time. In contrast, few isolates exhibited elevated ceftriaxone MICs (≥0.094 μg/mL), and the prevalence of elevated ceftriaxone MICs did not change. 23109293 Effects of bisphenol A on growth and nitrogen nutrition of roots of soybean seedlings. Bisphenol A (BPA) is an environmental endocrine disruptor that seriously threatens ecological systems. Plants are the primary producers in ecological systems, but little information is available concerning the toxic effect of BPA on plants. In the present study, the effects of BPA on the growth and nitrogen nutrition of roots of soybean seedlings were investigated by using a root automatic scan apparatus and biochemical methods. It was found that when soybean seedlings were treated with 1.5 mg/L BPA, the growth of roots was improved, the content of nitrate in roots was increased, the content of ammonium in roots was decreased, and the activities of nitrate reductase and nitrite reductase in roots were not changed. The opposite effects were observed in roots treated with 17.2 mg/L and 50.0 mg/L BPA, except for an increase in the content of nitrate in roots treated with 17.2 mg/L BPA and a decrease in the activities of nitrate reductase and nitrite reductase in roots of soybeans seedlings. Statistical analysis indicated that the change in the nitrogen nutrition of roots of soybean seedlings treated with BPA was one reason why the growth of roots was changed. The authors suggest that the potential environmental and ecological risk of BPA to plants should receive more consideration. 23850241 The evolution of December 2004 tsunami deposits: Temporal and spatial distribution of potentially toxic metalloids. The article presents the results of research into the content of metalloid fractions in the tsunami deposits from southern Thailand. The following fractions, which are potentially most easily released from deposits to the environment, have been distinguished: the water soluble fraction, the exchangeable fraction extracted with the phosphate buffer and the fraction eluted with the solution of hydrochloric acid. The analytical technique atomic absorption spectrometry with hydride generation was applied. Spatial variability of the metalloid fractions in deposits and changes occurring in deposits over a period of several years of observation were determined. Based on the statistical analysis of the results, an attempt was made to determine the post-depositional release of deposits components to the environment. Based on the conducted research, the 4years forming process of the arsenic, antimony and selenium occurrence after the deposition of sediments on land were described, as well as the balance in the amount of deposit components released to the environment. 23966730 Integration of Problem-based Learning and Innovative Technology Into a Self-Care Course. Objective. To assess the integration of problem-based learning and technology into a self-care course. Design. Problem-based learning (PBL) activities were developed and implemented in place of lectures in a self-care course. Students used technology, such as computer-generated virtual patients and iPads, during the PBL sessions. Assessments. Students' scores on post-case quizzes were higher than on pre-case quizzes used to assess baseline knowledge. Student satisfaction with problem-based learning and the use of technology in the course remained consistent throughout the semester. Conclusion. Integrating problem-based learning and technology into a self-care course enabled students to become active learners. 23934749 Crystal Structures of α-Dioxygenase from Oryza sativa: Insights into Substrate Binding and Activation by Hydrogen Peroxide. α-dioxygenases (α-DOX) are heme-containing enzymes found predominantly in plants and fungi, where they generate oxylipins in response to pathogen attack. α-DOX oxygenate a variety of 14-20 carbon fatty acids containing up to three unsaturated bonds through stereoselective removal of the pro-R hydrogen from the α-carbon by a tyrosyl radical generated via the oxidation of the heme moiety by hydrogen peroxide (H2 O2 ). We determined the X-ray crystal structures of wild type α-DOX from Oryza sativa, the wild type enzyme in complex with H2 O2 , and the catalytically inactive Y379F mutant in complex with the fatty acid palmitic acid (PA). PA binds within the active site cleft of α-DOX such that the carboxylate forms ionic interactions with His-311 and Arg-559. Thr-316 aids in the positioning of carbon-2 for hydrogen abstraction. Twenty-five of the twenty eight contacts made between PA and residues lining the active site occur within the carboxylate and first eight carbons, indicating that interactions within this region of the substrate are responsible for governing selectivity. Comparison of the wild type and H2 O2 structures provides insight into enzyme activation. The binding of H2 O2 at the distal face of the heme displaces residues His-157, Asp-158, and Trp-159 ~2.5Å from their positions in the wild type structure. As a result, the Oδ2 atom of Asp-158 interacts with the Ca atom in the calcium binding loop, the side chains of Trp-159 and Trp-213 reorient, and the guanidinium group of Arg-559 is repositioned near Tyr-379, poised to interact with the carboxylate group of the substrate. 23436821 Sustained Beneficial Effects of a Protocolized Treat-to-Target Strategy in Very Early Rheumatoid Arthritis: Three-Year Results of the Dutch Rheumatoid Arthritis Monitoring Remission Induction Cohort. Treat-to-target (T2T) leads to improved clinical outcomes in early rheumatoid arthritis (RA). The question is whether these results sustain in the long term. Our objective was to investigate the 3-year results of a protocolized T2T strategy in daily clinical practice. In the Dutch Rheumatoid Arthritis Monitoring remission induction cohort, patients newly diagnosed with RA were treated according to a T2T strategy aimed at remission (Disease Activity Score in 28 joints [DAS28] <2.6). Patients were treated with methotrexate, followed by the addition of sulfasalazine, and exchange of sulfasalazine with anti-tumor necrosis factor α agents in case of failure. Primary outcomes were disease activity, Health Assessment Questionnaire (HAQ) score, Short Form 36 physical component summary (PCS) and mental component summary (MCS) scores, and the Sharp/van der Heijde score (SHS) after 3 years. Secondary outcomes were sustained DAS28 remission (≥6 months) and remission according to the provisional American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) definition. After 3 years (n = 342), 61.7% of patients were in DAS28 remission and 25.3% met the provisional ACR/EULAR definition of remission. Sustained remission was experienced by 70.5%, which in the majority was achieved with conventional disease-modifying antirheumatic drugs only. The median scores were 0.4 (interquartile range [IQR] 0.0-1.0) for the HAQ, 45.0 (IQR 38.4-53.2) for the PCS, 53.1 (IQR 43.2-60.8) for the MCS, and 6.0 (IQR 3.0-13.0) for the total SHS. In very early RA, T2T leads to high (sustained) remission rates, improved physical function and health-related quality of life, and limited radiographic damage after 3 years in daily clinical practice. 23879444 Cognitive performance following spontaneous subarachnoid haemorrhage versus other forms of intracranial haemorrhage. Objective. The exact cause of cognitive deficits following intracranial haemorrhage is unclear. This prospective study examines the abilities after spontaneous subarachnoid haemorrhage (SAH), intracerebral haemorrhage (ICH) and chronic subdural haematoma (SDH) to elucidate the cognitive outcome. Patients and methods. Ninety-nine patients with SAH (N = 60), ICH (N = 25), and SDH (N = 14) were followed up for an average of 6 and 12 months post-haemorrhage. Cognitive tests were used to examine attention, memory, concentration, and executive function. Following were used for analysis: 1. the percentage of patients falling below the 25th percentile per test, 2. the general development from the first to second test point and 3. the incidence of significant changes between the test points. Significance was established as p ≤ 0.05. Results. All three types of haemorrhage resulted in deficits as concerns abstract language (53%-75%). The processing speed was below the normal levels in more than 70% of the patients tested. The cognitive performance of SAH patients was similar to that of patients with SDH and ICH patients after 6 months. The number of patients with outcomes falling below the 25th percentile (to some extent more than 75% in patients post-SAH) is high in all patient groups and mostly decreases over the course. Nevertheless, patients with SAH reveal improvements in many more areas than with ICH and SDH (p ≤ 0.006). Conclusions. The cognitive impairments following SAH, ICH and SDH deficits appear to develop in a similar way regardless of the type of haemorrhage. Cognitive improvement is most pronounced in patients with SAH. 23223517 Altered UDP-glucuronosyltransferase and sulfotransferase expression and function during progressive stages of human nonalcoholic fatty liver disease. The UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) represent major phase II drug-metabolizing enzymes that are also responsible for maintaining cellular homeostasis by metabolism of several endogenous molecules. Perturbations in the expression or function of these enzymes can lead to metabolic disorders and improper management of xenobiotics and endobiotics. Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver damage ranging from steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Because the liver plays a central role in the metabolism of xenobiotics, the purpose of the current study was to determine the effect of human NAFLD progression on the expression and function of UGTs and SULTs in normal, steatosis, NASH (fatty), and NASH (not fatty/cirrhosis) samples. We identified upregulation of UGT1A9, 2B10, and 3A1 and SULT1C4 mRNA in both stages of NASH, whereas UGT2A3, 2B15, and 2B28 and SULT1A1, 2B1, and 4A1 as well as 3'-phosphoadenosine-5'-phosphosulfate synthase 1 were increased in NASH (not fatty/cirrhosis) only. UGT1A9 and 1A6 and SULT1A1 and 2A1 protein levels were decreased in NASH; however, SULT1C4 was increased. Measurement of the glucuronidation and sulfonation of acetaminophen (APAP) revealed no alterations in glucuronidation; however, SULT activity was increased in steatosis compared with normal samples, but then decreased in NASH compared with steatosis. In conclusion, the expression of specific UGT and SULT isoforms appears to be differentially regulated, whereas sulfonation of APAP is disrupted during progression of NAFLD. 23469681 Influence of aqueous media properties on aggregation and solubility of four structurally related meso-porphyrin photosensitizers evaluated by spectrophotometric measurements. Porphyrin photosensitizers tend to aggregate in aqueous solutions even in the micromolar concentration range. This is a challenge during formulation of e.g., parenteral preparations for photodynamic cancer therapy, or preparations for local or topical administration in antimicrobial photodynamic therapy. Monomerization is essential to achieve biocompatible drug formulations of high bioavailability and physiological response (i.e., photoreactivity) and low toxicity. The aggregation and solubilization of four structurally related meso-tetraphenyl porphyrin photosensitizers with nonionic (4-hydroxy), anionic (4-sulphonate; 4-carboxy) and cationic (4-trimethylanilinium) substituents were evaluated in various vehicles by use of UV-Vis spectroscopy. Substituents, overall charge and charge distribution influenced the pKa-values and interaction of the porphyrins with different solvents, excipients and impurities. Modification of medium polarity and solubilization by the nonionic surfactant Tween 80 adjusted the acid-base equilibria and increased the solubility by reduction of porphyrin aggregation. The selected porphyrins were sensitive towards ionic strength, temperature and inorganic impurities to various extents. The results will be further used during development of parenteral and topical formulations of porphyrin photosensitizers for use in photodynamic therapy of cancer and bacterial infections. 23874563 Distribution of Bartonella henselae Variants in Patients, Reservoir Hosts and Vectors in Spain. We have studied the diversity of B. henselae circulating in patients, reservoir hosts and vectors in Spain. In total, we have fully characterized 53 clinical samples from 46 patients, as well as 78 B. henselae isolates obtained from 35 cats from La Rioja and Catalonia (northeastern Spain), four positive cat blood samples from which no isolates were obtained, and three positive fleas by Multiple Locus Sequence Typing and Multiple Locus Variable Number Tandem Repeats Analysis. This study represents the largest series of human cases characterized with these methods, with 10 different sequence types and 41 MLVA profiles. Two of the sequence types and 35 of the profiles were not described previously. Most of the B. henselae variants belonged to ST5. Also, we have identified a common profile (72) which is well distributed in Spain and was found to persist over time. Indeed, this profile seems to be the origin from which most of the variants identified in this study have been generated. In addition, ST5, ST6 and ST9 were found associated with felines, whereas ST1, ST5 and ST8 were the most frequent sequence types found infecting humans. Interestingly, some of the feline associated variants never found on patients were located in a separate clade, which could represent a group of strains less pathogenic for humans. 23946218 Severity Scoring Index for Crimean Congo Hemorrhagic Fever virus infection and the impact of Ribavirin and Corticosteroids on Fatality. Background. The patients infected with Crimean Congo Hemorrhagic Fever (CCHF) virus present wide range of clinical spectrum. In observational studies, the effects of therapeutic agents are confounded by severity. We described clinical severity scoring index (SSI) for CCHF patients, and assessed the effect of ribavirin and corticosteroids on fatality by the adjustment of SSI. Methods. The study group included hospitalized patients with diagnosis of CCHF in Infectious Diseases and Clinical Microbiology clinic of Ankara Numune Education and Research Hospital between 2004 and 2011. Severity scoring index (SSI) included platelet count, bleeding, fibrinogen, activated partial thromboplastin time, and somnolence. The effects of ribavirin and corticosteroid on fatality were studied by univariate and multivariate analysis by the adjustment of SSI. Results. Two hundred eighty one confirmed cases of CCHF were included to the study. Out of 281 patients 23 (8%) died. Mean age of the patients was 47 (sd 16). The proportion of the females was 49%. The mean duration of admission to our clinic after onset of symptoms was 4.4 days ranging from 1 to 14 days. In multivariate analysis for the prediction of fatality, SSI (Odds ratio 3.27, confidence interval 2.09-5.13) and ribavirin use (OR 0.04, CI 0.004-0.48) were found to be statistically significant. Conclusion. Severity scoring index predicts the fatality effectively. It is necessary for the case management and for drug assessment studies. By adjustment of SSI, ribavirin was found to be effective in reducing case fatality rate especially among moderately ill patients, whereas steroids were found to be beneficial especially among severe patients. 23704138 Treatment of Obstructive Hypertrophic Cardiomyopathy Symptoms and Gradient Resistant to First-Line Therapy With β-Blockade or Verapamil. Background- There is controversy about preferred methods to relieve obstruction in hypertrophic cardiomyopathy patients still symptomatic after β-blockade or verapamil. Methods and Results- Of 737 patients prospectively registered at our institution, 299 (41%) required further therapy for obstruction for limiting symptoms, rest gradient 61±45, provoked gradient 115±49 mm Hg, and followed up for 4.8 years. Disopyramide was added in 221 (74%) patients and pharmacological control of symptoms was achieved in 141 (64%) patients. Overall, 138 (46%) patients had surgical relief of obstruction (91% myectomy) and 6 (2%) alcohol septal ablation. At follow-up, resting gradients in the 299 patients had decreased from 61±44 to 10±25 mm Hg (P<0.0001); New York Heart Association class decreased from 2.7±0.7 to 1.8±0.5 (P<0.0001). Kaplan-Meier survival at 10 years in the 299 advanced-care patients was 88% and did not differ from nonobstructed patients (P=0.28). Only 1 patient had sudden death, a low annual rate of 0.06%/y. Kaplan-Meier survival at 10 years in the advanced-care patients did not differ from that expected in a matched cohort of the US population (P=0.90). Conclusions- Patients with obstruction and symptoms resistant to initial pharmacological therapy with β-blockade or verapamil may realize meaningful symptom relief and low mortality through stepped management, adding disopyramide in appropriately selected patients, and when needed, by surgical myectomy. 23764010 Ewe lambs with higher breeding values for growth achieve higher reproductive performance when mated at age 8 months. We studied the relationships among growth, body composition and reproductive performance in ewe lambs with known phenotypic values for depth of eye muscle (EMD) and fat (FAT) and Australian Sheep Breeding Values for post-weaning live weight (PWT) and depth of eye muscle (PEMD) and fat (PFAT). To detect estrus, vasectomized rams were placed with 190 Merino ewe lambs when on average they were 157 days old. The vasectomized rams were replaced with entire rams when the ewe lambs were, on average, 226 days old. Lambs were weighed every week and blood was sampled on four occasions for assay of ghrelin, leptin and ß-hydroxybutyrate. Almost 90% of the lambs attained puberty during the experiment, at an average live weight of 41.4 kg and average age of 197 days. Ewe lambs with higher values for EMD (P < 0.001), FAT (P < 0.01), PWT (P < 0.001), PEMD (P < 0.05) and PFAT (P < 0.05) were more likely to achieve puberty by 251 days of age. Thirty-six percent of the lambs conceived and, at the estimated date of conception, the average live weight was 46.9 ± 0.6 kg and average age was 273 days. Fertility, fecundity and reproductive rate were positively related to PWT (P < 0.05) and thus live weight at the start of mating (P < 0.001). Reproductive performance was not correlated with blood concentrations of ghrelin, leptin or ß-hydroxybutyrate. Many ewe lambs attained puberty, as detected by vasectomized rams, but then failed to become pregnant after mating with entire rams. Nevertheless, we can conclude that in ewe lambs mated at 8 months of age, higher breeding values for growth, muscle and fat are positively correlated with reproductive performance, although the effects of breeding values and responses to live weight are highly variable. 22975839 A multiscale approach in the computational modeling of the biophysical environment in artificial cartilage tissue regeneration. Tissue Engineering is a strongly interdisciplinary scientific area aimed at understanding the principles of tissue growth to produce biologically functional replacements for clinical use. To achieve such an ambitious goal, complex biophysical phenomena must be understood in order to provide the appropriate environment to cells (nutrient delivery, fluid-mechanical loading and structural support) in the bioengineered device. Such a problem has an inherent multiphysics/multiscale nature, as it is characterized by material heterogeneities and interplaying processes occurring within a wide range of temporal and spatial scales. In this context, computational models are useful to gain a quantitative and comprehensive understanding of phenomena often difficult to be accessed experimentally. In this paper, we propose a mathematical and computational model that represents, to our knowledge, the first example of a self-consistent multiscale description of coupled nutrient mass transport, fluid-dynamics and biomass production in bioengineered constructs. We specifically focus on articular cartilage regeneration based on dynamically perfused bioreactors, and we investigate by numerical simulations three issues critical in this application. First, we study oxygen distribution in the construct, since achieving an optimal level throughout the construct is a main control variable to improve tissue quality. Second, we provide a quantitative evaluation of how interstitial perfusion can enhance nutrient delivery and, ultimately, biomass production, compared with static culture. Third, we perform a sensitivity analysis with respect to biophysical parameters related to matrix production, assessing their role in tissue regeneration. 23913488 Modeling the effect of copper availability on bacterial denitrification. When denitrifying bacteria such as Paracoccus denitrificans respire anaerobically they convert nitrate to dinitrogen gas via a pathway which includes the potent greenhouse gas, nitrous oxide (N2 O). The copper-dependent enzyme Nitrous Oxide reductase (Nos) catalyzes the reduction of N2 O to dinitrogen. In low-copper conditions, recent experiments in chemostats have demonstrated that Nos efficiency decreases resulting in significant N2 O emissions. For the first time, a chemostat-based mathematical model is developed that describes the anaerobic denitrification pathway based on Michaelis-Menten kinetics and published kinetic parameters. The model predicts steady-state enzyme levels from experimental data. For low copper concentrations, the predicted Nos level is significantly reduced, whereas the levels for the non copper-dependent reductases in the pathway remain relatively unaffected. The model provides time courses for the pathway metabolites that accurately reflect previously published experimental data. In the absence of experimental data purely predictive analyses can also be readily performed by calculating the relative Nos level directly from the copper concentration. Here, the model quantitatively estimates the increasing level of emitted N2 O as the copper level decreases. 23517733 Synthesis and selected immunological properties of substituted quino[3,2-b]benzo[1,4]thiazines. A new type of azaphenothiazines - tetracyclic quino[3,2-b]benzo[1,4]thiazines, possessing common substituents (H, CH3, Cl, Br, F, CF3, SCH3) in positions 8-10 and pharmacophoric aminoalkyl substituents in position 6, were obtained from diquinodithiin and 2,2'-dichloro-3,3'-diquinolinyl disulfide in several-step syntheses. Sixty one compounds, grouped as the 6H, 6-dialkylaminoalkyl, 6-acylaminoalkyl and sulfonylaminoalkyl derivatives, were tested for cytotoxicity, their effects on phytohemagglutin A (PHA)-induced proliferative response of human peripheral blood mononuclear cells (PBMC) and lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α) production by these cells. The compounds exhibited differential inhibitory activities in these tests and significantly varied in terms of cytotoxicity. The most promising compounds were tested for growth inhibition of leukemia L-1210 cells, colon cancer SV-948 cells and epidermal carcinoma A-341 cells. The most active compounds exhibited anticancer activity against these cell lines comparable to that of cisplatin. The structure-activity relationship of the compounds were discussed. 23524170 Adherence to hormonal contraception among women veterans: differences by race/ethnicity and contraceptive supply. The objective of the study was to assess the adherence to hormonal contraception (pill, patch, ring, or injectable) among women veterans and examine the relationships between race/ethnicity and the months of contraceptive supply dispensed with contraceptive adherence. We conducted a retrospective analysis of the Department of Veterans Affairs (VA) national databases to examine the adherence to hormonal contraception over 12 months among women aged 18-45 years who had hormonal contraceptive coverage during the first week of fiscal year 2008. We examined several adherence indicators including gaps between refills and months of contraceptive coverage. Descriptive statistics and multivariable models were used to examine the associations between race/ethnicity and contraceptive supply dispensed with adherence. Our cohort included 6946 women: 47% were white, 6% were Hispanic, 22% were black, and 25% were other race or had missing race information. Most women (83%) received a 3 month supply of contraception at each fill. More than 64% of women had at least 1 gap in coverage of 7 days or longer. Only 22% of women received a full 12 months of contraception without any gaps (perfect adherence). Compared with whites, Hispanics were significantly more likely to experience gaps (64% vs 70%; P = .02), and Hispanics and blacks received fewer months of contraceptive coverage (9.3 vs 8.9 and 9.0, P < .001). Compared with women receiving 3 month supplies, those receiving 1 month supplies had a higher likelihood of a gap (63% vs 72%, P < .001), fewer months of coverage (9.3 vs 6.9, P < .001), and a lower likelihood of perfect adherence (22% vs 11%, P < .001). Adherence to hormonal contraception among women veterans is poor. Efforts to improve contraceptive adherence and lower risk of unintended pregnancy are needed; dispensing more months of supply for hormonal contraception may be a promising strategy. 23548702 The putative JAK-STAT inhibitor AG490 exacerbates LPS-fever, reduces sickness behavior, and alters the expression of pro- and anti-inflammatory genes in the rat brain. The functional significance for activation of inflammatory transcription factors, such as signal transducer and activator of transcription (STAT3), nuclear factor (NF)κB or NF-interleukin (IL)6 and their contribution to the induction of brain controlled sickness responses, such as fever, during infection and inflammation is unknown. Using AG490, previously shown to inhibit the STAT3- and NF-IL6-signaling pathway, we therefore investigated the central involvement of these two signaling pathways in mediating sickness behavior, fever and accompanying brain inflammation induced by peripheral lipopolysaccharide (LPS)-stimulation. Rats pre-treated i.c.v. with AG490 1 h before the i.p. LPS-challenge (100 μg/kg) showed a modestly exaggerated fever, attenuated adipsia and almost unimpaired locomotor activity compared to LPS-controls receiving vehicle (i.c.v.). The LPS-induced anorexia was not altered and AG490 did not have any effect on rats receiving PBS (i.p.). We did observe effects of AG490 on STAT3-signaling at 4 h, while AG490-mediated changes in brain activity of inflammatory transcription factors at 8 h were not significant. Increased NF-IL6 and suppressor of cytokines 3 mRNA-expression in AG490/LPS-treated rats were indicative of a compensative activation at 24 h. Moreover, a significant decrease in hypothalamic anti-inflammatory IL-10-expression and an increase in inflammatory microsomal prostaglandin E synthase (mPGES) mRNA-expression 8 h after LPS-injection was revealed in AG490 pre-treated animals compared to solvent-treated LPS-controls. In summary, we have shown a dissociation between the effects of central AG490 treatment on fever and components of sickness behavior, which appears to be related to reduced IL-10 and increased mPGES-expression in the brain. Thus, AG490 might have therapeutic potential to reduce sickness behavior. 23892362 Temporal Trends in Presentation and Survival for HIV-Associated Lymphoma in the Antiretroviral Therapy Era. Lymphoma is the leading cause of cancer-related death among HIV-infected patients in the antiretroviral therapy (ART) era. We studied lymphoma patients in the Centers for AIDS Research Network of Integrated Clinical Systems from 1996 until 2010. We examined differences stratified by histology and diagnosis year. Mortality and predictors of death were analyzed using Kaplan-Meier curves and Cox proportional hazards. Of 23 050 HIV-infected individuals, 476 (2.1%) developed lymphoma (79 [16.6%] Hodgkin lymphoma [HL]; 201 [42.2%] diffuse large B-cell lymphoma [DLBCL]; 56 [11.8%] Burkitt lymphoma [BL]; 54 [11.3%] primary central nervous system lymphoma [PCNSL]; and 86 [18.1%] other non-Hodgkin lymphoma [NHL]). At diagnosis, HL patients had higher CD4 counts and lower HIV RNA than NHL patients. PCNSL patients had the lowest and BL patients had the highest CD4 counts among NHL categories. During the study period, CD4 count at lymphoma diagnosis progressively increased and HIV RNA decreased. Five-year survival was 61.6% for HL, 50.0% for BL, 44.1% for DLBCL, 43.3% for other NHL, and 22.8% for PCNSL. Mortality was associated with age (adjusted hazard ratio [AHR] = 1.28 per decade increase, 95% confidence interval [CI] = 1.06 to 1.54), lymphoma occurrence on ART (AHR = 2.21, 95% CI = 1.53 to 3.20), CD4 count (AHR = 0.81 per 100 cell/µL increase, 95% CI = 0.72 to 0.90), HIV RNA (AHR = 1.13 per log10copies/mL, 95% CI = 1.00 to 1.27), and histology but not earlier diagnosis year. HIV-associated lymphoma is heterogeneous and changing, with less immunosuppression and greater HIV control at diagnosis. Stable survival and increased mortality for lymphoma occurring on ART call for greater biologic insights to improve outcomes. 23917814 Antimicrobial activity of a neem cake extract in a broth model meat system. This work reports on the antimicrobial activity of an ethyl acetate extract of neem (Azadirachta indica) cake (NCE) against bacteria affecting the quality of retail fresh meat in a broth model meat system. NCE (100 µg) was also tested by the agar disc diffusion method. It inhibited the growth of all tested microorganisms. The NCE growth inhibition zone (IZ) ranged 11.33-22.67 mm while the ciprofloxacin (10 µg) IZ ranged from 23.41-32.67 mm. There was no significant difference (p ≤ 0.05) between the antimicrobial activity of NCE and ciprofloxacin vs. C. jejuni and Leuconostoc spp. The NCE antibacterial activity was moreover determined at lower concentrations (1:10-1:100,000) in micro-assays. The percent growth reduction ranged from 61 ± 2.08-92 ± 3.21. The higher bacterial growth reduction was obtained at 10 µg concentration of NCE. Species-specific PCR and multiplex PCR with the DNA dye propidium monoazide were used to directly detect viable bacterial cells from experimentally contaminated meat samples. The numbers of bacterial cells never significantly (p ≤ 0.05) exceeded the inocula concentration used to experimentally contaminate the NCE treated meat. This report represents a screening methodology to evaluate the antimicrobial capability of a herbal extract to preserve meat. 23948522 New ST-segment elevation myocardial infarction criteria for left bundle branch block based on QRS area. ECG detection of ST-segment elevation myocardial infarction (STEMI) in the presence of left bundle-branch block (LBBB) is challenging due to ST deviation from the altered conduction. The purpose of this study was to introduce a new algorithm for STEMI detection in LBBB and compare the performance to three existing algorithms. Source data of the study group (143 with acute MI and 239 controls) comes from multiple sources. ECGs were selected by computer interpretation of LBBB. Acute MI reference was hospital discharge diagnosis. Automated measurements came from the Philips DXL algorithm. Three existing algorithms were compared, (1) Sgarbossa criteria, (2) Selvester 10% RS criteria and (3) Smith 25% S-wave criteria. The new algorithm uses an ST threshold based on QRS area. All algorithms share the concordant ST elevation and anterior ST depression criteria from the Sgarbossa score. The difference is in the threshold for discordant ST elevation. The Sgarbossa, Selvester, Smith and Philips discordant ST elevation criteria are (1) ST elevation ≥500μV, (2) ST elevation ≥10% of |S|-|R| plus STEMI limits, (3) ST elevation ≥25% of the S-wave amplitude and (4) ST elevation ≥100μV+1050μV/Ash * QRS area. The Smith S-wave and Philips QRS area criteria were tested using both a single and 2 lead requirement. Algorithm performance was measured by sensitivity, specificity, and positive likelihood ratio (LR+). Algorithm performance can be organized in bands of similar sensitivity and specificity ranging from Sgarbossa score ≥3 with the lowest sensitivity and highest specificity, 13.3% and 97.9%, to the Selvester 10% rule with the highest sensitivity and lower specificity of 30.1% and 93.2%. The Smith S-wave and Philips QRS area algorithms were in the middle band with sensitivity and specificity of (20.3%, 94.9%) and (23.8%, 95.8%) respectively. As can be seen from the difference between Sgarbossa score ≥3 and other algorithms for STEMI in LBBB, a discordant ST elevation criterion improves the sensitivity for detection but also results in a drop in specificity. For applications of automated STEMI detection that require higher sensitivity, the Selvester algorithm is better. For applications that require a low false positive rate such as relying on the algorithm for pre-hospital activation of cardiac catheterization laboratory for urgent PCI, it may be better to use the 2 lead Philips QRS area or Smith 25% S-wave algorithm. 23845180 Carbamoyl Pyridone HIV-1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744). We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the integrase catalytic active site. Structure-activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereoselective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of 3 and 4, which are currently in clinical development. 23735484 Regulation of alcohol oxidase 1 (AOX1) promoter and peroxisome biogenesis in different fermentation processes in Pichia pastoris. Production of recombinant proteins is affected by process conditions, where transcriptional regulation of Pichia pastoris alcohol oxidase 1 (PpAOX1) promoter has been a key factor to influence expression levels of proteins of interest. Here, we demonstrate that the AOX1 promoter and peroxisome biogenesis are regulated based on different process conditions. Two types of GFP-fusion proteins, Ub-R-GFP (short-lived GFP in the cytosol) and GFP-SKL (peroxisomal targeting GFP), were successfully used to characterize the time-course of the AOX1 promoter and peroxisome biogenesis, respectively. The activity of the AOX1 promoter and peroxisome biogenesis was highly subjected to different fermentation process conditions - methanol-limited condition at normoxy (ML), switched feeding of carbon sources (e.g., glucose and methanol) under carbon-limited condition at normoxy (SML), and oxygen-limited (OL) condition. The AOX1 promoter was most active under the ML, but less active under the OL. Peroxisome biogenesis showed a high dependency on methanol consumption. In addition, the proliferation of peroxisomes was inhibited in a medium containing glucose and stimulated in the methanol phase under a carbon-limited fed-batch culture condition. The specific productivity of a monoclonal antibody (qp) under the AOX1 promoter was higher at 86h of induction in the ML than in the OL (0.026 vs 0.020mgg(-1)h(-1)). However, the oxygen-limited condition was a robust process suitable for longer induction (180h) due to high cell fitness. Our study suggests that the maximal production of a recombinant protein is highly dependent on methanol consumption rate that is affected by the availability of methanol and oxygen molecules. 23910689 A simulation model of building intervention impacts on indoor environmental quality, pediatric asthma, and costs. Although indoor environmental conditions can affect pediatric asthmatic patients, few studies have characterized the effect of building interventions on asthma-related outcomes. Simulation models can evaluate such complex systems but have not been applied in this context. We sought to evaluate the impact of building interventions on indoor environmental quality and pediatric asthma health care use, and to conduct cost comparisons between intervention and health care costs and energy savings. We applied our previously developed discrete event simulation model (DEM) to simulate the effect of environmental factors, medication compliance, seasonality, and medical history on (1) pollutant concentrations indoors and (2) asthma outcomes in low-income multifamily housing. We estimated health care use and costs at baseline and subsequent to interventions, and then compared health care costs with energy savings and intervention costs. Interventions, such as integrated pest management and repairing kitchen exhaust fans, led to 7% to 12% reductions in serious asthma events with 1- to 3-year payback periods. Weatherization efforts targeted solely toward tightening a building envelope led to 20% more serious asthma events, but bundling with repairing kitchen exhaust fans and eliminating indoor sources (eg, gas stoves or smokers) mitigated this effect. Our pediatric asthma model provides a tool to prioritize individual and bundled building interventions based on their effects on health and costs, highlighting the tradeoffs between weatherization, indoor air quality, and health. Our work bridges the gap between clinical and environmental health sciences by increasing physicians' understanding of the effect that home environmental changes can have on their patients' asthma. 23828394 Predictors of satisfaction with treatment decision, decision-making preferences, and main treatment goals in patients with advanced cancer. This study investigated satisfaction with treatment decision (SWTD), decision-making preferences (DMP), and main treatment goals, as well as evaluated factors that predict SWTD, in patients receiving palliative cancer treatment at a Swiss oncology network. Patients receiving a new line of palliative treatment completed a questionnaire 4-6 weeks after the treatment decision. Patient questionnaires were used to collect data on sociodemographics, SWTD (primary outcome measure), main treatment goal, DMP, health locus of control (HLoC), and several quality of life (QoL) domains. Predictors of SWTD (6 = worst; 30 = best) were evaluated by uni- and multivariate regression models. Of 480 participating patients in eight hospitals and two private practices, 445 completed all questions regarding the primary outcome measure. Forty-five percent of patients preferred shared, while 44 % preferred doctor-directed, decision-making. Median duration of consultation was 30 (range: 10-200) minutes. Overall, 73 % of patients reported high SWTD (≥24 points). In the univariate analyses, global and physical QoL, performance status, treatment goal, HLoC, prognosis, and duration of consultation were significant predictors of SWTD. In the multivariate analysis, the only significant predictor of SWTD was duration of consultation (p = 0.01). Most patients indicated hope for improvement (46 %), followed by hope for longer life (26 %) and better quality of life (23 %), as their main treatment goal. Our results indicate that high SWTD can be achieved in most patients with a 30-min consultation. Determining the patient's main treatment goal and DMP adds important information that should be considered before discussing a new line of palliative treatment. 23375352 Intrauterine infusion of lidocaine does not reduce pain scores during IUD insertion. Potential pain with IUD insertion is a concern for women. Studies have found that systemic and local cervical therapies do not reduce pain scores. Since intrauterine infusion of lidocaine may reduce pain with endometrial aspiration, in this pilot study, we tested whether such infusion through an inexpensive endometrial aspirator could reduce IUD insertion pain scores with IUD insertion. In this randomized, double-blinded, placebo control pilot study of 40 women undergoing IUD insertion, pain scores of women receiving 1.2 mL 2% lidocaine versus normal saline (1:1) infused 3 min prior to IUD insertion were measured using a 0-9-point scale. Pain at tenaculum placement was similar between groups. There was no difference in mean pain scores during IUD insertion of women infused with lidocaine (2.95) versus normal saline (3.75), p=.37. Considerable variation in pain scores was noted; 46% of subjects had pain scores ≤2 while 33% had pain scores ≥5. Use of 2% lidocaine administered through an endometrial aspirator did not significantly reduce IUD insertion pain scores in this pilot study. 23846781 Imaging Response and Residual Metastatic Axillary Lymph Node Disease after Neoadjuvant Chemotherapy for Primary Breast Cancer. Although surgical management of the breast after neoadjuvant chemotherapy (NAC) may be governed by treatment response, axillary management continues to be determined by stage at presentation. Axillary ultrasound (AUS) with fine-needle aspiration (FNA) is used to detect lymph node (LN) metastases for pre-NAC staging, but imaging assessment of treatment response in the axilla remains undefined. We evaluated post-NAC axillary imaging and surgical pathology to understand how imaging might direct axillary surgery. We evaluated pre- and post-NAC axillary imaging and clinicopathologic data in 272 patients who received NAC for primary breast cancer and underwent operation at our institution from 2010 to 2012. Treatment response on imaging was categorized as complete (CR), partial (PR), and none/progression (NR). Pre-NAC axillary staging classified patients as AUS negative/no FNA (n = 61), FNA/LN negative (n = 42), and FNA/LN positive (n = 169). Post-NAC axillary imaging included AUS (n = 146), MRI (n = 139), and PET-CT (n = 38). At operation, 128 of 272 patients (47 %) were LN positive: 23.3 % (24 of 103) of cN0 and 61.5 % (104 of 169) of cN1-AUS/FNA-positive patients at presentation. Of the 65 cN1-ypN0 patients, 58.1 % (25 of 43) had an imaging CR by US, 58.6 % (17 of 29) by MRI, and 84.6 % (11 of 13) by PET-CT. The sensitivity of post-NAC axillary imaging in detecting persistent LN metastases for cN1-AUS/FNA-positive patients was 69.8 % for US, 61.0 % for MRI, and 63.2 % for PET-CT. Performance characteristics of AUS, MRI, and PET-CT, while informative, were inadequate to preclude surgical axillary staging of in breast cancer patients after NAC. Whether this information might be used to tailor surgical and postsurgical treatment requires further investigation. 23893640 Electron impact, electron capture negative ionization and positive chemical ionization mass spectra of organophosphorus flame retardants and plasticizers. Phosphate esters are important commercial products that have been used both as flame retardants and as plasticizers. To analyze these compounds by gas chromatographic mass spectrometry, it is important to understand the mass spectra of these compounds using various ionization modes. This paper is a systematic overview of the electron impact (EI), electron capture negative ionization (ECNI) and positive chemical ionization (PCI) mass spectra of 13 organophosphate esters. These data are useful for developing and optimizing analytical measurements. The EI spectra of these 13 compounds are dominated by ions such as H4 PO4 (+) , (M - Cl)(+) , (M - CH2 Cl)(+) or (M)(+) depending on specific chemical structures. The ECNI spectra are generally dominated by (M - R)(-) . The PCI spectra are mainly dominated by the protonated molecular ion (M + H)(+) . The branching of the alkyl substituents, the halogenation of the substituents and, for aromatic phosphate esters, ortho alkylation of the ring are all significant factors controlling the details of the fragmentation processes. EI provides the best sensitivity for the quantitative measurement of these compounds, but PCI and ECNI both have considerable qualitative selectivity. Copyright © 2013 John Wiley & Sons, Ltd. 23812910 Can the diagnosis of NF1 be excluded clinically? A lack of pigmentary findings in families with spinal neurofibromatosis demonstrates a limitation of clinical diagnosis. Consensus clinical diagnostic criteria for neurofibromatosis type I (NF1) include café-au-lait macules and skinfold freckling. The former are frequently the earliest manifestation of NF1, and as such are of particular significance when assessing young children at risk of the condition. A phenotype of predominantly spinal neurofibromatosis has been identified in a small minority of families with NF1, often in association with a relative or absolute lack of cutaneous manifestations. An association with splicing and missense mutations has previously been reported for spinal neurofibromatosis, but on the basis of molecular results in only a few families. Patients with spinal NF1 were identified through the Manchester nationally commissioned service for complex NF1. Five families with spinal NF1 were identified, with a broad spectrum of NF1 mutations, providing further evidence that this phenotype may arise in association with any genre of mutation in this gene. Pigmentary manifestations were absent or very mild in affected individuals. Several further affected individuals, some with extensive spinal root tumours, were ascertained when additional family members were assessed. Clinical NF1 consensus criteria cannot be used to exclude the diagnosis of spinal NF1, especially in childhood. This emphasises the importance of molecular confirmation in individuals and families with atypical presentations of NF1. 23790990 A participatory physical activity intervention in preschools: a cluster randomized controlled trial. Previous studies on physical activity interventions in preschools have reported limited effectiveness. Participatory community-based approaches hold promise for increasing intervention effectiveness and involving parents as key stakeholders in a sustainable way. To assess whether a participatory parent-focused approach using parents as agents of behavioral change enhances the efficacy of a preschool physical activity (PA) intervention. Two-armed, cluster-RCT with preschool as unit of randomization and children as unit of analysis. 39 South German preschools applying for an existing state-sponsored PA program with 826 children (52% boys, aged 5.0±0.2 years), with 441 allocated to the intervention arm. Control preschools received a state-sponsored program consisting of twice-weekly gym classes over 6 months. In intervention preschools, this program was augmented by motivating parents to develop and implement their own project ideas for promoting children's PA. Primary outcomes included mean accelerometry counts and time spent in moderate- to vigorous-intensity PA or sedentary behavior. Secondary outcomes were BMI, percentage body fat, quality of life, sleep quality, and general health. Outcomes were measured at baseline and at 6 and 12 months in both study arms (time period: 2008-2010). Using an intention-to-treat-analysis, linear multilevel regression models assessed change over time and across study arms, adjusted for age, gender, season, and preschool location. Analysis was conducted in 2011. In 15 intervention preschools, parents implemented 25 PA projects. Compared with controls, intervention arm children were 11 minutes less sedentary per day (95% CI=5.39, 17.01, p=0.014); had significantly more mean accelerometry counts (1.4 counts/15 seconds [95% CI=0.22, 2.54], p=0.019); and showed benefits in perceived general health and quality of life. All other outcomes showed no difference between study arms. A participatory preschool intervention focusing on parents as agents of behavioral change may be able to promote PA and reduce sedentary behavior in preschoolers. These benefits may go beyond the effects of existing nonparticipatory interventions. This study is registered at clinicaltrials.gov NCT00987532. 23911711 DNA Prime and Virus-like Particle Boost from a Single H5N1 Strain Elicits Broadly Neutralizing Antibody Responses against Head Region of H5 Hemagglutinin. Since 1996 highly pathogenic avian influenza (HPAI) H5N1 virus has presented a persistent threat to public health. Its high degree of genetic diversity also poses enormous challenges in developing effective vaccines. To search for vaccine regimens that could elicit broadly neutralizing antibody responses against diverse HPAI H5N1 strains, in the present study we tested H5 hemagglutinin (HA) from an A/Thailand/1(KAN)-1/2004 strain in a heterologous prime-boost vaccination. We demonstrated that priming mice with DNA and boosting with VLP induced antibody responses that cross-neutralize all reported clades and subclades of HPAI H5N1 viruses and protect mice from high lethal dose HPAI H5N1 challenge in both active and passive immunizations. Unexpectedly, cross-divergent H5 neutralizing antibodies are directed to the HA head and block both attachment and post-attachment of virus entry. Thus, we conclude that as a promising pan-H5 vaccine candidate this prime-boost regimen could be further developed in ferrets and in humans. 23631939 Kinetic control of contaminant release from NAPLs--experimental evidence. Mass transfer processes of pollutants from non-aqueous phase liquids (NAPL) may control groundwater pollution at abandoned industrial sites. We studied release kinetics of polycyclic aromatic hydrocarbons (PAHs) from fresh and aged tar phases using a dialysis tubing technique. Time for equilibration ranged from several days to more than three years. For fresh tar materials the release seems to be limited by retarded pore diffusion, while for two of three aged tars diffusion limited release influenced by dissolved organic matter (DOM) was assumed. The equilibration process was driven by solubilization thermodynamics expressed by Raoult's law. Yet, solubility enhancement was observed potentially due to the presence of organic mobile sorbents. The results show that the release of PAHs from tar phases is generally rate limited and partitioning according to Raoult's law is the driving mechanism of the exchanges process. 23492193 Size-dependent uptake of particles by pulmonary antigen-presenting cell populations and trafficking to regional lymph nodes. The respiratory tract is an attractive target organ for novel diagnostic and therapeutic applications with nano-sized carriers, but their immune effects and interactions with key resident antigen-presenting cells (APCs) such as dendritic cells (DCs) and alveolar macrophages (AMs) in different anatomical compartments remain poorly understood. Polystyrene particles ranging from 20 nm to 1,000 nm were instilled intranasally in BALB/c mice, and their interactions with APC populations in airways, lung parenchyma, and lung-draining lymph nodes (LDLNs) were examined after 2 and 24 hours by flow cytometry and confocal microscopy. In the main conducting airways and lung parenchyma, DC subpopulations preferentially captured 20-nm particles, compared with 1,000-nm particles that were transported to the LDLNs by migratory CD11blow DCs and that were observed in close proximity to CD3⁺ T cells. Generally, the uptake of particles increased the expression of CD40 and CD86 in all DC populations, independent of particle size, whereas 20-nm particles induced enhanced antigen presentation to CD4⁺ T cells in LDLNs in vivo. Despite measurable uptake by DCs, the majority of particles were taken up by AMs, irrespective of size. Confocal microscopy and FACS analysis showed few particles in the main conducting airways, but a homogeneous distribution of all particle sizes was evident in the lung parenchyma, mostly confined to AMs. Particulate size as a key parameter determining uptake and trafficking therefore determines the fate of inhaled particulates, and this may have important consequences in the development of novel carriers for pulmonary diagnostic or therapeutic applications. 23631389 Site-specific and Far-Red Light-Activatable Prodrug of Combretastain A-4 Using Photo-Unclick Chemistry. Although tissue-penetrable light (red and NIR) has a great potential for spatiotemporally controlled release of therapeutic agents, it has been hampered because of the lack of chemistry translating the photonic energy to a cleavage of a chemical bond. Recently, we discovered that an aminoacrylate group could be cleaved to release parent drugs after oxidation by SO, and have called this "photo-unclick chemistry". We demonstrate its application to far-red light-activated prodrugs. A prodrug of combretastatin A-4 (CA4) was prepared, CMP-L-CA4: CMP (dithiaporphyrin, a photosensitizer) and L (aminoacrylate linker). Upon irradiation with 690 nm diode laser, the aminoacrylate linker of the prodrug was cleaved rapidly releasing CA4 (> 80% in 10 min) in CDCl3. In the tissue culture, it showed about a 6-fold increase in its IC50 in MCF-7 after the irradiation, most likely, because of the released CA4. Most significantly, CMP-L-CA4 had better antitumor efficacy in vivo than its non-cleavable (NC) analog, CMP-NCL-CA4. This is the first demonstration of the in vivo efficacy of the novel low-energy light-activatable prodrug using the photo-unclick chemistry. 23966916 Explorations of object and location memory using fMRI. Content-specific sub-systems of visual working memory (VWM) have been explored in many neuroimaging studies with inconsistent findings and procedures across experiments. The present study employed functional magnetic resonance imaging (fMRI) and a change detection task using a high number of trials and matched stimulus displays across object and location change (what vs. where) conditions. Furthermore, individual task periods were studied independently across conditions to identify differences corresponding to each task period. Importantly, this combination of task controls has not previously been described in the fMRI literature. Composite results revealed differential frontoparietal activation during each task period. A separation of object and location conditions yielded a distributed system of dorsal and ventral streams during the encoding of information corresponding to bilateral inferior parietal lobule (IPL) and lingual gyrus activation, respectively. Differential activity was also shown during the maintenance of information in middle frontal structures bilaterally for objects and the right IPL and left insula for locations. Together, these results reflect a domain-specific dissociation spanning several cortices and task periods. Furthermore, differential activations suggest a general caudal-rostral separation corresponding to object and location memory, respectively. 23962262 Does isotretinoin therapy of acne cure or cause depression? Cosmetic defects in acne may provoke a wide range of mental disorders (depressive, social-phobic, etc.). Isotretinoin is a very effective acne treatment; hence, it usually resolves the associated mental disorders. However, more available data show the possible association of taking isotretinoin and the onset of a depressive syndrome that includes frank depression and even suicidal ideation. The frequency of depressive disorders during isotretinoin treatment varies from 1% to 11% in different studies, and it is unclear whether this is a consequence of isotretinoin therapy. Since it crosses the blood-brain barrier, isotretinoin affects the expression of a broad spectrum of genes in the limbic structures, thus affecting the function of the dopaminergic, serotonergic, and noradrenergic neurons involved in the regulation of mood and emotion. It was suggested that isotretinoin in high concentrations inhibits hippocampal neurogenesis and induces apoptosis of hippocampal cells. However, some studies do not confirm this pathogenic role, and isotretinoin was even reported to have a therapeutic effect in acne-associated depression. In this review, we highlight epidemiological data, the underlying molecular pathogenesis, and the aspects of prevention concerning retinoid-induced depression in acne from the practical point of view of a dermatologist. 23644145 Indoor allergen assessment quantified by a thin-layer electrochemical cell and magnetic beads. We report the electrochemical determination of mite allergen in real house dust by using a thin layer electrochemical flow cell and magnetic beads. Der p1, which is an allergen from Dermatophagoides pteronyssinus, was immunochemically sandwiched between two dispersed monoclonal antibodies; one was modified on the surface of magnetic beads and the other was modified with alkaline phosphatase. After washing the beads, a small volume of p-aminophenol phosphate (p-APP) was added to produce p-aminophenol (p-AP). And then the p-AP concentration was measured electrochemically with a homemade electrochemical cell. The Der p1 assay was completed within 30 min and a low detection limit of 0.3 ng/mL was achieved. This is because the diffusion distance of Der p1 and the detection antibody was reduced to 22.3 μm by using dispersed magnetic beads. Only 10 min was required to complete the entire immunoreaction, and 54% of the Der p1 was confirmed to have immunoreacted in only 1 min of mixing. Furthermore, the p-APP volume could be reduced using the thin-layer electrochemical flow cell. This is advantageous in terms of concentrating p-AP, and provides a high signal-to-noise ratio measurement in a short time. We achieved a high correlation (r=0.967, p<0.001) between our assay and a conventional enzyme-linked immunosorbent assay (ELISA) for real house dust measurements. 23834527 Asymmetric Allylation/Ring Closing Metathesis: One-Pot Synthesis of Benzo-fused Cyclic Homoallylic Amines. Application to the Formal Synthesis of Sertraline Derivatives. A one-pot asymmetric allylation/ring closing metathesis (RCM) sequence for the synthesis of cyclic homoallylic amines has been developed. A library of six- and seven-membered benzo-fused products has been synthesized in good yields and complete diastereoselectivity. The new methodology has been applied to the formal syntheses of the antidepressant Sertraline and the epimeric Norsertraline. The methodology is amenable for the synthesis of analogs. 23760502 An Out-of-frame Overlapping Reading Frame in the Ataxin-1 Coding Sequence Encodes a Novel Ataxin-1 Interacting Protein. Spinocerebellar ataxia type 1 is an autosomal dominant cerebellar ataxia associated with the expansion of a polyglutamine tract within the ataxin-1 (ATXN1) protein. Recent studies suggest that understanding the normal function of ATXN1 in cellular processes is essential to decipher the pathogenesis mechanisms in spinocerebellar ataxia type 1. We found an alternative translation initiation ATG codon in the +3 reading frame of human ATXN1 starting 30 nucleotides downstream of the initiation codon for ATXN1 and ending at nucleotide 587. This novel overlapping open reading frame (ORF) encodes a 21-kDa polypeptide termed Alt-ATXN1 (Alternative ATXN1) with a completely different amino acid sequence from ATXN1. We introduced a hemagglutinin tag in-frame with Alt-ATXN1 in ATXN1 cDNA and showed in cell culture the co-expression of both ATXN1 and Alt-ATXN1. Remarkably, Alt-ATXN1 colocalized and interacted with ATXN1 in nuclear inclusions. In contrast, in the absence of ATXN1 expression, Alt-ATXN1 displays a homogenous nucleoplasmic distribution. Alt-ATXN1 interacts with poly(A)(+) RNA, and its nuclear localization is dependent on RNA transcription. Polyclonal antibodies raised against Alt-ATXN1 confirmed the expression of Alt-ATXN1 in human cerebellum expressing ATXN1. These results demonstrate that human ATXN1 gene is a dual coding sequence and that ATXN1 interacts with and controls the subcellular distribution of Alt-ATXN1. 23887013 A Novel Enrichment Program Using Cascading Mentorship to Increase Diversity in the Health Care Professions. The authors describe an innovative summer enrichment program based on a cascading mentorship model to transfer knowledge and skills from faculty to medical students to undergraduate students and finally to high school students. The program was designed to give high school students a glimpse of life in medical school and enhance the teaching and leadership skills of underrepresented undergraduate and medical students. Started in 2010 with 30 high school students and 9 college and medical student coaches, the University of California, Irvine, School of Medicine Summer Premed Program expanded rapidly over the next two summers and enrolled a total of 253 high school students, 48 college students, and 12 medical students. The college and medical student coaches, the majority of whom were underrepresented in medicine (URIM), reported that the program enhanced their teaching and leadership skills and self-confidence, motivated them toward careers in academic medicine, and raised their awareness about the importance of cultural diversity. The authors present the details of this interactive, structured program and describe how URIM student empowerment, near-peer teaching, science socialization, and support from the institution's leadership and faculty members provided a climate that fostered belonging, a sense of personal transformation, and professional development among students from different levels of education and diverse backgrounds. Long-term follow-up of the participants' career choices is needed. 23600364 Concentration and Strain Fields inside a Ag/Au Core-Shell Nanowire Studied by Coherent X-ray Diffraction. Three-dimensional coherent diffraction patterns of an isolated, single-crystalline Ag/Au core-shell nanowire were recorded at different X-ray beam energies close to the Au LIII absorption edge. Two-dimensional slices of the three-dimensional diffraction pattern, with the diffraction vector oriented perpendicular to the wire axis, were investigated in detail. In reciprocal space, facet streaks with thickness fringes were clearly observed in the two-dimensional diffraction patterns, from which the shape and size of the corresponding cross sections of the nanowire could be revealed. Comparison with simulated diffraction patterns exhibited the coherency strain field in the nanowire. During in situ annealing at temperatures which would lead to significant intermixing by volume diffusion in bulk material, according to literature data, a core-shell morphology was preserved; that is, intermixing in the nanowire was pronouncedly decelerated compared to bulk diffusion. 23350725 Genome wide association studies for diabetes: perspective on results and challenges. Recent results of genome wide association study (GWAS) for diabetes genes, while reaching impressive technical milestones and implicating new findings for research, have been uniformly disappointing in terms of immediate clinical utility. The relative risk associated with any of the newly reported genetic loci, or even considering all of them together, is far less than simply that which can be obtained by taking a history and a physical exam. For type 2 diabetes (T2D), GWAS have implicated novel pathways, supported previously known associations, and highlighted the importance of the beta cell and insulin secretion. Monogenic forms of diabetes, on the other hand, continue to yield interesting insights into genes controlling human beta cell function but most cases of monogenic diabetes are simply not diagnosed. Here, we briefly review recent results related to type 1, type 2 and maturity onset diabetes of youth (MODY) diabetes and suggest that future studies emphasizing quantitative traits are likely to yield even more insights. 23906095 Role of tip chemical reactivity on atom manipulation process in dynamic force microscopy. The effect of tip chemical reactivity on the lateral manipulation of intrinsic Si adatoms toward a vacancy site on a Si(111)-(7×7) surface has been investigated by noncontact atomic force microscopy at room temperature. Here we measure the atom-hopping probabilities associated with different manipulation processes as a function of the tip-surface distance by means of constant height scans with chemically different types of tips. The interactions between different tips and Si atoms are evaluated by force spectroscopic measurements. Our results demonstrate that the ability to manipulate Si adatoms depends extremely on the chemical nature of the tip apex and is correlated with the maximal attractive force measured over Si adatoms. We rationalize the observed dependence of the atom manipulation process on tip-apex chemical reactivity by means of density functional theory calculations. The results of these calculations suggest that the ability to reduce the energy barrier associated with the Si adatom movement depends profoundly on tip chemical reactivity and that the level of energy barrier reduction is higher with tips that exhibit high chemical reactivity with Si adatoms. The results of this study provide a better way to control the efficiency of the atomic manipulation process for chemisorption systems. 23902828 Synthesis of polysubstituted benzofuran derivatives as novel inhibitors of parasitic growth. A series of polysubstituted benzofuran derivatives was easily and rapidly prepared using a tandem Sonogashira coupling/cyclization reaction. Subsequent acylation afforded a small library of 39 new compounds that were assayed in cellulo on Plasmodium falciparum and Trypanosoma brucei parasites. Some of them exhibited good inhibitory activity on T. brucei proliferation. 23908065 Influence of Age on Thrombolysis Outcome in Wake-Up Stroke. Thrombolysis in patients >80 years remains controversial; we hypothesized that >80-year-old patients with wake-up ischemic stroke (WUIS) will benefit from thrombolysis despite risks because of poor outcomes with no treatment. The study included 68 thrombolysed patients with WUIS (33 [48%] >80 years), 54 nonthrombolysed patients with WUIS (21 [39%] >80 years), and 117 patients (>80 years old) thrombolysed within 4.5 hours of symptom onset (reference group). Mortality and modified Rankin Scale (mRS) were assessed at 90 days. Baseline characteristics of thrombolysed and nonthrombolysed >80 and ≤80-year-old patients with WUIS were comparable. Thrombolysis outcomes in >80-year-old patients with WUIS were better than in nonthrombolysed >80-year-old patients with WUIS (90-day mortality: 24% versus 47%, P=0.034; mRS 0-2: 30% versus 5%, P=0.023; mRS 0-1: 15% versus 5%, P=0.24) and comparable with thrombolysed ≤80-year-old patients with WUIS. Thrombolysis was associated with odds ratio 0.27 (95% confidence interval, 0.05-0.97) for mortality and odds ratio 28.6 (95% confidence interval, 1.8-448) for mRS 0 to 2 at 90 days in >80-year-old patients with WUIS after adjusting for stroke severity and risk factors. Thrombolysis may be associated with greater benefit in >80-year-old patients with WUIS but a selection bias favoring thrombolysis in those most likely to benefit may significantly reduce interpretability of these findings. 23948004 The Impact of Obesity on US Mortality Levels: The Importance of Age and Cohort Factors in Population Estimates. Objectives. To estimate the percentage of excess death for US Black and White men and women associated with high body mass, we examined the combined effects of age variation in the obesity-mortality relationship and cohort variation in age-specific obesity prevalence. Methods. We examined 19 National Health Interview Survey waves linked to individual National Death Index mortality records, 1986-2006, for age and cohort patterns in the population-level association between obesity and US adult mortality. Results. The estimated percentage of adult deaths between 1986 and 2006 associated with overweight and obesity was 5.0% and 15.6% for Black and White men, and 26.8% and 21.7% for Black and White women, respectively. We found a substantially stronger association than previous research between obesity and mortality risk at older ages, and an increasing percentage of mortality attributable to obesity across birth cohorts. Conclusions. Previous research has likely underestimated obesity's impact on US mortality. Methods attentive to cohort variation in obesity prevalence and age variation in obesity's effect on mortality risk suggest that obesity significantly shapes US mortality levels, placing it at the forefront of concern for public health action. (Am J Public Health. Published online ahead of print August 15, 2013: e1-e7. doi:10.2105/AJPH.2013.301379). 23822157 Dynamic defrosting on nanostructured superhydrophobic surfaces. Water suspended on chilled superhydrophobic surfaces exhibits delayed freezing; however, the interdrop growth of frost through subcooled condensate forming on the surface seems unavoidable in humid environments. It is therefore of great practical importance to determine whether facile defrosting is possible on superhydrophobic surfaces. Here, we report that nanostructured superhydrophobic surfaces promote the growth of frost in a suspended Cassie state, enabling its dynamic removal upon partial melting at low tilt angles (<15°). The dynamic removal of the melting frost occurred in two stages: spontaneous dewetting followed by gravitational mobilization. This dynamic defrosting phenomenon is driven by the low contact angle hysteresis of the defrosted meltwater relative to frost on microstructured superhydrophobic surfaces, which forms in the impaled Wenzel state. Dynamic defrosting on nanostructured superhydrophobic surfaces minimizes the time, heat, and gravitational energy required to remove frost from the surface, and is of interest for a variety of systems in cold and humid environments. 23902221 Time for reflection. The Department of Health (DH) announced in May that £650,000 will be spent to help 40 NHS trusts implement Schwartz Center Rounds, a scheme developed in the United States to improve compassion in health care. 23550150 Regulation of Mac-2BP secretion is mediated by its N-glycan binding to ERGIC-53. The leguminous-type (L-type) lectin ER-Golgi intermediate compartment (ERGIC)-53, a homo-oligomeric endoplasmic reticulum (ER)-Golgi recycling protein, functions as a transport receptor for newly synthesized glycoproteins in the early secretory pathway. Although a limited subset of cargo glycoproteins transported by ERGIC-53, such as the coagulation factors V and VIII, cathepsin C and Z and α1-antitrypsin, has been identified, the exact role of the N-glycan binding of ERGIC-53 in the transport of secretory glycoproteins for ER exit has yet to be clarified. By screening a cDNA library isolated from HepG2 cells via a green fluorescent protein fragment complementation assay, we assessed several candidate luminal ERGIC-53-interacting partners and identified Mac-2 binding protein (Mac-2BP) as a novel ERGIC-53-transported cargo glycoprotein. Using an N-glycan-binding-deficient mutant of ERGIC-53 (N156A) or treatment with N-glycosylation processing inhibitors, as well as the introduction of the ER-mis-targeting mutant (KKAA), we demonstrated that the high-mannose-type N-glycan binding of ERGIC-53 contributes to its interaction with Mac-2BP, which is essential for the ERGIC-53-mediated ER-Golgi transport of nascent proteins during early secretion. Furthermore, we also provide evidence that MCFD2 is involved in the secretion of Mac-2BP. These observations reveal a distinct role for the N-glycan binding of ERGIC-53 in the receptor-mediated ER exit of newly synthesized Mac-2BP in the early secretion pathway. 23921834 Bone mineral density in patients with destructive arthrosis of the hip joint. Recent reports have shown the existence of subchondral insufficiency fracture in rapidly destructive arthrosis of the hip joint (RDA), and the findings suggest that osteopenia is related to the pathogenesis of the rapid progression of this disease. Therefore, we measured bone mineral density (BMD) in RDA patients. We measured BMD of the lumbar spine, radius, and calcaneus using dual-energy X-ray absorptiometry in 19 patients with RDA and 75 with osteoarthritis of the hip (OA) and compared BMD at different skeletal sites between RDA and OA patients. No significant differences were observed in BMD of the lumbar spine, ultradistal radius, mid-radius, and calcaneous between the RDA and OA groups. Our data suggest that RDA is not accompanied by generalized osteoporosis. Factors other than generalized bone status, for example, BMD around the affected hip joint before destruction, need to be analyzed to elucidate the pathophysiological mechanism of RDA. 23820313 Disappearance of breach rhythm heralding recurrent tumor progression in a patient with astrocytoma. The breach rhythm is sometimes considered the consequence of reduced resistance between the cortex and the scalp electrode in the region of a skull defect. On the other hand, the electroencephalographic (EEG) changes after craniotomy were attributed to an activation of EEG activity by meningocortical adhesions with admixed gliosis. We report changes of the breach rhythm in a patient with astrocytoma, which give further evidence that the breach rhythm is not merely the result of physical changes in the area of a skull defect. In our patient, the breach rhythm was no longer detectable before a new tumor progression took place, showed up again, and at the end changed into localized slowing before the deterioration of the patient's general medical condition. This case suggests that in patients with brain tumors, the loss or attenuation in frequency of an established breach rhythm might be considered as an indication of a new tumor progression. 23919916 Symmetry-amplified j splittings for quadrupolar spin pairs: a solid-state NMR probe of homoatomic covalent bonds. Chemically informative J couplings between pairs of quadrupolar nuclei in dimetallic and dimetalloid coordination motifs are measured using J-resolved solid-state NMR experiments. It is shown that the application of a double-quantum filter is necessary to observe the J splittings and that, under these conditions, only a simple doublet is expected. Interestingly, the splitting is amplified if the spins are magnetically equivalent, making it possible to measure highly precise J couplings and unambiguously probe the symmetry of the molecule. This is demonstrated experimentally by chemically breaking the symmetry about a pair of boron spins by reaction with an N-heterocyclic carbene to form a β-borylation reagent. The results show that the J coupling is a sensitive probe of bonding in diboron compounds and that the J values quantify the weakening of the B-B bond which occurs when forming an sp(2)-sp(3) diboron compound, which is relevant to their reactivity. Due to the prevalence of quadrupolar nuclei among transition metals, this work also provides a new approach to probe metal-metal bonding; results for Mn2(CO)10 are provided as an example. 23906655 Outcome of 6 fractions of 5.3Gray HDR brachytherapy in combination with external beam radiotherapy for treatment of cervical cancer. To review the characteristics, outcomes and toxicities of cervical cancer patients treated with 6 fractions of brachytherapy after external beam radiotherapy (EBRT). All patients diagnosed with cervical cancer from 2000 to 2009 who were referred for radical treatment and who received 6 fractions of brachytherapy were retrospectively reviewed. Overall survival (OS), disease free survival (DFS), local control (LC), distant control (DC) rate, acute and late toxicities were the primary endpoints. Thirty-two patients with mainly advanced stage squamous cell carcinoma were identified and reviewed. Patients received EBRT of 45 to 50.4Gy in 1.8Gy daily fractions followed by 6 sessions of 3 channel brachytherapy of 5.3Gy prescribed to point H. Response rates to treatment were good, with no residual disease in 84% six weeks after the completion of treatment. With a median follow up time of 8.1years, the five-year OS, DFS, LC and distant control rates were 75%, 68.5%, 92.8% and 76.9% respectively. None of the patients developed any G3-4 acute toxicity but one patient who had advanced disease developed G3-4 proctitis with a fistula formation. HDR brachytherapy utilizing 6 fractions of 5.3Gy prescribed to point H with concurrent chemo-radiation is superior in terms of OS and LC to regimens that deliver a lower EQD2 dose to point A/H and is associated with very low rates of toxicities. 23686006 Transcriptional regulation of glutathione biosynthesis genes, γ-glutamyl-cysteine ligase and glutathione synthetase in response to cadmium and nonylphenol in Chironomus riparius. We characterized Chironomus riparius glutathione (GSH) biosynthesis genes, γ-glutamyl-cysteine ligase catalytic subunit (cr-gcl) and glutathione synthetase (cr-gs) and studied their expression after cadmium (Cd) and nonylphenol (NP) exposure. The full length cDNA of the Cr-GCL catalytic subunit was 2185 base pair (bp) in length containing an open reading frame of 1905bp, a 13bp 5' and 267bp 3' untranslated regions. The theoretical molecular mass of the deduced amino acid sequence (633) was 72.65kDa with an estimated pI of 5.42. The partial cDNA of Cr-GS was 739bp in length consisting 221 amino acids. The deduced amino acid sequence of Cr-GCL and Cr-GS cDNAs showed high conservation with homologs from other species. In phylogenetic analysis Cr-GCL and Cr-GS were grouped with equivalent genes from insects belonging to the dipteran order. The expression of cr-gcl and cr-gs was measured using quantitative real-time PCR after exposure to sub lethal concentrations of Cd (2, 10 and 20mg/L) and NP (10, 50 and 100μg/L) for 12, 24, 48 and 72h using real-time PCR methods. The mRNA expression of Cr-GCL and Cr-GS was significantly modulated after exposure to different concentrations of Cd and NP for different time periods. Total GSH levels showed a non-significant decrease after exposure to Cd for 24h. However, no change in GSH levels was observed after exposure to NP for 24h. These results suggest that Cr-GS and Cr-GCL expression is modulated by Cd and NP stress and may play an important role in detoxification of xenobiotics and antioxidant defense. We conclude that Cr-GS and Cr-GCL could be used as biomarkers of Cd and NP stress in aquatic environment for the studied species. 23262514 IFN-γ Release Assays in the Diagnosis of Latent Tuberculosis Infection among Immunocompromised Adults. Immunocompromised persons with latent tuberculosis infection (LTBI) are at increased risk for tuberculosis reactivation compared with the general population. The tuberculin skin test, the traditional assay for diagnosing LTBI, has reduced accuracy in immunocompromised patients. IFN-γ release assays (IGRAs) are in vitro blood tests that measure T-cell release of IFN-γ after stimulation with antigens unique to Mycobacterium tuberculosis. Here we review the data for the use of QuantiFERON-TB Gold In-Tube and T-SPOT.TB, the two currently available IGRAs, in immunocompromised adults, including persons infected with HIV, patients with immune-mediated inflammatory disorders, candidates for treatment with tumor necrosis factor-α inhibitors, patients receiving hemodialysis, solid-organ transplant recipients, and patients with cancer. On the basis of the available data, IGRAs have advantages over the tuberculin skin test in specific patient populations and in certain situations. Further studies are needed to more accurately define the usefulness of IGRAs in immunocompromised patients. 23948675 Nonlinear simultaneous reconstruction of inhomogeneous compressibility and mass density distributions in unidirectional pulse-echo ultrasound imaging. In diagnostic ultrasound imaging, the image reconstruction quality is crucial for reliable diagnosis. Applying reconstruction algorithms based on the acoustic wave equation, the obtained image quality depends significantly on the physical material parameters accounted for in the equation. In this contribution, we extend a proposed iterative nonlinear one-parameter compressibility reconstruction algorithm by the additional reconstruction of the object's inhomogeneous mass density distribution. The improved iterative algorithm is able to reconstruct inhomogeneous maps of the object's compressibility and mass density simultaneously using only one conventional linear transducer array at a fixed location for wave transmission and detection. The derived approach is based on an acoustic wave equation including spatial compressibility and mass density variations, and utilizes the Kaczmarz method for iterative material parameter reconstruction. We validate our algorithm numerically for an unidirectional pulse-echo breast imaging application, and thus generate simulated measurements acquired from a numerical breast phantom with realistic compressibility and mass density values. Applying these measurements, we demonstrate with two reconstruction experiments the necessity to calculate the mass density in case of tissues with significant mass density inhomogeneities. When reconstructing spatial mass density variations, artefacts in the breast's compressibility image are reduced resulting in improved spatial resolution. Furthermore, the compressibility relative error magnitude within a diagnostically significant region of interest (ROI) decreases from 3.04% to 2.62%. Moreover, a second image showing the breast's inhomogeneous mass density distribution is given to provide additional diagnostic information. In the compressibility image, a spatial resolution moderately higher than the classical half-wavelength limit is observed. 23970542 Immune mechanisms in polymyositis and dermatomyositis and potential targets for therapy. PM and DM are characterized clinically by weakness and low endurance of skeletal muscle. Other organs are frequently involved, suggesting that idiopathic inflammatory myopathies (IIMs) are systemic inflammatory diseases. Involvement of immune mechanisms in IIMs is supported by the presence of T cells, macrophages and dendritic cells in muscle tissue, by the presence of autoantibodies and by HLA-DR being a strong genetic risk factor. T cells may have direct and indirect toxic effects on muscle fibres, causing muscle fibre necrosis and muscle weakness, but the target of the immune reaction is not known. A newly identified T cell subset, CD28(null) T cells, may have cytotoxic effects in the CD4(+) and CD8(+) T cell phenotype. These cells are apoptosis resistant and may contribute to treatment resistance. Several myositis-specific autoantibodies have been identified, but they are all directed against ubiquitously expressed autoantigens and the specificity of the T cell reactivity is not known. These autoantibodies are associated with distinct clinical phenotypes and some with distinct molecular pathways; e.g. sera from patients with anti-Jo-1 autoantibodies may activate the type I IFN system and these sera also contain high levels of B cell activating factor compared with other IIM subsets. The characterization of patients into subgroups based on autoantibody profiles seems to be a promising way to learn more about the specificities of the immune reactions. Careful phenotyping of infiltrating immune cells in muscle tissue before and after specific therapies and relating the molecular findings to clinical outcome measures may be another way to improve knowledge on specific immune mechanism in IIMs. Such information will be important for the development of new therapies. 23910725 Accuracy of force and center of pressure measures of the Wii Balance Board. The Nintendo Wii Balance Board (WBB) is increasingly used as an inexpensive force plate for assessment of postural control; however, no documentation of force and COP accuracy and reliability is publicly available. Therefore, we performed a standard measurement uncertainty analysis on 3 lightly and 6 heavily used WBBs to provide future users with information about the repeatability and accuracy of the WBB force and COP measurements. Across WBBs, we found the total uncertainty of force measurements to be within ±9.1N, and of COP location within ±4.1mm. However, repeatability of a single measurement within a board was better (4.5N, 1.5mm), suggesting that the WBB is best used for relative measures using the same device, rather than absolute measurement across devices. Internally stored calibration values were comparable to those determined experimentally. Further, heavy wear did not significantly degrade performance. In combination with prior evaluation of WBB performance and published standards for measuring human balance, our study provides necessary information to evaluate the use of the WBB for analysis of human balance control. We suggest the WBB may be useful for low-resolution measurements, but should not be considered as a replacement for laboratory-grade force plates. 23951713 A role for indirect facilitation in maintaining diversity in a guild of African acacia ants. Determining how competing species coexist is essential to understanding patterns of biodiversity. Indirect facilitation, in which a competitively dominant species exerts a positive effect on one competitor by more strongly suppressing a third, shared competitor, is a potentially potent yet understudied mechanism for competitive coexistence. Here we provide evidence for indirect facilitation in a guild of four African Acacia ant species that compete for nesting space on the host plant Acacia drepanolobium, showing that a competitively dominant acacia ant species indirectly creates establishment opportunities for the most subordinate species that may help to maintain diversity. Using long-term observational data and field experiments, we demonstrate that the competitively dominant ant species outcompetes two competitively intermediate species, while tolerating colonies of the subordinate competitor; this creates opportunities for local colonization and establishment of colonies of the subordinate species within the dominant species' territories. Host plants occupied by this subordinate species are then more likely to be colonized by the intermediate species, which in turn are more likely to be displaced by the dominant species. This process has the potential to generate a cyclical succession of ant species on host trees, contributing to stable coexistence within this highly competitive community. 22763644 Genotoxicity evaluation for single-walled carbon nanotubes in a battery of in vitro and in vivo assays. The genotoxicity of single-walled carbon nanotubes (SWCNTs) was determined using a battery of genotoxicity assays, comprising a bacterial reverse mutation test, an in vitro mammalian chromosomal aberration test and a mammalian erythrocytes micronucleus test. SWCNTs had no mutagenicity in S. typhimurium TA98, TA100, TA1535 or TA1537, or in E. coli WP2uvrA, in the absence or presence of metabolic activation. SWCNTs did not increase the number of structural or numerical chromosomal aberrations after short-term or continuous exposure. In the micronucleus test using CD-1 mice, SWCNTs did not affect the proportion of immature erythrocytes, the total proportion of erythrocytes or the number of micronuclei in immature erythrocytes. SWCNTs appear not to pose a genotoxic risk. Copyright © 2012 John Wiley & Sons, Ltd. 23892908 Neural architecture design based on extreme learning machine. Selection of the optimal neural architecture to solve a pattern classification problem entails to choose the relevant input units, the number of hidden neurons and its corresponding interconnection weights. This problem has been widely studied in many research works but their solutions usually involve excessive computational cost in most of the problems and they do not provide a unique solution. This paper proposes a new technique to efficiently design the MultiLayer Perceptron (MLP) architecture for classification using the Extreme Learning Machine (ELM) algorithm. The proposed method provides a high generalization capability and a unique solution for the architecture design. Moreover, the selected final network only retains those input connections that are relevant for the classification task. Experimental results show these advantages. 23892730 Explaining Seemingly Paradoxical Consumer Experiences: Conjoining Weekly Road Rage and Church Attendance. The purposes of the current study are threefold: Provide evidence that an extreme paradoxical group exists-people frequently attending church and exhibiting road rage, profile this group, and frame possible explanations for the seemingly paradoxical behaviors. This study employs data from a national (USA) lifestyle survey conducted by Market Facts with 3,350 American respondents. The major questions asked about church participation and road-rage behavior ("giving a finger" and "flashing headlights"). Nomologically, relevant activities include 3 items for church goers and 3 items for road-rage givers. Additionally, 14 items profiled the lifestyles of the unique paradoxical behavior segment. Utilizing cross-tabulation tables, property space analyses identify the double extreme (XX) group (18 people) and other 6 groups with a significant chi-square test, confirming the extreme group exists. Analyses of variance test results show that comparing nomologically relevant activities among the seven groups is all statistically significant, indicating the nomological validity is met. Overall, the XX group tends to have more males, be younger, and have a higher proportion of people working in sales. The profile of lifestyle analyses shows the XX group members have both high ambitions and expectations, might be very frustrated individuals, and equip with the adventurous and masculine traits related to aggression. The XX behavior group's demographic and psychographic characteristics portray similar lifestyles that differ from other groups. Case-based analyses provide further contextual information of nuances to XX segment individuals. The limited energy theory, the Eagleman's theory of unconscious mind, and justification theory help to explain why people conjointly go to church and commit road rage. Addressing chronic paradoxical behaviors provides implications for social de-marketing to reduce aggressive anti-social behavior such as road rage. Frequent church attendance may help make people more sensitive to their wrongdoings and gradually revise the anti-social behavior. 23161470 Two-stage metal-catalyst-free growth of high-quality polycrystalline graphene films on silicon nitride substrates. By using two-stage, metal-catalyst-free chemical vapor deposition (CVD), it is demonstrated that high-quality polycrystalline graphene films can directly grow on silicon nitride substrates. The carrier mobility can reach about 1500 cm(2) V(-1) s(-1) , which is about three times the value of those grown on SiO(2) /Si substrates, and also is better than some examples of metal-catalyzed graphene, reflecting the good quality of the graphene lattice. 23831728 Inhibition of methyleugenol bioactivation by the herb-based constituent nevadensin and prediction of possible in vivo consequences using physiologically based kinetic modeling. Methyleugenol (ME) occurs naturally in a variety of spices, herbs, including basil, and their essential oils. ME induces hepatomas in rodent bioassays following its conversion to a DNA reactive metabolite. In the present study, the basil constituent nevadensin was shown to be able to inhibit SULT-mediated DNA adduct formation in HepG2 cells exposed to the proximate carcinogen 1'-hydroxymethyleugenol in the presence of nevadensin. To investigate possible in vivo implications of SULT inhibition by nevadensin on ME bioactivation, the rat physiologically based kinetic (PBK) model developed in our previous work to describe the dose-dependent bioactivation and detoxification of ME in male rat was combined with the recently developed PBK model describing the dose-dependent kinetics of nevadensin in male rat. The resulting binary ME-nevadensin PBK model was used to predict the possible nevadensin mediated reduction in ME DNA adduct formation and resulting carcinogenicity at the doses of ME used by the NTP carcinogenicity study. Using these data an updated risk assessment using the Margin of Exposure (MOE) approach was performed. The results obtained point at a potential reduction of the cancer risk when rodents are orally exposed to ME within a relevant food matrix containing SULT inhibitors compared to exposure to pure ME. 23844780 Hypertension in pregnancy after Escherichia coli O157:H7 gastroenteritis: a cohort study. Background. Escherichia coli O157:H7 is a common cause of bacterial gastroenteritis and may increase the risk of hypertension. We studied the risk of hypertension in pregnancy following a large E. coli O157:H7 outbreak that occurred in Walkerton, Canada, in the year 2000. Methods: We linked data collected from Walkerton residents to provincial healthcare databases. We studied the pregnancies of three groups of women: two groups from Walkerton (those with and without acute gastroenteritis during outbreak) and a third group from neighboring rural communities unaffected by the outbreak. The primary outcome was a composite of gestational hypertension or preeclampsia. Secondary outcomes were gestational hypertension and preeclampsia examined separately. Results: The median time to pregnancy after cohort entry was five years. The composite outcome was not significantly higher among women with gastroenteritis during the outbreak compared with residents of neighboring communities (8 of 117 (6.8%) versus 96 of 2166 (4.4%) pregnancies, respectively; adjusted relative risk 1.5 (95% confidence interval (CI) 0.8 to 3.2)). When examined separately the risk of preeclampsia was significantly higher among women with gastroenteritis (4 of 117 (3.4%) versus 17 of 2166 (0.8%) pregnancies; adjusted relative risk 3.8 (95% CI 1.3 to 11.6)). However, the risk of preeclampsia was lower than expected in the referent group and overall there were a small number of events in all the groups. Conclusion: There was no significant association between E. coli O157:H7 gastroenteritis and our primary assessment of hypertension in pregnancy. 23896263 Comprehensive high-resolution genomic profiling and cytogenetics of two pediatric and one adult medulloblastoma. Medulloblastoma (WHO grade IV) is a rare, malignant, invasive, embryonal tumor which mainly occurs in children and represents less than 1% of all adult brain tumors. Systematic comprehensive genetic analyses on medulloblastomas are rare but necessary to provide more detailed information. Therefore, we performed comprehensive cytogenetic analyses (blood and tissue) of two pediatric and one adult medulloblastoma, using trypsin-Giemsa staining, spectral karyotyping (tissues only), SNP-arrays, and gene expression analyses. We confirmed frequently detected chromosomal aberrations in medulloblastoma, such as +7q, -8p/q, -9q, -11q, -12q, and +17q and identified novel genetic events. Applying SNP-array, we identified constitutional de novo losses 5q21.1, 15q11.2, 17q21.31, 19p12 (pediatric medulloblastoma), 9p21.1, 19p12, 19q13.3, 21q11.2 (adult medulloblastoma) and gains 16p11.1-16p11.2, 18p11.32, Yq11.223-Yq11.23 (pediatric medulloblastoma), Xp22.31 (adult medulloblastoma) possibly representing inherited causal events for medulloblastoma formation. We show evidence for somatic segmental uniparental disomy in regions 1p36, 6q16.3, 6q24.1, 14q21.2, 17p13.3, and 17q22 not previously described for primary medulloblastoma. Gene expression analysis supported classification of the adult medulloblastoma to the WNT-subgroup and classification of pediatric medulloblastomas to group 3 tumors. Analyses of tumors and matched normal tissues (blood) with a combination of complementary techniques will help to further elucidate potentially causal genetic events for medulloblastomas. 23890555 Comprehensive profiling analysis of bioamines and their acidic metabolites in human urine by gas chromatography/mass spectrometry combined with selective derivatization. A comprehensive analytical method was developed for the profiling of biogenic amines in human urine using GC/MS in SIM mode. Biogenic amines and their acidic metabolites were converted into their volatile O-trimethylsilyl/N-heptafluorobutyryl (OTMS/-NHFBA) derivatives for GC/MS analysis. Dual hexamethyldisilazane (HMDS)/-N-methyl-bis-heptafluorobutyramide (MBHFBA) derivatizations have been shown to be quite effective, with high derivatization yields and the absence of side products for primary biogenic amines. In this study, selective derivatization conditions by HMDS/MBHFBA were optimized in terms of the reagent amount, reaction temperature and reaction time period. The highest derivatization reaction yield was obtained at 40°C for 10min for OTMS derivatization and 80°C for 5min for N-HFBA derivatization. The use of MCX SPE cartridges with different SPE elution solvents was effective for the pre-concentration and selective cleanup of the biogenic amines and their acidic metabolites in human urine. The selection of appropriate ions in SIM mode provided reliable quantification and identification and a reduction in background effects. The established method was validated in terms of linearity, limits of detection (LOD), limits of quantification (LOQ), precision, and accuracy. The present method was linear (r(2)>0.996), reproducible (relative standard deviation range 1.1-6.9%), and accurate (range 87.9-111.9%), with LOQs of 0.17-17.84ng/mL. The biogenic amine profiling of human urine was successfully accomplished by GC/MS in SIM mode combined with selective HMDS/MBHFBA derivatization and MCX SPE cleanup. 23357249 Erythropoiesis-stimulating agents (ESAs): Do they still have a role in chemotherapy-induced anemia (CIA)? Anemia in cancer patients can be a result of the underlying cancer or related to treatment. Erythropoiesis-stimulating agents (ESAs) are an important option for many patients with chemotherapy-induced anemia, but are immersed in controversy. This article aims to reconcile conflicting opinions and provide expert guidance for appropriate ESA use. Teleconference, email, and a face-to-face meeting were used to assess ESA therapy "interpretive" data, which included two current meta-analyses, expert guidelines, and regulatory approved indications from Canada, Europe, and the USA. Risks and benefits are associated with both red blood cell transfusions and ESA therapy, including improvements in hemoglobin levels and quality of life. ESAs have been associated with concerns regarding survival and progression of cancer, particularly when used in patients with cancer-related anemia. Although safety concerns do exist, ESA therapy can be considered for use in patients with chemotherapy-induced anemia in accordance with Health Canada labeling. 23943355 Udder health in relation to udder and teat morphometry in Holstein Friesian × Sahiwal crossbred dairy cows. The present investigation involved 261 Holstein Friesian (HF) × Sahiwal cows to study the udder health as well as the udder and teat morphometry. The udder health was defined on the basis of bacteriology and California mastitis test of quarter foremilk. The morphometry parameters included udder fore depth (UFD, distance from the point where the fore udder merges within the abdomen to a point in front of the fore teats at the level of the udder base), udder rear depth (URD, distance from the bottom of the vulva to the base of the rear udder), udder depth (UD, level of the udder base with respect to hock joint), height of the udder from the floor, teat length, teat diameter (at mid of the teat barrel), teat-tip to floor distance and distance between the teats. The URD, UD and height of udder from the floor showed a significant (P < 0.05) relation to the udder health with mastitic cows having larger URD, smaller udder distance from the floor and the udder base placed below the hock joint. The cows with teat length larger than 4.5 cm and teat diameter 3.0 cm or larger had significantly more quarters affected with mastitis. Further, cows with teats placed nearer to the floor were more susceptible to mastitis (P < 0.01). No significant differences were found between healthy and mastitic udders with respect to UFD and distance between teats. It can be concluded that selection for optimum udder and teat morphometry in breeding programmes may help to reduce susceptibility to intramammary infections in HF × Sahiwal cows. 23592864 Factors Associated With Mortality of HIV-Positive Clients Receiving Methadone Maintenance Treatment in China. Background. Little is known about mortality of opiate users attending methadone maintenance treatment (MMT) clinics. We sought to investigate mortality and its predictors among human immunodeficiency virus (HIV)-positive MMT clients. Methods. Records of 306 786 clients enrolled in China's MMT program from 24 March 2004 to 30 April 2011 were abstracted. Mortality rates were calculated for all HIV-positive antiretroviral treatment (ART)-naive and ART-experienced clients. Risk factors were examined using stratified proportional hazard ratios (HRs). Results. The observed mortality rate for all clients was 11.8/1000 person-years (PY, 95% confidence interval [CI], 11.5-12.1) and 57.2/1000 PY (CI, 54.9-59.4) for HIV-positive clients (n = 18 193). An increase in average methadone doses to >75 mg/day was associated with a 24% reduction in mortality (HR = 0.76, CI, .70-.82), a 48% reduction for ART-naive HIV-positive clients (HR = 0.52, CI, .42-.65), and a 47% reduction for ART-experienced HIV-positive clients (HR = 0.53, CI, .46-.62). Among ART-experienced clients, initiation of ART when the CD4(+) T-cell count was >300 cells/mm(3) (HR = 0.64, CI, .43-.94) was also associated with decreased risk of death. Conclusions. We found high mortality rates among HIV-positive MMT clients, yet decreased risk of death, with earlier ART initiation and higher methadone doses. A higher daily methadone dose was associated with reduced mortality in both HIV-infected and HIV-uninfected clients, independent of ART. 23744345 Repulsive guidance molecule a regulates hippocampal mossy fiber branching in vitro. Repulsive guidance molecule a (RGMa), which binds to its receptor neogenin, has been well determined as a repulsive axon guidance molecule. However, whether RGMa affects the growth of hippocampal mossy fibers, the axons of dentate granule cells, has been unknown. In the present study, we found that the primary neurons in the hippocampus express both RGMa and neogenin in the postnatal rats. To examine the role of RGMa in the mossy fiber growth, the morphology of granule cells was clearly visualized by transfecting membrane-targeted green fluorescent protein using a single-cell electroporation method in cultured hippocampal slices. In the slice cultures, we found that intrinsic RGMa is required to inhibit excess branching of the hippocampal mossy fibers. Furthermore, hyperexcitability-induced aberrant branching of the mossy fibers in the cultured slices was blocked by applying the recombinant RGMa protein. Therefore, this study suggests that RGMa regulates the proper axonal branching of hippocampal mossy fibers. 23968723 Draft genome sequence of the cellulolytic Clostridium thermocellum wild-type strain BC1 playing a role in cellulosic biomass degradation. The bacterium Clostridium thermocellum BC1, a thermophilic, anaerobic bacterium of the family Clostridiaceae, was isolated from a compost treatment site in Germany. It is able to grow efficiently on cellulose and cellodextrins. The draft genome sequence of C. thermocellum BC1 has been established and provides the genetic basis for application of this microorganism in thermophilic degradation of cellulosic biomass. 23343445 Efficacy and safety of long acting injectable atypical antipsychotics: a review. Schizophrenia is a chronic, severe and recurrent brain disorder that requires continuous, long-term treatment with antipsychotic medication to minimize relapse and provide clinical benefit to patients. For patients with schizophrenia, non-adherence to medication is a major risk factor for relapse and re-hospitalization. Long-acting injectable formulations of second-generation antipsychotics (SGAs-LAIs) provide constant medication delivery and the potential for improved adherence. Currently, three drugs are available for the treatment of schizophrenia, risperidone longacting injectable, olanzapine pamoate and paliperidone palmitate. Several studies have also demonstrated efficacy and safety of such drugs in patients with acute schizophrenia. In the present paper the literature on LAI atypical antipsychotics will be reviewed and practical advice will be given concerning the use of these drugs in the clinical practice. 23665995 One-pot, sequential four-component synthesis of benzo[c]pyrano[3,2-a]phenazine, bis-benzo[c]pyrano[3,2-a]phenazine and oxospiro benzo[c]pyrano[3,2-a]phenazine derivatives using 1,4-diazabicyclo[2.2.2]octane (DABCO) as an efficient and reusable solid base catalyst. 1,4-Diazabicyclo[2.2.2]octane (DABCO) has been used as an efficient and reusable solid base catalyst for the one-pot, two-step, four-component synthesis of pyrano[3,2-a]phenazine derivatives by the condensation reaction of 2-hydroxy-1,4-naphthoquinone, 1,2-diamines, carbonyl compounds and alkylmalonates under conventional heating as well as microwave irradiation. This procedure has also been applied successfully for the synthesis of novel bis- benzo[c]pyrano[3,2-a]phenazine and oxospiro benzo[c]pyrano[3,2-a]phenazine derivatives. Using this procedure, all the products were obtained in good to excellent yields. The catalyst has been recovered and reused several times without any loss of reactivity. 23712793 Neutral Lipid Content and Biomass Production in Skeletonema marinoi (Bacillariophyceae) Culture in Response to Nitrate Limitation. Microalgae are one of the most promising biodiesel feedstocks due to their efficiency in CO2 fixation and high neutral lipid productivity. Nutrient-stress conditions, including nitrogen starvation, enhance neutral lipid content, but at the same time lead to a reduction of biomass. To maximize lipid production in the diatom Skeletonema marinoi, we investigated two different nitrogen starvation approaches. In the first experimental approach, inocula were effectuated in modified f/2 media with decreasing nitrogen concentration, while in the second experiment, nitrate concentration was gradually reduced through a collection/resuspension system in which the culture was periodically collected and resuspended in culture medium with a lower nitrate concentration. In the first approach, the neutral lipid accumulation was accompanied by a strong biomass reduction, as was expected, whereas the second experiment generated cultures with significantly higher neutral lipid content without affecting biomass production. The total proteins and total carbohydrates, which were also quantified in both experiments, suggest that in S. marinoi, neutral lipid accumulation during nutrient starvation did not derive from a new carbon partition of accumulated carbohydrates. 23398311 SiO2@Au core-shell nanospheres self-assemble to form colloidal crystals that can be sintered and surface modified to produce pH-controlled membranes. We prepared colloidal crystals by self-assembly of gold-coated silica nanospheres, and free-standing nanoporous membranes by sintering these colloidal crystals. We modified the nanopore surface with ionizable functional groups, by forming a monolayer of L-cysteine or by surface-initiated polymerization of methacrylic acid. Diffusion experiments for the cationic dye Rhodamine B through L-cysteine-modified membranes showed a decrease in flux upon addition of an acid due to the nanopore surface becoming positively charged. Diffusion experiments for the neutral dye, ferrocenecarboxaldehyde, through the PMAA-modified membranes showed a 13-fold increase in flux upon addition of an acid resulting from the protonated polymer collapsing onto the nanopore surface leading to larger pore size. Our results demonstrate that SiO2@Au core-shell nanospheres can self-assemble into colloidal crystals and that transport through the corresponding surface-modified Au-coated colloidal membranes can be controlled by pH. 23895164 THetA: Inferring intra-tumor heterogeneity from high-throughput DNA sequencing data. Tumor samples are typically heterogeneous, containing admixture by normal, non-cancerous cells and one or more subpopulations of cancerous cells. Whole-genome sequencing of a tumor sample yields reads from this mixture, but does not directly reveal the cell of origin for each read. We introduce THetA (Tumor Heterogeneity Analysis), an algorithm that infers the most likely collection of genomes and their proportions in a sample, for the case where copy number aberrations distinguish subpopulations. THetA successfully estimates normal admixture and recovers clonal and subclonal copy number aberrations in real and simulated sequencing data. THetA is available at http://compbio.cs.brown.edu/software/. 23856785 Unusually Severe Cases of Kingella kingae Osteoarticular Infections in Children. With the development of molecular biology and specific PCR, Kingella kingae has become the primary diagnosis of osteoarticular infections in young children. Clinical features of these osteoarticular infections are typically mild, and outcome is almost always favorable. We report a series of unusually severe cases of K. kingae osteoarticular infections. All patients with severe osteoarticular infections at presentation were reviewed retrospectively in 2 European pediatric centers. K. kingae was identified using real-time PCR (rtPCR) in blood, fluid joint or osseous samples. Clinical, laboratory tests and radiographic data during hospitalization and follow-up were analyzed. Ten children (mean age 21±12 months) with severe osteoarticular infections caused by K. kingae were identified between 2008 and 2011. Diagnostic delay averaged 13.2±8 days. Only 1 patient was febrile at admission and 50% children had normal CRP values (≤10 mg/dl) at presentation. Surgical treatment was performed in all cases. Intravenous antibiotic therapy by cephalosporins for an average of 8±6 days was followed by oral treatment for 27±6 days. Mean follow-up was 24.8±9 months, and satisfactory outcomes were reported in all cases. Two patients (20%) developed a central epiphysiodesis of the proximal humerus during follow-up, but without significant clinical consequence for the moment. Because of their mild clinical features at onset, diagnosis of K. kingae osteoarticular infections can be delayed. Care should be taken for early detection and treatment of these infections, because bony lytic lesions and potentially definitive growth cartilage damage can occur. 23603383 Juniperus oxycedrus L. subsp. oxycedrus and Juniperus oxycedrus L. subsp. macrocarpa (Sibth. & Sm.) Ball. "berries" from Turkey: Comparative evaluation of phenolic profile, antioxidant, cytotoxic and antimicrobial activities. This work aimed to evaluate and compare the phenolic profile and some biological properties of the ripe "berries" methanol extracts of Juniperus oxycedrus L. subsp. oxycedrus (Joo) and Juniperus oxycedrus L. subsp. macrocarpa (Sibth. & Sm.) Ball. (Jom) from Turkey. The total phenolic content resulted about 3-fold higher in Jom (17.89±0.23mg GAE/g extract) than in Joo (5.14±0.06mg GAE/g extract). The HPLC-DAD-ESI-MS analysis revealed a similar flavonoid fingerprint in Joo and Jom, whereas a difference in their quantitative content was found (4632μg/g extract and 12,644μg/g extract). In addition, three phenolic acids were detected in Jom only (5765μg/g extract), and protocatechuic acid was the most abundant one. The antioxidant capacity of the extracts was evaluated by different in vitro assays: in the DPPH and in the TBA tests a stronger activity in Jom was highlighted, while Joo exhibited higher reducing power and metal chelating activity. Joo and Jom did not affect HepG2 cell viability and both extracts resulted virtually non-toxic against Artemia salina. The extracts were also studied for their antimicrobial potential, displaying efficacy against Gram-positive bacteria. 23930624 The risk of acquiring bacterial meningitis following surgery in Denmark, 1996-2009: a nationwide retrospective cohort study with emphasis on ear, nose and throat (ENT) and neurosurgery. SUMMARY This paper estimates the risk of bacterial meningitis following surgery between 1996 and 2009 in Denmark. We conducted two retrospective nationwide cohort studies; first by linking notified bacterial meningitis cases to the National Patient Registry to see how many had undergone a surgical procedure; second, we scrutinized notified bacterial meningitis cases to see if the clinician suspected a surgical procedure to be the aetiology. We found that ear, nose and throat surgery had an 11-fold, and neurosurgery a sevenfold, increased risk compared to the reference group in the first 10 days following surgery. Streptococcus pneumoniae was the pathogen most often involved. Operation procedures involving penetration of dura mater was associated with increased risk for post-operative bacterial meningitis. In absolute numbers we found few bacterial meningitis cases after surgery; however, patients undergoing certain surgical procedures are at-risk and should be considered when national vaccination guidelines are revised. 23538242 Risk factors for delayed hematuria following photoselective vaporization of the prostate. Photoselective vaporization of the prostate has become an increasingly popular option for the treatment of benign prostatic hyperplasia. However, delayed bleeding has been raised as a potential issue as more cases are performed. We characterize delayed bleeding after photoselective vaporization of the prostate and identify associated risk factors. We defined delayed gross hematuria as any complaint of hematuria following hospital discharge, and further stratified it as delayed gross hematuria requiring emergency department evaluation, hospital admission, continuous bladder irrigation, transfusions or reoperation. We performed an explicit chart review of 290 patients who underwent photoselective vaporization of the prostate at a single center from 2002 through 2009. Exposures of interest included age, prostate volume, followup duration, operative factors (watts/joules), and use of oral anticoagulation therapy or 5α-reductase inhibitors. Delayed gross hematuria occurred in 33.8% of patients during an average followup of 33 months. For 8.5% of patients the bleeding was severe enough to prompt presentation to the emergency department. For 4.8% of patients hospitalization was required and for 4.5% reoperation was required. Multivariate analysis revealed that the odds of bleeding increased with prostate size (OR 1.08, 1.03-1.14), longer followup (OR 1.35, 1.12-1.62) and anticoagulant use (OR 3.35, 1.43-7.83), and decreased with increasing age (OR 0.71, 0.51-0.98) and use of a 5α-reductase inhibitor (OR 0.41, 0.24-0.73). Delayed hematuria occurs commonly after photoselective vaporization of the prostate but severe hematuria is rare. Larger prostate size, longer followup and use of anticoagulation were associated with a higher risk of delayed gross hematuria while preoperative 5α-reductase inhibitor use and older age were protective. 23925578 Association of the ATM gene polymorphisms with papillary thyroid cancer. Papillary thyroid cancer (PTC) is the most common type of thyroid cancer, yet few genetic markers of PTC risk useful for screening exist. Our study aimed to evaluate the association between single nucleotide polymorphisms (SNPs) of the ataxia telangiectasia mutated (ATM) gene and PTC risk. 358 patients with PTC and 360 healthy controls were included in the case-control study. Four ATM SNPs (rs664677, rs373759, rs4988099, and rs189037) were genotyped by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). The analysis of genetic data was performed using the SNPStats program. The allele frequencies and genotype distributions of the four ATM SNPs were not different between PTC patients and controls. We did not observe any tendency of increasing the frequency of the risk allele from controls, patients without metastasis to patients with metastasis (P trend > 0.05). Interestingly, the AG genotype of rs373759 was associated with PTC risk under an overdominant model of inheritance (adjusted OR = 1.38; 95 % CI, 1.03-1.87; P = 0.03). No haplotype was observed to be significantly associated with PTC risk. Our results suggest that heterozygosity for the ATM rs373759 polymorphism may be a potential risk factor for PTC. 23628652 A multicentre Spanish study for multivariate prediction of perioperative in-hospital cerebrovascular accident after coronary bypass surgery: the PACK2 score. OBJECTIVES To develop a multivariate predictive risk score of perioperative in-hospital stroke after coronary artery bypass grafting (CABG) surgery. METHOD A total of 26 347 patients were enrolled from 21 Spanish hospital databases. Logistic regression analysis was used to predict the risk of perioperative stroke (ictus or transient ischaemic attack). The predictive scale was developed from a training set of data and validated by an independent test set, both selected randomly. The assessment of the accuracy of prediction was related to the area under the ROC curve. The variables considered were: preoperative (age, gender, diabetes mellitus, arterial hypertension, previous stroke, cardiac failure and/or left ventricular ejection fraction <40%, non-elective priority of surgery, extracardiac arteriopathy, chronic kidney failure and/or creatininemia ≥2 mg/dl and atrial fibrillation) and intraoperative (on/off-pump). RESULTS Global perioperative stroke incidence was 1.38%. Non-elective priority of surgery (priority; OR = 2.32), vascular disease (arteriopathy; OR = 1.37), cardiac failure (cardiac; OR = 3.64) and chronic kidney failure (kidney; OR = 6.78) were found to be independent risk factors for perioperative stroke in uni- and multivariate models in the training set of data; P < 0.0001; AUC = 0.77, 95% CI 0.73-0.82. The PACK2 stroke CABG score was established with 1 point for each item, except for chronic kidney failure with 2 points (range 0-5 points); AUC = 0.76, 95% CI 0.72-0.80. In patients with PACK2 score ≥2 points, off-pump reduced perioperative stoke incidence by 2.3% when compared with on-pump CABG. CONCLUSIONS PACK2 risk scale shows good predictive accuracy in the data analysed and could be useful in clinical practice for decision making and patient selection. 23722947 Expression and Displaying of β-Glucosidase from Streptomyces Coelicolor A3 in Escherichia coli. Two genes encoding β-glucosidase from Streptomyces coelicolor A3(2) were cloned and expressed in Escherichia coli BL21 (DE3). Two recombinant enzymes (SC1059 and SC7558) were purified and characterized. The molecular mass of the purified SC1059 and SC7558 as determined by SDS-PAGE agrees with the calculated values (51.0 and 52.2 kDa, respectively). Optimal temperature and pH for the two enzymes were both at 35 °C and 6.0. SC7558 exhibited to be much more active than SC1059 under optimal conditions, and it was recombined with ice nucleation protein which could anchor on the surface of the cell. The optimal temperature and pH of the recombinant cells were 55 °C and 8.0, respectively. The resultant cells were to be used as material for immobilized β-glucosidase, which is convenient to catalyze substrates in various complicated conditions. 23561073 Dummy-template molecularly imprinted solid phase extraction for selective analysis of ractopamine in pork. Molecularly imprinted polymers (MIPs) for selective adsorption of ractopamine hydrochloride (RAC) were synthesised by an in situ method, in which salbutamol (SAL) was used as the dummy-template to avoid the template leakage. Scanning electron microscopy (SEM), mercury porosimerty and Fourier transform infrared spectroscopy (FTIR) were used to investigate the physical and morphological characteristics of the dummy-template MIPs. The test of adsorption selectivity indicated that the dummy-template MIPs exhibited high selectivity to RAC. The saturated adsorption capacity for RAC on dummy-template MIPs was 90.9μgg(-1). Based on the dummy-template polymers, a liquid chromatography-mass spectrometry (LC-MS) method was developed for the selective analysis of RAC in real pork samples. The averages of intra- and inter-day accuracy ranged from 78.9% to 92.2% and from 90.7% to 93.1%, respectively. The RSD% of repeatability ranged from 1.9% to 6.3%, and the RSD% of intermediate precision ranged from 3.5% to 9.2%, while the limit of detection (LOD) was 0.02μgkg(-1). 23031352 Neonatal ascending aortic thrombus: successful medical treatment. Neonatal aortic thrombosis is a potentially life-threatening condition with significant morbidity and mortality if undiagnosed and untreated. The most common location of arterial thrombosis in neonates is in the abdominal aorta and is associated with umbilical artery catheterisation. There are only a few previous reports of thrombosis in the ascending aorta. We describe a case of ascending aortic thrombosis in a neonate who underwent successful thrombolytic therapy. 23187747 Intraoperative and pathological findings of intramedullary amputation neuroma associated with spinal ependymoma. Amputation neuromas typically arise in injured peripheral nerves; rarely, however, they arise in the spinal cord. We report a rare case of intramedullary amputation neuroma associated with ependymoma in the cervical spinal cord. A 73-year-old woman presented with a 5-year history of progressive gait disturbance. Neurological examination revealed complete motor deficit of her hands and legs. Magnetic resonance imaging of the cervical spine revealed an enhancing mass within the spinal cord at the C6/7 level. The patient underwent C5-C7 laminectomy surgery. During resection of the spinal tumor, we found a whitish string resembling an aberrant nerve root or schwannoma with adhesion to the tumor on the ventral side of the spinal cord. After resecting the tumor, the surgical specimen was cut and separated into a soft greyish tumor (spinal tumor) and the tough whitish string. Histopathological and immunohistochemical examination revealed the former was a spinal ependymoma and the latter was a neuroma. An intramedullary amputation neuroma associated with a spinal ependymoma is rare, and this is the first known case in which intraoprerative findings were clearly shown. Neurosurgeons should be aware that spinal ependymomas might coexist with neuromas. 23887050 Morphological and Functional Outcome after Brilliant Blue G-Assisted Macular Hole Surgery. Purpose of the Study: To investigate the outcome of brilliant blue G (BBG)-assisted internal limiting membrane peeling in macular hole surgery after a follow-up of 6 months. Procedures: In this retrospective study 20 eyes have been treated with BBG-assisted macular hole surgery. After a follow-up of 6 months, the functional and anatomical outcomes have been analyzed. Results: The mean preoperative best-corrected visual acuity (BCVA) was 0.7 logMAR units (mean ± SD 0.66 ± 0.27). After 3 months, the mean BCVA increased not significantly to 0.4 (0.54 ± 0.30), but a significant improvement to 0.2 logMAR units (0.28 ± 0.23) could be detected after 6 months compared to baseline (p < 0.01). Primary macular hole closure after a single surgery was found in 17 of 20 eyes. Conclusion and Message: BBG exhibits sufficient staining qualities and safety profile leading to a significant functional improvement after successful macular hole surgery. 23865596 The protective effect of recombinant Lactococcus lactis oral vaccine on a Clostridium difficile-infected animal model. Oral immunization with vaccines may be an effective strategy for prevention of Clostridium difficile infection (CDI). However, application of previously developed vaccines for preventing CDI has been limited due to various reasons. Here, we developed a recombinant Lactococcus lactis oral vaccine and evaluated its effect on a C. difficile-infected animal model established in golden hamsters in attempt to provide an alternative strategy for CDI prevention. Recombinant L. lactis vaccine was developed using the pTRKH2 plasmid, a high-copy-number Escherichia coli-L. shuttle vector: 1) L. lactis expressing secreted proteins was constructed with recombinant pTRKH2 (secreted-protein plasmid) carrying the Usp45 signal peptide (SPUsp45), nontoxic adjuvanted tetanus toxin fragment C (TETC), and 14 of the 38 C-terminal repeats (14CDTA) of nontoxic C. difficile toxin A (TcdA); and 2) L. lactis expressing secreted and membrane proteins was constructed with recombinant pTRKH2 (membrane-anchored plasmid) carrying SPUsp45, TETC, 14CDTA, and the cell wall-anchored sequence of protein M6 (cwaM6). Then, 32 male Syrian golden hamsters were randomly divided into 4 groups (n = 8 each) for gavage of normal saline (blank control) and L. lactis carrying the empty shuttle vector, secreted-protein plasmid, and membrane-anchored plasmid, respectively. After 1-week gavage of clindamycin, the animals were administered with C. difficile spore suspension. General symptoms and intestinal pathological changes of the animals were examined by naked eye and microscopy, respectively. Protein levels of anti-TcdA IgG/IgA antibodies in intestinal tissue and fluid were analyzed by enzyme-linked immunosorbent assay (ELISA). A cell culture cytotoxicity neutralization assay was done by TcdA treatment with or without anti-TcdA serum pre-incubation or treatment. Apoptosis of intestinal epithelial cells was examined by flow cytometry (FL) assay. Expression of mucosal inflammatory cytokines in the animals was detected by polymer chain reaction (PCR) assay. After the C. difficile challenge, the animals of control group had severe diarrhea symptoms on day 1 and all died on day 4, indicating that the CDI animal model was established in hamster. Of the 3 immunization groups, secreted-protein and membrane-anchored plasmid groups had significantly lower mortalities, body weight decreases, and pathological scores, with higher survival rate/time than the empty plasmid group (P < 0.05). The tilter of IgG antibody directed against TcdA was significantly higher in serum and intestinal fluid of secreted-protein and membrane-anchored plasmid groups than in the empty plasmid group (P < 0.05) while the corresponding titer of IgA antibody directed against TcdA had no substantial differences (P > 0.05). The anti-TcdA serum of membrane-anchored plasmid group neutralized the cytotoxicity of 200 ng/ml TcdA with the best protective effect achieved by anti-TcdA serum pre-incubation. The incidences of TcdA-induced death and apoptosis of intestinal epithelial cells were significantly reduced by cell pre-incubation or treatment with anti-TcdA serum of membrane-anchored plasmid group (P < 0.05). MCP-1, ICAM-1, IL-6, and Gro-1 mRNA expression levels were the lowest in cecum tissue of the membrane-anchored groups compared to the other groups. Recombinant L. lactis live vaccine is effective for preventing CDI in the hamster model, thus providing an alternative for immunization of C. difficile-associated diseases. 23969221 Management of large coronary dissection after STAR. The guided-STAR technique is an alternative anterograde approach for treatment of coronary chronic total occlusion (CTO) and it is usually followed by implantation of multiple stents. We describe a case of residual long coronary dissection left unstented after guided-STAR, with good results at 2months follow-up. This case emphasizes the fact that sometimes even the longest coronary dissections can be left unstented especially in the contest of a CTO. 23645191 Enzymatic synthesis and characterization of fructooligosaccharides and novel maltosylfructosides by inulosucrase from Lactobacillus gasseri DSM 20604. The ability of an inulosucrase (IS) from Lactobacillus gasseri DSM 20604 to synthesize fructooligosaccharides (FOS) and maltosylfructosides (MFOS) in the presence of sucrose and sucrose-maltose mixtures was investigated after optimization of synthesis conditions, including enzyme concentration, temperature, pH, and reaction time. The maximum formation of FOS, which consist of β-2,1-linked fructose to sucrose, was 45% (in weight with respect to the initial amount of sucrose) and was obtained after 24 h of reaction at 55°C in the presence of sucrose (300 g liter(-1)) and 1.6 U ml(-1) of IS-25 mM sodium acetate buffer-1 mM CaCl2 (pH 5.2). The production of MFOS was also studied as a function of the initial ratios of sucrose to maltose (10:50, 20:40, 30:30, and 40:20, expressed in g 100 ml(-1)). The highest yield in total MFOS was attained after 24 to 32 h of reaction time and ranged from 13% (10:50 sucrose/maltose) to 52% (30:30 sucrose/maltose) in weight with respect to the initial amount of maltose. Nuclear magnetic resonance (NMR) structural characterization indicated that IS from L. gasseri specifically transferred fructose moieties of sucrose to either C-1 of the reducing end or C-6 of the nonreducing end of maltose. Thus, the trisaccharide erlose [α-d-glucopyranosyl-(1→4)-α-d-glucopyranosyl-(1→2)-β-d-fructofuranoside] was the main synthesized MFOS followed by neo-erlose [β-d-fructofuranosyl-(2→6)-α-d-glucopyranosyl-(1→4)-α-d-glucopyranose]. The formation of MFOS with a higher degree of polymerization was also demonstrated by the transfer of additional fructose residues to C-1 of either the β-2,1-linked fructose or the β-2,6-linked fructose to maltose, revealing the capacity of MFOS to serve as acceptors. 23673489 Copper doped TiO2 nanoparticles characterized by X-ray absorption spectroscopy, total scattering, and powder diffraction--a benchmark structure-property study. Metal functionalized nanoparticles potentially have improved properties e.g. in catalytic applications, but their precise structures are often very challenging to determine. Here we report a structural benchmark study based on tetragonal anatase TiO2 nanoparticles containing 0-2 wt% copper. The particles were synthesized by continuous flow synthesis under supercritical water-isopropanol conditions. Size determination using synchrotron PXRD, TEM, and X-ray total scattering reveals 5-7 nm monodisperse particles. The precise dopant structure and thermal stability of the highly crystalline powders were characterized by X-ray absorption spectroscopy and multi-temperature synchrotron PXRD (300-1000 K). The combined evidence reveals that copper is present as a dopant on the particle surfaces, most likely in an amorphous oxide or hydroxide shell. UV-VIS spectroscopy shows that copper presence at concentrations higher than 0.3 wt% lowers the band gap energy. The particles are unaffected by heating to 600 K, while growth and partial transformation to rutile TiO2 occur at higher temperatures. Anisotropic unit cell behavior of anatase is observed as a consequence of the particle growth (a decreases and c increases). 23818095 Diisopinocampheylborane-Mediated Reductive Aldol Reactions: Highly Enantio- and Diastereoselective Synthesis of syn Aldols from N-Acryloylmorpholine. Cutting costs, cutting corners: In an inexpensive and straightforward synthesis of syn-propionamide aldols, formation of the Z enolborinate by the hydroboration of 4-acryloylmorpholine with diisopinocampheylborane ((Ipc)2 BH) was followed by aldol reactions with achiral and chiral aldehydes to provide syn-α-methyl-β-hydroxymorpholinecarboxamides with excellent enantio- and diastereoselectivity (see scheme; R=alkyl, alkenyl, aryl, heteroaryl). 23537156 Disseminating evidence-based care into practice. Abstract The Centers for Medicare and Medicaid Services (CMS) has launched the Partnership for Patients initiative, promising a 20% reduction in readmissions nationally across all payers by December 31, 2013. To address this ambitious goal, CMS has awarded grants to Hospital Engagement Networks, Pioneer Accountable Care Organizations, and the Community-based Care Transitions Program, as well as instituted new penalties for excessive readmission that began in October 2012. National efforts aimed at realizing this goal are predicated, in part, on our effectiveness in disseminating evidence-based care models into practice to improve outcomes and reduce costs. The Care Transitions Intervention (CTI) has been developed, tested, and disseminated to over 750 health care organizations in 40 states nationwide. Four factors promote wide-scale CTI dissemination. The first factor focuses on model fidelity whereby adopters are given insight into which elements of the intervention can be adapted and customized. The second factor concerns the selection of Transitions Coaches and reinforcement of their role through training and participation in a national peer learning network. The third factor relates to model execution with attention to integrating the intervention into existing workflows and fostering relationships with community stakeholders. The fourth factor involves cultivating the support to sustain or expand the intervention through continually making the business case in a changing health care landscape. The lessons learned through the dissemination and implementation of the CTI may be generalizable to the spread of a variety of evidence-based care models. (Population Health Management 2013;16:227-234). 23913994 'Active ageing': from empty rhetoric to effective policy tool. 'Active ageing' is a topic of increasing attention in scientific and policy discussions on ageing, yet there is no consensus on its actual meaning. The current paper proposes a detailed classification of various definitions that have been used since its introduction. These definitions are subjected to critical investigation, and subtle differences with regard to such terms as 'healthy ageing' and 'productive ageing' are clarified. Bearing the hazards of previous definitions in mind, a comprehensive strategy is initiated. Given that earlier definitions have tended to exclude frail older adults, this strategy pays particular attention to the translation of the active-ageing concept to situations of dependency by centring on three key principles: fostering adaptability, supporting the maintenance of emotionally close relationships and removing structural barriers related to age or dependency. 23922988 Trivalent combination vaccine induces broad heterologous immune responses to norovirus and rotavirus in mice. Rotavirus (RV) and norovirus (NoV) are the two major causes of viral gastroenteritis (GE) in children worldwide. We have developed an injectable vaccine design to prevent infection or GE induced with these enteric viruses. The trivalent combination vaccine consists of NoV capsid (VP1) derived virus-like particles (VLPs) of GI-3 and GII-4 representing the two major NoV genogroups and tubular RV recombinant VP6 (rVP6), the most conserved and abundant RV protein. Each component was produced in insect cells by a recombinant baculovirus expression system and combined in vitro. The vaccine components were administered intramuscularly to BALB/c mice either separately or in the trivalent combination. High levels of NoV and RV type specific serum IgGs with high avidity (>50%) as well as intestinal IgGs were detected in the immunized mice. Cross-reactive IgG antibodies were also elicited against heterologous NoV VLPs not used for immunization (GII-4 NO, GII-12 and GI-1 VLPs) and to different RVs from cell cultures. NoV-specific serum antibodies blocked binding of homologous and heterologous VLPs to the putative receptors, histo-blood group antigens, suggesting broad NoV neutralizing activity of the sera. Mucosal antibodies of mice immunized with the trivalent combination vaccine inhibited RV infection in vitro. In addition, cross-reactive T cell immune responses to NoV and RV-specific antigens were detected. All the responses were sustained for up to six months. No mutual inhibition of the components in the trivalent vaccine combination was observed. In conclusion, the NoV GI and GII VLPs combination induced broader cross-reactive and potentially neutralizing immune responses than either of the VLPs alone. Therefore, trivalent vaccine might induce protective immune responses to the vast majority of circulating NoV and RV genotypes. 23460075 Mortality among workers at Oak Ridge National Laboratory. Workers employed at the Oak Ridge National Laboratory (ORNL) were potentially exposed to a range of chemical and physical hazards, many of which are poorly characterized. We compared the observed deaths among workers to expectations based upon US mortality rates. The cohort included 22,831 workers hired between January 1, 1943 and December 31, 1984. Vital status and cause of death information were ascertained through December 31, 2008. Standardized mortality ratios (SMRs) were computed separately for males and females using US and Tennessee mortality rates; SMRs for men were tabulated separately for monthly-, weekly-, and hourly-paid workers. Hourly-paid males had more deaths due to cancer of the pleura (SMR = 12.09, 95% CI: 4.44, 26.32), cancer of the bladder (SMR = 1.89, 95% CI: 1.26, 2.71), and leukemia (SMR = 1.33, 95% CI: 0.87, 1.93) than expected based on US mortality rates. Female workers also had more deaths than expected from cancer of the bladder (SMR = 2.20, 95% CI: 1.20, 3.69) and leukemia (SMR = 1.64, 95% CI: 1.09, 2.36). The pleural cancer excess has only appeared since the 1980s, approximately 40 years after the start of operations. The bladder cancer excess was larger among workers who also had worked at other Oak Ridge nuclear weapons facilities, while the leukemia excess was among people who had not worked at other DOE facilities. Occupational hazards including asbestos and ionizing radiation may contribute to these excesses. 23912442 Domino Reactions Triggered by Hydroformylation. HF reaction represents a selective method for the synthesis of aldehydes starting from alkenes. Because of versatile aldehydes reactivity, it is possible to perform different domino protocols based on contemporary HF, including Michael's reaction, reductive amination, cyclopropanation, lactonization, and many others. This overview reports on the last 5 years' results obtained on this field. 23936194 Crystal structure of pim1 kinase in complex with a pyrido[4,3-d]pyrimidine derivative suggests a unique binding mode. Human Pim1 kinase is a serine/threonine protein kinase that plays important biological roles in cell survival, apoptosis, proliferation, and differentiation. Moreover, Pim1 is up-regulated in various hematopoietic malignancies and solid tumors. Thus, Pim1 is an attractive target for cancer therapeutics, and there has been growing interest in developing small molecule inhibitors for Pim1. Here, we describe the crystal structure of Pim1 in complex with a newly developed pyrido[4,3-d]pyrimidine-derivative inhibitor (SKI-O-068). Our inhibitor exhibits a half maximum inhibitory concentration (IC50) of 123 (±14) nM and has an unusual binding mode in complex with Pim1 kinase. The interactions between SKI-O-068 and the Pim1 active site pocket residue are different from those of other scaffold inhibitor-bound structures. The binding mode analysis suggests that the SKI-O-068 inhibitor can be improved by introducing functional groups that facilitate direct interaction with Lys67, which aid in the design of an optimized inhibitor. 23770367 WW domain-containing oxidoreductase is involved in upregulation of matrix metalloproteinase 9 by Epstein-Barr virus latent membrane protein 2A. WW domain-containing oxidoreductase (WOX1) participates in tumor suppression and many other biologic functions, but its molecular and functional interactions with viral proteins remain largely unknown. This study reveals that WOX1 is physically associated with latent membrane protein 2A (LMP2A), an oncoprotein of Epstein-Barr virus. The molecular interaction involves the tyrosine residue 33 of WOX1 and the proline-rich motifs of LMP2A. Interestingly, endogenous WOX1 is required for some LMP2A-triggered, cancer-promoting effects, including activation of extracellular signal-regulated kinase-1/2, upregulation of matrix metalloproteinase 9 (MMP9) and promotion of cell invasion. Upon knockdown of endogenous WOX1, LMP2A-triggered MMP9 induction is restored by exogenous wild-type WOX1, but not by a WOX1 mutant defective in LMP2A binding. These results indicate that, through interaction with LMP2A, WOX1 is involved in MMP9 induction, suggesting a novel role of WOX1 in Epstein-Barr virus-associated cancer progression. 23743328 Label-free and reagentless electrochemical detection of microRNAs using a conducting polymer nanostructured by carbon nanotubes: Application to prostate cancer biomarker miR-141. In this paper, a label-free and reagentless microRNA sensor based on an interpenetrated network of carbon nanotubes and electroactive polymer is described. The nanostructured polymer film presents very well-defined electroactivity in neutral aqueous medium in the cathodic potential domain from the quinone group embedded in the polymer backbone. Addition of microRNA miR-141 target (prostate cancer biomarker) gives a "signal-on" response, i.e. a current increase due to enhancement of the polymer electroactivity. On the contrary, non-complementary miRNAs such as miR-103 and miR-29b-1 do not lead to any significant current change. A very low detection limit of ca. 8fM is achieved with this sensor. 23706223 Preparation of a novel potassium ion imprinted polymeric nanoparticles based on dicyclohexyl 18C6 for selective determination of K+ ion in different water samples. This work reports the first application of the ion imprinting technology for determination of potassium ion by precipitation polymerization method. Ion imprinted polymeric (IIP) nanoparticles were prepared by using dicyclohexyl 18C6 (DC18C6) as a K(+) ion selective crown ether, in the acetonitrile-dimethylsulfoxide (3:1; v/v) mixture as porogen. The imprint potassium ion was removed from the polymeric matrix using 0.5 M HNO3. The scanning electron microscopy (SEM) micrographs showed colloidal nanoparticles of 60-90 nm in diameter and slightly irregular in shape. The obtained ion-imprinted particles for K(+) showed selective recognition with rapid adsorption and desorption processes. It was found that imprinting results in increased affinity of the material toward K(+) ion over other competitor metal ions with the same charge and/or close ionic radius. The synthesized IIP nanobeads were shown to be promising for solid-phase extraction coupled with flame photometry for determination of trace K(+) ion in different water samples. 23933505 Paranormal believers are more prone to illusory agency detection than skeptics. It has been hypothesized that illusory agency detection is at the basis of belief in supernatural agents and paranormal beliefs. In the present study a biological motion perception task was used to study illusory agency detection in a group of skeptics and a group of paranormal believers. Participants were required to detect the presence or absence of a human agent in a point-light display. It was found that paranormal believers had a lower perceptual sensitivity than skeptics, which was due to a response bias to 'yes' for stimuli in which no agent was present. The relation between paranormal beliefs and illusory agency detection held only for stimuli with low to intermediate ambiguity, but for stimuli with a high number of visual distractors responses of believers and skeptics were at the same level. Furthermore, it was found that illusory agency detection was unrelated to traditional religious belief and belief in witchcraft, whereas paranormal beliefs (i.e. Psi, spiritualism, precognition, superstition) were strongly related to illusory agency detection. These findings qualify the relation between illusory pattern perception and supernatural and paranormal beliefs and suggest that paranormal beliefs are strongly related to agency detection biases. 23597866 Modeling novelty habituation during exploratory activity in Drosophila. Habituation is a common form of non-associative learning in which the organism gradually decreases its response to repeated stimuli. The decrease in exploratory activity of many animal species during exposure to a novel open field arena is a widely studied habituation paradigm. However, a theoretical framework to quantify how the novelty of the arena is learned during habituation is currently missing. Drosophila melanogaster display a high mean absolute activity and a high probability for directional persistence when first introduced to a novel arena. Both measures decrease during habituation to the arena. Here, we propose a phenomenological model of habituation for Drosophila exploration based on two principles: Drosophila form a spatial representation of the arena edge as a set of connected local patches, and repeated exposure to these patches is essential for the habituation of the novelty. The level of exposure depends on the number of visitations and is quantified by a variable referred to as "coverage". This model was tested by comparing predictions against the experimentally measured behavior of wild type Drosophila. The novelty habituation of wild type Canton-S depends on coverage and is specifically independent of the arena radius. Our model describes the time dependent locomotor activity, ΔD, of Canton-S using an experimentally established stochastic process Pn(ΔD), which depends on the coverage. The quantitative measures of exploration and habituation were further applied to three mutant genotypes. Consistent with a requirement for vision in novelty habituation, blind no receptor potential A(7) mutants display a failure in the decay of probability for directional persistence and mean absolute activity. The rutabaga(2080) habituation mutant also shows defects in these measures. The kurtz(1) non-visual arrestin mutant demonstrates a rapid decay in these measures, implying reduced motivation. The model and the habituation measures offer a powerful framework for understanding mechanisms associated with open field habituation. 23689940 Proteomic Analysis of Protein Expression in the Induction of the Viable But Nonculturable State of Vibrio harveyi SF1. Vibrio harveyi has been reported to enter into a viable but nonculturable (VBNC) state. One marine V. harveyi strain, SF1 became nonculturable when incubated in seawater microcosm at 4 °C within 60 days. We investigated protein expression in the exponential phase of V. harveyi SF1 and compared it to the VBNC state. Cytosolic proteins were resolved by two-dimensional polyacrylamide gel electrophoresis using pH 4-7 linear gradients. Among these proteins, sixteen proteins which were strongly downregulated or upregulated in the VBNC cells were identified by MALDI-TOF-TOF mass spectrometry. The results indicated that the differentially expressed proteins were mainly focused on stress response proteins and key components of central and intermediary metabolism, like carbohydrate metabolism, transport, and translation. This study provided clues for understanding the mechanism of adaptation to the VBNC state. 23685167 Ondansetron prevents changes in respiratory pattern provoked by LiCl: a new approach for studying pro-emetic states in rodents? There are a limited number of biological indices for assessing pro-emetic states in laboratory rodents as they do not possess the vomiting response. In the present study we tested the hypothesis that in rats, pro-emetic intervention would affect the respiratory pattern. To this end, using whole-body plethysmography, in adult male Wistar rats we recorded respiration after i.p. administration of either the emetic agent LiCl or Ringer. Quantification of respiratory signals (from 5 to 35 min post-injection) revealed that post-LiCl, mean respiratory rate was significantly lower (126 ± 9 vs. 178 ± 10 cpm, p < 0.005) and less variable (Kvar 59 ± 8% vs. 73 ± 3%; p<0.05) compared to the post-Ringer condition. Furthermore, while mode values of respiratory rate histograms did not differ between the treatments (indicating that the dominant respiratory frequency remained unchanged), LiCl reduced the fraction of time spent at high respiratory rate (>200 cpm) from 25 ± 3% to 9 ± 2% (p = 0.004). Thus, reduction of the mean respiratory rate by LiCl was predominantly due to reduced contribution of high-frequency breathing that is normally associated with motor activity and/or arousal. Non-linear multifractal analysis of respiratory signals revealed that post-LiCl, respiration becomes less random and more orderly. 5-HT3 antagonist ondansetron prevented respiratory changes elicited by LiCl. We conclude that the observed changes likely reflect effects of LiCl on animals' motion, and that this effect is mediated via 5-HT3 receptors. Providing that the effects observed in our study were quite robust, we suggest that simple and non-invasive respiratory monitoring may be a promising approach for studying emesis in rodents. 23147390 Combined and interactive effects of global climate change and toxicants on populations and communities. Increased temperature and other environmental effects of global climate change (GCC) have documented impacts on many species (e.g., polar bears, amphibians, coral reefs) as well as on ecosystem processes and species interactions (e.g., the timing of predator-prey interactions). A challenge for ecotoxicologists is to predict how joint effects of climatic stress and toxicants measured at the individual level (e.g., reduced survival and reproduction) will be manifested at the population level (e.g., population growth rate, extinction risk) and community level (e.g., species richness, food-web structure). The authors discuss how population- and community-level responses to toxicants under GCC are likely to be influenced by various ecological mechanisms. Stress due to GCC may reduce the potential for resistance to and recovery from toxicant exposure. Long-term toxicant exposure can result in acquired tolerance to this stressor at the population or community level, but an associated cost of tolerance may be the reduced potential for tolerance to subsequent climatic stress (or vice versa). Moreover, GCC can induce large-scale shifts in community composition, which may affect the vulnerability of communities to other stressors. Ecological modeling based on species traits (representing life-history traits, population vulnerability, sensitivity to toxicants, and sensitivity to climate change) can be a promising approach for predicting combined impacts of GCC and toxicants on populations and communities. 23950818 Correction: In Vitro Analysis of Breast Cancer Cell Line Tumourspheres and Primary Human Breast Epithelia Mammospheres Demonstrates Inter- and Intrasphere Heterogeneity. [This corrects the article on p. e64388 in vol. 8.]. 23864008 Efficient microwave-assisted synthetic protocols and in silico behaviour prediction of per-substituted β-cyclodextrins. Selective per-substituted cyclodextrin design enables the carrier's physicochemical and binding properties to be tailored and can even modify some biological native structure effects. We herein report a number of highly efficient microwave-assisted synthetic protocols for the preparation of several amino, ureido and thioureido per-substituted β-cyclodextrin derivatives. A rapid parallel synthetic approach has given a set of 14 different CD derivatives. Our strategy is supported by computational analyses which were used to estimate the physicochemical behaviour of per-substituted derivatives and to tailor suitable substituents. 23918574 Treatment response and adverse reactions in older tuberculosis patients with immunocompromising comorbidities. Purpose: The aim of this study was to elucidate the effects of immunocompromising comorbidities on treatment response and adverse reactions in older tuberculosis (TB) patients. Materials and Methods: The medical records of 182 patients older than 65 years with proven TB by positive culture of Mycobacterium tuberculosis and with available drug susceptibility tests were reviewed retrospectively. These patients were subsequently assigned to either the comorbidity group (n=78) or non-comorbidity group (n=104) depending on whether they had immunocompromising comorbidities. Results: The mean durations of treatment were 9.9±3.3 months in the comorbidity group and 9.3±3.2 months in the non-comorbidity group (p=0.21). M. tuberculosis culture results converted to negative in most patients with available follow-up cultures at two months after treatment. The successful treatment rates were 94.9% and 98.9% in the comorbidity and non-comorbidity groups, respectively (p=0.30). The most common side effects of anti-TB treatment were skin rash/pruritus (13% in the comorbidity group vs. 11% in the non-comorbidity group, p=0.79), gastro-intestinal problems (14% vs. 9%, p=0.25) and hepatotoxicity (14% vs. 7%, p=0.09). Conclusion: The present study shows that the successful treatment rate for TB is high and that immunocompromising comorbidities have no effect on the response to treatment and adverse effects in older TB patients. 23860446 Chromatin dynamics at the hTERT promoter during transcriptional activation and repression by c-Myc and Mnt in Xenopus leavis oocytes. The transcription factors c-Myc and Mnt regulate gene expression through dimerization with Max and binding to E-boxes in target genes. While c-Myc activates gene expression via recruitment of histone modifying complexes, Mnt acts as a transcriptional repressor. Here, we used the Xenopus leavis oocyte system to address the effect of c-Myc and Mnt on transcription and chromatin remodeling over the E-box region in the human telomerase reverse transcriptase (hTERT) promoter. As expected we found elevated and decreased levels of hTERT transcription upon exogenously expressed c-Myc/Max and Mnt/Max, respectively. In addition, we confirmed binding of these heterodimers to both E-boxes already enriched with H3K9ac and H4K16ac. These chromatin marks were further enhanced upon c-Myc/Max binding followed by increased DNA accessibility in the E-box region. In contrast, Mnt/Max inhibited Myc-induced transcription and mediated repression through complete chromatin condensation and deacetylation of H3K9 and H4K16 across the E-box region. Importantly, Mnt was able to counteract c-Myc mediated activation even when expressed at low levels, suggesting Mnt to act as a strong repressor by closing the chromatin structure. Collectively our data demonstrate that the balance between c-Myc and Mnt activity determines the transcriptional outcome of the hTERT promoter by modulation of the chromatin architecture. 23411262 In vitro digestibility and starch content, predicted glycemic index and potential in vitro antidiabetic effect of lentil sprouts obtained by different germination techniques. The study focuses on changes in starch content and expected glycemic index (eGI) caused by different sprouting methods of lentil. On germination, a decrease was observed in total starch content (TS), α-amylase inhibitors activity (αAI) and eGI values. After elicitation, the highest TS content was determined in 3-day-old control sprouts (100.9 mg/gf.m.), whereas the lowest was in 4-day-old sprouts induced with 300 mM NaCl (57.8 mg/gf.m.). Resistant starch (RS) content was most effectively increased by induction with 600 mM mannitol. The highest eGI values were determined for 3-day-old sprouts induced with 300 mM NaCl, whereas the lowest were for 6-day-old sprouts induced with 100mM NaCl. In treated sprouts starch digestibility was connected with αAI activity and RS content. Sprouting conditions can modify starch content, its potential bioavailability and eGI values. Optimization of this process will allow for the maximum nutritional benefit. 23906498 Glucocorticoid receptor β regulates injury-mediated astrocyte activation and contributes to glioma pathogenesis via modulation of β-catenin/TCF transcriptional activity. Astrocytes react to central nervous system (CNS) injury and participate in gliotic responses, imparting negative, as well as positive effects on axonal regeneration. Despite the considerable biochemical and morphological changes astrocytes undergo following insult, and the known influence of steroids on glial activation, details surrounding glucocorticoid receptor expression and activity are lacking. Such mechanistic information is essential for advancing and enhancing therapies in the treatment of CNS injuries. Using an in vitro wound-healing assay, we found glucocorticoid receptor β (GRβ), not GRα, is upregulated and acts as a regulator of gliosis after injury. In addition, our results suggest that GRβ interacts with β-catenin and is a necessary component for proliferation and migration in both injured astrocytes and glioma cells. Further analysis indicated GRβ/β-catenin interaction as a key modulator of astrocyte reactivity through sustained Wnt/β-catenin/TCF signaling in its dominant-negative effect on GRα mediated trans-repression by a GSK-3β-independent manner. These findings expand our knowledge of the mechanism of GRβ action in promoting astrocyte proliferation and migration following injury and in glioma. This information furthers our understanding the function of glucocorticoid receptor in CNS injury and disease, as well as in the basic biochemical responses astrocytes undergo in response to injury and glioma pathogenesis. 23692358 Multifunctional compartmentalized capsules with a hierarchical organization from the nano to the macro scales. Inspired by the cells' structure, we present compartmentalized capsules with temperature and magnetic-based responsiveness and hierarchical organization ranging from the nano- to the visible scales. Liquefied alginate macroscopic beads coated with a layer-by-layer (LbL) chitosan/alginate shell served as containers both for model fluorophores and microcapsules, which in their turn encapsulated either another fluorophore or magnetic nanoparticles (MNPs). The microcapsules were coated with a temperature-responsive chitosan/elastin-like recombinamer (ELR) nanostructured shell. By varying the temperature from 25 to 37 °C, the two-hour release of rhodamine encapsulated within the microcapsules and its diffusion through the external compartment decreased from 84% and 71%. The devices could withstand handling and centrifugal stress, with 50% remaining intact at a rotation speed of 2000g. MNPs attributed magnetic responsiveness toward external magnetic fields. Such a customizable system can be envisaged to transport bioactive agents and cells in tissue engineering applications. 23894185 Rapid storage and retrieval of genomic intervals from a relational database system using nested containment lists. Efficient storage and retrieval of genomic annotations based on range intervals is necessary, given the amount of data produced by next-generation sequencing studies. The indexing strategies of relational database systems (such as MySQL) greatly inhibit their use in genomic annotation tasks. This has led to the development of stand-alone applications that are dependent on flat-file libraries. In this work, we introduce MyNCList, an implementation of the NCList data structure within a MySQL database. MyNCList enables the storage, update and rapid retrieval of genomic annotations from the convenience of a relational database system. Range-based annotations of 1 million variants are retrieved in under a minute, making this approach feasible for whole-genome annotation tasks. Database URL: https://github.com/bushlab/mynclist. 23373458 Is thyrotropin-releasing hormone a novel neuroendocrine modulator of keratin expression in human skin? Hair and epithelial keratins constitute the major structural components of the skin and its appendages, including the hair fibre. While it is appreciated that selected steroid hormones regulate specific keratins, little is known about the neuroendocrine control of human hair keratin expression. Preliminary evidence had suggested that thyrotropin-releasing hormone (TRH) may regulate keratin gene transcription. To clarify whether TRH operates as a novel neuroendocrine regulator of human hair and epithelial keratin expression under physiologically relevant conditions in situ. Microdissected human female scalp hair follicles (HFs) and female scalp skin were treated in serum-free organ culture for 12 h to 6 days with 100 ng mL(-1) TRH or vehicle. Both quantitative immunohistomorphometry and quantitative real-time polymerase chain reaction were utilized to assess expression of selected keratins. TRH significantly increased expression of the hair keratins K31 and K32, while that of K85 and K86, and of the epithelial keratins K14 and K17, was reduced. In the interfollicular epidermis, TRH stimulated expression of K6, K14 and K17, both at the mRNA and protein levels. Stimulation of the same keratins was also evident in the eccrine sweat and sebaceous glands. Selected human hair and epithelial keratins are modulated in situ. This may be relevant to explain hair shaft growth-promoting effects of TRH. Our pilot study suggests that the neuroendocrine controls that regulate the expression of human keratins deserve more systematic exploration and that these may be harnessed therapeutically. 23937969 A population based study of hospitalised seriously injured in a region of Northern Italy. Injury is a public health problem in terms of mortality, morbidity and disability. The implementation of a regionalised trauma system has been proved to significantly reduce the social impact of severe trauma on population. A population-based registry may be useful to obtain reliable epidemiologic data.Aim: To perform an exhaustive analysis of severe trauma patients hospitalised in Lombardia, a region of northern Italy.Materials and methods: The regional Hospital Discharge Registry (HDR) was used to retrieve data of all patients who suffered from serious injuries from 2008 to 2010. ICD9-CM codes of discharge diagnoses were analysed and patients coded from 800.0 to 939.9 or from 950.0 to 959.9 have been retrieved. Femur fractures in elderly and patients with length of hospital stay less than 2 days were excluded. Patients have been considered seriously injured if discharged dead or any of followings: admission or transit in ICU, need of mechanical ventilation, tracheotomy, invasive hemodynamic monitoring. Average reimbursement based on DRG has been evaluated.Statistics: Student's t test, ANOVA for continuous data, chi-square test for categorical data were used, and a p value less than 0.05 was considered significant. The severely injured patients hospitalised in Lombardia in three years were 11704, 391 per million per year. Overall mortality was 24.17% and increased with age. Males aging from 18 to 64 years had more occupational injuries, trauma on the road and violence by others. Females were more susceptible to domestic injuries and self inflicted violence, mostly in older ages. Acute mortality was higher after traffic accidents, while late mortality was increased in domestic trauma. Pediatric cases were unusual. A significant increase (+10.18%) in domestic trauma, with a concomitant decrease (-17.76%) in road-related accidents was observed in the three years study period. Rembursement paid to hospitals for seriously injured was insufficient with regard to estimated costs of care. Serious injury requiring hospitalisation in Lombardia is still an healthcare problem, with a trend toward a decrease of traffic accidents, increase in domestic trauma and involvement of older people. These results may help to plan a new regionalised Trauma System. 23017387 Cellular assessment of the extract of bambangan (Mangifera pajang) as a potential cytoprotective agent for the human hepatocellular HepG2 cell line. This study was conducted to investigate the potential of bambangan (Mangifera pajang) fruit extracts in the protection against oxidative damage caused by tert-butyl hydroperoxide in the human hepatocellular HepG2 cell line. Proteins which might be involved in the cytoprotective mechanism were investigated using western blotting technique. Quercetin was used as a positive control. The results showed that only the kernel extract of M. pajang and quercetin displayed cytoprotective activity in HepG2 cells, with EC(50) values of 1.2 and 5.3μg/ml, respectively. Expression of quinone reductase, glutathione reductase and methionine sulfoxide reductase A proteins were significantly up-regulated by quercetin, suggesting their involvement in the cytoprotective activity of quercetin. However, expressions of only glutathione reductase and methionine sulfoxide reductase A proteins were significantly up-regulated by the kernel extract, again suggesting their involvement in the cytoprotective activity of bambangan kernel extract. Future study is needed to investigate the involvement of other cytoprotective proteins in the cytoprotection mechanism. 23319180 Effective fragment potential method in Q-CHEM: A guide for users and developers. A detailed description of the implementation of the effective fragment potential (EFP) method in the Q-CHEM electronic structure package is presented. The Q-CHEM implementation interfaces EFP with standard quantum mechanical (QM) methods such as Hartree-Fock, density functional theory, perturbation theory, and coupled-cluster methods, as well as with methods for electronically excited and open-shell species, for example, configuration interaction, time-dependent density functional theory, and equation-of-motion coupled-cluster models. In addition to the QM/EFP functionality, a "fragment-only" feature is also available (when the system is described by effective fragments only). To aid further developments of the EFP methodology, a detailed description of the C++ classes and EFP module's workflow is presented. The EFP input structure and EFP job options are described. To assist setting up and performing EFP calculations, a collection of Perl service scripts is provided. The precomputed EFP parameters for standard fragments such as common solvents are stored in Q-CHEM's auxiliary library; they can be easily invoked, similar to specifying standard basis sets. The instructions for generating user-defined EFP parameters are given. Fragments positions can be specified by their center of mass coordinates and Euler angles. The interface with the IQMOL and WEBMO software is also described. © 2013 Wiley Periodicals, Inc. 23562928 Anti-inflammatory activity of hexane extracts from bones and internal organs of Anguilla japonica suppresses cyclooxygenase-2-dependent prostaglandin D2 generation in mast cells and anaphylaxis in mice. The purpose of this study is to investigate the effects of n-hexane extracts from bones and internal organs of Japanese eel, Anguilla japonica (HEE), on cyclooxygenase-2 (COX-2)-dependent prostaglandin D2 (PGD2) generation in stem cell factor (SCF), IL-10, plus LPS-induced mouse bone marrow-derived mast cells (BMMCs) and on passive cutaneous anaphylaxis (PCA) in mice. HEE suppressed SCF/IL-10/LPS-induced PGD2 generation, and concomitantly reduced COX-2 protein expression dose-dependently. To understand the mechanistic basis for the inhibition of PGD2 generation by HEE, we examined the effects of HEE on upstream signaling pathways essential for COX-2 induction. HEE was found to inhibit the translocation of nuclear factor-κB (NF-κB) p65 subunit to the nucleus and its DNA-binding ability through the inhibition of TAK1, IKK and IκB phosphorylation. Furthermore, HEE also attenuated mitogen-activated protein kinase (MAPK)-mediated regulation of DNA binding of activator protein-1 (AP-1). Moreover, oral administration of HEE inhibited anti-dinitrophenyl (DNP) IgE-induced PCA in a dose dependent manner. Taken together, the present study provides new insights into the anti-inflammatory activity of HEE, which could be a promising candidate to be used for an inflammatory therapy. 23436492 Bioactive formulations with sugar-derived surfactants: a new approach for photoprotection and controlled release of promethazine. Skin deep: A bioactive formulation for dermal delivery of antihistamines is obtained by using the original properties of catanionic associations towards self-assembly in water. The drug, which participates in its own transport, is preserved from photodegradation when solubilised in the bioactive formulation. The drug release through the skin is also delayed. 23122098 Identification of a novel phenolic compound in litchi (Litchi chinensis Sonn.) pericarp and bioactivity evaluation. Litchi (Litchi chinensis Sonn.) is a delicious fruit widely accepted by consumers all over the world. In this work, phytochemical investigation of litchi pericarp methanol extracts led to the isolation of a novel phenolic, 2-(2-hydroxyl-5-(methoxycarbonyl) phenoxy) benzoic acid, together with kaempferol, isolariciresinol, stigmasterol, butylated hydroxytoluene, 3,4-dihydroxyl benzoate, methyl shikimate and ethyl shikimate. Most were found in litchi pericarp for the first time. Their structures were mainly elucidated by NMR and MS evidences. Antioxidant activities of the eight compounds were determined by a DPPH radical scavenging assay and the results showed that 2-(2-hydroxy-5-(methoxycarbonyl) phenoxy)benzoic acid, kaempferol, isolariciresinol, butylated hydroxytoluene and 3,4-dihydroxy benzoate exhibited good antioxidant activities. An interesting finding was that butylated hydroxytoluene was detected as a natural antioxidant in this work, which was usually taken as a synthesized antioxidant. Furthermore, the novel compound exhibited no inhibitory effects against tyrosinase and α-glucosidase activities. 23949000 A Longitudinal Study of the Teacch Program in Different Settings: The Potential Benefits of Low Intensity Intervention in Preschool Children with Autism Spectrum Disorder. We conducted a longitudinal study of 30 preschool children with autism spectrum disorders (ASDs) to evaluate the potential benefits of the Treatment and Education of Autistic and related Communication Handicapped Children (TEACCH). Fifteen children following a low intensity TEACCH program were assessed four times for autism severity, adaptive functioning, language skills, maladaptive behaviors and parental stress and compared with a control group of 15 children following a non-specific approach. Findings suggest that a low intensity home and school TEACCH program may provide benefits for children with ASD by reducing autistic symptoms and maladaptive behaviors. Furthermore, a decrease in parental stress indicates that parents' involvement in the rehabilitation program is a crucial factor and contributes greatly to treatment efficacy. 23918906 The Geriatrician and Geriatric Psychiatrist Workforce in Texas: Characteristics, Challenges, and Policy Implications. This study provides a current analysis of the size and characteristics of the board-certified geriatrician and geriatric psychiatrist workforce in Texas, and thereby its capacity to meet increasing health needs of elders. Secondary data on Texas board-certified geriatricians and geriatric psychiatrists from American Board of Medical Specialties database were analyzed. The study found 1 geriatrician per 5,132 elders, and 1 geriatric psychiatrist per 21,327 elders, in Texas. Over 62% of geriatricians had active certification, 30% were females and the average age was 55.2 years. Rural geriatricians were disproportionately scarce (p < .001). The study indicated a serious shortage of board-certified geriatricians and geriatric psychiatrists in Texas. This shortage is worse than that at the national level, and more marked along the Texas-Mexico border and counties lacking large health facilities. Addressing this workforce deficiency requires improvements in the geriatric training pipeline, reimbursements, and practice environments. 23356786 Design and synthesis of cyclopropylamide analogues of combretastatin-A4 as novel microtubule-stabilizing agents. A series of novel cyclopropylamide analogues of combretastatin-A4 (CA-4) were designed and synthesized. Most of them had significant in vitro antiproliferative activities, particularly for compounds 7i4, 7c4, 8a4, and 8c4. Moreover, compound 8c4 was also equally potent against paclitaxel resistant cancer cells. Interestingly, the novel cyclopropylamide analogues had different binding mechanisms from CA-4. Instead of inhibiting tubulin polymerization, these CA-4 derivatives were able to stimulate tubulin polymerization. Flow cytometry revealed that compound 8c4 arrested A549 cancer cells in the G2/M phase and resulted in cellular apoptosis. Further immunofluorescence assays revealed that compound 8c4 induced mitotic arrest in A549 cells through disrupting microtubule dynamics. In addition, compound 8c4 also effectively inhibited the tumor growth in the A549 xenograft model without causing significant loss of body weight. Compound 8c4 represents a novel class of microtubule-stabilizing agent and can be used as a promising lead for the development of new antitumor agents. 23892872 A reversible strain-induced electrical conductivity in cup-stacked carbon nanotubes. We have used in situ current-voltage measurements of cup-stacked carbon nanotubes (CSCNTs) to establish reversible strain induced (compressive bending) semiconducting to metallic behavior. The corresponding electrical resistance decreases by two orders of magnitude during the process, and reaches values comparable to those of highly crystalline multi-walled carbon nanotubes (MWCNTs) and graphite. Joule heating experiments on the same CSCNTs showed that the edges of individual cups merge to form "loops" induced by the heating process. The resistance of these looped CSCNTs was close to that of highly deformed CSCNTs (and crystalline MWCNTs), thus suggesting that a similar conduction mechanism took place in both cases. Using a combination of molecular dynamics and first-principles calculations based on density functional theory, we conclude that an edge-to-edge interlayer transport mechanism results in conduction channels at the compressed side of the CSCNTs due to electronic density overlap between individual cups, thus making CSCNTs more conducting. This strain-induced CSCNT semiconductor to metal transition could potentially be applied to enable functional composite materials (e.g. mechanical sensors) with enhanced and tunable conducting properties upon compression. 23869967 Isolation of lesbian, gay, bisexual and transgender youth: a dimensional concept analysis. To present the findings of a dimensional analysis of isolation in the context, and from the perspective, of lesbian, gay, bisexual and transgender youth. Lesbian, gay, bisexual and transgender youth are often at greater risk for negative health outcomes compared with heterosexual youth. Isolation is one risk factor cited throughout the literature; however, the concept is complicated and has many uses and thus warrants clarification. Concept Analysis. Sources comprise 35 English language research articles retrieved from CINAHL and EBSCOHost (1987-2012). A dimensional concept analysis was undertaken to analyse how the concept, isolation, is socially constructed. This dimensional analysis revealed five socially constructed dimensions and four sub-dimensions. These findings indicate that there is substantial variability in the concept of isolation. These differences and variations are most notably observed in the 20 articles (57%) that had more than one dimension. Although some of these articles were explicit with the different meanings and use of the concept, most of the papers had wide variability in the use and meaning of the concept. The disproportionately greater physical and mental health disparities between lesbian, gay, bisexual and transgender and heterosexual youth are a signal to conduct more research to clarify the concept of isolation, to develop instrumentation to identify at-risk youth and to explore predictors and consequences of isolation. Nurses and others can lead the way in translating this knowledge into strategies that will improve the health and lives of these young people. 23852805 On the "Tertiary Structure" of Poly-Carbenes; Self-Assembly of sp(3) -Carbon-Based Polymers into Liquid-Crystalline Aggregates. The self-assembly of poly(ethylidene acetate) (st-PEA) into van der Waals-stabilized liquid-crystalline (LC) aggregates is reported. The LC behavior of these materials is unexpected, and unusual for flexible sp(3) -carbon backbone polymers. Although the dense packing of polar ester functionalities along the carbon backbone of st-PEA could perhaps be expected to lead directly to rigid-rod behavior, molecular modeling reveals that individual st-PEA chains are actually highly flexible and should not reveal rigid-rod induced LC behavior. Nonetheless, st-PEA clearly reveals LC behavior, both in solution and in the melt over a broad elevated temperature range. A combined set of experimental measurements, supported by MM/MD studies, suggests that the observed LC behavior is due to self-aggregation of st-PEA into higher-order aggregates. According to MM/MD modeling st-PEA single helices adopt a flexible helical structure with a preferred trans-gauche syn-syn-anti-anti orientation. Unexpectedly, similar modeling experiments suggest that three of these helices can self-assemble into triple-helical aggregates. Higher-order assemblies were not observed in the MM/MD simulations, suggesting that the triple helix is the most stable aggregate configuration. DLS data confirmed the aggregation of st-PEA into higher-order structures, and suggest the formation of rod-like particles. The dimensions derived from these light-scattering experiments correspond with st-PEA triple-helix formation. Langmuir-Blodgett surface pressure-area isotherms also point to the formation of rod-like st-PEA aggregates with similar dimensions as st-PEA triple helixes. Upon increasing the st-PEA concentration, the viscosity of the polymer solution increases strongly, and at concentrations above 20 wt % st-PEA forms an organogel. STM on this gel reveals the formation of helical aggregates on the graphite surface-solution interface with shapes and dimensions matching st-PEA triple helices, in good agreement with the structures proposed by molecular modeling. X-ray diffraction, WAXS, SAXS and solid state NMR spectroscopy studies suggest that st-PEA triple helices are also present in the solid state, up to temperatures well above the melting point of st-PEA. Formation of higher-order aggregates explains the observed LC behavior of st-PEA, emphasizing the importance of the "tertiary structure" of synthetic polymers on their material properties. 23930817 Analytical cone-beam SPECT reconstruction algorithm with non-uniform attenuation for general non-circular orbit. In single photon emission computed tomography (SPECT), due to the attenuation of gamma photons, the analytical reconstruction is complicated, where attenuation should be compensated to obtain quantitative results. We know that the resolution of SPECT is low. The cone-beam SPECT reconstruction can improve the photon density and spatial resolution of the reconstructed image. In practice, to minimize the effect of distance-dependent resolution variation (DDRV), the detector should be set as close as possible to the patient. Therefore it would be more efficacious for the orbit of the detector to be elliptical or another shape. In this paper, based on the Novikov's reconstruction formula and our Ray-driven Technology, we present an analytical cone-beam SPECT reconstruction algorithm for general non-circular orbit. The simulation results demonstrate the accuracy and robustness of our method. 23842286 Cerebral Subcortical Small Vessel Disease in Subjects With Pathologically Confirmed Alzheimer Disease: A Clinicopathologic Study in the Oxford Project to Investigate Memory and Ageing (OPTIMA). The understanding of how cerebrovascular disease (CVD) contributes to dementia is hampered by a lack of agreed and validated pathologic methods to accord weight to the contribution of different aspects of CVD to dementia. A previous study from the Oxford Project to Investigate Memory and Ageing (OPTIMA) validated a scheme for assessing the contribution of subcortical small vessel disease (SVD) toward dementia in the elderly by showing a significant inverse relationship between the severity of SVD and cognition in subjects without any other dementia pathology using this method. In the present paper, the method has been used to assess severity of SVD in 161 cases of neuropathologically confirmed Alzheimer disease. The results showed there was no relationship between the SVD score and cognitive scores acquired in the last 2 years of life. SVD scores were significantly related to age (P<0.0017) and were slightly but significantly higher in females than males (P<0.049). SVD scores were not related to blood pressure at entry to OPTIMA and were significantly lower when compared with the cohort of OPTIMA cases with only CVD (mean 5.06±1.85 vs. 5.9±2.67; P<0.0065). We conclude that when Alzheimer disease pathology is present in elderly subjects, it overwhelms the modest contribution that SVD makes to cognitive impairment. 23851711 Chemoselective alcoholysis/acetolysis of trans-ketals over cis-ketals and its application in the total synthesis of the cellular second messenger, d-myo-inositol-1,4,5-trisphosphate. The involvement of natural phosphoinositols in various cellular signalling processes and the use of synthetic inositol derivatives in catalysis, supramolecular chemistry, natural product synthesis etc. gave momentum to myo-inositol chemistry. The presence of six secondary hydroxyl groups necessitates efficient protection-deprotection strategies for the synthesis of inositol derivatives. An important strategy for the initial protection of myo-inositol is the di-ketalization, which gives a mixture of three diketals, each having both cis-fused and trans-fused ketals. It is important to have methodologies either to selectively hydrolyze one of the two ketals or to convert one of the two acid labile ketals to an orthogonal base labile protecting group. By exploiting the difference in strain between trans-ketals and cis-ketals, we developed two operationally simple, high yielding methodologies for the chemoselective hydrolysis/acetolysis of trans-ketals (both isopropylidene and cyclohexylidene) of inositols, leaving the cis-ketal undisturbed, using cheap and easily preparable H2SO4-silica as the catalyst. Also, terminal ketal moieties of carbohydrates and acyclic polyols could be selectively hydrolyzed/acetolyzed leaving the internal ketals intact. The use of methanol as the solvent leads to chemoselective alcoholysis but the use of DCM and acetic anhydride leads to chemoselective acetolysis. Applying this methodology, a short synthesis of d-myo-inositol-1,4,5-trisphosphate has been achieved. 23954606 Ischemic Stroke in Evolution: Predictive Value of Perfusion Computed Tomography. Various perfusion computed tomography (PCT) parameters have been used to identify tissue at risk of infarction in the setting of acute stroke. The purpose of this study was to examine predictive value of the PCT parameters commonly used in clinical practice to define ischemic penumbra. The patient selection criterion aimed to exclude the effect of thrombolysis from the imaging data. Consecutive acute stroke patients were screened and a total of 18 patients who initially underwent PCT and CT angiogram (CTA) on presentation but did not qualify to receive thrombolytic therapy were selected. The PCT images were postprocessed using a delay-sensitive deconvolution algorithm. All the patients had follow-up noncontrast CT or magnetic resonance imaging to delineate the extent of their infarction. The extent of lesions on PCT maps calculated from mean transit time (MTT), time to peak (TTP), cerebral blood flow, and cerebral blood volume were compared and correlated with the final infarct size. A collateral grading score was used to measure collateral blood supply on the CTA studies. The average size of MTT lesions was larger than infarct lesions (P < .05). The correlation coefficient of TTP/infarct lesions (r = .95) was better than MTT/infarct lesions (r = .66) (P = .004). A widely accepted threshold to define MTT lesions overestimates the ischemic penumbra. In this setting, TTP with appropriate threshold is a better predictor of infarct in acute stroke patients. The MTT/TTP mismatch correlates with the status of collateral blood supply to the tissue at risk of infarction. 23825074 Macrophage-derived TGF-beta in renal fibrosis: not a macro- impact after all. editorial focus for F-624-2012. 23966637 Land-use change, not climate, controls organic carbon burial in lakes. Lakes are a central component of the carbon cycle, both mineralizing terrestrially derived organic matter and storing substantial amounts of organic carbon (OC) in their sediments. However, the rates and controls on OC burial by lakes remain uncertain, as do the possible effects of future global change processes. To address these issues, we derived OC burial rates in (210)Pb-dated sediment cores from 116 small Minnesota lakes that cover major climate and land-use gradients. Rates for individual lakes presently range from 7 to 127 g C m(-2) yr(-1) and have increased by up to a factor of 8 since Euro-American settlement (mean increase: 2.8×). Mean pre-disturbance OC burial rates were similar (14-22 g C m(-2) yr(-1)) across all land-cover categories (prairie, mixed deciduous and boreal forest), indicating minimal effect of the regional temperature gradient (approx. 4°C) on background carbon burial. The relationship between modern OC burial rates and temperature was also not significant after removal of the effect of total phosphorus. Contemporary burial rates were strongly correlated with lake-water nutrients and the extent of agricultural land cover in the catchment. Increased OC burial, documented even in relatively undisturbed boreal lake ecosystems, indicates a possible role for atmospheric nitrogen deposition. Our results suggest that globally, future land-cover change, intensification of agriculture and associated nutrient loading together with atmospheric N-deposition will enhance OC sequestration by lakes. 23745014 The Synthesis and Characterization of a Group of Transition Metal Octabutoxynaphthalocyanines and the Absorption and Emission Properties of the Co, Rh, Ir, Ni, Pd and Pt Members of This Group. The synthesis and photophysical properties of new metallo-octabutoxynaphthalocyanines with Rh(III), Ir(III), and Pt(II) are reported. Various metals were inserted into the metal-free octabutoxynaphthalocyanine and the resultant metal complexes were fully characterized by NMR, UV-vis spectroscopy, and mass spectrometry. The absorption and emission properties of these new complexes were also examined and compared to those of Co(II), Ni(II), and Pd(II) octabutoxynaphthalocyanines. The results provide useful information to understand the effect of these transition metals on the properties of this macrocyclic ring. 23861164 SPE-HPLC-MS/MS method for the trace analysis of tobacco-specific N-nitrosamines and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in rabbit plasma using tetraazacalix[2]arene[2]triazine-modified silica as a sorbent. Tobacco-specific N-nitrosamines (TSNAs), including N'-nitrosonornicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, N'-nitrosoanatabine, and N'-nitrosoanabasine, have been implicated as a source of carcinogenicity in tobacco and cigarette smoke. We present a rapid and effective method comprising SPE based on tetraazacalix[2]arene[2]triazine-modified silica as sorbent and analysis with HPLC-MS/MS for the determination of TSNAs and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, in rabbit plasma. The linear dynamic ranges were 10-2000 pg/mL for NNAL and 4-2000 pg/mL for the four TSNAs with good correlation coefficients (>0.9965). The LODs were in the range of 0.9-3.7 pg/mL, and the LOQs were between 2.9 and 12.3 pg/mL. The accuracies of the method were also evaluated and found to be in the range of 90.1-113.3%. This method is promising to be applied to the preconcentration and determination of TSNAs and NNAL in smoke and human body fluids. 23926171 Evaluating the reproductive performance of British beef and dairy herds using national cattle movement records. National cattle movement databases provide a valuable opportunity to monitor the reproductive performance of breeding cattle on an industry-wide scale. In this analysis, records from the Cattle Tracing System database were used to derive key measures of reproductive efficiency for British beef and dairy herds, including calving spread, age at first calving, calving interval, culling rate and calf mortality rate. At the animal level, only 8.5 per cent of beef heifers and 6.9 per cent of dairy heifers calved by the target age of 24 months. The average calving interval was 394 days for beef dams (median: 371) and 426 days for dairy dams (median: 400). Differences in performance were noted between cattle breeds. An estimated 43.9 per cent calves born in dairy herds were crossbreed beef animals, which may limit the availability of replacement dairy heifers. At the herd level, calving spread and calf mortality rates increased with herd size, while average age at first calving, calving interval, and crossbreeding generally decreased with herd size. Dam age, calving month, breed and twinning were significant risk factors for culling and calf mortality at the animal level. Wide variation in performance between individual herds highlights the potential for improving the efficiency of British cattle production. 23542052 In vitro biocompatiblity of modified polycarbonate as a biomaterial. Nitrated and aminated polycarbonates were prepared chemically, characterized and tested in vitro as a possible biomaterial. Adhesion of Staphylococcus aureus NCIM 5021, Escherichia coli NCIM 2931 and Proteus vulgaris NCIM 2813 and the presence of carbohydrate, protein, CFU and ATP on these surfaces were examined. Cytotoxicity of these surfaces was investigated by growing L929 mouse fibroblast cells. NO2-PC was more hydrophilic than un-PC and reduced adhesion of bacterial protein and carbohydrate. NH2-PC was the most hydrophilic surface biofilm prevention and increased proliferation of the fibroblast cells. The motility of all the three organisms decreased on aminated surface when compared to that on the other two. This study indicated that reducing the surface hydrophobicity alone was not sufficient to develop a biocompatible material, but providing favorable surface functional groups was also a necessary criterion. A strong correlation was observed between the hydrophobicity of the polymer surface and the zeta potential of the organism with bacterial attachment (CFU/ml). A multi-linear regression model with these two parameters was able to fit the observed bacterial attachment data well. 23486325 99mTc-Pertechnetate SPECT/CT for Detecting Recurrent Foregut Duplication Cyst in a Case With Negative Planar Scintigraphy. Recurrence can occur after incomplete surgical excision of foregut duplication cysts. We here present Tc-pertechnetate SPECT/CT images of a 3-year-old girl with recurrence of foregut duplication cyst. Planar Tc-pertechnetate scintigraphy was negative in this case. 23891215 Isolation and extraction of lucidin primeveroside from Rubia tinctorum L. and crystal structure elucidation. Madder (Rubia tinctorum L.) has been used as a dye for over 2000years with alizarin and purpurin the major natural dyes analysed from extractions undertaken. The use of ethanol as the solvent in the extraction process produced an extract that yielded four anthraquinone compounds lucidin primeveroside, ruberythric acid, alizarin and lucidin-ω-ethyl ether. Gravitational separation of the extract was used to record the first crystal structure of lucidin primeveroside, which is also the first ever known crystal structure of a glycoside containing anthraquinone moiety. The crystal structure along with (1)H and (13)C NMR helped elucidate and confirm the structure of this overlooked natural dye which has been shown to be a major compound in R. tinctorum L. 23948182 Pseudomonas aeruginosa-mannose-sensitive hemagglutinin inhibits epidermal growth factor receptor signaling pathway activation and induces apoptosis in bladder cancer cells in vitro and in vivo. Pseudomonas aeruginosa-mannose-sensitive hemagglutinin (PA-MSHA), a peritrichous P. aeruginosa strain with MSHA fimbriae, has been shown to be a valuable anticancer drug in many kinds of cancers. However, the effect of PA-MSHA on bladder cancer has not been elucidated. In this study, we focused on the antitumor activities and related mechanisms of PA-MSHA on bladder cancer in vitro and in vivo. SV-40-immortalized normal uroepithelial cells (SV-HUC-1) and human bladder cancer cell lines (T24, 5637, and HT-1376) were treated with PA-MSHA or PA (heat-killed P. aeruginosa). At first, the effect of PA-MSHA on cancer cell proliferation was measured using Cell Counting Assay Kit-8 (CCK-8), whereas the changes of cell morphology were observed by transmission electron microscopy. The early apoptosis induced by PA-MSHA was evaluated by flow cytometry, and the expression level of apoptosis-related molecules was detected using Western blot assay. We then investigated the activation of the epidermal growth factor receptor signaling pathway stimulated by PA-MSHA; the expression and phosphorylation of several key regulators involved in the EGFR signaling pathway were detected. At last, xenograft tumor in nude mice was used to further investigate the antitumor effect of PA-MSHA in vivo. Our results showed that PA-MSHA could efficiently inhibit proliferation and induce apoptosis in human bladder cancer cell lines. Furthermore, cells stimulated with PA-MSHA exhibited an inactivation of EGFR signaling. In vivo, PA-MSHA treatment significantly suppressed tumor growth and induced apoptosis in xenografts tumor in nude mice. PA-MSHA could efficiently inhibit proliferation and induce apoptosis in human bladder cancer cells in vitro and in vivo, which is associated with the inactivation of EGFR signaling pathway, and it might be used as a potential therapeutic agent for bladder cancer. 23835087 Overexpression of the Rv0805 phosphodiesterase elicits a cAMP-independent transcriptional response. The Rv0805 gene in Mycobacterium tuberculosis encodes a metallophosphoesterase which shows cAMP-hydrolytic activity. Overexpression of Rv0805 has been used as a tool to lower intracellular cAMP levels and thereby elucidate the roles of cAMP in mycobacteria. Here we show that levels of cAMP in M. tuberculosis were lowered by only ∼30% following overexpression of Rv0805, and transcript levels of a number of genes, which include those associated with virulence and the methyl citrate cycle, were altered. The genes that showed altered expression were distinct from those differentially regulated in a strain deleted for the cAMP-receptor protein (CRP(Mt)), consistent with the relatively low dependence on cAMP of CRP(Mt) binding to DNA. Using mutants of Rv0805 we show that the transcriptional signature of Rv0805 overexpression is a combination of catalysis-dependent and independent effects, and that the structurally flexible C-terminus of Rv0805 is crucial for the catalysis-independent effects of the protein. Our study demonstrates the dissociation of Rv0805 and cAMP-regulated gene expression, and reveals alternate functions for this phosphodiesterase from M. tuberculosis. 23969224 Coronary artery bypass graft surgery using the radial artery as a secondary conduit improves patient survival. The clinical benefits of the left internal thoracic artery-to-left anterior descending coronary artery graft are well established in coronary artery bypass graft surgery (CABG). However, limited data are available regarding the long-term outcome of the radial artery (RA) as a secondary conduit over the established standard of the saphenous venous graft. We compared the 12-year survival outcome in a set of propensity-matched CABG patients who received either the RA or the saphenous vein as a secondary conduit. A multivariable logistic regression that included 18 baseline characteristics was used to define the propensity of receiving an RA graft. The propensity model resulted in 260 matched pairs who underwent first-time isolated CABG from 1996 to 2001 with similar preoperative characteristics (C statistic=0.86). The cumulative 12-year survival estimated by use of the Kaplan-Meier method was higher for the RA graft patients (hazard ratio 0.76; P=0.03). This survival advantage was especially significant in diabetics (P=0.005), in women (P=0.02), and in the elderly (P=0.04.) The protective effect appeared beginning at year 5 post surgical intervention. The RA as a secondary conduit provided superior long-term survival after CABG, especially in diabetic patients, women, and the elderly. This effect was most pronounced >5 years after surgery. 23942154 Effective Teaching and Feedback Skills for International Emergency Medicine "Train the Trainers" Programs. As the specialty of Emergency Medicine (EM) develops around the world, it has become common for practitioners from countries with mature EM systems to assist those in regions with developing systems. One effective and frequently used model is "train the trainers," in which a group of consultant teachers instructs a cadre of clinicians in the host region to then become the future teachers of EM in that area. This model has the advantage of overcoming cultural barriers to instruction and can lead to providing a lasting training infrastructure in the region. A key to a successful program is the use of effective and culturally appropriate teaching and feedback skills. The goal of this article is to bring together experts in adult education with experts in training in the international setting to present teaching and feedback skills and how they can be applied in different settings and cultures. Cutting edge instruction and evaluation techniques that can be employed in intercultural "train the trainers" programs will be presented. The characteristics of successful programs, using specifics from actual programs, will also be shared. Applying the described teaching and evaluation skills with modifications based on local culture will help empower newly trained teachers who will contribute in turn to the longevity of EM in the region and set a high teaching standard that will benefit generations of future colleagues. 23964748 Characterization of Carbapenem Nonsusceptible Pseudomonas aeruginosa in Denmark: A Nationwide, Prospective Study. From January 1st 2011 through June 30th 2011, 116 nonreplicate, noncystic fibrosis-related Pseudomonas aeruginosa isolates with reduced carbapenem susceptibility were collected from 12 out of 13 Danish departments of clinical microbiology. The presence of acquired β-lactamases was assessed with combination tablet-diffusion methodology and polymerase chain reaction. In addition, antimicrobial susceptibility testing, an efflux pump inhibitor assay, and pulsed-field gel electrophoresis (PFGE) were performed. Isolates producing acquired β-lactamases were further investigated by serotyping and multi locus sequence typing. Eight isolates produced the metallo-β-lactamase (MBL) VIM-2, and one isolate produced OXA-10 and VEB-1-like extended-spectrum beta-lactamase (ESBL). Phenotypic indications of derepressed AmpC and efflux pump were seen in 56 and 43 isolates, respectively. Overall, the results indicate that mutational factors related to permeability-often combined with derepressed, chromosomal AmpC-is the main factor behind carbapenem nonsusceptibility in Danish P. aeruginosa isolates. The ESBL producer and all the VIM producers belonged to international clones. PFGE revealed that most of the isolates were unrelated, but clonal spread was seen; the 116 isolates distributed in 97 PFGE types, with the largest cluster consisting of 4 isolates (including three isolates from the same hospital with 100% similarity). Thirty-two isolates were pair-wise related, while the remaining isolates were clonally unrelated, as were all nine ESBL/MBL producers. 23009351 pH-and thermo-sensitive pluronic/poly(acrylic acid) in situ hydrogels for sustained release of an anticancer drug. In this study, we developed oral in situ gelling formulations composed of pluronic (Plu) and polyacrylic acid (PAA) for the delivery of an anticancer drug, epirubicin (Epi). We investigated various Plu/PAA/Epi formulations for their physicochemical properties and in vitro permeation and accumulation, as well as for in vivo pharmacokinetic and antitumor efficacy. A scanning electron microscopic (SEM) image of Plu 14%/PAA 0.75%/Epi hydrogel showed a sponge-like structure. This formulation has suitable gelation time, water content, bioadhesive force, structural stability, and a high permeation percentage of Epi, with sustained drug release characteristics for 96 h. This hydrogel was retained at the end of the ileum near the colon of Sprague-Dawley (SD) rats for at least 12 h. An in vivo pharmacokinetic study using SD rats showed that after oral administration in this formulation, Epi had prolonged half-life, greater area under the curve, and higher relative bioavailability than in an oral Epi solution. In vivo tumor growth inhibition of Epi in this formulation was more pronounced compared with oral Epi and intravenous Epi solutions in CT-26 mouse colon adenocarcinoma bearing Balb/c mice. This study highlights the advantages of using oral in situ temperature- and pH-sensitive hydrogels for future cancer therapy. 23887147 Computational detection of abundant long-range nucleotide covariation in Drosophila genomes. Functionally important nucleotide base-pairing often manifests itself in sequence alignments in the form of compensatory base changes (covariation). We developed a novel index-based computational method (CovaRNA) to detect long-range covariation on a genomic scale, as well as another computational method (CovStat) for determining the statistical significance of observed covariation patterns in alignment pairs. Here we present an all-versus-all search for nucleotide covariation in Drosophila genomic alignments. The search is genome wide, with the restriction that only alignments that correspond to euchromatic regions, which consist of at least 10 Drosophila species, are being considered (59% of the euchromatic genome of Drosophila melanogaster). We find that long-range covariations are especially prevalent between exons of mRNAs as well as noncoding RNAs; the majority of the observed covariations appear as not reverse complementary, but as synchronized mutations, which could be due to interactions with common interaction partners or due to the involvement of genomic elements that are antisense of annotated transcripts. The involved genes are enriched for functions related to regionalization as well as neural and developmental processes. These results are computational evidence that RNA-RNA long-range interactions are a widespread phenomenon that is of fundamental importance to a variety of cellular processes. 23887061 Vigorous physical activity and longitudinal associations with cardiometabolic risk factors in youth. Objective:To examine the longitudinal associations between different physical activity (PA) intensities and cardiometabolic risk factors among a sample of Canadian youth.Methods:The findings are based on a 2-year prospective cohort study in a convenience sample of 315 youth aged 9-15 years at baseline from rural and urban schools in Alberta, Canada. Different intensities (light, moderate and vigorous) of PA were objectively assessed with Actical accelerometers. The main outcome measures were body mass index (BMI) z-score, waist circumference, cardiorespiratory fitness and systolic blood pressure at 2-year-follow-up and conditional BMI z-score velocity. A series of linear regression models were conducted to investigate the associations after adjusting for potential confounders.Results:At follow-up, cardiorespiratory fitness increased (quartile 1 vs quartile 4=43.3 vs 50.2; Ptrend<0.01) and waist circumference decreased (quartile 1 vs quartile 4=79.0 vs 72.6; Ptrend=0.04; boys only) in a dose-response manner across quartiles of baseline vigorous-intensity PA. A similar trend was observed for systolic blood pressure (quartile 1 vs quartile 4=121.8 vs 115.3; Ptrend=0.07; boys only). Compared with quartile 1 of vigorous-intensity PA, BMI z-score at follow-up and conditional BMI z-score velocity were significantly lower in the quartile 2 and 3 (P<0.05). Waist circumference at follow-up also decreased (quartile 1 vs quartile 4=75.3 vs 73.8; Ptrend=0.04) across quartiles of baseline moderate-intensity PA.Conclusions:Time spent in vigorous-intensity PA was associated with several positive health outcomes 2 years later. These findings suggest that high-intensity activities in youth help to reduce the risk for several chronic diseases.International Journal of Obesity advance online publication, 20 August 2013; doi:10.1038/ijo.2013.135. 23838820 Baclofen for the Treatment of Pediatric Gastroesophageal Reflux Disease: A Single Tertiary Center Experience. Baclofen, a GABA(B) receptor agonist, has been shown to reduce the episodes of gastroesophageal reflux (GER) by reducing the incidence of transient lower esophageal sphincter relaxations. Although baclofen has been shown to reduce reflux symptoms in adults, data in pediatric patients is limited. The aim of the study was to evaluate the efficacy of baclofen in children with refractory GER. Medical charts of patients 1-18 years of age treated with baclofen for persistent GER symptoms were reviewed retrospectively. Short-term (at first clinic visit) and long-term (12 months) clinical responses were assessed. 53 patients were included in the final analysis. The mean duration of illness was 1.5 years and the mean age was 6.1 years. All patients were on either once (53%) or twice daily (47%) doses of proton pump inhibitors (PPIs) at the time of initiation of baclofen. Thirty-five (66%) patients experienced a significant reduction in clinical symptoms at their first follow-up visit. In the remaining 18 patients, however, baclofen was stopped due either to no response (n = 15) or adverse events (n = 3). 27 patients continued treatment and were assessed for long-term response. Of those, 22 (81%) had a sustained response to baclofen at 12 months while 5 (19%) lost response. We recognized no clinical characteristic differences between those with and without a response to baclofen at either time point. Baclofen can be used as supplemental therapy to PPIs in children with refractory GER; however, prospective trials are needed to further validate our results and assess safety. 23827645 Uncertain areas in the diagnosis of allergic bronchopulmonary aspergillosis in patients with asthma. The prevalence of allergic bronchopulmonary aspergillosis (ABPA) in patients with bronchial asthma remains unknown. We evaluated the roles of various laboratory tests in the diagnosis of ABPA, including, skin prick test (SPT) for Aspergillus fumigatus (Af), and serum Af specific IgE and IgG antibody measurement. A total of 50 asthma patients with more than 1000cell/μL of peripheral blood eosinophils were prospectively collected between January 2007 and September 2011. Evaluations using SPT for Af, serum total IgE and specific IgE antibody to Af by CAP system, IgG antibody to Af by enzyme immunoassay (EIA) or CAP system were performed according to the essential minimal criteria for the diagnosis of ABPA - asthma, immediate cutaneous reactivity to Af, elevated total IgE, and raised Af specific IgE and IgG. Among 50 patients, three patients (6.0%) were diagnosed as ABPA, of whom each confirmed five items of the essential minimal diagnostic criteria for the diagnosis of ABPA. Six patients (12.0%) showed negative responses to Af in SPT, but positive responses in specific IgE by CAP system. Eight patients (16.0%) showed negative responses to IgG to Af by CAP system, but positive responses by enzyme immunoassay (EIA). SPT and serum IgE to Af measurement by CAP system should be performed simultaneously. It is reasonable to set up cut-off values in Af specific IgE/IgG by CAP system for the differentiation of ABPA from Af sensitised asthma patients. 23287100 Validity and reliability of the Spanish sign language version of the KIDSCREEN-27 health-related quality of life questionnaire for use in deaf children and adolescents. The aim of this paper was to test the validity and reliability of a Spanish sign language (SSL) adaptation of KIDSCREEN-27, a health-related quality of life (HRQoL) questionnaire for use in deaf children and adolescents. We performed an observational cross-sectional study of 114 deaf children and adolescents aged 8 to 18 years old. The Spanish version of the KIDSCREEN-27 was adapted to SSL through the translation-back translation technique. The adapted questionnaire was then administered using a web tool to ensure complete access to study participants. Floor and ceiling effects were calculated. Structural and cultural validity were tested using exploratory and confirmatory factor analysis. Cronbach's α was used to assess internal consistency. The questionnaire was administered for a second time to the entire sample after 2 to 4 weeks (test-retest reliability). In the SSL version of the KIDSCREEN-27, as in the original Spanish scale, five dimensions explained 59% of the variance. None of the participants obtained the minimum or maximum scores on the scale (floor and ceiling effect, respectively). Confirmatory factor analysis showed the goodness-of-fit of the factor solution with five dimensions of the SSL version. The Cronbach's α of both the total scale and of each of the distinct dimensions was above 0.75. The intra-class correlation coefficient of the test-retest scale was considered acceptable in all the dimensions. The reliability and validity of the SSL version of the KIDSCREEN-27 are similar to those of the original Spanish version, providing a new tool for measuring HRQoL in deaf children and adolescents. 23489984 Contribution of contaminated sites to the global mercury budget. Global mercury emission inventories include anthropogenic emissions, contributing via current use or presence of mercury in a variety of products and processes, as well as natural source emissions. These inventories neglect the contribution of areas contaminated with mercury from historical accumulation, which surround mines or production plants associated with mercury production or use. Although recent studies have shown that releases of mercury from these historical sites can be significant, a database of the global distribution of mercury contaminated sites does not exist, nor are there means of scaling up such releases to estimate fluxes on a regional and global basis. Therefore, here we estimated for the first time the contribution of mercury releases from contaminated sites to the global mercury budget. A geo-referenced database was built, comprising over 3000 mercury contaminated sites associated with mercury mining, precious metal processing, non-ferrous metal production and various polluted industrial sites. In the assessment, mercury releases from these sites to both the atmosphere as well as the hydrosphere were considered based on data available for selected case studies, their number, the reported extent of contamination and geographical location. Annual average global emissions of mercury from identified contaminated sites amount to 198 (137-260) Mgyr(-1). Of that, 82 (70-95)Mgyr(-1) contribute to atmospheric releases, while 116 (67-165) Mgyr(-1) is estimated to be transported away from these sites by hydrological processes. Although these estimates are associated with large uncertainties, our current understanding of mercury releases from contaminated sites indicates that these releases can also be of paramount importance on the global perspective. This is especially important as it is known that these sites represent a long-term source of releases if not managed properly. Therefore, the information presented here is needed by governments and NGO's in order to re-focus resources in making decisions regarding mitigation and remediation strategies on a global level. 23910143 Endovascular repair of a chronic arch dissecting aneurysm with a branched endograft. Acute type A dissection requires emergent surgery that often includes ascending aorta replacement. Regular follow-up with computed tomography (CT) can identify aneurysmal dilatation of the false lumen distal to the open repair. Because redo operations can be high risk, we performed an endovascular repair on a patient deemed unfit for open operation using an aortic arch branched device with 2 internal branches for the innominate trunk and the left common carotid artery. This endovascular approach is a possible alternative to open surgical procedures in selected cases. 23625576 Biographical sketch: harald tscherne, MD (1933-present). This biographical sketch on Prof. Harald Tscherne corresponds to the historic text, The Classic: Der Straßenunfall [Traffic Accidents]. Wien Med Wochenschr. 1966;116:105-108 (Translated by Dr. Roman Pfeifer), available at DOI 10.1007/s11999-013-3012-9 . 23912227 Destructive Adsorption of Diazinon Pesticide by Activated Carbon Nanofibers Containing Al2O 3 and MgO Nanoparticles. We report the destructive adsorption of Diazinon pesticide by porous webs of activated carbon nanofibers containing Al2O3 and MgO nanoparticles. The results show that, the presence of Al2O3 and MgO nanoparticles in the activated carbon nanofibers increases the amount of destructively adsorbed Diazinon pesticide by activated carbon nanofibers. Moreover, type, amount, and specific surface area of metal oxide nanoparticles affect the adsorption rate as well as the total destructively adsorbed Diazinon. Liquid chromatography proved the degradation of Diazinon by chemical reaction with Al2O3 and MgO nanoparticles. Liquid chromatography-mass spectrometry showed that the main product of reaction between Diazinon and the metal oxides is 2-isopropyl-6-methyl-4-pyrimidinol with less toxicity than Diazinon. 23910955 Waterjet drilling in porcine bone: The effect of the nozzle diameter and bone architecture on the hole dimensions. Using waterjets instead of rigid drill bits for bone drilling can be beneficial due to the absence of thermal damage and a consequent sharp cut. Additionally, waterjet technology allows the development of flexible instruments that facilitate maneuvering through complex joint spaces. Controlling the drilling depth is of utmost importance to ensure clinical safety, but is challenging given the local variations in structural properties of the bone. The goal of this study was to deduce a descriptive mathematical equation able to predict the hole depth and diameter based on the local structural properties of the bone at given waterjet diameters. 210 holes were drilled in porcine femora and tali with waterjet diameters (Dnozzle) of 0.3, 0.4, 0.5 and 0.6mm at a pressure of 700bar and a 5s jet time. Hole depths (Lhole), diameters (Dhole) and bone architectural properties were determined using microCT scans. The most important bone architectural property is the bone volume fraction (BV/TV), resulting in the significant predictive equations: Lhole=34.3 (⁎) Dnozzle(2)-17.6 (⁎) BV/TV+10.7 (R(2)=0.90, p<0.001), and hole Dhole=3.1(⁎) Dnozzle-0.45(⁎)BV/TV+0.54 (R(2)=0.58, p=0.02), with Lhole, Dhole and Dnozzle in mm. Drilling to a specific depth in bone tissue with a known BV/TV is possible, thereby contributing to the safe application of waterjet technology in orthopedic surgery. 23317098 The impact of oxidative stress on islet transplantation and monitoring the graft survival by non-invasive imaging. Islet transplantation is an attractive strategy to treat severe diabetic conditions in patients suffering from autoimmune derived diabetes, and it has currently been considered a forefront research arena in diabetes. Major aim of islet transplantation is to achieve successful insulin independent disease free survival. The key challenges in transplanted islets are the generation of reactive oxygen species (ROS) and associated oxidative stress, pro-inflammatory cytokine - (TNFα) mediated apoptotic induction, attack by immune cells, and achieving revascularization with minimal hypoxic microenvironment. Free radicals and their derivatives are constantly produced in living systems, but at relatively low level, and in a balanced state. Oxidative stress, which occurs as a result of an imbalance between the intracellular free radicals production and the cellular antioxidant defense mechanisms in the transplanted islets, can lead to cell death. The balance between oxidants and antioxidants in a cell can be easily disturbed by increase in ROS production or reduction in the level of cellular antioxidant defensive substances, which can cause many metabolic complications, including pancreatic β-cell damage. Antioxidants function as blockers of radical processes by eliminating harmful ROS produced during normal cellular metabolism. A complex antioxidant defense mechanism has been developed by nature in cells to protect the cellular homeostasis. This system mainly includes antioxidant enzymes, vitamins and minerals. As transplanted islet survival is crucial for achieving successful therapy, most of these antioxidants can be used as a supplement to scavenge the local ROS thereby improving the survival of transplanted islets. Currently, very few techniques have been routinely used to qualitatively and quantitatively assess the survival and function of islet grafts, especially to confirm the success of treatment, which includes metabolic parameters such as blood glucose, insulin and C-peptide levels. These biochemical measurements provide markers at only the late stages of islet rejection. Use of molecular imaging techniques has the potential for real-time non-invasive monitoring of the functional status and viability of transplanted islet grafts in living animals. This review mainly focuses on the current status of islet transplantations, potential preventive strategies used to reduce oxidative stress-mediated toxicity in islet grafts, and use of molecular imaging as a tool to quantitatively evaluate the functional status of the transplanted islets in living animals. 23885899 Investigating Uptake and Translocation of Mercury Species by Sawgrass ( Cladium jamaicense ) Using a Stable Isotope Tracer Technique. The role of macrophytes in mercury (Hg) cycling in the Florida Everglades ecosystem has not been fully understood. In this study, a stable isotope ((199)Hg(2+)) addition technique was used to trace the methylation, uptake, and translocation of Hg by sawgrass ( Cladium jamaicense ) and quantitatively evaluate the contribution of atmospheric and soil Hg to Hg in sawgrass leaves and below-ground biomass. The results showed that spiked (199)Hg(2+) could be rapidly methylated to monomethylmercury (Me(199)Hg) in the soil of the sawgrass pots. Only small portions of total Hg (THg) and monomethylmercury (MeHg) in the soil could be taken up by sawgrass, indicated by the ratios of T(199)Hg and Me(199)Hg (tracer) concentrations in the sawgrass below-ground biomass (BGBM) over that in the soil (6.50 ± 1.9% and 12.8 ± 3.6% for THg and MeHg, respectively). Concentrations of T(199)Hg (tracer) and Me(199)Hg (tracer) in sawgrass leaves only accounted for 5.50 ± 2.8% and 15.6 ± 4.0%, respectively, of that in the BGBM, implying that the fractions of mercury species transported upward by sawgrass were also small. Statistical analysis (t test) showed that sawgrass preferred MeHg over THg in both uptake and upward translocation. The majority (>90%) of THg in sawgrass leaves were estimated to be obtained from atmospheric Hg, rather than from soil, suggesting that assimilation of atmospheric Hg could increase the overall Hg stock in the Florida Everglades ecosystem. The finding about foliar uptake of Hg is especially important for a better understanding of mercury cycling in the Everglades, given the large amount of sawgrass biomass in this ecosystem. 23948431 Irony of fate: role of iron-mediated ROS in Leishmania differentiation. The protozoan parasite Leishmania experiences extreme environmental changes as it alternates between insect and mammalian hosts. In some species, differentiation of insect promastigotes into mammalian-infective amastigotes is induced by elevated temperature and low pH, conditions found within macrophage parasitophorous vacuoles (PVs). However, the signaling events controlling amastigote differentiation remain poorly understood. Recent studies revealed a novel role for iron uptake in orchestrating the differentiation of amastigotes, through a mechanism that involves production of reactive oxygen species (ROS) and is independent from pH and temperature changes. ROS are generally thought to be deleterious for pathogens, but it is becoming increasingly apparent that they can also function as signaling molecules regulating Leishmania differentiation, in a process that is tightly controlled by iron availability. 23934046 Rocuronium reversed by sugammadex versus mivacurium during high-risk eye surgery: An institutional anaesthetic practice evaluation. This institutional anaesthetic practice evaluation compared patient safety with respect to residual neuromuscular blockade (NMB) at the time of tracheal extubation in patients undergoing high-risk eye surgery. Two muscle relaxation regimens were compared: rocuronium administered via intravenous (i.v.) bolus dosing combined with reversal through sugammadex at end of surgery (group R/S; 17 patients); mivacurium administered via continuous i.v. infusion without antagonization (group M; 22 patients). Train-of-four (TOF) monitoring determined the depth of NMB. The TOF ratio at the time of tracheal extubation was greater in group R/S (median 1.03) than in group M (median 0.62). Time from end of surgery to tracheal extubation was not significantly different. The surgeons were 100% satisfied with the working conditions provided under both relaxation regimens. Residual postoperative curarization at the time of extubation was frequently observed in group M, whereas there was complete recovery in group R/S. Reversal of NMB by sugammadex provides an additional safety dimension to patient care and should thus be considered especially for those at risk of airway complications or aspiration, in addition to frail patients. 23797228 Radiation Exposure to Family Caregivers and Nurses of Pediatric Neuroblastoma Patients Receiving 131I-Metaiodobenzylguanidine (131I-MIBG) Therapy. I-MIBG provides molecularly targeted radiotherapy for pediatric neuroblastoma patients with relapsed or refractory disease. At our institution, designated family caregivers and nurses participate in the care of the child during hospital isolation for approximately 3-5 days post-administration. The purpose of this study was to measure radiation exposure to family caregivers and nurses caring for children with neuroblastoma during their stay in the hospital for I-MIBG therapy. Iodine-I-MIBG therapy was administered to 14 children (mean age 6.7 ± 3.8 years, range 3-13 years) for relapsed or refractory neuroblastoma from 2009 to 2010. The administered activity ranged from 5.92 to 23.31 GBq (mean 13.65 ± 5.22 GBq). The mean administered activities were 8.77 ± 2.07 GBq (range 5.92-11.1 GBq) and 17.32 ± 3.4 GBq (range 11.84-23.31 GBq) for children less than 7 and 7 years or older, respectively. One or two designated caregivers received specific radiation safety training prior to treatment. One caregiver was allowed to stay in a room adjacent to the child to provide general patient care as instructed by nursing. Nurses assigned to the care of the patient also received specific radiation instructions. The total caregiver and nursing whole body radiation dose was determined using real-time personal dosimetry. There was no correlation between caregiver (r = -0.068, P = 0.817) or nursing (r = -0.031, P = 0.916) whole-body radiation dose and the patient-administered activity. The overall mean caregiver radiation dose was 1.79 ± 1.04 mSv, but the range of caregiver radiation doses varied by more than an order of magnitude (0.35-3.81 mSv), with no caregiver receiving more than 4.0 mSv. The overall mean nursing radiation dose was 0.44 ± 0.27 mSv per treatment, ranging from 0.15 to 1.08 mSv, with no nurse receiving more than 1.1 mSv. When grouped by patient age, there was no significant difference (P = 0.673) in the mean caregiver exposure for children less than 7 years, 1.94 ± 1.17 mSv (n = 6, range 0.7-3.81 mSv), compared to 1.69 ± 0.99 mSv (n = 8, range 0.35-3.37 mSv) for children 7 years or older. Similarly, there was no significant difference (P = 0.511) in mean nursing exposure for children less than 7 years, 0.5 ± 0.31 mSv (n = 6, range 0.18-1.08 mSv), compared to 0.4 ± 0.24 mSv (n = 8, range 0.15-0.94 mSv) for children 7 years or older. There was no significant correlation between caregiver or nursing radiation exposure and patient-administered activity or no significant difference between patient age. This may suggest that older children who tend to receive higher administered activities may require less direct caregiver support during their hospital stay. Most importantly, all caregivers and nurses received radiation doses allowed under current regulations for individuals exposed to therapy patients during hospital isolation (<5.0 mSv), although this does not include exposure the caregivers may receive once the patient leaves the hospital. 22944593 Toxicity of terpenes on fibroblast cells compared to their hemolytic potential and increase in erythrocyte membrane fluidity. Terpenes are considered potent skin permeation enhancers with low toxicity. Electron paramagnetic resonance (EPR) spectroscopy of the spin label 5-doxyl stearic acid (5-DSA) was used to monitor the effect of sesquiterpene nerolidol and various monoterpenes on membrane fluidity in erythrocyte and fibroblast cells. In addition, the hemolytic levels and cytotoxic effects on cultured fibroblast cells were also measured to investigate possible relationships between the cellular irritation potentials of terpenes and the ability to modify membrane fluidity. All terpenes increased cell membrane fluidity with no significant differences between the monoterpenes, but the effect of sesquiterpene was significantly greater than that of the monoterpenes. The IC(50) values for the terpenes in the cytotoxicity assay indicated that 1,8-cineole showed lower cytotoxicity and α-terpineol and nerolidol showed higher cytotoxicity. The correlation between the hemolytic effect and the IC(50) values for fibroblast viability was low (R=0.61); however, in both tests, nerolidol was among the most aggressive of terpenes and 1,8-cineole was among the least aggressive. Obtaining information concerning the toxicity and potency of terpenes could aid in the design of topical formulations optimized to facilitate drug absorption for the treatment of many skin diseases. 23962418 Model-based Iterative Reconstruction for Multi-Detector Row CT Assessment of the Adamkiewicz Artery. Purpose:To determine if model-based iterative reconstruction (MBIR) can improve visualization of the Adamkiewicz artery on multi-detector row computed tomographic (CT) images compared with adaptive statistical iterative reconstruction (ASIR) and filtered back projection (FBP).Materials and Methods:This retrospective study was approved by the institutional review board, and written informed consent for the CT examination was obtained. Thirty-three patients underwent contrast material-enhanced 64-section multi-detector row CT for assessment of aortic aneurysm or dissection. Helical data were reconstructed by using FBP, ASIR, and MBIR. The signal-to-noise ratio of the aorta and contrast-to-noise ratio of the anterior spinal artery relative to the spinal cord were measured on multiplanar reformatted images. Visualization of the Adamkiewicz artery and its continuity with the intercostal or lumbar artery were evaluated by using a four-point scale. All image analyses were performed by two blinded, independent observers. The one-way analysis of variance and the Wilcoxon signed-rank test were used for statistical analysis.Results:MBIR showed significantly better signal-to-noise and contrast-to-noise ratios than did ASIR and FBP (P < .05 for all comparisons) with good interobserver agreement (intraclass correlation coefficient of 0.93 for signal-to-noise ratio and 0.75 for contrast-to-noise ratio). The visualization score of the Adamkiewicz artery was also significantly better when MBIR was used (3.4 ± 0.8 and 3.6 ± 0.7 for observers A and B, respectively) than when ASIR (2.7 ± 1.1 and 3.0 ± 1.0, respectively) or FBP (2.5 ± 1.2 and 3.1 ± 0.9, respectively) was used.Conclusion:Use of the MBIR algorithm led to improved multi-detector row CT visualization of the Adamkiewicz artery when compared with the use of ASIR and FBP.© RSNA, 2013. 23736744 A prospective photographic study of the ocular fundus in obstructive sleep apnea. The prevalence of optic nerve and retinal vascular changes within the obstructive sleep apnea (OSA) population are not well-known, although it has been postulated that optic nerve ischemic changes and findings related to an elevated intracranial pressure may be more common in OSA patients. We prospectively evaluated the ocular fundus in unselected patients undergoing overnight diagnostic polysomnography (PSG). Demographic data, medical/ocular history, and nonmydriatic fundus photographs were prospectively collected in patients undergoing PSG at our institution and reviewed for the presence of optic disc edema for which our study was appropriately powered a priori. Retinal vascular changes were also evaluated. OSA was defined using the measures of both sleep-disordered breathing and hypoxia. Of 250 patients evaluated in the sleep center, fundus photographs were performed on 215 patients, among whom 127 patients (59%) had an apnea/hypopnea index (AHI) ≥15 events per hour, including 36 with severe OSA. Those with AHI <15 served as the comparison group. None of the patients had optic disc edema (95% confidence interval [CI]: 0%-3%). There was no difference in rates of glaucomatous appearance or pallor of the optic disc among the groups. Retinal arteriolar changes were more common in severe OSA patients (odds ratio: 1.09 per 5 unit increase in AHI; 95% CI, 1.02-1.16; P = 0.01), even after controlling for mean arterial blood pressure. We did not find an increased prevalence of optic disc edema or other optic neuropathies in our OSA population. However, retinal vascular changes were more common in patients with severe OSA, independent of blood pressure. 22533633 A new lignan with anti-tumour activity from Polygonum perfoliatum L. The methanol extract of the tubers of Polygonum perfoliatum L. afforded a new lignan: 8-oxo-pinoresinol (1), and five known compounds 3',5-dihydroxy-3,4',5',7-tetramethoxy-flavone (2), catechin (3), quercetin (4), quercetin-3-O-β-D-glucuronide (5) and rutin (6). Their structures were established by MS, one- and two-dimensional NMR experiments. Compound 1 showed cytotoxicity against human mammary carcinoma (Bcap-37), human colon carcinoma (RKO), human hepatocellular carcinoma (SMMC-7721), human prostate carcinoma (PC3) and human erythroleukaemia (K562) cells. 23828871 The link between resting-state functional connectivity and cognition in MS patients. The objective of this paper is to explore differences in resting-state functional connectivity between cognitively impaired and preserved multiple sclerosis (MS) patients. Sixty MS patients and 18 controls were assessed with the Brief Repeatable Battery of Neuropsychological Tests (BRB-N). A global Z score of the BRB-N was obtained and allowed us to classify MS patients as cognitively impaired and cognitively preserved (n = 30 per group). Functional connectivity was assessed by independent component analysis of resting-state networks (RSNs) related to cognition: the default mode network, left and right frontoparietal and salience network. Between-group differences were evaluated and a regression analysis was performed to describe relationships among cognitive status, functional connectivity and radiological variables. Compared to cognitively preserved patients and healthy controls, cognitively impaired patients showed a lesser degree of functional connectivity in all RSNs explored. Cognitively preserved patients presented less connectivity than the control group in the left frontoparietal network. Global Z scores were positively and negatively correlated with brain parenchymal fraction and lesion volume, respectively. Decreased cognitive performance is accompanied by reduced resting state functional connectivity and directly related to brain damage. These results support the use of connectivity as a powerful tool to monitor and predict cognitive impairment in MS patients. 23932332 The genetics of insomnia - Evidence for epigenetic mechanisms? Sleep is a complex physiological process and still remains one of the great mysteries of science. Over the past 10 y, genetic research has provided a new avenue to address the regulation and function of sleep. Gene loci that contribute quantitatively to sleep characteristics and variability have already been identified. However, up to now, a genetic basis has been established only for a few sleep disorders. Little is yet known about the genetic background of insomnia, one of the most common sleep disorders. According to the conceptualisation of the 3P model of insomnia, predisposing, precipitating and perpetuating factors contribute to the development and maintenance of insomnia. Growing evidence from studies of predisposing factors suggests a certain degree of heritability for insomnia and for a reactivity of sleep patterns to stressful events, explaining the emergence of insomnia in response to stressful life events. While a genetic susceptibility may modulate the impact of stress on the brain, this finding does not provide us with a complete understanding of the capacity of stress to produce long-lasting perturbations of brain and behaviour. Epigenetic gene-environment interactions have been identified just recently and may provide a more complex understanding of the genetic control of sleep and its disorders. It was recently hypothesised that stress-response-related brain plasticity might be epigenetically controlled and, moreover, several epigenetic mechanisms have been assumed to be involved in the regulation of sleep. Hence, it might be postulated that insomnia may be influenced by an epigenetic control process of both sleep mechanisms and stress-response-related gene-environment interactions having an impact on brain plasticity. This paper reviews the evidence for the genetic basis of insomnia and recent theories about epigenetic mechanisms involved in both sleep regulation and brain-stress response, leading to the hypothesis of an involvement of epigenetic mechanisms in the development and maintenance of insomnia. 23928896 Physical Activity in Daily Life in Fibrotic Idiopathic Interstitial Pneumonia. ABSTRACT The six-minute walk test (6MWT) is commonly used to assess exercise capacity in patients with fibrotic idiopathic interstitial pneumonias (f-IIP). However, it is not known whether these patients have reduced levels of physical activity in daily life (DLPA) or whether pulmonary function tests and the 6MWT correlate with their DLPA.The aim of this study was to measure DLPA in patients with f-IIP and determine the relationships between DLPA and the 6MWT, pulmonary functional parameters, and anxiety and depression scores. Fifty f-IIP patients and 25 sex- and age-matched healthy control subjects were enrolled. Markers of DLPA were assessed with a physical activity monitor for four consecutive days. Hospital Anxiety and Depression Scale (HADS) scores were evaluated.DLPA parameters were significantly reduced in f-IIP patients compared with controls subjects (all p < 0.001). The mean number of steps per day correlated strongly with DLco, FVC, the 6MWT distance and the 6MWT lowest SpO2. DLPA was unrelated to HADS scores. Multivariate analysis showed that DLco and 6MWT distance explained only 31% of the variance in the number of steps per day. DLco, 6MWT distance, 6MWT lowest SpO2 and DLPA were significant predictors of mortality, but only DLco and 6MWT distance were independent predictors.Quantitation of DLPA is a novel patient-centred approach to assess function in f-IIP, and may be a useful tool for clinical care and assessing response to therapy. 23929850 Flow field modulation. The nonlinear and nonstationary nature of Navier-Stokes equations produces fluid flows that can be noticeably different in appearance with subtle changes. In this paper, we introduce a method that can analyze the intrinsic multiscale features of flow fields from a decomposition point of view, by using the Hilbert-Huang transform method on 3D fluid simulation. We show how this method can provide insights to flow styles and help modulate the fluid simulation with its internal physical information. We provide easy-to-implement algorithms that can be integrated with standard grid-based fluid simulation methods and demonstrate how this approach can modulate the flow field and guide the simulation with different flow styles. The modulation is straightforward and relates directly to the flow's visual effect, with moderate computational overhead. 23493372 Dexamethasone-mediated changes in adipose triacylglycerol metabolism are exaggerated, not diminished, in the absence of a functional GR dimerization domain. The glucocorticoid (GC) receptor (GR) has multiple effector mechanisms, including dimerization-mediated transactivation of target genes via DNA binding and transcriptional repression mediated by protein-protein interactions. Much attention has been focused on developing selective GR modulators that would dissociate adverse effects from therapeutic anti-inflammatory effects. The GR(dim/dim) mouse has a mutation in the dimerization domain of GR and has been shown to have attenuated transactivation with intact repression. To understand the role of GR dimerization-dependent targets in multiple tissues, we measured metabolic fluxes through several disease-relevant GC target pathways using heavy water labeling and mass spectrometry in wild-type and GR(dim/dim) mice administered the potent GC dexamethasone (DEX). Absolute triglyceride synthesis was increased in both wild-type and GR(dim/dim) mice by DEX in the inguinal and epididymal fat depots. GR(dim/dim) mice showed an exaggerated response to DEX in both depots. De novo lipogenesis was also greatly increased in both depots in response to DEX in GR(dim/dim), but not wild-type mice. In contrast, the inhibitory effect of DEX on bone and skin collagen synthesis rates was greater in wild-type compared with GR(dim/dim) mice. Wild-type mice were more sensitive to DEX-dependent decreases in insulin sensitivity than GR(dim/dim) mice. Wild-type and GR(dim/dim) mice were equally sensitive to DEX-dependent decreases in muscle protein synthesis. Chronic elevation of GCs in GR(dim/dim) mice results in severe runting and lethality. In conclusion, some metabolic effects of GC treatment are exaggerated in adipose tissue of GR(dim/dim) mice, suggesting that selective GR modulators based on dissociating GR transactivation from repression should be evaluated carefully. 23579947 Effect of ghrelin and anamorelin (ONO-7643), a selective ghrelin receptor agonist, on tumor growth in a lung cancer mouse xenograft model. Anamorelin (ONO-7643) is an orally active ghrelin receptor agonist in development for non-small cell lung cancer (NSCLC)-related anorexia/cachexia. It displays both orexigenic and anabolic properties via ghrelin mimetic activity and transient increases in growth hormone (GH). However, increasing GH and insulin-like growth factor-1 in cancer patients raises concerns of potentially stimulating tumor growth. Therefore, we investigated the effect of ghrelin and anamorelin on tumor growth in a murine NSCLC xenograft model. Female nude mice (15-21/group) with established A549 tumors were administered ghrelin (2 mg/kg i.p.), anamorelin (3, 10, or 30 mg/kg p.o.), or vehicle controls daily for 28 days. Tumor growth, food consumption, and body weight were monitored. Murine growth hormone (mGH) and murine insulin-like growth factor-1 (mIGF-1) were measured in plasma. Tumor growth progressed throughout the study, with no significant differences between treatment groups. Daily food consumption was also relatively unchanged, while the percentage of mean body weight gain at the end of treatment was significantly increased in animals administered 10 and 30 mg/kg compared with controls (p < 0.01). Peak mGH levels were significantly higher in ghrelin- and anamorelin-treated animals than in controls, while peak mIGF-1 levels were slightly elevated but not statistically significant. All regimens were well tolerated. These findings demonstrate that neither anamorelin nor ghrelin promoted tumor growth in this model, despite increased levels of mGH and a trend of increased mIGF-1. Together with anamorelin's ability to increase body weight, these results support the clinical development of ghrelin receptor agonist treatments for managing NSCLC-related anorexia/cachexia. 23937571 Nucleotide-binding oligomerization domain containing-like receptor family, caspase recruitment domain (CARD) containing 4 (NLRC4) regulates intrapulmonary replication of aerosolized Legionella pneumophila. Legionella pneumophila (Lp) flagellin activates signaling pathways in murine macrophages that control Lp replication. Nucleotide-binding oligomerization domain (NOD) containing-like receptor (NLR) family, caspase recruitment domain (CARD) containing 4 (NLRC4) and Toll-like Receptor (TLR5) both recognize Lp flagellin in vitro, but whether these two receptors play redundant or separate functional roles in vivo is unknown. The immune response of Nlrc4-/-, Nlrc4-/-/Tlr5-/-, and wild type C57Bl/6 mice was analyzed after in vivo infection with aerosolized Lp. Lp clearance from the lungs was delayed in Nlrc4-/- mice over seven days in comparison to wild type controls. Nlrc4-/-/Tlr5-/- mice had no additional defect. In contrast to TLR5, NLRC4 did not regulate recruitment of neutrophils to the lung. Although there were no differences among the mouse strains in the lung transcriptome at 4 hours, Nlrc4-/- and Nlrc4-/-Tlr5-/- mice had increased lung inflammation at 72 hours in comparison to WT. Nlrc4-/-/Tlr5-/- mice also had altered cytokine production at both 4 and 24 hours post infection when compared to wild-type (WT) and Nlrc4-/- mice. Lp replication in murine alveolar macrophages was NLRC4-dependent and TLR5-independent. These studies reveal that NLRC4 and TLR5 mediate different roles in the inflammatory response to Lp flagellin in an aerosolized infection model and NLRC4 regulates replication in both lungs and alveolar macrophages. 23376587 Impaired release of corticosterone from adrenals contributes to impairment of circadian rhythms of activity in hyperammonemic rats. Patients with liver cirrhosis may present impaired sleep-wake and circadian rhythms, relative adrenal insufficiency and altered hypothalamus-pituitary-adrenal gland (HPA) axis. The underlying mechanisms remain unclear. Circadian rhythms are modulated by corticosteroids which secretion is regulated by HPA axis. Hyperammonemia alters circadian rhythms of activity and corticosterone in rats. The aims were: (1) assessing whether corticosterone alterations are responsible for altered circadian rhythm in hyperammonemia: (2) to shed light on the mechanism by which corticosterone circadian rhythm is altered in hyperammonemia. The effects of daily corticosterone injection at ZT10 on circadian rhythms of activity, plasma corticosterone, adreno-corticotropic hormone (ACTH) and hypothalamic corticotropic releasing hormone (CRH) were assessed in control and hyperammonemic rats. ACTH-induced corticosterone release was analyzed in cultured adrenal cells. Corticosterone injection restores the corticosterone peak in hyperammonemic rats and their activity and circadian rhythm. Plasma ACTH and CRH in hypothalamus are increased in hyperammonemic rats. Corticosterone injection normalizes ACTH. Chronic hyperammonemia impairs adrenal function, reduces corticosterone content and ACTH-induced corticosterone release in adrenals, leading to reduced feedback modulation of HPA axis by corticosterone which contributes to impair circadian rhythms of activity. Impaired circadian rhythms and motor activity may be corrected in hyperammonemia and hepatic encephalopathy by corticosterone treatment. 23666934 Pigment pattern formation in the guppy, Poecilia reticulata, involves the Kita and Csf1ra receptor tyrosine kinases. Males of the guppy (Poecilia reticulata) vary tremendously in their ornamental patterns, which are thought to have evolved in response to a complex interplay between natural and sexual selection. Although the selection pressures acting on the color patterns of the guppy have been extensively studied, little is known about the genes that control their ontogeny. Over 50 years ago, two autosomal color loci, blue and golden, were described, both of which play a decisive role in the formation of the guppy color pattern. Orange pigmentation is absent in the skin of guppies with a lesion in blue, suggesting a defect in xanthophore development. In golden mutants, the development of the melanophore pattern during embryogenesis and after birth is affected. Here, we show that blue and golden correspond to guppy orthologs of colony-stimulating factor 1 receptor a (csf1ra; previously called fms) and kita. Most excitingly, we found that both genes are required for the development of the black ornaments of guppy males, which in the case of csf1ra might be mediated by xanthophore-melanophore interactions. Furthermore, we provide evidence that two temporally and genetically distinct melanophore populations contribute to the adult camouflage pattern expressed in both sexes: one early appearing and kita-dependent and the other late-developing and kita-independent. The identification of csf1ra and kita mutants provides the first molecular insights into pigment pattern formation in this important model species for ecological and evolutionary genetics. 23925432 Use of Glucagon-Like Peptide-1 Agonists to Improve Islet Graft Performance. Human islet transplantation is an effective and promising therapy for type I diabetes. However, long-term insulin independence is both difficult to achieve and inconsistent. De novo or early administration of incretin-based drugs is being explored for improving islet engraftment. In addition to its glucose-dependent insulinotropic effects, incretins also lower postprandial glucose excursion by inhibiting glucagon secretion, delaying gastric emptying, and can protect beta-cell function. Incretin therapy has so far proven clinically safe and tolerable with little hypoglycemic risk. The present review aims to highlight the new frontiers in research involving incretins from both in vitro and in vivo animal studies in the field of islet transplant. It also provides an overview of the current clinical status of incretin usage in islet transplantation in the management of type I diabetes. 23897586 Dynamics of survival of motor neuron (SMN) protein interaction with the mRNA-binding protein IMP1 facilitates its trafficking into motor neuron axons. Spinal muscular atrophy (SMA) is a lethal neurodegenerative disease specifically affecting spinal motor neurons. SMA is caused by the homozygous deletion or mutation of the survival of motor neuron 1 (SMN1) gene. The SMN protein plays an essential role in the assembly of spliceosomal ribonucleoproteins. However, it is still unclear how low levels of the ubiquitously expressed SMN protein lead to the selective degeneration of motor neurons. An additional role for SMN in the regulation of the axonal transport of mRNA-binding proteins (mRBPs) and their target mRNAs has been proposed. Indeed, several mRBPs have been shown to interact with SMN, and the axonal levels of few mRNAs, such as the β-actin mRNA, are reduced in SMA motor neurons. In this study we have identified the β-actin mRNA-binding protein IMP1/ZBP1 as a novel SMN-interacting protein. Using a combination of biochemical assays and quantitative imaging techniques in primary motor neurons, we show that IMP1 associates with SMN in individual granules that are actively transported in motor neuron axons. Furthermore, we demonstrate that IMP1 axonal localization depends on SMN levels, and that SMN deficiency in SMA motor neurons leads to a dramatic reduction of IMP1 protein levels. In contrast, no difference in IMP1 protein levels was detected in whole brain lysates from SMA mice, further suggesting neuron specific roles of SMN in IMP1 expression and localization. Taken together, our data support a role for SMN in the regulation of mRNA localization and axonal transport through its interaction with mRBPs such as IMP1. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013. 23913437 DNA fragmentation induced by all-trans retinoic acid and its steroidal analogue EA-4 in C2 C12 mouse and HL-60 human leukemic cells in vitro. We have recently shown that retinoic acid induces micronucleation mainly via chromosome breakage (Alakhras et al. Cancer Lett 2011; 306: 15-26). To further study retinoic acid clastogenicity and evaluate DNA damaging potential we investigated the ability of (a) all-trans retinoic acid and its steroidal analogue EA-4 to induce DNA fragmentation by using Comet assay under alkaline unwinding and neutral condition electrophoresis, and (b) the retinoids under study to induce small (0-1 kb) DNA fragments. Two cell lines, C2C12 mouse cells and HL-60 human leukemic cells were used in this study. We found that all-trans retinoic acid and its steroidal analogue EA-4 (a) provoke DNA migration due to DNA fragmentation as it is shown by the increased values of Comet parameters, and (b) induce significantly small-size fragmented genomic DNA as indicated by the quantification of necrotic/apoptotic small DNA segments in both cell systems. A different response between the two cell lines was observed in relation to retinoid ability to increase the percentage of DNA in the tail as well as break DNA in to small fragments. Our findings confirm the ability of retinoic acid to provoke micronucleation by disrupting DNA into fragments, among which small pieces of double-stranded DNA up to 1 kb are identified. Copyright © 2013 John Wiley & Sons, Ltd. 23820732 The Relationship Between Sluggish Cognitive Tempo and Impairment in Children With and Without ADHD. This study examined impairment in multiple domains of functioning in children with and without ADHD who present with high or low levels of sluggish cognitive tempo (SCT) while taking into account the total symptom ratings of ADHD. Participants were 584 children in kindergarten through eighth grade (55.7 % male, 91.7 % Caucasian), drawn from five archival datasets. Two, 2 (SCT groups: high and low) x 3 (ADHD Status: ADHD-I, ADHD-C, and non-ADHD) MANCOVAs were conducted with the total ADHD symptom ratings and child age as covariates. One MANCOVA was conducted on scores on the teacher Impairment Rating Scale (IRS; Fabiano et al. Journal of Clinical Child and Adolescent Psychology 35:369-385, 2006) and the other on the 6 scores on the parent IRS. The results indicated that the presence of SCT symptoms was associated with greater functional impairment at home according to parent report while it was associated with less functional impairment at school according to teacher report. Thus, the relationship between SCT symptoms and impairment differs depending on the informant and the context in which impairment is evaluated. 23952453 Growing multiplex networks. We propose a modeling framework for growing multiplexes where a node can belong to different networks. We define new measures for multiplexes and we identify a number of relevant ingredients for modeling their evolution such as the coupling between the different layers and the distribution of node arrival times. The topology of the multiplex changes significantly in the different cases under consideration, with effects of the arrival time of nodes on the degree distribution, average shortest path length, and interdependence. 23260348 Discovery of a new series of [1,2,4]triazolo[4,3-a]quinoxalines as dual phosphodiesterase 2/phosphodiesterase 10 (PDE2/PDE10) inhibitors. The synthesis, preliminary evaluation and structure-activity relationship (SAR) of a series of 1-aryl-4-methyl[1,2,4]triazolo[4,3-a]quinoxalines as dual phosphodiesterase 2/phosphodiesterase 10 (PDE2/PDE10) inhibitors are described. From this investigation compound 31 was identified, showing good combined potency, acceptable brain uptake and high selectivity for both PDE2 and PDE10 enzymes. Compound 31 was subjected to a microdosing experiment in rats, showing preferential distribution in brain areas where both PDE2 and PDE10 are highly expressed. These promising results may drive the further development of highly potent combined PDE2/PDE10 inhibitors, or even of selective inhibitors of PDE2 and/or PDE10. 23460404 Ni(II)-NTA Modified Poly(ethylene imine) Glycopolymers: Physicochemical Properties and First In Vitro Study of Polyplexes Formed with HIV-Derived Peptides. Alternative delivery entities are desirable in immunotherapies in which polyplexes are widely formed by electrostatic interactions to induce cellular uptake processes for bioactive molecules. In our study, biocompatible Ni(II)-nitrilo(triacetic acid)-modified poly(ethylene imine)-maltose (Ni-NTA-DG) is realized and evaluated as complexation agent against His-tagged peptides using fluorescence polarization and dynamic light scattering. The polyplexes are stable until a pH of 6.5-6.0, and also up to 50 mM of imidazole. A first uptake approach shows that polyplexes lead to an increase in peptide uptake in monocyte-derived immature dendritic cells. In summary, Ni-NTA-DG represents a promising (delivery) platform for forthcoming in vitro applications. 23866013 Nonplanar tertiary amides in rigid chiral tricyclic dilactams. Peptide group distortions and vibrational optical activity. We investigate amide nonplanarity in vibrational optical activity (VOA) spectra of tricyclic spirodilactams 5,8-diazatricyclo[6,3,0,0(1,5)]undecan-4,9-dione (I) and its 6,6',7,7'-tetradeuterio derivative (II). These rigid molecules constrain amide groups to nonplanar geometries with twisted pyramidal arrangements of bonds to amide nitrogen atoms. We have collected a full range vibrational circular dichroism (VCD) and Raman optical activity (ROA) spectra including signals of C-H and C-D stretching vibrations. We report normal-mode analysis and a comparison of calculated to experimental VCD and ROA. The data provide band-to-band assignment and offer a possibility to evaluate roles of constrained nonplanar tertiary amide groups and rigid chiral skeletons. Nonplanarity shows as single-signed VCD and ROA amide I signals, prevailing the couplets expected to arise from the amide-amide interaction. Amide-amide coupling dominates amide II (mainly C'-N stretching, modified in tertiary amides by the absence of a N-H bond) transitions (strong couplet in VCD, no significant ROA) probably due to the close proximity of amide nitrogen atoms. At lower wavenumbers, ROA spectra exhibit another likely manifestation of amide nonplanarity, showing signals of amide V (δoop(N-C) at ∼570 cm(-1)) and amide VI (δoop(C'═O) at ∼700 cm(-1) and ∼650 cm(-1)) vibrations. 22940402 Deep vein thrombosis: current status and nanotechnology advances. Deep vein thrombosis (DVT) affects up to 2 million people in the United States, and worldwide incidence is 70 to 113 cases per 100,000 per year. Mortality from DVT is often due to subsequent pulmonary embolism (PE). Precise diagnosis and treatment is thereby essential for the management of DVT. DVT is diagnosed by a thorough history and physical examination followed by laboratory and diagnostic tests. The choice of laboratory and diagnostic test is dependent on clinical pretest probability. Available laboratory and diagnostic techniques mainly involve D-dimer test, ultrasound, venography, and magnetic resonance imaging. The latter two diagnostic tools require high doses of contrast agents including either radioactive or toxic materials. The available treatment options include lifestyle modifications, mechanical compression, anticoagulant therapy, inferior vena cava filter, and thrombolysis/thrombolectomy. All of these medical and surgical treatments have serious side effects including improper clot clearance and increased risk of hemorrhage occurrence. Therefore, research in this field has recently focused on the development of non-invasive and accurate diagnostics, such as ultrasound enhanced techniques and molecular imaging methods, to assess thrombus location and its treatment course. The frontier of nanomedicine also shows high prospects in tackling DVT with efficient targeted drug delivery. This review describes the pathology of DVT along with successive medical problems such as PE and features a detailed listing of various diagnostic and therapeutic modalities that have been in use and are under development. 23722328 Rhinoviruses as an underestimated cause of influenza-like illness in pregnancy during the 2009-2010 influenza pandemic. During the 2009-2010 influenza pandemic, pregnant women were identified at high risk for severe infection. In case of influenza-like illness they were systematically treated with oseltamivir. When performed, virological diagnosis showed that some of these women were not influenza-infected. The objectives of the study were to identify viruses which could induce an influenza-like illness in pregnant women during the 2009-2010 pandemic, then to establish possible links between detected viruses and symptoms, and then characterize human rhinoviruses (HRV) strains detected in some samples. Nasal swabs from 78 pregnant women presenting with influenza-like illness and previously tested for influenza virus by RT-PCR in 2009-2010 were further assayed by multiplex RespiFinder assay and bocavirus PCR to search for 13 other viruses. Genotyping of HRV strains was carried out using partial genomic sequencing in the VP4/VP2 region. Influenza A virus infection was confirmed in 33 women (42%). Non-influenza viruses were detected in 18 additional cases (23%). Rhinoviruses were the most numerous (13%) and belonged to 9 different genotypes distributed between the 3 genogroups. When comparing symptoms observed in influenza-infected women and women infected by other viruses, shivers were more frequent in the former group (P=0.02), and expectorations in the latter (P=0.03). During the influenza pandemic 2009-2010, non-influenza viruses and mostly rhinoviruses were an underestimated cause of influenza-like illness in pregnant women. Viral diagnosis should help to stop empiric oseltamivir therapy in influenza-negative patients and antibiotic treatment in patients infected with a non-influenza virus. 23880337 Endoplasmic reticulum localization of poly(ω-aminohexyl methacrylamide)s conjugated with (l-)-arginines in plasmid DNA delivery. In this work, we first synthesized a ω-amino group Boc-protected poly(ω-aminohexyl methacrylamide) PAHMAA-Boc precursor via controlled reversible addition-fragmentation chain transfer (RAFT) polymerization of the Boc-AHMAA monomer in THF solution, and poly(ω-aminohexyl methacrylamide) (PAHMAA) was then prepared via Boc deprotection, and was further conjugated with (l-)-arginines at the ω-amino group sites to give a series of new (l-)-arginine conjugated PAHMAA-R7, PAHMAA-R16 and PAHMAA-R22. Employing these PAHMAA and PAHMAA-Rs as functional gene vectors, their plasmid DNA binding affinities were examined by agarose gel retardant assay. By means of dynamic light scattering (DLS), mean particle sizes and zeta potentials of the polyplexes were analyzed. Moreover, cytotoxicities of the PAHMAA and PAHMAA-Rs were evaluated by MTT and lactate dehydrogenase (LDH) release assays with COS-7 cells, and luciferase and EGFP gene transfection efficacies by these vectors were assayed in COS-7 and HeLa cells. Furthermore, intracellular uptake of the vector/Cy3-labeled pDNA polyplexes was studied with a flow cytometer (FACS), and the most efficient PAHMAA-R16 vector was employed to investigate the endocytic gateways with various inhibitors. In addition, colocalization of the Cy3-labeled pDNA and Oregon Green labeled PAHMAA-R16 vector in the intracellular organelles of COS-7 cells was visualized on a fluorescence microscopy. As a result, it was revealed that the PAHMAA-R vectors showed lower cytotoxicities and transfection efficacies significantly higher than those of the PAHMAA, strongly depending on their percentage of arginine conjugation, and that the results of endocytic inhabitation and fluorescence colocalization in endoplasmic reticulum may suggest a caveolae-mediated efficient intracellular trafficking route for the synthesized PAHMAA-R vectors. 23843630 Parenting stress among caregivers of children with chronic illness: a systematic review. To critically review, analyze, and synthesize the literature on parenting stress among caregivers of children with asthma, cancer, cystic fibrosis, diabetes, epilepsy, juvenile rheumatoid arthritis, and/or sickle cell disease. Method PsychInfo, MEDLINE, and Cumulative Index to Nursing and Allied Health Literature were searched according to inclusion criteria. Meta-analysis of 13 studies and qualitative analysis of 96 studies was conducted. Results Caregivers of children with chronic illness reported significantly greater general parenting stress than caregivers of healthy children (d = .40; p = ≤.0001). Qualitative analysis revealed that greater general parenting stress was associated with greater parental responsibility for treatment management and was unrelated to illness duration and severity across illness populations. Greater parenting stress was associated with poorer psychological adjustment in caregivers and children with chronic illness. Conclusion Parenting stress is an important target for future intervention. General and illness-specific measures of parenting stress should be used in future studies. 23411196 Classification of Spanish extra virgin olive oils by data fusion of visible spectroscopic fingerprints and chemical descriptors. The potential of visible fingerprints and physical-chemical parameters in combination with multivariate data analysis was examined to classify extra virgin olive oils (EVOOs) from different Spanish regions according to their geographical origin. Firstly, spectral and quality parameters matrices were processed separately and subsequently were joined to evaluate the effect of synergy on the information obtained from the different methodologies. Linear discriminant analysis (LDA) and partial least squares discriminant analysis (PLS-DA) were performed as classification methods. The results revealed a perfect discrimination between the defined categories after performing PLS-DA on the Fused matrix, reaching 100% of correct classifications and showed a clear improvement in the overall prediction rates (92.5%), so that the effect of synergy was confirmed. These accurate results emphasise the feasibility of the proposed strategy and encourage the development of similar approaches based on visible spectroscopy in olive oil quality and traceability determination. 23945230 Facial Reanimation Procedures Depicted on Radiologic Imaging. SUMMARY:Various facial reanimation procedures can be performed for treating patients with chronic facial nerve paralysis. The radiologic imaging features of static and dynamic techniques are reviewed in this article with clinical correlation, including brow lift, eyelid weights and springs, gracilis free flaps, fascia lata grafts, temporalis flaps, and Gore-Tex suspension slings. Although the anatomic alterations resulting from facial reanimation surgery may not necessarily be the focus of the imaging examination, it is important to recognize such changes and be familiar with MR imaging compatibility of the associated implanted materials. Furthermore, imaging is sometimes used to specifically evaluate the postoperative results, such as vessel patency following free gracilis transfer. 23879791 Local Conformation and Intermolecular Interaction of Rigid Ring Polymers Are Not Always the Same as the Linear Analogue: Cyclic Amylose Tris(phenylcarbamate) in Θ Solvents. Small-angle X-ray scattering and static and dynamic light scattering measurements were made for cyclic amylose tris(phenylcarbamate) (cATPC) of which weight-average molar mass Mw ranges from 1.3 × 10(4) to 1.5 × 10(5) to determine their z-average mean square radius of gyration ⟨S(2)⟩z, particle scattering function P(q), hydrodynamic radius RH, and second virial coefficient A2 in methyl acetate (MEA), ethyl acetate (EA), and 4-methyl-2-pentanone (MIBK). The obtained ⟨S(2)⟩z, P(q), and RH data were analyzed in terms of the wormlike ring to estimate the helix pitch per residue h and the Kuhn segment length λ(-1) (the stiffness parameter, twice the persistence length). Both h and λ(-1) for cATPC in MEA, EA, and MIBK are smaller than those for linear amylose tris(phenylcarbamate) (ATPC) in the corresponding solvent and the discrepancy becomes more significant with increasing the molar volume of the solvent. This indicates that not every rigid ring has the same local helical structure and chain stiffness as that for the linear polymer in the Mw range investigated while infinitely long ring chains should have the same local conformation. This conformational difference also affects A2. In actuality, negative A2 was observed for cATPC in MIBK at the Θ temperature of linear ATPC whereas intermolecular topological interaction of ring polymers increases A2. 23849252 Quality of frozen transfusable plasma prepared from whole blood donations in Canada: An update. Transfusable plasma is obtained by processing whole blood donations, by apheresis, or as solvent/detergent plasma (SD plasma), a pooled pathogen-reduced plasma product. The quality of plasma is typically assessed by testing the activities of multiple coagulation-related plasma proteins, due to a lack of clinical trial data linking plasma composition to clinical endpoints. We sought to update previous quality surveys of Canadian frozen plasma (FP; manufactured from single donor whole blood donation and frozen within 24h of phlebotomy), to provide transfusionists with a more complete picture of its characteristics. FP units (n=131) were tested for: the activity of factors V, VII, VIII, X, and XI, protein S (PS), α2-antiplasmin (AP), and fibrinogen; and the activated partial thromboplastin (APTT) and prothrombin (PT) times. Comparisons were made to: previous Canadian FP surveys; and to studies of single-donor plasma and SD plasma from other nations. Mean FVIII, fibrinogen, or APTT values did not differ from the previous annual survey of Canadian FP; FV activity was increased and PT values decreased. FP produced with or without leukoreduction differed only in mean APTT. Canadian FP exhibited generally similar quality to that reported by other organizations in Europe and Asia for similarly manufactured single-donor plasma, but contained notably higher PS and AP (∼four-fold) activities than did SD plasma. Our results indicate that Canadian FP is of similar quality to single-donor products produced in other jurisdictions. While it is of arguably superior in vitro quality to an SD plasma product recently licensed in Canada, these differences are highly unlikely to have clinical significance for most indications for plasma transfusion. 23850133 Is there a role for autotransplants in patients with follicular lymphoma in the rituximab era? Patients with low grad follicular lymphoma were shown to be able to achieve long-term disease-free survival when transplanted after relapse in the era before the wide spread use of rituximab. It appears that the availability of rituximab has not diminished the value of transplantation (i.e., either autologous or allogeneic) in the care of these patients. A similar overall survival and less treatment related toxicity make autologous transplantation the better choice for most patients transplanted at first treatment failure. 23411304 Volatile profiling of high quality hazelnuts (Corylus avellana L.): chemical indices of roasting. The study proposes an investigation strategy to identify sensitive, robust and reliable chemical markers of hazelnut roasting. A fully-automated and validated analytical method, based on Headspace Solid Phase Microextraction (HS-SPME) coupled with Gas Chromatography-Mass Spectrometric detection (GC-MS), for effective off-line monitoring of changes in the volatile profile of high-quality hazelnuts was developed. Samples from two different harvests were submitted to roasting, following different time/temperature protocols and different technologies, enabling chemical changes to be correlated with technological processing and sensory quality. Chemical indices, expressed as analyte response ratio, were defined and their trend observed across roasting profiles. Reliability and robustness of chemical indices were also evaluated, in view of their application to on-line monitoring with Mass Spectrometry-based electronic nose technology (MS-nose). Experiments, simulating on-line chemical characterisation of the volatile fraction, were performed through a fully-automated system. The results confirmed: (a) the effectiveness of single process indicators of roasting selected by the separative method (5-methylfurfural, 1(H)-pyrrole, furfuryl alcohol, 1(H)-pyrrole-2-carboxaldehyde, 1-hydroxy-2-propanone, dihydro-2(3H)-furanone, 5-methyl-(E)-2-hepten-4-one, acetic acid, pyridine, furfural, pyrazine, and several alkyl-pyrazines); and, (b) the reliability of proposed chemical indices: 5-methylfurfural/2,5-dimethylpyrazine, 5-methylfurfural/2-methylpyrazine, 2,5-dimethylpyrazine/2,3-dimethylpyrazine; these maintained a consistent trend versus harvest and sampling/analysis technology. 22668801 HDL-C: Does it matter? An update on novel HDL-directed pharmaco-therapeutic strategies. It has long been recognized that elevated levels of low-density lipoprotein cholesterol (LDL-C) increase the risk of cardiovascular disease (CHD) and that pharmacologic therapy to decrease LDL-C significantly reduces cardiovascular events. Despite the effectiveness of statins for CHD risk reduction, even optimal LDL-lowering therapy alone fails to avert 60% to 70% of CHD cases. A low plasma concentration of high-density lipoprotein cholesterol (HDL-C) is also associated with increased risk of CHD. However, the convincing epidemiologic data linking HDL cholesterol (HDL-C) to CHD risk in an inverse correlation has not yet translated into clinical trial evidence supporting linearity between HDL-C increases and CHD risk reduction. It is becoming clear that a functional HDL is a more desirable target than simply increasing HDL-C levels. Discoveries in the past decade have shed light on the complex metabolic and antiatherosclerotic pathways of HDL. These insights, in turn, have fueled the development of new HDL-targeted drugs, which can be classified according to four different therapeutic approaches: directly augmenting the concentration of apolipoprotein A-I (apo A-I), the major protein constituent of HDL; indirectly augmenting the concentration of apo A-I and HDL cholesterol; mimicking the functionality of apo A-I and enhancing reverse cholesterol transport. This review discusses the latest in novel HDL directed therapeutic strategies. 23357723 Ketogenic diet for infantile spasms refractory to first-line treatments: an open prospective study. Ketogenic diet (KD) is an efficient treatment for refractory epilepsy including infantile spasms (IS). We evaluated the effect of a KD to treat IS as a third-line treatment, after vigabatrin (VGB) and steroids. We evaluated the efficacy and the tolerability of KD in IS using the rate of seizure-free patients at 1 month. We conducted an open study using the data from a prospective database of two French child neurology departments (Amiens & Robert Debré-Paris, France) over a three-year period. All the patients followed the KD for 6 months. The addition of an antiepileptic drug was allowed after 1 month of KD in the non-seizure-free patients. 17 patients were treated by KD for IS. The KD was initiated at the mean age of 9.4±1.1 months. After 1 month with KD, 6/17 (35%) patients were seizure free while 11/17 (65%) were seizure-free after the third month. However, an additional antiepileptic drug (felbamate or topiramate) was given to all patients that were not seizure-free under KD. The KD was well tolerated. Our responder rate is similar to previous studies despite an early use (before 1-year-old) and the use of KD after VGB and steroids. The KD was well-tolerated in this population of young infants. Felbamate leads to an increase in the responder rate after the use of KD. 23187890 Genome-wide mapping of human DNA-replication origins: levels of transcription at ORC1 sites regulate origin selection and replication timing. We report the genome-wide mapping of ORC1 binding sites in mammals, by chromatin immunoprecipitation and parallel sequencing (ChIP-seq). ORC1 binding sites in HeLa cells were validated as active DNA replication origins (ORIs) using Repli-seq, a method that allows identification of ORI-containing regions by parallel sequencing of temporally ordered replicating DNA. ORC1 sites were universally associated with transcription start sites (TSSs) of coding or noncoding RNAs (ncRNAs). Transcription levels at the ORC1 sites directly correlated with replication timing, suggesting the existence of two classes of ORIs: those associated with moderate/high transcription levels (≥1 RNA copy/cell), firing in early S and mapping to the TSSs of coding RNAs; and those associated with low transcription levels (<1 RNA copy/cell), firing throughout the entire S and mapping to TSSs of ncRNAs. These findings are compatible with a scenario whereby TSS expression levels influence the efficiency of ORC1 recruitment at G(1) and the probability of firing during S. 23417566 Gastroprotection in Low-Dose Aspirin Users for Primary and Secondary Prevention of ACS: Results of a Cost-Effectiveness Analysis Including Compliance. Low-dose aspirin (ASA) increases the risk of upper gastrointestinal (GI) complications. Proton pump inhibitors (PPIs) reduce these upper GI side effects, yet patient compliance to PPIs is low. We determined the cost-effectiveness of gastroprotective strategies in low-dose ASA users considering ASA and PPI compliance. Using a Markov model we compared four strategies: no medication, ASA monotherapy, ASA+PPI co-therapy and a fixed combination of ASA and PPI for primary and secondary prevention of ACS. The risk of acute coronary syndrome (ACS), upper GI bleeding and dyspepsia was modeled as a function of compliance and the relative risk of developing these events while using medication. Costs, quality adjusted life years and number of ACS events were evaluated, applying a variable risk of upper GI bleeding. Probabilistic sensitivity analyses were performed. For our base case patients using ASA for primary prevention of ACS no medication was superior to ASA monotherapy. PPI co-therapy was cost-effective (incremental cost-effectiveness ratio [ICER] 10,314) compared to no medication. In secondary prevention, PPI co-therapy was cost-effective (ICER 563) while the fixed combination yielded an ICER < 20,000 only in a population with elevated risk for upper GI bleeding or moderate PPI compliance. PPI co-therapy had the highest probability to be cost-effective in all scenarios. PPI use lowered the overall number of ACS. Considering compliance, PPI co-therapy is likely to be cost-effective in patients taking low dose ASA for primary and secondary prevention of ACS, given low PPI prices. In secondary prevention, a fixed combination seems cost-effective in patients with elevated risk for upper GI bleeding or in those with moderate PPI compliance. Both strategies reduced the number of ACS compared to ASA monotherapy. 23962961 Markov chain Monte Carlo sampling of gene genealogies conditional on unphased SNP genotype data. Abstract The gene genealogy is a tree describing the ancestral relationships among genes sampled from unrelated individuals. Knowledge of the tree is useful for inference of population-genetic parameters and has potential application in gene-mapping. Markov chain Monte Carlo approaches that sample genealogies conditional on observed genetic data typically assume that haplotype data are observed even though commonly-used genotyping technologies provide only unphased genotype data. We have extended our haplotype-based genealogy sampler, sampletrees, to handle unphased genotype data. We use the sampled haplotype configurations as a diagnostic for adequate sampling of the tree space based on the reasoning that if haplotype sampling is restricted, sampling from the tree space will also be restricted. We compare the distributions of sampled haplotypes across multiple runs of sampletrees, and to those estimated by the phase inference program, PHASE. Performance was excellent for the majority of individuals as shown by the consistency of results across multiple runs. However, for some individuals in some datasets, sampletrees had problems sampling haplotype configurations; longer run lengths would be required for these datasets. For many datasets though, we expect that sampletrees will be useful for sampling from the posterior distribution of gene genealogies given unphased genotype data. 23933511 The antigenic architecture of the hemagglutinin of influenza H5N1 viruses. Human infection with the highly pathogenic avian influenza A virus H5N1 is associated with a high mortality and morbidity. H5N1 continues to transmit from poultry to the human population, raising serious concerns about its pandemic potential. Current influenza H5N1 vaccines are based upon the elicitation of a neutralizing antibody (Ab) response against the major epitope regions of the viral surface glycoprotein, hemagglutinin (HA). However, antigenic drift mutations in immune-dominant regions on the HA structure allow the virus to escape Ab neutralization. Epitope mapping using neutralizing monoclonal antibodies (mAb) helps define mechanisms of antigenic drift, neutralizing escape and can facilitate pre-pandemic vaccine design. This review explores the current knowledge base of the antigenic sites of the H5N1 HA molecule. The relationship between the epitope architecture of the H5N1 HA, antigenic evolution of the different H5N1 lineages and the antigenic complexity of the H5N1 virus lineages that constitute potential pandemic strains are discussed in detail. 23665288 A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. Disease progression in non-alcoholic fatty liver disease (NAFLD) is not well understood and there is controversy about whether non-alcoholic fatty liver (NAFL, i.e., steatosis alone or with mild inflammation not qualifying for steatohepatitis) can evolve towards steatohepatitis (NASH) with fibrosis. We reviewed 70 patients with untreated NAFLD and with two biopsies performed more than one year apart. Clinical and biological data were recorded at the time of both biopsies. Alcohol consumption did not change during follow-up. Initially 25 patients had NAFL and 45 had NASH and/or advanced fibrosis. After a mean follow-up of 3.7years (s.d. 2.1), 16 NAFL patients developed NASH, eight with severe ballooning and six with bridging fibrosis on the follow-up biopsy. Patients with mild lobular inflammation or any degree of fibrosis were at higher risk of progression than those with steatosis alone. Those with unambiguous disease progression were older and had worsening of their metabolic risk factors (higher weight and more diabetes at baseline and during follow-up). In the whole cohort, ballooning progression and bridging fibrosis often occurred together and co-existed with a reduction in ALT, higher weight gain, and a higher incidence of diabetes during follow-up. A substantial proportion of patients with NAFL can progress towards well-defined NASH with bridging fibrosis, especially if metabolic risk factors deteriorate. Even mild inflammation or fibrosis could substantially increase the risk of progression when compared to steatosis alone. Current monitoring practices of these patients should be revised. 23623820 Ethnopharmacological and bioactivity guided investigation of five TCM anticancer herbs. ETHNOPHARMACOLOGICAL RELEVANCE: Five herbs, Curcuma longa L. (CL), Scutellaria baicalensis Georgi (SBC), Scutellaria barbata D. Don (SBB), Hedyotis diffusa Willd. (HD) and Solanum nigrum L. (SN), are often prescribed in the polyherbal formulas for cancer treatment by traditional Chinese medicine (TCM) practitioners. The purpose of the present study was to identify important anticancer herbs used in TCM and carry out bioactivity-directed fractionation and isolation (BDFI) using six cancer cell lines as well as peripheral blood mononuclear cells (PBMCs), to identify constituents with anticancer activity but devoid of toxic effects against healthy immune cells. MATERIALS AND METHODS: Of 243 document anticancer TCM treatments, 199 anticancer TCM herbs were ranked by the number of literature reports for each herb. Five herbs were identified from the top 50 ranked herbs by at least two out of three TCM practitioners as frequently used in the TCM treatment of cancer. BDFI using MTS assay was applied to determine the active anticancer extracts, fractions, and finally discrete compounds. RESULTS: Five herbs were selected for study of their anticancer activities. The extracts of Curcuma longa L., Scutellaria barbata D. Don, and Hedyotis diffusa showed antiproliferative activity to various extents, extracts of Scutellaria baicalensis Georgi and Solanum nigrum L. showed little anticancer activity. Seven out of the 21 fractions obtained from Hedyotis diffusa showed anticancer activity. One new compound, ethyl 13(2) (S)-hydroxy-chlorophyllide a(1), along with 10 known compounds, i.e. 2-methyl-3-methoxyanthraquinone (2), 2-hydroxymethylanthraquinone(3), 2-hydroxy-3-methylanthraquinone(4), 2-hydroxymethy-1-hydroxyanthraquinone(5), 1-methoxy-2-hydroxyanthraquinone(6), 2-hydroxy-3-methyl-1-methoxyanthraquinone (7), oleanolic acid (8), ursolic acid (9), stigmasterol (10) and docosanoic acid (11), were isolated and identified. Compounds 2-6, 8 and 9 dose-dependently inhibited the cell viability of cancer cells within a concentration range of 1-200µM. Furthermore, compounds 2, 3, 5 and 9 showed significantly stronger inhibition of tested cancer cell lines than on that of PBMCs. CONCLUSION: This study identified anticancer herbs, extracts, fractions and eventually compounds from the documented anticancer TCM herbs by using BDFI. It also determined the antiproliferative activity in cancer and healthy immune cells of the isolated compounds from Hedyotis diffusa. The results will be useful in the validation of the clinical application of these herbs and the development of novel anticancer therapeutics. 23924495 Liver steatosis correlates with iron overload but not with HFE gene mutations in chronic hepatitis C. Liver steatosis and iron overload, which are frequently observed in chronic hepatitis C (CHC), may contribute to the progression of liver injury. This study aimed to evaluate the correlation between liver steatosis and iron overload in Polish patients with CHC compared to non-alcoholic fatty liver disease (NAFLD) and HFE-hereditary hemochromatosis (HH) patients. A total of 191 CHC patients were compared with 67 NAFLD and 21 HH patients. Liver function tests, serum markers of iron metabolism, cholesterol and triglycerides were assayed. The inflammatory activity, fibrosis, iron deposits and steatosis stages were assessed in liver specimens. HFE gene polymorphisms were investigated by PCR-RFLP. Liver steatosis was associated with obesity and diabetes mellitus. This disease was confirmed in 76/174 (44%) CHC patients, most of whom were infected with genotype 1. The average grade of steatosis was higher in NAFLD patients. CHC patients had significantly higher iron concentrations and transferrin saturations than NAFLD patients. Compared with CHC patients, HH patients had higher values of serum iron parameters and more intensive hepatocyte iron deposits without differences in the prevalence and intensity of liver steatosis. In the CHC group, lipids accumulation in hepatocytes was significantly associated with the presence of serum markers of iron overload. No correlation between the HFE gene polymorphism and liver steatosis in CHC patients was found. Liver steatosis was diagnosed in nearly half of CHC patients, most of whom were infected with genotype 1. The intensity of steatosis was lower in CHC patients than that in NAFLD patients because of a less frequent diagnosis of metabolic syndrome. Only in CHC patients were biochemical markers of iron accumulation positively correlated with liver steatosis; these findings were independent of HFE gene mutations. 23778981 Interaction of cisplatin and analogue Pt(en)Cl2 with the copper metallo-chaperone Atox1. The human metallo-chaperone protein Atox1 features a high affinity Cu(I) binding site Cys(12)GlyGlyCys(15) (KD = 10(-17.4) M at pH 7.0) and delivers copper to the trans-Golgi network (TGN). Atox1 may participate in the metabolism of the drug cis-Pt(NH3)2Cl2 (cisplatin), either as a component of its delivery to the nucleus or of its loss via transport to the TGN and beyond. The species of stoichiometry [Pt(NH3)2(Atox1)] was the sole adduct of stoichiometry Pt : Atox1 = 1 : 1 detected by mass spectrometry under non-denaturing conditions from solutions containing cisplatin and apo-Atox1. The ions [Atox1 + Pt(NH3)2(2+) + (z - 2)H(+)](z+) (z = 3 to 7) were observed and correspond to different protonation states of the 1 : 1 adduct. Adducts of stoichiometry Pt : Atox1 = 2 : 1 were also detected but 1 : 2 adducts were not detected. The related complex Pt(en)Cl2 (en = 1,2-diaminoethane) behaved similarly. Tandem mass spectrometry experiments using top-down and bottom-up sequencing techniques were carried out, respectively, on the intact platinated protein and on platinated peptides formed from proteolysis by trypsin. A new software programme (PolyCut) designed to analyse the complex high-resolution tandem mass spectra of fragment ions derived from proteins containing transition metal ions was applied to establish the binding site(s) of the platinum atom(s). The analysis, based on the entire isotope patterns, is consistent with the cysteine residues in the Cu(I)-binding sequence Cys(12)GlyGlyCys(15) being the primary coordination site. 23899622 Suitability of Public Use Secondary Data Sets to Study Multiple Activities. Purpose of the Study: The aims of this study were to inventory activity items within and across U.S. public use data sets, to identify gaps in represented activity domains and challenges in interpreting domains, and to assess the potential for studying multiple activity engagement among older adults using existing data. We engaged in content analysis of activity measures of 5U.S. public use data sets with nationally representative samples of older adults. Data sets included the Health & Retirement Survey (HRS), Americans' Changing Lives Survey (ACL), Midlife in the United States Survey (MIDUS), the National Health Interview Survey (NHIS), and the Panel Study of Income Dynamics survey (PSID). Two waves of each data set were analyzed. We identified 13 distinct activity domains across the 5 data sets, with substantial differences in representation of those domains among the data sets, and variance in the number and type of activity measures included in each. Our findings indicate that although it is possible to study multiple activity engagement within existing data sets, fuller sets of activity measures need to be developed in order to evaluate the portfolio of activities older adults engage in and the relationship of these portfolios to health and wellness outcomes. Importantly, clearer conceptual models of activity broadly conceived are required to guide this work. 23885001 Escherichia coli Sequence Type 131 (ST131) as a Prominent Cause of Antibiotic Resistance among Urinary Escherichia coli Isolates from Reproductive-age Women. The recent emergence of multidrug-resistant Escherichia coli sequence type (ST) 131, has coincided with an increase in antibiotic resistance among E. coli generally, suggesting a contributing role for ST131 in resistance. However, there is little information about the contribution of ST131 to different clinical syndromes or the basis for its impressive emergence and epidemic spread. To investigate this, we studied 953 E. coli isolates, from women of reproductive-age in the Central West region of New South Wales, Australia: 623 urinary isolates from patients with cystitis (322) or pyelonephritis (301), and 330 fecal isolates from healthy controls. The characteristics studied included ST131 clonal group status, antibiotic resistance, virulence factor (VF) genes, and biofilm production. As expected, fecal isolates differed significantly from urinary (cystitis and pyelonephritis) isolates for most of the studied characteristics. Antibiotic resistance was significantly more common among ST131 than non-ST131 isolates. Both antibiotic resistance and ST131 were more common among pyelonephritis than cystitis isolates and least so among fecal isolates. Within each source group, individual VF genes were more prevalent, and VF scores higher, for ST131 than non-ST131 isolates. For ST131 only, the prevalence of most individual VF genes, and VF scores increased from lowest among fecal, through cystitis, to pyelonephritis isolates. Biofilm production was strongly associated with ST131 and antibiotic resistance. These results clarify the distribution of the ST131 clonal group, and its epidemiological associations in our region and suggest that it exhibits both enhanced virulence and increased antibiotic resistance, compared with other E. coli UTI and fecal isolates from reproductive-age women. 23902360 UV-Vis Spectroscopy and Dynamic Light Scattering Study of Gold Nanorods Aggregation. Gold nanorods (AuNRs) were used as spectroscopic sensing elements to detect specific DNA sequences with a single-base mismatch sensitivity. The assay was based on the observation that the stabilizing repulsive forces between CTA(+)-coated AuNRs can be removed by citrate ions, which causes aggregation among AuNRs; whereas nucleic acids of different structures[ i.e., peptide nucleic acid (PNA), single-stranded DNA (ssDNA), PNA-DNA complex, and double-stranded DNA (dsDNA)] can retard the aggregation. Moreover, the dsDNA PNA-DNA duplexes provide larger retardation than that by unhybridized ssDNA and PNA probe. This assay can differentiate single-base mismatched targets with base substitution at different locations (center and end) with AuNRs of a larger aspect ratio. Besides ultraviolet-visable spectroscopy measurement of particle assembly-induced plasmonic coupling that in turn provides a spectroscopic detection of the specific DNA, dynamic light scattering and transmission electron microscope (TEM) were used to measure smaller degree of aggregation that can reveal sodium citrate- and dsDNA-AuNRs interactions in fine detail. 23706233 Rapid response oxygen-sensing nanofibers. Molecular oxygen has profound effects on cell and tissue viability. Relevant sensor forms that can rapidly determine dissolved oxygen levels under biologically relevant conditions provide critical metabolic information. Using 0.5 μm diameter electrospun polycaprolactone (PCL) fiber containing an oxygen-sensitive probe, tris (4,7-diphenyl-1,10-phenanthroline) ruthenium(II) dichloride, we observed a response time of 0.9±0.12 s while the t95 for the corresponding film was more than two orders of magnitude greater. Interestingly, the response and recovery times of slightly larger diameter PCL fibers were 1.79±0.23 s and 2.29±0.13 s, respectively, while the recovery time was not statistically different likely due to the more limited interactions of nitrogen with the polymer matrix. A more than 10-fold increase in PCL fiber diameter reduces oxygen sensitivity while having minor effects on response time; conversely, decreases in fiber diameter to less than 0.5 μm would likely decrease response times even further. In addition, a 50°C heat treatment of the electrospun fiber resulted in both increased Stern-Volmer slope and linearity likely due to secondary recrystallization that further homogenized the probe microenvironment. At exposure times up to 3600 s in length, photobleaching was observed but was largely eliminated by the use of either polyethersulfone (PES) or a PES-PCL core-shell composition. However, this resulted in 2- and 3-fold slower response times. Finally, even the non-core shell compositions containing the Ru oxygen probe result in no apparent cytotoxicity in representative glioblastoma cell populations. 23384061 Surface behavior of malonic acid adsorption at the air/water interface. The presence of organic materials adsorbed to the surfaces of aerosol particles has been demonstrated to be a determining factor in relevant atmospheric processes. Malonic acid is a small, water-soluble organic acid that is common in aerosols and is surface-active. A comprehensive investigation of the adsorption of malonic acid to the air/water interface was accomplished using vibrational sum frequency spectroscopy (VSFS) and surface tension measurements as functions of concentration and pH. Malonic acid was found to be weakly solvated at the air/water interface, and its orientation as a function of concentration was explored through different VSFS polarization schemes. pH-dependent experiments revealed that the surface-active species is the fully protonated species. Computational analyses were used to obtain depth-specific geometries of malonic acid at the air/water interface that confirm and enrich the experimental results. 23334529 Designing high-performance electrochemical energy-storage nanoarchitectures to balance rate and capacity. The impressive specific capacitance and high-rate performance reported for many nanometric charge-storing films on planar substrates cannot impact a technology space beyond microdevices unless such performance translates into a macroscale form factor. In this report, we explore how the nanoscale-to-macroscale properties of the electrode architecture (pore size/distribution, void volume, thickness) define energy and power performance when scaled to technologically relevant dimensions. Our test bed is a device-ready electrode architecture in which scalable, manufacturable carbon nanofoam papers with tunable pore sizes (5-200 nm) and thickness (100-300 μm) are painted with ~10 nm coatings of manganese oxide (MnOx). The quantity of capacitance and the rate at which it is delivered for four different MnOx-C variants was assessed by fabricating symmetric electrochemical capacitors using a concentrated aqueous electrolyte. Carbon nanofoam papers containing primarily 10-20 nm mesopores support high MnOx loadings (60 wt%) and device-level capacitance (30 F g(-1)), but the small mesoporous network hinders electrolyte transport and the low void volume restricts the quantity of charge-compensating ions within the electrode, making the full capacitance only accessible at slow rates (5 mV s(-1)). Carbon nanofoam papers with macropores (100-200 nm) facilitate high rate operation (50 mV s(-1)), but deliver significantly lower device capacitance (13 F g(-1)) as a result of lower MnOx loadings (41 wt%). Devices comprising MnOx-carbon nanofoams with interconnecting networks of meso- and macropores balance capacitance and rate performance, delivering 33 F g(-1) at 5 mV s(-1) and 23 F g(-1) at 50 mV s(-1). The use of carbon nanofoam papers with size-tunable pore structures and thickness provides the opportunity to engineer the electrode architecture to deliver scalable quantities of capacitance (F cm(-2)) in tens of seconds with a single device. 23702810 Efficacy of Infliximab in Intestinal Behçet's Disease: A Korean Multicenter Retrospective Study. Although infliximab is widely accepted as a therapeutic option for inflammatory bowel disease, its therapeutic efficacy for the treatment of intestinal Behçet's disease (BD) is unknown. We investigated the short-term and long-term response rates to infliximab in intestinal BD and predictive factors of sustained treatment response following infliximab treatment. This study was conducted using a retrospective noncontrolled review of medical records from 8 tertiary hospitals in Korea. We collected clinical, demographic, and laboratory data for patients with 28 patients with intestinal BD who received at least 1 dose of infliximab. Response rates of infliximab at 2, 4, 30, and 54 weeks for each patient and factors predictive of sustained response were investigated. Adverse events were also identified. The median duration of follow-up after initial infliximab infusion was of 29.5 months. The clinical response rates at 2, 4, 30, and 54 weeks were 75%, 64.3%, 50%, and 39.1%, respectively, with clinical remission rates of 32.1%, 28.6%, 46.2%, and 39.1%, respectively. After multivariate analysis, older age at diagnosis (≥40 yr), female sex, a longer disease duration (≥5 yr), concomitant immunomodulator use, and achievement of remission at week 4 were found to be predictive factors of sustained response. There was 1 serious infection but no malignancies or deaths in this study. Infliximab was a well-tolerated and effective therapy for patients with moderate-to-severe intestinal BD. Moreover, we found 5 predictive factors associated with sustained response, which might assist in optimal patient selection for infliximab treatment. 23064475 The association of serum 25-hydroxyvitamin D and vertebral fractures in patients with type 2 diabetes. Vitamin D is an important regulator of bone health. Previous studies examining the association between vitamin D deficiency and osteoporotic fractures have reported conflicting results. The relationship between vitamin D status and risk of vertebral fractures in diabetic patients is unknown. The objective of this study was to examine whether low serum 25-hydroxyvitamin D [25(OH)D] levels were associated with vertebral fractures in patients with type 2 diabetes. This cross-sectional study was conducted among 161 postmenopausal women and 180 men with type 2 diabetes. Serum concentrations of 25(OH)D were measured and the presence of vertebral fracture was assessed using lateral plain radiographs of the thoracolumbar spine. Women had lower 25(OH)D levels than men (31.3 ± 17.7 vs. 41.3 ± 26.5 ng/mL, p<0.001). Vertebral fractures were found in 16% of patients. Men with a serum 25(OH)D concentration greater than 30 ng/mL showed a lower prevalence of vertebral fractures compared to those with 20-29.9 ng/mL or those with less than 20 ng/mL (9.4% vs. 17.9% vs. 21.7%, p for trend=0.036). However, there was no significant association between vitamin D status and the prevalence of vertebral fractures in women (14.4% vs. 19.2% vs. 26.6%, p for trend=0.111). After adjusting for multiple confounding factors, men with a serum 25(OH)D concentration of less than 20 ng/mL were associated with an increased risk of vertebral fractures (OR 7.87; 95% CI 1.69-36.71), but not women. In conclusion, serum 25(OH)D levels below 20 ng/mL were associated with an increased vertebral fracture risk in men with type 2 diabetes. 23867097 Effects of water on reactions for waste treatment, organic synthesis, and bio-refinery in sub- and supercritical water. Current research analyzing the effects of water in the field of homogeneous and heterogeneous reactions of organics in sub- and supercritical water are reviewed in this article. Since the physical properties of water (e.g., density, ion product and dielectric constants) can affect the reaction rates and mechanisms of various reactions, understanding the effects that water can have is important in controlling reactions. For homogeneous reactions, the effects of water on oxidation, hydrolysis, aldol condensation, Beckman rearrangement and biomass refining were introduced including recent experimental results up to 100 MPa using special pressure-resistance equipment. For heterogeneous reactions, the effects of ion product on acid/base-catalyzed reactions, such as hydrothermal conversion of biomass-related compounds, organic synthesis in the context of bio-refinery, and hydration of olefins were described and how the reaction paths are controlled by the concentration of water and hydrogen ions was summarized. 23690278 The spatial buildup of compression and suppression in the Mammalian cochlea. We recorded responses of the gerbil basilar membrane (BM) to wideband tone complexes. The intensity of one component was varied and the effects on the amplitude and phase of the others were assessed. This suppression paradigm enabled us to vary probe frequency and suppressor frequency independently, allowing the use of simple scaling arguments to analyze the spatial buildup of the nonlinear interaction between traveling waves. Most suppressors had the same effects on probe amplitude and phase as did wideband intensity increments. The main exception were suppressors above the characteristic frequency (CF) of the recording location, for which the frequency range of most affected probes was not constant, but shifted upward with suppressor frequency. BM displacement reliably predicted the effectiveness of low-side suppressors, but not high-side suppressors. We found "anti-suppression" of probes well below CF, i.e., suppressor-induced enhancement of probe response amplitude. Large (>1 cycle) phase effects occurred for above-CF probes. Phase shifts varied nonmonotonically, but systematically, with suppressor level, probe frequency, and suppressor frequency, reconciling apparent discrepancies in the literature. The analysis of spatial buildup revealed an accumulation of local effects on the propagation of the traveling wave, with larger BM displacement reducing the local forward gain. The propagation speed of the wave was also affected. With larger BM displacement, the basal portion of the wave slowed down, while the apical part sped up. This framework of spatial buildup of local effects unifies the widely different effects of overall intensity, low-side suppressors, and high-side suppressors on BM responses. 23857865 Pd(II) -Catalyzed Spiroketalization of Ketoallylic Diols. A high-yielding stereoselective method for forming spiroketals from simple ketoallylic diols is reported. Employing catalytic [PdCl2 (MeCN)2 ] in THF at 0 °C, these dehydrative cyclization reactions require only mild conditions to produce vinyl-substituted spiroketals in high yields after brief reaction times with water as the only byproduct. Using this method, the stereochemical information embedded at the nucleophile is transmitted "down-the-chain" and efficiently sets the stereochemistry at both the anomeric carbon atom and the newly formed allylic stereocenter. 23827717 Auditory signal processing in communication: Perception and performance of vocal sounds. Learning and maintaining the sounds we use in vocal communication require accurate perception of the sounds we hear performed by others and feedback-dependent imitation of those sounds to produce our own vocalizations. Understanding how the central nervous system integrates auditory and vocal-motor information to enable communication is a fundamental goal of systems neuroscience, and insights into the mechanisms of those processes will profoundly enhance clinical therapies for communication disorders. Gaining the high-resolution insight necessary to define the circuits and cellular mechanisms underlying human vocal communication is presently impractical. Songbirds are the best animal model of human speech, and this review highlights recent insights into the neural basis of auditory perception and feedback-dependent imitation in those animals. Neural correlates of song perception are present in auditory areas, and those correlates are preserved in the auditory responses of downstream neurons that are also active when the bird sings. Initial tests indicate that singing-related activity in those downstream neurons is associated with vocal-motor performance as opposed to the bird simply hearing itself sing. Therefore, action potentials related to auditory perception and action potentials related to vocal performance are co-localized in individual neurons. Conceptual models of song learning involve comparison of vocal commands and the associated auditory feedback to compute an error signal that is used to guide refinement of subsequent song performances, yet the sites of that comparison remain unknown. Convergence of sensory and motor activity onto individual neurons points to a possible mechanism through which auditory and vocal-motor signals may be linked to enable learning and maintenance of the sounds used in vocal communication. This article is part of a Special Issue entitled "Vocalizations and Hearing". 23532537 Validation of the species sensitivity distribution in retrospective risk assessment of herbicides at the river basin scale-the Scheldt river basin case study. Species sensitivity distribution (SSD) is commonly used in prospective risk assessment to derive predicted no-effect concentrations, toxicity exposure ratios, and environmental quality standards for individual chemicals such as pesticides. The application of SSD in the retrospective risk assessment of chemical mixtures at the river basin scale (i.e., the estimation of "multiple substance potentially affected fractions" [msPAFs]) has been suggested, but detailed critical assessment of such an application is missing. The present study investigated the impact of different data validation approaches in a retrospective model case study focused on seven herbicides monitored at the Scheldt river basin (Belgium) between 1998 and 2009. The study demonstrated the successful application of the SSD approach. Relatively high impacts of herbicides on aquatic primary producers were predicted. Often, up to 40 % of the primary producer communities were affected, as predicted by chronic msPAF, and in some cases, the predicted impacts were even more pronounced. The risks posed by the studied herbicides decreased during the 1998-2009 period, along with decreasing concentrations of highly toxic pesticides such as simazine or isoproturon. Various data validation approaches (the removal of duplicate values and outliers, the testing of different exposure durations and purities of studied herbicides, etc.) substantially affected SSD at the level of individual studied compounds. However, the time-consuming validation procedures had only a minor impact on the outcomes of the retrospective risk assessment of herbicide mixtures at the river basin scale. Selection of the appropriate taxonomic group for SSD calculation and selection of the species-specific endpoint (i.e., the most sensitive or average value per species) were the most critical steps affecting the final risk values predicted. The present validation study provides a methodological basis for the practical use of SSD in the retrospective risk assessment of chemical mixtures. 23653108 AgS2O6CF3: the first trifluoromethylsulfonylsulfate(VI). We describe the synthetic route towards a novel class of salts, trifluoromethylsulfonylsulfates, as exemplified by the silver(I) derivative (AgS2O6CF3). Formation proceeds via direct reaction between a triflate precursor, AgSO3CF3, and SO3. The title compound crystallizes in the P2(1)/c unit cell with a = 5.15746(14) Å, b = 25.8563(9) Å, c = 5.53970(14) Å and β = 101.1749(19)°. The structure is layered with the puckered [AgS2O6] 2D sheets; the terminal CF3 groups are separated by the van der Waals gap, as seen also for related metal triflates. The compound is very fragile thermally and it decomposes endothermally to AgSO3CF3 with concomitant evolution of SO3 even at 65 °C or upon grinding in an agate mortar; thus it may serve as a solid store of--otherwise volatile and corrosive--SO3. The IR and Raman spectra of AgS2O6CF3 have been tentatively assigned based on similarities to those of related Ag2S2O7 and AgSO3CF3 and phonon calculations. Synthesis and properties of KS2O6CF3 are also briefly described. 23847580 Consciousness, brain, neuroplasticity. Subjectivity, intentionality, self-awareness and will are major components of consciousness in human beings. Changes in consciousness and its content following different brain processes and malfunction have long been studied. Cognitive sciences assume that brain activities have an infrastructure, but there is also evidence that consciousness itself may change this infrastructure. The two-way influence between brain and consciousness has been at the center of philosophy and less so, of science. This so-called bottom-up and top-down interrelationship is controversial and is the subject of our article. We would like to ask: how does it happen that consciousness may provoke structural changes in the brain? The living brain means continuous changes at the synaptic level with every new experience, with every new process of learning, memorizing or mastering new and existing skills. Synapses are generated and dissolved, while others are preserved, in an ever-changing process of so-called neuroplasticity. Ongoing processes of synaptic reinforcements and decay occur during wakefulness when consciousness is present, but also during sleep when it is mostly absent. We suggest that consciousness influences brain neuroplasticity both during wakefulness as well as sleep in a top-down way. This means that consciousness really activates synaptic flow and changes brain structures and functional organization. The dynamic impact of consciousness on brain never stops despite the relative stationary structure of the brain. Such a process can be a target for medical intervention, e.g., by cognitive training. 23876843 On the dynamics of SEIRS epidemic model with transport-related infection. Transportation amongst cities is found as one of the main factors which affect the outbreak of diseases. To understand the effect of transport-related infection on disease spread, an SEIRS (Susceptible, Exposed, Infectious, Recovered) epidemic model for two cities is formulated and analyzed. The epidemiological threshold, known as the basic reproduction number, of the model is derived. If the basic reproduction number is below unity, the disease-free equilibrium is locally asymptotically stable. Thus, the disease can be eradicated from the community. There exists an endemic equilibrium which is locally asymptotically stable if the reproduction number is larger than unity. This means that the disease will persist within the community. The results show that transportation among regions will change the disease dynamics and break infection out even if infectious diseases will go to extinction in each isolated region without transport-related infection. In addition, the result shows that transport-related infection intensifies the disease spread if infectious diseases break out to cause an endemic situation in each region, in the sense of that both the absolute and relative size of patients increase. Further, the formulated model is applied to the real data of SARS outbreak in 2003 to study the transmission of disease during the movement between two regions. The results show that the transport-related infection is effected to the number of infected individuals and the duration of outbreak in such the way that the disease becomes more endemic due to the movement between two cities. This study can be helpful in providing the information to public health authorities and policy maker to reduce spreading disease when its occurs. 23836429 Drosophila as a model for context-dependent tumorigenesis. Drosophila can exhibit classic hallmarks of cancer, such as evasion of apoptosis, sustained proliferation, metastasis, prolonged survival, genome instability and metabolic reprogramming, when cancer-related genes are perturbed. In the last two decades studies in flies have identified several tumor suppressor and oncogenes. However, the greatest strength of the fly lies in its ability to model cancer hallmarks in a variety of tissue types, which enables the study of context-dependent tumorigenesis. We review the organs and tissues that have been used to model tumor formation, and propose new strategies to maximize the potential of Drosophila in cancer research. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc. 22982684 Comparative gene expression profiling in human-induced pluripotent stem cell--derived cardiocytes and human and cynomolgus heart tissue. Cardiotoxicity is one of the leading causes of drug attrition. Current in vitro models insufficiently predict cardiotoxicity, and there is a need for alternative physiologically relevant models. Here we describe the gene expression profile of human-induced pluripotent stem cell-derived cardiocytes (iCC) postthaw over a period of 42 days in culture and compare this profile to human fetal and adult as well as adult cynomolgus nonhuman primate (NHP, Macaca fascicularis) heart tissue. Our results indicate that iCC express relevant cardiac markers such as ion channels (SCN5A, KCNJ2, CACNA1C, KCNQ1, and KCNH2), tissue-specific structural markers (MYH6, MYLPF, MYBPC3, DES, TNNT2, and TNNI3), and transcription factors (NKX2.5, GATA4, and GATA6) and lack the expression of stem cell markers (FOXD3, GBX2, NANOG, POU5F1, SOX2, and ZFP42). Furthermore, we performed a functional evaluation of contractility of the iCC and showed functional and pharmacological correlations with myocytes isolated from adult NHP hearts. These results suggest that stem cell-derived cardiocytes may represent a novel in vitro model to study human cardiac toxicity with potential ex vivo and in vivo translation. 23810847 Classification of tea category using a portable electronic nose based on an odor imaging sensor array. A developed portable electronic nose (E-nose) based on an odor imaging sensor array was successfully used for classification of three different fermentation degrees of tea (i.e., green tea, black tea, and Oolong tea). The odor imaging sensor array was fabricated by printing nine dyes, including porphyrin and metalloporphyrins, on the hydrophobic porous membrane. A color change profile for each sample was obtained by differentiating the image of sensor array before and after exposure to tea's volatile organic compounds (VOCs). Multivariate analysis was used for the classification of tea categories, and linear discriminant analysis (LDA) achieved 100% classification rate by leave-one-out cross-validation (LOOCV). This study demonstrates that the E-nose based on odor imaging sensor array has a high potential in the classification of tea category according to different fermentation degrees. 23432591 ATP synthase: a molecular therapeutic drug target for antimicrobial and antitumor peptides. In this review we discuss the role of ATP synthase as a molecular drug target for natural and synthetic antimicrobial/ antitumor peptides. We start with an introduction of the universal nature of the ATP synthase enzyme and its role as a biological nanomotor. Significant structural features required for catalytic activity and motor functions of ATP synthase are described. Relevant details regarding the presence of ATP synthase on the surface of several animal cell types, where it is associated with multiple cellular processes making it a potential drug target with respect to antimicrobial peptides and other inhibitors such as dietary polyphenols, is also reviewed. ATP synthase is known to have about twelve discrete inhibitor binding sites including peptides and other inhibitors located at the interface of α/β subunits on the F1 sector of the enzyme. Molecular interaction of peptides at the β DEELSEED site on ATP synthase is discussed with specific examples. An inhibitory effect of other natural/synthetic inhibitors on ATP is highlighted to explore the therapeutic roles played by peptides and other inhibitors. Lastly, the effect of peptides on the inhibition of the Escherichia coli model system through their action on ATP synthase is presented. 23553487 Photophysics of novel coumarin-labeled depsipeptides in solution: sensing interactions with SDS micelle via TICT model. N-Acylbenzotriazoles enable the synthesis (69-92% yield) of blue to green fluorescent coumarin-labeled depsidipeptides 8a-f (quantum yields 0.004-0.97) and depsitripeptides 12a-d (quantum yields 0.02-0.96). Detailed photophysical studies of fluorescent coumarin-labeled depsipeptides 8a-f and 12a-d are reported for both polar protic and polar aprotic solvents. 7-Methoxy and 7-diethylaminocoumarin-3-ylcarbonyl depsipeptides 8c,f and 12d are highly solvent sensitive. These highly fluorescent compounds could be useful for peptide assays. Further photophysical studies of 7-diethylaminocoumarin-labeled depsipeptides 8c,12d within the micellar microenvironment of SDS reflect their ability to bind with the biological membrane, suggesting potential applications in the fields of bio- and medicinal chemistry. 23465959 Factors associated with quality of life of people with dementia in long-term care facilities: A systematic review. Quality of life has become an important outcome measure in dementia research. Currently there is no convincing evidence about which factors are associated with quality of life of people with dementia living in long-term care facilities. This study aims to investigate which factors are associated with quality of life, including factors associated with change over time, of people with dementia living in long-term care facilities. A systematic literature review was performed. Cochrane, Pubmed, CINAHL, Web of Science, and PsycINFO were searched. Three researchers independently assessed studies for eligibility. The inclusion criteria were: (1) the primary focus was on factors related to quality of life; (2) the study was performed in long-term care facilities; (3) the study regarded quality of life as multidimensional construct. Methodological quality of studies included in the review was assessed with a quality criteria checklist. Ten cross-sectional and three longitudinal articles were included in the review. In cross-sectional studies, depressive symptoms were negatively related to self-rated quality of life of people with dementia. The association between depressive symptoms and proxy-rated quality of life was less clear. Behavioural disturbances, especially agitation, appeared to be negatively related to proxy-rated quality of life. There appeared to be a negative relation between quality of life, activities of daily living and cognition, although this could not be confirmed in all studies. In longitudinal studies, depressive symptoms were negatively related and cognition was positively related to self-rated quality of life, whereas dependency and depressive symptoms were negatively related to proxy-rated quality of life. There are only few high quality studies that investigate associations of (change in) quality of life of people with dementia living in long-term care facilities. Our results suggest that depressive symptoms and agitation are related to lower quality of life. Perspective of quality of life measurement, i.e. self- or proxy rating, may influence its associations. Longitudinal studies are needed to determine which factors are related to change in quality of life over time. This information is essential for the development of interventions that aim to improve quality of life. 23674227 Hydrocephalus associated with vestibular schwannomas: perioperative changes in cerebrospinal fluid. Cerebrospinal fluid (CSF) protein levels are known to increase in patients with vestibular schwannomas (VS) with concomitant hydrocephalus, however the only information available on perioperative changes in CSF in these patients comes from case reports. Here, we investigated the relation between CSF protein and hydrocephalus in a large series of patients undergoing resection of VS. We classified 376 patients undergoing resection for VS at our institute into two groups, namely VS and no hydrocephalus (control, n = 319) and VS with concomitant hydrocephalus (n = 57), and compared clinical parameters. Among the 57 patients diagnosed with hydrocephalus, hydrocephalus status was examined by lumbar puncture in 20 patients with communicative hydrocephalus, and pre- and postoperative scores in CSF properties were compared. Patients in the hydrocephalus group were significantly older than those in the control group (mean, 55.8 vs. 43.8 years), and had a longer disease duration (median, 76 vs. 12 months), larger tumors (median, 15.6 vs. 5.5 ml), and a higher protein concentration in CSF (median, 147.3 vs. 65.1 mg/dl). Perioperative CSF samples of hydrocephalus patients showed a significantly decrease in cerebrospinal pressure after tumor removal (median, -75mmH2O), followed by a decrease in CSF protein (median, -74.5 mg/dl). No patients required the placement of a shunt. Extended disease duration and elevated CSF protein secondary to the presence of a tumor contribute to the occurrence of hydrocephalus. Primary maximal tumor removal for VS with coexisting hydrocephalus avoids an unnecessary shunt. 23842796 BACE1 as a Therapeutic Target in Alzheimer's Disease: Rationale and Current Status. Alzheimer's disease (AD) is a neurodegenerative disease of the central nervous system that causes dementia in a large percentage of the aged population and for which there are only symptomatic treatments. Disease-modifying therapies that are currently being pursued are based on the amyloid cascade theory. This states that accumulation of amyloid β (Aβ) in the brain triggers a cascade of cellular events leading to neurodegeneration. Aβ, which is the major constituent of amyloid plaques, is a peptidic fragment derived from proteolytic processing of the amyloid precursor protein (APP) by sequential cleavages that involve β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase. Targeting BACE1 is a rational approach as its cleavage of APP is the rate-limiting step in Aβ production and this enzyme is elevated in the brain of patients with AD. Furthermore, knocking out the BACE1 gene in mice showed little apparent consequences. Ten years of intensive research has led to the design of efficacious BACE1 inhibitors with favorable pharmacological properties. Several drug candidates have shown promising results in animal models, as they reduce amyloid plaque pathology in the brain and rescue cognitive deficits. Phase I clinical trials indicate that these drugs are well tolerated, and the results from further trials in AD patients are now awaited eagerly. Yet, recent novel information on BACE1 biology, and the discovery that BACE1 cleaves a selection of substrates involved in myelination, retinal homeostasis, brain circuitry, and synaptic function, alert us to potential side effects of BACE1 inhibitors that will require further evaluation to provide a safe therapy for AD. 23793641 Facility-specific "house" microbiome drives microbial landscapes of artisan cheesemaking plants. Cheese fermentations involve the growth of complex microbial consortia, which often originate in the processing environment and drive the development of regional product qualities. However, the microbial milieus of cheesemaking facilities are largely unexplored and the true nature of the fermentation-facility relationship remains nebulous. Thus, a high-throughput sequencing approach was employed to investigate the microbial ecosystems of two artisanal cheesemaking plants, with the goal of elucidating how the processing environment influences microbial community assemblages. Results demonstrate that fermentation-associated microbes dominated most surfaces, primarily Debaryomyces and Lactococcus, indicating that establishment of these organisms on processing surfaces may play an important role in microbial transfer, beneficially directing the course of sequential fermentations. Environmental organisms detected in processing environments dominated the surface microbiota of washed-rind cheeses maturing in both facilities, demonstrating the importance of the processing environment for populating cheese microbial communities, even in inoculated cheeses. Spatial diversification within both facilities reflects the functional adaptations of microbial communities inhabiting different surfaces and the existence of facility-specific "house" microbiota, which may play a role in shaping site-specific product characteristics. 23842928 The influence of type of vascular pedicle occlusion on the viability of skin island flaps: a postoperative quantitative assessment of flap survival in an experimental model in rats. To evaluate the role of pedicle occlusion on the viable area of a skin island flap. An epigastric skin island flap was performed in 160 Wistar rats. The animals were randomly divided into four groups: G-1: occlusion of inferior epigastric artery; G-2: inferior epigastric vein; G-3: inferior epigastric vessels (artery/vein). At varying times postoperatively (2,3,4,5th day), animals from each group were randomly selected, and the pedicle was occluded. On the 10th. postop. day, the skin flaps were evaluated by templates to determine the percentage of surviving skin. The computer HP™ 9830A captured the photographs and the mean flap necrosis area was assessed. An increasing area of flap survived with less area of necrosis with increased time of days intervals. In the G-1, the mean area of necrosis observed (two to five days) were 95.2, 60.8, 31 and 3.7 % respectively. In the G-2 were 95.5, 57.6, 19.5 and 5.6 % respectively. In the G-3, a 100, 80, 32.4 and 14.9 % of mean area was observed. The arterial suppy/venous drainage is important for flap circulation up to five days following pedicle occlusion. After this period, the pedicle can be interrupted once the circulation through the flap margins has already been established. 23957328 Ultrafine particles: Exposure and source apportionment in 56 Danish homes. Particle number (PN) concentrations (10 - 300 nm in size) were continuously measured over a period of ~45 hours in 56 residences of non-smokers in Copenhagen, Denmark. The highest concentrations were measured when occupants were present and awake (geometric mean, GM: 22.3 × 10^3 cm-3), the lowest when the homes were vacant (GM: 6.1 × 10^3 cm-3) or the occupants were asleep (GM: 5.1 × 10^3 cm-3). Diary entries regarding occupancy and particle related activities were used to identify source events and apportion the daily integrated exposure among sources. Source events clearly resulted in increased PN concentrations and decreased average particle diameter. For a given event, elevated particle concentrations persisted for several hours after the emission of fresh particles ceased. The residential daily integrated PN exposure in the 56 homes ranged between 37 × 10^3 and 6.0 × 10^6 particles per cm3•h/day (GM: 3.3 × 10^5 cm-3•h/day). On average, ~90% of this exposure occurred outside of the period from midnight to 6 AM. Source events, especially candle burning, cooking, toasting and unknown activities, were responsible on average for ~65% of the residential integrated exposure (51% without the unknown activities). Candle burning occurred in half of the homes where, on average, it was responsible for almost 60% of the integrated exposure. 23862114 Determining influenza virus shedding at different time points in madin-darby canine kidney cell line. Monitoring of influenza virus shedding and optimization of multiplicities of infection (MOI) is important in the investigation of a virus one step growth cycle and for obtaining a high yield of virus in vaccine development and conventional basic diagnostic methods. However, eluted infectious viruses may still be present immediately after virus inoculation and when cells are washed following virus cultivation which may lead to a false positive virus infectivity assay. In this experimental study, we investigated influenza virus progeny production in Madin-Darby canine kidney (MDCK) cells with five different MOI at determined time points. The results were analyzed by end point titration tests and immunofluorescence assay. Higher titers of eluted virus were observed following a high MOI inoculation of virus in cell culture. Most probably, this was the result of sialic acid residues from viral hemagglutin in proteins that were cleaved by neuraminidase glycoproteins on the surface of the influenza virus, which promoted viral spread from the host cell to the culture supernatant or during endocytosis, where viruses recycle to the cell surface by recycling endosomes which culminated in virus shedding without replication. We demonstrated that the pattern of influenza virus progeny production was dose-dependent and not uniform. This production was influenced by several factors, particularly MOI. Understanding the exact features of viral particle propagation has a major impact in producing high virus yields in the development of vaccines. Use of lower MOI (0.01) could result in accurate, precise quantitative assays in virus diagnosis and titration methods. 23887194 5-Aminolevulinic-Acid-Induced Protoporphyrin IX Fluorescence in Meningioma: Qualitative and Quantitative Measurements In Vivo. The use of 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) fluorescence has shown promise as a surgical adjunct for maximizing the extent of surgical resection in gliomas. To date, the clinical utility of 5-ALA in meningiomas is not fully understood, with most descriptive studies using qualitative approaches to 5-ALA-PpIX. To assess the diagnostic performance of 5-ALA-PpIX fluorescence during surgical resection of meningioma. ALA was administered to 15 patients with meningioma undergoing PpIX fluorescence-guided surgery at our institution. At various points during the procedure, the surgeon performed qualitative, visual assessments of fluorescence using the surgical microscope, followed by a quantitative fluorescence measurement using an intraoperative probe. Specimens were collected at each point for subsequent neuropathological analysis. Clustered data analysis of variance was used to ascertain a difference between groups and receiver operating characteristic (ROC) analyses performed to assess diagnostic capabilities. Red-pink fluorescence was observed in 80% (12/15) of patients, with visible fluorescence generally demonstrating a strong, homogeneous character. Quantitative fluorescence measured diagnostically significant PpIX concentrations (cPpIX) in both visibly and non-visibly fluorescent tissues, with significantly higher cPpIX in both visibly fluorescent (p<0.001) and tumor tissue (p=0.0023). ROC analyses also showed diagnostic accuracies up to 90% for differentiating tumor from normal dura. ALA-induced PpIX fluorescence guidance is a potential and promising adjunct in accurately detecting neoplastic tissue during meningioma resective surgery. These results suggest a broader reach for PpIX as a biomarker for meningiomas than was previously noted in the literature. 23866099 Psychiatric symptoms as a clinical presentation of Cushing's syndrome. Cushing's syndrome can present with a spectrum of symptoms; however, it is less recognised that psychiatric symptoms can form part of the clinical presenting features. In the investigations for an organic cause for a psychiatric illness, Cushing's syndrome needs to be considered, especially if there are other features such as hirsutism or hypertension. In this article, the two cases reported demonstrate that a prompt diagnosis is not only important for psychiatric management but also crucial for timely institution of the necessary treatment of life-threatening causes of hypercortisolaemia such as metastatic adrenal carcinoma. 23844764 Lichenysin is produced by most Bacillus licheniformis strains. The aim of this study was to elucidate the prevalence of lichenysin production in Bacillus licheniformis and to see whether this feature was restricted to certain genotypes. Secondly, we wanted to see whether cytotoxicity reflected the measured levels of lichenysin. Fifty-three genotyped strains of B. licheniformis, representing a wide variety of sources, were included. lchAA gene fragments were detected in all strains by polymerase chain reaction (PCR). All 53 strains produced lichenysins with four molecular masses as confirmed by LC-MS/MS (liquid chromatography-tandem mass spectrometry) analysis. The amounts of lichenysin varied more than two orders of magnitude between strains and were irrespective of genotype. Finally, there was a strong association between lichenysin concentrations and toxicity towards boar spermatozoa, erythrocytes and Vero cells. Lichenysin synthesis was universal among the 53 B. licheniformis strains examined. The quantities varied considerably between strains, but were not specifically associated with genotype. Cytotoxicity was evident at lichenysin concentrations above 10 Î¼g ml(-1) , which is in accordance with previous studies. This study might be of interest to those working on B. licheniformis for commercial use as well as for authorities who make risk assessments of B. licheniformis when used as a food and feed additive. 23832138 Urofacial syndrome: a genetic and congenital disease of aberrant urinary bladder innervation. The urofacial, or Ochoa, syndrome is characterised by congenital urinary bladder dysfunction together with an abnormal grimace upon smiling, laughing and crying. It can present as fetal megacystis. Postnatal features include urinary incontinence and incomplete bladder emptying due to simultaneous detrusor muscle and bladder outlet contractions. Vesicoureteric reflux is often present, and the condition can be complicated by urosepsis and end-stage renal disease. The syndrome has long been postulated to have neural basis, and it can be familial when it is inherited in an autosomal recessive manner. Most individuals with urofacial syndrome genetically studied to date carry biallelic, postulated functionally null mutations of HPSE2 or, less commonly, of LRIG2. Little is known about the biology of the respective encoded proteins, heparanase 2 and leucine-rich repeats and immunoglobulin-like domains 2. Nevertheless, the observations that heparanase 2 can bind heparan sulphate proteolgycans and inhibit heparanase 1 enzymatic activity and that LRIG2 can modulate receptor tyrosine kinase growth factor signalling each point to biological roles relevant to tissue differentiation. Moreover, both heparanase 2 and LRIG2 proteins are detected in autonomic nerves growing into fetal bladders. The collective evidence is consistent with the hypothesis that urofacial syndrome genes code for proteins which work in a common pathway to facilitate neural growth into, and/or function within, the bladder. This molecular pathway may also have relevance to our understanding of the pathogenesis of other lower tract diseases, including Hinman-Allen syndrome, or non-neurogenic neurogenic bladder, and of the subset of individuals who have primary vesicoureteric reflux accompanied by bladder dysfunction. 23578628 A new method for detection of five alternaria toxins in food matrices based on LC-APCI-MS. A new method for the detection of alternariol (AOH), alternariol monomethyl ether (AME), altenuene (ALT), tentoxin (TEN), and tenuazonic acid (TeA), five alternaria toxins (ATs) was developed by liquid chromatography-triple quadrupole mass spectrometry equipped with atmospheric pressure chemical ionisation (APCI). A single extraction was used to recover the five ATs by apple juices, beers, tomato sauces, olives and dried basil. Different Solid Phase Extractions (SPE) and clean-up were selected to optimise the purification step for each food matrix. Limits of detection and quantification were, respectively, in the range 0.16-12.31 and 0.54-41.04ngg(-1). Recovery rates were generally above 70%, except for dried basil and olives. Thirty out of 70 samples analysed (7 apple juices, 14 beers and 9 tomato sauces) resulted positive to at least one alternaria toxin investigated. AOH was the most common AT (14 samples), followed by ALT (10 samples). The highest concentration of ATs was found in commercial apple juices (35.33ngg(-1)). 23567916 Observing the translocation of a mitochondria-penetrating peptide with solid-state NMR. A new class of penetrating peptides that can target the mitochondria with high specificity was recently discovered. In this work, we developed a model inner mitochondrial membrane, equipped with a transmembrane gradient, suitable for solid-state NMR experiments. Using solid-state NMR, we observed a mitochondria-penetrating peptide interacting with the model inner mitochondrial membrane to gain insight into the mechanism of translocation. The paramagnetic relaxation effect due to Mn(2+) ions on (13)C magic angle spinning NMR was used to measure the insertion depth of the peptide and its distribution in each monolayer of the membrane. We found that at low peptide concentration the peptide binds to the outer leaflet and at high concentration, it crosses the hydrophobic bilayer core and is distributed in both leaflets. In both concentration regimes, the peptide binds at the C2 position on the lipid acyl chain. The mitochondria-penetrating peptide crossed to the inner leaflet of the model membranes without disrupting the lamellarity. These results provide evidence that supports the electroporation model of translocation. We estimated the energy associated with crossing the inner mitochondrial membrane. We found that the transmembrane potential provides sufficient energy for the peptide to cross the hydrophobic core, which is the most unfavorable step in translocation. 23832838 Lower preoperative fluctuation of heart rate variability is an independent risk factor for postoperative atrial fibrillation in patients undergoing major pulmonary resection. OBJECTIVESThe following study presents a special independent atrial fibrillation (AF) risk factor-preoperative fluctuation of heart rate variability (HRV), as well as other perioperative AF risk factors in patients qualified for pneumonectomy and undergoing pneumonectomy or lobectomy for lung cancer.METHODSThe prospective study was performed in patients who had undergone anatomical resection for non-small-cell lung cancer. A total of 117 patients (92 men and 25 women) qualified for statistical research. In order to determine the risk factors, all patients were divided into two groups: Group A-98 patients without AF and Group B-19 patients with AF during the perioperative time. A number of different risk factors of AF have been analysed and further divided into preoperative, operative and postoperative.RESULTSPostoperative AF occurred in 19 patients (16%), all of them were male. The patients with higher short-term HRV parameters (SD1, RMSSD), slower mean heart rate and those with a lower fluctuation of HRV-related parameters (HRV Afternoon, Night, Day (A/N/D)) before the operation, were more prone to AF. Postoperative risk of AF was higher in patients with a higher number of ventricular ectopic beats before the operation, a higher number of supraventricular and ventricular ectopic beats and a higher maximal heart rate after the operation. Statistical analysis revealed that male gender and the extent of pulmonary resection, particularly left pneumonectomy, constituted significant risk factors. AF was more often observed in patients who had ASA physical status score of III, in comparison with ASAI and ASAII patients.CONCLUSIONSAlong with other concomitant AF risk factors presented in this work, the evaluation of the fluctuation tendencies of HRV parameters should be taken into consideration before any major lung resection. The balance disturbance between the sympathetic and parasympathetic nervous systems is responsible for AF. 23007945 Maohuoside A Acts in a BMP-dependent Manner during Osteogenesis. There has been a strong interest in searching for natural therapies for osteoporosis. Epimedium koreanum Nakai is an herb that is commonly used in East Asia to treat osteoporosis, and most studies of its activity have focused on its major ingredient, icariin. In this study, maohuoside A (MHA), a single compound isolated from the E. koreanum, was found to promote osteogenesis in mouse bone marrow-derived mesenchymal stem cells. We hypothesise that, if MHA potently induces osteogenic differentiation in a bone morphogenetic protein-dependent manner, it may be used to broaden the sources for cell transplantation and thereby establish more efficient bone regeneration systems. Real-time polymerase chain reaction and western blot were used to detect the expression of SMAD4, a marker of bone formation. Microcomputed tomography and histomorphometric techniques showed that oral treatment with MHA was followed by an increase in the bone mineral density of the lumbar vertebrae in mice. This result also indicates that MHA may directly activate osteopontin gene transcription. In conclusion, MHA seems to enhance the osteogenesis of bone marrow-derived mesenchymal stem cells at least partly via bone morphogenetic protein signalling. Copyright © 2012 John Wiley & Sons, Ltd. 23926928 Surface Tension, Surface Energy, and Chemical Potential Due to Their Difference. It is well-known that surface tension and surface energy are distinct quantities for solids. Each can be regarded as a thermodynamic property related first by Shuttleworth. Mullins and others have suggested that the difference between surface tension and surface energy cannot be sustained and that the two will approach each other over time. In this work we show that in a single-component system where changes in elastic energy can be neglected, the chemical potential difference between the surface and bulk is proportional to the difference between surface tension and surface energy. By further assuming that mass transfer is driven by this chemical potential difference, we establish a model for the kinetics by which mass transfer removes the difference between surface tension and surface energy. 23685882 N-truncated amyloid β (Aβ) 4-42 forms stable aggregates and induces acute and long-lasting behavioral deficits. N-truncated Aβ4-42 is highly abundant in Alzheimer disease (AD) brain and was the first Aβ peptide discovered in AD plaques. However, a possible role in AD aetiology has largely been neglected. In the present report, we demonstrate that Aβ4-42 rapidly forms aggregates possessing a high aggregation propensity in terms of monomer consumption and oligomer formation. Short-term treatment of primary cortical neurons indicated that Aβ4-42 is as toxic as pyroglutamate Aβ3-42 and Aβ1-42. In line with these findings, treatment of wildtype mice using intraventricular Aβ injection induced significant working memory deficits with Aβ4-42, pyroglutamate Aβ3-42 and Aβ1-42. Transgenic mice expressing Aβ4-42 (Tg4-42 transgenic line) developed a massive CA1 pyramidal neuron loss in the hippocampus. The hippocampus-specific expression of Aβ4-42 correlates well with age-dependent spatial reference memory deficits assessed by the Morris water maze test. Our findings indicate that N-truncated Aβ4-42 triggers acute and long-lasting behavioral deficits comparable to AD typical memory dysfunction. 23828544 Treatment of vaginal bleeding irregularities induced by progestin only contraceptives. Despite their high effectiveness, progestin-only contraceptives are considered less than ideal by the many women who experience irregular vaginal bleeding when using them. Current treatments to control these bleeding problems are not sufficiently effective. We evaluated preventive and therapeutic approaches to normalise bleeding irregularities associated with the use of progestin-only contraceptives. Literature was identified through database searches, reference lists, organisations and individuals, covering the period until May-June 2012. Trials with random or systematic allocation, testing interventions for the prevention or treatment of bleeding irregularities associated with the use of progestin-only contraceptives were eligible. Results are expressed as relative risks (RR) with 95% confidence interval (CI) for categorical data and as weighted mean difference (WMD) with 95% CI for continuous data. When we encountered heterogeneity (visual or statistical) we used the random-effects model (quantitative) or did not produce a summary estimate (qualitative). Thirty-three randomised controlled trials enrolling 3677 participants were included. Two thirds of the trials were determined to reflect low to moderate risk of bias.Estrogen treatments reduced the number of days of an ongoing bleeding episode in DMPA and Norplant users. However, treatment frequently led to more discontinuation due to gastrointestinal upset.Combinations of oral ethinyl estradiol and levonorgestrel improved bleeding patterns in Norplant users, but method discontinuation rates were unchanged. One trial reported successful use of combined oral contraceptives in treating amenorrhea among DMPA users.Norplant users, but not Implanon users, administered the anti-progestin mifepristone reported fewer days of bleeding during treatment than those given placebo. Mifepristone used monthly by new Norplant acceptors reduced bleeding, when compared to placebo.A variety of NSAIDS have been evaluated for their ability to treat abnormal bleeding, with mixed results.Norplant users receiving SERM (tamoxifen) had less unacceptable bleeding after treatment and were more likely to continue using Norplant than those receiving placebo.Tranexamic acid, mifepristone combined with an estrogen and doxycycline were more effective than placebo in terminating an episode of bleeding in women using progestin-only contraceptives, according to three small studies. Some women may benefit from the interventions described, particularly with cessation of current bleeding. Several regimens offer promise in regulating bleeding, but findings need to be reproduced in larger trials. The results of this review do not support routine clinical use of any of the regimens included in the trials, particularly for long-term effect. 23791122 Schmallenberg virus in Italy: a retrospective survey in Culicoides stored during the bluetongue Italian surveillance program. Following the first case of Schmallenberg (SBV) in northern Italy in February 2012, virus detection was conducted on midges collected during the national entomological surveillance program for bluetongue (BT). Six cattle farms, within a radius of 50km from the SBV case, were selected for a 12 month study, aiming to determine when the virus entered the area, if it was capable of overwintering, and the possible role played by each species of the Obsoletus complex in disseminating the infection. A total of 33,724 Culicoides were collected at the six sites between June 2011 and June 2012. Species belonging to the Obsoletus Complex were the most abundant (94.44%) and, within the complex, Culicoides obsoletus was the most prevalent species in the studying area (65.4%). Nearly 7000 Culicoides midges were screened, either in pools or individually, for SBV by real-time RT-PCR. Viral genome was detected in six pools of the Obsoletus complex, collected at three sites between September and November 2011, and in a single parous female of C. obsoletus, collected in May 2012. As a result of the BT surveillance program in Italy it was possible to demonstrate, retrospectively, that SBV has circulated in at least three Italian provinces since early September 2011, nearly 5 months prior and as far as 40km away from the first detected case. Similarly, the survey confirmed the presence of SBV in the vector population 3 months after the outbreak, following a cold winter during which the blacklight traps failed to catch active adult midges. 23927673 Increased T Cell Glucose Uptake Reflects Acute Rejection in Lung Grafts. Although T cells are required for acute lung rejection, other graft-infiltrating cells such as neutrophils accumulate in allografts and are also high glucose utilizers. Positron emission tomography (PET) with the glucose probe [(18) F]fluorodeoxyglucose ([(18) F]FDG) has been employed to image solid organ acute rejection, but the sources of glucose utilization remain undefined. Using a mouse model of orthotopic lung transplantation, we analyzed glucose probe uptake in the grafts of syngeneic and allogeneic recipients with or without immunosuppression treatment. Pulmonary microPET scans demonstrated significantly higher [(18) F]FDG uptake in rejecting allografts when compared to transplanted lungs of either immunosuppressed or syngeneic recipients. [(18) F]FDG uptake was also markedly attenuated following T cell depletion therapy in lung recipients with ongoing acute rejection. Flow cytometric analysis using the fluorescent deoxyglucose analog 2-NBDG revealed that T cells, and in particular CD8(+) T cells, were the largest glucose utilizers in acutely rejecting lung grafts followed by neutrophils and antigen-presenting cells. These data indicate that imaging modalities tailored toward assessing T cell metabolism may be useful in identifying acute rejection in lung recipients. 23410798 Spiro heterocycles as potential inhibitors of SIRT1: Pd/C-mediated synthesis of novel N-indolylmethyl spiroindoline-3,2'-quinazolines. Novel N-indolylmethyl substituted spiroindoline-3,2'-quinazolines were designed as potential inhibitiors of SIRT1. These compounds were synthesized in good yields by using Pd/C-Cu mediated coupling-cyclization strategy as a key step involving the reaction of 1-(prop-2-ynyl)-1'H-spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione with 2-iodoanilides. Some of the compounds synthesized have shown encouraging inhibition of Sir 2 protein (a yeast homologue of mammalian SIRT1) in vitro and three of them showed dose dependent inhibition of Sir 2. The docking results suggested that the benzene ring of 1,2,3,4-tetrahydroquinazolin ring system of these molecules occupied the deep hydrophobic pocket of the protein and one of the NH along with the sulfonyl group participated in strong H-bonding interaction with the amino acid residues. 23290121 Neuropsychiatric predictors of conversion to dementia both in patients with amnestic mild cognitive impairment and those with subcortical vascular MCI. The aim of this study was to investigate whether specific neuropsychiatric domains could predict a conversion to dementia in those patients either with amnestic subtype of mild MCI (aMCI) or subcortical vascular MCI (svMCI). At baseline, all subjects underwent neuropsychological tests, Neuropsychiatric Inventory (NPI), and MRI. We compared the baseline NPI scores between converters (CV) and non-converters (NCV) both in the aMCI and svMCI groups. The mean follow-up duration was 16.74±8.02 months (range: 4.2-43.9). At the second time point, about 30% of aMCI and svMCI patients converted to dementia with 7.5% of aMCI patients exhibiting improvement to normal cognitive state. In female aMCI patients, those who later improved to normal cognition exhibited higher baseline depression scores than the CV group. However, baseline depression scores were higher in the CV group than the NCV group in svMCI patients, and this difference was significant only in males. Our results suggest that depression might serve as a predictive marker of conversion to dementia in patients with svMCI, albeit only in males. On the other hand, patients who later improved to normal cognition showed higher scores of depression at baseline in female aMCI patients, suggesting that longer follow-ups are warranted in female patients with aMCI and depression. 23318398 Novel biodegradable electrospun nanofibrous P(DLLA-CL) balloons for the treatment of vertebral compression fractures. Significant interest has been expressed by the spinal surgeon community for the use of calcium phosphate cement (CPC) in the treatment of vertebral compression fractures (VCFs), but the water-induced collapsibility and poor mechanical properties limit its clinical use. Here we fabricated novel electrospun nanofibrous P(DLLA-CL) balloons (ENPBs) using the nanotechnique of electrospinning. The ENPBs could separate the cements from the surrounding environment, and therefore can prevent the water-induced collapsibility of CPC and eliminate cement leakage. The ENPBs filling with CPC had enough load-bearing ability to restore the height of the fractured vertebral body and had no obvious effects on the initial strength and stiffness of natural bones. Further, the ENPBs had good biodegradability and cell proliferation ability. Calcium can be released from ENPBs filling with CPC. All these results strongly demonstrate ENPBs can be potentially used as CPC filling containers that keep the advantages and eliminate the disadvantages of CPC. Calcium phosphate cement (CPC) is a promising modality in vertebral compression fracture treatment, but its water-induced collapsibility limits clinical applications. This team of investigators fabricated novel nanofibrous balloons using electrospinning, which enabled the separation of CPC from its surrounding environment, and therefore prevented water-induced collapsibility of CPC and eliminated cement leakage while maintaining all the advantages of CPC treatment. 23792635 Mesophilic anaerobic co-digestion of sewage sludge and a lixiviation of sugar beet pulp: Optimisation of the semi-continuous process. This study examine the effect of an increased organic loading rate on the efficiency of the stirred tank reactor treating sewage sludge and sugar beet pellets and to report on its steady-state performance. The digester was subjected to a program of steady-state operation over a range of hydraulic retention times (HRTs) of 30 to 6days and organic loading rates (OLRs) of up to 1.7kgCOD/m(3)d to evaluate its treatment capacity. The COD removal efficiency was found to be 84.23% COD in the digester when treating mixture sewage sludge/lixiviation of sugar beet pulp at 1.27kgCOD/m(3)d (10-days SRT). The volumetric methane level produced in the digester reached 0.7m(3)CH4/m(3)d and the methane yield was 0.64m(3)CH4/kgCODremoval. Therefore, anaerobic co-digestion of sewage sludge and lixiviation of sugar beet pulp improve the biogas productivity and the organic matter removal in addition to lowering solids retention times in the system. 23733443 Improvement of Major Depression is Associated with Increased Erythrocyte DHA. The aim of this study was to determine if changes in omega-3 polyunsaturated fatty acid status following tuna oil supplementation correlated with changes in scores of depression. A total of 95 volunteers receiving treatment for major depression were randomised to consume 8 Ã— 1 g capsules per day of HiDHA (2 g DHA, 0.6 g EPA and 10 mg Vitamin E) or olive oil (placebo) for 16 weeks, whilst undergoing weekly counseling sessions by trained clinical psychologists using a standard empirically validated psychotherapy. Depression status was assessed using the 17 item Hamilton rating scale for depression and the Beck Depression Inventory by a psychodiagnostician who was blind to the treatment. Blood was taken at baseline and 16 weeks (n = 48) for measurement of erythrocyte fatty acids. With HiDHA supplementation, erythrocyte DHA content rose from 4.1 ± 0.2 to 7.9 ± 0.4 % (mean ± SEM, p < 0.001) of total fatty acids but did not change (4.0 ± 0.2 to 4.1 ± 0.2 %) in the olive oil group. The mean changes in scores of depression did not differ significantly between the two groups (-12.2 ± 2.1 for tuna oil and -14.4 ± 2.3 for olive oil). However, analysis of covariance showed that in the fish oil group there was a significant correlation (r = -0.51) between the change in erythrocyte DHA and the change in scores of depression (p < 0.05). Further study of the relationship between DHA and depression is warranted. 23534444 Calculation of Electron Transfer Rates Using Mixed Quantum Classical Approaches: Nonadiabatic Limit and Beyond. We investigate the applicability of the Ehrenfest and surface hopping methods to calculate electron transfer rates using the spin-boson model with different parameters. Rate constants are obtained from short time dynamics performed in both the diabatic and adiabatic basis sets. Numerical results and theoretical analysis show that these two methods can be reasonably accurate in the nonadiabatic limit, by staying close to an approximate Fermi's golden rule. Beyond the nonadiabatic limit, the calculated mixed quantum classical rates are compared with numerical exact results, and similar accuracy was found as in the nonadiabatic limit. The relation between the current finding and recent studies using the surface hopping method based on long time dynamics is also discussed. It is found that the short time dynamics could be more accurate in calculating rate constants using the mixed quantum classical methods. 23463090 Analysis of Factors that Influence the Accuracy of Magnetic Resonance Imaging for Predicting Response after Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer. The purpose of this study was to evaluate the accuracy of breast magnetic resonance imaging (MRI) to predict residual lesion size after neoadjuvant chemotherapy (NAC) and to determine the factors that influence the accuracy of response prediction. This study comprised 166 patients who underwent MRI before and after NAC, but before surgery. The longest diameter of the residual cancer was measured using MRI and correlated with pathologic findings. Patients were further divided into subgroups according to various radiologic and histopathologic factors. Pathologic complete response (pCR) was defined as the absence of residual invasive cancer cells. The Pearson correlation was used to correlate tumor size as determined by MRI and pathology, and the Mann-Whitney U test and Kruskal-Wallis test were used to compare MRI-pathologic size discrepancies according to various clinical, histopathologic factors, and MRI findings. Of the 166 women, 40 achieved pCR. The overall sensitivity, specificity, and accuracy for diagnosing invasive residual disease by using MRI were 96, 65, and 89 %, respectively. The Pearson's correlation coefficient between the tumor sizes measured using MRI and pathology was 0.749 (P < 0.001). The size discrepancy was significantly greater in patients with estrogen receptor-positive cancer (P = 0.037), in cancers with low nuclear grade (P = 0.007), and in cancers shown as diffuse non-mass-like enhancement on MRI (P = 0.001). Size prediction is less accurate in cases with estrogen receptor-positive breast cancer, low nuclear grade, and diffuse non-mass-like enhancement on initial MRI. 23956200 Thermosensitive Macroporous Cryogels Functionalized With Bioactive Chitosan/Bemiparin Nanoparticles. Thermosensitive macroporous scaffolds of poly(N-isopropylacrylamide) (polyNIPA) loaded with chitosan/bemiparin nanoparticles are prepared by the free radical polymerization in cryogenic conditions. Chitosan/bemiparin nanoparticles of 102 ± 6.5 nm diameter are prepared by complex coacervation and loaded into polyNIPA cryogels. SEM image reveal the highly porous structure of cryogels and the integration of nanoparticles into the macroporous system. Volume phase transition temperature (VPT) and total freezing water content of cryogels are established by differential scanning calorimetry, and their porosity is determined by image-NMR. Swelling of cryogels (above and below the VPT) is highly dependent on nanoparticles concentration. In vitro release profile of bemiparin from cryogel is highly modulated by the presence of chitosan. Bemiparin released from nanoparticles preserves its biological activity, as shown by the BaF32 cell proliferation assay. Cryogels are not cytotoxic for the human fibroblast cells and present excellent properties for application on tissue engineering and controlled release of heparin. 23867013 High prevalence of antibodies against canine adenovirus (CAV) type 2 in domestic dog populations in South Africa precludes the use of CAV-based recombinant rabies vaccines. Rabies in dogs can be controlled through mass vaccination. Oral vaccination of domestic dogs would be useful in the developing world, where greater vaccination coverage is needed especially in inaccessible areas or places with large numbers of free-roaming dogs. From this perspective, recent research has focused on development of new recombinant vaccines that can be administered orally in a bait to be used as adjunct for parenteral vaccination. One such candidate, a recombinant canine adenovirus type 2 vaccine expressing the rabies virus glycoprotein (CAV2-RG), is considered a promising option for dogs, given host specificity and safety. To assess the potential use of this vaccine in domestic dog populations, we investigated the prevalence of antibodies against canine adenovirus type 2 in South African dogs. Blood was collected from 241 dogs from the Gauteng and KwaZulu-Natal provinces. Sampled dogs had not previously been vaccinated against canine adenovirus type 1 (CAV1) or canine adenovirus type 2 (CAV2). Animals from both provinces had a high percentage of seropositivity (45% and 62%), suggesting that CAV2 circulates extensively among domestic dog populations in South Africa. Given this finding, we evaluated the effect of pre-existing CAV-specific antibodies on the efficacy of the CAV2-RG vaccine delivered via the oral route in dogs. Purpose-bred Beagle dogs, which received prior vaccination against canine parvovirus, canine distemper virus and CAV, were immunized by oral administration of CAV2-RG. After rabies virus (RABV) infection all animals, except one vaccinated dog, developed rabies. This study demonstrated that pre-existing antibodies against CAV, such as naturally occurs in South African dogs, inhibits the development of neutralizing antibodies against RABV when immunized with a CAV-based rabies recombinant vaccine. 23953141 Out of sight but not gone: Sero-surveillance for cattle grubs, Hypoderma spp., in western Canada between 2008 and 2010. Despite the lack of evidence of clinically infected cattle in western Canada since the late 1990s there is persistent evidence from serological sampling that warble fly infections remain endemic. As part of a general survey of cattle parasites conducted on calves entering a feedlot in southern Alberta sera were tested for the presence of anti-Hypoderma antibodies using an established ELISA. Calves for the study were drawn from auction markets in Manitoba, Saskatchewan, Alberta and British Columbia and serum samples were collected, according to a randomization scheme, as the calves entered a single feedlot in October through December (Survey) of three consecutive years (2008-2010). In addition, a sub-sample of calves originating on a ranch in southeastern Alberta (Ranch 1) that had been the subject of previous surveillance was tested. Sero-prevalence of anti-Hypoderma antibodies of the Survey calves ranged from 0.0% to 100.0% depending on origin and overall varied among the three years with the sero-prevalence being 45.6%, 26.9%, 28.5% in 2008, 2009 and 2010 respectively. Sero-prevalence in Ranch 1 calves varied among years, with one year being much higher and was different from overall Survey sero-prevalence in two of three years (31.7%, 64.1%, 38.5% in 2008, 2009, 2010 respectively). In the Survey population there was a trend to lower sero-prevalence over the three years while on Ranch 1 there was no clear trend. In the samples with ELISA adjusted absorbance values above the positive cut-off an examination of the cumulative relative frequency showed that in all years approximately 90% of the samples were in the lower 3 of 14 bins in both populations and in two of three years in Ranch 1 population. The clustering of the positive ELISA data at the lower end of the range is suggestive of low level grub infestations. The increased frequency of high positive ELISA results from Ranch 1 in 2009 potentially indicate an 'outbreak year' in which pupal and adult fly survival was higher than for other years of this study resulting in more infested animals with higher burdens. Examination of precipitation and temperature profiles from the subject ranch support this suggestion. 23369488 Left and right ventricular diastolic function in adults with surgically repaired tetralogy of Fallot: a multi-institutional study. Our purpose was to assess the prevalence and clinical implications of left ventricular (LV) and right ventricular (RV) diastolic dysfunction (DD) in patients with repaired tetralogy of Fallot (TOF). Adults with repaired TOF at 11 North American congenital heart disease centres were included. Of 556 patients analyzed, 325 had sufficient Doppler data to evaluate for LV DD, defined as mitral lateral e' < 10 cm/s and E/e' ratio > 9. Abnormal RV diastolic function was defined as tricuspid E/A ratio of 0.8 to 2.1 with E/e' ratio > 6 or a tricuspid ratio E/A > 2.1 with a deceleration time < 120 milliseconds, and 105 patients were found to have sufficient Doppler data. Abnormal LV diastolic Doppler indices were prevalent in 13.8% and associated with hypertension, dyslipidemia, 3 or more cardiac operations, and a history of ventricular tachycardia. Abnormal RV indices were prevalent in 52.4% and associated with hypertension, dyslipidemia, diabetes mellitus, and 3 or more cardiac operations. Ventricular tachycardia was more common in those with abnormal RV diastolic function. Further prospective studies are needed to evaluate these associations with DD and the impact of treatment risk factors on diastolic function and arrhythmia burden. 23897058 Avoidance of Wrong-Level Thoracic Spine Surgery Using Sterile Spinal Needles. A technical report. To present an improvement on localization techniques employed for use in the thoracic spine using sterile spinal needles docked on the transverse process of each vertebra, which can be performed in both percutaneous and open spinal procedures. Wrong level surgery may have momentous clinical and emotional implications for a patient and surgeon. It is reported that one in every two spine surgeons will operate on the wrong level during his or her career. Correctly localizing specific thoracic level remains a significant challenge during spine surgery. Fluoroscopic anteroposterior and lateral views were obtained starting in the lower lumbar spine and an 18-gauge spinal needle was placed in the transverse process of L3 counting up from the sacrum and also at T12. The fluoroscopy was then moved cephalad and counting from the spinal needle at T12 the other spinal needles were placed at the targeted operating thoracic vertebrae. Once this was done, we were able to accurately determine the thoracic levels for surgical intervention. Using this presented technique, the markers were kept in place even after the incisions were made. This prevented us from losing our location in the thoracic spine. Correctly placed instrumentation was made evident with postoperative imaging. We have described the successful use of a new technique using spinal needles docked against transverse processes to correctly and reliably identify thoracic levels prior to instrumentation. The technique was reproducible in both open surgeries and for a percutaneous procedure. This technique maintains the correct spinal level during an open procedure. We posit that wrong level thoracic spine surgery may be preventable. 23836623 Authors' reply. Article: http://dx.doi.org/10.1002/bimj.201100221 Letter to the Editor: http://dx.doi.org/10.1002/bimj.201200254. 23458411 Biliary and vascular anomalies in living liver donors: the role and accuracy of pre-operative radiological mapping. The aim of the present study was to determine the utility of computed tomography (CT) and magnetic resonance imaging (MRI) anatomic mapping in the detection of biliary and vascular anomalies prior to a living liver donor (LLD) operation. A retrospective study of all LLD patient charts, operative and radiology reports from 1 January 2002 to 1 January 2012 was conducted. Primary post-operative outcomes assessed included mortality, re-operation, readmission and need for endoscopic or percutaneous intervention. Sensitivity and specificity of MR and CT pre-operative screening was calculated against the gold standard of intra-operative findings. A total of 34 donors had an average age of 38 years (range: 22-58) with a body mass index (BMI) of 25.6 kg/m(2) (range: 19.8-32.5) and a length of stay (LOS) of 10.1 days (range: 5-41). There were no donor mortalities. Sensitivity and specificity of CT was 70.0% and 91.3%, and of MRI screening 23.1% and 100.0%, respectively. Patients with inaccurate pre-operative CT or MRI did not have an increased risk of complications. Even although it was specific, pre-operative MR screening missed up to 77.0% of biliary anomalies. An impeccable surgical technique remains the key in preventing biliary complications of a living donor hepatectomy where pre-operative MRI screening is false. 23572345 Minimally invasive versus open transforaminal lumbar interbody fusion: a meta-analysis based on the current evidence. This is a meta-analysis of randomized and non-randomized studies comparing the clinical and radiological efficacy of minimally invasive (MI) and conventional open transforaminal lumbar interbody fusion (open-TLIF) for degenerative lumbar diseases. A literature search of the MEDLINE database identified 11 studies that met our inclusion criteria. A total of 785 patients were examined. Pooled estimates of clinical and radiological outcomes, and corresponding 95 % confidence intervals were calculated. The pooled data revealed that MI-TLIF was associated with less blood loss, shorter hospital stay, and a trend of better functional outcomes when compared with open-TLIF. However, MI-TLIF significantly increased the intraoperative X-ray exposure. Both techniques had similar operative time, complication rate, and re-operation rate. Based on the available evidence, MI-TLIF for degenerative lumbar diseases might lead to better patient-based outcomes. MI-TLIF would be a promising procedure, but extra efforts are needed to reduce its intraoperative radiation exposure. More randomized controlled trials are needed to compare these two surgical options. 23357360 Improvement of p-cymene antinociceptive and anti-inflammatory effects by inclusion in β-cyclodextrin. Previously, we have demonstrated the analgesic-like property of p-cymene in rodents. Short half-life is a limitation for p-cymene application and several approaches have been used to improve pharmaceutical properties of monoterpenes, including the employment of drug-delivery systems. Here, we used p-cymene/β-cyclodextrin (β-CD) complex and p-cymene (PC) isolated to evaluated whether the complex formulation is able to improve the antinociceptive activity of this monoterpene. Male mice (26-30g) were pretreated with PC/β-CD (20 or 40mg/kg, p.o.), PC (20 or 40mg/kg, p.o.) or vehicle (distilled water), 0.5h before painful tests and antinociceptive effect was evaluated at times: 0.5, 1, 2, 4, 8, and 16h after treatment. We evaluated the analgesic-like effect of PC/β-CD and PC in acetic acid-induced abdominal writhes, hot-plate, carrageenan-induced paw edema and in rota-rod apparatus. Our results demonstrated that acute treatment with complex PC/β-CD produced an antinocicepitve effect (p<0.01 or p<0.001) for 8h followed whereas isolated PC produced the same effect for 2h. Similar results were obtained in hot-plate test, PC/β-CD, in all doses, significantly reduces (p<0.01 or p<0.001) nociceptive behavior for 8h while isolated PC for 1h, did so only in higher dose. Such results were unlikely to be caused by motor abnormality. Systemic pretreatment with PC/β-CD and PC inhibited the development paw edema by carrageenan 1%, but PC/β-CD did so during a longer period when compared with isolated monoterpene alone. Our results provide evidence to propose that the complex with β-CD improved analgesic and anti-inflammatory effects of p-cymene. 23970494 Model selection of generalized estimating equations with multiply imputed longitudinal data. Longitudinal data often encounter missingness with monotone and/or intermittent missing patterns. Multiple imputation (MI) has been popularly employed for analysis of missing longitudinal data. In particular, the MI-GEE method has been proposed for inference of generalized estimating equations (GEE) when missing data are imputed via MI. However, little is known about how to perform model selection with multiply imputed longitudinal data. In this work, we extend the existing GEE model selection criteria, including the "quasi-likelihood under the independence model criterion" (QIC) and the "missing longitudinal information criterion" (MLIC), to accommodate multiple imputed datasets for selection of the MI-GEE mean model. According to real data analyses from a schizophrenia study and an AIDS study, as well as simulations under nonmonotone missingness with moderate proportion of missing observations, we conclude that: (i) more than a few imputed datasets are required for stable and reliable model selection in MI-GEE analysis; (ii) the MI-based GEE model selection methods with a suitable number of imputations generally perform well, while the naive application of existing model selection methods by simply ignoring missing observations may lead to very poor performance; (iii) the model selection criteria based on improper (frequentist) multiple imputation generally performs better than their analogies based on proper (Bayesian) multiple imputation. 23463282 Spatial distribution and mobility of organic carbon (POC and DOC) in a coastal Mediterranean environment (Saronikos Gulf, Greece) during 2007-2009 period. Particulate (POC) and dissolved organic carbon (DOC) is an important parameter for the pollution assessment of coastal marine systems, especially those affected by anthropogenic, domestic, and industrial activities. In the present paper, a similar marine system (Saronikos Gulf) located in the west-central Aegean Sea (eastern Mediterranean Sea) was examined, in terms of the temporal and spatial distribution of organic carbon (POC and DOC), with respect to marine sources and pathways. POC was maximum in winter in the Saronikos Gulf, due to the bloom of phytoplankton, whereas in the Elefsis Bay (located in the north side of the Saronikos Gulf) in summer, since phytoplankton grazes in the Bay in the end of summer (except for winter). Approximately 60 % of the bulk DOC of the water column was estimated as non-refractory (labile and semi-labile), due to the major anthropogenic, domestic, and industrial effects of the region and the shallow depths. The spatial distribution of POC and DOC mainly affects the northeastern section of the Gulf, since that region has been accepted major organic discharges for a long time period, in connection to the relatively long renewal times of its waters. 23521206 Diagnostic criteria for erosive lichen planus affecting the vulva: an international electronic-Delphi consensus exercise. There is no defined set of criteria for diagnosing erosive lichen planus affecting the vulva (ELPV) and there is geographical variation in management. To reach consensus on clinicopathological diagnostic criteria for ELPV. This was a three-stage international electronic-Delphi exercise with a subsequent formal feedback process. In the first two rounds participants were asked to rate the importance of a list of clinicopathological criteria. Responses from round 1 were summarized and presented in round 2, along with additional criteria suggested by participants. In round 3, participants were asked to rate the items that had reached consensus as 'essential' or 'supportive' features in diagnosing ELPV. Consensus was defined as being reached if 75% of participants agreed on the importance of an item. A total of 73 experts representing dermatology, gynaecology, histopathology and genitourinary medicine participated; 69 (95%) completed all three rounds. Consensus was achieved for the following 'supportive' diagnostic criteria: (i) well-demarcated erosions/erythematous areas at the vaginal introitus; (ii) presence of a hyperkeratotic border to lesions and/or Wickham striae in surrounding skin; (iii) symptoms of pain/burning; (iv) scarring/loss of normal architecture; (v) presence of vaginal inflammation; (vi) involvement of other mucosal surfaces; (vii) presence of a well-defined inflammatory band involving the dermoepidermo junction; (viii) presence of an inflammatory band consisting predominantly of lymphocytes; and (ix) signs of basal layer degeneration. It was suggested that at least three supportive features should be present to make a diagnosis of ELPV, although this number is subject to further discussion. This study has identified a diagnostic dataset for ELPV that can be adopted into clinical practice and clinical trials. 23819774 Hydroalkoxylation of unactivated olefins with carbon radicals and carbocation species as key intermediates. A unique Markovnikov hydroalkoxylation of unactivated olefins with a cobalt complex, silane, and N-fluoropyridinium salt is reported. Further optimization of reaction conditions yielded high functional group tolerance and versatility of alcoholic solvent employed, including methanol, i-propanol, and t-butanol. Use of trifluorotoluene as a solvent made the use of alcohol in stoichiometric amount possible. Mechanistic insight into this novel catalytic system is also discussed. Experimental results suggest that catalysis involves both carbon radical and carbocation intermediates. 23356865 Identification of α-tocopherol and α-tocopheryl acetate from the cuticle of soybean pods armyworm (Spodoptera cosmioides). The chemical composition of the soybean pods armyworm Spodoptera cosmioides (Walker, 1858) (Lepidoptera: Noctuidae) and Anticarsia gemmatalis Hübner, 1818 (Lepidoptera: Erebidae) larval cuticles was evaluated using gas chromatography coupled to a mass detector (GC-MS). Among the usual lipids found in the insect cuticle, α-tocopherol and α-tocopheryl acetate were also isolated from S. cosmioides. On the other hand, no vitamin E derivative was found in A. gemmatalis exuvia. This is the first report of vitamin E occurrence in the insect's cuticle. 23499479 Hospital-associated MRSA and antibiotic resistance-What have we learned from genomics? In many parts of the world, MRSA are responsible for a high proportion of S. aureus infections in patients in contact with healthcare. Molecular studies have shown this is due to one or more MRSA clones that have become endemic in each hospital or healthcare facility, resulting in hospital- or healthcare-associated MRSA (HA-MRSA). The infection rate and clones responsible for HA-MRSA can vary substantially in different geographical locations. Molecular methods have allowed clones to be categorized, as well as the opportunity to track the evolution and spread of clones in healthcare settings and around the world. The genomes of HA-MRSA isolates belonging to the same clonal group can show dramatic variability particularly in the carriage of mobile genetic elements (MGEs) encoding virulence and resistance genes. HA-MRSA are potentially resistant to all classes of antibiotics, although individual isolates that are fully drug resistant are not reported. The incidence of fluoroquinolone resistance in HA-MRSA is remarkably high, suggesting use of this class of antibiotics as well as the β-lactams contributes to the selection and success of HA-MRSA clones in the hospital setting. 23701446 Diverticulitis in the young is not more aggressive than in the elderly, but it tends to recur more often: Systematic review and meta-analysis. For years, the natural course of diverticulitis in the young has been debatable in terms of its severity and recurrence rate, and no consensus has been reached regarding its treatment and timing of surgery. Thus, the study aims to evaluate by meta-analysis the natural course of acute diverticulitis in the young. Data were obtained from electronic databases and manual search of studies comparing the course of diverticulitis in young versus elderly patients. The age cut-off was selected to be 40-50 years, and only studies using computed tomography as the sole modality for diagnosis were included. Primary outcomes were surgery during hospitalization and disease recurrence. Relative risks (RRs) with 95% confidence intervals (CIs) are reported. One thousand eighty publications were found, 12 of which were included. The total number of patients was 4982. Most young patients were males (RR 1.70, 95% CI 1.31-2.21), without tendency toward a more complicated disease at admission (RR 0.95, 95% CI 0.46-1.97). While there was no significant difference in the rate of surgery during hospitalization (RR 0.69, 95% CI 0.46-1.06), young patients underwent more elective surgeries (RR 2.39, 95% CI 1.82-3.15). No mortality was recorded among young patients. The disease recurrence rate was significantly higher than that of elderly patients (RR 1.70, 95% CI 1.31-2.21); however, no study specified the mean follow-up period for each group. The course of diverticulitis in the young is not more severe than that in elderly patients; however, the disease tends to recur more often. Therefore, while choosing a therapeutic regimen, factors other than age should also be considered. 23423728 The albino mutation of tyrosinase alters ocular angiogenic responsiveness. We have observed substantial differences in angiogenic responsiveness in mice and have mapped the genetic loci responsible for these differences. We have found that the albino mutation is one of the loci responsible for such differences. Using B6.A consomic strains, we determined that chromosome 7 bears a locus that inhibits VEGF-induced corneal neovascularization. F2 crosses between B6.A consomic mice and C57BL/6J parents along with AXB and BXA recombinant inbred strains demonstrated highest linkage near the tyrosinase gene. This region was named AngVq4. Congenic animals confirmed this locus, but could not demonstrate that the classical tyrosinase albino (c) mutation was causative because of the existence of additional linked loci in the congenic region. However, in 1970, a second tyrosinase albino mutation (c-2J) arose in the C57BL/6J background at Jackson Labs. Testing this strain (C57BL/6J) demonstrated that the albino mutation is sufficient to completely explain the alteration in angiogenic response that we observed in congenic animals. Thus, we conclude that the classical tyrosinase mutation is responsible for AngVq4. In contrast to the cornea, where pigmented animals exhibit increased angiogenic responsiveness, iris neovascularization was inhibited in pigmented animals. These results may partially explain increased aggressiveness in amelanotic melanoma, as well as ethnic differences in diabetic retinopathy and macular degeneration. 23861139 Attitudes of australian chiropractic students toward whole body donation: A cross-sectional study. Cadavers play an important role in anatomy education. In Australia, bodies for anatomy education are acquired only through donations. To gain insight into educational dynamics in an anatomy laboratory as well as to facilitate body donation programs and thanksgiving ceremonies, it is important to understand students' attitudes toward body donation. In this cross-sectional study, the attitudes of Macquarie University's first, second, and fifth year chiropractic students toward body donation were investigated. Macquarie University chiropractic students have a four semester long anatomy program, which includes cadaver-based instruction on prosected specimens. A questionnaire was used to record respondents' demographics and attitudes toward body donation: personal, by a relative, and by a stranger. It was found that ethnicity and religion affect attitudes toward body donation, with Australian students being more willing to donate a stranger's body and atheists and agnostics being more willing to donate in general. Furthermore, willingness to donate one's own or a family member's body decreases as year of study increases, suggesting a possible negative impact of exposure to cadavers in the anatomy laboratory. This was only true, however, after controlling for age. Thus, the impact of viewing and handling prosected specimens, which is the norm in anatomy classes in Australia, may not be as strong as dissecting cadavers. It is suggested that anatomists and educators prepare students for cadaver-based instruction as well as exhibit sensitivity to cultural differences in how students approach working with cadavers, when informing different communities about body donation programs and in devising thanksgiving ceremonies. Anat Sci Educ. © 2013 American Association of Anatomists. 23966592 Induction of cotton ovule culture fibre branching by co-expression of cotton BTL, cotton SIM, and Arabidopsis STI genes. The highly elongated single-celled cotton fibre consists of lint and fuzz, similar to the Arabidopsis trichome. Endoreduplication is an important determinant in Arabidopsis trichome initiation and morphogenesis. Fibre development is also controlled by functional homologues of Arabidopsis trichome patterning genes, although fibre cells do not have a branched shape like trichomes. The identification and characterization of the homologues of 10 key Arabidopsis trichome branching genes in Gossypium arboreum are reported here. Nuclear ploidy of fibres was determined, and gene function in cotton callus and fibre cells was investigated. The results revealed that the nuclear DNA content was constant in fuzz, whereas a limited and reversible change occurred in lint after initiation. Gossypeum arboreum BRANCHLESS TRICHOMES (GaBLT) was not transcribed in fibres. The homologue of STICHEL (STI), which is essential for trichome branching, was a pseudogene in Gossypium. Targeted expression of GaBLT, Arabidopsis STI, and the cytokinesis-repressing GaSIAMESE in G. hirsutum fibre cells cultured in vitro resulted in branching. The findings suggest that the distinctive developmental mechanism of cotton fibres does not depend on endoreduplication. This important component may be a relic function that can be activated in fibre cells. 23924339 Traumatic pseudoaneurysm of the basilar artery presenting with fatal epistaxis: A rare case report. Abstract Background: To the best of the authors' knowledge, this is the first report of a traumatic pseudoaneurysm of the basilar artery presenting with epistaxis. Case study: This study reports a rare case in which a patient suffered from fatal epistaxis because of a pseudoaneurysm of basilar artery and fracture of skull base after a motorcycle accident. Clinical manifestation, diagnostic imaging and endovascular treatment are described. Formation mechanisms and the treatment of traumatic pseudoaneurysm of basilar artery are discussed. 23816620 Augmin-dependent microtubule nucleation at microtubule walls in the spindle. The formation of a functional spindle requires microtubule (MT) nucleation from within the spindle, which depends on augmin. How augmin contributes to MT formation and organization is not known because augmin-dependent MTs have never been specifically visualized. In this paper, we identify augmin-dependent MTs and their connections to other MTs by electron tomography and 3D modeling. In metaphase spindles of human cells, the minus ends of MTs were located both around the centriole and in the body of the spindle. When augmin was knocked down, the latter population of MTs was significantly reduced. In control cells, we identified connections between the wall of one MT and the minus end of a neighboring MT. Interestingly, the connected MTs were nearly parallel, unlike other examples of end-wall connections between cytoskeletal polymers. Our observations support the concept of augmin-dependent MT nucleation at the walls of existing spindle MTs. Furthermore, they suggest a mechanism for maintaining polarized MT organization, even when noncentrosomal MT initiation is widespread. 23692472 Smoke, smoking and cessation: the views of children with respiratory illness. Abstract Objective: To explore the attitudes of Māori (indigenous New Zealanders) and Pacific children with respiratory illness towards smoking, secondhand smoke (SHS) and smoking cessation. Methods: Forty-one Māori and Pacific children (aged 6-11 years) in New Zealand (NZ) were interviewed about their attitudes towards smoking, how SHS affects them and their respiratory disease, ideas they have about how to reduce SHS exposure, their fears and concerns about smoking, and experience asking parents to quit smoking. The interviews were transcribed and deductively analysed. Results: The children said that SHS made them feel "bad," "angry," "uncomfortable" and "really sick," making them want to get away from the smoke. They were aware that smoking "is dangerous" and that "you could die from it." Many children had fears for smokers around them. The children reported on rules restricting smoking around children: "You're not allowed smoke in the car where babies are." A number of children reported that adults complied with those rules, but some reported that people still smoked around them. The children had experienced people around them quitting and had an awareness of how difficult it is to quit smoking. The most common reason perceived for quitting was concern for children. A lot of the children thought they could ask parents to quit and other suggestions included hiding people's tobacco, and use of smoke-free pamphlets, or signs. Conclusions: Even young children from low socioeconomic minority groups are aware of the dangers of smoking and SHS, and hold negative views about smoking. Health promotion messages for parents could have more weight if they convey the concerns voiced by children. 23274878 Results of transoral laser microsurgery in 102 patients with squamous cell carcinoma of the tonsil. The objective of this study is to assess the feasibility of transoral laser microsurgery (TLM) in the treatment of squamous cell cancer of the tonsil and to report the oncological and functional outcomes, using retrospective chart review in the setting of single-institute, academic tertiary referral center. Between October 1987 and December 2006, 102 patients were eligible for this study, mostly suffering from advanced disease: 13% presented with stage I and II (UICC/AJCC 2002) tumors and 87% with stages III and IVa. The median follow-up was 63 months. All patients were treated by TLM with (or without) neck dissection (95%) and with (66%) postoperative radiotherapy. Overall survival, recurrence-free survival, disease-free survival, local control and loco-regional control were analyzed as end points. Rate of tracheotomies, postoperative complications and swallowing function were also analyzed. 5-year Kaplan-Meier local and loco-regional control was 78% for pT1 and pT2 and 75 % for pT3 and pT4a tumors. 5-year Kaplan-Meier disease-free survival, recurrence-free survival, and overall survival and was 74, 64 and 59% for stage I and II, 68, 60 and 56 % for stage III and IVa, respectively. Our data supports the conclusion, that TLM should be considered as a therapeutic option for the treatment of cancer of the tonsil. The oncological and functional results are comparable to any other treatment regimen, while the morbidity and complications tend to be lower. 23844668 The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles:reply to a rebuttal. We thank Dr. Shetty and colleagues for their interest in our work and for providing comparative data from the Indian Type 3 VWD population. They provide results on 77 Type 3 VWD patients, and in contrast to our study, did not see higher bleeding scores (BS) in those with mutations in the VWF propeptide. In the Canadian study, the BS in those with VWF propeptide mutations is BS = 21 vs. BS = 11 for those with non-propeptide mutations compared with BS = 10 for propeptide and BS = 8 for non-propeptide in the Indian study This article is protected by copyright. All rights reserved. 23897886 Tubulin glycylases and glutamylases have distinct functions in stabilization and motility of ependymal cilia. Microtubules are subject to a variety of posttranslational modifications that potentially regulate cytoskeletal functions. Two modifications, glutamylation and glycylation, are highly enriched in the axonemes of most eukaryotes, and might therefore play particularly important roles in cilia and flagella. Here we systematically analyze the dynamics of glutamylation and glycylation in developing mouse ependymal cilia and the expression of the corresponding enzymes in the brain. By systematically screening enzymes of the TTLL family for specific functions in ependymal cilia, we demonstrate that the glycylating enzymes TTLL3 and TTLL8 were required for stability and maintenance of ependymal cilia, whereas the polyglutamylase TTLL6 was necessary for coordinated beating behavior. Our work provides evidence for a functional separation of glutamylating and glycylating enzymes in mammalian ependymal cilia. It further advances the elucidation of the functions of tubulin posttranslational modifications in motile cilia of the mammalian brain and their potential importance in brain development and disease. 23902788 Meat intake and cause-specific mortality: a pooled analysis of Asian prospective cohort studies. Total or red meat intake has been shown to be associated with a higher risk of mortality in Western populations, but little is known of the risks in Asian populations. We examined temporal trends in meat consumption and associations between meat intake and all-cause and cause-specific mortality in Asia. We used ecological data from the United Nations to compare country-specific meat consumption. Separately, 8 Asian prospective cohort studies in Bangladesh, China, Japan, Korea, and Taiwan consisting of 112,310 men and 184,411 women were followed for 6.6 to 15.6 y with 24,283 all-cause, 9558 cancer, and 6373 cardiovascular disease (CVD) deaths. We estimated the study-specific HRs and 95% CIs by using a Cox regression model and pooled them by using a random-effects model. Red meat consumption was substantially lower in the Asian countries than in the United States. Fish and seafood consumption was higher in Japan and Korea than in the United States. Our pooled analysis found no association between intake of total meat (red meat, poultry, and fish/seafood) and risks of all-cause, CVD, or cancer mortality among men and women; HRs (95% CIs) for all-cause mortality from a comparison of the highest with the lowest quartile were 1.02 (0.91, 1.15) in men and 0.93 (0.86, 1.01) in women. Ecological data indicate an increase in meat intake in Asian countries; however, our pooled analysis did not provide evidence of a higher risk of mortality for total meat intake and provided evidence of an inverse association with red meat, poultry, and fish/seafood. Red meat intake was inversely associated with CVD mortality in men and with cancer mortality in women in Asian countries. 23953621 Possible association of Toll-like receptor 9 polymorphisms with cytokine levels and posttraumatic symptoms in individuals with various types of orthopaedic trauma: Early findings. Although TLR9 polymorphisms may be associated with cytokine dysregulation, its role in regulation of cytokines due to bodily trauma or in relation to acute stress symptoms or posttraumatic stress symptoms (ASS/PTS) has not been evaluated. To assess serum cytokine levels and levels of ASS and PTS in relation to four common TLR9 single-nucleotide polymorphisms (SNPs) in individuals with various types of orthopaedic trauma. Forty-eight accident-injured individuals, aged 20-60 years were studied. Serum cytokine levels and TLR9 SNPS (1486T/C, 1237T/C, 1174G/A and 2848G/A) were assessed together with intensity of ASS and PTS symptoms. Statistically significant higher serum levels of IL-12 and IL-1β (p<.05) were found in individuals heterozygous for TLR9-1237 (TC) than in individuals expressing the most common TLR9-1237 type (TT), while differences in levels of IL-6 were not significant. Also, marginally significant levels of IL-6 were found in individuals expressing the common TLR9-1174 (GG) compared with individuals homozygous (AA) or heterozygous (GA) for this SNP. They also had non-significant higher intensity of ASS symptoms. A trend of higher PTS levels in individuals expressing the most common type TLR9-1174 (GG) was found, contrary to homozygous (AA) and heterozygous individuals (GA). The results of this pilot study suggest that accident-injured individuals with certain TLR9 polymorphisms express higher levels of pro-inflammatory cytokines (IL-1β, IL-6 and IL-12). The associations of TLR9 SNPSs with increased risk of ASS or PTS should be further studied in larger groups of such patients. 23870025 The effect of free air carbon dioxide enrichment and nitrogen fertilisation on the chemical composition and nutritional value of wheat and barley grain. A rising atmospheric CO2 concentration might influence the nutrient composition of feedstuffs and consequently the nutritional value for livestock. The present study investigates the effects of atmospheric CO2 enrichment on the chemical composition and nutritional value of winter wheat cv. "Batis" and winter barley cv. "Theresa". Both cereals were grown at two different atmospheric CO2 concentrations (ambient CO2 [AMBI]: 380 ppm and enriched CO2 [free air carbon dioxide enrichment, FACE]: 550 ppm) for two growing seasons. The influence of two different nitrogen (N) fertilisation levels (adequate N supply [N100] and nearly 50% of adequate N supply [N50]) were studied as well. A significant effect was observed for the crude protein content, which declined at FACE condition in a range of 8-16 g kg(-1) in wheat and of 10-20 g kg(-1) in barley. A reduced N fertilisation level resulted in a strong reduction of crude protein concentration in both cereal species. In wheat, a decrease in N supply significantly enhanced the concentration of starch and crude fibre. In barley, only the concentration of fructose increased under FACE condition and reduced N fertilisation. The FACE did not have major effects on the concentrations of minerals, while the influence of N fertilisation was different for both cereals. Whereas no effects could be observed for barley, a reduced N supply caused a significant reduction in concentrations of zinc, manganese and iron in wheat. Furthermore, an undirected effect of atmospheric CO2 and N fertilisation levels were found for the amino acid concentrations. Based on these results, future scenarios of climate change would have an impact on the nutritional value of cereal grains. 23890073 Phenotypic selection of a wild Saccharomyces cerevisiae strain for simultaneous saccharification and co-fermentation of AFEXTM pretreated corn stover. Simultaneous saccharification and co-fermentation (SSCF) process involves enzymatic hydrolysis of pretreated lignocellulosic biomass and fermentation of glucose and xylose in one bioreactor. The optimal temperatures for enzymatic hydrolysis are higher than the standard fermentation temperature of ethanologenic Saccharomyces cerevisiae. Moreover, degradation products resulting from biomass pretreatment impair fermentation of sugars, especially xylose, and can synergize with high temperature stress. One approach to resolve both concerns is to utilize a strain background with innate tolerance to both elevated temperatures and degradation products. In this study, we screened a panel of 108 wild and domesticated Saccharomyces cerevisiae strains isolated from a wide range of environmental niches. One wild strain was selected based on its growth tolerance to simultaneous elevated temperature and AFEXTM (Ammonia Fiber Expansion) degradation products. After engineering the strain with two copies of the Scheffersomyces stipitis xylose reductase, xylitol dehydrogenase and xylulokinase genes, we compared the ability of this engineered strain to the benchmark 424A(LNH-ST) strain in ethanol production and xylose fermentation in standard lab medium and AFEX pretreated corn stover (ACS) hydrolysates, as well as in SSCF of ACS at different temperatures. In SSCF of 9% (w/w) glucan loading ACS at 35[degree sign]C, the engineered strain showed higher cell viabilities and produced a similar amount of ethanol (51.3 g/L) compared to the benchmark 424A(LNH-ST) strain. These results validate our approach in the selection of wild Saccharomyces cerevisiae strains with thermo-tolerance and degradation products tolerance properties for lignocellulosic biofuel production. The wild and domesticated yeast strains phenotyped in this work are publically available for others to use as genetic backgrounds for fermentation of their pretreated biomass at elevated temperatures. 23934715 Genetic heterogeneity and risk of acute respiratory distress syndrome. Genetic variation explains some of the observed heterogeneity in patients' risk for developing the acute respiratory distress syndrome (ARDS). Although the lack of extant family pedigrees for ARDS precludes an estimate of heritability of the syndrome, ARDS may function as a pattern of response to injury or infection, traits that exhibit strong heritability. A total of 34 genes have now been reported to influence ARDS susceptibility, the majority of which arose as candidate genes based on the current pathophysiological understanding of ARDS, with particular focus on inflammation and endothelial or epithelial injury. In addition, novel candidate genes have emerged from agnostic genetic approaches, including genome-wide association studies, orthologous gene expression profiling across animal models of lung injury, and human peripheral blood gene expression data. The genetic risk for ARDS seems to vary both by ancestry and by the subtype of ARDS, suggesting that both factors may be valid considerations in clinical trial design. 23849655 A big data approach to the ultra-fast prediction of DFT-calculated bond energies. The rapid access to intrinsic physicochemical properties of molecules is highly desired for large scale chemical data mining explorations such as mass spectrum prediction in metabolomics, toxicity risk assessment and drug discovery. Large volumes of data are being produced by quantum chemistry calculations, which provide increasing accurate estimations of several properties, e.g. by Density Functional Theory (DFT), but are still too computationally expensive for those large scale uses. This work explores the possibility of using large amounts of data generated by DFT methods for thousands of molecular structures, extracting relevant molecular properties and applying machine learning (ML) algorithms to learn from the data. Once trained, these ML models can be applied to new structures to produce ultra-fast predictions. An approach is presented for homolytic bond dissociation energy (BDE). Machine learning models were trained with a data set of >12,000 BDEs calculated by B3LYP/6-311++G(d,p)//DFTB. Descriptors were designed to encode atom types and connectivity in the 2D topological environment of the bonds. The best model, an Associative Neural Network (ASNN) based on 85 bond descriptors, was able to predict the BDE of 887 bonds in an independent test set (covering a range of 17.67--202.30 kcal/mol) with RMSD of 5.29 kcal/mol, mean absolute deviation of 3.35 kcal/mol, and R2 = 0.953. The predictions were compared with semi-empirical PM6 calculations, and were found to be superior for all types of bonds in the data set, except for O-H, N-H, and N-N bonds. The B3LYP/6-311++G(d,p)//DFTB calculations can approach the higher-level calculations B3LYP/6-311++G(3df,2p)//B3LYP/6-31G(d,p) with an RMSD of 3.04 kcal/mol, which is less than the RMSD of ASNN (against both DFT methods). An experimental web service for on-line prediction of BDEs is available at http://joao.airesdesousa.com/bde CONCLUSION: Knowledge could be automatically extracted by machine learning techniques from a data set of calculated BDEs, providing ultra-fast access to accurate estimations of DFT-calculated BDEs. This demonstrates how to extract value from large volumes of data currently being produced by quantum chemistry calculations at an increasing speed mostly without human intervention. In this way, high-level theoretical quantum calculations can be used in large-scale applications that otherwise would not afford the intrinsic computational cost. 23958608 Comparing the antiswelling and analgesic effects of three different ice pack therapy durations: a randomized controlled trial on cases with soft tissue injuries. Ice pack therapy has been widely used in treatment for soft tissue injuries. However, no studies have yet explored the most appropriate and effective duration for ice therapy with ice packs. This study explored the antiswelling and analgesic effects of different ice pack therapy durations on soft tissue injuries as well as patient discomfort. An experimental design including pretest and three posttests with three groups was used in this study. Using convenience sampling and randomized block assignment, 99 participants with soft tissue injuries from the emergency department of a medical center in southern Taiwan were included in this study. With 33 participants in each group, three groups with ice pack therapy for 10, 20, and 30 minutes were indicated to compare skin temperature, swelling, and pain differences in ice-treated areas as well as participant discomfort. This study found no significant differences in the effect of different ice pack therapy durations among the three groups. However, this study identified significant differences between pretest and each posttest in terms of changes in skin temperature, pain, and numbness and rash-related discomfort in each group. Research results found that the three different ice pack therapy durations could lower skin temperature and reduce partial pain. The different ice pack therapy durations would cause similar discomfort incidence rates in the three groups. Ice pack therapy for 10 minutes could reduce partial swelling and pain effectively. Accordingly, we suggest that 10 minutes is the optimal ice pack therapy duration for persons with soft tissue injuries. However, the ice pack therapy duration should be adjusted according to individual needs and situation. 23916323 Vitamin D deficiency in alcohol-use disorders and its relationship to comorbid major depression: A cross-sectional study of inpatients in Nepal. Mounting evidence suggests that deficiency of vitamin D may be associated with major health problems, including alcohol-use disorders (AUD) and major depression (MD). This study aimed to identify the vitamin D status of Nepalese inpatients with an AUD. We explored socio-demographic and alcohol-use related correlates and the relationship between vitamin D deficiency and comorbid MD. A cross-sectional study was conducted on AUD inpatients (N=174) at eight alcohol/drug treatment centres around Kathmandu. Structured questionnaires were administered to assess the socio-demographic and alcohol-use parameters and to establish DSM-IV diagnoses of AUD and MD. Vitamin D deficiency was defined as a serum 25-hydroxyvitamin D (25(OH)D) concentration of <50nmol/L. The prevalence of vitamin D deficiency was 64%. Higher age, having a stable job or business, shorter time since last alcohol intake and winter serum samples were related to having lower 25(OH)D levels. Several features of AUD severity were associated with low vitamin D levels: guilt about drinking, using alcohol as eye-opener, and history of relapse after alcohol treatment (p≤0.03). Patients with a comorbid major depression, in particular secondarily depressed cases, were less likely to have vitamin D deficiency (X(2)=6.8; p=0.01). This study confirms high rates of vitamin D deficiency in alcohol treatment sample and shows a positive association between vitamin D deficiency and severity of alcohol-use disorders. Competing risk and other confounders may help explain the vitamin D status among patients with alcohol-use disorders and comorbid major depression. 23828184 Massage therapy and exercise therapy in patients with multiple sclerosis: a randomized controlled pilot study. Objective:The primary aim was to investigate the comparative effects of massage therapy and exercise therapy on patients with multiple sclerosis. The secondary aim was to investigate whether combination of both massage and exercise has an additive effect.Design:Randomized controlled pilot trial with repeated measurements and blinded assessments.Setting:Local Multiple Sclerosis Society.Subjects:A total of 48 patients with multiple sclerosis were randomly assigned to four equal subgroups labelled as massage therapy, exercise therapy, combined massage-exercise therapy and control group.Interventions:The treatment group received 15 sessions of supervised intervention for five weeks. The massage therapy group received a standard Swedish massage. The exercise therapy group was given a combined set of strength, stretch, endurance and balance exercises. Patients in the massage-exercise therapy received a combined set of massage and exercise treatments. Patients in the control group were asked to continue their standard medical care.Main measures:Pain, fatigue, spasticity, balance, gait and quality of life were assessed before and after intervention.Results:Massage therapy resulted in significantly larger improvement in pain reduction (mean change 2.75 points, P = 0.001), dynamic balance (mean change, 3.69 seconds, P = 0.009) and walking speed (mean change, 7.84 seconds, P = 0.007) than exercise therapy. Patients involved in the combined massage-exercise therapy showed significantly larger improvement in pain reduction than those in the exercise therapy (mean change, 1.67 points, P = 0.001).Conclusions:Massage therapy could be more effective than exercise therapy. Moreover, the combination of massage and exercise therapy may be a little more effective than exercise therapy alone. 23915027 Influence of Cement Film Thickness on the Retention of Implant-Retained Crowns. The main goal of this study was to establish a new, high precision procedure to evaluate the influence of cement film thickness on the retention of cemented implant-retained crowns. Ninety-six tapered titanium abutments (6° taper, 4.3 mm diameter, Camlog) were shortened to 4 mm. Computer-aided design was used to design the crowns, and selective laser sintering, using a cobalt-chromium alloy, was used to produce the crowns. This method used a focused high-energy laser beam to fuse a localized region of metal powder to build up the crowns gradually. Before cementing, preset cement film thicknesses of 15, 50, 80, or 110 Î¼m were established. Glass ionomer, polycarboxylate, or resin cements were used for cementation. After 3 days storage in demineralized water, the retention of the crowns was measured in tension using a universal testing machine. The cement film thicknesses could be achieved with a high level of precision. Interactions between the factors cement and cement film thickness could be found (p ≤ 0.001). For all cements, crown retention decreased significantly between a cement film thickness of 15 and 50 Î¼m (p ≤ 0.001). At 15 Î¼m cement film thickness, the resin cement was the most retentive cement, followed by the polycarboxylate and then the glass ionomer cement (p ≤ 0.05). The results suggest that cement film thickness has an influence on the retentive strength of cemented implant-retained crowns. 23689010 The nemaline myopathy-causing E117K mutation in β-tropomyosin reduces thin filament activation. The effect of the nemaline myopathy-causing E117K mutation in β-tropomyosin (TM) on the structure and function of this regulatory protein was studied. The E117K mutant was found to have indistinguishable actin affinity compared with wild-type (WT) and similar secondary structure as measured by circular dichroism. However the E117K mutation significantly lowered maximum activation of actomyosin ATPase. To explain the molecular mechanism of impaired ATPase activation, WT and E117K TMs were covalently labeled at Cys-36 with 5-iodoacetimido-fluorescein and incorporated into ghost muscle fibers. The changes in the position and flexibility of tropomyosin strands on the thin filaments were observed at simulation of weak and strong binding states of actomyosin at high or low Ca(2+) by polarized fluorescence techniques. The E117K mutation was found to shift the tropomyosin strands towards the closed position and restrict the tropomyosin displacement during the transformation of actomyosin from weak to strong binding state thus leading to a reduction in thin filament activation. 23891502 Population immunity to polioviruses in the context of a large-scale wild poliovirus type 1 outbreak in Tajikistan, 2010. A serosurvey to evaluate population immunity to polioviruses (PVs) in the context of the importation-related wild PV1 outbreak in Tajikistan in 2010 (461 confirmed cases among children and young adults) was conducted. Serum specimens from a nationwide sample of 1-24 year-old persons selected through stratified cluster sampling (n=2447) were tested for neutralizing antibodies to all three PV types. Samples with titers<1:8 were considered seronegative. The serosurvey was conducted during the interval after mOPV1 supplementary immunization activities (SIAs) and before tOPV SIAs (targeting ages≤15 years) implemented to control the outbreak. In the absence of pre-outbreak specimens, results for PV3 were used as a proxy for pre-outbreak PV1 immunity patterns. Overall, PV1 seroprevalence was 98.9%, PV2 seroprevalence was 98.8%, and PV3 seroprevalence was 86.9%. PV1 and PV2 seroprevalence exceeded 95% in all age groups and regions. PV3 seroprevalence was <90% in all age groups and regions, except 15-19 year-olds (91.7%) and Dushanbe (90.0%). PV3 seroprevalence was lowest among 1-4 (82.7%) and 5-9 (84.4%) year-olds, particularly among 1-4 year-olds in Kurgan-Tube (76.3%) and RRS (80.0%) regions. Birth cohorts immunized only through routine services (ages, 1-7 years) had lower PV3 seroprevalence than birth cohorts targeted by the SIAs during 1995-2002 (8-19 years): 82.5% versus 89.3%, p<0.001. Suboptimal (<90%) PV3 seroprevalence across wide age range suggests the outbreak resulted from accumulation of susceptibles due to suboptimal coverage over a long time period, particularly in the birth cohorts immunized only through routine services and in areas where the outbreak began (Kurgan-Tube and RRS). High PV1 seroprevalence indicates that mOPV1 SIAs with expanded target age (≤15 years) succeeded in closing the immunity gap and ongoing WPV1 transmission is unlikely. To accelerate outbreak control in areas which have been polio-free for long time, expanding SIA target age should be considered. 23830499 Treatment of dural arteriovenous fistula by balloon-assisted transarterial embolization with Onyx. This study evaluated the feasibility, safety, and efficacy of embolization of dural arteriovenous fistula via a very small, short feeding artery with the assistance of a balloon placed proximal to the tip of the microcatheter, such that the balloon serves as a plug. Eight patients who underwent treatment of DAVF by balloon-assisted transarterial embolization with Onyx were retrospectively reviewed. Gender, age, angiography findings, procedure details, clinical and angiographic outcomes, complications, and follow-up were recorded and analyzed. Nine embolization procedures were performed in eight male patients via extracranial arteries. Balloon-assisted embolization was successful in all eight patients. A Hyperglide balloon was used in five patients, and a Hyperform balloon was used in three patients. Angiographic resolution of the fistula was achieved in all patients without complications. All patients recovered uneventfully. During the follow-up period of 7-19 months, all patients were asymptomatic except for one patient who experienced mild headaches. Treatment of DAVF by balloon-assisted embolization with Onyx achieved promising results, even in patients with very small and short feeding arteries. This technique allowed the treatment of DAVF cases where other techniques have failed. 23847103 Characterization of PA-N terminal domain of Influenza A polymerase reveals sequence specific RNA cleavage. Influenza virus uses a unique cap-snatching mechanism characterized by hijacking and cleavage of host capped pre-mRNAs, resulting in short capped RNAs, which are used as primers for viral mRNA synthesis. The PA subunit of influenza polymerase carries the endonuclease activity that catalyzes the host mRNA cleavage reaction. Here, we show that PA is a sequence selective endonuclease with distinct preference to cleave at the 3' end of a guanine (G) base in RNA. The G specificity is exhibited by the native influenza polymerase complex associated with viral ribonucleoprotein particles and is conferred by an intrinsic G specificity of the isolated PA endonuclease domain PA-Nter. In addition, RNA cleavage site choice by the full polymerase is also guided by cap binding to the PB2 subunit, from which RNA cleavage preferentially occurs at the 12th nt downstream of the cap. However, if a G residue is present in the region of 10-13 nucleotides from the cap, cleavage preferentially occurs at G. This is the first biochemical evidence of influenza polymerase PA showing intrinsic sequence selective endonuclease activity. 23886794 Evaluation of Fetal Vocal Cords to Select Candidates for Successful Fetoscopic Treatment of Congenital High Airway Obstruction Syndrome: Preliminary Case Series. Objective: Congenital high airway obstruction syndrome (CHAOS) normally has a dire prognosis due to laryngeal atresia and association with other anomalies. However, rare cases with an isolated tracheal membrane have been described. We assessed systematically the larynx and vocal cords in fetuses with CHAOS, with the goal of identifying such cases and attempting fetoscopic deobstruction. Methods: Between 2008 and 2012, 7 cases of CHAOS were referred to our institution. The ultrasonographic aspect of the larynx and trachea was assessed. We report the ultrasound findings, necropsy findings of 6 cases and perinatal outcome in 1 case undergoing therapy. Results: In 6 cases, laryngeal atresia was presumed by ultrasound and confirmed by necropsy after termination of pregnancy. In 1 case, normal appearance of the vocal cords led to suspicion of a possible isolated tracheal web completely occluding the trachea. Fetoscopy confirmed the finding, thus the membrane was perforated. Lung size normalized and hydrops resolved. A normal fetus was delivered at term, requiring no respiratory support. At 9 months of age, the infant showed a normal laryngoscopy and was developing well. Conclusions: Systematic ultrasound assessment of the vocal cords can be performed in fetuses with CHAOS. We report the first case of long-term intact survival after fetoscopic airway deobstruction. 23910651 Reduced ADP-ribosylation by PARP1 natural polymorphism V762A and by PARP1 inhibitors enhance Hepatitis B virus replication. HepG2 and Huh7 cell lines are frequently used as models to study viral hepatitis and hepatocellular carcinoma. However, they exhibit significantly different capacities in their ability to support hepatitis B virus (HBV) replication. To investigate the basis for this, transcription factor-binding motifs at the HBV core promoter (HBVCP) were tested in luciferase reporter constructs to identify the possible role of host factors. Among the transcription factors screened: PARP1, SP1, HNF4α, HNF3, hB1F and HNF1, deletion of the PARP1 binding motif abrogated transcriptional activity at the HBVCP in HepG2 but not Huh7 cells. Sequencing of the PARP1 gene revealed that HepG2 cells carried an Ala762 allele which has low ADP-ribosylation activity, which was shown to have increased PARP1 binding affinity to its cognate motif thus resulting in higher transcriptional activity. PARP1 inhibitors that are being developed as broad cancer therapeutics also target PARP1 ADP-ribosylation enzymatic function. Four PARP1 inhibitors: PJ-34, ABT888, AZD2281 and AG014699 were tested for their effect on HBV replication. All four small molecules effectively enhanced HBV replication in vitro, confirming the role of PARP1 in HBV replication and that alteration of ADP-ribosylation by mutation or drugs can affect HBV replication. Our data demonstrate that natural polymorphisms in the host affecting proteins such as PARP1 can have a significant effect on HBV replication. Hence, patients who are infected with HBV and are on clinical trials involving PARP1 inhibitors may be at risk from unintended side-effects such as exacerbation of HBV replication. 23834206 The Health of Adults Living with a Clinically Significant Haemoglobinopathy in NSW, Australia. The NSW Haemoglobinopathy Project. To comprehensively review the health needs of patients living with clinically significant haemoglobinopathies (thalassaemia and sickle cell disease(SCD)) in NSW, Australia. A survey based health needs assessment was undertaken in outpatients cared for at five tertiary institutions in metropolitan and regional centres. Sixty three of 121 adults (approximately 80-90% of adult patients with transfusion-requiring haemoglobinopathies in NSW) completed an inhouse and commercial health-related quality assessment survey (SF36v2). Subjects came from more than 8 world regions; with those with SCD being more likely to be born outside of Australia than subjects with thalassaemia (p<0.001, LR 20.64) as well as more likely to have been refugees (26% vs 2%). The population contained socially disadvantaged subjects with 13 subjects (20.6%) having incomes below the Australian poverty line. Complications of thalassaemia were comparable to previous international reports although our subjects had a high rate of secondary amenorrhea (>12 months = 27%), and surgical splenectomy (55.6%).Use of HU in SCD was less than expected with only 46.6% of subjects having prior use. Lack of universal access to MRI guided chelation (international best practice) was evident, although 65.5% had been able to access MRI via clinical trial, or self-funding. Patients with SCD and thalassaemia experience considerable morbidity and mortality and require complex, multidisciplinary care. This study revealed both variance from international best practice and between specialist units. The results of this research may provide the impetus for the development of clinical and research networks to enable the uniform delivery of health services benchmarked against international standards. 23875004 Is ritonavir-boosted atazanavir a risk for cholelithiasis compared to other protease inhibitors? To compare the incidence of complicated cholelithiasis in patients receiving ritonavir-boosted atazanavir (ATV/r)- containing antiretroviral therapy with those on other protease inhibitors (PIs). We conducted a single-center retrospective cohort study of patients who started either ritonavir-boosted ATV/r- or other PIs (ritonavir-boosted fosamprenavir, unboosted fosamprenavir, lopinavir/ritonavir, and ritonavir-boosted darunavir) -containing antiretroviral therapy. The incidence of complicated cholelithiasis was determined in each group. Complicated cholelithiasis was defined as follows: 1) cholelithiasis complicated by cholecystitis, cholangitis, or pancreatitis or 2) symptomatic cholelithiasis or choledocholithiasis which required invasive procedures such as cholecystomy and endoscopic retrograde cholangiopancreatography. The effects of ATV/r were estimated by univariate and multivariate Cox hazards models as the primary exposure. Complicated cholelithiasis was diagnosed in 3 patients (2.23 per 1000 person-years) in the ATV/r group (n = 466), and 3 (1.64 per 1000 person-years) in the other PIs group (n = 776), respectively. The incidence was not statistically different in the two groups by log-rank test (P = 0.702). By univariate and multivariate analysis adjusted for age and body weight, ATV/r use was not associated with cholelithiasis. (HR = 1.365; 95% CI, 0.275-6.775; p = 0.704) (adjusted HR = 1.390; 95% CI, 0.276-7.017; p = 0.690). For the 3 patients who developed cholelithiasis in the ATV/r group, the time to the diagnosis of cholelithiasis was 18, 34, and 39 months, respectively. In this study, the incidence of complicated cholelithiasis was low and was not different between patients on ATV/r and those on other PIs. On the contrary to ATV/r-associated nephrolithiasis, the possible risk of cholelithiasis should not preclude the use of ATV/r. 21880514 MicroRNA expression profiles in the progression of prostate cancer-from high-grade prostate intraepithelial neoplasia to metastasis. Models of the multistep process related to cancer progression have been designed for many cancers including prostate. The aim of this study is to propose a new model including a possible role for recently described micro RNAs in prostate cancer (CaP) progression. Sixty-three patients underwent radical prostatectomy to treat localized prostate carcinoma. The specimens of 15 patients were representative of high grade prostate intraepithelial neoplasia (HGPIN). Fourteen specimens represented localized favorable CaP, and 34 unfavorable, mostly non-organ-confined disease. Representing the advanced disease we studied 4 metastatic androgen-independent CaP and 2 cell lines. Micro RNAs were isolated using the mirVana miRNA Isolation kit and cDNA was obtained using the TaqMan miRNA Reverse Transcription kit to the miRNAs: hsa-miR-let7c, hsa-miR-15a, hsa-miR-16, hsa-miR-21, hsa-miR-25, hsa-miR-32, hsa-miR-100, hsa-miR-143, hsa-miR-145, hsa-miR-146a, hsa-miR-191, hsa-miR-199a, hsa-miR-206, and hsa-miR-218. Quantitative RT-PCR was carried out using the ABI 7500 Fast Real-Time PCR System and the TaqMan Universal PCR Master Mix. miRNA expression levels were measured by relative quantification, and fold expression changes were determined by the 2(-ΔΔCT) method. The small nucleolar RNA RNU43 was used as an endogenous control. Except for miR-21 and miR-206, the expression levels of all miRNAs significantly changed during the progression of CaP. Interestingly, there was a significant global loss of miRNA expression between HGPIN and metastasis at 2 important steps. The first was related to the transition from HGPIN to invasive adenocarcinoma, and the second was related to the transition from localized to metastatic adenocarcinomas. Through the analysis of 14 miRNAs in 4 groups of prostate lesions, which reproduced the progression of CaP, we showed that there is a global loss of miRNA expression at 2 distinct steps. The first related to the transition between HGPIN and localized invasive carcinoma, and the second associated with the transition from localized to metastatic CaP. The importance of our study is in the identification of possible miRNAs and miRNA-targeted genes involved in the progression of prostate carcinogenesis that may help the development of potential diagnostic or prognostic markers as well as the design of new target therapies. 23716589 The B55α Regulatory Subunit of Protein Phosphatase 2A Mediates Fibroblast Growth Factor-Induced p107 Dephosphorylation and Growth Arrest in Chondrocytes. Fibroblast growth factor (FGF)-induced growth arrest of chondrocytes is a unique cell type-specific response which contrasts with the proliferative response of most cell types and underlies several genetic skeletal disorders caused by activating FGF receptor (FGFR) mutations. We have shown that one of the earliest key events in FGF-induced growth arrest is dephosphorylation of the retinoblastoma protein (Rb) family member p107 by protein phosphatase 2A (PP2A), a ubiquitously expressed multisubunit phosphatase. In this report, we show that the PP2A-B55α holoenzyme (PP2A containing the B55α subunit) is responsible for this phenomenon. Only the B55α (55-kDa regulatory subunit, alpha isoform) regulatory subunit of PP2A was able to bind p107, and this interaction was induced by FGF in chondrocytes but not in other cell types. Small interfering RNA (siRNA)-mediated knockdown of B55α prevented p107 dephosphorylation and FGF-induced growth arrest of RCS (rat chondrosarcoma) chondrocytes. Importantly, the B55α subunit bound with higher affinity to dephosphorylated p107. Since the p107 region interacting with B55α is also the site of cyclin-dependent kinase (CDK) binding, B55α association may also prevent p107 phosphorylation by CDKs. FGF treatment induces dephosphorylation of the B55α subunit itself on several serine residues that drastically increases the affinity of B55α for the PP2A A/C dimer and p107. Together these observations suggest a novel mechanism of p107 dephosphorylation mediated by activation of PP2A through B55α dephosphorylation. This mechanism might be a general signal transduction pathway used by PP2A to initiate cell cycle arrest when required by external signals. 23808559 Isosteric heats of gas and liquid adsorption. The heat of adsorption is an indicator of the strength of the interaction between an adsorbate and a solid adsorbent. This parameter can be determined from the heat released in calorimetric experiments or from the analysis of adsorption isotherms at different temperatures. The latter, called isosteric heats of adsorption, are commonly used in the characterization of materials for gas- and liquid-phase adsorption. Although the equations for the determination of isosteric heats of adsorption from the gas phase are well-known, approximate equations are frequently used for liquid-phase adsorption. We present here the rigorous equations for determining the isosteric heats of gas- and liquid-phase adsorption and their relation to the commonly used approximate equations. These equations are used to compute the isosteric heats of liquid adsorption based on the adsorption isotherms obtained from simulations for two well-defined systems, one ideal and the other nonideal. The results of using the rigorous equations are compared with those from the approximate equations. The main conclusion is that the commonly used approximate equations provide reasonable, but not perfect, estimates of the isosteric heats of liquid adsorption using only the experimental adsorption isotherms. The more accurate rigorous equations require additional information, including the heat of vaporization and, for nonideal mixtures, the heat of mixing. 23934255 Biocompatible Glycol Chitosan-Coated Gold Nanoparticles for Tumor-Targeting CT Imaging. The application of gold nanoparticles (AuNPs) in biomedical field was limited due to the low stability in the biological condition. Herein, to enhance stability and tumor targeting ability of AuNPs, their surface was modified with biocompatible glycol chitosan (GC) and the in vivo biodistribution of GC coated AuNPs (GC-AuNPs) were studied through computed tomography (CT). Polymer-coated gold nanoparticles were produced using GC as a reducing agent and a stabilizer. Their feasibility in biomedical application was explored through CT in tumor-bearing mice. Stability of gold nanoparticles increased in the physiological condition due to the GC coating layer on the surface. Tomographic images of tumor were successfully obtained in the tumor-xenografted animal model when the GC-AuNPs were used as a CT contrast agent. The tumor targeting property of the gold nanoparticles was due to the properties of GC because GC-AuNPs were accumulated in the tumor, while most of heparin-coated nanoparticles were found in the liver and spleen. The polymer properties on the surface played an important role in the behavior of gold nanoparticles in the biological condition and the enhanced stability and tumor targeting property of nanoparticles were inherited from GC on the surface. 23500185 Molecular cloning, characterization and immunological response analysis of Toll-like receptor 21 (TLR21) gene in grass carp, Ctenopharyngodon idella. TLR21, a non-mammalian Toll-like receptor, has been recently identified in fishes, frogs and birds. In the present study, the full-length cDNA sequence of TLR21 (CiTLR21) from Ctenopharyngodon idella has been isolated and characterized. The CiTLR21 full-length cDNA sequence consists of 3578bp, with an open reading frame (ORF) of 2958bp encoding 985 amino acid residues. The putative CiTLR21 protein contains a signal peptide sequence, 17 leucine-rich (LRR) motifs, a transmembrane region and a Toll/interleukin-1 receptor (TIR) domain. The CiTLR21 gene is expressed in a wide range of tissues with the highest expression in skin. Upon induction by Aquareovirus, CiTLR21 expression is significantly down-regulated in liver and spleen, whereas is significantly up-regulated in liver and spleen after Aeromonas hydrophila infection. These results suggest that CiTLR21 plays an important role in Aquareovirus and A. hydrophila-related diseases. This work may provide the basis for further investigations into the immune system of grass carp and other teleost fishes. 23422407 Cognitive processing speed is related to fall frequency in older adults with multiple sclerosis. To examine mobility, balance, fall risk, and cognition in older adults with multiple sclerosis (MS) as a function of fall frequency. Retrospective, cross-sectional design. University research laboratory. Community-dwelling persons with MS (N=27) aged between 50 and 75 years were divided into 2 groups-single-time (n=11) and recurrent (n=16; >2 falls/12 mo) fallers-on the basis of fall history. Not applicable. Mobility was assessed using a variety of measures including Multiple Sclerosis Walking Scale-12, walking speed (Timed 25-Foot Walk test), endurance (6-Minute Walk test), and functional mobility (Timed Up and Go test). Balance was assessed with the Berg Balance Scale, posturography, and self-reported balance confidence. Fall risk was assessed with the Physiological Profile Assessment. Cognitive processing speed was quantified with the Symbol Digit Modalities Test and the Paced Auditory Serial Addition Test. Recurrent fallers had slower cognitive processing speed than single-time fallers (P≤.01). There was no difference in mobility, balance, or fall risk between recurrent and single-time fallers (P>.05). Results indicated that cognitive processing speed is associated with fall frequency and may have implications for fall prevention strategies targeting recurrent fallers with MS. 23288142 Inhibition of matrix metalloproteinase-9 expression by docosahexaenoic acid mediated by heme oxygenase 1 in 12-O-tetradecanoylphorbol-13-acetate-induced MCF-7 human breast cancer cells. Matrix metalloproteinase-9 (MMP-9) plays a crucial role in tumor metastasis. Previous studies showed that polyunsaturated fatty acids exhibit an anti-cancer effect in various human carcinoma cells, but the effect of docosahexaenoic acid (DHA) and linoleic acid (LA) on metastasis of breast cancer cells is not fully clarified. We studied the anti-metastasis potential of DHA and LA in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MCF-7 cells. We found that TPA (100 ng/ml) induced MMP-9 enzyme activity both dose- and time-dependently, and 200 μM DHA and LA significantly inhibited MMP-9 mRNA and protein expression, enzyme activity, cell migration, and invasion. Treatment with PD98059 (10 μM), wortmannin (10 μM), and GF109203X (0.5 μM) decreased TPA-induced MMP-9 protein expression and enzyme activity. TPA-induced activation of ERK1, Akt, and PKCδ was attenuated by DHA, whereas LA attenuated only ERK1 activation. GF109203X also suppressed ERK1 activation. EMSA showed that DHA, LA, PD98059, and wortmannin decreased TPA-induced NF-κB and AP-1 DNA-binding activity. Furthermore, DHA rather than LA dose-dependently increased HO-1 expression. HO-1 siRNA alleviated the inhibition by DHA of TPA-induced MMP-9 protein expression and enzyme activity in MCF-7 cells, and HO-1 knockdown reversed the DHA inhibition of cell migration. These results suggest that DHA and LA have both similar and divergent signaling pathways in the suppression of TPA-induced MCF-7 metastasis. 23913310 Use of social networking sites by parents of very low birth weight infants: experiences and the potential of a dedicated site. The objective of this study was to study the experiences of parents of preterm infants who use social networking sites and the potential of such sites for gathering information and facilitating personal exchange. An anonymous self-reporting questionnaire was administered to parents of infants below 1,500 g birth weight born between January 1, 2009 and December 31, 2010 in two tertiary neonatal intensive care units. Of the 278 families who were sent a questionnaire, 141 responded; 53.6 % of respondents claimed to be presently members of online social networking sites. However, only 10.7 and 18.6 % used the Internet to exchange information about their infants during the NICU stay and after discharge, respectively. Most (64.0 %) responding parents considered that currently available commercial Internet sites inadequately met their need to exchange information as parents of preterm infants. Overall, 79.1 % of respondents reported that they would be interested in joining a native-language online networking site providing (1) general information on prematurity, (2) explanations of abbreviations commonly used in a hospital setting, and (3) details of common medical problems and the treatment thereof, including the availability of local therapists and follow-up services. Also, parents wanted to engage in personal exchange online not only with other parents but also with medical staff. Conclusion: The support of parents of hospitalized preterm infants by neonatal nurses and doctors could be extended by developing an expert-controlled, online networking site providing reliable and updated information and facilitating personal exchange among parents. 23800738 Diversity assessment of Listeria monocytogenes biofilm formation: Impact of growth condition, serotype and strain origin. The foodborne pathogen Listeria monocytogenes has the ability to produce biofilms in food-processing environments and then contaminate food products, which is a major concern for food safety. The biofilm forming behavior of 143 L. monocytogenes strains was determined in four different media that were rich, moderate or poor in nutrients at 12°C, 20°C, 30°C and 37°C. The biofilm formation was mostly influenced by temperature, resulting in decreased biofilm formation with decreasing temperature. Biofilm formation was enhanced in nutrient-poor medium rather than in nutrient-rich medium, and especially in nutrient-poor medium significantly enhanced biofilm production was observed early in biofilm maturation underlining the effect of medium on biofilm formation rate. Also serotype had a significant effect on biofilm formation and was influenced by medium used because strains from both serotype 1/2b and 1/2a formed more biofilm than serotype 4b strains in nutrient-rich medium at 20°C, 30°C and 37°C, whereas in nutrient-poor medium the biofilm production levels of serotype 1/2a and 4b strains were rather similar and lower than serotype 1/2b strains. The strains used originated from various origins, including dairy, meat, industrial environment, human and animal, and the level of biofilm formation was not significantly affected by the origin of isolation, irrespective of medium used and temperature tested. A linear model was used to correlate crystal violet staining of biofilm production to the number of viable cells within the biofilm. This showed that crystal violet staining was poorly correlated to the number of viable cells in nutrient-poor medium, and LIVE/DEAD staining and DNase I treatment revealed that this could be attributed to the presence of non-viable cells and extracellular DNA in the biofilm matrix. The significant impact of intrinsic and extrinsic factors on biofilm production of L. monocytogenes underlined that niche-specific features determine the levels of biofilm produced, and insights in biofilm formation characteristics will allow us to further optimize strategies to control the biofilm formation of L. monocytogenes. 23902963 Artificial neural network models for prediction of cardiovascular autonomic dysfunction in general Chinese population. The present study aimed to develop an artificial neural network (ANN) based prediction model for cardiovascular autonomic (CA) dysfunction in the general population. We analyzed a previous dataset based on a population sample consisted of 2,092 individuals aged 30--80 years. The prediction models were derived from an exploratory set using ANN analysis. Performances of these prediction models were evaluated in the validation set. Univariate analysis indicated that 14 risk factors showed statistically significant association with CA dysfunction (P < 0.05). The mean area under the receiver-operating curve was 0.762 (95% CI 0.732--0.793) for prediction model developed using ANN analysis. The mean sensitivity, specificity, positive and negative predictive values were similar in the prediction models was 0.751, 0.665, 0.330 and 0.924, respectively. All HL statistics were less than 15.0. ANN is an effective tool for developing prediction models with high value for predicting CA dysfunction among the general population. 23929054 Management of seizure disorders in the deployed environment: a treatment guide for the non-neurologist in theater. Patients with seizures can present a common and challenging problem for medical providers in the deployed environment. Unfortunately, there is a paucity of controlled clinical trial data that can be used to formulate evidence-based guidelines for management. In an attempt to aid the non-neurologist deployed provider in the care of patients presenting with seizures, the authors describe two cases illustrative of common presentations. Thereafter, the authors address many facets of the management questions commonly raised by such cases and offer suggestions regarding such issues as initial pharmacologic management, the need for admission and evacuation, seizure precautions, differentiation from syncope and nonepileptic seizures, addressing patient and command concerns regarding evaluation and duty restrictions, and obtaining online management assistance. 23933469 Language comprehension interrupted: Both language errors and word degradation activate Broca's area. The proposal of a general conflict resolution mechanism in lIFG was investigated further in relation to language errors. In an fMRI study participants read sentences containing syntactic and plausibility violations. Furthermore, they were presented with sentences that were difficult to comprehend, due to degradation of the bottom-up signal (i.e., the visual form) of the language. We were interested whether comprehension difficulties caused by degradation would activate cognitive control mechanisms in the same manner as other language violations. To localize cognitive control processes participants performed a Stroop task. Both the violations and the visual degradation condition elicited co-localized lIFG activation with the Stroop conflict. These results indicate that lIFG implements control adjustments to resolve situations in which extra attention is needed more generally. Next to biasing attention to resolve representational conflicts arising from different types of errors, lIFG may also adjust control to compensate for a temporary lack of bottom-up information. 23937163 Limit of miscibility and nanophase separation in associated mixtures. We present a detailed analysis of the mixing process in an associating system, the water-tert-butanol (2-methyl-2-propanol) mixture. Using molecular dynamics simulations, together with neutron, X-ray diffraction experiments, and pulsed gradient spin-echo NMR, we study the local structure and dynamic properties over the full concentration range, and thereby provide quantitative data that reveal relationships between local structure and macroscopic behavior. For an alcohol-rich mixture, diffraction patterns from both neutron and X-ray experiments exhibit a peak at low wavelength vector (q ≈ 0.7 Å(-1)) characteristic of supermolecular structures. On increasing the water content, this "prepeak" progressively flattens and shifts to low wave vector . We identify hydrogen bonds in the system as the driving force for the specific organization that appears in mixtures, and provide an analysis of the variation of the cluster size distribution with composition. We find that the sizes of local hydrogen-bonded clusters observed in alcohol-rich mixtures become larger as the mole fraction, xw, of water is increased; a nanophase separation is seen for xw in the range 0.6-0.7. This corresponds to several changes in some macroscopic properties of the liquid mixture. Thus, we propose a microscopic description of the effect of water addition in alcohol, which is in agreement with both neutron diffraction pattern and mobility of water and alcohol species. In summary we present a full and comprehensive description of miscibility at its limit in an associated system. 23820080 Estimates of the timing of reductions in genital warts and high grade cervical intraepithelial neoplasia after onset of human papillomavirus (HPV) vaccination in the United States. The objective of this study was to estimate the number of years after onset of a quadrivalent HPV vaccination program before notable reductions in genital warts and cervical intraepithelial neoplasia (CIN) will occur in teenagers and young adults in the United States. We applied a previously published model of HPV vaccination in the United States and focused on the timing of reductions in genital warts among both sexes and reductions in CIN 2/3 among females. Using different coverage scenarios, the lowest being consistent with current 3-dose coverage in the United States, we estimated the number of years before reductions of 10%, 25%, and 50% would be observed after onset of an HPV vaccination program for ages 12-26 years. The model suggested female-only HPV vaccination in the intermediate coverage scenario will result in a 10% reduction in genital warts within 2-4 years for females aged 15-19 years and a 10% reduction in CIN 2/3 among females aged 20-29 years within 7-11 years. Coverage had a major impact on when reductions would be observed. For example, in the higher coverage scenario a 25% reduction in CIN2/3 would be observed with 8 years compared with 15 years in the lower coverage scenario. Our model provides estimates of the potential timing and magnitude of the impact of HPV vaccination on genital warts and CIN 2/3 at the population level in the United States. Notable, population-level impacts of HPV vaccination on genital warts and CIN 2/3 can occur within a few years after onset of vaccination, particularly among younger age groups. Our results are generally consistent with early reports of declines in genital warts among youth. 23631425 The Governing Role of Surface Hydration in Ion Specific Adsorption to Silica - an AFM Based Account of the Hofmeister Universality and its Reversal. AFM measurements of the force acting between silica surfaces in the presence of varied alkali-chloride salts and pH's elucidate the origin of the Hofmeister adsorption series and its reversal. At low pH, electrostatics is shown to be insignificant. The preferential adsorption of Cs+ to the silica surface is traced to the weak hydration of neutral silanols and the resulting hydrophobic expulsion of weakly hydrated ions from bulk solution to the interface. The same interactions keep the strongly hydrated Li+ and Na+ in solution. As pH is increased, a tightly bound hydration layer forms on deprotonating silanols. Cs+ is correspondingly expelled from the surface and adsorption of small ions is encouraged. The deduced role of surface hydration is corroborated by hydration repulsion observed at high pH, surface over-charging at low pH, and data in other oxides. 23728256 Dispersion of Al2O3 nanoparticles stabilized with mussel-inspired amphiphilic copolymers in organic solvents and formation of hierarchical porous films by the breath figure technique. Hierarchical porous inorganic materials have attracted much attention, due to their large surface area and fast substance diffusion. We have prepared hierarchical porous films composed of Al2O3 nanoparticles (NPs) using the breath figure technique. The Al2O3 NPs were stabilized using an amphiphilic copolymer that contained catechol moieties. Porous films of polymer-stabilized Al2O3 NPs were prepared using water droplets as templates. The films were sintered to produce hierarchical porous Al2O3 films that were thermally and chemically stable. 23953243 An association between kidney stone composition and urinary metabolic disturbances in children. To determine kidney stone composition in children and to correlate stone fractions with urinary pH and metabolic urinary risk factors. We studied 135 pediatric patients with upper urinary tract lithiasis in whom excreted or extracted stones were available for analyses. Composition of stones was analyzed. A 24-hour urine assessment included volume, pH and daily excretions of calcium, oxalate, uric acid, cystine, creatinine, phosphate, magnesium and citrate. Calcium oxalate was the major component of 73% stones, followed by struvite (13%) and calcium phosphate (9%). Uric acid was present in almost half of stones, but in rudimentary amounts. The calcium oxalate content in calculi showed a strong relationship with calciuria, and moderate association with oxaluria, magnesuria and acidification of urine. The percent content of struvite presented reverse and lower correlations with regard to the above parameters. Calcium phosphate stone proportion had low associations with urinary risk factors. Calciuria, oxaluria, magnesuria and low urine pH exerted the biggest influence on calcium oxalate content in pediatric renal stones. Relationships of urinary risk factors with calculi calcium phosphate content were of unclear significance. Urinary citrate excretion did not significantly correlate with kidney stone composition in children. 23773620 Adiponectin protects Leydig cells against proinflammatory cytokines by suppressing the nuclear factor-κB signaling pathway. Adiponectin is an adipocyte hormone that is predominantly secreted by adipocytes, and has important roles in glucose and lipid homeostasis. Recent studies have shown that adiponectin is also involved in the regulation of many endocrine organs, such as the ovary, adrenal gland, and pituitary. However, its biological role in male testes is largely unexplored. The present findings demonstrate the presence of adeponectin receptors (adiponectin receptor 1 and adiponectin receptor 2) in TM3 cells derived from mouse Leydig cells. Proinflammatory cytokine treatment significantly downregulated mRNA and protein levels of adiponectin receptor 1 and adiponectin receptor 2. However, adiponectin pretreatment successfully inhibited the signaling pathway mediated by proinflammatory cytokines. At the molecular level, we provide compelling evidence that adeponectin achieves this by suppressing nuclear factor-κB activation through promotion of AMP-activated protein kinase phosphorylation. Thus, our data clearly indicate that adiponectin plays a protective role in Leydig cells through its anti-inflammatory actions. 23896187 Factors Associated with Breastfeeding Initiation in Adolescent Mothers. To identify the most influential factors on breastfeeding initiation in adolescent mothers in order to identify the highest risk population to focus education and support services. Retrospective population-based cohort study of all non-anomalous live births in Ohio (2006-2007). Breastfeeding initiation rates were compared between adolescent mothers age ≤19 years and a reference group age >19 years. A multivariate logistic regression model assessed the association between breastfeeding initiation in adolescent mothers while adjusting for important concomitant risk factors including race, socioeconomic, demographic, prenatal, and delivery factors. Of 308 380 births during the study period, following exclusions there were 30 402 mothers ≤19 years of age (10.5% of study population) and 257 840 mothers age >19 years. Of adolescent mothers, 44% initiated breastfeeding compared with 65% of older mothers, P < .001. Adolescents were 33% less likely to breastfeed after adjusting for important coexisting factors, adjusted relative risk 0.77 (95% CI 0.75-0.80). Socioeconomic factors had the most significant influence on breastfeeding initiation in adolescent mothers. Adolescent mothers who have the least social support and are socioeconomically disadvantaged are the least likely to breastfeed their newborn infants. In addition, maternal perception, societal barriers, and a lack of prenatal intervention contribute unique barriers to breastfeeding in adolescence. Opportunities exist for school programs, baby-friendly hospitals, and postpartum education to improve breastfeeding rates in this population. 23873148 A two-step mechanism for epigenetic specification of centromere identity and function. The basic determinant of chromosome inheritance, the centromere, is specified in many eukaryotes by an epigenetic mark. Using gene targeting in human cells and fission yeast, chromatin containing the centromere-specific histone H3 variant CENP-A is demonstrated to be the epigenetic mark that acts through a two-step mechanism to identify, maintain and propagate centromere function indefinitely. Initially, centromere position is replicated and maintained by chromatin assembled with the centromere-targeting domain (CATD) of CENP-A substituted into H3. Subsequently, nucleation of kinetochore assembly onto CATD-containing chromatin is shown to require either the amino- or carboxy-terminal tail of CENP-A for recruitment of inner kinetochore proteins, including stabilizing CENP-B binding to human centromeres or direct recruitment of CENP-C, respectively. 23405984 Solution structure and in silico binding of a cyclic peptide with hepatitis B surface antigen. A specific ligand targeting the immunodominant region of hepatitis B virus (HBV) is desired in neutralizing the infectivity of the virus. In a previous study, a disulfide constrained cyclic peptide cyclo S(1) ,S(9) Cys-Glu-Thr-Gly-Ala-Lys-Pro-His-Cys (S(1) , S(9) -cyclo-CETGAKPHC) was isolated from a phage displayed cyclic peptide library using an affinity selection method against HBV surface antigen (HBsAg). The cyclic peptide binds tightly to HBsAg with a relative dissociation constant (K(D) (rel) ) of 2.9 nM. The binding site of the peptide was located at the immunodominant region on HBsAg. Consequently, this study was aimed to elucidate the structure of the cyclic peptide and its interaction with HBsAg in silico. The solution structure of this cyclic peptide was solved using (1) H, (13) C and (15) N NMR spectroscopy and molecular dynamics (MD) simulations with NMR-derived distance and torsion angle restraints. The cyclic peptide adopted two distinct conformations due to the isomerization of the Pro residue with one structured region in the ETGA sequence. Docking studies of the peptide ensemble with a model structure of HBsAg revealed that the cyclic peptide can potentially be developed as a therapeutic drug that inhibits the virus-host interactions. © 2013 John Wiley & Sons A/S. 23968580 Developmental programming in skeletal muscle in response to overnourishment in the immediate postnatal life in rats. Overnourishment during the suckling period [small litter (SL)] results in the development of adult-onset obesity. To investigate the mechanisms that underlie the development of insulin resistance in the skeletal muscle of young and adult female SL rats, the litter size was reduced to 3 female pups/dam (SL) while the control litter had 12 pups/dam from the postnatal Day 3 until Day 21. Protein content, mRNA expression and methylation status of the promoter region of key components in the insulin signaling pathway were determined in the skeletal muscle of SL rats. Overnutrition during the suckling period resulted in increased body weight gains, hyperphagia and adult-onset obesity as well as increased levels of serum insulin, glucose and leptin in SL rats. No differences in the expression of total protein as well as tyrosine phosphorylation of insulin receptor β and glucose transporter 4 (Glut4) were observed in skeletal muscle between two groups at both ages. A significant decrease of total insulin receptor substrate 1 (IRS-1) and an increase in serine phosphorylation of IRS-1 were observed in skeletal muscle from adult SL rats. Hypermethylation of specific cytidyl-3',5'phospho-guanylyl (CpG) dinucleotides in the proximal promoter region was observed for the Irs1 and Glut4 genes, which correlated with the reduction in Irs1 and Glut4 mRNA levels in skeletal muscle of adult SL rats. Our results suggest that epigenetic modifications of the key genes involved in the insulin signaling pathway in skeletal muscle could result in the development of insulin resistance in SL female rats. 23833285 Reduced Myocardial 123-Iodine Meta-iodobenzylguanidine Uptake: A Prognostic Marker in Familial Amyloid Polyneuropathy. -Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a hereditary form of amyloidosis characterized by sensorimotor and autonomic neuropathy, cardiac conduction defects and infiltrative cardiomyopathy. Previous studies have suggested that myocardial sympathetic denervation assessed by 123-iodine metaiodobenzylguanidine (MIBG) imaging occurs early in disease progression. However, its prognostic significance was never evaluated. We aimed to study the long-term prognostic value of myocardial sympathetic denervation detected by MIBG imaging in TTR-FAP. -A total of 143 individuals with V30M TTR mutation underwent Holter, ambulatory blood pressure monitoring, echocardiography and MIBG imaging. Time to all-cause death was compared with late heart-to-mediastinum MIBG uptake ratio (H/M) [either in relation to the estimated lower limit of normal (1.60) or as a continuous variable] using Cox proportional hazards regression. Multivariable analyses were performed to test the prognostic accuracy of clinical, neurological and cardiovascular parameters. During a median follow-up of 5.5 years, 32 (22%) patients died. Five-year mortality rate was 42% for late H/M <1.60 and 7% for late H/M ≥1.60 (hazard ratio 7.19, p < 0.001). Late H/M was identified as an independent prognostic predictor. Fifty-three patients were submitted to liver transplantation. In comparison to neurophysiological score-matched controls, transplanted patients had lower long-term mortality (hazard ratio 0.32, p = 0.012). Patients with late H/M <1.60 were at higher risk of unfavourable outcome but seemed to benefit from liver transplantation. -Cardiac sympathetic denervation as assessed by MIBG imaging is a useful prognostic marker in TTR-FAP. 23672928 Phase II study of temsirolimus (CCI-779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. A trial of the NCIC Clinical Trials Group (NCIC CTG IND 199). HPV infection has been associated with deregulation of the PI3K-Akt-mTOR pathway in invasive cervical carcinomas. This 2-stage phase II study assessed the activity of the mTOR inhibitor, temsirolimus, in patients with measurable metastatic and/or locally advanced, recurrent carcinoma of the cervix. Temsirolimus 25mg i.v. was administered weekly in 4week cycles. One response among the first 18 patients was required to proceed to the second stage of accrual. Correlative molecular studies were performed on archival tumor tissue. Thirty-eight patients were enrolled. Thirty-seven patients were evaluable for toxicity and 33 for response. One patient experienced a partial response (3.0%). Nineteen patients had stable disease (57.6%) [median duration 6.5months (range 2.4-12.0mo)]. The 6-month progression free survival rate was 28% (95% CI: 14-43%). The median progression free survival was 3.52months [95% CI (1.81-4.70)]. Adverse effects were mild-moderate in most cases and similar to other temsirolimus studies. No toxicity>grade 3 was observed. Assessment of PTEN and PIK3CA by IHC, copy number analyses and PTEN promoter methylation status did not reveal subsets associated with disease stability. Single agent temsirolimus has modest activity in cervical carcinoma with about two-thirds of patients exhibiting stable disease. Molecular markers for treatment benefit remain to be identified. 23850459 Mutations in HIV-1 reverse transcriptase cause misfolding and miscleavage by the viral protease. Previous work on mutations in the thumb of HIV-1 reverse transcriptase (RT) showed that the majority of the mutant RTs were degraded (by the viral protease) to various extents in virions. This degradation was, in most cases, temperature sensitive, and presumably was due to a partial unfolding of the protein at 37°C. We used recombinant proteins to investigate the effects of the mutations on the thermal stability and proteolytic degradation of RT. Both subunits contribute to the stability of RT. In general, the differences in stability between the mutants and WT were greater if the mutation was in p51 rather than p66. Expressing the Pol polyprotein containing the RT mutants in Escherichia coli produced results similar to what was seen in virions; the mutant RTs were misfolded and/or degraded at 37°C, but were better folded and processed at 30°C. 23837873 How should I approach standard endocrine evaluation in patients with coeliac disease? Endocrine evaluation is an important consideration in the longitudinal assessment of patients with coeliac disease (CD). In addition to wide-ranging nutritional implications, this common autoimmune disorder has a significant impact on bone health. A strategy to prevent osteomalacia, in conjunction with regular assessment of bone mineral density, is essential to minimize the possibility of increased fracture risk. Clinicians should readily acknowledge that patients with CD have a higher risk of developing a coexisting autoimmune condition. A considered clinical assessment and timely biochemical evaluation, as indicated in the wider context of continued emphasis on a gluten-free diet, will ensure optimal patient management. 23765576 Phosphatidylinositol-3,4,5-trisphosphate: tool of choice for class I PI 3-kinases. Class I PI 3-kinases signal by producing the signaling lipid phosphatidylinositol(3,4,5) trisphosphate, which in turn acts by recruiting downstream effectors that contain specific lipid-binding domains. The class I PI 3-kinases comprise four distinct catalytic subunits linked to one of seven different regulatory subunits. All the class I PI 3-kinases produce the same signaling lipid, PIP3, and the different isoforms have overlapping expression patterns and are coupled to overlapping sets of upstream activators. Nonetheless, studies in cultured cells and in animals have demonstrated that the different isoforms are coupled to distinct ranges of downstream responses. This review focuses on the mechanisms by which the production of a common product, PIP3, can produce isoform-specific signaling by PI 3-kinases. 23608623 A validated clinical tool for the prediction of varices in PBC: The Newcastle Varices in PBC Score. Gastro-oesophageal varices (GOV) can occur in early stage primary biliary cirrhosis (PBC), making it difficult to identify the appropriate time to begin screening with oesophageo-gastro-duodenoscopy (OGD). Our aim was to develop and validate a clinical tool to predict the probability of finding GOV in PBC patients. A cross-sectional retrospective study analysing clinical data of 330 PBC patients who underwent an OGD at the Freeman Hospital, Newcastle was used to create a predictive tool, the Newcastle Varices in PBC (NVP) Score, that was externally validated in PBC patients from Cambridge (UK) and Toronto (Canada). 48% of the Newcastle, 31% of the Cambridge, and 22% of the Toronto cohorts of PBC patients had GOV. Twenty-five percent (95% CI 18-32%) of the Newcastle cohort had GOV diagnosed at an index variceal bleed. Of the others, 37% (95% CI 28-46%) bled after a median of 1.5years (IQR 3.75). Transplant-free survival was significantly better in those without GOV than in those with GOV (p<0.001), but similar in patients with GOV that bled and those that did not (p=0.1). The NVP score (%Probability)=1/[1+exp^-(9.186+0.001*alkaline phosphatase in IU-0.178*albumin in g/L-0.015*platelet×10(9)) was validated in 2 external cohorts and was highly discriminant (AUROC 0.86). Cost consequences analyses revealed the NVP score to be as accurate as, but more economical than using either OGD directly or other risk scores for screening PBC patients. The NVP score is an inexpensive, non-invasive, externally validated tool that accurately predicts GOV in PBC. 23545129 Reduction of mosquito biting-pressure: spatial repellents or mosquito traps? A field comparison of seven commercially available products in Israel. The present study assessed the personal protection efficiency of seven commercially available mosquito control devices (MCD) under field conditions in Israel. Trials were performed in a high biting-pressure area inhabited by large populations of mosquito and biting midge species, using human volunteers as bait in landing catch experiments. Results show that under minimal air-movement, three spatial repellent based products (ThermaCELL(®) Patio Lantern, OFF!(®) PowerPad lamp, and Terminix(®) ALLCLEAR Tabletop Mosquito Repeller) significantly reduced the biting-pressure (t-test - P<0.01) when positioned at short distances from a volunteer (3, 7.5, and 10ft.), with the ThermaCELL unit being most effective (96.1, 89.9, and 76.66% reduction, respectively). No significant differences were seen between the three aforementioned devices at distances of 3 and 7.5ft., while at a distance of 10ft., only the ThermaCELL patio lantern repelled significantly more mosquitoes then the Terminix ALLCLEAR Tabletop Mosquito Repeller (t-test, P<0.05). In contrast, mosquito traps using attracting cues to bait mosquitoes (Dynatrap(®), Vortex(®) Electronic Insect Trap, Blue Rhino(®) SV3100) either significantly increased or had no effect on the biting-pressure at short distances compared with the unprotected control. Trials conducted over large areas showed that only the Blue Rhino trap was able to significantly reduce the biting-pressure (40.1% reduction), but this was only when operating four units at the corners of an intermediate sized area. 23899419 Quantum Chemical Investigation on Indole: Vibrational Force Field and Theoretical Determination of Its Aqueous pKa Value. Indole and its derivatives are molecules which play important roles in different fields, from biology to pharmacology. Here we report a thorough investigation on the anharmonic force fields of indole as well as the ab initio determinations of its gas phase basicity and aqueous pKa value. For the geometry optimizations, the calculations have been performed using both density functional (DFT) and second-order Møller-Plesset (MP2) levels of theory employing different basis sets. Anharmonic force fields have been obtained employing both the B3LYP and the B97-1 functionals and an hybrid approach: the best agreement to the experimental data has been determined employing the B3LYP functional combined with the recently developed N07D basis set (mean unsigned error, MUE, of 5.1 cm(-1) and a root-mean-square error, RMSE, of 7.2 cm(-1)). Gas phase basicity and proton affinity have been computed employing several computational schemes, namely the G3 and G4 Gaussian models, the complete basis set (CBS) extrapolation methods of Petersson and co-workers, several DFT calculations, and different hybrid extrapolation schemes based on combining single-point energy calculations performed at MP2 as well as at coupled cluster level of theory with single, double and perturbative triple excitations, CCSD(T). Regarding the aqueous pKa computations, two implicit solvation models (SMD and SM8) have been employed to determine the free energy of solvation and the corresponding pKa value. 23548760 Feral swine brucellosis in the United States and prospective genomic techniques for disease epidemiology. Brucellosis is a common infection of feral swine throughout the United States. With the recent expansion of feral swine populations across the country, this disease poses an increasing threat to agriculture and hunters. The standard approach to Brucella surveillance in feral swine has been serological testing, which gives an indication of past exposure and is a rapid method of determining populations where Brucella is present. More in-depth analyses require bacterial isolation to determine the Brucella species and biovar involved. Ultimately, for a comprehensive understanding of Brucella epizootiology in feral swine, incorporation of genotyping assays has become essential. Fortunately, the past decade has given rise to an array of genetic tools for assessing Brucella transmission and dispersal. This review aims to synthesize what is known about brucellosis in feral swine and will cover prospective genomic techniques that may be utilized to develop more complete understanding of the disease and its transmission history. 23817619 Immunosuppressive Property within the Streptococcus pneumoniae Cell Wall That Inhibits Generation of T Follicular Helper, Germinal Center, and Plasma Cell Response to a Coimmunized Heterologous Protein. We previously demonstrated that intact, inactivated Streptococcus pneumoniae (unencapsulated strain R36A) inhibits IgG responses to a number of coimmunized soluble antigens (Ags). In this study, we investigated the mechanism of this inhibition and whether other extracellular bacteria exhibited similar effects. No inhibition was observed if R36A was given 24 h before or after immunization with soluble chicken ovalbumin (cOVA), indicating that R36A acts transiently during the initiation of the immune response. Using transgenic cOVA-specific CD4(+) T cells, we observed that R36A had no significant effect on T-cell activation (24 h) or generation of regulatory T cells (day 7) and only a modest effect on T-cell proliferation (48 to 96 h) in response to cOVA. However, R36A mediated a significant reduction in the formation of Ag-specific splenic germinal center T follicular helper (GC Tfh) and GC B cells and antibody-secreting cells in the spleen and bone marrow in response to cOVA or cOVA conjugated to 4-hydroxy-3-nitrophenylacetyl hapten (NP-cOVA). Of note, the inhibitory effect of intact R36A on the IgG anti-cOVA response could be reproduced using R36A-derived cell walls. In contrast to R36A, neither inactivated, unencapsulated, intact Neisseria meningitidis nor Streptococcus agalactiae inhibited the OVA-specific IgG response. These results suggest a novel immunosuppressive property within the cell wall of Streptococcus pneumoniae. 23897186 Cardiovascular events and mortality in chronic kidney disease (stages I-IV). Introduction: Cardiovascular events (CV) are the major cause of mortality in chronic kidney disease patients (CKD). The aim of the present study was to determine the independent predictors of CV and mortality in CKD patients (stages 1-4). Methods: A prospective study was conducted with 218 patients (62% male), with a median age of 69 years (interquartile range 56-78). Basally, demographic variables, CV risk factors and biochemical values were collected. During follow-up, new CV events and deaths were collected (final variable). Results: During follow-up (38 [37-39] months), 50 patients suffered a final event: 37 patients (17%) had a CV and 13 (6%) died due to a non-CV death. Having a final event was associated to male sex, smoker, diabetes mellitus, history of CV event, low diastolic blood pressure values, low glomerular filtration, urine albumin/creatinine higher than 1000 mg/g, higher troponin T levels, higher BNP levels, higher CRP levels and lower haemoglobin levels. Multivariate analysis, showed that only male sex, diabetes mellitus, previous CV event and lower glomerular filtration independently predicted having the final event. Conclusion: Male sex, diabetes mellitus, previous CV event and lower glomerular filtration independently predicted having a CV event or death in CKD patients. We could not demonstrate the superiority of emerging CV risk markers compared to the classic ones. 23707812 Prevalence of multiple behavioral risk factors for chronic diseases in adults aged 50+, from eleven European countries - the SHARE study (2004). To estimate the prevalence and the associations between multiple behavioral risk factors (MBRFs) for chronic diseases in European adults. Data from 26,743 individuals, aged 50+years, participating in the Survey of Health, Ageing and Retirement in Europe (SHARE) (2004/05) were used. MBRFs included physical inactivity, high body weight, smoking habits and risky alcohol consumption. Estimations were based on weights according to the complex sampling design. In total, 71.2% of individuals were physically inactive, while 59.8% had high body weight. 53.4% had 2+ MBRFs, while males presented higher prevalence of MBRF clusters than females (P<0.001). Females displayed lower odds of increased alcohol consumption (OR=0.16, P<0.001) and higher odds of physical inactivity (OR=1.47, P<0.001) than males. Individuals who lived alone, compared to living with a partner and those with more, compared to fewer education years, exhibited a significantly higher and lower, respectively, mean MBRF score (P<0.001). The prevalence of MBRFs was considerably high in this sample of European adults, while not living alone and having higher education may prove protective. These findings could be used for the design of primary healthcare programs by health professionals. 23965991 Recruitment of a cytoplasmic chaperone relay by the A2A-adenosine receptor. The A2A-adenosine receptor is a prototypical rhodopsin-like G protein-coupled receptor (GPCR), but has several unique structural features, in particular a long C-terminus (of > 120 residues) devoid of a palmitoylation site. It is known to interact with several accessory proteins other than those canonically involved in signaling. However, it is evident that many more proteins must interact with the A2A-receptor, if the trafficking trajectory of the receptor is taken into account from its site of synthesis in the endoplasmic reticulum (ER) to its disposal by the lysosome. Affinity-tagged versions of the A2A-receptor were expressed in HEK293 cells to identify interacting partners residing in the ER by a proteomics approach based on tandem-affinity purification. The receptor/protein complexes were purified in quantities affording the analysis by mass spectrometry. We identified molecular chaperones (heat-shock protein HSP90α and HSP70-1A) that interact with and retain partially folded A2A-receptor prior to ER exit. Complex formation between the A2A-receptor and HSP90α (but not HSP90β) and HSP70-1A was confirmed by co-affinity-precipitation. HSP90 inhibitors also enhanced surface expression of the receptor in PC12 cells, which endogenously express the A2A-receptor. Finally, proteins of the HSP relay machinery (e.g., HOP/HSC70-HSP90 organizing protein and P23/HSP90 co-chaperone) were recovered in complexes with the A2A-receptor. These observations are consistent with the proposed chaperone/coat protein complex-II (COPII) exchange model. This posits that cytosolic HSP proteins are sequentially recruited to folding intermediates of the A2A-receptor. Release of HSP90 is required prior to recruitment of COPII components. This prevents premature ER export of partially folded receptors. 23712441 Complete genomic sequences and comparative analysis of Mamestra brassicae nucleopolyhedrovirus isolated in Korea. Mamestra brassicae nucleopolyhedrovirus-K1 (MabrNPV-K1) was isolated from naturally infected M. brassicae (Lepidoptera: Noctuidae) larvae in Korea. The full genome sequences of MabrNPV-K1 were determined, analysed and compared to those of other baculoviruses. The MabrNPV-K1 genome consisted of 152,710 bp and had an overall G + C content of 39.9 %. Computer-assisted analysis predicted 158 open reading frames (ORFs) of 150 nucleotides or greater that showed minimal overlap. Two inhibitor of apoptosis (iap) and six baculovirus repeated ORFs were interspersed in the MabrNPV-K1 genome. The unique MabrNPV-K1 ORF133 was identified in the MabrNPV-K1 genome that was not previously reported in baculoviruses. The gene content and arrangement in MabrNPV-K1 had the highest similarity with those of Helicoverpa armigera MNPV (HearMNPV) and Mamestra configurata NPV-B (MacoNPV-B), and their shared homologous genes were 99 % collinear. The MabrNPV-K1 genome contained four homologous repeat regions (hr1, hr2, hr3 and hr4) that accounted for 3.3 % of the genome. The genomic positions of the four MabrNPV-K1 hr regions were conserved among those of HearMNPV and MacoNPV-B. The gene parity plot, percent identity of the gene homologues and a phylogenetic analysis suggested that these three viruses are closely related not only to each other but also to the same virus strains rather than different virus species. 23625695 Effects of Soil Trace Elements on Longevity Population in China. Based on background concentrations of elements in soils and the sixth population census data of China, this study discussed the distribution characteristics of soil elements and longevity population at province level in China. Percentages of the aging population are high in Southwest China and the eastern coastal region but low in western and northwestern regions. Provinces in South and Southwest China gain a high level of longevity, while the northern part of China has a low level of longevity. The background concentration of Se in soil has a significant positive correlation with longevity index, while Ba and Ni have a significant negative correlation with longevity indexes. By regression analysis, longevity index C/100,000 can be expressed as C/100,000 = 1.679-0.205 Ni + 0.413 Co + 0.006 Se (with R (2) = 0.402 and p < 0.01), C/65+ can be expressed as C/65+=3.425-0.262 Ni + 0.435 Co + 0.006 Se (with R (2) = 0.369 and p < 0.01). 23872226 Consolidation trend design based on Young's modulus of clarithromycin single crystals. The key aim of this study was to determine single mechanical properties of clarithromycin polymorphic forms in order to select some of them as more suitable for the tableting process. For this purpose, AFM single-point nanoindentation was used. The Young's moduli of clarithromycin polymorphs were substantially different, which was consistent with the structural variations in their packing motifs. The presence of the adjacent layers, which can easily slide over each other due to the low energy barrier (the lowest Young's modulus was 0.25GPa) resulted in better bulk compressibility (the highest Heckel coefficient) of clarithromycin Form I. We also addressed the importance of tip geometry screening because the stress during the force mode often results in tip apex fracture. Even the initial manufacture of the diamond-coated tips can result in defects such as double-apex tips. 23839997 Circulation of Respiratory Viruses Among Pilgrims During the 2012 Hajj Pilgrimage. Background. The Hajj is the oldest and largest annual mass gathering in the world and may increase the risk of spread of respiratory viruses. Methods. We performed a prospective survey among a cohort of pilgrims departing from Marseille, France, to Mecca in the Kingdom of Saudi Arabia (KSA) for the 2012 Hajj season. Nasal swabs were collected from participants and tested for 11 respiratory viruses by real-time reverse transcription polymerase chain reaction. Results. Of 165 participants sampled before departing to the KSA, 8 (4.8%) were positive for at least 1 virus (5 rhinovirus, 1 influenza C, 1 adenovirus, and 1 enterovirus). Seventy symptomatic pilgrims underwent additional nasal swabs during their pilgrimage in the KSA, of which 27 (38.6%) were positive for at least 1 virus (19 rhinovirus, 6 influenza A, 1 influenza C, 1 respiratory syncytial virus B, 1 metapneumovirus, 1 adenovirus, and 1 enterovirus). This was significantly higher than the 4.8% who were positive before departing for the KSA (P < .001). Of 154 pilgrims sampled before leaving the KSA, 17 (11%) were positive for at least 1 virus (13 rhinovirus, 3 adenovirus, 2 influenza B, and 1 enterovirus), which was also significantly higher than the percentage of positive pilgrims (4.8%), before departing for the KSA (P = .040). Conclusions. This study suggests a rapid acquisition of respiratory viruses among pilgrims during their stay in the KSA, most notably rhinovirus, and highlights the potential of spreading these infections in the pilgrims' home countries upon their return. 23756234 Vertebral fractures and abdominal aortic calcification in postmenopausal women. A cohort study. Vertebral fracture assessment (VFA) imaging with a bone densitometer can simultaneously detect prevalent vertebral fractures (VFs) and abdominal aortic calcification (AAC). To study the relation between the prevalence of VFs using VFA in asymptomatic women and the prevalence and severity of AAC. This is a cross-sectional study. Subjects were recruited in a third care center from asymptomatic women selected from the general population. We enrolled 908 post-menopausal women with a mean age of 60.9years±7.7 (50 to 91) with no prior known diagnosis of osteoporosis or taking medication interfering with bone metabolism. Lateral VFA images and scans of the lumbar spine and proximal femur were obtained using a GE Healthcare Lunar Prodigy densitometer. VFs were defined using a combination of Genant semiquantitative (SQ) approach and morphometry. VFA images were scored for AAC using a validated 24 point scale. VFA images showed that 179 of the participants (19.7%) had at least one grade 2/3 VF, 81% did not have any detectable AAC whereas the prevalence of significant atherosclerotic burden, defined as AAC score of 5 or higher, was 12%. The group of women with 2/3 VFs had a statistically significant higher AAC score and higher proportion of subjects with extended AAC, and lower weight, height, and lumbar spine and hip BMD and T-scores than those without VFA-identified VFs. Multiple regression analysis showed that the presence of grade 2/3 VFs was significantly associated with age, BMI, history of peripheral fracture, AAC score≥5 and densitometric osteoporosis. In post-menopausal women, extended AAC is independently associated with prevalent VFs regardless of age, BMI, history of fractures, and BMD. 23959909 Level Anti-Crossings are a Key Factor for Understanding para-Hydrogen-Induced Hyperpolarization in SABRE Experiments. Various hyperpolarization methods are able to enhance the sensitivity of nuclear magnetic resonance (NMR) spectroscopy and magnetic resonance imaging (MRI) by several orders of magnitude. Among these methods are para-hydrogen-induced polarization (PHIP) and signal amplification by reversible exchange (SABRE), which exploit the strong nuclear alignment of para-hydrogen. Several SABRE experiments have been reported but, so far, it has not been possible to account for the experimentally observed sign and magnetic-field dependence of substrate polarization. Herein, we present an analysis based on level anti-crossings (LACs), which provides a complete understanding of the SABRE effect. The field-dependence of both net and anti-phase polarization is measured for several ligands, which can be reproduced by the theory. The similar SABRE field-dependence for different ligands is also explained. In general, the LAC concept allows complex spin dynamics to be unraveled, and is crucial for optimizing the performance of novel hyperpolarization methods in NMR and MRI techniques. 23540490 Stereotactic body radiation therapy planning with duodenal sparing using volumetric-modulated arc therapy vs intensity-modulated radiation therapy in locally advanced pancreatic cancer: A dosimetric analysis. Stereotactic body radiation therapy (SBRT) achieves excellent local control for locally advanced pancreatic cancer (LAPC), but may increase late duodenal toxicity. Volumetric-modulated arc therapy (VMAT) delivers intensity-modulated radiation therapy (IMRT) with a rotating gantry rather than multiple fixed beams. This study dosimetrically evaluates the feasibility of implementing duodenal constraints for SBRT using VMAT vs IMRT. Non-duodenal sparing (NS) and duodenal-sparing (DS) VMAT and IMRT plans delivering 25Gy in 1 fraction were generated for 15 patients with LAPC. DS plans were constrained to duodenal Dmax of<30Gy at any point. VMAT used 1 360° coplanar arc with 4° spacing between control points, whereas IMRT used 9 coplanar beams with fixed gantry positions at 40° angles. Dosimetric parameters for target volumes and organs at risk were compared for DS planning vs NS planning and VMAT vs IMRT using paired-sample Wilcoxon signed rank tests. Both DS VMAT and DS IMRT achieved significantly reduced duodenal Dmean, Dmax, D1cc, D4%, and V20Gy compared with NS plans (all p≤0.002). DS constraints compromised target coverage for IMRT as demonstrated by reduced V95% (p = 0.01) and Dmean (p = 0.02), but not for VMAT. DS constraints resulted in increased dose to right kidney, spinal cord, stomach, and liver for VMAT. Direct comparison of DS VMAT and DS IMRT revealed that VMAT was superior in sparing the left kidney (p<0.001) and the spinal cord (p<0.001), whereas IMRT was superior in sparing the stomach (p = 0.05) and the liver (p = 0.003). DS VMAT required 21% fewer monitor units (p<0.001) and delivered treatment 2.4 minutes faster (p<0.001) than DS IMRT. Implementing DS constraints during SBRT planning for LAPC can significantly reduce duodenal point or volumetric dose parameters for both VMAT and IMRT. The primary consequence of implementing DS constraints for VMAT is increased dose to other organs at risk, whereas for IMRT it is compromised target coverage. These findings suggest clinical situations where each technique may be most useful if DS constraints are to be employed. 23841983 Mitochondrial DNA damage can promote atherosclerosis independently of reactive oxygen species through effects on smooth muscle cells and monocytes and correlates with higher-risk plaques in humans. Mitochondrial DNA (mtDNA) damage occurs in both circulating cells and the vessel wall in human atherosclerosis. However, it is unclear whether mtDNA damage directly promotes atherogenesis or is a consequence of tissue damage, which cell types are involved, and whether its effects are mediated only through reactive oxygen species. mtDNA damage occurred early in the vessel wall in apolipoprotein E-null (ApoE(-/-)) mice, before significant atherosclerosis developed. mtDNA defects were also identified in circulating monocytes and liver and were associated with mitochondrial dysfunction. To determine whether mtDNA damage directly promotes atherosclerosis, we studied ApoE(-/-) mice deficient for mitochondrial polymerase-γ proofreading activity (polG(-/-)/ApoE(-/-)). polG(-/-)/ApoE(-/-) mice showed extensive mtDNA damage and defects in oxidative phosphorylation but no increase in reactive oxygen species. polG(-/-)/ApoE(-/-) mice showed increased atherosclerosis, associated with impaired proliferation and apoptosis of vascular smooth muscle cells, and hyperlipidemia. Transplantation with polG(-/-)/ApoE(-/-) bone marrow increased the features of plaque vulnerability, and polG(-/-)/ApoE(-/-) monocytes showed increased apoptosis and inflammatory cytokine release. To examine mtDNA damage in human atherosclerosis, we assessed mtDNA adducts in plaques and in leukocytes from patients who had undergone virtual histology intravascular ultrasound characterization of coronary plaques. Human atherosclerotic plaques showed increased mtDNA damage compared with normal vessels; in contrast, leukocyte mtDNA damage was associated with higher-risk plaques but not plaque burden. We show that mtDNA damage in vessel wall and circulating cells is widespread and causative and indicates higher risk in atherosclerosis. Protection against mtDNA damage and improvement of mitochondrial function are potential areas for new therapeutics. 23758219 Overexpression of Jagged-1 and Its Intracellular Domain in Human Mesenchymal Stromal Cells Differentially Affect the Interaction with Hematopoietic Stem and Progenitor Cells. Mesenchymal stromal cells (MSC) are an important component of the bone marrow microenvironment. Notch ligands expressed by MSC are known to play a regulatory role for hematopoietic stem and progenitor cells (HSPC) and in support of bone marrow homeostasis. While the role of Notch signaling in HSPC, their progeny, and MSC has been relatively well studied, little is known about the Notch-independent regulatory impact of Notch ligands on MSC themselves. In the present study, we used genetically engineered bone marrow-derived human MSC to study the function role of Jagged-1 and the Jagged-1 intracellular domain (JICD) with regard to the interaction with HSPC. We demonstrate that Jagged-1 in human MSC undergoes cleavage to produce an intracellular domain that translocates into the nucleus. JICD but not Jagged-1 overexpression was associated with an increased expression of stromal cell-derived factor-1. Short-term co-culture (7 days) of HSPC with JICD-overexpressing MSC, but not with Jagged-1-overexpressing MSC, led to increased proliferation of CD34(+) progenitors. In contrast, long-term co-culture of HSPC with Jagged-1-overexpressing MSC (up to 6 weeks) led to a significantly better support of cobblestone area-forming cells and long-term culture-initiating cells (LTC-ICs) compared with JICD-overexpressing MSC. Taken together, results of this study indicate that full-length Jagged-1 and JICD have differential effects on MSC and on their interaction with HSPC ex-vivo. JICD-overexpressing MSC induce proliferation of HSPCs in short-term culture at the expense of immature precursors (LTC-ICs), whereas Jagged-1 overexpressing MSC favor LTC-IC formation. 23926180 Protective role of the endothelial isoform of nitric oxide synthase in angiotensin II induced inflammatory responses in the kidney. In the present study, we examine the hypothesis that the nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays a protective role in the development of angiotensin II (AngII) induced hypertension and renal injury by minimizing oxidative stress and the inflammation induced by tumor necrosis factor-alpha (TNF-α). Systemic blood pressure (SBP) and renal injury responses to chronic infusions of AngII (via implanted mini-pumps) were evaluated for 2 weeks in wild type (WT) and in eNOS knockout mice (KO) co-treated with or without a superoxide (O2-) scavenger, tempol (400 mg/L in the drinking water) or a TNF-α receptor blocker, etanercept (5 mg/kg/day i.p.). In study 1, when AngII was given at a dose of 25 ng/min, it increased mean SBP in WT (Δ 36± 3 mmHg; n=7) and this effect was attenuated in mice pretreated with tempol (Δ 24±3 mmHg; n=6). In KO mice (n=9), this dose of AngII resulted in severe renal injury associated with high mortality. To avoid this high mortality in KO, study 2 was conducted with a lower dose of AngII (10 ng/min) that increased SBP slightly in WT (Δ 17 ± 7 mmHg; n=6) but exaggeratedly in KO (Δ 48 ± 12 mmHg, n=6) associated with severe renal injury. Co-treatment with either tempol (n=6) or etanercept (n=6) ameliorated the hypertensive as well as the renal injury responses in KO compared to WT. These data demonstrate a protective role for eNOS activity in preventing renal inflammatory injury and hypertension induced by chronic increases in AngII. 23883207 JOURNAL CLUB: CT Dose Optimization for Whole-Body PET/CT Examinations. OBJECTIVE. The objective of this study was to optimize CT protocols for whole-body PET/CT by reducing radiation dose while minimizing effects on image quality. MATERIALS AND METHODS. Before protocol optimization, a survey of 140 consecutive patients was conducted to establish the baseline dose from a whole-body PET/CT examination. Another sample of 100 patients was surveyed to evaluate the reduction of radiation dose after implementation of the new protocol. Effective dose from the CT component of the examination was estimated using dose-length product (DLP) values from reports generated by the scanner and anatomy-specific conversion factors. Twenty-six patients who underwent studies before and after the optimization were included in an analysis of image quality. All 26 patients had maintained the same weight between the examinations and were scanned in the same position using a similar technique except for the changes made for CT dose optimization. The studies were randomized and blinded for an experienced PET and CT reader who graded the imaging quality of anatomic structures. RESULTS. CT protocol optimization resulted in a 32% reduction of the mean CT radiation dose: The mean effective dose was reduced from 8.1 to 5.5 mSv. The blinded analysis of image quality showed no clinically significant degradation of the lower-dose studies. The only structures visualized statistically better on the higher-dose CT scans were the carotid arteries and the region of the posterior triangle. CONCLUSION. The results of this study showed that optimization of CT acquisition can effectively reduce radiation dose in a whole-body PET/CT examination without significantly sacrificing image quality. 23411341 Combined effect of starter culture and temperature on phenolic compounds during fermentation of Taggiasca black olives. The influence of two operative parameters on the fermentation process of table olives from Taggiasca cultivar were investigated. Laboratory scale fermentations were performed using Lactobacillus plantarum as the only starter and in combination with Saccharomyces cerevisiae at three different temperatures (23, 30 and 37°C). Control tests used for each trial were fermented only by indigenous microflora. pH and phenolic compounds were monitored in the brine and olive flesh during the fermentation. Higher temperatures (37°C) enhanced notably the release of phenolic compounds in the brine. High performance liquid chromatography (HPLC) analysis of brines evidenced the complete hydrolysis of oleuropein after 100 days of fermentation at 37°C for all treatments. The antioxidant power of the extracts was linearly correlated to their polyphenol contents. The results confirmed the efficiency of treatments compared with the control tests for debittering process of table black olives. Phenolic compounds in the brines can be then extracted and used in food, cosmetic and pharmaceutical industries. 23845806 Identification of novel immunoreactive proteins of Streptococcus zooepidemicus with potential as vaccine components. Streptococcus zooepidemicus is an important opportunistic pathogen of the equine respiratory and reproductive tracts. A normal tonsillar and mucosal commensal, it becomes invasive under conditions of stress such as virus infection, weaning, high temperature, prolonged transportation and failure of uterine involution. The aim of this study was to evaluate the vaccine potential of several surface exposed and secreted proteins of a novel mucoid clone of SzNC78 (ST-307) from an epizootic of equine respiratory disease. An expression gene library of SzNC78 was probed with a pool of convalescent equine sera from a clonal epizootic of respiratory disease. Eleven proteins were selected and purified based on putative function, surface expression or secretion and possible importance as virulence factors. Three additional proteins (AhpC, GAPDH and enolase) were also included based on their putative virulence function. Groups of ICR mice were vaccinated subcutaneously with each recombinant antigen and QuilA and later challenged with SzNC78. SzM protected 100% mice (P<0.01), followed by SzP and HylC which protected 90% mice (P=0.01). MAP, SzMAC and ScpC each protected 63% (P<0.05) mice. No control mouse survived challenge. SzM, MAP and ScpC in combination protected mice against a 10 fold higher dosage of SzNC78 than each antigen given separately. Protection against heterologous challenge (SzW60) was conferred by combinations of HylC+ScpC (60%; P=0.05), followed by HylC+MAP (50%; P=0.06) and ScpC+MAP (40%; P=0.1). Serum antibody responses of horses recently recovered from Sz respiratory infection were highest against ScpC, MAP and SzP. A combination of SKC and Sz115 stimulated no protection against challenge with SzW60. A subset of Sz proteins reactive with convalescent equine antibody have potential as components of experimental vaccines to aid in prevention of opportunistic Sz infections. 23594297 Silver nanoparticles enhance Pseudomonas aeruginosa PAO1 biofilm detachment. Abstract Objectives: Silver nanoparticles (AgNPs) with a size ranging from 7 to 70 nm were synthesized using the ascorbic acid-citrate seed-mediated growth approach at room temperature. Methods: The 8 nm silver particles were prepared using gallic acid in alkaline conditions and used as seed to prepare AgNPs. Results: The presence of ascorbic acid and citrate allows the regulation of size and size distribution of the nanoparticles. The increase in free silver ion-to-seed ratio (Ag(+)/Ag(0)) resulted in changes of particle shape from spherical to pseudo-spherical and minor cylindrical shape. Further, a repetitive seeding approach resulted in the formation of pseudo-spherical particles with higher polydispersity index and minor distributions of tetrahedral particles. Citrate-capped AgNPs were stable and did not agglomerate upon centrifugation. The effect of AgNPs on biofilm reduction was evaluated using static culture on 96-well microtiter plates. Results showed that AgNPs with the smallest average diameter were most effective in the reduction of Pseudomonas aeruginosa biofilm colonies, which accounted for 90% of removal. Conclusion: The biofilm removal activities of the nanoparticles were found to be concentration-independent particularly for the concentration within the range of 80-200 µg/mL. 23942251 Does hormone therapy affect blood pressure changes in the Diabetes Prevention Program? This study aims to examine whether blood pressure reductions differ by estrogen use among overweight glucose-intolerant women. We conducted a secondary analysis of Diabetes Prevention Program postmenopausal participants who used oral estrogen with or without progestogen at baseline and 1-year follow-up (n = 324) versus those who did not use oral estrogen with or without progestogen at either time point (n = 382). Changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) were examined by randomization arm (intensive lifestyle change [ILS], metformin 850 mg twice daily, or placebo). Associations between changes in blood pressure and changes in sex hormone-binding globulin, estradiol, testosterone, and dehydroepiandrosterone were also examined. Estrogen users and nonusers had similar prevalences of baseline hypertension (33% vs 34%, P = 0.82) and use of blood pressure medications at baseline (P = 0.25) and on follow-up (P = 0.10). Estrogen users and nonusers randomized to ILS had similar decreases in SBP (-3.3 vs -4.7 mm Hg, P = 0.45) and DBP (-3.1 vs -4.7 mm Hg, P = 0.16). Among estrogen users, women randomized to ILS had significant declines in SBP (P = 0.016) and DBP (P = 0.009) versus placebo. Among nonusers, women randomized to ILS had significant declines in DBP (P = 0.001) versus placebo, but declines in SBP were not significant (P = 0.11). Metformin was not associated with blood pressure reductions versus placebo regardless of estrogen therapy. Blood pressure changes were not associated with changes in sex hormones regardless of estrogen therapy. Among overweight women with dysglycemia, the magnitude of blood pressure reductions after ILS is unrelated to postmenopausal estrogen use. 23792094 Increasing the electron-transfer ability of Cyanidioschyzon merolae ferredoxin by a one-point mutation - A high resolution and Fe-SAD phasing crystal structure analysis of the Asp58Asn mutant. Cyanidioschyzon merolae (Cm) is a single cell red algae that grows in rather thermophilic (40-50°C) and acidic (pH 1-3) conditions. Ferredoxin (Fd) was purified from this algae and characterized as a plant-type [2Fe-2S] Fd by physicochemical techniques. A high resolution (0.97Å) three-dimensional structure of the CmFd D58N mutant molecule has been determined using the Fe-SAD phasing method to clarify the precise position of the Asn58 amide, as this substitution increases the electron-transfer ability relative to wild-type CmFd by a factor of 1.5. The crystal structure reveals an electro-positive surface surrounding Asn58 that may interact with ferredoxin NADP(+) reductase or cytochrome c. 23796272 Lewis Acid Catalyzed SN2-Type Ring Opening of N-Activated Aziridines with Electron-Rich Arenes/Heteroarenes. An efficient Lewis acid catalyzed SN2-type ring opening of substituted aziridines with electron-rich arenes/heteroarenes to provide substituted 2,2-diaryl/heteroarylethylamines in excellent yields and stereoselectivity (er, dr >99:1) is described. 23292453 Food use is affected by the experience of nest predation: implications for indirect predator effects on clutch size. Indirect predator effects on prey demography include any effect not attributable to direct killing and can be mediated by perceived predation risk. Though perceived predation risk clearly affects foraging, few studies have yet demonstrated that it can chronically alter food intake to an extent that affects demography. Recent studies have used stable isotopes to gauge such chronic effects. We previously reported an indirect predator effect on the size of subsequent clutches laid by song sparrows (Melospiza melodia). Females that experienced frequent experimental nest predation laid smaller clutches and were in poorer physiological condition compared to females not subject to nest predation. Every female was provided with unlimited supplemental food that had a distinctive (13)C signature. Here, we report that frequent nest predation females had lower blood δ(13)C values, suggesting that the experience of nest predation caused them to eat less supplemental food. Females that ate less food gained less fat and were in poorer physiological condition, consistent with the effect on food use contributing to the indirect predator effect on clutch size. Tissue δ(15)N values corroborated that clutch size was not likely constrained by endogenous resources. Finally, we report that the process of egg production evidently affects egg δ(13)C values, and this may mask the source of nutrients to eggs. Our results indicate that perceived predation risk may impose food limitation on prey even where food is unlimited and such predator-induced food limitation ought to be added to direct killing when considering the total effect of predators on prey numbers. 23857473 CAPE promotes TRAIL-induced apoptosis through the upregulation of TRAIL receptors via activation of p38 and suppression of JNK in SK-Hep1 hepatocellular carcinoma cells. Caffeic acid phenethyl ester (CAPE), a phenolic compound derived from honeybee propolis, has been reported to possess anticancer activities in several types of malignant cells. Here, we show that treatment with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in combination with CAPE significantly sensitized SK-Hep1 cells to TRAIL-induced apoptosis. The sensitization to TRAIL was accompanied by the activation of extrinsic and intrinsic apoptotic pathways, leading to the activation of caspases, mitochondrial disruption and PARP cleavage. Moreover, TRAIL receptors, such as DR4 and DR5 were significantly upregulated by CAPE treatment, and both DR4/Fc and DR5/Fc chimera markedly abrogated apoptosis induced by CAPE and TRAIL, demonstrating the critical role of these death receptors in combination-induced apoptosis. The effect of CAPE on mitogen-activated protein kinases (MAPKs) was further examined, where CAPE treatment resulted in the activation of p38 and the inhibition of JNK, without affecting levels of phospho-ERK. Our results showed that p38 and JNK exhibited the opposite role in SK-Hep1 cells. The inhibition of p38, using SB203580, blocked the CAPE-induced expression of death receptors and attenuated the combination‑induced apoptosis, suggesting the pro-apoptotic role of p38. In contrast, JNK-specific inhibition, by SP600125, triggered upregulation of DR4 and DR5, and sensitized SK-Hep1 cells to TRAIL, indicating that the CAPE-induced suppression of JNK may contribute to the sensitizing effect of CAPE through the upregulation of death receptors. Taken together, these results indicate that CAPE potentiated TRAIL-induced apoptosis in SK-Hep1 cells, through upregulation of TRAIL receptors via modulation of p38 and JNK signaling pathways. 23376996 4-Nerolidylcatechol and its synthetic analogues: Antioxidant activity and toxicity evaluation. 4-Nerolidylcatechol (1) is a secondary metabolite of plants and is described as a promising anti-inflammatory, antimalarial, antiulcerogenic, analgesic and cytotoxic compound possibly due to its antioxidant profile. In this study, we evaluated the pharmacologic activity and the antioxidant and toxicological profiles of compound (1) and its synthetic analogues (2-6). The synthetic analogues were designed from the lead compound, (1), using a molecular-simplification strategy. Compound 5 showed, by 1,1-diphenyl-2-picrylhydrazyl (DPPH) and β-carotene systems, similar antioxidant activity when compared to compound (1). The oxidative stress in erythrocyte membrane demonstrated the highly protective effect of compounds (4), (5) and (6) and high antioxidant/pro-oxidant activity in relation to the concentrations of compounds (1) and (3). Compounds (2), (4), (5) and (6) were haemobiocompatible. All compounds (1-6) showed cytotoxic effects in 3T3 cells, but compounds (2) and (6) were highly cytotoxic in this lineage when compared to compound (1). Compound (5) had a lower myelosuppressive effect in haematopoietic progenitor cells compared to (1). Both compounds, (1) and (5), showed low genotoxic effects in vitro, on human lymphocyte cells. In addition, these compounds also showed low-toxicity in vivo as defined a LD50 > 2000 mg/kg. In this assay, we did not observe death in the animals exposed to treatment with (1) and (5) compound. In conclusion, the structural design of the analogues as validated once compound (5) was found to have an antioxidant profile that was as potent as the lead compound (1). In addition, considering the safety profile, these compounds are promising as preventive and/or therapeutic agents against oxidative damage. 23841915 Disruption of focal adhesion kinase and p53 interaction with small molecule compound R2 reactivated p53 and blocked tumor growth. Focal Adhesion Kinase (FAK) is a 125 kDa non-receptor kinase that plays a major role in cancer cell survival and metastasis. We performed computer modeling of the p53 peptide containing the site of interaction with FAK, predicted the peptide structure and docked it into the three-dimensional structure of the N-terminal domain of FAK involved in the complex with p53. We screened small molecule compounds that targeted the site of the FAK-p53 interaction and identified compounds (called Roslins, or R compounds) docked in silico to this site. By different assays in isogenic HCT116p53+/+ and HCT116 p53-/- cells we identified a small molecule compound called Roslin 2 (R2) that bound FAK, disrupted the binding of FAK and p53 and decreased cancer cell viability and clonogenicity in a p53-dependent manner. In addition, dual-luciferase assays demonstrated that the R2 compound increased p53 transcriptional activity that was inhibited by FAK using p21, Mdm-2, and Bax-promoter targets. R2 also caused increased expression of p53 targets: p21, Mdm-2 and Bax proteins. Furthermore, R2 significantly decreased tumor growth, disrupted the complex of FAK and p53, and up-regulated p21 in HCT116 p53+/+ but not in HCT116 p53-/- xenografts in vivo. In addition, R2 sensitized HCT116p53+/+ cells to doxorubicin and 5-fluorouracil. Thus, disruption of the FAK and p53 interaction with a novel small molecule reactivated p53 in cancer cells in vitro and in vivo and can be effectively used for development of FAK-p53 targeted cancer therapy approaches. 23668802 Expression of Toll-like receptor-3 is enhanced in active inflammatory bowel disease and mediates the excessive release of lipocalin 2. Anti-microbial peptides might influence the pathogenesis and course of inflammatory bowel disease (IBD). We sought to clarify the role of the anti-microbial glycoprotein lipocalin 2 (LCN2) in the colon by determining its localization and regulation in IBD. Following a microarray gene expression study of colonic biopsies from a large IBD population (n = 133), LCN2 was localized using immunohistochemistry and in-situ hybridization. Moreover, we examined the regulation of LCN2 in HT-29 cells with a panel of pattern recognition receptors (PRRs) and sought evidence by immunohistochemistry that the most relevant PRR, the Toll-like receptor (TLR)-3, was indeed expressed in colonic epithelium in IBD. LCN2 was among the 10 most up-regulated genes in both active ulcerative colitis (UCa) and active Crohn's disease (CDa) versus healthy controls. LCN2 protein was found in both epithelial cells and infiltrating neutrophils, while mRNA synthesis was located solely to epithelial cells, indicating that de-novo synthesis and thus regulation of LCN2 as measured in the gene expression analysis takes place in the mucosal epithelial cells. LCN2 is a putative biomarker in faeces for intestinal inflammation, different from calprotectin due to its epithelial site of synthesis. LCN2 release from the colonic epithelial cell line HT-29 was enhanced by both interleukin (IL)-1β and the TLR-3 ligand poly(I:C), and TLR-3 was shown to be expressed constitutively in colonic epithelial cells and markedly increased during inflammation. 23746532 Assessing liver dysfunction in cirrhosis: Role of the model for end-stage liver disease and its derived systems. The model for end-stage liver disease (MELD) has replaced the role of the Child-Turcotte-Pugh system as a more commonly used system in evaluating the severity of liver dysfunction in patients with chronic liver disease, owing to its superior ability to predict survival. The United Network of Organ Sharing (UNOS) in the USA has used the MELD system for prioritizing donor grafts in advanced cirrhotic patients awaiting liver transplantation since 2002. Serum sodium level is another important prognostic predictor in cirrhosis. Consequently, by incorporating serum sodium into the original MELD, the MELD-Na, MELDNa, the MELD-to-sodium ratio (MESO) index, and the ReFit MELDNa were proposed in an attempt to improve the predictive ability of the original MELD. Nevertheless, there are some limitations of the MELD-based systems that need to be refined. The MELD-based systems merely use laboratory data as parameters for the equation, therefore, any lack in unification and standardization of laboratory methods will result in inconsistent data that affect the prioritization of liver transplantation. Furthermore, the MELD system includes creatinine as a parameter, and serum creatinine level may represent different degrees of renal dysfunction in men and women. Therefore, these limitations may compromise the fair process of organ allocation for female cirrhotic patients. Currently, the application of the MELD system has been extended to tumor staging of hepatocellular carcinoma. Several studies have replaced the Child-Turcotte-Pugh system with the MELD as a parameter, indicating that the use of different criteria of liver dysfunction in cancer staging may enhance prognostic accuracy. Although the outcome data of the modified staging systems need to be confirmed, the concept of using the MELD as a reference system for evaluating the severity of liver dysfunction has globally become an important issue. 23835591 Patient Injuries from Anesthesia Gas Delivery Equipment: A Closed Claims Update. Improvements in anesthesia gas delivery equipment and provider training may increase patient safety. The authors analyzed patient injuries related to gas delivery equipment claims from the American Society of Anesthesiologists Closed Claims Project database over the decades from 1970s to the 2000s. After the Institutional Review Board approval, the authors reviewed the Closed Claims Project database of 9,806 total claims. Inclusion criteria were general anesthesia for surgical or obstetric anesthesia care (n = 6,022). Anesthesia gas delivery equipment was defined as any device used to convey gas to or from (but not involving) the airway management device. Claims related to anesthesia gas delivery equipment were compared between time periods by chi-square test, Fisher exact test, and Mann-Whitney U test. Anesthesia gas delivery claims decreased over the decades (P < 0.001) to 1% of claims in the 2000s. Outcomes in claims from 1990 to 2011 (n = 40) were less severe, with a greater proportion of awareness (n = 9, 23%; P = 0.003) and pneumothorax (n = 7, 18%; P = 0.047). Severe injuries (death/permanent brain damage) occurred in supplemental oxygen supply events outside the operating room, breathing circuit events, or ventilator mishaps. The majority (85%) of claims involved provider error with (n = 7) or without (n = 27) equipment failure. Thirty-five percent of claims were judged as preventable by preanesthesia machine check. Gas delivery equipment claims in the Closed Claims Project database decreased in 1990-2011 compared with earlier decades. Provider error contributed to severe injury, especially with inadequate alarms, improvised oxygen delivery systems, and misdiagnosis or treatment of breathing circuit events. 23862578 Are the Aging Male's Symptoms (AMS) scale and the Androgen Deficiency in the Aging Male (ADAM) questionnaire suitable for the screening of late-onset hypogonadism in aging Chinese men? Abstract The Aging Male's Symptoms (AMS) scale and the Androgen Deficiency in the Aging Male (ADAM) questionnaire have been widely used for screening men suspected of late-onset hypogonadism (LOH). We evaluated the consistency of the two questionnaires with sex hormone levels. A total of 985 men completed the two questionnaires, as well as an analysis of the serum levels of total testosterone (TT), bioavailable testosterone (BT), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), prolactin (PRL) and sex hormone-binding globulin (SHBG). No correlation was observed between any hormone level and the psychological or somatic section of the AMS score, whereas the sexual section was correlated with the levels of FT, LH, FSH, SHBG and BT. Significant correlations were observed between the result of the two questionnaires and these hormone levels. When LOH was defined as TT < 300 ng/dl and FT < 5 ng/dl, the sensitivity and specificity of the AMS scale were 54.0% and 41.2% compared with 78.7% and 14.8% for the ADAM questionnaire. Several sex hormone levels correlated with the two questionnaires, but neither of these questionnaires had sufficient sensitivity and specificity. It is necessary to provide a new questionnaire applicable to the Chinese population to screening LOH. 23869387 Employing bifunctional enzymes for enhanced extraction of bioactives from plants: flavonoids as an example. A cost-effective and environmentally friendly approach was developed to improve the extraction of active ingredients from plants, in which a bifunctional enzyme was employed for not only facilitating cell wall degradation but also increasing the bioactivity of target compounds in the extract. In the aqueous extraction of flavonoids from Glycyrrhizae radix , Trichoderma viride cellulase, a commercial cell-wall-degrading enzyme, was found to efficiently deglycosylate liquiritin and isoliquiritin, which are of high content but low bioactivity, into their aglycones that have much higher physiological activities for dietary and medicinal uses. Under optimized conditions, the extraction yield of liquiritigenin and isoliquiritigenin aglycones reached 4.23 and 0.39 mg/g of dry weight (dw) with 6.51- and 3.55-fold increases, respectively. The same approach was expanded to the extraction of flavonoids from Scutellariae radix using Penicillium decumbens naringinase, where enhanced production of more bioactive bacalein and wogonin was achieved via enzymatic deglycosylation of bacalin and wogonoside. 23780310 Evidence for the utricular origin of the vestibular short-latency-evoked potential (VsEP) to bone-conducted vibration in guinea pig. Previous studies have shown that the vestibular short-latency-evoked potential (VsEP) in response to the brief head acceleration stimulus is a compound action potential of neurons innervating the otolith organs. However, due to the lack of direct evidence, it is currently unclear whether the VsEP is primarily generated by the activity of utricular or saccular afferent neurons, or some mixture of the two. Here, we investigated the origin of the VsEP evoked by brief bone-conducted vibration pulses in guinea pigs, using selective destruction of the cochlea, semicircular canals (SCCs), saccule, or utricle, along with neural blockade with tetrodotoxin (TTX) application, and mechanical displacements of the surgically exposed utricular macula. To access each end organ, either a dorsal or a ventral surgical approach was used. TTX application abolished the VsEP, supporting the neurogenic origin of the response. Selective cochlear, SCCs, or saccular destruction had no significant effect on VsEP amplitude, whereas utricular destruction abolished the VsEP completely. Displacement of the utricular membrane changed the VsEP amplitude in a non-monotonic fashion. These results suggest that the VsEP evoked by BCV in guinea pigs represents almost entirely a utricular response. Furthermore, it suggests that displacements of the utricular macula may alter its response to bone-conduction stimuli. 23665351 Pharmacodynamic study of the 7,8-dihydroxy-4-methylcoumarin-induced selective cytotoxicity toward U-937 leukemic cells versus mature monocytes: cytoplasmic p21(Cip1/WAF1) as resistance factor. The development of tumor-selective drugs with low systemic toxicity has always been a major challenge in cancer treatment. Our group previously identified the 7,8-dihydroxy-4-methylcoumarin (DHMC) as a potential chemotherapeutic agent due to its potent, selective anti-proliferative and apoptosis-inducing effects on several cancer cell lines over peripheral blood mononuclear cells. However, there are still no published reports that can explain such selectivity of action. Herein, we addressed this question by using the U-937 promonocytic leukemia cell line, which can be forced to differentiate into a monocyte-like phenotype in vitro. U-937 cells differentiation is dependent on the nuclear expression of p21(Cip1/WAF1), a protein that is absent in immature U-937 cells but present in both the nucleus and the cytoplasm of normal DHMC-resistant monocytes. Considering that induction of differentiation rendered U-937 cells resistant to DHMC, we evaluated the possible causal role of cytoplasmic p21(Cip1/WAF1) in the onset of such resistance by employing U-937 cells stably transfected with a ZnCl2-inducible p21(Cip1/WAF1) variant lacking the nuclear localization signal (U-937/CB6-ΔNLS-p21 cells). Expression of cytoplasmic p21(Cip1/WAF1) did not induce differentiation of the cells but turned them resistant to DHMC through inhibition of JNK, a crucial mediator of DHMC-induced apoptosis in U-937 cells. Sub-acute toxicity evaluation of DHMC in Balb/c mice indicated that DHMC administered intraperitoneally at doses up to 100mg/kg induced no systemic damage. Collectively, our results explain for the first time the selective cytotoxicity of DHMC for tumor cells over normal monocytes, and encourage further in vivo studies on this compound as potential anti-leukemic agent. 23639362 Cyperi Rhizoma inhibits the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced reduction in nigrostriatal dopaminergenic neurons in estrogen-deprived mice. ETHNOPHARMACOLOGICAL RELEVANCE: Cyperi Rhizoma has commonly been used for the treatment of gynecological and neuropsychiatric disorders in traditional medicine. The aim of this study was to evaluate the estrogenic properties and neuroprotective effects of Cyperi Rhizoma under estrogen-deprived condition in female mice. MATERIALS AND METHODS: To determine the estrogen-like effect of Cyperi Rhizoma extract (CRE), we measured luciferase expression after transfection of a promoter construct containing an estrogen response element (ERE) and treatment of CRE. To evaluate the neuroprotective effect of CRE, we measured striatal dopamine, movement ability, tyrosine hydroxylase (TH) immunoreactivity, and apoptosis-related protein expression levels after treatment of CRE either with or without 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in ovariectomized female mice. RESULTS: CRE significantly induced the luciferase expression driven by an ERE in PC12 cells, a dopaminergic cell line, in a dose-dependent manner. In mice, MPTP significantly decreased the levels of dopamine in the striatum and behavior performance; in contrast, both CRE and 17β-estradiol benzoate (EB) recovered these parameters to normal levels. CRE and EB treatment also recovered TH immunopositive fibers and cells, respectively, from MPTP toxicity. Additionally, MPTP significantly down-regulated Bcl-2 expression in the mitochondria of dopaminergic cells in the SN, followed by an increase in Bax expression, cytochrome C translocation to the cytosol, andcleaved-caspase-3 expression, whereas these were inhibited by CRE or EB treatment. CONCLUSIONS: These findings provide the first evidence that CRE has estrogen-like and neuroprotective effects on dopaminergic neurons in estrogen-deprived mice treated with MPTP-toxin. 23281267 Proteome profiling of peripheral mononuclear cells from human blood. Peripheral blood mononuclear cells (MNCs) are accessible through blood collection and represent a useful source for investigations on disease mechanisms and treatment response. Aiming to build a reference proteome database, we generated three proteome data sets from MNCs using a combination of SDS-PAGE and nanoflow LC-MS. Experiments were performed in triplicates and 514 unique proteins were identified by at least two non-redundant peptides with 95% confidence for all replicates. Identified proteins are associated with a range of dermatologic, inflammatory and neurological conditions as well as molecular processes, such as free radical scavenging and cellular growth and proliferation. Mapping the MNC proteome provides a valuable resource for studies on disease pathogenesis and the identification of therapeutic targets. 23880343 Substrate binding to a GH131 β-glucanase catalytic domain from Podospora anserina. β-Glucanases have been utilized widely in industry to treat various carbohydrate-containing materials. Recently, the Podospora anserina β-glucanase 131A (PaGluc131A) was identified and classified to a new glycoside hydrolases GH131 family. It shows exo-β-1,3/exo-β-1,6 and endo-β-1,4 glucanase activities with a broad substrate specificity for laminarin, curdlan, pachyman, lichenan, pustulan, and cellulosic derivatives. Here we report the crystal structures of the PaGluc131A catalytic domain with or without ligand (cellotriose) at 1.8Å resolution. The cellotriose was clearly observed to occupy the +1 to +3 subsites in substrate binding cleft. The broadened substrate binding groove may explain the diverse substrate specificity. Based on our crystal structures, the GH131 family enzyme is likely to carry out the hydrolysis through an inverting catalytic mechanism, in which E99 and E139 are supposed to serve as the general base and general acid. 23618801 Special article: sites and artifacts related to horace wells in hartford, connecticut. Horace Wells, a contender for recognition as the discoverer of anesthesia, is celebrated in the town where he conducted most of his work, Hartford, CT. His only descendant was his son, Charles Thomas Wells (1839-1909), an influential and successful business executive at Aetna Insurance Company. He was a man of considerable influence, and he worked tirelessly with city officials and the Connecticut Dental Association in celebrating the 50th anniversary of his father's contribution to medicine. This discovery is unique because events and individuals in 1 country, the United States, contributed entirely to the birth of a medical specialty. Sites in Jefferson, GA; Hartford, CT; and Boston, MA and their environs celebrate this most precious contribution to modern medicine, especially since the introduction of safe anesthesia permitted the development of surgical specialties and obstetrics. We trace the history and relationship between Horace Wells and several sites and artifacts in Hartford, CT. These sites span the most important, distinctive, and attractive parts of the city: Bushnell Park, Trinity College, Cedar Hill Cemetery, the Athenaeum, and the Connecticut Historical Society. 23756454 Development and validation of an intraoperative predictive model for unplanned postoperative intensive care. The allocation of intensive care unit (ICU) beds for postoperative patients is a challenging daily task that could be assisted by the real-time detection of ICU needs. The goal of this study was to develop and validate an intraoperative predictive model for unplanned postoperative ICU use. With the use of anesthesia information management system, postanesthesia care unit, and scheduling data, a data set was derived from adult in-patient noncardiac surgeries. Unplanned ICU admissions were identified (4,847 of 71,996; 6.7%), and a logistic regression model was developed for predicting unplanned ICU admission. The model performance was tested using bootstrap validation and compared with the Surgical Apgar Score using area under the curve for the receiver operating characteristic. The logistic regression model included 16 variables: age, American Society of Anesthesiologists physical status, emergency case, surgical service, and 12 intraoperative variables. The area under the curve was 0.905 (95% CI, 0.900-0.909). The bootstrap validation model area under the curves were 0.513 at booking, 0.688 at 3 h before case end, 0.738 at 2 h, 0.791 at 1 h, and 0.809 at case end. The Surgical Apgar Score area under the curve was 0.692. Unplanned ICU admissions had more ICU-free days than planned ICU admissions (5 vs. 4; P < 0.001) and similar mortality (5.6 vs. 6.0%; P = 0.248). The authors have developed and internally validated an intraoperative predictive model for unplanned postoperative ICU use. Incorporation of this model into a real-time data sniffer may improve the process of allocating ICU beds for postoperative patients. 23963777 Olanzapine Solvates. Olanzapine was crystallized from 12 organic solvents alone or in mixture, by cooling in the freezer, by slow evaporation of the solvent, or by suspending olanzapine powder for some time in the solvent. All the samples thus obtained were examined by thermal analysis (differential scanning calorimetry-DSC and thermogravimetry-TG) to certify the formation of a solvate, the presence of polymorph (form 1 or 2) in the desolvated olanzapine, comparing the different profile of the thermograms, and to calculate the stoichiometry of the possible solvate. According to the DSC thermogram, the solvents can be divided into four classes: those that do not form solvates and leave olanzapine form 1 (ethyl acetate, toluene, diethyl ether, and acetone); those that form solvate and leave form 1 of olanzapine after desolvation (methanol, 1- and 2-propanol); those that after desolvation of the solvate show a polymorph transition in the thermogram indicating the presence of form 2 of olanzapine (ethanol); other solvents (tetrahydrofuran, chloroform, acetonitrile) give solvate thermograms, where this last thermal trace is only poorly evident. With few exceptions, each solvent forms solvate both when pure and in mixture (10%, v/v, in ethyl acetate). Methanol monosolvate displays complex thermogram and thermogravimetric desolvation profiles, depending on the crystallization experimental conditions, used to prepare the solvates. Dichloromethane solvate was found by X-ray diffraction analysis to be amorphous and, on heating during DSC analysis, allowed the crystallization of both form 1 and 2, with different weight ratio, according to the experimental conditions of the solvate preparation. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci. 23171198 Quantitative autistic traits ascertained in a national survey of 22 529 Japanese schoolchildren. Recent epidemiologic studies worldwide have documented a rise in prevalence rates for autism spectrum disorders (ASD). Broadening of diagnostic criteria for ASD may be a major contributor to the rise in prevalence, particularly if superimposed on an underlying continuous distribution of autistic traits. This study sought to determine the nature of the population distribution of autistic traits using a quantitative trait measure in a large national population sample of children. The Japanese version of the Social Responsiveness Scale (SRS) was completed by parents on a nationally representative sample of 22 529 children, age 6-15. Social Responsiveness Scale scores exhibited a skewed normal distribution in the Japanese population with a single-factor structure and no significant relation to IQ within the normal intellectual range. There was no evidence of a natural 'cutoff' that would differentiate populations of categorically affected children from unaffected children. This study provides evidence of the continuous nature of autistic symptoms measured by the SRS, a validated quantitative trait measure. The findings reveal how paradigms for diagnosis that rest on arbitrarily imposed categorical cutoffs can result in substantial variation in prevalence estimation, especially when measurements used for case assignment are not standardized for a given population. 23925506 Impact evaluation of a quality improvement intervention on maternal and child health outcomes in Northern Ghana: early assessment of a national scale-up project. /st>To evaluate the influence of the early phase of Project Fives Alive!, a national child survival improvement project, on key maternal and child health outcomes. /st>The evaluation used multivariable interrupted time series analyses to determine whether change categories tested were associated with improvements in the outcomes of interest. /st>The evaluation used program and outcome data from interventions focused on health-care staff in 27 facilities. /st>Northern Ghana. /st>The project uses a quality improvement (QI) approach whereby process failures are identified by health staff and process changes are tested in the health facilities and corresponding communities to address those failures. /st>The maternal health outcomes were early antenatal care attendance and skilled delivery, and the child health outcomes were underweight infants attending child wellness clinics, facility-level neonatal mortality and facility-level infant mortality. /st>Postnatal care changes for the first 1-2 days of life (β= 0.10, P = 0.07) and the first 6-7 days of life (β = 0.10, P = 0.07) were associated with a higher rate of visits by underweight infants to child wellness clinics. There was an association between the early pregnancy identification change category with increased skilled delivery (β = 1.36 P = 0.07). In addition, a greater number of change categories tested was associated with increased skilled delivery (β = 0.05, P = 0.01). /st>The QI approach of testing and implementing simple and low cost locally inspired changes has the potential to lead to improved health outcomes at scale both in Ghana and other low- and middle-income countries. 23688800 Credence quality coordination and consumers' willingness-to-pay for certified halal labelled meat. This paper reports on halal credence quality coordination and Muslim consumers' willingness to buy and pay for certified halal labelled meat at the supermarket and the Islamic butcher. Cross-sectional data were collected through a survey with 202 Muslim consumers in Belgium. Findings indicate that more acculturated and female consumers are more in favour of purchasing certified halal labelled meat in a supermarket. Important conditions are that supermarkets can provide a guarantee of separating halal from non-halal meat and of the organisation of adequate verification and control. Results further show that more Muslim consumers are willing to pay a price premium (of 13% on average) for halal labelled meat at the Islamic butcher shop than at the supermarket. The higher the importance attached to a certified halal label and the more distrust in the actual halal meat status, the higher the likelihood that a Muslim consumer is willing to pay a higher price for certified halal labelled meat at the Islamic butcher shop. Gender and generation determine the actual premium Muslim consumers are willing to pay. 22285449 Axon degeneration in Parkinson's disease. Parkinson's disease (PD) is the most common neurodegenerative disease of the basal ganglia. Like other adult-onset neurodegenerative disorders, it is without a treatment that forestalls its chronic progression. Efforts to develop disease-modifying therapies to date have largely focused on the prevention of degeneration of the neuron soma, with the tacit assumption that such approaches will forestall axon degeneration as well. We herein propose that future efforts to develop neuroprotection for PD may benefit from a shift in focus to the distinct mechanisms that underlie axon degeneration. We review evidence from human post-mortem studies, functional neuroimaging, genetic causes of the disease and neurotoxin models that axon degeneration may be the earliest feature of the disease, and it may therefore be the most appropriate target for early intervention. In addition, we present evidence that the molecular mechanisms of degeneration of axons are separate and distinct from those of neuron soma. Progress is being made in understanding these mechanisms, and they provide possible new targets for therapeutic intervention. We also suggest that the potential for axon re-growth in the adult central nervous system has perhaps been underestimated, and it offers new avenues for neurorestoration. In conclusion, we propose that a new focus on the neurobiology of axons, their molecular pathways of degeneration and growth, will offer novel opportunities for neuroprotection and restoration in the treatment of PD and other neurodegenerative diseases. 23933950 An exploration of the perceptions and experiences of living with chronic Anorexia Nervosa (cAN) whilst an Inpatient on an Eating Disorders Unit (EDU): An Interpretative Phenomenological Analysis (IPA) Study. Chronic anorexia nervosa (cAN) is a challenging presentation for the clinician. Motivation to recover is low, and outcomes are often poor. Within this study. six participants, currently in treatment, were interviewed. These interview transcripts were analysed using Interpretative Phenomenological Analysis. The results highlighted five superordinate themes resulted from the analysis and these referred to the following points: (1) 'making sense of AN', (2) 'experience of treatment/treatment', (3) 'interpersonal relationships', (4) 'battling with anorexia' and (5) 'staff pessimism in the treatment of cAN'. These results highlighted how the self is entwined with anorexia nervosa and thus making it incredibly difficult to perceive a life without cAN. 23907581 Lys63-linked polyubiquitination of BRAF at lysine 578 is required for BRAF-mediated signaling. The RAF kinase family is essential in mediating signal transduction from RAS to ERK. BRAF constitutively active mutations correlate with human cancer development. However, the precise molecular regulation of BRAF activation is not fully understood. Here we report that BRAF is modified by Lys63-linked polyubiquitination at lysine 578 within its kinase domain once it is activated by gain of constitutively active mutation or epidermal growth factor (EGF) stimulation. Substitution of BRAF lysine 578 with arginine (K578R) inhibited BRAF-mediated ERK activation. Furthermore, ectopic expression of BRAF K578R mutant inhibited anchorage-independent colony formation of MCF7 breast cancer cell line. Our studies have identified a previously unrecognized regulatory role of Lys63-linked polyubiquitination in BRAF-mediated normal and oncogenic signalings. 23804030 Asymmetrically substituted 5,5'-bistriazoles - nitrogen-rich materials with various energetic functionalities. In this contribution the synthesis and full structural and spectroscopic characterization of three asymmetrically substituted bis-1,2,4-triazoles, along with different energetic moieties like amino, nitro, nitrimino and azido moieties, is presented. Additionally, selected nitrogen-rich ionic derivatives have been prepared and characterized. This comparative study on the influence of these energetic moieties on structural and energetic properties constitutes a complete characterization including IR, Raman and multinuclear NMR spectroscopy. Single crystal X-ray crystallographic measurements were performed and provide insight into structural characteristics as well as inter- and intramolecular interactions. The standard enthalpies of formation were calculated for all compounds at the CBS-4M level of theory, revealing highly positive heats of formation for all compounds. The detonation parameters were calculated using the EXPLO5 program and compared to the common secondary explosive RDX as well as recently published symmetric bistriazoles. As expected, the measured sensitivities to mechanical stimuli and decomposition temperatures strongly depend on the energetic moiety of the triazole ring. All compounds were characterized in terms of sensitivities (impact, friction, electrostatic) and thermal stabilities, the ionic derivatives were found to be thermally stable, insensitive compounds. 23949309 Thiolated 2-methacryloyloxyethyl phosphorylcholine for an antifouling biosensor platform. We developed a new building block for a protein- and cell-repellant self-assembled monolayer (SAM) from 2-methacryloyloxyethyl phosphorylcholine (MPC) via a simple Michael-type addition to one mercapto group in alkanedithiol. The thiolated MPC can enable functionalization of a noble metal electrode to minimize noise signal in biosensing. 23787405 Bioavailability of iron in geophagic earths and clay minerals, and their effect on dietary iron absorption using an in vitro digestion/Caco-2 cell model. Geophagy, the deliberate consumption of earth, is strongly associated with iron (Fe) deficiency. It has been proposed that geophagy may be practiced as a means to improve Fe status by increasing Fe intakes and, conversely, that geophagy may cause Fe deficiency by inhibiting Fe absorption. We tested these hypotheses by measuring Fe concentration and relative bioavailable Fe content of 12 samples of geophagic earth and 4 samples of pure clay minerals. Further, we assessed the impact of these samples on the bioavailability of Fe from an Fe-rich test meal (cooked white beans, WB). Fe concentrations were measured with inductively coupled plasma atomic emission spectroscopy. Fe bioavailability was determined using an in vitro digestion/Caco-2 cell model in which ferritin formation was used as an index of Fe bioavailability. Geophagic earth and clay mineral samples were evaluated with this model, both alone and in combination with WB (1 : 16 ratio, sample : WB). Median Fe concentration of the geophagic earth was 3485 (IQR 2462, 14 571) μg g(-1) and mean Fe concentration in the clay minerals was 2791 (±1782) μg g(-1). All specimens had Fe concentrations significantly higher (p ≤ 0.005) than the Fe concentration of WB (77 μg g(-1)). Ferritin formation (i.e. Fe uptake) in cells exposed to geophagic earths and clay minerals was significantly lower than in cells exposed to WB (p ≤ 0.05) and Fe uptake responses of 11 of the 16 samples were not significantly different from the blank, indicating no bioavailable Fe. When samples were combined with WB, 5 of 16 had mean ferritin levels that were significantly lower (p ≤ 0.05, one tail) than the WB alone, indicating that the samples inhibited Fe uptake from the WB. None of the ferritin responses of cells exposed to both WB and earth/clay were significantly higher than WB alone. Thus, although geophagic earths and mineral clays are high in total Fe, very little of this Fe is bioavailable. Further, some geophagic earth and clay mineral samples inhibit Fe absorption from foods. In vivo research is warranted to confirm these observations and to determine if geophagic earth samples can be a source of Fe and/or inhibit Fe absorption. 23851354 Pediatric oncology survivorship: conveying risks and communicating information at the right time for the individual. To summarize and discuss recent research (2011-2013) examining the communication needs of childhood cancer survivors with respect to long-term health risks and considering the developmental needs of children, adolescents and young adults. Survivors' levels of awareness of ongoing health risks are low, indicating that clinical strategies for communicating risks and empowering young people as active partners in their own healthcare are lacking. Research examining the information needs of very young survivors is sparse. Adolescent and young adults may be particularly vulnerable given their lack of health-risk knowledge combined with expected developmental risk-taking behaviors. Strategies to manage individual information preferences of survivors are required, along with strategies to manage the triadic (child, parent, health professional) nature of communications. Internet technologies offer an important mechanism for communication of health risks to survivors, families and primary healthcare providers. International efforts must continue to articulate systematic yet flexible approaches to communication with children, adolescents and young adults that can be applied across the cancer treatment continuum and into surveillance and long-term survivorship. Information and communication needs of this population are complex and reliance on age as a proxy for capacity to participate in healthcare communication is inadequate. 23751604 Protein C and protein S deficiency presenting as Budd-Chiari syndrome. Protein C and S are vitamin K-dependent natural anticoagulants. They play a major role in hemostasis by degrading the activated factor V and factor VIII. Deficiencies of protein C and protein S are associated with increased risk of thrombotic events. The combined occurrence of protein C and S deficiency has been rarely reported. We report a 6-year-old boy with Budd-Chiari syndrome due to combined protein C and protein S deficiency. He was managed with low molecular weight heparin and discharged on long-term warfarin therapy. 23942176 A narrative review of recent progress in understanding the relationship between tuberculosis and protein energy malnutrition. Protein energy malnutrition (PEM) and tuberculosis (TB) are the major public health issues, particularly in the developing country setting. Malnutrition is an underlying cause of many deaths and when left untreated devastates normal physical and cognitive development. TB continues to gather momentum as a serious infectious killer. They have both rightly been highlighted as important global health issues by their inclusion in the Millennium Development Goals. But what is known of their relationship with one another? It is historically accepted that PEM and TB have a synergistic relationship adversely having an impact on one another. However, researchers have sought to apply this understanding in an examination of the relationship between TB and PEM with often inconclusive results. This narrative review of recently published research and current knowledge may help delineate the association between PEM and TB mortality. Such results will assist future research in this important area of health-an area lacking evidence-based guidance.European Journal of Clinical Nutrition advance online publication, 14 August 2013; doi:10.1038/ejcn.2013.143. 23352843 Perfluorocarbon-loaded lipid nanocapsules as oxygen sensors for tumor tissue pO(2) assessment. The assessment of tumor oxygenation is a crucial factor in cancer therapy and may be carried out using fluorine MRI once fluorine probes have been distributed within the tumor. However, the deposit of those highly fluorinated compounds often jeopardizes anatomical image quality and requires emulsification of the probes. Due to the high density and the high lipophilicity of perfluorocarbons, nanoemulsion of these molecules usually requires high-energy processes. In the present work, we discuss the synthesis and the physico-chemical characterization of perfluorocarbon nanocapsules using a low-energy phase-inversion process. The nanocapsules were tested on a mouse tumor brain model to assess oxygenation. 23844056 Shear stress regulates late EPC differentiation via mechanosensitive molecule-mediated cytoskeletal rearrangement. Previous studies have demonstrated that endothelial progenitor cells (EPCs), in particular late EPCs, play important roles in endothelial maintenance and repair. Recent evidence has revealed shear stress as a key regulator for EPC differentiation. However, the underlying mechanisms regulating the shear stress-induced EPC differentiation have not been understood completely. The present study was undertaken to further investigate the effects of shear stress on the late EPC differentiation, and to elucidate the signal mechanism involved. In vitro and in vivo assays revealed that cytoskeletal remodeling was involved in the shear stress-upregulated expression of endothelial markers vWF and CD31 in late EPCs, with subsequently increased in vivo reendothelialization after arterial injury. Moreover, shear stress activated several mechanosensitive molecules including integrin β1, Ras, ERK1/2, paxillin and FAK, which were all involved in both cytoskeletal rearrangement and cell differentiation in response to shear stress in late EPCs. Shear stress is a key regulator for late EPC differentiation into endothelial cells, which is important for vascular repair, and the cytoskeletal rearrangement mediated by the activation of the cascade of integrin β1, Ras, ERK1/2, paxillin and FAK is crucial in this process. 23148988 Efficient serum-resistant lipopolyplexes targeted to the folate receptor. In this work, we have developed and evaluated a new targeted lipopolyplex (LPP), by combining polyethylenimine (PEI), 1,2-dioleoyl-3-(trimethylammonium) propane (DOTAP)/Chol liposomes, the plasmids pCMVLuc/pCMVIL-12, and the ligand folic acid (FA), able to transfect HeLa and B16-F10 cells in the presence of very high concentration of serum (60% FBS). These complexes (Fol-LPP) have a net positive surface charge. The combination of folic acid with lipopolyplexes also enhanced significantly the transfection activity of the therapeutic gene interleukin-12 (IL-12), without any significant cytotoxicity. The specificity of the folate receptor (FR)-mediated gene transfer was corroborated by employing a folate receptor deficient cell line (HepG2). This formulation improved gene delivery showed by conventional lipoplexes or polyplexes resulting an efficient, simple, and nontoxic method for gene delivery of therapeutic genes in vitro and very probably in vivo. 23230100 The Midregional Fragment of Pro-A-Type Natriuretic Peptide, Blood Pressure, and Mortality in a Prospective Cohort Study of Patients With Type 2 Diabetes (ZODIAC-25). OBJECTIVE Evidence that midregional fragment of pro-A-type natriuretic peptide (MR-proANP) is a marker of mortality in patients with type 2 diabetes is limited. Therefore, we aimed to investigate the capabilities of MR-proANP in predicting mortality. We also investigated whether MR-proANP influences the relationship between blood pressure and mortality in old age. RESEARCH DESIGN AND METHODS In 1998, 1,143 primary care patients with type 2 diabetes participated in the ZODIAC study. Because blood was drawn for 867 patients (76%) and confounders were missing for 19 patients, the final study sample comprised 848 patients. After a follow-up time of 10 years, we used Cox proportional hazard models to evaluate the relationship between MR-proANP and (cardiovascular) mortality. Harrell C statistic was used to compare models with and without MR-proANP. The regression analyses were repeated without MR-proANP for patients aged older than 75 years. RESULTS Median MR-proANP in the total study sample was 75 pmol/L (interquartile range, 48-124 pmol/L). During follow-up, 354 (42%) out of 848 patients had died, of whom 152 (43%) deaths were attributable to cardiovascular factors. MR-proANP was independently associated with all-cause and cardiovascular mortality, irrespective of age. During old age, there was a significant inverse relationship between blood pressure and mortality. This relationship did not change after adjustment for MR-proANP. CONCLUSIONS MR-proANP is independently associated with mortality in patients with type 2 diabetes. MR-proANP did not influence the inverse relationship between blood pressure and mortality in elderly patients. 23892947 The Chain of Survival for ST-Segment Elevation Myocardial Infarction: Insights Into the Middle East. Although coronary heart disease is the leading cause of morbidity and mortality in the Middle East (ME), not much is known about patients with ST-segment elevation myocardial infarction (STEMI) from this region. The STEMI Chain of Survival can be used to target regional improvements in patient care. We tried to adopt a modified chain of survival for STEMI to highlight the challenges and difficulties and the possible solutions to improve the STEMI care in the Middle East based on the few data available. 23806317 Building an evidence base in complementary and integrative healthcare for child and adolescent psychiatry. Complementary and integrative strategies are widely used by families with children who have mental health diagnoses. The therapies used by these children include herbs, dietary supplements, massage, acupuncture, meditation, and naturopathy. The literature on efficacy of complementary and alternative approaches is of limited value, and studies are needed to test efficacy and safety. Interpretation of complementary and integrative health care studies for symptomatic management of mental health conditions is hampered by study design and methodological limitations. Well-designed, adequately powered, and suitably controlled clinical trials on promising complementary and integrative modalities are needed for children and adolescents with psychiatric conditions. 23903799 Clinical experience with Zarzio® in Europe: what have we learned? Biosimilars are similar, but non-identical, versions of existing biological drugs for which patents have expired. Despite the rigorous approval process for biosimilars, concerns have been expressed about the efficacy and safety of these products in clinical practice. Biosimilars of filgrastim, based on the originator product Neupogen®, have been available since 2008 and are now in widespread clinical use in Europe and elsewhere. Three biosimilar G-CSFs have been approved based on a combination of physicochemical and biological protein characterisation, pharmacokinetic and pharmacodynamic assessment in healthy volunteers and efficacy and safety data in patients with cancer. To assess whether biosimilars are effective in the real-world clinical practice setting, a pooled analysis of five post-approval studies of biosimilar G-CSF (Zarzio®) that included 1,302 adult patients who received at least one cycle of chemotherapy with G-CSF support for the prevention of neutropenia was conducted. A total of 36 % of patients had a febrile neutropenia risk of >20 %, while 39.6 % had a risk of 10-20 % based on chemotherapy regimen. The occurrence of severe or febrile neutropenia was within the range of that observed in previous studies of originator G-CSF. In addition, the safety profile of Zarzio® was consistent with that reported for originator G-CSF and the known safety profile of G-CSF. Initial concerns about the use of biosimilars, at least with regard to biosimilar G-CSFs, appear to be unfounded. Adoption of cost-effective biosimilars should help reduce healthcare costs and improve patient access to biological treatments. 23887853 Structure-activity relationship (SAR) of withanolides to inhibit Hsp90 for its activity in pancreatic cancer cells. Withaferin A (WA), a naturally occurring steroidal lactone, directly binds to Hsp90 and leads to the degradation of Hsp90 client protein. The purpose of this study is to investigate the structure activity relationship (SAR) of withanolides for their inhibition of Hsp90 and anti-proliferative activities in pancreatic cancer cells. In pancreatic cancer Panc-1 cells, withaferin A (WA) and its four analogues withanolide E (WE), 4-hydroxywithanolide E (HWE), 3-aziridinylwithaferin A (AzWA) inhibited cell proliferation with IC50 ranged from 1.0 to 2.8 Î¼M. WA, WE, HWE, and AzWA also induced caspase-3 activity by 21-, 6-, 11- and 15-fold, respectively, in Panc-1 cells, while withaperuvin (WP) did not show any activity. Our data showed that WA, WE, HWE, and AzWA, but not WP, all directly bound to Hsp90 and induced Hsp90 aggregation,hence inhibited Hsp90 chaperone activity to induce degradation of Hsp90 client proteins Akt and Cdk4 through proteasome-dependent pathway in pancreatic cancer cells. However, only WA, HWE and AzWA disrupted Hsp90-Cdc37 complexes but not WE and WP. SAR study suggested that the C-5(6)-epoxy functional group contributes considerably for withanolide to bind to Hsp90, inhibit Hsp90 chaperone activity, and result in Hsp90 client protein depletion. Meanwhile, the hydroxyl group at C-4 of ring A may enhance withanolide to inhibit Hsp90 activity and disrupt Hsp90-Cdc37 interaction. These SAR data provide possible mechanisms of anti-proliferative action of withanolides. 23256622 Application of a liquid chromatography-electrospray mass spectrometry (LC/MS) method to the biodistribution and excretion studies of novel 5'-chloro-2, 3-didehydroindolo (2', 3': 2, 3) betulinic acid (DRF-4012) in tumour-bearing mice. Novel betulinic acid derivative 5'-chloro-2, 3-didehydroindolo [2', 3': 2, 3] betulinic acid (DRF-4012) is a new effective lupane type triterpenes with greater anticancer activity and efficacy than betulinic acid and currently under advanced preclinical investigation phase. In this study, a sensitive and rapid liquid chromatography-electrospray mass spectrometric (LC/MS) method has been developed for the determination of DRF-4012 in tumour-bearing mice plasma, urine, feces and tissues (liver, brain, lungs, heart, spleen, stomach, thigh muscle, kidneys, urinary bladder, small intestine and tumour). Biodistribution and excretion studies were performed for DRF-4012 nanoparticle (30 mg/kg body weight) after intravenous (i.v.) injection in tumour-bearing mice. DRF-4012 rapidly distributed throughout the body. After 0.5 h, tumour showed the second highest concentration, which was nearly half of the liver. After 4 and 24 h, the highest concentration of DRF-4012 was found in tumour indicating its retention in tumour site for a longer time. Excretion studies revealed that very low amount of unchanged DRF-4012 was observed in urine and primarily excreted through fecal route. This study may be useful to explain the manner in which DRF-4012 can inhibit tumour growth without apparent toxicity and preclinical/clinical evaluation of this potential antitumour agent. 23421368 Clinical analysis of the cranial complications of endoscopic sinus surgery. The most frequently affected sites of cranial complications of endoscopic sinus surgery (ESS) are the boundary between the anterior and posterior ethmoid roof, the frontal recess, and the cribriform plate. Being aware of cranial complications in time and provision of appropriate treatment may minimize the serious consequences. To investigate the reasons for cranial complications secondary to ESS and to find optimal prevention of cranial complications of ESS. The cranial complications of 19 patients were retrospectively reviewed. Eight patients underwent surgery in our hospital and the others underwent surgery in eight other hospitals, and were then transferred to our hospital for further examination and management of their complications. The type of cranial complications involved defects of the skull base (n = 19), cerebrospinal fluid leak (n = 14), frontal lobe injury (n = 3), subarachnoid hemorrhage (n = 1), meningitis (n = 2), and concomitant pneumocephalus (n = 3). In 10 cases, the boundary between the anterior and posterior ethmoid roof was damaged. The frontal recess was involved in five cases and the cribriform plate was damaged in three patients. All of the complications resolved completely after treatment. 23798498 Fabrication of 3D Microstructures from Interactions of Immiscible Liquids with a Structured Surface. A new lithography technique is presented that exploits the interactions of immiscible liquids with a structured surface. This highly parallel, "low-tech" method requires no dedicated equipment and easily produces curved and/or multi-level structures out of a variety of photoactive and non-photoactive materials. 23970556 Schizophrenia and the Sense of Self. Sense of self (SOS)-understood as the foundation upon which individuals experience their daily lives-has been increasingly investigated in schizophrenia. A disrupted SOS is thought to represent a platform for the experience of psychiatric symptoms, social cognitive deficits, and other abnormalities of consciousness. Few studies, however, have investigated the specificity of disrupted SOS to schizophrenia. The primary objective of the present study was to test the hypothesis that SOS is deficient in schizophrenia patients compared to both nonpsychiatric controls and patients with psychotic bipolar disorder. Using select scales from the Assessment of Self Descriptions, the present study assessed SOS from spontaneous narratives provided by schizophrenia patients (N = 50), bipolar patients with psychotic features (N = 17), and nonpsychiatric controls (N = 24). Our findings indicate that facets of SOS-in particular, certain aspects of agency and relatedness to others-are deficient in schizophrenia compared to nonpsychiatric controls and bipolar patients with psychotic features, even when overall level of functioning and psychiatric symptoms are accounted for. Implications of these results are discussed. 23833308 Phase II Study of Bevacizumab in Combination with Sorafenib in Recurrent Glioblastoma (N0776): A North Central Cancer Treatment Group Trial. We hypothesized that vertical blockade of VEGF signaling by combining bevacizumab with sorafenib in patients with recurrent glioblastoma would result in a synergistic therapeutic effect. We also investigated whether VEGF, VEGFR2 and hypoxia-inducible factor-1α single-nucleotide polymorphisms (SNP), circulating biomarkers of angiogenesis, and MRI markers such as apparent diffusion coefficient (ADC) are correlated with treatment efficacy and/or toxicity.EXPERIMENTAL DESIGN: Patients received bevacizumab (5 mg/kg every 2 weeks) with sorafenib (200 mg twice a day, weekly, days 1-5; group A). Due to toxicity, the starting sorafenib dose was subsequently modified to 200 mg every day (group B).RESULTS: Fifty-four patients were enrolled: 19 patients in group A and 35 in group B. Objective response rate was 18.5% with median duration of 6.7 months (range 0.5-24.1 months). Six-month progression-free survival (PFS6) was 20.4% (11/54), and median overall survival (OS) was 5.6 months [95% confidence interval (CI), 4.7-8.2]; outcome was similar between the two dose groups. We identified SNPs in the VEGF and VEGFR2 promoter regions, which were associated with PFS6 (P < 0.022). Among molecular markers of angiogenesis, a higher log2 baseline level of stromal cell-derived factor-1 was associated with PFS6 success (P = 0.04). Circulating endothelial cells decreased during treatment with subsequent increase at disease progression (P = 0.022). Imaging analysis showed a trend associating ADC-L with poor outcome.CONCLUSIONS: The bevacizumab/sorafenib combination did not improve outcome of patients with recurrent glioblastoma versus historic bevacizumab-treated controls. Biologic markers of response and resistance to bevacizumab in gliomas were identified which merit prospective validation. Clin Cancer Res; 19(17); 1-8. ©2013 AACR. 23438417 The effect of a coupling medium on color and translucency of CAD-CAM ceramics. To evaluate color and translucency of ceramics and the influence of a coupling medium (G - glycerin) on these optical properties, testing the hypothesis that glycerin influences the translucency values regardless the evaluation method. Five specimens from A2-shaded ceramics (IPS e.max CAD HT and LT, IPS Empress CAD HT and LT, Paradigm C, and Vita Mark II) were fabricated from ceramic blocks and polished to 1.0±0.01mm in thickness. A spectrophotometer (Vita Easyshade) was used to measure the CIELAB coordinates and the reflectance value (Y) of specimens placed on white and black backgrounds. The translucency parameter (TP) and the contrast ratio (CR) were calculated. Another spectrophotometer (Lambda 20) was used to measure the direct light transmittance (T%) of the specimens. The color and the CIELAB coordinates were evaluated using the Vita Easyshade on neutral grey background and values were used to calculate difference in color (ΔE). All evaluations were repeated using G and values were recorded. Data were statistically analyzed using Anova, Tukey and Student's t-test (α=0.05) and Pearson's correlation. Although the mean translucency values were significantly different for each method (TP and CR), they were strongly correlated (r(2)=0.97), even when G was used (r(2)=0.96). The coupling medium significantly influenced the mean values of ΔE and translucency. Color and translucency values cannot be compared if measured using different coupling media (e.g. air and liquid glycerin). 23847308 Inflammatory biomarkers and progression of diabetic retinopathy in african americans with type 1 diabetes. We examined whether baseline plasma levels of markers of inflammation and endothelial dysfunction are associated with the incidence of diabetic retinopathy (DR) in African Americans with type 1 insulin-dependent diabetes mellitus (T1DM). At baseline and follow-up examinations, detailed ocular examination, structured clinical interview, venous blood specimens, and masked grading of seven standard field retinal photographs were obtained. Baseline plasma levels of 28 inflammatory biomarkers, measured using multiplex bead analysis system, were measured in the participants. After adjusting for age, glycemic control, and other potential confounders, baseline plasma levels of E-selectin were associated significantly with progression of DR, E-selectin and tumor necrosis factor-α (TNF-α) levels with incidence of proliferative DR (PDR), and soluble intercellular adhesion molecule-1 (sICAM-1) and TNF-α levels with incidence of macular edema (ME). In African Americans with T1DM, inflammation and endothelial dysfunction precede the development of DR, thus supporting the notion that inflammation may influence progression/incidence of disease. 23113923 Recognizing misplacement of a dialysis catheter in the azygos vein. Uneventful central venous catheterization for hemodialysis patients may not always result in a correct tip position. A case of inadvertent cannulation of the azygos vein is described. Radiographic features for its early recognition are emphasized and mechanisms related with azygos unintended catheterization are discussed. 23905761 Anisotropic nanoparticles as shape-directing catalysts for the chemical etching of silicon. Anisotropic Au nanoparticles have been used to create a library of complex features on silicon surfaces. The technique provides control over feature size, shape, and depth. Moreover, a detailed study of the etching rate as a function of the nanoparticle surface facet interfaced with the silicon substrate suggested that the etching is highly dependent upon the facet surface energy. Specifically, the etching rate for Au nanocubes with {100}-terminated facets was ∼1.5 times higher than that for triangular nanoprisms with {111} facets. Furthermore, this work gives fundamental insight into the mechanism of metal-catalyzed chemical etching. 23846931 Update on novel therapies for pancreatic neuroendocrine tumors: 2013. Neuroendocrine tumors of the pancreas (pNETs) are classified on the basis of their differentiation as well as the functional status. Current treatment options for non resectable disease include everolimus, sunitinib, somatostatin analogs and chemotherapy. A number of trials with novel compounds and drug combinations were reported at the recent ASCO Annual Meeting. Pasireotide is a novel somatostatin analog with broader affinity for the somatostatin receptors compared to the traditional octreotide and lantreotide and it appears to be safe in patients with pNETs according to a phase I study (Abstract #e15126). The combination of octreotide with everolimus showed promising response rate and progression free survival in a phase II study (Abstract #4136). In another phase II study, the AKT inhibitor MK-2206 was well tolerated with moderate efficacy (Abstract #e15133). Last but not least, we discuss the updated data from a phase II study that used the combination of temsirolimus with bevacizumab in patients with advanced pNETs (Abstract #4032). 23916838 Epitope-based DNA vaccine for Alzheimer's disease: Translational study in macaques. Clinical trials with passive and active Alzheimer's disease (AD) vaccines suggest that early interventions are needed for improvement of cognitive and/or functional performance in patients, providing impetus for the development of safe and immunologically potent active vaccines targeting amyloid β (Aβ). The AN-1792 trial has indicated that Aβ-specific T cells may be unsafe for humans; therefore, other vaccines based on small Aβ epitopes are undergoing preclinical and clinical testing. Humoral and cellular immune responses elicited in response to a novel DNA epitope-based vaccine (AV-1955) delivered to rhesus macaques using the TriGrid electroporation device were evaluated. Functional activities of anti-Aβ antibodies generated in response to vaccination were assessed in vitro. AV-1955 generates long-term, potent anti-Aβ antibodies and cellular immune responses specific to foreign T-helper epitopes but not to self-Aβ. This translational study demonstrates that a DNA-based epitope vaccine for AD could be appropriate for human clinical testing. 23831434 Purification of bacteriophage lambda repressor. Bacteriophage lambda repressor controls the lysogeny/lytic growth switch after infection of E. coli by lambda phage. In order to study in detail the looping of DNA mediated by the protein, tag-free repressor and a loss-of-cooperativity mutant were expressed in E.coli and purified by (1) ammonium sulfate fractionation, (2) anion-exchange chromatography and (3) heparin affinity chromatography. This method employs more recently developed and readily available chromatography resins to produce highly pure protein in good yield. In tethered particle motion looping assays and atomic force microscopy "footprinting" assays, both the wild-type protein and a C-terminal His-tagged variant, purified using immobilized metal affinity chromatography, bound specifically to high affinity sites to mediate loop formation. In contrast the G147D loss-of-cooperativity mutant bound specifically but did not secure loops. 23735106 Advanced EUS imaging for early detection of pancreatic cancer. Endoscopic ultrasound (EUS)-fine needle aspiration remains the gold standard for diagnosing pancreatic malignancy. However, in a subset of patients, limitations remain in regards to image quality and diagnostic yield of biopsies. Several new devices and processors have been developed that allow for enhancement of the EUS image. Initial studies of these modalities do show promise. However, cost, availability, and overall incremental benefit to EUS-fine needle aspiration have yet to be determined. 23473747 The surgical management of Spitz naevi and atypical spitzoid neoplasms: A review of the literature. Melanocytic lesions with spitzoid differentiation represent a difficult management paradigm. Spitzoid lesions form a spectrum of distinct entities encompassing Spitz naevi, atypical Spitz naevi and spitzoid melanoma which range from benign to malignant. Differentiation between benign and malignant lesions can be challenging making surgical management difficult. In this article we highlight clinical conundrums regarding Spitz naevi. We review the literature in terms of the newer histological tools available to more explicitly classify these lesions which may have an impact on the clinical care that these patients receive. The article also examines the controversy which surrounds the role of sentinel lymph node biopsy (SLNB) and completion lymph node dissection in the management of melanocytic proliferations with Spitz differentiation. 23830490 Influence of attentional focus on skilled motor performance: Performance decrement under unfamiliar focus conditions. Recent studies have demonstrated that the direction of attentional focus exerts a substantial influence on motor performance. We argue that in well-learned skills, this variable might be confounded with athletes' familiarity with focus conditions. We studied the effect of familiarity and the direction of attentional focus on performance in two experiments using 2 (familiarity)×2 (direction) within-subject designs. A significant main effect of familiarity-that is, better performance under familiar compared with unfamiliar focus conditions-confirmed the influence of familiarity on motor performance. Results are consistent with existing concepts, but lead to different consequences when applied to sport and exercise. 23708780 Withaferin A inhibits matrix metalloproteinase-9 activity by suppressing the Akt signaling pathway. Withaferin A (Wit A), a steroidal lactone isolated from Withania somnifera, exhibits anti-inflammatory, immuno-modulatory and anti-angiogenic properties and antitumor activities. In the present study, we investigated the effects of Wit A on protease-mediated invasiveness of the human metastatic cancer cell lines Caski and SK-Hep1. We found that treatment with Wit A resulted in marked inhibition of the TGF‑β‑induced increase in expression and activity of matrix metalloproteinase (MMP)‑9 in Caski cell line. These effects of Wit A were dose-dependent and showed a correlation with suppression of MMP‑9 mRNA expression levels. Treatment with Wit A resulted in an ~1.6-fold induction of MMP-9 promoter activity, which was also suppressed by treatment with Wit A in Caski cells. We found that treatment with Wit A resulted in inhibition of TGF‑β‑induced phosphorylation of Akt, which was involved in the downregulation of expression of MMP-9 at the protein level. Introduction with constitutively active (CA)‑Akt resulted in a partial increase in the secretion of TGF-β-induced MMP-9 blocked by treatment with Wit A in Caski cells. According to these results, Wit A may inhibit the invasive and migratory abilities of Caski cells through a reduction in MMP-9 expression through suppression of the pAkt signaling pathway. These findings indicate that use of Wit A may be an effective strategy for control of metastasis and invasiveness of tumors. 23859994 The effect of acute moderate-intensity exercise on the accuracy of air-displacement plethysmography in young adults. Background/Objectives:Air-displacement plethysmography (ADP) body composition systems utilize a precise pre-test protocol that must be followed for each trial. Previous research has shown that body temperature changes influence the results when using ADP as a measurement. The objective of this study is to determine the effect of post-exercise body temperature changes on body composition results using ADP.Subjects/Methods:Forty young adults (18-30 years) participated in the study (23 females, 17 males). Resting heart rate was measured to calculate exercise intensity. First, an ADP test was done according to the instructions outlined by the manufacturer. Upon completion of the ADP test, the subject exercised on a treadmill at moderate intensity (∼65% heart rate reserve) for 30 min to increase body temperature. Another ADP measurement followed the physical activity. Chamber temperature (CT) was measured during each of the trials using a thermistor to assess changes. Fat mass (FM), fat-free mass (FFM), percentage body fat (%BF) and CT were compared pre- and post exercise.Results:Paired sample t-tests revealed significant differences (P<0.05) between pre-exercise %BF and post-exercise %BF (21.3±9.8% vs 19.6±10.2%), pre-exercise CT and post-exercise CT (22.7±1.2 vs 23.0±1.1 °C), and pre-exercise FM and post-exercise FM (14.9±7.9 vs 13.8±8.0 kg). FFM showed no significant difference.Conclusion:This investigation demonstrates the importance of following the manufacturer's recommended pre-test protocol as the accuracy of the ADP testing may be compromised, resulting in lower FM and %BF estimations.European Journal of Clinical Nutrition advance online publication, 17 July 2013; doi:10.1038/ejcn.2013.133. 23861328 Adherence to antihypertensive therapy prior to the first presentation of stroke in hypertensive adults: population-based study. Antihypertensive drug therapy is a major strategy of stroke prevention among hypertensive patients. The aim of this study was to estimate the excess risk of stroke associated with non-adherence to antihypertensive drug therapy among hypertensive patients. We conducted a population-based study using records from Finnish national registers for 1 January 1995 to 31 December 2007. Of the 73 527 hypertensive patients aged 30 years or older and without pre-existing stroke or cardiovascular disease, 2144 died from stroke and 24 560 were hospitalized due to stroke during the follow-up. At the 2- and 10-year follow-up after the start of continuous antihypertensive medication, non-adherent patients had 3.81 [95% confidence interval (CI) 2.85-5.10] and 3.01 (95% CI: 2.37-3.83) times higher odds of stroke death when compared with the adherent patients. The corresponding odds ratio (OR) for stroke hospitalization was 2.74 (95% CI: 2.35-3.20) at Year 2 and 1.71 (95% CI: 1.49-1.96) at Year 10. In the stroke-event year, the ORs were higher, 5.68 (95% CI: 5.05-6.39) for stroke death and 1.87 (95% CI: 1.72-2.03) for hospitalization. Among those using agents acting on the renin-angiotensin system combined with diuretics or β-blockers, these ORs were 7.49 (95% CI: 5.62-9.98) and 3.91 (95% CI: 3.23-4.75), respectively. The associations between non-adherence and stroke followed a dose-response pattern-the poorer the adherence, the greater the risk of death and hospitalization due to stroke. These data suggest that poor adherence to antihypertensive therapy substantially increases near- and long-term risk of stroke among hypertensive patients. 23855619 Comment on 'Predicting treatment response in psoriasis using serum levels of adalimumab and etanercept: a single centre, cohort study' reply from authors. We welcome the above comments from Menting et al, which are supportive of an approach involving serum drug level measurements (as opposed to isolated anti-drug antibody measurements) for monitoring clinical response to adalimumab in psoriasis. We agree that given the pharmacokinetic properties of adalimumab, trough serum sampling is recommended for accurate determination of anti-drug antibodies, and have discussed the potential for drug-mediated interference of bridging ELISAs in our article. Despite sampling serum at patients' routine clinic appointments, we found an association between low adalimumab levels at 4 weeks and non-response to treatment at 6 months. This article is protected by copyright. All rights reserved. 23895433 Trephination for Canalicular Obstruction: Experience in 45 Eyes. Abstract Purpose: To evaluate efficacy of a trephination procedure for resolution of primary canalicular obstruction or obstruction secondary to failed dacryocystorhinostomy (DCR). Methods: Retrospective review of patients in a single surgeon's practice who underwent trephination with Crawford tube insertion between 2001 and 2011, with a minimum follow-up period of 12 months. Indications for surgery included symptomatic patients either with primary canalicular obstruction or secondary obstruction after a failed DCR. Results: Trephination was carried out on 45 eyes of 43 patients; 78% were female, and average age at trephination was 61.0 years (range 32 to 89). Thirty-two eyes had previous DCR (75% endonasal, 25% external); mean interval of trephination after DCR was 1.4 years (range 0.3-9.1). Crawford stent tubes were left in-situ in 2 patients; in the remainder, tubes were removed at a mean interval of 5.6 months (range 0.3-20.6). The vast majority of presenting canalicular obstructions were in the common canalicus (73%). Sixteen eyes (36%) underwent a single trephination, and 29 eyes (64%) required repeat intervention; of these, 16 eyes had DCR (3 endonasal, 13 external) and 13 eyes had either repeat trephination with stenting (10 eyes) or repeat stenting alone (3 eyes). When separated into those with primary versus secondary obstruction, re-operation rate was similar in both groups (63% versus 69%). No patients developed complications after trephination. Conclusions: Trephination is a simple and effective intervention for canalicular obstruction that allowed 64% of patients, through one or two procedures, to avoid the morbidity of DCR. 23840928 Direct single molecule measurement of TCR triggering by agonist pMHC in living primary T cells. T cells discriminate between self and foreign antigenic peptides, displayed on antigen presenting cell surfaces, via the TCR. While the molecular interactions between TCR and its ligands are well characterized in vitro, quantitative measurements of these interactions in living cells are required to accurately resolve the physical mechanisms of TCR signaling. We report direct single molecule measurements of TCR triggering by agonist pMHC in hybrid junctions between live primary T cells and supported lipid membranes. Every pMHC:TCR complex over the entire cell is tracked while simultaneously monitoring the local membrane recruitment of ZAP70, as a readout of TCR triggering. Mean dwell times for pMHC:TCR molecular binding of 5 and 54 s were measured for two different pMHC:TCR systems. Single molecule measurements of the pMHC:TCR:ZAP70 complex indicate that TCR triggering is stoichiometric with agonist pMHC in a 1:1 ratio. Thus any signal amplification must occur downstream of TCR triggering. DOI:http://dx.doi.org/10.7554/eLife.00778.001. 23932026 A dual-channel gas chromatography method for the quantitation of low and high concentrations of NF3 and CF4 to study membrane separation of the two compounds. A dual-channel gas chromatographic method is described in this paper that can be conveniently used for quantitation of NF3/CF4 mixtures with a thermal conductivity detector (TCD) on one channel for the quantitation of high-concentrations, and a pulsed discharge helium ionization detector (PDHID) on a second channel for the quantitation of low concentrations. It is shown that adequate separation is achieved on both channels with this dual single-column setup in which column switching as used for NF3/CF4 analysis in industrial chromatographic methods are not required, thus yielding an effective analysis method for laboratory-scale investigations. In addition, the use of packed columns with purified divinylbenzene-styrene co-polymers as the sole stationary phase yields satisfactory resolution between NF3 and CF4 at isothermal conditions of 30°C, with elution times of less than 8min on the TCD channel and less than 4min on the PDHID channel. Consequently, this method allows for reliable, straight-forward quantitation of NF3/CF4 mixtures, which is necessary when studying the commercially important problem of NF3 and CF4 separation by different methods. Therefore, the applicability of the method to studying membrane separation of NF3 and CF4 is briefly discussed and illustrated, for which the dual-channel setup is especially beneficial. 23504707 Toward improved models for predicting bioconcentration of well-metabolized compounds by rainbow trout using measured rates of in vitro intrinsic clearance. Models were developed to predict the bioconcentration of well-metabolized chemicals by rainbow trout. The models employ intrinsic clearance data from in vitro studies with liver S9 fractions or isolated hepatocytes to estimate a liver clearance rate, which is extrapolated to a whole-body biotransformation rate constant (kMET ). Estimated kMET values are then used as inputs to a mass-balance bioconcentration prediction model. An updated algorithm based on measured binding values in trout is used to predict unbound chemical fractions in blood, while other model parameters are designed to be representative of small fish typically used in whole-animal bioconcentration testing efforts. Overall model behavior was shown to be strongly dependent on the relative hydrophobicity of the test compound and assumed rate of in vitro activity. The results of a restricted sensitivity analysis highlight critical research needs and provide guidance on the use of in vitro biotransformation data in a tiered approach to bioaccumulation assessment. 23384968 Epigenetic modifications in rheumatoid arthritis, a review. Rheumatoid arthritis is an autoimmune disease characterized by chronic joint inflammation and progressive destruction of cartilage and bone which leads to ultimately loss of function and pain. Activated synovial fibroblasts are key effector cells in the pathogenesis of rheumatoid arthritis. In the recent years, epigenetic changes including DNA methylation, histone acetylation and other histone modifications were identified that are associated with an intrinsic activation and the aggressive phenotype of these cells. So far, no therapies targeting rheumatoid arthritis synovial fibroblasts exist. This review comprises recent research efforts that propose epigenetic mechanisms behind the activation of rheumatoid arthritis synovial fibroblasts and other cell types. 23948726 Depolymerization and decolorization of kraft lignin by bacterium Comamonas sp. B-9. There is no commercial or industrial-scale process for the remediation of black liquor using microorganisms to date. One of the most important causes is that most microorganisms are not able to use lignin as their principal metabolic carbon or energy source. The bacterial strain Comamonas sp. B-9 has shown remarkable ability to degrade kraft lignin and decolorize black liquor using lignin as its principal metabolic carbon and energy source. This report looks at the depolymerization and decolorization of kraft lignin by Comamonas sp. B-9. The degradation, decolorization, and total carbon removal reached 45, 54, and 47.3 %, respectively, after 7 days treatment. Comamonas sp. B-9 was capable of depolymerizing kraft lignin effectively as analyzed by gel permeation chromatography and decolorization via degrading benzene ring structures as shown using Fourier transform infrared spectroscopy analysis. 23510074 Acoustics as a Tool for Better Characterization of Ionic Liquids: A Comparative Study of 1-Alkyl-3-methylimidazolium Bis[(trifluoromethyl)sulfonyl]imide Room-Temperature Ionic Liquids. Acoustic properties of three (1-ethyl-, 1-butyl-, and 1-octyl-) 1-alkyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl] imide room-temperature ionic liquids are reported and discussed. The speeds of sound in RTILs were measured as a function of temperature in the range 288-323 K by means of a sing around method. The densities and isobaric heat capacities were determined from 288.15 to 363.15 K and from 293.15 to 323.15 K, respectively. The related properties, like isentropic and isothermal compressibilities, isobaric coefficients of thermal expansion, molar isochoric heat capacities, and internal pressures, were calculated. It was found that for some ionic liquids, temperature dependence of isobaric coefficients of thermal expansion is small and negative. All investigations were completed by the ultrasound absorption coefficient measurements in 1-ethyl- and 1-octyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl] imide as a function of frequency from 10 to 300 MHz at temperatures 293.15-298.15 K. The ultrasound absorption spectra indicate relaxation frequencies in the megahertz range. 23636437 (1)H-MR spectroscopy of adult-onset autosomal dominant leukodystrophy with autonomic symptoms. Adult-onset ADLD with autonomic symptoms is a rare disease with a clinical course somewhat similar to chronic progressive MS but with different imaging findings consisting of extensive white matter changes in the cerebrum and cerebellar peduncles. Patients usually present in the fourth to sixth decade with autonomic symptoms, manifesting later symptoms from the pyramidal tracts and ataxia. Here, we present magnetic resonance spectroscopy (MRS) findings in this disease. Fourteen subjects, from two non-related families, with genetic linkage to the disease were studied with magnetic resonance imaging and single-voxel MRS. Clinically, they ranged from asymptomatic to wheelchair-using. Their results were compared to those of age- and sex-matched healthy controls. One MRS was excluded due to suboptimal quality. The remaining 13 subjects manifested characteristic evidence of pathology on MRI, 11 of them exhibited extensive changes. The metabolite concentrations of total Cr, total Cho, and total NAA measured in millimolars, using internal water as a reference, were significantly lower in these 11 subjects compared to controls, and we found linear correlations between all these metabolite levels. When total Cr was used as a reference, we found no difference between subjects and controls. No lactate was detected. The decreased metabolite concentrations measured using internal water as a reference are most likely due to increased water content in the tissues, diluting all metabolites to a similar degree. This is also in agreement with the high signal intensity exhibited in the white matter on T2-weighted MR images and with the reported histopathological findings of vacuolated myelin. 23927520 Genetic susceptibility to anthracycline-related congestive heart failure in survivors of haematopoietic cell transplantation. Haematopoietic cell transplantation (HCT) survivors are at increased risk for developing congestive heart failure (CHF), primarily due to pre-HCT exposure to anthracyclines. We examined the association between the development of CHF after HCT and polymorphisms in 16 candidate genes involved in anthracycline metabolism, iron homeostasis, anti-oxidant defence, and myocardial remodelling. A nested case-control study design was used. Cases (post-HCT CHF) were identified from 2950 patients who underwent HCT between 1988 and 2007 at City of Hope and had survived ≥1 year. This cohort formed the sampling frame for selecting controls (without CHF) matched on: age, race/ethnicity, cumulative anthracycline exposure, stem cell source (allogeneic, autologous), and length of follow-up. Seventy-seven cases with pre-HCT germline DNA and 178 controls were genotyped. Multivariate analysis revealed that the odds of CHF was higher in females [Odds Ratio (OR) = 2·9, P < 0·01], individuals with pre-HCT chest radiation (OR = 4·7, P = 0·05), hypertension (OR = 2·9, P = 0·01), and with variants of genes coding for the NAD(P)H-oxidase subunit RAC2 (rs13058338, 7508T→A; OR = 2·8, P < 0·01), HFE (rs1799945, 63C→G; OR = 2·5, P = 0·05) or the doxorubicin efflux transporter ABCC2 (rs8187710, 1515G→A; OR = 4·3, P < 0·01). A combined (clinical and genetic) CHF predictive model performed better [area under the curve (AUC), 0·79] than the genetic (AUC = 0·67) or the clinical (AUC = 0·69) models alone. 22827453 Integrating an evidence-based intervention into clinical practice: 'transitional relationship model' The transitional relationship model (TRM) facilitates the discharge of psychiatric clients from hospital to community by providing hospital staff involvement until a therapeutic relationship has been established with a community care provider as well as peer support. Psychiatric wards at six hospital sites implemented the TRM in three waves. Monthly summaries, progress reports, meeting minutes and focus group discussions were reviewed in order to uncover facilitators and barriers to TRM implementation. Factors that facilitated TRM implementation included: educational modules for staff and peer training, the presence of on-site champions, and supportive documentation systems. Barriers included: feeling swamped/overwhelmed, death by process, team dynamics and changes in champions. Implementation strategies suggested by the initial hospital wards were used to enhance implementation on subsequent wards, leading to positive outcomes. This study highlights the need to address work environment issues when implementing healthcare interventions, particularly for interprofessional teams. The transitional relationship model (TRM) facilitates the discharge process by providing peer support and hospital staff involvement until a therapeutic relationship has been established with a community care provider. A quasi-experimental, action-oriented research design was employed in which psychiatric wards at six hospital sites implemented the model in three waves. Helpful strategies were identified by each wave of wards for consideration by subsequent wards. Using an ethnographic approach, qualitative data were examined to uncover experiences and perceptions of TRM implementation and to help identify key issues that were supporting or hampering implementation. Specific strategies that facilitate the implementation of TRM include: (1) the use of educational modules for on-ward hospital staff training and peer training; (2) presence of on-site champions; and (3) supportive documentation systems. Issues identified as barriers to implementation included: (1) feeling drowned, swamped and overwhelmed; (2) death by process; (3) team dynamics; and (4) changes in champions. Staged large-scale implementation of the TRM allowed for iterative improvements to the model leading to positive outcomes. This study highlights the need to address work environment issues, particularly interprofessional teams. 23528299 Discovery of a synthetic Aminopeptidase N inhibitor LB-4b as a potential anticancer agent. APN inhibitors have been considered as potential anticancer agents for years. LB-4b is the first synthetic APN inhibitor to be evaluated for both of its anti-invasion and anti-angiogenesis effects. As a potent synthetic APN inhibitor (IC50=850nM, versus bestatin of 8.1μM), LB-4b was determined to have more significant block effects to cancer cell invasion and angiogenesis than bestatin. Besides, it is able to be easily synthesized with a high total yield, while the reported synthetic methods of bestatin are much more complex. 23201039 Assessment of candidacy for pneumococcal vaccination in intensive care patients. The 23-valent pneumococcal vaccine has been shown to be effective in reducing mortality and complications from pneumonia. The US Centers for Disease Control (CDC) have published guidelines for vaccination eligibility. The intensive care unit (ICU) may represent a missed opportunity for administration of the pneumococcal vaccine to eligible patients. This study assessed the characteristics of patients in an ICU in relation to their candidacy for pneumococcal vaccination. RESEARCH METHODOLOGY/SETTING: A retrospective chart review was performed of all patients with a single admission to a mixed 25 bed ICU of a tertiary-care community teaching hospital from October 2010 to January 2011. Information procured included demographic information, pneumococcal vaccine eligibility, documentation of prior vaccination status or vaccine administration and patient outcomes. Two-hundred and sixty three individual medical and surgical admissions to the ICU occurred during the study period. The mean number of indicator risk factors for pneumococcal vaccine was 2.3 (95% CI (2.117-2.513), with the majority of patients being over age 65 (57%) and having chronic heart or lung disease (81%). Despite this only seven patients had immunisation status documented and only 14 patients received pneumococcal vaccination during the index hospital stay. In a large tertiary-care teaching hospital, most patients admitted to the ICU had multiple indications for pneumococcal vaccination. However, only a small percentage were assessed or given vaccination during their hospital stay. ICU protocols that give nurses the ability to assess and administer pneumococcal vaccines may improve immunisation rates. 23953035 A prospective video-based observational and analytical approach to evaluate management during brain tumour surgery at a university hospital. The operating room (OR) is a high-risk complex setting, where patient safety relies on the coordinated efforts of multiple team members. However, little attention has been paid to evaluating the strategies employed by OR practitioners to prevent and correct incidents that inevitably occur during surgery. Therefore, we were prompted to investigate human factor (HF) engineering methods that have been used in an innovative way in order to systematically observe and analyze the management of incidents in the neurosurgical OR of a French university hospital. A technical case report illustrates our approach that associates the following procedures: the recording of OR team member activities and behaviour by video cameras and direct observation of a HF researcher, with the description and the explicit demonstration of safety related procedures in self- and cross-confrontation interviews of OR team members. This technical report emphasizes complementary aspects of clinical performance related to safety skills. Moreover, individual and team performances rely on complementary abilities that associate practical knowledge, skills, and attitudes, which are engaged at various degrees to prevent and manage incidents. This report also enlightens new quality-improvement opportunities as well as further objectives for future studies. 23821642 Control of Reproductive Floral Organ Identity Specification in Arabidopsis by the C Function Regulator AGAMOUS. The floral organ identity factor AGAMOUS (AG) is a key regulator of Arabidopsis thaliana flower development, where it is involved in the formation of the reproductive floral organs as well as in the control of meristem determinacy. To obtain insights into how AG specifies organ fate, we determined the genes and processes acting downstream of this C function regulator during early flower development and distinguished between direct and indirect effects. To this end, we combined genome-wide localization studies, gene perturbation experiments, and computational analyses. Our results demonstrate that AG controls flower development to a large extent by controlling the expression of other genes with regulatory functions, which are involved in mediating a plethora of different developmental processes. One aspect of this function is the suppression of the leaf development program in emerging floral primordia. Using trichome initiation as an example, we demonstrate that AG inhibits an important aspect of leaf development through the direct control of key regulatory genes. A comparison of the gene expression programs controlled by AG and the B function regulators APETALA3 and PISTILLATA, respectively, showed that while they control many developmental processes in conjunction, they also have marked antagonistic, as well as independent activities. 23706500 Aflibercept therapy for exudative age-related macular degeneration resistant to bevacizumab and ranibizumab. To evaluate the outcome of intravitreal injection of aflibercept in cases with exudative age-related macular degeneration, (AMD) resistant to injections of bevacizumab or ranibizumab. Retrospective observational case series. A retrospective chart review at a single institution was conducted to identify patients with exudative AMD and choroidal neovascularization (CNV) in 1 or both eyes resistant to treatment with ranibizumab or bevacizumab who were switched to treatment with at least 3 monthly injections of aflibercept. In total, 36 eyes from 31 patients were included. The demographic data, visual acuities, central macular thickness on optical coherence tomography (OCT), complications, and number of injections were reviewed. The mean patient age was 79 years (range 60-88). There were 13 male and 18 female patients. The number of prior injections with either bevacizumab or ranibizumab ranged from 6-74. After 3 monthly injections of aflibercept, there was a reduction of either subretinal or intraretinal fluid in 18 of 36 (50.0%) of the treated eyes; the amount of fluid remained stable in 15 eyes (41.7%) and worsened in 3 eyes (8.3%). A significant average decrease was observed for the central macular thickness after 3 injections of 65 Î¼m (P = 2.9 Ã— 10(-6)), with no significant change in visual acuity. Aflibercept therapy appears to be beneficial in a subset of patients with neovascular age-related macular degeneration who exhibit recurrent or resistant intraretinal or subretinal fluid following multiple injections with either bevacizumab or ranibizumab. 23142506 Novel potassium channel blocker venom peptides from Mesobuthus gibbosus (Scorpiones: Buthidae). In the present study, we report for the first time, the molecular, biochemical and electrophysiological characterization of the components present in the soluble venom from Mesobuthus gibbosus (Brullé, 1832). According to the epidemiological and clinical situation of scorpion envenomation cases M. gibbosus scorpion is one of the most important health-threatening species of Turkey. Despite the medical importance reported for M. gibbosus, there is no additional information on toxin peptides and venom components to clarify the toxic effect of the M. gibbosus sting. Biochemical characterization of the venom was performed using different protocols and techniques following a bioassay-guided strategy (HPLC, mass spectrometry and Edman degradation sequencing). Venom fractions were tested in electrophysiological assays on a panel of six K(+) channels (K(v)1.1-1.6) by using the two-electrode voltage clamp technique. Three new α-KTx peptides were found and called MegKTx1, MegKTx2 and MegKTx3 (M. gibbosus, K(+) channel toxin number 1-3). A cDNA library from the telson was constructed and specific screening of transcripts was performed. Biochemical and molecular characterization of MegKTx peptides and transcripts shows a relation with toxins of three different α-KTx subfamilies (α-KTx3.x, α-KTx9.x and α-KTx16.x). 22560565 Safety essentials: acute reactions to iodinated contrast media. The objectives of this article are to review the diagnosis and management of acute nonrenal reactions to iodinated contrast media. We will begin by discussing the types of contrast media and their correlative rates of reaction. The mechanism of contrast reactions, predisposing risk factors, and preventative measures will then be discussed. The remainder of the article will review the assessment of potential reactions, initial management, and treatment algorithms for specific reactions. 23753413 P2Y1 Receptors Expressed by C1 Neurons Determine Peripheral Chemoreceptor Modulation of Breathing, Sympathetic Activity, and Blood Pressure. Catecholaminergic C1 cells of the rostral ventrolateral medulla (RVLM) are key determinants of the sympathoexcitatory response to peripheral chemoreceptor activation. Overactivation of this reflex is thought to contribute to increased sympathetic activity and hypertension; however, molecular mechanisms linking peripheral chemoreceptor drive to hypertension remain poorly understood. We have recently determined that activation of P2Y1 receptors in the RVLM mimicked effects of peripheral chemoreceptor activation. Therefore, we hypothesize that P2Y1 receptors regulate peripheral chemoreceptor drive in this region. Here, we determine whether P2Y1 receptors are expressed by C1 neurons in the RVLM and contribute to peripheral chemoreceptor control of breathing, sympathetic activity, and blood pressure. We found that injection of a specific P2Y1 receptor agonist (MRS2365) into the RVLM of anesthetized adult rats increased phrenic nerve activity (≈55%), sympathetic nerve activity (38±6%), and blood pressure (23±1 mm Hg), whereas application of a specific P2Y1 receptor antagonist (MRS2179) decreased peripheral chemoreceptor-mediated activation of phrenic nerve activity, sympathetic nerve activity, and blood pressure. To establish that P2Y1 receptors are expressed by C1 cells, we determine in the brain slice preparation using cell-attached recording techniques that cells responsive to MRS2365 are immunoreactive for tyrosine hydroxylase (a marker of C1 cells), and we determine in vivo that C1-lesioned animals do not respond to RVLM injection of MRS2365. These data identify P2Y1 receptors as key determinants of peripheral chemoreceptor regulation of breathing, sympathetic nerve activity, and blood pressure. 23471540 Global analysis of Drosophila Cys2-His2 zinc finger proteins reveals a multitude of novel recognition motifs and binding determinants. Cys2-His2 zinc finger proteins (ZFPs) are the largest group of transcription factors in higher metazoans. A complete characterization of these ZFPs and their associated target sequences is pivotal to fully annotate transcriptional regulatory networks in metazoan genomes. As a first step in this process, we have characterized the DNA-binding specificities of 129 zinc finger sets from Drosophila using a bacterial one-hybrid system. This data set contains the DNA-binding specificities for at least one encoded ZFP from 70 unique genes and 23 alternate splice isoforms representing the largest set of characterized ZFPs from any organism described to date. These recognition motifs can be used to predict genomic binding sites for these factors within the fruit fly genome. Subsets of fingers from these ZFPs were characterized to define their orientation and register on their recognition sequences, thereby allowing us to define the recognition diversity within this finger set. We find that the characterized fingers can specify 47 of the 64 possible DNA triplets. To confirm the utility of our finger recognition models, we employed subsets of Drosophila fingers in combination with an existing archive of artificial zinc finger modules to create ZFPs with novel DNA-binding specificity. These hybrids of natural and artificial fingers can be used to create functional zinc finger nucleases for editing vertebrate genomes. 22532505 Extracts of Scutellaria baicalensis reduced body weight and blood triglyceride in db/db Mice. Scutellaria baicalensis has been extensively employed for the clinical treatment of hyperlipidemia, atherosclerosis, hypertension, dysentery, inflammatory diseases, and the common cold. The present study was performed to investigate the anti-obesity and anti-dyslipidemia effect of Scutellaria baicalensis extracts (SBE) in type 2 diabetic db/db mice. Male db/db mice were divided into three groups (n = 5) and orally administrated vehicle (control), SBE 10, and 100 mg/kg body weight/day for 4 weeks everyday. Administration of SBE improves weight gain, hypertriglyceridemia, and hyperinsulinemia in db/db mice. In obese db/db mice, SBE treatment also reduced plasma alanine aminotransferase levels. In the livers of db/db mice, SBE promoted 5' AMP-activated protein kinase activity and restored metabolic process and insulin signaling pathways. Our data demonstrate that SBE exerts potent anti-obesity and anti-hypertriglyceride effects suggesting its useful potential function as adjuvant therapeutic agent for the treatment of weight gain and hypertriglyceridemia. 23886308 Isolation of a 2-hydroxytetrahydrofuran complex from copper-promoted hydroxylation of THF. A complex of a binucleating macrocyclic ligand comprising a [Cu(II)(μ-OH)Na](2+) core reacts with CuI in THF/CH3CN to yield a novel species with a deprotonated 2-hydroxytetrahydrofuran (THF-2-ol) bridging between Cu(II) and Na(I) ions. The complexes were characterized by X-ray crystallography, electron paramagnetic resonance spectroscopy, and electrospray ionization mass spectrometry. (18)O-labeling studies support incorporation of the O atom from μ-OH into the coordinated THF-2-ol ligand. 23897023 The validity and reliability of a customized rigid supportive harness during Smith Machine back squat exercise: Harness back squat validity and reliability. While the back squat exercise is commonly prescribed to both athletic and clinical populations, individuals with restricted glenohumeral mobility may be unable to safely support the bar on the upper trapezius using their hands. The aims of this study were to investigate the validity and reliability of a back squat variation using a rigid supportive harness that does not require unrestricted glenohumeral mobility for quantifying 1-repetition maximum (1RM). Thirteen young men (age = 25.3 ± 4.5 yr, height = 179.2 ± 6.9 cm, body mass = 86.6 ± 12.0 kg) with at least two years resistance training experience volunteered to participate in the study. Subjects reported to the lab on three occasions, each separated by one week. During testing sessions, subjects were assessed for 1RM using the traditional back squat (session 1) and harness back squat (HBS; sessions 2 and 3) exercises. Mean 1RM for the traditional back squat, and two testing sessions of the HBS (HBS1 and HBS2) were 148.4 ± 25.0 kg, 152.5 ± 25.7 kg and 150.4 ± 22.6 kg, respectively. Back squat and mean HBS 1RM scores were very strongly correlated (r = 0.96; p < 0.001). There were no significant differences in 1RM scores between the three trials. The test-retest 1RM scores with the HBS demonstrated high reliability, with an intraclass correlation coefficient of 0.98 (95% confidence interval [CI] = 0.93-0.99), and a coefficient of variation of 2.6% (95% CI = 1.9-4.3). Taken together, these data suggest that the HBS exercise is a valid and reliable method for assessing 1RM in young men with previous resistance training experience, and may be useful for individuals with restricted glenohumeral mobility. 23543601 Theoretical Considerations and Practical Approaches to Address the Effect of Anti-drug Antibody (ADA) on Quantification of Biotherapeutics in Circulation. Continuous improvement in bioanalytical method development is desired in order to ensure the quality of the data and to better support pharmacokinetic (PK) and safety studies of biotherapeutics. One area that has been getting increasing attention recently is in the assessment of "free" and "total" analyte and the impact of the assay format on those assessments. To compliment these considerations, the authors provide a critical review of available literature and prospectively explore methods to mitigate the potential impact of anti-drug antibody on PK assay measurement. This challenge is of particular interest and importance since biotherapeutic drugs often elicit an immune response, and thus may have a direct impact on quantification of the drug for its PK and safety evaluations. 23416985 Evolution and dynamics of pancreatic cancer progression. Efficient metastasis is believed as the result of multiple genetic, epigenetic and/or post-translational events in the lifetime of a carcinoma. At the genetic level, these events may be categorized into those that occur during carcinogenesis, and those that occur during subclonal evolution. This review summarizes current knowledge of the genetics of pancreatic cancer from its initiation within a normal cell until the time that is has disseminated to distant organs, many features of which can be extrapolated to other solid tumor types. The implications of these findings to personalize genome analyses of an individual patient's tumor are also discussed.Oncogene advance online publication, 18 February 2013; doi:10.1038/onc.2013.29. 23925421 CuOx-TiO2 junction: what is the active component for photocatalytic H2 production? CuOx based junctions e.g. CuOx-TiO2 have been demonstrated to be very effective in photocatalytic H2 production, but the active component at the junction is less understood. We herein report that an as-prepared CuOx-TiO2 photocatalyst undergoes an in situ restructuring process during photocatalytic H2 production under solar light irradiation to form the active Cu2O-TiO2 interfacial structure on the surface. These results unambiguously demonstrate that Cu2O is the active copper species in CuOx-TiO2 photocatalysts. 23799294 Efficacy of gemcitabine plus platinum agents for biliary tract cancers: a meta-analysis. The objective of this study was to carry out a meta-analysis of the efficacy of gemcitabine+platinum agent regimens in the treatment of advanced biliary tract cancer (BTC). PubMed and Google Scholar were searched using the following combination of search terms: gemcitabine, oxaliplatin, cholangiocarcinoma, biliary, gallbladder, bile duct. Studies were eligible for inclusion in the meta-analysis if they were randomized trials on the use of gemcitabine plus a platinum agent for the treatment of advanced (unresectable or metastatic cancer) BTC. Outcomes of interest were response rate, overall survival, and progression-free survival. Pooled odds ratios/differences in median survival and 95% confidence intervals (CIs) were determined for each outcome. A total of 47 records were identified in the initial search. Ultimately, three open-label randomized trials (two phase 2 and one phase 3) met the eligibility criteria and were included in the meta-analysis. Two studies compared gemcitabine plus cisplatin with gemcitabine alone, whereas the other study compared gemcitabine plus oxaliplatin with fluorouracil-folinic acid. The total number of patients in the studies ranged from 54 to 410. The overall analyses revealed that all survival outcomes assessed were significantly more favorable for patients treated with gemcitabine plus platinum agents than for patients not treated with this combination. Response rates: odds ratio=2.639, 95% CI=1.210-5.757, Z=2.439, P=0.015; pooled difference in median overall survival=3.822 months, 95% CI=1.798-5.845 months, Z=3.702, P<0.001; pooled difference in median progression-free survival=3.268 months, 95% CI=1.996-4.541 months, Z=5.035, P<0.001. Patients with advanced BTC who are treated with gemcitabine plus platinum agents may experience better survival outcomes compared with patients who are not treated with this combination of chemotherapy. 23643799 Bioconcentration of chromium in edible mushrooms: influence of environmental and genetic factors. Chromium concentrations were determined in 167 samples of wild edible mushrooms, collected from three different sites (urban, traffic and pastureland areas) in Lugo (NW Spain). The hymenophore (H) and the rest of the fruiting body (RFB) were analysed separately. The analyses were performed using inductively coupled plasma optical emission spectrometry (ICP-OES). The highest mean chromium levels (mg/kg dry weight) of 3.5 and 8.0, 4.5 and 6.2, and 6.2 and 4.3 were found in Lycoperdon utriforme, Coprinus comatus and Agaricus campestris in H and RFB, respectively. The highest concentrations of chromium were observed in terrestrial saprophytic species in relation to mycorrhizal species. With respect to the underlying substrates, chromium concentration was lowest in the pastureland area (24.6 mg/kg dw). All mushroom species were bioexclusors of chromium (BCF<1) with statistically significant differences (p<0.001). The consumption of mushrooms harvested from the areas investigated poses no toxicological risk to human health due to chromium. 23305949 Two distinct mechanisms of Topoisomerase 1-dependent mutagenesis in yeast. Topoisomerase 1 (Top1) resolves transcription-associated supercoils by generating transient single-strand breaks in DNA. Top1 activity in yeast is a major source of transcription-associated mutagenesis, generating a distinctive mutation signature characterized by deletions in short, tandem repeats. A similar signature is associated with the persistence of ribonucleoside monophosphates (rNMPs) in DNA, and it also depends on Top1 activity. There is only partial overlap, however, between Top1-dependent deletion hotspots identified in highly transcribed DNA and those associated with rNMPs, suggesting the existence of both rNMP-dependent and rNMP-independent events. Here, we present genetic studies confirming that there are two distinct types of hotspots. Data suggest a novel model in which rNMP-dependent hotspots are generated by sequential Top1 reactions and are consistent with rNMP-independent hotspots reflecting processing of a trapped Top1 cleavage complex. 23969386 Handwritten chinese/japanese text recognition using semi-markov conditional random fields. This paper proposes a method for handwritten Chinese/Japanese text (character string) recognition based on semi-Markov conditional random fields (semi-CRFs). The high-order semi-CRF model is defined on a lattice containing all possible segmentation-recognition hypotheses of a string to elegantly fuse the scores of candidate character recognition and the compatibilities of geometric and linguistic contexts by representing them in the feature functions. Based on given models of character recognition and compatibilities, the fusion parameters are optimized by minimizing the negative log-likelihood loss with a margin term on a training string sample set. A forward-backward lattice pruning algorithm is proposed to reduce the computation in training when trigram language models are used, and beam search techniques are investigated to accelerate the decoding speed. We evaluate the performance of the proposed method on unconstrained online handwritten text lines of three databases. On the test sets of databases CASIA-OLHWDB (Chinese) and TUAT Kondate (Japanese), the character level correct rates are 95.20 and 95.44 percent, and the accurate rates are 94.54 and 94.55 percent, respectively. On the test set (online handwritten texts) of ICDAR 2011 Chinese handwriting recognition competition, the proposed method outperforms the best system in competition. 23845167 Defect-induced loss mechanisms in polymer-inorganic planar heterojunction solar cells. The effect of ZnO defects on photoexcited charge carrier recombination and forward induced charge transfer was studied in organic-inorganic bilayer organic heterojunction solar cells. Decreased bimolecular recombination via passivation of ZnO nanopariticle defects resulted in longer carrier lifetime as determined by transient photovoltage (TPV) measurements. It was also found by time-resolved photoluminescence (TRPL) measurements that defect passivation decreased the fluorescence lifetime which indicated higher exciton dissociation efficiency. Through passivation of the ZnO nanoparticles defects, the two loss mechanisms were reduced and the power conversion efficiency (PCE) is significantly enhanced. 23363020 Pharmacological chaperones as therapeutics for lysosomal storage diseases. Lysosomal enzymes are responsible for the degradation of a wide variety of glycolipids, oligosaccharides, proteins, and glycoproteins. Inherited mutations in the genes that encode these proteins can lead to reduced stability of newly synthesized lysosomal enzymes. While often catalytically competent, the mutated enzymes are unable to efficiently pass the quality control mechanisms of the endoplasmic reticulum, resulting in reduced lysosomal trafficking, substrate accumulation, and cellular dysfunction. Pharmacological chaperones (PCs) are small molecules that bind and stabilize mutant lysosomal enzymes, thereby allowing proper cellular translocation. Such compounds have been shown to increase enzyme activity and reduce substrate burden in a number of preclinical models and clinical studies. In this Perspective, we review several of the lysosomal diseases for which PCs have been studied and the SAR of the various classes of molecules. 23876426 Blurring the boundaries: developmental and activity-dependent determinants of neural circuits. The human brain comprises approximately 100 billion neurons that express a diverse, and often subtype-specific, set of neurotransmitters and voltage-gated ion channels. Given this enormous complexity, a fundamental question is how is this achieved? The acquisition of neurotransmitter phenotype was viewed as being set by developmental programs 'hard wired' into the genome. By contrast, the expression of neuron-specific ion channels was considered to be highly dynamic (i.e., 'soft wired') and shaped largely by activity-dependent mechanisms. Recent evidence blurs this distinction by showing that neurotransmitter phenotype can be altered by activity and that neuron type-specific ion channel expression can be set, and perhaps limited by, developmental programs. Better understanding of these early regulatory mechanisms may offer new avenues to avert the behavioral changes that are characteristic of many mental illnesses. 23745700 Comparing the molecular pharmacology of CGRP and adrenomedullin. CGRP and adrenomedullin [AM] are peptides that have a number of physiological effects, including vasodilation, through the activation of a shared GPCR, the family B calcitonin receptor-like receptor [CLR]. Specificity to each ligand is conferred through the unusual association of CLR with a single transmembrane accessory protein. For CGRP this is receptor activity-modifying protein 1 [RAMP1] and for AM acting at the AM1 receptor this is RAMP2. Receptor signalling by two specific peptide ligands through a common GPCR provides researchers with vital and unique information into similarities and differences of GPCR activation. Understanding the structure and function of these receptors will also provide a platform for future drug design for a number of cardiovascular and metabolic diseases in which CGRP and AM have been implicated. This review summarises the latest information and data concerning ligand binding, receptor activation and structural studies for both the CGRP and AM receptors. 23712914 Iridium-catalyzed enantioselective allylic alkynylation. No leaving group needed: With an Ir(P,olefin) complex as catalyst, the direct enantioselective allylic alkynylation of secondary allylic alcohols with potassium alkynyltrifluoroborates as alkynylating reagents has been achieved. High levels of enantioselectivity and high yields were achieved with this operationally easy and robust protocol, the use of which was demonstrated in the synthesis of GPR40 receptor agonist AMG 837. cod=1,5-cyclooctadiene. 23613184 Motivational influences in persons found not criminally responsible on account of mental disorder: a review of legislation and research. This paper provides a review of the legislative reforms and case law that have impacted the defense of Not Criminally Responsible on Account of Mental Disorder (NCRMD) in Canada over the past three decades. As in other jurisdictions internationally, we observe that legislative reforms of procedural, as opposed to substantive, aspects of the NCRMD defense have impacted the manner in which NCRMD criteria are applied in common practice. More people are being declared NCRMD in recent years, and there is greater heterogeneity in the offending and psychiatric profiles of these individuals, suggesting that NCRMD criteria are being applied more liberally over time. In light of the substantial growth of the forensic mental health system over the past two decades, witnessed both in Canada and abroad, we propose that the study of motivational influences underlying the offending behaviors of persons with serious mental illness (SMI) is necessary to begin disentangling symptom-based offending from violent and antisocial behaviors that may have other motives. This, in turn, can help to determine legal issues, better define the nature of each person's offending and treatment needs, and provide a more fine-grained analysis of the drivers behind the growth experienced by the forensic system. Copyright © 2013 John Wiley & Sons, Ltd. 23818501 Plant mobile small RNAs. In plants, RNA silencing is a fundamental regulator of gene expression, heterochromatin formation, suppression of transposable elements, and defense against viruses. The sequence specificity of these processes relies on small noncoding RNA (sRNA) molecules. Although the spreading of RNA silencing across the plant has been recognized for nearly two decades, only recently have sRNAs been formally demonstrated as the mobile silencing signals. Here, we discuss the various types of mobile sRNA molecules, their short- and long-range movement, and their function in recipient cells. 23085546 Solid-state dependent dissolution and oral bioavailability of piroxicam in rats. The aim of this study was to gain understanding about the effects of different solid-state forms of a poorly water-soluble piroxicam on drug dissolution and oral bioavailability in rats. Three different solid-state forms of piroxicam were studied: anhydrate I (AH), monohydrate (MH), and amorphous form in solid dispersion (SD). In addition, the effect of a new polymeric excipient Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) on oral bioavailability of piroxicam was investigated. Significant differences in the dissolution and oral bioavailability were found between the solid-state forms of piroxicam. Amorphous piroxicam in SD showed the fastest dissolution in vitro and a solid-state transformation to MH in the dissolution medium. Despite the presence of solid-state transformation, SD exhibited the highest rate and extent of oral absorption in rats. Oral bioavailability of other two solid-state forms decreased in the order AH and MH. The use of Soluplus® was found to enhance the dissolution and oral bioavailability of piroxicam in rats. The present study shows the importance of solid-state form selection for oral bioavailability of a poorly water-soluble drug. 23712559 Understanding crystallization features of P(VDF-TrFE) copolymers under confinement to optimize ferroelectricity in nanostructures. The successful development of ferroelectric polymer devices depends on the effective fabrication of polar ferroelectric crystalline nanostructures. We demonstrate, by scanning X-ray microdiffraction using synchrotron light, the heterogeneous character of high aspect ratio one-dimensional nanoarrays of poly(vinylidene fluoride-co-trifluoroethylene) copolymers supported by a residual polymer film. They were prepared by melt and solution template wetting, using porous anodic aluminum oxide as a template. The spatial evolution of different polymorphs from the mixture of paraelectric and ferroelectric crystal forms (residual film) to the pure ferroelectric form (nanoarray) is evidenced for the samples prepared by solution wetting. However, for samples prepared by melt wetting the ferroelectric phase is exclusively obtained in both the residual film and nanoarray. The crystal nuclei formed in the polymer film connected to the nanoarray play a key role in determining the formation of a crystallinity distribution gradient, where the crystallinity decreases along the first 5-10 microns in the nanorods reaching a steady value afterwards. The minimum decrease in crystallinity is revealed for samples prepared by melt wetting. The results reported in this work endeavour to enhance the understanding of crystallization under confinement for ferroelectric copolymers and reveal the parameters for improving the ferroelectric character of polymer nanostructures. 23454114 Yeast and human mitochondrial helicases. Mitochondria are semiautonomous organelles which contain their own genome. Both maintenance and expression of mitochondrial DNA require activity of RNA and DNA helicases. In Saccharomyces cerevisiae the nuclear genome encodes four DExH/D superfamily members (MSS116, SUV3, MRH4, IRC3) that act as helicases and/or RNA chaperones. Their activity is necessary for mitochondrial RNA splicing, degradation, translation and genome maintenance. In humans the ortholog of SUV3 (hSUV3, SUPV3L1) so far is the best described mitochondrial RNA helicase. The enzyme, together with the matrix-localized pool of PNPase (PNPT1), forms an RNA-degrading complex called the mitochondrial degradosome, which localizes to distinct structures (D-foci). Global regulation of mitochondrially encoded genes can be achieved by changing mitochondrial DNA copy number. This way the proteins involved in its replication, like the Twinkle helicase (c10orf2), can indirectly regulate gene expression. Here, we describe yeast and human mitochondrial helicases that are directly involved in mitochondrial RNA metabolism, and present other helicases that participate in mitochondrial DNA replication and maintenance. This article is part of a Special Issue entitled: The Biology of RNA helicases - Modulation for life. 23886688 A novel necroptosis inhibitor-necrostatin-21 and its SAR study. An initial structure-activity relationship study of the novel necroptosis inhibitor Nec-21 was described. Any changes of the tetracyclic scaffold were detrimental for the activity. Introduction of a substituent to 7 or 8 position (e.g., cyano or methoxy group, respectively), would increase the activity. The 7 and 8-position disubstituted compound 17b was 35-fold as potent as the lead, while EC50 reached 14nM. 23890796 Correction of a Severe Poliomyelitic Equinocavovarus Foot Using an Adjustable External Fixation Frame. One-stage surgical correction of severe equinocavovarus deformity can result in complications ranging from skin necrosis to tibial nerve palsy. Fewer complications have been reported when severe deformities were treated by gradual correction using external frames such as the Ilizarov external fixator or the Taylor Spatial Frame™. We describe a case of a 64-year-old female patient with severe poliomyelitic equinocavovarus whose deformity required her to ambulate using the dorsum of her right foot as a weightbearing surface. We treated the deformity with gradual correction using a Taylor Spatial Frame™, followed by ankle arthrodesis. At the most recent postoperative evaluation, 20 months after the initial surgery, the patient was pain free and ambulating on the sole of her right foot. 23814252 The effect of excision of the posterior arch of C1 on C1/C2 fusion using transarticular screws. Transarticular screw fixation with autograft is an established procedure for the surgical treatment of atlantoaxial instability. Removal of the posterior arch of C1 may affect the rate of fusion. This study assessed the rate of atlantoaxial fusion using transarticular screws with or without removal of the posterior arch of C1. We reviewed 30 consecutive patients who underwent atlantoaxial fusion with a minimum follow-up of two years. In 25 patients (group A) the posterior arch of C1 was not excised (group A) and in five it was (group B). Fusion was assessed on static and dynamic radiographs. In selected patients CT imaging was also used to assess fusion and the position of the screws. There were 15 men and 15 women with a mean age of 51.2 years (23 to 77) and a mean follow-up of 7.7 years (2 to 11.6). Stable union with a solid fusion or a stable fibrous union was achieved in 29 patients (97%). In Group A, 20 patients (80%) achieved a solid fusion, four (16%) a stable fibrous union and one (4%) a nonunion. In Group B, stable union was achieved in all patients, three having a solid fusion and two a stable fibrous union. There was no statistically significant difference between the status of fusion in the two groups. Complications were noted in 12 patients (40%); these were mainly related to the screws, and included malpositioning and breakage. The presence of an intact or removed posterior arch of C1 did not affect the rate of fusion in patients with atlantoaxial instability undergoing C1/C2 fusion using transarticular screws and autograft. 23841487 Antimicrobial particles from emulsion polymerization of methyl methacrylate in the presence of quaternary ammonium surfactants. The purpose of this Article is to characterize polymeric particles of poly(methylmethacrylate) (PMMA) synthesized in the presence of one of two different quaternary ammonium surfactants (QACs): cetyltrimethylammonium bromide (CTAB) or dioctadecyldimethylammonium bromide (DODAB). The methods used are dynamic light scattering for sizing, polydispersity and zeta potential analysis, scanning electron microscopy (SEM) for morphology visualization, and plating plus colony-forming unities (CFU) counting for the determination of antimicrobial activity. The results point out the high QAC concentration required to obtain cationic and bioactive antimicrobial particles with good colloidal stability and a permanent load of the polymeric network with QACs. Over a range of micromolar QAC concentrations, there is remarkable antimicrobial activity of PMMA/CTAB or PMMA/DODAB particles, which is much higher than those determined for the QACs by themselves. Loading the biocompatible polyacrylate particles with QACs is a facile, fast, low-cost approach to obtaining highly efficient antimicrobial nanoparticles. 23688715 Improvement of brain uptake for in vivo PET imaging of astrocytic oxidative metabolism using benzyl [1-(11)C]acetate. Brain uptake of acetate is insufficient for obtaining a quantitative image of astrocytic oxidative metabolism. To improve the brain uptake of [1-(11)C]acetate, we synthesized benzyl [1-(11)C]acetate ([1-(11)C]BA) and conducted a positron emission tomography (PET) study assessing astrocytic oxidative metabolism. The brain uptake of [1-(11)C]BA was markedly higher compared with [1-(11)C]acetate, and disappeared with a half-life of 20 min in all regions studied. The brain uptake of [1-(11)C]BA was significantly decreased by fluorocitrate. The results indicate that [1-(11)C]BA could be a useful PET probe for assessing astrocytic oxidative metabolism. 23960120 Regulation of selenoprotein P concentration and expression by different sources of selenium in broiler breeders and their offspring. An 8-wk experiment using 180 Lingnan Yellow broiler breeders was conducted to investigate the effect of different sources of Se on the concentration and gene expression of selenoprotein P (SEPP1) in broiler breeders and their offspring. After receiving a low-Se basal diet for 8 wk, broiler breeders were randomly allocated to 3 treatments (6 replicates per treatment) and fed corn-soy-based diets supplemented with 0.15 mg/kg of Se from sodium selenite (SS), Se-enriched yeast (SY), and selenomethionine (SM), respectively. Fertile eggs from different replicates were collected during the last week of the experiment and then incubated in different incubator trays in the same incubator. The concentrations and mRNA levels of SEPP1 were determined in liver and kidney of broiler breeders and their offspring, as well as the serum SEPP1 concentration. Compared with SS, both SY and SM significantly increased (P < 0.05) the concentration and mRNA level of SEPP1 in 1-d-old chicks. In broiler breeders, the serum and liver SEPP1 concentrations were notably increased by the use of organic Se (P < 0.05), whereas no differences were found in the kidney. Moreover, the SEPP1 mRNA level in the liver was remarkably elevated (P < 0.05) in organic Se treatments, but also no differences were observed in the kidney. Results of this study indicate that the use of organic Se (SY or SM) in maternal diets is very effective for increasing the concentration and mRNA level of SEPP1, especially in their offspring. No differences between SY and SM were observed. 23884905 A real-time system for biomechanical analysis of human movement and muscle function. Mechanical analysis of movement plays an important role in clinical management of neurological and orthopedic conditions. There has been increasing interest in performing movement analysis in real-time, to provide immediate feedback to both therapist and patient. However, such work to date has been limited to single-joint kinematics and kinetics. Here we present a software system, named human body model (HBM), to compute joint kinematics and kinetics for a full body model with 44 degrees of freedom, in real-time, and to estimate length changes and forces in 300 muscle elements. HBM was used to analyze lower extremity function during gait in 12 able-bodied subjects. Processing speed exceeded 120 samples per second on standard PC hardware. Joint angles and moments were consistent within the group, and consistent with other studies in the literature. Estimated muscle force patterns were consistent among subjects and agreed qualitatively with electromyography, to the extent that can be expected from a biomechanical model. The real-time analysis was integrated into the D-Flow system for development of custom real-time feedback applications and into the gait real-time analysis interactive lab system for gait analysis and gait retraining. 23532110 A prognostic nomogram for prediction of recurrence in desmoid fibromatosis. To construct a postoperative nomogram to estimate the risk of local recurrence for patients with desmoid tumors. The standard management of desmoid tumors is resection, but many recur locally. Other options include observation or novel chemotherapeutics, but little guidance exists on selecting treatment. Patients undergoing resection during 1982-2011 for primary or locally recurrent desmoids were identified from a single-institution prospective database. Cox regression analysis was used to assess risk factors and to create a recurrence nomogram, which was validated using an international, multi-institutional data set. Desmoids were treated surgically in 495 patients (median follow-up of 60 months). Of 439 patients undergoing complete gross resection, 100 (23%) had recurrence. Five-year local recurrence-free survival was 69%. Eight patients died of disease, all after R2 resection. Adjuvant radiation was not associated with improved local recurrence-free survival. In multivariate analysis, factors associated with recurrence were extremity location, young age, and large tumor size, but not margin. Abdominal wall tumors had the best outcome (5-year local recurrence-free survival rate of 91%). Age, site, and size were used to construct a nomogram with concordance index of 0.703 in internal validation and 0.659 in external validation. Integration of additional variables (R1 margin, sex, depth, and primary vs recurrent presentation) did not importantly improve concordance (internal concordance index of 0.707). A postoperative nomogram including only size, site, and age predicts local recurrence and can aid in counseling patients. Systemic therapies may be appropriate for young patients with large, extremity desmoids, but surgery alone is curative for most abdominal wall lesions. 23957946 Long-term Continence Outcomes in Men Undergoing Radical Prostatectomy for Clinically Localized Prostate Cancer. Urinary incontinence is a common short-term complication of radical prostatectomy (RP). Little is known about the long-term impact of RP on continence. To elucidate the long-term progression of continence after RP. From October 2000 through September 2012, 1788 men undergoing open RP for clinically localized prostate cancer by a single surgeon at an urban tertiary care center prospectively signed consent to be followed before RP and at 3, 6, 12, 24, 96, and 120 mo after RP. A consecutive sampling method was used and all men were included in this study. Men underwent open RP. Regression models controlled for preoperative University of California, Los Angeles-Prostate Cancer Index urinary function score (UCLA-PCI-UFS), age, prostate-specific antigen level, Gleason score, stage, nerve-sparing status, race, and marital status were used to evaluate the association of time since RP with two dependent variables: UCLA-PCI-UFS and continence status. The mean UCLA-PCI-UFS declined between 2 yr and 8 yr (83.8 vs 81.8; p=0.007) and marginally between 8 yr and 10 yr (81.8 vs 79.6; p=0.036) after RP, whereas continence rate did not significantly change during these intervals. Men ≥60 yr old experienced a decline in mean UCLA-PCI-UFS between 2 yr and 8 yr (p=0.002) and a marginal decline in continence rate between 2 yr and 10 yr (p=0.047), whereas these variables did not change significantly in men <60 yr old. These outcomes are for an experienced surgeon, so caution should be exercised in generalizing these results. Between 2 yr and 10 yr after RP, there were slight decreases in mean UCLA-PCI-UFS and continence rates in this study. Men aged <60 yr had better long-term outcomes. These results provide realistic long-term continence expectations for men undergoing RP. 23900962 Relaxation by amplitude modulation: A rapid T1 measurement method. A novel longitudinal relaxation time (T1 ) measurement method using complex amplitude modulation is presented. The method applies a series of inversion pulses to the imaged region in accordance with a binary modulation sequence. The longitudinal magnetization acquired in a given pulse repetition time (TR) interval is the sum of the individual longitudinal magnetization recovered during each previous TR interval, weighted by T1 decay factors and the combined effect of all the radiofrequency pulses they have experienced. The demodulated signal for each voxel is an exponential curve with a decaying rate determined by T1 and the acquisition flip angle θ. Sequences using a 15-cycle pseudorandom binary code were implemented on Siemens 3T Trio with standard gradient echo readout and multislice gradient echo-planar imaging. The sequences were tested on T1 phantoms and human and compared against inversion recovery method. Our studies on phantoms and a human volunteer show that T1 estimated from this method is very accurate and well reproducible. The average scan time is ∼1.6 s per slice (full k-space gradient echo-planar imaging with matrix size 128 × 128). The current protocol is almost twice as fast as two fastest existing methods. Optimizing protocols and incorporating common acceleration techniques will make it even faster. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc. 23962554 An Unusual Cause of Occlusion of Fully Covered Self Expandable Metallic Stent by Biliary Ascarides. A 46 years old male presented with history of recurrent episodes of acute on chronic pancreatitis which was alcohol related for the past 2 years. Six months ago, he had developed jaundice and cholangitis due to distal common bile duct stricture for which a plastic stent followed by a biliary fully covered self expandable metallic stent (FCSEMs) was placed elsewhere. During the six months, he had intermittent pain in epigastrium associated with intermittent fever with chills with no history of jaundice. He came to our hospital for further management. His physical examination was unremarkable. Laboratory analysis showed total leukocyte count of 11400 cell/mm3 (Normal ,N <11000 cells /mm3) and total bilirubin of 2.3 mg/dl (N < 1.2 mg/dl) with mildly elevated liver enzymes ; serum aspartate transaminase of 76 U/L (N 0-40 U/L) and alanine transaminase of 80 U/L (N<40 U/L). Serum amylase and lipase were elevated with 200 IU/L (N < 96 IU/L) and 134 IU/L (N< 50 IU/L) respectively. Ultrasound abdomen showed chronic pancreatitis with no peripancreatic edema. On gastroduodenoscopy , the FCSEMs was seen to be occluded by three live round worms (Figure A, Ascaris lumbricoides).They were entwined in the proximal retrieval lasso of the stent (Figure B) and the worms could only be extracted along with the FCSEMS (Figure C).The patient was then started on anti-helminthic therapy. 23764855 Persistent enhancement of the carrier density in electron irradiated InAs nanowires. We report a significant and persistent enhancement of the conductivity in free-standing non-intentionally doped InAs nanowires upon irradiation in ultra-high vacuum. Combining four-point probe transport measurements performed on nanowires with different surface chemistries, field effect based measurements and numerical simulations of the electron density, the change in the conductivity is found to be caused by an increase in the surface free carrier concentration. Although an electron beam of a few keV, typically used for the inspection and the processing of materials, propagates through the entire nanowire cross-section, we demonstrate that the electrical properties of the nanowire are predominantly affected by radiation-induced defects occurring at the nanowire surface and not in the bulk. 23806556 Rational design and generation of recombinant control reagents for bispecific antibodies through CDR mutagenesis. Developments in the field of bispecific antibodies have progressed rapidly in recent years, particularly in their potential role for the treatment of malignant disease. However, manufacturing stable molecules has proven to be costly and time-consuming, which in turn has hampered certain aspects of preclinical evaluation including the unavailability of appropriate "negative" controls. Bispecific molecules (e.g., bispecific tandem scFv) exhibit two specificities, often against a tumor antigen as well as an immune-activation ligand such as CD3. While for IgG antibodies, isotype-matched controls are well accepted, when considering smaller antibody fragments it is not possible to adequately control for their biological activity through the use of archetypal isotypes, which differ dramatically in affinity, size, structure, and design. Here, we demonstrate a method for the rapid production of negative control tandem scFvs through complementarity determining region (CDR) mutagenesis, using a recently described bispecific T-cell engager (BiTE) targeting a tumor-specific mutation of the epidermal growth factor receptor (EGFRvIII) as an example. Four independent control constructs were developed by this method through alteration of residues spanning individual CDR domains. Importantly, while target antigen affinity was completely impaired, CD3 binding affinity was conserved in each molecule. These results have a potential to enhance the sophistication by which bispecific antibodies can be evaluated in the preclinical setting and may have broader applications for an array of alternative antibody-derived therapeutic platforms. 23940123 Scientists and the 3Rs: attitudes to animal use in biomedical research and the effect of mandatory training in laboratory animal science. The 3Rs principle of replacement, reduction, and refinement has increasingly been endorsed by legislators and regulatory bodies as the best approach to tackle the ethical dilemma presented by animal experimentation in which the potential benefits for humans stand against the costs borne by the animals. Even when animal use is tightly regulated and supervised, the individual researcher's responsibility is still decisive in the implementation of the 3Rs. Training in laboratory animal science (LAS) aims to raise researchers' awareness and increase their knowledge, but its effect on scientists' attitudes and practice has not so far been systematically assessed. Participants (n = 206) in eight LAS courses (following the Federation of European Laboratory Animal Science Associations category C recommendations) in Portugal were surveyed in a self-administered questionnaire during the course. Questions were related mainly to the 3Rs and their application, attitudes to animal use and the ethical review of animal experiments. One year later, all the respondents were asked to answer a similar questionnaire (57% response rate) with added self-evaluation questions on the impact of training. Our results suggest that the course is effective in promoting awareness and increasing knowledge of the 3Rs, particularly with regard to refinement. However, participation in the course did not change perceptions on the current and future needs for animal use in research. 23888034 Holographic vortex liquids and superfluid turbulence. Superfluid turbulence is a fascinating phenomenon for which a satisfactory theoretical framework is lacking. Holographic duality provides a systematic approach to studying such quantum turbulence by mapping the dynamics of a strongly interacting quantum liquid into the dynamics of classical gravity. We use this gravitational description to numerically construct turbulent flows in a holographic superfluid in two spatial dimensions. We find that the superfluid kinetic energy spectrum obeys the Kolmogorov -5/3 scaling law, with energy injected at long wavelengths undergoing a direct cascade to short wavelengths where dissipation by vortex annihilation and vortex drag becomes efficient. This dissipation has a simple gravitational interpretation as energy flux across a black hole event horizon. 23904365 Role of brain-derived neurotrophic factor in bone marrow angiogenesis in multiple myeloma. This study examined the expression of brain-derived neurotrophic factor (BDNF) in multiple myeloma (MM) and its role in bone marrow angiogenesis. The peripheral blood plasma was harvested from 71 MM patients and 63 patients without hematological malignancy. The BDNF level in the blood plasma was determined by ELISA. Human bone marrow endothelial cells (HBMECs) were cultured. The mRNA and protein expression levels of the BDNF receptor TrkB in HBMECs were detected by using RT-PCR and flow cytometry, respectively. The viability of HBMECs treated with recombinant human (rh) BDNF or not was measured by using MTT assay. The migration of HBMECs in the presence of rhBDNF or not was determined by modified Boyden chamber assay. In vitro tube formation assay was used to assess the effect of rhBDNF on HBMECs differentiation. The results of ELISA revealed that the BDNF level was significantly higher in peripheral blood plasma of MM patients than in that of control patients (4.39±0.67 vs. 1.96±0.39 ng/mL, P<0.05). The BDNF receptor TrkB was expressed in HBMECs at mRNA and protein level. MTT assay manifested that rhBDNF could significantly concentration-dependently promote the HBMECs proliferation. The number of HBMECs treated with 160 ng/mL rhBDNF for 48 h was 1.57±0.10 folds higher than that in control group (P<0.05). Moreover, rhBDNF could enhance HBMECs migration in a concentration-dependent manner and the maximal migration was reached in the presence of 100 ng/mL rhBDNF. The migration indexes were 1.40±0.11, 1.64±0.16, 2.06±0.25 and 2.18±0.21 in 25, 50, 100 ng/mL rhBDNF groups and 25 ng/mL rhVEGF group, respectively. In vitro tube formation assay demonstrated that the area of the formed tubular structure was increased with the rhBDNF concentration. In control group, there was no formation of intact tubular structure and the HBMECs on the matrigel were irregularly dispersed. HBMECs treated with 100 ng/mL rhBDNF could form intact tubular structure and the area and the diameter of tubes were significantly greater than those in control group (P<0.05). There was no significant difference in the formed tubular area between 25 ng/mL VEGF group and 100 ng/mL rhBDNF group. It was concluded that BDNF plays an important role in myeloma cell-induced angiogenesis, and it may become a new target of anti-angiogenesis treatment for MM. 23797059 The three α1-adrenoceptor subtypes show different spatio-temporal mechanisms of internalization and ERK1/2 phosphorylation. We analyzed the kinetic and spatial patterns characterizing activation of the MAP kinases ERK 1 and 2 (ERK1/2) by the three α1-adrenoceptor (α1-AR) subtypes in HEK293 cells and the contribution of two different pathways to ERK1/2 phosphorylation: protein kinase C (PKC)-dependent ERK1/2 activation and internalization-dependent ERK1/2 activation. The different pathways of phenylephrine induced ERK phosphorylation were determined by western blot, using the PKC inhibitor Ro 31-8425, the receptor internalization inhibitor concanavalin A and the siRNA targeting β-arrestin 2. Receptor internalization properties were studied using CypHer5 technology and VSV-G epitope-tagged receptors. Activation of α1A- and α1B-ARs by phenylephrine elicited rapid ERK1/2 phosphorylation that was directed to the nucleus and inhibited by Ro 31-8425. Concomitant with phenylephrine induced receptor internalization α1A-AR, but not α1B-AR, produced a maintained and PKC-independent ERK phosphorylation, which was restricted to the cytosol and inhibited by β-arrestin 2 knockdown or concanavalin A treatment. α1D-AR displayed constitutive ERK phosphorylation, which was reduced by incubation with prazosin or the selective α1D antagonist BMY7378. Following activation by phenylephrine, α1D-AR elicited rapid, transient ERK1/2 phosphorylation that was restricted to the cytosol and not inhibited by Ro 31-8425. Internalization of the α1D-AR subtype was not observed via CypHer5 technology. The three α1-AR subtypes present different spatio-temporal patterns of receptor internalization, and only α1A-AR stimulation translates to a late, sustained ERK1/2 phosphorylation that is restricted to the cytosol and dependent on β-arrestin 2 mediated internalization. 23664018 Service-based health human resources planning for older adults. To test a service-based health human resources (HHR) planning approach for older adults in the context of home and long term care (LTC); to create a practical template/tools for use in various jurisdictions and/or health care settings. The most serious health needs of seniors in 2 Canadian jurisdictions were identified and linked to the specific services and associated competencies required of health care providers (HCPs) to address those needs. The amounts of each service required were quantified and compared against the capacity of HCPs to perform the services, measured using a self-assessment survey, by using a previously developed analytical framework. Home and LTC sectors in Nova Scotia and Nunavut, Canada. Regulated and nonregulated HCPs were invited to complete either an online or paper-based competency self-assessment survey. Survey response rates in Nova Scotia and Nunavut were 11% (160 responses) and 20% (22 responses), respectively. Comparisons of the estimated number of seniors likely to need each service with the number who can be served by the workforces in each jurisdiction indicated that the workforces in both jurisdictions are sufficiently numerous, active, productive, and competent to provide most of the services likely to be required. However, significant gaps were identified in pharmacy services, ongoing client assessment, client/family education and involvement, and client/family functional and social supports. Service-based HHR planning is feasible for identifying gaps in services required by older adults, and can guide policy makers in planning hiring/recruitment, professional development, and provider education curricula. Implementation will require commitment of policy makers and other stakeholders, as well as ongoing evaluation of its effectiveness. More broadly, the ongoing effectiveness of the approach will depend on workforce planning being conducted in an iterative way, driven by regular reevaluation of population health needs and HHR effectiveness. 23820846 Human skin in vitro permeation of bentazon and isoproturon formulations with or without protective clothing suit. Skin exposures to chemicals may lead, through percutaneous permeation, to a significant increase in systemic circulation. Skin is the primary route of entry during some occupational activities, especially in agriculture. To reduce skin exposures, the use of personal protective equipment (PPE) is recommended. PPE efficiency is characterized as the time until products permeate through material (lag time, Tlag). Both skin and PPE permeations are assessed using similar in vitro methods; the diffusion cell system. Flow-through diffusion cells were used in this study to assess the permeation of two herbicides, bentazon and isoproturon, as well as four related commercial formulations (Basagran(®), Basamais(®), Arelon(®) and Matara(®)). Permeation was measured through fresh excised human skin, protective clothing suits (suits) (Microchem(®) 3000, AgriSafe Pro(®), Proshield(®) and Microgard(®) 2000 Plus Green), and a combination of skin and suits. Both herbicides, tested by itself or as an active ingredient in formulations, permeated readily through human skin and tested suits (Tlag < 2 h). High permeation coefficients were obtained regardless of formulations or tested membranes, except for Microchem(®) 3000. Short Tlag, were observed even when skin was covered with suits, except for Microchem(®) 3000. Kp values tended to decrease when suits covered the skin (except when Arelon(®) was applied to skin covered with AgriSafe Pro and Microgard(®) 2000), suggesting that Tlag alone is insufficient in characterizing suits. To better estimate human skin permeations, in vitro experiments should not only use human skin but also consider the intended use of the suit, i.e., the active ingredient concentrations and type of formulations, which significantly affect skin permeation. 22400809 Chemical constituents comparison between Rhizoma Smilacis Glabrae and Rhizoma Smilacis Chinae by HPLC-DAD-MS/MS. Rhizoma Smilacis Glabrae (RSG) and Rhizoma Smilacis Chinae (RSC) are two herbal materials that belong to the same genera and are both listed in the Chinese Pharmacopoeia. Chemical constituents in the two species were compared by HPLC-DAD-MS/MS. Many common constituents were found in both species, including shikimic acid, 5-O-caffeoylshikimic acid, trans-resveratrol, taxifolin, astilbin and its three stereoisomers, engeletin and isoengeletin. However, syringic acid was found only in RSG, while chlorogenic acid was found only in RSC. 23630364 Histidine-Rich Protein 2 Plasma Levels Predict Progression to Cerebral Malaria in Malawian Children With Plasmodium falciparum Infection. Some children with uncomplicated malaria progress to cerebral malaria despite appropriate treatment; identifying them in advance might improve their care. The objective of this study was to determine if plasma concentrations of a malaria protein, HRP2 (histidine-rich protein 2) would serve this purpose. Cases and controls were children presenting with uncomplicated malaria; the cases (n = 25) developed cerebral malaria, and the controls (n = 125) did not. Mean plasma HRP2 concentrations were significantly higher in the cases, and an HRP2 cutoff was identified that could predict disease progression (sensitivity and specificity, 88% for each). Quantitative measurements of HRP2 may be a useful screening tool. 23227829 MiR-383 is downregulated in medulloblastoma and targets peroxiredoxin 3 (PRDX3). Accumulating evidence suggests that microRNAs (miRNAs) are over- or under-expressed in tumors, and abnormalities in miRNA expression may contribute to carcinogenesis. MiR-383 was previously identified as one of the under-expressed miRNAs in medulloblastoma (MB) by miRNA expression profiling. Quantitative reverse transcription polymerase chain reaction (RT-PCR)-based miRNA assays showed an enrichment of miR-383 in normal brain. Based on these data, we speculated that miR-383 is important in MB pathogenesis. In this study, we demonstrated significant downregulation of miR-383 in 23/29 (79%) MB samples and 7/7 (100%) MB cells lines. Ectopic expression of miR-383 in MB cells led to suppression of cell growth, cell accumulation at sub-G1 phase and alteration of apoptosis-related proteins. By transcriptomic analysis and computational algorithms, we identified peroxiredoxin 3 (PRDX3) as a target gene of miR-383. Luciferase reporter assay confirmed that miR-383 negatively regulated PRDX3 by interaction between miR-383 and complementary sequences in the 3' UTR of PRDX3. MiR-383 repressed PRDX3 at transcriptional and translational levels as revealed by quantitative RT-PCR and Western blot analysis. Furthermore, depletion of PRDX3 by siRNAs resulted in similar effects as observed in miR-383-transfected cells. In conclusion, miR-383 acts as a regulator controlling cell growth of MB, at least in part, through targeting PRDX3. 23538615 Gauging interest of the general public in laser-assisted in situ keratomileusis eye surgery. To assess interest among members of the general public in laser-assisted in situ keratomileusis (LASIK) surgery and how levels of interest in this procedure have changed over time in the United States and other countries. Using the Google Trends Web site, we determined the weekly frequency of queries involving the term "LASIK" from January 1, 2007, through January 1, 2011, in the United States, United Kingdom, Canada, and India. We fit separate regression models for each of the countries to assess whether residents of these countries differed in their querying rates on specific dates and over time. Similar analyses were performed to compare 4 US states. Additional regression models compared general public interest in LASIK surgery before and after the release of a 2008 Food and Drug Administration report describing complaints associated with this procedure. During 2007 to 2011, the Google query rate for "LASIK" was highest among persons residing in India, followed by the United Kingdom, Canada, and the United States. During this time period, the query rate declined by 40% in the United States, 24% in India, and 22% in the United Kingdom, and it increased by 8% in Canada. In all 4 of the US states examined, the query rate declined-by 52% in Florida, 56% in New York, 54% in Texas, and 42% in California. Interest in LASIK declined further among US citizens after the Food and Drug Administration report release. Interest among the general public in LASIK surgery has been waning in recent years. 23850587 Occurrence, removal and bioaccumulation of steroid estrogens in Dianchi Lake catchment, China. The occurrence, removal and bioaccumulation of steroid estrogens such as the natural estrone (E1), 17β-estradiol (E2) and estriol (E3), as well as the synthetic 17α-ethynylestradiol (EE2) were investigated in Dianchi Lake catchment, China. The results show that traditional secondary treatment processes in eight sewage treatment plants (STPs) of Kunming were not efficient enough to completely remove steroid estrogens, but ultraviolet (UV) photodegradation in advanced treatment displayed more effectively for the removal of the residual compounds. The amount of total steroid estrogens (∑SEs) discharged to Dianchi Lake catchment by the eight STPs was 35.8g/day, in which STP-3 was the dominant source, accounting for 50.8%. Because of the pollution input from treated and untreated sewages, estrogens were widely detected in surface water and sediment samples collected from 21 inflow rivers of Dianchi Lake, 10 National Surface Water Quality Monitoring Sites of the lake itself and its unique outflow river, with the mean concentration of ∑SEs in the range of 5.3-798.2ng/L (water) and 3.7-202.4ng/g (dry weight, sediment), 1.5-39.2ng/L (water) and 2.7-20.9ng/g (sediment), and 4.2ng/L (water) and 6.6ng/g (sediment), respectively. Due to the continuous input of estrogens to Dianchi Lake from STPs and inflow rivers, present estrogen levels in various tissues of wild fish species sampled from the lake (2013) were higher than the values detected in the previous years (2009 and 2010). The bioaccumulation of steroid estrogens in wild fish species from different sampling sites was in the order of STP-5>Dianchi Lake (2013)>Dianchi Lake (2010)≈Dianchi Lake (2009)≫field control>laboratory control, which is mainly affected by exposure concentrations. By employing risk quotient (RQ), it is found that eco-toxicological risk of steroid estrogens in Dianchi Lake catchment was in a sequence of 22 rivers>effluents of eight STPs>Dianchi Lake (2013)>Dianchi Lake (2010), and high RQs were found in EE2, which should be controlled preferentially in this catchment. 23068187 Buccal fat augmentation for insufficient neoglottal closure after supracricoid laryngectomy with cricohyoidoepiglottopexy. Supracricoid laryngectomy with Cricohyoidoepiglottopexy (SCL-CHEP) is a functional organ preservation surgery for laryngeal cancers. Post-operative laryngeal function is generally promising. Some patients, however, cannot attain satisfactory functional results because of an excessively wide neoglottis resulting in an insufficient neoglottal closure. Autologous buccal fat augmentation was conducted to correct the insufficiency. Two patients underwent intervention. Under general anesthesia, autologous fat was harvested from the buccal fat pad. Fat tissue was injected into the widest plane of the neoglottis under direct laryngoscopy; a navigation system was incorporated to identify the responsible site. Acoustic, aerodynamic, and perceptual analyses along with videofluoroscopic swallowing study and screening questionnaires were used for functional evaluation. A total of 0.8ml (Case 1) and 0.7ml (Case 2) of fat tissues were injected into the submucosal space of the responsible sites. Both patients experienced functional improvement subjectively after augmentation; psychological parameters for voice and swallowing also improved. Buccal fat augmentation to correct insufficient neoglottal closure after SCL-CHEP was technically feasible. A navigation system was helpful for confirmation. Fat absorption occurred and one third of the volume remained at 3 and 6 months. Although, vocal measurements remained unchanged, psychological parameters for voice and swallowing improved. 23775905 Synthesis and Characterization of Various Photosensitive Copper(II) Complexes with 5-(1-Methylhydrazinyl)-1H-tetrazole as Ligand and Perchlorate, Nitrate, Dinitramide, and Chloride as Anions. The preparation of 5-(1-methylhydrazinyl)-1H-tetrazole monohydrate (1⋅H2 O) and various copper(II) complexes with perchlorate (2 and 3), nitrate (4, 5, and 6), dinitramide (7), and chloride (8) is described. The coordination compounds (monomers, dimers, and polymers) were characterized through infrared spectroscopy and elemental analysis. Further, the structures of 2 and 4-8 were determined by single-crystal X-ray diffraction. Compound 1 can act as a bidentate ligand in its neutral form (HMHT) and as a μ2 - or μ3 -bridging ligand in its deprotonated form (MHT). The energetic properties of the synthesized complexes, such as their sensitivities toward impact and friction, were determined, and laser ignition tests were performed. New information about the laser initiation process and the role of the anion in the initiation criterion was obtained. The perchlorate complexes 2 (Tdecomp =217 °C) and 3 (Tdecomp =206 °C) are potential primary explosives. 23929689 Kupffer cell-derived IL-10 plays a key role in maintaining humoral immune tolerance in HBV-persistent mice. The liver is considered as a unique lymphoid organ favoring the induction of immune tolerance rather than immunity. Biologists and clinicians alike have a long-standing interest in how liver induces systemic immune tolerance, but the mechanism has not yet been well elucidated. Here, we employed HBV-carrier mice generated by hydrodynamically injecting pAAV/HBV1.2 plasmid as a model for adult chronic HBV infection, which we found were unable to respond to HBsAg vaccination. Humoral tolerance induced in HBV- carrier mice could be transferred into Rag1(-/-) mice, since anti-HBV immunity in immunologically reconstituted Rag1(-/-) mice were inhibited by adoptive transfer of splenocytes from HBV-carrier mice. The humoral tolerance need at least 7 days for induction and persist to 3 months after a single HBV plasmid injection. Kupffer cell depletion or IL-10 deficiency broke this humoral tolerance, and exogenous injection of IL-10 could effectively induce this tolerance. Meanwhile, KCs in HBV-carrier mice expressed more IL-10 and mediated the systemic tolerance induction in an IL-10-dependent manner. This previously un-described humoral tolerance about HBV infection will help to explore new approaches to reverse liver-sustained systemic immune tolerance in liver disease. (Hepatology 2013;). 23584994 Regulation of copper toxicity by Candida albicans GPA2. Copper is an essential nutrient that is toxic to cells when present in excess. The fungal pathogen Candida albicans employs several mechanisms to survive in the presence of excess copper, but the molecular pathways that govern these responses are not completely understood. We report that deletion of GPA2, which specifies a G-protein α subunit, confers increased resistance to excess copper and propose that the increased resistance is due to a combination of decreased copper uptake and an increase in copper chelation by metallothioneins. This is supported by our observations that a gpa2Δ/Δ mutant has reduced expression of the copper uptake genes, CTR1 and FRE7, and a marked decrease in copper accumulation following exposure to high copper levels. Furthermore, deletion of GPA2 results in an increased expression of the copper metallothionein gene, CRD2. Gpa2p functions upstream in the cyclic AMP (cAMP)-protein kinase A (PKA) pathway to govern hyphal morphogenesis. The copper resistance phenotype of the gpa2Δ/Δ mutant can be reversed by artificially increasing the intracellular concentration of cAMP. These results provide evidence for a novel role of the PKA pathway in regulation of copper homeostasis. Furthermore, the connection between the PKA pathway and copper homeostasis appears to be conserved in the pathogen Cryptococcus neoformans but not in the nonpathogenic Saccharomyces cerevisiae. 23922705 Piriformospora indica Root Colonization Triggers Local and Systemic Root Responses and Inhibits Secondary Colonization of Distal Roots. Piriformosporaindica is a basidiomycete fungus colonizing roots of a wide range of higher plants, including crop plants and the model plant Arabidopsis thaliana. Previous studies have shown that P. indica improves growth, and enhances systemic pathogen resistance in leaves of host plants. To investigate systemic effects within the root system, we established a hydroponic split-root cultivation system for Arabidopsis. Using quantitative real-time PCR, we show that initial P. indica colonization triggers a local, transient response of several defense-related transcripts, of which some were also induced in shoots and in distal, non-colonized roots of the same plant. Systemic effects on distal roots included the inhibition of secondary P. indica colonization. Faster and stronger induction of defense-related transcripts during secondary inoculation revealed that a P. indica pretreatment triggers root-wide priming of defense responses, which could cause the observed reduction of secondary colonization levels. Secondary P. indica colonization also induced defense responses in distant, already colonized parts of the root. Endophytic fungi therefore trigger a spatially specific response in directly colonized and in systemic root tissues of host plants. 23630055 A question prompt list for patients with advanced cancer in the final year of life: Development and cross-cultural evaluation. Background: Clinicians and patients find prognosis and end-of-life care discussions challenging. Misunderstanding one's prognosis can contribute to poor decision-making and end-of-life quality of life. A question prompt list (booklet of questions patients can ask clinicians) targeting these issues may help overcome communication barriers. None exists for end-of-life discussions outside the palliative care setting. Aim: To develop/pilot a question prompt list facilitating discussion/planning of end-of-life care for oncology patients with advanced cancer from Australia and the United States and to explore acceptability, perceived benefits/challenges of using the question prompt list, suggestions for improvements and the necessity of country-specific adaptations. Design: An expert panel developed a question prompt list targeting prognosis and end-of-life issues. Australian/US semi-structured interviews and one focus group elicited feedback about the question prompt list. Transcribed data were analysed using qualitative methods. Setting/participants: Thirty-four patients with advanced cancer (15 Australian/19 US) and 13 health professionals treating such patients (7 Australian/6 US) from two Australian and one US cancer centre participated. Results: Most endorsed the entire question prompt list, though a minority queried the utility/appropriateness of some questions. Analysis identified four global themes: (1) reinforcement of known benefits of question prompt lists, (2) appraisal of content and suggestions for further developments, (3) perceived benefits and challenges in using the question prompt list and (4) contrasts in Australian/US feedback. These contrasts necessitated distinct Australian/US final versions of the question prompt list. Conclusions: Participants endorsed the question prompt list as acceptable and useful. Feedback resulted in two distinct versions of the question prompt list, accommodating differences between Australian and US approaches to end-of-life discussions, highlighting the appropriateness of tailoring communication aides to individual populations. 23842564 Introducing reproductive life plan-based information in contraceptive counselling: an RCT. Can reproductive life plan (RLP)-based information in contraceptive counselling before pregnancy increase women's knowledge of reproduction, and of the importance of folic acid intake in particular? The RLP-based information increased women's knowledge of reproduction including knowledge of folic acid intake. Many women have insufficient knowledge of reproduction, including a health-promoting lifestyle prior to conception, and highly educated women in particular postpone childbearing until an age when their fertile capacity has started to decrease. The study was an randomized controlled trial with one intervention group (IG) and two control groups (CG1, CG2). A sample size calculation indicated that 82 women per group would be adequate. Recruitment took place during 3 months in 2012 and 299 women were included. The women were randomized in blocks of three. All groups received standard care (contraceptive counselling, Chlamydia testing, cervical screening). In addition, women in the IG were given oral and written RLP-based information about reproduction. A total of 299 out of 338 (88%) Swedish-speaking women visiting a Student Health Centre were included (mean age 23 years); response rate was 88%. Before the counselling, women in the IG and the CG1 completed a baseline questionnaire, including questions about lifestyle changes in connection to pregnancy planning, family planning intentions and knowledge of reproduction (e.g. the fecundity of an ovum). At follow-up 2 months after inclusion, a structured telephone interview was performed in all groups (n = 262, 88% participation rate). There was no difference between the groups regarding the mean knowledge score at baseline. The IG scored higher at follow-up than at baseline (P < 0.001); the mean increased from 6.4 to 9.0 out of a maximum 20 points. The women in the CG1 scored no differently at follow-up than at baseline. The difference in the knowledge score between the IG and the two CGs was significant (P < 0.001), whereas no difference was shown between the two CGs. There was no difference between the groups at baseline regarding how many women could mention folic acid intake among the things to do when planning to get pregnant. At follow-up, 22% in the IG, 3% in CG1 and 1% in CG2 mentioned folic acid intake (P < 0.001). At follow-up, more women in the IG also wished to have their last child earlier in life (P < 0.001) than at baseline, while there was no difference in the CG1. As the study sample consisted of university students, it is possible that the effect of the intervention was connected to a high level of education and conclusions for all women of reproductive age should be drawn with caution. The provision of RLP-based information seems to be a feasible tool for promoting reproductive health. Study funding was received from the Faculty of Medicine, Uppsala University, Sweden. There are no conflicts of interest. ClinicalTrial.gov Identifier NCT01739101. 23290487 Anti-diabetic property of Tinospora cordifolia and its active compound is mediated through the expression of Glut-4 in L6 myotubes. Tinospora cordifolia is a well reported plant possessing numerous medicinal values including anti-diabetic property. Aim of the present study is to study the mechanism of action of Tinospora cordifolia and its active compound in differentiated myocytes, L6 cells. Key marker of diabetes in cells is the insulin dependent glucose transporter-4 (Glut-4) which also responds to exogenous chemicals, and is over expressed up to 5- and 4-fold, by Tinospora cordifolia and palmatine, respectively. Next to Glut-4, the predominant protein influencing glucose metabolism is PPARα and γ whose expressions were also positively modulated. Further, the inhibitors of insulin pathway prevented glucose uptake mediated by Tinospora cordifolia and palmatine which shows that the activity is majorly mediated through insulin pathway. 23906474 Biodegradation of phenanthrene in bioaugmented microcosm by consortium ASP developed from coastal sediment of Alang-Sosiya ship breaking yard. A phenanthrene-degrading bacterial consortium (ASP) was developed using sediment from the Alang-Sosiya shipbreaking yard at Gujarat, India. 16S rRNA gene-based molecular analyses revealed that the bacterial consortium consisted of six bacterial strains: Bacillus sp. ASP1, Pseudomonas sp. ASP2, Stenotrophomonas maltophilia strain ASP3, Staphylococcus sp. ASP4, Geobacillus sp. ASP5 and Alcaligenes sp. ASP6. The consortium was able to degrade 300ppm of phenanthrene and 1000ppm of naphthalene within 120h and 48h, respectively. Tween 80 showed a positive effect on phenanthrene degradation. The consortium was able to consume maximum phenanthrene at the rate of 46mg/h/l and degrade phenanthrene in the presence of other petroleum hydrocarbons. A microcosm study was conducted to test the consortium's bioremediation potential. Phenanthrene degradation increased from 61% to 94% in sediment bioaugmented with the consortium. Simultaneously, bacterial counts and dehydrogenase activities also increased in the bioaugmented sediment. These results suggest that microbial consortium bioaugmentation may be a promising technology for bioremediation. 23959577 Meniscal Cysts: Treatment Options and Algorithm. Meniscal cysts are commonly seen in the knee. Symptomatic meniscal cysts tend to be located on the lateral side but magnetic resonance imaging studies indicate that medial cysts are more common. Meniscal cysts are commonly associated with horizontal meniscal tears. The arthroscopic management of symptomatic cysts should include debriding the horizontal meniscal tear (if nonrepairable) to fully decompress the cyst and the creation of a 5-mm channel from the joint into the cyst. If a vertical peripheral meniscal tear exists or is created, meniscal repair for appropriately selected cases should be performed. 23958904 The micronutrient zinc inhibits EAEC strain 042 adherence, biofilm formation, virulence gene expression, and epithelial cytokine responses benefiting the infected host. Enteroaggregative Escherichia coli (EAEC) is a major pathogen worldwide, associated with diarrheal disease in both children and adults, suggesting the need for new preventive and therapeutic treatments. We investigated the role of the micronutrient zinc in the pathogenesis of an E. coli strain associated with human disease. A variety of bacterial characteristics-growth in vitro, biofilm formation, adherence to IEC-6 epithelial cells, gene expression of putative EAEC virulence factors as well as EAEC-induced cytokine expression by HCT-8 cells-were quantified. At concentrations (≤ 0.05 mM) that did not alter EAEC growth (strain 042) but that are physiologic in serum, zinc markedly decreased the organism's ability to form biofilm (P < 0.001), adhere to IEC-6 epithelial cells (P < 0.01), and express putative EAEC virulence factors (aggR, aap, aatA, virK) (P < 0.03). After exposure of the organism to zinc, the effect on virulence factor generation was prolonged (> 3 h). Further, EAEC-induced IL-8 mRNA and protein secretion by HCT-8 epithelial cells were significantly reduced by 0.05 mM zinc (P < 0.03). Using an in vivo murine model of diet-induced zinc-deficiency, oral zinc supplementation (0.4 µg/mouse daily) administered after EAEC challenge (10 ( 10) CFU/mouse) significantly abrogated growth shortfalls (by > 90%; P < 0.01); furthermore, stool shedding was reduced (days 9-11) but tissue burden of organisms in the intestine was unchanged. These findings suggest several potential mechanisms whereby physiological levels of zinc alter pathogenetic events in the bacterium (reducing biofilm formation, adherence to epithelium, virulence factor expression) as well as the bacterium's effect on the epithelium (cytokine response to exposure to EAEC) to alter EAEC pathogenesis in vitro and in vivo. These effects may help explain and extend the benefits of zinc in childhood diarrhea and malnutrition. 23945252 Progression of Carotid Intima-Media Thickness and Coronary Artery Calcium Over 6 Years in an HIV-Infected Cohort. To evaluate changes in cardiovascular disease risk surrogate markers in a longitudinal cohort of HIV-infected adults over 6 years. Internal carotid artery (ICA) and common carotid artery (CCA) intima-media thickness (IMT), coronary artery calcium (CAC), vascular, and HIV risk factors were prospectively examined over 6 years in HIV-infected adults from 2002 to 2010. Longitudinal cohort study with participants from urban center and surrounding communities. Three hundred forty-five HIV-infected participants were recruited from a longitudinal cohort study. Two hundred eleven participants completed the study and were included in this analysis. Total and yearly ICA and CCA IMT change; CAC score progression. Participants were 27% female and 49% nonwhite; mean age at start was 45 ± 7 years. The median change in ICA and CCA over 6 years was 0.15 mm (0.08, 0.28) and 0.12 mm (0.09, 0.15), respectively. Age, baseline triglycerides ≥150 mg/dL, and pack-years smoking were associated with ICA IMT change; age, cholesterol, nadir CD4 count, and protease inhibitor use were associated with CCA IMT change. Diabetes, HIV viral load, and highly active antiretroviral therapy duration were associated with CAC progression. Carotid IMT and CAC progressed in this HIV-infected cohort. Some HIV-specific characteristics were associated with surrogate marker changes, but the majority of risk factors continue to be traditional. Aggressive identification and management of modifiable risk factors may reduce progression of cardiovascular disease risk in this population. 23584433 Progression rates from HbA1c 6.0-6.4% and other prediabetes definitions to type 2 diabetes: a meta-analysis. AIMS/HYPOTHESIS: Precise estimates of progression rates from 'prediabetes' to type 2 diabetes are needed to optimise prevention strategies for high-risk individuals. There is acceptance of prediabetes defined by impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), but there is some controversy surrounding HbA1c-defined prediabetes ranges, with some favouring 6.0-6.4% (42-46 mmol/mol). Comparing progression rates between groups might aid this issue, thus we aimed to accurately estimate progression rates to diabetes from different prediabetes categories. METHODS: Meta-analysis of prospective observational studies in which participants had prediabetes at baseline (ADA-defined IFG [5.6-6.9 mmol/l], WHO-defined IFG [6.1-6.9 mmol/l], IGT (7.8-11.0 mmol/l) or raised HbA1c [6.0-6.4%/42-46 mmol/mol]) and were followed up for incident diabetes. Incidence rates were combined using Bayesian random effects models. RESULTS: Overall, 70 studies met the inclusion criteria. In the six studies that used raised HbA1c, the pooled incidence rate (95% credible interval) of diabetes was 35.6 (15.1, 83.0) per 1,000 person-years. This rate was most similar to that for ADA-defined IFG (11 studies; 35.5 [26.6, 48.0]) and was non-significantly lower than WHO-defined IFG (34 studies; 47.4 [37.4, 59.8]), IGT (46 studies, 45.5 [37.8, 54.5]) and IFG plus IGT (15 studies, 70.4 [53.8, 89.7]). Similar results were seen when the data were analysed by the criteria used to diagnose diabetes. CONCLUSIONS/INTERPRETATION: This study provides evidence that progression rates differ by prediabetes definition, which has implications for the planning and implementation of diabetes prevention programmes. HbA1c 6.0-6.4% might identify people at a lower diabetes risk than other prediabetes definitions, but further research is needed. 23523560 5-HT1A receptors direct the orientation of plasticity in layer 5 pyramidal neurons of the mouse prefrontal cortex. Several psychiatric disorders involving the prefrontal cortex (PFC) are associated with a dysfunction of 5-HT1A receptors (5-HT1AR). These receptors, located on interneurons and pyramidal neurons, may influence neuronal excitability through a regulation of the balance between excitation (E) and inhibition (I). Patch-clamp recordings in mouse cortical slices were performed to determine the modulatory role of 5-HT1AR on the excitability and the synaptic plasticity of layer 5 pyramidal neurons (L5PyNs) of the PFC. This was done by a comparison of postsynaptic currents evoked by electrical stimulation in layer 2/3 of 5-HT1AR-KO and wild-type (WT) mice. We observed that the E-I balance was significantly changed from 20% E-80% I in WT mice to 23% E-77% I in 5-HT1AR-KO mice, demonstrating that 5-HT1ARs contribute to the control of the balance between excitation and inhibition. Furthermore, we show that interfering with 5-HT1AR reduced the magnitude of the long term potentiation of excitation (eLTP) (induced by high frequency stimulation). In addition, we show that 5-HT1ARs determine the orientation of the synaptic plasticity towards LTP or LTD or no plasticity through the modulation of NMDAR-mediated currents. Our data point out to a unique role of 5-HT1A postsynaptic receptors in PFC to adapt the functional plasticity of L5PyNs towards LTP, LTD or no plasticity. This brings a new way to intervene on neuronal networks of the PFC in anxiety disorders and schizophrenia. 23789917 A remote Lewis acid trigger dramatically accelerates biaryl reductive elimination from a platinum complex. A strategy for the control of electron density at a metal center is reported, which uses a remote chemical switch involving second-sphere Lewis acid binding that modulates electron density in the first coordination sphere. Binding of the Lewis acid B(C6F5)3 at remote nitrogen positions of a bipyrazine-diarylplatinum(II) complex accelerates biaryl reductive elimination by a factor of 64,000. 23884266 Placenta increta after hysteroscopic myomectomy. Most cases of abnormal placentation are associated with a history of one or more cesarean deliveries. Uterine leiomyomas and treatment for such a diagnosis are also risk factors for placenta accreta and should be viewed as such. A 34-year-old woman underwent a hysteroscopic myomectomy and became pregnant 6 months later. Ultrasonography and magnetic resonance imaging suggested a placenta percreta. Multidisciplinary care allowed for a safe delivery of her neonate and little maternal morbidity. Patients with a history of hysteroscopic myomectomy or other uterine leiomyoma treatment are at an increased risk for abnormal placentation. Imaging studies are suggested in such patients to coordinate multidisciplinary care to decrease maternal and fetal morbidity and mortality. 23918037 Long-term safety and efficacy of certolizumab pegol in combination with methotrexate in the treatment of rheumatoid arthritis: 5-year results from the RAPID 1 trial and open-label extension. To examine the safety and efficacy of 5-year administration of certolizumab pegol (CZP)+methotrexate (MTX) in patients with active rheumatoid arthritis (RA). Eligible patients from the Rheumatoid Arthritis Prevention of Structural Damage (RAPID)1 randomised controlled trial (RCT) were treated in open-label extension (OLE) with CZP 400 mg every other week (Q2W), reduced to 200 mg Q2W after ≥6 months, +MTX. Combined safety data from RCT and OLE are presented from initiation of CZP treatment to 12 wks post last visit in patients receiving ≥1 dose of CZP (Safety population, N=958). Efficacy data are presented to start of first site closure (wk 256 of CZP treatment: 52 wks in RCT+204 wks in OLE) for all patients randomised to receive CZP (intent-to-treat (ITT) population, N=783) and CZP patients who completed the 52 wk RCT and enrolled into OLE (wk 52 CZP completers, N=508). Disease Activity Score (DAS)28 (Erythrocyte Sedimentation Rate (ESR)), American College of Rheumatology Criteria (ACR) 20/50/70, Health Assessment Questionnaire - Disability Index (HAQ-DI), and patient retention (Kaplan-Meier analysis) were assessed. Overall event rate per 100 patient-years (ER) of adverse events (AEs) was 290.4, most frequently: urinary tract infections (ER=7.9), nasopharyngitis (ER=7.3) and upper respiratory tract infections (ER=7.3). ER of serious AEs was 20.3 (infections=5.9, malignancies=1.2). 21 patients (2.2%) experienced an AE resulting in death (incidence rate=0.6). At wk 256 of treatment, 55.3% of the CZP ITT population were estimated to remain on treatment (68.7% if solely withdrawals due to AE or lack of efficacy were considered). In wk 52 CZP completers and CZP ITT population, DAS28 (ESR) remission rates and improvements from baseline were sustained to wk 256. CZP+MTX treatment provided a favourable risk-benefit profile over 5 years in patients with active RA. No new safety signals were identified. 23830952 Diagnosis and treatment of coagulopathy following percutaneous cryoablation of liver tumors: Experience in 372 patients. Coagulopathy after liver cryoablation was first reported many years ago; the cause is local platelet trapping and destruction within the margin of the cryolesion. However, the prognosis and therapeutic effects of coagulopathy remain unclear. This study retrospectively reviewed clinical data from 372 patients (525 sessions) who underwent liver cryoablation in our hospital during the past 4.5years. Small tumors (major diameter<6cm) were treated with a single complete ablation; massive tumors (major diameter 6-10cm or >10cm) were divided into two or three parts that were dealt with in turn. Platelet counts decreased to an average of (46.12±68.13)×10(9)/L after each session of cryoablation. The decline was most evident in patients with high pretreatment platelet counts, while those with low pretreatment counts had the highest risk of coagulopathy. Change in platelet count was not correlated with the diameter of the tumor. Slight coagulopathy (platelet count (70-100)×10(9)/L) can resolve without treatment within 1week and administration of recombinant human interleukin-11 can assist recovery from severe coagulopathy (platelet count<70×10(9)/L). 23837841 Water-level fluctuations and metapopulation dynamics as drivers of genetic diversity in populations of three Tanganyikan cichlid fish species. Understanding how genetic variation is generated and maintained in natural populations, and how this process unfolds in a changing environment, remains a central issue in biological research. In this work, we analysed patterns of genetic diversity from several populations of three cichlid species from Lake Tanganyika in parallel, using the mitochondrial DNA control region. We sampled populations inhabiting the littoral rocky habitats in both very deep and very shallow areas of the lake. We hypothesized that the former would constitute relatively older, more stable and genetically more diverse populations, because they should have been less severely affected by the well-documented episodes of dramatic water-level fluctuations. In agreement with our predictions, populations of all three species sampled in very shallow shorelines showed traces of stronger population growth than populations of the same species inhabiting deep shorelines. However, contrary to our working hypothesis, we found a significant trend towards increased genetic diversity in the younger, demographically less stable populations inhabiting shallow areas, in comparison with the older and more stable populations inhabiting the deep shorelines. We interpret this finding as the result of the establishment of metapopulation dynamics in the former shorelines, by the frequent perturbation and reshuffling of individuals between populations due to the lake-level fluctuations. The repeated succession of periods of allopatric separation and secondary contact is likely to have further increased the rapid pace of speciation in lacustrine cichlids. 23823700 Trends in health-related quality of life among adolescents in the United States, 2001-2010. Health-related quality of life (HRQOL) measures are often used to track changes in population health, mostly among adults. Prompted by the recent US recession, we assessed trends in adolescent HRQOL by using cross-sectional data from the 2001-2010 National Health and Nutrition Examination Survey. Adolescents' self-rated health and reported mental health declined significantly, especially among those in low-income families, but their physical health and activity limitation did not change. Because these HRQOL declines occurred at the end of the decade and especially among adolescents from low-income families, we conclude that these declines are consistent with recession effects and warrant further study. 23969391 Multiview face detection and registration requiring minimal manual intervention. Most face recognition systems require faces to be detected and localized a priori. In this paper, an approach to simultaneously detect and localize multiple faces having arbitrary views and different scales is proposed. The main contribution of this paper is the introduction of a face constellation, which enables multiview face detection and localization. In contrast to other multiview approaches that require many manually labeled images for training, the proposed face constellation requires only a single reference image of a face containing two manually indicated reference points for initialization. Subsequent training face images from arbitrary views are automatically added to the constellation (registered to the reference image) based on finding the correspondences between distinctive local features. Thus, the key advantage of the proposed scheme is the minimal manual intervention required to train the face constellation. We also propose an approach to identify distinctive correspondence points between pairs of face images in the presence of a large amount of false matches. To detect and localize multiple faces with arbitrary views, we then propose a probabilistic classifier-based formulation to evaluate whether a local feature cluster corresponds to a face. Experimental results conducted on the FERET, CMU, and FDDB datasets show that our proposed approach has better performance compared to the state-of-the-art approaches for detecting faces with arbitrary pose. 23843264 Evaluation of retinal pigment epithelium-Bruch's membrane complex thickness in dry age-related macular degeneration using optical coherence tomography. To compare retinal pigment epithelium-Bruch's membrane (RPE-BM) complex thickness in patients with early and intermediate dry age-related macular degeneration (AMD) and age-matched controls using spectral domain optical coherence tomography (SD-OCT). In this retrospective, cross-sectional study, 25 patients with dry AMD and 25 controls were recruited. SD-OCT scans were manually segmented by two independent investigators. Thickness values were calculated for the nine Early Treatment Diabetic Retinopathy Study (ETDRS) subfields. RPE-BM thickness was significantly thicker in the dry AMD group (32.3, 30.6 and 28.4 μm for central, inner and outer subfields, respectively) compared with the normal eyes (22.7, 21.8 and 21.6 μm, respectively). RPE-BM thickness was positively correlated with age in the normal group but not in the AMD group. RPE-BM thickness in the dry AMD group was negatively correlated with visual acuity in the central and inner subfields but not in the outer. We observed good intraobserver and inter-observer reliability for both groups in all ETDRS subfields. This study reports novel data concerning RPE-BM segmentation in dry AMD and performs a direct comparison with age-matched normal controls. Our findings confirm the electron and light microscopy derived data and also establish the value of OCT in the quantification of the RPE-BM complex. 23673450 Management of malignant pleural effusions: questions that need answers. Malignant pleural effusion (MPE) is common. However, regardless of the differences between patients, their underlying cancer type, and pleural fluid characteristics, management options are often limited. These have not advanced significantly over the last 80 years since pleurodesis was first described. Correspondingly, patient-related outcome measures have been neglected. The evidence (or lack of) behind the current treatment recommendations is reviewed and key research questions are described. Talc continues to be the most effective sclerosant available for pleurodesis in MPE. A recent randomized controlled trial comparing talc pleurodesis and indwelling pleural catheter insertion as first-line therapy suggests these approaches are equally effective, and utilized a patient-based symptom score as the primary outcome. The need to acknowledge the advances in translational medicine and oncological therapies to measure patient-related trial outcomes and to target pleural fluid formation in MPE is discussed. Pulmonologists should be aware of the staggering lack of progress in the evidence that supports the current 'recommended' management of MPE. The need for a re-think about MPE management with a focus on alternative therapeutic targets and treatment objectives should be appreciated, in order to optimize future patient care. 23735715 Production of chimeric embryos by aggregation of bovine egfp eight-cell stage blastomeres with two-cell fused and asynchronic embryos. Embryo disaggregation allows the production of two to four identical offspring from a single cow embryo. In addition, embryo complementation has become the technique of choice to demonstrate the totipotency of embryonic stem cells and induced pluripotent stem cells. Therefore, the aim of this study was to generate a new and simple method by aggregation in the well-of-the-well system to direct each single enhanced green fluorescent protein (egfp) eight-cell blastomere derived from bovine in vitro fertilization embryos to the inner cell mass (ICM) of chimeras produced with fused and asynchronic embryos. To this end, the best conditions to generate in vitro fertilization-fused embryos were determined. Then, the fused (F) and nonfused (NF) embryos were aggregated in two distinct conditions: synchronically (S), with both transgenic and F embryos produced on the same day, and asynchronically (AS), with transgenic embryos produced one day before F embryos. The highest fusion and blastocysts rates were obtained with two pulses of 40 V. The 2ASF and 2ASNF groups showed the best number of blastocysts expressing the EGFP protein (48% and 41%, respectively). Furthermore, the 2ASF group induced the highest localization rates of the egfp-expressing blastomere in the ICM (6/13, 46% of ICM transgene-expressing blastocysts). This technique will have great application for multiplication of embryos of high genetic value or transgenic embryos and also with the generation of truly bovine embryonic stem cells and induced pluripotent stem cells. 23747751 In vitro drug susceptibility of Leishmania infantum isolated from humans and dogs. Visceral leishmaniasis (VL) caused by parasites of Leishmania donovani complex is a severe human disease which often leads to death if left untreated. Domestic dogs are the main reservoir hosts for zoonotic human visceral infection caused by Leishmania infantum. In the absence of effective human and dog vaccines, the only feasible way to treat and control leishmaniasis is through the use of suitable medications. To know the drug susceptibility of human and canine Leishmania strains from Lisbon-Portugal, a study on a panel of strains was conducted by testing the susceptibility of promastigotes and intracellular amastigotes to the common drugs used in canine leishmaniasis (CanL) and human VL (meglumine antimoniate, amphotericin B, miltefosine and allopurinol). Although a high heterogeneity of susceptibilities was obtained to each drug on both axenic promastigote and intracellular amastigote assays, intracellular amastigotes system correlated better with treatment outcome. Parasites isolated from the refractory human case were the least susceptible to the drugs used highlighting that the emergence of cross-resistance to the drugs available for human therapy should not be neglected. Furthermore, parasites isolated from dogs showed low susceptibility to the main drugs used in CanL treatment. Our results focus the importance of reducing/avoiding the emergence and spread of resistant parasites in the canine and human populations, a factor that requires special consideration when dogs are treated using the same available anti-Leishmania drugs for human VL. In addition, efforts should be made in order to standardize the conditions used to test drug susceptibility (methodologies, drug formulations and media) in order to compare results between laboratories. 23607708 Neuronal differentiation requires a biphasic modulation of gap junctional intercellular communication caused by dynamic changes of connexin43 expression. It was suggested that gap junctional intercellular communication (GJIC) and connexin (Cx) proteins play a crucial role in cell proliferation and differentiation. However, the mechanisms of cell coupling in regulating cell fate during embryonic development are poorly understood. To study the role of GJIC in proliferation and differentiation, we used a human neural progenitor cell line derived from the ventral mesencephalon. Fluorescence recovery after photobleaching (FRAP) showed that dye coupling was extensive in proliferating cells but diminished after the induction of differentiation, as indicated by a 2.5-fold increase of the half-time of fluorescence recovery. Notably, recovery half-time decreased strongly (five-fold) in the later stage of differentiation. Western blot analysis revealed a similar time-dependent expression profile of Cx43, acting as the main gap junction-forming protein. Interestingly, large amounts of cytoplasmic Cx43 were retained mainly in the Golgi network during proliferation but decreased when differentiation was induced. Furthermore, down-regulation of Cx43 by small interfering RNA reduced functional cell coupling, which in turn resulted in a 50% decrease of both the proliferation rate and neuronal differentiation. Our findings suggest a dual function of Cx43 and GJIC in the neural development of ReNcell VM197 human progenitor cells. GJIC accompanied by high Cx43 expression is necessary (1) to maintain cells in a proliferative state and (2) to complete neuronal differentiation, including the establishment of a neural network. However, uncoupling of cells is crucial in the early stage of differentiation during cell fate commitment. 23823605 Use of phosphate-binding agents is associated with a lower risk of mortality. Hyperphosphatemia has been associated with higher mortality risk in CKD 5 patients receiving dialysis. Here, we determined the association between the use of single and combined phosphate-binding agents and survival in 6797 patients of the COSMOS study: a 3-year follow-up, multicenter, open-cohort, observational prospective study carried out in 227 dialysis centers from 20 European countries. Patient phosphate-binding agent prescriptions (time-varying) and the case-mix-adjusted facility percentage of phosphate-binding agent prescriptions (instrumental variable) were used as predictors of the relative all-cause and cardiovascular mortality using Cox proportional hazard regression models. Three different multivariate models that included up to 24 variables were used for adjustments. After multivariate analysis, patients prescribed phosphate-binding agents showed a 29 and 22% lower all-cause and cardiovascular mortality risk, respectively. The survival advantage of phosphate-binding agent prescription remained statistically significant after propensity score matching analysis. A decrease of 8% in the relative risk of mortality was found for every 10% increase in the case-mix-adjusted facility prescription of phosphate-binding agents. All single and combined therapies with phosphate-binding agents, except aluminum salts, showed a beneficial association with survival. The findings made in the present association study need to be confirmed by randomized controlled trials to prove the observed beneficial effect of phosphate-binding agents on mortality.Kidney International advance online publication, 3 July 2013; doi:10.1038/ki.2013.185. 23527505 Is sensitivity to reward associated with the malleability of implicit inclinations toward high-fat food? Two experiments examined the effect of positive and negative priming on implicit approach and avoidance inclinations toward high-fat food stimuli in participants high or low in reward sensitivity, using personalized unipolar variants of the Implicit Association Test (IAT; A. G. Greenwald, D. E. McGhee, & J. L. K. Schwartz, 1998, "Measuring individual differences in implicit cognition: The Implicit Association Test," Journal of Personality and Social Psychology, Vol. 74, pp. 1464-1480). Participants high in reward sensitivity showed an automatic processing bias that is characterized by a dual vulnerability of being particularly susceptible to priming of the rewarding aspects of high-fat foods, while being unaffected by priming of the negative aspects of those foods. In contrast, participants low in reward sensitivity generally showed no facilitation of implicit-approach inclinations following positive priming, but consistently showed facilitation of implicit-avoidance inclinations following negative priming. These results are consistent with the revised reinforcement sensitivity theory ( J. A. Gray & N. McNaughton, 2000, The neuropsychology of anxiety: An enquiry into the functions of the septo-hippocampal system, 2nd ed., New York, NY, Oxford University Press.) and suggest that the systems mediating reward sensitivity and punishment sensitivity are not orthogonal, as predicted by the separable subsystems hypothesis, but can be interdependent, as predicted by the joint subsystems hypothesis. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23207247 Objective outcomes 14 years after laparoscopic anterior 180-degree partial versus nissen fundoplication: results from a randomized trial. To investigate late objective outcomes 14 years after laparoscopic anterior 180-degree partial versus Nissen fundoplication. Clinical outcomes from randomized clinical trials suggest good outcomes for anterior 180-degree partial fundoplication, with similar control of reflux symptoms and less side effects, compared with Nissen fundoplication. However, objective outcomes at late follow-up have not been reported. A subset of participants from a randomized trial of anterior 180-degree versus Nissen fundoplication underwent stationary esophageal high-resolution manometry and ambulatory 24-hour impedance-pH monitoring at 14 years' follow-up. The subset and other patients in the trial also completed a standardized clinical questionnaire to ensure that they were representative of the overall trial. Eighteen patients (8 anterior, 10 Nissen) underwent objective testing and had a symptom profile similar to those who did not (n = 59) have testing. Total esophageal acid exposure time and the total number of acid and weakly acidic reflux episodes per 24 hours were higher after anterior fundoplication than after Nissen fundoplication. Proximal, midesophageal and distal reflux were proportionately increased after anterior 180-degree fundoplication. The number of liquid and mixed reflux episodes was also higher after anterior fundoplication, which was accompanied by higher clinical heartburn scores. There were no differences in gas reflux, gastric belches, and supragastric belches, which is in line with the observation that gas-related symptoms were similar for both groups. Mean LES resting and relaxation nadir pressure were lower after anterior fundoplication, which was reflected by lower dysphagia scores. Patient satisfaction was similar after both procedures. At 14 years after randomization, this study demonstrated that acid, weakly acidic, liquid and mixed reflux episodes are more common after anterior 180-degree fundoplication than after Nissen fundoplication. On the contrary, gas reflux and gastric belching and patient satisfaction are similar for both procedures. Mean LES resting and relaxation nadir pressure are lower after anterior fundoplication. Overall, these findings suggest less effective reflux control after anterior 180-degree partial fundoplication, offset by less dysphagia, leading to a clinical outcome that is equivalent to Nissen fundoplication at late follow-up. 22349823 Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor. The epidermal growth factor receptor (EGFR) has an essential role in multiple signaling pathways, including cell proliferation and migration, through extracellular ligand binding and subsequent activation of its intracellular tyrosine kinase (TK) domain. The non-small cell lung cancer (NSCLC)-associated EGFR mutants, L858R and G719S, are constitutively active and oncogenic. They display sensitivity to TK inhibitors, including gefitinib and erlotinib. In contrast, the secondary mutation of the gatekeeper residue, T790M, reportedly confers inhibitor resistance on the oncogenic EGFR mutants. In this study, our biochemical analyses revealed that the introduction of the T790M mutation confers gefitinib resistance on the G719S mutant. The G719S/T790M double mutant has enhanced activity and retains high gefitinib-binding affinity. The T790M mutation increases the ATP affinity of the G719S mutant, explaining the acquired drug resistance of the double mutant. Structural analyses of the G719S/T790M double mutant, as well as the wild type and the G719S and L858R mutants, revealed that the T790M mutation stabilizes the hydrophobic spine of the active EGFR-TK conformation. The Met790 side chain of the G719S/T790M double mutant, in the apo form and gefitinib- and AMPPNP-bound forms, adopts different conformations that explain the accommodation of these ligands. In the L858R mutant structure, the active-site cleft is expanded by the repositioning of Phe723 within the P-loop. Notably, the introduction of the F723A mutation greatly enhanced the gefitinib sensitivity of the wild-type EGFR in vivo, supporting our hypothesis that the expansion of the active-site cleft results in enhanced gefitinib sensitivity. Taken together, our results provide a structural basis for the altered drug sensitivities caused by distinct NSCLC-associated EGFR mutations. 23802661 The use of transient elastography and non-invasive serum markers of fibrosis in pediatric liver transplant recipients. The use of non-invasive markers to diagnose liver allograft fibrosis is not well established in children after LTx. TE, FT, and ELF score were performed in 117 liver-transplanted children (60M, 8.9 [0.5-18.5] yr) and 336 healthy controls. Liver biopsy was available in 36 children. Results of histology and non-invasive markers were compared using correlation coefficient or Mann-Whitney U-test as appropriate. TE correlated best with histological degree of fibrosis (r = 0.85 vs. r = 0.04 [FT] or r = -0.38 [ELF]). Liver stiffness values for transplanted children without fibrosis were significantly higher than those of healthy controls (7.55 [5.4-20.4] kPa vs. 4.5 [2.5-8.9] kPa). Presence of rejection was a potent confounder for the performance of TE. Both TE and FT reflected clinical changes (acute rejection, cholestasis, increasing fibrosis) in a total of 16 patients who underwent serial measurements. TE correlates better with histological degree of fibrosis in liver-transplanted children than FT or ELF, but an individual baseline value needs to be determined for each patient. Normal or cutoff values for pathological degrees of fibrosis cannot be transferred from non-transplanted children. Follow-up studies, preferably with protocol biopsies, might help to improve the diagnostic quality of TE. 23512074 UHV-Alginate as Matrix for Neurotrophic Factor Producing Cells-A Novel Biomaterial for Cochlear Implant Optimization to Preserve Inner Ear Neurons From Degeneration. Ultra high viscous (UHV-) alginate is a suitable matrix for brain-derived neurotrophic factor (BDNF) producing cells, enabling cell survival and BDNF release out of the matrix and subsequent protection of auditory neuronal cells. Cochlear implant (CI) target cells, spiral ganglion cells (SGC), undergo a progressive degeneration. BDNF prevents SGC from degeneration but has to be delivered locally to the inner ear for months. A permanent growth factor application may be realized via a cell-based drug delivery system. Encapsulation of this delivery system into a matrix could avoid immune response of the recipient, migration, and uncontrolled proliferation of the cells. NIH3T3-fibroblasts producing endogenous BDNF were incorporated in UHV-alginate. The survival of the cells in the alginate was examined by cell counts of cryogenic slices, and the BDNF production was determined by performing ELISA. The supernatant of the alginate-cell culture was added to primary SGC culture, and the neuroprotective effect of the produced BDNF was observed performing SGC counts. BDNF-producing cells cultivated in UHV-alginate survived for up to 30 days, which was the latest time point observed. The BDNF concentration in cell culture medium, produced from in UHV-alginate incorporated fibroblasts and released out of the alginate matrix into the medium, was significantly increased after 30 days of cultivation. Supernatant of 7 days incubated UHV-alginate containing NIH3T3/BDNF cells significantly increased the SGC survival in vitro. This study demonstrates UHV-alginate to be a suitable scaffold for BDNF-producing fibroblasts. UHV-alginates are a promising biomaterial for cochlear implant biofunctionalization. 23838869 Complete Obstetric Anal Sphincter Tear and Risk of Long-term Fecal Incontinence: A Cohort Study. Women with anal sphincter injuries have an increased risk of developing fecal incontinence despite surgical intervention. The aim of this study was to evaluate the long-term risk of fecal incontinence after primary anal sphincter reconstruction and its impact on quality of life. This was a cohort study. This study was performed at Aarhus University Hospital. Women with complete anal sphincter rupture (exposed) from 1976 to 1991 and a control group of parous women (nonexposed) were included. The primary outcomes measured were fecal incontinence, Wexner score, St Mark incontinence score, and quality of life. A total of 363 women were included (125 exposed and 238 nonexposed). The mean age was 50.4 years (95%CI: 49.8-51.0), with 22.2 years (95% CI: 21.7-22.6) of follow-up. At the time of follow-up, 49% of exposed women and 74% of nonexposed women were continent. Complete anal sphincter tear increases the risk of fecal incontinence twofold (relative risk = 2.00; 95%CI: 1.52-2.63). No other risk factors were identified. The mean Wexner score was 1.7 (95%CI: 1.3-2.1) vs 1.1 (95%CI: 0.7-1.4) (p = 0.02), and the mean St Mark score was 2.8 (95% CI: 2.1-3.4) vs 1.4 (95%CI: 1.0-1.9) (p < 0.001) in the exposed and nonexposed groups. Severity of fecal incontinence had a significant impact on the quality of life independent of exposure. The cohort is relatively young; a short postmenopausal period limits the assessment of hormonal status and the effect of postmenopausal hormone replacement therapy. Complete obstetric anal sphincter tear increases the long-term risk of fecal incontinence twofold. When present, the severity of the incontinence symptoms is minor and the risk of incontinence for solid stool is not increased in comparison with the general population. Anal sphincter rupture is the only independent risk factor for fecal incontinence. The severity of fecal incontinence had the same impact on quality of life in both groups. 22584460 Profiling of drug-metabolizing enzymes/transporters in CD33+ acute myeloid leukemia patients treated with Gemtuzumab-Ozogamicin and Fludarabine, Cytarabine and Idarubicin. Genetic heterogeneity in drug-metabolizing enzyme/transporter (DMET) genes affects specific drug-related cancer phenotypes. To investigate the relationships between genetic variation and response to treatment in acute myeloid leukemia (AML), we genotyped 1931 variants on DMET genes in 94 CD33-positive AML patients enrolled in a phase III multicenter clinical trial combining Gemtuzumab-Ozogamicin (GO) with Fludarabine-Cytarabine-Idarubicin (FLAI) regimen, with the DMET Plus platform. Two ADH1A variants showed statistically significant differences (odds ratio (OR)=5.68, P=0.0006; OR=5.35, P=0.0009) in allele frequencies between patients in complete/partial remission and patients without response, two substitutions on CYP2E1 (OR=0.13, P=0.001; OR=0.09, P=0.003) and one on SLCO1B1 (OR=4.68, P=0.002) were found to differently influence liver toxicity, and two nucleotide changes on SULTB1 and SLC22A12 genes correlated with response to GO (OR=0.24, P=0.0009; OR=2.75, P=0.0029). Genetic variants were thus found for the first time to be potentially associated with differential response and toxicity in AML patients treated with a combination of GO-FLAI regimen. 23652804 The microenvironment of AIDS-related diffuse large B-cell lymphoma provides insight into the pathophysiology and indicates possible therapeutic strategies. Despite the use of highly active antiretroviral therapy (HAART), AIDS-related lymphoma remains common. We investigated the tumor, microenvironment, and viral components in 41 AIDS-related diffuse large B-cell lymphomas (AR-DLBCLs) in the pre- and post-HAART era. The outcome has improved and the frequency of the prognostically unfavorable immunoblastic histology has decreased after HAART. Compared with sporadic cases, AR-DLBCL demonstrated increased hyperproliferation (P < .001) and c-Myc rearrangements, reduced CD4(+) (P < .001) and FOXP3(+) T cells (P < .001), increased activated cytotoxic cells (P < .001), but no difference in tumor-associated macrophages. Our analysis showed that AR-DLBCL is highly angiogenic with higher blood-vessel density than sporadic cases (P < .001) and highlighted the role of Epstein-Barr virus in angiogenesis. We recognized viral profiles and as a second step examined the reactive cytotoxic cell infiltrates. Our observation of markedly higher numbers of cytotoxic cells in AR-DLBCL with LMP1 and/or p24 compared with cases lacking viral antigens (P < .001) has important clinical implications, implicitly linked to the immunosurveillance theory. Whereas early initiation of HAART should improve immunosurveillance and reduce the incidence of LMP1-positive AR-DLBCL, cases without viral antigens appear able to avoid immunologic reaction and likely require additional strategies to improve surveillance. 23917544 Flow-Through Divided Latissimus Dorsi Musculocutaneous Flap for Large Extremity Defects. Reconstructing large defects of the extremities is a challenging problem for reconstructive microsurgeons. The latissimus dorsi musculocutaneous flap (LDMCF) is widely used for this purpose, but a skin graft is needed when the defect is wider than available flaps. We used flow-through divided LDMCFs to reconstruct large defects of the extremities in 5 consecutive patients from 2010 through 2012. The semicircular skin island was split longitudinally, and 1 skin island was advanced over the other to close a round or oval defect without a skin graft. Postoperatively, all flaps survived completely, and the mean Enneking score was 90.0%. The flow-through divided LDMCF is a reliable and versatile option for reconstructing large defects of the extremities. 23529902 Generation of a novel germline stem cell line expressing a germline-specific reporter in the mouse. Germline stem (GS) cells are stem cell lines derived from postnatal male germline cells. Remarkably, GS cells can form functional spermatozoa when transplanted into infertile host mouse testes, indicating that GS cells have spermatogonial stem cell (SSC) activity. As GS cells are the only type with SSC activity, they are most suitable for in vitro studies on male germ cell differentiation. However, GS cells can deviate from the germ cell state to become other types of cells, depending on culture conditions. Therefore, it is desirable to have a monitor system to ensure that GS cells are kept at the germ cell state in culture. Here, we established GS cell lines from neonatal testes of transgenic mice that express the fluorescent protein, Venus, whose gene expression is driven by the promoter of Mvh (mouse Vasa homolog), a gene highly specific to mammalian germ cells. This novel cell line has genuine GS cell properties equivalent to existing GS lines, including the ability to generate viable offspring. This Mvh-Venus GS cell line, to our knowledge, is the first one expressing a germ cell-specific reporter. This valuable resource should provide new opportunities for studies on male germ cell differentiation. genesis 51:498-505. © 2013 Wiley Periodicals, Inc. 23966296 Novel Insights Into Appropriate Encapsulation Methods for Bioactive Compounds Into Polymers: A Study With Peptides and HDAC Inhibitors. The use of different nanoparticles (NPs) for successful encapsulation of bioactive substances is discussed. The inclusion efficiency into liposomes, acetalated dextran (Ac-Dex), and variants of poly[(lactic acid)-co-(glycolic acid)] (PLGA) NPs is analyzed after chemical degradation. Efficient inclusion of SIRT1 inhibitor Ex527 in liposomes, Ac-Dex- and PLGA-NPs is observed for all procedures used. Activity of Ex527 is demonstrated by monitoring the acetylation status of SIRT1-target p53. In contrast, small peptides are only incorporated into acid-terminated PLGA-NPs and marginally into Ac-Dex-NPs. The yield depends on peptide sequence and terminal modifications. Activity is exemplified for angiotensin II using the dynamic mass redistribution technology. 23313620 Enhanced chemopreventive activity of hydroxytyrosol on HL60 and HL60R cells by chemical conversion into thio derivatives. Thio derivatives of hydroxytyrosol containing thiol, thioacetate and disulfide functionalities were synthesized from natural hydroxytyrosol (3,4-DHPEA) via 3,4-dihydroxyphenethyl halides. These compounds, containing the combination of catechol moiety and divalent sulfur functions, were tested for the pro-apoptotic and anti-proliferative activities on both parental HL60 and multi-drug resistant HL60R cells. It was found that all synthesized compounds were more effective than 3,4-DHPEA in inducing apoptosis on HL60R cells, and that the hydroxytyrosol disulfide was the most active pro-apoptotic and anti-proliferative compound on both HL60 and HL60R cells. Different from 3,4-DHPEA, all thio derivatives of hydroxytyrosol induced apoptosis by a mechanism not involving the release of H(2)O(2) in the culture medium. The data on HL60R cells suggest that these compounds could be able to reverse the resistance toward the most common drugs in cancer therapy. 23414838 Discovery of a novel series of quinolone α7 nicotinic acetylcholine receptor agonists. High throughput screening led to the identification of a novel series of quinolone α7 nicotinic acetylcholine receptor (nAChR) agonists. Optimization of an HTS hit (1) led to 4-phenyl-1-(quinuclidin-3-ylmethyl)quinolin-2(1H)-one, which was found to be potent and selective. Poor brain penetrance in this series was attributed to transporter-mediated efflux, which was in turn due to high pKa. A novel 4-fluoroquinuclidine significantly lowered the pKa of the quinuclidine moiety, reducing efflux as measured by a Caco-2 assay. 23925523 Synthesis and biological evaluation of non-isomerizable analogues of Ala-tRNA(Ala.). Aminoacyl-tRNAs serve as amino acid donors in many reactions in addition to protein synthesis by the ribosome, including synthesis of the peptidoglycan network in the cell wall of bacterial pathogens. Synthesis of analogs of aminoacylated tRNAs is critical to further improve the mechanism of these reactions. Here we have described the synthesis of two non-isomerizable analogues of Ala-tRNA(Ala) containing an amide bond instead of the isomerizable ester that connects the amino acid with the terminal adenosine in the natural substrate. The non-isomerizable 2' and 3' regioisomers were not used as substrates by FemXWv, an alanyl-transferase essential for peptidoglycan synthesis, but inhibited this enzyme with IC50 of 5.8 and 5.5 μM, respectively. 23850240 Levofloxacin oxidation by ozone and hydroxyl radicals: Kinetic study, transformation products and toxicity. This work was carried out to investigate the fate of the antibiotic levofloxacin upon oxidation with ozone and hydroxyl radicals. A kinetic study was conducted at 20°C for each oxidant. Ozonation experiments were performed using a competitive kinetic method with carbamazepin as competitor. Significant levofloxacin removal was observed during ozonation and a rate constant value of 6.0×10(4)M(-1)s(-1) was obtained at pH 7.2. An H2O2/UV system was used for the formation of hydroxyl radicals HO. The rate constant of HO was determined in the presence of a high H2O2 concentration. The kinetic expressions yielded a [Formula: see text] value of 4.5×10(9)M(-1)s(-1) at pH 6.0 and 5.2×10(9)M(-1)s(-1) at pH 7.2. These results were used to develop a model to predict the efficacy of the ozonation process and pharmaceutical removal was estimated under different ozonation conditions (i.e. oxidant concentrations and contact times). The results showed that levofloxacin was completely degraded by molecular ozone during ozonation of water and that hydroxyl radicals had no effect in real waters conditions. Moreover, LC/MS/MS and toxicity assays using Lumistox test were performed to identify ozonation transformation products. Under these conditions, four transformation products were observed and their chemical structures were proposed. The results showed an increase in toxicity during ozonation, even after degradation of all of the observed transformation products. The formation of other transformation products not identified under our experimental conditions could be responsible for the observed toxicity. These products might be ozone-resistant and more toxic to Vibrio fisheri than levofloxacin. 23916678 Quantitation of influenza virus using field flow fractionation and multi-angle light scattering for quantifying influenza A particles. Recent advances in instrumentation and data analysis in field flow fractionation and multi-angle light scattering (FFF-MALS) have enabled greater use of this technique to characterize and quantitate viruses. In this study, the FFF-MALS technique was applied to the characterization and quantitation of type A influenza virus particles to assess its usefulness for vaccine preparation. The use of FFF-MALS for quantitation and measurement of control particles provided data accurate to within 5% of known values, reproducible with a coefficient of variation of 1.9%. The methods, sensitivity and limit of detection were established by analyzing different volumes of purified virus, which produced a linear regression with fitting value R(2) of 0.99. FFF-MALS was further applied to detect and quantitate influenza virus in the supernatant of infected MDCK cells and allantoic fluids of infected eggs. FFF fractograms of the virus present in these different fluids revealed similar distribution of monomeric and oligomeric virions. However, the monomer fraction of cell grown virus had greater size variety. Notably, β-propialactone (BPL) inactivation of influenza viruses did not influence any of the FFF-MALS measurements. Quantitation analysis by FFF-MALS was compared to infectivity assays and real-time RT-PCR (qRT-PCR) and the limitations of each assay were discussed. 23106845 The antecedents and consequences of racial/ethnic discrimination during adolescence: Does the source of discrimination matter? In the current study, we examined the precursors and consequences of discrimination for 876 Latino, African American, and Asian American adolescents (Mage = 16.9 years, SD = 0.43). The race/ethnic characteristics of schools and neighborhoods influenced adolescents' perceptions of the race/ethnic climates of these contexts. In turn, adolescents who viewed climates more negatively were more likely to perceive discriminatory treatment by school personnel, peers, and societal institutions. Discrimination from these 3 sources exerted differential influence on developmental outcomes: Greater discrimination from school personnel was associated with poorer academic performance, greater discrimination from peers was associated with more psychological maladjustment, and greater societal discrimination was associated with heightened racial awareness. Relations were consistent across race/ethnic groups and gender. Implications for intervening to reduce racial discrimination and other social stigmas are discussed. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23689722 Clinical validation of the analysis of linezolid and clarithromycin in oral fluid of patients with multidrug-resistant tuberculosis. Linezolid plays an increasingly important role in the treatment of multidrug-resistant tuberculosis (MDR-TB). However, patients should be carefully monitored due to time- and dose-dependent toxicity. Clarithromycin plays a more modest role. Therapeutic drug monitoring may contribute to assessment of treatment regimens, helping to reduce toxicity while maintaining adequate drug exposure. Oral fluid sampling could provide a welcome alternative in cases where conventional plasma sampling is not possible or desirable. The aim of this study was to clinically validate the analysis of linezolid and clarithromycin and its metabolite hydroxyclarithromycin in oral fluid of patients with multidrug-resistant tuberculosis. Serum and oral fluid samples were simultaneously obtained and analyzed by using validated methods, after extensive cross-validation between the two matrices. Passing-Bablok regressions and Bland-Altman analysis showed that oral fluid analysis of linezolid and clarithromycin appeared to be suitable for therapeutic drug monitoring in MDR-TB patients. No correction factor is needed for the interpretation of linezolid oral fluid concentrations with a ratio of the linezolid concentration in serum to that in oral fluid of 0.97 (95% confidence interval [CI], 0.92 to 1.02). However, the clarithromycin concentration serum/clarithromycin concentration in oral fluid ratio is 3.07 (95% CI, 2.45 to 3.69). Analysis of hydroxyclarithromycin in oral fluid was not possible in this study due to a nonlinear relationship between the concentration in serum and that in oral fluid. In conclusion, the analysis of linezolid (no correction factor) and clarithromycin (correction factor of 3) in oral fluid is applicable for therapeutic drug monitoring in cases of multidrug-resistant tuberculosis as an alternative to conventional serum sampling. Easy sampling using a noninvasive technique may facilitate therapeutic drug monitoring for specific patient categories. 23812161 A correlated ab initio quantum chemical study of the interaction of the Na(+), Mg(2+), Ca(2+) and Zn(2+) ions with the tautomers of cytosine in the presence of polar solvent. The interactions of the metal ions Na(+), Mg(2+), Ca(2+) and Zn(2+) with cytosine have been investigated with inclusion of solvent effects. Computations have been performed at the density functional and Møller-Plesset levels of theory within the IEFPCM solvent model. It has been found that the inclusion of the solvent environment is essential for giving more biologically realistic results. Earlier gas-phase findings of the stabilisation of rare tautomeric forms by the metal ions have been reproduced, with the presence of the solvent further affecting the relative stabilities. 23151667 Gastric cancer screening compliance is influenced by the weight status. Obesity is associated with decreased compliance with cancer screening, but with an increased risk for cancer development. However, the relationship between weight status and compliance with stomach cancer screening has not been not studied as yet. We examined men and women aged between 40 and 80 years from the 4th Korea National Health and Nutrition Examination Survey from 2007 to 2009. BMI was classified into ≤18.4 kg/m (underweight), 18.5-22.9 kg/m (normal), 23-24.9 kg/m (overweight), 25.0-29.9 kg/m (moderate obesity), and ≥30.0 kg/m (severe obesity). Screening compliance was defined as undergoing stomach cancer screening every 2 years with either gastroscopy or upper gastrointestinal series. The overall screening rates of stomach cancer were 43.2 (0.9)% for men and 43.4 (0.8)% for women. After adjustment for covariates, the screening rates were higher in overweight men (adjusted odds ratio, 1.19; 95% confidence interval, 0.98-1.44), with a marginal significance, and significantly lower in women with severe obesity (adjusted odds ratio, 0.55; 95% confidence interval, 0.40-0.76). The difference was mainly driven by the lower acceptance of gastroscopy rather than upper gastrointestinal series. In conclusion, obesity is associated with lower compliance with stomach cancer screening in Korean women. Therefore, new strategies need to be developed to improve the cancer screening compliance in obese women. 22906567 Skin phototoxicity of cosmetic formulations containing photounstable and photostable UV-filters and vitamin A palmitate. The aim of this study was to evaluate the in vitro skin phototoxicity of cosmetic formulations containing photounstable and photostable UV-filters and vitamin A palmitate, assessed by two in vitro techniques: 3T3 Neutral Red Uptake Phototoxicity Test and Human 3-D Skin Model In Vitro Phototoxicity Test. For this, four different formulations containing vitamin A palmitate and different UV-filters combinations, two of them considered photostable and two of them considered photounstable, were prepared. Solutions of each UV-filter and vitamin under study and solutions of four different combinations under study were also prepared. The phototoxicity was assessed in vitro by the 3T3 NRU phototoxicity test (3T3-NRU-PT) and subsequently in a phototoxicity test on reconstructed human skin model (H3D-PT). Avobenzone presented a pronounced phototoxicity and vitamin A presented a tendency to a weak phototoxic potential. A synergistic effect of vitamin A palmitate on the phototoxicity of combinations containing avobenzone was observed. H3D-PT results did not confirm the positive 3T3-NRU-PT results. However, despite the four formulations studied did not present any acute phototoxicity potential, the combination 2 containing octyl methoxycinnamate (OMC), avobenzone (AVB) and 4-methylbenzilidene camphor (MBC) presented an indication of phototoxicity that should be better investigated in terms of the frequency of photoallergic or chronic phototoxicity in humans, once these tests are scientifically validated only to detect phototoxic potential with the aim of preventing phototoxic reactions in the general population, and positive results cannot predict the exact incidence of phototoxic reactions in humans. 23880978 Ignition of Eyelash Extensions During Routine Minor Eyelid Surgery. Preoperative patient questionnaires enquiring about the presence of prosthetics are routine. Eyelash extensions are not part of standard preoperative questionnaires. This case illustrates how this impacts patient safety during minor eyelid surgery. 22366239 ADHD medication vacations and parent-child interactions by gender. Objective: The purpose of the current study was to examine medication vacations among children with ADHD according to parent-child dyads (e.g., mother-son, father-daughter, mother-daughter, and father-son). Method: In a survey study of 259 parents of children with ADHD, the use of medication vacations according to parent-child sex dyads was examined. Results: Results of the current study suggest that fathers seem to report endorsing medication vacations more with their sons with ADHD as opposed to their daughters with ADHD. There did not seem to be any significant differences among mothers. Conclusion: Results of the current study conclude with directions for future research and practice. 23237841 2'-Fluoro-6'-methylene-carbocyclic adenosine phosphoramidate (FMCAP) prodrug: in vitro anti-HBV activity against the lamivudine-entecavir resistant triple mutant and its mechanism of action. Novel 2'-fluoro-6'-methylene-carbocyclic adenosine (FMCA) monophosphate prodrug (FMCAP) was synthesized and evaluated for its in vitro anti-HBV potency against a lamivudine-entecavir resistant clone (L180M+M204V+S202G). FMCA demonstrated significant antiviral activity against wild-type as well as lamivudine-entecavir resistant triple mutant (L180M+M204V+S202G). The monophosphate prodrug (FMCAP) demonstrated greater than 12-fold (12×) increase in anti-HBV activity without increased cellular toxicity. Mitochondrial and cellular toxicity studies of FMCA indicated that there is no significant toxicity up to 100 μM. Mode of action studies by molecular modeling indicate that the 2'-fluoro moiety by hydrogen bond as well as the Van der Waals interaction of the carbocyclic ring with the phenylalanine moiety of the polymerase promote the positive binding, even in the drug-resistant mutants. 23862590 Justice between age groups: an objection to the prudential lifespan approach. Societal aging raises challenging ethical questions regarding the just distribution of health care between young and old. This article considers a proposal for age-based rationing of health care, which is based on the prudential life span account of justice between age groups. While important objections have been raised against the prudential life span account, it continues to dominate scholarly debates. This article introduces a new objection, one that develops out of the well-established disability critique of social contract theories. I show the implications of this critique for the prudential life span account and for the special case of age-group justice. The result is that age-based rationing based on the prudential life span approach is not supported, and that the prudential life span approach itself is not the best way to think about allocating health care between age groups. I propose an alternative approach that avoids the disability objection, and consider its implications for specific proposals for age-based rationing of health care. 23583354 Resolution of inflammation: mechanisms and opportunity for drug development. Inflammation is a beneficial host reaction to tissue damage and has the essential primary purpose of restoring tissue homeostasis. Inflammation plays a major role in containing and resolving infection and may also occur under sterile conditions. The cardinal signs of inflammation dolor, calor, tumor and rubor are intrinsically associated with events including vasodilatation, edema and leukocyte trafficking into the site of inflammation. If uncontrolled or unresolved, inflammation itself can lead to further tissue damage and give rise to chronic inflammatory diseases and autoimmunity with eventual loss of organ function. It is now evident that the resolution of inflammation is an active continuous process that occurs during an acute inflammatory episode. Successful resolution requires activation of endogenous programs with switch from production of pro-inflammatory towards pro-resolving molecules, such as specific lipid mediators and annexin A1, and the non-phlogistic elimination of granulocytes by apoptosis with subsequent removal by surrounding macrophages. These processes ensure rapid restoration of tissue homeostasis. Here, we review recent advances in the understanding of resolution of inflammation, highlighting the pharmacological strategies that may interfere with the molecular pathways which control leukocyte survival and clearance. Such strategies have proved beneficial in several pre-clinical models of inflammatory diseases, suggesting that pharmacological modulation of the resolution process may be useful for the treatment of chronic inflammatory diseases in humans. 23831124 An RFID solution for enhancing inpatient medication safety with real-time verifiable grouping-proof. The occurrence of a medication error can threaten patient safety. The medication administration process is complex and cumbersome, and nursing staffs are prone to error when they are tired. Proper Information Technology (IT) can assist the nurse in correct medication administration. We review a recent proposal [15] regarding a leading-edge solution to enhance inpatient medication safety by using RFID technology. The proof mechanism is the kernel concept in their design and worth studying to develop a well-designed grouping-proof scheme. Other RFID grouping-proof protocols [17-21] could be similarly applied in administering physician orders. We improve on the weaknesses of previous works and develop a reading-order independent RFID grouping-proof scheme in this paper. In our scheme, tags are queried and verified under the direct control of the authorized reader without connecting to the back-end database server. Immediate verification in our design makes this application more portable and efficient and critical security issues have been analyzed by the threat model. Our scheme is suitable for the safe drug administration scenario and the drug package scenario in a hospital environment to enhance inpatient medication safety. It automatically checks for correct drug unit-dose and appropriate inpatient treatments. 23807538 A Comparison of the EQ-5D-3L and ICECAP-O in an Older Post-Acute Patient Population Relative to the General Population. The measurement and valuation of quality of life forms a major component of economic evaluation in health care and is a major issue in health services research. However, differing approaches exist in the measurement and valuation of quality of life from a health economics perspective. While some instruments such as the EQ-5D-3L focus on health-related quality of life alone, others assess quality of life in broader terms, for example, the newly developed ICECAP-O. The aim of this study was to utilize two generic preference-based instruments, the EQ-5D-3L and the ICECAP-O, to measure and value the quality of life of older adult patients receiving post-acute care. An additional objective was to compare the values obtained by each instrument with those generated from two community-based general population samples. Data were collected from a clinical patient population of older adults receiving post-acute outpatient rehabilitation or residential transition care and two Australian general population samples of individuals residing in the general community. The individual responses to the ICECAP-O and EQ-5D-3L instruments were scored using recently developed Australian general population algorithms. Empirical comparisons were made of the resulting patient and general population sample values for the total population and dis-aggregated according to age (65-79 and 80+ years) and gender. A total of 1,260 participants aged 65-99 years (n = 86 clinical patient sample, n = 385 EQ-5D-3L general population sample, n = 789 ICECAP-O general population sample) completed one or both of the EQ-5D-3L and ICECAP-O instruments. As expected, the patient group demonstrated lower quality of life than the general population sample as measured by both quality-of-life instruments. The difference in values between the patient and general population groups was found to be far more pronounced for the EQ-5D-3L than for the ICECAP-O. The ICECAP-O was associated with a mean difference in values of 0.04 (patient group mean 0.753, SD 0.18; general population group mean 0.795, SD 0.17, respectively, p = 0.033). In contrast, the EQ-5D-3L was associated with a mean difference in values of 0.19 (patient group mean 0.595, SD 0.20; general population group mean 0.789, SD 0.02, respectively, p â‰¤ 0.001). The study findings illustrate the magnitude of the difference in patient and general population values according to the instrument utilized, and highlight the differences in both the theoretical underpinnings and valuation algorithms for the EQ-5D-3L and ICECAP-O instruments. Further empirical work is required in larger samples and alternative patient groups to investigate the generalizability of the findings presented here. 23881388 TIMP1 overexpression mediates resistance of MCF-7 human breast cancer cells to fulvestrant and down-regulates progesterone receptor expression. High levels of Tissue Inhibitor of Metalloproteinases-1 (TIMP1) are associated with poor prognosis, reduced response to chemotherapy, and, potentially, also poor response to endocrine therapy in breast cancer patients. Our objective was to further investigate the hypothesis that TIMP1 is associated with endocrine sensitivity. We established a panel of 11 MCF-7 subclones with a wide range of TIMP1 mRNA and protein expression levels. Cells with high expression of TIMP1 versus low TIMP1 displayed significantly reduced sensitivity to the antiestrogen fulvestrant (ICI 182,780, Faslodex®), while TIMP1 levels did not influence the sensitivity to 4-hydroxytamoxifen. An inverse correlation between expression of the progesterone receptor and TIMP1 was found, but TIMP1 levels did not correlate with estrogen receptor levels or growth-promoting effects of estrogen (estradiol, E2). Additionally, the effects of fulvestrant, 4-hydroxytamoxifen, or estrogen on estrogen receptor expression were not associated with TIMP1 levels. Gene expression analyses revealed associations between expression of TIMP1 and genes involved in metabolic pathways, epidermal growth factor receptor 1/cancer signaling pathways, and cell cycle. Gene and protein expression analyses showed no general defects in estrogen receptor signaling except from lack of progesterone receptor expression and estrogen inducibility in clones with high TIMP1. The present study suggests a relation between high expression level of TIMP1 and loss of progesterone receptor expression combined with fulvestrant resistance. Our findings in vitro may have clinical implications as the data suggest that high tumor levels of TIMP1 may be a predictive biomarker for reduced response to fulvestrant. 23183138 Long-term anticholinergic use and the aging brain. Older Americans are facing an epidemic of chronic diseases and are thus exposed to anticholinergics (ACs) that might negatively affect their risk of developing mild cognitive impairment (MCI) or dementia. To investigate the association between impairment in cognitive function and previous AC exposure. A retrospective cohort study. Primary care clinics in Indianapolis, Indiana. A total of 3690 older adults who have undergone cognitive assessment and had a 1-year medication-dispensing record. Cognitive function was measured in two sequential steps: a two-step screening process followed by a formal diagnostic process for participants with positive screening results. Three patterns of AC exposure were defined by the duration of AC exposure, the number of AC medications dispensed at the same time, and the severity of AC effects as determined by the Anticholinergic Cognitive Burden list. Compared with older adults with no AC exposure and after adjusting for age, race, gender, and underlying comorbidity, the odds ratio for having a diagnosis of MCI was 2.73 (95% confidence interval, 1.27-5.87) among older adults who were exposed to at least three possible ACs for at least 90 days; the odds ratio for having dementia was 0.43 (95% confidence interval, 0.10-1.81). Exposure to medications with severe AC cognitive burden may be a risk factor for developing MCI. 23889431 Phonon bottleneck in graphene-based josephson junctions at millikelvin temperatures. We examine the nature of the transitions between the normal and superconducting branches in superconductor-graphene-superconductor Josephson junctions. We attribute the hysteresis between the switching (superconducting to normal) and retrapping (normal to superconducting) transitions to electron overheating. In particular, we demonstrate that the retrapping current corresponds to the critical current at an elevated temperature, where the heating is caused by the retrapping current itself. The superconducting gap in the leads suppresses the hot electron outflow, allowing us to further study electron thermalization by phonons at low temperatures (T≲1  K). The relationship between the applied power and the electron temperature was found to be P∝T^{3}, which we argue is consistent with cooling due to electron-phonon interactions. 23888194 Response of blood pressure after percutaneous transluminal renal artery angioplasty and stenting. To evaluate the short and intermediate term outcome of percutaneous transluminal renal artery angioplasty (PTRA) and stenting particularly on blood pressure (BP) control and renal function and to evaluate predictors of poor BP response after successful PTRA and stenting. We conducted a prospective analysis of all patients who underwent PTRA and stenting in our institute between August 2010 to September 2012. A total number of 86 patients were underwent PTRA and renal stenting. Selective angiography was done to confirm at least 70% angiographic stenosis. The predilatation done except few cases with critical stenosis, direct stenting was done in the rest of cases. All patients received aspirin 325 mg orally, and clopidogrel 300 mg orally within 24 h before the procedure. Heparin was used as the procedural anticoagulant agent. Optimal results with TIMI-III flow obtained in all cases. Following stent placement, aspirin 150 mg orally once daily was continued for a minimum of 12 mo and clopidogrel 75 mg orally once daily for at least 4 wk. The clinical, radiological, electrocardiography, echocardiography and treatment data of all patients were recorded. The BP measurement, serum creatinine and glomerular filtration rate (GFR) were recorded before the procedure and 1 and 6 mo after PTRA. A total of 86 patients were included in the study. The mean age of study population was 55.87 ± 11.85 years old and 67 (77.9%) of patients were male. There was a significant reduction in both systolic and diastolic BP at 1 mo after the procedure: 170.15 ± 20.10 mmHg vs 146.60 ± 17.32 mmHg and 98.38 ± 10.55 mmHg vs 89.88 ± 9.22 mmHg respectively (P = 0.0000). The reduction in BP was constant throughout the follow-up period and was evident 6 mo after the procedure: 144.23 ± 18.19 and 88.26 ± 9.79 mmHg respectively (P = 0.0000). However, no improvement in renal function was observed at any time during the follow-up period. After multivariate analysis, we found male sex, low GFR (< 60 mL/min) and higher baseline mean BP as a poor predictors of successful outcome on BP response after PTRA and stenting. The PTRA and stenting can be considered as an effective therapeutic intervention for improving BP control with minimal effect on renal function. The male sex, higher baseline BP and low GFR are associated with poor BP response after successful PTRA and stenting. 23188119 Highlights on contemporary recognition and sensing of fluoride anion in solution and in the solid state. The fluoride anion has recently gained well deserved attention among the scientific community for its importance in many fields of human activities, but also for concerns on its effect on health and the environment. Although surprisingly overlooked in systematic studies in the past, fluoride has nowadays become a topical target in the field of anion recognition. A multitude of scientific reports are published every year where the establishment of efficient and specific interaction with fluoride is sought in polar and aqueous media. Here, the emphasis is directed to a detailed description of the most interesting contemporary studies in the field, with a particular focus given to those published in the last few years. 23872941 Incidence and Behavioral Correlates of Epileptiform Abnormalities in Autism Spectrum Disorders. Autism spectrum disorders (ASD) are associated with an increased incidence of epilepsy and of epileptiform discharges on electroencephalograms. It is unknown whether epileptiform discharges correlate with symptoms of ASD. We completed a retrospective chart review of 101 patients with ASD who had overnight electroencephalograms. We looked for a relationship between epileptiform abnormalities and diagnosis, history of regression, communication skills, and other features associated with ASD. There was a higher incidence of epileptiform activity in children with stereotypies and aggressive behavior. The incidence of epileptiform abnormalities was significantly lower in Asperger's compared with more severe forms of autism. Results suggest that increasing severity of autistic symptoms may be associated with higher likelihood of epileptiform abnormalities. Whether treatment alters outcome is unknown. 23067271 Dose-response relationships between mouse allergen exposure and asthma morbidity among urban children and adolescents. Home mouse allergen exposure is associated with asthma morbidity, but little is known about the shape of the dose-response relationship or the relevance of location of exposure within the home. Asthma outcome and allergen exposure data were collected every 3 months for 1 year in 150 urban children with asthma. Participants were stratified by mouse sensitization, and relationships between continuous measures of mouse allergen exposure and outcomes of interest were analyzed. Every tenfold increase in the bed mouse allergen level was associated with an 87% increase in the odds of any asthma-related health care use among mouse-sensitized [Odds Ratio (95% CI): 1.87 (1.21-2.88)], but not non-mouse-sensitized participants. Similar relationships were observed for emergency department visit and unscheduled doctor visit among mouse-sensitized participants. Kitchen floor and bedroom air mouse allergen concentrations were also associated with greater odds of asthma-related healthcare utilization; however, the magnitude of the association was less than that observed for bed mouse allergen concentrations. In this population of urban children with asthma, there is a linear dose-response relationship between mouse allergen concentrations and asthma morbidity among mouse-sensitized asthmatics. Bed and bedroom air mouse allergen exposure compartments may have a greater impact on asthma morbidity than other compartments. 23958402 In vitro susceptibility of Conidiobolus lamprauges recovered from sheep to antifungal agents. Data regarding the susceptibility of Conidiobolus lamprauges is limited and there is no consensus about the optimal treatment for infections caused by Conidiobolus spp. In this context, the objective of this study was to evaluate the in vitro susceptibility of six C. lamprauges strains isolated from sheep conidiobolomycosis to amphotericin B, ketoconazole, fluconazole, itraconazole, posaconazole, voriconazole, anidulafungin, caspofungin, micafungin, flucytosine, and terbinafine using the CLSI M38-A2 microdilution technique. Terbinafine was the most active (MIC range <0.06-0.5μg/mL). Resistance or reduced susceptibility was observed for amphotericin B and azole and echinocandin antifungals. Additional studies are necessary to determine the therapeutic potential of terbinafine as monotherapy or in combination therapy with other antifungals. 23949936 Diagnostic imaging of ankle impingement syndromes in athletes. The chronic ankle pain is a very frequent clinical problem, which is often characterized by a painful mechanical limitation of full-range ankle movement. A large amount of causes are involved in its pathogenesis, but the most common forms are secondary to an osseous or soft tissue abnormality. Especially for professional athletes, impingement lesions are the most important causes of chronic pain; however, this symptomatology can also affect ordinary people, mostly in those who work in environments that cause severe mechanical stress on the joints. This group of pathologies is characterized by a joint conflict secondary to an abnormal contact among bone surfaces or between bones and soft tissues. Diagnosis is mainly clinic and secondly supported by imaging in order to localize the critical area of impingement and determine the organic cause responsible for the joint conflict. Treatments for different forms of impingement are similar. Usually, the first step is a conservative approach (rest, physiotherapy, ankle bracing, shoe modification and local injection of corticosteroids), and only in case of unsuccessful response, the second step is the operative treatment with open and arthroscopic techniques. The aim of the study is to describe different MR imaging patterns, comparing our data with those reported in the literature, in order to identify the best accurate diagnostic protocol. 23614462 Aromatic glycosides from the flower buds of Lonicera japonica. Six new glycosides (1-6) have been isolated from the flower buds of Lonicera japonica. Their structures including the absolute configurations were determined by spectroscopic and chemical methods as ( - )-2-hydroxy-5-methoxybenzoic acid 2-O-β-d-(6-O-benzoyl)-glucopyranoside (1), ( - )-4-hydroxy-3,5-dimethoxybenzoic acid 4-O-β-d-(6-O-benzoyl)-glucopyranoside (2), ( - )-(E)-3,5-dimethoxyphenylpropenoic acid 4-O-β-d-(6-O-benzoyl)-glucopyranoside (3), ( - )-(7S,8R)-(4-hydroxyphenylglycerol 9-O-β-d-[6-O-(E)-4-hydroxy-3,5-dimethoxyphenylpropenoyl]-glucopyranoside (4), ( - )-(7S,8R)-(4-hydroxy-3-methoxyphenylglycerol 9-O-β-d-[6-O-(E)-4-hydroxy-3,5-dimethoxyphenylpropenoyl]-glucopyranoside (5), and ( - )-4-hydroxy-3-methoxyphenol β-d-{6-O-[4-O-(7S,8R)-(4-hydroxy-3-methoxyphenylglycerol-8-yl)-3-methoxybenzoyl]}-glucopyranoside (6), respectively. 23827740 Gender differences in cognitive impairment and mobility disability in old age: A cross-sectional study in Ouagadougou, Burkina Faso. This study aims to examine differences in cognitive impairment and mobility disability between older men and women in Ouagadougou, Burkina Faso, and to assess the extent to which these differences could be attributable to gender inequalities in life course social and health conditions. Data were collected on 981 men and women aged 50 and older in a 2010 cross-sectional health survey conducted in the Ouagadougou Health and Demographic Surveillance System. Cognitive impairment was assessed using the Leganés cognitive test. Mobility disability was self-reported as having any difficulty walking 400m without assistance. We used logistic regression to assess gender differences in cognitive impairment and mobility disability. Prevalence of cognitive impairment was 27.6% in women and 7.7% in men, and mobility disability was present in 51.7% of women and 26.5% of men. The women to men odds ratio (95% confidence interval) for cognitive impairment and mobility disability was 3.52 (1.98-6.28) and 3.79 (2.47-5.85), respectively, after adjusting for the observed life course social and health conditions. The female excess was only partially explained by gender inequalities in nutritional status, marital status and, to a lesser extent, education. Among men and women, age, childhood hunger, lack of education, absence of a partner and being underweight were independent risk factors for cognitive impairment, while age, childhood poor health, food insecurity and being overweight were risk factors for mobility disability. Enhancing nutritional status and education opportunities throughout life span could prevent cognitive impairment and mobility disability and partly reduce the female excess in these disabilities. 23852993 Identification of the metabolites of anti-inflammatory compound clematichinenoside AR in rat intestinal microflora. Clematichinenoside AR (C-AR), a pentacyclic triterpenoid saponin with anti-inflammatory and anti-rheumatoid activities, is the main active component of the traditional Chinese medicine Clematidis Radix et Rhizoma. However, its poor oral absorption indicated that not only the parent compound C-AR itself, but also its metabolites could be responsible for the pharmacological effects in rats. The present study aimed to investigate the metabolism of C-AR in rat intestinal microflora, where C-AR was extensively metabolized. C-AR was incubated with the content of the large intestine. The culture solution was collected at different time points and analyzed for the metabolites of C-AR. Eight metabolites were identified by liquid chromatography/quadrupole time-of-flight mass spectrometry. M1, M2 and M5 were the major metabolites. In addition, it was proposed that deglycosylation was the only pathway contributing to the biotransformation of C-AR in rat intestinal microflora. Copyright © 2013 John Wiley & Sons, Ltd. 23376947 Methods used for the assessment of LV systolic function: common currency or tower of Babel? The last decade has produced a proliferation of techniques for the assessment of left ventricular systolic function, and there now seems to be more choice than seems rational for the questions that we need answers to. In some instances, simple estimation is all that is required-the risk stratification process is inexact, as emphasised by the variety of modalities used to characterise ejection fraction (EF) in studies that validated the efficacy of treatments selected on the basis of EF. Nonetheless, while technical advances often cause disruption and confusion, it would be wrong to dismiss them as lacking benefit. The purpose of this review is to try to provide rational grounds for selecting both test modality and physiological parameter in various specific clinical situations. 23824561 Psychosocial screening effects on health-related outcomes in patients receiving radiotherapy. A cluster randomised controlled trial. This study examined the short-term and long-term effects of using a screening instrument on psychological distress and health-related quality of life (HRQoL) among cancer patients receiving radiotherapy. In addition, we investigated the effect of early psychosocial treatment on patients' overall health-related outcomes as previous research showed that patients in the screening condition were referred to a psychosocial caregiver at an earlier stage. A cluster randomised controlled trial with a randomisation at the levels of 14 radiotherapists, 568 patients was conducted. Patients were asked to complete questionnaires at 3 and 12 months follow-up. Mixed models analyses showed no significant intervention effects on patients' overall extent of psychosocial distress and HRQoL, both on the short and long terms. Post-hoc analyses revealed significant interactions of the intervention with early referral and improved HRQoL and anxiety, suggesting that earlier referral might influence short-term HRQoL and experienced anxiety in patients. Our results suggest that the use of a psychosocial screening instrument among patients receiving radiotherapy in itself does not sufficiently improve patients' health-related outcome. The effective delivery of psychosocial care depends upon several components such as identification of distress and successful implementation of screening procedures. One of the challenges is to get insight in the effects of early referral of cancer patients for psychosocial support because early referral might have a favourable effect on some of the patients' health-related outcomes. Copyright © 2013 John Wiley & Sons, Ltd. 22760006 The antimicrobial peptide cathelicidin modulates Clostridium difficile-associated colitis and toxin A-mediated enteritis in mice. Clostridium difficile mediates intestinal inflammation by releasing toxin A (TxA), a potent enterotoxin. Cathelicidins (Camp as gene name, LL-37 peptide in humans and mCRAMP peptide in mice) are antibacterial peptides that also posses anti-inflammatory properties. To determine the role of cathelicidins in models of Clostridium difficile infection and TxA-mediated ileal inflammation and cultured human primary monocytes. Wild-type (WT) and mCRAMP-deficient (Camp(-/-)) mice were treated with an antibiotic mixture and infected orally with C difficile. Some mice were intracolonically given mCRAMP daily for 3 days. Ileal loops were also prepared in WT mice and treated with either saline or TxA and incubated for 4 h, while some TxA-treated loops were injected with mCRAMP. Intracolonic mCRAMP administration to C difficile-infected WT mice showed significantly reduced colonic histology damage, apoptosis, tissue myeloperoxidase (MPO) and tumour necrosis factor (TNF)α levels. Ileal mCRAMP treatment also significantly reduced histology damage, tissue apoptosis, MPO and TNFα levels in TxA-exposed ileal loops. WT and Camp(-/-) mice exhibited similar intestinal responses in both models, implying that C difficile/TxA-induced endogenous cathelicidin may be insufficient to modulate C difficile/TxA-mediated intestinal inflammation. Both LL-37 and mCRAMP also significantly reduced TxA-induced TNFα secretion via inhibition of NF-κB phosphorylation. Endogenous cathelicidin failed to control C difficile and/or toxin A-mediated inflammation and even intestinal cathelicidin expression was increased in humans and mice. Exogenous cathelicidin modulates C difficile colitis by inhibiting TxA-associated intestinal inflammation. Cathelicidin administration may be a new anti-inflammatory treatment for C difficile toxin-associated disease. 23857067 Patch Testing for Noncontact Dermatitis: The Atopy Patch Test for Food and Inhalants. The atopy patch test (APT) is defined as a patch test procedure to assess delayed type hypersensitivity reactions against those protein allergens known to elicit IgE-mediated type I reactions in atopic patients. This patch test procedure uses intact protein allergens instead of haptens in an optimized test setting and with a special reading key. It may be clinically useful especially for atopic dermatitis, as the currently available test procedures either target the wrong reaction type (type I and not type IV) or use the wrong allergens (haptens and not protein allergen). A positive APT reaction correlates with a positive lymphocyte transformation test and allergen-specific Th2 cells in the peripheral blood. As even small changes in the test procedure influence the sensitivity, specificity, and reproducibility of the APT, the European Task Force on Atopic Dermatitis (ETFAD) has developed a standardized APT technique: Intact protein allergens, purified in petrolatum, are applied in 12-mm-diameter Finn chambers mounted on Scanpor tape for 48 h to non-irritated, non-abraded, or tape-stripped skin of the upper back for 48 h; the evaluation of the test reaction is done after 48 and 72 h using the ETFAD reading key, assessing erythema as well as number and distribution pattern of the papules. The APT may reveal type IV sensitization in patients who are negative for the respective type I tests. Limited availability of the expensive test substances and limited reimbursement is among the factors restricting the routine use of the APT. 23748092 Molecular fingerprinting of bacterial communities in enriched azo dye (Reactive Violet 5R) decolorising native acclimatised bacterial consortia. Reactive Violet 5R (RV5R) decolorising acclimatised bacterial consortia were enriched from industrial effluent contaminated and pristine samples from Gujarat, India on several different media. Twelve acclimatised consortia were selected for the study which were able to decolorise 100mg/L RV5R in 30h under shaking or static conditions. Eubacterial diversity was studied by 16S rRNA gene based culture-independent methods, using HaeIII and Hinf1 enzymes for ARDRA and V3 region based DGGE analysis, forming total 6 clusters in both analysis. Decolorised end products of all the consortia were analysed by FTIR showing cleavage of the azo bond and group modifications. GC-MS data of dye decolorised end products of Gly consortium obtained from hydrocarbon contaminated soil demonstrated benzene ring cleavage activity. Present study suggests that enrichment of acclimatised consortia under different conditions can result in diverse microbial communities that differentially degrade RV5R and can provide rich source of dye decolorising strains. 23438446 Increased risk of hip fracture among older people using antidepressant drugs: data from the Norwegian Prescription Database and the Norwegian Hip Fracture Registry. hip fractures are usually caused by a combination of reduced bone mineral density and falls; using antidepressant drugs may affect both of these. we aimed to examine associations between exposure to antidepressant drugs and the risk of hip fracture among older people, and, provided associations found, to estimate the attributable risk of hip fracture. we conducted a nationwide prospective cohort study of the 906,422 people in Norway born before 1945. information on all prescriptions of antidepressants dispensed in 2004-10 and all primary hip fractures in 2005-10 was obtained from the Norwegian Prescription Database, and the Norwegian Hip Fracture Registry, respectively. The incidence rates of hip fracture during the time people were exposed and unexposed to antidepressant drugs were compared by calculating the standardised incidence ratio (SIR). altogether 39,938 people (4.4%) experienced a primary hip fracture. The risk of hip fracture was increased for people exposed to any antidepressant [SIR = 1.7, 95% confidence interval (CI) 1.7-1.8]; tricyclic antidepressants (SIR = 1.4, 95% CI: 1.3-1.5); selective serotonin reuptake inhibitors (SSRIs) (SIR = 1.8, 95% CI: 1.7-1.8) and other antidepressants (SIR = 1.6, 95% CI: 1.5-1.7). The risk of hip fracture attributable to exposure to antidepressant drugs was 4.7%. this study indicated an increased risk of hip fracture among people exposed to antidepressants, especially those with serotonergic properties such as SSRIs. This association needs to be explored further in clinical studies. 23863758 Quantifying the Dose-Response Relationship Between Circulating Folate Concentrations and Colorectal Cancer in Cohort Studies: A Meta-Analysis Based on a Flexible Meta-Regression Model. Most epidemiologic studies on folate intake suggest that folate may be protective against colorectal cancer, but the results on circulating (plasma or serum) folate are mostly inconclusive. We conducted a meta-analysis of case-control studies nested within prospective studies on circulating folate and colorectal cancer risk by using flexible meta-regression models to test the linear and nonlinear dose-response relationships. A total of 8 publications (10 cohorts, representing 3,477 cases and 7,039 controls) were included in the meta-analysis. The linear and nonlinear models corresponded to relative risks of 0.96 (95% confidence interval (CI): 0.91, 1.02) and 0.99 (95% CI: 0.96, 1.02), respectively, per 10 nmol/L of circulating folate in contrast to the reference value. The pooled relative risks when comparing the highest with the lowest category were 0.80 (95% CI: 0.61, 0.99) for radioimmunoassay and 1.03 (95% CI: 0.83, 1.22) for microbiological assay. Overall, our analyses suggest a null association between circulating folate and colorectal cancer risk. The stronger association for the radioimmunoassay-based studies could reflect differences in cohorts and study designs rather than assay performance. Further investigations need to integrate more accurate measurements and flexible modeling to explore the effects of folate in the presence of genetic, lifestyle, dietary, and hormone-related factors. 23866773 The Lyme disease spirochete Borrelia burgdorferi induces inflammation and apoptosis in cells from dorsal root ganglia. Lyme neuroborreliosis (LNB), caused by the spirochete Borrelia burgdorferi, affects both the peripheral and the central nervous systems. Radiculitis or nerve root inflammation, which can cause pain, sensory loss, and weakness, is the most common manifestation of peripheral LNB in humans. We previously reported that rhesus monkeys infected with B. burgdorferi develop radiculitis as well as inflammation in the dorsal root ganglia (DRG), with elevated levels of neuronal and satellite glial cell apoptosis in the DRG. We hypothesized that B. burgdorferi induces inflammatory mediators in glial and neuronal cells and that this inflammatory milieu precipitates glial and neuronal apoptosis. To model peripheral neuropathy in LNB we incubated normal rhesus DRG tissue explants with live B. burgdorferi ex vivo and identified immune mediators, producer cells, and verified the presence of B. burgdorferi in tissue sections by immunofluorescence staining and confocal microscopy. We also set up primary cultures of DRG cells from normal adult rhesus macaques and incubated the cultures with live B. burgdorferi. Culture supernatants were subjected to multiplex ELISA to detect immune mediators, while the cells were evaluated for apoptosis by the in situ TUNEL assay. A role for inflammation in mediating apoptosis was assessed by evaluating the above phenomena in the presence and absence of various concentrations of the anti-inflammatory drug dexamethasone. As Schwann cells ensheath the dorsal roots of the DRG, we evaluated the potential of live B. burgdorferi to induce inflammatory mediators in human Schwann cell (HSC) cultures. Rhesus DRG tissue explants exposed to live B. burgdorferi showed localization of CCL2 and IL-6 in sensory neurons, satellite glial cells and Schwann cells while IL-8 was seen in satellite glial cells and Schwann cells. Live B. burgdorferi induced elevated levels of IL-6, IL-8 and CCL2 in HSC and DRG cultures and apoptosis of sensory neurons. Dexamethasone reduced the levels of immune mediators and neuronal apoptosis in a dose dependent manner. In this model, B. burgdorferi induced an inflammatory response and neuronal apoptosis of DRG. These pathophysiological processes could contribute to peripheral neuropathy in LNB. 23578949 A randomized controlled trial of fallopian tube sperm perfusion compared with standard intrauterine insemination for women with non-tubal infertility. Does fallopian tube sperm perfusion (FSP) result in better pregnancy and live birth rates than standard intrauterine insemination (SIUI) for couples with non-tubal infertility with or without gonadotrophin or clomiphene stimulation? There was no evidence of an improvement in live birth rates with FSP compared with SIUI. Previous randomized controlled trials have suggested improved live birth rates with FSP but these trials were small. A systematic review published in 2004 suggested heterogeneity in results. This pragmatic, multicentre, randomized controlled trial compared SIUI and FSP in 417 women with non-tubal infertility. The patients were treated at fertility clinics in New Zealand, Australia and the United Arab Emirates. Four hundred and seventeen women were randomized to SIUI (n = 210) or FSP (n = 207). Data were available for analysis from 198 women in the SIUI group and 198 women in the FSP group. There were 19 women with incomplete data because of cycle cancellation or withdrawals and 2 women who conceived prior to commencing treatment. There were no significant differences in live birth rates between the two groups with 27 (12.9%) in the SIUI group and 21 in the FSP group (10.1%) [Odds Ratio (OR) 1.31 (0.71, 2.39), P = 0.48]. Two ectopic pregnancies were reported in the SIUI group and one was reported in the FSP group. Different ovulation protocols were used in the different clinics. Approximately 10% of the cycles involved donor sperm and ∼5% of the cycles did not complete the assigned intervention. There was no evidence of an improvement in live birth rates with FSP compared with SIUI. The study was funded in part by the A+ trust of the Auckland District Health Board. No commercial funding was received. ANZCTR Number ACTRN12612001303831. 23948472 Cryptic impacts of temperature variability on amphibian immune function. Ectothermic species living in temperate regions can experience rapid and potentially stressful changes in body temperature driven by abrupt weather changes. Yet, among amphibians, the physiological impacts of short-term temperature variation are largely unknown. Using an ex situ population of Cryptobranchus alleganiensis, an aquatic North American salamander, we tested the hypothesis that naturally-occurring periods of temperature variation negatively impact amphibian health, either through direct effects on immune function or by increasing physiological stress. We exposed captive salamanders to repeated cycles of temperature fluctuations recorded in the population's natal stream and evaluated behavioral and physiological responses, including plasma complement activity (i.e., bacteria killing) against Pseudomonas aeruginosa, Escherichia coli and Aeromonas hydrophila. The best-fit model (ΔAICc = 0, wi = 0.9992) revealed 70% greater P. aeruginosa killing after exposure to variable temperatures and no evidence of thermal acclimation. The same model predicted 50% increased E. coli killing, but had weaker support (ΔAICc = 1.8, wi = 0.2882). In contrast, plasma defenses were ineffective against A. hydrophila, and other health indicators (leukocyte ratios, growth rates and behavioral patterns) were maintained at baseline values. Our data suggest that amphibians can tolerate, and even benefit from, natural patterns of rapid warming/cooling. Specifically, temperature variation can elicit increased activity of the innate immune system. This immune response may be adaptive in an unpredictable environment, and is undetectable by conventional health indicators (and hence considered cryptic). Our findings highlight the need to consider naturalistic patterns of temperature variation when predicting species' susceptibility to climate change. 23876357 Epidemiology of Infective Endocarditis in Spain in the Last 20 Years. Infective endocarditis is an uncommon disease, with an estimated incidence of 3.1 to 3.7 episodes per 100 000 inhabitants/year. The incidence is highest in elderly people. The microorganisms most frequently isolated in infective endocarditis are staphylococci and streptococci. In the last few decades, the spectrum of heart diseases predisposing to infective endocarditis has changed, since degenerative heart disease is the most common valve disease, and there are an increasing number of infective endocarditis patients without previously known valve disease. In addition, up to one-third of infective endocarditis patients become infected through contact with the health system. These patients are more frail, which leads to higher in-hospital mortality. As a result of substantial epidemiological changes, few cases of infective endocarditis can be prevented by antibiotic prophylaxis. Despite advances in medical and surgical treatment, in-hospital mortality among infective endocarditis patients is high. Nevertheless, there is room for improvement in reducing the rate of nosocomial bacteremia, the prompt diagnosis of infective endocarditis in at-risk patients, and the early identification of patients with a highest risk of complications, as well as in the creation of multidisciplinary teams for the management of this disease. 23810553 Regulation of Tcf7l1 DNA Binding and Protein Stability as Principal Mechanisms of Wnt/β-Catenin Signaling. Wnt/β-catenin signal transduction requires direct binding of β-catenin to Tcf/Lef proteins, an event that is classically associated with stimulating transcription by recruiting coactivators. This molecular cascade plays critical roles throughout embryonic development and normal postnatal life by affecting stem cell characteristics and tumor formation. Here, we show that this pathway utilizes a fundamentally different mechanism to regulate Tcf7l1 (formerly named Tcf3) activity. β-catenin inactivates Tcf7l1 without a switch to a coactivator complex by removing it from DNA, which leads to Tcf7l1 protein degradation. Mouse genetic experiments demonstrate that Tcf7l1 inactivation is the only required effect of the Tcf7l1-β-catenin interaction. Given the expression of Tcf7l1 in pluripotent embryonic and adult stem cells, as well as in poorly differentiated breast cancer, these findings provide mechanistic insights into the regulation of pluripotency and the role of Wnt/β-catenin in breast cancer. 23266728 Studies on a rhein-producing endophytic fungus isolated from Rheum palmatum L. Rheum palmatum L. (Chinese rhubarb) is a highly regarded medicinal plant. Its dominant active constituents are anthraquinones including emodin, aloe-emodin, rhein, etc. Rhein naturally occurs in anthraquinone (1, 3, 8-trihydroxy-6-methyl anthraquinone), which is found in R. palmatum L. and related plants such as rhubarb. It has good antitumor, anti-inflammatory, anticancer, antimicrobial and hemostatic properties. In this study, a total of 14 strains of endophytic fungi were isolated from R. palmatum L. All fungal isolates were fermented in liquid PDA medium and their extracts were preliminarily analyzed by antibacterial reactions, magnesium acetate-methanol reagent and Borntraiger's reaction, and the strain reselection was made by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC) and LC-MS to identify the fermentation products of the selected strains and confirmed through a comparison with authentic standards. Extract from one strain, R13, showed positive reactions with both reagents. The strain R13 had a component with the same TLC (Rf) value and HPLC, LC-MS retention time as authentic rhein standards. The yield of rhein in R13 can reach 5.672mgl(-1). The fungi were identified as Fusarium solani by using both ITS rDNA sequencing and spore morphology. 23932797 Influence of joint angle on EMG-torque model during constant-posture, quasi-constant-torque contractions. Electromyogram (EMG)-torque modeling is of value to many different application areas, including ergonomics, clinical biomechanics and prosthesis control. One important aspect of EMG-torque modeling is the ability to account for the joint angle influence. This manuscript describes an experimental study which relates the biceps/triceps surface EMG of 12 subjects to elbow torque at seven joint angles (spanning 45-135°) during constant-posture, quasi-constant-torque contractions. Advanced EMG amplitude (EMGσ) estimation processors (i.e., whitened, multiple-channel) were investigated and three non-linear EMGσ-torque models were evaluated. When EMG-torque models were formed separately for each of the seven distinct joint angles, a minimum "gold standard" error of 4.23±2.2% MVCF90 resulted (i.e., error relative to maximum voluntary contraction at 90° flexion). This model structure, however, did not directly facilitate interpolation across angles. The best model which did so (i.e., parameterized the angle dependence), achieved an error of 4.17±1.7% MVCF90. Results demonstrated that advanced EMGσ processors lead to improved joint torque estimation. We also contrasted models that did vs. did not account for antagonist muscle co-contraction. Models that accounted for co-contraction estimated individual flexion muscle torques that were ∼29% higher and individual extension muscle torques that were ∼68% higher. 23756227 Silk microgels formed by proteolytic enzyme activity. The proteolytic enzyme α-chymotrypsin selectively cleaves the amorphous regions of silk fibroin protein (SFP) and allows the crystalline regions to self-assemble into silk microgels (SMGs) at physiological temperature. These microgels consist of lamellar crystals in the micrometer scale, in contrast to the nanometer-scaled crystals in native silkworm fibers. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and zeta potential results demonstrated that α-chymotrypsin utilized only the non-amorphous domains or segments of the heavy chain of SFP to form negatively charged SMGs. The SMGs were characterized in terms of size, charge, structure, morphology, crystallinity, swelling kinetics, water content and thermal properties. The results suggest that the present technique of preparing SMGs by α-chymotrypsin is simple and efficient, and that the prepared SMGs have useful features for studies related to biomaterial and pharmaceutical needs. This process is also an easy way to obtain the amorphous peptide chains for further study. 23851901 Reliability and validity of the Japanese Orthopaedic Association hip disease evaluation questionnaire (JHEQ) for patients with hip disease. The Japanese Orthopaedic Association hip disease evaluation questionnaire (JHEQ) was developed to evaluate the quality of life (QOL) in patients with hip disease. This questionnaire consists of three subscales: pain; movement; and mental. The purpose of this study was to assess the reliability and validity of the JHEQ for use as a clinical evaluation tool. We investigated patients who visited the outpatient department at our hospital and affiliated hospital between April and May 2010. The study population comprised 286 patients (239 women) with a mean age of 56.8 years. The diagnosis was osteoarthritis of the hip in 230 patients, avascular osteonecrosis of the femoral head in 49 patients, and other conditions in 7 patients. The JHEQ questionnaire, the SF-36 questionnaire as a generic QOL scale, and the Oxford hip score (OHS) as a disease-specific scale, were filled out by the patient while waiting in the outpatient department. Pearson's correlation coefficients of 0.6 were observed between JHEQ pain and SF-36 bodily pain (BP) subscales, and between JHEQ movement and SF-36 physical functioning (PF) subscales. The JHEQ mental subscale correlated with SF-36 social functioning (SF) and BP subscales. A strong negative correlation was seen between JHEQ pain and OHS pain subscales (r = -0.817). JHEQ movement subscale also showed a strong negative correlation with the OHS function subscale (r = -0.715). These results indicated the convergent validity of JHEQ. The internal consistency of pain, movement, and mental subscales of JHEQ was satisfactory, indicated by Cronbach's α coefficients of 0.92, 0.91, and 0.94, respectively. Each subscale also showed high test-retest reliability with intra-class correlation coefficients of 0.89, 0.93, and 0.85, respectively. We determined the reliability and validity of JHEQ as a self-administered questionnaire that evaluates hip disease. JHEQ is useful as a tool for evaluating patients with hip disease. 23945073 Association between health worker motivation and healthcare quality efforts in Ghana. Ghana is one of the sub-Saharan African countries making significant progress towards universal access to quality healthcare. However, it remains a challenge to attain the 2015 targets for the health related Millennium Development Goals (MDGs) partly due to health sector human resource challenges including low staff motivation.Purpose: This paper addresses indicators of health worker motivation and assesses associations with quality care and patient safety in Ghana. The aim is to identify interventions at the health worker level that contribute to quality improvement in healthcare facilities. The study is a baseline survey of health workers (n = 324) in 64 primary healthcare facilities in two regions in Ghana. Data collection involved quality care assessment using the SafeCare Essentials tool, the National Health Insurance Authority (NHIA) accreditation data and structured staff interviews on workplace motivating factors. The Spearman correlation test was conducted to test the hypothesis that the level of health worker motivation is associated with level of effort by primary healthcare facilities to improve quality care and patient safety. The quality care situation in health facilities was generally low, as determined by the SafeCare Essentials tool and NHIA data. The majority of facilities assessed did not have documented evidence of processes for continuous quality improvement and patient safety. Overall, staff motivation appeared low although workers in private facilities perceived better working conditions than workers in public facilities (P <0.05). Significant positive associations were found between staff satisfaction levels with working conditions and the clinic's effort towards quality improvement and patient safety (P <0.05). As part of efforts towards attainment of the health related MDGs in Ghana, more comprehensive staff motivation interventions should be integrated into quality improvement strategies especially in government-owned healthcare facilities where working conditions are perceived to be the worst. 23883999 Using focus groups to inform innovative approaches to care. A powerful tool for gathering qualitative data can advance patient advocacy in a changing health care climate. 23708383 Evodiamine induces apoptosis and inhibits metastasis in MDA‑MB-231 human breast cancer cells in vitro and in vivo. Breast cancer remains the leading cause of cancer-related deaths among women. Owing to high efficiency and low toxic effects, further exploration of natural compounds from Chinese herbal medicine may be an efficient approach for breast cancer drug discovery. In this study, we investigated the effects of evodiamine on the growth and metastasis of MDA-MB-231 human breast cancer cells in vitro and in vivo. In vitro, evodiamine inhibited cell migration and invasion abilities through downregulation of MMP-9, urokinase-type plasminogen activator (uPA) and uPAR expression. Evodiamine-induced G0/G1 arrest and apoptosis were associated with a decrease in Bcl-2, cyclin D1 and cyclin-dependent kinase 6 (CDK6) expression and an increase in Bax and p27Kip1 expression. Moreover, evodiamine regulated p-ERK and p-p38 MAPK expression. Evodiamine-induced apoptosis was enhanced by its combination with the extracellular signal-regulated kinase (ERK) inhibitor PD98059 or the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580. Evodiamine-inhibited metastasis was partly blocked by combination with PD98059 or SB203580. In vivo, the administration of evodiamine (10 mg/kg) significantly reduced tumor growth and pulmonary metastasis. These results demonstrate that evodiamine possesses antitumor activities via inhibition of cell migration and invasion, arrest of the cell cycle and induction of cell apoptosis in MDA-MB-231 cells. 23831700 Pharmacokinetic comparisons of different combinations of Shaoyao-Gancao-Decoction in rats: Simultaneous determination of ten active constituents by HPLC-MS/MS. A specific HPLC-MS/MS method was developed and validated for simultaneous determination of ten constituents including albiflorin, oxypaeoniflorin, paeoniflorin, liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin, ononin, glycyrrhizin and glycyrrhetinic acid in rat plasma using genistein as an internal standard (IS). The rat plasma samples were prepared by a one-step direct protein precipitation procedure with methanol. HPLC separation was achieved on a Zorbax XDB-C18 column (2.1mm×50mm i.d., 3.5μm) with gradient elution (A: 0.1% aqueous formic acid; B: methanol with 0.1% formic acid) at a flow rate of 0.5mL/min in a run time of 7min. All analytes and IS were detected by multiple reaction monitoring scanning with electrospray ionization in the negative ion mode. Calibration curves showed good linearity (r>0.998) over a wide concentration range for all analytes. The intra- and inter-day precisions were all within 15% and the accuracies were in the range of -6.2% to 10.1%. The validated method was successfully applied to determination and comparative pharmacokinetics investigation of the ten constituents in rat plasma after oral administration of different combinations (Radix Paeoniae Alba:Glycyrrhiza uralensis=1:1 or 4:1) of Shaoyao-Gancao-Decoction (SGD) extracts. Pharmacokinetic parameters were evaluated by a compartment model. There were perceptible differences in pharmacokinetic parameters (Cmax, AUC0-t, CL) of the analytes except for liquiritin between the two groups of SGD. 23905796 Cleaning of conveyor belt materials using ultrasound in a thin layer of water. Cleaning of conveyor belts in the food industry is imperative for preventing the buildup of microorganisms that can contaminate food. New technologies for decreasing water and energy consumption of cleaning systems are desired. Ultrasound can be used for cleaning a wide range of materials. Most commonly, baths containing fairly large amounts of water are used. One possibility to reduce water consumption is to use ultrasonic cavitation in a thin water film on a flat surface, like a conveyor belt. In order to test this possibility, a model system was set up, consisting of an ultrasound transducer/probe with a 70-mm-diameter flat bottom, operating at 19.8 kHz, and contaminated conveyor belt materials in the form of coupons covered with a thin layer of water or water with detergent. Ultrasound was then applied on the water surface at different power levels (from 46 to 260 W), exposure times (10 and 20 s), and distances (2 to 20 mm). The model was used to test two different belt materials with various contamination types, such as biofilms formed by bacteria in carbohydrate- or protein-fat-based soils, dried microorganisms (bacteria, yeasts, and mold spores), and allergens. Ultrasound treatment increased the reduction of bacteria and yeast by 1 to 2 log CFU under the most favorable conditions compared with water or water-detergent controls. The effect was dependent on the type of belt material, the power applied, the exposure time, and the distance between the probe and the belt coupon. Generally, dried microorganisms were more easily removed than biofilms. The effect on mold spores was variable and appeared to be species and material dependent. Spiked allergens were also efficiently removed by using ultrasound. The results in this study pave the way for new cleaning designs for flat conveyor belts, with possibilities for savings of water, detergent, and energy consumption. 23944195 Phonetic complexity and stuttering in Arabic. Abstract The current study investigated whether phonetic complexity affected stuttering rate in Jordanian Arabic speakers. Speakers were assigned to three age groups (6-11, 12-17 and 18+ years). An Arabic index of phonetic complexity (AIPC) was developed. Each word was given a score based on the number of complex phonetic properties out of a total of nine that it contained in the AIPC. The results showed that stuttering on function words for Jordanian Arabic did not correlate significantly with the AIPC score for any age group. The AIPC scores of content and function-content words correlated positively with stuttering rate for the 6-11 age group alone with the function-content words affecting fluency more severely than did the content words. The AIPC scores of stuttered function, content and stuttered function-content words were higher than those of fluent words. The non-stuttered words had lower AIPC scores than the stuttered corresponding classes. This showed that the higher the AIPC score on stuttered words, the greater the chance for these word categories to be stuttered. The AIPC factors that most affected fluency in Jordanian Arabic were place of articulation, manner of articulation, word length, word shape and consonant length. We conclude that Arabic is similar to other languages with regard to the loci of stuttering, their phonetic complexity and AIPC factors affecting stuttering most. The correlation between phonetic complexity and the order of the AIPC factors are different between Arabic and other languages. 23815827 Mojokerto revisited: Evidence for an intermediate pattern of brain growth in Homo erectus. Brain development in Homo erectus is a subject of great interest, and the infant calvaria from Mojokerto, Indonesia, has featured prominently in these debates. Some researchers have suggested that the pattern of brain development in H. erectus resembled that of non-human apes, while others argue for a more human-like growth pattern. In this study, we retested hypotheses regarding brain ontogeny in H. erectus using new methods (resampling), and data from additional H. erectus crania. Our results reveal that humans achieve 62% (±10%) and chimpanzees 80% (±9%) of their adult endocranial volume by 0.5-1.5 years of age. Using brain mass data, humans achieve on average 65% and chimpanzees 81% of adult size by 0.5-1.5 years. When compared with adult H. erectus crania (n = 9) from Indonesian sites greater than 1.2 million years old, Mojokerto had reached ∼70% of its adult cranial capacity. Mojokerto thus falls almost directly between the average growth in humans and chimpanzees, and well within the range of both. We therefore suggest that brain development in H. erectus cannot be dichotomized as either ape-like or human-like; it was H. erectus-like. These data indicate that H. erectus may have had a unique developmental pattern that should be considered as an important step along the continuum of brain ontogeny between apes and humans. 23932634 Cloacogenic polyps in an adolescent: A rare cause of rectal bleeding. Cloacogenic polyps are rare inflammatory lesions occurring around the anal transitional zone and in the lower rectum which can mimic neoplasia. They should be given diagnostic consideration in patients presenting with symptoms of rectal bleeding, tenesmus, and altered bowel habits. 23890612 Profile of a drunk driver and risk factors for drunk driving. Findings in roadside testing in the province of Uusimaa in Finland 1990-2008. The aim of the present study was to define the profile of a drunk driver and to determine risk factors for drunk driving by analyzing data on both sober and drunk drivers. Systematic roadside surveys have been carried out in Southern Finland for over 18 years, with 20,000-30,000 drivers breath tested annually. During the study period, 1241 drunk drivers were caught (legal blood alcohol limit 0.50‰). The comparison material consisted of 3407 sober drivers. The surveys were designed to further investigate demographic features and driving habits of drivers. The prevalence of drunk driving has been 0.2% over the time period, with only random variations. According to the data, a typical drunk driver is a man aged 40-49 who has a valid driving license and drives his own car, usually alone, with a blood alcohol concentration (BAC) of 1.0‰. He has a job and is married or cohabiting. The profile remained consistent throughout the study period. The risk of drunk driving was found to be five times higher for men than for women. Divorcees and widow(er)s had a substantially higher risk factor for being caught drunk driving than married drivers. Drunk drivers are most likely to be caught by roadside testing on Saturday mornings. During the study period the blood alcohol limit for aggravated drunk driving was lowered in 1994 from 1.5 to 1.2‰. In 2004 the taxation of alcohol beverages was reduced by 30%. Neither of these measures affected the prevalence of drunk driving or the mean BAC of drunk drivers (p=0.63). 23756039 Alkali activation processes for incinerator residues management. Incinerator bottom ash (BA) is produced in large amount worldwide and in Italy, where 5.1 millionstons of municipal solid residues have been incinerated in 2010, corresponding to 1.2-1.5 millionstons of produced bottom ash. This residue has been used in the present study for producing dense geopolymers containing high percentage (50-70wt%) of ash. The amount of potentially reactive aluminosilicate fraction in the ash has been determined by means of test in NaOH. The final properties of geopolymers prepared with or without taking into account this reactive fraction have been compared. The results showed that due to the presence of both amorphous and crystalline fractions with a different degree of reactivity, the incinerator BA geopolymers exhibit significant differences in terms of Si/Al ratio and microstructure when reactive fraction is considered. 21967467 Effects of formulation parameters on encapsulation efficiency and release behavior of thienorphine loaded PLGA microspheres. To develop a long-acting injectable thienorphine biodegradable poly (d, l-lactide-co-glycolide) (PLGA) microsphere for the therapy of opioid addiction, the effects of formulation parameters on encapsulation efficiency and release behavior were studied. The thienorphine loaded PLGA microspheres were prepared by o/w solvent evaporation method and characterized by HPLC, SEM, laser particle size analysis, residual solvent content and sterility testing. The microspheres were sterilized by gamma irradiation (2.5 kGy). The results indicated that the morphology of the thienorphine PLGA microspheres presented a spherical shape with smooth surface, the particle size was distributed from 30.19 ± 1.17 to 59.15 ± 0.67 μm and the drug encapsulation efficiency was influenced by drug/polymer ratio, homogeneous rotation speed, PVA concentration in the water phase and the polymer concentration in the oil phase. These changes were also reflected in drug release. The plasma drug concentration vs. time profiles were relatively smooth for about 25 days after injection of the thienorphine loaded PLGA microspheres to beagle dogs. In vitro and in vivo correlation was established. 23909607 Atopy, the barrier, urine and genital lichen sclerosus (LS). We thank Dr Bunker for adding another condition playing a role in the pathogenesis of LS. Indeed the "warm, moist, urine-exposed environment" was postulated as predilecting BXO in the observation of Depasquale and al. (1) We refer to this theory in our review of 225 cases of LS in boys. (2) We could confirm the observation of recurrence of LS after circumcision in a boy whose obesity had led to a pseudoprepuce caused by the phenomenon of buried penis. So exposure to urine is probably a factor. There are a lot of studies and data in literature indicating a relationship between autoimmunity and LS. (3) This article is protected by copyright. All rights reserved. 23780887 Inhibition of Protein Phosphatase 2A Radiosensitizes Pancreatic Cancers by Modulating CDC25C/CDK1 and Homologous Recombination Repair. To identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer and thus improve survival, we conducted an siRNA library screen in pancreatic cancer cells. We investigated PPP2R1A, a scaffolding subunit of protein phosphatase 2A (PP2A) as a lead radiosensitizing target. We determined the effect of PP2A inhibition by genetic (PPP2R1A siRNA) and pharmacologic (LB100, a small molecule entering phase I clinical trials) approaches on radiosensitization of Panc-1 and MiaPaCa-2 pancreatic cancer cells both in vitro and in vivo. PPP2R1A depletion by siRNA radiosensitized Panc-1 and MiaPaCa-2 cells, with radiation enhancement ratios of 1.4 (P < 0.05). Likewise, LB100 produced similar radiosensitization in pancreatic cancer cells, but minimal radiosensitization in normal small intestinal cells. Mechanistically, PPP2R1A siRNA or LB100 caused aberrant CDK1 activation, likely resulting from accumulation of the active forms of PLK1 (pPLK1 T210) and CDC25C (pCDC25C T130). Furthermore, LB100 inhibited radiation-induced Rad51 focus formation and homologous recombination repair (HRR), ultimately leading to persistent radiation-induced DNA damage, as reflected by γ-H2AX expression. Finally, we identified CDC25C as a key PP2A substrate involved in LB100-mediated radiosensitization as depletion of CDC25C partially reversed LB100-mediated radiosensitization. In a mouse xenograft model of human pancreatic cancer, LB100 produced significant radiosensitization with minimal weight loss. Collectively, our data show that PP2A inhibition radiosensitizes pancreatic cancer both in vitro and in vivo via activation of CDC25C/CDK1 and inhibition of HRR, and provide proof-of-concept evidence that PP2A is a promising target for the improvement of local therapy in pancreatic cancer. Clin Cancer Res; 19(16); 4422-32. ©2013 AACR. 23867230 The effects of serotonin, dopamine, gonadotropin-releasing hormones, and corazonin, on the androgenic gland of the giant freshwater prawn, Macrobrachium rosenbergii. Neurotransmitters and neurohormones are agents that control gonad maturation in decapod crustaceans. Of these, serotonin (5-HT) and dopamine (DA) are neurotransmitters with known antagonist roles in female reproduction, whilst gonadotropin-releasing hormones (GnRHs) and corazonin (Crz) are neurohormones that exercise both positive and negative controls in some invertebrates. However, the effects of these agents on the androgenic gland (AG), which controls testicular maturation and male sex development in decapods, via insulin-like androgenic gland hormone (IAG), are unknown. Therefore, we set out to assay the effects of 5-HT, DA, l-GnRH-III, oct-GnRH and Crz, on the AG of small male Macrobrachium rosenbergii (Mr), using histological studies, a BrdU proliferative cell assay, immunofluorescence of Mr-IAG, and ELISA of Mr-IAG. The results showed stimulatory effects by 5-HT and l-GnRH-III through significant increases in AG size, proliferation of AG cells, and Mr-IAG production (P<0.05). In contrast, DA and Crz caused inhibitory effects on the AG through significant decreases in AG size, proliferation of AG cells, and Mr-IAG production (P<0.05). Moreover, the prawns treated with Crz died before day 16 of the experimental period. We propose that 5-HT and certain GnRHs can be now used to stimulate reproduction in male M. rosenbergii, as they induce increases in AG and testicular size, IAG production, and spermatogenesis. The mechanisms by which these occur are part of our on-going research. 23865738 Occiput posterior position diagnosis: vaginal examination or intrapartum sonography? A clinical review. Abstract The occiput posterior position is one of the most frequent malposition during labor. During the first stage of labor the fetal head may stay in the occiput posterior position in 30% of the cases, but of these only 5-7% remains as such at time of delivery. The diagnosis of occiput posterior position in the second stage of labor is made ​​difficult by the presence of the caput succedaneum or scalp hair, both of which may give some problem in the identification of fetal head sutures and fontanels and their location in relationship to maternal pelvic landmarks. The capability of diagnosing a fetus in occiput posterior position by digital examination has been extremely inaccurate, whereas an ultrasound approach, transabdominal, transperineal and transvaginal, has clearly shown its superior diagnostic accuracy. This is true not only for diagnosis of malpositions, detected in both first and second stage of labor, but also in cases of marked asynclitism. 23887857 Nutrition and bioprocess development for efficient biosynthesis of an antitumor compound from marine-derived fungus. An integrated nutrition and bioprocess strategy was developed for improving the biosynthesis of an antitumor compound, 1403C, by a marine-derived fungus, Halorosellinia sp. (no. 1403). First, statistical design strategies were synthetically applied to optimize the nutritional composition. The resulting 1403C production reached 2.07 g/l, which was 143.5 % higher than the original production. However, it only produced 0.44 g/l of 1403C in 5-l bioreactor fermentation. Thus, the operating parameters including culture pH, dissolved oxygen, agitation speed, impeller type and inoculum level were considered to improve the fermentation process, and an effective control strategy for 1403C production by Halorosellinia sp. submerged in a 5-l bioreactor was established. When inoculating 0.22 g/l dry biomass, controlling dissolved oxygen not lower than 30 % during the growth phase but ranging between 30 and 40 % during the stationary phase, using a double-layer six-flat-blade Rushton disc turbine agitated at 400 rpm, keeping short-term low pH and rapid-rising pH with glucose starvation, the highest 1403C production was finally obtained at 1.32 g/l, which was promoted by 200 % compared to before optimization. Fermentation scale-up was finally performed in a 500-l bioreactor, and 1403C production of 1.09 g/l was obtained. 23435543 Climate change and levels of violence in socially disadvantaged neighborhood groups. The current study examines the link between climate change and neighborhood levels of violence using 20 years of monthly climatic and crime data from St. Louis, MO, USA. St. Louis census tracts are aggregated in neighborhood groups of similar levels of social disadvantage, after which each group is subjected to time series analysis. Findings suggest that neighborhoods with higher levels of social disadvantage are very likely to experience higher levels of violence as a result of anomalously warm temperatures. The 20 % of most disadvantaged neighborhoods in St. Louis, MO, USA are predicted to experience over half of the climate change-related increase in cases of violence. These results provide further evidence that the health impacts of climate change are proportionally higher among populations that are already at high risk and underscore the need to comprehensively address climate change. 23791315 Systematic review of interventions used in or relevant to occupational therapy for children with feeding difficulties ages birth-5 years. Research articles on the effectiveness of feeding interventions for infants and young children were identified, appraised, and synthesized. Thirty-four studies met the inclusion criteria and were reviewed. Three broad intervention themes regarding feeding approaches were identified on the basis of their theoretical orientations. These three feeding approaches were (1) behavioral interventions, (2) parent-directed and educational interventions, and (3) physiological interventions. Synthesis of the evidence suggested that various feeding approaches may result in positive outcomes in the areas of feeding performance, feeding interaction, and feeding competence of parents and children. This synthesis of empirical evidence supporting interventions for feeding problems provides a foundation for future research to define the types of outcomes that can be expected for children with different diagnoses or functional impairments and to develop best practice guidelines. 23433476 Infantile inflammatory pseudotumor of the facial nerve as a complication of epidermal nevus syndrome with cholesteatoma. The first reported case of facial paralysis due to an inflammatory pseudotumor (IPT) of the facial nerve as a complication of epidermal nevus syndrome (ENS) is herein presented. A 10-month-old female patient was diagnosed with ENS at 3 months of age. She was referred to us because of moderate left facial paralysis. Epidermal nevi of her left auricle extended deep into the external ear canal. Otoscopy revealed polypous nevi and cholesteatoma debris filling the left ear. Computed tomography showed a soft mass filling the ear canal, including the middle ear, and an enormously enlarged facial nerve. Surgical exploration revealed numerous polypous nevi, external ear cholesteatoma, and tumorous swelling of the facial nerve. The middle ear ossicles were completely lost. The facial paralysis was improved after decompression surgery, but recurred 5 months later. A second operation was conducted 10 months after the first. During this operation, facial nerve decompression was completed from the geniculate ganglion to near the stylomastoid foramen. Histological diagnosis of the facial nerve tumor was IPT probably caused by chronic external ear inflammation induced by epidermal nevi. The facial paralysis gradually improved to House-Blackmann grade III 5 years after the second operation. 23793639 Relationship between Presence of Cows with Milk Positive for Mycobacterium avium subsp. paratuberculosis-Specific Antibody by Enzyme-Linked Immunosorbent Assay and Viable M. avium subsp. paratuberculosis in Dust in Cattle Barns. Paratuberculosis, or Johne's disease, in cattle is caused by Mycobacterium avium subsp. paratuberculosis, which has recently been suspected to be transmitted through dust. This longitudinal study on eight commercial M. avium subsp. paratuberculosis-positive dairy farms studied the relationship between the number of cows with M. avium subsp. paratuberculosis antibody-positive milk and the presence of viable M. avium subsp. paratuberculosis in settled-dust samples, including their temporal relationship. Milk and dust samples were collected in parallel monthly for 2 years. M. avium subsp. paratuberculosis antibodies in milk were measured by enzyme-linked immunosorbent assay (ELISA) and used as a proxy for M. avium subsp. paratuberculosis shedding. Settled-dust samples were collected by using electrostatic dust collectors (EDCs) at six locations in housing for dairy cattle and young stock. The presence of viable M. avium subsp. paratuberculosis was identified by liquid culture and PCR. The results showed a positive relationship (odds ratio [OR], 1.2) between the number of cows with ELISA-positive milk and the odds of having positive EDCs in the same airspace as the adult dairy cattle. Moreover, the total number of lactating cows also showed an OR slightly above 1. This relationship remained the same for settled-dust samples collected up to 2 months before or after the time of milk sampling. The results suggest that removal of adult cows with milk positive for M. avium subsp. paratuberculosis-specific antibody by ELISA might result in a decrease in the presence of viable M. avium subsp. paratuberculosis in dust and therefore in the environment. However, this decrease is likely delayed by several weeks at least. In addition, the data support the notion that M. avium subsp. paratuberculosis exposure of young stock is reduced by separate housing. 23839509 Buffalo Colostrum β-lactoglobulin Inhibits VEGF-Induced Angiogenesis by Interacting with G protein-Coupled Receptor Kinase. β-lactoglobulin (β-lg), a major whey protein was purified and characterised from buffalo colostrum. The in silico analysis of the tryptic peptides based on LC-CID-MS/MS facilitated the identification of protein as β-lg. The sequences IIVTQ f[1-5] and LSFNPTQLEEQCHV f(149-162) of m/z 933(+) and 851(2+) were found to match N- and C-extreme of β-lg while IDALNENK f(84-91) and TPEVDDEALEKFDK f(125-138) sequences deduced for m/z 916(+) and 818(2+) were in compliance to buffalo milk β-lg. Considering the sequence similarity of β-lg to glycodelin, a proven angiogenic protein, similar role for β-lg from buffalo colostrum (BLG-col) was examined. Interestingly, BLG-col exhibited anti-angiogenic activity by potently inhibiting cell proliferation, micro-vessel sprouting, cell migration and tube formation of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner but having varied effect on Ehrlich ascites tumor cells, MCF-7, MDA-MB 435 and MDA-MB 231 cell lines. The anti-angiogenic potential of BLG-col was found to be vascular endothelial growth factor mediated. The immunolocalisation of BLG-col on the cell surface of HUVECs evidenced using FITC-labelled β-lg antibody indicated its extra-cellular binding. Furthermore, BLG-col interacting HUVEC membrane protein (64 kDa) was detected by immunoblot and its identity was established by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry analysis, which showed peptide sequence homology to G protein-coupled receptor kinase 4. 23896369 Delirium During Acute Illness in Nursing Home Residents. To ascertain the incidence of delirium during acute illness in nursing home residents, describe the timing of delirium after acute illness onset, describe risk factors for delirium, and explore the relationship between delirium and complications of acute illness. Prospective observational cohort study. Three nursing homes in metropolitan New York. Individuals who were expected to remain in the nursing home for at least 2 months, who, as part of a parent study, were receiving opioids, antidepressants, or antipsychotics on a routine basis, and who did not have an acute medical illness at the time of screening. Acute illness surveillance was performed twice weekly through communication with nursing home nursing staff and medical providers using established clinical criteria for incipient cases. We followed patients for 14 days after illness onset, and, if applicable, an additional 14 days each after hospital admission and hospital discharge. Delirium was assessed 3 times weekly using the Confusion Assessment Method (CAM). Physical function decline was calculated using change in the Minimum Data Set Activities of Daily Living Scale (MDS-ADL) and cognitive function decline using change in the Minimum Data Set Cognitive performance scale (MDS-CPS). Falls were ascertained by record review. Among 136 nursing home patients followed for a mean of 11.7 months, 78 experienced 232 acute illnesses, of which 162 (71%) were managed in the nursing home. The most common diagnoses were urinary tract infection (20%), cellulitis (15%), and lower respiratory tract infection (9%). Subjects experienced delirium during 41 (17.7%) of 232 acute illnesses. Female sex was associated with a greater risk of delirium (odds ratio 2.59; 95% confidence interval [CI] 1.04-6.43) but there were no other risk factors identified. Delirium was a risk factor for cognitive function decline (odds ratio 4.59; 95% CI 1.99-10.59; P = .0004), but not ADL function decline or falling. Delirium occurred frequently as a complication of acute illness in the nursing home, and was a risk factor for cognitive function decline. This finding supports the rationale to target individuals at the onset of an acute medical problem in the design of interventions to prevent delirium in the nursing home setting. 23122876 Asymmetry of the leg alignment affects trunk bending in the coronal plane after unilateral total knee arthroplasty. Unilateral total knee arthroplasty (TKA) would produce asymmetric changes of lower extremity in patients with bilateral varus deformity. Our purpose was to investigate whether asymmetry of the leg alignment would affect trunk bending in the coronal plane after unilateral TKA. Twenty patients (mean 76years old) with bilateral end-stage knee osteoarthritis (OA) participated. Spine images during relaxed standing were obtained on pre- and postoperative day 21. As a result, the shoulder tilted more to the TKA side and the pelvis inclined more to the contralateral OA side. These results suggested that the trunk would bend away from the contralateral OA side after unilateral TKA in patients with bilateral end-stage knee OA and varus deformity. Asymmetry of the leg alignment led to asymmetric trunk bending. 23573952 Circumcision related to urinary tract infections, sexually transmitted infections, human immunodeficiency virus infections, and penile and cervical cancer. Male circumcision has been carried out as a prophylactic measure against future diseases, as well as a rite of passage due to religious practice and definite medical indication. The present review discusses the benefits of male circumcision on the prevention of urinary tract infections, and the importance of circumcision in congenital urinary system anomalies, such as vesicoureteral reflux. Additionally the present review examines the associations between circumcision and sexually transmitted infections, including human immunodeficiency virus, and the preventive effect of circumcision on penile cancer and cervical cancer of female partners. 23850243 Myeloproliferative Neoplasia Remodels the Endosteal Bone Marrow Niche into a Self-Reinforcing Leukemic Niche. Multipotent stromal cells (MSCs) and their osteoblastic lineage cell (OBC) derivatives are part of the bone marrow (BM) niche and contribute to hematopoietic stem cell (HSC) maintenance. Here, we show that myeloproliferative neoplasia (MPN) progressively remodels the endosteal BM niche into a self-reinforcing leukemic niche that impairs normal hematopoiesis, favors leukemic stem cell (LSC) function, and contributes to BM fibrosis. We show that leukemic myeloid cells stimulate MSCs to overproduce functionally altered OBCs, which accumulate in the BM cavity as inflammatory myelofibrotic cells. We identify roles for thrombopoietin, CCL3, and direct cell-cell interactions in driving OBC expansion, and for changes in TGF-β, Notch, and inflammatory signaling in OBC remodeling. MPN-expanded OBCs, in turn, exhibit decreased expression of many HSC retention factors and severely compromised ability to maintain normal HSCs, but effectively support LSCs. Targeting this pathological interplay could represent a novel avenue for treatment of MPN-affected patients and prevention of myelofibrosis. 23639360 Rokumi-jio-gan-containing prescriptions regulate oxidative stress through improving dyslipidemia in a subtotal nephrectomized rat model. ETHNOPHARMACOLOGICAL RELEVANCE: Rokumi-jio-gan-containing prescriptions, traditional medicine, are widely used to treat renal dysfunction in Japan. AIM OF THE STUDY: The present study was conducted to examine whether two Rokumi-jio- gan-containing prescriptions (Hachimi-jio-gan and Bakumi-jio-gan) have an ameliorative effect on dyslipidemia in nephrectomized rats. MATERIALS AND METHODS: Each prescription was orally administered to nephrectomized rats at 150mg/kg body weight per day for 10 weeks, and its effect was compared with vehicle-treated nephrectomized rats. RESULTS: Rats given Hachimi-jio-gan and Bakumi-jio-gan showed an improvement of renal functional parameters such as serum urea nitrogen, creatinine, creatinine clearance, and urinary protein. The increased triglyceride, total cholesterol, non-esterified fatty acid, high-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol/low-density lipoprotein cholesterol levels in serum, and triglyceride and total cholesterol contents in the kidney of nephrectomized rats were significantly decreased by Hachimi-jio-gan and Bakumi-jio-gan administration. Furthermore, Hachimi-jio-gan acts as a regulator of peroxisome proliferator-activated receptor α, sterol regulatory element binding protein (SREBP)-1, and SREBP-2. On the contrary, the increased reactive oxygen species and thiobarbituric acid-reactive substance were decreased, while superoxide dismutase and the reduced glutathione/oxidized glutathione ratio were augmented by Hachimi-jio-gan rather than Bakumi-jio-gan. The improvement of nuclear factor-kappa Bp65, cyclooxygenase-2, inducible nitric oxide synthase, NF-E2-related factor 2, and heme oxygenase-1 was marked in the group administered Bakumi-jio-gan. However, oil red O staining showed that the increased lipid deposition in the kidney of nephrectomized rats improved on Hachimi-jio-gan and Bakumi-jio-gan administration. CONCLUSION: This study provides scientific evidence that two Rokumi-jio-gan-containing prescriptions (Hachimi-jio-gan and Bakumi-jio-gan) improves oxidative stress via dyslipidemia in the remnant kidney of nephrectomized rats. 23897231 Evoked centripetal Ca2+ mobilization in cardiac Purkinje cells;Insight from a model of three Ca2+ release regions. Despite strong suspicion that abnormal Ca2+ handling in Purkinje cells (P-cells) is implicated in life-threatening forms of ventricular tachycardias, the mechanism underlying the Ca2+ cycling of these cells under normal conditions is still unclear. There is mounting evidence that P-cells have a unique Ca2+ handling system. Notably a complex spontaneous Ca2+ activity was previously evidenced in canine P-cells and was explained by a mechanistic hypothesis involving a triple layered system of Ca2+ release channels. Here we examined the validity of this hypothesis for the electrically-evoked Ca2+ transient which was shown, in the dog and rabbit, to occur progressively from the periphery to the interior of the cell. To do so, the hypothesis was incorporated in a model of intracellular Ca2+ dynamics which was used, then, to reproduce numerically the Ca2+ activity of P-cells under stimulated conditions. The modeling was performed through a 2D computational array that encompassed 3 distinct Ca2+ release nodes arranged, respectively, into 3 consecutive adjacent regions. A system of partial differential equations (PDE) addressed numerically the principal cellular functions that modulate the local cytosolic Ca2+ concentration (Cai). The apparent node-to-node progression of elevated Cai was obtained by combining Ca2+ diffusion and "Ca2+-induced Ca2+-release". To provide the modeling with a reliable experimental reference, we first re-examined the Ca2+ mobilization in swine stimulated P-cells by 2D confocal microscopy. As reported earlier for the dog and rabbit, a centripetal Ca2+ transient was readily visible in 22 stimulated P-cells from 6 adult Yucatan swine hearts (pacing rate: 0.1Hz; pulse duration: 25ms, pulse amplitude: 10% above threshold; 1mM Ca2+; 35oC; pH 7.3). An accurate replicate of the centripetal Ca2+ propagation was generated by the model for four representative cell examples and confirmed by statistical comparisons of simulations against cell data. Selective inactivation of Ca2+ release regions of the computational array showed that an intermediate layer of Ca2+ release nodes with about 30-40 percent lower Ca2+ activation threshold was required to reproduce the phenomenon. Our computational analysis was therefore fully consistent with the activation of a triple layered system of Ca2+ release channels as mechanism of centripetal Ca2+ signaling in P-cells. Moreover, the model clearly indicated that the intermediate Ca2+ release region layer with increased sensitivity for Ca2+ plays an important role in the specific intracellular Ca2+ mobilization of Purkinje fibers and could be therefore a relevant determinant of cardiac conduction. 23612195 Gram-negative bacteria that produce carbapenemases causing death attributed to recent foreign hospitalization. Overseas travel, as a risk factor for the acquisition of infections due to antimicrobial-resistant organisms, has recently been linked to carbapenemase-producing Gram-negative bacteria. Multiresistant Klebsiella pneumoniae, Escherichia coli, and Acinetobacter baumannii strains were isolated from a wound of a Canadian patient with a recent history of hospitalization in India. This resulted in the initiation of outbreak management that included surveillance cultures. Epidemiological and molecular investigations showed that NDM-1-producing K. pneumoniae ST16 and OXA-23-producing A. baumannii ST10 strains were transmitted to 5 other patients, resulting in the colonization of 4 patients and the death of 1 patient due to septic shock caused by the OXA-23-producing A. baumannii strain. The high rate of false positivity of the screening cultures resulted in additional workloads and increased costs for infection control and clinical laboratory work. We believe that this is the first report of an infection with carbapenemase-producing Gram-negative bacteria resulting in death attributed to a patient with recent foreign hospitalization. We recommend routine rectal and wound screening for colonization with multiresistant bacteria for patients who have recently been admitted to hospitals outside Canada. 22651800 New 5-(nitroheteroaryl)-1,3,4-thiadiazols containing acyclic amines at C-2: synthesis and SAR study for their antileishmanial activity. A novel series of 5-(5-nitrofuran-2-yl)-and 5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazole-2-amines bearing acyclic amine at C-2 position of thiadiazole ring were synthesized and evaluated in vitro against promastigote and amastigote forms of Leishmania major. The structure-activity of series was investigated by studying 40 compounds. The most active derivatives were hydroxypropylamino- and methoxypropylamino- analogs of 5-(5-nitrothiophen-2-yl)-1,3,4-thiadiazole (compounds 29 and 32, respectively) with highest selectivity index (SI >12). 23746365 Degradation of pesticide mixture on modified matrix of a biopurification system with alternatives lignocellulosic wastes. The biobed systems were designed to retain and to degrade pesticides through the properties of a biomixture composed of straw (ST), topsoil and peat (PT) 2:1:1 v/v. The ST is the main substrate in the biomixture, as it allows the proliferation of fungi that promotes pesticide degradation. The use of readily available components in the biomixture is an important aspect to build a biobed. Therefore, potential use of readily available wastes as barley husk (BH), sawdust (SW) and oat husk (OH), as total or partial substitutes of ST were tested in pesticide degradation studies. Metabolite formation and the biological activities were also evaluated. Biomixture composed of OH was highly efficient in pesticide degradation, with t½ values of 28.6, 58.9 and 26.8 d for atrazine (ATZ), chlorpyrifos (CHL) and isoproturon (ISP). On the other hand, comparable for degrading capacities with the ST based biomixture were obtained with SW and BH, but only as partial replacement. Contrarily, high t½ values (more than 100 d) were obtained in biomixtures with total substitution of ST by SW or BH. Metabolite formation was observed in all biomixtures tested, but without clear formation patterns. Moreover, high and stable biological activity was observed in the biomixtures composed of OH. Therefore, our results demonstrated that ST can be partial or totally replaced by OH in the biomixture allowing an efficient degradation of pesticide mixture. However, it is recommended that ST can be only partially replaced by BH and SW in the biomixture to allow efficient pesticide degradation. 23850369 Adenosquamous carcinoma of the head and neck: report of 20 cases and review of the literature. To assess the clinical profile and prognostic factors in patients with adenosquamous carcinoma (ASC) of the head and neck treated by surgery and/or radiation therapy with or without chemotherapy. Data from 20 patients with stage I-II (n = 4), III (n = 5), or IVA (n = 11) head and neck ASC, treated between 1989 and 2010 were collected in a retrospective multicenter Rare Cancer Network study. Surgery was performed in 16 patients. Seventeen patients received combined modality treatment. After a median follow-up of 15.5 months, 12 patients recurred. The 3-year and median overall survival, disease-free survival (DFS), and loco-regional control were 52% and 39 months, 32% and 12 months, and 47% and 33 months respectively. In multivariate analysis, DFS was negatively influenced by the presence of extracapsular extension and advanced stage. Overall prognosis of locoregionally advanced ASC remains poor. However, early stage ASC patients managed with combined modality treatment may have prolonged DFS. 22614005 MicroRNA-7 functions as an anti-metastatic microRNA in gastric cancer by targeting insulin-like growth factor-1 receptor. Metastasis is a major clinical obstacle in the treatment of gastric cancer (GC) and it accounts for the majority of cancer-related mortality. MicroRNAs have recently emerged as regulators of metastasis by acting on multiple signaling pathways. In this study, we found that miR-7 is significantly downregulated in highly metastatic GC cell lines and metastatic tissues. Both gain-of-function and loss-of-function experiments showed that increased miR-7 expression significantly reduced GC cell migration and invasion, whereas decreased miR-7 expression dramatically enhanced cell migration and invasion. In vivo metastasis assays also demonstrated that overexpression of miR-7 markedly inhibited GC metastasis. Moreover, the insulin-like growth factor-1 receptor (IGF1R) oncogene, which is often mutated or amplified in human cancers and functions as an important regulator of cell growth and tumor invasion, was identified as a direct target of miR-7. Silencing of IGF1R using small interefering RNA (siRNA) recapitulated the anti-metastatic function of miR-7, whereas restoring the IGF1R expression attenuated the function of miR-7 in GC cells. Furthermore, we found that suppression of Snail by miR-7, through targeting IGF1R, increased E-cadherin expression and partially reversed the epithelial-mesenchymal transition (EMT). Finally, analyses of miR-7 and IGF1R levels in human primary GC with matched lymph node metastasis tissue arrays revealed that miR-7 is inversely correlated with IGF1R expression. The present study provides insight into the specific biological behavior of miR-7 in EMT and tumor metastasis. Targeting this novel miR-7/IGF1R/Snail axis would be helpful as a therapeutic approach to block GC metastasis. 23950921 Real-time strategy game training: emergence of a cognitive flexibility trait. Training in action video games can increase the speed of perceptual processing. However, it is unknown whether video-game training can lead to broad-based changes in higher-level competencies such as cognitive flexibility, a core and neurally distributed component of cognition. To determine whether video gaming can enhance cognitive flexibility and, if so, why these changes occur, the current study compares two versions of a real-time strategy (RTS) game. Using a meta-analytic Bayes factor approach, we found that the gaming condition that emphasized maintenance and rapid switching between multiple information and action sources led to a large increase in cognitive flexibility as measured by a wide array of non-video gaming tasks. Theoretically, the results suggest that the distributed brain networks supporting cognitive flexibility can be tuned by engrossing video game experience that stresses maintenance and rapid manipulation of multiple information sources. Practically, these results suggest avenues for increasing cognitive function. 23881290 Potential Interactions with Anticancer Agents: A Cross-Sectional Study. Background: Patients with cancer are particularly susceptible to drug interactions (DIs), but the extent of the problem has received limited attention. We aimed to evaluate the frequency of interactions with anticancer agents in a group of cancer patients. Methods : The study was performed in a Belgian teaching hospital. One hundred and twenty-two patients with solid malignancies were included. A comprehensive drug history was performed by a clinical pharmacist. Three renowned DI compendia were used to identify DIs. Results: Forty-one potential interactions involving an anticancer agent and considered to be clinically significant were identified among 25% of patients. The anticancer drugs mostly involved were cisplatin and methotrexate, and the most frequent co-medications involved were vitamin K antagonists, proton pump inhibitors and diuretics. In the majority of cases, the potential adverse consequence was increased toxicity of the anticancer agent and/or of the co-medication. Less than 10% of DIs were identified by the three compendia. Conclusions: Preventive measures should be taken to avoid increased toxicity or decreased efficacy of the drugs. Most of the time, this simply involves surveillance of biological or clinical parameters. Collaboration with a clinical pharmacist may be useful for the prescribing physician. © 2013 S. Karger AG, Basel. 23094685 Dry powder inhalation exposures of the endotracheally intubated rat lung, ex vivo and in vivo: the pulmonary pharmacokinetics of fluticasone furoate. Abstract Background: The isolated perfused rat lung (IPL) is a suitable model for studying lung-specific pharmacokinetics (PK) of inhaled drugs. So far, little has been known, however, whether the PK measured in the ex vivo organ corresponds to the PK measured in similarly exposed animals in vivo, in particular the endotracheally intubated rat (EIR). The purpose of the current research was to compare the PK of inhaled corticosteroid fluticasone furoate (FF) in the IPL and the EIR. Method: Aerosols of FF with mass median aerodynamic diameters ranging from 2.2 to 3.2 μm were generated with the DustGun aerosol generator. The IPL, perfused in the single-pass mode, was exposed via inhalation to 5.6 and 46 μg of FF. Following inhalation, the perfusate was repeatedly sampled for 100 min, after which the lungs were recovered for quantitation of remaining FF. Two groups of EIR were also exposed via inhalation to 7 μg of FF. One group was immediately euthanized for determination of the initial deposition of FF in the lungs. From the second group, four venous blood samples were drawn up to 4 hr after exposure. The animals were then sacrificed for determination of FF remaining in the lungs. Results: Following inhalation, FF was slowly disappearing from both the IPL and the lungs of the EIR, with a half-life of pulmonary retention of 4.3-4.9 hr for all three exposure series. For the low exposure levels, the concentration curve of FF in the IPL perfusate was similar in shape to that in venous blood of the EIR, with a Cmax of 1.0 and 0.8 nM for the IPL and the EIR, respectively. Conclusions: The results indicate that the IPL and the EIR, when used jointly in PK studies, can provide a detailed characterization of inhaled drugs or toxicants. 23459102 Does low and oscillatory wall shear stress correlate spatially with early atherosclerosis? A systematic review. Low and oscillatory wall shear stress is widely assumed to play a key role in the initiation and development of atherosclerosis. Indeed, some studies have relied on the low shear theory when developing diagnostic and treatment strategies for cardiovascular disease. We wished to ascertain if this consensus is justified by published data. We performed a systematic review of papers that compare the localization of atherosclerotic lesions with the distribution of haemodynamic indicators calculated using computational fluid dynamics. The review showed that although many articles claim their results conform to the theory, it has been interpreted in different ways: a range of metrics has been used to characterize the distribution of disease, and they have been compared with a range of haemodynamic factors. Several studies, including all of those making systematic point-by-point comparisons of shear and disease, failed to find the expected relation. The various pre- and post-processing techniques used by different groups have reduced the range of shears over which correlations were sought, and in some cases are mutually incompatible. Finally, only a subset of the known patterns of disease has been investigated. The evidence for the low/oscillatory shear theory is less robust than commonly assumed. Longitudinal studies starting from the healthy state, or the collection of average flow metrics derived from large numbers of healthy vessels, both in conjunction with point-by-point comparisons using appropriate statistical techniques, will be necessary to improve our understanding of the relation between blood flow and atherogenesis. 23839315 TAP block for Abdominal Surgery. Background: Interest in techniques and applications of the transversus abdominis plane (TAP) block has expanded exponentially since its introduction over ten years ago. The choice of techniques and approaches has been assisted with the availability of ultrasound, but the optimal injection for certain surgical incisions are not yet clear. Methods: A literature search was performed looking at anatomical and distribution studies, and clinical trials evaluating the effects of TAP blocks in patients undergoing abdominal surgery. Case reports were also included. Conclusions:Clinical and contrast studies indicate that the landmark and ultrasound guided TAP blocks differ in their spread and mode of action. Regardless, both techniques provide effective analgesia for abdominal surgery. Further research is required to compare TAP blocks with epidural analgesia. 23789782 Muscle volume alterations in spastic muscles immediately following botulinum toxin type-A treatment in children with cerebral palsy. With evidence for an atrophic effect of botulinum toxin type A (BoNT-A) documented in typically developing muscles, this study investigated the immediate morphological alterations of muscles in children with cerebral palsy (CP) after BoNT-A treatment. Fifteen children (10 males, five females; age range 5-11y, mean age 8y 5mo, SD 1y 10mo) with spastic diplegic CP [Gross Motor Function Classification System Levels I (n=9) and II (n=6)] receiving BoNT-A injections for spasticity management were included. None of the children was a first-time receiver of BoNT-A. Magnetic resonance imaging and Mimics software assessed muscle volume, timed 2 weeks before and 5 weeks after injection. All participants received BoNT-A bilaterally to the gastrocnemius muscle, and five participants also received BoNT-A bilaterally to the medial hamstring muscles. Functional assessment measures used were the 6-Minute Walk Test (6-MWT), the Timed Up and Go (TUG) test, and hand-held dynamometry. Whilst total muscle group volume of the injected muscle group remained unchanged, a 4.47% decrease in the injected gastrocnemius muscle volume (p=0.01) and a 3.96% increase in soleus muscle volume (p=0.02) was evident following BoNT-A. There were no statistically significant changes in function after BoNT-A as assessed by the TUG. There was also no statistically significant change in distance covered in the 6-MWT. Muscle strength, as assessed using hand-held dynamometry was also not statistically different after BoNT-A treatment. Muscle volume decreases were observed in the injected muscle (gastrocnemius), with synergistic muscle hypertrophy that appeared to compensate for this decrement. The 4% to 5% decrease in the volume of BoNT-A injected muscles are not dramatic in comparison to reports in recent animal studies, and are a positive indication for BoNT-A, particularly as it also did not negatively alter function. 23790883 First mass spectrometry metabolic fingerprinting of bacterial metabolism in a model cheese. Metabolic fingerprinting is an untargeted approach which has not yet been undertaken to investigate cheese. This study is a proof of concept, concerning the ability of mass spectrometry (MS) metabolic fingerprinting to investigate modifications induced by bacterial metabolism in cheese over time. An ultrafiltrated milk concentrate was used to manufacture model cheeses inoculated with Lactococcus lactis LD61. Metabolic fingerprints were acquired after 0, 8 and 48h from two different fractions of the metabolome: the water-soluble fraction using liquid chromatography-high resolution-MS and a volatile fraction using gas chromatography-MS. Metabolic fingerprints differed significantly over time. Forty-five metabolites were identified, including well-known cheese metabolites, such as 12 amino acids and 25 volatile metabolites, and less studied ones, such as four vitamins, uric acid, creatine and l-carnitine. These results showed the relevance of cheese MS fingerprinting to generate new findings and to detect even slight differences between two conditions. 23789686 Pancreatic involvement in neuroblastoma with radiologic-pathologic correlation: a single-institution experience. Pancreatic involvement in neuroblastoma is extremely rare, with few cases reported in the literature. We present imaging findings of pancreatic involvement in neuroblastoma with clinical and pathologic correlation in the largest documented series to date. We prospectively reported pancreatic involvement evident on multimodality imaging in neuroblastoma patients presenting to our institution from 1997 to 2011. Lesions were classified according to location within the pancreas, and imaging features were correlated with cytogenetic and surgicopathologic findings. Neuroblastoma involving the pancreas was evident on imaging of seven of 1031 patients (mean age, 6.6 years). One patient had pancreatic involvement at presentation, and six developed pancreatic disease at relapse or disease progression. Pancreatic lesions were most frequently initially identified on concurrent CT and (123)I-metaiodobenzylguanidine scintigraphy, and additional lesions initially were found on MRI and ultrasound. Five of seven patients had focal lesions, one had diffuse pancreatic involvement, and one had pancreatic extension from contiguous disease. The distribution of lesions favored the pancreatic body and tail. All patients had International Neuroblastoma Staging System stage 3 or 4 disease, Children's Oncology Group intermediate- or high-risk disease, and unfavorable histology at initial diagnosis. For the five patients with surgical correlation, pancreatic surgical specimens revealed neuroblastoma in three cases and ganglioneuroblastoma in two cases. Although rare, pancreatic involvement in neuroblastoma occurs. Its variable imaging appearance should be considered when evaluating the retroperitoneum in patients with known or suspected neuroblastoma, particularly because increased patient survival holds the potential for uncommon patterns of recurrence. 23890723 Molecular cloning, expression and enzymatic characterization of glutathione S-transferase from Antarctic sea-ice bacteria Pseudoalteromonas sp. ANT506. A glutathione S-transferase (GST) gene from Antarctic sea-ice bacteria Pseudoalteromonas sp. ANT506 (namely PsGST), was cloned and expressed in Escherichia coli. The open reading frame of PsGST comprised 654bp encoding a protein of 217 amino acids with a calculated molecular size of 24.3kDa. The rPsGST possesses the conserved amino acid defining the binding sites of glutathione (G-site) and substrate binding pocket (H-site) in GST N_3 family. PsGST was expressed in E. coli and the recombinant PsGST (rPsGST) was purified by Ni-affinity chromatography with a high specific activity of 74.21U/mg. The purified rPsGST showed maximum activity at 40°C and exhibited 14.2% activity at 0°C. It was completely inactivated at 50°C for 40min. These results indicated that rPsGST was a typical cold active GST with low thermostability. The enzyme was little affected by H2O2 and Triton X-100, and 50.2% of the remaining activity was detected in the presence of high salt concentrations (2M NaCl). The enzymatic Km values for CDNB and GSH was 0.22mM and 1.01mM, respectively. These specific enzyme properties may be related to the survival environment of Antarctic sea ice bacteria. 23664448 Clinical perspective of afatinib in non-small cell lung cancer. Reversible ATP-competitive inhibitors targeting the epidermal growth factor receptor (EGFR) have been established as the most effective treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring "activating" mutations in exons 19 and 21 of the EGFR gene. However, clinical activity is limited by acquired resistance which on average develops within 10 months of continued treatment. The mechanisms for acquired resistance include selection of the EGFR T790M mutation in approximately 50% of cases, and MET gene amplification, PIK3CA gene mutation, transdifferentiation into small-cell lung cancer and additional rare or unkown mechanisms. Afatinib is a small molecule covalently binding and inhibiting the EGFR, HER2 and HER4 receptor tyrosine kinases. In preclinical studies, afatinib not only inhibited the growth of models with common activating EGFR mutations, but was also active in lung cancer models harboring wild-type EGFR or the EGFR L858R/T790M double mutant. Clinical efficacy of afatinib has been extensively studied in the LUX-Lung study program. These trials showed promising efficacy in patients with EGFR-mutant NSCLC or enriched for clinical benefit from EGFR tyrosine kinase inhibitors gefitinib or erlotinib. Here we review the current status of clinical application of afatinib in NSCLC. We also discuss clinical aspects of resistance to afatinib and strategies for its circumvention. 23895598 Gold medal award for life achievement in the science of psychology. The American Psychological Foundation (APF) Gold Medal Awards recognize distinguished and enduring records of accomplishment in four areas of psychology: the application of psychology, the practice of psychology, psychology in the public interest, and the science of psychology. The 2013 recipient of the Gold Medal Award for Life Achievement in the Science of Psychology is Elizabeth F. Loftus. This article presents Loftus' award citation, a brief biography, and a selected bibliography. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23876926 Between the idea and the reality: GP liaison in a rural setting. To describe the organisational, clinical and pragmatic features of a GP liaison service established by the Division of Mental Health in the Darling Downs Hospital and Health Service catchment to facilitate the care of rural patients and improve communication between primary and specialist care. The GP liaison service was created using funding from the Commonwealth STP initiative to provide weekly registrar clinics to primary care providers in the Darling Downs. The service was eagerly accepted by providers who saw patient benefits outweighing financial considerations. Expectations of a greater level of care than the assessment and advice provided reflects the large unmet need for mental health services in rural areas. GPs expressed enthusiasm for true collaborative care, such as case management overseen by the public mental health service but based at GP offices. 23970112 Twenty-five years with the biopsychosocial model of low back pain - is it time to celebrate? A report from the Twelfth International Forum for Primary Care Research on Low Back Pain. Study Design. An integrated review of current knowledge about the biopsychosocial model of back pain for understanding aetiology, prognosis and interventions, as presented at the plenary sessions of theXII International Forum on LBP Research in Primary Care (Denmark 17-19 October 2012).Objective. To evaluate the utility of the model in reference to rising rates of back pain related disability, by identifying a) the most promising avenues for future research in biological, psychological and social approaches, b) promising combinations of all three approaches and c) obstacles to effective implementation of biopsychosocial based research and clinical practice.Summary of Background Data. The biopsychosocial model of back pain has become a dominant model in the conceptualisation of the aetiology and prognosis of back pain, and has led to the development and testing of many interventions. Despite this back pain remains a leading source of disability worldwide.Methods. The review is a synthesis based on the plenary sessions and discussions at the XII International Forum on LBP Research in Primary Care. The presentations included evidence-based reviews of the current state of knowledge in each of the three areas (biological, psychological and social), identification of obstacles to effective implementation and missed opportunities, and identification of the most promising paths for future research.Results. While there is good evidence for the role of biological, psychological and social factors in the aetiology and prognosis of back pain, synthesis of the three in research and clinical practice has been suboptimal.Conclusion. The utility of the biopsychosocial framework cannot be fully assessed until we truly adopt and apply it in research and clinical practice. 23918096 Primary care and upfront computed tomography scanning in the diagnosis of chronic rhinosinusitis: A cost-based decision analysis. To diagnose chronic rhinosinusitis (CRS), current guidelines require either endoscopic or computed tomography (CT) findings of sinus disease. To a primary care physician, this means a referral to an otolaryngologist or obtaining a CT scan. Unfortunately, the sensitivity of endoscopy for detecting CRS is low, and examination by the Otolaryngologist may not yield a definitive diagnosis. This leaves CT scanning. However, this is contradicted by recommendations to limit CT scanning for only preoperative planning purposes due to cost concerns. This study aims to provide an evidence-based cost-efficient recommendation for primary care practice. Health care economics-based decision analysis model. A cost-based decision analysis based on literature-reported probabilities and Medicare costs was constructed for two scenarios: 1) primary care physicians who are comfortable initiating first-line treatment for chronic rhinosinusitis, rhinitis, and atypical facial pain; and 2) primary care physicians who are less comfortable with medical management of these conditions. Under both scenarios and the extremes of sensitivity analysis, upfront CT scanning provides cost-efficient diagnosis over presuming a diagnosis of chronic rhinosinusitis. Primary care physicians who attempt first-line treatment can expect $503 (range = $296-$761) saved per patient. Meanwhile, primary care physicians who prefer to refer may expect $326 (range = $299-$353) saved per patient. In all scenarios, confirming diagnosis with CT scanning prior to treatment or referral is more cost-efficient than presuming a diagnosis of CRS based on symptoms alone. 2c. Laryngoscope, 2013. 23800715 Dopamine release regulation by astrocytes during cerebral ischemia. Brain ischemia triggers excessive release of neurotransmitters that mediate neuronal damage following ischemic injury. The striatum is one of the areas most sensitive to ischemia. Release of dopamine (DA) from ischemic neurons is neurotoxic and directly contributes to the cell death in affected areas. Astrocytes are known to be critically involved in the physiopathology of cerebrovascular disease. However, their response to ischemia and their role in neuroprotection in striatum are not completely understood. In this study, we used an in vitro model to evaluate the mechanisms of ischemia-induced DA release, and to study whether astrocytes modulate the release of DA in response to short-term ischemic conditions. Using slices of adult mouse brain exposed to oxygen and glucose deprivation (OGD), we measured the OGD-evoked DA efflux using fast cyclic voltammetry and also assessed metabolic impairment by 2,3,5-triphenyltetrazolium chloride (TTC) and tissue viability by propidium iodide (PI) staining. Our data indicate that ischemia induces massive release of DA by dual mechanisms: one which operates via vesicular exocytosis and is action potential dependent and another involving reverse transport by the dopamine transporter (DAT). Simultaneous blockade of astrocyte glutamate transporters and DAT prevented the massive release of dopamine and reduced the brain tissue damage. The present results provide the first experimental evidence that astrocytes function as a key cellular element of ischemia-induced DA release in striatum, constituting a novel and promising therapeutic target in ischemia. 23887135 An experimental test of the persuasive effect of source similarity in narrative and nonnarrative health blogs. Blogs, or websites containing online personal journals, are a form of popular personal communication with immense potential for health promotion. Narratives are stories with a beginning, middle, and end that provide information about the characters and plot. Source similarity refers to the degree to which the message source and each recipient are alike with respect to certain attributes. Narratives and source similarity have seldom been examined in tandem as strategies for health persuasion. Personal health blogs provide a suitable platform for such an investigation. This study examined the persuasive effects of message type and source similarity on participants' intentions to adopt a specific health behavior (running for exercise). A total of 150 participants were randomly assigned to conditions (n=25 per condition) in a completely crossed, 2 (message type: narrative and nonnarrative) × 3 (source similarity: no similarity, non-health-related similarity, and health-related similarity) between-subjects experiment. First, in an online questionnaire, participants provided personal information in 42 categories and rated the relatedness of each category to running and then completed pretest measures of the dependent variables. Based on their responses, 150 personal health blogs were created. Two weeks later, the initial participants read the blog created with their personal characteristics and completed a questionnaire online. The source similarity effect was stronger in nonnarrative than narrative blogs. When the blogs were nonnarrative, those with health-related similarities were more persuasive than those with non-health-related similarities. Narrative blogs generated more positive thoughts and stronger blogger identification than nonnarrative blogs. Health-related source similarity is key for persuasive health communication, especially when the messages are nonnarrative. 23767990 Nox as a target for diabetic complications. Oxidative stress has been linked to the pathogenesis of the major complications of diabetes in the kidney, the heart, the eye or the vasculature. NADPH oxidases of the Nox family are a major source of ROS (reactive oxygen species) and are critical mediators of redox signalling in cells from different organs afflicted by the diabetic milieu. In the present review, we provide an overview of the current knowledge related to the understanding of the role of Nox in the processes that control cell injury induced by hyperglycaemia and other predominant factors enhanced in diabetes, including the renin-angiotensin system, TGF-β (transforming growth factor-β) and AGEs (advanced glycation end-products). These observations support a critical role for Nox homologues in diabetic complications and indicate that NADPH oxidases are an important therapeutic target. Therefore the design and development of small-molecule inhibitors that selectively block Nox oxidases appears to be a reasonable approach to prevent or retard the complications of diabetes in target organs. The bioefficacy of these agents in experimental animal models is also discussed in the present review. 23559145 Exploring the zebrafish embryo as an alternative model for the evaluation of liver toxicity by histopathology and expression profiling. The whole zebrafish embryo model (ZFE) has proven its applicability in developmental toxicity testing. Since functional hepatocytes are already present from 36 h post fertilization onwards, whole ZFE have been proposed as an attractive alternative to mammalian in vivo models in hepatotoxicity testing. The goal of the present study is to further underpin the applicability of whole ZFE for hepatotoxicity testing by combining histopathology and next-generation sequencing-based gene expression profiling. To this aim, whole ZFE and adult zebrafish were exposed to a set of hepatotoxic reference compounds. Histopathology revealed compound and life-stage-specific effects indicative of toxic injury in livers of whole ZFE and adult zebrafish. Next-generation sequencing (NGS) was used to compare transcript profiles in pooled individual RNA samples of whole ZFE and livers of adult zebrafish. This revealed that hepatotoxicity-associated expression can be detected beyond the overall transcription noise in the whole embryo. In situ hybridization verified liver specificity of selected highly expressed markers in whole ZFE. Finally, cyclosporine A (CsA) was used as an illustrative case to support applicability of ZFE in hepatotoxicity testing by comparing CsA-induced gene expression between ZFE, in vivo mouse liver and HepaRG cells on the levels of single genes, pathways and transcription factors. While there was no clear overlap on single gene level between the whole ZFE and in vivo mouse liver, strong similarities were observed between whole ZFE and in vivo mouse liver in regulated pathways related to hepatotoxicity, as well as in relevant overrepresented transcription factors. In conclusion, both the use of NGS of pooled RNA extracts analysis combined with histopathology and traditional microarray in single case showed the potential to detect liver-related genes and processes within the transcriptome of a whole zebrafish embryo. This supports the applicability of the whole ZFE model for compound-induced hepatotoxicity screening. 23966038 Double Strand Breaks and Cell-Cycle Arrest Induced by the Cyanobacterial Toxin Cylindrospermopsin in HepG2 Cells. The newly emerging cyanobacterial cytotoxin cylindrospermopsin (CYN) is increasingly found in surface freshwaters, worldwide. It poses a potential threat to humans after chronic exposure as it was shown to be genotoxic in a range of test systems and is potentially carcinogenic. However, the mechanisms of CYN toxicity and genotoxicity are not well understood. In the present study CYN induced formation of DNA double strand breaks (DSBs), after prolonged exposure (72 h), in human hepatoma cells, HepG2. CYN (0.1-0.5 µg/mL, 24-96 h) induced morphological changes and reduced cell viability in a dose and time dependent manner. No significant increase in lactate dehydrogenase (LDH) leakage could be observed after CYN exposure, indicating that the reduction in cell number was due to decreased cell proliferation and not due to cytotoxicity. This was confirmed by imunocytochemical analysis of the cell-proliferation marker Ki67. Analysis of the cell-cycle using flow-cytometry showed that CYN has an impact on the cell cycle, indicating G0/G1 arrest after 24 h and S-phase arrest after longer exposure (72 and 96 h). Our results provide new evidence that CYN is a direct acting genotoxin, causing DSBs, and these facts need to be considered in the human health risk assessment. 23842686 Simultaneous Biliary Drainage and Portal Vein Embolization Before Extended Hepatectomy for Hilar Cholangiocarcinoma: Preliminary Experience. Patients with resectable hilar cholangiocarcinoma often present obstructive jaundice and a small future remnant liver (FRL) ratio. A sequential approach comprising preoperative biliary drainage followed by portal vein embolization (PVE) is usually performed but leads to long preoperative management (6-12 weeks) before patients can undergo resection. To simplify and shorten this phase of liver preparation, we developed a new preoperative approach that involves percutaneous biliary drainage and PVE during the same procedure. We report the outcomes of this combined procedure. During 1 year, four patients underwent simultaneous biliary drainage and PVE followed 1 month later by surgical resection of hilar cholangiocarcinoma. Liver volumes were assessed by CT before, and 1, and 3 months after the combined procedure. Serum liver enzymes were assessed before and 1 month after the combined procedure. The combined procedure was feasible in all cases, with no related complications. After the combined procedure, transaminases remained stable or decreased, whereas gamma-glutamyl-transpeptidase, alkaline phosphatase, and bilirubin decreased. During the first month, the left lobe volume increased by +27.9 % (range 19-40.9 %). The FRL ratio increased from 24.9 to 33.2 %. All patients underwent R0 liver resection with a favorable postoperative outcome. The remnant liver volume increased by +132 % (range 78-245 %) between 1 and 3 months. Simultaneous percutaneous biliary drainage and PVE is feasible. This all-in-one preoperative approach greatly decreases waiting time until surgical resection. These encouraging results warrant further investigation to confirm the safety and to evaluate the reduction in the dropout rate for liver resection in this tumor with poor prognosis. 23761328 Canonical Wnt Signaling Is Required for Pancreatic Carcinogenesis. Wnt ligand expression and activation of the Wnt/β-catenin pathway have been associated with pancreatic ductal adenocarcinoma, but whether Wnt activity is required for the development of pancreatic cancer has remained unclear. Here, we report the results of three different approaches to inhibit the Wnt/β-catenin pathway in a established transgenic mouse model of pancreatic cancer. First, we found that β-catenin null cells were incapable of undergoing acinar to ductal metaplasia, a process associated with development of premalignant pancreatic intraepithelial neoplasia lesions. Second, we addressed the specific role of ligand-mediated Wnt signaling through inducible expression of Dkk1, an endogenous secreted inhibitor of the canonical Wnt pathway. Finally, we targeted the Wnt pathway with OMP-18R5, a therapeutic antibody that interacts with multiple Frizzled receptors. Together, these approaches showed that ligand-mediated activation of the Wnt/β-catenin pathway is required to initiate pancreatic cancer. Moreover, they establish that Wnt signaling is also critical for progression of pancreatic cancer, a finding with potential therapeutic implications. Cancer Res; 73(15); 4909-22. ©2013 AACR. 23832774 Transcript response of soft coral (Scleronephthya gracillimum) on exposure to polycyclic aromatic hydrocarbons. Polycyclic aromatic hydrocarbons (PAHs) are the most persistent organic pollutants in worldwide aquatic environments. The extensive isolation of genes responsive to PAH pollution in soft coral (Scleronephthya gracillimum) is described herein. Soft coral colonies were exposed to 100 Î¼g/L of a standard mixture of PAHs. Gene candidates with transcript levels that changed in response to PAH exposure were identified by differential display polymerase chain reaction (DD-PCR). There were 37 types of candidate genes identified, of which 20 were upregulated in expression and 17 were downregulated. The functions of the genes identified included oxidative stress response, ribosomal structure maintenance, molecular chaperone activity, protein kinase activation and tumorigenesis, defense mechanisms, transcription, and other biological responses. mRNA quantification was carried out using real-time quantitative PCR in eight selected genes: cytosolic malate dehydrogenase, protein disulfide isomerase, ribosomal protein L6, ral guanine nucleotide dissociation stimulator-like 1, poly(ADP-ribose) polymerase 4, peptidylglycine α-hydroxylating monooxygenase, a disintegrin and metalloproteinase (ADAM) metallopeptidase protein, and eukaryotic initiation factor 4 gamma 3. Changes in transcript levels were consistent with DD-PCR results. The gene candidates isolated in this study were differentially expressed and therefore have potential as molecular biomarkers for understanding coral responses to environmental stressors. 23143891 Metabolic pathways of inhaled glucocorticoids by the CYP3A enzymes. Asthma is one of the most prevalent diseases in the world, for which the mainstay treatment has been inhaled glucocorticoids (GCs). Despite the widespread use of these drugs, approximately 30% of asthma sufferers exhibit some degree of steroid insensitivity or are refractory to inhaled GCs. One hypothesis to explain this phenomenon is interpatient variability in the clearance of these compounds. The objective of this research is to determine how metabolism of GCs by the CYP3A family of enzymes could affect their effectiveness in asthmatic patients. In this work, the metabolism of four frequently prescribed inhaled GCs, triamcinolone acetonide, flunisolide, budesonide, and fluticasone propionate, by the CYP3A family of enzymes was studied to identify differences in their rates of clearance and to identify their metabolites. Both interenzyme and interdrug variability in rates of metabolism and metabolic fate were observed. CYP3A4 was the most efficient metabolic catalyst for all the compounds, and CYP3A7 had the slowest rates. CYP3A5, which is particularly relevant to GC metabolism in the lungs, was also shown to efficiently metabolize triamcinolone acetonide, budesonide, and fluticasone propionate. In contrast, flunisolide was only metabolized via CYP3A4, with no significant turnover by CYP3A5 or CYP3A7. Common metabolites included 6β-hydroxylation and Δ(6)-dehydrogenation for triamcinolone acetonide, budesonide, and flunisolide. The structure of Δ(6)-flunisolide was unambiguously established by NMR analysis. Metabolism also occurred on the D-ring substituents, including the 21-carboxy metabolites for triamcinolone acetonide and flunisolide. The novel metabolite 21-nortriamcinolone acetonide was also identified by liquid chromatography-mass spectrometry and NMR analysis. 23625910 Effect of paraoxonase 1 192 Q/R polymorphism on paraoxonase and acetylcholinesterase enzyme activities in Turkish population exposed to organophosphate. Organophosphate (OP) compounds are the most commonly used pesticide groups and they are commercially used in the market for local and industrial purposes. Paraoxonase 1 (PON1) enzyme plays an important role in biotransformation of OP compounds, which shows toxic effects via inhibiting the acetylcholinesterase (AChE). The aim of this study was to determine the effects of PON1 gene polymorphism and its effects on PON and AChE enzyme activities in individuals who were exposed to organophosphorus insecticides due to occupational reasons, and to profile the probability of susceptibility to organophosphorus compounds. For this purpose, 54 individuals who were exposed to OPs and 54 healthy unrelated controls were studied. First, PON1 and AChE enzyme activities were measured. Second, PON1 192 Q/R polymorphism was determined by standard polymerase chain reaction-restriction fragment length polymorphism technique. When the PON1 192 Q/R polymorphism was compared with PON1 enzyme activities, statistically significant association was found in both OP-exposed and control groups (p < 0.05). PON1 192 R(+) (QR + RR genotypes) genotype carriers had higher PON1 activities than 192 R(-) (QQ) genotype carriers. On the other hand, results were statistically analyzed in terms of AChE enzyme activities and there were statistically significant differences only in the OP-exposed group (p < 0.05). The mean AChE concentration in the OP-exposed group was determined as 33.79 ± 6.84 U/g haemoglobin (Hb) for PON1 192 R(+) carriers and 30.37 ± 7.62 U/g Hb for PON1 192 R(+) carriers. As a conclusion, PON1 and AChE activities were increasing according to the genotypes found in individuals having been exposed to OPs at a chronic level; 192 R(+) > 192 R(-), respectively. 23889735 Alcohol Exposure in Utero Increases Susceptibility to Prostate Tumorigenesis in Rat Offspring. Prenatal alcohol exposure has been shown to increase offspring susceptibility to some chemical carcinogens. Whether prenatal exposure to alcohol makes the offspring more susceptible to the development of prostate cancer is not known. Therefore, we determined whether any functional abnormalities and increased cancer susceptibility exist in the prostate of fetal alcohol-exposed male rats during the adult period. Pregnant rats were fed with a liquid diet containing alcohol (alcohol-fed [AF]), or pair-fed with isocaloric liquid diet (PF) or ad libitum fed with rat chow (ad lib-fed). Male offspring of these rats were given N-Nitroso-N-methylurea and testosterone to induce prostate neoplasia or left untreated. Around 6 to 8 months of age, the prostates of these animals were processed for determination of biochemical changes and histopathologies. Prostates of noncarcinogen treated animals that were alcohol exposed during the prenatal period demonstrated inflammatory cell infiltration and epithelial atypia and increased number of proliferative cells in the ventral lobe of this gland, but the prostate of control animal showed normal cytoarchitecture. In addition, prenatal alcohol-exposed rats showed decreased levels of cell-cell adhesion marker and increased estrogenic activity in the ventral prostate. Prenatally ethanol (EtOH)-exposed rats, when treated with carcinogen and testosterone, showed histological evidence for high-grade prostatic intraepithelial neoplasia (PIN) primarily in the ventral prostate, whereas control animals showed only low-grade PIN. Prenatally EtOH-exposed rats treated with carcinogen and testosterone also showed increased number of proliferative cells and androgen receptor with concomitant decreased levels of tumor suppressor proteins in the ventral prostate. These results suggest for the first time that prenatal EtOH exposures induce histophysiological changes in the prostate as well as it increases the susceptibility of the prostate to develop neoplasia during adulthood. 23567540 Selecting significant genes by randomization test for cancer classification using gene expression data. Gene selection is an important task in bioinformatics studies, because the accuracy of cancer classification generally depends upon the genes that have biological relevance to the classifying problems. In this work, randomization test (RT) is used as a gene selection method for dealing with gene expression data. In the method, a statistic derived from the statistics of the regression coefficients in a series of partial least squares discriminant analysis (PLSDA) models is used to evaluate the significance of the genes. Informative genes are selected for classifying the four gene expression datasets of prostate cancer, lung cancer, leukemia and non-small cell lung cancer (NSCLC) and the rationality of the results is validated by multiple linear regression (MLR) modeling and principal component analysis (PCA). With the selected genes, satisfactory results can be obtained. 23949943 Primary lymphoma of the central nervous system-a diagnostic challenge. Primary lymphoma of the central nervous system is a distinct diffuse large B-cell lymphoma confined to the nervous system. Whereas classical cases can be classified easily, differential diagnosis can be a challenge in particular in patients who had received treatment prior to biopsy. In the differential diagnosis, other tumours and inflammatory diseases of autoimmune and infectious aetiology need to be considered. Copyright © 2013 John Wiley & Sons, Ltd. 22340730 Suppression of survival signalling pathways by the phosphatase PHLPP. The recently discovered pleckstrin homology (PH) domain leucine-rich repeat protein phosphatase (PHLPP) family is emerging as a central component in suppressing cell survival pathways. Originally discovered in a rational search for a phosphatase that directly dephosphorylates and inactivates Akt, PHLPP is now known to potently suppress cell survival both by inhibiting proliferative pathways and by promoting apoptotic pathways. In the first instance, PHLPP directly dephosphorylates a conserved regulatory site (termed the hydrophobic motif) on Akt, protein kinase C and S6 kinase, thereby terminating signalling by these pro-survival kinases. In the second instance, PHLPP dephosphorylates and thus activates the pro-apoptotic kinase Mst1, thereby promoting apoptosis. PHLPP is deleted in a large number of cancers and the genetic deletion of one isozyme in a PTEN (phosphatase and tensin homologue located on chromosome 1) +/- (or heterozygous) prostate cancer model results in increased tumourigenesis, underscoring the role of PHLPP as a tumour suppressor. This review summarizes the targets and cellular actions of PHLPP, with emphasis on its role as a tumour suppressor in the oncogenic phosphoinositide 3-kinase (PI3K)/Akt signalling cascade. 23829325 H435-containing immunoglobulin G3 allotypes are transported efficiently across the human placenta: implications for alloantibody-mediated diseases of the newborn. The neonatal receptor (FcRn) extends the half-life of human immunoglobulin (Ig)G and transports it across the placenta, providing the newborn with humoral immunity. Of the four subclasses, IgG3 stands out with strong effector functions, short half-life (7 days vs. 21 days for other subclasses), and poor placental transport. We recently described how a single-amino-acid polymorphism at Position 435 in IgG3 is sufficient to explain the short half-life of R435-containing IgG3 and demonstrated that H435-IgG3 has a normal half-life of 21 days. Here, we investigated whether the R435 also explains the relatively poor placental transport of IgG3. Sera were collected from paired mothers and newborns at birth. The study included six mothers expressing R435-IgG diagnosed with fetal and neonatal alloimmune thrombocytopenia and treated with intravenous immune globulin (IVIG; containing H435-IgG3, also known as G3m16 or G3m(s,t) allotype), as well as 33 paired samples of both G3m16(-) and G3m16(+) mothers. Placental IgG transport was estimated by comparing cord and maternal concentrations of IgG subclass and G3m16 allotype. The placental transport of naturally occurring H435-IgG3 allotypes was significantly more efficient than that of other R435-IgG3 allotypes and was comparable to IgG1 transport. We demonstrate that the poor maternal-fetal transport of IgG3 is only true for most individuals of western populations where the G3m16 is not common. In G3m16(+) individuals, expressing H435-containing IgG3, IgG3 transport is similar to IgG1, which may give rise to enhanced complications in pregnancy-associated alloimmune disease in ethnic communities where this naturally occurring H435 containing IgG3 allotype is more frequent. 23890152 Women's Sexuality: From Aging to Social Representations. Studies designed in northern countries show that most women are still sexually active after the age of 50. Many factors other than hormones influence sexual life in and after middle age; they include social status, personal characteristics, physical and psychological conditions, relationship factors, and social representations of sexuality. This study aims to analyze various components of sexuality, including its social representations, among women aged 45-55 years, as they reach menopause. Comparison of three groups: all postmenopausal women (277), postmenopausal women not currently using hormonal treatment (HT) (209), postmenopausal women currently using HT (68), with a reference group of premenopausal women (408). All were recruited in a national general population-based survey of sexual behaviors and interviewed by telephone. Practices, sexual function, satisfaction, and representations and expectations concerning sexuality. The women did not differ according to menopausal status for sexual activity, practices (wide range of practices beyond sexual intercourse), dysfunction, or satisfaction. They also attributed equal importance to sexuality. Nevertheless, although postmenopausal women not using HT did not report less sexual activity than premenopausal women, they were less likely to consider that a 3-month period without sex is a sign of difficulty in a relationship (30.3% vs. 47.7%; odds ratio: 0.35 [0.21-0.57], P = 0.000). This difference was not observed between postmenopausal women using HT and premenopausal women. Our results suggest that for middle-aged women who are at the onset of menopause, the biological/hormonal changes characterizing menopause do not negatively affect sexual life. Any negative reported effects on sexuality are more likely due to anticipation or negative representations of sexuality around menopause than to biological or hormonal effects. The effect of menopause at this point in women's lives may thus be more symbolic than biological, expressed as a form of anticipation of old age. Ringa V, Diter K, Laborde C, and Bajos N. Women's sexuality: From aging to social representations. J Sex Med **;**:**-**. 23786564 New approach for multilayered microstructures fabrication based on a water-soluble backing substrate. We demonstrate a new approach for woodpile microstructure fabrication. The method involves the use of polyvinyl alcohol (PVA) as a sacrificial substrate for the transfer of SU-8 films to prepatterned structures. The surface activated PVA substrate allows good wettability of SU-8 film and its solubility in water eliminates the need of delaminating SU-8 structures from the substrate. This makes the fabrication process much simplified and we successfully demonstrate eight-layer stacking of gratings. Fourier transform infrared spectra of single-layer and four-layer grating structures show a broader transmission dip spectrum compared to their film counterparts, indicating their potential use as broadband terahertz (THz) absorbers. 23937694 Resistance gene enrichment sequencing (RenSeq) enables re-annotation of the NB-LRR gene family from sequenced plant genomes and rapid mapping of resistance loci in segregating populations. RenSeq is a NB-LRR gene-targeted, Resistance gene enrichment and sequencing method that enables discovery and annotation of pathogen resistance gene family members in plant genome sequences. We successfully applied RenSeq to the sequenced potato Solanum tuberosum clone DM, and increased the number of identified NB-LRRs from 438 to 755. The majority of these identified R gene loci reside in poorly- or previous un-annotated regions of the genome. Sequence and positional details on the twelve chromosomes have been established for 704 NB-LRRs and can be accessed through a genome browser that we provide. We compared these NB-LRR genes and the corresponding oligonucleotide baits with the highest sequence similarity and demonstrated that ~80% sequence identity is sufficient for enrichment. Analysis of the sequenced tomato S. lycopersicum extended the NB-LRR complement to 394 loci. We further describe a methodology that applies RenSeq to rapidly identify molecular markers that co-segregate with a trait of interest. In two independent segregating populations involving the wild Solanum species S. berthaultii (Rpi-ber2) and S. ruiz-ceballosii (Rpi-rzc1), we were able to apply RenSeq to successfully identify markers that co-segregate with resistance towards the late blight pathogen Phytophthora infestans. These SNP identification workflows were designed as easy-to-adapt Galaxy pipelines. This article is protected by copyright. All rights reserved. 23535883 Geographical differences in the prevalence of chronic polypharmacy in older people: eleven years of the EPIFARM-Elderly Project. PURPOSE: To compare the geographical differences in the prevalence of chronic polypharmacy in community-dwelling older people over 11 years. METHODS: This study analyzed nearly two million patients aged 65-94 years recorded in the Drug Administrative Database of the Lombardy Region (Northern Italy) from 2000 to 2010. Chronic polypharmacy was defined as taking five or more drugs in 1 month for at least 6 months (consecutive or not) in a year. RESULTS: There was a significant spatial autocorrelation that increased at the municipality level from 2000 (Moran's I Index = 0.26, z score = 16.91, p < 0.0001) to 2010 (Moran's I Index = 0.36, z score = 23.78, p < 0.0001). Clusters of high (Z(G) > 1.96) and low (Z(G) < -1.96) prevalence rates of chronic polypharmacy were found and were not influenced by age. Chronic polypharmacy weakly correlated with hospital admission (2000: ρ = 0.08, p = 0.0032; 2005: ρ = 0.11, p < 0.0001; 2010: ρ = 0.18, p < 0.0001), but not with mortality. CONCLUSIONS: There were geographical differences in the prevalence of older people with chronic polypharmacy that were only partly explained by health indicators. Targeted activities on prescription practice to ensure that the prescribing of chronic polypharmacy is appropriate are required. 23123140 The use of bioelectrical impedance analysis to estimate total body water in young children with cerebral palsy. Body composition assessment is an essential component of nutritional evaluation in children with cerebral palsy. This study aimed to validate bioelectrical impedance to estimate total body water in young children with cerebral palsy and determine best electrode placement in unilateral impairment. 55 young children with cerebral palsy across all functional ability levels were included. Height/length was measured or estimated from knee height. Total body water was estimated using a Bodystat 1500MDD and three equations, and measured using the gold standard, deuterium dilution technique. Comparisons were made using Bland Altman analysis. For children with bilateral impairment, the Fjeld equation estimated total body water with the least bias (limits of agreement): 0.0 L (-1.4 L to 1.5 L); the Pencharz equation produced the greatest: 2.7 L (0.6 L-4.8 L). For children with unilateral impairment, differences between measured and estimated total body water were lowest on the unimpaired side using the Fjeld equation 0.1 L (-1.5 L to 1.6 L)) and greatest for the Pencharz equation. The ability of bioelectrical impedance to estimate total body water depends on the equation chosen. The Fjeld equation was the most accurate for the group, however, individual results varied by up to 18%. A population specific equation was developed and may enhance the accuracy of estimates. Australian New Zealand Clinical Trials Registry (ANZCTR) number: ACTRN12611000616976. 23828111 Surfer's Myelopathy: A Radiologic Study of 23 Cases. BACKGROUND AND PURPOSE:Surfing is an uncommon cause of an acute nontraumatic myelopathy. This study describes the MR imaging characteristics and clinical correlates in 23 subjects with surfer's myelopathy.MATERIALS AND METHODS:This was a retrospective review of 23 cases of surfer's myelopathy from 2003-2012. Spinal cord MR imaging characteristics and neurologic examinations with the use of the American Spinal Injury Association scale were reviewed. Logistic regression was used to determine associations between MR imaging characteristics, American Spinal Injury Association scale, and clinical improvement.RESULTS:All subjects (19 male, 4 female; mean age, 26.3 ± 7.4 years) demonstrated "pencil-like," central T2-hyperintense signal abnormalities in the spinal cord extending from the midthoracic region to the conus with associated cord expansion and varying degrees of conus enlargement on spinal cord MR imaging within 24 hours of symptom onset. T1 signal was normal. Faint gadolinium enhancement was present in a minority. Although there was a strong correlation between initial American Spinal Injury Association score and clinical improvement (P = .0032), MR imaging characteristics were not associated with American Spinal Injury Association score or clinical improvement.CONCLUSIONS:Surfer's myelopathy should be considered in the radiographic differential diagnosis of a longitudinally extensive T2-hyperintense spinal cord lesion. MR imaging characteristics do not appear to be associated with severity on examination or clinical improvement. 23828610 First-principles model potentials for lattice-dynamical studies: general methodology and example of application to ferroic perovskite oxides. We present a scheme to construct model potentials, with parameters computed from first principles, for large-scale lattice-dynamical simulations of materials. We mimic the traditional solid-state approach to the investigation of vibrational spectra, i.e., we start from a suitably chosen reference configuration of the compound and describe its energy as a function of arbitrary atomic distortions by means of a Taylor series. Such a form of the potential-energy surface is general, trivial to formulate for any material, and physically transparent. Further, such models involve clear-cut approximations, their precision can be improved in a systematic fashion, and their simplicity allows for convenient and practical strategies to compute/fit the potential parameters. We illustrate our scheme with two challenging cases in which the model potential is strongly anharmonic, namely, the ferroic perovskite oxides PbTiO3 and SrTiO3. Studying these compounds allows us to better describe the connection between the so-called effective-Hamiltonian method and ours (which may be seen as an extension of the former), and to show the physical insight and predictive power provided by our approach-e.g., we present new results regarding the factors controlling phase-transition temperatures, novel phase transitions under elastic constraints, an improved treatment of thermal expansion, etc. 23720791 Echinocandin and Triazole Antifungal Susceptibility Profiles for Clinical Opportunistic Yeast and Mold Isolates Collected from 2010 to 2011: Application of New CLSI Clinical Breakpoints and Epidemiological Cutoff Values for Characterization of Geographic and Temporal Trends of Antifungal Resistance. The SENTRY Antimicrobial Surveillance Program monitors global susceptibility and resistance rates of newer and established antifungal agents. We report the echinocandin and triazole antifungal susceptibility patterns for 3,418 contemporary clinical isolates of yeasts and molds. The isolates were obtained from 98 laboratories in 34 countries during 2010 and 2011. Yeasts not presumptively identified by CHROMagar, the trehalose test, or growth at 42°C and all molds were sequence identified using internal transcribed spacer (ITS) and 28S (yeasts) or ITS, translation elongation factor (TEF), and 28S (molds) genes. Susceptibility testing was performed against 7 antifungals (anidulafungin, caspofungin, micafungin, fluconazole, itraconazole, posaconazole, and voriconazole) using CLSI methods. Rates of resistance to all agents were determined using the new CLSI clinical breakpoints and epidemiological cutoff value criteria, as appropriate. Sequencing of fks hot spots was performed for echinocandin non-wild-type (WT) strains. Isolates included 3,107 from 21 Candida spp., 146 from 9 Aspergillus spp., 84 from Cryptococcus neoformans, 40 from 23 other mold species, and 41 from 9 other yeast species. Among Candida spp., resistance to the echinocandins was low (0.0 to 1.7%). Candida albicans and Candida glabrata that were resistant to anidulafungin, caspofungin, or micafungin were shown to have fks mutations. Resistance to fluconazole was low among the isolates of C. albicans (0.4%), Candida tropicalis (1.3%), and Candida parapsilosis (2.1%); however, 8.8% of C. glabrata isolates were resistant to fluconazole. Among echinocandin-resistant C. glabrata isolates from 2011, 38% were fluconazole resistant. Voriconazole was active against all Candida spp. except C. glabrata (10.5% non-WT), whereas posaconazole showed decreased activity against C. albicans (4.4%) and Candida krusei (15.2% non-WT). All agents except for the echinocandins were active against C. neoformans, and the triazoles were active against other yeasts (MIC90, 2 μg/ml). The echinocandins and triazoles were active against Aspergillus spp. (MIC90/minimum effective concentration [MEC90] range, 0.015 to 2 μg/ml), but the echinocandins were not active against other molds (MEC90 range, 4 to >16 μg/ml). Overall, echinocandin and triazole resistance rates were low; however, the fluconazole and echinocandin coresistance among C. glabrata strains warrants continued close surveillance. 23933577 Adult motor axons preferentially reinnervate predegenerated muscle nerve. Preferential motor reinnervation (PMR) is the tendency for motor axons regenerating after repair of mixed nerve to reinnervate muscle nerve and/or muscle rather than cutaneous nerve or skin. PMR may occur in response to the peripheral nerve pathway alone in juvenile rats (Brushart, 1993; Redett et al., 2005), yet the ability to identify and respond to specific pathway markers is reportedly lost in adults (Uschold et al., 2007). The experiments reported here evaluate the relative roles of pathway and end organ in the genesis of PMR in adult rats. Fresh and 2-week predegenerated femoral nerve grafts were transferred in correct or reversed alignment to replace the femoral nerves of previously unoperated Lewis rats. After 8weeks of regeneration the motoneurons projecting through the grafts to recipient femoral cutaneous and muscle branches and their adjacent end organs were identified by retrograde labeling. Motoneuron counts were subjected to Poisson regression analysis to determine the relative roles of pathway and end organ identity in generating PMR. Transfer of fresh grafts did not result in PMR, whereas substantial PMR was observed when predegenerated grafts were used. Similarly, the pathway through which motoneurons reached the muscle had a significant impact on PMR when grafts were predegenerated, but not when they were fresh. Comparison of the relative roles of pathway and end organ in generating PMR revealed that neither could be shown to be more important than the other. These experiments demonstrate unequivocally that adult muscle nerve and cutaneous nerve differ in qualities that can be detected by regenerating adult motoneurons and that can modify their subsequent behavior. They also reveal that two weeks of Wallerian degeneration modify the environment in the graft from one that provides no modality-specific cues for motor neurons to one that actively promotes PMR. 23828210 Determination of EGFR mutations in single cells microdissected from enriched lung tumor cells in peripheral blood. A minimally invasive and repeatable approach for real-time epidermal growth factor receptor (EGFR) mutation surveillance would be highly beneficial for individualized therapy of late stage lung cancer patients whose surgical specimens are often not available. We aim to develop a viable method to detect EGFR mutations in single circulating tumor cells (CTCs). Using a model CTC system of spiked tumor cells in whole blood, we evaluated EGFR mutation determination in single tumor cells enriched from blood. We used magnetic beads labeled with antibody against leukocyte surface antigens to deplete leukocytes and enrich native CTCs independent of epithelial marker expression level. We then used laser cell microdissection (LCM) to isolate individual CTCs, followed by whole-genome amplification of the DNA for exon 19 microdeletion, L858R and T790M mutation detection by PCR sequencing. EGFR mutations were successfully measured in individual spiked tumor cells enriched from 7.5 ml whole blood. Whole-genome amplification provided sufficient DNA for mutation determination at multiple sites. Ninety-five percent of the single CTCs microdissected by LCM (19/20) yielded PCR amplicons for at least one of the three mutation sites. The amplification success rates were 55 % (11/20) for exon 19 deletion, 45 % (9/20) for T790M, and 85 % (17/20) for L858R. Sequencing of the amplicons showed allele dropout in the amplification reactions, but mutations were correctly identified in 80 % of the amplicons. EGFR mutation determination from single captured tumor cells from blood is feasible with the approach described here. However, to overcome allele dropout and to obtain reliable information about the tumor's EGFR status, multiple individual tumor cells should be assayed. 23860736 Persistence of physical activity in middle age: a nonlinear dynamic panel approach. No prior investigation has considered the effects of state dependence and unobserved heterogeneity on the relationship between regular physical activity (RPA) and latent health stock (LHS). Accounting for state dependence corrects the possible overestimation of the impact of socioeconomic factors. We estimated the degree of the state dependence of RPA and LHS among middle-aged Japanese workers. The 5 years' longitudinal data used in this study were taken from the Longitudinal Survey of Middle and Elderly Persons. Individual heterogeneity was found for both RPA and LHS, and the dynamic random-effects probit model provided the best specification. A smoking habit, low educational attainment, longer work hours, and longer commuting time had negative effects on RPA participation. RPA had positive effects on LHS, taking into consideration the possibility of confounding with other lifestyle variables. The degree of state dependence of LHS was positive and significant. Increasing the intensity of RPA had positive effects on LHS and caused individuals with RPA to exhibit greater persistence of LHS compared to individuals without RPA. This result implies that policy interventions that promote RPA, such as smoking cessation, have lasting consequences. We concluded that smoking cessation is an important health policy to increase both the participation in RPA and LHS. 23788112 Rings and threads as linkers in metal-organic frameworks and poly-rotaxanes. Coordination polymers and metal-organic rotaxane frameworks are reported where the organic linker is replaced by functionalised inorganic clusters that act as bridging ligands. 23782848 Microbiological Evaluation of Bacterial and Mycotic Seal in Implant Systems With Different Implant-Abutment Interfaces and Closing Torque Values. The aim of this study was to evaluate the possible leakage of 3 species of bacteria (Streptococcus sanguinis, Fusobacterium nucleatum, and Actinomyces odontolyticus) and of Candida albicans and Candida glabrata in osseointegrated implants with different implant-abutment interface (IAI) geometry. Two groups of implants, (1) implant-abutment unit with a tube-in-tube interface and (2) implant-abutment unit with a flat-to-flat interface closed with different torque values, were compared in the study. In the first phase, the implants were assembled and cultured in vitro for 7 days. The implants and abutments were disconnected and samples were taken and cultured. In the second phase, the internal part of each implant was inoculated with 0.1 µL of microbial broth and then connected to the respective abutments. Afterward, medium samples were taken and cultured. The group 1 implants were more resistant to colonization than those of group 2 (P < 0.05). The intragroup difference was significant between the implant-abutment units assembled with the recommended torque values and those with lower torque values (P < 0.01) for both the groups. IAI geometry influences both bacterial and yeast colonization inside the implants as well as the torque value used to connect abutments to implants. 23876431 Rapid genotyping of three polymorphisms in the LBP gene using a triplex pyrosequencing approach. We described a triplex polymerase chain reaction (PCR) and triplex pyrosequencing assay which allowed a simultaneous determination of three tag single nuleotide polymorphisms (tag SNPs) in the lipopolysaccharide-binding protein (LBP) gene: rs1780623, rs11536972 and rs2232618. This method enables a fast and cost-effective genotyping and a simultaneous determination of the three tag SNPs. 23845264 Application of intraoperative indocyanine green videoangiography for resection of spinal cord hemangioblastoma: Advantages and limitations. Hemangioblastomas constitute 2-15% of intramedullary spinal cord tumors. Identification of the feeding arteries and draining veins is crucial for an en bloc tumor resection and cure. We report our experience using intraoperative indocyanine green (ICG) videoangiography during the surgical resection of spinal cord hemangioblastomas (SH) and evaluate the advantages and limitations of this technique. Seven patients with an SH underwent resection with the assistance of intraoperative ICG videoangiography. The ICG videoangiography images were analyzed, and the preoperative, intraoperative, and postoperative images were compared. ICG videoangiography clearly revealed the feeding arteries and enlarged draining veins and assisted in defining the tumor borders in five of the seven patients (patients one, two, four, five, and seven). By contrast, patient three had a devascularized residual tumor located deep in the spinal cord parenchyma, which did not take up the fluorescent dye and therefore was not visualized by ICG videoangiography. In addition, in patient six, only the draining veins could be visualized in the ventrolateral tumor, because it was covered by the spinal cord parenchyma. Six tumors were completely removed, and one was partially removed. None of our patients had significant neurological deterioration after surgery. ICG videoangiography provided real-time information about the tumor vasculature during surgery for SH and aided in intraoperative decision-making. However, for deep tumors and ventral tumors, the benefits of this technique might be limited. 23361653 Narrow bandgap colloidal metal chalcogenide quantum dots: synthetic methods, heterostructures, assemblies, electronic and infrared optical properties. The chemistry, material processing and fundamental understanding of colloidal semiconductor nanocrystals (quantum dots) are advancing at an astounding rate, bringing the prospects of widespread commercialization of these novel and exciting materials ever closer. Interest in narrow bandgap nanocrystals in particular has intensified in recent years, and the results of research worldwide point to the realistic prospects of applications for these materials in solar cells, infrared optoelectronics (e.g. lasers, optical modulators, photodetectors and photoimaging devices), low cost/large format microelectronics, and in biological imaging and biosensor systems to name only some technologies. Improvements in fundamental understanding and material quality are built on a vast body of experience spread over many different methods of colloidal synthetic growth, each with their own strengths and weaknesses for different materials and sometimes with regard to particular applications. The nanocrystal growth expertise is matched by a rapidly expanding, and highly interdisciplinary, understanding of how best to assemble these materials into films or hybrid composites and thereby into useful devices, and again there are many different strategies that can be adopted. In this review we have attempted to survey and compare the recent work on colloidal synthesis, film and nanocrystal composite material fabrication, concentrating on narrow bandgap chalcogenide materials and some of their topical applications in the solar energy and biological fields. Since these applications are attracting rising interest across a wide range of disciplines, from the biological sciences, device engineering, and materials processing fields as well as the physics and synthetic chemistry communities, we have endeavoured to make the review of these narrow bandgap nanomaterials both comprehensive and accessible to newcomers to the area. 23639631 The role of p21 Waf1/Cip1 in large airway epithelium in smokers with and without COPD. Airway epithelium alterations, including squamous cell metaplasia, characterize smokers with and without chronic obstructive pulmonary disease (COPD). The p21 regulates cell apoptosis and differentiation and its role in COPD is largely unknown. Molecules regulating apoptosis (cytoplasmic p21, caspase-3), cell cycle (nuclear p21), proliferation (Ki67/PCNA), and metaplasia (survivin) in central airways from smokers (S), smokers-COPD (s-COPD) and non-smokers (Controls) were studied. The role of cigarette smoke extracts (CSE) in p21, survivin, apoptosis (caspase-3 and annexin-V binding) and proliferation was assessed in a bronchial epithelial cell line (16HBE). Immunohistochemistry, image analysis in surgical samples and flow-cytometry and carboxyfluorescein succinimidyl ester proliferative assay in 16HBE with/without CSE were applied. Cytoplasmic and nuclear p21, survivin, and Ki67 expression significantly increased in large airway epithelium in S and in s-COPD in comparison to Controls. Caspase-3 was similar in all the studied groups. p21 correlated with epithelial metaplasia, PCNA, and Ki67 expression. CSE increased cytoplasmic p21 and survivin expression but not apoptosis and inhibited the cell proliferation in 16HBE. In large airway epithelium of smokers with and without COPD, the cytoplasmic p21 inhibits cell apoptosis, promotes cell proliferation and correlates with squamous cell metaplasia thus representing a potential pre-oncogenic hallmark. 23950959 Analysis of the Dominant Effects Mediated by Wild Type or R120G Mutant of αB-crystallin (HspB5) towards Hsp27 (HspB1). Several human small heat shock proteins (sHsps) are phosphorylated oligomeric chaperones that enhance stress resistance. They are characterized by their ability to interact and form polydispersed hetero-oligomeric complexes. We have analyzed the cellular consequences of the stable expression of either wild type HspB5 or its cataracts and myopathies inducing R120G mutant in growing and oxidative stress treated HeLa cells that originally express only HspB1. Here, we describe that wild type and mutant HspB5 induce drastic and opposite effects on cell morphology and oxidative stress resistance. The cellular distribution and phosphorylation of these polypeptides as well as the oligomerization profile of the resulting hetero-oligomeric complexes formed by HspB1 with the two types of exogenous polypeptides revealed the dominant effects induced by HspB5 polypeptides towards HspB1. The R120G mutation enhanced the native size and salt resistance of HspB1-HspB5 complex. However, in oxidative conditions the interaction between HspB1 and mutant HspB5 was drastically modified resulting in the aggregation of both partners. The mutation also induced the redistribution of HspB1 phosphorylated at serine 15, originally observed at the level of the small oligomers that do not interact with wild type HspB5, to the large oligomeric complex formed with mutant HspB5. This phosphorylation stabilized the interaction of HspB1 with mutant HspB5. A dominant negative effect towards HspB1 appears therefore as an important event in the cellular sensitivity to oxidative stress mediated by mutated HspB5 expression. These observations provide novel data that describe how a mutated sHsp can alter the protective activity of another member of this family of chaperones. 23796361 Preventing diabetes blindness: Cost effectiveness of a screening programme using digital non-mydriatic fundus photography for diabetic retinopathy in a primary health care setting in South Africa. South Africa like many other developing countries is experiencing an epidemiologic transition with a marked increase in the non-communicable disease (NCD) burden. Diabetic retinopathy is the most common cause of incidental blindness in adults. A screening programme using a mobile fundal camera in a primary care setting has been shown to be effective in the country. Information on affordability and cost is essential for policymakers to consider its adoption. Economic evaluation is the comparative analysis of competing alternative interventions in terms of costs and consequences. A cost effectiveness analysis was done using actual costs from the primary care screening programme. A total of 14,541 patients were screened in three primary healthcare facilities in the Western Cape. Photographs were taken by a trained technician with supervision by an ophthalmic nurse. The photographs were then read by a medical officer with ophthalmic experience. A cost effective ratio of $1206 per blindness case averted was obtained. This included costs for screening and treating an individual. The cost just to screen a patient for retinopathy was $22. The costs of screening and treating all incident cases of blindness due to diabetes in South Africa would be 168,000,000 ZAR ($19,310,344) per annum. Non mydriatic digital fundoscopy is a cost effective measure in the screening and diagnosis of diabetic retinopathy in a primary care setting in South Africa. The major savings in the long term are a result of avoiding government disability grant for people who suffer loss of vision. 23694806 Budesonide-loaded nanostructured lipid carriers reduce inflammation in murine DSS-induced colitis. The challenge for the treatment of inflammatory bowel disease (IBD) is the delivery of the drug to the site of inflammation. Because nanoparticles have the ability to accumulate in inflamed regions, the aim of the present study was to evaluate nanostructured lipid carriers (NLCs) as nanoparticulate drug delivery systems for the treatment of IBD. Budesonide (BDS) was chosen as a candidate anti-inflammatory drug. BDS-loaded NLCs (BDS-NLC) produced by high-pressure homogenization had a size of 200nm and a negative zeta potential. BDS-NLCs reduced the TNF-α secretion by activated macrophages (J774 cells). BDS-NLCs were more active in a murine model of dextran sulfate-induced colitis when compared with Blank-NLCs or a BDS suspension: BDS-NLCs decreased neutrophil infiltration, decreased the levels of the pro-inflammatory cytokines IL-1β and TNF-α in the colon and improved the histological scores of the colons. These data suggest that NLCs could be a promising alternative to polymeric nanoparticles as a targeted drug delivery system for IBD treatment. 23053079 Changes in biofilm structure during the colonization of chalcopyrite by Acidithiobacillus thiooxidans. Biofilms of Acidithiobacillus thiooxidans were grown on the surface of massive chalcopyrite electrodes (MCE) where different secondary sulfur phases were previously formed by potentiostatic oxidation of MCE at 0.780≤Ean≤0.965 V (electrooxidized MCE, eMCE). The formation of mainly S⁰ and minor amounts of CuS and Sn²⁻ were detected on eMCEs. The eMCEs were incubated with A. thiooxidans cells for 1, 12, 24, 48, and 120 h in order to temporally monitor changes in eMCE's secondary phases, biofilm structure, and extracellular polymeric substance (EPS) composition (lipids, proteins, and polysaccharides) using microscopic, spectroscopic, electrochemical, and biochemical techniques. The results show significant cell attachments with stratified biofilm structure since the first hour of incubation and EPS composition changes, the most important being production after 48-120 h when the highest amount of lipids and proteins were registered. During 120 h, periodic oxidation/formation of S⁰/Sn²⁻ was recorded on biooxidized eMCEs, until a stable CuS composition was formed. In contrast, no evidence of CuS formation was observed on the eMCEs of the abiotic control, confirming that CuS formation results from microbial activity. The surface transformation of eMCE induces a structural transformation of the biofilm, evolving directly to a multilayered biofilm with more hydrophobic EPS and proteins after 120 h. Our results suggest that A. thiooxidans responded to the spatial and temporal distribution and chemical reactivity of the Sn²⁻/S⁰/CuS phases throughout 120 h. These results suggested a strong correlation between surface speciation, hydrophobic domains in EPS, and biofilm organization during chalcopyrite biooxidation by A. thiooxidans. 23816644 Activity of recombinant and natural defensins from Vigna unguiculata seeds against Leishmania amazonensis. Antimicrobial peptides (AMPs), which are differentiated from other antibiotic peptides, such as gramicidins and polymyxins, because they are synthesized by large enzymatic complex and bear modified amino acids including d-amino acids, are short polymers of l-amino acids synthesized by ribosomes upon which all living organisms rely to defend themselves from invaders or competitor microorganisms. AMPs have received a great deal of attention from the scientific community as potential new drugs for neglected diseases such as Leishmaniasis. In plants, they include several families of compounds, including the plant defensins. The aim of the present study was to improve the expression of recombinant defensin from Vigna unguiculata seeds (Vu-Defr) and to test its activity against Leishmania amazonensis promatigotes. Recombinant expression was performed in LB and TB media and under different conditions. The purification of Vu-Defr was achieved by immobilized metal ion affinity and reversed-phase chromatography. The purified Vu-Defr was analyzed by circular dichroism (CD), and its biological activity was tested against L. amazonenis promastigotes. To demonstrate that the recombinant production of Vu-Defr did not interfere with its fold and biological activity, the results of all experiments were compared with the results from the natural defensin (Vu-Def). The CD spectra of both peptides presented good superimposition indicating that both peptides present very similar secondary structure and that the Vu-Defr was correctly folded. L. amazonensis treated with Vu-Defr led to the elimination of 54.3% and 46.9% of the parasites at 24 and 48h of incubation time, respectively. Vu-Def eliminated 50% and 54.8% of the parasites at 24 and 48h, respectively. Both were used at a concentration of 100μg/mL. These results suggested the potential for plant defensins to be used as new antiparasitic substances. 23635017 Increase in skin autofluorescence and release of heart-type Fatty Acid binding protein in plasma predicts mortality of hemodialysis patients. Advanced glycation end-products (AGEs) are uremic toxins that accumulate progressively in hemodialysis (HD) patients. The aim of this study was to assess the 1-year increase in skin autofluorescence (ΔAF), a measure of AGEs accumulation and plasma markers, as predictors of mortality in HD patients. One hundred sixty-nine HD patients were enrolled in this study. Skin autofluorescence was measured twice, 1 year apart using an AGE Reader (DiagnOptics Technologies BV, Groningen, The Netherlands). Besides routine blood chemistry, additional plasma markers including superoxide dismutase, myeloperoxydase, intercellular adhesion molecule 1 (ICAM-1), C-reactive protein (hs-CRP), heart-type fatty acid binding protein (H-FABP), and von Willebrand factor were measured at baseline. The mortality of HD patients was followed for 36 months. Skin autofluorescence values of the HD patients at the two time points were significantly higher (P < 0.001) than those of healthy subjects of the same age. Mean 1-year ΔAF of HD patients was 0.16 ± 0.06, which was around seven- to ninefold higher than 1-year ΔAF in healthy subjects. Multivariate Cox regression showed that age, hypertension, 1-year ΔAF, hs-CRP, ICAM-1, and H-FABP were independent predictors of overall mortality. Hypertension, 1-year ΔAF, hs-CRP, and H-FABP were also independent predictors of cardiovascular mortality. One-year ΔAF and plasma H-FABP, used separately and in combination, are strong predictors of overall and cardiovascular mortality in HD patients. 23590602 Long-term results of enriched environment and erythropoietin after hypobaric hypoxia in rats. After global cerebral hypoxia, many patients are severely disabled even after intensive neurorehabilitation. Secondary mechanisms of brain injury as a result of biochemical and physiological events occur within a period of hours to months, and provide a window of opportunity for therapeutic intervention. Erythropoietin (EPO) has been shown to be neuroprotective in the brain subjected to a variety of injuries. Fifty-nine 3-month-old male Wistar rats were randomly distributed to experimental groups with respect to the housing (enriched environment - EE, standard housing - SH), to hypoxia exposure, and to EPO treatment. An acute mountain sickness model was used as a hypobaric hypoxia simulating an altitude of 8000 m. One half of the animals received erythropoietin injections, while the others were injected saline. Spatial memory was tested in a Morris water maze (MWM). The escape latency and the path length were measured. Better spatial learning in MWM was only seen in the group that received erythropoietin together with enriched environment. EPO administration itself had no influence on spatial memory. The results were very similar for both latencies and path lengths. These results support the idea that after brain injuries, the recovery can be potentiated by EPO administration combined with neurorehabilitation. 23512255 Lengthening the moment arm of the patella confers enhanced extensor mechanism power following total knee arthroplasty. We investigated whether a postulated biomechanical advantage conferred to the extensor mechanism by a change in knee implant design was detectable in patients by direct physical testing. 212 TKA patients were enrolled in a double blind randomized controlled trial to receive either a traditional implant or one which incorporated new design features. Extensor mechanism power output and physical performance on a battery of timed functional activities was assessed pre-operatively and then at 6, 26, and 52 weeks post-operatively. Significantly enhanced power output was observed in both groups post-arthroplasty; however, the new design implant group demonstrated a greater change in power output than the traditional implant group. Posthoc testing of between group differences highlighted greater improvement at all post-operative assessments. At 52 weeks, patients receiving the implant with the postulated biomechanical advantage achieved 116% of the power output of their contralateral limb, whereas patients with the traditional design achieved 90%. No between group difference was detected in the patient's time to complete functional tasks. Thus, patients receiving a knee implant of a modern design (theoretically able to confer a mechanical advantage to the extensor mechanism) were found to generate significantly greater extensor power than those receiving a traditional implant without the postulated mechanical advantage. 23819618 Central auditory maturation and behavioral outcome in children with auditory neuropathy spectrum disorder who use cochlear implants. Abstract Objective: We examined cortical auditory development and behavioral outcomes in children with ANSD fitted with cochlear implants (CI). Design: Cortical maturation, measured by P1 cortical auditory evoked potential (CAEP) latency, was regressed against scores on the infant toddler meaningful auditory integration scale (IT-MAIS). Implantation age was also considered in relation to CAEP findings. Study sample: Cross-sectional and longitudinal samples of 24 and 11 children, respectively, with ANSD fitted with CIs. Results: P1 CAEP responses were present in all children after implantation, though previous findings suggest that only 50-75% of ANSD children with hearing aids show CAEP responses. P1 CAEP latency was significantly correlated with participants' IT-MAIS scores. Furthermore, more children implanted before age two years showed normal P1 latencies, while those implanted later mainly showed delayed latencies. Longitudinal analysis revealed that most children showed normal or improved cortical maturation after implantation. Conclusion: Cochlear implantation resulted in measureable cortical auditory development for all children with ANSD. Children fitted with CIs under age two years were more likely to show age-appropriate CAEP responses within six months after implantation, suggesting a possible sensitive period for cortical auditory development in ANSD. That CAEP responses were correlated with behavioral outcome highlights their clinical decision-making utility. 23904037 Synthesis and characterization of homo- and heteronuclear molecular Al(3+) and Th(4+) species chelated by the ethylenediaminetetraacetate (edta) ligand. Four molecular species chelated by edta have been synthesized from aqueous solutions and characterized by single-crystal X-ray diffraction, infrared spectroscopy, and thermogravimetric analysis. [Th(H2O)4(edta)] () crystallized in monoclinic space group P21/c with unit cell parameters of a = 8.5275(5) Å, b = 12.0635(7) Å, c = 15.8825(9) Å, and β = 105.340(2)°. Monoclinic space group C2 was identified for [Al2(edta)(OH)2(H2O)2] () with a = 11.1089(10) Å, b = 9.4830(8) Å, c = 7.6116(7) Å, and β = 112.026(3)°. [Th4(H2O)4Al10(H2O)8(OH)28(edta)4]·Cl2(H2O)29 () formed the triclinic space group P1[combining macron] with a = 9.3172(8) Å, b = 16.6099(14) Å, c = 19.5080(14) Å, α = 102.314(3)°, β = 95.615(3)°, and γ = 92.473(3)°. [Th2(H2O)2Al6(H2O)10(OH)14(edta)2]·(NO3)4(H2O)18 () also crystallized in triclinic space group P1[combining macron] with unit cell parameters a = 10.9899(12) Å, b = 11.6107(12) Å, c = 14.3350(17) Å, α = 73.012(4)°, β = 87.411(4)°, and γ = 75.717(4)°. Small molecular species are observed in the and compounds, while the metal cations hydrolyze to create nanometer-sized heterometallic clusters in the and materials. The topological characteristics of each species are described and related to aqueous speciation in Th(4+), Al(3+)-edta systems. 23645211 Role of quercetin in cadmium-induced oxidative stress, neuronal damage, and apoptosis in rats. The present study was carried out to evaluate the neuroprotective effect of quercetin (QE) in protecting the cadmium (Cd)-induced neuronal injury in frontal cortex of rats. A total of 30 adult male Sprague-Dawley rats were randomly divided into three groups of 10 animals each: control, Cd treated and Cd treated with QE. The Cd-treated group was injected subcutaneously with cadmium chloride (CdCl2) dissolved in saline at a dose of 2 ml/kg/day for 30 days, resulting in a dosage of 1 mg/kg Cd. The rats in QE-treated groups were given QE (15 mg/kg body weight) once a day intraperitoneally starting 2 days prior to Cd injection, during the study period. Rats were sacrificed at the end of the study and the frontal cortex tissues were removed for biochemical and histopathological investigation. To date, there is no available information on the effect of QE on neuronal injury after Cd exposure. Rats intoxicated with Cd for 30 days, significantly increased tissue malondialdehyde (MDA) levels and significantly decreased enzymatic antioxidants superoxide dismutase, glutathione peroxidase and catalase in the frontal cortex tissue. Administration of QE with Cd significantly diminished the levels of MDA and significantly elevated the levels of enzymatic antioxidants in the frontal cortex tissue. The histopathological studies in the brain of rats also supported that QE markedly reduced the Cd-induced histopathological changes and well preserved the normal histological architecture of the frontal cortex tissue. The caspase-3 immunopositivity was increased in degenerating neurons of the Cd group. Treatment with QE markedly reduced the immunoreactivity of degenerating neurons. In conclusion, the results of the current study suggest that QE may be beneficial in combating the Cd-induced neurotoxicity in the brain of rats. We believe that further preclinical research into the utility of QE may indicate its usefulness as a potential treatment for neurodegeneration after Cd exposure in rats. 23884992 Use of cell-free circulating schistosome DNA in serum, urine, semen and saliva to monitor a case of refractory imported schistosomiasis haematobia. This case of imported refractory schistosomiasis has highlighted the usefulness of cell-free parasite DNA as a diagnostic marker to assess active schistosome infection. Contrary to the rapiddisappearance of ova in urine, parasite DNA remained persistent in several specimen types even after the fourth treatment of praziquantel. This result was consistent with the presence of morphologically intact ova in bladder biopsy, and symptoms. 23581551 Design, Synthesis, and Structure-Activity Relationship Studies of Novel 3-Alkylindole Derivatives as Selective and Highly Potent Myeloperoxidase Inhibitors. Due to its production of potent antimicrobial oxidants including hypochlorous acid, human myeloperoxidase (MPO) plays a critical role in innate immunity and inflammatory diseases. Thus MPO is an attractive target in drug design. (Aminoalkyl)fluoroindole derivatives were detected to be very potent MPO inhibitors; however, they also promote inhibition of the serotonin reuptake transporter (SERT) at the same concentration range. Via structure-based drug design, a new series of MPO inhibitors derived from 3-alkylindole were synthesized and their effects were assessed on MPO-mediated taurine chlorination and low-density lipoprotein oxidation as well as on inhibition of SERT. The fluoroindole compound with three carbons in the side chain and one amide group exhibited a selectivity index of 35 (Ki/IC50) with high inhibition of MPO activity (IC50 = 18 nM), whereas its effect on SERT was in the micromolar range. Structure-function relationships, mechanism of action, and safety of the molecule are discussed. 23929273 Separation and phase transition investigation of Yb(3+)/Er(3+) co-doped NaYF4 nanoparticles. Density gradient ultracentrifuge separation was employed to study the phase transition of Yb(3+)/Er(3+) co-doped NaYF4 from α-phase to β-phase. It was found that the cubic α-phased NaYF4 was rich in Y, exhibited predominantly red luminescence, whilst the newly formed hexagonal β-phased NaYF4 had relatively higher Yb and Er atomic ratios, exhibited green luminescence most strongly. 23781025 αvβ3-integrin-mediated adhesion is regulated through an AAK1L- and EHD3-dependent rapid-recycling pathway. Protein transport through the endosome is critical for maintaining proper integrin cell surface integrin distribution to support cell adhesion, motility and viability. Here we employ a live-cell imaging approach to evaluate the relationship between integrin function and transport through the early endosome. We discovered that two early endosome factors, AAK1L and EHD3, are critical for αvβ3-integrin-mediated cell adhesion in HeLa cells. siRNA-mediated depletion of either factor delays short-loop β3 integrin recycling from the early endosome back to the cell surface. Total internal reflection fluorescence-based colocalization analysis reveals that β3 integrin transits AAK1L- and EHD3-positive endosomes near the cell surface, a subcellular location consistent with a rapid-recycling role for both factors. Moreover, structure-function analysis reveals that AAK1L kinase activity, as well as its C-terminal domain, is essential for cell adhesion maintenance. Taken together, these data reveal an important role for AAK1L and EHD3 in maintaining cell viability and adhesion by promoting αvβ3 integrin rapid recycling from the early endosome. 23360348 Discovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase PI3Kα. PI3Kα has been identified as an oncogene in human tumors. By use of rational drug design, a targeted covalent inhibitor 3 (CNX-1351) was created that potently and specifically inhibits PI3Kα. We demonstrate, using mass spectrometry and X-ray crystallography, that the selective inhibitor covalently modifies PI3Kα on cysteine 862 (C862), an amino acid unique to the α isoform, and that PI3Kβ, -γ, and -δ are not covalently modified. 3 is able to potently (EC(50) < 100 nM) and specifically inhibit signaling in PI3Kα-dependent cancer cell lines, and this leads to a potent antiproliferative effect (GI(50) < 100 nM). A covalent probe, 8 (CNX-1220), which selectively bonds to PI3Kα, was used to investigate the duration of occupancy of 3 with PI3Kα in vivo. This is the first report of a PI3Kα-selective inhibitor, and these data demonstrate the biological impact of selectively targeting PI3Kα. 23318728 Effects of nicotine, its metabolites and tobacco extracts on human platelet function in vitro. Cigarette smoking is a leading cause of cardiovascular disease. The cardiovascular effects of smoking are probably multifactorial, including effects on platelets. Previous reports investigating the effects of nicotine and tobacco on platelet function are inconsistent. The present study investigated in vitro effects of nicotine, its major metabolites, tobacco extracts and extract of tobacco-free snuff on human platelets. None of the metabolites cotinine, cotinine-N-oxide, nicotine-1'-N-oxide or trans-3'-hydroxycotinine (0.1-10 μM) affected platelet aggregation or P-selectin expression. Nicotine (10 μM) weakly increased platelet aggregation, whereas trans-3'-hydroxycotinine (0.1 μM) and nicotine-1'-N-oxide (1-10 μM) weakly inhibited adhesion to fibrinogen. To elucidate the influence of other tobacco compounds, we investigated the impact of moist tobacco and smoke extracts on platelet function. Filtered extracts of oral snuff, cigarette smoke and tobacco free snuff inhibited platelet adhesion concentration-dependently. The inhibitory effects of tobacco extracts on platelet adhesion were independent of nicotine content and the nitric-oxide-pathway and not mediated through a platelet-nicotine-receptor. Taken together, tobacco extracts inhibit platelet activation during short-term in vitro challenge. As only limited effects of nicotine and nicotine metabolites were seen, the tobacco-induced platelet inhibition are likely induced by other compounds present in tobacco and tobacco free snuff. 23729565 In vitro maturation of Drosophila melanogaster Spätzle protein with refolded Easter reveals a novel cleavage site within the prodomain. Dorsoventral patterning during Drosophila melanogaster embryogenesis is mediated by a well-defined gradient of the mature NGF-like ligand Spätzle. Easter, the ultimate protease of a ventrally-restricted serine protease cascade, plays a key role in the regulation of the morphogenic gradient, catalyzing the activation cleavage of proSpätzle. As a result of alternative splicing, proSpätzle exists in multiple isoforms, almost all of which differ only in their prodomain. Although this domain is unstructured in isolation, it has a stabilizing influence on the mature cystine knot domain and is involved in the binding to the Toll receptor. Here, we report the expression and refolding of Easter, and show that the renatured enzyme performs the activation cleavage of two Spätzle isoforms. We determine the affinity of the prodomain for the cystine knot domain, and show that Easter performs a previously unknown secondary cleavage in each prodomain. 23842952 Radioprotection provides functional mechanics but delays healing of irradiated tendon allografts after ACL reconstruction in sheep. Successful protection of tissue properties against ionizing radiation effects could allow its use for terminal sterilization of musculoskeletal allografts. In this study we functionally evaluate Achilles tendon allografts processed with a previously developed radioprotective treatment based on (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) crosslinking and free radical scavenging using ascorbate and riboflavin, for ovine anterior cruciate ligament reconstruction. Arthroscopic anterior cruciate ligament (ACL) reconstruction was performed using double looped allografts, while comparing radioprotected irradiated and fresh frozen allografts after 12 and 24 weeks post-implantation, and to control irradiated grafts after 12 weeks. Radioprotection was successful at preserving early subfailure mechanical properties comparable to fresh frozen allografts. Twelve week graft stiffness and anterior-tibial (A-T) translation for radioprotected and fresh frozen allografts were comparable at 30 % of native stiffness, and 4.6 and 5 times native A-T translation, respectively. Fresh frozen allograft possessed the greatest 24 week peak load at 840 N and stiffness at 177 N/mm. Histological evidence suggested a delay in tendon to bone healing for radioprotected allografts, which was reflected in mechanical properties. There was no evidence that radioprotective treatment inhibited intra-articular graft healing. This specific radioprotective method cannot be recommended for ACL reconstruction allografts, and data suggest that future efforts to improve allograft sterilization procedures should focus on modifying or eliminating the pre-crosslinking procedure. 23965825 The feasibility of non-contact ultrasound for medical imaging. High intensity focused ultrasound in air may provide a means for medical and biological imaging without direct coupling of an ultrasound probe. In this study, an approach based on highly focused ultrasound in air is described and the feasibility of the technique is assessed. The overall method is based on the observations that (1) ultrasound in air has superior focusing ability and stronger nonlinear harmonic generation as compared to tissue propagation and (2) a tightly focused field directed into tissue causes point-like spreading that may be regarded as a source for generalized diffraction tomography. Simulations of a spherically-curved transducer are performed, where the transducer's radiation pattern is directed from air into tissue. It is predicted that a focal pressure of 162 dB (2.5 kPa) is sufficient to direct ultrasound through the body, and provide a small but measurable signal (∼1 mPa) upon exit. Based on the simulations, a 20 cm diameter array consisting of 298 transducers is constructed. For this feasibility study, a 40 kHz resonance frequency is selected based on the commercial availability of such transducers. The array is used to focus through water and acrylic phantoms, and the time history of the exiting signal is evaluated. Sufficient data are acquired to demonstrate a low-resolution tomographic reconstruction. Finally, to demonstrate the feasibility to record a signal in vivo, a 75 mm Ã— 55 mm section of a human hand is imaged in a C-mode configuration. 23521128 Immune thrombocytopenia in patients with chronic lymphocytic leukemia treated with cladribine-based regiments or chlorambucil--follow-up of PALG-CLL randomized trials. The relationship between treatments of chronic lymphocytic leukemia (CLL) with cladribine (2-CdA) or chlorambucil and immune thrombocytopenia (IT) has not been yet determined. The records of 777 patients in two randomized Polish Adult Leukemia Group (PALG)-CLL programs treated with these agents were retrospectively analyzed. Immune thrombocytopenia occurred in 55 of 777 (7.1%) patients. No significant differences in IT prevalence were seen between patients on chlorambucil or 2-CdA-based regiments (P = 0.33). IT developed at a median time of 0.499 yr (0.06-4.8) from the start of CLL therapy. This time was significantly longer in patients treated with chlorambucil (2.03 yr, 95% CI: 0.06-4.22) in relation to patients treated with 2-CdA-based regiments (0.52 yr, 95%CI: 0.34-0.69, P = 0.049). Overall survival (OS) of patients with IT and those without IT were similar (2.65 yr vs. 3.2 yr P = 0.23) but the severity of bleeding was more pronounced in the 2-CdA group. The responses to IT therapy were 35%, 54% and 75% for steroids, chemotherapy and splenectomy, respectively. In this study, an unexpectedly high percentage of IT incidence was demonstrated in patients with CLL requiring chemotherapy. Although no marked differences were seen in IT frequency in patients treated with 2-CdA-based regiments compared to chlorambucil regimen, the clinical course of hemorrhagic diathesis was more severe in 2-CdA group. Also, the time elapsed from study screening to IT diagnosis was significantly shorter in the 2-CdA group than in the chlorambucil group suggesting a causative relationship. The appearance of IT did not influence the median time of OS. 23910906 A prospective, phase II, open-label study (JO22903) of first-line erlotinib in Japanese patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor erlotinib is associated with survival benefits in patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC). This phase II, single-arm study examined the efficacy and safety of first-line erlotinib in Japanese patients with EGFR mutation-positive NSCLC. Eligible patients received erlotinib 150mg/day until disease progression or unacceptable toxicity. The primary endpoints were progression-free survival (PFS) and safety. A high degree of concordance was observed between different mutation testing methodologies, suggesting feasibility of early, rapid detection of EGFR mutations. Median PFS was 11.8 months (95% confidence interval [CI]: 9.7-15.3) at data cut-off (1 June 2012) (n=102). Exon 19 deletions seemed to be associated with longer PFS compared with L858R mutations; T790M mutations were tentatively linked with shorter PFS. The safety profile was as expected: rash (any grade; 83%) and diarrhea (any grade; 81%) were most common. Six interstitial lung disease (ILD)-like cases were reported, and 5 were confirmed as ILD-like events by the extramural committee. Two patients died of treatment-related pneumonitis (JAPIC Clinical Trials Information number: Japic CTI-101085). Erlotinib should be considered for first-line treatment in this subset of Japanese patients, with close monitoring for ILD-like events. 23711524 Molecular Cloning, Overexpression, and Enzymatic Characterization of Glycosyl Hydrolase Family 16 β-Agarase from Marine Bacterium Saccharophagus sp. AG21 in Escherichia coli. An agar-degrading bacterium was isolated from red seaweed (Gelidium amansii) on a natural seawater agar plate, and identified as Saccharophagus sp. AG21. The β-agarase gene from Saccharophagus sp. AG21 (agy1) was screened by long and accurate (LA)-PCR. The predicted sequence has a 1,908 bp open reading frame encoding 636 amino acids (aa), and includes a glycosyl hydrolase family 16 (GH16) β-agarase module and two carbohydrate binding modules of family 6 (CBM6). The deduced aa sequence showed 93.7% and 84.9% similarity to β-agarase of Saccharophagus degradans and Microbulbifer agarilyticus, respectively. The mature agy1 was cloned and overexpressed as a His-tagged recombinant β-agarase (rAgy1) in Escherichia coli, and had a predicted molecular mass of 69 kDa and an isoelectric point of 4.5. rAgy1 showed optimum activity at 55oC and pH 7.6, and had a specific activity of 85 U/mg. The rAgy1 activity was enhanced by FeSO4 (40%), KCl (34%), and NaCl (34%), compared with the control. The newly identified rAgy1 is a β-agarase, which acts to degrade agarose to neoagarotetraose (NA4) and neoagarohexaose (NA6) and may be useful for applications in the cosmetics, food, bioethanol, and reagent industries. 23888269 Contemporary multidisciplinary treatment of pregnancy-associated breast cancer. Breast cancer diagnosed during pregnancy poses unique challenges. Application of standard treatment algorithms is limited by lack of level I evidence from randomized trials. This study describes contemporary multidisciplinary treatment of pregnancy-associated breast cancer (PABC) in an academic setting and explores early maternal and fetal outcomes. A search of the Dana-Farber/Harvard Cancer Center clinical databases was performed to identify PABC cases. Sociodemographic, disease, pregnancy, and treatment information, as well as data on short-term maternal and fetal outcomes, were collected through retrospective chart review. 74 patients were identified, the majority with early-stage breast cancer. Most (73.5%) underwent surgical resection during pregnancy, including 40% with sentinel lymph node biopsy and 32% with immediate reconstruction. A total of 36 patients received anthracycline-based chemotherapy during pregnancy; of those, almost 20% were on a dose-dense schedule and 8.3% also received paclitaxel. 68 patients delivered liveborn infants; over half were delivered preterm (< 37 weeks), most scheduled to allow further maternal cancer therapy. For the infants with available data, all had normal Apgar scores and over 90% had birth weight >10(th) percentile. The rate of fetal malformations (4.4%) was not different than expected population rate. Within a multidisciplinary academic setting, PABC treatment followed contemporary algorithms without apparent increase in maternal or fetal adverse outcomes. A considerable number of preterm deliveries were observed, the majority planned to facilitate cancer therapy. Continued attention to maternal and fetal outcomes after PABC is required to determine the benefit of this delivery strategy. 23718933 Is the progression free survival advantage of concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin in patients with advanced cervical cancer worth the additional cost? A cost-effectiveness analysis. The objective of this study is to determine whether concurrent and adjuvant chemoradiation with gemcitabine/cisplatin is cost-effective in patients with stage IIB to IVA cervical cancer. A cost-effectiveness model compared two arms of the trial performed by Duenas-Gonzalez et al. [1]: concurrent and adjuvant chemoradiation with gemcitabine/cisplatin (RT/GC+GC) versus concurrent radiation with cisplatin (RT/C). Major adverse events (AEs) and progression free survival (PFS) rates of each arm were incorporated in the model. AEs were defined as any hospitalization including grade 4 anemia, grade 4 neutropenia, and death. Medicare data and literature review were used to estimate costs. Incremental cost-effectiveness ratios (ICERs) per progression-free life-year saved (PF-LYS) were calculated. Sensitivity analyses were performed for pertinent uncertainties. For 10,000 women with locally advanced cervical cancer, the cost of therapy and AEs was $173.9million (M) for RT/C versus $259.8M for RT/GC+GC. There were 879 additional 3-year progression-free survivors in the RT/GC+GC arm. The ICER for RT/GC+GC was $97,799 per PF-LYS. When the rate of hospitalization was equalized to 4.3%, the ICER for RT/GC+GC exceeded $80,000. The resultant ICER when increasing PFS in the RT/GC+GC arm by 5% was $62,605 per PF-LYS. When the cost of chemotherapy was decreased by 50%, the ICER was below $50,000 at $41,774 per PF-LYS. Radiation and gemcitabine/cisplatin for patients with stage IIB to IVA cervical cancer are not cost-effective. The increased financial burden of radiation with gemcitabine/cisplatin and associated toxicities appears to outweigh the benefit of increased 3-year PFS and is primarily dependent on chemotherapy drug costs. 22781580 Harmonization of description and classification of fetal observations: achievements and problems still unresolved: report of the 7th Workshop on the Terminology in Developmental Toxicology Berlin, 4-6 May 2011. This article summarizes the 7th Workshop on the Terminology in Developmental Toxicology held in Berlin, May 4-6, 2011. The series of Berlin Workshops has been mainly concerned with the harmonization of terminology and classification of fetal anomalies in developmental toxicity studies. The main topics of the 7th Workshop were knowledge on the fate of anomalies after birth, use of Version 2 terminology for maternal-fetal observations and non-routinely used species, reclassification of "grey zone" anomalies and categorization of fetal observations for human health risk assessment. The paucity of data on health consequences of the postnatal permanence of fetal anomalies is relevant and further studies are needed. The Version 2 terminology is an important step forward and the terms listed in this glossary are considered also to be appropriate for most observations in non-routinely used species. Continuation of the Berlin Workshops was recommended. Topics suggested for the next Workshop were grouping of fetal observations for reporting and statistical analysis. 23537577 Evaluation of a dedicated MDCT protocol using iterative image reconstruction after cervical spine trauma. To evaluate radiation exposure for 64-row computed tomography (CT) of the cervical spine comparing two optimized protocols using filtered back projection (FBP) and adaptive statistical iterative reconstruction (ASIR), respectively. Sixty-seven studies using FBP (scanner 1) were retrospectively compared with 80 studies using ASIR (scanner 2). The key scanning parameters were identical (120 kV dose modulation, 64 × 0.625 mm collimation, pitch 0.531:1). In protocol 2, the noise index (NI) was increased from 5 to 25, and ASIR and the high-definition (HD) mode were used. The scan length, CT dose index (CTDI), and dose-length product (DLP) were recorded. The image quality was analysed subjectively by using a three-point scale (0; 1; 2), and objectively by using a region of interest (ROI) analysis. Mann-Whitney U and Wilcoxon's test were used. In the FBP group, the mean CTDI was 21.43 mGy, mean scan length 186.3 mm, and mean DLP 441.15 mGy cm. In the ASIR group, the mean CTDI was 9.57 mGy, mean scan length 195.21 mm, and mean DLP 204.23 mGy cm. The differences were significant for CTDI and DLP (p < 0.001) and scan length (p = 0.01). There was no significant difference in the subjective image quality (p > 0.05). The estimated mean effective dose decreased from 2.38 mSv (FBP) to 1.10 mSv (ASIR). The radiation dose of 64-row MDCT can be reduced to a level comparable to plain radiography without loss of subjective image quality by implementation of ASIR in a dedicated cervical spine trauma protocol. These results might contribute to an improved relative risk-to-benefit ratio and support the justification of CT as a first-line imaging tool to evaluate cervical spine trauma. 23832741 Interleukin-6 is overexpressed and augments invasiveness of human glioma stem cells in vitro. In the present study, we carried out a series of assays to investigate the expression of interleukin-6 in glioma stem cells and its role in glioma stem cells invasion. Glioma stem cells from eight surgical glioma specimens were cultured and identified. Real-time reverse transcription polymerase chain reaction and immunoassay were used to measure and compare the expression levels of interleukin-6 in glioma stem cells and matched primary glioma cells. Subsequently, neutralizing antibody against interleukin-6 or exogenous interleukin-6 was used in a Matrigel-invasion assay and effects of interleukin-6 on glioma stem cells invasiveness was then determined. The results revealed that interleukin-6 mRNA and protein expression levels were significantly higher in glioma stem cells than in primary glioma cells from the same tumor. However, its expression levels were not apparently higher in glioma stem cells from grade IV gliomas than from grade III gliomas. In Matrigel-invasion assay, glioma stem cells invasiveness markedly decreased after interleukin-6 was blocked with neutralizing antibody, but significantly increased when exogenous interleukin-6 was added. Additionally, the similar effects of interleukin-6 were also found on primary glioma cells invasiveness. Our results suggest that glioma stem cells are likely to be the major tumor source of immunosuppressive cytokines interleukin-6 and thereby play a crucial role in determining glioma malignancy, immunosuppression and immune evasion. Furthermore, interleukin-6 can significantly augment glioma stem cells invasiveness in vitro, suggesting a potential target in future therapy for glioma stem cells rather than for their derivatives. 23669493 Longitudinal assessment of skill development in children with first febrile seizure. To determine whether first febrile seizure (FS) has detrimental effects on development, 159 children (aged 6 months to 5 years) with FS were compared to 142 controls on measures of cognition, motor ability, and adaptive behavior. Participants were identified through the emergency department in an urban, low-income community. Children were evaluated within one month of the ED visit and one year later, and difference in performance over one year was examined. Performance did not differ between cases and controls on measures of cognition (baseline: p=0.5, one year: p=0.2, change over time: p=0.1) or motor skills (baseline: p=0.9, one year: p=0.7, change over time, p=0.6). The adaptive behavior composite score did not differ by FS case status at baseline (p=0.2) or one year later (p=0.6); however, between-group differences over time approached significance (p=0.05). Findings support the idea that first FS does not pose developmental or behavioral consequences in a low socioeconomic environment. 23927571 Envelope protein gene based molecular characterization of Japanese encephalitis virus clinical isolates from West Bengal, India: a comparative approach with respect to SA14-14-2 live attenuated vaccine strain. Increasing virulence of Japanese encephalitis virus (JEV), a mosquito-borne zoonotic pathogen is of grave concern because it causes a neurotrophic killer disease Japanese Encephalitis (JE) which, in turn, is responsible globally for viral acute encephalitis syndrome (AES). Despite the availability of vaccine, JE/AES cases and deaths have become regular features in the different rural districts of West Bengal (WB) state, India, indicating either the partial coverage of vaccine or the emergence of new strain of JEV. Therefore, a study was undertaken to characterize and compare the complete envelope (E) protein gene based molecular changes/patterns of JEVs circulating in WB. Total of 98 AES case-patients' samples were tested to detect the presence of JEV specific immunoglobulin M (IgM) antibody by Mac-ELISA method. Only JEV IgM negative samples with a history of <=3 days' illness were screened for virus isolation and RT-PCR. E gene sequences of JEV isolates were subjected to molecular phylogeny and immunoinformatics analysis. Present study confirmed JEV etiology in 39.7% and 29.1% of patients presenting <=15 days' febrile illness, as determined by Mac-ELISA and RT-PCR respectively. Phylogenetic analysis based on complete E gene sequences of JEV isolates showed the co-circulation of JEV genotype I (GI) with genotype III (GIII). This study also demonstrated that isolate-specific crucial amino acid substitutions were closely related to neurovirulence/neuroinvasiveness of JE. On the basis of immunoinformatics analysis, some substitutions were predicted to disrupt T-cell epitope immunogenicity/antigenicity that might largely influence the outcome of vaccine derived from JEV GIII SA14-14-2 strain and this has been observed in a previously vaccinated boy with mild JE/AES due to JEV GI infection. Based on molecular evolutionary and bioinformatic approaches, we report evolution of JEV at a local level. Such naturally occurring evolution is likely to affect the disease profile and the vaccine efficacy to protect against JEV GI may demand careful evaluation. 23910971 Differential isotope dansylation labeling combined with liquid chromatography mass spectrometry for quantification of intact and N-terminal truncated proteins. The N-terminal amino acids of proteins are important structure units for maintaining the biological function, localization, and interaction networks of proteins. Under different biological conditions, one or several N-terminal amino acids could be cleaved from an intact protein due to processes, such as proteolysis, resulting in the change of protein properties. Thus, the ability to quantify the N-terminal truncated forms of proteins is of great importance, particularly in the area of development and production of protein-based drugs where the relative quantity of the intact protein and its truncated form needs to be monitored. In this work, we describe a rapid method for absolute quantification of protein mixtures containing intact and N-terminal truncated proteins. This method is based on dansylation labeling of the N-terminal amino acids of proteins, followed by microwave-assisted acid hydrolysis of the proteins into amino acids. It is shown that dansyl labeled amino acids are stable in acidic conditions and can be quantified by liquid chromatography mass spectrometry (LC-MS) with the use of isotope analog standards. 23518478 Titanium particle-challenged osteoblasts promote osteoclastogenesis and osteolysis in a murine model of periprosthestic osteolysis. The current study investigates the interactive behavior of titanium alloy particle-challenged osteoblastic bone marrow stromal cells (BMSCs) and macrophage lineage cells in a murine knee-prosthesis failure model. BMSCs were isolated from male BALB/c mice femurs and induced in osteogenic medium. At 24h after isolation, BMSCs in complete induction medium were challenged with 1, 3 or 5mgml(-1) titanium particles for 7days. Culture media were collected at 2, 4 and 6days and cells were harvested at 7days for alkaline phosphatase (ALP) assay/stains. Cell proliferation in the presence of Ti particles was periodically evaluated by MTT assay. Mice implanted with titanium-pin tibial implants were given an intra-articular injection of 50μl medium containing 5×10(5) Ti particles-challenged bone-marrow-derived osteoblastic cells, followed by a repeat injection at 2weeks post-operation. Control mice with titanium-pin implants received a naïve osteoblastic cell transfusion. After sacrifice at 4weeks, the implanted knee joint of each group was collected for biomechanical pin-pullout testing, histological evaluation and reverse transcriptase polymerase chain reaction analysis of mRNA extracted from the joint tissues. Ti particles significantly stimulated the proliferation of BMSC-derived osteoblastic cells at both high and low particle concentrations (p<0.05), with no marked differences between the particle doses. ALP expression was diminished following Ti particle interactions, especially in the high-dose particle group (p<0.05). In addition, the culture media collected from short-term challenged (48h) osteoblasts significantly increased the numbers of TRAP+ cells when added to mouse peripheral blood monocytes cultures, in comparison with the monocytes cells receiving naïve osteoblasts media (p<0.05). Intra-articular introduction of the osteoblastic cells to the mouse pin-implant failure model resulted in reduced implant interfacial shear strength and thicker peri-implant soft-tissue formation, suggesting that titanium particles-challenged osteoblasts contributed to periprosthetic osteolysis. Comparison of the gene expression profiles among the peri-implant tissue samples following osteoblast injection did not find significant difference in RunX2 or Osterix/Sp7 between the groups. However, MMP-2, IL-1, TNF-α, RANKL, and TRAP gene expressions were elevated in the challenged-osteoblast group (p<0.05). In conclusion, titanium alloy particles were shown to interfere with the growth, maturation, and functions of the bone marrow osteoblast progenitor cells. Particle-challenged osteoblasts appear to express mediators that regulate osteoclastogenesis and peri-prosthetic osteolysis. 23692853 The co-receptor BTLA negatively regulates human Vγ9Vδ2 T-cell proliferation: a potential way of immune escape for lymphoma cells. Vγ9Vδ2 cells, the major γδ T-cell subset in human peripheral blood, represent a T-cell subset that displays reactivity against microbial agents and tumors. The biology of Vγ9Vδ2 T cells remains poorly understood. We show herein that the interaction between B- and T-lymphocyte attenuator (BTLA) and herpesvirus entry mediator (HVEM) is a major regulator of Vγ9Vδ2 T-cell proliferation control. BTLA was strongly expressed at the surface of resting Vγ9Vδ2 T cells and inversely correlated with T-cell differentiation. BTLA-HVEM blockade by monoclonal antibodies resulted in the enhancement of Vγ9Vδ2 T-cell receptor-mediated signaling, whereas BTLA-HVEM interaction led to a decrease in phosphoantigen-mediated proliferation by inducing a partial S-phase arrest. Our data also suggested that BTLA-HVEM might participate in the control of γδ T-cell differentiation. In addition, the proliferation of autologous γδ T cells after exposition to lymphoma cells was dramatically reduced through BTLA-HVEM interaction. These data suggest that HVEM interaction with BTLA may play a role in lymphomagenesis by interfering with Vγ9Vδ2 T-cell proliferation. Moreover, BTLA stimulation of Vγ9Vδ2 T cells appears as a new possible mechanism of immune escape by lymphoma cells. 23896797 An acoustofluidic micromixer based on oscillating sidewall sharp-edges. Rapid and homogeneous mixing inside a microfluidic channel is demonstrated via the acoustic streaming phenomenon induced by the oscillation of sidewall sharp-edges. By optimizing the design of the sharp-edges, excellent mixing performance and fast mixing speed can be achieved in a simple device, making our sharp-edge-based acoustic micromixer a promising candidate for a wide variety of applications. 23920212 REFERENCE EQUATION FOR THE TWO-MINUTE WALK TEST IN ADULTS AND THE ELDERLY. The two-minute walk test (2MWT) has been used in several health conditions, but the interpretation of its results is limited due to lack of reference values. The aim of this study was to establish a reference equation to predict the distance walked (DW) in the 2MWT for healthy adults and the elderly, and to test its reproducibility. We evaluated 390 healthy subjects (195 male), aged 18-89 years, with normal spirometry and no history of previous chronic diseases. Two 2MWTs were performed on the same day, 30 minutes apart. To test the reliability of the prediction equation, 70 subjects (35 male) were prospectively included in the study. Males walked farther than females (221 [202-240] m vs. 199 [164-222] m, respectively; p <0.0001). Significant correlations were observed between DW and age (r = -0.50), weight (r = 0.23), height (r = 0.40), and gender (r = 0.35) (p <0.001 for all). Age and gender persisted in the model to predict DW (R(2): 0.51). There was no difference between the DW by the subjects (197 [182 -216]) and that estimated by the prediction equation (197 [179-222]) (p = 0.68). We established a prediction equation that may be used as a reference to interpret performance on the 2MWT performed by adults and the elderly with different health conditions. 23884453 Tension-induced neurite growth in microfluidic channels. The generation of an effective method for stimulating neuronal growth in specific directions, along well-defined geometries, and in numerous cells could impact areas ranging from fundamental studies of neuronal evolution and morphogenesis, to applications in biomedical diagnostics and nerve regeneration. Applied mechanical stress can regulate neurite growth. Indeed, previous studies have shown that neuronal cells can develop and extend neurites with rapid growth rates under applied "towing" tensions imparted by micropipettes. Yet, such methods are complex and exhibit low throughputs, as the tension is applied serially to individual cells. Here we present a novel approach to inducing neurite growth in multiple cells in parallel, by using a miniaturized platform with numerous microchannels. Upon connection of a vacuum to these microchannels, tension can be applied on multiple cells simultaneously to induce the growth of neurites. A theoretical model was also developed to understand the effect of tension on the dynamics of neurite development. 23538036 Apoptotic and proinflammatory effect of combustion-generated organic nanoparticles in endothelial cells. Air pollution exposure in industrialized cities is associated with an increased risk of morbidity and mortality attributed to cardiovascular diseases. Combustion exhausts emitted from motor vehicles and industries represent a major source of nanoparticles in the atmosphere. Flame-generated organic carbon nanoparticles (OC NPs) provide interesting model nanoparticles that simulate fresh combustion emissions near roadways or combustion sources. These model nanoparticles can be produced by controlling flame operating conditions and used to test possible toxicological mechanisms responsible for the observed health effects. OC NPs were used to investigate their possible effect on endothelial cells (EC) growth and production of proinflammatory lipid mediators. Results indicated a dose and time-dependent reduction in cell viability following incubation of EC with OC NPs for 24 and 48h. Fluorescence-activated cell sorting revealed that EC treated with OC NPs showed a cell proliferation index significantly lower than that of control cells and an increased apoptotic cell death. The annexin assay confirmed the increased apoptotic cell death. Moreover, OC NPs also induced a time-dependent increase of proinflammatory lysophospholipid production. These results, establishing that OC NPs induce EC proinflammatory lysophosholipid production and apoptotic cell death, provide the first evidence of the detrimental effect of OC NPs on EC. 23571270 CB₁ cannabinoid receptors promote maximal FAK catalytic activity by stimulating cooperative signaling between receptor tyrosine kinases and integrins in neuronal cells. Tyrosine phosphorylation (Tyr-P) of focal adhesion kinase (FAK) regulates FAK activation. Phosphorylated FAK Tyr 397 binds Src family kinases (Src), which in turn directly phosphorylate FAK Tyr 576/577 to produce maximal FAK enzymatic activity. CB₁ cannabinoid receptors (CB₁) are abundantly expressed in the nervous system and influence FAK activation by presently unknown mechanisms. The current investigation determined that CB₁-stimulated maximal FAK catalytic activity is mediated by Gi/o proteins in N18TG2 neuronal cells, and that G12/13 regulation of Rac1 and RhoA occurs concomitantly. Immunoblotting analyses using antibodies against FAK phospho-Tyr 397 and phospho-Tyr 576/577 demonstrated that the time-course of CB₁-stimulated FAK 576/577 Tyr-P occurred in three phases: Phase I (0-2 min) maximal Tyr-P, Phase II (5-20 min) rapid decline in Tyr-P, and Phase III (>20 min) plateau in Tyr-P at submaximal levels. In contrast, FAK 397 Tyr-P was monophasic and significantly lower in magnitude. FAK 397 Tyr-P and Phase I FAK 576/577 Tyr-P involved protein tyrosine phosphatase (PTP1B and Shp1/Shp2)-mediated Src activation, Protein Kinase A (PKA) inhibition, and integrin activation. Phase I maximal FAK 576/577 Tyr-P also required cooperative signaling between receptor tyrosine kinases (RTKs) and integrins. The integrin antagonist RGDS peptide, Flk-1 vascular endothelial growth factor receptor (VEGFR) antagonist SU5416, and epidermal growth factor receptor (EGFR) antagonist AG 1478 blocked Phase I FAK 576/577 Tyr-P. CB₁ agonists failed to stimulate FAK Tyr-P in the absence of integrin activation upon suspension in serum-free culture media. In contrast, cells grown on the integrin ligands fibronectin and laminin displayed increased FAK 576/577 Tyr-P that was augmented by CB₁ agonists and blocked by the Src inhibitor PP2 and Flk-1 VEGFR antagonist SU5416. Taken together, these studies have identified a complex integrative pathway utilized by CB₁ to stimulate maximal FAK 576/577 Tyr-P in neuronal cells. 23645090 Cytokine gene polymorphism and graft-versus-host disease: a survey in Iranian bone marrow transplanted patients. Graft versus host disease (GVHD) is a major complication of bone marrow transplantation (BMT). Numerous studies have shown the potential role of cytokine genotypes in the occurrence of GVHD. In this retrospective, case-control study we aimed to investigate the association between 13 cytokine genes and acute GVHD (aGVHD) after HLA-identical sibling BMT in 91 Iranian subjects. Negative association was found between aGVHD and donor IL-10/GCC haplotype or donor IL-4Ra-A allele in the population study. When compared within the leukemia subgroup, we observed positive association between recipient IL-1α -889/C allele and aGVHD. Also there were negative association between recipient IL-10/CAA haplotype and donor IL-4Ra/A allele and development of aGVHD. Among the different genotypes only donor IL-4Ra and donor IL-12 showed significant association. We conclude that several cytokine polymorphisms are positively and negatively associated with aGVHD in Iranian HLA matched siblings, of which IL-4Ra and IL-12 may play important roles. 23819577 A clinical study of serum lipid disturbance in Chinese patients with sudden deafness. Pathological levels of blood lipids could be one of the causes of sudden sensorineural hearing loss (SSNHL). The objective of this manuscript is therefore to evaluate the relationship between blood lipid content and sudden sensorineural hearing loss (SSNHL). The correlation between serum lipid parameters, including total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein AI (apo AI), apolipoprotein B (apo B), and lipoprotein A (Lp(a)), and the onset of SSNHL was analyzed from a data set of 250 patients and an age, gender and weight matched control group of 250 subjects. The result of single factor logistic regression shows that TC (p<0.01), LDL-C (p<0.01), and apo B (p=0.03) of SSNHL group were significantly higher than those of the control group. The odds ratio of TC, LDL, and apo B are higher than 1, while the confidence intervals of the odds rations do not include 1. No significant difference was found with the prevalence of hypertension (P=0.818), diabetes (P=0.869) and smoking habits (P=0.653) between SSNHL group and control group. Total cholesterol, low density lipoprotein cholesterol and apolipoprotein B concentrations may be important factors in the pathogenesis of sudden sensorineural hearing loss, and should be assessed during the investigation of patients with this condition. 23489335 Tissue-specific effector functions of innate lymphoid cells. Innate lymphoid cells (ILCs) is the collective term for a group of related innate lymphocytes, including natural killer (NK) cells and the more recently discovered non-NK ILCs, which all lack rearranged antigen receptors such as those expressed by T and B cells. Similar to NK cells, the newly discovered ILCs depend on the transcription factor Id2 and the common γ-chain of the interleukin-2 receptor for development. However, in contrast to NK cells, non-NK ILCs also require interleukin-7. In addition to the cytotoxic functions of NK cells, assuring protection against tumour development and viruses, new data indicate that ILCs contribute to a wide range of homeostatic and pathophysiological conditions in various organs via specialized cytokine production capabilities. Here we summarize current knowledge on ILCs with a particular emphasis on their tissue-specific effector functions, in the gut, liver, lungs and uterus. When possible, we try to highlight the role that these cells play in humans. 23703326 Evidence on antimicrobial properties and mode of action of a chitosan obtained from crustacean exoskeletons on Pseudomonas syringae pv. tomato DC3000. Pseudomonas syringae pv. tomato DC3000 (Pto DC3000) causes bacterial speck of tomato, a widely spread disease that causes significant economical losses worldwide. It is representative of many bacterial plant diseases for which effective controls are still needed. Despite the antimicrobial properties of chitosan has been previously described in phytopathogenic fungi, its action on bacteria is still poorly explored. In this work, we report that the chitosan isolated from shrimp exoskeletons (70 kDa and 78 % deacetylation degree) exerts cell damage on Pto DC3000. Chitosan inhibited Pto DC3000 bacterial growth depending on its concentration, medium-pH, and presence of metal ion (Mg(+2)). Biochemical and cellular changes resulting in cell aggregation and impaired bacterial growth were also viewed. In vivo studies using fluorescent probes showed cell aggregation, increase in membrane permeability, and cell death, suggesting the chitosan antibacterial activity is due to its interaction as a polycation with Pto DC3000 membranes. Transmission electron microscopic analysis revealed that chitosan also caused morphological changes and damage in bacterial surfaces. Also, the disease incidence in tomato inoculated with Pto DC3000 was significantly reduced in chitosan pretreated seedlings, revealing a promising action of chitosan as nontoxic biopesticide in tomato plants. Indeed, a wider comprehensive knowledge of the mechanism of action of chitosan in phytopathogenic bacterial cells will increase the chances of its successful application to the control of spread disease in plants. 23560877 Detection of Epstein-Barr virus-specific memory CD4+ T cells using a peptide-based cultured enzyme-linked immunospot assay. Approaches to evaluate T-cell responses to Epstein-Barr virus (EBV) include enzyme-linked immunospot (ELISPOT), which quantifies cells capable of immediate interferon-γ secretion upon antigen stimulation. However, evaluation of expandable EBV-specific memory T cells in an ELISPOT format has not been described previously. We quantified EBV-specific T-cell precursors with high proliferative capacity by using a peptide-based cultured interferon-γ ELISPOT assay. Standard and cultured ELISPOT responses to overlapping peptide pools (15-mers overlapping by 11 amino acids) covering the lytic (BZLF1 and BMRF1) and latent (EBNA1, EBNA3a, EBNA3b, EBNA3c, LMP1 and LMP2) EBV proteins were evaluated in 20 healthy subjects with remote EBV infection and, for comparison, in four solid organ transplant recipients. Cultured ELISPOT responses to both lytic and latent EBV antigens were significantly higher than standard ELISPOT responses. The distribution of EBV-specific T-cell responses detected in healthy virus carriers showed more consistent cultured ELISPOT responses compared with standard ELISPOT responses. T-cell responses quantified by cultured ELISPOT were mainly mediated by CD4+ T cells and a marked pattern of immunodominance to latent-phase antigens (EBNA1 > EBNA3 family antigens > LMP2 > LMP1) was shown. Both the magnitude and distribution of EBV-specific T-cell responses were altered in solid organ transplant recipients; in particular, cultured ELISPOT responses were almost undetectable in a lung-transplanted patient with EBV-associated diseases. Analysis of T-cell responses to EBV by ELISPOT assays might provide new insights into the pathogenesis of EBV-related diseases and serve as new tools in the monitoring of EBV infection in immunocompromised patients. 23892286 Architecturally diverse proteins converge on an analogous mechanism to inactivate Uracil-DNA glycosylase. Uracil-DNA glycosylase (UDG) compromises the replication strategies of diverse viruses from unrelated lineages. Virally encoded proteins therefore exist to limit, inhibit or target UDG activity for proteolysis. Viral proteins targeting UDG, such as the bacteriophage proteins ugi, and p56, and the HIV-1 protein Vpr, share no sequence similarity, and are not structurally homologous. Such diversity has hindered identification of known or expected UDG-inhibitory activities in other genomes. The structural basis for UDG inhibition by ugi is well characterized; yet, paradoxically, the structure of the unbound p56 protein is enigmatically unrevealing of its mechanism. To resolve this conundrum, we determined the structure of a p56 dimer bound to UDG. A helix from one of the subunits of p56 occupies the UDG DNA-binding cleft, whereas the dimer interface forms a hydrophobic box to trap a mechanistically important UDG residue. Surprisingly, these p56 inhibitory elements are unexpectedly analogous to features used by ugi despite profound architectural disparity. Contacts from B-DNA to UDG are mimicked by residues of the p56 helix, echoing the role of ugi's inhibitory beta strand. Using mutagenesis, we propose that DNA mimicry by p56 is a targeting and specificity mechanism supporting tight inhibition via hydrophobic sequestration. 23561070 Antioxidant capacity of anthocyanins from Rhodomyrtus tomentosa (Ait.) and identification of the major anthocyanins. The anthocyanins in the fruits of Rhodomyrtus tomentosa (ACN) were extracted by 1% TFA in methanol, and then purified by X-5 resin column and C18 (SPE) cartridges. The purified anthocyanin extract (ART) from the fruits of R. tomentosa showed strong antioxidant activities, including DPPH radical-scavenging capacity, ABTS radical scavenging capacity, reducing power and oxygen radical absorbance capacity (ORAC). The purified anthocyanin extract was analyzed by high performance liquid chromatography (HPLC). The major anthocyanins were purified by semi-preparative HPLC and Sephadex LH-20 column chromatography, and were identified as cyanidin-3-O-glucoside, peonidin-3-O-glucoside, malvidin-3-O-glucoside, petunidin-3-O-glucoside, delphinidin-3-O-glucoside and pelargonidin-3-glucoside by HPLC-ESI/MS and nuclear magnetic resonance spectroscopy (NMR). Cyanidin-3-O-glucoside was considered as the most abundant anthocyanin, which was 29.4mg/100g dry weight of R. tomentosa fruits. Additionally, all the major anthocyanins were identified from R. tomentosa fruit for the first time. 23612362 Polysaccharide extraction from Malva sylvestris and its anti-oxidant activity. The effects of extraction temperature, extraction time, the ratio of water to raw material, and number of extraction on extraction yield of crude polysaccharides from the leaves of Malva sylvestris (MSLCP) were optimized by statistical analysis using response surface methodology. The response surface methodology (RSM) was used to optimize MSLCP extraction yield by implementing the CCD design. The experimental data obtained were fitted to a second-order polynomial equation using multiple regression analysis and also analyzed by appropriate statistical methods (ANOVA). Statistical analysis of the results showed that the linear and quadratic terms of these four variables had significant effects. The optimal conditions for higher extraction yield of MSLCP were extraction temperature: 90°C, extraction time: 4h, number of extraction: 2 and the ratio of water to raw material: 21. Under these conditions, the experimental yield was 8.377±0.38%, which is well in close agreement with the value predicted by the model 8.608%. The results demonstrated that MSLCP had strong scavenging activities in vitro on DPPH and hydroxyl radicals. Overall, MSLCP may have potential applications in the medical and food industries. 23919729 The distinct expression patterns of claudin-2, -6, and -11 between human gastric neoplasms and adjacent non-neoplastic tissues. Cancers have a multifactorial etiology a part of which is genetic. Recent data indicate that expression of the tight junction claudin proteins is involved in the etiology and progression of cancer. To explore the correlations of the tight junction proteins claudin-2,-6, and -11 in the pathogenesis and clinical behavior of gastric cancer, 40 gastric cancer tissues and 28 samples of non-neoplastic tissues adjacent to the tumors were examined for expression of claudin-2,-6, and -11 by streptavidin-perosidase immunohistochemical staining method. The positive expression rates of claudin-2 in gastric cancer tissues and adjacent tissues were 25% and 68% respectively (P<0.001). The positive expression rates of claudin-6 in gastric cancer tissues and adjacent tissues were 55% and 79% respectively (P=0.045<0.05). In contrast, the positive expression rates of claudin-11 in gastric cancer tissues and gastric cancer adjacent tissues were 80% and 46% (P=0.004<0.01). Thus in our study, the expression of claudin-2, and claudin-6 was down regulated in gastric cancer tissue while the expression of claudin-11 was up regulated. Correlations between claudin expression and clinical behavior were not observed. Our study provides the first evidence that claudin-2,-6, and -11 protein expression varies between human gastric cancers and adjacent non-neoplastic tissues. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5470513569630744. 23929827 Predictors of Short-Term Outcome to Exercise and Manual Therapy for People With Hip Osteoarthritis. Physical therapy for hip osteoarthritis (OA) has shown short-term effects but limited long-term benefit. There has been limited research, with inconsistent results, in identifying prognostic factors associated with a positive response to physical therapy. To identify potential predictors of response to physical therapy (exercise therapy (ET) with or without adjunctive manual therapy (MT)) for hip OA based on baseline patient-specific and clinical characteristics. Prognostic study. Secondary analysis of data from a multicentre RCT (n=131) which evaluated the effectiveness of ET and ET+MT for hip OA was undertaken. Treatment response was defined using OMERACT/OARSI responder criteria. Ten baseline measures were used as predictor variables. Regression analyses were undertaken to identify predictors of outcome. Discriminative ability (sensitivity, specificity and likelihood ratios) of significant variables was calculated. The RCT results showed no significant difference in most outcomes between ET and ET+MT post-treatment (9 weeks) and 18 weeks. Forty-six patients were classified as responders at 9 weeks and 36 at 18 weeks. Four baseline variables were predictive of positive outcome at 9 weeks: male gender, pain with activity (<6/10), Western Ontario and McMaster University physical function (<34/68) and psychological health (Hospital Anxiety and Depression Scale <9/42). No predictor variables were identified for 18- week follow-up. Prognostic accuracy was fair for all four variables (sensitivity: 0.5-0.58; specificity: 0.57-0.72, likelihood ratios 1.25-1.77), indicating fair discriminative ability at predicting treatment response. We were unable to identify baseline variables in patients with hip OA that indicate those most likely to respond to treatment due to low discriminative ability. Further validation studies are required to definitively define the best predictors of response to physical therapy in hip OA. 23129213 Prediction of crizotinib-midazolam interaction using the Simcyp population-based simulator: comparison of CYP3A time-dependent inhibition between human liver microsomes versus hepatocytes. Crizotinib (Xalkori) is an orally available potent inhibitor of multiple tyrosine kinases, including anaplastic lymphoma kinase and mesenchymal-epithelial transition factor. Objectives of the present study were as follows: 1) to characterize crizotinib time-dependent inhibition (TDI) potency for CYP3A in human liver microsomes (HLM) and cryopreserved human hepatocytes suspended in human plasma (HSP); 2) to characterize crizotinib enzyme induction potency on CYP3A4 in cryopreserved human hepatocytes; 3) to predict crizotinib steady-state plasma concentrations in patients (e.g., autoinhibition and autoinduction) using the mechanistic dynamic model, Simcyp population-based simulator; and 4) to predict a clinical crizotinib-midazolam interaction using the dynamic model as well as the static mathematical model. Crizotinib inactivation constant (K(I)) and maximum inactivation rate constant (k(inact)) for TDI were estimated as, respectively, 0.37 µM and 6.9 h(-1) in HLM and 0.89 µM and 0.78 h(-1) in HSP. Thus, crizotinib inactivation efficiency (k(inact)/K(I)) was ∼20-fold lower in HSP relative to HLM. Crizotinib E(max) and EC(50) for CYP3A4 induction (measured as mRNA expression) were estimated as 6.4- to 29-fold and 0.47 to 3.1 µM, respectively. Based on these in vitro parameters, the predicted crizotinib steady-state area under plasma concentration-time curve (AUC) with HLM-TDI was 2.1-fold higher than the observed AUC, whereas that with HSP-TDI was consistent with the observed result (≤1.1-fold). The increase in midazolam AUC with coadministration of crizotinib (21-fold) was significantly overpredicted using HLM-TDI, whereas the prediction using HSP-TDI (3.6-fold) was consistent with the observed result (3.7-fold). Collectively, the present study demonstrated the value of HSP to predict in vivo CYP3A-mediated drug-drug interaction. 23751050 The required beta cell research for improving treatment of type 2 diabetes. In healthy individuals, insulin resistance is associated with physiological conditions such as pregnancy or body weight gain and triggers an increase in beta cell number and insulin secretion capacity to preserve normoglycaemia. Failure of this beta cell compensation capacity is a fundamental cause of diabetic hyperglycaemia. Incomplete understanding of the molecular mechanisms controlling the plasticity of adult beta cells mechanisms and how these cells fail during the pathogenesis of diabetes strongly limits the ability to develop new beta cell-specific therapies. Here, current knowledge of the signalling pathways controlling beta cell plasticity is reviewed, and possible directions for future research are discussed. 23765281 miR-200b and miR-429 function in mouse ovulation and are essential for female fertility. Ovulation in the mouse and other mammals is controlled by hormones secreted by the hypothalamo-pituitary-ovarian axis. We describe anovulation and infertility in female mice lacking the microRNAs miR-200b and miR-429. Both miRNAs are strongly expressed in the pituitary gland, where they suppress expression of the transcriptional repressor ZEB1. Eliminating these miRNAs, in turn, inhibits luteinizing hormone (LH) synthesis by repressing transcription of its β-subunit gene, which leads to lowered serum LH concentration, an impaired LH surge, and failure to ovulate. Our results reveal roles for miR-200b and miR-429, and their target the Zeb1 gene, in the regulation of mammalian reproduction. Thus, the hypothalamo-pituitary-ovarian axis was shown to require miR-200b and miR-429 to support ovulation. 23214953 Analysis of 15N-1H NMR relaxation in proteins by a combined experimental and molecular dynamics simulation approach: picosecond-nanosecond dynamics of the Rho GTPase binding domain of plexin-B1 in the dimeric state indicates allosteric pathways. We investigate picosecond–nanosecond dynamics of the Rho-GTPase Binding Domain (RBD) of plexin-B1, which plays a key role in plexin-mediated cell signaling. Backbone 15N relaxation data of the dimeric RBD are analyzed with the model-free (MF) method, and with the slowly relaxing local structure/molecular dynamics (SRLS-MD) approach. Independent analysis of the MD trajectories, based on the MF paradigm, is also carried out. MF is a widely popular and simple method, SRLS is a general approach, and SRLS-MD is an integrated approach we developed recently. Corresponding parameters from the RBD dimer, a previously studied RBD monomer mutant, and the previously studied complex of the latter with the GTPase Rac1, are compared. The L2, L3, and L4 loops of the plexin-B1 RBD are involved in interactions with other plexin domains, GTPase binding, and RBD dimerization, respectively. Peptide groups in the loops of both the monomeric and dimeric RBD are found to experience weak and moderately asymmetric local ordering centered approximately at the C(i–1)(α)–C(i)(α) axes, and nanosecond backbone motion. Peptide groups in the α-helices and the β-strands of the dimer (the β-strands of the monomer) experience strong and highly asymmetric local ordering centered approximately at the C(i–1)(α)–C(i)(α) axes (N–H bonds). N–H fluctuations occur on the picosecond time scale. An allosteric pathway for GTPase binding, providing new insights into plexin function, is delineated. 23927056 Radiographic and safety details of vertebral body stenting: results from a multicenter chart review. Up to one third of BKP treated cases shows no appreciable height restoration due to loss of both restored height and kyphotic realignment after balloon deflation. This shortcoming has called for an improved method that maintains the height and realignment reached by the fully inflated balloon until stabilization of the vertebral body by PMMA-based cementation. Restoration of the physiological vertebral body height for pain relief and for preventing further fractures of adjacent and distant vertebral bodies must be the main aim for such a method. A new vertebral body stenting system (VBS) stabilizes the vertebral body after balloon deflation until cementation. The radiographic and safety results of the first 100 cases where VBS was applied are presented. During the planning phase of an ongoing international multicenter RCT, radiographic, procedural and followup details were retrospectively transcribed from charts and xrays for developing and testing the case report forms. Radiographs were centrally assessed at the institution of the first/senior author. 100 patients (62 with osteoporosis) with a total of 103 fractured vertebral bodies were treated with the VBS system. 49 were females with a mean age of 73.2 years; males were 66.7 years old. The mean preoperative anterior-middle-posterior heights were 20.3-17.6-28.0 mm, respectively. The mean local kyphotic angle was 13.1[degree sign]. The mean preoperative Beck Index (anterior edge height/posterior edge height) was 0.73, the mean alternative Beck Index (middle height/posterior edge height) was 0.63. The mean postoperative heights were restored to 24.5-24.6-30.4 mm, respectively. The mean local kyphotic angle was reduced to 8.9[degree sign]. The mean postoperative Beck Index was 0.81, the mean alternative one was 0.82. The overall extrusion rate was 29.1%, the symptomatic one was 1%. In the osteoporosis subgroup there were 23.8% extrusions. Within the three months followup interval there were 9% of adjacent and 4% of remote new fractures, all in the osteoporotic group. VBS showed its strengths especially in realignment of crush and biconcave fractures. Given that fracture mobility is present, the realignment potential is sound and increases with the severity of preoperative vertebral body deformation. 23540839 Small Molecule Regulation of Protein Conformation by Binding in the Flap of HIV Protease. The fragment indole-6-carboxylic acid (1F1), previously identified as a flap site binder in a fragment-based screen against HIV protease (PR), has been cocrystallized with pepstatin-inhibited PR and with apo-PR. Another fragment, 3-indolepropionic acid (1F1-N), predicted by AutoDock calculations and confirmed in a novel inhibition of nucleation crystallization assay, exploits the same interactions in the flap site in two crystal structures. Both 1F1 and 1F1-N bind to the closed form of apo-PR and to pepstatin:PR. In solution, 1F1 and 1F1-N raise the Tm of apo-PR by 3.5-5 °C as assayed by differential scanning fluorimetry (DSF) and show equivalent low-micromolar binding constants to both apo-PR and pepstatin:PR, assayed by backscattering interferometry (BSI). The observed signal intensities in BSI are greater for each fragment upon binding to apo-PR than to pepstatin-bound PR, consistent with greater conformational change in the former binding event. Together, these data indicate that fragment binding in the flap site favors a closed conformation of HIV PR. 23017394 A novel one-step microbial transformation of betulin to betulinic acid catalysed by Cunninghamella blakesleeana. Betulinic acid and its derivatives are potential bioactive compounds present in nature. This study investigated the biotransformation of betulin to betulinic acid by Cunninghamella blakesleeana cells. LC-MS analysis demonstrated that betulin could be transformed into at least five products from cultured C. blakesleeana cells, among which betulinic acid was the most important. The presented method provides an attractive alternative approach to chemical synthesis, because is less time-consuming and more environmentally friendly. C. blakesleeana can transform betulin into potent derivatives with high pharmacological activities. 23584849 Long-term side effects of treatment with mTOR inhibitors in children after renal transplantation. mTOR inhibitors (mTORI) have emerged as alternative and additive immunosuppressive agents in pediatric renal transplantation (pRTx). Their immunosuppressive, anti-proliferative, and anti-neoplastic mechanisms have been described to be effective, whereas some side effects are alarming. In particular, growth and pubertal development are of concern. The aim of this study was to look for long-term side effects of mTORI therapy in pRTx. The retrospective analysis focused on side effects, growth, and pubertal development under mTORI therapy in 31 children. Eighteen children were routinely monitored for estradiol, testosterone, LH, and FSH levels. The occurrence of bacterial infections, lymphoceles, myelosuppression, and the course of overall linear growth was comparable with other pediatric renal transplant cohorts. According to the clinical puberty status, all but one patient showed normal age-related development in parallel to normal serum hormone levels. Only one patient experienced cytomegaly virus infection under mTORI, no post-transplant lymphoproliferative disorders (PTLD) occurred. Long-term mTORI therapy is safe in pRTx. No negative impact on growth and pubertal development was observed. 23685153 Potential roles of adenosine deaminase-2 in diabetic retinopathy. The early activation of microglia that induces retinal inflammation in DR may serve as a target for therapeutic intervention of DR. Our demonstration that retinal inflammation is attenuated via adenosine receptor A(2A)AR supports the hypothesis that a mechanism to maintain extracellular concentrations of adenosine important in normal physiology is impaired in DR. Extracellular concentrations of adenosine are regulated by the interplay of equiliberative nucleoside transporter (ENT)s with enzymes of adenosine metabolism including adenosine deaminase-1 (ADA1), adenosine kinase (AK) and CD73. In the vertebrates but not rodents, a macrophage-associated ADA2 is identified. The role of ADA2 is, therefore, understudied as the sequencing probes or antibodies to mouse ADA2 are not available. We identified increased ADA2 expression and activity in human and porcine retinas with diabetes, and in Amadori glycated albumin (AGA)- or hyperglycemia-treated porcine and human microglia. In rodent as well as porcine cells, modulation of TNF-α release is mediated by A(2A)AR. Quantitative analysis of normal and diabetic porcine retinas reveals that while the expression levels of ADA2, A2AAR, ENT1, TNF-α and MMP9 are increased, the levels of AK are reduced during inflammation as an endogenous protective mechanism. To determine the role of ADA2, we found that AGA induces ADA2 expression, ADA2 activity and TNF-α release, and that TNF-α release is blocked by ADA2-neutralizing antibody or ADA2 siRNA, but not by scrambled siRNA. These results suggest that retinal inflammation in DR is mediated by ADA2, and that the anti-inflammatory activity of A(2A)AR signaling is impaired in diabetes due to increased ADA2 activity. 23924239 Structural Analyses of Experimental (13)C Edited Amide I' IR and VCD for Peptide β-Sheet Aggregates and Fibrils Using DFT-Based Spectral Simulations. In the preceding paper, computational models based on density functional theory (DFT) were presented to characterize the sensitivity of vibrational spectroscopic methods (IR, VCD, and Raman) to structural features of β-sheets. Isotopically edited amide I' IR for peptides labeled with (13)C in multiple different sites provides the most structurally distinct signatures of strand alignment, while VCD is sensitive to the sheet twist and intersheet stacking. In this report, we simulate the IR and VCD spectra for models approximating structures of four β-sheet forming peptides previously experimentally studied using these methods with (13)C isotopic editing. Various register alignments are tested. Agreement with experiment is evaluated based on frequency shifts of both the (12)C and (13)C IR amide I' signals, relative intensity patterns, and VCD spectra where available. While for the simulation of IR spectra canonical planar sheets provide a sufficient model system, for VCD simulation twisted, stacked sheets are required in order to reproduce strong couplet-like amide I' VCD. Effects of the solvent (water) and amino acid side chains are also tested by using a simplified, electrostatic solvent model and atomic partial charges for the side chains. Very good agreement with experimental spectra is obtained, particularly for the relative (12)C and (13)C band frequencies. All four peptide models are shown to be antiparallel as had previously been assumed. However, in some cases our simulations are consistent with different register alignment of strands than originally proposed. 23895198 Bone marrow-derived mesenchymal stem cells become anti-angiogenic when chondrogenically or osteogenically differentiated: Implications for bone and cartilage tissue engineering. Osteochondral tissue repair requires formation of vascularised bone and avascular cartilage. Mesenchymal stem cells stimulate angiogenesis both in vitro and in vivo but it is not known if these pro-angiogenic properties change as a result of chondrogenic or osteogenic differentiation. We investigated the angiogenic/anti-angiogenic properties of equine bone marrow-derived mesenchymal stem cells (eBMSCs) before and after differentiation in vitro. Conditioned media from chondrogenic and osteogenic cell pellets and undifferentiated cells was applied to endothelial tube formation assays using Matrigel™. Additionally, the cell secretome was analysed using LC-MS/MS mass spectrometry and screened for angiogenesis and neurogenesis-related factors using protein arrays. Endothelial tube-like formation was supported by conditioned media from undifferentiated eBMSCs. Conversely, chondrogenic and osteogenic conditioned media was anti-angiogenic as shown by significantly decreased length of endothelial tube-like structures and degree of branching compared to controls. Undifferentiated cells produced higher levels of angiogenesis-related proteins compared to chondrogenic and osteogenic pellets. In summary, eBMSCs produce an array of angiogenesis-related proteins and support angiogenesis in vitro via a paracrine mechanism. However, when these cells are differentiated chondrogenically or osteogenically, they produce a soluble factor(s) that inhibits angiogenesis. With respect to osteochondral tissue engineering, this may be beneficial for avascular articular cartilage formation but unfavourable for bone formation where a vascularised tissue is desired. 23944844 3D Motion of DNA-Au Nanoconjugates in Graphene Liquid Cell Electron Microscopy. Liquid-phase transmission electron microscopy (TEM) can probe and visualize dynamic events with structural or functional details at the nanoscale in a liquid medium. Earlier efforts have focused on the growth and transformation kinetics of hard material systems, relying on their stability under electron beam. Our recently developed graphene liquid cell technique pushed the spatial resolution of such imaging to the atomic scale but still focused on growth trajectories of metallic nanocrystals. Here, we adopt this technique to imaging three-dimensional (3D) dynamics of soft materials instead, double strand (dsDNA) connecting Au nanocrystals as one example, at nanometer resolution. We demonstrate first that a graphene liquid cell can seal an aqueous sample solution of a lower vapor pressure than previously investigated well against the high vacuum in TEM. Then, from quantitative analysis of real time nanocrystal trajectories, we show that the status and configuration of dsDNA dictate the motions of linked nanocrystals throughout the imaging time of minutes. This sustained connecting ability of dsDNA enables this unprecedented continuous imaging of its dynamics via TEM. Furthermore, the inert graphene surface minimizes sample-substrate interaction and allows the whole nanostructure to rotate freely in the liquid environment; we thus develop and implement the reconstruction of 3D configuration and motions of the nanostructure from the series of 2D projected TEM images captured while it rotates. In addition to further proving the nanoconjugate structural stability, this reconstruction demonstrates 3D dynamic imaging by TEM beyond its conventional use in seeing a flattened and dry sample. Altogether, we foresee the new and exciting use of graphene liquid cell TEM in imaging 3D biomolecular transformations or interaction dynamics at nanometer resolution. 23928404 Adipose Tissue and Liver Expression of SIRT1, 3 and 6 Increase after Extensive Weight Loss in Morbid Obesity. Severe obesity is associated with a state of chronic inflammation. Sirtuins (SIRT) are a family of conserved enzymes which are able to affect many metabolic and inflammatory pathways thereby potentially improving health and increasing lifespan. We investigated the effect of weight loss on subcutaneous adipose tissue and liver mRNA and immunohistochemical expression of SIRT1, SIRT3 and SIRT6. Twenty-nine severely obese patients undergoing laparoscopic adjustable gastric banding (LAGB) were studied. Tissue samples were collected before and 6 months after LAGB surgery. Tissue mRNA expression levels of SIRT1, SIRT3 and SIRT6 were correlated with clinical, biochemical, and histological parameters. In vitro, we studied sirtuin expression in native and stimulated monocytes, adipocytes and hepatocytes. SIRT1, SIRT3 and SIRT6 mRNA expressions were higher in subcutaneous adipose tissue than in liver. Weight loss resulted in a significant induction of SIRT1, SIRT3 and SIRT6 expression in the subcutaneous adipose tissue. In the liver a significant increase after weight loss was observed, particularly for SIRT3 and SIRT6 mRNA expression; immunohistochemically SIRT1 and SIRT3 expression were up-regulated. Endotoxin and tumor necrosis factor-alpha suppressed SIRT1, SIRT3 and SIRT6 expressions in human monocytes. The same stimuli suppressed total sirtuin deacetylase activity again mainly in monocytes and less in adipocytes and hepatocytes. The relative abundance of adipose tissue mRNA expression of certain sirtuins exceeds its expression in the liver. Extensive weight loss increases sirtuin expression significantly both in adipose tissue and liver, probably as a consequence of reduced inflammation. (244 words). 23899524 Synergistic activation of lipopolysaccharide-stimulated glial cells by propofol. Despite the extensive use of propofol in general anesthetic procedures, the effects of propofol on glial cell were not completely understood. In lipopolysaccharide (LPS)-stimulated rat primary astrocytes and BV2 microglial cell lines, co-treatment of propofol synergistically induced inflammatory activation as evidenced by the increased production of NO, ROS and expression of iNOS, MMP-9 and several cytokines. Propofol augmented the activation of JNK and p38 MAPKs induced by LPS and the synergistic activation of glial cells by propofol was prevented by pretreatment of JNK and p38 inhibitors. When we treated BV2 cell culture supernatants treated with LPS plus propofol on cultured rat primary neuron, it induced a significant neuronal cell death. The results suggest that the repeated use of propofol in immunologically challenged situation may induce glial activation in brain. 23896389 Role of the intrinsic apoptotic pathway in cataractogenesis in type 2 diabetic patients. To determine and compare the expression of caspase-3 and caspase-9 in human lens epithelial cells of cataract patients with and without diabetic retinopathy (DR). St. Mary's Hospital, Catholic University of Korea, Seoul, South Korea. Randomized prospective study. Patients were classified into 3 groups as follows: patients without diabetes mellitus (DM) (Group 1), patients with DM but without DR (Group 2), and patients with DM and DR (Group 3). An anterior capsulotomy specimen was obtained from each patient during cataract surgery, and immunohistochemical staining was performed for caspase-3 and caspase-9. The results were observed using confocal microscopy and were analyzed by reactivity scoring. The duration of DM and the hemoglobin A1c (HbA1c) levels were recorded. The study evaluated 60 patients. The level of caspase-3 and caspase-9 expression was highest in Group 3 followed by Group 2 and Group 1 (both P < .00). Expression of caspase-3 and caspase-9 was higher with a longer duration of DM and with higher HbA1c levels. The intrinsic apoptotic pathway may be associated with diabetic cataract in patients with type 2 DM. No author has a financial or proprietary interest in any material or method mentioned. 23845764 Wear Analysis of 39 Conserve Plus Metal-on-Metal Hip Resurfacing Retrievals. There have been increasing concerns regarding adverse local tissue reactions (ALTR) following metal-on-metal (MOM) hip arthroplasties. This study examined wear rates in retrievals of one design of MOM resurfacing arthroplasty, and assessed the differences in wear between those with and without ALTR. Wear measurements were made on 39 MOM resurfacing components (30 femoral, 9 acetabular) which were at least 2years in vivo. Seven hips (6 patients; 4 acetabular components, 7 femoral components) were identified to have ALTR. Acetabular component abduction and anteversion angles were determined using EBRA, and the contact-patch-to-rim (CPR) distance was calculated. The ALTR group had higher linear femoral and acetabular wear rates, acetabular anteversion and abduction angles, lower CPR, and longer time to revision. Given the increased risk for ALTR associated with acetabular component malpositioning, patients with malpositioned acetabular components may require closer clinical follow-up and monitoring. 23725320 Colonisation by Faecalibacterium prausnitzii and maintenance of clinical remission in patients with ulcerative colitis. Although incrimination of the intestinal microbiota in the pathogenesis of IBD is widely accepted, few data are available about the role of specific bacteria. Potentially, Faecalibacterium prausnitzii, bacteria with anti-inflammatory properties, might be deficient in ulcerative colitis (UC). To quantify F. prausnitzii in the faecal microbiota of UC patients in remission and determine its relationship with relapse. A cross-sectional study included 116 UC patients in remission, 29 first-degree relatives and 31 healthy controls. A subset of eighteen patients, recruited during the first month of remission, underwent a 1-year follow-up. Total bacteria and F. prausnitzii were measured by quantitative Real Time PCR (qPCR, copies/g). Calprotectin was determined as inflammatory index (μg/g). We found that F. prausnitzii was reduced in patients (median, IQR: 1.4 × 10⁸ , 5.1 × 10⁷-4.5 × 10⁸) and relatives (1.7 × 10⁸, 9.3 × 10⁷-5.1 × 10⁸) vs. controls (6.5 × 10⁸, 3.7 × 10⁸-1.6 × 10⁹, P < 0.0001). Moreover, low counts of F. prausnitzii were associated with less than 12 months of remission (8.0 × 10⁷, 2.0 × 10⁷-3.5 × 10⁸ vs. 2.1 × 10⁸, 1.0 × 10⁸-7.9 × 10⁸, P < 0.001) and more than 1 relapse/year (8.0 × 10⁷, 3.2 × 10⁷-3.8 × 10⁸ vs. 1.9 × 10⁸, 6.8 × 10⁷-6.0 × 10⁸, P < 0.01). When patients were followed up, F. prausnitzii increased steadily until reaching similar levels to those of controls if remission persisted (2.9 × 10⁸, 9.3 × 10⁶-1.2 × 10⁹; calprotectin: 76, 19-212), whereas it remained low if patients relapsed (2.2 × 10⁸, 1.4 × 10⁶-3.3 × 10⁸; calprotectin: 1760, 844-3662 P < 0.05 vs. controls). Defective gut colonisation by F. prausnitzii occurred in UC patients during remission and in their unaffected relatives. The recovery of the F. prausnitzii population after relapse is associated with maintenance of clinical remission. 23941670 Targeting 2.5 versus 4 g/kg/day of Amino Acids for Extremely Low Birth Weight Infants: A Randomized Clinical Trial. To compare the effect of 2.5 vs 4 g/kg/d of amino acid (AA) in parenteral nutrition of extremely low birth weight infants on metabolic tolerance, short-term growth, and neurodevelopment. One hundred thirty-one infants with birth weight between 500 and 1249 g were randomized to 2.5 (standard AA [SAA] group) or 4 (high AA [HAA] group) g/kg/d AA intake, with equal nonprotein energy. The primary outcome was body size at 36 weeks. One hundred thirty-one patients were randomized and 114 analyzed (58 SAA group and 56 HAA group). Study groups had similar demographics and clinical characteristics. Elevated blood urea (BU >70 mg/dL = BU nitrogen >32.6 mg/dL) occurred in 24% vs 59% (P = .000) and hyperglycemia (>175 mg/dL) in 34% vs 11% (P = .003) of the SAA and HAA patients, respectively. Body weight, length, and head circumference at 36 weeks and 2 years were similar between groups. Bayley Scales of Infant and Toddler Development, Third Edition score was 94 ± 13 in the SAA group and 97 ± 15 in the HAA group (P = .35). The HAA group had higher BU levels and better glucose control. An extra 8 g/kg of AA over the first 10 days of life did not improve growth and neurodevelopment. 22926699 An overview of transcriptional regulation in response to toxicological insult. The completion of the human genome project and the subsequent advent of DNA microarray and high-throughput sequencing technologies have led to a renaissance in molecular toxicology. Toxicogenomic data sets, from both in vivo and in vitro studies, are growing exponentially, providing a wealth of information on regulation of stress pathways at the transcriptome level. Through such studies, we are now beginning to appreciate the diversity and complexity of biological responses to xenobiotics. In this review, we aim to consolidate and summarise the major toxicologically relevant transcription factor-governed molecular pathways. It is becoming clear that different chemical entities can cause oxidative, genotoxic and proteotoxic stress, which induce cellular responses in an effort to restore homoeostasis. Primary among the response pathways involved are NFE2L2 (Nrf2), NFE2L1 (Nrf1), p53, heat shock factor and the unfolded protein response. Additionally, more specific mechanisms exist where xenobiotics act as ligands, including the aryl hydrocarbon receptor, metal-responsive transcription factor-1 and the nuclear receptor family of transcription factors. Other pathways including the immunomodulatory transcription factors NF-κB and STAT together with the hypoxia-inducible transcription factor HIF are also implicated in cellular responses to xenobiotic exposure. A less specific but equally important aspect to cellular injury controlled by transcriptional activity is loss of tissue-specific gene expression, resulting in dedifferentiation of target cells and compromise of tissue function. Here, we review these pathways and the genes they regulate in order to provide an overview of this growing field of molecular toxicology. 23880364 Evaluation of a new vaccination program for infants born to HBsAg-positive mothers in Stockholm County. To overcome previous shortcomings in the routines for prophylaxis to newborns of hepatitis B infected pregnant women, we established a new program in 2005. This program combined monovalent hepatitis B vaccine at birth and at one month with three doses of hexavalent vaccine, including a hepatitis B vaccine component, at 3, 5 and 12 months, respectively. The hexavalent vaccine and follow-up serologies were administered at the well baby clinics. Three hundred and eighty babies born to 356 HBsAg positive mothers (9% HBeAg positive), were evaluated. Twenty-two children were lost to follow-up, 329 of the remaining 358 children (92%) completed follow-up serology at ages 13-18 months, with protective anti-HBs levels in 99%. For comparison, in a previous cohort from 2000 to 2001, only 63% completed follow-up serology. We conclude that the adherence to the new program was good and that it resulted in a very high rate of protective antibody levels. 23846546 Daikenchuto, a traditional Japanese herbal medicine, ameliorates postoperative ileus by anti-inflammatory action through nicotinic acetylcholine receptors. Daikenchuto (DKT), a gastrointestinal prokinetic Japanese herbal medicine, is prescribed for patients with postoperative ileus (POI) and adhesive bowel obstruction following abdominal surgery. Several mechanisms for the amelioration of POI by DKT have been suggested; however, it has remained unclear whether DKT shows anti-inflammatory effects in POI. In the present study, we investigated the effects of DKT in a mouse POI model and attempted to clarify the detailed mechanisms of action. Intestinal manipulation (IM) was applied to the distal ileum of mice. DKT was administered orally to the animals 4 times before and after IM. Gastrointestinal transit in vivo, leukocyte infiltration, cytokine mRNA expression and gastrointestinal motility were analyzed. We also investigated the effects of the α7nAChR antagonist methyllycaconitine citrate (MLA) on the DKT-mediated ameliorative action against POI, and we studied the effects of DKT on inflammatory activity in α7nAChR knockout mice. DKT treatment led to recovery of the delayed intestinal transit induced by IM. DKT significantly inhibited the infiltration of neutrophils and CD68-positive macrophages, and inhibited mRNA expressions of TNF-α and MCP-1. MLA significantly reduced the anti-inflammatory action of DKT, and the amelioration of macrophage infiltration by DKT was partially suppressed in α7nAChR knockout mice. In conclusion, in addition to the gastrointestinal prokinetic action, DKT serves as a novel therapeutic agent for POI characterized by its anti-inflammatory potency. The DKT-induced anti-inflammatory activity may be partly mediated by activation of α7nAChR. 23790417 Cloning, expression, and purification of the hemolysin/cytolysin (HlyE antigen) from Salmonella enterica serovar Typhi: potential application for immunoassay development. The hemolysin (HlyE) protein of Salmonella enterica serovar Typhi was reported to be antigenic. This work describes the cloning, expression, and purification of a hexahistidine-tagged HlyE protein under native conditions. Immunoblot analysis and a competitive enzyme-linked immunosorbent assay using sera from typhoid patients showed the presence of HlyE-specific antibodies in circulation. 23604020 Two types of muscarinic acetylcholine receptors in Drosophila and other arthropods. Muscarinic acetylcholine receptors (mAChRs) play a central role in the mammalian nervous system. These receptors are G protein-coupled receptors (GPCRs), which are activated by the agonists acetylcholine and muscarine, and blocked by a variety of antagonists. Mammals have five mAChRs (m1-m5). In this study, we cloned two structurally related GPCRs from the fruit fly Drosophila melanogaster, which, after expression in Chinese hamster ovary cells, proved to be muscarinic acetylcholine receptors. One mAChR (the A-type; encoded by gene CG4356) is activated by acetylcholine (EC50, 5 Ã— 10(-8) M) and muscarine (EC50, 6 Ã— 10(-8) M) and blocked by the classical mAChR antagonists atropine, scopolamine, and 3-quinuclidinyl-benzilate (QNB), while the other (the B-type; encoded by gene CG7918) is also activated by acetylcholine, but has a 1,000-fold lower sensitivity to muscarine, and is not blocked by the antagonists. A- and B-type mAChRs were also cloned and functionally characterized from the red flour beetle Tribolium castaneum. Recently, Haga et al. (Nature 2012, 482: 547-551) published the crystal structure of the human m2 mAChR, revealing 14 amino acid residues forming the binding pocket for QNB. These residues are identical between the human m2 and the D. melanogaster and T. castaneum A-type mAChRs, while many of them are different between the human m2 and the B-type receptors. Using bioinformatics, one orthologue of the A-type and one of the B-type mAChRs could also be found in all other arthropods with a sequenced genome. Protostomes, such as arthropods, and deuterostomes, such as mammals and other vertebrates, belong to two evolutionarily distinct lineages of animal evolution that split about 700 million years ago. We found that animals that originated before this split, such as cnidarians (Hydra), had two A-type mAChRs. From these data we propose a model for the evolution of mAChRs. 23737041 Iterative cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for recurrent peritoneal metastases. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) achieves disease control within the peritoneum but recurrences occur. This study examines the outcomes of iterative CRS (iCRS) HIPEC for treatment of recurrent peritoneal metastases. Patients who underwent iCRS in a single tertiary referral center were identified from a prospective database. Safety analysis was performed and clinicopathological variables were analyzed to assess factors predictive of major morbidity and survival. The demographics of patients who underwent primary cytoreductive surgery (pCRS) (n = 466) and iCRS (n = 79) were balanced between groups. pCRS was shown to require more blood transfusion (P = 0.019) and albumin use (P = 0.013). The mortality and major complication rates were comparable (1.2% vs. 0%; P = 0.600, and 42% vs. 41%; P = 0.806). Residual pneumothorax occurred more frequently after pCRS (12% vs. 4%; P = 0.030). Factors associated with major complications after iCRS include use of HIPEC (P = 0.042) and length of hospital stay (P = 0.024). The overall median survival was 48 months and 5-year survival was 34%. By cancer type, the 3-year survival was 0%, 74%, 80%, and 72% for colorectal, appendiceal pseudomyxoma, peritoneal mesothelioma, and appendix cancer, respectively. Independent predictors of survival include age (P = 0.049), interval between pCRS and iCRS (P = 0.008), small bowel resection (P < 0.001), and use of HIPEC (P = 0.005). Iterative CRS achieved further peritoneal disease control without adverse effects on morbidity. Patients with appendiceal tumors and peritoneal mesothelioma appear to benefit most after iCRS. Intraoperative HIPEC remains important in the repetoire of managing these patients. J. Surg. Oncol. 2013; 108:81-88 © 2013 Wiley Periodicals, Inc. 23822836 Neopierisoids A and B, Two New Chlorinated 3,4-seco-Grayanane Diterpenoids with Antifeedant Activity from Flowers of Pieris japonica. Two new chlorinated multiacylated 3,4-seco-grayanane diterpenoids, neopierisoids A and B (1 and 2), were isolated from flowers of the poisonous plant Pieris japonica and were identified from spectroscopic analysis and X-ray diffraction data. Both compounds showed obvious antifeedant activity against Pieris brassicae with an EC50 of 10.07 μg/cm(2) for 1 and 5.33 μg/cm(2) for 2, indications of toxic properties. Chlorinated 3,4-seco-grayanane diterpenoids in P. japonica may play a defensive role against herbivores. 23411243 Investigation of the effect of gelatine, egg albumin and cross-flow microfiltration on the phenolic composition of Pinotage wine. The effect of fining and cross-flow microfiltration on the phenolic composition of red wine was investigated. Both gelatine (G) and egg albumin (EA) fining decreased the mean degree of polymerisation (mDP) of tannin significantly by 26.4% and 25.2%, respectively, compared to the control (C). Cross-flow microfiltration (CF) also decreased the mDP significantly by 25%. Thus, the fining agents and cross-flow microfiltration selectively removed the highly polymerised phenols. After 3.5 months of bottle ageing, differences between the different treatments and the control decreased. CF had the most significant effect on the flavan-3-ol and polymeric phenol (tannin) content of the wines compared to the control followed by G fining. CF and EA treatments significantly decreased the total pigment content compared to C. CF was also the only treatment that could be distinguished from the other treatments by sensory analysis. All treatments improved clarity of the wines with cross-flow microfiltration having the largest effect. 23774780 Influence of temperature and regeneration cycles on Hg capture and efficiency by structured Au/C regenerable sorbents. The objective of this work is to evaluate a novel regenerable sorbent for mercury capture based on gold nanoparticles supported on a honeycomb structured carbon monolith. A new methodology for gold nanoparticles deposition onto carbon monolith support has been developed to obtain an Au sorbent based on the direct reduction of a gold salt onto the carbon material. For comparison purposes, colloidal gold method was also used to obtain Au/C sorbents. Both types of sorbents were characterized by different techniques in order to obtain the bulk gold content, the particle size distribution and the chemical states of gold after deposition. The mercury capture capacity and mercury capture efficiency of sorbents were tested in a bench scale facility at different experimental conditions. The regenerability of the sorbents was tested along several cycles of Hg capture-regeneration. High retention efficiencies are found for both types of sorbents comparing their gold content. Moreover, the high retention efficiency is maintained along several cycles of Hg capture-regeneration. The study of the fresh sorbent, the sorbent after Hg exposition and after regeneration by XPS and XRD gives insight to explain those results. 23950814 Correction: Influenza Vaccination in Adults with Chronic Obstructive Pulmonary Disease: The Impact of a Diagnostic Breathing Test on Vaccination Rates. [This corrects the article on p. e67600 in vol. 8.]. 22360946 A Poiseuille-based coronary angiographic index for prediction of fractional flow reserve. Coronary revascularization is commonly based on the angiographic finding of percent diameter stenosis (%DS) >50 while lesion length (LL), which contributes to flow-limitation according to Poiseuille's equation, is disregarded. Fractional flow reserve (FFR) is superior to assessment of %DS for identifying flow-limiting lesions, but the technology is invasive and relatively expensive. We developed a Poiseuille-based angiographic index, incorporating both minimal lumen diameter (MLD) and LL, for improved assessment of the hemodynamic significance of intermediate coronary lesions. The present study was designed to test the hypothesis that the Poiseuille-based angiographic index correlated better with FFR measurements than angiographic assessment of %DS. We performed quantitative coronary angiography (QCA) and FFR measurements in 46 intermediate coronary lesions in 41 symptomatic patients referred for diagnostic coronary angiography. From QCA we determined LL, MLD and %DS and calculated an angiographic index, the LL/MLD(4) ratio. Mean LL was 14.2±7.8 (range: 4.3-38.8) mm, MLD 1.4±0.4 (range: 0.6-2.3) mm, %DS 46±12 (range: 25-74) and FFR 0.85±0.09 (range: 0.55-1.00). Fractional flow reserve correlated inversely with %DS (R=-0.39, p=0.008) and with the LL/MLD(4) ratio (R=-0.66, p<0.0001). An FFR cut-off value of 0.80 corresponded with a LL/MLD(4) ratio of 12 (p=0.003) but not with a %DS of 50 (p=NS). A LL/MLD(4) ratio ≤12 had a specificity of 94% and negative predictive value of 82% for excluding hemodynamically significant lesions with FFR (≥0.80). The LL/MLD(4) ratio was superior to standard angiographic measurement of %DS for exclusion of hemodynamically significant coronary lesions. 23936202 Ergonomic status of laparoscopic urologic surgery: survey results from 241 urologic surgeons in china. The prolonged and frequent use of laparoscopic equipment raises ergonomic risks that may cause physical distress for surgeons. We aimed to assess the prevalence of urologic surgeons' physical distress associated with ergonomic problems in the operating room (OR) and their awareness of the ergonomic guidelines in China. A sample of 300 laparoscopic urologists in China was assessed using a questionnaire on demographic information, ergonomic issues in the OR, musculoskeletal symptoms, and awareness of the ergonomic guidelines for the OR. There were 241 survey respondents (86.7%) with valid questionnaires. Among the respondents, only 43.6% placed the operating table at pubic height during the actual operation. The majority of the respondents (63.5%) used only one monitor during the procedure. Only 29.9% placed the monitor below the eye level. More than half of the respondents (50.6%) preferred to use manual control instead of the foot pedal. Most of the respondents (95.0%) never used the body support. The respondents experienced discomfort in the following regions, in ascending order: leg (21.6%), hand (30.3%), wrist (32.8%), shoulder (33.6%), back (53.1%), and neck (58.1%). The respondents with over 250 total operations experienced less discomfort than those with less than 250 total operations. Most of the respondents (84.6%) were unaware of the ergonomic guidelines. However, almost all of the respondents (98.3%) regarded the ergonomic guidelines to be important in the OR. Most of the laparoscopic urologists were not aware of the ergonomic guidelines for the OR; hence, they have been suffering from varying degrees of physical discomfort caused by ergonomic issues. There is an urgent need for education regarding ergonomic guidelines in the OR for laparoscopic urologists in China. 23939427 Mechanisms of Lin28-Mediated miRNA and mRNA Regulation-A Structural and Functional Perspective. Lin28 is an essential RNA-binding protein that is ubiquitously expressed in embryonic stem cells. Its physiological function has been linked to the regulation of differentiation, development, and oncogenesis as well as glucose metabolism. Lin28 mediates these pleiotropic functions by inhibiting let-7 miRNA biogenesis and by modulating the translation of target mRNAs. Both activities strongly depend on Lin28's RNA-binding domains (RBDs), an N-terminal cold-shock domain (CSD) and a C-terminal Zn-knuckle domain (ZKD). Recent biochemical and structural studies revealed the mechanisms of how Lin28 controls let-7 biogenesis. Lin28 binds to the terminal loop of pri- and pre-let-7 miRNA and represses their processing by Drosha and Dicer. Several biochemical and structural studies showed that the specificity of this interaction is mainly mediated by the ZKD with a conserved GGAGA or GGAGA-like motif. Further RNA crosslinking and immunoprecipitation coupled to high-throughput sequencing (CLIP-seq) studies confirmed this binding motif and uncovered a large number of new mRNA binding sites. Here we review exciting recent progress in our understanding of how Lin28 binds structurally diverse RNAs and fulfills its pleiotropic functions. 23921697 Appendico-cutaneous fistula 20 years after groin hernia repair with a polypropylene plug. The formation of an appendico-cutaneous fistula is rare. Few case reports have been published; most describe the formation of a fistula after appendicitis. Here we describe the case of a 79-year-old woman presenting with an appendico-cutaneous fistula after groin hernia repair. She was referred to our outpatient department with a painful mass in the right groin. An ultrasound showed a fluid containing mass. Incision and drainage was performed. After 9 weeks she was referred again with a persisting open wound. Fistulogram and CT scan showed a fistuleous tract involving the appendix. Wound culture showed Escherichia coli. Diagnostic laparoscopy showed an appendix stuck to the ventral wall of the abdomen without any sign of previous infection. After an appendectomy, pathological investigation revealed an appendix sana. After operation, the fistula persisted due to a polypropylene plug from the previous groin hernia correction. The (infected) plug was removed and the fistula healed. 23900229 Efficient photoelectrochemical water oxidation over cobalt-phosphate (Co-Pi) catalyst modified BiVO4/1D-WO3 heterojunction electrodes. We report the design, synthesis and photoelectrochemical characterization of cobalt phosphate (Co-Pi) oxygen evolution catalyst modified heterojunction photoelectrodes consisting of one-dimensional WO3 nanorods (1D-WO3) and highly porous BiVO4 layers. The 1D-WO3 nanorods were prepared by the decomposition of the tetrabutylammonium decatungstate precursor in the presence of poly(ethylene glycol) as a binding agent. The porous BiVO4 layers were spray deposited using a surfactant assisted metal-organic decomposition method. The Co-Pi oxygen evolution catalyst was deposited onto the BiVO4/1D-WO3/FTO heterojunction electrode using a photoassisted electrodeposition method. The Co-Pi catalyst modified heterojunction electrodes exhibited a sustained enhancement in the photocurrent compared to the unmodified BiVO4/1D-WO3/FTO heterojunction electrodes. The improved photoelectrochemical properties profited from the enhanced charge carrier separation achieved through the integration of highly porous BiVO4 layers on top of 1D-WO3 nanorods and from the superior kinetics due to the presence of the Co-Pi oxygen evolution catalyst on top of BiVO4/1D-WO3/FTO heterojunction electrodes. 23624852 Ventral tegmental area α6β2 nicotinic acetylcholine receptors modulate phasic dopamine release in the nucleus accumbens core. RATIONALE: Phasic dopamine (DA) signaling underlies reward learning. Cholinergic and glutamatergic inputs into the ventral tegmental area (VTA) are crucial for modulating burst firing activity and subsequent phasic DA release in the nucleus accumbens (NAc), but the specific VTA nicotinic receptor subtypes that regulate phasic DA release have not been identified. OBJECTIVE: The goal was to determine the role of VTA N-methyl-D-aspartate receptors (NMDARs) and specific subtypes of nicotinic acetylcholine receptors (nAChRs) in regulating phasic DA release in the NAc core. METHODS: Fast-scan cyclic voltammetry in anesthetized rats was combined with intra-VTA micro-infusion to evaluate the ability of glutamatergic and cholinergic drugs to modulate stimulated phasic DA release in the NAc core. RESULTS: VTA NMDAR blockade with AP-5 decreased, while VTA NMDAR activation with NMDA increased NAc peak phasic DA release. Intra-VTA administration of the nonspecific nAChR antagonist mecamylamine produced a persistent decrease in phasic DA release. Infusion of the α6-selective antagonist α-conotoxin MII (α-ctx MII) produced a robust, but transient decrease in phasic DA, whereas infusion of selective doses of either the α4β2-selective antagonist, dihydro-beta-erythroidine, or the α7 antagonist, methyllycaconitine, had no effect. Co-infusion of AP-5 and α-ctx MII produced a similar phasic DA decrease as either drug alone, with no additive effect. CONCLUSIONS: The results suggest that VTA α6β2 nAChRs, but not α4β2 or α7 nAChRs, regulate phasic DA release in the NAc core and that VTA α6β2 nAChRs and NMDA receptors act at a common site or target to regulate NAc phasic DA signaling. 23965757 Outbreak of chikungunya virus infection, vanimo, papua new Guinea. In June 2012, health authorities in Papua New Guinea detected an increase in febrile illnesses in Vanimo. Chikungunya virus of the Eastern/Central/Southern African genotype harboring the E1:A226V mutation was identified. This ongoing outbreak has spread to ≥8 other provinces and has had a harmful effect on public health. 23194824 Chrysin suppresses renal carcinogenesis via amelioration of hyperproliferation, oxidative stress and inflammation: plausible role of NF-κB. Flavonoid family is a rich source of polyphenolic compounds and hence possess strong antioxidant and anti inflammatory properties. The aim of this study was to determine the efficacy of chrysin; a bio-active flavonoid as an anticancer agent. Renal cancer was initiated by single intraperitoneal (i.p.) injection of N-nitrosodiethylamine (DEN 200 mg/kg BW body weight) and promoted by twice weekly administration of ferric nitrilotriacetate (Fe-NTA) 9 mg Fe/kg BW for 16 wk. In the present study, we report the chemopreventive effects of chrysin against (Fe-NTA) induced renal oxidative stress, inflammation, hyperproliferative response, and two-stage renal carcinogenesis. To ascertain the molecular mechanism implicated in the antitumor promoting activity of chrysin, its effect was investigated on markers of tumor promotion and inflammation: ornithine decarboxylase (ODC) activity, proliferating cell nuclear antigen (PCNA), inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2) expression, and on levels of proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and prostaglandin E(2) (PGE(2)). Pretreatment of animals with chrysin at both doses (20 and 40 mg/kg body weight) markedly inhibited all. Further, Fe-NTA enhances renal lipid peroxidation, with concomitant reduction in reduced glutathione content (GSH), antioxidant enzymes, and phase II metabolizing enzymes. It induces serum toxicity markers, viz., blood urea nitrogen (BUN), creatinine and lactate dehydrogenase (LDH). Prophylactic treatment of animals with chrysin before the administration of Fe-NTA was effective in modulating oxidative and renal injury markers and resulted in the diminution of Fe-NTA mediated injury. These results suggest chrysin as an effective chemopreventive agent having the capability to obstruct DEN initiated and Fe-NTA promoted renal cancer in the rat model. 23468189 Benzenesulfonamides: a unique class of chemokine receptor type 4 inhibitors. The interaction of CXCR4 with CXCL12 (SDF-1) plays a critical role in cancer metastasis by facilitating the homing of tumor cells to metastatic sites. Based on our previously published work on CXCR4 antagonists, we have synthesized a series of aryl sulfonamides that inhibit the CXCR4/CXCL12 interaction. Analogue bioactivities were assessed with binding affinity and Matrigel invasion assays. Computer modeling was employed to evaluate a selection of the new analogues docked into the CXCR4 X-ray structure and to rationalize discrepancies between the affinity and Matrigel in vitro assays. A lead compound displays nanomolar potency in the binding affinity assay (IC(50)=8.0 nM) and the Matrigel invasion assay (100 % blockade of invasion at 10 nM). These data demonstrate that benzenesulfonamides are a unique class of CXCR4 inhibitors with high potency. 23852381 Oral human papillomavirus infection and head and neck cancers in HIV-infected individuals. HIV-infected individuals are living longer due to effective antiretroviral therapy and may therefore have a greater opportunity to develop human papillomavirus (HPV)-associated malignancies. This review describes the risk factors and burden of oral HPV infection and HPV-associated head and neck cancer (HNC) among HIV-infected individuals. Oral HPV infection is commonly detected in HIV-infected individuals and is elevated among those with a higher number of lifetime oral sexual partners, current tobacco use and immunosuppression. There are limited data on the natural history of oral HPV, but initial studies suggest that the majority of infections clear within 2 years. Although HIV-infected individuals are at a much higher risk of most HPV-associated cancers than the general population, studies suggest HIV-infected individuals have a more modest 1.5-4-fold greater risk for HPV-associated HNC. HIV-infected individuals are living longer, have a high prevalence of oral HPV infection and have many of the currently determined risk factors for HPV-associated HNC. 23643679 Epidemiology of Paget's disease of Bone: A systematic review and meta-analysis of secular changes. CONTEXT: Several studies have suggested that the prevalence and severity of PDB have fallen in recent years. The magnitude of this trend and its globalization have not been well established. OBJECTIVE: To estimate the pooled magnitude of the changes in the prevalence of PDB. As a secondary objective, to make up a world atlas of PDB prevalence. METHODS: Systematic review of English and non-English articles using MEDLINE (1946 to 2013) and EMBASE (1980 to 2013). Search terms included epidemiology, incidence, prevalence, cohort studies, osteitis deformans or Paget disease of bone. Studies with incidence and/or prevalence rate for PDB were included. Two authors independently extracted the data using predefined data fields and quality assessment. A pooled analyses based on random-effects models was carried out for secular trends. RESULTS: Twenty-eight articles documented the prevalence of PDB; four articles the incidence and two articles the rate of new referrals. The prevalence of PDB varied greatly between the different countries, from 0.00028% in Japan to 5.4% in UK. There were available data on changes in prevalence from two different surveys over two different time frames in Europe and New Zealand. In all but one city (Turin), a drop in the prevalence of PDB was recorded (pooled OR 0.64: 95% CI: 0.45-0.91). CONCLUSION: The incidence and prevalence rates of PDB vary widely between populations but both have decreased in most regions over recent years. The changes are heterogeneous however and within countries, the largest changes have been in areas that previously had a high prevalence. The reasons for these changes remain unclear at present but are likely to be due to an interaction between genetic factors and environmental triggers which may differ in different regions. 23894469 TCTP is an androgen-regulated gene implicated in prostate cancer. TCTP has been implicated in a plethora of important cellular processes related to cell growth, cell cycle progression, malignant transformation and inhibition of apoptosis. In addition to these intracellular functions, TCTP has extracellular functions and plays an important role in immune cells. TCTP expression was previously shown to be deregulated in prostate cancer, but its function in prostate cancer cells is largely unknown. Here we show that TCTP expression is regulated by androgens in LNCaP prostate cancer cells in vitro as well as human prostate cancer xenografts in vivo. Knockdown of TCTP reduced colony formation and increased apoptosis in LNCaP cells, implicating it as an important factor for prostate cancer cell growth. Global gene expression profiling in TCTP knockdown LNCaP cells showed that several interferon regulated genes are regulated by TCTP, suggesting that it may have a role in regulating immune function in prostate cancer. In addition, recombinant TCTP treatment increased colony formation in LNCaP cells suggesting that secreted TCTP may function as a proliferative factor in prostate cancer. These results suggest that TCTP may have a role in prostate cancer development. 23964998 WholeCellViz: data visualization for whole-cell models. Whole-cell models promise to accelerate biomedical science and engineering. However, discovering new biology from whole-cell models and other high-throughput technologies requires novel tools for exploring and analyzing complex, high-dimensional data. We developed WholeCellViz, a web-based software program for visually exploring and analyzing whole-cell simulations. WholeCellViz provides 14 animated visualizations, including metabolic and chromosome maps. These visualizations help researchers analyze model predictions by displaying predictions in their biological context. Furthermore, WholeCellViz enables researchers to compare predictions within and across simulations by allowing users to simultaneously display multiple visualizations. WholeCellViz was designed to facilitate exploration, analysis, and communication of whole-cell model data. Taken together, WholeCellViz helps researchers use whole-cell model simulations to drive advances in biology and bioengineering. 23942527 Prospective Randomized Trial of Hybrid NOTES Colectomy Versus Conventional Laparoscopic Colectomy for Left-sided Colonic Tumors. We conducted a randomized study of a laparoscopic technique for removing left-sided colon tumors that can reduce postoperative pain and other wound-related complications compared to the conventional technique. It is a novel technique of hybrid natural orifice translumenal endoscopic surgery (NOTES) colectomy (HNC) whereby laparoscopic colonic mobilization, transection, and anastomosis are performed intracorporeally. The specimen is then delivered through the anus using the transanal endoscopic operation (TEO) device, precluding the need for mini-laparotomy. We compared the short-term outcomes of patients who underwent HNC with those who underwent conventional laparoscopic colectomy (CL). Patients suffering left-sided colonic tumor were recruited and were randomized into two groups: HNC and CL. Operative data and complications were prospectively recorded and analyzed. During a 3-year period, we recruited 70 patients (35 per group). No significant difference was observed between the two groups with respect to operating time (105 vs. 100 min, p = 0.851), blood loss (30 vs. 30 ml, p = 0.954), or length of hospital stay (5 vs. 5 days, p = 0.990). The maximum pain score during the first week was significantly lower in the HNC group (1 vs. 2, p = 0.017). No patients in the HNC group developed wound infection, whereas four patients in the CL group did so (p = 0.005). With this hybrid NOTES technique, selected patients with left-sided colonic tumors can enjoy the full benefits of minimally invasive surgery with significantly less wound pain and a lower wound infection rate than are observed with CL. 23718750 Spatially-Directed Protein Identification from Tissue Sections by Top-Down LC-MS/MS with Electron Transfer Dissociation. MALDI imaging mass spectrometry (MALDI-IMS) has become a powerful tool for localizing both small molecules and intact proteins in a wide variety of tissue samples in both normal and diseased states. Identification of imaged signals in MALDI-IMS remains a bottleneck in the analysis and limits the interpretation of underlying biology of tissue specimens. In this work, spatially directed tissue microextraction of intact proteins followed by LC-MS/MS with electron transfer dissociation (ETD) was used to identify proteins from specific locations in three tissue types; ocular lens, brain, and kidney. Detection limits were such that a 1 μL extraction volume was sufficient to deliver proteins to the LC-MS/MS instrumentation with sufficient sensitivity to detect 50-100 proteins in a single experiment. Additionally, multiple modified proteins were identified; including truncated lens proteins that would be difficult to assign to an imaged mass using a bottom-up approach. Protein separation and identification are expected to improve with advances in intact protein fractionation/chromatography and advances in interpretation algorithms leading to increased depth of proteome coverage from distinct tissue locations. 23210706 Catechol-initiated polyethers: multifunctional hydrophilic ligands for PEGylation and functionalization of metal oxide nanoparticles. Bifunctional CA-PEG (catechol-poly(ethylene glycol)) and multifunctional CA-PEG-PGA/PEVGE (poly(glycidyl amine)/poly(ethylene glycol vinyl glycidyl ether)) ligands for the functionalization and solubilization of nanoparticles are introduced. Tunable polymers with polydispersities <1.25 and molecular weights in the range 500-7700 g mol(-1) containing a catechol moiety for conjugation to metal oxide nanoparticles were prepared. The functional PEG ligands were synthesized starting from the acetonide-protected catechol initiator 2,2-dimethyl-1,3-benzodioxole-5-propanol (CA-OH) for oxyanionic polymerization. CA-OH was used both for homopolymerization of ethylene oxide (EO) as well as copolymerization with functional epoxides N,N-diallyl glycidyl amine (DAGA), releasing primary amino groups and ethylene glycol vinyl glycidyl ether (EVGE), exhibiting a double bond for click-type reactions, to generate CA-PEG and CA-PEG-PGA/PEVGE. We demonstrate the potential of the functional ligands by binding to MnO nanoparticles, rendering the PEGylated nanoparticles highly stable in aqueous environment. Furthermore, addressability of the functional groups has been proven, for example, by coupling with fluoresceine isothiocyanate (FITC), to allow for optical monitoring of the nanoparticle fate in biological systems. 23514733 Double-Blind, Randomized Study Evaluating the Glycemic and Anti-inflammatory Effects of Subcutaneous LY2189102, a Neutralizing IL-1β Antibody, in Patients With Type 2 Diabetes. OBJECTIVE Inflammation is associated with pancreatic β-cell apoptosis and reduced insulin sensitivity. Literature suggests that interleukin (IL)-1β may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). This study aimed to determine the efficacy, safety, and tolerability of LY2189102, a neutralizing IL-1β antibody, in T2DM patients. RESEARCH DESIGN AND METHODS Phase II, randomized, double-blind, parallel, placebo-controlled study of subcutaneous LY2189102 (0.6, 18, and 180 mg) administered weekly for 12 weeks in T2DM patients on diet and exercise, with or without approved antidiabetic medications. RESULTS LY2189102 reduced HbA1c at 12 weeks (adjusted mean differences versus placebo: -0.27, -0.38 and -0.25% for 0.6, 18 and 180 mg doses, respectively), and fasting glucose at multiple time points compared with placebo. LY2189102 also reduced postprandial glycemia, and inflammatory biomarkers, including hs-CRP and IL-6. LY2189102 was generally well tolerated. CONCLUSIONS Weekly subcutaneous LY2189102 for 12 weeks was well tolerated, modestly reduced HbA1c and fasting glucose, and demonstrated significant anti-inflammatory effects in T2DM patients. Neutralizing IL-1β holds promise as a convenient adjuvant treatment for T2DM. 23740597 Sex- and age-dependent activity of glutathione peroxidase in reproductive organs in pre- and post-pubertal cattle in relation to total antioxidant capacity. Antioxidative/oxidative balance is crucial for proper functioning of cells and tissues. It is suggested that this balance can be partly controlled by sex steroid hormones and in consequence can exhibit age- and sex-related dependency. The aim of present study was to describe sex- and age-related changes in the activity of glutathione peroxidase (GSH-Px) with respect to total antioxidant activity (TAC) in reproductive organs of cattle. Biological samples were collected from slaughterhouse and comprised of ovaries, uterus, testes as well as livers as reference tissue. Animals were divided into group of bulls (aged between 13 and 24 months; n = 12), cows (aged between 14 and 27 months; n = 12) and female calves (aged between 2 weeks and 2 months; n = 12). Examined parameters were determined spectrophotometrically and the presence of GSH-Px isoform was confirmed by Western blotting technique. Activity of GSH-Px in genital tissues regardless of sex was significantly higher than in livers, while TAC showed opposite relationship. The differences in antioxidative parameters between testes and mature ovaries (e.g. GSH-Px-1.42 ± 0.47 nkat/mg prot vs. 1.08 ± 0.24 and 1.15 ± 0.23) were noticed as well as in chosen values between cows and female calves. Western blotting allowed the detection of cytosolic GSH-Px in all examined tissues with molecular weight around 21 kDa as monomer and around 84 kDa as tetramer depending on conditions of electrophoresis. The results may confirm the influence and regulatory role of sex steroid hormones on GSH-Px activity because the alterations were sex and age dependent. 23856469 Organochlorine compounds, nitro musks and perfluorinated substances in breast milk - Results from Bavarian Monitoring of Breast Milk 2007/8. The aim of the Bavarian Monitoring of Breast Milk (BAMBI) project was to examine 10 organochlorine pesticides (OPs), 3 nitro musks, 6 indicator polychlorinated biphenyls (PCBs), 7 polychlorinated dibenzo-p-dioxins (PCDDs), 10 polychlorinated dibenzofurans (PCDFs), 12 dioxin-like PCBs (dl-PCBs) and several perfluorinated alkyl compounds in breast milk samples. A total of 516 breast milk samples were collected from seven regions in Bavaria and were analyzed by means of GC/ECD, GC/HRMS, and LC/MS-MS. Concerning the OPs, only hexachlorobenzene and a metabolite of DDT, 1,1-dichloro-2,2-bis(4-chlorophenyl) ethylene (p,p'-DDE), could be quantified in all samples (median: 16ngg(-1) lipid and 63ngg(-1) lipid, respectively). Median concentrations of 150ngg(-1) lipid (range: 3-1900ngg(-1) lipid) were found for the sum of the indicator PCBs. The concentrations of the PCDDs/PCDFs and the dl-PCBs ranged from 0.8 to 15.1 (median 5.7) pg WHO-TEQ1998g(-1) lipid and from 1.5 to 18.9pg (median 6.4) WHO-TEQ1998g(-1) lipid, respectively. The median perfluorooctane sulfonate concentration was 0.05μgL(-1) (range: <0.02-0.26μgL), while the other PFCs were observed only in a subset of samples. On the basis of the median and 95th percentile concentration, "medium" and "high" intake levels were estimated for a 3-month-old exclusively breastfed infant. In particular, "medium" and "high" intake levels were calculated of 69 and 133pg WHO1998 TEQkg(-1) b.w. for PCDDs/PCDFs, 8 and 21ngkg(-1) b.w. for dl-PCBs, and 6 and 25ngkg(-1) b.w. for perfluorooctane sulfonate, respectively. The calculated intake for perfluorinated substances is clearly below the tolerable daily intake (TDI), while the established TDI values are still clearly exceeded for PCDDs/PCDFs and dl-PCBs. 23389079 Effect of laparoscopic cholecystectomy on gastric emptying and dyspepsia. Laparoscopic cholecystectomy has become the gold standard for treatment of symptomatic gallstone disease. Nonresolution of dyspepsia postoperatively is of major concern nowadays. The present study was conducted to study the effect of laparoscopic cholecystectomy on gastric emptying in symptomatic gallstone disease using (99m)Tc sulfur colloid scintigraphy. This pilot study sought to obtain preliminary data and to establish a base for further detailed study. A total of 25 patients with a diagnosis of symptomatic gallstone disease scheduled for laparoscopic cholecystectomy were included in the study. All patients underwent gastric scintigraphic emptying study preoperatively and 2 weeks after laparoscopic cholecystectomy. Laparoscopic cholecystectomy was done as a day care procedure. Mean ± standard deviation preoperative gastric percentage clearance was 51.36 ± 12.67 %. Preoperative gastric emptying half-time was 62.72 ± 21.59 min. Forty percent of patients experienced dyspeptic symptoms before surgery. Twenty-four percent of patients had dyspeptic symptoms during postoperative follow-up at 2 weeks. Postoperative percentage gastric clearance was 49.92 ± 13.17 %. Postoperative gastric emptying half-time was 64.12 ± 19.13 min. Statistical analysis revealed no significant effect of laparoscopic cholecystectomy on gastric emptying parameters. Laparoscopic cholecystectomy does not alter gastric emptying or stomach percentage clearance in gallstone patients who have preoperative delayed gastric emptying on scintigraphy. Laparoscopic cholecystectomy has no effect on gastric emptying in symptomatic gallstone patients. 23921257 RNA-Seq analysis reveals genes associated with resistance to Taura syndrome virus (TSV) in the Pacific white shrimp Litopenaeus vannamei. Outbreak of Taura syndrome virus (TSV) is one of the major pathogens of the Pacific white shrimp Litopenaeus vannamei. Although selective breeding for improvement of TSV resistance in L. vannamei has been successfully developed and has led to a great benefit to the shrimp farming industry worldwide. The molecular mechanisms underlying the viral resistance in shrimp remain largely unknown. In the present study, we conducted the first transcriptomic profiling of host responses in hemolymph and hemocytes in order to identify the differentially expressed genes associated with resistance to TSV in L. vannamei. High-throughput RNA-Seq was employed, obtaining 193.6 and 171.2 million high-quality Illumina reads from TSV-resistant and susceptible L. vannamei lines respectively. A total of 61,937 contigs were generated with an average length of 546.26bp. BLASTX-based gene annotation (E-value<10(-5)) allowed the identification of 12,398 unique proteins against the NCBI non-redundant NR database. In addition, comparison of digital gene expression between resistant and susceptible strains revealed 1374 significantly differentially expressed contigs (representing 697 unigenes). Gene pathway analysis of the differentially expressed gene set highlighted several putative genes involved in the immune response activity including (1) pathogen/antigen recognition including immune regulator, adhesive protein and signal transducer; (2) coagulation; (3) proPO pathway cascade; (4) antioxidation; and (5) protease. The expression patterns of 22 differentially expressed genes involving immune response were validated by quantitative real-time RT-PCR (average correlation coefficients 0.94, p-value<0.001). Our results provide valuable information on gene functions associated with resistance to TSV in L. vannamei. 23820989 Hospital readmissions in patients with inflammatory bowel disease. We aimed to identify the frequency and costs of, and the disease predictors and inpatient process issues that may predispose to, 30-day readmission for an inflammatory bowel disease (IBD) patient. IBD patients admitted to an inpatient gastroenterology service were followed for a time-to-readmission analysis assessing factors associated with readmission within 30 days. Index admissions were more costly among those readmitted than among those not readmitted. Patients admitted with evidence of increased inflammation, infection, or obstruction or for dehydration or pain control had a higher risk of readmission. Patients treated with opioid analgesia during index admission were no less likely to be readmitted, and there was a 2.2-fold increase in readmissions when patients were discharged with no opioid analgesia. Scheduling variability and outpatient follow-up compliance were associated with readmission. Predicting readmission is complex. A predictive model developed to be used at discharge yielded an area under the curve of 0.757. 23554148 Sexually dimorphic expression and estradiol mediated up-regulation of a sex-linked ribosomal gene, RPS6, in the zebra finch brain. Sex-linked genes are considered to be a major contributor to neural sex differences in zebra finches. While several candidates have been identified, additional ones are continuously being discovered. Here we report on a novel Z-linked ribosomal gene (rpS6) that is enhanced in the male brain as compared to the female's throughout life. In both sexes, expression of rpS6 is highest at P3 and P8 (just before the onset of morphologically detectable sex differences), decreases around P15, and then remains decreased through adulthood. Analysis of rpS6 mRNA revealed widespread distribution throughout the brain. However, within song regions HVC and RA, mRNA containing cells were greater in males as compared to females. Hormones are also involved in the development of neural dimorphisms, so we additionally investigated whether rpS6 might interact with estradiol (E2 ). An up-regulation of rpS6 gene was observed in both sexes following treatment with E2 and the effect was approximately twice as large in males as compared with females. These data suggest that rpS6 may be involved in sexual differentiation of the zebra finch brain, and that the effect is facilitated by E2 . © 2013 Wiley Periodicals, Inc. Develop Neurobiol 73: 599-608, 2013. 23834662 The artery of Percheron: an anatomic study with potential neurosurgical and neuroendovascular importance. Background. One variant branch of the P1 segment of the posterior cerebral artery (PCA) is the artery of Percheron (AOP). This unilateral trunk supplies thalami and potentially mesencephalic structures. As studies of this vessel are scant in the literature and damage to this artery can have catastrophic results, the authors performed this study to better elucidate its morphology. Materials and methods. Twenty-five adult latex-injected cadaveric heads underwent brain removal and microdissection with specific attention to the presence of the AOP. When identified, measurements were made and observations given to the origin and course of this vessel. A case illustration is also presented that demonstrates bilateral thalamic and midbrain infarctions most likely due to thrombosis of the AOP. Results. An AOP was identified in three specimens (12%)-2 right and 1 left side (1 male and 2 female specimens) and arose, on average, 8 mm lateral to the basilar artery bifurcation. The average diameter was 2.1 mm, and the length between the origin and brain penetration had a mean distance of 1.5 cm. In all specimens, the AOP had a coiled appearance, especially in its proximal extraparenchymal segment. The contralateral P1 segment of the PCA was not absent or hypoplastic in any of the three specimens. All arteries supplied small branches to the ipsilateral and contralateral thalami and midbrain. Conclusions. Knowledge of the AOP may be important during surgical or neuroendovascular approaches to the basilar bifurcation or during interpretation of imaging, especially in patients presenting with bilateral thalamic and midbrain infarctions. 23901927 Genetic variability among Schistosoma japonicum isolates from the Philippines, Japan and China revealed by sequence analysis of three mitochondrial genes. Abstract The present study examined sequence variability in the mitochondrial (mt) protein-coding genes cytochrome b (cytb), NADH dehydrogenase subunits 2 and 6 (nad2 and nad6) among 24 isolates of Schistosoma japonicum from different endemic regions in the Philippines, Japan and China. The complete cytb, nad2 and nad6 genes were amplified and sequenced separately from individual schistosome. Sequence variations for isolates from the Philippines were 0-0.5% for cytb, 0-0.6% for nad2, and 0-0.9% for nad6. Variation was 0-0.5%, 0.1-0.8%, 0-0.7% for corresponding genes for schistosome samples from mainland China. For worms in Japan, genetic variations were 0-0.2%, 0.1-0.2% and 0 for the three genes, respectively. Sequence variations were 0-1.0%, 0-1.8% and 0-1.1% for cytb, nad2 and nad6, respectively, among schistosome isolates from different geographical strains in the Philippines, Japan and China. Of the three countries, lowest sequence variations were found between isolates from mainland China and the Philippines and highest were detected between Japan and the Philippines in three mtDNA genes. Phylogenetic analyses based on the combined sequences of cytb, nad2 and nad6 revealed that all isolates in the Philippines clustered together sistered to samples from Yunnan and Zhejiang provinces in China, while isolates from Yamanashi in Japan were in a solitary clade. These results demonstrated the usefulness of the combined three mtDNA sequences for studying genetic diversity and population structure among S. japonicum isolates from the Philippines, China and Japan. 23541221 Germline HOXB13 p.Gly84Glu mutation and risk of colorectal cancer. The HOXB13 pGly84Glu mutation has recently been associated with an increased risk of prostate cancer but the association of other cancer sites with this allele has not been assessed. Data has suggested that HOXB13 expression levels are decreased in colorectal cancer (CRC) cell lines indicating this gene may be involved in colorectal tumourigenesis. To evaluate a potential association of this mutation with CRC, we genotyped the mutation in 2695 CRC cases and 4593 controls from population-based registries in Canada and Australia. The HOXB13 pGly84Glu mutation was more common in CRC cases than controls (0.48% vs. 0.17%, P=0.02) indicating a significant association between the HOXB13 variant and CRC risk (OR=2.8; 95%CI: 1.2-6.8). This association was attenuated but remained significant with the inclusion of previously published and publicly available genotype data. Pedigree analysis of cases and controls revealed that 7/21 HOXB13 mutation carriers had a family history of prostate cancer. This report is the first to suggest a risk of CRC associated with mutations in the HOXB13 gene. These findings require further validation but may be of importance in the screening and genetic counseling of families known to carry the HOXB13 pGly84Glu mutation. 23727822 Reagents and assay strategies for quantifying active enzyme analytes using a personal glucose meter. This communication describes small molecule reagents and a rapid single-step assay for quantifying nanomolar levels of active enzyme analytes using a personal glucose meter. 23868202 Effects of Aural Atresia on Speech Development and Learning: Retrospective Analysis From a Multidisciplinary Craniofacial Clinic. IMPORTANCE Aural atresia (AA) is associated with maximal conductive hearing loss in affected ears, and children with bilateral AA require amplification. Some recent research has suggested an increased risk for speech and learning problems among children with unilateral sensorineural hearing loss. OBJECTIVE To investigate whether increased risk for speech and learning problems exists among children with AA. DESIGN Retrospective medical record review. SETTING Multidisciplinary craniofacial clinic. PARTICIPANTS Children with unilateral or bilateral AA. INTERVENTIONS Records review, including evaluations by audiologists, speech pathologists, and psychologists. MAIN OUTCOME MEASURES Rates of speech and/or language delay, prevalence of speech therapy and educational interventions, and parental report of psychosocial problems. RESULTS A total of 74 patients were identified who met inclusion and exclusion criteria: 48 with right-sided AA, 19 with left-sided AA, and 7 with bilateral AA. Children with AA demonstrated high rates of speech therapy (86% among bilateral, 43% among unilateral). Reports of school problems were more common among children with right-sided AA (31%) than those with left-sided AA (11%) or bilateral AA (0%) (P = .06). Educational interventions were common in all groups (33% right, 21% left, 43% bilateral). In the case of bilateral AA, all children who received additional interventions were enrolled in schools for the hearing impaired, without any identified learning deficiencies. CONCLUSIONS AND RELEVANCE Children with unilateral AA may be at greater risk of speech and learning difficulties than previously appreciated, similar to children with unilateral sensorineural hearing loss. Whether amplification may alleviate this risk is unclear and warrants further study. 23846997 Subcortical connectivity in dementia with Lewy bodies and Alzheimer's disease. Resting-state functional magnetic resonance imaging (fMRI) can be used to measure correlations in spontaneous low-frequency fluctuations in the blood oxygen level-dependent (BOLD) signal which represent functional connectivity between key brain areas. To investigate functional connectivity with regions hypothesised to be differentially affected in dementia with Lewy bodies (DLB) compared with Alzheimer's disease and controls. Fifteen participants with probable DLB, 16 with probable Alzheimer's disease and 16 controls were scanned in the resting-state using a 3T scanner. The BOLD signal time-series of fluctuations in seed regions were correlated with all other voxels to measure functional connectivity. Participants with DLB and Alzheimer's disease showed greater caudate and thalamic connectivity compared with controls. Those with DLB showed greater putamen connectivity compared with those with Alzheimer's disease and the controls. No regions showed less connectivity in DLB or Alzheimer's disease v. controls, or in DLB v. Alzheimer's disease. Altered connectivity in DLB and Alzheimer's disease provides new insights into the neurobiology of these disorders and may aid in earlier diagnosis. 23532914 Fast and scalable purification of a therapeutic full-length antibody based on process crystallization. The potential of process crystallization for purification of a therapeutic monoclonal IgG1 antibody was studied. The purified antibody was crystallized in non-agitated micro-batch experiments for the first time. A direct crystallization from clarified CHO cell culture harvest was inhibited by high salt concentrations. The salt concentration of the harvest was reduced by a simple pretreatment step. The crystallization process from pretreated harvest was successfully transferred to stirred tanks and scaled-up from the mL-scale to the 1 L-scale for the first time. The crystallization yield after 24 h was 88-90%. A high purity of 98.5% was reached after a single recrystallization step. A 17-fold host cell protein reduction was achieved and DNA content was reduced below the detection limit. High biological activity of the therapeutic antibody was maintained during the crystallization, dissolving, and recrystallization steps. Crystallization was also performed with impure solutions from intermediate steps of a standard monoclonal antibody purification process. It was shown that process crystallization has a strong potential to replace Protein A chromatography. Fast dissolution of the crystals was possible. Furthermore, it was shown that crystallization can be used as a concentrating step and can replace several ultra-/diafiltration steps. Molecular modeling suggested that a negative electrostatic region with interspersed exposed hydrophobic residues on the Fv domain of this antibody is responsible for the high crystallization propensity. As a result, process crystallization, following the identification of highly crystallizable antibodies using molecular modeling tools, can be recognized as an efficient, scalable, fast, and inexpensive alternative to key steps of a standard purification process for therapeutic antibodies. Biotechnol. Bioeng. 2013; 110:2452-2461. © 2013 Wiley Periodicals, Inc. 23378111 Aquihabitans daechungensis gen. nov., sp. nov., an actinobacterium isolated from reservoir water. A novel Gram-reaction-positive bacterium, strain CH22-21(T), was isolated from a water sample taken from Daechung Reservoir, Republic of Korea, during the late-blooming period of cyanobacteria. Cells of strain CH22-21(T) were non-motile, ciliated short rods that formed creamy-white colonies on half-strength modified R2A agar. Chemotaxonomic results showed menaquinone MK-9(H6) as the predominant respiratory menaquinone, diphosphatidylglycerol, phosphatidylinositol and phosphatidylinositolmannoside as major polar lipids, 16 : 1ω5c, 16 : 0, 17 : 1ω8c and 18 : 1ω9c as major fatty acids, and a DNA G+C content of 71.8 mol%. Phylogenetic analysis based on 16S rRNA gene sequencing indicated that the strain formed a separate lineage within the order Acidimicrobiales, showing similarity values of <92.3 % with its closest phylogenetic neighbours. The combined genotypic and phenotypic data showed that strain CH22-21(T) could be distinguished from all genera within the order Acidimicrobiales and represented a novel species of a new genus in the family Iamiaceae, for which the name Aquihabitans dachungensis gen. nov., sp. nov. is proposed. The type strain of Aquihabitans dachungensis is CH22-21(T) ( = KCTC 19849(T) = JCM 17787(T)). 23398257 The flexibility of letter-position flexibility: Evidence from eye movements in reading Hebrew. Hebrew provides an intriguing contrast to European languages. On the one hand, like any European language, it has an alphabetic script. On the other hand, being a Semitic language, it differs in the structure of base words. By monitoring eye movements, we examined the time-course of processing letter transpositions in Hebrew and assessed their impact on reading different types of Hebrew words that differ in their internal structure. We found that letter transposition resulted in dramatic reading costs for words with Semitic word structure, and much smaller costs for non-Semitic words. Moreover, the strongest impact of transposition occurred where root-letter transposition resulted in a pseudo-root, where significant interference emerged already in first fixation duration. Our findings thus suggest that Hebrew readers differentiate between Semitic and non-Semitic forms already at first fixation, at the early phase of word recognition. Moreover, letters are differentially processed across the visual array, given their morphological structure and their contribution to recovering semantic meaning. We conclude that flexibility or rigidity in encoding letter position is determined by cues regarding the internal structure of printed words. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23842480 Fatal gunshot injuries in Benin City, Nigeria. An upsurge in gun violence in recent times in our environment necessitated this study, which aims to document the patterns of fatal gunshot injuries with the hope of finding a solution to this problem. The study was a retrospective analysis of cases of fatal gunshot injuries on which autopsies were carried out over the 5-year period from January 1998 to December 2002 at Police Medical Services, Benin City - a Nigerian ancient town located in the South-South zone of the country. Most cases of medico-legal death in Benin City and environs are referred to the Police Pathologist at the center for autopsy. A total of 210 cases representing 27.2% of all medico-legal deaths during the study period were reviewed. Males were far more affected than females (M:F = 10.7:1). The intent for the fatal gunshots was murder (88.5%), excusable homicide (4.8%), accident (4.3%) and suicide (0.5%). In 1.9% of the deaths, the circumstances were not clear. Armed robbers, thugs and assassins accounted for 88.1% of the fatal shots, while the Police accounted for 9.0%. The trunk was affected much more than the head, neck and limbs. There is a need to improve security in the country and reduce poverty. Illegal firearms should also be removed from circulation. An improvement in emergency health services will reduce deaths from gunshots. 23934754 Apoptotic cells enhance sphingosine-1-phosphate receptor 1-dependent macrophage migration. The lipid sphingosine-1-phosphate (S1P) is a chemokine for a variety of immune cells including lymphocytes and monocytes. Migration towards S1P is determined by the S1P receptor expression profile, with S1PR1/3 stimulating and S1PR2 attenuating migration. However, the impact and physiological significance of S1P-induced migration of macrophages is largely unclear. We observed that alternative activation of human macrophages, by IL-4 or apoptotic cells (ACs), enhanced S1PR1 expression. Moreover, ACs provoked macrophage migration towards S1P in an S1PR1-dependent manner as confirmed by pharmacological receptor inhibition and S1PR1-deficient murine macrophages. In a mouse model of resolving peritoneal inflammation, F4/80-driven deletion of S1PR1 reduced post-inflammatory macrophage emigration from inflammatory sites. S1PR1 expression on macrophages might therefore be relevant for restoring tissue homeostasis during the resolution of inflammation. This article is protected by copyright. All rights reserved. 23947513 Disseminated microsporidiosis in a renal transplant recipient: case report and review of the literature. Microsporidia are opportunistic pathogens that usually cause a limited disease in the gastrointestinal tract. Occasionally, they can cause disseminated disease. In solid organ transplant recipients, disseminated disease has been reported only rarely. We describe a 68-year-old woman who presented with fever, cough, and acute kidney injury 6 months after kidney transplantation. Dissemination was confirmed by identification of microsporidial spores in urine and bronchoalveolar lavage fluid. Polymerase chain reaction analysis identified the species as Encephalitozoon cuniculi. 23869108 Comparison of haemoglobin measurement methods in the operating theatre. /st>Various methods of haemoglobin (Hb) measurement are available to guide transfusion including several methods that allow for measurement at the bedside. This study directly compared their absolute and trend accuracy compared with values from the central lab (reference method). /st>Adult patients undergoing surgery with expected blood loss wore a rainbow ReSposable sensor connected to a Radical-7 Pulse CO-Oximeter (SpHb). Arterial samples were analysed with a haematology analyser (HbLab), a satellite CO-Oximeter (HbSat), and a point-of-care haemoglobinometer (HemoCue; HcueArt). Concomitantly, ear capillary blood was tested using the same haemoglobinometer (HcueCap). Absolute accuracy and the clinical significance of error were assessed with Bland-Altman plots and three-zone error grids. Trend analysis was performed using a modified polar plot, testing both directionality and magnitude of Hb changes compared with the reference. /st>Two hundred and nineteen measurements from 53 patients with HbLab ranging between 6.8 and 16.3 g dl(-1) (4.2 and 10.1 mmol litre(-1)) were recorded. Compared with the reference method, bias (precision) was 0.2 (0.2) g dl(-1) [0.1 (0.1) mmol litre(-1)] for HcueArt, 0.8 (0.3) g dl(-1) [0.5 (0.2) mmol litre(-1)] for HbSat, 0.5 (0.5) g dl(-1) [0.3 (0.3) mmol litre(-1)] for HcueCap and 1.0 (1.2) g dl(-1) [0.6 (0.7) mmol litre(-1)] for SpHb. None of the devices tested would have led to unnecessary or delayed transfusion according to 2006 ASA transfusion criteria. Trend accuracy was better for HcueArt and HbSat than for HcueCap and SpHb. /st>Bedside Hb measurement methods differ in their agreement to a laboratory haematology analyser but none would have led to transfusion errors.Trial Registry NumberRCB 2009-AO1144-53. 23948031 The cosmetic allergy conundrum: inference of an immunoregulatory response to cosmetic allergens. The ability to be sensitized to experimental contact allergens declines significantly with increasing age, from as early as age 40 years. In contrast, the rate of contact allergy to chemical allergens (haptens) in cosmetic products significantly increases with age. This has been explained previously on the basis of greater cumulative exposure in the older age groups. However, outbreaks of contact allergy to preservatives in cosmetic products recorded soon after their introduction to the market have also shown a significantly higher rate among older adult age groups. This association with increasing age cannot be readily explained by exposure history or pattern, and is not compatible with a sensitizing/stimulatory reaction that degrades with age as the sole immune response. From this, the existence of a second, tolerizing/regulatory arm to the immune response to cutaneous haptens that possibly becomes less effective with age at a higher rate than the sensitizing/stimulatory arm can be inferred. This reinforces the view that current clinical and experimental observations of allergic contact dermatitis are best explained by an immune system with the functional ability to produce both sensitizing/stimulatory and tolerizing/regulatory responses. 23919145 Developmental trajectories and breakdown in F1 interpopulation hybrids of Tribolium castaneum. When hybrid inviability is an indirect by-product of local adaptation, we expect its degree of severity between pairs of populations to vary and to be sensitive to the environment. While complete reciprocal hybrid inviability is the outcome of the gradual process of local adaptation, it is not representative of the process of accumulation of incompatibility. In the flour beetle, Tribolium castaneum, some pairs of populations exhibit complete, reciprocal F1 hybrid incompatibility while other pairs are fully or partially compatible. We characterize this naturally occurring variation in the degree and timing of expression of the hybrid incompatible phenotype to better understand the number of genes or developmental processes contributing to speciation. We assessed the morphological and developmental variation in four Tribolium castaneum populations and their 12 possible F1 hybrids at each life-history stage from egg to adult. We find that the rate of hybrid larval development is affected in all interpopulation crosses, including those eventually producing viable, fertile adults. Hybrid incompatibility manifests early in development as changes in the duration of instars and diminished success in the transition between instars are relative to the parent populations. Parent populations with similar developmental profiles may produce hybrids with disrupted development. The degree and timing of expression of hybrid inviability depends upon populations crossed, direction of the cross, and environment in which hybrids are raised. Our findings suggest that the coordinated expression of genes involved in transitional periods of development is the underlying cause of hybrid incompatibility in this species. 23595128 A bloodspot-based diagnostic test for fibromyalgia syndrome and related disorders. The aim of this study was to investigate the ability of a rapid biomarker-based method for diagnosis of fibromyalgia syndrome (FM) using mid-infrared microspectroscopy (IRMS) to differentiate patients with FM from those with osteoarthritis (OA) and rheumatoid arthritis (RA), and to identify molecular species associated with the spectral patterns. Under IRB approval, blood samples were collected from patients diagnosed with FM (n = 14), RA (n = 15), or OA (n = 12). Samples were prepared, placed onto a highly reflective slide, and spectra were collected using IRMS. Spectra were analyzed using multivariate statistical modeling to differentiate groups. Aliquots of samples also were subjected to metabolomic analysis. IRMS separated subjects into classes based on spectral information with no misclassifications among FM and RA or OA patients. Interclass distances of 15.4 (FM vs. RA), 14.7 (FM vs. OA) and 2.5 (RA vs. OA) among subjects, demonstrating the ability of IRMS to achieve reliable resolution of unique spectral patterns specific to FM. Metabolomic analysis revealed that RA and OA groups were metabolically similar, whereas biochemical differences were identified in the FM that were quite distinctive from those found in the other two groups. Both IRMS and metabolomic analysis identified changes in tryptophan catabolism pathway that differentiated patients with FM from those with RA or OA. 23852263 Anaesthetic drugs and survival: a Bayesian network meta-analysis of randomized trials in cardiac surgery. /st>Many studies have compared desflurane, isoflurane, sevoflurane, total i.v. anaesthesia (TIVA), or all in cardiac surgery to assess their effects on patient survival. /st>We performed standard pairwise and Bayesian network meta-analyses; the latter allows indirect assessments if any of the anaesthetic agents were not compared in head-to-head trials. Pertinent studies were identified using BioMedCentral, MEDLINE/PubMed, Embase, and the Cochrane Library (last updated in June 2012). /st>We identified 38 randomized trials with survival data published between 1991 and 2012, with most studies (63%) done in coronary artery bypass grafting (CABG) patients with standard cardiopulmonary bypass. Standard meta-analysis showed that the use of a volatile agent was associated with a reduction in mortality when compared with TIVA at the longest follow-up available [25/1994 (1.3%) in the volatile group vs 43/1648 (2.6%) in the TIVA arm, odds ratio (OR)=0.51, 95% confidence interval (CI) 0.33-0.81, P-value for effect=0.004, number needed to treat 74, I(2)=0%] with results confirmed in trials with low risk of bias, in large trials, and when including only CABG studies. Bayesian network meta-analysis showed that sevoflurane (OR=0.31, 95% credible interval 0.14-0.64) and desflurane (OR=0.43, 95% credible interval 0.21-0.82) were individually associated with a reduction in mortality when compared with TIVA. /st>Anaesthesia with volatile agents appears to reduce mortality after cardiac surgery when compared with TIVA, especially when sevoflurane or desflurane is used. A large, multicentre trial is warranted to confirm that long-term survival is significantly affected by the choice of anaesthetic. 22900982 Formulation and development of oral dry suspension using taste masked Ornidazole particles prepared using Kollicoat(®) Smartseal 30 D. The purpose of this work was to taste mask highly bitter active, Ornidazole by means of particle coating. The aim of the work was further extended into formulating these coated particles into an acceptable oral dosage form such as dry suspension. Ornidazole drug particles were coated using Kollicoat(®) Smartseal 30 D as a taste masking polymer. Kollicoat(®) Smartseal 30 D is a methyl methacrylate - diethylaminoethyl methacrylate copolymer (6:4). Successful taste masking was achieved for Ornidazole with both top spray and bottom spray techniques using fluid bed processor. Effective taste masking was achieved at a weight gain of 50% w/w and 40% w/w for bottom and top spray techniques respectively without having a significant effect on the release pattern. A taste masked dry suspension was prepared with around 80% w/w coated Ornidazole particles and pH was maintained around 7-8. The suspension prepared with these coated Ornidazole particles, which were maintained in the alkaline pH was found to be stable for 7 days without affecting the taste. The bitter taste intensity was evaluated using volunteers by comparison of test samples with standard solutions containing Ornidazole at various concentrations. Thus, Kollicoat(®) Smartseal 30 D was found to be an effective polymer for taste masking of a bitter active like Ornidazole. The formulation development of taste masked dry suspensions was only possible due to unique properties possessed by Kollicoat(®) Smartseal 30 D. 20883711 Risk management of undesirable substances in feed following updated risk assessments. Directive 2002/32/EC of 7 May 2002 of the European Parliament and of the Council on undesirable substances in animal feed is the framework for the EU action on undesirable substances in feed. This framework Directive provides: Based on the provisions and principles laid down in this framework Directive, maximum levels for a whole range of undesirable substances have been established at EU level. During the discussions in view of the adoption of Directive 2002/32/EC, the European Commission made the commitment to review all existing provisions on undesirable substances on the basis of updated scientific risk assessments. Following requests of the European Commission, the Panel on Contaminants in the Food Chain (CONTAM) from the European Food Safety Authority (EFSA) has completed a series of 30 risk assessments undertaken over the last 5years on undesirable substances in animal feed reviewing the possible risks for animal and human health due to the presence of these substances in animal feed. EU legislation on undesirable substances has undergone recently several changes to take account of these most recent scientific opinions. Furthermore EFSA has assessed the risks for public and animal health following the unavoidable carry-over of coccidiostats into non target feed. Maximum levels for the unavoidable carry-over have been established for the non-target feed and the food of animal origin from non-target animal species. 23419834 A kavalactone derivative inhibits lipopolysaccharide-stimulated iNOS induction and NO production through activation of Nrf2 signaling in BV2 microglial cells. Neuroinflammation and oxidative stress are involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's diseases and Parkinson's disease. Naturally derived kavalactones isolated from Piper methysticum (Piperaceae) have been shown to exhibit neuroprotective effects. We have previously reported that a chemically synthesized kavalactone derivative, 2',6'-dichloro-5-methoxymethyl-5,6-dehydrokawain (compound 1) protects against oxidative stress-induced neuronal cell death through activation of Nrf2 signaling. In the present study, we examined the effect of compound 1 on neuroinflammation. In BV2 microglial cells, compound 1 strongly inhibited LPS-stimulated iNOS induction and NO production, but did not affect LPS-stimulated induction of COX2. At 6h after LPS challenge, when iNOS induction was not clearly seen, treatment with LPS or compound 1 alone increased expression of heme oxygenase 1 (HO-1) whose transcription is regulated by Nrf2. When treated with both, compound 1 enhanced LPS-stimulated HO-1 induction, which was more evident at 24h after LPS treatment. Furthermore, LPS-stimulated activation of Nrf2 signaling and nuclear translocation of Nrf2 were potentiated by compound 1. The mechanism by which compound 1 activated Nrf2 signaling was supposed to be a covalent modification of the sulfhydryl groups of Keap1 by an α,β-unsaturated carbonyl group present in the compound 1. Treatment with hemin, a HO-1 inducer, and with [Ru(CO)3Cl2]2, a CO donor, decreased LPS-stimulated iNOS induction and NO production. In contrast, siRNA-mediated knockdown of HO-1 expression reduced the inhibitory effect of compound 1 on LPS-stimulated iNOS induction and NO production. The compound 1 inhibited LPS-stimulated ERK phosphorylation after LPS treatment. Finally, compound 1 suppressed LPS/IFN-γ-stimulated NO production in primary microglial cells. These results suggest that compound 1 is capable of inhibiting LPS-stimulated iNOS induction and NO production via activation of Nrf2 signaling and HO-1 induction in microglial cells. Taken together, compound 1 has a potential to reduce neuroinflammation as well as oxidative stress in neurodegenerative diseases through activation of Nrf2 signaling. 23662600 Sensitivity of assays for the detection of HPA-1a antibodies: results of an international workshop demonstrating the impact of cation chelation from integrin αIIbβ3 on three widely used assays. HPA-1a antibodies account for 70-80% of cases of fetal-neonatal alloimmune thrombocytopenia (FNAIT) in Caucasians. However, numerous workshops have demonstrated variability in their detection. We recently showed that exposure of αIIbβ3 to ethylene diamine tetraacetic acid (EDTA) affected binding of many anti-αIIbβ3 monoclonal, and HPA-1a allo-, antibodies; this adversely affected sensitivity of the monoclonal antibody-specific immobilization of platelet antigens (MAIPA) assay and indirect platelet immunofluorescence test (PIFT). This study presents results from an international workshop studying the impact of cation chelation on HPA-1a antibody detection in routine diagnostic laboratories. Serum and EDTA-anticoagulated plasma samples containing anti-HPA-1a were distributed to 39 laboratories. Participants were asked to detect and identify any HPA antibodies present. 2/39 (5·1%) participants were able to detect and identify anti-HPA-1a in the serum, but not in the plasma sample. EDTA plasma reduced MAIPA assay sensitivity by ≥20% in 17/24 (70·8%) laboratories and by ≥50% in 9/24 (37·5%) when using HPA-1a1a platelets (mean: 27·7%, range 0-85·1%); when using HPA-1a1b platelets 3/4 (75%), participants reported ≥50% loss of sensitivity (mean 65·6%, range 0-96·6%). A small but significant increase in optical densities was observed in antigen capture ELISA assays when using plasma (mean difference: 0·081, P < 0·01). Insufficient PIFT data were returned to draw firm conclusions. Use of EDTA plasma significantly affects the sensitivity of the MAIPA assay and can affect detection of even potent, FNAIT-causing examples of anti-HPA-1a. These data highlight the importance of use of αIIbβ3 in an appropriate conformation for the sensitive detection of anti-HPA-1a. 23755863 Cytoprotective and antioxidant effects of the edible halophyte Sarcocornia perennis L. (swampfire) against lead-induced toxicity in renal cells. Lead (Pb) exposure is considered as a risk factor responsible for renal impairment in humans. On the other hand, the halophyte Sarcocornia perennis is a fresh vegetable crop suitable for leafy vegetable production. This study was designed to evaluate the in vitro protective activity of S. perennis against lead-induced damages in HEK293 kidney cells. Morphological and biochemical indicators were used to assess cytotoxicity and oxidative damages caused by Pb treatment on the cells. Our results showed that lead induced (1) a decrease in cell viability (MTT), (2) cell distortion and cohesion loss, (3) superoxide anion production and lipid peroxidation. Conversely, addition of S. perennis extract to the lead-containing medium alleviated every above syndrome. Thus, cell survival was increased and the production of reactive oxygen species caused by Pb treatment was inhibited. Taken together, our study revealed that S. perennis has potent cytoprotective effect against Pb-induced toxicity in HEK 293 cell. Such action would proceed through the decrease in ROS levels and resulting oxidative stress, which suggests a potential interest of this halophyte in the treatment of oxidative-stress related diseases. 23887863 Enhancer of Zeste Homolog 2 (EZH2) Promotes Progression of Cholangiocarcinoma Cells by Regulating Cell Cycle and Apoptosis. Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2). When present in PRC2, EZH2 catalyzes trimethylation on lysine 27 residue of histone H3, resulting in epigenetic silencing of gene expression and cancer progression. We investigated the expression and function of EZH2 in intrahepatic and extrahepatic cholangiocarcinoma (ICC and ECC). The influence of EZH2 on cell growth and apoptosis was assessed by knockdown experiments. Target gene of EZH2 was searched by quantitative RT-PCR. Clinical significance of EZH2 in 86 cholangiocarcinoma patients (45 ICC and 41 ECC) who underwent curative surgery was examined by immunohistochemistry. In vitro analysis, knockdown of EZH2 reduced cell growth, induced G1 arrest, and induced apoptosis, as confirmed by Annexin V staining and increased sub-G1 populations in cholangiocarcinoma cell lines. The expression levels of p16 (INK4a) and p27 (KIP1) were remarkably increased by knockdown of EZH2 in these cell lines. In immunohistochemical study, EZH2 upregulation correlated with tumor diameter (p = 0.0103) in ICC, lymph node metastasis (p = 0.0292) in ECC, and Ki67 index in both ICC (p = 0.0364) and ECC (p = 0.0017). In addition, EZH2 expression was correlated with poor prognosis in both ICC (p = 0.0447) and ECC (p = 0.0227). The current study demonstrated relationships between EZH2 expression and acceleration of the cell cycle and antiapoptosis, and poor prognosis in cholangiocarcinoma. These results suggest that EZH2 may represent a potential therapeutic target in patients with cholangiocarcinoma. 23630161 Primary homologies of the circumorbital bones of snakes. Some snakes have two circumorbital ossifications that in the current literature are usually referred to as the postorbital and supraorbital. We review the arguments that have been proposed to justify this interpretation and provide counter-arguments that reject those conjectures of primary homology based on the observation of 32 species of lizards and 81 species of snakes (both extant and fossil). We present similarity arguments, both topological and structural, for reinterpretation of the primary homologies of the dorsal and posterior orbital ossifications of snakes. Applying the test of similarity, we conclude that the posterior orbital ossification of snakes is topologically consistent as the homolog of the lacertilian jugal, and that the dorsal orbital ossification present in some snakes (e.g., pythons, Loxocemus, and Calabaria) is the homolog of the lacertilian postfrontal. We therefore propose that the terms postorbital and supraorbital should be abandoned as reference language for the circumorbital bones of snakes, and be replaced with the terms jugal and postfrontal, respectively. The primary homology claim for the snake "postorbital" fails the test of similarity, while the term "supraorbital" is an unnecessary and inaccurate application of the concept of a neomorphic ossification, for an element that passes the test of similarity as a postfrontal. This reinterpretation of the circumorbital bones of snakes is bound to have important repercussions for future phylogenetic analyses and consequently for our understanding of the origin and evolution of snakes. J. Morphol. 274:973-986, 2013. © 2013 Wiley Periodicals, Inc. 23836765 Megalocytivirus infection in orbiculate batfish Platax orbicularis. Megalocytiviruses cause systemic disease in both marine and freshwater fishes, negatively impacting ornamental and food fish aquaculture. In this report, we characterize a megalocytivirus infection in a captive marine ornamental fish, the orbiculate batfish Platax orbicularis. Histologic examination revealed cytomegalic cells characterized by strongly basophilic granular intracytoplasmic inclusions within various organs. Transmission electron microscopy revealed icosahedral virus particles within the cytoplasm of cytomegalic cells consistent with an iridovirus infection. Analysis of the major capsid protein gene sequence confirmed that the orbiculate batfish virus is a member of the family Iridoviridae and is identical to the only other megalocytivirus reported from a marine ornamental fish, the Banggai cardinalfish Pterapogon kauderni iridovirus. 23891048 Inferior Mesenteric Artery Collaterals to the Uterus during Uterine Artery Embolization: Prevalence, Risk Factors, and Clinical Outcomes. To evaluate the prevalence of inferior mesenteric artery (IMA) collaterals to the uterus found during uterine artery embolization (UAE), associated risk factors, and clinical outcomes. The records of 559 women who underwent UAE during the period 2008-2011 for uterine fibroids or adenomyosis found on magnetic resonance imaging were retrospectively analyzed. If IMA collaterals to the uterus were suspected on aortography performed after embolization, selective angiography was performed. Risk factors for IMA collaterals to the uterus were analyzed, including the presence of adenomyosis, baseline uterine volume, or prior pelvic surgery. Collaterals to the uterus were found from the ovarian artery (n = 21; 3.8%), IMA (n = 7; 1.3%), round ligament artery (n = 1; 0.2%), and internal pudendal artery (n = 1; 0.2%). IMA collaterals were found in seven patients. Of 185 patients, 6 (3.2%) had adenomyosis, with or without fibroids, which was significantly more frequent than the 1 (0.27%) of 374 patients who had fibroids only (P = .006). On multiple logistic regression analysis, the presence of adenomyosis (odds ratio, 19.556; P = .0168) and uterine volume (odds ratio, 1.003; P = .0069) were independent factors for the presence of IMA collaterals. Of the seven patients with IMA collaterals, embolization was not attempted in six, resulting in clinical failure in four. One patient who underwent IMA embolization with coils experienced clinical improvement. The IMA was the second most common (1.3%) source of collaterals to the uterus. IMA collaterals were more frequent in patients with adenomyosis than in patients with fibroids only, resulting in high frequency of treatment failure. 23831331 CK2-mediated TEL2 phosphorylation augments nonsense-mediated mRNA decay (NMD) by increase of SMG1 stability. Nonsense-mediated mRNA decay (NMD) is the best-characterized mRNA surveillance mechanism that degrades a premature-termination codon (PTC)-containing mRNA. During mammalian NMD, SMG1 and UPF1, key proteins in NMD, join at a PTC and form an SMG1-UPF1-eRF1-eRF3 (SURF) complex by binding UPF1 to eRF3 after PTC-recognition by the translating ribosome. Subsequently, UPF1 is phosphorylated after UPF1-SMG1 moves onto the downstream exon junction complex (EJC). However, the cellular events that induce UPF1 and SMG1 complex formation and increase NMD efficiency before PTC recognition remain unclear. Here, we show that telomere-maintenance 2 (TEL2) phosphorylation by casein-kinase 2 (CK2) increases SMG1 stability, which increases UPF1 phosphorylation and, ultimately, augments NMD. Inhibition of CK2 activity or downregulation of TEL2 impairs NMD. Intriguingly, loss of TEL2 phosphorylation reduces UPF1-bound PTC-containing mRNA and the formation of the SMG1-UPF1 complex. Thus, our results identify a new function of CK2-mediated TEL2 phosphorylation in a mammalian NMD. 22918703 CCAAT/Enhancer-binding protein-homologous protein sensitizes to SU5416 by modulating p21 and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma cells. SU5416, vascular endothelial cell growth factor receptor inhibitor, suppresses hypoxia-induced angiogenesis, growth, proliferation, and metastasis in cancer cells. CCAAT/enhancer-binding protein-homologous protein (CHOP) has pivotal roles in regulation of growth and survival. In the present study, we evaluated the effects of SU5416 on cell survival, p21, and PI3K/Akt signal pathway in FRO anaplastic thyroid carcinoma (ATC) cells. Moreover, we investigated the roles of CHOP in cell survival under condition of SU5416 treatment in FRO ATC cells. After SU5416 treatment, cell viability, PARP-1, and caspase-3 protein levels were not changed. p53 and p27 protein levels decreased while p21 protein levels increased. Phospho-Akt protein levels were not altered. In SU5416-treated situation, cell viability was not different before and after administration of either p21 siRNA or LY294002 whereas it was lessened after co-administration of p21 siRNA and LY294002. Compared to SU5416 treatment alone, cell viability was reduced with CHOP plasmid but it was unchanged with CHOP siRNA. PARP-1 and caspase-3 protein levels with CHOP plasmid were elevated whereas the protein levels with CHOP siRNA were similar. While CHOP plasmid transfection diminished p21 and phospho-Akt protein levels, CHOP siRNA transfection did not alter the protein levels. In conclusion, these results suggest that CHOP may sensitize FRO ATC cells to SU5416 thereby inhibiting cell survival by modulating p21 and PI3K/Akt signal pathway. Furthermore, these findings imply that CHOP may be a possible candidate as the chemosensitizing factor for induction of cytotoxicity in ATC cells exposed to SU5416. 23856658 Hexanuclear and undecanuclear iron(iii) carboxylates as catalyst precursors for cyclohexane oxidation. Two multinuclear complexes [Fe6(μ3-O)2(μ4-O2)L10(OAc)2(H2O)2]·2.625Et2O·2.375H2O () and [Fe(III)11Cl(μ4-O)3(μ3-O)5L16(dmf)2.5(H2O)0.5]·Et2O·1.25dmf·3.8H2O (), where HL = 3,4,5-trimethoxybenzoic acid and dmf = dimethylformamide, have been prepared from trinuclear iron(iii) carboxylates via their structural rearrangement in dimethylformamide or diethyl ether-dimethylformamide 9 : 1, respectively, and slow vapor diffusion of diethyl ether into the reaction mixture. Both compounds have been characterized by X-ray diffraction, optical, Mössbauer spectroscopy, and magnetic measurements. Complex possesses a hexanuclear ferric peroxido-dioxido {Fe6(O2)(O)2}(12+) core unit, which adopts a recliner conformation, while complex contains an unprecedented {Fe11O8Cl}(16+) core, in which 9 ferric ions are six-coordinate and the remaining two are five-coordinate. Another structural feature of note of the undecanuclear core is the presence of a deformed cubane entity {Fe4(μ3-O)(μ4-O)3}(4+). Both complexes act as catalyst precursors for the oxidation of cyclohexane to cyclohexanol and cyclohexanone with aqueous H2O2, in the presence of pyrazinecarboxylic acid. Remarkable TONs and TOFs (the latter mainly for ) with concomitant quite good yields have been achieved under mild conditions. Moreover, exhibits remarkably high activity in an exceptionally short reaction time (45 min), being unprecedented for any metal catalyzed alkane oxidation by H2O2. The catalytic reactions proceed via Fenton type chemistry. 23939933 Vinylsulfonamide and Acrylamide Modification of DNA for Cross-linking with Proteins. Bioorthogonal covalent cross-linking of DNA-binding proteins (p53) to DNA was achieved through novel DNA probes bearing a reactive vinylsulfonamide (VS) group. The VS-modified dCTP served as building block for polymerase synthesis of modified DNA, which was readily conjugated with cysteine-containing peptides and proteins by Michael addition. 23286512 Cationic liposomes as non-viral vector for RNA delivery in cancer immunotherapy. This review presents the current status in the use of liposomes as non-viral vector for nucleic acid delivery in cancer immunotherapy. Currently, cancer treatment uses surgery, radiotherapy and/or chemotherapy. The search for new strategies to improve the efficiency of conventional treatments is a challenge, and biological therapy has emerged as a promising technique. Immunotherapy is a branch of biological therapy that uses the body's immune system to detect and destroy cancer cells. One immunotherapy approach is the activation of T lymphocytes from cancer patients by dendritic cells (DCs) loaded with tumor antigens. Among different antigens, mRNA coding the tumor antigens is advantageous due to its capability to be amplified from small amounts of tumor tissue, its safety because it is easily degraded without integrating into the host genome, and it does not need to cross the nuclear barrier to exert its biological activity. Nanotechnology is an approach to deliver tumor antigens into DCs. Specially; we review the use of nanoliposomes in the field of cancer therapy because cationic liposomes can be used as non-viral vectors for mRNA delivery. Aside from the promise of liposomes, the development of scalable processes and facilities to the use this individualized therapy is still a challenge. Thus, we also present the recent techniques used for liposome production. In this context, the integration between technological knowledge in the production of cationic liposomes and immunotherapy using mRNA may contribute to the development of new strategies for cancer therapy. 23368969 Comparison of intravitreal vancomycin and daptomycin application in experimental methicillin-resistant Staphylococcus aureus (MRSA) endophthalmitis in rabbits. Abstract Purpose: To compare bactericidal activities of daptomycin and vancomycin in an experimental rabbit model of methicillin-resistant Staphylococcus aureus (MRSA) endophthalmitis. Methods: The right eyes of 19 New Zealand rabbits weighing 2 to 2.5 kg were used. Each eye was inoculated with 1000 colony-forming units (cfu) of MRSA into the vitreous cavity. 24 h after the inoculation, the rabbits were randomly distributed into three groups: control group (n = 5) was given 0.1 ml of balanced saline solution, daptomycin group 2 (n = 7) was given 0.2 mg/0.1 ml daptomycin and vancomycin group 3 (n = 7) was given 1 mg/0.1 ml vancomycin intravitreally. Clinical examination scores were recorded and vitreous aspirates were obtained for microbiological analysis on days 2 and 3 after MRSA inoculation. Rabbits were sacrificed, and the eyes were enucleated for histopathological examination. Results: There was no difference between the daptomycin group, vancomycin group and control in terms of the clinical grading of endophthalmitis 24 h after the inoculation. In all treatment groups, mean number of cfu and histopathological scores were significantly lower compared to the control group. There was no difference between the daptomycin and vancomycin group in terms of the histopathological and clinical examination scores. Culture negativity achieved on day 3 was 71.4% and 57.1% in the daptomycin treatment group and the vancomycin treatment group, respectively. Conclusions: Although both daptomycin and vancomycin are effective in treatment of experimental MRSA endophthalmitis, daptomycin has superior bactericidal activity 72 h after inoculation. 23160910 Coupling between resting cerebral perfusion and EEG. While several studies have investigated interactions between the electroencephalography (EEG) and functional magnetic resonance imaging BOLD signal fluctuations, less is known about the associations between EEG oscillations and baseline brain haemodynamics, and few studies have examined the link between EEG power outside the alpha band and baseline perfusion. Here we compare whole-brain arterial spin labelling perfusion MRI and EEG in a group of healthy adults (n = 16, ten females, median age: 27 years, range 21-48) during an eyes closed rest condition. Correlations emerged between perfusion and global average EEG power in low (delta: 2-4 Hz and theta: 4-7 Hz), middle (alpha: 8-13 Hz), and high (beta: 13-30 Hz and gamma: 30-45 Hz) frequency bands in both cortical and sub-cortical regions. The correlations were predominately positive in middle and high-frequency bands, and negative in delta. In addition, central alpha frequency positively correlated with perfusion in a network of brain regions associated with the modulation of attention and preparedness for external input, and central theta frequency correlated negatively with a widespread network of cortical regions. These results indicate that the coupling between average EEG power/frequency and local cerebral blood flow varies in a frequency specific manner. Our results are consistent with longstanding concepts that decreasing EEG frequencies which in general map onto decreasing levels of activation. 23966505 Impact of blood volume, tube shaking, and incubation time on the reproducibility of QuantiFERON-TB Gold In-Tube assay. Interferon gamma release assays (IGRAs) are functional assays used serially to measure the efficacy of novel tuberculosis (TB) vaccines and to screen health care workers for latent tuberculosis infection (LTBI). Yet, studies are showing non-reproducible IGRA results. In this study we investigated the effect of blood volume (0.8, 1.0, and 1.2 ml), tube shaking (gentle vs. vigorous), and incubation duration (16, 20, and 24 hour) on the reproducibility of QuantiFERON-TB Gold In-Tube (QFT-GIT) results in 50 (33 uninfected and 17 infected) subjects. The median IFN-γ TB response (TB Antigen (Ag) minus Nil) was significantly higher with 0.8 ml blood (1.04 IU/ml) compared to 1.0 ml (0.85 IU/ml; P=0.002) and 1.2 ml (0.49 IU/ml; P<0.001) in subjects with LTBI. Compared to 0.8 ml (11.8%), there were higher proportions of false negative results with 1.0 ml (29.4%; P=0.2) and 1.2 ml (41.2%; P=0.05) of blood in infected subjects. Blood volume did not significantly change the proportion of positive results in uninfected controls. Compared to gentle shaking, vigorous shaking increased the median IFN-γ response in Nil (0.04 vs. 0.06 IU/ml; P<0.001) and TB Ag (0.12 vs. 0.24 IU/ml; P=0.004) tubes and increased TB response (TB AgVigorous minus NilGentle) (0.02 vs. 0.08, P=0.004). The duration of incubation did not have a significant impact on the proportion of positive results in uninfected or infected subjects. This study identified blood volume and tube shaking as novel preanalytical sources of variability which require further standardization in order to improve the quality and reproducibility of QFT-GIT results. 23685803 Synthesis, characterization and equilibrium studies of some potential antimicrobial and antitumor complexes of Cu(II), Ni(II), Zn(II) and Cd(II) ions involving 2-aminomethylbenzimidazole and glycine. The ternary complexes of Cu(II), Zn(II), Ni(II) and Cd(II) with 2-aminomethylbenzimidazole (AMBI) and glycine as a representative example of amino acids have been isolated and characterized by elemental analyses, IR, ESR, UV-vis, magnetic moment, molar conductance and (1)H NMR spectra. AMBI behaves as neutral bidentate ligands with coordination through imidazole and amino group nitrogens while the glycine amino acid behaves as a monodenate anion with coordination involving the amino group and carboxylate oxygen after deprotonation. The magnetic and spectral data indicates a square planar geometry for both Cu(2+) and Ni(2+) complexes and a tetrahedral geometry for both Zn(2+) and Cd(2+) complexes. The isolated chelates have been screened for their antifungal and antibacterial activities using the disc diffusion method. A cytotoxicity of the compounds against colon (HCT116) and larynx (HEP2) cancer cells have been studied. The stability constants of ternary M-AMBI-Gly complexes were determined potentiometrically in aqueous solution at I=0.1 mol dm(-3) NaCl. 23958037 Joint symbolic analyses of heart rate, blood pressure and respiratory dynamics. The dynamics of cardiovascular variables are modulated by respiration. The aim of this study was to assess baroreflex function in normal subjects based on the joint symbolic dynamics of heart rate, blood pressure and respiration. ECG, continuous blood pressure and respiration were recorded in ten healthy subjects during rest in the supine position and upon standing. Beat-to-beat time series of heart rate, systolic blood pressure and respiratory phase were extracted and transformed into binary symbol sequences. Words of length two that were reflective of baroreflex activity were statistically analysed with respect to the respiratory phase. Symbolic analysis showed a significant influence of the respiratory phase on the occurrence of baroreflex patterns. Upon standing, the frequency of baroreflex words increased and the effect of respiration appeared to be reduced. Symbolic dynamics provide a simple representation of cardiovascular dynamics and may be useful for assessing baroreflex function. 23860734 The influence of shell thickness of Au@TiO2 core-shell nanoparticles on the plasmonic enhancement effect in dye-sensitized solar cells. Plasmonic core-shell nanoparticles (PCSNPs) can function as nanoantennas and improve the efficiency of dye-sensitized solar cells (DSSCs). To achieve maximum enhancement, the morphology of PCSNPs needs to be optimized. Here we precisely control the morphology of Au@TiO2 PCSNPs and systematically study its influence on the plasmonic enhancement effect. The enhancement mechanism was found to vary with the thickness of the TiO2 shell. PCSNPs with a thinner shell mainly enhance the current, whereas particles with a thicker shell improve the voltage. While pronounced plasmonic enhancement was found in the near infrared regime, wavelength-independent enhancement in the visible range was observed and attributed to the plasmonic heating effect. Emission lifetime measurement confirms that N719 molecules neighboring nanoparticles with TiO2 shells exhibit a longer lifetime than those in contact with metal cores. Overall, PCSNPs with a 5 nm shell give the highest efficiency enhancement of 23%. Our work provides a new synthesis route for well-controlled Au@TiO2 core-shell nanoparticles and gains insight into the plasmonic enhancement in DSSCs. 23958990 Intraperitoneal bladder rupture. A 24-year old man was referred to the authors' institution with severe abdominal pain after involvement in a road traffic incident. 23912910 Quantification of Cardiomyocyte Hypertrophy by Cardiac Magnetic Resonance: Implications on Early Cardiac Remodeling. Cardiomyocyte hypertrophy is a critical precursor to the development of heart failure. Methods to phenotype cellular hypertrophy non-invasively are limited. The goal was to validate a CMR-based approach for the combined assessment of extracellular matrix expansion and cardiomyocyte hypertrophy. Two murine models of a) hypertension (N=18, with N=15 controls) induced by L-NG-Nitroarginine Methyl Ester (L-NAME) and b) pressure-overload (N=11) from transaortic constriction (TAC), were imaged by CMR at baseline and 7-weeks after L-NAME treatment, or up to 7 weeks following TAC. T1 relaxation times were measured before and after gadolinium contrast. The intracellular lifetime of water (τic), a cell size dependent parameter, and extracellular volume fraction (ECV), a marker of interstitial fibrosis, were determined with a model for transcytolemmal water exchange. Cardiomyocyte diameter and length were measured on FITC-wheat germ agglutinin stained sections. τic correlated strongly with histologic cardiomyocyte volume-to-surface ratio (r=0.78, P<0.001) and cell volume (r=0.75; P<0.001). Histological cardiomyocyte diameters and cell volume were higher in mice treated with L-NAME compared to controls (P<0.001). In the TAC model, CMR and histology showed an cell hypertrophy at two weeks post TAC, without significant fibrosis at this early time point. Mice exposed to TAC demonstrated a significant, longitudinal, and parallel increase in histological cell volume, volume-to-surface ratio, and τic, between 2 and 7 weeks after TAC. The intracellular lifetime (τic) measured by contrast-enhanced CMR provides a non-invasive measure of cardiomyocyte hypertrophy. ECV and τic can track myocardial tissue remodeling from pressure overload. 23950225 Priming the Brain to Capitalize on Metaplasticity in Stroke Rehabilitation. Repetitive transcranial magnetic stimulation (rTMS) is emerging as a potentially valuable intervention to augment the effects of behavioral therapy for stroke. When used in conjunction with other therapies, rTMS embraces the concept of metaplasticity. Due to homeostatic mechanisms inherent to metaplasticity, interventions known in isolation to enhance excitability can interact when applied successively under certain timing conditions and produce enhanced or opposite effects. It will be shown that similar to "muscular wisdom", with its self-protective mechanisms, there also appears to be synaptic wisdom in neural networks with homeostatic processes that prevent over- and under-excitability. These processes hold implications for both enhancing and suppressing the desired effects from behavioral therapy. The purpose of this paper is to relate the concept of metaplasticity, as derived from studies in healthy humans, to stroke rehabilitation and consider how it can be leveraged to maximize stroke outcomes. 23553598 Identification of tissue-preferential expression patterns of rice miRNAs. It is imperative to understand the mechanisms of growth and development in higher plants for improving plant adaptation during different developmental stages. Plant microRNAs (miRs) play crucial regulatory roles in various developmental processes. As many as 15 miR families having multiple members are known to regulate plant development, yet the spatio-temporal expression patterns of individual members are not fully characterized. It is likely that different members of miR families can make specific contributions to the spatio-temporal control of targets. To understand the functional complexity of miRs and the amount of degeneracy existing in miR-mediated regulation of differentiated but developing tissues, we have identified the Osa-miR-sequences that are expressed in specific tissues. We adopted the approach of comparative miR profiling using next-generation sequencing technology followed by experimental validation. It was observed that 59 Osa-miR-sequences show tissue-preferential expression in local basmati rice variety; while 126 miRs belonging to 81 families are differentially regulated in these tissues. The 21 nt miRs were predominant in all tissues, but the 24 nt miRs were the most abundantly expressed. This indicates that target cleavage and chromatin state regulation are involved in organ development. This study also identified the expression patterns of individual members of Osa-miR families that were common and divergent between the indica and japonica rice varieties. The expression patterns of the predicted targets were also analyzed. The possible implications of the miR distribution patterns with respect to the regulation of their respective targets are discussed. J. Cell. Biochem. 114: 2071-2081, 2013. © 2013 Wiley Periodicals, Inc. 23640361 Characterization of four TCE-dechlorinating microbial enrichments grown with different cobalamin stress and methanogenic conditions. To investigate the important supportive microorganisms responsible for trichloroethene (TCE) bioremediation under specific environmental conditions and their relationship with Dehalococcoides (Dhc), four stable and robust enrichment cultures were generated using contaminated groundwater. Enrichments were maintained under four different conditions exploring two parameters: high and low TCE amendments (resulting in inhibited and uninhibited methanogenic activity, respectively) and with and without vitamin B₁₂ amendment. Lactate was supplied as the electron donor. All enrichments were capable of reductively dechlorinating TCE to vinyl chloride and ethene. The dechlorination rate and ethene generation were higher, and the proportion of electrons used for dechlorination increased when methanogenesis was inhibited. Biologically significant cobalamin biosynthesis was detected in the enrichments without B₁₂ amendment. Comparative genomics using a genus-wide microarray revealed a Dhc genome similar to that of strain 195 in all enrichments, a strain that lacks the major upstream corrin ring biosynthesis pathway. Seven other bacterial operational taxonomic units (OTUs) were detected using clone libraries. OTUs closest to Pelosinus, Dendrosporobacter, and Sporotalea (PDS) were most dominant. The Clostridium-like OTU was most affected by B₁₂ amendment and active methanogenesis. Principal component analysis revealed that active methanogenesis, rather than vitamin B₁₂ limitation, exerted a greater effect on the community structures even though methanogens did not seem to play an essential role in providing corrinoids to Dhc. In contrast, acetogenic bacteria that were abundant in the enrichments, such as PDS and Clostridium sp., may be potential corrinoid providers for Dhc. 23044265 Lipid peroxidation triggers neurodegeneration: A redox proteomics view into the Alzheimer disease brain. Lipid peroxidation involves a cascade of reactions in which production of free radicals occurs selectively in the lipid components of cellular membranes. Polyunsaturated fatty acids easily undergo lipid peroxidation chain reactions, which, in turn, lead to the formation of highly reactive electrophilic aldehydes. Among these, the most abundant aldehydes are 4-hydroxy-2-nonenal (HNE) and malondialdehyde, while acrolein is the most reactive. Proteins are susceptible to posttranslational modifications caused by aldehydes binding covalently to specific amino acid residues, in a process called Michael adduction, and these types of protein adducts, if not efficiently removed, may be, and generally are, dangerous for cellular homeostasis. In the present review, we focused the discussion on the selective proteins that are identified, by redox proteomics, as selective targets of HNE modification during the progression and pathogenesis of Alzheimer disease (AD). By comparing results obtained at different stages of the AD, it may be possible to identify key biochemical pathways involved and ideally identify therapeutic targets to prevent, delay, or treat AD. 22417089 Grewialin and optivanin new constituents from the stem bark of Grewia optiva Drummond ex Burret (Tiliaceae). Studies on the chemical constituents from the stem bark of Grewia optiva have led to the isolation of two new compounds, grewialin (1) and optivanin (2), along with three known constituents which were hitherto unreported from this species. The structures of the new constituents have been elucidated by spectral studies including 1D and 2D NMR experiments (HSQC, HMBC, COSY, NOESY and J-resolved) as well as HR EI-MS spectroscopic data analysis, as 2S*-(3-hydroxy-4-methoxyphenyl)-3R*-methyl-2H-[1,4]-dioxin [2,3]-chromen-7(3H)-one (1); a coumarinolignan and 3-hydroxy-1-(3-hydroxy-4-methoxyphenyl) propan-1-one (2). The known compounds were identified as β-sitosterol, stigmasterol and lupeol by comparing their spectral data with those reported in the literature. 23701881 Food-intake dysregulation in type 2 diabetic Goto-Kakizaki rats: Hypothesized role of dysfunctional brainstem thyrotropin-releasing hormone and impaired vagal output. Thyrotropin-releasing hormone (TRH), a neuropeptide contained in neural terminals innervating brainstem vagal motor neurons, enhances vagal outflow to modify multisystemic visceral functions and food intake. Type 2 diabetes (T2D) and obesity are accompanied by impaired vagal functioning. We examined the possibility that impaired brainstem TRH action may contribute to the vagal dysregulation of food intake in Goto-Kakizaki (GK) rats, a T2D model with hyperglycemia and impaired central vagal activation by TRH. Food intake induced by intracisternal injection of TRH analog was reduced significantly by 50% in GK rats, compared to Wistar rats. Similarly, natural food intake in the dark phase or food intake after an overnight fast was reduced by 56-81% in GK rats. Fasting (48h) and refeeding (2h)-associated changes in serum ghrelin, insulin, peptide YY, pancreatic polypeptide and leptin, and the concomitant changes in orexigenic or anorexigenic peptide expression in the brainstem and hypothalamus, all apparent in Wistar rats, were absent or markedly reduced in GK rats, with hormone release stimulated by vagal activation, such as ghrelin and pancreatic polypeptide, decreased substantially. Fasting-induced Fos expression accompanying endogenous brainstem TRH action decreased by 66% and 91%, respectively, in the nucleus tractus solitarius (NTS) and the dorsal motor nucleus of the vagus (DMV) in GK rats, compared to Wistar rats. Refeeding abolished fasting-induced Fos-expression in the NTS, while that in the DMV remained in Wistar but not GK rats. These findings indicate that dysfunctional brainstem TRH-elicited vagal impairment contributes to the disturbed food intake in T2D GK rats, and may provide a pathophysiological mechanism which prevents further weight gain in T2D and obesity. 23411242 Moisture diffusivity in food materials. This paper investigates whether moisture diffusion can be predicted for food materials. We focus especially on mixtures of glucose homopolymers and water. The predictions are based on three theories: (1) the Darken relation, linking the mutual diffusivity to the self diffusivities, (2) the generalised Stokes-Einstein relation for the solute self diffusivity, and (3) the free volume theory for water self diffusivity. Using literature data obtained for the whole class of glucose homopolymer, we show that these theories predict the moisture diffusivity for the whole range of volume fractions, from zero to one, and a broad range of temperatures. Furthermore, we show that the theories equally holds for other hydrophilic biopolymers one finds in food. In the concentrated regime, all experimental data collapse to a single curve. This universal behaviour arises because these biopolymers form a hydrogen bonded network, where water molecules move via rearrangement of the free volume. 23849536 Determinants of sexual dysfunction in women with multiple sclerosis. The aim of present study was to determine disease-related and psychological risk factors for sexual dysfunction in women with multiple sclerosis (MS). This was a clinical-based study conducted from September 2009 to June 2010 in Tehran, Iran. A consecutive sample of female patients with MS was recruited from an outpatient clinic. The Female Sexual Function Index (FSFI) was used to evaluate sexual function. In addition neurological impairment was measured using the Kurtzke Expanded Disability Status Scale (EDSS), and depression was assessed using the Beck Depression Inventory-II (BDI-II). Univariate and multiple logistic regression analyses were performed in order to examine the association between sexual dysfunction and independent variables. In all, 226 women participated in the study. Of these, 125 women (55.3%) met the criteria for sexual dysfunction. The mean age of participants was 35.7 years (SD = 8.07). The results obtained from multiple logistic regression analysis indicated that the disease duration (OR for the disease duration of equal or greater than 9 years = 3.13,%95 CI = 1.29-7.57, P = 0.01), the disease course (OR for secondary progressive MS = 3.96,%95 CI = 1.55-10.10, P = 0.004) and the BDI score (OR = 1.11,%95 CI = 1.07-1.16, P < 0.001) were significant factors contributing to sexual dysfunction in these patients. The findings from this study indicated that the duration and severity of the disease in addition to depression were the most significant factors that contributed to sexual dysfunction in women with multiple sclerosis. The burden of disease and sexual dysfunction suggests the need for further attention to this patient population. 23448941 Low immature platelet fraction suggests decreased megakaryopoiesis in neonates with sepsis or necrotizing enterocolitis. Objective:In order to conclude on the megakaryopoietic activity during thrombocytopenia in sepsis or necrotizing enterocolitis (NEC), we analyzed the immature platelet fraction (IPF).Study design:Serial measurements of platelet counts and IPF in neonates with blood culture-proven late-onset sepsis (n=21) or surgical NEC (n=12) at T0: prior to the diagnosis of sepsis/NEC; T1: at diagnosis; T2: days 3 to 5 after onset; T3: days 8 to 12 after onset.Result:In parallel to declining platelet counts, the median absolute IPF significantly decreased between T0 and T2 in neonates with sepsis or NEC. We found a significant positive correlation between the platelet count and absolute IPF (r=0.71; P<0.001). In patients with low IPF (<2 per nl), the platelet count did not subsequently increase. Neonates with NEC who died exhibited significantly lower IPF compared with survivors (P<0.05).Conclusion:Low absolute IPF values during the course of neonatal sepsis/NEC suggest suppression of megakaryopoietic activity. 23948879 Neprilysin-Like Activity Correlates with CSF-Tau and Phospho-Tau in Patients with Alzheimer's Disease. A relation between amyloid-β peptide (Aβ) accumulation and neprilysin (NEP), an Aβ degrading enzyme, has been proposed but studies of NEP and the levels of the pathological hallmarks of Alzheimer's disease (AD), Aβ and tau, in cerebrospinal fluid (CSF) are scarce. In this study, we measured the level and enzyme activity of NEP in serum and CSF, using a sandwich enzyme-linked immunosorbent assay and a fluorescence resonance energy transfer assay, respectively, in patients with AD, frontotemporal dementia (FTD), Creutzfeldt-Jakob disease (CJD), and depression. Results were correlated with the levels of CSF AD biomarkers Aβ42, hyperphosphorylated tau (p-tau), and total tau (t-tau). In serum, we found no differences in NEP-like activity or concentration between the groups and there were no correlations between NEP and AD biomarkers. In CSF, no influence of age or gender on NEP levels or enzyme activity was seen. However, NEP concentration was lower and the specific activity was higher in FTD compared to AD. Aβ42 levels in CSF did not correlate with NEP concentration or activity in the AD, CJD, or depression groups, but NEP-like activity and Aβ42 levels correlated significantly in the FTD group. In AD and depression, the NEP-like activity in CSF correlated with levels of p-tau, and, in the AD group, it also was correlated with t-tau levels. Our results suggest that the relation between the specific activity of NEP and t-tau and p-tau is a characteristic trait of AD. The correlation between NEP concentration and Aβ42 in FTD is unexpected and warrants further investigation. 23947819 Rapid Oligonucleotide Suspension Array-Based Multiplex Detection of Bacterial Pathogens. Abstract A gene-specific microsphere suspension array coupled with 15-plex polymerase chain reaction (PCR) was developed to screen bacterial samples rapidly for 10 strains of bacteria: Shigella spp. (S. flexneri, S. dysenteriae, and S. sonnei), Staphylococcus aureus, Vibrio cholerae (serology O1 and O139), Legionella pneumophila, and Clostridium botulinum (types A, B, and E). Fifteen sets of highly validated primers were chosen to amplify target genes simultaneously. Corresponding oligonucleotide probes directly conjugated with microsphere sets were used to specifically identify PCR amplicons. Sensitivity tests revealed that the array coupled with single PCR was able to detect purified genomic DNA at concentrations as low as 10 copies/μL, while the multiplex detection limit was 10-10(4) copies/μL. The assay was validated using water samples artificially spiked with S. aureus and S. dysenteriae, as well as water specimens from swimming pools previously identified to contain S. aureus. 23872508 Role of Protein Kinase C in Ischemic "Conditioning": From First Evidence to Current Perspectives. Since the discovery of ischemic preconditioning (IPC) 26 years ago, numerous studies attempted to determine the mechanism of this powerful form of cardioprotection. One of the first proposed pathways of IPC suggested that the preconditioning stimulus activated phospholipase C via G-protein, and diacylglycerol released from phospholipid moieties activated protein kinase C (PKC) by translocating it from the cytosol to the sarcolemmal membranes. The major protective isoform of PKC was found to be the PKC-∈. Despite some contradictions and controversies, today even the most skeptical opponents acknowledge that PKC plays a significant role in the mechanism of IPC. During recent years, both the role and the place of PKC-∈ in the mechanism of IPC have been revised. The current review presents the evolution of the "PKC theory" and summarizes the most recent data regarding the role of PKC in IPC. In addition to classical IPC, PKC appears to play a role in the mechanisms of newer conditioning protocols, that is, remote IPC and ischemic postconditioning. 23892923 Suppression of granzyme B activity and caspase-3 activation in leukaemia cells constitutively expressing the protease inhibitor 9. Immune surveillance against malignant cells is mediated by cytotoxic T-lymphocytes and NK-cells (CTL/NK) that induce apoptosis through the granzyme-B-dependent pathway. The serine protease inhibitor serpinB9/protease inhibitor-9 (PI-9) is a known inhibitor of granzyme B. Ectopic expression of PI-9 in tumour cells has been reported. However, the impact of PI-9 on granzyme-B-induced apoptosis in tumour cells remains unclear. The aim of this study was to investigate the influence of constitutive PI-9 expression in leukaemia cell lines on the activity of granzyme B and apoptosis induction. PI-9 negative (lymphoblastic Jurkat cells; myeloblastic U937 cells) and PI-9-expressing cell lines (myeloblastic K562 cells, EBV-transformed LCL-1 and LCL-2 B-cells, lymphoblastic Daudi cells, AML-R cells f leukaemia and the U937 subclone U937PI-9(+)). For accurate granzyme B activity determination a quantitative substrate (Ac-IEPD-pNA) cleavage assay was established and caspase-3 activation measured for apoptosis assessment. Cells were treated with a cytotoxic granule isolate that has previously been shown to induce apoptosis through granzyme B signalling. We found a robust correlation between constitutive PI-9 expression levels and the suppression of granzyme B activity. Further, inhibition of granzyme B translated into reduced caspase-3 activation. We conclude, suppression of granzyme B initiated apoptosis in PI-9-expressing cells could contribute to immune evasion and the measurement of granzyme B activity with our assay might be a useful predictive marker in immune-therapeutic approaches against cancer. 23832827 Role of leptin in legg-calvé-perthes disease. Obesity is considered a clinical risk sign for Legg-Calvé-Perthes disease (LCPD). Leptin is primarily secreted by adipocytes, and it regulates adipose tissue mass and body weight. Furthermore, obesity is clearly associated with increased leptin levels. We investigated the roles of leptin and the soluble leptin receptor (sOB-R) in LCPD. This matched case-control study included 38 male and 3 female patients with LCPD, and an equal number of age-(range was 4-12) and sex-matched control patients with healthy fractures. Serum leptin and sOB-R levels were quantified with ELISA. The free leptin index (FLI) was defined as the ratio of leptin to sOB-R levels. Serum leptin levels, sOB-R, and FLI were compared between groups. The relationship between leptin, disease severity, and treatment outcomes were analyzed in the LCPD group. There were no significant differences between groups in terms of age, sex, and body mass index (BMI) percentile. Mean leptin levels (p = 0.042), sOB-R levels (p = 0.003), and FLI (p = 0.013) differed significantly between groups. In the LCPD group, the serum leptin levels, sOB-R levels, and FLI differed significantly between the lateral pillar and Stulberg classification groups (p < 0.05). Also, the leptin levels and FLI increased significantly according to the lateral pillar and Stulberg classifications even after adjusting for age and BMI percentile (p < 0.05). Circulating leptin and FLI were significantly higher in the LCPD group. Furthermore, leptin, disease severity, and treatment outcomes were associated. This correlation suggests that leptin might play an important role in LCPD pathogenesis. © 2013 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. J Orthop Res 31:1605-1610, 2013. 23969114 Adherence of Randomized Trials Within Children's Surgical Specialties Published During 2000 to 2009 to Standard Reporting Guidelines. Randomized clinical trials (RCTs) are uncommon in pediatric surgical specialties and the quality of reporting is unknown. Our primary purpose was to analyze published surgical RCTs involving children to measure adherence to the Consolidated Standards of Reporting Trials (CONSORT) guidelines. Published RCTs from January 1, 2000 through December 31, 2009 were reviewed. The trials were evaluated for the presence of 7 CONSORT guidelines and also graded according to the Jadad scale. Two hundred and twenty-eight trials were included. Five trials met all 7 CONSORT criteria (2%) and 53 had a Jadad score of ≥3 (23%). Slightly more than 50% of all trials specified primary outcomes and <25% described power calculations according to CONSORT. Adherence to CONSORT guidelines for allocation concealment, randomization description, and attrition details was even lower. There were significant differences between surgical specialties with regard to CONSORT adherence to the majority of the guidelines. Pediatric general surgery had the largest number of published RCTs. Pediatric orthopaedic surgery had the highest proportion of trials with a Jadad score ≥3 (40%). Adherence to CONSORT guidelines is low across the spectrum of children's surgical specialties, although significant differences do exist. Future RCTs in children's surgical specialties should specifically focus on areas of low adherence to reporting guidelines. 23932458 Validation and psychometric properties of the Asthma Control Questionnaire among children. The Asthma Control Questionnaire (ACQ) is a patient-centered tool for evaluating asthma control. It has been validated in adults, but not well-validated among children. We evaluated the reliability, validity, and responsiveness to change of the ACQ for assessing asthma control in children ages 6 to 17 years. A threshold value for poor disease control and a minimally important difference were also determined. Data from 305 asthmatic children enrolled in a clinical trial were examined. The ACQ was administered at 8 visits. We analyzed results for the combined age group and for the 6- to 11-year-old and 12- to 17-year-old age groups separately. Overall, the Cronbach α value (internal consistency) for the ACQ was 0.74 at baseline, and the intraclass correlation coefficient (test-retest reliability) for repeated questionnaires among stable patients was 0.53. The Pearson correlations between the ACQ and other asthma questionnaires were moderate to strong (-0.64 to -0.73). Mean ACQ scores were higher (worse) in patients whose peak flow decreased, who used more rescue medications, or who sought medical care for asthma than in patients who were stable (P < .0001 for all measures). Changes in ACQ scores were significantly different among patients with deteriorating, improving, or stable asthma symptoms (P â‰¤ .01). The optimal threshold indicating poor asthma control was 1.25 or greater. The minimally important difference was established to be 0.40. Results for the separate age groups were similar. The ACQ is a moderately reliable, valid, and responsive tool with adequate psychometric properties for assessing recent asthma control among children. 23615957 Laparoscopic adjustable gastric banded plication: a case-matched comparative study with laparoscopic sleeve gastrectomy. Laparoscopic sleeve gastrectomy (LSG) has been accepted as stand-alone restrictive bariatric procedure; laparoscopic adjustable gastric banded plication (LAGBP) is an innovative technique combining gastric banding and plication of the stomach. This study aims to compare LAGBP with LSG in terms of percent excess weight loss (%EWL), resolution of comorbidities, and complications. This study was conducted in a university hospital. We retrospectively analyzed data of 60 patients: 30 each receiving LSG and LAGBP between May 2009 to October 2010. Demographics, operative data, complications, % EWL, and resolution of comorbidities were analyzed and compared. All the patients were followed for at least 1 year. LSG and LAGBP were matched for age, sex, body mass index and comorbidity ratio. Mean operative time was significantly longer in LAGBP: 62.45 ±â€‰30.1 vs. 86.01 ±â€‰21.88 (p = 0.001). Both groups had similar complication rates (6.67 %) and most of the patients achieved significant resolution of comorbidities. The mean %EWL was statistically significant for LSG till 18 months follow-up as compared to LAGBP, but there was no difference at 2 years (p = 0.971). Mean frequency of band adjustment after LAGBP in 2 years was 1.50 ±â€‰1.51. There was no significant difference in comorbidity resolution in both groups. LAGBP is a dual restrictive bariatric procedure offering similar results with LSG at 2 years in terms of complications, % EWL, and comorbidity resolution with potential of continual weight loss due to band. 23826741 Efficacy and safety of rupatadine for allergic rhino-conjunctivitis: a systematic review of randomized, double-blind, placebo-controlled studies with meta-analysis. Abstract Background: Allergic rhinitis is a complex inflammatory disease whose pathophysiology involves local and systemic mechanisms. Rupatadine, a molecule with intense antihistaminic activity and with antagonist PAF effects through its interaction with specific receptors, is indicated for the treatment of intermittent or persistent allergic rhinitis and urticaria. Scope: This systematic review was aimed at identifying in the most important databases, up to January 2013, the double-blind placebo-controlled randomized trials administering rupatadine in allergic rhinitis. No restriction was introduced for treatment duration and dose, study design, population age, allergen exposition and disease classification. The methodological quality of included studies and risk of bias were systematically assessed. Meta-analysis was performed when possible to summarize information. Findings: Seventeen of 413 initially identified records were fully assessed for eligibility. Ten trials involving 2573 patients overall met the inclusion criteria and entered the analysis. Their internal validity was satisfactory. Data synthesis showed that rupatadine is superior to placebo in relieving the overall allergy symptoms on reflective (SMD: -0.37, 95% CI -0.46 to -0.27; p < 0.00001) and instantaneous (SMD: -0.41, 95% CI -0.71 to -0.11; p = 0.007) assessment, the nasal symptoms considered together (reflective SMD: -0.36, 95% CI -0.48 to -0.25; p < 0.00001; instantaneous SMD: -0.39, 95% CI -0.61 to -0.17; p = 0.0004) or individually and ocular symptoms. Inter-study heterogeneity was low for the main outcomes and the risk of publication bias was judged as unlikely. A number of secondary endpoints were favorably affected by rupatadine. No difference was observed in the incidence of total adverse reactions between rupatadine and placebo (OR 1.23, 95% CI 0.95 to 1.59; p = 0.12). Conclusion: Randomized double-blind controlled trials show a favorable risk-benefit ratio in rupatadine for the treatment of allergic rhino-conjunctivitis. This evidence is strengthened when data are pooled in the form of meta-analysis, where accurate and robust effect estimations are derived from a large population. 23954065 Outbreak of ertapenem-resistant Enterobacter cloacae urinary tract infections due to a contaminated ureteroscope. Outbreaks of urinary tract infections (UTIs) due to contaminated ureteroscopes have been rarely reported. To report such an outbreak at a regional teaching hospital in southern Taiwan. From October to December 2010, ertapenem-resistant Enterobacter cloacae were identified from urine cultures of 15 patients who had undergone ureteroscopy prior to the infection. Three batches of surveillance cultures were obtained from the environmental objects and healthcare workers related to the procedures. Pulsed-field gel electrophoresis (PFGE) was used for bacterial typing. Antimicrobial susceptibility was assessed by disc diffusion and E-test methods. Polymerase chain reaction and sequencing were used to analyse β-lactamase genes. A total of 70 specimens were obtained during the first surveillance operation. One ertapenem-resistant E. cloacae was isolated from a ureteroscope. Although the disinfection protocols for ureteroscopes were revised and implemented, seven additional UTI cases were identified thereafter. The pathogen was identified from two subsequent surveillance cultures and was not eliminated until ethylene oxide sterilization was added to the disinfection protocol. PFGE revealed that all 15 isolates from the patients and the three isolates from the ureteroscope shared a common pattern with minor variance. Most isolates were resistant to gentamicin, levofloxacin, ceftriaxone, ceftazidime, and ertapenem. All isolates were susceptible to amikacin, imipenem, and meropenem. SHV-12 and IMP-8 genes were simultaneously identified in 16 of the 18 isolates. The outbreak of ertapenem-resistant E. cloacae was caused by a contaminated ureteroscope and was terminated by the implementation of a revised disinfection protocol for ureteroscopes. 23932169 Hormone concentrations temporally associated with contralateral and ipsilateral relationships between the CL and preovulatory follicle during the third follicular wave in heifers. Concentrations of circulating hormones after Day 14 (Day 0 = ovulation) were determined daily in 87 interovulatory intervals (IOIs) in heifers. The IOIs were grouped into four permutations according to an ipsilateral (Ipsi) or contralateral (Contra) relationship between the CL and the preovulatory follicle and two (2W) or three (3W) follicular waves per IOI. The number of IOIs per group differed (P < 0.005) from equality among the Ipsi-2W (n = 27), Contra-2W (n = 31), Ipsi-3W (n = 9), and Contra-3W (n = 20) groups. A continuous decrease in progesterone (luteolysis) began later (P < 0.05) in the Contra-3W group (Day 18.0 ± 0.4) than in each of the Ipsi-2W (15.4 ± 0.2), Contra-2W (15.6 ± 0.2), and Ipsi-3W (16.2 ± 0.5) groups. Concentrations of LH and estradiol began to increase near the beginning of luteolysis in each group. A minor FSH surge that did not stimulate a major follicular wave developed in about 50% of the IOIs in each group, except that none were detected in the Ipsi-3W group. The minor FSH surge reached a peak about 4 days before ovulation and several days after wave 3 had emerged. The hypothesis that luteolysis begins earliest in two-wave IOIs, intermediate in three-wave IOIs with an ipsilateral CL/follicle relationship, and latest in three-wave IOIs with a contralateral relationship was supported. The hypothesis that a minor FSH surge occurs most frequently in association with three follicular waves was not supported. 23852768 Superatom networks in thiolate-protected gold nanoparticles. The next super model: The Au8 (4+) core of [Au20 (SR)16 ] can be viewed as two non-conjugate 4 center-2 electron (4c-2e) tetrahedral Au4 superatoms. The four valence electrons are delocalized in each Au4 unit as 4c-2e σ bonds. Chemical bonding analysis confirms that a 2e-superatom network exists in [Au20 (SR)16 ] (see picture: Au yellow, SR purple, superatoms tetrahedra/red), this model explains the properties of this species. 23924612 Gram-positive siderophore-shuttle with iron-exchange from Fe-siderophore to apo-siderophore by Bacillus cereus YxeB. Small molecule iron-chelators, siderophores, are very important in facilitating the acquisition of Fe(III), an essential element for pathogenic bacteria. Many Gram-negative outer-membrane transporters and Gram-positive lipoprotein siderophore-binding proteins have been characterized, and the binding ability of outer-membrane transporters and siderophore-binding proteins for Fe-siderophores has been determined. However, there is little information regarding the binding ability of these proteins for apo-siderophores, the iron-free chelators. Here we report that Bacillus cereus YxeB facilitates iron-exchange from Fe-siderophore to apo-siderophore bound to the protein, the first Gram-positive siderophore-shuttle system. YxeB binds ferrioxamine B (FO, Fe-siderophore)/desferrioxamine B (DFO, apo-siderophore) in vitro. Disc-diffusion assays and growth assays using the yxeB mutant reveal that YxeB is responsible for importing the FO. Cr-DFO (a FO analog) is bound by YxeB in vitro and B. cereus imports or binds Cr-DFO in vivo. In vivo uptake assays using Cr-DFO and FO and growth assays using DFO and Cr-DFO show that B. cereus selectively imports and uses FO when DFO is present. Moreover, in vitro competition assays using Cr-DFO and FO clearly demonstrate that YxeB binds only FO, not Cr-DFO, when DFO is bound to the protein. Iron-exchange from FO to DFO bound to YxeB must occur when DFO is initially bound by YxeB. Because the metal exchange rate is generally first order in replacement ligand concentration, protein binding of the apo-siderophore acts to dramatically enhance the iron exchange rate, a key component of the Gram-positive siderophore-shuttle mechanism. 23414067 Spectroscopic characterization and constitutional and rotational isomerism of ClC(O)SCN and ClC(O)NCS. Chlorocarbonylthio- and isothiocyanate (ClC(O)SCN and ClC(O)NCS) have been isolated and characterized by IR (Ar matrix, gas), Raman (liquid), (13)C NMR and UV-visible spectroscopies. Vibrational and quantum chemical studies suggest the presence of the syn and anti conformers (SCN group with respect to the C═O bond) in the gas phase for both constitutional isomers. syn-ClC(O)SCN is preferred by ΔH° (anti/syn) = 1.3(0.3) kcal mol(-1). The solid-state structure of ClC(O)SCN has been determined by single crystal X-ray diffraction analysis at low temperature. The crystalline solid consists exclusively of molecules in the syn conformation. On the other hand, the anti form is more stable for the ClC(O)NCS isomer. The structure of ClC(O)NCS and its conformational composition were determined by gas electron diffraction. An unusual low syn → anti interconversion energy barrier of 0.98 (0.15) kcal mol(-1) was detected for ClC(O)NCS at cryogenic temperatures. The photochemistry of both constitutional isomers isolated in solid argon at 15 K was studied. Rearrangement of ClC(O)SCN to ClC(O)NCS was observed in the neat liquid and under UV-vis irradiation of ClC(O)SCN isolated in solid argon. Properties have been discussed in terms of the valence electronic structure, including the analysis of the He(I) photoelectron spectrum of ClC(O)SCN. 23703380 Risk stratification among diabetic patients undergoing stress myocardial perfusion imaging. Previous studies have suggested that diabetic patients undergoing single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) are at greater risk for cardiac events than non-diabetic patients with both normal and abnormal imaging results. However, the impact of stress modality on outcomes in this patient group has not been examined. The data on all patients undergoing exercise stress or vasodilator stress SPECT MPI from 1996 to 2005 were reviewed. After excluding patients based on our predefined criteria, we subcategorized the study population into diabetic patients and non-diabetic patients. Among the diabetic patients, we identified patients with known coronary artery disease (CAD) and no known CAD. All studies were interpreted using the 17-segment ASNC model. The presence, extent, and severity of perfusion defects were calculated using the summed stress score (SSS), and patients were classified into normal (SSS < 4), mildly abnormal (SSS 4-8), and moderate-severely abnormal (SSS > 8) categories. The annualized cardiac event rate including cardiac death and non-fatal myocardial infarction was calculated over a mean follow-up period of 2.4 ± 1.4 years with a maximum of 6 years. The cardiac event rate was statistically significantly lower in diabetic patients undergoing exercise stress MPI when compared to the diabetic patients undergoing pharmacological stress MPI across all three perfusion categories (1.3% vs 3.4%, 2.3% vs 5.7%, 4.2% vs 10.7%, respectively). Diabetic patients with no known CAD, who underwent exercise stress MPI had significantly lower cardiac events across all three perfusion categories as compared to the remainder of the diabetic population. Ability to perform exercise stress test was the strongest multivariate predictor of favorable outcome, whereas ejection fraction < 50%, abnormal perfusion imaging on SPECT MPI, and increasing age stood out as independent predictors of adverse outcome in the diabetic patients. Within the abnormal perfusion category, the annualized cardiac event rate among patients undergoing exercise stress SPECT MPI was not statistically different between the diabetic and non-diabetic cohorts. Diabetic patients undergoing exercise SPECT MPI have a significantly better prognosis than those undergoing pharmacological stress, more similar to patients without diabetes. In patients with diabetes exercise stress test MPI identifies low risk patients and provides precise risk stratification. 23529380 Suppression of methylglyoxal hyperactivity by mangiferin can prevent diabetes-associated cognitive decline in rats. Evidences indicate that methylglyoxal, a highly reactive metabolite of hyperglycemia, can enhance protein glycation, oxidative stress, or inflammation. Mangiferin, a polyphenol compound of C-glucoside, has many beneficial biological activities, including anti-inflammation, anti-oxidation, neuroprotection, cognitive enhancement, etc. Whether mangiferin alleviates diabetes-associated cognitive impairment is still unclear. The present study was designed to investigate the effects of mangiferin on the behavioral deficits of diabetic rats induced by streptozotocin; the mechanisms associated with methylglyoxal toxicity are especially investigated. Diabetic rats were treated with mangiferin (15, 30, and 60 mg/kg, p.o.) for 9 weeks. Cognitive performances were evaluated with the Morris water maze. Hippocampus and blood were obtained for evaluation of the effects of mangiferin on protein glycation, oxidative stress, and inflammation in diabetic state. Mangiferin significantly improved the behavioral performances of diabetic rats, evidenced by a decrease in escape latency as well as increases in numbers of crossing the platform and percentage of time spent in the target quadrant, which were accompanied by decreases in the levels of advanced glycation end-products and their receptor (RAGE), interleukin-1β, TNF-α, and malondialdehyde and increases in the activity and expression of glyoxalase 1 as well as glutathione level in the hippocampus of diabetic rats. Furthermore, mangiferin produced a significant decrease in malondialdehyde level and increased glutathione level and superoxide dismutase activity in the serum of diabetic rats. This study demonstrates that mangiferin can markedly ameliorate diabetes-associated cognitive decline in rats, which is done likely through suppressing methylglyoxal hyperactivity (promoting protein glycation, oxidative stress, and inflammation) mediated noxious effects. 23842842 Preferences Regarding Treatment for Alcohol Problems. The aim of the study was to investigate preferences in the general population regarding type of treatment for alcohol problems and the preferred setting for delivery of treatment and reasons for not seeking treatment for alcohol problems. Method: Data were from a random, cross-sectional, interview survey of 9005 of the Swedish general population. Proportions of respondents preferring a certain treatment and source of treatment, and reasons suggested for why people do not seek treatment, were analysed in relation to number of standard drinks, employment status, education and income. Most frequently endorsed forms of treatment were alcoholics anonymous or similar support groups and psychotherapy. More than 50% preferred psychiatric or addiction specialist treatment. Around 10% preferred primary health care and around 20% the occupational health services. About 5% preferred the social services. Respondents rated 'feeling ashamed' as the most important reason why people would not seek help for alcohol problems. Large majorities of the respondents preferred treatment in the health care services and few in the social services. Internet-based treatment and pharmacological treatment attracted few respondents, the majority preferring more traditional forms of treatment. Alcohol treatment remains a stigmatized field, evidenced by shame being the most commonly reported reason for not seeking treatment. 23749747 The Human Eye Proteome Project: Perspectives on an emerging proteome. There are an estimated 285 million people with visual impairment worldwide, of whom 39 million are blind. The pathogenesis of many eye diseases remains poorly understood. The human eye is currently an emerging proteome that may provide key insight into the biological pathways of disease. We review proteomic investigations of the human eye and present a catalogue of 4842 nonredundant proteins identified in human eye tissues and biofluids to date. We highlight the need to identify new biomarkers for eye diseases using proteomics. Recent advances in proteomics do now allow the identification of hundreds to thousands of proteins in tissues and fluids, characterization of various PTMs and simultaneous quantification of multiple proteins. To facilitate proteomic studies of the eye, the Human Eye Proteome Project (HEPP) was organized in September 2012. The HEPP is one of the most recent components of the Biology/Disease-driven Human Proteome Project (B/D-HPP) whose overarching goal is to support the broad application of state-of-the-art measurements of proteins and proteomes by life scientists studying the molecular mechanisms of biological processes and human disease. The large repertoire of investigative proteomic tools has great potential to transform vision science and enhance understanding of physiology and disease processes that affect sight. 23759512 Assessment of Brd4 Inhibition in Idiopathic Pulmonary Fibrosis Lung Fibroblasts and in Vivo Models of Lung Fibrosis. Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of high unmet medical need. Although bromodomain (Brd) and extra terminal domain isoforms have recently been implicated in mediating inflammatory and oncologic indications, their roles in lung fibrosis have not been comprehensively assessed. We investigated the role of Brd on the profibrotic responses of lung fibroblasts (LFs) in patients with rapidly progressing IPF and a mouse bleomycin model of lung fibrosis. The enhanced migration, proliferation, and IL-6 release observed in LFs from patients with rapidly progressing IPF are attenuated by pharmacologic inhibition of Brd4. These changes are accompanied by enhanced histone H4 lysine5 acetylation and association of Brd4 with genes involved in the profibrotic responses in IPF LFs as demonstrated using chromatin immunoprecipitation and quantitative PCR. Oral administration of 200 mg/kg per day Brd4 inhibitor JQ1 in a therapeutic dosing regimen substantially attenuated lung fibrosis induced by bleomycin in C57BL/6 mice. In conclusion, this study shows that the Brd4 inhibitor JQ1, administered in a therapeutic dosage, is capable of inhibiting the profibrotic effects of IPF LFs and attenuates bleomycin-induced lung fibrosis in mice. These results suggest that Brd4 inhibitors may represent a novel therapy for the treatment of rapidly progressing IPF. 23905526 An official american thoracic society clinical practice guideline: classification, evaluation, and management of childhood interstitial lung disease in infancy. Background: There is growing recognition and understanding of the entities that cause interstitial lung disease (ILD) in infants. These entities are distinct from those that cause ILD in older children and adults. Methods: A multidisciplinary panel was convened to develop evidence-based guidelines on the classification, diagnosis, and management of ILD in children, focusing on neonates and infants under 2 years of age. Recommendations were formulated using a systematic approach. Outcomes considered important included the accuracy of the diagnostic evaluation, complications of delayed or incorrect diagnosis, psychosocial complications affecting the patient's or family's quality of life, and death. Results: No controlled clinical trials were identified. Therefore, observational evidence and clinical experience informed judgments. These guidelines: (1) describe the clinical characteristics of neonates and infants (<2 yr of age) with diffuse lung disease (DLD); (2) list the common causes of DLD that should be eliminated during the evaluation of neonates and infants with DLD; (3) recommend methods for further clinical investigation of the remaining infants, who are regarded as having "childhood ILD syndrome"; (4) describe a new pathologic classification scheme of DLD in infants; (5) outline supportive and continuing care; and (6) suggest areas for future research. Conclusions: After common causes of DLD are excluded, neonates and infants with childhood ILD syndrome should be evaluated by a knowledgeable subspecialist. The evaluation may include echocardiography, controlled ventilation high-resolution computed tomography, infant pulmonary function testing, bronchoscopy with bronchoalveolar lavage, genetic testing, and/or lung biopsy. Preventive care, family education, and support are essential. 23940002 Analysis of microRNAs expressions in chondrosarcoma. MicroRNAs (miRNAs) are small non-coding RNAs capable of inhibiting gene expression post-transcriptionally and expression profiling can provide therapeutic targets and tools for cancer diagnosis. Chondrosarcoma is a mesenchymal tumor with unknown cause and differentiation status. Here, we profiled miRNA expression of chondrosarcoma, namely clinical samples from human conventional chondrosarcoma tissue, established chondrosarcoma cell lines, and primary non-tumorous adult articular chondrocytes, by miRNA array and quantitative real-time PCR. A wide variety of miRNAs were differently downregulated in chondrosarcoma compared to non-tumorous articular chondrocytes; 27 miRNAs: miR-10b, 23b, 24-1*, 27b, 100, 134, 136, 136*, 138, 181d, 186, 193b, 221*, 222, 335, 337-5p, 376a, 376a*, 376b, 376c, 377, 454, 495, 497, 505, 574-3p, and 660, were significantly downregulated in chondrosarcoma and only 2: miR-96 and 183, were upregulated. We further validated the expression levels of miRNAs by quantitative real-time PCR for miR-181a, let-7a, 100, 222, 136, 376a, and 335 in extended number of chondrosarcoma clinical samples. Among them, all except miR-181a were found to be significantly downregulated in chondrosarcoma derived samples. The findings provide potential diagnostic value and new molecular understanding of chondrosarcoma. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. 23824777 Comparison of the FilmArray RP, Verigene RV+, and Prodesse ProFLU+/FAST+ Multiplex Platforms for Detection of Influenza Viruses in Clinical Samples from the 2011-2012 Influenza Season in Belgium. Respiratory tract infections (RTIs) are caused by a plethora of viral and bacterial pathogens. In particular, lower RTIs are a leading cause of hospitalization and mortality. Timely detection of the infecting respiratory pathogens is crucial to optimize treatment and care. In this study, three U.S. Food and Drug Administration-approved molecular multiplex platforms (Prodesse ProFLU+/FAST+, FilmArray RP, and Verigene RV+) were evaluated for influenza virus detection in 171 clinical samples collected during the Belgian 2011-2012 influenza season. Sampling was done using mid-turbinate flocked swabs, and the collected samples were stored in universal transport medium. The amount of viral RNA present in the swab samples ranged between 3.07 and 8.82 log10 copies/ml. Sixty samples were concordant influenza A virus positive, and 8 samples were found to be concordant influenza B virus positive. Other respiratory viruses that were detected included human rhinovirus/enterovirus, respiratory syncytial virus, parainfluenza virus type 1, human metapneumovirus, and coronavirus NL63. Twenty-five samples yielded discordant results across the various assays which required further characterization by sequencing. The FilmArray RP and Prodesse ProFLU+/FAST+ assays were convenient to perform with regard to sensitivity, ease of use, and low percentages of invalid results. Although the limit of sensitivity is of utmost importance, many other factors should be taken into account in selecting the most convenient molecular diagnostic assay for the detection of respiratory pathogens in clinical samples. 23836135 Illness, phenomenology, and philosophical method. In this article, I propose that illness is philosophically revealing and can be used to explore human experience. I suggest that illness is a limit case of embodied experience. By pushing embodied experience to its limit, illness sheds light on normal experience, revealing its ordinary and thus overlooked structure. Illness produces a distancing effect, which allows us to observe normal human behavior and cognition via their pathological counterpart. I suggest that these characteristics warrant illness a philosophical role that has not been articulated. Illness can be used as a philosophical tool for the study of normally tacit aspects of human existence. I argue that illness itself can be integral to philosophical method, insofar as it facilitates a distancing from everyday practices. This method relies on pathological or limit cases to illuminate normally overlooked aspects of human perception and action. I offer Merleau-Ponty's analysis of the case of Schneider as an example of this method. 23861776 Specialized yeast ribosomes: a customized tool for selective mRNA translation. Evidence is now accumulating that sub-populations of ribosomes - so-called specialized ribosomes - can favour the translation of subsets of mRNAs. Here we use a large collection of diploid yeast strains, each deficient in one or other copy of the set of ribosomal protein (RP) genes, to generate eukaryotic cells carrying distinct populations of altered 'specialized' ribosomes. We show by comparative protein synthesis assays that different heterologous mRNA reporters based on luciferase are preferentially translated by distinct populations of specialized ribosomes. These mRNAs include reporters carrying premature termination codons (PTC) thus allowing us to identify specialized ribosomes that alter the efficiency of translation termination leading to enhanced synthesis of the wild-type protein. This finding suggests that these strains can be used to identify novel therapeutic targets in the ribosome. To explore this further we examined the translation of the mRNA encoding the extracellular matrix protein laminin β3 (LAMB3) since a LAMB3-PTC mutant is implicated in the blistering skin disease Epidermolysis bullosa (EB). This screen identified specialized ribosomes with reduced levels of RP L35B as showing enhanced synthesis of full-length LAMB3 in cells expressing the LAMB3-PTC mutant. Importantly, the RP L35B sub-population of specialized ribosomes leave both translation of a reporter luciferase carrying a different PTC and bulk mRNA translation largely unaltered. 23771522 Dietary Soy Effects on Mammary Gland Development during the Pubertal Transition in Nonhuman Primates. While epidemiologic studies suggest that soy intake early in life may reduce breast cancer risk, there are also concerns that exposure to soy isoflavones during childhood may alter pubertal development and hormonal profiles. Here, we assessed the effect of a high-soy diet on pubertal breast development, sex hormones, and growth in a nonhuman primate model. Pubertal female cynomolgus monkeys were randomized to receive a diet modeled on a typical North American diet with one of two protein sources for approximately 4.5 years: (i) casein/lactalbumin (CL, n = 12, as control) or (ii) soy protein isolate with a human equivalent dose of 120 mg/d isoflavones (SOY, n = 17), which is comparable to approximately four servings of soy foods. Pubertal exposure to the SOY diet did not alter onset of menarche, indicators of growth and pubertal progression, or circulating estradiol and progesterone concentrations. Greater endometrial area was seen in the SOY group on the first of four postmenarchal ultrasound measurements (P < 0.05). There was a subtle effect of diet on breast differentiation whereby the SOY group showed higher numbers of differentiated large-sized lobular units and a lower proportion with immature ducts following menarche (P < 0.05). Numbers of small lobules and terminal end buds and mammary epithelial cell proliferation did not differ by diet. Expression of progesterone receptor was lower in immature lobules of soy-fed animals (P < 0.05). Our findings suggest that consumption of soy starting before menarche may result in modest effects consistent with a more differentiated breast phenotype in adulthood. Cancer Prev Res; 6(8); 832-42. ©2013 AACR. 23941199 An integrative model of the control of ovule primordia formation. Upon hormonal signaling, ovules develop as lateral organs from the placenta. Ovule numbers ultimately determine the number of seeds that can develop and thereby contribute to the final seed yield in crop plants. We demonstrate here that CUP-SHAPED COTYLEDON 1 (CUC1), CUC2 and AINTEGUMENTA (ANT) have additive effects on ovule primordia formation. We show that expression of the CUC1 and CUC2 genes is required to redundantly regulate PINFORMED1 (PIN1) expression, which in turn is needed for ovule primordia formation. Furthermore, our results suggest that the auxin response factor MONOPTEROS (MP/ARF5) might directly bind ANT, CUC1 and CUC2 and promote their transcription. Based on our findings we propose an integrative model to describe the molecular mechanisms of the early stages of ovule development. This article is protected by copyright. All rights reserved. 23483103 The induction of mitochondria-mediated apoptosis in cancer cells by ruthenium(ii) asymmetric complexes. Four ruthenium(ii) asymmetric complexes, [Ru(bpy)2(PAIDH)](2+) (bpy = 2,2'-bipyridine, PAIDH = 2-pyridyl-1H-anthra[1,2-d]imidazole-6,11-dione, ), [Ru(phen)2(PAIDH)](2+) (phen = 1,10-phenanthroline, ), [Ru(dmp)2(PAIDH)](2+) (dmp = 4,7-dimethyl-1,10-phenanthroline, ) and [Ru(dip)2(PAIDH)](2+) (dip = 4,7-diphenyl-1,10-phenanthroline, ), have been synthesized and characterized. These complexes displayed potent anti-proliferation activity against various cancer cell lines and had high selectivity between tumor cells and normal cells. HeLa cells exhibited the highest sensitivity to complex , accounting for the greatest cellular uptake. Complex was shown to accumulate preferentially in the mitochondria of HeLa cells and induced apoptosis via the mitochondrial pathway, which involved ROS generation, mitochondrial membrane potential depolarisation, and Bcl-2 and caspase family members activation. These results demonstrated that complex induced cancer cell apoptosis by acting on mitochondrial pathways. 23591653 A Replication Study for Association of 53 Single Nucleotide Polymorphisms in a Scoliosis Prognostic Test With Progression of Adolescent Idiopathic Scoliosis in Japanese. A genetic association study of single nucleotide polymorphisms (SNPs) previously reported to be associated with curve progression of adolescent idiopathic scoliosis (AIS). To determine whether the association of 53 SNPs with curve progression reported in white patients with AIS are replicated in Japanese patients with AIS. Predicting curve progression is important in clinical practice of AIS. The progression of AIS is reported to be associated with a number of genes. Associations with 53 SNPs have been reported, and the SNPs are used for a progression test in white patients with AIS; however, there has been no replication study for their association. We recruited 2117 patients with AIS with 10° or more (Cobb angle) of scoliosis curves. They were divided into progression and nonprogression groups according to their Cobb angle. We defined the progression of the curve as Cobb angle more than 50° for skeletally mature subjects and more than 40° for immature patients, subjects. We defined the nonprogression of the curve as Cobb angle 50° or less only for skeletally mature subjects. Of the 2117 patients, 1714 patients with AIS were allocated to either the progression or nonprogression group. We evaluated the association of 53 SNPs with curve progression by comparing risk allele frequencies between the 2 groups. We evaluated the progression (N = 600) and nonprogression (N = 1114) subjects. Their risk allele frequencies were not different significantly. We found no replication of the association on AIS curve progression in any of the SNPs. The associations of the 53 SNPs with progression of AIS curve are not definite. Large-scale association studies based on appropriate criteria for progression would be necessary to identify SNPs associated with the curve progression.Level of Evidence: N/A. 23232092 Changes in eating and physical activity behaviors across seven semesters of college: living on or off campus matters. The transition from adolescence to adulthood is an important period for establishing behavioral patterns that affect long-term health and chronic disease risk. Nelson and colleagues speculated that developmental changes and changes in living situation may play an important role in the nutrition and physical activity behaviors of college students. Data from the University Life Study, a longitudinal study of college students that includes web-based surveys administered 14 consecutive days each semester, were used to examine fruit, vegetable, and sugared soda consumption, physical activity, and sedentary activity behaviors across seven semesters. Estimates for each semester were calculated to determine the frequency with which students consumed fruits, vegetables, and sugared soda, engaged in moderate to vigorous physical activity, and engaged in sedentary activities. Four models, estimated with HLM 6.04, were used to predict changes in these behaviors across the seven semesters. Living on or off campus was included to determine if this explained additional variance. Results indicated that few college students consumed fruits and vegetables or exercised at optimal levels during the seven semesters surveyed. Daily fruit and vegetable consumption and daily physical activity declined significantly from the first to the seventh semester. For both of these findings, living off campus exacerbated the problem. Average number of hours of sedentary behaviors declined over time, as did number of days on which at least one sugared soda was consumed. Living location did not explain additional variance in these positive trends. Implications for policy, practice, and future research are discussed. 23719731 Enhanced cycling performance and electrochemical reversibility of a novel sulfur-impregnated mesoporous hollow TiO2 sphere cathode for advanced Li-S batteries. A novel, designed sulfur-impregnated mesoporous hollow TiO2 sphere cathode with a 68 wt% S loading was efficiently tailored for advanced Li-S batteries, and yielded an intriguing capacity retention (71%) and a high coulombic efficiency (93%) over 100 cycles, at a 1 C rate. 23477677 Use of preimplantation genetic diagnosis for serious adult onset conditions: a committee opinion. PGD for adult-onset conditions is ethically justified when the condition is serious and no safe, effective interventions are available. It is ethically allowed for conditions of lesser severity or penetrance. The Committee strongly recommends that an experienced genetic counselor play a major role in counseling patients considering such procedures. 23176135 Leaf senescence in rice due to magnesium deficiency mediated defect in transpiration rate before sugar accumulation and chlorosis. Magnesium (Mg) is an essential macronutrient supporting various functions, including photosynthesis. However, the specific physiological responses to Mg deficiency remain elusive. In this study, 2-week-old rice seedlings (Oryza sativa. cv. Nipponbare) with three expanded leaves (L2-L4) were transferred to Mg-free nutrient solution for 8 days. In the absence of Mg, on day 8, L5 and L6 were completely developed, while L7 just emerged. We also studied several mineral deficiencies to identify specific responses to Mg deficiency. Each leaf was analyzed in terms of chlorophyll, starch, anthocyanin and carbohydrate metabolites, and only absence of Mg was found to cause irreversible senescence of L5. Resupply of Mg at various time points confirmed that the borderline of L5 death was between days 6 and 7 of Mg deficiency treatment. Decrease in chlorophyll concentration and starch accumulation occurred simultaneously in L5 and L6 blades on day 8. However, nutrient transport drastically decreased in L5 as early as day 6. These data suggest that the predominant response to Mg deficiency is a defect in transpiration flow. Furthermore, changes in myo-inositol and citrate concentrations were detected only in L5 when transpiration decreased, suggesting that they may constitute new biological markers of Mg deficiency. 23574003 Hidden acidosis: an explanation of acid-base and lactate changes occurring in umbilical cord blood after delayed sampling. To explore the 'hidden acidosis' phenomenon, in which there is a washout of acid metabolites from peripheral tissues in both vaginal and abdominal deliveries, by investigating temporal umbilical cord blood acid-base and lactate changes after delayed blood sampling. Prospective comparative study. University hospital. Umbilical cord blood from 124 newborns. Arterial and venous cord blood was sampled immediately after birth (T₀), and at 45 seconds (T₄₅), from unclamped cords with intact pulsations taken from 66 neonates born vaginally and 58 neonates born via planned caesarean section at 36-42 weeks of gestation. Non-parametric tests were used for statistical comparisons, with P < 0.05 considered significant. Temporal changes (T₀-T₄₅) in umbilical cord blood pH, the partial pressure of CO₂ (PCO₂) and O₂ (PO₂), and in the concentrations of lactate, haematocrit (Hct), and haemoglobin (Hb). In both groups all arterial parameters, except for PCO₂ in the group delivered by caesarean section, changed significantly (pH decreased and the other variables increased). There were corresponding changes in venous acid-base parameters. When temporal arterial changes were compared between the two groups, the decrease in pH and increase in PCO₂ were more pronounced in the group delivered vaginally. Neonates born vaginally had significantly lower pH and higher lactate, Hct, and Hb concentrations at T₀ and T₄₅ in both the artery and the vein. At T₄₅, arterial PCO₂ and PO₂ levels in the group delivered vaginally were also significantly higher. Delayed umbilical cord sampling affected the acid-base balance and haematological parameters after both vaginal and caesarean deliveries, although the effect was more marked in the group delivered vaginally. The hidden acidosis phenomenon explains this change towards acidaemia and lactaemia. Arterial haemoconcentration was not the explanation of the acid-base drift. 23828032 Revisional Bariatric Surgery for Unsuccessful Weight Loss and Complications. There are growing numbers of patients who require revisional bariatric surgery due to the undesirable results of their primary procedures. The aim of this study was to review our experience with bariatric patients undergoing revisional surgery. We conducted a retrospective analysis to review the indications for revisional bariatric procedures and assess their postoperative outcomes. From 04/04 to 01/11, 2,918 patients underwent bariatric surgery at our institution. A total of 154 patients (5.3 %) of these cases were coded as revisional procedures. The mean age at revision was 49.1 ±â€‰11.3 and the mean BMI was 44.0 ±â€‰13.7 kg/m(2). Revisional surgery was performed laparoscopically in 121 patients (78.6 %). Laparoscopic revisions had less blood loss, shorter length of hospital stay, and fewer complications compared to open revisions. Two groups (A and B) were defined by the indication for revision: patients with unsuccessful weight loss (group A, n = 106) and patients with complications of their primary procedures (group B, n = 48). In group A, 74.5 % of the patients were revised to a bypass procedure and 25.5 % to a restrictive procedure. Mean excess weight loss was 53.7 ±â€‰29.3 % after revision of primary restrictive procedures and 37.6 ±â€‰35.1 % after revision of bypass procedures at >1-year follow-up (p < 0.05). In group B, the complications prompting revision were effectively treated by revisional surgery. Revisional bariatric surgery effectively treated the undesirable results from primary bariatric surgery. Laparoscopic revisional surgery can be performed after both failed open and laparoscopic bariatric procedures without a prohibitive complication rate. Carefully selected patients undergoing revision for weight regain have satisfactory additional weight loss. 23927992 The population genomics of repeated evolution in the blind cavefish Astyanax mexicanus. Distinct populations of Astyanax mexicanus cavefish offer striking examples of repeatable convergence or parallelism in their independent evolutions from surface to cave phenotypes. However, the extent to which the repeatability of evolution occurred at the genetic level remains poorly understood. To address this, we first characterized the genetic diversity of 518 single nucleotide polymorphisms (SNPs), obtained through RAD tag sequencing and distributed throughout the genome, in seven cave and three groups of surface populations. The cave populations represented two distinct lineages ("old" and "new"). Thirty-one SNPs were significantly differentiated between surface and old cave populations, two SNPs were differentiated between surface and new cave populations, and 44 SNPs were significantly differentiated in both old and new cave populations. In addition, we determined if these SNPs map to the same locations of previously described quantitative trait loci (QTL) between surface and cave populations. A total of 25 differentiated SNPs co-map with several QTL, such as one containing a fibroblast growth factor gene (Fgf8) involved in eye development and lens size. Further, the identity of many SNPs that co-mapped with QTL was the same in independently derived cave populations. These conclusions were further confirmed by haplotype analyses of SNPs within QTL regions. Our findings indicate that the repeatability of evolution at the genetic level is substantial, suggesting that ancestral standing genetic variation significantly contributed to the population genetic variability used in adaptation to the cave environment. 23874667 Assessment of the magnitude of contextual and individual demographic effects on diabetes mellitus and glucose intolerance in rural southwest china: a multilevel analysis. This study aimed to determine the contribution of individual and contextual socioeconomic status (SES) to the prevalence of diabetes mellitus and glucose intolerance in the adult population in rural southwest China. A population-based cross-sectional study of diabetes was performed in 4801(2152 men) Chinese adults (≥25 years old). Multilevel logistic regression model was used to examine the association between individuals' and townships' variables and the prevalence of diabetes mellitus and glucose intolerance. The age-and gender-standardized prevalence of diabetes mellitus and glucose intolerance were 7.1% (3.6% for undiagnosed) and 8.8% in adults aged ≥25 years, respectively, and increasing with age. Females were more likely to develop diabetes than males. The probability of developing diabetes increased with BMI. Both contextual and individual educational level and yearly household income were found to be negatively associated with the prevalence of diabetes. Residence in communities with a higher percentage of ethnic minorities was associated with higher prevalence of diabetes. Smoking had a protective effect for diabetes, drinking had a positive association with diabetes mellitus and glucose intolerance. Diabetes mellitus and glucose intolerance are common in rural adults of southwest China by international standards. These results indicate that diabetes mellitus has become a major public health problem in rural areas in southwest China, and strategies aimed at the prevention and treatment of diabetes mellitus and glucose intolerance are needed. 23859463 A novel long-acting glucose-dependent insulinotropic peptide analogue: enhanced efficacy in normal and diabetic rodents. Glucose-dependent insulinotropic peptide (GIP) is an incretin hormone that is released from intestinal K cells in response to nutrient ingestion. We aimed to investigate the therapeutic potential of the novel N- and C-terminally modified GIP analogue AC163794. AC163794 was synthesized by solid-phase peptide synthesis. Design involved the substitution of the C-terminus tail region of the dipeptidyl peptidase IV (DPP-IV)-resistant GIP analogue [d-Ala(2) ]GIP(1-42) with the unique nine amino acid tail region of exenatide. The functional activity and binding of AC163794 to the GIP receptor were evaluated in RIN-m5F β-cells. In vitro metabolic stability was tested in human plasma and kidney membrane preparations. Acute insulinotropic effects were investigated in isolated mouse islets and during an intravenous glucose tolerance test in normal and diabetic Zucker fatty diabetic (ZDF) rats. The biological actions of AC163794 were comprehensively assessed in normal, ob/ob and high-fat-fed streptozotocin (STZ)-induced diabetic mice. Acute glucoregulatory effects of AC163794 were tested in diet-induced obese mice treated subchronically with AC3174, the exendatide analogue [Leu(14) ] exenatide. Human GIP or [d-Ala(2) ]GIP(1-42) were used for comparison. AC163794 exhibited nanomolar functional GIP receptor potency in vitro similar to GIP and [d-Ala(2) ]GIP(1-42). AC163794 was metabolically more stable in vitro and displayed longer duration of insulinotropic action in vivo versus GIP and [d-Ala(2) ]GIP(1-42). In diabetic mice, AC163794 improved HbA1c through enhanced insulinotropic action, partial restoration of pancreatic insulin content and improved insulin sensitivity with no adverse effects on fat storage and metabolism. AC163794 provided additional baseline glucose-lowering when injected to mice treated with AC3174. These studies support the potential use of a novel GIP analogue AC163794 for the treatment of type 2 diabetes. 23861252 Relationships between organizational workplace characteristics and perceived workplace strain in call-centers in France. Our objective was to study the associations between organizational workplace characteristics (OC) reported by call-center (CC) managers and workplace stressors reported by call-handlers. The managers of 107 CCs were interviewed by their occupational physicians using a questionnaire designed to specifically explore OC in the CCs. Four thousand two call-handlers from these CCs completed a self-report questionnaire including the Karasek and Siegrist work stressor questionnaires and two specific items on other workplace stressors. Around one-third of the OC examined were associated with the demand/control ratio, the perception of demanding work and ethical conflicts, however, far fewer OC were associated with the effort/reward ratio. Most OC were associated with higher levels of job stressors. Some had strong, systematic negative associations with stressors (e.g., highly formatted instructions for the client relationship). These findings could help in targeting job stressor prevention and health improvement strategies in CCs. Am. J. Ind. Med. 9999:1-13, 2013. © 2013 Wiley Periodicals, Inc. 23925141 pH-Triggered Conformational Switching along the Membrane Insertion Pathway of the Diphtheria Toxin T-Domain. The translocation (T)-domain plays a key role in the action of diphtheria toxin and is responsible for transferring the catalytic domain across the endosomal membrane into the cytosol in response to acidification. Deciphering the molecular mechanism of pH-dependent refolding and membrane insertion of the T-domain, which is considered to be a paradigm for cell entry of other bacterial toxins, reveals general physicochemical principles underlying membrane protein assembly and signaling on membrane interfaces. Structure-function studies along the T-domain insertion pathway have been affected by the presence of multiple conformations at the same time, which hinders the application of high-resolution structural techniques. Here, we review recent progress in structural, functional and thermodynamic studies of the T-domain archived using a combination of site-selective fluorescence labeling with an array of spectroscopic techniques and computer simulations. We also discuss the principles of conformational switching along the insertion pathway revealed by studies of a series of T-domain mutants with substitutions of histidine residues. 23803392 Energy levels of interacting curved nanomagnets in a frustrated geometry: increasing accuracy when using finite difference methods. The accuracy of finite difference methods is related to the mesh choice and cell size. Concerning the micromagnetism of nano-objects, we show here that discretization issues can drastically affect the symmetry of the problem and therefore the resulting computed properties of lattices of interacting curved nanomagnets. In this paper, we detail these effects for the multi-axis kagome lattice. Using the OOMMF finite difference method, we propose an alternative way of discretizing the nanomagnet shape via a variable moment per cell scheme. This method is shown to be efficient in reducing discretization effects. 23643681 Diminished response to in vivo mechanical loading in trabecular and not cortical bone in adulthood of female C57Bl/6 mice coincides with a reduction in deformation to load. Bone loss occurs during adulthood in both women and men and affects trabecular bone more than cortical bone. The mechanism responsible for trabecular bone loss during adulthood remains unexplained, but may be due at least in part to a reduced mechanoresponsiveness. We hypothesized that trabecular and cortical bone would respond anabolically to loading and that the bone response to mechanical loading would be reduced and the onset delayed in adult compared to postpubescent mice. We evaluated the longitudinal adaptive response of trabecular and cortical bone in postpubescent, young (10 week old) and adult (26 week old) female C57Bl/6J mice to axial tibial compression using in vivo microCT (day 0, 5, 10, and 15) and dynamic histomorphometry (day 15). Loading elicited an anabolic response in both trabecular and cortical bone in young and adult mice. As hypothesized, trabecular bone in adult mice exhibited a reduced and delayed response to loading compared to the young mice, apparent in trabecular bone volume fraction and architecture after 10 days. No difference in mechanoresponsiveness of the cortical bone was observed between young and adult mice. Finite element analysis showed that load-induced strain was reduced with age. Our results suggest that trabecular bone loss that occurs in adulthood may in part be due to a reduced mechanoresponsiveness in this tissue and/or a reduction in the induced tissue deformation which occurs during habitual loading. Therapeutic approaches that address the mechanoresponsiveness of the bone tissue may be a promising and alternate strategy to maintain trabecular bone mass during aging. 23481562 Zinc finger protein A20 inhibits maturation of dendritic cells resident in rat liver allograft. In organ transplant field, although viewed traditionally as instigators of organ allograft rejection, donor-derived interstitial dendritic cells (DCs), including those resident in liver, or host DCs have also been implicated in transplant tolerance in experimental models. This functional dichotomy of DC is governed by various factors, the most important of which appears to be their stage of maturation. This study was designed to examine the effect of zinc finger protein A20 on maturation of DCs resident in rat liver allograft. Allogeneic (Dark Agouti [DA] rat to Lewis rat) liver transplantation was performed. Adenovirus carrying the full length of A20 was introduced into liver allografts by ex vivo perfusion via the portal vein during preservation (group A20), physiological saline (group PS), and empty Ad vector rAdEasy (group rAdEasy) that served as controls. Acute liver allograft rejection was assessed, and DCs resident in liver allografts were isolated on day 7 after transplantation. Nuclear factor kappa B (NF-κB)-binding activities, surface expression of costimulatory molecules (CD40, CD80, and CD86), expression of interleukin (IL) 12 messenger RNA (mRNA), and allocostimulatory capacity of DCs were measured with electrophoretic mobility shift assay, flow cytometry, reverse transcription-polymerase chain reaction, and mixed lymphocyte reaction (MLR), respectively. Ex vivo transfer of A20 adenovirus by portal vein infusion resulted in overexpression of A20 protein in liver allograft after transplantation. On day 7 after transplantation, histologic examination revealed a mild rejection in group A20 but a more severe rejection in group PS and group rAdEasy. DCs from group A20 liver allografts exhibited features of immature DC with detectable but very low level of NF-κB activity, IL-12 mRNA expression, and surface expression of costimulatory molecules (CD40, CD80, and CD86), whereas DCs from group rAdEasy and group PS liver allograft displayed features of mature DC with high level of NF-κB activity, IL-12 mRNA expression, and surface expression of costimulatory molecules (CD40, CD80, and CD86). DCs from group PS and group rAdEasy liver allograft were potent inducers of DNA synthesis and interferon γ production in MLR, and DCs from group A20 liver allografts induced only minimal levels of cell proliferation and interferon γ production in MLR. These data suggest that A20 overexpression could effectively inhibit maturation of DCs resident in liver allograft and consequently suppress acute liver allograft rejection. 23287020 In vivo functional calcium imaging of induced or spontaneous activity in the fly brain using a GFP-apoaequorin-based bioluminescent approach. Different optical imaging techniques have been developed to study neuronal activity with the goal of deciphering the neural code underlying neurophysiological functions. Because of several constraints inherent in these techniques as well as difficulties interpreting the results, the majority of these studies have been dedicated more to sensory modalities than to the spontaneous activity of the central brain. Recently, a novel bioluminescence approach based on GFP-aequorin (GA) (GFP: Green fluorescent Protein), has been developed, allowing us to functionally record in-vivo neuronal activity. Taking advantage of the particular characteristics of GA, which does not require light excitation, we report that we can record induced and/or the spontaneous Ca(2+)-activity continuously over long periods. Targeting GA to the mushrooms-bodies (MBs), a structure implicated in learning/memory and sleep, we have shown that GA is sensitive enough to detect odor-induced Ca(2+)-activity in Kenyon cells (KCs). It has been possible to reveal two particular peaks of spontaneous activity during overnight recording in the MBs. Other peaks of spontaneous activity have been recorded in flies expressing GA pan-neurally. Similarly, expression in the glial cells has revealed that these cells exhibit a cell-autonomous Ca(2+)-activity. These results demonstrate that bioluminescence imaging is a useful tool for studying Ca(2+)-activity in neuronal and/or glial cells and for functional mapping of the neurophysiological processes in the fly brain. These findings provide a framework for investigating the biological meaning of spontaneous neuronal activity. This article is part of a Special Issue entitled: 12th European Symposium on Calcium. 23845283 Design and synthesis of novel 1,25-dihydroxyvitamin D3 analogues having a spiro-oxetane fused at the C2 position in the A-ring. Four structurally novel stereoisomeric analogues of 1,25-dihydroxyvitamin D3 (3a-d) bearing a spiro-oxetane fused at the C2 position of the A-ring have been designed and synthesised in a convergent manner. The requisite A-ring enyne precursors (13a,b) for the vitamin D analogues (3a,b) and (3c,d), respectively, were synthesised from pentaerythritol according to an eleven-step procedure. Preliminary biological evaluation of the analogues using the bovine thymus vitamin D receptor (VDR) suggested that the incorporation of the spiro-oxetane moiety instead of a gem-dimethyl group at the C2 position had a beneficial effect on the VDR affinity. 23605323 Imaging and therapy of hSSTR2-transfected tumors using radiolabeled somatostatin analogs. The aim of this study was to introduce human somatostatin receptors subtype-2 (hsstr2) gene into A549 lung carcinoma cells in order to investigate the role of these receptors, and to observe the lethal effect of (131)I-RC-160 (RC-160, vapreotide, an analog of somatostatin) on transfected cells through tumor scintigraphy. Clones overexpressing SSTR2 were selected for radioligand-receptor binding assay and assessment of (125)I-RC-160 internalization. The methylthiazolyl tetrazolium test was used to observe the lethal effect of (131)I-RC-160, Na(131)I, and RC-160 on hSSTR2-transfected A549 cells (A549-hSSTR2). Planar imaging was performed with a gamma camera equipped with pinhole collimator in nude mice bearing both A549-hSSTR2 tumors overexpressing SSTR2 and A549-pcDNA3 (pcDNA3-transfected A549 cells) tumors as control. Images were obtained at 0.5, 6, and 24 h after injection of 3.7 × 10(6) Bq (99m)Tc-RC-160 via the tail vein. The inhibitory effects of (131)I-RC-160, RC-160, and Na(131)I on the tumors were recorded by measuring the tumor volumes. At the end of the study, the tumors were excised and HE staining was performed. The binding radioactivity (sum of membrane-bound and internalized radioligand) of A549-hSSTR2 cells was 18.24 ±â€‰1.9 % of total counts added after 1 h of incubation, and was higher than that of A549-pcDNA3 cells 5.7 ±â€‰1.4 % (P < 0.05). The inhibition ratio of A549-hSSTR2 cells was 78.8 ±â€‰5.9 %. Clear images of tumor lesions in nude mice were achieved at 0.5 h post injection. In the A549-hSSTR2 xenograft tumor group, the growth of the tumors treated with (131)I-RC-160 was significantly inhibited as compared to tumors in the group treated with RC-160 (P < 0.01). This study demonstrated that it was possible to introduce hsstr2 to non-expressing tumor cell lines and treat tumors with radiolabeled somatostatin analogs. 23766131 A Role for Phosphodiesterase 3B in Acquisition of Brown Fat Characteristics by White Adipose Tissue in Male Mice. Obesity is linked to various diseases, including insulin resistance, diabetes, and cardiovascular disorders. The idea of inducing white adipose tissue (WAT) to assume characteristics of brown adipose tissue (BAT), and thus gearing it to fat burning instead of storage, is receiving serious consideration as potential treatment for obesity and related disorders. Phosphodiesterase 3B (PDE3B) links insulin- and cAMP-signaling networks in tissues associated with energy metabolism, including WAT. We used C57BL/6 PDE3B knockout (KO) mice to elucidate mechanisms involved in the formation of BAT in epididymal WAT (EWAT) depots. Examination of gene expression profiles in PDE3B KO EWAT revealed increased expression of several genes that block white and promote brown adipogenesis, such as C-terminal binding protein, bone morphogenetic protein 7, and PR domain containing 16, but a clear BAT-like phenotype was not completely induced. However, acute treatment of PDE3B KO mice with the β3-adrenergic agonist, CL316243, markedly increased the expression of cyclooxygenase-2, which catalyzes prostaglandin synthesis and is thought to be important in the formation of BAT in WAT and the elongation of very long-chain fatty acids 3, which is linked to BAT recruitment upon cold exposure, causing a clear shift toward fat burning and the induction of BAT in KO EWAT. These data provide insight into the mechanisms of BAT formation in mouse EWAT, suggesting that, in a C57BL/6 background, an increase in cAMP, caused by ablation of PDE3B and administration of CL316243, may promote differentiation of prostaglandin-responsive progenitor cells in the EWAT stromal vascular fraction into functional brown adipocytes. 23879613 Effects of leg dominance on performance of ballet turns (pirouettes) by experienced and novice dancers. Turns (pirouettes) are an important movement in ballet and may be affected by "lateral bias". This study investigated physiological differences exhibited by experienced and novice dancers, respectively, when performing pirouette with dominant and non-dominant leg supports, respectively. Thirteen novice and 13 experienced dancers performed turns on dominant or non-dominant legs. The maximum ankle plantarflexion, knee extension and hip extension were measured during the single-leg support phase. The inclination angle of rotation axis is the angle between instantaneous rotation axis and global vertical axis in the early single-leg support phase. Both groups exhibited a greater hip extension, knee extension, and ankle plantarflexion when performing a turn on the non-dominant leg. For experienced dancers, the inclination angle of rotation axis during the pre-swing phase was generally smaller for dominant leg support than non-dominant leg. However, no significant difference was found in inclination angle of rotation axis of novice dancers. For experienced dancers, an improved performance is obtained when using the dominant leg for support. By contrast, for novice dancers, the performance is independent of choice of support leg. The significant lateral bias in experienced dancers indicates the possible influence of training. That is, repetitive rehearsal on the preferred leg strengthens the impact of side dominance in experienced dancers. 23944926 Parenting Styles and Practices in Children's Obesogenic Behaviors: Scientific Gaps and Future Research Directions. Abstract Given the emerging global childhood obesity epidemic and the specter of a generation of children who will have a shorter life expectancy than that of their parents, recent research has focused on factors that influence children's weight status and obesogenic behaviors (i.e., eating, physical activity, and screen media use). Parents act as primary socializing agents for children, and thus growing evidence supports the role of parenting styles and practices in children's obesity-related behaviors and weight. Studying these processes in children and adolescents is important for several reasons. First, diet and physical activity behaviors and weight status track from childhood and adolescence into adulthood. Furthermore, diet and physical activity behaviors and weight status confer significant risk for cancer, diabetes, cardiovascular disease, and other chronic diseases. The purpose of this article is to describe the scientific gaps that need to be addressed to develop a more informed literature on parenting styles and practices in the domains of weight status and obesogenic behaviors, as identified by an expert panel assembled by the National Cancer Institute. 23780801 Pupillary motility: bringing neuroscience to the psychiatry clinic of the future. Modern pupillometry has expanded the study and utility of pupil responses in many new domains, including psychiatry, particularly for understanding aspects of cognitive and emotional information processing. Here, we review the applications of pupillometry in psychiatry for understanding patients' information processing styles, predicting treatment, and augmenting function. In the past year pupillometry has been shown to be useful in specifying cognitive/affective occurrences during experimental tasks and informing clinical diagnoses. Such studies demonstrate the potential of pupillary motility to be used in clinical psychiatry much as it has been in neurology for the past century. 23612971 The von Hippel-Lindau Protein pVHL Inhibits Ribosome Biogenesis and Protein Synthesis. pVHL, product of von Hippel-Lindau (VHL) tumor suppressor gene, functions as the substrate recognition component of an E3-ubiquitin ligase complex that targets hypoxia inducible factor alpha (HIFalpha) for ubiquitination and degradation. Besides HIFalpha, pVHL also interacts with other proteins and has multiple functions. Here, we report that pVHL inhibits ribosome biogenesis and protein synthesis. We find that pVHL associates with the 40S ribosomal protein S3 (RPS3) but does not target it for destruction. Rather, the pVHL-RPS3 association interferes with the interaction between RPS3 and RPS2. Expression of pVHL also leads to nuclear retention of pre-40S ribosomal subunits, diminishing polysomes and 18S rRNA levels. We also demonstrate that pVHL suppresses both cap-dependent and cap-independent protein synthesis. Our findings unravel a novel function of pVHL and provide insight into the regulation of ribosome biogenesis by the tumor suppressor pVHL. 23855378 Indirect Competitive Immunoassay for Detection of Vitamin B2 in Foods and Pharmaceuticals. An indirect immunoassay for the determination of vitamin B2 in food samples and vitamin tablets was developed. A carbodiimide-modified active ester method was used to synthesize the immunogen for vitamin B2. The coupling ratio of vitamin B2 to carrier protein in immunogen was 19.98:1. The titer of the polyclonal antibody was 1:64000, and the antibody showed high specificity in the presence of vitamin B2 photolytic products and other B group vitamins. The immunoassay showed detection limits (LODs) of 1.07 ng/mL in PBS, 24.6 ng/g in vitamin drink, and 0.50 mg/kg in milk powder. Recovery was 99.58-110.91% in milk powder and 70.20-100.5% in vitamin drink. Vitamin B2 samples were analyzed by high-pressure liquid chromatography (HPLC) and the immunoassay, and results showed good agreement. Finally, this method was applied to detect vitamin B2 in commercial milk powder and vitamin tablets, and the detected amount correlated well with the labeled amount. 23925857 Study of the EFG tensor at (75) As nuclei in Ge-As-Se chalcogenide glasses. Asymmetry parameters of the electric field gradient tensor at (75) As nuclei were determined for chalcogenide glassy semiconductors (CGS) of the Ge-As-Se system by comparing the experimental and simulated (75) As nuclear quadrupole resonance nutation interferograms. The electric field gradient asymmetry in CGS was analyzed, and it is believed that a structural change in these glassy semiconductors takes place at r¯ =  2.425. Electron paramagnetic resonance spectra of the Ge-As-Se system were obtained for the first time. A comparison was made between the results of analysis of the Ge-As-Se system by nuclear quadrupole resonance and electron paramagnetic resonance methods, and this allowed us to make the supposition that a structural phase transition occurs at r¯ = 2.4 from two-dimensional to three-dimensional CGS structure. Copyright © 2013 John Wiley & Sons, Ltd. 23916674 Peer-assessment of medical communication skills: The impact of students' personality, academic and social reputation on behavioural assessment. Peer-assessment of communication skills may contribute to mastery of assessment criteria. When students develop the capacity to judge their peers' performance, they might improve their capacity to examine their own clinical performance. In this study peer-assessment ratings are compared to teacher-assessment ratings. The aim of this paper is to explore the impact of personality and social reputation as source of bias in assessment of communication skills. Second year students were trained and assessed history taking communication skills. Peers rated the students' personality and academic and social reputation. Peer-assessment ratings were significantly correlated with teacher-ratings in a summative assessment of medical communication. Peers did not provide negative ratings on final scales but did provide negative ratings on subcategories. Peer- and teacher-assessments were both related to the students' personality and academic reputation. Peer-assessment cannot replace teacher-assessment if the assessment should result in high-stake decisions about students. Our data do not confirm the hypothesis that peers are overly biased by personality and reputation characteristics in peer-assessment of performance. Early introduction of peer-assessment in medical education would facilitate early acceptance of this mode of evaluation and would promote early on the habit of critical evaluation of professional clinical performance and acceptance of being evaluated critically by peers. 23935130 Polymorphisms of TCF7L2 gene in South Brazilian women with polycystic ovary syndrome: a cross-sectional study. To assess whether TCF7L2 single nucleotide polymorphisms rs7903146 C/T and rs11196236 C/T are associated with polycystic ovary syndrome (PCOS) in South Brazilian women. Cross-sectional study. 200 PCOS patients and 102 non-hirsute, ovulatory controls were genotyped by real-time polymerase-chain reaction. Haplotypes were constructed from the combination of both polymorphisms. Frequencies were inferred using the PHASE 2.1.1 software. The distribution of rs7903146 (PCOS, 54.4% CC; 28.5% CT; 17.1% TT; controls, 51.0% CC; 37.0% CT; 12.0% TT) and rs11196236 (PCOS, 4.3% CC; 33.5% CT; 62.2% TT; controls, 3.2% CC; 35.5% CT; 61.3% TT) was similar between the groups. rs7903146 and rs11196236 were not in linkage disequilibrium (|D´|=0.34; r2=0.07). PCOS participants were younger, with higher age-adjusted BMI, waist circumference, blood pressure, triglycerides, insulin, HOMA-IR and total testosterone, and lower HDL-c and SHBG vs. controls. In PCOS, no differences between genotypes and haplotypes were found for clinical and metabolic variables. However, for each T (rs7903146) and T (rs11196236) allele added to the haplotypes, a variation of 5.87 cm in waist (P trend=0.01), 10.7 mg/dL in total cholesterol (P trend=0.03), and 10.3 mg/dL in LDL-c (P trend=0.01) was recorded. TCF7L2 variants are probably not implicated in PCOS development in South Brazilian women. 23289806 Common single nucleotide polymorphisms and keratoconus in the han chinese population. ABSTRACT Objective: To investigate whether the tag single nucleotide polymorphisms (tSNPs) in VSX1, COL4A3, COL4A4, IL1A and IL1B genes were associated with keratoconus (KTCN) in the Han Chinese population. Methods: Ninety-seven KTCN patients and 101 healthy controls were enrolled in this study. All cases were diagnosed on the basis of clinical examination. Twenty-one tSNPs were selected for association study in five genes. SNP genotyping was performed by Sequenom MassARRAY RS1000. Sequenom Typer 4.0 Software, PLINK, Haploview and SHEsis software platform were used to perform data management and analyses. Results: Three tSNPs in the VSX1 gene were observed to be associated with KTCN risk at a 5% level by χ(2) test (rs56157240 and rs12480307, p = 0.0499, OR: 6.42, 95% CI: 0.77-53.78; rs6050307, p = 1.22 × 10(-7), OR: 0.05, 95% CI: 0.01-0.23). Rs2071376 in the IL1A gene was also associated with KTCN (p = 0.0487, OR: 1.51, 95% CI: 1.00-2.26). Three haplotypes in the VSX1 gene were found to be associated with risk of KTCN (p < 0.05). Conclusions: Our findings confirmed previous reports that polymorphisms of VSX1 and IL1A genes were associated with risk of KTCN in the Chinese population, suggesting an important determinant of KTCN development by VSX1 and IL1A genes. 23918470 NOSH-aspirin (NBS-1120), a novel nitric oxide and hydrogen sulfide releasing hybrid, attenuates neuroinflammation induced by microglial and astrocytic activation: A new candidate for treatment of neurodegenerative disorders. Hydrogen sulfide (H2 S) and nitric oxide (NO) have been described as gasotransmitters. Anti-inflammatory activity in the central and peripheral nervous systems may be one of their functions. Previously we demonstrated that several SH(-) donors including H2 S-releasing aspirin (S-ASA) exhibited anti-inflammatory and neuroprotective activity in vitro against toxins released by activated microglia and astrocytes. Here we report that NOSH-ASA, an NO- and H2 S-releasing hybrid of aspirin, has a significantly greater anti-inflammatory and neuroprotective effect than S-ASA or NO-ASA. When activated by LPS/IFNγ, human microglia and THP-1 cells release materials that are toxic to differentiated SH-SY5Y cells. These phenomena also occur with IFNγ-stimulated human astroglia and U373 cells. When the cells were treated with the S-ASA or NO-ASA, there was a significant enhancement of neuroprotection. However, NOSH-ASA had significantly more potent protection properties than NO-ASA or S-ASA. The effect was concentration-dependent, as well as incubation time-dependent. Such treatment not only reduced the release of the TNFα and IL-6, but also attenuated activation of P38 MAPK and NFκB proteins. All the compounds tested were not harmful when applied directly to SH-SY5Y cells. These data suggest that NOSH-ASA has significant anti-inflammatory properties and may be a new candidate for treating neurodegenerative disorders that have a prominent neuroinflammatory component such as Alzheimer disease and Parkinson disease. GLIA 2013;61:1724-1734. 23774960 Image-guided robotic interventions for prostate cancer. Robotic prostatectomy is a common surgical treatment for men with prostate cancer, with some studies estimating that 80% of prostatectomies now performed in the USA are done so robotically. Despite the technical advantages offered by robotic systems, functional and oncological outcomes of prostatectomy can still be improved further. Alternative minimally invasive treatments that have also adopted robotic platforms include brachytherapy and high-intensity focused ultrasonography (HIFU). These techniques require real-time image guidance-such as ultrasonography or MRI-to be truly effective; issues with software compatibility as well as image registration and tracking currently limit such technologies. However, image-guided robotics is a fast-growing area of research that combines the improved ergonomics of robotic systems with the improved visualization of modern imaging modalities. Although the benefits of a real-time image-guided robotic system to improve the precision of surgical interventions are being realized, the clinical usefulness of many of these systems remains to be seen. 23142710 Superoxide anion mediates the L-selectin down-regulation induced by non-steroidal anti-inflammatory drugs in human neutrophils. Non-steroidal anti-inflammatory drugs (NSAIDs) induce the shedding of L-selectin in human neutrophils through a mechanism still not well understood. In this work we studied both the functional effect of NSAIDs on the neutrophils/endothelial cells dynamic interaction, and the potential involvement of reactive oxygen species (ROS) in the NSAIDs-mediated down-regulation of L-selectin. When human neutrophils were incubated with diclofenac, a significant reduction in the number of cells that rolled on activated endothelial cells was observed. Different NSAIDs (flufenamic acid, meclofenamic acid, diclofenac, indomethacin, nimesulide, flurbiprofen, meloxicam, phenylbutazone, piroxicam, ketoprofen and aspirin) caused variable increase in neutrophil intracellular ROS concentration, which was inversely proportional to the change produced in L-selectin surface expression. Pre-incubation of neutrophils with superoxide dismutase, but not with catalase, showed both a significant protective effect on the L-selectin down-regulation induced by several NSAIDs and a diminished effect of diclofenac on neutrophil rolling. Interestingly, diclofenac and flufenamic acid but not piroxicam significantly increased the extracellular superoxide anion production by neutrophils, and inhibition of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase activity with diphenyleneiodonium prevented the down-regulation of L-selectin by diclofenac. In accordance with these results, neutrophils from patients with chronic granulomatous disease, a hereditary disease in which neutrophils show a reduced capacity to form superoxide radicals, exhibited a lower down-regulation of L-selectin (IC50: 15.3 μg/ml) compared to normal controls (IC50: 5.6 μg/ml) in response to diclofenac. CONCLUSION: A group of NSAIDs is capable of interfering with the ability of neutrophils to interact with endothelial cells by triggering L-selectin-shedding through the NADPH-oxidase-dependent generation of superoxide anion at the plasma membrane. 23857872 Bridging current issues in science and society. This bioethics article by Robin Pierce, examines the current challenges in bridging science and society. Dr. Pierce discusses the "bi-directionality challenge" and how a meaningful dialogue between scientists and society can be established for socially responsible innovations. (Image: © XtravaganT - Fotolia.com). 23912500 Combined Auditory and Vibrotactile Feedback for Human-Machine-Interface Control. The purpose of this study was to determine the effect of the addition of binary vibrotactile stimulation to continuous auditory feedback (vowel synthesis) for human-machine-interface (HMI) control. Sixteen healthy participants controlled facial surface electromyography to achieve two-dimensional (2D) targets (vowels). Eight participants used only real-time auditory feedback to locate targets whereas the other eight participants were additionally alerted to having achieved targets with confirmatory vibrotactile stimulation at the index finger. All participants trained using their assigned feedback modality (auditory alone or combined auditory and vibrotactile) over three sessions on three days and completed a fourth session on the third day using novel targets to assess generalization. Analyses of variance performed on the 1) percentage of targets reached and 2) percentage of trial time at the target revealed a main effect for feedback modality: participants using combined auditory and vibrotactile feedback performed significantly better than those using auditory feedback alone. No effect was found for session or the interaction of feedback modality and session, indicating a successful generalization to novel targets but lack of improvement over training sessions. Future research is necessary to determine the cognitive cost associated with combined auditory and vibrotactile feedback during HMI control. 22695309 Regulation of gene expression in human prostate cancer cells with artificially constructed promoters that are activated in response to ultrasound stimulation. We chose promoters responsive to sonication in LNCap cells, a prostate cancer cell line, out of a library composed of DNA fragments constructed by linking the TATA box sequence to randomly combined cis-acting elements of transcription factors activated in response to radiation in prostate cancer cells. When a plasmid containing the luciferase gene under control of a promoter was transfected into LNCap cells and sonicated with 1 MHz ultrasound at 0.5 W/cm(2), 10% DF for 60s, 13 promoters showed more than 10-fold enhancement compared with their counterparts without sonication 12h after sonication. As to their responsiveness to sonication, the best two promoters were then compared to clone 880-8, a derivative from clone 880 that was created by random introduction of point mutations and was shown to have an improved response to X-ray irradiation. We then took clone 880-8 for further analyses since it showed the highest enhancement to sonication, though not statistically significant from the others. Next, we employed a retrovirus vector and stably introduced the luciferase gene under control of clone 880-8 into LNCap cells to establish a cell line. When the cell line was sonicated with 1 MHz ultrasound at 0.5 W/cm(2), 10% DF for 60s, luciferase expression was enhanced up to 14.8-fold 12h after sonication. We then established another cell line by replacing the luciferase gene with the fcy::fur gene, a suicide gene, and when the cell line was sonicated with 1 MHz ultrasound at 0.5 W/cm(2), 10% DF for 60s, expression of the gene was enhanced, showing the maximum expression 12-24h after sonication. When the cells were incubated in medium containing 5-fluorocytosine, cell survival ratio decreased dose dependently with 5-fluorocytosine only after sonication treatment, suggesting this promoter could be utilized for gene expression control with ultrasound. 23937933 RNA cell typing and DNA profiling of mixed samples: Can cell types and donors be associated? Forensic samples regularly involve mixtures, which are readily recognised in forensic analyses. Combined DNA and mRNA profiling is an upcoming forensic practice to examine donors and cell types from the exact same sample. From DNA profiles individual genotypes may be deconvoluted, but to date no studies have established whether the cell types identified in corresponding RNA profiles can be associated with individual donors. Although RNA expression levels hold many variables from which an association may not be expected, proof of concept is important to forensic experts who may be cross examined about this possible correlation in court settings. Clearly, the gender-specificity of certain body fluids (semen, vaginal mucosa, menstrual secretion) can be instructive. However, when donors of the same gender or gender-neutral cell types are involved, alternatives are needed. Here we analyse basic two-component mixtures (two cell types provided by different donors) composed of six different cell types, and assess whether the heights of DNA and RNA peaks may guide association of donor and cell type. Divergent results were obtained; for some mixtures RNA peak heights followed the DNA results, but for others the major DNA component did not present higher RNA peaks. Also, variation in mixture ratios was observed for RNA profiling replicates and when different donor couples gave the same two body fluids. As sample degradation may affect the two nucleic acids and/or distinct cell types differently (and thus influence donor and cell type association), mixtures were subjected to elevated temperature or UV-light. Variation in DNA and RNA stability was observed both between and within cell types and depended on the method inducing degradation. Taken together, we discourage to associate cell types and donors from peak heights when performing RNA and DNA profiling. 23928128 Quantitative evaluation of plasma after methylene blue and white light treatment in four Chinese blood centers. Pathogen reduction technology is an important process in the blood safety system, including solvent/detergent treatment, filtration and methylene blue-photochemical technology (MB-PCT). To investigate the quality of MB-PCT-treated plasma, plasma samples from four Chinese blood centers were analyzed over 12months of storage to determine the recovery of activities and levels of various plasma proteins. Ten plasma units each from the Suzhou, Yancheng, Chongqing and Shandong blood centers were divided into two aliquots. One was subjected to treatment with one of two methylene blue-photochemical technology instruments and the other was used as control. The treated and untreated sample pairs were stored at -30°C. The recovery rates of coagulation factors, inhibitor proteins, total protein, immunoglobulins, and complement proteins were measured at different time points after storage. The mean recovery of most proteins exceeded 80% after MB treatment. The exceptions were factor XI and fibrinogen, of which only 71.3-74% and 69.0-92.3% were retained during storage. The two equipment types differed in terms of residual MB concentration in the plasma samples (0.18μM and 0.29μM, respectively). They had similar protein recovery rates at 0.5month but differed at later time points. The four blood centers differed significantly with regard to factor II, V, VIII and fibrinogen activities. Only the samples from the Shandong blood center met the methylene blue treated fresh frozen plasma requirement. The major factor that influenced the quality of the MB-FFP samples was the time taken between blood collection and storage. Methylene blue treated plasma showed reduced coagulation factor (CF) activity and protein levels. The MB treatment-induced damage to the proteins was acceptable at the four Chinese blood centers, but the quality of the MB-treated plasma in general was not satisfactory. The main factor affecting plasma quality may be the duration of the collection and processing. 23128353 Cell cycle regulation by glucosamine in human pulmonary epithelial cells. Airway epithelial cells play an important role against intruding pathogens. Glucosamine, a commonly used supplemental compound, has recently begun to be regarded as a potential anti-inflammatory molecule. This study aimed to uncover how glucosamine impacts on cellular proliferation in human alveolar epithelial cells (A549) and bronchial epithelial cells (HBECs). With trypan blue-exclusion assay, we observed that glucosamine (10, 20, 50 mM) caused a decrease in cell number at 24 and 48 h; with a flow cytometric analysis, we also noted an enhanced cell accumulation within the G(0)/G(1) phase at 24 h and induction of late apoptosis at 24 and 48 h by glucosamine (10, 20, 50 mM) in A549 cells and HBECs. Examination of phosphorylation in retinoblastoma (Rb) protein, we found an inhibitory effect by glucosamine at 20 and 50 mM. Glucosamine at 50 mM was demonstrated to elevate both the mRNA and protein expression of p53 and heme oxygenase-1 (HO-1), but also caused a reduction in p21 protein expression. In addition, glucosamine attenuated p21 protein stability via the proteasomal proteolytic pathway, as well as inducing p21 nuclear accumulation. Altogether, our results suggest that a high dose of glucosamine may inhibit cell proliferation through apoptosis and disturb cell cycle progression with a halt at G(0)/G(1) phase, and that this occurs, at least in part, by a reduction in Rb phosphorylation together with modulation of p21, p53 and HO-1 expression, and nuclear p21 accumulation. 23648511 The LIM-Homeodomain transcription factor Islet-1 is required for the development of sympathetic neurons and adrenal chromaffin cells. Islet-1 is a LIM-Homeodomain transcription factor with important functions for the development of distinct neuronal and non-neuronal cell populations. We show here that Islet-1 acts genetically downstream of Phox2B in cells of the sympathoadrenal cell lineage and that the development of sympathetic neurons and chromaffin cells is impaired in mouse embryos with a conditional deletion of Islet-1 controlled by the wnt1 promotor. Islet-1 is not essential for the initial differentiation of sympathoadrenal cells, as indicated by the correct expression of pan-neuronal and catecholaminergic subtype specific genes in primary sympathetic ganglia of Islet-1 deficient mouse embryos. However, our data indicate that the subsequent survival of sympathetic neuron precursors and their differentiation towards TrkA expressing neurons depends on Islet-1 function. In contrast to spinal sensory neurons, sympathetic neurons of Islet-1 deficient mice did not display ectopic expression of genes normally present in the CNS. In Islet-1 deficient mouse embryos the numbers of chromaffin cells were only mildly reduced, in contrast to that of sympathetic neurons, but the initiation of the adrenaline synthesizing enzyme PNMT was abrogated and the expression level of chromogranin A was diminished. Microarray analysis revealed that developing chromaffin cells of Islet-1 deficient mice displayed normal expression levels of TH, DBH and the transcription factors Phox2B, Mash-1, Hand2, Gata3 and Insm1, but the expression levels of the transcription factors Gata2 and Hand1, and AP-2ß were significantly reduced. Together our data indicate that Islet-1 is not essentially required for the initial differentiation of sympathoadrenal cells, but has an important function for the correct subsequent development of sympathetic neurons and chromaffin cells. 23754659 Local selection of human populations shapes complex evolution patterns of CXCL10 gene. CXC motif chemokine 10 (CXCL10) is a small cytokine belonging to the CXC chemokine family, and it is secreted by several cell types in response to IFN-γ and regulates immune responses through the recruitment and activation of lymphocytes. As CXCL10 is very important in T-cell immunity and infectious diseases, we studied the effect of natural selection on the CXCL10 locus. By sequencing 74 individuals from three human populations, we found a complex pattern of natural selection acting on the CXCL10 locus. We discovered a signature of balancing selection in the European population with a significant positive Tajima's D value (2.57, P = 0.005) and an excess of intermediate frequency alleles. However, we observed an excess of high frequency-derived alleles and a significant Fay and Wu's test statistics (P = 0.015) in the Chinese population, which suggests that recent selective sweeps under positive selection had occurred. Also, there are a lot of alleles showing great frequency difference among populations. These results demonstrate that local selection has shaped CXCL10 evolution and indicates that there exist different actions of natural selection on the CXCL10 locus in different populations. This study provides insights into the likely relative roles of natural selection and population history in shaping today's genetic variation at the CXCL10 locus, indicates the relationship between adaptation to past infection and predisposition to autoimmunity in modern populations, improves our understanding of CXCL10 evolution, and motivates further investigations of the role of CXCL10 in infectious diseases and autoimmune diseases. 23758140 Polymer nanowrinkles with continuously tunable wavelengths. This paper describes a parallel method to generate polymer nanowrinkles over large areas with wavelengths that were continuously tuned down to 30 nm. Reactive ion etching using fluorinated gases was used to chemically treat thermoplastic polystyrene films, which resulted in a stiff skin layer. Upon heating, the treated thermoplastic, microscale, and nanoscale wrinkles were formed. We used variable-angle spectroscopic ellipsometry to characterize the thickness of the skin layer; this thickness could then be used to predict and control the nanowrinkle wavelength. Because the properties of these nanotextured polymer surfaces can be tuned over a large range of wrinkle wavelengths, they are promising for a broad range of applications, especially those that require large-area and uniform surface patterning. 23951266 A Comparison of the Performance of the I-gel™ vs. the LMA-S™during Anesthesia: A Meta-Analysis of Randomized Controlled Trials. Conflicting results were found between the I-gel™ and the LMA-Supreme™ during anesthesia, so we conducted a meta-analysis of randomized controlled trials (RCTs) to compare the effectiveness and safety of the I-gel™ vs. the LMA-Supreme™during anesthesia. A comprehensive search was conducted using Pubmed, EMbase, ISI Web of Knowledge, the Cochrane Library, China Journal Full-text Database, Chinese Biomedical Database, Chinese Scientific Journals Full-text Database, CMA Digital Periodicals, and Google scholar to find RCTs that compare the LMA-S™ with the i-gel™during anesthesia. Two reviewers independently selected trials, extracted data, and assessed the methodological qualities and evidence levels. Data were analyzed by RevMan 5.0 and comprehensive meta-analysis software. Ten RCTs were included. There were no significant differences in oropharyngeal leak pressures (mean difference [MD] 0.72, 95% confidence interval [CI] -1.10 2.53), device placement time (MD -1.3, 95%CI -4.07 1.44), first attempt insertion success (risk ratio [RR] 1.01, 95% CI 0.9 1.14), grade 3 and 4 fiberoptic view (RR 0.89, 95%CI 0.65 1.21), and blood on removal (RR 0.62, 95%CI 0.32 1.22) between the i-gel™ and the LMA-Supreme™, respectively. However, the LMA-Supreme™was associated with easier gastric tube insertion (RR 1.17, 95%CI 1.07 1.29), and more sore throat (RR 2.56, 95%CI 1.60 4.12) than the i-gel™ group. The LMA-Supreme™ and i-gel™ were similarly successful and rapidly inserted. However, the LMA-Supreme™ was shown to be easier for gastric tube insertion and associated with more sore throat compared with the i-gel™. 23507787 Adding serial N-terminal pro brain natriuretic peptide measurements to optimal clinical management in outpatients with systolic heart failure: a multicentre randomized clinical trial (NorthStar monitoring study). This study was designed to evaluate a new NT-proBNP monitoring concept in outpatients with systolic heart failure (HF). This was a multicentre, prospective randomized open-label blinded endpoint study. A total of 407 systolic HF patients were allocated to either clinical management (n = 208) or clinical management + NT-proBNP monitoring (n = 199) and followed for 2.5 years. If NT-proBNP increased >30%, a clinical checklist was completed and treatment initiated. The patients were matched at randomization and were 73 years old, 25% were females, 85% were NYHA class I-II, LVEF was 30%, and NT-proBNP 1955 pg/mL. NT-proBNP monitoring did not improve outcome, the hazard ratio for the primary composite endpoint (death or a cardiovascular admission) being 0.96 [95% confidence interval (CI) 0.71-1.29, P = 0.766]. NT-proBNP monitoring did not induce a significant change in the pharmacological strategy (P > 0.05 for all comparisons). In patients in whom NT-proBNP increased >30% (25% of the patients) during follow-up, a higher frequency of admission (69% vs. 47%, P = 0.002), a higher number of admission days (14 vs. 5 days, P = 0.003) and number of admissions (2 vs. 1, P = 0.009), and a lower quality of life (P = 0.032) and a poorer functional class (37% vs. 18% in NYHA class III-IV, P < 0.001) were observed. Adding serial measurements of NT-proBNP to optimal clinical management was not associated with a change in pharmacological strategy and did not improve outcome. However, survivors in whom NT-proBNP increased >30% showed a poorer functional class, clinical outcome, and quality of life. www.centerwatch: 173491 (NorthStar). 23797230 18F Sodium Fluoride PET/CT Detects Osseous Metastases From Breast Cancer Missed on FDG PET/CT With Marrow Rebound. Intense FDG uptake by bone marrow following recent chemotherapy limits evaluation for osseous metastases. The impact of marrow rebound on accuracy of F-fluoride PET/CT is unclear. A 73-year-old woman with breast cancer presented for restaging FDG PET/CT, which showed intense activity throughout almost the entire axial skeleton and no osseous metastases. An F-fluoride PET/CT performed 7 days later identified multiple osseous metastases in the spine, ribs, and pelvis. This case demonstrates that F-fluoride PET/CT should be considered for the evaluation of osseous metastases in patients with rebound marrow uptake on FDG PET/CT. 23884057 Hepatitis C virus reinfection following treatment among people who use drugs. Most new cases of hepatitis C virus (HCV) infections in the developed world are associated with injection drug use. However, treatment for people who inject drugs (PWID) is controversial, as successful treatment risks being followed by new infection. Reinfection after sustained virologic response has been reported, but is the risk so great that treatment should be withheld from this large HCV population? Preliminary evidence suggests that the reinfection incidence is low, but studies to date have been limited by small sample size and few cases of reinfection. In this review, we assess data from studies among PWID of HCV reinfection following treatment to give a reasonable estimate on how frequently reinfection appears and try to characterize those most at risk, The observation that spontaneous clearance of HCV reinfection following treatment occurs is suggestive of a partial protective immunity against persistent infection. 23893548 Difference in the Photophysical Properties of a Perylenetetracarboxylic Diimide Dimer and a Hexamer Linked by the Same Hexaphenylbenzene Group. A perylenetetracarboxylic diimide hexamer (6PDI) and a dimer (2PDI) linked with the same hexaphenylbenzene group were prepared, and the structures were fully characterized by (1) H NMR spectroscopy, mass spectrometry, and elemental analysis. Due to the similar molecular structure of these two compounds, similar interactions between/among the PDI subunits as well as similar photophysical properties are expected. However, the stationary UV/Vis absorption spectra reveal that the interactions among/between the PDI subunits in 6PDI are significantly stronger than those in 2PDI. This can be attributed to blocked rotation along the long axis of the PDI subunits in 6PDI due to steric hindrance of the two neighboring PDI subunits. The stronger interactions among the PDI subunits in 6PDI lead to long-wavelength emission, which can be assigned to "excimer-like" excited states. A similar conclusion can also be deduced from the fluorescence quantum yields and the fluorescence lifetimes. Electrochemical studies revealed that interactions between/among the PDI subunits in both 2PDI and 6PDI are still in the range of weak interactions. Ultrafast transient anisotropy decay dynamics revealed that excitation delocalization between the PDI subunits within 2PDI and 6PDI is quick and efficient. More interestingly, delocalization is faster in 6PDI than in 2PDI, probably because of the stronger interactions among the PDI subunits in the former. 23943021 Resolution of New-Onset Diabetes After Radical Pancreatic Resection Predicts Long-term Survival in Patients with Pancreatic Ductal Cell Adenocarcinoma. To demonstrate the effect of diabetes mellitus (DM) (stratified by long-term/new-onset presurgical diabetes, resolved/unresolved postsurgical diabetes) on prognosis for pancreatic ductal cell adenocarcinoma (PDAC) after radical resection. One hundred ninety-nine patients who underwent radical resection for PDAC between 2007 and 2011 at Ruijin Hospital (Shanghai, China) were retrospectively analyzed. Clinical and pathologic characteristics, surgical and adjuvant chemotherapy related outcomes, disease-free survival (DFS), and postoperative survival were compared among patients with long-term (≥2 years)/new-onset (<2 years) presurgical diabetes and resolved/unresolved postsurgical diabetes. Univariate and multivariable analysis was performed to determine factors associated with DFS and overall survival (OS). Of 199 patients, 90 (44.7 %) had DM, 64 of which were new onset and 26 of which were long-standing. Resolution of DM after radical pancreatic resection was observed in 65 % (42 of 64) in the new-onset group, but in none of the long-standing group. Resolved new-onset DM patients had larger, well-differentiated tumors compared to patients with unresolved new-onset DM. Patients with long-standing DM had shorter postoperative DFS and OS than nondiabetic/new-onset DM, whereas postoperative resolved new-onset DM is associated with longer DFS and OS than unresolved DM. Morbidity was higher and postoperative hospital stay was longer in patients with new-onset DM compared with patients with long-standing DM and patients without DM. There was no difference in the adjuvant chemotherapy toxicity rate among patients with long-standing or new-onset DM and those without DM. Different status of DM has different effects on outcome after resection for PDAC. Long-standing DM is related to progression of disease, whereas postsurgical resolved new-onset DM is a favorable prognostic factor. 23603369 Intermediate-term results of image-guided brachytherapy and high-technology external beam radiotherapy in cervical cancer: Chiang Mai University experience. To evaluate the outcomes of image-guided brachytherapy combined with 3D conformal or intensity modulated external beam radiotherapy (3D CRT/IMRT) in cervical cancer at Chiang Mai University. From 2008 to 2011, forty-seven patients with locally advanced cervical cancer were enrolled in this study. All patients received high-technology (3D CRT/IMRT) whole pelvic radiotherapy with a total dose of 45-46 Gy plus image-guided High-Dose-Rate intracavitary brachytherapy 6.5-7 Gy × 4 fractions to a High-Risk Clinical Target Volume (HR-CTV) according to GEC-ESTRO recommendations. The dose parameters of the HR-CTV for bladder, rectum and sigmoid colon were recorded, as well as toxicity profiles. In addition, the endpoints for local control, disease-free, metastasis-free survival and overall survival were calculated. At the median follow-up time of 26 months, the local control, disease-free survival, and overall survival rates were 97.9%, 85.1%, and 93.6%, respectively. The mean dose of HR-CTV, bladder, rectum and sigmoid were 93.1, 88.2, 69.6, and 72 Gy, respectively. In terms of late toxicity, the incidence of grade 3-4 bladder and rectum morbidity was 2.1% and 2.1%, respectively. A combination of image-guided brachytherapy and IMRT/3D CRT showed very promising results of local control, disease-free survival, metastasis-free survival and overall survival rates. It also caused a low incidence of grade 3-4 toxicity in treated study patients. 23928731 The role of cyclophosphamide in enhancing antitumor efficacy of an adenovirus oncolytic vector in subcutaneous Syrian hamster tumors. We have previously reported that intratumoral injection of VRX-007-an Ad5 (a species C adenovirus)-based vector overexpressing adenovirus death protein-can suppress the growth of subcutaneous HaK (hamster renal cancer) tumors. VRX-007 replication and tumor growth inhibition are enhanced when the hamsters are immunosuppressed by a high dose of cyclophosphamide (CP), an immunosuppressive and chemotherapeutic agent. Here, we report that continuous immunosuppression with CP was not required for increased oncolytic activity of VRX-007 because short-term dosing or continuous dosing with the drug yielded similar antitumor results. Prolonged viral replication was found only in animals on continuous CP treatment. We used 007-Luc, a replication-competent, luciferase-expressing vector similar to VRX-007, to investigate the replication of the vector over time. Tumor growth inhibition was similar in hamsters given CP treatment either 1 week before or 1 week after 007-Luc injection, which suggests that CP exerts its antitumor efficacy independently of vector therapy. 007-Luc did not spread far from the inoculation site, even in immunosuppressed, CP-treated animals. Our results indicate that the enhanced effectiveness that is produced by the combination of VRX-007 and CP therapies is due to their two independent mechanisms and that they do not have to be given simultaneously for the improved outcome.Cancer Gene Therapy advance online publication, 9 August 2013; doi:10.1038/cgt.2013.49. 23884027 Bone mineral density in women on long-term mud-bath therapy in a Salus per Aquam (SPA) environment. The objective of this study was to assess bone mineral density (BMD) in women on long-term mud-bath therapy (MBT) for osteoarthritis in a Salus per Aquam (SPA) environment. Two hundred and fifty female patients were randomly enrolled in this study in the SPA center of Sardara (Cagliari, Italy) where they were treated with a combination of daily full body mudpacks and bicarbonate-alkaline mineral water baths at cycles of 2 weeks/year. BMD was evaluated by means of calcaneus ultrasonometry (Sahara Hologic Inc., Bedford, MA, USA) and results analyzed according to duration of treatment and clinical variables. In the group of patients undergoing MBT for more than 10 years (group A) and for 3 to 10 years (group B) a reduced frequency of osteopenia and osteoporosis was detected (35.8% and 7.6% group A; 38.4% and 8.5% group B, respectively) compared to controls (group C) (48.9% and 23.4%, P<0.01 and P<0.001). Furthermore, higher T-score values were detected in group A and B (-1.05±1.28 and -1.24±0.94, respectively) compared to group C (-1.93±0.78) (P<0.0002 and P<0.0001). Similar results were observed in the analysis of data restricted to women in menopause only. Long-term mud-bath therapy in SPA environment appeared to be beneficial for BMD. 23414837 Triazolo and imidazo dihydropyrazolopyrimidine potassium channel antagonists. Previously disclosed C6 amido and benzimidazole dihydropyrazolopyrimidines were potent and selective blockers of IKur current. Syntheses and SAR for C6 triazolo and imidazo dihydropyrazolopyrimidines series are described. Trifluoromethylcyclohexyl N(1) triazole, compound 51, was identified as a potent and selective Kv1.5 inhibitor with an acceptable PK and liability profile. 23841916 Randomized BioBrick Assembly: A Novel DNA Assembly Method for Randomizing and Optimizing Genetic Circuits and Metabolic Pathways. The optimization of genetic circuits and metabolic pathways often involves constructing various iterations of the same construct or using directed evolution to achieve the desired function. Alternatively, a method that randomizes individual parts in the same assembly reaction could be used for optimization by allowing for the ability to screen large numbers of individual clones expressing randomized circuits or pathways for optimal function. Here we describe a new assembly method to randomize genetic circuits and metabolic pathways from modular DNA fragments derived from PCR-amplified BioBricks. As a proof-of-principle for this method, we successfully assembled CMY (Cyan-Magenta-Yellow) three-gene circuits using Gibson Assembly that express CFP, RFP, and YFP with independently randomized promoters, ribosome binding sites, transcriptional terminators, and all parts randomized simultaneously. Sequencing results from 24 CMY circuits with various parts randomized show that 20/24 circuits are distinct and expression varies over a 200-fold range above background levels. We then adapted this method to randomize the same parts with enzyme coding sequences from the lycopene biosynthesis pathway instead of fluorescent proteins, designed to independently express each enzyme in the pathway from a different promoter. Lycopene production is improved using this randomization method by about 40% relative to the highest polycistronic-expressing pathway. These results demonstrate the potential of generating nearly 20,000 unique circuit or pathway combinations when three parts are permutated at each position in a three-gene circuit or pathway, and the methodology can likely be adapted to other circuits and pathways to maximize products of interest. 23839996 Metabolic profiling reveals differences in concentrations of oxylipins and fatty acids secreted by the infrapatellar fat pad of end-stage osteoarthritis and normal donors. Objective: The infrapatellar fat pad (IPFP) in the knee joint is hypothesized to contribute to osteoarthritis (OA) development possibly by influencing inflammatory processes. Oxylipins are essential mediators in the inflammatory process. We aimed to identify the secretion of fatty acids and oxylipins derived thereof by the IPFP. Methods: IPFP explants of 13 OA (joint replacement surgery) and 10 normal (post-mortem) donors were cultured for 24 hours and supernatants were collected (FCM). Liquid chromatography-tandem mass spectrometry detected fatty acids and oxylipins in FCM samples. Univariate and multivariate (PLS-DA; Partial Least Squares Discriminant Analysis) analyses were performed followed by pathway analysis. To validate these outcomes a second set of OA FCM samples was measured (n=23). Results: Twenty nine oxylipins and fatty acids could be detected in FCM. Univariate analysis showed no differences between normal and OA FCM, however PLS-DA revealed an oxylipin/fatty acid profile consisting of 14 mediators associated with OA (accuracy rate 72%). Most important contributors to the model were lipoxin A4 (decreased), thromboxane B2 (increased) and arachidonic acid (increased). The statistical model predicted 64% of the second set of OA FCM samples correctly. Pathway analysis indicated differences on individual mediators rather than complete pathways. Conclusion: IPFP secretes multiple and different oxylipins and a subset thereof provides a distinctive profile for OA donors. The observed changes are likely regulated by the OA process rather than a consequence of basal metabolism changes as the increase in fatty acid levels was not necessarily associated with an increase in oxylipins derived from this fatty acid. © 2013 American College of Rheumatology. 23184409 Patient attitudes toward community pharmacist attire. The white coat has symbolized professionalism, while representing provider-patient fiduciary relationship. Although well described in the literature for physicians, few studies examine the impact of pharmacist attire on patients' opinions regarding professionalism and trust. Therefore, understanding patient perceptions regarding pharmacist's attire and its influence on comfort, confidence, trust, and professionalism may provide guidance on ways to enhance the quality of the provider-patient relationship. A 43-item Likert-type questionnaire was administered to 347 adults in a community pharmacy setting to determine preferences about the pharmacist's attire, accessories, and body art incorporating 8 photographs depicting a male pharmacist in various degrees of dress formality (ie, casual to professional). Descriptive and inferential statistics were used to summarize and analyze the data. Survey respondents reported it was desirable/strongly desirable that pharmacists be dressed in a shirt and tie, dress shoes, white coat, and name tag (mean 4.21-4.72), whereas they should not be dressed in jeans, casual shoes, or have visible body art (mean 2.17-2.78). Over 86% of the respondents felt that a pharmacist with a white coat instilled feelings of comfort, confidence, trust, and professionalism. In a community pharmacy setting, a pharmacist wearing a white coat appears to be the mainstay in displaying professionalism and inspiring trust in adult patients. 23952302 B═B and B≡E (E = N and O) Multiple Bonds in the Coordination Sphere of Late Transition Metals. Because of their unusual structural and bonding motifs, multiply bonded boron compounds are fundamentally important to chemists, leading to enormous research interest. To access these compounds, researchers have introduced sterically demanding ligands that provide kinetic as well as electronic stability. A conceptually different approach to the synthesis of such compounds involves the use of an electron-rich, coordinatively unsaturated transition metal fragment. To isolate the plethora of borane, boryl, and borylene complexes, chemists have also used the coordination sphere of transition metals to stabilize reactive motifs in these molecules. In this Account, we summarize our results showing that increasingly synthetically challenging targets such as iminoboryl (B≡N), oxoboryl (B≡O), and diborene (B═B) fragments can be stabilized in the coordination sphere of late transition metals. This journey began with the isolation of two new iminoboryl ligands trans-[(Cy3P)2(Br)M(B≡N(SiMe3))] (M = Pd, Pt) attached to palladium and platinum fragments. The synthesis involved oxidative addition of the B-Br bond in (Me3Si)2N═BBr2 to [M(PCy3)2] (M = Pt, Pd) and the subsequent elimination of Me3SiBr at room temperature. Variation of the metal, the metal-bound coligands, and the substituent at the nitrogen atom afforded a series of analogous iminoboryl complexes. Following the same synthetic strategy, we also synthesized the first oxoboryl complex trans-[(Cy3P)2BrPt(BO)]. The labile bromide ligand adjacent to platinum makes the complex a viable candidate for further substitution reactions, which led to a number of new oxoboryl complexes. In addition to allowing us to isolate these fundamental compounds, the synthetic strategy is very convenient and minimizes byproducts. We also discuss the reaction chemistry of these types of compounds. In addition to facilitating the isolation of compounds with B≡E (E = N, O) triple bonds, the platinum fragment can also stabilize a diborene (RB═BR) moiety, a bonding motif that thus far had only been accessible when stabilized by N-heterocyclic carbenes (NHCs). In the new π-diborene [(Et3P)2Pt(B2Dur2)] (Dur = 2,3,5,6-Me4-C6H) complex, the diborene ligand receives electron density from Pt, leading to a strong Pt-B bond and a B═B bond. We attribute this result to the very short B═B bond distance (1.51(2) Å) while coordinated to platinum. Overall, an increasing number of chemists are examining the chemistry of multiply bound boron compounds. The isolation of an oxoboryl complex is of special interest not only from a structural standpoint but also because of its orbital similarities to the ubiquitous CO ligand. Detailed computational studies of the π-diborene complex [(Et3P)2Pt(B2Dur2)] show that the bonding properties of this molecule violate the widely accepted Dewar-Chatt-Duncanson (DCD) bonding model. 23266730 Phytochemical analysis of the triterpenoids with cytotoxicity and QR inducing properties from the total tea seed saponin of Camellia sinensis. The tea seed triterpene saponin (TS) from Camellia sinensis was found to exhibit better antitumor activity in vivo in S180 implanted ICR mice and QR inducing activity for hepa lclc7 cells respectively compared with the total tea seed saponin (TTS), hydrolysate of the TTS and tea seed flavonoid glycosides (TF). By bioassay-guided isolation, the TS fraction was separated and seven major components were purified and identified as theasaponin E1 (1), theasaponin E2 (2), theasaponin C1 (3), assamsaponin C (4), theasaponin H1 (5), theasaponin A9 (6), and theasaponin A8 (7), among which compounds 4 and 5 were isolated from this genus for the first time. The antitumor bioassay of the isolated compounds showed that compounds 1, 2 and 3 exhibited potential activities against the human tumor cell lines K562 and HL60. Furthermore, compound 1 (the major constituent with a mass content of over 1%) showed significant QR inducing activity with an IR value of 4.2 at 4μg/ml. So it can be concluded that tea seed especially the compound 1 (theasaponin E1) could be used as an antitumor agent and a chemoprevention agent of cancer. The preliminary structure-activity relationship in the anti-tumor activity and QR inducing activity of tea saponins was discussed briefly. 23740837 Tumor promotion through the mesenchymal stem cell compartment in human hepatocellular carcinoma. Although the infiltration of mesenchymal stem (stromal) cells (MSCs) into different tumors is widely recognized in animal models, the question whether these MSCs have a positive or negative effect on disease progression remains unanswered. The aim of this study is to investigate whether human hepatocellular carcinoma (HCC) harbors MSCs and whether these MSCs affect tumor growth. We observed that cells capable of differentiation into both adipocyte and osteocyte lineages and expressing MSC markers can be cultured from surgically resected HCC tissues. In situ staining of human HCC tissues with a STRO-1 antibody showed that the tumor and tumor-stromal region are significantly enriched with candidate MSCs compared with adjacent tissue (n = 12, P < 0.01). In mice, coengraftment of a human HCC cell line (Huh7) with MSCs resulted in substantially larger tumors compared with paired engraftment of Huh7 alone (n = 8, P < 0.01). Consistently, coculturing Huh7 with irradiated MSCs significantly increased the number and the size of colonies formed. This enhancement of Huh7 colony formation was also observed by treatment of MSC-conditioned medium (MSC-CM), suggesting that secreted trophic factors contribute to the growth-promoting effects. Genome-wide gene expression array and pathway analysis confirmed the upregulation of cell growth and proliferation-related processes and downregulation of cell death-related pathways by treatment of MSC-CM in Huh7 cells. In conclusion, these results show that MSCs are enriched in human HCC tumor compartment and could exert trophic effects on tumor cells. Thus, targeting of HCC tumor MSCs may represent a new avenue for therapeutic intervention. 23398986 Soil moisture influences the development of Haemonchus contortus and Trichostrongylus colubriformis to third stage larvae. Two climate chamber experiments were conducted to determine the effect of varying initial soil moisture (0, 10 and 15%), simulated rainfall amount (0, 12 and 24mm) and simulated rainfall timing (days -1, 0 and 3 relative to faecal deposition) on development (day 14) of Haemonchus contortus and Trichostrongylus colubriformis to the third stage larvae (L3) and faecal moisture (FM). Increasing initial soil moisture content from 0 to 10 or 15% led to higher recovery of total L3 (P<0.001). Total L3 recovery increased with each level of simulated rainfall (P<0.001) in the ascending order of 0, 12 and 24mm. There was an interaction between the effects of initial soil moisture and simulated rainfall amount on the recovery of total L3, showing that the benefit of increased simulated rainfall lessened with increasing soil moisture. Simulated rainfall on the day of deposition resulted in higher recovery of L3 (P<0.001) than simulated rainfall on other days. FM on day 3 relative to faecal deposition was best associated with recovery of total H. contortus and T. colubriformis L3 (R(2)=0.32-0.46), reinforcing the importance of sufficient moisture soon after faecal deposition. The effects of initial soil moisture, and the amount and timing of simulated rainfall on development to L3 were largely explained by changes to FM and soil moisture values within 4 days relative to faecal deposition. These results highlight the influence of soil moisture and its interaction with rainfall on development of H. contortus and T. colubriformis to L3. Consequently we recommend that soil moisture be given greater importance and definition in the conduct of ecological studies of parasitic nematodes, in order to improve predictions of development to L3. 23786334 Dibenzosilanorbornadienyl cations and their fragmentation into silyliumylidenes. The terphenyl-substituted dibenzosilanorbornadienyl cation 11 was synthesized and isolated in the form of its [B(C6F5)4](-) salt. The salt was characterized by NMR spectroscopy supported by quantum mechanical computations and by an XRD analysis of a corresponding acetonitrilium salt. The thermal fragmentation of 11[B(C6F5)4] in benzene results in the high-yield formation of diphenylterphenylsilylium borate 17[B(C6F5)4]. High-lying intermediates in this process are solvent-complexed terphenylsilyliumylidene 8 and the hydrogen- and phenyl-substituted silylium ion 20. The formation of silylium ion 20 by reaction of silyliumylidene 8 with the solvent benzene demonstrates the high potential of this four valence electron species in C-H bond activation reactions. In addition, the instability of the hydrogen-substituted silylium ion 20 in benzene opens new mechanistic perspectives particular for dihydrogen activation by silyl cationic frustrated Lewis pairs and in general for the dihydrogen activation by strong Lewis acids. 23939894 The Contribution of Efflux Pumps, Porins and β-Lactamases to Multi-drug Resistance in Clinical Isolates of Acinetobacter baumannii. We investigated mechanisms of resistance to carbapenems, aminoglycosides, glycylcyclines, tetracyclines and quinolones in 90 multi-resistant clinical strains of A.baumannii isolated from two genetically unrelated A. baumannii clones: clone PFGE-ROC-1 (53 strains producing OXA58 β-lactamase enzyme and 18 strains with the OXA24 β-lactamase) and clone PFGE-HUI-1 (19 strains susceptible to carbapenems). We used real-time reverse transcriptase PCR to correlate antimicrobial resistance (MICs) with expression of genes encoding chromosomal β-lactamases (AmpC and OXA 51), porins (OmpA, CarO, Omp33, Dcap-like, OprB, Omp25, OprC, OprD and OmpW) and proteins integral to six efflux systems (AdeABC, AdeIJK, AdeFGH, CraA, AbeM and AmvA). Overexpression of the AdeABC system (relative expression 30-45 fold) was significantly associated with resistance to tigecycline, minocycline and gentamicin and other biological functions. However, hyperexpression of the AdeIJK efflux pump (relative expression 8-10 fold) was only significantly associated with resistance to tigecycline and minocycline (to which the TetB efflux system also contributed). TetB and TetA (39) efflux pumps were detected in clinical strains and were associated with resistance to tetracyclines and doxycycline. The absence of AdeABC system and lack of expression of other mechanisms suggest that tigecycline resistant strains of the PFGE-HUI-1 clone may be associated with a novel RND efflux pump (decreased MICs in presence of the inhibitor Phe-Arg β-naphthylamide dihydrochloride) and TetA (39) system. 23917803 Systematic review of the diagnostic utility of SPECT imaging in dementia. Single-photon emission-computed tomography (SPECT) may potentially contribute to the diagnostic work up of patients with neurodegenerative dementia. This systematic review aims to establish the diagnostic utility of (99m)Tc-hexamethylpropyleneamine ((99m)Tc-HMPAO) and (99m)Tc-ethylcysteine dimer SPECT in distinguishing between Alzheimer's disease (AD) and frontotemporal dementia (FTD), AD and vascular dementia (VD), AD and dementia with Lewy bodies (DLB), and AD and normal controls (NC). We searched MEDLINE and Embase databases via OVID for articles from January 1985 to May 2012 and identified additional studies from reviews and references. Of 755 studies, 49 studies met the inclusion and exclusion criteria for this systematic review; AD versus FTD (n = 13), AD versus VD (n = 18), AD versus DLB (n = 5), and AD versus NC (n = 18). We compiled relevant data and graded the studies with an internal and external validity criteria checklist. We pooled the studies with a clinical diagnosis and those using (99m)Tc-HMPAO SPECT in a meta-analysis, calculating the pooled weighted sensitivity, specificity, likelihood ratios, and diagnostic odds ratios using DerSimonian-Laird random-effects model. The pooled weighted sensitivity and specificity of (99m)Tc-HMPAO-SPECT in distinguishing clinically diagnosed AD from FTD are 79.7 and 79.9 %, respectively, AD from VD are 74.5 and 72.4 %, AD from DLB are 70.2 and 76.2 %, and AD from NC are 76.1 and 85.4 %. SPECT does have diagnostic value, particularly in differentiating Alzheimer's disease from frontotemporal dementia and normal controls; however, it should not be used in isolation, rather as an adjunct, and interpreted in the context of clinical information and paraclinical test results. 23848063 Extracellular vesicles in chronic lymphocytic leukemia. Abstract Extracellular vesicles (EVs) are membrane-enclosed nanoparticles 30 to 1000 nm in size and represent a novel mechanism of cell communication. By transferring RNA and protein from their cell of origin, they can reprogram target cells and thus are involved in changes within the cellular microenvironment - a key player in CLL pathogenesis. In the current study, we were able to isolate EVs of 20 to 300 nm from blood plasma of CLL patients as well as from supernatant of primary CLL cells in culture. Further, proteomic profiling by Coomassie staining of SDS-PAGE gels and by mass spectrometry revealed an EV-specific protein profile. These findings suggest that EVs represent an important mean of CLL cells to interact with other cells, which might contribute to the establishment of a pro-survival microenvironment for CLL cells. 23134486 Regulation of glycogen synthase from mammalian skeletal muscle--a unifying view of allosteric and covalent regulation. It is widely accepted that insufficient insulin-stimulated activation of muscle glycogen synthesis is one of the major components of non-insulin-dependent (type 2) diabetes mellitus. Glycogen synthase, a key enzyme in muscle glycogen synthesis, is extensively regulated, both allosterically (by glucose-6-phosphate, ATP, and others) and covalently (by phosphorylation). Although glycogen synthase has been a topic of intense study for more than 50 years, its kinetic characterization has been confounded by its large number of phosphorylation states. Questions remain regarding the function of glycogen synthase regulation and the relative importance of allosteric and covalent modification in fulfilling this function. In this review, we consider both earlier kinetic studies and more recent site-directed mutagenesis and crystal structure studies in a detailed qualitative discussion of the effects of regulation on the kinetics of glycogen synthase. We propose that both allosteric and covalent modification of glycogen synthase may be described by a Monod-Wyman-Changeux model in terms of apparent changes to L, the equilibrium constant for transition between the T and R conformers. As, with the exception of L, all parameters of this model are independent of the glycogen synthase phosphorylation state, the need to determine kinetic parameters for all possible states is eliminated; only the relationship between a particular state and L must be established. We conclude by suggesting that renewed efforts to characterize the relationship between phosphorylation and the kinetics of glycogen synthase are essential in order to obtain a better quantitative understanding of the function of glycogen synthesis regulation. The model we propose may prove useful in this regard. 23728519 Comparison of Ga-68 DOTA-TATE and Ga-68 DOTA-LAN PET/CT imaging in the same patient group with neuroendocrine tumours: preliminary results. Recent studies have suggested that PET imaging with Ga-68-labelled DOTA-somatostatin analogues such as octreotide and octreotate is useful in diagnosing neuroendocrine tumours (NETs) and has superior value over both computed tomography and planar and SPECT somatostatin receptor scintigraphy. The aim of the present study was to evaluate the role of Ga-68 DOTA-lanreotide (Ga-68-DOTA-LAN) in patients with somatostatin receptor (sst)-expressing tumours and to compare the results of Ga-68 DOTA-D-Phe1-Tyr3-octreotate (Ga-68-DOTA-TATE) in the same patient population. Twelve patients with NETs who were referred to our department for somatostatin receptor scintigraphy were included in the study. There were four patients with well-differentiated neuroendocrine tumour (WDNET) grade 1, two patients with WDNET grade 2, and three patients with poorly differentiated neuroendocrine carcinoma (PDNEC) grade 3. There was also one patient with medullary thyroid cancer, one patient with meningioma and one patient with MEN-1. All patients underwent two consecutive PET imaging studies with Ga-68-DOTA-TATE and Ga-68 DOTA-LAN. All images were evaluated visually, and maximum standardized uptake value was calculated for quantitative evaluation. On visual examination of maximum intensity projection images, GA-68 DOTA-LAN was seen to have high background activity and high bone marrow uptake. Both tracers defined 67 lesions. Ga-68 DOTA-TATE images revealed 63 (94%) clearly defined lesions, missing four lesions. In contrast, Ga-68 DOTA-LAN images defined only 23 (44%) lesions, missing 44 (56%) lesions. Thirty-two bone lesions were detected on Ga-68-DOTA-TATE images. Among them, only 11 (34%) were positive on Ga-68 DOTA-LAN images, whereas 21 (66%) were negative. When we evaluated liver, mediastinum and gastrointestinal tract lesions, Ga-68 DOTA-LAN was seen to be positive for 12 (34%) lesions and negative for 23 (66%) lesions. Although the results are preliminary, the image quality obtained by Ga-68-DOTA-TATE seems to be superior to that obtained by Ga-68 DOTA-LAN. With its significantly higher lesion uptake and higher ability to detect lesions, Ga-68-DOTA-TATE seems to be a better radioligand compared with Ga-68-DOTA-LAN for the diagnosis of NETs. 23885662 Creation of RTOG compliant patient CT-atlases for automated atlas based contouring of local regional breast and high-risk prostate cancers. Increasing use of IMRT to treat breast and prostate cancers at high risk of regional nodal spread relies on accurate contouring of targets and organs at risk, which is subject to significant inter- and intra-observer variability. This study sought to evaluate the performance of an atlas based deformable registration algorithm to create multi-patient CT based atlases for automated contouring. Breast and prostate multi-patient CT atlases (n = 50 and 14 respectively) were constructed to be consistent with RTOG consensus contouring guidelines. A commercially available software algorithm was evaluated by comparison of atlas-predicted contours against manual contours using Dice Similarity coefficients. High levels of agreement were demonstrated for prediction of OAR contours of lungs, heart, femurs, and minor editing required for the CTV breast/chest wall. CTVs generated for axillary nodes, supraclavicular nodes, prostate, and pelvic nodes demonstrated modest agreement. Small and highly variable structures, such as internal mammary nodes, lumpectomy cavity, rectum, penile bulb, and seminal vesicles had poor agreement. A method to construct and validate performance of CT-based multi-patient atlases for automated atlas based auto-contouring has been demonstrated, and can be adopted for clinical use in planning of local regional breast and high-risk prostate radiotherapy. 23280377 Is acute myeloid leukemia a liquid tumor? Extramedullary manifestations of acute myeloid leukemia (AML) were described as early as the 19th century. However, the incidence, clinical significance and pathobiology of extramedullary AML remain ill defined. We reviewed case reports, retrospective case series, pilot studies and imaging studies of extramedullary leukemia (EML) to determine its frequency, characteristics, clinical presentation and significance. EML precedes or accompanies development of AML and occurs during or following treatment, even during remission. Although imaging studies are rarely conducted and the true incidence of EML has yet to be verified, authors have reported several estimates based on retrospective and autopsy studies. The incidence of EML in patients with AML of all ages is estimated to be about 9% and EML in children with AML was detected in 40% of patients at diagnosis. The combination of positron emission tomography and computed tomography were the most sensitive and reliable techniques of detecting and monitoring EML. Based on our literature review, the frequency of EML is likely underreported. The well-documented nature of EML in patients with AML suggests that AML can manifest as a solid tumor. The extent to which EML accompanies AML and whether EML is derived from bone marrow are unknown. Furthermore, questions remain regarding the role of the microenvironment, which may or may not facilitate the survival and proliferation of EML, and the implications of these interactions with regard to minimal residual disease, tumor cell quiescence and relapse. Therefore, prospective studies of detection and characterization of EML in patients with AML are warranted. 23872312 Sandfly-borne phleboviruses of Eurasia and Africa: Epidemiology, genetic diversity, geographic range, control measures. Sandfly-borne phleboviruses may cause a transient febrile illness (sandfly fever) or more severe neuroinvasive disease. In the Old World, they are vectored by phlebotomine flies, which are widely distributed in the Mediterranean basin, North Africa, the Indian subcontinent, the Middle East and central Asia. High seroprevalence rates have been recorded in humans and domestic animals in areas where sandflies are present. Most published studies have focused on phlebovirus infections of travelers and of soldiers stationed in endemic areas, but the health impact on local populations should not be underestimated, as seroprevalence studies indicate massive circulation of these viruses, even if disease is seldom documented. Except for Toscana virus, which shows a marked neurotropism and is a leading cause of aseptic meningitis in endemic regions, phlebovirus infections are inadequately considered by physicians and are generally underestimated. However, several properties of these viruses suggest that they will extend their geographic range. First, changes in the areas occupied by sandflies as a result of climate change have a direct impact on the epidemiology of associated human and animal diseases. Second, phleboviruses exhibit a high mutation rate, and their tri-segmented genome is prone to reassortment and recombination. Third, distinct virus strains can be transmitted by the same arthropod species. Recent studies have documented the distribution of sandfly-borne phleboviruses in Western Europe, but data for Eastern Europe, the Middle East and Africa are very limited. With the goal of filling knowledge gaps and planning new research programs, we have examined available information and present it as a comprehensive review, with a specific focus on understudied regions. We also discuss the need to conduct studies aimed at developing new antiviral drugs and vaccines. 23830412 Mice deficient in the St3gal3 gene product α2,3 sialyltransferase (ST3Gal-III) exhibit enhanced allergic eosinophilic airway inflammation. Sialic acid-binding immunoglobulin-like lectin (Siglec)-F is a proapoptotic receptor on mouse eosinophils, but little is known about its natural tissue ligand. We previously reported that the St3gal3 gene product α2,3 sialyltransferase (ST3Gal-III) is required for constitutive Siglec-F lung ligand synthesis. We therefore hypothesized that attenuation of ST3Gal-III will decrease Siglec-F ligand levels and enhance allergic eosinophilic airway inflammation. C57BL/6 wild-type mice and St3gal3 heterozygous or homozygous deficient (St3gal3(+/-) and St3gal3(-/-)) mice were used. Eosinophilic airway inflammation was induced through sensitization to ovalbumin (OVA) and repeated airway OVA challenge. Siglec-F human IgG1 fusion protein (Siglec-F-Fc) was used to detect Siglec-F ligands. Lung tissue and bronchoalveolar lavage fluid (BALF) were analyzed for inflammation, as well as various cytokines and chemokines. Serum was analyzed for allergen-specific immunoglobulin levels. Western blotting with Siglec-F-Fc detected approximately 500-kDa and approximately 200-kDa candidate Siglec-F ligands that were less abundant in St3gal3(+/-) lung extracts and nearly absent in St3gal3(-/-) lung extracts. After OVA sensitization and challenge, Siglec-F ligands were increased in wild-type mouse lungs but less so in St3gal3 mutants, whereas peribronchial and BALF eosinophil numbers were greater in the mutants, with the following rank order: St3gal3(-/-) â‰¥ St3gal3(+/-) > wild-type mice. Levels of various cytokines and chemokines in BALF were not significantly different among these 3 types of mice, although OVA-specific serum IgG1 levels were increased in St3gal3(-/-) mice. After OVA sensitization and challenge, St3gal3(+/-) and St3gal3(-/-) mice have more intense allergic eosinophilic airway inflammation and less sialylated Siglec-F ligands in their airways. One possible explanation for these findings is that levels of sialylated airway ligands for Siglec-F might be diminished in mice with attenuated levels of ST3Gal-III, resulting in a reduction in a natural proapoptotic pathway for controlling airway eosinophilia. 23741049 Sorting of GLUT4 into its insulin-sensitive store requires the Sec1/Munc18 protein mVps45. Insulin stimulates glucose transport in fat and muscle cells by regulating delivery of the facilitative glucose transporter, glucose transporter isoform 4 (GLUT4), to the plasma membrane. In the absence of insulin, GLUT4 is sequestered away from the general recycling endosomal pathway into specialized vesicles, referred to as GLUT4-storage vesicles. Understanding the sorting of GLUT4 into this store is a major challenge. Here we examine the role of the Sec1/Munc18 protein mVps45 in GLUT4 trafficking. We show that mVps45 is up-regulated upon differentiation of 3T3-L1 fibroblasts into adipocytes and is expressed at stoichiometric levels with its cognate target-soluble N-ethylmaleimide-sensitive factor attachment protein receptor, syntaxin 16. Depletion of mVps45 in 3T3-L1 adipocytes results in decreased GLUT4 levels and impaired insulin-stimulated glucose transport. Using sub-cellular fractionation and an in vitro assay for GLUT4-storage vesicle formation, we show that mVps45 is required to correctly traffic GLUT4 into this compartment. Collectively our data reveal a crucial role for mVps45 in the delivery of GLUT4 into its specialized, insulin-regulated compartment. 23890254 Clinical review: Efficacy of antimicrobial-impregnated catheters in external ventricular drainage - a systematic review and meta-analysis. To assess the efficacy of antimicrobial-impregnated catheters in preventing catheter-related infections during external ventricular drainage (EVD), we performed a meta-analysis and systematic review. We systematically searched Medline, Embase, and the Cochrane Library. All randomized controlled trials (RCTs) and nonrandomized prospective studies (NPSs) related to antimicrobial-impregnated EVD catheters were included. The primary outcome was the rate of cerebrospinal fluid infection (CFI). The secondary outcomes included the rate of time-dependent CFI and catheter bacterial colonization. We further performed subgroup analysis, meta-regression analysis, and microbial spectrum analysis. Four RCTs and four NPSs were included. The overall rate of CFIs was 3.6% in the antimicrobial-impregnated catheter group and 13.7% in the standard catheter group. The pooled data demonstrated that antimicrobial-impregnated catheters were superior to standard catheters in lowering the rate of CFIs (odds ratio (OR) = 0.25, 95% confidence interval (CI) = 0.12 to 0.52, P <0.05). In survival analysis, the 20-day infection rate was significantly reduced with the use of antimicrobial-impregnated catheters (hazard ratio = 0.52, 95% CI = 0.29 to 0.95, P <0.05). Furthermore, a significantly decreased rate of catheter bacterial colonization was noticed for antimicrobial-impregnated catheters (OR = 0.37, 95% CI = 0.21 to 0.64, P <0.05). In subgroup analyses, although significant results remained for RCTs and NPSs, a subgroup difference was revealed (P <0.05). Compared with standard catheters, a significantly lower rate of CFIs was noticed for clindamycin/rifampin-impregnated catheters (OR = 0.27, 95% CI = 0.10 to 0.73, P <0.05) and for minocycline/rifampin-impregnated catheters (OR = 0.11, 95% CI = 0.06 to 0.21, P <0.05). However, no statistical significance was found when compared with silver-impregnated catheters (OR = 0.33, 95% CI = 0.07 to 1.69, P = 0.18). In microbial spectrum analysis, antimicrobial-impregnated catheters were shown to have a lower rate of Gram-positive bacterial infection, particularly the coagulase-negative Staphylococcus. In conclusion, the use of antimicrobial-impregnated EVD catheters could be beneficial for the prevention of CFI and catheter bacterial colonization. Although antibiotic-coated catheters seem to be effective, no sufficient evidence supports the efficacy of silver-impregnated catheters. 23964023 Genetic and genomic analyses of musculoskeletal differences between BEH and BEL strains. Berlin high (BEH) and Berlin low (BEL) strains selected for divergent growth differ 3-fold in body weight. We aimed at examining muscle mass, which is a major contributor to body weight, by exploring anatomical characteristics of the soleus muscle, its fiber numbers and their cross sectional area (CSA), by analysing transcriptome of the gastrocnemius and by initiating quantitative trait locus (QTL) mapping. BEH muscles were 4-to-8 times larger compared to BEL strain. In sub-strain BEH+/+, mutant myostatin was replaced with a wild type allele, however, BEH+/+muscles still were 2-to-4 times larger compared to the BEL strain. BEH soleus contained 2-times more (P<0.0001) and 2-times larger in CSA (P<0.0001) fibers compared to BEL strain. In addition, soleus femoral attachment anomaly (SFAA) was observed in all BEL mice. One significant (chromosome 1) and four suggestive (chromosomes 3, 4, 6 and 9) muscle weight QTLs were mapped in 21-day old F2 intercross (n=296) between BEH and BEL strains. The frequency of SFAA incidence in the F2 and in the backcross to BEL strain (BCL) suggested the presence of more than one causative gene. Two suggestive SFAA QTLs were mapped in BCL, however, their peak markers were not associated with the phenotype in F2. RNA-Seq analysis revealed 2,148 differentially expressed (P<0.1) genes and 45,673 SNPs and >2,000 indels between BEH+/+ and BEL males. In conclusion, contrasting muscle traits, genomic and gene expression differences between BEH and BEL strains provide a promising model for the search of genes involved in muscle growth and musculoskeletal morphogenesis. 23551108 Maternal outcomes in women supplemented with a high-protein drink in labour. Because of the potential aspiration risk, oral intake is restricted during labour. To determine whether high-protein drink supplementation in labour decreases nausea and emesis and promotes patient satisfaction. The study was registered with www.clinicaltrials.gov (NCT01414478). Labouring women were randomised into two groups: Group P received a high-protein drink (325 mL) with ice chips/water PRN; and Group C served as control and received only ice chips/water PRN (Study 1). Incidences of nausea and emesis were measured hourly until delivery and at 1 h postdelivery. Patient satisfaction was measured the following day. A secondary aim was to evaluate the rate of gastric emptying (t½ ) in women who ingested either 325 mL of a high-protein drink or ice chips/water (Study 2) using ultrasound. In Study 1, 150 women were recruited (Group P = 75; Group C = 75). There were no differences in the overall incidences of nausea (P = 0.14), emesis (P = 0.15) or in the incidences at the measured time periods (MANOVA, P > 0.05). Median patient satisfaction scores were higher in Group P than in Group C (P = 0.007). In Study 2, 18 additional patients (Group PG  = 9; Group CG  = 9) were analysed to determine US gastric emptying t½ rates (PG : 25.56 ± 15.90 min [95% CI: 15.17 - 35.94] compared with CG : 20.00 ± 8.70 min [95% CI: 14.34 - 25.66], P = 0.19). In labour, patient satisfaction is improved with high-protein drink supplementation compared with ice chips/water with comparable gastric emptying rates. 23579037 Transcriptomic analysis of the SSV2 infection of Sulfolobus solfataricus with and without the integrative plasmid pSSVi. The fusellovirus SSV2 and the integrative plasmid pSSVi, which constitute a unique helper-satellite virus system, replicate in Sulfolobus solfataricus P2. In this study, we investigated the interplay among SSV2, pSSVi and their host by transcriptomic analysis. Following infection of S. solfataricus P2, SSV2 activated its promoters in a temporal and distributive fashion, starting from the transcription of ORF305. Expression of several host genes encoding DNA replication and transcription proteins was up-regulated, suggesting that SSV2 depended heavily on the host replication machinery for its replication. SSV2 gene expression appeared to follow a similar pattern in S. solfataricus P2 harboring pSSVi to that in S. solfataricus P2 lacking the plasmid. Several early genes of the virus were transcribed earlier and more efficiently in the presence of pSSVi than in its absence. These results provide valuable clues to the understanding of the three-way interactions among SSV2, pSSVi and the host. 23860442 Validation Of Visual Analogue Scale For Anxiety (Vas-A) In Preanesthesia Evaluation. Background: Anxiety is a relevant but still underscored perioperative problem. The Visual Analogue Scale for Anxiety (VAS-A) seems to be effective, fast and manageable, but has not been fully validated yet. The aim of this study is to validate VAS-A comparing it to, Corah's Dental Anxiety Scale (CDAS) Spielberger's State Trait Anxiety Inventory (STAI) and Beck Depression Inventory (BDI). Methods: 100 consecutive patients (38 males and 62 females, median age 49) submitted to oral surgery filled out the VAS-A, CDAS, STAI forms Y1 and Y2, and BDI at preoperative examination; the order of administration of tests was randomized. Results: VAS-A score was significantly correlated to CDAS (p<0.0001), STAI-Y1 (p<0.0001), STAI-Y2 (p<0.002) but not to BDI (p=0.18). ROC curve analysis suggested VAS-A equal to 46 mm as threshold for anxiety when using STAI Y1 equal to 40 as reference cutoff. Conclusions: Our study confirms that VAS-A is a reliable indicator of preoperative anxiety and may detect patients with depressive symptoms also. Values of VAS-A around 50 mm are a reliable threshold for a clinically meaningful level of preoperative anxiety. 23843582 Thiosulfate in urine as a facilitator in the diagnosis of prostate cancer for patients with prostate-specific antigen less or equal 10 ng/mL. Abstract Background: The aim of this study was to examine the level of thiosulfate in the urine of prostate cancer (PCa) patients and evaluate its usefulness in the diagnosis and monitoring of prostate malignant transformation. Thiosulfate is a naturally occurring product of hydrogen sulfide (H2S) metabolism. H2S is involved in many physiological and pathological processes including inflammation and tumorigenesis. Methods: The determination of thiosulfate in the urine of PCa patients and healthy controls was performed by reverse-phased liquid chromatography using 2-chloro-1-methylquinolinium tetrafluoroborate as a derivatization reagent. Thiosulfate concentrations were normalized to urinary creatinine levels to compensate for variable diuresis. Results: In the urine samples of PCa patients, the mean thiosulfate level was almost 50 times higher than in the control groups and five times higher than in the benign prostatic hyperplasia group. The level of thiosulfate did not correlate with the serum prostate-specific antigen (PSA) level or PSA density. Neither tumor stage nor tumor grade was associated with thiosulfate level. Conclusions: The results suggest that thiosulfate concentration in urine may be a good facilitator in the diagnostics of PCa. The predictive accuracy of this method is particularly valuable for the diagnosis of patients with low serum PSA level and negative digital rectal examination and transrectal ultrasound results. 23449464 Epidemiological survey of tick-borne protozoal infection in iriomote cats and tsushima leopard cats in Japan. This epidemiological survey was conducted to determine the prevalence of Hepatozoon, Babesia and Theileria infection in the Iriomote cat (IC) and the Tsushima leopard cat (TLC). Blood samples from 43 ICs and 14 TLCs were collected between November 2002 and January 2012. Polymerase chain reaction and DNA sequencing analyses detected a Hepatozoon felis infection prevalence of 72.0% (31/43 cats) and 100% (14/14 cats) in ICs and TLCs, respectively. The degree of Hepatozoon parasitemia observed on blood smears ranged from 0.1 to 4.7%. However, no cases had obvious clinical signs of hepatozoonosis. Neither Babesia- nor Theileria-infected wildcats were detected in this study. 23870536 Melatonin protects mast cells against cytotoxicity mediated by chemical stimuli PMACI: Possible clinical use. Melatonin has documented cytoprotective effects on a wide variety of immune cells. The mechanism of action on mast cells (RBL-2H3) still remains in the dark. We found that melatonin significantly attenuated phorbol 12-myristate 13-acetate plus calcium ionophore A23187 (PMACI)-induced cytotoxicity in a concentration and time-dependent manner. It appears that the effect of melatonin on mast cells is two-fold: dependent (MT1 and MT2) and independent membrane receptors. In conclusion, melatonin treatment reduced the cytotoxicity, mediated by PMACI, and could provide a useful therapeutic option in processes where an excessive activation of mast cells occurs. 23768398 Reactive oxygen species responsible for beta-glucan degradation. The presence of iron(II) in beta-glucan in solution causes the formation of hydroxyl radical, which further oxidises the polysaccharide. This degradation can be enhanced by the presence of a reducing agent, such as ascorbic acid. In this study we investigated the effect the iron(II) concentration on the hydroxyl radical-mediated degradation of beta-glucan and identified the intermediate species involved in the formation of hydroxyl radicals. An increase in the iron(II) concentration did not have a significant effect on the degradation in the presence of a reducing agent (ascorbic acid), while in the mere presence of iron(II) it accelerates the degradation. The addition of catalase and superoxide dismutase (SOD) prevented the hydroxyl radical driven-degradation of beta-glucan induced by iron(II) or ascorbic acid/iron(II), demonstrating the involvement of both superoxide and hydrogen peroxide in the hydroxyl radical formation. SOD, which catalyses the dismutation of superoxide into hydrogen peroxide, should have stimulated the formation of radicals, since these radicals are generated from the reaction between hydrogen peroxide and iron(II). In the present study, we hypothesise the mechanism of the inhibition of beta-glucan degradation by superoxide dismutase. 23666867 Multiobjective evolutionary algorithm with many tables for purely ab initio protein structure prediction. This article focuses on the development of an approach for ab initio protein structure prediction (PSP) without using any earlier knowledge from similar protein structures, as fragment-based statistics or inference of secondary structures. Such an approach is called purely ab initio prediction. The article shows that well-designed multiobjective evolutionary algorithms can predict relevant protein structures in a purely ab initio way. One challenge for purely ab initio PSP is the prediction of structures with β-sheets. To work with such proteins, this research has also developed procedures to efficiently estimate hydrogen bond and solvation contribution energies. Considering van der Waals, electrostatic, hydrogen bond, and solvation contribution energies, the PSP is a problem with four energetic terms to be minimized. Each interaction energy term can be considered an objective of an optimization method. Combinatorial problems with four objectives have been considered too complex for the available multiobjective optimization (MOO) methods. The proposed approach, called "Multiobjective evolutionary algorithms with many tables" (MEAMT), can efficiently deal with four objectives through the combination thereof, performing a more adequate sampling of the objective space. Therefore, this method can better map the promising regions in this space, predicting structures in a purely ab initio way. In other words, MEAMT is an efficient optimization method for MOO, which explores simultaneously the search space as well as the objective space. MEAMT can predict structures with one or two domains with RMSDs comparable to values obtained by recently developed ab initio methods (GAPFCG , I-PAES, and Quark) that use different levels of earlier knowledge. 23841667 Self-assembled and highly selective sensors based on air-bridge-structured nanowire junction arrays. We describe a strategy for creating an air-bridge-structured nanowire junction array platform that capable of reliably discriminating between three gases (hydrogen, carbon monoxide, and nitrogen dioxide) in air. Alternatively driven dual nanowire species of ZnO and CuO with the average diameter of ∼30 nm on a single substrate are used and decorated with metallic nanoparticles to form two-dimensional microarray, which do not need to consider the post fabrications. Each individual nanowires in the array form n-n, p-p, and p-n junctions at the micro/nanoscale on single substrate and the junctions act as electrical conducting path for carriers. The adsorption of gas molecules to the surface changes the potential barrier height formed at the junctions and the carrier transport inside the straight semiconductors, which provide the ability of a given sensor array to differentiate among the junctions. The sensors were tested for their ability to distinguish three gases (H2, CO, and NO2), which they were able to do unequivocally when the data was classified using linear discriminant analysis. 23821757 Consent form heterogeneity in cancer trials: the cooperative group and institutional review board gap. Cooperative group (CG) provided consent forms (CGP-CFs) undergo re-review and revision by local institutional review boards (IRB) before institutional approval. We compared the relative readability and length of IRB-approved consent forms (IRB-CFs) used at seven academic institutions with their corresponding CGP-CFs. We also assessed the variability of these metrics across our institutions. This study included 197 consent forms (CFs) from 56 CG trials that were open in at least two of the participating institutions. The Flesch Reading Ease Score (FRES), the Flesch-Kincaid Grade Level (FKGL), and document length were collected on all CFs. Unpaired t test was used to compare length and readability of CGP-CF with the IRB-CF. Analysis of variance and Bonferroni-Dunn tests were used to assess interinstitutional variability in readability for all IRB-CFs. All statistical tests were two-sided. IRB-CFs were statistically significantly longer than CGP-CFs (mean number of pages = 17 vs 13; P < .001). Mean FKGLs were higher (10.3 vs 9.4; P < .0001) and the mean FRESs were lower (53.1 vs 57.1; P < .0001) for IRB-CFs compared with CGP-CFs. Readability varied statistically significantly between institutions for all sections of the IRB-CF (P < .0001). Finalized IRB-CFs for identical clinical trials at different institutions demonstrated substantial heterogeneity of readability and length. As CFs progress from National Cancer Institute (NCI)-sponsored CGs to local IRBs, they seem to become longer and less readable. Interinstitutional heterogeneity in CF readability is substantial and widespread. More consistent adherence to CGP-CFs based on the newly revised NCI CF template with minimal modification by local IRBs should help simplify and standardize CFs used in cancer clinical trials. 23522711 Influenza vaccination knowledge and perceptions among Veterans Affairs nurses. Flu vaccination among nurses in the Veterans Health Administration system is crucial in the prevention of influenza. Nurses working at a Veterans Administration Medical Center completed the Influenza Vaccination Knowledge and Perceptions Survey. The findings from this survey suggest the need for additional education for nurses as it relates to flu vaccination. 23850351 Pharmacological effect of gelsemine on anxiety-like behavior in rat. The chemical compound gelsemine is the major active principle of the yellow jasmine (Gelsemium) that is generally claimed as possessing anxiolytic properties based on empirical and indirect knowledge. Surprisingly, gelsemine effect on anxiety has until now received only little attention. Here, we used the well-validated method for anxiety assessment, the elevated plus-maze combined with video-tracking, to measure gelsemine action on rat anxiety-like behavior. Rats were intraperitoneally injected (500μl/daily/7days) with gelsemine (10(-6), 10(-10) or 10(-14)M) or control solution. Diazepam (DZP) was used as positive standard anxiolytic and additional controls were naive rats similarly manipulated except being injected. Gelsemine or diazepam treatment did not affect the number of closed arm entries and rears illustrating the rat general activity. In contrast, gelsemine (10(-6) to 10(-10)M) or DZP increased dose-dependently the number of entries and the percent of time spent in the open arms indicating that gelsemine is an anxiolytic. Consistently, we observed that gelsemine (10(-6) to 10(-10)M) or DZP also decreased dose-dependently the percent of protected stretched attend postures, an ethological index of anxiety-like state. Altogether, our results constitute a solid set of fundamental data directly demonstrating anxiolytic properties of gelsemine. The report also opens new perspectives for the development of safe and effective gelsemine- or Gelsemium-based strategies against pathological anxiety. 23684886 Human chorionic gonadotropin and its free β-subunit stimulate trophoblast invasion independent of LH/hCG receptor. Both paracrine and autocrine factors are involved in the regulation of trophoblast invasion. One of these factors is human chorionic gonadotropin (hCG), which stimulates trophoblast invasion. The stimulatory activity has especially been ascribed to a hyperglycosylated form of hCG (hCG-h) that is expressed in early pregnancy. We compared the stimulatory activities of different forms of hCG and its free β-subunit (hCGβ) on trophoblast invasion. hCG, hCG-h, hCGβ, and its hyperglycosylated form (hCGβ-h) stimulated the invasion of JEG-3 choriocarcinoma cells. The stimulatory effect of hCGβ was also confirmed with primary human trophoblasts. Down-regulation of the LH/hCG receptor by RNA-interference did not significantly reduce the effect of hCGβ and hCG on cell invasion. Increased invasion was associated with increased levels of MMP-2, MMP-9 and activity of uPA. Our findings suggest that hCG, hCGβ and their hyperglycosylated forms stimulate the invasion of trophoblast cells independent of the classical LH/hCG-receptor. 23959088 microRNA-199a-3p, DNMT3A, and aberrant DNA methylation in testicular cancer. It was previously demonstrated that miR-199a was downregulated in testicular germ cell tumor (TGCT), probably due to hypermethylation of its promoter. Further study found that re-expression of miR-199a in testicular cancer cells (NT2) led to suppression of cell growth, cancer migration, invasion and metastasis. More detailed analyses showed that these properties of miR-199a could be assigned to miR-199a-5p, one of its two derivatives. The biological role of the other derivative, miR-199a-3p in TGCT (testicular germ cell tumor), remains largely uncharacterized. In this report, we identified DNA (cytosine-5)-methyltransferase 3A (DNMT3A), the de novo methyltransferase, as a direct target of miR-199a-3p using a 3'-UTR reporter assay. Transient expression of miR-199a-3p in NT2 cells led to decrease, while knocking down of miR-199a-3p in a normal human testicular cell line (HT) led to elevation, of DNMT3A2 (DNMT3A gene isoform 2) mRNA and protein levels. In clinical samples, DNMT3A2 was significantly overexpressed in malignant testicular tumor, and the expression of DNMT3A2 was inversely correlated with the expression of miR-199a-3p. However, DNMT3A did not affect miR-199a expression in NT2 cells. Further characterization of miR-199a-3p revealed that it negatively regulated DNA methylation, partly through targeting DNMT3A. Overexpression of miR-199a-3p restored the expression of APC and MGMT tumor-suppressor genes in NT2 cells by affecting DNA methylation of their promoter regions. Our studies demonstrated the deregulation of miR-199a-3p expression in TGCT may provide novel mechanistic insights into TGCT carcinogenesis and suggested a potentially therapeutic use of synthetic miR-199a-3p oligonucleotides as effective hypomethylating compounds in the treatment of TGCT. 23959671 An automated insertion tool for cochlear implants with integrated force sensing capability. Minimally invasive cochlear implantation and residual hearing preservation require both the surgical approach to the cochlea as well as the implant insertion to be performed in an atraumatic fashion. Considering the geometric limitations of this approach, specialized instrumentation is required to insert the electrode while preserving intracochlear membranes carrying the sensory hair cells. An automated insertion tool for cochlear implants, which is capable of sensing insertion forces with a theoretical resolution of [Formula: see text], is presented. In contrast to previous designs, the custom force sensor is integrated in the insertion mechanism. Moreover, a test bench for insertion studies under constant and reproducible boundary conditions is proposed. It is used to experimentally validate the force sensing insertion tool, which is achieved by comparing the acquired forces to a ground truth measurement. The results of insertion studies on both an acrylic cochlear phantom and temporal bone specimen are given and discussed. Results reveal that friction, occurring between the electrode carrier and the inside of the insertion tool guide tube, is likely to affect the force output of the proposed sensor. An appropriate method to compensate for these disturbances is presented and experimentally validated. Using the proposed approach to friction identification, a mean accuracy of [Formula: see text] is observed. The force information provided by the proposed, automated insertion tool can be used to detect complications during electrode insertion. However, in order to obtain accurate results, an identification of frictional forces prior to insertion is mandatory. The insertion tool is capable of automatically executing the appropriate trajectories. 23914868 Transcatheter embolization for the management of acute active inferior epigastric artery hemorrhages. Purpose : To report a retrospective review of all patients who were admitted to the interventional radiology unit at our hospital for transcatheter arterial embolization (TAE) of an acute active hemorrhage of the inferior epigastric artery. Methods : From 1996 to 2012, 52 consecutive patients (26 men; mean age 63±15 years) with hemodynamically relevant active abdominal wall hematoma were admitted for TAE of the inferior epigastric artery. Of these, 19 patients had spontaneous hemorrhage due to use of anticoagulants, 18 due to abdominal trauma, and 15 due to an iatrogenic complication. All superselective embolizations were performed using a coaxial catheter technique with a 0.018-inch microcatheter introduced through the diagnostic macrocatheter. Various embolization methods, alone or in combination, were applied, including primarily microcoils and polyvinyl alcohol particles. Results : Primary technical success was achieved in 47/52 (90%) patients; the remainder needed a second embolization session (secondary success 100%). The mean puncture-to-hemostasis time was 65.4±35 minutes. No patient developed a large hematoma or pseudoaneurysm at the puncture site. The 30-day mortality was 19% (n=10) and the total cumulative mortality rate was 23% (n=12). Over a mean 67-month follow-up of 39/40 survivors (1 lost to follow-up), no complications from the embolization procedure, such as abdominal wall ischemia, were observed. There were no differences in outcomes based on etiology of the hemorrhage. Conclusion : In selected patients with acute active hemorrhage of the IEA in the anterior abdominal wall, TAE is a fast, safe, minimally invasive, and reliable method with a high technical success rate and no long-term complications. 23515891 Constructing Bacillus thuringiensis strain that co-expresses Cry2Aa and chitinase. A triple recombineering technique was used with plasmid pHT315 to produce pHTEC, a construct carrying chitinase and cry2Aa genes from Bacillus thuringiensis subsp. kurstaki 4.0718. Transformation of wild-type B. thuringiensis strain HD73 and the acrystalliferous strain Cry-B with pHTEC resulted in the recovery of recombinant strains that expressed Cry2Aa as cubic crystals in the cell pellet and soluble chitinase protein. The toxicity of HD73 (pHTEC) against Helicoverpa armigera larvae increased sevenfold when compared with HD73 (pHT315) harboring pHT315 vector. The triple recombineering protocol was optimized by comparing recombination efficacy mediated by RecE/RecT and Redα/Redβ and by using single-strand DNA as substrate. 23831208 Organic cation transporter 1 mediates the uptake of monocrotaline and plays an important role in its hepatotoxicity. Monocrotaline (MCT) is a kind of toxic retronecine-type pyrrolizidine alkaloids (PAs) from plants of Crotalaria, which can be bio-activated by cytochrome P450 (CYP) enzymes in liver and then induce hepatotoxicity. Since CYPs are localized in the endoplasmic reticulum, the influx of MCT to the liver is the key step for its hepatotoxicity. The objective of the present study was to investigate the role of organic cation transporter 1 (OCT1), a transporter mainly expressed in liver, in the uptake of MCT and in hepatotoxicity induced by MCT. The results revealed that MCT markedly inhibited the uptake of 1-methyl-4-phenylpyridinium (MPP(+)), an OCT1 substrate, in Madin-Darby canine kidney (MDCK) cells stably expressing human OCT1 (MDCK-hOCT1) with the IC50 of 5.52±0.56μM. The uptake of MCT was significantly higher in MDCK-hOCT1 cells than in MDCK-mock cells, and MCT uptake in MDCK-hOCT1 cells followed Michaelis-Menten kinetics with the Km and Vmax values of 25.0±6.7μM and 266±64pmol/mg protein/min, respectively. Moreover, the OCT1 inhibitors, such as quinidine, d-tetrahydropalmatine (d-THP), obviously inhibited the uptake of MCT in MDCK-hOCT1 cells and isolated rat primary hepatocytes, and attenuated the viability reduction and LDH release of the primary cultured rat hepatocytes caused by MCT. In conclusion, OCT1 mediates the hepatic uptake of MCT and may play an important role in MCT induced-hepatotoxicity. 22961427 The influence of pH on phosphatidylethanolamine monolayer at the air/aqueous solution interface. The dependence of the interfacial tension of a phosphatidylethanolamine (PE) monolayer on the pH of the aqueous solution has been studied. A theoretical equation is derived to describe this dependence. A simple model of the influence of pH on the phosphatidylethanolamine monolayer at the air/hydrophobic chains of PE is presented. The contributions of additive phosphatidylethanolamine forms (both interfacial tension values and molecular area values) depend on pH. The interfacial tension values and the molecular area values for PEH(+) and PEOH(-) forms of phosphatidylethanolamine were calculated. The assumed model was verified experimentally. The experimental results agreed with those derived from the theoretical equation in a whole range of pH values. 23758058 Effect of laundry surfactants on surface charge and colloidal stability of silver nanoparticles. The stability of silver nanoparticles (Ag NPs) potentially released from clothing during a laundry cycle and their interactions with laundry-relevant surfactants [anionic (LAS), cationic (DTAC), and nonionic (Berol)] have been investigated. Surface interactions between Ag NPs and surfactants influence their speciation and stability. In the absence of surfactants as well as in the presence of LAS, the negatively charged Ag NPs were stable in solution for more than 1 day. At low DTAC concentrations (≤1 mM), DTAC-Ag NP interactions resulted in charge neutralization and formation of agglomerates. The surface charge of the particles became positive at higher concentrations due to a bilayer type formation of DTAC that prevents from agglomeration due to repulsive electrostatic forces between the positively charged colloids. The adsorption of Berol was enhanced when above its critical micelle concentration (cmc). This resulted in a surface charge close to zero and subsequent agglomeration. Extended DLVO theory calculations were in compliance with observed findings. The stability of the Ag NPs was shown to depend on the charge and concentration of the adsorbed surfactants. Such knowledge is important as it may influence the subsequent transport of Ag NPs through different chemical transients and thus their potential bioavailability and toxicity. 23932995 Gastric cancer: adding glycosylation to the equation. Gastric cancer has a high incidence and mortality, so there is a pressing need to understand the underlying molecular mechanisms in order to discover novel biomarkers. Glycosylation alterations are frequent during gastric carcinogenesis and cancer progression. This review describes the role of glycans from the initial steps of the carcinogenesis process, in which Helicobacter pylori adheres to host mucosa glycans and modulates the glycophenotype, as well as how glycans interfere with epithelial cell adhesion by modulating epithelial cadherin functionality in gastric cancer progression. Other mechanisms regulating gastric cancer malignant behavior are discussed, such as increased sialylation interfering with key signaling pathways and integrin glycosylation leading to an invasive phenotype. Applications of these glycosylation alterations in the clinical management of gastric cancer patients are discussed. 23788655 α4α6β2* Nicotinic Acetylcholine Receptor Activation on Ventral Tegmental Area Dopamine Neurons Is Sufficient to Stimulate a Depolarizing Conductance and Enhance Surface AMPA Receptor Function. Tobacco addiction is a serious threat to public health in the United States and abroad, and development of new therapeutic approaches is a major priority. Nicotine activates and/or desensitizes nicotinic acetylcholine receptors (nAChRs) throughout the brain. nAChRs in ventral tegmental area (VTA) dopamine (DA) neurons are crucial for the rewarding and reinforcing properties of nicotine in rodents, suggesting that they may be key mediators of nicotine's action in humans. However, it is unknown which nAChR subtypes are sufficient to activate these neurons. To test the hypothesis that nAChRs containing α6 subunits are sufficient to activate VTA DA neurons, we studied mice expressing hypersensitive, gain-of-function α6 nAChRs (α6L9'S mice). In voltage-clamp recordings in brain slices from adult mice, 100 nM nicotine was sufficient to elicit inward currents in VTA DA neurons via α6β2* nAChRs. In addition, we found that low concentrations of nicotine could act selectively through α6β2* nAChRs to enhance the function of 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) receptors on the surface of these cells. In contrast, α6β2* activation did not enhance N-methyl-d-aspartic acid receptor function. Finally, AMPA receptor (AMPAR) function was not similarly enhanced in brain slices from α6L9'S mice lacking α4 nAChR subunits, suggesting that α4α6β2* nAChRs are important for enhancing AMPAR function in VTA DA neurons. Together, these data suggest that activation of α4α6β2* nAChRs in VTA DA neurons is sufficient to support the initiation of cellular changes that play a role in addiction to nicotine. α4α6β2* nAChRs may be a promising target for future smoking cessation pharmacotherapy. 23818217 Biomimetic dehydrogenative diels-alder cycloadditions: total syntheses of brosimones a and B. Passing (H2 ) gas: Concise syntheses of the natural products brosimones A and B have been achieved using sequential dehydrogenative Diels-Alder (DHDA) cycloadditions. The syntheses employ either Pt/C-cyclopentene or DDQ to effect dehydrogenation of prenylchalcone substrates in combination with silver nanoparticles to promote subsequent Diels-Alder cycloadditions. 23918743 A METHOD TO ACCOUNT FOR TRACK OVERLAP IN CR-39 DETECTORS. Solid-state nuclear track detectors are commonly used for the detection of indoor radon levels. However, despite numerous advantages, this technique still presents many unsolved problems. An important source of error is represented by the reduction in the detection efficiency due to overlapping tracks, which results in a sensible underestimation of the radon levels. This paper presents a new experimental procedure to address the effect of overlapping tracks by establishing a relationship between the detection efficiency and the number of detected tracks. Experimental data have been collected at the radon chamber of the Istituto Nazionale di Metrologia delle Radiazioni Ionizzanti (INMRI), at the ENEA centre in Casaccia, using CR-39 detectors provided by Radosys Ltd. It has been proved that the method, applied to the experimental settings of this study, gives reliable results up to 7607 kBq h m(-3). Finally, the method has been validated through a Monte Carlo simulation, exploring a wide range of radon exposure. 23757351 microRNA 223 Is Upregulated in the Multistep Progression of Barrett's Esophagus and Modulates Sensitivity to Chemotherapy by Targeting PARP1. Recent microarray and RNA-sequencing studies have uncovered aberrantly expressed microRNAs (miRNA) in Barrett's esophagus-associated esophageal adenocarcinoma. The functional significance of these miRNAs in esophageal adenocarcinoma initiation and progression is largely unknown. Expression levels of miR-199a/b-3p, -199a-5p, -199b-5p, -200b, -200c, -223, and -375 were determined in microdissected tissues from cardiac mucosa, Barrett's esophagus, dysplastic Barrett's esophagus, and esophageal adenocarcinoma using quantitative real-time PCR. miR-223 expression was validated in precursors and esophageal adenocarcinomas from 95 patients with esophageal adenocarcinoma by in situ hybridization (ISH). miR-223 was transfected into two esophageal adenocarcinoma cell lines, and in vitro assays were conducted. Target genes were identified using Illumina microarray, and results were validated in cell lines and human specimens. miR-199 family members and miR-223 were significantly overexpressed in esophageal adenocarcinoma, however, only miR-223 showed a stepwise increase during esophageal adenocarcinoma carcinogenesis. A similar trend was observed by ISH, which additionally showed that miR-223 is exclusively expressed by the epithelial compartment. miR-223-overexpressing cells had statistically significantly more migratory and invasive potential than scramble sequence-transfected cells. PARP1 was identified as a direct target gene of miR-223 in esophageal adenocarcinoma cells. Increased sensitivity to chemotherapy was observed in cells with enforced miR-223 expression and reduced PARP1. miR-223 is significantly upregulated during the Barrett's esophagus-dysplasia-esophageal adenocarcinoma sequence. Although high miR-223 levels might contribute to an aggressive phenotype, our results also suggest that patients with esophageal adenocarcinoma with high miR-223 levels might benefit from treatment with DNA-damaging agents. Clin Cancer Res; 19(15); 4067-78. ©2013 AACR. 23828893 Role of FADD Phosphorylation in Regulating Glucose Homeostasis: from Proteomic Discovery to Physiological Validation. Fas-associated death domain-containing protein (FADD), a classical apoptotic signaling adaptor, participates in different non-apoptotic processes regulated by its phosphorylation. However, the influence of FADD on metabolism, especially glucose homeostasis, has not been evaluated to date. Here, using both two-dimensional electrophoresis (2-DE) and liquid chromatography linked to tandem mass spectrometry (LC/MS/MS), we found that glycogen synthesis, glycolysis and gluconeogenesis were dysregulated due to FADD phosphorylation, both in MEFs and liver tissue of the mice bearing phosphorylation-mimicking mutation form of FADD (FADD-D). Further physiological studies showed that FADD-D mice exhibited lower blood glucose, enhanced glucose tolerance and increased liver glycogen content without alterations in insulin sensitivity. Moreover, investigations on the molecular mechanisms revealed that, under basal conditions, FADD-D mice had elevated phosphorylation of Akt with alterations in its downstream signaling, leading to increased glycogen synthesis and decreased gluconeogenesis. Thus, we uncover a novel role of FADD in the regulation of glucose homeostasis by proteomic discovery and physiological validation. 23966242 Effects of ACE I/D Polymorphism and Aerobic Training on the Immune-Endocrine Network and Cardiovascular Parameters of Postmenopausal Women. Context:Estrogen deficiency, systemic low-grade inflammation, and reduction of adrenal gland function have central roles in noncommunicable chronic disease (NCD) development. With angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism, the deletion variant (DD) is related to higher levels of circulating angiotensin II, which might interact with all of these molecular pathways to increase NCD risk. On the other hand, physical exercise counteracts the occurrence of NCDs, potentially acting on the same pathways.Objectives:The aim of the study was to investigate the effects of walking training on adrenal steroid and cytokine levels and on cardiovascular parameters in postmenopausal women with ACE I/D genotypes.Methods:Thirty-six (DD = 15, II/ID = 21) sedentary postmenopausal women (mean age, 56 ± 4 y) participated in a 13-week program of walking training at moderate intensity. Heart rate, blood pressure, double product, TNF-α, dehydroepiandrosterone sulfate (DHEA-S), and cortisol were evaluated before and after the intervention program.Results:Before walking training, the ACE DD genotype showed significantly higher TNF-α (P = .007) and lower DHEA-S concentrations (P = .022) than the ACE II/ID individuals. After walking training, both subgroups significantly decreased TNF-α plasma levels and cortisol/DHEA-S ratio (P = .001 and P = .016, respectively) and significantly increased DHEA-S levels (P < .001). Moreover, all the cardiovascular parameters were significantly reduced in the ACE DD participants (P ≤ .05), whereas the ACE I-allele carriers showed a decrease in heart rate (P ≤ .05) and the double product (P ≤ .05).Conclusion:ACE I/D polymorphism is linked to different adrenal steroid and cytokine levels, and ACE I-allele carriers show a better adrenal activity and systemic inflammatory profile. The introduction of walking training positively influences the menopause immune-neuroendocrine changes, independent of ACE I/D genotype. 23820740 N-linked glycosylation of cortical N-methyl-D-aspartate and kainate receptor subunits in schizophrenia. Dysfunctional glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia. Abnormal expressions in schizophrenia of ionotropic glutamate receptors (iGluRs) and the proteins that regulate their trafficking have been found to be region and subunit specific in brain, suggesting that abnormal trafficking of iGluRs may contribute toward altered glutamatergic neurotransmission. The post-translational modification N-glycosylation of iGluR subunits can be used as a proxy for their intracellular localization. Receptor complexes assemble in the lumen of the endoplasmic reticulum, where N-glycosylation begins with the addition of N-linked oligomannose glycans, and is subsequently trimmed and replaced by more elaborate glycans while trafficking through the Golgi apparatus. Previously, we found abnormalities in N-glycosylation of the GluR2 AMPA receptor subunit in schizophrenia. Here, we investigated N-glycosylation of N-methyl-D-aspartate and kainate (KA) receptor subunits in the dorsolateral prefrontal cortex from patients with schizophrenia and a comparison group. We used enzymatic deglycosylation with two glycosidases: endoglycosidase H (Endo H), which removes immature high mannose-containing sugars, and peptide-N-glycosidase F (PNGase F), which removes all N-linked sugars. The NR1, NR2A, NR2B, GluR6, and KA2 subunits were all sensitive to treatment with Endo H and PNGase F. The GluR6 KA receptor subunit was significantly more sensitive to Endo H-mediated deglycosylation in schizophrenia, suggesting a larger molecular mass of N-linked high mannose and/or hybrid sugars on GluR6. This finding, taken with our previous work, suggests that a cellular mechanism underlying abnormal glutamate neurotransmission in schizophrenia may involve abnormal trafficking of both AMPA and KA receptors. 23505966 Cell Durotaxis on Polyelectrolyte Multilayers with Photogenerated Gradients of Modulus. Behaviors of rat aortic smooth muscle (A7r5) and human osteosarcoma (U2OS) cells on photo-cross-linked polyelectrolyte multilayers (PEMUs) with uniform, or gradients of, moduli were investigated. The PEMUs were built layer-by-layer with the polycation poly(allylamine hydrochloride) (PAH) and a polyanion poly(acrylic acid) (PAA) that was modified with photoreactive 4-(2-hydroxyethoxy) benzophenone (PAABp). PEMUs with different uniform and gradients of modulus were generated by varying the time of uniform ultraviolet light exposure and by exposure through optical density gradient filters. Analysis of adhesion, morphology, cytoskeletal organization, and motility of the cells on the PEMUs revealed that A7r5 cells established a polarized orientation toward increasing modulus on shallow modulus gradients (approximately 4.7 MPa mm(-1)) and durotaxed toward stiffer regions on steeper gradients (approximately 55 MPa mm(-1)). In contrast, U2OS cells exhibited little orientation or durotaxis on modulus gradients. These results demonstrate the utility of photo-cross-linked PEMUs to direct vascular and osteoblast cell behavior, a potential application for PEMU coatings on biomedical implants. 23776222 Nonlinear effects of group size on collective action and resource outcomes. For decades, scholars have been trying to determine whether small or large groups are more likely to cooperate for collective action and successfully manage common-pool resources. Using data gathered from the Wolong Nature Reserve since 1995, we examined the effects of group size (i.e., number of households monitoring a single forest parcel) on both collective action (forest monitoring) and resource outcomes (changes in forest cover) while controlling for potential confounding factors. Our results demonstrate that group size has nonlinear effects on both collective action and resource outcomes, with intermediate group size contributing the most monitoring effort and leading to the biggest forest cover gain. We also show how opposing effects of group size directly and indirectly affect collective action and resource outcomes, leading to the overall nonlinear relationship. Our findings suggest why previous studies have observed differing and even contradictory group-size effects, and thus help guide further research and governance of the commons. The findings also suggest that it should be possible to improve collective action and resource outcomes by altering factors that lead to the nonlinear group-size effect, including punishing free riding, enhancing overall and within-group enforcement, improving social capital across groups and among group members, and allowing self-selection during the group formation process so members with good social relationships can form groups autonomously. 23384618 Metabolomic analyses of faeces reveals malabsorption in cirrhotic patients. The study of faeces offers a unique opportunity to observe cooperation between the microbiome and the metabolism of mammalian hosts, an essential element in the study of the human metabolome. In the present study, a global metabolomics approach was used to identify metabolites differentially excreted in the faeces of cirrhotic patients compared to controls. Seventeen cirrhotic patients and 24 healthy individuals were recruited. Faecal metabolites were detected through non-targeted reversed-phase ultra-performance liquid chromatography coupled to electrospray ionization quadrupole time-of-flight mass spectrometry. A total of 9215 peaks were detected. Using unequal variance t-tests, 2393 peaks were observed with P≤0.05, approximately 74.0% of which were due to decreased faecal metabolite concentrations in liver cirrhosis vs. healthy controls. Integrating multivariate data analyses, we identified six major groups of metabolites. Relative levels of identified metabolites were as follows: strong increase in lysophosphatidylcholines, aromatic amino acids, fatty acids, and acylcarnitines, and a dramatic decrease in bile acids and bile pigments. With severe hepatic injury in patients with liver cirrhosis, malabsorption occurs along with disorders of fatty acid metabolism, potentially due to changes in gut microflora. 23959684 Local anaesthetic sympathetic blockade for complex regional pain syndrome. This is an update of the original Cochrane review published in The Cochrane Library, 2005, Issue 4, on local anaesthetic blockade (LASB) of the sympathetic chain used to treat complex regional pain syndrome (CRPS). To assess the efficacy of LASB for the treatment of pain in CRPS and to evaluate the incidence of adverse effects of the procedure. We updated searches of the Cochrane Pain, Palliative and Supportive Care Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) on the Cochrane Library (Issue 11 of 12, 2012), MEDLINE (1966 to 22/11/12), EMBASE (1974 to 22/11/12), LILACS (1982 to 22/11/12), conference abstracts of the World Congresses of the International Association for the Study of Pain (1995 to 2010), and various clinical trial registers (inception to 2012). We also searched bibliographies from retrieved articles for additional studies. We considered for inclusion randomised controlled trials (RCTs) that evaluated the effect of sympathetic blockade with local anaesthetics in children or adults with CRPS. The outcomes of interest were reduction in pain intensity levels, the proportion who achieved moderate or substantial pain relief, the duration of pain relief, and the presence of adverse effects in each treatment arm. We included an additional 10 studies (combined n = 363) in this update. Overall we include 12 studies (combined n = 386). All included studies were assessed to be at high or unclear risk of bias.Three small studies compared LASB to placebo/sham. We were able to pool the results from two of these trials (intervention n = 23). Pooling did not demonstrate significant short-term benefit for LASB (in terms of the risk of a 50% reduction of pain scores).Of two studies that investigated LASB as an addition to rehabilitation treatment, the only study that reported pain outcomes demonstrated no additional benefit from LASB.Eight small randomised studies compared sympathetic blockade to another active intervention. Most studies found no difference in pain outcomes between sympathetic block and other active treatments.Only five studies reported adverse effects, all with minor effects reported. This update has found similar results to the original systematic review. There remains a scarcity of published evidence to support the use of local anaesthetic sympathetic blockade for CRPS. From the existing evidence it is not possible to draw firm conclusions regarding the efficacy or safety of this intervention but the limited data available do not suggest that LASB is effective for reducing pain in CRPS. 23409715 Peptide based macrocycles: selective histone deacetylase inhibitors with antiproliferative activity. Histone deacetylase inhibitors (HDACi) have been enthusiastically investigated as a novel generation of chemotherapeutics for cancers usually called as epigenetic therapeutics. Histone deacetylases have been found to influence cellular function by catalyzing the removal of acetyl groups from ε-N-acetylated lysine residues of several protein substrates including histones, transcription factors, α-tubulin, and nuclear importers. Cyclic peptides represent the most structurally complicated and diverse class of histone deacetylase inhibitors. Each subtype of the Histone Deacetylase (HDAC) family perform a distinct role in the gene expression and cyclic peptides with their plentiful set of surface contacts, zinc binding group and macrocyclic cap, can target enzyme precisely through adequate modulation of the amino acid configurational and structural assortment. The present article summarizes current status of different peptide based macrocyclic compounds being developed as HDACi for the treatment of cancer. 22898212 Cresyl saligenin phosphate makes multiple adducts on free histidine, but does not form an adduct on histidine 438 of human butyrylcholinesterase. Cresyl saligenin phosphate (CBDP) is a suspected causative agent of "aerotoxic syndrome", affecting pilots, crew members and passengers. CBDP is produced in vivo from ortho-containing isomers of tricresyl phosphate (TCP), a component of jet engine lubricants and hydraulic fluids. CBDP irreversibly inhibits butyrylcholinesterase (BChE) in human plasma by forming adducts on the active site serine (Ser-198). Inhibited BChE undergoes aging to release saligenin and o-cresol. The active site histidine (His-438) was hypothesized to abstract o-hydroxybenzyl moiety from the initial adduct on Ser-198. Our goal was to test this hypothesis. Mass spectral analysis of CBDP-inhibited BChE digested with Glu-C showed an o-hydroxybenzyl adduct (+106amu) on lysine 499, a residue far from the active site, but not on His-438. Nevertheless, the nitrogen of the imidazole ring of free l-histidine formed a variety of adducts upon reaction with CBDP, including the o-hydroxybenzyl adduct, suggesting that histidine-CBDP adducts may form on other proteins. 23901832 Understanding the Structure and Electronic Properties of Molecular Crystals Under Pressure: Application of Dispersion Corrected DFT to Oligoacenes. Oligoacenes form a fundamental class of polycyclic aromatic hydrocarbons (PAH) which have been extensively explored for use as organic (semi) conductors in the bulk phase and thin films. For this reason it is important to understand their electronic properties in the condensed phase. In this investigation, we use density functional theory with Tkatchenko-Scheffler dispersion correction to explore several crystalline oligoacenes (naphthalene, anthracene, tetracene, and pentacene) under pressures up to 25 GPa in an effort to uncover unique electronic/optical properties. Excellent agreement with experiment is achieved for the pressure dependence of the crystal structure unit cell parameters, densities, and intermolecular close contacts. The pressure dependence of the band gaps is investigated as well as the pressure induced phase transition of tetracene using both generalized gradient approximated and hybrid functionals. It is concluded that none of the oligoacenes investigated become conducting under elevated pressures, assuming that the molecular identity of the system is maintained. 23938180 New insights into the ear region anatomy and cranial blood supply of advanced stem Strepsirhini: Evidence from three primate petrosals from the Eocene of Chambi, Tunisia. We report the discovery of three isolated primate petrosal fragments from the fossiliferous locality of Chambi (Tunisia), a primate-bearing locality dating from the late early to the early middle Eocene. These fossils display a suite of anatomical characteristics otherwise found only in strepsirhines, and as such might be attributed either to Djebelemur or/and cf. Algeripithecus, the two diminutive stem strepsirhine primates recorded from this locality. Although damaged, the petrosals provide substantial information regarding the ear anatomy of these advanced stem strepsirhines (or pre-tooth-combed primates), notably the patterns of the pathway of the arterial blood supply. Using μCT-scanning techniques and digital segmentation of the structures, we show that the transpromontorial and stapedial branches of the internal carotid artery (ICA) were present (presence of bony tubes), but seemingly too small to supply enough blood to the cranium alone. This suggests that the ICA was not the main cranial blood supply in stem strepsirhines, but that the pharyngeal or vertebral artery primitively ensured a great part of this role instead, an arterial pattern that is reminiscent of modern cheirogaleid, lepilemurid lemuriforms and lorisiforms. This could explain parallel loss of the ICA functionality among these families. Specific measurements made on the cochlea indicate that the small strepsirhine primate(s) from Chambi was (were) able to hear airborne sound ranging from 51.44 Hz to 10.39 kHz. These estimations show that these taxa may have had an intermediate low-frequency limit between adapiforms and extant strepsirhines, an observation that points out a shift of the low-frequency limit of hearing of strepsirhines toward higher rather than lower frequencies. Finally, variance from orthogonality of the plane of the semicircular canals (SCs) calculated on one petrosal (CBI-1-569) suggests that Djebelemur or cf. Algeripithecus likely moved (at least its head) in a way similar to that of modern mouse lemurs. 23959899 Hypothalamo-pituitary and immune-dependent adrenal regulation during systemic inflammation. Inflammation-related dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is central to the course of systemic inflammatory response syndrome or sepsis. The underlying mechanisms, however, are not well understood. Initial activation of adrenocortical hormone production during early sepsis depends on the stimulation of hypothalamus and pituitary mediated by cytokines; in late sepsis, there is a shift from neuroendocrine to local immune-adrenal regulation of glucocorticoid production. Therefore, the modulation of the local immune-adrenal cross talk, and not of the neuroendocrine circuits involved in adrenocorticotropic hormone production, may be more promising in the prevention of the adrenal insufficiency associated with prolonged sepsis. In the present work, we investigated the function of the crucial Toll-like receptor (TLR) adaptor protein myeloid differentiation factor 88 (MyD88) in systemic and local activation of adrenal gland inflammation and glucocorticoid production mediated by lipopolysachharides (LPSs). To this end, we used mice with a conditional MyD88 allele. These mice either were interbred with Mx1 Cre mice, resulting in systemic MyD88 deletion, predominantly in the liver and hematopoietic system, or were crossed with Akr1b7 Cre transgenic mice, resulting thereby in deletion of MyD88, which was adrenocortical-specific. Although reduced adrenal inflammation and HPA-axis activation mediated by LPS were found in Mx1(Cre+)-MyD88(fl/fl) mice, adrenocortical-specific MyD88 deletion did not alter the adrenal inflammation or HPA-axis activity under systemic inflammatory response syndrome conditions. Thus, our data suggest an important role of immune cell rather than adrenocortical MyD88 for adrenal inflammation and HPA-axis activation mediated by LPS. 22540676 Effect of immediate functional loading on osseointegration of implants used for single tooth replacement. A human histological study. To analyze hard tissue reactions to immediate functionally loaded single implants that were installed either with a conventional drill preparation procedure or with an osteotome preparation technique. Thirteen subjects with two sites requiring single tooth rehabilitation by means of implants volunteered for the study. Each subject received one test (immediate functionally loaded) and one control (non-loaded) implant. In six subjects (group 1) the implants were placed using a conventional drilling procedure, whereas in the remaining seven subjects (group 2) an osteotome preparation procedure was performed. Block biopsies containing test and control implants and peri-implant bone tissues were collected at 1 month in four of the subjects in group 1 and in five subjects of group 2. The remaining implant sites were sampled at 3 months after implant placement. The biopsies were prepared for histological examination. Two implants of the test-2 group (osteotome preparation) representing 1 month of healing and another test-2 implant representing 3 months of healing failed to integrate. A multilevel multivariate statistical analysis demonstrated that no differences in bone-to-implant contact (BIC)% were found in between test and control implants, the density of newly formed peri-implant bone was significantly higher around test than control implants at 1 and 3 months of healing. Sections representing osteotome technique sites showed fractured trabeculae and large amounts of bone particles. It is suggested that immediate loading of implants does not influence the osseointegration process, whereas the density of newly formed peri-implant bone at such sites appears to be increased in relation to unloaded control implants. The use of an osteotome preparation technique during installation results in damage of peri-implant bone and enhances the risk for failure in osseointegration. 22963753 Protein flexibility and conformational states of Leishmania antigen eIF-4A: identification of a novel plausible protein adjuvant using comparative genomics and molecular modeling. Recent homology modeling studies have identified specific residues (epitope) of the Leishmania RNA helicase protein (LmeIF) that stimulates production of IL-12 cytokine. However, question remains concerning how LmeIF's N-terminal moiety initiates adjuvant effects. Extensive molecular modeling combining the normal mode analysis (NMA) and molecular dynamics simulations, in the present study, has demonstrated that the LmeIF structure may exist in two different forms corresponding to the extended and collapsed (closed) states of the entire structure. The computational results showed that the two domains of the LmeIF structure tend to undergo large fluctuations in a concerted fashion and have strong effect on the solvent accessible surface of the epitope situated on the N-terminal structure. The conformational freedom of the C-terminal domains may explain why the entire LmeIF protein is not as active as the N-terminal moiety. Thereafter, a comparative genome analysis with subsequent homology modeling and molecular electrostatic potential (MEP) techniques allowed us to predict a novel and plausible RNA helicase (LI-helicase) from the Listeria source with adjuvant property as observed for the Leishmania eIF-4A protein. The structural folding and MEP maps revealed similar topologies of the epitope of both LmeIF and LI-helicase proteins and striking identity in the local disposition of the charged groups. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:7. 23785022 DNA fragmentation is higher in spermatozoa with chromosomally unbalanced content in men with a structural chromosomal rearrangement. It has been previously shown that men with chromosomal structural abnormality had a higher rate of sperm DNA fragmentation. We studied 11 male carriers of a chromosomal structural abnormality (seven with a balanced reciprocal translocation, three with a Robertsonian translocation, one with a pericentric inversion) to determine whether spermatozoa with unbalanced chromosomes were more likely to have fragmented DNA. A sequential method combining analysis of DNA fragmentation using the TUNEL assay followed by analysis of meiotic segregation by fluorescent in situ hybridization was performed on the same spermatozoa. A statistically significant higher number of spermatozoa with unbalanced chromosomal content were found to have fragmented DNA for each man. The rate of spermatozoa with DNA fragmentation was higher than the rate of those without fragmented DNA in particular modes of segregation. Our findings provide a better understanding of the mechanisms involved in male infertility ascribable to chromosomal structural abnormality. 23454337 A glucose biosensor based on surface active maghemite nanoparticles. A simple carbon paste (CP) electrode, modified with novel maghemite (γ-Fe2O3) nanoparticles, called SAMNs (surface active maghemite nanoparticles) and characterized by a mean diameter of about 10nm, has been developed. The electrode catalyzes the electro-reduction of hydrogen peroxide at low applied potentials (-0.1 V vs SCE). In order to improve the electrocatalytic properties of the modified electrode an ionic liquid, namely 1-butyl-3-methylimidazolium hexafluorophosphate (BMIM-PF6), was introduced. At -0.1 V, the sensitivity of the SAMN-BMIM-PF6-CP electrode was 206.51 nA μM(-1)cm(-2), with a detection limit (S/N=3) of 0.8 μM, in the 0-1.5mM H2O2 concentration range. Furthermore, glucose oxidase was immobilized on the surface of maghemite nanoparticles as a monomolecular layer, by a bridge constituted of rhodamine B isothiocyanate, leading to a fluorescent, magnetic drivable nanocatalyst, containing 10 ± 2 enzyme molecules per nanoparticle. The resulting enzyme electrode presents a linear calibration curve toward glucose in solution in the concentration range of 0-1.5mM glucose, characterized by a sensitivity of 45.85 nA μM(-1)cm(-2) and a detection limit (S/N=3) of 0.9 μM. The storage stability of the system was evaluated and a half-life of 2 months was calculated, if the electrode is stored at 4°C in buffer. The present work demonstrates the feasibility of these surface active maghemite nanoparticles as efficient hydrogen peroxide electro-catalyst, which can be easily coupled to hydrogen peroxide producing enzymes in order to develop oxidase based reagentless biosensor devices. 22564070 Dynamical Genetic Programming in XCSF. A number of representation schemes have been presented for use within learning classifier systems, ranging from binary encodings to artificial neural networks. This paper presents results from an investigation into using a temporally dynamic symbolic representation within the XCSF learning classifier system. In particular, dynamical arithmetic networks are used to represent the traditional condition-action production system rules to solve continuous-valued reinforcement learning problems and to perform symbolic regression, finding competitive performance with traditional genetic programming on a number of composite polynomial tasks. In addition, the network outputs are later repeatedly sampled at varying temporal intervals to perform multistep-ahead predictions of a financial time series. 23515603 Ethnic differences in the number of miscarriages, number of children, perceived family support and the impact of the disease on daily living in patients with systemic lupus erythematosus. Our aim was to test for ethnic differences in the number of children, number of miscarriages, family support and the impact of the disease on daily living among patients with systemic lupus erythematosus (SLE). Patients with SLE (n = 54) who attended two hospitals in Essex, UK, were asked to complete a semi-structured, validated questionnaire. The number of children and the number of miscarriages were reported numerically. The level of family support and the impact of the disease on daily living were reported using 10 cm visual analogue scales (VAS) in which 10 cm represented the maximum support and worst effect on daily living, respectively. There were 20 Caucasian, 22 Asian and 12 African/Afro-Caribbean patients. There were 50 females and four males. The mean ± standard deviation (SD) age was 45.9 ±â€‰12.2 years, and the mean ± SD age at disease onset was 35.6 ±â€‰11.1 years. Overall, 34/50 female patients (68 %) reported having children of their own, while 17/50 female patients (34 %) reported one or more miscarriages. The miscarriages were mostly reported by Caucasian patients (45 % versus 18.1 % for Asian and 33.3 % for African/Afro-Caribbean patients; P < 0.05). All of the groups received support from their families (90.7 % overall), but the level of support was greater for Caucasian (mean ± SD VAS, 6.6 ±â€‰3.4 cm) than for Asian (5.4 ±â€‰3.9 cm) and African/Afro-Caribbean (5.4 ±â€‰4.9 cm) patients (P = 0.06). More than half of the patients (53.7 %) reported a severe impact of SLE on daily living, while 13 % reported a moderate impact, 22.2 % reported a mild impact and 11.1 % reported no impact. The impact of SLE on daily living was significantly worse for African/Afro-Caribbean patients compared with Asian patients (P < 0.05). Overall, one in two patients with SLE reported having children of their own, while one in three patients reported having at least one miscarriage. Ninety percent of the patients received family support for their disease. Miscarriages and family support were more frequently reported by Caucasian patients. Asian patients had more children and experienced fewer miscarriages, while African/Afro-Caribbean patients reported a worse impact of the disease on daily living compared with the other ethnic groups. 23339682 Assessment of effects of IR and IPC on activities of cytochrome P450 isozymes in rats by a five-drug cocktail approach. Abstract Background and objective: To evaluate the effects of ischemia and reperfusion (IR) and ischemic preconditioning (IPC) on the metabolic activities of cytochrome P450 (CYP) isozymes in rats by a five-drug cocktail approach. Methods: Cocktail approach was used to evaluate the influence of IR and IPC on the activities of CYP1A2, CYP2C9, CYP2E1, CYP2D6 and CYP3A4, which were reflected by the changes of pharmacokinetic parameters of five specific probe drugs: caffeine, chlorzoxazone, tolbutamide, metoprolol and midazolam, respectively. Rats were randomly divided into IR, IPC and sham groups, and then injected the mixture of five probe drugs. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by a HPLC method with UV detection. The pharmacokinetic parameters were calculated by the software of DAS 2.0. Results: The parameters including t(1/2β), CLs, AUC, MRT and K(10) exhibited a similar tendency for both IR and IPC groups. Compared with sham group, CLs and K(10) of five probe drugs were significantly lower (p < 0.05), AUC and t(1/2β) of five or some probe drugs were significantly increased in IR and IPC groups (p < 0.05). Compared with IPC group, CLs of five probe drugs were decreased and AUC were significantly increased in the IR group (p < 0.05). Conclusion: IR can variably decrease the activities of CYP isozymes in rats and this decrease can be attenuated by IPC. 23242429 How to form and close the brain: insight into the mechanism of cranial neural tube closure in mammals. The development of the embryonic brain critically depends on successfully completing cranial neural tube closure (NTC). Failure to properly close the neural tube results in significant and potentially lethal neural tube defects (NTDs). We believe these malformations are caused by disruptions in normal developmental programs such as those involved in neural plate morphogenesis and patterning, tissue fusion, and coordinated cell behaviors. Cranial NTDs include anencephaly and craniorachischisis, both lethal human birth defects. Newly emerging methods for molecular and cellular analysis offer a deeper understanding of not only the developmental NTC program itself but also mechanical and kinetic aspects of closure that may contribute to cranial NTDs. Clarifying the underlying mechanisms involved in NTC and how they relate to the onset of specific NTDs in various experimental models may help us develop novel intervention strategies to prevent NTDs. 23509923 A novel case of natural killer cell deficiency associated with Joubert syndrome. Joubert syndrome (JS) is a rare, complex autosomal recessive inherited disorder mostly characterized by partial or complete agenesis of the cerebellar vermis. There is a wide clinical and genetic heterogeneity in the syndrome. The main clinical features of JS are hypotonia, ataxia, developmental delay, oculomotor apraxia, breathing abnormalities and peculiar neuroimaging findings. A lot of additional features have been reported. Here, we first reported a case of the syndrome with natural killer (NK) cell deficiency. NK cell deficiency in JS might be not an incidental phenomenon. NK cell deficiency might be associated with JS when there are additional features such as recurrent infections and tumors. NK cell deficiency may be part of the clinical spectrum of JS. Reduced cellular immunity in association with NK cell deficiency may be a feature in a subset of JS patients, especially if there is a history of recurrent infections, tumors and autoimmune disorders. 23571097 Integrative avenues for exploring the dynamics and evolution of protein interaction networks. Over the past decade, the study of protein interaction networks (PINs) has shed light on the organizing principles of living cells. However, PINs have been mostly mapped in one single condition. We outline three of the most promising avenues of investigation in this field, namely the study of first, how PINs are rewired by mutations and environmental perturbations; secondly, how inter-species interactions affect PIN achitectures; thirdly, what mechanisms and forces drive PIN evolution. These investigations will unravel the dynamics and condition dependence of PINs and will thus lead to a better functional annotation of network architecture. One major challenge to reach these goals is the integration of PINs with other cellular regulatory networks in the context of complex cellular phenotypes. 23889300 Rapid, reversible heterolytic cleavage of bound h2. Heterolytic cleavage of dihydrogen into a proton and a hydride ion is a fundamentally important step in many reactions, including the oxidation of hydrogen by hydrogenase enzymes and ionic hydrogenation of organic compounds. We report the facile, reversible heterolytic cleavage of H2 in a manganese complex bearing a pendant amine, leading to the formation of a manganese hydride and a protonated amine that undergo H(+)/H(-) exchange at an estimated rate of >10(7) s(-1) at 25 °C. 23383865 Isolation of a mixed valence diiron hydride: evidence for a spectator hydride in hydrogen evolution catalysis. The mixed-valence diiron hydrido complex (μ-H)Fe2(pdt)(CO)2(dppv)2 ([H1](0), where pdt =1,3-propanedithiolate and dppv = cis-1,2-C2H2(PPh2)2), was generated by reduction of the differous hydride [H1](+) using decamethylcobaltocene. Crystallographic analysis shows that [H1](0) retains the stereochemistry of its precursor, where one dppv ligand spans two basal sites and the other spans apical and basal positions. The Fe---Fe bond elongates to 2.80 from 2.66 Å, but the Fe-P bonds only change subtly. Although the Fe-H distances are indistinguishable in the precursor, they differ by 0.2 Å in [H1](0). The X-band electron paramagnetic resonance (EPR) spectrum reveals the presence of two stereoisomers, the one characterized crystallographically and a contribution of about 10% from a second symmetrical (sym) isomer wherein both dppv ligands occupy apical-basal sites. The unsymmetrical (unsym) arrangement of the dppv ligands is reflected in the values of A((31)P), which range from 31 MHz for the basal phosphines to 284 MHz for the apical phosphine. Density functional theory calculations were employed to rationalize the electronic structure of [H1](0) and to facilitate spectral simulation and assignment of EPR parameters including (1)H and (31)P hyperfine couplings. The EPR spectra of [H1](0) and [D1](0) demonstrate that the singly occupied molecular orbital is primarily localized on the Fe center with the longer bond to H, that is, Fe(II)-H···Fe(I). The coupling to the hydride is A((1)H) = 55 and 74 MHz for unsym- amd sym-[H1](0), respectively. Treatment of [H1](0) with H(+) gives 0.5 equiv of H2 and [H1](+). Reduction of D(+) affords D2, leaving the hydride ligand intact. These experiments demonstrate that the bridging hydride ligand in this complex is a spectator in the hydrogen evolution reaction. 23824390 The comprehensive description of stress fractures: a new classification system. Stress fractures represent a fatigue failure of bone, occurring with a spectrum of severity of structural injury, and healing potential varies by location. There is no comprehensive classification system for stress fractures incorporating both clinical and radiographic characteristics of the injury that is applicable to all bones. We introduce a system that is reproducible, generalizable, easy to use, and clinically relevant, with three descriptors: fracture grade, fracture location, and imaging modality. After a review of current classification systems, a five-tier system was proposed to determine fracture grade: Grade I indicated asymptomatic stress reaction on imaging, Grade II indicated pain with no fracture line, Grade III indicated non-displaced fracture, Grade IV indicated displaced fracture, and Grade V indicated nonunion. Example cases of each grade with clinical vignettes and images were prepared to test the interobserver and intraobserver reliability of the system by the test and retest evaluation among fifteen clinicians. A questionnaire and recall test assessed the ease of use, clinical applicability, and recall accuracy. Test and retest analysis showed that the system had almost perfect agreement in intraobserver reliability with a kappa value of 0.81. The overall intraobserver reliability showed almost perfect agreement with a kappa value of 0.81. Almost perfect agreement with a kappa value of 0.83 was also produced when these responses were compared with our assessment. The overall interobserver reliability had substantial agreement with a kappa value of 0.78. The reliability of the group compared with that of the answer key was almost perfect with a kappa value of 0.83. The recall test showed an overall accuracy of 97.3%. Of the fifteen evaluators who completed questionnaires, fourteen (93.3%) said that the system would be easily remembered, would facilitate communication among colleagues, and would be useful in clinical practice. The proposed stress fracture classification system is clinically relevant, easily applied, and generalizable, and has excellent interobserver and intraobserver reliability. 23561304 Symptom burden and quality of life in advanced non-small cell lung cancer patients in France and Germany. To assess patient reported symptom burden and impact on disease specific health related quality of life (HRQOL) in advanced non-small cell lung cancer (NSCLC) patients. Patients with advanced (stage IIIB/IV) NSCLC in France (n = 613) and Germany (n = 600) were recruited into a multicenter, patient record-based cross-sectional study. Patient reported symptoms using the Lung Cancer Symptom Scale, which assesses fatigue, loss of appetite, shortness of breath, cough, pain and blood in sputum on a 0-100 visual analog scale. Disease specific and generic HRQOL were assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) and the EuroQol five-dimensional questionnaire (EQ-5D) respectively. A multivariate regression analysis was performed with total FACT-L score as the dependent variable and symptom scores as predictors. Age, gender, stage and performance status were used as control variables. Majority of the patients were male (67%), Caucasian (93%) with an average age of 63 years. Fatigue, loss of appetite, shortness of breath, cough and pain were reported by ≥ 90% of patients. The mean health utility index score was found to be 0.58 and the mean general health status score was 58.0. Fatigue (β = -0.122; p < 0.001), loss of appetite (β = -0.170; p < 0.001), pain (β = -0.145; p < 0.001), shortness of breath (β = -0.118; p < 0.001) were found to be significant predictors of lung cancer specific quality of life as measured by the FACT-L total score. Fatigue, loss of appetite, shortness of breath and pain have a significant negative impact on patient reported disease specific HRQOL in advanced NSCLC patients. 23825366 Myocardin Regulates Vascular Response to Injury Through miR-24/-29a and Platelet-Derived Growth Factor Receptor β Myocardin, a potent transcriptional coactivator of serum response factor, is involved in vascular development and promotes a contractile smooth muscle phenotype. Myocardin levels are reduced during vascular injury, in association with phenotypic switching of smooth muscle cells (SMCs). However, the direct role of myocardin in vascular disease is unclear. We show that re-expression of myocardin prevents the vascular injury response in murine carotid arteries, with reduced neointima formation due to decreased SMC migration and proliferation. Myocardin reduced SMC migration by downregulating platelet-derived growth factor receptor β expression. Expression of platelet-derived growth factor receptor β was regulated by myocardin-induced miR-24 and miR-29a expression, and antagonizing these microRNAs restored SMC migration. Furthermore, using miR-24 and miR-29a mimics, we demonstrated that miR-29a directly regulates Pdgfrb expression at the 3' untranslated region while miR-24 has an indirect effect on Pdgfrb levels. Myocardin heterozygous-null mice showed an augmented neointima formation with increased SMC migration and proliferation, demonstrating that endogenous levels of myocardin are a critical regulator of vessel injury responses. Our results extend the function of myocardin from a developmental role to a pivotal regulator of SMC phenotype in response to injury, and this transcriptional coactivator may be an attractive target for novel therapeutic strategies in vascular disease. 23590840 Fronto-limbic function in unaffected offspring at familial risk for bipolar disorder during an emotional working memory paradigm. Evidence from neuroimaging studies indicate that individuals with bipolar disorder (BD) exhibit altered functioning of fronto-limbic systems implicated in voluntary emotion regulation. Few studies, however, have examined the extent to which unaffected youth at familial risk for BD exhibit such alterations. Using an fMRI emotional working memory paradigm, we investigated the functioning of fronto-limbic systems in fifteen healthy bipolar offspring (8-17 years old) with at least one parent diagnosed with BD (HBO), and 16 age-matched healthy control (HC) participants. Neural activity and functional connectivity analyses focused on a priori neural regions supporting emotion processing (amygdala and ventral striatum) and voluntary emotion regulation (ventrolateral prefrontal cortex (VLPFC), dorsolateral prefrontal cortex (DLPFC), and anterior cingulate cortex (ACC)). Relative to HC, HBO exhibited greater right VLPFC (BA47) activation in response to positive emotional distracters and reduced VLPFC modulation of the amygdala to both the positive and negative emotional distracters; there were no group differences in connectivity for the neutral distracters. These findings suggest that alterations in the functioning of fronto-limbic systems implicated in voluntary emotion regulation are present in unaffected bipolar offspring. Future longitudinal studies are needed to determine the extent to which such alterations represent neurodevelopmental markers of risk for future onset of BD. 23953651 Adsorption of alkaloids on ordered mesoporous carbon. An ordered mesoporous carbon (OMC) adsorbent was synthesized, characterized, and evaluated for effective separation and purification of alkaloid compounds from aqueous solutions. The OMC adsorbent has a large BET specific surface area (1532.2m(2)/g), large pore volume (2.13cm(3)/g), and narrow pore diameter distribution with a median pore diameter of 4.21nm. Berberine hydrochloride, colchicine, and matrine were selected as the model compounds for evaluating the adsorption properties of the OMC adsorbent for alkaloid purification. Batch adsorption experiments of pure components in water were carried out to measure both adsorption equilibria and kinetics, and column breakthrough and desorption experiments were performed to validate the separation and regeneration efficacy of the OMC adsorbent. The adsorption equilibrium capacities of berberine hydrochloride, colchicine, and matrine on the OMC adsorbent at 0.100mg/L and 298K are 450, 600, and 480mg/g, respectively, which are more than double the adsorption capacities of these compounds on two commonly used commercial resins (HPD300 and HPD100B) at similar conditions. Adsorption equilibrium of all three alkaloids could be obtained within 120min at 298K. The dynamic adsorption capacities determined from the breakthrough experiments are within 12% of the estimated equilibrium capacities from the Langmuir isotherms; and 74.3-92.8% of the adsorbed amounts could be recovered by desorbing with a 70% alcohol solution. The adsorption isotherms are analyzed with both Langmuir and Freundlich models, the adsorption kinetic data with the pseudo-first-order and pseudo-second-order models, and the breakthrough curves with four breakthrough models. The large adsorption capacity, fast adsorption rate, and easy regeneration make the ordered mesoporous carbon a promising adsorbent for adsorption and purification of alkaloid compounds from the extracts of herbal plants. 23250632 Patient-reported impacts of a conservative management programme for the clinically inapparent adrenal mass. The aim of this study was to assess patient-reported impacts and health-related quality of life (HRQL) of a 2-year follow-up programme in a large cohort of patients with stationary, non-functioning, adrenal incidentalomas (AIs) in western Sweden. 145 patients (mean age 68 years, 62 % females) with AI from a prospective study in western Sweden were studied. All had completed a 2-year follow-up programme by November 2007, without evidence of adrenal malignancy or hormone over-production. To evaluate patient-reported impacts and HRQL, an eight-item adrenal incidentaloma impact questionnaire was used retrospectively, together with the hospital anxiety and depression scale, and the short form-36. There were 111 patients (mean age 67 years, 63 % females) who responded to the questionnaire (response rate 77 %). 77 % reported that the AI diagnosis had caused them to be worried; however, fewer than 20 % had thought about the lesion often during the follow-up programme, and only 3 % had felt that it had a large impact on their current daily life. Only 4 % stated that the follow-up programme had been a negative experience, nevertheless 10 % reported a negative impact on their HRQL during the follow-up programme. Only 2 % stated that release from follow-up caused worry to any degree. In total, 29 % had possible anxiety, and 30 % had possible depression, probably reflecting significant co-morbidity. Possible anxiety correlated with a more negative experience of the follow-up programme. In conclusion, the 2-year follow-up programme for patients with AI was well tolerated. Nonetheless, a small number remained worried throughout follow-up, suggesting the need for tailored counselling in individual patients to ameliorate negative impacts of follow-up. 23791869 Chemically modified siRNAs and miRNAs bearing urea/thiourea-bridged aromatic compounds at their 3'-end for RNAi therapy. We have developed chemically modified siRNAs and miRNAs bearing urea/thiourea-bridged aromatic compounds at their 3'-end for RNAi therapy. Chemically modified RNAs possessing urea/thiourea-bridged aromatic compounds instead of naturally occurring dinucleotides at the 3'-overhang region were easily prepared in good yields and were more resistant to nucleolytic hydrolysis than unmodified RNA. siRNAs containing urea or thiourea derivatives showed the desired knockdown effect. Furthermore, modified miR-143 duplexes carrying the urea/thiourea compounds in the 3'-end of each strand were able to inhibit the growth of human bladder cancer T24 cells. 23441824 Factors associated with quality of life after attempted suicide: a cross-sectional study. To describe factors associated with the subjective quality of life of individuals who had attempted suicide. Although quality of life has been a focus of concern in mental health care, data are lacking on what life is like and what factors are related to an individual's quality of life after a suicide attempt. A cross-sectional, descriptive design was used. Participants comprised a convenience sample of 103 individuals who had attempted suicide within the previous three months and received follow-up care from one suicide-prevention centre in northern Taiwan. Participants were assessed for depression and quality of life using the Beck Depression Inventory, Taiwan version and the World Health Organisation Quality of Life Instrument-BREF, Taiwan version, respectively. Almost half the participants (n = 49) had severe depression and one-third of them (n = 30) reattempted suicide while receiving follow-up care. Depression and quality-of-life scores were statistically significantly inversely correlated. participants' quality-of-life scores were most associated with their depressive level, reattempting suicide during suicidal follow-up care, high educational level and older age. The present study indicates that factors associated with quality of life decreased more in individuals with moderate/severe depression than in those with mild depression. In addition, individuals who reattempted suicide during follow-up care were more likely to suffer from poor life quality. Mental health professionals should include frequent evaluation of depressive status and quality of life in follow-up care for patients who have recently attempted suicide. Particularly, mental health professionals must treat suicidal individuals with a high tendency to reattempt suicide by establishing trust with them and allowing them to narrate their painful experiences during follow-up care. 23256623 Characterization of in vitro metabolites of luotonin A in human liver microsomes using electrospray/tandem mass spectrometry. 1. The pharmacological activity of luotonin A varies, depending on the type of functional group and the site of derivatization. To understand the in vivo efficacy of luotonin A, the in vitro metabolism of luotonin A was investigated in human liver microsomes and recombinant cDNA-expressed cytochromeP450 (CYP). 2. Incubation of luotonin A with pooled human liver microsomes in the presence of NADPH-generating system resulted in the formation of four metabolites and the structures of each metabolite were tentatively characterized on the basis of electrospray tandem mass spectra. 3. The main metabolic pathway of luotonin A in human liver microsomes was hydroxylation, resulting in the generation of two mono-hydroxyl metabolites (M1 and M2) and two di-hydroxyl metabolites (M3 and M4). CYP1A2 was primarily involved in hydroxylation of the quinolone moiety (M1 andM3), while CYP3A4 was mainly responsible for hydroxylation of the quinazoline moiety of luotonin A (M2 and M4) in human liver microsomes. 23882084 Cost of rNTP/dNTP pool imbalance at the replication fork. The concentration of ribonucleoside triphosphates (rNTPs) in cells is far greater than the concentration of deoxyribonucleoside triphosphates (dNTPs), and this pool imbalance presents a challenge for DNA polymerases (Pols) to select their proper substrate. This report examines the effect of nucleotide pool imbalance on the rate and fidelity of the Escherichia coli replisome. We find that rNTPs decrease replication fork rate by competing with dNTPs at the active site of the C-family Pol III replicase at a step that does not require correct base-pairing. The effect of rNTPs on Pol rate generalizes to B-family eukaryotic replicases, Pols δ and ε. Imbalance of the dNTP pool also slows the replisome and thus is not specific to rNTPs. We observe a measurable frequency of rNMP incorporation that predicts one rNTP incorporated every 2.3 kb during chromosome replication. Given the frequency of rNMP incorporation, the repair of rNMPs is likely rapid. RNase HII nicks DNA at single rNMP residues to initiate replacement with dNMP. Considering that rNMPs will mark the new strand, RNase HII may direct strand-specificity for mismatch repair (MMR). How the newly synthesized strand is recognized for MMR is uncertain in eukaryotes and most bacteria, which lack a methyl-directed nicking system. Here we demonstrate that Bacillus subtilis incorporates rNMPs in vivo, that RNase HII plays a role in their removal, and the RNase HII gene deletion enhances mutagenesis, suggesting a possible role of incorporated rNMPs in MMR. 23572126 The ancient tropical rainforest tree Symphonia globulifera L. f. (Clusiaceae) was not restricted to postulated Pleistocene refugia in Atlantic Equatorial Africa. Understanding the history of forests and their species' demographic responses to past disturbances is important for predicting impacts of future environmental changes. Tropical rainforests of the Guineo-Congolian region in Central Africa are believed to have survived the Pleistocene glacial periods in a few major refugia, essentially centred on mountainous regions close to the Atlantic Ocean. We tested this hypothesis by investigating the phylogeographic structure of a widespread, ancient rainforest tree species, Symphonia globulifera L. f. (Clusiaceae), using plastid DNA sequences (chloroplast DNA [cpDNA], psbA-trnH intergenic spacer) and nuclear microsatellites (simple sequence repeats, SSRs). SSRs identified four gene pools located in Benin, West Cameroon, South Cameroon and Gabon, and São Tomé. This structure was also apparent at cpDNA. Approximate Bayesian Computation detected recent bottlenecks approximately dated to the last glacial maximum in Benin, West Cameroon and São Tomé, and an older bottleneck in South Cameroon and Gabon, suggesting a genetic effect of Pleistocene cycles of forest contraction. CpDNA haplotype distribution indicated wide-ranging long-term persistence of S. globulifera both inside and outside of postulated forest refugia. Pollen flow was four times greater than that of seed in South Cameroon and Gabon, which probably enabled rapid population recovery after bottlenecks. Furthermore, our study suggested ecotypic differentiation-coastal or swamp vs terra firme-in S. globulifera. Comparison with other tree phylogeographic studies in Central Africa highlighted the relevance of species-specific responses to environmental change in forest trees. 23757040 Mastering methodological pitfalls for surviving the metagenomic jungle. Metagenomics is a culture- and PCR-independent approach that is now widely exploited for directly studying microbial evolution, microbial ecology, and developing biotechnologies. Observations and discoveries are critically dependent on DNA extraction methods, sequencing technologies, and bioinformatics tools. The potential pitfalls need to be understood and, to some degree, mastered if the resulting data are to survive scrutiny. In particular, methodological variations appear to affect results from different ecosystems differently, thus increasing the risk of biological and ecological misinterpretation. Part of the difficulty is derived from the lack of knowledge concerning the true microbial diversity and because no approach can guarantee accessing microorganisms in the same proportion in which they exist in the environment. However, the variation between different approaches (e.g. DNA extraction techniques, sequence annotation systems) can be used to evaluate whether observations are meaningful. These methodological variations can be integrated into the error analysis before comparing microbial communities. 23897870 Cranial autonomic symptoms in pediatric migraine are the rule, not the exception. The presence of cranial autonomic symptoms often leads to a misdiagnosis of "sinus headache" in adult migraineurs, leading to unnecessary treatments and delaying appropriate migraine therapy. In this study, we examined the frequency of cranial autonomic symptoms in pediatric/adolescent patients with migraine. This cross-sectional study included all pediatric and adolescent patients with migraine evaluated by a single investigator at 4 different sites over the course of the study period. Of 125 pediatric migraineurs, 62% had at least one cranial autonomic symptom based on current International Classification of Headache Disorders, second edition (ICHD-II) criteria, and 70% based on proposed ICHD-III criteria. The majority had more than one cranial autonomic symptom and the symptoms tended to be bilateral. Age, sex, laterality of headache, presence of aura, and whether migraine was episodic vs chronic did not influence the likelihood of having cranial autonomic symptoms. In pediatric/adolescent migraine, the presence of cranial autonomic symptoms appears to be the rule rather than the exception. Clinicians should be careful to consider migraine when evaluating a child with headache and associated ocular or nasal symptoms so as to avoid giving a misdiagnosis of sinus headache. 23886452 Prevalence and associated features of restless legs syndrome in a population of Iranian women during pregnancy. To investigate the prevalence of restless legs syndrome (RLS) during pregnancy and to evaluate factors associated with RLS in a population of Iranian pregnant women. In the present cross-sectional study, 443 consecutive pregnant women admitted for delivery underwent an interview within 2days of parturition. The diagnosis of RLS was established by the 4 criteria of the International Restless Legs Syndrome Study Group (IRLSSG). The severity of RLS was assessed through the IRLSSG Rating Scale. Seventy-nine (17.8%) women met the RLS diagnostic criteria, with most (74.7%) having RLS of moderate severity. The mean RLS duration before delivery was 3.1±2.1months among 69 (87.3%) women; 10 (12.7%) had RLS onset before pregnancy. Sleep disturbances including insomnia and early awakening were significantly more common among women with RLS than among those without (P<0.001), and the frequency of cesarean delivery was also significantly higher (58.2% versus 44.5%, P=0.027; odds ratio 2.4). There were no significant differences between the 2 groups in terms of age, number of pregnancies, folate and iron supplementation, hemoglobin level, and neonatal anthropometric data. Restless legs syndrome is common during pregnancy and is associated with poor sleep and an increased risk of cesarean delivery. 23385891 Study of Environmental and Antimicrobial Agents Impact on Features of Bacterial Growth. Continuous, real-time observation of bacterial growth has a great advantage for studying the mechanisms of interactions of various compounds with the bacterial cell membrane. With the use of physical methods, which are specific for assessment of continuous changes in turbidity over time, we have shown that bacterial growth was affected by not only on types of antibiotics and phages, but also by their concentration in media. Low concentration of antibiotics and bacteriophages in media has no effect on the bacterial growth process. Our research has shown that if bacterial cell membrane is not completely saturated with antibiotics membrane sensitive sites (MSS), or bacteriophages free unbounded receptors are remained, bacterial growth continues unimpeded. 23458451 Post-concussion symptom reporting after multiple mild traumatic brain injuries. Abstract The relationship between previous mild traumatic brain injury/injuries (MTBI) and recovery from a subsequent MTBI may be complex. The present study investigated three factors hypothesized to influence this relation: (1) the number of prior MTBIs, (2) the interval between MTBIs, and (3) the certainty level of previous MTBIs. The study design was retrospective cross-sectional. Participants (N=105) were evaluated at a concussion clinic on average 1 month after sustaining an MTBI, defined by World Health Organization diagnostic criteria. Approximately half the sample had at least one previous MTBI. Subgroups with 0, 1, or 2+ previous MTBIs did not differ in levels of current post-concussion symptom reporting on the British Columbia Post-Concussion Symptom Inventory. Time since the most recent previous MTBI was significantly associated with current post-concussion symptom reporting. This relation was best characterized as logarithmic; i.e., the impact of previous MTBI(s) lessens exponentially as time elapses to a subsequent MTBI. Defining previous MTBIs with a higher certainty level (i.e., probable versus possible) was not consistently associated with greater post-concussion symptom reporting. In conclusion, participants with multiple MTBIs did not report more post-concussion symptoms than those with no history of MTBI. Previous MTBI(s), however, were associated with increased symptom reporting from a subsequent MTBI to the extent they occurred closer in time. Having one or two previous remote MTBIs was not associated with worse outcome from subsequent MTBI in this sample. 23884930 Developmental Changes in Structural and Functional Properties of Hippocampal AMPARs Parallels the Emergence of Deliberative Spatial Navigation in Juvenile Rats. The neural mechanisms that support the late postnatal development of spatial navigation are currently unknown. We investigated this in rats and found that an increase in the duration of AMPAR-mediated synaptic responses in the hippocampus was related to the emergence of spatial navigation. More specifically, spontaneous alternation rate, a behavioral indicator of hippocampal integrity, increased at the end of the third postnatal week in association with increases in AMPAR response duration at SC-CA1 synapses and synaptically driven postsynaptic discharge of CA1 pyramidal neurons. Pharmacological prolongation of glutamatergic synaptic transmission in juveniles increased the spontaneous alternation rate and CA1 postsynaptic discharge and reduced the threshold for the induction of activity-dependent synaptic plasticity at SC-CA1 synapses. A decrease in GluA1 and increases in GluA3 subunit and transmembrane AMPAR regulatory protein (TARP) expression at the end of the third postnatal week provide a molecular explanation for the increase in AMPAR response duration and reduced efficacy of AMPAR modulators with increasing age. A shift in the composition of AMPARs and increased association with AMPAR protein complex accessory proteins at the end of the third postnatal week likely "turns on" the hippocampus by increasing AMPAR response duration and postsynaptic excitability and reducing the threshold for activity-dependent synaptic potentiation. 23757733 Cold agglutinin disease. Cold agglutinin disease is a rare and poorly understood disorder affecting 15% of patients with autoimmune hemolytic anemia. We reviewed the clinical and pathologic features, prognosis, and management in the literature and describe our institutional experience to improve strategies for accurate diagnosis and treatment. Retrospective analysis identified 89 patients from our institution with cold agglutinin disease from 1970 through 2012. Median age at symptom onset was 65 years (range, 41 to 83 years), whereas the median age at diagnosis was 72 years (range, 43 to 91 years). Median survival of all patients was 10.6 years, and 68 patients (76%) were alive 5 years after the diagnosis. The most common symptom was acrocyanosis (n = 39 [44%]), and many had symptoms triggered by cold (n = 35 [39%]) or other factors (n = 20 [22%]). An underlying hematologic disorder was detected in 69 patients (78%). Thirty-six patients (40%) received transfusions during their disease course, and 82% received drug therapy. Rituximab was associated with the longest response duration (median, 24 months) and the lowest proportion of patients needing further treatment (55%). Our institution's experience and review of the literature confirms that early diagnostic evaluation and treatment improves outcomes in cold agglutinin disease. 23838232 A road map to a comprehensive regulation on ventilation technology for operating rooms. Among strategies to reduce surgical site infection (SSI) risk, we concentrate on the optimization of the air quality through the heating, ventilation, and air conditioning (HVAC) system. Current ventilation standards applied by some European countries have been compared and show uncertainty in the criteria for dimensioning the HVAC system. The development of a comprehensive regulation needs further discussion. 23848376 Epithelial-mesenchymal transition enhances nanoscale actin filament dynamics of ovarian cancer cells. Epithelial ovarian cancer cells enhance their ability to migrate and invade through the epithelial-mesenchymal transition (EMT), resulting in cell seeding and metastasis in the peritoneal cavity and onto adjacent organ surfaces. It has been speculated that cytoskeletal dynamics, such as those of the actin filament, play a role in enhanced cell motility; however, direct evidence has not been provided. Herein, we have directly measured pico- to nanonewton-scale mechanical forces generated by actin dynamics of ovarian cancer SKOV-3 cells upon binding of integrin α5β1 to fibronectin (FN), i.e., formation of a focal adhesion, using real-time atomic force microscopy (AFM) in a force spectroscopy mode. The dendrimer surface chemistry through which FN was immobilized on the AFM probe surfaces further enhanced the sensitivity of the force measurement by 1.5-fold. Post-EMT SKOV-3 cells, induced by transforming growth factor-β, generated larger focal adhesion mechanical forces (17 and 41 nN before and after EMT, respectively) with migration faster than that of pre-EMT cells. Importantly, 22% of the forces transmitted through a single FN-integrin α5β1 pair from post-EMT cells were shown to be sufficient to rupture the binding between FN and integrin α5β1 on the cells, a result which is not observed on pre-EMT cells. This implies that post-EMT cells, by generating forces strong enough to break the FN-integrin binding, migrate and metastasize beyond the ovary, whereas pre-EMT cancer cells are confined in the ovary without such force generation. These results demonstrate quantitative and direct evidence for the role of actin dynamics in the enhanced motility of post-EMT ovarian cancer cells, providing a fundamental insight into the mechanism of ovarian cancer metastasis. 23651909 Diarrheogenic Escherechia coli in potable water sources of West Bengal, India. Diarrheal diseases are a major cause of morbidity and mortality in developing countries. Among the bacterial pathogens, diarrheagenic Escherichia coli are most frequently connected in cases with epidemic and endemic diarrhea worldwide. Environmental surveillance for monitoring of E.coli is very rare. In the present study, we have applied a modified technique to quantify coliform and E. coli in different potable water sources and their subsequent characterization (in relation to diarrheal pathogenicity) in the diarrhea endemic foci of West Bengal. More than one-fifth of the targeted sources (21.4%) have been identified harboring E. coli. Serotyping and molecular analysis reveals multidrug resistant EPEC, EIEC and ETEC among 9% of positive sources. Rainy season seems to be the most conducive period for E. coli induced diarrhea. While non-diarrheogenic E.coli were sensitive to most of the drugs, diarrheogenic E. coli, possessing toxicity, showed resistance against tetracycline, kanamycin, furazolidone, amoxicillin, ampicillin, norfloxacin, ciprofloxacin. Presence of multidrug resistant diarrheogenic E.coli justifies the potentiality of potable water sources as its vehicle and as a potent diarrheal inducer in diarrhea prone area along with increasing concern of drug resistance. Presence of diarrheogenic E. coli stresses the urgent need of its environmental surveillance like diarrheogenic Vibrios. 23795682 Molecular imaging: an innovative force in musculoskeletal radiology. OBJECTIVE. A review of the innovative role molecular imaging plays in musculoskeletal radiology is provided. Musculoskeletal molecular imaging is under development in four key areas: imaging the activity of osteoblasts and osteoclasts, imaging of molecular and cellular biomarkers of arthritic joint destruction, cellular imaging of osteomyelitis, and imaging generators of musculoskeletal pain. CONCLUSION. Together, these applications suggest that next-generation musculoskeletal radiology will facilitate quantitative visualization of molecular and cellular biomarkers, an advancement that appeared futuristic just a decade ago. 23966635 Ongoing applicative studies of plant thioredoxins. Studies triggered by the discovery of the function of thioredoxin (Trx) in photosynthesis have revealed its role throughout biology. Parallel biochemical and proteomic analyses have led to the identification of its numerous putative targets. Recently, to verify the biological significance of these targets, in vivo studies using transformants in which Trx is overexpressed or suppressed are in progress, and the transformants themselves that are being used in such studies show their potential applicative values. Moreover, Trx's mitigation of allergenicity for some proteins offers promising prospects in the food industry. Practical studies based on redox regulation, once only on the horizon, are now achieving new dimensions. This short review focuses on the industrial applications of Trx studies, the current situation, and future perspectives. The putative targets obtained by the proteomics approach in comparison with in vivo observations of the transformants are also examined. Applicative studies of glutathione, a counterpart of Trx, are also discussed briefly. 23935888 Cardiotrophin-1 induces matrix metalloproteinase-1 in human aortic endothelial cells. Rupture of an atherosclerotic plaque is a key event in the development of cardiovascular disorders, in which matrix metalloproteinase-1 (MMP-1) plays a crucial role by degradation of extracellular matrix resulting in plaque instability. Cardiotrophin-1 (CT-1), a member of interleukin-6-type proinflammatory cytokines, has potent cardiovascular actions and is highly expressed in vascular endothelium, however its role in atherosclerosis has not been fully elucidated to date. The present study was designed to investigate whether CT-1 induces MMP-1 in human aortic endothelial cells (HAECs). Ribonuclease protection assay demonstrated that MMP-1 gene level in HAECs was enhanced by the treatment of CT-1 in a dose- and time-dependent manner. Immunocytochemical staining, Western immunoblot analysis and enzyme-linked immunosorbent assay revealed that CT-1 augmented MMP-1 protein synthesis and secretion. MMP-1 activity assay revealed that MMP-1 present in the supernatant of HAECs was exclusively precursor form. Casein zymography disclosed proteolytic activity in the supernatant of HAECs, which was enhanced by CT-1 treatment. Furthermore, pharmacological inhibitor study indicated the important roles of extracellular signal-regulated kinase (ERK) 1/2, p38 mitogen-activated protein (MAP) kinase, c-Jun N-terminal kinase (JNK) and Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways in mediating CT-1-induced MMP-1 gene and protein expression. These data reveal for the first time that CT-1 induces the proteolytic potential in HAECs by upregulating MMP-1 expression through ERK1/2, p38 MAP kinase, JNK and JAK/STAT pathways, and suggest that CT-1 may play an important role in the pathophysiology of atherosclerosis and plaque instability. 23424996 Rheological properties and tunable thermoplasticity of phenolic rich fraction of pyrolysis bio-oil. In this work we report on the preparation, characterization, and properties of a thermally treated lignin-derived, phenolic-rich fraction (PRF) of wood pyrolysis bio-oil obtained by ethyl acetate extraction. The PRF was characterized for viscoelastic and rheological behavior using dynamic mechanical analysis (DMA) and cone and plate rheology. A unique thermoplastic behavior was evidenced. Heat-treated PRFs acquire high modulus but show low temperatures of thermal flow which can be systematically manipulated through the thermal pretreatment. Loss of volatiles, changes in molecular weight, and glass transition temperature (Tg) were investigated using thermogravimetric analysis (TGA), mass spectrometry (MS), and differential scanning calorimetry (DSC), respectively. Underlying mechanisms for the thermal and rheological behavior are discussed with regard to interactions between pyrolytic lignin nanoparticles present in the system and the role of volatile materials on determining the properties of the material resembling in several aspects to colloidal suspension systems. Low thermal flow temperatures and reversible thermal effects can be attributed to association of pyrolytic lignin particles due to intermolecular interactions that are easily ruptured at higher temperatures. The thermoplastic behavior of PRF and its low Tg is of particular interest, as it gives opportunities for application of this fraction in several melt processing and adhesive technologies. 23612197 In vitro, in vivo, and clinical studies of tedizolid to assess the potential for peripheral or central monoamine oxidase interactions. Tedizolid phosphate is a novel oxazolidinone prodrug whose active moiety, tedizolid, has improved potency against Gram-positive pathogens and pharmacokinetics, allowing once-daily administration. Given linezolid warnings for drug-drug and drug-food interactions mediated by monoamine oxidase (MAO) inhibition, including sporadic serotonergic toxicity, these studies evaluated tedizolid for potential MAO interactions. In vitro, tedizolid and linezolid were reversible inhibitors of human MAO-A and MAO-B; the 50% inhibitory concentration (IC50) for tedizolid was 8.7 μM for MAO-A and 5.7 μM for MAO-B and 46.0 and 2.1 μM, respectively, with linezolid. Tedizolid phosphate was negative in the mouse head twitch model of serotonergic activity. Two randomized placebo-controlled crossover clinical studies assessed the potential of 200 mg/day tedizolid phosphate (at steady state) to enhance pressor responses to coadministered oral tyramine or pseudoephedrine. Sensitivity to tyramine was determined by comparing the concentration of tyramine required to elicit a ≥ 30-mmHg increase in systolic blood pressure (TYR30) when administered with placebo versus tedizolid phosphate. The geometric mean tyramine sensitivity ratio (placebo TYR30/tedizolid phosphate TYR30) was 1.33; a ratio of ≥ 2 is considered clinically relevant. In the pseudoephedrine study, mean maximum systolic blood pressure was not significantly different when pseudoephedrine was coadministered with tedizolid phosphate versus placebo. In summary, tedizolid is a weak, reversible inhibitor of MAO-A and MAO-B in vitro. Provocative testing in humans and animal models failed to uncover significant signals that would suggest potential for hypertensive or serotonergic adverse consequences at the therapeutic dose of tedizolid phosphate. Clinical studies are registered at www.clinicaltrials.gov as NCT01539473 (tyramine interaction study conducted at Covance Clinical Research Center, Evansville, IN) and NCT01577459 (pseudoephedrine interaction study conducted at Vince and Associates Clinical Research, Overland Park, KS). 23910851 A report of five cases of self-mutilation for the purpose of insurance fraud. Self-mutilation means direct and deliberate destruction of one's own body tissue without intending suicide. Some of the forensic referrals are the fraudulent persons who wish to obtain insurance benefits by simulating self-induced harms as injuries due to accidents. In this article we report five cases of self-mutilation for the purpose of obtaining insurance payments. These cases were interesting because of the following reasons: (1) Fracture of the tibia bone for the purpose of obtaining insurance payments is extremely rare. To our knowledge, the specialised literature does not present a similar case study as we described here. (2) In the cases we describe here, nobody had prior history of social and psychiatric problems and violence. In addition, on examination, no sign of previous scars was found in the whole body skin. (3) Self-mutilation injuries are often painless, parallel and delicate lines which are most frequently in the upper limb opposite to the dominant hand and in the areas that can be easily reached. In one of our cases, self-mutilation of the leg shin and the dominant hand were on the same side of the body. (4) In our study, all of the cases had high school education and were from small counties. Four patients were within the age range of 20-30 years, living in a populous family (six-member family) and of middle socioeconomic status. These results are consistent with previously available data for self-mutilation in Iran. 23943045 Squaring the cube: a family of octametallic lanthanide complexes including a Dy8 single-molecule magnet. A series of isostructural octanuclear lanthanide complexes of general formula [Ln8(sao)4(μ3-OH)4(NO3)12(DMF)12] (Ln = Nd (), Sm (), Eu (), Gd (), Tb (), Dy (), Ho (), Er (); DMF = dimethylformamide) have been prepared via reactions of salicylaldoxime (saoH2), tetramethylammonium hydroxide (Me4NOH) with the appropriate lanthanide nitrate salt (Ln(NO3)3·6H2O). The metallic skeletons of the complexes describe [Ln4] tetrahedra encapsulated inside a [Ln4] square with the inner core stabilised through μ3-OH(-) ions and the periphery by μ4-sao(2-) ligands. The magnetic properties of compounds were investigated by dc and ac magnetometry. Temperature dependent ac magnetic susceptibility data reveal that the dysprosium analogue () displays an out-of-phase signal in the absence of an applied magnetic field indicative of slow relaxation of the magnetization typical of a Single-Molecule Magnet (SMM). Micro-SQUID measurements reveal temperature and sweep rate dependent hysteresis below 1.0 K. 23931953 The development of the rotigotine transdermal patch: a historical perspective. The rotigotine transdermal system is a dopamine receptor agonist delivered over a 24-hour period. It is approved for the treatment of idiopathic Parkinson's disease (PD). This article reviews the development of the rotigotine transdermal system, including rotigotine's receptor profile, steady-state pharmacokinetics, and metabolism. Preclinical studies of rotigotine in animal models of PD and proof-of-concept studies in patients with PD are reviewed. These preclinical and clinical studies established this system as an effective method for providing continuous rotigotine delivery across the skin providing the basis for continued clinical development of rotigotine for the treatment of early and advanced PD. 23780400 An experimental evaluation of the Agility MLC for motion-compensated VMAT delivery. An algorithm for dynamic multileaf-collimator (dMLC) tracking of a target performing a known a priori, rigid-body motion during volumetric modulated arc therapy (VMAT), has been experimentally validated and applied to investigate the potential of the Agility (Elekta AB, Stockholm, Sweden) multileaf-collimator (MLC) for use in motion-compensated VMAT delivery. For five VMAT patients, dosimetric measurements were performed using the Delta(4) radiation detector (ScandiDos, Uppsala, Sweden) and the accuracy of dMLC tracking was evaluated using a gamma-analysis, with threshold levels of 3% for dose and 3 mm for distance-to-agreement. For a motion trajectory with components in two orthogonal directions, the mean gamma-analysis pass rate without tracking was found to be 58.0%, 59.0% and 60.9% and was increased to 89.1%, 88.3% and 93.1% with MLC tracking, for time periods of motion of 4 s, 6 s and 10 s respectively. Simulations were performed to compare the efficiency of the Agility MLC with the MLCi MLC when used for motion-compensated VMAT delivery for the same treatment plans and motion trajectories. Delivery time increases from a static-tumour to dMLC-tracking VMAT delivery were observed in the range 0%–20% for the Agility, and 0%–57% with the MLCi, indicating that the increased leaf speed of the Agility MLC is beneficial for MLC tracking during lung radiotherapy. 23831018 Antihistaminergics and inverse agonism: Potential therapeutic applications. The accurate characterization of the molecular mechanisms involved in the action of receptor ligands is important for their appropriate therapeutic use and safety. It is well established that ligands acting at the histamine system currently used in the clinic exert their actions by specifically antagonizing G-protein coupled H1 and H2 receptors. However, most of these ligands, assumed to be neutral antagonists, behave as inverse agonists displaying negative efficacy in experimental systems. This suggests that their therapeutic actions may involve not only receptor blockade, but also the decrease of spontaneous receptor activity. The mechanisms whereby inverse agonists achieve negative efficacy are diverse. Theoretical models predict at least three possible mechanisms, all of which are supported by experimental observations. Depending on the mechanism of action engaged, the inverse agonist could interfere specifically with signaling events triggered by unrelated receptors. This possibility opens up new venues to explain the therapeutic actions of inverse agonists of the histamine receptor and perhaps new therapeutic applications. 23411332 Effects of fish protein hydrolysate and freeze-thaw treatment on physicochemical and gel properties of natural actomyosin from Pacific cod. The properties of natural actomyosin (NAM) containing 2% or 8% fish protein hydrolysate (FPH-2, FPH-8) or 8% sucrose-sorbitol blend (SuSo) were compared to control NAM before and after freeze-thaw treatment. Surface hydrophobicity of control and FPH-2 increased after freeze-thaw treatment, while that of FPH-8 did not change, which may be related to greater thermostability of actin and myosin in FPH-8 as observed by differential scanning calorimetry. The cooked gel of freeze-thawed control had 39% expressible moisture after an 8.5% cook loss, whereas gels of freeze-thawed SuSo, FPH-2 and FPH-8 had significantly lower expressible moisture (15-22%) and no cook loss. Gels of freeze-thawed FPH-2 and FPH-8 were similar to unfrozen control gel in hardness, cohesiveness and gumminess. This study demonstrates that FPH effectively stabilised NAM protein structure and function during freeze-thaw treatment. 23943302 Mortality Disparities Among Groups Participating in an East Africa Surveying Expedition: The Herbert Henry Austin Expedition of 1900-1901. In the late nineteenth and early twentieth centuries, a number of European expeditions traveled to the region of Lake Rudolf, now largely in northern Kenya. Although diverse in intent, many of these were undertaken in the interests of furthering colonial territorial claims. In 1900-1901, Major Herbert Henry Austin led a British expedition down to the lake from Khartoum in the north. Of the 62 African, Arab, and European members of this expedition, only 18 (29 %) arrived at its final destination at Lake Baringo in Kenya. Because of a confluence of adverse climatic, social, and political conditions, the expedition ran short of food supplies when it arrived at the northern end of the lake in April 1901. For the next 4 months, the members of the expedition struggled down the west side of the lake and beyond. The greatest mortality (91 %) occurred among the 32 African transport drivers who were the most marginally nourished at the outset of the trip. The lowest mortality among the Africans on the expedition (15 %) occurred among the members of the Tenth Sudanese Rifles Battalion, who had an excellent nutritional status at the start of the expedition. Major Austin himself suffered from severe scurvy with retinal hemorrhages which left him partially blind in his right eye. An analysis of the mortality rates among the groups that participated in this expedition was undertaken. This revealed that poor nutritional status at the start of the trip was predictive of death from starvation. 23923003 Regulation of Coronaviral Poly(A) Tail Length during Infection. The positive-strand coronavirus genome of ~30 kilobase in length and subgenomic (sg) mRNAs of shorter lengths, are 5' and 3'-co-terminal by virtue of a common 5'-capped leader and a common 3'-polyadenylated untranslated region. Here, by ligating head-to-tail viral RNAs from bovine coronavirus-infected cells and sequencing across the ligated junctions, it was learned that at the time of peak viral RNA synthesis [6 hours postinfection (hpi)] the 3' poly(A) tail on genomic and sgmRNAs is ~65 nucleotides (nt) in length. Surprisingly, this length was found to vary throughout infection from ~45 nt immediately after virus entry (at 0 to 4 hpi) to ~65 nt later on (at 6 h to 9 hpi) and from ~65 nt (at 6 h to 9 hpi) to ~30 nt (at 120-144 hpi). With the same method, poly(U) sequences of the same lengths were simultaneously found on the ligated viral negative-strand RNAs. Functional analyses of poly(A) tail length on specific viral RNA species, furthermore, revealed that translation, in vivo, of RNAs with the longer poly(A) tail was enhanced over those with the shorter poly(A). Although the mechanisms by which the tail lengths vary is unknown, experimental results together suggest that the length of the poly(A) and poly(U) tails is regulated. One potential function of regulated poly(A) tail length might be that for the coronavirus genome a longer poly(A) favors translation. The regulation of coronavirus translation by poly(A) tail length resembles that during embryonal development suggesting there may be mechanistic parallels. 23867077 When less is more: a functional magnetic resonance imaging study of verbal working memory in remitted depressed patients. Patients with depression show abnormalities in the neural circuitry supporting working memory. However, it is unclear if these abnormalities are present in unmedicated remitted depressed patients. To address this question, the current study employed functional magnetic resonance imaging (fMRI), in combination with a simple verbal n-back task, in a cohort of unmedicated remitted depressed patients. Method We studied 15 healthy control subjects (HC) and 15 unmedicated remitted depressed patients (rMDD). Participants performed a verbal working memory task of varying cognitive load (n-back) while undergoing fMRI. We used multiple regression analyses to assess overall capacity (1-, 2-, 3-back versus 0-back) as well as quadratic modulation of cognitive demand. Performance accuracy and response latency did not differ between groups, and overall capacity was similar. However, rMDD showed a positive quadratic load response in the bilateral hippocampus; the converse was true for HC. Our data suggest that remitted depression was associated with a perturbed pattern of activation in the bilateral hippocampus during a verbal working memory task. We propose that a reduced ability to dampen task-irrelevant activity may reflect a neurobiological risk factor for recurrent depression. 23856812 Composition and sources of aliphatic lipids and sterols in sediments of a tropical island, southern South China Sea: preliminary assessment. Near-shore surface sediment was collected from five stations off Redang Island located on the eastern coast of Peninsular Malaysia. Freeze-dried sediments were Soxhlet extracted and then fractionated using column chromatography into aliphatic and polar fractions. Determination of these fractions was carried out using gas chromatography mass spectrometry. The concentration of total resolved aliphatic hydrocarbons in sediments ranged from 157 to 308 ng/g. The distribution of aliphatic fraction showed the presence of n-alkanes ranging from nC15 to nC33 with a minor odd-to-even predominance exhibiting carbon maximum, depending on station, at nC17, nC26, nC29 or nC31. Calculation of Carbon Preference Index (CPI) for CPI15-33 gave values ranging from 1.09 to 1.46. n-Alkanol in all sediment exhibits even-to-odd carbon predominance ranging from nC16 to nC28 and maximising at nC22. n-Fatty acids distribution ranged from nC14 to nC24 with a dominant maximum at nC16 and exhibiting high values of short chain fatty acids (≤nC20) to long chain fatty acids (>nC20) ratios. Unsaturated fatty acids, particularly nC16:1 and nC18:1 is also ubiquitous in all samples. Cholesterol is the most abundant compound amongst the sterol group ranging from 42.8 to 62.6 % of the total sterols. β-Sitosterol, brassicasterol and stigmasterol, are also present but of relatively lower amount. These observations suggest that the aliphatic lipids and sterols in the study area originate, mainly, from biogenic sources of marine microbial with minor contribution from epiticular waxes of terrestrial plants. 23874431 Human dermal stem/progenitor cell-derived conditioned medium ameliorates ultraviolet a-induced damage of normal human dermal fibroblasts. Adult skin stem cells are considered an attractive cell resource for therapeutic potential in aged skin. We previously reported that multipotent human dermal stem/progenitor cells (hDSPCs) can be enriched from (normal human dermal fibroblasts (NHDFs) using collagen type IV. However, the beneficial effects of hDSPCs on aged skin remain to be elucidated. In the present study, we analyzed the growth factors secreted from hDSPCs in conditioned medium (CM) derived from hDSPCs (hDSPC-CM) and found that hDSPCs secreted higher levels of bFGF, IGFBP-1, IGFBP-2, HGF, VEGF and IGF-1 compared with non-hDSPCs. We then investigated whether hDSPC-CM has an effect on ultraviolet A (UVA)-irradiated NHDFs. Real-time RT-PCR analysis revealed that the treatment of UVA-irradiated NHDFs with hDSPC-CM significantly antagonized the UVA-induced up-regulation of the MMP1 and the UVA-induced down-regulation of the collagen types I, IV and V and TIMP1 mRNA expressions. Furthermore, a scratch wound healing assay showed that hDSPC-CM enhanced the migratory properties of UVA-irradiated NHDFs. hDSPC-CM also significantly reduced the number of the early and late apoptotic cell population in UVA-irradiated NHDFs. Taken together, these data suggest that hDSPC-CM can exert some beneficial effects on aged skin and may be used as a therapeutic agent to improve skin regeneration and wound healing. 23926172 Tuberculin sensitivity testing and treatment of latent tuberculosis remains effective for tuberculosis control in human immunodeficiency virus-infected patients in Hong Kong. OBJECTIVE. To evaluate whether a policy to treat latent tuberculosis identified by annual tuberculin sensitivity testing is effective for tuberculosis control in human immunodeficiency virus-infected patients in Hong Kong. DESIGN. Historical cohort study. SETTING. Integrated Treatment Centre, Department of Health, Hong Kong. PATIENTS. Patients infected with human immunodeficiency virus without a history of tuberculosis were offered annual tuberculin sensitivity testing, coupled with treatment of latent tuberculosis if they tested positive. All such patients were followed for new tuberculosis. RESULTS. In all, 1154 patients on antiretroviral therapy, contributing to 5587 patient-years of observation, were analysed; 1032 patients (89%) received annual tuberculin sensitivity testing. Their baseline characteristics, including CD4 counts and other risk factors for tuberculosis, did not differ significantly from those who declined testing. The overall incidence rate of tuberculosis was 0.59 case per 100 patient-years. It was lower in those who received annual tuberculin sensitivity testing than those who did not (0.41 vs 3.85 per 100 patient-years; P<0.0001). Only a low baseline CD4 count and a history of tuberculin sensitivity testing were shown to be significant indicators of incident tuberculosis using multivariate analysis. The hazard ratio was 0.36 (95% confidence interval, 0.16-0.85; P=0.02) for those with a baseline CD4 count of 100/mm3 or above, and 0.26 (95% confidence interval, 0.08-0.77; P=0.016) for those who received annual tuberculin sensitivity testing. The incidence of tuberculosis was highest within 90 days of antiretroviral therapy initiation. CONCLUSION. The established policy continues to be effective. The high risk of tuberculosis during the early period of antiretroviral therapy supports early use of tuberculin sensitivity testing. Alternatively, the strategy of universal isoniazid preventive therapy at antiretroviral therapy initiation could be studied for those with very low baseline CD4 counts. 23969086 Development of a (13)C-optimized 1.5-mm high temperature superconducting NMR probe. We report a 1.5-mm NMR probe based on high temperature superconductors operating at 14.1T optimized for (13)C detection. The probe has a total sample volume of about 35microliters (μL) with an active volume of 20μL and provides exceptional mass sensitivity for (13)C detection. The probe also has excellent (1)H sensitivity and employs a (2)H lock; (15)N irradiation capability can be added in the future. The coils are cooled to about 20K using a standard Agilent cryogenic refrigeration system, and the sample temperature is regulated near room temperature. The coil design considerations are discussed in detail. This probe is ideal for directly detected (13)C NMR experiments for natural products chemistry and metabolomics applications, for which 35μL is an optimal sample volume. The outstanding (13)C sensitivity of this probe allowed us to directly determine the (13)C connectivity on 1.1mg of natural abundance histidine using an INADEQUATE experiment. We demonstrated the utility of this probe for (13)C-based metabolomics using a synthetic mixture of common natural abundance metabolites whose concentrations ranged from 1 to 5mM (40-200nmol). 23951021 Ratio of pro-resolving and pro-inflammatory lipid mediator precursors as potential markers for aggressive periodontitis. Aggressive periodontitis (AgP) is a rapidly progressing type of periodontal disease in otherwise healthy individuals which causes destruction of the supporting tissues of the teeth. The disease is initiated by pathogenic bacteria in the dental biofilm, and the severity of inflammation and attachment loss varies with the host response. Recently, there has been an increased interest in determining the role of lipid mediators in inflammatory events and the concept of pro-inflammatory and pro-resolution lipid mediators has been brought into focus also in periodontal disease. The present study aimed to determine the profile of omega-3 or n3- as well as omega-6 or n6- polyunsaturated fatty acids (PUFAs) and PUFA-metabolites of linoleic acid, arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in gingival crevicular fluid (GCF), saliva and serum in AgP patients and healthy controls. In total, 60 selected n3- and n6-PUFAs and various PUFA metabolites were measured using high performance liquid chromatography-tandem electrospray ionisation mass spectrometry (HPLC-ESI-MS-MS). Of these, 51 could be quantified in this study. The concentrations of the majority were low in saliva samples compared with serum and GCF, but were mainly higher in AgP patients compared with healthy controls in all three kinds of sample. Ratios of n3- to n6-PUFAs (DHA + EPA)/AA were significantly lower in the GCF of AgP patients than in the healthy controls. Furthermore, various ratios of the direct precursors of the pro-resolution lipid mediators (precursors of resolvins and protectins) were calculated against the precursors of mainly pro-inflammatory lipid mediators. These ratios were mainly lower in GCF and saliva of AgP patients, compared with healthy controls, but only reached significance in GCF (P<0.05). To conclude, the ratios of precursors of pro-resolution/pro-inflammatory lipid mediators seem to be more relevant for describing the disease status of AgP than the concentration of specific lipid mediators. 23576041 Genetic improvement of Saccharomyces cerevisiae wine strains for enhancing cell viability after desiccation stress. In the last few decades spontaneous grape must fermentations have been replaced by inoculated fermentation with Saccharomyces cerevisiae strains as active dry yeast (ADY). Among the essential genes previously characterized to overcome the cell-drying/rehydration process, six belong to the group of very hydrophilic proteins known as hydrophilins. Among them, only SIP18 has shown early transcriptional response during dehydration stress. In fact, the overexpression in S. cerevisiae of gene SIP18 increases cell viability after the dehydration process. The purpose of this study was to characterize dehydration stress tolerance of three wild and one commercial S. cerevisiae strains of wine origin. The four strains were submitted to transformation by insertion of the gene SIP18. Selected transformants were submitted to the cell-drying-rehydration process and yeast viability was evaluated by both viable cell count and flow cytometry. The antioxidant capacity of SIP18p was illustrated by ROS accumulation reduction after H2 O2 attack. Growth data as cellular duplication times and lag times were calculated to estimate cell vitality after the cell rehydration process. The overexpressing SIP18 strains showed significantly longer time of lag phase despite less time needed to stop the leakage of intracellular compounds during the rehydration process. Subsequently, the transformants were tested in inoculated grape must fermentation at laboratory scale in comparison to untransformed strains. Chemical analyses of the resultant wines indicated that no significant change for the content of secondary compounds was detected. The obtained data showed that the transformation enhances the viability of ADY without affecting fermentation efficiency and metabolic behaviour. Copyright © 2013 John Wiley & Sons, Ltd. 23839790 Subicular-parahippocampal projections revisited. The development of a complex topography in the rat. The subicular-parahippocampal projection has been proposed as the major output pathway of the hippocampus. This projection shows a striking topographical organization along its three dimensional axes. Here we aimed to study the development of this projection system. We found that an adult-like topography of subiculum-to-parahippocampal projections is present by postnatal day 7 (P7). The cellular morphology in the subiculum is immature at this age, reaching maturity by P15-19. The density of projections increases from P7 to P15-19, but does so within the constraints of the adult-topography. Projections to the entorhinal cortex show a clear arrangement in line with the adult data in that distal portions of the subiculum project to the medial entorhinal cortex while proximal portions project the lateral entorhinal cortex. Our results add new details to the proximodistal organization of projections to the pre- and parasubiculum. First we show that these projections arise exclusively from the more distal part, sharing their origin with that of medial entorhinal projections. Within this distal portion of the subiculum, a proximodistal gradient of origin maps onto a presubicular termination gradient starting in proximal presubiculum extending gradually until it covers the proximodistal extent. Proximally located neurons in the distal part of the subiculum target the distal portion of the parasubiculum and distal subicular neurons target the proximal most portion of parasubiculum. Given the specificity of the known topographical projections this early in development, we expect that these newly described topographical features will be maintained in the adult. J. Comp. Neurol., 2013. © 2013 Wiley Periodicals, Inc. 23893433 IRMPD Action Spectroscopy of Alkali Metal Cation-Cytosine Complexes: Effects of Alkali Metal Cation Size on Gas Phase Conformation. The gas-phase structures of alkali metal cation-cytosine complexes generated by electrospray ionization are probed via infrared multiple photon dissociation (IRMPD) action spectroscopy and theoretical calculations. IRMPD action spectra of five alkali metal cation-cytosine complexes exhibit both similar and distinctive spectral features over the range of ~1000-1900 cm(-1). The IRMPD spectra of the Li(+)(cytosine), Na(+)(cytosine), and K(+)(cytosine) complexes are relatively simple but exhibit changes in the shape and shifts in the positions of several bands that correlate with the size of the alkali metal cation. The IRMPD spectra of the Rb(+)(cytosine) and Cs(+)(cytosine) complexes are much richer as distinctive new IR bands are observed, and the positions of several bands continue to shift in relation to the size of the metal cation. The measured IRMPD spectra are compared to linear IR spectra of stable low-energy tautomeric conformations calculated at the B3LYP/def2-TZVPPD level of theory to identify the conformations accessed in the experiments. These comparisons suggest that the evolution in the features in the IRMPD action spectra with the size of the metal cation, and the appearance of new bands for the larger metal cations, are the result of the variations in the intensities at which these complexes can be generated and the strength of the alkali metal cation-cytosine binding interaction, not the presence of multiple tautomeric conformations. Only a single tautomeric conformation is accessed for all five alkali metal cation-cytosine complexes, where the alkali metal cation binds to the O2 and N3 atoms of the canonical amino-oxo tautomer of cytosine, M(+)(C1). 23848299 Oregano essential oil as an antimicrobial additive to detergent for hand washing and food contact surface cleaning. To investigate the potential use of oregano essential oil as an antimicrobial agent in liquid soap for hand washing and for food contact surface cleaning. Oregano essential oil (O.E.O.) was emulsified in liquid detergent solution. This was challenge tested against a commercial antimicrobial soap in hand washing trials using natural flora. Soap with O.E.O. was as effective as the commercial antimicrobial soap at reducing aerobic plate count on the hands and more effective than plain soap with no additives. Cloths wetted with soap with O.E.O. were used to clean three different surfaces contaminated with four bacterial pathogens. For three of the four pathogens, the addition of 0·5% v/v O.E.O. to the soap solution enhanced cleaning performance and also reduced bacterial survival on the cloth after cleaning. Oregano essential oil (0·5%) is effective as an antimicrobial additive to detergent solutions for hand washing and surface cleaning. This preliminary study has shown that oregano essential oil is a potential alternative to antimicrobials used in various detergents, such as chloroxylenol and triclosan, which can have adverse environmental and health effects. Further development could lead to a commercial product. 23538201 EZETIMIBE INCREASES HEPATIC IRON LEVELS IN MICE FED A HIGH-FAT DIET. Accumulating evidence suggests that ezetimibe may be a promising agent for treatment of non-alcoholic fatty liver disease and steatohepatitis (NAFLD/NASH). Phlebotomy and dietary iron restriction reduces serum transaminase in NAFLD/NASH patients. Recent studies showed that mutual effects exist between lipid metabolism and iron metabolism. Accordingly, the effects of ezetimibe on iron metabolism were examined in mice fed a high-fat diet with or without iron. C57BL/6 mice were fed the following diets for 12 weeks. Experiment 1:1) a control diet; C 2) C plus ezetimibe (0.3mg/day; 4 weeks); CE 3) a high-fat diet; H 4) H plus ezetimibe; HE. Experiment 2: 1) C containing carbonyl iron (average; 22.4mg/day; 6 weeks); CI 2) CI plus ezetimibe; CIE 3) H containing carbonyl iron; HI 4) HI plus ezetimibe; HIE. Blood, livers, and duodenum were removed after 12 weeks. In Experiment 1, hepatic iron levels were higher in HE than H, whereas there was no difference between C and CE. Hepatic mRNA expression of transferrin receptor 1 and 2, ferritins, and hepcidin were increased more in CE than C, and in HE than H. In duodenum, DMT1, ferritinH, and hephaestin mRNA levels were increased in CE compared to C. In Experiment 2, hepatic iron concentrations were higher in HIE than HI. Hepatic mRNA expression of ferritinL and hepcidin were increased in HIE compared to HI. In duodenum, ferritinL mRNA was increased in HIE compared to CIE. Ezetimibe induced hepatic iron uptake transporter expression in mice fed a high-fat diet, causing increased hepatic iron concentrations. 23882221 The sigma-1 receptor: a regulator of cancer cell electrical plasticity? Originally mistaken as an opioid receptor, the sigma-1 receptor (Sig1R) is a ubiquitous membrane protein that has been involved in many cellular processes. While the precise function of Sig1R has long remained mysterious, recent studies have shed light on its role and the molecular mechanisms triggered. Sig1R is in fact a stress-activated chaperone mainly associated with the ER-mitochondria interface that can regulate cell survival through the control of calcium homeostasis. Sig1R functionally regulates ion channels belonging to various molecular families and it has thus been involved in neuronal plasticity and central nervous system diseases. Interestingly, Sig1R is frequently expressed in tumors but its function in cancer has not been yet clarified. In this review, we discuss the current understanding of Sig1R. We suggest herein that Sig1R shapes cancer cell electrical signature upon environmental conditions. Thus, Sig1R may be used as a novel therapeutic target to specifically abrogate pro-invasive functions of ion channels in cancer tissue. 23810915 PTGS2 (Cyclooxygenase-2) Expression and Survival among Colorectal Cancer Patients: A Systematic Review. Studies have examined whether tumor expression of PTGS2 (also known as COX-2), an enzyme inhibited by nonsteroidal anti-inflammatory drugs such as aspirin, is associated with prognosis in patients with colorectal cancer. However, results to date have been mixed. Using terms for PTGS2 and colorectal cancer, the Medline, Embase, and Web of Science databases were systematically searched for studies published, in any language, until December 2011. Random effects meta-analyses were used to calculate pooled HRs [95% confidence intervals (CI)] for the association between PTGS2 expression and tumor recurrence, colorectal cancer-specific survival, and overall survival. In total, 29 studies, which had prognostic data on 5,648 patients, met the inclusion criteria. PTGS2-positive patients were at an increased risk of tumor recurrence (n = 9 studies; HR, 2.79; 95% CI, 1.76-4.41; P < 0.001) and had poorer colorectal cancer-specific survival (n = 7; HR, 1.36; 95% CI, 1.02-1.82; P = 0.04). However, there was funnel plot asymmetry, possibly due to publication bias, for the association with cancer-specific survival but less so for recurrence. PTGS2 expression was not associated with overall survival [(n = 16; pooled unadjusted HR, 1.30; 95% CI, 0.94-1.79; P = 0.11) and (n = 9; pooled adjusted HR, 1.02; 95% CI, 0.72-1.45; P = 0.91)]. PTGS2 expression was associated with an increased risk of tumor recurrence and poorer colorectal cancer-specific survival but not overall survival among patients with colorectal cancer. However, confounding by tumor characteristics such as tumor stage seems likely. There is insufficient evidence to recommend PTGS2 expression as a prognostic marker in patients with colorectal cancer. Furthermore, studies providing adjusted results are required. Cancer Epidemiol Biomarkers Prev; 1-8. ©2013 AACR. 23744733 Synthetic, Spectroscopic, and DFT Studies of Iron Complexes with Iminobenzo(semi)quinone Ligands: Implications for o-Aminophenol Dioxygenases. The oxidative CC bond cleavage of o-aminophenols by nonheme Fe dioxygenases is a critical step in both human metabolism (the kynurenine pathway) and the microbial degradation of nitroaromatic pollutants. The catalytic cycle of o-aminophenol dioxygenases (APDOs) has been proposed to involve formation of an Fe(II) /O2 /iminobenzosemiquinone complex, although the presence of a substrate radical has been called into question by studies of related ring-cleaving dioxygenases. Recently, we reported the first synthesis of an iron(II) complex coordinated to an iminobenzosemiquinone (ISQ) ligand, namely, [Fe( Ph 2Tp)((tBu) ISQ)] (2 a; where  Ph 2Tp=hydrotris(3,5-diphenylpyrazol-1-yl)borate and (tBu) ISQ is the radical anion derived from 2-amino-4,6-di-tert-butylphenol). In the current manuscript, density functional theory (DFT) calculations and a wide variety of spectroscopic methods (electronic absorption, Mössbauer, magnetic circular dichroism, and resonance Raman) were employed to obtain detailed electronic-structure descriptions of 2 a and its one-electron oxidized derivative [3 a](+) . In addition, we describe the synthesis and characterization of a parallel series of complexes featuring the neutral supporting ligand tris(4,5-diphenyl-1-methylimidazol-2-yl)phosphine ( Ph 2TIP). The isomer shifts of about 0.97 mm s(-1) obtained through Mössbauer experiments confirm that 2 a (and its  Ph 2TIP-based analogue [2 b](+) ) contain Fe(II) centers, and the presence of an ISQ radical was verified by analysis of the absorption spectra in light of time-dependent DFT calculations. The collective spectroscopic data indicate that one-electron oxidation of the Fe(II) -ISQ complexes yields complexes ([3 a](+) and [3 b](2+) ) with electronic configurations between the Fe(III) -ISQ and Fe(II) -IBQ limits (IBQ=iminobenzoquinone), highlighting the ability of o-amidophenolates to access multiple oxidation states. The implications of these results for the mechanism of APDOs and other ring-cleaving dioxygenases are discussed. 23395667 Growth factor delivery from hydrogel particle aggregates to promote tubular regeneration after acute kidney injury. Local delivery of growth factors (GFs) can accelerate regeneration of injured tissue, but for many medical applications, injectable GF delivery systems are required for clinical success. Viscoelastic, injectable aggregates of micrometer-sized hydrogel particles made of multiarmed polyethylene glycol (starPEG) and heparin were prepared and tested for site-specific paracrine stimulation of tissue regeneration. Heparin was used as it binds, protects and releases numerous GFs. Hydrogel based delivery of basic fibroblast growth factor (bFGF) and murine epidermal growth factor (EGF) was monitored utilizing enzyme-linked immunosorbent assay (ELISA). bFGF was released slowly because of its high affinity to the heparin while the significantly higher release of the non-specific binding EGF was controlled by diffusion only. To investigate GF delivery in vivo, a hydrogel loaded with murine EGF or bFGF was injected subcapsularly into the left kidney of mice with experimental acute kidney injury caused by glycerol induced rhabdomyolysis. Visual examination confirmed sustained stability of the injected gel aggregates during the timescale of the experiment. The number of proliferating kidney tubular epithelial cells was quantified both in the injected kidney and the non-injected contralateral kidney. bFGF delivery from hydrogels induced a significant increase in cell proliferation in the injected kidney, although small effects were also seen in the non-injected kidney due to a systemic effect. EGF delivery strongly increased cell proliferation for both kidneys, but also showed a local effect on the injected kidney. The hydrogel without loaded GFs was used as a control and showed no increase in cell proliferation. Our results suggest that this novel starPEG-heparin hydrogel system can be an effective approach to deliver GFs locally. 23913246 Influence of endotoxin-mediated retinal inflammation on phenotype of diabetic retinopathy in Ins2Akita mice. To evaluate the impact of systemic exposure to bacterial lipopolysaccharide (LPS) on a rodent model of background diabetic retinopathy. Toll-like receptor 4 (TLR4)-mediated systemic inflammation was induced in Ins2(Akita) heterozygotes and age-matched C57BL6/J-Ins2(+) littermates by single or repeated intraperitoneal injections of the TLR4 ligand LPS (9 µg/g body weight). 24 hours after a single injection in 7-week-old mice retinal Il1b, Tnfa and Vegf transcripts were measured with real-time PCR. Vascular endothelial growth factor (VEGF) protein levels were evaluated with bead-based immunoassay. Leukostasis and endothelial injury were assessed in retinal wholemounts following perfusion with rhodamine or FITC conjugated concanavalin A to label leukocytes and propidium iodide to label dead or injured cells. In mice which had received three fortnightly injections between 10 and 16 weeks of age, retinal thicknesses and vascular structure were evaluated at 17-18 weeks of age using optical coherence tomography (OCT) and fluorescein angiography. Retinal architecture was assesed using resin-based histology. Compared with normoglycaemic controls, systemic LPS exposure in Ins2(Akita) mice was associated with a 3.5-fold increase in endothelial cell injury and attenuated leukostasis in the retinal vasculature. Hyperglycaemia or acute LPS inflammation did not increase retinal VEGF content. Thinning (10-13 µm) of posterior retina was detected with OCT 2 weeks after repeated exposure to LPS in Ins2(Akita) mice but not in normoglycaemic controls. Capillary networks and retinal morphology were unaffected by recurrent LPS inflammation in Ins2(Akita) and control mice. In hyperglycaemic mice, exposure to systemic LPS was associated with two hallmark pathologies of early background diabetic retinopathy, namely, the injury of capillary endothelium and in vivo thinning of the retina. 23892034 Impedimetric detection of in situ interaction between anti-cancer drug bleomycin and DNA. Surface confined interaction of anti-cancer drug bleomycin (BLM) with nucleic acids: single stranded and double stranded DNA was investigated herein by using electrochemical impedance spectroscopy (EIS) technique in combination with a graphite sensor technology. The experimental conditions were optimized: such as, dsDNA concentration, BLM concentration and interaction time. The main features of impedimetric DNA biosensor, such as its detection limit and the repeatability, were also discussed. The in situ interaction of BLM with dsDNA was also tested impedimetrically in the absence or presence of other chemotherapeutic agents, such as mitomycin C (MC) and cis-platin (cis-DDP) for testing the selectivity. 22882349 Enhancing motivation to change in eating disorders with an online self-help program. Ambivalence to change is a major obstacle to treating people with eating disorders. Enhancing motivation to change can contribute to recovery from the disorders. This study used an Internet-based self-help program developed in the Asia-Pacific region to identify the motivational stages of change in people with eating disorders. It explored their perceptions of the benefits and costs of taking action against their eating disorders, and assessed their involvement in motivational enhancement exercises and their improvement in eating disorder psychopathology. A total of 185 participants, aged 16-50 years (mean age, 26.5) were involved in the open-trial program with a motivational enhancement component and completed the Motivational Stages of Change Questionnaire (MSCARED), the Eating Disorder Examination Questionnaire version 5 (EDE-Q5) and the Eating Disorder Inventory version 3 (EDI-3). The results show that more participants perceived the benefits of taking action against their eating disorders than the costs. Completer analysis shows that they experienced significant improvement in motivational stages of change and eating disorder psychopathology, from a baseline assessment to 1-month and 3-month follow ups. The self-help program has potential benefit for people with eating disorders and its use could be encouraged by health-care professionals to enhance the motivation to change and facilitate recovery. 22836546 Hydatid cyst of the thyroid gland: report of three cases. Cystic Echinococcosis is a parasitic infestation that is distributed world-wide. It may be found in nearly any part of the body, most often in the liver and the lungs, but occasionally in other structures such as the thyroid gland. The present study reports three cases of hydatid cysts of the thyroid gland, in patient ranging from 18 to 25 years of age. Two patients had concomitant hydatid disease involving organs other than the thyroid gland (secondary disease), and one had, sole, involvement of the thyroid gland itself (primary disease). Moreover, an occult papillary thyroid carcinoma was detected incidentally in one case, involving the unilateral thyroid lobe as the hydatid cyst. While several surgical procedures including left lobectomy and isthmectomy were undertaken in one patient, two patients underwent total thyroidectomy. No disease recurrence was observed in any of the three patients during the postoperative follow-up period. No study reporting the concomitance of hydatid cyst and neoplasia of the thyroid gland has been previously published. This concomitance indicates the importance of the differential diagnosis of lesions characterized by calcifications in the thyroid gland, especially in endemic regions. 23856892 Molecular imaging in gastroenterology. Molecular imaging is a novel field in gastroenterology that uses fluorescently labelled probes to specifically highlight neoplastic lesions on the basis of their molecular signature. The development of molecular imaging has been driven by the need to improve endoscopic diagnosis and by progress in targeted therapies in gastrointestinal oncology to provide individualized treatment, which coincides with progress in endoscopy techniques and further miniaturization of detection devices. Different exogenous molecular probes for imaging include labelled antibodies, oligopeptides, affibodies(™) (Affibody AB, Bromma, Sweden), aptamers and activatable probes. Molecular imaging has been evaluated in two major indications: many trials have studied molecular imaging as a red flag technique to improve detection of lesions in wide-field imaging; on the other hand, microscopic analysis has been investigated for in vivo characterization of the molecular fingerprint of tumours with the ultimate goal of assessing the likelihood of response to targeted therapy. This Review focusses on the applications of molecular imaging that have immediate potential for translational science or imminent transition into clinical practice of gastrointestinal endoscopy. 23951125 Landscape level variation in tick abundance relative to seasonal migration in red deer. Partial migration is common among northern ungulates, typically involving an altitudinal movement for seasonally migratory individuals. The main driving force behind migration is the benefit of an extended period of access to newly emerged, high quality forage along the green up gradient with increasing altitude; termed the forage maturation hypothesis. Any other limiting factor spatially correlated with this gradient may provide extra benefits or costs to migration, without necessarily being the cause of it. A common ectoparasite on cervids in Europe is the sheep tick (Ixodes ricinus), but it has not been tested whether migration may lead to the spatial separation from these parasites and thus potentially provide an additional benefit to migration. Further, if there is questing of ticks in winter ranges in May before spring migration, deer migration may also play a role for the distribution of ticks. We quantified the abundance of questing sheep tick within winter and summer home ranges of migratory (n = 42) and resident red deer (Cervus elaphus) individuals (n = 32) in two populations in May and August 2009-2012. Consistent with predictions, there was markedly lower abundance of questing ticks in the summer areas of migrating red deer (0.6/20 m(2)), both when compared to the annual home range of resident deer (4.9/20 m(2)) and the winter home ranges of migrants (5.8/20 m(2)). The reduced abundances within summer home ranges of migrants were explained by lower abundance of ticks with increasing altitude and distance from the coast. The lower abundance of ticks in summer home ranges of migratory deer does not imply that ticks are the main driver of migration (being most likely the benefits expected from forage maturation), but it suggests that ticks may add to the value of migration in some ecosystems and that it may act to spread ticks long distances in the landscape. 23830324 An overview of short bowel syndrome management: adherence, adaptation, and practical recommendations. Short bowel syndrome (SBS) refers to the clinical consequences resulting from loss of small bowel absorptive surface area due to surgical resection or bypass. The syndrome is characterized by maldigestion, malabsorption, and malnutrition. Survival of patients with SBS is dependent on adaptation in the remaining bowel and a combination of pharmacologic and nutrition therapies. Individual plans of care are developed based on the length and sites of remaining bowel, the degree of intestinal adaptation, and the patient's ability to adhere to the medication and dietary regimens. Antisecretory and antidiarrheal medications are prescribed to slow intestinal transit times and optimize fluid and nutrient absorption. Based on postsurgical anatomy, enteral feedings, parenteral infusions, complex diet plans, and vitamin and mineral supplementation are used in various combinations to nourish patients with SBS. In the acute care setting, registered dietitians (RDs) assist with infusion therapy, diet education, and discharge planning. Long-term, as the small intestine adapts, RDs revise the nutrition care plan and monitor for nutrient deficiencies, metabolic bone disease, and anemia. The frequent monitoring and revision of care plans, plus the appreciable benefits from proper medical nutrition therapy, make this patient population extremely challenging and rewarding for RDs to manage. This article provides a brief, case study-based overview of the medical and nutrition management of SBS. 23015541 Caffeine, extraversion and working memory. Research has shown that extraverts performing a working memory task benefit more from caffeine than do introverts. The present study aimed to replicate this and extend our knowledge by using a lower dose of caffeine (65 mg) and a range of tasks related to different components of working memory. In addition, tasks assessing psychomotor speed and the encoding of new information were included to determine whether caffeine-extraversion interactions were restricted to working memory tasks. A double-blind design was used, with 128 participants being randomly assigned to caffeinated or de-caffeinated coffee conditions. The results showed that caffeine interacted with extraversion in the predicted direction for serial recall and running memory tasks. Caffeine improved simple reaction time and the speed of encoding of new information, effects which were not modified by extraversion. These results suggest possible biological mechanisms underlying effects of caffeine on cognitive performance. 23880129 Effects of total ammonia nitrogen concentration on solid-state anaerobic digestion of corn stover. The inhibitive effect of total ammonia nitrogen (TAN) (including NH3 and NH4(+)) on solid-state anaerobic digestion of corn stover was investigated in batch reactors at 37°C. The highest methane yield of 107.0L/kg VSfeed was obtained at a TAN concentration of 2.5g/kg (based on total weight). TAN concentrations greater than 2.5g/kg resulted in decreased methane yields, with a 50% reduction observed at a concentration of 6.0g/kg. Reduced reaction rates and microbial activities for hydrolysis of cellulose and methanogenesis from acetate were observed at TAN concentrations higher than 4.3g/kg. Strong ammonia stress was indicated at butyrate concentrations higher than 300mg/kg. Result showed that the effluent of liquid anaerobic digestion can provide enough nitrogen for solid-state anaerobic digestion of corn stover. 23889077 Cycloxaprid insecticide: nicotinic acetylcholine receptor binding site and metabolism. Cycloxaprid (CYC) is a novel neonicotinoid prepared from the (nitromethylene)imidazole (NMI) analogue of imidacloprid. In this study we consider whether CYC is active per se or only as a proinsecticide for NMI. The IC50 values (nM) for displacing [(3)H]NMI binding are 43-49 for CYC and 2.3-3.2 for NMI in house fly and honeybee head membranes and 302 and 7.2, respectively, in mouse brain membranes, potency relationships interpreted as partial conversion of some CYC to NMI under the assay conditions. The 6-8-fold difference in toxicity of injected CYC and NMI to house flies is consistent with their relative potencies as in vivo nicotinic acetylcholine receptor (nAChR) inhibitors in brain measured with [(3)H]NMI binding assays. CYC metabolism in mice largely involves cytochrome P450 pathways without NMI as a major intermediate. Metabolites of CYC tentatively assigned are five monohydroxy derivatives and one each of dihydroxy, nitroso, and amino modifications. CYC appears be a proinsecticide, serving as a slow-release reservoir for NMI with selective activity for insect versus mammalian nAChRs. 23759948 Ectopic expression of the TERE1 (UBIAD1) protein inhibits growth of renal clear cell carcinoma cells: altered metabolic phenotype associated with reactive oxygen species, nitric oxide and SXR target genes involved in cholesterol and lipid metabolism. Current studies of the TERE1 (UBIAD1) protein emphasize its multifactorial influence on the cell, in part due to its broad sub-cellular distribution to mitochondria, endoplasmic reticulum and golgi. However, the profound effects of TERE1 relate to its prenyltransferase activity for synthesis of the bioactive quinones menaquinone and COQ10. Menaquinone (aka, vitamin K-2) serves multiple roles: as a carrier in mitochondrial electron transport, as a ligand for SXR nuclear hormone receptor activation, as a redox modulator, and as an alkylator of cellular targets. We initially described the TERE1 (UBIAD1) protein as a tumor suppressor based upon reduced expression in urological cancer specimens and the inhibition of growth of tumor cell lines/xenografts upon ectopic expression. To extend this potential tumor suppressor role for the TERE1 protein to renal cell carcinoma (RCC), we applied TERE1 immunohistochemistry to a TMA panel of 28 RCC lesions and determined that in 57% of RCC lesions, TERE1 expression was reduced (36%) or absent (21%). Ectopic TERE1 expression caused an 80% decrease in growth of Caki-1 and Caki-2 cell lines, a significantly decreased colony formation, and increased caspase 3/7 activity in a panel of RCC cell lines. Furthermore, TERE1 expression increased mitochondrial oxygen consumption and hydrogen production, oxidative stress and NO production. Based on the elevated cholesterol and altered metabolic phenotype of RCC, we also examined the effects of TERE1 and the interacting protein TBL2 on cellular cholesterol. Ectopic TERE1 or TBL2 expression in Caki-1, Caki-2 and HEK 293 cells reduced cholesterol by up to 40%. RT-PCR analysis determined that TERE1 activated several SXR targets known to regulate lipid metabolism, consistent with predictions based on its role in menaquinone synthesis. Loss of TERE1 may contribute to the altered lipid metabolic phenotype associated with progression in RCC via an uncoupling of ROS/RNS and SXR signaling from apoptosis by elevation of cholesterol. 23727224 Treatment of uterine arteriovenous malformation by myometrial lesion resection combined with artery occlusion under laparoscopy: a case report and literature review. Uterine arteriovenous malformation (AVM) is an uncommon, potentially life-threatening condition, and the primary therapeutic method is embolization. We describe a case of a 36-year-old woman with acquired uterine AVM accompanied by abnormal vaginal bleeding. The diagnosis was established by Doppler flow ultrasonography combined with magnetic resonance arteriography. Because this uterine AVM was extensive and multiple, uterine arterial embolization could not be considered. We therefore employed a combined method under laparoscopy, in which the uterine arteries were first occluded, then uterine myometrial lesions were resected and abnormal pelvic blood vessels were ablated. Finally, the uterus was reconstructed with an intact uterine cavity. Abnormal vaginal bleeding was successfully stopped after operation, but amenorrhea due to uterine adhesions occurred. This method is suitable for the treatment of uterine AVM with extensive and multiple lesions, but it should be chosen cautiously for women of reproductive age with AVM and fertility requirement. 23209193 Application of hybrid approach based on empirical and physiological concept for predicting pharmacokinetics in humans--usefulness of exponent on prospective evaluation of predictability. We developed a hybrid method for predicting plasma concentration-time curves in humans by integrating species differences in in vitro intrinsic clearance (CL(int)) into the Dedrick approach based on the allometry concept. With prediction of clearance (CL) by allometric scaling, taking in vitro CL(int) into consideration improved the accuracy and reduced the average fold error from 2.72 to 1.99. With the hybrid approach of applying the same concept to the Dedrick approach, the predictability of plasma concentration profiles was compared with the results of the conventional Dedrick approach and the physiologically based pharmacokinetic model using 15 compounds with widely ranging physicochemical and pharmacokinetic profiles. The hybrid approach showed the highest predictability among the examined methods. For CL and the apparent volume of distribution at the steady state (V(ss)), the relationship between the exponent of allometric equation and fold error was also evaluated with the hybrid approach. The relationship appeared to be a horseshoe curve. Six compounds with exponents ranging from 0.7 to 1.1 for both CL and V(ss) [antipyrine, caffeine, epiroprim, propafenone, theophylline, and verapamil] displayed higher predictability. Three compounds with an exponent ranging from 0.7 to 1.1 for CL showed better predictability for CL, and the other four compounds appeared to display similar relationship between the exponent and predictability for V(ss). These findings indicated that the exponent becomes a preliminary index to speculate on predictability. Combination of the hybrid approach and exponent allows us to prospectively draw human plasma concentration-time curves, with the implication of possible prediction accuracy prior to clinical studies. 23534692 Atomically precise gold nanoclusters as new model catalysts. Many industrial catalysts involve nanoscale metal particles (typically 1-100 nm), and understanding their behavior at the molecular level is a major goal in heterogeneous catalyst research. However, conventional nanocatalysts have a nonuniform particle size distribution, while catalytic activity of nanoparticles is size dependent. This makes it difficult to relate the observed catalytic performance, which represents the average of all particle sizes, to the structure and intrinsic properties of individual catalyst particles. To overcome this obstacle, catalysts with well-defined particle size are highly desirable. In recent years, researchers have made remarkable advances in solution-phase synthesis of atomically precise nanoclusters, notably thiolate-protected gold nanoclusters. Such nanoclusters are composed of a precise number of metal atoms (n) and of ligands (m), denoted as Aun(SR)m, with n ranging up to a few hundred atoms (equivalent size up to 2-3 nm). These protected nanoclusters are well-defined to the atomic level (i.e., to the point of molecular purity), rather than defined based on size as in conventional nanoparticle synthesis. The Aun(SR)m nanoclusters are particularly robust under ambient or thermal conditions (<200 °C). In this Account, we introduce Aun(SR)m nanoclusters as a new, promising class of model catalyst. Research on the catalytic application of Aun(SR)m nanoclusters is still in its infancy, but we use Au25(SR)18 as an example to illustrate the promising catalytic properties of Aun(SR)m nanoclusters. Compared with conventional metallic nanoparticle catalysts, Aun(SR)m nanoclusters possess several distinct features. First of all, while gold nanoparticles typically adopt a face-centered cubic (fcc) structure, Aun(SR)m nanoclusters (<2 nm) tend to adopt different atom-packing structures; for example, Au25(SR)18 (1 nm metal core, Au atomic center to center distance) has an icosahedral structure. Secondly, their ultrasmall size induces strong electron energy quantization, as opposed to the continuous conduction band in metallic gold nanoparticles or bulk gold. Thus, nanoclusters become semiconductors and possess a sizable bandgap (e.g., ∼1.3 eV for Au25(SR)18). In addition, Aun(SR)m can be doped with a single atom of other metals, which is of great interest for catalysis, because the catalytic properties of nanoclusters can be truly tuned on an atom-by-atom basis. Overall, atomically precise Aun(SR)m nanoclusters are expected to become a promising class of model catalysts. These well-defined nanoclusters will provide new opportunities for achieving fundamental understanding of metal nanocatalysis, such as insight into size dependence and deep understanding of molecular activation, active centers, and catalytic mechanisms through correlation of behavior with the structures of nanoclusters. Future research on atomically precise nanocluster catalysts will contribute to the fundamental understanding of catalysis and to the new design of highly selective catalysts for specific chemical processes. 23160820 RBCK1, an E3 ubiquitin ligase, interacts with and ubiquinates the human pregnane X receptor. The pregnane X receptor (PXR, NR1I2) plays a pivotal role in the disposition and detoxification of numerous foreign and endogenous chemicals by increasing transcription of numerous target genes, including phase I and II drug-metabolizing enzymes and transporters. In the present study, yeast two-hybrid screening identified an E3 ubiquitin ligase, RBCK1 (Ring-B-box-coiled-coil protein interacting with protein kinase C-1), as a human pregnane X receptor (hPXR)-interacting protein. Coimmunoprecipitation studies confirmed the interaction between RBCK1 and hPXR when both were ectopically expressed in AD-293 cells. Domain mapping studies showed that the interaction between RBCK1 and hPXR involves all RBCK1 domains. We further demonstrate that RBCK1 ubiquitinates hPXR, and this may target hPXR for degradation by the ubiquitin-proteasome pathway. Simultaneous ectopic overexpression of RBCK1 and PXR decreased PXR levels in AD-293 cells, and this decrease was inhibited by the proteasomal inhibitor MG-132 (carbobenzoxy-Leu-Leu-leucinal). Furthermore, overexpression of RBCK1 decreased endogenous levels of PXR in HepG2 cells. Of importance, ectopic overexpression and silencing of endogenous RBCK1 in primary human hepatocytes resulted in a decrease and increase, respectively, in endogenous PXR protein levels and in the induction of PXR target genes by rifampicin. These results suggest that RBCK1 is important for the ubiquitination of PXR and may play a role in its proteasomal degradation. 23903153 4.8 Î¼m difference-frequency generation using a waveguide-PPLN crystal and its application to mid-infrared Lamb-dip spectroscopy. Difference-frequency generation of 4.8 Î¼m mid-infrared light was performed using a waveguide periodically poled LiNbO3 (PPLN) crystal. 871 and 1064 nm external-cavity diode lasers followed by tapered amplifiers were used as pump sources. A conversion efficiency of ∼2%/W with the output power of 2 mW was achieved even under considerable absorption of the crystal at this wavelength. Lamb-dip spectroscopy of carbonyl sulfide was demonstrated showing the satisfactory performance of this device for saturation spectroscopy. The observed dip width shows that the laser linewidth is ∼2  MHz, which corresponds to those of the pump lasers. 23412395 Rutin ameliorates free radical mediated cataract by enhancing the chaperone activity of α-crystallin. Cataract, the leading cause of blindness, is associated with oxidative damage and protein modification in the lens. The present study was carried out to assess the efficacy of rutin on rat-lens crystallins in selenite-induced in-vivo cataract models. Eight-day-old Sprague-Dawley rat pups were grouped as control (G I), experimental (G II) and rutin-treated (G III). The rat pups in G II, and G III received a single subcutaneous injection of sodium selenite (4 Î¼g/g body weight) and G I received a single subcutaneous injection of sterile water on the 10th day. The treatment groups (G III) were administered with rutin (1 Î¼g/g body weight) respectively from the 8th to 15th day. Cataract was visualized from the 16th day. Lens crystallins (α, β, and γ) were isolated by size exclusion chromatography. Chaperone activity of isolated crystallins was measured by heat, DTT, and oxidation-induced aggregation and refolding assays. Concentration of total protein (soluble and insoluble) and SDS-PAGE analysis of soluble proteins were also done. Treatment with rutin prevented the loss of α crystallin chaperone property, and protein insolubilization prevailed during selenite-induced cataract. These results suggest the therapeutic potential of rutin, a bioflavonoid, against selenite-induced cataract, which has been reported in this paper for the first time. The work assumes significance, as this is a novel approach in modulating the chaperone activity of lens crystallins in selenite-induced cataract by a natural product. 23731233 Do measures commonly used in body image research perform adequately with African American college women? This study examines reliability and validity estimates for 3 widely used measures in body image research in a sample of African American college women (N = 278). Internal consistency estimates were adequate (α coefficients above .70) for all measures, and evidence of convergent and discriminant validity was found. Confirmatory factor analyses failed to replicate the hypothesized factor structures of these measures. Exploratory factor analyses indicated that 4 factors found for the Sociocultural Attitudes Toward Appearance Questionnaire were similar to the hypothesized subscales, with fewer items. The factors found for the Multidimensional Body-Self Relations Questionnaire-Appearance Scales and the Body Dissatisfaction subscale of the Eating Disorders Inventory-3 were not similar to the subscales developed by the scale authors. Validity and reliability evidence is discussed for the new factors. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23860797 Plant biotechnology for food security and bioeconomy. This year is a special year for plant biotechnology. It was 30 years ago, on January 18 1983, one of the most important dates in the history of plant biotechnology, that three independent groups described Agrobacterium tumefaciens-mediated genetic transformation at the Miami Winter Symposium, leading to the production of normal, fertile transgenic plants (Bevan et al. in Nature 304:184-187, 1983; Fraley et al. in Proc Natl Acad Sci USA 80:4803-4807, 1983; Herrera-Estrella et al. in EMBO J 2:987-995, 1983; Vasil in Plant Cell Rep 27:1432-1440, 2008). Since then, plant biotechnology has rapidly advanced into a useful and valuable tool and has made a significant impact on crop production, development of a biotech industry and the bio-based economy worldwide. 23942327 Current considerations in the management of facial nerve palsy. Facial nerve palsy is a potentially devastating condition that can arise from many different causes. Appropriate management is complicated by the wide spectrum of clinical presentation and disease severity that characterizes this condition. As such, recent studies have focused on augmenting our understanding of the underlying anatomy and pathophysiology of facial nerve palsy, while also exploring different treatment options. There have been a multitude of radiologic investigations that have delineated anatomical considerations pertinent to facial neuropathy, whereas various grading schemes and software programs have been developed to facilitate the clinical assessment of patients. Furthermore, a wide variety of medical and surgical treatment options have been proposed - whereas some are variants of previously described methods, others represent novel approaches. Appropriate management of facial nerve palsy is dependent on a multitude of factors and must be tailored to patients on an individual basis. The studies summarized in this article highlight the recent advancements geared toward refining the assessment and treatment of patients with facial neuropathy. 23962606 Disability as a risk factor? Development of psychopathology in children with disabilities. Empirical research has established that children with disabilities are more likely to develop psychopathology than children without disabilities. But too little is known about the association between disability and psychopathology. The aim of this article is to discuss developmental psychopathological models that conceptualise the connection between childhood disability and psychopathology. Empirical studies of psychopathology among children with a congenital hearing impairment and children with cerebral palsy will be reviewed, representing in-depth examples of association between disability and psychopathology. Both a congenital hearing impairment and cerebral palsy were found to be dominating risk factors for all types of psychopathology, but no relationship was identified between degree of disability and risk of psychopathology. The higher risk cannot be explained by biological impairments alone. To explain the contradictory findings, developmental models of disability and psychopathology are applied. Within a multi-factorial developmental psychopathological perspective and a dialectical model of disability (Vygotsky, 1993), it is suggested that disability can be understood as an incongruence between the individual development of the child and demands and expectations in the specific relations and institutions in which the child participates. This incongruence creates and strengthens negative factors for the child with disability and results in a higher risk of psychopathology. 23111930 MAOA and MAOB polymorphisms and anger-related traits in suicidal participants and controls. MAOA and, to a lesser extent, MAOB polymorphisms have been related to aggression traits and suicidality. We aimed to investigate the role of MAOA and MAOB in suicidal versus non-suicidal participants and interactions between genetic variation and suicidal status on aggression and anger-related traits. The sample was composed of three groups: one group of suicide attempters (n = 171, males 35.1 %), one group of suicide completers (n = 90, males 57.8 %) and a healthy control group (n = 317, males 43.8 %). We examined the following markers: MAOA rs909525, rs6323, and rs2064070, and MAOB rs1799836. Anger traits were measured with the state-trait anger expression inventory (STAXI) and aggression traits with the questionnaire for measuring factors of aggression (FAF). Associations were separately examined for males and females. Variation in the three MAOA variants was associated with higher levels of anger expressed outwards (STAXI "anger-out" subscale) in male suicidal patients compared to controls (p < 0.001). In females, the C allele of rs6323 showed higher scores on the same subscale ("anger out") (p = 0.002). Allele frequencies of the MAOA rs909525 were associated with suicidality (p < 0.007). Our findings show an association between genetic variation in three polymorphisms of the MAOA and anger traits in suicidal males and one replication for the functional variant rs6323 in females. This relationship was stronger than a direct genetic association with suicide status. Future studies incorporating endophenotypic measures of anger and aggression in suicidal participants are warranted. 23464759 Slip length measurement of confined air flow on three smooth surfaces. An experimental measurement of the slip length of air flow close to three different solid surfaces is presented. The substrate was driven by a nanopositioner moving toward an oscillating glass sphere glued to an atomic force microscopy (AFM) cantilever. A large separation distance was used to get more effective data. The slip length value was obtained by analyzing the amplitude and phase data of the cantilever. The measurements show that the slip length does not depend on the oscillation amplitude of the cantilever. Because of the small difference among the slip lengths of the three surfaces, a simplified analysis method was used. The results show that on glass, graphite, and mica surfaces the slip lengths are 98, 234, and 110 nm, respectively. 23716050 Theaflavin-3,3'-digallate and lactic Acid combinations reduce herpes simplex virus infectivity. The present study examined the efficacy of using multiple mechanisms as part of a topical microbicide to inactivate herpes simplex virus (HSV) by combining theaflavin-3,3'-digallate (TF-3) and lactic acid (LA) over the pH range of 4.0 to 5.7 to mimic conditions in the female reproductive tract. Six clinical isolates of HSV-2 and two clinical isolates of HSV-1 were almost completely inactivated when TF-3 (100 μM) was present with LA over the pH range of 4.5 to 5.7, whereas four additional HSV-1 clinical isolates required TF-3 concentrations of 250 to 500 μM for comparable virus titer reduction. LA (1%) alone at pH 4.0 reduced the titers of laboratory and clinical isolates of HSV-1 and HSV-2 by ≥5 log10, but most LA-dependent antiviral activity was lost at a pH of ≥4.5. When HSV-1 and HSV-2 were incubated at pH 4.0 without LA virus titers were not reduced. At pH 4.0, HSV-1 and HSV-2 titers were reduced 5 log10 in 20 min by LA alone. TF-3 reduced HSV-2 titers by 5 log10 in 20 to 30 min at pH 4.5, whereas HSV-1 required 60 min for comparable inactivation. Mixtures of TF-3 and LA stored at 37°C for 1 month at pH 4.0 to 5.7 maintained antiviral activity. Semen, but not cervical vaginal fluid, decreased LA-dependent antiviral activity at pH 4.0, but adding TF-3 to the mixture reduced HSV titers by 4 to 5 log10. These results indicate that a combination microbicide containing TF-3 and LA could reduce HSV transmission. 23410885 The effects of vitamin D(3) supplementation on serum total 25[OH]D concentration and physical performance: a randomised dose-response study. Vitamin D deficiency is common in the general public and athletic populations and may impair skeletal muscle function. We therefore assessed the effects of vitamin D3 supplementation on serum 25[OH]D concentrations and physical performance. 30 club-level athletes were block randomised (using baseline 25[OH]D concentrations) into one of three groups receiving either a placebo (PLB), 20 000 or 40 000 IU/week oral vitamin D3 for 12 weeks. Serum 25[OH]D and muscle function (1-RM bench press and leg press and vertical jump height) were measured presupplementation, 6 and 12 weeks postsupplementation. Vitamin D deficiency was defined in accordance with the US Institute of Medicine guideline (<50 nmol/l). 57% of the subject population were vitamin D deficient at baseline (mean±SD value 51±24 nmol/l). Following 6 and 12 weeks supplementation with 20 000 IU (79±14 and 85±10 nmol/l, respectively) or 40 000 IU vitamin D3 (98±14 and 91±24 nmol/l, respectively), serum vitamin D concentrations increased in all participants, with every individual achieving concentrations greater than 50 nmol/l. In contrast, vitamin D concentration in the PLB group decreased at 6 and 12 weeks (37±18 and 41±22 nmol/l, respectively). Increasing serum 25[OH]D had no significant effect on any physical performance parameter (p>0.05). Both 20 000 and 40 000 IU vitamin D3 supplementation over a 6-week period elevates serum 25[OH]D concentrations above 50 nmol/l, but neither dose given for 12 weeks improved our chosen measures of physical performance. 23913690 Agonist-Biased Trafficking of the Somatostatin Receptor 2A in Enteric Neurons. Somatostatin-14 (SST) and SST-28 activate somatostatin2A receptors (SSTR2A) on enteric neurons to control gut functions. SST analogs are treatments of neuroendocrine and bleeding disorders, cancer and diarrhea, with gastrointestinal side-effects of constipation, abdominal pain and nausea. How endogenous agonists and drugs differentially regulate neuronal SSTR2A is unexplored. We evaluated SSTR2A trafficking in murine myenteric neurons and neuroendocrine AtT-20 cells by microscopy, and determined whether agonist degradation by endosomal endothelin-converting enzyme-1 (ECE-1) controls SSTR2A trafficking and association with β-arrestins, key regulators of receptors. SST-14, SST-28 and peptide analogs (octreotide, lanreotide, vapreotide) stimulated clathrin- and dynamin-mediated internalization of SSTR2A, which colocalized with ECE-1 in endosomes and the Golgi. After incubation with SST-14, SSTR2A recycled to the plasma membrane, which required active ECE-1 and an intact Golgi. SSTR2A activated by SST-28, octreotide, lanreotide or vapreotide was retained within the Golgi and did not recycle. Whereas ECE-1 rapidly degraded SST-14, SST-28 was resistant to degradation, and ECE-1 did not degrade SST analogs. SST-14 and SST-28 induced transient interactions between SSTR2A and β-arrestins, which were stabilized by an ECE-1 inhibitor. Octreotide induced sustained SSTR2A/β-arrestin interactions that were not regulated by ECE-1. Thus, when activated by SST-14, SSTR2A internalizes and recycles via the Golgi, which requires ECE-1 degradation of SST-14 and receptor dissociation from β-arrestins. After activation by ECE-1-resistant SST-28 and analogs, SSTR2A remains in endosomes due to sustained β-arrestin interactions. Therapeutic SST analogs are ECE-1 resistant and retain SSTR2A in endosomes, which may explain their long-lasting actions. 23843971 Movements and Habitat-Use of Loggerhead Sea Turtles in the Northern Gulf of Mexico during the Reproductive Period. Nesting strategies and use of important in-water habitats for far-ranging marine turtles can be determined using satellite telemetry. Because of a lack of information on habitat-use by marine turtles in the northern Gulf of Mexico, we used satellite transmitters in 2010 through 2012 to track movements of 39 adult female breeding loggerhead turtles (Caretta caretta) tagged on nesting beaches at three sites in Florida and Alabama. During the nesting season, recaptured turtles emerged to nest 1 to 5 times, with mean distance between emergences of 27.5 km; however, several turtles nested on beaches separated by ∼250 km within a single season. Mean total distances traveled throughout inter-nesting periods for all turtles was 1422.0±930.8 km. In-water inter-nesting sites, delineated using 50% kernel density estimation (KDE), were located a mean distance of 33.0 km from land, in water with mean depth of -31.6 m; other in-water inter-nesting sites, delineated using minimum convex polygon (MCP) approach, were located a mean 13.8 km from land and in water with a mean depth of -15.8 m. Mean size of in-water inter-nesting habitats were 61.9 km(2) (50% KDEs, n = 10) and 741.4 km(2) (MCPs, n = 30); these areas overlapped significantly with trawling and oil and gas extraction activities. Abundance estimates for this nesting subpopulation may be inaccurate in light of how much spread there is between nests of the same individual. Further, our results also have consequences for critical habitat designations for northern Gulf loggerheads, as protection of one nesting beach would not encompass the entire range used by turtles during breeding seasons. 23892941 The HEART Score for the Assessment of Patients With Chest Pain in the Emergency Department: A Multinational Validation Study. The HEART score for the early risk stratification of patients presenting to the emergency department with chest pain contains 5 elements: history, electrocardiogram, age, risk factors, and troponin. It has been validated in The Netherlands. The purpose of this investigation was to perform an external validation of the HEART score in an Asia-Pacific population. Data were used from 2906 patients presenting with chest pain to the emergency departments of 14 hospitals. HEART scores were determined retrospectively. Three risk groups were composed based on previous research. The predictive values for the occurrence of 30-day major adverse coronary events (MACE) were assessed. A comparison was made with the Thrombolysis in Myocardial Infarction (TIMI) score in terms of the value of C-statistics. The low-risk group, HEART score ≤3, consisted of 820/2906 patients (28.2%). Fourteen (1.7%) patients were incorrectly defined as low risk (false negatives). The high-risk population, HEART score 7-10, consisted of 464 patients (16%) with a risk of MACE of 43.1%. The C-statistics were 0.83 (0.81-0.85) for HEART and 0.75 (0.72-0.77) for TIMI (P < 0.01). Utilization of the HEART score provided excellent determination of risk for 30-day MACE, comparing well with the Thrombolysis in Myocardial Infarction score. This study externally validates previous findings that HEART is a powerful clinical tool in this setting. It quickly identifies both a large proportion of low-risk patients, in whom early discharge without additional testing goes with a risk of MACE of only 1.7%, and high-risk patients who are potential candidates for early invasive strategies. 23810391 Efficient myogenic differentiation of human adipose-derived stem cells by the transduction of engineered MyoD protein. Human adipose-derived stem cells (hASCs) have great potential as cell sources for the treatment of muscle disorders. To provide a safe method for the myogenic differentiation of hASCs, we engineered the MyoD protein, a key transcription factor for myogenesis. The engineered MyoD (MyoD-IT) was designed to contain the TAT protein transduction domain for cell penetration and the membrane-disrupting INF7 peptide, which is an improved version of the HA2 peptide derived from influenza. MyoD-IT showed greatly improved nuclear targeting ability through an efficient endosomal escape induced by the pH-sensitive membrane disruption of the INF7 peptide. By applying MyoD-IT to a culture, hASCs were efficiently differentiated into long spindle-shaped myogenic cells expressing myosin heavy chains. Moreover, these cells differentiated by an application of MyoD-IT fused to myotubes with high efficiency through co-culturing with mouse C2C12 myoblasts. Because internalized proteins can be degraded in cells without altering the genome, the myogenic differentiation of hASCs using MyoD-IT would be a safe and clinically applicable method. 23792640 Exposure to estrogen and ionizing radiation causes epigenetic dysregulation, activation of mitogen-activated protein kinase pathways, and genome instability in the mammary gland of ACI rats. The impact of environmental mutagens and carcinogens on the mammary gland has recently received a lot of attention. Among the most generally accepted carcinogenic agents identified as factors that may increase breast cancer incidence are ionizing radiation and elevated estrogen levels. However, the molecular mechanisms of mammary gland aberrations associated with radiation and estrogen exposure still need to be further elucidated, especially the interplay between elevated hormone levels and radiation. Therefore, in the present study, we investigated molecular changes induced in rat mammary gland tissue by estrogen, ionizing radiation, and the combined action of these two carcinogens using a well-established ACI rat model. We found that continuous exposure of intact female ACI rats to elevated levels of estrogen or to both estrogen and radiation resulted in significant hyperproliferative changes in rat mammary glands. In contrast, radiation exposure alone did not induce hyperplasia. Interestingly, despite the obvious disparity in mammary gland morphology, we did not detect significant differences in the levels of genomic methylation among animals exposed to estrogen, radiation, or both agents together. Specifically, we observed a significant global genomic hypomethylation at 6 weeks of exposure. However, by 12 and 18 weeks, the levels of global DNA methylation returned to those of age-matched controls. We also found that combined exposure to radiation and estrogen significantly altered the levels of histone H3 and H4 methylation and acetylation. Most importantly, we for the first time demonstrated that estrogen and radiation exposure caused a significant induction of p42/44 MAPK and p38 pathways that was paralleled by elevated levels of H3S10 phosphorylation, a well-established biomarker of genome and chromosome instability. The precise role of MAPK pathways and their inter-relationship with H3S10 phosphorylation and genome instability in mammary gland tissues needs to be explored further. 23874826 Spaceflight Influences both Mucosal and Peripheral Cytokine Production in PTN-Tg and Wild Type Mice. Spaceflight is associated with several health issues including diminished immune efficiency. Effects of long-term spaceflight on selected immune parameters of wild type (Wt) and transgenic mice over-expressing pleiotrophin under the human bone-specific osteocalcin promoter (PTN-Tg) were examined using the novel Mouse Drawer System (MDS) aboard the International Space Station (ISS) over a 91 day period. Effects of this long duration flight on PTN-Tg and Wt mice were determined in comparison to ground controls and vivarium-housed PTN-Tg and Wt mice. Levels of interleukin-2 (IL-2) and transforming growth factor-beta1 (TGF-β1) were measured in mucosal and systemic tissues of Wt and PTN-Tg mice. Colonic contents were also analyzed to assess potential effects on the gut microbiota, although no firm conclusions could be made due to constraints imposed by the MDS payload and the time of sampling. Spaceflight-associated differences were observed in colonic tissue and systemic lymph node levels of IL-2 and TGF-β1 relative to ground controls. Total colonic TGF-β1 levels were lower in Wt and PTN-Tg flight mice in comparison to ground controls. The Wt flight mouse had lower levels of IL-2 and TGF-β1 compared to the Wt ground control in both the inguinal and brachial lymph nodes, however this pattern was not consistently observed in PTN-Tg mice. Vivarium-housed Wt controls had higher levels of active TGF-β1 and IL-2 in inguinal lymph nodes relative to PTN-Tg mice. The results of this study suggest compartmentalized effects of spaceflight and on immune parameters in mice. 23689430 Vandetanib Plus Chemotherapy for Induction Followed by Vandetanib or Placebo As Maintenance for Patients with Advanced Non-Small-Cell Lung Cancer: A Randomized Phase 2 PrECOG Study (PrE0501). After early reports of vandetanib's efficacy in the induction setting, we evaluated the effect of combination docetaxel, carboplatin, and vandetanib, followed by maintenance therapy with either vandetanib, or placebo on progression-free survival (PFS) in patients with advanced non-small-cell lung cancer. Patients with advanced non-small-cell lung cancer were randomized to induction docetaxel (75 mg/m) + carboplatin (area under the curve of 6) on day 1 of a 21-day cycle, and daily vandetanib (100 mg/day orally) for four cycles, followed by daily vandetanib (300 mg/day orally) or placebo until progression. Eligible patients had measurable disease, Eastern Cooperative Oncology Group performance status 0 of 1, and no prior cytotoxic or targeted agents for advanced disease. One hundred sixty-two patients were randomized; 158 began induction treatment. Fifty-eight patients began maintenance vandetanib or placebo (median, 3.5 cycles). Median PFS for patients randomized to maintenance vandetanib was 4.5 months (95% confidence interval, 3.3-5.8 months), and for patients randomized to maintenance placebo was 4.2 months (95% confidence interval, 2.8-4.9 months). An exploratory analysis showed prolonged PFS for patients randomized to vandetanib maintenance (stratified log-rank p= 0.07) as also in a multivariate model adjusting for sex and stage (p= 0.02). Differences in PFS were not observed among patients who began maintenance therapy. Toxicities were similar to other studies of these agents. Neither arm showed improvement over historical median PFS of 4.6 months, although patients who began maintenance and were randomized to vandetanib had somewhat better outcomes than those randomized to placebo. Given its acceptable toxicity profile, there may be a role for vandetanib in maintenance. 23685640 Sodium bicarbonate infusion to reduce cardiac surgery-associated acute kidney injury: a phase II multicenter double-blind randomized controlled trial. Cardiac surgery-associated acute kidney injury occurs in up to 50% of patients and is associated with increased mortality and morbidity. This study aimed to discover if perioperative urinary alkalinization with sodium bicarbonate infusion reduces the prevalence of cardiac surgery-associated acute kidney injury. This study was a phase IIb multicenter double-blind randomized controlled trial. This study was conducted in three tertiary hospitals in New Zealand and Australia. A total of 427 patients scheduled to undergo elective cardiac surgery, who were at increased risk of development of cardiac surgery-associated acute kidney injury using recognized risk factors. Patients were randomly allocated to receive either sodium bicarbonate (n = 215) or sodium chloride (n = 212) infusion, commencing at the start of anesthesia, in a dose of 0.5 mEq/kg/hr for the first hour and then 0.2 mmol/kg/hr for 23 hours. The primary outcome measure was the number of patients with development of cardiac surgery-associated acute kidney injury, defined as an increase in creatinine greater than 25% or 0.5 mg/dL (44 µmol/L) from baseline to peak value within the first five postoperative days. Significant differences among the groups in both plasma and urinary biochemistry were achieved 6 hours after commencement of the infusion, and these changes persisted for more than 24 hours. A total of 100 out of 215 patients (47% [95% CI, 40%-53%]) in the sodium bicarbonate group and 93 of 212 patients (44% [95% CI, 37%-51%]) in the sodium chloride group with development of acute kidney injury within the first five postoperative days (p = 0.58). There were also no significant differences in ventilation hours, ICU or hospital length of stay, or mortality. Perioperative alkalinization of blood and urine using an infusion of sodium bicarbonate did not result in a decrease in the prevalence of acute kidney injury in patients following cardiac surgery. 23631538 Non-destructive monitoring of creaming of oil-in-water emulsion-based formulations using magnetic resonance imaging. Abstract A non-destructive method for monitoring creaming of emulsion-based formulations is in great demand because it allows us to understand fully their instability mechanisms. This study was aimed at demonstrating the usefulness of magnetic resonance (MR) techniques, including MR imaging (MRI) and MR spectroscopy (MRS), for evaluating the physicochemical stability of emulsion-based formulations. Emulsions that are applicable as the base of practical skin creams were used as test samples. Substantial creaming was developed by centrifugation, which was then monitored by MRI. The creaming oil droplet layer and aqueous phase were clearly distinguished by quantitative MRI by measuring T1 and the apparent diffusion coefficient. Components in a selected volume in the emulsions could be analyzed using MRS. Then, model emulsions having different hydrophilic-lipophilic balance (HLB) values were tested, and the optimal HLB value for a stable dispersion was determined. In addition, the MRI examination enables the detection of creaming occurring in a polyethylene tube, which is commonly used for commercial products, without losing any image quality. These findings strongly indicate that MR techniques are powerful tools to evaluate the physicochemical stability of emulsion-based formulations. This study will make a great contribution to the development and quality control of emulsion-based formulations. 23851311 Phosphoproteome of Cryptococcus neoformans. Cryptococcus neoformans is an encapsulated pathogenic yeast, which causes life threatening meningitis in immunocompromised individuals. C. neoformans var. grubii is the most prevalent and virulent form among the two varieties of C. neoformans - C. neoformans var. grubii and C. neoformans var. neoformans. The virulence of C. neoformans is mainly conferred by its capsule and melanin. cAMP dependent PKA-induced phosphorylation events are reported to be associated with the expression of these virulence traits, which highlights the importance of phosphoproteins in virulence and infection. Therefore, we performed global profiling of phosphoproteome of C. neoformans to enable a better understanding of molecular regulation of its virulence and pathogenesis. High resolution mass spectrometry of TiO2 enriched phosphopeptides from C. neoformans var. grubii grown in culture led to the identification of 1089 phosphopeptides derived from 648 proteins including about 45 kinases. Motif enrichment analysis revealed that most CDK family substrates were found to be phosphorylated. This indicates that cyclin-dependent kinases were among the active kinases in the pathogen in culture. These studies provide a framework for understanding virulence mechanisms in the context of signalling pathways in pathogenic yeast. This article is part of a Special Issue entitled: Trends in Microbial Proteomics. C. neoformans is a pathogenic yeast responsible for cryptococcal meningitis. Melanin and polysaccharide capsule have been established as some of the key virulence factors that play a major role in the pathogenesis of C. neoformans. Recent studies have shown the role of kinase mediated signalling pathways in governing biosynthesis of these virulence factors. This study revealed 1540 phosphorylation sites in 648 proteins providing a comprehensive view of phosphoproteins in C. neoformans. This should serve as a useful resource to explore activated signalling pathways in C. neoformans and their association with its virulence and pathogenesis. 23912590 Vapour processed self-rolled poly(dimethylsiloxane) microcapillaries form microfluidic devices with engineered inner surface. We propose a microfluidics device whose main functional part consists of a microcapillary produced by the self-rolling of a thin poly(dimethylsiloxane) film. Rolling is caused by inhomogeneous swelling of the film, pre-treated by oxygen plasma, in the vapour of chloroform. The capillaries are integrated with external electrical circuits by co-rolling electrodes and micro-resistors. The local control of temperature in the tubes by Joule heating is illustrated via the rate of an intra-tubular chemiluminescent reaction. The novel tubes with engineered inner structure can find numerous advanced applications such as functional elements of integrated microfluidics circuits. 23969052 Complete Genome Sequence of a Very Virulent Porcine Epidemic Diarrhea Virus Strain, CH/GDGZ/2012, Isolated in Southern China. The classical symptoms of porcine epidemic diarrhea (PED) are acute diarrhea and dehydration. The isolated porcine epidemic diarrhea virus (PEDV) CH/GDGZ/2012 strain was obtained from the feces of diseased pigs in 2012 in southern China. We report the complete genome sequence of strain CH/GDGZ/2012, which might be useful for better understanding the molecular characteristics of this virus. 23831598 Neuron-to-Neuron Transmission of Neurodegenerative Pathology. One of the hallmarks of neurodegenerative dementia diseases is the progressive loss of mental functions and the ability to manage activities of daily life. This progression is caused by the spread of the disease to more and more brain areas via anatomical connections. The pathophysiological process responsible for this spread of disease has long been sought after. There has been an increased understanding that the driving force of these neurodegenerative diseases could be the small, soluble intraneuronal accumulations of neurodegenerative proteins rather than the large, extracellular accumulations. Recently we have shown that the mechanism of spread of Alzheimer's disease most likely depends on the neuron-to-neuron spread of such soluble intraneuronal accumulations of β-amyloid through neuritic connections. Similar transmissions have been shown for several other neurodegenerative proteins but little is known about the cellular mechanisms and about any potential strategies that might stop this spread. Resolving these questions requires good cellular models. We have established a unique model of synaptic transmission between human neuronal-like cells, something that has previously been difficult to target. This opens the possibility of developing potential inhibitors of progression of these devastating diseases. 23954948 Full screening and accurate subtyping of HLA-A*02 alleles through group-specific amplification and mono-allelic sequencing. HLA-A*02 is the most prevalent and polymorphic major histocompatibility complex (MHC) allele family in humans. Functional differences have been revealed among subtypes, demanding further subtyping of HLA-A*02 in basic and clinical settings. However, the fast growing polymorphisms render traditional primer- or probe-based typing methods impractical and result in increasing ambiguities in direct sequence-based typing. In this study, we combined group-specific amplification and mono-allelic sequencing to design and validate a simple scheme for the complete screening and accurate subtyping of all 540 reported HLA-A*02 alleles. This scheme could be performed in routine labs to facilitate studies with an interest in HLA-A*02.Cellular & Molecular Immunology advance online publication, 19 August 2013; doi:10.1038/cmi.2013.33. 23857381 Differential epigenome-wide DNA methylation patterns in childhood obesity-associated asthma. While DNA methylation plays a role in T-helper (Th) cell maturation, its potential dysregulation in the non-atopic Th1-polarized systemic inflammation observed in obesity-associated asthma is unknown. We studied DNA methylation epigenome-wide in peripheral blood mononuclear cells (PBMCs) from 8 obese asthmatic pre-adolescent children and compared it to methylation in PBMCs from 8 children with asthma alone, obesity alone and healthy controls. Differentially methylated loci implicated certain biologically relevant molecules and pathways. PBMCs from obese asthmatic children had distinctive DNA methylation patterns, with decreased promoter methylation of CCL5, IL2RA and TBX21, genes encoding proteins linked with Th1 polarization, and increased promoter methylation of FCER2, a low-affinity receptor for IgE, and of TGFB1, inhibitor of Th cell activation. T-cell signaling and macrophage activation were the two primary pathways that were selectively hypomethylated in obese asthmatics. These findings suggest that dysregulated DNA methylation is associated with non-atopic inflammation observed in pediatric obesity-associated asthma. 23899625 Impulse control disorders in Parkinson's disease: decreased striatal dopamine transporter levels. Impulse control disorders are commonly associated with dopaminergic therapy in Parkinson's disease (PD). PD patients with impulse control disorders demonstrate enhanced dopamine release to conditioned cues and a gambling task on [(11)C]raclopride positron emission tomography (PET) imaging and enhanced ventral striatal activity to reward on functional MRI. We compared PD patients with impulse control disorders and age-matched and gender-matched controls without impulse control disorders using [(123)I]FP-CIT (2β-carbomethoxy-3β-(4-iodophenyl)tropane) single photon emission computed tomography (SPECT), to assess striatal dopamine transporter (DAT) density. The [(123)I]FP-CIT binding data in the striatum were compared between 15 PD patients with and 15 without impulse control disorders using independent t tests. Those with impulse control disorders showed significantly lower DAT binding in the right striatum with a trend in the left (right: F(1,24)=5.93, p=0.02; left: F(1,24)=3.75, p=0.07) compared to controls. Our findings suggest that greater dopaminergic striatal activity in PD patients with impulse control disorders may be partly related to decreased uptake and clearance of dopamine from the synaptic cleft. Whether these findings are related to state or trait effects is not known. These findings dovetail with reports of lower DAT levels secondary to the effects of methamphetamine and alcohol. Although any regulation of DAT by antiparkinsonian medication appears to be modest, PD patients with impulse control disorders may be differentially sensitive to regulatory mechanisms of DAT expression by dopaminergic medications. 23893079 The oxygenase CAO-1 of Neurospora is a resveratrol cleavage enzyme. The genome of the ascomycete Neurospora crassa encodes CAO-1 and CAO-2, two members of the carotenoid cleavage oxygenase family that target double bonds in different substrates. Previous studies demonstrated the role of CAO-2 in cleaving the C40 carotene torulene, a key step in the synthesis of the C35 apocarotenoid pigment neurosporaxanthin. In this work, we investigated the activity of CAO-1, assuming that it may provide retinal, the chromophore of the NOP-1 rhodopsin, by cleaving β-carotene. For this purpose, we tested CAO-1 activity with carotenoid substrates that were, however, not converted. In contrast and consistent with its sequence similarity to family members that act on stilbenes, CAO-1 cleaved the interphenyl Cα-Cβ double bond of resveratrol and its derivative piceatannol. CAO-1 did not convert five other similar stilbenes, indicating a requirement for a minimal number of unmodified hydroxyl groups in the stilbene background. Confirming its biological function in converting stilbenes, adding of resveratrol led to a pronounced increase in cao-1 mRNA levels, while light, a key regulator of carotenoid metabolism did not alter them. Targeted Δcao-1 mutants were not impaired by the presence of resveratrol, a phytoalexin active against different fungi, which did not significantly affect the growth and development of Neurospora wild type. However, under partial sorbose toxicity, the Δcao-1 colonies exhibited a faster radial growth than control strains in the presence of resveratrol, suggesting a moderate toxic effect of resveratrol cleavage products. 23938021 Electron microscopy of human peripheral nerves of clinical relevance to the practice of nerve blocks. A structural and ultrastructural review based on original experimental and laboratory data. The goal is to describe the ultrastructure of normal human peripheral nerves, and to highlight key aspects that are relevant to the practice of peripheral nerve block anaesthesia. Using samples of sciatic nerve obtained from patients, and dural sac, nerve root cuff and brachial plexus dissected from fresh human cadavers, an analysis of the structure of peripheral nerve axons and distribution of fascicles and topographic composition of the layers that cover the nerve is presented. Myelinated and unmyelinated axons, fascicles, epineurium, perineurium and endoneurium obtained from patients and fresh cadavers were studied by light microscopy using immunohistochemical techniques, and transmission and scanning electron microscopy. Structure of perineurium and intrafascicular capillaries, and its implications in blood-nerve barrier were revised. Each of the anatomical elements is analyzed individually with regard to its relevance to clinical practice to regional anaesthesia. Routine practice of regional anaesthetic techniques and ultrasound identification of nerve structures has led to conceptions, which repercussions may be relevant in future applications of these techniques. In this regard, the ultrastructural and histological perspective accomplished through findings of this study aims at enlightening arising questions within the field of regional anaesthesia. 23712193 Impact of resin bonded bridgework on quality of life of patients with hypodontia. To determine the impact of hypodontia on the quality of life of adolescent and young adult patients, and, to assess the impact of restoring tooth spaces with resin bonded bridgework on quality of life of patients with hypodontia. In a prospective study, 82 patients with a confirmed diagnosis of hypodontia participated. The primary outcome was oral health related quality of life (OHRQoL) and this was measured using the OHIP-49 prior to treatment. The pre-treatment sample was then divided into two groups: the test group (n=40 patients) who had completed orthodontic treatment and had tooth spaces restored with resin bonded bridgework, and, a control group (n=42 patients) who were still in the process of orthodontic treatment. All patients completed a follow-up OHIP-49, and between and within group comparisons made. The pre-treatment sample included 43 females and 39 males, age ranged from 16 to 34 years (median age 19). Forty-three patients had more than 4 congenitally missing teeth and thirty-nine had ≤4 congenitally missing teeth. There were no differences between the groups prior to treatment. For the test group, there was a significant improvement in median OHIP summary scores (p<0.001) after treatment. OHIP scores deteriorated to a significant degree for control subjects (p=0.002). The effect sizes for the pre-post treatment change in both groups were moderate to large. Hypodontia has a significant impact on oral health related quality of life. Provision of resin bonded bridges has a positive impact on oral health related quality of life of patients with hypodontia. 23956942 A case of large B-cell intravascular lymphoma in the brain. Intravascular lymphoma is a rare and fatal disease that can have central nervous system (CNS) manifestations. It is usually a diagnosis made postmortem. This is partly due to its varied presentation, which lends itself to the complexity of diagnosis. We report a rare case of intravascular lymphoma in the brain found antemortem. Review of the literature shows that a timely diagnostic tissue biopsy together with aggressive combination chemotherapy treatment can improve patient outcome. 23601402 Voluntary food fortification with folic acid in Spain: Predicted contribution to children's dietary intakes as assessed with new food folate composition data. The Spanish market offers a significant number of folic acid (FA) voluntarily fortified foods. We analysed FA and (6S)-5-methyltetrahydrofolic acid ((6S)-5-CH3-H4PteGlu) content in ready-to-eat cereals (RTEC) (n=68) and cow's milk (n=25) by a previously validated affinity chromatography-HPLC method. Contribution to potential FA intakes for children aged 2-13years, was assessed using food consumption data from a representative nationwide study, folate Recommended Dietary Intakes (RDI), and Upper Levels (UL). Results showed that at all food fortification levels obtained, fortified products provided more than tenfold FA than (6S)-5-CH3-H4PteGlu. For RTEC, the high fortification level provided 6-21%, per serving, of RDI and ⩽32% of ULs at 90th percentile of RTEC consumption (P90). Milk products fortified at the higher level reached on average 54-136% of RDI per serving and only exceeded UL at P90 of milk consumption in children aged 2-5years. 23851905 Fungal hallucinogens psilocin, ibotenic Acid, and muscimol: analytical methods and biologic activities. : Psychoactive drugs of fungal origin, psilocin, ibotenic acid, and muscimol among them have been proposed for recreational use and popularized since the 1960s, XX century. Despite their well-documented neurotoxicity, they reached reputation of being safe and nonaddictive. Scientific efforts to find any medical application for these hallucinogens in psychiatry, psychotherapy, and even for religious rituals support are highly controversial. Even if they show any healing potential, their usage in psychotherapy is in some cases inadequate and may additionally harm seriously suffering patients. Hallucinogens are thought to reduce cognitive functions. However, in case of indolealkylamines, such as psilocin, some recent findings suggest their ability to improve perception and mental skills, what would motivate the consumption of "magic mushrooms." The present article offers an opportunity to find out what are the main symptoms of intoxication with mushrooms containing psilocybin/psilocin, muscimol, and ibotenic acid. The progress in analytical methods for detection of them in fungal material, food, and body fluids is reviewed. Findings on the mechanisms of their biologic activity are summarized. Additionally, therapeutic potential of these fungal psychoactive compounds and health risk associated with their abuse are discussed. 23954560 Home-based treadmill training to improve gait performance in persons with a chronic transfemoral amputation. To investigate the effectiveness of a home-based multiple-speed treadmill training program to improve gait performance in persons with a transfemoral amputation (TFA). Repeated measures SETTING: Research Laboratory PARTICIPANTS: Eight individuals with a TFA participated in the study. Each had undergone a unilateral amputation at least 3 years prior due to limb trauma or cancer. Home-based treadmill walking for a total of 30 min/day, 3 days/week for 8 weeks. Each 30 minute training session involved 5 cycles of walking for 2 minutes at 3 speeds. Participants were tested pre-training, and after 4 and 8 weeks of training. The primary measures were temporal-spatial gait performance [symmetry ratios for stance phase duration (SRstance) and step length (SRstep)], physiological gait performance [energy expenditure (EE) and energy cost (EC)], and functional gait performance [self-selected walking speed (SSWS), maximum walking speed (MWS), and 2-minute walk test (2MWT)]. Eight weeks of home-based training improved temporal-spatial gait symmetry at SSWS but not at MWS. A relative interlimb increase in stance duration for the prosthetic limb and proportionally greater increases in step length for the limb taking shorter steps produced the improved symmetry. The training effect was significant for SRstep within the first 4 weeks of the program. EE decreased progressively during the training with a nearly 10% improvement observed across the range of walking speeds. SSWS, MWS and 2MWT all increased by 16-20%. Home-based treadmill walking is an effective method to improve gait performance in persons with TFA. The results support the application of training interventions beyond the initial rehabilitation phase even in individuals considered highly functional. 23643094 Nordihydroguaiaretic acid induces Nrf2 nuclear translocation in vivo and attenuates renal damage and apoptosis in the ischemia and reperfusion model. It has been shown that the pretreatment with nordihydroguaiaretic acid (NDGA), a lignan with direct and indirect antioxidant properties, protects against the ischemia-reperfusion (I/R)-induced renal oxidant damage. Although it has been shown that NDGA induces Nrf2 nuclear translocation in renal epithelial LLC-PK1 cells in culture, it is unknown if NDGA may induce Nrf2 translocation in vivo. In this work was explored if NDGA is able to induce in vivo Nrf2 nuclear translocation in kidneys of rats submitted to uni-nephrectomy (U-NX) or I/R injury. Four groups of male Wistar rats were used: U-NX, NDGA, I/R, and I/R+NDGA. NDGA was injected i.p. (10mg/kg/day) starting 48h before I/R. Kidney samples were obtained at 3h of reperfusion after to measure Nrf2 translocation. Additional groups of rats were studied at 24h of reperfusion to measure histological damage and apoptosis. NDGA was able to induce Nrf2 translocation in vivo in kidneys of rats submitted to both U-NX and I/R injury and to protect against renal histological damage and apoptosis. It is concluded that the pretreatment of NDGA is able to induce in vivo nuclear Nrf2 translocation in kidney of rats suggesting that this may be involved in the renoprotection against I/R. 23885964 Factors Associated with Permanent Hearing Impairment in Infants Treated with Therapeutic Hypothermia. To define the incidence of hearing impairment, document plasma gentamicin concentrations, and identify factors associated with permanent hearing impairment in infants subjected to therapeutic hypothermia for moderate or severe neonatal encephalopathy. Data were collected prospectively in a regional center providing therapeutic hypothermia. Cooled infants at ≥36 weeks gestation with moderate or severe neonatal encephalopathy were analyzed if a full dataset was available (n = 108), including clinical variables and gentamicin trough levels. Infants with hearing impairment were identified, and survivors were followed up with neurodevelopmental evaluation at age 18 months. Stepwise logistic regression identified factors associated with hearing impairment. Nine infants died, and among the survivors, 10.1% developed a permanent hearing impairment. The trough gentamicin level was above the recommended cutoff of 2 mg/L in 37% of the infants in the entire cohort and in 90% of the infants with hearing impairment. Logistic regression analysis identified high trough gentamicin level, low cord pH, and hypoglycemia (<46.8 mg/dL) in the first postnatal hour as significantly associated with hearing impairment. The need for inotropic support was close to significant (P = .055). Hearing impairment was a common finding among cooled infants. Plasma gentamicin levels were commonly >2 mg/L. Based on these findings, we propose changes in gentamicin dosing interval and trough level monitoring to minimize the risk of potentially toxic levels in cooled newborns. 23842651 Microbial and viral metagenomes of a subtropical freshwater reservoir subject to climatic disturbances. Extreme climatic activities, such as typhoons, are widely known to disrupt our natural environment. In particular, studies have revealed that typhoon-induced perturbations can result in several long-term effects on various ecosystems. In this study, we have conducted a 2-year metagenomic survey to investigate the microbial and viral community dynamics associated with environmental changes and seasonal variations in an enclosed freshwater reservoir subject to episodic typhoons. We found that the microbial community structure and the associated metagenomes continuously changed, where microbial richness increased after typhoon events and decreased during winter. Among the environmental factors that influenced changes in the microbial community, precipitation was considered to be the most significant. Similarly, the viral community regularly showed higher relative abundances and diversity during summer in comparison to winter, with major variations happening in several viral families including Siphoviridae, Myoviridae, Podoviridae and Microviridae. Interestingly, we also found that the precipitation level was associated with the terrestrial viral abundance in the reservoir. In contrast to the dynamic microbial community (L-divergence 0.73±0.25), we found that microbial metabolic profiles were relatively less divergent (L-divergence 0.24±0.04) at the finest metabolic resolution. This study provides for the first time a glimpse at the microbial and viral community dynamics of a subtropical freshwater ecosystem, adding a comprehensive set of new knowledge to aquatic environments.The ISME Journal advance online publication, 11 July 2013; doi:10.1038/ismej.2013.118. 23548940 Identification of a novel sperm motility-stimulating protein from caprine serum: its characterization and functional significance. To identify and characterize a novel sperm motility-stimulating protein (MSP) from caprine serum. Prospective experimental study. Research laboratory. Rabbits and male and female BALB/c mice. Protein purification by conventional methods and functional and immunological characterization. MSP was purified, purity was checked, and molecular weight was determined. Surface localization, tissue distribution, and IVF for contraceptive efficacy were studied. MSP is a heat-stable 66-kDa monomeric novel protein. At 0.9 μM, it showed much higher forward motility and longer motility maintenance than other known activators. Studies with the motility analyzers CASA and SPERMA showed an increase in horizontal and vertical velocities, respectively. MSP action was cyclic AMP independent. Its occurrence was higher in testis, although blood was the richest source. MSP was localized throughout the cell surface of spermatozoa. Its antibody caused significant inhibition of sperm motility and inhibited fertilization up to 100% at 1:25 dilution, which showed its contraceptive efficacy. MSP has high efficacy to stimulate sperm forward motility and thus may be used in biomedical application in infertility clinics, animal breeding centers, poultries, and animal conservation centers. 23636107 A novel intellectual disability syndrome caused by GPI anchor deficiency due to homozygous mutations in PIGT. To delineate the molecular basis for a novel autosomal recessive syndrome, characterised by distinct facial features, intellectual disability, hypotonia and seizures, in combination with abnormal skeletal, endocrine, and ophthalmologic findings. We examined four patients from a consanguineous kindred with a strikingly similar phenotype, by using whole exome sequencing (WES). Functional validation of the initial results were performed by flow cytometry determining surface expression of glycosylphosphatidylinositol (GPI) and GPI anchored proteins and, in addition, by in vivo assays on zebrafish embryos. The results from WES identified a homozygous mutation, c.547A>C (p.Thr183Pro), in PIGT; Sanger sequencing of additional family members confirmed segregation with the disease. PIGT encodes phosphatidylinositol-glycan biosynthesis class T (PIG-T) protein, which is a subunit of the transamidase complex that catalyses the attachment of proteins to GPI. By flow cytometry, we found that granulocytes from the patients had reduced levels of the GPI anchored protein CD16b, supporting pathogenicity of the mutation. Further functional in vivo validation via morpholino mediated knockdown of the PIGT ortholog in zebrafish (pigt) showed that, unlike human wild-type PIGT mRNA, the p.Thr183Pro encoding mRNA failed to rescue gastrulation defects induced by the suppression of pigt. We identified mutations in PIGT as the cause of a novel autosomal recessive intellectual disability syndrome. Our results demonstrate a new pathogenic mechanism in the GPI anchor pathway and expand the clinical spectrum of disorders belonging to the group of GPI anchor deficiencies. 23677139 Long-term Echographic Surveillance of Elevated Choroidal Nevi. To report the outcomes of choroidal nevi monitoring and to compare the detection of ultrasonographic hollowness, a risk factor of malignant transformation, from a B-scan with results from an A-scan examination. Retrospective cohort study. Standardized A- and B-scan echography and ophthalmoscopy in 358 consecutive patients with median age 69 years and baseline choroidal nevus higher or lower than 1.5 mm in 51 (14%) and 307 (86%) eyes, respectively. No growth or change in echographic or ophthalmoscopic features were found in 307 nevi with a median elevation of 0.9 mm (range, 0.7 to 1.5 mm) and a median follow-up of 6 years (range, 4 to 9 years). After 2 to 6 years, decreased internal reflectivity on standardized A-scan and ultrasonographic hollowness on B-scan were detected in 7 (18%) of 38 initially highly reflective choroidal nevi (thickness, 1.98 ± 0.37 mm); 2 (5%) nevi grew into melanoma 15 years after the first observation. Of 13 choroidal nevi (thickness, 2.75 ± 0.66 mm), with initial atypical medium to high reflectivity on standardized A-scan (100%) and hollowness on B-scan (85%), 6 (46%) were plaqued 6 to 15 months later because of the presence of multiple risk factors. No changes in thickness or echographic features of choroidal nevi elevated up to 1.5 mm were recorded during the follow-up period. In initially typical choroidal nevi higher than 1.5 mm, strong agreement was detected between decreased reflectivity on standardized A-scan and ultrasonographic hollowness on B-scan found after up to 15 years of stability. The vast majority of choroidal nevi with initial atypical standardized A-scan features showed ultrasonographic hollowness. 23836412 Phase I study of intraprostatic vaccine administration in men with locally recurrent or progressive prostate cancer. The primary end point of this study was to determine the safety and feasibility of intraprostatic administration of PSA-TRICOM vaccine [encoding transgenes for prostate-specific antigen (PSA) and 3 costimulatory molecules] in patients with locally recurrent or progressive prostate cancer. This trial was a standard 3 + 3 dose escalation with 6 patients each in cohorts 4 and 5 to gather more immunologic data. Nineteen of 21 patients enrolled had locally recurrent prostate cancer after definitive radiation therapy, and 2 had no local therapy. All cohorts received initial subcutaneous vaccination with recombinant vaccinia (rV)-PSA-TRICOM and intraprostatic booster vaccinations with recombinant fowlpox (rF)-PSA-TRICOM. Cohorts 3-5 also received intraprostatic rF-GM-CSF. Cohort 5 received additional subcutaneous boosters with rF-PSA-TRICOM and rF-GM-CSF. Patients had pre- and post-treatment prostate biopsies, and analyses of peripheral and intraprostatic immune cells were performed. There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. The most common grade 2 adverse events were fever (38 %) and subcutaneous injection site reactions (33 %); the single grade 3 toxicity was transient fever. Overall, 19 of 21 patients on trial had stable (10) or improved (9) PSA values. There was a marked increase in CD4(+) (p = 0.0002) and CD8(+) (p = 0.0002) tumor infiltrates in post- versus pre-treatment tumor biopsies. Four of 9 patients evaluated had peripheral immune responses to PSA or NGEP. Intraprostatic administration of PSA-TRICOM is safe and feasible and can generate a significant immunologic response. Improved serum PSA kinetics and intense post-vaccination inflammatory infiltrates were seen in the majority of patients. Clinical trials examining clinical end points are warranted. 23918287 The importance of rehabilitation after lower limb fractures in elderly osteoporotic patients. Improving rehabilitation strategies after lower limb fractures among elderly patients is an urgent public health challenge due to the increasing proportion of older population and therefore the raised number of falls and fractures. Due to their strategic positioning, physiatrists should aim not only to improve functional outcomes after acute fracture treatment but also to address the underlying osteoporotic condition in order to prevent the devastating socioeconomic consequences of osteoporotic fractures. 23293839 Thermodynamic studies of ionic hydration and interactions for amino acid ionic liquids in aqueous solutions at 298.15 K. Amino acid ionic liquids are a special class of ionic liquids due to their unique acid-base behavior, biological significance, and applications in different fields such as templates in synthetic chemistry, stabilizers for biological macromolecules, etc. The physicochemical properties of these ionic liquids can easily be altered by making the different combinations of amino acids as anion along with possible cation modification which makes amino acid ionic liquids more suitable to understand the different kinds of molecular and ionic interactions with sufficient depth so that they can provide fruitful information for a molecular level understanding of more complicated biological processes. In this context, volumetric and osmotic coefficient measurements for aqueous solutions containing 1-ethyl-3-methylimidazolium ([Emim]) based amino acid ionic liquids of glycine, alanine, valine, leucine, and isoleucine are reported at 298.15 K. From experimental osmotic coefficient data, mean molal activity coefficients of ionic liquids were estimated and analyzed using the Debye-Hückel and Pitzer models. The hydration numbers of ionic liquids in aqueous solutions were obtained using activity data. Pitzer ion interaction parameters are estimated and compared with other electrolytes reported in the literature. The nonelectrolyte contribution to the aqueous solutions containing ionic liquids was studied by calculating the osmotic second virial coefficient through an application of the McMillan-Mayer theory of solution. It has been found that the second osmotic virial coefficient which includes volume effects correlates linearly with the Pitzer ion interaction parameter estimated independently from osmotic data as well as the hydrophobicity of ionic liquids. The enthalpy-entropy compensation effect, explained using the Starikov-Nordén model of enthalpy-entropy compensation, and partial molar entropy analysis for aqueous [Emim][Gly] solutions are made by using experimental Gibb's free energy data and literature enthalpy data. This study highlights that the hydrophobic interaction persists even in the limit of infinite dilution where the hydration effects are usually dominant, implying importance of hydrophobic hydration. Analysis of the results further shows that the hydration of amino acid ionic liquids occurs through the cooperative H-bond formation with the kosmotropic effect in contrast to the usual inorganic salts or hydrophobic salts like tetraalkylammonium halides. 23921338 Platelet-Rich Plasma for Arthroscopic Repair of Large to Massive Rotator Cuff Tears: A Randomized, Single-Blind, Parallel-Group Trial. BACKGROUND:Platelet-rich plasma (PRP) is expected to have a biological augmentation potential in the healing of various diseases and injuries, including rotator cuff tears. However, few evaluations have been performed specifically for large to massive tears. PURPOSE:To assess the efficacy of PRP augmentation in patients undergoing arthroscopic repair for large to massive rotator cuff tears. STUDY DESIGN:Randomized controlled trial; Level of evidence, 1. METHODS:A total of 48 patients scheduled for arthroscopic repair of large to massive rotator cuff tears were randomly assigned to receive either PRP-augmented (PRP group) or conventional treatment (conventional group). In the PRP group, 3 PRP gels (3 × 3 mL) were applied to each patient between the torn end and the greater tuberosity. The primary outcome measure was the retear rate assessed by magnetic resonance imaging (MRI) or computed tomographic arthrography (CTA) at a minimum of 9 months after surgery. Secondary outcome measures included pain, range of motion, muscle strength, overall satisfaction, functional scores, and the change in cross-sectional area (CSA) of the supraspinatus. RESULTS:The retear rate of the PRP group (20.0%) was significantly lower than that of the conventional group (55.6%) (P = .023). Clinical outcomes showed no statistical difference between the 2 groups (all P > .05) except for the overall function (P = .043). The change in 1-year postoperative and immediately postoperative CSA was significantly different between the 2 groups: -15.54 ± 94.34 mm(2) in the PRP group versus -85.62 ± 103.57 mm(2) in the conventional group (P = .047). CONCLUSION:The application of PRP for large to massive rotator cuff repairs significantly improved structural outcomes, as evidenced by a decreased retear rate and increased CSA of the supraspinatus compared with repairs without PRP augmentation. While there was no significant difference in clinical outcomes except the overall shoulder function after 1-year follow-up, better structural outcomes in the PRP group might suggest improved clinical outcomes at longer term follow-up. 23947395 Early Adolescent Cortical Thinning Is Related to Better Neuropsychological Performance. Adolescence is characterized by significant neuromaturation, including extensive cortical thinning, particularly in frontal regions. The goal of this study was to examine the behavioral correlates of neurostructural development in early adolescence. Participants were 185 healthy 12- to 14-year-olds (44% female) recruited from local schools. Participants completed a comprehensive neuropsychological test battery and magnetic resonance imaging session. Cortical surface reconstruction and thickness estimates were performed via FreeSurfer. Age and cortical thickness were negatively correlated in 10 brain regions, 7 of which were in frontal areas (β = -.15 to -.25, ps ≤ .05). Hierarchical linear regressions examined the influence of cortical thickness on working memory, attention, verbal learning and memory, visuospatial functioning, spatial planning and problem solving, and inhibition, controlling for age and intracranial volume. Thinner parietal cortices predicted better performances on tests of verbal learning and memory, visuospatial functioning, and spatial planning and problem solving (β = -.14 to -.24, ps ≤ .05). Age, spanning from 12 to 14 years, accounted for up to 6% of cortical thickness, suggesting substantial thinning during early adolescence, with males showing more accelerated thinning than females between ages 12 and 14. For both males and females, thinner parietal association cortices corresponded with better neurocognitive functioning above and beyond age alone. (JINS, 2013, 19, 1-9). 23423574 Targeting pyruvate carboxylase reduces gluconeogenesis and adiposity and improves insulin resistance. We measured the mRNA and protein expression of the key gluconeogenic enzymes in human liver biopsy specimens and found that only hepatic pyruvate carboxylase protein levels related strongly with glycemia. We assessed the role of pyruvate carboxylase in regulating glucose and lipid metabolism in rats through a loss-of-function approach using a specific antisense oligonucleotide (ASO) to decrease expression predominantly in liver and adipose tissue. Pyruvate carboxylase ASO reduced plasma glucose concentrations and the rate of endogenous glucose production in vivo. Interestingly, pyruvate carboxylase ASO also reduced adiposity, plasma lipid concentrations, and hepatic steatosis in high fat-fed rats and improved hepatic insulin sensitivity. Pyruvate carboxylase ASO had similar effects in Zucker Diabetic Fatty rats. Pyruvate carboxylase ASO did not alter de novo fatty acid synthesis, lipolysis, or hepatocyte fatty acid oxidation. In contrast, the lipid phenotype was attributed to a decrease in hepatic and adipose glycerol synthesis, which is important for fatty acid esterification when dietary fat is in excess. Tissue-specific inhibition of pyruvate carboxylase is a potential therapeutic approach for nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. 23861593 Two-dimensional and Doppler echocardiographic evaluation of patients presenting at Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria: a prospective study of 2501 subjects. Echocardiography remains a key noninvasive cardiac investigative tool in the management of patients, especially in a developing economy like Nigeria. In this study, we investigated the indications for transthoracic echocardiography and spectrum of cardiac disease found in patients referred to our cardiac unit for echocardiography. A prospective two-dimensional, pulsed, continuous, and color-flow Doppler echocardiographic evaluation was done using the transthoracic approach in 2501 patients over an eight-year period. Univariate data analysis was performed for mean age, gender, clinical indications, and diagnoses. The subject age range was less than 12 months to 97 years (mean 52.39 years). There were 1352 (54.06%) males and 1149 (45.94%) females. The most common indication for echocardiography was hypertension (52.1%) followed by congestive cardiac failure (13.9%). Others were for screening (6.1%), arrhythmias (5%), cerebrovascular disease (5%), chest pain (3.3%), chronic kidney disease (3.2%), congenital heart disease (2.6%), cardiomyopathy (1.8%), rheumatic heart disease (1.7%), diabetes mellitus (1.3%), thyrocardiac disease (1.2%), ischemic heart disease (1.2%), and pericardial disease (1.1%). The echocardiographic diagnosis was hypertensive heart disease in 59.4% of subjects and normal in 14.1%. Other echocardiographic diagnoses included rheumatic heart disease (3.1%), congenital heart disease (2.1%), cardiomyopathy (1.7%), pericardial disease (1.1%), and ischemic heart disease (0.1%). Hypertension and its cardiac complications is the most common echocardiographic indication and diagnosis at our unit. 23756735 Propidium monoazide-quantitative polymerase chain reaction for viable Escherichia coli and Pseudomonas aeruginosa detection from abundant background microflora. Nucleic acid-based techniques represent a promising alternative to cultivation-based microbial water quality assessment methods. However, their application is hampered by their innate inability to differentiate between living and dead organisms. Propidium monoazide (PMA) treatment was proposed as an efficient approach for alleviating this limitation. In this study, we demonstrate the performance of PMA-quantitative polymerase chain reaction (qPCR) for the detection of indicator organisms (Escherichia coli and Pseudomonas aeruginosa) in a background of a highly abundant and complex microflora. Treatment with 10μM PMA resulted in the complete or significant reduction of the false positive signal arising from the amplification of DNA from dead cells. 23839751 Effect of soy protein isolate supplementation on biochemical recurrence of prostate cancer after radical prostatectomy: a randomized trial. Soy consumption has been suggested to reduce risk or recurrence of prostate cancer, but this has not been tested in a randomized trial with prostate cancer as the end point. To determine whether daily consumption of a soy protein isolate supplement for 2 years reduces the rate of biochemical recurrence of prostate cancer after radical prostatectomy or delays such recurrence. Randomized, double-blind trial conducted from July 1997 to May 2010 at 7 US centers comparing daily consumption of a soy protein supplement vs placebo in 177 men at high risk of recurrence after radical prostatectomy for prostate cancer. Supplement intervention was started within 4 months after surgery and continued for up to 2 years, with prostate-specific antigen (PSA) measurements made at 2-month intervals in the first year and every 3 months thereafter. Participants were randomized to receive a daily serving of a beverage powder containing 20 g of protein in the form of either soy protein isolate (n=87) or, as placebo, calcium caseinate (n=90). Biochemical recurrence rate of prostate cancer (defined as development of a PSA level of ≥0.07 ng/mL) over the first 2 years following randomization and time to recurrence. The trial was stopped early for lack of treatment effects at a planned interim analysis with 81 evaluable participants in the intervention group and 78 in the placebo group. Overall, 28.3% of participants developed biochemical recurrence within 2 years of entering the trial (close to the a priori predicted recurrence rate of 30%). Among these, 22 (27.2%) occurred in the intervention group and 23 (29.5%) in the placebo group. The resulting hazard ratio for active treatment was 0.96 (95% CI, 0.53-1.72; log-rank P = .89). Adherence was greater than 90% and there were no apparent adverse events related to supplementation. Daily consumption of a beverage powder supplement containing soy protein isolate for 2 years following radical prostatectomy did not reduce biochemical recurrence of prostate cancer in men at high risk of PSA failure. clinicaltrials.gov Identifier: NCT00765479. 23791978 Rosiglitazone-loaded nanospheres for modulating macrophage-specific inflammation in obesity. PPARγ nuclear receptor agonists have been shown to attenuate macrophage inflammatory responses implicated in the metabolic complications of obesity and in atherosclerosis. However, PPARγ agonists currently in clinical use, including rosiglitazone (RSG), are often associated with severe side effects that limit their therapeutic use. Here, 200nm PLGA/PVA nanospheres were formulated for the systemic delivery of RSG specifically to macrophages. RSG was encapsulated with over 50% efficiency in the hydrophobic PLGA core and released specifically within the acidifying macrophage phagosomes. In bone marrow derived macrophages, RSG-loaded nanoparticles (RSG-NPs) induce a dose dependent upregulation (1.5 to 2.5-fold) of known PPARγ target genes, with maximal induction at 5μM; and downregulate the expression of genes related to the inflammatory process, with a maximum effect at 10μM. In Ldlr(-/-) mice fed high fat diet, treatment with RSG-NPs alleviated inflammation in white adipose tissue and liver but, unlike treatment with free RSG, did not alter genes associated with lipid metabolism or cardiac function, indicating a reduction in the RSG side effect profile. These biocompatible, biodegradable RSG-NPs represent a preliminary step towards the specific delivery of nuclear receptor agonists for the treatment of macrophage-mediated inflammatory conditions associated with obesity, atherosclerosis and other chronic disease states. 23927685 Amino Acid-Functionalized Ionic Liquid Solid Sorbents for Post-Combustion Carbon Capture. Amino acid ionic liquids (AAILs) are potential green substitutes of aqueous amine solutions for carbon dioxide (CO2) capture. However, the viscous nature of AAILs greatly hinders their further development in CO2 capture applications. In this contribution, 1-ethyl-3-methylimidazolium lysine ([EMIM][Lys]) was synthesized and immobilized into a porous poly(methyl methacrylate) (PMMA) microsphere support for post-combustion CO2 capture. The [EMIM][Lys] exhibited good thermal stability and could be facilely immobilized into porous microspheres. Significantly, the [EMIM][Lys]-PMMA sorbents retained their porous structure after [EMIM][Lys] loading and exhibited fast kinetics. When exposed to CO2 at 40 °C, [EMIM][Lys]-PMMA sorbent exhibited the highest CO2 capacity compared to other counterparts studied and achieved a capacity of 0.87 mol/(mol AAIL) or 1.67 mmol/(g sorbent). The capture process may be characterized by two stages: CO2 adsorption on the surface of sorbent and CO2 diffusion into sorbent for further adsorption. The calculated activation energies of the two-stage CO2 sorption were 4.1 and 4.3 kJ/mol, respectively, indicating that, overall, the CO2 can easily adsorb onto this sorbent. Furthermore, multiple cycle tests indicated that the developed sorbents had good long-term stability. The developed sorbent may be a promising candidate for post-combustion CO2 capture. 22841906 Temporary biventricular pacing decreases the vasoactive-inotropic score after cardiac surgery: A substudy of a randomized clinical trial. Vasoactive medications improve hemodynamics after cardiac surgery but are associated with high metabolic and arrhythmic burdens. The vasoactive-inotropic score was developed to quantify vasoactive and inotropic support after cardiac surgery in pediatric patients but may be useful in adults as well. Accordingly, we examined the time course of this score in a substudy of the Biventricular Pacing After Cardiac Surgery trial. We hypothesized that the score would be lower in patients randomized to biventricular pacing. Fifty patients selected for increased risk of left ventricular dysfunction after cardiac surgery and randomized to temporary biventricular pacing or standard of care (no pacing) after cardiopulmonary bypass were studied in a clinical trial between April 2007 and June 2011. Vasoactive agents were assessed after cardiopulmonary bypass, after sternal closure, and 0 to 7 hours after admission to the intensive care unit. Over the initial 3 collection points after cardiopulmonary bypass (mean duration, 131 minutes), the mean vasoactive-inotropic score decreased in the biventricular pacing group from 12.0 ± 1.5 to 10.5 ± 2.0 and increased in the standard of care group from 12.5 ± 1.9 to 15.5 ± 2.9. By using a linear mixed-effects model, the slopes of the time courses were significantly different (P = .02) and remained so for the first hour in the intensive care unit. However, the difference was no longer significant beyond this point (P = .26). The vasoactive-inotropic score decreases in patients undergoing temporary biventricular pacing in the early postoperative period. Future studies are required to assess the impact of this effect on arrhythmogenesis, morbidity, mortality, and hospital costs. 23885670 A new approach for the estimation of expanded uncertainty of results of an analytical method developed for determining antibiotics in seawater using solid-phase extraction disks and liquid chromatography coupled with tandem mass spectrometry technique. Although the uncertainty estimate should be a necessary component of an analytical result, the presentation of measurements together with their uncertainties is still a serious problem, especially in the monitoring of the presence of pharmaceuticals in the environment. Here we discuss the estimation of expanded uncertainty in analytical procedures for determining residues of twelve pharmaceuticals in seawaters using solid-phase extraction (SPE) with H2O-Philic BAKERBOND speed disks and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Matrix effects, extraction efficiency and absolute recovery of the developed analytical method were determined. A validation was performed to obtain the method's linearity, precision, accuracy, limits of detection (LODs) and quantification (LOQs). The expanded uncertainty of the data obtained was estimated according to the Guide to the Expression of Uncertainty in Measurement and ISO 17025:2005 standard. We applied our method to the analysis of drugs in seawaters samples from the coastal area of the southern Baltic Sea. As a result, a new approach (concerning the uncertainty estimation as well as the development of analytical method) to the analysis of pharmaceutical residues in environmental samples is presented. The information given here should facilitate the introduction of uncertainty estimation in chromatographic measurements on a much greater scale than is currently the case. 23965591 The Role of Intraoperative Nerve Monitoring (IONM) in Thyroidectomy: Where Do We Stand Today? Objective. Intraoperative nerve monitoring (IONM) gains daily ground, being used during thyroidectomy to help the surgeon identify the recurrent laryngeal nerve (RLN). But its value still remains debatable among endocrine surgeons. In this review article, we aim to present current knowledge on the subject. Data sources. The MEDLINE/PubMed database was searched for publications with the medical subject heading "Intraoperative Nerve Monitoring (IONM)" and keywords "thyroidectomy," "recurrent laryngeal nerve (RLN)" or "vocal cord paresis or vocal cord paralysis (VCP)." The search was conducted both on basis of the MESH tree and as a text search. Study selection/Data extraction. We restricted our search to English till July 2012. In this review, we only included 34 articles and abstracts that were available in English. Conclusions. RLN IONM adds a functional dimension to surgery that aids, but does not replace, visual identification. For the time being, intraoperative visual identification of the nerve and preoperative and postoperative laryngoscopic assessment of vocal cord function remain the gold standard of RLN management in thyroid surgery. Whether IONM will become a standard of care or not depends on the familiarization of each surgeon with this technique as well as on the publication of studies involving large series of thyroidectomies, where the evaluation of IONM will have significant statistical power. 23630169 A Detailed Experimental and Theoretical Study into the Properties of C60 Dumbbell Junctions. A combined experimental and theoretical investigation is carried out into the electrical transport across a fullerene dumbbell one-molecule junction. The newly designed molecule comprises two C60 s connected to a fluorene backbone via cyclopropyl groups. It is wired between gold electrodes under ambient conditions by pressing the tip of a scanning tunnelling microscope (STM) onto one of the C60 groups. The STM allows us to identify a single molecule before the junction is formed through imaging, which means unambiguously that only one molecule is wired. Once lifted, the same molecule could be wired many times as it was strongly fixed to the tip, and a high conductance state close to 10(-2) G0 is found. The results also suggest that the relative conductance fluctuations are low as a result of the low mobility of the molecule. Theoretical analysis indicates that the molecule is connected directly to one electrode through the central fluorene, and that to bind it to the gold fully it has to be pushed through a layer of adsorbates naturally present in the experiment. 23873233 Induction of SHP2-deficiency in chondrocytes causes severe scoliosis and kyphosis in mice. Study Design. Genetic engineering techniques were used to develop an animal model of juvenile scoliosis during a postnatal skeletal-growth stage.Objective. To investigate the effect of targeted SHP2 (Src homology-2)-deficiency in chondrocytes on the development of scoliosis during a juvenile growth stage in mice.Summary of Background Data. Juvenile idiopathic scoliosis can lead to progressive severe spinal deformity. The pathophysiology and molecular mechanisms responsible for this are largely unknown. Here, we investigated the role of SHP2-deficiency in chondrocytes as a potential cause of juvenile scoliosis development.Methods. Genetically engineered mice with inducible deletion of SHP2 in chondrocytes were generated. The SHP2 function in chondrocytes was inactivated during a juvenile growth stage from the mouse age of 4-weeks. Radiographic, micro-CT, and histological assessments were used to analyze spinal changes.Results. When SHP2-deficiency was induced during the juvenile stage, a progressive kyphoscoliotic deformity (thoracic lordosis and thoracolumbar kyphoscoliosis) developed within 2 weeks of the initiation of SHP2-deficiency. The 3-dimensional micro-CT analysis confirmed the kyphoscoliotic deformity with a rotational deformity of the spine and osteophyte formation. The histological analysis revealed disorganization of the vertebral growth plate cartilage. Interestingly, when SHP2 was disrupted during the adolescent to adult stages, no spinal deformity developed.Conclusion. SHP2 plays an important role in normal spine development during skeletal maturation. Chondrocyte-specific deletion of SHP2 at a juvenile stage produced a kyphoscoliotic deformity. This new mouse model will be useful for future investigations of the role of SHP2-deficiency in chondrocytes as a mechanism leading to the development of juvenile scoliosis. 23917788 Pharmacokinetics and Biodistribution of 99mTc N-MPO in Healthy Human Volunteers. Tc N-MPO ([Tc N(MPO)(PNP5)]: HMPO = 2-mercaptopyridine N-oxide, and PNP5 = N-ethoxyethyl-N,N-bis[2-(bis(3-methoxypropyl)phosphino)ethyl]amine) is a new Tc radiotracer useful for myocardial perfusion imaging. This study was designed to determine its pharmacokinetics and biodistribution in healthy volunteers. Ten healthy volunteers were involved in this study. Each subject was administered approximately 925 MBq of Tc N-MPO under rest or stress conditions (n = 5 per group). Whole-body planar images were obtained at 10, 30, 60, 240, and 1440 minutes after injection. Organ uptake was quantified by region-of-interest analysis. The blood clearance and urine excretion kinetics were determined by collecting blood and urine samples at different time points. Tc N-MPO showed significant accumulation in myocardium with prolonged retention. At rest, its percentage of injected dose (%ID) uptake in the heart, lungs, and liver at 10 minutes after injection was 2.47% (0.64%), 1.84% (0.64%), and 20.88% (5.23%), respectively. The liver uptake decreased to 6.79%ID (1.60%ID) at 60 minutes after injection and 4.50%ID (1.86%ID) at 240 minutes after injection. Under stress conditions, the heart uptake was slightly increased (2.57%ID [0.21%ID]). The rapid liver clearance led to favorable heart-to-liver ratios, reaching values of 0.27%ID (0.07%ID) under rest condition and 0.28%ID (0.05%ID) under stress condition at 60 minutes after injection. Tc N-MPO demonstrates a highly favorable biodistribution in humans. The high heart uptake and the fast liver washout of Tc N-MPO will allow SPECT images of the left ventricle to be acquired as early as 10 minutes after injection. 23850809 Rapid assessment of high-dose radiation exposures through scoring of cell-fusion-induced premature chromosome condensation and ring chromosomes. Analysis of premature chromosome condensation (PCC) mediated by fusion of G0-lymphocytes with mitotic CHO cells in combination with rapid visualization and quantification of rings (PCC-Rf) is proposed as an alternative technique for dose assessment of radiation-exposed individuals. Isolated lymphocytes or whole blood from six individuals were γ-irradiated with 5, 10, 15 and 20Gy at a dose rate of 0.5Gy/min. Following either 8- or 24-h post-exposure incubation of irradiated samples at 37°C, chromosome spreads were prepared by standard PCC cytogenetic procedures. The protocol for PCC fusion proved to be effective at doses as high as 20Gy, enabling the analysis of ring chromosomes and excess PCC fragments. The ring frequencies remained constant during the 8-24-h repair time; the pooled dose relationship between ring frequency (Y) and dose (D) was linear: Y=(0.088±0.005)×D. During the repair time, excess fragments decreased from 0.91 to 0.59 chromatid pieces per Gy, revealing the importance of information about the exact time of exposure for dose assessment on the basis of fragments. Compared with other cytogenetic assays to estimate radiation dose, the PCC-Rf method has the following benefits: a 48-h culture time is not required, allowing a much faster assessment of dose in comparison with conventional scoring of dicentrics and rings in assays for chemically-induced premature chromosome condensation (PCC-Rch), and it allows the analysis of heavily irradiated lymphocytes that are delayed or never reach mitosis, thus avoiding the problem of saturation at high doses. In conclusion, the use of the PCC fusion assay in conjunction with scoring of rings in G0-lymphocytes offers a suitable alternative for fast dose estimation following accidental exposure to high radiation doses. 23443752 When direct health-care professional communications have an impact on inappropriate and unsafe use of medicines. Serious safety issues relating to drugs are communicated to health-care professionals via Direct Health-Care Professional Communications (DHPCs). We explored which characteristics determined the impact of DHPCs issued in the Netherlands for ambulatory-care drugs (2001-2008). With multiple linear regression, we examined the impact on the relative change in new drug use post-DHPC of the following: time to DHPC, trend in use, degree of innovation, specialist drug, first/repeated DHPC, DHPC template, and type of safety issue. DHPCs have less impact on use of specialist drugs than nonspecialist drugs (P < 0.05). The DHPCs' impact increased after availability of a template emphasizing the main problem (P < 0.05), and for safety issues with a risk of death and/or disability (both P < 0.05) (adjusted R² = 0.392). Risk communication can be effective, specifically in case of well-structured information, and very serious safety issues. Effectiveness may improve by tailoring DHPCs and adding other communication channels, for example for drugs that are increasingly being used. 23461378 Dissecting the relative contribution of OATP1B1-mediated uptake of xenobiotics into human hepatocytes using siRNA. Abstract 1. Organic anion transporting polypeptide 1B1 plays a pivotal role in the disposition of many anionic drugs. Significant overlap in substrate specificity between individual OATP isoforms has hampered the identification of the relative importance of individual isoforms for hepatic uptake of xenobiotics. 2. The present study focused on the use of siRNA technology to decrease OATP1B1 selectively in human hepatocytes. Following delivery of siRNA by the novel lipid, AtuFECT01, mRNA expression of OATP1B1 was reduced by 94%-98% with no significant toxicity. Off-target effects were also shown to be minimal as evidenced by the expression of common drug metabolizing enzymes, transporters, nuclear receptors and associated co-regulators. Uptake of estrone-3-sulfate (5 nM) by OATP1B1 was reduced by 82%-95%. This methodology was subsequently used to assess the relative contribution of OATP1B1 uptake in human hepatocytes for olmesartan (42%-62%), valsartan (28%-81%), rosuvastatin (64%-72%), pitavastatin (84%-98%) and lopinavir (64%-89%). These data are consistent with previous values obtained using a relative activity factor approach. 3. The siRNA approach provides a robust and reproducible method for assessing the relative contribution of OATP1B1 to hepatic uptake of new chemical entities. The technique also has potential utility in facilitating detailed characterization of drug-drug interactions involving hepatic drug transporters. 23935068 Contributions of the RAD51 N-terminal domain to BRCA2-RAD51 interaction. RAD51 DNA strand exchange protein catalyzes the central step in homologous recombination, a cellular process fundamentally important for accurate repair of damaged chromosomes, preservation of the genetic integrity, restart of collapsed replication forks and telomere maintenance. BRCA2 protein, a product of the breast cancer susceptibility gene, is a key recombination mediator that interacts with RAD51 and facilitates RAD51 nucleoprotein filament formation on single-stranded DNA generated at the sites of DNA damage. An accurate atomistic level description of this interaction, however, is limited to a partial crystal structure of the RAD51 core fused to BRC4 peptide. Here, by integrating homology modeling and molecular dynamics, we generated a structure of the full-length RAD51 in complex with BRC4 peptide. Our model predicted previously unknown hydrogen bonding patterns involving the N-terminal domain (NTD) of RAD51. These interactions guide positioning of the BRC4 peptide within a cavity between the core and the NTDs; the peptide binding separates the two domains and restricts internal dynamics of RAD51 protomers. The model's depiction of the RAD51-BRC4 complex was validated by free energy calculations and in vitro functional analysis of rationally designed mutants. All generated mutants, RAD51(E42A), RAD51(E59A), RAD51(E237A), RAD51(E59A/E237A) and RAD51(E42A/E59A/E237A) maintained basic biochemical activities of the wild-type RAD51, but displayed reduced affinities for the BRC4 peptide. Strong correlation between the calculated and experimental binding energies confirmed the predicted structure of the RAD51-BRC4 complex and highlighted the importance of RAD51 NTD in RAD51-BRCA2 interaction. 23856169 Modelling counter-current chromatography using a temperature dependence plate model. So far, research workers have built several math models of counter-current chromatography (CCC), such as cell model, eluting counter-current distribution model, continuous-stirred tank reactors model, and probability model. Based on plate theory and Van't Hoff equation, a new temperature dependence plate model has been established in this paper. When temperature was taken into consideration, the error of retention time was significantly reduced. The relationship between temperature and partition coefficient K can be summarized into linear equations (logK=A-B/T), which can be introduced to the plate model where A and B are constant and T is the temperature in Kelvin. K values decreased with the increasing temperature. Since resolution values (R) are related to K values, the change of temperature finally leads to the change of resolutions between different compounds. K values at different temperatures of a certain compound in a given system were calculated according to the equation above. New program with a temperature parameter was applied in prediction of experimental results, which diminished the error in modelling prediction. Besides, it is difficult for the CCC work when two compounds have similar K values. However, separation can be achieved by changing temperature, which can be directed by this new model. 23781102 Helical flow of surface protein required for bacterial gliding motility. Cells of Flavobacterium johnsoniae and of many other members of the phylum Bacteroidetes exhibit rapid gliding motility over surfaces by a unique mechanism. These cells do not have flagella or pili; instead, they rely on a novel motility apparatus composed of Gld and Spr proteins. SprB, a 669-kDa cell-surface adhesin, is required for efficient gliding. SprB was visualized by electron microscopy as thin 150-nm-long filaments extending from the cell surface. Fluorescence microscopy revealed movement of SprB proteins toward the poles of the cell at ∼2 μm/s. The fluorescent signals appeared to migrate around the pole and continue at the same speed toward the opposite pole along an apparent left-handed helical closed loop. Movement of SprB, and of cells, was rapidly and reversibly blocked by the addition of carbonyl cyanide m-chlorophenylhydrazone, which dissipates the proton gradient across the cytoplasmic membrane. In a gliding cell, some of the SprB protein appeared to attach to the substratum. The cell body moved forward and rotated with respect to this point of attachment. Upon reaching the rear of the cell, the attached SprB often was released from the substratum, and apparently recirculated to the front of the cell along a helical path. The results suggest a model for Flavobacterium gliding, supported by mathematical analysis, in which adhesins such as SprB are propelled along a closed helical loop track, generating rotation and translation of the cell body. 23179722 Dissolved inorganic nutrients and chlorophyll A in an estuary receiving sewage treatment plant effluents: Cachoeira River estuary (NE Brazil). Sampling was conducted monthly during a transition period between the dry and rainy seasons in order to evaluate the effectiveness of a municipal sewage treatment plant (STP) in eutrophication control. STP effluent and fluvial input data were also estimated. In the dry period, high concentrations of nutrients, chlorophyll a (up to 360 Î¼g L(-1)), and anoxia in bottom waters were observed in the upper portion of the estuary. Nitrate was scarce during the dry months, although high concentrations were observed at the river sources and the upper estuary. The N:P and Si:P molar ratios were usually below 16:1, and the Si:N ratio was higher than 1:1. The fluvial inputs were a greater source of nutrients to the estuary than the STP, but nutrient loading by these effluents were also important in contributing to the eutrophication of the upper estuarine zone, especially in the dry season when symptoms were more intense. 23580626 Exercise intensity levels in children with cerebral palsy while playing with an active video game console. Children with cerebral palsy (CP) are prone to secondary complications related to physical inactivity and poor cardiorespiratory capacity. This problem could be greatly attenuated through the use of video games that incorporate physical activity for 2 reasons: Video games already represent an important component of leisure time in younger people, and such games can lead to a high level of exercise intensity in people who are healthy. The study objective was to evaluate exercise intensity in children with spastic diplegic CP and children who were typically developing while playing with an active video game console. This was a cross-sectional study. Ten children (7-12 years old) with spastic diplegic CP (Gross Motor Function Classification System level I or II) and 10 children who were age matched and typically developing were evaluated in a movement analysis laboratory. Four games were played with the active video game console (jogging, bicycling, snowboarding, and skiing) for 40 minutes. Heart rate was recorded during the entire playing period with a heart rate belt monitor. Exercise intensity was defined as the percentage of heart rate reserve (HRR). In addition, lower extremity motion analysis was carried out during the final minute of the playing period for the jogging and bicycling games. No difference between groups was observed for any variables. A main effect of games was observed for the amount of time spent at an intensity greater than 40% of HRR. Specifically, more than 50% of the playing time for the jogging game and more than 30% of the playing time for the bicycling game were spent at an intensity greater than 40% of HRR. In addition, the jogging game produced a larger range of motion than the bicycling game. A limitation of this study was the relatively small and heterogeneous sample. For all 4 games, similar exercise intensity levels were observed for children who were typically developing and children with CP, suggesting that children with CP could obtain exercise-related benefits similar to those obtained by children without CP while playing with an active video game console. 23962031 Prehospital use of cervical collars in trauma patients - a critical review. The cervical collar has been routinely used for trauma patients for more than 30 years and is a hallmark of state-of-the-art prehospital trauma care. However, the existing evidence for this practice is limited: randomized controlled trials are largely missing, and there are uncertain effects on mortality, neurological injury, and spinal stability. Even more concerning, there is a growing body of evidence and opinion against the use of collars. It has been argued that collars cause more harm than good, and that we should simply stop using them. In this critical review, we discuss the pros and cons of collar use in trauma patients, and reflect on how we can move our clinical practice forward. Conclusively, we propose a safe and effective strategy for prehospital spinal immobilization that does not include routine use of collars. 23540813 Surface Engineering of Ultrafine Cellulose Nanofibrils toward Polymer Nanocomposite Materials. Surface grafting of crystalline and ultrafine cellulose nanofibrils with poly(ethylene glycol) (PEG) chains via ionic bonds was achieved by a simple ion-exchange treatment. The PEG-grafted cellulose nanofibrils exhibited nanodispersibility in organic solvents such as chloroform, toluene, and tetrahydrofuran. Then, the PEG-grafted cellulose nanofibril/chloroform dispersion and poly(l-lactide) (PLLA)/chloroform solution were mixed, and the PEG-grafted cellulose nanofibril/PLLA composite films with various blend ratios were prepared by casting the mixtures on a plate and drying. The tensile strength, Young's modulus, and work of fracture of the composite films were remarkably improved, despite low cellulose addition levels (<1 wt %). The highly efficient nanocomposite effect was explained in terms of achievement of nanodispersion states of the PEG-grafted cellulose nanofibrils in the PLLA matrix. Moreover, some attractive interactions mediated by the PEG chains were likely to be formed between the cellulose nanofibrils and PLLA molecules in the composites, additionally enhancing the efficient nanocomposite effect. 23811129 TOCATTA: a dynamic transfer model of (3)H from the atmosphere to soil-plant systems. This paper describes a dynamic compartment model (TOCATTA) that simulates tritium transfer in agricultural plants of several categories including vegetables, pasture and annual crops, exposed to time-varying HTO concentrations of water vapour in the air and possibly in irrigation and rainwater. Consideration is also given to the transfer pathways of HTO in soil. Though the transfer of tritium is quite complex, from its release into the environment to its absorption and its incorporation within the organic material of living organisms, the TOCATTA model is relatively simple, with a limited number of compartments and input parameters appropriate to its use in an operational mode. In this paper, we took the opportunity to have data obtained on an ornamental plant - an indoor palm tree - within an industrial building where tritium was released accidentally over several weeks (or months). More specifically, the model's ability to provide hindsight on the chronology of the release scenario is discussed by comparing model predictions of TFWT and OBT activity concentrations in the plant leaves with measurements performed on three different leaves characterized by different developmental stages. The data-model comparison shows some limitations, mainly because of a lack of knowledge about the initial conditions of the accident and when it actually started and about the processes involved in the transfer of tritium. Efforts are needed in both experimental and modelling areas for future evaluation of tritium behaviour in agricultural soil and plants exposed to gaseous HTO releases and/or to irrigation with contaminated water. 23492985 Endovascular management of nonvariceal upper gastrointestinal hemorrhage. Upper gastrointestinal bleeding (UGIB) remains a frequent presentation in the emergency department. There are several causes of UGIB, which can be generally classified into variceal and nonvariceal bleeding. Although most cases of nonvariceal UGIB spontaneously resolve or respond to medical management and/or endoscopic treatment, transcatheter arterial embolization (TAE) remains an important available tool in the emergency evaluation and management of nonvariceal UGIB. In this article, we will discuss the current strategies for rendering a specific diagnosis of nonvariceal UGIB, and we will focus on the various TAE techniques for its management. We will also provide an algorithm for the diagnostic work-up of these patients. The majority of patients with nonvariceal UGIB that is refractory to endoscopic treatment is successfully treated with minimally invasive TAE and can avoid undergoing surgery. 22083351 A genomic approach to predict synergistic combinations for breast cancer treatment. We leverage genomic and biochemical data to identify synergistic drug regimens for breast cancer. In order to study the mechanism of the histone deacetylase (HDAC) inhibitors valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) in breast cancer, we generated and validated genomic profiles of drug response using a series of breast cancer cell lines sensitive to each drug. These genomic profiles were then used to model drug response in human breast tumors and show significant correlation between VPA and SAHA response profiles in multiple breast tumor data sets, highlighting their similar mechanism of action. The genes deregulated by VPA and SAHA converge on the cell cycle pathway (Bayes factor 5.21 and 5.94, respectively; P-value 10(-8.6) and 10(-9), respectively). In particular, VPA and SAHA upregulate key cyclin-dependent kinase (CDK) inhibitors. In two independent datasets, cancer cells treated with CDK inhibitors have similar gene expression profile changes to the cellular response to HDAC inhibitors. Together, these results led us to hypothesize that VPA and SAHA may interact synergistically with CDK inhibitors such as PD-033299. Experiments show that HDAC and CDK inhibitors have statistically significant synergy in both breast cancer cell lines and primary 3-dimensional cultures of cells from pleural effusions of patients. Therefore, synergistic relationships between HDAC and CDK inhibitors may provide an effective combinatorial regimen for breast cancer. Importantly, these studies provide an example of how genomic analysis of drug-response profiles can be used to design rational drug combinations for cancer treatment. 23920158 Developmental changes in BDNF protein in the song control nuclei of zebra finches. The zebra finch song system provides an excellent model to study the mechanisms underlying the development of sex difference in brain structure and function. Only male zebra finches sing and the brain nuclei controlling song learning and production are considerably larger than in females. Sexual differentiation may in part be regulated by estrogen, but other molecules including neurotrophic factors likely also affect masculinization. Brain derived neurotrophic factor (BDNF) plays a crucial role in numerous aspects of vertebrate brain development and function, including neurogenesis, cell survival, growth of axonal projections, synaptogenesis and processes linked to learning and memory. The current study investigated the expression of BDNF protein in juvenile males and females at four ages, as well as in adults, to begin to evaluate the potential roles of endogenous BDNF in particular stages of structural and functional development of the song system. In both HVC and the robust nucleus of the arcopallium (RA), males had more BDNF+ cells than females. The number of immunopositive cells increased in males and decreased in females as they matured, in a pattern generally consistent with a role for BDNF in sensorimotor integration of song learning. In addition, in HVC (but not RA) the ratio of mature BDNF compared to its precursor proBDNF was greater in adult males than those at post-hatching day 25, indicating a region-specific shift in the relative availability of the two forms. Collectively, the data suggest that changes in BDNF protein expression across development may be associated with song system maturation, particularly during the sensorimotor integration of masculine vocalizations. 23229440 Phase transition-induced elasticity of α-helical bioelastomeric fibres and networks. Natural elastomeric fibres play central structural and functional roles in a variety of tissues produced by many organisms from diverse Phyla. Most of these fibres feature amorphous structure and their long-range elastic response is well described within the framework of entropic (rubber-like) elasticity. Recently, it has been recognized that long-range reversible deformation can also occur in biomacromolecular fibres or networks that feature significant secondary structure and long-range order. Their elastomeric response is then associated with conformational changes of the backbone of the constitutive protein-based polymers. Under axially imposed loads, several groups of proteins whose structure is dominated by α-helical coiled-coil structures can undergo unfolding transitions and secondary structure transformations, for example from coiled-coil α-helices to β-sheet strands. In contrast to rubber-like biopolymers, the retractive elastic force in these biomacromolecular materials is not dominated by a return to a maximum entropic state, but is mostly the result of variations in internal energy associated with the conformational changes. Here, a review of α-helix based elastomeric materials is presented that encompasses examples and experimental evidence across multiple length scales, from the molecular to the macroscopic scale. We begin by summarizing the basic thermodynamic formalism of thermoelasticity. While this formalism is well established for amorphous (entropically-dominated) fibres under tensile loading, its extension towards conformational (internal energy-dominated) elasticity is less known. Recent experimental evidence as well as corroborating computer simulations are then reviewed and discussed in the light of secondary structure and nano-scale features of these biopolymers. Comparisons are also drawn with physiologically important structural fibres that share common characteristics at the molecular and the nano-scale, including intermediate filament (IF) proteins from the cell cytoskeleton, myosins from motor proteins, and fibrin from blood clot. We conclude with a discussion on future directions and opportunities for these materials from a biomimetics engineering perspective. 23861160 Cervical disc deformation during flexion-extension in asymptomatic controls and single-level arthrodesis patients. The aim of this study was to characterize cervical disc deformation in asymptomatic subjects and single-level arthrodesis patients during in vivo functional motion. A validated model-based tracking technique determined vertebral motion from biplane radiographs collected during dynamic flexion-extension. Level-dependent differences in disc compression-distraction and shear deformation were identified within the anterior and posterior annulus (PA) and the nucleus of 20 asymptomatic subjects and 15 arthrodesis patients using a mixed-model statistical analysis. In asymptomatic subjects, disc compression and shear deformation per degree of flexion-extension progressively decreased from C23 to C67. The anterior and PA experienced compression-distraction deformation of up to 20%, while the nucleus region was compressed between 0% (C67) and 12% (C23). Peak shear deformation ranged from 16% (at C67) to 33% (at C45). In the C5-C6 arthrodesis group, C45 discs were significantly less compressed than in the control group in all disc regions (all p ≤ 0.026). In the C6-C7 arthrodesis group, C56 discs were significantly less compressed than the control group in the nucleus (p = 0.023) and PA (p = 0.014), but not the anterior annulus (AA; p = 0.137). These results indicate in vivo disc deformation is level-dependent, and single-level anterior arthrodesis alters the compression-distraction deformation in the disc immediately superior to the arthrodesis. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. 23411313 Effects of various pressing programs and yields on the antioxidant activity, antimicrobial activity, phenolic content and colour of pomegranate juices. Pomegranate juice (PJ) samples were produced with three different pressing programs: (1) 1.2-4.8 bar for 25 min, (2) 1.2-2.4 bar for 15 min and (3) 1.2-1.8 bar for 5.5 min. Respective juice yields were 39.2%, 33.2% and 27.2%. Effects of pressing pressure-time and yield on total phenolic (TP) content, condensed tannin (CT) content, monomeric anthocyanin (MA) content, antioxidant activity (AOA) and antimicrobial activity (AMA) of the samples were determined. Strong positive linear correlations were found between the pressing pressure with AOA (r=0.973) and TP content (r=0.979), while negative logarithmic correlations were found between pressing pressure with the contents of CT (r=-0.778) and MA (r=-0.955). Among 12 microorganisms tested, Bacillus megaterium, Bacillus subtilis, Staphyloccocus aureus and Pseudomonas sp. were found to be sensitive to juice samples. However, increasing pressing pressure and yield did not lead to a significant change on the AMAs of the juices. 23829423 Factors Impacting Treatment Outcomes in the Endoscopic Management of Walled-off Pancreatic Necrosis. Treatment outcomes are suboptimal for patients undergoing endoscopic treatment of walled-off pancreatic necrosis (WOPN). The objective of this study is to identify factors that impact treatment outcomes in this patient subset. This is a retrospective study of patients with WOPN treated endoscopically over 10 years. Patients underwent placement of stents and nasocystic catheters within the necrotic cavity. In select patients, the multiple transluminal gateway technique (MTGT) was adopted to create several openings in the stomach or duodenum to facilitate drainage of necrosis. In patients with disconnected pancreatic duct syndrome (DPDS) the transmural stents were left in place indefinitely to decrease pancreatic fluid collection (PFC) recurrence. Endoscopic treatment was successful in 53 of 76 (69.7%) patients. Treatment success was higher in patients undergoing MTGT than conventional drainage (94.4% vs. 62.1%, p=0.009). On multivariate logistic regression analysis, only MTGT (OR 15.8; 95% CI, 1.77-140.8, p=0.01) and the need for fewer endoscopic sessions (OR 4.0; 95% CI, 1.16-14.0, p=0.03) predicted treatment success. PFC recurrence was significantly lower in patients with indwelling transmural stents than when the stents were removed (0 vs. 20.8%; p=0.02). Creating multiple gateways for drainage of necrotic debris improves treatment success and not removing the transmural stents decreases PFC recurrence in patients undergoing endoscopic drainage of WOPN. 23916705 Canonical Wnts, specifically Wnt-10b, show ability to maintain dermal papilla cells. Although Wnts are expressed in hair follicles (HFs) and considered to be crucial for maintaining dermal papilla (DP) cells, the functional differences among them remain largely unknown. In the present study, we investigated the effects of Wnts (Wnt-3a, 5a, 10b, 11) on the proliferation of mouse-derived primary DP cells in vitro as well as their trichogenesis-promoting ability using an in vivo skin reconstitution protocol. Wnt-10b promoted cell proliferation and trichogenesis, while Wnt-3a showed those abilities to a limited extent, and Wnt-5a and 11 had no effects. Furthermore, we investigated the effects of these Wnts on cultured DP cells obtained from versican-GFP transgenic mice and found that Wnt-10b had a potent ability to sustain their GFP-positivity. These results suggest that canonical Wnts, specifically Wnt-10b, play important roles in the maintenance of DP cells and trichogenesis. 23092130 Thermosensitive polymeric hydrogels as drug delivery systems. Thermosensitive hydrogels are very important biomaterials used in drug delivery systems (DDSs), which gained increasing attention of researchers. Thermosensitive hydrogels have great potential in various applications, such as drug delivery, cell encapsulation, tissue engineering, and etc. Especially, injectable thermosensitive hydrogels with lower sol-gel transition temperature around physiological temperature have been extensively studied. By in vivo injection, the hydrogels formed non-flowing gel at body temperature. Upon incorporation of pharmaceutical agents, the hydrogel systems could act as sustained drug release depot in situ. Injectable thermosensitive hydrogel systems have a number of advantages, including simplicity of drug formulation, protective environment for drugs, prolonged and localized drug delivery, and ease of application. The objective of this review is to summarize fundamentals, applications, and recent advances of injectable thermosensitive hydrogel as DDSs, including chitosan and related derivatives, poly(N-isopropylacrylamide)-based (PNIPAAM) copolymers, poly(ethylene oxide)/poly(propylene oxide) (PEO/PPO) copolymers and its derivatives, and poly(ethylene glycol)/ biodegradable polyester copolymers. 23907512 Tat-Collapsin Response Mediator Protein 2 (CRMP2) Increases the Survival of Neurons After NMDA Excitotoxity by Reducing the Cleavage of CRMP2. Collapsin response mediator protein 2 (CRMP2) is a brain-specific multifunctional adaptor protein involved in neuronal polarity and axonal guidance. Our previous results showed CRMP2 may be involved in the hypoxic preconditioning and ischemic injury, but the mechanism was not clear. This study explored whether CRMP2 was involved in NMDA-induced neural death, and the possible mechanism. Western blot analysis demonstrated that NMDA reduced the phosphorylation of CRMP2 and inspired the cleavage of CRMP2. Also, it was detected that NMDA treatment did not affect the phosphorylation of CRMP2 in early stage (<6 h). Over-expression of CRMP2 aggravated the NMDA-induced injury, suggesting the vital role of CRMP2 in excitotoxicity. Tat-CRMP2 was designed to provide the cleavage site of calpain. Thiazolyl blue tetrazolium bromide assay, Hoechst33342/Propidium Iodide staining and Western blot assay showed that Tat-CRMP2 pretreatment increased cell viability compared with the control group against NMDA exposure by decreasing the cleavage of CRMP2. In conclusion, these studies indicated that cleavage of CRMP2 plays an important role involved in the NMDA-induced injury. The cleavage of CRMP2 may be a promising target for excitatory amino acid-related ischemic and hypoxic injury. 23281421 Inclusion of pediatric samples in an opt-out biorepository linking DNA to de-identified medical records: pediatric BioVU. The Vanderbilt DNA repository, BioVU, links DNA from leftover clinical blood samples to de-identified electronic medical records (EMRs). After initiating adult sample collection, pediatric extension required consideration of ethical concerns specific to pediatrics and implementation of specialized DNA extraction methods. In the first year of pediatric sample collection, more than 11,000 samples from individuals younger than 18 years were included. We compared data from the pediatric BioVU cohort with those from the overall Vanderbilt University Medical Center pediatric population and found similar demographic characteristics; however, the BioVU cohort had higher rates of select diseases, medication exposures, and laboratory testing, demonstrating enriched representation of severe or chronic disease. The fact that the sample accumulation is not balanced may accelerate research in some cohorts while limiting the study of relatively benign conditions and the accrual of unaffected and unbiased control samples. BioVU represents a feasible model for pediatric DNA biobanking but involves both ethical and practical considerations specific to the pediatric population. 23595698 Doxycycline restrains glia and confers neuroprotection in a 6-OHDA Parkinson model. Neuron-glia interactions play a key role in maintaining and regulating the central nervous system. Glial cells are implicated in the function of dopamine neurons and regulate their survival and resistance to injury. Parkinson's disease is characterized by the loss of dopamine neurons in the substantia nigra pars compacta, decreased striatal dopamine levels and consequent onset of extrapyramidal motor dysfunction. Parkinson's disease is a common chronic, neurodegenerative disorder with no effective protective treatment. In the 6-OHDA mouse model of Parkinson's disease, doxycycline administered at a dose that both induces/represses conditional transgene expression in the tetracycline system, mitigates the loss of dopaminergic neurons in the substantia nigra compacta and nerve terminals in the striatum. This protective effect was associated with: (1) a reduction of microglia in normal mice as a result of doxycycline administration per se; (2) a decrease in the astrocyte and microglia response to the neurotoxin 6-OHDA in the globus pallidus and substantia nigra compacta, and (3) the astrocyte reaction in the striatum. Our results suggest that doxycycline blocks 6-OHDA neurotoxicity in vivo by inhibiting microglial and astrocyte expression. This action of doxycycline in nigrostriatal dopaminergic neuron protection is consistent with a role of glial cells in Parkinson's disease neurodegeneration. The neuroprotective effect of doxycycline may be useful in preventing or slowing the progression of Parkinson's disease and other neurodegenerative diseases linked to glia function. 23314682 Freezing Fingers Syndrome, Primary and Secondary Raynaud's Phenomenon: Characteristic Features with Hand Thermography. The aim of the present study was to establish a thermographic model of healthy subjects' hands and compare it with a model of the hands of patients with freezing fingers syndrome, a group usually regarded as a healthy population. A further aim was to establish the thermographic parameters that distinguish primary Raynaud's pheno-menon (RP) from secondary RP. The study was conducted on a group of 74 subjects, divided into 3 groups: patients with freezing hands symptoms (G1), those with primary RP (G2), and those with limited scleroderma (G3). In addition, 69 healthy volunteers served as a control group (G4). The most distinctive features of healthy subjects' hands are the thermal symmetry between left to right measurements (ΔT<0.5°C) and between mean temperatures of the metacarpus and digits (ΔT<0.5°C (1°C maximum)). A negative correlation was found between mean hands temperature and age of subjects in G4 (p < 0.0001). All the temperatures observed in G4 subjects were significantly higher than among patients in G1, G2 and G3 (p < 0.001). No significant differences were found between mean temperatures in G2 and G3. RP should be suspected when differences between mean temperatures of the metacarpus and digits are ≥ to 3ºC. Moreover, we suggest that a cut-off point > 1ºC is established for subjects with "freezing" symptoms. 23552625 Temporal variability in soil microbial communities across land-use types. Although numerous studies have investigated changes in soil microbial communities across space, questions about the temporal variability in these communities and how this variability compares across soils have received far less attention. We collected soils on a monthly basis (May to November) from replicated plots representing three land-use types (conventional and reduced-input row crop agricultural plots and early successional grasslands) maintained at a research site in Michigan, USA. Using barcoded pyrosequencing of the 16S rRNA gene, we found that the agricultural and early successional land uses harbored unique soil bacterial communities that exhibited distinct temporal patterns. α-Diversity, the numbers of taxa or lineages, was significantly influenced by the sampling month with the temporal variability in α-diversity exceeding the variability between land-use types. In contrast, differences in community composition across land-use types were reasonably constant across the 7-month period, suggesting that the time of sampling is less important when assessing β-diversity patterns. Communities in the agricultural soils were most variable over time and the changes were significantly correlated with soil moisture and temperature. Temporal shifts in bacterial community composition within the successional grassland plots were less predictable and are likely a product of complex interactions between the soil environment and the more diverse plant community. Temporal variability needs to be carefully assessed when comparing microbial diversity across soil types and the temporal patterns in microbial community structure can not necessarily be generalized across land uses, even if those soils are exposed to the same climatic conditions. 23880595 Are dopamine D2 receptors out of control in psychosis? It is known that schizophrenia patients are behaviorally supersensitive to dopamine-like drugs (amphetamine, methylphenidate). There is evidence for an increased release of dopamine, a slight increase of dopamine D2 receptors and an increase of dopamine D2High receptors in schizophrenia, all possibly explaining the clinical supersensitivity to dopamine. The elevation in apparent D2High receptors in vivo in schizophrenia matches the elevation in D2High receptors in many animal models of psychosis. The increased amounts of D2High receptors in psychotic-like behavior in animals may result from a loss of control of D2 by various factors. These factors include the rate of phosphorylation and desensitization of D2 receptors by kinases, the attachment of arrestin to D2 receptors, internalization of D2 receptors, the rate of receptor de-phosphorylation, formation of D2 receptor dimers, and GTP regulation by various GTPases. While at present there are no statistically significant associations of any of these controlling factors and their genes with schizophrenia, investigation of D2High receptors in schizophrenia will require a new radioligand in order to selectively label D2High receptors in vivo in patients. Finally, haloperidol reduces the number of D2High receptors that are elevated by amphetamine, indicating that this therapeutic effect may occur clinically. 23879623 The expanding roles of 1-methyl-tryptophan (1-MT): In addition to inhibiting kynurenine production, 1-MT activates the synthesis of melatonin in skin cells. Indoleamine 2,3-dioxygenase (IDO1), the rate-limiting enzyme of tryptophan catabolism, has been strongly associated with the progression of malignancy and poor survival in melanoma patients. As a result, IDO1 is a leading target for interventions aimed at restoring melanoma immune surveillance. Here, in a scenario involving the tryptophan catabolism, we report that melatonin biosynthesis is driven by 1-methyl-tryptophan (1-MT), a competitive inhibitor of IDO1, in human fibroblasts, melanocytes and melanoma cells. In addition to melatonin biosynthesis, 1-MT induced the expression of tryptophan hydroxylase, arylalkylamine-N-acetyltransferase and hydroxyindole O-methyltransferase mRNA in fibroblasts and melanocytes. We observed a great variability in the levels of IDO1 mRNA expression and kynurenine release between skin cells and melanoma cell lines in response to IFN-γ, a classical IDO1 inducer. In this setting, melatonin was shown to down-regulate kynurenine production. Furthermore, in a condition of low basal activity of IDO1, it was observed that 1-MT, as well melatonin, inhibited the proliferation of human melanoma cells. Taken together, our results suggest that 1-MT may serve as more than just a tool to disrupt tumor immune escape (via the inhibition of IDO1) because it was shown to directly act on the proliferation of human melanoma cells and induce melatonin biosynthesis in the tumor milieu. Moreover, 1-MT-mediated inhibition of IDO occurs in normal skin and melanoma cells, which addresses the possibility that all cells in the skin microenvironment can be targeted by 1-MT. Our findings provide innovative approaches into understanding tumor therapy related to the control of tryptophan metabolism by 1-MT. This article is protected by copyright. All rights reserved. 23668258 Postoperative pain, nausea and vomiting following adeno-tonsillectomy - a long-term follow-up. Adenotonsillectomy is a common pediatric surgical procedure. Our knowledge of the recovery profile, parental understanding, and expectations is limited. We aimed to assess the incidence of pain, nausea, and vomiting in children undergoing adenotonsillectomy on postoperative day 3 and 7. We also wished to evaluate parental understanding regarding discharge instructions as well as parental expectations and experience of their child's recovery. We enrolled 100 children (0-16 years) undergoing elective adenotonsillectomy. On day 3 and 7, parents were questioned about their child's level of pain, nausea/vomiting and their understanding regarding postoperative instructions. Hundred children (median, 6.68 years) were recruited. 52% of parents rated their child's pain as VAS â‰¥ 5 on day 3, dropping to 30% by day 7. Almost 33% of patients experienced nausea on day 3, dropping to 11.6% by day 7. A similar trend was observed for postoperative vomiting. Most parents, 89%, agreed that postoperative instructions were clear. However, knowledge regarding when to seek emergency medical advice was found to be lacking. On day 7, only 44% of parents reported that their child's recovery met their expectations. Adenotonsillectomy is associated with significant pain and PONV, persisting into the seventh postoperative day. Parental education and information seems inadequate and needs to be improved. 23850490 Histone H2B Ubquitination Regulates Retinoic Acid Signaling through the Cooperation of ASXL1 and BAP1. Despite the importance of retinoic acid (RA) signaling and histone monoubiquitination in determining cell fate, the underlying mechanism linking the two processes is poorly explored. We describe that additional sex comb-like 1 (ASXL1) represses RA receptor activity by cooperating with BRCA1-associated protein 1 (BAP1), which contains the ubiquitin C-terminal hydrolase (UCH) domain. Both the UCH- and ASXL1-binding domains of BAP1 were required for cooperation. In contrast to Drosophila BAP1, mammalian BAP1 cleaved ubiquitin from histone H2B. As supported by BAP1 mutants, ASXL1 was critical for BAP1 recruitment to chromatin and its activation therein. ASXL1 requirement was supported using Asxl1 null mice embryonic fibroblasts. Both ASXL1 and BAP1 were downregulated during RA-induced P19 cell differentiation with concomitant increase of ubiquitinated H2B, leading to activation of Hox genes. Our data demonstrate the critical role of ASXL1 cooperation with BAP1 in cell differentiation through the regulation of RA signaling associated with H2B ubiquitination. 23853104 Depletion of the transcriptional coactivators megakaryoblastic leukaemia 1 and 2 abolishes hepatocellular carcinoma xenograft growth by inducing oncogene-induced senescence. Megakaryoblastic leukaemia 1 and 2 (MKL1/2) are coactivators of the transcription factor serum response factor (SRF). Here, we provide evidence that depletion of MKL1 and 2 abolishes hepatocellular carcinoma (HCC) xenograft growth. Loss of the tumour suppressor deleted in liver cancer 1 (DLC1) and the subsequent activation of RhoA were prerequisites for MKL1/2 knockdown-mediated growth arrest. We identified oncogene-induced senescence as the molecular mechanism underlying the anti-proliferative effect of MKL1/2 knockdown. MKL1/2 depletion resulted in Ras activation, elevated p16 expression and hypophosphorylation of the retinoblastoma (Rb) protein in DLC1-deficient HCC cells. Interestingly, reconstitution of HuH7 HCC cells with DLC1 also induced senescence. Evaluation of the therapeutic efficacy of MKL1/2 knockdown in vivo revealed that systemic treatment of nude mice bearing HuH7 tumour xenografts with MKL1/2 siRNAs complexed with polyethylenimine (PEI) completely abolished tumour growth. The regression of the xenografts was associated with senescence. Importantly, PEI-complexed MKL1 siRNA alone was sufficient for complete abrogation of HCC xenograft growth. Thus, MKL1/2 represent promising novel therapeutic targets for the treatment of HCCs characterized by DLC1 loss. 23347038 The mannose 6-phosphate-binding sites of M6P/IGF2R determine its capacity to suppress matrix invasion by squamous cell carcinoma cells. The M6P (mannose 6-phosphate)/IGF2R (insulin-like growth factor II receptor) interacts with a variety of factors that impinge on tumour invasion and metastasis. It has been shown that expression of wild-type M6P/IGF2R reduces the tumorigenic and invasive properties of receptor-deficient SCC-VII squamous cell carcinoma cells. We have now used mutant forms of M6P/IGF2R to assess the relevance of the different ligand-binding sites of the receptor for its biological activities in this cellular system. The results of the present study demonstrate that M6P/IGF2R does not require a functional binding site for insulin-like growth factor II for inhibition of anchorage-independent growth and matrix invasion by SCC-VII cells. In contrast, the simultaneous mutation of both M6P-binding sites is sufficient to impair all cellular functions of the receptor tested. These findings highlight that the interaction between M6P/IGF2R and M6P-modified ligands is not only important for intracellular accumulation of lysosomal enzymes and formation of dense lysosomes, but is also crucial for the ability of the receptor to suppress SCC-VII growth and invasion. The present study also shows that some of the biological activities of M6P/IGF2R in SCC-VII cells strongly depend on a functional M6P-binding site within domain 3, thus providing further evidence for the non-redundant cellular functions of the individual carbohydrate-binding domains of the receptor. 23790872 Structural characterization and immunostimulatory activity of a novel protein-bound polysaccharide produced by Hirsutella sinensis Liu, Guo, Yu & Zeng. HS002-II, a novel protein-bound polysaccharide with 44kDa molecular weight, was fractionated from submerged cultures of Hirsutella sinensis Liu, Guo, Yu & Zeng by DEAE-Sepharose and Sephacryl S200 chromatography. Based on the results of infrared spectroscopy, high performance liquid chromatography, methylation, amino acid analysis, NMR spectroscopy and atomic force microscopy, the polysaccharide moieties of HS002-II mainly contained a long backbone of (1→3)-linked α-d-ribofuranosyl units (1→4)-linked α-d-xylopyranosyl units and (1→4)-linked β-d-glucopyranosyl units, which was substituted at C-6. The two branches were β-d-mannopyranosyl residues and β-d-galactopyranosyl residues terminated with α-l-arabinopyranosyl residues, respectively. HS002-II consisted of 57.9% polysaccharide and 42.1% protein with the existence of N-type carbohydrate-protein linkage. In terms of the pro-inflammatory cytokines assay (NO, TNF-α, IL-1β and NF-κB) using murine macrophages cell line (RAW264.7), HS002-II exhibited significant immunomodulatory activity by stimulating the IκB-NF-κB pathway. 23946685 Curcumin attenuates radiation-induced inflammation and fibrosis in rat lungs. A beneficial radioprotective agent has been used to treat the radiation-induced lung injury. This study was performed to investigate whether curcumin, which is known to have anti-inflammatory and antioxidant properties, could ameliorate radiation-induced pulmonary inflammation and fibrosis in irradiated lungs. Rats were given daily doses of intragastric curcumin (200 mg/kg) prior to a single irradiation and for 8 weeks after radiation. Histopathologic findings demonstrated that macrophage accumulation, interstitial edema, alveolar septal thickness, perivascular fibrosis, and collapse in radiation-treated lungs were inhibited by curcumin administration. Radiation-induced transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF) expression, and collagen accumulation were also inhibited by curcumin. Moreover, western blot analysis revealed that curcumin lowered radiation-induced increases of tumor necrosis factor-α (TNF-α), TNF receptor 1 (TNFR1), and cyclooxygenase-2 (COX-2). Curcumin also inhibited the nuclear translocation of nuclear factor-κ B (NF-κB) p65 in radiation-treated lungs. These results indicate that long-term curcumin administration may reduce lung inflammation and fibrosis caused by radiation treatment. 23806684 LOX-1, a bridge between GLP-1R and mitochondrial ROS generation in human vascular smooth muscle cells. A growing body of evidence indicates that glucagon-like peptide-1 (GLP-1) agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors play an important role in modulating oxidant stress in vascular beds. However, the underlying mechanism of this process remains unclear. In recent studies, we observed an increase in GLP-1 receptor (GLP-1R) expression in the aorta of LOX-1 knock-out mice. Since LOX-1 is a pivotal regulator of reactive oxygen species (ROS), we conducted studies to identify relationship between LOX-1, ROS and GLP-1 agonism or DPP-4 antagonism. We observed a sustained decrease in GLP-1R expression in human vascular smooth muscle cells (VSMCs) treated with ox-LDL. When VSMCs were treated with different concentration of liraglutide (a GLP-1 agonist) or NVPDPP728 (a DPP-4 inhibitor), expression of ROS decreased compared with ox-LDL alone treatment. To further prove that LOX-1 plays a pivotal role in ROS and GLP-1R expression, we treated VSMCs with LOX-1 antibody or transfected cells with human LOX-1 cDNA. The inhibitory effect of ox-LDL on GLP-1R expression was reversed with anti-LOX-1 antibody treatment, while the inhibitory effect of liraglutide and NVPDPP728 on ROS generation was attenuated when cells were transfected with LOX-1 cDNA. Our results suggest that LOX-1 may play a bridging role in GLP-1 activation and ROS interaction. 23813702 Estimated Kidney Function Based on Serum Cystatin C and Risk of Subsequent Coronary Artery Calcium in Young and Middle-aged Adults With Preserved Kidney Function: Results From the CARDIA Study. Whether kidney dysfunction is associated with coronary artery calcium (CAC) in young and middle-aged adults who have a cystatin C-derived estimated glomerular filtration rate (eGFRcys) greater than 60 mL/min/1.73 m(2) is unknown. In the Coronary Artery Risk Development in Young Adults (CARDIA) cohort (recruited in 1985 and 1986 in Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California), we examined 1) the association of eGFRcys at years 10 and 15 and detectable CAC over the subsequent 5 years and 2) the association of change in eGFRcys and subsequent CAC, comparing those with stable eGFRcys to those whose eGFRcys increased (>3% annually over 5 years), declined moderately (3%-5%), or declined rapidly (>5%). Generalized estimating equation Poisson models were used, with adjustment for age, sex, race, educational level, income, family history of coronary artery disease, diabetes, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and tobacco use. Among 3,070 participants (mean age 35.6 (standard deviation, 4.1) years and mean eGFRcys 106.7 (standard deviation, 18.5) mL/min/1.73 m(2)), 529 had detectable CAC. Baseline eGFRcys was not associated with CAC. Moderate eGFRcys decline was associated with a 33% greater relative risk of subsequent CAC (95% confidence interval: 5, 68; P = 0.02), whereas rapid decline was associated with a 51% higher relative risk (95% confidence interval: 10, 208; P = 0.01) in adjusted models. In conclusion, among young and middle-aged adults with eGFRcys greater than 60 mL/min/1.73 m(2), annual decline in eGFRcys is an independent risk factor for subsequent CAC. 23861766 Cognitive Manic Symptoms in Bipolar Disorder Associated with Polymorphisms in the DAOA and COMT Genes. Bipolar disorder is characterized by severe mood symptoms including major depressive and manic episodes. During manic episodes, many patients show cognitive dysfunction. Dopamine and glutamate are important for cognitive processing, thus the COMT and DAOA genes that modulate the expression of these neurotransmitters are of interest for studies of cognitive function. Focusing on the most severe episode of mania, a factor was found with the combined symptoms of talkativeness, distractibility, and thought disorder, considered a cognitive manic symptoms (CMS) factor. 488 patients were genotyped, out of which 373 (76%) had talkativeness, 269 (55%) distractibility, and 372 (76%) thought disorder. 215 (44%) patients were positive for all three symptoms, thus showing CMS (Table 1). As population controls, 1,044 anonymous blood donors (ABD) were used. Case-case and case-control design models were used to investigate genetic associations between cognitive manic symptoms in bipolar 1 disorder and SNPs in the COMT and DAOA genes. [Table: see text]. The finding of this study was that cognitive manic symptoms in patients with bipolar 1 disorder was associated with genetic variants in the DAOA and COMT genes. Nominal association for DAOA SNPs and COMT SNPs to cognitive symptoms factor in bipolar 1 disorder was found in both allelic (Table 2) and haplotypic (Table 3) analyses. Genotypic association analyses also supported our findings. However, only one association, when CMS patients were compared to ABD controls, survived correction for multiple testing by max (T) permutation. Data also suggested interaction between SNPs rs2391191 in DAOA and rs5993883 in COMT in the case-control model. [Table: see text] [Table: see text]. Identifying genes associated with cognitive functioning has clinical implications for assessment of prognosis and progression. Our finding are consistent with other studies showing genetic associations between the COMT and DAOA genes and impaired cognition both in psychiatric disorders and in the general population. 23348497 ALDH16A1 is a novel non-catalytic enzyme that may be involved in the etiology of gout via protein-protein interactions with HPRT1. Gout, a common form of inflammatory arthritis, is strongly associated with elevated uric acid concentrations in the blood (hyperuricemia). A recent study in Icelanders identified a rare missense single nucleotide polymorphism (SNP) in the ALDH16A1 gene, ALDH16A1*2, to be associated with gout and serum uric acid levels. ALDH16A1 is a novel and rather unique member of the ALDH superfamily in relation to its gene and protein structures. ALDH16 genes are present in fish, amphibians, protista, bacteria but absent from archaea, fungi and plants. In most mammalian species, two ALDH16A1 spliced variants (ALDH16A1, long form and ALDH16A1_v2, short form) have been identified and both are expressed in HepG-2, HK-2 and HK-293 human cell lines. The ALDH16 proteins contain two ALDH domains (as opposed to one in the other members of the superfamily), four transmembrane and one coiled-coil domains. The active site of ALDH16 proteins from bacterial, frog and lower animals contain the catalytically important cysteine residue (Cys-302); this residue is absent from the mammalian and fish orthologs. Molecular modeling predicts that both the short and long forms of human ALDH16A1 protein would lack catalytic activity but may interact with the hypoxanthine-guanine phosphoribosyltransferase (HPRT1) protein, a key enzyme involved in uric acid metabolism and gout. Interestingly, such protein-protein interactions with HPRT1 are predicted to be impaired for the long or short forms of ALDH16A1*2. These results lead to the intriguing possibility that association between ALDH16A1 and HPRT1 may be required for optimal HPRT activity with disruption of this interaction possibly contributing to the hyperuricemia seen in ALDH16A1*2 carriers. 22965921 Self-rated right-left confusability and performance on the Money Road-Map Test. This study assessed the relationship between self-rated right-left confusability and performance on the Money Road-Map Test (MRMT). Eighty-six undergraduate university students (44 women and 42 men) rated right-left subjective confusability using a questionnaire, and then completed the MRMT. Low- and high-confusability groups were determined using self-rated confusability scores. The high-confusability participants were less accurate and slower than the low-confusability participants in completing the MRMT. Self-confusability ratings significantly correlated with both accuracy scores and completion times on the MRMT. Although, women showed a significantly greater inclination than men to judge themselves as being more prone to confusion in right-left discrimination, the male advantage was not observed in terms of accuracy of response: there was a significant difference only in the completion time on the MRMT. 23931943 From altruism to monetisation: Australian women's ideas about money, ethics and research eggs. We report the results of a qualitative study carried out in metropolitan Australia between 2009 and 2011 that canvassed the issue of payment for research oöcyte donation with participants drawn from three potential donor groups; fertility patients, reproductive donors and young, non-patient women. Research oöcytes are controversial tissues because women around the world have proved largely unwilling to donate them altruistically. In the ensuing international debate about procurement, the issue of money and its appropriate and inappropriate uses in tissue donation has taken centre stage. While there is now an abundance of expert commentary on this matter, there are almost no studies that probe this issue with potential donor populations. Our study asked the three groups of women about their understandings of altruistic, reimbursed, subsidised, compensated and paid donation for both reproductive and research eggs. We identify a resistance to the introduction of money into the sphere of reproductive donation, which the majority of respondents felt should remain an area of personalised gift relations. In the area of research donation we find a strong relationship between degrees of liquidity (the extent to which money is constrained or unconstrained) and a sense of ethical appropriateness. We also describe a culturally specific sense of fairness and equity among participants, associated with the relatively high public subsidisation of fertility treatment in Australia, which they used to benchmark their sense of appropriate and inappropriate uses of money. While the participant responses reflect the regulatory environment in Australia, particularly the absence of a US style market in reproductive oöcytes, they also make an important contribution to the global debate. 23935197 Type I IFNs Downregulate Myeloid Cell IFN-γ Receptor by Inducing Recruitment of an Early Growth Response 3/NGFI-A Binding Protein 1 Complex That Silences ifngr1 Transcription. The ability of type I IFNs to increase susceptibility to certain bacterial infections correlates with downregulation of myeloid cell surface IFNGR, the receptor for the type II IFN (IFN-γ), and reduced myeloid cell responsiveness to IFN-γ. In this study, we show that the rapid reductions in mouse and human myeloid cell surface IFNGR1 expression that occur in response to type I IFN treatment reflect a rapid silencing of new ifngr1 transcription by repressive transcriptional regulators. Treatment of macrophages with IFN-β reduced cellular abundance of ifngr1 transcripts as rapidly and effectively as actinomycin D treatment. IFN-β treatment also significantly reduced the amounts of activated RNA polymerase II (pol II) and acetylated histones H3 and H4 at the ifngr1 promoter and the activity of an IFNGR1-luc reporter construct in macrophages. The suppression of IFNGR1-luc activity required an intact early growth response factor (Egr) binding site in the proximal ifngr1 promoter. Three Egr proteins and two Egr/NGFI-A binding (Nab) proteins were found to be expressed in bone macrophages, but only Egr3 and Nab1 were recruited to the ifngr1 promoter upon IFN-β stimulation. Knockdown of Nab1 in a macrophage cell line prevented downregulation of IFNGR1 and prevented the loss of acetylated histones from the ifngr1 promoter. These data suggest that type I IFN stimulation induces a rapid recruitment of a repressive Egr3/Nab1 complex that silences transcription from the ifngr1 promoter. This mechanism of gene silencing may contribute to the anti-inflammatory effects of type I IFNs. 23357359 FTIR spectroscopic imaging of protein aggregation in living cells. Protein misfolding and aggregation are the hallmark of a number of diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and the prion diseases. In all cases, a naturally-occurring protein misfolds and forms aggregates that are thought to disrupt cell function through a wide range of mechanisms that are yet to be fully unraveled. Fourier transform infrared (FTIR) spectroscopy is a technique that is sensitive to the secondary structure of proteins and has been widely used to investigate the process of misfolding and aggregate formation. This review focuses on how FTIR spectroscopy and spectroscopic microscopy are being used to evaluate the structural changes in disease-related proteins both in vitro and directly within cells and tissues. Finally, ongoing technological advances will be presented that are enabling time-resolved FTIR imaging of protein aggregation directly within living cells, which can provide insight into the structural intermediates, time scale, and mechanisms of cell toxicity associated with aggregate formation. This article is part of a Special Issue entitled: FTIR in membrane proteins and peptide studies. 23768023 Cervical spine alignment, sagittal deformity, and clinical implications. This paper is a narrative review of normal cervical alignment, methods for quantifying alignment, and how alignment is associated with cervical deformity, myelopathy, and adjacent-segment disease (ASD), with discussions of health-related quality of life (HRQOL). Popular methods currently used to quantify cervical alignment are discussed including cervical lordosis, sagittal vertical axis, and horizontal gaze with the chin-brow to vertical angle. Cervical deformity is examined in detail as deformities localized to the cervical spine affect, and are affected by, other parameters of the spine in preserving global sagittal alignment. An evolving trend is defining cervical sagittal alignment. Evidence from a few recent studies suggests correlations between radiographic parameters in the cervical spine and HRQOL. Analysis of the cervical regional alignment with respect to overall spinal pelvic alignment is critical. The article details mechanisms by which cervical kyphotic deformity potentially leads to ASD and discusses previous studies that suggest how postoperative sagittal malalignment may promote ASD. Further clinical studies are needed to explore the relationship of cervical malalignment and the development of ASD. Sagittal alignment of the cervical spine may play a substantial role in the development of cervical myelopathy as cervical deformity can lead to spinal cord compression and cord tension. Surgical correction of cervical myelopathy should always take into consideration cervical sagittal alignment, as decompression alone may not decrease cord tension induced by kyphosis. Awareness of the development of postlaminectomy kyphosis is critical as it relates to cervical myelopathy. The future direction of cervical deformity correction should include a comprehensive approach in assessing global cervicalpelvic relationships. Just as understanding pelvic incidence as it relates to lumbar lordosis was crucial in building our knowledge of thoracolumbar deformities, T-1 incidence and cervical sagittal balance can further our understanding of cervical deformities. Other important parameters that account for the cervical-pelvic relationship are surveyed in detail, and it is recognized that all such parameters need to be validated in studies that correlate HRQOL outcomes following cervical deformity correction. 23494186 LDL Cholesterol Goals in High-Risk Patients: How Low Do We Go and How Do We Get There? It is widely recognised that low-density lipoprotein cholesterol (LDL-C) is one of the most important and modifiable risk factors for cardiovascular disease (CVD). Statins (HMG-CoA reductase inhibitors) have consistently been shown to decrease both LDL-C and CVD risk in almost all patient categories, with the exception of heart and kidney failure as well as advanced aortic stenosis. As a consequence, statins have become the cornerstone in current prevention guidelines. In patients who do not reach the LDL-C target, combination therapy with additional LDL-C lowering drugs (e.g. ezetimibe, bile acid sequestrants or fibrates) should be considered. Guidelines provide different LDL-C levels to strive for, depending on the CVD risk. In this review, we describe the rationale for these LDL-C targets and how these goals might be reached by current and future therapies. 23757334 Solvent-free synthesis of C10 and C11 branched alkanes from furfural and methyl isobutyl ketone. Our best results jet: C10 and C11 branched alkanes, with low freezing points, are synthesized through the aldol condensation of furfural and methyl isobutyl ketone from lignocellulose, which is then followed by hydrodeoxygenation. These jet-fuel-range alkanes are obtained in high overall yields (≈90%) under solvent-free conditions. 23454146 Neuroprotective effects of neolignans isolated from Magnoliae Cortex against glutamate-induced apoptotic stimuli in HT22 cells. In the course of screening for neuroprotective natural products, Magnoliae Cortex showed potent inhibition of hippocampal neuronal HT22 cell death. Obovatol, honokiol, and magnolol were isolated from the ethanolic extract of Magnoliae Cortex. Isolated compounds obovatol, honokiol, and magnolol were protective against 5mM glutamate-induced cell death. When cells were stressed using glutamate, cell viability decreased to 16.98±4.58% over the control (100.00±10.15%). In contrast, 10μM obovatol, 10μM honokiol, and 50μM magnolol increased cell viability to 91.80±1.70%, 93.59±1.93%, and 85.36±7.40%, respectively. The neuroprotective effects of obovatol and honokiol were attributable to the inhibition of intracellular reactive oxygen species production, followed by protection of the mitochondrial membrane potential (ΔΨm), recovery of Bcl-2 and Bid levels, inhibition of apoptosis-inducing factor expression, and phosphorylation of mitogen-activated protein kinases such as p38 kinases, extracellular signal-regulated kinases, and c-Jun N-terminal kinases. On the contrary, magnolol did not show any significant effect on the ΔΨm and apoptotic factors. Among three compounds, obovatol most strongly scavenged 2,2-diphenyl-1-picrylhydrazyl radicals and inhibited the elevation of intracellular reactive oxygen species levels in glutamate-stressed HT22 cells. These data suggest that obovatol and honokiol may have clinical applications for preventing neurodegenerative disorders. 23951078 De Novo Assembly and Characterization of the Transcriptome, and Development of SSR Markers in Wax Gourd (Benicasa hispida). Wax gourd is a widely used vegetable of Cucuribtaceae, and also has important medicinal and health values. However, the genomic resources of wax gourd were scarcity, and only a few nucleotide sequences could be obtained in public databases. In this study, we examined transcriptome in wax gourd. More than 44 million of high quality reads were generated from five different tissues of wax gourd using Illumina paired-end sequencing technology. Approximately 4 Gbp data were generated, and de novo assembled into 65,059 unigenes, with an N50 of 1,132 bp. Based on sequence similarity search with known protein database, 36,070 (55.4%) showed significant similarity to known proteins in Nr database, and 24,969 (38.4%) had BLAST hits in Swiss-Prot database. Among the annotated unigenes, 14,994 of wax gourd unigenes were assigned to GO term annotation, and 23,977 were found to have COG classifications. In addition, a total of 18,713 unigenes were assigned to 281 KEGG pathways. Furthermore, 6,242 microsatellites (simple sequence repeats) were detected as potential molecular markers in wax gourd. Two hundred primer pairs for SSRs were designed for validation of the amplification and polymorphism. The result showed that 170 of the 200 primer pairs were successfully amplified and 49 (28.8%) of them exhibited polymorphisms. Our study enriches the genomic resources of wax gourd and provides powerful information for future studies. The availability of this ample amount of information about the transcriptome and SSRs in wax gourd could serve as valuable basis for studies on the physiology, biochemistry, molecular genetics and molecular breeding of this important vegetable crop. 23777599 Stearoyl-CoA desaturase 1, elongase 6 and their fatty acid products and precursors are altered in ovariectomized rats with 17β-estradiol and progesterone treatment. Sex differences in monounsaturated fatty acid (MUFA) levels suggest ovarian hormones may affect MUFA biosynthesis. Sprague-Dawley rats (8 weeks of age) were ovariectomized or sham operated with ovariectomized rats implanted with a constant-release hormone pellet providing 17β-estradiol, progesterone, both or neither at 10 weeks of age. After 14 days, rats were fasted overnight and sacrificed to collect plasma and livers for analysis. Hepatic stearoyl-CoA desaturase (SCD1) expression was unchanged between ovariectomized and sham controls, as determined by microarray and immunoblotting. However, SCD1 protein was increased in rats treated with estradiol plus progesterone. Elongase 6 protein levels were increased with 17β-estradiol treatment compared with sham. Rats treated with 17β-estradiol and 17β-estradiol plus progesterone had increased 16:0, 18:0, 16:1n-7 and 18:1n-7 in hepatic and plasma phospholipids. Ovarian hormones appear to be involved with MUFA biosynthesis, but the relationship appears complex and involves elongase 6 and SCD1. 23611152 Attachment of pathogenic prion protein to model oxide surfaces. Prions are the infectious agents in the class of fatal neurodegenerative diseases known as transmissible spongiform encephalopathies, which affect humans, deer, sheep, and cattle. Prion diseases of deer and sheep can be transmitted via environmental routes, and soil is has been implicated in the transmission of these diseases. Interaction with soil particles is expected to govern the transport, bioavailability and persistence of prions in soil environments. A mechanistic understanding of prion interaction with soil components is critical for understanding the behavior of these proteins in the environment. Here, we report results of a study to investigate the interactions of prions with model oxide surfaces (Al2O3, SiO2) using quartz crystal microbalance with dissipation monitoring and optical waveguide light mode spectroscopy. The efficiency of prion attachment to Al2O3 and SiO2 depended strongly on pH and ionic strength in a manner consistent with electrostatic forces dominating interaction with these oxides. The presence of the N-terminal portion of the protein appeared to promote attachment to Al2O3 under globally electrostatically repulsive conditions. We evaluated the utility of recombinant prion protein as a surrogate for prions in attachment experiments and found that its behavior differed markedly from that of the infectious agent. Our findings suggest that prions would tend to associate with positively charged mineral surfaces in soils (e.g., iron and aluminum oxides). 23839420 153 Cost-Utility and Comparative Effectiveness Analyses of Surgery vs Comprehensive Medical Management for Lumbar Spondylosis in Elderly. Surgical treatments of structural low back diseases are facing increasing scrutiny on whether their cost justifies the benefit to patients. This is particularly true in the management of the elderly, where perceived risk is higher and clinical utility less known. We performed a comparative effectiveness and CUA of surgery vs medical management in elderly with surgical degenerative lumbar disorders utilizing a prospective registry in a real-world practice setting. Ninety-five patients (≥65 yrs) with degenerative lumbar spondylosis (disc herniation, stenosis or spondylolisthesis) managed at a single institution were entered into a prospective registry. Surgical management consisted of lumbar diskectomy, laminectomy or fusion, while comprehensive medical management included spinal steroid injections, physical therapy, oral medications, and other therapies. Two-year patient-reported outcomes (PRO), medical resource utilization, and work-day losses were prospectively assessed via phone interview and used to calculate Medicare fee-based direct cost and indirect costs from occupation loss. Difference in mean total 2-year cost per QALY gained was assessed as incremental cost-effectiveness ratio (ICER). A total of 95 patients were included (surgical management = 45, medical management = 50). Baseline characteristics were similar between the 2 cohorts. Surgical management resulted in a significant (P < .001) 2-year improvement in all PROs (VAS, ODI, SF-12, EQ5D:QALY), while comprehensive medical management failed to provide significant improvement. Two-year gain in QALY was significantly greater after surgery (0.67) vs medical management (0.18). Total 2-year cost was significantly greater for surgery ($41,500) vs medical management ($14,000). The cost per QALY gained for surgery vs medical management (ICER) was $56,437. In this prospective real-world registry, surgery vs medical management for degenerative spine disease was shown to be cost-effective and provide greater 2-year improvement in pain, disability, and quality of life in elderly population. From a short-term cost-based purchasing prospective, prolonged medical management appears favorable (cheaper) in the elderly population. From a value-based purchasing perspective, prolonged medical management is an inferior treatment option. 23947625 HSV-1 activates NF-kappaB in mouse astrocytes and increases TNF-alpha and IL-6 expression via Toll-like receptor 3. To investigate the effect of HSV-1 infection via TLR3 on the transcriptional activity of NF-kappaB and the expression of cytokines TNF-alpha and IL-6 in astrocytes. HSV-1-infected primary astrocytes were cultured until the third passage and the mRNA and protein levels of TLR3, NF-kappaB, TNF-alpha, and IL-6 were assessed by immunofluorescence, RT-PCR, and Western blot. The effects of the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) and TLR3-neutralizing antibody on the expression of NF-kappaB, TNF-alpha, and IL-6 were investigated. Uninfected astrocytes expressed TLR3 and NF-kappaB at the mRNA and protein levels. After infection with HSV-1, the TLR3 mRNA and protein levels were up-regulated and NF-kappaB protein was highly expressed. Also, the mRNA and protein levels of TNF-alpha and IL-6 were up-regulated. Pyrrolidine dithiocarbamate inhibited NF-kappaB activation, resulting in the down-regulation of nuclear NF-kappaB protein, which led to the down-regulation of the mRNA and protein levels of TNF-alpha and IL-6. After blocking astrocyte membrane TLR3, the nuclear NF-kappaB protein expression was down-regulated and the mRNA and protein levels of TNF-alpha and IL-6 were increased. The antiviral functions of astrocytes were weaker, as reflected by higher HSV-1 glycoprotein D (gD) mRNA expression and increased HSV-1 titers. Astrocytes infected with HSV-1 can activate NF-kappaB via TLR3 so as to up-regulate the expression of TNF-alpha and IL-6 that have antiviral functions. 23927112 Influence of stimulus parameters on amplitude-modulated stimulus frequency otoacoustic emissions. The present study evaluated the influence of suppressor frequency (fs) and level (Ls) on stimulus-frequency otoacoustic emissions (SFOAEs) recorded using the amplitude-modulated (AM) suppressor technique described by Neely et al. [J. Acoust. Soc. Am. 118, 2124-2127 (2005a)]. Data were collected in normal-hearing subjects, with data collection occurring in two phases. In phase 1, SFOAEs were recorded with probe frequency (fp) = 1, 2, and 4 kHz and probe levels (Lp) ranging from 0 to 60 dB sound pressure level (SPL). At each fp, Ls ranged from Ls = Lp to Ls = Lp + 30 dB. Additionally, nine relationships between fs and fp were evaluated, ranging from fs/fp = 0.80 to fs/fp = 1.16. Results indicated that for low suppressor levels, suppressors higher in frequency than fp (fs > fp) resulted in higher AM-SFOAE levels than suppressors lower in frequency than fp (fs < fp). At higher suppressor levels, suppressors both higher and lower in frequency than fp produced similar AM-SFOAE levels, and, in many cases, low-frequency suppressors produced the largest response. Recommendations for stimulus parameters that maximize AM-SFOAE level were derived from these data. In phase 2, AM-SFOAEs were recorded using these parameters for fp = 0.7-8 kHz and Lp = 20-60 dB SPL. Robust AM-SFOAE responses were recorded in this group of subjects using the parameters developed in phase 1. 23588320 Intracellular drug concentrations and transporters: measurement, modeling, and implications for the liver. Intracellular concentrations of drugs and metabolites are often important determinants of efficacy, toxicity, and drug interactions. Hepatic drug distribution can be affected by many factors, including physicochemical properties, uptake/efflux transporters, protein binding, organelle sequestration, and metabolism. This white paper highlights determinants of hepatocyte drug/metabolite concentrations and provides an update on model systems, methods, and modeling/simulation approaches used to quantitatively assess hepatocellular concentrations of molecules. The critical scientific gaps and future research directions in this field are discussed. 23932225 Interoceptive-reflective regions differentiate alexithymia traits in depersonalization disorder. It is unclear to what degree depersonalization disorder (DPD) and alexithymia share abnormal brain mechanisms of emotional dysregulation. We compared cerebral processing of facial expressions of emotion in individuals with DPD to normal controls (NC). We presented happy and sad emotion expressions in increasing intensities from neutral (0%) through mild (50%) to intense (100%) to DPD and non-referred NC subjects in an implicit event-related fMRI design, and correlated respective brain activations with responses on the 20-item Toronto Alexithymia Scale (TAS-20) and its three subscales F1-F3. The TAS-20 predicts clinical diagnosis of DPD with a unique variance proportion of 38%. Differential regression analysis was utilized to ascertain brain regions for each alexithymia subscale. Differential regions of total alexithymia severity for happy emotion were the globus pallidus externus; for identifying feelings (TAS-20 F1 subscale), the right anterior insula; for description of feelings (F2), the right dorsal mid-anterior cingulate gyrus (BA 24); and for externally oriented cognitive style (F3), the left paracingulate gyrus (BA 32). For sad emotion, the differential region for the total TAS-20 score was the dorsal anterior cingulate gyrus (BA 24); for TAS-20 F1, the left inferior anterior insula; for TAS-20 F2, the right PCC (BA 31); and for TAS-20 F3, the right orbital gyrus (BA 10). Supporting our hypotheses, the ascertained brain regions for TAS-20 subscales subserve interoception, monitoring and reflection of internal states and emotion. The presented analyses provide evidence that alexithymia plays a substantial role in emotional dysregulation in DPD, presumably based on restrictions in interoception. 23836766 Nyctiphanes couchii as intermediate host for Rhadinorhynchus sp. (Acanthocephala, Echinorhynchidae) from NW Iberian Peninsula waters. In the mesozooplanktonic community of the coastal upwelling system of the Ría de Vigo (NW Spain), the euphausiid Nyctiphanes couchii has been identified for the first time in temperate waters of the NE Atlantic as the intermediate host for cystacanths of Rhadinorhynchus sp. Parasites were identified using morphological characters described in 20 cystacanths. The hooks of the proboscis were arranged in 14 rows of 26 hooks each, while the hooks of the basal circle were only slightly erected and were longer than remaining spines. A maximum-likelihood estimation (ML) tree inferred from the 18S rRNA data set of Palaeacantocephala revealed that our specimens belong to a highly supported clade with Rhadinorhynchus sp., Pararhadinorhynchus sp. and Transvena annulospinosa. Nonetheless, our morphological and phylogenetic analyses suggested that the status of Rhadinorhynchus pristis should be re-examined. The prevalences of parasites were 0.0019% and 0.0001% for frontal and coastal summer communities, and 0.0068% and 0.0008% for coastal and oceanic autumn communities, respectively. The presence of these cystacanths in different mesozooplankton communities throughout the study suggests that the recruitment of parasites may be affected by the oceanography. 23668224 Influence of periodic vs continuous daily bright light exposure on development of experimental myopia in the chick. In children, time spent outdoors has a protective effect against myopia development. In animal models, bright light reduces the development of experimental myopia. This study investigates how an increase in daily light exposure, presented either continuously during the day or periodically at different times of day, influences the development of experimental myopia in the chick. Myopia was induced in Cobb Chicks (Gallus domesticus) by monocular deprivation (MD) of form vision with a translucent diffuser for 3 days (from 4 days of age) under a 12:12 light: dark cycle. MD control chicks were exposed to constant 300 lux (n = 11) during the light period. MD treatment groups received either constant 2000 lux (n = 11) during the light period or 300 lux for 10 h with a 2 h period of bright light (10 000 lux), either in the morning (n = 10), midday (n = 10) or evening (n = 10), giving the same total daily light exposure as the 2000 lux group. After 3 days of MD, refractive status, corneal curvature and axial eye dimensions were measured for all eyes under anaesthesia. Myopia in the constant 2000 lux group (-4.94 ± 1.21 D) was significantly less than in the 300 lux control group (-9.73 ± 0.96 D; p = 0.022). However, compared to the 300 lux control group, 2 h periods of 10 000 lux did not produce significant effects on refraction when presented either in the morning (-9.98 ± 0.85; p = 1.00), midday (-8.00 ± 1.26; p = 0.80), or evening (-13.14 ± 1.16 D; p = 0.20), although significantly less myopia was induced in the midday group compared to the evening group (p = 0.018). Orthogonal regression showed that myopia development was matched by changes in vitreous chamber depth (R(2)  = 0.69; p < 0.0001). In chicks, an increase in daily light exposure continuously during the day is more effective at inhibiting myopia than adding an equivalent dose within a 2 h period of bright light. A weak time-of-day effect also appears to be present in the response to bright light exposure. Our results suggest that future light-based myopia therapies in humans may be more effective if light levels are increased over the whole day, rather than through short periods of bright light exposure. 23809292 Lab tests on the biodegradation of chemically dispersed oil should consider the rapid dilution that occurs at sea. Most crude oils spread on open water to an average thickness as low as 0.1mm. The application of dispersants enhances the transport of oil as small droplets into the water column, and when combined with the turbulence of 1m waves will quickly entrain oil into the top 1m of the water column, where it rapidly dilutes to concentrations less than 100ppm. In less than 24h, the dispersed oil is expected to mix into the top 10m of the water column and be diluted to concentrations well below 10ppm, with dilution continuing as time proceeds. Over the multiple weeks that biodegradation takes place, dispersed oil concentrations are expected to be below 1ppm. Measurements from spills and wave basin studies support these calculations. Published laboratory studies focused on the quantification of contaminant biodegradation rates have used concentrations orders of magnitude greater than this, as it was necessary to ensure the concentrations of hydrocarbons and other chemicals were higher than the detection limits of chemical analysis. However, current analytical methods can quantify individual alkanes and PAHs (and their alkyl homologues) at ppb and ppm levels. To simulate marine biodegradation of dispersed oil at dilute concentrations commonly encountered in the field, laboratory studies should be conducted at similarly low hydrocarbon concentrations. 23927388 Mesenteric Fat Thickness Is Associated With Increased Risk Of Obstructive Sleep Apnea. Mesenteric fat is a type of intraperitoneal adipose tissue draining into portal circulation. The objective of this study was to investigate the relationships between mesenteric fat thickness and obstructive sleep apnea (OSA) in patients with suspected OSA. 149 subjects (men:114, women:35) with suspected OSA underwent ultrasound examinations of mesenteric, preperitoneal and subcutaneous fat thickness after overnight polysomnography. BMI and neck circumference were recorded. The subjects with OSA (n=130, AHI>5/hr) had greater neck circumference, higher BMI, greater mesenteric and preperitoneal fat thickness than those without OSA (n=19, AHI<5/hr). There was positive correlation of AHI with mesenteric (r=0.43, p<0.001) and preperitoneal fat thickness (r=0.3, p<0.001) whereas no significant association was observed between AHI and subcutaneous fat thickness (r=0.09, p=0.27). On multivariate logistic regression, after adjustments for sex, age, BMI, neck circumference, preperitoneal and subcutaneous fat thickness, the mesenteric fat thickness had a positive association with the presence of moderate OSA and severe OSA, with odds ratios of 7.18 and 7.45 for every 1cm increase in mesenteric fat thickness when AHI was defined as >15/hr and AHI>30/hr respectively. Mesenteric fat thickness is associated with increased risk of OSA, independent of other abdominal fat thickness, BMI and neck circumference. Sonographic measurement is potentially a useful tool for further evaluating the complex association of visceral fat, metabolic syndrome and OSA. 23880142 The incidence of Parkinson's disease in the North-East of England. Parkinson's disease is a common disorder among older people. Accurate epidemiological information is essential to identify possible aetiological factors, plan health services and set priorities for medical research. to determine the incidence of idiopathic Parkinson's disease in a defined geographical area in the North-East of England. using a prospective, longitudinal design, we sought to identify every new case of Parkinson's disease arising in the Newcastle and Gateshead area in the North-East of England. The base population comprised 488 576 individuals and multiple sources of case ascertainment were employed. All the patients with newly diagnosed idiopathic Parkinson's disease or parkinsonism between 1 June 2009 and 31 May 2011 were invited to participate. Patients were examined by a specialist and followed longitudinally to permit diagnostic review. we identified 257 potential cases, of whom 181 had suspected idiopathic Parkinson's disease. After a follow-up period of 18 months, 155 patients retained a clinical diagnosis of probable Parkinson's disease. The mean age at diagnosis was 72.4 ± 10 years. The crude incidence of PD in Newcastle and Gateshead was 15.9 per 100 000 persons per year (95% CI: 13.4-18.4). Age-standardised to the European population the incidence of Parkinson's disease was 12.0 per 100 000 (95% CI: 10.1-14.0). We found a higher crude incidence among men 17.7 per 100 000 (95% CI: 14.0-21.4) than women 14.0 per 100 000 (95% CI: 10.7-17.4). in this prospective longitudinal study, the incidence rate of Parkinson's disease in North-East England is similar to that of other modern European and American studies. 23917905 Automated Measures of Hand Hygiene Compliance among Healthcare Workers Using Ultrasound: Validation and a Randomized Controlled Trial. Objective. The primary objective of this study was to validate a novel method of assessing hand hygiene compliance using ultrasound transmitters in patient zones and staff tagged with receivers. The secondary objective was to assess the impact of audio reminders and quantified individual feedback. Design. An observational comparison against manual assessment followed by assessment using an open-label randomized control method. Setting. Patient zones were established in 3 wards of 2 large teaching hospitals, including 88 general and 18 intensive care unit ward beds. Participants. Consented regular ward nursing, medical, and allied health staff. Methods. Concordance between 40 hours of manual observation using trained hand hygiene auditors and automated measures of opportunities and compliance. Subsequent measured interventions were reminder beeps and written individual feedback. Results. When compared with manual observations, ultrasound monitoring underestimated percentage compliances by a nonsignificant mean (95% confidence interval [CI]) difference of 5.2% (-20.1% to 9.8%; [Formula: see text]). After the intervention, adjusted multivariate analysis showed mean (95% CI) overall compliance in the intervention arm was 6.8% (2.5%-11.1%; [Formula: see text]) higher than in the control arm. Results stratified by compliance at entry and exit showed that the effect of intervention was stronger for compliance at exit than at entry. Conclusions. Our automated measure of hand hygiene compliance is valid when compared with the traditional gold standard of manual observations. As an interventional tool, ultrasound-based automated hand hygiene audits have significant benefit that can be built upon with enhancements and find increasing acceptance with time. 23163352 Solid-state NMR structure determination of whole anchoring threads from the blue mussel Mytilus edulis. The molecular structure of the blue mussel Mytilus edulis whole anchoring threads was studied by two-dimensional (13)C solid-state NMR on fully labeled fibers. This unique material proves to be well ordered at a molecular level despite its heterogeneous composition as evidenced by the narrow measured linewidths below 1.5 ppm. The spectra are dominated by residues in collagen environments, as determined from chemical shift analysis, and a complete two-dimensional assignment (including minor amino acids) was possible. The best agreement between predicted and experimental backbone chemical shifts was obtained for collagen helices with torsion angles (-75°, +150°). The abundant glycine and alanine residues can be resolved in up to five different structural environments. Alanine peaks could be assigned to collagen triple-helices, β-sheets (parallel and antiparallel), β-turns, and unordered structures. The use of ATR-FTIR microscopy confirmed the presence of these structural environments and enabled their location in the core of the thread (collagen helices and antiparallel β-sheets) or its cuticle (unordered structures). The approach should enable characterization at the molecular level of a wide range of byssus macroscopic properties. 23558600 Lixisenatide: first global approval. The selective once-daily prandial glucagon-like peptide-1 (GLP-1) receptor agonist lixisenatide (Lyxumia(®)) is under development with Sanofi for the treatment of type 2 diabetes mellitus. Lixisenatide belongs to a class of GLP-1 compounds designed to mimic the endogenous hormone GLP-1. Native GLP-1 stimulates insulin secretion in a glucose-dependent manner, as well as suppressing glucagon production and slowing gastric emptying. A once-daily subcutaneous formulation of lixisenatide has been approved in the EU, Iceland, Liechtenstein, Norway and Mexico for the treatment of type 2 diabetes, and is under regulatory review in the USA, Switzerland, Brazil, Canada, Ukraine, South Africa, Japan and Australia. This article summarizes the milestones in the development of lixisenatide, leading to this first approval for use in adults with type 2 diabetes. 23607712 Synaptotagmin 1 is required for vesicular Ca(2+) /H(+) -antiport activity. A low-affinity Ca(2+) /H(+) -antiport was described in the membrane of mammalian brain synaptic vesicles. Electrophysiological studies showed that this antiport contributes to the extreme brevity of excitation-release coupling in rapid synapses. Synaptotagmin-1, a vesicular protein interacting with membranes upon low-affinity Ca(2+) -binding, plays a major role in excitation-release coupling, by synchronizing calcium entry with fast neurotransmitter release. Here, we report that synaptotagmin-1 is necessary for expression of the vesicular Ca(2+) /H(+) -antiport. We measured Ca(2+) /H(+) -antiport activity in vesicles and granules of pheochromocytoma PC12 cells by three methods: (1) Ca(2+) -induced dissipation of the vesicular H(+) -gradient; (2) bafilomycin-sensitive calcium accumulation and (3) pH-jump-induced calcium accumulation. The results were congruent and highly significant: Ca(2+) /H(+) -antiport activity is detectable only in acidic organelles expressing functional synaptotagmin-1. In contrast, synaptotagmin-1-deficient cells - and cells where transgenically encoded synaptotagmin-1 was acutely photo-inactivated - were devoid of any Ca(2+) /H(+) -antiport activity. Therefore, in addition to its previously described functions, synaptotagmin-1 is involved in a rapid vesicular Ca(2+) sequestration through a Ca(2+) /H(+) antiport. This article is protected by copyright. All rights reserved. 23017416 Determination of volatile compounds in New Zealand Greenshell™ mussels (Perna canaliculus) during chilled storage using solid phase microextraction gas chromatography-mass spectrometry. Greenshell™ mussels (Perna canaliculus) were dry-stored at 6.44±0.54°C for 8 days during which time volatile organic compounds (VOCs) were monitored using SPME GC-MS. Thirty-four VOCs were identified in homogenised mussel meat and 29 in the mussel liquor (i.e. the seawater enclosed in the mantle cavity). Of the 34 VOCs identified 20 were reliably identified throughout the storage treatment and 9 were found to change in relative concentration in homogenised mussel meat. Dimethyl sulphide, 1-penten-3-ol, 1-hexen-3-ol and 1-octen-3-ol increased during storage, whereas pentanal, hexanal, heptanal, octanal and 3-undecen-2-one decreased. In the mussel liquor, dimethyl sulphide was undetectable pre-storage, becoming detectable after 2 days, and a large increase was noted after 6 days. SPME GC-MS was a useful tool for monitoring VOC profiles of Greenshell™ mussels and could aid in the development of technologies that monitor and improve product quality and consistency. 23194558 Principal component analysis of proteolytic profiles as markers of authenticity of PDO cheeses. The casein fraction of 13 Portuguese PDO cheeses were analysed using Urea-PAGE and reverse phase-high performance liquid chromatography (RP-HPLC) and then subjected to chemometric evaluation. The chemometric techniques of cluster analysis (CA) and principal component analysis (PCA) were used for the classification studies. Peptide mapping using Urea-PAGE followed by CA revealed two major clusters according to the similarity of the proteolytic profile of the cheeses. PCA results were in accordance with the grouping performed using CA. CA of RP-HPLC results of the matured cheeses revealed the presence of one major cluster comprising samples manufactured with only ovine milk or milk admixtures. When the results of CA technique were compared with the two PCA approaches performed, it was found that the grouping of the samples was similar. Both approaches, revealed the potential of proteolytic profiles (which is an essential aspect of cheese maturation) as markers of authenticity of PDO cheeses in terms of ripening time and milk admixtures not mentioned on the label. 22963188 Inferential dependencies in causal inference: A comparison of belief-distribution and associative approaches. Causal evidence is often ambiguous, and ambiguous evidence often gives rise to inferential dependencies, where learning whether one cue causes an effect leads the reasoner to make inferences about whether other cues cause the effect. There are 2 main approaches to explaining inferential dependencies. One approach, adopted by Bayesian and propositional models, distributes belief across multiple explanations, thereby representing ambiguity explicitly. The other approach, adopted by many associative models, posits within-compound associations-associations that form between potential causes-that, together with associations between causes and effects, support inferences about related cues. Although these fundamentally different approaches explain many of the same results in the causal literature, they can be distinguished, theoretically and experimentally. We present an analysis of the differences between these approaches and, through a series of experiments, demonstrate that models that distribute belief across multiple explanations provide a better characterization of human causal reasoning than models that adopt the associative approach. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23892451 Rapid and specific sensing of gallic acid with a photoelectrochemical platform based on polyaniline-reduced graphene oxide-TiO2. A novel photoelectrochemical sensor has been designed with polyaniline-reduced graphene oxide-titanium dioxide, which was further applied to sense gallic acid and exhibited extraordinary rapid response, high sensitivity and excellent anti-inference. Meanwhile, the mechanism has been elaborately explored. 23582969 Mannheimia haemolytica A1-induced Fibrinosuppurative Meningoencephalitis in a Naturally-infected Holstein-Friesian Calf. Mannheimia haemolytica is an opportunistic bacterium that is widely recognized among the bovine respiratory disease complex as the predominant pathogen causing broncho- and pleuropneumonia in cattle. Among the characterized M. haemolytica serotypes, A1 is the major cause of severe pulmonary lesions in cattle. This report describes post-mortem findings in a Holstein-Friesian calf with fibrinosuppurative meningoencephalitis and fibrinonecrotizing, haemorrhagic broncho- and pleuropneumonia, from which M. haemolytica and bovine viral diarrhoea virus (BVDV) were isolated. Microscopical evaluation showed expansion of the brainstem and cerebellar leptomeninges by neutrophils and fibrin, associated with gram-negative coccobacilli. Occasional blood vessels within the midbrain and cerebellum contained fibrin thrombi. Bacterial culture of cerebellum and lung yielded M. haemolytica with unusually high haemolytic activity. The isolates were confirmed as serotype A1 by rapid plate agglutination. Lung tissue was positive for BVDV by polymerase chain reaction. The broncho- and pleuropneumonia in this calf were consistent with typical mannheimiosis due to serotype A1; however, extrapulmonary infections due to M. haemolytica, as seen in this case, are rarely reported. To our knowledge, this is the first documentation of a natural BVDV and M. haemolytica co-infection associated with fibrinosuppurative meningoencephalitis in a calf. 23336826 The efficacy of outpatient and community-based aphasia group interventions: A systematic review. Abstract This paper examines the evidence for community and outpatient aphasia groups using the International Classification of Functioning, Disability and Health (ICF) framework. A systematic search of the literature using eight electronic databases was completed; 29 studies met inclusion and exclusion criteria. Level of evidence and methodological quality was assessed and effect sizes calculated where possible. Evidence favouring community and outpatient groups centred on four level ii and level iii-i studies that examined the efficacy of highly structured group activities for improving specific linguistic processes with five medium-large effect sizes calculated. Medium and large effect sizes were also calculated on a level iii-i study examining number of friendships and community access. No effect sizes were available for level ii or level iii studies examining communication activity and participation. Overall, the results indicate that community and outpatient group participation can improve specific linguistic processes. There is also some evidence that group participation can benefit social networks and community access. However, there is limited evidence demonstrating improvement in functional communication as a consequence of group participation. The current evidence is not comprehensive. Further well-designed studies, particularly examining activity and participation, and contextual factors are required to advance community and outpatient aphasia group practice and participation. 23670032 Pathology of spinal ependymomas: an institutional experience over 25 years in 134 patients. Ependymomas constitute approximately 40% of primary intraspinal tumors. Current World Health Organization (WHO) grading may not correlate with observed progression-free survival (PFS). This retrospective study of prospectively collected data examines whether PFS is influenced by the histological grade or by the extent of resection. It also analyzes the usage and effectiveness of postoperative adjuvant radiotherapy. We reviewed 134 consecutive patients with ependymomas of all grades. Pathology slides were re-reviewed and the histological grades were confirmed by a single neuropathologist. Postoperative residual or recurrence was evaluated with follow-up magnetic resonance imaging. There were 85 male and 49 female patients, ranging from 10 to 79 (median 41) years of age. Thirty patients had WHO grade I tumors, 101 had grade II tumors, and 3 had grade III tumors. Kaplan-Meier analysis of PFS demonstrated a mean duration of 6 years for grade I, 14.9 years for grade II, and 3.7 years for grade III (P < .001). In grade II ependymomas, mean PFS was 11.2 years with subtotal resection and 17.8 years with gross total resection (P < .01). PFS of patients who underwent subtotal resection was not significantly changed by adjuvant radiotherapy (P < .36). Patients with grade II ependymoma have significantly longer PFS than patients with grade I ependymoma. The extent of resection did not affect PFS in grade I ependymoma but it did in grade II. Contrary to its higher grade, WHO grade II ependymoma carries a better prognosis than WHO grade I ependymoma. ANOVA, analysis of varianceAWD, alive with diseaseDOC, dead of concurrent/intercurrent diseaseDUC, dead of unknown causeGTR, gross total resectionNED, alive with no evidence of diseasePFS, progression-free survivalSTR, subtotal resectionWHO, World Health OrganizationXRT, adjuvant radiotherapy. 23567080 Lysophosphatidylcholine acyltransferase 1 altered phospholipid composition and regulated hepatoma progression. Several lipid synthesis pathways play important roles in the development and progression of hepatocellular carcinoma (HCC), although the precise molecular mechanisms remain to be elucidated. Here, we show the relationship between HCC progression and alteration of phospholipid composition regulated by lysophosphatidylcholine acyltransferase (LPCAT). Molecular lipidomic screening was performed by imaging mass spectrometry (IMS) in 37 resected HCC specimens. RT-PCR and Western blotting were carried out to examine the mRNA and protein levels of LPCATs, which catalyze the conversion of lysophosphatidylcholine (LPC) into phosphatidylcholine (PC) and have substrate specificity for some kinds of fatty acids. We examined the effect of LPCAT1 overexpression or knockdown on cell proliferation, migration, and invasion in HCC cell lines. IMS revealed the increase of PC species with palmitoleic acid or oleic acid at the sn-2-position and the reduction of LPC with palmitic acid at the sn-1-position in HCC tissues. mRNA and protein of LPCAT1, responsible for LPC to PC conversion, were more abundant in HCCs than in the surrounding parenchyma. In cell line experiments, LPCAT1 overexpression enriched PCs observed in IMS and promoted cell proliferation, migration, and invasion. LPCAT1 knockdown did viceversa. Enrichment or depletion of some specific PCs, was found in HCC by IMS. Alteration of phospholipid composition in HCC would affect tumor character. LPCAT1 modulates phospholipid composition to create favorable conditions to HCC cells. LPCAT1 is a potent target molecule to inhibit HCC progression. 23793049 Data quality assessment for comparative effectiveness research in distributed data networks. Electronic health information routinely collected during health care delivery and reimbursement can help address the need for evidence about the real-world effectiveness, safety, and quality of medical care. Often, distributed networks that combine information from multiple sources are needed to generate this real-world evidence. We provide a set of field-tested best practices and a set of recommendations for data quality checking for comparative effectiveness research (CER) in distributed data networks. Explore the requirements for data quality checking and describe data quality approaches undertaken by several existing multi-site networks. There are no established standards regarding how to evaluate the quality of electronic health data for CER within distributed networks. Data checks of increasing complexity are often used, ranging from consistency with syntactic rules to evaluation of semantics and consistency within and across sites. Temporal trends within and across sites are widely used, as are checks of each data refresh or update. Rates of specific events and exposures by age group, sex, and month are also common. Secondary use of electronic health data for CER holds promise but is complex, especially in distributed data networks that incorporate periodic data refreshes. The viability of a learning health system is dependent on a robust understanding of the quality, validity, and optimal secondary uses of routinely collected electronic health data within distributed health data networks. Robust data quality checking can strengthen confidence in findings based on distributed data network. 23900346 Fluorescent organic nanocrystals and non-doped nanoparticles for biological applications. The recently developed fluorescent organic nanocrystals and non-doped nanoparticles (FONs) occupy a special position among other nanoparticle systems that are used for studying a variety of fundamental processes in the life sciences. Understanding their particular photophysical behavior allows proper design of FONs. The usual preparation methods are described. It is shown that FONs lead to original applications as biochemical sensors and biolabels for immunoassays. They also show high potentialities for bio-imaging of cell cultures, drug-delivery control, angiography and in vivo bio-imaging of solid tumors. 23886684 Synthesis of quaternary α-amino acid-based arginase inhibitors via the Ugi reaction. The Ugi reaction has been successfully applied to the synthesis of novel arginase inhibitors. In an effort to decrease conformational flexibility of the previously reported series of 2-amino-6-boronohexanoic acid (ABH) analogs 1, we designed and synthesized a series of compounds, 2, in which a piperidine ring is linked directly to a quaternary amino acid center. Further improvement of in vitro activity was achieved by adding two carbon bridge in the piperidine ring, that is, tropane analogs 11. These improvements in activity are rationalized by X-ray crystallography analysis, which show that the tropane ring nitrogen atom moves into direct contact with Asp202 (arginase II numbering). The synthetic routes described here enabled the design of novel arginase inhibitors with improved potency and markedly different physico-chemical properties compared to ABH. Compound 11c represents the most in vitro active arginase inhibitor reported to date. 23902642 Impacts of international sanctions on Iranian pharmaceutical market. Iran in recent decade faced several regional and international sanctions in foreign trade, financial and banking services. Iran national pharmaceutical industry has always played a major role in providing medicines to the Iranian patients. However, following the sanctions it has faced profound difficulties for importing of both finished products and pharmaceutical raw materials. Although medicines are exempted from sanctions, due to restriction on money transaction and proper insurance Iranian pharmaceutical companies have to pay cash in advance for imports of medicines and raw materials or to secure offshore funds at very high risks. Current situation in Iran pharmaceutical market confirms that the sanctions against Iran are affecting ordinary citizens and national health sector which resulted to reduction of availability of lifesaving medicines in the local market and has caused increasing pain and suffering for Iranian patients. 23291312 Cognitive, affective, and conative theory of mind (ToM) in children with traumatic brain injury. We studied three forms of dyadic communication involving theory of mind (ToM) in 82 children with traumatic brain injury (TBI) and 61 children with orthopedic injury (OI): Cognitive (concerned with false belief), Affective (concerned with expressing socially deceptive facial expressions), and Conative (concerned with influencing another's thoughts or feelings). We analyzed the pattern of brain lesions in the TBI group and conducted voxel-based morphometry for all participants in five large-scale functional brain networks, and related lesion and volumetric data to ToM outcomes. Children with TBI exhibited difficulty with Cognitive, Affective, and Conative ToM. The perturbation threshold for Cognitive ToM is higher than that for Affective and Conative ToM, in that Severe TBI disturbs Cognitive ToM but even Mild-Moderate TBI disrupt Affective and Conative ToM. Childhood TBI was associated with damage to all five large-scale brain networks. Lesions in the Mirror Neuron Empathy network predicted lower Conative ToM involving ironic criticism and empathic praise. Conative ToM was significantly and positively related to the package of Default Mode, Central Executive, and Mirror Neuron Empathy networks and, more specifically, to two hubs of the Default Mode Network, the posterior cingulate/retrosplenial cortex and the hippocampal formation, including entorhinal cortex and parahippocampal cortex. 23774818 The glomerular basement membrane as a barrier to albumin. The glomerular basement membrane (GBM) is the central, non-cellular layer of the glomerular filtration barrier that is situated between the two cellular components-fenestrated endothelial cells and interdigitated podocyte foot processes. The GBM is composed primarily of four types of extracellular matrix macromolecule-laminin-521, type IV collagen α3α4α5, the heparan sulphate proteoglycan agrin, and nidogen-which produce an interwoven meshwork thought to impart both size-selective and charge-selective properties. Although the composition and biochemical nature of the GBM have been known for a long time, the functional importance of the GBM versus that of podocytes and endothelial cells for establishing the glomerular filtration barrier to albumin is still debated. Together with findings from genetic studies in mice, the discoveries of four human mutations affecting GBM components in two inherited kidney disorders, Alport syndrome and Pierson syndrome, support essential roles for the GBM in glomerular permselectivity. Here, we explain in detail the proposed mechanisms whereby the GBM can serve as the major albumin barrier and discuss possible approaches to circumvent GBM defects associated with loss of permselectivity. 23824592 Anti-obesity and hypolipidaemic effects of Nelumbo nucifera seed ethanol extract in human pre-adipocytes and rats fed a high-fat diet. We conducted this investigation in order to examine the anti-obesity and hypolipidaemic effects of Nelumbo nucifera seed ethanol extract (NSEE) in vitro and in vivo. To study the anti-obesity effect of NSEE in vitro and in vivo, human pre-adipocytes were treated with NSEE, and male Sprague-Dawley rats were fed with a normal diet and a high-fat diet with or without NSEE, respectively. In vitro treatment with NSEE resulted in inhibition of lipid accumulation and decreased expression of peroxisome proliferator-activated receptor gamma (PPARγ), glucose transporter 4 (GLUT4), and leptin in cultured human adipocytes, indicating that it inhibited the differentiation of pre-adipocytes into adipocytes. Administration of NSEE resulted in significantly reduced body weight gain and adipose tissue weights in rats. Serum triglyceride and leptin level of the high-fat diet + NSEE group was significantly lower, compared to the high-fat group. These results demonstrate an inhibitory effect of NSEE on adipogenesis. In addition, NSEE had a beneficial effect, reducing adipose tissue weights, ameliorating blood lipid profile, and modulating serum leptin level in rats fed a high-fat diet. Therefore, we suggest that lotus seed has a potential to be developed as an effective agent against obesity-related diseases. © 2013 Society of Chemical Industry. 23962091 Atomic Layer Deposition of Platinum Catalysts on Nanowire Surfaces for Photoelectrochemical Water Reduction. The photocathodic hydrogen evolution reaction (HER) from p-type Si nanowire (NW) arrays was evaluated using platinum deposited by atomic layer deposition (ALD) as a HER cocatalyst. ALD of Pt on the NW surface led to a highly conformal coating of nanoparticles with sizes ranging from 0.5 to 3 nm, allowing for precise control of the Pt loading in deep submonolayer quantities. The catalytic performance was measured using as little as 1 cycle of Pt ALD, which corresponded to a surface mass loading of ∼10 ng/cm(2). The quantitative exploration of the lower limits of Pt cocatalyst loading reported here, and its application to high-surface-area NW photoelectrodes, establish a general approach for minimizing the cost of precious-metal cocatalysts for efficient and affordable solar-to-fuel applications. 23894005 Hyalinizing clear cell carcinoma of the parotid gland: Report of a recurrent case with aggressive cytomorphology and behavior diagnosed on fine-needle cytology sample. A case of recurrent hyalinizing clear cell carcinoma (HCCC) of the parotid gland in a 46-year-old female is here introduced. The patient had undergone a left superficial parotidectomy 6 months ago in another institution for an alleged benign, circumscribed mass 2.4 cm in diameter of the left parotid gland. Histopathological examination revealed a poorly differentiated HCCC bearing a EWSR-1 translocation on FISH examination. Fine Needle Cytology (FNC) was performed on three separate soft tissue masses in the pre-masseterine area and a cytological diagnosis of recurrent, poorly differentiated, possibly aggressive variant of HCCC, was rendered. FISH performed on a destained Diff Quik stained smear demonstrated an ESWR-1 translocation, which supported the cytopathological diagnosis. The cytomorphologic features and the differential diagnosis of this aggressive variant of HCCC are briefly discussed. Diagn. Cytopathol. 2013;. © 2013 Wiley Periodicals, Inc. 23524103 Lysozyme binds onto functionalized carbon nanotubes. Single walled carbon nanotubes have singular physicochemical properties making them attractive in a wide range of applications. Studies on carbon nanotubes and biological macromolecules exist in literature. However, ad hoc investigations are helpful to better understand the interaction mechanisms. We report on a system consisting of single walled carbon nanotubes and lysozyme. The phenomenology of nanotube-protein interactions and its effects on protein conformation were determined. We investigated the formation of oxidized nanotube-lysozyme conjugates, by studying the effect of both protein concentration and pH. Electrophoretic mobility, dielectric spectroscopy and dynamic light scattering were used to determine the interaction pathways, monitoring the surface charge density and the size of the complexes. The results allowed identifying the conditions of surface saturation at different pH values. The secondary structure of nanotube-adsorbed protein was controlled by circular dichroism; it was observed that it substantially retains its native conformation. Interestingly, we found that the interactions among oxidized nanotubes and lysozyme molecules are mainly of electrostatic nature and easily tunable by varying the pH of the solutions. 23703981 Quantum chemical study of the reactions between Pd+/Pt+ and H2O/H2S. The study of the reactions of water and hydrogen sulfide with palladium and platinum cations has been completed in this work, in both low- and high-spin states. Our calculations predict that only the formation of platinum sulfide is exothermic (in both spin states), whereas for the remaining species the oxides and sulfides are found to be more reactive than their corresponding bare metal cations. An in-depth analysis of the reaction paths leading to metal oxide and sulfide species is given, including various minima, and several important transition states. All results have been compared with existing experimental and theoretical data, and earlier works covering the reaction of nickel cation with water and hydrogen sulfide to observe the trends for the group 10 transition metals. 23701706 False-positive diatom test: A real challenge? A post-mortem study using standardized protocols. The main criticism of the validity of the diatom test for the diagnosis of drowning is based on the potential ante- and post-mortem penetration of diatoms and the finding of diatoms in bodies of non-drowned human beings. However, qualitative and quantitative studies on diatoms in organs of the non-drowned have yielded both conflicting and contradictory results. In the present study, we have analysed under standardised methods the diatom content in several organs of 14 non-drowned human bodies. Overall, only 9 diatoms (6 entire, 3 fragmented) were disclosed in 6 of the 14 non-drowned bodies. Each of these 6 cadavers had only a single "positive" organ. Six diatoms were found in the bone marrow, 2 in the lung, and one in the pleural liquid. No diatoms were recovered from the brain, liver, kidney, or blood samples of any of these 14 bodies. Moreover, in five additional cadavers, whose lungs were injected, prior autopsy, with a 3.5L solution containing a bi-cellulate diatom culture (Thalassiosira baltica, Thalassiosira levanderi) via tracheostomy, a few diatoms appeared in the pleural cavity and in the blood from the left heart chamber, but none in any other internal organs investigated. The results of the presented study demonstrate that the issue of the false-positive diatom test should not be a logical impediment to the performance of the diatom method. However, strict and standardized protocols aimed at avoiding contamination during sample preparation must be used, appropriate separation values set and taxonomic analysis of all diatoms performed. 23950675 Nuurcala obesa sp. n. (Blattida, Caloblattinidae) from the Lower Cretaceous Yixian Formation in Liaoning Province, China. Nuurcala obesa sp. n., in the cockroach family Caloblattinidae, is described from the Lower Cretaceous Yixian Formation (Liaoning Province, China) based on a combination of differential characters of fore- and hind wing venation, colouration and body structures. Systematically, Nuurcala (Vršanský, 2003), known from the Cretaceous sediments of Bon Tsagaan and Khurilt, Mongolia, is closely related to other genera of Caloblattinidae known from the Jurassic and Cretaceous localities in other parts of Asia. 23860622 The CTLA4 +49A/G polymorphism is associated with an increased risk of Hashimoto's thyroiditis in Asian but not Caucasian populations: an updated meta-analysis. The polymorphism +49A/G in the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene has been implicated in susceptibility to Hashimoto's thyroiditis (HT), but the findings are not clear-cut. This study aimed to investigate the association between CTLA-4 polymorphisms and HT risk using an updated meta-analysis. A meta-analysis was carried out of 14 previous studies that investigated the CTLA-4 +49A/G polymorphism and HT risk. +49A/G was associated with a significantly increased HT risk in both allele analysis and all genetic models (allele analysis: G vs. A: P < 0.001, OR = 1.379, 95 % CI = 1.244-1.529). Subgroup analysis by ethnicity showed a significantly increased HT risk with the G allele and all other genetic models in the Asian subgroup (P < 0.001). In the Caucasian subgroup, no significant association was detected between the CTLA-4 +49 G allele and HT, or in the genetic model analysis (P = 0.05). This gene-based analysis indicates that the cumulative effect of the +49A/G polymorphism in CTLA-4 is associated with HT in Asians, but appears to have no effect on HT in Caucasians. 23515965 Use of MTT assay for determination of the biofilm formation capacity of microorganisms in metalworking fluids. Biofilm formation is a well-known problem in management of metalworking fluid systems. Due to persistence of microorganisms within biofilms, the reappearance of various species of bacteria, including nontuberculous mycobacteria is often observed after the use of biocides and/or cleaning of delivery systems and replacement of cooling fluid. The aim of this study was to determine the usefulness of the tetrazolium salt assay (MTT assay) for assessing the viability of bacteria in biofilms formed in vitro in fresh and used cutting oils, as well as their susceptibility to antimicrobial biocides. Biofilms were established in the microtiter plate format. The results showed that quantification of formazan, a product of the tetrazolium salt reduction by electron transport system could be used for determination of the propensity of bacteria to form biofilms in these complex media. The use of the assay allows also determination of antimicrobial activity of biocides against biofilms in fresh and used metalworking fluids. Biofilms produced by Gram-negative isolates recovered from field metalworking fluids as well as the wild bacterial communities differed in metabolic activity depending on the type of fresh coolants. The MTT assay has high-throughput potential and can be efficiently used for determination of biofilm-forming capacity of microorganisms from individual machines in metalworking industry. The use of the assay may also guide the selection of the most appropriate biocide to fight these microorganisms. 23954467 Teroxirone inhibited growth of human non-small cell lung cancer cells by activating p53. In this work, we demonstrated that the growth of human non-small-cell-lung-cancer cells H460 and A549 cells can be inhibited by low concentrations of an epoxide derivative, teroxirone, in both in vitro and in vivo models. The cytotoxicity was mediated by apoptotic cell death through DNA damage. The onset of ultimate apoptosis is dependent on the status of p53. Teroxirone caused transient elevation of p53 that activates downstream p21 and procaspase-3 cleavage. The presence of caspase-3 inhibitor reverted apoptotic phenotype. Furthermore, we showed the cytotoxicity of teroxirone in H1299 cells with stable ectopic expression of p53, but not those of mutant p53. A siRNA-mediated knockdown of p53 expression attenuated drug sensitivity. The in vivo experiments demonstrated that teroxirone suppressed growth of xenograft tumors in nude mice. Being a potential therapeutic agent by restraining cell growth through apoptotic death at low concentrations, teroxirone provides a feasible perspective in reversing tumorigenic phenotype of human lung cancer cells. 23782695 Crystal Structures and RNA-binding Properties of the RNA Recognition Motifs of Heterogeneous Nuclear Ribonucleoprotein L: INSIGHTS INTO ITS ROLES IN ALTERNATIVE SPLICING REGULATION. Heterogeneous nuclear ribonucleoprotein L (hnRNP L) is an abundant RNA-binding protein implicated in many bioprocesses, including pre-mRNA processing, mRNA export of intronless genes, internal ribosomal entry site-mediated translation, and chromatin modification. It contains four RNA recognition motifs (RRMs) that bind with CA repeats or CA-rich elements. In this study, surface plasmon resonance spectroscopy assays revealed that all four RRM domains contribute to RNA binding. Furthermore, we elucidated the crystal structures of hnRNP L RRM1 and RRM34 at 2.0 and 1.8 Å, respectively. These RRMs all adopt the typical β1α1β2β3α2β4 topology, except for an unusual fifth β-strand in RRM3. RRM3 and RRM4 interact intimately with each other mainly through helical surfaces, leading the two β-sheets to face opposite directions. Structure-based mutations and surface plasmon resonance assay results suggested that the β-sheets of RRM1 and RRM34 are accessible for RNA binding. FRET-based gel shift assays (FRET-EMSA) and steady-state FRET assays, together with cross-linking and dynamic light scattering assays, demonstrated that hnRNP L RRM34 facilitates RNA looping when binding to two appropriately separated binding sites within the same target pre-mRNA. EMSA and isothermal titration calorimetry binding studies with in vivo target RNA suggested that hnRNP L-mediated RNA looping may occur in vivo. Our study provides a mechanistic explanation for the dual functions of hnRNP L in alternative splicing regulation as an activator or repressor. 23932772 Cardiovascular Disorders in Pregnancy: Diagnosis and Management. Cardiovascular diseases (CVDs) are a major cause of complications in pregnancy worldwide and the number of patients who develop cardiac problems during pregnancy is increasing. This review summarises recent literature on the aetiology and the underlying pathophysiology, diagnostic tools, risk stratification and prognosis in women who develop heart failure during pregnancy and in the peri-partum phase as well as in patients with pre-existing cardiomyopathies undergoing pregnancy. We specifically highlight peri-partum cardiomyopathy, valvular disease and Marfan's syndrome. Furthermore, we provide overviews on established treatment concepts and novel therapeutic strategies for these different disease types, stressing the point that pregnancy-associated cardiac disease requires interdisciplinary concepts for diagnosis, management and treatment. 23264586 Reconstruction with fascia lata after extensive chest wall resection: results. Following extensive chest wall resection, the reconstruction technique should fulfill two opposing functional requirements: adequate rigidity and flexibility of the chest wall during the breathing phases. Reconstruction with fascia lata enables a balance between these two parameters, thus favouring the patients' respiratory dynamics and producing low morbidity and good functional results. Sixty patients underwent chest wall reconstruction using fascia lata alone or in combination with titanium plates between 2006 and 2011, due to primary tumours in 28 patients, metastases in 23 and local recurrences in 9. The mean area of resected tissue was 107.7 cm(2), distributed among the anterior, anterolateral, lateral and posterior zones. One-to-eight ribs were resected, and additional sternum resection was performed in 75% of patients. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were evaluated in 33 patients. 46.6% of patients underwent reconstruction with fascia lata alone, 1.6% with fascia lata, DualMesh® and titanium plates and 51.6% with fascia lata and titanium plates. There was no 30-day mortality. All patients were extubated after the operation with no need for reintubation. Five patients had postoperative complications: 2 wound dehiscences, 2 haematomas and 1 seroma. There were no significant differences between preoperative and postoperative FEV1 and FVC measurements in patients with or without lobectomy and wedge resections. Chest wall reconstruction with fascia lata, alone or in combination with titanium plates, allows the surgeon to perform a dynamic reconstruction without flail chest in extensive exeresis. Risks of infection associated with the use of prosthetic materials are also minimized. In addition, the characteristic flexibility of this tissue makes it a precious tool in paediatric chest wall reconstruction, since fascia lata naturally adapts to the physiological growth of younger bodies, thus reducing the risk of scoliosis and local deformities. 23548478 The effects of bee pollen extracts on the broiler chicken's gastrointestinal microflora. The aim of this study was to investigate the effects of bee pollen ethanolic extracts on the in vivo gastrointestinal tract microflora colonization of broiler chickens. A completely randomized experiment based on six treatments (different concentrations of bee pollen - 0, 5, 15, 25, 35 and 45 g kg(-1) diet) was used during 7 weeks. The highest count of faecal Enterococci was found in the experimental group with the addition of 15 g of pollen (8.85 ± 0.87 log CFU g(-1)) per 1 kg of feed mixture. The highest count of Lactobacilli was detected in the experimental group with 35 g of pollen per 1 kg of feed mixture and the highest number of the Enterobacteriaceae genera count was found in the control group (8.43 ± 0.15 log CFU g(-1)). Moreover, the MALDI TOF MS Biotyper identified the following genera: Escherichia coli, Proteus mirabilis, Klebsiella oxytoca, as well as Lactobacillus acidophilus, L. crispatus, L. fermentum and L. salivarius from the Lactobacilli group and Enterococcus avium, E. casseliflavus, E. cecorum, E. faecalis, E. faecium, E. gallinarum, E. hirae and E. malodoratus from the Enterococci group. Additionally, the in vitro antimicrobial activities of pollen against five bacteria species isolated from gastrointestinal tracts of chickens were tested. The best antimicrobial effect of the pollen extract was detected against K. oxytoca. 23934631 Volume-to-creatinine clearance ratio in patients undergoing coronary angiography with or without percutaneous coronary intervention: Implications of varying definitions of contrast-induced nephropathy. Objectives - Whether predicting the risk of early serum creatinine rise using the ratio of the volume of contrast media administered to the estimated creatinine clearance (V/CrCl) is applicable to the broader definition of contrast-induced nephropathy (CIN) (≥0.5 mg/dL absolute and/or 25% relative increase from baseline serum creatinine) is unknown. Background - A V/CrCl ≥4 has been proven to predict the risk of ≥0.5 mg/dL post-procedural absolute rise in serum creatinine. Methods - A total of 722 patients undergoing coronary angiography±percutaneous coronary intervention (PCI) between March 2011 and October 2011 with paired serum creatinine determinations at pre- and within 72 hours post-procedure were analyzed. The V/CrCl ratio was calculated by dividing the volume of contrast received by the patient's creatinine clearance. CIN using different definitions was termed as CINnarrow (rise in serum creatinine ≥0.5 mg/dL) and CINbroad (rise in serum creatinine ≥0.5 mg/dL and/or ≥25% increase in baseline serum creatinine). Results - The mean age was 66±11 years and the mean baseline serum creatinine was 1.1±0.8 mg/dL. Patients with V/CrCl ≥4 were significantly older and more frequently underwent ad-hoc PCI compared with those with V/CrCl <4. CINnarrow and CINbroad were observed in 13% vs 3% (P<0.001) and 23% vs 11% (P<0.001) of patients with or without V/CrCl ≥4, respectively. After statistical adjustment, a V/CrCl ratio ≥4 remained significantly associated with the risk of both CINnarrow (adjusted OR 3.5, 95% CI 1.7-7.3; P<0.001) and CINbroad (adjusted OR 2.5, 95% 1.6-3.9; P<0.001). Conclusions - A volume-to-creatinine clearance ratio ≥4 significantly predicts the risk of early post-procedural rise in serum creatinine regardless of the CIN definition adopted. © 2013 Wiley Periodicals, Inc. 23892986 Autonomous molecular cascades for evaluation of cell surfaces. Molecular automata are mixtures of molecules that undergo precisely defined structural changes in response to sequential interactions with inputs. Previously studied nucleic acid-based automata include game-playing molecular devices (MAYA automata) and finite-state automata for the analysis of nucleic acids, with the latter inspiring circuits for the analysis of RNA species inside cells. Here, we describe automata based on strand-displacement cascades directed by antibodies that can analyse cells by using their surface markers as inputs. The final output of a molecular automaton that successfully completes its analysis is the presence of a unique molecular tag on the cell surface of a specific subpopulation of lymphocytes within human blood cells. 22914904 Prognostic value of highly sensitive troponin T on cardiac events in patients with chronic kidney disease not on dialysis. Serum troponin T levels using a highly sensitive assay (hsTnT) in patients with chronic kidney disease (CKD) not on dialysis have not been examined. The aim of this prospective cohort study was to investigate the association of hsTnT with cardiac events in ambulatory CKD patients not on dialysis. The serum hsTnT level was measured in 442 ambulatory CKD patients not on dialysis whose estimated glomerular filtration rate was <60 ml/min/1.73 m(2). Patients were divided into quartiles according to hsTnT levels, and were followed up for 3 years. Cardiac events were defined as a cardiac death, acute myocardial infarction, unstable angina pectoris that required emergency coronary revascularization, or hospitalization for worsening heart failure. During the follow-up period (median 22 months), 63 cardiac events occurred. Kaplan-Meier incidence rates of cardiac events for 3 years were 0.88 %, 11.5 %, 19.0 %, and 41.4 % among quartiles of hsTnT levels (P < 0.0001). After adjusting for other confounders, elevated hsTnT level was an independent predictor for cardiac events (hazard ratio 6.18, 95 % confidence interval 1.38-27.7, P = 0.0080 for highest quartile vs lowest quartile). In addition, C-index for receiver-operating characteristic curves for cardiac events was greater in an established risks plus hsTnT model than in the established risk alone model (0.857 vs 0.844, P = 0.026). Using a highly sensitive assay, serum hsTnT level was shown to be an independent predictor of cardiac events and a promising risk stratification tool in patients with CKD not on dialysis. 23097416 Parenting stress and neurocognitive late effects in childhood cancer survivors. Surveillance of neurocognitive late effects has typically focused on the pediatric survivor alone and rarely has focused on the potential family burden. We investigated the impact of child neurocognitive effects on parenting stress and hypothesized that parents of childhood cancer survivors with greater executive difficulties experience higher stress relative to parents of children with less adverse impact. Parents of 44 children who survived cancer involving central nervous system-directed treatments and who had documented neurocognitive deficits completed standardized questionnaires assessing their perceived level of stress and perception of their child's executive functioning abilities in daily life. Data from performance-based cognitive tests were obtained on the children. Multiple regression models examined socio-demographic, clinical, and child's executive functioning as predictors of parent stress. Differences in parenting stress based on child's level of executive functioning were evaluated. Parent stress was significantly associated with both performance-based and parent report measures of child executive functioning. Child executive functioning significantly predicted parent stress even after controlling for socio-demographic and clinical factors, and the final model accounted for 42% of the variance in parent stress levels. Significant differences in parent stress were found when comparing higher versus lower levels of child executive functioning. The nature of the executive difficulties, however, appears important, as we found increased parenting stress among children with behavioral regulation problems rather than metacognitive difficulties. The associations between parenting stress and neurocognitive problems found in this study suggest the need for further research, along with professional monitoring and appropriate intervention. Copyright © 2012 John Wiley & Sons, Ltd. 23872003 Stopped-flow DNA polymerase assay by continuous monitoring of dNTP incorporation by fluorescence. DNA polymerase activity was measured by a stopped-flow assay that monitors polymerase extension using an intercalating dye. Double-stranded DNA formation during extension of a hairpin substrate was monitored at 75°C for 2min. Rates were determined in nucleotides per second per molecule of polymerase (nt/s) and were linear with time and polymerase concentration from 1 to 50nM. The concentrations of 15 available polymerases were quantified and their extension rates determined in 50mM Tris, pH 8.3, 0.5mg/ml BSA, 2mM MgCl2, and 200μM each dNTP as well as their commercially recommended buffers. Native Taq polymerases had similar extension rates of 10-45nt/s. Three alternative polymerases showed faster speeds, including KOD (76nt/s), Klentaq I (101nt/s), and KAPA2G (155nt/s). Fusion polymerases including Herculase II and Phusion were relatively slow (3-13nt/s). The pH optimum for Klentaq extension was between 8.5 and 8.7 with no effect of Tris concentration. Activity was directly correlated to the MgCl2 concentration and inversely correlated to the KCl concentration. This continuous assay is relevant to PCR and provides accurate measurement of polymerase activity using a defined template without the need of radiolabeled substrates. 23861087 Development of a simple pressure and heat stimulator for intra- and interdigit functional magnetic resonance imaging. For this study, we developed a simple pressure and heat stimulator that can quantitatively control pressure and provide heat stimulation to intra- and interdigit areas. The developed stimulator consists of a control unit, drive units, and tactors. The control unit controls the stimulation parameters, such as stimulation types, intensity, time, and channel, and transmits a created signal of stimulation to the drive units. The drive units operate pressure and heat tactors in response to commands from the control unit. The pressure and heat tactors can display various stimulation intensities quantitatively, apply stimulation continuously, and adjust the stimulation areas. Additionally, they can easily be attached to and detached from the digits. The developed pressure and heat stimulator is small in total size, easy to install, and inexpensive to manufacture. The new stimulator operated stably in a magnetic resonance imaging (MRI) environment without affecting the obtained images. A preliminary functional magnetic resonance imaging (fMRI) experiment confirmed that differences in activation of somatosensory areas were induced from the pressure and heat stimulation. The developed pressure and heat stimulator is expected to be utilized for future intra- and interdigit fMRI studies on pressure and heat stimulation. 22972002 Clinical significance of preoperative peripheral blood neutrophil count in patients with non-metastatic upper urinary tract carcinoma. Preoperative elevation of markers of systemic inflammation is associated with a poor outcome in several cancers. The purpose of this study was to evaluate the prognostic significance of preoperative systemic inflammatory markers in patients with non-metastatic upper urinary tract cancer (UUTC). The records of 84 patients with non-metastatic UUTC who had undergone nephroureterectomy were reviewed, and the associations between preoperative clinical variables and recurrence-free survival (RFS) were analyzed by univariate and multivariate analyses. Clinical tumor stage, neutrophil count, and neutrophil-to-lymphocyte ratio were significantly associated with RFS in univariate analysis. Multivariate analysis showed that clinical T stage (hazard ratio [HR], 3.009; 95 % confidence interval [CI], 1.149-9.321; p = 0.024) and neutrophil count (HR, 3.521; 95 % CI, 1.423-9.108; p = 0.007) were independent predictors of RFS. The 3-year RFS in patients with a neutrophil count <4,000/μL was significantly higher than that in patients with a neutrophil count ≥4,000/μL (82.9 vs. 51.0 %, p = 0.004). Based on clinical T stage (T2 or less vs. T3 or greater) and neutrophil count (<4,000 vs. ≥4,000/μL), patients were stratified into 3 groups: low, intermediate, and high risk groups. RFS rates were significantly different between the 3 groups (p = 0.0005). Preoperative neutrophil count was an independent predictor of RFS in patients with non-metastatic UUTC. Stratification of patients based on neutrophil count and clinical T stage may be valuable for preoperative patient counseling and identifying patients with poor prognosis who may be candidates for neoadjuvant chemotherapy. 23649668 The corneal transplant score: a simple corneal graft candidate calculator. Shortage of corneas for transplantation has created long waiting lists in most countries. Transplant calculators are available for many organs. The purpose of this study is to describe a simple automatic scoring system for keratoplasty recipient candidates, based on several parameters that we consider most relevant for tissue allocation, and to compare the system's accuracy in predicting decisions made by a cornea specialist. Twenty pairs of candidate data were randomly created on an electronic spreadsheet. A single priority score was computed from the data of each candidate. A cornea surgeon and the automated system then decided independently which candidate in each pair should have surgery if only a single cornea was available. The scoring system can calculate values between 0 (lowest priority) and 18 (highest priority) for each candidate. Average score value in our randomly created cohort was 6.35 ± 2.38 (mean ± SD), range 1.28 to 10.76. Average score difference between the candidates in each pair was 3.12 ± 2.10, range 0.08 to 8.45. The manual scoring process, although theoretical, was mentally and emotionally demanding for the surgeon. Agreement was achieved between the human decision and the calculated value in 19 of 20 pairs. Disagreement was reached in the pair with the lowest score difference (0.08). With worldwide donor cornea shortage, waiting for transplantation can be long. Manual sorting of priority for transplantation in a long waiting list is difficult, time-consuming and prone to error. The suggested system may help achieve a justified distribution of available tissue. 23852275 Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3(+) regulatory T cells. Foxp3(+) regulatory T (Treg) cells are a crucial immunosuppressive population of CD4(+) T cells, yet the homeostatic processes and survival programs that maintain the Treg cell pool are poorly understood. Here we report that peripheral Treg cells markedly alter their proliferative and apoptotic rates to rapidly restore numerical deficit through an interleukin 2-dependent and costimulation-dependent process. By contrast, excess Treg cells are removed by attrition, dependent on the Bim-initiated Bak- and Bax-dependent intrinsic apoptotic pathway. The antiapoptotic proteins Bcl-xL and Bcl-2 were dispensable for survival of Treg cells, whereas Mcl-1 was critical for survival of Treg cells, and the loss of this antiapoptotic protein caused fatal autoimmunity. Together, these data define the active processes by which Treg cells maintain homeostasis via critical survival pathways. 23669337 Evaluation of an ompA-based phage-mediated DNA vaccine against Chlamydia abortus in piglets. Chlamydia abortus (C. abortus) is an obligate intracellular pathogen that causes abortion in pigs and poses a zoonotic risk in pregnant women. Although attenuated and inactivated vaccines are available, they do not provide complete protection in animals underlining the need to develop new vaccines. In this study, we tested the hypothesis that intramuscular immunization with an ompA-based phage-mediated DNA chlamydial vaccine candidate will induce significant antigen-specific cellular and humoral immune responses. Thus, groups of piglets (five per group) were immunized intramuscularly with the phage-MOMP vaccine (λ-MOMP) or a commercial live-attenuated vaccine (1B vaccine) or a GFP-expressing phage (λ-GFP) or phosphate buffered saline (PBS) (control) and antigen-specific cell-mediated and humoral immune responses were evaluated. By day 63 post-immunization, the λ-MOMP vaccine elicited significantly higher (P<0.05) levels of antigen-specific serum IgG antibody responses than the 1B vaccine or control did. Also, piglets immunized with λ-MOMP vaccine had significantly higher (P<0.05) MOMP-specific lymphocyte proliferative responses compared to those immunized with the 1B vaccine or control. Furthermore, the total T-cell numbers (CD3+) and the proportion of CD4+ and CD8+ T-cell subsets as well as the ratio of CD4+/CD8+ T cells elicited following immunization were comparable between the λ-MOMP- and 1B-vaccinated animals on both days 63 and 70. Interestingly, although the proportion of CD3+CD4-CD8- double negative T cells on day 63 was significantly higher (P<0.05) in the 1B vaccine group compared to the λ-MOMP-immunized group, there was a significant decrease in the proportion of this T-cell population on day 70 in the 1B compared to the λ-MOMP vaccinated group. These results indicate that the λ-MOMP DNA vaccine is capable of inducing antigen-specific cellular and humoral immune responses that may provide protective immunity against a live challenge infection with C. abortus. 23710833 Nerve stimulation for chronic pelvic pain and bladder pain syndrome: a systematic review. Chronic pelvic pain (CPP) and bladder pain syndrome (BPS) can have a negative impact on quality of life. Neuromodulation has been suggested as a possible treatment for refractory pain. To assess the effectiveness of tibial and sacral nerve stimulation in the treatment of BPS and CPP. We searched until July 2012: the Cochrane Library, EMBASE (1980-2012), Medline (1950-2012), Web of knowledge (1900-2012), LILACS (1982-2012) and SIGLE (1990-2012) with no language restrictions. We manually searched through bibliographies and conference proceedings of the International Continence Society. Randomized and prospective quasi-randomized controlled studies vs. sham nerve stimulation treatment or usual care of patients with CPP and BPS who underwent sacral or tibial nerve stimulation were included. Any studies involving transcutaneous stimulation were excluded. The outcome was a cure or improvement in symptoms. Three studies with 169 patients treated with tibial nerve stimulation were included; two for CPP and one for BPS. There were improvements in pain, urinary and quality of life scores. There were no reported data for sacral nerve stimulation. There is scanty literature reporting variable success of posterior tibial nerve stimulation in improving pain, urinary symptoms and quality of life in CPP and BPS. In view of the dearth of quality literature, a large multi-centered clinical trial investigating the effectiveness of electrical nerve stimulation to treat BPS and CPP along with the cost-analysis of this treatment is recommended. 23535158 Diagnosis and therapy of myasthenia gravis with antibodies to muscle-specific kinase. Myasthenia gravis (MG) with antibodies to the muscle-specific receptor tyrosine kinase (MuSK-MG) is a rare disease which covers 5-8% of all MG patients. Symptoms are nearly always generalized, though more focal than in MG with anti-acetylcholine receptor antibodies, with predominant involvement of cranial, bulbar and axial muscles; early respiratory crises are frequent. Focal atrophy, mostly of facial, masseter and tongue muscles, occurs in a proportion of patients. Diagnosis is often challenging on account of atypical presentation with little or no symptom fluctuations, lack of response to acetylcholinesterase inhibitors in a high proportion of patients and negative results of electrodiagnostic studies when performed on limb muscles. Immunosuppression is the mainstay of treatment, since the response to acetylcholinesterase inhibitors is generally unsatisfactory and thymectomy does not appear to improve the course of the disease. Although corticosteroids result in marked improvement, disease flares are frequent during prednisone dosage tapering and most patients remain dependent on treatment. Since treatment with rituximab, in uncontrolled studies, induced sustained benefit in patients with refractory disease, B cell depletion is an attractive option for MuSK-MG patients unresponsive to conventional immunosuppressants. 23098819 Negative regulation of inflammation by SIRT1. Sirtuin 1 (SIRT1), the mammalian Sir2 homologue, is a class III histone deacetylase shown to act on a wide range of histones and non-histone substrates. Numerous studies have demonstrated that SIRT1 regulates critical metabolic and physiological processes including senescence, stress resistance, metabolism and apoptosis. Recently, SIRT1 was also found to play an important role in modulating the development and progression of inflammation through deacetylating histones and critical transcription factor such as nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1), thus leading to transcriptional repression of various inflammation-related genes. There is increasing evidence that reduction of SIRT1 levels is closely correlated with many inflammatory diseases while pharmacologic activation of SIRT1 would be a promising therapeutic strategy for inflammation-related diseases. 23170960 Structure Based Lead Optimization Approach in Discovery of Selective DPP4 Inhibitors. Diabetes mellitus is a chronic progressive metabolic disorder that has profound consequences for individuals, families, and society. To date, main available oral antidiabetic medications target either insulin resistance (metformin, glitazones), or insulin deficiency (sulfonylureas, glinides), but leading to shortfalls in medication. Advancement in modern oral hypoglycemic agents may be encouraged with or in place of traditional therapies. The lower risk for hypoglycemic events as compared with other insulinotropic or insulin-sensitizing agents make DPP-4 inhibitors very promising candidates for a more physiological treatment of type-2 diabetes. Only some DPP-4 inhibitors are currently used for the treatment of type 2 diabetes (T2DM) and various inhibitors currently undergoing animal and human testing. A number of catalytically active DPPs distinct from DPP-4 (DPP II, FAP, DPP-8, and DPP-9) have been described that is associated with side-effect and toxicity. To discover potent and selective and safer drugs in a shorter time frame and with reduced cost it requires using an innovative approach for designing novel inhibitors. This review article focuses on the status of advanced lead candidates of DPP group and their binding affinity with the active site residue of target structure which help in discovery of potent and selective DPP-4 inhibitors by lead optimization approach. 23937440 Weak evidence for anticipatory parental effects in plants and animals. The evolution of adaptive phenotypic plasticity relies on the presence of cues that enable organisms to adjust their phenotype to match local conditions. Although mostly studied with respect to nonsocial cues, it is also possible that parents transmit information about the environment to their offspring. Such 'anticipatory parental effects' or 'adaptive transgenerational plasticity' can have important consequences for the dynamics and adaptive potential of populations in heterogeneous environments. Yet, it remains unknown how widespread this form of plasticity is. Using a meta-analysis of experimental studies with a fully factorial design, we show that there is only weak evidence for higher offspring performance when parental and offspring environments are matched compared with when they are mismatched. Estimates of heterogeneity among studies suggest that effects, when they occur, are subtle. Study features, environmental context, life stage and trait categories all failed to explain significant amounts of variation in effect sizes. We discuss theoretical and methodological reasons for the limited evidence for anticipatory parental effects and suggest ways to improve our understanding of the prevalence of this form of plasticity in nature. 23909738 Cross-Linked Potato Starch-Based Blend Films Using Ascorbic Acid as a Plasticizer. The main objects of this study were to prepare the cross-linked potato starch/polyvinyl alcohol blend films with ascorbic acid (AsA) added as a plasticizer with and without heat curing and to examine their mechanical properties, elongation at break, degree of swelling, solubility, water vapor absorption, thermal properties, optical properties, and biodegradability. The specific surface area, pore volume, and topography of the films with and without heat curing were also investigated via nitrogen adsorption and desorption isotherms and atomic force microscopy analysis. The results indicate that the cured films possess mechanical, thermal, and optical properties enhanced compared to those of noncured films. The mechanical and water barrier properties of the AsA-added film were also found to be superior to those of other films with polyol plasticizers (glycerol and xylitol). The biodegradability test revealed that the prepared films are degraded by ∼35-80% after 165 days. 23862743 Evaluating Radiation-induced White Matter Changes in Patients Treated with Stereotactic Radiosurgery Using Diffusion Tensor Imaging: A Pilot Study. Stereotactic radiosurgery (SRS) has been an effective treatment method for brain tumors; however, few data are available regarding radiation-induced white matter (WM) damage by SRS. In this work, diffusion tensor imaging (DTI) was used to investigate WM changes following SRS. Fifteen patients with gliomas were enrolled, with prescription doses ranging 18-25 Gy. Patients were scanned with magnetic resonance imaging (MRI) including DTI before and after SRS. Diffusion tensors were calculated and fiber tracking was performed. Non-irradiated WM volumes and irradiated WM volumes receiving ≥ 12 Gy and ≥ Gy were contoured as volumes of interest (VOI). Apparent diffusion coefficient (〈D〉), fractional anisotropy (FA) and number of fibers (NF) were calculated and assessed using the Wilcoxon signed-rank test. Compared with those of non-irradiated VOIs, FA and NF decreased considerably after two months of SRS in the irradiated WM VOIs. The variation in (〈D〉 was however small and was not statistically significant. The preliminary results suggested that FA and NF might potentially be more sensitive indicators than (〈D〉 in measuring radiation-induced WM changes and DTI could be a valuable tool to assess radiation-induced WM changes in SRS. Although it is still preliminary, this pilot study may be useful to provide insights for future studies. 23446650 Synthesis of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones as potential antimicrobial agents. Synthesis of new derivatives of pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one via reaction of 7-(4-bromophenyl)-1,2-dihydro-5-(4-fluorophenyl)-2-thioxopyrido[2,3-d] pyrimidin-4(3H)-one with hydrazonoyl chlorides or reaction of 2-hydrazino-pyrido[2,3-d]pyrimidin-4(3H)-one with different aldehydes followed by cyclization of the products. All the newly synthesized compounds were evaluated for their antimicrobial activities and also their minimum inhibitory concentration against most of test organisms was performed. Amongst the tested compounds displayed excellent activity against all the tested microorganisms except SR and PA. 23670855 Cytochrome P450 compound I in the plane wave pseudopotential framework: GGA electronic and geometric structure of thiolate-ligated iron(IV)-oxo porphyrin. The cytochromes P450 constitute a ubiquitous family of metalloenzymes, catalyzing manifold reactions of biological and synthetic importance via a thiolate-ligated iron-oxo (IV) porphyrin radical species denoted compound I (Cpd I). Experimental investigations have implicated this intermediate in a broad spectrum of biophysically interesting phenomena, further augmenting the importance of a Cpd I model system. Ab initio molecular dynamics, including Car-Parrinello and path integral methods, conjoin electronic structure theory with finite temperature simulation, affording tools most valuable to approach such enzymes. These methods are typically driven by density functional theory (DFT) in a plane-wave pseudopotential framework; however, existing studies of Cpd I have been restricted to localized Gaussian basis sets. The appropriate choice of density functional and pseudopotential for such simulations is accordingly not obvious. To remedy this situation, a systematic benchmarking of thiolate-ligated Cpd I is performed using several generalized-gradient approximation (GGA) functionals in the Martins-Troullier and Vanderbilt ultrasoft pseudopotential schemes. The resultant electronic and structural parameters are compared to localized-basis DFT calculations using GGA and hybrid density functionals. The merits and demerits of each scheme are presented in the context of reproducing existing experimental and theoretical results for Cpd I. 23850409 How to Evaluate Three Dimensional Angle Error From Plain Radiographs. Evaluating three-dimensional angle error is necessary because we cannot get every patient's CT or MRI at all times. Creating a method that can calculate angle error from plain radiographs is therefore important. Using vector and trigonometric mathematics, we gradually deduct our formula which can calculate angle error from goal angles (the angles we plan to achieve before operation) to result angles (the angles we get after operation) by two perpendicular radiographs. We also encode it into Micorsoft Excel (Redmond Campus, Redmond, Washington, U.S.) so that it becomes more user-friendly. We hope this tool can be used when evaluating TKR, corrective osteotomy, fracture fixation, and so on. 23850014 Implementation of a School-based Internet Obesity Prevention Program for Adolescents. To evaluate the reach, adoption, and implementation of HEALTH[e]TEEN, a school-based Internet obesity prevention program, and examine differences in student participation and satisfaction by school, gender, age, and race/ethnicity. Concurrent mixed method evaluation. Three public high schools in Connecticut. Three hundred eighty-four adolescents, 8 teachers. HEALTH[e]TEEN vs HEALTH[e]TEEN plus coping skills training. Demographic and state-available data, measurements of student satisfaction and participation, interviews with school administrators and teachers. Mixed and logistic models, content analysis. The sample (n = 384) was diverse (35% white), with a mean age of 15.3 years and mean body mass index of 24.7 kg/m(2). Student participation (83% of lessons completed) and satisfaction (mean 3.6 out of 5) was high. Schools implementing the program in class had higher satisfaction and participation compared with schools that implemented the program as homework (P ≤ .001 and < .001, respectively). Girls had higher satisfaction and participation compared with boys (P = .02 and .03, respectively). Younger students had higher participation compared with older students, but no difference in satisfaction was noted (P = .03). Two school-based Internet programs to decrease obesity reached diverse adolescents, and were adopted and implemented with high student satisfaction and participation. Implementation of the intervention was influenced by setting (classroom vs homework), teacher characteristics, student age, and gender. 23869981 Two-hour post-load plasma glucose levels are associated with carotid intima-media thickness in subjects with normal glucose tolerance. Elevated post-load plasma glucose levels may increase the risk of cardiovascular disease, even when they are within the normoglycaemic range. We examined the association of carotid artery intima-media thickness, a marker of early atherosclerosis, with glycaemic variables, including post-load plasma glucose levels, in Japanese subjects with normal glucose tolerance. The study participants were 663 Japanese subjects with normal glucose tolerance (565 men, mean age 47 ± 9 years) who underwent both a 75-g oral glucose tolerance test and carotid artery intima-media thickness measurement by B-mode ultrasonography during a health examination. Associations between maximal common carotid artery intima-media thickness and fasting plasma glucose, 1-h and 2-h plasma glucose during an oral glucose tolerance test, and HbA1c were examined. The carotid artery intima-media thickness gradually increased across the tertiles of 1-h plasma glucose, 2-h plasma glucose and HbA1c . In multiple linear regression analysis, 2-h plasma glucose (β = 0.09, P = 0.012), as well as age, male gender, hypertension, dyslipidaemia, and current smoking were independent determinants of carotid artery intima-media thickness. In contrast, other glycaemic variables were not independent determinants of carotid artery intima-media thickness. The carotid artery intima-media thickness in hypertensive subjects with the highest tertile of 2-h plasma glucose [0.70 (95% CI 0.64-0.76) mm] was significantly greater than in normotensive subjects, with the lowest tertile of 2-h plasma glucose [0.60 (95% CI 0.58-0.63) mm, P = 0.037], even after adjusting for the multiple potential confounders. The 2-h plasma glucose during an oral glucose tolerance test was positively and independently associated with carotid artery intima-media thickness in Japanese subjects with normal glucose tolerance. In particular, the combination of elevated 2-h plasma glucose and hypertension may contribute to an increased carotid artery intima-media thickness. 23942241 Complement anaphylatoxin C3a is a potent inducer of embryonic chick retina regeneration. Identifying the initiation signals for tissue regeneration in vertebrates is one of the major challenges in regenerative biology. Much of the research thus far has indicated that certain growth factors have key roles. Here we show that complement fragment C3a is sufficient to induce complete regeneration of the embryonic chick retina from stem/progenitor cells present in the eye, independent of fibroblast growth factor receptor signaling. Instead, C3a induces retina regeneration via STAT3 activation, which in turn activates the injury- and inflammation-responsive factors, IL-6, IL-8 and TNF-α. This activation sets forth regulation of Wnt2b, Six3 and Sox2, genes associated with retina stem and progenitor cells. Thus, our results establish a mechanism for retina regeneration based on injury and inflammation signals. Furthermore, our results indicate a unique function for complement anaphylatoxins that implicate these molecules in the induction and complete regeneration of the retina, opening new avenues of experimentation in the field. 23943805 Developing Lipid Nanoparticle-based siRNA Therapeutics for Hepatocellular Carcinoma Using an Integrated Approach. Successful siRNA therapeutics requires the optimal integration of multiple components, including an efficient delivery system, a disease indication that is appropriate for siRNA-based therapy, and a potent and non-toxic siRNA against a robust therapeutic target. Although all currently available delivery systems have limitations, it is important to recognize that a careful selection of the disease indication, therapeutic target, and siRNA molecule could partially compensate for deficiencies associated with the delivery system and makes it possible to advance a therapeutic siRNA regimen with an imperfect delivery platform. In this study, we presented the development of siRNA therapeutics for hepatocellular carcinoma using an integrated approach, including the development of an efficient lipid nanoparticle delivery system, the identification of a robust therapeutic target that do not trigger liver toxicity upon target knockdown, and the selection of potent and non-immunogenic siRNA molecules against the target. The resulting siRNA-containing lipid nanoparticles produced significant anti-tumor efficacy in orthotopic hepatocellular carcinoma models, and thus, represent a promising starting point for the development of siRNA therapeutics for hepatocellular carcinoma. 23815518 A combined natural supplement lowers LDL cholesterol in subjects with moderate untreated hypercholesterolemia: a randomized placebo-controlled trial. Abstract Objective: To investigate the effect of a natural cholesterol-lowering supplement (NCLS) containing red yeast rice, policosanols and artichoke leaf extracts on blood lipid concentrations as well as on safety parameters when given over 16 weeks in 100 volunteers with untreated moderate hypercholesterolemia, in a randomized, double-blind, placebo-controlled trial. Results: Reduction of primary outcome low-density lipoprotein cholesterol [-0.22 g/L (95% confidence interval, CI: -0.31 to -0.12) corresponding to -14.3% from baseline (95% CI: -21.5 to -7.2) compared to placebo], as well as total cholesterol, apolipoprotein B100 and apolipoprotein B100/apolipoprotein A-I ratio, were observed after 16 weeks of supplementation with NCLS. These effects were already observed at Week 4 and 10 of supplementation. No significant changes were observed in high-density lipoprotein, triacylglycerol, creatine kinase, lactate dehydrogenase and coenzyme Q10 levels, as well as in markers of liver and renal function. Conclusions: The NCLS was effective in reducing low-density lipoprotein cholesterol and apolipoprotein B100 in subjects with moderate hypercholesterolemia, without modifying safety parameters. 23078347 Femtosecond laser-assisted cataract surgery compared with conventional cataract surgery. To investigate the safety and efficacy of the Catalys (Optimedica, Santa Clara, CA, USA) femtosecond laser-assisted cataract surgery system compared with conventional phacoemulsification cataract extraction. Prospective, consecutive, parallel cohort study. The first 200 eyes undergoing conventional cataract surgery to the first 200 eyes undergoing femtosecond laser-assisted cataract surgery between April and July 2012. Femtosecond laser-assisted cataract surgery involved anterior capsulotomy and lens fragmentation based on optical coherence tomography-guided treatment mapping. Conventional cataract surgery involved manual continuous curvilinear capsulorhexis. Both procedures were completed by standard phacoemulsification and insertion of an intraocular lens. Effective phacoemulsification time and intraoperative complication rates. Patient demographics were similar between both groups. There was no statistically significant difference in intraoperative complications between femtosecond laser-assisted cataract surgery and conventional surgery. There was one posterior capsule rupture in both groups (0.5%; not significant). One hundred per cent of cases treated with the femtosecond laser had a complete capsulotomy. Vacuum time decreased with experience. Effective phacoemulsification time was reduced by 70% in the femtosecond group (P < 0.0001). Twenty-six cases in the femtosecond group versus one case in the conventional group had 0 effective phacoemulsification time (P < 0.0001). Femtosecond laser-assisted cataract surgery appears to be as safe as conventional cataract surgery in the short term and results in significantly lower effective phacoemulsification time. Although it may allow for greater efficiency and decreased postoperative complications, further research is needed into long-term safety aspects such as corneal endothelial cell loss. 23160270 Emergence of superconductivity from the dynamically heterogeneous insulating state in La(2-x)Sr(x)CuO4. A central issue for copper oxides is the nature of the insulating ground state at low carrier densities and the emergence of high-temperature superconductivity from that state with doping. Even though this superconductor-insulator transition (SIT) is a zero-temperature transition, measurements are not usually carried out at low temperatures. Here we use magnetoresistance to probe both the insulating state at very low temperatures and the presence of superconducting fluctuations in La(2-x)Sr(x)CuO(4) films, for doping levels that range from the insulator to the superconductor (x  =  0.03-0.08). We observe that the charge glass behaviour, characteristic of the insulating state, is suppressed with doping, but it coexists with superconducting fluctuations that emerge already on the insulating side of the SIT. The unexpected quenching of the superconducting fluctuations by the competing charge order at low temperatures provides a new perspective on the mechanism for the SIT. 23864492 Influence of 3 Months Endurance Training on Red Cell Deformability in Non Insulin Dependent Type 2 Diabetes Mellitus Patients. The main purpose of the study was to examine if 3 months of bicycle endurance training alters the red cell deformability in non insulin dependent type 2 diabetes mellitus men.The red cell deformability was measured with the Laser assisted optical rotational cell analyzer. The maximal elongation index and the semimaximal shear stress were measured with the Lineweaver Burke model.At the beginning and the end of the intervention the patients passed a bicycle ergometry test. As a reference group, 13 males without diabetes passed the same testing procedure. Blood samplings were taken before testing, immediately after physical exhaustion and after a 30 min recovery phase.After the training period diabetic patients could significantly reduce BMI, fasting glucose and HbA1c. The reference group had significantly higher elongation indices than the diabetes patients independent from training status. After the training period the basal values of the maximal elongation index did not change significantly. However, maximal elongation indices were significantly reduced after physical examination and in resting time.The semimaximal shear stress of diabetes patients did not alter during the training period. In comparison to the reference group semimaximal shear stress was significantly reduced at all measurement times.This pilot study proves that the maximal elongation index is significantly decreased in diabetes mellitus patients. After 3 months endurance training the red cells become more rigid while the semimaximal shear stress remains constant. Further interventions are required to analyze the exact cause of the presented findings. 23957248 Modifed Colloidal Primitive Model as a Homogeneous Surface Charge Distribution: ζ-Potential. An integral equations theory is derived and applied to a modified colloidal primitive model (MCPM), for finite concentration colloidal dispersions. In MCPM the charge on the colloidal particle is assumed to be smeared on its surface. We find important quantitative and qualitative differences of the ζ-potential, induced charge, and the colloid-colloid electric effective force, calculated in the MCPM, with those obtained from the colloidal primitive model (CPM), where the colloidal charge is assumed to be in the center of the particle, in spite of the fact that, due to Gauss's law, both models have the same particle distribution function. In particular, for the same parameters, while the ζ-potential is positive in MCPM, is negative in the CPM, implying opposite electrophoretic mobilities, μ. An inverse μ has been theoretically predicted in the past, for infinite dilution colloidal dispersions. The MCPM could be a better model for some colloidal particles.In both models, the CPM and the MCPM, it is found a very longrange colloid-colloid correlation, in accordance with previous Monte Carlo simulations. The electrostatic, as well as entropic, like-charged colloid-colloid forces are oscillatory, implying a long-range attraction. 23915421 The Expression of KLF11 (TIEG2), a Monoamine Oxidase B Transcriptional Activator in the Prefrontal Cortex of Human Alcohol Dependence. The biochemical pathways underlying alcohol abuse and dependence are not well understood, although brain cell loss and neurotoxicity have been reported in subjects with alcohol dependence. Monoamine oxidase B (MAO B; an enzyme that catabolizes neurotransmitters such as dopamine) is consistently increased in this psychiatric illness. MAO B has been implicated in the pathogenesis of alcohol dependence and alcohol-induced brain neurotoxicity. Recently, the cell growth inhibitor protein, Kruppel-like factor 11 (KLF11), has been reported to be an MAO transcriptional activator. KLF11 is also known as TIEG2 (transforming growth factor-beta-inducible early gene 2) and mediates apoptotic cell death. This study investigates the protein expression of KLF11 and its relationship with MAO B using human postmortem prefrontal cortex from subjects with alcohol dependence. Twelve subjects with alcohol dependence and the respective psychiatrically normal control subjects were investigated. Expression of KLF11 and MAO B proteins in the prefrontal cortex was measured by Western blot analysis. Correlation studies involving KLF11 and MAO B protein expression were performed. Localization of KLF11 in the human prefrontal cortex was also determined by immunohistochemistry. Levels of KLF11 protein were significantly increased by 44% (p < 0.03) in the postmortem prefrontal cortex of subjects with alcohol dependence as compared to age- and gender-matched, psychiatrically normal control subjects. Furthermore, KLF11 levels were significantly and positively correlated with both the increased MAO B protein levels and blood alcohol content in alcohol-dependent subjects. In addition, KLF11 protein expression was visualized in both neuronal and glial cells. This novel study shows the important role of KLF11, an MAO transcriptional activator, in human alcohol dependence. It further supports that the KLF11-MAO B cell death cascade may contribute to chronic alcohol-induced brain damage. This argues a case for KLF11-MAO B inhibition as a novel therapeutic strategy that may impact this highly prevalent illness. 23290863 Morphology of two new marine peritrich ciliates from Yellow Sea, Pseudovorticella dingi nov. spec. and P. wangi nov. spec., with supplementary descriptions of P. plicata, P. banatica and P. anomala (Ciliophora, Peritrichia). Two new marine peritrich ciliates, Pseudovorticella dingi nov. spec. and Pseudovorticella wangi nov. spec. were collected from coastal waters of Qingdao, China. Their living morphology, infraciliature and silverline system were studied using light microscopy and silver staining methods. Pseudovorticella dingi is characterized mainly by the apically located contractile vacuole and the presence of pellicular granules. There are 28-36 and 13-18 transverse silverlines above and below the trochal band, respectively. Infundibular polykinety 3 is composed of three rows, with row 1 conspicuously shorter than the other two. P. wangi is distinguished mainly by having two ventrally located contractile vacuoles. There are 17-20 and 9-11 transverse silverlines above and below the trochal band, respectively. Abstomal end of row 1 of infundibular polykinety 3 diverges from the other two and ends alongside row 3 of infundibular polykinety 2. Pseudovorticella plicata, P. banatica, and P. anomala have been described in Sun et al. (2009); we supplement morphometric data and photographs from life and after silver staining of these three species in the present study. 23846659 Characterization and implications of intradecadal variations in length of day. Variations in Earth's rotation (defined in terms of length of day) arise from external tidal torques, or from an exchange of angular momentum between the solid Earth and its fluid components. On short timescales (annual or shorter) the non-tidal component is dominated by the atmosphere, with small contributions from the ocean and hydrological system. On decadal timescales, the dominant contribution is from angular momentum exchange between the solid mantle and fluid outer core. Intradecadal periods have been less clear and have been characterized by signals with a wide range of periods and varying amplitudes, including a peak at about 6 years (refs 2-4). Here, by working in the time domain rather than the frequency domain, we show a clear partition of the non-atmospheric component into only three components: a decadally varying trend, a 5.9-year period oscillation, and jumps at times contemporaneous with geomagnetic jerks. The nature of the jumps in length of day leads to a fundamental change in what class of phenomena may give rise to the jerks, and provides a strong constraint on electrical conductivity of the lower mantle, which can in turn constrain its structure and composition. 22696069 Cerebellar vermis volume in major depressive disorder. The vermis is located in the midline of the cerebellum and is involved in the regulation of affect and cognitive processes. Although changes in vermis size have been reported in several psychiatric disorders such as schizophrenia and bipolar disorder, no volumetric studies have been conducted on samples of patients with major depressive disorder (MDD). One-hundred and five adult subjects were recruited: 35 patients who were presenting for first treatment (FT; 22 females), 35 patients with known previous treatment (PT; 22 females), and 35 healthy controls (NC; 22 females), matched for age and gender. We compared the volumes of the total vermis, the anterior lobe (V1), the superior-posterior lobe (V2), and the inferior-posterior lobe (V3), among these study groups. Anterior vermis (V1) was larger in patients with MDD with a long history of antidepressant treatment compared to healthy controls. This finding was evident only in men [F(2, 36) = 9.23, p = .001]. Patients in the FT group did not differ from healthy controls in any vermian region. We found no correlations between vermian subregional volumes and clinical variables such as illness duration or age at onset of illness. We speculate that the larger anterior vermis volumes might arise from abnormalities in connectivity or as compensatory responses to the prefrontal dysfunction noted in patients with MDD but confirmation of this hypothesis awaits further studies. 23376707 Obesity is Associated with Worse Outcomes in Patients with T1 High Grade Urothelial Carcinoma of the Bladder. To our knowledge the impact of body mass index on oncologic outcomes in nonmuscle invasive bladder cancer has not been evaluated. We hypothesized that higher body mass index is associated with worse outcomes in patients with clinical primary T1 high grade urothelial carcinoma of the bladder. We retrospectively analyzed data from 892 patients with primary nonmuscle invasive bladder cancer from 7 centers. Patients were treated with transurethral resection of the bladder with or without intravesical therapy. Body mass index was analyzed as a continuous and a categorical variable (nonobese-body mass index less than 30 kg/m(2) vs obese-body mass index 30 kg/m(2) or greater). Disease progression was defined as the development of T2 or higher tumor stage. Median followup was 42.8 months (IQR 56). Of the patients 44.3% were obese and median body mass index was 29.2 kg/m(2) (IQR 8). On univariable analyses higher body mass index and age were associated with an increased risk of disease recurrence, progression, cancer specific mortality and any cause mortality (all p ≤0.001). On multivariable analyses that adjusted for the effects of gender, concomitant carcinoma in situ, tumor size, number of tumors and intravesical therapy, higher body mass index and age remained independent predictors of disease recurrence, progression, cancer specific mortality and any cause mortality (all p <0.05). This study was limited by its design (ie lack of data on repeat transurethral resection of the bladder and intravesical therapy protocol). Patients diagnosed with clinical T1 high grade urothelial carcinoma of the bladder who are obese have worse cancer specific outcomes compared to their nonobese counterparts. Further work is needed to improve our understanding of clinical T1 high grade outcomes in the growing population of obese patients. 23844257 Neuroanatomy of the Marine Jurassic Turtle Plesiochelys etalloni (Testudinata, Plesiochelyidae). Turtles are one of the least explored clades regarding endocranial anatomy with few available descriptions of the brain and inner ear of extant representatives. In addition, the paleoneurology of extinct turtles is poorly known and based on only a few natural cranial endocasts. The main goal of this study is to provide for the first time a detailed description of the neuroanatomy of an extinct turtle, the Late Jurassic Plesiochelysetalloni, including internal carotid circulation, cranial endocast and inner ear, based on the first digital 3D reconstruction using micro CT scans. The general shape of the cranial endocast of P. etalloni is tubular, with poorly marked cephalic and pontine flexures. Anteriorly, the olfactory bulbs are clearly differentiated suggesting larger bulbs than in any other described extinct or extant turtle, and indicating a higher capacity of olfaction in this taxon. The morphology of the inner ear of P. etalloni is comparable to that of extant turtles and resembles those of slow-moving terrestrial vertebrates, with markedly low, short and robust semicircular canals, and a reduced lagena. In P. etalloni the arterial pattern is similar to that found in extant cryptodires, where all the internal carotid branches are protected by bone. As the knowledge of paleoneurology in turtles is scarce and the application of modern techniques such as 3D reconstructions based on CT scans is almost unexplored in this clade, we hope this paper will trigger similar investigations of this type in other turtle taxa. 22274798 The role of chemoradiotherapy in patients with unresectable T4 breast tumors. Unresectable T4 tumors of the breast are usually treated with systemic therapies, while the role of local therapies remains debatable. This study aims to evaluate the effectiveness of chemoradiotherapy as a part of T4 breast cancer treatment, and to assess the role of local radiotherapies in patients with unresectable T4 breast tumors. Between February 1998 and June 2010, 39 unresectable T4 breast tumors were treated with chemoradiotherapy at our institutes. Clinical stages included stage IIIB (n = 15), stage IIIC (n = 3), and stage IV (n = 21). Twenty-one cases had undergone previous systemic therapies, whereas the remaining 18 cases reported no history of previous treatment. Radiation doses of 59-66 Gy (median 60 Gy) were administered to the breast in addition to concurrent chemotherapies. Acute adverse effects were assessed on a weekly basis during treatment to 2 weeks after completion of treatment, and were scored by the Common Terminology Criteria for Adverse Events v3.0. Treatment response was assessed at 1 month after completion of chemoradiotherapy. Statistical analysis of survival was calculated using the Kaplan-Meier method. Chemoradiotherapy was completed in all cases. Greater than grade 3 hematological toxicities were observed with regard to lymphocytes (33%), platelets (8%), neutrophils (3%), and hemoglobin (3%). Greater than grade 3 nonhematologic toxicities included chemoradiation dermatitis (23%) and pneumonitis (5%). Sixteen T4 tumors (41%) achieved complete response, whereas 23 (59%) achieved partial response. All patients were treated with chemotherapy and/or endocrine therapy following chemoradiotherapy. The median follow-up period was 20 months (range 3-96 months). Nineteen patients died because of progressive breast cancer. Infield recurrence or relapse was observed in 11 cases during the course of treatment, but only 3 cases were symptomatic. The 2-year overall local control rate was 73.6%, and the survival rate was 65.9%. Chemoradiotherapy represents a viable option for local treatment of unresectable T4 breast tumors. 23908358 Bim polymorphisms: influence on function and response to treatment in children with acute lymphoblastic leukemia. Corticosteroids (CS) induce apoptosis in the malignant lymphoid cells and are critical component of combination therapy for acute lymphoblastic leukemia (ALL). Several genome-wide microarray studies demonstrated major implication of proapoptotic Bim in mediating CS-related resistance in leukemia cells. We investigated Bim gene polymorphisms and their association with childhood ALL outcome, and the mechanism underlying the observed finding. Lower overall survival (OS) was associated with Bim C29201T located in BH3 domain (p=0.01). An association remained significant in multivariate model (p=0.007), was more apparent in high risk (HR) patients (p=0.004) and patients treated with dexamethasone (p=0.009), and was subsequently confirmed in the replication patient cohort (p=0.03). RNA analysis revealed that C29201T affects generation of gamma isoforms (gamma1) that lack pro-apoptotic BH3 domain. The phenotypic effect was minor suggesting the influence of additional factors that may act in conjunction with Bim genotype. Combined analysis with Mcl gene polymorphism (G -486T) revealed profound reduction in OS in individuals with both risk genotypes (p<0.0005 in discovery and p=0.002 in replication cohort) and particularly in HR patients (p≤0.008). Increased expression of pro-survival Mcl1 and presence of Bim isoforms lacking pro-apoptotic function might explain marked reduction of OS in a disease and dose dependent manner in ALL patients carrying Bim and Mcl1 risk genotypes. 23127917 Angiotensin-(1-7) modulates renin-angiotensin system associated with reducing oxidative stress and attenuating neuronal apoptosis in the brain of hypertensive rats. Angiotensin-(1-7) [Ang-(1-7)] has beneficial effects against hypertension-induced damage in heart and kidney, but its effects in brain are not clear as yet. The present study aimed to investigate the protective effects of Ang-(1-7) on the physiopathologic changes caused by hypertension in brain of spontaneously hypertensive rats (SHRs). Wistar-Kyoto rats received intracerebroventricular (I.C.V.) infusion of artificial cerebrospinal fluid (aCSF) while SHRs received I.C.V. infusion of Ang-(1-7), Mas receptor antagonist A-779 and aCSF for 4 weeks. Brain tissues were collected and analyzed by western blot, enzyme immunoassay, spectrophotometric assays and terminal deoxynucleotidyl transferase-mediated dUTP end-labeling (TUNEL) staining. Our study showed that infusion of Ang-(1-7) for 4 weeks significantly reduced the expression of Angiotensin II and Angiotensin II type 1 receptors in SHR brain. Additionally, it decreased the levels of malondialdehyde and elevated total superoxide dismutase activity, which was accompanied by reductions of NADPH oxidase subunit gp91(phox) and inducible nitric oxide synthase in the brain of SHR. The increases of the percentage of TUNEL-positive neurons and Bax to Bcl-2 ratio in SHR brain were also attenuated by Ang-(1-7). The anti-oxidative and anti-apoptosis effects of Ang-(1-7) are independent of blood pressure reduction and can be partially abolished by A-779. These findings suggest that chronic treatment with Ang-(1-7) is beneficial to attenuate hypertension-induced physiopathologic changes in brain and may be helpful to prevent hypertension-related cerebrovascular diseases. 23944993 Bioaccumulation of CdTe Quantum Dots in a Freshwater Alga Ochromonas danica: A Kinetics Study. The bioaccumulation kinetics of thioglycolic acid stabilized CdTe quantum dots (TGA-CdTe-QDs) in a freshwater alga Ochromonas danica was comprehensively investigated. Their photoluminescence (PL) was determined by flow cytometry. Its cellular intensity increased hyperbolically with exposure time suggesting real internalization of TGA-CdTe-QDs. This hypothesis was evidenced by the nanoparticle uptake experiment with heat-killed or cold-treated cells and by their localization in the vacuoles. TGA-CdTe-QD accumulation could further be well simulated by a biokinetic model used previously for conventional pollutants. Moreover, macropinocytosis was the main route for their internalization. As limited by their diffusion from the bulk medium to the cell surface, TGA-CdTe-QD uptake rate increased proportionally with their ambient concentration. Quick elimination in the PL of cellular TGA-CdTe-QDs was also observed. Such diminishment resulted mainly from their surface modification by vacuolar biomolecules, considering that these nanoparticles remained mostly undissolved and their expulsion out of the cells was slow. Despite the significant uptake of TGA-CdTe-QDs, they had no direct acute effects on O. danica. Overall, the above research shed new light on nanoparticle bioaccumulation study and would further improve our understanding about their environmental behavior, effects and fate. 23561151 Anthocyanins in the ripe fruits of Rubus coreanus Miquel and their protective effect on neuronal PC-12 cells. Phenolics of the fresh ripe fruits of Rubus coreanus Miquel were extracted and separated into anthocyanin and the non-anthocyanin fractions, which were used for the evaluation for antioxidant capacity and neuroprotective effects. The anthocyanin fraction accounted for approximately 47-55% of the total antioxidant capacity of the whole extract and had significantly higher free radical-scavenging capacity than the non-anthocyanin fraction. Furthermore, the anthocyanins alleviated intracellular oxidative stress, as assayed by in vitro fluorescent measurements. The anthocyanins showed neuroprotective effects on PC-12 cells in vitro against oxidative stress in a dose-dependent manner. Triple quadrupole LC/MS and Q-TOF LC/MS analyses revealed four major anthocyanins; cyanidin 3-O-sambubioside, cyanidin 3-O-glucoside, cyanidin 3-O-xylosylrutinoside, and cyanidin 3-O-rutinoside in increasing order of amounts. These results demonstrated that anthocyanins are the major components and contributors to the antioxidant capacity of ripe R. coreanus Miquel fruits. Further studies are warranted to determine whether consumption of the fruits reduces oxidative stress in the brain and promotes health. 23267011 DNA polymerase minor groove interactions modulate mutagenic bypass of a templating 8-oxoguanine lesion. A major base lesion resulting from oxidative stress is 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxoG) that has ambiguous coding potential. Error-free DNA synthesis involves 8-oxoG adopting an anti-conformation to base pair with cytosine whereas mutagenic bypass involves 8-oxoG adopting a syn-conformation to base pair with adenine. Left unrepaired the syn-8-oxoG/dAMP base pair results in a G-C to T-A transversion. During base excision repair of this mispair, DNA polymerase (pol) β is confronted with gap filling opposite 8-oxoG. To determine how pol β discriminates between anti- and syn-8-oxoG, we introduced a point mutation (R283K) to alter insertion specificity. Kinetic studies demonstrate that this substitution results in an increased fidelity opposite 8-oxoG. Structural studies with R283K pol β show that the binary DNA complex has 8-oxoG in equilibrium between anti- and syn-forms. Ternary complexes with incoming dCTP resemble the wild-type enzyme, with templating anti-8-oxoG base pairing with incoming cytosine. In contrast to wild-type pol β, the ternary complex of the R283K mutant with an incoming dATP-analogue and templating 8-oxoG resembles a G-A mismatched structure with 8-oxoG adopting an anti-conformation. These results demonstrate that the incoming nucleotide is unable to induce a syn-8-oxoG conformation without minor groove DNA polymerase interactions that influence templating (anti-/syn-equilibrium) of 8-oxoG while modulating fidelity. 23897754 Unraveling the Pathways to UVA-Induced DNA Photodamage: (6-4) Photoproduct as a Potential "Trojan Horse" Double jeopardy: The Pyo chromophore in the (6-4) photoproduct is able to induce a secondary photoproduct in DNA by excitation with UVA light. 23589542 Hypoglycemia and diabetes: a report of a workgroup of the american diabetes association and the endocrine society. OBJECTIVE To review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice. PARTICIPANTS Five members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report. EVIDENCE The writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions. CONSENSUS PROCESS Consensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association's Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society's Clinical Affairs Core Committee in October 2012 and by Council in November 2012. CONCLUSIONS The workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided. 23607270 C1-inhibitor efficiently inhibits Escherichia coli-induced tissue factor mRNA up-regulation, monocyte tissue factor expression and coagulation activation in human whole blood. Both the complement system and tissue factor (TF), a key initiating component of coagulation, are activated in sepsis, and cross-talk occurs between the complement and coagulation systems. C1-inhibitor (C1-INH) can act as a regulator in both systems. Our aim in this study was to examine this cross-talk by investigating the effects of C1-INH on Escherichia coli-induced haemostasis and inflammation. Fresh human whole blood collected in lepirudin was incubated with E. coli or ultrapurified E. coli lipopolysaccharide (LPS) in the absence or presence of C1-INH or protease-inactivated C1-INH. C3 activation was blocked by compstatin, a specific C3 convertase inhibitor. TF mRNA was measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and TF surface expression was measured by flow cytometry. In plasma, the terminal complement complex, prothrombin F1·2 (PTF1·2) and long pentraxin 3 (PTX3) were measured by enzyme-linked immunosorbent assay (ELISA). Cytokines were analysed using a multiplex kit. C1-INH (1·25-5 mg/ml) reduced both LPS- and E. coli-induced coagulation, measured as a reduction of PTF1·2 in plasma, efficiently and dose-dependently (P < 0·05). Both LPS and E. coli induced marked up-regulation of TF mRNA levels and surface expression on whole blood monocytes. This up-regulation was reduced efficiently by treatment with C1-INH (P < 0·05). C1-INH reduced the release of PTX3 (P < 0·05) and virtually all cytokines measured (P < 0·05). Complement activation was inhibited more efficiently with compstatin than with C1-INH. C1-INH inhibited most of the other readouts more efficiently, consistent with additional non-complement-dependent effects. These results indicate that complement plays a role in activating coagulation during sepsis and that C1-INH is a broad-spectrum attenuator of the inflammatory and haemostatic responses. 23832168 Leptin is differentially expressed and epigenetically regulated across monochorionic twin placenta with discordant fetal growth. Severely growth-discordant monochorionic (MC) twins offer a unique opportunity to study fetal and placental growth based on a similar genetic background and maternal host environment where the healthy twin serves as an ideal control. Differences in development of MC twins may therefore be due to differential epigenetic regulation of genes involved in placental development and function. Growth-discordant twins are known for abnormal angio-architecture in the placenta of the smaller twin. Since the reasons for this phenotype are mostly unknown this study was aimed to investigate the expression and regulation of genes known to be involved in angiogenesis. We studied 10 severely growth-discordant MC twin placentas (birthweight difference ≥20%) without twin-twin-transfusion syndrome and 5 growth-concordant MC twin placentas. Growth-discordant twin placentas were phenotyped by histology. Placental mRNA expression of 88 angiogenesis-related genes was measured by PCR array. ELISA assay and immunohistochemistry were used to confirm PCR results. EpiTYPTER for DNA methylation was used to determine if methylation ratios were responsible for differential gene expression. The PCR array analysis showed significant mRNA up-regulation in the placental share of the smaller twin for several genes. These included leptin (24.6-fold, P = 0.017), fms-like tyrosine kinase 1 (Flt1, 2.4-fold, P = 0.016) and Endoglin (Eng, 1.86-fold, P = 0.078). None of the other 84 angiogenesis-related genes showed significant differences. ELISA confirmed significantly increased leptin protein expression (49.22 versus 11.03 pg/ml, P = 0.049) in the smaller twin of the discordant growth cohort. Leptin expression in smaller twins' placentas was associated with elevated DNA methylation of the leptin promotor region suggesting the inhibition of binding of a transcriptional activator/inhibitor in that region. We attempted to overcome the limitation of sample size by careful patient selection. We minimized any bias in placental sampling by random sampling from two different sites and by avoiding sampling from areas with grossly visible abnormalities using a standardized sampling protocol. In conclusion, the smaller twin's placenta is characterized by differentially increased gene expressions for Flt1 and Eng mRNA that may be causally associated with the villous pathology driven by abnormal feto-placental angiogenesis. The substantial up-regulation of leptin mRNA may be epigenetically conferred and relevant to the post-natal risk of metabolic syndrome in intrauterine growth restriction offspring with placental pathology. Growth-discordant MC twins offer unique insights into the epigenetic basis of perinatal programming. 23861542 Release of Nonmuscle Myosin II from the Cytosolic Domain of Tumor Necrosis Factor Receptor 2 Is Required for Target Gene Expression. Tumor necrosis factor-α (TNF-α) elicits its biological activities through activation of TNF receptor 1 (TNFR1, also known as p55) and TNFR2 (also known as p75). The activities of both receptors are required for the TNF-α-induced proinflammatory response. The adaptor protein TNFR-associated factor 2 (TRAF2) is critical for either p55- or p75-mediated activation of nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling, as well as for target gene expression. We identified nonmuscle myosin II (myosin) as a binding partner of p75. TNF-α-dependent signaling by p75 and induction of target gene expression persisted substantially longer in cells deficient in myosin regulatory light chain (MRLC; a component of myosin) than in cells replete in myosin. In resting endothelial cells, myosin was bound constitutively to the intracellular region of p75, a region that overlaps with the TRAF2-binding domain, and TNF-α caused the rapid dissociation of myosin from p75. At early time points after exposure to TNF-α, p75 activated Rho-associated kinase 1 (ROCK1). Inhibition of ROCK1 activity blocked TNF-α-dependent phosphorylation of MRLC and the dissociation of myosin from p75. ROCK1-dependent release of myosin was necessary for the TNF-α-dependent recruitment of TRAF2 to p75 and for p75-specific activation of NF-κB and MAPK signaling. Thus, our findings have revealed a previously uncharacterized, noncanonical regulatory function of myosin in cytokine signaling. 23398811 Performance of Computed Tomographic Urography for the Detection of Bladder Tumors in Patients With Microscopic Hematuria. Our objective was to evaluate the sensitivity, specificity, predictive value, and accuracy of computed tomographic urography for the detection of bladder tumors in patients with microscopic hematuria. Patients with microscopic hematuria initially evaluated with computed tomography and cystoscopy from January 2006 to December 2009 were evaluated. Computed tomography detecting a bladder lesion suspicious of malignancy was considered positive. Cystoscopy was classified as positive when a lesion requiring biopsy or resection was found. Performance characteristics of computed tomography were determined by comparing with cystoscopic and pathological findings. A total of 112 patients were eligible for analysis. Seven tumors were found on cystoscopy; of these, 2 were correctly diagnosed by computed tomography and 5 were missed. An additional case was considered erroneously positive. The results are a sensitivity of 29%, specificity of 99%, positive predictive value of 67%, negative predictive value of 95%, and accuracy of 95%. Although computed tomography has a high specificity its sensitivity is limited. For this reason conventional cystoscopy should be considered the standard for bladder evaluation of patients with microscopic hematuria. 23967307 Cis Association of Galectin-9 with Tim-3 Differentially Regulates IL-12/IL-23 Expressions in Monocytes via TLR Signaling. Human monocytes/macrophages (M/MФ) of the innate immunity sense and respond to microbial products via specific receptor coupling with stimulatory (such as TLR) and inhibitory (such as Tim-3) receptors. Current models imply that Tim-3 expression on M/MØ can deliver negative signaling to TLR-mediated IL-12 expression through trans association with its ligand Galectin-9 (Gal-9) presented by other cells. However, Gal-9 is also expressed within M/MØ, and the effect of intracellular Gal-9 on Tim-3 activities and inflammatory responses in the same M/MØ remains unknown. In this study, our data suggest that Tim-3 and IL-12/IL-23 gene transcriptions are regulated by enhanced or silenced Gal-9 expression within monocytes through synergizing with TLR signaling. Additionally, TLR activation facilitates Gal-9/Tim-3 cis association within the same M/MØ to differentially regulate IL-12/IL-23 expressions through STAT-3 phosphorylation. These results reveal a ligand (Gal-9) compartment-dependent regulatory effect on receptor (Tim-3) activities and inflammatory responses via TLR pathways-a novel mechanism underlying cellular responses to external or internal cues. 23820276 Novel thrombosis risk index as predictor of left ventricular assist device thrombosis. Left ventricular assist devices (LVADs) are an effective therapy for patients with advanced heart failure, increasing patient survival and quality of life. Left ventricular assist devices are associated with the risks of bleeding and thrombosis. We used lactate dehydrogenase (LDH) and brain natriuretic peptide (BNP) as biomarkers for developing a thrombosis risk index. Data from a single center was retrospectively queried between January 1, 2008, and 10/15, 2011, to identify LVAD patients and related complications. Of 75 consecutive patients implanted with an LVAD, nine had device thrombosis. Analysis of the relationship among international normalized ratio (INR), BNP, LDH, and device thrombosis was performed. Of nine patients with thrombosis, seven had at least 30% of INR readings below 1.5 and two had at least 22% below the therapeutic range from the time of LVAD implant to date of thrombosis. Timeline variability in INR, BNP, and LDH were used to calculate thrombosis risk index (TRI). The TRI retrospectively was able to accurately predict patients with impending device thrombosis. Indexed rise in BNP and LDH in LVAD patients may be useful to identify early device dysfunction and possible future thrombosis. Fibrinogen and D-dimer assays are currently being evaluated in these patients for their possible inclusion and added value to the TRI. 23909588 The transformation of disabilities organizations. Abstract This article summarizes the five major characteristics of the transformation era and describes how intellectual and closely related developmental disabilities organizations can apply specific transformation strategies associated with each characteristic. Collectively, the characteristics and strategies provide a framework for transformation thinking, learning, and acting. Specific application examples are given. 23933437 Novel o-naphthoquinones induce apoptosis of EL-4 T lymphoma cells through the increase of reactive oxygen species. Novel β-lapachone analogs 2-phenyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (NQ1), 2-p-tolyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (NQ3) and 2-methyl-2-phenyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (NQ7), which have trypanocidal activity, were assayed for cytotoxic effects on murine EL-4 T lymphoma cells. The NQs inhibited the proliferation of EL-4 cells at concentrations above 1μM. Nuclear staining of the EL-4 cells revealed chromatin condensation and a nuclear morphology compatible with the induction of apoptosis. Flow cytometry assays with annexin V-FITC and propidium iodide confirmed the cell death by apoptosis. Using electron paramagnetic resonance (EPR), a semiquinone radical was detected in EL-4 cells treated with NQs. In addition, a decrease in the GSH level in parallel with reactive oxygen species (ROS) production was observed. Preincubation with n-acetyl-l-cysteine (NAC) was able to reverse the inhibitory effects of the NQs on cell proliferation, indicating that ROS generation is involved in NQ-induced apoptosis. In addition, the NQs induced a decrease in the mitochondrial membrane potential and increased the proteolytic activation of caspases 9 and 3 and the cleavage of Poly (ADP-Ribose) Polymerase (PARP). In conclusion, these results indicate that redox cycling is induced by the NQs in the EL-4 cell line, with the generation of ROS and other free radicals that could inhibit cellular proliferation as a result of the induction of the intrinsic apoptosis pathway. 23246792 Failure to generate bone marrow adipocytes does not protect mice from ovariectomy-induced osteopenia. A reciprocal association between bone marrow fat and bone mass has been reported in ovariectomized rodents, suggesting that bone marrow adipogenesis has a negative effect on bone growth and turnover balance. Mice with loss of function mutations in kit receptor (kit(W/W-v)) have no bone marrow adipocytes in tibia or lumbar vertebra. We therefore tested the hypothesis that marrow fat contributes to the development of osteopenia by comparing the skeletal response to ovariectomy (ovx) in growing wild type (WT) and bone marrow adipocyte-deficient kit(W/W-v) mice. Mice were ovx at 4 weeks of age and sacrificed 4 or 10 weeks post-surgery. Body composition was measured at necropsy by dual-energy X-ray absorptiometry. Cortical (tibia) and cancellous (tibia and lumbar vertebra) bone architecture were evaluated by microcomputed tomography. Bone marrow adipocyte size and density, osteoblast- and osteoclast-lined bone perimeters, and bone formation were determined by histomorphometry. Ovx resulted in an increase in total body fat mass at 10 weeks post-ovx in both genotypes, but the response was attenuated in the in kit(W/W-v) mice. Adipocytes were present in bone marrow of tibia and lumbar vertebra in WT mice and bone marrow adiposity increased following ovx. In contrast, marrow adipocytes were not detected in either intact or ovx kit(W/W-v) mice. However, ovx in WT and kit(W/W-v) mice resulted in statistically indistinguishable changes in cortical and cancellous bone mass, cortical and cancellous bone formation rate, and cancellous osteoblast and osteoclast-lined bone perimeters. In conclusion, our findings do not support a causal role for increased bone marrow fat as a mediator of ovx-induced osteopenia in mice. 23943779 Application of an Improved Proteomics Method for Abundant Protein Cleanup: Molecular and Genomic Mechanisms Study in Plant Defense. High abundance proteins like Ribulose-1,5-bisphosphate carboxylase oxygenase (Rubisco) impose a consistent challenge for the whole proteome characterization using shot-gun proteomics. In order to address this challenge, we developed and evaluated Polyethyleneimine (PEI) Assisted Rubisco Cleanup (PARC) as a new method by combining both abundant protein removal and fractionation. The new approach was applied to a plant insect interaction study to validate the platform and investigate mechanisms for plant defense against herbivorous insects. Our results indicated that PARC can effectively remove Rubisco, improve the protein identification, and discover almost three times more differentially regulated proteins. The significantly enhanced shot-gun proteomics performance was translated into in-depth proteomic and molecular mechanisms for plant insect interaction, where carbon re-distribution was used to play an essential role. Moreover, the transcriptomic validation also confirmed the reliability of PARC analysis. Finally, functional studies were carried out for two differentially regulated genes as revealed by PARC analysis. Insect resistance was induced by over-expressing either jacalin-like or cupin-like genes in rice. The results further highlighted that PARC can serve as an effective strategy for proteomics analysis and gene discovery. 23910644 Relationship between IL-10 gene -1082A/G and -592C/A polymorphisms and the risk of hepatitis C infection: a meta-analysis. Increasing evidence suggests that interleukin-10 (IL-10) gene promoter polymorphisms may be associated with chronic hepatitis C virus (HCV) infection and HCV clearance. To more precisely estimate the association between these variants and the risk of HCV infection, we performed a meta-analysis of 26 studies describing the IL-10-1082A/G, -819C/T, -592C/A genotypes, including 4039 chronic HCV infection cases and 2902 controls. When compared with a healthy population, the -1082GG allele had a 43% increased risk of chronic HCV infection in combined populations (GG vs GA + AA: odds ratio (OR) = 1.433, 95% confidence interval (CI) = 1.052-1.952, P = 0.023). In subgroup analysis by ethnicity, a significant increased risk was associated with the -1082GG genotype in the Caucasian population (GG vs AA: OR = 1.390, 95% CI: 1.108-1.744, P = 0.004; GG vs GA + AA: OR = 1.621, 95% CI: 1.267-2.075, P = 0.000). However, no significant association was found in Asian, African or Chinese populations. Moreover, a higher distribution of -592A was found in the spontaneously recovered population (AA vs CC: OR = 0.585, 95% CI = 0.387-0.884, P = 0.011; AA + AC vs CC: OR = 0.738, 95% CI = 0.551-0.988, P = 0.041; AA vs AC + CC: OR = 0.788, 95% CI = 0.664-0.935, P = 0.006) than that in the chronic HCV infection population. In conclusion, the IL-10-1082GG allele may increase the risk of chronic HCV infection in Caucasian population, and people carrying the IL-10-592A allele are more likely to clear HCV spontaneously. 23836906 Mechanisms responsible for the compositional heterogeneity of nascent high density lipoprotein. Apolipoprotein (apo) A-I-containing nascent HDL particles produced by the ATP binding cassette transporter A1 have different sizes and compositions. To understand the molecular basis for this heterogeneity, the HDL particles produced by apoA-I-mediated solubilization of phospholipid (PL)/free (unesterified) cholesterol (FC) bilayer membranes in cell and cell-free systems are compared. Incubation of apoA-I with ATP binding cassette transporter A1-expressing baby hamster kidney cells leads to formation of two populations of FC-containing discoidal nascent HDL particles. The larger 11-nm diameter particles are highly FC-enriched (FC/PL = 1.2/1 mol/mol) relative to the smaller 8 nm particles and the cell plasma membrane (FC/PL = 0.4/1). ApoA-I-mediated spontaneous solubilization of either multilamellar or unilamellar vesicles made of a membrane-PL mixture and FC yields discoidal HDL particles with diameters in the range 9-17 nm and, as found with the cell system, the larger particles are relatively enriched in FC despite the fact that all particles are created by solubilization of a common FC/PL membrane domain. The size-dependent distribution of FC among HDL particles is due to varying amounts of PL being sequestered in a boundary layer by interaction with apoA-I at the disc edge. The presence of a relatively large boundary layer in smaller discoidal HDL promotes preferential distribution of phosphatidylserine to such particles. However, phosphatidylcholine and sphingomyelin which are the primary PL constituents of nascent HDL do not exhibit selective incorporation into HDL discs of different sizes. This understanding of the mechanisms responsible for the heterogeneity in lipid composition of nascent HDL particles may provide a basis for selecting subspecies with preferred cardio-protective properties. 23561193 Effect of floral sources on the antioxidant, antimicrobial, and anti-inflammatory activities of honeys in Taiwan. We evaluated the antioxidant, antibacterial, and anti-inflammatory activities of honey made from different floral sources, including the medicinal herb Bidens pilosa, fruit trees, Dimocarpus longan, Litchi chinensis, and Citrus maxima, the Taiwanese endemic plant Aglaia formosana, and a multifloral forest. The total phenolic and flavonoid contents of the honey made from B. pilosa were significantly higher than those of the other honeys. The honey from B. pilosa also had significantly greater scavenging activities for 1,1-diphenyl-2-picrylhydrazyl (DPPH·) and hydroxyl radical, and substantially more reducing power. In addition, the honey from B. pilosa showed greater antibacterial activity against Gram-positive and Gram-negative bacteria. However, B. pilosa honey showed little inhibitory activity against IL-8 secretion, whereas the other honeys did. These findings suggest that the levels of antioxidant and antibacterial activities are attributable to the total phenolic and flavonoid contents of honeys, while the IL-8 inhibition is attributable to components other than phenols. 23173872 Prevalence of β-lactamase-producing bacteria in human periodontitis. Beta-lactam antibiotics prescribed in periodontal therapy are vulnerable to degradation by bacterial β-lactamases. This study evaluated the occurrence of β-lactamase-positive subgingival bacteria in chronic periodontitis subjects of USA origin, and assessed their in vitro resistance to metronidazole at a breakpoint concentration of 4 μg/mL. Subgingival plaque specimens from deep periodontal pockets with bleeding on probing were removed from 564 adults with severe chronic periodontitis before treatment. The samples were transported in VMGA III and then plated onto: (i) nonselective enriched Brucella blood agar (EBBA) and incubated anaerobically for 7 d; and (ii) selective trypticase soy-bacitracin-vancomycin (TSBV) and incubated for 3 d in air + 5% CO2 . At the end of the incubation periods, the bacterial test species were identified and quantified. Specimen dilutions were also plated onto EBBA plates supplemented with 2 μg/mL of amoxicillin, a combination of 2 μg/mL of amoxicillin plus 2 μg/mL of the β-lactamase inhibitor clavulanic acid, or 4 μg/mL of metronidazole, followed by anaerobic incubation for 7 d. Bacterial test species presumptively positive for β-lactamase production were identified by growth on EBBA primary isolation plates supplemented with amoxicillin alone and no growth on EBBA primary isolation plates containing both amoxicillin plus clavulanic acid. A subset of such isolates was subjected to nitrocefin-based chromogenic disk testing to confirm the presence of β-lactamase activity. In vitro resistance to 4 μg/mL of metronidazole was noted when growth of test species occurred on metronidazole-supplemented EBBA culture plates. Two-hundred and ninety-four (52.1%) of the study subjects yielded β-lactamase-producing subgingival bacterial test species, with Prevotella intermedia/nigrescens, Fusobacterium nucleatum and other Prevotella species most frequently identified as β-lactamase-producing organisms. Of the β-lactamase-producing bacterial test species strains recovered, 98.9% were susceptible in vitro to metronidazole at 4 μg/mL. The occurrence of β-lactamase-positive subgingival bacterial species in more than half of the subjects with severe chronic periodontitis raises questions about the therapeutic potential of single-drug regimens with β-lactam antibiotics in periodontal therapy. The in vitro effectiveness of metronidazole against nearly all recovered β-lactamase-producing subgingival bacterial species further supports clinical periodontitis treatment strategies involving the combination of systemic amoxicillin plus metronidazole. 23391297 Hollow block copolymer nanoparticles through a spontaneous one-step structural reorganization. The spontaneous one-step synthesis of hollow nanocages and nanotubes from spherical and cylindrical micelles based on poly(acrylic acid)-b-polylactide (P(AA)-b-P(LA)) block copolymers (BCPs) has been achieved. This structural reorganization, which occurs simply upon drying of the samples, was elucidated by transmission electron microscopy (TEM) and atomic force microscopy (AFM). We show that it was necessary to use stain-free imaging to examine these nanoscale assemblies, as the hollow nature of the particles was obscured by application of a heavy metal stain. Additionally, the internal topology of the P(AA)-b-P(LA) particles could be tuned by manipulating the drying conditions to give solid or compartmentalized structures. Upon resuspension, these reorganized nanoparticles retain their hollow structure and display significantly enhanced loading of a hydrophobic dye compared to the original solid cylinders. 23860281 Differences in responses to repeated fear-relevant stimuli between Nagoya and White Leghorn chicks. Freezing responses to fearful stimuli are crucial for survival among all animal species within a prey-predator system. Generally, the degree of fearfulness correlates with intensity, duration, and frequency of freezing behaviours in response to fear-relevant stimuli. The present study examines innate fear responses to human handling in 144 newly hatched chicks through a tonic immobility (TI) test. Two fear responses-freezing duration and number of TI inductions-were examined. Individual variations in innate fear were investigated in chicks 1-2 days post-hatching when the restraint procedure was successively repeated 3 times within each day. Chicks showed sensitivity to fearful stimuli and considerable inter-individual variation in freezing duration and number of attempts required to induce TI. Moreover, differences were observed between breeds; White Leghorn chicks showed relatively low fear levels with gradual increases in TI duration, whereas Nagoya chicks showed extended TI duration and habituation to fearful stimuli. Our results suggest that TI reactions among newly hatched chicks are an innately determined behaviour specific to a breed or strain of chicken. Further, fearful responses among newborn chicks are not simple, but complex behaviours that involve multiple factors, such as breed-specific contextual fear learning and habituation processes. 23602081 Length of the luteal phase and frequency of the four permutations between two or three follicular waves and ipsilateral or contralateral locations of the corpus luteum and preovulatory follicle in heifers. In Survey 1, the records for 196 interovulatory intervals (IOIs) from 24 heifers were used to study the frequency and repeatability for number of follicular waves per IOI and to study the ipsilateral and contralateral relationships between the extant corpus luteum and ovulatory follicle. In Survey 2, 96 IOIs were used from the controls of the previous experiments that included the day of the end of the luteolytic period (progesterone <1.0 ng/mL). In Survey 1, the percentage of two-wave IOIs (63%) was greater (P < 0.0002) than for three-wave IOIs (37%). The percentage of ovulatory periods with a contralateral relationship (59%) was greater (P < 0.003) than with the ipsilateral relationship (41%). There were more repeats (66%) than reverses (34%) between adjacent IOIs in number of waves per IOI (P < 0.004), but there was no difference in number of corpus luteum/follicle relationships between the ovulatory periods at the beginning and end of an IOI. For the four permutations of ipsilateral and two waves, contralateral and two waves, ipsilateral and three waves, and contralateral and three waves in Survey 2, the interval (days) from ovulation to the day the progesterone was <1.0 ng/mL was 17.8 ± 0.2(a), 17.6 ± 0.2(a), 20.0 ± 0.3(b), and 21.4 ± 0.3(c), respectively, and the number of IOIs was 33 (34%)(a), 34 (35%)(a), 8 (8%)(b), and 22 (23%)(a), respectively; means with different superscripts are different (P < 0.05). The luteal phase was longer for the contralateral relationship than for the ipsilateral relationship for three-wave IOIs but not for two-wave IOIs. The hypothesis was supported that the frequency of the ipsilateral and three-wave permutation was less than for each of the other three permutations. 23962819 Iron sensing and regulation in Saccharomyces cerevisiae: Ironing out the mechanistic details. Regulation of iron metabolism in Saccharomyces cerevisiae is achieved at the transcriptional level by low (Aft1 and Aft2) and high iron-sensing (Yap5) transcription factors, and at the post-transcriptional level by mRNA-binding proteins (Cth1 and Cth2). In this review we highlight recent studies unveiling the critical role that iron-sulfur clusters play in control of Aft1/2 and Yap5 activity, as well as the complex relationship between iron homeostasis and thiol redox metabolism. In addition, new insights into the localization and regulation of Cth1/Cth2 have added another layer of complexity to the cell's adaptation to iron deficiency. Finally, biophysical studies on subcellular iron speciation changes in response to environmental and genetic factors have further illuminated the elaborate control mechanisms required to manage iron bioavailability in the cell. 23968533 Integrating child health services into malaria control services of village malaria workers in remote Cambodia: service utilization and knowledge of malaria management of caregivers. Malaria and other communicable diseases remain major threats in developing countries. In Cambodia, village malaria workers (VMWs) have been providing malaria control services in remote villages to cope with the disease threats. In 2009, the VMW project integrated child health services into the original malaria control services. However, little has been studied about the utilization of VMWs' child health services. This study aimed to identify determinants of caregivers' VMW service utilization for childhood illness and caregivers' knowledge of malaria management. A cross-sectional study was conducted in 36 VMW villages of Kampot and Kampong Thom provinces in July-September 2012. An equal number of VMW villages with malaria control services only (M) and those with malaria control plus child health services (M+C) were selected from each province. Using structured questionnaires, 800 caregivers of children under five and 36 VMWs, one of the two VMWs who was providing VMW services in each study village were interviewed. Among the caregivers, 23% in M villages and 52% in M+C villages utilized VMW services for childhood illnesses. Determinants of caregivers' utilization of VMWs in M villages included their VMWs' length of experience (AOR = 11.80, 95% confidence interval [CI] = 4.46-31.19) and VMWs' service quality (AOR = 2.04, CI = 1.01-4.11). In M+C villages, VMWs' length of experience (AOR = 2.44, CI = 1.52-3.94) and caregivers' wealth index (AOR = 0.35, CI = 0.18-0.68) were associated with VMW service utilization. Meanwhile, better service quality of VMWs (AOR = 3.21, CI = 1.34-7.66) and caregivers' literacy (AOR = 9.91, CI = 4.66-21.05) were positively associated with caregivers' knowledge of malaria management. VMWs' service quality and length of experience are important determinants of caregivers' utilization of VMWs' child health services and their knowledge of malaria management. Caregivers are seeking VMWs' support for childhood illnesses even if they are providing only malaria control services. This underlines the importance of scaling-up VMWs' capacity by adding child health services of good quality, which will result in improving child health status in remote Cambodia. 23849084 Longitudinal measurement of cortisol in association with mental health and experience of domestic violence and abuse: study protocol. Domestic violence and abuse is threatening behavior, violence/abuse used by one person to control the other within an intimate or family-type relationship. Women experience more severe physical and sexual domestic violence and abuse and more mental health consequences than men. The current study aims at exploring of the role of hypothalamic-pituitary-adrenocortical axis activity in abuse impact on women's mental health. Study objectives: 1) To evaluate diurnal cortisol slope, cortisol awakening response, and the mean cortisol concentration in women with a current or recent experience of abuse; 2) To estimate whether cortisol secretion is associated with type, severity, duration and cessation of abuse; 3) To investigate whether cortisol acts as mediator between abuse and mental health condition; 4) To examine whether there is any distinction in cortisol levels between those women exposed to both childhood abuse and domestic violence and abuse and those experienced only the latter. 4) To explore whether cortisol secretion differs between women living in refuge and those still living in the community. To meet study objectives 128 women will be recruited in a domestic violence agency and local communities. Baseline and 3-month follow-up measures will be taken over 6 months after recruitment. Each assessment will include: (1) standardized self-administered questionnaires to evaluate socio-demographics, experience of violence and abuse, mental and physical health; (2) weight and height measurement; (3) self-completion of wakening, post-wakening and evening saliva samples. Saliva will be analysed for cortisol and cortisone using Ultra performance liquid chromatography-tandem mass spectrometry. We will compare diurnal cortisol parameters between non-abused controls and abuse survivors with and without mental health conditions. First following descriptive statistics for all the cortisol and mental health outcomes, relationships between them will be investigated using appropriate regression models. Second, these techniques will be used to investigate the extent to which cortisol measures act as potential mediators between type, severity, duration of abuse and mental disorders. Results of the study will increase our understanding of the pathophysiological mechanisms of abuse-related mental health disorders in women and inform researchers and practitioners on the possibility of using salivary cortisol as a biological marker for prognosis, diagnosis, and treatment evaluation among abuse survivors. ClinicalTrials.gov registration NCT01632553. 23952647 Effect of recombinant human soluble thrombomodulin on clinical outcomes of patients with coagulopathy after hematopoietic stem cell transplantation. From 2001 to 2012, 71 individuals with hematological diseases received HSCT in our institution. Of these, 41 developed disseminated intravascular coagulation (DIC) in association with various underlying conditions. The patients who developed DIC after 2008 (n=23) were treated by recombinant human soluble thrombomodulin (rTM), and the others (n=11) were treated by either heparin and/or antithrombin III concentrate. Seven patients did not receive any anticoagulant therapy. Of note, treatment of coagulopathy by rTM significantly improved clinical outcomes of patients at day 100 and dramatically prolonged their overall survival (p=0.044). Taken together, rTM is useful to improve clinical outcomes of transplant recipients with coagulopathy. This article is protected by copyright. All rights reserved. 23872693 The QT interval and risk of incident atrial fibrillation. Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine. To determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF. We examined a prolonged QT interval corrected by using the Framingham formula (QTFram) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by using other formulas. Among 14,538 ARIC study participants, a prolonged QTFram predicted a roughly 2-fold increased risk of AF (hazard ratio [HR] 2.05; 95% confidence interval [CI] 1.42-2.96; P < .001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in Cardiovascular Health Study and Health, Aging, and Body Composition study and were similar across various QT correction methods. Also in the ARIC study, each 10-ms increase in QTFram was associated with an increased unadjusted (HR 1.14; 95% CI 1.10-1.17; P < .001) and adjusted (HR 1.11; 95% CI 1.07-1.14; P < .001) risk of AF. Findings regarding a short QT interval were inconsistent across cohorts. A prolonged QT interval is associated with an increased risk of incident AF. 23910853 Incidental bilateral xanthogranuloma of the lateral ventricles at autopsy - A case report. We report the case of a woman found dead in a public garden. She had multiple contusions, bruises and lacerations of the face due to blunt force trauma. Microscopic examination of the brain was consistent with a death due to severe craniocerebral injury. The neuropathologist also found yellow nodular lesions located in each lateral ventricle and composed by cholesterol clefts, foamy macrophages, and giant cells. A diagnosis of xanthogranuloma of the choroid plexus was made. According to the literature, xanthogranulomas are uncommon benign lesions of the central nervous system. Mostly are found incidentally at post-mortem examination. However, some of them are symptomatic and can lead to severe nervous central damages if they remain untreated. 23930994 Structure and Reactivity Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR). A novel series of small molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modelling this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the L858R activating mutant, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH) based assay has been used to measure thiol reactivity towards the electrophilic functionality of the inhibitor series enabling both the identification of a suitable reactivity window for potency and the development of reactivity quantitative structure property relationship (QSPR) to support design. 23858468 Structure and function of CarD, an essential mycobacterial transcription factor. CarD, an essential transcription regulator in Mycobacterium tuberculosis, directly interacts with the RNA polymerase (RNAP). We used a combination of in vivo and in vitro approaches to establish that CarD is a global regulator that stimulates the formation of RNAP-holoenzyme open promoter (RPo) complexes. We determined the X-ray crystal structure of Thermus thermophilus CarD, allowing us to generate a structural model of the CarD/RPo complex. On the basis of our structural and functional analyses, we propose that CarD functions by forming protein/protein and protein/DNA interactions that bridge the RNAP to the promoter DNA. CarD appears poised to interact with a DNA structure uniquely presented by the RPo: the splayed minor groove at the double-stranded/single-stranded DNA junction at the upstream edge of the transcription bubble. Thus, CarD uses an unusual mechanism for regulating transcription, sensing the DNA conformation where transcription bubble formation initiates. 23086402 Review and discussion of tubular biomarkers in the diagnosis and management of diabetic nephropathy. The prevalence of diabetic nephropathy has tremendously increased with the relentless rise in the incidence of diabetes over the last couple decades. Diabetic nephropathy is a leading cause of morbidity and mortality, and it invariably leads to an end-stage renal disease (ESRD). In an effort to delay the onset of ESRD systematic screening and appropriate management are needed to evaluate the progression of renal damage in diabetic nephropathy. The reliability of current tests in predicting the onset, progression and response to various regimens for diabetic nephropathy is still under debate; and it has engendered a search for more sensitive and specific urinary biomarkers, especially those reflective of tubular dysfunctions. It is well-known that there is a good correlation between the degree of damage to the tubulo-interstitial compartment and the deterioration of renal functions. In view of this, the utility of urinary biomarkers, reflective of tubular injury, reported in the literature is discussed in this brief review. 23570818 Challenging expectancies to prevent nonmedical prescription stimulant use: A randomized, controlled trial. College students continue to report nonmedical prescription stimulant use to enhance alertness and concentration. Despite increasing prevalence of this behavior, techniques for preventing or treating it are lacking. An intervention that focuses on challenging positive consequence-oriented beliefs about prescription stimulants may be efficacious in preventing use. The current study examined the efficacy of a randomized controlled expectancy challenge intervention to prevent nonmedical prescription stimulant use among 96 at-risk, stimulant-naïve college students (i.e., low grade point average, Greek involvement, binge drinking, cannabis use). Forty-seven participants completed a brief expectancy challenge intervention aimed at modifying positive expectancies for prescription stimulants, to consequently deter initiation of use. The remaining participants received no intervention. The expectancy challenge successfully modified expectancies related to prescription stimulant effects. Nevertheless, this intervention group and a control group showed comparable rates of nonmedical prescription use at 6-month follow-up. However, negative expectancies were significant predictors of reduced odds of future use. A challenge session appears to modify stimulant-related expectancies, which are related to nonmedical prescription stimulant use. Nevertheless, a more potent challenge or booster sessions might be essential for longer-term changes. 23920230 Synergistic interaction of Rhizobium leguminosarum bv. viciae and arbuscular mycorrhizal fungi as a plant growth promoting biofertilizers for faba bean (Vicia faba L.) in alkaline soil. Egyptian soils are generally characterized by slightly alkaline to alkaline pH values (7.5-8.7) which are mainly due to its dry environment. In arid and semi-arid regions, salts are less concentrated and sodium dominates in carbonate and bicarbonate forms, which enhance the formation of alkaline soils. Alkaline soils have fertility problems due to poor physical properties which adversely affect the growth and the yield of crops. Therefore, this study was devoted to investigating the synergistic interaction of Rhizobium and arbuscular mycorrhizal fungi for improving growth of faba bean grown in alkaline soil. A total of 20 rhizobial isolates and 4 species of arbuscular mycorrhizal fungi (AMF) were isolated. The rhizobial isolates were investigated for their ability to grow under alkaline stress. Out of 20 isolates 3 isolates were selected as tolerant isolates. These 3 rhizobial isolates were identified on the bases of the sequences of the gene encoding 16S rRNA and designated as Rhizobium sp. Egypt 16 (HM622137), Rhizobium sp. Egypt 27 (HM622138) and Rhizobium leguminosarum bv. viciae STDF-Egypt 19 (HM587713). The best alkaline tolerant was R. leguminosarum bv. viciae STDF-Egypt 19 (HM587713). The effect of R. leguminosarum bv. viciae STDF-Egypt 19 and mixture of AMF (Acaulospora laevis, Glomus geosporum, Glomus mosseae and Scutellospora armeniaca) both individually and in combination on nodulation, nitrogen fixation and growth of Vicia faba under alkalinity stress were assessed. A significant increase over control in number and mass of nodules, nitrogenase activity, leghaemoglobin content of nodule, mycorrhizal colonization, dry mass of root and shoot was recorded in dual inoculated plants than plants with individual inoculation. The enhancement of nitrogen fixation of faba bean could be attributed to AMF facilitating the mobilization of certain elements such as P, Fe, K and other minerals that involve in synthesis of nitrogenase and leghaemoglobin. Thus it is clear that the dual inoculation with Rhizobium and AMF biofertilizer is more effective for promoting growth of faba bean grown in alkaline soils than the individual treatment, reflecting the existence of synergistic relationships among the inoculants. 23964354 A luminescence lifetime-based capillary oxygen sensor utilizing monolithically integrated organic photodiodes. A novel optical sensor device monolithically integrated on a glass capillary is presented. Therefore, we took advantage of the ability to fabricate organic optoelectronic devices on non-planar substrates. The functionality of the concept is demonstrated by realizing an integrated oxygen sensor based on luminescence decay time measurement. 23876672 Incorporating prosocial behavior to promote physical activity in older adults: Rationale and design of the Program for Active Aging and Community Engagement (PACE). Despite the benefits of regular physical activity among older adults, physical activity rates are low in this population. The Program for Active Aging and Community Engagement (PACE) is an ongoing randomized controlled trial designed to compare the effects of two interventions on physical activity at 12months among older adults. A total of 300 men and women aged 55years or older will be randomized into either a healthy aging (HA) control intervention (n=150), which is largely based upon educational sessions, or a prosocial behavior physical activity (PBPA) intervention (n=150), which incorporates structured physical activity sessions, cognitive-behavioral counseling, and opportunities to earn food for donation to a regional food bank based on weekly physical activity and volunteering. The PBPA intervention is delivered at a local YMCA, and a regional grocery store chain donates the food to the food bank. Data will be collected at baseline, 3, 6, and 12months. The primary outcome is physical activity as assessed by the Community Healthy Activities Model Program for Seniors (CHAMPS) Questionnaire at 12months. Secondary outcomes include physical function and health-related quality of life. If successful, the PACE study will demonstrate that prosocial behavior and volunteerism may be efficaciously incorporated into interventions and will provide evidence for a novel motivating factor for physical activity. 23903464 AMGET, an R-Based Postprocessing Tool for ADAPT 5. ADAPT 5 is a powerful modeling software for population pharmacokinetic and pharmacodynamic systems analysis, but provides limited built-in functionality for creating pre- and post-analysis diagnostic plots. ADAPT 5 Model Evaluation Graphical Toolkit (AMGET), an external package written in the open source R programming language, was developed specifically to support efficient postprocessing of ADAPT 5 runs, as well as NONMEM and S-ADAPT runs. Using interactive navigational menus, users of AMGET are able to rapidly create informative diagnostic plots enriched by the display of numerical and graphical elements with a high degree of customization using a simple settings spreadsheet. This article describes each feature of the AMGET package and illustrates how it allows users to utilize the powerful numerical routines of the ADAPT 5 package in a more efficient manner through the use of a simulated dataset and a simple pharmacokinetic model optimized using the maximum likelihood expectation maximization (MLEM) algorithm of ADAPT 5.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e61; doi:10.1038/psp.2013.36; published online 31 July 2013. 23942141 Grid-free powder averages: On the applications of the Fokker-Planck equation to solid state NMR. We demonstrate that Fokker-Planck equations in which spatial coordinates are treated on the same conceptual level as spin coordinates yield a convenient formalism for treating magic angle spinning NMR experiments. In particular, time dependence disappears from the background Hamiltonian (sample spinning is treated as an interaction), spherical quadrature grids are avoided completely (coordinate distributions are a part of the formalism) and relaxation theory with any linear diffusion operator is easily adopted from the Stochastic Liouville Equation theory. The proposed formalism contains Floquet theory as a special case. The elimination of the spherical averaging grid comes at the cost of increased matrix dimensions, but we show that this can be mitigated by the use of state space restriction and tensor train techniques. It is also demonstrated that low correlation order basis sets apparently give accurate answers in powder-averaged MAS simulations, meaning that polynomially scaling simulation algorithms do exist for a large class of solid state NMR experiments. 23770420 Immunohistochemical localization of mesenchymal stem cells in ossified human spinal ligaments. Mesenchymal stem cells (MSCs) have been isolated from various tissues and used for elucidating the pathogenesis of numerous diseases. In our previous in vitro study, we showed the existence of MSCs in human spinal ligaments and hypothesized that these MSCs contributed to the pathogenesis of ossification of spinal ligaments. The purpose of this study was to use immunohistochemical techniques to analyze the localization of MSCs in ossified human spinal ligaments in situ. Ossified (OLF) or non-ossified ligamentum flavum (non-OLF) samples from the thoracic vertebra were obtained from patients who had undergone posterior spinal surgery. Serial sections were prepared from paraffin-embedded samples, and double immunofluorescence staining was performed using antibodies against markers for MSCs (CD73, CD90 and CD105), endothelial cells (CD31), pericytes (α-smooth muscle actin), and chondrocytes (S100). Immunolocalization of MSCs was observed in the perivascular area and collagenous matrix in spinal ligaments. Markers for MSCs and pericytes were co-expressed in the perivascular area. Compared with non-OLF, OLF had a large amount of neovascularization in the fragmented ligament matrix, and a high accumulation of MSCs around blood vessels. The prevalence of MSCs in OLF within collagenous matrix was significantly higher than that in non-OLF. Chondrocytes near the ossification front in OLF also presented expression of MSC markers. MSCs may contribute to the ectopic ossification process of OLF through endochondral ossification. 23906741 Crimean-Congo hemorrhagic fever: History, epidemiology, pathogenesis, clinical syndrome and genetic diversity. Crimean-Congo hemorrhagic fever (CCHF) is the most important tick-borne viral disease of humans, causing sporadic cases or outbreaks of severe illness across a huge geographic area, from western China to the Middle East and southeastern Europe and throughout most of Africa. CCHFV is maintained in vertical and horizontal transmission cycles involving ixodid ticks and a variety of wild and domestic vertebrates, which do not show signs of illness. The virus circulates in a number of tick genera, but Hyalomma ticks are the principal source of human infection, probably because both immature and adult forms actively seek hosts for the blood meals required at each stage of maturation. CCHF occurs most frequently among agricultural workers following the bite of an infected tick, and to a lesser extent among slaughterhouse workers exposed to the blood and tissues of infected livestock and medical personnel through contact with the body fluids of infected patients. CCHFV is the most genetically diverse of the arboviruses, with nucleotide sequence differences among isolates ranging from 20% for the viral S segment to 31% for the M segment. Viruses with diverse sequences can be found within the same geographic area, while closely related viruses have been isolated in far distant regions, suggesting that widespread dispersion of CCHFV has occurred at times in the past, possibly by ticks carried on migratory birds or through the international livestock trade. Reassortment among genome segments during co-infection of ticks or vertebrates appears to have played an important role in generating diversity, and represents a potential future source of novel viruses. In this article, we first review current knowledge of CCHFV, summarizing its molecular biology, maintenance and transmission, epidemiology and geographic range. We also include an extensive discussion of CCHFV genetic diversity, including maps of the range of the virus with superimposed phylogenetic trees. We then review the features of CCHF, including the clinical syndrome, diagnosis, treatment, pathogenesis, vaccine development and laboratory animal models of CCHF. The paper ends with a discussion of the possible future geographic range of the virus. For the benefit of researchers, we include a Supplementary Table listing all published reports of CCHF cases and outbreaks in the English-language literature, plus some principal articles in other languages, with total case numbers, case fatality rates and all CCHFV strains on GenBank. 23832668 Chromosomal location of wheat genes of the carotenoid biosynthetic pathway and evidence for a catalase gene on chromosome 7A functionally associated with flour b* colour variation. Knowledge of molecular and genetic mechanisms controlling wheat grain quality characteristics is significant for improving flour for end-product functionality. Flour b* colour is an important quality trait for breeding wheat varieties to produce grain for specific market requirements. The degree of flour yellowness is due to the accumulation of carotenoids in grain, particularly lutein. Flour b* is under polygenic control and quantitative trait loci (QTL) have frequently been reported on chromosome 7AL. Analysis of carotenoid genes showed that phytoene synthase (PSY) co-located to the QTL on 7AL but other genes at this locus are also thought to contribute flour b* colour variation. This study used the wheat genome survey sequence and identified the chromosomal location of all wheat carotenoid genes, but none other than PSY were located on 7AL and, therefore, other genes may control flour b* colour variation including oxidative genes that degrade carotenoids. An investigation of EST bin mapped to 7AL identified a gene encoding a catalase enzyme (Cat3-A1) that was phylogenetically related to other plant class III enzymes, co-located to the QTL for flour b* colour variation on 7AL in three mapping populations and expressed during seed development. Therefore, Cat3-A1 was functionally associated with flour b* colour variation. Catalase acts upon hydrogen peroxide as a substrate and it was postulated that Cat3-A1 alleles control varying degrees of bleaching action on lutein in developing wheat grain. Markers for Cat3-A1 developed in this study can be used in conjunction with other candidate gene markers including phytoene synthase and lycopene-ε-cylase to develop a molecular signature for selecting lines with specific flour b* colour values in wheat breeding. 23783759 Intestinal parasites in HIV-seropositive patients in the Continental Region of Equatorial Guinea: its relation with socio-demographic, health and immune systems factors. Prevalence of intestinal parasitic infections in HIV-positive people and its association with clinical and socioeconomic factors has been investigated on the mainland of Equatorial Guinea, in order to define the precise measures for improvement of their quality of life. In August 2010, 273 HIV-positive and 60 HIV-negative were recruited. A sample of faeces, T-CD4+ cell counts, and clinical, socioeconomic and demographic data were collected from each patient. Stool samples were analysed by microscopy and immunochromatography. Data were analysed by Pearson's χ2 test and the risk of each factor was measured by odds ratio bivariate analysis. Two hundred and ten (76.9%) HIV-positive participants were infected by intestinal parasites and 16 parasite species were identified; 246 (48.9%) were pathogenic helminths, 159 (22.9%) pathogenic protozoa and 142 (28.2%) opportunistic protozoa. Trichuris trichiura, Entamoeba histolytica/dispar/moshkovskii, Ascaris lumbricoides and Giardia duodenalis were the most prevalent parasites; 52 (86.7%) of HIV-negative participants were parasitized. HIV was related to co-infection by Entamoeba spp., E. nana and Blastocystis hominis. The high rates of parasitic infections found highlights the urgent need of environmental sanitation, health education and water distribution actions, as well as early diagnosis and treatment of intestinal parasites. 23829349 Identification of nitrogen dopants in single-walled carbon nanotubes by scanning tunneling microscopy. Using scanning tunnelling microscopy and spectroscopy, we investigated the atomic and electronic structure of nitrogen-doped single walled carbon nanotubes synthesized by chemical vapor deposition. The insertion of nitrogen in the carbon lattice induces several types of point defects involving different atomic configurations. Spectroscopic measurements on semiconducting nanotubes reveal that these local structures can induce either extended shallow levels or more localized deep levels. In a metallic tube, a single doping site associated with a donor state was observed in the gap at an energy close to that of the first van Hove singularity. Density functional theory calculations reveal that this feature corresponds to a substitutional nitrogen atom in the carbon network. 23874673 Intralesional injection of rose bengal induces a systemic tumor-specific immune response in murine models of melanoma and breast cancer. Intralesional (IL) injection of PV-10 has shown to induce regression of both injected and non-injected lesions in patients with melanoma. To determine an underlying immune mechanism, the murine B16 melanoma model and the MT-901 breast cancer model were utilized. In BALB/c mice bearing MT-901 breast cancer, injection of PV-10 led to regression of injected and untreated contralateral subcutaneous lesions. In a murine model of melanoma, B16 cells were injected into C57BL/6 mice to establish one subcutaneous tumor and multiple lung lesions. Treatment of the subcutaneous lesion with a single injection of IL PV-10 led to regression of the injected lesion as well as the distant B16 melanoma lung metastases. Anti-tumor immune responses were measured in splenocytes collected from mice treated with IL PBS or PV-10. Splenocytes isolated from tumor bearing mice treated with IL PV-10 demonstrated enhanced tumor-specific IFN-gamma production compared to splenocytes from PBS-treated mice in both models. In addition, a significant increase in lysis of B16 cells by T cells isolated after PV-10 treatment was observed. Transfer of T cells isolated from tumor-bearing mice treated with IL PV-10 led to tumor regression in mice bearing B16 melanoma. These studies establish that IL PV-10 therapy induces tumor-specific T cell-mediated immunity in multiple histologic subtypes and support the concept of combining IL PV10 with immunotherapy for advanced malignancies. 23672875 Ultrafast molecular motor driven nanoseparation and biosensing. Portable biosensor systems would benefit from reduced dependency on external power supplies as well as from further miniaturization and increased detection rate. Systems built around self-propelled biological molecular motors and cytoskeletal filaments hold significant promise in these regards as they are built from nanoscale components that enable nanoseparation independent of fluidic pumping. Previously reported microtubule-kinesin based devices are slow, however, compared to several existing biosensor systems. Here we demonstrate that this speed limitation can be overcome by using the faster actomyosin motor system. Moreover, due to lower flexural rigidity of the actin filaments, smaller features can be achieved compared to microtubule-based systems, enabling further miniaturization. Using a device designed through optimization by Monte Carlo simulations, we demonstrate extensive myosin driven enrichment of actin filaments on a detector area of less than 10 μm², with a concentration half-time of approximately 40 s. We also show accumulation of model analyte (streptavidin at nanomolar concentration in nanoliter effective volume) detecting increased fluorescence intensity within seconds after initiation of motor-driven transportation from capture regions. We discuss further optimizations of the system and incorporation into a complete biosensing workflow. 23817230 The outcomes of laparoscopic resection of bowel endometriosis. To present the outcome of laparoscopic resection for bowel endometriosis. In the last 12 months, numerous articles have been published to demonstrate and underline the efficiency and feasibility of the laparoscopic approach in the treatment of bowel endometriosis. Endometriosis is a common condition that can affect women in their reproductive age. It can have an intestinal involvement, and when it occurs rectum and rectosigmoid junction are the most frequent sites; other lesser frequent sites are the appendix, the distal ileum, and the cecum. It is widely agreed that surgical management is the primary treatment for symptomatic bowel endometriosis. Laparoscopic bowel resection has become increasingly popular because it represents a well tolerated and feasible technique. 23926302 Platelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of Sitosterolemia. Sitosterolemia is a rare, autosomal recessive disease caused by mutations in the adenosine triphosphate-binding cassette transporter genes, ABCG5 or ABCG8, that result in accumulation of xenosterols in the body. Clinical manifestations include tendon xanthomas, premature coronary artery disease, hemolytic anemia, macrothrombocytopenia, and bleeding. While the effect of sterol accumulation on the predisposition for atherosclerosis is evident, how xenosterol accumulation leads to defects in platelet physiology is unknown. Sitosterolemia induced in Abcg5- and Abcg8-deficient mice fed a high plant sterol diet resulted in accumulation of free sterols in platelet plasma membranes, leading to hyperactivatable platelets characterized by constitutive binding of fibrinogen to its αIIbβ3 integrin receptor, internalization of the αIIbβ3 complex, generation of platelet-derived microparticles, and changes in the quantity and subcellular localization of filamin. The latter was associated with macrothrombocytopenia, shedding of GPIbα, impaired platelet adhesion to von Willebrand Factor, and inability to form stable thrombi. Plasma levels of soluble GPIbα were strongly correlated with plasma sitosterol levels in samples from human sitosterolemic patients, implicating a similar mechanism of sterol-induced platelet passivation in the human disease. Intercalation of plant sterols into the plasma membrane therefore results in dysregulation of multiple platelet activation pathways, leading to macrothrombocytopenia and bleeding. 23587769 Genetics of diabetes - Are we missing the genes or the disease? Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the beta-cells of the pancreas with consequent insulin deficiency to abnormalities that result in resistance to insulin action (American Diabetes Association, 2011). The vast majority of cases of diabetes fall into two broad categories. In type 1 diabetes (T1D), the cause is an absolute deficiency of insulin secretion, whereas in type 2 diabetes (T2D), the cause is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. However, the subdivision into two main categories represents a simplification of the real situation, and research during the recent years has shown that the disease is much more heterogeneous than a simple subdivision into two major subtypes assumes. Worldwide prevalence figures estimate that there are 280 million diabetic patients in 2011 and more than 500 million in 2030 (http://www.diabetesatlas.org/). In Europe, about 6-8% of the population suffer from diabetes, of them about 90% has T2D and 10% T1D, thereby making T2D to the fastest increasing disease in Europe and worldwide. This epidemic has been ascribed to a collision between the genes and the environment. While our knowledge about the genes is clearly better for T1D than for T2D given the strong contribution of variation in the HLA region to the risk of T1D, the opposite is the case for T2D, where our knowledge about the environmental triggers (obesity, lack of exercise) is much better than the understanding of the underlying genetic causes. This lack of knowledge about the underlying genetic causes of diabetes is often referred to as missing heritability (Manolio et al., 2009) which exceeds 80% for T2D but less than 25% for T1D. In the following review, we will discuss potential sources of this missing heritability which also includes the possibility that our definition of diabetes and its subgroups is imprecise and thereby making the identification of genetic causes difficult. 23953638 Can differences in life cycle explain differences in invasiveness? - A study on Anguillicola novaezelandiae in the European eel. SUMMARY Anguillicola crassus is the most invasive species of its genus and it is a successful colonizer of different eel species worldwide. It is so far the only species of the genus Anguillicola whose life cycle has been studied completely. To analyse whether differences in life cycle may explain differences in invasiveness, we infected European eels with Anguillicola novaezelandiae under laboratory conditions. Anguillicola novaezelandiae shows a synchronized development in the European eel. Eggs with second-stage larvae appeared 120 days after infection. No density-dependent effect in parasite development could be found for A. novaezelandiae. The present study shows that the life cycle of A. novaezelandiae differs on final host level compared with A. crassus in ways which result in a less successful invasion of new host species. 23252952 Improving clinical trial sampling for future research - an international approach: outcomes and next steps from the DIA future use sampling workshop 2011. Clinical trial samples collected for pharmacogenomic and future research are vital resources for the development of safe and effective drugs, yet collecting adequate, representative sample sets in global trials is challenging. The Drug Information Association (DIA) sponsored a workshop on future use sampling in September 2011, bringing together experts from regulatory agencies, academia and industry to discuss challenges to future use sample collection and identify actions to improve collection. Several common themes and associated action items emerged, including the need for international guidance on the collection of samples for future research; additional discussion related to coding, scope of research, and return of research results; and additional education about pharmacogenomic/future research and the importance of long-term storage of specimens. 23462581 Effectiveness of home- and community-based rehabilitation in a large cohort of patients disabled by cerebrovascular accident: evidence of a dose-response relationship. To (1) assess the effectiveness of home- and community-based rehabilitation (HCBR) in a large cohort of individuals with disabilities secondary to cerebrovascular accident (CVA); and (2) evaluate the responsiveness to treatment of the Mayo-Portland Adaptability Inventory (MPAI-4) to changes resulting from HCBR in this patient group. Retrospective analysis of program evaluation data for treatment completers and noncompleters. HCBR conducted in 7 geographically distinct U.S. cities. Individuals with CVA (n=738) who completed the prescribed course of rehabilitation (completed course of treatment [CCT]) compared with 150 individuals who were precipitously discharged (PD) before program completion. HCBR delivered by certified professional staff on an individualized basis. Mayo-Portland Adaptability Inventory (MPAI-4) completed by professional consensus on admission and at discharge. With the use of analysis of covariance, MPAI-4 total scores at discharge for CCT participants were compared with those of PD participants, with admission MPAI-4, age, length of stay, and time since event as covariates. CCT participants showed greater improvement than PD participants (F=99.48, P<.001) with a moderate effect size (partial η(2)=.10). Group differences and effect sizes were similar for the 3 index scores: Ability (F=75.96, P<.001; partial η(2)=.08), Adjustment (F=99.67, P<.001; partial η(2)=.10), and Participation (F=69.15, P<.001; partial η(2)=.07). Individuals in the CCT group who received the entire planned course of HCBR showed greater improvement on all MPAI-4 indexes than those in the PD group who were discharged before completing the prescribed program. This dose-response relationship provides evidence of a causal relationship between treatment and outcome. 23245588 Can hip anatomy be reconstructed with femoral components having only one neck morphology? A study on 466 hips. This extensive radiographic study asks if there is a statistical relationship between the size of the stem that will best fit the femur and the vertical and lateral offsets of the reconstructed acetabular center, what is the distribution of vertical and lateral offsets in this large and if there is a statistical difference among surgeons in the planned location of the reconstructed acetabular center. On 466 radiographs, five surgeons separately templated stem size and acetabular cup location. The vertical and horizontal coordinates of the reconstructed acetabulum center were measured relative to the planned position of the stem. We found a strong correlation between the stem size and the average lateral and vertical offsets. Acetabular reaming associated with the anatomic variability of native femoral necks, leads to a span of 36mm in lateral offset, and a span of 39mm in vertical offset. Statistically significant differences were also found in the way surgeons plan acetabular reaming. 23886914 The pivotal position of the actin cytoskeleton in the initiation and regulation of B cell receptor activation. The actin cytoskeleton is a dynamic cellular network known for its function in cell morphology and motility. Recent studies using high resolution and real time imaging techniques have revealed that actin plays a critical role in signal transduction, primarily by modulating the dynamics and organization of membrane-associated receptors and signaling molecules. This review summarizes what we have learned so far about a regulatory niche of the actin cytoskeleton in the signal transduction of the B cell receptor (BCR). The activation of the BCR is initiated and regulated by a close coordination between the dynamics of surface BCRs and the cortical actin network. The actin cytoskeleton is involved in regulating the signaling threshold of the BCR to antigenic stimulation, the kinetics and amplification of BCR signaling activities, and the timing and kinetics of signaling downregulation. Actin exerts its regulatory function by controlling the kinetics, magnitude, subcellular location, and nature of BCR clustering and BCR signaling complex formation at every stage of signaling. The cortical actin network is remodeled by initial detachment from the plasma membrane, disassembly and subsequent reassembly into new actin structures in response to antigenic stimulation. Signaling responsive actin regulators translate BCR stimulatory and inhibitory signals into a series of actin remodeling events, which enhance signaling activation and down-regulation by modulating the lateral mobility and spatial organization of surface BCR. The mechanistic understanding of actin-mediated signaling regulation in B cells will help us explore B cell-specific manipulations of the actin cytoskeleton as treatments for B cell-mediated autoimmunity and B cell cancer. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. 23891089 Residual γH2AX foci predict local tumour control after radiotherapy. Evaluation of micromilieu-dependent quantified γH2AX foci as a potential predictive biomarker in well-oxygenated tumour areas in 9 HNSCC xenograft models in vivo. GammaH2AX foci were quantified in perfused tumour areas 30min (initial γH2AX foci) and 24h (residual γH2AX foci) after exposure to a single dose of 4Gy. The initial and residual normalised γH2AX foci were correlated with TCD50 after single dose irradiation under clamped blood flow (SDclamp) or a fractionated irradiation setting under ambient blood flow (fx). A significant negative correlation between initial and residual normalised γH2AX foci and TCD50 SDclamp and TCD50 fx for 9 HNSCC tumour xenograft models in vivo was found. Residual normalised γH2AX foci showed higher intertumoural variability and their correlation with TCD50 was more robust. For the first time a significant negative correlation between γH2AX foci and local tumour control after irradiation has been demonstrated. Our results underline the potential of residual γH2AX foci as a predictive biomarker for local tumour control after radiotherapy. 23641942 Influence of histidine incorporation on buffer capacity and gene transfection efficiency of HPMA-co-oligolysine brush polymers. One of the major intracellular barriers to non-viral gene delivery is efficient endosomal escape. The incorporation of histidine residues into polymeric constructs has been found to increase endosomal escape via the proton sponge effect. Statistical and diblock copolymers of N-(2-hydroxypropyl)methacrylamide (HPMA), oligolysine, and oligohistidine were synthesized via reversible-addition fragmentation chain transfer (RAFT) polymerization, and tested for in vitro transfection efficiency, buffering ability, and polyplex uptake mechanism via the use of chemical endocytic inhibitors. Interestingly, histidine-containing statistical and diblock polymers exhibited increased buffer capacity in different endosomal pH ranges. Statistical copolymers transfected better than block copolymers that contained similar amounts of histidine. In addition, only the polymer containing the highest incorporation of oligohistidine residues led to increases in transfection efficiency over the HPMA-oligolysine base polymer. Thus, for these polymer architectures, high histidine incorporation may be required for efficient endosomal escape. Furthermore, uptake studies indicate that non-acidified caveolae-mediated endocytosis may be the primary route of transfection for these copolymers, suggesting that alternative approaches for increasing endosomal escape may be beneficial for enhancing transfection efficiency with these HPMA-oligolysine copolymers. 23925146 Early Lactate Elevations Following Resuscitation From Pediatric Cardiac Arrest Are Associated With Increased Mortality. To describe the association of lactate levels within the first 12 hours after successful resuscitation from pediatric cardiopulmonary arrest with hospital mortality. Retrospective cohort study. Fifteen children's hospital associated with the Pediatric Emergency Care Applied Research Network. Patients between 1 day and 18 years old who had a cardiopulmonary arrest, received chest compressions more than 1 minute, had a return of spontaneous circulation more than 20 minutes, and had lactate measurements within 6 hours of arrest. None. Two hundred sixty-four patients had a lactate sampled between 0 and 6 hours (lactate0-6) and were evaluable. Of those, 153 patients had a lactate sampled between 7 and 12 hours (lactate7-12). One hundred thirty-eight patients (52%) died. After controlling for arrest location, total number of epinephrine doses, initial rhythm, and other potential confounders, the odds of death per 1 mmol/L increase in lactate0-6 was 1.14 (1.08, 1.19) (p < 0.001) and the odds of death per 1 mmol/L increase in lactate7-12 was 1.20 (1.11, 1.30) (p < 0.0001). Area under the curve for in-hospital arrest mortality for lactate0-6 was 0.72 and for lactate7-12 was 0.76. Area under the curve for out-of-hospital arrest mortality for lactate0-6 was 0.8 and for lactate7-12 was 0.75. Elevated lactate levels in the first 12 hours after successful resuscitation from pediatric cardiac arrest are associated with increased mortality. Lactate levels alone are not able to predict outcomes accurately enough for definitive prognostication but may approximate mortality observed in this large cohort of children's hospitals. 23500779 Dietary exposure of juvenile female mice to polyhalogenated seafood contaminants (HBCD, BDE-47, PCB-153, TCDD): Comparative assessment of effects in potential target tissues. Fish represents source of nutrients and major dietary vehicle of lipophilic persistent contaminants. The study compared the effects of two legacy and two emerging fish pollutants (Hexabromocyclododecane HBCD; 2,2',4,4'-Tetrabromodiphenyl ether BDE-47; 2,2',4,4',5,5'-Hexachlorobiphenyl PCB-153; 2,3,7,8-Tetrachlorodibenzo-p-doxin TCDD) in juvenile female mice exposed through a salmon based rodent diet for 28days (dietary doses: HBCD 199mg/kg bw/day; BDE-47 450μg/kg bw/day; PCB-153 195μg/kg bw/day; TCDD 90ng/kg bw/day). Dose levels were comparable to previously reported developmental Lowest Observed Adverse Effect Levels. None of the treatments elicited signs of overt toxicity, but HBCD increased relative liver weight. All compounds caused changes in liver, thymus and thyroid; spleen was affected by BDE-47 and PCB-153; no effects were seen in uterus and adrenals. Strongest effects in thyroid follicles were elicited by PCB-153, in thymus and liver by BDE-47. HBCD and BDE-47 induced liver fatty changes, but appeared to be less potent in the other tissues. HBCD, BDE-47 and TCDD increased serum testosterone levels and the testosterone/estradiol ratio, suggesting a potential involvement of pathways related to sex steroid biosynthesis and/or metabolism. The results support the role of toxicological studies on juvenile rodents in the hazard characterization of chemicals, due to endocrine and/or immune effects. 23952537 The carboxyl group of Glu113 is required for stabilization of the diferrous and bis-FeIV states of MauG. The diheme enzyme MauG catalyzes a six-electron oxidation required for posttranslational modification of a precursor of methylamine dehydrogenase (preMADH) to complete the biosynthesis of its protein-derived tryptophan tryptophylquinone (TTQ) cofactor. Crystallographic studies have implicated Glu113 in the formation of the bis-FeIV state of MauG, in which one heme is FeIV=O and the other is FeIV with His-Tyr axial ligation. An E113Q mutation had no effect on the structure of MauG, but significantly altered its redox properties. E113Q MauG could not be converted to the diferrous state by reduction with dithionite, but was only reduced to a mixed valence FeII/FeIII state, which is never observed in wild-type (WT) MauG. Addition of H2O2 to E113Q MauG generated a high valence state that formed more slowly and was less stable than the bis-FeIV state of WT MauG. E113Q MauG exhibited no detectable TTQ biosynthesis activity in a steady-state assay with preMADH as the substrate. It did catalyze the steady-state oxidation of quinol MADH to the quinone, but 1000-fold less efficiently than WT MauG. Addition of H2O2 to a crystal of the E113Q MauG-preMADH complex resulted in partial synthesis of TTQ. Extended exposure of these crystals to H2O2 resulted in hydroxylation of Pro107 in the distal pocket of the high-spin heme. It is concluded that the loss of the carboxylic group of Glu113 disrupts the redox cooperativity between hemes that allows rapid formation of the diferrous state, and alters the distribution of high-valence species that participate in charge-resonance stabilization of the bis-FeIV redox state. 23649223 Swiss contributions to war surgery during the great war. The role of neutral Switzerland during World War I is somewhat mysterious and its diplomatic history has never been fully disclosed. One of the activities might have determined its role: based on its relationship to the International Committee of the Red Cross, wounded multinational prisoners-of-war were interned in Swiss hospitals and Swiss physicians worked in a medical capacity in military hospitals on both sides of the front. The main question is whether the activities of the Swiss authorities reflected a charitable diplomatic role while retaining the country's traditional neutral stance. Supplementary practical questions included: How did Switzerland carry out the exchange of severely wounded prisoners of war? How did Swiss physicians function in the war zones? What were the medical objectives and the ultimate results of wartime surgery in Switzerland? This study is based on archival material from the Swiss Federal Archive in Bern (BAR) and original publications of Swiss and German physicians in professional journals. The search was performed manually in the BAR evaluating the file "Landesverteidigung (national defense)" from 1848 to 2009. Original publications and journals were searched manually in the central libraries of Munich, Heidelberg, Zurich, and Bern. The evaluation of Swiss diplomatic activities confirmed that Switzerland's charitable mission was aimed to enforce its neutral position and that Swiss authorities were able to efficiently manage the resulting problems. The engagement of Swiss surgeons in war surgery contributed to their experience and knowledge and yielded the development of many innovative medical devices and operating procedures, numerous of which are still known today. While maintaining its neutral position, Switzerland was able to deal with the practical problems while gaining innovative medical knowledge still valid today. 23811821 Role of Outer-pore Residue Y380 in U-type Inactivation of KV2.1 Channels. The interpretation of slow inactivation in potassium channels has been strongly influenced by work on C-type inactivation in Shaker channels. Slow inactivation in Shaker and some other potassium channels can be dramatically modulated by the state of the pore, including mutations at outer pore residue T449, which altered inactivation kinetics up to 100-fold. KV2.1, another voltage-dependent potassium channel, exhibits a biophysically distinct inactivation mechanism with a U-shaped voltage-dependence and preferential closed-state inactivation, termed U-type inactivation. However, it remains to be demonstrated whether U-type and C-type inactivation have different molecular mechanisms. This study examines mutations at Y380 (homologous to Shaker T449) to investigate whether C-type and U-type inactivation have distinct molecular mechanisms, and whether C-type inactivation can occur at all in KV2.1. Y380 mutants do not introduce C-type inactivation into KV2.1 and have little effect on U-type inactivation of KV2.1. Interestingly, two of the mutants tested exhibit twofold faster recovery from inactivation compared to wild-type channels. The observation that mutations have little effect suggests KV2.1 lacks C-type inactivation as it exists in Shaker and that C-type and U-type inactivation have different molecular mechanisms. Kinetic modeling predicts that all mutants inactivate preferentially, but not exclusively, from partially activated closed states. Therefore, KV2.1 exhibits a single U-type inactivation process including some inactivation from open as well as closed states. 23784083 The molecular features of tongue epithelium treated with the carcinogen 4-nitroquinoline-1-oxide and alcohol as a model for HNSCC. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer affecting humans worldwide. To determine the potential mechanisms by which chronic tobacco and alcohol abuse lead to HNSCC of the oral cavity, we have used both the 4-nitroquinoline-1-oxide (4-NQO) murine oral carcinogenesis and the Meadows-Cook alcohol models. In this study, we treated mice with 4-NQO in drinking water for 10 weeks and then administered 20% (w:v) ethanol (EtOH) for another 10 weeks. We observed increased levels and/or activation of signaling proteins [p38 mitogen-activated protein kinase (MAPK), β-catenin and Erk 1/2] that are typically altered during HNSCC initiation in humans. We found that EtOH administration alone increased the expression of p38 MAPK but not Erk 1/2 MAPK. Total β-catenin levels in the tongues increased by 2- to 3-fold after 4-NQO treatment, with or without EtOH. However, EtOH combined with 4-NQO reduced phosphorylated β-catenin levels, whereas 4-NQO treatment alone did not. These data implicate EtOH as a regulator of β-catenin signaling in this HNSCC model. We also utilized K14-CreER(TAM); ROSA26 mice to mark permanently stem/progenitor cells in the tongue epithelia. We found that 4-NQO alone and 4-NQO plus EtOH treatment resulted in massive, horizontal expansion of stem/progenitor cell populations arising from single stem cells in the basal layer of the epithelia. This expansion is consistent with carcinogen-associated, symmetric division of stem/progenitor cells. Our data suggest that specific therapeutic targets for prevention of HNSCC of the oral cavity associated with both alcohol and tobacco use are p38 MAPK and β-catenin. 23500386 Bioactive carbazole alkaloids from Murraya koenigii (L.) Spreng. Four new carbazole alkaloids (1-4) and fourteen known carbazole alkaloids (5-18) were isolated from Murraya koenigii. Their structures were elucidated on the basis of extensive spectroscopic analysis. Compounds 4, 6, 16, and 17 (10μM) had moderate hepatoprotective activities against d-galactosamine-induced HL-7702 cell damage. Compounds 11, 12 and 18 showed significant PTP1B inhibitory activity with IC50 values of 1.773, 1.875 and 2.286μM, respectively. 23603917 Genetic Information and the Prediction of Incident Type 2 Diabetes in a High-Risk Multi-Ethnic Population: The EpiDREAM Genetic Study. OBJECTIVESTo determine if 16 single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2DM) in Europeans are also associated with T2DM in South Asians and Latinos, and if they can add to the prediction of incident T2DM in a high-risk population.RESEARCH DESIGN AND METHODSIn the EpiDREAM prospective cohort study, physical measures, questionnaires, and blood samples were collected from 25,063 individuals at risk for dysglycemia. Sixteen SNPs that have been robustly associated with T2DM in Europeans were genotyped. Among 15,466 European, South Asian, and Latino subjects, we examined the association of these 16 SNPs alone and combined in a gene score with incident cases of T2DM (n = 1,016) that developed during 3.3 years of follow-up.RESULTSNine of the 16 SNPs were significantly associated with T2DM, and their direction of effect was consistent across the three ethnic groups. The gene score was significantly higher among subjects who developed incident T2DM (cases vs. noncases: 16.47 [2.50] vs. 15.99 [2.56]; P = 0.00001). The gene score remained an independent predictor of incident T2DM with an odds ratio of 1.08 (95% CI, 1.05-1.11) per additional risk allele after adjustment for T2DM risk factors. The gene score in those with no family history of T2DM was 16.02, whereas it was 16.19 in those with one parent with T2DM and it was 16.32 in those with two parents with T2DM (P trend = 0.0004). The C statistic of T2DM risk factors was 0.708 (0.691-0.725) and increased only marginally to 0.714 (0.698-0.731) with the addition of the gene score (P for C statistic change = 0.0052).CONCLUSIONT2DM genetic associations are generally consistent across ethnic groups, and a gene score only adds marginal information to clinical factors for T2DM prediction. 23903861 Analysis of the color alteration and radiopacity promoted by bismuth oxide in calcium silicate cement. The aim of the study was to determine if the increase in radiopacity provided by bismuth oxide is related to the color alteration of calcium silicate-based cement. Calcium silicate cement (CSC) was mixed with 0%, 15%, 20%, 30% and 50% of bismuth oxide (BO), determined by weight. Mineral trioxide aggregate (MTA) was the control group. The radiopacity test was performed according to ISO 6876/2001. The color was evaluated using the CIE system. The assessments were performed after 24 hours, 7 and 30 days of setting time, using a spectrophotometer to obtain the ΔE, Δa, Δb and ΔL values. The statistical analyses were performed using the Kruskal-Wallis/Dunn and ANOVA/Tukey tests (p<0.05). The cements in which bismuth oxide was added showed radiopacity corresponding to the ISO recommendations (>3 mm equivalent of Al). The MTA group was statistically similar to the CSC/30% BO group (p>0.05). In regard to color, the increase of bismuth oxide resulted in a decrease in the ΔE value of the calcium silicate cement. The CSC group presented statistically higher ΔE values than the CSC/50% BO group (p<0.05). The comparison between 24 hours and 7 days showed higher ΔE for the MTA group, with statistical differences for the CSC/15% BO and CSC/50% BO groups (p<0.05). After 30 days, CSC showed statistically higher ΔE values than CSC/30% BO and CSC/50% BO (p<0.05). In conclusion, the increase in radiopacity provided by bismuth oxide has no relation to the color alteration of calcium silicate-based cements. 23962248 Ask the Experts: Automation: Part II. Bioanalysis invited a selection of leading researchers to express their views on automation in the bioanalytical laboratory. The topics discussed include the challenges that the modern bioanalyst faces when integrating automation into existing drug development processes, the impact of automation and how they envision the modern bioanalytical laboratory changing in the near future. Their enlightening responses provide a valuable insight into the impact of automation and the future of the constantly evolving bioanalytical laboratory. 23903107 Influence of the waist diameters on transmission characteristics and strain sensitivity of microtapered long-period fiber gratings. Transmission characteristics of microtapered long-period fiber gratings (MTLPGs) and their strain and temperature sensitivities with variations in the waist diameters are investigated theoretically and experimentally. Transmission characteristics of MTLPGs strongly depend on the waist diameter of the tapered optical fiber (TOF) because of the modification of the effective index difference between the core and the cladding modes. Based on the photoelastic effect, the resonant wavelengths of MTLPGs with variations in strain shift to shorter wavelengths. The strain sensitivity of the MTLPG with a waist diameter of 25 Î¼m is improved by a factor of 20 compared with that of a 125 Î¼m long-period fiber grating. The temperature sensitivities of MTLPGs are also enhanced by reducing the waist diameter of the TOF. 23874835 Preference of a Polyphagous Mirid Bug, Apolygus lucorum (Meyer-Dür) for Flowering Host Plants. Apolygus lucorum (Meyer-Dür) (Hemiptera: Miridae) is one of the most important herbivores in a broad range of cultivated plants, including cotton, cereals, vegetables, and fruit crops in China. In this manuscript, we report on a 6-year long study in which (adult) A. lucorum abundance was recorded on 174 plant species from 39 families from early July to mid-September. Through the study period per year, the proportion of flowering plants exploited by adult A. lucorum was significantly greater than that of non-flowering plants. For a given plant species, A. lucorum adults reached peak abundance at the flowering stage, when the plant had the greatest attraction to the adults. More specifically, mean adult abundance on 26 species of major host plants and their relative standard attraction were 10.3-28.9 times and 9.3-19.5 times higher at flowering stage than during non-flowering periods, respectively. Among all the tested species, A. lucorum adults switched food plants according to the succession of flowering plant species. In early July, A. lucorum adults preferred some plant species in bloom, such as Vigna radiata, Gossypium hirsutum, Helianthus annuus and Chrysanthemum coronarium; since late July, adults dispersed into other flowering hosts (e.g. Ricinus communis, Impatiens balsamina, Humulus scandens, Ocimum basilicum, Agastache rugosus and Coriandrum sativum); in early September, they largely migrated to flowering Artemisia spp. (e.g. A. argyi, A. lavandulaefolia, A. annua and A. scoparia). Our findings underscore the important role of flowering plays in the population dynamics and inter-plant migration of this mirid bug. Also, our work helps understand evolutionary aspects of host plant use in polyphagous insects such as A. lucorum, and provides baseline information for the development of sustainable management strategies of this key agricultural pest. 23883529 Possible involvement of nerve growth factor in dysmenorrhea and dyspareunia associated with endometriosis. Nerve growth factor (NGF) has been recently proposed as one of the key factors responsible not only for promotion of nerve fiber growth but also for the onset and maintenance of pain in a variety of diseases. The aim of this study was to investigate the role of NGF in the pelvic pain associated with endometriosis. Tissue and peritoneal fluid samples were collected from 95 women with laparoscopically and histopathologically confirmed endometriosis and 59 control women without endometriosis. Expression levels of NGF mRNA and protein were examined using real-time RT-PCR and immunohistochemistry, respectively. Concentration of NGF in the peritoneal fluid (PF-NGF) was measured using ELISA. The degree of dyspareunia and dysmenorrhea was evaluated using a verbal rating scale. Real-time RT-PCR analysis revealed that NGF mRNA was significantly more abundant in the ovarian endometriomas and peritoneal endometriosis than in the normal control endometrium. Immunohistochemical analyses demonstrated that NGF was prominently expressed and preferentially localized to the glands of the ovarian endometriomas and peritoneal endometriosis, whereas it was only weakly detectable in the normal endometrium. Although PF-NGF was undetectable in some normal subjects and endometriosis patients, elevated PF-NGF in the peritoneal fluid was more frequently observed in endometriosis patients with severe pain than in those with less severe pain. Our results suggest that NGF produced locally in the peritoneal cavity may be involved in the generation of endometriosis-associated pelvic pain. 23889103 Aryl-Substituted Cyclopropyl Acetylenes as Sensitive Mechanistic Probes in the Gold-Catalyzed Hydration of Alkynes. Comparison to the Ag(I)-, Hg(II)-, and Fe(III)-Catalyzed Processes. The gold-catalyzed hydration of 2-phenyl- or 2,2-diphenylcyclopropyl acetylene, sensitive probes to trace the formation of vinyl carbocations, provides exclusively the corresponding cyclopropyl methyl ketones. On the other hand, in the Ag(I)- or Fe(III)-catalyzed hydration, a profound vinyl carbocationic character appears in the initially formed metal-alkyne complexes, as judged by the partial (Ag(+)) or exclusive (Fe(3+)) formation of allene-type rearrangement products. These findings provide clear evidence for subtle electronic differences in metal-alkyne complexes, including Au(I or III), Ag(I), Fe(III), and Hg(II). 23564612 Combined silicone oil removal with secondary implantation of anterior chamber or sclera-fixed posterior chamber intraocular lenses. Purpose: To compare the outcomes and complication rates of silicone oil removal (SOR) combined with secondary implantation of modern anterior chamber intraocular lenses (AC IOLs) versus scleral-fixated, posterior chamber IOLs (SF IOLs) in patients who lack capsular support.
Methods: A prospective, nonrandomized study was performed to compare 2 groups of patients between January 2006 and February 2011. Forty eyes of 40 patients undergoing AC IOL implantation (group 1) and 34 eyes of 34 patients undergoing SF IOL implantation (group 2) were included. The mean follow-up was 22.3 ± 6.3 (range 6-42) months. 
Results: The mean postoperative corrected distance visual acuity (CDVA) recorded at the last follow-up in groups 1 and 2 was 0.70 ± 0.50 and 0.65 ± 0.55, respectively (p = 0.71). A total of 
35 eyes (87.5%) and 29 eyes (85.3%) in groups 1 and 2 had an improved or unchanged CDVA; 
5 eyes (12.5%) and 5 eyes (14.7%) had a deteriorated CDVA. The most frequent postoperative complications in the 2 groups were transient corneal edema, elevated intraocular pressure, hypotony, and retinal detachment. The differences in the number of eyes and the total number of complications were not statistically significant for early (p = 0.06) and late (p = 0.13) complications between the 2 groups. 
Conclusions: Both secondary AC IOL and SF IOL implantation with simultaneous pars plana approach of SOR are suitable for treating silicone oil-filled, aphakic eyes. No significant difference in visual outcome or major complication rates was found between the 2 groups. 22704873 Mucopolysaccharidosis type VI: a cardiologist's guide to diagnosis and treatment. Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome) is an inborn error of metabolism, with incidences at birth ranging from 1 in 1.5 million to 1 in 43,000 live births. This disorder is rarely considered when evaluating patients with common populational cardiovascular diseases. A significant number of MPS VI patients, however, do present cardiovascular disease and MPS VI should be considered as a potential differential diagnosis for other cardiovascular disorders. This article reviews the clinical features, diagnostic tests and treatment options for MPS VI. Although MPS VI affects many organs and systems of the human body this review focuses on MPS VI diseases of the heart and vessels. The most characteristic cardiac presentation of MPS VI is valvular disease, but heart failure, pulmonary hypertension, cardiomyopathy, fibroelastosis and cardiac conduction system disorders may also occur. Cardiovascular disease in MPS VI patients may emerge silently. An early diagnosis is difficult due to joint stiffness, respiratory system involvement or skeletal malformations that limit exercise capacity and mask the underlining heart failure. This article is supposed to serve as a very practical reference for cardiologists who may come across MPS VI in their daily practices. A greater awareness of cardiovascular manifestations of MPS VI among cardiologists can help to reduce misdiagnosis and promote early detection of this inborn disorder and aid the implementation of adequate therapy at the earliest stage possible which is crucial for its efficacy. 23898222 Intratumoral chemotherapy for lung cancer: re-challenge current targeted therapies. Strategies to enhance the already established doublet chemotherapy regimen for lung cancer have been investigated for more than 20 years. Initially, the concept was to administer chemotherapy drugs locally to the tumor site for efficient diffusion through passive transport within the tumor. Recent advances have enhanced the diffusion of pharmaceuticals through active transport by using pharmaceuticals designed to target the genome of tumors. In the present study, five patients with non-small cell lung cancer epidermal growth factor receptor (EGFR) negative stage IIIa-IV International Union Against Cancer 7 (UICC-7), and with Eastern Cooperative Oncology Group (ECOG) 2 scores were administered platinum-based doublet chemotherapy using combined intratumoral-regional and intravenous route of administration. Cisplatin analogues were injected at 0.5%-1% concentration within the tumor lesion and proven malignant lymph nodes according to pretreatment histological/cytological results and the concentration of systemic infusion was decreased to 70% of a standard protocol. This combined intravenous plus intratumoral-regional chemotherapy is used as a first line therapy on this short series of patients. To the best of our knowledge this is the first report of direct treatment of involved lymph nodes with cisplatin by endobronchial ultrasound drug delivery with a needle without any adverse effects. The initial overall survival and local response are suggestive of a better efficacy compared to established doublet cisplatin-based systemic chemotherapy in (higher) standard concentrations alone according to the UICC 7 database expected survival. An extensive search of the literature was performed to gather information of previously published literature of intratumoral chemo-drug administration and formulation for this treatment modality. Our study shows a favorable local response, more than a 50% reduction, for a massive tumor mass after administration of five sessions of intratumoral chemotherapy plus two cycles of low-dose intravenous chemotherapy according to our protocol. These encouraging results (even in very sick ECOG 2 patients with central obstructive non-small cell lung cancer having a worse prognosis and quality of life than a non-small cell lung cancer in ECOG 0 of the same tumor node metastasis [TNM]-stage without central obstruction) for a chemotherapy-only protocol that differs from conventional cisplatin-based doublet chemotherapy by the route, target site, and dose paves the way for broader applications of this technique. Finally, future perspectives of this treatment and pharmaceutical design for intratumoral administration are presented. 23668189 Honey bee promoter sequences for targeted gene expression. The honey bee, Apis mellifera, displays a rich behavioural repertoire, social organization and caste differentiation, and has an interesting mode of sex determination, but we still know little about its underlying genetic programs. We lack stable transgenic tools in honey bees that would allow genetic control of gene activity in stable transgenic lines. As an initial step towards a transgenic method, we identified promoter sequences in the honey bee that can drive constitutive, tissue-specific and cold shock-induced gene expression. We identified the promoter sequences of Am-actin5c, elp2l, Am-hsp83 and Am-hsp70 and showed that, except for the elp2l sequence, the identified sequences were able to drive reporter gene expression in Sf21 cells. We further demonstrated through electroporation experiments that the putative neuron-specific elp2l promoter sequence can direct gene expression in the honey bee brain. The identification of these promoter sequences is an important initial step in studying the function of genes with transgenic experiments in the honey bee, an organism with a rich set of interesting phenotypes. 23917541 VITRECTOMY FOR MYOPIC FOVEOSCHISIS WITH INTERNAL LIMITING MEMBRANE PEELING AND NO GAS TAMPONADE. To evaluate the outcome of vitrectomy with internal limiting membrane peeling and no gas tamponade in the treatment of eyes with myopic foveoschisis. Medical records of 10 eyes of 9 consecutive patients with myopic foveoschisis without macular hole treated by vitrectomy were reviewed. The patients' refractive error was -4.00 diopters to -34.00 diopters, and axial length was 28.38 mm to 35.90 mm. Six eyes had foveal retinal detachment with retinoschisis. All cases were treated by vitrectomy with internal limiting membrane removal without gas tamponade. The mean preoperative best-corrected visual acuity was 0.61 ± 0.42 in logarithm of the minimum angle of resolution units (Snellen equivalent of 20/82). Myopic foveoschisis was reduced in 8 eyes (80%) with a single surgery. Two eyes without improvement developed a postoperative macular hole and were treated by additional vitreoretinal surgery. All 10 eyes showed anatomical repair, and 5 eyes showed improvement in best-corrected visual acuity to 0.47 ± 0.48 (Snellen equivalent of 20/60), by 17 months after the initial surgery. Vitrectomy with internal limiting membrane peeling and no gas tamponade can effectively treat some cases of myopic foveoschisis, suggesting that tractional forces at the vitreoretinal interface may contribute to the pathogenesis of myopic foveoschisis, thereby avoiding gas tamponade. 23729661 In vitro characterization of axitinib interactions with human efflux and hepatic uptake transporters: implications for disposition and drug interactions. Axitinib is an inhibitor of tyrosine kinase vascular endothelin growth factor receptors 1, 2, and 3. The ATP-binding cassette (ABC) and solute carrier (SLC) transport properties of axitinib were determined in selected cellular systems. Axitinib exhibited high passive permeability in all cell lines evaluated (Papp ≥ 6 × 10(-6) cm/s). Active efflux was observed in Caco-2 cells, and further evaluation in multidrug resistance gene 1 (MDR1) or breast cancer resistance protein (BCRP) transfected Madin-Darby canine kidney cells type 2 (MDCK) cells indicated that axitinib is at most only a weak substrate for P-glycoprotein (P-gp) but not BCRP. Axitinib showed incomplete inhibition of P-gp-mediated transport of digoxin in Caco-2 cells and BCRP transport of topotecan in BCRP-transfected MDCK cells with IC50 values of 3 μM and 4.4 μM, respectively. Axitinib (10 mg) did not pose a risk for systemic drug interactions with P-gp or BCRP per regulatory guidance. A potential risk for drug interactions through inhibition of P-gp and BCRP in the gastrointestinal tract was identified because an axitinib dose of 10 mg divided by 250 mL was greater than 10-fold the IC50 for each transporter. However, a GastroPlus simulation that considered the low solubility of axitinib resulted in lower intestinal concentrations and suggested a low potential for gastrointestinal interactions with P-gp and BCRP substrates. Organic anion transporting polypeptide 1B1 (OATP1B1) and OATP1B3 transfected human embryonic kidney 293 (HEK293) cells transported axitinib to a minor extent but uptake into suspended hepatocytes was not inhibited by rifamycin SV suggesting that high passive permeability predominates. Mouse whole-body autoradiography revealed that [(14)C]axitinib-equivalents showed rapid absorption and distribution to all tissues except the brain. This suggests that efflux transport of axitinib may occur at the mouse blood-brain barrier. 23692922 Effect of fat content, casing type and smoking procedures on PAHs contents of Portuguese traditional dry fermented sausages. Portuguese dry fermented sausages are traditionally processed through direct drying/smoking, making them susceptible to polycyclic aromatic hydrocarbons (PAHs) contamination. The purpose of this study was to assess the effect of added fat (20% and 40%), casing type (hog and collagen) and smoking procedures (direct and indirect exposure) on the 16 EPA priority PAHs in dry fermented sausages manufactured according traditional processing. The total PAHs content (sum of 16 PAHs) found in whole product (casing included) varied between 150 and 870μgkg(-1), with more than 99% of this content corresponding to harmless low molecular weight compounds. Concerning benzo(a)pyrene (BaP) and PAH4, the respective maximum contents (0.32 and 10.35μgkg(-1), respectively) did not exceed the imposed limits regulated by the European Union. According to our results, casing type was the most influential factor. For hog samples, fat content and smoking regime alone did not influenced the total PAHs amount. However, significantly higher (p<0.05) contamination levels were detected in hog casing samples combining high fat content and direct smoking procedures. In opposition, irrespective of the fat content and smoking regime, safer products, with significantly lower (p<0.001) contamination levels, were obtained when collagen casing was used. 23417652 The effects of an environmentally relevant 58-congener polychlorinated biphenyl (PCB) mixture on cardiac development in the chick embryo. Chicken (Gallus domesticus) embryonic exposure in ovo to a 58-congener polychlorinated biphenyl (PCB) mixture resulted in teratogenic heart defects in chick embryos at critical heart developmental stages Hamburger-Hamilton (HH) stages 10, 16, and 20. The 58-congener mixture contained relative proportions of primary congeners measured in belted sandpiper (Megaceryle alcyon) and spotted sandpiper (Actitis macularia) eggs collected along the upper Hudson River, New York, USA, and chicken doses were well below observed environmental exposure levels. Embryos were injected with 0.08 µg PCBs/g egg weight and 0.50 µg PCBs/g egg weight (0.01 and 0.064 ng toxic equivalent/g, respectively) at embryonic day 0, prior to incubation. Mortality of exposed embryos was increased at all developmental stages, with a marked rise in cardiomyopathies at HH16 and HH20 (p < 0.05). Heart abnormalities occurred across all treatments, including abnormal elongation and expansion of the heart tube at HH10, improper looping and orientation, indentations in the emerging ventricular wall (HH16 and HH20), and irregularities in overall heart shape (HH10, HH16, and HH20). Histology was conducted on 2 cardiac proteins critical to embryonic heart development, ventricular myosin heavy chain and titin, to investigate potential mechanistic effects of PCBs on heart development, but no difference was observed in spatiotemporal expression. Similarly, cellular apoptosis in the developing heart was not affected by exposure to the PCB mixture. Conversely, cardiomyocyte proliferation rates dramatically declined (p < 0.01) at HH16 and HH20 as PCB exposure concentrations increased. Early embryonic cardiomyocyte proliferation contributes to proper formation of the morphology and overall thickness of the ventricular wall. Therefore, in ovo exposure to this 58-congener PCB mixture at critical stages adversely affects embryonic heart development. Environ Toxicol Chem 2013;32:1317-1324. © 2013 SETAC. 23702807 Incidence, Presentation, and Prognosis of Small Bowel Adenocarcinoma in Patients with Small Bowel Crohn's Disease: A Prospective Observational Study. Patients with Crohn's disease (CD) of the colon are at risk for colorectal cancer and should be screened for dysplasia and cancer of the colon. Small bowel adenocarcinoma (SBA) is a complication of small bowel CD and carries a poor prognosis. However, there is no screening test for SBA in patients with small bowel CD. The aim of this study was to assess the risk and incidence of SBA in a large prospective cohort of patients with small bowel CD and to compare it with the risk of colorectal cancer in patients with CD involving the colon, recruited in the same cohort. In a nationwide French cohort, 11,759 patients with CD were enrolled by 680 gastroenterologists. The SBA risk was obtained by dividing the observed cases in our cohort to the expected cases in the general population. At baseline, 8222 (69.9%) patients had small bowel CD (either alone or associated with colonic CD); their median follow-up was 35 months (interquartile range, 29-40). Five new cases of SBA were diagnosed, all in patients with small bowel CD, within inflamed areas. Among the 5 patients with incident SBA, 4 died of SBA and 1 is in remission 7 years after the diagnosis of SBA. The incidence rates of SBA were 0.235 per 1000 patient-years (95% confidence interval [CI], 0.076-0.547) among patients with small bowel CD and 0.464 per 1000 patient-years (95% CI, 0.127-1.190) among those with small bowel CD for >8 years. This accounted for approximately 30% of the risk of colorectal cancer in patients with CD of the colon. Patients with small bowel CD and small bowel CD for >8 years had an SBA standardized incidence ratio of 34.9 (95% CI, 11.3-81.5) and 46.0 (95% CI, 12.5-117.8), respectively. SBA in patients with small bowel CD carries a poor prognosis, and its risk is approximately 30% of colorectal cancer risk in patients with CD of the colon. Further studies should determine if small bowel endoscopic screening in high-risk patients is feasible and effective. 23303616 Congenital rubella with agenesis of the inferior cerebellar vermis and total anomalous pulmonary venous drainage. Congenital rubella infection has been associated with a number of abnormalities including cardiac, central nervous system and placental complications. We present a case with multiple fetal abnormalities detected on prenatal ultrasound, and confirmed postnatally, that included a single umbilical artery, severe tricuspid regurgitation, micrognathia and agenesis of the inferior cerebellar vermis. Postnatal echocardiography additionally revealed unobstructed total anomalous pulmonary venous drainage (TAPVD) into the coronary sinus. Placental examination showed signs of placentitis, and polymerase chain reaction on neonatal serum was positive for rubella. Following a multidisciplinary team review, it was decided to provide only supportive care, and the infant died at 6 months of age owing to a respiratory tract infection. To our knowledge, TAPVD and agenesis of the inferior cerebellar vermis have not been reported previously in association with congenital rubella infection. This case illustrates how congenital infection may present in atypical ways and stresses the importance of considering congenital infection in the differential diagnosis of fetal anomalies when multiple features are present. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd. 23911968 The replication of a mouse adapted SARS-CoV in a mouse cell line stably expressing the murine SARS-CoV receptor mACE2 efficiently induces the expression of proinflammatory cytokines. Infection of conventional mice with a mouse adapted (MA15) severe acute respiratory syndrome (SARS) coronavirus (CoV) reproduces many aspects of human SARS such as pathological changes in lung, viremia, neutrophilia, and lethality. However, established mouse cell lines highly susceptible to mouse-adapted SARS-CoV infection are not available. In this work, efficiently transfectable mouse cell lines stably expressing the murine SARS-CoV receptor angiotensin converting enzyme 2 (ACE2) have been generated. These cells yielded high SARS-CoV-MA15 titers and also served as excellent tools for plaque assays. In addition, in these cell lines, SARS-CoV-MA15 induced the expression of proinflammatory cytokines and IFN-β, mimicking what has been observed in experimental animal models infected with SARS-CoV and SARS patients. These cell lines are valuable tools to perform in vitro studies in a mouse cell system that reflects the species used for in vivo studies of SARS-CoV-MA15 pathogenesis. 23758211 Generation of antibubbles from core-shell double emulsion templates produced by microfluidics. We report the preparation of antibubbles by microfluidic methods. More specifically, we demonstrate a two-step approach, wherein a monodisperse water-in-oil-in-water (W/O/W) emulsion of core-shell construction is first generated via microfluidics and freeze-dried thereafter to yield, upon subsequent reconstitution, an aqueous dispersion of antibubbles. Stable antibubbles are attained by stabilization of the air-water interfaces through a combination of adsorbed particles and polymeric surfactant. The antibubbles strongly resemble the double emulsion templates from which they were formed. When triggered to release, antibubbles show complete release of their cores within about 100 ms. 23537600 Analysis of MC-LR and MC-RR in tissue from freshwater fish (Tinca tinca) and crayfish (Procambarus clarkii) in tench ponds (Cáceres, Spain) by liquid chromatography-mass spectrometry (LC-MS). In the present study a new method has been developed and validated for detecting free microcystins (MCs) (MC-RR, MC-LR and MC-YR) by liquid chromatography-mass spectrometry (LC-MS) in the cyprinid Tinca tinca and in the crayfish Procambarus clarkii collected from three ponds in Extremadura (Spain) where the presence of the cyanobacteria species Microcystis aeruginosa and Anabaena spiroides has been confirmed. Once the method had been validated, free MCs were determined in fish (tench, T. tinca) and crayfish from different ponds in order to understand how they are bioaccumulated through the food web. MCs were not detected in any of the fish samples analyzed. It was confirmed that P. clarkii accumulated MCs in their tissues without losing their organoleptic characteristics, with MC-LR (2.3-18.1μg MC-LR/g body weight) being the predominant MC variant detected in all the crayfish samples. MC-RR was measured in 50% of the samples analyzed, ranging between 1.4 and 7.8μg MC-RR/g body weight and no MC-YR was detected. The results indicated that crayfish can accumulate free MCs in higher quantities than tench that live in ponds contaminated by toxic cyanobacteria species, and emphasized the need for regular monitoring if the health risks associated with their consumption are to be avoided. 23846721 Dynamics of case-fatalilty rates of recurrent thromboembolism and major bleeding in patients treated for venous thromboembolism. In patients with venous thromboembolism (VTE), assessment of the risk of fatal recurrent VTE and fatal bleeding during anticoagulation may help to guide intensity and duration of therapy. We aimed to provide estimates of the case-fatality rate (CFR) of recurrent VTE and major bleeding during anticoagulation in a 'real life' population, and to assess these outcomes according to the initial presentation of VTE and its etiology. The study included 41,826 patients with confirmed VTE from the RIETE registry who received different durations of anticoagulation (mean 7.8 ± 0.6 months). During 27,110 patient-years, the CFR was 12.1% (95% CI, 10.2-14.2) for recurrent VTE, and 19.7% (95% CI, 17.4-22.1) for major bleeding. During the first three months of anticoagulant therapy, the CFR of recurrent VTE was 16.1% (95% CI, 13.6-18.9), compared to 2.0% (95% CI, 0-4.2) beyond this period. The CFR of bleeding was 20.2% (95% CI, 17.5-23.1) during the first three months, compared to 18.2% (95% CI, 14.0-23.2) beyond this period. The CFR of recurrent VTE was higher in patients initially presenting with PE (18.5%; 95% CI, 15.3-22.1) than in those with DVT (6.3%; 95% CI, 4.5-8.6), and in patients with provoked VTE (16.3%; 95% CI, 13.6-19.4) than in those with unprovoked VTE (5.5%; 95% CI, 3.5-8.0). In conclusion, the CFR of recurrent VTE decreased over time during anticoagulation, while the CFR of major bleeding remained stable. The CFR of recurrent VTE was higher in patients initially presenting with PE and in those with provoked VTE. 23808685 Matrix removal of labyrinthine fistulae by non-suction technique with intraoperative dexamethasone injection. Abstract Conclusion: Matrix removal by a non-suction technique with intraoperative dexamethasone injection is a safe and effective management modality, regardless of fistula size. Objective: Our goal was to evaluate the outcome of hearing treated by non-suction technique with intraoperative dexamethasone injection. Methods: This was a retrospective chart review of 720 mastoidectomy cases for cholesteatoma, performed at our tertiary otolaryngologic care centers between 2005 and 2012. A total of 17 patients with a unilateral labyrinthine fistula were encountered. Results: There was no recurrent cholesteatoma in any of the patients. In all cases, the matrix was removed by intraoperative dexamethasone injection with a bimanual non-suction technique, regardless of the fistula size. None of the patients showed deteriorated bone conduction (BC). Averaged BC was unchanged (n = 13) or improved (n = 4) in all patients and did not decrease by 10 dB more in any patient. The mean threshold of postoperative BC was significantly improved compared with preoperative mean threshold. Fistulae on the preoperative CT scans ranged from 1.41 to 7.12 mm and averaged 2.89 mm. There was no correlation between the fistula size and the postoperative BC level. Even with a large fistula, postoperative hearing preservation was possible with one-stage matrix removal. 23843229 Broad gap junction blocker carbenoxolone disrupts uterine preparation for embryo implantation in mice. Gap junctions have an important role in cell-to-cell communication, a process obviously required for embryo implantation. Uterine luminal epithelium (LE) is the first contact for an implanting embryo and is critical for the establishment of uterine receptivity. Microarray analysis of the LE from peri-implantation mouse uterus showed low-level expression of 19 gap junction proteins in preimplantation LE and upregulation of gap junction protein, beta 2 (GJB2, connexin 26, Cx26) in postimplantation LE. Time course study using in situ hybridization and immunofluorescence revealed upregulation of GJB2 in the LE surrounding the implantation site before decidualization. Similar dynamic expression of GJB2 was observed in the LE of artificially decidualized mice but not pseudopregnant mice. To determine the potential function of uterine gap junctions in embryo implantation, carbenoxolone (CBX), a broad gap junction blocker, was injected i.p. (100 mg/kg) or via local uterine fat pad (10 mg/kg) into pregnant mice on Gestation Day 3 at 1800 h, a few hours before embryo attachment to the LE. These CBX treatments disrupted embryo implantation, suggesting local effects of CBX in the uterus. However, i.p. injection of glycyrrhizic acid (100 mg/kg), which shares similar structure and multiple properties with CBX but is ineffective in blocking gap junctions, did not affect embryo implantation. Carbenoxolone also inhibited oil-induced artificial decidualization, concomitant with suppressed molecular changes and ultrastructural transformations associated with uterine preparation for embryo implantation, underscoring the adverse effect of CBX on uterine preparation for embryo implantation. These data demonstrate that uterine gap junctions are important for embryo implantation. 23773585 Determination of anionic surface active agents using silica coated magnetite nanoparticles modified with cationic surfactant aggregates. The development of a novel methodology for extraction and preconcentration of the most commonly used anionic surface active agents (SAAs), linear alkylbenzene sulfonates (LAS), is presented herein. The present method, based on the use of silica-magnetite nanoparticles modified with cationic surfactant aggregates, was developed for determination of C10-C13 LAS homologues. The proposed methodology allowed quantitative recoveries of C10-C13 LAS homologues by using a reduced amount of magnetic nanoparticles. Limits of detection were in the range 0.8-1.9μgL(-1) for C10-C13 LAS homologues, while the repeatability, expressed as relative standard deviation (RSD), ranged from 2.0 to 3.9% (N=6). Finally, the proposed method was successfully applied to the analysis of a variety of natural water samples. 23933306 Gustatory solitary tract development: A role for neuropilins. The rostral nucleus of the solitary tract (rNST) receives orosensory information from taste bud cells in the tongue and palate via cranial nerves VII and IX. These nerves enter the brainstem, form the solitary tract (ST) and synapse with neurons in the rNST, which then relay incoming sensory information to other brain areas to process external gustatory stimuli. Factors that direct or regulate the trajectory of the developing ST are largely unknown. We used 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) to identify ST projections originating from cells in the geniculate ganglia of embryonic rats from embryonic day 14 through 18 (E14-E18). After identifying the ST fibers, immunolabeling for and protein expression analysis of the axon guidance molecules neuropilin-1 (Npn-1) and neuropilin-2 (Npn-2) and their binding partners, semaphorin-3A (Sema-3A) and semaphorin-3F (Sema-3F) were performed. The results detail the formation of ST projections into the gustatory brainstem and their relationship to developing rNST neurons. DiI-labeled ST fibers were present in the brainstem as early as E14. Npn-1 was expressed in the ST and in the trigeminal tract at E14, but levels of the protein declined through E18. The expression levels of the binding partner of Npn-1, Sema-3A, increased from E14 to E18. Npn-2 was expressed in the ST and, additionally, in radially oriented, tuft-like structures within the brainstem at E14. Expression levels of Npn-2 also declined through E18, in contrast to the expression levels of its binding partner, Sema-3F, which increased during this time period. For the first time, the time course and particular molecular components involved in development of the ST have been identified. These results indicate that the neuropilin and semaphorin families of axon guidance molecules are potential molecular participants in ST formation. 23914726 The use of a thermoexpandable metal alloy stent in the minimally invasive management of retroperitoneal fibrosis (RPF) - a single centre experience from the UK. Purpose: To review our experience with and the effectiveness of the ureteric Memokath 051™ metallic stent for the minimally invasive management of retroperitoneal fibrosis patients. Materials and Methods: We retrospectively reviewed the records of patients with RPF treated between April 2008 and February 2013. Success was defined as improvement of renal function and lack of complications following stent placement. Follow up was at 6 weeks, 3 months, 6 months and annually thereafter. Results: A total of 14 patients were identified. The study included eight (8) female and six (6) male patients. Mean age was 60.2 years+/-8.4 SD. The majority of patients had idiopathic RPF (n=12, 85.7%). A total of 23 renal units were stented in14 patients, nine of which had bilateral disease (64.3%). Ten patients (71.4%) had previously received medical treatment, while three (21.4%) presented with recurrent disease post ureterolysis. The mean length of follow up was 22.5 months (range 3 to 56 months). Mean stricture length was 7.6 cm +/- 6.2 SD on the right and 7.7 cm +/- 5.1 SD (p=0.925) on the left. Patients tolerated the stents well with minimal discomfort. Ureteral obstruction was managed successfully in 78.6% of patients (n=11/14). All patients presented with improvement of renal function. Conclusions: To our knowledge, this is the first study using metal stents in retroperitoneal fibrosis patients.Retrograde placement of the ureteric Memokath 051™ metal stent can be considered as a promising alternative for initial or salvage post ureterolysis minimally invasive management of ureteral obstruction in retroperitoneal fibrosis. 23831064 Suppression of Arabidopsis RING E3 ubiquitin ligase AtATL78 increases tolerance to cold stress and decreases tolerance to drought stress. AtATL78 is an Arabidopsis RING E3 ubiquitin ligase. RT-PCR and promoter-GUS assays revealed that AtATL78 was up-regulated by cold stress and down-regulated by drought. AtATL78 was localized at the plasma-membrane. Suppression of AtATL78 increased tolerance to cold stress but decreased tolerance to drought. Our data suggests that AtATL78 is a negative regulator of cold stress response and a positive regulator of drought stress response in Arabidopsis. These results further suggest that AtATL78 plays opposing roles in cold and drought stress responses. 23881658 First-line allogeneic hematopoietic stem cell transplantation of HLA-matched sibling donors compared with first-line ciclosporin and/or antithymocyte or antilymphocyte globulin for acquired severe aplastic anemia. Acquired severe aplastic anemia is a rare and potentially fatal disease, which is characterized by hypocellular bone marrow and pancytopenia. The major signs and symptoms are severe infections, bleeding, and exhaustion. First-line allogeneic hematopoietic stem cell transplantation (HSCT) of a human leukocyte antigen (HLA)-matched sibling donor (MSD) is a treatment for newly diagnosed patients with severe aplastic anemia. First-line treatment with ciclosporin and/or antithymocyte or antilymphocyte globulin (as first-line immunosuppressive therapy) is an alternative to MSD-HSCT and is indicated for patients where no MSD is found. To evaluate the effectiveness and adverse events of first-line allogeneic hematopoietic stem cell transplantation of HLA-matched sibling donors compared to first-line immunosuppressive therapy including ciclosporin and/or antithymocyte or antilymphocyte globulin in patients with acquired severe aplastic anemia. We searched the electronic databases MEDLINE (Ovid), EMBASE (Ovid), and The Cochrane Library CENTRAL (Wiley) for published articles from 1946 to 22 April 2013. Further searches included trial registries, reference lists of recent reviews, and author contacts. The following prospective study designs were eligible for inclusion: randomized controlled trials (RCTs) and non-randomized controlled trials if the allocation of patients to treatment groups was consistent with 'Mendelian randomization'. We included participants with newly diagnosed severe aplastic anemia who received MSD-HSCT or immunosuppressive therapy without prior HSCT or immunosuppressive therapy, and with a minimum of five participants per treatment group. We did not apply limits on publication year or languages. Two review authors abstracted the data on study and patient characteristics and assessed the risk of bias independently. We resolved differences by discussion or by appeal to a third review author. The primary outcome was overall mortality. Secondary outcomes were treatment-related mortality, graft failure, no response to first-line immunosuppressive therapy, graft-versus-host-disease (GVHD), relapse after initial successful treatment, secondary clonal and malignant disease, health-related quality of life, and performance score. We identified three trials that met the inclusion criteria. None of these trials was a RCT. 302 participants are included in this review. The three included studies were prospectively conducted and had features consistent with the principle of 'Mendelian randomization' as defined in the present review. All studies had a high risk of bias due to the study design. All studies were conducted more than 10 years ago and may not be applicable to the standard of care of today. Primary and secondary outcome data showed no statistically significant difference between treatment groups. We present results for first-line allogeneic hematopoietic stem cell transplantation of an HLA-matched sibling donor, which we denote as the MSD-HSCT group, versus first-line treatment with ciclosporin and/or antithymocyte or antilymphocyte globulin, which we denote as the immunosuppressive therapy group in the following section.The pooled hazard ratio for overall mortality for the MSD-HSCT group versus the immunosuppressive therapy group was 0.95 (95% confidence interval 0.43 to 2.12, P = 0.90, low quality evidence). Therefore, overall mortality was not statistically significantly different between the groups. Treatment-related mortality ranged from 20% to 42% for the MSD-HSCT group and was not reported for the immunosuppressive therapy group (very low quality evidence). The authors reported graft failure from 3% to 16% for the MSD-HSCT group and GVHD from 26% to 51% (both endpoints not applicable for the immunosuppressive therapy group, very low quality evidence). The authors did not report any data on response and relapse for the MSD-HSCT group. For the immunosuppressive therapy group, the studies reported no response from 15% (not time point stated) to 64% (three months) and relapse in one of eight responders after immunosuppressive therapy at 5.5 years (very low quality evidence). The authors reported secondary clonal disease or malignancies for the MSD-HSCT group versus the immunosuppressive therapy group in 1 of 34 versus 0 of 22 patients in one study and in 0 of 28 versus 4 of 86 patients in the other study (low quality evidence). None of the included studies addressed health-related quality of life. The percentage of the evaluated patients with a Karnofsky performance status score in the range of 71% to 100% was 92% in the MSD-HSCT group and 46% in the immunosuppressive therapy group. There are insufficient and biased data that do not allow any conclusions to be made about the comparative effectiveness of first-line allogeneic hematopoietic stem cell transplantation of an HLA-matched sibling donor and first-line treatment with ciclosporin and/or antithymocyte or antilymphocyte globulin (as first-line immunosuppressive therapy). We are unable to make firm recommendations regarding the choice of intervention for treatment of acquired severe aplastic anemia. 23720527 Predator-Prey Pursuit-Evasion Games in Structurally Complex Environments. Pursuit and evasion behaviors in many predator-prey encounters occur in a geometrically structured environment. The physical structures in the environment impose strong constraints on the perception and behavioral responses of both antagonists. Nevertheless, no experimental or theoretical study has tackled the issue of quantifying the role of the habitat's architecture on the joint trajectories during a predator-prey encounter. In this study, we report the influence of microtopography of forest leaf litter on the pursuit-evasion trajectories of wolf spiders Pardosa sp. attacking the wood cricket Nemobius sylvestris. Fourteen intact leaf litter samples of 1 m × 0.5 m were extracted from an oak-beech forest floor in summer and winter, with later samples having the most recently fallen leaves. Elevation was mapped at a spatial resolution of 0.5 mm using a laser scanner. Litter structuring patterns were identified by height transects and experimental semi-variograms. Detailed analysis of all visible leaf-fragments of one sample enabled us to relate the observed statistical patterns to the underlying geometry of individual elements. Video recording of pursuit-evasion sequences in arenas with flat paper or leaf litter enabled us to estimate attack and fleeing distances as a function of substrate. The compaction index, the length of contiguous flat surfaces, and the experimental variograms showed that the leaf litter was smoother in summer than in winter. Thus, weathering as well as biotic activities compacted and flattened the litter over time. We found good agreement between the size of the structuring unit of leaf litter and the distance over which attack and escape behaviors both were initiated (both ∼3 cm). There was a four-fold topographical effect on pursuit-escape sequences; compared with a flat surface, leaf litter (1) greatly reduced the likelihood of launching a pursuit, (2) reduced pursuit and escape distances by half, (3) put prey and predator on par in terms of pursuit and escape distances, and (4) reduced the likelihood of secondary pursuits, after initial escape of the prey, to nearly zero. Thus, geometry of the habitat strongly modulates the rules of pursuit-evasion in predator-prey interactions in the wild. 23830060 Epidemiology of heart failure in Spain over the last 20 years. Heart failure is a major health care problem in Spain, although its precise impact is unknown due to the lack of data from appropriately designed studies. In contrast with the 2% prevalence of heart failure elsewhere in Europe and in the United States, studies in Spain report figures of 5%, probably because of methodological limitations. Heart failure consumes enormous quantities of health care resources; it is the first cause of hospitalization in persons aged 65 years or older and represents 3% of all hospital admissions and 2.5% of health care costs. There are two patterns of heart failure: one with preserved systolic function, more often associated with high blood pressure, and another with depressed systolic function, more often associated with ischemic heart disease. In 2010, heart failure accounted for 3% of all deaths in men and for 10% of all deaths in women. In recent years, the mortality rate from heart failure has gradually fallen. The rise in hospital admissions for heart failure and the decrease in mortality from this cause could partly be explained by temporary changes in diagnostic coding, but there is evidence that the reduced mortality could also be due to adherence to clinical practice guidelines. Full English text available from:www.revespcardiol.org/en. 23855507 Low testosterone and diabetes. There have been a lot of discussions concerning the relationship between testosterone serum levels in males and diabetes. Low testosterone is commonly associated with type 2 diabetes and metabolic syndrome. Testosterone therapy alters the body composition in a metabolically favorable manner. In this article we shed some light on the bidirectional relation between hypotestosteronemia and diabetes discussing also the possible mechanisms and the benefit of treatment. 23791867 Substituents effects on activity of kynureninase from Homo sapiens and Pseudomonas fluorescens. A series of substituted kynurenines (3-bromo-DL, 3-chloro-DL, 3-fluoro-DL, 3-methyl-DL, 5-bromo-L, 5-chloro-L, 3,5-dibromo-L and 5-bromo-3-chloro-DL) have been synthesized and tested for their substrate activity with human and Pseudomonas fluorescens kynureninase. All of the substituted kynurenines examined have substrate activity with both human as well as P. fluorescens kynureninase. For the human enzyme, 3- and 5-substituted kynurenines have kcat and kcat/Km values higher than L-kynurenine, but less than that of the physiological substrate, 3-hydroxykynurenine. However, 3,5-dibromo- and 5-bromo-3-chlorokynurenine have kcat and kcat/Km values close to that of 3-hydroxykynurenine with human kynureninase. The effects of the 3-halo substituents on the reactivity with human kynureninase may be due to electronic effects and/or halogen bonding. In contrast, for the bacterial enzyme, 3-methyl, 3-halo and 3,5-dihalokynurenines are much poorer substrates, while 3-fluoro, 5-bromo, and 5-chlorokynurenine have kcat and kcat/Km values comparable to that of its physiological substrate, L-kynurenine. Thus, 5-bromo and 5-chloro-L-kynurenine are good substrates for both human as well as bacterial enzyme, indicating that both enzymes have space for substituents in the active site near C-5. The increased activity of the 5-halokynurenines may be due to van der Waals contacts or hydrophobic effects. These results may be useful in the design of potent and/or selective inhibitors of human and bacterial kynureninase. 23856489 Novel Role of NOD2 in Mediating Ca2+ Signaling: Evidence From NOD2-Regulated Podocyte TRPC6 Channels in Hyperhomocysteinemia. Although hyperhomocysteinemia (hHcys) has been recognized as an important independent risk factor in the progression of end-stage renal disease and in the development of cardiovascular complications related to end-stage renal disease, the mechanisms triggering the pathogenic actions of hHcys are not yet fully understood. The present study was designed to investigate the contribution of nucleotide-binding oligomerization domain containing 2 (NOD2), an intracellular innate immunity mediator, to the development of glomerulosclerosis in hHcys. Our results showed that NOD2 deficiency ameliorated renal injury in mice with hHcys. We further discovered the novel role of NOD2 in mediating Ca(2+) signaling and found that homocysteine-induced NOD2 expression enhanced transient receptor potential cation channel 6 (TRPC6) expression and TRPC6-mediated calcium influx and currents, leading to intracellular Ca(2+) release, ultimately resulting in podocyte cytoskeleton rearrangement and apoptosis. Moreover, we found that nephrin expression was downregulated dependently by NOD2, and overexpression of nephrin attenuated homocysteine-induced TRPC6 expression in podocytes. The results add evidence to support the essential role of nephrin in mediating NOD2-induced TRPC6 expression in hHcys. In conclusion, our results for the first time establish a previously unknown function of NOD2 for the regulation of TRPC6 channels, suggesting that TRPC6-dependent Ca(2+) signaling is one of the critical signal transduction pathways that links innate immunity mediator NOD2 to podocyte injury. Pharmacological targeting of NOD2 signaling pathways at multiple levels may help design a new approach to develop therapeutic strategies for treatment of hHcys-associated end-stage renal disease. 23764128 Underdiagnosis and overdiagnosis of asthma in the morbidly obese. The prevalence of obesity and asthma has increased concurrently over the last decades, suggesting a link between obesity and asthma. However, asthma might not be adequately diagnosed in this population. To investigate whether not only overdiagnosis but also underdiagnosis of asthma is present in an obese population. Morbidly obese subjects with or without physician-diagnosed asthma were recruited from a pre-operative screening programme for bariatric surgery, and were characterized using an extensive diagnostic algorithm. 473 subjects were screened; 220 met inclusion criteria, and 86 agreed to participate. Among the 32 participating subjects who had a physician diagnosis of asthma, reversible airway obstruction and/or bronchial hyperresponsiveness could only be detected in 19 patients (59%, 95% CI [0.41-0.76]), whereas in 13 patients (41%, 95% CI [0.24-0.50]) the diagnosis of asthma could not be confirmed (overdiagnosis). In contrast, in the remaining 54 patients, 17 (31%, 95% CI [0.20-0.46]) were newly diagnosed with asthma (underdiagnosis). Besides overdiagnosis, there is also substantial underdiagnosis of asthma in the morbidly obese. Symptoms could be incorrectly ascribed to either obesity or asthma, and therefore also in the morbidly obese the diagnosis of asthma should also be based on pulmonary function testing. 23836502 Imaging Tumor Growth Non-invasively Using Expression of MagA or Modified Ferritin Subunits to Augment Intracellular Contrast for Repetitive MRI. The bacterial gene MagA imparts magnetic properties to mammalian cells and provides a basis for cell tracking by magnetic resonance imaging (MRI). In a mouse model of tumor growth from transplanted cells, we used repetitive MRI to demonstrate the in vivo imaging potential of MagA expression relative to a modified ferritin overexpression system, lacking regulation through iron response elements (HF + LF). Subcutaneous tumor xenografts were monitored weekly from days 2 to 34 post-injection. Small animal MRI employed balanced steady-state free precession. Imaging was correlated with tumor histology using hematoxylin, Prussian Blue, Ki-67, and BS-1 lectin. Tumor heterogeneity with respect to tissue morphology and magnetic resonance (MR) contrast was apparent within a week of cell transplantation. In MagA- and HF + LF-expressing tumors, MR contrast enhancement was recorded up to day 20 post-injection and 0.073-cm(3) tumor volumes. MagA-expressing tumors showed increases in both quantity and quality of MR contrast as measured by fractional void volume and contrast-to-noise ratio, respectively. MR contrast in both MagA- and HF + LF-expressing tumors was maximal by day 13, doubling fractional void volume 1 week ahead of controls. MagA- and HF + LF-expressing tumor xenografts augment MR contrast after 1 week of growth. MagA expression increases MR contrast within days of cell transplantation and provides MR contrast comparable to HF + LF. MagA has utility for monitoring cell growth and differentiation, with potential for in vivo detection of reporter gene expression using MRI. 23928911 Low-temperature selective catalytic reduction of NO with NH3 over nanoflaky MnOx on carbon nanotubes in situ prepared via a chemical bath deposition route. Nanoflaky MnOx on carbon nanotubes (nf-MnOx@CNTs) was in situ synthesized by a facile chemical bath deposition route for low-temperature selective catalytic reduction (SCR) of NO with NH3. This catalyst was mainly characterized by the techniques of X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), N2 adsorption-desorption analysis, X-ray photoelectron spectroscopy (XPS), H2 temperature-programmed reduction (H2-TPR) and NH3 temperature-programmed desorption (NH3-TPD). The SEM, TEM, XRD results and N2 adsorption-desorption analysis indicated that the CNTs were surrounded by nanoflaky MnOx and the obtained catalyst exhibited a large surface area as well. Compared with the MnOx/CNT and MnOx/TiO2 catalysts prepared by an impregnation method, the nf-MnOx@CNTs presented better NH3-SCR activity at low temperature and a more extensive operating temperature window. The XPS results showed that a higher atomic concentration of Mn(4+) and more chemisorbed oxygen species existed on the surface of CNTs for nf-MnOx@CNTs. The H2-TPR and NH3-TPD results demonstrated that the nf-MnOx@CNTs possessed stronger reducing ability, more acid sites and stronger acid strength than the other two catalysts. Based on the above mentioned favourable properties, the nf-MnOx@CNT catalyst has an excellent performance in the low-temperature SCR of NO to N2 with NH3. In addition, the nf-MnOx@CNT catalyst also presented favourable stability and H2O resistance. 23907667 BRSK2 is a valosin-containing protein (VCP)-interacting protein that affects VCP functioning in endoplasmic reticulum-associated degradation. Endoplasmic reticulum-associated protein degradation (ERAD) removes improperly-folded proteins from the ER membrane into the cytosol where they undergo proteasomal degradation. Valosin-containing protein (VCP)/p97 mediates in the extraction of ERAD substrates from the ER. BRSK2 (also known as SAD-A), a serine/threonine kinase of the AMP-activated protein kinase family affected VCP/p97 activity in ERAD. In addition, BRSK2 interacted with VCP/p97 via three of the four functional domains of VCP/p97. Immunofluorescence demonstrated that BRSK2 and VCP/p97 were co-localized and also that knockdown of endogenous BRSK2 induced increased levels of CD3δ, a substrate in ERAD for VCP/p97. Thus, BRSK2 might affect the activity of VCP/p97 in ERAD. 23715679 Proteomic analysis of schistosomiasis japonica vaccine candidate antigens recognized by UV-attenuated cercariae-immunized porcine serum IgG2. Many studies have showed that the radiation-attenuated cercariae (RAC) vaccine could induce the high protection of laboratory animals to resist the schistosoma infection by cellular and humoral mechanism. Here, we aimed to identify possible vaccine antigens by using specific IgG2 antibody from RAC-vaccinated pigs or vaccination and challenge pigs. The antigens from the schistosomal soluble worm antigen preparation (SWAP) recognized by the porcine IgG2 antibody were obtained using immunoprecipitation technique. These antigens were separated by 2-D electrophoresis, and 116 spots were successfully identified by MALDI-TOF MS from about 400 putative spots in gels. Among these spots, 113 spots could match to the Schistosoma japonicum. These identified proteins in four groups were classified by Gene Ontology (Go) database, and the mainly functions of these proteins were involved in binding, catalytic activity (thioredoxin peroxidase-2, et al.), signal transduction class (MAP Kinase, et al.), cell process (the heat shock 70-kDa protein 9B, et al.), and the intracellular component (tektin, et al.). Our methods suggested that it was possible to pull-down the interesting proteins recognized by specific antibodies. Our results may provide new clues for exploring the mechanism of high protection induced by RAC and shed some light on the research for anti-schistosomiasis japonica vaccine. 23812308 Atypical parkinsonism: an update. This update discusses novel aspects on genetics, diagnosis, and treatments of atypical parkinsonism published over the past 2 years. A genome-wide association study identified new genetic risk factors for progressive supranuclear palsy and new genetic conditions presenting with atypical parkinsonism have been described. The clinical criteria for diagnosis of corticobasal degeneration have been revised, and for progressive supranuclear palsy are under revision. Novel molecular techniques to identify possible biomarkers, as in other neurodegenerative disorders, have started being studied on atypical parkinsonian conditions, and although preliminary results seem promising, further studies are urgently warranted. Therapeutic trials based on disease-specific targets have shown no clinical improvement. The knowledge obtained recently on atypical parkinsonian conditions points out the major deficits in this field. With the expanding phenotypical spectrum of atypical parkinsonian conditions, the early identification of patients has become difficult. The inability of conventional methods to identify these disorders earlier and better than clinicians, and the recent failure of promising therapeutic compounds, highlight the fact that the lack of biomarkers is probably the greatest limitation for developing treatments for these disorders. Thus, current and future research in this direction will be crucial. 23833302 Phase I Safety, Pharmacokinetic and Pharmacodynamic Evaluation of the Vascular Disrupting Agent Ombrabulin (AVE8062) in Patients with Advanced Solid Tumors. The vascular disrupting agent ombrabulin rapidly reduces tumor blood flow and causes necrosis in vivo. A phase I dose-escalation study was designed to determine the recommended phase II dose (RP2D) of single-agent ombrabulin administered once every three weeks in patients with advanced solid malignancies.EXPERIMENTAL DESIGN: Ombrabulin (30-minute infusion) was escalated from 6 to 60 mg/m(2), with RP2D cohort expansion. Safety, tumor response, pharmacokinetics, and pharmacodynamic biomarkers were evaluated.RESULTS: Eleven dose levels were evaluated in 105 patients. Two patients had dose-limiting toxicities in cycle 1 during escalation: grade 3 abdominal pain at 50 mg/m(2), grade 3 tumor pain/grade 3 hypertension at 60 mg/m(2), and the RP2D was 50 mg/m(2) (39 patients). Common toxicities were headache, asthenia, abdominal pain, nausea, diarrhea, transient hypertension, anemia, and lymphopenia. No clinically significant QTc prolongations or left ventricular ejection fraction (LVEF) decreases occurred. Ombrabulin was rapidly converted to its active metabolite RPR258063 (half-life 17 minutes and 8.7 hours, respectively), both having dose-proportional exposure. Weak inhibition of CYP2C19-mediated metabolism occurred at the clinical doses used and there was no effect on CYP1A2 and CYP3A4. A patient with rectal cancer had a partial response and eight patients had stable disease lasting four months or more. Circulating endothelial cells (CEC), VEGF, and matrix metalloproteinase (MMP)-9 levels increased significantly six to 10 hours postinfusion in a subset of patients.CONCLUSIONS: The recommended schedule for single-agent ombrabulin is 50 mg/m(2) every 3 weeks. CECs, VEGF, and MMP-9 are potential biomarkers of ombrabulin activity. Clin Cancer Res; 19(17); 1-11. ©2013 AACR. 23939348 Inhibition of IKKβ in Enterocytes Exacerbates Sepsis-Induced Intestinal Injury and Worsens Mortality. Nuclear factor-κB is a critical regulator of cell-survival genes and the host inflammatory response. The purpose of this study was to investigate the role of enterocyte-specific NF-kB in sepsis through selective ablation of IkB kinase. Prospective, randomized controlled study. Animal laboratories in university medical centers. Mice lacking functional NF-kB in their intestinal epithelium (Vil-Cre/Ikkβ) and wild-type mice were subjected to sham laparotomy or cecal ligation and puncture. Animals were killed at 24 hours or followed 7 days for survival. Septic wild-type mice had decreased villus length compared with sham mice, whereas villus atrophy was further exacerbated in septic Vil-Cre/Ikkβ mice. Sepsis induced an increase in intestinal epithelial apoptosis compared with sham mice, which was further exacerbated in Vil-Cre/Ikkβ mice. Sepsis induced intestinal hyperpermeability in wild-type mice compared with sham mice, which was further exacerbated in septic Vil-Cre/Ikkβ mice. This was associated with increased intestinal expression of claudin-2 in septic wild-type mice, which was further increased in septic Vil-Cre/Ikkβ mice. Both, pro-inflammatory and anti-inflammatory cytokines were increased in serum following cecal ligation and puncture, and interleukin 10 and monocyte chemoattractant protein-1 levels were higher in septic Vil-Cre/Ikkβ mice than in septic wild-type mice. All septic mice were bacteremic, but no differences in bacterial load were identified between wild-type and Vil-Cre/Ikkβ mice. To determine the functional significance of these results, animals were followed for survival. Septic wild-type mice had lower mortality than septic Vil-Cre/Ikkβ mice (47% vs 80%, p < 0.05). Antitumor necrosis factor administration decreased intestinal apoptosis, permeability, and mortality in wild-type septic mice, and a similar improvement in intestinal integrity and survival were seen when antitumor necrosis factor was given to Vil-Cre/Ikkβ mice. Enterocyte-specific NF-kB has a beneficial role in sepsis by partially preventing sepsis-induced increases in apoptosis and permeability, which are associated with worsening mortality. 23623842 Comparative evaluation of oral and dermal cypermethrin exposure on antioxidant profile in Bubalus bubalis. Cypermethrin, a type II synthetic pyrethroid insecticide, @ 0.5mg/kg/day for 14 consecutive weeks produced mild signs of toxicity in buffalo calves. Significant changes were observed in various antioxidant parameters in blood. There was a marked increase in the extent of lipid peroxidation (33.9%) and enzymic activity of glutathione peroxidase (6.7%), superoxide dismutase (35.0%), catalase (43.7%), glutathione-S-transferase (64.4%), glutathione reductase (36.7%) and glucose-6-phosphate dehydrogenase (32.1%). A significant decrease in blood glutathione (16.7%), total antioxidant activity (45.4%) and vitamin E (40.8%) was observed and no significant effect was found on blood selenium levels. However, the extent of lipid peroxidation (42%) and the depletion of glutathione (28.8%) was greater after dermal sub-acute toxicity of cypermethrin (0.25%) for 14 consecutive days. Similarly, it was observed that the incline in the enzymic activity of glutathione peroxidase (29.7%), superoxide dismutase (38.3%) and glutathione reductase (38.3%) was higher in dermally cypermethrin exposed animals. Thus, the present investigation contemplates that oxidative stress is the important mechanisms involved in cypermethrin-induced toxicity and the oxidative insult produced by dermal route is more severe as compared to oral intoxication. 23936017 Gene Expression-Based Biomarkers for Anopheles gambiae Age Grading. Information on population age structure of mosquitoes under natural conditions is fundamental to the understanding of vectorial capacity and crucial for assessing the impact of vector control measures on malaria transmission. Transcriptional profiling has been proposed as a method for predicting mosquito age for Aedes and Anopheles mosquitoes, however, whether this new method is adequate for natural conditions is unknown. This study tests the applicability of transcriptional profiling for age-grading of Anopheles gambiae, the most important malaria vector in Africa. The transcript abundance of two An. gambiae genes, AGAP009551 and AGAP011615, was measured during aging under laboratory and field conditions in three mosquito strains. Age-dependent monotonic changes in transcript levels were observed in all strains evaluated. These genes were validated as age-grading biomarkers using the mark, release and recapture (MRR) method. The MRR method determined a good correspondence between actual and predicted age, and thus demonstrated the value of age classifications derived from the transcriptional profiling of these two genes. The technique was used to establish the age structure of mosquito populations from two malaria-endemic areas in western Kenya. The population age structure determined by the transcriptional profiling method was consistent with that based on mosquito parity. This study demonstrates that the transcription profiling method based on two genes is valuable for age determination of natural mosquitoes, providing a new approach for determining a key life history trait of malaria vectors. 23632159 Detecting subarachnoid hemorrhage: Comparison of combined FLAIR/SWI versus CT. Aim of this study was to compare the utility of susceptibility weighted imaging (SWI) with the established diagnostic techniques CT and fluid attenuated inversion recovery (FLAIR) in their detecting capacity of subarachnoid hemorrhage (SAH), and further to compare the combined SWI/FLAIR MRI data with CT to evaluate whether MRI is more accurate than CT. Twenty-five patients with acute SAH underwent CT and MRI within 6 days after symptom onset. Underlying pathology for SAH was head trauma (n=9), ruptured aneurysm (n=6), ruptured arteriovenous malformation (n=2), and spontaneous bleeding (n=8). SWI, FLAIR, and CT data were analyzed. The anatomical distribution of SAH was subdivided into 8 subarachnoid regions with three peripheral cisterns (frontal-parietal, temporal-occipital, sylvian), two central cisterns and spaces (interhemispheric, intraventricular), and the perimesencephalic, posterior fossa, superior cerebellar cisterns. SAH was detected in a total of 146 subarachnoid regions. CT identified 110 (75.3%), FLAIR 127 (87%), and SWI 129 (88.4%) involved regions. Combined FLAIR and SWI identified all 146 detectable regions (100%). FLAIR was sensitive for frontal-parietal, temporal-occipital and Sylvian cistern SAH, while SWI was particularly sensitive for interhemispheric and intraventricular hemorrhage. By combining SWI and FLAIR, MRI yields a distinctly higher detection rate for SAH than CT alone, particularly due to their complementary detection characteristics in different anatomical regions. Detection strength of SWI is high in central areas, whereas FLAIR shows a better detection rate in peripheral areas. 22294440 Prevention of cytotoxicity of nickel by quercetin: the role of reactive oxygen species and histone acetylation. Excessive exposure to nickel may cause health effects on the blood, lung, nose, kidney, reproductive system, skin and the unborn child. In the present study, we found that Ni(2+) exposure led to a time- and dose-dependent proliferation arrest and death in human leukemia HL-60 cells. In the presence of 1 mM Ni(2+), reactive oxygen species (ROS) generation (indicated by the level of malondialdehyde) increased to 323% and histone acetylation decreased to 32%. Interestingly, quercetin (QU) dose dependently prevented Ni(2+)-induced cell proliferation arrest and death from 0 to 80 μM but showed similar activity of scavenging ROS at the concentrations of 20, 40 and 80 µM. When the effect of QU on histone acetylation was studied, QU significantly prevented Ni(2+)-induced histone hypoacetylation at 40 or 80 µM. Moreover, increase in histone acetylation by trichostatin A could also significantly enhance the protection effect of QU at 10 or 20 µM but not at higher concentrations. Thus, our results further confirmed the critical role of ROS and histone hypoacetylation in the cytotoxicity of Ni(2+) exposure and proved that QU is a potentially useful native dietary compound to efficiently prevent Ni(2+)-caused cytotoxicity through both diminishing ROS generation and increasing histone acetylation. 23696317 A flexible TiO₂(B)-based battery electrode with superior power rate and ultralong cycle life. A flexible film electrode is fabricated by growing TiO2 (B) nanosheets on electrospun carbon nanofiber fabric. The hybrid electrode exhibits remarkable electrochemical performance with high reversible capacity, excellent rate capability, and ultralong cycle life for thousands of cycles, which makes it highly attractive for high-power flexible lithium-ion batteries. 23810020 Universal health coverage in Turkey: enhancement of equity. Turkey has successfully introduced health system changes and provided its citizens with the right to health to achieve universal health coverage, which helped to address inequities in financing, health service access, and health outcomes. We trace the trajectory of health system reforms in Turkey, with a particular emphasis on 2003-13, which coincides with the Health Transformation Program (HTP). The HTP rapidly expanded health insurance coverage and access to health-care services for all citizens, especially the poorest population groups, to achieve universal health coverage. We analyse the contextual drivers that shaped the transformations in the health system, explore the design and implementation of the HTP, identify the factors that enabled its success, and investigate its effects. Our findings suggest that the HTP was instrumental in achieving universal health coverage to enhance equity substantially, and led to quantifiable and beneficial effects on all health system goals, with an improved level and distribution of health, greater fairness in financing with better financial protection, and notably increased user satisfaction. After the HTP, five health insurance schemes were consolidated to create a unified General Health Insurance scheme with harmonised and expanded benefits. Insurance coverage for the poorest population groups in Turkey increased from 2·4 million people in 2003, to 10·2 million in 2011. Health service access increased across the country-in particular, access and use of key maternal and child health services improved to help to greatly reduce the maternal mortality ratio, and under-5, infant, and neonatal mortality, especially in socioeconomically disadvantaged groups. Several factors helped to achieve universal health coverage and improve outcomes. These factors include economic growth, political stability, a comprehensive transformation strategy led by a transformation team, rapid policy translation, flexible implementation with continuous learning, and simultaneous improvements in the health system, on both the demand side (increased health insurance coverage, expanded benefits, and reduced cost-sharing) and the supply side (expansion of infrastructure, health human resources, and health services). 23665259 Description and phylogeny of Zelenkaia trichopterae gen. et sp. nov. (Microsporidia), an aquatic microsporidian parasite of caddisflies (Trichoptera) forming spore doublets. Two novel microsporidia infecting the fat body tissues in larvae of two hosts, Halesus digitatus and Micropterna sequax (Trichoptera, Limnephilidae), were investigated using light and electron microscopy and rDNA sequence analyses. The molecular and morphological characters of these isolates warrant creation of a new microsporidian genus, Zelenkaia gen. n., with two species, one named herein. Developmental stages of Zelenkaia spp. have single nuclei. In sporogony, a plasmodium with four nuclei gives rise by rosette-like budding to two pairs of uninucleate sporoblasts, each within a thin-walled, subpersistent sporophorous vesicle. Sporoblasts and mature spores adhere temporary together, forming doublets oriented in parallel, within the sporophorous vesicle. Spores are long-oval and uninucleate, and those of the type species Z. trichopterae measure 10.3×3.5μm and have 24-25 polar filament coils. Phylogenetic analysis based on rDNA places Zelenkaia spp. within the aquatic clade of microsporidia and, more specifically, in the clade containing some microporidia from amphipod hosts. 23740247 The MID1 E3 Ligase Catalyzes the Polyubiquitination of Alpha4 (α4), a Regulatory Subunit of Protein Phosphatase 2A (PP2A): NOVEL INSIGHTS INTO MID1-MEDIATED REGULATION of PP2A. Alpha4 (α4) is a key regulator of protein phosphatase 2A (PP2A) and mTOR in steps essential for cell-cycle progression. α4 forms a complex with PP2A and MID1, a microtubule-associated ubiquitin E3 ligase that facilitates MID1-dependent regulation of PP2A and the dephosphorylation of MID1 by PP2A. Ectopic overexpression of α4 is associated with hepatocellular carcinomas, breast cancer, and invasive adenocarcinomas. Here, we provide data suggesting that α4 is regulated by ubiquitin-dependent degradation mediated by MID1. In cells stably expressing a dominant-negative form of MID1, significantly elevated levels of α4 were observed. Treatment of cells with the specific proteasome inhibitor, lactacystin, resulted in a 3-fold increase in α4 in control cells and a similar level in mutant cells. Using in vitro assays, individual MID1 E3 domains facilitated monoubiquitination of α4, whereas full-length MID1 as well as RING-Bbox1 and RING-Bbox1-Bbox2 constructs catalyzed its polyubiquitination. In a novel non-biased functional screen, we identified a leucine to glutamine substitution at position 146 within Bbox1 that abolished MID1-α4 interaction and the subsequent polyubiquitination of α4, indicating that direct binding to Bbox1 was necessary for the polyubiquitination of α4. The mutant had little impact on the RING E3 ligase functionality of MID1. Mass spectrometry data confirmed Western blot analysis that ubiquitination of α4 occurs only within the last 105 amino acids. These novel findings identify a new role for MID1 and a mechanism of regulation of α4 that is likely to impact the stability and activity level of PP2Ac. 23848303 Transport and catabolism of the sialic acids N-glycolylneuraminic acid and 3-keto-3-deoxy-d-glycero-d-galactonononic acid by Escherichia coli K-12. Escherichia coli can transport and catabolize the common sialic acid, N-acetylneuraminic acid (Neu5Ac), as a sole source of carbon and nitrogen, which is an important mucus-derived carbon source in the mammalian gut. Herein we demonstrate that E. coli can also grow efficiently on the related sialic acids, N-glycolylneuraminic acid (Neu5Gc) and 3-keto-3-deoxy-d-glycero-d-galactonononic acid (KDN), which are transported via the sialic acid transporter NanT and catabolized using the sialic acid aldolase NanA. Catabolism of Neu5Gc uses the same pathway as Neu5Ac, likely producing glycolate instead and acetate during its breakdown and catabolism of KDN requires NanA activity, while other components of the Neu5Ac catabolism pathway are non-essential. We also demonstrate that these two sialic acids can support growth of an E. coli ∆nanT strain expressing sialic acid transporters from two bacterial pathogens, namely the tripartite ATP-independent periplasmic transporter SiaPQM from Haemophilus influenzae and the sodium solute symport transporter STM1128 from Salmonella enterica ssp. Typhimurium, suggesting that the ability to use Neu5Gc and KDN in addition to Neu5Ac is present in a number of human pathogens. 23896216 Can Computer Meridian Diagnostic be useful in diagnosis and management of diseases? The need for the development of appropriate guidelines for effective or safe use of antioxidants and herbs has always been a concern, especially for the alternative medicine practices. Computer Meridian Diagnostic (CMD) is one of emerging computer-based diagnostic technologies available to alternative medicine practitioners. However, case report of the agents monitored with CMD is uncommon; and concerted effort to bring this into conventional medical practice is yet to be. This hypothesis builds on an anecdotal observation of anti-stress effect monitored with CMD, with a view to highlight a potential tool that requires expatiation, as well as proof of concept and validation studies for possible integration in conventional and traditional medicine practices for therapeutic monitoring. 23913013 Nitric oxide regulation of leaf phosphoenolpyruvate carboxylase-kinase activity: implication in sorghum responses to salinity. Nitric oxide (NO) is a signaling molecule that mediates many plant responses to biotic and abiotic stresses, including salt stress. Interestingly, salinity increases NO production selectively in mesophyll cells of sorghum leaves, where photosynthetic C4 phosphoenolpyruvate carboxylase (C4 PEPCase) is located. PEPCase is regulated by a phosphoenolpyruvate carboxylase-kinase (PEPCase-k), which levels are greatly enhanced by salinity in sorghum. This work investigated whether NO is involved in this effect. NO donors (SNP, SNAP), the inhibitor of NO synthesis NNA, and the NO scavenger cPTIO were used for long- and short-term treatments. Long-term treatments had multifaceted consequences on both PPCK gene expression and PEPCase-k activity, and they also decreased photosynthetic gas-exchange parameters and plant growth. Nonetheless, it could be observed that SNP increased PEPCase-k activity, resembling salinity effect. Short-term treatments with NO donors, which did not change photosynthetic gas-exchange parameters and PPCK gene expression, increased PEPCase-k activity both in illuminated leaves and in leaves kept at dark. At least in part, these effects were independent on protein synthesis. PEPCase-k activity was not decreased by short-term treatment with cycloheximide in NaCl-treated plants; on the contrary, it was decreased by cPTIO. In summary, NO donors mimicked salt effect on PEPCase-k activity, and scavenging of NO abolished it. Collectively, these results indicate that NO is involved in the complex control of PEPCase-k activity, and it may mediate some of the plant responses to salinity. 23823653 Fatal Transplant-Associated West Nile Virus Encephalitis and Public Health Investigation-California, 2010. In December 2010, a case of West Nile virus (WNV) encephalitis occurring in a kidney recipient shortly after organ transplantation was identified. A public health investigation was initiated to determine the likely route of transmission, detect potential WNV infections among recipients from the same organ donor, and remove any potentially infected blood products or tissues. Available serum, cerebrospinal fluid, and urine samples from the organ donor and recipients were tested for WNV infection by nucleic acid testing and serology. Two additional recipients from the same organ donor were identified, their clinical and exposure histories were reviewed, and samples were obtained. WNV RNA was retrospectively detected in the organ donor's serum. After transplantation, the left kidney recipient had serologic and molecular evidence of WNV infection and the right kidney recipient had prolonged but clinically inapparent WNV viremia. The liver recipient showed no clinical signs of infection but had flavivirus IgG antibodies; however, insufficient samples were available to determine the timing of infection. No remaining infectious products or tissues were identified. Clinicians should suspect WNV as a cause of encephalitis in organ transplant recipients and report cases to public health departments for prompt investigation of the source of infection. Increased use of molecular testing and retaining pretransplantation sera may improve the ability to detect and diagnose transplant-associated WNV infection in organ transplant recipients. 23111372 Mediterranean studies of cardiovascular disease and hyperglycemia: analytical modeling of population socio-economic transitions (MedCHAMPS)-rationale and methods. In response to the escalating epidemic of cardiovascular disease (CVD) in the Mediterranean Region (MR), an international collaboration aiming at understanding the burden of CVD and evaluating cost-effective strategies to combat it was recently established. This paper describes the rationale and methods of the project MedCHAMPS to disseminate this successful experience. The framework of MedCHAMPS is exceptional in combining multiple disciplines (e.g. epidemiology, anthropology, economics), countries [Turkey, Syria, occupied Palestinian territory (oPt), Tunisia, UK, Ireland], research methods (situational and policy analysis, quantitative and qualitative studies, statistical modeling), and involving local stakeholders at all levels to assess trends of CVD/diabetes in the society and attributes of the local health care systems to provide optimal policy recommendations to reduce the burden of CVD/diabetes. MedCHAMPS provides policy makers in the MR and beyond needed guidance about the burden of CVD, and best cost-effective ways to combat it. Our approach of building developed-developing countries collaboration also provides a roadmap for other researchers seeking to build research base into CVD epidemiology and prevention in developing countries. 23845962 De novo transcript sequence reconstruction from RNA-seq using the Trinity platform for reference generation and analysis. De novo assembly of RNA-seq data enables researchers to study transcriptomes without the need for a genome sequence; this approach can be usefully applied, for instance, in research on 'non-model organisms' of ecological and evolutionary importance, cancer samples or the microbiome. In this protocol we describe the use of the Trinity platform for de novo transcriptome assembly from RNA-seq data in non-model organisms. We also present Trinity-supported companion utilities for downstream applications, including RSEM for transcript abundance estimation, R/Bioconductor packages for identifying differentially expressed transcripts across samples and approaches to identify protein-coding genes. In the procedure, we provide a workflow for genome-independent transcriptome analysis leveraging the Trinity platform. The software, documentation and demonstrations are freely available from http://trinityrnaseq.sourceforge.net. The run time of this protocol is highly dependent on the size and complexity of data to be analyzed. The example data set analyzed in the procedure detailed herein can be processed in less than 5 h. 23333833 More than two decades of Apc modeling in rodents. Mutation of tumor suppressor gene adenomatous polyposis coli (APC) is an initiating step in most colon cancers. This review summarizes Apc models in mice and rats, with particular concentration on those most recently developed, phenotypic variation among different models, and genotype/phenotype correlations. 23632316 Mass spectrometry investigation of glycosylation on the NXS/T sites in recombinant glycoproteins. We used a targeted proteomics approach to investigate whether introduction of new N-linked glycosylation sites in a chimeric protein influence the glycosylation of the existing glycosylation sites. To accomplish our goals, we over-expressed and purified a chimeric construct that contained the Fc region of the IgG fused to the exons 7 & 8 of mouse ZP3 (IgG-Fc-ZP3E7 protein). Immunoglobulin heavy chain (IgG-HC protein) was used as control. We then analyzed the IgG-HC and IgG-Fc-ZP3E7 proteins by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and by Western blotting (WB). We concluded that in control experiments, the glycosylation site was occupied as expected. However, in the IgG-Fc-ZP3E7 protein, we concluded that only one out of three NXS/T glycosylation sites is occupied by N-linked oligosaccharides. We also concluded that in the IgG-Fc-ZP3E7 protein, upon introduction of additional potential NXS/T glycosylation sites within its sequence, the original NST/S glycosylation site from the Fc region of the IgG-Fc-ZP3E7 protein is no longer glycosylated. The biomedical significance of our findings is discussed. 23904589 Mechanisms of self-organization for the collagen fibril lattice in the human cornea. The transparency of the human cornea depends on the regular lattice arrangement of the collagen fibrils and on the maintenance of an optimal hydration-the achievement of both depends on the presence of stromal proteoglycans (PGs) and their linear sidechains of negatively charged glycosaminoglycans (GAGs). Although the GAGs produce osmotic pressure by the Donnan effect, the means by which they exert positional control of the lattice is less clear. In this study, a theoretical model based on equilibrium thermodynamics is used to describe restoring force mechanisms that may control and maintain the fibril lattice and underlie corneal transparency. Electrostatic-based restoring forces that result from local charge density changes induced by fibril motion, and entropic elastic restoring forces that arise from duplexed GAG structures that bridge neighbouring fibrils, are described. The model allows for the possibility that fibrils have a GAG-dense coating that adds an additional fibril force mechanism preventing fibril aggregation. Swelling pressure predictions are used to validate the model with results showing excellent agreement with experimental data over a range of hydration from 30 to 200% of normal. The model suggests that the electrostatic restoring force is dominant, with the entropic forces from GAG duplexes being an order or more smaller. The effect of a random GAG organization, as observed in recent imaging, is considered in a dynamic model of the lattice that incorporates randomness in both the spatial distribution of GAG charge and the topology of the GAG duplexes. A striking result is that the electrostatic restoring forces alone are able to reproduce the image-based lattice distribution function for the human cornea, and thus dynamically maintain the short-range order of the lattice. 23921301 Electrocardiographic Safety of Cangrelor, a New Intravenous Anti-platelet Agent: A Randomized, Double-Blind, Placebo- and Moxifloxacin-Controlled Thorough QT Study. Cangrelor is an intravenous P2Y12 inhibitor under investigation as an antiplatelet drug in the setting of acute coronary syndromes. To determine the electrophysiologic safety of parenteral cangrelor, cardiac repolarization effects were measured in 67 healthy volunteers (ages 18-45 years) in a randomized crossover design including four treatment sequences of cangrelor therapeutic, cangrelor supratherapeutic, placebo, and moxifloxacin (positive control). Triplicate electrocardiogram measurements and pharmacokinetic samples were collected at baseline and nine time points post-dose on Day 1. For both cangrelor and moxifloxacin, time-matched, placebo-adjusted change in QT from baseline was evaluated using an individual (QTcI) heart rate correction. After cangrelor dosing, change in QTcI was <5 milliseconds (ms) at all times points, and all corresponding upper two-sided 90% confidence intervals (CI) were <10 ms. While moxifloxacin failed to show a lower CI >5 ms, expected time trends and lower CI >4.0 ms demonstrate assay sensitivity. QTcI was not affected by plasma concentrations of cangrelor metabolites and cangrelor had no other adverse effects on electrocardiographic parameters. Clinically, cangrelor exposure was well tolerated. Thus, this thorough QT study demonstrated that therapeutic and supratherapeutic cangrelor doses do not adversely affect cardiac repolarization in normal volunteers. (clinicaltrials.gov identifier NCT00699504). 23850739 In vitro blood-brain barrier model adapted to repeated-dose toxicological screening. Toxicity to the central nervous system (CNS) is a key feature in the toxicological profile of compounds and there is a growing interest to use in vitro cell assays. The blood-brain barrier (BBB) is a highly restrictive barrier that preserves homeostasis within the brain microenvironment. By modelling the BBB it is possible to investigate whether a compound is likely to compromise its functionality, which would cause unwanted effects on brain cells. These investigations are usually performed using a single exposure to drugs, whereas CNS side effects usually result from repeated exposures. The main objective of this study was to adapt our established BBB model to the evaluation of repeated-dose toxicity at the BBB. Studies were undertaken within the European Predict-IV consortium to study the effect on BBB permeability of 12 selected drugs after 14days of repeated treatment to a single pre-selected concentration. Compared to single exposure, a 100-fold lower colchicine concentration in 14days repeated-dose treatment was toxic. This demonstrates the importance to evaluate the BBB toxicity in repeated-dose testing. Finally, the potentiating effects of cyclosporin A on the BBB toxicity of colchicine illustrate the possibility to use in vitro BBB models to make risk assessment of drug-drug interactions. 23952785 Changes to CMS Reimbursement Rules for Intraoperative Neurophysiological Monitoring: Implications for Telemedicine. Abstract Intraoperative neurophysiological monitoring (IONM) is used as an adjunct for surgeries that pose risk to nervous system structures. IONM is performed by a technologist in the operating room and is overseen by a highly trained fellowship-trained physician clinical neurophysiologist. Telemedicine has allowed the professional oversight component to be done remotely, with reimbursement for multiple simultaneous cases. Recent changes to Current Procedure Terminology coding and Medicare reimbursement policies provide options only for exclusive 1:1 technologist:oversight physician billing. This policy change may create profound repercussions in the practice of telemedicine by actively discouraging the leveraging of highly specialized and scarce expertise through on-site physician extenders. 23590194 Deletion of the major peroxiredoxin Tsa1 alters telomere length homeostasis. Reactive oxygen species (ROS) are proposed to play a major role in telomere length alterations during aging. The mechanisms by which ROS disrupt telomeres remain unclear. In Saccharomyces cerevisiae, telomere DNA consists of TG(1-3) repeats, which are maintained primarily by telomerase. Telomere length maintenance can be modulated by the expression level of telomerase subunits and telomerase activity. Additionally, telomerase-mediated telomere repeat addition is negatively modulated by the levels of telomere-bound Rap1-Rif1-Rif2 protein complex. Using a yeast strain defective in the major peroxiredoxin Tsa1 that is involved in ROS neutralization, we have investigated the effect of defective ROS detoxification on telomere DNA, telomerase, telomere-binding proteins, and telomere length. Surprisingly, the tsa1 mutant does not show significant increase in steady-state levels of oxidative DNA lesions at telomeres. The tsa1 mutant displays abnormal telomere lengthening, and reduction in oxidative exposure alleviates this phenotype. The telomere lengthening in the tsa1 cells was abolished by disruption of Est2, subtelomeric DNA, Rap1 C-terminus, or Rif2, but not by Rif1 deletion. Although telomerase expression and activity are not altered, telomere-bound Est2 is increased, while telomere-bound Rap1 is reduced in the tsa1 mutant. We propose that defective ROS scavenging can interfere with pathways that are critical in controlling telomere length homeostasis. 23769240 Productive vs non-productive infection by cell-free varicella zoster virus of human neurons derived from embryonic stem cells is dependent upon infectious viral dose. Varicella Zoster virus (VZV) productively infects humans causing varicella upon primary infection and herpes zoster upon reactivation from latency in neurons. In vitro studies using cell-associated VZV infection have demonstrated productive VZV-infection, while a few recent studies of human neurons derived from stem cells incubated with cell-free, vaccine-derived VZV did not result in generation of infectious virus. In the present study, 90%-pure human embryonic stem cell-derived neurons were incubated with recombinant cell-free pOka-derived virus made with an improved method or VZV vaccine. We found that cell-free pOka and vOka at higher multiplicities of infection elicited productive infection in neurons followed by spread of infection, cytopathic effect and release of infectious virus into the medium. These results further validate the use of this unlimited source of human neurons for studying unexplored aspects of VZV interaction with neurons such as entry, latency and reactivation. 23426869 Dissecting the roles of the N- and C-flanking residues of acetyllysine substrates for SIRT1 activity. SIRT1 specificity: The multispecific SIRT1 enzyme catalyzes the deacetylation of acetyllysine residues within protein targets. However, little is known regarding the molecular basis for SIRT1 substrate recognition. Kinetic analysis of SIRT1 with a panel of peptide substrates shows the high importance of the region N-flanking the target acetyllysine and its high conservation through evolution. 23748904 Elevated blood pressure, heart rate and body temperature in mice lacking the XLαs protein of the Gnas locus is due to increased sympathetic tone. Imbalances of energy homeostasis are often associated with cardiovascular complications. Previous work has shown that Gnasxl deficient mice have a lean and hypermetabolic phenotype with increased sympathetic stimulation of adipose tissue. The Gnasxl transcript from the imprinted Gnas locus encodes the trimeric G-protein subunit XLαs, which is expressed in brain regions that regulate energy homeostasis and sympathetic nervous system (SNS) activity. To determine whether Gnasxl knock-out (KO) mice display additional SNS related phenotypes, we have now investigated the cardiovascular system. Gnasxl KO mice were ≈20 mmHg hypertensive compared to wild-type (WT) littermates (p≤0.05) and hypersensitive to the sympatholytic drug reserpine. Using telemetry, we detected an increased waking heart rate (HR) in conscious KOs (630±10 vs 584±12 bpm, KO vs WT, p≤0.05). Body temperature was also elevated (38.1±0.3 vs 36.9±0.4 °C, KO vs WT, p≤0.05). To investigate autonomic nervous system influences, we used heart rate variability (HRV) analyses. We empirically defined frequency power bands using atropine and reserpine and verified high frequency (HF) power and low frequency (LF) LF/HF power ratio to be indicators of parasympathetic and sympathetic activity, respectively. LF/HF power ratio was greater in KOs and more sensitive to reserpine than in WTs, consistent with elevated SNS activity. By contrast, atropine and exendin-4 (Ex-4), a centrally acting agonist of the glucagon-like peptide-1 (GLP-1) receptor, which influences cardiovascular physiology and metabolism, reduced HF power equally in both genotypes. This was associated with a stronger increase in HR in KOs. Mild stress had a blunted effect on LF/HF ratio in KOs consistent with elevated basic sympathetic activity. We conclude that XLαs is required for the inhibition of sympathetic outflow towards cardiovascular and metabolically relevant tissues. 23347064 Pharmacological potential of biogenic amine-polyamine interactions beyond neurotransmission. Histamine, serotonin and dopamine are biogenic amines involved in intercellular communication with multiple effects on human pathophysiology. They are products of two highly homologous enzymes, histidine decarboxylase and l-aromatic amino acid decarboxylase, and transmit their signals through different receptors and signal transduction mechanisms. Polyamines derived from ornithine (putrescine, spermidine and spermine) are mainly involved in intracellular effects related to cell proliferation and death mechanisms. This review summarizes structural and functional evidence for interactions between components of all these amine metabolic and signalling networks (decarboxylases, transporters, oxidases, receptors etc.) at cellular and tissue levels, distinct from nervous and neuroendocrine systems, where the crosstalk among these amine-related components can also have important pathophysiological consequences. The discussion highlights aspects that could help to predict and discuss the effects of intervention strategies. This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1. 23650094 Concise enantioselective synthesis of cephalosporolide B, (4R)-4-OMe-cephalosporolide C, and (4S)-4-OMe-cephalosporolide C. Ring around the rosie: The effective enantioselective synthesis of the antimalarial nonenolide title compounds was achieved in a convergent strategy. Oxy-Michael addition reaction was used to introduce the chiral methoxy group at C-4, and ring-closing metathesis (RCM) reaction (53 % yield) facilitated the key construction of the 10-membered ring. 23228175 Terpenoids from Incarvillea arguta. One new monoterpenoid, (+)-argutoid A (1), three new iridoids, ( - )-incarvoid A (2), (+)-incarvoid B (3), and incarvoid C (4), and five known compounds were isolated from Incarvillea arguta. Their structures were characterized by means of spectroscopic methods. 23736833 Quality of gastric cancer care in designated cancer care hospitals in Japan. /st> To develop a set of process-of-care quality indicators (QIs) that would cover a wide range of gastric cancer care modalities and to examine the current state of the quality of care provided by designated cancer care hospitals in Japan. /st> A retrospective medical record review. Eighteen designated cancer care hospitals throughout Japan. /st> A total of 1685 patients diagnosed with gastric cancer in 2007. /st> Provision of care to eligible patients as described in the 29 QIs, which were developed using an adaptation of the RAND/UCLA (University of California, Los Angeles) appropriateness method by a panel of nationally recognized experts in Japan. /st> Overall, the patients received 68.3% of the care processes recommended by the QIs. While 'deep venous thrombosis prophylaxis before major surgery' was performed for 99% of the cases, 'documentation before endoscopic resection' was completed for only 12% of the cases. The chemotherapy care was less likely to meet the QI standards (61%) than pre-therapeutic care (76%), surgical treatment (66%) and endoscopic resection (71%; overall difference: P < 0.001). A comparison based on the types of care showed that documentation and patient explanation were performed less frequently (60 and 53%, respectively) than were diagnostic and therapeutic processes as recommended in the QIs (85%; overall P < 0.001). /st> Although many required care processes were provided, some areas with room for improvement were revealed, especially with respect to chemotherapy, documentation and patient explanation. Continuous efforts to improve the quality and develop a system to monitor this progress would be beneficial in Japan. 23116938 Endocrine disruptive potential of endosulfan on the reproductive axis of Cichlasoma dimerus (Perciformes, Cichlidae). Endosulfan (ES), a persistent organochlorine pesticide, is widely used despite its toxicity to non-target animals. Upon reaching water bodies, ES can cause negative effects on aquatic animals, including disruption of hormonal systems. However, the action of ES on fish reproductive axis has been hardly studied thus far. The aim of the present work was to assess the endocrine disruptive potential of endosulfan on the pituitary gonadotropins levels and on the testes function due to ES in the South American freshwater fish Cichlasoma dimerus, using in vitro and in vivo approaches. In vitro experiments showed that ES inhibited the LH-stimulated steroidogenesis in gonads; no change was observed in gonadotropins release from pituitaries in culture. Laboratory waterborne ES (0.1, 0.3 and 1 μg/L) exposure for two months caused decrease in βFSH pituitary content and γGT activity in the testes (Sertoli cell function marker). Testicular histology revealed pathologies such as scarce intermediate stages of spermatogenesis, release of immature germ cells into the lobular lumen, presence of foam cells and interstitial fibrosis. As FSH and FSH-mediated steroidogenesis regulate spermatogenesis and Sertoli cell function, the effect of ES on FSH could be responsible for the morphological alterations observed in testes. In vitro, ES disrupted steroidogenesis in gonads, therefore similar effects in vivo cannot be ruled out. Based on this evidence, ES exhibits an endocrine disruptive action on the reproductive axis of C. dimerus, causing disruption at the pituitary and/or at the gonad level. These effects could acquire ecological significance under prolonged exposure to the pesticide in nature. 23212106 Prospects for treatment of latent HIV. Recent advances in antiretroviral therapy (ART) have drastically improved the quality of life for people with HIV infection. However, owing to the persistence of latent HIV in the presence of therapy, patients must remain on therapy indefinitely. Currently, the solution to the HIV pandemic rests on the prevention of new infections and many decades of ART for the steadily expanding number of people infected worldwide. ART is costly, requires ongoing medical care, and can have side effects, thereby preventing its universal availability. Therefore, to escape the ironic burdens of therapy, efforts have begun to develop treatments for latent HIV infection. Current approaches propose either complete eradication of infection or induction of a state of stringent control over viral replication without ART. This review will discuss these strategies in detail and their potential for clinical development. 23444286 Comparing the pharmacokinetics of doxylamine/pyridoxine delayed-release combination in nonpregnant women of reproductive age and women in the first trimester of pregnancy. Although Diclectin (doxylamine/pyridoxine delayed-released combination) is widely used in Canada, its pharmacokinetics (PK) during pregnancy has never been described. The objective of this study was to compare the PK of doxylamine/pyridoxine delayed-released combination in pregnant versus nonpregnant women. The apparent clearances (CL) of doxylamine and pyridoxal 5'-phosphate (PLP; the active metabolite of vitamin B(6) ) during the first-trimester pregnancy in women who participated in a Diclectin randomized trial were compared with those of healthy, adult, nonpregnant women who participated in a voluntary PK trial. Eighteen nonpregnant women were compared with 50 pregnant women who were treated with Diclectin. There was no difference in the apparent CL of doxylamine in women in their first trimester of pregnancy when compared with nonpregnant women on day 4 (median = 196.7 vs 249.5 mL/h/kg, respectively, P = .065), day 8 (median = 248.4 vs 249.5 mL/h/kg, respectively, P = .82), and day 15 (median = 200.9 vs 249.5 mL/h/kg, respectively, P = .55). No difference was found in the apparent CL of PLP on day 15 (median = 342.3 vs 314.7 mL/h/kg, respectively, P = .92). There was no pregnancy-induced effect in the apparent CL of either doxylamine or PLP in women during the first trimester of pregnancy despite the existence of morning sickness. 23895340 Relationships between absorption efficiency of elements in mammals and chemical properties. Abstract Oral absorption efficiency is an important factor to consider in human risk assessment and varies widely between elements. Linking absorption efficiency to chemical properties facilitates the understanding of underlying processes and enables extrapolation across elements. In our study, oral absorption efficiency in humans was predicted for a number of elements based on their ionization energy and electronegativity. Data on oral absorption efficiency in humans were retrieved via a literature survey. A model was developed based on the assumption that ionic species readily react with biotic ligands. Accordingly, ionization energy was presumed to represent the reactivity and absorption of atoms in the gastrointestinal tract. The coefficients of the model were parameterized by fitting the quantitative relationship between absorption efficiency and ionization energy to data collected from well-standardized studies. Generally, absorption efficiency was strongly related to ionization energy, explaining 94% of the variability in absorption efficiency between elements reported by the International Commission on Radiological Protection (ICRP). In addition, the absorption efficiencies predicted based on ionization energy were within a factor of two of those given by the ICRP (ME = -0.05; RMSE = 0.31). However, the model is not applicable to alkaline metals and molybdenum because of the uniquely high solubility of their compounds or the flexible electron configuration of these elements. Approximately 56% of the variability in absorption efficiency between elements could be explained by electronegativity. These strong relationships between absorption efficiency and ionization energy and, to a lesser extent, electronegativity indicate potential for extrapolation across elements using atomic properties. 23275095 Management of domoic acid monitoring in shellfish from the Catalan coast. Monitoring of amnesic shellfish poisoning (ASP) toxins in shellfish from the Catalan coast started in 2001. No ASP toxins were detected in any of the analyses performed before 2008. On 22 January 2008, domoic acid (DA) was detected in Donax trunculus (0.5 mg kg(-1)) and confirmed by rapid resolution liquid chromatography-tandem mass spectrometry (0.6 mg kg(-1)). A total of 974 shellfish samples were analyzed from January 2008 to December 2011, covering all the Catalan production areas and the most important marketed species. DA was detected in 23.8 % of the samples and was recorded every month in all areas and all species, except Ostrea edulis, although the percentage of samples with DA and DA content varied widely among samples. DA exceeded the regulatory level of 20 mg kg(-1) twice: in Callista chione sampled on February 2008 and in D. trunculus sampled on April 2010. DA content in Bolinus brandaris appeared constant and close to 4.5 mg kg(-1) for months in 2009. Mytilus galloprovincialis, Crassostrea gigas, and Ruditapes sp. presented very low concentrations of DA in the Ebro Delta bays, despite 113 alert situations according to Pseudo-nitzschia spp. abundances and the high number of shellfish samples analyzed. The origin of DA in Catalan shellfish remains unknown. 23597210 Molecular Mechanisms in the Pyrolysis of Unsaturated Chlorinated Hydrocarbons: Formation of Benzene Rings Part II - Experimental and Kinetic Modeling Studies. The mechanism of formation of benzene rings during the pyrolysis of dichloro- and trichloroethylene has been investigated by the method of Laser Powered Homogeneous Pyrolysis coupled with product analysis by gas chromatography. Additionally, selected (co)-pyrolyses between the chlorinated ethylenes, CH2Cl2, C4Cl4, C4Cl6, and C2H2 have been performed to explicitly probe the roles of 2C3 and C4/C2 reaction pairs in aromatic growth. The presence of odd-carbon products in neat C4Cl6 pyrolyses indicates 2C3 processes are operative in these systems; however, comparison with product yields from C2HCl3 suggests C4/C2 processes dominate most other systems. This is further evidenced by an absence of C3 and other odd-carbon species in (co)-pyrolyses with dichloromethane which should seed C3-based growth. The reactions of perchlorinated C4 species C4Cl5, C4Cl3, and C4Cl4 with C2Cl2 were subsequently explored through extensive kinetic simulations of the possible reaction pathways based on previous kinetic models and the exhaustive quantum chemical investigations of our preceding work. The experimental and theoretical results strongly suggest that, at moderate temperatures, aromatic ring formation from chlorinated ethylenes normally follows a Diels-Alder coupling of C4 and C2 molecular units followed by internal shifts; the one exception is the C4Cl4 + C2Cl2 system, where steric factors lead to the formation of non-aromatic products. There is little evidence for radical-based routes in these systems. 23807045 Cell-cell communication via extracellular membrane vesicles and its role in the immune response. The host immune response involves a variety of cell types, including specialized immune and non-immune cells. The delicate coordination among these cells via close communication is central for the proper operation of immune system. Cell-cell communication is mediated by a complex network that includes soluble factors such as cytokines, chemokines, and metabolites exported from cells, as well as membrane-bound receptors and their ligands. Cell-cell communication is also mediated by membrane vesicles (e.g., exosomes, ectosomes), which are either shed by distant cells or exchanged by cells that are making direct contact. Intercellular communication via extracellular membrane vesicles has drawn much attention recently, as they have been shown to carry various biomolecules that modulate the activities of recipient cells. In this review, I will discuss current views on cell-cell communication via extra-cellular membrane vesicles, especially shedded membrane vesicles, and their effects on the control of the immune system. 23932199 The molecular switches controlling the interaction between complement proteases of the classical and lectin pathways and their substrates. Complement represents a major bridge between the innate and adaptive immune systems of the body. It plays a vital role in host defences against pathogens, but has also been implicated in numerous inflammatory diseases. The system has been the subject of intensive research in recent times with a number of key structural insights into the functioning of the system. Here, we will give an overview of the activation of each pathway, following which recent developments in our understanding of the mechanisms governing the interaction between enzymes and substrates in the classical and lectin pathways in particular will be discussed. 23411256 Multiple mutations of the critical amino acid residues for the sweetness of the sweet-tasting protein, brazzein. We have previously identified critical residues important for sweetness of the sweet protein brazzein by site-directed mutagenesis (Yoon, Kong, Jo, & Kong, 2011). In order to elucidate the interaction mechanisms of brazzein with the sweet taste receptor, we made multiple mutations of three residues (His31 in loop 30-33, Glu36 in β-strand III, and Glu41 in loop 40-43). We found that all double mutations (H31R/E36D, H31R/E41A and E36D/E41A) made the molecules sweeter than des-pE1M-brazzein and three single mutants. Moreover, the triple mutation (H31R/E36D/E41A) made the molecule significantly sweeter than three double mutants. These results strongly support the hypothesis that brazzein binds to the multisite surface of the sweet taste receptor. Our findings also suggest that mutations reducing the overall negative charge and/or increasing the positive charge favour sweet-tasting protein potency. 23818063 Incidence of osteoporotic fractures in Sado, Japan in 2010. We conducted a survey of fracture incidences associated with senile osteoporosis in 2010 in Sado City, Niigata Prefecture, Japan, including compression vertebral fractures, hip fractures, distal radius fractures, and fractures of the proximal end of the humerus. We previously conducted a similar survey from 2004-2006 in Sado City. The purpose of the current study was to determine the incidence of osteoporotic fractures in Sado City in 2010 and to examine changes over time. We calculated the incidence of each fracture per 100,000 person-years based on the population of Sado City. Hip and vertebral fractures showed marked increases from 2004-2006, but a similar increase was not found from 2006-2010. The average age at injury increased in 2010 compared to 2004, except for fractures of the radius. Among the subjects with hip fractures, 14 % had a history of contralateral hip fracture. The percentage of patients taking medication for osteoporosis before injury was higher in 2010 compared with 2004, but these percentages were still only 7 and 13 % for those with subsequent hip and vertebral fractures, respectively. 23291061 The oral cavity as a biological barrier system: Design of an advanced buccal in vitro permeability model. An important area for future research lies in finding a drug delivery system across or into the oral mucosa. However, to design such systems, simplified biological models are necessary so that the mechanisms and/or interactions of interest can readily be studied. The oral epithelium is covered by a complex mucus layer, which enables exchange of nutrients and provides lubrication. However, it has been demonstrated that mucus has an impact on the mobility of nanoparticles and drug molecules. Thus, we aimed to develop an advanced buccal in vitro model for studying transport of nanoparticles, taking the mucus layer into account. First, animal mucins (porcine gastric, bovine submaxillary) were compared with natural human mucin regarding chemical and morphological structure. Second, an "external" mucus layer was prepared by a film method and deposited onto an oral cell line (TR 146), cultured on transwells®. Adherence of the mucin fibers was evaluated and the viability of the model was assessed. Nanoparticle transport studies were performed with this advanced in vitro model and an ex vivo diffusion system. The results revealed that porcine mucin is most similar to human natural mucin in chemical structure and morphology. Both the bovine and porcine mucin fibers adhered onto the oral cells: Due to the different morphology of bovine mucin, the viability of the oral cells decreased, whereas porcine mucin maintained the viability of the model for more than 48h. Comparison of in vitro data with ex vivo data suggested reliability of the advanced buccal in vitro model. Additionally, it was demonstrated that the mucus layer in the oral cavity also acts as a strong barrier for the mobility of nanoparticles. 23964744 Theoretical Study of Gas Hydrate Decomposition Kinetics - Model Development. In order to provide an estimate of the order of magnitude of intrinsic gas hydrate dissolution and dissociation kinetics the "Consecutive Desorption and Melting Model" (CDM) is developed by applying only theoretical considerations. The process of gas hydrate decomposition is assumed to comprise of two consecutive and repetitive quasi chemical reaction steps. These are desorption of the guest molecule followed by local solid body melting. The individual kinetic steps are modelled according to the "Statistical Rate Theory of Interfacial Transport" and the Wilson-Frenkel-approach. All missing required model parameters are directly linked to geometric considerations and a thermodynamic gas hydrate equilibrium model. 23602788 Transmission of Rickettsia slovaca and Rickettsia raoultii by male Dermacentor marginatus and Dermacentor reticulatus ticks to humans. We analyzed rickettsial DNA of ticks from tick-borne lymphadenopathy (TIBOLA) patients. Dermacentor marginatus (9/17) and Dermacentor reticulatus (8/17) transmitted rickettsiae to a similar extent. Rickettsia raoultii was detected in more ticks than Rickettsia slovaca. We observed the development of TIBOLA symptoms after the bite of males of both tick species. 23836613 Enantiomeric separation of citalopram base by supercritical fluid chromatography. The chiral separation of citalopram base by supercritical fluid chromatography on a semipreparative Chiralpak AD column was studied with the use of three alcohol-type modifiers (methanol, ethanol, and 2-propanol) with different volume percentages (5, 10, and 15%). The best separation was achieved when 10% 2-propanol was used in the presence of 0.1% diethylamine as additive. Under these conditions, the resolution reached 2.15 and the selectivity was 1.388. In addition, other parameters that affected the retention and separation properties, i.e. temperature, pressure, and density, were studied in detail. At the same pressure, a decrease in the temperature improved the enantioselectivity as the experimental temperature range was below the isoelution temperature. However, the temperature dependence of the retention factor was complicated. As a rule, the retention factor decreased when the temperature increased at the same density. A satisfactory regression of the logarithm of the retention factor versus density and temperature was obtained using a simplified lattice-fluid model. Surprisingly, the relationship between the Henry constant and density can be accurately correlated by using the same quadratic equation. 23777866 Photoinduced charge transfer process in p-Cu2O/n-Cu2O homojunction film and its photoelectric gas-sensing properties. In this study, the p-Cu2O/n-Cu2O homojunction film was prepared by a simple two-step electrodeposition method. The photoinduced charge transfer process in p-Cu2O/n-Cu2O homojunction film was studied using surface photovoltage technique. Then, the p-Cu2O/n-Cu2O homojunction film was assembled into a photoelectric gas sensor for sensing acetaldehyde both under 405 nm and 532 nm light irradiation at room temperature. For 532 nm light irradiation, excess photoinduced electrons migrate to the irradiated n-Cu2O side affected by the interfacial built-in electric field and promote desorption of acetaldehyde, which results in a higher sensitivity than that under 405 nm light. Our results demonstrated that constructing junction structure in photoelectric gas-sensing materials is an effective approach to achieve high sensitivity at room temperature. 23921250 Orbitofrontal and striatal circuits dynamically encode the shift between goal-directed and habitual actions. Shifting between goal-directed and habitual actions allows for efficient and flexible decision making. Here we demonstrate a novel, within-subject instrumental lever-pressing paradigm, in which mice shift between goal-directed and habitual actions. We identify a role for orbitofrontal cortex (OFC) in actions following outcome revaluation, and confirm that dorsal medial (DMS) and lateral striatum (DLS) mediate different action strategies. Simultaneous in vivo recordings of OFC, DMS and DLS neuronal ensembles during shifting reveal that the same neurons display different activities depending on whether presses are goal-directed or habitual, with DMS and OFC becoming more and DLS less engaged during goal-directed actions. Importantly, the magnitude of neural activity changes in OFC following changes in outcome value positively correlates with the level of goal-directed behavior. Chemogenetic inhibition of OFC disrupts goal-directed actions, whereas optogenetic activation of OFC specifically increases goal-directed pressing. These results also reveal a role for OFC in action revaluation, which has implications for understanding compulsive behavior. 23892391 Angiographic features help predict outcome after stereotactic radiosurgery for the treatment of pediatric arteriovenous malformations. Arteriovenous malformations (AVMs) are a frequent cause of hemorrhagic stroke in children. Stereotactic radiosurgery (SRS) is an established treatment for these lesions, particularly those that are surgically inaccessible. Because only complete AVM obliteration is believed to protect against the future risk of hemorrhage, identifying lesion characteristics that predict response to therapy is an important objective. The goal of this study is to evaluate the influence of angiographic features of AVMs on the rate of obliteration following treatment with SRS. This is a retrospective cohort study of pediatric patients (age ≤18 years) treated with Gamma Knife SRS for cerebral AVMs between 2000 and 2012. Detailed angiographic data at the time of initial angiographic evaluation were prospectively recorded by experienced neurointerventional radiologists. The primary outcome was the rate of obliteration on a 3-year follow-up angiogram. We identified 42 pediatric patients treated with SRS for cerebral AVMs. Twenty-seven patients completed 3-year angiographic follow-ups. Complete obliteration was seen in 30 %, partial response in 67 %, and no response in 4 %. Higher SRS dose was associated with complete obliteration. Larger AVM diameter, presence of multiple draining veins, and presence of multiple draining veins reaching a sinus were associated with partial response. In this small cohort, diffuse AVM borders, presence of aneurysm, and pre-SRS embolization were not associated with obliteration. Our study identifies AVMs in the pediatric population with a nidus diameter of <2.5 cm and a solitary draining vein as the most likely to undergo complete obliteration after SRS treatment. 23836405 Invasion potential of H22 hepatocarcinoma cells is increased by HMGB1-induced tumor NF-κB signaling via initiation of HSP70. The functional relationship and cross-regulation between damage-associated molecular patterns and NF‑κB in the tumor microenvironment remains unclear. In the present study, high-mobility group protein B1 (HMGB1) was secreted in response to feed second phase of NF‑κB activation from heat shock protein (HSP) 70 that may result in a higher invasion potential of hepatocarcinoma cells. HSP70 promoted the proliferation of H22 hepatocarcinoma cells through Toll-like receptor (TLR) 2 and TLR4 signaling and induced the early phosphorylation of NF-κB, which reached maximum levels within 30 min. However, HSP70 promoted the upregulation of Beclin-1 expression via Jun N-terminal kinase (JNK) activation in tumor cells and the release of HMGB1 from tumor cells. Inhibition of Beclin-1/c-JNK production prevented the second, but not the first, phase of NF-κB phosphorylation, implicating Beclin-1/c-JNK in the second phase of phosphorylation. HSP70 induced Beclin-1-derived HMGB1 production at 4 h, which occurred before the rise in the second phosphorylation that occurred at 6 h. Exogenous HMGB1 also induced the rapid phosphorylation of NF-κB and upregulated the expression of MMP-9, inhibited the rapid phosphorylation of NF-κB and reduced MMP-9 by receptor for advanced glycation end products (RAGE) inhibitor that prevented HMGB1-induced cell invasion in vitro, which demonstrated that the biological significance of HMGB1/RAGE is key to the second, but not the first, phase of NF-κB phosphorylation in tumor cells. HSP70 triggered a positive feedback loop of NF-κB activation in H22 cells. The second phase of NF-κB phosphorylation mediated by HSP70 is implicated in the increase of tumor cell malignant invasion. 23869896 Brain natriuretic peptide and NT-proBNP levels reflect pulmonary artery systolic pressure in trekkers at high altitude. Our objective was to evaluate the utility of the natriuretic peptides BNP (brain natriuretic peptide) and NT-proBNP as markers of pulmonary artery systolic pressure (PASP) in trekkers ascending to high altitude (HA). 20 participants had BNP and NT-proBNP assayed and simultaneous echocardiographic assessment of PASP performed during a trek to 5150 m. PASP increased significantly (p=0.006) with ascent from 24+/-4 to 39+/-11 mm Hg at 5150 m. At 5150 m those with a PASP>/=40 mm Hg (n=8) (versus those with PASP<40 mm Hg) had higher post-exercise BNP (pg/ml): 54.5+/-36 vs 13.4+/-17 (p=0.012). Their resting BNP at 5150 m was also higher: 57.3+/-43.4 vs 12.6+/-13 (p=0.017). In those with a pathological (>/=400 pg/ml) rise in NT-proBNP at 5150 m (n=4) PASP was significantly higher: 45.9+/-7.5 vs 32.2+/-6.2 mm Hg (p=0.015). BNP and NT-proBNP may reflect elevated PASP, a central feature of high altitude pulmonary oedema, at HA. 23389245 Aurora kinase inhibitor AZD1152 has an additional effect of platinum on a sequential application at the human ovarian cancer cell line SKOV3. The treatment of ovarian tumors is carried out with platinum medicine which can lead to incompatibilities or resistances. Thus, it is of great interest to check new medicine suitability for its application. AZD1152 is an Aurora kinase inhibitor predominantly works against Aurora kinase B involved in the chromosome segregation. Cells become polyploidy and reduce the proliferation by this impairment. To investigate whether AZD1152, may play a role in the treatment of ovarian carcinoma we serving it to the cisplatinum-resistant cell line SKOV3 alone and in combination with platinum. We look at the proliferation, the ploidy, the phases of cell cycle and the apoptosis activity of the cells. We could show that the combination of both medicines in the preclinical experiment produces a working advantage. 22968670 Palatal implant versus zygoma plate anchorage for distalization of maxillary posterior teeth. This study aimed to examine the skeletal, dental, and soft tissue effects of the implant-supported pendulum (ISP) and the zygoma anchorage system (ZAS) used for the distalization of maxillary posterior teeth. Among 30 patients showing Angle class II malocclusion, 15 patients with a mean age of 14.3±1.6 years and treated with ISP were included in the first group; 15 patients with a mean age of 14.7±2.5 years and treated with ZAS were included in the second group. The predistalization and postdistalization lateral cephalograms were analysed. Statistical evaluation was carried out using SPSS. Point A and upper incisors protruded in the ISP group, retruded in the ZAS group. Upper posterior teeth were distalized in both groups, but more in the ZAS group. Significant differences were observed between the groups for the sagittal movements of Point A, incisors, and posterior teeth. Overbite decreased in the ISP group, overjet decreased in the ZAS group, upper and lower lips retruded only in the ZAS group. Both methods provided absolute anchorage for distalization of posterior teeth, but the skeletal and soft tissue outcome and distalization obtained was greater in the ZAS group. Both methods can be used as alternatives to extraoral traction and conventional molar distalization appliances with different patient requirements. 23863153 Nutrients and growth factors in mTORC1 activation. Growth factors and nutrients regulate the mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] by different mechanisms. The players that link growth factors and mTORC1 activation have been known for several years and mouse models have validated its relevance for human physiology and disease. In contrast with the picture for growth factor signalling, the means by which nutrient availability leads to mTORC1 activation have remained elusive until recently, with the discovery of the Rag GTPases upstream of mTORC1. The Rag GTPases recruit mTORC1 to the outer lysosomal surface, where growth factor signalling and nutrient signalling converge on mTORC1 activation. A mouse model of constitutive RagA activity has revealed qualitative differences between growth-factor- and nutrient-dependent regulation of mTORC1. Regulation of mTORC1 activity by the Rag GTPases in vivo is key for enduring early neonatal starvation, showing its importance for mammalian physiology. 23950929 The Transmembrane Protein of the Human Endogenous Retrovirus - K (HERV-K) Modulates Cytokine Release and Gene Expression. Numerous copies of endogenous retroviruses are present in the genome of mammals including man. Although most of them are defective, some, e.g., the human endogenous retroviruses HERV-K, were found to be expressed under certain physiological conditions. For instance, HERV-K is expressed in germ cell tumours and melanomas as well as in the placenta. Most exogenous retroviruses including the human immunodeficiency virus HIV-1 induce severe immunodeficiencies and there is increasing evidence that the transmembrane envelope (TM) proteins of these retroviruses may be involved. We show here that HERV-K particles released from a human teratocarcinoma cell line, a recombinant TM protein and a peptide corresponding to a highly conserved so-called immunosuppressive domain in the TM protein of HERV-K inhibit the proliferation of human immune cells, induce modulation of the expression of numerous cytokines, and modulate the expression of cellular genes as detected by a microarray analysis. The changes in cytokine release and gene expression induced by the TM protein of HERV-K are similar to those found previously induced by the TM protein of HIV-1. These data suggest that the mechanism of immunosuppression may be similar for different retroviruses and that the expression of the TM protein in tumours and in the placenta may suppress immune responses and thus prevent rejection of the tumour and the embryo. 23155049 Inhibition of glycogen synthase kinase-3 ameliorates β-amyloid pathology and restores lysosomal acidification and mammalian target of rapamycin activity in the Alzheimer disease mouse model: in vivo and in vitro studies. Accumulation of β-amyloid (Aβ) deposits is a primary pathological feature of Alzheimer disease that is correlated with neurotoxicity and cognitive decline. The role of glycogen synthase kinase-3 (GSK-3) in Alzheimer disease pathogenesis has been debated. To study the role of GSK-3 in Aβ pathology, we used 5XFAD mice co-expressing mutated amyloid precursor protein and presenilin-1 that develop massive cerebral Aβ loads. Both GSK-3 isozymes (α/β) were hyperactive in this model. Nasal treatment of 5XFAD mice with a novel substrate competitive GSK-3 inhibitor, L803-mts, reduced Aβ deposits and ameliorated cognitive deficits. Analyses of 5XFAD hemi-brain samples indicated that L803-mts restored the activity of mammalian target of rapamycin (mTOR) and inhibited autophagy. Lysosomal acidification was impaired in the 5XFAD brains as indicated by reduced cathepsin D activity and decreased N-glycoyslation of the vacuolar ATPase subunit V0a1, a modification required for lysosomal acidification. Treatment with L803-mts restored lysosomal acidification in 5XFAD brains. Studies in SH-SY5Y cells confirmed that GSK-3α and GSK-3β impair lysosomal acidification and that treatment with L803-mts enhanced the acidic lysosomal pool as demonstrated in LysoTracker Red-stained cells. Furthermore, L803-mts restored impaired lysosomal acidification caused by dysfunctional presenilin-1. We provide evidence that mTOR is a target activated by GSK-3 but inhibited by impaired lysosomal acidification and elevation in amyloid precursor protein/Aβ loads. Taken together, our data indicate that GSK-3 is a player in Aβ pathology. Inhibition of GSK-3 restores lysosomal acidification that in turn enables clearance of Aβ burdens and reactivation of mTOR. These changes facilitate amelioration in cognitive function. 23932335 Hormone receptor loss in endometrial carcinoma curettage predicts lymph node metastasis and poor outcome in prospective multicentre trial. Preoperative histologic examination of tumour tissue is essential when deciding if endometrial cancer surgery should include lymph node sampling. We wanted to investigate if biomarkers could improve prediction of lymph node metastasis and outcome. Curettage specimens from 832 endometrial carcinoma patients prospectively recruited from 10 centres in the MoMaTEC trial (Molecular Markers in Treatment of Endometrial Cancer) were investigated for hormone receptor and p53 status. Eighteen per cent of tumours were double negative for oestrogen- and progesterone receptors (ER/PR loss), 24% overexpressed p53. Pathologic expression of all markers correlated with nodal metastases, high FIGO (Federation International of Gynecology and Obstetrics) stage, non-endometrioid histology, high grade and poor prognosis (all P<0.001). ER/PR loss independently predicted lymph node metastasis (odds ratios (OR) 2.0, 95% confidence interval (CI) 1.1-3.7) adjusted for preoperative curettage histology and predicted poor disease-specific survival adjusted for age, FIGO stage, histologic type, grade and myometrial infiltration (hazard ratio (HR) 2.3, 95% CI 1.4-3.9). For lymph node negative endometrioid tumours, ER/PR loss influenced survival independent of grade. Double negative hormone receptor status in endometrial cancer curettage independently predicts lymph node metastasis and poor prognosis in a prospective multicentre setting. Implementing hormone receptor status to improve risk-stratification for selecting patients unlikely to benefit from lymphadenectomy seems justified. 23694929 Down-regulation of Smad3 Accelerates Palatal Wound Repair. Smad3-deficient mice exhibit accelerated re-epithelialization and tissue remodeling during palatal wound repair. In addition, transforming growth factor beta 1 (TGF-β1) and other inflammatory factors are down-regulated compared with those in wild-type mice. The aim of this study was to examine whether targeting of Smad3 with small interfering RNA (siRNA) accelerates wound-healing and inhibits wound contraction in palatal mucoperiosteal wounds. An initial histological examination of wound closure in mouse palates treated with Smad3-targeted siRNA vs. a scrambled siRNA found that wound-healing was accelerated when levels of Smad3 were decreased. Furthermore, with real-time PCR, mRNA levels of Smad3, TGF-β1, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1α (MIP-1α) were found to be significantly down-regulated in palatal tissue treated with Smad3-targeted siRNA vs. a control siRNA. Protein and mRNA levels of α-smooth-muscle actin (α-SMA), type I collagen, and fibronectin were also lower in palates treated with Smad3-targeted siRNA vs. control siRNA. Taken together, these results indicate that down-regulation of Smad3 expression by siRNA can accelerate wound-healing and may inhibit wound contraction. Therefore, siRNA-targeted inhibition of Smad3 may represent a valuable therapeutic tool for palatal mucoperiosteal wound-healing. 23278451 U1 snRNP Control of 3´-End Processing and the Therapeutic Application of U1 Inhibition Combined with RNA Interference. U1 snRNP (U1 small nuclear ribonucleoprotein) is a well-characterized splicing factor. Besides, when U1 snRNP binds close to a putative polyadenylation site, mostly located in introns, it prevents premature cleavage and polyadenylation and controls the length of most cellular mRNAs. On the other hand, U1 snRNP binding close to the 3´-end of some mRNAs, inhibits polyadenylation and, therefore, gene expression. The inhibition of polyadenylation by U1 snRNP is the basis of U1i (U1 snRNP-based inhibition), a technique used to inhibit gene expression. U1i consists of the expression of a U1 snRNP modified to interact with a target mRNA and inhibit target gene expression. U1i has been used to inhibit the expression of reporter or endogenous genes both in tissue culture and in animal models. Furthermore, combination of U1i and RNA interference (RNAi) results in synergistic increased inhibitions which allow the dose of inhibitors to be decreased whilst at the same time obtaining good inhibitions with fewer unwanted secondary effects. The combination of RNAi and U1i is of special interest for antiviral therapy, as a functional decrease of the expression of replicative viral RNAs may require high inhibition and the combination of two or more inhibitors should decrease the possibility of escape mutants resistant to treatment. In fact, a therapy with U1i combined with RNAi is currently being developed for the treatment of HBV infections. We believe that this review will clarify the hallmarks of U1i technology and will encourage many laboratories to use U1i for functional studies and therapeutic applications. 23941474 Effectiveness of lithium in subjects with treatment-resistant depression and suicide risk: a protocol for a randomised, independent, pragmatic, multicentre, parallel-group, superiority clinical trial. Data on therapeutic interventions following deliberate self harm (DSH) in patients with treatment-resistant depression (TRD) are very scant and there is no unanimous consensus on the best pharmacological option for these patients. There is some evidence that lithium treatment might be effective in reducing the risk of completed suicide in adult patients with unipolar affective disorders, however no clear cut results have been found so far. The primary aim of the present study is to assess whether adding lithium to standard therapy is an effective treatment strategy to reduce the risk of suicidal behaviour in long term treatment of people with TRD and previous history of DSH. We will carry out a randomised, parallel group, assessor-blinded superiority clinical trial. Adults with a diagnosis of major depression, an episode of DSH in the previous 12 months and inadequate response to at least two antidepressants given sequentially at an adequate dose for an adequate time for the current depressive episode will be allocated to add lithium to current therapy (intervention arm) or not (control arm). Following randomisation, treatment is to be taken daily for 1 year unless some clear reason to stop develops. Suicide completion and acts of DSH during the 12 months of follow-up will constitute the composite primary outcome. To preserve outcome assessor blindness, an independent adjudicating committee, blind to treatment allocation, will anonymously review all outcome events. The results of this study should indicate whether lithium treatment is associated with lower risk of completed suicide and DSH in adult patients with treatment resistant unipolar depression, who recently attempted suicide. ClinicalTrials.gov identifier: NCT00927550. 23857642 Current Perspectives: Calcium Phosphate Nanocoatings and Nanocomposite Coatings in Dentistry. The purpose of coatings on implants is to achieve some or all of the improvements in biocompatibility, bioactivity, and increased protection from the release of harmful or unnecessary metal ions. During the last decade, there has been substantially increased interest in nanomaterials in biomedical science and dentistry. Nanocomposites can be described as a combination of two or more nanomaterials. By this approach, it is possible to manipulate mechanical properties, such as strength and modulus of the composites, to become closer to those of natural bone. This is feasible with the help of secondary substitution phases. Currently, the most common composite materials used for clinical applications are those selected from a handful of available and well-characterized biocompatible ceramics and natural and synthetic polymers. This approach is currently being explored in the development of a new generation of nanocomposite coatings with a wider range of oral and dental applications to promote osseointegration. The aim of this review is to give a brief introduction into the new advances in calcium phosphate nanocoatings and their composites, with a range of materials such as bioglass, carbon nanotubes, silica, ceramic oxide, and other nanoparticles being investigated or used in dentistry. 23670120 Challenges and Limitations in the Interpretation of Systematic Reviews: Making Sense of Clopidogrel and CYP2C19 Pharmacogenetics. From 2010 to 2012, nine systematic reviews reported highly variable conclusions regarding the association between carriage of a cytochrome P450 2C19 loss-of-function allele and the risk of adverse cardiovascular (CV) events in individuals using clopidogrel. Possible contributors to the variable findings include differences in patient populations, CV end points, and statistical models utilized by the systematic reviews, as well as unexplained heterogeneity, inconsistent/incomplete reporting, and risk of publication bias with respect to the primary studies. 23714575 PDGF-C: a new performer in the neurovascular interplay. The importance of neurovascular crosstalk in development, normal physiology, and pathologies is increasingly being recognized. Although vascular endothelial growth factor (VEGF), a prototypic regulator of neurovascular interaction, has been studied intensively, defining other important regulators in this process is warranted. Recent studies have shown that platelet-derived growth factor C (PDGF-C) is both angiogenic and a neuronal survival factor, and it appears to be an important component of neurovascular crosstalk. Importantly, the expression pattern and functional properties of PDGF-C and its receptors differ from those of VEGF, and thus the PDGF-C-mediated neurovascular interaction may represent a new paradigm of neurovascular crosstalk. 23618837 Is a diagnostic system based exclusively on agar gel immunodiffusion adequate for controlling the spread of equine infectious anaemia? To improve the efficiency of the National equine infectious anaemia (EIA) surveillance program in Italy, a three-tiered diagnostic system has been adopted. This procedure involves initial screening by ELISA (Tier 1) with test-positive samples confirmed by the agar gel immunodiffusion test (AGIDT) (Tier 2) and, in the case of ELISA positive/AGIDT negative results, final determination by immunoblot (IB) (Tier 3). During this evaluation, 74,880 samples, principally collected from two Regions of Central Italy (Latium and Abruzzo) were examined, with 44 identified as negative in AGIDT but positive in both ELISA and IB. As the majority of these reactions occurred in mules, an observational study was conducted in this hybrid equid species to investigate if there is a correlation between plasma-associated viral loads and serological reactivity, to test the hypothesis that false-negative or very weak positive AGIDT results are associated with elite control of EIA virus (EIAV) replication accompanied by reduced transmission risks. The study animals consisted of 5 mules with positive AGIDT readings, along with another 5 giving negative or very weak positive results in this test. All mules were seropositive in Elisa and IB. Samples were collected routinely during an initial 56-day observation period, prior to dexamethasone treatment lasting 10 days, to determine the effect of immune suppression (IS) on clinical, humoral and virological responses. All mules were monitored for a further 28 days from day 0 of IS. None of the animals experienced relevant clinical responses before IS and there were no significant changes in antibody levels in ELISA, IB or AGIDT. However, plasma-associated viral-RNA (vRNA) loads, as determined using TaqMan(®) based RT-PCR, showed unexpectedly high sample to sample variation in all mules, demonstrating host-mediated control of viral replication is not constant over time. Furthermore, there was no apparent correlation between vRNA loads and antibody reactivity in serological tests. Analysis of PCR products established all mules were infected with viruses possessing nucleotide sequence similarity, varying from 77 to 96%, to previously identified European EIAV strains. Following IS, all mules showed increases in plasma-associated vRNA loads, suggesting control of EIAV replication is mediated by immune responses in this hybrid species. However, only three mules showed anamnestic humoral responses to rises in viral loads, as defined by at least a four-fold increase in ELISA titre, while two remained AGIDT-negative. This study demonstrates that viral loads in equids with consistent ELISA/IB positive-AGIDT negative to very weak positive test results (Group N) can be equivalent to those that produce clearly positive results in all three serologic tests (Group P). Therefore, such animals do not pose inherently lower risks for the transmission of EIAV. Consequently, the exclusive use of the AGIDT, as prescribed by the World Organization of Animal Health (OIE) for diagnosis of EIA prior to the international movement of horses, can report as negative some EIAV-infected equids. These results dramatically underscore the necessity of combining the specificity of AGIDT with tests with higher sensitivity, such as the ELISA and the power of the IB to enhance the accuracy of EIA diagnosis. 23666861 Stroke and obstructive sleep apnea: a review. Obstructive sleep apnea (OSA) has been found to be an independent risk factor for stroke in large epidemiological studies. The mechanisms underlying this relationship have been investigated over the past 2-3 decades, with a particular focus on identifying pathophysiological pathways and risk modification strategies. Despite the advancements made, the specific understanding of the implicated mechanisms is still limited. This brief review focuses on presenting some of the epidemiological evidence of the linkage between OSA and stroke, discussing mechanistic pathways and the potential effect of OSA treatment in modulating the risk for stroke in these patients. Future directions for research in this field are also discussed. 23848554 MicroRNAome profiling in benign and malignant neurofibromatosis type 1-associated nerve sheath tumors: evidences of PTEN pathway alterations in early NF1 tumorigenesis. Neurofibromatosis type 1 (NF1) is a common dominant tumor predisposition syndrome affecting 1 in 3,500 individuals. The hallmarks of NF1 are the development of peripheral nerve sheath tumors either benign (dermal and plexiform neurofibromas) or malignant (MPNSTs). To comprehensively characterize the role of microRNAs in NF1 tumorigenesis, we analyzed 377 miRNAs expression in a large panel of dermal and plexiform neurofibromas, and MPNSTs. The most significantly upregulated miRNA in plexiform neurofibromas was miR-486-3p that targets the major tumor suppressor gene, PTEN. We confirmed PTEN downregulation at mRNA level. In plexiform neurofibromas, we also report aberrant expression of four miRNAs involved in the RAS-MAPK pathway (miR-370, miR-143, miR-181a, and miR-145). In MPNSTs, significant deregulated miRNAs were involved in PTEN repression (miR-301a, miR-19a, and miR-106b), RAS-MAPK pathway regulation (Let-7b, miR-195, and miR-10b), mesenchymal transition (miR-200c, let-7b, miR-135a, miR-135b, and miR-9), HOX genes expression (miR-210, miR-196b, miR-10a, miR-10b, and miR-9), and cell cycle progression (miR-195, let-7b, miR-20a, miR-210, miR-129-3p, miR-449a, and miR-106b). We confirmed the implication of PTEN in genesis of plexiform neurofibromas and MPNSTs in NF1. Markedly deregulated miRNAs might have potential diagnostic or prognostic value and could represent novel strategies for effective pharmacological therapies of NF1 tumors. 23350737 Chiral bicyclic tetramates as non-planar templates for chemical library synthesis. Chemoselective Dieckmann cyclization reactions may be used on oxazolidine and thiazolidine templates derived from various aldehydes to access bicyclic tetramates, which have potential as templates for chemical library construction. Bioassay against Staphylococcus aureus and Escherichia coli showed that these systems have little or no intrinsic antibacterial bioactivity. 23637098 Microbial community structure and functioning along metal pollution gradients. Toxic effects of heavy metals on soil microorganisms have been confirmed in a number of laboratory studies. However, most real-field studies do not allow for strong general conclusions due to a range of problems, such as pseudoreplication and confounding factors, which are almost impossible to control for with the most commonly used polluted versus unpolluted or random sampling designs. Effects of metal contamination on soil microbial community traits were measured along 2 pollution gradients in southern Poland. Employing an experimental regression design, using 2 separate gradients, the authors aimed to control for effects of soil properties and beta-diversity of microbial communities. General microbial activity was measured as soil basal respiration rate and substrate-induced respiration, while microbial functional and structural diversity were analyzed with community-level physiological profiles and phospholipid fatty acid patterns, respectively. Metal concentrations were normalized to their toxicity and integrated in a toxicity index (TI). Microbial activity (basal and substrate-induced respiration) decreased in both gradients with increasing TI. Community-level physiological profiles for fungi correlated positively with TI, but no impact of TI on the community-level physiological profiles of bacteria was observed. The phospholipid fatty acids a:15 and i:17 were positively correlated with TI, whereas 16:1ω9 and 18:2ω9 were negatively correlated with TI. The use of 2 gradients (Olkusz and Miasteczko Śląskie) allowed the authors to reveal a clear effect of pollution on general microbial structure and activities, even though they were not able to control completely for all confounding factors. Soil pH, organic matter content, and nutrient level appeared to be at least as important as TI in determining microbial community structure and activities. Environ Toxicol Chem 2013;32:1992-2002. © 2013 SETAC. 23934269 The LIVE Network: A Music-Based Messaging Program to Promote ART Adherence Self-Management. We developed and pilot-tested the efficacy, acceptability, and feasibility of a music program, The LIVE Network (LN), compared to standard care on outcomes of ART adherence, clinical indicators, and self-efficacy. The study was powered to detect differences at p < 0.1. We enrolled and followed 77 participants for 12 weeks (T3). Mean monthly pill counts (PC) declined over time in both groups. Although not significant, the LN had higher PC and a larger proportion had plasma antiretroviral trough levels within therapeutic range. The LN group did have significantly (p < 0.1) increased levels of adherence self-efficacy and decrease in viral loads. 23537377 Lipopolysaccharide Interactions of C-Terminal Peptides from Human Thrombin. Interactions with bacterial lipopolysaccharide (LPS), both in aqueous solution and in lipid membranes, were investigated for a series of amphiphilic peptides derived from the C-terminal region of human thrombin, using ellipsometry, dual polarization interferometry, fluorescence spectroscopy, circular dichroism (CD), dynamic light scattering, and z-potential measurements. The ability of these peptides to block endotoxic effects caused by LPS, monitored through NO production in macrophages, was compared to peptide binding to LPS and its endotoxic component lipid A, and to size, charge, and secondary structure of peptide/LPS complexes. While the antiendotoxic peptide GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE) displayed significant binding to both LPS and lipid A, so did two control peptides with either selected D-amino acid substitutions or with maintained composition but scrambled sequence, both displaying strongly attenuated antiendotoxic effects. Hence, the extent of LPS or lipid A binding is not the sole discriminant for the antiendotoxic effect of these peptides. In contrast, helix formation in peptide/LPS complexes correlates to the antiendotoxic effect of these peptides and is potentially linked to this functionality. Preferential binding to LPS over lipid membrane was furthermore demonstrated for these peptides and preferential binding to the lipid A moiety within LPS inferred. 23561084 Improved sample preparation and rapid UHPLC analysis of SO2 binding carbonyls in wine by derivatisation to 2,4-dinitrophenylhydrazine. Sulphur dioxide (SO2) is essential for the preservation of wines. The presence of SO2 binding compounds in musts and wines may limit sulphite efficacy leading to higher total SO2 additions, which may exceed SO2 limits permitted by law and pose health risks for sensitive individuals. An improved method for the quantification of significant wine SO2 binding compounds is presented that applies a novel sample treatment approach and rapid UHPLC separation. Glucose, galacturonic acid, alpha-ketoglutarate, pyruvate, acetoin and acetaldehyde were derivatised with 2,4-dinitrophenylhydrazine and separated using a solid core C18 phase by ultra high performance liquid chromatography. Addition of EDTA to samples prevented de novo acetaldehyde formation from ethanol oxidation. Optimised derivatisation duration enhanced reproducibility and allowed for glucose and galacturonic acid quantification. High glucose residues were found to interfere with the recovery of other SO2 binders, but practical SO2 concentrations and red wine pigments did not affect derivatisation efficiency. The calibration range, method accuracy, precision and limits of detection were found to be satisfactory for routine analysis of SO2 binders in wines. The current method represents a significant improvement in the comprehensive analysis of SO2 binding wine carbonyls. It allows for the quantification of major SO2 binders at practical analyte concentrations, and uses a simple sample treatment method that prevents treatment artifacts. Equipment utilisation could be reduced by rapid LC separation while maintaining analytical performance parameters. The improved method will be a valuable addition for the analysis of total SO2 binder pools in oenological samples. 23924164 Children's voices - Differentiating a child perspective from a child's perspective. Abstract Objective: The aim of this paper was to discuss differences between having a child perspective and taking the child's perspective based on the problem being investigated. Methods: Conceptual paper based on narrative review. Results: The child's perspective in research concerning children that need additional support are important. The difference between having a child perspective and taking the child's perspective in conjunction with the need to know children's opinions has been discussed in the literature. From an ideological perspective the difference between the two perspectives seems self-evident, but the perspectives might be better seen as different ends on a continuum solely from an adult's view of children to solely the perspective of children themselves. Depending on the research question, the design of the study may benefit from taking either perspective. In this article, we discuss the difference between the perspectives based on the problem being investigated, children's capacity to express opinions, environmental adaptations and the degree of interpretation needed to understand children's opinions. Conclusion: The examples provided indicate that children's opinions can be regarded in most research, although to different degrees. 23837617 Influence of Nucleation Precursors on the Reaction Kinetics of Methanol with the OH Radical. The mechanism and kinetics of the reaction of methanol with the OH radical in the absence and presence of common atmospheric nucleation precursors (H2O, NH3, and H2SO4) have been investigated using different computational methods. The statistical Gibb's free energy of formation has been calculated using M06-2X/6-311++G(3df,3pd) in order to assess cluster stability. Methanol is found to have an unfavorable interaction with water and ammonia but form stable complexes with sulfuric acid. The reaction kinetics with the OH radical and methanol with or without the presence of nucleation precursors has been studied using a CCSD(T)-F12a/VDZ-F12//BH&HLYP/aug-cc-pVTZ∥Eckart methodology, and it is found that the presence of water is unlikely to change the overall reaction rate and mechanism of hydrogen abstraction from methanol. Ammonia is able to both enhance the reaction rate and change the reaction mechanism, but due to a very weak interaction with methanol, this process is unlikely to occur under atmospheric conditions. Sulfuric acid is, in contrast, found to be able to act as a stabilizing factor for methanol and is able to change the reaction mechanism. These findings show the first indications that nucleation precursors such as ammonia and sulfuric acid are able to alter the reaction mechanism of an atmospherically relevant organic compound. 23949580 Time trends in mortality rates in type 1 diabetes from 2002 to 2011. The aim of this study was to estimate absolute and relative mortality rates in patients with type 1 diabetes at the Steno Diabetes Centre relative to the general Danish background population. Patients with type 1 diabetes (n = 4,821) were followed from 1 January 2002 until 1 January 2011, with death from any cause as the main outcome. Poisson regression was used to model mortality rates by age, diabetes duration and calendar time, according to sex. In the period 2002-2010, a total of 673 deaths (402 men, 271 women) occurred in the study population during 33,847 years of follow-up of type 1 diabetes. The predominant cause of death in patients with type 1 diabetes was cardiovascular disease. Mortality rates were highest among those with the lowest age at onset, particularly men. The mortality rate in the diabetic population decreased over that time period by 6.6% and 4.8% per year in men and women, respectively; this was substantially greater than the decrease in mortality rates in the background population. The decline in standard mortality rate was 4.3% per year in men and 2.6% per year in women. Patients who did not develop nephropathy had only slightly elevated mortality rates compared with the background population. Despite advances in care, mortality rates in the past decade continue to be greater in patients with type 1 diabetes than in those without diabetes; however, the mortality rate in patients decreased over the study period faster than that of the background population. Nephropathy seems to be the main driver of the excess mortality. 23602374 Tapping insertional torque allows prediction for better pedicle screw fixation and optimal screw size selection. There is currently no reliable technique for intraoperative assessment of pedicle screw fixation strength and optimal screw size. Several studies have evaluated pedicle screw insertional torque (IT) and its direct correlation with pullout strength. However, there is limited clinical application with pedicle screw IT as it must be measured during screw placement and rarely causes the spine surgeon to change screw size. To date, no study has evaluated tapping IT, which precedes screw insertion, and its ability to predict pedicle screw pullout strength. The objective of this study was to investigate tapping IT and its ability to predict pedicle screw pullout strength and optimal screw size. In vitro human cadaveric biomechanical analysis. Twenty fresh-frozen human cadaveric thoracic vertebral levels were prepared and dual-energy radiographic absorptiometry scanned for bone mineral density (BMD). All specimens were osteoporotic with a mean BMD of 0.60±0.07 g/cm(2). Five specimens (n=10) were used to perform a pilot study, as there were no previously established values for optimal tapping IT. Each pedicle during the pilot study was measured using a digital caliper as well as computed tomography measurements, and the optimal screw size was determined to be equal to or the first size smaller than the pedicle diameter. The optimal tap size was then selected as the tap diameter 1 mm smaller than the optimal screw size. During optimal tap size insertion, all peak tapping IT values were found to be between 2 in-lbs and 3 in-lbs. Therefore, the threshold tapping IT value for optimal pedicle screw and tap size was determined to be 2.5 in-lbs, and a comparison tapping IT value of 1.5 in-lbs was selected. Next, 15 test specimens (n=30) were measured with digital calipers, probed, tapped, and instrumented using a paired comparison between the two threshold tapping IT values (Group 1: 1.5 in-lbs; Group 2: 2.5 in-lbs), randomly assigned to the left or right pedicle on each specimen. Each pedicle was incrementally tapped to increasing size (3.75, 4.00, 4.50, and 5.50 mm) until the threshold value was reached based on the assigned group. Pedicle screw size was determined by adding 1 mm to the tap size that crossed the threshold torque value. Torque measurements were recorded with each revolution during tap and pedicle screw insertion. Each specimen was then individually potted and pedicle screws pulled out "in-line" with the screw axis at a rate of 0.25 mm/sec. Peak pullout strength (POS) was measured in Newtons (N). The peak tapping IT was significantly increased (50%) in Group 2 (3.23±0.65 in-lbs) compared with Group 1 (2.15±0.56 in-lbs) (p=.0005). The peak screw IT was also significantly increased (19%) in Group 2 (8.99±2.27 in-lbs) compared with Group 1 (7.52±2.96 in-lbs) (p=.02). The pedicle screw pullout strength was also significantly increased (23%) in Group 2 (877.9±235.2 N) compared with Group 1 (712.3±223.1 N) (p=.017). The mean pedicle screw diameter was significantly increased in Group 2 (5.70±1.05 mm) compared with Group 1 (5.00±0.80 mm) (p=.0002). There was also an increased rate of optimal pedicle screw size selection in Group 2 with 9 of 15 (60%) pedicle screws compared with Group 1 with 4 of 15 (26.7%) pedicle screws within 1 mm of the measured pedicle width. There was a moderate correlation for tapping IT with both screw IT (r=0.54; p=.002) and pedicle screw POS (r=0.55; p=.002). Our findings suggest that tapping IT directly correlates with pedicle screw IT, pedicle screw pullout strength, and optimal pedicle screw size. Therefore, tapping IT may be used during thoracic pedicle screw instrumentation as an adjunct to preoperative imaging and clinical experience to maximize fixation strength and optimize pedicle "fit and fill" with the largest screw possible. However, further prospective, in vivo studies are necessary to evaluate the intraoperative use of tapping IT to predict screw loosening/complications. 23532633 Implication of circulating omentin-1 level on the arterial stiffening in type 2 diabetes mellitus. Omentin-1 is an adipokine implicated in diabetes, inflammation, and cardiovascular disease. However, no prospective studies have examined the impact of circulating omentin-1 levels on arterial stiffening in patients with type 2 diabetes mellitus. For the purpose of this study, we recruited 120 patients with type 2 diabetes mellitus and measured serum omentin-1, adiponectin, and high-sensitivity C-reactive protein levels as well as other cardiovascular risk factors. Arterial stiffness was assessed by brachial ankle pulse wave velocity (baPWV). An increase in the level of circulating omentin-1 over a period of 1 year was positively correlated with changes in levels of HbA1c and serum adiponectin as well as baPWV. Subjects with higher baseline serum omentin-1 levels tended to have a reduced arterial stiffness after 1 year (P for linear trend = 0.03). In the group with increased baPWV after 1 year, the magnitude of increase of circulating omentin-1 levels was significantly higher than in the group with a lower baPWV after 1 year (134.3 [16.6, 277.1] ng/mL vs. 15.9 [-67.6, 145.7] ng/mL, P < 0.01). Multiple stepwise logistic regression analysis revealed that an increase in systolic blood pressure and an increase in serum omentin-1 level were independently correlated with arterial stiffening, even after adjusting for other cardiovascular risk factors and medication history. Baseline serum omentin-1 levels can predict arterial stiffness changes occurring within a year. Furthermore, changes in serum omentin-1 levels after a year can function as independent markers of arterial stiffening in patients with type 2 diabetes mellitus. 23832962 11-Dehydrocorticosterone causes metabolic syndrome which is prevented when 11β-HSD1 is knocked-out in livers of male mice. Metabolic syndrome (MetS) is growing in importance with the rising levels of obesity, type 2 diabetes and insulin resistance. MetS shares many characteristics with Cushing's syndrome which has led to investigation of the link between excess glucocorticoids and MetS. Indeed, increased glucocorticoids from intracellular regeneration by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) drives insulin resistance and increases adiposity, but these metabolic changes are assumed to be due to increased circulating glucocorticoids. We hypothesised that increasing the substrate for 11β-HSD1 (11-dehydrocorticosterone, 11-DHC) would adversely affect metabolic parameters. We found that chronic administration of 11-DHC to male C57BL/6J mice, resulted in increased circulating glucocorticoids, and down-regulation of the hypothalamic-pituitary-adrenal (HPA) axis. This elevated 11β-HSD1 derived corticosterone led to increased body weight gain and adiposity and produced marked insulin resistance. Surprisingly liver-specific 11β-HSD1 knock-out (LKO) mice given 11-DHC did not show any of the adverse metabolic effects seen in wild-type mice. This occurred despite the 11-DHC administration resulting in elevated circulating corticosterone, presumably from adipose tissue. Mice with global deletion of 11β-HSD1 (GKO) were unaffected by treatment with 11-DHC, having no increase in circulating corticosterone and exhibiting no signs of metabolic impairment. Taken together, these data show that in the absence of 11β-HSD1 in the liver, mice are protected from the metabolic effects of 11-DHC administration, even though circulating glucocorticoids are increased. This implies that liver-derived intra-tissue glucocorticoids, rather than circulating glucocorticoids, contribute significantly to the development of MetS and suggest that local action within hepatic tissue mediates these effects. 23770704 Widespread DNA hypomethylation at gene enhancer regions in placentas associated with early-onset pre-eclampsia. Pre-eclampsia is a serious complication of pregnancy that can affect both maternal and fetal outcomes. Early-onset pre-eclampsia (EOPET) is a severe form of pre-eclampsia that is associated with altered physiological characteristics and gene expression in the placenta. DNA methylation is a relatively stable epigenetic modification to DNA that can reflect gene expression, and can provide insight into the mechanisms underlying such expression changes. This case-control study focused on DNA methylation and gene expression of whole chorionic villi samples from 20 EOPET placentas and 20 gestational age-matched controls from pre-term births. DNA methylation was also assessed in placentas affected by late-onset pre-eclampsia (LOPET) and normotensive intrauterine growth restriction (nIUGR). The Illumina HumanMethylation450 BeadChip was used to assess DNA methylation at >480 000 cytosine-guanine dinucleotide (CpG) sites. The Illumina HT-12v4 Expression BeadChip was used to assess gene expression of >45 000 transcripts in a subset of cases and controls. DNA methylation analysis by pyrosequencing was used to follow-up the initial findings in four genes with a larger cohort of cases and controls, including nIUGR and LOPET placentas. Bioinformatic analysis was used to identify overrepresentation of gene ontology categories and transcription factor binding motifs. We identified 38 840 CpG sites with significant (false discovery rate <0.01) DNA methylation alterations in EOPET, of which 282 had >12.5% methylation difference compared with the controls. Significant sites were enriched at the enhancers and low CpG density regions of the associated genes and the majority (74.5%) of these sites were hypomethylated in EOPET. EOPET, but not associated clinical features, such as intrauterine growth restriction (IUGR), presented a distinct DNA methylation profile. CpG sites from four genes relevant to pre-eclampsia (INHBA, BHLHE40, SLC2A1 and ADAM12) showed different extent of changes in LOPET and nIUGR. Genome-wide expression in a subset of samples showed that some of the gene expression changes were negatively correlated with DNA methylation changes, particularly for genes that are responsible for angiogenesis (such as EPAS1 and FLT1). Results could be confounded by altered cell populations in abnormal placentas. Larger sample sizes are needed to fully address the possibility of sub-profiles of methylation within the EOPET cohort. Based on DNA methylation profiling, we conclude that there are widespread DNA methylation alterations in EOPET that may be associated with changes in placental function. This property may provide a useful tool for early screening of such placentas. This study identifies DNA methylation changes at many loci previously reported to have altered gene expression in EOPET placentas, as well as in novel biologically relevant genes we confirmed to be differentially expressed. These results may be useful for DNA- methylation-based non-invasive prenatal diagnosis of at-risk pregnancies. 23560773 Unaccompanied refugee children--vulnerability and agency. The numbers of refugee adolescents that arrive in Europe without their families has increased in recent years, particularly in Sweden. Research has demonstrated that these children have high rates of mental health problems, particularly depression and post-traumatic stress disorder, during the first years after resettlement. Despite this, there are also indications that many of these unaccompanied children are resourceful and arrive with a clear vision of a positive future in the new country. Follow-up studies in the United States and Norway have indicated fairly good social outcomes in the long term. The education and care that unaccompanied minors receive during the first years after resettlement, together with their own drive to create a positive future, are key factors in their mental health and long-term adjustment. 23839909 Elevated serum B-cell activating factor (BAFF / BLyS) is associated with rising anti-dsDNA antibody levels and flare following B-cell depletion therapy in systemic lupus erythematosus. Objectives: To determine whether serum BAFF levels correlate with relapse or remission in patients with SLE following B-cell depletion therapy (BCDT) and to assess the relationship between serum BAFF, B-cell numbers, immunoglobulins and autoantibodies during active disease both before and after BCDT. Methods: 35 patients with active SLE underwent BCDT using rituximab, and were followed up with clinical and serological measures of disease activity for a minimum of 18 months. Serum BAFF was measured sequentially by ELISA before BCDT and during disease relapse or remission after B-cell repopulation. Results: Serum BAFF prior to BCDT was positively correlated with CD19+ B-cell numbers, and with IgG and IgA. Following BCDT and subsequent B-cell repopulation, BAFF levels were significantly higher during relapse, as compared with disease remission, and were significantly greater than at disease flare prior to BCDT. At relapse, serum BAFF was inversely correlated with B-cell numbers, with flare at lower B-cell numbers associated with highest BAFF levels. The correlations between serum BAFF and IgG and IgA were lost following BCDT but changes in serum BAFF positively correlated with changes in anti-dsDNA antibodies during relapse or remission after BCDT. Conclusion: The present data suggest a significant role for BAFF in driving disease flare after B-cell repopulation following BCDT. Sequential BCDT may promote ever increasing BAFF levels accompanied by rising anti-DNA antibodies and flare even at low B-cell numbers. Therefore, our data justifies the judicious use of BAFF blockade in a subgroup of lupus patients after BCDT. © 2013 American College of Rheumatology. 23294025 Effect of dietary interventions in the maintenance of normoglycaemia in glycogen storage disease type 1a: a systematic review and meta-analysis. Untreated glycogen storage disease (GSD)-1a patients experience hypoglycaemia and growth retardation. The present study examined the effects of dietary interventions on the maintenance of normoglycaemia. Clinical trials were identified from EMBASE (January 1980 to November 2011), MEDLINE (January 1948 to November 2011) and the Cochrane Central Register of Controlled Trials (2011, Issue 4). The intermittent administration of uncooked cornstarch was compared with: (i) continuous nocturnal feeding of dextrose; (ii) modified uncooked cornstarch; and (iii) dextrose and an uncooked cornstarch-dextrose mixture. One author extracted the data, and assessed the trial eligibility and risk of bias. Quality assessment and data extraction were conducted and checked independently. Of 41 articles retrieved, five controlled trials (49 participants) were identified with follow-up at 2 days to 14 years. Results from three nonrandomised controlled trials comparing uncooked cornstarch with continuous nocturnal feeding of dextrose were pooled in a meta-analysis based on a fixed-effect model. Twenty-six participants (three trials) receiving uncooked cornstarch showed a significant increase in blood glucose concentration: mean difference (MD) 0.62 mmol L(-1) [95% confidence interval (CI) = 0.23-1.00] (P = 0.002), 21 (two trials) increased serum insulin: MD 62.37 pmol L(-1) (95% CI = 32.19-92.55) (P < 0.0001) and 22 (three trials) increased plasma total cholesterol: MD 0.68 mmol L(-1) (95% CI = 0.17- 1.20) (P = 0.01) compared to continuous nocturnal feeding of dextrose. Twenty-eight subjects (three trials) showed decreased plasma lactate after nocturnal feeding: MD -0.42 mmol L(-1) (95% CI = -0.58 to -0.25) (P < 0.00001). Short- to long-term overnight intermittent administration of uncooked cornstarch prevents nocturnal hypoglycaemia in GSD-1a children more effectively than continuous nocturnal feeding of dextrose. 23465614 Anti-adipogenic diarylheptanoids from Alnus hirsuta f. sibirica on 3T3-L1 cells. A new diarylheptanoid, (5S)-hydroxy-1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl)-hepta-1E-en-3-one (1), was isolated along with seventeen known diarylheptanoids (2-18) from the methanol extract of Alnus hirsuta f. sibirica leaves using bioactivity-guided fractionation. Among the isolated compounds, compounds 1 and 2 and 4-12 reduced lipid accumulation dose-dependently in 3T3-L1 preadipocytes. Of the compounds active in the present assay system, the most potent compound 7, platyphyllonol-5-O-β-d-xylopyranoside, significantly suppressed the induction of peroxisome proliferator activated receptor γ (PPARγ and CCAAT/enhancer binding protein α (C/EBPα) protein expression, and inhibited adipocyte differentiation induced by troglitazone, a PPARγ agonist. It was demonstrated that compound 7 has anti-adipogenic activity mediated by the regulation of PPARγ dependent pathways. 23440918 The C-terminal extended serine residue is absolutely required in nosiheptide maturation. Serine qua non: Substitution of the extended Ser13 in the core peptide of nosiheptide by analogous amino acids prevented enamide dealkylation of the terminal residue for nosiheptide maturation. 23908638 "Early Psychosis" as a mirror of biologist controversies in post-war German, Anglo-Saxon, and Soviet Psychiatry. The English term "early psychosis" was coined in the 1930s to refer to feelings of irritability, loss of concentration, hypochondriac ideas, moodiness, and lassitude that were seen to precede the onset of clear-cut hallucinations and delusions. The history of thinking about "early psychosis" under names such as "latent," "masked," "mild," "simple" or "sluggish" schizophrenia before World War II and afterwards on the different sides of the Wall and the Iron Curtain reveals "early psychosis" as a mirror of quite aged international biologist controversies that are still alive today and to the same extent as they are misunderstood, are influential in their implications in today's psychiatry. 23800668 Molecular characterization of major and minor rDNA repeats and genetic variability assessment in different species of mahseer found in North India. Relationship among the mahseer species (Family: Cyprinidae) has long been debated in fish systematics. Present study concentrates on the nature of the phylogenetic relationship among the five mahseer species using the sequence of major ribosomal DNA (45S rDNA). We have covered rDNA sequence of approximately 5.2kb per individual, 26.0kb per species and 130.0kb as a whole. We also characterized the 45S and 5S rDNA regions with respect to their nucleotide composition. For phylogenetic analyses, nucleotide sequences were divided into four datasets. First and second datasets contained 18S rDNA and ITS1 sequence, whereas third and fourth datasets consisted of ITS2 and complete 18S-ITS1-5.8S-ITS2-28S, respectively. The NJ tree was constructed for all the datasets. The mahseer species under study formed a monophyletic group well separated from the outgroup species. Similarly, the individuals of Neolissochilus hexagonolepis form monophyletic group with Tor species, indicating Neolissochilus as a sister genus of Tor. The findings from the present study provide greater insights into taxonomic status of mahseer, and set the stage for future investigations dealing with phylo-geography, taxonomy, conservation and co-evolution within this interesting and important group of fish. 23864683 D1 Dopamine Receptor-Mediated LTP at GABA Synapses Encodes Motivation to Self-Administer Cocaine in Rats. Enhanced motivation to take drugs is a central characteristic of addiction, yet the neural underpinning of this maladaptive behavior is still largely unknown. Here, we report a D1-like dopamine receptor (DRD1)-mediated long-term potentiation of GABAA-IPSCs (D1-LTPGABA) in the oval bed nucleus of the stria terminalis that was positively correlated with motivation to self-administer cocaine in rats. Likewise, in vivo intra-oval bed nucleus of the stria terminalis DRD1 pharmacological blockade reduced lever pressing for cocaine more effectively in rats showing enhanced motivation toward cocaine. D1-LTPGABA resulted from enhanced function and expression of G-protein-independent DRD1 coupled to c-Src tyrosine kinases and required local release of neurotensin. There was no D1-LTPGABA in rats that self-administered sucrose, in those with limited cocaine self-administration experience, or in those that received cocaine passively (yoked). Therefore, our study reveals a novel neurophysiological mechanism contributing to individual motivation to self-administer cocaine, a critical psychobiological element of compulsive drug use and addiction. 23683844 Incidence patterns and trends of malignant gonadal and extragonadal germ cell tumors in Germany, 1998-2008. Malignant gonadal (GGCT) and extragonal germ cell tumors [GCT (EGCT)] are thought to originate from primordial germ cells. In contrast to well reported population-based data of GGCTs in males, analyses of GGCTs in females and EGCTs in both sexes remain limited. In a pooling project of nine population-based cancer registries in Germany for the years 1998-2008, 16,883 malignant GCTs and their topographical sites were identified using ICD-O morphology and topography for persons aged 15 years and older. We estimated age-specific and age-standardized incidence rates. Among males, the incidence of testicular GCTs increased over time. In contrast, there was no increase in the incidence of EGCTs. Among females, rates of ovarian GCTs were stable, while rates of EGCTs declined over time. The most frequent extragonadal sites were mediastinum among males and placenta among females. Our results underline different incidence trends and distinct age-specific incidence patterns of malignant GGCTs and EGCTs, as reported recently by several population-based registries. The differences suggest that GGCT and EGCT may have different etiologies. 23250485 Androgens promote prostate cancer cell growth through induction of autophagy. Androgens regulate both the physiological development of the prostate and the pathology of prostatic diseases. However, the mechanisms by which androgens exert their regulatory activities on these processes are poorly understood. In this study, we have determined that androgens regulate overall cell metabolism and cell growth, in part, by increasing autophagy in prostate cancer cells. Importantly, inhibition of autophagy using either pharmacological or molecular inhibitors significantly abrogated androgen-induced prostate cancer cell growth. Mechanistically, androgen-mediated autophagy appears to promote cell growth by augmenting intracellular lipid accumulation, an effect previously demonstrated to be necessary for prostate cancer cell growth. Further, autophagy and subsequent cell growth is potentiated, in part, by androgen-mediated increases in reactive oxygen species. These findings demonstrate a role for increased fat metabolism and autophagy in prostatic neoplasias and highlight the potential of targeting underexplored metabolic pathways for the development of novel therapeutics. 23638940 Health professionals' beliefs about domestic abuse and the issue of disclosure: a critical incident technique study. Domestic abuse is increasingly recognised as a serious, worldwide public health concern. There is a significant body of literature regarding domestic abuse, but little is known about health professionals' beliefs about domestic abuse disclosure. In addition, the intersection between health professionals' beliefs and abused women's views remains uninvestigated. We report on a two-phase, qualitative study using Critical Incident Technique (CIT) that aimed to explore community health professionals' beliefs about domestic abuse and the issue of disclosure. We investigated this from the perspectives of both health professionals and abused women. The study took place in Scotland during 2011. The study was informed theoretically by the Common Sense Model of Self-Regulation of Health and Illness (CSM). This model is typically used in disease-orientated research. In our innovative use, however, CSM was used to study the social phenomenon, domestic abuse. The study involved semi-structured, individual CIT interviews with health professionals and focus groups with women who had experienced domestic abuse. Twenty-nine health professionals (Midwives, Health Visitors and General Practitioners) participated in the first phase of the study. In the second phase, three focus groups were conducted with a total of 14 women. Data were analysed using a combination of an inductive classification and framework analysis. Findings highlight the points of convergence and divergence between abused women's and health professionals' beliefs about abuse. Although there was some agreement, they do not always share the same views. For example, women want to be asked about abuse, but many health professionals do not feel confident or comfortable discussing the issue. Overall, the study shows the dynamic interaction between women's and health professionals' beliefs about domestic abuse and readiness to discuss and respond to it. Understanding these complex dynamics assists in the employment of appropriate strategies to support women post-disclosure. 23474198 Development of a home-made extraction device for vortex-assisted surfactant-enhanced-emulsification liquid-liquid microextraction with lighter than water organic solvents. We have developed a novel vortex-assisted surfactant-enhanced-emulsification liquid-liquid microextraction using the low density solvent for the determination of eight organophosphorus pesticides (OPPs) in water samples. The key point of this method is the application of a special home-made extraction device. The influence parameters relevant to this method were systemically investigated and the optimum conditions were as follow: 35μL of toluene was used as extraction solvent and 0.2mmol L-1 Triton X-100 was chosen as the surfactant to enhance the emulsification. Under the optimum experimental conditions, the limit of detections (LODs) of the method was ranged between 0.01 and 0.05μgL(-1) and the relative standard deviations (RSDs) were 2.9-8.1%. The calibration curve was linear in the range of 0.1-50.0μgL(-1), with the correlation coefficients (r) varying from 0.9949 to 0.9991. Finally, the developed method has been successfully applied to the determination of eight organophosphorus pesticides in river, reservoir and well water samples with recoveries between 82.1% and 98.7%. 23876126 The use of the head louse as a remedy for jaundice in Spanish folk medicine: an overview. In Spain, head lice are considered a therapeutic resource for the treatment of jaundice. All folk remedies based on the ingestion of these insects meet in the present document, previously dispersed among a large number of references. An overview of the Spanish literature has been carried out. The most important databases have been consulted. All related works have been examined. Although the method of preparation is diverse and the dose varies, the primary recommendation is a transference ritual consisting of taking nine live lice for nine days on an empty stomach without the patient's knowledge. This traditional knowledge survives in Spanish society, and constitutes an example of the interrelation between Spanish and Latin American folk medicines. The survival of this therapy in the worldview of certain rural communities suggests the need to take into account the beliefs, ideas and behaviour patterns of popular culture in relation to health and disease. 23903022 Comparison of Two Doses of Tranexamic Acid in Adults Undergoing Cardiac Surgery with Cardiopulmonary Bypass. The optimal dose of tranexamic acid (TA) is still an issue. The authors compared two doses of TA during cardiac surgery in a multicenter, double-blinded, randomized study. Patients were stratified according to transfusion risk, then randomized to two TA doses: 10 mg/kg bolus followed by 1 mg·kg·h infusion (low dose) until the end of surgery or 30 mg/kg bolus followed by 16 mg·kg·h infusion (high dose). The primary endpoint was the incidence of blood product transfusion up to day 7. Secondary ones were incidences of transfusion for each type of blood product and amounts transfused, blood loss, repeat surgery, TA-related adverse events, and mortality. The low-dose group comprised 284 patients and the high-dose one 285. The primary endpoint was not significantly different between TA doses (63% for low dose vs. 60% for high dose; P = 0.3). With the high dose, a lower incidence of frozen plasma (18 vs. 26%; P = 0.03) and platelet concentrate (15 vs. 23%; P = 0.02) transfusions, lower amounts of blood products (2.5 ± 0.38 vs. 4.1 ± 0.39; P = 0.02), fresh frozen plasma (0.49 ± 0.14 vs.1.07 ± 0.14; P = 0.02), and platelet concentrates transfused (0.50 ± 0.15 vs. 1.13 ± 0.15; P = 0.02), lower blood loss (590 ± 50.4 vs. 820 ± 50.7; P = 0.01), and less repeat surgery (2.5 vs. 6%; P = 0.01) were observed. These results are more marked in patients with a high risk for transfusion. A high dose of TA does not reduce incidence of blood product transfusion up to day 7, but is more effective than a low dose to decrease transfusion needs, blood loss, and repeat surgery. 23945153 Accelerated uptake of VWF/platelet complexes in macrophages contribute to VWD-type 2B associated thrombocytopenia. Von Willebrand Disease (VWD)-type 2B is characterized by mutations causing enhanced binding of von Willebrand factor (VWF) to platelets. Bleeding tendency is associated with heterogeneous clinical manifestations, including moderate to severe thrombocytopenia. The underlying mechanism of the thrombocytopenia has remained unclear. Here, a mouse model of VWD-type 2B was used to investigate pathways contributing to thrombocytopenia. Immuno-histochemical analysis of blood smears revealed that mutant VWF was exclusively detected on platelets of thrombocytopenic VWD-type 2B mice, suggesting that VWF binding to platelets is needed to induce thrombocytopenia. Platelet counts in thrombocytopenic VWD-type 2B mice were elevated 2-3-fold upon chemical macrophage depletion. Co-localization of platelets with CD68-positive Kupffer cells and CD168-positive marginal macrophages in liver and spleen, respectively, confirmed the involvement of macrophages in the removal of VWF/platelet complexes. Significantly more platelets were found in liver and spleen of VWD-type 2B mice compared to control mice. Finally, platelet survival was significantly shorter in VWD-type 2B mice compared to control mice, providing a rationale for lower platelet counts in VWD-type 2B mice. In conclusion, our data indicate that VWF-type 2B binds to platelets and this is a signal for clearance by macrophages, which could contribute to the thrombocytopenia in patients with VWD-type 2B. 23764275 Engagement of soluble resistance-related calcium binding protein (sorcin) with foot-and-mouth disease virus (FMDV) VP1 inhibits type I interferon response in cells. Foot-and-mouth disease (FMD) is an acute, highly contagious animal disease caused by FMD virus (FMDV). Although FMDV-induced immunosuppression in host has been well established, the exact molecular mechanism for such induction is not very clear. We report here the identification of FMDV VP1 as an interferon-suppressor by interacting with soluble resistance-related calcium binding protein (sorcin). We found that VP1 suppressed tumor necrosis factor (TNF)-α or Sendai virus (SeV)-induced type I interferon response in HEK293T cells, and that this suppression could be completely abolished by knockdown of sorcin by shRNA. Furthermore, overexpression of sorcin inhibited type I interferon response. Conversely, TNF- or SeV-induced type I interferon response increased when sorcin knocked down, leading to inhibition of vesicular stomatitis virus (VSV) replication. Thus, VP1-induced suppression of type I interferon is mediated by interacting with sorcin, a protein that appears to regulate cell response to viral infections. 23776235 Smoke carcinogens cause bone loss through the aryl hydrocarbon receptor and induction of Cyp1 enzymes. Smoking is a major risk factor for osteoporosis and fracture, but the mechanism through which smoke causes bone loss remains unclear. Here, we show that the smoke toxins benzo(a)pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) interact with the aryl hydrocarbon receptor (Ahr) to induce osteoclastic bone resorption through the activation of cytochrome P450 1a/1b (Cyp1) enzymes. BaP and TCDD enhanced osteoclast formation in bone marrow cell cultures and gavage with BaP stimulated bone resorption and osteoclastogenesis in vivo. The osteoclastogenesis triggered by BaP or RANK-L was reduced in Ahr(-/-) cells, consistent with the high bone mass noted in Ahr(-/-) male mice. The receptor activator of NF-κB ligand (RANK-L) also failed to induce the expression of Cyp1 enzymes in Ahr(-/-) cells. Furthermore, the osteoclastogenesis induced by TCDD was lower in Cyp1a1/1a2(-/-) and Cyp1a1/1a2/1b1(-/-) cultures, indicating that Ahr was upstream of the Cyp enzymes. Likewise, the pharmacological inhibition of the Cyp1 enzymes with tetramethylsilane or proadifen reduced osteoclastogenesis. Finally, deletion of the Cyp1a1, Cyp1a2, and Cyp1b1 in triple knockout mice resulted in reduced bone resorption and recapitulated the high bone mass phenotype of Ahr(-/-) mice. Overall, the data identify the Ahr and Cyp1 enzymes not only in the pathophysiology of smoke-induced osteoporosis, but also as potential targets for selective modulation by new therapeutics. 23870607 Mixed treatment comparison meta-analysis of aspirin, warfarin, and new anticoagulants for stroke prevention in patients with nonvalvular atrial fibrillation. Warfarin and aspirin are used to prevent stroke in patients with atrial fibrillation (AF). There are inherent challenges with both treatments, including variable and inconsistent benefit and increased bleeding risks. The availability of new anticoagulants offers some alternatives. A mixed treatment comparison meta-analysis to evaluate direct and indirect treatment data including aspirin, warfarin apixaban, dabigatran, edoxaban, and rivaroxaban for the prevention of primary or secondary stroke in patients with AF. A comprehensive, systematic literature search was conducted to identify randomized trials comparing aspirin, warfarin, apixaban, dabigatran, edoxaban, and rivaroxaban in patients with AF requiring treatment for stroke prevention. Open-label and blinded designs were included if they evaluated any stroke or any bleeding event. Data on stroke and bleeding events were abstracted, verified, evaluated, scored, and entered into Aggregate Data Drug Information System version 1.16 to generate a mixed treatment comparison meta-analysis. Direct and indirect comparisons were evaluated, and we looked for inconsistency in closed loop structures. Data are reported as rate ratios with 95% credible intervals. In addition, we reviewed variance statistics and explored variance with node-splitting models. Our literature search yielded 30 articles, 21 of which were included. All treatments except aspirin reduced the risk of any stroke compared with placebo. Warfarin (0.43 [0.33-0.57]), apixaban (0.37 [0.27-0.54]), dabigatran (0.34 [0.21-0.57]), rivaroxaban (0.36 [0.22-0.60]), and aspirin with clopidogrel (0.73 [0.53-0.99]) were more protective than aspirin alone. Warfarin and the new anticoagulants were similar in the reduction of stroke, vascular death, and mortality. There was no difference in major bleeding between any treatment group. There were more nonmajor bleeding events when comparing warfarin and apixaban (1.83 [1.05-4.03]); no other differences between warfarin and the other new anticoagulants were found. This mixed treatment comparison meta-analysis found similarity between warfarin and the new anticoagulants with the exception of one comparison, in which warfarin was associated with more non-major bleeding than apixaban. Thus, the new anticoagulants are therapeutically comparable when warfarin is inappropriate. 23002089 When did decapods invade hydrothermal vents? Clues from the Western Pacific and Indian Oceans. Hydrothermal vents are typically located in midocean ridges and back-arc basins and are usually generated by the movement of tectonic plates. Life thrives in these environments despite the extreme conditions. In addition to chemoautotrophic bacteria, decapod crustaceans are dominant in many of the hydrothermal vents discovered to date. Contrary to the hypothesis that these species are remnants of relic fauna, increasing evidence supports the notion that hydrothermal vent decapods have diversified in more recent times with previous research attributing the origin of alvinocarid shrimps to the Miocene. This study investigated seven representative decapod species from four hydrothermal vents throughout the Western Pacific and Indian Oceans. A partitioned mix-model phylogenomic analysis of mitochondrial DNA produced a consistent phylogenetic topology of these vent-endemic species. Additionally, molecular dating analysis calibrated using multiple fossils suggested that both bythograeid crabs and alvinocarid shrimps originated in the late Mesozoic and early Cenozoic. Although of limited sampling, our estimates support the extinction/repopulation hypothesis, which postulates recent diversification times for most hydrothermal vent species due to their mass extinction by global deep-water anoxic/dysoxic events during the Late Cretaceous and Early Tertiary. The continental-derived property of the West Pacific province is compatible with the possibility that vent decapods diversified from ancestors from shallow-water regions such as cold seeps. Our results move us a step closer toward understanding the evolutionary origin of hydrothermal vent species and their distribution in the Western Pacific-Indian Ocean Region. 23564651 Structure-Property Investigations of Substituted Triarylamines and Their Applications as Fluorescent pH Sensors. Fourteen triphenylamine derivatives functionalized with fluorophenyl, methoxyphenyl, and pyridinyl groups as respective donors and acceptors were synthesized and characterized. Their photophysical properties were systematically investigated in various solvents with different polarities. The solvent-dependent Stokes shifts of these compounds were observed and analyzed by the Lippert-Mataga equation. The synthesized compounds, especially tris(4-(pyridin-4-yl)phenyl) amine, presented pH-dependent absorptions and emissions, indicating that these compounds might be used as pH sensors. 23636618 Effects of acute and chronic administration of fenproporex on DNA damage parameters in young and adult rats. Obesity is a chronic and multifactorial disease, whose prevalence is increasing in many countries. Pharmaceutical strategies for the treatment of obesity include drugs that regulate food intake, thermogenesis, fat absorption, and fat metabolism. Fenproporex is the second most commonly consumed amphetamine-based anorectic worldwide; this drug is rapidly converted in vivo into amphetamine, which is associated with neurotoxicity. In this context, the present study evaluated DNA damage parameters in the peripheral blood of young and adult rats submitted to an acute administration and chronic administration of fenproporex. In the acute administration, both young and adult rats received a single injection of fenproporex (6.25, 12.5 or 25 mg/kg i.p.) or vehicle. In the chronic administration, both young and adult rats received one daily injection of fenproporex (6.25, 12.5, or 25 mg/kg i.p.) or Tween for 14 days. 2 h after the last injection, the rats were killed by decapitation and their peripheral blood removed for evaluation of DNA damage parameters by alkaline comet assay. Our study showed that acute administration of fenproporex in young and adult rats presented higher levels of damage index and frequency in the DNA. However, chronic administration of fenproporex in young and adult rats did not alter the levels of DNA damage in both parameters of comet assay. The present findings showed that acute administration of fenproporex promoted damage in DNA, in both young and adult rats. Our results are consistent with other reports which showed that other amphetamine-derived drugs also caused DNA damage. We suggest that the activation of an efficient DNA repair mechanism may occur after chronic exposition to fenproporex. Our results are consistent with other reports that showed some amphetamine-derived drugs also caused DNA damage. 23811700 Imaging of prostate carcinoma. Imaging of prostate carcinoma is an important adjunct to clinical evaluation and prostate specific antigen measurement for detecting metastases and tumor recurrence. In the past, the ability to assess intraprostatic tumor was limited. Pertinent literature was reviewed to describe the capabilities and limitations of the currently available imaging techniques for assessing prostate carcinoma. Evaluation of primary tumor and metastatic disease by ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine techniques is discussed. Ultrasonography and MRI have limited usefulness for local staging of prostate cancer because of suboptimal sensitivity and specificity for identifying tumor extent and capsular penetration. Additional MRI techniques such as magnetic resonance-based perfusion imaging, diffusion imaging, and spectroscopy may provide incremental benefit. CT and bone scanning provide an assessment of metastatic disease but are also limited by the poor sensitivity of lymph node size as a criterion for detecting metastases. Novel imaging techniques such as hybrid imaging devices in the form of single-photon emission CT/CT gamma cameras, positron emission tomography/CT cameras, and, in the near future, positron emission tomography/MRI combined with tumor specific imaging radiotracers may have a significant impact on tumor staging and treatment response. Cross-sectional imaging and scintigraphy have an important role in assessing prostate carcinoma metastases and treatment response. Increasingly, the incremental value of primary tumor imaging through MRI is being realized. 23782968 Diverse Attitudes to and Understandings of Spontaneous Awakening Trials: Results From a Statewide Quality Improvement Collaborative* Spontaneous awakening trials (SATs) improve outcomes in mechanically ventilated patients, but implementation remains erratic. We examined variation in reported practice, prevalence of attitudes and fears regarding spontaneous awakening trials, and organizational practices associated with routine implementation of spontaneous awakening trials in an ICU quality improvement collaborative. Written survey. Michigan Health and Hospital Association's Keystone ICU, a quality improvement collaborative of 73 hospitals. Attendees of the yearly Keystone ICU meeting, January 2011, including nurses, physicians, hospital administrators, and other healthcare professionals. Respondents were asked about institutional characteristics, spontaneous awakening trial practice, attitudes and barriers regarding spontaneous awakening trials, and organizational cultural characteristics that might influence SAT practice. The association of organizational cultural characteristics and attitudes with reported spontaneous awakening trial use was evaluated using logistic regression. Three hundred nineteen participants attended the meeting. The survey response rate was 83.4%. Respondents reported wide variation in approach to spontaneous awakening trial performance and patient selection. 48.6% of respondents reported regular spontaneous awakening trial use, defined as greater than 75% of mechanically ventilated patients undergoing spontaneous awakening trials each day. In bivariable analysis, addressing sedation goals routinely in rounds and having spontaneous awakening trials as part of unit culture were positively associated with regular spontaneous awakening trial use, whereas the perception that spontaneous awakening trials increased short-term adverse effects, staff fears of spontaneous awakening trials, and the perception that spontaneous awakening trials are hard work were negatively associated with regular spontaneous awakening trial use. In multivariable analysis, only addressing sedation in rounds (odds ratio, 2.85 [95% CI, 1.55-5.23]), incorporation of spontaneous awakening trials into unit culture (odds ratio, 3.36 [95% CI, 1.75-6.43]), and the perception that spontaneous awakening trials are hard work (odds ratio, 0.53 [95% CI, 0.30-0.96]) remained statistically significantly associated with regular spontaneous awakening trial use. Respondents in managerial positions were less likely to perceive spontaneous awakening trials as hard work (odds ratio, 0.44 [95% CI, 0.22-0.85]). Even in a motivated statewide quality improvement collaborative, spontaneous awakening trial practice varies widely and concerns persist regarding spontaneous awakening trials. Cultural practices may counteract the effect of concerns regarding spontaneous awakening trials and are associated with increased performance of this beneficial intervention. Patient selection should be a focus for continuing medical education. Differences in perception of work between management and staff may also be a focus for improved communication. 23564940 Twisted Signatures of GC-Biased Gene Conversion Embedded in an Evolutionary Stable Karyotype. The genomes of many vertebrates show a characteristic heterogeneous distribution of GC content, the so-called GC isochore structure. The origin of isochores has been explained via the mechanism of GC-biased gene conversion (gBGC). However, although the isochore structure is declining in many mammalian genomes, the heterogeneity in GC content is being reinforced in the avian genome. Despite this discrepancy, which remains unexplained, examinations of individual substitution frequencies in mammals and birds are both consistent with the gBGC model of isochore evolution. On the other hand, a negative correlation between substitution and recombination rate found in the chicken genome is inconsistent with the gBGC model. It should therefore be important to consider along with gBGC other consequences of recombination on the origin and fate of mutations, as well as to account for relationships between recombination rate and other genomic features. We therefore developed an analytical model to describe the substitution patterns found in the chicken genome, and further investigated the relationships between substitution patterns and several genomic features in a rigorous statistical framework. Our analysis indicates that GC content itself, either directly or indirectly via interrelations to other genomic features, has an impact on the substitution pattern. Further, we suggest that this phenomenon is particularly visible in avian genomes due to their unusually low rate of chromosomal evolution. Because of this, interrelations between GC content and other genomic features are being reinforced, and are as such more pronounced in avian genomes as compared with other vertebrate genomes with a less stable karyotype. 23834625 Evidence for isolated evolution of deep-sea ciliate communities through geological separation and environmental selection. Deep hypersaline anoxic basins (DHABs) are isolated habitats at the bottom of the eastern Mediterranean Sea, which originate from the ancient dissolution of Messinian evaporites. The different basins have recruited their original biota from the same source, but their geological evolution eventually constituted sharp environmental barriers, restricting genetic exchange between the individual basins. Therefore, DHABs are unique model systems to assess the effect of geological events and environmental conditions on the evolution and diversification of protistan plankton. Here, we examine evidence for isolated evolution of unicellular eukaryote protistan plankton communities driven by geological separation and environmental selection. We specifically focused on ciliated protists as a major component of protistan DHAB plankton by pyrosequencing the hypervariable V4 fragment of the small subunit ribosomal RNA. Geospatial distributions and responses of marine ciliates to differential hydrochemistries suggest strong physical and chemical barriers to dispersal that influence the evolution of this plankton group. Ciliate communities in the brines of four investigated DHABs are distinctively different from ciliate communities in the interfaces (haloclines) immediately above the brines. While the interface ciliate communities from different sites are relatively similar to each other, the brine ciliate communities are significantly different between sites. We found no distance-decay relationship, and canonical correspondence analyses identified oxygen and sodium as most important hydrochemical parameters explaining the partitioning of diversity between interface and brine ciliate communities. However, none of the analyzed hydrochemical parameters explained the significant differences between brine ciliate communities in different basins. Our data indicate a frequent genetic exchange in the deep-sea water above the brines. The "isolated island character" of the different brines, that resulted from geological events and contemporary environmental conditions, create selective pressures driving evolutionary processes, and with time, lead to speciation and shape protistan community composition. We conclude that community assembly in DHABs is a mixture of isolated evolution (as evidenced by small changes in V4 primary structure in some taxa) and species sorting (as indicated by the regional absence/presence of individual taxon groups on high levels in taxonomic hierarchy). 23709223 The Nucleic Acid-binding Domain and Translational Repression Activity of a Xenopus Terminal Uridylyl Transferase. Terminal uridylyl transferases (TUTs) catalyze the addition of uridines to the 3' ends of RNAs and are implicated in the regulation of both messenger RNAs and microRNAs. To better understand how TUTs add uridines to RNAs, we focused on a putative TUT from Xenopus laevis, XTUT7. We determined that XTUT7 catalyzed the addition of uridines to RNAs. Mutational analysis revealed that a truncated XTUT7 enzyme, which contained solely the nucleotidyl transferase and poly(A) polymerase-associated domains, was sufficient for catalytic activity. XTUT7 activity decreased upon removal of the CCHC zinc finger domains and a short segment of basic amino acids (the basic region). This basic region bound nucleic acids in vitro. We also demonstrated that XTUT7 repressed translation of a polyadenylated RNA, to which it added a distinct number of uridines. We generated a predicted structure of the XTUT7 catalytic core that indicated histidine 1269 was likely important for uridine specificity. Indeed, mutation of histidine 1269 broadened the nucleotide specificity of XTUT7 and abolished XTUT7-dependent translational repression. Our data reveal key aspects of how XTUT7 adds uridines to RNAs, highlight the role of the basic region, illustrate that XTUT7 can repress translation, and identify an amino acid important for uridine specificity. 23702096 Effect of feeding selectivity on the transfer of methylmercury through experimental marine food chains. The present study established an experimental marine food chain of three levels (microalgae â†’ zooplankton â†’ fish) to investigate the effect of feeding selectivity on the transfer of methylmercury (MeHg) through the food chain. Total Hg concentrations in Chlorella sp., Nitzschia closterium and Isochrysis galbana exposed to 1 Î¼g L(-1) MeHg for three days were 27.91, 32.74 and 40.03 Î¼g g(-1) respectively and were significantly different (p < 0.05) between species. Moina mongolica and Artemia sp. primarily selected Chlorella sp. as the sole diet, though the Artemia sp. partly grazed on I. galbana as well. Harpacticus uniremis, however, preferred to graze N. closterium and I. galbana and avoided Chlorella sp. The varying concentration of Hg in the microalgae species as well as the selectivity of zooplankton to the algal diet resulted in varying Hg accumulation in three zooplankton species (M. mongolica < Artemia sp. < H. uniremis with total Hg concentrations of 0.14, 0.66 and 0.82 Î¼g g(-1), respectively). Scophthalmus maximus and Paralichthys olivaceus mainly preyed on H. uniremis and partly on M. mongolica, while Fugu rubripes primarily preyed on M. mongolica and secondarily on Artemia sp. Thus, similar reasoning as above could explain the significant difference in Hg accumulation in the fish (S. maximus > P. olivaceus > F. rubripes with total Hg concentrations of 0.0042, 0.0031 and 0.0020 Î¼g g(-1), respectively). These investigations suggested feeding selectivity plays a key role in the transfer of MeHg along marine food chains. 23444005 "Bounded" empowerment: analyzing tensions in the practice of youth-led participatory research in urban public schools. This multi-method study examines tensions in the practice of youth-led participatory research (YPAR) in urban high schools among 15 semester-cohorts. Student participants in the present study were 77 ethnically diverse youth from four high schools in a major metropolitan school district. Data were gathered using systematic classroom observations, interviews with teachers and students involved in the projects, and participant observation. The two most commonly-constrained phases of the YPAR project were issue selection and action steps. A central tension in the issue selection phase for projects enacted across multiple semester cohorts was the tension between original inquiry and "traction:" Sticking with the same topic enabled sustained building of strategic alliances and expertise for making change, but limited the incoming cohort's power to define the problem to be addressed. In further analyses, we identified processes that promoted student power despite continuity-related constraints-teachers' framing and buy-in strategies, "micro-power" compensation, and alignment of students' interests with the prior cohort-as well as constraints in other phases of the projects. This study's findings regarding the promotion of youth power in the face of constraints advance the integration of theory and practice in youth-led research and have implications for participatory research more broadly. 23420411 Can clinical tests help monitor human papillomavirus vaccine impact? As immunization programs for human papillomavirus (HPV) are implemented more widely around the world, interest is increasing in measuring their impact. One early measurable impact of HPV vaccine is on the prevalence of specific HPV types in a population. In low-resource settings, a potentially attractive strategy would be to monitor HPV prevalence using clinical cervical cancer screening test results to triage specimens for HPV typing. We assessed this approach in a nationally representative population of U.S. females aged 14-59 years. Using self-collected cervico-vaginal swab specimens from 4,150 women participating in the National Health and Nutrition Examination Survey during 2003-2006, we evaluated type-specific HPV prevalence detected by the Roche linear array (LA) research test on all specimens, compared with type-specific HPV prevalence detected by LA conducted only on specimens positive by the digene hybrid capture 2 (HC-2) clinical test. We calculated weighted prevalence estimates and their 95% confidence intervals (CIs), and examined relative type-specific HPV prevalence according to the two testing approaches. The population prevalence of oncogenic HPV vaccine types 16/18 was 6.2% (CI:5.4-7.1) by LA if all specimens were tested, and 2.4% (CI:1.9-3.0) if restricted to positive HC-2. Relative prevalence of individual HPV types was similar for both approaches. Compared with typing all specimens, a triage approach would require testing fewer specimens, but a greater reduction in HPV prevalence or a larger group of specimens would be needed to detect vaccine impact. Further investigation is warranted to inform type-specific HPV monitoring approaches around the world. 23813573 Evaluation of the staging systems for gastric cancer. Some staging systems for gastric cancer (GC) have been developed as alternatives to the 6th and 7th TNM staging systems, including the Hybrid, tumor-ratio-metastasis (TRM), and Kiel staging systems. This study evaluated the overall performance of these systems for GC. A total of 540 GC patients undergoing surgical resection were staged using these five systems. Homogeneity, discrimination power, predictive accuracy, and complexity of these systems were compared. Multivariate analyses showed that all of 7th pT, pN, and pM classifications were independent factors for GC prognosis (P < 0.001 for all). Compared with the other four systems, 7th TNM system had improved stage groups homogeneity (7 of 8 stage groups homogeneous), enhanced discrimination power (4 of 5, 5 of 7, 4 of 7, 3 of 7, and 1 of 4 adjacent stage groups were differentiated by the 6th, 7th TNM, Hybrid, TRM, and Kiel systems, respectively), and better prediction value for GC patients' outcome (AUC = 0.801, P < 0.001). In addition, the 7th TNM system did not increase the staging complexity (9 groups and 21 subgroups). The 7th TNM staging system represents advancement in GC staging system for better prediction of clinical outcomes. J. Surg. Oncol. 2013; 108:93-105. © 2013 Wiley Periodicals, Inc. 22683771 Cognitive hostility predicts all-cause mortality irrespective of behavioural risk at late middle and older age. Most but not all evidence supports hostility-related attributes to increase mortality risk. However, studies usually include single attributes, their effects have been studied predominantly in younger populations, and behavioural pathways explaining the mortality effect seem to differ by age. We examined the relationship between all-cause mortality and cognitive hostility, anger, aggression and rebelliousness, and their independence of health behaviours in a late middle-aged and older population. Data were derived from the longitudinal Dutch Study of Medical Information and Lifestyles in the city of Eindhoven, in the Southeast of the Netherlands study among 2679 late middle-aged and older Dutch people. Psychological characteristics were self-reported in 2004/2005, and mortality was monitored from 2005 to 2010. Cox regression analyses were used to calculate the mortality risk by each unique psychological variable with additional adjustments for the other psychological variables and for health behaviours. Baseline adjustments included age, sex, educational level and prevalent morbidity. Cognitive hostility was associated with all-cause mortality, independent of health behaviours (on a scale ranging from 6 to 30, the hazard ratio (HR) was 1.05; 95% confidence interval [95% CI): 1.01-1.09]. Anger, aggression and rebelliousness were not associated with mortality risk. Conclusions: In diminishing excess mortality risks, hostile cognitions might be acknowledged separately and additionally to the risk posed by unhealthy lifestyles. 23770330 Roux-en-Y gastric bypass surgery in rats alters gut microbiota profile along the intestine. Roux-en-Y gastric bypass (RYGB) surgery might modify the gut microbiota composition differently in the three distinct anatomical sections of the small intestine compared to sham surgery. We showed that RYGB induced changes in the microbiota of the alimentary limb and the common channel resembling those seen after prebiotic treatment or weight loss by dieting. These changes may be associated with altered production of intestinal hormones known to control energy balance. Postsurgical modulation of gut microbiota may significantly contribute to the beneficial metabolic effects of RYGB surgery. 23550185 Proposal to utilize simplified Swensen protocol in diagnosis of isolated pulmonary nodule. The problem of diagnosing whether a solitary pulmonary nodule is benign or malignant is even greater in developing countries due to a higher prevalence of infectious diseases. These infections generate a large number of patients who are generally asymptomatic and with a pulmonary nodule that cannot be accurately defined as having benign or malignant etiology. To verify the percentages of benign versus malignant non-calcified nodules, the length of time after contrast agent injection is spiral computed tomography (CT) most sensitive and specific, and whether three postcontrast phases are necessary. We studied 23 patients with solitary pulmonary nodules identified on chest radiographs or CT. Spiral scans were obtained with Swensen protocol, but at 3, 4, and 5 min after contrast injection onset. Nodules were classified as benign or malignant by histopathological examination or by an absence or presence of growth after 2 years of follow-up CT. Of the 23 patients studied, 18 (78.2%) showed a final diagnosis of benign and five (21.7%) malignant nodules. Despite the small sample size, we obtained results similar to those of Swensen et al., with 80.0% sensitivity, 55.5% specificity, and 60.8% accuracy. Four minutes gave the greatest mean enhancement in both malignant and benign lesions. Small non-calcified benign nodules were much more frequent than malignant nodules. The best time for dynamic contrast-enhanced CT density analysis was 4 min postcontrast. As well as saving time and money, this simplified Swensen protocol with only precontrast and 4 min postcontrast phases also reduces patient exposure to ionizing radiation. 23622783 Clonal dissemination of methicillin-resistant Staphylococcus aureus in patients and the hospital environment. Methicillin is the drug of choice to treat infections caused by resistant strains of Staphylococcus aureus. However, methicillin-resistant S. aureus (MRSA) is now becoming endemic in many hospitals worldwide and is the cause of nosocomial outbreaks. To assess clonality and dissemination of MRSA strains in the hospitals of Tehran, a total of 60 MRSA strains were isolated from hospitalized patients (n=44) and hospital equipment and environment (n=16) of three metropolitan hospitals in Tehran between July 2009 and March 2010. These strains were subjected to antimicrobial susceptibility testing, pulsed-field gel electrophoresis (PFGE), and biochemical fingerprinting using the PhPlate system. Results showed the presence of between one and three dominant clonal groups within each hospital, with most equipment and environmental strains being identical to the dominant clones of hospitalized patient strains. The rate of resistance of these strains to the 13 antibiotics tested ranging from 2% to 100%, with resistance being highest for penicillin, ciprofloxacin, and tetracycline (>98% of the isolates). Comparison of the strains isolated from the three hospitals using a combination of PFGE and PhP types showed the presence of 11 clonal groups of MRSA among these hospitals; of these, three common clonal groups also had identical antibiotic resistance patterns and were found in more than one hospital. These data suggest dissemination of a few dominant clonal groups of MRSA strains in hospitals in Tehran, with high level resistance to other commonly used antibiotics. 23727948 Titanium dxy ferromagnetism at the LaAlO3/SrTiO3 interface. A number of recent transport and magnetization studies have shown signs of ferromagnetism in the LaAlO3/SrTiO3 heterostructure, an unexpected property with no bulk analogue in the constituent materials. However, no experiment thus far has provided direct information on the host of the magnetism. Here we report spectroscopic investigations of the magnetism using element-specific techniques, including X-ray magnetic circular dichroism and X-ray absorption spectroscopy, along with corresponding model calculations. We find direct evidence for in-plane ferromagnetic order at the interface, with Ti(3+) character in the dxy orbital of the anisotropic t2g band. These findings establish a striking example of emergent phenomena at oxide interfaces. 23041078 Anatomical and functional damage in experimental glaucoma. Glaucoma is a progressive neurodegenerative disease caused by retinal ganglion cell (RGC) loss. One important risk factor for glaucoma is elevated intraocular pressure and thus many animal models are based on spontaneous or induced ocular hypertension (OHT). Using these models it has been shown that RGCs initially suffer an impairment of the active axonal transport that progresses to a lack of passive diffusion along the axon. This axonal damage eventually causes the death of the parent RGCs in pie-shaped sectors of the retina, but there is also diffuse RGC loss, without involving displaced amacrine cells. Recent data show that OHT results in a protracted insult to the inner and outer retina that causes functional alterations and ultimately, degeneration and death of cones. 23519149 Predictive factors of sensitivity to elisidepsin, a novel kahalalide f-derived marine compound. Elisidepsin (PM02734, Irvalec®) is a synthetic marine-derived cyclic peptide of the Kahalalide F family currently in phase II clinical development. Elisidepsin was shown to induce rapid oncosis in ErbB3-expressing cells. Other predictive factors of elisidepsin sensitivity remained unknown. A panel of 23 cancer cell lines of different origin was assessed for elisidepsin cytotoxicity and correlated with mutational state, mRNA and protein expression of selected genes. Elisidepsin showed potent and broad cytotoxic effects in our cancer cell line panel, being active at concentrations ranging from 0.4 to 2 μM that may be relevant for clinical settings. We have shown that elisidepsin is more active in cells harboring epithelial phenotype with high E-cadherin and low vimentin expression. In addition, high ErbB3 and Muc1 expression was correlated with sensitivity to elisidepsin, whereas the presence of KRAS activating mutations was associated with resistance. In DU-PM cells with acquired resistance to elisidepsin, ErbB3 expression was decreased, while Bcl2 was increased. DU-PM cells displayed higher sensitivity to ErbB1-inhibitors suggesting possible cross-talk of ErbB1 and ErbB3 signaling pathways. Combinations of elisidepsin with lapatinib and several chemotherapies including 5-FU and oxaliplatin resulted in synergistic effects that offer the potential of clinical use of elisidepsin in combination settings. 23710625 Xenon treatment protects against cold ischemia associated delayed graft function and prolongs graft survival in rats. Prolonged hypothermic storage causes ischemia-reperfusion injury (IRI) in the renal graft, which is considered to contribute to the occurrence of the delayed graft function (DGF) and chronic graft failure. Strategies are required to protect the graft and to prolong renal graft survival. We demonstrated that xenon exposure to human proximal tubular cells (HK-2) led to activation of range of protective proteins. Xenon treatment prior to or after hypothermia-hypoxia challenge stabilized the HK-2 cellular structure, diminished cytoplasmic translocation of high-mobility group box (HMGB) 1 and suppressed NF-κB activation. In the syngeneic Lewis-to-Lewis rat model of kidney transplantation, xenon exposure to donors before graft retrieval or to recipients after engraftment decreased caspase-3 expression, localized HMGB-1 within nuclei and prevented TLR-4/NF-κB activation in tubular cells; serum pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were reduced and renal function was preserved. Xenon treatment of graft donors or of recipients prolonged renal graft survival following IRI in both Lewis-to-Lewis isografts and Fischer-to-Lewis allografts. Xenon induced cell survival or graft functional recovery was abolished by HIF-1α siRNA. Our data suggest that xenon treatment attenuates DGF and enhances graft survival. This approach could be translated into clinical practice leading to a considerable improvement in long-term graft survival. 23719739 Hybridisation at the organic-metal interface: a surface-scientific analogue of Hückel's rule? We demonstrate that cyclooctatetraene (COT) can be stabilised in different conformations when adsorbed on different noble-metal surfaces due to varying molecule-substrate interactions. While at first glance the behaviour seems to be in accordance with Hückel's rule, a theoretical analysis reveals no significant charge transfer. The driving mechanism for the conformational change is hybridisation at the organic-metal interface and does not necessitate any charge transfer. 23965066 World in brief. What's happening in nursing across the globe. 23602848 Effects of dietary supplementation of probiotic Shewanella colwelliana WA64, Shewanella olleyana WA65 on the innate immunity and disease resistance of abalone, Haliotis discus hannai Ino. The effects of dietary administration of two probiotics, Shewanella colwelliana WA64 and Shewanella olleyana WA65, on the innate immunity of abalone (Haliotis discus hannai Ino), and survival of juvenile abalone challenged with Vibrio harveyi have been studied. Two groups of abalone were fed with three different diets: one control, and two diets supplemented with 10(9) cell g(-1) of probiotic WA64 (WA64 diet) and WA65 (WA65 diet) for up to four weeks. Results showed that abalone fed diets containing S. colwelliana WA64 and S. olleyana WA65 had led to an enhanced cellular and humoral immune response, notably higher haemocytes, respiratory burst activity, serum lysozyme activity and total protein levels were recorded after one week of probiotic administration. On the other hand, mortality after the challenges with V. harveyi in the group fed with control diet ranged from 77 to 80%, while mortality rates observed in the groups fed with diets supplemented with WA64 and WA65 ranged from 27 to 50% and 30-43%, respectively. The results demonstrated potential for S. colwelliana WA64 and S. olleyana WA65 to improve innate immunity and disease resistance in H. discus hannai. 23171227 Weight bias among UK trainee dietitians, doctors, nurses and nutritionists. Trainee dietitians, nutritionists, nurses and doctors will direct the future of obesity treatment and prevention. To do so effectively, they must be willing and able to engage empathically with overweight and obese people. The present study aimed to assess weight bias among UK trainee healthcare professionals and to investigate the factors predicting weight bias, both static and potentially modifiable. A self-completed questionnaire collected data on demographics, weight and height, the Fat Phobia Scale (F-scale), and the Beliefs about Obese People (BOAP) scale from 1130 students. Overall, participants demonstrated significant levels of fat phobia [F-scale score mean (SD) = 3.8 (0.5)]. Only 1.4% of participants could be said to have expressed 'positive or neutral attitudes' (i.e. achieved a F-scale score â‰¤ 2.5). Hierarchical multiple regression revealed that lower fat phobia (as measured by the F-scale) was uniquely predicted by a higher self-reported body mass index, being on the Nursing BSc course and a stronger perception that obesity is not under a person's control (as measured by the BOAP scale). There are unacceptable levels of weight bias among UK students training to become nurses, doctors, nutritionists and dietitians. The results of the present study suggest that a promising approach for future interventions would be the provision of balanced education about the controllability of obesity, focusing upon genetic and environmental factors, as well as diet and exercise. 23608485 The anxiolytic buspirone shifts coping strategy in novel environmental context of mice with different anxious phenotype. Patients suffering from anxiety disorders show increased fear when encounter a novel environment. Rodents, placed in new environmental context may respond either with increased novelty seeking (active), or enhanced anxiety (passive coping style), which may depend on the trait anxiety of the animal. Here, the connection between the initial level of anxiety and the behavioral responses in a novel environment was investigated. Two inbred mouse strains having either high- or low-anxiety related behavior (AX and nAX) were exposed to elevated plus maze (EPM), a standard test for assessing anxiety level, for 8 consecutive days. The initial anxiety level was modulated by chronic treatment with buspirone (bus) treatment, a clinically effective anxiolytic, using 2.5mg/kg and 5.0mg/kg doses. Both strains showed a gradual decrease of open-arm exploration, which was not prevented by bus treatment. Another cohort of animals was exposed to EPM for 2 days, and then we changed to blue light illumination and used a different cleaning substance with citrus odor (context change, CC). It was found that upon CC AX mice exhibited increased, while nAX mice showed decreased anxiety. Bus in 2.5mg/kg changed the coping strategy from passive to active exploration after CC in the AX mice; however, the same treatment rendered nAX mice passive upon CC. Bus in 5.0mg/kg failed to alter the overall coping style in the novel environment of both strains. These results suggest that these mouse lines use different coping strategy in novel context, which can be changed with bus treatment. 23570789 Substituted imidazopyridazines are potent and selective inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1). A series of imidazopyridazines which are potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was identified from a high-throughput screen against the isolated enzyme. Subsequent exploration of the SAR and optimisation has yielded leading members which show promising in vitro anti-parasite activity along with good in vitro ADME and selectivity against human kinases. Initial in vivo testing has revealed good oral bioavailability in a mouse PK study and modest in vivo efficacy in a Plasmodium berghei mouse model of malaria. 23870158 Are discordant PET and pathological assessments of the mediastinum in non-small cell lung cancer significant? Many patients with non-small cell lung cancer have positive mediastinal lymph nodes on preoperative positron emission tomography (PET) but do not have mediastinal involvement after surgery. The prognostic significance of this discordance was assessed. This Institutional Review Board-approved study evaluated patients treated with upfront surgery at Duke Cancer Institute (Durham, NC) for non-small cell lung cancer from 1995 to 2008. Those staged with PET with pN0-1 disease after negative invasive mediastinal assessment were included. Mediastinal lymph nodes were scored as positive or negative based on visual analysis of the preoperative PET. Clinical outcomes of the PET-positive and PET-negative cohorts were estimated using the Kaplan-Meier method and compared using a log-rank test. Prognostic factors were assessed using a multivariate analysis. A total of 547 patients were assessed, of whom 105 (19%) were PET positive in the mediastinum. The median number of mediastinal lymph node stations sampled was 4 (range, 1-9). The 5-year risk of local recurrence was 26% in PET-positive versus 21% in PET-negative patients (P = .50). Patterns of local failure were similar between the 2 groups. Distant recurrence (35% vs 29%; P = .63) and overall survival (44% vs 54%; P = .52) were comparable for PET-positive and PET-negative patients. On multivariate analysis, a positive PET was not significant for local recurrence (hazard ratio [HR], 1; P = 1), distant recurrence (HR, 0.82; P = .42), or overall survival (HR, 1.08; P = .62). Patients with positive mediastinal lymph nodes on preoperative PET, but negative on histologic analysis, are not at increased risk of disease recurrence. Pathologic staging remains the standard. 23643593 Obesity and its association to phenotype and clinical course in hypertrophic cardiomyopathy. This study sought to assess the impact of body mass index (BMI) on cardiac phenotypic and clinical course in a multicenter hypertrophic cardiomyopathy (HCM) cohort. It is unresolved whether clinical variables promoting left ventricular (LV) hypertrophy in the general population, such as obesity, may influence cardiac phenotypic and clinical course in patients with HCM. In 275 adult HCM patients (age 48 ± 14 years; 70% male), we assessed the relation of BMI to LV mass, determined by cardiovascular magnetic resonance (CMR) and heart failure progression. At multivariate analysis, BMI proved independently associated with the magnitude of hypertrophy: pre-obese and obese HCM patients (BMI 25 to 30 kg/m(2) and >30 kg/m(2), respectively) showed a 65% and 310% increased likelihood of an LV mass in the highest quartile (>120 g/m(2)), compared with normal weight patients (BMI <25 kg/m(2); hazard ratio [HR]: 1.65; 95% confidence interval [CI]: 0.73 to 3.74, p = 0.22 and 3.1; 95% CI: 1.42 to 6.86, p = 0.004, respectively). Other features associated with LV mass >120 g/m(2) were LV outflow obstruction (HR: 4.9; 95% CI: 2.4 to 9.8; p < 0.001), systemic hypertension (HR: 2.2; 95% CI: 1.1 to 4.5; p = 0.026), and male sex (HR: 2.1; 95% CI: 0.9 to 4.7; p = 0.083). During a median follow-up of 3.7 years (interquartile range: 2.5 to 5.3), obese patients showed an HR of 3.6 (95% CI: 1.2 to 10.7, p = 0.02) for developing New York Heart Association (NYHA) functional class III to IV symptoms compared to nonobese patients, independent of outflow obstruction. Noticeably, the proportion of patients in NYHA functional class III at the end of follow-up was 13% among obese patients, compared with 6% among those of normal weight (p = 0.03). In HCM patients, extrinsic factors such as obesity are independently associated with increase in LV mass and may dictate progression of heart failure symptoms. 23912759 Three-dimensional anterior segment imaging in patients with type 1 Boston Keratoprosthesis with switchable full depth range swept source optical coherence tomography. ABSTRACT. A high-speed (100 kHz A-scans/s) complex conjugate resolved 1 Î¼m swept source optical coherence tomography (SS-OCT) system using coherence revival of the light source is suitable for dense three-dimensional (3-D) imaging of the anterior segment. The short acquisition time helps to minimize the influence of motion artifacts. The extended depth range of the SS-OCT system allows topographic analysis of clinically relevant images of the entire depth of the anterior segment of the eye. Patients with the type 1 Boston Keratoprosthesis (KPro) require evaluation of the full anterior segment depth. Current commercially available OCT systems are not suitable for this application due to limited acquisition speed, resolution, and axial imaging range. Moreover, most commonly used research grade and some clinical OCT systems implement a commercially available SS (Axsun) that offers only 3.7 mm imaging range (in air) in its standard configuration. We describe implementation of a common swept laser with built-in k-clock to allow phase stable imaging in both low range and high range, 3.7 and 11.5 mm in air, respectively, without the need to build an external MZI k-clock. As a result, 3-D morphology of the KPro position with respect to the surrounding tissue could be investigated in vivo both at high resolution and with large depth range to achieve noninvasive and precise evaluation of success of the surgical procedure. 23680849 Management of urinary tract infection in a tertiary children's hospital before and after publication of the NICE guidelines. The UK National Institute for Health and Clinical Excellence (NICE) introduced guidelines for the diagnosis, treatment and management of urinary tract infection (UTI) in children and adolescents in August 2007. The primary aim was to determine whether publication of NICE guidelines was associated with a change in the use of diagnostic imaging investigations in patients with a documented first UTI in a tertiary children's hospital. Secondary aims were to describe the epidemiology, microbiology, prescription of prophylactic antibiotics and follow-up for these children, and the incidence of structural renal tract abnormalities, vesicoureteric reflux and renal uptake defects identified. Retrospective review of the case notes of patients presenting to Princess Margaret Hospital, Perth, Western Australia with a first UTI over a 4-year period (August 2005-2009). Details of demographics, radiological investigations, microbiology and follow-up were obtained. Data for subjects presenting before and after 31 August 2007 were compared. Data from 659 subjects, median age 6 (range 0-186) months were analysed. Compared with the pre-NICE period, there was no change in the proportion of patients undergoing renal USS in the 2 years following publication of the guidelines. There was a decrease in the proportion undergoing MCUG (p<0.0001) and receiving antibiotic prophylaxis (p<0.0001) and an increase in the proportion undergoing DMSA (p<0.001). Practice changed following publication of the NICE guidelines. While the reduction in MCUG requests and prescription of antibiotic prophylaxis is in line with NICE guidelines, the increase in DMSA requests is contrary to the recommendations. 23836061 Copresentation of Antigen and Ligands of Siglec-G Induces B Cell Tolerance Independent of CD22. Differentiation of self from nonself is indispensable for maintaining B cell tolerance in peripheral tissues. CD22 and Siglec-G (sialic acid-binding Ig-like lectin G) are two inhibitory coreceptors of the BCR that are implicated in maintenance of tolerance to self Ags. Enforced ligation of CD22 and the BCR by a nanoparticle displaying both Ag and CD22 ligands induces a tolerogenic circuit resulting in apoptosis of the Ag-reactive B cell. Whether Siglec-G also has this property has not been investigated in large part owing to the lack of a selective Siglec-G ligand. In this article, we report the development of a selective high-affinity ligand for Siglec-G and its application as a chemical tool to investigate the tolerogenic potential of Siglec-G. We find that liposomal nanoparticles decorated with Ag and Siglec-G ligand inhibit BCR signaling in both B1 and B2 B cells compared with liposomes displaying Ag alone. Not only is inhibition of B cell activation observed by ligating the BCR with Siglec-G, but robust tolerance toward T-independent and T-dependent Ags is also induced in mice. The ability of Siglec-G to inhibit B cell activation equally in both B1 and B2 subsets is consistent with our observation that Siglec-G is expressed at a relatively constant level throughout numerous B cell subsets. These results suggest that Siglec-G may contribute to maintenance of B cell tolerance toward self Ags in various B cell compartments. 23868198 Remarkable alkaline stability of an engineered protein A as immunoglobulin affinity ligand: C domain having only one amino acid substitution. Protein A affinity chromatography is the standard purification process for the capture of therapeutic antibodies. The individual IgG-binding domains of protein A (E, D, A, B, C) have highly homologous amino acid sequences. From a previous report, it has been assumed that the C domain has superior resistance to alkaline conditions compared to the other domains. We investigated several properties of the C domain as an IgG-Fc capture ligand. Based on cleavage site analysis of a recombinant protein A using a protein sequencer, the C domain was found to be the only domain to have neither of the potential alkaline cleavage sites. Circular dichroism (CD) analysis also indicated that the C domain has good physicochemical stability. Additionally, we evaluated the amino acid substitutions at the Gly-29 position of the C domain, as the Z domain (an artificial B domain) acquired alkaline resistance through a G29A mutation. The G29A mutation proved to increase the alkaline resistance of the C domain, based on BIACORE analysis, although the improvement was significantly smaller than that observed for the B domain. Interestingly, a number of other amino acid mutations at the same position increased alkaline resistance more than did the G29A mutation. This result supports the notion that even a single mutation on the originally alkali-stable C domain would improve its alkaline stability. An engineered protein A based on this C domain is expected to show remarkable performance as an affinity ligand for immunoglobulin. 23751362 Differential subcellular localization of the glucocorticoid receptor in distinct neural stem and progenitor populations of the mouse telencephalon in vivo. Glucocorticoids are given to pregnant women at risk for premature delivery to promote lung maturation. Despite reports of detrimental effects of glucocorticoids on telencephalic neural stem/progenitor cells (NSPCs), the regional and cellular expressions of the glucocorticoid receptor (GR) in various NSPC populations in the intact brain have not been thoroughly assessed. Therefore in this study we performed a detailed analysis of GR protein expression in the developing mouse ventral and dorsal telencephalon in vivo. At embryonic day 11.5 (E11.5), the majority of Pax6-positive radial glial cells (RGCs) and Tbr2-positive intermediate progenitor cells (IPCs) expressed nuclear GR, while a small number of RGCs on the apical ventricular zone (aVZ), expressed cytoplasmic GR. However, on E13.5, the latter population of RGCs increased in size, whereas abventricular NSPCs and especially neurons of the cortical plate, expressed nuclear GR. In IPCs, GR was always nuclear. A similar expression profile was observed throughout the ventral telencephalon, hippocampus and olfactory bulb, with NSPCs of the aVZ primarily expressing cytoplasmic GR, while abventricular NSPCs and mature cells primarily expressed nuclear GR. Close to birth, nuclear GR accumulated within specific cortical areas such as layer V, the subplate and CA1 area of the hippocampus. In summary, our data show that GR protein is present in early NSPCs of the dorsal and ventral telencephalon at E11.5 and primarily occupies the nucleus. Moreover, our study suggests that the subcellular localization of the receptor may be subjected to region and neurodevelopmental stage-specific regulation. 23850732 The anticancer potential of flavonoids isolated from the stem bark of Erythrina suberosa through induction of apoptosis and inhibition of STAT signaling pathway in human leukemia HL-60 cells. Erythrina suberosa is an ornamental tall tree found in India, Pakistan, Nepal, Bhutan, Burma, Thailand and Vietnam. We have isolated four known distinct metabolites designated as α-Hydroxyerysotrine, 4'-Methoxy licoflavanone (MLF), Alpinumisoflavone (AIF) and Wighteone. Among the four isolated metabolites the two flavonoids, MLF and AIF were found to be the most potent cytotoxic agent with IC50 of ∼20μM in human leukemia HL-60 cells. We are reporting first time the anticancer and apoptotic potential of MLF and AIF in HL-60 cells. Both MLF and AIF inhibited HL-60 cell proliferation and induce apoptosis as measured by several biological endpoints. MLF and AIF induce apoptosis bodies formation, enhanced annexinV-FITC binding of the cells, increased sub-G0 cell fraction, loss of mitochondrial membrane potential (Δψm), release of cytochrome c, Bax, activation of caspase-9, caspase-3 and PARP (poly ADP Ribose polymers) cleavage in HL-60 cells. MLF and AIF also increase the expression of apical death receptor, Fas, with inhibition of anti-apoptotic protein Bid. All the above parameters revealed that these two flavonoids induce apoptosis through both extrinsic and intrinsic apoptotic pathways in HL-60 cells. In spite of apoptosis, these two flavonoids significantly inhibit nuclear transcription factor NF-κB and STAT (Signal Transducer and Activator of Transcription) signaling pathway, which are highly expressed in leukemia. The present study provide an insight of molecular mechanism of cell death induced by MLF and AIF in HL-60 cells which may be useful in managing and treating leukemia. 23865855 CELDA -- an ontology for the comprehensive representation of cells in complex systems. The need for detailed description and modeling of cells drives the continuous generation of large and diverse datasets. Unfortunately, there exists no systematic and comprehensive way to organize these datasets and their information. CELDA (Cell: Expression, Localization, Development, Anatomy) is a novel ontology for the association of primary experimental data and derived knowledge to various types of cells of organisms. CELDA is a structure that can help to categorize cell types based on species, anatomical localization, subcellular structures, developmental stages and origin. It targets cells in vitro as well as in vivo. Instead of developing a novel ontology from scratch, we carefully designed CELDA in such a way that existing ontologies were integrated as much as possible, and only minimal extensions were performed to cover those classes and areas not present in any existing model. Currently, ten existing ontologies and models are linked to CELDA through the top-level ontology BioTop. Together with 15.439 newly created classes, CELDA contains more than 196.000 classes and 233.670 relationship axioms. CELDA is primarily used as a representational framework for modeling, analyzing and comparing cells within and across species in CellFinder, a web based data repository on cells (http://cellfinder.org). CELDA can semantically link diverse types of information about cell types. It has been integrated within the research platform CellFinder, where it exemplarily relates cell types from liver and kidney during development on the one hand and anatomical locations in humans on the other, integrating information on all spatial and temporal stages. CELDA is available from the CellFinder website: http://cellfinder.org/about/ontology. 23870553 Metallothionein 2A inhibits NF-κB pathway activation and predicts clinical outcome segregated with TNM stage in gastric cancer patients following radical resection. Metallothionein 2A (MT2A) as a stress protein, plays a protective role in gastric mucosal barrier. Its role in the development of gastric cancer (GC) is unclear. The mechanism of MT2A will be investigated in gastric tumorigenesis. MT2A expression was detected in 973 gastric specimens. The biological function was determined through ectopic expressing MT2A in vitro and in vivo. The possible downstream effectors of MT2A were investigated in NF-κB signaling. The protein levels of MT2A, IκB-α and p-IκB-α (ser32/36) expression were analyzed in a subset of 258 patients by IHC staining. The prognostic effects of MT2A, status of IκB-α and TNM stage were evaluated using the Kaplan-Meier method and compared using the log-rank test. Decreased MT2A expression was detected in cell lines and primary tumors of GC. In clinical data, loss of MT2A (MT2A + in Normal (n =171, 76.0%); Intestinal metaplasia (n = 118, 50.8%); GC (n = 684. 22.4%, P < 0.001)) was associated with poor prognosis (P < 0.001), advanced TNM stage (P = 0.05), and down-regulation of IκB-α expression (P < 0.001). Furthermore, MT2A was the independent prognostic signature segregated from the status of IκB-α and pathological features. In addition, MT2A inhibited cell growth through apoptosis and G2/M arrest, which negatively regulated NF-κB pathway through up-regulation of IκB-α and down-regulation of p-IκB-α and cyclin D1 expression. MT2A might play a tumor suppressive activity through inhibiting NF-κB signaling and may be a prognostic biomarker and potential target for individual therapy of GC patients. 23402907 Enzymatic catalyzed palm oil hydrolysis under ultrasound irradiation: diacylglycerol synthesis. Diacylglycerol (DAG) rich oils have an organoleptic property like that of regular edible oils, but these oils do not tend to be accumulated as fat. Palm oil ranks first in the world in terms of edible oil production owing to its low cost. The aim of this study was to propose a new methodology to produce diacylglycerol by hydrolysis of palm oil using Lipozyme RM IM commercial lipase as a catalyst under ultrasound irradiation. The reactions were carried out at 55 °C with two different methods. First, the reaction system was exposed to ultrasonic waves for the whole reaction time, which led to enzymatic inactivation and water evaporation. Ultrasound was then used to promote emulsification of the water/oil system before the hydrolysis reaction, avoiding contact between the probe and the enzymes. An experimental design was used to optimize the ultrasound-related parameters and maximize the hydrolysis rate, and in these conditions, with a change in equilibrium, DAG production was evaluated. Better reaction conditions were achieved for the second method: 11.20 wt.% (water+oil mass) water content, 1.36 wt.% (water+oil mass) enzyme load, 12 h of reaction time, 1.2 min and 200 W of exposure to ultrasound. In these conditions diacylglycerol yield was 34.17 wt.%. 23633435 Reproductive success of belted kingfishers on the upper Hudson River. Belted kingfishers (Megaceryle alcyon) are predators in many North American aquatic ecosystems; as such, they are prone to bioaccumulation of certain environmental contaminants. In 2002 and 2004, kingfisher eggs collected near the upper Hudson River in New York had elevated concentrations of polychlorinated biphenyls (PCBs), and the kingfisher population in this area was reported to be at risk because of PCB exposure. From 2007 to 2009, the authors monitored 69 kingfisher nests on the Hudson River to track both nest success and survival of individual nestlings. The study site consisted of 2 adjacent sections of the Hudson River, 1 upstream and 1 downstream of a historic PCB source. The authors compared models of nest success that differentially incorporated the following 4 variables that they deemed most likely to affect reproductive output: 1) river section (upstream vs downstream of PCB source), 2) year, 3) hatch date, and 4) abandonment by 1 parent. After ranking models according to Akaike's information criterion for small sample sizes, it was clear that parental abandonment was the most important of the factors examined. River section was not an important parameter, and overall nesting success was slightly higher in the PCB-contaminated section than in the upstream area. These findings support the conclusion that kingfisher productivity is not adversely impacted by PCB contamination in the upper Hudson River. Environ Toxicol Chem 2013;32:1855-1863. © 2013 SETAC. 23897112 Glucose Intolerance, Insulin Resistance, and Pathological Features of Alzheimer Disease in the Baltimore Longitudinal Study of Aging. IMPORTANCE Peripheral glucose homeostasis has been implicated in the pathogenesis of Alzheimer disease (AD). The relationship among diabetes mellitus, insulin, and AD is an important area of investigation. However, whether cognitive impairment seen in those with diabetes is mediated by excess pathological features of AD or other related abnormalities, such as vascular disease, remains unclear. OBJECTIVE To investigate the association between serial measures of glucose intolerance and insulin resistance and in vivo brain β-amyloid burden, measured with carbon 11-labeled Pittsburgh Compound B (11C-PiB), and AD pathology at autopsy. DESIGN Scores calculated from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) and Braak criteria were correlated with measures of hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance in 197 participants who underwent autopsy after death and who had undergone 2 or more oral glucose tolerance tests (OGTT) using grouped analyses and a continuous mixed-models analysis. The same measures of glucose intolerance and insulin resistance were also correlated with brain 11C-PiB retention in an additional 53 living subjects from the Baltimore Longitudinal Study of Aging neuroimaging study. SETTING Prospective, serially assessed cohort of community-dwelling subjects. PARTICIPANTS Cohort 1 consisted of 197 participants enrolled in the Baltimore Longitudinal Study of Aging who had 2 or more OGTTs during life and a complete brain autopsy after death. Cohort 2 consisted of 53 living subjects who had 2 or more OGTTs and underwent brain 11C-PiB positron emission tomography. EXPOSURES Autopsy and 11C-PiB positron emission tomography. MAIN OUTCOMES AND MEASURES The correlation of brain markers of AD, including CERAD score, Braak score, and 11C-PiB retention, with serum markers of glucose homeostasis using grouped and continuous mixed-models analyses. RESULTS We found no significant correlations between measures of brain AD pathology or 11C-PiB β-amyloid load and glucose intolerance or insulin resistance in subjects who had a mean (SD) of 6.4 (3.2) OGTTs during 22.1 (8.0) years of follow-up. Thirty subjects with frank diabetes mellitus who received medications also had AD pathology scores that were similar to those of the cohort as a whole. CONCLUSIONS AND RELEVANCE In this prospective cohort with multiple assessments of glucose intolerance and insulin resistance, measures of glucose and insulin homeostasis are not associated with AD pathology and likely play little role in AD pathogenesis. Long-term therapeutic trials are important to elucidate this issue. 23833299 Tumor Genetic Analyses of Patients with Metastatic Melanoma Treated with the BRAF Inhibitor Dabrafenib (GSK2118436). Dabrafenib is a selective inhibitor of V600-mutant BRAF kinase, which recently showed improved progression-free survival (PFS) as compared with dacarbazine, in metastatic melanoma patients. This study examined potential genetic markers associated with response and PFS in the phase I study of dabrafenib.EXPERIMENTAL DESIGN: Baseline (pretreatment or archival) melanoma samples were evaluated in 41 patients using a custom genotyping melanoma-specific assay, sequencing of PTEN, and copy number analysis using multiplex ligation amplification and array-based comparative genomic hybridization. Nine patients had on-treatment and/or progression samples available.RESULTS: All baseline patient samples had BRAF(V600E/K) confirmed. Baseline PTEN loss/mutation was not associated with best overall response to dabrafenib, but it showed a trend for shorter median PFS [18.3 (95% confidence interval, CI, 9.1-24.3) vs. 32.1 weeks (95% CI, 24.1-33), P = 0.059]. Higher copy number of CCND1 (P = 0.009) and lower copy number of CDKN2A (P = 0.012) at baseline were significantly associated with decreased PFS. Although no melanomas had high-level amplification of BRAF, the two patients with progressive disease as their best response had BRAF copy gain in their tumors.CONCLUSIONS: Copy number changes in CDKN2A, CCND1, and mutation/copy number changes in PTEN correlated with the duration of PFS in patients treated with dabrafenib. The results suggest that these markers should be considered in the design and interpretation of future trials with selective BRAF inhibitors in advanced melanoma patients. Clin Cancer Res; 1-11. ©2013 AACR. 23267661 Effect of long-term co-administration of Wuzhi tablet (Schisandra sphenanthera extract) and prednisone on the pharmacokinetics of tacrolimus. Tacrolimus (TAC) is an immunosuppressant that has been widely used alone or in combination with prednisone (PRED) to prevent acute rejection after organ transplantation. Wuzhi tablet (WZ, Schisandra sphenanthera extract) is often prescribed with TAC to prevent drug-induced hepatitis. We recently reported that WZ could significantly increase TAC blood exposure by inhibiting P-gp-mediated efflux and CYP3A-mediated metabolism of TAC. PRED is also a substrate of P-gp and is a weak inducer of CYP3A, and drug-drug interactions within this combination therapy might occur. Therefore, the purpose of this study was to investigate the effect of long-term treatment of WZ and PRED on the pharmacokinetics of TAC in rats. After 14 days of co-administration of WZ and PRED, the AUC(0-24h) of oral TAC was increased (from 59.6±37.3 to 95.3±39.4 ng h/ml, p=0.18) and the clearance was decreased (from 38.4±28.4 to 17.7±6.4 l/h/kg, p=0.15). When only co-administered with WZ, AUC(0-24h) of TAC was demonstrated a significantly increase (from 59.6±37.3 to 135.9±34.8 ng h/ml, p<0.05). The concomitant administration of PRED resulted in a reduction in the systemic exposure of TAC and an increase in its clearance, though neither was statistically significant. Thus, our study suggested that the presence of WZ and PRED still could increase the systemic exposure of TAC in rats. The drug-drug interactions among this combination therapy should still be taken into consideration in clinical practice. 23756369 Structures and biosynthesis of 12-membered macrocyclic depsipeptides from Streptomyces sp. ML55. Two novel depsipeptides (1-2) were isolated from Streptomyces sp. ML55 together with two known analogues (3-4). Their structures were elucidated using a combination of NMR experiments, as well as detailed MS/MS experiments. The biosynthetic pathway of isolated compounds was dissected by genome sequencing data analysis for a hybrid nonribosomal peptide synthetase (NRPS) and polyketide synthetase (PKS) assembly line. 23234496 Design and assessment of a microfluidic network system for oxygen transport in engineered tissue. Oxygen and nutrients cannot be delivered to cells residing in the interior of large-volume scaffolds via diffusion alone. Several efforts have been made to meet the metabolic needs of cells in a scaffold by constructing mass transport channels, particularly in the form of bifurcated networks. In contrast to progress in fabrication technologies, however, an approach to designing an optimal network based on experimental evaluation has not been actively reported. The main objective of this study was to establish a procedure for designing an effective microfluidic network system for a cell-seeded scaffold and to develop an experimental model to evaluate the design. We proposed a process to design a microfluidic network by combining an oxygen transport simulation with biomimetic principles governing biological vascular trees. The simulation was performed with the effective diffusion coefficient (D(e,s)), which was experimentally measured in our previous study. Porous scaffolds containing an embedded microfluidic network were fabricated using the lost mold shape-forming process and salt leaching method. The reliability of the procedure was demonstrated by experiments using the scaffolds. This approach established a practical basis for designing an effective microfluidic network in a cell-seeded scaffold. 23411337 Rapid quantification of muscle fat content and subcutaneous adipose tissue in fish using MRI. The potentiality of MRI to quantify fat content in flesh and subcutaneous fat in fish cutlets was investigated. Low measurement time was aimed at in a view to handling large number of samples needed in selective breeding programs for example. Results on fresh and frozen-thawed cutlets were compared to assess this way of conservation. As MRI generates unwanted spatial variations of the signal, a correction method was developed enabling the measurement on several cutlets simultaneously in less than 3 min per sample. For subcutaneous fat, the results were compared with vision measurements. High correlations between both techniques were found (R(2)=0.77 and 0.87 for the ventral and dorsal part). Fat in flesh was validated vs NMR measurements. No statistical difference was found between fresh and frozen-thawed cutlets. RMSE was respectively 0.8% and 0.89%. These results confirmed the potentiality of MRI for fat measurement in fish particularly for a large number of samples. 23411285 Enhancing the production of galacto-oligosaccharides by mutagenesis of Sulfolobus solfataricus β-galactosidase. Galacto-oligosaccharides (GOS), an important class of functional food, are commonly produced from lactose using β-galactosidase. In the present study, β-galactosidase (LacS) from Sulfolobus solfataricus P2 was cloned and site-directed mutagenesis was performed to obtain two mutants, F359Q and F441Y. All of the wild-type enzyme and mutants were expressed in Escherichia coli BL21(DE3) and purified to homogeneity. The enzymatic properties and optimal condition for transglycosylation reaction of the enzymes were investigated in detail. Under their individual optimal conditions, yields of GOS could reach 50.9% for wild-type enzyme, 58.3% for F359Q, and 61.7% for F441Y. In addition, the potential mechanism for this enhancement was analysed. 23939812 Tandem Orthogonal Chemically Induced Dimerization. Switch on and off: Chemically induced dimerization (CID) has been shown to be a powerful tool for dissecting and emulating signaling pathways. What has been missing so far is the reproduction of reversibility in signal transduction. This problem could be resolved by applying two orthogonal CID systems in tandem, which allow switching signaling on and off through a double translocation strategy. 23916147 Biotransformation of ent-pimaradienoic acid by cell cultures of Aspergillus niger. Microbial transformation stands out among the many possible semi-synthetic strategies employed to increase the variety of chemical structures that can be applied in the search for novel bioactive compounds. In this paper we obtained ent-pimaradienoic acid (1, PA, ent-pimara-8(14),15-dien-19-oic acid) derivatives by fungal biotransformation using Aspergillus niger strains. To assess the ability of such compounds to inhibit vascular smooth muscle contraction, we also investigated their spasmolytic effect, along with another five PA derivatives previously obtained in our laboratory, on aortic rings isolated from male Wistar rats. The microbial transformation experiments were conducted at 30°C using submerged shaken liquid culture (120rpm) for 10days. One known compound, 7α-hydroxy ent-pimara-8(14),15-dien-19-oic acid (2), and three new derivatives, 1β-hydroxy ent-pimara-6,8(14),15-trien-19-oic acid (3), 1α,6β,14β-trihydroxy ent-pimara-7,15-dien-19-oic acid (4), and 1α,6β,7α,11α-tetrahydroxy ent-pimara-8(14),15-dien-19-oic acid (5), were isolated and identified on the basis of spectroscopic analyses and computational studies. The compounds obtained through biotransformation (2-5) did not display a significant antispasmodic activity (values ranging from 0% to 16.8% of inhibition); however the previously obtained diterpene, methyl 7α-hydroxy ent-pimara-8(14),15-dien-19-oate (8), showed to be very effective (82.5% of inhibition). In addition, our biological results highlight the importance to study the antispasmodic potential of a large number of novel diterpenes, to conduct further structure-activity relationship investigations. 23407783 The CRF(1) receptor antagonist SSR125543 prevents stress-induced cognitive deficit associated with hippocampal dysfunction: Comparison with paroxetine and D-cycloserine. RATIONALE: The selective CRF(1) (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term cognitive deficit produced by traumatic stress exposure. Memory disturbances described in post-traumatic stress disorder (PTSD) patients are believed to be associated with changes in neuronal activity, in particular at the level of the hippocampus. OBJECTIVES: The present study aims at investigating whether the effects of SSR125543 (10 mg/kg/day for 2 weeks) on cognitive impairment induced by traumatic stress exposure are associated with changes in hippocampal excitability. Effects of SSR125543 were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day), and the partial N-methyl-D-aspartate (NMDA) receptor agonist, D-cycloserine (10 mg/kg/day), two compounds which have demonstrated clinical efficacy against PTSD. METHODS: Mice received two unavoidable electric foot-shocks. Then, 1 or 16 days after stress, they were tested for their memory performance using the object recognition test. Neuronal excitability was recorded during the third week post-stress in the CA1 area of the hippocampus. Drugs were administered from day 1 post-stress to the day preceding the electrophysiological study. RESULTS: Application of electric shocks produced cognitive impairment 16, but not 1 day after stress, an effect which was associated with a decrease in hippocampal neuronal excitability. Both stress-induced effects were prevented by repeated administration of SSR125543, paroxetine and D-cycloserine. CONCLUSIONS: These findings confirm that the CRF(1) receptor antagonist SSR125543 is able to attenuate the behavioral effects of traumatic stress exposure and indicate that these effects are associated with a normalization of hippocampal neuronal excitability impaired by stress. 23969654 The use of diffuse laser photonic energy and indocyanine green photosensitiser as an adjunct to periodontal therapy. Light-activated chemical therapy - generally known as photodynamic therapy (PDT) - has been developed within medicine, to allow the use of an applied agent (photosensitiser) that could be activated using laser photonic energy, leading to the destruction of target cellular structures. In clinical dentistry, PDT has been utilised within a wide scope of topical application in endodontic, periodontal and oral epithelial pathology where specifically, anti-bacterial action may prove useful. Underlying the complex and multi-factorial aetiology, periodontal disease remains of essentially-bacterial origin and anti-bacterial PDT (aPDT) has been investigated as an adjunctive to other periodontal treatment therapies. Of several topically-applied photosensitisers, one agent, indocyanine green, may be activated using a diode laser wavelength (810 nm) that is commonly-available in clinical dental practice, to provide generalised bacteriocidal effect. Unlike antibiotics and antibacterial mouthwashes, the mode of action appears to be nonspecific to bacterial species and is linked to cell death through a process of oxidative stress. Additionally, indocyanine green has otherwise low toxicity to non-target host tissue and dental restorative materials. This paper explores the background to this therapy, its position within the broader delivery of periodontal treatment and the specific application of indocyanine green in clinical dental practice. 23967153 Grape Seed Procyanidin Reversal of P-glycoprotein Associated Multi-Drug Resistance via Down-regulation of NF-κB and MAPK/ERK Mediated YB-1 Activity in A2780/T Cells. The expression and function of P-glycoprotein (P-gp) is associated with the phenotype of multi-drug resistance (MDR), leading chemotherapy failure of patients suffered with cancer. Grape seed procyanidin(GSP) is a natural polyphenol supplement with anti-inflammatory effect. Present study assessed a new use of GSP on the MDR reversal activity and its possible molecular mechanisms in MDR1-overpressing paclitaxel resistant ovarian cancer cells. Our results showed GSP significantly enhanced the cytotoxicity of paclitaxel and adriamycin in paclitaxel resistant A2780/T cells but its parental A2780 cells. Furthermore, GSP strongly inhibited P-gp expression by blocking MDR1 gene transcription, as well as, increased the intracellular accumulation of the P-gp substrate rhodamine-123 in A2780/T cells. Nuclear factor-κB(NF-κB) activity, IκB degradation level and NF-κB/p65 nuclear translocation induced by lipopolysaccharide (LPS) and receptor activator for nuclear factor-κB ligand (RANKL) were markedly inhibited by pre-treatment with GSP. Meanwhile, GSP inhibited MAPK/ERK pathway by decreasing the phosphorylation of ERK1/2, resulting in reduced the Y-box binding protein 1 (YB-1) activation with blocking its nuclear translocation. Moreover, the up-regulation of P-gp expression, the activation of AKT/NF-κB and MAPK/ERK pathway induced by LPS was attenuated by GSP administration. Compared with PDTC and U1026, inhibitor of NF-κB and MAPK/ERK respectively, GSP showed the same tendency of down-regulating NF-κB and MAPK/ERK mediated YB-1 activities. Thus, GSP reverses P-gp associated MDR by inhibiting the function and expression of P-gp through down-regulation of NF-κB activity and MAPK/ERK pathway mediated YB-1 nuclear translocation, offering insight into the mechanism of reversing MDR by natural polyphenol supplement compounds. GSP could be a new potential MDR reversal agent used for combination therapy with chemotherapeutics in clinic. 23599037 The effect of pore-formers and plasticizers on the release kinetic of diltiazem hydrochloride from the controlled porosity osmotic pumps. The aim of this study was to design a controlled porosity osmotic pump (CPOP) tablet of diltiazem hydrochloride (DLTZ) to deliver the drug according to the zero order kinetic model over 24 h.CPOPs were prepared by incorporating DLTZ in the tablet core followed by coating with cellulose acetate solution containing various types of pore-formers (PVP, PEG 2000, PEG 6000 and PEG 20000) and plasticizers (glycerol, castor oil and diethylphthalate). In vitro release study was conducted for the prepared formulations and the dissolution profiles were compared throughout four parameters, namely, D24 h (cumulative release in 24 h), tL (lag time), RSQzero (squared correlation coefficient of zero order kinetic) and MPDzero (mean percent deviation from zero order equation).Scanning electron microscopy showed formation of the pores in the semi-permeable membrane after coming in contact with dissolution medium. All formulations released more than 76% of contained drug during 24 h.Drug release rate and lag time were found to be directly proportional to the type and concentration of pore-formers as well as hydrophilicity of plasticizers. Our findings indicated that by optimizing formulation variables, CPOP tablets obeying zero order drug release kinetic could be obtained. 23656428 Cotton plasma membrane intrinsic protein 2s (PIP2s) selectively interact to regulate their water channel activities and are required for fibre development. Aquaporins are thought to be associated with water transport and play important roles in cotton (Gossypium hirsutum) fibre elongation. Among aquaporins, plasma membrane intrinsic proteins (PIPs) constitute a plasma-membrane-specific subfamily and are further subdivided into PIP1 and PIP2 groups. In this study, four fibre-preferential GhPIP2 genes were functionally characterized. The selective interactions among GhPIP2s and their interaction proteins were studied in detail to elucidate the molecular mechanism of cotton fibre development. GhPIP2;3 interacted with GhPIP2;4 and GhPIP2;6, but GhPIP2;6 did not interact with GhPIP2;4. Coexpression of GhPIP2;3/2;4 or GhPIP2;3/2;6 resulted in a positive cooperative effect which increased the permeability coefficient of oocytes, while GhPIP2;4/2;6 did not. GhBCP2 (a blue copper-binding protein) inhibited GhPIP2;6 water channel activity through their interaction. Overexpression of GhPIP2 genes in yeast induced longitudinal growth of the host cells. By contrast, knockdown of expression of GhPIP2 genes in cotton by RNA interference markedly hindered fibre elongation. In conclusion, GhPIP2 proteins are the primary aquaporin isoforms in fibres. They selectively form hetero-oligomers in order to regulate their activities to meet the requirements for rapid fibre elongation. 23784945 Enantioselective photochromism of diarylethenes in human serum albumin. Making light work of chromism: Enantioselective photochromic ring-closing reactions of three bisthienylethene compounds possessing either no or two hydroxy groups were carried out in the hydrophobic pockets of human serum albumin (HSA) in aqueous media. When 10 equivalents of HSA were used, 1,2-bis(5-hydroxymethyl-2-methyl-3-thienyl)hexafluorocyclopentene predominantly produced the S,S closed form (see scheme; O=open, C=closed), in 63 % ee at RT and 71 % ee at -4 °C upon irradiation with 313 nm light. 23625947 Structural Determinants of Agonist Efficacy at the Glutamate Binding Site of NMDA Receptors. NMDA receptors are ligand-gated ion channels assembled from GluN1 and GluN2 subunits. We utilized a series of N-hydroxypyrazole-5-glycine (NHP5G) partial agonists at the GluN2 glutamate binding site as tools to study activation of GluN1/GluN2A and GluN1/GluN2D NMDA receptor subtypes. We show using two-electrode voltage-clamp electrophysiology, fast-application patch-clamp, and single channel recordings that propyl- and ethyl-substituted NHP5G agonists have a broad range of agonist efficacies relative to the full agonist glutamate (<1%-72%). Crystal structures of the agonist binding domains (ABDs) of GluN2A and GluN2D do not reveal any differences in the overall domain conformation induced by binding of the full agonist glutamate or the partial agonist propyl-NHP5G, which is strikingly different from ABD structures of AMPA and kainate receptors bound to full and partial agonists. Subsequent evaluation of relative NHP5G agonist efficacy at GluN2A-GluN2D chimeric subunits implicates the amino-terminal domain (ATD) as a strong determinant of agonist efficacy, suggesting that interdomain interactions between the ABD and the ATD may be a central element in controlling the manner by which agonist binding leads to channel opening. We propose that variation in the overall receptor conformation, which is strongly influenced by the nature of interdomain interactions in resting and active states, mediates differences in agonist efficacy and partial agonism at the GluN2 subunits. 23625907 Pirimicarb-based formulation-induced genotoxicity and cytotoxicity in the fresh water fish Cnesterodon decemmaculatus (Jenyns, 1842) (Pisces, Poeciliidae). We analyzed the aspects of lethality, genotoxicity, and cytotoxicity in the ten spotted live-bearer exposed under laboratory conditions to the pirimicarb-based formulation Patton Flow(®) (50% active ingredient (a.i.)). Acute effects were evaluated using different end points for lethality, genotoxicity, and cytotoxicity. Median lethal concentration (LC50) estimation was employed as a bioassay for lethality, whereas micronucleus (MN) induction and alterations in erythrocyte/erythroblast frequency were used as end points for genotoxicity and cytotoxicity, respectively. Results demonstrated an LC5096h value of 88 mg/L. Patton Flow(®) increased the MN frequency in fish erythrocytes after 48 h of exposure at a concentration of 66 mg/L, whereas a concentration range of 22-66 mg/L was able to exert the same genotoxic effect at 96 h of treatment. Furthermore, cytotoxicity was also observed by alterations in erythrocyte/erythroblast frequencies within the concentration range of 22-66 mg/L, regardless of the exposure time. Our current observations provide evidence that Patton Flow(®) (50% a.i.) should be considered a clear lethal, cytotoxic, and genotoxic agent on Cnesterodon decemmaculatus. Thus, repeated applications of this carbamic insecticide can enter the aquatic environment and exert deleterious effects on aquatic organisms other than the evaluated species C. decemmaculatus. 23696107 Are network-based interventions a useful antiobesity strategy? An application of simulation models for causal inference in epidemiology. Recent research suggests that social networks may present an avenue for intervention against obesity. By using a simulation model in which artificial individuals were nested in a social network, we assessed whether interventions targeting highly networked individuals could help reduce population obesity. We compared the effects of targeting antiobesity interventions at the most connected individuals in a network with those targeting individuals at random. We tested 2 interventions, the first "preventing" obesity among 10% of the population at simulation outset and the second "treating" obesity among 10% of the obese population yearly, each in 2 separate simulations. One simulation featured a literature-based parameter for the network spread of obesity, and the other featured an artificially high parameter. Interventions that targeted highly networked individuals did not outperform at-random interventions in simulations featuring the literature-based parameter. However, in simulations featuring the artificially high parameter, the targeted prevention intervention outperformed the at-random intervention, whereas the treatment intervention implemented at random outperformed the targeted treatment intervention. Results were qualitatively similar across network topologies and intervention scales. Although descriptive studies suggest that social networks influence the spread of obesity, policies targeting well-connected individuals in social networks may not improve obesity reduction. We highlight and discuss the potential applications of counterfactual simulations in epidemiology. 23952841 Fabrication of a Stretchable Solid-State Micro-Supercapacitor Array. We fabricated a stretchable micro-supercapacitor array with planar SWCNT electrodes and an ionic liquid-based triblock copolymer electrolyte. The mechanical stability of the entire supercapacitor array upon stretching was obtained by adopting strategic design concepts. First, the narrow and long serpentine metallic interconnections were encapsulated with polyimide thin film to ensure that they were within the mechanical neutral plane. Second, an array of two-dimensional planar micro-supercapacitor with SWCNT electrodes and an ion-gel-type electrolyte was made to achieve all-solid-state energy storage devices. The formed micro-supercapacitor array showed excellent performances which were stable over stretching up to 30% without any noticeable degradation. This work shows the strong potential of a stretchable micro-supercapacitor array in applications such as wearable computers, power dressing, electronic newspapers, paper-like mobile phones, and other easily collapsible gadgets. 23928656 Comparison of aggregating agents for the surface-enhanced Raman analysis of benzodiazepines. Benzodiazepines are among the most prescribed compounds and are commonly present in many toxicological screens. They are also of concern forensically in cases of drug facilitated sexual assault. Currently these compounds are predominantly analyzed using immunoassay techniques; however more specific screening methods are needed. This paper demonstrates the applicability of surface enhanced Raman spectroscopy as a method for the analysis and detection of benzodiazepines. The procedure involves mixing urine extracts with gold nanoparticles and appropriate aggregating agents for trace detection of these compounds and their metabolites. In this paper we will discuss the optimization of various parameters of this technique as well as its application to screening urine samples. Eleven different benzodiazepines and metabolites were examined, including 1,2-triazolo-benzodiazepines and 1,4-benzodiazpines. Experiments were performed using four different chloride salts, MgCl2, CaCl2, KCl, and NaCl, as aggregating agents for the colloidal gold nanoparticles. Overall it was found that each aggregating agent produced different levels of signal enhancement for each drug. MgCl2 provided the lowest limit of detection at 2.5 ng mL(-1), and linearity over a wide range of concentrations for a variety of drugs chosen. It was also determined that the optimum MgCl2 concentration was 1.67 M. This method has shown the applicability of SERS for the detection of trace quantities of benzodiazepines in aqueous solutions as well as the optimization of the technique over a wide range of compounds. This technique can be utilized in the detection of trace benzodiazepines in toxicological samples following extraction of the analyte. 23621709 OxyR acts as a transcriptional repressor of hydrogen peroxide-inducible antioxidant genes in Corynebacterium glutamicum R. OxyR, a LysR-type transcriptional regulator, has been established as a redox-responsive activator of antioxidant genes in bacteria. This study shows that OxyR acts as a transcriptional repressor of katA, dps, ftn and cydA in Corynebacterium glutamicum R. katA encodes H2O2-detoxifing enzyme catalase, dps and ftn are implicated in iron homeostasis and cydA encodes a subunit of cytochrome bd oxidase. Quantitative RT-PCR analyses revealed that expression of katA and dps, but not of ftn and cydA, was induced by H2O2. Disruption of the oxyR gene encoding OxyR resulted in a marked increase in katA and dps mRNAs to a level higher than that induced by H2O2, and the oxyR-deficient mutant showed a H2O2-resistant phenotype. This is in contrast to the conventional OxyR-dependent regulatory model. ftn and cydA were also upregulated by oxyR disruption but to a smaller extent. Electrophoretic mobility shift assays revealed that the OxyR protein specifically binds to all four upstream regions of the respective genes under reducing conditions. We observed that the oxidized form of OxyR similarly bound to not only the target promoter regions, but also nonspecific DNA fragments. Based on these findings, we propose that the transcriptional repression by OxyR is alleviated under oxidative stress conditions in a titration mechanism due to the decreased specificity of its DNA-binding activity. DNase I footprinting analyses revealed that the OxyR-binding site in the four target promoters is ~ 50 bp in length and has multiple T-N11-A motifs, a feature of LysR-type transcriptional regulators, but no significant overall sequence conservation. 23870663 Highlights of the 16th annual scientific sessions of the Society for Cardiovascular Magnetic Resonance. The 16th Annual Scientific Sessions of the Society for Cardiovascular Magnetic Resonance (SCMR) took place in San Francisco, USA at the end of January 2013. With a faculty of experts from across the world, this congress provided a wealth of insight into cutting-edge research and technological development. This review article intends to provide a highlight of what represented the most significant advances in the field of cardiovascular magnetic resonance (CMR) during this year's meeting. 23583806 Short-term heating reduces the anti-inflammatory effects of fresh raw garlic extracts on the LPS-induced production of NO and pro-inflammatory cytokines by downregulating allicin activity in RAW 264.7 macrophages. Garlic has a variety of biologic activities, including anti-inflammatory properties. Although garlic has several biologic activities, some people dislike eating fresh raw garlic because of its strong taste and smell. Therefore, garlic formulations involving heating procedures have been developed. In this study, we investigated whether short-term heating affects the anti-inflammatory properties of garlic. Fresh and heated raw garlic extracts (FRGE and HRGE) were prepared with incubation at 25°C and 95°C, respectively, for 2h. Treatment with FRGE and HRGE significantly reduced the LPS-induced increase in the pro-inflammatory cytokine concentration (TNF-α, IL-1β, and IL-6) and NO through HO-1 upregulation in RAW 264.7 macrophages. The anti-inflammatory effect was greater in FRGE than in HRGE. The allicin concentration was higher in FRGE than in HRGE. Allicin treatment showed reduced production of pro-inflammatory cytokines and NO and increased HO-1 activity. The results show that the decrease in LPS-induced NO and pro-inflammatory cytokines in RAW 264.7 macrophages through HO-1 induction was greater for FRGE compared with HRGE. Additionally, the results indicate that allicin is responsible for the anti-inflammatory effect of FRGE. Our results suggest a potential therapeutic use of allicin in the treatment of chronic inflammatory disease. 23763545 Mycobacterium llatzerense Lung Infection in a Liver Transplant Recipient: Case Report and Review of the Literature. Nontuberculous mycobacteria are increasingly encountered pathogens in organ transplant recipients. We report the first case of human disease attributed to Mycobacterium llatzerense that occurred in a liver transplant recipient in the midwestern United States who developed pneumonia and describe the treatment of this patient. 23411237 Determination of ethyl carbamate in cachaça produced from copper stills by HPLC. Ethyl carbamate (EC) is a common substance in fermented foods and drinks, and its quantification is important because of its carcinogenic nature and its usually presence in alcoholic beverages. The present work involved the development and validation of an analytical method for the evaluation of EC in cachaça by HPLC-FLD after previous derivatization with xanthydrol. The method presented a mean recovery of 94.88%, an intra-day precision of 4.19% (30.0 μgL(-1)) and 3.32% (75.0 μgL(-1)), a coefficient of determination (r(2)) equal to 0.9985, and limits of detection and quantification equal to 6.39 and 21.32 μgL(-1), respectively. The results show that the analytical method is accurate, reproducible and linear over the concentration range from 5.0 to 160 μg of EC per litre. The method was applied to the analysis of EC in cachaça, the analyses being rapid and efficient. 23845146 Unraveling the Photoluminescence Response of Light-Switching Ruthenium(II) Complexes Bound to Amyloid-β. Photoluminescent molecules are widely used for real-time monitoring of peptide aggregation. In this Article, we detail both experimental and computational modeling to elucidate the interaction between [Ru(bpy)2dppz](2+) and amyloid-β (Aβ1-40) aggregates. The transition from monomeric to fibrillar Aβ is of interest in the study of Alzheimer's disease. Concentration-dependent experiments allowed the determination of a dissociation constant of 2.1 μM, while Job plots provided a binding stoichiometry of 2.6 Aβ monomers per [Ru(bpy)2dppz](2+). Our computational approach that combines molecular docking (both rigid and flexible) and all-atom molecular dynamics (MD) simulations predicts that the hydrophobic cleft between Val18 and Phe20 is a plausible binding site, which could also explain the increase in photoluminescence of [Ru(bpy)2dppz](2+) upon binding. This binding site is parallel to the fibril axis, in marked contrast to the binding site of these complexes in DNA (perpendicular to the DNA axis). Other binding sites may exist at the edges of the Aβ fibril, but they are actually of low abundance in an Aβ fibril several micrometers long. The assignment of the binding site was confirmed by binding studies in an Aβ fragment (Aβ25-35) that lacked the amino acids necessary to form the binding site. The agreement between the experimental and computational work is remarkable and provides a general model that can be used for studying the interaction of amyloid-binding molecules to Aβ. 23797270 L-Proline catalyzed reaction of N-confused porphyrin and active methylene compounds. Active methylene compounds such as acetone, butanone, cyclopentanone, nitromethane, malononitrile, ethyl 2-cyanoacetate, diethyl malonate, and ethyl acetylacetate react with the C3 position of N-confused porphyrin in the presence of L-proline in refluxing THF-EtOH affording a variety of N-confused porphyrin derivatives in moderate yield. L-Proline catalyzes the reaction facilitating the formation of the carbanion derived from an active methylene compound simultaneously delivering protons to the N-confused porphyrin. Both processes are key factors of this reaction. 23928498 Fabrication of pRNA nanoparticles to deliver therapeutic RNAs and bioactive compounds into tumor cells. RNA nanotechnology is a term that refers to the design, fabrication and use of nanoparticles that are mainly composed of RNAs via bottom-up self-assembly. The packaging RNA (pRNA) of the bacteriophage phi29 DNA packaging motor has been developed into a nanodelivery platform. This protocol describes the synthesis, assembly and functionalization of pRNA nanoparticles on the basis of three 'toolkits' derived from pRNA structural features: interlocking loops for hand-in-hand interactions, palindrome sequences for foot-to-foot interactions and an RNA three-way junction for branch extension. siRNAs, ribozymes, aptamers, chemical ligands, fluorophores and other functionalities can also be fused to the pRNA before the assembly of the nanoparticles, so as to ensure the production of homogeneous nanoparticles and the retention of appropriate folding and function of the incorporated modules. The resulting self-assembled multivalent pRNA nanoparticles are thermodynamically and chemically stable, and they remain intact at ultralow concentrations. Gene-silencing effects are progressively enhanced with increasing numbers of siRNAs in each pRNA nanoparticle. Systemic injection of the pRNA nanoparticles into xenograft-bearing mice has revealed strong binding to tumors without accumulation in vital organs or tissues. The pRNA-based nanodelivery scaffold paves a new way for nanotechnological application of pRNA-based nanoparticles for disease detection and treatment. The time required for completing one round of this protocol is 3-4 weeks when including in vitro functional assays, or 2-3 months when including in vivo studies. 23743531 Partial posterior hyaloidectomy for macular disorders. PurposeTo evaluate the effect of partial posterior hyaloidectomy (PPH) in preventing iatrogenic retinal breaks related to the induction of a posterior vitreous detachment (IPVD)MethodsFifty-nine patients who necessitated IPVD for an epiretinal membrane or macular hole were included in this prospective, interventional case series. Extensive removal of vitreous gel, close to the retina, was conducted before IPVD under 23 G (gauge)-vitrectomy system. The PPH involved the limited extent of IPVD and limited removal of the outermost vitreous cortex to an area slightly beyond the margin of the temporal major vascular arcade. The incidence of retinal breaks related to the surgery was compared with 57 eyes that had undergone conventional 23-G total vitrectomy accompanied by extensive IPVD using χ(2)-test.ResultsPatients were followed-up for a mean of 14.3 months (6-30 months) after the surgery. The incidence of peripheral retinal breaks after the PPH was 3.4% (2/59 eyes), which was significantly lower than that in the eyes that underwent conventional 23 G vitrectomy (15.8%, 9/57 eyes, P=0.023) for the same disorders that required an IPVD. No patient complained of postoperative floaters, postoperatively.ConclusionsPPH would be an efficient procedure to prevent iatrogenic peripheral retinal breaks related to an IPVD. 23919824 Ligand-Protein interactions of Selective Casein Kinase 1δ inhibitors. Casein Kinase 1 (CK1) δ and ε are believed necessary enzymes for the regulation of circadian rhythms in all mammals. Based on our previously published work demonstrating that a CK1ε preferring compound to be ineffective circadian clock modulator, we have synthesized a series of pyrazole-substitued pyridine inhibitors, selective for the CK1δ isoform. Additionally, using structure-based drug design, we have been able to exploit differences in the hinge region between CK1δ and p38 to find selective inhibitors that have minimal p38 activity. The SAR, brain exposure and the effect of these inhibitors on mouse circadian rhythms are described. The in vivo evaluation of these inhibitors demonstrates that selective inhibition of CK1δ at sufficient central exposure levels is capable of modulating of circadian rhythms. 23733886 The LXR-IDOL axis defines a clathrin-, caveolae-, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation. Low density lipoprotein (LDL) cholesterol is taken up into cells via clathrin-mediated endocytosis of the LDL receptor (LDLR). Following dissociation of the LDLR-LDL complex, LDL is directed to lysosomes whereas the LDLR recycles to the plasma membrane. Activation of the sterol-sensing nuclear receptors liver X receptors (LXRs) enhances degradation of the LDLR. This depends on the LXR target gene inducible degrader of the LDLR (IDOL), an E3-ubiquitin ligase that promotes ubiquitylation and lysosomal degradation of the LDLR. How ubiquitylation of the LDLR by IDOL controls its endocytic trafficking is currently unknown. Using genetic- and pharmacological-based approaches coupled to functional assessment of LDL uptake, we show that the LXR-IDOL axis targets a LDLR pool present in lipid rafts. IDOL-dependent internalization of the LDLR is independent of clathrin, caveolin, macroautophagy, and dynamin. Rather, it depends on the endocytic protein epsin. Consistent with LDLR ubiquitylation acting as a sorting signal, degradation of the receptor can be blocked by perturbing the endosomal sorting complex required for transport (ESCRT) or by USP8, a deubiquitylase implicated in sorting ubiquitylated cargo to multivesicular bodies. In summary, we provide evidence for the existence of an LXR-IDOL-mediated internalization pathway for the LDLR that is distinct from that used for lipoprotein uptake. 23354921 Causes and costs of a decade of litigation following emergency appendectomy in England. There has been recent interest in the delayed and nonoperative management of appendicitis. The present study assessed the causes and costs of litigation against surgeons following emergency appendectomy, with an emphasis on claims relating to preoperative management. Data were obtained from the English NHS Litigation Authority for claims relevant to appendectomy between 2002 and 2011. Two authors independently extracted data and classified it against predetermined criteria. Successful litigation occurred in 66 % of closed cases (147/223) with a total payout of £8.1 million. There were 24 claims against organizational operating room delays (9 % of total) and 27 against delayed diagnosis (10 %), with respective success rates of 70 and 68 %. From 21 claims relating to damage to fertility, nine were due to either delayed diagnosis or organizational operating room delays. Misdiagnosis was the second most common cause for litigation (16 %), but it had the lowest likelihood of success (49 %). Faulty surgical technique was the most common reason for litigation (39 %), with a 70 % likelihood of success. Of eight claims related to fatality, one was due to unacceptable preoperative delay leading to preventable perforated appendicitis. The overall highest median payouts were for claims of damage to fertility (£52,384), operating list delays (£44,716), and delayed diagnosis (£42,292). There were significant medicolegal risks surrounding delays related to access to operating lists and diagnosis. Whereas future evidence regarding the safety of delayed appendectomy may provide scientific defense against these claims, the present study provides evidence of the current medicolegal risk to surgeons following delayed treatment of appendicitis. 23907816 Seasonal reproduction of yellowish myotis, Myotis levis (chiroptera: Vespertilionidae), from a Neotropical highland. With a nearly global distribution the vespertilionid bat Myotis represents one of the most exceptional examples of adaptive radiation among mammals. We investigated the reproductive activity of the vespertilionid bat yellowish myotis, Myotis levis, from a highland area in Southeastern Brazil. The data were obtained through histological analyses of the male and female genital systems from February 2010 to May 2011. The testes of the adult yellowish myotis showed seasonal morphological characteristics which were categorized in the following stages: rest, maturing, mature, and mating. Rest and maturing males were recorded throughout the rainy season (October-March). In the rest stage no spermatogenesis was observed and the epididymal duct was devoid of spermatozoa. Maturing individuals had started spermatogenesis and few spermatozoa were found in the epididymal duct. Mature males were found toward the end (February-March) of the rainy season, when full spermatogenic activity was recorded and spermatozoa were packed in the epididymal duct. Although not recorded, mating probably occurred in the middle of the dry season (April-September) when the cauda epididymis was enlarged and packed with sperm. The spermatozoa remained stored in the cauda epididymis for at least three months when the testes entered into regression. The ovaries showed all types of ovarian follicles throughout the study period except mature follicles which were registered only in July (mid-dry season). Lactating females were captured in the beginning of the rainy season. The seasonal reproductive characteristics of the yellowish myotis from this Neotropical highland area were similar those of epididymal sperm-storing temperate vespertilionids. J. Morphol., 2013. © 2013 Wiley Periodicals, Inc. 23438693 Mdm2 increases cellular invasiveness by binding to and stabilizing the Slug mRNA. Mdm2 is an oncoprotein that induces the degradation of the tumor suppressor, p53. Here, we show that Mdm2 increases the mRNA levels of Slug by binding to and stabilizing the Slug mRNA. While this effect of Mdm2 was observed in both p53-null and p53-expressing cancer cells, it increased the protein levels of Slug only in the former cells. Mdm2 consistently induced Slug-dependent events, such as decreases in E-cadherin levels and increases in cellular invasiveness, only in p53-null cells. Therefore, the binding of Mdm2 to the Slug mRNA appears to provide a novel mechanism through which Mdm2 promotes tumor progression in a manner independent of the presence of p53. 23922405 Prescribing errors on admission to hospital and their potential impact: a mixed-methods study. Medication errors are an important cause of morbidity and mortality and adversely affect clinical outcomes. Prescribing errors constitute one type of medication error and occur particularly on admission to hospital; little is known about how they arise. This study investigated how doctors obtain the information necessary to prescribe on admission to hospital, and the number and potential impact of any errors. English teaching hospital-acute medical unit. Ethics approval was granted. Data were collected over four 1-week periods; November 2009, January 2010, April 2010 and April 2011. The patient admission process was directly observed, field notes were recorded using a standard form. Doctors participated in a structured interview; case notes of all patients admitted during study periods were reviewed. There were differences between perceived practice stated in interviews and actual practice observed. All 19 doctors interviewed indicated that they would sometimes or always use more than one source of information for a medication history; a single source was used in 31/68 observed cases. 7/12 doctors both observed and interviewed indicated that they would confirm medication with patients; observations showed they did so for only 2/12 patients. In 66/68 cases, the patient/carer was able to discuss medication, 14 were asked no medication-related questions. Of 688 medication charts reviewed, 318 (46.2%) had errors. A total of 851 errors were identified; 737/851 (86.6%) involved omission of a medicine; 94/737 (12.8%) of these were potentially significant. Although doctors know the importance of obtaining an accurate medication history and checking prescriptions with patients, they often fail to put this into practice, resulting in prescribing errors. 23631431 Association between the LCE3C_LCE3B deletion polymorphism and susceptibility to psoriasis: a meta-analysis of published studies. To determine whether a deletion comprising the LCE3C and LCE3B genes (LCE3C_LCE3B-del) confers susceptibility to psoriasis. A meta-analysis was conducted to assess the association between the LCE3C_LCE3B-del polymorphism and psoriasis. A total of 12,196 patients with psoriasis and 13,092 controls from 19 comparative studies were included in this meta-analysis. The meta-analysis showed a significant association between psoriasis and the LCE3C_LCE3B-del allele (odds ratio [OR], 1.220; 95% confidence interval [CI], 1.152-1.292; p<1.0×10(-9)). Stratification by ethnicity indicated an association between the LCE3C_LCE3B-del allele and psoriasis in Europeans and Asians (OR, 1.213; 95% CI, 1.130-1.302; p=8.0×10(-9) and OR, 1.260; 95% CI, 1.135-1.398; p=1.4×10(-6), respectively). Analysis using a recessive model, dominant model, and homozygote contrast showed the same pattern for the LCE3C_LCE3B-del allele. The analysis performed in a single Tunisian study showed no association between the LCE3C_LCE3B-del allele and psoriasis. Meta-analysis of the LCE3C_LCE3B-del allele showed no association between psoriatic arthritis and the LCE3C_LCE3B-del polymorphism (OR, 1.087; 95% CI, 0.870-1.359; p=0.464). Our meta-analysis demonstrates a significant association between psoriasis and the LCE3C_LCE3B-del polymorphism in Europeans and Asians, but no association with psoriatic arthritis. 22933114 Bcl-2 and Bcl-xL suppress glucose signaling in pancreatic β-cells. B-cell lymphoma 2 (Bcl-2) family proteins are established regulators of cell survival, but their involvement in the normal function of primary cells has only recently begun to receive attention. In this study, we demonstrate that chemical and genetic loss-of-function of antiapoptotic Bcl-2 and Bcl-x(L) significantly augments glucose-dependent metabolic and Ca(2+) signals in primary pancreatic β-cells. Antagonism of Bcl-2/Bcl-x(L) by two distinct small-molecule compounds rapidly hyperpolarized β-cell mitochondria, increased cytosolic Ca(2+), and stimulated insulin release via the ATP-dependent pathway in β-cell under substimulatory glucose conditions. Experiments with single and double Bax-Bak knockout β-cells established that this occurred independently of these proapoptotic binding partners. Pancreatic β-cells from Bcl-2(-/-) mice responded to glucose with significantly increased NAD(P)H levels and cytosolic Ca(2+) signals, as well as significantly augmented insulin secretion. Inducible deletion of Bcl-x(L) in adult mouse β-cells also increased glucose-stimulated NAD(P)H and Ca(2+) responses and resulted in an improvement of in vivo glucose tolerance in the conditional Bcl-x(L) knockout animals. Our work suggests that prosurvival Bcl proteins normally dampen the β-cell response to glucose and thus reveals these core apoptosis proteins as integrators of cell death and physiology in pancreatic β-cells. 23708672 Generation and annihilation of localized persistent-activity states in a two-population neural-field model. We investigate the generation and annihilation of persistent localized activity states, so-called bumps, in response to transient spatiotemporal external input in a two-population neural-field model of the Wilson-Cowan type. Such persistent cortical states have been implicated as a biological substrate for short-term working memory, that is, the ability to store stimulus-related information for a few seconds and discard it once it is no longer relevant. In previous studies of the same model it has been established that the stability of bump states hinges on the relative inhibitory constant τ, i.e., the ratio of the time constants governing the dynamics of the inhibitory and excitatory populations: persistent bump states are typically only stable for values of τ smaller than a critical value τcr. We find here that τ is also a key parameter determining whether a transient input can generate a persistent bump state (in the regime where τ<τcr) or not. For small values of τ generation of the persistent states is found to depend only on the overall strength of the transient input, i.e., as long as the magnitude and duration of the excitatory transient input are larger and/or long enough, the persistent state will be activated. For higher values of τ we find that only specific combinations of amplitude and duration leads to persistent activation. For the corresponding annihilation process, no such delicate selectivity on the transient input is observed. 23643568 Individual determinants of fish choosing in open-air street markets from Santo André, SP/Brazil. The objective of this study was to identify the determinants of fish consumption in the population that attends open-air street markets in the city of Santo André, SP, Brazil.We performed a survey, covering approximately 482 people in 49 street markets.It consisted of free-answer questions, half open choice and half multiple-choice options, for the identification and evaluation of socioeconomic factors that facilitate and hinder fish consumption.A descriptive analysis of the data and further tests were used to determine the association between variables and linearity with consumption, with a significance level of 5%. The most commonly cited types of fish consumed were hake, sardine and dogfish. The factors that facilitate the purchase and consumption of fish are listed as follows: a preference for purchasing fish at street markets, appearance, firmness, fresh presentation, frozen presentation, as well as the respondent's education and individual monthly income. Limiting factors were identified as the price and the presence of spines. Perishability, odour, ethnicity, proximity to points of sale of residence and work, gender, age, number of people in the household, presence of children and acquisition supermarket were not characteristics that influenced decisions about fish consumption. 23910649 The effects of nucleoside analogue prophylactic treatment on HBV activation in HBcAb+ patients undergoing immunosuppressive therapy. We investigated the effects of prophylactic nucleoside analogue treatment on HBV activation in patients with antibodies against core antigen (HBcAb+) patients undergoing immunosuppressive therapy. Patients (113), who were HBcAb+, with various autoimmune diseases, undergoing immunosuppressive therapy, were divided into two groups. The control group, not treated with antivirals, and the prophylactic group, treated with antiviral drugs. The two groups were evaluated for changes in serum biochemical marker (alanine aminotransferase ALT), virological marker (HBV DNA) and for seroconversion. In the control group, the number of patients with an increase in ALT in patients with isolated HBcAb and HBcAb and antibodies against HBsAg (HBsAb +) were five (20.0%) and one (2.8%), respectively (P < 0.05). There were six cases (24.0%) with an increase in HBV DNA in the isolated HBcAb+ subgroup and one case (2.8%) in HBsAb+/HBcAb+ subgroup (P < 0.05). In the HBcAb+ only population, six patients (24.0%) in the control group had an increase in HBV DNA compared with none in the antiviral prophylactic group (P < 0.05). One patient (4.0%) with HBcAb+ in the control group underwent an HBsAg seroconversion when receiving immunosuppressive therapy for 18 months, while none in the antiviral prophylactic group underwent reversion to HBsAg positivity (P = 0.4949). Under immunosuppressive condition, the risk of HBV activation was much higher in patients with HBcAb than in patients with both HBcAb and antibodies to HBsAb group. Antiviral prophylactic therapy could significantly reduce the risk of HBV reactivation. 23934955 Palladium-Catalyzed Intermolecular Asymmetric Allylic Dearomatization Reaction of Naphthol Derivatives. Baring all: The title reaction provides β-naphthalenones bearing an all-carbon quaternary center in good to excellent yields, as well as excellent chemo- and enantioselectivity. 23918530 Screening for lung cancer: The US studies. Efforts in lung cancer screening with chest X-ray (CXR) and sputum cytology in the 1970s and 1980s were negative. In the ensuing decade, the early lung cancer action project (ELCAP), and the Mayo screening study showed the promise of low-dose CT. These and other studies led to the National lung screening study (NLST), which showed definitively that low-dose spiral computed tomography had a measurable impact on mortality and could be justified as a tool for lung cancer screening. This review examines the results of past and recent studies of lung cancer screening. J. Surg. Oncol. © 2013 Wiley Periodicals, Inc. 23742859 Solajiangxins A-C, three new cytotoxic sesquiterpenoids from Solanum lyratum. One new eudesmane-type (1, named solajiangxin A) and two new eudesmane-related sesquiterpenoids (2-3, named solajiangxins B-C) were isolated from the whole plant of Solanum lyratum. Their structures were elucidated on the basis of integrated spectroscopic techniques. In vitro, three new sesquiterpenoids were found to show significant cytotoxicities against three human cancer lines (P-388, HONE-1 and HT-29), and gave ED50 values in the range of 1.9-3.7μg/ml. 23261680 Comparative analysis of genetic toxicity of antiretroviral combinations in somatic cells of Drosophila melanogaster. Nucleoside reverse-transcriptase inhibitor (NRTI) drugs are a major component of highly-active antiretroviral therapy (HAART). NRTI combinations have been demonstrated as producing a sustained reduction in plasma viremia with an increased CD4 count, thereby showing clear clinical benefits. Therefore, the secondary effects caused by the combination of two NRTIs, mainly those related to amplification of genotoxic effects, due to increased risk of DNA damage caused by these drugs, should be carefully examined. We employed the standard version of the wing SMART in Drosophila melanogaster to obtain more detailed knowledge about the genotoxic profile of NRTI combinations of AZT+ddI, AZT+3TC and AZT+d4T. Our results showed that all combinations increased the frequencies of induction of mutant spots. The combinations AZT+ddI and AZT+3TC were shown to induce recombination rates ranging from 86.38% to 98.36% while AZT+d4T showed a large discrepancy between recombination and mutation percentages. The combination index demonstrated that 3TC and d4T produced antagonism while ddI showed synergistic effects in combination with AZT. 23651643 Porous orthopedic steel implant as an antibiotic eluting device: prevention of post-surgical infection on an ovine model. Traumatology and orthopedic surgery can benefit from the use of efficient local antibiotic-eluting systems to avoid bacterial contamination of implanted materials. In this work a new percutaneous porous-wall hollow implant was successfully used as a local antibiotic-eluting device both in vitro and in vivo. The implant is a macroporous 316 L stainless steel filter tube with a nominal filtration cut-off size of 200 nm with one open end which was used to load the synthetic antibiotic linezolid and an opposite blind end. The antibiotic release kinetics from the device on a simulated biological fluid under in vitro conditions demonstrated an increased concentration during the first five days that subsequently was sustained for at least seven days, showing a kinetic close to a zero order release. Antibiotic-loaded implants were placed in the tibia of four sheep which were trans-surgically experimentally infected with a biofilm forming strain of Staphylococcus aureus. After 7 and 9 days post infection, sheep did not show any evidence of infection as demonstrated by clinical, pathological and microbiological findings. These results demonstrate the capability of such an antibiotic-loaded implant to prevent infection in orthopedic devices in vivo. Further research is needed to assess its possible use in traumatology and orthopedic surgery. 23809308 Topical medications as treatment of neuropathic orofacial pain. Understanding mechanisms of neuropathic orofacial pain, targets of treatment, and basic pharmacology and working with informed compounding pharmacists may result in significant benefit for patients. The clinical significance of topical medications is improvement of quality of life for patients by providing a unique medication delivery system for neuropathic orofacial pain and other dental and extraoral conditions. The use of this route of administration has decreased or minimized side effects compared with other methods and is especially useful in medically compromised and elderly patients. These innovations, supported and improved by ongoing research, will augment the armamentarium of the clinician treating orofacial pain disorders. 23855987 Resolving the Chemical Nature of Nanodesigned Silica Surface Obtained via a Bottom-up Approach. The covalent grafting on silica surfaces of a functional dendritic organosilane coupling agent inserted, in a long alkyl chain monolayer, is described. In this paper, we show that depending on experimental parameters, particularly the solvent, it is possible to obtain a nanodesigned surface via a bottom-up approach. Thus, we succeed in the formation of both homogeneous dense monolayer and a heterogeneous dense monolayer, the latter being characterized by a nanosized volcano-type pattern (4-6 nm of height, 100 nm of width, and around 3 volcanos/μm(2)) randomly distributed over the surface. The dendritic attribute of the grafted silylated coupling agent affords enough anchoring sites to immobilize covalently functional gold nanoparticles (GNPs), coated with amino PEG polymer to resolve the chemical nature of the surfaces and especially the volcano type nanopattern structures of the heterogeneous monolayer. Thus, the versatile surface chemistry developed herein is particularly challenging as the nanodesign is straightforward achieved in a bottom-up approach without any specific lithography device. 23407257 Staged Rotation Advancements Provide Improved Nasal Results Compared to 1-Stage Repairs in Patients With Complete Bilateral Cleft Lip and Palate. After an experience of 32 complete bilateral cleft patients treated with staged rotation advancement to lip repairs and McComb nasal corrections during an 8-year period, improved nasal results with columella and lobule of normal dimensions have been noted, and the author feels that this method can be recommended for general use. 23583367 Electrical stimulation promotes nerve growth factor-induced neurite outgrowth and signaling. Neurotrophins are important regulators for neural development and regeneration. Nerve growth factor (NGF) therapy has been tested in various models of neural injury and degeneration. However, whether NGF can reach target tissues and maintain effective concentration for a certain period of time remains uncertain. To facilitate neural regeneration, we investigate the possibility of combining NGF and electrical stimulation (ES) in promoting neurite outgrowth, an essential process during neural regeneration. PC12 cells were seeded on collagen and indium tin oxide (ITO)-coated area on the transparent conductive devices. Cells were then subjected to the combination of ES and NGF treatment. Neurite outgrowth was compared. Our findings suggest that ES of 100mV/mm together with NGF provides optimal effect on neurite outgrowth of PC12 cells. ES increases NGF-induced neurite length but reduces neurite branching, indicative of its primary effect on neurite elongation instead of initiation. One mechanism that ES enhances neurite outgrowth is through increasing NGF-induced phosphorylation of ERK1/2 (pERK1/2) and expression of Egr1 gene. ES has previously been demonstrated to increase the activity of protein kinase C (PKC). Our result indicates that activating PKC further increases NGF-induced pERK1/2 and thus neurite outgrowth. It is likely that ES promotes NGF-induced neurite outgrowth through modulating the activity of ERK1/2. Findings from this study suggest that combining ES and NGF provides a promising strategy for promoting neurite outgrowth. 23822630 Pharmacological interventions in acute respiratory distress syndrome. Pharmacological interventions are commonly considered in acute respiratory distress syndrome (ARDS) patients. Inhaled nitric oxide (iNO) and neuromuscular blockers (NMBs) are used in patients with severe hypoxemia. No outcome benefit has been observed with the systematic use of iNO. However, a sometimes important improvement in oxygenation can occur shortly after starting administration. Therefore, its ease of use and its good tolerance justify iNO optionally combined with almitirne as a rescue therapy on a trial basis. Recent data from the literature support the use of a 48-h infusion of NMBs in patients with a PaO2 to FiO2 ratio <120 mmHg. No strong evidence exists on the increase of ICU-acquired paresis after a short course of NMBs. Fluid management with the goal to obtain zero fluid balance in ARDS patients without shock or renal failure significantly increases the number of days without mechanical ventilation. On the other hand, patients with hemodynamic failure must receive early and adapted fluid resuscitation. Liberal and conservative fluid strategies therefore are complementary and should ideally follow each other in time in the same patient whose hemodynamic state progressively stabilizes. At present, albumin treatment does not appear to be justified for limitation of pulmonary edema and respiratory morbidity. Aerosolized β2-agonists do not improve outcome in patients with ARDS and one study strongly suggests that intravenous salbutamol may worsen outcome in those patients. The early use of high doses of corticosteroids for the prevention of ARDS in septic shock patients or in patients with confirmed ARDS significantly reduced the duration of mechanical ventilation but had no effect or even increased mortality. In patients with persistent ARDS after 7 to 28 days, a randomized trial showed no reduction in mortality with moderate doses of corticosteroids but an increased PaO2 to FiO2 ratio and thoracopulmonary compliance were found, as well as shorter durations of mechanical ventilation and of ICU stay. Conflicting data exist on the interest of low doses of corticosteroids (200 mg/day of hydrocortisone) in ARDS patients. In the context of a persistent ARDS with histological proof of fibroproliferation, a corticosteroid treatment with a progressive decrease of doses can be proposed. 23949441 Frailty and Technology: A Systematic Review of Gait Analysis in Those with Frailty. Background: New technologies for gait assessment are emerging and have provided new avenues for accurately measuring gait characteristics in home and clinic. However, potential meaningful clinical gait parameters beyond speed have received little attention in frailty research. Objective: To study gait characteristics in different frailty status groups for identifying the most useful parameters and assessment protocols for frailty diagnosis. Methods: We searched PubMed, Embase, PsycINFO, CINAHL, Web of Science, Cochrane Library, and Age Line. Articles were selected according to the following criteria: (1) population: individuals defined as frail, prefrail, or transitioning to frail, and (2) outcome measures: quantitative gait variables as obtained by biomechanical analysis. Effect sizes (d) were calculated for the ability of parameters to discriminate between different frailty status groups. Results: Eleven publications met inclusion criteria. Frailty definitions, gait protocols and parameters were inconsistent, which made comparison of outcomes difficult. Effect sizes were calculated only for the three studies which compared at least two different frailty status groups. Gait speed shows the highest effect size to discriminate between frailty subgroups, in particular during habitual walking (d = 0.76-6.17). Gait variability also discriminates between different frailty status groups in particular during fast walking. Prominent parameters related to prefrailty are reduced cadence (d = 1.43) and increased step width variability (d = 0.64), whereas frailty (vs. prefrail status) is characterized by reduced step length during habitual walking (d = 1.32) and increased double support during fast walking (d = 0.78). Interestingly, one study suggested that dual-task walking speed can be used to predict prospective frailty development. Conclusion: Gait characteristics in people with frailty are insufficiently analyzed in the literature and represent a major area for innovation. Despite the paucity of work, current results suggest that parameters beyond speed could be helpful in identifying different categories of frailty. Increased gait variability might reflect a multisystem reduction and may be useful in identifying frailty. In addition, a demanding task such as fast walking or adding a cognitive distractor might enhance the sensitivity and specificity of frailty risk prediction and classification, and is recommended for frailty assessment using gait analysis. 23578391 Perinatal exposure to BDE-99 causes learning disorders and decreases serum thyroid hormone levels and BDNF gene expression in hippocampus in rat offspring. Exposure of pregnant women to polybrominated diphenyl ethers (PBDEs) may mean serious health risks. The main goal of the present study was to examine the neurobehavioral changes in rat offspring that were perinatally exposed to one of the most prevalent PBDEs congeners found in humans, 2,2',4,4',5-pentaBDE (BDE-99). Rat dams were exposed to 0, 1 and 2mg/kg/day of BDE-99 from gestation day 6 to post-natal day 21. When pups were weaning, cortex and hippocampal gene expressions of brain-derived neurotrophic factor (BDNF) of the different isoforms of the thyroid hormone (TH) receptors (TRs) were evaluated. Serum TH levels were also determined. The remaining pups were assessed by neurobehavioral testing for learning and memory function. The results showed that maternal transference of BDE-99 produced a delay in the spatial learning task in the water maze test. Moreover, the open-field test revealed a significant dose-response anxiolytic effect. It was also found that the serum levels of triiodothyronine (T3), tetraiiodothyronine (T4) and free-T4 (FT4) decreased. Although no effect on the gene expression of the different isoforms of TRs was observed, the expression of the TH-mediated gene BDNF was down-regulated in the hippocampus. These results indicate a clear signal disruption of TH and reinforce previous studies in which neurotoxic effects of PBDEs in animal research were observed at levels comparable to those found in humans. 23707931 A putative terpene cyclase, vir4, is responsible for the biosynthesis of volatile terpene compounds in the biocontrol fungus Trichoderma virens. A putative terpene cyclase vir4, which is a member of a secondary metabolite cluster, has been deleted in Trichoderma virens to determine its function. The deletion mutants were compared for volatile production with the wild-type as well as two other Trichoderma spp. This gene cluster was originally predicted to function in the synthesis of viridin and viridiol. However, the experimental evidence demonstrates that this gene cluster is involved in the synthesis of volatile terpene compounds. The entire vir4-containing gene cluster is absent in two other species of Trichoderma, T. atroviride and T. reesei. Neither of these two species synthesizes volatile terpenes associated with this cluster in T. virens. We have thus identified a novel class of volatile fungal sesquiterpenes as well as the gene cluster involved in their biosynthesis. 23463159 Visualisation of the rectoanal inhibitory reflex with a modified contrast enema in children with suspected Hirschsprung disease. Patients with Hirschsprung disease lack the normal rectoanal inhibitory reflex, which can be studied with anorectal manometry or US. To see whether the rectoanal inhibitory reflex could be visualised with a modified contrast enema, thereby increasing the diagnostic accuracy of the contrast enema and reducing the number of rectal biopsies. Fifty-nine boys and 42 girls (median age, 12 months) with suspected Hirschsprung disease were examined with a modified contrast enema, supplemented with two injections of cold, water-soluble contrast medium, to induce the reflex. Two paediatric radiologists evaluated the anonymised examinations in consensus. The contrast enema findings were correlated with the results of rectal biopsy or clinical follow-up. Five boys and one girl (median age, 7.5 days) were diagnosed with Hirschsprung disease. The negative predictive value of the rectoanal inhibitory reflex was 100%. A contrast enema with signs of Hirschsprung disease in combination with an absent rectoanal inhibitory reflex had the specificity of 98% and sensitivity of 100% for Hirschsprung disease. The modified contrast enema improves the radiological diagnosis of Hirschsprung disease. By demonstrating the rectoanal inhibitory reflex in children without Hirschsprung disease, we can reduce the proportion of unnecessary rectal biopsies. 23873557 Effects of growth patterns and dietary crude protein levels during rearing on body composition and performance in broiler breeder females during the rearing and laying period. The combined effects of growth pattern (GP) and dietary CP level during rearing (2 to 22 wk of age) on body composition and performance were investigated in broiler breeder females from 0 to 40 wk of age. One-day-old pullets (n = 768) were randomly allotted to 48 pens according to 2 growth patterns (standard = SGP and high = HGP) and fed using 1 of 3 dietary CP levels (high = CPh, medium = CPm, and low = CPl). From 19 to 22 wk of age, feeding level was gradually adjusted to obtain a similar target BW for all birds, and then until 40 wk of age, all birds received similar amounts of a standard breeder diet. During the rearing period, the HGP pullets were fed a higher feed intake level (6.5%) than SGP pullets. To meet BW targets at 22 wk of age, feed intake from d 14 onward had to be increased for the CPm (4.6%) and CPl (10.0%) treatments. Breast muscle percentages of HGP and SGP pullets were similar at any age, although abdominal fat pad at 20 wk was 0.18% higher for HGP pullets. Pullets fed the CPl diet had a lower breast muscle percentage compared with pullets fed the CPm and CPh diets (0.46 and 0.85% at wk 10, 0.81 and 1.45% at wk 20, respectively). Abdominal fat pads in CPl pullets were 0.18 and 0.22% (wk 10), and 0.24 and 0.42% (wk 20) higher compared with CPm and CPh pullets, respectively. At 40 wk of age, no effects on breast muscle and abdominal fat pad were found among all treatments. Egg production, sexual maturation, and egg weight were not affected by GP and CP levels during rearing. It was concluded that a low CP diet during rearing decreased breast muscle and increased abdominal fat pad, whereas a high GP only increased abdominal fat pad, at the end of the rearing period. Decreasing dietary CP level seems to be more effective in increasing abdominal fat pad than increasing GP. 23376120 Gastrodin attenuation of the inflammatory response in H9c2 cardiomyocytes involves inhibition of NF-κB and MAPKs activation via the phosphatidylinositol 3-kinase signaling. The phenolic glucoside gastrodin, a main constituent of a Chinese traditional herbal medicine, has been known to display several biological and pharmacological properties. However, the role and precise molecular mechanisms explaining how gastrodin suppresses the inflammatory response in septic cardiac dysfunction are unknown. To study this, rat H9c2 cardiomyocytes were treated with gastrodin and/or lipopolysaccharide (LPS). Our results showed that gastrodin treatment strongly suppressed nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) family activation and upregulation of the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in LPS-stimulated H9c2 cardiomyocytes. Simultaneously, gastrodin obviously upregulated the phosphatidylinositol 3-kinase (PI3-K)/Akt signaling in a dose-dependent manner. However, wortmannin, a specific PI3-K inhibitor, blocked the inhibitory effects of gastrodin on LPS-stimulated H9c2 cardiomyocytes. Furthermore, PI3-K/Akt inhibition partially abolished the inhibitory effects of gastrodin on the phosphorylation of inhibitor κB-α (IκB-α), extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK), and activity of NF-κB. Here we report activation of the PI3-K/Akt signaling by gastrodin and that inhibition of this pathway reverses the inhibitory effects of gastrodin on NF-κB and MAPKs activation in H9c2 cardiomyocytes. 23927876 Comparative toxicity and apoptosis induced by diorganotins in rat pheochromocytoma (PC12) cells. As ubiquitous environmental toxicants, organotin (IV) compounds (OTC) accumulate in the food chain and potential effects on human health are disquieting. The present study compared the cytotoxicity of three diorganotins, namely, dimethyltin (DMT), dibutyltin (DBT) and diphenyltin (DPT), in rat pheochromocytoma (PC12) cells, and the molecular mechanisms responsible for their cytotoxic effects were also explored. Twenty-four hours exposure of PC12 cells to DBT and DPT resulted in a concentration-dependent decrease in cell viability with median lethal concentration (LC50) of 2.97μM and 7.24μM, respectively. However, DMT at concentrations up to 128μM had no obvious effect on cell viability. The mechanistic study revealed that the extent of apoptosis was greater for DBT than that for DPT, followed by DMT, as evidenced by acridine orange/ethidium bromide (AO/EB) fluorescent staining method and annexin V-FITC/PI staining flow cytometry analysis, as well as generation of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP) disruption, release of cytochrome c (Cyt c), and consequent activation of caspase-9, and -3. These investigations suggested that the cytotoxic potency of three diorganotins in PC12 cells was in the order of DBT>DPT≫DMT, and these compounds could induce PC12 cells apoptosis through ROS mediated mitochondrial pathway. 23913271 Prolonged dopamine signalling in striatum signals proximity and value of distant rewards. Predictions about future rewarding events have a powerful influence on behaviour. The phasic spike activity of dopamine-containing neurons, and corresponding dopamine transients in the striatum, are thought to underlie these predictions, encoding positive and negative reward prediction errors. However, many behaviours are directed towards distant goals, for which transient signals may fail to provide sustained drive. Here we report an extended mode of reward-predictive dopamine signalling in the striatum that emerged as rats moved towards distant goals. These dopamine signals, which were detected with fast-scan cyclic voltammetry (FSCV), gradually increased or-in rare instances-decreased as the animals navigated mazes to reach remote rewards, rather than having phasic or steady tonic profiles. These dopamine increases (ramps) scaled flexibly with both the distance and size of the rewards. During learning, these dopamine signals showed spatial preferences for goals in different locations and readily changed in magnitude to reflect changing values of the distant rewards. Such prolonged dopamine signalling could provide sustained motivational drive, a control mechanism that may be important for normal behaviour and that can be impaired in a range of neurologic and neuropsychiatric disorders. 23884933 The organization of dorsal frontal cortex in humans and macaques. The human dorsal frontal cortex has been associated with the most sophisticated aspects of cognition, including those that are thought to be especially refined in humans. Here we used diffusion-weighted magnetic resonance imaging (DW-MRI) and functional MRI (fMRI) in humans and macaques to infer and compare the organization of dorsal frontal cortex in the two species. Using DW-MRI tractography-based parcellation, we identified 10 dorsal frontal regions lying between the human inferior frontal sulcus and cingulate cortex. Patterns of functional coupling between each area and the rest of the brain were then estimated with fMRI and compared with functional coupling patterns in macaques. Areas in human medial frontal cortex, including areas associated with high-level social cognitive processes such as theory of mind, showed a surprising degree of similarity in their functional coupling patterns with the frontal pole, medial prefrontal, and dorsal prefrontal convexity in the macaque. We failed to find evidence for "new" regions in human medial frontal cortex. On the lateral surface, comparison of functional coupling patterns suggested correspondences in anatomical organization distinct from those that are widely assumed. A human region sometimes referred to as lateral frontal pole more closely resembled area 46, rather than the frontal pole, of the macaque. Overall the pattern of results suggest important similarities in frontal cortex organization in humans and other primates, even in the case of regions thought to carry out uniquely human functions. The patterns of interspecies correspondences are not, however, always those that are widely assumed. 23183772 Nanoporous silicon networks as anodes for lithium ion batteries. Nanoporous silicon (Si) networks with controllable porosity and thickness are fabricated by a simple and scalable electrochemical process, and then released from Si wafers and transferred to flexible and conductive substrates. These nanoporous Si networks serve as high performance Li-ion battery electrodes, with an initial discharge capacity of 2570 mA h g(-1), above 1000 mA h g(-1) after 200 cycles without any electrolyte additives. 23949064 The effects of pilates on balance, mobility and strength in patients with multiple sclerosis. Although there are evidences as to Pilates developing dynamic balance, muscle strength and flexibility in healthy people, evidences related to its effects on Multiple Sclerosis patients are insufficient. Objectives: The aims of this study were to investigate the effects of Pilates on balance, mobility, and strength in ambulatory patients with Multiple Sclerosis. Twenty six patients were divided into two groups as experimental (n = 18) and control (n = 8) groups for an 8-week treatment program. The experimental group underwent Pilates and the control group did abdominal breathing and active extremity exercises at home. Balance and mobility were measured with Berg Balance Scale and Timed up and go test, upper and lower muscle strength with hand-held dynamometer. Confidence in balance skills while performing daily activities was evaluated with Activities Specific Balance Confidence Scale. Improvements were observed in balance, mobility, and upper and lower extremity muscle strength in the Pilates group (p < 0.05). No significant differences in any outcome measures were observed in the control group (p > 0.05). Due to its structure which is made up of balance and strengthening exercises, Pilates training may develop balance, mobility and muscle strength of MS patients. For this reason, we think that, Pilates exercises which are appropriate for the disability level of the patient may be suggested. 23886114 In vitro OATP1B1 and OATP1B3 inhibition is associated with observations of benign clinical unconjugated hyperbilirubinemia. Abstract 1.  Transient benign unconjugated hyperbilirubinemia has been observed clinically with several drugs including indinavir, cyclosporine, and rifamycin SV. Genome-wide association studies have shown significant association of OATP1B1 and UGT1A1 with elevations of unconjugated bilirubin, and OATP1B1 inhibition data correlated with clinical unconjugated hyperbilirubinemia for several compounds. 2.  In this study, inhibition of OATP1B3 and UGT1A1, in addition to OATP1B1, was explored to determine whether one measure offers value over the other as a potential prospective tool to predict unconjugated hyperbilirubinemia. OATP1B1 and OATP1B3-mediated transport of bilirubin was confirmed and inhibition was determined for atazanavir, rifampicin, indinavir, amprenavir, cyclosporine, rifamycin SV and saquinavir. To investigate the intrinsic inhibition by the drugs, both in vivo Fi (fraction of intrinsic inhibition) and R-value (estimated maximum in vivo inhibition) for OATP1B1, OATP1B3 and UGT1A1 were calculated. 3.  The results indicated that in vivo Fi values >0.2 or R-values >1.5 for OATP1B1 or OATP1B3, but not UGT1A1, are associated with previously reported clinical cases of drug-induced unconjugated hyperbilirubinemia. 4.  In conclusion, inhibition of OATP1B1 and/or OATP1B3 along with predicted human pharmacokinetic data could be used pre-clinically to predict potential drug-induced benign unconjugated hyperbilirubinemia in the clinic. 23132841 A model for evaluating the activities of a coalition-based policy action group: the case of Hermosa Vida. Scholars and clinicians are increasingly recognizing the complexity of social contexts of health and the need for multifunctioning approaches to health care problems including community- and policy-level strategies. Barriers to change in health care policy can sometimes be attributed to the actions of advocacy coalitions who operate from a limited view of "policy change." Advocates have a tendency to pressure stakeholders to mandate laws as a final resolution of a movement, often leading to failure or, worse, stigmatizing of issues. A more inclusive focus on health policy change as an ongoing process increases the efficacy of advocacy and outcomes measurement. This article presents a tool for policy action that coalition members developed through the implementation of a 3-year grant to improve the safety net for preventing childhood obesity. Scholars and policy makers developed the Policy Coalition Evaluation Tool with the intent to create a model to guide and measure efforts and outcomes of a local community-based policy coalition. The authors suggest using community-based participatory research approaches for developing a coalition-specific Policy Coalition Evaluation Tool to increase the effectiveness of advocacy groups and the documentation of coalition activities over time. 23882243 Adaptation to implied tilt: extensive spatial extrapolation of orientation gradients. To extract the global structure of an image, the visual system must integrate local orientation estimates across space. Progress is being made toward understanding this integration process, but very little is known about whether the presence of structure exerts a reciprocal influence on local orientation coding. We have previously shown that adaptation to patterns containing circular or radial structure induces tilt-aftereffects (TAEs), even in locations where the adapting pattern was occluded. These spatially "remote" TAEs have novel tuning properties and behave in a manner consistent with adaptation to the local orientation implied by the circular structure (but not physically present) at a given test location. Here, by manipulating the spatial distribution of local elements in noisy circular textures, we demonstrate that remote TAEs are driven by the extrapolation of orientation structure over remarkably large regions of visual space (more than 20°). We further show that these effects are not specific to adapting stimuli with polar orientation structure, but require a gradient of orientation change across space. Our results suggest that mechanisms of visual adaptation exploit orientation gradients to predict the local pattern content of unfilled regions of space. 23954161 Results of Baha® implantation using a small horizontal incision. Techniques for Baha® implantation continue to evolve. The Weber technique, utilizing a 1.5cm horizontal incision for Baha® implantation is evaluated. Retrospective review of patients undergoing Baha® implantation by a single surgeon over three years. 33 Baha®s implanted in 30 patients. Fourteen used an Inverted J (IJ) incision with an anteriorly-based skin-flap, 13 with the Weber technique (W). Five were not included as other techniques were used. Demographics and weeks to activation (14.58 vs 13.4, p=0.12) were similar. There were no differences in the number of patients with minor complications (5 vs 2, p=0.22) or number of minor complications (20 vs 4, p=0.09). One patient in the IJ Group required operative revision for overgrowth. There were no infections in the IJ Group, and one requiring oral antibiotics in the W Group. Follow-up was longer in the IJ Group (41 vs 13 weeks, p=0.016), no complications occurred after 14weeks post-op. Mean operative times were similar (43 vs 39min, p=0.59). There were no cases of skin flap necrosis in either group. A small incision for Baha® implantation proved as effective, without increased complications as a skin-flap based technique. 23874837 Overexpressed MicroRNA-182 Promotes Proliferation and Invasion in Prostate Cancer PC-3 Cells by Down-Regulating N-myc Downstream Regulated Gene 1 (NDRG1). MicroRNAs, non-coding 20-22 nucleotide single-stranded RNAs, result in translational repression or degradation and gene silencing of their target genes, and significantly contribute to the regulation of gene expression. In the current study, we report that miR-182 expression was significantly upregulated in prostate cancer tissues and four cell lines, compared to benign prostatic hyperplasia tissues and normal prostatic epithelial (RWPE-1) cells. Ectopic overexpression of miR-182 significantly promotes the proliferation, increases the invasion, promotes the G1/S cell cycle transition and reduces early apotosis of PC-3 cells, while suppression of miR-182 decreased the proliferation and invasion, inhibits the G1/S cell cycle transition and increase early apotosis of PC-3 cells. Additionally, we demonstrated that miR-182 could downregulate expression of NDRG1 by directly targeting the NDRG1 3'-untranslated region. In conclusion, our results suggest that miR-182 plays an important role in the proliferation of human prostate cancer cells by directly suppressing the tumor supressor gene NDRG1. We uncovered a new epigenetic regulation of NDRG1. 23578393 Reward and aversion in a heterogeneous midbrain dopamine system. The ventral tegmental area (VTA) is a heterogeneous brain structure that serves a central role in motivation and reward processing. Abnormalities in the function of VTA dopamine (DA) neurons and the targets they influence are implicated in several prominent neuropsychiatric disorders including addiction and depression. Recent studies suggest that the midbrain DA system is composed of anatomically and functionally heterogeneous DA subpopulations with different axonal projections. These findings may explain a number of previously confusing observations that suggested a role for DA in processing both rewarding as well as aversive events. Here we will focus on recent advances in understanding the neural circuits mediating reward and aversion in the VTA and how stress as well as drugs of abuse, in particular cocaine, alter circuit function within a heterogeneous midbrain DA system. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. 23828139 Lipopolysaccharide-induced toll-like receptor 4 signaling in cancer cells promotes cell survival and proliferation in hepatocellular carcinoma. Recent studies have shown that toll-like receptor 4 (TLR4) is involved in hepatocarcinogenesis. However, the significance of TLR4 signaling in cancer development and progression remains unclear. The purpose of this study was to investigate the role of TLR4 in cancer cell survival and proliferation in hepatocellular carcinoma (HCC). Fifty-three HCC and ten normal liver specimens were analyzed by immunohistochemistry, and three cell lines (HL-7702, PLC/PRF/5 and HepG2) were used for in vitro studies. Lipopolysaccharide (LPS), a specific ligand of TLR4, was used to activate TLR4 signaling. The effects of LPS-TLR4 signaling on cell survival, proliferation and invasion were examined. Specific inhibitors of NF-κB and MAPK (JNK, ERK and p38) signaling pathways were used to explore the role of each pathway in LPS-TLR4 signaling. TLR4 was overexpressed in HCC cell lines and in human HCC tissues, where it correlated with Ki-67 expression. LPS-induced activation of TLR4 signaling promoted cancer cell survival and proliferation. LPS-TLR4 signaling was associated with regulation on the activation of NF-κB and MAPK signaling pathways. LPS-TLR4-induced activation of ERK and JNK signaling promotes cell proliferation through regulating Bax translocation to mitochondria. Activation of NF-κB and p38 mediates cytotoxicity of LPS, and inhibition on these two pathways promotes cell proliferation in HCC cells. Our results indicate that TLR4 signaling in cancer cells promotes cell survival and proliferation in HCC. 23878110 Memories of Shame Experiences with Others and Depression Symptoms: The Mediating Role of Experiential Avoidance. Background Shame experiences have been suggested to be related with psychopathological symptoms and with self-relevant beliefs. Recent studies also suggest that avoidant-focused strategies (e.g., rumination, thought suppression and dissociation) mediate the impact of shame memories and depression symptoms. However, experiential avoidance has been found to mediate the relation between early experience of abuse and psychopathological symptoms. Our goal was to test the mediating effect of experiential avoidance in the relation between both the nature of shame experiences at the hands of caregivers and the centrality of shame memories with others, and depression symptoms. Method Using structural equation modelling, we assessed the frequency and nature of recalled shame experiences at the hands of caregivers, the centrality of shame experiences with others throughout childhood and adolescence, experiential avoidance and depression symptomatology in 161 participants from general population. Results Experiential avoidance mediates the impact of shame experiences with caregivers and depression symptoms. Experiential avoidance also mediated the association between the centrality of shame experiences with others and depression symptoms. Conclusion Our results suggest that shame memories with others do not per se impact on depression symptoms, but rather the unwillingness to experience them and the attempts to control them. Hence, our results emphasize the importance of addressing affect regulation processes such as avoidance when dealing with shame memories, particularly with patients who experience depression symptoms. Key Practitioner Message The recall of shame experiences with caregivers is associated with the experience of depression symptoms, even when these experiences are not perceived as central points to one's life identity and story. This seems to suggest a necessity to explore these experiences in a therapeutic setting. Our findings suggest that experiential avoidance is a key process through which these memories of shame experiences impact on depression symptomatology. Hence, it seems to be of great importance to reduce experiential avoidance and help people change the way they relate with these memories.Copyright © 2013 John Wiley & Sons, Ltd. 23707041 Comparison of Outcomes Using the Sirolimus-Eluting Stent in Calcified Versus Non-Calcified Native Coronary Lesions in Patients On- Versus Not On-Chronic Hemodialysis (from the j-Cypher Registry). The impact of lesion calcium on long-term outcomes after drug-eluting stent implantation has not been adequately addressed. In 10,595 patients (16,803 lesions) who were exclusively treated with sirolimus-eluting stents in the j-Cypher registry, 5-year outcomes were compared between patients with ≥1 lesion with moderate or severe calcification (the calcium group) and those with noncalcified lesions only (the noncalcium group). Analyses were stratified by hemodialysis (HD) status (non-HD stratum [calcium n = 3,191, noncalcium n = 6,824] and HD stratum [calcium n = 415, noncalcium n = 165]). Adjusted risk in the calcium group for death and target lesion revascularization was significant in the non-HD stratum (hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.18 to 1.52, p <0.0001, and HR 1.2, 95% CI 1.07 to 1.36, p = 0.003) and the HD stratum (HR 1.4, 95% CI 1.06 to 1.86, p = 0.02, and HR 2.25, 95% CI 1.51 to 3.36, p <0.0001). Risk for definite stent thrombosis tended to be higher in the calcium group in the HD stratum (HR 5.05, 95% CI 0.66 to 38.9, p = 0.12) but not in then non-HD stratum (HR 1.16, 95% CI 0.81 to 1.67, p = 0.41). The use of rotational atherectomy in patients with severe calcification did not have a significant impact on the cumulative incidence of target lesion revascularization in the non-HD stratum (17.7% [n = 268] with vs 18.2% [n = 588] without rotational atherectomy, p = 0.68) and the HD stratum (54.7% [n = 115] with vs 51.9% [n = 118] without rotational atherectomy, p = 0.19). In conclusion, regardless of HD status, patients with calcified lesions have increased long-term risk for death and target lesion revascularization after sirolimus-eluting stent implantation. 23727199 Post-embryonic root organogenesis in cereals: branching out from model plants. The root architecture of higher plants is amazingly diverse. In this review, we compare the lateral root developmental programme in cereals and Arabidopsis thaliana. In cereals, cells in the endodermis are recruited to form the new root cap and overlying cortical cells divide to facilitate the emergence of the lateral root primordium. The TIR1/ABF2 auxin receptors and the AUX/IAA, ARF, and LBD transcriptional regulatory proteins are conserved in cereals and Arabidopsis. Several elements of this regulatory network are common to lateral and crown roots in cereals. Also, the ground meristem from which crown roots differentiate shows similarities with the root pericycle. Studies in cereals promise to give complementary insights into the mechanisms regulating the development of post-embryonic roots in plants. 23435301 Immunosenescence is associated with presence of Kaposi's sarcoma in antiretroviral treated HIV infection. Some antiretroviral treated HIV-infected patients develop Kaposi's sarcoma despite long-term suppression of HIV replication. These Kaposi's sarcoma lesions are consistent with Kaposi's sarcoma observed in the elderly uninfected population ('classical Kaposi's sarcoma'). We investigated potential mechanisms for this phenomenon, focusing on measures of immune activation and T-cell senescence. We compared markers of immunosenescence, naive T cells, activation, and inflammation in CD4+ and CD8+ T cells from antiretroviral-treated participants with new-onset Kaposi's sarcoma (cases, n =  19) and from treated individuals without Kaposi's sarcoma (controls, n  = 47). There was increased frequency of CD4+ and CD8+ T cells with an immunosenescence phenotype (CD57+ and CD28-) in cases vs. controls (CD4+ T cells: CD57+ 7.4 vs. 3.7%, P = 0.025; CD28- 9.1 vs. 4.8%, P  = 0.025; CD8+ T cells: CD57+ 41.5 vs. 27.7%, P  =  0.003; CD28- 60.5 vs. 51.3%, P  = 0.041). Cases had lower proportions of naïve T cells (CD27+ CD28+ CD45RA+) in CD4+ (23.0 vs. 32.2%, P = 0.023) and CD8+ (11.3 vs. 20.7%, P  <  0.001) T-cell compartments. CCR5 was more highly expressed in CD4+ (16.3 vs. 11.0%, P  = 0.025), and CD8+ (43.1 vs. 28.3%, P < 0.001) T-cell compartments in cases vs. controls. There was no difference in telomere length or telomerase activity in peripheral blood mononuclear cells, or in T-cell expression of activation markers (HLADRCD38). Among antiretroviral-treated patients, increased frequencies of T cells with an immunosenescence phenotype and lower frequencies of naive T cells were associated with presence of Kaposi's sarcoma among effectively treated patients. These data suggest that certain immunologic perturbations--including those associated with aging--might be causally associated with development of Kaposi's sarcoma. 23483540 Prognosis of early breast cancer by immunohistochemistry defined intrinsic sub-types in patients treated with adjuvant chemotherapy in the NEAT/BR9601 trial. Breast cancer can be classified into molecular sub-types that have distinct survival patterns. We evaluated the prognostic significance of breast cancer sub-types in a cohort of women taking part in the NEAT and BR9601 clinical trials comparing cyclophosphamide, methotrexate and fluorouracil (CMF) with ECMF (epirubicin and CMF). Furthermore, we evaluated whether the sub-types were predictive of the added benefit of epirubicin in these trials. Tumour tissue microarrays were stained and scored for ER, PR, HER2, EGFR and CK5/6. These were used to classify the tumours into six intrinsic sub-types. We used Cox regression to compare overall survival (OS), breast cancer-specific survival (BCSS) and relapse-free survival (RFS) in the different sub-groups. We also compared the effect of ECMF with CMF by sub-group. Immunohistochemistry data were available for 1,725 cases of whom 805 were luminal 1-basal negative. Median follow-up time was 7 years. The luminal 1-basal negative tumours were associated with the best prognosis in five years after surgery and the HER2-like tumours were associated with the poorest prognosis. There was little evidence for significant heterogeneity of this effect by tumour sub-type (OS p = 0.40, BCSS p = 0.53 RFS p = 0.50) - the largest additional benefit of epirubicin was in women with tumours of the 5-negative phenotype (OS HR = 0.39 95% CI: 0.21-0.73) and the smallest was in Luminal 1-basal negative tumours (OS HR = 0.86 95% CI: 0.64-1.16). We confirmed that breast cancer sub-types show distinct behaviour with differences in short- and long-term survival. The benefit of ECMF over CMF was statistically similar in all disease sub-types. 23873739 Hospital-acquired anemia: Prevalence, outcomes, and healthcare implications. Evidence suggests that patients with normal hemoglobin (Hgb) levels on hospital admission who subsequently develop hospital-acquired anemia (HAA) may be at risk for adverse outcomes. Our objectives were to (1) determine the prevalence of HAA and (2) examine whether HAA is associated with increased mortality, length of stay (LOS), and total hospital charges. The population consisted of 417,301 adult hospitalizations from January 1, 2009 to August 31, 2011, in an academic medical center and 9 community hospitals. Patients with anemia on admission, and hospitals in the health system without available laboratory data were excluded; 188,447 hospitalizations were included in the analysis. Demographics, comorbidities, and outcomes were retrieved from administrative data; Hgb values were taken from the electronic medical record. Regression modeling was used to examine the association between demographics, comorbidity, hospitalization type, and HAA variables (mild: Hgb >11 and <12 g/dL for women, and >11 and <13 g/dL for men; moderate: Hgb 9.1 to ≤11.0 g/dL; severe: Hgb ≤9.0 g/dL) on mortality, LOS, and hospital charges. Among 188,447 hospitalizations, 139,807 patients (74%) developed HAA: mild, 40,828 (29%); moderate, 57,184 (41%); and severe, 41,795 (30%). Risk-adjusted odds ratios and 95% confidence intervals for in-hospital mortality with HAA were: mild, 1.0 (0.88-1.17; P = 0.8); moderate, 1.51 (1.33-1.71, P < 0.001); and severe, 3.28 (2.90-3.72, P < 0.001). Risk-adjusted relative mean LOS and hospital charges relative to no HAA were higher with HAA: LOS: mild, 1.08 (1.08-1.10, P < 0.001); moderate, 1.28 (1.26-1.29, P < 0.001); severe, 1.88 (1.86-1.89, P < 0.001). Hospital charges: mild, 1.06 (1.06-1.07, P < 0.001); moderate, 1.18 (1.17-1.19, P < 0.001); severe, 1.80 (1.79-1.82, P < 0.001). HAA is common and associated with increased mortality and resource utilization. Factors related to its development necessitate further study. Journal of Hospital Medicine 2013;. © 2013 Society of Hospital Medicine. 23949201 Dietary aflatoxin B1 intake, genetic polymorphisms of CYP1A2, CYP2E1, EPHX1, GSTM1, and GSTT1, and gastric cancer risk in Korean. We investigated the effects of aflatoxin B1 (AFB1) intake, genetic polymorphisms of AFB1 metabolic enzymes, and interactions between the polymorphisms and intake of AFB1 with regard to the risk of gastric cancer in Korean. The participants in the study included 477 gastric cancer patients and 477 age- and sex-matched control subjects. Direct interviews and a structured questionnaire were used to determine the level of exposure to AFB1, and the GoldenGate assay and multiplex polymerase chain reaction were used for genotypic analyses of the cytochrome P450 1A2 (CYP1A2), cytochrome P450 1E1, epoxide hydrolase 1, and glutathione S-transferase genes. The probable daily intake of AFB1 was significantly higher among gastric cancer patients than among control subjects (cases vs. controls: 1.91 ± 0.87 vs. 1.65 ± 0.72 ng/kg bw/day, p < 0.0001), and increased AFB1 intake was significantly associated with an elevated risk of gastric cancer (odds ratio 1.94; 95 % confidence interval 1.43-2.63). However, genetic polymorphisms of AFB1 metabolic enzymes were not associated with gastric cancer, with the exception of CYP1A2. Moreover, there was no interaction between AFB1 intake and the genotypes of metabolic enzymes that affect gastric cancer risk. Our results suggest that dietary AFB1 exposure might be associated with a risk of gastric cancer. However, the effect of AFB1 on gastric carcinogenesis may not be modulated by genetic polymorphisms of AFB1 metabolic enzymes. 23924446 Efficacy of immediate instillation combined with regular instillations of pirarubicin for Ta and T1 transitional cell bladder cancer after transurethral resection: a prospective, randomized, multicenter study. Immediate intravesical instillation of chemotherapeutic agents after transurethral resection (TUR) of nonmuscle invasive transitional cell bladder cancer has recently been suggested and has been proven to decrease the tumor recurrence rate significantly. This study is to evaluate the efficacy and safety of immediate intravesical instillation combined with regular instillations of Pirarubicin (THP(®)) as prophylaxis compared to regular instillations only after TUR operation. This was a prospective, randomized, multi-center, clinical study. Patients diagnosed with non-muscle invasive bladder cancer (Ta and T1) pathologically and suitable for TUR were enrolled randomly into two groups. In the study group, the patients received intravesical instillation within 24-hour post TURBT, followed by regular intravesical therapy using 30 mg/50 ml of THP(®) once a week for 8 weeks, and then once a month to 1 year postoperatively Among the patients. In the control group, patients received regular instillation only. A total of 403 patients were enrolled into this study from 26 institutions in China. Among the potients, 210 were enrolled into the study group and 193 were enrolled into the control group. At the median follow-up of 18 months, the recurrence rate was 7.8% in the study group, significantly lower than that in the control group (14.3%; P = 0.042). Subgroup analysis showed that the recurrence rate in low and intermediate-risk patients was significantly lower in the study group (6.8%) than in the control group (14.0%; P = 0.047), although no significant differences were found in high-risk patients. One immediate dose of THP(®) 30 mg after TURBT followed by regular intravesical therapy appears well tolerated and more effective than regular intravesical therapy for preventing tumor recurrence, especially in low and intermediate-risk patients. 23806416 Halloysite nanotubule clay for efficient water purification. Halloysite clay has chemical structure similar to kaolinite but it is rolled in tubes with diameter of 50nm and length of ca. 1000nm. Halloysite exhibits higher adsorption capacity for both cationic and anionic dyes because it has negative SiO2 outermost and positive Al2O3 inner lumen surface; therefore, these clay nanotubes have efficient bivalent adsorbancy. An adsorption study using cationic Rhodamine 6G and anionic Chrome azurol S has shown approximately two times better dye removal for halloysite as compared to kaolin. Halloysite filters have been effectively regenerated up to 50 times by burning the adsorbed dyes. Overall removal efficiency of anionic Chrome azurol S exceeded 99.9% for 5th regeneration cycle of halloysite. Chrome azurol S adsorption capacity decreases with the increase of ionic strength, temperature and pH. For cationic Rhodamine 6G, higher ionic strength, temperature and initial solution concentration were favorable to enhanced adsorption with optimal pH 8. The equilibrium adsorption data were described by Langmuir and Freundlich isotherms. 23931693 Kinetic study of a novel thermo-stable α-carbonic anhydrase for biomimetic CO2 capture. Biomimetic CO2 capture includes environmentally friendly solutions based on carbonic anhydrase (CA), an enzyme that increases CO2 absorption rate in conventional acid-gas scrubbing processes. The present contribution reports the characterization of a new recombinant carbonic anhydrase, SspCA, isolated from the thermophile bacterium Sulphurhydrogenibium yellowstonense sp. YO3AOP1. The kinetics of SspCA was characterized in terms of first order CO2 hydration rate according to a procedure based on CO2 absorption tests in a stirred cell apparatus. The first order kinetic constant at 25°C was 9.16×10(6)L/(mols). An appropriate investigation on SspCA stability was carried out to assess its long-term resistance to high temperatures as in all capture processes based on absorption/vacuum-desorption cycles. Its half-life was 53 and 8 days at 40°C and 70°C, respectively. 23849627 A P(E)RM(I)T for BMP Signaling. In this issue, Xu et al. (2013) report their interesting discovery of a critical step for initiating BMP signal transduction that requires arginine methylation at the plasma membrane. 23905674 High-risk clinical target volume delineation in CT-guided cervical cancer brachytherapy: Impact of information from FIGO stage with or without systematic inclusion of 3D documentation of clinical gynecological examination. Purpose. The aim of the study was to improve computed tomography (CT)-based high-risk clinical target volume (HR CTV) delineation protocols for cervix cancer patients, in settings without any access to magnetic resonance imaging (MRI) at the time of brachytherapy. Therefore the value of a systematic integration of comprehensive three-dimensional (3D) documentation of repetitive gynecological examination for CT-based HR CTV delineation protocols, in addition to information from FIGO staging, was investigated. In addition to a comparison between reference MRI contours and two different CT-based contouring methods (using complementary information from FIGO staging with or without additional 3D clinical drawings), the use of standardized uterine heights was also investigated. Material and methods. Thirty-five cervix cancer patients with CT- and MR-images and 3D clinical drawings at time of diagnosis and brachytherapy were included. HR CTVstage was based on CT information and FIGO stage. HR CTVstage + 3Dclin was contoured on CT using FIGO stage and 3D clinical drawing. Standardized HR CTV heights were: 1/1, 2/3 and 1/2 of uterine height. MRI-based HR CTV was delineated independently. Resulting widths, thicknesses, heights, and volumes of HR CTVstage, HR CTVstage + 3Dclin and MRI-based HR CTV contours were compared. Results. The overall normalized volume ratios (mean± SD of CT/MRIref volume) of HR CTVstage and HR stage + 3Dclin were 2.6 (± 0.6) and 2.1 (± 0.4) for 1/1 and 2.3 (± 0.5) and 1.8 (± 0.4), for 2/3, and 1.9 (± 0.5) and 1.5 (± 0.3), for 1/2 of uterine height. The mean normalized widths were 1.5 ± 0.2 and 1.2 ± 0.2 for HR CTVstage and HR CTVstage + 3Dclin, respectively (p < 0.05). The mean normalized heights for HR CTVstage and HR CTVstage + 3Dclin were both 1.7 ± 0.4 for 1/1 (p < 0.05.), 1.3 ± 0.3 for 2/3 (p < 0.05) and 1.1 ± 0.3 for 1/2 of uterine height. Conclusion. CT-based HR CTV contouring based on FIGO stage alone leads to large overestimation of width and volume. Target delineation accuracy can systematically improve through incorporation of additional information from comprehensive 3D documentation of repetitive gynecological examination in the contouring protocol, and thus help to improve the accuracy of dose optimization in settings with limited access to imaging facilities at the time of brachytherapy. If CT information is only available, minimum 2/3 of uterine height may be a good surrogate for the height of HR CTV. 22820076 Loop-mediated isothermal amplification for rapid detection of the causal agents of cassava brown streak disease. The causal agents of cassava brown streak disease have recently been identified as Cassava brown streak virus (CBSV) and Ugandan cassava brown streak virus (UCBSV). Primers have been developed for rapid detection of these viruses by reverse transcription loop-mediated isothermal amplification (RT-LAMP). Performance of the RT-LAMP assays compared favourably with published RT-PCR and real-time RT-PCR methods. Furthermore, amplification by RT-LAMP is completed in 40 min and does not require thermal cycling equipment. Modification of the RT-LAMP reactions to use labelled primers allowed rapid detection of amplification products using lateral flow devices containing antibodies specific to the incorporated labels, avoiding the need for fluorescence detection or gel electrophoresis. 23865901 Palladium(II)-Catalyzed Direct Carboxylation of Alkenyl C-H Bonds with CO2. Pd-catalyzed direct carboxylation of alkenyl C-H bonds with carbon dioxide was realized for the first time. Treatment of 2-hydroxystyrenes and a catalytic amount of Pd(OAc)2 with Cs2CO3 under atmospheric pressure of CO2 afforded corresponding coumarins in good yield. Furthermore, isolation of the key alkenylpalladium intermediate via C-H bond cleavage was achieved. The reaction was proposed to undergo reversible nucleophilic addition of the alkenylpalladium intermediate to CO2. 22547144 The PPAR alpha gene is associated with triglyceride, low-density cholesterol and inflammation marker response to fenofibrate intervention: the GOLDN study. As a peroxisome proliferator-activated receptor alpha (PPARα) agonist, fenofibrate favorably modulates dyslipidemia and inflammation markers, which are associated with cardiovascular risk. To determine whether variation in the PPARα receptor gene was associated with lipid and inflammatory marker response, we conducted a 3-week trial of fenofibrate in 861 men and women. Mixed linear models that controlled for age and sex, as well as family pedigree and study center, were constructed using single-nucleotide polymorphisms (SNPs) in the PPARα gene as predictors and changes in fasting triglycerides (TGs), cholesterol and inflammatory markers as outcomes. Significant associations with low-density cholesterol and interleukin-2 (P<0.001) responses to fenofibrate were found. Although there were suggestive associations with tumor necrosis factor-alpha and TG responses (P<0.05), these did not survive the correction for multiple testing. We conclude that variants in the PPARα gene may contribute to future pharmacogenomic paradigms seeking to predict fenofibrate responders from both an anti-dyslipidemic and anti-inflammatory perspective. 23889934 The Small GTPase Arf1 Modulates Arp2/3-Mediated Actin Polymerization via PICK1 to Regulate Synaptic Plasticity. Inhibition of Arp2/3-mediated actin polymerization by PICK1 is a central mechanism to AMPA receptor (AMPAR) internalization and long-term depression (LTD), although the signaling pathways that modulate this process in response to NMDA receptor (NMDAR) activation are unknown. Here, we define a function for the GTPase Arf1 in this process. We show that Arf1-GTP binds PICK1 to limit PICK1-mediated inhibition of Arp2/3 activity. Expression of mutant Arf1 that does not bind PICK1 leads to reduced surface levels of GluA2-containing AMPARs and smaller spines in hippocampal neurons, which occludes subsequent NMDA-induced AMPAR internalization and spine shrinkage. In organotypic slices, NMDAR-dependent LTD of AMPAR excitatory postsynaptic currents is abolished in neurons expressing mutant Arf1. Furthermore, NMDAR stimulation downregulates Arf1 activation and binding to PICK1 via the Arf-GAP GIT1. This study defines Arf1 as a critical regulator of actin dynamics and synaptic function via modulation of PICK1. 23550658 Markers of systemic inflammation in psoriasis: a systematic review and meta-analysis. Studies investigating systemic inflammation in psoriasis use different serum markers and report discrepant results. We set out to determine whether systemic inflammation is elevated in patients with psoriasis compared with healthy controls, and to measure the extent of this elevation, by summarizing available data on serum inflammatory markers. PubMed, Embase and Web of Science were searched from inception to March 2011. We included studies comparing the serum inflammatory markers interleukin (IL)-1β, IL-6, IL-10, C-reactive protein (CRP), intracellular adhesion molecule (ICAM)-1, E-selectin and tumour necrosis factor (TNF)-α in patients with psoriasis and healthy controls. Differences in serum marker levels between patients and controls were pooled as standardized mean differences (SMDs; Cohen's d) using a random-effects model. Seventy-eight studies were eligible. Of the 7852 individuals included, 3085 had (severe plaque) psoriasis. The pooled SMDs were higher in patients with psoriasis than in healthy controls for IL-6 [d = 1·32, 95% confidence interval (CI) 0·83-1·81], CRP (d = 1·83, 95% CI 0·76-2·90), TNF-α (d = 1·32, 95% CI 0·86-1·79), E-selectin (d = 1·78, 95% CI 1·32-2·25) and ICAM-1 (d = 1·77, 95% CI 1·15-2·39). The SMD between cases and controls for IL-1β and IL-10 was not significant. Age had a significant effect on the SMD for IL-6 and TNF-α. For IL-6 the effect size was higher for plaque psoriasis studies (d = 1·98). The effect size was not influenced by the Psoriasis Area and Severity Index, measurement method or quality assessment. The pooled analyses suggest modest but significantly elevated levels of the proinflammatory cytokines in the serum of patients with psoriasis with predominantly severe disease. To what extent this modest increment is clinically relevant could be investigated in a synthesis of all studies measuring inflammation before and after antipsoriatic therapy. 23764528 Effect of acetone accumulation on structure and dynamics of lipid membranes studied by molecular dynamics simulations. The modulation of the properties and function of cell membranes by small volatile substances is important for many biomedical applications. Despite available experimental results, molecular mechanisms of action of inhalants and organic solvents, such as acetone, on lipid membranes remain not well understood. To gain a better understanding of how acetone interacts with membranes, we have performed a series of molecular dynamics (MD) simulations of a POPC bilayer in aqueous solution in the presence of acetone, whose concentration was varied from 2.8 to 11.2mol%. The MD simulations of passive distribution of acetone between a bulk water phase and a lipid bilayer show that acetone favors partitioning into the water-free region of the bilayer, located near the carbonyl groups of the phospholipids and at the beginning of the hydrocarbon core of the lipid membrane. Using MD umbrella sampling, we found that the permeability barrier of ∼0.5kcal/mol exists for acetone partitioning into the membrane. In addition, a Gibbs free energy profile of the acetone penetration across a bilayer demonstrates a favorable potential energy well of -3.6kcal/mol, located at 15-16Å from the bilayer center. The analysis of the structural and dynamics properties of the model membrane revealed that the POPC bilayer can tolerate the presence of acetone in the concentration range of 2.8-5.6mol%. The accumulation of the higher acetone concentration of 11.2mol% results, however, in drastic disordering of phospholipid packing and the increase in the membrane fluidity. The acetone molecules push the lipid heads apart and, hence, act as spacers in the headgroup region. This effect leads to the increase in the average headgroup area per molecule. In addition, the acyl tail region of the membrane also becomes less dense. We suggest, therefore, that the molecular mechanism of acetone action on the phospholipid bilayer has many common features with the effects of short chain alcohols, DMSO, and chloroform. 23301856 In vitro evaluation of (99m)Tc-EDDA/tricine-HYNIC-Q-Litorin in gastrin-releasing peptide receptor positive tumor cell lines. Abstract Bombesin and its derivatives exhibit a high affinity for gastrin-releasing peptide receptor (GRPr), which is over-expressed in a variety of human cancers (prostate, pancreatic, lung, etc.). The aim of this study was to investigate the in vitro potential of the hydrazinonicotinamide (HYNIC)-Q-Litorin. (99m)Tc labeling was performed by using different co-ligands: tricine and ethylenediamine diacetic acid (EDDA). The radiochemical stability of radiolabeled peptide conjugates was checked at room temperature and in cysteine solution up to 24 h. The in vitro cell uptake of (99m)Tc-EDDA-HYNIC-Q-Litorin and (99m)Tc-tricine-HYNIC-Q-Litorin were evaluated on pancreatic tumor and control cell lines. Optimum specific activity and incubation time were determined for all the cell lines. The results showed that the cell uptake of the radiolabeled peptide conjugates in tumor cell lines were higher than in the control cell line. The findings of this study indicated the need for further development of in vivo study as a radiopharmaceutical for pancreatic tumor imaging. 23820120 Prenatal programming of insulin secretion in intrauterine growth restriction. Intrauterine growth restriction (IUGR) impairs insulin secretion in humans and in animal models of IUGR. Several underlying mechanisms have been implicated, including decreased expression of molecular regulators of β-cell mass and function, in some cases shown to be due to epigenetic changes initiated by an adverse fetal environment. Alterations in cell cycle progression contribute to loss of β-cell mass, whereas decreased islet vascularity and mitochondrial dysfunction impair β-cell function in IUGR rodents. Animal models of IUGR sharing similar insulin secretion outcomes as the IUGR human are allowing underlying mechanisms to be identified. This review will focus on models of uteroplacental insufficiency. 23664095 Characterization of interleukin-1β in Helicobacter pylori-induced gastric inflammation and DNA methylation in interleukin-1 receptor type 1 knockout (IL-1R1(-/-)) mice. Helicobacter pylori infection induced interleukin-1β (IL-1β) production and is associated with aberrant DNA methylation and gastric diseases. Here, we investigated the role of IL-1β in H. pylori-induced gastric inflammation and DNA methylation using IL-1 receptor type 1 knockout (IL-1R1(-/-)) mice, and compared the therapeutic efficacy of antimicrobial therapy with IL-1 receptor antagonist (IL-1ra). IL-1R1(-/-) and wild-type (WT) mice were infected with H. pylori for 16, 24 and 32weeks. Infected WT mice at 24weeks were given either antimicrobial therapy or IL-1ra. Comparing to the IL-1R1(-/-) mice, infected WT mice with functional IL-1β signaling had higher gastritis scores, higher IL-1β and iNOS mRNA expression, higher nitric oxide (NO) production and increased frequency of E-cadherin (E-cad) methylation at all the time points analyzed. IL-1β release was significantly elevated in infected WT mice than normal controls at 16weeks post-infection (p<0.005). Treatment of infected mice with antimicrobial therapy and IL-1ra significantly reduced the degree of gastritis (p<0.005; p<0.05, respectively), iNOS expression (p<0.0001; p<0.01, respectively) and NO production (both p<0.001) compared with untreated controls. Mice receiving antimicrobial therapy had significantly lower IL-1β expression than untreated controls (p<0.0001). Both treatments reduced the incidence of E-cad methylation in infected mice compared with controls, however, no statistical significance was observed. There was no significant alteration of total DNA methyltransferase (DNMT) activity. These results demonstrated that IL-1β played a crucial role in H. pylori-induced gastric inflammation and DNA methylation. H. pylori eradication and IL-1ra administration could ameliorate inflammatory stress. 23967444 Optimizing the synthesis of red- and near-infrared CuInS2 and AgInS2 semiconductor nanocrystals for bioimaging. This work reports the study of optimization of the reaction parameters on the synthesis of high quality CuInS2 and AgInS2 nanocrystals for bioimaging applications. The concentration of reaction precursors (e.g. Ag, Cu, In and S) plays a key role in determining the emission profile of these ternary quantum dots (QDs). By carefully varying the precursor compositions, the emission of QD can be tuned from red to near infrared (NIR) region. Taking the advantages of NIR emission, which possesses minimal absorption in biological tissues, we have also prepared water-dispersible CuInS2/ZnS and AgInS2/ZnS nanocrystals and demonstrated the high biocompatibility for both deep tissue penetration and tumor targeting. The QDs were stabilized in Pluronic F127 block copolymer micelles, offering us optically and colloidally stable contrast agents for in vitro and in vivo imaging. Two-photon excitation of QD has also been demonstrated, accomplishing a NIR-to-NIR transaction. This study devotes the key steps in promoting the use of ternary QDs as low-toxic, photostable, and cadmium-free semiconductor nanocrystal formulation for multiple imaging applications. 23954768 Nanoparticle release from nano-silver antimicrobial food containers. Polymer nanocomposites incorporating metal or metal oxide nanoparticles have been developed to improve their characteristics (flexibility, gas barrier properties, antimicrobial or antioxidant properties, etc.). Among them silver nanoparticles are used because of their antimicrobial effect in many daily life materials, i.e. food packaging. However, there is not any reference to the migration of nanoparticles to the food. In this paper the results of migration studies (with different simulant solutions and times) in three commercial nanosilver plastic food containers are shown. Migration solutions were evaluated by ICP-MS and SEM-EDX analysis and silver in dissolved form and silver as nanoparticles were analyzed, a key aspect for the toxicity. Silver migration was observed for all samples studied, with the total silver migration values ranging between 1.66 and 31.46ng/cm(2) (lower than the permissible limits). Size and morphology of the silver nanoparticles changed for the different samples (ranging between 10 and 60nm) and migration of other nanosized materials was also confirmed. 23843899 Urokinase receptor counteracts vascular smooth muscle cell functional changes induced by surface topography. Current treatments for human coronary artery disease necessitate the development of the next generations of vascular bioimplants. Recent reports provide evidence that controlling cell orientation and morphology through topographical patterning might be beneficial for bioimplants and tissue engineering scaffolds. However, a concise understanding of cellular events underlying cell-biomaterial interaction remains missing. In this study, applying methods of laser material processing, we aimed to obtain useful markers to guide in the choice of better vascular biomaterials. Our data show that topographically treated human primary vascular smooth muscle cells (VSMC) have a distinct differentiation profile. In particular, cultivation of VSMC on the microgrooved biocompatible polymer E-shell induces VSMC modulation from synthetic to contractile phenotype and directs formation and maintaining of cell-cell communication and adhesion structures. We show that the urokinase receptor (uPAR) interferes with VSMC behavior on microstructured surfaces and serves as a critical regulator of VSMC functional fate. Our findings suggest that microtopography of the E-shell polymer could be important in determining VSMC phenotype and cytoskeleton organization. They further suggest uPAR as a useful target in the development of predictive models for clinical VSMC phenotyping on functional advanced biomaterials. 23884607 Chromatin-to-nucleoprotamine transition is controlled by the histone H2B variant TH2B. The conversion of male germ cell chromatin to a nucleoprotamine structure is fundamental to the life cycle, yet the underlying molecular details remain obscure. Here we show that an essential step is the genome-wide incorporation of TH2B, a histone H2B variant of hitherto unknown function. Using mouse models in which TH2B is depleted or C-terminally modified, we show that TH2B directs the final transformation of dissociating nucleosomes into protamine-packed structures. Depletion of TH2B induces compensatory mechanisms that permit histone removal by up-regulating H2B and programming nucleosome instability through targeted histone modifications, including lysine crotonylation and arginine methylation. Furthermore, after fertilization, TH2B reassembles onto the male genome during protamine-to-histone exchange. Thus, TH2B is a unique histone variant that plays a key role in the histone-to-protamine packing of the male genome and guides genome-wide chromatin transitions that both precede and follow transmission of the male genome to the egg. 23829936 Mercury methylation in mesocosms with and without the aquatic macrophyte Eichhornia crassipes (mart.) Solms. Mercury is a toxic pollutant and spreads to several compartments in the environment. Previous in-vitro studies showed that roots of aquatic macrophytes are sites of methylmercury formation, performed mainly by sulfate-reducing bacteria (SRB). The objective of this study was to observe MMHg formation and distribution among filtered water (0.2µm), suspended and settled particles and macrophyte roots during seventeen days, in (203)Hg- spiked mesocosms with and without live Eichhornia crassipes whole plants and a SRB inhibitor. Root samples were also incubated in-vitro for comparison of MM(203)Hg formation under in-vitro and in-vivo conditions. To evaluate the effect of SRB inhibition by sodium molybdate on total heterotrophic activity, the latter was measured by (3)H-leucine uptake. Inhibition of Hg methylation by sodium molybdate decreased with time in mesocosms. MMHg averaged 10, 12.4 and 0.23 percent of total (203)Hg present in filtered water, suspended particles and roots respectively. In vitro MMHg formation in roots averaged 5.54 percent of total added (203)Hg, with a clearer SRB inhibition effect than in mesocosms. Though significant, MMHg formation in roots from in-vivo mesocosms was one order of magnitude lower than previously found in in-vitro incubations of roots alone. 23532797 High-Grade Prostatic Intraepithelial Neoplasia (HGPIN) and topographical distribution in 1,374 prostatectomy specimens: Existence of HGPIN near prostate cancer. PURPOSE: High-grade prostatic intraepithelial neoplasia (HGPIN) is believed to be a precursor of prostate cancer (PCa). This study evaluated whether HGPIN was located close to PCa in whole radical prostatectomy specimens (RPSs). MATERIALS AND METHODS: We evaluated 1,374 prostate specimens from 1999 to 2010 using a cMDX-based map model of the prostate. The distribution of 10,439 PCa foci was analyzed and visualized on a heat map. The color gradient of the heat map was reduced to six colors representing the frequency classification of the relative frequency of PCa using an image posterization effect. We defined 22 regions in the prostate according to the frequency of PCa occurrence. Seven hundred ninety RPSs containing 6,374 PCa foci and 4,502 HGPIN foci were evaluated. The topographical association between PCa and HGPIN in the RPSs was analyzed by estimating the frequencies of PCa and HGPIN in 22 regions. A logistic regression analysis was performed to assess the odds ratios of HGPIN for the presence of PCa in 22 regions. RESULTS: Fifty-eight percent of PCa specimens included HGPIN and had significantly more favorable Gleason scores, lower PSA levels and smaller relative tumor volumes than isolated PCa specimens. HGPIN (68%) and PCa (69%) were predominantly localized to the apical half of the prostate. HGPIN was mainly concentrated in the peripheral zone medial to regions with high PCa frequencies. Upon logistic regression analysis, HGPIN was a significant predictor of PCa co-existence in 11 regions. CONCLUSIONS: HGPIN was located adjacent to PCa in whole RPSs. PCa concomitant with HGPIN had more favorable pathologic features than isolated PCa. Prostate © 2013 Wiley Periodicals, Inc. 23063003 An omics based assessment of cadmium toxicity in the green alga Chlamydomonas reinhardtii. The effects of cadmium were assessed in the freshwater alga Chlamydomonas reinhardtii. Algae were exposed to concentrations of 0, 8.1 or 114.8 μM of cadmium and growth rates, gene transcription and metabolite profiles were examined after 48 and 72 h of exposure. In algae exposed to 8.1 μM Cd, several genes were differentially transcribed after 48 h but no adverse growth related effects were detected. A transient effect on both gene transcription patterns and metabolite profiles could be discerned after 48 h of exposure but the majority of these changes disappeared after 72 h. In contrast, all effects were more pronounced at the 114.8 μM cadmium exposure. Here growth was clearly reduced and transcription of a large number of genes involved in oxidative stress defense mechanisms was differentially increased. Metabolites involved in the glutathione synthesis pathway (an important antioxidant defense) were also affected but the effects of cadmium were found to be more pronounced at the transcript level than in the metabolome, suggesting that the former exhibits greater sensitivity toward cadmium exposure. 23968774 Hospital care of children with a cleft in England. To analyse hospital admissions in the first 2 years of life among children with cleft lip and/or palate in England. Analysis of national administrative data of hospital admissions. National Health Service hospitals. Patients born alive between 1997 and 2008 who underwent surgical cleft repair. Number of admissions, including the birth episode, and days spent in hospital were examined. Children were analysed according to cleft type and whether or not they had additional congenital anomalies. 10 892 children were included. In their first 2 years, children without additional anomalies (n=8482) had on average 3.2 admissions and 13.2 days in hospital, which varied from 2.6 admissions and 9.2 days with cleft lip to 4.7 admissions and 19.7 days with bilateral cleft lip and palate (BCLP). Children with additional anomalies (n=2410) had on average 6.7 admissions and 51.4 days in hospital, which varied from 6.4 admissions and 48.5 days with cleft palate to 8.8 admissions and 67.5 days with BCLP. The mean number and duration of cleft-related admissions was similar in children without (1.6 admissions and 6.4 days) and in those with additional anomalies (1.5 admissions and 8.5 days). 35.2% of children without additional anomalies had at least one emergency admission, whereas the corresponding figure was 67.3% with additional anomalies. The burden of hospital care in the first 2 years of life varied according to cleft type and presence of additional anomalies. However, cleft-specific hospital care did not differ between children with and without additional anomalies. 23867216 Spinning and translational motion of Sb nanoislands manipulated on MoS2. Antimony nanoislands grown on a MoS2 surface in ultra-high vacuum have been manipulated by atomic force microscopy (AFM) in ambient conditions. The island profiles have been digitized and provided as an input to a collisional algorithm based on classical mechanics. Assuming that the islands are rigid and static friction is high enough to prevent further motion after the passage of the probing tip, the direction of motion and the angle of rotation of the islands have been reproduced numerically. For a given spacing between the scan lines, the angle of deflection with respect to the fast scan direction and the angular speed of the islands are expected to vary with the friction between islands and substrate. From a comparison between model and experiment a shear strength in the order of 0.2 MPa is estimated. 23711109 Differential immunohistochemical localization of desmosomal plaque-related proteins in non-small-cell lung cancer. Immunohistochemistry is a highly valuable and widely used tool in the subtyping of lung carcinomas. The aim of this study was to identify markers for the differential diagnosis of non-small-cell carcinomas. We report on the immunohistochemical localization of plakophilin-1 (PKP1), keratin-15 (KRT15) and desmoglein-3 (DSG3) intercellular adhesion proteins in samples from 75 primary non-small-cell lung cancers in non-treated patients. The staining pattern of these proteins differed between squamous cell carcinomas and adenocarcinomas, with no membrane staining in the latter. Membrane staining for all three proteins was characteristic of squamous cell carcinomas. We observed a relationship between the presence/absence of these proteins in the membranes of squamous cell carcinomas and the differentiation grade, with more intense staining in better differentiated areas. Staining for these proteins marked intercellular junctions that are characteristic of stratified squamous epithelium and of neoplasias with this type of differentiation, and can be useful in the diagnosis of patients with squamous cell carcinoma of the lung. The high specificity of membrane staining for PKP1 and DSG3 and high sensitivity of cytoplasmic and membrane staining for KRT15 for the diagnosis of squamous cell carcinoma may be useful for the differential diagnosis of non-small-cell carcinomas. 23842206 Vascular Endothelial Function and Self-reported Sleep. The authors investigated the relationship between self-reported sleep characteristics and brachial artery flow-mediated dilation (FMD) in a community-based population. Previous studies document that sleep apnea may be related to endothelial dysfunction but disagree whether subjective reports of sleep may also reflect such associations. In 684 subjects (32% male) aged between 37 and 60 years enrolled in the Emory-Georgia Tech Predictive Health Institute study, the authors measured reported sleep characteristics using the Epworth Sleepiness Scale and the Pittsburgh Sleep Quality Index (PSQI) along with cardiovascular risk factors. Endothelial function was assessed using brachial artery FMD. Multivariate analysis of covariance was used to adjust for various cardiovascular risk factors including age, race, gender, smoking, hypertension, diabetes and body mass index. Lower brachial artery FMD values were correlated with higher Epworth Sleepiness Scale scores (P = 0.0275), even after adjustment for risk factors (P = 0.03). Total PSQI score was unrelated to brachial artery FMD. However, lower sleep quality (PSQI component 1) was associated with lower brachial artery FMD (multivariate P = 0.038), and participants who coughed or snored during sleep also had lower brachial artery FMD (6.24% ± 3.42%) compared with those who did not (6.92% ± 4.30%) (P = 0.056). This difference remained significant after adjustment for risk factors (P = 0.03). In a community-based population, our analysis indicates a significant association between sleepiness and snoring assessed by questionnaires and endothelial function. Simple subjective reports about individuals' sleep may be highly revealing indicators of endothelial function impairment and thus important indicators of cardiovascular disease risk. 23835656 Incorporating deliverable monitor unit constraints into spot intensity optimization in intensity-modulated proton therapy treatment planning. The purpose of this study is to investigate the feasibility and impact of incorporating deliverable monitor unit (MU) constraints into spot intensity optimization (SIO) in intensity-modulated proton therapy (IMPT) treatment planning. The current treatment planning system (TPS) for IMPT disregards deliverable MU constraints in the SIO routine. It performs a post-processing procedure on an optimized plan to enforce deliverable MU values that are required by the spot scanning proton delivery system. This procedure can create a significant dose distribution deviation between the optimized and post-processed deliverable plans, especially when small spot spacings are used. In this study, we introduce a two-stage linear programming approach to optimize spot intensities and constrain deliverable MU values simultaneously, i.e., a deliverable SIO (DSIO) model. Thus, the post-processing procedure is eliminated and the associated optimized plan deterioration can be avoided. Four prostate cancer cases at our institution were selected for study and two parallel opposed beam angles were planned for all cases. A quadratic programming based model without MU constraints, i.e., a conventional SIO (CSIO) model, was also implemented to emulate commercial TPS. Plans optimized by both the DSIO and CSIO models were evaluated for five different settings of spot spacing from 3 to 7 mm. For all spot spacings, the DSIO-optimized plans yielded better uniformity for the target dose coverage and critical structure sparing than did the CSIO-optimized plans. With reduced spot spacings, more significant improvements in target dose uniformity and critical structure sparing were observed in the DSIO than in the CSIO-optimized plans. Additionally, better sparing of the rectum and bladder was achieved when reduced spacings were used for the DSIO-optimized plans. The proposed DSIO approach ensures the deliverability of optimized IMPT plans that take into account MU constraints. This eliminates the post-processing procedure required by the TPS as well as the resultant deteriorating effect on ultimate dose distributions. This approach therefore allows IMPT plans to adopt all possible spot spacings optimally. Moreover, dosimetric benefits can be achieved using smaller spot spacings. 23957615 The Legionella pneumophila kai operon is implicated in stress response and confers fitness in competitive environments. Legionella pneumophila uses aquatic protozoa as replication niche and protection from harsh environments. Although L. pneumophila is not known to have a circadian clock, it encodes homologues of the KaiBC proteins of Cyanobacteria that regulate circadian gene expression. We show that L. pneumophila kaiB, kaiC and the downstream gene lpp1114, are transcribed as a unit under the control of the stress sigma factor RpoS. KaiC and KaiB of L. pneumophila do not interact as evidenced by yeast and bacterial two-hybrid analyses. Fusion of the C-terminal residues of cyanobacterial KaiB to Legionella KaiB restores their interaction. In contrast, KaiC of L. pneumophila conserved autophosphorylation activity, but KaiB does not trigger the dephosphorylation of KaiC like in Cyanobacteria. The crystal structure of L. pneumophila KaiB suggests that it is an oxidoreductase-like protein with a typical thioredoxin fold. Indeed, mutant analyses revealed that the kai operon-encoded proteins increase fitness of L. pneumophila in competitive environments, and confer higher resistance to oxidative and sodium stress. The phylogenetic analysis indicates that L. pneumophila KaiBC resemble Synechosystis KaiC2B2 and not circadian KaiB1C1. Thus, the L. pneumophila Kai proteins do not encode a circadian clock, but enhance stress resistance and adaption to changes in the environments. 23607804 The effect of targeted rheumatoid arthritis therapies on anti-citrullinated protein autoantibody levels and B cell responses. Rheumatoid arthritis (RA) is a complex inflammatory disorder associated with synovitis and joint destruction that affects an estimated 1·3 million Americans and causes significant morbidity, a reduced life-span and lost work productivity. The use of biological therapies for the treatment of RA is costly, and the selection of therapies is still largely empirical and not guided by the underlying biological features of the disease in individual patients. The synovitis associated with RA is characterized by an influx of B and T cells, macrophages and neutrophils and the expansion of fibroblast-like synoviocytes, which form pannus and lead to cartilage and bone destruction. RA is associated with synovial production of rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA) and with the production of inflammatory cytokines, including interleukin (IL)-1, IL-6, IL-17 and tumour necrosis factor (TNF)-α, which are targets for RA therapeutics. Recent ideas about the pathogenesis of RA emphasize a genetic predisposition to develop RA, a preclinical phase of disease that is associated with the production of ACPA and the development of symptomatic disease following inflammatory initiating events that are associated with expression of citrullinated epitopes in the joints of patients. However, we still have a limited understanding of the cytokine and intracellular pathways that regulate ACPA levels. In humans, therapy with biological agents affords a unique opportunity to better understand the cytokine and signalling pathways regulating ACPA levels and the impact of ACPA level changes on disease activity. In this study we summarize the effect of RA therapies on ACPA levels and B cell responses. 22975162 Four new coumarinolignoids from seeds of Solanum indicum. Activity-guided fractionation of seeds of Solanum indicum for anti-HBV activity led to the isolation of two novel coumarinolignoid alkaloids (indicumines A-B, 1-2) and two new coumarinolignoids (indicumines C-D, 3-4), together with four known coumarins (5-8). Their structures were established on the basis of spectroscopic data. The two novel coumarinolignoid alkaloids shows anti-HBV activities through specifically inhibiting the secretion of HBsAg in HepG2.2.15. 23899232 Breastfeeding and tacrolimus: is it a reasonable approach? Evaluation of: Bramham K, Chusney G, Lee J, Lightstone L, Nelson-Piercy C. Breastfeeding and tacrolimus: serial monitoring in breast-fed and bottle-fed infants. CJASN 8(4), 563-567 (2013). Successful pregnancy after transplantation has become more common and more recipients are choosing to breastfeed their infants, despite the controversy surrounding the safety of breastfeeding while the mother is taking immunosuppressive medications, such as tacrolimus. Data collected to date by the National Transplantation Pregnancy Registry have not revealed specific problems related to breastfeeding; however, individual circumstances must be considered when counseling transplant recipients regarding breastfeeding. Bramham et al. reported on a series of transplant recipients who were maintained on tacrolimus during pregnancy and lactation and concluded that women should not be discouraged from breastfeeding while on tacrolimus. Recently, other authors have also supported the option of breastfeeding while recipients are maintained on tacrolimus. Herein, we review the Bramham article and discuss the key issues to be considered regarding the compatibility of breastfeeding and immunosuppression. 23763350 C-Cl Activation by Group IV Metal Oxides in Solid Argon Matrixes: Matrix Isolation Infrared Spectroscopy and Theoretical Investigations of the Reactions of MOx (M = Ti, Zr; x = 1, 2) with CH3Cl. Reactions of the ground-state titanium and zirconium monoxide and dioxide molecules with monochloromethane in excess argon matrixes have been investigated in solid argon by infrared absorption spectroscopy and density functional theoretical calculations. The results show that the ground-state MOx (M = Ti, Zr; x = 1, 2) molecules react with CH3Cl to first form the weakly bound MO(CH3Cl) and MO2(CH3Cl) complexes. The MO(CH3Cl) complexes can rearrange to the CH3M(O)Cl isomers with the Cl atom of CH3Cl coordination to the metal center of MO upon UV light irradiation (λ < 300 nm). Theoretical calculations indicate that the electronic state crossings exist from the MO + CH3Cl reaction to the more stable CH3M(O)Cl molecules via the MO(CH3Cl) complexes traversing their corresponding transition states. The MO2(CH3Cl) complexes can isomerize to the more stable CH3OM(O)Cl molecules with the addition of the C-Cl bond of CH3Cl to one of the O═M bonds of MO2 upon annealing after broad-band light irradiation. The C-Cl activation by the MOx mechanism was interpreted by the calculated potential energy profiles. 23962094 Angiogenesis Inhibitors in Cancer Therapy: Mechanistic perspective on classification and treatment rationales. Angiogenesis, a process of new blood vessels formation, is a prerequisite for tumor growth to supply the proliferating tumor with oxygen and nutrients. Angiogenic process may contribute tumor progression, invasion, and metastasis and is generally accepted as an indicator of tumor prognosis. Therefore, targeting tumor angiogenesis has become of high clinical relevance. The current review aims to highlight mechanistic details of antiangiogenic therapies and how they relate to classification and treatment rationales. Angiogenesis inhibitors are classified into either direct inhibitors that target endothelial cells in the growing vasculature or indirect inhibitors that prevent the expression or block the activity of angiogenesis inducers. The latter class extends to include targeted therapy against oncogenes, conventional chemotherapeutic agents and drugs targeting other cells of the tumor microenvironment. Angiogenesis inhibitors may be used as either monotherapy or in combination with other anticancer drugs. In this context, many preclinical and clinical studies revealed higher therapeutic effectiveness of the combined treatments compared with individual treatments. The proper understanding of synergistic treatment modalities of angiogenesis inhibitors as well as their wide range of cellular targets could provide effective tools for future therapies of many types of cancer. 23283806 The bishop score as a predictor of labor induction success: a systematic review. Objective To assess the ability of the Bishop score to predict the mode of delivery in women scheduled for induction of labor at term.Study Design We performed a systematic literature search of electronic databases from inception to July 2009. Studies reporting on both the Bishop score and the outcome of labor in women scheduled for induction of labor at term were eligible. We used a bivariate model to estimate a summary receiver operating characteristic (sROC) curve for the outcome cesarean delivery.Results We included 40 primary articles reporting on 13,757 women. Study quality was mediocre. The sROC curve of the Bishop score in the prediction of cesarean delivery indicated a poor predictive capacity. For the prediction of cesarean delivery, the sensitivity-specificity combinations were 47%-75%, 61%-53% and 78%-44% for the Bishop scores of 4, 5, and 6, respectively. For a Bishop score below 9, the sensitivity-specificity combination was 95%-30%.Conclusion The Bishop score is a poor predictor for the outcome of induced labor at term and should not be used to decide whether to induce labor or not. 23785004 Gβγ-Independent Recruitment of G-Protein Coupled Receptor Kinase 2 Drives Tumor Necrosis Factor α-Induced Cardiac β-Adrenergic Receptor Dysfunction. Proinflammatory cytokine tumor necrosis factor-α (TNFα) induces β-adrenergic receptor (βAR) desensitization, but mechanisms proximal to the receptor in contributing to cardiac dysfunction are not known. Two different proinflammatory transgenic mouse models with cardiac overexpression of myotrophin (a prohypertrophic molecule) or TNFα showed that TNFα alone is sufficient to mediate βAR desensitization as measured by cardiac adenylyl cyclase activity. M-mode echocardiography in these mouse models showed cardiac dysfunction paralleling βAR desensitization independent of sympathetic overdrive. TNFα-mediated βAR desensitization that precedes cardiac dysfunction is associated with selective upregulation of G-protein coupled receptor kinase 2 (GRK2) in both mouse models. In vitro studies in β2AR-overexpressing human embryonic kidney 293 cells showed significant βAR desensitization, GRK2 upregulation, and recruitment to the βAR complex following TNFα. Interestingly, inhibition of phosphoinositide 3-kinase abolished GRK2-mediated βAR phosphorylation and GRK2 recruitment on TNFα. Furthermore, TNFα-mediated βAR phosphorylation was not blocked with βAR antagonist propranolol. Additionally, TNFα administration in transgenic mice with cardiac overexpression of Gβγ-sequestering peptide βARK-ct could not prevent βAR desensitization or cardiac dysfunction showing that GRK2 recruitment to the βAR is Gβγ independent. Small interfering RNA knockdown of GRK2 resulted in the loss of TNFα-mediated βAR phosphorylation. Consistently, cardiomyocytes from mice with cardiac-specific GRK2 ablation normalized the TNFα-mediated loss in contractility, showing that TNFα-induced βAR desensitization is GRK2 dependent. TNFα-induced βAR desensitization is mediated by GRK2 and is independent of Gβγ, uncovering a hitherto unknown cross-talk between TNFα and βAR function, providing the underpinnings of inflammation-mediated cardiac dysfunction. 23958389 ICRP PUBLICATION 123: Assessment of Radiation Exposure of Astronauts in Space. During their occupational activities in space, astronauts are exposed to ionising radiation from natural radiation sources present in this environment. They are, however, not usually classified as being occupationally exposed in the sense of the general ICRP system for radiation protection of workers applied on Earth. The exposure assessment and risk-related approach described in this report is clearly restricted to the special situation in space, and should not be applied to any other exposure situation on Earth. The report describes the terms and methods used to assess the radiation exposure of astronauts, and provides data for the assessment of organ doses. Chapter 1 describes the specific situation of astronauts in space, and the differences in the radiation fields compared with those on Earth. In Chapter 2, the radiation fields in space are described in detail, including galactic cosmic radiation, radiation from the Sun and its special solar particle events, and the radiation belts surrounding the Earth. Chapter 3 deals with the quantities used in radiological protection, describing the Publication 103 (ICRP, 2007) system of dose quantities, and subsequently presenting the special approach for applications in space; due to the strong contribution of heavy ions in the radiation field, radiation weighting is based on the radiation quality factor, Q, instead of the radiation weighting factor, wR. In Chapter 4, the methods of fluence and dose measurement in space are described, including instrumentation for fluence measurements, radiation spectrometry, and area and individual monitoring. The use of biomarkers for the assessment of mission doses is also described. The methods of determining quantities describing the radiation fields within a spacecraft are given in Chapter 5. Radiation transport calculations are the most important tool. Some physical data used in radiation transport codes are presented, and the various codes used for calculations in high-energy radiation fields in space are described. Results of calculations and measurements of radiation fields in spacecraft are given. Some data for shielding possibilities are also presented. Chapter 6 addresses methods of determining mean absorbed doses and dose equivalents in organs and tissues of the human body. Calculated conversion coefficients of fluence to mean absorbed dose in an organ or tissue are given for heavy ions up to Z=28 for energies from 10MeV/u to 100GeV/u. For the same set of ions and ion energies, mean quality factors in organs and tissues are presented using, on the one hand, the Q(L) function defined in Publication 60 (ICRP, 1991), and, on the other hand, a Q function proposed by the National Aeronautics and Space Administration. Doses in the body obtained by measurements are compared with results from calculations, and biodosimetric measurements for the assessment of mission doses are also presented. In Chapter 7, operational measures are considered for assessment of the exposure of astronauts during space missions. This includes preflight mission design, area and individual monitoring during flights in space, and dose recording. The importance of the magnitude of uncertainties in dose assessment is considered. Annex A shows conversion coefficients and mean quality factors for protons, charged pions, neutrons, alpha particles, and heavy ions(2150). CLI was more frequent in PLR>150 patients (410(45.9%)) compared to PLR≤150 patients (270(22.0%)) (p<0.001), as was prior myocardial infarction (51(5.7%) vs. 42(3.5%), p = 0.02). Regarding inflammatory parameters, C-reactive protein (median 7.0 mg/l (3.0-24.25) vs. median 5.0 mg/l (2.0-10.0)) and fibrinogen (median 457 mg/dl (359.0-583.0) vs. 372 mg/dl (317.25-455.75)) also significantly differed in the two patient groups (both p<0.001). Finally, a PLR>150 was associated with an OR of 1.9 (95%CI 1.7-2.1) for CLI even after adjustment for other well-established vascular risk factors. An increased PLR is significantly associated with patients at high risk for CLI and other cardiovascular endpoints. The PLR is a broadly available and cheap marker, which could be used to highlight patients at high risk for vascular endpoints. 23906999 Topiramate treatment for alcoholic outpatients recently receiving residential treatment programs: A 12-week, randomized, placebo-controlled trial. Initiation of a relapse prevention medication is crucial at the end of alcohol detoxification. This study aimed to examine the efficacy and safety of topiramate for alcoholism in patients receiving a residential treatment program of alcohol detoxification and post-acute treatment. This was a 12-week, randomized, double-blind, placebo-controlled trial of topiramate for alcoholism in patients receiving a residential treatment program. Individuals with DSM-IV alcohol dependence with minimal withdrawal were enrolled. Participants were randomly assigned to receive either 100-300mg/day of topiramate or placebo. Primary outcomes were given as percentages of heavy drinking days and time to first day of heavy drinking. Other drinking outcomes, craving, and health-related quality of life were evaluated. A total of 106 participants were randomized to receive topiramate (n=53) or placebo (n=53). Twenty-eight participants of the topiramate group (52.8%) and 25 participants of the placebo group (47.2%) completed the study. Averaged over the trial period, there was no significant difference between groups on the mean percentages of heavy drinking days [1.96 (-1.62 to 5.54), p=.28]. Log rank survival analysis found no difference of time to first day of heavy drinking between topiramate and placebo groups (61.8 vs. 57.5 days, respectively; χ(2)=0.61, d.f.=1, p=.81). Other secondary outcomes were not significantly different between groups. By using a conservative model for data analysis, we could not detect the effectiveness of topiramate in this particular population. As the sensitivity analysis showed a trend of its benefit, further studies in larger sample sizes are still warranted. 23943405 Murine Model of Disseminated Fusariosis: Evaluation of the Fungal Burden by Traditional CFU and Quantitative PCR. Systemic disease is the most severe clinical form of fusariosis, and the treatment involves a challenge due to the refractory response to antifungals. Treatment for murine Fusarium solani infection has been described in models that employ CFU quantitation in organs as a parameter of therapeutic efficacy. However, CFU counts do not precisely reproduce the amount of cells for filamentous fungi such as F. solani. In this study, we developed a murine model of disseminated fusariosis and compared the fungal burden with two methods: CFU and quantitative PCR. ICR and BALB/c mice received an intravenous injection of 1 Ã— 10(7) conidia of F. solani per mouse. On days 2, 5, 7, and 9, mice from each mice strain were killed. The spleen and kidneys of each animal were removed and evaluated by qPCR and CFU determinations. Results from CFU assay indicated that the spleen and kidneys had almost the same fungal burden in both BALB/c and ICR mice during the days of the evaluation. In the qPCR assay, the spleen and kidney of each mouse strain had increased fungal burden in each determination throughout the entire experiment. The fungal load determined by the qPCR assay was significantly greater than that determined from CFU measurements of tissue. qPCR could be considered as a tool for quantitative evaluation of fungal burden in experimental disseminated F. solani infection. 23868710 Serum S100A12 levels are associated with the presence and severity of obstructive sleep apnea syndrome in male patients. Inflammation plays a critical role in the pathogenesis of obstructive sleep apnea syndrome (OSAS). S100A12 is a newly identified inflammatory biomarker. This study aims to investigate whether serum S100A12 levels are associated with the presence and severity of OSAS in male patients. A total of 126 male patients with OSAS and 74 controls were enrolled in this study. The presence and severity of OSAS was assessed by apnea-hypopnea index (AHI). Serum S100A12 levels were detected by enzyme-linked immunosorbent assay. Serum S100A12 levels were significantly higher in the OSAS group than in the control group (132.17 (range 101.86 to 174.49) ng/ml vs. 78.40 (range 58.35 to 129.44) ng/ml, P < 0.01). Multivariate logistic regression demonstrated that S100A12 was the only significant and independent predictor of OSAS (odds ratio 1.012, 95 % confidence interval 1.006 to 1.017; P < 0.01). Serum S100A12 levels elevated with the increase in the severity of OSAS (S100A12 levels of 106.04 (range 83.92 to 135.13) ng/ml in mild OSAS group, 133.51 (range 109.64 to 208.95) ng/ml in moderate OSAS group, and 173.04 (range 131.88 to 275.77) ng/ml in severe OSAS group; P < 0.001). Serum S100A12 levels were independently correlated with AHI scores (r = 0.324, P < 0.001) CONCLUSIONS: Serum S100A12 levels were independently associated with the presence and severity of OSAS. These findings suggest that serum S100A12 level could be a potential biomarker for reflecting the presence and severity of OSAS. 23850626 Nanostructured lipid carriers loaded with CoQ10: Effect on human dermal fibroblasts under normal and UVA-mediated oxidative conditions. Nanostructured lipid carriers (NLC) represent an emerging tool for drug delivery and are characterized by important features which promote increased bioavailability and epithelial penetration of lipophilic compounds. However, despite these advantages, their potential cytotoxicity should not be underestimated, especially under in vivo usage conditions. Here we analyzed the viability, intracellular reactive oxygen species (ROS), oxidative DNA damage and mitochondrial functionality in human dermal fibroblasts (HDF) in the presence of NLC either empty or loaded with the reduced or oxidized form of Coenzyme Q10. Experiments were carried out under standard culture conditions and under oxidative stress induced by UVA irradiation, where the latter treatment significantly affected all the endpoints tested above compared to the non-UVA condition. The data show that NLC alone, whether exposed or not exposed to UVA, produce a slight, though significant decrease in cell viability associated with enhanced oxidative stress, which did not however lead to oxidative DNA damage nor mitochondrial impairment. Reduced CoQ10-NLC, differently from oxidized CoQ10-NLC, were able to efficiently counteract UVA-associated mitochondrial depolarization suggesting a potential role of this molecule in antiageing cosmetological formulations. In conclusion, our results suggest that interactions of NLC with cells and biomolecules should be routinely assessed for understanding their compatibility and toxicity, not only under normal conditions, but also under any chemical or physical stress which these delivery systems might be subjected to during their employment. 23271000 Antidiabetic effect of secoisolariciresinol diglucoside in streptozotocin-induced diabetic rats. Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia. Its complications such as neuropathy, cardiopathy, nephropathy, and micro and macro vascular diseases are believed to be due to the increase in oxidative stress and decrease in the level of antioxidants. The aim of this study was to determine the antihyperglycemic activity of synthetic Secoisolariciresinol diglucoside (SDG) in streptozotocin (STZ)-induced diabetic rats. The synthetic SDG in a single-dose (20 mg/kg b.w.) two-day study showed dose-dependent reduction in glucose levels with maximum effect of 64.62% at 48 h post drug treatment (p<0.05), which is comparable to that of the standard drug tolbutamide (20 mg/kg b.w.). In a multi-dose fourteen-day study, lower doses of SDG (5 and 10 mg/kg b.w.) exhibited moderate reduction in glucose levels, lipid profile, restoration of antioxidant enzymes and improvement of the insulin and c-peptide levels which shows the regeneration of β-cell which secretes insulin. Altered levels of lipids and enzymatic antioxidants were also restored by the SDG to the considerable levels in diabetic rats. Results of the present investigation suggest that diabetes is associated with an increase in oxidative stress as shown by increase in serum malondialdehyde (MDA), decreased levels of catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH). Also, diabetes is associated with an increase in serum total cholesterol as well as triglycerides levels and decrease in insulin and c-peptide levels. SDG is effective in retarding the development of diabetic complications. We propose that synthetic SDG exerts anti hyperglycemic effect by preventing the liver from peroxidation damage through inhibition of ROS level mediated increased level of enzymatic and non-enzymatic antioxidants. And, also maintaining tissue function which results in improving the sensitivity and response of target cells in STZ-induced diabetic rats to insulin. 23117572 Sodium/iodide symporter is expressed in the majority of seminomas and embryonal testicular carcinomas. Testicular cancer is the most frequent cancer in young men. The large majority of patients have a good prognosis, but in a small group of tumors, the current treatments are not effective. Radioiodine is routinely used in the treatment of thyroid cancer and is currently investigated as a potential therapeutic tool even for extra-thyroid tumors able to concentrate this radioisotope. Expression of Na(+)/I(-) symporter (NIS (SLC5A5)), the glycoprotein responsible for iodide transport, has been demonstrated in normal testicular tissue. In this study, we analyzed NIS expression in a large series of testicular carcinomas. Our retrospective series included 107 patients operated for testicular tumors: 98 typical seminomas, six embryonal carcinomas, one mixed embryonal choriocarcinoma, and two Leydig cells tumors. Expression and regulation of NIS mRNA and protein levels were also investigated in human embryonal testicular carcinoma cells (NTERA) by real-time RT-PCR and western blotting respectively. Immunohistochemical analysis showed the presence of NIS in the large majority of seminomas (90/98) and embryonal carcinomas (5/7) of the testis but not in Leydig cell carcinomas. Expression of NIS protein was significantly associated with lymphovascular invasion. In NTERA cells treated with the histone deacetylase inhibitors SAHA and valproic acid, a significant increase in NIS mRNA (about 60- and 30-fold vs control, P<0.001 and P<0.01 respectively) and protein levels, resulting in enhanced ability to uptake radioiodine, was observed. Finally, NIS expression in testicular tumors with the more aggressive behavior is of interest for the potential use of targeting NIS to deliver radioiodine in malignant cells. 23370066 Chronobiological characteristics of neuropathic pain: clinical predictors of diurnal pain rhythmicity. Neuropathic pain is often worse at night; however, little is known about pain rhythmicity during waking hours. We aimed to replicate previous observations of diurnal pain progression, evaluate associations between diurnal rhythmicity and clinical factors, and evaluate the impact of diurnal rhythmicity on treatment response. We performed exploratory analyses of 2 trials (The New England Journal of Medicine 2005; 352:1324; The Lancet 2009; 374:1252) in diabetic neuropathy and postherpetic neuralgia. Pain recorded at 8:00 AM, 4:00 PM, and 8:00 PM, at baseline and during drug treatment was examined. Data from the latest trial replicated our previous observation of diurnal pain progression with a relative pain intensity difference of 33% between 8:00 AM and 8:00 PM. This pattern was preserved during treatment with gabapentin, nortriptyline, and their combination. Pooled multivariable analyses suggested that difference in pain intensity from 8:00 AM to 8:00 PM was more pronounced in females (vs. males) and in diabetic peripheral neuropathy (vs. postherpetic neuralgia). The baseline magnitude of pain intensity difference from 8:00 AM to 8:00 PM failed to predict treatment response. These observations suggest that neuropathic pain progressively increases throughout the day with clinically relevant morning-evening differences and further indicate that sex and underlying etiology may be important determinants of diurnal rhythmicity in neuropathic pain. Consideration of these patterns may guide improved therapeutic strategies and stimulate new directions of research that will improve our understanding and treatment of neuropathic pain. 23296210 Make your own cigarettes: characteristics of the product and the consumer. Despite a worldwide increase in the use of Make Your Own (MYO) cigarettes, there is little research characterizing MYO smokers in the United States and the cigarettes they make. In a single laboratory visit, exclusive MYO smokers brought 5 MYO cigarettes they prepared at home, completed demographic and smoking history questionnaires, and prepared 25 cigarettes using their own tobacco and materials. Participants were mostly male (86.7%), average age of 41.3 years, and smoked an average of 19.5 (SD = 7.9) MYO cigarettes per day. They produced two types of cigarettes-by rolling tobacco in a paper leaf (Roll Your Own [RYO, n = 56]) and by injecting tobacco into a tube (Personal Machine Made [PMM, n = 42]). The PMM cigarettes were significantly larger than RYO cigarettes (p < .001). Home- (0.97 g) and laboratory-produced (0.95 g) PMM cigarettes did not differ by weight; however, the RYO cigarettes made at home (0.45 g) were slightly, but significantly, larger than those produced in the laboratory [0.43 g (p < .05)]. There was significant internal consistency in the weight of RYO and PMM cigarettes (intraclass correlation coefficient = 0.82, 0.84, respectively). Time to produce RYO cigarettes (53 s/cigarette) was significantly longer than that of PMM cigarettes (42 s/cigarette) (p < .01). By using commercially available tobacco, tubes, and paper, experienced MYO smokers can quickly and consistently prepare cigarettes that may be useful in laboratory smoking topography and exposure experiments. Increasing the regulation of Factory Made (FM) cigarettes may lead to increased use of MYO cigarettes with unknown toxicant exposure and health risks to their consumers. 23839088 Retrotransposon Insertional Polymorphism in Iranian Bread Wheat Cultivars and Breeding Lines Revealed by IRAP and REMAP Markers. Inter-retrotransposon amplified polymorphisms (IRAPs) and retrotransposon-microsatellite amplified polymorphisms (REMAPs) were used to detect retrotransposon integration events and genetic diversity in 101 Iranian bread wheat (Triticum aestivum L.) cultivars and breeding lines. The 9 IRAP primers amplified 128 loci, and 20 REMAP primers amplified 263 loci. Percentage of polymorphic loci, average expected heterozygosity, number of effective alleles, and Shannon's information index for the REMAP markers were slightly higher than those for the IRAP markers. The same estimated parameters calculated for native and nonnative retrotransposons were not considerably different. A Mantel test between IRAP and REMAP cophenetic matrices evidenced no significant correlation. Cluster analysis based on the Dice similarity coefficient and complete linkage algorithm using IRAP+REMAP loci identified five groups among the genotypes studied that could be applied as crossing parents in T. aestivum breeding programs. 23820671 Preschool Motor Skills Following Physical and Occupational Therapy Services Among Non-Disabled Very Low Birth Weight Children. Children born very low birth weight (VLBW) are at an increased risk of delayed development of motor skills. Physical and occupational therapy services may reduce this risk. Among VLBW children, we evaluated whether receipt of physical or occupational therapy services between 9 months and 2 years of age is associated with improved preschool age motor ability. Using data from the Early Childhood Longitudinal Study Birth Cohort we estimated the association between receipt of therapy and the following preschool motor milestones: skipping eight consecutive steps, hopping five times, standing on one leg for 10 seconds, walking backwards six steps on a line, and jumping distance. We used propensity score methods to adjust for differences in baseline characteristics between children who did and did not receive physical or occupational therapy, since children receiving therapy may be at higher risk of impairment. We applied propensity score weights and modeled the estimated effect of therapy on the distance that the child jumped using linear regression. We modeled all other end points using logistic regression. Treated VLBW children were 1.70 times as likely to skip eight steps (RR 1.70, 95 % CI 0.84, 3.44) compared to the untreated group and 30 % more likely to walk six steps backwards (RR 1.30, 95 % CI 0.63, 2.71), although these differences were not statistically significant. We found little effect of therapy on other endpoints. Providing therapy to VLBW children during early childhood may improve select preschool motor skills involving complex motor planning. 23942033 The evolution of ACh and GABA as neurotransmitters: A hypothesis. The development of a signaling system requires the evolution of a mechanism for producing signals, receptors and adaptive reactions to the signal. It is reasonable to assume that the evolution of such a system cannot be the consequence of a coordinated set of mutations resulting in a complete signaling system. It is more likely that each component evolved due to an advantage that was independent of its role in the signaling system. We hypothesize how the neurotransmitters acetylcholine (ACh) and gamma-aminobutyric acid (GABA) evolved gradually, from an initial stage in which the efflux of these molecules from the cell was an inevitable consequence of specific metabolic activities of the cell. The efflux later served as a cue that reflects the activity of the cell that released the molecules. These cues can later evolve into paracrine signals. We further suggest that the signals used in paracrine signaling were adopted by the central nervous system, as peripheral cells were already attentive to these signals. Signaling molecules released by the target cells of neurons, as an inevitable consequence of the activities of the target cells, could function as retrograde signals of the activity of the target cell. We hypothesize that ACh released by innervated myocytes functions as a retrograde signal of myocyte response to neuronal stimulation. 23964788 Identification of the KDM2/7 Histone Lysine Demethylase Subfamily Inhibitor and its Antiproliferative Activity. Histone N(epsilon)-methyl lysine demethylases KDM2/7 have been identified as potential targets for cancer therapies. Based on the crystal structure of KDM7B, we designed and prepared a series of hydroxamate analogues bearing an alkyl chain. Enzyme assays revealed that compound 9 potently inhibits KDM2A, KDM7A, and KDM7B with IC50s of 6.8 μM, 0.2 μM, and 1.2 μM, respectively. While inhibitors of KDM4s did not show any effect on cancer cells tested, the KDM2/7-subfamily inhibitor 9 exerted antiproliferative activity, indicating the potential for KDM2/7 inhibitors as anticancer agents. 23845927 Estimating the potential life-shortening effect of continuous sedation until death: a comparison between two approaches. In some cases, physicians estimate that continuous sedation until death may have a life-shortening effect. The accuracy of these estimations can be questioned. The aim of this study is to compare two approaches to estimate the potential life-shortening effect of continuous sedation until death. In 2008, 370 Dutch physicians filled out a questionnaire and reported on their last patient who received continuous sedation until death. The potential life-shortening effect of continuous sedation was estimated through a direct approach (question: Did continuous sedation, according to your estimation, hasten the patient's death? If yes: by how much time?) and an indirect approach (estimated life expectancy minus duration of sedation). The intrarater agreement between both approaches was determined with a weighted κ. According to the direct approach, sedation might have had a life-shortening effect in 51% of the cases and according to the indirect approach in 84%. The intrarater agreement between both approaches was fair (weighted κ=0.38). In 10% of all cases, the direct approach yielded higher estimates of the extent to which life had been shortened; in 58% of the cases, the indirect approach yielded higher estimates. The results show a discrepancy between different approaches to estimate the potential life-shortening effect of continuous sedation until death. 23312340 Working memory and impulsivity predict marijuana-related problems among frequent users. Although marijuana is the most commonly used illicit substance in the US, only a small portion of users go on to develop dependence, suggesting that there are substantial individual differences in vulnerability to marijuana-related problems among users. Deficits in working memory and high trait impulsivity are two factors that may place marijuana users at increased risk for experiencing related problems. Using baseline data from an experimental study that recruited 104 frequent marijuana users (M=71.86% of prior 60 days, SD=22%), we examined the associations of working memory and trait impulsivity with marijuana-related problems. Lower working memory, as measured by Trail Making Test B, but not short-term memory capacity, predicted more marijuana-related problems. Higher trait impulsivity scores were independently associated with greater number of problems. Results suggest that marijuana users with reduced executive cognitive ability are more susceptible to developing problems related to their use. Trait impulsivity and executive working memory appear to be independent risk factors for experiencing marijuana-related problems. 23288700 Calculation of wave-functions with frozen orbitals in mixed quantum mechanics/molecular mechanics methods. II. Application of the local basis equation. The application of the local basis equation (Ferenczy and Adams, J. Chem. Phys. 2009, 130, 134108) in mixed quantum mechanics/molecular mechanics (QM/MM) and quantum mechanics/quantum mechanics (QM/QM) methods is investigated. This equation is suitable to derive local basis nonorthogonal orbitals that minimize the energy of the system and it exhibits good convergence properties in a self-consistent field solution. These features make the equation appropriate to be used in mixed QM/MM and QM/QM methods to optimize orbitals in the field of frozen localized orbitals connecting the subsystems. Calculations performed for several properties in divers systems show that the method is robust with various choices of the frozen orbitals and frontier atom properties. With appropriate basis set assignment, it gives results equivalent with those of a related approach [G. G. Ferenczy previous paper in this issue] using the Huzinaga equation. Thus, the local basis equation can be used in mixed QM/MM methods with small size quantum subsystems to calculate properties in good agreement with reference Hartree-Fock-Roothaan results. It is shown that bond charges are not necessary when the local basis equation is applied, although they are required for the self-consistent field solution of the Huzinaga equation based method. Conversely, the deformation of the wave-function near to the boundary is observed without bond charges and this has a significant effect on deprotonation energies but a less pronounced effect when the total charge of the system is conserved. The local basis equation can also be used to define a two layer quantum system with nonorthogonal localized orbitals surrounding the central delocalized quantum subsystem. 23460588 Hemoglobin Shady Grove: a novel fetal methemoglobin variant. Recommendations by the US Department of Health and Human Services Secretary's Advisory Committee on Heritable Disorders in Newborns and Children aim to increase congenital heart disease screening by pulse oximetry in the nursery. Here, we describe a novel fetal methemoglobin variant discovered in a newborn found to have oxygen saturations significantly below normal upon pulse oximetry screening for congenital heart disease. As universal newborn screening with pulse oximetry is implemented, hereditary variant hemoglobins should be considered in the diagnostic work-up in otherwise well newborns with low SpO2 . 23900732 Reach task-associated excitatory overdrive of motor cortical neurons following infusion with ALS-CSF. Converging evidence from transgenic animal models of amyotrophic lateral sclerosis (ALS) and human studies suggest alterations in excitability of the motor neurons in ALS. Specifically, in studies on human subjects with ALS the motor cortex was reported to be hyperexcitable. The present study was designed to test the hypothesis that infusion of cerebrospinal fluid from patients with sporadic ALS (ALS-CSF) into the rat brain ventricle can induce hyperexcitability and structural changes in the motor cortex leading to motor dysfunction. A robust model of sporadic ALS was developed experimentally by infusing ALS-CSF into the rat ventricle. The effects of ALS-CSF at the single neuron level were examined by recording extracellular single unit activity from the motor cortex while rats were performing a reach to grasp task. We observed an increase in the firing rate of the neurons of the motor cortex in rats infused with ALS-CSF compared to control groups. This was associated with impairment in a specific component of reach with alterations in the morphological characteristics of the motor cortex. It is likely that the increased cortical excitability observed in the present study could be the result of changes in the intrinsic properties of motor cortical neurons, a dysfunctional inhibitory mechanism and/or an underlying structural change culminating in a behavioral deficit. 23633551 Tetraploidy in hydatidiform moles. How does tetraploidy develop in hydatidiform moles (HMs), and what is the frequency of the different origins? Most molar pregnancies with tetraploid cells appear to be produced by somatic endoreduplications, while a minority originate from a tetraploid zygote. The frequency of zygotic tetraploidy was estimated to be 0.7%. The parental origin of the genome in tetraploid HMs has only been evaluated in a few cases, most showing three genome sets from the father (PPPM). Estimates of the proportion of HMs that are tetraploid vary between 2 and 28%. From 1986 to 2010, unfixed samples of clinically suspected molar pregnancies were forwarded to the Danish Mole Project. For this cohort study 442 samples fulfilled the following criteria for inclusion: macroscopic appearance of HM and ≥ 10 vesicular chorionic villi with a diameter of ≥ 1 mm. Of 403 karyotyped samples, 21 cases disclosed ≥ 2 tetraploid metaphases. The 21 cases were scrutinized by karyotyping, flow cytometry (FC) and DNA-marker analysis. Among 20 HMs, 3 showed the genotype PPPM: one with the sex chromosomes XXYY and two with XXXY, indicating that they originated in tetraploid zygotes. In 14 androgenetic, one likely androgenetic and two mosaics, the tetraploid cells likely developed by endoreduplications of diploid cells. One case did not fulfil the histopathological criteria for HM. As an inclusion criterion was the macroscopic observation of vesicular chorionic villi, some non-molar hydropic placentas may have been included and some early moles may have been excluded. In future, studies to determine that an HM is tetraploid and discriminate cases of mosaicism and to deduce the origin of the tetraploidy must use the techniques of karyotyping, DNA-marker analysis and FC in combination. 22464487 Trends in stroke incidence after hospitalization for atrial fibrillation in Sweden 1987 to 2006. To investigate recent trends in incidence of hemorrhagic and non-hemorrhagic strokes in patients with atrial fibrillation (AF). The Swedish Hospital Discharge and Cause of Death Registries were linked to provide outcome data. 321,276 patients 35 to 84years (56.5% male, mean age 71.5years) free of prior stroke with a first AF diagnosis during 1987-2006 were included. Over 3year follow-up 24,733 patients (7.7%) were diagnosed with ischemic stroke and 2292 (0.7%) with hemorrhagic stroke. The 3-year incidence of ischemic stroke decreased from 8.7% for patients diagnosed in 1987-1991 to 6.6% for those diagnosed in 2002 to 2006. The corresponding incidence of hemorrhagic stroke increased from 0.38% for patients diagnosed in 1987-1991 to 0.57% for those diagnosed in 2002 to 2006. Covariable-adjusted risk of ischemic stroke was significantly reduced (HR 0.65; 0.63-0.68) while risk of hemorrhagic stroke was significantly increased (HR 1.19; 1.05-1.36). Compared to the general population, total stroke risk decreased more among AF patients. We found a considerable decrease in risk of ischemic stroke in Sweden in patients without prior stroke and with a first hospital diagnosis of AF. There was an increased risk of hemorrhagic stroke, but because hemorrhagic stroke represented only a small proportion of all strokes, the overall risk of stroke declined. 23793623 Roles of the Yap1 Transcription Factor and Antioxidants in Saccharomyces cerevisiae's Tolerance to Furfural and 5-Hydroxymethylfurfural, Which Function as Thiol-Reactive Electrophiles Generating Oxidative Stress. Development of the tolerance of Saccharomyces cerevisiae strains to furfural and 5-hydroxymethylfurfural (HMF) is an important issue for cellulosic ethanol production. Although furfural and HMF are known to induce oxidative stress, the underlying mechanisms are largely unknown. In this study, we show that both furfural and HMF act as thiol-reactive electrophiles, thus directly activating the Yap1 transcription factor via the H2O2-independent pathway, depleting cellular glutathione (GSH) levels, and accumulating reactive oxygen species in Saccharomyces cerevisiae. However, furfural showed higher reactivity than did HMF toward GSH in vitro and in vivo. In line with such toxic mechanisms, overexpression of YAP1(C620F), a constitutively active mutant of YAP1, and Yap1 target genes encoding catalases (CTA1 and CTT1) increased tolerance to furfural and HMF. However, increasing GSH levels by overexpression of genes for GSH biosynthesis (GSH1 and GLR1) or by the exogenous addition of GSH to the culture medium enhanced tolerance to furfural but not to HMF. 23968851 The effect of substrate surface nanotopography on the behavior of multipotnent mesenchymal stromal cells and osteoblasts. Hexagonally arranged Gold nanoparticles with controllable diameters and inter-particle distances were deposited on thick SiO2 layers on top of Si wafers and used as masks during subsequent reactive ion etching. In this way, arrays of nanopillars are obtained with well-defined diameters (10/30 nm), inter-pillar distances (50-120 nm) and heights (20-35 nm), all on the nanoscale. Such nanotopographies served as substrate for multipotent mesenchymal stromal cells (MSC) and human osteoblasts (OB) allowing to study cellular responses to purely topographically patterned interfaces. Focus was put on adhesion, proliferation and differentiation of the cells. It turned out experimentally that adhesion is comparable for both cell types practically independent of topographical details at the substrate surface. Topography induced proliferation enhancement, however, is again independent of geometrical details in case of MSC, but significantly sensitive to pillar height in case of OB with a clear preference towards short nanopillars (20 nm). A high sensitivity to topographic details is also observed for osteogenic differentiation of MSC, in that case with a preference towards higher nanopillars (50 nm). The present experimental data also allow the important conclusion that cell proliferation and differentiation can be optimized simultaneously by fine-tuning nanoscaled topographical parameters. 23896520 Estimating pathway-specific contributions to biodegradation in aquifers based on dual isotope analysis: Theoretical analysis and reactive transport simulations. At field sites with varying redox conditions, different redox-specific microbial degradation pathways contribute to total contaminant degradation. The identification of pathway-specific contributions to total contaminant removal is of high practical relevance, yet difficult to achieve with current methods. Current stable-isotope-fractionation-based techniques focus on the identification of dominant biodegradation pathways under constant environmental conditions. We present an approach based on dual stable isotope data to estimate the individual contributions of two redox-specific pathways. We apply this approach to carbon and hydrogen isotope data obtained from reactive transport simulations of an organic contaminant plume in a two-dimensional aquifer cross section to test the applicability of the method. To take aspects typically encountered at field sites into account, additional simulations addressed the effects of transverse mixing, diffusion-induced stable-isotope fractionation, heterogeneities in the flow field, and mixing in sampling wells on isotope-based estimates for aerobic and anaerobic pathway contributions to total contaminant biodegradation. Results confirm the general applicability of the presented estimation method which is most accurate along the plume core and less accurate towards the fringe where flow paths receive contaminant mass and associated isotope signatures from the core by transverse dispersion. The presented method complements the stable-isotope-fractionation-based analysis toolbox. At field sites with varying redox conditions, it provides a means to identify the relative importance of individual, redox-specific degradation pathways. 23055538 Regulation of hepatic phase II metabolism in pregnant mice. Phase II enzymes, including Ugts, Sults, and Gsts, are critical for the disposition and detoxification of endo- and xenobiotics. In this study, the mRNA and protein expression of major phase II enzymes, as well as key regulatory transcription factors, were quantified in livers of time-matched pregnant and virgin control C57BL/6 mice on gestation days (GD) 7, 11, 14, 17, and postnatal days (PND) 1, 15, and 30. Compared with virgin controls, the mRNA expression of Ugt1a1, 1a6, 1a9, 2a3, 2b1, 2b34, and 2b35 decreased 40 to 80% in pregnant dams. Protein expression of Ugt1a6 also decreased and corresponded with reduced in vitro glucuronidation of bisphenol A in S9 fractions from livers of pregnant mice. Similar to Ugts levels, Gsta1 and a4 mRNAs were reduced in pregnant dams in mid to late gestation; however no change in protein expression was observed. Conversely, Sult1a1, 2a1/2, and 3a1 mRNAs increased 100 to 500% at various time points in pregnant and lactating mice and corresponded with enhanced in vitro sulfation of acetaminophen in liver S9 fractions. Coinciding with maximal decreases in Ugts as well as increases in Sults, the expression of transcription factors CAR, PPARα, and PXR and their target genes were downregulated, whereas ERα mRNA was upregulated. Collectively, these data demonstrate altered regulation of hepatic phase II metabolism in mice during pregnancy and suggest that CAR, PPARα, PXR, and ERα signaling pathways may be candidate signaling pathways responsible for these changes. 23895042 The Badger-Bauer Rule Revisited: Correlation of Proper Blue Frequency Shifts in the OC Hydrogen Acceptor with Morphed Hydrogen Bond Dissociation Energies in OC-HX (X = F, Cl, Br, I, CN, CCH). Potential morphing has been applied to the investigation of proper blue frequency shifts, Δν0 in CO, the hydrogen acceptor complexing in the hydrogen bonded series OC-HX (X= F, Cl, Br, I, CN, CCH). Linear correlations of morphed hydrogen bonded ground dissociation energies D0 with experimentally determined Δν0 free from matrix and solvent effects demonstrate consistency with original tenets of the Badger-Bauer rule (J. Chem. Phys. 1937, 5, 839-51). A model is developed that provides a basis for explaining the observed linear correlations in the range of systems studied. Furthermore, the generated calibration curve enables prediction of dissociation energies for other related but different complexes. The latter include D0 for H2O-CO, H2S-CO, and CH3OH-CO which are predicted by interpolation and found to be 355(13), 171(11), and 377(14) cm(-1) respectively from available experimentally determined proton acceptor shifts. Results from this study will also be discussed in relation to investigations in which CO has been used as a probe of heme protein active sites. 23111465 Do proton pump inhibitors protect against cancer progression in GERD? Gastro-duodenal content reflux from gastro-esophageal reflux disease (GERD) induces the inflammation-metaplasia-dysplasia-adenocarcinoma sequence. Proton pump inhibitors (PPIs) are potent blockers of gastric acid secretion, which are widely used for treating GERD and peptic ulcer-associated acid-secreting diseases. The effect of PPI therapy on esophageal carcinogenesis remains unclear. While some studies suggest PPIs result in a significant reduction in the risk of developing dysplasia and adenocarcinoma in patients with Barrett's esophagus, others suggest that PPIs have no effect. Recent studies have revealed that PPIs can exert anti-inflammatory effects such as anti-oxidant properties and immunomodulatory effects through their interactions with neutrophils, monocytes, endothelial and epithelial cells. In addition, PPIs have the ability to prevent adhesion molecule binding in malignant cells and suppress metastasis. This article reviews the role of PPIs in esophageal carcinogenesis and their use as antitumor agents. 23878342 Woody encroachment and forest degradation in sub-Saharan Africa's woodlands and savannas 1982-2006. We review the literature and find 16 studies from across Africa's savannas and woodlands where woody encroachment dominates. These small-scale studies are supplemented by an analysis of long-term continent-wide satellite data, specifically the Normalized Difference Vegetation Index (NDVI) time series from the Global Inventory Modeling and Mapping Studies (GIMMS) dataset. Using dry-season data to separate the tree and grass signals, we find 4.0% of non-rainforest woody vegetation in sub-Saharan Africa (excluding West Africa) significantly increased in NDVI from 1982 to 2006, whereas 3.52% decreased. The increases in NDVI were found predominantly to the north of the Congo Basin, with decreases concentrated in the Miombo woodland belt. We hypothesize that areas of increasing dry-season NDVI are undergoing woody encroachment, but the coarse resolution of the study and uncertain relationship between NDVI and woody cover mean that the results should be interpreted with caution; certainly, these results do not contradict studies finding widespread deforestation throughout the continent. However, woody encroachment could be widespread, and warrants further investigation as it has important consequences for the global carbon cycle and land-climate interactions. 23876134 Dye Stabilization and Enhanced Photoelectrode Wettability in Water-Based Dye-Sensitized Solar Cells through Post-assembly Atomic Layer Deposition of TiO2. Detachment (desorption) of molecular dyes from photoelectrodes is one of the major limitations for the long-term operation of dye-sensitized solar cells. Here we demonstrate a method to greatly inhibit this loss by growing a transparent metal oxide (TiO2) on the dye-coated photoelectrode via atomic layer deposition (ALD). TiO2-enshrouded sensitizers largely resist detachment, even in pH 10.7 ethanol, a standard solution for intentional removal of molecular dyes from photoelectrodes. Additionally, the ALD post-treatment renders the otherwise hydrophobic dye-coated surface hydrophilic, thereby enhancing photoelectrode pore-filling with aqueous solution. 23958049 Respiratory tract rather than cutaneous atopic allergy inversely associate with multiple sclerosis: A case-control study. It has been previously shown that genetic or environmental factors, which promote susceptibility to allergic conditions, prevent the development of Th1-mediated inflammatory disease of multiple sclerosis (MS). To investigate the prediction value of lifetime atopic allergy in development of the future MS, a case-control study was designed. Cases and controls were interviewed between December 2007 and April 2008 and they were asked if they had symptoms or diagnosis of allergies (including respiratory tract allergy, RTA; coetaneous allergy, CA; food/drug allergy, FDA) before MS diagnosis. Of 390 participants (195 controls and 195 cases), 125 healthy controls (64.1%) and 105 cases (53.8%) reported history of at least one type of atopic allergy (P=0.04). A positive history of RTA (OR 0.43; 95% CI 0.28-0.66) or FDA (OR 0.24; 95% CI 0.13-0.43) was inversely associated with the risk of MS. No statistically significant association was found between the history of CA and MS. There is a significant inverse association between RTA and MS that is compatible with a Th1/Th2 imbalance. History of RTA can be considered as a clinically useful risk reducing factor of MS. 23841977 The role of endothelial activation in dengue hemorrhagic fever and hantavirus pulmonary syndrome. The loss of the endothelium barrier and vascular leakage play a central role in the pathogenesis of hemorrhagic fever viruses. This can be caused either directly by the viral infection and damage of the vascular endothelium, or indirectly by a dysregulated immune response resulting in an excessive activation of the endothelium. This article briefly reviews our knowledge of the importance of the disruption of the vascular endothelial barrier in two severe disease syndromes, dengue hemorrhagic fever and hantavirus pulmonary syndrome. Both viruses cause changes in vascular permeability without damaging the endothelium. Here we focus on our understanding of the virus interaction with the endothelium, the role of the endothelium in the induced pathogenesis, and the possible mechanisms by which each virus causes vascular leakage. Understanding the dynamics between viral infection and the dysregulation of the endothelial cell barrier will help us to define potential therapeutic targets for reducing disease severity. 23719340 Detection of biological warfare agents using ultra violet-laser induced fluorescence LIDAR. This review has been written to highlight the threat of biological warfare agents, their types and detection. Bacterial biological agent Bacillus anthracis (bacteria causing the disease anthrax) which is most likely to be employed in biological warfare is being discussed in detail. Standoff detection of biological warfare agents in aerosol form using Ultra violet-Laser Induced Fluorescence (UV-LIF) spectroscopy method has been studied. Range-resolved detection and identification of biological aerosols by both nano-second and non-linear femto-second LIDAR is also discussed. Calculated received fluorescence signal for a cloud of typical biological agent Bacillus globigii (Simulants of B. anthracis) at a location of ~5.0 km at different concentrations in presence of solar background radiation has been described. Overview of current research efforts in internationally available working UV-LIF LIDAR systems are also mentioned briefly. 23404237 Characteristics of patients with definite septic arthritis at Hamad General Hospital, Qatar: a hospital-based study from 2006 to 2011. The aim of this retrospective study was to determine the epidemiological and clinical characteristics, coexisting conditions, causative organisms, and outcomes of all adult patients 15 years of age or older who had definite septic arthritis at Hamad General Hospital, Qatar, from 2006 to 2011. During this period, 56 patients were diagnosed with septic arthritis (mean age ± SD, 49.0 ±â€‰16.6 years). In 53 of 56 (94.6 %) patients, arthritis was diagnosed in a single joint, while polyarthritis was diagnosed in 3 of 56 (5.4 %) patients; the most commonly involved joint was the knee (40 of 59 joints, 67.7 %). The most frequent coexisting condition was diabetes mellitus (24 of 56 patients, 42.8 %). Joint pain and restriction of movement were reported by all patients. Gram-positive bacteria accounted for 36 of all 57 (63.0 %) isolated microorganisms, and Staphylococcus aureus was the most common pathogen (20 of 57 microorganisms, 35.0 %). Three cases of tuberculous arthritis were seen. The most favored antibiotic combinations were cloxacillin/ciprofloxacin, cefazolin/ciprofloxacin, and vancomycin/ciprofloxacin. Repeated needle aspiration, open joint drainage, and arthroscopic techniques were performed in 18 (32.1 %), 22 (39.3 %), and 11 (19.6 %) of the 56 patients, respectively. The 30-day mortality was 3.6 %, and the remaining patients showed clinical improvement upon discharge. In conclusion, there was no specific sign or symptom for diagnosing septic arthritis. Isolation of bacteria from the synovial fluid confirmed the diagnosis, and S. aureus and streptococci were the most common pathogens isolated. Prompt treatment with appropriate antibiotics and synovial drainage are mandatory to improve the outcome. 23613014 Decreased Permeability Surface Area for Glucose in Obese Women with Postprandial Hyperglycemia: No Effect of Phosphodiesterase-5 (PDE-5) Inhibition. Insulin-mediated microvascular recruitment is recognized as a potential mechanism contributing to insulin resistance. In this study, we compared a marker of microvascular function, the permeability surface area for glucose (PSglu), and forearm glucose uptake after an OGTT in obese women with impaired glucose metabolism and healthy lean nondiabetic women, with the aim to characterize whether decreased permeability surface area for glucose or decreased glucose uptake may contribute to postprandial hyperglycemia in the obese group. In addition, we evaluated whether the phosphodiesterase-5 (PDE-5) inhibitor tadalafil, in a randomized double blind placebo controlled design, might attenuate postprandial glucose levels in obese women. For these purposes, intramuscular microdialysis, blood sampling from arterial and venous blood of the forearm, and measurements of forearm blood flow were performed. The results showed an impaired permeability surface area for glucose (IAUC PSglu 31±13 vs. 124±31; p<0.05) in obese when compared with lean participants, but no differences in forearm glucose uptake appeared between the groups. Furthermore, a single dose of tadalafil 10 mg showed no improvement of the permeability surface area for glucose, glucose uptake, or circulating glucose levels in obese participants. In conclusion, the postprandial PSglu response was impaired in obese women showing postprandial hyperglycemia, indicating a compromised microcirculation. However, we were unable to demonstrate any acute effect on either vascular function or glucose uptake of the phosphodiesterase-5 (PDE-5) inhibitor tadalafil. 23962347 Nausea and vomiting in pregnancy: associations with maternal gestational diet and lifestyle factors in the Norwegian Mother and Child Cohort Study. To investigate primarily the dietary intake, as well as demographics and selected lifestyle factors, of women experiencing nausea and vomiting in pregnancy, nausea only, or women who are symptom free. Prospective cohort study. The Norwegian Mother and Child Cohort Study, a population-based pregnancy cohort. Analyses were based on 51 675 Norwegian pregnancies. Dietary intake was assessed by a self-reported food frequency questionnaire answered in the first trimester of pregnancy, as were data regarding nausea and vomiting. Chi-squared tests, one-way analysis of variance, and multiple linear regression were used. Nausea and vomiting in pregnancy (NVP), gestational weight gain (GWG), and dietary intake. We found that 17 070 (33%) women experienced NVP, 20 371 (39%) experienced only nausea, and 14 234 (28%) were symptom free. Women with NVP were younger and heavier at pregnancy onset, with the lowest GWG and highest energy intake during pregnancy, primarily from carbohydrates and added sugars, compared with the other groups (P < 0.001). In multiple linear regression analysis of GWG and group adjusted for body mass index (BMI), gestational length, smoking during pregnancy, and energy intake, a significant interaction was found between BMI and group (P < 0.001). A significant effect of group (P < 0.001) was found in all BMI strata, except among underweight women (P = 0.65). Our study suggests that women with NVP are characterised by high intakes of carbohydrates and added sugar, primarily from sugar-containing soft drinks. Whether higher intakes of carbohydrates are a response aimed to alleviate symptoms, or are actually provoking the condition, is not known. 23968171 The advent of a new pseudoephedrine product to combat methamphetamine abuse. Abstract Background: The personal and societal effects of methamphetamine abuse are well documented. The ease of accessibility to methamphetamine and the quality of the "high" it produces makes the drug highly desired by its abusers. Over time, many methamphetamine users will also become methamphetamine cooks, where pseudoephedrine in over-the-counter cold products is converted to methamphetamine through a simple, albeit extremely dangerous, process. New laws limiting access to these products have had limited success. No existing commercial pseudoephedrine products offer significant impediments to slow or limit the extraction and conversion of pseudoephedrine in clandestine methamphetamine laboratories. Objective and Methods: A new pseudoephedrine 30 mg tablet product using Impede technology (Nexafed®) to deter methamphetamine production has recently been introduced into the marketplace. Using methods designed to mimic clandestine laboratory processes, the ability of this product to disrupt extraction and conversion of pseudoephedrine to methamphetamine yet provide therapeutic effectiveness was evaluated. Results: Impede™ technology tablets limited the extraction and/or conversion of pseudoephedrine to methamphetamine when compared to a commercially marketed pseudoephedrine product (Sudafed®). Nexafed® tablets were also shown to be bioequivalent to the same control product, thus ensuring therapeutic equivalence. Conclusions: With the advent of new pseudoephedrine products in the marketplace with features to limit the extraction and conversion of pseudoephedrine to methamphetamine, new tools are now available to minimize the clandestine manufacture of the drug and potentially limit its social impact. 23116642 Platycodin D attenuates bile duct ligation-induced hepatic injury and fibrosis in mice. Platycodin D (PD) is the major triterpene saponin in the root of Platycodon grandiflorum. The aim of the present study was to evaluate the protective effects of PD on bile duct ligation (BDL)-induced cholestasis in mice. Mice were allocated to five groups: sham, BDL alone, and BDL with PD treatment at 1, 2, and 4mg/kg. PD was administered to the mice for 28 consecutive days after the BDL operation. PD treatment of BDL-operated mice decreased serum alanine aminotransferase, serum aspartate aminotransferase, and total bilirubin levels by up to 37%, 31%, and 41%, respectively, in comparison with the levels in mice that underwent BDL alone. PD treatment attenuated oxidative stress, as evidenced by an increase in anti-oxidative enzyme levels glutathione and superoxide dismutase together with a decrease in lipid peroxidation and oxidative stress indices levels of malondialdehyde and nitric oxide. Histopathological studies further confirmed the protective effects of PD on cholestasis-induced hepatic injury and liver fibrosis in mice. In addition, nuclear factor-kappa B and inducible nitric oxide synthase levels significantly decreased after PD treatment, as did the levels of hepatocyte apoptosis. Taken together, these results suggest that PD treatment might be beneficial in cholestasis-induced hepatotoxicity. 23567866 Vogt-Koyanagi-Harada syndrome. The objectives of this study are to review our current knowledge of the aetiopathogenesis of Vogt-Koyanagi-Harada syndrome, including viral infection, genetic factors and immunomediated mechanisms, and to discuss pathogenesis and its relevance to pharmacotherapy. Relevant publications from 1965 to 2012 on the aetiopathogenesis and pharmacotherapy of VKHS were analysed. Vogt-Koyanagi-Harada syndrome (VKHS) is a rare multisystemic autoimmune disease that affects tissues containing melanin, including the eye, inner ear, meninges, and skin. The disease is characterised by bilateral uveitis associated with a varying constellation of auditory, neurological and cutaneous manifestations. The disease occurs more frequently among people with darker skin pigmentation. Asians, Native Americans, and Hispanics are most frequently affected. It predominates in patients aged between 20 and 50years, and females are affected more frequently, with a female:male ratio of 2:1. The classic clinical course is characterised by bilateral panuveitis, hypoacusis, and meningitis, in addition to cutaneous involvement with poliosis, vitiligo, and alopecia. Although the exact cause of VKH disease remains unknown, it is thought to be a T-cell-mediated autoimmune process directed against melanocytes. VKHS classically begins with vague systemic symptoms suggestive of a viral infection, although a clear association between a specific viral agent and the disease has not been established. Genetic factors may play an important role in the loss of self-tolerance in VKHS. The HLA-DRB1*0405 allele is the main susceptibility allele for VKHS. Early and aggressive systemic corticosteroids are still the primary initial therapy for VKHS. Ocular complications may require an intravitreous injection of corticosteroids. Despite proper treatment with steroids, a number of patients experience recurrent attacks or steroid-associated complications. Thus, non steroid immunomodulatory therapy (IMT) has become necessary for the treatment of VKHS. 23950811 Correction: Transcriptional Effects of E3 Ligase Atrogin-1/MAFbx on Apoptosis, Hypertrophy and Inflammation in Neonatal Rat Cardiomyocytes. [This corrects the article on p. e53831 in vol. 8.]. 23872881 Carnosine and taurine treatments decreased oxidative stress and tissue damage induced by D-galactose in rat liver. D-galactose (GAL) causes aging-related changes and oxidative stress in the organism. We investigated the effect of carnosine (CAR) or taurine (TAU), having antioxidant effects, on hepatic injury and oxidative stress in GAL-treated rats. Rats received GAL (300 mg/kg; s.c.; 5 days/week) alone or together with CAR (250 mg/kg/daily; i.p.; 5 days/week) or TAU (2.5 % w/w; in rat chow) for 2 months. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and hepatic malondialdehyde (MDA), protein carbonyl (PC) and glutathione (GSH) levels and superoxide dismutase (SOD), glutathione peroxidase (GSH-0050x), and glutathione transferase (GST) activities were determined. Hepatic expressions of B cell lymphoma-2 (Bcl-2), Bax and Ki-67 were evaluated. Serum ALT, AST, hepatic MDA, and PC levels were observed to increase in GAL-treated rats. Hepatic Bax expression, but not Bcl-2, increased, Ki-67 expression decreased. GAL treatment caused decreases in GSH levels, SOD and GSH-Px activities in the liver. Hepatic mRNA expressions of SOD, but not GSH-Px, also diminished. CAR or TAU treatments caused significant decreases in serum ALT and AST activities. These treatments decreased apoptosis and increased proliferation and ameliorated histopathological findings in the livers of GAL-treated rats. Both CAR and TAU reduced MDA and PC levels and elevated GSH levels, SOD and GSH-Px (non significant in TAU + GAL group) activities. These treatments did not alter hepatic mRNA expressions of SOD and GSH-Px enzymes. Our results indicate that CAR and TAU restored liver prooxidant status together with histopathological amelioration in GAL-induced liver damage. 23842451 Tetrahydrobiopterin responsiveness in phenylketonuria: prediction with the 48-hour loading test and genotype. How to efficiently diagnose tetrahydrobiopterin (BH4) responsiveness in patients with phenylketonuria remains unclear. This study investigated the positive predictive value (PPV) of the 48-hour BH4 loading test and the additional value of genotype. Data of the 48-hour BH4 loading test (20 mg BH4/kg/day) were collected at six Dutch university hospitals. Patients with >=30% phenylalanine reduction at >=1 time points during the 48 hours (potential responders) were invited for the BH4 extension phase, designed to establish true-positive BH4 responsiveness. This is defined as long-term >=30% reduction in mean phenylalanine concentration and/or >=4 g/day and/or >=50% increase of natural protein intake. Genotype was collected if available. 177/183 patients successfully completed the 48-hour BH4 loading test. 80/177 were potential responders and 67/80 completed the BH4 extension phase. In 58/67 true-positive BH4 responsiveness was confirmed (PPV 87%). The genotype was available for 120/177 patients. 41/44 patients with >=1 mutation associated with long-term BH4 responsiveness showed potential BH4 responsiveness in the 48-hour test and 34/41 completed the BH4 extension phase. In 33/34 true-positive BH4 responsiveness was confirmed. 4/40 patients with two known putative null mutations were potential responders; 2/4 performed the BH4 extension phase but showed no true-positive BH4 responsiveness. The 48-hour BH4 loading test in combination with a classified genotype is a good parameter in predicting true-positive BH4 responsiveness. We propose assessing genotype first, particularly in the neonatal period. Patients with two known putative null mutations can be excluded from BH4 testing. 23772637 Venous access catheter-related thrombosis in patients with cancer. Patients with cancer are at high risk for developing venous thromboembolism (VTE), and the presence of a central venous catheter (CVC) further increases this risk. CVC-related VTE has serious implications related to the loss of vascular access, development of pulmonary embolism, recurrent VTE, infections and post-thrombotic syndrome. The pathogenesis of CVC-related VTE is complex and multifactorial, with risk factors associated with the catheter, the vessel selected for insertion and the underlying cancer as well as the anti-cancer therapy. Clinical presentation of CVC-related VTEs is often non-specific, and ultrasonography is the most commonly used radiological diagnostic test. Management of CVC-related VTE in patients with cancer requires a balance between the need for venous access, the risk of VTE recurrence and the risk of bleeding from treatment-induced thrombocytopenia. Effective VTE prophylaxis methods have yet to be defined. Ongoing studies are evaluating the role of newer oral antithrombotic agents and alternative interventional strategies for the prevention and treatment of CVC-related VTE in patients with cancer. 23924120 Medicines management. I have just taken over as a ward manager. What do I need to know about medicine fridges? 23907471 Evaluation of the Predictive Value of a Clinical Worsening Definition Using 2-Year Outcomes in Patients With Pulmonary Arterial Hypertension: A REVEAL Registry Analysis. Time to clinical worsening has been proposed as a primary endpoint in clinical trials of pulmonary arterial hypertension (PAH); however, there are neither standardized nor validated definitions of clinical worsening across PAH trials. This study aims to evaluate a proposed definition of clinical worsening within a large prospective, observational registry of patients with PAH with respect to its value as a predictor of proximate (within 1 year) risk for subsequent major events (ie, death, transplantation, or atrial septostomy). We assessed overall 2-year survival and survival free from major events to determine the relationship between clinical worsening and major events among adults (N=3,001) with hemodynamically defined PAH. Freedom from clinical worsening was defined as freedom from worsening functional class (FC), a ≥15% reduction in 6-minute walk distance (6MWD), all-cause hospitalization, or the introduction of a parenteral prostacyclin analogue therapy. In the 2 years of follow-up, 583 deaths occurred; a total of 426 patients died after a documented clinical worsening event including FC worsening (n=128), a ≥15% reduction in 6MWD (n=118), all-cause hospitalization (n=370), or introduction of a prostacyclin analogue (n=91). Patients who experienced clinical worsening had significantly poorer subsequent 1-year survival post-worsening than patients who did not worsen (P < .001). Clinical worsening was highly predictive of subsequent proximate mortality in this analysis from an observational study. These results validate the use of clinical worsening as a meaningful prognostic tool in clinical practice and as a primary endpoint in clinical trial design. NCT00370214. 23470204 New surface-enhanced Raman scattering platforms: composite calcium carbonate microspheres coated with astralen and silver nanoparticles. Surface-enhanced Raman scattering (SERS) microspectroscopy is a very promising label-free, noncontact, and nondestructive method for real-time monitoring of extracellular matrix (ECM) development and cell integration in scaffolds for tissue engineering. Here, we prepare a new type of micrometer-sized SERS substrate, core-shell microparticles composed of solid carbonate core coated with silver nanoparticles and polyhedral multishell fullerene-like structure, astralen. Astralen has been assembled with polyallylamine hydrochloride (PAH) by the layer-by-layer manner followed by Ag nanoparticle formation by means of a silver mirror reaction, giving the final structure of composite particles CaCO3(PAH/astralen)x/Ag, where x = 1-3. The components of the microparticle carry multiple functionalities: (i) an easy identification by Raman imaging (photostable astralen) and (ii) SERS due to a rough surface of Ag nanoparticles. A combination of Ag and astralen nanoparticles provides an enhancement of astralen Raman signal by more than 1 order of magnitude. Raman signals of commonly used scaffold components such as polylactide and polyvinyl alcohol as well as ECM component (hyaluronic acid) are significantly enhanced. Thus, we demonstrate that new mechanically robust and easily detectable (by astralen signal or optically) core-shell microspheres based on biocompatible CaCO3 can be used as SERS platform. Particle design opens many future perspectives for fabrication of SERS platforms with multiple functions for biomedical applications, for example, for theranostic. 23948639 Loss of MeCP2 function is associated with distinct gene expression changes in the striatum. Rett syndrome (RTT) is a neurodevelopmental disorder characterized by developmental regression beginning 6-18months after birth, followed by a lifetime of intellectual disability, stereotyped behaviors, and motor deficits. RTT is caused by mutations in the gene encoding MeCP2, a methyl-CpG binding protein believed to modulate gene transcription. Gene expression studies of individual brain regions have reported that Mecp2 loss-of-function leads to both activation and repression of its gene targets in mice. Conditional deletion of MeCP2 from different brain regions has revealed unique insights into the role of these structures in mediating particular RTT-like phenotypes. However, the function of MeCP2 in the striatum, a major brain region involved in motor control and executive cognitive functions, has yet to be studied. Here, we characterized the gene expression changes in the striatum of Mecp2 mutant mice. We found a number of differentially expressed genes in the striatum of both constitutive Mecp2-null mice and mice lacking MeCP2 only from forebrain GABAergic neurons. These changes only occurred when MeCP2 expression levels had reached mature levels and RTT-like symptoms were manifest, supporting a role for MeCP2 in maintaining proper brain function. Many of the gene expression changes identified in the striatum have not previously been shown to change in the hypothalamus or cerebellum. Bioinformatic analysis of differentially expressed genes in striatum as well as hypothalamus and cerebellum revealed that loss of MeCP2 does not affect the global landscape of gene expression. Additionally, we uncovered a number of differentially expressed genes in the liver of Mecp2-null mice suggesting an important role for MeCP2 in non-neuronal tissues. Collectively, our data suggest that the differential expression of genes following loss of MeCP2 occurs in a tissue- or cell-type specific manner and thus MeCP2 function should be understood in a cellular context. 23081760 Use of transgenic GFP reporter strains of the nematode Caenorhabditis elegans to investigate the patterns of stress responses induced by pesticides and by organic extracts from agricultural soils. As a free-living nematode, C. elegans is exposed to various pesticides used in agriculture, as well as to persistent organic residues which may contaminate the soil for long periods. Following on from our previous study of metal effects on 24 GFP-reporter strains representing four different stress-response pathways in C. elegans (Anbalagan et al. Ecotoxicology 21:439-455, 2012), we now present parallel data on the responses of these same strains to several commonly used pesticides. Some of these, like dichlorvos, induced multiple stress genes in a concentration-dependent manner. Unusually, endosulfan induced only one gene (cyp-34A9) to very high levels (8-10-fold) even at the lowest test concentration, with a clear plateau at higher doses. Other pesticides, like diuron, did not alter reporter gene expression detectably even at the highest test concentration attainable, while others (such as glyphosate) did so only at very high concentrations. We have also used five responsive GFP reporters to investigate the toxicity of soil pore water from two agricultural sites in south-east Spain, designated P74 (used for cauliflower production, but significantly metal contaminated) and P73 (used for growing lettuce, but with only background levels of metals). Both soil pore water samples induced all five test genes to varying extents, yet artificial mixtures containing all major metals present had essentially no effect on these same transgenes. Soluble organic contaminants present in the pore water were extracted with acetone and dichloromethane, then after evaporation of the solvents, the organic residues were redissolved in ultrapure water to reconstitute the soluble organic components of the original soil pore water. These organic extracts induced transgene expression at similar or higher levels than the original pore water. Addition of the corresponding metal mixtures had either no effect, or reduced transgene expression towards the levels seen with soil pore water only. We conclude that the main toxicants present in these soil pore water samples are organic rather than metallic in nature. Organic extracts from a control standard soil (Lufa 2.2) had negligible effects on expression of these genes, and similarly several pesticides had little effect on the expression of a constitutive myo-3::GFP transgene. Both the P73 and P74 sites have been treated regularly with (undisclosed) pesticides, as permitted under EU regulations, though other (e.g. industrial) organic residues may also be present. 23157624 Neurotransmitters, psychotropic drugs and microglia: clinical implications for psychiatry. Psychiatric disorders have long and dominantly been regarded to be induced by disturbances of neuronal networks including synapses and neurotransmitters. Thus, the effects of psychotropic drugs such as antipsychotics and antidepressants have been understood to modulate synaptic regulation via receptors and transporters of neurotransmitters such as dopamine and serotonin. Recently, microglia, immunological/inflammatory cells in the brain, have been indicated to have positive links to psychiatric disorders. Positron emission tomography (PET) imaging and postmortem studies have revealed microglial activation in the brain of neuropsychiatric disorders such as schizophrenia, depression and autism. Animal models of neuropsychiatric disorders have revealed the underlying microglial pathologies. In addition, various psychotropic drugs have been suggested to have direct effects on microglia. Until now, the relationship between microglia, neurotransmitters and psychiatric disorders has not been well understood. Therefore, in this review, at first, we summarize recent findings of interaction between microglia and neurotransmitters such as dopamine, serotonin, norepinephrine, acetylcholine and glutamate. Next, we introduce up-to-date knowledge of the effects of psychotropic drugs such as antipsychotics, antidepressants and antiepileptics on microglial modulation. Finally, we propose the possibility that modulating microglia may be a key target in the treatment of various psychiatric disorders. Further investigations and clinical trials should be conducted to clarify this perspective, using animal in vivo studies and imaging studies with human subjects. 23829872 Physical activity intensities in youth: the effect of month of assessment. Abstract Background: There is clear evidence that environmental factors play an important role regarding physical activity (PA) and sedentary behaviour (SB) in youth. This short report highlights seasonal differences in the amount and intensities of PA and SB, in Portuguese youth. Methods: Three hundred and eighty-seven participants (aged 14.7 ± 1.9 years), 220 girls, used the Actigraph GT1M accelerometer for 7 days (15-second epochs), between January and June in 2008. PA and SB differences were assessed using an ANCOVA. Results: Boys had significantly higher values of PA, with the exception of Light intensity. Girls were significantly more sedentary. PA intensities and SB changed significantly according to gender and month of assessment. SB (Gender F = 16.32, p < 0.001; Month F = 2.95, p < 0.013), Light PA (Gender F = 9.30, p = 0.002; Month F = 8.37, p < 0.001; Gender*Month F = 2.24, p = 0.050), Moderate PA (Gender F = 40.04, p < 0.001), Vigorous PA (Gender F = 32.89, p < 0.001; Month F = 2.56, p = 0.027). Both genders increased PA from winter to summer months and SB decreased. Conclusions: Seasonality in PA intensities and SB suggest that interventions to promote PA and decrease SB must be tailored to take into consideration the month of the year they are going to be implemented and also gender characteristics. 23883682 Effect of intensified training on muscle ion kinetics, fatigue development and repeated short term performance in endurance trained cyclists. The effects of intensified training in combination with a reduced training volume on muscle ion kinetics, transporters and work capacity were examined. Eight well-trained cyclists replaced their regular training with speed-endurance training (12x30-s sprints) 2-3 times per wk and aerobic high-intensity training (4-5x3-4min at 90-100% of maximal heart rate) 1-2 times per wk for 7 wks, and reduced training volume by 70% (intervention period; IP). The duration of an intense exhaustive cycling bout (EX2; 356±6 W), performed 2.5min after a 2-min intense cycle bout (EX1), was longer (p<0.05) after than before IP (4:16±0:34 vs. 3:37±0:28 min:s), and mean and peak power during a repeated sprint test improved (p<0.05) by 4 and 3%, respectively. Femoral venous K+ concentration in recovery from EX1 and EX2 was lowered (p<0.05) after compared to before IP, whereas muscle interstitial K+ concentration and net muscle K+ release during exercise was unaltered. No changes in muscle lactate and H+ release during and after EX1 and EX2 were observed, but the in vivo buffer capacity was higher (p<0.05) after IP. Expression of the K+ATP channel 2 (Kir6.2) decreased by IP, with no change in the strong inward rectifying K+ channel (Kir2.1), muscle Na+-K+ pump subunits, monocarboxylate transporters 1 and 4 (MCT1 and MCT4) and Na+-H+ exchanger 1 (NHE1). In conclusion, 7wks of intensified training with a reduced training volume improved performance during repeated intense exercise, which was associated with a greater muscle re-uptake of K+ and muscle buffer capacity but not with the amount of muscle ion transporters. 23880403 Accelerated Weightbearing Rehabilitation After Matrix-Induced Autologous Chondrocyte Implantation in the Tibiofemoral Joint: Early Clinical and Radiological Outcomes. BACKGROUND:Matrix-induced autologous chondrocyte implantation (MACI) has become an established technique for the repair of full-thickness chondral defects in the knee, although best patient outcomes appear limited by a lack of evidence-based knowledge on how to progressively increase postoperative weightbearing (WB) and rehabilitation exercises. HYPOTHESIS:To determine the safety and efficacy of an accelerated WB regimen after MACI in the tibiofemoral joint. STUDY DESIGN:Randomized controlled trial; Level of evidence, 1. METHODS:Clinical and radiological assessments were performed in 28 knees at 12 months after MACI to the medial or lateral femoral condyle. Both rehabilitation interventions sought to protect the implant for an initial period and then incrementally increase load bearing. Under the "accelerated" (AR) protocol, patients reached full WB at 6 weeks after surgery compared with 8 weeks for what was considered to be the current "best practice" (CR) WB regimen based on previous research. Assessments included the Knee Injury and Osteoarthritis Outcome Score (KOOS), 36-Item Short Form Health Survey (SF-36), visual analog scale, 6-minute walk test, and active knee range of motion (ROM). High-resolution magnetic resonance imaging (MRI) was used to describe the quality and quantity of repair tissue via the assessment of pertinent parameters of graft repair as well as an MRI composite score. RESULTS:Patients in both groups demonstrated significant improvement (P < .05) in all clinical measures over the preoperative and postoperative timeline from before surgery to 12 months after surgery. The AR group reported significantly better (P < .05) SF-36 physical component scores at 8 weeks and significantly greater (P < .05) KOOS quality of life scores at 6 and 12 months postoperatively. Although no differences (P > .05) were observed between the 2 groups for active knee ROM, the AR group did achieve full active knee extension as early as 4 weeks compared with the CR group at 12 weeks. There was no difference (P > .05) in graft quality as assessed by MRI (MOCART composite score: AR, 3.34; CR, 3.04), with no patients suffering any adverse effects from the implant up to 12 months, regardless of the rehabilitation protocol employed. CONCLUSION:The AR approach that reduced the length of time spent ambulating on crutches resulted in improved general physical function and quality of life and an earlier attainment of full active knee extension when compared with the CR approach. There were no graft complications ascertained through MRI. This regimen appears safe and may potentially speed up the recovery of normal gait function. A larger patient cohort and follow-up are required to observe long-term graft outcomes. 23669235 Platelet-rich plasma in the pathologic processes of cartilage: review of basic science evidence. The purpose of this study was to systematically review the basic science evidence for the use of platelet-rich plasma (PRP) in the treatment of pathologic processes of cartilage, both as an adjunct to cartilage repair and as a conservative management strategy for osteoarthritis, with the intent of determining the effect of PRP and whether a proof of concept for its use has been established to facilitate further investigation at a clinical level. Using the terms "platelet-rich plasma OR PRP OR autologous conditioned plasma OR ACP AND cartilage OR chondrocytes OR chondrogenesis OR osteoarthritis OR arthritis" we searched EMBASE and PubMed/Medline in April 2012. Two authors performed the search, 3 authors independently assessed the studies for inclusion, and 2 authors extracted the data. Extracted data included cytologic analysis of PRP, study design, and results. Twenty-one studies (12 in vitro, 8 in vivo, one in vitro and in vivo) met the inclusion criteria. The effects of PRP in these studies included increasing chondrocyte and mesenchymal stem cell proliferation, proteoglycan deposition, and type II collagen deposition. PRP was also found to increase the cell viability of chondrocytes and the migration and chondrogenic differentiation of mesenchymal stem cells (MSCs) and to inhibit the effect of catabolic cytokines. In vivo, PRP was used as an adjunct to concomitant surgical management, including microfracture surgery and implant, scaffold, and graft insertion. Not all studies concluded that PRP has a positive effect on cartilage repair. The current basic science evidence suggests that PRP has several potential effects on cartilage repair and osteoarthritis, and a proof of concept has been established. Well-designed randomized controlled trials (RCTs) are needed to extrapolate this evidence to the clinical setting. 23796563 Inhibition of AMPK and Krebs Cycle Gene Expression Drives Metabolic Remodeling of Pten-Deficient Preneoplastic Thyroid Cells. Rapidly proliferating and neoplastically transformed cells generate the energy required to support rapid cell division by increasing glycolysis and decreasing flux through the oxidative phosphorylation (OXPHOS) pathway, usually without alterations in mitochondrial function. In contrast, little is known of the metabolic alterations, if any, which occur in cells harboring mutations that prime their neoplastic transformation. To address this question, we used a Pten-deficient mouse model to examine thyroid cells where a mild hyperplasia progresses slowly to follicular thyroid carcinoma. Using this model, we report that constitutive phosphoinositide 3-kinase (PI3K) activation caused by PTEN deficiency in nontransformed thyrocytes results in a global downregulation of Krebs cycle and OXPHOS gene expression, defective mitochondria, reduced respiration, and an enhancement in compensatory glycolysis. We found that this process does not involve any of the pathways classically associated with the Warburg effect. Moreover, this process was independent of proliferation but contributed directly to thyroid hyperplasia. Our findings define a novel metabolic switch to glycolysis driven by PI3K-dependent AMPK inactivation with a consequent repression in the expression of key metabolic transcription regulators. Cancer Res; 73(17); 1-14. ©2013 AACR. 23292193 Synthesis of selenolate-protected Au18(SeC6H5)14 nanoclusters. This work reports the first synthesis of selenophenolate-protected Au(18)(SePh)(14) nanoclusters. This cluster exhibits distinct differences from its thiolate analogue in terms of optical absorption properties. The Au(18)(SePh)(14) nanoclusters were obtained via a controlled reaction of Au(25)(SCH(2)CH(2)Ph)(18) with selenophenol. Electrospray ionization time-of-flight mass spectrometry (ESI-TOF-MS) revealed the crude product to contain predominantly Au(18)(SePh)(14) nanoclusters, and side products include Au(15)(SePh)(13), Au(19)(SePh)(15) and Au(20)(SePh)(16). High-performance liquid chromatography (HPLC) was employed to isolate Au(18)(SePh)(14) nanoclusters. The results of thermogravimetric analysis (TGA), elemental analysis (EA), and (1)H/(13)C NMR spectroscopy confirmed the cluster composition. To the best of our knowledge, this is the first report of selenolate-protected Au(18) nanoclusters. Future theoretical and X-ray crystallographic work will reveal the geometric structure and the nature of selenolate-gold bonding in the nanocluster. 23122119 Nutrients, phytochemicals and bioactivity of wild Roman chamomile: a comparison between the herb and its preparations. Roman chamomile, Chamaemelum nobile L. (Asteraceae), has been used for medicinal applications, mainly through oral dosage forms (decoctions and infusions). Herein, the nutritional characterisation of C. nobile was performed, and herbal material and its decoction and infusion were submitted to an analysis of phytochemicals and bioactivity evaluation. The antioxidant activity was determined by free radicals scavenging activity, reducing power and inhibition of lipid peroxidation, the antitumour potential was tested in human tumour cell lines (breast, lung, colon, cervical and hepatocellular carcinomas), and the hepatotoxicity was evaluated using a porcine liver primary cell culture. C. nobile proved to be an equilibrated valuable herb rich in carbohydrates and proteins, and poor in fat, providing tocopherols, carotenoids and essential fatty acids (C18:2n6 and C18:3n3). Moreover, the herb and its infusion are a source of phenolic compounds (flavonoids such as flavonols and flavones, phenolic acids and derivatives) and organic acids (oxalic, quinic, malic, citric and fumaric acids) that showed antioxidant and antitumour activities, without hepatotoxicity. The most abundant compounds in the plant extract and infusion were 5-O-caffeoylquinic acid and an apigenin derivative. These, as well as other bioactive compounds, are affected in C. nobile decoction, leading to a lower antioxidant potential and absence of antitumour potential. The plant bioactivity could be explored in the medicine, food, and cosmetic industries. 23297161 Cynomolgus monkey as a potential model to assess drug interactions involving hepatic organic anion transporting polypeptides: in vitro, in vivo, and in vitro-to-in vivo extrapolation. Organic anion-transporting polypeptides (OATP) 1B1, 1B3, and 2B1 can serve as the loci of drug-drug interactions (DDIs). In the present work, the cynomolgus monkey was evaluated as a potential model for studying OATP-mediated DDIs. Three cynomolgus monkey OATPs (cOATPs), with a high degree of amino acid sequence identity (91.9, 93.5, and 96.6% for OATP1B1, 1B3, and 2B1, respectively) to their human counterparts, were cloned, expressed, and characterized. The cOATPs were stably transfected in human embryonic kidney cells and were functionally similar to the corresponding human OATPs (hOATPs), as evident from the similar uptake rate of typical substrates (estradiol-17β-d-glucuronide, cholecystokinin octapeptide, and estrone-3-sulfate). Moreover, six known hOATP inhibitors exhibited similar IC(50) values against cOATPs. To further evaluate the appropriateness of the cynomolgus monkey as a model, a known hOATP substrate [rosuvastatin (RSV)]-inhibitor [rifampicin (RIF)] pair was examined in vitro; the monkey-derived parameters (RSV K(m) and RIF IC(50)) were similar (within 3.5-fold) to those obtained with hOATPs and human primary hepatocytes. In vivo, the area under the plasma concentration-time curve of RSV (3 mg/kg, oral) given 1 hour after a single RIF dose (15 mg/kg, oral) was increased 2.9-fold in cynomolgus monkeys, consistent with the value (3.0-fold) reported in humans. A number of in vitro-in vivo extrapolation approaches, considering the fraction of the pathways affected and free versus total inhibitor concentrations, were also explored. It is concluded that the cynomolgus monkey has the potential to serve as a useful model for the assessment of OATP-mediated DDIs in a nonclinical setting. 23736112 Effects of antihypertensive drugs on central blood pressure in humans: a preliminary observation. Central blood pressure (BP) is considered a better predictor of cardiovascular events than brachial BP. Modifications of central, beyond brachial BP, can be assessed by pressure amplification, a potential new cardiovascular risk factor. Comparison between drugs' effect on central hemodynamics has been poorly studied. Our aim was to assess the hemodynamic effect of a 12-week treatment with amlodipine 5mg, or candesartan 8mg, or indapamide sustained-release 1.5mg, in comparison with placebo. We analyzed 145 out-patients with essential hypertension in primary prevention enrolled in the Natrilix SR Versus Candesartan and Amlodipine in the Reduction of Systolic Blood Pressure in Hypertensive Patients (X-CELLENT) study, a multicenter, randomized, double-blinded, placebo-controlled trial. Arterial stiffness, central BP, pressure amplification, and wave reflection were measured by applanation tonometry. Baseline characteristics of patients were homogeneous between groups. After treatment, we found that active drugs produced similar reduction of both central and peripheral BPs, with no significant interdrug differences (all P < 0.05; excluded peripheral pulse pressure, compared with placebo). Second, amlodipine (1.9% ± 15.3%), candesartan (3.0% ± 14.6%) and indapamide (4.1% ± 14.4%) all increased pulse pressure amplification, but only indapamide was statistically different from placebo (P = 0.02). Finally, no significant changes were observed on pulse wave velocity, heart rate, and augmentation index. The 3 antihypertensive drugs similarly reduced peripheral and central BP, as compared with placebo, but a significant increase in pulse pressure amplification was obtained only with indapamide, independently of arterial stiffness modifications. 3283161 by BIOPHARMA. 23832538 Differential miRNA profile on photoaged primary human fibroblasts irradiated with ultraviolet A. Photoaging is cell aging caused by long-wave ultraviolet (UVA) radiation which is the main cause of human skin aging produced by exogenous environment. As an endogenous noncoding small RNA, microRNAs (miRNAs) are sensitive to environmental changes, and the expression change of miRNAs is an important manner to adjust to environment. However, the miRNA profile on photoaged human skin irradiated with UVA remains unknown and whether UVA responsive miRNAs participate in the UVA-caused stress reaction of skin cells is also unclear. In this study, we established an in vitro photoaging model with UVA-radiated human primary cultured fibroblasts, which could mimic UVA-induced photoaging of skin. Differentially expressed miRNAs during photoaging, including five up- and seven downregulated miRNAs, were found by microarray analysis and were verified by quantitative real-time PCR. With bioinformatics methods, the predicted miRNA targets were suggested to be associated with pathways in cancers. Among the significantly UVA-downregulated miRNAs, miR-146a overexpression antagonized the UVA-induced proliferation inhibition and suppressed the upregulation of aging-related genes in photoaging of our model. Western blot and luciferase assay showed that Smad4 might be a target of miR-146a to exert miR-146a functions during photoaging. Therefore, UVA radiation-induced photoaging results in specific patterns of miRNA response and miR-146a are able to antagonize UVA-caused photoaging partially through targeting Smad4. 23685244 The antioxidant activity and active component of Gnaphalium affine extract. The antioxidant activity of Gnaphalium affine extract (GAE) against H2O2-induced oxidative injury in Caco-2 cells was evaluated, and the main antioxidant component was isolated and identified by column chromatography, high performance liquid chromatography, time-of-flight mass spectrometer and nuclear magnetic resonance. In vitro assays, GAE showed remarkable antioxidant activity to scavenge free radicals (ABTS, DPPH, superoxide and hydroxyl radicals), inhibit lipid peroxidation and show reducing power. In food system, GAE exhibited the obvious capacity to inhibit the oxidation of peanut oil and lard, which may be attributed to its high content of phenolic compounds. Moreover, GAE could effectively protect Caco-2 cell against H2O2-induced oxidative injury. With the isolation and purification by chromatography, quercetin was identified as the main antioxidant component of GAE, which was capable of scavenging ABTS, DPPH, superoxide and hydroxyl radicals. These results suggest that G. affine is a potential source for preparing functional foods and nutraceuticals in food industry. 23944287 Retraction techniques in laparoscopic colorectal surgery: a literature based review. To systematically review the published literature and describe the various techniques of bowel and mesentery retraction available for use in laparoscopic colorectal resection. A comprehensive search of the literature was undertaken using MESH terms "retraction", "laparoscopic" and "colorectal". All articles describing methods of retraction in laparoscopic colorectal surgery were included. Twelve methods of retraction in laparoscopic colorectal surgery were described. Five case based series and three case studies were reported on 108 patients. Techniques were classified into those offering retraction of the small or large bowel or according to the mode of retraction. Many retraction methods are available to the surgeon varying in cost, invasiveness and complexity. Adequate retraction remains a challenge for optimal exposure and dissection during laparoscopic colorectal surgery. This article is protected by copyright. All rights reserved. 23858103 Conserved Tryptophan Residues within Putative Transmembrane Domain 6 Affect Transport Function of Organic Anion Transporting Polypeptide 1B1. The organic anion-transporting polypeptides (OATPs, gene symbol SLCO) are a family of transporters that play important roles in the absorption, distribution, metabolism and excretion of various drugs. Although substrate specificity of transporter proteins is under extensive study, the underlying mechanisms for substrate binding and/or recognition remain largely unknown. Transmembrane domain 6 (TM6) is a relatively conserved region within OATP family members and several amino acid residues on its extracellular half are part of the OATP family signature sequence D-X-RW-(I,V)-GAWWX-G-(F,L)-L. In the present study, two adjacent tryptophan residues (Trp258 and Trp259) within TM6 were identified as critical amino acids for the transport function of OATP1B1. Kinetic studies showed that substitution of Trp258 with alanine resulted in monophasic kinetics for estrone-3-sulfate uptake, with a significantly higher Km value (Km=12.0±2.8μM) compared to the high affinity component of wild-type OATP1B1 (Km=0.38±0.06μM). On the other hand, W259A retained the biphasic characteristic of the transporter. Km values of the high and low affinity components for estrone-3-sulfate of W259A are 1.93±0.76μM and 30.8±4.4μM, respectively. Further studies revealed that W258A retained transport function of another prototypic substrate taurocholate; while W259A displayed a dramatically reduced uptake of the substrate and exhibited an eight-fold increase in the Km value compared with that of the wild-type and W258A. Our results suggested that Trp258 and Trp259 may play different roles for the uptake of different substrates by OATP1B1. 23806415 Influence of surface conductivity on the apparent zeta potential of TiO2 nanoparticles: Application to the modeling of their aggregation kinetics. Titanium dioxide nanoparticles (TiO2 NPs) are extensively used in consumer products. The release of these NPs into aquatic environments raises the question of their possible risks to the environment and human health. The magnitude of the threat may depend on whether TiO2 NPs are aggregated or dispersed. Currently, limited information is available on this subject. A new approach based on DLVO theory is proposed to describe aggregation kinetics of TiO2 NPs in aqueous dispersions. It has the advantage of using zeta potentials directly calculated by an electrostatic surface complexation model whose parameters are calibrated by ab initio calculations, crystallographic studies, potentiometric titration and electrophoretic mobility experiments. Indeed, the conversion of electrophoretic mobility measurements into zeta potentials is very complex for metal oxide nanoparticles. This is due to their very high surface electrical conductivity associated with the electromigration of counter and co-ions in their electrical double layer. Our model has only three adjustable parameters (the minimum separation distance between NPs, the Hamaker constant, and the effective interaction radius of the particle), and predicts very well the stability ratios of TiO2 NPs measured at different pH values and over a broad range of ionic strengths (KCl aqueous solution). We found an effective interaction radius that is significantly smaller than the radius of the aggregate and corresponds to the radius of surface crystallites or small clusters of surface crystallites formed during synthesis of primary particles. Our results confirm that DLVO theory is relevant to predict aggregation kinetics of TiO2 NPs if the double layer interaction energy is estimated accurately. 23957881 A larger weight reduction is necessary to elicit an increase in adiponectin and a decrease in leptin levels. We read the article 'Effects of individual and combined dietary weight loss and exercise interventions in postmenopausal women on adiponectin and leptin levels' by Abbenhardt et al. with interest [1]. The authors concluded that diet-induced weight loss with or without exercise increased the serum adiponectin concentration and resulted in a reduction in leptin levels [1]. This article is protected by copyright. All rights reserved. 23907764 Intranasal insulin increases regional cerebral blood flow in the insular cortex in men independently of cortisol manipulation. Insulin and cortisol play a key role in the regulation of energy homeostasis, appetite, and satiety. Little is known about the action and interaction of both hormones in brain structures controlling food intake and the processing of neurovisceral signals from the gastrointestinal tract. In this study, we assessed the impact of single and combined application of insulin and cortisol on resting regional cerebral blood flow (rCBF) in the insular cortex. After standardized periods of food restriction, 48 male volunteers were randomly assigned to receive either 40 IU intranasal insulin, 30 mg oral cortisol, both, or neither (placebo). Continuous arterial spin labeling (CASL) sequences were acquired before and after pharmacological treatment. We observed a bilateral, locally distinct rCBF increase after insulin administration in the insular cortex and the putamen. Insulin effects on rCBF were present regardless of whether participants had received cortisol or not. Our results indicate that insulin, but not cortisol, affects blood flow in human brain structures involved in the regulation of eating behavior. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc. 23773140 In Vitro and in Vivo Characterization of a Tunable Dual-Reactivity Probe of the Nrf2-ARE Pathway. The cell utilizes the Keap1/Nrf2-ARE signaling pathway to detoxify harmful chemicals in order to protect itself from oxidative stress and to maintain its reducing environment. When exposed to oxidative stress and xenobiotic inducers, the redox sensitive Keap1 is covalently modified at specific cysteine residues. Consequently, the latent transcription factor Nrf2 is stabilized and translocates into the nucleus, where it transactivates the expression of detoxification genes through binding to the antioxidant response element (ARE). In the pursuit of potent and bioavailable activators of the ARE, we validated hits from a pathway-directed high-throughput screening campaign by testing them in cell culture and a reporter strain of a whole animal model, Caenorhabditis elegans. These studies allowed us to identify AI-3 as an ARE activator that induces cytoprotective genes in human cells and in worms, which also translated into in vivo activity in mice. AI-3 is an electrophilic ARE activator with two thiol sensitive sites toward a nucleophilic aromatic substitution, and SAR studies indicated the tunability of the system. Tandem LC-MS analysis revealed that AI-3 alkylates Keap1 primarily at Cys151, while AI-3 is reactive toward additional cysteine residues at higher doses in vitro and in vivo. The immediate effects of such alkylation included the disruption of Keap1-Cul3 (low [AI-3]) and/or Keap1-Nrf2 (high [AI-3]) interactions that both led to the stabilization of Nrf2. This further translated into the downstream Nrf2-ARE regulated cytoprotective gene activation. Collectively, AI-3 may become a valuable biological tool and may even provide therapeutic benefits in oxidative stress related diseases. 23815124 Nitroglycerin 0.4% ointment vs placebo in the treatment of pain resulting from chronic anal fissure: a randomized, double-blind, placebo-controlled study. Complications of chronic anal fissure (CAF) treatments are prompting interest in lower-risk therapies. This study was conducted to compare nitroglycerin (NTG) 0.4% ointment with placebo for pain associated with CAF. In this randomized, double-blind, placebo-controlled trial, patients with one CAF and moderate-to-severe pain (>=50 mm on a 100 mm visual analog scale [VAS]) received 375 mg NTG 0.4% (1.5 mg active ingredient) or 375 mg placebo ointment applied anally every 12 hours for 21 days. The primary end point was change from baseline VAS score in 24-hour pain averaged over days 14--18. Review of data from patients who withdrew early was blinded to treatment. To control for the confounding effects of analgesics, all patients received 650 mg acetaminophen for headache prophylaxis before each application. A total of 247 patients were enrolled (NTG, n = 123; placebo, n = 124). The prespecified baseline observation carried forward (BOCF) analysis found no significant difference between groups; however, a last observation carried forward (LOCF) analysis showed a significant advantage for NTG. A post hoc analysis (LOCF/BOCF hybrid) demonstrated a significant adjusted mean difference of -7.0 mm in favor of NTG 0.4% (95% CI -13.6, --0.4; P = .038). Headache was the most common adverse event in the NTG (69.9%) and placebo (47.6%) groups. This was the first placebo-controlled study that also controlled for the confounding effects of analgesics used to treat NTG-induced headache. In patients with moderate-to-severe CAF pain, NTG 0.4% ointment effectively reduced CAF pain compared with placebo.Trial registration: ClinicalTrials.gov, NCT00522041. 23836510 The Yin and Yang of Intestinal (Cancer) Stem Cells and their Progenitors. The intestine has developed over the last few years into a prime model system for adult stem cell research. Intestinal cells have an average lifetime of five days, moving within this time from the bottom of intestinal crypts to the top of villi. This rapid self-renewal capacity combined with an easy to follow (mostly) unidirectional movement of cells offers an ideal site to conduct adult stem cell research. The delineation of the active pathways in the intestinal epithelium together with the development of molecular techniques to prove stemness laid the grounds for the identification of the intestinal stem cell. In vitro systems and transgenic mouse models broaden our knowledge on the role of the stem cell niche and those cells that re-establish homeostasis after perturbation of the system. These insights expedited also research on the role of normal adult stem cells in cancer initiation and the factors influencing the maintenance of cancer stem cells. 23852167 The wheat powdery mildew genome shows the unique evolution of an obligate biotroph. Wheat powdery mildew, Blumeria graminis forma specialis tritici, is a devastating fungal pathogen with a poorly understood evolutionary history. Here we report the draft genome sequence of wheat powdery mildew, the resequencing of three additional isolates from different geographic regions and comparative analyses with the barley powdery mildew genome. Our comparative genomic analyses identified 602 candidate effector genes, with many showing evidence of positive selection. We characterize patterns of genetic diversity and suggest that mildew genomes are mosaics of ancient haplogroups that existed before wheat domestication. The patterns of diversity in modern isolates suggest that there was no pronounced loss of genetic diversity upon formation of the new host bread wheat 10,000 years ago. We conclude that the ready adaptation of B. graminis f.sp. tritici to the new host species was based on a diverse haplotype pool that provided great genetic potential for pathogen variation. 23915320 CIP4 is required for the hypertrophic growth of neonatal cardiac myocytes. CIP4 is a scaffold protein that regulates membrane deformation and tubulation, organization of the actin cytoskeleton, endocytosis of growth factor receptors, and vesicle trafficking. Although expressed in the heart, CIP4 has not been studied with regards to its potential function in cardiac myocytes. We now show using RNA interference that CIP4 expression in neonatal rat ventricular myocytes is required for the induction of non-mitotic, hypertrophic growth by the α-adrenergic agonist phenylephrine, the IL-6 cytokine leukemia inhibitor factor, and fetal bovine serum, as assayed using morphometry, immunocytochemistry for the hypertrophic marker atrial natriuretic factor and [3H]leucine incorporation for de novo protein synthesis. This requirement was consistent with the induction of CIP4 expression by hypertrophic stimulation. The inhibition of myocyte hypertrophy by CIP4 small interfering oligonucleotides (siRNA) was rescued by expression of a recombinant CIP4 protein, but not by a mutant lacking the N-terminal FCH domain responsible for CIP4 intracellular localization. These results imply that CIP4 plays a significant role in the intracellular hypertrophic signal transduction network that controls the growth of cardiac myocytes in heart disease. 22959595 Exosomes for drug delivery - a novel application for the mesenchymal stem cell. Exosomes are the most extensively characterized class of secreted membrane vesicles that carry proteins and RNAs for intercellular communication. They are increasingly seen as possible alternatives to liposomes as drug delivery vehicles. Like liposomes, they could deliver their cargo across the plasma membrane and provide a barrier against premature transformation and elimination. In addition, these naturally-occurring secreted membrane vesicles are less toxic and better tolerated in the body as evidenced by their ubiquitous presence in biological fluids, and have an intrinsic homing ability. They are also amenable to in vivo and in vitro loading of therapeutic agents, and membrane modifications to enhance tissue-specific homing. Here we propose human mesenchymal stem cells as the ideal cell source of exosomes for drug delivery. Mesenchymal stem cell transplantation for various disease indications has been extensively tested and shown to be safe in numerous clinical trials. These cells are also prolific producers of immunologically inert exosomes. Immortalization of these cells does not compromise the quantity or quality of exosome production, thus enabling infinite and reproducible exosome production from a single cell clone. 22985529 NMR and mass spectrometric characterization of vinblastine, vincristine and some new related impurities - Part I. In the course of exploring the possibilities of developing a new, improved process at Gedeon Richter for the production of the "bisindole" alkaloids vinblastine (VLB) and vincristine (VCR), some novel VLB/VCR-related trace impurities were detected by analytical HPLC. Following isolation by preparative HPLC, a combination of 1D and 2D ultra high-field NMR and high-resolution (HR) (LC-)MS/MS studies allowed the structural identification and complete spectral characterization of several hitherto unpublished VLB/VCR-analogue impurities. Since the impurities could not be isolated in entirely pure forms and were available only in minute, mass-limited quantities, accessing the spectral information needed for their ab initio structure determination was met with various practical difficulties. Successful structure determination therefore relied heavily on the availability and use of detailed and definitive spectral data for both VLB and VCR. In particular, the utilization of detailed (1)H, (13)C, and (15)N NMR assignments as well as (1)H-(1)H, (1)H-(13)C and (1)H-(15)N spin-spin connectivities pertaining to different solvents for VLB/VCR base and sulphate salt was required. Although NMR studies on VLB base and other bisindoles were reported earlier in the literature, an NMR characterization of VLB and VCR under the above-mentioned circumstances and using ultra-high field instrumentation is either scarcely available or entirely lacking, therefore the necessary data had to be obtained in-house. Likewise, a modern tandem HR-ESI-MS/MS(n) fragmentation study of VLB and VCR has not been published yet. In the present paper we therefore give a thorough NMR and MS characterization of VLB and VCR specifically with a view to filling this void and to provide sufficiently extensive and solid reference data for the structural investigation of the aforementioned VLB/VCR impurities. Besides being scientifically relevant in its own right, the disclosed data should be useful for anyone interested in VLB/VCR-related molecules at a structural level. 23704036 Conceptual Limitations of Balance Measures for Community-Dwelling Older Adults. Psychometric limitations of balance measures for community-dwelling elderly may be related to gaps in task and environmental representation. The purposes of this study were: (1) to conduct item-level content analysis of balance measures for community-dwelling elderly people based on task and environmental factors and (2) to develop profiles of individual measures summarizing their task and environment representation. A systematic content analysis was conducted. A literature search was conducted to identify balance measures. Item-level content analysis was based on 7 criteria related to task and environment: (1) task role, (2) environmental variation, (3) object interaction, (4) obstacle negotiation, (5) external forces, (6) dual-tasking, and (7) moving people or objects in the environment. Twenty-six measures, containing 167 items, were identified. Task role was fairly evenly distributed, with the majority of items examining gait tasks (32.3%), followed by dynamic body stability (29.9%) and static body stability (25.1%). The majority of items involved no environmental variation (58.1%), followed by variation of support surfaces (20.4%), visual conditions (13.2%), and both support and visual conditions (8.4%). Limited task role variability was seen within measures, with 73.1% of measures examining only one task role. Environmental variation was present in 65.3% of measures, primarily during static body stability tasks. Few measures involved object interaction (23.1%), obstacle negotiation (38.5%), external forces (11.5%), dual-tasking (7.7%), or moving people or objects (0%). The classification framework was not externally validated. Existing measures focus on single-task assessment in static environments, underrepresenting postural control demands in daily-life situations involving dynamic changing environments, person-environment interactions, and multitasking. New items better reflecting postural control demands in daily-life situations are needed for more ecologically valid balance assessment. Individual balance measure profiles provided can help identify the most appropriate measure for a given purpose. 23913513 The role of macrophage migration inhibitory factor (MIF) in autoimmune liver disease. The role of the cytokine macrophage migration inhibitory factor (MIF) and its receptor, CD74, was assessed in autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). Two MIF promoter polymorphisms, a functional -794 CATT5-8 microsatellite repeat (rs5844572) and a -173 G/C single nucleotide polymorphism (rs755622), were analyzed in DNA samples from over 500 patients with AIH, PBC, and controls. We found a higher frequency of the pro-inflammatory and high expression -794 CATT7 allele in AIH compared to PBC, while lower frequency was found in PBC compared to both AIH and healthy controls. MIF and soluble MIF receptor (CD74) were measured by ELISA in 165 serum samples of AIH, PBC, and controls. Circulating serum and hepatic MIF expression was elevated in patients with AIH and PBC vs. healthy controls. We also identified a truncated circulating form of the MIF receptor CD74 that is released from hepatic stellate cells and that binds MIF, neutralizing its signal transduction activity. Significantly higher levels of CD74 were found in patients with PBC vs. AIH and controls. Conclusions: These data suggest a distinct genetic and immunopathogenic basis for AIH and PBC at the MIF locus. Circulating MIF and MIF receptor profiles distinguish PBC from the more inflammatory phenotype of AIH and may play a role in the pathogenesis and as biomarkers of these diseases. (Hepatology 2013;). 23834931 Etiological analysis and predictive diagnostic model building of community-acquired pneumonia in adult outpatients in Beijing, China. Etiological epidemiology and diagnosis are important issues in adult community-acquired pneumonia (CAP), and identifying pathogens based on patient clinical features is especially a challenge. CAP-associated main pathogens in adults include viruses as well as bacteria. However, large-scale epidemiological investigations of adult viral CAP in China are still lacking. In this study, we analyzed the etiology of adult CAP in Beijing, China and constructed diagnostic models based on combinations of patient clinical factors. A multicenter cohort was established with 500 adult CAP outpatients enrolled in Beijing between November 2010 to October 2011. Multiplex and quantitative real-time fluorescence PCR were used to detect 15 respiratory viruses and mycoplasma pneumoniae, respectively. Bacteria were detected with culture and enzyme immunoassay of the Streptococcus pneumoniae urinary antigen. Univariate analysis, multivariate analysis, discriminatory analysis and Receiver Operating Characteristic (ROC) curves were used to build predictive models for etiological diagnosis of adult CAP. Pathogens were detected in 54.2% (271/500) of study patients. Viruses accounted for 36.4% (182/500), mycoplasma pneumoniae for 18.0% (90/500) and bacteria for 14.4% (72/500) of the cases. In 182 of the patients with viruses, 219 virus strains were detected, including 166 single and 53 mixed viral infections. Influenza A virus represented the greatest proportion with 42.0% (92/219) and 9.1% (20/219) in single and mixed viral infections, respectively. Factors selected for the predictive etiological diagnostic model of viral CAP included cough, dyspnea, absence of chest pain and white blood cell count (4.0-10.0) × 109/L, and those of mycoplasma pneumoniae CAP were being younger than 45 years old and the absence of a coexisting disease. However, these models showed low accuracy levels for etiological diagnosis (areas under ROC curve for virus and mycoplasma pneumoniae were both 0.61, P < 0.05). Greater consideration should be given to viral and mycoplasma pneumoniae infections in adult CAP outpatients. While predictive etiological diagnostic models of viral and mycoplasma pneumoniae based on combinations of demographic and clinical factors may provide indications of etiology, diagnostic confirmation of CAP remains dependent on laboratory pathogen test results. 23013536 Platelet activation, function, and reactivity in atherosclerotic carotid artery stenosis: a systematic review of the literature. An important proportion of transient ischemic attack or ischemic stroke is attributable to moderate or severe (50-99%) atherosclerotic carotid stenosis or occlusion. Platelet biomarkers have the potential to improve our understanding of the pathogenesis of vascular events in this patient population. A detailed systematic review was performed to collate all available data on ex vivo platelet activation and platelet function/reactivity in patients with carotid stenosis. Two hundred thirteen potentially relevant articles were initially identified; 26 manuscripts met criteria for inclusion in this systematic review. There was no consistent evidence of clinically informative data from urinary or soluble blood markers of platelet activation in patients with symptomatic moderate or severe carotid stenosis who might be considered suitable for carotid intervention. Data from flow cytometry studies revealed evidence of excessive platelet activation in patients in the early, sub-acute, or late phases after transient ischemic attack or stroke in association with moderate or severe carotid stenosis and in asymptomatic moderate or severe carotid stenosis compared with controls. Furthermore, pilot data suggest that platelet activation may be increased in recently symptomatic than in asymptomatic severe carotid stenosis. Excessive platelet activation and platelet hyperreactivity may play a role in the pathogenesis of first or subsequent transient ischemic attack or stroke in patients with moderate or severe carotid stenosis. Larger longitudinal studies assessing platelet activation status with flow cytometry and platelet function/reactivity in symptomatic vs. asymptomatic carotid stenosis are warranted to improve our understanding of the mechanisms responsible for transient ischemic attack or stroke. 23835478 Channel gating pore: a new therapeutic target. Each subunit of voltage-gated cation channels comprises a voltage-sensing domain and a pore region. In a paper recently published in Cell Research, Li et al. showed that the gating charge pathway of the voltage sensor of the KCNQ2 K channel can accommodate small opener molecules and offer a new target to treat hyperexcitability disorders. 23523831 Cytotoxic mechanism of Piper gaudichaudianum Kunth essential oil and its major compound nerolidol. Piper gaudichaudianum Kunth is used in popular medicine as anti-inflamatory and against liver disorders. One of the most studied components of the plant is the essential oil for which chemical analysis revealed (E)-nerolidol as major compound. Recently, we have shown that P. gaudichaudianum essential oil possesses strong cytotoxic effects in mammalian V79 cells. The aim of this study was to analyze the cytotoxicity and mutagenicity of P. gaudichaudianum essential oil and nerolidol using Saccharomyces cerevisiae as model study. Treatment of the XV185-14c and N123 strains with essential oil and nerolidol led to cytotoxicity but did not induce mutagenicity. Our results revealed an important role of base excision repair (BER) as the ntg1, ntg2, apn1 and apn2 mutants showed pronounced sensitivity to essential oil and nerolidol. In the absence of superoxide dismutase (in sod1Δ mutant strain) sensitivity to the essential oil and nerolidol increased indicating that this oil and nerolidol are generating reactive oxygen species (ROS). The ROS production was confirmed by DCF-DA probing assay in Sod-deficient strains. From this, we conclude that the observed cytotoxicity to P. gaudichaudianum essential oil and nerolidol is mainly related to ROS and DNA single strand breaks generated by the presence of oxidative lesions. 23743271 Polybrominated diphenyl ethers do not affect metamorphosis but alter the proteome of the invasive slipper limpet Crepidula onyx. Man-made polybrominated diphenyl ethers (PBDEs) used as flame retardants in various consumer products may be harmful to marine organisms. Larvae of some marine invertebrates, especially invasive species, can develop resistance to PBDEs through altered protein expression patterns or proteome plasticity. This is the first report of a proteomics approach to study BDE-47 induced molecular changes in the invasive limpet Crepidula onyx. Larvae of C. onyx were cultured for 5days (hatching to metamorphosis) in the presence of BDE-47 (1μgL(-1)). Using a 2-DE proteomics approach with triple quadrupole and high-resolution TOF-MS, we showed that BDE-47 altered the proteome structure but not the growth or metamorphosis of C. onyx larvae. We found eight significant differentially expressed proteins in response to BDE-47, deemed the protein expression signature, consisting of cytoskeletal, stress tolerance, metabolism and energy production related proteins. Our data suggest C. onyx larvae have adequate proteome plasticity to tolerate BDE-47 toxicity. 23934911 Direct-to-Consumer Stem Cell Marketing and Regulatory Responses. There is a large, poorly regulated international market of putative stem cell products, including transplants of processed autologous stem cells from various tissues, cell processing devices, cosmetics, and nutritional supplements. Despite the absence of rigorous scientific research in the form of randomized clinical trials to support the routine use of such products, the market appears to be growing and diversifying. Very few stem cell biologics have passed regulatory scrutiny, and authorities in many countries, including the United States, have begun to step up their enforcement activities to protect patients and the integrity of health care markets. 23942278 The effect of copper pre-cleaning on graphene synthesis. Copper foil is the most common substrate to synthesize monolayer graphene by chemical vapor deposition (CVD). The surface morphology and conditions of the copper foil can be very different depending on the various suppliers or different batches. These surface properties of copper strongly affect the growth behavior of graphene, thus rendering the growth conditions irreproducible when different batches of Cu foil are used. Furthermore, the quality of the graphene is severely affected as well. In this work, we report a facile method of copper pre-cleaning to improve the graphene quality and the reproducibility of the growth process. We found that the commercial Ni etchant (based on nitric acid) or nitric acid is the most effective cleaning agent among various acidic or basic solutions. The graphene grown on thus-treated copper surfaces is very clean and mostly monolayer when observed under scanning electron microscopy (SEM) and optical imaging, as compared to the graphene grown on untreated copper foil. Different batches (but with the same catalog number) of copper foil from Alfa Aesar Company were examined to explore the effect of copper pre-cleaning; consistent growth results were obtained when pre-cleaning was used. This method overcomes a commonly encountered problem in graphene growth and could become one of the standard protocols for preparing the copper foil substrate for growing graphene or other 2D materials. 23774477 The "anger superiority effect" in the discrimination task is independent of temporal task demands. Extensive studies have showed that threatening faces are preferentially processed. This preferential processing may be due to more and earlier attentional allocation to threat-related stimuli, which is required for organisms to adopt appropriate reactions. In the present study, two different display durations were introduced and the N2pc was measured to investigate whether the preferential processing of threatening faces was impacted by temporal task demands. The "anger superiority effect" existed with both display durations, indicating that the "anger superiority effect" per se may be independent of temporal task demands. However, the behavioral "anger superiority effect" was modulated by different temporal task demands, which may be due to the execution of external responses rather than attentional processing. At electrophysiological level, the N2pc patterns were not impacted by different display durations, which suggested that the preferential processing of threatening faces, in terms of attentional processing, was independent of different temporal task demands. 23411111 Regulatory decisions on endocrine disrupting chemicals should be based on the principles of endocrinology. For years, scientists from various disciplines have studied the effects of endocrine disrupting chemicals (EDCs) on the health and wellbeing of humans and wildlife. Some studies have specifically focused on the effects of low doses, i.e. those in the range that are thought to be safe for humans and/or animals. Others have focused on the existence of non-monotonic dose-response curves. These concepts challenge the way that chemical risk assessment is performed for EDCs. Continued discussions have clarified exactly what controversies and challenges remain. We address several of these issues, including why the study and regulation of EDCs should incorporate endocrine principles; what level of consensus there is for low dose effects; challenges to our understanding of non-monotonicity; and whether EDCs have been demonstrated to produce adverse effects. This discussion should result in a better understanding of these issues, and allow for additional dialog on their impact on risk assessment. 23967114 Validity of physician billing claims to identify deceased organ donors in large healthcare databases. We evaluated the validity of physician billing claims to identify deceased organ donors in large provincial healthcare databases. We conducted a population-based retrospective validation study of all deceased donors in Ontario, Canada from 2006 to 2011 (n = 988). We included all registered deaths during the same period (n = 458,074). Our main outcome measures included sensitivity, specificity, positive predictive value, and negative predictive value of various algorithms consisting of physician billing claims to identify deceased organ donors and organ-specific donors compared to a reference standard of medical chart abstraction. The best performing algorithm consisted of any one of 10 different physician billing claims. This algorithm had a sensitivity of 75.4% (95% CI: 72.6% to 78.0%) and a positive predictive value of 77.4% (95% CI: 74.7% to 80.0%) for the identification of deceased organ donors. As expected, specificity and negative predictive value were near 100%. The number of organ donors identified by the algorithm each year was similar to the expected value, and this included the pre-validation period (1991 to 2005). Algorithms to identify organ-specific donors performed poorly (e.g. sensitivity ranged from 0% for small intestine to 67% for heart; positive predictive values ranged from 0% for small intestine to 37% for heart). Primary data abstraction to identify deceased organ donors should be used whenever possible, particularly for the detection of organ-specific donations. The limitations of physician billing claims should be considered whenever they are used. 23764357 Anti-cancer effects of dioscin on three kinds of human lung cancer cell lines through inducing DNA damage and activating mitochondrial signal pathway. Dioscin, a natural steroid saponin, has been widely investigated. However, its anti-cancer activities on human lung cancer cells are still unknown. In the present paper, the inhibitory effects of dioscin were investigated, and the results showed that dioscin inhibited the proliferation of human A549, NCI-H446 and NCI-H460 cancer cells. DNA damage and cell apoptosis in dioscin-treated cells were found through single cell gel electrophoresis and in situ terminal deoxynucleotidyl transferase dUTP nick-end labeling assays. Furthermore, dioscin caused mitochondrial structure changes and blocked cell cycle at S phase based on transmission electron microscope and flow cytometry analysis. In addition, dioscin treatment caused the release of cytochrome c from mitochondria into cytosol. The activities of Caspase-3 and -9 in dioscin-treated groups were significantly increased compared with control group. Western blotting analysis showed that dioscin significantly down-regulated the expressions of Bcl-2 and Bcl-xl, and up-regulated the expressions of Bax, Bak and Bid. Our results indicate that dioscin has anticancer activities against human lung cancer cells through inducing cell cycle arrest, DNA damage and activating mitochondrial signal pathway. 23888116 The emerging role of RNA polymerase I transcription machinery in human malignancy: a clinical perspective. Ribosome biogenesis - the complex and highly coordinated cellular process leading to the production of ribosomes - is strictly dependent on the activity of RNA polymerase I (Pol I) transcriptional machinery. Pol I activity is continually increased in proliferating cells to sustain the increased demand for ribosome production and protein synthesis, which are necessary for appropriate cell growth and division. The integrity of the process of ribosome biogenesis represents an important sensor of cellular stress: when this process is altered, a tumor suppressor response is triggered, which leads to proliferative arrest. The present review focuses on the possible implications of Pol I targeting in the treatment of human malignancies. 22925545 Regionalisation of Climate Change sensitive forest development types for potential afforestation areas. This paper describes how to use sectoral planning information from forestry to predict and up-scale information on Climate Change sensitive forest development types for potential afforestation areas. The method was developed and applied in the frame of the project RegioPower with focus on the case study region 'Oberes Elbtal-Osterzgebirge'. The data for our study was taken from forest management planning at level of the Federal State of Saxony, Germany. Here, a silvicultural system is implemented, which describes best practices to develop our actual forests into Climate Change adapted forest development types. That includes the selection of drought resistant tree species, a broad range of tree species mixtures per eligible forest development type and the tending, harvesting and regeneration strategies to be applied. This information however, exists only for forest areas and not for areas which could be potentially afforested. The eligibility of the forest development types within the actual forest areas depends on site information, such as nutrient potential, exposition and hydrological soil parameters. The regionalisation of the forest development types to landscape scale had to be based on topographical parameters from the digital elevation model and hydrological soil parameters from soil mapping. In result, we could provide maps for regional planning and decision making with spatially explicit information on the eligible forest development types based on forest management planning information. These maps form a valuable input for testing and optimising afforestation areas with regard to improving the ability of our case study region to mitigate Climate Change effects such as water erosion or drought. 23557926 Prevalence and mechanisms of resistance to carbapenems in Enterobacteriaceae isolates from 24 hospitals in Belgium. To determine the point prevalence of carbapenem-non-susceptible Enterobacteriaceae (CNSE) and carbapenemase-producing Enterobacteriaceae (CPE) isolates among hospitalized patients in Belgium. Twenty-four hospital-based laboratories prospectively collected 200 non-duplicated Enterobacteriaceae isolates from clinical specimens of hospitalized patients over a 2 month period. All isolates were screened locally for decreased susceptibility to carbapenem drugs using a disc diffusion method according to CLSI interpretative criteria. CNSE strains were referred centrally for confirmation of carbapenemase by phenotypic and molecular testing. From February to April 2012, 158 of the 4564 screened Enterobacteriaceae isolates were categorized as non-susceptible to carbapenems, resulting in a point prevalence of CNSE of 3.5% (95% CI: 2.9%-4.2%; range per centre: 0.5%-8.5%). Of the 125 referred CNSE isolates, 11 Klebsiella pneumoniae isolates [OXA-48 (n = 7), KPC type (n = 3) and NDM type (n = 1)], 1 OXA-48-positive Escherichia coli isolate and 1 KPC-positive Klebsiella oxytoca isolate were detected in eight hospitals. None of the 72 carbapenem-non-susceptible Enterobacter spp. isolates were confirmed as CPE. The minimal estimated point prevalence of CPE isolates was 0.28% (13/4564; 95% CI: 0.13%-0.44%) overall (range per centre: 0%-1.5%). Despite the overall low prevalence of CNSE found in this study, the detection of CPE isolates in one-third of the participating centres raises concerns and highly suggests the spread and establishment of CPE in Belgian hospitals. 23262027 Glast-expressing progenitor cells contribute to heterotopic ossification. Heterotopic ossification (HO), acquired or hereditary, is the formation of true bone outside the normal skeleton. Although the lineages of cells contributing to bone formation during normal development are well defined, the precise lineages of cells that contribute to HO are not clear. This study utilized Cre-lox based genetic lineage tracing to examine the contribution to HO of cells that expressed either FoxD1 or Glast. Both lineages contributed broadly to different normal tissues, and FoxD1-cre labeled cells contributed to normal bone formation. Despite the similarity in labeling patterns of normal tissues, and the significant contribution of FoxD1-cre labeled cells to normal bone, only Glast-creERT labeled progenitors contributed significantly to HO at all stages, suggesting that the cell populations that normally contribute to physiological bone formation, such as the Foxd1-cre labeled cells, may not participate in pathological HO. Further, identification of Glast-expressing cells as precursors that give rise to HO should help with the molecular targeting of this population both for the prevention and for the treatment of HO. 23927681 P(1) /P(2) genotyping of known and novel null alleles in the P1PK and GLOB histo-blood group systems. The rare but clinically important null phenotypes of the P1PK and GLOB blood group systems are due to alterations in A4GALT and B3GALNT1, respectively. A recently identified single-nucleotide polymorphism in Exon 2a of A4GALT predicts the common P1 and P2 phenotypes but rare variants have not been tested. The aim of this study was to analyze 84 p, P1 (k) , and P2 (k) samples, with special emphasis on unknown alleles and the P(1) /P(2) marker. Of these, 27 samples came from individuals not previously investigated genetically and were therefore subjected to sequencing of A4GALT or B3GALNT1, and a subset was tested by flow cytometry. The P(1) /P(2) genotyping linked 20 p-inducing mutations in A4GALT to P(1) or P(2) allelic background. Eight p alleles remain unlinked due to compound heterozygosity. For 23 of 25 P(k) samples, concordant results were observed: P1 (k) samples had at least one P(1) allele while P2 (k) had P(2) only. The two remaining samples typed as P1+ and P1+(w) but were genetically P(2) /P(2) . A tendency toward higher P(k) antigen expression was observed on P1 (k) cells compared to P2 (k) . In total, six previously unknown null mutations were found and characterized in A4GALT while four new changes were revealed in B3GALNT1. For the first time, p alleles were shown to occur on both P(1) and P(2) allelic backgrounds. Furthermore, P(1) /P(2) genotyping predicted the P1 (k) versus P2 (k) phenotype in more than 90% of globoside-deficient samples. The number of GLOB-null alleles was increased by 50% and several P1PK-null alleles were identified. 23344718 Implicit chaining in cotton-top tamarins (Saguinus oedipus) with elements equated for probability of reinforcement. Three experiments examined the implicit learning of sequences under conditions in which the elements comprising a sequence were equated in terms of reinforcement probability. In Experiment 1 cotton-top tamarins (Saguinus oedipus) experienced a five-element sequence displayed serially on a touch screen in which reinforcement probability was equated across elements at .16 per element. Tamarins demonstrated learning of this sequence with higher latencies during a random test as compared to baseline sequence training. In Experiments 2 and 3, manipulations of the procedure used in the first experiment were undertaken to rule out a confound owing to the fact that the elements in Experiment 1 bore different temporal relations to the intertrial interval (ITI), an inhibitory period. The results of Experiments 2 and 3 indicated that the implicit learning observed in Experiment 1 was not due to temporal proximity between some elements and the inhibitory ITI. The results taken together support two conclusion: First that tamarins engaged in sequence learning whether or not there was contingent reinforcement for learning the sequence, and second that this learning was not due to subtle differences in associative strength between the elements of the sequence. 23597306 Jejunal morphology and blood metabolites in tail biting, victim and control pigs. Tail biting has several identified feeding-related risk factors. Tail biters are often said to be lighter and thinner than other pigs in the pen, possibly because of nutrition-related problems such as reduced feed intake or inability to use nutrients efficiently. This can lead to an increase in foraging behavior and tail biting. In this study, a total of 55 pigs of different ages were selected according to their tail-biting behavior (bouts/hour) and pen-feeding system to form eight experimental groups: tail-biting pigs (TB), victim pigs (V) and control pigs from a tail-biting pen (Ctb) and control pen (Cno) having either free access to feed with limited feeding space or meal feeding from a long trough. After euthanasia, a segment of jejunal cell wall was cut from 50 cm (S50) and 100 cm (S100) posterior to the bile duct. Villus height, crypt depth and villus : crypt ratio (V : C) were measured morphometrically. Blood serum concentration of minerals and plasma concentration of amino acids (AA) was determined. Villus height was greater in Cno than Ctb pigs in the proximal and mid-jejunum (P < 0.05), indicative of better ability to absorb nutrients, and increased with age in the proximal jejunum (P < 0.001). Serum mineral concentration of inorganic phosphate (Pi) and calcium (Ca) was lower in Ctb compared with Cno pigs, and that of Pi in V compared with all the other pigs. Many non-essential AA were lower in pigs from tail-biting pens, and particularly in victim pigs. Free access feeding with shared feeding space was associated with lower levels of essential AA in blood than meal feeding with simultaneous feeding space. Our data suggest that being a pig in a tail-biting pen is associated with decreased jejunal villus height and blood AA levels, possibly because of depressed absorption capacity, feeding behavior or environmental stress associated with tail biting. Victim pigs had lower concentrations of AA and Pi in plasma, possibly as a consequence of being bitten. 23819559 Reactivity of TEMPO toward 16- and 17-Electron Organometallic Reaction Intermediates: A Time-Resolved IR Study. The (2,2,6,6-tetramethylpiperidin-1-yl)oxyl radical (TEMPO) has been employed for an extensive range of chemical applications, ranging from organometallic catalysis to serving as a structural probe in biological systems. As a ligand in an organometallic complex, TEMPO can exhibit several distinct coordination modes. Here we use ultrafast time-resolved infrared spectroscopy to study the reactivity of TEMPO toward coordinatively unsaturated 16- and 17-electron organometallic reaction intermediates. TEMPO coordinates to the metal centers of the 16-electron species CpCo(CO) and Fe(CO)4, and to the 17-electron species CpFe(CO)2 and Mn(CO)5, via an associative mechanism with concomitant oxidation of the metal center. In these adducts, TEMPO thus behaves as an anionic ligand, characterized by a pyramidal geometry about the nitrogen center. Density functional theory calculations are used to facilitate interpretation of the spectra and to further explore the structures of the TEMPO adducts. To our knowledge, this study represents the first direct characterization of the mechanism of the reaction of TEMPO with coordinatively unsaturated organometallic complexes, providing valuable insight into its reactions with commonly encountered reaction intermediates. The similar reactivity of TEMPO toward each of the species studied suggests that these results can be considered representative of TEMPO's reactivity toward all low-valent transition metal complexes. 23881342 Transient pseudo-hypertriglyceridemia: a useful biochemical marker of fructose-1,6-bisphosphatase deficiency. Fructose-1,6-bisphosphatase (FBP) deficiency is an autosomal-recessive disorder of gluconeogenesis resulting from mutations within the FBP1 gene. During periods of trivial illness, individuals with FBP deficiency may develop ketotic hypoglycemia, metabolic acidosis, lactic acidemia, and an increased anion gap. Although detection of urinary excretion of glycerol by urine organic acid analysis has been previously described, the presence of transient pseudo-hypertriglyceridemia in serum during metabolic decompensation has not been reported before. This study describes four consanguineous Pakistani families, in which four patients were diagnosed with FBP deficiency. All showed transient pseudo-hypertriglyceridemia during the acute phase of metabolic decompensation, which resolved in a metabolically stable phase. Mutations in the FBP1 gene have been described from various ethnicities, but there is very limited literature available for the Pakistani population. This study also describes one novel mutation in the FBP1 gene which seems to be prevalent in Pakistani-Indian patients. Conclusion: As a result of this study, transient pseudo-hypertriglyceridemia should be added to glyceroluria, ketotic hypoglycemia, metabolic acidosis, and lactic acidosis as a useful biochemical marker of FBP deficiency. 23855265 Evidence-based paramedic models of care to reduce unnecessary emergency department attendance--feasibility and safety. As demand for Emergency Department (ED) services continues to exceed increases explained by population growth, strategies to reduce ED presentations are being explored. The concept of ambulance paramedics providing an alternative model of care to the current default 'see and transport to ED' has intuitive appeal and has been implemented in several locations around the world. The premise is that for certain non-critically ill patients, the Extended Care Paramedic (ECP) can either 'see and treat' or 'see and refer' to another primary or community care practitioner, rather than transport to hospital. However, there has been little rigorous investigation of which types of patients can be safely identified and managed in the community, or the impact of ECPs on ED attendance. St John Ambulance Western Australia paramedics will indicate on the electronic patient care record (e-PCR) of patients attended in the Perth metropolitan area if they consider them to be suitable to be managed in the community. 'Follow-up' will examine these patients using ED data to determine the patient's disposition from the ED. A clinical panel will then develop a protocol to identify those patients who can be safely managed in the community. Paramedics will then assess patients against the derived ECP protocols and identify those deemed suitable to 'see and treat' or 'see and refer'. The ED disposition (and other clinical outcomes) of these 'ECP protocol identified' patients will enable us to assess whether it would have been appropriate to manage these patients in the community. We will also 'track' re-presentations to EDs within seven days of the initial presentation. This is a 'virtual experiment' with no direct involvement of patients or changes in clinical practice. A systems modelling approach will be used to assess the likely impact on ED crowding. To date the efficacy, cost-effectiveness and safety of alternative community-based models of emergency care have not been rigorously investigated. This study will inform the development of ECP protocols through the identification of types of patient presentation that can be considered both safe and appropriate for paramedics to manage in the community. 23943272 Natural cooperators: Food sharing in humans and other primates. The study of cooperation is rich with theoretical models and laboratory experiments that have greatly advanced our knowledge of human uniqueness, but have sometimes lacked ecological validity. We therefore emphasize the need to tie discussions of human cooperation to the natural history of our species and its closest relatives, focusing on behavioral contexts best suited to reveal underlying selection pressures and evolved decision rules. Food sharing is a fundamental form of cooperation that is well-studied across primates and is particularly noteworthy because of its central role in shaping evolved human life history, social organization, and cooperative psychology. Here we synthesize available evidence on food sharing in humans and other primates, tracing the origins of offspring provisioning, mutualism, trade, and reciprocity throughout the primate order. While primates may gain some benefits from sharing, humans, faced with more collective action problems in a risky foraging niche, expanded on primate patterns to buffer risk and recruit mates and allies through reciprocity and signaling, and established co-evolving social norms of production and sharing. Differences in the necessity for sharing are reflected in differences in sharing psychology across species, thus helping to explain unique aspects of our evolved cooperative psychology. 23212442 The role of native salinity regime on grass shrimp (Palaemonetes pugio) sensitivity to cadmium. In euryhaline crustaceans, sensitivity to toxic trace metals may be linked to osmoregulation and salinity conditions. This study investigated if grass shrimp (Palaemonetes pugio) populations from different salinity regimes differed in sensitivity to cadmium (Cd). Grass shrimp were collected in May 2011 from two marsh sites with average salinities of ~3.0 ppt and 24.0 ppt. Groups were acclimated for 3-32 weeks in either their respective native salinity (3.0 ppt → 3.0 ppt and 24.0 ppt → 24.0 ppt), or the average of the salinities of the two collection sites (3.0 ppt → 13.5 ppt and 24.0 ppt → 13.5 ppt). After acclimation, groups were exposed to equivalent free-ion Cd concentration (4.8 ± 0.3 mg/L, Cd(2+)) in their respective acclimated salinity to compare survival among salinity treatments. Results of Kaplan-Meier survival analysis indicated that 3.0 ppt → 3.0 ppt shrimp were more sensitive to Cd(2+) than any other group (p < 0.0001). Additionally, 3.0 ppt → 13.5 ppt shrimp were less sensitive to Cd(2+) than were 24.0 ppt → 13.5 ppt shrimp (p = 0.0013). These results suggest that sensitivity of grass shrimp to Cd is dependent upon the salinity during exposure, and the salinity regime from which the tested population originated. The implication is that toxicity studies and risk assessments using euryhaline crustaceans should consider the salinity of test population collection sites when interpreting and comparing results. 23868910 Plasma Lipid Profiling in a Large Population Based Cohort. We have performed plasma lipid profiling using liquid chromatography electrospray ionisation tandem mass spectrometry on a population cohort of more than 1000 individuals. From 10 uL of plasma we were able to acquire comparative measures of 312 lipids across 23 lipid classes and subclasses including sphingolipids, phospholipids glycerolipids and cholesterol esters, in 20 minutes. Using linear and logistic regression we identified statistically significant associations of lipid classes, subclasses and individual lipid species with anthropometric and physiological measures. In addition to the expected associations of cholesterol ester and triacylglycerol with age, sex and body mass index, ceramide was significantly higher in males and was independently associated with age and body mass index. Associations were also observed for sphingomyelin with age but this lipid subclass was lower in males. Lysophospholipids were associated with age and higher in males, but showed a strong negative association with body mass index. Many of these lipids have previously been associated with chronic diseases including cardiovascular disease and may mediate the interactions of age, sex and obesity with disease risk. 23961700 pH effects on the molecular structure of β-Lactoglobulin modified air-water interfaces and its impact on foam rheology. Macroscopic properties of aqueous β-lactoglobulin (BLG) foams and the molecular properties of BLG modified air-water interfaces as their major structural element were investigated with a unique combination of foam rheology measurements and interfacial sensitive methods such as sum-frequency generation and interfacial dilatational rheology. The molecular structure and protein-protein interactions at the air-water interface can be changed substantially with the solution pH and result in major changes in interfacial dilational and foam rheology. At a pH near the interfacial isoelectric point BLG molecules carry zero net charge and disordered multilayers with the highest interfacial dilatational elasticity are formed at the air-water interface. Increasing or decreasing the pH with respect to the isoelectric point leads to the formation of a BLG monolayer with repulsive electrostatic interactions among the adsorbed molecules which decrease the interfacial dilational elasticity. The latter molecular information does explain the behaviour of BLG foams in our rheological studies, where in fact the highest apparent yield stresses and storage moduli are established with foams from electrolyte solutions with a pH close to the isoelectric point of BLG. At this pH the gas bubbles of the foam are stabilized by BLG multilayers with attractive intermolecular interactions at the ubiquitous air-water interfaces, while BLG layers with repulsive interactions decrease the apparent yield stress and storage moduli as stabilization of gas bubbles with a monolayer of BLG is less effective. 23937750 Quality of information on the internet about carpal tunnel syndrome: an update. The use of the Internet for health-related information has increased significantly. In 2000, the current authors examined the source and content of orthopedic information on the Internet. At that time, Internet information regarding carpal tunnel syndrome was found to be of limited quality and poor informational value. The purposes of the current study were to reevaluate the type and quality of information on the Internet regarding carpal tunnel syndrome and to determine whether the quality of information available has improved compared with 1 decade ago. The phrase carpal tunnel syndrome was entered into the 5 most commonly used Internet search engines. The top 50 nonsponsored and the top 5 sponsored universal resource locators identified by each search engine were collected. Each unique Web site was evaluated for authorship and content, and an informational score ranging from 0 to 100 points was assigned. Approximately one-third of nonsponsored Web sites were commercial sites or selling commercial products. Seventy-six percent of sponsored sites were selling a product for the treatment of carpal tunnel syndrome. Thirty-eight percent of nonsponsored sites provided unconventional information, and 48% of sponsored sites provided misleading information. Just more than half of nonsponsored sites were authored by a physician or academic institution. The informational mean score was 53.8 points for nonsponsored sites and 14.5 points for sponsored sites. The informational quality on the Internet on carpal tunnel syndrome has improved over the past decade. Despite this progress, significant room exists for improvement in the quality and completeness of the information available. 23910067 Chemotherapy Outcomes by Histologic Subtypes of Non-Small-Cell Lung Cancer: Analysis of the Southwest Oncology Group Database for Antimicrotubule-Platinum Therapy. Histologic subtyping has been advocated to select chemotherapy for patients with advanced-stage non-small-cell lung cancer (NSCLC). To determine whether histologic subtype was associated with efficacy for the commonly used antimicrotubule (AMT) agents, paclitaxel, docetaxel, and vinorelbine plus a platinum compound, we examined the Southwest Oncology Group (SWOG) lung cancer database. Data from 4 randomized trials (S9308, S9509, S9806, and S0003) administering an AMT agent plus platinum in patients receiving first-line treatment for advanced-stage NSCLC were analyzed. Overall survival (OS) and progression-free survival (PFS) comparisons were performed using Cox proportional hazard regression, adjusting for sex. Median survival times were estimated by Kaplan-Meier. Of 1146 patients included in this analysis, 640 had adenocarcinoma (56%), 220 had squamous cell carcinoma (19%), 121 had large cell carcinoma (11%), and 165 had NSCLC not otherwise specified (NOS) (14%). Median OS times by histologic subtypes were 8.5, 8.4, 8.2, and 9.6 months, respectively, and median PFS times were 4.2, 4.3, 4.3, and 4.6 months, respectively. No difference in OS or PFS was observed by histologic subtype and, specifically, between nonsquamous and squamous histologies. This pooled analysis from 4 SWOG trials using an AMT-platinum regimen did not show a difference in survival outcomes by histologic subtype. Because the majority of patients with advanced NSCLC continue to receive chemotherapy, defining molecular-based predictive markers of responsiveness is warranted. 23918528 Osteogenesis imperfecta in adults: phenotypic characteristics and response to treatment in an Irish cohort. Osteogenesis imperfecta (OI) is a heritable disorder of variable phenotype that is characterised by bone fragility and frequent fractures, with deformities and short stature in more severe cases. We sought to review the response to treatment in a cohort of adult patients with OI. Charts of 16 patients with OI attending a metabolic bone disease clinic were reviewed, particularly with respect to the response to treatment using bisphosphonates and recombinant human parathyroid hormone (rhPTH). The response to treatment was assessed by monitoring bone mineral density (BMD) and bone turnover markers (BTMs). In response to bisphosphonate therapy, median (range) BMD increased at the spine by 15.1(6.9-43.7) %. In response to rhPTH in 2 cases, spinal BMD increased by 40.3 and 27.2 %. OI is debilitating disorder, but the course of the disease may be altered by treatment that increases BMD such as bisphosphonates and rhPTH. Both serial BMD and BTM aid in assessing response to intervention. Further study is needed with regard to fracture prevention. 23066091 β-Adrenergic agonists mediate enhancement of β1-adrenergic receptor N-terminal cleavage and stabilization in vivo and in vitro. The β(1)-adrenergic receptor (β(1)AR) is the predominant βAR in the heart and is the main target for β-adrenergic antagonists, widely used in the treatment of cardiovascular diseases. Previously, we have shown that the human (h) β(1)AR is cleaved in its N terminus by a metalloproteinase, both constitutively and in a receptor activation-dependent manner. In this study, we investigated the specific events involved in β(1)AR regulation, focusing on the effects of long-term treatment with β-adrenergic ligands on receptor processing in stably transfected human embryonic kidney 293(i) cells. The key findings were verified using the transiently transfected hβ(1)AR and the endogenously expressed receptor in neonatal rat cardiomyocytes. By using flow cytometry and Western blotting, we demonstrated that isoproterenol, S-propranolol, CGP-12177 [4-[3-[(1,1-dimethylethyl)amino]2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one], pindolol, and timolol, which displayed agonistic properties toward the β(1)AR in either the adenylyl cyclase or the mitogen-activated protein kinase signaling pathways, induced cleavage of the mature cell-surface receptor. In contrast, metoprolol, bisoprolol, and CGP-20712 [1-[2-((3-carbamoyl-4-hydroxy)phenoxy)ethylamino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl)phenoxy]-2-propanol], which showed no agonistic activity, had only a marginal or no effect. Importantly, the agonists also stabilized intracellular receptor precursors, possibly via their pharmacological chaperone action, and they stabilized the receptor in vitro. The opposing effects on the two receptor forms thus led to an increase in the amount of cleaved receptor fragments at the plasma membrane. The results underscore the pluridimensionality of β-adrenergic ligands and extend this property from receptor activation and signaling to the regulation of β(1)AR levels. This phenomenon may contribute to the exceptional resistance of β(1)ARs to downregulation and tendency toward upregulation following long-term ligand treatments. 23622974 Antithrombotic drugs are risk factors for delayed postoperative bleeding after endoscopic submucosal dissection for gastric neoplasms. The discontinuation of antithrombotic drugs is recommended during endoscopic submucosal dissection (ESD) for gastric neoplasms; however, controversy remains as to whether antithrombotic drugs are risk factors for postoperative bleeding. To determine the risk factors for post-ESD bleeding. Single-institution, retrospective review. University hospital. From June 2000 to December 2010, we treated 1192 gastric neoplasms in 1032 consecutive patients. The ESD procedures were performed by using the standard techniques. Antithrombotic drug therapy was principally interrupted preoperatively and was restarted when hemostasis was confirmed by second-look endoscopy. Risk factors for postoperative bleeding after ESD (early, delayed, and overall [combined] occurrence of bleeding during the first 5 postoperative days or thereafter) were analyzed by using logistic regression analysis. Among 1166 ESD-induced ulcer lesions, overall postoperative bleeding was evident in 62 lesions (5.3%); early and delayed bleeding occurred in 30 and 32 lesions (2.6% and 2.7%), respectively. Based on a multivariate analysis, a specimen size of >40 mm was the sole independent risk factor for overall bleeding. Moreover, oral antithrombotic drug therapy was selected as independent risk factor for delayed but not early bleeding, according to the multivariate analysis. The delayed bleeding rate in patients who had a specimen size of >40 mm and who used antithrombotic drugs was 11.6%. Retrospective design and single-site data collection. Interruption of antithrombotic drug therapy may be adequate for preventing early post-ESD bleeding; however, reinitiating antithrombotic drug therapy is a significant independent risk factor for delayed post-ESD bleeding. 23920032 Cancer Risk Following Resection of Polypoid Dysplasia in Patients with Long-Standing Ulcerative Colitis: a Meta-Analysis. American and European guidelines propose complete endoscopic resection of polypoid dysplasia (adenomas or adenoma-like masses) in patients with long-standing colitis, with close endoscopic follow up. The incidence of cancer following detection of flat low-grade dysplasia or adenoma-like masses is estimated at 14 cases /1000 y of patient follow up. However, the risk for polypoid dysplasia has not been determined with precision. We investigated the risk of cancer following endoscopic resection of polypoid dysplasia in patients with ulcerative colitis. MEDLINE, EMBASE, PubMed, and the Cochrane library were searched for studies of patients with colitis and resected polypoid dysplasia, with reports of colonoscopic follow up and data on cancers detected. Outcomes from included articles were pooled to provide a single combined estimate of outcomes using Poisson regression. Of 425 articles retrieved, we analyzed data from 10 studies, comprising 376 patients with colitis and polypoid dysplasia with a combined 1704 y of follow up. A median of 2.8 colonoscopies were performed for each patient the index procedure (range, 0-15 colonoscopies). The pooled incidence of cancer was 5.3 cases (95% confidence interval, 2.7-10.1 cases) /1000 y of patient follow up. There was no evidence of heterogeneity or publication bias. The pooled rate of any dysplasia was 65 cases (95% confidence interval, 54-78 cases) /1000 patient y. Patients with colitis have a low risk of colorectal cancer following resection of polypoid dysplasia; these findings support the current strategy of resection and surveillance. However, these patients have a 10-fold greater risk of developing any dysplasia than CRC, and should undergo close endoscopic follow up. 23664943 Classic EEG motor potentials track the emergence of value-based decisions. Making a value-based decision is a cognitively complex phenomenon and divisible into several sub-processes, such as the perception, evaluation, and final selection of choice options. Although previous research has attempted to dissociate these processes in the brain, there is emerging evidence that late action selection mechanisms are influenced continuously throughout the entire decision act. We used electroencephalography (EEG) and an established sequential decision making paradigm to investigate the extent to which the readiness potential (RP) and the lateralized readiness potential (LRP), two classic preparatory EEG motor components, reflect the ongoing evaluation process in value-based choices. During the task, human participants sequentially sampled probabilistic information to buy or reject offers of unknown value (using both hands) and were allowed to respond at any time. The pressure to respond was manipulated by charging low or high costs for collecting information. We modeled how and when decisions were made and found that participants adaptively lowered their threshold for required evidence with information costs and elapsed time. These shifts were accompanied by an increased RP-like signal during the decision process. The RP was further influenced by the amount of accumulated evidence. In addition, an LRP could be measured from the start of the decision process, well in advance and independent of the final decision. Our results are consistent with a continuous involvement of the brain's motor system in emerging value-based decisions and advocate using classic EEG motor potentials for studying neurocognitive theories of decision making. 23884694 Elevated ornithine decarboxylase activity promotes skin tumorigenesis by stimulating the recruitment of bulge stem cells but not via toxic polyamine catabolic metabolites. Elevated expression of ornithine decarboxylase (ODC), the regulatory enzyme in polyamine biosynthesis, targeted to the epidermis is sufficient to promote skin tumor development following a single subthreshold dose of dimethylbenz(a)anthracene (DMBA). Since skin tumor promotion involves recruitment of hair follicle bulge stem cells harboring genetic lesions, we assessed the effect of increased epidermal ODC on recruitment of bulge stem cells in ODC-ER transgenic mice in which ODC activity is induced de novo in adult skin with 4-hydroxytamoxifen (4OHT). Bromodeoxyuridine-pulse labeling and use of K15.CrePR1;R26R;ODC-ER triple transgenic mice demonstrated that induction of ODC activity is sufficient to recruit bulge stem cells in quiescent skin. Because increased ODC activity not only stimulates proliferation but also increases reactive oxygen species (ROS) generation via subsequent induction of polyamine catabolic oxidases, we used an inhibitor of polyamine catabolic oxidase activity, MDL72527, to investigate whether ROS generation by polyamine catabolic oxidases contributes to skin tumorigenesis in DMBA-initiated ODC-ER transgenic skin. Newborn ODC-ER transgenic mice and their normal littermates were initiated with a single topical dose of DMBA. To assess tumor development originating from dormant bulge stem cells that possess DMBA-initiated mutations, epidermal ODC activity was induced in ODC-ER mice with 4OHT 5 weeks after DMBA initiation followed by MDL72527 treatment. MDL72527 treatment resulted in a shorter tumor latency time, increased tumor burden, increased conversion to carcinomas, and lower tumor levels of p53. Thus, elevated epidermal ODC activity promotes tumorigenesis by stimulating the recruitment of bulge stem cells but not via ROS generation by polyamine catabolic oxidases. 23875660 Current, new and novel therapy for castration-resistant prostate cancer. Androgen deprivation therapy is the standard of care for the initial treatment of metastatic prostate cancer. However, the majority of these patients live long enough to experience disease progression despite castration. This scenario is defined as castration-resistant prostate cancer (CRPC) and has a poor outcome and limited options for treatment. First-line treatment after hormonal therapy failure include secondary hormonal manipulation and docetaxel. Advances in the understanding of the molecular mechanisms underlying CRPC have translated into a recent increase in the number of effective systemic agents, and some of them have been already approved as first and second-line treatment. Despite these advances, the median survival in the first-line setting of metastatic CRPC is approximately 20 months and in the postdocetaxel setting is approximately 15 months. Promising and necessary new therapies in Phase III trials include hormonal agents, new cytotoxics agents, as well as other immunotherapeutics and antiprostate-specific membrane antigen therapies. 23838120 Challenges to Traditional Clinical Definitions of Depression in Young Black Men. Despite high rates of unemployment, incarceration, violence, and suicide experienced by young Black men in America, research conducted in inner-city environments consistently report nonsignificant levels of depression among Black men. The unique history of social exclusion, stereotyping, and discrimination experienced by Black men has significant implications for the accurate assessment of depression. A review of significant historical and current sociological, educational, and legal-justice circumstances that affect the mental health of young Black men is presented. Barriers and limitations to traditional depression assessment and measurement is discussed and followed by recommendations for advancing knowledge of depression in young Black men. Research and practice that seeks to explore and explain sociocultural variances in traditional definitions of depression among young Black men will improve mental health, mental health outreach, and social function in this population. 23194530 Development and validation of an HPLC method for the determination of six penicillin and three amphenicol antibiotics in gilthead seabream (Sparus Aurata) tissue according to the European Union Decision 2002/657/EC. A confirmatory high performance liquid chromatography method for the determination of six penicillin antibiotics and three amphenicol antibiotics in gilthead seabream (Sparus Aurata) tissue was developed. Ampicillin (AMP), penicillin G (PG), penicillin V (PV), oxacillin (OXA), cloxacillin (CLO), dicloxacillin (DICLO), thiamphenicol (TAP), florfenicol (FFC) and chloramphenicol (CAP) were separated on an Inertsil, C(8) (250×4 mm, 5 μm) column by gradient elution with a mobile phase consisting of ammonium acetate 0.05 M and acetonitrile at 25°C. Diode array detection with monitoring at 225 nm (for the determination of AMP, PG, PV, TAP and FFC), 240 nm (for OXA, CLO and DICLO) and 278 nm (for CAP) was applied. Examined antibiotics were isolated from gilthead seabream tissue by liquid-liquid extraction and further clean-up was performed by solid phase extraction using Oasis HLB (200 mg/6 mL) cartridges. The developed method was fully validated in terms of selectivity, linearity, accuracy, precision, stability and sensitivity according to the European Union Decision 2002/657/EC. 23859492 The incidence of acute pancreatitis: impact of social deprivation, alcohol consumption, seasonal and demographic factors. The incidence of acute pancreatitis has increased sharply in many European countries and the USA in recent years. To establish trends in incidence and mortality for acute pancreatitis in Wales, UK, and to assess how incidence may be linked to factors including social deprivation, seasonal effects and alcohol consumption. Use of record linked inpatient, mortality and primary care data for 10 589 hospitalised cases of acute pancreatitis between 1999 and 2010. The incidence of acute pancreatitis was 30.0 per 100 000 population overall, mortality was 6.4% at 60 days. Incidence increased significantly from 27.6 per 100 000 in 1999 to 36.4 in 2010 (average annual increase = 2.7% per year), there was little trend in mortality (0.2% average annual reduction). The largest increases in incidence were among women aged <35 years (7.9% per year) and men aged 35-44 (5.7%) and 45-54 (5.3%). Incidence was 1.9 times higher among the most deprived quintile of patients compared with the most affluent (3.9 times higher for alcoholic acute pancreatitis and 1.5 for gallstone acute pancreatitis). Acute pancreatitis was increased significantly during the Christmas and New Year weeks by 48% (95% CI = 24-77%) for alcoholic aetiology, but not for gallstone aetiology (9%). Alcoholic admissions were increased with higher consumption of spirits and beer, but not wine. The study shows an elevated rate of alcoholic acute pancreatitis during the Christmas and New Year period. Acute pancreatitis continues to rise, most rapidly for young women, while alcoholic acute pancreatitis is linked strongly with social deprivation. 23950108 A Biomechanical Analysis of Controllable Intraoperative Variables Affecting the Strength of Rotator Cuff Repairs at the Suture-Tendon Interface. BACKGROUND:The tissue-suture interface remains the weakest aspect of a rotator cuff repair, highlighting the importance of identifying techniques to improve stitch strength. Choice of suture-passing devices, size of the tissue bite, and stitch configuration are variables that may influence stitch strength and therefore repair stability. PURPOSE:To evaluate the effect that size of the tissue penetrator device and tissue bite size have upon the holding strength of commonly used stitches. STUDY DESIGN:Controlled laboratory study. METHODS:Three different-sized tissue-penetrating devices, small circular, midsized circular, and large rectangular, were used to place sutures in 192 infraspinatus tendon grafts of sheep. Tissue bite sizes of either 0.5 cm or 1.0 cm for 4 different stitches, a simple, mattress, modified Mason-Allen (MMA), and massive cuff (MAC) stitch, were tested. Grafts were cyclically loaded and then loaded to failure. Mixed multivariate regression analysis was used to test the effect of instrument, bite size, and stitch configuration on peak-to-peak displacement, cyclic elongation, and load to failure. RESULTS:The average ultimate load to failure with the smallest penetrating device was 112 N, significantly higher than with both the midsized (95 N) and large devices (91 N) (P < .001). The average load to failure was 31 N higher for a 1.0-cm bite size when compared with a 0.5-cm bite size (P < .001). The largest load-to-failure differences were found with the type of stitch placed: simple, 48 N; mattress, 69 N; MMA, 130 N; and MAC, 152 N (all P < .02). For simple and mattress stitches, each additional pass of the suture increased the load to failure by 21 N. In MMA and MAC stitches, an additional pass resulted in an increase in the load to failure by 50 N. Cyclic elongation did not differ by instrument type (all P > .5). The elongation of stitches with a 1.0-cm bite size was 0.14 mm higher than stitches with a 0.5-cm bite size (P < .001). No meaningful difference in peak-to-peak displacement was seen for bite size, instrument type, or stitch construct. CONCLUSION:The strength of rotator cuff stitches was significantly affected by the different-sized tissue-penetrating instruments and size of the bite. However, the greatest predictor of time-zero stitch strength is the type of stitch placed. CLINICAL RELEVANCE:This study highlights the importance of stitch configuration in the repair of rotator cuff tears. 23553997 Impact of Phytolacca americana Extracts on Gene Expression of Colon Cancer Cells. Native Americans have used Phytolacca americana to treat breast ailments, gastrointestinal disorders, rashes, and inflammation. Some anti-cancer and anti-viral research has been reported on this perennial herb, but none has been published concerning the effects of its extracts on cancer cell genes. In this study, changes in gene expression at the transcription level were evaluated in HCT-116 colon cancer cells after exposure to P. americana ethanol extract and its water fraction using the Human Cancer Pathway Finder PCR Array. Of the genes significantly affected in HCT-116 cells exposed to the ethanol extract at 3200 µg/ml, changes in expression of MYC, PLAU, and TEK may benefit the treatment of colon cancer. Exposing the cells to 1600 µg/ml of the water fraction resulted in several gene changes that may also be beneficial in the treatment of colon cancer: NME4, TEK, and THBS1. A few genes on this array that are known to play a specific role in colon cancer had activities changed in a way that may be detrimental in the treatment of colon cancer. Further studies should be performed to understand how these changes would impact colon cancer treatment. Copyright © 2013 John Wiley & Sons, Ltd. 23822195 Markovnikov-Selective Hydrothiolation of Styrenes: Application to the Synthesis of Stereodefined Trisubstituted Olefins. BT-sulfones react with aromatic aldehydes to furnish trisubstituted alkenes with excellent Z stereoselectivity. These sulfones are synthesized by hydrothiolation of styrene and styrenyl derivatives (followed by oxidation). This method provides a conceptually novel way to prepare these important sulfur compounds. 23751331 Application of bacterial lipopolysaccharide to improve survival of the black tiger shrimp after Vibrio harveyi exposure. This study investigates an effect of bacterial lipopolysaccharide (LPS) as feed supplement to improve immunity of the black tiger shrimp (Penaeus monodon). LPS was coated to commercial feed pellets and given to the shrimp once or twice a day for 10days before an exposure with shrimp pathogenic bacterium Vibrio harveyi. The growth rates, percent weight gains, total hemocyte and granulocyte counts and survival rates of shrimp between the LPS-coated pellet fed groups and a control group where shrimp fed with commercial feed pellets were compared. After 10days of the feeding trials, growth rates were not significantly different in all groups, suggesting no toxicity from LPS supplement. To determine beneficial effect of LPS diets, each group was subsequently exposed to V. harveyi by immersion method and the survival rates were recorded for seven days after the immersion. Regardless of the dosages of LPS, the shrimp groups fed with LPS-coated pellets showed higher survival rates than the control group. There was no significant difference in survival rates between the two LPS dosages groups. In addition to survival under pathogen challenge, we also determine effect of LPS on immune-related genes after 10-day feeding trial. Gene expression analysis in the P. monodon intestines revealed that antilipopolysaccharide factor isoform 3 (ALF3), C-type lectin, and mucine-like peritrophin (mucin-like PM) were expressed significantly higher in a group fed with LPS supplemental diet once or twice a day than in a control group. The transcript levels of C-type lectin and mucin-like PM had increased significantly when LPS was given once a day, while significant induction of ALF3 transcripts was observed when shrimp were fed with LPS twice a day. The up-regulation of the immune gene levels in intestines and higher resistance to V. harveyi of the shrimp fed with LPS provide the evidence for potential application of LPS as an immunostimulant in P. monodon farming. 23461708 Efficacy of pulmonary vein isolation on left atrial function in paroxysmal and persistent atrial fibrillation and the dependency on its baseline function. The effects of pulmonary vein (PV) isolation in atrial fibrillation (AF) on left atrial (LA) function or PV flow have not been well documented. We examined the LA function and PV flow before and 3-6 months after PV isolation in 67 AF patients (34 paroxysmal [PAF] and 33 persistent [CAF]) using transesophageal echocardiography. AF recurred in 6/34 patients with PAF and in 6/33 patients with CAF 6 months after PV isolation. A larger LA dimension, a lower systolic PV flow velocity, and a lower ratio of systolic to diastolic PV flow velocity were related to a higher incidence of AF recurrence. The increment of left atrial appendage (LAA) flow velocity (55% vs. 22%) and systolic PV flow velocity (57% vs. 20%) after PV isolation tended to be greater in CAF than in PAF. The changes in LAA flow velocity had reverse correlations with the baseline values before PV isolation (PAF: r = -0.73, CAF: r = -0.58). The changes in mitral flow velocity during atrial contraction in PAF had reverse correlations with the baseline values before PV isolation (r = -0.84). The changes in systolic and diastolic PV flow velocity of PAF had reverse correlations with the baseline values before PV isolation (r = -0.56, r = -0.66). The baseline LA function may affect AF recurrence as well as the improvement of LA function, and the benefit of successful PV isolation might be greater in CAF than in PAF. 23728619 A homology/ab initio hybrid algorithm for sampling near-native protein conformations. One of the major challenges for protein tertiary structure prediction strategies is the quality of conformational sampling algorithms, which can effectively and readily search the protein fold space to generate near-native conformations. In an effort to advance the field by making the best use of available homology as well as fold recognition approaches along with ab initio folding methods, we have developed Bhageerath-H Strgen, a homology/ab initio hybrid algorithm for protein conformational sampling. The methodology is tested on the benchmark CASP9 dataset of 116 targets. In 93% of the cases, a structure with TM-score ≥ 0.5 is generated in the pool of decoys. Further, the performance of Bhageerath-H Strgen was seen to be efficient in comparison with different decoy generation methods. The algorithm is web enabled as Bhageerath-H Strgen web tool which is made freely accessible for protein decoy generation (http://www.scfbio-iitd.res.in/software/Bhageerath-HStrgen1.jsp). © 2013 Wiley Periodicals, Inc. 23584554 Proteasomal cleavage site prediction of protein antigen using BP neural network based on a new set of amino acid descriptor. The accurate identification of cytotoxic T lymphocyte epitopes is becoming increasingly important in peptide vaccine design. The ubiquitin-proteasome system plays a key role in processing and presenting major histocompatibility complex class I restricted epitopes by degrading the antigenic protein. To enhance the specificity and efficiency of epitope prediction and identification, the recognition mode between the ubiquitin-proteasome complex and the protein antigen must be considered. Hence, a model that accurately predicts proteasomal cleavage must be established. This study proposes a new set of parameters to characterize the cleavage window and uses a backpropagation neural network algorithm to build a model that accurately predicts proteasomal cleavage. The accuracy of the prediction model, which depends on the window sizes of the cleavage, reaches 95.454 % for the N-terminus and 95.011 % for the C-terminus. The results show that the identification of proteasomal cleavage sites depends on the sequence next to it and that the prediction performance of the C-terminus is better than that of the N-terminus on average. Thus, models based on the properties of amino acids can be highly reliable and reflect the structural features of interactions between proteasomes and peptide sequences. 23917333 Clinical marine toxicology: a European perspective for clinical toxicologists and poison centers. Clinical marine toxicology is a rapidly changing area. Many of the new discoveries reported every year in Europe involve ecological disturbances-including global warming-that have induced modifications in the chorology, behavior, and toxicity of many species of venomous or poisonous aquatic life including algae, ascidians, fish and shellfish. These changes have raised a number of public issues associated, e.g., poisoning after ingestion of contaminated seafood, envenomation by fish stings, and exposure to harmful microorganism blooms. The purpose of this review of medical and scientific literature in marine toxicology is to highlight the growing challenges induced by ecological disturbances that confront clinical toxicologists during the everyday job in the European Poison Centers. 23429432 Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype. Wolfram syndrome is a degenerative, recessive rare disease with an onset in childhood. It is caused by mutations in WFS1 or CISD2 genes. More than 200 different variations in WFS1 have been described in patients with Wolfram syndrome, which complicates the establishment of clear genotype-phenotype correlation. The purpose of this study was to elucidate the role of WFS1 mutations and update the natural history of the disease. This study analyzed clinical and genetic data of 412 patients with Wolfram syndrome published in the last 15 years. (i) 15% of published patients do not fulfill the current -inclusion criterion; (ii) genotypic prevalence differences may exist among countries; (iii) diabetes mellitus and optic atrophy might not be the first two clinical features in some patients; (iv) mutations are nonuniformly distributed in WFS1; (v) age at onset of diabetes mellitus, hearing defects, and diabetes insipidus may depend on the patient's genotypic class; and (vi) disease progression rate might depend on genotypic class. New genotype-phenotype correlations were established, disease progression rate for the general population and for the genotypic classes has been calculated, and new diagnostic criteria have been proposed. The conclusions raised could be important for patient management and counseling as well as for the development of treatments for Wolfram syndrome. 23816754 Complex I inhibition in the visual pathway induces disorganization of the node of Ranvier. Mitochondrial defects can have significant consequences on many aspects of neuronal physiology. In particular, deficiencies in the first enzyme complex of the mitochondrial respiratory chain (complex I) are considered to be involved in a number of human neurodegenerative diseases. The current work highlights a tight correlation between the inhibition of complex I and the state of axonal myelination of the optic nerve. Exposing the visual pathway of rats to rotenone, a complex I inhibitor, resulted in disorganization of the node of Ranvier. The structure and function of the node depend on specific cell adhesion molecules, among others, CASPR (contactin associated protein) and contactin. CASPR and contactin are both on the axonal surfaces and need to be associated to be able to anchor their myelin counterpart. Here we show that inhibition of mitochondrial complex I by rotenone in rats induces reactive oxygen species, disrupts the interaction of CASPR and contactin couple, and thus damages the organization and function of the node of Ranvier. Demyelination of the optic nerve occurs as a consequence which is accompanied by a loss of vision. The physiological impairment could be reversed by introducing an alternative NADH dehydrogenase to the mitochondria of the visual system. The restoration of the nodal structure was specifically correlated with visual recovery in the treated animal. 23337530 Anagliptin, a DPP-4 inhibitor, suppresses proliferation of vascular smooth muscles and monocyte inflammatory reaction and attenuates atherosclerosis in male apo E-deficient mice. Dipeptyl peptidase-4 (DPP-4) inhibitors modulate the progression of atherosclerosis. To gain insights into their mechanism of action, 9-wk-old male apolipoprotein E (apoE)-deficient mice were fed a DPP-4 inhibitor, anagliptin-containing diet. The effects of anagliptin were investigated in, a monocyte cell line, human THP-1 cells, and rat smooth muscle cells (SMCs). Treatment with anagliptin for 16 wk significantly reduced accumulation of monocytes and macrophages in the vascular wall, SMC content in plaque areas, and oil red O-stained area around the aortic valve without affecting glucose tolerance or body weight. Serum DPP-4 concentrations were significantly higher in apoE-deficient mice than control mice, and the levels increased with aging, suggesting the involvement of DPP-4 in the progression of atherosclerosis. Indeed, soluble DPP-4 augmented cultured SMC proliferation, and anagliptin suppressed the proliferation by inhibiting ERK phosphorylation. In THP-1 cells, anagliptin reduced lipopolysaccharide-induced TNF-α production with inhibiting ERK phosphorylation and nuclear translocation of nuclear factor-κB. Quantitative analysis also showed that anagliptin reduced the area of atherosclerotic lesion in apoE-deficient mice. These results indicated that the anti-atherosclerotic effect of anagliptin is mediated, at least in part, through its direct inhibition of SMC proliferation and inflammatory reaction of monocytes. 23628581 Cytochrome c conjugated to ZnO-MAA nanoparticles: the study of interaction and influence on protein structure. Nanoparticle-protein conjugates have potential for numerous applications due to the combination of the properties of both components. In this paper we studied the conjugation of horse heart cytochrome c with ZnO nanoparticles modified by mercaptoacetic acid (MAA) which may be a material with great potential in anticancer therapy as a consequence of synergic effect of both components. Cyt c adsorption to the ZnO-MAA NPs surface was studied by UV-vis spectroscopy and by a dynamic light scattering in various pH. The results indicate that the optimal pH for the association of protein with modified nanoparticles is in range 5.8-8.5 where 90-96% of cytochrome c was assembled on ZnO-MAA nanoparticles. The interaction of proteins with nanoparticles often results in denaturation or loss of protein function. Our observations from UV-vis spectroscopy and circular dichroism performed preserved protein structure after the interaction with modified nanoparticles. 23706402 Cannabinoid CB2 receptor activation attenuates cytokine-evoked mucosal damage in a human colonic explant model without changing epithelial permeability. Cannabinoid receptor activation is protective in animal colitis models. We sought to investigate if cannabinoids attenuated colitis-like tissue damage in human colonic specimens, with the hypothesis that cannabinoids would be protective in a cytokine-driven model of human colonic mucosal damage. Healthy human colonic mucosa was incubated with pro-inflammatory cytokines TNF-α and IL-1β to elicit colitis-like tissue damage. The cytokine-driven increase in scored crypt and mucosal damage and lymphocyte density was attenuated with concomitant hydrocortisone pretreatment. The cannabinoid receptor 2 (CB2) receptor-selective agonist JWH-015 significantly reduced colitis scores following cytokine incubation, as evidenced by a reduction in mucosal crypt and luminal epithelial damage and lymphocyte density in the lamina propria. The effect of JWH-015 was reversed in the presence of the CB2 receptor inverse agonist JTE-907. Anandamide was also protective in the cytokine-incubated explant colitis model in a manner reversible with JTE-907, while CB1 receptor agonism with ACEA was without effect. TNF-α and IL-1β together evoked an increase in paracellular epithelial permeability in Caco-2 cell monolayers over 48h of incubation. However, neither CB2 nor CB1 receptor activation altered the cytokine-evoked increase in permeability. These findings support a discrete role for CB2 receptors in the attenuation of detrimental pro-inflammatory cytokine-mediated mucosal damage in the human colon without directly affecting mucosal epithelial barrier function. 23434639 Synthesis, biological evaluation of new oxazolidino-sulfonamides as potential antimicrobial agents. A number of linezolid-like oxazolidino-sulfonamides (7a-y and 8a-b) were designed and synthesized with a view to develop antimicrobial agents with improved properties. Most of the synthesized compounds showed good to moderate activity against a panel of standard Gram-positive and Gram-negative bacteria and fungal strains. The compounds 7i and 7v exhibited significant activity, with a MIC value of 2.0-6.0 μg/mL against a panel of Gram-positive and Gram-negative bacteria. These compounds also showed activity against Candida albicans, with a MIC value of 4.0 μg/mL. A correlation of the antimicrobial activity with calculated lipophilicity values (C log P) is also presented. 23907247 Imaging Recommendations for Acute Stroke and Transient Ischemic Attack Patients: A Joint Statement by the American Society of Neuroradiology, the American College of Radiology, and the Society of NeuroInterventional Surgery. SUMMARY:Stroke is a leading cause of death and disability worldwide. Imaging plays a critical role in evaluating patients suspected of acute stroke and transient ischemic attack, especially before initiating treatment. Over the past few decades, major advances have occurred in stroke imaging and treatment, including Food and Drug Administration approval of recanalization therapies for the treatment of acute ischemic stroke. A wide variety of imaging techniques has become available to assess vascular lesions and brain tissue status in acute stroke patients. However, the practical challenge for physicians is to understand the multiple facets of these imaging techniques, including which imaging techniques to implement and how to optimally use them, given available resources at their local institution. Important considerations include constraints of time, cost, access to imaging modalities, preferences of treating physicians, availability of expertise, and availability of endovascular therapy. The choice of which imaging techniques to employ is impacted by both the time urgency for evaluation of patients and the complexity of the literature on acute stroke imaging. Ideally, imaging algorithms should incorporate techniques that provide optimal benefit for improved patient outcomes without delaying treatment. 23352550 Ultrasound changes after rotator cuff repair: is supraspinatus tendon thickness related to pain? Little is known about the morphology of healing rotator cuffs after surgical repair. This investigation aimed to determine whether there are changes in tendon thickness, subacromial bursa, anatomical footprint, tendon vascularity, and capsular thickness after rotator cuff repair, and whether supraspinatus tendon thickness correlates with pain. Fifty-seven patients completed a validated pain questionnaire. Using a standardized protocol, their shoulders were scanned by the same ultrasonographer at 1 week, 6 weeks, 3 months, and 6 months postarthroscopic repair by a single surgeon. The contralateral shoulders, if uninjured, were also scanned. Of 57 patients, 4 re-tore their tendons at 6 weeks and 4 retore at 3 months. Sixteen of the remaining 49 patients had intact contralateral supraspinatus tendons. The repaired supraspinatus tendon thickness remained unchanged throughout the 6 months. Compared to week 1, at 6 months, bursal thickness decreased from 1.9 (0.7) mm to 0.7 (0.5) mm (P < .001); anatomical footprint increased from 7.0 (2.0) mm to 9.3 (1.5) mm; tendon vascularity decreased from mild to none (P < .001); posterior capsule thickness decreased from 2.3 (0.8) mm to 1.3 (0.6) mm (P < .001). Frequency and severity of pain and shoulder stiffness decreased (P < .001). There was no correlation between tendon thickness and pain. After rotator cuff repair, there was an immediate increase in subacromial bursa thickness, tendon vascularity, and posterior glenohumeral capsular thickness. These normalized after 6 months. Tendon thickness was unchanged while footprint contact was comparable with the contralateral tendons. There was no correlation between tendon thickness and pain. 23768899 The application of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) scaffolds for tendon repair in the rat model. Tendon injuries and defects present a substantial burden to global healthcare economies. There are no synthetic/biosynthesised implants available which can restore full function or match the mechanical properties of native tendon. Therefore, poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) was investigated for its utility as a scaffold in a rat Achilles tendon repair model. Porous PHBHHx tubes and fibres were prepared with particle leaching and extrusion methods, respectively. Collagen gels reinforced by polymer fibres were inserted into the lumen of scaffold tubes to create the operational scaffold unit. Mechanical testing demonstrated that PHBHHx scaffolds had comparable mechanical properties to rat tendon, with maximal loads of 23.73 ± 1.08 N, compared to 17.35 ± 1.76 N in undamaged rat Achilles tendon. Sprague-Dawley (SD) rats were split into four experimental groups: control, PHBHHx scaffold only, PHBHHx scaffold and collagen, PHBHHx scaffold, collagen and tenocyte compositions for implantation to repair an induced Achilles tendon defect. No secondary immune response to PHBHHx was observed over a 40 days period of implantation. Movement was restored in PHBHHx scaffold-collagen-tenocyte recipient rats at an earlier time point than in other experimental groups, with complete load-bearing and function returning 20 days post-surgery as determined by the Achilles Functional Index. In vitro testing of tendon constructs after 40 days demonstrated reductions in PHBHHx molecular weight and polydispersity index accompanied by an increase in mean chain length indicating degradation of smaller polymer chain subunits. Similarly a reduction in PHBHHx tube ultimate tensile strength and elastic modulus was observed. Histological analysis provided evidence of tissue remodelling and cell alignment. In summary, PHBHHx scaffolds have been successfully applied in an in vivo tendon repair model raising promise for future utility in tissue engineering applications. 23639006 Anti-HIV and NO production inhibition activities of epi-aleuritolic acid derivatives. Fifteen epi-aleuritolic acid derivatives were synthesized and evaluated for anti-HIV activity in 293 T cells and NO production inhibition activity. Of the derivatives, 1, 2, 3, 4, 11, and 13 showed relatively potent anti-HIV activity with EC50 values ranging from 5.80 to 13.30 μM. The most potent compound, 3α-2',2'-dimethylsuccinic acyl epi-aleuritolic acid (11), displayed significant anti-HIV activity with an EC50 value of 5.80 μM. Compounds 1, 3, 4, and 11 showed NO inhibition activity, with IC50 values ranging from 3.40 to 7.10 μM and compound 1 inhibited NO production with an IC50 value of 3.40 μM. 23807945 Melamine modified gold nanoprobe for "on-spot" colorimetric recognition of clonazepam from biological specimens. Inexpensive, rapid, and reliable methods of detection are crucial to the control of toxicological investigations. Here we report a highly sensitive, selective and cost effective method for the detection of trace amounts of clonazepam based on gold nanoparticles (AuNPs) in the presence of melamine. Hydrogen bonding interactions between clonazepam and melamine resulted in the aggregation of AuNPs and a consequent color change of AuNPs from wine red to blue. The results showed that the absorption ratio (A636/A552) was linear for clonazepam concentrations in the range of 10 × 10(-8) to 1.0 × 10(-9) M (R(2) = 0.999). The detection limit was 8.9 × 10(-10) M (S/N = 3), which was much lower than that of most existing methods. Coexisting substances including alprazolam, diazepam, nitrazepam and lorazepam did not affect the determination of clonazepam. The sensor developed by this new approach could be used as a spot test and a good alternative means for on-site and real time screening of clonazepam. This proposed scheme was also supported by the use of real samples such as skeletal remains and blood to illustrate the applicability of the developed nanosensor by a series of experiments. 23807231 A cytometric bead assay for sensitive DNA detection based on enzyme-free signal amplification of hybridization chain reaction. A versatile flow cytometric bead assay (CBA) is developed for sensitive DNA detection by integrating the advantages of hybridization chain reaction (HCR) for enzyme-free signal amplification, flow cytometry for robust and rapid signal readout as well as magnetic beads (MBs) for facile separation. In this HCR-CBA, a biotinylated hairpin DNA (Bio-H1) is firstly immobilized on streptavidin-functionalized MBs. Upon the addition of target DNA, each target would hybridize with one Bio-H1 to open its hairpin structure and subsequently initiate a cascade of hybridization events between two species of fluorescent DNA hairpin probes (H1*/H2*) to form a nicked double helical DNA structure, resulting in amplified accumulation of numerous fluorophores on the MBs. Finally, the fluorescent MBs are directly analyzed by flow cytometry. This technique enables quantitative analysis of the HCR products anchored on the MBs as a function of target DNA concentration, and analysis of each sample can be completed within few minutes. Therefore, the HCR-CBA approach provides a practical DNA assay with greatly improved sensitivity. The detection limit of a model DNA target is 0.5pM (3σ), which is about 3 orders of magnitude lower compared with traditional hybridization methods without HCR. Furthermore, the signal of complementary target can be clearly distinguished from that of single-base mismatched sequences, indicating the high specificity of the HCR-CBA. Moreover, this strategy is also successfully applied to the DNA analysis in complex biological samples, showing great potential in gene analysis and disease diagnosis in clinical samples. 23334083 Microcalcifications in breast cancer: Lessons from physiological mineralization. Mammographic mammary microcalcifications are routinely used for the early detection of breast cancer, however the mechanisms by which they form remain unclear. Two species of mammary microcalcifications have been identified; calcium oxalate and hydroxyapatite. Calcium oxalate is mostly associated with benign lesions of the breast, whereas hydroxyapatite is associated with both benign and malignant tumors. The way in which hydroxyapatite forms within mammary tissue remains largely unexplored, however lessons can be learned from the process of physiological mineralization. Normal physiological mineralization by osteoblasts results in hydroxyapatite deposition in bone. This review brings together existing knowledge from the field of physiological mineralization and juxtaposes it with our current understanding of the genesis of mammary microcalcifications. As an increasing number of breast cancers are being detected in their non-palpable stage through mammographic microcalcifications, it is important that future studies investigate the underlying mechanisms of their formation in order to fully understand the significance of this unique early marker of breast cancer. 23453957 A mitochondrial ribosomal and RNA decay pathway blocks cell proliferation. Proliferating cells require coordinated gene expression between the nucleus and mitochondria in order to divide, ensuring sufficient organelle number in daughter cells [1]. However, the machinery and mechanisms whereby proliferating cells monitor mitochondria and coordinate organelle biosynthesis remain poorly understood. Antibiotics inhibiting mitochondrial translation have emerged as therapeutics for human cancers because they block cell proliferation [2, 3]. These proliferative defects were attributable to modest decreases in mitochondrial respiration [3, 4], even though tumors are mainly glycolytic [5] and mitochondrial respiratory chain function appears to play a minor role in cell proliferation in vivo [6]. Here we challenge this interpretation by demonstrating that one class of antiproliferative antibiotic induces stalled mitochondrial ribosomes, which triggers a mitochondrial ribosome and RNA decay pathway. Rescue of the stalled mitochondrial ribosomes initiates a retrograde signaling response to block cell proliferation and occurs prior to any loss of mitochondrial respiration. The loss of respiratory chain function is simply a downstream effect of impaired mitochondrial translation and not the antiproliferative signal. This mitochondrial ribosome quality-control pathway is actively monitored in cells and constitutes an important organelle checkpoint for cell division. 23647822 Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism. Keap1 binds to the Nrf2 transcription factor to promote its degradation, resulting in the loss of gene products that protect against oxidative stress. While cell-active small molecules have been identified that modify cysteines in Keap1 and effect the Nrf2 dependent pathway, few act through a non-covalent mechanism. We have identified and characterized several small molecule compounds that specifically bind to the Keap1 Kelch-DC domain as measured by NMR, native mass spectrometry and X-ray crystallography. One compound upregulates Nrf2 response genes measured by a luciferase cell reporter assay. The non-covalent inhibition strategy presents a reasonable course of action to avoid toxic side-effects due to non-specific cysteine modification. 23916817 Species-specific effects of near-future CO2 on the respiratory performance of two tropical prey fish and their predator. Ocean surface CO2 levels are increasing in line with rising atmospheric CO2 and could exceed 900μatm by year 2100, with extremes above 2000μatm in some coastal habitats. The imminent increase in ocean pCO2 is predicted to have negative consequences for marine fishes, including reduced aerobic performance, but variability among species could be expected. Understanding interspecific responses to ocean acidification is important for predicting the consequences of ocean acidification on communities and ecosystems. In the present study, the effects of exposure to near-future seawater CO2 (860μatm) on resting (M˙ O2rest) and maximum (M˙O2max) oxygen consumption rates were determined for three tropical coral reef fish species interlinked through predator-prey relationships: juvenile Pomacentrus moluccensis and Pomacentrus amboinensis, and one of their predators: adult Pseudochromis fuscus. Contrary to predictions, one of the prey species, P. amboinensis, displayed a 28-39% increase in M˙O2max after both an acute and four-day exposure to near-future CO2 seawater, while maintaining M˙O2rest. By contrast, the same treatment had no significant effects on M˙O2rest or M˙O2max of the other two species. However, acute exposure of P. amboinensis to 1400 and 2400μatm CO2 resulted in M˙O2max returning to control values. Overall, the findings suggest that: (1) the metabolic costs of living in a near-future CO2 seawater environment were insignificant for the species examined at rest; (2) the M˙O2max response of tropical reef species to near-future CO2 seawater can be dependent on the severity of external hypercapnia; and (3) near-future ocean pCO2 may not be detrimental to aerobic scope of all fish species and it may even augment aerobic scope of some species. The present results also highlight that close phylogenetic relatedness and living in the same environment, does not necessarily imply similar physiological responses to near-future CO2. 23834733 Caspofungin benefit on phagocytes from patients with renal dysfunction infected with multidrug-resistant Candida glabrata. Aim: We evaluated the potential impact of caspofungin (CAS) on the functional activities of polymorphonuclear leukocytes (PMNs) from hemodialyzed patients (HDs) and renal transplant recipients (RTRs) against a multidrug-resistant clinical strain of Candida glabrata compared with those of PMNs from healthy subjects (HSs). Materials & methods: Effects of CAS on PMN phagocytosis and intracellular killing towards multidrug-resistant C. glabrata were evaluated in 66 HDs, 54 RTRs and 30 HSs in the absence and presence of CAS at MIC and sub-MICs. Results: When HD PMNs and RTR PMNs were exposed to both MICs and sub-MICs of CAS, their fungicidal activity against the multidrug-resistant C. glabrata strain was significantly higher than that of drug-free controls, with survival index values that overlapped with those achieved by HS PMNs. Conclusion: The obtained results underline the role of CAS in the restoration of the impaired PMN functions in HDs and RTRs. CAS might still constitute an effective therapeutic option for the treatment of invasive fungal infections caused by multidrug-resistant C. glabrata in patients with altered phagocyte-dependent innate immunity. 23891874 Detection of cytomegalovirus DNA on dried blood spots collected from infants infected with HIV: An in-house method adaptable in resource-limited settings. In countries with limited resources, infants infected with HIV are highly exposed to CMV co-infection which probably represents a major risk factor for disease progression in this population. This study aimed to evaluate the performance of a low cost CMV DNA extraction method from DBS and the feasibility of its implementation in laboratories of 4 countries with limited resources. DNA was extracted from DBS with a cationic resin (chelex 100) and amplified with an "in house" real time CMV PCR. Dilutions of a quantified whole blood sample were spotted on paper to evaluate the 95% detection limit. A DBS quality control panel was analyzed in all laboratories. CMV PCR was compared between DBS and liquid whole blood (gold standard) in 2 populations: 418 transplanted patients and 59 infants infected with HIV (median age of 2 months). The CMV PCR 95% detection limit in DBS was 3.87log10copies/mL. Its positive and negative predictive values for CMV diagnosis in infants infected with HIV were 100% and 87.5% respectively. Quality control panels gave consistent qualitative results in all laboratories. This assay had high predictive values for CMV diagnosis in infants infected with HIV and its implementation in resource-limited countries with limited resources is feasible. 23853079 Identifying Rare Variants Associated with Complex Traits via Sequencing. Although genome-wide association studies have been successful in detecting associations with common variants, there is currently an increasing interest in identifying low-frequency and rare variants associated with complex traits. Next-generation sequencing technologies make it feasible to survey the full spectrum of genetic variation in coding regions or the entire genome. The association analysis for rare variants is challenging, and traditional methods are ineffective, however, due to the low frequency of rare variants, coupled with allelic heterogeneity. Recently a battery of new statistical methods has been proposed for identifying rare variants associated with complex traits. These methods test for associations by aggregating multiple rare variants across a gene or a genomic region or among a group of variants in the genome. In this unit, we describe key concepts for rare variant association for complex traits, survey some of the recent methods, discuss their statistical power under various scenarios, and provide practical guidance on analyzing next-generation sequencing data for identifying rare variants associated with complex traits. Curr. Protoc. Hum. Genet. 78:1.26.1-1.26.22. © 2013 by John Wiley & Sons, Inc. 23673515 New avenues in the medical treatment of Cushing's disease: corticotroph tumor targeted therapy. Cushing's disease (CD) is a condition of chronic hypercortisolism caused by an adrenocorticotropic hormone-secreting pituitary adenoma. First-line transsphenoidal surgery is not always curative and disease sometimes recurs. Radiotherapy often requires months or years to be effective, and is also not curative in many cases. Consequently, effective medical therapies for patients with CD are needed. Corticotroph adenomas frequently express both dopamine (D2) and somatostatin receptors (predominantly sstr5). Pasireotide, a somatostatin analog with high sstr5 binding affinity, has shown urinary free cortisol (UFC) reductions in most patients with CD in a large phase 3 trial, with UFC normalization and tumor shrinkage in a subset of patients. Adverse events were similar to other somatostatin analogs, with the exception of the degree and severity of hyperglycemia. Two small trials (one prospective and one retrospective) have suggested that cabergoline, a D2 receptor agonist, could be effective in normalizing UFC, but current long-term data results are conflicting. Combination treatment with pasireotide plus cabergoline and the adrenal steroidogenesis inhibitor ketoconazole has been successful, but further investigation in larger trials is necessary. Retinoic acid also showed interesting results in a recent very small prospective study. Glucocorticoid receptor blockade with mifepristone has recently demonstrated improvement in signs and symptoms of Cushing's and glycemic control; however, this modality does not address the etiology of the disease and has inherent adverse events related to its mechanism of action. Pituitary-targeted medical therapies will soon play a more prominent role in treating CD, and may potentially become first-line medical therapy when surgery fails or is contraindicated. 23968218 Self-concept organisation and mental toughness in sport. Abstract The present study examines the relationship between individual differences in evaluative self-organisation and mental toughness in sport, proposing that motivation and emotional resiliency (facets of mental toughness) stem from differences in core self. A cross-sectional assessment of 105 athletes competing at a range of performance levels took part in an online study including measures of self-reported mental toughness (Sport Mental Toughness Questionnaire; Sheard, M., Golby, J., & van Wersch, A. (2009). Progress towards construct validation of the Sports Mental Toughness Questionnaire (SMTQ). European Journal of Psychological Assessment, 25(3), 186-193. doi:10.1027/1015-5759.25.3.186) and self-organisation (self-descriptive attribute task; Showers, C. J. (2002). Integration and compartmentalisation: A model of self-structure and self-change. In D. Cervone & W. Mischel (Eds.), Advances in personality science (pp. 271-291). New York, NY: Guilford Press). As predicted, global mental toughness was associated with self-concept positivity, which was particularly high in individuals with positive-integrative self-organisation (individuals who distribute positive and negative self-attributes evenly across multiple selves). Specifically, positive integration was associated with constancy (commitment to goal achievement despite obstacles and the potential for failure), which extends presumably from positive integratives' emotional stability and drive to resolve negative self-beliefs. 23831057 Sprouty2 but not Sprouty4 is a potent inhibitor of cell proliferation and migration of osteosarcoma cells. As negative regulators of receptor tyrosine kinase-mediated signalling, Sprouty proteins fulfil important roles during carcinogenesis. In this report, we demonstrate that Sprouty2 protein expression inhibits cell proliferation and migration in osteosarcoma-derived cells. Although earlier reports describe a tumour-promoting function, these results indicate that Sprouty proteins also have the potential to function as tumour suppressors in sarcoma. In contrast to Sprouty2, Sprouty4 expression failed to interfere with proliferation and migration of the osteosarcoma-derived cells, possibly due to a less pronounced interference with mitogen-activated protein kinase activity. Sequences within the NH2-terminus are responsible for the specific inhibitory function of Sprouty2 protein. 23814017 A prospective study of 67 serum immune and inflammation markers and risk of non-Hodgkin lymphoma. Although severe immune dysregulation is an established risk factor for non-Hodgkin lymphoma (NHL), the importance of subclinical immunologic effects is unclear. We compared baseline serum levels of 67 immune and inflammation markers between 301 patients with NHL diagnosed 5+ years after blood collection and 301 control patients within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We observed associations with NHL for elevated B-cell-attracting chemokine 1 (BCA-1; fourth quartile vs first: odds ratio [OR], 2.7; 95% confidence interval [CI], 1.7-4.2; Ptrend = 1.0 × 10(-6)), soluble tumor necrosis factor receptor 2 (sTNFR2; OR, 3.4; 95% CI, 2.0-5.8; Ptrend = 1.1 × 10(-6)), and soluble vascular endothelial growth factor receptor 2 (sVEGFR2; OR, 2.3; 95% CI, 1.4-3.9; Ptrend = .0005) that remained significant after Bonferroni correction, simultaneous model adjustment, and restriction to cases diagnosed 8 to 13 years after blood collection. Associations with other markers were observed, although none remained associated with NHL after adjustment for BCA-1, sTNFR2, and sVEGFR2. Our findings suggest that circulating BCA-1, sTNFR2, and sVEGFR2 are associated with NHL risk well in advance of diagnosis. Additional research is needed to replicate these findings and elucidate the underlying biologic mechanisms. 23125282 Trans-chromosomic mice containing a human CYP3A cluster for prediction of xenobiotic metabolism in humans. Human CYP3A is the most abundant P450 isozyme present in the human liver and small intestine, and metabolizes around 50% of medical drugs on the market. The human CYP3A subfamily comprises four members (CYP3A4, CYP3A5, CYP3A7, CYP3A43) encoded on human chromosome 7. However, transgenic mouse lines carrying the entire human CYP3A cluster have not been constructed because of limitations in conventional cloning techniques. Here, we show that the introduction of a human artificial chromosome (HAC) containing the entire genomic human CYP3A locus recapitulates tissue- and stage-specific expression of human CYP3A genes and xenobiotic metabolism in mice. About 700 kb of the entire CYP3A genomic segment was cloned into a HAC (CYP3A-HAC), and trans-chromosomic (Tc) mice carrying a single copy of germline-transmittable CYP3A-HAC were generated via a chromosome-engineering technique. The tissue- and stage-specific expression profiles of CYP3A genes were consistent with those seen in humans. We further generated mice carrying the CYP3A-HAC in the background homozygous for targeted deletion of most endogenous Cyp3a genes. In this mouse strain with 'fully humanized' CYP3A genes, the kinetics of triazolam metabolism, CYP3A-mediated mechanism-based inactivation effects and formation of fetal-specific metabolites of dehydroepiandrosterone observed in humans were well reproduced. Thus, these mice are likely to be valuable in evaluating novel drugs metabolized by CYP3A enzymes and in studying the regulation of human CYP3A gene expression. Furthermore, this system can also be used for generating Tc mice carrying other human metabolic genes. 23052214 Reactivation of the inactive X chromosome in development and reprogramming. In mammals, one of the two X chromosomes of female cells is inactivated for dosage compensation between the sexes. X chromosome inactivation is initiated in early embryos by the noncoding Xist RNA. Subsequent chromatin modifications on the inactive X chromosome (Xi) lead to a remarkable stability of gene repression in somatic cell lineages. In mice, reactivation of genes on the Xi accompanies the establishment of pluripotent cells of the female blastocyst and the development of primordial germ cells. Xi reactivation also occurs when pluripotency is established during the reprogramming of somatic cells to induced pluripotent stem cells. The mechanism of Xi reactivation has attracted increasing interest for studying changes in epigenetic patterns and for improving methods of cell reprogramming. Here, we review recent advances in the understanding of Xi reactivation during development and reprogramming and illustrate potential clinical applications. 23968746 Pediatric Global Health Education: Correlation of Website Information and Curriculum. Web sites describing residency programs are initial sources of information for applicants. The correlation of global health content on pediatric residency program Web sites with reported curricula is unknown. To determine the accuracy of global health education, information on program Web sites was compared with queried program content responses. The Fellowship and Residency Electronic Interactive Database was used to assess pediatric residency programs' Web sites for global health education, applying American Academy of Pediatrics consensus guidelines. The authors developed a questionnaire using these consensus guidelines and contacted each program to assess Web site findings, and χ(2) tests were used to compare data from these 2 sources. Of 194 programs, 177 had operational Web sites, of which 98 participated in the questionnaire (55%). Ninety-three of 177 programs (53%) reported global health education on Web sites, whereas 80 of 98 programs (82%) reported global health education through direct questioning (P < .001). Results include provision of resident salaries during global health elective (Web site 5% vs questionnaire 98%, P < .001), mandatory training before global health elective (8% vs 20%, P = .02), presence of global health elective curriculum (24% vs 75%, P < .001), postexperience debriefing (16% vs 29%, P = .05), and bidirectional resident exchange (2% vs 13%, P = .01). Results indicate continued expansion of pediatric global health education, but significant differences exist between information on Web sites and data obtained through direct questioning. Accurate representation of global health opportunities would allow for more informed decision-making among prospective applicants. Findings also suggest substantial variability in global health curricula that needs to be addressed through improved planning and cooperation among training programs. 23770092 Functional study of diacylglycerol acyltransferase type 2 family in Chlamydomonas reinhardtii. Algal triacylglycerol biosynthesis is of increasing interest for potential biodiesel production. A model microalga, Chlamydomonas, has multiple isoforms of diacylglycerol acyltransferase type 2 (DGTT) catalyzing the final step of triacylglycerol biosynthesis; however, the functions of the isoforms are poorly understood. Here, we performed heterologous complementation assay of Chlamydomonas DGTT1 to 4 in a yeast mutant defective in triacylglycerol biosynthesis. DGTT1, 2 and 3 but not 4 complemented the phenotype, including triacylglycerol levels. Interestingly, complementation by DGTT2 increased triacylglycerol content by 9-fold. 23053113 Chicken- and duck-associated Bacteroides-Prevotella genetic markers for detecting fecal contamination in environmental water. Bacteroides-Prevotella group is one of the most promising targets for detecting fecal contamination in water environments, principally due to its host-specific distributions and high concentrations in feces of warm-blooded animals. We developed real-time PCR assays for quantifying chicken/duck-, chicken-, and duck-associated Bacteroides-Prevotella 16S rRNA genetic markers (Chicken/Duck-Bac, Chicken-Bac, and Duck-Bac). A reference collection of DNA extracts from 143 individual fecal samples and wastewater treatment plant influent was tested by the newly established markers. The quantification limits of Chicken/Duck-Bac, Chicken-Bac, and Duck-Bac markers in environmental water were 54, 57, and 12 copies/reaction, respectively. It was possible to detect possible fecal contaminations from wild ducks in environmental water with the constructed genetic marker assays, even though the density of total coliforms in the identical water samples was below the detection limit. Chicken/Duck-Bac marker was amplified from feces of wild duck and chicken with the positive ratio of 96 and 61 %, respectively, and no cross-reaction was observed for the other animal feces. Chicken-Bac marker was detected from 70 % of chicken feces, while detected from 39 % of cow feces, 8.3 % of pig feces, and 12 % of swan feces. Duck-Bac marker was detected from 85 % of wild duck feces and cross-reacted with 31 % of cow feces. These levels of detection specificity are common in avian-associated genetic markers previously proposed, which implies that there is a practical limitation in the independent application of avian-associated Bacteroides-Prevotella 16S rRNA genetic markers and a combination with other fecal contamination markers is preferable for detecting fecal contamination in water environments. 23847133 A Promising Mid-Temperature Thermoelectric Material Candidate: Pb/Sn-Codoped In4 Pbx Sny Se3. A facile polycrystalline Pb/Sn-codoped In4 Pb0.01 Sny Se3 material is obtained, and its thermoelectric performance is evaluated and the intrinsic reasons have been studied. This material shows excellent ZT value of 1.4 at 733 Kelvin, among the best values of the relative materials, thus making it a promising candidate for the mid-temperature thermoelectric application. 23639187 Amelioration of palmitate-induced insulin resistance in C2C12 muscle cells by rooibos (Aspalathus linearis). Increased levels of free fatty acids (FFAs), specifically saturated free fatty acids such as palmitate are associated with insulin resistance of muscle, fat and liver. Skeletal muscle, responsible for up to 80% of the glucose disposal from the peripheral circulation, is particularly vulnerable to increased levels of saturated FFAs. Rooibos (Aspalathus linearis) and its unique dihydrochalcone C-glucoside, aspalathin, shown to reduce hyperglycemia in diabetic rats, could play a role in preventing or ameliorating the development of insulin resistance. This study aims to establish whether rooibos can ameliorate experimentally-induced insulin-resistance in C2C12 skeletal muscle cells. Palmitate-induced insulin resistant C2C12 cells were treated with an aspalathin-enriched green (unfermented) rooibos extract (GRE), previously shown for its blood glucose lowering effect in vitro and in vivo or an aqueous extract of fermented rooibos (FRE). Glucose uptake and mitochondrial activity were measured using 2-deoxy-[(3)H]-d-glucose, MTT and ATP assays, respectively. Expression of proteins relevant to glucose metabolism was analysed by Western blot. GRE contained higher levels of all compounds, except the enolic phenylpyruvic acid-2-O-glucoside and luteolin-7-O-glucoside. Both rooibos extracts increased glucose uptake, mitochondrial activity and ATP production. Compared to FRE, GRE was more effective at increasing glucose uptake and ATP production. At a mechanistic level both extracts down-regulated PKC θ activation, which is associated with palmitate-induced insulin resistance. Furthermore, the extracts increased activation of key regulatory proteins (AKT and AMPK) involved in insulin-dependent and non-insulin regulated signalling pathways. Protein levels of the glucose transporter (GLUT4) involved in glucose transport via these two pathways were also increased. This in vitro study therefore confirms that rooibos can ameliorate palmitate-induced insulin resistance in C2C12 skeletal muscle cells. Inhibition of PKC θ activation and increased activation of AMPK and AKT offer a plausible mechanistic explanation for this ameliorative effect. 23698305 Age and immune status of rhesus macaques impact simian varicella virus gene expression in sensory Ganglia. Simian varicella virus (SVV) infection of rhesus macaques (RMs) recapitulates the hallmarks of varicella-zoster virus (VZV) infection of humans, including the establishment of latency within the sensory ganglia. Various factors, including age and immune fitness, influence the outcome of primary VZV infection, as well as reactivation resulting in herpes zoster (HZ). To increase our understanding of the role of lymphocyte subsets in the establishment of viral latency, we analyzed the latent SVV transcriptome in juvenile RMs depleted of CD4 T, CD8 T, or CD20 B lymphocytes during acute infection. We have previously shown that SVV latency in sensory ganglia of nondepleted juvenile RMs is associated with a limited transcriptional profile. In contrast, CD4 depletion during primary infection resulted in the failure to establish a characteristic latent viral transcription profile in sensory ganglia, where we detected 68 out of 69 SVV-encoded open reading frames (ORFs). CD-depleted RMs displayed a latent transcriptional profile that included additional viral transcripts within the core region of the genome not detected in control RMs. The latent transcriptome of CD20-depleted RMs was comparable to the latent transcription in the sensory ganglia of control RMs. Lastly, we investigated the impact of age on the establishment of SVV latency. SVV gene expression was more active in ganglia from two aged RMs than in ganglia from juvenile RMs, with 25 of 69 SVV transcripts detected. Therefore, immune fitness at the time of infection modulates the establishment and/or maintenance of SVV latency. 23525489 Periosteal spindle cell hemangioma of the fibula: a case report. Spindle cell hemangioma is a rare benign tumor characterized by cavernous blood vessels and spindle cell proliferation. It typically arises in the subcutis of the distal extremities, particularly in the hand. Spindle cell hemangioma of periosteal origin is extremely rare, and our extensive literature search did not find any reports of this condition. We report here a case of spindle cell hemangioma of periosteal origin arising from the right fibula of a 49-year-old woman. Pathological examination of a needle biopsy specimen indicated the possibility of low-grade spindle cell sarcoma, and the patient underwent resection of the fibular diaphysis with a wide margin. Subsequent examination of the surgical specimen revealed a diagnosis of periosteal spindle cell hemangioma. Follow-up examination at 10 months showed no evidence of local recurrence or metastasis. A large tissue sample was required for definitive diagnosis in this case. Spindle cell hemangioma behaves in a benign fashion, but recurrence occurs in about 60% of cases. Excision of the fibula was a reasonable course of management in this case because these patients usually maintain good function. Reports of additional cases will be required to determine the most appropriate treatment for this tumor. 23715290 Integrating palliative care: when and how? Lung cancer is the leading cause of cancer mortality in men and women. Most patients present with advanced disease and face significant morbidity, with many reporting distressing symptoms throughout the course of their illness. The purpose of this review is to highlight the recent studies that support the integration of early palliative care into the standard oncology care of patients with advanced lung cancer. Historically, palliative care was provided predominantly as a hospital-based consultation service; however, recent data support an outpatient delivery model of early palliative care alongside standard oncology care. In two randomized controlled trials, patients with advanced cancer who were assigned to early palliative care reported improved quality of life and mood. Numerous organizations have published guidelines to support the integration of palliative care into the routine care of patients with lung cancer. Palliative care is appropriate for patients at any point in a serious illness. Unlike hospice, palliative care is not limited by prognosis and may be provided at the same time as disease-directed therapies. There is strong evidence underscoring the importance of integrating palliative care across the trajectory of lung cancer. The primary oncology team should routinely assess for pain and other symptoms, and regularly inquire about a patient's understanding of his disease and his goals of care. Specialty palliative care can provide an extra layer of support for patients with lung cancer and their families by helping with more challenging symptom management, psychosocial support, complex decision-making, advance care planning, and transitions in care. 23549766 Predictive factors for the diagnosis of severe acute cholecystitis in an emergency setting. The aim of this study was to assess predictive factors for the diagnosis of severe acute cholecystitis. The medical records of 295 patients with pathologically confirmed acute cholecystitis were reviewed. Patients were divided, based on pathology findings, into a group with nonsevere acute cholecystitis and a group with severe acute cholecystitis. Preoperative data were compared by univariate and multivariate analyses. Therefore, diagnostic values were assessed based on the statistically significant predictive factors. The same approach was attempted for differential diagnosis between gangrenous and phlegmonous cholecystitis. Among ten variables found to be significantly different at univariate analysis, four were found to be independent predictive factors of severe acute cholecystitis: fever, distension of the gallbladder, wall edema, and preoperative adverse events. Common bile duct stones were confirmed as a protective factor. Leukocyte count, cardiovascular diseases, age, gender, and diabetes were not found to be significant predictive factors of severe acute cholecystitis. No differences were found in any of the preoperative data by comparing phlegmonous and gangrenous cholecystitis. Severe acute cholecystitis may be differentiated preoperatively from nonsevere acute cholecystitis based on clinical and US data, and predictive diagnostic values may be estimated according to the number of observed predictive factors. No differences were found when comparing phlegmonous and gangrenous cholecystitis. 23899161 Experimental transmission of enzootic nasal adenocarcinoma in sheep. Enzootic nasal adenocarcinoma (ENA) is a contagious neoplasm of the secretory epithelial cells of the nasal mucosa of sheep and goats. It is associated with the betaretrovirus, enzootic nasal tumor virus (ENTV), but a causative relationship has yet to be demonstrated. In this study, 14-day-old lambs were experimentally infected via nebulization with cell-free tumor filtrates derived from naturally occurring cases of ENA. At 12 weeks post-infection (wpi), one of the five infected lambs developed clinical signs, including continuous nasal discharge and open mouth breathing, and was euthanized. Necropsy revealed the presence of a large bilateral tumor occupying the nasal cavity. At 45 wpi, when the study was terminated, none of the remaining infected sheep showed evidence of tumors either by computed tomography or post-mortem examination. ENTV-1 proviral DNA was detected in the nose, lung, spleen, liver and kidney of the animal with experimentally induced ENA, however there was no evidence of viral protein expression in tissues other than the nose. Density gradient analysis of virus particles purified from the experimentally induced nasal tumor revealed a peak reverse transcriptase (RT) activity at a buoyant density of 1.22 g/mL which was higher than the 1.18 g/mL density of peak RT activity of virus purified from naturally induced ENA. While the 1.22 g/mL fraction contained primarily immature unprocessed virus particles, mature virus particles with a similar morphology to naturally occurring ENA could be identified by electron microscopy. Full-length sequence analysis of the ENTV-1 genome from the experimentally induced tumor revealed very few nucleotide changes relative to the original inoculum with only one conservative amino acid change. Taken together, these results demonstrate that ENTV-1 is associated with transmissible ENA in sheep and that under experimental conditions, lethal tumors are capable of developing in as little as 12 wpi demonstrating the acutely oncogenic nature of this ovine betaretrovirus. 23877055 The Development and Evaluation of an Internet-Based Intervention to Increase Awareness about Food Portion Sizes: A Randomized Controlled Trial. To develop a Web-based tool (PortionSize@warenessTool) and to evaluate its effectiveness in increasing awareness of reference serving sizes and factors that may contribute to overeating in response to large portion sizes. A randomized, controlled trial (intervention, n = 167; control, n = 143) was conducted. The authors measured awareness of reference serving size and overeating triggers from larger portions by an online questionnaire, assessed at baseline and 1 week later. Exposure dose reflected online activity (eg, number of Web pages viewed). Process evaluation data were collected within the intervention group. The intervention group demonstrated significantly higher awareness of reference serving sizes (η(2) = .062; P < .001) and overeating triggers from larger portions (η(2) = .061; P < .001) at posttest. Also, the authors observed a dose-dependent effect that led to improved awareness. The PortionSize@warenessTool constitutes a promising tool to improve portion size awareness. 23455597 Assessment of the abuse liability of ABT-288, a novel histamine H3 receptor antagonist. RATIONALE: Histamine H3 receptor antagonists, such as ABT-288, have been shown to possess cognitive-enhancing and wakefulness-promoting effects. On the surface, this might suggest that H3 antagonists possess psychomotor stimulant-like effects and, as such, may have the potential for abuse. OBJECTIVES: The aim of the present study was to further characterize whether ABT-288 possesses stimulant-like properties and whether its pharmacology gives rise to abuse liability. METHODS: The locomotor-stimulant effects of ABT-288 were measured in mice and rats, and potential development of sensitization was addressed. Drug discrimination was used to assess amphetamine-like stimulus properties, and drug self-administration was used to evaluate reinforcing effects of ABT-288. The potential development of physical dependence was also studied. RESULTS: ABT-288 lacked locomotor-stimulant effects in both rats and mice. Repeated administration of ABT-288 did not result in cross-sensitization to the stimulant effects of d-amphetamine in mice, suggesting that there is little overlap in circuitries upon which the two drugs interact for motor activity. ABT-288 did not produce amphetamine-like discriminative stimulus effects in drug discrimination studies nor was it self-administered by rats trained to self-administer cocaine. There were no signs of physical dependence upon termination of repeated administration of ABT-288 for 30 days. CONCLUSIONS: The sum of these preclinical data, the first of their kind applied to H3 antagonists, indicates that ABT-288 is unlikely to possess a high potential for abuse in the human population and suggests that H3 antagonists, as a class, are similar in this regard. 23417438 A study on influential factors of high-phosphorus wastewater treated by electrocoagulation-ultrasound. A combined treatment of electrocoagulation and ultrasound was proposed to solve some problems which exist in the phosphorus removal processes in fine chemical industry. The intermittently discharged wastewater has the features of high initial phosphorus concentration and wide initial pH variation. The electrocoagulation-ultrasound effective performance for the removal of phosphorus was investigated. The results obtained from synthetic wastewater showed that the total phosphorus (TP) decreased from 86 to about 0.4 mg/L, and the removal efficiency reached about 99.6 %, when ultrasound was applied to the electrocoagulation cell under the optimum working conditions in 10 min. Comparatively, the TP removal efficiency of electrocoagulation group was 81.3 % and the ultrasound group has almost no change. Therefore, we can conclude that the electrocoagulation and ultrasound synergistic effect can effectively degrade high-phosphorus wastewater. We have discussed the impact of various parameters on the electrocoagulation-ultrasound based on the phosphorus removal efficiency. The results obtained from synthetic wastewater showed that the optimum working pH was found to be 6, allowing the effluent to be met the emission standards without pH adjustment. An increased current enhanced the speed of treatment significance, but higher current (>40 mA/cm(2)) enhanced ultrasonic cavitation effect causing flocculation ineffective. In addition, it was found that the optimum ultrasonic power was 4 W/cm(2) and the frequency was 20 kHz. The best ultrasound intervention and ultrasonic irradiation time were processed with electrocoagulation simultaneously. The results indicated that the electrocoagulation-ultrasound could be utilized as an attractive technique for removal of phosphate in the real wastewater. 23883761 The use of non-interactive scenarios in social neuroscience. Although we fundamentally agree with Schilbach et al., we argue here that there is still some residual utility for non-interactive scenarios in social neuroscience. They may be useful to quantify individual differences in prosocial inclination that are not influenced by concerns about reputation or social pressure. 23891567 Surfactant treatments influence drying mechanics in human stratum corneum. We describe a high-throughput method capable of quantifying the elastic modulus and drying stress of ex vivo samples of human stratum corneum. Spatially resolved drying deformations in circular tissue samples are measured, azimuthally averaged and fitted with a profile based on a linear elastic model. Our approach enables the comparison of the physical effects of different cleansers. We find that cleansing can cause dramatic changes to the mechanical properties of stratum corneum. In some cases, cleansing can lead to an order of magnitude increase in elastic modulus and drying stress. We expect that these mechanical properties have a direct impact on cracking and chapping skin as well as the milder sensation of perceived tightness often experienced after washing. Mechanical drying studies are also combined with drop wetting studies and pyranine staining experiments. This combination of techniques allows one to establish a multidimensional profile of stratum corneum including stiffness, susceptibility to drying, hydrophilicity and barrier functionality. 23725522 The nature of outsourced preclinical research - the example of chemical synthesis. The possibility to buy standardized external services or even new and innovative methods within drug discovery has increased dramatically during the last decades. Service providers are able to provide timely and efficient solutions to any given problem within preclinical research. The outsourcing behavior depends on the specific company type. Generally, the outsourcing level of emerging pharmaceutical and biotechnology companies is much higher than established companies due to low or missing internal resources. Whereas the "make-or-buy" decisions of large and fully integrated pharmaceutical companies are mainly competency driven, those of mid-size and small pharmaceutical, as well as biotech companies show a specific combination of cost/capacity and competency. The three different cooperation models "price competition", "project selection," and "strategic partnership" were identified. For all types of companies, the cooperation model of "strategic partnership" offers access to high-level expertise while reducing fixed costs and complexity. This was shown using chemical synthesis as an example but is also true for other areas of preclinical research. 23925387 Phosphonium phosphonate-type zwitterion-water mixed systems showing variable hydrogen bonding ability as a function of temperature. Zwitterion in which a long-chain alkyl phosphonium cation is tethered with a phosphonate-derivative anion shows stimuli responsible variable hydrogen bonding ability by a slight temperature change in the presence of water. 23868007 Cerebellar location may predict an unfavourable prognosis in paediatric high-grade glioma. Background:High-grade glioma (HGG) of the cerebellum accounts for only 5% of paediatric HGG. Since little is known about these tumours, the present study aimed at their further characterisation.Methods:Twenty-nine paediatric patients with centrally reviewed cerebellar HGG were identified from the HIT-GBM/HIT-HGG database. Clinical and epidemiological data were compared with those of 180 paediatric patients with cortical HGG.Results:Patients with cerebellar tumours were younger (median age of 7.6 vs 11.7 years, P=0.028), but both groups did not differ significantly with regard to gender, tumour predisposing syndromes, secondary HGG, primary metastasis, tumour grading, extent of tumour resection, chemotherapy regimen, or radiotherapy. Except for an increased incidence of anaplastic pilocytic astrocytoma (APA) in the cerebellar subset (20.7% vs 3.3%; P<0.001), histological entities were similarly distributed in both groups. As expected, tumour grading had a prognostic relevance on survival. Compared with cortical HGG, overall survival in the cerebellar location was significantly worse (median overall survival: 0.92±0.02 vs 2.03±0.32 years; P=0.0064), and tumour location in the cerebellum had an independent poor prognostic significance as shown by Cox-regression analysis (P=0.019).Conclusion:High-grade glioma represents a group of tumours with an obviously site-specific heterogeneity associated with a worse survival in cerebellar location. 23921071 Efficient soluble expression of secreted matrix metalloproteinase 26 in Brevibacillus choshinensis. Matrix metalloproteinase 26 (MMP-26) is a novel member of the matrix metalloproteinase family with minimal domain constitution and unknown physiological function. The three-dimensional (3D) structure of the enzyme also remains to be deciphered. Previous studies show that MMP-26 may be expressed in Escherichia coli (E. coli) as inclusion bodies and re-natured with catalytic activity. However, the low re-naturation rate of this method limits its usage in structural studies. In this paper, we tried to clone, express and purify the pro form and catalytic form of MMP-26 (ProMMP-26 and CatMMP-26) in several widely used expression vectors and express the recombinant MMP-26 proteins in E. coli cells. These constructs resulted in insoluble expressions or soluble expressions of MMP-26 with little catalytic activity. We then used Brevibacillus choshinensis (B. choshinensis) as the host system for the soluble and active expression of MMP-26. The enzyme was secreted in soluble form in the supernatant of cell culture medium and purified via a two-step purification process that included Ni(2+) affinity chromatography followed by gel filtration. The yields of purified ProMMP-26 and CatMMP-26 were 12 and 18mg/L, respectively, with high purity and homogeneity. Both ProMMP-26 and CatMMP-26 showed gelatin zymography activity and the purified CatMMP-26 had high enzymatic activity against DQ-gelatin substrate. The large-scale soluble and active protein production for future structural studies of MMP-26 is thus feasible using the B. choshinensis host system. 23116965 Antiarrhythmic effects of (-)-epicatechin-3-gallate, a novel sodium channel agonist in cultured neonatal rat ventricular myocytes. (-)-Epicatechin-3-gallate (ECG), a polyphenol extracted from green tea, has been proposed as an effective compound for improving cardiac contractility. However, the therapeutic potential of ECG on the treatment of arrhythmia remains unknown. We investigated the direct actions of ECG on the modulation of ion currents and cardiac cell excitability in the primary culture of neonatal rat ventricular myocyte (NRVM), which is considered a hypertrophic model for analysis of myocardial arrhythmias. By using the whole-cell patch-clamp configurations, we found ECG enhanced the slowly inactivating component of voltage-gated Na(+) currents (I(Na)) in a concentration-dependent manner (0.1-100 μM) with an EC(50) value of 3.8 μM. ECG not only shifted the current-voltage relationship of peak I(Na) to the hyperpolarizing direction but also accelerated I(Na) recovery kinetics. Working at a concentration level of I(Na) enhancement, ECG has no notable effect on voltage-gated K(+) currents and L-type Ca(2+) currents. With culture time increment, the firing rate of spontaneous action potential (sAP) in NRVMs was gradually decreased until spontaneous early after-depolarization (EAD) was observed after about one week culture. ECG increased the firing rate of normal sAP about two-fold without waveform alteration. Interestingly, the bradycardia-dependent EAD could be significantly restored by ECG in fast firing rate to normal sAP waveform. The expression of dominant cardiac sodium channel subunit, Nav1.5, was consistently detected throughout the culture periods. Our results reveal how ECG, the novel I(Na) agonist, may act as a promising candidate in clinical applications on cardiac arrhythmias. 23846124 Nanofiltration and granular activated carbon treatment of perfluoroalkyl acids. Perfluoroalkyl acids (PFAAs) are of concern because of their persistence in the environment and the potential toxicological effects on humans exposed to PFAAs through a variety of possible exposure routes, including contaminated drinking water. This study evaluated the efficacy of nanofiltration (NF) and granular activated carbon (GAC) adsorption in removing a suite of PFAAs from water. Virgin flat-sheet NF membranes (NF270, Dow/Filmtec) were tested at permeate fluxes of 17-75Lm(-2)h(-1) using deionized (DI) water and artificial groundwater. The effects of membrane fouling by humic acid on PFAA rejection were also tested under constant permeate flux conditions. Both virgin and fouled NF270 membranes demonstrated >93% removal for all PFAAs under all conditions tested. GAC efficacy was tested using rapid small-scale columns packed with Calgon Filtrasorb(®)300 (F300) carbon and DI water with and without dissolved organic matter (DOM). DOM effects were also evaluated with F600 and Siemens AquaCarb(®)1240C. The F300 GAC had <20% breakthrough of all PFAAs in DI water for up to 125,000 bed volumes (BVs). When DOM was present, >20% breakthrough of all PFAAs by 10,000 BVs was observed for all carbons. 23129183 A mechanism for NaCl inhibition of Reactive Blue 19 decolorization and ABTS oxidation by laccase. Laccases produced by white rot fungi have been extensively evaluated for their potential to decolorize textile wastewaters which contain salts like sodium chloride and sodium sulfate. The effect of sodium chloride and sodium sulfate on Trametes versicolor laccase during the decolorization of an anthraquinone dye (Reactive Blue 19) and the oxidation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) were evaluated by steady-state kinetic analysis. The results showed that, while sodium sulfate did not affect laccase activity, sodium chloride inhibited both ABTS oxidation and dye decolorization. However, the type of inhibition was substrate-dependent: it was hyperbolic, noncompetitive with ABTS and parabolic, noncompetitive with Reactive Blue 19. Furthermore, the results suggested that two chlorides may bind to laccase in the presence of the dye unlike recent inhibition models which suggest that there is only one inhibition site. This investigation is the first to provide evidence for and to propose a two-site model of laccase inhibition, providing new insight into NaCl inhibition of laccase. The proposed model is also useful to predict decolorization rates in the presence of sodium chloride and to determine operating conditions that will minimize inhibition. 23402272 Diosmin protects against trichloroethylene-induced renal injury in Wistar rats: plausible role of p53, Bax and caspases. Diosmin (DM) is a naturally occurring flavone and has been found to possess numerous therapeutic properties. In this study, we used DM as a protective agent against the nephrotoxic effects of the environmental toxicant trichloroethylene (TCE). Male Wistar rats were divided into five groups (I-V, n 6). Groups II, III and IV received an oral administration of TCE at a dose of 1000 mg/kg body weight for twenty consecutive days. The animals in groups II and III received an oral treatment of DM at doses of 20 and 40 mg/kg body weight, respectively, for twenty consecutive days, while groups I and V were given maize oil (5 ml/kg body weight and DM 40 mg/kg body weight, respectively) for 20 d. The protective effects of DM on TCE-induced oxidative stress and caspase-dependent apoptosis were investigated by assaying oxidative stress biomarkers, lipid peroxidation (LPO), serum toxicity markers, alkaline unwinding assay, caspase-3, -7 and -9, Bax and p53 expression. Oral administration of TCE in rats enhanced renal LPO, depleted glutathione content and antioxidant enzymes, induced DNA strand breaks (P< 0·001), modulated the expression of Bax and p53 protein and induced the expression of caspase-3, -7 and -9. Co-treatment with DM prevented oxidative stress by restoring the levels of antioxidant enzymes; furthermore, a significant dose-dependent decrease in DNA disintegration and kidney toxicity markers such as blood urea N, creatinine, lactate dehydrogenase and kidney injury molecule-1 was observed. DM also effectively decreased the TCE-induced up-regulation of Bax and p53. Data from the present study establish the protective role of DM against TCE-induced renal damage. 23927115 Simultaneous masking additivity for short Gaussian-shaped tones: Spectral effects. Laback et al. [(2011). J. Acoust. Soc. Am. 129, 888-897] investigated the additivity of nonsimultaneous masking using short Gaussian-shaped tones as maskers and target. The present study involved Gaussian stimuli to measure the additivity of simultaneous masking for combinations of up to four spectrally separated maskers. According to most basilar membrane measurements, the maskers should be processed linearly at the characteristic frequency (CF) of the target. Assuming also compression of the target, all masker combinations should produce excess masking (exceeding linear additivity). The results for a pair of maskers flanking the target indeed showed excess masking. The amount of excess masking could be predicted by a model assuming summation of masker-evoked excitations in intensity units at the target CF and compression of the target, using compressive input/output functions derived from the nonsimultaneous masking study. However, the combinations of lower-frequency maskers showed much less excess masking than predicted by the model. This cannot easily be attributed to factors like off-frequency listening, combination tone perception, or between-masker suppression. It was better predicted, however, by assuming weighted intensity summation of masker excitations. The optimum weights for the lower-frequency maskers were smaller than one, consistent with partial masker compression as indicated by recent psychoacoustic data. 23699388 Plasma membrane Ca2+-ATPase 4 in murine epididymis: secretion of splice variants in the luminal fluid and a role in sperm maturation. Plasma membrane Ca(2+)-ATPase isoform 4 (PMCA4) is the primary Ca(2+) efflux pump in murine sperm, where it regulates motility. In Pmca4 null sperm, motility loss results in infertility. We have shown that murine sperm PMCA4b interacts with Ca(2+)/CaM-dependent serine kinase (CASK) in regulating Ca(2+) homeostasis and motility. However, recent work indicated that the bovine PMCA4a splice variant (missing in testis) is epididymally expressed, along with 4b, and may be transferred to sperm. Here we show, via conventional and in situ RT-PCR, that both the splice variants of Pmca4 mRNA are expressed in murine testis and throughout the epididymis. Immunofluorescence localized PMCA4a to the apical membrane of the epididymal epithelium, and Western analysis not only confirmed its presence but showed for the first time that PMCA4a and PMCA4b are secreted in the epididymal luminal fluid (ELF), from which epididymosomes containing PMCA4a were isolated. Flow cytometry indicated the presence of PMCA4a on mature caudal sperm where it was increased ~5-fold compared to caput sperm (detected by Western blotting) and ~2-fold after incubation in ELF, revealing in vitro uptake and implicating PMCA4a in epididymal sperm maturation. Coimmunoprecipitation using pan-PMCA4 antibodies, revealed that both variants associate with CASK, suggesting their presence in a complex. Because they have different kinetic properties for Ca(2+) transport and different abilities to bind to CASK, our study suggests a mechanism for combining the functional attributes of both PMCA4 variants, leading to heightened efficiency of the pump in the maintenance of Ca(2+) homeostasis, which is crucial for normal motility and male fertility. 23707528 Compartmentalized Ras signaling differentially contributes to phenotypic outputs. Ras isoforms are membrane bound proteins that differentially localize to the plasma membrane and subcellular compartments within the cell. Whilst the cell surface is the main site for Ras activity the extent to which intracellular pools contribute to Ras function is debated. We have generated Ras chimeras targeting Ras to the ER, Golgi, mitochondria and endosomes to compare the capacity of each of these locations to support activity equivalent to normal Ras function. We find that all locations are capable of regulating the MAP kinase and Akt pathways. Furthermore, whilst endomembranous Ras pools show location-specific competence to support proliferation and transformation, Golgi-Ras is as potent as N-Ras. 23951116 Resistance Mutation R292K Is Induced in Influenza A(H6N2) Virus by Exposure of Infected Mallards to Low Levels of Oseltamivir. Resistance to neuraminidase inhibitors (NAIs) is problematic as these drugs constitute the major treatment option for severe influenza. Extensive use of the NAI oseltamivir (Tamiflu®) results in up to 865 ng/L of its active metabolite oseltamivir carboxylate (OC) in river water. There one of the natural reservoirs of influenza A, dabbling ducks, can be exposed. We previously demonstrated that an influenza A(H1N1) virus in mallards (Anas platyrhynchos) exposed to 1 µg/L of OC developed oseltamivir resistance through the mutation H274Y (N2-numbering). In this study, we assessed the resistance development in an A(H6N2) virus, which belongs to the phylogenetic N2 group of neuraminidases with distinct functional and resistance characteristics. Mallards were infected with A(H6N2) while exposed to 120 ng/L, 1.2 µg/L or 12 µg/L of OC in their sole water source. After 4 days with 12 µg/L of OC exposure, the resistance mutation R292K emerged and then persisted. Drug sensitivity was decreased ≈13,000-fold for OC and ≈7.8-fold for zanamivir. Viral shedding was similar when comparing R292K and wild-type virus indicating sustained replication and transmission. Reduced neuraminidase activity and decrease in recovered virus after propagation in embryonated hen eggs was observed in R292K viruses. The initial, but not the later R292K isolates reverted to wild-type during egg-propagation, suggesting a stabilization of the mutation, possibly through additional mutations in the neuraminidase (D113N or D141N) or hemagglutinin (E216K). Our results indicate a risk for OC resistance development also in a N2 group influenza virus and that exposure to one NAI can result in a decreased sensitivity to other NAIs as well. If established in influenza viruses circulating among wild birds, the resistance could spread to humans via re-assortment or direct transmission. This could potentially cause an oseltamivir-resistant pandemic; a serious health concern as preparedness plans rely heavily on oseltamivir before vaccines can be mass-produced. 23425040 Engineering Interface and Surface of Noble Metal Nanoparticle Nanotubes toward Enhanced Catalytic Activity for Fuel Cell Applications. In order for fuel cells to have commercial viability as alternative fuel sources, researchers need to develop highly active and robust fuel cell electrocatalysts. In recent years, the focus has been on the design and synthesis of novel catalytic materials with controlled interface and surface structures. Another goal is to uncover potential catalytic activity and selectivity, as well as understand their fundamental catalytic mechanisms. Scientists have achieved great progress in the experimental and theoretical investigation due to the urgent demand for broad commercialization of fuel cells in automotive applications. However, there are still three main problems: cost, performance, and stability. To meet these targets, the catalyst needs to have multisynergic functions. In addition, the composition and structure changes of the catalysts during the reactions still need to be explored. Activity in catalytic nanomaterials is generally controlled by the size, shape, composition, and interface and surface engineering. As such, one-dimensional nanostructures such as nanowires and nanotubes are of special interest. However, these structures tend to lose the nanoparticle morphology and inhibit the use of catalysts in both fuel cell anodes and cathodes. In 2003, Rubinstein and co-workers proposed the idea of nanoparticle nanotubes (NNs), which combine the geometry of nanotubes and the morphology of nanoparticles. This concept gives both the high surface-to-volume ratio and the size effect, which are both appealing in electrocatalyst design. In this Account, we describe our developments in the construction of highly active NNs with unique surface and heterogeneous interface structures. We try to clarify enhanced activity and stability in catalytic systems by taking into account the activity impact factors. We briefly introduce material structural effects on the electrocatalytic reactivity including metal oxide/metal and metal/metal interfaces, dealloyed pure Pt, and mixed Pt/Pd surfaces. In addition, we discuss the geometric structure and surface composition changes and evolutions on the activity, selectivity, and stability under fuel cell operation conditions. We expect that these nanostructured materials with particular nanostructured characteristics, physical and chemical properties, and remarkable structure changes will offer new opportunities for wide scientific communities. 23968824 Design, synthesis and ex vivo evaluation of colon-specific azo based prodrugs of anticancer agents. Colon-specific azo based prodrugs of anticancer agents like methotrexate (6), gemcitabine (7) and analogue of oxaliplatin (RTB-4) (8) were synthesized and characterized by modern analytical techniques. The prepared prodrugs were stable in acidic (pH 1.2) and basic (pH 7.4) buffers which showed their stability in upper GIT environment. Further, an assay was performed which demonstrated the presence of azoreductase enzyme in the rat fecal material, rat cecum content and other parts of intestinal content which reduce specifically the azo bond and release the drug. The in vitro cytotoxicity assay was also performed which clearly indicated that these azo based prodrugs are active against human colorectal cancer cell lines (COLO 205, COLO 320 DM and HT-29). The release behavior of prodrugs (10, 11 and 15) was 60-70% after 24h incubation at 37°C. Therefore, the synthesized azo linked prodrugs of methotrexate, gemcitabine and RTB-4 are the potential candidates for colon targeted drug delivery system with minimal undesirable side effects. 23907331 Stress Distribution Within Rotator Cuff Tendons With a Crescent-Shaped and an L-Shaped Tear. BACKGROUND:There are 2 representative shapes of full-thickness rotator cuff tears commonly observed: crescent-shaped and L-shaped tears. To date, the exact process of tear propagation in each shape remains unknown. PURPOSE:To determine the stress distribution pattern in rotator cuff tendons with a crescent-shaped tear and an L-shaped tear. STUDY DESIGN:Descriptive laboratory study. METHODS:The computed tomography (CT) data of a normal cadaveric shoulder from a 69-year-old man were used to develop a 3-dimensional finite element model of the rotator cuff tendons. Three different sizes (1.0-, 2.0-, and 3.0-cm widths) of crescent-shaped and L-shaped tears were created. Tensile load was applied to each cuff tendon that simulated shoulder abduction and external rotation in the hanging-arm position. Elastic analysis was performed, and distribution of the von Mises equivalent stress was calculated. Then, the stress distribution pattern was compared between the 2 tear shapes and among the 3 different tear sizes. RESULTS:In the crescent-shaped tear models, stress concentration was seen in both the anterior and the posterior edges of the torn tendon stump. In the L-shaped tear models, stress concentration was seen in the posterior torn tendon edge as well as the bottom of the longitudinal tear. The areas with high stress concentration increased with increasing tear size. At the posterior torn tendon edge, a common site of delamination, the articular half represented a higher equivalent stress than the bursal half in all models. The highest equivalent stress increased with an increase in tear size for both the abduction and the external rotation loads. CONCLUSION:A high stress concentration was seen in both the anterior and the posterior tendon edge in crescent-shaped tears and in both the posterior tendon edge and the bottom of the longitudinal tear in L-shaped tears. Stress concentration inside the tendon increased with increasing tear size. CLINICAL RELEVANCE:Crescent-shaped tears may propagate in the anterior and posterior directions, whereas L-shaped tears may propagate in the posterior and medial directions. Tear propagation may accelerate with an increase in tear size. 23931383 Composite boson mapping for lattice boson systems. We present a canonical mapping transforming physical boson operators into quadratic products of cluster composite bosons that preserves matrix elements of operators when a physical constraint is enforced. We map the 2D lattice Bose-Hubbard Hamiltonian into 2×2 composite bosons and solve it within a generalized Hartree-Bogoliubov approximation. The resulting Mott insulator-superfluid phase diagram reproduces well quantum Monte Carlo results. The Higgs boson behavior in the superfluid phase along the unit density line is unraveled and in remarkable agreement with experiments. Results for the properties of the ground and excited states are competitive with other state-of-the-art approaches, but at a fraction of their computational cost. The composite boson mapping here introduced can be readily applied to frustrated many-body systems where most methodologies face significant hurdles. 23959434 Evaluation of the Simplexa Flu A/B and RSV test for the rapid detection of influenza viruses. Recently, various molecular systems have been introduced for the detection of influenza viruses. Among these, the Simplexa Flu A/B and respiratory syncytial virus (RSV) test can provide results in approximately 2 hr. Nasopharyngeal swabs from 241 patients (influenza A, n = 81; influenza B, n = 80; influenza A and influenza B mixed, n = 1; influenza A and RSV A mixed, n = 2; and influenza and RSV negative, n = 77) were analyzed using the Simplexa Flu A/B and RSV test, a conventional reverse-transcription polymerase chain reaction (RT-PCR) assay, and a real-time RT-PCR assay. Compared to conventional RT-PCR, the Simplexa test had respective sensitivities and specificities of 100% and 100% for influenza A and 100% and 99.4% for influenza B with extracted RNA samples, and 91.7% and 99.4% for influenza A, and 97.5% and 98.1% for influenza B with unprocessed patient specimens. All RSV A specimens were successfully detected by the Simplexa test using both extracted RNA samples and unprocessed patient specimens. The real-time RT-PCR assay had respective sensitivities and specificities of 96.4% and 99.4% for influenza A, and 98.8% and 99.4% for influenza B. The Simplexa test was effective at detecting influenza viruses from extracted RNA samples as well as from unprocessed patient specimens. The assay was not only simple and rapid for influenza detection, but the performance was also comparable to that of other conventional molecular methods. J. Med. Virol. © 2013 Wiley Periodicals, Inc. 23516963 Substituted 7-Amino-5-thio-thiazolo[4,5-d]pyrimidines as Potent and Selective Antagonists of the Fractalkine Receptor (CX3CR1). We have developed two parallel series, A and B, of CX3CR1 antagonists for the treatment of multiple sclerosis. By modifying the substituents on the 7-amino-5-thio-thiazolo[4,5-d]pyrimidine core structure, we were able to achieve compounds with high selectivity for CX3CR1 over the closely related CXCR2 receptor. The structure-activity relationships showed that a leucinol moiety attached to the core-structure in the 7-position together with α-methyl branched benzyl derivatives in the 5-position displayed promising affinity, and selectivity as well as physicochemical properties, as exemplified by compounds 18a and 24h. We show the preparation of the first potent and selective orally available CX3CR1 antagonists. 23396144 Protective effect of Codium fragile against UVB-induced pro-inflammatory and oxidative damages in HaCaT cells and BALB/c mice. Acute exposure to ultraviolet (UV) radiation causes pro-inflammatory responses via diverse mechanisms including oxidative stress. Codium fragile is a green alga of Codiales family and has been reported to exhibit anti-edema, anti-allergic, anti-protozoal and anti-mycobacterial activities. In this study, we have investigated a novel anti-inflammatory potential of C. fragile using in vitro cell culture as well as in vivo animal models. In HaCaT cells, buthanol and ethylacetate fractions of 80% methanol C. fragile extract (CFB or CFE) and a single compound, clerosterol (CLS) isolated from CFE attenuated UVB (60mJ/cm(2))-induced cytotoxicity and reduced expression of pro-inflammatory proteins including cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF- α). Moreover, CFB, CFE and CLS effectively suppressed UVB-induced production of pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO). In another experiment, topical application of CFB, CFE or CLS prior to UVB irradiation (200mJ/cm(2)) on BALB/c mice, inhibited the UVB-elevated protein levels of COX-2, iNOS, and TNF-α. Furthermore, CFB, CFE and CLS suppressed oxidative damages caused by UVB irradiation for example lipid peroxidation and/or protein carbonylation, which seemed to be mediated by up-regulation of antioxidant defense enzymes. These results suggest that C. fragile could be an effective therapeutic agent providing protection against UVB-induced inflammatory and oxidative skin damages. 23545127 Parasite-induced and parasite development-dependent alteration of the swimming behavior of fish hosts. Parasites with complex life cycles have the ability to change the behavior of their intermediate host in a way that increases their transmission rate to the next host. However, the level of behavioral changes can vary considerably, depending on the stage of parasite development and parasite intensity. To investigate the influence of such parameters, we evaluated the locomotory activity of the fish Poecilia vivipara prior to experimental infections, 7 days post-infection (dpi) and 14dpi with cercariae of the digenean Ascocotyle (Phagicola) pindoramensis. The locomotory activity was monitored using an image system, Videomex(®), linked to with a video camera able to record the swimming behavior of the fishes. At the end of the experiments, fishes were dissected and all metacercariae from the gills and mesenteries, the specific sites utilized by A. (P.) pindoramensis, were recovered and counted. There was a significant decrease in the swimming behavior of fishes after 14dpi. Similarly, we found a significant correlation between the swimming behavior of the fishes and parasite intensity in both sites of infection. It is surmised that the decrease in locomotory activity of P. vivipara caused by A. (P.) pindoramensis can disturb its predator-prey relationship in natural environment. 23630181 Extracellular Electron Transfer across Bacterial Cell Membranes via a Cytocompatible Redox-Active Polymer. A redox-active phospholipid polymer with a phospholipid-mimicking structure (2-methacryloyloxyethyl phosphorylcholine; MPC) was synthesized to construct a biocompatible electron mediator between bacteria and an electrode. In this study, a copolymer of MPC and vinylferrocene [VF; poly(MPC-co-VF)] (PMF) is synthesized. When PMF is added to cultures of the bacterial species Escherichia coli (Gram negative) and Lactobacillus plantarum (Gram positive), which have different cell wall structures, a catalytic current mediated by PMF is observed. In addition, growth curves and live/dead assays indicate that PMF does not decrease metabolic activity or cell viability. These results indicate that PMF mediates extracellular electron transfer across bacterial cell membranes without associated cytotoxicity. 23103563 Ibandronate increases the expression of the pro-apoptotic gene FAS by epigenetic mechanisms in tumor cells. There is growing evidence that aminobisphosphonates like ibandronate show anticancer activity by an unknown mechanism. Biochemically, they prevent posttranslational isoprenylation of small GTPases, thus inhibiting their activity. In tumor cells, activated RAS-GTPase, the founding member of the gene family, down-regulates the expression of the pro-apoptotic gene FAS via epigenetic DNA-methylation by DNMT1. We compared ibandronate treatment in neoplastic human U-2 osteosarcoma and in mouse CCL-51 breast cancer cells as well as in the immortalized non-neoplastic MC3T3-E1 osteoblastic cells. Ibandronate attenuated cell proliferation in all cell lines tested. In the neoplastic cells we found up-regulation of caspases suggesting apoptosis. Further we found stimulation of FAS-expression as a result of epigenetic DNA demethylation that was due to down-regulation of DNMT1, which was rescued by re-isoprenylation by both geranylgeranyl-pyrophosphate and farnesylpyrophosphate. In contrast, ibandronate did not affect FAS and DNMT1 expression in MC3T3-E1 non-neoplastic cells. Data suggest that bisphosphonates via modulation of the activity of small-GTPases induce apoptosis in neoplastic cells by DNA-CpG-demethylation and stimulation of FAS-expression. In conclusion the shown epigenetic mechanism underlying the anti-neoplastic activity of farnesyl-transferase-inhibition, also explains the clinical success of other drugs, which target this pathway. 23890649 Thermogenesis in decomposing carcasses. It is of fundamental importance in forensic entomology that the factors controlling carcass temperatures during decomposition are thoroughly understood. The thermal environment to which fly larvae are exposed is the primary influence on their growth rate, and hence affects any estimate of minimum time since death using such specimens in homicide investigations. To date, much of the entomological research on maggot masses has focused on their elevation of carcass temperatures, with very little focus on the bacteria associated with larval activity. The aim of this study was to investigate the heat associated with decay and the types of bacteria present during the decomposition of a carcass, both in the presence and in the absence of maggots. Three treatments were imposed: fresh, frozen and maggot-infested, each consisting of five replicate pig carcasses. Temperature measurements and bacterial swabs were taken from the gastro-intestinal region of each pig and temperatures and bacterial communities compared between treatments. All carcasses reached average maximum temperatures above 32°C in a temperature controlled room set at 23°C. Treatment had no statistically significant effect on the temperatures recorded in each carcass but did significantly affect the community structure of the bacteria. However, bacterial community structure varied across time. This study suggests that bacterial metabolism plays a significant role in carcass thermogenesis, and that maggot masses, while contributing to localised heating within the carcass, may have less of a role in elevating carcass temperatures than previously assumed. 23509889 Acute lymphoblastic leukemia in early childhood as the presenting sign of ataxia-telangiectasia variant. Ataxia-telangiectasia (A-T), an autosomal recessive disorder is characterized by progressive neurodegeneration, immunodeficiency, sensitivity to ionizing radiation, and predisposition to cancer, especially to lymphoid malignancies. A-T variant is characterized by a milder clinical phenotype and is caused by missense or leaky splice site mutations that produce residual ataxia telangiectasia mutated (ATM) kinase activity. Lymphoid malignancy can precede the diagnosis of A-T, particularly in young children with mild neurological symptoms. We studied a consanguineous family with four A-T variant patients, three of them developed T-ALL at a young age before the diagnosis of A-T was established. ATM mutation analysis detected two new missense mutations both within exon 12: c.1514T>C and c.1547T>C. All four patients are homozygous for the two mutations, while their parents are heterozygous for the mutations. ATM protein level was low in all patients and the response to the radiomimetic agent, neocarzinostatin, was reduced. Leukemic presentation in a young age in three members of consanguineous family led to the identification of a new missense mutation in the ATM gene. The diagnosis of A-T or A-T variant should be considered in children with neurological abnormalities who develop T-ALL at a young age. 23871495 Gene suppression via U1 small nuclear RNA interference (U1i) machinery using oligonucleotides containing 2'-modified-4'-thionucleosides. Gene suppression via U1 small nuclear RNA interference (U1i) is considered to be one of the most attractive approaches, and takes the place of general antisense, RNA interference (RNAi), and anti-micro RNA machineries. Since the U1i can be induced by short oligonucleotides (ONs), namely U1 adaptors consisting of a 'target domain' and a 'U1 domain', we prepared adaptor ONs using 2'-modified-4'-thionucleosides developed by our group, and evaluated their U1i activity. As a result, the desired gene suppression via U1i was observed in ONs prepared as a combination of 2'-fluoro-4'-thionucleoside and 2'-fluoronucleoside units as well as only 2'-fluoronucleoside units, while those prepared as combination of 2'-OMe nucleoside/2'-OMe-4'-thionucleoside and 2'-fluoronucleoside units did not show significant activity. Measurement of Tm values indicated that a higher hybridization ability of adaptor ONs with complementary RNA is one of the important factors to show potent U1i activity. 23820110 Severity of pre-existing psychiatric illness and response to the Great East Japan Earthquake. Reports have described how psychiatric patients respond to disasters. However, previous reports on the response depending on diagnostic categories have provided no clear consensus. Here we analyzed response to the Great East Japan Earthquake of March 11, 2011, among psychiatric patients in light of severity of pre-existing psychiatric illness. We studied psychiatric change among a population of psychiatric outpatients in Tochigi prefecture, located ∼160km (∼100 miles) southeast of the Fukushima nuclear power plant, in an area that suffered moderate damage from the earthquake and radiation. A total of 294 psychiatric outpatients was assessed using the Global Assessment of Functioning (GAF-F). A change of ≥10 points in the GAF-F score was counted as a change in symptoms. The data were stratified by disease category, gender, and GAF-F score and analyzed using the Fisher's exact test. In the 2 months after the earthquake, 5.4% of patients showed evidence of a change in symptoms, with 4.1% worsening and 1.4% improving. Compared with patients having a GAF-F score ≤50, significantly more patients with a score >50 showed evidence of worsening symptoms. No significant difference was found with respect to gender or diagnostic category for patients with worsened or improved symptoms. Our findings reveal that a relatively small percent of patients with pre-existing psychiatric diseases showed evidence of a change in symptoms and that patients with mild-to-moderate psychiatric illness are potentially vulnerable to the impacts of a natural disaster. 23687344 The correlation of achilles tendinopathy and body mass index. With this study we intend to determine if there is a correlation between body mass index (BMI) and Achilles tendon pathology. A retrospective chart review of 197 patients was performed with CPT codes of Achilles tendinosis/tendonitis. These 197 patients were then compared with 100 random new patient encounters excluding Achilles pathology, plantar fasciitis, and surgical consults. Statistical analysis was then performed to identify correlation of BMI to incidence of Achilles tendinosis compared with patients without Achilles pathology. A total of 197 Achilles tendon pathology patients (113 male, 84 female) were analyzed and had a mean age of 52.77 ± 11.8 years (21-82) with a BMI of 34.69 ± 7.54 (17.9-75.9). The control group had a mean age of 42.74 ± 12.1 years (21-78) and mean BMI of 30.56 ± 7.55 (19.7-61.5). A significant difference was found in mean BMI between the Achilles tendinopathy group versus the control group (P < .001). There was a very significant difference in age noted between the 2 cohorts (52.77 years vs 42.74 years, P < .001), perhaps reenforcing the involvement of age-related degenerative changes. In this study, patients with Achilles pathology exhibited a significantly higher BMI than non-Achilles patients (P < .001) even after accounting for age. Levels of Evidence: Prognostic Level II. 23773306 Differential associations between maternal scaffolding and toddler emotion regulation in toddlers born preterm and full term. Parental "scaffolding" behavior has been associated with developmental outcomes in at-risk children. Because there are limited empirical data regarding how scaffolding is associated with emotion-based developmental skills, the purpose of this study was to compare associations between maternal verbal scaffolding and toddler emotion regulation, including fewer displays of negative affect and increased contentment and enjoyment during play, in toddlers born preterm and full term. This study was a cross-sectional cohort design. Maternal and toddler behavior was assessed during 5min of videotaped free play with standardized toys. 131 toddlers (18-22months) and their mothers were included (77 born preterm; 54 born full term). Toddler emotion regulation, negative affect, and dyadic mutual enjoyment were coded from videotaped play. The association between maternal scaffolding and emotion regulation was different for dyads with a toddler born preterm versus full term, wherein the association was positive for toddlers born preterm and non-significant for toddlers born full term. Similarly, the association between maternal scaffolding and negative affect was different for the two groups: negative for toddlers born preterm and non-significant for toddlers born full term. Finally, the association between maternal scaffolding and mutual enjoyment was positive for toddlers born preterm and non-significant for toddlers born full term. Our findings highlight early differences in mother-child interactive style correlates of children born preterm compared to those born full term. Maternal scaffolding behavior may be uniquely associated with emotion regulation and a positive dyadic encounter for toddlers born preterm. 23871108 Cross-Border Use of Food Databases: Equivalence of US and Australian Databases for Macronutrients. When estimating dietary intake across multiple countries, the lack of a single comprehensive dietary database may lead researchers to modify one database to analyze intakes for all participants. This approach may yield results different from those using the country-specific database and introduce measurement error. We examined whether nutrient intakes of Australians calculated with a modified US database would be similar to those calculated with an Australian database. We analyzed 3-day food records of 68 Australian adults using the US-based Nutrition Data System for Research, modified to reflect food items consumed in Australia. Modification entailed identifying a substitute food whose energy and macronutrient content were within 10% of the Australian food or by adding a new food to the database. Paired Wilcoxon signed rank tests were used to compare differences in nutrient intakes estimated by both databases, and Pearson and intraclass correlation coefficients measured degree of association and agreement between intake estimates for individuals. Median intakes of energy, carbohydrate, protein, and fiber differed by <5% at the group level. Larger discrepancies were seen for fat (11%; P<0.0001) and most micronutrients. Despite strong correlations, nutrient intakes differed by >10% for an appreciable percentage of participants (35% for energy to 69% for total fat). Adding country-specific food items to an existing database resulted in similar overall macronutrient intake estimates but was insufficient for estimating individual intakes. When analyzing nutrient intakes in multinational studies, greater standardization and modification of databases may be required to more accurately estimate intake of individuals. 23053706 The influence of parotid gland sparing on radiation damages of dental hard tissues. The aim of the present study was to evaluate whether radiation damage on dental hard tissue depends on the mean irradiation dose the spared parotid gland is subjected to or on stimulated whole salivary flow rate. Between June 2002 and October 2008, 70 patients with neck and cancer curatively irradiated were included in this study. All patients underwent dental treatment referring to the guidelines and recommendations of the German Society of Dental, Oral and Craniomandibular Sciences prior, during, and after radiotherapy (RT). During the follow-up period of 24 months, damages on dental hard tissues were classified according to the RTOG/EORTC guidelines. The mean doses (D(mean)) during spared parotid gland RT were determined. Stimulated whole saliva secretion flow rates (SFR) were measured before RT and 1, 6, 12, 24 months after RT. Thirty patients showed no carious lesions (group A), 18 patients developed sporadic carious lesions (group B), and 22 patients developed general carious lesions (group C). Group A patients received a D mean of 21.2 ± 11.04 Gy. Group B patients received a D(mean) of 26.5 ± 11.59 Gy and group C patients received a D(mean) of 33.9 ± 9.93 Gy, respectively. The D(mean) of group A was significantly lower than the D(mean) of group C (p < 0.001). Additionally, the mean SFR 6 months after RT of group A was significantly higher than the mean SFR of group C (p < 0.01). Irradiation damage on dental hard tissue correlates with increased mean irradiation doses as well as decreased salivary flow rates. Parotid gland sparing resulting in a dose below 20 Gy reduces radiation damage on dental hard tissues, and therefore, the dose may act as a predictor for the damage to be expected. 23565884 Effects of amoxicillin treatment on the salivary microbiota in children with acute otitis media. Amoxicillin is a first-line antibiotic treatment for acute otitis media in children and one of the most commonly used antibiotics for human bacterial infections. We investigated changes in salivary bacterial communities among children treated with amoxicillin for acute otitis media (n = 18), using a culture-independent approach based on pyrosequencing of the V3 region of the bacterial 16S rRNA gene. The control group consisted of children with acute otitis media who were not given antibiotics (n = 15). One species-level phylotype assigned to the genus Streptococcus was identified across all (n = 99) saliva samples. Two additional species-level phylotypes from the genera Gemella and Granulicatella were shared by all (n = 45) samples of control subjects. Amoxicillin treatment resulted in reduced species richness and diversity, and a significant shift in the relative abundance of 35 taxa at different ranks from phylum to species-level phylotype. At the phylum level, prevalence of TM7 and Actinobacteria decreased at the end of treatment, whereas Proteobacteria had a higher relative abundance post-treatment. Multivariate analysis showed that samples from the same control subject taken over time intervals tended to cluster together. Among antibiotic-treated subjects, samples taken before and at the end of amoxicillin treatment formed two relatively well-separated clusters both of which greatly overlapped with samples taken about 3 weeks post-treatment. Our results point to a substantial but incomplete recovery of the salivary bacterial community from the antibiotic about 3 weeks after the end of treatment. 23519822 Treatment of Primary Chronic Glomerulonephritis with Rehmannia Glutinosa Acteosides in Combination with the Angiotensin Receptor Blocker Irbesartan: A Randomized Controlled Trial. This study aims to assess the efficacy and safety of Rehmannia glutinosa acteosides used in combination with the angiotensin receptor blocker irbesartan to treat primary chronic glomerulonephritis. A total of 479 patients diagnosed with primary chronic glomerulonephritis were recruited from outpatient clinics and were randomly assigned to the treatment group (Rehmannia glutinosa acteosides, two 200-mg capsules, bid; and irbesartan, one 150-mg tablet, qd) or the control group (irbesartan, one 150-mg tablet, qd). The primary outcome was 24-h urinary protein. Secondary outcome measures included blood pressure, estimated glomerular filtration rate, erythrocyturia, serum alanine aminotransferase, aspartate transaminase and electrolytes. After 8 weeks of treatment, the treatment group showed a mean reduction in 24-h proteinuria of 36.42% compared to baseline, which was significantly higher than the mean reduction from baseline of 27.97% in the control group (P = 0.0278).Adverse drug reactions occurred at a similarly low rate in the treatment group (0.4%) and control group (1.2%, P = 0.3724). In the treatment of chronic glomerulonephritis, the combination of Rehmannia glutinosa acteosides and irbesartan can reduce proteinuria more effectively than irbesartan alone. Copyright © 2013 John Wiley & Sons, Ltd. 23956263 Primary repair of sternal cleft with a double osteochondroplasty flap. Sternal cleft is a rare congenital malformation affecting the anterior part of the chest wall. Surgical closure is recommended. It should be done early during the neonatal period because of the chest's flexibility. Associated abnormalities may have been previously excluded. Different surgical repairs have been described, but none has been proved to be superior to the others. We present the description of 2 cases managed with an original surgical technique. After dissecting the two sternal bars, they were approximated with several intercostal sutures under close cardiac and respiratory monitoring. A double perichondrium flap technique was then used and resulted in a double perichondrium layer. This technique is suitable for most cases and offers satisfying anatomical restoring and cosmetic results. 23543879 Changes in alkaline band formation and calcification of corticated charophyte Chara globularis. Calcification by charophytes improves the quality of water, although most studies on calcification have only examined ecorticate species. We investigated the formation and relationship of alkalines and acids with regard to calcification on internodal cells in Chara corallina, an ecorticate species, and Chara globularis, a corticate species. We observed that alkaline and acidic areas with distinct banding patterns form on the internodal cells of C. corallina. The entire periphery of internodal cells was alkalized, and no distinct acidic area developed in C. globularis. By electron microscopy of these internodal cells, the calcified areas occurred primarily in alkaline areas with a banding pattern in C. coralline. However, phenomenon also occurred homogeneously inside of the entire cortex and cell wall in C. globularis. We also investigated the formation and relatiohship of alkalines and acids with regard to calcification on internodal cells of various ages from a single thallus of C. globularis. For internodal cells of C. globularis, a uniform calcified area lay between the cell wall and cortex on all cells, irrespective of age. In contrast, young cells bore an alkaline area that was uniform and widespread throughout their entire periphery, but the alkaline area in older cells was split into smaller segments in a banding pattern. Acidic areas were absent in young cells. These results indicate that the mechanisms by which alkaline and acid areas form differ in the presence and absence of cortex and between species. 23894079 Disruption of Interactions between Hydrophobic Residues on Nonpolar Faces is a Key Determinant in Decreasing Hemolysis and Increasing Antimicrobial Activities of α-Helical Amphipathic Peptides. To design antimicrobial peptides with decrease pore-forming activity in eukaryotic (host) membranes, an amphipathic α-helical model peptide composed of Leu and Lys was modified to probe the balance in antimicrobial and hemolytic activities. Among analogues with broken hydrophobic interactions, L8N derivative exhibited an 8000-fold decrease in hemolytic activity and an eightfold improvement in antimicrobial activity, affording a 64 000-fold increase in therapeutic index against E. coli. 23756254 The effects of VEGF-A on atherosclerosis, lipoprotein profile, and lipoprotein lipase in hyperlipidaemic mouse models. The role of vascular endothelial growth factor (VEGF-A) in atherogenesis has remained controversial. We addressed this by comparing the effects of adenoviral VEGF-A gene transfer on atherosclerosis and lipoproteins in ApoE(-/-), LDLR(-/-), LDLR(-/-)ApoE(-/-), and LDLR(-/-)ApoB(100/100) mice. After 4 weeks on western diet, systemic adenoviral gene transfer was performed with hVEGF-A or control vectors. Effects on atherosclerotic lesion area and composition, lipoprotein profiles, and plasma lipoprotein lipase (LPL) activity were examined. On day 4, VEGF-A induced alterations in lipoprotein profiles and a significant negative correlation was observed between plasma LPL activity and VEGF-A levels. One month after gene transfer, no changes in atherosclerosis were observed in LDLR(-/-) and LDLR(-/-)ApoB(100/100) models, whereas both ApoE(-/-) models displayed increased en face lesion areas in thoracic and abdominal aortas. VEGF-A also reduced LPL mRNA in heart and white adipose tissue, whereas Angptl4 was increased, potentially providing further mechanistic explanation for the findings. VEGF-A gene transfer induced pro-atherogenic changes in lipoprotein profiles in all models. As a novel finding, VEGF-A also reduced LPL activity, which might underlie the observed changes in lipid profiles. However, VEGF-A was observed to increase atherosclerosis only in the ApoE(-/-) background, clearly indicating some mouse model-specific effects. 23839375 108 Human electrocorticography-based stimulation. Numerous experiments using non-invasive cortical stimulation have demonstrated transient increases in motor cortical plasticity and improved functional rehabilitation in humans. We examined the feasibility and the effects of performing repetitive human electrocorticography (ECoG) based stimulation in an activity-dependent manner. Four epileptic patients undergoing subdural ECoG grid implants were enrolled in this study. Electrical stimuli were triggered by spontaneous movement leading to upper extremity electromyographic (EMG) activity, or increases in ECoG high gamma (HG) power overlying motor cortex, exclusively. An FDA-approved EMG stimulator was used to provide 5000 stimuli over 30 minutes; afterwards, ECoG recordings were taken while the subject performed cued motor tasks. No subjects experienced any adverse events. A consistent decrease in event-related high-gamma activity after conditioning was seen. One subject, who had received 2 sessions of 5000 stimuli, also demonstrated a broadband increase in HG power and a decrease in low frequency band (LFB) power during the resting state. These spectral changes were more apparent at sites closer to the stimulated electrodes, and lasted for at least 30 minutes. No significant changes in resting motor thresholds or correlation values between stimulation sites and the rest of the grid were noted. Latencies calculated for EMG-trigger to stimulation pulse delivery were normally distributed with a mean of 31-32 ms. These surprising results suggest that, with this stimulation paradigm, repetitive electrical stimulation caused blunting of the normal HG response seen during motor movement. In the subject with the sustained broadband resting state changes, the prolonged effects perhaps suggest physiological phenomena such as changes in neuronal resistivities or local neurotransmitter levels, or potentially reflect local charge build-up on the ECoG grid. This experiment demonstrates that invasive activity-driven human cortical stimulation is safe, feasible to accomplish within the window for spike timing dependent plasticity, and underlines the need for further investigation. 23918387 Efficient multiplex biallelic zebrafish genome editing using a CRISPR nuclease system. A simple and robust method for targeted mutagenesis in zebrafish has long been sought. Previous methods generate monoallelic mutations in the germ line of F0 animals, usually delaying homozygosity for the mutation to the F2 generation. Generation of robust biallelic mutations in the F0 would allow for phenotypic analysis directly in injected animals. Recently the type II prokaryotic clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (Cas) system has been adapted to serve as a targeted genome mutagenesis tool. Here we report an improved CRISPR/Cas system in zebrafish with custom guide RNAs and a zebrafish codon-optimized Cas9 protein that efficiently targeted a reporter transgene Tg(-5.1mnx1:egfp) and four endogenous loci (tyr, golden, mitfa, and ddx19). Mutagenesis rates reached 75-99%, indicating that most cells contained biallelic mutations. Recessive null-like phenotypes were observed in four of the five targeting cases, supporting high rates of biallelic gene disruption. We also observed efficient germ-line transmission of the Cas9-induced mutations. Finally, five genomic loci can be targeted simultaneously, resulting in multiple loss-of-function phenotypes in the same injected fish. This CRISPR/Cas9 system represents a highly effective and scalable gene knockout method in zebrafish and has the potential for applications in other model organisms. 23727988 Effects of external electric fields on lysozyme adsorption by molecular dynamics simulations. Lysozyme adsorption on carboxyl-terminated self-assembled monolayers under external electric fields has been studied by all-atom molecular dynamics simulations. Lysozyme adsorption on negatively charged surfaces could generally be enhanced by positive electric fields and retarded by negative ones. Under positive electric fields, electrostatic interactions between protein and surface are strengthened; however, the interaction energy descends with field strength increases probably due to the co-adsorption of counterions onto the surface to neutralize surface charge. Comparison of orientation distributions of lysozyme adsorption on the surface in the presence and in the absence of electric fields reveals that an applied electric field could narrow the distribution and therefore helps to immobilize protein on surface with uniform orientation. Orientation angle analysis shows that lysozyme is adsorbed on the surface with "bottom end-on", "side-on", "back-on" or "top end-on" orientation under different field strengths, suggesting the possibility of controlling the preferred orientation of lysozyme on surface by applying electric fields. Conformation analysis of protein implies that the structure deformation of adsorbed lysozyme does not increase monotonically with the rising field strength. Under some field strengths, there is no additional structure deformation caused by the electric fields compared with that in the absence of electric fields; while under some other field strengths, there are larger conformational change occurrences. We propose that due to the rearrangement of positions of the local atomic charges of protein to couple its dipole with an external electric field, large position alterations of atoms might be avoided and thus conformational changes be restricted. This work may provide guidance for controlling protein adsorption behaviors via external electric fields for applications of protein immobilization and anti-fouling surfaces. 23218859 Medical student intrauterine device knowledge and attitudes: an assessment of clerkship training. Studies demonstrate that many clinician populations have poor knowledge of and harbor negative attitudes towards intrauterine devices (IUDs). We set out to assess the impact of the clinical clerkship in obstetrics and gynecology on medical student IUD knowledge and attitudes. In this prospective cohort study, students at seven diverse US medical schools were surveyed at the start and completion of their obstetrics and gynecology clinical clerkships regarding IUD exposure, knowledge and attitudes. Subject responses were compared pre- and postclerkship. One hundred six students returned completed paired surveys (response rate 82%). The preclerkship mean knowledge percent correct (54%, SD 17%) increased significantly at postclerkship assessment (72%, SD 18%) (p<.0001). The mean attitudes score also increased significantly from pre- (34%, SD 31%) to postclerkship (59%, SD 26%) (p<.0001). US medical student IUD knowledge and attitudes are significantly improved through the obstetrics and gynecology clerkship. However, significant gaps in knowledge persist postclerkship. 23911393 Differential expression and function of human IL-12Rβ2 polymorphic variants. The receptor for interleukin-12, formed by IL-12Rβ1 and IL-12Rβ2, mediates the type I immune responses of various types of lymphocytes. Polymorphisms in IL12RB2, the gene encoding IL-12Rβ2, were reported to be associated with several immune related diseases, such as Crohn's disease. Because the IL23R and IL12RB2 genes are located in close proximity on the genome, the reported associations might also be attributable to linked polymorphisms in IL23R, which were found to be associated with immune related diseases as well. To clarify the role of IL-12Rβ2 in immune diseases, we investigated the functional consequences of thirteen amino acid substitutions in IL-12Rβ2. We developed a model with retroviral expression of IL-12Rβ2 in B cell lines. With the use of this model the expression and function of the variants was compared within the same genetic background. Four of the IL-12Rβ2 variants, N271Y, R313G, A604V and L808R showed reduced IL-12 responses compared to the wild type variant. Two of these are relatively common in some populations and may be used in future association studies to reveal a role for IL-12 in infectious and/or immune related diseases. 22840697 A review of the treatment of endocrine responsive metastatic breast cancer in postmenopausal women. Endocrine therapy is the corner stone treatment for postmenopausal women with hormone receptor-positive metastatic breast cancer (MBC). Besides tamoxifen and many older agents, recently developed endocrine agents for the treatment of MBC include the third generation aromatase inhibitors (AI) - anastrozole, exemestane, letrozole - and the pure oestrogen receptor antagonist fulvestrant. As treatment of breast cancer evolves, both tamoxifen and the AIs are being increasingly used in the adjuvant setting. As such, a significant proportion of patients with hormone receptor-positive MBC will have previously received tamoxifen, an AI or both, as adjuvant treatment. This has changed the metastatic landscape and has an impact on treatment choices for patients with hormone receptor-positive MBC. In this review, we evaluate the available evidence supporting the use of endocrine therapy for the treatment of hormone receptor-positive MBC. Additionally, we consider the effect of prior adjuvant therapy on treatment choice in the metastatic setting and the optimal treatment sequence. Finally, we discuss endocrine-responsive HER2 positive tumours and the ongoing research initiatives which aim to improve outcomes for patients with MBC. 23810165 Neoadjuvant chemotherapy and salvage surgery for an aldosterone-producing adrenal carcinoma with inferior vena cava thrombus: case report and literature review. Inferior vena cava (IVC) thrombus is a rare presentation of adrenal carcinoma. Hyperladosteronism is rarely associated with it. We report a case of an aldosterone-producing left adrenal carcinoma with IVC thrombus and invasion of multiple organs, treated with neoadjuvant chemotherapy and salvage surgery. The patient is alive and asymptomatic after 46 months. Surgical aspects and therapeutic options are discussed and compared with the current medical literature. This is believed to be the first report of multiple organ resection combined with IVC thrombus removal for a functioning adrenal carcinoma. 23466081 Life-stage-dependent sensitivity of the cyclopoid copepod Mesocyclops leuckarti to triphenyltin. The effects of triphenyltin (TPT) on non-target aquatic groups like copepods have not yet been studied in detail. Recently, Mesocyclops leuckarti was suggested as a representative species for freshwater cyclopoid copepods to study the effects of plant protection products. We conducted 96h acute toxicity tests in the laboratory to study the effects of TPT on the different life stages of M. leuckarti. We used the recently proposed General Unified Threshold model of Survival (GUTS) to mechanistically describe the underlying toxicokinetic and toxicodynamic process for the nauplii, copepodites and adults (males and females) of M. leuckarti. Experimental results showed that nauplii were significantly more sensitive to TPT compared to the other stages. Also, the 96h LC50 values were much lower than the 48h LC50 values, suggesting that standard acute toxicity test durations for aquatic invertebrates may underestimate toxic effects with respect to compounds like TPT which have a slow mechanism of action. The GUTS analysis, which mechanistically described the toxicity of TPT to the different life stages of M. leuckarti, suggested that the differences in sensitivity were a consequence of a lower threshold of effects in the nauplii compared to a higher threshold in the later stages. This study shows the potential of using the GUTS to understand how toxic compounds interact with different life-stages. Further experiments to provide a more detailed understanding of toxicokinetics of TPT in copepods could be useful. 23706903 Jugular vascular access port implantation for frequent, long-term blood sampling in cats: Methodology, assessment, and comparison with jugular catheters. Long-term, frequent venous access for diagnostic, therapeutic, or research purposes in cats is problematic. Frequent blood sampling over extended periods is necessary for some therapeutic regimes and often required for clinical research in veterinary science. In this paper, we describe the implantation of vascular access ports (VAPs) and assess their use for repeated blood sampling over 16weeks and 38weeks, as well as the use of jugular catheters for one week. The VAP placement procedure was well-tolerated with few minor complications (minor swelling, contusion, or superficial dermatitis from self-trauma), which were not observed when neck bandages were applied immediately after surgery. Thromboembolism occurred in two cats, but did not occur after switching to a smaller catheter with a rounded tip and taurolidine-citrate locking solution. Although duration of access was much longer with VAPs compared to jugular catheters, patency rates were similar (89% (n=28) to 92% (n=12) after 16weeks and 75% (n=12) after 38weeks for VAPs; 88% (n=49) after one week for jugular catheters). Behavioural reactions to blood collection from 30 cats-assessed over 16weeks and comprising 378 collections-were absent or minor in 99% of collections. These findings indicate that VAPs offer a viable alternative to jugular catheters for studies requiring frequent blood sampling and lasting more than 2weeks. 23852706 Characterization and biocompatibility of glucan: a safe food additive from probiotic Lactobacillus plantarum DM5. Exopolysaccharide produced by lactic acid bacteria are the subject of an increasing number of studies for their potential applications in the food industry as stabilizing, bio-thickening and immunostimulating agents. In this regard, the authors isolated an exopolysaccharide producing probiotic lactic acid bacterium from fermented beverage Marcha of north eastern Himalayas. The isolate Lactobacillus plantarum DM5 showed extracellular glucansucrase activity of 0.48 U mg(-1) by synthesizing natural exopolysaccharide glucan (1.87 mg mL(-1) ) from sucrose. Zymogram analysis of purified enzyme confirms the presence of glucosyltransferase of approximately 148 kDa with optimal activity of 18.7 U mg(-1) at 30 °C and pH 5.4. The exopolysaccharide was purified by gel permeation chromatography and had an average molecular weight of 1.11 × 10(6) Da. Acid hydrolysis and structural characterization of exopolysaccharide revealed that it was composed of d-glucose residues, containing 86.5% of α-(1→6) and 13.5% of α-(1→3) linkages. Rheological study exhibited a shear thinning effect of glucan appropriate for food additives. A cytotoxicity test of glucan on human embryonic kidney 293 (HEK 293) and human cervical cancer (HeLa) cell lines revealed its nontoxic biocompatible nature. This is the first report on the structure and biocompatibility of homopolysaccharide α-d-glucan (dextran) from probiotic Lactobacillus plantarum strain and its unique physical and rheological properties that facilitate its application in the food industry as viscosifying and gelling agent. © 2013 Society of Chemical Industry. 23782156 Genome-wide methylation profiling demonstrates hypermethylation in maternal leukocyte DNA in preeclamptic compared to normotensive pregnancies. Objective: To compare genome-wide methylation profiles in maternal leukocyte DNA between normotensive and preeclamptic pregnant women at delivery. Methods: Age, body mass index matched case-control comparison of methylation at 27,578 cytosine- guanine sites in 14,495 genes in maternal leukocyte DNA in women with preeclampsia (PE; n = 14) and normotensive controls (n = 14). Results: PE was associated with widespread differential methylation favoring hypermethylation. Pathway analysis identified the best matched process as a neuropeptide signaling pathway (p < 10(-5)); best matched disease as eclampsia (p < 9.97 × 10(-20)). Significantly differentially methylated genes (GRIN2b. GABRA1. PCDHB7, and BEX1) are associated with seizures. Conclusion: Altered maternal leukocyte DNA methylation is associated with PE at delivery, and differential methylation of certain neuronal genes may explain the risk for eclampsia. 23896165 The sensate fibular osteoneurocutaneous flap in oromandibular reconstruction: Clinical outcomes in 31 cases. Thirty-one patients requiring composite mandibular resection were reconstructed with sensate fibula osteocutaneous flaps. Preoperatively, all patients underwent lower extremity sensory testing at the location of the proposed flap site. Intraoperatively, either the Lateral Sural Cutaneous Nerve (LSCN) or the Recurrent Superficial Peroneal Nerve (RSPN) was chosen as donor. It was then joined to either the lingual or the greater auricular nerve. Both end-to-end and end-to-side neurorrhaphies were used. At least six months postoperatively, the intraoral flaps were tested for sensory function. Twenty-eight patients achieved sensory return, including hot/cold and pinprick sensation. Both the LSCN and RSPN groups demonstrated improved two-point discrimination in static and moving studies. Better results were obtained when the lingual rather than the greater auricular nerve was the recipient. Only three patients underwent end-to-side repair, with improved two-point discrimination in two patients. The average follow-up for all patients was 11.7 months. The most dramatic return of sensory function was seen in the end-to-end lingual nerve neurorrhaphies, followed by end-to-side lingual nerve neurorrhaphies. Of the five repairs using the greater auricular nerve, only three demonstrated any measurable postoperative sensory return. Functional outcomes of postoperative patients were measured via analysis of speech, type of food consumption, and oral continence. The majority of patients exhibited normal or easily intelligible speech, was able to consume a soft food or normal diet, and could maintain normal to manageable oral continence. A subset of patients enrolled in the study went on to pursue dental rehabilitation. 23773432 Pediatric lateral distraction injury of the lumbar spine: a case report. Lateral distraction injuries represent a very rare pattern of injury with only five cases reported in the literature. Such injuries are a result of high-energy trauma and have a high association with severe concomitant injuries. All previous reports of this injury are in skeletally mature individuals, and this has not been previously described in young children. To report a case of a lateral distraction injury in a young child secondary to improper seat belt use. Case report and review of the literature. Case report of an 8-year-old girl involved in a highway speed head-on collision. We report here on an 8-year-old girl who was lying supine in the backseat of a motor vehicle while wearing a lap belt when the vehicle was involved in a high-speed motor vehicle crash. She presented with focal back pain, abdominal pain, and a seat belt sign. Imaging demonstrated focal coronal plane deformity with unilateral ligamentous disruption. The patient was diagnosed with a ligamentous lateral distraction injury of the lumbar spine. This injury was treated with open reduction and posterior spinal fusion with pedicle screw fixation. The patient tolerated the procedure well and had an uneventful postoperative course. In this case, we describe a lateral distraction injury in a young child secondary to improper seat belt use. This represents the first description of such an injury in this age group, and this case highlights the spectrum of injury caused by improper seat belt use in the pediatric population. 23824546 Temporal-spatial parameters of gait in transfemoral amputees: Comparison of bionic and mechanically passive knee joints. Background:A symmetrical gait affords the most efficient walking pattern. Bionic prostheses should provide better gait symmetry than mechanically passive prostheses with respect to a nonpathological gait.Objectives:To compare the basic temporal-spatial parameters of gait in transfemoral amputees fitted with bionic or mechanically passive prosthetic knees with those of subjects with a nonpathological gait.Study design:Three-dimensional gait analysis using an optoelectronic device.Methods:Eight transfemoral amputees participated in the study. Subjects walked across two dynamometric platforms a total of 15 times. Movement kinematics were measured using optoelectronic stereophotogrammetry.Results:The swing time of the affected limb in patients fitted with a mechanically passive knee joint was longer than that of the nonaffected limb by 0.055 s (effect size = 1.57). Compared with the control group, the swing time of the prosthetic limb in patients fitted with a mechanically passive knee was longer by 0.042 s (effect size = 2.1). Similarly, the stance time of the nonaffected limb was longer by 0.047 s (effect size = 1.07).Conclusions:Compared with a mechanically passive knee joint, a bionic knee joint evinced gait symmetry. Both the stance time and the swing time for amputees with a bionic knee were similar to those of nonamputees.Clinical relevanceProsthetists aim to design prostheses that achieve a good symmetry between the healthy and affected limbs. The use of bionic technology achieves a level of symmetry approaching that observed in nonamputees. 23844157 RNAi Screen Reveals Potentially Novel Roles of Cytokines in Myoblast Differentiation. Cytokines are cell-secreted signaling molecules that modulate various cellular functions, with the best-characterized roles in immune responses. The expression of numerous cytokines in skeletal muscle tissues and muscle cells has been reported, but their function in skeletal myogenesis, the formation of skeletal muscle, has been largely underexplored. To systematically examine the potential roles of cytokines in skeletal myogenesis, we undertook an RNAi screen of 134 mouse cytokine genes for their involvement in the differentiation of C2C12 myoblasts. Our results have uncovered 29 cytokines as strong candidates for novel myogenic regulators, potentially conferring positive and negative regulation at distinct stages of myogenesis. These candidates represent a diverse collection of cytokine families, including interleukins, TNF-related factors, and chemokines. Our findings suggest the fundamental importance of cytokines in the cell-autonomous regulation of myoblast differentiation, and may facilitate future identification of novel therapeutic targets for improving muscle regeneration and growth in health and diseases. 23735427 Financial implications of installing air filtration systems to prevent PRRSV infection in large sow herds. Air filtration systems implemented in large sow herds have been demonstrated to decrease the probability of having a porcine reproductive and respiratory syndrome virus (PRRSV) outbreak. However, implementation of air filtration represents a considerable capital investment, and does not eliminate the risk of new virus introductions. The specific objectives of the study were: 1) to determine productivity differences between a cohort of filtered and non-filtered sow farms; and 2) to employ those productivity differences to model the profitability of filtration system investments in a hypothetical 3000 sow farm. Variables included in the study were production variables (quarterly) from respective herds; air filtration status; number of pig sites within 4.7km of the farm; occurrence of a PRRSV outbreak in a quarter, and season. For the investment analyses, three Scenarios were compared in a deterministic spreadsheet model of weaned pig cost: (1) control, (2) filtered conventional attic, and (3) filtered tunnel ventilation. Model outputs indicated that a filtered farm produced 5927 more pigs than unfiltered farms. The payback periods for the investments, were estimated to be 5.35 years for Scenario 2 and 7.13 years for Scenario 3 based solely on sow herd productivity. Payback period sensitivity analyses were performed for both biological and financial inputs. The payback period was most influenced by the premium for weaned pig sales price for PRRSV-negative pigs, and the relative proportions of time that filtered vs. unfiltered farms produced PRRSV-negative pigs. A premium of $5 per pig for PRRS-negative weaned pigs reduced the estimated payback periods to 2.1 years for Scenario 2 and 2.8 years for Scenario 3. 23846406 Symptoms, visual function, and mucin expression of eyes with tear film instability. We examined symptoms, tear stability, visual function, and conjunctival cytology in eyes with an unstable tear film (UTF), expressed as a short tear film breakup time without epithelial damage or low tear secretion, and compared the results with those from eyes with aqueous deficiency (AD) associated with epithelial damage, and healthy eyes. We divided the patients with ocular discomfort into 2 groups according to the breakup time, Schirmer value, and epithelial staining score: UTF group (≤5 seconds, >5 mm, and <3 points; 21 eyes of 21 patients) and AD group (≤5 seconds, ≤5 mm, and ≥3 points; 21 eyes of 21 patients). We examined all patients and 17 healthy subjects for symptoms, tear functions, tear film stability by tear film lipid layer interferometry and tear film analysis system, and functional visual acuity. Conjunctival impression cytology was performed to investigate changes in goblet cell density, squamous metaplasia, and messenger RNA expression of MUC5AC and MUC16. The symptom scores, tear film analysis system index, and functional visual acuity testing were significantly worse in the UTF and AD groups compared with those in the control group (P < 0.05). The messenger RNA expression levels of MUC5AC and MUC16 were significantly lower in UTF and AD eyes compared with those in the control eyes (P < 0.0001). An UTF itself can cause dry eye symptoms and visual disturbance comparable with those of AD dry eyes. 23849073 Detection of the new HLA-B*08:57 allele in a voluntary platelet donor. HLA-B*08:57 has 1 nt change from HLA-B*08:01:01 at nt 108 where G→C (codon 36 ATG→ATC). 23354531 Subchronic memantine induced concurrent functional disconnectivity and altered ultra-structural tissue integrity in the rodent brain: revealed by multimodal MRI. BACKGROUND: An effective NMDA antagonist imaging model may find key utility in advancing schizophrenia drug discovery research. We investigated effects of subchronic treatment with the NMDA antagonist memantine by using behavioural observation and multimodal MRI. METHODS: Pharmacological MRI (phMRI) was used to map the neuroanatomical binding sites of memantine after acute and subchronic treatment. Resting state fMRI (rs-fMRI) and diffusion MRI were used to study the changes in functional connectivity (FC) and ultra-structural tissue integrity before and after subchronic memantine treatment. Further corroborating behavioural evidences were documented. RESULTS: Dose-dependent phMRI activation was observed in the prelimbic cortex following acute doses of memantine. Subchronic treatment revealed significant effects in the hippocampus, cingulate, prelimbic and retrosplenial cortices. Decreases in FC amongst the hippocampal and frontal cortical structures (prelimbic, cingulate) were apparent through rs-fMRI investigation, indicating a loss of connectivity. Diffusion kurtosis MRI showed decreases in fractional anisotropy and mean diffusivity changes, suggesting ultra-structural changes in the hippocampus and cingulate cortex. Limited behavioural assessment suggested that memantine induced behavioural effects comparable to other NMDA antagonists as measured by locomotor hyperactivity and that the effects could be reversed by antipsychotic drugs. CONCLUSION: Our findings substantiate the hypothesis that repeated NMDA receptor blockade with nonspecific, noncompetitive NMDA antagonists may lead to functional and ultra-structural alterations, particularly in the hippocampus and cingulate cortex. These changes may underlie the behavioural effects. Furthermore, the present findings underscore the utility and the translational potential of multimodal MR imaging and acute/subchronic memantine model in the search for novel disease-modifying treatments for schizophrenia. 23953099 Expanded Criteria for Pneumatic Retinopexy and Potential Cost Savings. To provide insight into the preoperative factors that affect outcome after pneumatic retinopexy (PR) for treatment of primary rhegmatogenous retinal detachment repair. Additionally, we sought to analyze the cost of rhegmatogenous retinal detachment repair in the United States to determine potential cost savings with pneumatic retinopexy. Single-center, retrospective, observational consecutive case series and third party payer-perspective comparative cost analysis. We included 141 eyes undergoing pneumatic retinopexy for the treatment of primary rhegmatogenous retinal detachment. Preoperative characteristics, anatomic outcomes, and best-available visual acuity were collected. Anatomic and visual outcomes were analyzed based on the presence of selected preoperative factors. The primary cohort was divided into 2 groups based on preoperative characteristics: (1) traditional pneumatic retinopexy and (2) nontraditional pneumatic retinopexy. Comparative cost analyses were performed between pneumatic retinopexy, scleral buckling, and vitrectomy. Anatomic and visual outcomes at 6 months. Overall anatomic success was 78.7% and visual acuity improved significantly (logarithm of the minimum angle of resolution [logMAR] 0.48-0.25; P <0.005). A 97.6% final anatomic success rate was achieved. Anatomic outcomes were similar between traditional versus nontraditional (84.1% vs 74.4%; P = 0.16), phakic versus pseudophakic (79.1% vs 78.0%; P = 0.88), and macula-on versus macula-off (77.9% vs 81.1%; P = 0.68) groups. Anatomic failure was predicted by the presence of an inferior retinal break (P <0.005) or visible vitreous traction on a retinal break (P = 0.04). Visual outcomes were similar between each of the traditional versus nontraditional (logMAR 0.21 vs 0.27; P >0.05) and phakic versus pseudophakic groups (logMAR 0.23 vs 0.28; P >0.05). Visual outcomes were better in macula-on detachments compared with those in which the macula was detached (logMAR 0.18 vs 0.42; P <0.005). Annual health care cost savings in the United States ranging from $6 to $30 million are theoretically possible by increasing pneumatic retinopexy utilization from the current rate of 15% to 20%-35%. Pneumatic retinopexy is an effective treatment modality for primary rhegmatogenous retinal detachment. Anatomic and visual outcomes are similar for traditional and nontraditional preoperative inclusion criteria, as well as phakic and pseudophakic eyes. Inferior breaks and visible vitreous traction on a tear predicted failure. Increased utilization of pneumatic retinopexy would achieve significant cost savings while maintaining outcomes. Proprietary or commercial disclosure may be found after the references. 23824334 Overlap of IgA Pemphigus and Linear IgA Dermatosis in a Patient with Ulcerative Colitis: A Mere Coincidence? Abstract is missing (Letter). 23668303 The secondary structure of apolipoprotein A-I on 9.6-nm reconstituted high-density lipoprotein determined by EPR spectroscopy. Apolipoprotein A-I (ApoA-I) is the major protein component of high-density lipoprotein (HDL), and is critical for maintenance of cholesterol homeostasis. During reverse cholesterol transport, HDL transitions between an array of subclasses, differing in size and composition. This process requires ApoA-I to adapt to changes in the shape of the HDL particle, transiting from an apolipoprotein to a myriad of HDL subclass-specific conformations. Changes in ApoA-I structure cause alterations in HDL-specific enzyme and receptor-binding properties, and thereby direct the HDL particle through the reverse cholesterol transport pathway. In this study, we used site-directed spin label spectroscopy to examine the conformational details of the ApoA-I central domain on HDL. The motional dynamics and accessibility to hydrophobic/hydrophilic relaxation agents of ApoA-I residues 99-163 on 9.6-nm reconstituted HDL was analyzed by EPR. In previous analyses, we examined residues 6-98 and 164-238 (of ApoA-I's 243 residues), and combining these findings with the current results, we have generated a full-length map of the backbone structure of reconstituted HDL-associated ApoA-I. Remarkably, given that the majority of ApoA-I's length is composed of amphipathic helices, we have identified nonhelical residues, specifically the presence of a β-strand (residues 149-157). The significance of these nonhelical residues is discussed, along with the other features, in the context of ApoA-I function in contrast to recent models derived by other methods. 23886073 Cross-reactive human B cell and T cell epitopes between influenza A and B viruses. Influenza A and B viruses form different genera, which were originally distinguished by antigenic differences in their nucleoproteins and matrix 1 proteins. Cross-protection between these two genera has not been observed in animal experiments, which is consistent with the low homology in viral proteins common to both viruses except for one of three polymerase proteins, polymerase basic 1 (PB1). Recently, however, antibody and CD4+ T cell epitopes conserved between the two genera were identified in humans. A protective antibody epitope was located in the stalk region of the surface glycoprotein, hemagglutinin, and a CD4+ T cell epitope was located in the fusion peptide of the hemagglutinin. The fusion peptide was also found to contain antibody epitopes in humans and animals. A short stretch of well-conserved peptide was also identified in the other surface glycoprotein, neuraminidase, and antibodies binding to this peptide were generated by peptide immunization in rabbits. Although PB1, the only protein which has relatively high overall sequence homology between influenza A and B viruses, is not considered an immunodominant protein in the T cell responses to influenza A virus infection, amino acid sequence comparisons show that a considerable number of previously identified T cell epitopes in the PB1 of influenza A viruses are conserved in the PB1 of influenza B viruses. These data indicate that B and T cell cross-reactivity exists between influenza A and B viruses, which may have modulatory effects on the disease process and recovery. Although the antibody titers and the specific T cell frequencies induced by natural infection or standard vaccination may not be high enough to provide cross protection in humans, it might be possible to develop immunization strategies to induce these cross-reactive responses more efficiently. 23187450 Pulsed Electromagnetic Field (PEMF) Plus BMP-2 Upregulates Intervertebral Disc-Cell Matrix Synthesis More Than Either BMP-2 Alone or PEMF Alone. An in vitro study using human intervertebral disc (IVD) cells. To determine if pulsed electromagnetic field (PEMF) plus bone morphogenetic protein (BMP)-2 could upregulate IVD-cell matrix synthesis more than either BMP-2 alone or PEMF alone. BMP-7 and BMP-2 can both upregulate IVD-cell matrix synthesis. There are problems associated with using either BMP-2 or BMP-7. They can diffuse away rather quickly after injection into the IVD space, they cost a lot, and they have side effects such as soft-tissue inflammation and swelling. PEMF has been reported to stimulate various types of cells. PEMF is safe, inexpensive, and noninvasive, thus multiple use is possible. However, PEMF alone has a rather weak effect on disc cells. We decided to carry out an experiment whereby we combined PEMF with BMP-2. Our thoughts were that BMP-2 plus PEMF could be better than either alone. The PEMF signal used was similar to that used in the clinical treatment of fracture nonunions or delayed fracture healing. Human disc cells were treated with BMP-2 alone or PEMF alone or PEMF plus BMP-2. Quantitative real-time PCR was performed to determine mRNA expression levels of aggrecan, collagen-2, transforming growth factor (TGF)-β, BMP-2, and BMP-7. Sulfated glycosaminoglycansynthesis was analyzed using the dimethylmethylene blue method. Western blot analysis was performed to determine the protein levels of TGF-β, BMP-2, and BMP-7. PEMF plus BMP-2 upregulates IVD-cell matrix synthesis more than BMP-2 alone or PEMF alone, and the effect seems to be synergistic. Also, PEMF plus BMP-2 induces more endogenous BMP-7 and BMP-2 mRNA levels as well as protein levels, as compared with either PEMF alone or BMP-2 alone. PEMF plus BMP-2 acts in synergy to upregulate intervertebral disc-cell matrix synthesis more than either BMP-2 alone or PEMF alone. 23955198 Value of FDG-PET/CT Examinations in Different Cancers of Children, Focusing on Lymphomas. The aim of the study was to assess sensitivity and specificity of FDG-PET/CT in different forms of childhood cancer. We retrospectively evaluated the results dedicated of 162 FDG-PET/CT examinations of 86 children treated with: Hodgkin lymphoma (HL; n = 31), non-Hodgkin lymphoma (NHL; n = 30) and other high grade solid tumors (n = 25). Patients were admitted and treated in two departments of pediatric hematology and oncology in Hungary. FDG-PET/CT was performed for staging (n = 25) and for posttreatment evaluation (n = 137). Imaging was performed in three FDG-PET/CT Laboratories, using dedicated PET/CT scanners. False positive results were defined as resolution or absence of disease progression over at least 1 year on FDG-PET/CT scans without any intervention. In some cases histopathological evaluation of suspicious lesions was performed. Fals negative results were defined as negative FDG-PET/CT results in case of active malignancy. Positive predictive values (PPV) and negative predictive values (NPV) were calculated. NPV was 100 %. The highest PPV was observed in high grade solid tumors (81 %), followed by HL (65 %) and NHL (61 %). There was a major difference of PPV in different histological types of HL (50 % in HL of mixed-cellularity subtype, 90 % in nodular sclerosing, and 100 % in lymphocyte-rich and lymphocyte depleted HL). We treated one patient with nodular lymphocyte predominant HL, who had 5 false positive FDG-PET/CT results. PPV of T- and B-lineage NHL were similar (60 % and 62 %, respectively). We observed an interesting difference of PPV in different stages of HL and NHL. In HL PPV was higher in early than in advanced disease forms: 66 % in stage II HL and 60 % in stage III HL, whereas there was an inverse relationship between PPV and disease stages in NHL 0 % in stage I and II patients, 67 % in stage III and 100 % in stage IV patients. PPV was lower in males (54 %) than in females (65 %). PPV were 64 % vs. 58 % in patients under vs. over 10 years of age. Negative FDG-PET/CT results during follow-up reliably predict the absence of malignancy. Positive FDG-PET/CT scan results in general have a low PPV. The relatively high PPV in patients with histologically proven high grade solid tumors, advanced stages of NHL and with nodular sclerosing, lymphocyte-rich and lymphocyte depleted subtypes of HL warrant a confirmation by biopsy, whereas the watch-and-wait approach can be used in other forms of childhood cancer patients with a positive FDG-PET/CT result in course of follow-up examinations. 23836194 EFFICIENT CAPTURE OF HIGH-QUALITY DATA ON OUTCOMES OF TREATMENT FOR MACULAR DISEASES: The Fight Retinal Blindness! Project. To describe the development of a web-based high-quality data collection tool to track the outcomes of treatment of macular disease in routine practice. Testing of a larger data collection tool established which fields a clinician would reliably fill out. The program, which was developed using freely available software, consists of modules interacting with a core system. The module for neovascular age-related macular degeneration is described here. Data for initial visits can be entered within 30 seconds, 15 seconds for follow-up visits. Fifteen centers from Australia, New Zealand, and Switzerland are currently contributing data. Finalized data from 2,052 eyes of 1,693 participants dating from January 2006 were analyzed. Median (25th and 75th percentiles) visual acuity at the index visit was 55 (41, 68) logarithm of the minimum angle of resolution letters with the following lesion types: minimally classic 17.2%, predominantly classic 24.6%, occult 52.0%, idiopathic polypoidal choroidal vasculopathy 1.2%, and retinal angiomatous proliferation 3.2%. This software tool will facilitate the collection of large amounts of data on the routine use of treatments of neovascular age-related macular degeneration. This will allow us to analyze important potentially modifiable variables, such as the effect of different treatment patterns on visual outcomes, and to evaluate new treatments as they are introduced into practice. 23391839 In not only vertebroplasty but also kyphoplasty, the resolution of vertebral deformities depends on vertebral mobility. It has not been clarified whether the postoperative resolution of vertebral deformities achieved by KP are superior to those achieved by VP. We compared the outcomes of KP and VP, taking into account the presence of vertebral mobility, to determine whether the balloon inflation in KP may contribute to postoperative resolution of the vertebral deformities in patients with VCFs. The subjects had 34 vertebral bodies treated by VP, and 43 vertebral bodies treated by KP. In all patients, preoperative dynamic imaging was performed to assess the presence of vertebral mobility. First, the vertebral height restoration and kyphotic change were compared between the VP and KP groups. Then, the patients were further divided into 2 groups on the basis of the presence of vertebral mobility, and they were compared within and between the VP and KP groups in relation to the presence of vertebral mobility. Overall, no significant differences were observed in either the vertebral height restoration or kyphotic change between the VP and KP groups (P > .20). Preoperative dynamic imaging identified 19 vertebral bodies each with vertebral mobility in the VP (56%) and KP groups (44%) (P = .21). Within the VP and KP groups, the vertebral height restoration and kyphotic changes were significantly better in patients with vertebral mobility than in those without (P < .01). There were no significant differences between the 2 treatment groups after adjustment for the presence of vertebral mobility (P > .30). In both the VP and KP groups, the vertebral height restoration and kyphotic change largely depended on the preoperative vertebral mobility. The use of the balloon itself contributed little to resolution of the vertebral deformities. 23274058 Jaceosidin, isolated from dietary mugwort (Artemisia princeps), induces G2/M cell cycle arrest by inactivating cdc25C-cdc2 via ATM-Chk1/2 activation. Jaceosidin, a flavonoid derived from Artemisia princeps (Japanese mugwort), has been shown to inhibit the growth of several human cancer cells, However, the exact mechanism for the cytotoxic effect of jaceosidin is not completely understood. In this study, we investigated the molecular mechanism involved in the antiproliferative effect of jaceosidin in human endometrial cancer cells. We demonstrated that jaceosidin is a more potent inhibitor of cell growth than cisplatin in human endometrial cancer cells. In contrast, jaceosidin-induced cytotoxicity in normal endometrial cells was lower than that observed for cisplatin. Jaceosidin induced G2/M phase cell cycle arrest and modulated the levels of cyclin B and p-Cdc2 in Hec1A cells. Knockdown of p21 using specific siRNAs partially abrogated jaceosidin-induced cell growth inhibition. Additional mechanistic studies revealed that jaceosidin treatment resulted in an increase in phosphorylation of Cdc25C and ATM-Chk1/2. Ku55933, an ATM inhibitor, reversed jaceosidin-induced cell growth inhibition, in part. Moreover, jaceosidin treatment resulted in phosphorylation of ERK, and pretreatment with the ERK inhibitor, PD98059, attenuated cell growth inhibition by jaceosidin. These data suggest that jaceosidin, isolated from Japanese mugwort, modulates the ERK/ATM/Chk1/2 pathway, leading to inactivation of the Cdc2-cyclin B1 complex, followed by G2/M cell cycle arrest in endometrial cancer cells. 23940237 Two-Year Outcomes of a Randomized Controlled Trial of Inhaled Nitric Oxide in Premature Infants. BACKGROUND AND OBJECTIVES:The European Union Nitric Oxide trial was designed to assess the potential benefits of inhaled nitric oxide (iNO) compared with placebo in infants with respiratory failure. This follow-up study evaluated respiratory, neurodevelopmental, and other outcomes for infants entered into the European Union Nitric Oxide trial to age 2 years.METHODS:In a multicenter, randomized, double-blind study, preterm infants born at <29 weeks' gestation with moderate respiratory failure were allocated to receive iNO (5 ppm) or placebo for 7 to 21 days. Subjects underwent assessments at 1 and 2 years corrected for prematurity.RESULTS:At 36 weeks' postmenstrual age, 696 of 792 infants were alive; 4 in the iNO arm subsequently died before age 2 years compared with 7 in the control arm. We evaluated 95% of the survivors at 12 months and 90% at 2 years. In the iNO arm, 244 of 363 (67.2%) infants had survived without disability at age 2 years compared with 270 of 374 (72.2%) who received placebo (P = .094). Mean (SD) cognitive composite scores (Bayley Scales of Infant and Toddler Development, third edition) were 94 (13) in the iNO group and 95 (14) in the placebo group; in the iNO group, 19% scored <85 and 9.5% developed cerebral palsy compared with 13.3% and 9%, respectively. There were no significant differences in hospitalizations overall or due to respiratory illness in use of home oxygen therapy or respiratory medications, in growth, or in other health outcomes.CONCLUSIONS:At 2 years of age, low-dose (5 ppm) iNO started early (<24 hours after birth) for a median of 20 days did not affect neurodevelopmental or other health outcomes. 23923059 Bacterial Cyclic AMP-Phosphodiesterase Activity Coordinates Biofilm Formation. Biofilm-related infections are a major contributor to human disease, and the capacity for surface attachment and biofilm formation are key attributes for the pathogenesis of microbes. Serratia marcescens type I fimbriae-dependent biofilms are coordinated by the adenylate cyclase, CyaA, and the cyclic 3',5'-adenosine monophosphate (cAMP)-cAMP receptor protein (CRP) complex. This study uses S. marcescens as a model system to test the role of cAMP-phosphodiesterase activity in controlling biofilm formation. Herein we describe the characterization of a putative S. marcescens cAMP-phosphodiesterase gene (SMA3506), designated as cpdS, and demonstrated to be a functional cAMP-phosphodiesterase both in vitro and in vivo. Deletion of cpdS resulted in defective biofilm formation and reduced type I fimbriae production, whereas multicopy expression of cpdS conferred a type I fimbriae-dependent hyper-biofilm. Together, these results support a model in which bacterial cAMP-phosphodiesterase activity modulates biofilm formation. 23473553 Influence of body condition on plasma prednisolone and prednisone concentrations in clinically healthy cats after single oral dose administration. Influence of body condition (over-conditioned vs. normal-conditioned) on plasma glucocorticoid concentrations after single dose oral prednisolone or prednisone in 11 cats (5 normal-conditioned and 6-over-conditioned) was investigated using a two-drug crossover trial (3-week washout interval). Body condition was determined using criterion-referenced bioelectrical impedance together with plasma drug concentrations (prednisolone [active drug] and prednisone [pro-drug]) measured by HPLC. Although interconversion of each drug to the other was confirmed, a single 2mg/kg body weight oral dose of prednisolone produced significantly higher plasma prednisolone concentration (∼4-fold higher AUC) compared to prednisone. Significantly higher plasma drug concentrations in over-conditioned cats (∼2-fold) compared to normal-conditioned cats might explain their perceived increased risk for glucocorticoid associated side effects (hepatic lipidosis, diabetes mellitus). Findings suggest low comparative bioavailability of oral prednisone compared to prednisolone in cats and consideration of lean body mass or ideal body weight for dosing practices. 23835891 Ethnographic Study of Experiences of Pakistani Women Immigrants With Pregnancy, Birthing, and Postpartum in the United States and Pakistan. Study PURPOSE: Describe the comparative birthing experiences of Pakistani immigrant women in Pakistan and the United States. Conceptual Framework: The framework was drawn from Berry's cultural adaptation, Glick-Schiller et al.'s transnationalism and Berkman's social network. Methodology: Qualitative DESIGN: Women experienced difficulties associated with inability to observe cultural traditions and loss of extended, gendered kin support. Adaptive strategies were evident through development of social networks of weak ties with nonkin groups in the United States, maintenance of transnational ties with kin back in Pakistan, and assimilation of less gender-defined roles by women and their spouses. 23597655 Volume conductor models in surface electromyography: applications to signal interpretation and algorithm test. Simulation of surface electromyogram (EMG) has provided support for the development and testing of algorithms (e.g., for the extraction of amplitude or spectral properties of the EMG or for the estimation of the muscle fiber conduction velocity) and for the interpretation of experimental results. This is the second part of a pair of papers: the first explains the methods for the development of structure based models of surface EMG; this one provides a summary of interesting applications for the interpretation of signals and testing of algorithms. Simulations from some models already introduced in the literature are compared. Moreover, estimation of indexes from an innovative layered volume conductor including a subcutaneous tissue with variable thickness in space is studied. 23840041 Time-lens based hyperspectral stimulated Raman scattering imaging and quantitative spectral analysis. We demonstrate a hyperspectral stimulated Raman scattering (SRS) microscope through spectral-transformed excitation. The 1064 nm Stokes pulse was from a synchronized time-lens source, generated through time-domain phase modulation of a continuous wave (CW) laser. The tunable pump pulse was from linear spectral filtering of a femtosecond laser output with an intra-pulse spectral scanning pulse shaper. By electronically modulating the time-lens source at 2.29 MHz, hyperspectral stimulated Raman loss (SRL) images were obtained on a laser-scanning microscope. Using this microscope, DMSO in aqueous solution with a concentration down to 28 mM could be detected at 2 μs time constant. Hyperspectral SRL images of prostate cancer cells were obtained. Multivariate curve resolution analysis was further applied to decompose the SRL images into concentration maps of CH2 and CH3 bonds. This method offers exciting potential in label-free imaging of live cells using fingerprint Raman bands. (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim). 23837893 Carbonate Precipitation under Pressure for Bioengineering in the Anaerobic Subsurface via Denitrification. A number of bioengineering techniques are being developed using microbially catalyzed hydrolysis of urea to precipitate calcium carbonate for soil and sand strengthening in the subsurface. In this study, we evaluate denitrification as an alternative microbial metabolism to induce carbonate precipitation for bioengineering under anaerobic conditions and at high pressure. In anaerobic batch culture, the halophile Halomonas halodenitrificans is shown to be able to precipitate calcium carbonate at high salinity and at a pressure of 8 MPa, with results comparable to those observed when grown at ambient pressure. A larger scale proof-of-concept experiment shows that, as well as sand, coarse gravel can also be cemented with calcium carbonate using this technique. Possible practical applications in the subsurface are discussed, including sealing of improperly abandoned wells and remediation of hydraulic fracturing during shale gas extraction. 23246353 Microarray analysis of isolated human islet transcriptome in type 2 diabetes and the role of the ubiquitin-proteasome system in pancreatic beta cell dysfunction. To shed light on islet cell molecular phenotype in human type 2 diabetes (T2D), we studied the transcriptome of non-diabetic (ND) and T2D islets to then focus on the ubiquitin-proteasome system (UPS), the major protein degradation pathway. We assessed gene expression, amount of ubiquitinated proteins, proteasome activity, and the effects of proteasome inhibition and prolonged exposure to palmitate. Microarray analysis identified more than one thousand genes differently expressed in T2D islets, involved in many structures and functions, with consistent alterations of the UPS. Quantitative RT-PCR demonstrated downregulation of selected UPS genes in T2D islets and beta cell fractions, with greater ubiquitin accumulation and reduced proteasome activity. Chemically induced reduction of proteasome activity was associated with lower glucose-stimulated insulin secretion, which was partly reproduced by palmitate exposure. These results show the presence of many changes in islet transcriptome in T2D islets and underline the importance of the association between UPS alterations and beta cell dysfunction in human T2D. 23845099 Effect of cognitive behavioural interventions on the quality of life in Chinese heroin-dependent individuals in detoxification: a randomised controlled trial. To determine whether cognitive behavioural interventions would improve the quality of life in Chinese heroin addicts. Drug dependence is one of the most serious health problems in the world, representing a real menace to mental and somatic health. However, effects of cognitive behavioural interventions on quality of life in Chinese heroin addicts are unclear. This randomised controlled study was conducted at a Drug-withdrawal Rehabilitation Center in China. Following ethics approval and heroin addicts' consent, 240 heroin addicts were randomly assigned to two groups. The experimental group (n = 120) received a six-month cognitive behavioural intervention comprising education intervention and behavioural intervention developed by the investigators. The control group (n = 120) received the hospital's routine care. The effects of the interventions on patients' quality of life were evaluated at baseline and six months and were compared. A Chinese version of Quality of Life in Drug Addiction Questionnaire was used in this study. Usefulness of the intervention and usual community services was evaluated at six months. The quality of life of participants with heroin addiction with physical and psychological disorders is poor. The experimental group showed a significant improvement in quality of life after nurse-managed cognitive behavioural intervention. The quality of life and the health status of Chinese heroin addicts were improved after they received a nurse-managed cognitive behavioural intervention. Appropriate nurse-managed cognitive behavioural intervention for heroin addicts can improve their quality of life and promote their health. It is important for clinical nurses to understand cognitive behavioural therapy, appraisal and coping to apply knowledge in practice when dealing with a client who has heroin addiction. 23954599 Infections Present on Admission Compared with Hospital-Acquired Infections in Acute Ischemic Stroke Patients. To date, few studies have assessed the influence of infections present on admission (POA) compared with hospital-acquired infections (HAIs) on neurologic deterioration (ND) and other outcome measures in acute ischemic stroke (AIS). Patients admitted with AIS to our stroke center (July 2010 to December 2010) were retrospectively assessed. The following infections were assessed: urinary tract infection, pneumonia, and bacteremia. Additional chart review was performed to determine whether the infection was POA or HAI. We assessed the relationship between infections in ischemic stroke patients and several outcome measures including ND and poor functional outcome. A mediation analysis was performed to assess the indirect effects of HAI, ND, and poor functional outcome. Of the 334 patients included in this study, 77 had any type of infection (23 POA). After adjusting for age, National Institutes of Health Stroke Scale at baseline, glucose on admission, and intravenous tissue plasminogen activator, HAI remained a significant predictor of ND (odds ratio [OR] = 8.8, 95% confidence interval [CI]: 4.2-18.7, P < .0001) and poor functional outcome (OR = 41.7, 95% CI: 5.2-337.9, P = .005), whereas infections POA were no longer associated with ND or poor functional outcome. In an adjusted analysis, we found that 57% of the effect from HAI infections on poor functional outcome is because of mediation through ND (P < .0001). Our data suggests that HAI in AIS patients increases the odds of experiencing ND and subsequently increases the odds of being discharged with significant disability. This mediated effect suggests a preventable cause of ND that can thereby decrease the odds of poor functional outcomes after an AIS. 23895666 Gold Nanoparticle-Conjugated Anti-Oxidized Low-Density Lipoprotein Antibodies for Targeted Lipidomics of Oxidative Stress Biomarkers. Oxidized low-density lipoproteins (OxLDLs), in particular, oxidized phosphatidylcholines (OxPCs), are known to be involved in pathophysiological processes such as cardiovascular diseases and are described as potential biomarkers, for example, for atherosclerosis. In our study, we used the specific affinity of anti-OxLDL antibodies (Abs) conjugated to gold nanoparticles (GNPs) for extraction and enrichment of OxPCs via selective trapping of OxLDLs from plasma combined with the sensitive detection by liquid chromatography/tandem-mass spectrometry (LC-MS/MS). Successful bioconjugation chemistry of Abs via a bifunctional polyethylene glycol (PEG) spacer and protein G linkage, respectively, was controlled by measuring the surface plasmon resonance (SPR) spectra, size, and zeta potentials. Furthermore, the amount of Ab immobilized onto GNP via the PEG linker was determined. With the optimized immobilization chemistry, the ability and potential of the GNP-based extraction procedure was used for the determination of the dissociation constant, Kd, of the OxLDL binding to the GNP-Ab conjugate. Moreover, apparent Kd's were determined for individual PCs and their oxidation products using the compound-specific selected reaction monitoring mode, which allows the characterization of the Ab affinity and, thus, assessment of the potential antigenicity of (Ox)PCs bound to OxLDLs. In summary, the application of GNP-based bioanalysis for selective targeting of OxLDLs and the fast and sensitive detection by LC-MS/MS offers new possibilities for targeted lipidomics in lipoproteins as well as for oxidative stress lipid biomarker screening. 23945906 Management of hypertension with fixed-dose triple-combination treatments. The objective of this review is to evaluate the role of fixed-dose triple-combination therapy for the management of hypertension. An assessment of clinical trials showed that half the patients with hypertension have uncontrolled blood pressure (BP), with underlying factors including therapeutic inertia and poor patient adherence. Many patients will require three antihypertensive agents to achieve BP goals, and current guidelines recommend combining drugs with complementary mechanisms of action. Three single-pill triple-combination treatments are available and each includes an agent affecting the renin-angiotensin-aldosterone pathway (either a direct renin inhibitor or an angiotensin II receptor blocker) in combination with a calcium channel blocker and diuretic. These triple-combination therapies consistently demonstrated significantly greater BP reduction relative to the component dual combinations, with BP reductions documented across a range of patient populations. Triple-combination treatments were well tolerated in all clinical trials reviewed. The use of single-pill, triple-combination antihypertensive therapy has been shown to be an effective, well-tolerated, and convenient treatment strategy that can help patients achieve BP control. 23276137 Histone deacetylase inhibitors: an attractive strategy for cancer therapy. Histone deacetylases are able to catalyze the hydrolysis of N-acetyl lysine residues of histones which package chromosomal DNA. Therefore they play an important role in mediating gene expression and cell proliferation. HDAC inhibitors have not only shown promise as antiparasitic, antineurodegenerative, antirheumatologic agents and immunosuppressant, but as potent anticancer agents by inducing cell cycle arrest, differentiation and apoptosis. This review highlights recent development in design, synthesis and biological evaluation of HDAC inhibitors for cancer therapy. 23952380 Kolmogorov-Zakharov Spectrum in AdS Gravitational Collapse. We study black hole formation during the gravitational collapse of a massless scalar field in asymptotically D-dimensional anti-de Sitter AdS_{D} spacetimes for D=4, 5. We conclude that spherically symmetric gravitational collapse in asymptotically AdS spaces is turbulent and characterized by a Kolmogorov-Zakharov spectrum. Namely, we find that after an initial period of weakly nonlinear evolution, there is a regime where the power spectrum of the Ricci scalar evolves as ω^{-s} with the frequency, ω, and s≈1.7±0.1. 23937122 Effect of Intracavernous Administration of Angiopoietin-4 on Erectile Function in the Streptozotocin-Induced Diabetic Mouse. Erectile dysfunction (ED) is a highly prevalent complication of diabetes, and the severity of endothelial dysfunction is one of the most important factors in reduced responsiveness to oral phosphodiesterase type 5 inhibitors. To study the effects of human angiopoietin-4 (Ang-4) protein on erectile function in diabetic mice. Diabetes was induced by intraperitoneal injection of streptozotocin into 8-week-old C57BL/6J male mice. At 8 weeks after the induction of diabetes, the animals were divided into four groups: control nondiabetic mice and diabetic mice receiving two successive intracavernous injections of phosphate buffered saline (days -3 and 0), a single intracavernous injection of Ang-4 protein (day 0), or two successive intracavernous injections of Ang-4 protein (days -3 and 0). One week after treatment, we measured erectile function by electrical stimulation of the cavernous nerve. The penis was harvested and stained with hydroethidine or antibodies to Ang-4, platelet/endothelial cell adhesion molecule-1, and phosphorylated endothelial nitric oxide synthase (eNOS). We also determined the differential expression of Ang-4 in cavernous tissue in the control and diabetic mice. The effect of Ang-4 protein on the phosphorylation of Tie-2, Akt, and eNOS was determined in human umbilical vein endothelial cells (HUVECs) by Western blot. The cavernous expression of Ang-4 was downregulated in diabetic mice; Ang-4 was mainly expressed in endothelial cells. Local delivery of Ang-4 protein significantly increased cavernous endothelial content, induced eNOS phosphorylation, and decreased the generation of superoxide anion and apoptosis in diabetic mice. Ang-4 protein strongly increased the phosphorylation of Tie-2, Akt, and eNOS in HUVECs. Repeated intracavernous injections of Ang-4 induced significant restoration of erectile function in diabetic mice (87% of control values), whereas a single intracavernous injection of Ang-4 protein elicited modest improvement. Cavernous endothelial regeneration by use of Ang-4 protein may have potential for the treatment of vascular disease-induced ED, such as diabetic ED. Kwon M-H, Ryu J-K, Kim WJ, Jin H-R, Song K-M, Kwon K-D, Batbold D, Yin GN, Koh GY, and Suh J-K. Effect of intracavernous administration of angiopoietin-4 on erectile function in the streptozotocin-induced diabetic mouse. J Sex Med **;**:**-**. 23770640 The nuclear receptor LXRα controls the functional specialization of splenic macrophages. Macrophages are professional phagocytic cells that orchestrate innate immune responses and have considerable phenotypic diversity at different anatomical locations. However, the mechanisms that control the heterogeneity of tissue macrophages are not well characterized. Here we found that the nuclear receptor LXRα was essential for the differentiation of macrophages in the marginal zone (MZ) of the spleen. LXR-deficient mice were defective in the generation of MZ and metallophilic macrophages, which resulted in abnormal responses to blood-borne antigens. Myeloid-specific expression of LXRα or adoptive transfer of wild-type monocytes restored the MZ microenvironment in LXRα-deficient mice. Our results demonstrate that signaling via LXRα in myeloid cells is crucial for the generation of splenic MZ macrophages and identify an unprecedented role for a nuclear receptor in the generation of specialized macrophage subsets. 23930983 AMIGAS: Building a Cervical Cancer Screening Intervention for Public Health Practice. Abstract Background: Many barriers to cervical cancer screening for Hispanic women have been documented, but few effective interventions exist. The Community Preventive Services Task Force recommends increasing cervical cancer screening through various methods. Building on this evidence, the Centers for Disease Control and Prevention funded the research and testing phases for an evidence-based and theoretically grounded intervention designed to increase cervical cancer screening among never and rarely screened Hispanic women of Mexican descent. In this article, we describe the development process of the AMIGAS (Ayudando a las Mujeres con Información, Guía, y Amor para su Salud) intervention, highlight the integration of scientific evidence and community-based participatory research principles, and identify opportunities for dissemination, adaptation, and implementation of this intervention. Methods: The AMIGAS team was a collaboration among researchers, promotoras (community health workers), and program administrators. The multiyear, multiphase project was conducted in Houston, Texas; El Paso, Texas; and Yakima, Washington. The team completed several rounds of formative research, designed intervention materials and methodology, conducted a randomized controlled trial, created a guide for program administrators, and developed an intervention dissemination plan. Results: Trial results demonstrated that AMIGAS was successful in increasing cervical cancer screening among Hispanic women. Adaptation of AMIGAS showed minimal reduction of outcomes. Dissemination efforts are underway to make AMIGAS available in a downloadable format via the Internet. Conclusions: Developing a community-based intervention that is evidence-based and theoretically grounded is challenging, time-intensive, and requires collaboration among multiple disciplines. Inclusion of key stakeholders-in particular program deliverers and administrators-and planning for dissemination and translation to practice are integral components of successful intervention design. By providing explicit directions for adaptation for program deliverers, relevant information for program administrators, and access to the intervention via the Internet, AMIGAS is available to help increase cervical cancer screening among Hispanic women and other women disproportionately affected by cervical cancer. 23843354 Design of Os(II) -based Sensitizers for Dye-Sensitized Solar Cells: Influence of Heterocyclic Ancillaries. A series of Os(II) sensitizers (TFOS-x, in which x=1, 2, or 3) with a single 4,4'-dicarboxy-2,2'-dipyridine (H2 dcbpy) anchor and two chelating 2-pyridyl (or 2-pyrimidyl) triazolate ancillaries was successfully prepared. Single-crystal X-ray structural analysis showed that the core geometry of the Os(II) -based sensitizers consisted of one H2 dcbpy unit and two eclipsed cis-triazolate fragments; this was notably different from the Ru(II) -based counterparts, in which the azolate (both pyrazolate and triazolate) fragments are located at the mutual trans-positions. The basic properties were extensively probed by using spectroscopic and electrochemical methods as well as time-dependent density functional theory (TD-DFT) calculations. Fabrication of dye-sensitized solar cells (DSCs) was then attempted by using the I(-) /I3 (-) -based electrolyte solution. One such DSC device, which utilized TFOS-2 as the sensitizer, showed promising performance characteristics with a short-circuit current density (JSC ) of 15.7 mA cm(-2) , an open-circuit voltage of 610 mV, a fill factor of 0.63, and a power conversion efficiency of 6.08 % under AM 1.5G simulated one-sun irradiation. Importantly, adequate incident photon-to-current conversion efficiency performances were observed for all TFOS derivatives over the wide spectral region of 450 to 950 nm, showing a panchromatic light harvesting capability that extended into the near-infrared regime. Our results underlined a feasible strategy for maximizing JSC and increasing the efficiency of DSCs. 23810134 Prevalence and predictors of pain in patients with major depressive disorder. Pain is common in patients with major depressive disorder (MDD). This paper aimed to determine the prevalence of and examine the predictors of pain in patients with MDD. This study was conducted at a university hospital. The prevalence of pain in adult outpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition MDD was compared with that in a matched age and sex control group of general patients in the waiting area within the hospital. Depression and pain were measured using the 17-item Hamilton Rating Scale for Depression (HAM-D) and a 10-point rating scale for pain (RSP) (from no pain at all to the most severe pain), respectively. Forty MDD and 40 general patients with matched age and sex (controls) participated in this study. Compared with the control group (47.5%), 95% of MDD patients had pain (p<0.001). The RSP scores of MDD patients were significantly higher than those of the controls (p<0.001). The mean number of pain locations was also significantly larger than in the MDD patients (p<0.001). Among the 11 male and 29 female patients with MDD, the multiple linear regression analysis revealed that the HAM-D score and history of sexual assault were significant predictors of pain. The present findings suggest that, compared with general patients, individuals with MDD have more pain in terms of the prevalence, severity, and number of locations. Severe depression and history of sexual assault are predictors of pain in MDD patients. Pain and depression are highly correlated and should be taken into account in individuals with these symptoms. 23436086 Defining technical errors in laparoscopic surgery: a systematic review. Technical errors, a distinct subcomponent of surgical proficiency, have a significant impact on patient safety and clinical outcomes. To date, only a few studies have been designed to describe and evaluate these errors. This review was performed to assess technical errors described in laparoscopic surgery. A literature search of Medline, Cochrane, EMBASE, and OVID databases (1946-2012, week 14) using the terms "technical/medical error," "technical skill," and "adverse event" in combination with the terms "laparoscopy/laparoscopic surgery" was conducted. English language peer review articles with a description of technical errors were included. Opinion papers, reviews, and articles not addressing laparoscopic surgery were excluded. The search returned 2,282 articles. Application of the inclusion criteria reduced the number of articles to 21. Of these 21 articles, 14 (67 %) were observational studies, 3 (14 %) were randomized trials, 2 (10 %) were prospective interventional studies, and 2 (10 %) were retrospective analyses. Eight articles (38 %) applied error analysis as an approach to determine error rates within routine procedures. The remaining 13 articles (62 %) used the assessment of errors to describe and quantify surgical skill in an educational setting. A number of approaches for the assessment of surgical technical errors exist. The error definitions vary greatly, making a comparison of error rates between groups impossible. Complexity of scale design and subjectivity in ratings have resulted in limited use of these scores outside the experimental setting. To facilitate error analysis as a self-assessment method of continuous learning and quality control, further research and better tools are required. 22431281 Dynamic brain structural changes after left hemisphere subcortical stroke. This study aimed to quantify dynamic structural changes in the brain after subcortical stroke and identify brain areas that contribute to motor recovery of affected limbs. High-resolution structural MRI and neurological examinations were conducted at five consecutive time points during the year following stroke in 10 patients with left hemisphere subcortical infarctions involving motor pathways. Gray matter volume (GMV) was calculated using an optimized voxel-based morphometry technique, and dynamic changes in GMV were evaluated using a mixed-effects model. After stroke, GMV was decreased bilaterally in brain areas that directly or indirectly connected with lesions, which suggests the presence of regional damage in these "healthy" brain tissues in stroke patients. Moreover, the GMVs of these brain areas were not correlated with the Motricity Index (MI) scores when controlling for time intervals after stroke, which indicates that these structural changes may reflect an independent process (such as axonal degeneration) but cannot affect the improvement of motor function. In contrast, the GMV was increased in several brain areas associated with motor and cognitive functions after stroke. When controlling for time intervals after stroke, only the GMVs in the cognitive-related brain areas (hippocampus and precuneus) were positively correlated with MI scores, which suggests that the structural reorganization in cognitive-related brain areas may facilitate the recovery of motor function. However, considering the small sample size of this study, further studies are needed to clarify the exact relationships between structural changes and recovery of motor function in stroke patients. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc. 23519881 6-Gingerol Inhibits Rosiglitazone-Induced Adipogenesis in 3T3-L1 Adipocytes. We investigated the effects of 6-gingerol ((S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone) on the inhibition of rosiglitazone (RGZ)-induced adipogenesis in 3T3-L1 cells. The morphological changes were photographed based on staining lipid accumulation by Oil-Red O in RGZ (1 µmol/l)-treated 3T3-L1 cells without or with various concentrations of 6-gingerol on differentiation day 8. Quantitation of triglycerides content was performed in cells on day 8 after differentiation induction. Differentiated cells were lysed to detect mRNA and protein levels of adipocyte-specific transcription factors by real-time reverse transcription-polymerase chain reaction and Western blot analysis, respectively. 6-gingerol (50 µmol/l) effectively suppressed oil droplet accumulation and reduced the sizes of the droplets in RGZ-induced adipocyte differentiation in 3T3-L1 cells. The triglyceride accumulation induced by RGZ in differentiated 3T3-L1 cells was also reduced by 6-gingerol (50 µmol/l). Treatment of differentiated 3T3-L1 cells with 6-gingerol (50 µmol/l) antagonized RGZ-induced gene expression of peroxisome proliferator-activated receptor (PPAR)γ and CCAAT/enhancer-binding protein α. Additionally, the increased levels of mRNA and protein in adipocyte-specific fatty acid binding protein 4 and fatty acid synthase induced by RGZ in 3T3-L1 cells were decreased upon treatment with 6-gingerol. Our data suggests that 6-gingerol may be beneficial in obesity, by reducing adipogenesis partly through the down-regulating PPARγ activity. Copyright © 2013 John Wiley & Sons, Ltd. 23710819 Consensus statement on the use of intravenous recombinant tissue plasminogen activator to treat acute ischemic stroke by the chinese stroke therapy expert panel. The last update of the consensus statement on intravenous recombinant tissue plasminogen activator (IV rt-PA) for acute ischemic stroke (AIS) by the Chinese Stroke Therapy Expert Panel was published in 2006. Great progress has been made since then. To provide another update on the new knowledge of IV rt-PA for AIS since 7 years ago. In summer of 2012, the Chinese Stroke Therapy Expert Panel was reconvened. New publications on the use of IV rt-PA for AIS were reviewed. In addition, all newly published consensus and guidelines from other countries were reviewed. The 2006 version of Chinese Consensus was then updated. There is now clinical evidence to support the use of IV rt-PA between 3 and 4.5 h after the onset with several exclusion criteria. More studies are needed to provide the evidence for IV rt-PA use beyond 4.5 h. There is benefit giving IV rt-PA within 3 h to patients who are older than 80 and in patients with ongoing atrial fibrillation. Patients with INR<1.7 while on warfarin, minor strokes, rapid improving strokes and severe strokes should be treated and can all be benefited from IV rt-PA. Since IV rt-PA was initially recommended in 1996, there is now more evidence support its use, efficacy and safety. The treatment time window is also being expanded. More public education on stroke recognition are needed so many stroke patients may benefit from the treatment. The 2013 version of Chinese IV rt-PA consensus contains the most up-to-date information on the use of IV rt-PA for AIS. It will be a useful tool and guideline to provide appropriate thrombolytic therapy to stroke patients who meet the criteria. 23877863 Tongue musculomucosal flap for soft palate reconstruction in patients with OSAHS - Clinical experience in technical strategy. With the idea of "replacing lost tissure with similar tissure in kind", vessel-pedicled palate mucosal flap, pedicled buccal musculomucosal flap and adjacent tongue musculomucosal flap could be the ideal approaches to soft palate reconstruction. To assess the adjacent tongue musculomucosal flap for soft palate reconstruction. From August 2010 to July 2011, we applied tongue musculomucosal flap for soft palate reconstruction in three patients with Obstructive Sleep Apnoea/Hypopnoes Syndrome (OSAHS) in order to release OSAHS symptom by glossal volume reduction. All patients recovered from intraoral operations with good objective as subjective speech and swallowing. Suffice it to say that OSAHS symptom was released for these patients. Here we provide a case to deal with problems related to OSAHS symptom when one works on oral surgery or reconstructing oral structure. 23959463 Treatment results and prognostic factors for advanced squamous cell carcinoma of the larynx treated with concurrent chemoradiotherapy. To review our experience with concurrent chemoradiotherapy (CCRT) for patients with advanced resectable squamous cell carcinoma (SCC) of the larynx and to evaluate the factors affecting survival and larynx preservation. Retrospective study. The records of 102 patients with stage III or IV resectable SCC of the larynx treated with CCRT between February 1994 and March 2009 were reviewed. Of 102 patients, 59 were treated with high-dose regimens, including cisplatin, 5-fluorouracil (5-FU), methotrexate, and leucovorin or docetaxel, cisplatin, and 5-FU, and 43 were treated with low-dose regimens, including carboplatin and uracil-tegafur or S-1. Radiotherapy was delivered 5 days a week using a single daily fraction of 1.8-2.0 Gray (Gy), to a total dose of 66.0-70.2 Gy. Overall survival (OS), disease-specific survival (DSS), and DSS with larynx preservation were estimated using Kaplan-Meier methods. The log-rank test and Cox proportional hazards regression were used to identify significant prognostic factors for DSS and DSS with larynx preservation. The 5-year OS and DSS for all patients treated with CCRT were 63.9 and 70.7 %, respectively. The 5-year DSS with larynx preservation was 54.1 %. On multivariate analysis, N stage, synchronous multiple primary cancers, and the contents of chemotherapy were significant predictors of OS for patients undergoing CCRT; T stage, N stage, and the contents of chemotherapy were significant prognostic factors for larynx preservation. The treatment method including the indication for CCRT may be determined by the contents of the chemotherapy and the T and N stages of laryngeal SCC. It is important to diagnose multiple synchronous primary cancers before CCRT. 23821483 mTORC2 regulates mechanically induced cytoskeletal reorganization and lineage selection in marrow derived mesenchymal stem cells. The cell cytoskeleton interprets and responds to physical cues from the microenvironment. Applying mechanical force to mesenchymal stem cells induces formation of a stiffer cytoskeleton, which biases against adipogenic differentiation and toward osteoblastogenesis. mTORC2, the mTOR complex defined by its binding partner rictor, is implicated in resting cytoskeletal architecture and is activated by mechanical force. We asked if mTORC2 played a role in mechanical adaptation of the cytoskeleton. We found that during bi-axial strain induced cytoskeletal restructuring, mTORC2 and Akt co-localize with newly assembled focal adhesions (FA). Disrupting the function of mTORC2, or that of its downstream substrate Akt, prevented mechanically-induced F-actin stress fiber development. mTORC2 becomes associated with vinculin during strain, and knock-down of vinculin prevents mTORC2 activation. In contrast, mTORC2 is not recruited to the FA complex during its activation by insulin, nor does insulin alter cytoskeletal structure. Further, when rictor was knocked down, the ability of MSC to enter the osteoblastic lineage was reduced, and when cultured in adipogenic medium, rictor-deficient MSC showed accelerated adipogenesis. This indicated that cytoskeletal remodeling promotes osteogenesis over adipogenesis. In sum, our data show that mTORC2 is involved in stem cell responses to biophysical stimuli, regulating both signaling and cytoskeletal reorganization. As such, mechanical activation of mTORC2 signaling participates in mesenchymal stem cell lineage selection, preventing adipogenesis by preserving β-catenin and stimulating osteogenesis by generating a stiffer cytoskeleton. 23845234 High dose genistein aglycone therapy is safe in patients with mucopolysaccharidoses involving the central nervous system. Genistein (4,5,7-trihydroexyisoflavone), a soy derived isoflavone, has been proposed as a substrate reduction therapy in patients with mucopolysaccharidoses (MPS) disorders with central nervous system involvement based on studies in cultured fibroblasts demonstrating that this agent inhibits glycosaminoglycan synthesis. Several studies have reported treatment of MPS III patients with low dose genistein (5-15mg/kg/day) with no serious adverse effects and variable neurocognitive outcomes. Mice with MPS IIIB treated with high dose (160mg/kg/day) genistein exhibited a significant decrease in heparan sulfate accumulation and neuroinflammation in the brain and improvement of the behavioral phenotype. No study to date has been performed using high dose genistein treatment in MPS patients. We initiated an open label study to assess the safety of high dose genistein treatment in MPS patients with neurological impairment. Twenty-two eligible patients were treated at least 12months with pure synthetic genistein at a dose of 150mg/kg/day. Safety labs, urine GAG levels, clinical status and history of adverse events were obtained every 3months and physical examination was performed by single examiner at least every 12months. While neurocognitive level was not a primary endpoint, participants were asked to obtain annual neurocognitive testing if available and a 9 point disability scale (FPSS) was recorded at each study visit. In the course of 12months of treatment, we observed no serious adverse events that were unexplained by the underlying condition and no severe adverse events that were felt to be potentially related to the genistein therapy. Two male subjects developed Tanner II breast development not present at baseline which could be related to the mild estrogenic effects of genistein. We observed no consistent decline in urine GAG levels; however, urinary GAG excretion was erratic. After 12months, the FPSS remained unchanged in 16 patients and declined by 1 point in 2 patients. Based on the results obtained so far, high dose oral genistein therapy appears to be safe in MPS patients and additional testing in a larger randomized placebo controlled trial is needed to further assess safety and efficacy. 23968366 Which patient and treatment factors are related to successful cardiovascular risk score reduction in general practice? Results from a randomized controlled trial. Cardiovascular disease is a leading cause of death. It is important to identify patient and treatment factors that are related to successful cardiovascular risk reduction in general practice. This study investigates which patient and treatment factors are related to changes in cardiovascular risk estimation, expressed as the Systematic Coronary Risk Evaluation (SCORE) 10 year risk of cardiovascular mortality. 179 general practice patients with mild-moderately elevated cardiovascular risk followed a one-year programme which included structured lifestyle and medication treatment by practice nurses, with or without additional self-monitoring. From the patient and treatment data collected as part of the "Self-monitoring and Prevention of RIsk factors by Nurse practitioners in the region of Groningen" randomized controlled trial (SPRING-RCT), the contribution of patient and treatment factors to the change in SCORE was analysed with univariate and multivariate analyses. In multivariate analyses with multiple patient and treatment factors, only SCORE at baseline, and addition of or dose change in lipid lowering or antihypertensive medications over the course of the study were significantly related to change in SCORE. Our analyses support the targeting of treatment at individuals with a high SCORE at presentation. Lipid lowering medication was added or changed in only 12% of participants, but nevertheless was significantly related to ΔSCORE in this study population. Due to the effect of medication in this practice-based project, the possible additional effect of the home monitoring devices, especially for individuals with no indication for medication, may have been overshadowed. trialregister.nl NTR2188. 23855879 Cytokine and chemokine responses to helminth and protozoan parasites and to fungus and mite allergens in neonates, children, adults, and the elderly. In rural sub-Saharan Africa, endemic populations are often infected concurrently with several intestinal and intravascular helminth and protozoan parasites. A specific, balanced and, to an extent, protective immunity will develop over time in response to repeated parasite encounters, with immune responses initially being poorly adapted and non-protective. The cellular production of pro-inflammatory and regulatory cytokines and chemokines in response to helminth, protozoan antigens and ubiquitous allergens were studied in neonates, children, adults and the elderly. In children schistosomiasis prevailed (33%) while hookworm and Entamoeba histolytica/E. dispar was found in up to half of adults and the elderly. Mansonella perstans filariasis was only present in adults (24%) and the elderly (25%). Two or more parasite infections were diagnosed in 41% of children, while such polyparasitism was present in 34% and 38% of adults and the elderly. Cytokine and chemokine production was distinctively inducible by parasite antigens; pro-inflammatory Th2-type cytokine IL-19 was activated by Entamoeba and Ascaris antigens, being low in neonates and children while IL-19 production enhanced "stepwise" in adults and elderly. In contrast, highest production of MIP-1delta/CCL15 was present in neonates and children and inducible by Entamoeba-specific antigens only. Adults and the elderly had enhanced regulatory IL-27 cytokine responses, with Th2-type chemokines (MCP-4/CCL13, Eotaxin-2/CCL24) and cytokines (IL-33) being notably inducible by helminth- and Entamoeba-specific antigens and fungus-derived allergens. The lower cellular responsiveness in neonates and children highlighted the development of a parasite-specific cellular response profile in response to repeated episodes of exposure and re-infection. Following repeated exposure to parasites, and as a consequence of host inability to prevent or eliminate intestinal helminth or protozoa infections, a repertoire of immune responses will evolve with lessened pro-inflammatory and pronounced regulatory cytokines and chemokines; this is required for partial parasite control as well as for preventing inadequate and excessive host tissue and organ damage. 23427191 Neural correlates of performance monitoring in chronic cannabis users and cannabis-naive controls. Chronic cannabis use is associated with residual negative effects on measures of executive functioning. However, little previous work has focused specifically on executive processes involved in performance monitoring in frequent cannabis users. The present study investigated event-related potential (ERP) correlates of performance monitoring in chronic cannabis users. The error-related negativity (ERN) and error positivity (Pe), ERPs sensitive to performance monitoring, were recorded from 30 frequent cannabis users (mean usage=5.52 days/week) and 32 cannabis-naïve control participants during a speeded stimulus discrimination task. The "oddball" P3 ERP was recorded as well. Users and controls did not differ on the amplitude or latency of the ERN; however, Pe amplitude was larger among users. Users also showed increased amplitude and reduced latency of the P3 in response to infrequent stimuli presented during the task. Among users, urinary cannabinoid metabolite levels at testing were unrelated to ERP outcomes. However, total years of cannabis use correlated negatively with P3 latency and positively with P3 amplitude, and age of first cannabis use correlated negatively with P3 amplitude. The results of this study suggest that chronic cannabis use is associated with alterations in neural activity related to the processing of motivationally-relevant stimuli (P3) and errors (Pe). 23964888 Point-of-care tests in general practice: Hope or hype? Point-of-care tests are biomedical tests on patients' specimens like blood, saliva, urine or faeces, which can be used near the patient, without interference of a laboratory. The use of these tests, many of which have been recently developed, is increasing in general practice, where they add to the GP's set of diagnostic instruments. The question is, however, whether they always contribute to an effective and high-quality diagnostic process by GPs. We present a set of criteria that can be used by guideline developers, regional primary care organizations and individual GPs to evaluate a new point-of-care test in a practice setting. These criteria do not relate only to their use and quality. A point-of-care test needs to be evaluated in the right population and for the right indications, and GPs then need to use them for the indications for which they were evaluated. Expanding the range of indications can lead to an increase in false-positive and false-negative test results. 23542512 Amelioration of cyclophosphamide-induced hepatotoxicity by the root extract of Decalepis hamiltonii in mice. Hepatoprotective potential of the aqueous extract of the roots of Decalepis hamiltonii (DHA) against cyclophosphamide (CP)-induced oxidative stress has been investigated in mice. Administration of CP (25mg/kg b.w., i.p) for 10 days induced hepatic damage as indicated by the serum marker enzymes aspartate and alanine transaminases (AST, ALT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). Parallel to these changes CP induced oxidative stress in the liver as evident from the increased lipid peroxidation (LPO), reactive oxygen species (ROS), depletion of glutathione (GSH), and reduced activities of the antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST). Treatment with DHA (50 and 100 mg/kg b.w., po) mitigated the CP-induced oxidative stress. Moreover, expression of genes for the antioxidant enzymes, were down-regulated by CP treatment which was reversed by DHA. Our study shows the DHA protected the liver from toxicity induced by CP and therefore, it could be serve as a safe medicinal supplement during cyclophosphamide chemotherapy. 22921427 Interactions between bufadienolides derived from toad venom and verapamil in langendorff-perfused guinea-pig hearts. Drug toxicity may occur due to dangerous drug combination. We aimed to investigate the influence of verapamil (a P-gp inhibitor)--bufadienolides interaction on cardiotoxicity and bufadienolide uptake by the isolated heart. The study was performed in Langendorff isolated perfused guinea-pig hearts by bufadienolides infusion in the absence and presence of verapamil (250, 500ng/ml). Arrhythmia parameters were evaluated by ECG and the content of bufadienolides in heart were measured by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS). In the present of verapamil, the wide QRS duration and lightly rapid heart rate (HR) were markedly reduced in the early stage of bufadienolide intoxication. However, the ECG changes characterized by prolonged P-R interval, and slow heart rate and low QRS amplitude in the late stage of bufadienolide intoxication were significantly enhanced. Furthermore, the contents of a variety of bufadienolide compounds in the verapamil+bufadienolide group were significantly higher when cardiac arrest occurred. Although verapamil reduced the bufadienolide-induced ventricular arrhythmias, verapamil worsened heart block and lethal bradycardia of bufadienolides partly via increasing the uptake of bufadienolides in heart tissue, which could compromise the protective effects of verapamil against bufadienolide intoxication. These results suggested that the verapamil may produce dangerous interactions with drugs containing bufadienolides. 23523929 The fluorescence detected guanidine hydrochloride equilibrium denaturation of wild-type staphylococcal nuclease does not fit a three-state unfolding model. A three-state equilibrium unfolding of a protein can be difficult to detect if two of the states fail to differ in some easily measurable way. It has been unclear whether staphylococcal nuclease unfolds in a two-state fashion, with only the native and denatured states significantly populated at equilibrium, or in a three-state manner, with a well-populated intermediate. Since equilibrium unfolding experiments are commonly used to determine protein stability and the course of denaturation are followed by changes in the fluorescence which has difficulty in distinguishing various states, this is a potential problem for many proteins. Over the course of twenty years we have performed more than one hundred guanidine hydrochloride equilibrium denaturations of wild-type staphylococcal nuclease; to our knowledge, a number of denaturations unrivaled in any other protein system. A careful examination of the data from these experiments shows no sign of the behavior predicted by a three-state unfolding model. Specifically, a three-state unfolding should introduce a slight, but characteristic, non-linearity to the plot of stability versus denaturant concentration. The average residuals from this large number of repeated experiments do not show the predicted behavior, casting considerable doubt on the likelihood of a three-state unfolding for the wild-type protein. The methods used for analysis here could be applied to other protein systems to distinguish a two-state from a three-state denaturation. 23403015 Spray-dried casein-based micelles as a vehicle for solubilization and controlled delivery of flutamide: Formulation, characterization, and in vivo pharmacokinetics. Novel casein (CAS)-based micelles loaded with the poorly soluble anti-cancer drug, flutamide (FLT), were successfully developed in a powdered form via spray-drying technique. Genipin (GNP) was used to crosslink CAS micelles as demonstrated by color variation of the micelles. Drug solubilization was enhanced by incorporation within the hydrophobic micellar core which was confirmed by solubility study and UV spectra. Spherical core-shell micelles were obtained with a particle size below 100nm and zeta potential around -30mV. At low drug loading, FLT was totally incorporated within micellar core as revealed by thermal analysis. However, at higher loading, excess non-incorporated drug at micelle surface caused a significant reduction in the surface charge density. Turbidity measurements demonstrated the high physical stability of micelles for 2weeks dependent on GNP-crosslinking degree. In a dry powdered form, the micelles were stable for 6months with no significant changes in drug content or particle size. A sustained drug release from CAS micelles up to 5days was observed. After i.v. administration into rats, CAS micelles exhibited a prolonged plasma circulation of FLT compared to drug solution. Furthermore, a more prolonged drug systemic circulation was observed for GNP-crosslinked micelles. Overall, this study reports the application of spray-dried natural protein-based micelles for i.v. delivery of hydrophobic anti-cancer drugs such as FLT. 23914928 Metal-based carboxamide-derived compounds endowed with antibacterial and antifungal activity. Abstract A series of three bioactive thiourea (carboxamide) derivatives, N-(dipropylcarbamothioyl)-thiophene-2-carboxamide (L(1)), N-(dipropylcarbamothioyl)-5-methylthiophene-2-carboxamide (L(2)) and 5-bromo-N-(dipropylcarbamothioyl)furan-2-carboxamide (L(3)) and their cobalt(II), copper(II), nickel(II) and zinc(II) complexes (1)-(12) have been synthesized and characterized by their IR,(1)H-NMR spectroscopy, mass spectrometry and elemental analysis data. The Crystal structure of one of the ligand, N-(dipropylcarbamothioyl)thiophene-2-carboxamide (L(1)) and its nickel(II) and copper(II) complexes were determined from single crystal X-ray diffraction data. All the ligands and metal(II) complexes have been subjected to in vitro antibacterial and antifungal activity against six bacterial species (Escherichia coli. Shigella flexneri. Pseudomonas aeruginosa. Salmonella typhi. Staphylococcus aureus and Bacillus subtilis) and for antifungal activity against six fungal strains (Trichophyton longifusus. Candida albicans. Aspergillus flavus. Microsporum canis. Fusarium solani and Candida glabrata). The in vitro antibacterial and antifungal bioactivity data showed the metal(II) complexes to be more potent than the parent ligands against one or more bacterial and fungal strains. 23770999 Mass and compositional changes, relevant to biorefining, in Miscanthus x giganteus plants over the harvest window. Miscanthus plants were sampled from several plantations in Ireland over the harvest window (October-April). These were separated into their anatomical components and the loss of leaves monitored. Three distinct phases were apparent: there was minimal loss in the "Early" (October to early December) and "Late" (March and April) phases, and rapid leaf loss in the interim period. Samples were analysed for constituents relevant to biorefining. Changes in whole-plant composition included increases in glucose and Klason lignin contents and decreases in ash and arabinose contents. These changes arose mostly from the loss of leaves, but there were some changes over time within the harvestable plant components. Although leaves yield less biofuel than stems, the added biomass provided by an early harvest (31.9-38.4%) meant that per hectare biofuel yields were significantly greater (up to 29.3%) than in a late harvest. These yields greatly exceed those from first generation feedstocks. 23896381 A biased random-key genetic algorithm for data clustering. Cluster analysis aims at finding subsets (clusters) of a given set of entities, which are homogeneous and/or well separated. Starting from the 1990s, cluster analysis has been applied to several domains with numerous applications. It has emerged as one of the most exciting interdisciplinary fields, having benefited from concepts and theoretical results obtained by different scientific research communities, including genetics, biology, biochemistry, mathematics, and computer science. The last decade has brought several new algorithms, which are able to solve larger sized and real-world instances. We will give an overview of the main types of clustering and criteria for homogeneity or separation. Solution techniques are discussed, with special emphasis on the combinatorial optimization perspective, with the goal of providing conceptual insights and literature references to the broad community of clustering practitioners. A new biased random-key genetic algorithm is also described and compared with several efficient hybrid GRASP algorithms recently proposed to cluster biological data. 23910845 Skin messages in suicide - An unusual occurrence. Notes are found in only a minority of cases of suicide and occasionally may involve writing messages on skin surfaces. A prospective study was undertaken for cases of suicide with skin messaging over a 12-year period from 1/1/2000 to 31/12/2011. A total of 498 cases of suicide were examined with only 2 cases (0.4%) having suicide notes written on their skin. Both cases involved young males (aged 18 and 30 years respectively) with the deaths occurring by hanging. In both cases typical parchmented ligature marks were present around the neck running up to the point of suspension. Both decedents had written messages on their hands/arms expressing mixtures of sorrow and hopelessness. There were no other suicide notes present. It is not clear whether writing on skin rather than on more conventional material suggests that the suicide may not have been planned, or instead that the decedent wanted to ensure that the message was found. Messages on skin may be slightly different to messages written on other surfaces, as space is limited and pens and markers may not write as effectively. An additional problem with skin messages is their vulnerability to erasure, making clear documentation of these findings at the scene important. 23238124 Osteocyte apoptosis. Apoptotic death of osteocytes was recognized over 15years ago, but its significance for bone homeostasis has remained elusive. A new paradigm has emerged that invokes osteocyte apoptosis as a critical event in the recruitment of osteoclasts to a specific site in response to skeletal unloading, fatigue damage, estrogen deficiency and perhaps in other states where bone must be removed. This is accomplished by yet to be defined signals emanating from dying osteocytes, which stimulate neighboring viable osteocytes to produce osteoclastogenic cytokines. The osteocyte apoptosis caused by chronic glucocorticoid administration does not increase osteoclasts; however, it does negatively impact maintenance of bone hydration, vascularity, and strength. This article is part of a Special Issue entitled "The Osteocyte". 23839372 105 DBS Lead Proximity to DTI-Based Sensory Thalamus Correlates With Pain Relief. Thalamic deep brain stimulation (DBS) for the treatment of medically refractory pain has been largely abandoned on account of its inconsistent and oftentimes poor efficacy. Given the inability to discern the internal anatomic detail of the thalamus on traditional magnetic resonance imaging (MRI), it is difficult to determine whether this poor clinical response is a failure of optimal simulation or a sequela of inappropriate targeting. We hypothesized that by using diffusion tensor imaging (DTI)-based segmentation to assess the internal thalamic nuclei of patients that have undergone thalamic DBS for intractable pain, we could retrospectively determine functional lead position and correlate it with clinical outcome. DTI-based segmentation was performed on 5 patients that underwent sensory thalamus DBS for chronic pain. Postoperative computed tomography (CT) images obtained for electrode placement were fused with preoperative MRIs that had undergone DTI-based thalamic segmentation. Sensory thalamus maps of 4 patients were transferred into standard MNI152 space via FSL tools non-linear image transformation (FNIRT) to investigate interpatient variability. The 2 patients that experienced significant pain relief following DBS demonstrated contact positions within the DTI-determined sensory thalamus, whereas those that did not respond to stimulation did not. One patient only experienced stimulation-induced intraoperative paresthesias when the electrode was repositioned posterior to the initial Schaltenbrand-Wahren Atlas coordinates, into what was later retrospectively confirmed to be the DTI-determined sensory thalamus. Only 4 voxels (2%) were shared by all 4 patients in common MNI space; 108 voxels (58%) were uniquely represented by single patients. Given the interpatient heterogeneity of thalamic nuclei, personalized stereotactic targeting is required. DTI-based segmentation of the thalamus can be used retrospectively to confirm thalamic lead placement relative to the sensory thalamus, and may serve as a useful tool to guide thalamic DBS in the future. 23872401 Enhancement of PLGF production by 15-(S)-HETE via PI3K-Akt, NF-κB and COX-2 pathways in rheumatoid arthritis synovial fibroblast. Metabolites from arachidonic acids play the pivotal roles in inflammatory arthritis. Arachidonic acid could be metabolized by cyclooxygenase (COX) and lipoxygenase (LOX) to produce the bioactive eicosanoids. Although the down-stream products of COX including prostaglandin E2 are well-known inflammatory stimulators, the role of LOX products in inflammatory arthritis is still unclear. Here we found that the downstream product of 15-LOX, 15-S-hydroxyeicosatetraenoic acid (15-(S)-HETE), can enhance the expression of placenta growth factor (PLGF), which is recently considered to play an important role in rheumatoid arthritis. 15-(S)-HETE increased the expression of PLGF in human rheumatoid arthritis synovial fibroblasts in a time-dependent and concentration-dependent manner. PI3K-Akt, NF-κB signaling pathways were involved in the potentiation effects of 15-(S)-HETE. In addition, COX-2 was up-regulated by the treatment of 15-(S)-HETE and the increase of COX-2 expression participated in 15-(S)-HETE-induced PLGF expression, which was confirmed by COX-2 shRNA or pharmacological COX-2 inhibitor. Moreover, it was found that treatment of prostaglandin E2 (PGE2), which was the main down-stream metabolite of COX-2, increased the expression of PLGF. EP1, EP2, EP3 and EP4 agonists could up-regulate PLGF as well. In animal studies, we found that the adjuvant-induced expression of PLGF and COX-2 was inhibited in 15-LOX knockout mice. These results indicated that PLGF up-regulation by 15-LOX downstream product may be involved in inflammatory arthritis. 23870535 Serum and cerebrospinal fluid light neurofilaments and antibodies against them in clinically isolated syndrome and multiple sclerosis. A release of light neurofilament subunits (NFL) into cerebrospinal fluid (CSF) and serum in multiple sclerosis (MS) may induce an immune response. We examined CSF and serum NFL levels and IgG antibodies against NFL in 19 patients with a clinically isolated syndrome (CIS) early converted into MS, 20 CIS-non-converters, 23 MS patients and 32 controls. CSF NFL levels were significantly higher in all patient groups. The highest CSF or intrathecally (IT) synthesized anti-NFL antibodies and CSF/serum ratios of anti-NFL antibodies were observed in CIS-converters. CSF NFL and CSF or IT anti-NFL antibodies could be surrogate biomarkers of axonal injury in early MS. 23932217 Selective Laser Trabeculoplasty Following Failed Combined Phacoemulsification Cataract Extraction and Ab Interno Trabeculectomy. To assess the effect of selective laser trabeculoplasty (SLT) following failed phacoemulsification cataract extraction combined with ab interno trabeculectomy (AIT) using the Trabectome (phaco-trabectome). Randomized, interventional case series. Retrospectively, the medical records of patients who underwent SLT between March 2010 and July 2012 by 1 surgeon at a single center after a failed phaco-AIT were evaluated. Inclusion criteria were age ≥18 years with no upper limit and prior failed phaco-AIT attributable to glaucoma progression. Exclusion criterion was performance of any additional glaucoma procedure with influence on intraocular pressure (IOP) during follow-up and a follow-up after surgery of <3 months. Success was defined by reduction of IOP of >3 mm Hg and 20% and number of antiglaucoma medications equal to or less than baseline. Main outcome measures were IOP, antiglaucoma medications, time to failure, and Kaplan-Meier survival curve. Fourteen eyes of 13 subjects were included. Mean follow-up after SLT was 12.9 ± 8.7 months. Total laser energy was 59.5 ± 8.7 mJ. Baseline IOP was 17.9 ± 3.3 mm Hg and number of antiglaucoma medications at baseline was 2.0 ± 1.0. All SLT procedures failed. Median time to failure after SLT was 3.6 ± 0.8 (range 2.1-5.1) months. Number of antiglaucoma medications did not change. In eyes in which the IOP was no longer controlled following phaco-trabectome, SLT had a limited duration of significant IOP-lowering effect. Other alternatives, such as incisional filtration surgery, should be considered following failed phaco-trabectome. 23404546 Treatment efficacy of algae-based sewage treatment plants. Lagoons have been traditionally used in India for decentralized treatment of domestic sewage. These are cost effective as they depend mainly on natural processes without any external energy inputs. This study focuses on the treatment efficiency of algae-based sewage treatment plant (STP) of 67.65 million liters per day (MLD) capacity considering the characteristics of domestic wastewater (sewage) and functioning of the treatment plant, while attempting to understand the role of algae in the treatment. STP performance was assessed by diurnal as well as periodic investigations of key water quality parameters and algal biota. STP with a residence time of 14.3 days perform moderately, which is evident from the removal of total chemical oxygen demand (COD) (60 %), filterable COD (50 %), total biochemical oxygen demand (BOD) (82 %), and filterable BOD (70 %) as sewage travels from the inlet to the outlet. Furthermore, nitrogen content showed sharp variations with total Kjeldahl nitrogen (TKN) removal of 36 %; ammonium N (NH4-N) removal efficiency of 18 %, nitrate (NO3-N) removal efficiency of 22 %, and nitrite (NO2-N) removal efficiency of 57.8 %. The predominant algae are euglenoides (in facultative lagoons) and chlorophycean members (maturation ponds). The drastic decrease of particulates and suspended matter highlights heterotrophy of euglenoides in removing particulates. 23815333 Complete mitochondrial genome of Lacerta agilis (Squamata, Lacertidae). Abstract The complete mitochondrial genome sequence of Lacerta agilis was determined in the present paper. The genome was 17,090 bp in length and contained 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and 1 control region (CR). The gene composition and order of which was similar to most other Squamate reptiles. The overall base composition of the genome in descending order was 31.29% A, 26. 39% C, 29.01% T and 13.29% G, with a slight AT bias of 60.30%. CR is located between the tRNA-Pro and tRNA-Phe genes and is 1688 bp in length, some tandem repeat sequences and conserved elements (CSB1-3) were found in the control region. 23898828 Angiotensin II produces nociceptive behavior through spinal AT1 receptor-mediated p38 mitogen-activated protein kinase activation in mice. It has been demonstrated that angiotensin II (Ang II) participates in either the inhibition or the facilitation of nociceptive transmission depending on the brain area. Neuronal Ang II is locally synthesized not only in the brain, but also in the spinal cord. Though the spinal cord is an important area for the modulation of nociception, the role of spinal Ang II in nociceptive transmission remains unclear. Therefore, in order to elucidate the role of Ang II in nociceptive transmission in the spinal cord, we examined the effect of intrathecal (i.t.) administration of Ang II into mice. I.t. administration of Ang II produced a behavioral response in mice mainly consisting of biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank. The behavior induced by Ang II (3 pmol) was dose-dependently inhibited by intraperitoneal injection of morphine (0.1-0.3 mg/kg), suggesting that the behavioral response is related to nociception. The nociceptive behavior was also inhibited dose-dependently by i.t. co-administration of losartan (0.3-3 nmol), an Ang II type 1 (AT1) receptor antagonist, and SB203580 (0.1-1 nmol), a p38 MAPK inhibitor. However, the Ang II type 2 (AT2) receptor antagonist PD123319, the upstream inhibitor of ERK1/2 phosphorylation U0126, and the JNK inhibitor SP600125 had no effect on Ang II-induced nociceptive behavior. Western blot analysis showed that the i.t. injection of Ang II induced phosphorylation of p38 MAPK in the lumbar dorsal spinal cord, which was inhibited by losartan, without affecting ERK1/2 and JNK. Furthermore, we found that AT1 receptor expression was relatively high in the lumbar superficial dorsal horn. Our data show that i.t. administration of Ang II induces nociceptive behavior accompanied by the activation of p38 MAPK signaling mediated through AT1 receptors. This observation indicates that Ang II may act as a neurotransmitter and/or neuromodulator in the spinal transmission of nociceptive information. 23824554 The Direct and Interactive Effects of Physical Abuse Severity and Negative Affectivity on Length of Psychiatric Hospitalization: Evidence of Differential Reactivity to Adverse Environments in Psychiatrically High-Risk Youth. The current study examined the interactive influence of multiple factors (i.e., physical abuse severity and negative affectivity) in predicting youth's inpatient psychiatric length of stay (LOS), extending previous research focused on identification of only single LOS predictors. Elevated physical abuse severity was hypothesized to predict longer youth LOS, and negative affectivity was anticipated to exacerbate this relationship. This study included 42 youth. Clinicians rated youth temperament, whereas physical abuse severity and LOS were coded from youth medical records. Controlling for other previously determined predictors of LOS (i.e., age, gender, and GAF), moderation analyses confirmed hypotheses, revealing a temperament by environment interaction. Specifically, physical abuse severity was positively associated with LOS only in the context of high negative affectivity. Findings highlighted the importance of disentangling the interactive effects of multiple factors in predicting LOS. Moreover, critical clinical implications involving prioritized trauma assessment and treatment for inpatient youth are discussed. 23925239 Connectomic reconstruction of the inner plexiform layer in the mouse retina. Comprehensive high-resolution structural maps are central to functional exploration and understanding in biology. For the nervous system, in which high resolution and large spatial extent are both needed, such maps are scarce as they challenge data acquisition and analysis capabilities. Here we present for the mouse inner plexiform layer--the main computational neuropil region in the mammalian retina--the dense reconstruction of 950 neurons and their mutual contacts. This was achieved by applying a combination of crowd-sourced manual annotation and machine-learning-based volume segmentation to serial block-face electron microscopy data. We characterize a new type of retinal bipolar interneuron and show that we can subdivide a known type based on connectivity. Circuit motifs that emerge from our data indicate a functional mechanism for a known cellular response in a ganglion cell that detects localized motion, and predict that another ganglion cell is motion sensitive. 23817806 Oropharyngeal Dysphagia in Patients with Obstructive Sleep Apnea Syndrome. Although previous studies demonstrated that patients with obstructive sleep apnea syndrome (OSAS) may present subclinical manifestations of dysphagia, in not one were different textures and volumes systematically studied. The aim of this study was to analyze the signs and symptoms of oropharyngeal dysphagia using fiberoptic endoscopic evaluation of swallowing (FEES) with boluses of different textures and volumes in a large cohort of patients with OSAS. A total of 72 OSAS patients without symptoms of dysphagia were enrolled. The cohort was divided in two groups: 30 patients with moderate OSAS and 42 patients with severe OSAS. Each patient underwent a FEES examination using 5, 10 and 20 ml of liquids and semisolids, and solids. Spillage, penetration, aspiration, retention, and piecemeal deglutition were considered. The penetration-aspiration scale (PAS), pooling score (PS), and dysphagia outcome and severity scale (DOSS) were used for quantitative analysis. Each patient completed the SWAL-QOL questionnaire. Forty-six patients (64 %) presented spillage, 20 (28 %) piecemeal deglutition, 26 (36 %) penetration, and 30 (44 %) retention. No differences were found in the PAS, PS, and DOSS scores between patients with moderate and severe OSAS. Patients with severe OSAS scored higher General Burden and Food selection subscales of the SWAL-QOL. Depending on the DOSS score, the cohort of patients was divided into those with and those without signs of dysphagia. Patients with signs of dysphagia scored lower in the General Burden and Symptoms subscales of the SWAL-QOL. OSAS patients show signs of swallowing impairment in about half of the population; clinicians involved in the management of these patients should include questions on swallowing when taking the medical history. 23534703 Two-dimensional penning ionization electron spectroscopy of open-shell metallocenes: outer valence ionic States of vanadocene and nickelocene. In order to investigate outer valence ionic states of open-shell metallocenes, we have applied two-dimensional collision-energy/electron-energy-resolved Penning ionization electron spectroscopy (2D-PIES) upon collision with metastable He*(2(3)S) excited atoms as well as a high level ab initio molecular orbital calculation (the partial third-order quasiparticle theory of the electron propagator (P3)) to ionization from neutral ground states of vanadocene ((4)A2g) and nickelocene ((3)A2g). Assignments of observed Penning ionization electron/He I ultraviolet photoelectron spectra were consistent with the P3 calculation results for ionization of α and β spin electrons except for electron correlation bands observed by PIES. Negative collision energy dependence of partial Penning ionization cross-sections (CEDPICS) indicate attractive interaction with He*(2(3)S) around the molecule. Results by model potential calculation utilizing Li(2(2)S) instead of He*(2(3)S) for interaction between He*(2(3)S) and open-shell metallocenes do not explain the strong negative CEDPICS of the bands observed in PIES. 23557071 Prevalence and Plasmid Characterization of the qnrD Determinant in Enterobacteriaceae Isolated from Animals, Retail Meat Products, and Humans. qnrD, unlike other qnr genes, is mainly located on small nonconjugative plasmids. We investigated the presence of qnrD among 1,373 Enterobacteriaceae isolates in China. Twelve qnrD-positive strains were detected, and all were nonsusceptible to fluoroquinolones. The complete sequence of plasmids showed that the qnrD determinants were located on two plasmids with a respective size of ∼4.2 and 2.7 k-bp. Interestingly, the identification of qnrD in this study revealed the highest prevalence of Proteeae among Enterobacteriaceae identified. 23920112 Kleptomania in Patients with Neuro-Behçet's Disease. Objective: This study was conducted to characterize the prevalence and clinical features of kleptomania, an impulse control disorder, in patients with Behçet's disease involving the central nervous system. Subjects and Methods: Medical records of 350 patients with neuro-Behçet's disease were evaluated, and clinical and neuropsychological features of patients with kleptomania were noted. Results: Of the 350 neuro-Behçet's disease patients 6 (1.7%) had presented with symptoms that fulfilled the criteria of kleptomania according to the revised 4th version of the Diagnostic and Statistical Manual of Mental Disorders. The 6 patients (5 men, 1 woman) had parenchymal lesions and had developed kleptomania during remission. Magnetic resonance imaging done on the 6 patients before the onset of kleptomania mostly revealed brainstem lesions. Psychiatric assessment did not show any comorbid psychiatric disorders and neuropsychological evaluation showed executive dysfunction in all patients. Conclusion: The 6 patients with kleptomania had developed a frontal lobe syndrome. 23903903 A novel neutral xylanase with high SDS resistance from Volvariella volvacea: characterization and its synergistic hydrolysis of wheat bran with acetyl xylan esterase. A neutral xylanase (XynII) from Volvariella volvacea was identified and characterized. Unlike other modular xylanases, it consists of only a single GH10 catalytic domain with a unique C-terminal sequence (W-R-W-F) and a phenylalanine and proline-rich motif (T-P-F-P-P-F) at N-terminus, indicating that it is a novel GH10 xylanase. XynII exhibited optimal activity at pH 7 and 60 °C and stability over a broad range of pH 4.0-10.0. XynII displayed extreme highly SDS resistance retaining 101.98, 92.99, and 69.84 % activity at the presence of 300 mM SDS on birchwood, soluble oat spelt, and beechwood xylan, respectively. It remained largely intact after 24 h of incubation with proteinase K at a protease to protein ratio of 1:50 at 37 °C. The kinetic constants K m value towards beechwood xylan was 0.548 mg ml(-1), and the k cat/K m ratio, reflecting the catalytic efficiency of the enzyme, was 126.42 ml mg(-1) s(-1) at 60 °C. XynII was a true endo-acting xylanase lacking cellulase activity. It has weak activity towards xylotriose but efficiently hydrolyzed xylans and xylooligosaccharides larger than xylotriose mainly to xylobiose. Synergistic action with acetyl xylan esterase (AXEI) from V. volvacea was observed for de-starched wheat bran. The highest degree of synergy (DS 1.42) was obtained in sequential reactions with AXEI digestion preceding XynII. The high SDS resistance and intrinsic stability suggested XynII may have potential applications in various industrial processes especially for the detergent and textile industries and animal feed industries. 23706201 Biosensor based on laccase immobilized on plasma polymerized allylamine/carbon electrode. In this work, a simple and rapid method was used to functionalize carbon electrode in order to efficiently immobilize laccase for biosensor application. A stable allylamine coating was deposited using a low pressure inductively excited RF tubular plasma reactor under mild plasma conditions (low plasma power (10 W), few minutes) to generate high density amine groups (N/C ratio up to 0.18) on rough carbon surface electrodes. The longer was the allylamine plasma deposition time; the better was the surface coverage. Laccase from Trametes versicolor was physisorbed and covalently bound to these allylamine modified carbon surfaces. The laccase activities and current outputs measured in the presence of 2,2'-azinobis-(3-ethylbenzothiazole-6-sulfonic acid) (ABTS) showed that the best efficiency was obtained for electrode plasma coated during 30 min. They showed also that for all the tested electrodes, the activities and current outputs of the covalently immobilized laccases were twice higher than the physically adsorbed ones. The sensitivity of these biocompatible bioelectrodes was evaluated by measuring their catalytic efficiency for oxygen reduction in the presence of ABTS as non-phenolic redox substrate and 2,6-dimethoxyphenol (DMP) as phenolic one. Sensitivities of around 4.8 μA mg(-1)L and 2.7 μA mg(-1)L were attained for ABTS and DMP respectively. An excellent stability of this laccase biosensor was observed for over 6 months. 23649772 The role of IL15 gene variants in visceral leishmaniasis among Iranian patients. The role of IL-15 in the protection against Leishmania (L) parasites has been clarified in previous studies, in which IL-15 similar to IFN-γ induces IL-12 production and stimulates the leishmaniacidal activity of the macrophages infected with L. infantum. Furthermore, the increased level of IL-15 in acute visceral leishmaniasis patients (VL) can suppress Th2 cytokines such as IL-4. Since different single nucleotide polymorphisms (SNPs) in the IL15 gene have been described, this study aimed to investigate the association of the SNPs at the positions 267, 367, 13,687 and 14,035 with VL. The IL15 gene variants were compared between two groups consisting of 117 VL patients and 146 healthy individuals using polymerase chain reaction-restriction fragment length polymorphism. The results showed that the frequencies of the alleles 267C (83.9 vs. 73.5 %, P = 0.0035), 13687A (22.4 vs. 12.8 %, P = 0.032), genotype 267CC (68.5 vs. 55.6 %, P = 0.031), haplotypes CGCA (16 vs. 8.3 %, P = 0.02) and TACA (11.2 vs. 4.8 %, P = 0.02) were significantly higher in the controls than those in the patients, while the genotypes 267TT (8.5 vs. 0.7 %, P = 0.0016), 13687CC (78.6 vs. 65.5 %, P = 0.015), the haplotypes TGCT (10 vs. 2.5 %, P = 0.00002) and TGCA (5.7 vs. 0.35 %, P = 0.000001) were significantly more frequent in the patients. In conclusion, it may be speculated that these gene variants with probable effects on the IL-15 production can serve as the factors influencing VL among Iranian population. However, to clarify the association of these variants with the level of IL-15, further studies are recommended. 23400747 Effects of amlodipine on the oral bioavailability of cephalexin and cefuroxime axetil in healthy volunteers. In this study, the authors compared the effects of amlodipine (AML) on the bioavailability of cephalexin (LEX) and cefuroxime axetil (CXM). Twenty-four healthy men were randomized to 4 treatments according to a crossover design with a 14-day washout. After an overnight fast, they were administered orally LEX 500 mg alone, LEX 500 mg 2 hours after oral administration of AML 5 mg, CXM 500 mg alone, and CXM 500 mg 2 hours after oral administration of AML 5 mg. All participants completed the whole study without side effects being observed. Pharmacokinetic data were analyzed by noncompartmental modeling with WinNonlin software. The geometric mean (GM) ratios were 1.38 (90% confidence interval [CI], 1.32-1.45) for the area under the concentration-time curve (AUC) for LEX and 1.27 (1.18-1.36) for the maximum concentration of drug in serum (C(max)) for LEX followed by AML versus alone. In contrast, no significant differences were found in the pharmacokinetic parameters of CXM between treatments (P < .05). They authors conclude that AML possesses an enhancement effect in β-lactam antibiotic bioavailability (in this case, LEX), and this interaction may be specific to the peptidomimetic β-lactam antibiotics. 23233535 Short-peptide fusion inhibitors with high potency against wild-type and enfuvirtide-resistant HIV-1. Peptides derived from the C-terminal heptad repeat (C peptides) of HIV-1 gp41 are potent inhibitors against virus entry. However, development of a short C peptide possessing high anti-HIV potency is considered a daunting challenge. We recently discovered that the residues Met626 and Thr627 preceding the pocket-binding domain of the C peptide adopt a unique M-T hook structure that is crucial for the design of HIV-1 fusion inhibitors. In this study, we first presented a proof-of-concept prototype that the M-T hook residues can dramatically improve the antiviral activity and thermostability of a short C peptide. We then generated a 24-mer peptide termed MT-SC22EK by incorporating the M-T hook structure to the N terminus of the poorly active short C peptide SC22EK. Amazingly, MT-SC22EK inhibited HIV-1-mediated cell fusion and infection at a level comparable to C34, T1249, SC29EK, and sifuvirtide, and it was highly active against diverse HIV-1 subtypes and variants, including those T20 (enfuvirtide) and SC29EK-resistant viruses. The high-resolution crystal structure of MT-SC22EK reveals the N-terminal M-T hook conformation folded by incorporated Met626 and Thr627 and identifies the C-terminal boundary critical for the anti-HIV activity. Collectively, our studies provide new insights into the mechanisms of HIV-1 fusion and its inhibition. 23842146 Successful Management of Multidrug-Resistant Pseudomonas aeruginosa Pneumonia after Kidney Transplantation in a Dog. An 8-year-old male mongrel dog that had undergone renal transplantation was presented 25 days later with an acute cough, anorexia and exercise intolerance. During the investigation, neutrophilic leukocytosis was noted, and thoracic radiographs revealed caudal lung lobe infiltration. While being treated with two broad-spectrum antibiotics, clinical signs worsened. Pneumonia due to infection with multidrug-resistant (MDR) Pseudomonas (P.) aeruginosa, sensitive only to imipenem and amikacin, was confirmed by bacteria isolation. After treatment with imipenem-cilastatin without reducing the immunosuppressant dose, clinical signs completely resolved. During the 2-year follow-up period, no recurrence was observed. To the best of authors' knowledge, this is the first report of pneumonia caused by MDR P. aeruginosa in a renal recipient dog and successful management of this disease. 23831275 Targeting autophagy as a potential therapeutic approach for melanoma therapy. Melanoma, occurring as a rapidly progressive skin cancer, is resistant to current chemo- and radiotherapy, especially after metastases to distant organs has taken place. Most chemotherapeutic drugs exert their cytotoxic effect by inducing apoptosis, which, however, is often deficient in cancer cells. Thus, it is appropriate to attempt the targeting of alternative pathways, which regulate cellular viability. Recent studies of autophagy, a well-conserved cellular catabolic process, promise to improve the therapeutic outcome in melanoma patients. Although a dual role for autophagy in cancer therapy has been reported, both protecting against and promoting cell death, the potential for using autophagy in cancer therapy seems to be promising. Here, we review the recent literature on the role of autophagy in melanoma with respect to the expression of autophagic markers, the involvement of autophagy in chemo- and immunotherapy, as well as the role of autophagy in hypoxia and altered metabolic pathways employed for melanoma therapy. 23835699 Complex chemoattractive and chemorepellent Kit signals revealed by direct imaging of murine mast cells in microfluidic gradient chambers. Besides its cooperating effects on stem cell proliferation and survival, Kit ligand (KL) is a potent chemotactic protein. While transwell assays permit studies of the frequency of migrating cells, the lack of direct visualization precludes dynamic chemotaxis studies. In response, we utilize microfluidic chambers that enable direct observation of murine bone marrow-derived mast cells (BMMC) within stable KL gradients. Using this system, individual Kit+ BMMC were quantitatively analyzed for migration speed and directionality during KL-induced chemotaxis. Our results indicated a minimum activating threshold of ∼3 ng ml(-1) for chemoattraction. Analysis of cells at KL concentrations below 3 ng ml(-1) revealed a paradoxical chemorepulsion, which has not been described previously. Unlike chemoattraction, which occurred continuously after an initial time lag, chemorepulsion occurred only during the first 90 minutes of observation. Both chemoattraction and chemorepulsion required the action of G-protein coupled receptors (GPCR), as treatment with pertussis toxin abrogated directed migration. These results differ from previous studies of GPCR-mediated chemotaxis, where chemorepulsion occurred at high ligand concentrations. These data indicate that Kit-mediated chemotaxis is more complex than previously understood, with the involvement of GPCRs in addition to the Kit receptor tyrosine kinase and the presence of both chemoattractive and chemorepellent phases. 23086461 Density functional conformational study of 2-O-sulfated 3,6 anhydro-α-D-galactose and of neo-κ- and ι-carrabiose molecules in gas phase and water. We examined the conformational preferences of the 2-O-sulfated-3,6-α-D-anhydrogalactose (compound I) and two 1,3 linked disaccharides constituting-κ or ι-carrageenans using density functional and ab initio methods in gas phase and aqueous solution. Systematic modifications of two torsion angles leading to 324 and 144 starting geometries for the compound I and each disaccharide were used to generate adiabatic maps using B3LYP/6-31G(d). The lower energy conformers were then fully optimized using B3LYP, B3PW91 and MP2 with several basis sets. Overall, we discuss the impact of full relaxation on the energy and structure of the dominant conformations, present the performance comparison with previous molecular mechanics calculations if available, and determine whether our results are impacted, when polarization and diffuse functions are added to the 6-31G(d) basis set, or when the MP2 level of theory is used. 23298867 Alternative splicing in the aldo-keto reductase superfamily: implications for protein nomenclature. The aldo-keto reductase superfamily contains 173 proteins which are present in all phyla. Examination of the human and mouse genomes has identified that in some instances a single AKR gene can give rise to alternatively spliced mRNA variants which in some cases can give rise to more than one protein isoform. This is currently well documented in the AKR6A subfamily which contains the β-subunits of the voltage-gated potassium ion channels. With the emergence of second generation sequencing it is likely that the occurrence of transcript variants and protein isoforms from a single AKR gene may become common place. To deal with this issue we recommend that the Ensembl data-base nomenclature be used to annotate the transcript variants from a single AKR gene. However, since multiple transcript variants could give rise to either the same or multiple protein isoforms from the same AKR gene we also propose to expand the nomenclature of the AKR protein superfamily, so that when a protein isoform is shown to be expressed and is functional it would be assigned the standard AKR name followed by a "period or full-stop" and a number for that unique isoform. Numbers will be assigned chronologically and linked to the respective transcripts annotated in Ensembl e.g. AKR6A5.1 (Kvβ2.1) (AKR6A5-001, -006 and -201), followed by AKR6A5.2 (Kvβ2.2) (AKR6A5-002,-202). This nomenclature is expandable and it enables multiple protein isoforms to be assigned to their respective transcripts when they arise from the same AKR gene or for a single protein isoform to be assigned to multiple transcripts when the transcripts encode the same AKR protein. 23948243 Surface stress-based biosensors. Surface stress-based biosensors, as one kind of label-free biosensors, have attracted lots of attention in the process of information gathering and measurement for the biological, chemical and medical application with the development of technology and society. This kind of biosensors offers many advantages such as short response time (less than milliseconds) and a typical sensitivity at nanogram, picoliter, femtojoule and attomolar level. Furthermore, it simplifies sample preparation and testing procedures. In this work, progress made towards the use of surface stress-based biosensors for achieving better performance is critically reviewed, including our recent achievement, the optimally circular membrane-based biosensors and biosensor array. The further scientific and technological challenges in this field are also summarized. Critical remark and future steps towards the ultimate surface stress-based biosensors are addressed. 23955276 Surface nucleated growth of dipeptide fibres. We report the surface nucleated growth of self-assembled dipeptide films. The seeding-layer was a thin dipeptide film with a globular structure. Placing the seeding-layer in contact with dipeptide led to growth of fibres overnight. Active enzymes were incorporated into the gel by adding them to the growth solution. 23446771 Evaluation of immobilized enzymes for industrial applications. In contrast to the application of soluble enzymes in industry, immobilized enzymes often offer advantages in view of stability, volume specific biocatalyst loading, recyclability as well as simplified downstream processing. In this tutorial review the focus is set on the evaluation of immobilized enzymes in respect to mass transport limitations, immobilization yield and stability, to enable industrial applications. 23174758 Angiotensin AT2 receptor activates the cyclic-AMP signaling pathway in eel. A unique angiotensin type 2 receptor (AT2) that induces a cAMP signaling pathway was cloned and characterized for the first time in fish, Anguilla japonica. Phylogeny and synteny results showed that the AT2s among fishes and tetrapods share the same origin despite a sub-cluster formation among eel, salmon, and zebrafish. The eel AT2 was expressed abundantly in the spleen and localized at straight arterioles and ellipsoid regions prior to the sinusoid, suggesting a role in the regulation of microcirculation and/or immune response. Various angiotensin (Ang) peptides, including Ang II, Ang III, and Ang IV, were detected in the spleen by a radioimmunoassay coupled with HPLC separation, and these endogenous peptides stimulated a cAMP signaling, which has no crosstalk with cGMP pathway. The common and contrasting features of AT2 between fishes and mammals imply some ancestral characters of AT2, which are important information for receptor binding and evolutionary studies. 23219717 Preservation of the gut by preoperative carbohydrate loading improves postoperative food intake. A carbohydrate (CHO) drink given preoperatively changes the fasted state into a fed state. The ESPEN guidelines for perioperative care include preoperative CHO loading and re-establishment of oral feeding as early as possible after surgery. An intestinal ischaemia reperfusion (IR) animal model was used to investigate whether preoperative CHO loading increases spontaneous postoperative food intake, intestinal barrier function and the catabolic response. Male Wistar rats (n = 65) were subjected to 16 h fasting with ad libitum water and: A) sham laparotomy (Sham fasted, n = 24); B) intestinal ischaemia (IR fasted, n = 27); and C) intestinal ischaemia with preoperatively access to a CHO drink (IR CHO, n = 14). Spontaneous food intake, intestinal barrier function, insulin sensitivity, intestinal motility and plasma amino acids were measured after surgery. The IR CHO animals started eating significantly earlier and also ate significantly more than the IR fasted animals. Furthermore, preoperative CHO loading improved the intestinal barrier function, functional enterocyte metabolic mass measured by citrulline and reduced muscle protein catabolism, as indicated by normalization of the biomarker 3-methylhistidine. Preoperative CHO loading improves food intake, preserves the GI function and reduces the catabolic response in an IR animal model. These findings suggest that preoperative CHO loading preserves the intestinal function in order to accelerate recovery and food intake. If this effect is caused by overcoming the fasted state or CHO loading remains unclear. 23834160 Licofelone abolishes survival of carcinogenic fibroblasts by inducing apoptosis. Abstract Dual inhibitors of cyclooxygenase (COX) and lipoxygenase (LOX) pathways of arachidonic acid metabolism prevent cancer development and induce apoptosis. One of the most promising compounds that blocks both of these pathways is licofelone. We questioned whether licofelone affects the survival and/or promotes apoptosis of H-ras transformed rat embryonic fibroblast (5RP7) cells in vitro. Using 5-fluorouracil (5-FU) and colchicine as positive controls, we determined cell viability with 3-3-(4,5-D-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, thyazolyl blue (MTT), apoptosis with flow cytometry and activity of caspase enzyme with real-time reverse transcription polymerase chain reaction (PCR). Compared to the control, all used six doses (10, 50, 100, 150, 250 and 250 µM) of 5-FU, colchicine and licofelone, which were cytotoxic and reduced the number of H-Ras transformed 5RP7 cells by as much as 78, 72 and 92%, respectively. In addition, we found that 150, 200 and 250 µM of licofelone induced apoptosis and necrosis of H-Ras transformed 5RP7 cells in a dose- and time-dependent manner. Each three tested drugs at 250 µM also increased the level of caspase-3 enzyme up to 5-fold. Although colchicine was effective in inducing early apoptosis, licofelone had much more capacity to induce the total of early plus late apoptosis by approximately 96% in cells after 48 hours. The present study reveals the possibility that licofelone posseses strong dose- and time-dependent anticancer and apoptotic properties on carcinogenic fibroblasts. 23725100 Early, But Not Late Onset Estrogen Replacement Therapy Prevents Oxidative Stress and Metabolic Alterations Caused by Ovariectomy. Abstract Aims: The usefulness of estrogen replacement therapy (ERT) in preventing oxidative stress associated with menopause is controversial. We aimed to study if there is a critical time window for effective treatment of the effects of ovariectomy with estrogens at the molecular, metabolic, and cellular level. Results: Our main finding is that early, but not late onset of ERT prevents an ovariectomy-associated increase in mitochondrial hydrogen peroxide levels, oxidative damage to lipids and proteins, and a decrease in glutathione peroxidase and catalase activity in rats. This may be due to a change in the estrogen receptor (ER) expression profile: ovariectomy increases the ER α/β ratio and immediate estrogen replacement prevents it. Positron emission tomography analysis shows that ovariectomy decreases the brain glucose uptake in vivo and that estrogen administration is beneficial, but only if administered immediately after deprivation. Ovariectomy decreases GLUT-1 and 3 glucose transporters in the brain, and only early onset estrogen administration prevents it. Plasma from rats treated with estrogens immediately after ovariectomy show similar metabolomics profiles as controls. Innovation: We provide molecular basis for the recommendation of early onset ERT and explain its lack of effectiveness if a significant time period elapses after ovariectomy and probably after the onset of menopause. Conclusion: Only early, but not late onset administration of estrogens after ovariectomy has beneficial effects at molecular levels on oxidative stress, brain glucose uptake, and metabolomic profiles. Antioxid. Redox Signal. 00, 000-000. 23420583 Effects of phosphate buffer in parenteral drugs on particle formation from glass vials. The characteristics of inorganic particles generated in glass vials filled with phosphate buffer solutions were investigated. During storage, particles were visually detected in the phosphate buffer solution in particular glass vials which pass compendial tests of containers for injectable drugs. These particles were considered to be different from ordinal glass delamination, which has been reported in a number of papers because the particles were mainly composed of Al, P and O, but not Si. The formation of the particles accelerated at higher storage temperatures. Among the surface treatments tested for the glass vials, sulfur treatment showed a protective effect on the particle formation in the vials, whereas the SiO2 coating did not have any protective effects. It was found that the elution ratio of Al and Si in the solution stored in the glass vials after the heating was similar to the ratio of Al and Si in borosilicate glass. However, the Al concentration decreased during storage (5°C, 6 months), and consequently, particle formation was observed in the solution. Adding citrate, which is a chelating agent for Al, effectively suppressed the particle formation in the heated solution. When 50 ppb and higher concentrations of Al ion were added to the phosphate buffer solution, the formation of white particles containing Al, P and O was detected. It is suggested that a phosphate buffer solution in a borosilicate glass vial has the ability to form particles due to interactions with the Al that is eluted from the glass during storage. 23963008 The Genetics and Heritability of Cervical Spondylotic Myelopathy and Ossification of the Posterior Longitudinal Ligament: Results of a Systematic Review. Study Design. Systematic Review.Objective. To answer the following three clinical questions: (1) What is the evidence supporting a heritable predisposition for cervical spondylotic myelopathy (CSM) and ossification of the posterior longitudinal ligament (OPLL)? (2) What specific genetic polymorphisms have been associated with CSM and OPLL? (3) What is the evidence supporting a genetic basis for predicting postoperative outcomes for CSM and OPLL patients?Summary of Background Data. OPLL and CSM are thought to be multifactorial conditions resulting from a combination of environmental and genetic factors.Methods. A systematic review of the English language literature was undertaken for articles published between 1980 and November 7, 2012. The strength of evidence was determined by two independent reviewers using the GRADE criteria for studies addressing the first question of heritability, and using the criteria set forth by the HuGENet Working Group in the Venice Interim Guidelines to address the last two questions of genetic association.Results. Of the 118 citations identified through the initial literature search, a total of 23 articles remained after application of inclusion/exclusion criteria. The three family association studies related to question #1 supported the principle of an inherited predisposition to CMS and OPLL however the strength of evidence supporting these findings was low. Within the 19 case control studies related to question #2, two SNPs (COL6A1/Intron 32(-29) and COL11A2/Intron 6(-4)) were observed at higher frequencies in OPLL cases as compared to controls in >1 study and may be associated with its development. There was insufficient evidence to support an association between CSM and any specific SNP or haplotype, or to support the association of specific gene alleles with post-operative CSM outcomes.Conclusion. Existing family studies provide support for the principle of an inherited predisposition to CSM and OPLL. Multiple studies support the association of 2 collagen gene related SNPs with OPLL, however there is insufficient evidence to support the association between CSM and any genetic polymorphism or to support a genetic predictor of surgical outcome.Statement #1: Existing family studies provide support for the principle of an inherited predisposition to CSM and OPLLStatement #2: Two SNPs related to the collagen 6A1 gene (COL6A1/Intron 32(-29)) and the collagen 11A2 gene (COL11A2/Intron 6(-4)) have been associated with OPLL in multiple studies and may be associated with its development.Statement #3: No statement can be made from the literature regarding the association of specific SNPs or haplotypes with CSM.Statement #4: No statement can be made from the literature regarding genetic predictors of surgical outcome in the context of OPLL or CSM. 23895786 Silver nanoparticles and silver nitrate induce high toxicity to Pseudokirchneriella subcapitata, Daphnia magna and Danio rerio. Silver nanoparticles (AgNP) have gained attention over the years due to the antimicrobial function of silver, which has been exploited industrially to produce consumer goods that vary in type and application. Undoubtedly the increase of production and consumption of these silver-containing products will lead to the entry of silver compounds into the environment. In this study we have used Pseudokirchneriella subcapitata, Daphnia magna and Danio rerio as model organisms to investigate the toxicity of AgNP and AgNO3 by assessing different biological endpoints and exposure periods. Organisms were exposed following specific and standardized protocols for each species/endpoints, with modifications when necessary. AgNP were characterized in each test-media by Transmission Electron Microscopy (TEM) and experiments were performed by Dynamic Light Scattering (DLS) to investigate the aggregation and agglomeration behavior of AgNP under different media chemical composition and test-period. TEM images of AgNP in the different test-media showed dissimilar patterns of agglomeration, with some agglomerates inside an organic layer, some loosely associated particles and also the presence of some individual particles. The toxicity of both AgNO3 and AgNP differ significantly based on the test species: we found no differences in toxicity for algae, a small difference for zebrafish and a major difference in toxicity for Daphnia magna. 23088527 Progression of osteogenic cell cultures grown on microtopographic titanium coated with calcium phosphate and functionalized with a type I collagen-derived Peptide. Background: The functionalization of metallic surfaces aims at promoting the cellular response at the biomaterial-tissue interface. This study investigates the effects of the functionalization of titanium (Ti) microtopography with a calcium phosphate (CaP) coating with and without peptide 15 (P-15), a synthetic peptide analog of the cell-binding domain of collagen I, on the in vitro progression of osteogenic cells. Methods: Sandblasting and acid etching (SBAE; control) Ti microtopography was coated with CaP, enabling the loading of two concentrations of P-15: 20 or 200 μg/mL. A machined Ti was also examined. Rat calvarial osteogenic cells were cultured on Ti disks with the surfaces mentioned above for periods up to 21 days (n = 180 per group). Results: CaP coating exhibited a submicron-scale needle-shaped structure. Although all surfaces were hydrophobic at time zero, functionalization increased hydrophilicity at equilibrium. Microtopographies exhibited a lower proportion of well-spread cells at 4 hours of culture and cells with long cytoplasmic extensions at day 3; modified SBAE supported higher cell viability and larger extracellular osteopontin (OPN) accumulation. For SBAE and modified SBAE, real-time polymerase chain reaction showed the following results: 1) lower levels for runt-related transcription factor 2 at 7 days and for bone sialoprotein at days 7 and 10 as well as higher OPN levels at days 7 and 10 compared to machined Ti; and 2) higher alkaline phosphatase levels at day 10 compared to day 7. At 14 and 21 days, modified SBAE supported higher proportions of red-dye-stained areas (calcium content). Conclusion: Addition of a CaP coating to SBAE Ti by itself may affect key events of in vitro osteogenesis, ultimately resulting in enhanced matrix mineralization; additional P-15 functionalization has only limited synergistic effects. 23518319 Oxidative DNA damage corresponds to the long term survival of human cells treated with silver nanoparticles. We examined the relation between DNA damage and the clonogenic potential of 3 human cell lines, HepG2, HT29 and A549, treated with bare 20nm or 200nm silver nanoparticles (AgNPs). The endpoints examined were the DNA breakage estimated by the comet assay, the oxidative base damage recognized by formamido-pyrimidine glycosylase (FPG) and estimated with the FPG+comet assay, and the frequencies of histone γH2AX foci and micronuclei. Each cell line studied had a different pattern of DNA breakage and base damage versus the NPs concentration and time of treatment. The overall pattern of DNA breakage and base damage induction corresponded to the intracellular generation of reactive oxygen species. There was no increase in the frequencies of histone γH2AX foci and micronuclei as compared to those in the untreated cells. The reported experiments suggest that only the oxidative DNA damage corresponds to the loss of the clonogenic ability of cells treated with AgNPs. 23900200 Modulation of molecular hybridization and charge screening in a carbon nanotube network channel using the electrical pulse method. In this paper, we investigate the effect of electrical pulse bias on DNA hybridization events in a biosensor platform, using a Carbon Nanotube Network (CNN) and Gold Nano Particles (GNP) as an electrical channel. The scheme provides both hybridization rate enhancement of bio molecules, and electrical measurement in a transient state to avoid the charge screening effect, thereby significantly improving the sensitivity. As an example, the probe DNA molecules oscillate with pulse trains, resulting in the enhancement of DNA hybridization efficiency, and accordingly of the sensor performances in Tris-EDTA (TE) buffer solution, by as much as over three times, compared to the non-biasing conditions. More importantly, a wide dynamic range of 10(6) (target-DNA concentration from 5 pM to 5 μM) is achieved in human serum. In addition, the pulse biasing method enables one to obtain the conductance change, before the ions within the Electrical Double Layer (EDL) are redistributed, to avoid the charge screening effect, leading to an additional sensitivity enhancement. 23950884 A possible explanation for the variable frequencies of cancer stem cells in tumors. A controversy surrounds the frequency of cancer stem cells (CSCs) in solid tumors. Initial studies indicated that these cells had a frequency ranging from [Formula: see text] to [Formula: see text] of the total cells. Recent studies have shown that this does not always seem to be the case. Some of these studies have indicated a frequency of [Formula: see text]. In this paper we propose a stochastic model that is able to capture this potential variability in the frequency of CSCs among the various type of tumors. Considerations regarding the heterogeneity of the tumor cells and its consequences are included. Possible effects on conventional treatments in clinical practice are also described. The model results suggest that traditional attempts to combat cancer cells with rapid cycling can be very stimulating for the cancer stem cell populations. 23607697 Recommendations for the Use of Prolonged-Release Fampridine in Patients with Multiple Sclerosis (MS). Prolonged-release fampridine (fampridine PR) is a potassium channel blocker that improves conductivity of signal on demyelinated axons in central nervous system. Fampridine PR has been approved to improve speed of walking in patients with multiple sclerosis. This statement provides a brief summary of data on fampridine PR and recommendations on practical use of the medication in clinical practice, prediction, and evaluation of response to treatment and patient management. 23910173 Dedifferentiated liposarcoma of the spermatic cord with a hemangioendothelioma-like component: A case report and review of the literature. Atypical lipomatous tumor or well-differentiated liposarcoma/dedifferentiated liposarcoma (DDLPS) is the most frequent subtype of malignant adipocytic tumor. This tumor typically presents in late adult life, most commonly in the retroperitoneum, extremities, or spermatic cord. It has been reported that the dedifferentiated component consists mainly of high-grade sarcoma, including undifferentiated pleomorphic sarcoma, fibrosarcoma, and myxofibrosarcoma, and it has been recently reported that the dedifferentiated component can be also made up of a low-grade sarcomatous component. Therefore, the dedifferentiated areas exhibit a wide morphological spectrum that commonly includes fibroblastic/myofibroblastic and fibrohistiocytic tumors but very rarely includes vascular tumors. We present here the first reported case of DDLPS with a hemangioendothelioma-like component in the spermatic cord. 23823130 Molecular cloning and functional characterization of Argonaute-3 gene from Penaeus monodon. Argonaute (Ago) proteins play a crucial role in the shrimp RNA interference pathway. In this study, we identified and characterized a novel Ago gene from black tiger shrimp, Penaeus monodon. The complete open reading frame of P. monodon Ago3 (PmAgo3) consisted of 2559 nucleotides encoding a polypeptide of 852 amino acids with a predicted molecular weight of 97 kDa and an isoelectric point of 9.42. Analysis of the deduced amino acid sequence of PmAgo3 revealed the presence of two signature domains of the proteins in Argonaute family including PAZ and PIWI. Phylogenetic analysis indicated that PmAgo3 is classified into Ago subfamily and shared the highest amino acid sequence identity (83%) with Litopenaeus vannamei Ago2. Monitoring of the PmAgo3 expression by quantitative real-time PCR revealed that this gene was significantly up-regulated following dsRNA administration, while no significant difference in its expression was observed following yellow head virus (YHV) challenge. In contrast, inhibition of YHV mRNA expression was observed in PmAgo3-knockdown shrimp. These data imply that PmAgo3 is involved in the dsRNA-mediated gene silencing mechanism and plays an important role in YHV replication in the black tiger shrimp. 23916606 Pitfalls in post-mortem CT-angiography - intravascular contrast induces post-mortem pericardial effusion. We present a case where multi-phase post-mortem computed tomography angiography (PMCTA) induced a hemorrhagic pericardial effusion during the venous phase of angiography. Post-mortem non-contrast CT (PMCT) suggested the presence of a ruptured aortic dissection. This diagnosis was confirmed by PMCTA after pressure controlled arterial injection of contrast. During the second phase of multi-phase PMCTA the presence of contrast leakage from the inferior cava vein into the pericardial sac was noted. Autopsy confirmed the post-mortem nature of this vascular tear. This case teaches us an important lesson: it underlines the necessity to critically analyze PMCT and PMCTA images in order to distinguish between artifacts, true pathologies and iatrogenic findings. In cases with ambiguous findings such as the case reported here, correlation of imaging findings with autopsy is elementary. 23200734 Detection of designer steroid methylstenbolone in "nutritional supplement" using gas chromatography and tandem mass spectrometry: elucidation of its urinary metabolites. The use of "nutritional supplements" containing unapproved substances has become a regular practice in amateur and professional athletes. This represents a dangerous habit for their health once no data about toxicological or pharmacological effects of these supplements are available. Most of them are freely commercialized online and any person can buy them without medical surveillance. Usually, the steroids intentionally added to the "nutritional supplements" are testosterone analogues with some structural modifications. In this study, the analyzed product was bought online and a new anabolic steroid known as methylstenbolone (2,17α-dimethyl-17β-hydroxy-5α-androst-1-en-3-one) was detected, as described on label. Generally, anabolic steroids are extensively metabolized, thus in-depth knowledge of their metabolism is mandatory for doping control purposes. For this reason, a human excretion study was carried out with four volunteers after a single oral dose to determine the urinary metabolites of the steroid. Urine samples were submitted to enzymatic hydrolysis of glucuconjugated metabolites followed by liquid-liquid extraction and analysis of the trimethylsilyl derivatives by gas chromatography coupled to tandem mass spectrometry. Mass spectrometric data allowed the proposal of two plausible metabolites: 2,17α-dimethyl-16ξ,17β-dihydroxy-5α-androst-1-en-3-one (S1), 2,17α-dimethyl-3α,16ξ,17β-trihydroxy-5α-androst-1-ene (S2). Their electron impact mass spectra are compatible with 16-hydroxylated steroids O-TMS derivatives presenting diagnostic ions such as m/z 231 and m/z 218. These metabolites were detectable after one week post administration while unchanged methylstenbolone was only detectable in a brief period of 45 h. 23697793 Hypothalamic expression of mutant huntingtin contributes to the development of depressive-like behavior in the BAC transgenic mouse model of Huntington's disease. Psychiatric symptoms such as depression and anxiety are important clinical features of Huntington's disease (HD). However, the underlying neurobiological substrate for the psychiatric features is not fully understood. In order to explore the biological origin of depression and anxiety in HD, we used a mouse model that expresses the human full-length mutant huntingtin, the BACHD mouse. We found that the BACHD mice displayed depressive- and anxiety-like features as early as at 2 months of age as assessed using the Porsolt forced swim test (FST), the sucrose preference test and the elevated plus maze (EPM). BACHD mice subjected to chronic treatment with the anti-depressant sertraline were not different to vehicle-treated BACHD mice in the FST and EPM. The behavioral manifestations occurred in the absence of reduced hippocampal cell proliferation/neurogenesis or upregulation of the hypothalamic-pituitary-adrenal axis. However, alterations in anxiety- and depression-regulating genes were present in the hypothalamus of BACHD mice including reduced mRNA expression of neuropeptide Y, tachykinin receptor 3 and vesicular monoamine transporter type 2 as well as increased expression of cocaine and amphetamine regulated transcript. Interestingly, the orexin neuronal population in the hypothalamus was increased and showed cellular atrophy in old BACHD mice. Furthermore, inactivation of mutant huntingtin in a subset of the hypothalamic neurons prevented the development of the depressive features. Taken together, our data demonstrate that the BACHD mouse recapitulates clinical HD with early psychiatric aspects and point to the role of hypothalamic dysfunction in the development of depression and anxiety in the disease. 23660181 Parathyroidectomy and Heart Rate Variability in Patients with Stage 5 CKD. Lower heart rate variability implies increased risk of cardiovascular disease. This study aimed to evaluate the relationship between mineral metabolism and heart rate variability and longitudinal changes of heart rate variability after parathyroidectomy in stage 5 CKD patients. This cross-sectional study included 118 stage 5 CKD patients, 87 controls, and a prospective study in two subgroups classified as successful (n=17) and unsuccessful (n=4) parathyroidectomy follow-up enrolled from March of 2011 to December of 2012. Blood examination and 24-hour Holter for heart rate variability were measured. Most heart rate variability indices were lower in stage 5 CKD patients. In multivariate stepwise regression models, serum intact parathyroid hormone was correlated with mean normal-to-normal R-R intervals, mean heart rate, and very low frequency, serum calcium was correlated with SD of 5-minute average of normal R-R intervals, and serum phosphorus was correlated with very low frequency and low frequency/high frequency. Compared with baseline, the successful parathyroidectomy subgroup had significant improvements in mean normal-to-normal R-R intervals, mean heart rate, SD of normal-to-normal R-R intervals, SD of 5-minute average of normal R-R intervals, very low frequency, high frequency, and low frequency/high frequency. There was no significant change of heart rate variability in patients after unsuccessful parathyroidectomy. Disorders of mineral metabolism are associated with decreased heart rate variability in stage 5 CKD. Successful parathyroidectomy may contribute to reverse this cardiovascular disease risk in severe secondary hyperparathyroidism patients. 23591579 Oxidative stress and MAPK involved into ATF2 expression in immortalized human urothelial cells treated by arsenic. ATF2 is a subfamily member of AP-1 and has an important role in cellular stress responses. ATF2 has been implicated in a transcriptional response leading to cell migration and malignant tumor progression. However, little is known about the effect of arsenic on expression of ATF2 and regulatory pathways in human urothelial cells. In this study, ATF2 expression was measured in NaAsO2-treated human uroepithelial cell line (SV-HUC-1) with 1, 2, 4, 8 and 10 μM concentrations in order to provide some basis data for the study on mechanism of bladder cancer induced by arsenic. We found that ATF2 expression levels at 2, 4, 8 and 10 μM arsenic-treated cells were significantly higher than those of control cells, and the strongest expression occurred in 4 μM NaAsO2-treated cells. Antioxidants (melatonin) and JNK or p38 inhibitors decreased significantly arsenic-induced ATF2 expression. Taken together, these data indicated that the increasing of ATF2 expression is mediated via oxidative stress induced by arsenic in SV-HUC-1 cells, and JNK or p38 rather than ERK is responsible for arsenic-induced ATF2 expression. ROS were also involved in arsenic induced the activation of JNK and p38 MAPK signaling pathway. 23832433 Efficacy and Safety of Curcumin in Major Depressive Disorder: A Randomized Controlled Trial. Curcumin, an active ingredient of Curcuma longa Linn (Zingiberaceae), has shown potential antidepressant-like activity in animal studies. The objectives of this trial were to compare the efficacy and safety of curcumin with fluoxetine in patients with major depressive disorder (MDD). Herein, 60 patients diagnosed with MDD were randomized in a 1:1:1 ratio for six weeks observer-masked treatment with fluoxetine (20 mg) and curcumin (1000 mg) individually or their combination. The primary efficacy variable was response rates according to Hamilton Depression Rating Scale, 17-item version (HAM-D17 ). The secondary efficacy variable was the mean change in HAM-D17 score after six weeks. We observed that curcumin was well tolerated by all the patients. The proportion of responders as measured by the HAM-D17 scale was higher in the combination group (77.8%) than in the fluoxetine (64.7%) and the curcumin (62.5%) groups; however, these data were not statistically significant (P = 0.58). Interestingly, the mean change in HAM-D17 score at the end of six weeks was comparable in all three groups (P = 0.77). This study provides first clinical evidence that curcumin may be used as an effective and safe modality for treatment in patients with MDD without concurrent suicidal ideation or other psychotic disorders. Copyright © 2013 John Wiley & Sons, Ltd. 22743614 Bleomycin in octaarginine-modified fusogenic liposomes results in improved tumor growth inhibition. Bleomycin (BLM) is an example of an anticancer drug that should be delivered into cytosol for its efficient therapeutic action. With this in mind, we developed octaarginine (R8)-modified fusogenic DOPE-liposomes (R8-DOPE-BLM). R8-modification dramatically increased (up to 50-fold) the cell-liposome interaction. R8-DOPE-liposomes were internalized via macropinocytosis and did not end up in the lysosomes. R8-DOPE-BLM led to a significantly stronger cell death and DNA damage in vitro relative to all controls. R8-DOPE-BLM demonstrated a prominent anticancer effect in the BALB/c mice bearing 4T1 tumors. Thus, R8-DOPE-BLM provided efficient intracellular delivery of BLM leading to strong tumor growth inhibition in vivo. 23856151 Impact of a Wheelchair Education Protocol based on Practice Guidelines for Preservation of Upper Limb Function: A Randomized Trial. To determine if strict utilization of the Paralyzed Veterans of America's Clinical Practice Guidelines for Preservation of Upper Limb Function impacts wheelchair set-up, selection, propulsion biomechanics, pain, satisfaction with life and participation of individuals with new spinal cord injuries DESIGN: Single blinded, randomized clinical trial SETTING: Model Spinal Cord Injury Systems Rehabilitation Facility and community in Pittsburgh, PA PARTICIPANTS: Volunteer sample of 37 manual wheelchair users with new spinal cord injuries MAIN OUTCOME MEASURES: Comparison of wheelchair set-up, selection, propulsion biomechanics, pain, Satisfaction With Life Scale and the Craig Handicap Assessment and Reporting Technique scores at the time of discharge from inpatient rehabilitation, six months and one year post discharge. The intervention group was strictly educated on the clinical practice guideline by a Physical and Occupational Therapist in an inpatient rehabilitation facility. The standard of care group received standard therapy services. Participants in the intervention group pushed on tile with significantly lower push frequency (p = 0.02) at the discharge visit. On the ramp, the intervention group used a significantly larger push length (p = 0.03) across all time points. No significant differences were found between groups related to wheelchair set up, selection, pain, satisfaction with life and participation. The IG showed better skills on key wheelchair propulsion biomechanics variables related to upper limb health. Use of a structured education program may be an effective method of educating new manual wheelchair users to prevent the development of upper limb impairments in an inpatient setting. Additional follow up testing is necessary to determine if differences seen in propulsion skills translate into decreased pain and improved quality of life in the long term. 23465760 Decreased skin temperature of the foot increases gait variability in healthy young adults. We investigated the effects of reduction in plantar skin temperature on gait. Thirty-four healthy subjects (20 men and 14 women; mean age 22.2±2.5 years; mean height 166.8±8.3cm) walked 16m under two different conditions - normal conditions (NC) with the skin at a basal temperature, and cold conditions (CC) after cooling of the plantar skin to about 15°C. Wireless motion-recording sensor units were placed on the back at the level of L3 and on both heels to measure acceleration and angular velocity. Gait velocity and mean stride, stance and swing times were calculated. The variability of lower limb movement was represented by the coefficients of variation (CVs) of stride, stance and swing times, and that of trunk movement was represented by autocorrelation coefficients (ACs) in three directions (vertical: VT; mediolateral: ML; and anteroposterior: AP). Gait velocity was significantly lower under CC conditions than under NC (p<0.0001). None of the temporal parameters were changed by plantar cooling. However, all parameters of gait variability were significantly worse under CC, and AC-VT, AC-ML, and AC-AP were significantly lower under CC than under NC, even after adjusting for gait velocity (p=0.0005, 0.0071, and 0.0126, respectively). Our results suggest that reducing plantar skin temperature induces gait variability among healthy young adults. Further studies are now needed to explore the relationship between plantar skin temperature and gait in the elderly. 23951171 Identification of Trypanosome Proteins in Plasma from African Sleeping Sickness Patients Infected with T. b. rhodesiense. Control of human African sleeping sickness, caused by subspecies of the protozoan parasite Trypanosoma brucei, is based on preventing transmission by elimination of the tsetse vector and by active diagnostic screening and treatment of infected patients. To identify trypanosome proteins that have potential as biomarkers for detection and monitoring of African sleeping sickness, we have used a 'deep-mining" proteomics approach to identify trypanosome proteins in human plasma. Abundant human plasma proteins were removed by immunodepletion. Depleted plasma samples were then digested to peptides with trypsin, fractionated by basic reversed phase and each fraction analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). This sample processing and analysis method enabled identification of low levels of trypanosome proteins in pooled plasma from late stage sleeping sickness patients infected with Trypanosoma brucei rhodesiense. A total of 254 trypanosome proteins were confidently identified. Many of the parasite proteins identified were of unknown function, although metabolic enzymes, chaperones, proteases and ubiquitin-related/acting proteins were found. This approach to the identification of conserved, soluble trypanosome proteins in human plasma offers a possible route to improved disease diagnosis and monitoring, since these molecules are potential biomarkers for the development of a new generation of antigen-detection assays. The combined immuno-depletion/mass spectrometric approach can be applied to a variety of infectious diseases for unbiased biomarker identification. 23053088 Nitrifying bacterial community structures and their nitrification performance under sufficient and limited inorganic carbon conditions. This study examined the hypothesis that different inorganic carbon (IC) conditions enrich different ammonia-oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB) populations by operating two laboratory-scale continuous-flow bioreactors fed with 15 and 100 mg IC/L, respectively. During this study, both bioreactors maintained satisfactory nitrification performance and stably oxidized 250 mg N/L of influent ammonium without nitrite accumulation. Based on results of cloning/sequencing and terminal restriction fragment length polymorphism targeting on the ammonia monooxygenase subunit A (amoA) gene, Nitrosomonas nitrosa lineage was identified as the dominant AOB population in the high-IC bioreactor, while Nitrosomonas europaea and Nitrosomonas nitrosa lineage AOB were dominant in the low-IC bioreactor. Results of real-time polymerase chain reactions for Nitrobacter and Nitrospira 16S rRNA genes indicated that Nitrospira was the predominant NOB population in the high-IC bioreactor, while Nitrobacter was the dominant NOB in the low-IC bioreactor. Furthermore, batch experiment results suggest that N. europaea and Nitrobacter populations are proliferated in the low-IC bioreactor due to their higher rates under low IC conditions despite the fact that these two populations have been identified as weak competitors, compared with N. nitrosa and Nitrospira, under low ammonium/nitrite environments. This study revealed that in addition to ammonium/nitrite concentrations, limited IC conditions may also be important in selecting dominant AOB/NOB communities of nitrifying bioreactors. 23775308 Knockdown of lipocalin-2 suppresses the growth and invasion of prostate cancer cells. Lipocalin-2 (LCN2) is a member of the lipocalin superfamily, and it has an important role in the regulation of cellular oncogenesis and apoptosis. However, the role for LCN2 in prostate cancer remains unclear. LCN2 expression has been determined by Western blotting, qRT-PCR, and immunohistochemistry in the human prostate cell lines PC3, DU145, LNCaP, and 22Rv, and in human prostate tissue array. In this study, we identified shRNA-LCN2 to determine the role of LCN2 in prostate-cancer cell proliferation, migration, and invasion. Cell proliferative ability was measured by MTT, colony-formation, and cell-cycle analysis. The role of LCN2 in prostate-cancer cell migration and invasion was analyzed by cell-migration assay and Matrigel invasion assay. The effect of LCN2 knockdown on prostate tumor growth was assessed in a subcutaneous xenograft model. LCN2 protein and mRNA expression are higher in PC3 and DU145 cells than in LNCaP and 22Rv cells, and prostate cancer tissue correlated significantly with tumor differentiation (P < 0.017) and Gleason's grade (P < 0.02). LCN2 knockdown in PC3 and DU145 cells decreased cell proliferation, colony formation, cell cycle arrest, migration, and invasion. Conversely, LCN2 overexpression in 22Rv cells produced the opposite effect. Subcutaneous xenografts in mice models showed decreased tumor growth in the LCN2-knockdown mice. Our results suggest that LCN2 might play an important role in regulation of proliferation and invasion of human prostate cancer, and that it can be a valuable marker of prostate cancer progression. Prostate 73: 1281-1290, 2013. © 2013 Wiley Periodicals, Inc. 23510308 Protected by nature? Effects of strenuous physical exercise on FVIII activity in moderate and mild haemophilia A patients: a pilot study. Increase of factor VIII activity (FVIII) after physical exercise has been reported in healthy subjects and small-scale studies in patients with coagulopathies. The aim was to study whether moderate and mild haemophilia A patients are able to increase their endogenous FVIII activity levels by physical activity. We studied changes in FVIII activity levels after high-intensity exercise in 15 haemophilia A patients, 20-39 years, eight with moderate, seven with mild haemophilia. Patients cycled until volitional exhaustion, blood samples were drawn before and 10 min after the exercise test. FVIII activity increased 2.5 times (range 1.8-7.0 times), for both severities. Absolute increases were markedly different: median 7 IU dL(-1) (range 3-9 IU dL(-1) ) in patients with moderate, compared to 15 IU dL(-1) (range 6-62 IU dL(-1) ) in mild haemophilia patients. VWF and VWFpp increased independently of severity; median 50% (range 8-123%) and median 165% (range 48-350%), respectively, reflecting acute release of VWF. These observations may be used to promote high-intensity activities before participating in sports for moderate and mild haemophilia A patients, to reduce bleeding risk. Further studies are warranted to fully appreciate the clinical significance of exercise on different levels of intensity in patients with mild and moderate haemophilia A. 23913697 Mechanically Controllable Break Junctions for Molecular Electronics. A mechanically controllable break junction (MCBJ) represents a fundamental technique for the investigation of molecular electronic junctions, especially for the study of the electronic properties of single molecules. With unique advantages, the MCBJ technique has provided substantial insight into charge transport processes in molecules. In this review, the techniques for sample fabrication, operation and the various applications of MCBJs are introduced and the history, challenges and future of MCBJs are discussed. 23861188 Characterization of macrolide resistance of Mycoplasma pneumoniae in children in Shenzhen, China. Macrolide-resistant Mycoplasma pneumoniae (MR-M. pneumoniae) was isolated from clinical specimens in Shenzhen, China from November 2010 to July 2011. A comparative study was conducted to determine whether macrolides are effective in treating patients infected with MR-M. pneumoniae. Of 57 M. pneumoniae strains, 36 harbored point mutations on A2063G in the 23S ribosomal RNA gene. A total of 36 (63%) strains were classified as MR-M. pneumonia and 21 (37%) as macrolide-susceptible M. pneumoniae (MS-M. pneumoniae). The clinical courses of MR-M. pneumoniae-infected patients (MR patients) treated with macrolides were compared with those of MS-M. pneumoniae-infected patients (MS patients). The patient demographics (sex, age), most laboratory findings, and diagnosis did not show significant differences between the two groups. The MR patients had higher mean total febrile days compared with MS patients (6.56 ± 6.17 days vs. 3.57 ± 3.80 days, P = 0.05). The MR patients were more likely to be have levels of high-sensitivity C-reactive protein than MS patients (42% (15/36) vs. 14% (3/21), P = 0.03). Although the febrile period was prolonged in MR patients treated with macrolides, the fever resolved even when the initial prescription was unchanged. Therefore, these results suggest that macrolides are less effective in MR patients than in MS patients. Pediatr Pulmonol. 2013; 9999:XX-XX. © 2013 Wiley Periodicals, Inc. 23855815 Postpartum symphysis pubis separation. We wish to call attention to a case of symphysis pubis separation after term vaginal birth in a 41-year old gravida 3, with insulin-regulated gestational diabetes, who previously had two spontaneous vaginal deliveries (4000 g and 3200 g babies 16 years and 11 years ago). She delivered a 4790 g baby vaginally with McRobert's maneuver due to shoulder dystocia, but without fetal complications. This article is protected by copyright. All rights reserved. 23894170 Incidence, Prevention, and Treatment of Parenteral Nutrition-Associated Cholestasis and Intestinal Failure-Associated Liver Disease in Infants and Children: A Systematic Review. Cholestasis is a significant life-threatening complication in children on parenteral nutrition (PN). Strategies to prevent/treat PN-associated cholestasis (PNAC) and intestinal failure-associated liver disease (IFALD) have reached moderate success with little supporting evidence. Aims of this systematic review were (1) to determine the incidence of PNAC/IFALD in children receiving PN for ≥14 days and (2) to review the efficacy of measures to prevent/treat PNAC/IFALD. Methods: Of 4696 abstracts screened, 406 relevant articles were reviewed, and studies on children with PN ≥14 days and cholestasis (conjugated bilirubin ≥ 2 mg/dL) were included. Analyzed parameters were (1) PNAC/IFALD incidence by decade and by PN length and (2) PNAC/IFALD prevention and treatment (prospective studies). Results: Twenty-three articles (3280 patients) showed an incidence of 28.2% and 49.8% of PNAC and IFALD, respectively, with no evident alteration over the last decades. The incidence of PNAC was directly proportional to the length of PN (from 15.7% for PN ≤1 month up to 60.9% for PN ≥2 months; P < .0001). Ten studies on PNAC met inclusion criteria. High or intermediate-dose of oral erythromycin and aminoacid-free PN with enteral whey protein gained significant benefits in preterm neonates (P < .05, P = .003, and P < .001, respectively). None of the studies reviewed met inclusion criteria for treatment. Conclusions: The incidence of PNAC/IFALD in children has no obvious decrease over time. PNAC is directly correlated to the length of PN. Erythromycin and aminoacid-free PN with enteral whey protein have shown to prevent PNAC in preterm neonates. There is a lack of high-quality prospective studies, especially on IFALD. 23746436 On the hysteresis of argon adsorption in a uniform closed end slit pore. We present a molecular simulation study of adsorption and desorption in slit mesopores of uniform width with one end closed and explore the effects of pore dimensions (width and length), temperature and surface affinity on the hysteresis loop: its position, lower and upper closure points, area and shape. Our results show that the metastability, brought about by structural change in the adsorbate, is the reason for the existence of hysteresis, and contrast with reports suggesting that reversibility invariably prevails for adsorption in closed end pores. The shape, area and position of the hysteresis loop are complex functions of pore width, length and temperature. We establish a parametric map of the boundary separating reversible and hysteretic regions. Our simulation results also show a number of interesting observations that have not been previously reported or generally recognised: (1) the fluid within the core of the pore behaves like a bulk liquid as the pore is progressively filled, via the movement of the meniscus from the closed end to the pore mouth, but as the pore fills, the fluid in the core becomes structured, (2) the shape of the meniscus changes as adsorption progresses but is constant during desorption because of the constant thickness of the adsorbed layer in the two-phase region, (3) the hysteresis loop is larger for a longer pore, (4) the area of the hysteresis loop increases with pore width up to a certain width, beyond which it decreases and finally disappears, (5) as temperature approaches the critical hysteresis temperature, the hysteresis loop area decreases, but it retains its Type H1 character. 23171163 The evolution of north-east Atlantic gadfly petrels using statistical phylogeography. Macaronesia (north-east Atlantic archipelagos) has been host to complex patterns of colonization and differentiation in many groups of organisms including seabirds such as gadfly petrels (genus Pterodroma). Considering the subspecies of widely distributed soft-plumaged petrel for many years, the taxonomic status of the three gadfly petrel taxa breeding in Macaronesia is not yet settled, some authors advocating the presence of three, two or one species. These birds have already been the subject of genetic studies with only one mtDNA gene and relatively modest sample sizes. In this study, using a total of five genes (two mitochondrial genes and three nuclear introns), we investigated the population and phylogeographical histories of petrel populations breeding on Madeira and Cape Verde archipelagos. Despite confirming complete lineage sorting with mtDNA, analyses with nucDNA failed to reveal any population structuring and Isolation with Migration analysis revealed the absence of gene flow during the differentiation process of these populations. It appears that the three populations diverged in the late Pleistocene in the last 150 000 years, that is 10 times more recently than previous estimates based solely on one mtDNA gene. Finally, our results suggest that the Madeira petrel population is ancestral rather than that from Cape Verde. This study strongly advocates the use of nuclear loci in addition to mtDNA in demographical and phylogeographical history studies. 23894480 Identification and Characterization of the Spodoptera Su(var) 3-9 Histone H3K9 trimethyltransferase and Its Effect in AcMNPV Infection. Histone H3-lysine(9) (H3K9) trimethyltransferase gene Su(var) 3-9 was cloned and identified in three Spodoptera insects, Spodopterafrugiperda (S. frugiperda), S. exigua and S. litura. Sequence analysis showed that Spodoptera Su(var) 3-9 is highly conserved evolutionarily. Su(var) 3-9 protein was found to be localized in the nucleus in Sf9 cells, and interact with histone H3, and the heterochromatin protein 1a (HP1a) and HP1b. A dose-dependent enzymatic activity was found at both 27 °C and 37 °C in vitro, with higher activity at 27 °C. Addition of specific inhibitor chaetocin resulted in decreased histone methylation level and host chromatin relaxation. In contrast, overexpression of Su(var) 3-9 caused increased histone methylation level and cellular genome compaction. In AcMNV-infected Sf9 cells, the transcription of Su(var) 3-9 increased at late time of infection, although the mRNA levels of most cellular genes decreased. Pre-treatment of Sf9 cells with chaetocin speeded up viral DNA replication, and increased the transcription level of a variety of virus genes, whereas in Sf9 cells pre-transformed with Su(var) 3-9 expression vector, viral DNA replication slow down slightly. These findings suggest that Su(var) 3-9 might participate in the viral genes expression an genome replication repression during AcMNPV infection. It provided a new insight for the understanding virus-host interaction mechanism. 23394702 Personalized medicine for targeted and platinum-based chemotherapy of lung and bladder cancer. The personalized medicine revolution is occurring for cancer chemotherapy. Biomarkers are increasingly capable of distinguishing genotypic or phenotypic traits of individual tumors, and are being linked to the selection of treatment protocols. This review covers the molecular basis for biomarkers of response to targeted and cytotoxic lung and bladder cancer treatment with an emphasis on platinum-based chemotherapy. Platinum derivatives are a class of drugs commonly employed against solid tumors that kill cells by covalent attachment to DNA. Platinum-DNA adduct levels in patient tissues have been correlated to response and survival. The sensitivity and precision of adduct detection has increased to the point of enabling subtherapeutic dosing for diagnostics applications, termed diagnostic microdosing, prior to the initiation of full-dose therapy. The clinical status of this unique phenotypic marker for lung and bladder cancer applications is detailed along with discussion of future applications. 23948786 Effects of Memantine on Clinical Ratings, Fluorodeoxyglucose Positron Emission Tomography Measurements, and Cerebrospinal Fluid Assays in Patients With Moderate to Severe Alzheimer Dementia: A 24-Week, Randomized, Clinical Trial. Most experts consider that memantine has a symptomatic treatment, but clinical trials have not yet provided compelling evidence to support a disease-modifying effect. We investigate the effects of memantine on clinical ratings; fluorodeoxyglucose positron emission tomography (FDG-PET) measurements, which can monitor disease-modifying effect; and cerebrospinal fluid (CSF) assays in patients with moderate to severe probable Alzheimer disease (AD) dementia. Twenty-two patients completed a 24-week, double-blind, placebo-controlled, randomized clinical trial of memantine, titrated up to 10 mg twice per day using the Severe Impairment Battery, AD Assessment Scale-Cognitive subscale, Mini-Mental State Examination, FDG-PET measurements of the regional cerebral metabolic rate for glucose (CMRgl), and CSF amyloid β (Aβ) and tau assays. An automated brain mapping algorithm and predefined regions of interest were each used to analyze treatment-related regional CMRgl effects. In comparison with the placebo group, the memantine treatment group had significantly less cognitive decline on the Severe Impairment Battery and significantly less CMRgl declines in regions preferentially affected by AD. There were no significant treatment effects on CSF Aβ1-42, CSF Aβ1-40, total tau, or phosphor-tau levels or ratios. This relatively small and brief randomized clinical trial suggests an association between memantine's clinical benefit and its effects on FDG-PET measurements in AD-affected brain regions. Larger and longer studies are needed to confirm these findings, extend them to earlier clinical and preclinical stages of AD, and help determine the extent to which FDG-PET should be qualified for use as a reasonably likely surrogate end point in the evaluation of putative AD-modifying treatments. 23613441 Erythrocytes labeled with [(18) F]SFB as an alternative to radioactive CO for quantification of blood volume with PET. Inhaled radioactive CO is currently the tracer of choice for blood volume quantification by positron emission tomography (PET). This measurement is of great interest for several clinical and research applications. However, owing to the short half-life of the radiolabeled CO, it can only be used in centers equipped with a cyclotron. In the present work, we propose an alternative method to label the red blood cells with [(18) F] in order to obtain blood volume measurements by PET. The use of the radioactive synthon [(18) F] N-succinimidyl 4-[(18) F]fluorobenzoate ([(18) F]SFB) was evaluated for erythrocyte labeling and PET blood volume imaging. The images provided by [(18) F]SFB labeled erythrocytes were compared with those obtained with inhaled [(11) C]CO. Blood volumes obtained with [(18) F]SFB labeled erythrocytes were similar to those obtained with [(11) C]CO in all of the evaluated organs with the exception of spleen, which presented lower uptake with this method. Since the [(18) F]-SFB binds irreversibly to red blood cells, in vivo stability of the radiolabel was higher compared with the [(11) C]CO method. Additionally, owing to the longer half-life and the shorter positron range of [(18) F], the image quality was also higher with the [(18) F]SFB radiolabeled erythrocytes. The labeling of red blood with [(18) F]SFB represents an advantageous alternative to radioactive CO for blood volume measurement by PET and cardiovascular isotopic imaging. 23943865 Strigolactones stimulate internode elongation independently of gibberellins. Strigolactone mutants in diverse species show reduced stature in addition to their extensive branching. Here we show that this dwarfism in pea (Pisum sativum) is not attributable to the strong branching of the mutants. The continuous supply of the synthetic SL GR24 via the root system using hydroponics can restore internode length of the SL-deficient rms1 mutant but not of the SL-response rms4 mutant indicating that SLs stimulate internode elongation via RMS4. Cytological analysis of internode epidermal cells indicates that SLs control cell number but not cell length, suggesting SL may affect stem elongation by stimulating cell division. Consequently, SLs can repress (in axillary buds) or promote (in the stem) cell division in a tissue-dependent manner. Because gibberellins (GAs) increase internode length by affecting both cell division and cell length, we tested if SLs stimulate internode elongation by affecting GA metabolism or signalling. Genetic analyses using SL-deficient and GA-deficient or della-deficient double mutants, together with molecular and physiological approaches suggest that SLs act independently from GAs to stimulate internode elongation. 23898380 Proteomic identification of proteins suggestive of immune-mediated response or neuronal degeneration in serum of achalasia patients. The primary pathophysiologic abnormality in achalasia is known to be a loss of inhibitory myenteric ganglion cells, which may result from an immune-mediated response or neuronal degeneration. The aim of this study was to identify proteins suggestive of an immune-mediated response or neuronal degeneration in the serum of achalasia patients using a proteomic analysis. Blood samples were collected from five symptomatic achalasia patients and five sex- and age-matched healthy controls. Serum proteomic analysis was conducted, and the protein spots were identified using matrix-assisted laser desorption ionization/time-of-flight and a proteomics analyzer. The serum level of C3 was measured by enzyme-linked immunosorbent assay in nine patients with achalasia and 18 sex- and age-matched healthy controls. Of the 658 matched protein spots, 28 spots were up-regulated over 2-fold in the serum from achalasia patients compared with that from controls. The up-regulated proteins included complement C4B5, complement C3, cyclin-dependent kinase 5, transthyretin, and alpha 2 macroglobulin. The serum levels of C3 in achalasia patients were significantly higher than those of controls. The serum proteomic analysis of achalasia patients suggests an immune-mediated response or neuronal degeneration. Further validation studies in larger samples and the esophageal tissue of achalasia patients are required. 23812894 Technological advances in the surgical treatment of movement disorders. Technological innovations have driven the advancement of the surgical treatment of movement disorders, from the invention of the stereotactic frame to the adaptation of deep brain stimulation (DBS). Along these lines, this review will describe recent advances in inserting neuromodulation modalities, including DBS, to the target, and in the delivery of therapy at the target. Recent radiological advances are altering the way that DBS leads are targeted and inserted, by refining the ability to visualize the subcortical targets using high-field strength magnetic resonance imaging and other innovations, such as diffusion tensor imaging, and the development of novel targeting devices enabling purely anatomical implantations without the need for neurophysiological monitoring. New portable computed tomography scanners also are facilitating lead implantation without monitoring, as well as improving radiological verification of DBS lead location. Advances in neurophysiological mapping include efforts to develop automatic target verification algorithms, and probabilistic maps to guide target selection. The delivery of therapy at the target is being improved by the development of the next generation of internal pulse generators (IPGs). These include constant current devices that mitigate the variability introduced by impedance changes of the stimulated tissue and, in the near future, devices that deliver novel stimulation patterns with improved efficiency. Closed-loop adaptive IPGs are being tested, which may tailor stimulation to ongoing changes in the nervous system, reflected in biomarkers continuously recorded by the devices. Finer-grained DBS leads, in conjunction with new IPGs and advanced programming tools, may offer improved outcomes via current steering algorithms. Finally, even thermocoagulation-essentially replaced by DBS-is being advanced by new minimally-invasive approaches that may improve this therapy for selected patients in whom it may be preferred. Functional neurosurgery has a history of being driven by technological innovation, a tradition that continues into its future. 23674363 The Impact of Renal Tubular Damage, as Assessed by Urinary β2-Microglobulin-Creatinine Ratio, on Cardiac Prognosis in Patients With Chronic Heart Failure. Background- Renal dysfunction was reported to be closely associated with clinical outcomes in patients with chronic heart failure (CHF). Renal tubulointerstitial damage has been shown to be an important factor in the development of renal dysfunction as well as glomerular damage. However, the impact of renal tubular damage on clinical outcomes in patients with CHF remains to be determined. Methods and Results- Urinary β2-microglobulin-creatinine ratio was measured in 315 patients with CHF. Renal tubular damage was defined as a urinary β2-microglobulin-creatinine ratio ≥300 μg/g, as previously reported. Patients were prospectively followed up for a median period of 1097 days. There were 91 cardiac events, including 16 cardiac deaths and 75 rehospitalizations for worsening heart failure. Log10 urinary β2-microglobulin-creatinine ratio was increased with worsening New York Heart Association functional class. Multivariate analysis revealed that renal tubular damage was an independent predictor of cardiac events. Kaplan-Meier analysis demonstrated that the rate of cardiac events was higher in patients with renal tubular damage compared with those without it. Patients were divided into 4 groups according to the presence of chronic kidney disease and renal tubular damage. The Cox proportional hazard analysis revealed that comorbidity of chronic kidney disease and renal tubular damage was associated with the highest risk for cardiac events compared with other groups. Conclusions- Renal tubular damage was related to the severity of heart failure and was associated with poor outcomes in patients with CHF. Renal tubular damage could add clinical information to chronic kidney disease in patients with CHF. 23770642 Highly efficient reduction of graphene oxide using ammonia borane. We introduce ammonia borane, a versatile reducing agent for graphene oxide (GO) reduction in both aqueous and organic solvents; it is nontoxic and more effective than hydrazine. More interestingly, ammonia borane reduction of GO tetrahydrofuran produced higher nitrogen- and boron-doped graphene that exhibited high supercapacitor performance. 23734844 Heart rate variability arterial hypertension in young heart-transplanted recipients: Association progression of cardiac allograft vasculopathy? Hypertension and reduced HRV are frequent in heart-transplanted recipients. We studied 26 young recipients to investigate the relationship between BP and HRV during simultaneous 24-h monitoring. Presence of CAV was considered. All HRV measures were significantly lower than normal values. Significant correlations were found between mean daytime systolic BP and the rMSSD (p = 0.04), and mean daytime DBP and SDANN for all 5-min segments (p = 0.03) and between rMSSD and mean nighttime DBP (p = 0.03). Four patients were hypertensive during daytime, seven had a reduced nocturnal fall and two had a nocturnal rise in BP. Eight patients showed severe CAV grade (grade IV) on the Stanford scale, 13 moderate (grade III) and five mild (grade I-II). After a follow-up time of 30 months, four of the 13 patients (30%) with CAV grade III showed an increase to grade IV and all showed abnormalities of both HRV and ABPM patterns. The relationship between HRV abnormalities and arterial hypertension and CAV should be further explored. 23524230 Determination of 63Ni and 59Ni in spent ion-exchange resin and activated charcoal from the IEA-R1 nuclear research reactor. A radiochemical method has been adapted to determine (59)Ni and (63)Ni in samples of radioactive wastes from the water cleanup system of the IEA-R1 nuclear research reactor. The process includes extraction chromatographic resin with dimethylglyoxime (DMG) as a functional group. Activity concentrations of (59)Ni and (63)Ni were measured, respectively, by X-ray spectrometry and liquid scintillation counting, whereas the chemical yield was determined by ICP-OES. The average ratio of measured activity concentrations of (63)Ni and (59)Ni agree well with theory. 23872029 Intravesical instillation of c-MYC inhibitor KSI-3716 suppresses orthotopic bladder tumor growth. c-MYC is a promising target for cancer therapy but its utilization is restricted by unwanted and devastating side effects. We explored whether intravesical instillation of the c-MYC inhibitor, KSI-3716 could suppress tumor growth in murine orthotopic bladder xenografts. The small molecule, KSI-3716, which blocks c-MYC/MAX binding to target gene promoters was utilized as an intravesical chemotherapeutic agent. The action of KSI-3716 was assessed by electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), transcription reporter assay and quantitative RT-PCR. Inhibition of cell proliferation and its mechanism were monitored by cell cytotoxicity assay, EdU incorporation assay and flow cytometry. The in vivo efficacy of KSI-3716 was examined by non-invasive luminescence imaging and histological analysis after intravesical instillation of KSI-3716 in murine orthotopic bladder xenografts. KSI-3716 blocked c-MYC/MAX from forming a complex with target gene promoters. c-MYC-mediated transcriptional activity was inhibited by KSI-3716 at concentrations as low as 1 #x03BC;M, and the expression of c-MYC target genes such as cyclin D2, CDK4, and hTERT were markedly reduced. KSI-3716 was demonstrated to exert cytotoxic effects on bladder cancer cells by inducing cell cycle arrest and apoptosis. Intravesical instillation of KSI-3716 at a dose of 5 mg/kg significantly suppressed tumor growth with minimal systemic toxicity. The c-MYC inhibitor, KSI-3716 could be developed as an effective intravesical chemotherapeutic agent for bladder cancer. 23880288 Treating neutrophilic inflammation in COPD by targeting ALX/FPR2 resolution pathways. Neutrophilic inflammation persists in COPD despite best current therapies and it is particularly resistant to inhaled glucocorticosteroids. Persistent neutrophil activation not only contributes to matrix breakdown, but can maintain inflammation through the release of endogenous damage associated molecule patterns (DAMPs). Inhibiting excessive neutrophilic inflammation is challenging as many pathogen recognition receptors can initiate migration and the targeting of downstream signaling molecules may compromise essential host defense mechanisms. Here, we discuss new strategies to combat this inflammation in COPD by focusing on the anti-inflammatory role of ALX/FPR2 receptors. ALX/FPR2 is a promiscuous G-protein coupled receptor (GPCR) responding to lipid and peptide agonists that can either switch on acute inflammation or promote resolution of inflammation. We highlight this receptor as an emerging target in the pathogenesis of COPD because known ALX/FPR2 endogenous agonists are enriched in COPD. Serum Amyloid A (SAA) has recently been discovered to be abundantly expressed in COPD and is a potent ALX/FPR2 agonist that unlike almost all other inflammatory chemoattractants, is induced by glucocorticosteroids. SAA not only initiates lung inflammation via ALX/FPR2 but can allosterically modify this receptor so that it no longer transduces pro-resolving signals from endogenous lipoxins that would otherwise promote tissue healing. We propose that there is an imbalance in endogenous and microbial ALX/FPR2 receptor agonists in the inflamed COPD lung environment that oppose protective anti-inflammatory and pro-resolution pathways. These insights open the possibility of targeting ALX/FPR2 receptors using synthetic agonists to resolve persistent neutrophilic inflammation without compromising essential host defense mechanisms. 23754526 Bite force and occlusal stress production in hominin evolution. Maximum bite force affects craniofacial morphology and an organism's ability to break down foods with different material properties. Humans are generally believed to produce low bite forces and spend less time chewing compared with other apes because advances in mechanical and thermal food processing techniques alter food material properties in such a way as to reduce overall masticatory effort. However, when hominins began regularly consuming mechanically processed or cooked diets is not known. Here, we apply a model for estimating maximum bite forces and stresses at the second molar in modern human, nonhuman primate, and hominin skulls that incorporates skeletal data along with species-specific estimates of jaw muscle architecture. The model, which reliably estimates bite forces, shows a significant relationship between second molar bite force and second molar area across species but does not confirm our hypothesis of isometry. Specimens in the genus Homo fall below the regression line describing the relationship between bite force and molar area for nonhuman anthropoids and australopiths. These results suggest that Homo species generate maximum bite forces below those predicted based on scaling among australopiths and nonhuman primates. Because this decline occurred before evidence for cooking, we hypothesize that selection for lower bite force production was likely made possible by an increased reliance on nonthermal food processing. However, given substantial variability among in vivo bite force magnitudes measured in humans, environmental effects, especially variations in food mechanical properties, may also be a factor. The results also suggest that australopiths had ape-like bite force capabilities. Am J Phys Anthropol 151:544-557, 2013. © 2013 Wiley Periodicals, Inc. 23668817 Reappraisal and suppression mediate the contribution of regulatory focus to anxiety in healthy adults. Theory and research link regulatory focus (RF) in the form of promotion and prevention goal orientation with internalizing symptoms (e.g., anxiety), but the relevant mechanisms are not well understood. This study investigated the role of two emotion regulation (ER) strategies (cognitive reappraisal and expressive suppression) as possible mediators. Path analysis using data from 179 healthy young participants (110 women, 69 men) revealed that stronger promotion orientation was significantly associated with less anxiety, and that the use of reappraisal and suppression partially mediated this association. Prevention was associated with more suppression but was not directly associated with anxiety. There were no gender differences in these effects. Collectively, these findings suggest that effective ER, through heightened use of reappraisal and dampened use of suppression, serves as a mechanism through which promotion confers protection against anxiety. This research provides empirical support to initiatives aimed at promoting healthy psychological adjustment and preventing anxiety, by optimizing ER strategies with respect to RF goal orientations. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23868492 Clinically diagnosed insomnia and risk of all-cause and diagnosis-specific sickness absence: A nationwide Swedish prospective cohort study. Aims: Insomnia is a large health problem. In some prior studies, positive associations between insomnia symptoms and sickness absence have been observed. There is, however, no previous nationwide cohort study of clinically diagnosed insomnia and risk of incident sickness absence. Methods: Prospective nationwide cohort study based on Swedish population-based registers including all 4,956,358 individuals registered as living in Sweden on 31 December 2004/2005, aged 17-64 years, not on disability pension, old-age pension or on-going sickness absence. Those having insomnia inpatient or outpatient care, defined as having at least one admission/specialist visit with a main or secondary diagnosis of disorders of initiating and maintaining sleep [insomnias] (ICD-10: G47.0) during 2000/2001-2005, were compared to those with no such care. All-cause and diagnosis-specific incident sickness absence were followed during 2006-2010. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression. Results: In models adjusted for prior sickness absence, socio-demographic factors and inpatient and specialized outpatient care, associations between insomnia and increased risks of all-cause sickness absence (IRR 1.18, 95% CI 1.04-1.35) and sickness absence due to mental diagnoses (IRR 1.75, 95% CI 1.36-2.25) were observed. After further adjustment for insomnia medications these associations disappeared. No associations between insomnia and risk of sickness absence due to cancer, circulatory or musculoskeletal diagnoses, or injuries, were observed. Conclusions: In this nationwide cohort study, we observed increased risks of all-cause sickness absence and sickness absence due to mental diagnoses after adjustment for several potential confounders that disappeared after further adjustment for insomnia medications. 23495999 From synaptic spines to nuclear signaling: nuclear and synaptic actions of the amyloid precursor protein. Despite intensive studies of the secretase-mediated processing of the amyloid precursor protein (APP) to form the amyloid β-peptide (Aβ), in relation to Alzheimer's disease (AD), no new therapeutic agents have reached the clinics based on reducing Aβ levels through the use of secretase inhibitors or immunotherapy. Furthermore, the normal neuronal functions of APP and its various metabolites still remain under-investigated and unclear. Here, we highlight emerging areas of APP function that may provide new insights into synaptic development, cognition, and gene regulation. By modulating expression levels of endogenous APP in primary cortical neurons, the frequency and amplitude of calcium oscillations is modified, implying a key role for APP in maintaining neuronal calcium homeostasis essential for synaptic transmission. Disruption of this homeostatic mechanism predisposes to aging and AD. Synaptic spine loss is a feature of neurogeneration resulting in learning and memory deficits, and emerging evidence indicates a role for APP, probably mediated via one or more of its metabolites, in spine structure and functions. The intracellular domain of APP (AICD) has also emerged as a key epigenetic regulator of gene expression controlling a diverse range of genes, including APP itself, the amyloid-degrading enzyme neprilysin, and aquaporin-1. A fuller understanding of the physiological and pathological actions of APP and its metabolic network could provide new opportunities for therapeutic intervention in AD. 23792894 Invited commentary: are dietary intakes and other exposures in childhood and adolescence important for adult cancers? In this issue of the Journal, Nimptsch et al. (Am J Epidemiol. 2013;178(2):172-183) report significant associations between female adolescents' poultry consumption in high school and subsequent reduced risk of colorectal adenomas in adulthood. Consumption of red meat or fish was not related to risk, but replacement with poultry reduced the risk of later adenomas. Most epidemiologic studies of adult diseases lack exposure data from the distant past. By focusing on a cancer precursor lesion and using a variety of methods to assess data quality, the investigators address concerns about the quality of distant recall. These findings add to the growing evidence that links childhood and adolescent lifestyle and environmental exposures with subsequent risk of cancers arising in adulthood. Highlights of the literature on this topic and methodological challenges are summarized. Future studies would benefit from incorporating measures of lifestyle, diet, environmental exposures, and other risk factors from early in life and from validation and other data quality checks of such measurements. Sources of historical data on children's and adolescents' exposures should be sought and evaluated in conjunction with subsequent exposures in relationship to adult-onset cancers. 23891444 Facile synthesis of gold core-polymer shell responsive particles. The free adsorption of an end-functionalised weak polybase, poly dimethylaminoethyl methacrylate (pDMAEMA), on the surface of colloidal gold nanoparticles (AuNPs) as a route to produce a responsive core-shell nanoparticle is explored here. Optimal conditions for the physisorption of the polymeric chains onto the colloidal nanoparticles are explored. A dense coverage is facilitated by rapidly mixing the well solvated pH responsive homopolymer, at low pH, into a relatively poor solvent environment, at higher pH, containing a stable dispersion of charge-stabilised gold nanoparticles. The rapid pH change causes the polymer chains to concurrently collapse and adsorb onto the gold nanoparticles. In order to achieve sterically stable, monodisperse and responsive core shell nanoparticles, a crucial factor is the pH difference of the systems prior to their mixing. Once adsorbed, end-functional thiol groups on the adsorbed polymer chains can form more permanent covalent attachments with the core particles. Dynamic light scattering coupled with mobility data of pH titration experiments show that the core-shell particles exhibit a responsive character consistent with the observed potentiometric titration data of the polymer. The same particles demonstrate reversible aggregation when cycled between pH extremes. This is confirmed by shifts in the SPR peak of the corresponding UV-Vis absorption profile. The ease and flexibility of this strategy for core-shell particle production, coupled with the stability and responsiveness of the product, make this a promising colloidal coating mechanism. 23891507 Platinum rechallenge in patients with advanced NSCLC: A pooled analysis. The sole agents pemetrexed (PEM), docetaxel and anti-EGFR agents are approved second-line therapies for non-small cell lung cancer (NSCLC) after failure with cisplatin-based doublets. The potential usefulness of platinum-based doublets as rechallenge for second-line chemotherapy has not yet been established. Studies that enrolled NSCLC platinum pre-treated patients were identified using electronic databases (MEDLINE and EMBASE). Pemetrexed and taxanes (TAXs)-based platinum combinations were considered. A systematic review was conducted using Comprehensive Meta-Analysis (version 2.2.064) software to calculate the event rate of response and 95% confidence interval. Median weighted progression-free survival (PFS) and overall survival (OS) time for PEM and TAXs-based doublets were compared by two-sided Student's t test. We tested for significant heterogeneity by Cochran's chi-square test and I(2) index. Eleven studies published between 1999 and 2012 were included in this analysis with a total of 607 patients enrolled; 468 were treated with PEM-doublets and 139 with TAXs-doublets. The overall response rate was 27.5% with a higher response rate of 37.8% (range, 29.7-46.7%) for TAXs-based treatment vs. 22% (range, 13.4-34.1%) for PEM-based combinations; (p<0.0001). Median PFS and OS were 3.9 and 8.7 months with weighted PFS of 3.9 vs. 5.3 months (p<0.0001) and similar OS for PEM vs. TAXs-based doublets. With the limitations of small and not randomised trials included, this pooled analysis shows that NSCLC patients who relapsed after a first-line platinum-based chemotherapy obtain a tumour response of 27% from a platinum rechallenge containing PEM or TAXs. Response rate and median PFS appear better with TAXs-than with PEM-doublets. 23863839 Analysis of epigenetic stability and conversions in Saccharomyces cerevisiae reveals a novel role of CAF-I in position-effect variegation. Position-effect variegation (PEV) phenotypes are characterized by the robust multigenerational repression of a gene located at a certain locus (often called gene silencing) and occasional conversions to fully active state. Consequently, the active state then persists with occasional conversions to the repressed state. These effects are mediated by the establishment and maintenance of heterochromatin or euchromatin structures, respectively. In this study, we have addressed an important but often neglected aspect of PEV: the frequency of conversions at such loci. We have developed a model and have projected various PEV scenarios based on various rates of conversions. We have also enhanced two existing assays for gene silencing in Saccharomyces cerevisiae to measure the rate of switches from repressed to active state and vice versa. We tested the validity of our methodology in Δsir1 cells and in several mutants with defects in gene silencing. The assays have revealed that the histone chaperone Chromatin Assembly Factor I is involved in the control of epigenetic conversions. Together, our model and assays provide a comprehensive methodology for further investigation of epigenetic stability and position effects. 23909373 Anxiety and Depression in Caregivers of Terminally Ill Cancer Patients: Impact on Their Perspective of the Patients' Symptom Burden. Abstract Background and Objective: Given the important role caregivers play in palliative care planning and decision making, anxiety and depression in caregivers of terminally ill cancer patients and their impact on the caregivers' evaluation of the patients' physical and psychological symptom burden were analyzed. Design and subjects: Thirty-three patients and their caregivers were recruited through the University Medical Center palliative care inpatient ward <24h after admission. Measurements: Patients completed the Memorial Symptom Assessment Scale (MSAS). Caregivers were instructed to evaluate the symptom burden of the patient. Anxiety and depression were measured in caregivers using the PHQ-9 and the GAD-7. Results: Fifty-five percent of male caregivers and 36% of female caregivers showed moderate or severe anxiety; 36% of male caregivers compared to 14% of female caregivers had moderate or severe depression. Caregivers' anxiety was associated with a discrepancy in the patients' symptom evaluation for shortness of breath (p<0.05); nausea (p<0.05); and frequency, intensity, and distress due to anxiety (p<0.01). Depression was associated with a discrepancy in the patients' evaluation of distress due to constipation (p<0.05), as well as intensity and distress due to anxiety (p<0.05). Both the caregivers' anxiety and depression were not significantly associated with an underestimation of symptoms. There was a trend towards a higher risk of overestimation in caregivers with higher levels of anxiety (r=0.32) (p=0.07) and depression (r=0.33) (p=0.06). Conclusion: Integrative palliative care should offer psychooncological care for the caregivers on a routine basis to avoid misleading perspectives possibly influencing end-of-life treatment decisions. 23859629 Improving the binding characteristics of tripodal compounds on single layer graphene. Graphene is an atomically thin, transparent, and conductive electrode material of interest for sensors and energy conversion and storage devices, among others. Fully realizing its potential will require robust and general methods to anchor active functionality onto its pristine basal plane. Such strategies should not utilize covalent bond formation, which disrupts the graphene's π-electron system, from which most of its desirable properties arise. We recently introduced a tripodal binding motif, which forms robust monolayers on graphene capable of immobilizing active proteins and preventing their denaturation. Here we describe structure-property relationships for a series of tripod binding groups with "feet" of different sizes. Each derivative adsorbs strongly (ΔGads ≈ -39 kJ mol(-1)) to graphene's basal plane, yet the resulting monolayers exhibit kinetic stabilities that vary over 2 orders of magnitude and molecular densities that vary by a factor of 2. This study identifies phenanthrene as a superior anchor relative to pyrene on the basis of its increased monolayer density and similar kinetic stability. We also demonstrate that varying the length of the methylene linkers between the feet and tripodal core does not affect binding substantially. These results represent the first demonstration of structure-property relationships in the assembly of molecular adsorbates on graphene and provide a paradigm for designing effective graphene binding motifs. 23920487 Environmentalist Thinking and the Question of Disease Causation in Late Spanish Philippines. The scientific understanding of disease causation was crucial to the ways in which the Spanish colonial state addressed epidemic diseases which periodically struck nineteenth-century Philippines. Scholars have often described Spanish colonial responses in terms of ineptitude and failure, and have often glossed over the multiple and competing scientific theories that preoccupied Spanish and Filipino physicians. This article examines the work and ideas of nineteenth-century Spanish colonial and patriotic Filipino physicians regarding disease causation in the tropical environment of the Philippines. It will focus on two key developments-Spanish environmentalist thinking and the emerging fields of microscopy and bacteriology. Much like the British and French colonialists, Spaniards viewed tropical climates as insalubrious and conducive to disease, perceiving themselves as constitutionally at risk in hot places, ill-suited, exposed, and vulnerable to so-called native diseases. By the 1880s, however, young Filipino researchers, some of whom had trained in Spain and France, were undertaking new research on polluted water, malaria, and cells. Influenced by the revolutionary new discoveries being made in bacteriology, these researchers questioned prevailing environmentalist explanations and focused, for the first time, on the nature of pathogens and microbial pathogenesis in disease development and transmission. But germ theory remained an idea among many. This article argues that although late nineteenth-century studies in microscopy by Filipinos slowly began to challenge Spanish colonial ideas, different streams of thinking overlapped and no single scientific explanation came to predominate. 23963354 Differential lung NK cell responses in avian influenza virus infected chickens correlate with pathogenicity. Infection of chickens with low pathogenicity avian influenza (LPAI) virus results in mild clinical signs while infection with highly pathogenic avian influenza (HPAI) viruses causes death of the birds within 36-48 hours. Since natural killer (NK) cells have been shown to play an important role in influenza-specific immunity, we hypothesise that NK cells are involved in this difference in pathogenicity. To investigate this, the role of chicken NK-cells in LPAI virus infection was studied. Next activation of lung NK cells upon HPAI virus infection was analysed. Infection with a H9N2 LPAI virus resulted in the presence of viral RNA in the lungs which coincided with enhanced activation of lung NK cells. The presence of H5N1 viruses, measured by detection of viral RNA, did not induce activation of lung NK cells. This suggests that decreased NK-cell activation may be one of the mechanisms associated with the enhanced pathogenicity of H5N1 viruses. 23270514 Theoretical characterization of X-ray absorption, emission, and photoelectron spectra of nitrogen doped along graphene edges. K-edge X-ray absorption (XAS), emission (XES), and photoelectron (XPS) spectra of nitrogen doped along graphene edges are systematically investigated by using first-principles methods. In this study we considered pyridinium-like, pyridine-like, cyanide-like, and amine-like nitrogens at armchair and zigzag edges and pyrrole-like nitrogen at armchair edge as well as graphite-like nitrogen at graphene interior site. Our results indicate that nitrogen configuration and its location (armchair or zigzag edge) in nitrogen-doped graphene can be identified via the spectral analysis. Furthermore, some controversial spectral features observed in experiment for N-doped graphene-like materials are unambiguously assigned. The present analysis gives an explanation to the reason why the peak assignment is usually made differently between XPS and XAS. 23839779 The Golgi puppet master: COG complex at center stage of membrane trafficking interactions. The central organelle within the secretory pathway is the Golgi apparatus, a collection of flattened membranes organized into stacks. The cisternal maturation model of intra-Golgi transport depicts Golgi cisternae that mature from cis to medial to trans by receiving resident proteins, such as glycosylation enzymes via retrograde vesicle-mediated recycling. The conserved oligomeric Golgi (COG) complex, a multi-subunit tethering complex of the complexes associated with tethering containing helical rods family, organizes vesicle targeting during intra-Golgi retrograde transport. The COG complex, both physically and functionally, interacts with all classes of molecules maintaining intra-Golgi trafficking, namely SNAREs, SNARE-interacting proteins, Rabs, coiled-coil tethers, vesicular coats, and molecular motors. In this report, we will review the current state of the COG interactome and analyze possible scenarios for the molecular mechanism of the COG orchestrated vesicle targeting, which plays a central role in maintaining glycosylation homeostasis in all eukaryotic cells. 23568405 Predictors of risk-based medical follow-up: a report from the childhood cancer survivor study. The purpose of this study is to conduct an intervention study designed to assess the effectiveness of using a newsletter to increase medical follow-up in pediatric cancer survivors at risk of selected treatment complications. Survivors participating in the Childhood Cancer Survivor Study who were at least 25 years of age and at risk of cardiovascular disease, breast cancer, or osteoporosis related to previous cancer treatment were randomly assigned to receive a newsletter featuring brief health risk information or a newsletter including an insert providing more comprehensive health risk information. A follow-up survey distributed 24 months after the newsletter intervention assessed predictors of medical follow-up. Overall, there were no differences found among the groups in terms of access to a treatment summary, medical follow-up, discussion of childhood cancer health risks, and medical screening for the targeted health behaviors. One exception, indicating borderline significance was that women at risk for osteoporosis who received the newsletter insert were more likely to have discussed their risk with a doctor than those who only received the brief information (10.1 % vs. 4.0 % p = 0.05). Discussion of breast cancer (OR = 2.15; 95 % CI = 1.74-2.66), heart disease (OR = 5.54; 95 % CI = 4.67-6.57) and osteoporosis (OR = 10.6; 95 % CI = 8.34-13.47) risk with physician significantly predicted report of undergoing screening for targeted behavior in previous 2 years as did physician access to treatment summary. More detailed content in a newsletter had minimal effect on recommended screening. However, survivor's discussion of cancer-related risks with one's doctor significantly influenced participation in health screening. These results highlight the integral role of communication in health behavior. This study is designed to assess communication strategies that increase medical follow-up in pediatric cancer survivors at risk of selected treatment complications. The results are of great importance not only to the pediatric oncology community but also the broad range of adult oncology medical specialties who are directly involved in the long-term medical care of this ever increasing population of cancer survivors. 23880378 The serotonin transporter linked polymorphic region and brain-derived neurotrophic factor valine to methionine at position 66 polymorphisms and maternal history of depression: Associations with cognitive vulnerability to depression in childhood. Preliminary work indicates that cognitive vulnerability to depression may be associated with variants of the serotonin transporter promoter polymorphism (5-HTTLPR) and the valine to methionine at position 66 (val66met) polymorphism of the brain-derived neurotrophic factor (BDNF) gene; however, existing reports come from small samples. The present study sought to replicate and extend this research in a sample of 375 community-dwelling children and their parents. Following a negative mood induction, children completed a self-referent encoding task tapping memory for positive and negative self-descriptive traits. Consistent with previous work, we found that children with at least one short variant of the 5-HTTLPR had enhanced memory for negative self-descriptive traits. The BDNF val66met polymorphism had no main effect but was moderated by maternal depression, such that children with a BDNF methionine allele had a heightened memory for negative self-descriptive traits when mothers had experienced depression during children's lifetimes; in contrast, children with a methionine allele had low recall of negative traits when mothers had no depression history. The findings provide further support for the notion that the 5-HTTLPR is associated with cognitive markers of depression vulnerability and that the BDNF methionine allele moderates children's sensitivity to contextual factors. 23882693 Perimetric evaluation of saccadic latency, saccadic accuracy, and visual threshold for peripheral visual stimuli in young compared with older adults. Using a novel automated perimetry technique, we tested the hypothesis that older adults will have increased latency and decreased accuracy of saccades, as well as higher visual thresholds, to peripheral visual stimuli when compared with younger adults. We tested 20 healthy subjects aged 18 to 30 years ("young") and 21 healthy subjects at least 60 years old ("older") for detection of briefly flashed peripheral stimuli of differing sizes in eight locations along the horizontal meridian (±4°, ±12°, ±20°, and ±28°). With the left eye occluded, subjects were instructed to look quickly toward any seen stimuli. Right eye movements were recorded with an EyeLink 1000 infrared camera system. Limiting our analysis to the four stimulus positions in the nasal hemifield (-4°, -12°, -20°, and -28°), we evaluated for group-level differences in saccadic latency, accuracy, and visual threshold at each stimulus location. Saccadic latency increased as stimulus size decreased in both groups. Older subjects had significantly increased saccadic latencies (at all locations; P < 0.05), decreased accuracies (at all locations; P < 0.05), and higher visual thresholds (at the -12°, -20°, and -28° locations; P < 0.05). Additionally, there were significant relationships between visual threshold and latency, visual threshold and accuracy, and latency and accuracy (P < 0.0001). Older adults have increased latency and decreased accuracy of saccades, as well as higher visual thresholds, to peripheral visual stimuli when compared with younger adults. Saccadic latency and accuracy are related to visual threshold, suggesting that saccadic latency and accuracy could be useful as perimetric outcome measures. 23864149 Stochastic Virtual Population of Subjects with Type 1 Diabetes for the Assessment of Closed Loop Glucose Controllers. Closed-loop glucose control is an emerging treatment approach to manage type 1 diabetes. Closed-loop systems consist of a continuous glucose monitor, an insulin infusion pump and a dosing algorithm that directs insulin delivery based on sensor levels. Testing of dosing algorithms in computer simulations may replace animal testing, accelerates development, and saves resources. We propose here a novel approach to generate a virtual population, to be used in metabolic simulators, from routine experimental data through process we term "stochastic e-cloning". We build on a non-linear physiologically-motivated time-varying model of glucose regulation. We adopt the Bayesian approach to estimate model parameters and to obtain the joint posterior probability distribution of time-invariant and time-varying parameters with the use of the Markov chain Monte Carlo methodology. The estimation process combines prior knowledge and experimental data to generate a sample from the posterior distribution which can be subsequently used to conduct in silico experiments reflecting population and individual variability, and associated uncertainty as closely as possible. The approach is exemplified using data collected in 12 young subjects with type 1 diabetes. We demonstrate unbiased fit to the data, physiological plausibility of parameter estimates, and results of in silico testing using a stochastic virtual subject. 23903258 Increase in Lipophilicity of Enalaprilat by Complexation with Copper(II) or Zinc(II) Ions. Enalaprilat (H2L), which is the active metabolite of the pro-drug enalapril, is an angiotensin-converting enzyme inhibitor. Some side effects such as neurodegeneration and taste disorder can be related to copper or zinc deficiency, which would be caused by the metal complex formation of dianionic elalaprilat (L(2-)). For a better understanding of this phenomenon, we investigated the solution species of enalaprilat in the presence of copper(II) or zinc(II) ions by pH titration analysis with I = 0.10 M (NaCl) at 25℃. The 1:1 complex formation constants (KML = [ML]/[M(2+)][L(2-)] M(-1)) of 10(7.4) for CuL and 10(4.4) for ZnL complexes were evaluated, indicating the presence of those complexes at a physiological pH. Furthermore, partition experiments with a two-phase system of 1-butanol/water at 25℃ disclosed that copper(II) and zinc(II) complexes of enalaprilat were partially extracted into the organic layer. In the absence of those metal ions, enalaprilat was not soluble in the 1-butanol phase. The increase in lipophilicity of enalaprilat by metal complexation suggests that the long-term administration of enalapril could be a possible risk factor for the disrupted distribution of those metal ions in biological systems. 23590164 The spectrum of histopathologic patterns secondary to the topical application of EMLA(®) on vulvar epithelium: clinicopathological correlation in three cases. EMLA(®) (eutectic mixture of local anesthetics, 2.5% each of lidocaine and prilocaine in an oil and water emulsion) is used as a topical anesthetic. We report three cases of EMLA(®) -induced histopathologic changes on the vulvar epithelium. While there are some similar histopathologic features to those reported in extragenital skin, we describe additional findings on vulvar epithelium, which, to our knowledge, have not been reported previously. The patients presented with clinical signs suggestive of lichen sclerosus or erosive lichen planus (LP), but were all confirmed histopathologically as LP. The biopsy was taken after 15 min of EMLA(®) application and intradermal injection of 1% lidocaine. Blistering prior to intradermal lidocaine and the biopsy procedure was observed in two patients. The histopathologic changes observed in the epithelium included pallor of the upper epidermis, mild spongiosis, intraepidermal subcorneal and suprabasal acantholysis, congestion of the papillary dermal capillaries and extravasated erythrocytes. Basophilic granules were present, but rare, while the necrosis with multifocal clefting was more marked than in extragenital skin. It is important to be aware of these changes occurring on genital mucosa; these may occur in the absence of clinical signs and may obscure the primary underlying pathology, thus representing a diagnostic pitfall. 23818627 Improved El Nino forecasting by cooperativity detection. Although anomalous episodic warming of the eastern equatorial Pacific, dubbed El Niño by Peruvian fishermen, has major (and occasionally devastating) impacts around the globe, robust forecasting is still limited to about 6 mo ahead. A significant extension of the prewarning time would be instrumental for avoiding some of the worst damages such as harvest failures in developing countries. Here we introduce a unique avenue toward El Niño prediction based on network methods, inspecting emerging teleconnections. Our approach starts from the evidence that a large-scale cooperative mode-linking the El Niño basin (equatorial Pacific corridor) and the rest of the ocean-builds up in the calendar year before the warming event. On this basis, we can develop an efficient 12-mo forecasting scheme, i.e., achieve some doubling of the early-warning period. Our method is based on high-quality observational data available since 1950 and yields hit rates above 0.5, whereas false-alarm rates are below 0.1. 23857153 Ocular MR Imaging: Evaluation of Different Coil Setups in a Phantom Study. Purpose: Small loop surface coils are generally recommended for ocular magnetic resonance (MR) imaging, but the optimal coil setup has not been systematically investigated. In this phantom study, we investigated which coil setup of those coils available for our MR imaging system provides the highest signal-to-noise ratio (SNR) in ocular MR imaging at 1.5 tesla. Materials and Methods: Using a phantom to simulate the eyeball and the orbital fat, we employed loop surface coils of 4- and 6-cm diameter and a multi-channel head coil to obtain images using a T1-weighted spin-echo sequence and then measured the SNR for each coil and coil combination. Results: Use of the 6-cm loop coil alone yielded the highest mean SNR (27.5). Even in superficial regions (mesial and temporal), the SNR was higher using the 6-cm loop coil (33.6 and 45.5) than the 4-cm loop coil (28.0 and 33.8). Additional use of the head coil reduced the mean SNR to 10.4. Conclusion: This quantitative analysis suggests that use of a 6-cm loop surface coil offers the best results in ocular MR imaging. Combinations of loop coils or additional use of a head coil cannot be recommended because higher noise degrades image quality. 23560542 Modeling the Conformational Preference of the Carbon-Bonded Covalent Adduct Formed upon Exposure of 2'-Deoxyguanosine to Ochratoxin A. The conformational flexibility of the C8-linked guanine adduct formed from attachment of ochratoxin A (OTA) was analyzed using a systematic computational approach and models ranging from the nucleobase to the adducted DNA helix. A focus was placed on the influence of the C8-modification of 2'-deoxyguanosine (dG) on the preferred relative arrangement of the nucleobase and the C8-substituent and, more importantly, the anti/syn conformational preference with respect to the glycosidic bond. Although OTA is twisted with respect to the base in the nucleobase model, addition of the deoxyribose sugar induces a further twist and restricts rotation about the C-C linkage due to close contacts between OTA and the sugar. The nucleoside model preferentially adpots a syn orientation (by 10-20 kJ mol(-1) depending on the OTA conformation) due to the presence of an O5'-H···N3 interaction. However, when this hydrogen bond is eliminated, which better mimics the DNA environment, a small (<5 kJ mol(-1)) anti/syn energy difference is predicted. Inclusion of the 5'-monophosphate group leads to an up to 20 kJ mol(-1) preference for the syn (nucleotide) conformation due to stabilizing base-phosphate interactions involving the amino group of guanine. Nevertheless, MD simulations and free energy analysis predict that both syn- and anti-conformations of OTB-dG are equally stable in helices when paired opposite cytosine. These results indicate that the adduct will likely adopt a syn conformation in an isolated nucleoside and nucleotide, while a mixture of syn and anti conformations will be observed in DNA duplexes. Since the syn conformation could stabilize base mismatches upon DNA replication or Z-DNA structures with varied biological outcomes, future computational and experimental work should elucidate the consequences of the conformational preference of this potentially harmful DNA lesion. 23551398 Structure-function relationship and biogenesis regulation of the human telomerase holoenzyme. Telomeres are nucleoprotein structures found at the ends of linear chromosomes. Telomeric DNA shortens with each cell division, effectively restricting the proliferative capacity of human cells. Telomerase, a specialized reverse transcriptase, is responsible for de novo synthesis of telomeric DNA, and is the major physiological means by which mammalian cells extend telomere length. Telomerase activity in human soma is developmentally regulated according to cell type. Failure to tightly regulate telomerase has dire consequences: dysregulated telomerase activity is observed in more than 90% of human cancers, while haplo-insufficient expression of telomerase components underlies several inherited premature aging syndromes. Over the past decade, we have significantly improved our understanding of the structure-activity relationships between the two core telomerase components: telomerase reverse transcriptase and telomerase RNA. Genetic screening for telomerase deficiency syndromes has identified new partners in the biogenesis of telomerase and its catalytic functions. These data revealed a level of regulation complexity that is unexpected when compared with the other cellular polymerases. In this review, we summarize current knowledge on the structure-activity relationships of telomerase reverse transcriptase and telomerase RNA, and discuss how the biogenesis of telomerase provides additional regulation of its actions. 23621420 Aggregation-Mediated Macromolecular Uptake by a Molecular Transporter. Endocytosis is a key process in cellular delivery of macromolecules by molecular transporters, although the mechanism of internalization remains unclear. Here, we probe the cellular uptake of streptavidin using biotinylated guanidinoneomycin (biotinGNeo), a low molecular weight guanidinium-rich molecular transporter. Two distinct modes were explored: (i) incubation of cells with a preformed tetravalent streptavidin-(biotinGNeo)4 conjugate and (ii) preincubation of cells with the biotinGNeo before exposure to streptavidin. A significant enhancement in uptake was observed after preincubation with biotinGNeo. FRET studies showed that the enhanced uptake was accompanied by extensive aggregation of streptavidin on the cell surface. Because guanidinylated neomycin was previously found to exclusively bind to heparan sulfate, our observations suggest that heparan sulfate proteoglycan aggregation is a pivotal step for endocytic entry into cells by guanidinoglycosides. These observations put forward a practical and general pathway for the cellular delivery of diverse macromolecules. 23759102 A chemical genetics approach reveals a role of brassinolide and cellulose synthase in hypocotyl elongation of etiolated Arabidopsis seedlings. The development of juvenile seedlings after germination is critical for the initial establishment of reproductive plants. Ethylene plays a pivotal role in the growth of seedlings under light or dark during early development. Previously, we identified small molecules sharing a quinazolinone backbone that suppressed the constitutive triple response phenotype in dark-grown eto1-4 seedlings. We designated these small molecules as ACSinhibitor quinazolinones (acsinones), which were uncompetitive inhibitors of 1-aminocyclopropane-1-carboxylic acid synthase. To explore the additional roles of acsinones in plants, we screened and identified 19 Arabidopsis mutants with reduced sensitivity to acsinone7303, which were collectively named revert to eto1 (ret) because of their recovery of the eto1 phenotype. A map-based cloning approach revealed that CELLULOSE SYNTHASE6 (CESA6) and DE-ETIOLATED2 (DET2) were mutated in ret8 (cesa6(ret8);eto1-4) and ret41 (det2(ret41);eto1-5), respectively. Etiolated seedlings of both ret8 and ret41 exhibit short hypocotyls and roots. Ethylene levels were similar in etiolated cesa6(ret8) and det2-1 and in eto1 mutants treated with acsinone7303. Chemical inhibitors of ethylene biosynthesis and perception did not significantly suppress the etiolated phenotype of cesa6(ret8) and det2(ret41). However, together with eto1, cesa6(ret8) and det2(ret41) exhibited an enhanced phenotype in the hypocotyls and apical hooks of etiolated seedlings. These results confirm that, in addition to ethylene, cellulose synthesis and brassinolides can independently contribute to modulate hypocotyl development in young seedlings. 23147375 Characteristic molecular signature for the early detection and prediction of polycyclic aromatic hydrocarbons in rat liver. Predictions of toxicity are central for the assessment of chemical toxicity, and the effects of environmental toxic compounds are still a major issue for predicting potential human health risks. Among the various environmental toxicants, polycyclic aromatic hydrocarbons (PAHs) are an important class of environmental pollutant, and many PAHs are known or suspected carcinogens. In the present study, to investigate whether characteristic expression profiles of PAHs exist in rat liver and whether a characteristic molecular signature can discriminate and predict among different PAHs at an early exposure time, we analyzed the genome-wide expression profiles of rat livers exposed to PAHs [benzo[a]anthracene (BA), benzo[a]pyrene (BP), phenanthrene (PA) and naphthalene (NT)]. At early time-point PAH exposure, large-scale gene expression analysis resulted in characteristic molecular signatures for each PAH, and supervised analysis identified 1183 outlier genes as a distinct molecular signature discerning PAHs from the normal control group. We identified 158 outlier genes as early predictive and surrogate markers for predicting each tested PAH by combination of two different multi-classification algorithms with 100% accuracy through a leave-one out cross-validation method. In conclusion, the characteristic gene expression signatures from a rat model system could be used as predictable and discernible gene-based biomarkers for the detection and prediction of PAHs, and these molecular markers may provide insights into the underlying mechanisms for genotoxicity of exposure to PAHs from environmental aspect. 23880363 Self-adjuvanting influenza candidate vaccine presenting epitopes for cell-mediated immunity on a proteinaceous multivalent nanoplatform. We exploit the features of a virus-like particle, adenoviral dodecahedron (Ad Dd), for engineering a multivalent vaccination platform carrying influenza epitopes for cell-mediated immunity. The delivery platform, Ad Dd, is a proteinaceous, polyvalent, and biodegradable nanoparticle endowed with remarkable endocytosis activity that can be engineered to carry 60 copies of a peptide. Influenza M1 is the most abundant influenza internal protein with the conserved primary structure. Two different M1 immunodominant epitopes were separately inserted in Dd external positions without destroying the particles' dodecahedric structure. Both kinds of DdFluM1 obtained through expression in baculovirus system were properly presented by human dendritic cells triggering efficient activation of antigen-specific T cells responses. Importantly, the candidate vaccine was able to induce cellular immunity in vivo in chickens. These results warrant further investigation of Dd as a platform for candidate vaccine, able to stimulate cellular immune responses. 23970116 Effects of low-intensity pulsed ultrasound on injured skeletal muscle. Low-intensity pulsed ultrasound (LIPUS) has been shown to stimulate tissue metabolism and accelerate muscle healing. However, the optimal parameters in the use of LIPUS are still not clear. The aim of this study was to analyze the effects of LIPUS on muscle healing in rats subjected to a cryolesion. Twenty rats were divided into the following groups: an injured control group (CG) and an injured treated group (TG). Both groups were divided into 2 sub-groups (n=5 each) that were sacrificed 7 and 13 days post-surgery. Treatments were started 24 hours after the surgical procedure and consisted of 3 or 6 sessions. After euthanasia, the muscles were submitted to standard histological procedures. Qualitative analyses were based on morphological assessments of the muscle. The histopathological analysis on day 7 revealed that the muscles in the CG and the TG presented an intense inflammatory infiltrate, a large necrotic area and a disorganized tissue structure. After 13 days, both the CG and the TG had granulation tissue and newly formed fibers. The TG presented a more organized tissue structure. The quantitative analysis of collagen indicated similar findings among the groups, although the qualitative analysis revealed a better organization of collagen fibers in the TG at 13 days. The immunohistochemical analysis indicated that, at both time points, the expression of cyclooxygenase-2 was upregulated in the TG compared to the CG. LIPUS used as a treatment for muscle injury induced a more organized tissue structure at the site of the injury and stimulated the expression of COX-2 and the formation of new muscle fibers. 23895643 Ictal EEG-fMRI in localization of epileptogenic area in patients with refractory neocortical focal epilepsy. To evaluate the usefulness of ictal electroencephalography (EEG)-combined functional magnetic resonance imaging ( MRI) (EEG-fMRI) in localizing epileptogenic zone in refractory neocortical focal epilepsy. From the EEG-fMRI database of our institution including 62 adult patients, 14 (age 18-46 years) experienced some ictal event during the test. Data were segmented into 10-s blocks, and the results were analyzed by contrasting each block to the contiguous 10-s block from the onset of seizure onward, in all cases. In seizures lasting >10 s (five cases), a supplementary analysis was performed, contrasting each block to a baseline condition, in the framework of the general linear model (GLM) of analysis. Regions of activations were compared to results from the different techniques performed during presurgical evaluation, such as SISCOM, positron emission tomography (PET), and invasive subdural EEG monitoring. Regarding the structural MRI findings, nine cases presented some lesion, with blood oxygen level- dependent (BOLD) signal activation placed in the same location in eight of them (89%). SISCOM studies were performed in 11 patients; 5 were concordant with the increase in BOLD signal in a sublobar level, whereas in 3 cases the concordance was in a lobar level. Eleven patients underwent PET studies, being also concordant in a sublobar level in four of them and in a lobar level in four additional cases. Finally, invasive EEG evaluation was performed in three patients and all of them had the seizure-onset zone in the initial area of BOLD activation. This study adds relevant information to support the integration of EEG-fMRI in the multidisciplinary presurgical workup in patients with refractory epilepsy. 23834949 Prevalence and molecular basis of glucose-6-phosphate dehydrogenase deficiency in Afghan populations: implications for treatment policy in the region. Glucose-6-phosphate dehydrogenase deficiency (G6PD), an x-linked inherited enzymopathy, is a barrier to malaria control because primaquine cannot be readily applied for radical cure in individuals with the condition. In endemic areas, including in Afghanistan, the G6PD status of vivax patients is not routinely determined so the drug is rarely, if ever, prescribed even though it is included as a recommended treatment in local, regional and global guidelines. This study assessed the prevalence and genotype of G6PD deficiency in Afghan populations and examined the need for routine G6PD testing as a malaria treatment and control tool. A cross-sectional household survey was conducted using random sampling in five Afghan cities to determine the prevalence of G6PD deficiency in Afghan ethnic groups. Filter-paper blood spots were analysed for phenotypic G6PD deficiency using a fluorescent spot test. Molecular analysis was conducted to identify the genetic basis of the disorder. Overall, 45/1,436 (3.1%) people were G6PD deficient, 36/728 (5.0%) amongst males and 9/708 (1.3%) amongst females. Amongst males the prevalence was highest in the Pashtun ethnic group (10%, 26/260) while in Tajik males it was 8/250 (3.2%); in Hazara males it was 1/77 (1.3%) and in Uzbek males is was 0/125. Genetic testing in those with deficiency showed that all were of the Mediterranean type (Med-) characterized by a C-T change at codon 563 of the G6PD gene. Prevalence of G6PD deficiency in Afghanistan varies considerably by ethnic group and is predominantly of the Mediterranean type. G6PD deficient individuals are susceptible to potentially severe and life-threatening haemolysis after standard primaquine treatment. If the aim of increasing access to radical treatment of vivax is to be successful reliable G6PD testing needs to be made routinely available within the health system. 23850766 Behaviour of pharmaceuticals and endocrine disrupting chemicals in simplified sewage treatment systems. This work assessed the behaviour of nine pharmaceuticals and/or endocrine disrupting chemicals (EDCs) in demo-scale upflow anaerobic sludge blanket reactors (UASB reactors) coupled to distinct simplified post-treatment units (submerged bed, polishing ponds, and trickling filters) fed on raw sewage taken from a municipality in Brazil. The dissolved concentration of the studied micropollutants in the raw and treated sewage was obtained using solid phase extraction (SPE) followed by analysis in a liquid chromatography system coupled to a hybrid high resolution mass spectrometer consisting of an ion-trap and time of flight (LC-MS-IT-TOF). The UASB reactors demonstrated that they were not appropriate for efficiently removing the assessed compounds from the sewage. Furthermore, this study demonstrated that the hydraulic retention time (HRT) was an important parameter for the removal of the hydrophilic and less biodegradable compounds, such as trimethoprim and sulfamethoxazole. The post-treatment units substantially increased the removal of most target micropollutants present in the anaerobic effluents, with a greater removal of micropollutants in simplified systems that require a large construction area, such as the submerged bed and polishing ponds, probably because of the higher HRT employed. Alternatively, compact post-treatment systems, such as trickling filters, tended to be less effective at removing most of the micropollutants studied, and the type of packing proved to be crucial for determining the fate of such compounds using trickling filters. 23860332 Activation of Gq Proteins Coupled with 5-HT2 Receptors in Rat Cerebral Cortical Membranes Assessed by Antibody-Capture Scintillation Proximity Assay/[S]GTPγS Binding. Background/Aims: Functional activation of Gq coupled with 5-HT2 receptors was investigated in rat cerebral cortical membranes. Methods: Antibody-capture scintillation proximity assay (SPA)/[(35)S]GTPγS binding with anti-Gαq antibody was performed. Results: The specific [(35)S]GTPγS binding to Gαq was increased by 5-hydroxytryptamine (5-HT) in a concentration-dependent but unsaturable manner. The increase elicited by micromolar concentrations of 5-HT was inhibited completely by ketanserin, whereas it inhibited the response by submillimolar to millimolar concentrations of 5-HT only partially. Analysis of the concentration-dependent increases by 5-HT in the absence and presence of ketanserin, methiothepin, WAY100635, and pirenzepine clearly indicates that there are two distinct components of 5-HT-stimulated [(35)S]GTPγS binding, one of which is a pharmacologically relevant increase elicited by lower concentrations (-30 μmol/l) of 5-HT mediated through 5-HT2 receptors and the other is pharmacologically undefined stimulation by higher concentrations of 5-HT. When 5-HT and carbachol were added simultaneously, there was apparently lack of additivity. Conclusion: It is concluded that by means of antibody-capture SPA/[(35)S]GTPγS binding it is possible to detect two distinct components of 5-HT-elicited activation of Gq shared by M1 muscarinic receptors, one of which is mediated through 5-HT2 receptors and the other is derived from unknown origin in rat cerebral cortical membranes. 23906609 Self-reported use of diabetes healthcare services in a Quebec community-based sample: impact of depression status. To ascertain the impact of minor and major depression on self-reported use of and access to diabetes healthcare services, and the care components received in a community-based Quebec sample with type 2 diabetes. Adults with type 2 diabetes who took part in baseline and 1-year follow-up telephone interviews for the Diabetes Health Study were assessed (n = 1175). Information was collected regarding depression status (i.e. minor or major depression), use of and access to diabetes healthcare services, sociodemographic and diabetes characteristics, treatment, diabetes complications, disability, body mass index, residential area and depression. People with major depression were more likely to be high users or non-users of diabetes healthcare services. The high users reported more diabetes complications. People with major depression also reported more problems with accessing diabetes healthcare services, specifically having to wait too long between making their appointment and their visit, specialist care not being available in their area, general health deterioration, being unable to leave their house due to their health and problems with transportation. People with major depression were less likely to report having their feet checked by their doctor, and were more likely to report problems with getting advice from their doctor. People with diabetes need to use healthcare services in order to receive recommended care components. People with major depression and no complications are less likely to report using healthcare services; conversely, people with major depression and complications are more likely to be high users of healthcare services. People with major depression perceive more problems with the health care they receive. 23843290 Spontaneous Renal Artery Aneurysm Rupture in a Patient With Neurofibromatosis Type 1 Without Risk Factors for Renal Artery Aneurysm Rupture. Vascular abnormalities in neurofibromatosis type 1 (NF-1) are rare but sometimes fatal. We report a case of spontaneous rupture of a left renal artery aneurysm in a patient with NF-1. A 41-year-old nonpregnant normotensive woman known to have NF-1 presented to our emergency department with left flank pain. Computed tomography showed a large retroperitoneal hematoma due to left renal artery aneurysm rupture. She was treated with selective transcatheter coil embolization and fully recovered. 23172910 Effect of powered gait orthosis on walking in individuals with paraplegia. The important purpose of a powered gait orthosis is to provide active joint movement for patients with spinal cord injury. The aim of this study was to clarify the effect of a powered gait orthosis on the kinematics and temporal-spatial parameters in paraplegics with spinal cord injury. Quasi-experimental. Four spinal cord injury individuals experienced gait training with a powered gait orthosis for a minimum of 6 weeks prior to participating in the following walking trials: walking with an isocentric reciprocating gait orthosis and walking with both separate and synchronized movements with actuated orthotic hip and knee joints in a powered gait orthosis. Specific parameters were calculated and compared for each of the test conditions. Using separate and synchronized actuated movement of the hip and knee joints in the powered gait orthosis increased gait speed and step length and reduced lateral and vertical compensatory motions when compared to the isocentric reciprocating gait orthosis, but there were no significant differences in these parameters. Using the new powered gait orthosis improved knee and hip joint kinematics. The powered gait orthosis increased speed and step length as well as hip and knee joint kinematics and reduced the vertical and lateral compensatory motions compared to an isocentric reciprocating gait orthosis in spinal cord injury patients. This new powered gait orthosis has the potential to improve hip and knee joint kinematics, the temporal-spatial parameters of gait in spinal cord injury patients walking. 23707263 Lysophosphatidic acid promotes secretion of VEGF by increasing expression of 150-kD Oxygen-regulated protein (ORP150) in mesenchymal stem cells. We previously reported that transplantation of lysophosphatidic acid (LPA) treated mesenchymal stem cells (MSCs) enhances capillary density in the myocardium and improves myocardial function in the ischemic heart. This effect may be mediated through the release of paracrine factors by MSC and potentially involves pro-angiogenic molecules such as vascular endothelial growth factor (VEGF). In this study, we examined the pharmacological and molecular regulation of VEGF secretion induced by LPA in rat MSCs. We showed that LPA stimulated VEGF secretion in MSCs but not in cardiomyocytes or cardiac fibroblasts. LPA-induced VEGF secretion occurred at the post-transcriptional levels and was mediated through the classical ER/Golgi-dependent protein secretory route. LPA also increased ORP150 protein expression. Inhibition of ORP150 upregulation by siRNA knockdown attenuated LPA-induced VEGF secretion. On the other hand, diazoxide, an activator of KATP channel, markedly inhibited LPA-induced ORP150 expression and VEGF secretion. Meanwhile, ATP concentration dependently increased VEGF secretion. In addition, l-Glutamate and NH4Cl significantly reduced VEGF secretion. Furthermore, inhibition of two major subtypes of LPA receptors by Ki16425 and specific siRNA for LPA receptors prevented LPA-induced VEGF secretion and ORP150 expression. Lastly, inhibition of Gi protein that couples with LPA receptors by PTX and siRNA knockdown had no effect on LPA-induced VEGF secretion. Taken together, our findings demonstrate that LPA promotes VEGF secretion at the post-translation level by up-regulating ORP150 expression. Both LPA1 and LPA3 are involved in the LPA-induced VEGF secretion that is independent of Gi protein coupling but associated with the inactivation of KATP channels and inhibition of Na(+)/K(+)-ATPase activity. 23580319 The pharmacological approach to the elderly COPD patient. The elderly patient (65 years and older) with chronic obstructive pulmonary disease (COPD) can be a challenge to the clinician. This begins with the correct and early diagnosis, the assessment of disease severity, recognizing complicating comorbidities, determining the burden of symptoms, and monitoring the frequency of acute exacerbations. Comprehensive management of COPD in the elderly patient should improve health-related quality of life, lung function, reduce exacerbations, and promote patient compliance with treatment plans. Only smoking cessation and oxygen therapy in COPD patients with hypoxemia reduce mortality. Bronchodilators, corticosteroids, methylxanthines, phosphodiesterase-4 inhibitors, macrolide antibiotics, mucolytics, and pulmonary rehabilitation improve some outcome measures such as spirometry measures and the frequency of COPD exacerbations without improving mortality. International treatment guidelines to reduce symptoms and reduce the risk of acute exacerbations exist. Relief of dyspnea and control of anxiety are important. The approach to each patient is best individualized. Earlier use of palliative care should be considered when traditional pharmacotherapy fails to achieve outcome measures and before consideration of end-of-life issues. 23746693 Efficiency of ciprofloxacin for bacterial control, post-thaw quality, and in vivo fertility of buffalo spermatozoa. Ciprofloxacin (CP) was evaluated for bacterial control, post-thaw quality, and fertility of buffalo semen. Pseudomonas aeruginosa, Escherichia coli, Proteus sp., Corynebacterium sp., Micrococcus sp., and Staphylococcus sp. were isolated from buffalo semen. Pseudomonas aeruginosa, Corynebacterium sp., and Micrococcus sp. were resistant to streptomycin, whereas P. aeruginosa and Proteus sp. were resistant to penicillin. All bacteria were susceptible to CP. In vitro dose toxicity was assessed in sodium citrate buffer containing 0, 200 to 2000 μg/mL of CP. CP up to 1000 μg/mL was found nontoxic to motility and viability of buffalo sperm. For post-thaw quality, buffalo semen was frozen in Tris-citric acid extender containing streptomycin-penicillin (SP; 1000 μg/mL-1000 IU/mL) or CP 600 μg/mL and was assessed for total aerobic bacterial count (post-thaw), motility, plasma membrane integrity, viability at 0, 2, and 4 hours post-thaw. At 4 hours post-thaw, plasma membrane integrity (%) was higher (P < 0.05) in extender containing CP than SP. Total aerobic bacterial count was 0.00 in extender containing CP compared with 0.07 × 10(4) cfu/mL with SP. To assess the in vivo fertility rate, semen (two bulls) frozen in Tris-citric acid extender containing SP or CP was used to inseminate, and 400 inseminations (200/group) were recorded. Higher (P â‰¤ 0.05) fertility rate was recorded with CP (55%) compared with SP (41%). In conclusion, use of CP in extender was efficient to control the bacterial contamination without compromising the post-thaw quality and fertility of cryopreserved water buffalo bull semen. 23831164 Effect of Baseline Gastrointestinal Risk and Use of Proton Pump Inhibitors on Frequency of Discontinuation of Aspirin for Secondary Cardiovascular Prevention in United Kingdom Primary Care. For patients at high cardiovascular and high gastrointestinal (GI) risk, coprescription of a proton pump inhibitor (PPI) with low-dose aspirin is recommended. We aimed to quantify the extent to which low-dose aspirin discontinuation in patients at high cardiovascular risk is affected by PPI use and baseline GI risk. Patients aged 50 to 84 years who had evidence of ischemic heart disease or cardiovascular disease and who were new users of low-dose aspirin in 2000 to 2007 were identified using The Health Improvement Network (n = 35,604). Aspirin discontinuation was defined as a period of at least 90 days after completion of the last prescribed course during which no repeat prescription was issued. The incidence of low-dose aspirin discontinuation was 26.8 per 100 person-years (95% confidence interval [CI] 26.2 to 27.4). The age-, gender-, and indication-adjusted risk of aspirin discontinuation was 15% less among continuous PPI users than among PPI nonusers (hazard ratio [HR] 0.85, 95% CI 0.78 to 0.92); after further adjusting for number of coprescribed medications, the HR was 0.95 (95% CI 0.87 to 1.03). Continuous PPI use was associated with a reduced risk of aspirin discontinuation among patients at high GI risk (HR 0.83; 95% CI 0.74 to 0.93) but not among those at low GI risk (HR 1.08; 95% CI 0.96 to 1.21). In conclusion, among patients at high GI risk, concomitant users of aspirin and PPI showed a greater aspirin adherence than aspirin users not on PPI. Further studies need to confirm factors with the potential to increase adherence to long-term aspirin. 23417696 A phase 2 multicenter study of tivantinib (ARQ 197) monotherapy in patients with relapsed or refractory germ cell tumors. Background Tivantinib is a selective, small-molecule inhibitor of the MET receptor tyrosine kinase. Preclinical and phase 1 data suggested a possible role for MET in the pathophysiology of germ cell tumors (GCTs) and a potential clinical benefit from tivantinib in patients with these tumors. Methods Men (≥16 years) with relapsed or refractory, histologically confirmed, non-central nervous system GCTs received oral tivantinib 360 mg twice daily in 28-day cycles until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate in the first 4 cycles, with study termination for <2 responses among the first 21 patients. Secondary endpoints included 12-week progression-free survival (PFS), overall survival (OS), and safety. Results Twenty-seven patients were enrolled in 9 months (median age, 32 years). Most patients had tumors with nonseminoma histology (n = 25), and primary tumor sites were testis (n = 24) and mediastinum (n = 3). Among 25 evaluable patients, no objective responses were observed; accrual was halted when the 21st patient became evaluable. Best response was stable disease (n = 5). Median PFS was 1 month, the 12-week PFS rate was 21 %, and median OS was 6 months. Grade 3 or 4 adverse events considered related to study drug included grade 3 pneumonia and grade 3 syncope (n = 1, each). Conclusions Tivantinib was well tolerated but did not demonstrate single-agent activity in patients with relapsed/refractory GCTs. Rapid accrual to this phase 2 trial was achieved in this rare patient population through multicenter collaboration. 23677522 Does the cement stiffness affect fatigue fracture strength of vertebrae after cement augmentation in osteoporotic patients? Normal progression of osteoporosis or the rigid reinforcement of the fractured vertebral body with polymethyl methacrylate (PMMA) cement is being discussed as a cause for adjacent-level fractures after vertebroplasty. The purpose of this study was to investigate whether augmentation with low stiffness cement can decrease the risk of adjacent-level fractures in low-quality bone. Eighteen female osteoporotic lumbar specimens (L1-L5) were harvested and divided into three groups according to bone mineral density: (I) native; (II) PMMA; (III) modified PMMA (lower stiffness). For the PMMA and modified PMMA groups, a compression fracture was first mechanically induced in L3, and then the fracture received vertebroplasty treatment. The cement stiffness reduction of the modified PMMA group was achieved via an addition of 8 mL of serum to the typical PMMA base. All specimens were exposed to cyclic loading (4 Hz) and a stepwise increasing applied peak force. Cement stiffness was tested according to ISO 5833. A 51% decrease in cement stiffness was achieved in the modified PMMA group (954 ± 141 vs. 1,937 ± 478 MPa, p < 0.001). Fatigue fracture force (the force level during cyclic loading at which the deformation experienced a sudden increase; FFF) was significantly affected by bone quality (r (2) = 0.39, p = 0.006) and by the initial fracture force (the force necessary to create the initial fracture in L3 prior to augmentation; r (2) = 0.82, p < 0.001). Using initial fracture force as a covariate, the FFF of the modified PMMA group (1,764 ± 49 N) was significantly higher than in the PMMA group (1,544 ± 55 N; p = 0.03). A possible method to reduce adjacent-level fractures after vertebroplasty in patients with reduced bone quality could be the use of a lower modulus cement. Therefore, mixing cement with biocompatible fluids could prove useful to tailor cement properties in the operating theater. 23238090 Repeated Sprint and Change-of-Direction Abilities in Soccer Players: Effects of Age Group. Dellal, A and Wong, DP. Repeated sprint and change-of-direction abilities in soccer players: effects of age group. J Strength Cond Res 27(9): 2504-2508, 2013-The purpose of the present study was to compare the performance in repeated sprint ability (RSA) and repeated changes-of-direction (RCOD) among elite soccer players with different age categories. Forty-nine elite soccer players from the same club and from different age categories (Pro2: n = 8, U19: n = 18, U17: n = 13, and U15: n = 10) participated in this study. Each player was tested in both a RSA straight-line sprints (10 × 20 m with active recovery) and a RCOD test including four 100° COD at every 4 m (10 × 20 m with active recovery). The average time (AT), fastest time (FT), total time (TT), percentage of decrement score (%Dec), and RSA/RCOD index were recorded and calculated during all the RSA and RCOD tests. Results showed significant age group effects on RSA and RCOD parameters (p < 0.01) and RSA/RCOD index parameters (p < 0.01). Compared with other groups, U15 has significant (p < 0.05) higher values in RSA-AT, RSA-FT, RSA-TT, RCOD-AT, RCOD-FT, RCOD-TT, index-AT, index-FT, and index-TT. However, the trend of performance time and RSA/RCOD index was always similar (i.e., U15 > U17 > U19 > Pro2; Pro2 > U19 > U17 > U15) showing an age dependant for RSA and RCOD performance. The %Dec in RSA of U15 and U17 was significantly (p < 0.05) higher than U19 and Pro2, whereas the %Dec in RCOD of U15 was significantly (p < 0.05) higher than U19. In conclusion, the present study showed that the RSA and RCOD are age dependent, and therefore, coaches should plan a specific program differentiating the RSA and RCOD, while the individualized training could begin in U17. 23916018 Diagnosing Delirium in Older Emergency Department Patients: Validity and Reliability of the Delirium Triage Screen and the Brief Confusion Assessment Method. Delirium is a common form of acute brain dysfunction with prognostic significance. Health care professionals caring for older emergency department (ED) patients miss delirium in approximately 75% of cases. This error results from a lack of available measures that can be performed rapidly enough to be incorporated into clinical practice. Therefore, we developed and evaluated a novel 2-step approach to delirium surveillance for the ED. This prospective observational study was conducted at an academic ED in patients aged 65 years or older. A research assistant and physician performed the Delirium Triage Screen (DTS), designed to be a highly sensitive rule-out test, and the Brief Confusion Assessment Method (bCAM), designed to be a highly specific rule-in test for delirium. The reference standard for delirium was a comprehensive psychiatrist assessment using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. All assessments were independently conducted within 3 hours of one another. Sensitivities, specificities, and likelihood ratios with their 95% confidence intervals (95% CIs) were calculated. Of 406 enrolled patients, 50 (12.3%) had delirium diagnosed by the psychiatrist reference standard. The DTS was 98.0% sensitive (95% CI 89.5% to 99.5%), with an expected specificity of approximately 55% for both raters. The DTS's negative likelihood ratio was 0.04 (95% CI 0.01 to 0.25) for both raters. As the complement, the bCAM had a specificity of 95.8% (95% CI 93.2% to 97.4%) and 96.9% (95% CI 94.6% to 98.3%) and a sensitivity of 84.0% (95% CI 71.5% to 91.7%) and 78.0% (95% CI 64.8% to 87.2%) when performed by the physician and research assistant, respectively. The positive likelihood ratios for the bCAM were 19.9 (95% CI 12.0 to 33.2) and 25.2 (95% CI 13.9 to 46.0), respectively. If the research assistant DTS was followed by the physician bCAM, the sensitivity of this combination was 84.0% (95% CI 71.5% to 91.7%) and specificity was 95.8% (95% CI 93.2% to 97.4%). If the research assistant performed both the DTS and bCAM, this combination was 78.0% sensitive (95% CI 64.8% to 87.2%) and 97.2% specific (95% CI 94.9% to 98.5%). If the physician performed both the DTS and bCAM, this combination was 82.0% sensitive (95% CI 69.2% to 90.2%) and 95.8% specific (95% CI 93.2% to 97.4%). In older ED patients, this 2-step approach (highly sensitive DTS followed by highly specific bCAM) may enable health care professionals, regardless of clinical background, to efficiently screen for delirium. Larger, multicenter trials are needed to confirm these findings and to determine the effect of these assessments on delirium recognition in the ED. 23751504 POSS-Enhanced Phase Separation in Air-Processed P3HT:PCBM Bulk Heterojunction Photovoltaic Systems. Nanoparticles have been shown in some cases to improve phase separation and morphology in bulk heterojunction organic photovoltaic cells. In this study, the effect of incorporation of polyhedral oligomeric silsesquioxane (POSS) molecules of different structures in air processed poly(3-hexylthiophene-2,5-diyl) (P3HT) and [6,6]-phenyl C61 butyric acid methyl ester (PCBM) films and photovoltaic cells was evaluated. Morphology and composition of the nanoscalephase-separated domains were determined via conductive atomic force microscopy in conjunction with nanomechanical mapping and Raman imaging. UV-vis and fluorescence spectroscopy analysis of the films was performed at different stages of the process and with different levels of solvent vapor and thermal annealing. It was found that POSS molecules of selected structures provided enhancement in morphology control in films, translating to improvements in fill factor and power conversion efficiency of laboratory-scale OPV cells. The findings indicate the potential for further improvements in solar cell performance with specifically tailored POSS/polymer phase-separated systems. 23915948 Pain relief, spiritual needs, and family support: Three central areas in intercultural palliative care. Objective: The purpose of this study was to draw out and coalesce the topic-specific information found in research literature regarding the provision of culturally sensitive palliative practice. Method: This was a literature study and Gadamerian hermeneutic text analysis. Results: It is more difficult to assess the level of pain in ethnic minority patients, and healthcare providers may become frustrated and interpret pain symptoms as fabrication. These patients are more likely to receive inadequate pain medication. Physical symptom management has become the priority in palliative care, but pain must also be viewed from the perspective of its social, cultural, and spiritual significance. Collectivist values may lead to an other-reliant and dependent coping style. This and religious demands may cause the family to rally around the patient. Many dying patients wish to be cared for at home by their families, but as the patient often has complex needs, the family may not be able to cope with the patient's care. Significance of results: Formal education and in-service programs are needed for healthcare providers, together with empirical studies regarding how to achieve more culturally appropriate care in intercultural palliative practice. The immigrant population needs to be educated about cancer and the various kinds of palliative and hospice care offered in the society in which they now live. 23348748 Neurochemical codes of sympathetic preganglionic neurons activated by glucoprivation. Glucoprivation or hypoglycemia induces a range of counterregulatory responses, including glucose mobilization, reduced glucose utilization, and de novo glucose synthesis. These responses are mediated in part by the sympathetic nervous system. The aim of this study was to determine the chemical codes of sympathetic preganglionic neurons (SPN) activated by glucoprivation, induced by 2-deoxy-D-glucose (2DG). SPN controlling the adrenal glands and celiac ganglia, which ultimately can innervate the liver and pancreas, were targeted together with the superior cervical ganglia (control). 23.9% ± 1.3% of SPN in the T4-T11 region contained c-Fos immunoreactivity following 2DG; 70.3% ± 1.8% of SPN innervating the adrenal glands and 37.4% ± 3% of SPN innervating celiac ganglia were activated. 14.8% ± 3.5% of SPN (C8-T3) innervating superior cervical ganglia were activated. In the C8-T3 region 55% ± 10% of SPN activated contained PPCART, with only 12% ± 3% expressing PPE mRNA, whereas, in the T4-T11 region, 78% ± 4% contained PPE, with only 6.0% ± 0.6% expressing PPCART mRNA. Thus CART is not involved in glucose mobilization. Two chemically distinct populations of SPN (PPE⁺ 57.4% ± 5%, PPE⁻ ∼40%) were identified to regulate adrenaline release in response to glucoprivation. Multiple chemically distinct SPN populations innervating a specific target could suggest their graded recruitment. The two distinct populations of SPN (PPE⁺ 67.6% ± 9%, PPE⁻ ∼30%) projecting to celiac ganglia activated by glucoprivation could direct pancreatic and hepatic or other counterregulatory responses. Nearly all SPN that expressed PPE mRNA and projected to the adrenal glands or celiac ganglia were activated, suggesting a role for the inhibitory peptide enkephalin in responses evoked by glucoprivation. 23631769 Synthetic ion channels. The objective of this historical review is to recall the development of the field of synthetic ion channels over the past three decades. The most inspiring and influential breakthroughs with regard to structure and function are brought together to give the general reader an easily accessible understanding of the field. Pioneering work in the 1980s is followed by the golden age in the 1990s with structures emphasizing crown ethers, calixarenes, and peptide mimetics. Following the emergence of questions concerning specific functions such as ion selectivity, voltage gating, ligand gating and blockage, and with π-stacks, metal-organic scaffolds, and DNA origami, a new wave of innovative structures has emerged. The perspectives outline promising directions and major challenges waiting to be addressed. 23806811 Profiling biopharmaceutical deciding properties of absorption of lansoprazole enteric-coated tablets using gastrointestinal simulation technology. The aim of the present study was to correlate in vitro properties of drug formulation to its in vivo performance, and to elucidate the deciding properties of oral absorption. Gastrointestinal simulation technology (GST) was used to simulate the in vivo plasma concentration-time curve and was implemented by GastroPlus™ software. Lansoprazole, a typical BCS class II drug, was chosen as a model drug. Firstly, physicochemical and pharmacokinetic parameters of lansoprazole were determined or collected from literature to construct the model. Validation of the developed model was performed by comparison of the predicted and the experimental plasma concentration data. We found that the predicted curve was in a good agreement with the experimental data. Then, parameter sensitivity analysis (PSA) was performed to find the key parameters of oral absorption. The absorption was particularly sensitive to dose, solubility and particle size for lansoprazole enteric-coated tablets. With a single dose of 30mg and the solubility of 0.04mg/ml, the absorption was complete. A good absorption could be achieved with lansoprazole particle radius down to about 25μm. In summary, GST is a useful tool for profiling biopharmaceutical deciding properties of absorption of lansoprazole enteric-coated tablets and guiding the formulation optimization. 23886042 Comparison of potentially preventable hospitalizations related to diabetes among Native Hawaiian, Chinese, Filipino, and Japanese elderly compared with whites, Hawai'i, December 2006-December 2010. Approximately 25% of individuals aged 65 years or older in the United States have diabetes mellitus. Diabetes rates in this age group are higher for Asian American and Pacific Islanders (AA/PI) than for whites. We examined racial/ethnic differences in diabetes-related potentially preventable hospitalizations (DRPH) among people aged 65 years or older for Japanese, Chinese, Filipinos, Native Hawaiians, and whites. Discharge data for hospitalizations in Hawai'i for people aged 65 years or older from December 2006 through December 2010 were compared. Annual rates of DRPH by patient were calculated for each racial/ethnic group by sex. Rate ratios (RRs) were calculated relative to whites. Multivariable models controlling for insurer, comorbidity, diabetes prevalence, age, and residence location provided final adjusted rates and RRs. A total of 1,815 DRPH were seen from 1,515 unique individuals. Unadjusted RRs for DRPH by patient were less than1 in all AA/PI study groups compared with whites, but were highest among Native Hawaiians and Filipinos. In fully adjusted models accounting for higher diabetes prevalence in AA/PI groups, Native Hawaiian (adjusted rate ratio [aRR] = 1.59), Filipino (aRR = 2.26), and Japanese (aRR = 1.86) men retained significantly higher rates of diabetes-related potentially preventable hospitalizations than whites, as did Filipino women (aRR = 1.61). Native Hawaiian, Filipino, and Japanese men and Filipino women aged 65 years or older have a higher risk than whites for DRPH. Health care providers and public health programs for elderly patients should consider effective programs to reduce potentially preventable hospitalizations among Native Hawaiian, Filipino, and Japanese men and Filipino women aged 65 years or older. 23913852 Significance of deeper molecular responses in patients with chronic myeloid leukemia in early chronic phase treated with tyrosine kinase inhibitors. Most patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with tyrosine kinase inhibitors (TKI) achieve complete cytogenetic response (CCyR). An increasing number of patients also achieve deep molecular responses (MR). We determined the frequency and significance of deep MR after TKI therapy for CML in CP. MR included: major molecular response (MMR), MR4, MR4.5, and undetectable transcripts (UND), ie BCR-ABL/ABL of ≤0.1%, ≤0.01%, ≤0.0032%, and undetectable transcripts, respectively. 483 patients received imatinib 400mg/day (IM400, 71, July 2000-April 2001), imatinib 800mg/day (IM800, 204, June 2001-July 2005), nilotinib (NILO, 106, July 2005 to date), or dasatinib (DASA, 102, November 2005 to date). UND rates at 36 months were 18.1%, 30.6%, 29.2%, and 28.6%, respectively. Patients achieving UND have superior transformation-free survival (TFS) and overall survival (OS) versus those obtaining ≤MMR, but not other MR levels. At the 18- and 24-month landmark analysis patients achieving UND have no advantage in TFS and OS compared to those achieving a lesser degree of MR. Among patients achieving MR4.5, those who maintain it for ≥2 years (susMR4·5) have no additional benefit in TFS or OS. Most patients with early CP CML receiving TKI achieve MMR. BCR-ABL transcripts become undetectable in a significant fraction of them. Deeper MR at 18 or 24 months are not associated with a benefit in TFS or OS. Furthermore, achieving susMR4·5 does not appear to further reduce the risk of transformation or death. 23966556 Immunogenicity and Safety of a Fully Liquid DTaP5-IPV-Hib Pediatric Combination Vaccine Compared With DTaP3-IPV/Hib Vaccine Administered at 3, 5, and 12 Months of Age: A Randomized, Controlled, Multicenter Study. This study compared the immunogenicity and safety of DTaP5-IPV-Hib and DTaP3-IPV/Hib vaccines at 3, 5, and 12 months of age. Post-Dose 3 noninferiority criteria comparing DTaP5-IPV-Hib to DTaP3-IPV/Hib using seroprotection rates was demonstrated against diphtheria, tetanus, and polio types 1-3, but not for PRP. While PRP did not meet noninferiority criteria, the seroprotection rate and geometric mean concentration (GMC) were high, indicating a clinically robust immune response. GMCs or titres for other antigens (including pertussis) and the safety profile were generally similar between groups. Fully liquid DTaP5-IPV-Hib can be administered using the 3, 5, and 12 month vaccination schedule. 23163768 Receptors, endocytosis, and trafficking: the biological basis of targeted delivery of antisense and siRNA oligonucleotides. The problem of targeted delivery of antisense and siRNA oligonucleotides can be resolved into two distinct aspects. The first concerns devising ligand-oligonucleotide or ligand-carrier moieties that bind with high selectivity to receptors on the cell type of interest and that are efficiently internalized by endocytosis. The second concerns releasing oligonucleotides from pharmacologically inert endomembrane compartments so that they can access RNA in the cytosol or nucleus. In this review, we will address both of these aspects. Thus, we present information on three important receptor families, the integrins, the receptor tyrosine kinases, and the G protein-coupled receptors in terms of their suitability for targeted delivery of oligonucleotides. This includes discussion of receptor abundance, internalization and trafficking pathways, and the availability of suitable high affinity ligands. We also consider the process of oligonucleotide uptake and intracellular trafficking and discuss approaches to modulating these processes in a pharmacologically productive manner. Hopefully, the basic information presented in this review will be of value to investigators involved in designing delivery approaches for oligonucleotides. 23688632 Membrane mimetic surface functionalization of nanoparticles: Methods and applications. Nanoparticles (NPs), due to their size-dependent physical and chemical properties, have shown remarkable potential for a wide range of applications over the past decades. Particularly, the biological compatibilities and functions of NPs have been extensively studied for expanding their potential in areas of biomedical application such as bioimaging, biosensing, and drug delivery. In doing so, surface functionalization of NPs by introducing synthetic ligands and/or natural biomolecules has become a critical component in regard to the overall performance of the NP system for its intended use. Among known examples of surface functionalization, the construction of an artificial cell membrane structure, based on phospholipids, has proven effective in enhancing biocompatibility and has become a viable alternative to more traditional modifications, such as direct polymer conjugation. Furthermore, certain bioactive molecules can be immobilized onto the surface of phospholipid platforms to generate displays more reminiscent of cellular surface components. Thus, NPs with membrane-mimetic displays have found use in a range of bioimaging, biosensing, and drug delivery applications. This review herein describes recent advances in the preparations and characterization of integrated functional NPs covered by artificial cell membrane structures and their use in various biomedical applications. 23740999 Integrated Analyses of Genome-Wide DNA Occupancy and Expression Profiling Identify Key Genes and Pathways Involved in Cellular Transformation by a Marek's Disease Virus Oncoprotein, Meq. Marek's disease (MD) is an economically significant disease in chickens that is caused by the highly oncogenic Marek's disease virus (MDV). A major unanswered question is the mechanism of MDV-induced tumor formation. Meq, a bZIP transcription factor discovered in the 1990s, is critically involved in viral oncogenicity, but only a few of its host target genes have been described, impeding our understanding of MDV-induced tumorigenesis. Using chromatin immunoprecipitation-sequencing (ChIP-seq) and microarray analysis, a high-confidence list of Meq binding sites in the chicken genome and a global transcriptome of Meq-responsive genes were generated. Meq binding sites were found to be enriched in the promoter regions of upregulated genes but not in those of downregulated genes. ChIP-seq was also performed for c-Jun, a known heterodimeric partner of Meq. The close location of binding sites of Meq and c-Jun was noted, suggesting cooperativity between these two factors in modulating transcription. Pathway analysis indicated that Meq transcriptionally regulates many genes that are part of several signaling pathways including the extracellular signal-regulated kinase /mitogen-activated protein kinase (ERK/MAPK), Jak-STAT, and ErbB pathways, which are critical for oncogenesis and/or include signaling mediators involved in apoptosis. Meq activates oncogenic signaling cascades by transcriptionally activating major kinases in the ERK/MAPK pathway and simultaneously repressing phosphatases, as verified using inhibitors of MEK and ERK1/2 in a cell proliferation assay. This study provides significant insights into the mechanistic basis of Meq-dependent cell transformation. 23847516 Facilitated acquisition of eyeblink conditioning in those vulnerable to anxiety disorders. Behavioral inhibition (BI) increases vulnerability to develop anxiety disorders and is typified by avoidance and withdrawal from novel objects, people, and situations. The present study considered the relationship between BI and temperamental risk factors, such as trait anxiety and acquisition rate of a classically conditioned eyeblink response. One-hundred seventy-four healthy undergraduate students (mean age 20.3 years, 71.8% female) were given the State-Trait Anxiety Inventory and a battery of self-report measures of BI consisting of the Adult and Retrospective Measures of Behavioral Inhibition (AMBI/RMBI) and the Concurrent and Retrospective Self Report of Inhibition (CSRI/RSRI). Participants then underwent standard delay classical eyeblink conditioning consisting of 45 trials with a 500-ms CS overlapping and co-terminating with a 10-ms airpuff US. Individuals with higher scores on the AMBI and Trait Anxiety Inventory, but not the other measures, showed faster acquisition of a conditioned eyeblink response than individuals with lower scores. Results support a relationship between facilitated acquisition of inter-stimulus relationships and risk for anxiety, and suggest that some measures assessing anxiety vulnerability better capture this relationship than others. 23902626 Increased detection of Plasmodium knowlesi in Sandakan division, Sabah as revealed by PlasmoNex™. Plasmodium knowlesi is a simian malaria parasite that is widespread in humans in Malaysian Borneo. However, little is known about the incidence and distribution of this parasite in the Sandakan division, Malaysian Borneo. Therefore, the aim of the present epidemiological study was to investigate the incidence and distribution of P. knowlesi as well as other Plasmodium species in this division based on a most recent developed hexaplex PCR system (PlasmoNex™). A total of 189 whole blood samples were collected from Telupid Health Clinic, Sabah, Malaysia, from 2008 to 2011. All patients who participated in the study were microscopically malaria positive before recruitment. Complete demographic details and haematological profiles were obtained from 85 patients (13 females and 72 males). Identification of Plasmodium species was conducted using PlasmoNex™ targeting the 18S ssu rRNA gene. A total of 178 samples were positive for Plasmodium species by using PlasmoNex™. Plasmodium falciparum was identified in 68 samples (38.2%) followed by 64 cases (36.0%) of Plasmodium vivax, 42 (23.6%) cases of P. knowlesi, two (1.1%) cases of Plasmodium malariae and two (1.1%) mixed-species infections (i e, P. vivax/P. falciparum). Thirty-five PlasmoNex™ positive P. knowlesi samples were misdiagnosed as P. malariae by microscopy. Plasmodium knowlesi was detected in all four districts of Sandakan division with the highest incidence in the Kinabatangan district. Thrombocytopaenia and anaemia showed to be the most frequent malaria-associated haematological complications in this study. The discovery of P. knowlesi in Sandakan division showed that prospective studies on the epidemiological risk factors and transmission dynamics of P. knowlesi in these areas are crucial in order to develop strategies for effective malaria control. The availability of advanced diagnostic tool PlasmoNex™ enhanced the accuracy and accelerated the speed in the diagnosis of malaria. 23927110 Optical multi-point measurements of the acoustic particle velocity with frequency modulated Doppler global velocimetry. To reduce the noise of machines such as aircraft engines, the development and propagation of sound has to be investigated. Since the applicability of microphones is limited due to their intrusiveness, contactless measurement techniques are required. For this reason, the present study describes an optical method based on the Doppler effect and its application for acoustic particle velocity (APV) measurements. While former APV measurements with Doppler techniques are point measurements, the applied system is capable of simultaneous measurements at multiple points. In its current state, the system provides linear array measurements of one component of the APV demonstrated by multi-tone experiments with tones up to 17 kHz for the first time. 23648090 Soluble interleukin-6 receptor is a serum biomarker for the response of esophageal carcinoma to neoadjuvant chemoradiotherapy. Preoperative chemoradiotherapy has been shown to improve the outcome of patients with esophageal cancer, but because response to this therapy varies, it is desirable to identify in advance individuals who would be unlikely to benefit, in order to avoid unnecessary adverse drug effects. The serum profiles of 84 cytokines and related proteins were determined in 37 patients with esophageal squamous cell carcinoma who received identical neoadjuvant preoperative chemoradiotherapy regimens and underwent surgical resection. Histological response to this therapy was assessed in surgically resected specimens. The serum soluble interleukin-6 receptor (sIL6R) level was significantly higher in 30 patients who failed to achieve a histological complete response (P = 0.005). Multivariate analysis revealed that the increased level of sIL6R was one of several significant independent predictors of an unfavorable outcome (hazard ratio, 2.87; P = 0.017). The increased level of this cytokine in patients who did not obtain a complete response was reproducibly observed in an independent cohort of 34 patients. Esophageal squamous cell carcinoma patients with an increased serum level of sIL6R are predicted to respond poorly to preoperative chemoradiotherapy, therefore, their exclusion from this treatment may be considered. Persistent systemic inflammation is implicated as a possible mechanism of resistance to this therapy. 23689095 Quantitative and qualitative differences in the metabolism of pesticides in biobed substrates and soil. Biobed substrates commonly exhibit high degradation capacity. However, degradation does not always lead to detoxification and information on the metabolic pathways of pesticides in biobeds is scarce. We studied the degradation and metabolism of three pesticides in selected biomixtures and soil. Biomixtures stimulated degradation of terbuthylazine and metribuzin, whereas chlorpyrifos degraded faster in soil. The latter was attributed to the lipophilicity of chlorpyrifos which increased adsorption and limited biodegradation in organic-rich biomixtures. Although the same metabolites were detected in all substrates, qualitative and quantitative differences in the metabolic routes of pesticides in the various substrates were observed. Chlorpyrifos was hydrolyzed to 3,5,6-tricholorpyridinol (TCP) which was further degraded only in compost-biomixture CBX1. Metabolism of terbuthylazine in compost biomixtures (BX) and soil resulted in the formation of desethyl-terbuthylazine (DES) which was fully degraded only in the compost-biomixture CBX2, whereas peat-based biomixture (OBX) promoted the hydroxylation of terbuthylazine. Desamino- (DA) (dominant) and diketo- (DK) metribuzin appear as intermediate metabolites in all substrates and were further transformed to desamino-diketo-metribuzin (DADK) which was fully degraded only in compost-biomixture GSBX. Overall, lower amounts of metabolites were accumulated in biomixtures compared to soil stressing the higher depuration efficiency of biobeds. 23594924 Selection of in vitro-matured porcine oocytes based on localization patterns of lipid droplets to evaluate developmental competence. Localization patterns of lipid droplets in the cytoplasm of porcine oocytes were evaluated as a novel marker for in vitro maturation (IVM) of oocytes with high developmental competence. Porcine oocytes were cultured in TCM-199, which is a complete synthetic medium, for 44 h at 38.5 C. Localization patterns were divided into 2 classes: lipid droplets localized uniformly in the whole cytoplasm (class I) and those that were centrally located (class II). After IVM in TCM-199, 60% of matured oocytes exhibited the class II pattern. To investigate the relation between the distribution of lipid droplets and the developmental rate of the oocyte, the developmental rates of class I and class II oocytes were compared after in vitro fertilization (IVF). Class II oocytes showed a significantly higher rate of blastocyst development than class I oocytes. These results suggest that porcine oocytes with high developmental competence can be selected based on the localization patterns of lipid droplets. 23838309 14q12 duplication including FOXG1: Is there a common age-dependent epileptic phenotype? Introduction: Duplications of 14q12 encompassing FOXG1 gene have been recently associated with developmental delay, severe speech impairment, epilepsy, aspecific neuroimaging findings and minor dysmorphisms. Aim and methods: In order to refine the epileptic phenotype associated with 14q12 duplications, we have performed a review of the electroclinical picture of the patients reported to date in the literature, adding a new personal case. A comprehensive set of clinical and instrumental data (with a particular focus on the electroclinical aspects including seizure type, age of onset, EEG at onset and after antiepileptic therapy, drug efficacy) has been taken into account. Results: 9/14 patients carrying 14q12 duplications developed seizures, all in the first months of life. Most of them developed infantile spasms (8/9 epileptic patients) and presented hypsarrhythmia or modified hypsarrhythmia on EEG. After therapy 5/9 patients became seizure free and 3/9 present a good seizure control. At last available follow up, 2/3 of the epileptic patients displayed an almost normal EEG, or a quite organized background activity, with diffuse or focal (mostly temporal) slowing. Conclusions: The review of the available data allowed to recognize a common epileptic core, characterized by early onset, age dependent epileptic encephalopathy with infantile spasms and typical, atypical or modified hypsarrhythmia. Antiepileptic therapy soon led to a good or complete control of seizures with a nearly normal background activity in most patients. 23929799 Imaging of Inflammation by PET, Conventional Scintigraphy, and Other Imaging Techniques. Nuclear medicine imaging procedures play an important role in the assessment of inflammatory diseases. With the advent of 3-dimensional anatomic imaging, there has been a tendency to replace traditional planar scintigraphy by CT or MRI. Furthermore, scintigraphic techniques may have to be combined with other imaging modalities to achieve high sensitivity and specificity, and some may require time-consuming labeling procedures. On the other hand, new developments such as combined SPECT/CT increase the diagnostic power of scintigraphy. Also, the advent of PET had a considerable impact on the use of nuclear medicine imaging techniques. In this review, we aim to provide nuclear medicine specialists and clinicians with the relevant information on rational and efficient use of nuclear medicine imaging techniques in the assessment of patients with osteomyelitis, infected vascular prostheses, metastatic infectious disease, rheumatoid arthritis, vasculitis, inflammatory bowel disease, sarcoidosis, and fever of unknown origin. 23601384 Health benefits of seafood; Is it just the fatty acids? There is a considerable body of literature suggesting a wide range of health benefits associated with diets high in seafood. However, the demand for seafood across the world now exceeds that available from capture fisheries. This has created a rapidly increasing market for aquaculture products, the nutrient composition of which is dependent on feed composition. The use of fishmeal in this food chain does little to counteract the environmental impact of fisheries and so the on-going development of alternative sources is to be welcomed. Nevertheless, an in-depth understanding as to which nutrients in seafood provide benefit is required to permit the production of foods of maximal health benefit to humans. This paper reviews our current knowledge of the beneficial nutrient composition of seafood, in particular omega-3 fatty acids, selenium, taurine, vitamins D and B12, in the context of the development of environmentally sustainable aquaculture. 23396078 Photochemical activation of TRPA1 channels in neurons and animals. Optogenetics is a powerful research tool because it enables high-resolution optical control of neuronal activity. However, current optogenetic approaches are limited to transgenic systems expressing microbial opsins and other exogenous photoreceptors. Here, we identify optovin, a small molecule that enables repeated photoactivation of motor behaviors in wild-type zebrafish and mice. To our surprise, optovin's behavioral effects are not visually mediated. Rather, photodetection is performed by sensory neurons expressing the cation channel TRPA1. TRPA1 is both necessary and sufficient for the optovin response. Optovin activates human TRPA1 via structure-dependent photochemical reactions with redox-sensitive cysteine residues. In animals with severed spinal cords, optovin treatment enables control of motor activity in the paralyzed extremities by localized illumination. These studies identify a light-based strategy for controlling endogenous TRPA1 receptors in vivo, with potential clinical and research applications in nontransgenic animals, including humans. 22233192 Accumulation patterns of some seed oil components from wild sources of Turkey. Accumulation profiles of fatty acids and α-tocopherol were analysed at three ripening stages in the seed oils of Primula and Echium species. Total seed oils were increased considerably with maturation, while α-tocopherol contents decreased in both species. Increased levels of ALA and oleic acid, and decrease in linoleic and palmitic acids at late ripening stages of Primula sibthorpii, and slightly fluctuations of all examined fatty acids in Echium italicum were observed. Considerable amounts of α-tocopherol (27.4 mg/100 g), linoleic acid (42.76%) and ALA (25.46%) and GLA (4.11%) were detected in Ribes alpinum. Typical accumulation patterns of the examined parameters may be useful for species characterisation and biochemical monitoring of seed development in natural conditions. 23364357 Extreme signet ring cell change in a large B-cell lymphoma of follicular origin. We report a large B-cell lymphoma of follicular origin with extreme signet ring cell differentiation. Initially classified as follicular lymphoma on a fine needle core biopsy, the presence of cohesive sheets of extrafollicular signet ring cells triggered an excisional biopsy for further characterization. The excised lymph node revealed focal follicular hyperplasia, follicular lymphoma, and a neoplasm composed of vague nodules and sheets of large atypical cells, all of which virtually exhibited large clear intracytoplasmic vacuoles with peripheral displacement of nuclei. The tumor cells were negative for mucin and lacked immunoreactivity with pancytokeratin, but were strongly immunoreactive with CD20, BCL-2, BCL-6, and CD10 antibodies. Electron microscopy studies revealed electron-lucent vacuoles with no particular internal structure. This case is unique in that extreme signet ring cell differentiation somewhat obscured the true cytological identity of the interfollicular lymphoma and suggested alternative diagnoses. 23836877 Vitamin D levels and risk of multiple sclerosis in patients with clinically isolated syndromes. Growing evidence suggests that vitamin D deficiency may be one of the most important environmental factors for the development of multiple sclerosis (MS). The objectives of this paper are to evaluate serum 25-hydroxyvitamin D (25(OH)D) levels in patients with clinically isolated syndromes (CIS) and to examine whether they are related to MS risk. This is a retrospective study of 100 CIS patients hospitalized from 2000 to 2009 at San Raffaele Hospital, Milan, Italy. We evaluated baseline 25(OH)D level as well as clinical, brain magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) data. A total of 52% of CIS patients had vitamin D deficiency (25(OH)D < 50 nmol/l). During follow-up (median: 7.17 years), 55 patients developed clinically definite MS (CDMS). Patients with very low (< 10th percentile) and low (< 25th percentile) 25(OH)D levels were particularly at risk of CDMS (HRs (95% CIs): 2.12 (0.91-4.96) and 1.61 (0.85-3.03), respectively), while no further reduction in the HRs of disease was observed at high levels of 25(OH)D. This association was even stronger after adjustment for additional risk factors for CDMS development (HRs (95% CIs) for 25(OH)D levels < 10th and 25th percentiles: 3.34 (1.32-8.45) and 2.04 (0.96-4.36), respectively). Low serum vitamin D is associated with increased MS risk in patients with CIS. 22458589 Early bone resorption after vertical bone augmentation--a comparison of calvarial and iliac grafts. OBJECTIVE AND AIM: Severe cases of bone atrophy in the maxilla or mandible are often reconstructed using bone from extraoral donor sides. Most commonly, grafts from the iliac crest are used for augmentation, however, frequently associated with bone resorption as possible late complication. Calvarial bone grafts, often reported to show less resorption, are an alternative. The aim of this study was to compare the bone stability of vertical bone grafts from the iliac crest and the calvarium. Twenty-three patients receiving vertical onlay bone grafts were included in this retrospective cohort study. In nine patients alveolar ridge defects were treated with bone from the iliac crest. Fourteen patients were reconstructed using calvarial bone grafts. To quantify bone resorption, the data of digital panographs were evaluated. Radiographs were taken prior to bone grafting, after augmentation surgery, 6 months after bone healing, prior to implant surgery, after implant surgery and at yearly intervals thereafter. Postoperative complications at the recipient site occurred equally in both groups. The complication rate was 35.7% for the calvarial group and 33.3% in the iliac crest group. No donor-site complications were reported in either group. After bone augmentation procedure, a mean vertical bone gain of 8.55 mm (SD 5.96) was measured. Bone grafts from the iliac crest showed a significantly higher bone loss of 24.16% (SD 8.47) than grafts from the calvarium (8.44%, SD 3.64) at the time of implant placement (P = 0.0003). Implant survival was similar in both groups. Both bone-grafting approaches are successful and reliable techniques, enabling implant placement in even highly atrophied alveolar ridges and with identical implant survival rates, although bone resorption differs. Within the limitations of this study bone from the calvarium shows higher bone stability in the early healing phase. 23229509 Regions on adenylyl cyclase VII required for selective regulation by the G13 pathway. Regulation of multiple adenylyl cyclases (AC) provides unique inputs to mediate the synthesis of cAMP, a ubiquitous second messenger that controls many aspects of cellular function. On stimulation by G(s), the activities of ACs can be further selectively modulated by other pathways to ensure precise control of intracellular cAMP responses to specific stimuli. Recently, we reported that one of the AC isoforms, AC7, is uniquely regulated by the G(13) pathway. To understand more fully the molecular mechanism of this regulation, we compared the regulation of AC7 with that of AC2 in bone marrow-derived macrophages devoid of AC7. Although both enzymes could fully restore regulation of cAMP by Gβγ, activation of the G(13) pathway preferentially synergized with AC7. Exchange of domains between the two isoforms indicates that the C1b domain and the N-terminus of the C1a domain are important for directing selective regulation of AC7 by the G(13) pathway. A mutagenesis screen identified more specific regions of AC7 that differentially mediate its regulation by distinct pathways. 23877834 Decreased hippocampal volume and increased anxiety in a transgenic mouse model expressing the human CYP2C19 gene. Selective serotonin reuptake inhibitors, tricyclic antidepressants, various psychoactive drugs, as well as endogenous steroids and cannabinoid-like compounds are metabolized by the polymorphic cytochrome P450 2C19 (CYP2C19). Absence of this enzyme has been recently shown to associate with lower levels of depressive symptoms in human subjects. To investigate endogenous functions of CYP2C19 and its potential role in brain function, we have used a transgenic mouse model carrying the human CYP2C19 gene. Here, CYP2C19 was expressed in the developing fetal, but not adult brain and was associated with altered fetal brain morphology, where mice homozygous for the CYP2C19 transgenic insert had severely underdeveloped hippocampus and complete callosal agenesis and high neonatal lethality. CYP2C19 expression was also found in human fetal brain. In adult hemizygous mice we observed besides decreased hippocampal volume, an altered neuronal composition in the hippocampal dentate gyrus. Reduced hippocampal volumes have been reported in several psychiatric disorders, supporting the relevance of this model. Here we found that adult hemizygous CYP2C19 transgenic mice demonstrate behavior indicative of increased stress and anxiety based on four different tests. We hypothesize that expression of the CYP2C19 enzyme prenatally may affect brain development by metabolizing endogenous compounds influencing this development. Furthermore, CYP2C19 polymorphism may have a role in interindividual susceptibility for psychiatric disorders.Molecular Psychiatry advance online publication, 23 July 2013; doi:10.1038/mp.2013.89. 23521048 Synthesis and Structure-Activity Relationships of 5,6,7-Substituted Pyrazolopyrimidines: Discovery of a Novel TSPO PET Ligand for Cancer Imaging. Focused library synthesis and structure-activity relationship development of 5,6,7-substituted pyrazolopyrimidines led to the discovery of 2-(5,7-diethyl-2-(4-(2-fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide (6b), a novel translocator protein (TSPO) ligand exhibiting a 36-fold enhancement in affinity compared to another pyrazolopyrimidine-based TSPO ligand, 6a (DPA-714). Radiolabeling with fluorine-18 ((18)F) facilitated production of 2-(5,7-diethyl-2-(4-(2-[(18)F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ((18)F-6b) in high radiochemical yield and specific activity. In vivo studies of (18)F-6b were performed which illuminated this agent as an improved probe for molecular imaging of TSPO-expressing cancers. 23356332 Measuring exertion during caregiving of children and young adults with cerebral palsy who require assistance for mobility and self-care. Our purpose was to compare objective and subjective measures of energy exertion during caregiving tasks. Participants were primary caregivers (N = 19) of children and young adults (aged 3 -22 years) with cerebral palsy (CP) who require assistance for mobility and self-care (67% classified in level V on the Gross Motor Function Classification System). Measures of exertion were collected during two caregiving tasks: (1) transfers and (2) dressing. Objective measures included volume of oxygen (V02), heart rate (HR), and the subjective measure was a rating of perceived exertion (Borg RPE). Controlling for baseline status, perceived exertion correlated with VO2 (0.43, p < .01) and HR (0.29, p < .01) during the tasks. Caregivers with high baseline HR and VO2, had high Borg RPE scores following a task. Correlations were found between HR and VO2 during caregiving tasks (0.63, p < .01). Patterns of association with caregiver and child characteristics were similar for VO2 and Borg RPE. Subjective measures of exertion appear to capture the strain of caregiving. Understanding a caregiver's perception of exertion can guide therapists in assessing the need for equipment, pharmacological, or respite interventions. 23407322 Intraocular lens power adjustment after myopic excimer laser surgery: validation studies for Geggel ratio and consensus group. To validate the Geggel ratio (GR) and consensus group in myopic excimer laser patients undergoing cataract surgery. Two separate consecutively collected case series (group 1, 32 eyes; group 2, 34 eyes) were retrospectively analyzed. Data from group 1 was used to generate a new linear regression formula for the GR based on the Haigis formula. Predicted implant powers based on the Shammas, Latkany, Savini, Seitz, Haigis-L, and GR based on either SRK/T or Haigis formulas and combined consensus methods were computed. Mean error, range, percent within ± 0.5 D, ± 1.0 D and -1.0/+0.5 D were calculated. In group 1, the original GR (SRK/T) formula produced higher mean values (-0.44 D) and lower percentage within ± 0.5 D (41%) compared with the other 5 formulas (-0.03 to -0.33 D; 65%-82%). A linear regression formula (-0.142*ΔSE +0.2) for the GR was derived as a correction factor added to the Haigis formula. Group 2 validated the 5 formulas again plus the GR (Haigis). All group 2 formulas gave excellent results with means ranging from -0.18 to -0.37 D, percentages with ± 0.5 D ranging from 55% to 78%, and percentages within -1.0/+0.5 D ranging from 85% to 100%. Consensus formulas produced mean error -0.30 D, 70% ± 0.5 D, 93% -1.0/+0.5 D with only 2 outliers at 0.6 D and -1.1 D. These six methods achieve high levels of IOL accuracy. The GR method works better based on the Haigis formula. Consensus calculations minimize both under- and overcorrections. 23490013 Influence of environment on the fatigue crack growth behaviour of 12% Cr steel. In the present work, the influence of different environments on the fatigue crack growth behaviour of 12% Cr steam turbine blade steel is investigated. Fatigue crack growth rates (FCGRs) in the near threshold regime are measured with ultrasonic fatigue testing technique. Fatigue tests are performed in vacuum, air and different aqueous environments with defined chloride and oxygen content. Furthermore, the influence of different stress ratios is investigated. It is found that crack propagation is not necessarily enhanced with increasing corrosiveness. In the aqueous environments, the FCGRs below 10(-8)m/cycle are lower than in air. The threshold stress intensity factor ranges are higher or equal. Observation of the fracture surfaces shows oxide formation and partly intergranular fracture for specimens tested in aqueous environments. Crack closure effects seem to be responsible for this unexpected behaviour. 23801631 Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Rearrangements of the MLL gene define a genetically distinct subset of acute leukemias with poor prognosis. Current treatment options are of limited effectiveness; thus, there is a pressing need for new therapies for this disease. Genetic and small molecule inhibitor studies have demonstrated that the histone methyltransferase DOT1L is required for the development and maintenance of MLL-rearranged leukemia in model systems. Here we describe the characterization of EPZ-5676, a potent and selective aminonucleoside inhibitor of DOT1L histone methyltransferase activity. The compound has an inhibition constant value of 80 pM, and demonstrates 37 000-fold selectivity over all other methyltransferases tested. In cellular studies, EPZ-5676 inhibited H3K79 methylation and MLL-fusion target gene expression and demonstrated potent cell killing that was selective for acute leukemia lines bearing MLL translocations. Continuous IV infusion of EPZ-5676 in a rat xenograft model of MLL-rearranged leukemia caused complete tumor regressions that were sustained well beyond the compound infusion period with no significant weight loss or signs of toxicity. EPZ-5676 is therefore a potential treatment of MLL-rearranged leukemia and is under clinical investigation. 23877799 Stroke in sub-Saharan Africa: An urgent call for prevention. In his Global Perspectives article, Dr. Chin(1) reported on the resource constraints related to the provision of stroke care in Africa. This was based on his experience visiting Mulago Hospital, Uganda's primary tertiary care referral center. He appropriately points out the very limited data related to stroke prevention and treatment in the region, and issued an urgent call for investment in optimizing preventive interventions. 23804322 A brief overview of some physical studies on the relaxation dynamics and förster resonance energy transfer of semiconductor quantum dots. This article highlights some physical studies on the relaxation dynamics and Förster resonance energy transfer (FRET) of semiconductor quantum dots (QDs) and the way these phenomena change with size, shape, and composition of the QDs. The understanding of the excited-state dynamics of photoexcited QDs is essential for technological applications such as efficient solar energy conversion, light-emitting diodes, and photovoltaic cells. Here, our emphasis is directed at describing the influence of size, shape, and composition of the QDs on their different relaxation processes, that is, radiative relaxation rate, nonradiative relaxation rate, and number of trap states. A stochastic model of carrier relaxation dynamics in semiconductor QDs was proposed to correlate with the experimental results. Many recent studies reveal that the energy transfer between the QDs and a dye is a FRET process, as established from 1/d(6) distance dependence. QD-based energy-transfer processes have been used in applications such as luminescence tagging, imaging, sensors, and light harvesting. Thus, the understanding of the interaction between the excited state of the QD and the dye molecule and quantitative estimation of the number of dye molecules attached to the surface of the QD by using a kinetic model is important. Here, we highlight the influence of size, shape, and composition of QDs on the kinetics of energy transfer. Interesting findings reveal that QD-based energy-transfer processes offer exciting opportunities for future applications. Finally, a tentative outlook on future developments in this research field is given. 23903780 Recognizing detachment-mode seafloor spreading in the deep geological past. Large-offset oceanic detachment faults are a characteristic of slow- and ultraslow-spreading ridges, leading to the formation of oceanic core complexes (OCCs) that expose upper mantle and lower crustal rocks on the seafloor. The lithospheric extension accommodated by these structures is now recognized as a fundamentally distinct "detachment-mode" of seafloor spreading compared to classical magmatic accretion. Here we demonstrate a paleomagnetic methodology that allows unequivocal recognition of detachment-mode seafloor spreading in ancient ophiolites and apply this to a potential Jurassic detachment fault system in the Mirdita ophiolite (Albania). We show that footwall and hanging wall blocks either side of an inferred detachment have significantly different magnetizations that can only be explained by relative rotation during seafloor spreading. The style of rotation is shown to be identical to rolling hinge footwall rotation documented recently in OCCs in the Atlantic, confirming that detachment-mode spreading operated at least as far back as the Jurassic. 23082005 Mineralocorticoid receptor antagonists and renal involvement in primary aldosteronism: opening of a new era. Primary aldosteronism (PA) is one of the commonest forms of curable hypertension, and use of the plasma aldosterone-to-renin ratio as a screening test has led to a more efficient identification of this condition. Both animal and human studies have indicated that PA is associated with a variety of cardiovascular and renal complications that reflect the capability of elevated aldosterone to induce tissue damage exceeding that induced by hypertension itself. Involvement of the kidney in PA is highly relevant because structural renal damage is associated with less favorable outcome, both in terms of blood pressure response to treatment and possibility to develop progressive renal failure. However, early involvement of the kidney in PA is characterized by functional changes that are largely reversible with treatment. Unilateral adrenalectomy or administration of mineralocorticoid receptor antagonists are the current options for treating an aldosterone-producing adenoma or idiopathic adrenal hyperplasia. Both treatments are effective in correcting hypertension and hypokalemia, and currently available information on their capability to prevent deterioration of renal function indicates that both surgery and medical treatment are of considerable value. 23887027 Numerical analysis of NMR diffusion measurements in the short gradient pulse limit. Pulsed gradient spin-echo (PGSE) NMR diffusion measurements provide a powerful technique for probing porous media. The derivation of analytical mathematical models for analysing such experiments is only straightforward for ideal restricting geometries and rapidly becomes intractable as the geometrical complexity increases. Consequently, in general, numerical methods must be employed. Here, a highly flexible method for calculating the results of PGSE NMR experiments in porous systems in the short gradient pulse limit based on the finite element method is presented. The efficiency and accuracy of the method is verified by comparison with the known solutions to simple pore geometries (parallel planes, a cylindrical pore, and a spherical pore) and also to Monte Carlo simulations. The approach is then applied to modelling the more complicated cases of parallel semipermeable planes and a pore hopping model. Finally, the results of a PGSE measurement on a toroidal pore, a geometry for which there is presently no current analytical solution, are presented. This study shows that this approach has great potential for modelling the results of PGSE experiments on real (3D) porous systems. Importantly, the FEM approach provides far greater accuracy in simulating PGSE diffraction data. 23814244 Use of a strontium-enriched calcium phosphate cement in accelerating the healing of soft-tissue tendon graft within the bone tunnel in a rabbit model of anterior cruciate ligament reconstruction. We investigated whether strontium-enriched calcium phosphate cement (Sr-CPC)-treated soft-tissue tendon graft results in accelerated healing within the bone tunnel in reconstruction of the anterior cruciate ligament (ACL). A total of 30 single-bundle ACL reconstructions using tendo Achillis allograft were performed in 15 rabbits. The graft on the tested limb was treated with Sr-CPC, whereas that on the contralateral limb was untreated and served as a control. At timepoints three, six, nine, 12 and 24 weeks after surgery, three animals were killed for histological examination. At six weeks, the graft-bone interface in the control group was filled in with fibrovascular tissue. However, the gap in the Sr-CPC group had already been completely filled in with new bone, and there was evidence of the early formation of Sharpey fibres. At 24 weeks, remodelling into a normal ACL-bone-like insertion was found in the Sr-CPC group. Coating of Sr-CPC on soft tissue tendon allograft leads to accelerated graft healing within the bone tunnel in a rabbit model of ACL reconstruction using Achilles tendon allograft. 23159710 Establishment of a triple co-culture in vitro cell models to study intestinal absorption of peptide drugs. In vitro cell culture models for studying oral drug absorption during early stages of drug development have become a useful tool in drug discovery and development, with respect to substance throughput and reproducibility. The aim of this study was to establish an in vitro cellular model based on human colon carcinoma Caco-2, mucus-producing HT29, and Raji B cells in order to design a model that more accurately mimics the small intestinal epithelial layer. Normal oriented model was set up by seeding co-cultures of Caco-2 and HT29 cells into Transwell filters and maintained under identical conditions following addition of Raji B to the basolateral chamber. Inverted model was set up seeding Caco-2 and HT29 cells on the basolateral chamber and then transferred in the Transwell device with the epithelial cells facing the basolateral chamber following Raji B addition to the apical compartment. Morphological differences on size and thickness of cell membranes were detected between the models studied by using fluorescence microscopy. On the triple co-culture models, cell membranes were increasing in size and thickness from the Caco-2 to Caco-2/HT29 and Caco-2/Raji B. Also, the nuclei seem to be larger than in the other studied models. Insulin permeation was higher on the triple co-culture model when compared to the Caco-2/HT29 co-culture model. Also, insulin permeation as mediated by nanoparticles and insulin solution permeation was higher on the normal oriented Caco-2/HT29/Raji B model as compared to the inverted model. Overall, our results suggest that Caco-2/HT29/Raji B triple co-culture normal oriented cellular model may be reliable to obtain a more physiological, functional, and reproducible in vitro model of the intestinal barrier to study protein absorption, both in solution and when delivered by nanocarriers. 23919763 Application of Exonuclease III-Aided Target Recycling in Flow Cytometry: DNA Detection Sensitivity Enhanced by Orders of Magnitude. DNA-functionalized microspheres in conjugation with flow cytometry detection are widely used for high-throughput nucleic acid assays. Although such assays are rapid and capable of simultaneous analysis of multiple nucleic acid analytes in a single test, the intrinsic limitation in sensitivity remains challenging. Here we report a simple, highly sensitive, and reproducible method based on Exonuclease III-aided target recycling technique applied for DNA quantification in flow cytometry. By loading a high density of Cy5-labeled probe DNA on microspheres (15 μm), we achieved hitherto unreported DNA detection limit of 3.2 pM in flow cytometry bead assay, enhancing the sensitivity by a factor of over 56.8 compared to the conventional direct hybridization bead assay. Furthermore, we evaluated multiplexing capability by simultaneous detections of two target DNAs with FAM and Cy5 reporter conjugated probes. Therefore, the novel Exonuclease III-amplified flow cytometry bead assay has great potential for the rapid, sensitive, and accurate detection and quantification of nucleic acids in clinical diagnosis and biomedical research. 23893639 Simultaneous identification of historical pigments Prussian blue and indigo in paintings by electrospray mass spectrometry. A new analytical protocol for identification of Prussian blue (PB) and indigo was proposed. Pigments useful for dating of artworks were detected by flow injection analysis/electrospray ionization mass spectrometry after alkalization of their suspensions in water, decomposition of PB to iron (III) hydroxide and hexacyanoferrate (II) and reduction of indigo to soluble leucoindigo using sodium dithionite. Limits of detection (PB 47 pg, indigo 59 pg) complied with requirements for analysis of microsamples of historical paintings. Potential of the developed method was proven in analysis of blue samples of two oil paintings from the 20(th) century. Further, PB was confirmed in a microsample from a painting of 'Crucifixion', St. Sebestian church on St. Hill in Mikulov, Czech Republic. Copyright © 2013 John Wiley & Sons, Ltd. 23639103 Phytochemical investigation on Atriplex halimus L. from Sardinia. In this study, we reported the phytochemical composition of the aerial parts of Atriplex halimus L. collected from Sardinia. This species is a halophytic shrub, typical of the Mediterranean Basin. Four new glycosylated flavonoids were isolated and their structures were elucidated on the basis of 1D, 2D NMR and MS spectra as 3',5'-dimethoxymyricetin-3-O-β-d-xylopyranosyl-7-O-fucopyranosyl-(1 → 3)-β-d-glucopyranoside (1), 3'-methoxyquercetin-7-O-β-d-fucopyranosyl-(1 → 3)-β-d-glucopyranosyl-3-O-β-xylopyranosyl-(1 → 4)-β-xylopyranoside (2), 3'-methoxyquercetin-7-O-α-l-rhamnopyranosyl-3-O-α-arabinofuranosyl-(1 → 6)-β-d-glucopyranoside (3) and 3',5'-dimethoxymyricetin-7-O-fucopyranosyl-(1 → 3)-β-d-glucopyranoside (4). LC-MS (n) analysis on the extract revealed the presence of other myricetin, quercetin, isorhamnetin glycosides, simple phenolic acids and esters. 23545425 Effect of high-fat diet on metabolic indices, cognition, and neuronal physiology in aging F344 rats. The prevalence of obesity and type 2 diabetes increases with age. Despite this, few studies have examined these conditions simultaneously in aged animals, and fewer studies have measured the impact of these conditions on brain function. Using an established animal model of brain aging (F344 rats), we investigated whether a high-fat diet (HFD) exacerbates cognitive decline and the hippocampal calcium-dependent afterhyperpolarization (a marker of age-dependent calcium dysregulation). Young and mid-aged animals were maintained on control or HFD for 4.5 months, and peripheral metabolic variables, cognitive function, and electrophysiological responses to insulin in the hippocampus were measured. HFD increased lipid accumulation in the periphery, although overt diabetes did not develop, nor were spatial learning and memory altered. Hippocampal adiponectin levels were reduced in aging animals but were unaffected by HFD. For the first time, however, we show that the AHP is sensitive to insulin, and that this sensitivity is reduced by HFD. Interestingly, although peripheral glucose regulation was relatively insensitive to HFD, the brain appeared to show greater sensitivity to HFD in F344 rats. 23884828 Do Akiskal & Mallya's affective temperaments belong to the domain of pathology or to that of normality? Kraepelin and Kretschmer hypothesized a continuum between full-blown affective pathology and premorbid temperaments. More recently Akiskal proposed a putative adaptive role for the four fundamental temperaments: the hyperthymic one characterized by emotional intensity, the cyclothymic one by emotional instability, the depressive one by a low energy level, and the irritable one by an excessive response to stimuli. Today it is widely debated whether affective temperaments belong to the domain of pathology or to that of normality. To make clear, by applying an integrated model, the position of affective temperaments within the continuum between normality and pathology. We reviewed several papers that explore the distribution of affective temperaments among the general population, and their involvement both in pathological conditions (somatic and psychiatric) and in human activities (professions and other occupations). Far from being intrinsically pathological conditions, affective temperaments seem to represent adaptive dispositions whose dysregulation can lead to full-blown affective pathology. All the temperamental types display some impact on people's lives by influencing personal skills and professional choices over a wide field of human activities. Affective temperaments are not problematic when they appear in a mild form, but when they occur in extreme form we have observed a gap between the hyperthymic temperament, which represents the most functional and desirable, and the cyclothymic, depressive, irritable and phobic anxious ones, which are closer to mood, anxiety, and substance use disorders, and imply a component of somatic diseases and life stressors. 23969530 Inhibition of MMP-9 using a pyrrole-imidazole polyamide reduces cell invasion in renal cell carcinoma. We investigated the clinical significance of the expression levels of matrix metalloproteinase 9 (MMP-9) in renal cell carcinoma (RCC). In addition, we validated the efficacy of pyrrole imidazole polyamide (PIP) targeting MMP-9 on inhibiting proliferation and invasion of RCC. We evaluated the expression levels of MMP-9 in 249 RCC specimens by immunostaining and analyzed the association between MMP-9 expression levels and cancer-specific survival. Furthermore, in a human RCC cell line, Caki-2, we tested the effect of a couple of PIPs targeting MMP-9 one recognizing an NF-κB binding site (MMP-9-NF-κB PIP) and another for the AP-1 binding site (MMP-9-AP-1 PIP) in the MMP-9 promoter. The expression levels of MMP-9, proliferative activity and invasive capability were tested by quantitative PCR, WST8 assay and Matrigel invasion assay, respectively. By immunostaining of the clinical specimens, strong MMP-9 staining was proven to be a significant predictor of poor prognosis for cancer-specific survival (P<0.01). In Caki-2 cells, MMP-9-NF-κB PIP significantly reduced the expression levels of MMP-9 mRNA and inhibited cell invasion, but did not affect the cell proliferation activity. On the other hand, no effect was found in MMP-9-AP-1 PIP on MMP-9 mRNA expression, cell proliferation and invasion. We confirmed the inhibitory effects of MMP-9-NF-κB PIP on the expression of MMP-9 and subsequent invasion of Caki-2 cells. Since it was clearly shown that high MMP-9 expression levels were associated with poor prognosis of RCC, MMP-9 is a potential candidate target for RCC treatment. Transcription therapy using a minor groove binder, such as NF-κB PIP, may be a potential therapeutic agent for RCC, although further investigation is required. 23862703 Ask the Experts: Increasing and maintaining productivity in the bioanalytical laboratory. Bioanalysis invited a selection of leading researchers to express their views on increasing and maintaining productivity in the bioanalytical laboratory. The topics discussed include the challenges of maintaining productivity when integrating new innovations into existing processes, the impact of automation on productivity, and how they effectively manage productivity in their own bioanalytical laboratories. Their enlightening responses provide a valuable insight into current methods of increasing productivity and the future of the constantly evolving bioanalytical laboratory. 23856077 What autoantibody tests should become widely available to help scleroderma diagnosis and management? Anti-Th/To autoantibodies have been recognized as serological markers of systemic sclerosis (SSc) for more than 20 years. However, validated immunoassay kits to test this specificity have not been commercially available. SSc autoantibodies are basically mutually exclusive and are associated with a certain subset of the disease and/or with organ involvement. Anti-Th/To are generally considered to be markers of the limited cutaneous type of SSc with the involvement of certain internal organs. The excellent correlation between anti-Rpp25 as detected by their novel chemiluminescent method and anti-Th/To as detected by immunoprecipitation suggest that the new assays may become widely available tests for clinicians in future and could help to clarify the clinical significance of anti-Th/To in SSc as well as other conditions over different races or countries. 23924215 Prevalence, correlates and pattern of Hepatitis B among antenatal clinic attenders in Yaounde-Cameroon: is perinatal transmission of HBV neglected in Cameroon? Few studies have evaluated the prevalence of HBV in the general Cameroonian population or among antenatal attendants. The aim of this study was to determine the prevalence, correlates and patterns of Hepatitis B surface antigen among pregnant women attending antenatal care in Yaounde-Cameroon. This was a cross-sectional multicenter study carried out in a referral hospital and two secondary hospitals in Yaounde, the capital of Cameroon. The study lasted 15 months (March 2011 to June 2012), and recruited 959 pregnant women. Patient recruitment was consecutive. The HBsAg was tested using the Monalisa HBsAg Ultra ELISA kit. Other hepatitis B markers were equally tested.We used the statistical package for social sciences (SPSS) version 14.0 software to conduct a quantitative analysis of the derived data. Simple descriptive statistics such as means, standard deviations, and proportions were used to describe the data. We tested for association in categorical variables using the chi-squared (chi2) test. The odds ratio (OR) and the corresponding 95% confidence intervals (95% CI) were used to summarise the strength of association between specific binary exposure and outcome variables. The level of statistical significance for the study was set at p < 0.05. The prevalence of hepatitis B infection (HBsAg) among antenatal clinic attenders in our setting was 7.7%. Amongst these women, just 5.4% were previously aware of their HBsAg status. The rate of HBV infectivity was high, with 28% of HBsAg positive women having evidence of HBeAg in their plasma, and up to 45.8% of these women lacking antibodies against hepatitis B e antigen (anti-HBe). About 41% of the pregnant women had had previous contact with HBV as evidenced by the positive status for anti-HBc.Just 2.7% of the pregnant women had previously been vaccinated against HBV. The mean age for HBsAg positivity in our setting was 26.9 +/-4.7 years, and the most affected age group was the 25 -- 29 years age group. There was no statistically significant association between age or other socio-demographic risk factors and HBsAg status. Numerous risk factors for HBV acquisition exists in our settings, but amongst these, only a history of a contact with hepatitis B infection was found to be significantly associated with HBsAg positivity (OR 1.63, 95% C.I 1.15-2.30). Finally, the coinfection rate of HBV/HIV was 0.74%. The prevalence of hepatitis B among pregnant women in Cameroon is high, and the pattern tends towards high infectivity and therefore increased risk of perinatal HBV transmission. These highlight the need to step up preventive efforts against hepatitis B infection and perinatal HBV transmission in our community. 23846241 Homogenization, sex, and differential motility predict spread of chronic wasting disease in mule deer in southern Utah. Chronic wasting disease (CWD) is an infectious prion disease that affects mule deer, along with other Cervids. It is a slow-developing, fatal disease which is rare in the free-ranging deer population of Utah. We present a sex-structured, spatial model for the spread of CWD over heterogeneous landscapes, incorporating both horizontal and environmental transmission pathways. To connect the local movement of deer to the regional spread of CWD, we use ecological diffusion with motility coefficients estimated from mule deer movement data. Ecological diffusion allows for aggregation of populations in desirable habitats and therefore allows for an interaction between density dependent disease transmission and landscape structure. The major innovation presented is use of homogenization to accelerate simulations of disease spread in southeastern Utah, from the La Sal Mountains near Moab to the Abajo Mountains near Monticello. The homogenized model provides accuracy while maintaining fidelity to small-scale habitat effects on deer distribution, including differential aggregation in land cover types with high residence times, with errors comparable to the order parameter measuring separation of small and large scales ([Formula: see text] in this case). We use the averaged coefficients from the homogenized model to explore asymptotic invasion speed and the impact of current population size on disease spread in southeastern Utah. 23862613 Clinical Relevance of Diagnosing COPD by Fixed Ratio or Lower Limit of Normal: A Systematic Review. Abstract Background: Different spirometric criteria in diagnosing COPD have been advocated by different groups, debilitating adequate diagnosis and treatment of COPD. We reviewed the clinical relevance of fixed ratio and lower limit of normal (LLN) in diagnosing COPD and explored if modifying factors may affect their clinical relevance. Methods: Two reviewers independently searched PubMed and Embase for papers that compared both criteria on any clinically relevant outcome, published before June 1st, 2012, without any language restriction. Two reviewers independently extracted the study characteristics, including study design, population characteristics and diagnostic criteria used, and summarized the results of clinical relevance. Study quality was assessed by scoring forms for bias and level of evidence. Results: Of 394 studies retrieved, 11 studies were included, with a median of 1,258 participants. Although both criteria appeared related with various clinically relevant outcomes, we were unable to prefer one criterion over the other, with various performances of the criteria for different outcomes. Should the criteria disagree on diagnosis, an alternative diagnosis should be suspected, in particular in those (elderly) with less severe airflow limitation for whom the LLN appears a better criterion. The fixed ratio appears to perform better in subjects with more severe airflow limitation. Conclusion: In diagnosing COPD, severity of airflow limitation appears an important factor for choosing whether the fixed ratio or LLN. Disagreement between the criteria is suggestive for an alternative diagnosis. Future studies on clinical relevance should further reveal the criterion of choice, in order to improve adequate diagnosis and consequent treatments. 23858419 Preventing Dental Caries in Children <5 Years: Systematic Review Updating USPSTF Recommendation. Screening and preventive interventions by primary care providers could improve outcomes related to early childhood caries. The objective of this study was to update the 2004 US Preventive Services Task Force systematic review on prevention of caries in children younger than 5 years of age. Searching Medline and the Cochrane Library (through March 2013) and reference lists, we included trials and controlled observational studies on the effectiveness and harms of screening and treatments. One author extracted study characteristics and results, which were checked for accuracy by a second author. Two authors independently assessed study quality. No study evaluated effects of screening by primary care providers on clinical outcomes. One good-quality cohort study found pediatrician examination associated with a sensitivity of 0.76 for identifying a child with cavities. No new trials evaluated oral fluoride supplementation. Three new randomized trials were consistent with previous studies in finding fluoride varnish more effective than no varnish (reduction in caries increment 18% to 59%). Three trials of xylitol were inconclusive regarding effects on caries. New observational studies were consistent with previous evidence showing an association between early childhood fluoride use and enamel fluorosis. Evidence on the accuracy of risk prediction instruments in primary care settings is not available. There is no direct evidence that screening by primary care clinicians reduces early childhood caries. Evidence previously reviewed by the US Preventive Services Task Force found oral fluoride supplementation effective at reducing caries incidence, and new evidence supports the effectiveness of fluoride varnish in higher-risk children. 23519966 In vitro stability of free and glucuronidated cannabinoids in blood and plasma following controlled smoked cannabis. Blood and plasma cannabinoid stability is important for test interpretation and is best studied in authentic rather than fortified samples. Low and high blood and plasma pools were created for each of 10 participants after they smoked a cannabis cigarette. The stabilities of Δ(9)-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC), 11-nor-9-carboxy-THC (THCCOOH), cannabidiol (CBD), cannabinol (CBN), THC-glucuronide, and THCCOOH-glucuronide were determined after 1 week at room temperature; 1, 2, 4, 12, and 26 (±2) weeks at 4 °C; and 1, 2, 4, 12, 26 (±2), and 52 (±4) weeks at -20 °C. Stability was assessed by Friedman test. Numbers of THC-glucuronide and CBD-positive blood samples were insufficient to assess stability. In blood, 11-OH-THC and CBN were stable for 1 week at room temperature, whereas THC and THCCOOH-glucuronide decreased and THCCOOH increased. In blood, THC, THCCOOH-glucuronide, THCCOOH, 11-OH-THC, and CBN were stable for 12, 4, 4, 12, and 26 weeks, respectively, at 4 °C and 12, 12, 26, 26, and 52 weeks at -20 °C. In plasma, THC-glucuronide, THC, CBN, and CBD were stable for 1 week at room temperature, whereas THCCOOH-glucuronide and 11-OH-THC decreased and THCCOOH increased. In plasma, THC-glucuronide, THC, THCCOOH-glucuronide, THCCOOH, 11-OH-THC, CBN, and CBD were stable for 26, 26, 2, 2, 26, 12, and 26 weeks, respectively, at 4 °C and 52, 52, 26, 26, 52, 52, and 52 weeks, respectively, at -20 °C. Blood and plasma samples should be stored at -20 °C for no more than 3 and 6 months, respectively, to assure accurate cannabinoid quantitative results. 23808813 Fludarabine, cyclophosphamide and rituximab plus granulocyte macrophage colony-stimulating factor as frontline treatment for patients with chronic lymphocytic leukemia. Fludarabine, cyclophosphamide and rituximab (FCR), the standard of care for the frontline treatment of patients with chronic lymphocytic leukemia (CLL), is associated with a high rate of neutropenia and infectious complications. Granulocyte macrophage colony-stimulating factor (GM-CSF) reduces myelosuppression and can potentiate rituximab activity. We conducted a clinical trial combining GM-CSF with FCR for frontline treatment of 60 patients with CLL. Eighty-six percent completed all six courses and 18% discontinued GM-CSF for toxicity: grade 3-4 neutropenia was observed in 30% of cycles, and severe infections in 16% of cases. The overall response rate was 100%. Both median event-free survival (EFS) and overall survival (OS) have not been reached. Longer EFS was associated with favorable cytogenetics. GM-CSF led to a lower frequency of infectious complications than in the historical FCR group, albeit similar EFS and OS. 23710562 Impact of osteoporosis and bone fracture on health-related quality of life in postmenopausal women. Background Osteoporosis is responsible for fragility fractures, which are associated with decreased physical and social function. The GINERISK study was a cross-sectional epidemiological study conducted in 4157 Spanish postmenopausal women initially diagnosed with osteoporosis according to WHO criteria within the last 2 years. Aim The aim of the study was to explore the impact of osteoporosis on health-related quality of life (HRQoL). Method Menopause-specific and generic HRQoL were assessed, respectively, with the specific Cervantes Scale and the generic SF-12v2 Health Survey. The impact of osteoporosis on HRQoL was ultimately evaluated in 3328 (80.1%) women who had measurements for both bone mineral densitometry (BMD) and HRQoL. Results Menopause-specific or generic HRQoL, respectively, were worse in women with current osteoporosis and prior osteoporotic bone fracture (BF) in comparison with current osteoporosis without BF or whose T-score had increased above -2.5 on the BMD after receiving osteoporosis drug therapy. Impaired HRQoL was found both in Spanish postmenopausal female populations and the Spanish general female population. Women with osteoporosis with BF had physical and mental summary component scores in the 20th and 30th percentiles, respectively, of the Spanish general population. Higher risk for cardiovascular death was also associated with greater HRQoL impairment. The use of selective estrogen receptor modulators in women with a BMD T-score ≤ -2.5 was associated with lower impact of osteoporosis on HRQoL, particularly in the domains of physical health and sexuality. Conclusion The HRQoL analysis results in this study demonstrated a loss of quality of life in postmenopausal women with osteoporosis and confirmed that this loss is greater in women with prior osteoporotic fracture. 23942220 Validity of the AHRQ Patient Safety Indicator for Postoperative Physiologic and Metabolic Derangement Based on a National Sample of Medical Records. The Agency for Healthcare Research and Quality Patient Safety Indicator (PSI) 10, "Postoperative Physiologic and Metabolic Derangement" (PPMD), uses administrative data to detect postoperative acute kidney injury (AKI) requiring dialysis and diabetes-related complications. We sought to evaluate the indicator's criterion validity. We conducted a retrospective cross-sectional study of hospitalization records flagged positive and negative by PSI 10 from a diverse set of 35 hospitals between February 1, 2006 and June 30, 2009. Trained nurse abstractors reviewed medical records. We determined the indicator's sensitivity, specificity, and positive and negative predictive values. Of 94 records flagged by PSI 10 (87 for AKI, 7 for diabetic complications, 1 for both), 69 (73%) involved an accurately coded event; 60 (64%; 95% CI, 46%-79%) represented true PPMD from a clinical perspective. Two of 8 records flagged for diabetic complications were true events. Nineteen false positives involved preoperative renal failure. Three of 230 records flagged negative (enriched with questionably negative records) represented true PPMD. The indicator's sensitivity was 66% (20%-94%), specificity 99.9% (99.5%-100%), and negative predictive value 99.9% (99.4%-100%). Considering dialysis access procedures tantamount to dialysis and excluding records with lower urinary tract obstruction might increase the sensitivity and positive predictive value to 98% (87%-100%) and 72% (50%-87%), respectively. PSI 10 mostly concerns AKI and currently has moderate criterion validity, which might improve with increased use of "present on admission" coding, abandonment of the diabetes criteria, and adjustments to the indicator specifications regarding dialysis access and urinary tract obstruction. 23916695 Interactions of serum cholesterol with anti-herpesvirus responses affect disease progression in clinically isolated syndromes. To investigate whether anti-herpesvirus antibodies are associated with serum cholesterol profiles in clinically isolated syndromes (CIS). Pre-treatment serum samples from 118 high-risk CIS patients were analyzed for IgG antibodies against cytomegalovirus (anti-CMV), Epstein Barr virus (EBV) viral capsid antigen (VCA) and EBV nuclear antigen-1 (EBNA-1). A lipid profile consisting of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) was obtained. Clinical and MRI assessments were obtained at baseline, 6, 12, and 24months after start of interferon-beta treatment. The study included 118 CIS patients (77 females, 41 males, 65.3% female; mean age: 28.1±SD 8.1years). Anti-EBV EBNA-1 antibody levels were associated with LDL-C (p=0.009) and TC (p=0.008) levels. Anti-CMV positivity status was associated with reduced time to relapse (p=0.006) and the greater number of relapses (p=0.009) in patients with high HDL-C. Anti-EBV VCA antibody levels were associated with greater number of new T2 lesions (p=0.002) and with increased brain atrophy (p<0.001) in patients with high LDL-C. Our results indicate that higher levels of anti-EBV EBNA-1 antibodies are associated with higher LDL-C and TC levels. Anti-CMV positive individuals have greater disease progression in the presence of higher HDL-C levels. Individuals with higher levels of anti-EBV VCA antibodies have greater progression on MRI measures in the presence of higher LDL-C. 23852578 Change of dynamics of raft-model membrane induced by amyloid-β protein binding. While the steady-state existence in the size and shape of liquid-ordered microdomains in cell membranes, the so-called "lipid rafts", still remain the subject of debate, glycosphingolipid-cholesterol rich regions in plasma membranes have been considered to have a function as platforms for signaling and sorting. In addition, recent spectroscopic studies show that the interaction between monosialoganglioside and amyloid beta (Aβ protein promotes the transition of Aβ from the native structure to the cross-beta fold in amyloid aggregates. However, there is few evidence on the dynamics of "lipid rafts" membranes. As the neutron spin-echo (NSE) technique is well known to detect directly slow dynamics of membrane systems in situ, by the combination of NSE and small-angle X-ray scattering we have studied the effect of the interaction between raft-model membrane and amyloid Aβ proteins on the structure and dynamics of a large uni-lamellar vesicle (LUV) consisting of monosialoganglioside-cholesterol-phospholipid ternary mixtures as a model of lipid-raft membrane. We have found that the interaction between the Aβ proteins and the model membrane at the liquid crystal phase significantly suppresses a bending-diffusion motion with a minor effect on the LUV structure. The present results would suggest a possibility of non-receptor-mediated disorder in signaling through a modulation of a membrane dynamics induced by the association of amyloidogenic peptides on a plasma membrane. 23883108 Migraine prevalence in patients with atrial septal defect. Patients with a patent foramen ovale have a high prevalence of migraine with aura (MA). However, whether patients with an atrial septal defect (ASD) have a high prevalence of migraine remains unclear. The present study aimed to determine the prevalence of migraine and its clinical characteristics in patients with ASD. Ninety-five patients (age >= 20 years) who had undergone percutaneous ASD closure responded to a questionnaire used by neurologists to diagnose migraine either with or without aura. We diagnosed migraine before ASD closure according to the criteria of the International Headache Society. The overall prevalence of migraine seemed to be higher in the present study than in the Japanese general population (24.2% vs. 9.4%, respectively). All patients with MA were female and significantly younger than those without migraine (p < 0.01). Our findings suggested that the susceptibility to the development of MA differs according to sex and age in patients with cardiac shunt. 23656997 Single-Nucleotide Polymorphisms in Adiponectin, AdipoR1, and AdipoR2 Genes: Insulin Resistance and Type 2 Diabetes Mellitus Candidate Genes. It has already been a decade and a half since the discovery of adiponectin and its role as an insulin sensitizer and only 7 years since its receptors, AdipoR1 and AdipoR2, were described. A single-nucleotide polymorphism (SNP) is a DNA sequence variation that affects only one nucleotide; it may vary from one population to another with different predisposing factors to diseases and other ailments. Once some of the effects of adiponectin and its receptors were known, it was not long until an effort was made to find the associations between specific SNPs of the genes of this hormone and its receptors as genetic risk factors for insulin resistance, type 2 diabetes mellitus, and metabolic syndrome, although these genes were investigated as possible candidates related to the development of these metabolic disorders. All of these possible associations were studied in different populations from France, Finland, the United Kingdom, North America, and Japan, showing hardly concluding results, and because of that it is highly controversial to directly associate one of the genes mentioned above to insulin resistance, type 2 diabetes mellitus, and metabolic syndrome. All of these inconsistencies lead to a review that summarizes the SNPs of the genes of adiponectin, AdipoR1, and AdipoR2 that are mostly related to insulin resistance syndrome, type 2 diabetes mellitus, and metabolic syndrome, although presenting the possible factors that should be taken into account to homogenize the results obtained until now. 23856410 Endowing carbon nanotubes with biological and biomedical properties by chemical modifications. The scope of nanotechnology is gaining importance in biology and medicine. Carbon nanotubes (CNTs) have emerged as a promising tool due to their unique properties, high specific surface area, and capacity to cross biological barriers. These properties offer a variety of opportunities for applications in nanomedicine, such as diagnosis, disease treatment, imaging, and tissue engineering. Nevertheless, pristine CNTs are insoluble in water and in most organic solvents; thereby functionalization of their surface is necessary to increase biocompatibility. Derivatization of CNTs also gives the possibility to conjugate different biological and bioactive molecules including drugs, proteins, and targeting ligands. This review focuses on the chemical modifications of CNTs that have been developed to impart specific properties for biological and medical purposes. Biomolecules can be covalently grafted or non-covalently adsorbed on the nanotube surface. In addition, the inner core of CNTs can be exploited to encapsulate drugs, nanoparticles, or radioactive elements. 23651626 Effects of combined antioxidant supplementation on human sperm motility and morphology during sperm manipulation in vitro. To evaluate the effect of antioxidant combinations on human sperm motility and morphologic normality during preparation and in vitro incubation to improve sperm quality for assisted reproductive technology (ART). Prospective study. Laboratory. Six fertile males, 21 to 25 years of age, after 3 days of sexual abstinence. Sperm retrieved from patients with normal fertility prepared and incubated in vitro in medium supplemented with taurine, cysteine, and/or glutathione. Motility indices, including motility (MOT), average path velocity (VAP), curvilinear velocity (VCL), straight-line velocity (VSL), and morphologic normality. Taurine supplementation during sperm preparation had no significant effects on motility or morphologic normality. However, when sperm was incubated for 24 hours under taurine-supplemented conditions, the rates of reduction in MOT, VAP, VCL, and VSL were statistically significantly decreased compared with taurine-free conditions. Morphologic normality was maintained, regardless of taurine treatment. The optimal taurine concentration for improving sperm motility and morphologic normality during preparation and in vitro incubation was 1 mM. Subsequently, combined treatment with 1 mM taurine, 1 mM cysteine, and 1 mM glutathione induced statistically significant synergistic effects on MOT, VAP, VCL, and VSL without any alteration of morphologic normality. Combined treatment with taurine, cysteine, and glutathione statistically significantly ameliorated the reduction in sperm motility during in vitro manipulation of human sperm. 23820955 Upregulated ZO-1 correlates with favorable survival of gastrointestinal stromal tumor. Zonula occludens-1 (ZO-1) is a membrane-scaffolding protein that plays an important role in maintaining tight-junction integrity, which is disrupted in many invasive cancers and intestinal diseases. However, the expression of ZO-1 in gastrointestinal stromal tumor (GIST) and its relationship with clinical characteristics of this disease remain poorly understood. In this study, immunohistochemical analysis using tissue microarray was employed to evaluate the expression of ZO-1 in GIST and to investigate the relationship between its expression and GIST prognosis. High ZO-1 expression was displayed in 71.8 % of GIST patients, which was related to tumor diameter (p < 0.05). The Kaplan-Meier method and log-rank test indicated that high ZO-1 expression, small tumor diameter, tumor position in the esophagus, and a borderline-to-intermediate tumor grade displayed significant correlations with longer survival of GIST patients. The data suggest that ZO-1 expression is correlated with malignant phenotypes of GIST and it may serve as a favorable prognostic factor for GIST. These results also support a role for ZO-1 as a tumor-suppressor gene in GIST. 23853116 Formation and geometrical control of polygon-like metal-coordination assemblies. Polygon-like [2+2]- and [3+3]-type metal complexes were prepared from dipyrrin dimers connected by acute-angled spacers. The electrical conduction depends strongly on the packing alignment of the compounds, revealing the presence of effective hopping pathways for holes with relatively high mobility up to 0.11 cm(2)  V(-1)  s(-1) along the aligned axis of [3+3]-type metal-bridged assemblies. These observations correlated with the geometrical control of the π-conjugated metal complexes in the cyclic structures, which enables their ordered arrangement in the assemblies. 23893076 Formation in aqueous solution of a non-oxido V(IV) complex with VN6 coordination. Potentiometric, ESI-MS, spectroscopic and computational characterization. The behaviour of the system formed by V(IV)O(2+) ion with all-cis-2,4,6-trimethoxycyclohexane-1,3,5-triamine (tmca) was characterized in aqueous solution through the combined application of electron paramagnetic resonance (EPR) and UV-Vis spectroscopy, electrospray ionization mass spectrometry (ESI-MS), pH-potentiometry and DFT methods. The formation of an unusual non-oxido [V(tmcaH-2)2] species with VN6 coordination, with the ligand in the bianionic form, was demonstrated. The geometry, EPR and UV-Vis spectra and electronic structure of [V(tmcaH-2)2] were simulated with Gaussian 09 and ORCA software and the results were compared with those of similar oxido and non-oxido vanadium(iv) species formed by other polyamine and polyol related ligands, such as 1,3,5-triamino-1,3,5-trideoxy-cis-inositol (taci), 1,3,5-trideoxy-1,3,5-tris(dimethylamino)-cis-inositol (tdci), cis-inositol (ino) and 1,3,5-trideoxy-1,3,5-trimethoxy-cis-inositol (tmci). The results indicate that V(IV)O(2+) species are formed in acid and weakly basic solution and that [V(tmcaH-2)2] is observed above pH 10. In the non-oxido complex, DFT calculations suggest that the two -NH2 groups are in trans position and that the pre-organization of the ligands favours the metal complexation and the formation of the hexa-coordinated species with VN6 coordination. 23626010 Aggressive variants of follicular cell derived thyroid carcinoma; the so called 'Real Thyroid Carcinomas'. The pathological diagnoses and classification schemes for thyroid carcinoma have changed over the past 20 years and continue to do so. New entities have been described and molecular analyses have suggested better characterisation and grouping of certain tumours. Because some of the lesions have been named differently by different authors, clinicians and patients may be confused as to what a specific patient's lesion represents. In this review, we discuss the thyroid tumours of follicular origin which are clinically unusual but important to recognise as their behaviour may be aggressive, they may not respond to radioiodine treatment and they may cause significant mortality. This paper describes these important but rare lesions, their pathological features, important clinicopathological correlations, molecular correlates and prognostic implications. 23837538 Selective and Sensitive Fluoride Detection through Alkyne Cruciform Desilylation. Desilylation of silylethynyl-substituted benzobisoxazole cruciforms can be achieved using stoichiometric amounts of fluoride, leading to a significant change in their UV-vis absorption and fluorescence. This response is observable at micromolar concentrations of fluoride, and, in the case of a triisopropylsilyl-substituted cruciform fluorophore, extraordinarily selective for fluoride over other small inorganic anions, including hydroxide, acetate, and phosphate. 23844637 Photodissociation of Anisole and Absolute Photoionization Cross-Section of the Phenoxy Radical. We have studied the photodissociation dynamics of anisole (C6H5OCH3) at 193 nm and determined the absolute photoionization cross-section of the phenoxy radical at 118.2 nm (10.486 eV) relative to the known cross-section of the methyl radical. Even at this energy, there is extensive fragmentation of the phenoxy radical upon photoionization, which is attributed to ionizing transitions that populate low-lying excited electronic states of the cation. For phenoxy radicals with less than ∼1 eV of internal energy, we find a cross-section for the production of the phenoxy cation of 14.8 ± 3.8 Mb. For radicals with higher internal energy, dissociative ionization is the dominant process, and for internal energies of ∼2.7-3.7 eV, we find a total cross-section (photoionization plus dissociative ionization) of 22.3 ± 4.1 Mb. The results are discussed relative to the recently reported photoionization cross-section of phenol. 23764028 In vivo, in vitro, and in silico studies suggest a conserved immune module that regulates malaria parasite transmission from mammals to mosquitoes. Human malaria can be caused by the parasite Plasmodium falciparum that is transmitted by female Anopheles mosquitoes. "Immunological crosstalk" between the mammalian and anopheline hosts for Plasmodium functions to control parasite numbers. Key to this process is the mammalian cytokine transforming growth factor-β1 (TGF-β1). In mammals, TGF-β1 regulates inducible nitric oxide (NO) synthase (iNOS) both positively and negatively. In some settings, high levels of NO activate latent TGF-β1, which in turn suppresses iNOS expression. In the mosquito, ingested TGF-β1 induces A. stephensi NOS (AsNOS), which limits parasite development and which in turn is suppressed by activation of the mosquito homolog of the mitogen-activated protein kinases MEK and ERK. Computational models linking TGF-β1, AsNOS, and MEK/ERK were developed to provide insights into this complex biology. An initial Boolean model suggested that, as occurs in mammalian cells, MEK/ERK and AsNOS would oscillate upon ingestion of TGF-β1. An ordinary differential equation (ODE) model further supported the hypothesis of TGF-β1-induced multiphasic behavior of MEK/ERK and AsNOS. To achieve this multiphasic behavior, the ODE model was predicated on the presence of constant levels of TGF-β1 in the mosquito midgut. Ingested TGF-β1, however, did not exhibit this behavior. Accordingly, we hypothesized and experimentally verified that ingested TGF-β1 induces the expression of the endogenous mosquito TGF-β superfamily ligand As60A. Computational simulation of these complex, cross-species interactions suggested that TGF-β1 and NO-mediated induction of As60A expression together may act to maintain multiphasic AsNOS expression via MEK/ERK-dependent signaling. We hypothesize that multiphasic behavior as represented in this model allows the mosquito to balance the conflicting demands of parasite killing and metabolic homeostasis in the face of damaging inflammation. 23642536 The role of exendin-4-conjugated superparamagnetic iron oxide nanoparticles in beta-cell-targeted MRI. Noninvasive targeted visualization of pancreatic beta cells or islets is becoming the focus of molecular imaging application in diabetes and islet transplantation studies, but it is currently unsuccessful due to the lack of specific beta cell biomarkers. Glucagon-like peptide 1 receptor (GLP-1R) is highly expressed in beta cells and considered as a promising target. We here developed a targeted superparamagnetic iron oxide (SPIO) nanoparticle using GLP-1 analog-exendin-4 which is conjugated to polyethylene glycol coated SPIO (PEG-SPIO). The results demonstrated that exendin-4 functionalized SPIO was able to specifically bind to and internalized by GLP-1R-expressing INS-1 cells, with the higher labeling efficiency than non-targeted nanoparticles. Notably, SPIO-exendin4 could differentially label islets in pancreatic slices or beta cell grafts in vitro. Systemic delivery of SPIO-exendin4 into nude mice bearing s.c. insulinomas (derived from INS-1 cells) leads to the accumulation of the nanoparticles in tumors, generating a strong magnetic resonance imaging contrast detectable by a clinical MRI scanner at field strength of 3.0 T, and the iron deposition in tumors was further confirmed by Prussian blue staining. Furthermore, preliminary biodistribution study indicated that SPIO-exendin4 had a tendency to accumulate in pancreas. Toxicity assessments demonstrated good biocompatibility in vivo. These results suggest that SPIO-exendin4 has potential as molecularly targeted imaging agents for in vivo imaging of insulinoma, and possibly for future beta cell imaging. 23431112 Effect of Ketoconazole on the Pharmacokinetics of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor ABT-384 and Its Two Active Metabolites in Healthy Volunteers: Population Analysis of Data from a Drug-Drug Interaction Study. ABT-384 [1-piperazineacetamide, N-[5-(aminocarbonyl) tricyclo[3.3.1.13,7]dec-2-yl]-α,α-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl]-,stereoisomer] is a potent and selective inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (HSD-1). ABT-384 has been shown to be safe and well tolerated in humans at doses up to 100 mg daily, and to fully inhibit both peripheral and brain HSD-1 at a dose of 2 mg daily. The effect of ketoconazole on the pharmacokinetics of ABT-384 and its two active metabolites, A-1331480 and A-847082, was investigated in healthy volunteers. When 10 mg of ABT-384 was coadministered with ketoconazole, ABT-384 exposures increased 18-fold for area under the plasma concentration-time curve from time 0 to infinity and 3.5-fold for Cmax. The results suggest that ABT-384 is a sensitive substrate of CYP3A. After ketoconazole coadministration, exposures of A-1331480 and A-847082 were also greatly increased. A population pharmacokinetic model was constructed for ABT-384 and its metabolites using NonMEM. A two-compartment model with three transit absorption compartments best described ABT-384 data. The model predicted a 69.3% decrease in ABT-384 clearance and 91.1% increase in the volume of distribution of ABT-384 in the presence of ketoconazole. A-1331480 was shown to be formation rate-limited and A-847082 was elimination rate-limited. Both metabolites were characterized by a one-compartment model with first-order rate constants of formation and elimination. Overall the model adequately captured the concentration-time profiles of ABT-384, A-1331480, and A-847082 in both ABT-384-alone and ketoconazole-coadministration conditions. Although ABT-384 exposures were greatly increased in the presence of ketoconazole, coadministration of ABT-384 with ketoconazole or other strong/moderate CYP3A inhibitors is not expected to contribute to any major clinical safety issues considering the favorable safety profile of ABT-384. 23923161 Finding a better way to support mentors. Students need high-quality mentoring to develop into safe, competent and compassionate nurses. NMC standards for mentors recognise the importance of the role and more support is being offered in difficult areas, such as failing unsatisfactory students. 23241390 PreCisIon: PREdiction of CIS-regulatory elements improved by gene's positION. Conventional approaches to predict transcriptional regulatory interactions usually rely on the definition of a shared motif sequence on the target genes of a transcription factor (TF). These efforts have been frustrated by the limited availability and accuracy of TF binding site motifs, usually represented as position-specific scoring matrices, which may match large numbers of sites and produce an unreliable list of target genes. To improve the prediction of binding sites, we propose to additionally use the unrelated knowledge of the genome layout. Indeed, it has been shown that co-regulated genes tend to be either neighbors or periodically spaced along the whole chromosome. This study demonstrates that respective gene positioning carries significant information. This novel type of information is combined with traditional sequence information by a machine learning algorithm called PreCisIon. To optimize this combination, PreCisIon builds a strong gene target classifier by adaptively combining weak classifiers based on either local binding sequence or global gene position. This strategy generically paves the way to the optimized incorporation of any future advances in gene target prediction based on local sequence, genome layout or on novel criteria. With the current state of the art, PreCisIon consistently improves methods based on sequence information only. This is shown by implementing a cross-validation analysis of the 20 major TFs from two phylogenetically remote model organisms. For Bacillus subtilis and Escherichia coli, respectively, PreCisIon achieves on average an area under the receiver operating characteristic curve of 70 and 60%, a sensitivity of 80 and 70% and a specificity of 60 and 56%. The newly predicted gene targets are demonstrated to be functionally consistent with previously known targets, as assessed by analysis of Gene Ontology enrichment or of the relevant literature and databases. 23661562 Multiple sclerosis lymphocytes upregulate A2A adenosine receptors that are antiinflammatory when stimulated. Multiple sclerosis (MS) is an autoimmune-mediated inflammatory disease characterized by multifocal areas of demyelination. Experimental evidence indicates that A2A adenosine receptors (ARs) play a pivotal role in the inhibition of inflammatory processes. The aim of this study was to investigate the contribution of A2A ARs in the inhibition of key pro-inflammatory mediators for the pathogenesis of MS. In lymphocytes from MS patients, A1 , A2A , A2B , and A3 ARs were analyzed by using RT-PCR, Western blotting, immunofluorescence, and binding assays. Moreover the effect of A2A AR stimulation on proinflammatory cytokine release such as TNF-α, IFN-γ, IL-6, IL-1β, IL-17, and on lymphocyte proliferation was evaluated. The capability of an A2A AR agonist on the modulation of very late antigen (VLA)-4 expression and NF-κB was also explored. A2A AR upregulation was observed in lymphocytes from MS patients in comparison with healthy subjects. The stimulation of these receptors mediated a significant inhibition of TNF-α, IFN-γ, IL-6, IL-1β, IL-17, and cell proliferation as well as VLA-4 expression and NF-κB activation. This new evidence highlights that A2A AR agonists could represent a novel therapeutic tool for MS treatment as suggested by the antiinflammatory role of A2A ARs in lymphocytes from MS patients. 23852883 False Accusations in an Investigative Context: Differences between Suggestible and Non-suggestible Witnesses. False sexual abuse allegations have spurred research on suggestibility, on the assumption that leading questions may produce false accusations. Most researchers, however, have not measured the likelihood that those who respond to suggestive questioning will take the next step and make a formal (false) accusation. The present study incorporates both aspects of abuse investigations: suggestibility (i.e., responsiveness to questions in a leading interview) and false accusations (i.e., signing a formal complaint against an innocent suspect). Participants (N = 129) were observed in a laboratory session and then interviewed twice about their experiences by an interviewer who suggested that the laboratory assistant had behaved inappropriately. Although only 17% of the participants were suggestible, 39% agreed to sign the complaint. Suggestible participants were significantly more likely to make a false accusation than were non-suggestible participants. However, because of the low rate of suggestibility, most false accusations were made by non-suggestible participants. Implications for the legal system are discussed. Copyright © 2013 John Wiley & Sons, Ltd. 23798309 Electronic structure and optical properties of Cu-doping and Zn vacancy impurities in ZnTe. The geometric structures of perfect ZnTe, that with Zn vacancy (Zn0.875Te), and Cu-doped ZnTe (Zn0.875Cu0.125Te) were optimized using the pseudopotential plane wave (PP-PW) method based on the density functional theory (DFT) within generalized gradient approximation (GGA). The cohesive energy, band structure, density of states, and Mulliken populations were calculated and discussed in detail. On the other hand, an accurate calculation of linear optical functions (the dielectric function, refraction index, reflectivity, conductivity function, and energy-loss spectrum) was performed. The results demonstrated that compared to the perfect ZnTe, the lattice parameters of Zn0.875Te and Zn0.875Cu0.125Te were changed and the cell volumes decreased to some extent due to the vacancy and introduction of impurity. A vacancy acceptor level and an acceptor impurity level were produced in Zn0.875Te and Zn0.875Cu0.125Te, respectively. By comparison, Cu doping in the ZnTe system is relatively stable while the monovacancy system is not. 23939930 Synthesis of Zwitterionic Cobaltocenium Borate and Borata-alkene Derivatives from a Borole-Radical Anion. Chemical single-electron reduction of 1-mesityl-2,3,4,5-tetraphenylborole (3) gave a stable radical anion [CoCp*2 ][3] as shown in earlier investigations. Herein, we present the reaction of [CoCp*2 ][3] with the 2,2,6,6-tetramethylpiperidine-N-oxyl radical (TEMPO), a common radical trap. Instead of radical recombination, the reaction proceeds through a redox pathway involving oxidation of the borole radical anion combined with reduction of TEMPO. This electron-transfer process is accompanied by a deprotonation reaction of the cobaltocenium counterion by the base TEMPO(-) to give TEMPO-H and a neutral cobalt(I) fulvene complex (7). The latter was not observed directly during the reaction, because it instantaneously reacts as a nucleophile attacking at the boron center of the in situ generated borole 3 to give the borate 6. However, 7 was synthesized independently by deprotonation of [CoCp*2 ][PF6 ]. In addition, the obtained zwitterionic cobaltocenium borate 6 undergoes a photolytic rearrangement to form the borata-alkene derivative 9 that thermally transforms to the chiral cobaltocenium borate 12. Our investigations are based on spectroscopic evidence, X-ray crystallography, elemental analysis, as well as DFT calculations. 23434471 Diagnostic impact of baseline cerebral blood flow in patients with acute ischemic stroke prior to intravenous recombinant tissue plasminogen activator therapy. To determine whether severe cerebral perfusion defects measured by SPECT prior to rt-PA therapy attribute to severe intracerebral hemorrhage (SICH). We measured baseline cerebral blood flow (CBF) using technetium-99m-labeled hexamethylpropyleneamine oxime (99mTc-HMPAO) SPECT qualitatively prior to rt-PA therapy, in 52 consecutive patients (range 38-93 years). The degree and extent of the asymmetry of local CBF were analyzed semi-quantitatively. We did not administrate rt-PA in patients with severe perfusion defects. Clinical outcome and the incidence of SICH were studied. Three (5.8%) patients had severe perfusion defects that were undetected by CT and/or DWI. The other 49 (94.2%) patients had mild perfusion defects. The asymmetry of local CBF was 0.08±0.08 (n=3) and 0.3±0.15 (n=49) in the two groups, respectively. The percentages of the ipsilateral hemisphere in which perfusion was impaired severely were 17.5±9.5% (n=3) and 0.43±0.87% (n=49). Two patients were found petechial hemorrhage, but there was no patient who developed SICH in the former group following conventional antithrombotic therapy. In the latter group, SICH occurred in 1/49 (2.0%) patient following rt-PA therapy. These results suggest that rt-PA therapy for patients with severe cerebral perfusion defects may cause SICH and baseline CBF may contribute to identify patients at high risk for SICH after intravenous rt-PA therapy. 23927070 Resolution of the plantar hyperkeratosis of pachyonychia congenita during chemotherapy for Ewing's sarcoma. A fifteen-year-old female with pachyonychia congenita (PC) confirmed by genetic testing presented with pain and a localized subcutaneous swelling on her right back. Biopsy confirmed Ewing's sarcoma of the posterior 10(th) rib. Preoperative tumor reduction chemotherapy was commenced as per Euro EWING 99 protocol with vincristine, ifosfamide, doxorubicin and etoposide (VIDE). Ifosfamide was subsequently replaced by cyclophosphamide as per protocol due to potential renal tubule toxicity (VCDE) (Juergens et al, 2006) (Table 1). Surgical resection was performed followed by radiotherapy to the primary site. This article is protected by copyright. All rights reserved. 23219887 Structural determinants of substrate specificity in aldehyde dehydrogenases. Within the aldehyde dehydrogenase (ALDH) superfamily, proteins belonging to the ALDH9, ALDH10, ALDH25, ALDH26 and ALDH27 families display activity as ω-aminoaldehyde dehydrogenases (AMADHs). These enzymes participate in polyamine, choline and arginine catabolism, as well as in synthesis of several osmoprotectants and carnitine. Active site aromatic and acidic residues are involved in binding the ω-aminoaldehydes in plant ALDH10 enzymes. In order to ascertain the degree of conservation of these residues among AMADHs and to evaluate their possible relevance in determining the aminoaldehyde specificity, we compared the known amino acid sequences of every ALDH family that have at least one member with known crystal structure, as well as the electrostatic potential surface of the aldehyde binding sites of these structures. Our analyses showed that four or three aromatic residues form a similar "aromatic box" in the active site of the AMADH enzymes, being the equivalents to Phe170 and Trp177 (human ALDH2 numbering) strictly conserved in all of them, which supports their relevance in binding the aminoaldehyde by cation-π interactions. In addition, all AMADHs exhibit a negative electrostatic potential surface in the aldehyde-entrance tunnel, due to side-chain carboxyl and hydroxyl groups or main-chain carbonyl groups. In contrast, ALDHs that have non-polar or negatively charged substrates exhibit neutral or positive electrostatic potential surfaces, respectively. Finally, our comparative sequence analyses revealed that the residues equivalent to Asp121 and Phe170 are highly conserved in many ALDH families irrespective of their substrate specificity-suggesting that they perform a role in catalysis additional or different to binding of the substrate-and that the positions Met124, Cys301, and Cys303 are hot spots changed during evolution to confer aldehyde specificity to several ALDH families. 23471292 New dedicated bifurcated silicone stent placement for stenosis around the primary right carina. Silicone stenting has been widely used to palliate respiratory symptoms in patients suffering from airway stenosis. Although many types and shapes of stents have been developed, there is no ideal stent for stenosis around the carina between the bronchus to the right upper lobe and the bronchus intermedius (primary right carina). The purpose of this study was to evaluate the feasibility, efficacy, and safety of a new silicone stent designed for treating airway stenosis around the primary right carina. We recruited 16 patients with suspected stenosis around the primary right carina. Ten of the patients met the inclusion criteria for inserting the study stent. All stenting procedures were performed with a rigid and flexible bronchoscope under general anesthesia. The study stent could be mounted successfully on the primary right carina in all 10 patients. Five patients underwent stenting using only the new stent, and the other five underwent stenting with it on the primary right carina and a silicone Y stent on the main carina. The dyspnea index improved in eight of the 10 patients, including one who was mechanically ventilated. Early complications developed in three patients (temporary pneumonia in two and retention of secretions in one), and late complications occurred in two patients (granuloma formation in one and hemoptysis in one). Stent placement with the new silicone stent designed to fit on the primary right carina is feasible, effective, and acceptably safe. UMIN-Clinical Trials Registry; No.: UMIN000001776; URL: www.umin.ac.jp/ctr. 23711415 A viral factor, CpBV15α, interacts with a translation initiation factor, eIF2, to suppress host gene expression at a post-transcriptional level. An endoparasitoid wasp, Cotesia plutellae, possesses its specific symbiotic virus called C. plutellae bracovirus (CpBV) and parasitizes young larvae of Plutella xylostella. CpBV encodes CpBV15α, which was previously shown to interfere with host protein translation. In vivo transient expression of CpBV15α induced a significant decrease in a storage protein level without its transcriptional level change. In vitro translation assay using rabbit reticulocyte lysate showed that CpBV15α suppressed translation efficiency of mRNAs extracted from fat body of P. xylostella. Transient expression of CpBV15α in nonparasitized P. xylostella suppressed humoral immunity and development to pupal and adult stages. Immunoprecipitation (IP) of CpBV15α co-precipitated eIF2 and eIF2B (a guanine nucleotide exchange factor of eIF2) in parasitized P. xylostella. Additionally, IP of eIF2 co-precipitated CpBV15α as well as eIF2B and eIF5 in parasitized larvae. IP with eIF5 antibody showed that relative amount of eIF2 bound to eIF5 was much decreased in parasitized larvae, while significant amount of eIF2 was bound to CpBV15α. These results suggest that CpBV15α inhibits some host mRNA translation by sequestering eIF2. 23925040 Vanadium-catalyzed deoxydehydration of glycols. A survey of several metavandate (VO3(-)) and chelated dioxovanadium derivatives shows that tetrabutylammonium dioxovanadium(v)dipicolinate most effectively catalyzes the deoxydehydration (DODH) of glycols to olefins in moderate to excellent yields with triphenylphosphine or sodium sulfite as reductants. 23959599 Flavopiridol can be safely administered using a pharmacologically derived schedule and demonstrates activity in relapsed and refractory Non-Hodgkin's Lymphoma. Flavopiridol is a broad cyclin-dependent kinase inhibitor (CDKI) that induces apoptosis of malignant lymphocytes in vitro and in murine lymphoma models. We conducted a phase I dose-escalation study to determine the maximum tolerated dose (MTD) for single-agent flavopiridol administered on a pharmacokinetically derived hybrid dosing schedule to patients with relapsed and refractory non-Hodgkin's lymphoma. Dose was escalated independently in one of four cohorts: indolent B-cell (cohort 1), mantle cell (cohort 2), intermediate grade B-cell including transformed lymphoma (cohort 3), and T-/NK-cell excluding primary cutaneous disease (cohort 4). Forty-six patients were accrued. Grade 3 or 4 leukopenia was observed in the majority of patients (60%), but infection was infrequent. Common non-hematologic toxicties included diarrhea and fatigue. Biochemical tumor lysis was observed in only 2 patients, and no patients required hemodialysis for its management. Dose escalation was completed in two cohorts (indolent and aggressive B-cell). Dose-limiting toxicities were not observed, and the MTD was not reached in either cohort at the highest dose tested (50 mg/m(2) bolus + 50 mg/m(2) continuous infusion weekly for 4 consecutive weeks of a 6 week cycle). Clinical benefit was observed in 26% of 43 patients evaluable for response, including 14% with partial responses (2 mantle cell, 3 indolent B-cell, and 1 diffuse large B-cell). The single-agent activity of this first-generation CDKI suggests that other agents in this class merit further study in lymphoid malignancies, both alone and in combination. 23817677 Impact of chronic respiratory symptoms in a rural area of sub-Saharan Africa: an in-depth qualitative study in the Masindi district of Uganda. Chronic obstructive pulmonary disease (COPD), once regarded as a disease of developed countries, is now recognised as a common disease in low- and middle-income countries. No studies have been performed to examine how the community in resourcepoor settings of a rural area in sub-Saharan Africa lives with chronic respiratory symptoms. To explore beliefs and attitudes concerning health (particularly respiratory illnesses), use of biomass fuels, tobacco smoking, and the use of health services. A qualitative study was undertaken in a rural area of Masindi district in Uganda, using focus group discussions with 10-15 members of the community in 10 randomly selected villages. Respiratory symptoms were common among men, women, and children. In several communities respiratory symptoms were stigmatised and often associated with tuberculosis. Almost all the households used firewood for cooking and the majority cooked indoors without any ventilation. The extent of exposure to tobacco and biomass fuel smoke was largely determined by their cultural tradition and gender, tribal origin and socioeconomic factors. Many people were unaware of the damage to respiratory health caused by these risk factors, notably the disproportionate effect of biomass smoke in women and children. The knowledge of chronic respiratory diseases, particularly COPD, is poor in the rural community in sub-Saharan Africa. The lack of knowledge has created different beliefs and attitudes concerning respiratory symptoms. Few people are aware of the relation between smoke and respiratory health, leading to extensive exposure to mostly biomass-related smoke. 23709272 Inferior vena cava thrombosis following endovascular repair of acute aortocaval fistula: a word of caution. Acute aortocaval fistula (ACF) is a rare, life-threatening condition with a complex clinical presentation, making prompt diagnosis challenging. Primary ACF is believed to be associated with abdominal aortic aneurysm (AAA) rupture in 80% of the cases. Thrombotic complications following endovascular repair for acute ACF are rare and less widely recognized. A high index of suspicion is required for diagnosis of this postoperative complication. We describe a novel, staged management approach using endovascular aortic stent grafts (Gore Excluder; Flagstaff, CA) in both the abdominal aorta and the inferior vena cava (IVC) in a patient with a ruptured AAA and acute ACF with subsequent acute IVC thrombosis. 23913791 Probing a Gas/Liquid Acid-Base Reaction by X-ray Photoelectron Spectroscopy. A mechanistic study: In a Brønsted acid/base reaction, gaseous triflic acid (OTfH) transfers its proton to the basic Cl(-) anion of the ionic liquid [C8 C1 Im]Cl forming volatile HCl and the IL [C8 C1 Im][TfO]. This anion exchange reaction is monitored in the near-surface region quantitatively by X-ray photoelectron spectroscopy as a function of time (see picture; BE=binding energy). 23480482 Isolation of two new Dehalococcoides mccartyi strains with dissimilar dechlorination functions and their characterization by comparative genomics via microarray analysis. Microbial reductive dechlorination of trichloroethene (TCE) in groundwater often results in the accumulation of dichloroethenes (DCEs). Dehalococcoides mccartyi (Dhc) are the only known bacteria capable of dechlorination beyond DCE to non-toxic ethene. In this study, two newly isolated Dhc strains (11a and 11a5) with dissimilar functional abilities are described. Strain 11a reductively dechlorinates TCE, 1,1-DCE, cis-DCE, trans-DCE, and vinyl chloride (VC) to ethene, while strain 11a5 dechlorinates TCE and all three DCE isomers only to VC. Each of these dechlorination reactions are coupled to growth by these strains. The VC dechlorination rate of strain 11a occurs at a rate of 258 nmol per min per mg of protein, about two times faster than previously reported stains. Strain 11a possesses the vcrA gene while strain 11a5 contains the tceA gene. Strains 11a and 11a5 share 100% 16S rRNA gene sequence identity with previously sequenced Dhc strains BAV1 and CBDB1, placing it within the Pinellas subgroup, and 85.4% and 89.5% of all genes present in the CBDB1 and BAV1 genomes were detected in strains 11a and 11a5, respectively, using a custom-designed microarray targeting four sequenced Dhc strains. Genes that were not detected in strains 11a and 11a5 are mostly within the high plasticity regions or integrated elements of the sequenced strains. This study reports the functional description and comparative genomics of two additional Dhc isolates and provides evidence that the observed functional incongruence between the activity and core genome phylogenies of Dhc strains is likely driven by the horizontal transfer of key reductive dehalogenase-encoding genes. 23773141 Cluster headache: conventional pharmacological management. Cluster headache pain is very intense, usually increases in intensity very rapidly from onset, and attacks are often frequent. These clinical features result in significant therapeutic challenges. The most effective pharmacological treatment options for acute cluster attack include subcutaneous sumatriptan, 100% oxygen, and intranasal zolmitriptan. Subcutaneous or intramuscular dihydroergotamine and intranasal sumatriptan are additional options. Transitional therapy is applicable mainly for patients with high-frequency (>2 attacks per day) episodic cluster headache, and options include short courses of high-dose oral corticosteroids, dihydroergotamine, and occipital nerve blocks with local anesthetic and steroids. Prophylactic therapy is important both for episodic and chronic cluster headache, and the main options are verapamil and lithium. Verapamil is drug of first choice but may cause cardiac arrhythmias, and periodic electrocardiograms (EKGs) during dose escalation are important. Many other drugs are also in current use, but there is an insufficient evidence base to recommend them. 23230826 Functional characterization of nonmetastatic paraganglioma and pheochromocytoma by (18) F-FDOPA PET: focus on missed lesions. To evaluate the clinical value of (18) F-fluorodihydroxyphenylalanine ((18) F-FDOPA) PET in relation to tumour localization and the patient's genetic status in a large series of pheochromocytoma/paraganglioma (PHEO/PGL) patients and to discuss in detail false-negative results. A retrospective study of PGL patients who were investigated with (18) F-FDOPA PET or PET/CT imaging in two academic endocrine tumour centres was conducted (La Timone University Hospital, Marseilles, France and National Institutes of Health (NIH), Bethesda, MD, USA). One hundred sixteen patients (39·7% harbouring germline mutations in known disease susceptibility genes) were evaluated for a total of 195 PHEO/PGL foci. (18) F-FDOPA PET correctly detected 179 lesions (91·8%) in 107 patients (92·2%). Lesion-based sensitivities for parasympathetic PGLs (head, neck, or anterior/middle thoracic ones), PHEOs, and extra-adrenal sympathetic (abdominal or posterior thoracic) PGLs were 98·2% [96·5% for Timone and 100% for NIH], 93·9% [93·8 and 93·9%] and 70·3% [47·1 and 90%] respectively (P < 0·001). Sympathetic (adrenal and extra-adrenal) SDHx-related PGLs were at a higher risk for negative (18) F-FDOPA PET than non-SDHx-related PGLs (14/24 vs 0/62, respectively, P < 0·001). In contrast, the risk of negative (18) F-FDOPA PET was lower for parasympathetic PGLs regardless of the genetic background (1/90 in SDHx vs 1/19 in non-SDHx tumours, P = 0·32). (18) F-FDOPA PET failed to detect two head and neck PGLs (HNPGL), likely due to their small size, whereas most missed sympathetic PGL were larger and may have exhibited a specific (18) F-FDOPA-negative imaging phenotype. (18) F-FDG PET detected all the missed sympathetic lesions. (18) F-FDOPA PET appears to be a very sensitive functional imaging tool for HNPGL regardless of the genetic status of the tumours. Patients with false-negative tumours on (18) F-FDOPA PET should be tested for SDHx mutations. 23246516 Torching the Haystack: modelling fast-fail strategies in drug development. By quickly clearing the development pipeline of failing or marginal products, fast-fail strategies release resources to focus on more promising molecules. The Quick-Kill model of drug development demonstrates that fast-fail strategies will: (1) reduce the expected time to market; (2) reduce expected R&D costs; and (3) increase R&D productivity. This paper outlines the model and demonstrates the impact of fast-fail strategies. The model is illustrated with costs and risks data from pharmaceutical and biopharmaceutical companies. 23958464 miR-128 and its target genes in tumorigenesis and metastasis. MicroRNAs (miRNAs) are a class of endogenous, non-coding, 18-24 nucleotide length single-strand RNAs that could modulate gene expression at post-transcriptional level. Previous studies have shown that miR-128 enriched in the brain plays an important role in the development of nervous system and the maintenance of normal physical functions. Aberrant expression of miR-128 has been detected in many types of human tumors and its validated target genes are involved in cancer-related biological processes such as cell proliferation, differentiation and apoptosis. In this review, we will summarize the roles of miR-128 and its target genes in tumorigenesis and metastasis. 23818171 Lifting della repression of Arabidopsis seed germination by nonproteolytic gibberellin signaling. DELLA repression of Arabidopsis (Arabidopsis thaliana) seed germination can be lifted either through DELLA proteolysis by the ubiquitin-proteasome pathway or through proteolysis-independent gibberellin (GA) hormone signaling. GA binding to the GIBBERELLIN-INSENSITIVE DWARF1 (GID1) GA receptors stimulates GID1-GA-DELLA complex formation, which in turn triggers DELLA protein ubiquitination and proteolysis via the SCF(SLY1) E3 ubiquitin ligase and 26S proteasome. Although DELLA cannot be destroyed in the sleepy1-2 (sly1-2) F-box mutant, long dry after-ripening and GID1 overexpression can relieve the strong sly1-2 seed dormancy phenotype. It appears that sly1-2 seed dormancy results from abscisic acid (ABA) signaling downstream of DELLA, since dormant sly1-2 seeds accumulate high levels of ABA hormone and loss of ABA sensitivity rescues sly1-2 seed germination. DELLA positively regulates the expression of XERICO, an inducer of ABA biosynthesis. GID1b overexpression rescues sly1-2 germination through proteolysis-independent DELLA down-regulation associated with increased expression of GA-inducible genes and decreased ABA accumulation, apparently as a result of decreased XERICO messenger RNA levels. Higher levels of GID1 overexpression are associated with more efficient sly1 germination and increased GID1-GA-DELLA complex formation, suggesting that GID1 down-regulates DELLA through protein binding. After-ripening results in increased GA accumulation and GID1a-dependent GA signaling, suggesting that after-ripening triggers GA-stimulated GID1-GA-DELLA protein complex formation, which in turn blocks DELLA transcriptional activation of the XERICO inhibitor of seed germination. 23417276 Treatment of huntington disease. Many pharmacological agents have been utilized in the treatment of Huntington disease (HD). Several excellent reviews about the treatment of HD are available. Formal treatment guidelines are however lacking. This is mainly the result of limited evidence available in the literature. Further, available treatment studies are frequently hard to compare due to variable outcomes/instruments used, differences in the study population, and confounding effects of complex medication regimens. Generally speaking, the treatment paradigm for an HD patient will depend on the constellation of 3 main clinical domains affected in HD: motor, behavioral/psychiatric, and cognitive. Symptoms within each of these domains remain dynamic throughout the course of HD. It is therefore necessary to monitor patients clinically and adjust drugs accordingly as the disease progresses. The most commonly used chorea drugs are antipsychotics and tetrabenazine (TBZ). Antipsychotic drugs are preferred in patients with coexistent psychiatric/behavioral comorbidities as well as in the presence of depression. Amantadine may be considered in the treatment of chorea, but data supporting its effectiveness remain conflicting. Selective serotonin reuptake inhibitors (SSRIs) are the treatment of choice for irritability and obsessive-compulsive behaviors associated with HD. Antipsychotic agents and antiepileptic mood stabilizers may be used as add-on therapies. There is very limited evidence for the treatment of cognitive impairment associated with HD. Each drug used in treatment of HD has a potential for causing significant side effects. It is, therefore, critical to assess the risk-benefit ratio on an individual basis, and carefully monitor patients throughout the course of treatment. Non-pharmacological and surgical treatment strategies for HD have not been systematically explored. Despite the lack of evidence, behavioral interventions, as well as physical, occupational, and speech therapies may provide additional benefits to a wide spectrum of disabilities associated with HD. 23138114 6-Mercaptopurine-induced Recurrent Acute Pancreatitis in Children With Acute Lymphoblastic Leukemia/Lymphoma. Two children with acute lymphoblastic leukemia/lymphoma developed recurrent acute pancreatitis during treatment; the etiology was presumed to be secondary to 6-mercaptopurine (6MP). Both had no further attacks after discontinuation of 6MP. Acute pancreatitis secondary to 6MP is extremely rare in acute leukemia/lymphoma although it has been reported in patients with other conditions like inflammatory bowel disease; the reason for this difference is not clearly understood. 23892415 EGFR activating mutations detected by different PCR techniques in Caucasian NSCLC patients with CNS metastases: short report. EGFR mutation testing has become an essential determination to decide treatment options for NSCLC. The mutation analysis is often conducted in samples with low percentage of tumour cells from primary tumour biopsies. There is very little evidence that samples from metastatic tissues are suitable for EGFR testing. We had evaluated the frequency of EGFR mutations with three highly sensitive PCR techniques in formalin-fixed, paraffin-embedded samples of 143 NSCLC patients with central nervous system (CNS) metastases. 32 corresponding primary tumours were also examined. We used PCR followed by DNA fragments length analysis (FLA), ASP-PCR and PNA-LNA PCR clamp techniques. We found 9 (6.29 %) EGFR gene mutations in CNS samples: 3 (2.1 %) in exon 19 and 6 (4.2 %) in exon 21. The full concordance between CNS metastases and primary tumour samples was observed. PCR followed by DNA-FLA and PNA-LNA PCR clamp were sensitive enough to detect exon 19 deletions. Two mutations in exon 21 were detected by ASP-PCR only, one L858R substitution was detected only by PNA-LNA PCR clamp. With respect to sensitivity, PCR followed by DNA-FLA achieved a level of detection of at least 10 % of mutated DNA for exon 19 deletion, as for ASP-PCR it was at least 5 % of mutated DNA for L858R substitution. Higher sensitivity of 1 % of mutated DNA was achieved by PNA-LNA PCR clamp technique for both mutations. The use of different methodological techniques authenticates the negative result of molecular tests. 23937094 Mannan-Conjugated Adenovirus Enhanced Gene Therapy Effects on Murine Hepatocellular Carcinoma Cells in Vitro and in Vivo. The incidence of advanced hepatocellular carcinoma (HCC) is increasing worldwide, and its prognosis is extremely poor. For some patients for whom surgical treatments are not appropriate, one can only rely on chemotherapy. In the conventional chemotherapy, side effects usually occurred in most cases due to high toxicity levels. Moreover, the development of drug resistance toward chemotherapeutic agents often prevents the successful long-term use of chemotherapy for HCC. Gene therapy represents the exciting biotechnological advance that may revolutionize the conventional fashion of cancer treatment. Overexpression of phosphatase and tensin homologue (PTEN) in cancer cells carrying deletion/mutant type of it can induce the apoptosis of cancer cells and inhibit cell proliferation. In this work, in order to make full use of the high transfectivity of adenovirus, we managed to conjugate the polysaccharide mannan (polymannose) to the surface of the adenovirus chemically under appropriate oxidizing conditions to prepare the mannan-modified adenovirus (Man-Ad5-PTEN). The cytotoxicity and anticancer activity of Man-Ad5-PTEN were assessed in vitro. Reporter gene expression of LacZ transferred by Man-Ad5-LacZ was verified on mannose receptor-deficient NIH/3T3 cells versus mannose receptor-efficient macrophages. Hepatocellular carcinoma cell lines transduced by mannan-modified adenovirus were assayed for cell cycle, apoptosis, invasion, and migration. Further, we detected the antitumor effect on intraperitoneal H22 tumor-bearing mice treated by Man-Ad5-PTEN alone or combined with chemotherapeutic agent of doxorubicin. The results demonstrated that cell growth suppression was not observed in Chang normal hepatocyte cells and the cell killing by Man-Ad5-PTEN is tumor selective. Further, the results showed that the strategy of mannan conjugation could enhance adenovirus-mediated PTEN gene therapy effects on murine hepatocellular carcinoma cells in vitro and in vivo. 23967178 Differential Post-Surgical Metastasis and Survival in SCID, NOD-SCID and NOD-SCID-IL-2Rγ(null) Mice with Parental and Subline Variants of Human Breast Cancer: Implications for Host Defense Mechanisms Regulating Metastasis. We compare for the first time, the metastatic aggressiveness of the parental MDA-MB-231 breast cancer cell line and two luciferase-tagged in vivo-derived and selected pro-metastatic variants (LM2-4/luc(+) and 164/8-1B/luc(+)) in SCID, NOD-SCID and NOD-SCID-IL-2Rγ(null) (NSG) mice following orthotopic implantation and primary tumour resection. The variants are known to be more aggressively metastatic in SCID mice, compared to the parental line which has limited spontaneous metastatic competence in these mice. When 2×10(6) cells were injected into the mammary fat pad, the growth of the resultant primary tumours was identical for the various cell lines in the three strains of mice. However, metastatic spread of all three cell lines, including the MDA-MB-231 parental cell line, was strikingly more aggressive in the highly immunocompromised NSG mice compared to both NOD-SCID and SCID mice, resulting in extensive multi-organ metastases and a significant reduction in overall survival. While these studies were facilitated by monitoring post-surgical spontaneous metastases using whole body bioluminescence imaging, we observed that the luciferase-tagged parental line showed altered growth and diminished metastatic properties compared to its untagged counterpart. Our results are the first to show that host immunity can have a profound impact on the spread of spontaneous visceral metastases and survival following resection of a primary tumour in circumstances where the growth of primary tumours is not similarly affected; as such they highlight the importance of immunity in the metastatic process, and by extension, suggest certain therapeutic strategies that may have a significant impact on reducing metastasis. 23344826 Systemic sclerosis: demographic, clinical and serological features in 100 Iranian patients. To evaluate demographic, clinical and laboratory features associated with scleroderma-specific auto-antibodies. Sera of 100 patients with systemic sclerosis (SSc) were analyzed by an indirect immunofluorescence technique with HEp-2 cells as a substrate. Specific ANA such as anti-centromere antibodies (ACA), anti-topoisomerase (TOPO), anti-RNA polymerase III (Pol 3), anti-U3-RNP (U3-RNP), anti-Th/To (Th/To) and anti-PM/Scl (PM/Scl) were detected by line immunoassay and anti-U1-RNP (U1-RNP) by ELISA. Frequency of clinical features associated with a specific antibody group was reported cumulatively over the follow-up period. Frequency of specific clinical features was compared across the two disease subtype including limited cutaneous (lcSSc) or diffuse cutaneous (dcSSc) as well as the auto-antibody groups. Ninety-four percent of patients were ANA positive with significant higher skin score, Raynauds and digital ulcer/gangrene. Anti-TOPO was detected in 71 % of all patients, in 90.5 % of dcSSC and in 65.8 % of lcSSc. Anti-TOPO was significantly associated with dcSSc, higher skin score, digital ulcer/gangrene, pulmonary fibrosis, DLCO <70 %. U1-RNP antibody was associated with lower fibrosis in lung. ACA was positive in 7 % of patients and exclusively in those with lcSSc. We did not find association between gender and presence of auto-antibodies. Anti-TOPO antibody had a high prevalence in contrast to low prevalence of ACA antibody. There were no differences in clinical subtypes of the disease in patients with positive anti-TOPO and positive ACA. Differences in prevalence of auto-antibodies are suggestive of further genetic study. 23855487 Benznidazole modulates cell proliferation in acute leukemia cells. Abstract Context: We have previously reported that benznidazole (BZL), known for its trypanocidal action, has anti-proliferative activity against different cell lines like HeLa and Raw 264.7 among others. At the moment, it has not been reported if the anti-proliferative effect of BZL is similar for non-adherent hematopoietic cells like was reported for adherent cancer cell lines. Objective: We aimed to investigate the efficacy of BZL on the growth of the leukemic cell lines THP-1 and OCI/AML3. Materials and methods: We evaluated cell proliferation by [(3)H]-thymidine incorporation and MTT reduction as well as cell death by lactate dehydrogenase (LDH) activity. We assessed apoptosis by flow cytometry for detection of annexin V-positive and propidium iodide-negative cells, along with nuclear morphology by diamidino-2-phenolindole (DAPI) staining. Western blot studies were performed to evaluate changes in cell cycle proteins in BZL-treated cells. Results: BZL significantly reduced proliferation of both cell lines without inducing cell death. Likewise it produced no significant differences in apoptosis between treated cells and controls. In addition, flow cytometry analysis indicated that BZL caused a larger number of THP-1 cells in G0/G1 phase and a smaller number of cells in S phase than controls. This was accompanied with an increase in the expression of the CDK inhibitor p27 and of cyclin D1, with no significant differences in the protein levels of CDK1, CDK2, CDK4, cyclins E, A and B as compared to controls. Conclusion: BZL inhibits the proliferation of leukemic non-adherent cells by controlling cell cycle at G0/G1 cell phase through up-regulation of p27. 23806341 Sex estimation using anthropometry of feet and footprints in a Western Australian population. An important component of forensic investigation is the identification of deceased (and increasingly living) individuals, which is often the role of the forensic anthropologist. One of the most valuable steps towards identification is via a biological profile, developed through the application of population specific standards. In disaster victim identification scenarios, fleshed feet are often recovered in footwear; footprints are another potential source of trace evidence found at crime scenes. In medico-legal investigations, feet and footprints can be useful for extrapolating living height, it is thus expedient to determine whether sex can be estimated from the same anthropometric data. The aim of the present study is to develop accurate sex estimation standards for a contemporary Western Australian population from measurements of the feet and footprints. The sample comprises 200 adults (90 males, 110 females). Three bilateral linear measurements were taken from each foot and seven bilateral measurements were acquired from static footprints obtained using a Podograph. A precision test was first conducted to assess data accuracy and reliability. Measurement data are then analysed using a range of parametric statistical tests. Results show that males were significantly (P<0.001) larger than females for all foot and footprint measurements; cross-validated sex classification accuracies ranged from 71% to 91%. Although in many instances the sex bias was large (>±5%), this study provides viable alternatives for estimating sex in Western Australian individuals with accuracy equivalent to established standards developed from foot bones. 23872986 Demonstration of the retention of 64Cu-ATSM in cardiac myocytes using a novel incubation chamber for screening hypoxia-dependent radiotracers. We have designed a low-cost, reusable incubation system that allows cells to be cultured in either plated or suspension culture under complete atmospheric control for radiotracer characterization. We demonstrate its utility here in the first quantification of the hypoxia-dependent accumulation of Cu-diacetyl bis(N4-methylthiosemicarbazone) (Cu-ATSM) in adult rat ventricular myocytes (ARVMs). ARVMs were allowed to adhere overnight in 9 cm culture plates (2×10 cells/dish) or were used in suspension culture, placed inside the chamber and equilibrated with either oxic (95 or 21% O2/5% CO2) or anoxic gas (95% N2/5% CO2). Cu-ATSM of 100 kBq was administered, and the cells were incubated for 30 or 60 min. Cells were then harvested, counted and fractionated to determine intracellular Cu biodistribution. After 1 h, the average cellular Cu retention in plated ARVMs under oxygenated conditions was 23.9±2.5 mBq/cell (95% O2), increasing to 27.3±5.1 under 21% O2 (P<0.05) and to 36.1±3.1 under 0% O2 (P<0.05). When ARVMs were cultured in suspension, normoxic-hypoxic contrast was less marked but still significant [63.2±14.1 vs. 53.4±10.9% mBq/cell after 30 min (P<0.05)]. Sixty percent of tracer accumulated in the cytosol, and, although total cellular retention increased during hypoxia, there was no enrichment in any particular cellular compartment. This apparatus allows the conduction of radiotracer uptake studies in cells under complete atmospheric control, as evidenced by our first demonstration of the hypoxia-dependent uptake of Cu-ATSM in ventricular myocytes. It is ideally suited for screening, validating and characterizing novel hypoxia-selective radiotracers. 23715865 Vagal Afferent NMDA Receptors Modulate CCK-Induced Reduction of Food Intake Through Synapsin I Phosphorylation in Adult Male Rats. Vagal afferent nerve fibers transmit gastrointestinal satiation signals to the brain via synapses in the nucleus of the solitary tract (NTS). Despite their pivotal role in energy homeostasis, little is known about the cellular mechanisms enabling fleeting synaptic events at vagal sensory endings to sustain behavioral changes lasting minutes to hours. Previous reports suggest that the reduction of food intake by the satiation peptide, cholecystokinin (CCK), requires activation of N-methyl-D-aspartate-type glutamate receptors (NMDAR) in the NTS, with subsequent phosphorylation of ERK1/2 (pERK1/2) in NTS vagal afferent terminals. The synaptic vesicle protein synapsin I is phosphorylated by pERK1/2 at serines 62 and 67. This pERK1/2-catalyzed phosphorylation increases synaptic strength by increasing the readily releasable pool of the neurotransmitter. Conversely, dephosphorylation of serines 62 and 67 by calcineurin reduces the size of the readily releasable transmitter pool. Hence, the balance of synapsin I phosphorylation and dephosphorylation can modulate synaptic strength. We postulated that CCK-evoked activation of vagal afferent NMDARs results in pERK1/2-catalyzed phosphorylation of synapsin I in vagal afferent terminals, leading to the suppression of food intake. We found that CCK injection increased the phosphorylation of synapsin I in the NTS and that this increase is abolished after surgical or chemical ablation of vagal afferent fibers. Furthermore, fourth ventricle injection of an NMDAR antagonist or the mitogen-activated ERK kinase inhibitor blocked CCK-induced synapsin I phosphorylation, indicating that synapsin phosphorylation in vagal afferent terminals depends on NMDAR activation and ERK1/2 phosphorylation. Finally, hindbrain inhibition of calcineurin enhanced and prolonged synapsin I phosphorylation and potentiated reduction of food intake by CCK. Our findings are consistent with a mechanism in which NMDAR-dependent phosphorylation of ERK1/2 modulates satiation signals via synapsin I phosphorylation in vagal afferent endings. 23955605 How Many Measurements Are Needed to Estimate Blood Pressure Variability Without Loss of Prognostic Information? Average real variability (ARV) is a recently proposed index for short-term blood pressure (BP) variability. We aimed to determine the minimum number of BP readings required to compute ARV without loss of prognostic information. ARV was calculated from a discovery dataset that included 24-hour ambulatory BP measurements for 1,254 residents (mean age = 56.6 years; 43.5% women) of Copenhagen, Denmark. Concordance between ARV from full (≥80 BP readings) and randomly reduced 24-hour BP recordings was examined, as was prognostic accuracy. A test dataset that included 5,353 subjects (mean age = 54.0 years; 45.6% women) with at least 48 BP measurements from 11 randomly recruited population cohorts was used to validate the results. In the discovery dataset, a minimum of 48 BP readings allowed an accurate assessment of the association between cardiovascular risk and ARV. In the test dataset, over 10.2 years (median), 806 participants died (335 cardiovascular deaths, 206 cardiac deaths) and 696 experienced a major fatal or nonfatal cardiovascular event. Standardized multivariable-adjusted hazard ratios (HRs) were computed for associations between outcome and BP variability. Higher diastolic ARV in 24-hour ambulatory BP recordings predicted (P < 0.01) total (HR = 1.12), cardiovascular (HR = 1.19), and cardiac (HR = 1.19) mortality and fatal combined with nonfatal cerebrovascular events (HR = 1.16). Higher systolic ARV in 24-hour ambulatory BP recordings predicted (P < 0.01) total (HR = 1.12), cardiovascular (HR = 1.17), and cardiac (HR = 1.24) mortality. Forty-eight BP readings over 24 hours were observed to be adequate to compute ARV without meaningful loss of prognostic information. 23968328 Acute myeloid leukemia in a 38-year-old hemodialyzed patient with von Hippel-Lindau disease. Von Hippel-Lindau disease (VHL disease) is a hereditary cancer predisposition syndrome caused by mutations of the von Hippel-Lindau tumor suppressor gene. The gene product, pVHL, regulates the level of proteins that play a central role in protecting cells against hypoxia. Clinical hallmarks of von Hippel-Lindau disease are the development of central nervous system hemangioblastomas, renal cell carcinoma, pheochromocytoma, neuroendocrine tumors and endolymphatic sac tumors.In this article the case of a 38-year old hemodialyzed patient who became ill with acute myeloid leukemia (AML) three years after being diagnosed with von Hippel-Lindau disease is presented.After cytostatic treatment the patient went into complete hematologic remission but there was still residual disease at the genetic level. After consolidation therapy patient developed bone marrow aplasia and severe pneumonia. Despite intensive treatment the patient died from acute respiratory failure.In this paper we present for the first time a case of von Hippel-Lindau disease associated with acute myeloid leukemia. No evidence of relationship between VHL disease and blood cancers has been demonstrated so far. Despite the fact that there is an increased risk of cancer development in hemodialyzed patients, cancer is a relatively rare cause of death in the dialysed population, and the most common malignancies are genitourinary cancers. It seems likely that development of acute myeloid leukemia in patient with VHL disease can be related to epigenetic alterations of the VHL gene, but further studies are needed. 23959317 Improved Lethal Effect of Cpl-7, a Pneumococcal Phage Lysozyme of Broad Bactericidal Activity by Inverting Net Charge of its Cell Wall-Binding Module. Phage endolysins are murein hydrolases that break the bacterial cell wall to provoke lysis and release of phage progeny. Recently, these enzymes have also been recognized as powerful and specific antibacterial agents when added exogenously. In the pneumococcal system, most cell-wall associated murein hydrolases reported so far depend on choline for activity and Cpl-7 lysozyme constitutes a remarkable exception. Here, we report the improvement of the killing activity of the Cpl-7 endolysin by inverting the sign of the charge of the cell wall-binding module (from -14.93 to +3.0 at neutral pH). The engineered variant, Cpl-7S, has 15 amino acid substitutions and an improved lytic activity against Streptococcus pneumoniae (including multiresistant strains), Streptococcus pyogenes, and other pathogens. Moreover, we have demonstrated that a single 25 μg dose of Cpl-7S significantly increased the survival rate of zebrafish embryos, infected with S. pneumoniae or S. pyogenes, confirming the killing effect of Cpl-7S in vivo. Interestingly, Cpl-7S, in combination with 0.01% carvacrol (an essential oil), was also found to efficiently kill Gram-negative bacteria such as Escherichia coli and Pseudomonas putida, an effect not described previously. Our findings provide a strategy to improve the lytic activity of phage endolysins based on facilitating their pass through the negatively charged bacterial envelope, and thereby their interaction with the cell wall target, by modulating the net charge of the cell wall-binding modules. 23956869 Clinical presentation, pathogenesis, diagnosis, and treatment of epidermolysis bullosa acquisita. Epidermolysis bullosa acquisita (EBA) is a chronic mucocutaneous autoimmune skin blistering disease. The pathogenic relevance of autoantibodies targeting type VII collagen (COL7) has been well-documented. Therefore, EBA is a prototypical autoimmune disease with a well-characterized pathogenic relevance of autoantibody binding to the target antigen. EBA is a rare disease with an incidence of 0.2 new cases per million and per year. The current treatment of EBA relies on general immunosuppressive therapy, which does not lead to remission in all cases. Therefore, there is a high, so far unmet medical need for the development of novel therapeutic options. During the last 10 years, several novel in vitro and in vivo models of EBA have been established. These models demonstrated a critical role of the genetic background, T cells, and cytokines for mediating the loss of tolerance towards COL7. Neutrophils, complement activation, Fc gamma receptor engagement, cytokines, several molecules involved in cell signaling, release of reactive oxygen species, and matrix metalloproteinases are crucial for autoantibody-induced tissue injury in EBA. Based on this growing understanding of the diseases' pathogenesis, several potential novel therapeutic targets have emerged. In this review, the clinical presentation, pathogenesis, diagnosis, and current treatment options for EBA are discussed in detail. 23884397 Ecological significance and complexity of N-source preference in plants. BackgroundPlants can utilize two major forms of inorganic N: NO3(-) (nitrate) and NH4(+) (ammonium). In some cases, the preference of one form over another (denoted as β) can appear to be quite pronounced for a plant species, and can be an important determinant and predictor of its distribution and interactions with other species. In many other cases, however, assignment of preference is not so straightforward and must take into account a wide array of complex physiological and environmental features, which interact in ways that are still not well understood.ScopeThis Viewpoint presents a discussion of the key, and often co-occurring, factors that join to produce the complex phenotypic composite referred to by the deceptively simple term 'N-source preference'.ConclusionsN-source preference is much more complex a biological phenomenon than is often assumed, and general models predicting how it will influence ecological processes will need to be much more sophisticated than those that have been so far developed. 23278395 Adjuvant and neoadjuvant chemotherapy for soft tissue sarcomas. Sarcomas of the soft tissue are a heterogeneous, rare and complex group of mesenchymal malignant tumors, accounting for less than 1% of all adult malignancies and about 10-15% of childhood cancer. Despite local disease control obtained with surgery and pre- or postoperative radiotherapy, roughly one half of patients with high-grade tumors experience metastatic disease. The adjunction of chemotherapy, either before or after resection, is not currently viewed as standard practice due to the lack of reproducible impact on survival. The 1997 SMAC meta-analysis based on individual data from randomized studies confirmed a significant impact of adjuvant chemotherapy on both local and metastatic relapse, without any significant benefit on survival. Further meta-analyses demonstrated a significant benefit also in overall survival. Yet, the latest adjuvant EORTC trial was disappointedly negative. To date, adjuvant chemotherapy may be recommended as a reasonable option for the high-risk individual patient who should be well informed on the possible risks and benefits of treatment. Also the indications for neoadjuvant chemotherapy remain controversial. A local benefit may be gained, facilitating surgery, but data on survival are limited and affected by a strong patient selection bias. In order to improve our knowledge on sarcomas and to offer patients the best of current standards, we strongly recommend that all patients be referred to a sarcoma multidisciplinary group, under whose supervision they could receive the correct combined-modality management as well as have access to new clinical trials appropriately stratified for risk and histological and/or molecular subtypes. 23841635 Copy number change: evolving views on gene amplification. The rapid pace of genomic sequence analysis is increasing the awareness of intrinsically dynamic genetic landscapes. Gene duplication and amplification (GDA) contribute to adaptation and evolution by allowing DNA regions to expand and contract in an accordion-like fashion. This process affects diverse aspects of bacterial infection, including antibiotic resistance and host-pathogen interactions. In this review, microbial GDA is discussed, primarily using recent bacterial examples that demonstrate medical and evolutionary consequences. Interplay between GDA and horizontal gene transfer further impact evolutionary trajectories. Complementing the discovery of gene duplication in clinical and environmental settings, experimental evolution provides a powerful method to document genetic change over time. New methods for GDA detection highlight both its importance and its potential application for genetic engineering, synthetic biology and biotechnology. 23910717 Populations and pigeons: Prosaic pluralism about evolutionary causes. Walsh (2007, 2010) was correct to conclude that the way a biological population is described should affect conclusions about whether natural selection occurs, but wrong to conclude that natural selection is therefore not a cause. After providing a new argument that (Walsh, 2007) ignored crucial biological details, I give a biological illustration that motivates a fairly extreme dependence on description. I argue that contrary to an implication of (Otsuka, Turner, Allen, & Lloyd, 2011), biologists allow much flexibility in describing populations, as contemporary research on recent human evolution shows. Properly understood, such description-dependence is consistent with descriptions capturing different causal relations involving the same population. I thus show that Walsh's (2007) arguments fail for reasons that have not previously been understood; I argue that Walsh's (2010) more recent "Sure Thing" argument fails for similar reasons. The resulting view provides a new perspective on causation in evolutionary processes. 23894424 Foliar symptoms triggered by ozone stress in irrigated holm oaks from the city of madrid, Spain. Despite abatement programs of precursors implemented in many industrialized countries, ozone remains the principal air pollutant throughout the northern hemisphere with background concentrations increasing as a consequence of economic development in former or still emerging countries and present climate change. Some of the highest ozone concentrations are measured in regions with a Mediterranean climate but the effect on the natural vegetation is alleviated by low stomatal uptake and frequent leaf xeromorphy in response to summer drought episodes characteristic of this climate. However, there is a lack of understanding of the respective role of the foliage physiology and leaf xeromorphy on the mechanistic effects of ozone in Mediterranean species. Particularly, evidence about morphological and structural changes in evergreens in response to ozone stress is missing. Our study was started after observing ozone -like injury in foliage of holm oak during the assessment of air pollution mitigation by urban trees throughout the Madrid conurbation. Our objectives were to confirm the diagnosis, investigate the extent of symptoms and analyze the ecological factors contributing to ozone injury, particularly, the site water supply. Symptoms consisted of adaxial and intercostal stippling increasing with leaf age. Underlying stippling, cells in the upper mesophyll showed HR-like reactions typical of ozone stress. The surrounding cells showed further oxidative stress markers. These morphological and micromorphological markers of ozone stress were similar to those recorded in deciduous broadleaved species. However, stippling became obvious already at an AOT40 of 21 ppm•h and was primarily found at irrigated sites. Subsequent analyses showed that irrigated trees had their stomatal conductance increased and leaf life -span reduced whereas the leaf xeromorphy remained unchanged. These findings suggest a central role of water availability versus leaf xeromorphy for ozone symptom expression by cell injury in holm oak. 23932083 Preparation of disk-like particles with micro/nano hierarchical structures. A facile, reproductive method has been successfully developed to produce disk-like microparticles self-assembled from monodispersed hybrid silica nanoparticles under certain circumstance. The disk-like microparticles with micro/nano hierarchical structures could be obtained in large amount under a mild condition and further used to biomimetic design of the superhydrophobic surface of lotus leaf. After traditional surface modification with dodecyltrichlorosiliane, the static contact angle of water on the surface with micro/nano hierarchical structure could reach 168.8°. The method of surface modification could be further simplified by click reaction with the introduction of thiol groups under mild condition. The present strategy for constructing the surface with micro/nano hierarchical structures offers the advantage of simple and large area fabrication, which enables a variety of superhydrophobic applications. 23815375 Why some children hospitalized for pneumonia do not consult with a general practitioner before the day of hospitalization. Background: Early consultation in primary care may provide an opportunity for early intervention in children developing pneumonia, but little is known about why some children do not consult a general practitioner (GP) before hospitalization. Objectives: To identify differences between children who consulted a GP and children who did not consult a GP before the day of hospital presentation with pneumonia or empyema. Methods: Carers of children aged six months to 16 years presenting to hospital with pneumonia or empyema completed a questionnaire, with a subset participating in an interview to identify physical, organizational and psychological barriers to consultation. Responses from those who had consulted a GP before the day of hospital presentation were compared with those who had not on a range of medical, social and environmental variables. Results: Fifty seven (38%) of 151 participants had not consulted a GP before the day of hospital presentation. On multivariate analysis, illness duration ≥ 3 days (odds ratio [OR] 4.36, 95% confidence interval [CI]: 1.67-11.39), prior antibiotic use (OR: 10.35, 95% CI: 2.16-49.55) and home ownership (OR: 3.17, 95% CI: 1.07-9.37) were significantly associated with early GP consultation (P < 0.05). Interviews with 28 carers whose children had not seen a GP before the day of presentation revealed that most had not considered it and/or did not think their child's initial symptoms were serious or unusual; 11 (39.3%) had considered consulting a GP but reported barriers to access. Conclusion: Lack of early GP consultation was strongly associated with rapid evolution of pneumonia. 23928468 Supratrochlear and Supraorbital Nerves: An Anatomical Study and Applications in the Head and Neck Area. This article elucidates the anatomical details of the course and territory of the supraorbital (SO) and supratrochlear (ST) nerves. Possible applications of the SO and ST nerves for sensory nerve transfer are also examined. The dissection of 3 fresh cadaver heads (6 hemifaces) was performed. In each hemiface, the ST and SO nerves were identified. The following data were recorded: 1) number of branches, 2) skin boundaries, 3) communicative branches, and 4) branch length. The feasibility of specific nerve-transfer procedures was also examined. In 4 hemifaces the SO nerve exited from the SO notch and in 2 hemifaces from the SO foramen. The position was lateral to the midline, with a mean distance of 1.93 cm. In all dissections, a maximum of 4 SO branches (range 2-4) were identified. The ST nerve exited the orbital rim medial to the SO nerve, and lateral to the midline with a mean distance of 0.866 cm. The mean distance between the SO and ST nerves at the level of the SO rim was 1.06 cm. In 5 of 6 hemifaces, several sub-branches emerged from the main trunk of the ST nerve. In 1 hemiface the ST nerve was divided in 2 main branches. The data presented in the current study are in agreement with previous anatomical studies. Both ST and SO nerves can be used as sensory nerve donors in the head and neck area for numerous expanding applications. 23931260 CONSANGUINITY ON ROBINSON CRUSOE ISLAND, AN ISOLATED CHILEAN POPULATION. Summary The population of Robinson Crusoe Island is estimated at 633 inhabitants. The current population has a common origin from the first eight families who colonized the island at the end of the 19th century. The objective of this study was to determine the rates of consanguinity, the average coefficients of inbreeding, the types of consanguineous marriages and the inbreeding evolution between 1900 and 2000 on the island. All marriages registered on the island, from the last colonization until 2000 (417 in total), were included in the analysis. In addition, extended genealogies were obtained. The consanguinity rate was 14.9% and the average coefficient of inbreeding (α) 54.05×10-4. The most frequent type of consanguineous marriages was between second cousins, followed by first cousins. The average value of the first/second cousin ratio was 1.11. The population of Robinson Crusoe Island has a high rate of inbreeding. The unique characteristic of the island - its small current population, originating from just a few families, with small rate of gene flow - could explain the observed high and increasing consanguinity. 23043625 Cognitive abilities of street children: Low-SES Bolivian boys with and without experience of living in the street. Objectives: This study compared results on cognitive tests measuring nonverbal visualization and reasoning, executive functions, and creativity between 36 boys with experience of living in the street and 31 housed yet socioeconomically equivalent boys, in Bolivia. Results: The street children scored significantly higher on the creativity measure, which is discussed in relation to contextual relevance. No significant differences were found on the other cognitive tests. Time elapsed after living in the street and drug use were strongly associated with cognition, while age was not. Both groups scored below average compared to Western norms. The results are discussed in terms of the cultural relevance of the tests and the impact of socioeconomic status, stress, and stimulation on cognition. 23958521 Sensitization of Peripheral Sensory Nerves by Mediators From Colonic Biopsies of Diarrhea-Predominant Irritable Bowel Syndrome Patients: A Role for PAR2. OBJECTIVES:This study examined whether mediators from biopsies of human irritable bowel syndrome (IBS) colons alter intrinsic excitability of colonic nociceptive dorsal root ganglion (DRG) neurons by a protease activated receptor 2 (PAR2)-mediated mechanism.METHODS:Colonic mucosal biopsies from IBS patients with constipation (IBS-C) or diarrhea (IBS-D) and from healthy controls were incubated in medium, and supernatants were collected. Small-diameter mouse colonic DRG neurons were incubated in supernatants overnight and perforated patch current-clamp recordings obtained. Measurements of rheobase and action potential discharge at twice rheobase were compared between IBS and controls to assess differences in intrinsic excitability.RESULTS:Supernatants from IBS-D patients elicited a marked increase in neuronal excitability compared with controls. These changes were consistent among individual patients but the relative contribution of rheobase and action potential discharge varied. In contrast, no differences in neuronal excitability were seen with IBS-C patient supernatants. The increased excitability seen with IBS-D supernatant was not observed in PAR2 knockout mice. A cysteine protease inhibitor, which had no effect on the pronociceptive actions of a serine protease, inhibited the proexcitatory actions of IBS-D supernatant.CONCLUSIONS:Soluble mediators from colonic biopsies from IBS-D but not IBS-C patients sensitized colonic nociceptive DRG neurons, suggesting differences between these two groups. PAR2 signaling plays a role in this action and this protease signaling pathway could provide novel biomarkers and therapeutic targets for treatment.Am J Gastroenterol advance online publication, 20 August 2013; doi:10.1038/ajg.2013.241. 23882242 An asymmetry of translational biological motion perception in schizophrenia. Background: Biological motion perception is served by a network of regions in the occipital, posterior temporal, and parietal lobe, overlapping areas of reduced cortical volume in schizophrenia. The atrophy in these regions is assumed to account for deficits in biological motion perception described in schizophrenia but it is unknown whether the asymmetry of atrophy found in previous studies has a perceptual correlate. Here we look for possible differences in sensitivity to leftward and rightward translation of point-light biological motion in data collected for a previous study and explore its underlying neurobiology using functional imaging. Methods: n = 64 patients with schizophrenia and n = 64 controls performed a task requiring the detection of leftward or rightward biological motion using a standard psychophysical staircase procedure. six control subjects took part in the functional imaging experiment. Results: We found a deficit of leftward but not rightward biological motion (leftward biological motion % accuracy patients = 57.9% ± 14.3; controls = 63.6% ± 11.3 p = 0.01; rightward biological motion patients = 62.7% ± 12.4; controls = 64.1% ± 11.7; p > 0.05). The deficit reflected differences in distribution of leftward and rightward accuracy bias in the two populations. Directional bias correlated with functional outcome as measured by the Role Functioning Scale in the patient group when co-varying for negative symptoms (r = -0.272, p = 0.016). Cortical regions with preferential activation for leftward or rightward translation were identified in both hemispheres suggesting the psychophysical findings could not be accounted for by selective atrophy or functional change in one hemisphere alone. Conclusion: The findings point to translational direction as a novel functional probe to help understand the underlying neural mechanisms of wider cognitive dysfunction in schizophrenia. 23314800 Improving the dispersity of detonation nanodiamond: differential scanning calorimetry as a new method of controlling the aggregation state of nanodiamond powders. Detonation nanodiamond (ND) is a suitable source material to produce unique samples consisting of almost uniform diamond nanocrystals (d = 3-5 nm). Such samples exist in the form of long stable aqueous dispersions with narrow size distribution of diamond particles. The material is finding ever increasing application in biomedicine. The major problem in producing monodispersed diamond colloids lies in the necessity of deagglomeration of detonation soot and/or removing of clusters formed by already isolated core particles in dry powders. To do this one must have an effective method to monitor the aggregation state or dispersity of powders and gels prior to the preparation of aqueous dispersions. In the absence of dispersity control at various stages of preparation the reproducibility of properties of existing ND materials is poor. In this paper we introduce differential scanning calorimetry (DSC) as a new tool capable to distinguish the state of aggregation in dry and wetted ND materials and to follow changes in this state under different types of treatment. Samples with identical X-ray diffraction patterns (XRD) and high resolution transmission electron microscopy (HRTEM) images gave visibly different DSC traces. Strong correlation was found between dynamic light scattering (DLS) data for colloids and DSC parameters for gels and powders of the same material. Based on DSC data we improved dispersity of existing ND materials and isolated samples with the best possible DSC parameters. These were true monodispersed easily dispersible fractions of ND particles with diameters of ca. 3 nm. 23824146 First spectroscopic identification of pyrocarbonate for high CO2 flux membranes containing highly interconnected three dimensional ionic channels. Identification of the existence of pyrocarbonate ion C2O5(2-) in molten carbonates exposed to a CO2 atmosphere provides key support for a newly established bi-ionic transport model that explains the mechanisms of high CO2 permeation flux observed in mixed oxide-ion and carbonate-ion conducting (MOCC) membranes containing highly interconnected three dimensional ionic channels. Here we report the first Raman spectroscopic evidence of C2O5(2-) as an active species involved in the CO2-transport process of MOCC membranes exposed to a CO2 atmosphere. The two new broad peaks centered at 1317 cm(-1) and 1582 cm(-1) are identified as the characteristic frequencies of the C2O5(2-) species. The measured characteristic Raman frequencies of C2O5(2-) are in excellent agreement with the DFT-model consisting of six overlapping individual theoretical bands calculated from Li2C2O5 and Na2C2O5. 23928200 (1)H magnetic resonance spectroscopy in multiple sclerosis and related disorders. Proton magnetic resonance spectroscopy ((1)H-MRS) is an unconventional technique that allows noninvasive characterization of metabolic abnormalities in the central nervous system. (1)H-MRS provides important insights into the chemical-pathologic changes that occur in patients with multiple sclerosis (MS). In this review article we present the main brain and spinal cord (1)H-MRS features in MS, their diagnostic value in differentiating pseudotumoral demyelinating lesions from primary brain tumors, and their relationship with clinical variables. Last, some data related to the use of (1)H-MRS in therapeutic trials is presented. 23892682 Challenges of Interdisciplinary Research: Reconciling Qualitative and Quantitative Methods for Understanding Human-Landscape Systems. While interdisciplinary research is increasingly practiced as a way to transcend the limitations of individual disciplines, our concepts, and methods are primarily rooted in the disciplines that shape the way we think about the world and how we conduct research. While natural and social scientists may share a general understanding of how science is conducted, disciplinary differences in methodologies quickly emerge during interdisciplinary research efforts. This paper briefly introduces and reviews different philosophical underpinnings of quantitative and qualitative methodological approaches and introduces the idea that a pragmatic, realistic approach may allow natural and social scientists to work together productively. While realism assumes that there is a reality that exists independently of our perceptions, the work of scientists is to explore the mechanisms by which actions cause meaningful outcomes and the conditions under which the mechanisms can act. Our task as interdisciplinary researchers is to use the insights of our disciplines in the context of the problem to co-produce an explanation for the variables of interest. Research on qualities necessary for successful interdisciplinary researchers is also discussed along with recent efforts by funding agencies and academia to increase capacities for interdisciplinary research. 23883746 Social affordances: Is the mirror neuron system involved? We question the idea that the mirror neuron system is the substrate of social affordances perception, and we suggest that most of the activity seen in the parietal and premotor cortex of the human brain is independent of mirroring activity as characterized in macaques, but rather reflects a process of one's own action specification in response to social signals. 23944353 Synthesis of Diverse Indene Derivatives from 1-Diazonaphthalen-2(1H)-ones via Thermal Cascade Reactions. A sequential Wolff rearrangement of 1-diazonaphthalen-2(1H)-ones followed by trapping of the ketene intermediate with primary and aromatic amines or alcohols and phenols in the presence of various aldehydes generates 1H-indene-3-carboxamides or 1H-indene-3-carboxylates. This constitutes an unprecedented three-component coupling reaction that allows for the synthesis of functionalized indene derivatives under catalyst-free thermal conditions. 23793479 Autologous double-barrel vascularized fibula bone graft for arthrodesis of the shoulder after tumor resection. Arthrodesis of the shoulder is a straightforward and established alternative to reconstruct the shoulder function after tumor resection of the proximal humerus. In most cases, some kind of intercalary bone graft is used to bridge the bony defect. However, due to low stability of a single fibula autograft and disadvantages of exogenous graft material when performing combined allo- and autograft reconstruction, efforts to develop new surgical techniques, with the intention to lower the complication rates, are ongoing. We present a detailed description of the surgical technique and the outcome of three patients with osteosarcomas of the proximal humerus, which were treated with tumor resection and autologous double-barrel vascularized fibula bone graft for arthrodesis of the shoulder. The construct was stabilized using a 4.5-mm pelvic reconstruction plate positioned on the scapular spine and the lateral aspect of the humerus. A wide surgical margin was achieved in all patients. Two of them could be reintegrated and are able to work with excellent shoulder function. In one patient, who developed metastasis, a deep infection under chemotherapy 16 months after index surgery complicated the postoperative course. The fibula's unique dual endosteal and periosteal blood supply makes it effective as a double-barrel bone graft for major long bone defects, which requires extra bone volume to prevent fractures until bone hypertrophy occurs. Additional bone and scar formation between the two struts are believed to provide a stable and long lasting construct, as seen in our patients. 22391561 Tumor angiogenesis is enforced by autocrine regulation of high-mobility group box 1. The endothelium plays a pivotal role in the progression of solid tumors and is considered a highly relevant target for therapy. However, it emerges that current clinical angiogenesis inhibitors that act through inhibition of tumor-derived growth factors are prone to inducing drug resistance. Therefore, markers of tumor endothelial cells (ECs) themselves provide attractive novel therapeutic targets. In a screen for markers of tumor angiogenesis, we recently identified high-mobility group box 1 (HMGB1), known to act as proinflammatory cytokine and chromatin-binding molecule. Here we report on the role of HMGB1 in angiogenesis by showing that its overexpression is associated with an increased angiogenic potential of ECs. HMGB1 stimulates the expression of players in vascular endothelial growth factor and platelet-derived growth factor signaling, both in vitro and in vivo. Importantly, we show that HMGB1 triggers and helps to sustain this proangiogenic gene expression program in ECs, additionally characterized by increased activity of matrix metalloproteinases, integrins and nuclear factor-κB. Moreover, we found that HMGB1 is involved in several autocrine and/or paracrine feedback mechanisms resulting in positive enforcement of HMGB1 expression, and that of its receptors, RAGE (receptor for advanced glycation end products) and Toll-like receptor 4 (TLR4). Interference in HMGB1 expression and/or function using knockdown approaches and antibody-mediated targeting to break this vicious circle resulted in inhibited migration and sprouting of ECs. Using different in vivo models, therapeutic efficacy of HMGB1 targeting was confirmed. First, we demonstrated induction of HMGB1 expression in the chicken embryo chorioallantoic membrane (CAM) neovasculature following both photodynamic therapy and tumor challenge. We subsequently showed that anti-HMGB1 antibodies inhibited vessel density in both models, accompanied by a reduced vascular expression of angiogenic growth factor receptors. Collectively, these data identify HMGB1 as an important modulator of tumor angiogenesis and suggest the feasibility of targeting HMGB1 for multi-level cancer treatment. 23726080 The fabrication of monolithic capillary column based on poly (bisphenol A epoxy vinyl ester resin-co-ethylene glycol dimethacrylate) and its applications for the separation of small molecules in high performance liquid chromatography. A new polymeric monolith was synthesized in fused-silica capillary by in situ polymerization technique. In the polymerization, bisphenol A epoxy vinyl ester resin (VER) was used as the functional monomer, ethylene glycol dimethacrylate (EDMA) as the crosslinking monomer, 1,4-butanediol, 1-propanol and water as the co-porogens, and azobisisobutyronitrile (AIBN) as the initiator. The conditions of polymerization have been optimized. Morphology of the prepared poly (VER-co-EDMA) monolith was investigated by the scanning electron microscopy (SEM); pore properties were assayed by mercury porosimetry and nitrogen adsorption. The optimized poly (VER-co-EDMA) monolith showed a uniform structure, good permeability and mechanical stability. Then, the column was used as the stationary phase of high performance liquid chromatography (HPLC) to separate the mixture of benzene derivatives. The best column efficiency achieved for phenol was 235790 theoretical plates per meter. Baseline separations of benzene derivatives and halogenated benzene compounds under optimized isocratic mode conditions were achieved with high column efficiency. The column showed good reproducibility: the relative standard deviation (RSD) values based on the retention times (n=3) for run-to-run, column-to-column and batch-to-batch were less than 0.98, 1.68, 5.48%, respectively. Compared with poly (BMA-co-EDMA) monolithic column, the proposed monolith exhibited more efficiency in the separation of small molecules. 23916667 Analysis of the modulated acoustic radiation-force profile for a dual-beam confocal geometry. A localized modulated radiation force can be produced when two confocal ultrasound beams of nearly equal frequencies interfere in an attenuating medium such as tissue. It is well-established that this force generates both shear and longitudinal waves. By scanning the focal point over a plane and observing the propagation of these waves, the mechanical properties of the medium can be imaged. In this paper, the modulated radiation force is analytically derived in the case of attenuating media, by expanding on the theory of ultrasound-stimulated-vibro-acoustography (USVA) for lossless media. Furthermore, weak nonlinearities are considered in the formulation, since higher source pressures may prove to be necessary to improve the radiation-force profile - only the fundamental component is, however, studied in this paper. An analysis of the generated radiation force is performed and the effects of various parameters are investigated on its amplitude and spatial distribution. It will be shown that by carefully selecting the confocal geometry of the beams, as well as, the source pressure and center frequency, the spatial profile of the radiation force can be optimized. This, subsequently, could improve not only the resolution of the point-spread-function in USVA, but also, the profile of the shear waves in elastography applications. 23410161 Rationally designed multi-targeted agents against neurodegenerative diseases. Neurodegenerative diseases are complex disorders with several pathoetiological pathways leading to cell death. Rationally designed multi-targeted agents, or "multi-targeted designed drugs" (MTDD) show significant promise in preclinical studies as neuroprotective and disease-modifying agents. In this review, we highlight the use of chemical scaffolds that lend themselves exquisitely to the development of MTDDs in neurodegeneration. Notably, synthetic polycyclic cage compounds have served as scaffolds for novel voltage-gated calcium channel blockers, NMDA receptor antagonists, and sigma-receptor ligands - attractive targets in neurodegeneration. In an entirely different approach, compounds containing the thiazolidinedione moiety (referred to as glitazones) alter mitochondrial function through the mitochondrial protein mitoNEET, an attractive new drug target for the treatment of neurodegenerative diseases. The design strategy for yet another agent, ladostigil, employed the amalgamation of active chemical moieties of the AChE inhibitor rivastigmine, and the monoamine oxidase-B (MAO-B) inhibitor rasagiline, leading to a single compound that targets both enzymes simultaneously. Natural products have also served as design templates for several MTDD design studies. In particular, the stilbene scaffold has become popular in particular due to the neuroprotective effects of the non-flavonoid natural product resveratrol. Recently, stilbene scaffold-based compounds were developed to reduce - through chelation with metal ions that interact with beta-amyloid - both metal-induced beta-amyloid protein aggregation, and ROS generated from this aggregate. Other subtle modifications of the stilbene motif led to the creation of reversible, non-competitive MAO inhibitors. Finally, compounds derived from the xanthine scaffold afford neuroprotection in Parkinson's disease through mechanisms that include dual adenosine A2A receptor antagonism and MAO-B inhibition. 23932595 Comparative performance of trace element bioaccumulation and biomonitoring in the plant species Typha domingensis, Phragmites australis and Arundo donax. Toxic levels of trace elements in the environment have been reported worldwide over the last few decades, and their increasing concentrations are of the utmost concern because of the adverse effects on human life and ecosystems. Several plant species are able to accumulate trace elements, and may be used for monitoring and remediation of polluted sites. This study compared the capacity of trace element bioaccumulation in three wetland plants distributed worldwide: Typha domingensis, Phragmites australis and Arundo donax. The aims were to identify which species show better potential for removal and monitoring of these elements: Al, As, Cd, Cr, Cu, Hg, Mn, Ni, Pb, Zn. Results showed that all species may be used as biomonitors of trace element contamination in sediment, but only P. australis and A. donax showed also a correlation with water. Overall, T. domingensis and P. australis showed a greater capacity of bioaccumulation as well as a greater efficiency of element removal than A. donax. In particular, T. domingensis and P. australis may be used for Hg phytostabilization, the former acted also as a hyperaccumulator for Hg phytoextraction and as a promising species for As phytostabilization. In contaminated wetlands, the presence of T. domingensis and P. australis may increase the general retention of trace elements, thus, their introduction is recommended for possible actions of phytoremediation and biomonitoring. 22903774 Outcome of expanded criteria donor kidneys that were transplanted at other Eurotransplant centers after being rejected by our institution. There is a growing discrepancy between the demand for renal transplants and the number of transplants conducted. For the many patients on the renal transplant waiting list, this means increased dialysis-associated morbidity, mortality and a reduced quality of life. The aim of this study was to ascertain whether it is justifiable for transplant centers to reject cadaveric donor organs on hand of marginal organ quality. We identified 110 kidneys that were primarily rejected for transplantation at Charité Universitätsmedizin Berlin, Campus Mitte, and later transplanted at another center within the Eurotransplant zone. Using data from the Collaborative Transplant Study, we analyzed various demographic donor data including cold ischemia times, as well as graft and recipient outcomes. The median follow-up was 54 months. The cold ischemia time averaged 16 h. The organs that were primarily rejected by our center and then transplanted at other Eurotransplant centers showed 31 % of recipients had creatinine levels under 1.47 mg/dl and 94 % had levels under 2.97 mg/dl at 3-year follow-up. The mean death-censored graft survival was 71.4 months. The mean renal transplant recipient survival was 87.5 months. Based on our findings, we propose that acceptance criteria for marginal donor kidneys need to be widened. 23913394 Structural and functional effects of metastases in rat brain determined by multimodal MRI. Metastasis to the brain results in significant impairment of brain function and poor patient survival. Currently, magnetic resonance imaging (MRI) is under-utilised in monitoring brain metastases and their effects on brain function. Here, we sought to establish a model of focal brain metastasis in the rat that enables serial multimodal structural and functional MRI studies, and to assess the sensitivity of these approaches to metastatic growth. Female Berlin-Druckrey-IX rats were injected intracerebrally with metastatic ENU1564 cells in the ventroposterior medial nucleus (VPM) of the thalamus, a relay node of the whisker-to-barrel cortex pathway. Animals underwent multimodal structural and vascular MRI, as well as functional MRI of the cortical blood oxygenation level dependent (BOLD) responses to whisker pad stimulation. T2 , diffusion, magnetisation transfer and perfusion weighted MRI enabled differentiation between a central area of more advanced metastatic growth and penumbral regions of co-optive perivascular micrometastatic growth, with magnetisation transfer MRI being the most sensitive to micrometastatic growth. Areas of cortical BOLD activation in response to whisker pad stimulation were significantly reduced in the hemisphere containing metastases in the VPM. The reduction in BOLD response correlated with metastatic burden in the thalamus, and was sensitive to the presence of smaller metastases than currently detectable clinically. Our findings suggest that multimodal MRI provides greater sensitivity to tumour heterogeneity and micrometastatic growth than single modality contrast-enhanced MRI. Understanding the relationships between these MRI parameters and the underlying pathology may greatly enhance the utility of MRI in diagnosis, staging and monitoring of brain metastasis. © 2013 Wiley Periodicals, Inc. 23325361 Genetic association study of WNT10B polymorphisms with BMD and adiposity parameters in Danish and Belgian males. Because of the importance of the Wnt pathway in the development and maintenance of both adipose and bone tissue, we wanted to evaluate the involvement of WNT10B, a Wnt pathway activator, in adipogenesis and osteoblastogenesis in humans. Genetic association between WNT10B polymorphisms and adiposity parameters as well as bone mineral density (BMD) measurements was analysed in two independent populations. The first is a population of 1,228 Danish men (702 aged 20-29 years; 532 aged 60-74 years) from the Odense Androgen Study (OAS), which was designed as a cross-sectional, population-based study. The second population, called SIBLOS, includes 922 Belgian men (34 ± 5 years old) and contains siblings selected from over 500 families. Four tagSNPs (rs833840, rs833841, rs10875902 and rs4018511) that capture variation of ten SNPs (MAF > 5 %) in a 15.2 kb region spanning the WNT10B gene and its flanking regions were genotyped. Although no association with body mass index was found, we found all tagSNPs to be associated with BMD parameters (BMD whole body, total hip and femoral neck) and height in the OAS population. The association of rs10875902 was most prominent (nominal p = 0.012) and confirmed a previously shown negative effect on BMD. No significant associations were observed in the SIBLOS population. In the present study, no association between WNT10B polymorphisms and adiposity parameters was found. However, our results clearly illustrate a role for WNT10B variants in determining human BMD. The effect of WNT10B polymorphisms on height should be evaluated in additional populations. 23534009 Starch tubing: an alternative method to build up microshear bond test specimens. Purpose: To evaluate an alternative device using starch tubes to build up resin composite specimens for microshear bond tests. Materials and Methods: Twenty human molars were selected and sectioned mesiodistally to obtain two sections. The teeth were randomly divided into 4 groups (n = 10) according to the adhesive system - a two-step etch-and-rinse adhesive (Adper Single Bond) and a two-step self-etching adhesive (Clearfil SE Bond) - and the type of tube, starch or polyethylene. The tubes were evaluated under a stereomicroscope at 25X magnification to observe the variation in internal diameter. The resin composite was bonded to flat enamel surfaces using one of the adhesive systems and tube types. After 24 h storage in distilled water, the microshear bond strength (µSBS) was determined and the fracture pattern was analyzed under a stereomicroscope (400X magnification). The microshear bond strength values were subjected to two-way ANOVA. The chi-square test was used to compare pre-test failures and fracture patterns between the groups (p < 0.05). Results: The type of tube, the adhesive system, and their interaction did not influence the bond strength values (p = 0.062, p = 0.122, and p = 0.301, respectively). No significant differences were observed for pre-test failures or fracture patterns (p = 0.320 and p = 0.561, respectively). Conclusion: Using starch tubes is an alternative to build up composite resin specimens for microshear bond strength testing with the two tested adhesive systems. 23776175 SASH1 is a scaffold molecule in endothelial TLR4 signaling. Recognition of microbial products by TLRs is critical for mediating innate immune responses to invading pathogens. In this study, we identify a novel scaffold protein in TLR4 signaling called SAM and SH3 domain containing protein 1 (SASH1). Sash1 is expressed across all microvascular beds and functions as a scaffold molecule to independently bind TRAF6, TAK1, IκB kinase α, and IκB kinase β. This interaction fosters ubiquitination of TRAF6 and TAK1 and promotes LPS-induced NF-κB, JNK, and p38 activation, culminating in increased production of proinflammatory cytokines and increased LPS-induced endothelial migration. Our findings suggest that SASH1 acts to assemble a signaling complex downstream of TLR4 to activate early endothelial responses to receptor activation. 23403984 Income and individual deprivation as predictors of health over time. Poverty, often defined as a lack of resources to achieve a living standard that is deemed acceptable by society, may be assessed using level of income or a measure of individual deprivation. However, the relationship between low income and deprivation is complex-for example, not everyone who has low income is deprived (and vice versa). In addition, longitudinal studies show only a small relationship between short-term changes in income and health but an alternative measure of poverty, such as deprivation, may have a stronger association with health over time. We aim to compare low income and individual deprivation as predictors of self-rated health (SRH), using longitudinal survey data, to test the hypothesis that different measures of poverty may have different associations with health. We used three waves from the longitudinal Survey of Family, Income and Employment and fixed-effect linear regression models to compare low income (<50% median income at each wave) and deprivation (reporting three or more items from the New Zealand individual deprivation index) as predictors of SRH (coded 1-5; SD 1.1-1.2). We also compared the impact of duration of low income and deprivation on SRH using mixed linear models. In the fixed-effect models, moving into deprivation between waves was associated with a larger decline in SRH compared to moving into low income, which persisted in models including both low income and deprivation. Similar findings were observed for duration of low income and deprivation in mixed models. Moving into high levels of individual deprivation is a stronger predictor of changes in SRH than moving into low income. When investigating the association of hardship poverty with health, using alternative measures, in addition to income, is advisable. 23688402 Risk assessments of human exposure to bioaccessible phthalate esters through market fish consumption. The bioaccessibility of phthalate esters in 20 fish species collected from Hong Kong market was evaluated using an in vitro gastrointestinal model. The ∑phthalate ester concentration detected in fresh water fish ranged from 1.66 to 3.14μg/g wet weight (ww) and in marine fish ranged from 1.57 to 7.10μg/g ww, respectively. di-2-Ethylhexyl phthalate (DEHP) and di-n-butyl phthalate (DBP) were the predominant compounds in both freshwater fish and marine fish. The digestible concentrations of phthalate esters ranged from 0.20 to 1.23μg/g ww (mean 0.35μg/g ww), and account for 2.44 to 45.5% (mean 16.8%) for raw concentrations of phthalate esters. In the present study, the accumulation ratio Rnn value of all phthalate esters was greater than 1 except for diisobutyl phthalate (DIBP), DBP and di-n-hexyl phthalate (DHP), suggesting that these phthalate esters could be accumulated during gastrointestinal digestion. Based on this health risk assessment, most of fish species were considered safe for consumption, however Hong Kong residents should take caution when consuming Mud carp and Bighead carp. 23913424 Engineered biosynthesis of disaccharide-modified polyene macrolides. Recent work has uncovered genes for two glycosyltransferases that are thought to catalyze mannosylation of the mycosaminyl sugar of a polyene macrolide. These are nypY from Pseudonocardia sp. P1 and pegA from Actinoplanes caeruleus. Here we analyze these genes by heterologous expression in various strains of Streptomyces nodosus, producer of amphotericins, and in Streptomyces albidoflavus, which produces candicidins. The NypY glycosyltransferase converted amphotericins A, B and 7-oxo-amphotericin B to disaccharide-modified forms in vivo. The enzyme did not act on amphotericin analogs lacking exocyclic carboxyl or mycosamine amino groups. Both NypY and PegA acted on candicidins. This work confirms the functions of these glycosyltransferases and provides insights into their acceptor substrate tolerance. Disaccharide-modified polyenes may have potential as less toxic antibiotics. 23868339 Scientific Evidence and Controversies About Pioglitazone and Bladder Cancer: Which Lessons Can Be Drawn? Pioglitazone, a peroxisome proliferator-activated receptors (PPAR) agonist, has been authorized for the management of type 2 diabetes since 1999 in the US and since 2000 in Europe. Since then, the risk of bladder cancer associated with pioglitazone use has been a serious concern. Following a warning from the Agence Française de Sécurité Sanitaire des Produits de Santé (Afssaps) [the French Agency for the Safety of Health Products], use of pioglitazone was suspended in France and Germany in June 2011. Elsewhere, restrictions on prescriptions were implemented, though for both the European Medicines Agency and the US Food and Drug Administration, the risk-benefit ratio remains favourable. Since the development of pioglitazone, its risk assessment has suffered from several inaccuracies such as its alleged specificity for the male rat, untrustworthy selective agonism for PPARγ and mistaken risk evaluation in the large PROactive trial (PROspective pioglitAzone Clinical Trial In macroVascular Events), where one case with a benign tumour in the placebo group was counted as a cancer case. It took until 2011 for the epidemiological data to be sufficiently numerous and conclusive to initiate application of safety measures. Today, the increased risk of bladder cancer associated with pioglitazone seems to be real, but the absolute risk is relatively low. However, in the context of weak efficacy in an extensive population of patients exposed to pioglitazone, the risk-benefit balance is now difficult to assess, and prescription restrictions do not ensure safety. For future risk management, the authors propose several suggestions, which involve an increasing role of health authorities and academic organizations. 23881866 Saturation recovery single-shot acquisition (SASHA) for myocardial T1 mapping. To validate a new saturation recovery single-shot acquisition (SASHA) pulse sequence for T1 mapping and to compare SASHA T1 values in heart failure patients and healthy controls. The SASHA sequence consists of 10 electrocardiogram-triggered single-shot balanced steady-state free precession images in a breath-hold. The first image is acquired without magnetization preparation and the remaining nine images follow saturation pulses with variable saturation recovery times. SASHA was validated through Bloch equation simulations, Monte Carlo simulations, and phantom experiments. Pre- and postcontrast myocardial and blood T1 values were measured in 29 healthy volunteers and 7 patients with heart failure. SASHA T1 values had excellent agreement (bias, 5 ± 5 ms) with spin echo experiments in phantoms with a wide range of physiologic T1 and T2 values and its accuracy was independent of flip angle, absolute T1 , T2 , and heart rate. The average baseline myocardial T1 in heart failure patients was higher than in healthy controls (1200 ± 32 vs. 1170 ± 9 ms, P < 0.05) at 1.5T, as was the calculated blood-tissue partition coefficient, λ, (0.42 ± 0.04 vs. 0.38 ± 0.02, P < 0.05), consistent with diffuse myocardial fibrosis. The SASHA sequence is a simple and fast approach to in vivo T1 mapping with good accuracy in simulations and phantom experiments. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc. 23455764 MRI for response assessment in metastatic bone disease. Beyond lesion detection and characterisation, and disease staging, the quantification of the tumour load and assessment of response to treatment are daily expectations in oncology. Bone lesions have been considered "non-measurable" for years as opposed to lesions involving soft tissues and "solid" organs like the lungs or liver, for which response evaluation criteria are used in every day practice. This is due to the lack of sensitivity, specificity and measurement capabilities of imaging techniques available for bone assessment, i.e. skeletal scintigraphy (SS), radiographs and computed tomography (CT). This paper reviews the possibilities and limitations of these techniques and highlights the possibilities of positron emission tomography (PET), but mainly concentrates on magnetic resonance imaging (MRI). Practical morphological and quantitative approaches are proposed to evaluate the treatment response of bone marrow lesions using "anatomical" MRI. Recent developments of MRI, i.e. dynamic contrast-enhanced (DCE) imaging and diffusion-weighted imaging (DWI), are also covered. KEY POINTS : • MRI offers improved evaluation of skeletal metastases and their response to treatment. • This new indication for MRI has wide potential impact on radiological practice. • MRI helps meet the expectations of the oncological community. • We emphasise the practical aspects, with didactic cases and illustrations. 23659897 Ataxin-3 protein modification as a treatment strategy for spinocerebellar ataxia type 3: Removal of the CAG containing exon. Spinocerebellar ataxia type 3 is caused by a polyglutamine expansion in the ataxin-3 protein, resulting in gain of toxic function of the mutant protein. The expanded glutamine stretch in the protein is the result of a CAG triplet repeat expansion in the penultimate exon of the ATXN3 gene. Several gene silencing approaches to reduce mutant ataxin-3 toxicity in this disease aim to lower ataxin-3 protein levels, but since this protein is involved in deubiquitination and proteasomal protein degradation, its long-term silencing might not be desirable. Here, we propose a novel protein modification approach to reduce mutant ataxin-3 toxicity by removing the toxic polyglutamine repeat from the ataxin-3 protein through antisense oligonucleotide-mediated exon skipping while maintaining important wild type functions of the protein. In vitro studies showed that exon skipping did not negatively impact the ubiquitin binding capacity of ataxin-3. Our in vivo studies showed no toxic properties of the novel truncated ataxin-3 protein. These results suggest that exon skipping may be a novel therapeutic approach to reduce polyglutamine-induced toxicity in spinocerebellar ataxia type 3. 23518196 Quality-of-Care Indicators Among Remote-Dwelling Hemodialysis Patients: A Cohort Study. We hypothesized that the higher mortality for hemodialysis patients who live farther from the closest attending nephrologist compared with patients living closer might be due to lower quality of care. Population-based longitudinal study. All adult maintenance hemodialysis patients with measurements of quality-of-care indicators initiating hemodialysis therapy between January 2001 and June 2010 in Northern Alberta, Canada. Hemodialysis patients were classified into categories based on the distance by road from their residence to the closest nephrologist: ≤50 (referent), 50.1-150, 150.1-300, and >300 km. Quality-of-care indicators were based on published guidelines. Quality-of-care indicators at 90 days following initiation of hemodialysis therapy and, in a secondary analysis, at 1 year. Measurements were available for 1,784 patients. At baseline, the proportions of patients residing in each category were 69% for ≤50 km to closest nephrologist; 17%, 50.1-150 km; 7%, 150.1-300 km; and 7%, >300 km. Those who lived farther away from the closest nephrologist were less likely to have seen a nephrologist 90 days prior to the initiation of hemodialysis therapy (P for trend = 0.008) and were less likely to receive Kt/V of 1.2 (adjusted OR, 0.50; 95% CI, 0.30-0.84; P for trend = 0.01). Remote location also was associated with suboptimal levels of phosphate control (P for trend = 0.005). There were no differences in the prevalence of arteriovenous fistulas or grafts or hemoglobin levels across distance categories. Registry data with limited data for non-guideline-based quality indicators. Although several quality-of-care indicators were less common in remote-dwelling hemodialysis patients, these differences do not appear sufficient to explain the previously noted disparities in clinical outcomes by residence location. 23844946 Vibration test method to study elastic stability of porous carbon nanocomposite counter electrode in dye sensitized solar cells. An out-of-plane elastic vibration test method is developed to directly study the elastic stability of elastic Ti foil-supported porous carbon nanocomposite (CNC) counter electrode (CE) of dye sensitized solar cells (DSSCs). The stability of CE, estimated by that of power conversion efficiency (PCE) of the CE-based DSSC device, is studied from the views of CNC morphology, equivalent resistances, exchange current density and contact model of CE. The results suggest thinner thickness and bigger interbundling degree of CNC layer is beneficial to the total internal impedance value of CE, and then beneficial to the CE stability. With optimal CNC structure, even if the CE is springed 1000 times with max amplification about 10 mm, the PCE of CE-based DSSC can remain 80% of the initial value. The test method is interesting and the results may have a potential use for elastic stability study of general elastic devices. 23232120 Treatment of postblepharoplasty lower eyelid malposition by Aptos thread. Lower eyelid malposition is the most common complication after lower eyelid blepharoplasty. Although the traditional techniques were effective for correcting lower eyelid malposition, they had potential disadvantages, including additional trauma, additional scar, and long recovery period. To evaluate the efficacy of a minimally invasive surgical technique using Aptos thread for postblepharoplasty lower eyelid malposition. A retrospective review of all patients undergoing lower eyelid malposition surgery via a minimal invasive, Aptos thread technique from June 2005 to June 2010. Symptoms, including epiphora, ocular irritation, conjunctivitis, and measurement of lower eyelid scleral show (measured from the inferior limbus of cornea) were recorded. Presurgery and postreconstruction photographs were reviewed for functional and cosmetic outcome. A total of 15 patients (24 eyelids) underwent successful lower eyelid malposition surgery using this minimally invasive technique. On clinical examination, all cases of lower eyelid retraction stemmed from overzealous excision of skin and orbicularis. After a follow-up interval of 12 to 25 months (mean, 15 months), inferior corneal exposure and ocular symptoms were corrected thoroughly. The decrease in lower eyelid retraction was 2.7 ± 0.9 mm. The functional and cosmetic result was satisfactory in all cases. Aptos thread technique is a safe, effective, and the least invasive method of managing mild and moderate postblepharoplasty lower eyelid malposition secondary to shortening anterior lamella. 23843949 Amyloid-β protofibrils: size, morphology and synaptotoxicity of an engineered mimic. Structural and biochemical studies of the aggregation of the amyloid-β peptide (Aβ) are important to understand the mechanisms of Alzheimer's disease, but research is complicated by aggregate inhomogeneity and instability. We previously engineered a hairpin form of Aβ called Aβcc, which forms stable protofibrils that do not convert into amyloid fibrils. Here we provide a detailed characterization of Aβ42cc protofibrils. Like wild type Aβ they appear as smooth rod-like particles with a diameter of 3.1 (±0.2) nm and typical lengths in the range 60 to 220 nm when observed by atomic force microscopy. Non-perturbing analytical ultracentrifugation and nanoparticle tracking analyses are consistent with such rod-like protofibrils. Aβ42cc protofibrils bind the ANS dye indicating that they, like other toxic protein aggregates, expose hydrophobic surface. Assays with the OC/A11 pair of oligomer specific antibodies put Aβ42cc protofibrils into the same class of species as fibrillar oligomers of wild type Aβ. Aβ42cc protofibrils may be used to extract binding proteins in biological fluids and apolipoprotein E is readily detected as a binder in human serum. Finally, Aβ42cc protofibrils act to attenuate spontaneous synaptic activity in mouse hippocampal neurons. The experiments indicate considerable structural and chemical similarities between protofibrils formed by Aβ42cc and aggregates of wild type Aβ42. We suggest that Aβ42cc protofibrils may be used in research and applications that require stable preparations of protofibrillar Aβ. 23888332 Caffeic acid regulates LPS-induced NF-κB activation through NIK/IKK and c-Src/ERK signaling pathways in endothelial cells. The redox sensitive, proinflammatory nuclear transcription factor NF-κB plays a key role in inflammation. In a redox state disrupted by oxidative stress, pro-inflammatory genes are upregulated by the activation of NF-κB via diverse kinases. Thus, the search and characterization of new substances that modulate NF-κB are topics of considerable research interest. Caffeic acid is a component of garlic, some fruits, and coffee, and is widely used as a phenolic agent in beverages. In the present study, caffeic acid was examined with respect to the modulation of inflammatory NF-κB activation via the redox-related c-Src/ERK and NIK/IKK pathways via the reduction of oxidative stress. YPEN-1 cells (an endothelial cell line) were used to explore the molecular mechanism underlying the anti-inflammatory effect of caffeic acid by examining its modulation of NF-κB signaling pathway by LPS. Our results show that LPS-induced oxidative stress-related NF-κB activation upregulated pro-inflammatory COX-2, NF-κB targeting gene which were all inhibited effectively by caffeic acid. Our study shows that caffeic acid inhibits the activation of NF-κB via the c-Src/ERK and NIK/IKK signal transduction pathways. Our results indicate that antioxidative effect of caffeic acid and its restoration of redox balance are responsible for its anti-inflammatory action. Thus, the study provides new information regarding the anti-inflammatory properties of caffeic acid and the roles in the regulation of LPS-induced oxidative stress induces alterations in signal transduction pathways. 23948594 Arteriolar diameter and spontaneous vasomotion: Importance of potassium channels and nitric oxide. Arterioles display cyclic variations in diameter, termed vasomotion initiated by smooth muscle cells (SMCs), but the endothelium should also be evaluated due to its modulatory role on vessel tone. Since nitric oxide (NO) and prostacyclin (PGI2) regulate SMC tone and activate K(+) currents, we have investigated their role on vasomotion, by observing effects of topical application of N(ω)-nitro-l-arginine (L-NA, NO synthesis inhibitor), glibenclamide (KATP channel inhibitor), sodium nitroprusside (SNP, NO donor), iloprost (PGI2 analogue) and methylene blue (MB, cGMP production inhibitor) on the cheek pouch preparation of anesthetized male hamsters. L-NA (10(-10)-10(-6)M) induced vasoconstriction, reduction and abolition of vasomotion. MB (10(-7) to 10(-5)M) reduced mean arteriolar diameter with no changes on vasomotion. In the presence of 10(-6)M of MB, addition of 10(-6)L-NA totally abolished vasomotion without further constriction. Glibenclamide (10(-6)M) in the presence of L-NA at equimolar concentration restored both vasomotion frequency and amplitude. This effect was not observed in the presence of TEA 5mM. SNP (10(-10)-10(-6)M) induced a dose-dependent increase of arteriolar diameter and decreased vasomotion. Iloprost (10(-12)-10(-6)M) induced a concentration dependent increase of arteriolar diameter, reduced vasomotion frequency, but in lower concentrations (10(-12)-10(-10)M) increased its amplitude and in higher concentrations (10(-9)-10(-6)M) decreased it. SNP and iloprost inhibited vasomotion at 10(-7)M; however, at this concentration SNP and iloprost induced an increment of 35% and 50% of the initial arteriolar diameter, respectively. In the presence of L-NA (10(-6)M), vasomotion was restored by SNP at 10(-10)M and iloprost 10(-12)M, which corresponded to 80% of the initial diameter value. Around the initial (control) arteriolar diameter value, vasomotion presented its highest frequencies and amplitudes. Cessation of vasomotion occurred with L-NA (10(-6)M) in the presence of SNP (10(-6)M) and iloprost (10(-7)M) when arteriolar diameter reached 150% and 120% of its initial value, respectively. In conclusion, the present study strongly suggests that vasomotion (1) is not solely related to vascular tone, (2) needs an interplay between vascular tone and membrane currents and (3) could be modulated by NO (but not cGMP) and KATP channels. In addition, our results point to the existence of dissociation between vasomotion frequency and amplitude. 23779109 Activity of ADAM17 (a Disintegrin and Metalloprotease 17) Is Regulated by Its Noncatalytic Domains and Secondary Structure of its Substrates. ADAM proteases are implicated in multiple diseases, but no drugs based on ADAM inhibition exist. Most of the ADAM inhibitors developed to date feature zinc-binding moieties that target the active site zinc, which leads to a lack of selectivity and off target toxicity. Targeting secondary substrate binding sites (exosites) can potentially work as an alternative strategy for drug discovery; however, there are only a few reports of potential exosites in ADAM protease structures. In the study presented here, we utilized a series of TNFα-based substrates to probe ADAM10 and 17 interactions with its canonical substrate to identify the structural features that determine ADAM protease substrate specificity. We found that noncatalytic domains of ADAM17 did not directly bind the substrates used in the study but affected the binding nevertheless, most likely because of steric hindrance. Additionally, noncatalytic domains of ADAM17 affected the size/shape of the carbohydrate-binding pocket contained within the catalytic domain of ADAM17. This suggests that noncatalytic domains of ADAM17 play a role in substrate specificity and might help explain differences in substrate repertoires of ADAM17 and its closest homologue, ADAM10. We also addressed the question of which substrate features can affect ADAM protease specificity. We found that all ADAM proteases tested (i.e., ADAM10, 12, and 17) significantly decreased activity when the TNFα-derived sequence was induced into α-helical conformation, suggesting that conformation plays a role in determining ADAM protease substrate specificity. These findings can help in the discovery of ADAM isoform- and substrate-specific inhibitors. 23407323 Deep stromal opacity after corneal cross-linking. To describe 3 cases with deep corneal stromal opacity that occurred several months after corneal cross-linking. A 36-year-old man, a 19-year-old man, and a 14-year-old girl underwent corneal cross-linking for their progressive keratoconus. Corneal cross-linking was performed according to the Dresden protocol. The corneal epithelium was ablated using an excimer laser in 2 cases and manually in 1 case. After 30 minutes of riboflavin presoaking, hypotonic riboflavin solution was applied until the corneal stroma swelled, after which the eyes were exposed to ultraviolet irradiation. Slit-lamp microscopy findings, uncorrected visual acuity, best-corrected visual acuity, manifest refraction, intraocular pressure, and corneal endothelial cell counts were evaluated, and corneal topography with Scheimpflug imaging was performed. In all cases, the epithelium healed without delay. All eyes showed mild stromal infiltration a few days after the procedure; however, the inflammation was resolved within 1 week. The corneal stroma revealed no opacity up to 1 month after the procedure. A deep stromal opacity that extended to the inferior paracentral area developed after a few months and remained for 6 months to 1 year. Because the opacity was not on the visual axis, the visual acuity was not involved. Deep stromal opacity developed several months after uneventful corneal cross-linking. Postoperative inflammation may play a crucial role in its pathogenesis. 23537230 Use of Spirometry in the Diagnosis of COPD: A Qualitative Study in Primary Care. Abstract Guidelines that recommend spirometry to confirm airflow obstruction among patients with suspected COPD are not routinely followed. We conducted a qualitative study to identify attitudes and barriers of primary care physicians to performing spirometry for patients with possible COPD. We conducted four focus groups, each with three primary care physicians (PCPs) who practice in an urban, academic medical center. In general, PCPs believed that spirometry was not necessary to confirm the diagnosis of COPD. Compared to other co-morbid conditions, in a patient with a diagnosis of COPD without self-reported symptoms, COPD was not a priority during a clinic visit. This was in part due to the belief that there was lack of evidence that medication used in COPD lead to improved outcomes and that there was no point of care measure for COPD compared to other co-morbid conditions such as diabetes mellitus or hypertension. Health system barriers specific to spirometry use was not identified. In conclusion, in our sample of PCPs, there was skepticism that spirometry is warranted to diagnose and manage COPD. Availability of spirometry was not a perceived barrier. Our results explain, in part, why previous interventions to improve access to spirometry and diagnosis of COPD in primary care settings have been difficult to conduct and/or have had marginal success. Our findings strongly suggest that a first step toward increasing the use of spirometry among primary care physicians is to have them believe in its utility in the diagnosis of COPD. 23931686 Specific detection of inflamed cells using TLR1 antibody and its secondary antibody-conjugated nano-beads. Chronic inflammation can lead to several diseases, thus analysis of the inflammation state of live cells may have important clinical applications. However, there is not currently well-established method for specific detection of inflamed cells via live cell imaging. In this study, we developed an effective antibody (Ab)-based cell imaging method for the detection of inflamed cells using Ab-conjugated nano-beads. Several receptors were tested as potential biomarkers for cell inflammation, and corresponding fluorescence-labeled Abs and/or Ab-conjugated nano-beads were used to detect inflamed cells via fluorescence imaging. Interestingly, when we employed sequential use of TLR1 primary Ab and size-optimized nano-beads conjugated with secondary Ab, we were able to clearly discriminate inflamed cells from normal ones. The Ab-based cell-imaging method described herein provides an important basis for the development of high-throughput analysis of cell inflammation, potentially leading to the identification of factors involved in inflammation and anti-inflammatory drug candidates. 23939058 Improvement of linearity in phase-modulated analog photonic link. A method to improve the linearity of the analog photonic link is proposed and experimentally demonstrated, which consists of a phase modulator and an optical tunable bandpass filter. By carefully optimizing the bandwidth and center wavelength of the filter, we can significantly suppress the third-order intermodulation distortion by ∼32  dB. Subsequently the spurious-free dynamic range of the link is improved by ∼14  dB. 23629013 Valuation of pollinator forage services provided by Eucalyptus cladocalyx. We assess the monetary value of forage provisioning services for honeybees as provided by an alien tree species in the Western Cape province of South Africa. Although Eucalyptus cladocalyx is not an officially declared invader, it is cleared on a regular basis along with other invasive Eucalyptus species such as Eucalyptus camaldulensis, and Eucalyptus conferruminata (which have been prioritised for eradication in South Africa). We present some of the trade-offs associated with the clearing of E. cladocalyx by means of a practical example that illustrates a situation where the benefits of the species to certain stakeholders could support the containment of the species in demarcated areas, while allowing clearing outside such areas. Given the absence of market prices for such forage provisioning services, the replacement cost is used to present the value of the loss in forage as provided by E. cladocalyx if the alien tree species is cleared along with invasive alien tree species. Two replacement scenarios formed the basis for our calculations. The first scenario was an artificial diet as replacement for the forage provisioning service, which yielded a direct cost estimate of US$7.5 m per year. The second was based on a Fynbos cultivation/restoration initiative aimed at substituting the forage provisioning service of E. cladocalyx, which yielded a direct cost of US$20.2 m per year. These figures provide estimates of the potential additional cost burden on the beekeeping industry if E. cladocalyx is completely eradicated from the Western Cape. The cost estimates should be balanced against the negative impacts of E. cladocalyx on ecosystem services in order to make an informed decision with regard to appropriate management strategies for this species. The findings therefore serve as useful inputs to balance trade-offs for alien species that are considered as beneficial to some, but harmful to other. 23966192 Temperature-compensated clock skew adjustment. This work analyzes several drift compensation mechanisms in wireless sensor networks (WSN). Temperature is an environmental factor that greatly affects oscillators shipped in every WSN mote. This behavior creates the need of improving drift compensation mechanisms in synchronization protocols. Using the Flooding Time Synchronization Protocol (FTSP), this work demonstrates that crystal oscillators are affected by temperature variations. Thus, the influence of temperature provokes a low performance of FTSP in changing conditions of temperature. This article proposes an innovative correction factor that minimizes the impact of temperature in the clock skew. By means of this factor, two new mechanisms are proposed in this paper: the Adjusted Temperature (AT) and the Advanced Adjusted Temperature (A2T). These mechanisms have been combined with FTSP to produce AT-FTSP and A2T-FTSP. Both have been tested in a network of TelosB motes running TinyOS. Results show that both AT-FTSP and A2T-FTSP improve the average synchronization errors compared to FTSP and other temperature-compensated protocols (Environment-Aware Clock Skew Estimation and Synchronization for WSN (EACS) and Temperature Compensated Time Synchronization (TCTS)). 23130659 Probing the binding of cationic lipids with dendrimers. Polycationic polymers are used extensively in biology to disrupt cell membranes and thus enhance the transport of materials into the cell. We report the bindings of several lipids cholesterol (Chol), 1,2-dioleoyl-3-trimethylammonium-propane(DOTAP), dioctadecyldimethylammoniumbromide (DDAB), and dioleoylphosphatidylethanolamine (DOPE) to dendrimers of different compositions such as mPEG-PAMAM (G3), mPEG-PAMAM (G4), and PAMAM (G4) under physiological conditions. FTIR, UV-visible spectroscopic, methods and molecular modeling were used to analyze the lipid binding mode, the binding constant, and the effects of lipid complexation on the dendrimer structure. The structural analysis showed that lipids bind dendrimers through both hydrophilic and hydrophobic contacts with overall binding constants of K(chol-mPEG-G3) = 1.7 × 10(3) M(-1), K(chol-mPEG-PAMAM-G4) = 2.7 × 10(3) M(-1), K(chol-PAMAM-G4) = 1.0 × 10(3) M(-1), K(DOPE-mPEG-G3) = 1.5 × 10(3) M(-1), K(DOPE-mPEG-PAMAM-G4) = 1.6 × 10(3) M(-1), K(DOPE-PAMAM-G4) = 5.3 × 10(2) M(-1), K(DDAB-mPEG-G3) = 1.5 × 10(3) M(-1), K(DDAB-mPEG-PAMAM-G4) = 1.9 × 10(2) M(-1), K(DDAB-PAMAM-G4) = 7.0 × 10(2) M(-1), K(DOTAP-mPEG-G3) = 1.9 × 10(3) M(-1), K(DOTAP-mPEG-PAMAM-G4) = 1.5 × 10(3) M(-1), and K(DOTAP-PAMAM-G4) = 5.7 × 10(2) M(-1). Weaker interaction was observed as dendrimer cationic charges increased. The free binding energies from docking were -5.15 (cholesterol), -5.79 (DDAB), and -5.36 kcal/mol (DOTAP) with the order of stability DDAB-PAMAM-G-4 > DOTAP-PAMAM-G4 > cholesterol-PAMAM-G4, consistent with the spectroscopic results. Dendrimers might act as carriers to transport lipids in vitro. 23706624 Trajectory optimization for intra-operative nuclear tomographic imaging. Diagnostic nuclear imaging modalities like SPECT typically employ gantries to ensure a densely sampled geometry of detectors in order to keep the inverse problem of tomographic reconstruction as well-posed as possible. In an intra-operative setting with mobile freehand detectors the situation changes significantly, and having an optimal detector trajectory during acquisition becomes critical. In this paper we propose an incremental optimization method based on the numerical condition of the system matrix of the underlying iterative reconstruction method to calculate optimal detector positions during acquisition in real-time. The performance of this approach is evaluated using simulations. A first experiment on a phantom using a robot-controlled intra-operative SPECT-like setup demonstrates the feasibility of the approach. 23892591 Potential Synergy between SNP and CpG-A or IL-1β in Regulating Transcriptional Activity of IL-20 Promoter. Psoriasis is a multifactorial cutaneous disorder that in many aspects is influenced by both genetic and environmental elements. Interleukin 20 (IL-20), a member of IL-10 family, is found to be involved in the development of psoriasis. In our previous study, a single nucleotide polymorphism (SNP) of IL-20 -1723CG (rs1713239) was found to be associated with psoriasis progression, especially in those induced by upper respiratory tract infection. To further explore the underlying mechanism, we investigated the function of this specific variant and its cooperative effect with bacterial-like DNA or IL-1β on regulating IL-20 expression. We found that in HaCat cells, both IL-1β and CpG-A triggered a stronger IL-20 promoter activity with the risk-associated G allele in comparison with the non-risk C allele of rs1713239. Furthermore, upon stimulation with IL-1β or CpG-A, an increased level of IL-20 expression was also observed in psoriatic lesions for those patients carrying the risk-associated G allele. This study demonstrates that rs1713239 and infection may have potential synergetic effect on modulating the transcriptional activity of IL-20.Journal of Investigative Dermatology accepted article preview online, 26 July 2013. doi:10.1038/jid.2013.314. 23287738 SAR analysis of novel non-peptidic NPBWR1 (GPR7) antagonists. In this Letter we report on the advances in our NPBWR1 antagonist program aimed at optimizing the 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one lead molecule previously obtained from a high-throughput screening (HTS)-derived hit. Synthesis and structure-activity relationships (SAR) studies around the 3,5-dimethylphenyl and 4-methoxyphenyl regions resulted in the identification of a novel series of non-peptidic submicromolar NPBWR1 antagonists based on a 5-chloro-4-(4-alkoxyphenoxy)-2-(benzyl)pyridazin-3(2H)-one chemotype. Amongst them, 5-chloro-2-(9H-fluoren-9-yl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one 9h (CYM50769) inhibited NPW activation of NPBWR1 with a submicromolar IC(50), and displayed high selectivity against a broad array of off-targets with pharmaceutical relevance. Our medicinal chemistry study provides innovative non-peptidic selective NPBWR1 antagonists that may enable to clarify the biological role and therapeutic utility of the target receptor in the regulation of feeding behavior, pain, stress, and neuroendocrine function. 23212854 The impact of information about the female condom on female condom use among males and females from a US urban community. This study investigates the impact of exposure to information about a relatively new prevention method, the female condom (FC), on actual FC use in a community of adults at risk of HIV/STI. A community-wide survey from a mid-size US city is used to estimate unbiased effects of information about the FC on FC use among sexually active men and women. To control for potential confounders we use propensity score matching (PSM) which matches the group exposed to FC information to participants who were not exposed, achieving a statistical quasi-randomization in terms of ten measured confounders. Comparisons of exposed to unexposed participants matched on their propensity scores conclude that information about the FC increases initiation of FC use, such that eleven percent more of the men and women who receive FC information reported ever using the FC. We demonstrate the use of PSM and illustrate some of its strengths and limitations. 23701518 Papillary balloon dilation is not itself a cause of post-endoscopic retrograde cholangiopancreatography pancreatitis; results of anterograde and retrograde papillary balloon dilation. The mechanism of pancreatitis development following endoscopic papillary balloon dilation (EPBD) remains unknown. Antegrade dilation with percutaneous transhepatic papillary balloon dilation (PTPBD) allows the removal of bile duct stones or fragments during percutaneous choledochoscopic lithotomy, with less mechanical trauma to the papilla than with EPBD-mediated stone removal. A total of 56 patients with bile duct stones underwent antegrade dilation with PTPBD from March 2006 to February 2011. A total of 208 patients with common bile duct stones underwent retrograde dilation with EPBD during the same period. The conditions of papillary balloon dilation were identical in both groups. The frequencies of pancreatitis and hyperamylasemia were compared in both groups. Pancreatitis occurred in 14 (6.7%) of 208 patients in the EPBD group (mild, nine; moderate, four; severe, one). There was no case of pancreatitis among 56 patients in the PTPBD group (P < 0.05). Hyperamylasemia developed in significantly more patients treated in the EPBD group (62, 29.8%) compared with the PTPBD group (4, 7.1%; P < 0.05). Complete bile duct clearance was achieved in 98.2% of PTPBD group and 97.1% of EPBD group. The rates of post-procedural pancreatitis and hyperamylasemia were significantly higher after retrograde dilation with EPBD than after antegrade dilation with PTPBD for the removal of bile duct stones. Although the mechanism of pancreatitis following papillary balloon dilation remains unclear, post-EPBD pancreatitis may be associated with procedures before and after balloon dilation similar to mechanical lithotripsy rather than balloon dilation itself. 23751289 Simple Technique for Spatially Separated Nanofibers/Nanobeads by Multinozzle Electrospinning toward White-Light Emission. Electrospun, emission color-tunable nanofibrous sheets were fabricated by multinozzle electrospinning equipped with a secondary electrode for the preparation of white-emissive sheets under a single excitation source, manipulating energy transfer between dyes. By control of the concentration of commercially available red, green, and blue dyes in the matrix polymer [poly(methyl methacrylate)], emission color tuning can be easily accomplished because each dye is located in spatially separated fibers to maintain enough distance to prevent or suppress energy transfer, allowing white-light emission. The application of dye separation for the white-light emission upon excitation with a blue light-emitting-diode lamp is demonstrated, indicative of its potential application for the easy and facile tuning of fluorescence color toward flexible illumination. 23777279 Does genital tract GBS colonization affect the latency period in patients with preterm premature rupture of membranes not in labor prior to 34 weeks? Abstract Objective: To determine if genital tract colonization with GBS at the time of preterm premature rupture of membranes (PPROM) affects the latency period. Study Design: A retrospective cohort study was performed of all gravidas admitted with PPROM between 23 and 34 weeks of gestation from 1 January 2003 to 29 February 2012. Vaginal/rectal specimens for GBS were performed on admission. The latency period and infectious complications were evaluated in GBS-positive and GBS-negative groups. Results: Hundred and eighty-nine women were identified with PPROM, 177 meet the inclusion criteria. 60 patients were GBS positive on admission, 117 were GBS negative. Median latency period in GBS-positive and GBS-negative groups did not differ (6.8 versus 7.3 days, p = 0.384). Risk of intra-amniotic, wound infection, maternal and neonatal sepsis, and composite infectious morbidity did not differ between the GBS-positive and GBS-negative groups. Among patients who underwent cesarean delivery, GBS-negative group had a higher risk of endomyometritis (25%) compared to the GBS-positive group (6%), p = 0.05. Conclusion: GBS genital tract colonization on admission does not appear to affect the latency period or increase the risk of intra-amniotic infection in patients with PPROM. 23735610 Should Follow-up Biopsies for Men on Active Surveillance for Prostate Cancer Be Restricted to Limited Templates? To investigate if prostate biopsy templates with fewer cores can be used during active surveillance (AS) for prostate cancer. At present, we use an AS protocol template (ASPT) consisting of 13-17 cores. We hypothesize in the setting of known cancer, sextant (6 cores) or standard extended (10-12 cores) templates, could be used with similar effect. We identified patients in our referral institution database (1997-2009) with entry prostate-specific antigen <10 ng/mL, stage â‰¤cT2, Gleason sum â‰¤6, â‰¤3 cores positive for cancer, <50% of single core involved, and age â‰¤75 years (N = 272). Patients fulfilling standard criteria for pathologic reclassification (N = 94) at any follow-up biopsy were selected for evaluation. By mapping tumor location on the pathologic reclassification determining biopsy, hypothetical scenarios of sextant or standard extended templates (SET) were compared with our ASPT and examined for frequency of cancer detection and pathologic reclassification. For the 94 patients analyzed, the median number of cores taken was 9.7 (6-22) at baseline and 15 (14-17) for the reclassification biopsy. The median time between baseline and the pathologic reclassification determining biopsy was 15.4 months. Analysis of subgroupings showed that sextant template would identify 84% of cancers and 47.9% of the reclassification events, whereas SET detected 99% of cancers and 81.9% of patients who pathologically reclassified. When only considering Gleason sum â‰¥7 related progression events, SET found 16.2% less (n = 57) compared with ASPT (n = 68). When monitoring patients on AS, a 13-17 core template detects more pathologic reclassification than standard sextant (18.1%) or extended (52.1%) biopsy templates. 23673005 Classification of ester oils according to their Equivalent Alkane Carbon Number (EACN) and asymmetry of fish diagrams of C10E4/ester oil/water systems. The phase behavior of well-defined C10E4/ester oil/water systems versus temperature was investigated. Fifteen ester oils were studied and their Equivalent Alkane Carbon Numbers (EACNs) were determined from the so-called fish-tail temperature T* of the fish diagrams obtained with an equal weight amount of oil and water (f(w)=0.5). The influence of the chemical structure of linear monoester on EACN was quantitatively rationalized in terms of ester bonds position and total carbon number, and explained by the influence of these polar oils on the "effective" packing parameter of the interfacial surfactant, which takes into account its entire physicochemical environment. In order to compare the behaviors of typical mono-, di-, and triester oils, three fish diagrams were entirely plotted with isopropyl myristate, bis (2-ethylhexyl) adipate, and glycerol trioctanoate. When the number of ester bonds increases, a more pronounced asymmetry of the three-phase body of the fish diagram with respect to T* is observed. In this case, T* is much closer to the upper limit temperature Tu than to the lower limit temperature Tl of the three-phase zone. This asymmetry is suggested to be linked to an increased solubility of the surfactant in the oil phase, which decreases the surfactant availability for the interfacial pseudo-phase. As a consequence, the asymmetry depends on the water-oil ratio, and a method is proposed to determine the fw value at which T* is located at the mean value of Tu and Tl. 23875050 Mycobacterium ulcerans Disease: Experience with Primary Oral Medical Therapy in an Australian Cohort. Mycobacterium ulcerans (MU) is responsible for disfiguring skin lesions and is endemic on the Bellarine peninsula of southeastern Australia. Antibiotics have been shown to be highly effective in sterilizing lesions and preventing disease recurrences when used alone or in combination with surgery. Our practice has evolved to using primarily oral medical therapy. From a prospective cohort of MU patients managed at Barwon Health, we describe those treated with primary medical therapy defined as treatment of a M. ulcerans lesion with antimicrobials either alone or in conjunction with limited surgical debridement. From 1/10/2010 through 31/12/11, 43 patients were treated with exclusive medical therapy, of which 5 (12%) also underwent limited surgical debridement. The median patient age was 50.2 years, and 86% had WHO category 1 and 91% ulcerative lesions. Rifampicin was combined with ciprofloxacin in 30 (70%) and clarithromycin in 12 (28%) patients. The median duration of antibiotic therapy was 56 days, with 7 (16%) receiving less than 56 days. Medication side effects requiring cessation of one or more antibiotics occurred in 7 (16%) patients. Forty-two (98%) patients healed without recurrence within 12 months, and 1 patient (2%) experienced a relapse 4 months after completion of 8 weeks of antimicrobial therapy. Our experience demonstrates the efficacy and safety of primary oral medical management of MU infection with oral rifampicin-based regimens. Further research is required to determine the optimal and minimum durations of antibiotic therapy, and the most effective antibiotic dosages and formulations for young children. 23856983 Intravitreal silicone oil induced changes in corneal biomechanics. Our aim was to detect the early effects of pars plana vitrectomy (PPV) combined with intravitreal silicone oil (SO) on corneal biomechanics. 19 eyes underwent PPV with SO tamponade (group 1) and 16 eyes underwent. PPV without tamponade (group 2). Corneal biomechanical parameters were measured preoperatively and at the first postoperative month by ocular response analyzer. The mean preoperative intraocular pressure (IOP) by Goldmann applanation tonometry (GAT) and the mean corneal-compensated intraocular pressure (IOPcc) were significantly lower in group 1 than group 2 (p = 0.005, p = 0.002, respectively). The mean preoperative corneal hysteresis (CH) and corneal resistance factor (CRF) were significantly higher in group 1 than group 2 (p = 0.017, p = 0.002, respectively). However, the difference in Goldmann-correlated intraocular pressure (IOPg) between the groups was not significant (p = 0.360). In group 1, IOPcc, IOPg and IOP-GAT significantly increased postoperatively (p = 0.002, p = 0.004, p = 0.002, respectively) but CH and CRF decreased (p = 0.007, p = 0.153, respectively). In group 2, IOPcc, IOPg and IOP (GAT) increased postoperatively but the differences were not significant (p = 0.851, p = 0.693, p = 0.336, respectively). The mean CRF increased significantly (p = 0.026) postoperatively but the decrease in CH was not significant (p = 0.196). Statistically significant differences were found in the changes of preoperative and postoperative means of IOPcc, IOPg, IOP-GAT and CRF between the groups (p = 0.024, p = 0.037, p = 0.014, p = 0.006, respectively). However, the difference in the decreases in CH between the two groups was not statistically significant (p = 0.206). SO tamponade may affect corneal biomechanical parameters in the early postoperative period, which may be related to the surgery itself, SO tamponade or IOP changes. 23909554 Upper cervical cord compression due to a C-1 posterior arch in a patient with ossification of the posterior longitudinal ligament and a kyphotic cervical spine in the protruded-head position. In this paper the authors report the case of a patient with ossification of the posterior longitudinal ligament (OPLL) below the axial vertebra (C-2) at the kyphotic cervical spine, with an atlas vertebra (C-1) posterior arch that compressed the spinal cord with the head in a pathognomonic position, similar to a protruded position. This condition appears to be very rare. The morphological findings between the kyphotic cervical spine and OPLL, the upper occipitocervical junction, and the protruded-head position are discussed. A 40-year-old man presented with severe pain radiating to both legs when he yawned, sneezed, or extended his jaw (a protruded-head position). A kyphotic cervical spine with OPLL below C-2 was observed using CT and radiography, yet sagittal T2-weighted MRI failed to identify abnormal findings in a neutral or extension position, except for a slight cervical canal stenosis. However, in a pathognomonic protruded-head position, sagittal T2-weighted MRI showed a C-1 posterior arch that severely compressed the spinal cord at the upper cervical level. Therefore, the authors believe that the severe pain radiating to both legs was caused by a spinal canal stenosis due to a C-1 posterior arch impingement. The C-1 posterior arch was resected, and after the surgery, the patient indicated that the intolerable pain had disappeared. In conclusion, in patients with OPLL and a kyphotic cervical spine, the authors propose that the pathognomonic protruded position is valuable for estimating disrupted compensatory mechanisms at the upper cervical junction. 23901887 Targeting of Tumor-Associated Macrophages Made Possible by PEG-Sheddable, Mannose-Modified Nanoparticles. It is increasingly evident that tumor-associated macrophages (TAMs) play an important role in tumor invasion, proliferation, and metastasis. While delivery of drugs, imaging agents, and vaccines to TAMs was achieved by exploiting membrane receptors on TAMs, the uptake by normal macrophages remains an issue. In this communication, we report a PEG-sheddable, mannose-modified nanoparticle platform that can efficiently target TAMs via mannose-mannose receptor recognition after acid-sensitive PEG shedding in the acidic tumor microenvironment, while their uptake by normal macrophages in the mononuclear phagocyte system (MPS) organs was significantly reduced due to effective PEG shielding at neutral pH. These nanoparticles have the potential to target drugs of interest to TAMs, with decreased uptake by normal macrophages. 23724778 Role of propagule pressure in colonization success: disentangling the relative importance of demographic, genetic and habitat effects. High propagule pressure is arguably the only consistent predictor of colonization success. More individuals enhance colonization success because they aid in overcoming demographic consequences of small population size (e.g. stochasticity and Allee effects). The number of founders can also have direct genetic effects: with fewer individuals, more inbreeding and thus inbreeding depression will occur, whereas more individuals typically harbour greater genetic variation. Thus, the demographic and genetic components of propagule pressure are interrelated, making it difficult to understand which mechanisms are most important in determining colonization success. We experimentally disentangled the demographic and genetic components of propagule pressure by manipulating the number of founders (fewer or more), and genetic background (inbred or outbred) of individuals released in a series of three complementary experiments. We used Bemisia whiteflies and released them onto either their natal host (benign) or a novel host (challenging). Our experiments revealed that having more founding individuals and those individuals being outbred both increased the number of adults produced, but that only genetic background consistently shaped net reproductive rate of experimental populations. Environment was also important and interacted with propagule size to determine the number of adults produced. Quality of the environment interacted also with genetic background to determine establishment success, with a more pronounced effect of inbreeding depression in harsh environments. This interaction did not hold for the net reproductive rate. These data show that the positive effect of propagule pressure on founding success can be driven as much by underlying genetic processes as by demographics. Genetic effects can be immediate and have sizable effects on fitness. 23962900 Acacetin and chrysin, two polyphenolic compounds, alleviate telomeric position effect in human cells. We took advantage of the ability of human telomeres to silence neighboring genes (telomere position effect or TPE) to design a high-throughput screening assay for drugs altering telomeres. We identified, for the first time, that two dietary flavones, acacetin and chrysin, are able to specifically alleviate TPE in human cells. We further investigated their influence on telomere integrity and showed that both drugs drastically deprotect telomeres against DNA damage response. However, telomere deprotection triggered by shelterin dysfunction does not affect TPE, indicating that acacetin and chrysin target several functions of telomeres. These results show that TPE-based screening assays represent valuable methods to discover new compounds targeting telomeres.Molecular Therapy-Nucleic Acids (2013) 2, e116; doi:10.1038/mtna.2013.42; published online 20 August 2013. 23966904 Progesterone inhibition of oxytocin signaling in endometrium. Expression of the oxytocin receptor (OXTR) in the endometrium of ruminant species is regulated by the ovarian steroids progesterone (P) and estradiol (E). Near the end of the estrous cycle, long-term exposure of endometrial epithelial cells to P results in loss of genomic P receptors (PGRs), leading to an increase in E receptors (ERs). Genomic regulation of the OXTR is mediated via suppression of ER signaling by P. Upon OT binding at the plasma membrane of endometrial cells, a signaling cascade is generated stimulating release of prostaglandin F2α (PGF2α). Transport of PGF2α to the ovary results in release of OT by luteal cells in a positive feedback loop leading to luteal regression. This signaling cascade can be rapidly blocked by exposing endometrial cells to physiologic levels of P. This mini review will focus on the mechanisms by which P may act to block OXTR signaling and the luteolytic cascade in the ruminant endometrium, with special focus on both non-genomic signaling pathways and non-receptor actions of P at the level of the plasma membrane. While this review focuses on ruminant species, non-classical blockage of OXTR signaling may be important for fertility in women. 23888003 Determination of Photocyanine in Human Serum by HPLC and Application to Pharmacokinetic Study. Photocyanine, a novel amphoteric phthalocyanine drug, showed favorable anticancer activity in vivo. Pharmacokinetic study in cancer patients is an important component in dose administration choice. In this study, a rapid, sensitive analytical method based on high-performance liquid chromatography with ultraviolet detection was developed and validated for the determination of four isomers of photocyanine (FD1-4) in cancer patients. Sample preparation involved liquid-liquid extraction with a combination of ultrasound and N,N-dimethyl formamide. Calibration curves (1/x(2)) offered satisfactory linearity for the four isomers of photocyanine. The lower limit of quantification (LLOQ) for FD1-3 isomers was 30 ng/mL, and LLOQ for FD-4 was 5 ng/mL. Inter- and intra-day accuracies for four isomers ranged from 96.6 to 105.5%, and 95.0 to 103.6%, respectively. Inter- and intra-day precision ranged from 4.8 to 8.9%, and 3.6 to 12.2%, respectively. Stability studies showed that photocyanine was stable. This method was successfully used to quantify photocyanine in a pharmacokinetic study in which a single-dose of photocyanine (0.1 mg/kg) was intravenously administered to patients with cancer. On the basis of the discovery that photocyanine has a half-life of 57.5 h in vivo, we suggest that avoiding light for a longer period is essential for patients undergoing photocyanine therapy. 23873035 Interpretation of low-vision rehabilitation outcome measures. This article presents a theoretical interpretation of patient-reported outcomes of low-vision rehabilitation (LVR) using rating scale questionnaires and uses previously published results of LVR outcome studies to illustrate theoretical points and validate assumptions. Patients' judgments of the difficulty they have performing tasks are interpreted as magnitude estimates of their functional reserve for each task, which is the difference between their visual ability and the visual ability demanded by the task. We assume that improvements in functional reserve can occur by increasing the patient's visual ability with medical, surgical, or refractive interventions or decreasing the visual ability demanded by the item with activity-specific vision assistive equipment, adaptations, and environmental modifications. Activity-specific interventions cause differential item functioning (intervention-related DIF). Intervention-related DIF makes the measured size of the treatment effect dependent on the item content and the mix of responsive and unresponsive items to intervention. Because intervention-related DIF depends on the choice of items, the outcome measure selected should be appropriate to the aims of the intervention and the impairment level of the sample to demonstrate the full effects of an intervention. Items that are given extreme positive ratings at preintervention baseline (e.g., "not difficult") have no room for improvement. These items must also be filtered out because they will dilute the measured effect of the activity-specific interventions of LVR. 23764402 Viral categorization and discovery in human circulation by transcriptome sequencing. Serum is the most common and easily accessible patient specimen in a minimally invasive manner. As a biological resource, RNA in serum has been less explored for its clinical utilization due to prevailing concerns regarding its high degradable nature. In the current study, however, we have documented the use of human serum RNA for viral categorization and discovery through transcriptome sequencing and analysis using well-curated databases and advanced bioinformatic tools. Such an integrated approach may have an immediate application in any clinical situations concerning with viral etiology. 23919971 Understanding diversity of hepatic metabolism and related adaptations in the early lactating dairy cow. The onset of lactation in dairy cows represents a major metabolic challenge that involves large adaptations in glucose, fatty acid, and mineral metabolism to support lactation and to avoid metabolic dysfunction. The complex system of adaptation can differ considerably between cows, and may have a genetic base. In the present review, the variation in adaptive reactions in dairy cows is discussed. In these studies, the liver being a key metabolic regulator for understanding the variation in adaptive performance of the dairy cow was the main focus of research. Liver function was evaluated through gene expression measurements; to explain the associated phenotypic variability and to identify descriptors for metabolic robustness in dairy cows. Hence, the identified genes involved act as a connecting link between the genotype encoded on the DNA and the phenotypic expression of the target factors at a protein level. The integration of phenotypic data, including gene expression profiles, and genomic data will facilitate a better characterization of the complex interplay between these levels, and will improve the genetic understanding necessary to unravel a certain trait or multi-trait such as metabolic robustness in dairy cows. Abstract available from the publisher. 23945941 Replication fork collapse is a major cause of the high mutation frequency at three-base lesion clusters. Unresolved repair of clustered DNA lesions can lead to the formation of deleterious double strand breaks (DSB) or to mutation induction. Here, we investigated the outcome of clusters composed of base lesions for which base excision repair enzymes have different kinetics of excision/incision. We designed multiply damaged sites (MDS) composed of a rapidly excised uracil (U) and two oxidized bases, 5-hydroxyuracil (hU) and 8-oxoguanine (oG), excised more slowly. Plasmids harboring these U-oG/hU MDS-carrying duplexes were introduced into Escherichia coli cells either wild type or deficient for DNA n-glycosylases. Induction of DSB was estimated from plasmid survival and mutagenesis determined by sequencing of surviving clones. We show that a large majority of MDS is converted to DSB, whereas almost all surviving clones are mutated at hU. We demonstrate that mutagenesis at hU is correlated with excision of the U placed on the opposite strand. We propose that excision of U by Ung initiates the loss of U-oG-carrying strand, resulting in enhanced mutagenesis at the lesion present on the opposite strand. Our results highlight the importance of the kinetics of excision by base excision repair DNA n-glycosylases in the processing and fate of MDS and provide evidence for the role of strand loss/replication fork collapse during the processing of MDS on their mutational consequences. 23967907 Reciprocity in the scattering coefficients of acoustic waveguide modes. In this Letter, a proof is provided for the reciprocity between modal scattering coefficients of the acoustic waveguides connected by a junction enclosure. The result holds for all waveguide modes and for junction enclosures with locally reactive boundary conditions away from the interfaces between the junction and waveguides. Also provided is a physical interpretation of the reciprocity of the modal scattering coefficients. The scattering of two-dimensional waveguide modes by a right-angled bend in a rectangular duct is used as an illustrating example. 23869571 Desymmetrization of Bicyclo[3.n.1]-3-one Derivatives by Palladium-Catalyzed Asymmetric Allylic Alkylation. Desymmetrization of carbon nucleophiles by palladium-catalyzed asymmetric allylic alkylation has been realized for the first time. Products with three chiral centers were obtained in good yield and with high diastereo- and enantioselectivity. The method offers an efficient access to optically active tropane derivatives. 23895073 Current trends in aortic valve replacement: development of the rapid deployment EDWARDS INTUITY valve system. Although conventional aortic valve replacement (AVR) surgery remains the gold standard for patients with aortic stenosis, transcutaneous aortic valve replacement is becoming increasingly common in high-risk patients. The techniques of minimal invasive surgery (MIS) have been well known for many years, but MIS is applied in a disappointingly low percentage of patients undergoing AVR surgery. The EDWARDS INTUITY rapid deployment aortic valve system is designed to facilitate the performance of MIS AVR surgery. In addition, the reduced implantation times may be beneficial in higher risk patients or those requiring concomitant procedures. The system combines established pericardial valve technology with modern stent expertise obtained from the transcutaneous aortic valve replacement experience. Preliminary results from a multicenter trial have shown low rates of morbidity and mortality, and excellent hemodynamic performance. The EDWARDS INTUITY promises to be an exciting device that may further change the landscape of aortic valve intervention. 23826804 Are systemic lupus erythematosus patients carrying MEFV gene less prone to renal involvement? Report of three cases and review of the literature. Abstract Familial Mediterranean fever (FMF) is an autosomal recessive auto inflammatory disease, characterized by acute attacks of serositis, arthritis or skin rash. Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease characterized by multisystem inflammatory lesions affecting any organ systems in the body. Coexistence of FMF and SLE is rare in literature. In this report, we present three patients with FMF associated with SLE. 23806600 Effect of blonanserin on methamphetamine-induced disruption of latent inhibition and c-Fos expression in rats. To clarify the psychopharmacological profile of blonanserin, a novel antipsychotic, we examined its effect on the methamphetamine-induced disruption of latent inhibition (LI) and the neural activation related to this effect in rats. To evaluate the LI, we used a conditioned emotional response in which a tone (conditioned stimulus) was paired with a mild foot shock (unconditioned stimulus). This paradigm was presented to rats licking water. Methamphetamine-induced (1.0mg/kg, i.p.) disruption of LI was significantly improved by the administration of a higher dose (3.0mg/kg, i.p.) of blonanserin and tended to be improved by 1.0-mg/kg blonanserin and 0.2-mg/kg haloperidol but not by a lower dose (0.3mg/kg) of blonanserin. Immunohistochemical examination showed blonanserin (3.0mg/kg, i.p.) increased c-Fos expression in the shell area but not in the core area of the nucleus accumbens while methamphetamine (3.0mg/kg, i.p.) produced the opposite expression pattern. Blonanserin also increased the number of c-Fos expressions in the central amygdala nucleus but not in the basolateral amygdala nucleus or the prefrontal cortex. Blonanserin ameliorates the methamphetamine-induced disruption of LI, as other antipsychotics do, and a neuronal activation and/or modulation of neurotransmission in the nucleus accumbens is related to the disruption of LI by methamphetamine and to its amelioration by blonanserin. 23958846 Diagnosing Diabetes Mellitus: Performance of Hemoglobin A1c Point-of-Care Instruments in General Practice Offices. BackgroundHemoglobin A1c (Hb A1c) measurement by hospital laboratory instruments, but not by point-of-care (POC) instruments, has been recommended for use to diagnose diabetes mellitus. We evaluated results from 13 Hb A1c external quality assurance (EQA) surveys over a 6-year period in Norway, from both POC instruments used in general practice (GP) offices and instruments in hospital laboratories, against the analytical quality specifications recommended for use of Hb A1c to diagnose diabetes mellitus.METHODS: All GP offices (n = 1288) and hospital laboratories (n = 52) measuring Hb A1c in Norway participated in the EQA survey. The percentage of participants that performed measurements within the quality specifications was calculated. Pooled within-laboratory CVs were estimated for the Afinion, DCA 2000, DCA 2000+, DCA Vantage(TM), and Nycocard Hb A1c Reader instruments and for hospital laboratory instruments.RESULTS: Between 60% to 90% of Afinion and DCA users and hospital laboratories performed Hb A1c measurements within the quality specifications for both trueness (6.0%) and imprecision (CV ≤2.0%) at 2 levels in each EQA survey. The pooled within-laboratory CVs for the Afinion and DCA instruments and hospital laboratories were below the recommended limits of 2.0% for most of the surveys.CONCLUSIONS: A large proportion of GP offices using Afinion and DCA POC instruments to measure Hb A1c fulfill the analytical quality specifications for diagnosing diabetes mellitus, and these instruments demonstrate analytical quality comparable to that of hospital laboratory instruments. When GP offices participate in a stringent quality assurance program and generate Hb A1c measurements that meet analytical quality specifications, these measurements can be recommended for use to diagnose diabetes mellitus. 23707583 Probabilistic functional tractography of the human cortex. Single-pulse direct electrical stimulation of cortical regions in patients suffering from focal drug-resistant epilepsy who are explored using intracranial electrodes induces cortico-cortical potentials that can be used to infer functional and anatomical connectivity. Here, we describe a neuroimaging framework that allows development of a new probabilistic atlas of functional tractography of the human cortex from those responses. This atlas is unique because it allows inference in vivo of the directionality and latency of cortico-cortical connectivity, which are still largely unknown at the human brain level. In this technical note, we include 1535 stimulation runs performed in 35 adult patients. We use a case of frontal lobe epilepsy to illustrate the asymmetrical connectivity between the posterior hippocampal gyrus and the orbitofrontal cortex. In addition, as a proof of concept for group studies, we study the probabilistic functional tractography between the posterior superior temporal gyrus and the inferior frontal gyrus. In the near future, the atlas database will be continuously increased, and the methods will be improved in parallel, for more accurate estimation of features of interest. Generated probabilistic maps will be freely distributed to the community because they provide critical information for further understanding and modelling of large-scale brain networks. 23205610 From an atypical wake-promoting agent to potent histamine-3 receptor inverse agonists. Utilizing atypical wake-promoting agent modafinil (inactive in both rH(3) and hH(3) binding assays) as a launching pad, a series of sulfinyl- and sulfone-derived H(3) receptor inverse agonists were developed. Brain-permeable compound 27, a potent member of the series displayed excellent selectivity against related family members (H(1), H(2), and H(4) receptors). 23824137 Can health public expenditure reduce the tragic consequences of road traffic accidents? The EU-27 experience. This study uses data for the EU-27 countries in the period 1999-2009 to estimate determinants of road traffic fatality rates. Controlling for country attributes and road safety policy variables, we examine the influence of variables related with the national health systems; the number of hospital beds per square kilometer, and the percentage of health expenditures over gross domestic product. We find evidence that the density of hospital beds contributes to the fall in traffic-related fatalities. Furthermore, the quality of general medical facilities and technology associated with increases in health expenditure may be also a relevant factor in reducing road traffic fatalities. 23827379 Nutritional assessment in neonatal and prepubertal children with a history of extrauterine growth restriction. Nutritional deficit during perinatal stage may induce significant alterations in adipose tissue and increase the risk of obesity, metabolic syndrome and cardiovascular disease in children with a history of extrauterine growth restriction (EUGR). To describe the nutritional status in neonatal and prepubertal with a history of EUGR and establish an association between EUGR and later conditions. Descriptive, analytical, observational case-control study. The study included a sample of 38 prepubertal children with a history of EUGR, and 123 gender-and-age matched controls. The EUGR group was asked to answer a food frequency questionnaire. Analysis of body composition in both groups included anthropometric measurements, assessment of blood pressure and biochemical markers. Newborns with EUGR received parenteral feeding with a standard nutritional regime and long-chain fatty acid support for 41±23days; enteral feeding with a special formula for premature infants was initiated at 7±11days of life. At the prepubertal stage, daily fiber and fatty acid intake in children who had experienced EUGR in the neonatal stage was below the recommended intake. In the EUGR group, the intake of vegetables, fruits and olive oil was below dietary recommendations, while the intake of butchery, fatty meats, pastries and snacks was above the recommendations for the Spanish population. Appropriate nutrition education strategies should be developed for children with a history of EUGR to prevent later associated pathologies, as neonatal nutritional support and feeding during childhood are associated with an increase in diseases in this risk group. 23639875 Prostaglandin E2 acts via bone marrow macrophages to block PTH-stimulated osteoblast differentiation in vitro. Intermittent PTH is the major anabolic therapy for osteoporosis while continuous PTH causes bone loss. PTH acts on the osteoblast (OB) lineage to regulate bone resorption and formation. PTH also induces cyclooxygenase-2 (COX-2), producing prostaglandin E2 (PGE2), that can act on both OBs and osteoclasts (OCs). Because intermittent PTH is more anabolic in Cox-2 knockout (KO) than wild type (WT) mice, we hypothesized COX-2 might contribute to the effects of continuous PTH by suppressing PTH-stimulated differentiation of mesenchymal stem cells into OBs. We compared effects of continuous PTH on bone marrow stromal cells (BMSCs) and primary OBs (POBs) from Cox-2 KO mice, mice with deletion of PGE2 receptors (Ptger4 and Ptger2 KO mice), and WT controls. PTH increased OB differentiation in BMSCs only in the absence of COX-2 expression or activity. In the absence of COX-2, PTH stimulated differentiation if added during the first week of culture. In Cox-2 KO BMSCs, PTH-stimulated differentiation was prevented by adding PGE2 to cultures. Co-culture of POBs with M-CSF-expanded bone marrow macrophages (BMMs) showed that the inhibition of PTH-stimulated OB differentiation required not only COX-2 or PGE2 but also BMMs. Sufficient PGE2 to mediate the inhibitory effect was made by either WT POBs or WT BMMs. The inhibitory effect mediated by COX-2/PGE2 was transferred by conditioned media from RANKL-treated BMMs and could be blocked by osteoprotegerin, which interferes with RANKL binding to its receptor on OC lineage cells. Deletion of Ptger4, but not Ptger2, in BMMs prevented the inhibition of PTH-stimulated OB differentiation. As expected, PGE2 also stimulated OB differentiation, but when given in combination with PTH, the stimulatory effects of both were abrogated. These data suggest that PGE2, acting via EP4R on BMMs committed to the OC lineage, stimulated secretion of a factor or factors that acted to suppress PTH-stimulated OB differentiation. This suppression of OB differentiation could contribute to the bone loss seen with continuous PTH in vivo. 23819468 Flexible palladium-based h2 sensor with fast response and low leakage detection by nanoimprint lithography. Flexible palladium-based H2 sensors have a great potential in advanced sensing applications, as they offer advantages such as light weight, space conservation, and mechanical durability. Despite these advantages, the paucity of such sensors is due to the fact that they are difficult to fabricate while maintaining excellent sensing performance. Here, we demonstrate, using direct nanoimprint lithography of palladium, the fabrication of a flexible, durable, and fast responsive H2 sensor that is capable of detecting H2 gas concentration as low as 50 ppm. High resolution and high throughput patterning of palladium gratings over a 2 cm × 1 cm area on a rigid substrate was achieved by heat-treating nanoimprinted palladium benzyl mercaptide at 250 °C for 1 h. The flexible and robust H2 sensing device was fabricated by subsequent transfer nanoimprinting of these gratings into a polycarbonate film at its glass transition temperature. This technique produces flexible H2 sensors with improved durability, sensitivity, and response time in comparison to palladium thin films. At ambient pressure and temperature, the device showed a fast response time of 18 s at a H2 concentration of 3500 ppm. At 50 ppm concentration, the response time was found to be 57 s. The flexibility of the sensor does not appear to compromise its performance. 23934886 Empirical Complexities in the Genetic Foundations of Lethal Mutagenesis. From population genetics theory, elevating the mutation rate of a large population should progressively reduce average fitness. If the fitness decline is large enough, the population will go extinct in a process known as lethal mutagenesis. Lethal mutagenesis has been endorsed in the virology literature as a promising approach to viral treatment, and several in vitro studies have forced viral extinction with high doses of mutagenic drugs. Yet only one empirical study has tested the genetic models underlying lethal mutagenesis, and the theory failed on even a qualitative level. Here we provide a new level of analysis of lethal mutagenesis by developing and evaluating models specifically tailored to empirical systems that may be used to test the theory. We first quantify a bias in the estimation of a critical parameter and consider whether that bias underlies the previously observed lack of concordance between theory and experiment. We then consider a seemingly ideal protocol that avoids this bias - mutagenesis of virions - but find that it is hampered by other problems. Last, results are derived that reveal difficulties in the mere interpretation of mutations assayed from double-stranded genomes. Our analyses expose unanticipated complexities in testing the theory. Nevertheless, the previous failure of the theory to predict experimental outcomes appears to reside in evolutionary mechanisms neglected by the theory (e.g., beneficial mutations) rather than from a mismatch between the empirical setup and model assumptions. This interpretation raises the specter that naïve attempts at lethal mutagenesis may augment adaptation rather than retard it. 23847597 Archaeal and bacterial diversity in an arsenic-rich shallow-sea hydrothermal system undergoing phase separation. Phase separation is a ubiquitous process in seafloor hydrothermal vents, creating a large range of salinities. Toxic elements (e.g., arsenic) partition into the vapor phase, and thus can be enriched in both high and low salinity fluids. However, investigations of microbial diversity at sites associated with phase separation are rare. We evaluated prokaryotic diversity in arsenic-rich shallow-sea vents off Milos Island (Greece) by comparative analysis of 16S rRNA clone sequences from two vent sites with similar pH and temperature but marked differences in salinity. Clone sequences were also obtained for aioA-like functional genes (AFGs). Bacteria in the surface sediments (0-1.5 cm) at the high salinity site consisted of mainly Epsilonproteobacteria (Arcobacter sp.), which transitioned to almost exclusively Firmicutes (Bacillus sp.) at ~10 cm depth. However, the low salinity site consisted of Bacteroidetes (Flavobacteria) in the surface and Epsilonproteobacteria (Arcobacter sp.) at ~10 cm depth. Archaea in the high salinity surface sediments were dominated by the orders Archaeoglobales and Thermococcales, transitioning to Thermoproteales and Desulfurococcales (Staphylothermus sp.) in the deeper sediments. In contrast, the low salinity site was dominated by Thermoplasmatales in the surface and Thermoproteales at depth. Similarities in gas and redox chemistry suggest that salinity and/or arsenic concentrations may select for microbial communities that can tolerate these parameters. Many of the archaeal 16S rRNA sequences contained inserts, possibly introns, including members of the Euryarchaeota. Clones containing AFGs affiliated with either Alpha- or Betaproteobacteria, although most were only distantly related to published representatives. Most clones (89%) originated from the deeper layer of the low salinity, highest arsenic site. This is the only sample with overlap in 16S rRNA data, suggesting arsenotrophy as an important metabolism in similar environments. 23858035 microRNA-17-92 Regulates IL-10 Production by Regulatory T Cells and Control of Experimental Autoimmune Encephalomyelitis. microRNAs (miRNA) are essential for regulatory T cell (Treg) function but little is known about the functional relevance of individual miRNA loci. We identified the miR-17-92 cluster as CD28 costimulation dependent, suggesting that it may be key for Treg development and function. Although overall immune homeostasis was maintained in mice with miR-17-92-deficient Tregs, expression of the miR-17-92 miRNA cluster was critical for Treg accumulation and function during an acute organ-specific autoimmune disease in vivo. Treg-specific loss of miR-17-92 expression resulted in exacerbated experimental autoimmune encephalitis and failure to establish clinical remission. Using peptide-MHC tetramers, we demonstrate that the miR-17-92 cluster was specifically required for the accumulation of activated Ag-specific Treg and for differentiation into IL-10-producing effector Treg. 23798313 Comparative analysis of the performance of commonly available density functionals in the determination of geometrical parameters for copper complexes. In this study, a set of 50 transition-metal complexes of Cu(I) and Cu(II), were used in the evaluation of 18 density functionals in geometry determination. In addition, 14 different basis sets were considered, including four commonly used Pople's all-electron basis sets; four basis sets including popular types of effective-core potentials: Los Alamos, Steven-Basch-Krauss, and Stuttgart-Dresden; and six triple-ζ basis sets. The results illustrate the performance of different methodological alternatives for the treatment of geometrical properties in relevant copper complexes, pointing out Double-Hybrid (DH) and Long-range Correction (LC) Generalized Gradient Approximation (GGA) methods as better descriptors of the geometry of the evaluated systems. These however, are associated with a computational cost several times higher than some of the other methods employed, such as the M06 functional, which has also demonstrated a comparable performance. Regarding the basis sets, 6-31+G(d) and 6-31+G(d,p) were the best performing approaches. In addition, the results show that the use of effective-core potentials has a limited impact, in terms of the accuracy in the determination of metal-ligand bond-lengths and angles in our dataset of copper complexes. Hence, these could become a good alternative for the geometrical description of these systems, particularly CEP-121G and SDD basis sets, if one is considering larger copper complexes where the computational cost could be an issue. © 2013 Wiley Periodicals, Inc. 23885955 Global informetric perspective studies on translational medical research. Translational medical research literature has increased rapidly in the last few decades and played a more and more important role during the development of medicine science. The main aim of this study is to evaluate the global performance of translational medical research during the past few decades. Bibliometric, social network analysis, and visualization technologies were used for analyzing translational medical research performance from the aspects of subject categories, journals, countries, institutes, keywords, and MeSH terms. Meanwhile, the co-author, co-words and cluster analysis methods were also used to trace popular topics in translational medical research related work. Research output suggested a solid development in translational medical research, in terms of increasing scientific production and research collaboration. We identified the core journals, mainstream subject categories, leading countries, and institutions in translational medical research. There was an uneven distribution of publications at authorial, institutional, and national levels. The most commonly used keywords that appeared in the articles were "translational research", "translational medicine", "biomarkers", "stroke", "inflammation", "cancer", and "breast cancer". The subject categories of "Research & Experimental Medicine", "Medical Laboratory Technology", and "General & Internal Medicine" play a key role in translational medical research both in production and in its networks. Translational medical research and CTS, etc. are core journals of translational research. G7 countries are the leading nations for translational medical research. Some developing countries, such as P.R China, also play an important role in the communication of translational research. The USA and its institutions play a dominant role in the production, collaboration, citations and high quality articles. The research trends in translational medical research involve drug design and development, pathogenesis and treatment of disease, disease model research, evidence-based research, and stem and progenitor cells. 23937860 Asbestos and erionite prime and activate the NLRP3 inflammasome that stimulates autocrine cytokine release in human mesothelial cells. Pleural fibrosis and malignant mesotheliomas (MM) occur after exposures to pathogenic fibers, yet the mechanisms initiating these diseases are unclear. We document priming and activation of the NLRP3 inflammasome in human mesothelial cells by asbestos and erionite that is causally related to release of IL-1β, IL-6, IL-8, and Vascular Endothelial Growth Factor (VEGF). Transcription and release of these proteins are inhibited in vitro using Anakinra, an IL-1 receptor antagonist that reduces these cytokines in a human peritoneal MM mouse xenograft model. These novel data show that asbestos-induced priming and activation of the NLRP3 inflammasome triggers an autocrine feedback loop modulated via the IL-1 receptor in mesothelial cell type targeted in pleural infection, fibrosis, and carcinogenesis. 23265414 A mathematical model for analyzing the elasticity, viscosity, and failure of soft tissue: comparison of native and decellularized porcine cardiac extracellular matrix for tissue engineering. The clinical success of tissue-engineered constructs commonly requires mechanical properties that closely mimic those of the human tissue. Determining the viscoelastic properties of such biomaterials and the factors governing their failure profiles, however, has proven challenging, although collecting extensive data regarding their tensile behavior is straightforward. The easily calculated Young's modulus remains the most reported mechanical measure, regardless of its limitations, even though single-relaxation-time (SRT) models can provide much more information, which remain scarce due to a lack of manageable tools for implementing these models. We developed an easy-to-use algorithm for applying the Zener SRT model and determining the elastic moduli, viscosity, and failure profiles of materials under different mechanical tests in a user-independent manner. The algorithm was validated on the data resulting from tensile tests on native and decellularized porcine cardiac tissue, previously suggested as a promising scaffold material for cardiac tissue engineering. This analysis yields new and more accurate measurements such as the elastic moduli and viscosity, the model's relaxation time, and information on the factors governing the materials' failure profiles. These measurements indicate that the viscoelasticity and strength of the decellularized acellular extracellular matrix (ECM) are similar to those of native tissue, although its elasticity and apparent viscosity are higher. Nonetheless, reseeding and culturing the ECM with mesenchymal stem cells was shown to partially restore the mechanical properties lost after decellularization. We propose this algorithm as a platform for soft-tissue analysis that can provide comparable and unbiased measures for characterizing viscoelastic biomaterials commonly used in tissue engineering. 23878507 The Collothecidae (Rotifera, Collothecacea) of Thailand, with the description of a new species and an illustrated key to the Southeast Asian fauna. Following previous reports indicating a remarkable high diversity of sessile rotifers in Southeast Asian freshwaters, we report on an extensive study of the diversity of Collothecidae rotifers from fifteen freshwater habitats in Thailand. A total of 13 species, including two additional infraspecific variants, of Collothecidae are recorded, one of which is described as a new species of Collotheca. We further add taxonomic remarks on some of the taxa on record and illustrate the uncinate trophi of several representatives by scanning electron microscopic images. Finally, we provide illustrated identification keys to the Collothecidae recorded to date from Southeast Asia. 23553619 Incidence and costs of adverse drug reactions in a tertiary care pediatric intensive care unit. Adverse drug reactions (ADRs) increase morbidity, mortality, and hospital costs in children treated in the Pediatric Intensive Care Unit (PICU). Few studies have reported the incidence and risk factors of ADRs in PICU. Our study aimed to evaluate incidence, risk factors, and economic burden of ADRs in PICU. An intensive ADR surveillance was conducted at the PICU of Children's Hospital of Michigan between November 1, 2010 and May 31, 2011. A trigger list was used to screen for suspected ADR cases. Of the 697 consecutive PICU admissions reviewed, 13.1% experienced at least one episode of ADR. The ADR incidence was 22% in patients with cardiovascular (CV) surgery and 11.5% in other patients. The most frequently detected ADR was electrolyte imbalance associated with diuretic exposure. Mean age at admission was 4 years (interquartile range: 9 months-13 years). Risk factors for ADR included young age (<1 year), Pediatric Risk of Mortality (PRISM) score upon admission ≥3, and administration of ≥16 medications. ADRs increased total ICU costs by 3.5-fold and length of ICU stay by 3.8-fold. Increased ADR surveillance of high risk patients in conjunction with early intervention may reduce drug related morbidity and costs in the PICU. 23837529 Redesign of Substrate Specificity and Identification of the Aminoglycoside Binding Residues of Eis from Mycobacterium tuberculosis. The upsurge in drug-resistant tuberculosis (TB) is an emerging global problem. The increased expression of the enhanced intracellular survival (Eis) protein is responsible for the clinical resistance to aminoglycoside (AG) antibiotics of Mycobacterium tuberculosis . Eis from M. tuberculosis (Eis_Mtb) and M. smegmatis (Eis_Msm) function as acetyltransferases capable of acetylating multiple amines of many AGs; however, these Eis homologues differ in AG substrate preference and in the number of acetylated amine groups per AG. The AG binding cavity of Eis_Mtb is divided into two narrow channels, whereas Eis_Msm contains one large cavity. Five bulky residues lining one of the AG binding channels of Eis_Mtb, His119, Ile268, Trp289, Gln291, and Glu401, have significantly smaller counterparts in Eis_Msm, Thr119, Gly266, Ala287, Ala289, and Gly401, respectively. To identify the residue(s) responsible for AG binding in Eis_Mtb and for the functional differences from Eis_Msm, we have generated single, double, triple, quadruple, and quintuple mutants of these residues in Eis_Mtb by mutating them into their Eis_Msm counterparts, and we tested their acetylation activity with three structurally diverse AGs: kanamycin A (KAN), paromomyin (PAR), and apramycin (APR). We show that penultimate C-terminal residue Glu401 plays a critical role in the overall activity of Eis_Mtb. We also demonstrate that the identities of residues Ile268, Trp289, and Gln291 (in Eis_Mtb nomenclature) dictate the differences between the acetylation efficiencies of Eis_Mtb and Eis_Msm for KAN and PAR. Finally, we show that the mutation of Trp289 in Eis_Mtb into Ala plays a role in APR acetylation. 23920017 Refining Angiographic Biomarkers of Revascularization: Improving Outcome Prediction After Intra-arterial Therapy. Angiographic revascularization grading after intra-arterial stroke therapy is limited by poor standardization, making it unclear which scale is optimal for predicting outcome. Using recently standardized criteria, we sought to compare the prognostic performance of 2 commonly used reperfusion scales. Inclusion criteria for this multicenter retrospective study were acute ischemic stroke attributable to middle cerebral artery M1 occlusion, intra-arterial therapy, and 90-day modified Rankin scale score. Post-intra-arterial therapy reperfusion was graded using the Thrombolysis in Myocardial Infarction (TIMI) and Modified Thrombolysis in Cerebral Infarction (mTICI) scales. The scales were compared for prediction of clinical outcome using receiver-operating characteristic analysis. Of 308 patients, mean age was 65 years, and median National Institutes of Health Stroke Scale score was 17. The mean time from stroke onset to groin puncture was 305 minutes. There was no difference in the time to treatment between patients grouped by final TIMI (ie, 0 versus 1 versus 2 versus 3) or mTICI grades (ie, 0 versus 1 versus 2a versus 2b versus 3). Good outcome (modified Rankin scale, 0-2) was achieved in 32.5% of patients, and mortality rate was 25.3% at 90 days. There was a 6.3% rate of parenchymal hematoma type 2. In receiver-operating characteristic analysis, mTICI was superior to TIMI for predicting 90-day modified Rankin scale 0 to 2 (c-statistic: 0.74 versus 0.68; P<0.0001). The optimal threshold for identifying a good outcome was mTICI 2b to 3 (sensitivity 78.0%; specificity 66.1%). mTICI is superior to TIMI for predicting clinical outcome after intra-arterial therapy. mTICI 2b to 3 is the optimal biomarker for procedural success. 23375209 Branched chain amino acids are novel biomarkers for discrimination of metabolic wellness. OBJECTIVE: To identify novel biomarkers through metabolomic profiles that distinguish metabolically well (MW) from metabolically unwell (MUW) individuals, independent of body mass index (BMI). MATERIALS/METHODS: This study was conducted as part of the Measurement to Understand the Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) project. Individuals from 3 cohorts were classified as lean (BMI<25kg/m(2)), overweight (BMI≥25kg/m(2), BMI<30kg/m(2)) or obese (BMI≥30kg/m(2)). Cardiometabolic abnormalities were defined as: (1) impaired fasting glucose (≥100mg/dL and ≤126mg/dL); (2) hypertension; (3) triglycerides ≥150mg/dL; (4) HDL-C <40mg/dL in men, <50mg/dL in women; and (5) insulin resistance (calculated Homeostatic Model Assessment (HOMA-IR) index of >5.13). MW individuals were defined as having <2 cardiometabolic abnormalities and MUW individuals had≥two cardiometabolic abnormalities. Targeted profiling of 55 metabolites used mass-spectroscopy-based methods. Principal components analysis (PCA) was used to reduce the large number of correlated metabolites into clusters of fewer uncorrelated factors. RESULTS: Of 1872 individuals, 410 were lean, 610 were overweight, and 852 were obese. Of lean individuals, 67% were categorized as MUW, whereas 80% of overweight and 87% of obese individuals were MUW. PCA-derived factors with levels that differed the most between MW and MUW groups were factors 4 (branched chain amino acids [BCAA]) [p<.0001], 8 (various metabolites) [p<.0001], 9 (C4/Ci4, C3, C5 acylcarnitines) [p<.0001] and 10 (amino acids) [p<.0002]. Further, Factor 4, distinguishes MW from MUW individuals independent of BMI. CONCLUSION: BCAA and related metabolites are promising biomarkers that may aid in understanding cardiometabolic health independent of BMI category. 23499892 Minnelide reduces tumor burden in preclinical models of osteosarcoma. Osteosarcoma is the most common bone cancer in children and adolescents with a 5-year survival rate of about 70%. In this study, we have evaluated the preclinical therapeutic efficacy of the novel synthetic drug, Minnelide, a prodrug of triptolide on osteosarcoma. Triptolide was effective in significantly inducing apoptosis in all osteosarcoma cell lines tested but had no significant effect on the human osteoblast cells. Notably, Minnelide treatment significantly reduced tumor burden and lung metastasis in the orthotopic and lung colonization models. Triptolide/Minnelide effectively downregulated the levels of pro-survival proteins such as heat shock proteins, cMYC, survivin and targets the NF-κB pathway. 23619297 Bile acid receptor TGR5 agonism induces NO production and reduces monocyte adhesion in vascular endothelial cells. TGR5 is a G-protein-coupled receptor for bile acids. So far, little is known about the function of TGR5 in vascular endothelial cells. In bovine aortic endothelial cells, treatment with a bile acid having a high affinity to TGR5, taurolithocholic acid (TLCA), significantly increased NO production. This effect was abolished by small interfering RNA-mediated depletion of TGR5. TLCA-induced NO production was also observed in human umbilical vein endothelial cells measured via intracellular cGMP accumulation. TLCA increased endothelial NO synthase(ser1177) phosphorylation in human umbilical vein endothelial cells. This response was accompanied by increased Akt(ser473) phosphorylation and intracellular Ca(2+). Inhibition of these signals significantly decreased TLCA-induced NO production. We next examined whether TGR5-mediated NO production affects inflammatory responses of endothelial cells. In human umbilical vein endothelial cells, TLCA significantly reduced tumor necrosis factor-α-induced adhesion of monocytes, vascular cell adhesion molecule-1 expression, and activation of nuclear factor-κB. TLCA also inhibited lipopolysaccharide-induced monocyte adhesion to mesenteric venules in vivo. These inhibitory effects of TLCA were abrogated by NO synthase inhibition. TGR5 agonism induces NO production via Akt activation and intracellular Ca(2+) increase in vascular endothelial cells, and this function inhibits monocyte adhesion in response to inflammatory stimuli. 23453550 Small for gestational age and intrauterine growth restriction decreases cognitive function in young adults. To examine the effect on adult cognitive function of being born small for gestational age (SGA), and to evaluate whether cognitive function is related to intrauterine growth restriction (IUGR). Fifty-nine SGA subjects (birth weight <10th percentile) and 81 controls (birth weight ≥10th percentile) born at term underwent cognitive assessment with the Wechsler Adult Intelligence Scale-Third Edition at age 19-20 years. Repeated ultrasound measures of fetal growth were available for weeks 25, 33, and 37 in a subgroup of 29 SGA subjects and 75 control subjects, and these were data used to dichotomize the 29 SGA subjects into those with IUGR and those without IUGR. IUGR was defined as growth deviating more than -2 SD from the mean value of the control group. The effect of maternal smoking during pregnancy was considered as well. Group differences were analyzed using a general linear model, controlling for sex and socioeconomic status. The SGA group had lower full IQ scores than the control group (mean difference, -6.3; 95% CI, -2.8 to -9.7; P = .001), including lower scores on 6 of the Wechsler Adult Intelligence Scale-Third Edition subtests. In the SGA subgroup with repeated ultrasound measures, 6 of 29 subjects (21%) had IUGR, and these subjects also had a lower IQ compared with controls (mean difference, -14.0; 95% CI: -4.8 to -23.3; P = .003). Maternal smoking during pregnancy was related to lower IQ in the control group but not in the SGA group, independent of IUGR or non-IUGR status. IQ scores were lower in young adults born SGA compared with controls. Our analysis suggest that this outcome is related to IUGR. 23371751 Arm-eye coordination test to objectively quantify motor performance and muscles activation in persons after stroke undergoing robot-aided rehabilitation training: a pilot study. This study designed an arm-eye coordination test to investigate the effectiveness of the robot-aided rehabilitation for persons after stroke. Six chronic poststroke subjects were recruited to attend a 20-session robot-aided rehabilitation training of elbow joint. Before and after the training program, subjects were asked to perform voluntary movements of elbow flection and extension by following sinusoidal trajectories at different velocities with visual feedback on their joint positions. The elbow angle and the electromyographic signal of biceps and triceps as well as clinical scores were evaluated together with the parameters. Performance was objectively quantified by root mean square error (RMSE), root mean square jerk (RMSJ), range of motion (ROM), and co-contraction index (CI). After 20 sessions, RMSE and ROM improved significantly in both the affected and the unaffected side based on two-way ANOVA (P < 0.05). There was significant lower RMSJ in the affected side at higher velocities (P < 0.05). There was significant negative correlation between average RMSE with different tracking velocities and Fugl-Meyer shoulder-elbow score (P < 0.05). There was also significant negative correlation between average RMSE and average ROM (P < 0.05), and moderate nonsignificant negative correlation with RMSJ, and CI. The characterization of velocity-dependent deficiencies, monitoring of training-induced improvement, and the correlation between quantitative parameters and clinical scales could enable the exploration of effects of different types of treatment and design progress-based training method to accelerate the processes of recovery. 23852153 Celerinatantimonas yamalensis sp. nov., a cold-adapted diazotrophic bacterium from a cold permafrost brine. A facultatively anaerobic nitrogen-fixing bacterial strain C7(T) was isolated from a permafrost cryopeg on the Yamal Peninsula, Russia. Comparative analysis of 16S rRNA gene sequences revealed that this bacterium was closely related to Celerinatantimonas diazotrophica with the 95.5 % similarity level. Strain C7(T) differed from the species C. diazotrophica in its ability to hydrolyze gelatin and inability to use D-mannose, mellibiose, L-rhamnose, m-inositol, lactose, lactulose, D-mannitol, methyl β-D-glucoside, trehalose, acetate, DL-lactate, glycogen, cyclodextrin and L-proline as sole carbon sources. In addition, strain C7(T) grew in a temperature range of 0-34°C with optimum 18-22°C. Whole-cell fatty acid profile included C16:0, C16:1ω7, C18:1ω7, C17cyc and feature 2 comprising C12:0ald and/or unknown fatty acid 10.913 (MIDI designation) and/or iso-C16:1 /C14:0 3OH were predominant. The DNA G+C content was 44.7 mol%. The strain C7(T) (=VKM B-2511(T)=DSM 21888(T)) was assigned to a new species, for which the name Celerinatantimonas yamalensis sp. nov. was proposed, and was suggested as the type strain. 23767973 The impact of social capital on depression among older Chinese and Korean immigrants: similarities and differences. Objectives: The objective of this study is to examine similarities and differences in terms of the influence of social capital on depression among older Chinese and Korean immigrants. Methods: The study used data collected from both 172 Chinese and 210 Korean immigrants living in Los Angeles County. The variables included depression Geriatric Depression Scale-Short Form, (GDS-SF), social capital (five indices of norms, trust, partnership in community, information sharing, and political participation), and demographics. Results: The study found that partnership in community was significantly associated with a lower level of depression for both the groups. On the other hand, political participation was only associated with a lower level of depression for older Chinese immigrants. Also, norms and information sharing were only associated with a lower level of depression for older Korean immigrants. Conclusion: There was an evidence for the correlation between social capital and depression in older Chinese and Korean immigrant population. It suggests the needs to develop social programs and service in order to build more social capital for older immigrants. 23171137 Metabolomics and mass isotopomer analysis as a strategy for pathway discovery: pyrrolyl and cyclopentenyl derivatives of the pro-drug of abuse, levulinate. We recently reported that levulinate (4-ketopentanoate) is converted in the liver to 4-hydroxypentanoate, a drug of abuse, and that the formation of 4-hydroxypentanoate is stimulated by ethanol oxidation. We also identified 3 parallel β-oxidation pathways by which levulinate and 4-hydroxypentanoate are catabolized to propionyl-CoA and acetyl-CoA. We now report that levulinate forms three seven-carbon cyclical CoA esters by processes starting with the elongation of levulinyl-CoA by acetyl-CoA to 3,6-diketoheptanoyl-CoA. The latter γ-diketo CoA ester undergoes two parallel cyclization processes. One process yields a mixture of tautomers, i.e., cyclopentenyl- and cyclopentadienyl-acyl-CoAs. The second cyclization process yields a methyl-pyrrolyl-acetyl-CoA containing a nitrogen atom derived from the ε-nitrogen of lysine but without carbons from lysine. The cyclic CoA esters were identified in rat livers perfused with levulinate and in livers and brains from rats gavaged with calcium levulinate ± ethanol. Lastly, 3,6-diketoheptanoyl-CoA, like 2,5-diketohexane, pyrrolates free lysine and, presumably, lysine residues from proteins. This may represent a new pathway for protein pyrrolation. The cyclic CoA esters and related pyrrolation processes may play a role in the toxic effects of 4-hydroxypentanoate. 23361834 A comparison of the anticancer properties of isoxanthohumol and 8-prenylnaringenin using in vitro models of colon cancer. The hops plant (Humulus lupulus L.) is an essential ingredient in beer and contains a number of potentially bioactive prenylflavonoids, the predominant being the weakly estrogenic isoxanthohumol (Ix), which can be converted to the more strongly estrogenic 8-PN by the colonic microbiota. The aim of this study was to investigate the biological activity of 8-PN and Ix using in vitro models representing key stages of colorectal carcinogenesis, namely cell growth and viability (MTT assay), cell-cycle progression (DNA content assay), DNA damage (Comet assay), and invasion (Matrigel assay). A significant decrease in Caco-2 cell viability was noted after both 8-PN and Ix treatments at the higher doses (40 and 50 μM, respectively) although the impact on cell cycle differed between the two compounds. The decreased cell viability observed after Ix treatment was associated with a concentration-dependent increase in G2/M and an increased sub-G1 cell-cycle fraction, whereas treatment with 8-PN was associated with an elevated G0/G1 and an increased sub-G1 cell-cycle fraction. Significant antigenotoxic activity was noted at all 8-PN concentrations tested (5-40 μM). Although significant antigenotoxic activity was also noted with Ix treatment at ≤25 μM, at a higher dose, Ix itself exerted genotoxic activity. In a dose-dependent manner, both compounds inhibited HT115 cell invasion with reductions up to 52 and 46% for Ix and 8-PN, respectively, in comparison to untreated cells. This study demonstrated that both Ix and its gut microbial metabolite 8-PN exert anticancer effects on models of key stages of colon tumourigenesis. © 2013 BioFactors, 39(4):441-447, 2013. 23970291 The withdrawal of the Liverpool Care Pathway in England: implications for clinical practice and policy. The Liverpool Care Pathway for the Dying Patient (LCP) was introduced as a structured guide to best practice in care of the dying for use by professional staff without specialist palliative care experience or knowledge (Ellershaw et al, 1997). Earlier this year, an independent review into the use of the LCP in England was convened at the request of Norman Lamb, MP, Minister of State for Care Support, as the culmination of a gathering media storm. 23784989 Conformational modulation of DNA by polyamide binding: structural effects of f-Im-Py-Im based derivatives on 5'-ACGCGT-3'. The DNA sequence 5'-ACGCGT-3' is in the core site of the Mlu 1 cell-cycle box, a transcriptional element in the promoter region of human Dbf4 gene that is highly correlated with a large number of aggressive solid cancers. The polyamide formamido-imidazole-pyrrole-imidazole-amine(+) (f-Im-Py-Im-Am(+) ) can target the minor groove of 5'-ACGCGT-3' as an antiparallel stacked dimer and has shown good activity in inhibiting transcription factor binding. Recently, f-Im-Py-Im-Am(+) derivatives that involve different orthogonally positioned substituents were synthesized to target the same binding site, and some of them have displayed improved binding and pharmacological properties. In this study, the gel electrophoresis-ligation ladders assay was used to evaluate the conformational effects of f-Im-Py-Im-Am(+) and derivatives on the target DNA, an essential factor for establishing the molecular basis of polyamide-DNA complexes and their transcription factor inhibition. The results show that the ACGCGT site in DNA has a relatively wide minor groove and a B-form like overall structure. After binding with f-Im-Py-Im-Am(+) derivatives, the DNA conformation is changed as indicated by the different mobilities in the gel. These conformational effects on DNA will at least help to point to the mechanism for the observed Mlu 1 inhibition activity of these polyamides. Therefore, modulating DNA transcription by locking the DNA shape or altering the minor groove geometry to affect the binding affinity of certain transcription factors is an attractive possible therapeutic mechanism for polyamides. Some of the substituents are charged with electrostatic interactions with DNA phosphate groups, and their charge effects on DNA gel mobility have been observed. 23440447 Pollution pathways of pharmaceutical residues in the aquatic environment on the island of Mallorca, Spain. This work determines the principal environmental pollution pathways of pharmaceuticals on the island of Mallorca (Spain). The evaluation was made on the basis of the quantification of pharmaceutical residues by liquid chromatography-tandem mass spectrometry in several environmental water samples, including wastewater-treatment plant effluents, municipal solid waste landfill leachates, groundwater (GW), and marine water. An overall set of 19 pharmaceuticals has been identified in the environment of the 27 human pharmaceuticals investigated in this study. WWTP effluents are the main source of discharge of the pharmaceuticals into the aquatic environment. The data indicate that reuse of treated domestic wastewater for irrigation (which supplies some 30 % of the total water demand in Mallorca) contributes to the contamination of GW. In addition, leaching from landfills is identified as another, but minor, possible source of introduction of pharmaceuticals to GW aquifers. Finally, WWTP effluents ending in the Mediterranean Sea, primarily highly urbanized coastal areas, cause pharmaceutical residues to occur in marine water bodies. 22646908 Intraspecific variability of the essential oil of Calamintha nepeta subsp. nepeta from Southern Italy (Apulia). The essential oil of 46 spontaneous plants of Calamintha nepeta (L.) Savi subsp. nepeta growing wild in Sud, Italy (Salento, Apulia), were investigated by GC/MS. Fifty-seven components were identified in the oil representing over the 98% of the total oil composition. Four chemotypes were identified: piperitone oxide, piperitenone oxide, piperitone-menthone and pulegone. 23934449 Induction of Krüppel-like factor 4 expression in reactive astrocytes following ischemic injury in vitro and in vivo. Krüppel-like factor 4 (KLF4) is a transcription factor with diverse and cell type-specific functions and is associated with a variety of pathophysiological processes. Recently, it has been proposed that the regulation of KLF4 is critical to neuronal differentiation and that neural progenitors overexpressing KLF4 take on a glial identity. The present study aimed to determine whether KLF4 is involved in the astroglial reaction induced by ischemia-reperfusion injury in the brain. No specific KLF4 immunoreactivity was observed in resting astrocytes of the control hippocampus, but significant induction was detected in reactive astrocytes preferentially located in the CA1 and dentate hilar regions of the hippocampus following transient forebrain ischemia. Astroglial KLF4 expression was induced in the nuclei and cytoplasm within 3 days of ischemia and persisted for at least 4 weeks. This pattern was reproduced in an in vitro astrogliosis model of rat primary cortical astrocytes exposed to oxygen-glucose deprivation (OGD). Furthermore, immunoblot assay showed that nuclear and cytosolic extracts from cortical astrocytes subjected to OGD had significantly higher levels of KLF4 protein compared to normoxic extracts. Thus, our data demonstrate that KLF4 expression was induced in astroglia by ischemic injury both in vivo and in vitro, suggesting that KLF4 may act as a transcription factor linked to the regulation of the astroglial reaction following ischemic injury. 23869897 Hypercapnia attenuates the hypoxia-induced blunting of the reactivity in chronically hypoxic rats. Chronic hypoxia causes oxidative injury of pulmonary vessels and attenuates their reactivity to different stimuli. When combined with hypercapnia, biochemical markers of this injury are reduced but the effect of concomitant hypoxia and hypercapnia on vascular reactivity is not fully understood. This study was therefore designed to test whether hypercapnia can prevent also the hypoxia-induced loss of reactivity of pulmonary vessels. The reactivity of vessels from rats exposed either to hypoxia or hypoxia combined with hypercapnia was tested using a small vessel myograph (M 500A, Linton, Norfolk, GB). The second and third intrapulmonary branches of pulmonary arteries were isolated under a dissecting microscope from lungs of 8 control rats (group N), 6 rats exposed to hypoxia for 5 days (isobaric, 10% O(2), group H) and 7 rats exposed to hypoxia combined with hypercapnia for 5 days (10% O(2), 5% CO(2), group H+CO(2)). The transmural pressure was set by automatic normalization to 30 mmHg. The vessel size did not vary among the groups. After stabilization we challenged the vessels twice with KCl (80 mM) and once with PGF(2alpha 0.1 mM). There were no significant differences in KCl induced contractions among the groups. The responses to PGF(2alpha were expressed as a ratio to the maximal tension obtained by the exposure to 80 mM KCl. Contractions induced by PGF(2alpha were markedly reduced in group H (0.07+/-0.02) and in group H+CO(2) (0.26+/-0.03) in comparison with group N (0.83+/-0.07). The vessels of group H responded to PGF(2alpha less than those of group H+CO(2). However we observed the attenuated reactivity also in group H+CO(2) in comparison with N. Hypercapnia therefore partially blunted the hypoxia-induced loss of reactivity in pulmonary arteries. This finding supports the hypothesis that hypercapnia significantly alters the nature of lung injury induced by chronic hypoxia. 23210783 From traditional European medicine to discovery of new drug candidates for the treatment of dementia and Alzheimer's disease: acetylcholinesterase inhibitors. The leading Alzheimer's disease (AD) therapeutics to date involves inhibitors of acetylcholinesterase (AChE), which should, in principle, elevate cholinergic signaling and limit inflammation. In spite of the effectiveness in 20%-30% of AD patients, more attention has been paid to find new anti-AChE agents from medicinal plants. Galanthamine, contained in the bulbs and flowers of Galanthus and related genera like Narcissus, represents a good example. The aim of this study is to review the role of possible AChE inhibitors (AChEI) present in plants traditionally used in European medicine for improving memory. Starting from Galanthamine, properties of Melissa species, Salvia officinalis, Arnica chamissonis and Ruta graveolens are discussed to point to the role of these plants as potential sources for the development of therapeutic agents for AD. 23323861 A new di-O-prenylated flavone from an actinomycete Streptomyces sp. MA-12. A new di-O-prenylated flavone, named 7,3'-di-(γ,γ-dimethylallyloxy)-5-hydroxy-4'-methoxyflavone (1), was isolated from the culture broth of the endophytic actinomycete Streptomyces sp. MA-12 isolated from the root of the semi-mangrove plant Myoporum bontioides A. Gray. The structure of 1 was determined by comprehensive spectroscopic methods, including 1D and 2D NMR experiments (COSY, HMQC, and HMBC). Primary bioassays showed that 1 at concentration of 0.25 mM had moderate inhibitory activity against three plant pathogenic fungi including Colletotrichum musae, Gibberella zeae (Schweinitz) Petch, and Penicillium citrinum Thom. 23932760 Dental stem cells as an alternative source for cardiac regeneration. Dental tissues contains stem cells or progenitors that have high proliferative capacity, are clonogenic in vitro and demonstrate the ability to differentiate to multiple type cells involving neurons, bone, cartilage, fat and smooth muscle. Numerous experiments have demonstrated that the multipotent stem cells are not rejected by immune system and therefore it may be possible to use these cells in allogeneic settings. In addition, these remarkable cells are easily abundantly available couple with less invasive procedure in isolating comparing to bone marrow aspiration. Here we proposed dental stem cells as candidate for cardiac regeneration based on its immature characteristic and propensity towards cardiac lineage via PI3-Kinase/Aktsignalling pathway. 23906568 Biomarkers of cardiorenal syndrome. Complex interactions existing between cardiac and renal diseases led to define 5 types of so-called cardiorenal syndromes. This classification is based on the organ primarily involved and the acute or chronic failure. The mutual impact of renal and cardiac functions makes it difficult to evaluate and manage patients with cardiorenal syndromes and worsen morbidity and mortality. This review seeks to discuss the place of biomarkers in diagnosis, management and follow-up of patients with cardiorenal syndromes. Biomarkers can be classified as functional (creatinine, cystatin C…) or lesional (neutrophil gelatinase-associated lipocalin, urinary cystatin C…) renal markers and functional (natriuretic peptides…) or lesional (troponin, fatty acid binding protein) cardiac markers. A last kind of biomarkers reflects the dialogue between heart and kidney (renin-angiotensin-aldosteron-system, indicators of activation of arginine vasopressin system) or the systemic impact (inflammation, oxidative stress…). In order to evaluate accurately the complex interactions that are the basis of cardiorenal syndromes, a multi-marker approach seems nowadays necessary. 23868183 Palladium-catalyzed regioselective synthesis of 2(2[Formula: see text]-biphenyl)benzimidazoles through C-H activation. An efficient palladium-catalyzed strategy through C-H bond activation for the synthesis of 2(2[Formula: see text]-biphenyl)-benzimidazoles is reported herein. The regioselective C-C bond formation proceeds in a sealed tube via oxidative C-H activation of ortho-directed 2-aryl-benzimidazole to couple with various iodobenzene analogs in high yields. This arylation exhibited high regioselectivity which is able to increase molecular diversity in difficult functionalized positions of parent molecules. This strategy provides a convenient and simple synthesis of biphenyl heterocyclic compounds with high regioselectivity. 23893769 Community perspectives on public health biobanking: an analysis of community meetings on the Michigan BioTrust for Health. Biobanks raise challenges for developing ethically sound and practicable consent policies. Biobanks comprised of dried bloodspots (DBS) left over from newborn screening, maintained for long-term storage, and potential secondary research applications are no exception. Michigan has been a leader in transforming its DBS collection, marketing its biobank of de-identified samples for health research use. The Michigan BioTrust for Health includes approximately 4 million unconsented retrospective samples collected as early as 1984 and prospective samples added since the fall of 2010 with blanket parental consent. We engaged Michigan citizens to ascertain public attitudes, knowledge, and beliefs about the BioTrust and informed consent. A convenience sampling of 393 participants from communities around the state of Michigan (oversampling for minority populations) participated in meetings addressing newborn screening, the BioTrust and informed consent, yielding quantitative and qualitative survey and discussion data. Participants affirmed the principle of voluntary informed participation in research and advocated for greater public awareness of the existence of the BioTrust. Most expressed support for the use of DBS for research and a desire for greater involvement in granting permission for research use. Opinions varied as to which specific research uses were acceptable. Participants indicated a desire for greater engagement, public awareness, and more active decision making on the part of biobank participants and parents. Diversity of opinion over which research areas were deemed acceptable problematizes the blanket consent model that currently applies to the BioTrust's prospective DBS collection and that could become the new norm for research using de-identified data under proposed changes to the Common Rule. 23773508 Marked changes in right ventricular contractile pattern after cardiothoracic surgery: Implications for post-surgical assessment of right ventricular function. Longitudinal shortening accounts for the majority of right ventricular (RV) contraction in normal hearts. This finding accounts for the correlation between longitudinal measures of RV contraction such as tricuspid annular plane systolic excursion (TAPSE) and global RV function. We hypothesized that, after cardiac surgery, there are major differences in the RV contractile pattern relative to normal hearts. We retrospectively studied 2 cardiac surgical cohorts who underwent cardiopulmonary bypass (CPB) with pericardial incision (OHT, n = 54; CABG, n = 23) and compared them with a lung transplant cohort (n = 25). We compared TAPSE, RV fractional area change (RVFAC) and relative change in RV transverse and longitudinal area in the surgical cohorts with data from normal subjects (n = 84). RVFAC was lower in the surgical groups compared with the normal group, yet still in the normal range (37% to 42% vs 47%; p < 0.01). TAPSE was markedly lower in OHT (15 ± 3 mm) and CABG (16 ± 4 mm) than in normal (26 ± 4 mm) subjects (p < 0.01), as was the relative contribution of longitudinal area change (OHT group 51 ± 11%, CABG group 54 ± 13%, normal group 78 ± 14%; p < 0.01). The ratio of TAPSE to RVFAC was markedly lower in CABG (40 ± 14 mm/%FAC) and OHT (37 ± 10 mm/%FAC) patients than in normal (56 ± 14 mm/%FAC) subjects (p < 0.001). However, OLT patients had a higher TAPSE (18 ± 3 mm) than OHT (15 ± 3 mm) and CABG (16 ± 4 mm) patients (p < 0.01) and a higher relative contribution of longitudinal area change: OLT 67 ± 10%; OHT 51 ± 11%; and CABG 54 ± 13% (p < 0.01). After cardiac surgery, the RV contractile pattern changes, with a relative loss of longitudinal shortening and gain in transverse shortening despite normal global RV function. These findings have major implications for quantitative assessment of RV function after cardiac surgery, suggesting that global measures of RV function assessment may be preferred in this setting and that lower normative ranges should be used when measurement of RV function is performed with longitudinal methods. 23832108 Recent advances in the heterologous expression of microbial natural product biosynthetic pathways. Covering: up to 2013The heterologous expression of microbial natural product biosynthetic pathways coupled with advanced DNA engineering enables optimisation of product yields, functional elucidation of cryptic gene clusters, and generation of novel derivatives. This review summarises the recent advances in cloning and maintenance of natural product biosynthetic gene clusters for heterologous expression and the efforts fundamental for discovering novel natural products in the post-genomics era, with a focus on polyketide synthases (PKSs) and non-ribosomal polypeptide synthetases (NRPS). 23770694 Structure and gene cluster of the O-antigen of Escherichia coli O76. The O-polysaccharide (O-antigen) of Escherichia coli O76 was studied by sugar analysis along with 1D and 2D (1)H,(13)C NMR spectroscopies. The following structure of the linear tetrasaccharide repeating unit was established: The degree of O-acetylation of 4-substituted β-GalNAc residue is ∼70%. The O-antigen gene cluster of E. coli O76 was sequenced. The functions of genes in the O-antigen gene cluster were tentatively assigned by comparison with sequences in the available databases and found to be in full agreement with the E. coli O76 O-antigen structure. 23912220 Site-directed spin labeling EPR spectroscopy in protein research. Abstract Site-directed spin labeling (SDSL) in combination with electron paramagnetic resonance (EPR) spectroscopy has emerged as an efficient tool to elucidate the structure and the conformational dynamics of proteins under conditions close to the native state. This review article summarizes the basics as well as recent progress in SDSL and EPR methods especially for investigations on protein structure, protein function, and interaction of proteins with other proteins or nucleic acids. Labeling techniques as well as EPR methods are introduced and exemplified with applications to systems that have been studied in the author's lab in the past 15 years, headmost the sensory rhodopsin-transducer complex mediating the photophobic response of the halophilic archaeum Natronomonas pharaonis. Further examples underline the application of SDSL EPR spectroscopy to answer specific questions about the system under investigation, e.g. the nature and influence of interactions of proteins with other proteins or nucleic acids. Finally, it is discussed how SDSL EPR can be combined with other biophysical techniques to combine the strengths of the different methodologies. 23963312 An optical deoxyribonucleic acid-based half-subtractor. This study introduces an optical DNA-based logic circuit that mimics a half-subtractor. The system contains an Au-surface immobilized molecular-beacon molecule that serves as a dual-gate molecule and outputs two series of fluorescence signals following Boolean INH and XOR patterns after interacting with one or two single-stranded DNA molecules as input. To the best of our knowledge, the system reported herein is rather concise compared to other molecular logic gate systems. 23184669 High physical fitness in young adulthood reduces the risk of fractures later in life in men: A nationwide cohort study. A few studies have indicated that self-reported physical activity is associated with the risk of fractures in middle-aged and elderly men. We investigated whether objectively measured physical fitness in young adulthood was associated with the risk of low-energy fractures later in life in men. Aerobic capacity and isometric muscle strength were measured in 435,445 Swedish men who were conscripted for military service from 1969 to 1978. Incident fractures were searched in national registers. During a median follow-up period of 35 years (range, 11-41 years), 8030 subjects sustained at least one fracture, increasing the risk of death 1.8 times (95% CI, 1.6-2.0) during follow up. When comparing men in the lowest and highest decile of physical fitness, the risk of a fracture was 1.8 times higher (95% CI, 1.6-2.1) and that of hip fracture was 2.7 times higher (95% CI, 1.6-4.7). The risk of fracture was also 1.4 to 1.5 times higher when comparing the extreme deciles of muscle strength (p < 0.001 for all). In a subcohort of 1009 twin pairs, up to 22% of the variation in physical fitness and 27% to 39% of the variation in muscle strength was attributable to environmental factors unique to one twin; eg, physical activity. In conclusion, low aerobic capacity and muscle strength in young adulthood are associated with an increased risk of low-energy fractures later in life. © 2013 American Society for Bone and Mineral Research. 23928824 A Brief History of the Changing Occupations and Demographics of Coleopterists from the 18th Through the 20th Century. Systematic entomology flourished as a branch of Natural History from the 1750s to the end of the nineteenth century. During this interval, the "era of Heroic Entomology," the majority of workers in the field were dedicated amateurs. This article traces the demographic and occupational shifts in entomology through this 150-year interval and into the early twentieth century. The survey is based on entomologists who studied beetles (Coleoptera), and who named sufficient numbers of species to have their own names abbreviated by subsequent taxonomists. In the eighteenth century, 27 entomologists achieved this level of prominence, of whom 37% were academics, 19% were doctors, 11% had private incomes, 19% were clergymen, and 8% were government officials. Many of those with private incomes were members of the European aristocracy, and all but one were European men. The nineteenth century list included 192 entomologists, of whom 17% were academics, 16% were museum curators, 2% were school teachers, 15% were doctors, 6% were military men, 7% were merchants, 2% were government entomologists, 6% had private incomes, 5% were clergymen, 5% were government officials, and 4% were lawyers. The demographics of entomology shifted dramatically in the nineteenth century. Whereas many of the noteworthy entomologists of the eighteenth century were German, Swedish, or French, in the nineteenth century, many more European countries are represented, and almost one-fifth of the noteworthy entomologists were from the United States. The nineteenth century list, like the eighteenth century list, contains no women. By the twentieth century, 63% of 178 noteworthy systematic entomologists were paid professionals, teaching entomology courses in universities, or studying insect taxonomy in museums and government-sponsored laboratories. Only one person on the twentieth century list had a private income, but women (ten individuals) were included on the list for the first time. 23643702 Hydroxytyrosyl alkyl ether derivatives inhibit platelet activation after oral administration to rats. The low lipophilicity of hydroxytyrosol (HT) has motivated efforts to synthesize homologous series with better lipid solubility, such as the ethers, which are more lipophilic than HT. Because HT inhibits platelet aggregation, the aim of the study was to assess the possible anti-platelet effect of five HT ether derivatives (ethyl, butyl, hexyl, octyl and dodecyl) after oral administration to rats. Whole blood collagen-induced platelet aggregation and calcium-induced thromboxane B2 (TxB2), aortic 6-keto-prostaglandin F1α (6-keto-PGF1α) and nitrites + nitrates, plasma concentration of lipid peroxides (TBARS) and red blood cell content of reduced glutathione (GSH) were measured. The administration of 20 mg/kg/day inhibited platelet aggregation, TxB2 and TBARS in a non-linear manner related to the length of the carbon chain, with a cut-off effect in the hexyl derivative. Aortic nitrite and red blood cell GSH production were also increased. The aortic production of 6-keto-PGF1α was unaltered except in the group treated with the dodecyl derivative. The administration of 50 mg/kg/day showed a similar pharmacodynamic profile but without the non-linear effect. In conclusion, HT ethers, especially the hexyl derivative, are a potential alternative to hydroxytyrosol, and their effect merits additional research to determine their role in the prophylaxis of vascular disease. 23926584 Immediate loading of 2(all-on-2) versus 4 (all-on-4) implants placed with a flapless technique supporting mandibular cross-arch fixed prostheses: 1-year results from a pilot randomised controlled trial. To evaluate the outcome of 2 versus 4 implants placed flapless in fully edentulous mandibles and immediately restored with metal-resin screw-retained cross-arch prostheses. Sixty patients from two different centres were randomised: 30 to the allon- 2 group and 30 to the all-on-4 group according to a parallel group design. To be immediately loaded, implants had to be inserted with a minimum torque of 40 Ncm. Outcome measures were prosthesis and implant failures, complications, and marginal bone level changes. Flaps were raised in 18 patients. A total of 2 implants in 2 patients did not reach the planned insertion torque and were immediately replaced by larger diameter ones. One year after loading, no drop-out or implant failure occurred. Eight biomechanical complications occurred in the all-on-2 group versus 8 complications in the all-on-4 group. There were no statistically significant differences for complications between groups. There were no statistically significant differences for marginal peri-implant bone levels between the two groups (estimate of the difference = -0.16; 95%CI -0.40 to 0.08; P (ANCOVA) = 0.074), with both groups losing a statistically significant amount of marginal bone (0.74 mm for all-on-2 implants and 0.58 mm for all-on-4 implants). There were statistically significant differences between the two centres, with more bone being lost for the Bologna centre (0.26 mm versus 1.07 mm). These preliminary results, up to 1 year after loading, suggest that immediately loaded mandibular cross-arch fixed prostheses can be supported by only 2 dental implants. Longer followups (approximately 10 years) are needed to properly evaluate this therapeutic option. 23138542 Electron-microscopy of Cherry Haemangioma in the Early Diagnosis of Fabry Disease. Abstract is missing (Letter). 23376438 Cellular mechanisms of the cytotoxic effects of the zearalenone metabolites α-zearalenol and β-zearalenol on RAW264.7 macrophages. Zearalenone (ZEN) and its metabolites are commonly found in many food commodities and are known to cause reproductive disorders and genotoxic effects. The major ZEN metabolites are α-zearalenol (α-ZOL) and β-zearalenol (β-ZOL). Although many studies have demonstrated the cytotoxic effects of these metabolites, the mechanisms by which α-ZOL or β-ZOL mediates their cytotoxic effects appear to differ according to cell type and the exposed toxins. We evaluated the toxicity of α-ZOL and β-ZOL on RAW264.7 macrophages and investigated the underlying mechanisms. β-ZOL not only more strongly reduced the viability of cells than did α-ZOL, but it also induced cell death mainly by apoptosis rather than necrosis. The ZEN metabolites induced loss of mitochondrial membrane potential (MMP), mitochondrial changes in Bcl-2 and Bax proteins, and cytoplasmic release of cytochrome c and apoptosis-inducing factor (AIF). Use of an inhibitor specific to c-Jun N-terminal kinase (JNK), p38 kinase or p53, but not pan-caspase or caspase-8, decreased the toxin-induced generation of reactive oxygen species (ROS) and also attenuated the α-ZOL- or β-ZOL-induced decrease of cell viability. Antioxidative enzyme or compounds such as catalase, acteoside, and (E)-1-(3,4-dihydroxyphenethyl)-3-(4-hydroxystyryl)urea suppressed the ZEN metabolite-mediated reduction of cell viability. Further, knockdown of AIF via siRNA transfection diminished the ZEN metabolite-induced cell death. Collectively, these results suggest that the activation of p53, JNK or p38 kinase by ZEN metabolites is the main upstream signal required for the mitochondrial alteration of Bcl-2/Bax signaling pathways and intracellular ROS generation, while MMP loss and nuclear translocation of AIF are the critical downstream events for ZEN metabolite-mediated apoptosis in macrophages. 23836793 Nonlinear flowering responses to climate: are species approaching their limits of phenological change? Many alpine and subalpine plant species exhibit phenological advancements in association with earlier snowmelt. While the phenology of some plant species does not advance beyond a threshold snowmelt date, the prevalence of such threshold phenological responses within plant communities is largely unknown. We therefore examined the shape of flowering phenology responses (linear versus nonlinear) to climate using two long-term datasets from plant communities in snow-dominated environments: Gothic, CO, USA (1974-2011) and Zackenberg, Greenland (1996-2011). For a total of 64 species, we determined whether a linear or nonlinear regression model best explained interannual variation in flowering phenology in response to increasing temperatures and advancing snowmelt dates. The most common nonlinear trend was for species to flower earlier as snowmelt advanced, with either no change or a slower rate of change when snowmelt was early (average 20% of cases). By contrast, some species advanced their flowering at a faster rate over the warmest temperatures relative to cooler temperatures (average 5% of cases). Thus, some species seem to be approaching their limits of phenological change in response to snowmelt but not temperature. Such phenological thresholds could either be a result of minimum springtime photoperiod cues for flowering or a slower rate of adaptive change in flowering time relative to changing climatic conditions. 23899910 Concomitant Headache Influences Long-term Prognosis After Acute Cerebral Ischemia of Noncardioembolic Origin. Acute cerebral ischemia is frequently associated with headache. It is unknown whether concomitant headache reflects a partly different pathogenesis, and thus, may influence long-term prognosis after stroke. Here, we compared the long-term risk of recurrent vascular events in patients in whom a transient ischemic attack or minor ischemic stroke of noncardioembolic origin was associated with headache with those without headache. We used data from the Life Long After Cerebral ischemia (LiLAC) cohort. Participants were grouped on the basis of presence or absence of headache at presentation. We calculated the hazard ratios (HRs) and corresponding 95% confidence intervals (CI) for any first vascular event (primary outcome) or any cardiac or cerebral event (secondary outcomes). Adjustments were made for baseline clinical characteristics. Of 2473 participants, 420 (17%) experienced headache during the acute event. Median follow-up was 14.1 years. For the primary outcome, the crude HR of headache versus no headache was 0.75 (95% CI, 0.66-0.89) and the adjusted HR 0.83 (95% CI, 0.71-0.97). For cardiac events the adjusted HR was 0.88 (95% CI, 0.67-1.14) and for cerebral events, 0.97 (95% CI, 0.76-1.24). The ratio of cardiac versus cerebral events, however, did not differ between the 2 groups. Participants with headache were at lower risk of vascular death (adjusted HR, 0.73; 95% CI, 0.61-0.87). Patients who experienced headache in association with a transient ischemic attack or minor ischemic stroke have a better vascular prognosis than those without concomitant headache. This may, at least partly, reflect a different pathogenesis. 23788630 The fas/fas ligand apoptotic pathway is involved in abrin-induced apoptosis. Abrin is a plant glycoprotein toxin from the seeds of Abrus precatorius, sharing similarity in structure and properties with ricin. Abrin is highly toxic, with an estimated human fatal dose of 0.1-1 µg/kg, causing death after accidental or intentional poisoning. It is a potent biological toxin warfare agent. There is no chemical antidote available against the abrin. The elucidation of molecular mechanism of abrin-induced cell death is important for development of therapy. Intrinsic pathway-mediated apoptosis has been well established in abrin-induced cell death. However, the detailed mechanism especially extrinsic receptor-mediated pathway remains uncharacterized. To assess whether some of the apoptosis known to occur after abrin exposure might be mediated by Fas/Fas ligand (Fas L) interactions, we analyzed effect of abrin on Fas pathway in Jurkat cells. Here, we report that activation of the Fas pathway is involved in abrin-induced apoptosis. Following treatment of abrin, Fas L was induced, which stimulated the Fas pathway by cross-linking Fas receptor (Fas R). Apoptosis was mediated by cleavage of the Fas R proximal caspase-8 and the downstream caspase-3, resulting in activation of the prototype caspase substrate poly-(ADP-ribose) polymerase and caspase-activated DNase. Blocking Fas L/Fas R interaction by using Fas inhibitor reduced abrin-induced apoptosis, further confirms involvement of Fas pathway. Activation of components of Fas pathway and caspases upon abrin treatment was also found in splenocytes in mice. Our findings offer new perspective for understanding the fundamental mechanism in abrin-induced apoptotic mechanism and may have implication in developing novel therapeutic strategies in the management for abrin-induced complications. 23228674 Phytochemical indicaxanthin suppresses 7-ketocholesterol-induced THP-1 cell apoptosis by preventing cytosolic Ca(2+) increase and oxidative stress. 7-Ketocholesterol (7-KC)-induced apoptosis of macrophages is considered a key event in the development of human atheromas. In the present study, the effect of indicaxanthin (Ind), a bioactive pigment from cactus pear fruit, on 7-KC-induced apoptosis of human monocyte/macrophage THP-1 cells was investigated. A pathophysiological condition was simulated by using amounts of 7-KC that can be reached in human atheromatous plaque. Ind was assayed within a micromolar concentration range, consistent with its plasma level after dietary supplementation with cactus pear fruit. Pro-apoptotic effects of 7-KC were assessed by cell cycle arrest, exposure of phosphatidylserine at the plasma membrane, variation of nuclear morphology, decrease of mitochondrial trans-membrane potential, activation of Bcl-2 antagonist of cell death and poly(ADP-ribose) polymerase-1 cleavage. Kinetic measurements within 24 h showed early formation of intracellular reactive oxygen species over basal levels, preceding NADPH oxidase-4 (NOX-4) over-expression and elevation of cytosolic Ca²⁺, with progressive depletion of total thiols. 7-KC-dependent activation of the redox-sensitive NF-κB was observed. Co-incubation of 2·5 μm of Ind completely prevented 7-KC-induced pro-apoptotic events. The effects of Ind may be ascribed to inhibition of NOX-4 basal activity and over-expression, inhibition of NF-κB activation, maintaining cell redox balance and Ca homeostasis, with prevention of mitochondrial damage and consequently apoptosis. The findings suggest that Ind, a highly bioavailable dietary phytochemical, may exert protective effects against atherogenetic toxicity of 7-KC at a concentration of nutritional interest. 23647421 Twenty-first century palliative care: a tale of four nations. Hospice and palliative care development, in terms of availability and services, occur to varying degrees in the developing world. In this paper, the evolution of palliative care practices in four developing nations (Nigeria, Georgia, Ethiopia and Tanzania) is described. By highlighting common problems as well as the unique individual perspectives of each country's practice, this paper aims at increasing global awareness of palliative care in the developing world. While the call for palliative care to become a fundamental human right is sustained, it is also hoped that this article will stimulate a global discussion on the best possible way to encourage the establishment and growth of palliative care services in other developing countries where hitherto it has not been in existence, with policymakers and healthcare professionals taking the lead through the institution of sound national policies to promote and provide palliative care to all citizenry. 23925708 A magnesium-based multifunctional metal-organic framework: synthesis, thermally induced structural variation, selective gas adsorption, photoluminescence and heterogeneous catalytic study. Three magnesium based carboxylate framework systems were prepared through a temperature-dependent synthesis. The compounds were synthesized by a hydrothermal method and characterized by single crystal X-ray diffraction analysis. A stepwise increase in the temperature of the medium resulted a stepwise increase in the dimensionality of the network, ultimately leading to the formation of a new 2D layered alkaline earth metal-organic framework (MOF) compound, {[Mg2(HL)2(H2O)4]·H2O}n () (H3L = pyrazole-3,5-dicarboxylate). Compound selectively adsorbs hydrogen (H2) (ca. 0.56 wt% at 77 K) over nitrogen at 1 atm and demonstrates a strong blue fluorescent emission band at 480 nm (λmax) upon excitation at 270 nm. Notably, the 2D framework compound efficiently catalyzes the aldol condensation reactions of various aromatic aldehydes with ketones in a heterogeneous medium under environmentally friendly conditions. The catalyst can be recycled and reused several times without any significant loss of activity. 23864378 Multichannel brain recordings in behaving Drosophila reveal oscillatory activity and local coherence in response to sensory stimulation and circuit activation. Neural networks in vertebrates exhibit endogenous oscillations that have been associated with functions ranging from sensory processing to locomotion. It remains unclear whether oscillations may play a similar role in the insect brain. We describe a novel "whole-brain" readout for Drosophila melanogaster, using a simple multichannel recording preparation to study electrical activity across the brain of flies exposed to different sensory stimuli. We recorded local field potential (LFP) activity from >2000 registered recording sites across the fly brain in >200 wild type and transgenic animals to uncover specific LFP frequency bands that correlate with: 1) brain region; 2) sensory modality (olfactory, visual, or mechanosensory); 3) activity in specific neural circuits. We found endogenous and stimulus-specific oscillations throughout the fly brain. Central (higher order) brain regions exhibited sensory modality-specific increases in power within narrow frequency bands. Conversely, in sensory brain regions such as the optic or antennal lobes, LFP coherence, rather than power, best defined sensory responses across modalities. By transiently activating specific circuits via expression of TrpA1, we found that several circuits in the fly brain modulate LFP power and coherence across brain regions and frequency domains. However, activation of a neuromodulatory octopaminergic circuit specifically increased neuronal coherence in the optic lobes during visual stimulation while decreasing coherence in central brain regions. Our multichannel recording and brain registration approach provides an effective way to track activity simultaneously across the fly brain in vivo, allowing investigation of functional roles for oscillations in processing sensory stimuli and modulating behavior. 23850108 Trends of underweight, overweight, and obesity in Brazilian children and adolescents. To describe and analyze the trends of occurrence of underweight, overweight, and obesity in schoolchildren. This was a longitudinal study of trends conducted in a voluntary sample of Brazilian children and adolescents. The sample was grouped by year of collection (period I: 2005 and 2006; period II: 2007 and 2008, and period III: 2009-2011), age category (children: 7 to 10 years, and adolescents: 11 to 14 years), and stratified by gender. The body mass index was used to classify the nutritional profile. Trend analysis was verified using multinomial logistic regression (p<0.05). Mean occurrences were 2.11% for underweight, 22.27% for overweight, and 6.8% for obesity. There was a decrease of underweight in male adolescents from period I to II, as well as an increase in female children from period II to III. Regarding overweight, there was an increase followed by a decrease in male children. Regarding obesity, there was an increase from period I to II in all age groups and for both genders. The prevalence of underweight was less than 5% in all categories of age and gender. However, the categories of overweight and obesity showed higher values, and together comprised almost 30% of the young Brazilian population; moreover, a trend toward increase in prevalence of obesity was observed up to the year 2008, followed by the maintenance of these high prevalence rates. 23498588 Molecular phylogenetic analysis of the coccidian cephalopod parasites Aggregata octopiana and Aggregata eberthi (Apicomplexa: Aggregatidae) from the NE Atlantic coast using 18S rRNA sequences. The coccidia genus Aggregata is responsible for intestinal coccidiosis in wild and cultivated cephalopods. Two coccidia species, Aggregata octopiana, (infecting the common octopus Octopus vulgaris), and A. eberthi, (infecting the cuttlefish Sepia officinalis), are identified in European waters. Extensive investigation of their morphology resulted in a redescription of A. octopiana in octopuses from the NE Atlantic Coast (NW Spain) thus clarifying confusing descriptions recorded in the past. The present study sequenced the 18S rRNA gene in A. octopiana and A. eberthi from the NE Atlantic coast in order to assess their taxonomic and phylogenetic status. Phylogenetic analyses revealed conspecific genetic differences (2.5%) in 18S rRNA sequences between A. eberthi from the Ria of Vigo (NW Spain) and the Adriatic Sea. Larger congeneric differences (15.9%) were observed between A. octopiana samples from the same two areas, which suggest the existence of two species. Based on previous morphological evidence, host specificity data, and new molecular phylogenetic analyses, we suggest that A. octopiana from the Ria of Vigo is the valid type species. 23958551 In Search of the Ideal Immunopanel to Distinguish Metastatic Mammary Carcinoma From Primary Lung Carcinoma: A Tissue Microarray Study of 207 Cases. Distinguishing metastatic carcinoma of breast origin (MCBO) to lung from primary lung carcinomas (PLC) is a diagnostic quandary with clinical ramifications. Immunostains CK7, CK20, ER, PR, and Mammaglobin as well as pertinent negative stains are utilized but prove insufficient. We set out to identify stains either alone or as a group that would better discern between these 2 entities. Tissue microarrays of 109 MCBO to lung and 102 PLC were stained with CK7, CK20, ER, PR, AR, Mammaglobin, Napsin A, GATA-3, and TTF-1. An H-score was calculated for each case and stain. The highest area under the receiver-operating characteristic curves for each stain was seen with GATA-3 (0.817), Napsin A (0.817), and TTF-1 (0.854). When all possible combinations were analyzed, GATA-3 and TTF-1 proved to correctly classify with the highest accuracy (0.934). Combinations of GATA-3 and Napsin A (0.920) and GATA-3, Napsin A, and TTF-1 (0.933) were not significantly different from GATA-3 and TTF-1. The odds ratios for each stain and combination of stains showed that those for GATA-3 and TTF-1 were divergent, signifying that cases with higher H-scores for GATA-3 and TTF-1 were more likely to be classified as MCBO and PLC, respectively. GATA-3 and TTF-1 can correctly classify a case as either MCBO or PLC in 93.4% of cases. Although highly specific and sensitive for PLC, Napsin A in lieu of TTF-1 or as an additional stain did not improve classification accuracy. 23733915 Failing Heart of Patients With Type 2 Diabetes Mellitus Can Adapt to Extreme Short-term Increases in Circulating Lipids and Does Not Display Features of Acute Myocardial Lipotoxicity. Background- Circulating lipid levels and myocardial lipid content (MyLC) is increased in type 2 diabetes mellitus. This may cause a state of lipotoxicity that compromises left ventricular function and aggravate heart failure. We investigated the relationship among circulating lipid levels, MyLC, and cardiac function together with the acute cardiac effects of high as opposed to low circulating free fatty acid (FFA) and triglyceride levels in patients with type 2 diabetes mellitus and heart failure. Methods and Results- Eighteen patients underwent 8-hour intralipid/heparin-infusion (high FFA) and hyperinsulinemic-euglycemic clamping (low FFA) in a randomized crossover-designed study. We applied magnetic resonance proton spectroscopy to measure MyLC. Cardiac function was assessed by advanced echocardiography, cardiopulmonary exercise, and MRI. MyLC correlated positively with circulating triglyceride (r=0.47; r(2)=0.22; P=0.003) and FFA (r=0.45; r(2)=0.20; P=0.001) levels and inversely with left ventricular ejection fraction (r=-0.54; r(2)=0.29; P=0.004). Circulating FFA concentrations differed between study arms (0.05±0.04 mmol/L [low FFA] versus 1.04±0.27 mmol/L [high FFA]; P<0.001) and MyLC increased from 0.78±0.59% (low FFA) to 1.16±0.73% (high FFA; P<0.01). Resting left ventricular ejection fraction and global strain did not differ between high and low FFA, whereas resting systolic mitral plane velocity (S'max) was highest during high FFA (3.6±0.8 cm/s [low FFA] versus 3.8±0.7 cm/s [high FFA]; P=0.02). Peak exercise capacity and oxygen consumption did not differ between the study arms, and neither did postexercise measurements of left ventricular ejection fraction, global strain, and S'max. Conclusions- Our findings indicate that the failing heart of patients with type 2 diabetes mellitus can adapt to short-term extreme changes in circulating substrates and does not display features of acute myocardial lipotoxicity. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01192373. 23954622 Associations of particulate air pollution and daily mortality in 16 Chinese cities: An improved effect estimate after accounting for the indoor exposure to particles of outdoor origin. People typically spend most of their time indoors. We modeled the daily indoor PM10 concentrations of outdoor origin using a set of exposure parameters, including the fraction of residences with air conditionings (AC), the fraction of time that windows are closed when cooling occurs for buildings with AC, the fractions of time that windows are open or closed for buildings with or without AC, the particle penetration factors, air change rates, and surface removal rate constant of PM10. We calculated the time-weighted average of the simulated indoor PM10 concentration of outdoor origin and the original recorded outdoor PM10 concentration. We then evaluated the acute effects of PM10 using traditional and amended exposure metrics in 16 Chinese cities. Compared with the original estimates, the new effect estimates almost doubled, with improved model fit and attenuated between-city heterogeneity. Conclusively, this proposed exposure assessment approach could improve the effect estimates of ambient particles. 23633455 Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations. High-grade serous carcinoma (HGSC) accounts for the majority of epithelial ovarian cancer deaths. Genomic and functional data suggest that approximately half of unselected HGSC have disruption of the BRCA pathway and defects in homologous recombination repair (HRR). Pathway disruption is regarded as imparting a BRCAness phenotype. We explored the molecular changes in HGSC arising in association with specific BRCA1/BRCA2 somatic or germline mutations and in those with BRCA1 DNA promoter methylation. We describe gene expression and copy number analysis of two large cohorts of HGSC in which both germline and somatic inactivation of HRR has been measured. BRCA1 disruptions were associated with the C2 (immunoreactive) molecular subtype of HGSC, characterized by intense intratumoral T-cell infiltration. We derived and validated a predictor of BRCA1 mutation or methylation status, but could not distinguish BRCA2 from wild-type tumors. DNA copy number analysis showed that cases with BRCA1 mutation were significantly associated with amplification both at 8q24 (frequencies: BRCA1 tumors 50%, BRCA2 tumors 32%, and wild-type tumors 9%) and regions of the X-chromosome specifically dysregulated in basal-like breast cancer (BLBC; BRCA1 62%, BRCA2 34%, and wild-type 35%). Tumors associated with BRCA1/BRCA2 mutations shared a negative association with amplification at 19p13 (BRCA1 0%, BRCA2 3%, and wild-type 20%) and 19q12 (BRCA1 6%, BRCA2 3%, and wild-type 29%). The molecular differences between tumors associated with BRCA1 compared with BRCA2 mutations are in accord with emerging clinical and pathologic data and support a growing appreciation of the relationship between HGSC and BLBC. 22659088 The interaction between mGluR1 and the calcium channel Cav₂.₁ preserves coupling in the presence of long Homer proteins. Group I metabotropic glutamate receptors (mGluR1 and 5) are G protein coupled receptors that regulate neuronal activity in a number of ways. Some of the most well studied functions of group I mGluRs, such as initiation of multiple forms of mGluR-dependent long-term depression, require receptor localization near the post-synaptic density (PSD). This localization is in turn dependent on the Homer family of scaffolding proteins which bind to a small motif on the distal C-termini of mGluR1 and 5, localize the receptors near the PSD, strengthen coupling to post-synaptic effectors and simultaneously uncouple the mGluRs from extra-synaptic effectors such as voltage dependent ion channels. Here the selectivity of this uncoupling process was examined by testing the ability of Homer-2b to uncouple mGluR1 from multiple voltage dependent calcium channels including Ca(V2.2) (N-type), Ca(V3.2) (T-type), and Ca(V2.1) (P/Q-type) expressed in rat sympathetic neurons from the superior cervical ganglion (SCG). Of these, only the mGluR1-Ca(V2.1) modulatory pathway was insensitive to Homer-2b expression. Uncoupling from this channel was achieved by co-expression of an mGluR1 C-terminal protein designed to disrupt a previously described direct interaction between these two proteins, suggesting that this interaction allows incorporation of Ca(V2.1) into the mGluR1/Homer signaling complex, thereby preserving modulation in the presence of scaffolding Homer proteins. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23826945 Association of smoked and smokeless tobacco use with migraine: a hospital-based case-control study in Dhaka, Bangladesh. Several studies in the past have reported inconclusive evidences on association of smoking and migraine. Nevertheless, no study so far reported association of smokeless tobacco with migraine. The objective of this study was to examine the association of smoked and smokeless tobacco use with migraine. A hospital-based case-control study was conducted at the neurology outpatient department of a tertiary care hospital in Dhaka, Bangladesh. We enrolled 138 migraine cases diagnosed during March-September 2010 in neurology outpatient department, and 276 gender and age matched healthy controls from among their attendants. Diagnosis of migraine was based on the International Headache Society criteria. Use of smokeless tobacco and smoking (cigarette/bidi/hukka) were determined by an interviewer administered questionnaire. Among the cases, 52.9% were overall tobacco users; 24.6% were only smokers, 15.9% only smokeless tobacco users and 12.3% used both. The respective figures among controls were 14.5%, 7.2%, 6.9% and 0.4% (P <0.001 for all). The conditional logistic regression analysis found that migraine had higher odds of exposure to smoked tobacco use, smokeless tobacco use, and both compared to control after adjusting for confounding variables (alcohol drinking, insufficient sleep, mental stress, and number of family members); adjusted odds ratio (aOR) was 6.6 (95% confidence interval [CI] = 2.2-19.6, P = 0.001), 5.8 (95%CI = 1.9-17.4, P = 0.001), and 54.2 (95%CI = 4.3-684.4, P = 0.002), respectively. The aOR of cigarette/bidi/hukka smoking for different doses was 5.5 (95%CI = 1.2-24.8, P = 0.027) for 1-5 times per day, 6.3 (95%CI = 1.8-21.2, P = 0.003) for 6-10 times per day, and 6.7 (95%CI = 1.9-23.2, P = 0.003) for >10 times per day relative to non users. Both smoked and smokeless tobaccos were found to be associated with migraine. There is a need to incorporate smokeless tobacco along with smoked tobacco into the anti-tobacco awareness programs to reduce the burden of migraine in Bangladesh. 23600368 Effect of hypolipidemic treatment on emerging risk factors in mixed dyslipidemia: a randomized pilot trial. The effects of different hypolipidemic treatment strategies on emerging atherosclerosis risk factors remain unknown. This is a prespecified analysis of a prospective, randomized, open-label, blinded end point (PROBE) study (ClinicalTrials.gov identifier: NCT01010516). Patients (n = 100) with mixed dyslipidaemia on a standard statin dose who had not achieved lipid targets were randomized to switch to the highest dose of rosuvastatin (40 mg/day) or to add-on-statin extended release nicotinic acid (ER-NA)/laropiprant (LRPT) or to add-on-statin micronized fenofibrate for a total of 3 months. Following 3 months of treatment, low-density lipoprotein (LDL) particle size increased equally in all groups. Similarly, all treatments were associated with comparable small dense LDL cholesterol reduction. Apolipoprotein B levels decreased by 15%, 7% and 4% in the rosuvastatin, add-on ER-NA/LRPT and add-on fenofibrate group, respectively (P < 0.01 for all compared with baseline, P < 0.01 for all comparisons between groups). Only add-on ER-NA/LRPT was associated with lipoprotein (a) reduction (26%, P < 0.01 compared with baseline). Rosuvastatin monotherapy and add-on ER-NA/LRPT groups were associated with 56% and 24% reduction in high-sensitivity C-reactive protein levels (hsCRP), respectively (P < 0.01 compared with baseline), while add-on fenofibrate was not associated with changes in hsCRP concentration. Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity decreased similarly in both rosuvastatin and add-on fenofibrate groups, while add-on ER-NA/LRPT was associated with a more pronounced Lp-PLA2 activity reduction. ER-NA/LRPT was associated with more side effects compared with rosuvastatin and add-on fenofibrate. Add-on ER-NA/LRPT followed by switch to the highest dose rosuvastatin were associated with more pronounced beneficial modifications in emerging cardiovascular risk factors compared with add-on fenofibrate in patients with mixed dyslipidaemia. 23821138 Taxane-containing induction chemotherapy followed by definitive chemoradiotherapy : Outcome in patients with locally advanced head and neck cancer. Induction chemotherapy followed by definitive chemoradiotherapy is an intensified treatment approach for locally advanced squamous cell carcinoma of the head and neck (HNSCC) that might be associated with high rates of toxicity. The data of 40 consecutive patients who underwent induction chemotherapy with docetaxel-containing regimens followed by intensity-modulated radiotherapy (IMRT) and concomitant systemic therapy for unresectable locally advanced HNSCC were retrospectively analyzed. Primary objectives were RT-related acute and late toxicity. Secondary objectives were response to induction chemotherapy, locoregional recurrence-free survival (LRRFS), overall survival (OS), and influencing factors for LRRFS and OS. The median follow-up for surviving patients was 21 months (range, 2-53 months). Patients received a median of three cycles of induction chemotherapy followed by IMRT to 72 Gy. Three patients died during induction chemotherapy and one during chemoradiotherapy. Acute RT-related toxicity was of grade 3 and 4 in 72 and 3 % of patients, respectively, mainly dysphagia and dermatitis. Late RT-related toxicity was mainly xerostomia and bone/cartilage necrosis and was of grade 3 and 4 in 15 % of patients. One- and 2-year LRRFS and OS were 72 and 49 % and 77 and 71 %, respectively. Induction chemotherapy followed by chemoradiotherapy using IMRT was associated with a high rate of severe acute and late RT-related toxicities in this selected patient cohort. Four patients were lost because of fatal complications. Induction chemotherapy did not compromise the delivery of full-dose RT; however, the use of three cycles of concomitant cisplatin was impaired. 23866081 Lyn, a Src family kinase, regulates activation of epidermal growth factor receptors in lung adenocarcinoma cells. Activation of receptors for growth factors on lung epithelial cells is essential for transformation into tumor cells, supporting their viability and proliferation. In most lung cancer patients, EGFR is constitutively activated without evidence of mutation. Defining mechanisms for constitutive activation of EGFR could elucidate additional targets for therapy of lung cancers. The approach was to identify lung cancer cell lines with constitutively activated EGFR and use systematic selection of inhibitors to evaluate their effects on specific EGFR phosphorylations and downstream signaling pathways. Interactions between receptors, kinases, and scaffolding proteins were investigated by co-immunoprecipitation plus Western blotting. The results revealed a dependence on Src family of tyrosine kinases for downstream signaling and cell growth. Lyn, a Src family kinase functional in normal and malignant B-lymphocytes, was a defining signal transducer required for EGFR signaling in Calu3 cell line. Src family kinase activation in turn, was dependent on PKCßII. Lyn and PKC exist in membrane complexes of RACK1 and in association with EGFR which pairs with other receptor partners. Silencing of Lyn expression with interfering siRNA decreased EGFR activation and cell viability. The importance of Src family kinases and PKCßII in the initiation of the EGFR signaling pathway in lung tumor cells was demonstrated. We conclude that phosphorylation of EGFR is mediated through PKCßII regulation of Lyn activation, and occurs in association with RACK1 and Cbp/PAG proteins. We suggest that protein complexes in cell membranes, including lipid rafts, may serve as novel targets for combination therapies with EGFR and Src Family Kinase inhibitors in lung cancer. 23732468 Associated lesions in posterior wall acetabular fractures: not a valid predictor of failure. The general outcome of posterior wall acetabular fractures is still the source of discussion. Posterior wall fractures are recognized throughout the literature as being difficult to treat. The aim of the present study was to analyze in our own patients the relevance of the classical prognostic criteria for the outcome of isolated posterior wall fractures and those with associated lesions. A prospective cohort of 33 consecutive patients treated operatively between 1996 and 2006 in a single level 1 trauma center for a posterior wall fracture of the acetabulum was analyzed retrospectively. Included were posterior wall acetabular fractures or associated posterior wall fractures, such as the combinations of posterior column with posterior wall, transverse with posterior wall, or T-shaped fracture with posterior wall fracture. Outcome measurement of the postoperative survival of the hip joints until the primary outcome reoperation (total hip replacement or fusion) and secondary outcome diagnosis of symptomatic osteoarthritis were performed. Twenty-six of the 33 patients with posterior wall fractures also had a dislocated joint. Twelve had isolated and 21 associated fractures. Six patients were reoperated with a THA (four patients within 2 years and one after 10 years), and one arthrodesis was done to treat a hematogenous septic arthritis in a degenerative hip joint. Secondary arthritis was observed in 10 patients. No difference was found between the outcome in cases of isolated posterior wall acetabular fracture and the outcome in those with associated lesions. The classical prognostic criteria were not found to be relevant to the outcome for our group. 23706570 Tumor associated macrophages in relapsed and refractory Hodgkin lymphoma. Growing evidence demonstrates that an increased number of CD68 positive tumor-associated macrophages (TAM) is associated with decreased survival in patients with newly diagnosed classic Hodgkin lymphoma (HL). However, the impact of TAM in relapsed and refractory disease is unknown. To investigate whether the presence of elevated CD68 retains its prognostic significance in the relapsed and refractory setting, we analyzed pre-salvage biopsy specimens of 81 patients with relapsed and refractory HL using a tissue microarray. Scoring of CD68 was based on the percentage of CD68 positive TAM compared to the total number of cells in representative areas. The final percent of CD68 positivity for each case was based on the average of cores available for examination. In a univariate analysis, we found that patients with elevated levels of CD68 positive TAM had inferior overall survival (OS) compared with patients who had lower CD68 levels. For patients undergoing autologous stem cell transplant after salvage treatment, elevated CD68 levels were predictive of both adverse OS and event free survival. However, after adjusting for other variables, increased CD68 positive TAM did not retain prognostic significance in a multivariate model. In our dataset of primary refractory and relapsed Hodgkin lymphoma biopsy specimens, TAM infiltration is unable to definitively predict outcome. In order to validate these findings, TAM infiltration of relapsed and refractory specimens should be assessed prospectively and paired to initial Hodgkin lymphoma biopsies at diagnosis. 23675996 Understanding differences in sexting behaviors across gender, relationship status, and sexual identity, and the role of expectancies in sexting. Abstract Sexting, or the exchange of sexually explicit material via Internet social-networking site or mobile phone, is an increasingly prevalent behavior. The study sought to (1) identify expectancies regarding sexting behaviors, (2) examine how demographics (i.e., gender, sexual identity, relationship status) might be differentially related to sexting expectancies and behaviors, and (3) examine whether these concurrent relationships are consistent with a theoretical causal model in which sexting expectancies influence sexting behaviors. The sample consisted of 278 undergraduate students (mean age=21.0 years, SD=4.56; 53.8% female; 76.3% caucasian). Factor analyses supported the validity and reliability of the Sextpectancies Measure (α=0.85-0.93 across subscales) and indicated two expectancy domains each for both sending and receiving sexts: positive expectancies (sexual-related and affect-related) and negative expectancies. Males reported stronger positive expectancies (F=4.64, p=0.03) while females reported stronger negative expectancies (F=6.11, p=0.01) about receiving sexts. There were also differences across relationship status regarding negative expectancies (F=2.25, p=0.05 for sending; F=4.24, p=0.002 for receiving). There were also significant effects of positive (F=45.98, p<0.001 for sending, F=22.42, p<0.001 for receiving) and negative expectancies (F=36.65, p=0.02 sending, F=14.41, p<0.001 receiving) on sexting behaviors (η(2) from 0.04-0.13). College students reported both positive and negative sextpectancies, although sextpectancies and sexting varied significantly across gender, race, sexual identity, and relationship status. Concurrent relationships were consistent with the causal model of sextpectancies influencing sexting behaviors, and this study serves as the first test of this model, which could inform future prevention strategies to mitigate sexting risks. 23760159 FMR1 low sub-genotype does not rescue BRCA1/2-mutated human embryos and does not explain primary ovarian insufficiency among BRCA1/2-carriers. Can we confirm in our population whether FMRI low sub-genotypes are associated with BRCA1/2 mutations, as recently proposed? Our results indicate that the distribution of the FMR1 sub-genotypes in female BRCA1/2-mutation carriers is significantly different from what has been reported previously and resembles that of the control population. FMRI low sub-genotypes are not associated with BRCA1/2 mutations and this association is also absent among male mutation carriers. Recently, BRCA1 mutations were reported to be associated with primary ovarian insufficiency (POI) in female carriers. In animal models, BRCA2-deficiency also results in impaired oogenesis. A recent study has reported that the POI in BRCA1/2-mutation carriers is most likely due to low FMR1 sub-genotype (CGG n < 26) and the authors also suggested that low sub-genotypes of the FMR1 gene might be important to rescue the BRCA1/2 embryos, which would otherwise be embryonically-lethal. This retrospective study was performed in October and November of 2012, using genetic material of 464 patients who underwent genetic screening in our centre in the past. We tested the FMR1 sub-genotypes in 60 female and 29 males with either BRCA1 or BRCA2 mutations and 375 controls by PCR amplification and size fragment analysis. We did not find any evidence for an association of FMR1 low sub-genotypes and BRCA1/2 mutations. This association study assumes that the female BRCA1/2 population tested has POI. Low FMR1 sub-genotypes are not responsible for the presumed rescue of embryos with BRCA1/2 mutations. Furthermore, the molecular mechanism of the POI in BRCA1/2-female carriers is not likely to be associated with low FMR1 sub-genotype. The Department of Clinical Genetics of the Maastricht University Medical Centre supported the study. The authors do not have any competing interests to declare. 23830019 Disparity of care for children with parent-reported autism spectrum disorders. Although children with autism spectrum disorders (ASDs) are eligible to receive special education services via an individualized education program (IEP), approximately 12% to 20% do not. Our objective was to determine which clinical and demographic characteristics are associated with IEP receipt among a nationally representative sample of children with ASD. Using data from the 2007 National Survey of Children's Health, we determined which clinical and demographic covariates are associated with IEP receipt for children ages 6 to 17 years with a current, parent-reported ASD diagnosis (n = 759). Logistic regression models were used to assess the association of covariates with IEP receipt. Application of weighting techniques made the findings representative of the noninstitutionalized population of US children 6 to 17 years old. In the weighted model, 90% of children with ASD receive an IEP. Maternal education level above high school (adjusted odds ratio [aOR] 4.08, P = .01) and presence of perceived need for coordination of care (aOR 3.62, P = .02) were associated with IEP receipt, while Hispanic children were less likely to receive an IEP compared with white children (aOR 0.12, P = .001). The following factors were not associated with IEP receipt: severity of ASD, speech, and behavior problems. For children with ASD in the United States, socioeconomic factors, not disability severity, are associated with IEP receipt. Future research should address methods to overcome this disparity in care. Health care providers may help to advocate for appropriate educational services for patients with ASD. 23889105 Antibiotic prophylaxis at elective cesarean section: a randomized controlled trial in a low resource setting. Abstract Objective: To determine the best time to administer prophylactic antibiotics at Cesarean delivery in order to reduce the postoperative maternal infectious morbidity in a low resource setting. Material and Methods: One hundred term primigravidae with singleton pregnancy were recruited and randomly allocated to two equal groups. Each woman received 2 g intravenous Cefazoline. Women in Group I received it prior to skin incision while those in Group II had it immediately after cord clamping. We measured the following outcome parameters: (1) Surgical site wound infection; (2) Endometritis and (3) Urinary tract infection. Results: There was no significant difference in any of the patients' characteristics between both groups. In Group I, three cases developed surgical site infections but four in Group II (p > 0.05). In Group I, the infected cases had Cesarean because of malpresentations while in Group II, two cases had Cesarean because of patients' request, one because of maternal heart disease and one due to intra-uterine growth restriction. Seven and nine cases had urinary tract infection in Groups I and II, respectively, (p > 0.05). Conclusion: Prophylactic antibiotic administration either prior to surgery or after cord clamping is probably equally effective in reducing the postoperative infectious morbidity after Cesarean in low resource settings. 23769354 Chewing activities and particle size of rumen digesta and feces of precision-fed dairy heifers fed different forage levels with increasing levels of distillers grains. The objective of this study was to determine the effects of 2 differing forage to concentrate ratios (F:C) and various levels of corn dry distillers grain with solubles (DDGS) replacing canola meal in precision-fed dairy heifer rations on chewing behavior, rumen pH and fill, and particle size of rumen contents and feces. A split plot design with F:C as whole plot and DDGS inclusion level as subplot was administered in a 4-period 4 × 4 Latin square. Eight rumen-cannulated Holstein heifers (12.5±0.5 mo of age and 344±15kg of body weight, respectively) housed in individual stalls were allocated to F:C 50:50 (low forage) or 75:25 [high forage (HF); dry matter basis] and to a sequence of DDGS level (0, 7, 14, and 21%; dry matter basis). Forage was a mix of 50% corn silage and 50% grass hay (dry matter basis). Diets were fed once daily and formulated to provide equal amounts of nutrients and body weight gain. No differences were found for rumen pH between dietary treatments. Time spent eating tended to be longer for HF and was not affected by DDGS inclusion rate. Ruminating time did not differ by F:C, but linearly increased as DDGS increased (422 to 450±21 min/d). Total chewing time tended to be longer for HF and to increase linearly as DDGS increased (553 to 579±33 min/d). Wet rumen digesta weight and volume were greater for HF. Geometric mean particle length of rumen contents was greater for HF 2h prefeeding when analyzed with solubles (particles <0.15mm). Proportion of rumen solubles decreased as DDGS increased 5h postfeeding. Fecal geometric mean particle length and proportion of particles >1.18mm increased with increasing levels of DDGS and did not change with F:C. Total chewing time increased by the addition of DDGS and higher F:C. Heifers can compensate for lower physically effective neutral detergent fiber by modifying their chewing behavior. Rumen pH was never at a level that could induce acidosis, and lower eating time at lower F:C was somewhat compensated by time spent ruminating per unit of physically effective neutral detergent fiber intake. Dry distillers grains with solubles, when used in dairy heifer rations as a replacement for canola meal, yielded similar rumen digestion traits. 23949095 Evaluations of the Selectivities of the Diacylglycerol Kinase Inhibitors R59022 and R59949 Among Diacylglycerol Kinase Isozymes Using a New Non-Radioactive Assay Method. Ten mammalian diacylglycerol kinase (DGK) isozymes (α-κ) have been identified. Recent studies have revealed that DGK isozymes play pivotal roles in a wide variety of pathophysiological functions. Thus, it is important to be able to easily check DGK activity in each pathophysiological event. Moreover, the conventional DGK assay is quite laborious because it requires the use of a radioisotope and thin-layer chromatography including multiple extraction steps. In order to minimize the laborious procedures, we established a non-radioactive, single well, two-step DGK assay system. We demonstrated that, compared to the conventional method, the new assay system has comparable sensitivity and much higher efficiency, and is effective in detecting potential agents with high reliability (Z'-factor = 0.69 ± 0.12; n = 3). Using the newly developed assay, we comprehensively evaluated the DGK isozyme selectivities of commercially available DGK inhibitors, R59022 and R59949, in vitro. We found that among 10 isozymes, R59022 strongly inhibited type I DGKα and moderately attenuated type III DGKε and type V DGKθ, and that R59949 strongly inhibited type I DGK α and γ, and moderately attenuated type II DGK δ and κ. 22936354 Inactivation of anoctamin-6/Tmem16f, a regulator of phosphatidylserine scrambling in osteoblasts, leads to decreased mineral deposition in skeletal tissues. During vertebrate skeletal development, osteoblasts produce a mineralized bone matrix by deposition of hydroxyapatite crystals in the extracellular matrix. Anoctamin6/Tmem16F (Ano6) belongs to a conserved family of transmembrane proteins with chloride channel properties. In addition, Ano6 has been linked to phosphatidylserine (PS) scrambling in the plasma membrane. During skeletogenesis, Ano6 mRNA is expressed in differentiating and mature osteoblasts. Deletion of Ano6 in mice results in reduced skeleton size and skeletal deformities. Molecular analysis revealed that chondrocyte and osteoblast differentiation are not disturbed. However, mutant mice display increased regions of nonmineralized, Ibsp-expressing osteoblasts in the periosteum during embryonic development and increased areas of uncalcified osteoid postnatally. In primary Ano6(-/-) osteoblasts, mineralization is delayed, indicating a cell autonomous function of Ano6. Furthermore, we demonstrate that calcium-dependent PS scrambling is impaired in osteoblasts. Our study is the first to our knowledge to reveal the requirement of Ano6 in PS scrambling in osteoblasts, supporting a function of PS exposure in the deposition of hydroxyapatite. 23239555 Boron-based inhibitors of acyl protein thioesterases 1 and 2. Ras proteins are of importance in cell proliferation, and hence their mutated forms play causative roles in many kinds of cancer in different tissues. Inhibition of the Ras-depalmitoylating enzyme acyl protein thioesterases APT1 and -2 is a new approach to modulating the Ras cycle. Here we present boronic and borinic acid derivatives as a new class of potent and nontoxic APT inhibitors. These compounds were detected by extensive library screening using chemical arrays and turned out to inhibit human APT1 and -2 in a competitive mode. Furthermore, one of the molecules was demonstrated to inhibit Erk1/2 phosphorylation significantly. 23924993 Antibacterial and Herbicidal Activity of Ring-Substituted 2-Hydroxynaphthalene-1-carboxanilides. In this study, a series of twenty-two ring-substituted 2-hydroxynaphthalene-1‑carboxanilides were prepared and characterized. Primary in vitro screening of the synthesized compounds was performed against Staphylococcus aureus, three methicillin-resistant S. aureus strains, Mycobacterium marinum, M. kasasii, M. smegmatis. and M. avium paratuberculosis. The compounds were also tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. 2-Hydroxy-N-phenylnaphthalene-1-carboxanilide and 2-hydroxy-N-(3-trifluoromethylphenyl)naphthalene-1-carboxamide (IC50 = 29 µmol/L) were the most active PET inhibitors. Some of tested compounds showed the antibacterial and antimycobacterial activity against the tested strains comparable or higher than the standards ampicillin or isoniazid. Thus, for example, 2-hydroxy-N-(3-nitrophenyl)naphthalene-1-carboxamide showed MIC = 26.0 µmol/L against methicillin-resistant S. aureus and MIC = 51.9 µmol/L against M. marinum, or 2-hydroxy-N-phenylnaphthalene-1-carboxamide demonstrated MIC = 15.2 µmol/L against M. kansasii. The structure-activity relationships for all compounds are discussed. 23874630 A high frequency of circulating th22 and th17 cells in patients with new onset graves' disease. T-helper (Th) 22 and Th17 cells are involved in the pathogenesis of autoimmune diseases. However, their roles in the pathogenesis of Graves'disease (GD) are unclear. This study is aimed at examining the frequency of peripheral blood Th22, Th17, and Th1 cells and the levels of plasma IL-22, IL-17, and IFN-γ in patients with GD. A total of 27 patients with new onset GD and 27 gender- and age-matched healthy controls (HC) were examined for the frequency of peripheral blood Th22, Th17, and IFN-γ cells by flow cytometry. The concentrations of plasma IL-22, IL-17, and IFN-γ were examined by enzyme-linked immunosorbent assay. The levels of serum TSHR antibodies (A-TSHR), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) were examined by radioimmunoassay and chemiluminescent assay, respectively. The levels of serum TSAb were examined by enzyme-linked immunosorbent assay. In comparison with those in the HC, significantly elevated percentages of Th22 and Th17 cells, but not Th1 cells, and increased levels of plasma IL-22 and IL-17, but not IFN-γ, were detected in GD patients (P<0.0001, for both). The percentages of both Th22 and Th17 cells and the levels of plasma IL-22 and IL-17 were correlated positively with the levels of serum TSAb in GD patients (r = 0.7944, P<0.0001; r = 0.8110, P<0.0001; r = 0.7101, p<0.0001; r = 0.7407, p<0.0001, respectively). Th22 and Th17 cells may contribute to the pathogenesis of GD. 23864165 Tumor-infiltrating lymphocytes in glioblastoma are associated with specific genomic alterations and related to transcriptional class. Tumor-infiltrating lymphocytes (TILs) have prognostic significance in many cancers, yet their roles in glioblastoma (GBM) have not been fully defined. We hypothesized TILs in GBM are associated with molecular alterations, histologies and survival. We used data from The Cancer Genome Atlas (TCGA) to investigate molecular, histologic and clinical correlates of TILs in GBMs. Lymphocytes were categorized as absent, present or abundant in histopathologic images from 171 TCGA GBMs. Associations were examined between lymphocytes and histologic features, mutations, copy number alterations, CpG island methylator phenotype, transcriptional class and survival. We validated histologic findings using CD3G gene expression. We found a positive correlation between TILs and GBMs with gemistocytes, sarcomatous cells, epithelioid cells and giant cells. Lymphocytes were enriched in the mesenchymal transcriptional class and strongly associated with mutations in NF1 and RB1. These mutations are frequent in the mesenchymal class and characteristic of gemistocytic, sarcomatous, epithelioid and giant cell histologies. Conversely, TILs were rare in GBMs with small cells and oligodendroglioma components. Lymphocytes were depleted in the classical transcriptional class and in EGFR-amplified and homozygous PTEN-deleted GBMs. These alterations are characteristic of GBMs with small cells and GBMs of the classical transcriptional class. No association with survival was demonstrated. TILs were enriched in GBMs of the mesenchymal class, strongly associated with mutations in NF1 and RB1 and typical of histologies characterized by these mutations. Conversely, TILs were depleted in the classical class, EGFR-amplified and homozygous PTEN-deleted tumors and rare in histologies characterized by these alterations. 23601411 Dietary fibre fractions in cereal foods measured by a new integrated AOAC method. The reliable determination of soluble, insoluble and total dietary fibre in baked goods and cereal flours is an important issue for research, nutritional labelling and marketing. We compared total dietary fibre (TDF) contents of selected cereal based foods determined by AOAC Method 991.43 and the new AOAC Method 2009.01. Fifteen bread and bakery products were included in the study. Our results showed that TDF values of cereal products determined by AOAC Method 2009.01 were always significantly higher than those determined by AOAC Method 991.43. This was explained by the inclusion of low molecular weight soluble fibre fractions and resistant starch fractions in the TDF measurement by AOAC 2009.01. This documents that nutritional labelling of cereal products poses the challenge how to update TDF data in nutrient databases in a reasonable time with an acceptable expenditure. 23920412 The Determination of Rotation Axis in the Rotation Electron Diffraction Technique. Methods to determine the rotation axis using the rotation electron diffraction technique are described. A combination of rotation axis tilt, beam tilt, and simulated experimental diffraction patterns with nonintegers zone axis has been used. Accurate knowledge of the crystallographic direction of the incident beam for deducing the excitation error of reflections simultaneously near Bragg positions is essential in quantitative electron diffraction. Experimental patterns from CoP3 are used as examples. 23863327 Graduate Medical Education in Humanism and Professionalism: A Needs Assessment Survey of Pediatric Gastroenterology Fellows. The deterioration of humanism and professionalism during graduate medical training is an acknowledged concern, and programs are required to provide professionalism education for pediatric fellows. We conducted a needs assessment survey in a national sample of 138 first- and second-year gastroenterology fellows (82% response rate). Most felt that current humanism and professionalism education met their needs, but this education was largely informal (e.g., role modeling). Areas for formal education desired by >70% included competing demands of clinical practice vs. research, difficult doctor-patient relationships, depression/burnout, angry parents, medical errors, work-life balance, and the patient illness experience. These results may guide curricula to formalize humanism and professionalism education in pediatric gastroenterology fellowships. 23922985 Plasma L-Ergothioneine Measurement by High-Performance Liquid Chromatography and Capillary Electrophoresis after a Pre-Column Derivatization with 5-Iodoacetamidofluorescein (5-IAF) and Fluorescence Detection. Two sensitive and reproducible capillary electrophoresis and high-performance liquid chromatography-fluorescence procedures were established for quantitative determination of L-egothioneine in plasma. After derivatization of L-ergothioneine with 5-iodoacetamidofluorescein, the separation was carried out by HPLC on an ODS-2 C-18 sperisorb column by using a linear gradient elution and by HPCE on an uncoated fused silica capillary, 50 µm id, and 60 cm length. The methods were validated and found to be linear in the range of 0.3 to 10 µmol/l. The limit of quantification was 0.27 µmol/l for HPCE and 0.15 µmol/l for HPLC. The variations for intra- and inter-assay precision were around 6 RSD%, and the mean recovery accuracy close to 100% (96.11%). 23754472 Jury panel member perceptions of interpersonal-affective traits of psychopathy predict support for execution in a capital murder trial simulation. Recent research with college undergraduate mock jurors suggests that how psychopathic they perceive a criminal defendant to be is a powerful predictor of whether they will support a death verdict in simulated capital murder trials. Perceived affective and interpersonal traits of psychopathy are especially predictive of support for capital punishment, with perceived remorselessness explaining a disproportionate amount of variance in these attitudes. The present study attempted to extend these findings with a more representative sample of community members called for jury duty (N = 304). Jurors reviewed a case vignette based on an actual capital murder trial, provided sentencing verdicts, and rated the defendant on several characteristics historically associated with the construct of psychopathy. Consistent with prior findings, remorselessness predicted death verdicts, as did the affective and interpersonal features of psychopathy - though the latter effect was more pronounced among jurors who were Caucasian and/or who described their political beliefs as moderate rather than conservative or liberal. Results are discussed in terms of the potentially stigmatizing effects of psychopathy evidence in capital cases. Copyright © 2013 John Wiley & Sons, Ltd. 23857501 Improving palm oil quality through identification and mapping of the lipase gene causing oil deterioration. The oil palm fruit mesocarp contains high lipase activity that increases free fatty acids and necessitates post-harvest inactivation by heat treatment of fruit bunches. Even before heat treatment the mesocarp lipase activity causes consequential oil losses and requires costly measures to limit free fatty acids quantities. Here we demonstrate that elite low-lipase lines yield oil with substantially less free fatty acids than standard genotypes, allowing more flexibility for post-harvest fruit processing and extended ripening for increased yields. We identify the lipase and its gene cosegregates with the low-/high-lipase trait, providing breeders a marker to rapidly identify potent elite genitors and introgress the trait into major cultivars. Overall, economic gains brought by wide adoption of this material could represent up to one billion dollars per year. Expected benefits concern all planters but are likely to be highest for African smallholders who would be more able to produce oil that meets international quality standards. 23837932 Systemic methotrexate therapy for psoriasis: past, present and future. Methotrexate (MTX) has remained the backbone of the treatment for moderate to severe psoriasis ever since its first use nearly half a century ago. Over the years, its high efficacy, low cost, relative ease of administration and usefulness in concomitant psoriatic arthritis have contributed in making MTX the drug of choice in managing severe psoriasis. Although the majority of patients achieve remission of disease activity with MTX, a significant proportion may experience mild and transient adverse effects. From time to time, various guidelines on the use of MTX have correctly and adequately stressed the need for strict monitoring of haematological and hepatic adverse events. Over the years, the safe total cumulative dose of MTX (above which the risk of developing liver fibrosis is significantly increased) has been raised. Simultaneously, there has been an increased emphasis on developing noninvasive tests such as scanning and serum biomarker assays for detecting early liver fibrosis, in order to obviate the need for liver biopsy. However, the recent discovery and subsequent proliferating use of biological response modifiers has gradually shifted the focus away from MTX, despite it still being the most commonly prescribed drug for psoriasis worldwide. The aim of this review is to present a detailed account of MTX therapy and its use in psoriasis, along with its current relevance in disease management in the evolving era of biological drugs. 23476712 Stacking of Short DNA Induces the Gyroid Cubic-to-Inverted Hexagonal Phase Transition in Lipid-DNA Complexes. Lyotropic phases of amphiphiles are a prototypical example of self-assemblies. Their structure is generally determined by amphiphile shape and their phase transitions are primarily governed by composition. In this paper, we demonstrate a new paradigm for membrane shape control where the electrostatic coupling of charged membranes to short DNA (sDNA), with tunable temperature-dependent end-to-end stacking interactions, enables switching between the inverted gyroid cubic structure (QII (G)) and the inverted hexagonal phase (HII (C)). We investigated the structural shape transitions induced in the QII (G) phase upon complexation with a series of sDNAs (5, 11, 24, and 48 bp) with three types of end structure ("sticky" adenine (A)-thymine (T) (dAdT) overhangs, no overhang (blunt), and "nonsticky" dTdT overhangs) using synchrotron small-angle X-ray scattering. Very short 5 bp sDNA with dAdT overhangs and blunt ends induce coexistence of the QII (G) and the HII (C) phase, with the fraction of QII (G) increasing with temperature. Phase coexistence for blunt 5 bp sDNA is observed from 27 °C to about 65 °C, where the HII (C) phase disappears and the temperature dependence of the lattice spacing of the QII (G) phase indicates that the sDNA duplexes melt into single strands. The only other sDNA for which melting is observed is 5 bp sDNA with dTdT overhangs, which forms the QII (G) phase throughout the studied range of temperature (27 °C to 85.2 °C). The longer 11 bp sDNA forms coexisting QII (G) and HII (C) phases (with the fraction of QII (G) again increasing with temperature) only for "nonsticky" dTdT overhangs, while dAdT overhangs and blunt ends exclusively template the HII (C) phase. For 24 and 48 bp sDNAs the HII (C) phase replaces the QII (G) phase at all investigated temperatures, independent of sDNA end structure. Our work demonstrates how the combined effects of sDNA length and end structure (which determine the temperature-dependent stacking length) tune the phase behavior of the complexes. These findings are consistent with the hypothesis that sDNAs and sDNA stacks with lengths comparable to or larger than the cubic unit cell length disfavor the highly curved channels present in the QII (G) phase, thus driving the QII (G)-to-HII (C) phase transition. As the temperature is increased, the breaking of stacks due to thermal fluctuations restores increasing percentages of the QII (G) phase. 23369094 Preparation, characterization, in vivo biodistribution and pharmacokinetic studies of donepezil-loaded PLGA nanoparticles for brain targeting. Abstract Objective: Alzheimer's disease (AD) is a progressive neurodegenerative disorder manifested by cognitive, memory deterioration and variety of neuropsychiatric symptoms. Donepezil is a reversible cholinesterase inhibitor used for the treatment of AD. The purpose of this work is to prepare a nanoparticulate drug delivery system of donepezil using poly(lactic-co-glycolic acid) (PLGA) for sustained release and efficient brain targeting. Materials and methods: PLGA nanoparticles (NPs) were prepared by the solvent emulsification diffusion-evaporation technique and characterized for particle size, particle-size distribution, zeta potential, entrapment efficiency, drug loading and interaction studies and in vivo studies using gamma scintigraphy techniques. Results and discussion: The size of drug-loaded NPs (drug polymer ratio 1:1) was found to be 89.67 ± 6.43 nm. The TEM and SEM images of the formulation suggested that particle size was within 20-100 nm and spherical in shape, smooth morphology and coating of Tween-80 on the NPs was clearly observed. The release behavior of donepezil exhibited a biphasic pattern characterized by an initial burst release followed by a slower and continuous sustained release. The biodistribution studies of donepezil-loaded PLGA NPs and drug solution via intravenous route revealed higher percentage of radioactivity per gram in the brain for the nanoparticulate formulation as compared with the drug solution (p < 0.05). Conclusion: The high concentrations of donepezil uptake in brain due to coated NPs may help in a significant improvement for treating AD. But further, more extensive clinical studies are needed to check and confirm the efficacy of the prepared drug delivery system. 23942222 Composite quality measures for common inpatient medical conditions. Public reporting on quality aims to help patients select better hospitals. However, individual quality measures are suboptimal in identifying superior and inferior hospitals based on outcome performance. To combine structure, process, and outcome measures into an empirically derived composite quality measure for heart failure (HF), acute myocardial infarction (AMI), and pneumonia (PNA). To assess how well the composite measure predicts future high and low performers, and explains variance in future hospital mortality. Using national Medicare data, we created a cohort of older patients treated at an acute care hospital for HF (n=1,203,595), AMI (n=625,595), or PNA (n=1,234,299). We ranked hospitals on the basis of their July 2005 to June 2008 performance on the composite. We then estimated the odds of future (July to December 2009) 30-day, risk-adjusted mortality at the worst versus best quintile of hospitals. We repeated this analysis using 2005-2008 performance on existing quality indicators, including mortality. The composite (vs. Hospital Compare) explained 68% (vs. 39%) of variation in future AMI mortality rates. In 2009, if an AMI patient had chosen a hospital in the worst versus best quintile of performance using 2005-2008 composite (vs. Hospital Compare) rankings, he or she would have had 1.61 (vs. 1.39) times the odds of dying in 30 days (P-value for difference <0.001). Results were similar for HF and PNA. Composite measures of quality for HF, AMI, and PNA performed better than existing measures at explaining variation in future mortality and predicting future high and low performers. 23440947 Cytologic features of the endometrial adenocarcinoma: Comparison of ThinPrep and BD surepath preparations. We compared the cytoarchitectural features used for the cytologic diagnosis of endometrial adenocarcinoma (EC) using ThinPrep® (TPS = ThinPrep Sample) and BD SurePath™ (SPS = SurePath Sample) preparations. In 20 patients, a direct endometrial sample using the Uterobrush was obtained. Nineteen cases of EA and one case of carcinosarcoma were studied. TPS and SPS were performed according to the manufacturer's recommendations. Moreover, after the TPS preparation, the residual material was also used to prepare an SPS sample (TP-SPS = ThinPrep-Surepath sample). The following points were investigated in both preparations: (1) number of cell clumps; SPS had a significantly higher (20.9) than TPS (1.7) and TP-SPS (10.3); (2) long axis of clumps; SPS had a significantly higher (215.4) than TPS (146.0); (3) rate of cell clumps with longer axes than 200 μm; SPS had a significantly higher (36.7) than TPS (15.2) and TP-SPS (24.2). TP-SPS showed higher values than TPS; (4) nuclear area; TPS had a significant higher (61.2) than SPS (40.8) and TP-SPS (38.6); (5) degree of overlapping nuclei; SPS (3.4) had a significantly higher number of overlapping nuclei than TPS (0.7) and TP-SPS (2.1); (6) nuclear chromatin pattern; no significant differences for the nuclear chromatin pattern were found in the three different methods. The poor performance of TPS versus SPS and TP-SPS was explained with the heavy blood contamination of the samples, and the absence of adhesive coating in the slides is used for TPS. Further investigation of technical differences in liquid-based cytology methodologies is needed. Diagn. Cytopathol. 2013;41:673-681. © 2013 Wiley Periodicals, Inc. 23696035 Reply to the comment of S. Rayne on "QSAR model reproducibility and applicability: A case study of rate constants of hydroxyl radical reaction models applied to polybrominated diphenyl ethers and (benzo-)triazoles". We appreciate the interest of Dr. Rayne on our article and we completely agree that the dataset of (benzo-)triazoles, which were screened by the hydroxyl radical reaction quantitative structure-activity relationship (QSAR) model, was not only composed of benzo-triazoles but also included some simpler triazoles (without the condensed benzene ring), such as the chemicals listed by Dr. Rayne, as well as some related heterocycles (also few not aromatic). We want to clarify that in this article (as well as in other articles in which the same dataset was screened), for conciseness, the abbreviations (B)TAZs and BTAZs were used as general (and certainly too simplified) notations meaning an extended dataset of benzo-triazoles, triazoles, and related compounds. 23749475 Rationalizing prescribing for older patients with multimorbidity: considering time to benefit. Given the growing number of older adults with multimorbidity who are prescribed multiple medications, clinicians need to prioritize which medications are most likely to benefit and least likely to harm an individual patient. The concept of time to benefit (TTB) is increasingly discussed in addition to other measures of drug effectiveness in order to understand and contextualize the benefits and harms of a therapy to an individual patient. However, how to glean this information from available evidence is not well established. The lack of such information for clinicians highlights a critical need in the design and reporting of clinical trials to provide information most relevant to decision making for older adults with multimorbidity. We define TTB as the time until a statistically significant benefit is observed in trials of people taking a therapy compared to a control group not taking the therapy. Similarly, time to harm (TTH) is the time until a statistically significant adverse effect is seen in a trial for the treatment group compared to the control group. To determine both TTB and TTH, it is critical that we also clearly define the benefit or harm under consideration. Well-defined benefits or harms are clinically meaningful, measurable outcomes that are desired (or shunned) by patients. In this conceptual review, we illustrate concepts of TTB in randomized controlled trials (RCTs) of statins for the primary prevention of cardiovascular disease. Using published results, we estimate probable TTB for statins with the future goal of using such information to improve prescribing decisions for individual patients. Knowing the relative TTBs and TTHs associated with a patient's medications could be immensely useful to a clinician in decision making for their older patients with multimorbidity. We describe the challenges in defining and determining TTB and TTH, and discuss possible ways of analyzing and reporting trial results that would add more information about this aspect of drug effectiveness to the clinician's evidence base. 23829357 Application of the Docking Program SOL for CSAR Benchmark. This paper is devoted to results obtained by the docking program SOL and the post-processing program DISCORE at the CSAR benchmark. SOL and DISCORE programs are described. SOL is the original docking program developed on the basis of the genetic algorithm, MMFF94 force field, rigid protein, precalculated energy grid including desolvation in the frame of simplified GB model, vdW, and electrostatic interactions and taking into account the ligand internal strain energy. An important SOL feature is the single- or multi-processor performance for up to hundreds of CPUs. DISCORE improves the binding energy scoring by the local energy optimization of the ligand docked pose and a simple linear regression on the base of available experimental data. The docking program SOL has demonstrated a good ability for correct ligand positioning in the active sites of the tested proteins in most cases of CSAR exercises. SOL and DISCORE have not demonstrated very exciting results on the protein-ligand binding free energy estimation. Nevertheless, for some target proteins, SOL and DISCORE were among the first in prediction of inhibition activity. Ways to improve SOL and DISCORE are discussed. 23900975 Novel Diabetes Autoantibodies and Prediction of Type 1 Diabetes. Autoantibodies are currently the most robust biomarkers of type 1 diabetes and are frequently used to establish entry criteria for the participation of genetically at-risk individuals in secondary prevention/intervention clinical trials. Since their original description almost 40 years ago, considerable efforts have been devoted toward identifying the precise molecular targets that are recognized. Such information can have significant benefit for developing improved metrics for identifying/stratifying of at-risk subjects, developing potential therapeutic targets, and advancing understanding of the pathophysiology of the disease. Currently, four major molecular targets ([pro]insulin, GAD65, IA-2, and ZnT8) have been confirmed, with approximately 94% of all subjects with a clinical diagnosis of type 1 diabetes expressing autoantibodies to at least one of these molecules at clinical onset. In this review, we summarize some of the salient properties of these targets that might contribute to their autoantigenicity and methods that have been used in attempts to identify new components of the humoral autoresponse. 23759386 Fabrication of conductive NGF-conjugated polypyrrole-poly(l-lactic acid) fibers and their effect on neurite outgrowth. In order to fabricate a tissue scaffold with the neurotrophic and electrical activities, conductive nerve growth factor (NGF)-conjugated polypyrrole-poly(l-lactic acid) (PPy-PLLA) composite fibers were prepared by oxidation polymerization and EDC chemistry with poly-l-lysine. PPy nanoparticles (∼70nm diameter) accumulated on PLLA fiber surface to form a rough thick shell (∼200nm thickness). These NGF-conjugated PPy-PLLA fibers could support PC12 neurite outgrowth and extension. Especially, 40% and 74% increase in PC12 neurite outgrowth and extension, respectively, could be obtained under electrical stimulation of 100mV/cm voltages through the composite fibers. A mechanism for the interaction between neurite extension and the NGF-conjugated PPy-PLLA fibers under electro-stimulation was proposed, to explain the synergistic effect of the rough PPy shell, conjugated NGF and electricity on neurite outgrowth and elongation. 23872874 Poorly differentiated carcinoma arising in the setting of erythema ab igne. : Erythema ab igne (EAI) is a reticulated, erythematous, or hyperpigmented dermatosis that is caused by chronic exposure to infrared radiation. Chronic lesions of EAI have significant potential for malignant transformation. We report a case of poorly differentiated carcinoma arising within a patch of long-standing EAI on the lower extremity of a 92-year-old female. This case highlights the importance of recognizing EAI early and counseling patients to avoid further exposure to the offending infrared source to reduce the risk of malignant transformation. EAI has been associated with several different types of cutaneous neoplasms including the Merkel cell carcinoma, squamous cell carcinoma, and cutaneous marginal zone lymphoma. 23894097 Strategic Targeting of Multiple Water-Mediated Interactions: A Concise and Rational Structure-Based Design Approach to Potent and Selective MMP-13 Inhibitors. Water in the architecture of life: Potent and selective matrix metalloproteinase-13 (MMP-13) inhibitors were rationally designed by targeting multiple water-mediated interactions between the target protein and small-molecule inhibitors. This structure-based design concept offers tremendous opportunities for the discovery of unique small molecules with tailored biological activity. 23885109 Prolactin is not required for the development of severe chronic experimental autoimmune encephalomyelitis. Predominance of multiple sclerosis (MS) in women, reductions of disease flares during pregnancy, and their increase in the postpartum period have suggested a hormonal influence on MS activity. The hormone prolactin (PRL) has long been debated as a potential immune-stimulating factor in several autoimmune disorders, including MS and its animal model experimental autoimmune encephalomyelitis (EAE). However, to date, no data clearly ascribe a pathogenic role to PRL in these diseases. Using PRL receptor-deficient (Prlr(-/-)) and PRL-deficient (Prl(-/-)) mice, we show that PRL plays a redundant role in the development of chronic EAE. In Prlr(-/-) and Prl(-/-) mice, EAE developed with a delayed onset compared with littermate control mice, but with full clinical severity. In line with the clinical outcome, T cell proliferation and production of IFN-γ, IL-17A, and IL-6 induced by myelin Ag were delayed in Prlr(-/-) and Prl(-/-) mice. Ag-specific IgG Ab responses were not affected by PRLR or PRL deficiency. We also show that mouse lymph node cells and purified CD4(+) T cells express transcript for Prlr, but not for Prl. These results reveal that PRL does not play a central role in the development of chronic EAE and optimal Th1 and Th17 responses against myelin. Moreover, they also rule out a possible contribution of PRL secreted by immune cells to the modulation of autoreactive T cell response in this model. 23770185 Specific kinematics and motor-related neurons for aversive chemotaxis in Drosophila. Chemotaxis, the ability to direct movements according to chemical cues in the environment, is important for the survival of most organisms. The vinegar fly, Drosophila melanogaster, displays robust olfactory aversion and attraction, but how these behaviors are executed via changes in locomotion remains poorly understood. In particular, it is not clear whether aversion and attraction bidirectionally modulate a shared circuit or recruit distinct circuits for execution. Using a quantitative behavioral assay, we determined that both aversive and attractive odorants modulate the initiation and direction of turns but display distinct kinematics. Using genetic tools to perturb these behaviors, we identified specific populations of neurons required for aversion, but not for attraction. Inactivation of these populations of cells affected the completion of aversive turns, but not their initiation. Optogenetic activation of the same populations of cells triggered a locomotion pattern resembling aversive turns. Perturbations in both the ellipsoid body and the ventral nerve cord, two regions involved in motor control, resulted in defects in aversion. Aversive chemotaxis in vinegar flies triggers ethologically appropriate kinematics distinct from those of attractive chemotaxis and requires specific motor-related neurons. 23900449 An unusual presentation of ruptured abdominal aorta aneurysm. Patient: Female, 65 Final Diagnosis: Ruptured abdominal aorta aneursym Symptoms: - Medication: - Clinical Procedure: After surgery the patient was discharged without sequelae Specialty: Surgery. Unusual clinical course. Rupture of an abdominal aortic aneurysm is the most frightening and potentially life threatening complication of an abdominal aorta aneurysm (AAA). Patients present with atypical symptoms such as abdominal or flank pain, gastrointestinal hemorrhage, or shock. A 65-year-old woman presented to our emergency department with gradually increasing left flank pain for 4-5 days. Her laboratory, radiologic, and physical examination revealed no significant pathology, so she was discharged, but 3 days later she was readmitted because her symptoms returned. Further research revealed a ruptured AAA and the patient was hospitalized for surgical intervention. Emergency physicians should keep in mind that AAA and its rupture can present with a wide range of symptoms that appear to be simple. 23893485 Structural Integrity of Centromeric Chromatin and Faithful Chromosome Segregation Requires Pat1. The kinetochore (centromeric DNA and associated protein complex) is essential for faithful chromosome segregation and maintenance of genome stability. Here we report that an evolutionarily conserved protein Pat1 is a structural component of Saccharomyces cerevisiae kinetochore and associates with centromeres in a NDC10-dependent manner. Consistent with a role for Pat1 in kinetochore structure and function, a deletion of PAT1 results in delay in sister chromatid separation, errors in chromosome segregation and defects in structural integrity of centromeric chromatin. Pat1 is involved in topological regulation of minichromosomes as altered patterns of DNA supercoiling were observed in pat1 cells. Studies with pat1 alleles uncovered an evolutionarily conserved region within the central domain of Pat1 that is required for its association with centromeres, sister chromatid separation, and faithful chromosome segregation. Taken together, our data have uncovered a novel role for Pat1 in maintaining the structural integrity of centromeric chromatin to facilitate faithful chromosome segregation and proper kinetochore function. 23608635 N-alkylation of highly quaternized chitosan derivatives affects the paracellular permeation enhancement in bronchial epithelia in vitro. This study describes the structure-activity relationship for carefully characterized N-alkyl-N-quaternary chitosan derivatives as permeation enhancers for drugs that are mainly absorbed through the paracellular pathway, such as macromolecular drugs and hydrophilic drugs, in a well defined bronchial epithelial cell line. The O-methyl free derivatives used in the study were fully trimethylated (100%) N,N,N-trimethyl chitosan (TMC) and N-propyl-(QuatPropyl), N-butyl-(QuatButyl) and N-hexyl (QuatHexyl)-N,N-dimethyl chitosan, with 85-91% degree of quaternization. The fully trimethylated TMC, from 0.25mg/ml, decreased transepithelial electrical resistance (TER) in a reversible manner and enhanced the permeation of the macromolecule FITC-dextran 4kDa (FD4) 2-5 fold. TMC did not cause any alterations in the tight junction (TJ) protein claudin-4 or in F-actin architecture. QuatHexyl was the most effective polymer to produce enhanced permeation and decreased TER from 0.016mg/ml. Nevertheless, this enhanced permeation was accompanied by reduced viability and dissociation of F-actin and claudin-4 proteins. The structure-activity relationship suggests that more lipophilic derivatives show more permeation enhancement, TJ disassembly, and less viability in the order of hexyl≈butyl>propyl>methyl and demonstrates that the permeation effect is not only mediated by permanent positive charge but also through by the extent of N-alkylation. These results are relevant to elucidate the structural factors contributing to the permeation enhancement of chitosan derivatives and for potential use in pulmonary applications. 23798386 S-nitrosylation therapy to improve oxygen delivery of banked blood. From the perspectives of disease transmission and sterility maintenance, the world's blood supplies are generally safe. However, in multiple clinical settings, red blood cell (RBC) transfusions are associated with adverse cardiovascular events and multiorgan injury. Because ∼85 million units of blood are administered worldwide each year, transfusion-related morbidity and mortality is a major public health concern. Blood undergoes multiple biochemical changes during storage, but the relevance of these changes to unfavorable outcomes is unclear. Banked blood shows reduced levels of S-nitrosohemoglobin (SNO-Hb), which in turn impairs the ability of stored RBCs to effect hypoxic vasodilation. We therefore reasoned that transfusion of SNO-Hb-deficient blood may exacerbate, rather than correct, impairments in tissue oxygenation, and that restoration of SNO-Hb levels would improve transfusion efficacy. Notably in mice, administration of banked RBCs decreased skeletal muscle pO2, but infusion of renitrosylated cells maintained tissue oxygenation. In rats, hemorrhage-induced reductions in muscle pO2 were corrected by SNO-Hb-repleted RBCs, but not by control, stored RBCs. In anemic awake sheep, stored renitrosylated, but not control RBCs, produced sustained improvements in O2 delivery; in anesthetized sheep, decrements in hemodynamic status, renal blood flow, and kidney function incurred following transfusion of banked blood were also prevented by renitrosylation. Collectively, our findings lend support to the idea that transfusions may be causally linked to ischemic events and suggest a simple approach to prevention (i.e., SNO-Hb repletion). If these data are replicated in clinical trials, renitrosylation therapy could have significant therapeutic impact on the care of millions of patients. 23261859 Sex hormones and mental rotation: an intensive longitudinal investigation. The present study used an intensive longitudinal design to examine whether mental rotation performance varies according to a monthly cycle in both males and females and whether these variations are related to variations in progesterone, estradiol, and testosterone levels. We collected reaction time and accuracy data for 10 males and seven females each workday over eight weeks using 136 pairs of mental rotation stimuli/day, and measured sexual hormones concentrations in the saliva twice a week. A mixed linear model statistical analysis revealed that all females and seven males showed significant cycle effects in mental rotation performance. The female cycle showed an amplitude that was twice as large compared with the amplitude found in males. For males and females, estradiol and testosterone were significantly linearly and quadratically related to interindividual variation in performance at the beginning of the study (progesterone was linearly related to performance for females). The association between testosterone and performance differed across sexes: for males, it had an inverse U-shape, for females it was U-shaped. Towards the end of the study, none of the hormones were significantly related to performance anymore. Thus, the relationship between hormones and mental rotation performance disappeared with repeated testing. Only estradiol levels were significantly elevated at the lowest point of the cycle in mental rotation performance in females. In conclusion, in this intensive longitudinal study spanning two months, a monthly cycle in mental rotation performance was found among both males and females, with a larger cycle's amplitude for females. 23065494 'In a twilight world'? Judging the value of life for the minimally conscious patient. The recent ruling from England on the case of M is one of very few worldwide to consider whether life-sustaining treatment, in the form of clinically assisted nutrition and hydration, should continue to be provided to a patient in a minimally conscious state. Formally concerned with the English law pertaining to precedent autonomy (specifically advance decision-making) and the best interests of the incapacitated patient, the judgment issued in M's case implicitly engages with three different accounts of the value of human life, which respectively emphasise its self-determined, intrinsic and instrumental value. The judge appeared to be most persuaded by the intrinsic value of life and he concluded that treatment ought to continue. Assessing whether his approach or conclusion were ethically appropriate involves significant substantive and evidential questions regarding where the burden of proof should lie and what standard of proof should be required when decisions are to be made about the fates of patients inhabiting 'twilight worlds'. 23812607 Quantitative observation of focused-ultrasound-induced vascular leakage and deformation via fluorescein angiography and optical coherence tomography. Focused ultrasound (FUS) is a recently discovered noninvasive technique for local and temporal enhancement of vascular permeability, which facilitates drug delivery from the vessels into the surrounding tissue. However, exposure to FUS at a high intensity may cause permanent damage. To investigate the effects of the FUS treatment on blood vessels, we propose to use fluorescein angiography (FA) and optical coherence tomography (OCT) for real-time observation of the diffusion of fluorescence dye from blood vessels and to evaluate the morphological changes of the vessels in vivo. With time-resolved FA imaging, the relationship between the exposed power and the improved permeability of the vessels can be assessed according to the enhancement of the fluorescent intensity due to the dye leakage. Furthermore, the variation of the time-resolved fluorescent intensities can be used to identify the occurrence of dye leakage. In contrast, OCT can be implemented for the reconstruction of tissue microstructures. To quantitatively evaluate the morphological changes of the vessels after the FUS exposure with OCT, a new algorithm was proposed to estimate the vessel area based on the comparison of backscattering properties resulting from the tissue and vascular structures. Results showed that the vessel area increased as the exposed power increased, and the area became significantly larger at a higher FUS exposure power of 10 W. In conclusion, integrated FA and OCT observation can be potentially effective for monitoring the outcome and investigating the effects of FUS treatment. 23647631 Telomere shortening in human diseases. The discovery of telomeres dates back to the early 20th century. In humans, telomeres are heterochromatic structures with tandem DNA repeats of 5'-TTAGGG-3' at the chromosomal ends. Telomere length varies greatly among species and ranges from 10 to 15 kb in humans. With each cell division, telomeres shorten progressively because of the 'end-replication problem'. Short or dysfunctional telomeres are often recognized as DNA DSBs, triggering cell-cycle arrest and result in cellular senescence or apoptotic cell death. Therefore, telomere shortening serves as an important tumor-suppressive mechanism by limiting cellular proliferative capacity by regulating senescence checkpoint activation. Although telomeres serve as a mitotic clock to cells, they also confer capping on chromosomes, with help from telomere-associated proteins. Over the past decades, many studies of telomere biology have demonstrated that telomeres and telomere-associated proteins are implicated in human genetic diseases. In addition, it has become more apparent that accelerated telomere erosion is associated with a myriad of metabolic and inflammatory diseases. Moreover, critically short or unprotected telomeres are likely to form telomeric fusions, leading to genomic instability, the cornerstone for carcinogenesis. In light of these, this minireview summarizes studies on telomeres and telomere-associated proteins in human diseases. Elucidating the roles of telomeres involved in the mechanisms underlying pathogenesis of these diseases may open up new possibilities for novel molecular targets as well as provide important diagnostic and therapeutic implications. 23910228 Use and Timing of Coronary Angiography and Associated In-hospital Outcomes in Canadian Non-ST-Segment Elevation Myocardial Infarction Patients: Insights from the Canadian Global Registry of Acute Coronary Events. Although an early invasive approach has become standard strategy for the management of non-ST-segment elevation myocardial infarction (NSTEMI), the frequency and timing in Canada is uncertain. We examined the use and timing of coronary angiography, revascularization, and cardiovascular outcomes of NSTEMI patients: (1) admitted on weekdays vs weekends; and (2) stratified according to presentation risk level, in the Canadian Global Registry of Acute Coronary Events (GRACE)/Expanded GRACE (GRACE(2))/Canadian Registry of Acute Coronary Events (CANRACE) population. Of 6711 NSTEMI patients, 1956 (29.1%) were admitted on the weekend. The median (interquartile range) wait time for coronary angiography was 58 (32-106) and 70 (50-112) hours for weekday and weekend patients, respectively (P = 0.32). Compared with lower-intermediate risk, higher-risk patients were less likely to undergo angiography (44.7% vs 69.7% for weekdays and 45.2% vs 69.6% for weekends; both P < 0.0001) and waited longer for angiography (median 71 vs 61 hours; P < 0.0001). Weekend admission was independently associated with higher mortality (adjusted odds ratio [OR], 1.52; 95% confidence interval [CI], 1.15-2.01; P = 0.004), recurrent ischemia (adjusted OR, 1.16; 95% CI, 1.01-1.32; P = 0.03), and heart failure (adjusted OR, 1.28; 95% CI, 1.00-1.63; P = 0.048) but not with reinfarction. Median wait time for angiography in Canadian NSTEMI patients admitted on the weekend was not significantly longer than for those who presented on a weekday. Patients admitted on weekends had higher adjusted mortality and cardiovascular event rates. Higher-risk patients were less likely to undergo angiography and waited longer, with higher observed in-hospital event rates. Systematic, guideline-recommended risk stratification should be considered to ensure that optimal management strategies (eg, timely coronary angiography in higher-risk patients) are matched to level of risk. 23761384 Familial lipoprotein lipase deficiency: a case of compound heterozygosity of a novel duplication (R44Kfs*4) and a common mutation (N291S) in the lipoprotein lipase gene. Familial lipoprotein lipase (LPL) deficiency (FLLD) is a rare autosomal recessive genetic disorder caused by homozygous or compound heterozygous mutations in the LPL gene. FLLD individuals usually express an impaired or non-functional LPL enzyme with low or absent triglyceride (TG) hydrolysis activity causing severe hypertriglyceridaemia. Here we report a case of FLLD in a 29-year-old man, who initially presented with eruptive cutaneous xanthomata, elevated plasma TG concentration but no other co-morbidities. Subsequent genetic testing of the patient revealed compound heterozygosity of a novel duplication (p.R44Kfs*4) leading to a premature stop codon in exon 2 and a known mutation (N291S) in exon 5 of the LPL gene. Further biochemical analysis of the patient's postheparin plasma confirmed a reduction of total lipase activity compared with his heterozygous father carrying the common N291S mutation and to a healthy control. Also the patient showed increased (1.85-fold) activity of hepatic lipase (HL), indicating a functional link between HL and LPL. In summary, we report a case of FLLD caused by compound heterozygosity of a new duplication and a common mutation in the LPL gene, resulting in residual LPL activity. With such mutations, individuals may not receive a diagnosis before classical FLLD symptoms appear later in adulthood. Nevertheless, early diagnosis and lipid-lowering treatment may favour a reduced risk of premature cardiovascular disease or acute pancreatitis in such individuals. 23889518 Hydrolysis of the E2P Phosphoenzyme of the Ca(2+)-ATPase: A Theoretical Study. Dephosphorylation of the E2P phosphoenzyme intermediate of the sarcoplasmic reticulum Ca(2+)-ATPase was studied using density functional theory. The hydrolysis reaction proceeds via a nucleophilic attack on the phosphorylated residue Asp351 by a water molecule, which is positioned by the nearby residue Glu183 acting as a base. The activation barrier was calculated to be 14.3 kcal/mol, which agrees well with values of 15-17 kcal/mol derived from experimentally observed rates. The optimized structure of the transition state reveals considerable bond breakage between phosphorus and the Asp351 oxygen (distance 2.19 Å) and little bond formation to the attacking water oxygen (distance 2.26 Å). Upon formation of the singly protonated phosphate product, Glu183 becomes protonated. The bridging aspartyl phosphate oxygen approaches Lys684 progressively when proceeding from the reactant state (distance 1.94 Å) via the transition state (1.78 Å) to the product state (1.58 Å). This stabilizes the negative charge that develops on the leaving group. The reaction was calculated to be slightly endergonic (+0.9 kcal/mol) and therefore reversible, in line with experimental findings. It is catalyzed by a preorganized active site with little movement of the nonreacting groups except for a rotation of Thr625 toward the phosphate group. 23945258 A Computational Study of Spike Time Reliability in Two Cases of Threshold Dynamics. Spike time reliability (STR) refers to the phenomenon in which repetitive applications of a frozen copy of one stochastic signal to a neuron trigger spikes with reliable timing while a constant signal fails to do so. Observed and explored in numerous experimental and theoretical studies, STR is a complex dynamic phenomenon depending on the nature of external inputs as well as intrinsic properties of a neuron. The neuron under consideration could be either quiescent or spontaneously spiking in the absence of the external stimulus. Focusing on the situation in which the unstimulated neuron is quiescent but close to a switching point to oscillations, we numerically analyze STR treating each spike occurrence as a time localized event in a model neuron. We study both the averaged properties as well as individual features of spike-evoking epochs (SEEs). The effects of interactions between spikes is minimized by selecting signals that generate spikes with relatively long inter-spike intervals (ISIs). Under these conditions, the frequency content of the input signal has little impact on STR. We study two distinct cases, Type I in which the f-I relation (f for frequency, I for applied current) is continuous and Type II where the f-I relation exhibits a jump. STR in the two types shows a number of similar features and differ in some others. SEEs that are capable of triggering spikes show great variety in amplitude and time profile. On average, reliable spike timing is associated with an accelerated increase in the ``action'' of the signal as a threshold for spike generation is approached. Here, ``action'' is defined as the average amount of current delivered during a fixed time interval. When individual SEEs are studied, however, their time profiles are found important for triggering more precisely timed spikes. The SEEs that have a more favorable time profile are capable of triggering spikes with higher precision even at lower action levels. 23651641 Solubility enhancement of paclitaxel using a linear-dendritic block copolymer. The solubilising capacities of micelles of a linear-dendritic copolymer (BE-PAMAM), formed by conjugating the poly(butylene oxide) (B)-poly(ethylene oxide) (E) block copolymer B16E42 (BE) with a G2 PAMAM dendrimer, have been compared with those of the diblock copolymer B16E42 for the anti-cancer drug paclitaxel. The BE-PAMAM copolymer showed a greater solubility enhancement than BE under equivalent conditions. Drug-loading efficiency was improved using a solvent-loading method compared with the conventional solution-loading method. The solubility of paclitaxel was increased 3700-fold by micellar encapsulation in a 2% (w/v) BE-PAMAM copolymer solution at 37°C using this solubilisation technique. Dynamic light scattering and transmission electron microscopy studies indicated a transition of spherical to worm-like micelles of the BE copolymer induced by the encapsulation of drug molecules. A sustained release of encapsulated drug was observed, with approximately 80% and 60% paclitaxel being released from 2% (w/v) solutions of BE and BE-PAMAM respectively after 24h of dialysis at 37°C. 23830593 LGR5 is a biomarker for stratification of HER-2 positive breast cancer patients and personalized treatment. VEGFR and HER2 are both important transmembrane proteins associated with several types of cancer. Overexpression of these 2 proteins had long been thought to contribute to cancer progression and poor outcomes, thus, therapies targeting HER-2 and VEGFA signaling pathways have been applied in recent years. Herceptin is a HER-2 targeted antibody that being widely used for the management of HER-2 positive breast cancer, which demonstrate significant benefits in both the metastatic and adjuvant settings. However, acquired resistance develops in most treated patients despite treatment in as early as 10months. Identification of subpopulations best suited for and most likely to respond to Herceptin is of utmost importance. We analyzed the signaling pathways of HER-2 and found that HER-2 shares a very similar downstream network with VEGFA, while LGR5 lies in the upstream of VEGFA and could promotes its expression through CTNNB1. This discovery suggests that the LGR5 directed VEGFA overexpression may activate downstream signals of HER-2 despite Herceptin treatment. Here, we hypothesized that in LGR5 overexpressing breast cancer cases, activation of VEGFA-VRGFR bypass may account for the resistance to HER-2 directed therapies. Concurrent inhibition of VEGFR might enhance Herceptin sensitivity and moreover reverse the resistant phenotype in HER-2 positive breast cancer. Thus, we proposed alternate regimens to increase the efficacy of Herceptin-based therapy. Nevertheless, wet lab experiments and clinical trials are still required. 23953422 Mandibular bone structure, bone mineral density, and clinical variables as fracture predictors: a 15-year follow-up of female patients in a dental clinic. To compare three mandibular trabeculation evaluation methods, clinical variables, and osteoporosis as fracture predictors in women. One hundred and thirty-six female dental patients (35-94 years) answered a questionnaire in 1996 and 2011. Using intra-oral radiographs from 1996, five methods were compared as fracture predictors: (1) mandibular bone structure evaluated with a visual radiographic index, (2) bone texture, (3) size and number of intertrabecular spaces calculated with Jaw-X software, (4) fracture probability calculated with a fracture risk assessment tool (FRAX), and (5) osteoporosis diagnosis based on dual-energy-X-ray absorptiometry. Differences were assessed with the Mann-Whitney test and relative risk calculated. Previous fracture, gluco-corticoid medication, and bone texture were significant indicators of future and total (previous plus future) fracture. Osteoporosis diagnosis, sparse trabeculation, Jaw-X, and FRAX were significant predictors of total but not future fracture. Clinical and oral bone variables may identify individuals at greatest risk of fracture. 23240742 Hepatozoon parasites (apicomplexa: adeleorina) in bats. Abstract : We provide the first evidence of Hepatozoon parasites infecting bats. We sequenced a short fragment of the 18S rRNA gene (∼600 base pairs) of Hepatozoon parasites from 3 Hipposideros cervinus bats from Borneo. Phylogenies inferred by model-based methods place these Hepatozoon within a clade formed by parasites of reptiles, rodents, and marsupials. We discuss the scenario that bats might be common hosts of Hepatozoon. 23697905 Hydrogel-embeded vesicles, as a novel approach for prolonged release and delivery of liposome, in vitro and in vivo. Abstract A novel delivery concept based on the integration of liposomes in hydrogel for the controlled release of liposomes was developed. As an in situ forming hydrogel, chitosan-glycerophosphate was used and gelation time at different temperatures was studied. Liposomes (DSPC/chol/DOPE) were labelled with (99m)Tc-hexamethylpropyleneamineoxime ((99m)Tc-HMPAO). (99m)Tc-HMPAO solution, hydrogel/(99m)Tc-HMPAO, (99m)Tc-HMPAO liposomes and hydrogel/(99m)Tc-HMPAO liposomes were injected into mouse peritoneum. The percentages of radioactive injected dose per gram of tissue (%ID/g) and %ID of peritoneum lavage were obtained. Results showed that free label left the peritoneal cavity rapidly in both solution and hydrogel forms, such that the activity was 2.5 and 3.8 (%ID) after one hour, respectively. The values for liposomes and liposomal hydrogel were 25.8 and 51.2 (%ID) and decreased to 1.9 and 19.2 after 24 h, respectively. The blood profile of liposomal hydrogel showed a two-phase profile including a descending trend in early hours regarding gel formation followed by an ascending trend due to gel disappearance by time. Free label had high activity in reticuloendothelial system (RES) and the gastrointestinal tract during the early hours and then dropped. In contrast, the accumulation of liposomes increased in RES during 24 h in the range of 1-34.5 and 1.1-35.1 (%ID/g) for plain liposomes and liposomal hydrogel, respectively. Overall, incorporation of liposomes in hydrogel could be a useful strategy to prolong the release of liposomes. 23262164 Anti-tumor efficacy of chitosan-g-poly(ethylene glycol) nanocapsules containing docetaxel: anti-TMEFF-2 functionalized nanocapsules vs. non-functionalized nanocapsules. The development and evaluation of PEGylated chitosan (CS) nanocapsules (NCs) conjugated to a monoclonal antibody anti-TMEFF-2 (CS-PEG-anti-TMEFF-2 mAb NCs) for targeted delivery of docetaxel (DCX) is presented. CS-PEG-Biotin NCs, displaying biotin tags at their surface, were obtained and efficiently functionalized with an anti-TMEFF-2 mAb through a convenient avidin-biotin approach. Cell cycle analysis after treatment with different DCX-loaded CS-PEG NC formulations indicated that the encapsulated drug remained fully active, showing a similar functional behavior to free DCX. In vivo efficacy studies using a non-small cell lung carcinoma xenograft revealed that CS-PEG-anti-TMEFF-2 NCs resulted as effective as free DCX (Taxotere®). Interestingly, differences on the pharmacodynamic behavior among the different DCX formulations were observed. Thus, while free DCX exhibited a fast and short effect on tumor volume reduction, CS-PEG-anti-TMEFF-2 mAb NCs showed a delayed and prolonged action, with no significant side effects of treatments. 23524202 Analysis of hydrological trend for radioactivity content in bore-hole water samples using wavelet based denoising. A wavelet transform based denoising methodology has been applied to detect the presence of any discernable trend in (137)Cs and (90)Sr activity levels in bore-hole water samples collected four times a year over a period of eight years, from 2002 to 2009, in the vicinity of typical nuclear facilities inside the restricted access zones. The conventional non-parametric methods viz., Mann-Kendall and Spearman rho, along with linear regression when applied for detecting the linear trend in the time series data do not yield results conclusive for trend detection with a confidence of 95% for most of the samples. The stationary wavelet based hard thresholding data pruning method with Haar as the analyzing wavelet was applied to remove the noise present in the same data. Results indicate that confidence interval of the established trend has significantly improved after pre-processing to more than 98% compared to the conventional non-parametric methods when applied to direct measurements. 23066089 Activation of group I metabotropic glutamate receptors potentiates heteromeric kainate receptors. Kainate receptors (KARs), a family of ionotropic glutamate receptors, are widely expressed in the central nervous system and are critically involved in synaptic transmission. KAR activation is influenced by metabotropic glutamate receptor (mGlu) signaling, but the underlying mechanisms are not understood. We undertook studies to examine how mGlu modulation affects activation of KARs. Confocal immunohistochemistry of rat hippocampus and cultured rat cortex revealed colocalization of the high-affinity KAR subunits with group I mGlu receptors. In hippocampal and cortical cultures, the calcium signal caused by activation of native KARs was potentiated by activation of group I mGlu receptors. In Xenopus laevis oocytes, activation of group I mGlu receptors potentiated heteromeric but not homomeric KAR-mediated currents, with no change in agonist potency. The potentiation of heteromeric KARs by mGlu1 activation was attenuated by GDPβS, blocked by an inhibitor of phospholipase C or the calcium chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), prolonged by the phosphatase inhibitor okadaic acid, but unaffected by the tyrosine kinase inhibitor lavendustin A. Protein kinase C (PKC) inhibition reduced the potentiation by mGlu1 of GluK2/GluK5, and conversely, direct activation of PKC by phorbol 12-myristate,13-acetate potentiated GluK2/GluK5. Using site-directed mutagenesis, we identified three serines (Ser833, Ser836, and Ser840) within the membrane proximal region of the GluK5 C-terminal domain that, in combination, are required for mGlu1-mediated potentiation of KARs. Together, these data suggest that phosphorylation of key residues in the C-terminal domain changes the overall charge of this domain, resulting in potentiated agonist responses. 23616470 Elucidation of in situ polycyclic aromatic hydrocarbon degradation by functional metaproteomics (protein-SIP). Current knowledge of the physiology and phylogeny of polycyclic aromatic hydrocarbon (PAH) degrading bacteria often relies on laboratory enrichments and isolations. In the present study, in situ microcosms consisting of activated carbon pellets (BACTRAP®s) were loaded with either (13) C-naphthalene or (13) C-fluorene and were subsequently exposed in the contaminant source and plume fringe region of an PAH contaminated aquifer. Metaproteomic analysis and protein-SIP revealed Burkholderiales, Actinomycetales and Rhizobiales as the most active microorganisms in the groundwater communities. Proteins identified of the naphthalene degradation pathway showed a relative (13) C isotope abundance of approximately 50 atom% demonstrating that the identified naphthalene degrading bacteria gained at least 80% of their carbon by PAH degradation. Although the microbial community grown on the fluorene-BACTRAPs showed a structure similar to the naphthalene-BACTRAPs, the identification of fluorene degraders and degradation pathways failed in situ. In complementary laboratory microcosms, a clear enrichment in proteins related to Rhodococcus and possible fluorene degradation enzymes was observed. This result demonstrates the impact of laboratory conditions on microbial community structure and activity of certain species and underlines the need on in situ exploration of microbial community functions. In situ microcosms in combination with protein-SIP may be a significant tool for in situ identification of metabolic key players as well as degradation pathways. This article is protected by copyright. All rights reserved. 23346991 A retrospective, dual-isotope approach reveals individual predispositions to winter-drought induced tree dieback in the southernmost distribution limit of Scots pine. Winter-drought induced forest diebacks in the low-latitude margins of species' distribution ranges can provide new insights into the mechanisms (carbon starvation, hydraulic failure) underlying contrasting tree reactions. We analysed a winter-drought induced dieback at the Scots pine's southern edge through a dual-isotope approach (Δ(13) C and δ(18) O in tree-ring cellulose). We hypothesized that a differential long-term performance, mediated by the interaction between CO(2) and climate, determined the fates of individuals during dieback. Declining trees showed a stronger coupling between climate, growth and intrinsic water-use efficiency (WUEi) than non-declining individuals that was noticeable for 25 years prior to dieback. The rising stomatal control of water losses with time in declining trees, indicated by negative Δ(13) C-δ(18) O relationships, was likely associated with their native aptitude to grow more and take up more water (suggested by larger tracheid lumen widths) than non-declining trees and, therefore, to exhibit a greater cavitation risk. Freeze-thaw episodes occurring in winter 2001 unveiled such physiological differences by triggering dieback in those trees more vulnerable to hydraulic failure. Thus, WUEi tightly modulated growth responses to long-term warming in declining trees, indicating that co-occurring individuals were differentially predisposed to winter-drought mortality. These different performances were unconnected to the depletion of stored carbohydrates. 23844618 On the Origins of Large Interaction-Induced First Hyperpolarizabilities in Hydrogen-Bonded π-Electronic Complexes. In this article we elucidate the origins of interaction-induced linear and nonlinear electro-optic properties of model hydrogen-bonded π-electronic complexes. In particular we report on contributions due to various interaction energy terms to excess dipole moments (Δμ), electric dipole polarizabilities (Δα), and first hyperpolarizabilities (Δβ), focusing on the latter. The analysis of intermolecular interaction-induced electric properties is performed for selected model systems including quasi-linear dimers of urea, diformamide, 4-pyridone, 4-nitroaniline, and the complex of hydrogen fluoride with nitroacetylene. The nature of intermolecular interactions as well as of the Δμ and Δα is very similar in all studied complexes. However, partitioning of Δβ into physically well-defined components reveals that the origins of this term, the magnitude of which is often comparable to the hyperpolarizabilities of isolated monomers, are different in each case. Our results indicate that, even though hydrogen bonding usually diminishes the nonlinear response of interacting species, the first hyperpolarizability of complexes with the nitro group acting as a proton acceptor is substantially increased, essentially due to field-induced changes of electrostatic interactions between subsystems. However, in the remaining complexes the origins of Δβ are much more involved. Even though at large intermolecular separations the origins of interaction-induced electric properties are essentially due to the field-induced electrostatic and induction interactions, in the vicinity of van der Waals minimum the overlap effects cannot be neglected since they may substantially alter the predicted excess properties or even determine their magnitude and sign. On the other hand the Δβ contribution due to dispersion interactions is usually negligible. Interestingly, the values of interaction-induced first hyperpolarizability in some cases depend strongly on the intermolecular separation in the vicinity of equilibrium geometry. 23966858 The Role of Selection in Shaping Diversity of Natural M. tuberculosis Populations. Mycobacterium tuberculosis (M.tb), the cause of tuberculosis (TB), is estimated to infect a new host every second. While analyses of genetic data from natural populations of M.tb have emphasized the role of genetic drift in shaping patterns of diversity, the influence of natural selection on this successful pathogen is less well understood. We investigated the effects of natural selection on patterns of diversity in 63 globally extant genomes of M.tb and related pathogenic mycobacteria. We found evidence of strong purifying selection, with an estimated genome-wide selection coefficient equal to -9.5×10(-4) (95% CI -1.1×10(-3) to -6.8×10(-4)); this is several orders of magnitude higher than recent estimates for eukaryotic and prokaryotic organisms. We also identified different patterns of variation across categories of gene function. Genes involved in transport and metabolism of inorganic ions exhibited very low levels of non-synonymous polymorphism, equivalent to categories under strong purifying selection (essential and translation-associated genes). The highest levels of non-synonymous variation were seen in a group of transporter genes, likely due to either diversifying selection or local selective sweeps. In addition to selection, we identified other important influences on M.tb genetic diversity, such as a 25-fold expansion of global M.tb populations coincident with explosive growth in human populations (estimated timing 1684 C.E., 95% CI 1620-1713 C.E.). These results emphasize the parallel demographic histories of this obligate pathogen and its human host, and suggest that the dominant effect of selection on M.tb is removal of novel variants, with exceptions in an interesting group of genes involved in transportation and defense. We speculate that the hostile environment within a host imposes strict demands on M.tb physiology, and thus a substantial fitness cost for most new mutations. In this respect, obligate bacterial pathogens may differ from other host-associated microbes such as symbionts. 23967308 Modulation of oxidative stress by twist oncoproteins. Expression of developmental genes Twist1 and Twist2 is reactivated in many human tumors. Among their oncogenic activities, induction of epithelial to mesenchymal transition is believed to increase cell motility and invasiveness and may be related to acquisition of cancer stem cell phenotype. In addition, Twist proteins promote malignant conversion by overriding two oncogene-induced failsafe programs: senescence and apoptosis. Reactive oxygen species (ROS) are also important mediators of apoptosis, senescence and motility and are tightly linked to disease, notably to cancer. We report here that Twist factors and ROS are functionally linked. In wild type cells both Twist1 and Twist2 exhibit antioxidant properties. We show that Twist-driven modulation of oncogene-induced apoptosis is linked to its effects on oxidative stress. Finally, we identify several targets that mediate Twist antioxidant activity. These findings unveil a new function of Twist factors that could be important in explaining their pleiotropic role during carcinogenesis. 23684763 Pharmacologically tunable polyethylene-glycol-based cell growth substrate. Biohybrid materials combining synthetic polymers with biological components are highly suited for tissue engineering in order to emulate the behavior of natural materials such as the extracellular matrix (ECM). In order to allow for an optimal cell-material interplay, the physical and biological parameters of the artificial matrix need to be dynamically remodeled during cultivation. Current tissue engineering concepts are mainly based on passive remodeling mechanisms including the degradation of the hydrogel and the release of incorporated biomolecules and therefore do not enable external adjustment of cultivation conditions. We present a novel hydrogel material that is able to serve as a cell growth matrix, whose degradation and presentation of cell-interacting biomolecules can be externally controlled by the addition of a pharmacological substance. The hydrogel is based on branched polyethylene glycol that is covalently decorated with the aminocoumarin-antibiotic switchable gyrase B protein conferring stimulus-responsive degradation. ECM properties were conferred to the hydrogels with cell attachment motifs and a general approach for the incorporation and inducible release of therapeutic biomolecules. This smart biohybrid material has the potential to serve as a next-generation tissue engineering device which allows for dynamic external adjustment of the physical and biological parameters, resulting in optimally controlled tissue formation. 23556542 Examining the interpersonal-psychological theory of suicide in an inpatient veteran sample. Suicide among veterans is a pressing public health concern. The interpersonal-psychological theory of suicide proposes that perceived burdensomeness and thwarted belongingness lead to suicidal desire, whereas the acquired capability for suicide leads to suicide attempt in the presence of suicidal desire (Joiner, 2005). Two hypotheses derived from the interpersonal-psychological theory of suicide were tested in 185 veterans (96 women) entering inpatient psychiatric treatment. Burdensomeness and its interaction with belongingness significantly predicted current suicidal ideation. The three-way interaction between burdensomeness, belongingness, and acquired capability did not significantly predict number of past suicide attempts. Clinical implications and directions for future research are discussed. 23824141 Floral divergence, pollinator partitioning and the spatiotemporal pattern of plant-pollinator interactions in three sympatric Adenophora species. Floral divergence among congeners may relate to differential utilization of pollinators and contribute to reducing overlap in pollination niches. To investigate whether and how floral differences are associated with differential utilization of pollinators in three sympatric Adenophora species, we analyzed floral traits and evaluated the contribution of different visitors to pollination. We compared visitation rates of different pollinator categories in different years and sites. A suite of floral traits differed among the three Adenophora species, suggesting adaptation to diurnal versus nocturnal pollination and an intermediate condition. However, many visitor species were shared among the three plant species, suggesting that floral traits did not rigorously filter visitors. Effective pollinators were large bees and moths. The importance of large bees as pollinators decreased whereas that of moths increased along the gradient from typically bee-pollinated to moth-pollinated flowers. The intermediate species (A. khasiana) differed substantially from the other two species in pollinator species but not in pollinator categories. The principal pollinator category of each species was constant across years and sites except in the intermediate species where it differed between two sites. Overall, the three sympatric species of Adenophora partition pollinators by floral divergence and the principal pollinators coincide with the predictions based on floral syndromes. 23748050 The Novartis view on emerging drugs and novel targets for the treatment of chronic obstructive pulmonary disease. Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease characterized by airflow limitation and chronic inflammation in the lungs. The mainstay of drug therapy for COPD is represented by long-acting bronchodilators, an important aspect of Novartis' development program. Novel once-daily dosing bronchodilators, such as the long-acting muscarinic antagonist (LAMA) glycopyrronium and the LAMA/long-acting β2-agonist (LABA) fixed-dose combination QVA149, have been shown to provide significant benefits to patients with COPD in terms of improvement in lung function, exercise tolerance, health-related quality of life, symptoms and reduction in the rate of exacerbations. Despite the benefits provided by these new treatment options, prevention of disease progression and control of exacerbations in certain patient phenotypes remain key challenges in the treatment of COPD. In order to address these needs and gain new insights into the complexity of COPD, Novartis is, in addition to bronchodilator-only therapies, developing LABA/inhaled corticosteroids (ICS) combinations to target inflammation, such as QMF149, as well as non-steroid based anti-inflammatory agents against key novel targets. These commitments are central to the Novartis' final goal of improving the standard of care in respiratory medicine and offering a better quality of life to patients with COPD. 23918114 Maximizing positive airway pressure adherence in adults: a common-sense approach. Positive airway pressure (PAP) therapy is considered the most efficacious treatment of obstructive sleep apnea (OSA), especially moderate to severe OSA, and remains the most commonly prescribed. Yet suboptimal adherence presents a challenge to sleep-medicine clinicians. The purpose of the current review is to highlight the efficacy of published interventions to improve PAP adherence and to suggest a patient-centered clinical approach to enhancing PAP usage. 23845241 Development: hippo signalling turns the embryo inside out. Lineage decisions in development are thought to be primarily due to differential activation of transcription factors. However, cell position and subcellular organization of signalling also play a role. New studies of the Hippo pathway in the early mouse embryo show how. 23597599 The rise of machine consciousness: studying consciousness with computational models. Efforts to create computational models of consciousness have accelerated over the last two decades, creating a field that has become known as artificial consciousness. There have been two main motivations for this controversial work: to develop a better scientific understanding of the nature of human/animal consciousness and to produce machines that genuinely exhibit conscious awareness. This review begins by briefly explaining some of the concepts and terminology used by investigators working on machine consciousness, and summarizes key neurobiological correlates of human consciousness that are particularly relevant to past computational studies. Models of consciousness developed over the last twenty years are then surveyed. These models are largely found to fall into five categories based on the fundamental issue that their developers have selected as being most central to consciousness: a global workspace, information integration, an internal self-model, higher-level representations, or attention mechanisms. For each of these five categories, an overview of past work is given, a representative example is presented in some detail to illustrate the approach, and comments are provided on the contributions and limitations of the methodology. Three conclusions are offered about the state of the field based on this review: (1) computational modeling has become an effective and accepted methodology for the scientific study of consciousness, (2) existing computational models have successfully captured a number of neurobiological, cognitive, and behavioral correlates of conscious information processing as machine simulations, and (3) no existing approach to artificial consciousness has presented a compelling demonstration of phenomenal machine consciousness, or even clear evidence that artificial phenomenal consciousness will eventually be possible. The paper concludes by discussing the importance of continuing work in this area, considering the ethical issues it raises, and making predictions concerning future developments. 23837891 Authentication of Monofloral Yemeni Sidr Honey Using Ultraviolet Spectroscopy and Chemometric Analysis. This work describes a simple model developed for the authentication of monofloral Yemeni Sidr honey using UV spectroscopy together with chemometric techniques of hierarchical cluster analysis (HCA), principal component analysis (PCA), and soft independent modeling of class analogy (SIMCA). The model was constructed using 13 genuine Sidr honey samples and challenged with 25 honey samples of different botanical origins. HCA and PCA were successfully able to present a preliminary clustering pattern to segregate the genuine Sidr samples from the lower priced local polyfloral and non-Sidr samples. The SIMCA model presented a clear demarcation of the samples and was used to identify genuine Sidr honey samples as well as detect admixture with lower priced polyfloral honey by detection limits >10%. The constructed model presents a simple and efficient method of analysis and may serve as a basis for the authentication of other honey types worldwide. 23299953 Surgical technique for symmetric patellar resurfacing during total knee arthroplasty. Patellar resurfacing is a commonly performed procedure during total knee arthroplasty (TKA). Common goals of patellar resurfacing are to obtain a stable, functional, patellofemoral joint with minimal pain. This is typically accomplished by resecting the patella in a symmetric fashion while attempting to restore native patellar thickness. Several cutting guides have been developed to assist with patellar resurfacing during TKA; however, we feel that the patella can be resected in a predictably symmetric fashion without the use of cutting guides or other specialized equipment. The following is a description of a novel patellar resurfacing technique that reproducibly results in a smoothly resected patella that is free of asymmetry and obliquity without the use of cutting guides. It can reliably be performed in an efficient manner that reduces equipment needs without prolonging operative time. 23459932 Otitis media in the Tgif knockout mouse implicates TGFβ signalling in chronic middle ear inflammatory disease. Otitis media with effusion (OME) is the most common cause of hearing loss in children and tympanostomy to alleviate the condition remains the commonest surgical intervention in children in the developed world. Chronic and recurrent forms of OM are known to have a very significant genetic component, however, until recently little was known of the underlying genes involved. The identification of mouse models of chronic OM has indicated a role of transforming growth factor beta (TGFβ) signalling and its impact on responses to hypoxia in the inflamed middle ear. We have, therefore, investigated the role of TGFβ signalling and identified and characterized a new model of chronic OM carrying a mutation in the gene for transforming growth interacting factor 1 (Tgif1). Tgif1 homozygous mutant mice have significantly raised auditory thresholds due to a conductive deafness arising from a chronic effusion starting at around 3 weeks of age. The OM is accompanied by a significant thickening of the middle ear mucosa lining, expansion of mucin-secreting goblet cell populations and raised levels of vascular endothelial growth factor, TNF-α and IL-1β in ear fluids. We also identified downstream effects on TGFβ signalling in middle ear epithelia at the time of development of chronic OM. Both phosphorylated SMAD2 and p21 levels were lowered in the homozygous mutant, demonstrating a suppression of the TGFβ pathway. The identification and characterization of the Tgif mutant supports the role of TGFβ signalling in the development of chronic OM and provides an important candidate gene for genetic studies in the human population. 23343976 Targeted drug delivery to treat pain and cerebral hypoxia. Limited drug penetration is an obstacle that is often encountered in treatment of central nervous system (CNS) diseases including pain and cerebral hypoxia. Over the past several years, biochemical characteristics of the brain (i.e., tight junction protein complexes at brain barrier sites, expression of influx and efflux transporters) have been shown to be directly involved in determining CNS permeation of therapeutic agents; however, the vast majority of these studies have focused on understanding those mechanisms that prevent drugs from entering the CNS. Recently, this paradigm has shifted toward identifying and characterizing brain targets that facilitate CNS drug delivery. Such targets include the organic anion-transporting polypeptides (OATPs in humans; Oatps in rodents), a family of sodium-independent transporters that are endogenously expressed in the brain and are involved in drug uptake. OATP/Oatp substrates include drugs that are efficacious in treatment of pain and/or cerebral hypoxia (i.e., opioid analgesic peptides, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors). This clearly suggests that OATP/Oatp isoforms are viable transporter targets that can be exploited for optimization of drug delivery to the brain and, therefore, improved treatment of CNS diseases. This review summarizes recent knowledge in this area and emphasizes the potential that therapeutic targeting of OATP/Oatp isoforms may have in facilitating CNS drug delivery and distribution. Additionally, information presented in this review will point to novel strategies that can be used for treatment of pain and cerebral hypoxia. 23965613 Divergent astrovirus associated with neurologic disease in cattle. Using viral metagenomics of brain tissue from a young adult crossbreed steer with acute onset of neurologic disease, we sequenced the complete genome of a novel astrovirus (BoAstV-NeuroS1) that was phylogenetically related to an ovine astrovirus. In a retrospective analysis of 32 cases of bovine encephalitides of unknown etiology, 3 other infected animals were detected by using PCR and in situ hybridization for viral RNA. Viral RNA was restricted to the nervous system and detected in the cytoplasm of affected neurons within the spinal cord, brainstem, and cerebellum. Microscopically, the lesions were of widespread neuronal necrosis, microgliosis, and perivascular cuffing preferentially distributed in gray matter and most severe in the cerebellum and brainstem, with increasing intensity caudally down the spinal cord. These results suggest that infection with BoAstV-NeuroS1 is a potential cause of neurologic disease in cattle. 23835618 Dual role of TGFBR3 in bladder cancer. Bladder cancer is one of the most common genitourinary malignant diseases worldwide. More than 90% of bladder cancer cases are bladder urothelial carcinoma (BUC). Although transforming growth factor-β III receptor (TGFBR3) has been suggested to play a dual role in cancer progression, little is known about TGFBR3 in bladder cancer. In the present study, fresh tumor and the corresponding paracarcinoma tissue specimens were collected from 56 bladder urothelial carcinoma patients. TGFBR3 expression in these tissues was determined by western blotting. TGFBR3 was also detected in the human normal urothelial cell line SV-HUC-1, the human superficial urothelial bladder cancer cell line 5637, and the human invasive bladder cancer cell line T24 using western blotting and quantitative PCR. Cell growth, motility and invasion were also analyzed in the control and the TGFBR3 gene-silenced T24 cells. As a result, the expression of TGFBR3 was reduced (18/30) in most superficial bladder urothelial carcinoma tissues compared to the corresponding normal tissues, whereas TGFBR3 expression was more enhanced (19/26) in the invasive samples. Similarly, an increase of TGFBR3 expression was found in T24 cells, but a decrease was observed in 5637 cells. Knockdown of TGFBR3 in T24 cells resulted in decreased cell growth, motility and invasion. In conclusion, these findings suggest that TGFBR3 may play a dichotomous role in human bladder cancer, acting as both a tumor suppressor and as a tumor promoter. 23580606 The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Nucleotide-binding oligomerization domain-Like Receptor with a Pyrin domain 3 (NLRP3) is considered necessary for initiating a profound sterile inflammatory response. NLRP3 forms multi-protein complexes with Apoptosis-associated Speck-like protein containing a Caspase recruitment domain (ASC) and Caspase-1, which activate pro-interleukin-1β (IL-1β) and pro-IL-18. The role of NLRP3 in cardiac cells is not known. Thus, we investigated the expression and function of NLRP3 during myocardial ischaemia. Myocardial infarction (MI) was induced in adult C57BL/6 mice and Wistar rats by ligation of the coronary artery. A marked increase in NLRP3, IL-1β, and IL-18 mRNA expression was found in the left ventricle after MI, primarily located to myocardial fibroblasts. In vitro studies in cells from adult mice showed that myocardial fibroblasts released IL-1β and IL-18 when primed with lipopolysaccharide and subsequently exposed to the danger signal adenosine triphosphate, a molecule released after tissue damage during MI. When hearts were isolated from NLRP3-deficient mice, perfused and subjected to global ischaemia and reperfusion, a marked improvement of cardiac function and reduction of hypoxic damage was found compared with wild-type hearts. This was not observed in ASC-deficient hearts, potentially reflecting a protective role of other ASC-dependent inflammasomes or inflammasome-independent effects of NLRP3. This study shows that the NLRP3 inflammasome is up-regulated in myocardial fibroblasts post-MI, and may be a significant contributor to infarct size development during ischaemia-reperfusion. 23940016 Quantitative magnetization transfer MRI of desmoplasia in pancreatic ductal adenocarcinoma xenografts. Quantitative assessment of desmoplasia in pancreatic ductal adenocarcinoma (PDAC) may be critical for staging or prediction of response to therapy. We performed quantitative magnetization transfer (qMT) MRI measurements in 18 mouse xenograft tumors generated from three PDAC cell lines. The qMT parameter bound proton fraction (BPF) was found to be significantly higher in tumors grown using the BxPC-3 cell line (5.31 ± 0.87, mean ± standard deviation) compared with the BPF measured for tumors grown from Panc-1 (3.65 ± 0.60) and Capan-1 (1.50 ± 0.58) cell lines (P < 0.05 for each comparison). Histologic measurements demonstrated a similar trend; BxPC-3 tumors had significantly higher fibrosis levels (percentage of fibrotic tissue area, 6.21 ± 2.10) compared with Panc-1 (2.88 ± 1.13) and Capan-1 (1.69 ± 1.01) tumors. BPF was well correlated with quantitative fibrosis levels (r = 0.77, P < 0.01). Our results indicate that qMT measurements offer the potential to noninvasively quantify fibrosis levels in PDAC mouse xenograft models and thus serve as a valuable in vivo biomarker of desmoplasia in PDAC. Copyright © 2013 John Wiley & Sons, Ltd. 23104247 Effects of Korean red ginseng extracts on neural tube defects and impairment of social interaction induced by prenatal exposure to valproic acid. Ginseng is one of the most widely used medicinal plants, which belongs to the genus Panax. Compared to uncured white ginseng, red ginseng has been generally regarded to produce superior pharmacological effects with lesser side/adverse effects, which made it popular in a variety of formulation from tea to oriental medicine. Using the prenatal valproic acid (VPA)-injection model of autism spectrum disorder (ASD) in rats, which produces social impairrment and altered seizure susceptibility as in human ASD patients as well as mild neural tube defects like crooked tail phenotype, we examined whether chronic administration of red ginseng extract may rescue the social impairment and crooked tail phenotype in prenatally VPA-exposed rat offspring. VPA-induced impairment in social interactions tested using sociability and social preference paradigms as well as crooked tail phenotypes were significantly improved by administration of Korean red ginseng (KRG) in a dose dependent manner. Rat offspring prenatally exposed to VPA showed higher sensitivity to electric shock seizure and increased locomotor activity in open-field test. KRG treatment reversed abnormal locomotor activity and sensitivity to electric shock to control level. These results suggest that KRG may modulate neurobehavioral and structural organization of nervous system adversely affected by prenatal exposure to VPA. 23810912 Highly selective detection of bacterial alarmone ppGpp with an off-on fluorescent probe of copper-mediated silver nanoclusters. In this study, a facile strategy for highly selective and sensitive detection of bacterial alarmone, ppGpp, which is generated when bacteria face stress circumstances such as nutritional deprivation, has been established by developing an off-on fluorescent probe of Cu(2+)-mediated silver nanoclusters (Ag NCs). This work not only achieves highly selective detection of ppGpp in a broad range concentration of 2-200μM, but also improves our understanding of the specific recognitions among DNA-Ag NCs, Cu(2+), and ppGpp. The present strategy, together with other reports on the Ag NCs-related analytical methods, has also identified that Ag NCs functionalized with different molecules on their surfaces can be engineered fluorescent probes for a wide range of applications such as biosensing and bioimaging. 23940753 Equal Contributions and Credit: An Emerging Trend in the Characterization of Authorship in Major Anaesthesia Journals during a 10-Yr Period. The practice of giving certain authors equal credit in original research publications was increasingly common in some specialty. This study aimed to investigate the prevalence and characteristics of designating some authors with equally credited authors (ECAs) in major anaesthesia journals. The practice of giving authors equal credit was searched and identified in the three major anaesthesia journals between January 1, 2002 and December 31, 2011. Papers with ECAs had a higher proportion of the total number of articles in 2011 versus published in 2002 (Anesthesiology, 8.8% vs. 0.9%; British Journal of Anaesthesia, 8.8% vs. 0%; Anesthesia & Analgesia, 3.4% vs. 0.3%; totally, 6.4% vs. 0.4%). A significant increasing trend in annual proportion of articles with ECA was found in the three journals. The first two authors listed in the byline had equal credit in most cases. The practice of giving authors equal credit in original research papers is increasingly common in major anaesthesia journals. It may be warranted for the journals to guide the authors how to regard this practice. 23430031 Elevated umbilical artery systolic/diastolic ratio in the absence of fetal growth restriction. To evaluate whether patients with isolated elevation of umbilical artery (UA) systolic/diastolic (S/D) ratio are at increased risk for adverse perinatal outcome. This is a retrospective cohort study of 330 patients who underwent routine evaluation at our maternal fetal medicine center. We regularly perform UA S/D ratio analysis with every third trimester sonogram. All identified patients were included and divided into four groups based on estimated fetal weight (EFW) and UA S/D ratio. Perinatal outcome was compared between the groups. Regardless of the EFW, fetuses with persistent elevated UA S/D ratio showed significantly more preterm deliveries (p < .001), neonatal intensive care unit (NICU) admissions (p < .001), longer stay in the NICU (p < .001) and lower birth weight (p < .001) relative to controls. Stepwise logistic regression analysis demonstrated that being a member in any study group significantly and independently predicted birth weight less than the 10th percentile and preterm delivery. Patients with persistently elevated S/D ratio were significantly and independently from other factors, more likely to have a newborn admitted to the NICU. Our results indicate a suboptimal perinatal outcome in all pregnancies with an elevated UA S/D ratio. These fetuses may benefit from intensive monitoring. 23721763 Medicago truncatula histidine-containing phosphotransfer protein: Structural and biochemical insights into the cytokinin transduction pathway in plants. Histidine-containing phosphotransfer proteins (HPts) take part in hormone signal transduction in higher plants. The overall pathway of this process is reminiscent of the two-component system initially identified in prokaryotes. HPts function in histidine-aspartate phosphorelays in which they mediate the signal from sensory kinases (usually membrane proteins) to RRs in the nucleus. Here, we report the crystal structure of an HPt protein from Medicago truncatula (MtHPt1) determined at 1.45 Ã… resolution and refined to an R-factor of 16.7% using low-temperature synchrotron-radiation X-ray diffraction data. There is one MtHPt1 molecule in the asymmetric unit of the crystal lattice with P21 21 21 symmetry. The protein fold consists of six α helices, four of which form a C-terminal helix bundle. The coiled-coil structure of the bundle is stabilized by a network of S-aromatic interactions involving highly conserved sulfur-containing residues. The structure reveals a solvent-exposed side chain of His79, which is the phosphorylation site, as demonstrated by autoradiography combined with site-directed mutation. It is surrounded by highly conserved residues present in all plant HPts. These residues form a putative docking interface for either the receiver domain of the sensory kinase, or for the RR. The biological activity of MtHPt1 was tested by autoradiography. It demonstrated phosphorylation by the intracellular kinase domain of the cytokinin receptor MtCRE1. Complex formation between MtHPt1 and the intracellular fragment of MtCRE1 was confirmed by thermophoresis, with a dissociation constant Kd of 14 Î¼m. The atomic coordinates and structure factors for the crystal structure of histidine-containing phosphotransfer protein MtHPt1 from Medicago truncatula have been deposited with the RCSB Protein Data Bank under the accession code 3us6. 23552261 Sensitive determination of lead, cadmium and nickel in soil, water, vegetable and fruit samples using STAT-FAAS after preconcentration with activated carbon. In this study, lead (Pb), cadmium (Cd) and nickel (Ni) were determined in soil, water, vegetable and fruit samples taken from around oil refinery region in Batman, Turkey. Digestion procedures for samples were optimized and all optimum parameters were used both in digestion and in determination steps. In order to determine Pb and Cd, slotted tube atom trap (STAT) was used to increase the sensitivity in atomic absorption spectrophotometry. Preconcentration procedure under the optimum conditions was applied to water, vegetable and fruit samples to determine Pb, Cd and Ni in trace levels. In soil samples, concentrations of analytes were found in the range of 4.0 ± 0.2-12,000 ± 60 mg/kg for Pb, 0.15 ± 0.01-3.0 ± 0.1 mg/kg for Cd and 21 ± 1-65 ± 3.4 mg/kg for Ni. In all water samples, concentration of Ni was expressed as nanogram per milliliter (ng/mL) and found to be higher than Pb and Cd levels. It was observed that Pb, Cd and Ni concentrations varied from both plant to plant and in same plants at different experimental sites. Pb concentrations in vegetable and fruit samples interested varied between 20 ± 2 and 160 ± 12 ng/g, and the highest level of Pb was found to be in green pepper taken from 1000 m away from refinery. 23839002 Clinical and anatomical study of the distally based lesser saphenous veno-lateral sural neurocutaneous flap for lower extremity coverage. The distally based sural flap has been widely and successfully used to reconstruct soft tissue defects of the distal third of the lower leg and foot. Sensory loss and venous congestion are possible complications of this treatment, but there has been limited research focused on improving the sensory loss and veneous congestion. This study aimed to determine the spatial relationship between the lesser saphenous vein and the cutaneous nerves, the venous anatomy in the lower leg, and the nerve distribution in the lateral dorsum of the foot, and we presented our clinical experience. Twenty freshly amputated lower limbs were dissected in the 2 h following amputation. The lesser saphenous vein, medial/lateral sural nerve, and sural nerve were identified. Based on the anatomical studies, an island flap supplied by the vascular axis of the lesser saphenous vein and the lateral sural nerve was designed for clinical reparative applications in 24 cases. We indicated the spatial relationship between the lesser saphenous vein and the cutaneous nerves and the venous anatomy in the lower leg. Among 24 flaps, 21 showed complete survival (87.5 %), while marginal flap necrosis occurred in two patients (8.33 %) and distal wound dehiscence in another (4.17 %). No symptomatic neuromas were observed. Their appearance and functioning were satisfactory, with filling maintained in the heel and lateral side of the foot. The distally based lesser saphenous veno-lateral sural neurocutaneous flap provides effective coverage of variable-sized soft tissue defects on the lower third of the lower leg and foot, without sensory loss and venous congestion. 23894233 Treating suspected uterine cavity abnormalities by hysteroscopy to improve reproductive outcome in women with unexplained infertility or prior to IUI, IVF, or ICSI. Endometrial polyps, submucous fibroids, uterine septa, and intrauterine adhesions can be found by ultrasound (US), HSG, hysteroscopy, or any combined in 10-15 % of infertile women. Observational studies suggest a better reproductive outcome when these anomalies are removed by operative hysteroscopy. The current Cochrane review assesses the effectiveness of hysteroscopy for treating these suspected anomalies in women with otherwise unexplained infertility or prior to intrauterine insemination, in vitro fertilization, or intracytoplasmic sperm injection. 23818521 The Bile Acid Receptor TGR5 Does Not Interact with β-Arrestins or Traffic to Endosomes but Transmits Sustained Signals from Plasma Membrane Rafts. TGR5 is a G protein-coupled receptor that mediates bile acid (BA) effects on energy balance, inflammation, digestion, and sensation. The mechanisms and spatiotemporal control of TGR5 signaling are poorly understood. We investigated TGR5 signaling and trafficking in transfected HEK293 cells and colonocytes (NCM460) that endogenously express TGR5. BAs (deoxycholic acid (DCA), taurolithocholic acid) and the selective agonists oleanolic acid and 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N, 5-dimethylisoxazole-4-carboxamide stimulated cAMP formation but did not induce TGR5 endocytosis or recruitment of β-arrestins, as assessed by confocal microscopy. DCA, taurolithocholic acid, and oleanolic acid did not stimulate TGR5 association with β-arrestin 1/2 or G protein-coupled receptor kinase (GRK) 2/5/6, as determined by bioluminescence resonance energy transfer. 3-(2-chlorophenyl)-N-(4-chlorophenyl)-N, 5-dimethylisoxazole-4-carboxamide stimulated a low level of TGR5 interaction with β-arrestin 2 and GRK2. DCA induced cAMP formation at the plasma membrane and cytosol, as determined using exchange factor directly regulated by cAMP (Epac2)-based reporters, but cAMP signals did not desensitize. AG1478, an inhibitor of epidermal growth factor receptor tyrosine kinase, the metalloprotease inhibitor batimastat, and methyl-β-cyclodextrin and filipin, which block lipid raft formation, prevented DCA stimulation of ERK1/2. Bioluminescence resonance energy transfer analysis revealed TGR5 and EGFR interactions that were blocked by disruption of lipid rafts. DCA stimulated TGR5 redistribution to plasma membrane microdomains, as localized by immunogold electron microscopy. Thus, TGR5 does not interact with β-arrestins, desensitize, or traffic to endosomes. TGR5 signals from plasma membrane rafts that facilitate EGFR interaction and transactivation. An understanding of the spatiotemporal control of TGR5 signaling provides insights into the actions of BAs and therapeutic TGR5 agonists/antagonists. 23823071 SIMIBI twins in protein targeting and localization. Signal recognition particle, MinD and BioD (SIMIBI)-type nucleoside triphosphate-binding proteins are an ancient subfamily of nucleotide-binding proteins that serve in a wide range of cellular processes. Notably, this class comprises dimeric ATPases as well as GTPases (SIMIBI 'twins') and a subset of SIMIBI-type proteins, including SRP GTPases, MinD-type ATPases and the Get3 ATPase, is essential to protein targeting and localization. Here, we define common mechanistic principles and differences for these SIMIBI proteins. 23690396 Pseudomonas aeruginosa Uses Multiple Pathways To Acquire Iron during Chronic Infection in Cystic Fibrosis Lungs. Pseudomonas aeruginosa chronically infects the lungs of more than 80% of adult patients with cystic fibrosis (CF) and is a major contributor to the progression of disease pathology. P. aeruginosa requires iron for growth and has multiple iron uptake systems that have been studied in bacteria grown in laboratory culture. The purpose of this research was to determine which of these are active during infection in CF. RNA was extracted from 149 sputum samples obtained from 23 CF patients. Reverse transcription-quantitative real-time PCR (RT-qPCR) was used to measure the expression of P. aeruginosa genes encoding transport systems for the siderophores pyoverdine and pyochelin, for heme, and for ferrous ions. Expression of P. aeruginosa genes could be quantified in 89% of the sputum samples. Expression of genes associated with siderophore-mediated iron uptake was detected in most samples but was at low levels in some samples, indicating that other iron uptake mechanisms are active. Expression of genes encoding heme transport systems was also detected in most samples, indicating that heme uptake occurs during infection in CF. feoB expression was detected in all sputum samples, implying an important role for ferrous ion uptake by P. aeruginosa in CF. Our data show that multiple P. aeruginosa iron uptake mechanisms are active in chronic CF infection and that RT-qPCR of RNA extracted from sputum provides a powerful tool for investigating bacterial physiology during infection in CF. 23606666 Chinese hamster ovary K1 host cell enables stable cell line development for antibody molecules which are difficult to express in DUXB11-derived dihydrofolate reductase deficient host cell. Therapeutic monoclonal antibodies (mAb) are often produced in Chinese hamster ovary (CHO) cells. Three commonly used CHO host cells for generating stable cell lines to produce therapeutic proteins are dihydrofolate reductase (DHFR) positive CHOK1, DHFR-deficient DG44, and DUXB11-based DHFR deficient CHO. Current Genentech commercial full-length antibody products have all been produced in the DUXB11-derived DHFR-deficient CHO host. However, it has been challenging to develop stable cell lines producing an appreciable amount of antibody proteins in the DUXB11-derived DHFR-deficient CHO host for some antibody molecules and the CHOK1 host has been explored as an alternative approach. In this work, stable cell lines were developed for three antibody molecules in both DUXB11-based and CHOK1 hosts. Results have shown that the best CHOK1 clones produce about 1 g/l for an antibody mAb1 and about 4 g/l for an antibody mAb2 in 14-day fed batch cultures in shake flasks. In contrast, the DUXB11-based host produced ∼0.1 g/l for both antibodies in the same 14-day fed batch shake flask production experiments. For an antibody mAb3, both CHOK1 and DUXB11 host cells can generate stable cell lines with the best clone in each host producing ∼2.5 g/l. Additionally, studies have shown that the CHOK1 host cell has a larger endoplasmic reticulum and higher mitochondrial mass. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 29:980-985, 2013. 23921446 Association of MITF and other melanosome-related proteins with chemoresistance in melanoma tumors and cell lines. Previous studies in cell lines have suggested a role for melanosomes and related protein trafficking pathways in melanoma drug response. We have investigated the expression of six proteins related to melanosomes and melanogenesis (MITF, GPR143, gp100/PMEL, MLANA, TYRP1, and RAB27A) in pretreatment metastases from melanoma patients (n=52) with different response to dacarbazine/temozolomide. Microphthalmia-associated transcription factor (MITF) and G-protein coupled receptor 143 (GPR143) showed significantly higher expression in nonresponders compared with responders. The premelanosome protein (gp100/PMEL) has been indicated previously in resistance to cisplatin in melanoma cells, but the expression levels of gp100/PMEL showed no association with response to dacarbazine/temozolomide in our clinical material. We also investigated the effects on chemosensitivity of siRNA inhibition of gp100/PMEL in the MNT-1 melanoma cell line. As expected from the study of the tumor material, no effect was detected with respect to response to temozolomide. However, knockdown of gp100/PMEL sensitized the cells to both paclitaxel and cisplatin. Overall, our results suggest that MITF, and several MITF-regulated factors, are associated with resistance to chemotherapy in melanoma and that different MITF targets can be of importance for different drugs. 23832382 Anteroseptal basal right ventricular entrainment is simple and superior to apical entrainment in identifying mechanism of supraventricular tachycardia. Differentiation between atrioventricular nodal reentry tachycardia (AVNRT) and atrioventricular reentrant tachycardia (AVRT) can be sometimes challenging. Apical right ventricular (RV) entrainment can help in differentiation; however, it has some fallacies. We thought to compare the accuracy of anteroseptal basal RV entrainment to RV apical entrainment in identifying the mechanism of supraventricular tachycardia (SVT). Forty-two consecutive patients with SVT who underwent catheter ablation were prospectively studied. Apical RV entrainment was performed initially followed by basal entrainment from the anteroseptal basal RV avoiding His or atrial capture. Postpacing interval (PPI), PPI-tachycardia cycle length (TCL), corrected PPI-TCL, and stimulus-atrial minus ventricular-atrial (VA) intervals were measured. Entrainment was achieved from both sites of RV in 34 patients (ten men; mean age 42 ±â€‰15 years), 20 with typical AVNRT, 1 with atypical AVNRT, and 13 with AVRT (eight left sided, four right sided, and one septal accessory pathways). PPI-TCL, corrected PPI (cPPI)-TCL, and stimulus-atrial-VA intervals were significantly longer with basal entrainment in AVNRT (171 ±â€‰30 vs. 153 ±â€‰22 ms (p = 0.003), 148 ±â€‰21 vs. 131 ±â€‰20 ms (p = 0.002), and 145 ±â€‰17 vs. 136 ±â€‰15 ms (p = 0.005), respectively). Receiver-operating characteristic curves showed higher AUC for the above parameters with basal entrainment compared to apical entrainment. Cutoff values of basal PPI-TCL of >110 ms and cPPI-TCL of >95 ms had better sensitivities (100 % for both vs. 95 and 90 %, respectively, for apical values) and specificities (85 and 92 % vs. 77 and 92 %, respectively) for diagnosis of AVNRT. Basal RV entrainment from the anteroseptal basal RV is a simple maneuver that is superior to apical ventricular entrainment in identifying the mechanism of SVT. 23810311 Retrospective Review of Angiography before Cannulation of Newly Created Vascular Accesses in Hemodialysis Patients. To investigate vascular access status before first cannulation and the clinical implications of angiography performed before cannulation. A retrospective review of 300 consecutive patients who underwent angiography after vascular access surgery and before cannulation between August 2004 and April 2010 was performed. Angiography was performed 4-6 weeks after the surgery but before the first cannulation. Angiography revealed 94 (31.3%) cases of severe stenosis (≥ 50% luminal narrowing) that required percutaneous transluminal angioplasty (PTA) or a second operation. No stenosis was observed in 122 (40.7%) cases, and mild stenosis (< 50% luminal narrowing) was observed in 84 (28%) cases. For the 94 cases with severe stenosis, PTA was performed in 66, and a second operation was performed in 16. In the other cases (n = 12), HD was maintained by a permanent catheter, or the patients were transferred to another institution. PTA was an immediate success in all patients who underwent the procedure except two. Of 84 patients with mild stenosis, 70 were followed for 1 year; vascular access dysfunction occurred in 15, and 11 of these underwent successful PTA. Of the 122 patients with normal angiographic findings, 102 were followed for 1 year, and vascular access dysfunction did not occur in any of these patients. Early postoperative angiography before the first hemodialysis is helpful for the early detection and treatment of vascular access dysfunction. 23969140 Double Circular Stapler Technique for Bowel Resection in Rectosigmoid Endometriosis. When surgery is indicated for bowel endometriosis (BE) there is no consensus on the most appropriate technique for resection of the disease. Rectosigmoidectomy (RS) has disadvantages in the short and medium-to-long term, with regard to bladder atony and alterations in bowel function. In order to reduce bladder function impairment, to avoid the serious complications of anastomotic leakage after segmental RS, and to minimize the persistence of endometriotic lesions after discoid resection, we used the Double Circular Stapling (DCS) technique. This technique allows, with less morbidity, excision of BE nodules larger than those that can be removed with the single load technique of the circular stapler. Of the 120 patients operated for BE , 24 (20%) underwent the shaving technique, 40 (33.3%) underwent discoid resection with a single circular stapling technique, and 55 (45.9%) underwent RS. Eleven patients (9.2% of the total) underwent the DCS technique. In the DCS group the size of the rectosigmoid lesion ranged from 2.2 to 4.2 cm. The median operative time for the DCS technique was 100 minutes. This contrasts with a median operative time of 150 minutes for patients who underwent RS (p=0.04). Only one (9%) of 11 patients had urinary retention compared with post-operative urinary retention in 14 (25%) of 55 patients who had undergone RS. Only one of 11 patients (9%), with the 4.2cm nodule, had a positive margin in the specimen obtained with the second stapling. The DCS is a promising technique and may avoid rectosigmoidectomy in selected cases. 23944925 General and specific approaches to media parenting: a systematic review of current measures, associations with screen-viewing, and measurement implications. Abstract Background: Parent-focused interventions may help to reduce youth screen-viewing (SV). This review synthesized current information on the links between parenting styles, parenting practices, and youth SV with a focus on measurement. Methods: A systematic review of electronic databases was conducted. Results: In all, 29 of 1189 studies met the inclusion criteria. Parenting practices were divided into rule and nonrule-based practices. Seven rules: (1) Limits on total time (n studies=23); (2) limits on time of day (n=7); (3) content restriction (n=11); (4) mealtime rules (n=2); (5) parental supervision (n=3); (6) contingent screentime (n=3); and (7) no-TV policy (n=1) were reported. Two nonrule-based practices were reported: Co-viewing (n=6) and encouragement to view (n=2). Three studies (10.3%) provided information on parenting styles. Only 12 studies (41.4%) provided information on the reliability/validity of the outcome measure, 15 (51.7%) studies provided information on the reliability/validity of the parenting measure, and 6 (20.7%) provided information on the reliability/validity of both outcome and exposure measures. Conclusions: There is mixed evidence that parenting styles and media-related parenting practices are associated with youth SV. The assessment of parental influence of youth media use is hampered by the diversity of measures that have been used. There is a need for new measures that assess a range of media parenting practices that are relevant to multiple forms of SV. 23949743 Bladder cancer cell in co-culture induces human stem cell differentiation to urothelial cells through paracrine FGF10 signaling. Fibroblast growth factor 10 (FGF10) is required for embryonic epidermal morphogenesis including brain development, lung morphogenesis, and initiation of limb bud formation. In this study, we investigated the role of FGF10 as a lead induction factor for stem cell differentiation toward urothelial cell. To this end, human multipotent stem cell in vitro system was employed. Human amniotic fluid stem cells were co-cultured with immortalized bladder cancer lines to induce directed differentiation into urothelial cells. Urothelial markers, uroplakin II, III, and cytokeratin 8, were monitored by RT-PCR, immunocytochemistry, and Western blot analysis. Co-cultured stem cells began to express uroplakin II, III, and cytokeratin 8. Targeted FGF10 gene knockdown from bladder cancer cells abolished the directed differentiation. In addition, when FGF10 downstream signaling was blocked with the Mek inhibitor, the co-culture system lost the capacity to induce urothelial differentiation. Exogenous addition of recombinant FGF10 protein promoted stem cell differentiation into urothelium cell lineage. Together, this report suggests that paracrine FGF10 signaling stimulates the differentiation of human stem cell into urothelial cells. Current study provides insight into the potential role of FGF10 as a lead growth factor for bladder regeneration and its therapeutic application for bladder transplantation. 23896499 Unanswered questions in thrombolytic therapy for acute ischemic stroke. This article reviews some of the current literature in support or against extension of the intravenous tissue plasminogen activator window, use of intra-arterial therapy or devices, as well alternative pharmacologic therapies that may extend the window for treatment of patients with acute ischemic stroke, with consideration of the relative risk of thrombolytic complications, factors for worse outcomes, and unclear stroke onset, as seen in patients with wake-up stroke. The issue of newer concomitant antithrombotic therapies as they affect the decision for acute ischemic stroke thrombolytic therapy is also explored. 23922417 Central expression of abnormal and unexplained skin sensations. A sub-group of patients present to dermatological services with unexplained skin sensations that characteristically evoked a subjective sense of infestation. The consequent psychological and behavioural impacts of these experiences are considerable and difficult to manage therapeutically. Underlying neurobiological mechanisms are unclear. We therefore undertook the first functional MRI study to test the hypothesis that such patients will differ from controls in central neural processing of affective and infestation-related stimuli. Participants: Five patients presenting with medically unexplained skin sensations were recruited from the specialist psychodermatology service at The Royal London Hospital, mean age 52.8 years, 4 female, 1 male. Five healthy controls were matched for age and gender. Image acquisition: Whole brain MRI data was acquired on a 1.5 T scanner. Task: In a randomized event- related design participants were shown 6 classes of images - insects on skin; insects on leaf; other objects on skin; other objects on leaf; neutral images; disgusting and fearful images. Analysis: Functional images were analyzed using SPM8. A full factorial model was used to analyze the results with two factors - group and stimulus type. Across all conditions patients showed greater activity in the right parahippocampus. Insect versus non insect images evoked greater activation within occipital regions. The main effect of presentation of skin rather than leaf stimuli was to activate inferior parietal lobule and the patients showed enhanced activity within this area. Formal testing of differential responses of patients v. controls to images of insects on skin (three way interaction) revealed differences in the engagement of dorsal anterior cingulate and right lateral prefrontal cortices. Patients also showed greater activity in bilateral temporal lobes when viewing disgusting/fearful images compared to neutral images. We confirm that regional neural activity differs between patients with abnormal skin sensations and controls to condition-relevant and affective visual stimuli. These data provide insight into central mechanisms that potentially represent novel treatment targets. 23786572 Phospholipidomics of human blood microparticles. The phospholipidome of blood microparticles (MPs) obtained from platelet-rich plasma of healthy individuals was characterized by hydrophilic interaction liquid chromatography (HILIC) coupled to electrospray ionization tandem mass spectrometry (ESI-MS/MS). The HILIC separation, performed on a silica stationary phase using an acetonitrile/methanol gradient, enabled the separation of several phospholipids (PL) classes, viz., phosphatidyl-cholines (PCs), -ethanolamines (PEs), -serines (PSs), -inositoles (PIs), sphyngomielins (SMs), and lyso forms of PCs and PEs. Structural characterization of species belonging to each class was performed by MS/MS measurements, in either positive or negative ion mode. The set of 131 phospholipids (including regioisomers) here identified represents the most comprehensive phospholipidomic characterization reported for human MPs. Although the phospholipidome composition of MPs and platelets, collected from the same donors, was found to be qualitatively the same, quantitative differences were evidenced for lyso-PCs, which appear to be significantly more abundant in MPs. 23877790 HIV Prevalence and Related Risk Behaviors in Men Who Have Sex with Men, Yemen 2011. Men who have sex with men (MSM) are at growing risk of HIV infection in many parts of the world; however, the epidemic has not been well explored among this population in most Arab countries. To estimate the prevalence of HIV and related risk behaviors among MSM in Yemen, we recruited 261 adult MSM from the port cities of Aden and Al-Hudaydah through venue- and facility-based sampling. Behavioral data were collected with a face-to-face questionnaire, and HIV status was determined by serological testing. HIV prevalence was 5.9 % (95 % CI 4.8-7.3). One-fourth (25.8 %, 95 % CI 20.7-31.5) had tested for HIV in the last year and received results; 27.8 % (95 % CI 22.5-33.7) had comprehensive knowledge about HIV; 20.0 % (95 % CI 15.8-25.0) reported condom use at last anal sex; and 31.4 % (95 % CI 25.9-37.3) reported that they or their sexual partner had a sexually transmitted disease symptom. Injecting drugs in the last year was reported by 0.8 % (95 % CI 0.1-9.2). Multiple risk behaviors, low HIV knowledge, few preventive behaviors, and HIV prevalence greater than 5 % denote a concentrated and potentially expanding HIV epidemic among MSM in Yemen. No time should be lost in intervening to prevent further expansion of the epidemic to levels already seen among MSM outside the Middle East. 23874327 Do antibiotic residues in soils play a role in amplification and transmission of antibiotic resistant bacteria in cattle populations? When we consider factors that contribute to the emergence, amplification, and persistence of antibiotic resistant bacteria, the conventional assumption is that antibiotic use is the primary driver in these processes and that selection occurs primarily in the patient or animal. Evidence suggests that this may not always be the case. Experimental trials show that parenteral administration of a third-generation cephalosporin (ceftiofur) in cattle has limited or short-term effects on the prevalence of ceftiofur-resistant bacteria in the gastrointestinal tract. While this response may be sufficient to explain a pattern of widespread resistance to cephalosporins, approximately two-thirds of ceftiofur metabolites are excreted in the urine raising the possibility that environmental selection plays an important additive role in the amplification and maintenance of antibiotic resistant E. coli on farms. Consequently, we present a rationale for an environmental selection hypothesis whereby excreted antibiotic residues such as ceftiofur are a significant contributor to the proliferation of antibiotic resistant bacteria in food animal systems. We also present a mathematical model of our hypothesized system as a guide for designing experiments to test this hypothesis. If supported for antibiotics such as ceftiofur, then there may be new approaches to combat the proliferation of antibiotic resistance beyond the prudent use mantra. 23968206 Psychometric Evaluation of a Cross-Culturally Adapted Felt Stigma Questionnaire Among People Living with HIV in Kenya. Abstract Psychometric properties of an 18-item HIV felt stigma questionnaire were evaluated utilizing data collected from a diverse ethnic and socioeconomic group of 370 people living with HIV/AIDS and receiving HIV/AIDS-related health services at an HIV clinic in Kenya. Factor analyses revealed a four factor solution (public attitudes, ostracize, discrimination, personal life disrupted) based on the Scree plot with explained variance of 44% that had Eigen values greater than 1.00. The retained felt stigma items revealed a Cronbach's alpha coefficient of 0.828, while the four factors had coefficient alphas ranging from 0.675 to 0.799. The adapted retained questionnaire was deemed a practical guide for measuring felt stigma in a Kenyan cultural context to necessitate provision of the most effective HIV-related mental health services to individuals living with HIV in Kenya. 23837792 Continuum model of tendon pathology - where are we now? Chronic tendon pathology is a common and often disabling condition, the causes of which remain poorly understood. The continuum model of tendon pathology was proposed to provide a model for the staging of tendon pathology and to assist clinicians in managing this often complex condition (Br. J. Sports Med., 43, 2009, 409). The model presents clinical, histological and imaging evidence for the progression of tendon pathology as a three-stage continuum: reactive tendinopathy, tendon disrepair and degenerative tendinopathy. It also provides clinical information to assist in identifying the stage of pathology, in addition to proposed treatment approaches for each stage. The usefulness of such a model is determined by its ability to incorporate and inform new and emerging research. This review examines the degree to which recent research supports or refutes the continuum model and proposes future directions for clinical and research application of the model. 23666037 Implications of dietary therapy into the 21st century: conclusion to special issue. The concept of dietary therapy for epilepsy has played an important role in the approach to the treatment of seizures for centuries-particularly with the development and utilization of the classic ketogenic diet over the past 90 years. Recently, there has been developing interest in the utilization of diet in other medical disorders, including autism spectrum disorders, traumatic brain injury, degenerative neurologic disorders, and cancer. As the utilization of dietary therapy expands, there are several issues that need to be addressed and better characterized to better understand the role of diet in the treatment of epilepsy and other disease. 23939389 Environmental drivers of west nile Fever epidemiology in europe and Western Asia-a review. Abiotic and biotic conditions are both important determinants of West Nile Fever (WNF) epidemiology. Ambient temperature plays an important role in the growth rates of vector populations, the interval between blood meals, viral replication rates and transmission of West Nile Virus (WNV). The contribution of precipitation is more complex and less well understood. In this paper we discuss impacts of climatic parameters (temperature, relative humidity, precipitation) and other environmental drivers (such as bird migration, land use) on WNV transmission in Europe. WNV recently became established in southeastern Europe, with a large outbreak in the summer of 2010 and recurrent outbreaks in 2011 and 2012. Abundant competent mosquito vectors, bridge vectors, infected (viremic) migrating and local (amplifying) birds are all important characteristics of WNV transmission. In addition, certain key climatic factors, such as increased ambient temperatures, and by extension climate change, may also favor WNF transmission, and they should be taken into account when evaluating the risk of disease spread in the coming years. Monitoring epidemic precursors of WNF, such as significant temperature deviations in high risk areas, could be used to trigger vector control programs and public education campaigns. 23874855 Mitochondrial Function in Human Neuroblastoma Cells Is Up-Regulated and Protected by NQO1, a Plasma Membrane Redox Enzyme. Recent findings suggest that NADH-dependent enzymes of the plasma membrane redox system (PMRS) play roles in the maintenance of cell bioenergetics and oxidative state. Neurons and tumor cells exhibit differential vulnerability to oxidative and metabolic stress, with important implications for the development of therapeutic interventions that promote either cell survival (neurons) or death (cancer cells). Here we used human neuroblastoma cells with low or high levels of the PMRS enzyme NADH-quinone oxidoreductase 1 (NQO1) to investigate how the PMRS modulates mitochondrial functions and cell survival. Cells with elevated NQO1 levels exhibited higher levels of oxygen consumption and ATP production, and lower production of reactive oxygen species. Cells overexpressing NQO1 were more resistant to being damaged by the mitochondrial toxins rotenone and antimycin A, and exhibited less oxidative/nitrative damage and less apoptotic cell death. Cells with basal levels of NQO1 resulted in increased oxidative damage to proteins and cellular vulnerability to mitochondrial toxins. Thus, mitochondrial functions are enhanced and oxidative stress is reduced as a result of elevated PMRS activity, enabling cells to maintain redox homeostasis under conditions of metabolic and energetic stress. These findings suggest that NQO1 is a potential target for the development of therapeutic agents for either preventing neuronal degeneration or promoting the death of neural tumor cells. 23585638 Nano-liquid chromatography in pharmaceutical and biomedical research. Miniaturized separation techniques have emerged as environmentally friendly alternatives to available separation methods. Nano-liquid chromatography (nano-LC), microchip devices and nano-capillary electrophoresis are miniaturized methods that minimize reagent consumption and waste generation. Furthermore, the low levels of analytes, especially in biological samples, promote the search for more highly sensitive techniques; coupled to mass spectrometry, nano-LC has great potential to become an indispensable tool for routine analysis of biomolecules. This short review presents the fundamental aspects of nano-LC analytical instrumentation, discussing practical considerations and the primary differences between miniaturized and conventional instrumentation. Some theoretical aspects are discussed to better explain both the potential and the principal limitations of nano-LC. Recent pharmaceutical and biomedical applications of this separation technique are also presented to indicate the satisfactory performance for complex matrices, especially for proteomic analysis, that is obtained with nano-LC. 23891547 Analyzing conformational dynamics of single P-glycoprotein transporters by Förster resonance energy transfer using hidden Markov models. Single-molecule Förster resonance energy (smFRET) transfer has become a powerful tool for observing conformational dynamics of biological macromolecules. Analyzing smFRET time trajectories allows to identify the state transitions occuring on reaction pathways of molecular machines. Previously, we have developed a smFRET approach to monitor movements of the two nucleotide binding domains (NBDs) of P-glycoprotein (Pgp) during ATP hydrolysis driven drug transport in solution. One limitation of this initial work was that single-molecule photon bursts were analyzed by visual inspection with manual assignment of individual FRET levels. Here a fully automated analysis of Pgp smFRET data using hidden Markov models (HMM) for transitions up to 9 conformational states is applied. We propose new estimators for HMMs to integrate the information of fluctuating intensities in confocal smFRET measurements of freely diffusing lipid bilayer bound membrane proteins in solution. HMM analysis strongly supports that under conditions of steady state turnover, conformational states with short NBD distances and short dwell times are more populated compared to conditions without nucleotide or transport substrate present. 23581456 A new isobenzofuranone from the mangrove endophytic fungus Penicillium sp. (ZH58). A new isobenzofuranone, 4-(methoxymethyl)-7-methoxy-6-methyl-1(3H)-isobenzofuranone (1), together with seven known compounds, dilation (2), lumichrome (3), curvulari (4), 5,5'-oxy-dimethylene-bis(2-furaldehyde) (5), chromone (6), harman(1-methyl-β-carboline) (7), N9-methyl-1methyl-β-carboline (8), was isolated from the mangrove endophytic fungus, Penicillium sp. ZH58 obtained from the South China Sea coast. Their structures were determined by analysis of spectroscopic data. Compound 1 exhibited cytotoxicity against KB and KBV200 cells with IC50 values of 6 and 10 μg/mL, respectively. 23323846 Dissecting single-molecule signal transduction in carbon nanotube circuits with protein engineering. Single-molecule experimental methods have provided new insights into biomolecular function, dynamic disorder, and transient states that are all invisible to conventional measurements. A novel, nonfluorescent single-molecule technique involves attaching single molecules to single-walled carbon nanotube field-effective transistors (SWNT FETs). These ultrasensitive electronic devices provide long-duration, label-free monitoring of biomolecules and their dynamic motions. However, generalization of the SWNT FET technique first requires design rules that can predict the success and applicability of these devices. Here, we report on the transduction mechanism linking enzymatic processivity to electrical signal generation by a SWNT FET. The interaction between SWNT FETs and the enzyme lysozyme was systematically dissected using eight different lysozyme variants synthesized by protein engineering. The data prove that effective signal generation can be accomplished using a single charged amino acid, when appropriately located, providing a foundation to widely apply SWNT FET sensitivity to other biomolecular systems. 23688582 A hypervariable STR polymorphism in the CFI gene: Southern origin of East Asian-specific group H alleles. Previous studies of four populations revealed that a hypervariable short tandem repeat (iSTR) in intron 7 of the human complement factor I (CFI) gene on chromosome 4q was unique, with 17 possible East Asian-specific group H alleles observed at relatively high frequencies. To develop a deeper anthropological and forensic understanding of iSTR, 1161 additional individuals from 11 Asian populations were investigated. Group H alleles of iSTR and c.1217A allele of a SNP in exon 11 of the CFI gene were associated with each other and were almost entirely confined to East Asian populations. Han Chinese in Changsha, southern China, showed the highest frequency for East Asian-specific group H alleles (0.201) among 15 populations. Group H alleles were observed to decrease gradually from south to north in 11 East Asian populations. This expansion of group H alleles provides evidence that southern China and Southeast Asia are a hotspot of Asian diversity and a genetic reservoir of Asians after they entered East Asia. The expected heterozygosity values of iSTR ranged from 0.927 in Thais to 0.874 in Oroqens, higher than those of an STR in the fibrinogen alpha chain (FGA) gene on chromosome 4q. Thus, iSTR is a useful marker for anthropological and forensic genetics. 23891899 Bioenergetic deficits in peripheral nerve sensory axons during chemotherapy-induced neuropathic pain resulting from peroxynitrite-mediated post-translational nitration of mitochondrial superoxide dismutase. Many of the widely used anticancer drugs induce dose-limiting peripheral neuropathies that undermine their therapeutic efficacy. Animal models of chemotherapy-induced painful peripheral neuropathy (CIPN) evoked by a variety of drug classes, including taxanes, vinca alkaloids, platinum-complexes, and proteasome-inhibitors, suggest that the common underlying mechanism in the development of these neuropathies is mitotoxicity in primary nerve sensory axons (PNSAs) arising from reduced mitochondrial bioenergetics [eg adenosine triphosphate (ATP) production deficits due to compromised respiratory complex I and II activity]. The causative mechanisms of this mitotoxicity remain poorly defined. However, peroxynitrite, an important pro-nociceptive agent, has been linked to mitotoxicity in several disease states and may also drive the mitotoxicity associated with CIPN. Our findings reveal that the development of mechano-hypersensitivity induced by paclitaxel, oxaliplatin, and bortezomib was prevented by administration of the peroxynitrite decomposition catalyst Mn(III) 5,10,15,20-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin (MnTE-2-PyP(5+)) without interfering with their anti-tumor effects. Peak CIPN was associated with the nitration and inactivation of superoxide dismutase in the mitochondria, but not in the cytosol, as well as a significant decrease in ATP production within the PNSAs; all of these events were attenuated by MnTE-2-PyP(5+). Our results provide continued support for the role of mitotoxicity in the development of CIPN across chemotherapeutic drug classes, and identify peroxynitrite as a key mediator in these processes, thereby providing the rationale towards development of "peroxynitrite-targeted" therapeutics for CIPN. 23578331 A computational study of the hemodynamic impact of open- versus closed-cell stent design in carotid artery stenting. The aim of this study is to analyze the shape and flow changes of a patient-specific carotid artery after carotid artery stenting (CAS) performed using an open-cell (stent-O) or a closed-cell (stent-C) stent design. First, a stent reconstructed from micro-computed tomography (microCT) is virtually implanted in a left carotid artery reconstructed from CT angiography. Second, an objective analysis of the stent-to-vessel apposition is used to quantify the lumen cross-sectional area and the incomplete stent apposition (ISA). Third, the carotid artery lumen is virtually perfused in order to quantify its resistance to flow and its exposure to atherogenic or thrombogenic hemodynamic conditions. After CAS, the minimum cross-sectional area of the internal carotid artery (ICA) (external carotid artery [ECA]) changes by +54% (-12%) with stent-O and +78% (-17%) with stent-C; the resistance to flow of the ICA (ECA) changes by -21% (+13%) with stent-O and -26% (+18%) with stent-C. Both stent designs suffer from ISA but the malapposed stent area is larger with stent-O than stent-C (29.5 vs. 14.8 mm(2) ). The untreated vessel is not exposed to atherogenic flow conditions whereas an area of 67.6 mm(2) (104.9) occurs with stent-O (stent-C). The area of the stent surface exposed to thrombogenic risk is 5.42 mm(2) (7.7) with stent-O (stent-C). The computer simulations of stenting in a patient's carotid artery reveal a trade-off between cross-sectional size and flow resistance of the ICA (enlarged and circularized) and the ECA (narrowed and ovalized). Such a trade-off, together with malapposition, atherogenic risk, and thrombogenic risk is stent-design dependent. 23847383 Selumetinib shows promise in metastatic uveal melanoma. Compared with temozolomide chemotherapy, the MEK inhibitor selumetinib extended progression-free survival by nearly 9 weeks in patients with melanoma of the eye participating in a phase II trial, making it the first effective drug for the rare disease. 23238968 Prostate cancer: Utility of diffusion-weighted imaging as a marker of side-specific risk of extracapsular extension. To assess the utility of diffusion-weighted imaging (DWI) findings as an indirect marker of side-specific risk of extracapsular extension (ECE) of prostate cancer. Fifty-one patients underwent 3T magnetic resonance imaging (MRI) before prostatectomy. Radiologists 1 and 2 (4 and 1 years experience) assessed each side for ECE using T2-weighted imaging (T2WI) and evaluated apparent diffusion coefficient (ADC) maps for the presence of apparent tumor in each lobe and to measure peripheral zone ADC. A uropathologist measured the extent of any ECE. In all, 28/102 lobes had ECE, of which 12 measured ≤1 mm, 11 measured >1 mm and ≤2 mm, and five measured >2 mm. Side-specific accuracies for detection of ECE for readers 1 and 2 were respectively: T2WI 68.6% and 74.5%; presence of apparent tumor on ADC map 66.7% and 60.8%; ADC value 75.5% and 69.6%. For ECE >2 mm, both readers achieved 100% sensitivity based on apparent tumor on ADC map or ADC values and 80% sensitivity using T2WI. For detection of ECE ≤2 mm, sensitivity for all combinations of the three methods and two readers ranged from 58.3%-81.8%, aside from assessment for ECE using T2WI by the less experienced reader, which exhibited sensitivity of 17.4%. Interreader agreement for the presence of ECE was 0.18 using T2WI, 0.37 using apparent tumor on ADC map, and 0.60 using ADC values. Compared with T2WI, DWI had comparable accuracy for side-specific assessment of ECE, greater sensitivity for ECE <2 mm for the less-experienced radiologist, and greater interreader agreement. J. Magn. Reson. Imaging 2013;38:312-319. © 2012 Wiley Periodicals, Inc. 23834894 Exaggerated anorexigenic response to restraint stress in A(y) mice is associated with elevated CRFR2 mRNA expression in the hypothalamus. The "lethal yellow" mutation at the mouse agouti locus (A(y)) results in hyperphagia, obesity, and type 2 diabetes at rest, but helps to reduce food intake under stress. The aim of this work was to investigate mechanisms of exaggerated anorectic response to stress in A(y) mice. All parameters were measured in C57BL/6J male mice of a/a (control) and A(y)/a genotypes before, 0, 1, and 3h after a 1-h restraint. Baseline food intake and plasma insulin concentrations were higher in A(y)/a mice compared to a/a mice. Restraint reduced food intake and plasma insulin concentrations only in A(y)/a mice. Stress-induced anorexia in A(y)/a mice was independent of pathways involving hypothalamic-pituitary-adrenal axis activity and hypothalamic orexigenic neuropeptide (agouti-related peptide and neuropeptide Y) gene expressions and corticotrophin-releasing factor type 1 receptor (CRFR1). Gene expression of CRFR2 was elevated in A(y)/a mice with genotype differences particularly manifested immediately after the restraint. Hypothalamic CRFR2 is known to mediate anorectic signals from CRF-related peptides. Thus, our data suggest that stress-induced anorexia in A(y)/a mice may be associated with increased anorectic signals mediated by CRFR2 in the hypothalamus. 23591608 Autoimmunity in immunodeficiency. Primary immunodeficiencies (PID) comprise a diverse group of clinical disorders with varied genetic defects. Paradoxically, a substantial proportion of PID patients develop autoimmune phenomena in addition to having increased susceptibility to infections from their impaired immunity. Although much of our understanding comes from data gathered through experimental models, there are several well-characterized PID that have improved our knowledge of the pathways that drive autoimmunity. The goals of this review will be to discuss these immunodeficiencies and to review the literature with respect to the proposed mechanisms for autoimmunity within each put forth to date. 23918809 Evolution along the mutation gradient in the dynamic mitochondrial genome of salamanders. Mitochondria are intracellular organelles where oxidative phosphorylation (OXPHOS) is carried out to complete ATP synthesis. Mitochondria have their own genome; in metazoans, this is a small, circular molecule encoding 13 electron transport proteins, 22 tRNAs, and two rRNAs. In invertebrates, mitochondrial gene rearrangement is common, and it is correlated with increased substitution rates. In vertebrates, mitochondrial gene rearrangement is rare, and its relationship to substitution rate remains unexplored. Mitochondrial genes can also show spatial variation in substitution rates around the genome due to the mechanism of mtDNA replication, which produces a mutation gradient. To date, however, (1) the strength of the mutation gradient, and (2) whether movement along the gradient in rearranged (or otherwise modified) genomes impacts genic substitution rates remain unexplored in the majority of vertebrates. Salamanders include both "normal" mitochondrial genomes and independently derived rearrangements and expansions, providing a rare opportunity to test the effects of large-scale changes to genome architecture on vertebrate mitochondrial gene sequence evolution. We show that (1) rearranged/expanded genomes have higher substitution rates. (2) Most genes in rearranged/expanded genomes maintain their position along the mutation gradient. Substitution rates of the genes that do move are unaffected by their new position; the gradient in salamanders is weak. (3) Genomic rearrangements/expansions occur independent of levels of selective constraint on genes. Together, our results demonstrate that large-scale changes to genome architecture impact mitochondrial gene evolution in predictable ways; however, despite these impacts, the same functional constraints act on mitochondrial protein-coding genes in both modified and normal genomes. 23625812 Transcranial doppler velocity and brain MRI/MRA changes in children with sickle cell anemia on chronic transfusions to prevent primary stroke. Chronic transfusions help prevent primary stroke in children with sickle cell anemia (SCA) and abnormal transcranial Doppler (TCD) velocities. However, the effects of transfusions on TCD velocities and brain MRI/MRA findings are incompletely described. We reviewed TCD and brain MRI/MRA results in 27 children with SCA and abnormal TCD velocities receiving transfusions to prevent primary stroke. All TCDs were performed by a single examiner, immediately prior to a scheduled transfusion. We also examined the effects of laboratory and clinical parameters on TCD responses to transfusion therapy. For the whole cohort, the average pre-transfusion HbS on transfusions was 31.7 ± 12.3%. The most significant decline in TCD velocities occurred within 10 months of starting transfusions. Follow-up TCD values trended upward with increasing pre-transfusion %HbS levels while on treatment. Half of the children had persistent conditional/abnormal TCD velocities despite transfusions and 28% had new/progressive stenosis on MRA, but none had primary stroke during 73 patient-years of follow-up. For children with SCA and abnormal TCD velocities, transfusions lower TCD velocities and help prevent stroke, but do not always result in normal velocities or protect against progression of cerebral vasculopathy. Improved adherence to transfusion goals may improve on-treatment TCD velocities. Pediatr Blood Cancer 2013;60:1499-1502. © 2013 Wiley Periodicals, Inc. 23103954 Bioassay-guided isolation of urease and α-chymotrypsin inhibitory constituents from the stems of Lawsonia alba Lam. (Henna). Seven constituents were isolated from the stems of Lawsonia alba Lam., following an activity-guided isolation, which include two new constituents, namely lawsorosemarinol (1) and lawsofructose (2), one known compound 2-(β-d-glucopyranosyloxy)-1, 4-naphthoquinone (3) and four compounds, 4-hydroxy coumarine (4), 3-(4-hyroxyphenyl)-triacontyl-(Z)-propenoate (5), 3-(4-hydroxy-3-methoxyphenyl)-triacontyl-(Z)-propenoate (6) and 7-hydroxy-4-methyl coumarin (7) first time isolated from Lawsonia alba. Their structure elucidation was based on spectroscopic data analyses. Compounds 3 and 7 showed a moderate inhibition of urease activity, while rest of them showed less than 50% inhibition. These compounds did not show any significant inhibition against α-chymotrypsin. 23757309 Intracoronary delivery of autologous cardiac stem cells improves cardiac function in a porcine model of chronic ischemic cardiomyopathy. Relevant preclinical models are necessary for further mechanistic and translational studies of c-kit+ cardiac stem cells (CSCs). The present study was undertaken to determine whether intracoronary CSCs are beneficial in a porcine model of chronic ischemic cardiomyopathy. Pigs underwent a 90-minute coronary occlusion followed by reperfusion. Three months later, autologous CSCs (n=11) or vehicle (n=10) were infused into the infarct-related artery. At this time, all indices of left ventricular (LV) function were similar in control and CSC-treated pigs, indicating that the damage inflicted by the infarct in the 2 groups was similar; 1 month later, however, CSC-treated pigs exhibited significantly greater LV ejection fraction (echocardiography) (51.7±2.0% versus 42.9±2.3%, P<0.01), systolic thickening fraction in the infarcted LV wall, and maximum LV dP/dt, as well as lower LV end-diastolic pressure. Confocal microscopy showed clusters of small α-sarcomeric actin-positive cells expressing Ki67 in the scar of treated pigs, consistent with cardiac regeneration. The origin of these cycling myocytes from the injected cells was confirmed in 4 pigs that received enhanced green fluorescent protein -labeled CSCs, which were positive for the cardiac markers troponin I, troponin T, myosin heavy chain, and connexin-43. Some engrafted CSCs also formed vascular structures and expressed α-smooth muscle actin. Intracoronary infusion of autologous CSCs improves regional and global LV function and promotes cardiac and vascular regeneration in pigs with old myocardial infarction (scar). The results mimic those recently reported in humans (Stem Cell Infusion in Patients with Ischemic CardiOmyopathy [SCIPIO] trial) and establish this porcine model of ischemic cardiomyopathy as a useful and clinically relevant model for studying CSCs. 23859772 Molecular Tension Sensors Report Forces Generated by Single Integrin Molecules in Living Cells. Living cells are exquisitely responsive to mechanical cues, yet how cells produce and detect mechanical force remains poorly understood due to a lack of methods that visualize cell-generated forces at the molecular scale. Here we describe Förster resonance energy transfer (FRET)-based molecular tension sensors that allow us to directly visualize cell-generated forces with single-molecule sensitivity. We apply these sensors to determine the distribution of forces generated by individual integrins, a class of cell adhesion molecules with prominent roles throughout cell and developmental biology. We observe strikingly complex distributions of tensions within individual focal adhesions. FRET values measured for single probe molecules suggest that relatively modest tensions at the molecular level are sufficient to drive robust cellular adhesion. 23181765 On improving the communication between models and data. The potential for model-data synthesis is growing in importance as we enter an era of 'big data', greater connectivity and faster computation. Realizing this potential requires that the research community broaden its perspective about how and why they interact with models. Models can be viewed as scaffolds that allow data at different scales to inform each other through our understanding of underlying processes. Perceptions of relevance, accessibility and informatics are presented as the primary barriers to broader adoption of models by the community, while an inability to fully utilize the breadth of expertise and data from the community is a primary barrier to model improvement. Overall, we promote a community-based paradigm to model-data synthesis and highlight some of the tools and techniques that facilitate this approach. Scientific workflows address critical informatics issues in transparency, repeatability and automation, while intuitive, flexible web-based interfaces make running and visualizing models more accessible. Bayesian statistics provides powerful tools for assimilating a diversity of data types and for the analysis of uncertainty. Uncertainty analyses enable new measurements to target those processes most limiting our predictive ability. Moving forward, tools for information management and data assimilation need to be improved and made more accessible. 23490021 Predictors of clinical and microbiological treatment failure in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia: a retrospective cohort study in a region with low MRSA prevalence. Invasive infections with methicillin-resistant Staphylococcus aureus (MRSA) have been associated with increased morbidity and mortality. The aim of the present study was to identify independent predictors of early mortality and treatment failure in patients with MRSA bacteraemia. A total of 132 adult patients who developed MRSA bacteraemia during hospitalization in the University Hospital of Vienna between 2000 and 2011 were screened and 124 were included in a retrospective cohort study. Patient demographics, source of bacteraemia, antimicrobial treatment and microbiological characteristics were evaluated. The 28-day crude mortality was 30.6%. Predictors of early mortality identified in multivariate Cox regression analysis included higher patient age (adjusted hazard ratio (aHR) 1.03, 95% CI 1.01-1.06, p 0.006), pneumonia (aHR 3.86, 95% CI 1.83-8.12, p <0.001) and failure to use MRSA active treatment (aHR 8.77, 95% CI 3.50-21.93, p <0.001). Ninety-one (73.4%) patients received glycopeptides as specific MRSA treatment. Of 63 patients treated with vancomycin, only 14 (22.6%) patients had aimed trough levels of 15-20 mg/L. Vancomycin MIC ≥2 mg/L was detected in 28.2% and was associated with glycopeptide pretreatment (p 0.001). All MRSA isolates were susceptible to linezolid and tigecycline. Persistent bacteraemia ≥7 days was documented in 25 (20.2%) patients. Independent determinants for microbiological eradication failure in patients with MRSA bacteraemia included endocarditis (p <0.001) and vancomycin trough levels (p 0.014), but not vancomycin MIC. Failure of clinical and microbiological eradication of MRSA among patients with MRSA bacteraemia was associated with clinical entity rather than with bacterial traits. Pharmacokinetic parameters seem to be decisive on microbiological and clinical success. 23903162 Effect of gold nanoparticles on depolarization characteristics of Intralipid tissue phantom. We report results of studies on the effect of different shapes and sizes of gold nanoparticles (GNPs) on the depolarization characteristics of Intralipid tissue phantoms. For a given extinction coefficient, the absorption characteristics of the GNPs contributed more to the depolarization of the turbid medium, and the contribution of scattering was significant only for the larger-sized particles. For rod-shaped GNPs, their depolarization plays an important role in the low scattering regime in which the depolarization properties of the nanoparticles (NPs) dominate in the turbid medium even if the contribution of the scattering from the NPs is about an order of magnitude less. For highly scattering samples, GNP absorption significantly modulates the depolarization spectra of the turbid medium. 23928688 Distance dependence of hole transfer rates from G radical cations to GGG traps in DNA. Relative reaction rates for hole transfer between G radical cations and GGG triplets in DNA, through different bridges of varying lengths, are numerically calculated and the obtained results are compared with corresponding experimental observations [Giese et al., 2001, Nature, 412, 318; Angew. Chem., Int. Ed., 1999, 38, 996]. Hole donors and acceptors are separated either by (T-A)n bridges or by N repeated barriers consisting of (T-A,T-A) double base-pairs which are connected through single G-C base-pairs. In the former case, hole transfer rates show a strong exponential decrease with the length of the bridge for short bridges, while a switching to weak distance dependence has been observed for longer bridges. In the latter case, a power law seems to better describe the distance dependence of charge transfer rates. All these experimental observations are qualitatively reproduced by our simulations without any adjustable parameter, considering only tunneling as the charge transfer mechanism. Physical insights into the mechanism providing the switching behavior in the case of (T-A)n bridges are presented through an analysis of the eigenfunctions of the system. 23926228 Exploring the role of human miRNAs in virus-host interactions using systematic overlap analysis. Human miRNAs have recently been found to have important roles in viral replication. Understanding the patterns and details of human miRNA interactions during virus-host interactions may help uncover novel antiviral therapies. Based on the abundance of knowledge available regarding protein-protein interactions, virus-host protein interactions, experimentally-validated human miRNA-target pairs, and transcriptional regulation of human miRNAs, it is possible to explore the complex regulatory network that exists between viral proteins and human miRNAs at the system level. By integrating current data regarding the virus-human interactome and human miRNA-target pairs, the overlap between targets of viral proteins and human miRNAs were identified, and found to represent topologically important proteins (e.g., hubs or bottlenecks) at the global center of the human protein-protein interaction network. Viral proteins and human miRNAs were also found to significantly target human protein-protein interaction (PPI) pairs. Furthermore, an overlap analysis of virus targets and transcription factors (TFs) of human miRNAs revealed that viral proteins preferentially target human miRNA TFs, representing a new pattern of virus-host interactions. Potential feedback loops formed by viruses, human miRNAs, and miRNA TFs were also identified, and these may be exploited by viruses resulting in greater virulence and more effective replication strategies. boxc@bmi.ac.cn; sqwang@bmi.ac.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. 23870199 Bufalin, a component in Chansu, inhibits proliferation and invasion of hepatocellular carcinoma cells. Hepatocellular carcinoma (HCC) is a common and aggressive cancer, and the treatment options are limited for patients with advanced HCC. Bufalin, the major digoxin-like component of the traditional Chinese medicine Chansu, exhibits significant anti-tumor activities in many tumor cell lines. In the present study, we investigated the effect of bufalin on the inhibition of an AKT-related signaling pathway, and examined the relationship between regulatory proteins and anti-tumor effects in hepatoma cells. Proliferation, wound healing, transwell-migration/invasion and adhesion assays were performed in HCCLM3 and HepG2 cell lines. The protein levels of pAKT, AKT, pGSK3β, GSK3β, pβ-catenin, β-catenin, E-cadherin, MMP-9, and MMP-2 were measured by western blot analysis. E-Cadherin and β-catenin expression levels were also evaluated by immunofluorescence. Bufalin inhibited hepatoma cell proliferation, migration, invasion and adhesion. In addition, treatment with bufalin significantly decreased the levels of pAKT, pGSK3β, MMP-9, and MMP-2, while increasing the levels of GSK3β and E-cadherin and suppressing the nuclear translocation of β-catenin. Bufalin is a potential anti-HCC therapeutic candidate through its inhibition of the AKT/GSK3β/β-catenin/E-cadherin signaling pathway. Further studies with bufalin are warranted in patients with HCC, especially those with the disease at advanced stages. 23835272 Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria. Methylmalonate semialdehyde dehydrogenase (MMSDH) deficiency is a rare autosomal recessive disorder with varied metabolite abnormalities, including accumulation of 3-hydroxyisobutyric, 3-hydroxypropionic, 3-aminoisobutyric and methylmalonic acids, as well as beta-alanine. Existing reports describe a highly variable clinical and biochemical phenotype, which can make diagnosis a challenge. To date, only three reported cases have been confirmed at the molecular level, through identification of homozygous mutations in ALDH6A1, the gene encoding MMSDH. Confirmation by enzyme assay has until now not been possible, due to the extreme instability of the enzyme substrate.Methods and results: We report a child with severe developmental delays, abnormal myelination on brain MRI, and transient/variable elevations in lactate, methylmalonic acid, 3-hydroxyisobutyric and 3-aminoisobutyric acids. Compound heterozygous mutations were identified by exome sequencing and confirmed by Sanger sequencing within exon 6 (c.514 T > C; p. Tyr172His) and exon 12 (c.1603C > T; p. Arg535Cys) of ALDH6A1. The resulting amino acid changes, both occurring in residues conserved among mammals, are predicted to be damaging at the protein level. Subsequent MMSDH enzyme assay demonstrated reduced activity in patient fibroblasts, measuring 2.5 standard deviations below the mean. We present the fourth reported case of MMSDH deficiency with confirmation at the molecular level, and expand on what is already an extremely variable clinical and biochemical phenotype. Furthermore, this is the first report to demonstrate a corresponding reduction in MMSDH enzyme activity. This report illustrates the emerging utilization of whole exome sequencing and variant data filtering using clinical data as an early tool in the diagnosis of rare and variable conditions. 23900834 Leg length discrepancy after total hip arthroplasty: a review of literature. Discrepancy of leg length is often considered to be a problem after total hip replacement and can adversely affect an otherwise excellent outcome. Furthermore, it has been associated with patient dissatisfaction and remains one of the most common reasons for litigation against the orthopedic community. As a consequence of the need to equalize leg length, several authors have sought to validate methods of minimizing limb length discrepancy based on preoperative planning with preoperative radiological templates or intraoperative methods of measurement. In this article, we present a review of the limb length discrepancy in total hip arthroplasty, its implications and several techniques to avoid it. We recommend that a combination of the above mentioned methods will give the best chance for the surgeon to minimise the risk of leg length discrepancy following total hip replacement. 23837723 Enhancing the egg's natural defence against bacterial penetration by increasing cuticle deposition. The cuticle is a proteinaceous layer covering the avian egg and is believed to form a defence to microorganism ingress. In birds that lay eggs in challenging environments, the cuticle is thicker, suggesting evolutionary pressure; however, in poultry, selection pressure for this trait has been removed because of artificial incubation. This study aimed to quantify cuticle deposition and to estimate its genetic parameters and its role on trans-shell penetration of bacteria. Additionally, cuticle proteins were characterised to establish whether alleles for these genes explained variation in deposition. A novel and reliable quantification was achieved using the difference in reflectance of the egg at 650 nm before and after staining with a specific dye. The heritability of this novel measurement was moderate (0.27), and bacteria penetration was dependent on the natural variation in cuticle deposition. Eggs with the best cuticle were never penetrated by bacteria (P < 0.001). The cuticle proteome consisted of six major proteins. A significant association was found between alleles of one of these protein genes, ovocleidin-116 (MEPE), and cuticle deposition (P = 0.015) and also between alleles of estrogen receptor 1 (ESR1) gene and cuticle deposition (P = 0.008). With the heritability observed, genetic selection should be possible to increase cuticle deposition in commercial poultry, so reducing trans-generational transmission of microorganisms and reversing the lack of selection pressure for this trait during recent domestication. 23562960 Does plant uptake or low soil mineral-N production limit mineral-N losses to surface waters and groundwater from soils under grass in summer? Summer minima and autumn/winter maxima in nitrate concentrations in rivers are reputedly due to high plant uptake of nitrate from soils in summer. A novel alternative hypothesis is tested here for soils under grass. By summer, residual readily mineralizable plant litter from the previous autumn/winter is negligible and fresh litter input low. Consequently little mineral-N is produced in the soil. Water-soluble and KCl-extractable mineral N in fresh soils and soils incubated outdoors for 7 days have been monitored over 12 months for soil transects at two permanent grassland sites near York, UK, using 6 replicates throughout. Vegetation-free soil is shown to produce very limited mineral-N in summer, despite the warm, moist conditions. Litter accumulates in autumn/winter and initially its high C:N ratio favours N accumulation in the soil. It is also shown that mineral-N generated monthly in situ in soil substantially exceeds the monthly mineral-N inputs via wet deposition at the sites. 23839984 Analgesia with breastfeeding in addition to skin-to-skin contact during heel prick. To investigate the analgesic effect (measured with Neonatal Infant Pain Scale (NIPS)) of breastfeeding (BF) in addition to skin-to-skin contact (SSC) versus other methods of non-pharmacological analgesia during blood sampling through heel lance in healthy term neonates. Randomised controlled trial. Tertiary level maternity ward. One hundred thirty-six healthy term newborns. Inclusion criteria: healthy term neonates, wish to breastfeed and absence of feeding during the previous 60 min. Neonates were randomly assigned to four groups: Group breastfed with SSC (BF+SSC Group) (n=35); Group sucrose with SSC (Sucrose+SSC Group) (n=35); SSC Group (n=33); or Sucrose Group (n=33). Babies were recorded with a video camera. Three observers watched the videos and measured NIPS score at three time points (t0: 2 min before heel prick; t1: During heel prick; and t2: 2 min after the heel prick). The influences of non-pharmacological methods on crying time, percentage of crying while sampling, heart rate, number of attempts and duration of sampling were also studied. BF+SSC Group achieved a significant lower median NIPS score (value=1) compared with other groups (value=2, 4 and 4, respectively). The percentage of neonates with moderate-to-severe pain was also lower in the BF+SSC Group. Both groups BF+SSC and Sucrose+SSC achieved a significant lower percentage of crying compared with SSC Group. This study suggests that BF in addition to SSC provides superior analgesia to other kinds of non-pharmacological analgesia in healthy term neonates during heel prick. NCT01576432. 23813979 Heterogeneous models place the root of the placental mammal phylogeny. Heterogeneity among life traits in mammals has resulted in considerable phylogenetic conflict, particularly concerning the position of the placental root. Layered upon this are gene- and lineage-specific variation in amino acid substitution rates and compositional biases. Life trait variations that may impact upon mutational rates are longevity, metabolic rate, body size, and germ line generation time. Over the past 12 years, three main conflicting hypotheses have emerged for the placement of the placental root. These hypotheses place the Atlantogenata (common ancestor of Xenarthra plus Afrotheria), the Afrotheria, or the Xenarthra as the sister group to all other placental mammals. Model adequacy is critical for accurate tree reconstruction and by failing to account for these compositional and character exchange heterogeneities across the tree and data set, previous studies have not provided a strongly supported hypothesis for the placental root. For the first time, models that accommodate both tree and data set heterogeneity have been applied to mammal data. Here, we show the impact of accurate model assignment and the importance of data sets in accommodating model parameters while maintaining the power to reject competing hypotheses. Through these sophisticated methods, we demonstrate the importance of model adequacy, data set power and provide strong support for the Atlantogenata over other competing hypotheses for the position of the placental root. 23263902 European public deliberation on brain machine interface technology: five convergence seminars. We present a novel procedure to engage the public in ethical deliberations on the potential impacts of brain machine interface technology. We call this procedure a convergence seminar, a form of scenario-based group discussion that is founded on the idea of hypothetical retrospection. The theoretical background of this procedure and the results of five seminars are presented. 22936016 Drug delivery patterns for different stenting techniques in coronary bifurcations: a comparative computational study. The treatment of coronary bifurcation lesions represents a challenge for the interventional cardiologists due to the lower rate of procedural success and the higher risk of restenosis. The advent of drug-eluting stents (DES) has dramatically reduced restenosis and consequently the request for re-intervention. The aim of the present work is to provide further insight about the effectiveness of DES by means of a computational study that combines virtual stent implantation, fluid dynamics and drug release for different stenting protocols currently used in the treatment of a coronary artery bifurcation. An explicit dynamic finite element model is developed in order to obtain realistic configurations of the implanted devices used to perform fluid dynamics analysis by means of a previously developed finite element method coupling the blood flow and the intramural plasma filtration in rigid arteries. To efficiently model the drug release, a multiscale strategy is adopted, ranging from lumped parameter model accounting for drug release to fully 3-D models for drug transport to the artery. Differences in drug delivery to the artery are evaluated with respect to local drug dosage. This model allowed to compare alternative stenting configurations (namely the Provisional Side Branch, the Culotte and the Inverted Culotte techniques), thus suggesting guidelines in the treatment of coronary bifurcation lesions and addressing clinical issues such as the effectiveness of drug delivery to lesions in the side branch, as well as the influence of incomplete strut apposition and overlapping stents. 23963329 Elevated Aerobic Fitness Sustained Throughout the Adult Lifespan Is Associated With Improved Cerebral Hemodynamics. Age-related impairments in cerebral blood flow and cerebrovascular reactivity to carbon dioxide (CVRCO2) are established risk factors for stroke that respond favorably to aerobic training. The present study examined to what extent cerebral hemodynamics are improved when training is sustained throughout the adult lifespan. Eighty-one healthy males were prospectively assigned to 1 of 4 groups based on their age (young, ≤ 30 years versus old, ≥ 60 years) and lifetime physical activity levels (trained, ≥ 150 minutes recreational aerobic activity/week versus sedentary, no activity). Middle cerebral artery blood velocity (MCAv, transcranial Doppler ultrasound), mean arterial pressure (MAP, finger photoplethysmography), and end-tidal partial pressure of carbon dioxide (PETCO2, capnography) were recorded during normocapnia and 3 mins of iso-oxic hypercapnea (5% CO2). Cerebrovascular resistance/conductance indices (CVRi/CVCi) were calculated as MAP/MCAv and MCAv/MAP, respectively, and CVRCO2 as the percentage increase in MCAv from baseline per millimeter of mercury (mm Hg) increase in PETCO2. Maximal oxygen consumption (VO2MAX, online respiratory gas analysis) was determined during cycling ergometry. By design, older participants were active for longer (49±5 versus 6±4 years, P<0.05). Physical activity attenuated the age-related declines in VO2MAX, MCAv, CVCi, and CVRCO2 and increase in CVRi (P<0.05 versus sedentary). Linear relationships were observed between VO2MAX and both MCAv and CVRCO2 (r = 0.58-0.77, P<0.05). These findings highlight the importance of maintaining aerobic fitness throughout the lifespan given its capacity to improve cerebral hemodynamics in later-life. 23516047 Sublethal silver and NaCl toxicity in Daphnia magna: a comparative study of standardized chronic endpoints and progeny phototaxis. Behavioral bioassays with the model freshwater cladoceran Daphnia magna have the potential to serve as nontraditional but sensitive endpoints of sublethal stress. However, few studies have examined the comparative sensitivity of neonate phototaxis perturbations to standardized endpoints commonly employed in chronic toxicity testing protocols. Even less understood are the consequences of prenatal exposure on neonate phototactic behavior. Here, we tested the hypothesis that D. magna neonate phototaxis is a more sensitive endpoint over a chronic study period than mortality and reproduction. D. magna 21 day studies were conducted with model stressors of sodium chloride and dissolved silver. Phototaxis assays of progeny response to relative light changes in small water columns were conducted for each brood. Significant differences in neonate phototactic behavior were observed among treatment level broods, suggesting that maternal exposure to sublethal levels of NaCl and Ag+ impacted offspring. In fact, progeny phototactic response was significantly affected at or below 21-day LOEC thresholds for fecundity in broods 2, 3, 5 and 6 of the NaCl experiment and in broods 2, 4, 5 and 6 of the dissolved Ag+ study. Because neonate phototaxis was generally more sensitive than standardized fecundity thresholds, we suggest employing neonate phototaxis as an ecologically important endpoint in future ecological risk assessments. 23701314 Genes and mutations causing retinitis pigmentosa. Retinitis pigmentosa (RP) is a heterogeneous set of inherited retinopathies with many disease-causing genes, many known mutations, and highly varied clinical consequences. Progress in finding treatments is dependent on determining the genes and mutations causing these diseases, which includes both gene discovery and mutation screening in affected individuals and families. Despite the complexity, substantial progress has been made in finding RP genes and mutations. Depending on the type of RP, and the technology used, it is possible to detect mutations in 30-80% of cases. One of the most powerful approaches to genetic testing is high-throughput 'deep sequencing', that is, next-generation sequencing (NGS). NGS has identified several novel RP genes but a substantial fraction of previously unsolved cases have mutations in genes that are known causes of retinal disease but not necessarily RP. Apparent discrepancy between the molecular defect and clinical findings may warrant reevaluation of patients and families. In this review, we summarize the current approaches to gene discovery and mutation detection for RP, and indicate pitfalls and unsolved problems. Similar considerations apply to other forms of inherited retinal disease. 23615707 In vitro effect of N-acetylcysteine on hepatocyte injury caused by dichlorodiphenyltrichloroethane and its metabolites. The organochlorine pesticide, dichlorodiphenyltrichloroethane (DDT), is still used to combat the spread of malaria in several developing countries despite its accumulation and known hepatotoxic effects that have been demonstrated both in vitro and in vivo. N-Acetylcysteine (NAC) is a recognized hepatoprotective agent that has been reported to reduce hepatotoxicity initiated by many different compounds. The aim of this study was to determine whether NAC could counter in vitro hepatocyte injury induced by DDT or its two major metabolites, dichlorodiphenyldichloroethylene and dichlorodiphenyldichloroethane. HepG2 cell cultures were used to assess the following parameters of toxicity: cellular viability, intracellular levels of reactive oxygen species (ROS), mitochondrial membrane potential and initiation of apoptosis. None of the three test compounds induced ROS generation, yet exposure to any of the three compounds produced mitochondrial hyperpolarization, which was countered by NAC pretreatment. All three test compounds also induced apoptotic cell death, which was inhibited by NAC. Despite NAC counteracting some adverse intracellular changes due to organochlorine exposure, it appeared to aggravate the cytotoxic effects of the organochlorine compounds at low test concentrations. As the same outcome may also occur in vivo, results from the present study raise concern about the use of NAC as treatment for DDT-induced hepatotoxicity. 23953809 Image-guided brachytherapy for cervical cancer: Analysis of D2 cc hot spot in three-dimensional and anatomic factors affecting D2 cc hot spot in organs at risk. To analyze the D2 cc hot spot in three-dimensional CT and anatomic factors affecting the D2 cc hot spot in organs at risk (OARs). Thirty-one patients underwent pelvic CT scan after insertion of the applicator. High-dose-rate treatment planning was performed with standard loading patterns. The D2 cc structures in OARs were generated in three dimensional if the total equivalent dose in 2 Gy exceeded our defined dose limits (hot spot). The location of D2 cc hot spot was defined as the center of the largest D2 cc fragment. The relationship between the hot spot and the applicator position was reported in Digital Imaging and Communication in Medicine coordinates. The location of sigmoid, small bowel, and bladder D2 cc hot spots was around the endocervix: The mean location of sigmoid hot spot for lateral view was 1.6 cm posteriorly and 2.3 cm superiorly (Y, 1.6 and Z, 2.3), small bowel was 1.6 cm anteriorly and 2.7 cm superiorly (Y, -1.6 and Z, 2.7). The mean location of bladder hot spot was 1.6 cm anteriorly and 1.6 cm superiorly (Y, -1.6 and Z, 1.6). These hot spots were near the plane of Point A (X, 2.0 or -2.0; Y, 0; and Z, 2.0). The mean location of rectal hot spot was 1.6 cm posteriorly and 1.9 cm inferiorly (Y, 1.6 and Z, -1.9). D2 cc hot spot was affected by uterine wall thickness, uterine tandem position, fibroids, bladder fullness, bowel gas, and vaginal packing. Because of the location of the D2 cc hot spots, larger tumors present a challenge for adequate tumor coverage with a conventional brachytherapy applicator without an interstitial implant. Additionally, anatomic factors were identified which affect the D2 cc hot spot in OARs. 23832205 Expression, derivatization, crystallization and experimental phasing of an extracellular segment of the human Robo1 receptor. Robo receptors participate in the orchestration of several developmental responses, most notably axonal guidance in the central nervous system. Robo1 contains five tandem Ig-like and three fibronectin type-III (FnIII) domains in its ectodomain, followed by a single-pass transmembrane segment and an intracellular region. A human Robo1 construct that includes the two extracellular membrane-proximal fibronectin (Fn) domains and the juxtamembrane linker was overexpressed in Escherichia coli and purified. Crystals were obtained using the vapour-diffusion method at 293 K and X-ray diffraction data were collected. Molecular-replacement attempts using related Fn domains as search models did not result in a solution. After introducing two additional methionine residues using PCR site-directed mutagenesis, selenomethionine-derivative crystals were produced. These crystals belonged to the primitive orthorhombic space group P212121, with unit-cell parameters a = 27.24, b = 77.64, c = 91.91 Å. Assuming the presence of a monomer in the asymmetric unit gave a crystal volume per protein weight (VM) of 1.97 Å(3) Da(-1) and a solvent content of 37.6%. Anisotropic diffraction data and a fragmented single-wavelength anomalous dispersion electron-density map, to which homology-modelled domains were docked, were obtained. 23918572 Evaluation of quality of life with the chronic obstructive pulmonary disease assessment test in chronic obstructive pulmonary disease and the effect of dyspnea on disease-specific quality of life in these patients. Purpose: The chronic obstructive pulmonary disease (COPD) assessment test (CAT) was recently introduced for use in assessing disease-specific quality of life and follow-up of patients with COPD. The purpose of this study was to evaluate the effect of the dyspnea on disease-specific quality of life detected by CAT score in patients with COPD. Materials and Methods: In this study, 90 stable patients with COPD as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria were included. The level of dyspnea was assessed with the Medical Research Council (MRC) dyspnea scale, and disease-specific quality of life was assessed with CAT score. Results: The mean±SD age was 68.5±10.9 (range 41-97) years. A significant relationship was established between CAT score, MRC dyspnea scale score and GOLD stage in patients with COPD. There was also a positive correlation between dyspnea scale scores and GOLD stage in the patients (p<0.001), as well as positive correlation between CAT score and dyspnea scale score (p<0.001). CAT score showed a significant correlation with hospitalization and exacerbations (p<0.05). Conclusion: Dyspnea is an important symptom that may impact quality of life in patients with COPD. CAT was shown to be a simple, fast and intelligible measurement of disease-specific quality of life, and was correlated with levels of dyspnea in patients with COPD. 23863454 Differential regulation of stiffness, topography, and dimension of substrates in rat mesenchymal stem cells. The physiological microenvironment of the stem cell niche, including the three factors of stiffness, topography, and dimension, is crucial to stem cell proliferation and differentiation. Although a growing body of evidence is present to elucidate the importance of these factors individually, the interaction of the biophysical parameters of the factors remains insufficiently characterized, particularly for stem cells. To address this issue fully, we applied a micro-fabricated polyacrylamide hydrogel substrate with two elasticities, two topographies, and three dimensions to systematically test proliferation, morphology and spreading, differentiation, and cytoskeletal re-organization of rat bone marrow mesenchymal stem cells (rBMSCs) on twelve cases. An isolated but not combinatory impact of the factors was found regarding the specific functions. Substrate stiffness or dimension is predominant in regulating cell proliferation by fostering cell growth on stiff, unevenly dimensioned substrate. Topography is a key factor for manipulating cell morphology and spreading via the formation of a large spherical shape in a pillar substrate but not in a grooved substrate. Although stiffness leads to osteogenic or neuronal differentiation of rBMSCs on a stiff or soft substrate, respectively, topography or dimension also plays a lesser role in directing cell differentiation. Neither an isolated effect nor a combinatory effect was found for actin or tubulin expression, whereas a seemingly combinatory effect of topography and dimension was found in manipulating vimentin expression. These results further the understandings of stem cell proliferation, morphology, and differentiation in a physiologically mimicking microenvironment. 23703121 LPS-Stimulating Astrocyte-Conditioned Medium Causes Neuronal Apoptosis Via Increasing CDK11(p58) Expression in PC12 Cells Through Downregulating AKT Pathway. Activation of astrocytes in central nervous system inflammation leads to a disturbance of crosstalk between astrocytes and neurons, and that this may contribute to the death of neurons. CDK11(p58) is a member of the large family of p34cdc2-related kinases. It specifically expresses in G2/M phase of the cell cycle and is closely related to cell cycle arrest and apoptosis. Here, we show that astrocyte-conditioned medium stimulated by lipopolysaccharide upregulates CDK11(p58) expression and meanwhile causes neuronal apoptosis. CDK11(p58) knockdown in PC12 cells represses neuronal apoptosis. CDK11(p58) overexpression in PC12 cells promotes neuronal apoptosis. AKT signaling pathway is involved in CDK11(p58)-induced neuronal apoptosis process. 23892493 Comfort response of three silicone hydrogel daily disposable contact lenses. To evaluate subjective ocular comfort across the day with three silicone hydrogel daily disposables (SHDDs) in a group of adapted lens wearers. Masked subjects (asymptomatic or symptomatic of end-of-day (EOD) dryness with habitual lenses) wore three SHDDs: DAILIES TOTAL1 (DT1), Clariti 1day (C1D), or 1-DAY ACUVUE TRUEYE (AVTE), each for 3 days. On day 2, wearing time (WT) and comfort ratings after insertion, at 4, 8, and 12 hours, and at EOD were recorded. Because not all subjects wore lenses for 12 hours, comfort was analyzed across the day (up to 8 hours, 8 to 12 hours), and a new variable ("cumulative comfort" [CC]) was calculated for EOD. One hundred four subjects completed the study (51 asymptomatic, 53 symptomatic). The two groups had different WTs (mean WT, 14.0 and 12.7 hours, respectively; p < 0.001). Ocular comfort was rated higher in the asymptomatic group throughout the day (p < 0.001). One hundred four subjects wore all three SHDDs for at least 8 hours, whereas 74 (45 asymptomatic, 29 symptomatic) subjects wore them for 12 hours or longer. Comfort ratings were higher with DT1 (least square means [LSM] = 91.0) than with C1D (LSM = 86.5; p < 0.001) and AVTE (LSM = 87.7; p = 0.011) for the first 8 hours and lower with C1D compared with DT1 (p = 0.012) from 8 to 12 hours. Mean EOD (± SD) comfort with the C1D lens was 72 ± 21, lower than both DT1 (mean, 79 ± 17; p = 0.001) and AVTE (mean, 78 ± 21; p = 0.010). Mean CC was higher in the asymptomatic group (mean, 1261 ± 59) compared with that in the symptomatic group (mean, 1009 ± 58; p < 0.001) and higher for DT1 (mean, 1184 ± 258) than C1D (mean, 1094 ± 318; p = 0.002) and AVTE (mean, 1122 ± 297; p = 0.046). All three SHDDs had average WTs of 12 hours or longer for 1 day. Comfort during the first 12 hours was highest with DT1 (similar to AVTE between 8 and 12 hours) and lowest with C1D. End-of-day comfort was lowest with C1D, and CC was highest for DT1. Cumulative comfort may be a valuable new metric to assess ocular comfort during the day. 23142577 Use of high content image analyses to detect chemical-mediated effects on neurite sub-populations in primary rat cortical neurons. Traditional developmental neurotoxicity tests performed in vivo are costly, time-consuming and utilize a large number of animals. In order to address these inefficiencies, in vitro models of neuronal development have been used in a first tier screening approach for developmental neurotoxicity hazard identification. One commonly used endpoint for assessing developmental neurotoxicity in vitro is measurement of neurite outgrowth. This biological process is amenable to high-throughput measurement using high content imaging (HCI) based methodologies. To date, a majority of HCI studies of neurite outgrowth have focused on measurements of total neurite outgrowth without examining whether stereotypic neuronal growth patterns are disrupted or whether specific sub-populations of neurites (i.e. axons or dendrites) are selectively affected. The present study describes the development and implementation of two HCI based analysis methods for assessing chemical effects on neuronal maturation. These methods utilize the stereotypical growth pattern of primary rat cortical neurons in culture (i.e. the Staging Method), as well as the differential cytoplasmic distribution of β(III)-tubulin and MAP2 (i.e. the Subtraction Method), to quantify inhibition of neurite initiation, axon outgrowth and secondary neurite (or dendrite) outgrowth in response to chemical exposure. Results demonstrate that these distinct maturational processes are differentially affected by pharmacological compounds (K252a, Na(3)VO(4), Bis-1) known to inhibit neurite outgrowth. Furthermore, a group of known developmental neurotoxicants also differentially affected the growth of axons and secondary neurites in primary cortical culture. This work improves upon previous HCI methods by providing a means in which to rapidly and specifically quantify chemical effects on the growth of axons and dendrites in vitro. 22810851 Emergency department of a university hospital: who is admitted and who is transferred? Our main aim was to describe the path of patients seen in our emergency department (ED) and either admitted or transferred and to compare the characteristics of patients hospitalized in our hospital with those of transferred patients. Our secondary aim was to compare the receipts linked to patient hospital stays. All patients seen in the ED of our hospital and ill enough to be either admitted or transferred were prospectively enrolled during 2 consecutive weeks. Information was obtained from the hospital discharge report and from local medical databases. The characteristics of the patients and receipts were compared according to their path. Among the 251 patients included in the study, 9% were transferred directly from the ED to another hospital. Among admitted patients, two-thirds were admitted to the short-stay unit (SSU). Schematically, patients transferred from the ED are more likely to be men around 50 years of age with few comorbidities, requiring surgery with relatively short hospital stays. Patients transferred from the SSU were more likely to be women around 67 years of age with severe comorbidities requiring medical care and longer stays. The mean receipt per day was two to three times greater for patients transferred from the ED as compared with patients hospitalized in our hospital. The mean receipt per day for patients transferred from the SSU also tended to be higher. Our results show that patients requiring shorter care are transferred, whereas more severe patients are hospitalized on site. Hospitals will need solutions to optimize their receipts while fulfilling their public missions such as continuity of care. 23906171 Educational interventions for primary healthcare professionals to promote the early diagnosis of cancer: a systematic review. Primary healthcare professionals seem to lack knowledge and skills in the area of diagnosing cancer which may lead to more advanced stage at diagnosis, poorer cancer survival figures and increased morbidity. The aim of this study was to examine the evidence of effectiveness of educational interventions for primary healthcare professionals to promote the early diagnosis of cancer. We searched bibliographic databases, the grey literature and reference lists for randomised controlled trials (RCTs) of educational interventions delivered at an individual clinician and practice level. We found sufficient evidence that interactive education, computerised reminder systems and audit and feedback delivered to clinicians may significantly increase several cancer detection measures in the short term and some evidence that they promote early diagnosis. Whilst educational outreach and local opinion leaders had some effect, formal education alone seemed ineffectual. Certain educational interventions delivered at a clinician as well as at a practice level may promote the early diagnosis of cancer in primary care. There is currently limited evidence for their long-term sustainability and effectiveness. 23731762 Combined treatment with platelet-rich plasma and brain-derived neurotrophic factor-overexpressing bone marrow stromal cells supports axonal remyelination in a rat spinal cord hemi-section model. Combining biologic matrices is becoming a better choice to advance stem cell-based therapies. Platelet-rich plasma (PRP) is a biologic product of concentrated platelets and has been used to promote regeneration of peripheral nerves after injury. We examined whether PRP could induce rat bone marrow stromal cells (BMSCs) differentiation in vitro and whether a combination of BMSCs, PRP and brain-derived neurotrophic factor (BDNF) could provide additive therapeutic benefits in vivo after spinal cord injury (SCI). BMSCs and BDNF-secreting BMSCs (BDNF-BMSCs) were cultured with PRP for 7 days and 21 days, respectively, and neurofilament (NF)-200, glial fibrillary acidic protein (GFAP), microtubule-associated protein 2 (MAP2) and ribosomal protein S6 kinase (p70S6K) gene levels were assessed. After T10 hemi-section in 102 rats, 15-μL scaffolds (PRP alone, BMSCs, PRP/BMSCs, BDNF-BMSCs or PRP/BDNF-BMSCs) were transplanted into the lesion area, and real-time polymerase chain reaction, Western blot, immunohistochemistry and ultrastructural studies were performed. The messenger RNA expression of NF-200, GFAP, MAP2 and p70S6K was promoted in BMSCs and BDNF-BMSCs after culture with PRP in vitro. BDNF levels were significantly higher in the injured spinal cord after implantation of BDNF-BMSCs. In the PRP/BDNF-BMSCs group at 8 weeks postoperatively, more GFAP was observed, with less accumulation of astrocytes at the graft-host interface. Rats that received PRP and BDNF-BMSC implants showed enhanced hind limb locomotor performance at 8 weeks postoperatively compared with control animals, with more axonal remyelination. A combined treatment comprising PRP and BDNF-overexpressing BMSCs produced beneficial effects in rats with regard to functional recovery after SCI through enhancing migration of astrocytes into the transplants and axonal remyelination. 23515375 'You need a support. When you don't have that . . . chocolate looks real good'. Barriers to and facilitators of behavioural changes among participants of a Healthy Living Program. Health behavioural change is complex, especially for underserved patients who have higher rates of obesity and physical inactivity. Behavioural change interventions that show high efficacy in clinical trials may be difficult to disseminate and may not be effective in the office. We sought to identify factors that facilitate or hinder behavioural change among past participants of a healthy lifestyle intervention in an urban underserved health centre. Between March and October 2011, we conducted five focus group sessions with a total of 23 past participants. The focus group transcripts were analysed with a framework approach using the Social Ecological Model as a coding structure. We found four interconnected levels of social contexts: individual, interpersonal, programmatic and community levels. Themes of social support and the importance of relationships for making and maintaining behavioural changes were found at all levels. Social support and relatedness were key facilitators of healthy lifestyle changes and influenced individual motivation and perseverance. Harnessing the power of social support and motivation may be a way for future behavioural change interventions to bridge the gap between efficacy and effectiveness. 23651737 Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans. It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination of serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence. 23727811 Characterization of a Fibrinolytic Enzyme Secreted by Bacillus amyloliquefaciens CB1 and Its Gene Cloning. Bacillus amyloliquefaciens CB1 was isolated from cheonggukjang, a Korean fermented soy food. B. amyloliquefaciens CB1 secretes proteases with fibrinolytic activities. A gene homologous to aprE of Bacillus subtilis, aprECB1, was cloned from B. amyloliquefaciens CB1, and DNA sequencing showed that aprECB1 can encode a prepro-type serine protease consisting of 382 amino acids. When aprECB1 was introduced into B. subtilis WB600 using an E. coli-Bacillus shuttle vector, pHY300PLK, transformants showed fibrinolytic activity and produced a 28 kDa protein, the size expected for the mature enzyme. The 28 kDa fibrinolytic enzyme was purified from the culture supernatant of B. subtilis WB600 transformant. AprECB1 was completely inhibited by phenylmethylsulfonyl fluoride and almost completely inhibited by EDTA and EGTA, indicating that it is a serine metalloprotease. AprECB1 exhibited the highest specificity for N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, a known substrate for α-chymotrypsin. Aα and Bβ chains of fibrinogen were quickly degraded by AprECB1, but the γ-chain was resistant. 23891664 Plasticization and antiplasticization of an acrylic pressure sensitive adhesive by ibuprofen and their effect on the adhesion properties. In transdermal patches, an unpredictable alteration of the mechanical behavior of the pressure sensitive adhesive (PSA) can occur if a drug is added. In the present study, the suitability of Dynamic Mechanical Analysis (DMA)/Dynamic Mechanical Thermal Analysis (DMTA) as methodologies to detect the change in adhesion properties caused by the addition of an API was examined. With DMA/DMTA, time- and temperature-dependent viscoelastic properties were determined. Tack and shear adhesion of blends of the acrylic adhesive DuroTak® 87-4287 and ibuprofen at increasing concentrations were investigated. Interestingly, the probe tack test showed highest values at 1% ibuprofen concentration in the PSA and decreasing values with increasing ibuprofen concentrations. The shear adhesion of the PSA was decreased at all investigated ibuprofen concentrations. With DMA/DMTA, it could be demonstrated that antiplasticization and plasticization are responsible for the change in tack. The main reason for the decrease in shear adhesion is a shift of the Tg to lower temperatures, while antiplasticization only has a marginal effect. The term "antiplasticizing space" was introduced because antiplasticization depends on time, temperature, stress, strain, and API concentration. In general, this antiplasticizing space can have an impact on processing, stability, and in vivo behavior of API/polymer blends in drug formulations. 23935033 Plasma protein denaturation with graded heat exposure. During cardiopulmonary bypass (CPB), perfusion at tepid temperatures (33-35°C) is recommended to avoid high temperature cerebral hyperthermia during and after the operation. However, the ideal temperature for uncomplicated adult cardiac surgery is an unsettled question. Typically, the heat exchanger maximum temperature is monitored between 40-42°C to prevent denaturation of plasma proteins, but studies have not been performed to make these conclusions. Therefore, our hypothesis was to determine the temperature in which blood plasma protein degradation occurs after 2 hours of heat exposure. As a result, blood plasma proteins were exposed to heat in the 37-50°C range for 2 hours. Plasma protein samples were loaded onto an 8-12% gradient gel for SDS-PAGE and low molecular weight plasma protein degradation was detected with graded heat exposure. Protein degradation was first detected between 43-45°C of heat exposure. This study supports the practice of monitoring the heat exchanger between 40-42°C to prevent denaturation of plasma proteins. 23353742 Design, synthesis and SAR of piperidyl-oxadiazoles as 11β-hydroxysteroid dehydrogenase 1 inhibitors. The potential roles of 11β-HSD1 inhibitors in metabolic syndrome, T2D and obesity were well established and currently several classes of 11β-HSD1 inhibitors have been developed as promising agents against metabolic diseases. To find potent compounds with good pharmacokinetics, we used the bioisosterism approach, and designed the compound 2 and 3 bearing an 1,2,4-oxadiazole ring to replace the amide group in compound 1. Guided by docking study, we then transformed compound 3 into a potent lead compound 4a by changing sulfonamide group to amide. To elaborate this series of piperidyl-oxadiazole derivatives as human 11β-HSD1 inhibitors, we explored the structure-activity relationship of several parts of the lead compound. Based on their potency toward human 11β-HSD1 two compounds 4h and 4q were advanced to pharmacokinetic study. It was found that 4h and 4q are potent and selective human 11β-HSD1 inhibitors with better pharmacokinetic properties than those of the original piperidine-3-carboxamide compound 1, and suitable for further in vivo preclinical study in primate model. 23892349 Structures, molecular orbitals and UV-vis spectra investigations on Br2C6H4: A computational study. The dibromobenzenes (1,2-, 1,3- and 1,4-Br2C6H4) have been studied by theoretical methods. The structures of these species are optimized and the structural characteristics are determined by density functional theory (DFT) and the second order Møller-Plesset perturbation theory (MP2) levels. The geometrical structures of Br2C6H4 show a little distortion of benzene ring due to the substitution of highly electronegativity of bromine atoms. The electronegativity of bromine atoms in 1,4-Br2C6H4 is predicted to be more negative than 1,2- and 1,3-Br2C6H4. In addition, dipole moment and frontier molecular orbitals (FMOs) of these Br2C6H4 are performed as well. The 1,4-Br2C6H4 is slightly more reactive than 1,2- and 1,3-Br2C6H4 because of its small HOMO-LUMO energy gap. The simulated UV-vis spectra are investigated by time-dependent density functional theory (TD-DFT) approach, which are in excellent agreement with the available experimental value. Our calculations show that a few of absorption features are between 140nm and 250nm, which is in ultraviolet C range, and the red shift of 1,3- and 1,4-Br2C6H4 are predicted. Moreover, the UV absorption features of these Br2C6H4 in water or methanol are predicted to be more intense than in gas phase due to solvent effect. 23888476 Dynamic Contrast Enhanced MRI of the Prostate: Comparison of Gadobutrol and Gd-DTPA. Purpose: To evaluate the enhancement profile of the macrocyclic contrast medium (CM) gadobutrol in comparison to linear CM Gd-DTPA in DCE-MRI of the prostate.Materials and Methods: In total 53 patients with prostata cancer (PCa) were included, who received a radical prostatectomy after multiparametric MRI of the prostate including DCE-MRI. Using circular regions of interests normal peripheral zone (PZ) and PCa foci > 5 mm in diameter (42 and 34 foci in Gd-DTPA and gadobutrol group, respectively) were analysed in DCE-MRI. Enhancement curves (Type I, II and III) and pharmacokinetic parameters were analyzed qualitatively and quantitatively and compared using mixed linear models (two sided p-values < 0.05 were regarded significant).Results: There was no significant difference in frequencies of curve types I, II or III in the normal PZ (p = 0.63) or in PCa foci (p = 0.75). PCa with a Gleason score ≥ 7 had in comparison to Gleason ≤ 6 significantly more often a Wash-Out-curve (Type III) with both CM (p = 0.02). The relative peak enhancement was in the PZ (Gd-DTPA 1.4 a. u. [1.20; 1.59], gadobutrol 1.58 a. u. [1.37; 1.78]) and in PCa foci (Gd-DTPA 1.56 a. u. [1.41; 1.71], gadobutrol 1.76 a. u. [1.59; 1.94]) significantly higher with gadobutrol (p = 0.04). The pharmacokinetic parameters Ktrans und kep were higher in PCa foci than in PZ (p < 0.0001 and p = 0.002, respectively) without significant difference of the parameter values between both CM (p = 0.65).Conlusion: This study is the first systematic comparison of gadobutrol and Gd-DTPA in DCE-MRI of the prostate. The relative peak enhancement is higher using gadobutrol compared to Gd-DTPA in DCE-MRI. There was no statistically significant difference in curve types or the pharmacokinetic parameters in PCa or normal PZ between both CM.Key Points:Citation Format: 23103450 Arsenic trioxide-induced hERG K(+) channel deficiency can be rescued by matrine and oxymatrine through up-regulating transcription factor Sp1 expression. The human ether-a-go-go-related gene (hERG) encodes the rapidly activating, delayed rectifier potassium channel (IKr) important for cardiac repolarization. Dysfunction of the hERG channel can cause Long QT Syndrome (LQTS). A wide variety of structurally diverse therapeutic compounds reduce the hERG current by acute direct inhibition of the hERG current or/and selective disruption of hERG protein expression. Arsenic trioxide (As(2)O(3)), which is used to treat acute promyelocytic leukemia, can cause LQTS type 2 (LQT2) by reducing the hERG current through the diversion of hERG trafficking to the cytoplasmic membrane. This cardiotoxicity limits its clinical applications. Our aim was to develop cardioprotective agents to decrease As(2)O(3)-induced cardiotoxicity. We reported that superfusion of hERG-expressing HEK293 (hERG-HEK) cells with matrine (1, 10 μM) increased the hERG current by promoting hERG channel activation. Long-term treatment with 1 μM matrine or oxymatrine increased expression of the hERG protein and rescued the hERG surface expression disrupted by As(2)O(3). In addition, Matrine and oxymatrine significantly shortened action potential duration prolonged by As(2)O(3) in guinea pig ventricular myocytes. These results were ascribed to the up-regulation of hERG at both mRNA and protein levels via an increase in the expression of transcription factor Sp1, an established transactivator of the hERG gene. Therefore, matrine and oxymatrine may have the potential to cure LQT2 as a potassium channel activator by promoting hERG channel activation and increasing hERG channel expression. 23806104 Influence of Cyclic Dimer Formation on the Phase Behavior of Carboxylic Acids. II. Cross-Associating Systems. The doubly bonded dimer association scheme (DBD) proposed by Sear and Jackson is extended to mixtures exhibiting both self- and cross-associations. The PC-SAFT equation of state is combined with the new DBD association contribution to describe the vapor-liquid equilibria of binary mixtures of carboxylic acids + associating compounds (water, alcohols, and carboxylic acids). The effect of doubly bonded dimers on the phase behavior in such systems is less important than in mixtures of carboxylic acids with nonassociating compounds, due to the cross-associations that compete with the formation of DBDs. Nevertheless, a clear improvement in the description of vapor-liquid coexistence curves is achieved over the classical 2B association model, particularly for the dew point curves. 23862560 Liver Abscess as a Complication of Laparoscopic Gastric Banding Bariatric Surgery. Abstract Background: The World Health Organization has identified the rapidly growing prevalence of obesity as one of today's serious health problems. Various surgical interventions categorized collectively as bariatric surgery now play an ever-increasing important role as the only known effective treatment for severe obesity. Laparoscopic gastric bypass is currently the most frequent bariatric surgical procedure performed. However, the laparoscopic adjustable gastric band (LAGB) is rapidly gaining in popularity as a minimally invasive surgical option with anticipated similarly efficacious outcomes. Gastric band erosion following LAGB is an uncommon yet potentially serious complication unique to this form of weight loss surgery. Methods: Case report and literature review. Results: We report a case of a pyogenic liver abscess related to a LAGB procedure. Apropos to this case, we review the presumed pathophysiologic mechanism of this particular infectious process, and discuss this and other complications associated with LAGB operations. Conclusions: As LAGB bariatric procedures become more popular, clinicians need to be aware of uncommon, but potentially serious complications unique to this form of weight loss surgery. 23961428 Is Age-targeted full-field digital mammography screening cost-effective in emerging countries? A micro simulation model. The present paper estimates the cost-effectiveness of population-based breast cancer (BC) screening strategies in Brazil for women under 50 years from the perspective of the Brazilian public health system. A Markov model, simulating the natural history of female BC sufferers in Brazil, was developed. This model compares the lifetime effects, costs, and cost-effectiveness of seven BC screening strategies in women between 40 to 49 years: (A) usual care; (B) annual screen-film mammography (SFM); (C) SFM every 2 years; (D) annual full-field digital mammography (FFDM); (E) FFDM every 2 years; and (F and G) age-targeted options, with FFDM annually until 49 years and SFM annually (or biannually) from 50 to 69 years. Adopting SFM every 2 years (Strategy C) was found to be slightly more costly but also more effective in terms of quality-adjusted life years (QALYs), yielding an incremental cost-effectiveness ratio (ICER) of R$ 1,509 per QALY gained. Annual SFM (Strategy B) was the next best option at an additional R$ 13,131 per QALY gained. FFDM annual screening (Strategy E) was dominated by Strategy F, the age-targeted option. For younger women, the age-based strategy had an ICER of R$ 30,520 per QALY gained. In the sensitivity analysis, the ICERs ranged from R$ 15,300 to R$ 257,899 in different regions of the country, depending on BC incidence, population age distribution, and mammography coverage. SFM every 2 years for all women starting between the ages of 40 and 49 would be a cost-effective strategy. Taking into account regional specificities, age-targeted FFDM is one option to improve the outcomes of BC patients in an emerging country. 23298277 Design and synthesis of potent inhibitor of apoptosis (IAP) proteins antagonists bearing an octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline mimetic. To develop novel inhibitor of apoptosis (IAP) proteins antagonists, we designed a bicyclic octahydropyrrolo[1,2-a]pyrazine scaffold as a novel proline bioisostere. This design was based on the X-ray co-crystal structure of four N-terminal amino acid residues (AVPI) of the second mitochondria-derived activator of caspase (Smac) with the X-chromosome-linked IAP (XIAP) protein. Lead optimization of this scaffold to improve oral absorption yielded compound 45, which showed potent cellular IAP1 (cIAP1 IC(50): 1.3 nM) and XIAP (IC(50): 200 nM) inhibitory activity, in addition to potent tumor growth inhibitory activity (GI(50): 1.8 nM) in MDA-MB-231 breast cancer cells. X-ray crystallographic analysis of compound 45 bound to XIAP and to cIAP1 was achieved, revealing the various key interactions that contribute to the higher cIAPI affinity of compound 45 over XIAP. Because of its potent IAP inhibitory activities, compound 45 (T-3256336) caused tumor regression in a MDA-MB-231 tumor xenograft model (T/C: -53% at 30 mg/kg). 23728818 Mannitol and the mannitol-specific enzyme IIB subunit activate Vibrio cholerae biofilm formation. Vibrio cholerae is a halophilic, Gram-negative rod found in marine environments. Strains that produce cholera toxin cause the diarrheal disease cholera. V. cholerae use a highly conserved, multicomponent signal transduction cascade known as the phosphoenolpyruvate phosphotransferase system (PTS) to regulate carbohydrate uptake and biofilm formation. Regulation of biofilm formation by the PTS is complex, involving many different regulatory pathways that incorporate distinct PTS components. The PTS consists of the general components enzyme I (EI) and histidine protein (HPr) and carbohydrate-specific enzymes II. Mannitol transport by V. cholerae requires the mannitol-specific EII (EII(Mtl)), which is expressed only in the presence of mannitol. Here we show that mannitol activates V. cholerae biofilm formation and transcription of the vps biofilm matrix exopolysaccharide synthesis genes. This regulation is dependent on mannitol transport. However, we show that, in the absence of mannitol, ectopic expression of the B subunit of EII(Mtl) is sufficient to activate biofilm accumulation. Mannitol, a common compatible solute and osmoprotectant of marine organisms, is a main photosynthetic product of many algae and is secreted by algal mats. We propose that the ability of V. cholerae to respond to environmental mannitol by forming a biofilm may play an important role in habitat selection. 23952613 Characterization of Interactions between Heparin/Glycosaminoglycan and Adeno-associated Virus. Adeno-associated virus (AAV) is a key candidate in the development of gene therapy. In this report, we used surface plasmon resonance spectroscopy to study the interaction between AAV and heparin and other glycosaminoglycans. Surface plasmon resonance results revealed that heparin binds to AAV with extremely high affinity. Solution competition studies shows that AAV binding to heparin is chain length dependent. AAV prefers to bind full chain heparin. All sulfo groups (especially N-sulfo and 6-O-sulfo groups) on heparin are important for the AAV- heparin interaction. Higher levels of sulfo group substitution in GAGs enhance their binding affinities. Atomic force microscopy was also performed to image AAV-2 complexed with heparin. 23629702 Gentamicin-loaded borate bioactive glass eradicates osteomyelitis due to Escherichia coli in a rabbit model. The treatment of osteomyelitis induced by Gram-negative bacilli is rarely reported in the literature. This study established a rabbit tibia model of osteomyelitis induced by the Gram-negative bacillus Escherichia coli. Using this model, pellets composed of a chitosan-bonded mixture of borate bioactive glass and gentamicin were evaluated in vitro and in vivo for the treatment of osteomyelitis induced by Escherichia coli. Our results showed that the pellets in phosphate-buffered saline released gentamicin continuously over 26 days. Without the simultaneous use of a systemic antibiotic, the implantation of the gentamicin-loaded pellets into the osteomyelitis region of the tibia resulted in the eradication of 81.82% of infections, as determined by microbiological, histological and radiographic evaluation, and supported the ingrowth of new bone into the tibia defects after 6 weeks of implantation. The results indicate that the gentamicin-loaded borate bioactive glass implant, combining sustained drug release with the ability to support new bone formation, could provide a method for treating osteomyelitis induced by Gram-negative bacilli. 23317008 Novel insights into the pervasive role of M(3) muscarinic receptor in cardiac diseases. Cardiac diseases remain the leading cause of morbidity and mortality worldwide. Heart functions are regulated by autonomic nervous systems through their transmitters and modulators, binding to cell surface receptors. Among them, the cardiac M(3) muscarinic acetylcholine receptor (M(3)-mAChR) has been studied for more than 2 decades since its first discovery in mammalian heart in 1990s. The location and pathophysiological role of M(3)-mAChR in the cardiovascular system have been extensively studied and many pathways involved have been uncovered. Gain- and loss-of-function studies have revealed the ubiquitous roles of M(3)-mAChR in physiological and pathological conditions. Recently, many new findings have been uncovered about the relationship between M(3)-mAChR and cardiac diseases, including cardiac ischemia, pathological cardiac hypertrophy, cardiac arrhythmias, cardiac conduction and heart failure. Furthermore, the novel potential cardioprotective role of M(3)-mAChR against heart injury by regulation of microRNAs (miRNAs) has been revealed in the most updated research. In this review, the current new findings on the role of M(3)-mAChR in heart diseases are updated, the downstream signaling pathways are summarized, perspectives and challenges of M(3)-mAChR as therapeutic targets are discussed. 23643972 Evolution of Manduca sexta hornworms and relatives: Biogeographical analysis reveals an ancestral center of diversification in Central America. The hawkmoth genus Manduca is a diverse group of very large, conspicuous moths that has served as an important model across many biological disciplines. Two species in particular, the tobacco hornworm (Manduca sexta) and the tomato hornworm (Manduca quinquemaculatus) have been researched extensively. Studies across biological fields have referred to these two species as being closely related or even sister species, but the extent to which these two model organisms are related remains largely unknown. We conducted a comprehensive multi-gene phylogenetic analysis of Manduca, based on both an ML and Bayesian framework, which resulted in a monophyletic Manduca but only when two other genera, Dolba and Euryglottis are included. We tentatively conclude that the sister group to Manduca sexta comprises the Caribbean M. afflicta and M. johanni, and the sister lineage to this clade includes M. quinquemaculatus and the Hawaiian M. blackburni. Thus, M. sexta and M. quinquemaculatus are closely related, but are not sister species. Biogeographical analyses reveal an ancestral center of diversification in Central America, and Manduca appears to have subsequently colonized North and South America. Our phylogeny provides an important foundation for comparative studies of two model organisms and their relatives. 23738965 Evaluation of biofilm production by Pseudomonas aeruginosa from canine ears and the impact of biofilm on antimicrobial susceptibility in vitro. Pseudomonas aeruginosa is a common cause of canine otitis; P. aeruginosa biofilm formation has been documented in human medicine, but the role of biofilms in canine disease is not well documented. Bacteria within biofilms can be more resistant to antibiotics compared with their planktonic form; therefore, understanding the biofilm-forming capacity of isolates and their susceptibility to antimicrobials is important when developing treatment regimens. To evaluate the biofilm-forming capacity of canine otic isolates of P. aeruginosa and to compare the minimal inhibitory concentration (MIC) of the planktonic versus biofilm-embedded bacteria. Biofilm-forming ability was assessed using a microtitre plate assay. Broth microdilution was used to assess the MICs of neomycin, polymyxin B, enrofloxacin and gentamicin for the planktonic and biofilm-embedded bacteria. Eighty-three isolates from dogs with otitis were tested; 33 (40%) were classified as biofilm producers. Biofilm MICs for polymyxin B, neomycin, gentamicin and enrofloxacin were significantly higher than for the planktonic form (P < 0.05). Biofilm production by otitis isolates of P. aeruginosa is common and may play a role in the pathogenesis of disease. The MICs for biofilm-embedded bacteria differ from their planktonic counterparts, potentially leading to a lack of response to treatment. If polymyxin B, gentamicin, neomycin or enrofloxacin is to be used for topical treatment of a Pseudomonas otitis, the concentration of the medication should be increased, in particular if addressing chronic otitis, because biofilms may have developed. 23660547 Reduction biodegradable brushed PDMAEMA derivatives synthesized by atom transfer radical polymerization and click chemistry for gene delivery. Novel reducible and degradable brushed poly(2-(dimethylamino) ethyl methacrylate) (PDMAEMA) derivatives were synthesized and evaluated as non-viral gene delivery vectors. First, alkyne-functionalized poly(aspartic acid) with a disulfide linker between the propargyl group and backbone poly([(propargyl carbamate)-cystamine]-α,β-aspartamide) (P(Asp-SS-AL)) was synthesized. Second, linear low molecular weight (LMW) monoazido-functionalized PDMAEMAs synthesized via atom transfer radical polymerization were conjugated to the polypeptide side-chains of P(Asp-SS-AL) via click chemistry to yield high molecular weight (HMW) polyaspartamide-based disulfide-containing brushed PDMAEMAs (PAPDEs). The PAPDEs were able to condense plasmid DNA to form 100 to 200nm polyplexes with positive ζ-potentials. Moreover, in the presence of dithiothreitol the PAPDEs degraded into LMW PDAMEMA, resulting in disintegration of the PAPDE/DNA polyplexes and subsequent release of plasmid DNA. In vitro experiments revealed that the PAPDEs were less cytotoxic and more effective in gene transfection than control 25kDa poly(ethyleneimine) and HMW linear PDMAEMA. In conclusion, reducible and degradable polycations composed of LMW PDMAEMAs coupled to a polypeptide backbone via reduction-sensitive disulfide bonds are effective gene vectors with an excellent cytocompatibility. 22747593 Genome-wide patterns of standing genetic variation in a marine population of three-spined sticklebacks. Since the end of the Pleistocene, the three-spined stickleback (Gasterosteus aculeatus) has repeatedly colonized and adapted to various freshwater habitats probably originating from ancestral marine populations. Standing genetic variation and the underlying genomic architecture both have been speculated to contribute to recent adaptive radiations of sticklebacks. Here, we expand on the current genomic resources of this fish by providing extensive genome-wide variation data from six individuals from a marine (North Sea) stickleback population. Using next-generation sequencing and a combination of paired-end and mate-pair libraries, we detected a wide size range of genetic variation. Among the six individuals, we found more than 7% of the genome is polymorphic, consisting of 2599111 SNPs, 233464 indels and structural variation (SV) (>50 bp) such as 1054 copy-number variable regions (deletions and duplications) and 48 inversions. Many of these polymorphisms affect gene and coding sequences. Based on SNP diversity, we determined outlier regions concordant with signatures expected under adaptive evolution. As some of these outliers overlap with pronounced regions of copy-number variation, we propose the consideration of such SV when analysing SNP data from re-sequencing approaches. We further discuss the value of this resource on genome-wide variation for further investigation upon the relative contribution of standing variation on the parallel evolution of sticklebacks and the importance of the genomic architecture in adaptive radiation. 23914352 Indacaterol/glycopyrronium bromide fixed-dose combination for the treatment of COPD. Chronic obstructive pulmonary disease (COPD) is a worldwide problem causing prolonged and progressive morbidity as well as premature mortality. Pharmacologic treatment consists primarily in the relief of symptoms and preventing or minimizing the consequences of exacerbations. Central to the pharmacologic management of COPD is the use of bronchodilator therapy. Two major classes of agents are frequently used: β-adrenoceptor agonists and antimuscarinic agents. These drugs are used mainly in the inhalational form, primarily as rescue medication, but occasionally for maintenance in combination therapy. The availability of "ultra-long"-acting β-adrenoceptor agonists and long-acting antimuscarinic agents opens the way for combinations of these agents to be used in maintenance therapy. Such a combination offers the potential of enhanced efficacy due to additive effects and better compliance as the result of once-daily treatment. This article reviews the rationale for current bronchodilator therapy of COPD as well as the current status of a fixed-dose combined inhaler using two novel long-acting agents: glycopyrronium bromide and indacaterol maleate. 23790998 A practical approach for content mining of Tweets. Use of data generated through social media for health studies is gradually increasing. Twitter is a short-text message system developed 6 years ago, now with more than 100 million users generating over 300 million Tweets every day. Twitter may be used to gain real-world insights to promote healthy behaviors. The purposes of this paper are to describe a practical approach to analyzing Tweet contents and to illustrate an application of the approach to the topic of physical activity. The approach includes five steps: (1) selecting keywords to gather an initial set of Tweets to analyze; (2) importing data; (3) preparing data; (4) analyzing data (topic, sentiment, and ecologic context); and (5) interpreting data. The steps are implemented using tools that are publically available and free of charge and designed for use by researchers with limited programming skills. Content mining of Tweets can contribute to addressing challenges in health behavior research. 23933201 The role of the sonic hedgehog signaling pathway in early brain injury after experimental subarachnoid hemorrhage in rats. Previous studies have demonstrated that the sonic hedgehog (Shh) pathway plays a neuro-protective role. However, whether the Shh pathway is induced by subarachnoid hemorrhage (SAH) has not been investigated. We sought to investigate Shh activation in the cortex in the early stage of SAH, and assessed the effect of cyclopamine (a specific inhibitor of the Shh pathway) on Shh pathway regulation and evaluated the impact of cyclopamine on SAH. We found that the Shh pathway was up-regulated in the cortex after SAH, and that blocking the Shh pathway increased cell apoptosis. Early brain damages, including brain edema, blood-brain barrier impairment, and cortical apoptosis were significantly aggravated following with cyclopamine treatment compared with vehicle treatment. Our results suggest that the Shh pathway should be activated in the brain after SAH, and plays a beneficial role in SAH development, possibly by inhibiting cerebral oxidative stress through induction of antioxidant and detoxifying enzymes. 23711928 Hyperprolactinemia impairs object recognition without altering spatial learning in male rats. Prolactin (PRL) exerts protective effects on the hippocampus against chronic stress exposure, or kainic acid insults. Further, PRL null mice were recently shown to exhibit learning and memory deficits. These findings suggest the hippocampus as a PRL target. To test this hypothesis, we analyzed the hippocampal formation function in dependence of serum PRL concentrations. Male Sprague-Dawley rats were either transplanted with 2 pituitary homografts (HPRL) or had a sham operation (SHAM). Other groups were given vehicle (VEH) or daily injections of bromocriptine (BRC, 4mg/kg) to reduce PRL levels. The animals were sequentially subjected to the Morris water maze (MWM), the object recognition test and the elevated plus maze. PRL concentrations were measured with ELISAs. Learning curves from the MWM showed a progressive reduction in distance over time but no significant differences were found between SHAM and HPRL, or between BRC and VEH groups. Also, memory retrieval was not affected in the probe trial between each pair of groups. However, in the object recognition test the HPRL group failed to discriminate between novel and familiar objects, and the discrimination index was significantly reduced from that of the VEH group. BRC rats exhibited a reduced exploration of both objects compared to VEH, but had a discrimination index similar to VEH. No significant differences were observed in the EPM. In conclusion, high PRL levels impair object recognition but do not alter spatial learning. These results show for the first time that PRL impairs object recognition, and thus modulates non-spatial cognitive tasks. 23586466 Smooth muscle relaxation and activation of the large conductance Ca(++)-activated K+ (BK(Ca)) channel by novel oestrogens. Oestrogens can interact directly with membrane receptors and channels and can activate vascular BK(Ca) channels. We hypothesized that novel oestrogen derivatives could relax smooth muscle by an extracllular effect on the α and β1 subunits of the BK(Ca) channel, rather than at an intracellular site. We studied the effects of novel oestrogens on the tension of pre-contracted isolated rat aortic rings, and on the electrophysiological properties of HEK 293 cells expressing the hSloα or hSloα+β1 subunits. Two of the derivatives incorporated a quaternary ammonium side-chain making them membrane impermeable. Oestrone, oestrone oxime and Quat DME-oestradiol relaxed pre-contracted rat aorta, but only Quat DME-oestradiol-induced relaxation was iberiotoxin sensitive. However, only potassium currents recorded in HEK 293 cells over-expressing both hSloα and hSloβ1 were activated by oestrone, oestrone oxime and Quat DME-oestradiol. The novel oestrogens were able to relax smooth muscle, but through different mechanisms. In particular, oestrone oxime required the presence of the endothelium to exert much of its effect, whilst Quat DME-oestradiol depended both on NO and BK(Ca) channel activation. The activation of BK(Ca) currents in HEK 293 cells expressing hSloα+β1 by Quat DME-oestradiol is consistent with an extracellular binding site between the two subunits. The binding site resides between the extracellular N terminal of the α subunit and the extracellular loop between TM1 and 2 of the β1 subunit. Membrane-impermeant Quat DME-oestradiol lacks an exchangeable hydrogen on the A ring obviating antioxidant activity. 23639544 Synthesis of proline analogues as potent and selective cathepsin S inhibitors. Cathepsin S is a potential target of autoimmune disease. A series of proline derived compounds were synthesized and evaluated as cathepsin S inhibitors. We discovered potent cathepsin S inhibitors through structure-activity relationship studies of proline analogues. In particular, compound 19-(S) showed promising in vitro/vivo pharmacological activities and properties as a selective cathepsin S inhibitor. 23604334 Pharmacological activation of kappa opioid receptors: aversive effects in adolescent and adult male rats. RATIONALE: The dynorphin (DYN)/kappa opioid receptor (KOR) system is involved in the dysphoric properties of drugs of abuse. Given that adolescents show reduced sensitivity to aversive effects of many drugs, alterations in the DYN/KOR system may contribute to the prevalence of drug use during adolescence. OBJECTIVES: The present study was designed to assess dysphoric properties of a selective kappa agonist, U62,066, in adolescent and adult rats using both conditioned taste aversion (CTA) and conditioned place aversion (CPA) paradigms. METHODS: For CTA, water-restricted rats were administered U62,066 following 30 min access to a saccharin solution, with subsequent saccharin consumption used to index aversion. For CPA, animals were allowed access to both compartments of a two-compartment chamber for a 15-min pre- and post-conditioning test. For conditioning, subjects were administered U62,066 prior to confinement to one side of the chamber and saline prior to confinement to the other side for a total of four pairings. RESULTS: Overall, adolescents displayed reduced sensitivity to the kappa agonist relative to adults. Adults demonstrated taste aversions to the 0.2 and 0.3 mg/kg doses of U62,066, whereas adolescents did not display aversions to any tested doses. Adults demonstrated a place aversion to the 0.1 and 0.2 mg/kg dose of U62,066 when paired with the preferred side of the conditioning chamber. Adolescents did not display aversions to any of the doses tested. CONCLUSIONS: Reduced sensitivity to DYN/KOR system activation during adolescence may be a contributing factor to the age-typical insensitivity to aversive properties of drugs commonly abused by adolescents. 23788474 Asymmetric ion pair catalysis of 6π electrocyclizations: brønsted Acid catalyzed enantioselective synthesis of optically active 1,4-dihydropyridazines. Electric slide: Described is a general, operationally simple, highly enantioselective Brønsted acid catalyzed condensation/6π-electrocyclization reaction between hydrazones and α,β-unsaturated aldehydes that yields valuable 1,4-dihydropyridazines. The reaction exhibits high tolerance towards functional groups and affords products with up to 98 % ee. 23861242 Pain and other non-neurological adverse events in children with sickle cell anemia and previous stroke who received hydroxyurea and phlebotomy or chronic transfusions and chelation: Results from the SWiTCH clinical trial. Purpose: To compare the non-neurological events in children with sickle cell anemia (SCA) and previous stroke enrolled in SWiTCH. Methods: The NHLBI-sponsored Phase III multicenter randomized clinical trial Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) (ClinicalTrials.gov NCT00122980) compared continuation of chronic blood transfusion/iron chelation to switching to hydroxyurea/phlebotomy for secondary stroke prevention and management of iron overload. All randomized children were included in the analysis (intention to treat). The Fisher's Exact test was used to compare the frequency of subjects who experienced at least one SCA-related adverse event (AE) or serious adverse event (SAE) in each arm and to compare event rates. Results: 133 subjects, mean age 13 ±3.9 years (range 5.2-19.0 years) and mean time of 7 years on chronic transfusion at study entry, were randomized and treated. Numbers of subjects experiencing non-neurological AEs were similar in the two treatment arms, including SCA-related events, SCA pain events, and low rates of acute chest syndrome and infection. However, fewer children continuing transfusion/chelation experienced SAEs (p=0.012), SCA-related SAEs (p=0.003), and SCA pain SAEs (p=0.016) as compared to children on the hydroxyurea/phlebotomy arm. The timing of phlebotomy did not influence SAEs. Older age at baseline predicted having at least 1 SCA pain event. Patients with recurrent neurological events during SWiTCH were not more likely to experience pain. Conclusions: In children with SCA and prior stroke, monthly transfusions and daily iron chelation provided superior protection against acute vaso-occlusive pain SAEs when compared to hydroxyurea and monthly phlebotomy. 23645666 The bacterial translocon SecYEG opens upon ribosome binding. In cotranslational translocation, the ribosome funnel and the channel of the protein translocation complex SecYEG are aligned. For the nascent chain to enter the channel immediately after synthesis, a yet unidentified signal triggers displacement of the SecYEG sealing plug from the pore. Here we show that ribosome binding to the resting SecYEG channel triggers this conformational transition. The purified and reconstituted SecYEG channel opens to form a large ion-conducting channel which has the conductivity of the plug deletion mutant. The number of ion conducting channels inserted into the planar bilayer per fusion event roughly equals the number of SecYEG channels counted by fluorescence correlation spectroscopy in a single proteoliposome. Thus, the open probability of the channel must be close to unity. To prevent the otherwise lethal proton leak, a closed post-translational conformation of the SecYEG complex bound to a ribosome must exist. 23892131 Anti-inflammatory effects of lipoic acid through inhibition of GSK-3β in lipopolysaccharide-induced BV-2 microglial cells. Activated microglial cells play an important role in immune and inflammatory responses in CNS and play a role in neurodegenerative diseases. We examined the effects of lipoic acid (LA) on inflammatory responses of BV-2 microglial cells activated by lipopolysaccharide (LPS), and explored the underlying mechanisms of action of LA. BV-2 cells treated with LPS showed an up-regulation of mRNA of the pro-inflammatory molecules, inducible nitric oxide synthase (iNOS). LA suppressed the expression of iNOS and furthermore, LPS-induced production of nitrite. Moreover, LA suppressed the nuclear translocation of RelA, a component of nuclear factor-kappa B (NF-κB) that contains transcriptional activator domain for LPS. The mechanisms of LA-mediated anti-inflammatory effects on microglia remain unknown, and we suggested an involvement of Akt/glycogen synthase kinase-3β (GSK-3β) phosphorylation. The results showed that inhibitor of phosphatidylinositol 3-kinase prevented LA-mediated suppression of LPS induction of RelA and expression of iNOS. Furthermore, these inflammatory actions were prevented by GSK-3β inhibitors. These data demonstrate a role for LA as a chemical modulator of inflammatory responses by microglia, and thus may be a therapeutic strategy for treating neurodegenerative diseases with an inflammatory component. 23780578 Ambulatory blood pressure changes after renal sympathetic denervation in patients with resistant hypertension. Catheter-based renal sympathetic denervation (RDN) reduces office blood pressure (BP) in patients with resistant hypertension according to office BP. Less is known about the effect of RDN on 24-hour BP measured by ambulatory BP monitoring and correlates of response in individuals with true or pseudoresistant hypertension. A total of 346 uncontrolled hypertensive patients, separated according to daytime ambulatory BP monitoring into 303 with true resistant (office systolic BP [SBP] 172.2±22 mm Hg; 24-hour SBP 154±16.2 mm Hg) and 43 with pseudoresistant hypertension (office SBP 161.2±20.3 mm Hg; 24-hour SBP 121.1±19.6 mm Hg), from 10 centers were studied. At 3, 6, and 12 months follow-up, office SBP was reduced by 21.5/23.7/27.3 mm Hg, office diastolic BP by 8.9/9.5/11.7 mm Hg, and pulse pressure by 13.4/14.2/14.9 mm Hg (n=245/236/90; P for all <0.001), respectively. In patients with true treatment resistance there was a significant reduction with RDN in 24-hour SBP (-10.1/-10.2/-11.7 mm Hg, P<0.001), diastolic BP (-4.8/-4.9/-7.4 mm Hg, P<0.001), maximum SBP (-11.7/-10.0/-6.1 mm Hg, P<0.001) and minimum SBP (-6.0/-9.4/-13.1 mm Hg, P<0.001) at 3, 6, and 12 months, respectively. There was no effect on ambulatory BP monitoring in pseudoresistant patients, whereas office BP was reduced to a similar extent. RDN was equally effective in reducing BP in different subgroups of patients. Office SBP at baseline was the only independent correlate of BP response. RDN reduced office BP and improved relevant aspects of ambulatory BP monitoring, commonly linked to high cardiovascular risk, in patients with true-treatment resistant hypertension, whereas it only affected office BP in pseudoresistant hypertension. http://www.clinicaltrials.gov. Unique identifiers: NCT00664638 and NCT00888433. 23940580 Increased cellular senescence and vascular rarefaction exacerbate the progression of kidney fibrosis in aged mice following transient ischemic injury. Recent findings indicate that elderly patients with acute kidney injury (AKI) have an increased incidence of progression to chronic kidney disease (CKD) due to incomplete recovery from an acute insult. In the current study, a co-morbid model of AKI was developed to better mimic the patient population and to investigate whether age exacerbates the fibrosis and inflammation that develop in the sequelae of progressive kidney disease following acute injury. Young (8-10 weeks) and aged (46-49 weeks) C57BL/6 mice were subjected to 30 min bilateral renal ischemia-reperfusion (I/R) to induce AKI. The aged animals have greater mortality and prolonged elevation of plasma creatinine correlating with less tubular epithelial cell proliferation compared to the young. Six weeks post-reperfusion, interstitial fibrosis is greater in aged kidneys based on picrosirius red staining and immunolocalization of cellular fibronectin, collagen III and collagen IV. Aged kidneys 6 weeks post-reperfusion also express higher levels of p53 and p21 compared to the young, correlating with greater increases in senescence associated (SA) β-galactosidase, a known marker of cellular senescence. A higher influx of F4/80(+) macrophages and CD4(+) T lymphocytes is measured and is accompanied by increases in mRNA of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α). Importantly, microvascular density is significantly less, correlating with an increase in nitro-tyrosine, a marker of oxidative stress. Collectively, these data demonstrate that prolonged acute injury in the aged animals results in an accelerated progression of kidney disease in a chronic state. 23929459 Local Perceptions of Changes in Traditional Ecological Knowledge: A Case Study from Malekula Island, Vanuatu. Traditional ecological knowledge (TEK) is a critical global resource that may be eroding amid social and environmental change. Here, we present data on local perceptions of TEK change from three communities on Malekula Island in Vanuatu. Utilizing a structured interview (n = 120), we find a common perception of TEK loss. Participants defined two key periods of TEK erosion (roughly 1940-1960 and 1980-present), and noted that TEK decline was driven both external (e.g., church) and internal (e.g., shifting values) processes. Erosion was perceived to more comprehensive in the worldview domain than in aspects of ethnobiological knowledge and practice. These data indicate the perceived fragility of TEK systems and the complexity of TEK change. TEK systems are critical to natural resource management, and data such as these will assist in designing nuanced responses to the ongoing loss of cultural knowledge and practice. 23825210 Phylogenetic correlates of extinction risk in mammals: species in older lineages are not at greater risk. Phylogenetic information is becoming a recognized basis for evaluating conservation priorities, but associations between extinction risk and properties of a phylogeny such as diversification rates and phylogenetic lineage ages remain unclear. Limited taxon-specific analyses suggest that species in older lineages are at greater risk. We calculate quantitative properties of the mammalian phylogeny and model extinction risk as an ordinal index based on International Union for Conservation of Nature Red List categories. We test for associations between lineage age, clade size, evolutionary distinctiveness and extinction risk for 3308 species of terrestrial mammals. We show no significant global or regional associations, and three significant relationships within taxonomic groups. Extinction risk increases for evolutionarily distinctive primates and decreases with lineage age when lemurs are excluded. Lagomorph species (rabbits, hares and pikas) that have more close relatives are less threatened. We examine the relationship between net diversification rates and extinction risk for 173 genera and find no pattern. We conclude that despite being under-represented in the frequency distribution of lineage ages, species in older, slower evolving and distinct lineages are not more threatened or extinction-prone. Their extinction, however, would represent a disproportionate loss of unique evolutionary history. 23906084 Resistance to the Weevils Cylas puncticollis and Cylas brunneus Conferred by Sweetpotato Root Surface Compounds. Seven resistant varieties of sweetpotato were compared with three susceptible varieties in field trials and laboratory bioassays and showed that resistance was an active process rather than an escape mechanism, as field resistant varieties also had reduced root damage and oviposition compared with susceptible varieties in the laboratory. Liquid chromatography-mass spectrometry (LC-MS) of root surface and epidermal extracts showed significant variation in the concentration of hexadecyl, heptadecyl, octadecyl, and quinic acid esters of caffeic and coumaric acid, with higher concentrations correlated with resistance. All compounds were synthesized to enable their positive identification. Octadecyl coumarate and octadecyl caffeate applied to the surface of susceptible varieties in laboratory bioassays reduced feeding and oviposition, as observed on roots of resistant varieties, and therefore are implicated in weevil resistance. Segregating populations from breeding programs can use these compounds to identify trait loci for resistance and enable the development of resistant varieties. 23688256 Phosphoproteomic analysis of differentiating Leishmania parasites reveals a unique stage-specific phosphorylation motif. Protists of the genus Leishmania are obligatory intracellular parasites that cause a wide range of cutaneous, mucocutaneous, and visceral diseases in humans. They cycle between phagolysosomes of mammalian macrophages and the sand fly midgut, proliferating as intracellular amastigotes and extracellular promastigotes, respectively. Exposure to a lysosomal environment, i.e. acidic pH and body temperature, signals promastigotes to differentiate into amastigotes. Time course analyses indicated that Leishmania differentiation is a highly regulated and coordinated process. However, the role of posttranslational events such as protein phosphorylation in this process is still unknown. Herein, we analyzed and compared the phosphoproteomes of L. donovani amastigotes and promastigotes using an axenic host-free system that simulates parasite differentiation. Shotgun phosphopeptide analysis revealed 1614 phosphorylation residues (p-sites) corresponding to 627 proteins. The analysis indicated that the majority of the p-sites are stage-specific. Serine phosphorylation in a previously identified trypanosomatid-specific "SF" motif was significantly enriched in amastigotes. We identified a few phosophotyrosines (pY), mostly in proteins known to participate in signal transduction pathways. The analysis indicated that Leishmania contains proteins with multiple p-sites that are phosphorylated at distinct stages of the life cycle. For over half of the phosphorylation events, changes in phosphoprotein abundance did not positively correlate with changes in protein abundance, suggesting functional regulation. This study compares, for the first time, the phosphoproteins of L. donovani axenic promastigotes and amastigotes and provides the largest data set of the Leishmania phosphoproteome to date. 23291401 Chlamydophila pneumoniae endonuclease IV prefers to remove mismatched 3' ribonucleotides: implication in proofreading mismatched 3'-terminal nucleotides in short-patch repair synthesis. DNA polymerase I (DNApolI) catalyzes DNA synthesis during Okazaki fragment maturation, base excision repair, and nucleotide excision repair. Some bacterial DNApolIs are deficient in 3'-5' exonuclease, which is required for removing an incorrectly incorporated 3'-terminal nucleotide during DNA elongation by DNA polymerase activity. The key amino acid residues in the exonuclease center of Chlamydophila pneumoniae DNApolI (CpDNApolI) are naturally mutated, resulting in the loss of 3'-5' exonuclease. Hence, the manner by which CpDNApolI proofreads the incorrectly incorporated nucleotide during DNA synthesis warrants clarification. C. pneumoniae encodes three 3'-5' exonuclease activities: one endonuclease IV and two homologs of the epsilon subunit of replicative DNA polymerase III. The three proteins were biochemically characterized using single- and double-stranded DNA substrate. Among them, C. pneumoniae endonuclease IV (CpendoIV) possesses 3'-5' exonuclease activity that prefers to remove mismatched 3'-terminal nucleotides in the nick, gap, and 3' recess of a double-stranded DNA (dsDNA). Finally, we reconstituted the proofreading reaction of the mismatched 3'-terminal nucleotide using the dsDNA with a nick or 3' recess as substrate. Upon proofreading of the mismatched 3'-terminal nucleotide by CpendoIV, CpDNApolI can correctly reincorporate the matched nucleotide and the nick is further sealed by DNA ligase. Based on our biochemical results, we proposed that CpendoIV was responsible for proofreading the replication errors of CpDNApolI. 23829704 Construction of Vicinal Tertiary and All-Carbon Quaternary Stereocenters via Ir-Catalyzed Regio-, Diastereo-, and Enantioselective Allylic Alkylation and Applications in Sequential Pd Catalysis. Highly congested vicinal stereocenters comprised of tertiary and all-carbon quaternary centers were generated via Ir-catalyzed asymmetric allylic alkylation of β-ketoesters. These catalytic reactions proceed in excellent yields with a broad scope on either reaction partner and with outstanding regio-, diastereo-, and enantiocontrol. Implementation of a subsequent Pd-catalyzed alkylation affords dialkylated products with pinpoint stereochemical control of both chiral centers. 23933849 Risk of syncope during work. Little is known regarding the overall prevalence of syncope in a population of workers and the risk of occurrence during working time.METHODS AND RESULTS: A total of 452 consecutive workers (mean age: 46 ± 9 years) were invited to answer an anonymous questionnaire. They had been employed for 22 ± 10 years for a total of 9765 years worked. In the cohort, 160 subjects (35%) reported a total of 465 episodes of syncope during their lives; 64 (14%) suffered a syncopal episode after the start of employment, but only 26 (5.7%) reported syncope at work, 7 (1.5%) having had 2 episodes, and 1 (0.2%) 3 episodes (total: 36 episodes). The risk of syncope during work was 4.6 times higher for those who had a prior history of syncope [18 of 138 (13%)] than for those who did not [8 of 314 (3%), P = 0.001]. The occurrence of syncope during work for the patients with a history of syncope was one syncopal episode in every 99 years worked and for those who had already had an episode during work, one episode in every 16 years worked. Only one patient experienced minor trauma as a consequence of syncope during work and three were referred to the emergency department. All patients continued their employment without any problems.CONCLUSION: The prevalence of syncope during work is low and its impact is benign. The probability of syncope during work is higher for subjects with a history of syncope. 23123251 Organophosphorus compound esterase profiles as predictors of therapeutic and toxic effects. Certain organophosphorus compounds (OPCs) inhibit various serine esterases (EOHs) via phosphorylation of their active site serines. We focused on 4 EOHs of particular toxicological interest: acetylcholinesterase (AChE: acute neurotoxicity; cognition enhancement), butyrylcholinesterase (BChE: inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors; cognition enhancement), carboxylesterase (CaE: inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors), and neuropathy target esterase (NTE: delayed neurotoxicity, OPIDN). The relative degree of inhibition of these EOHs constitutes the "esterase profile" of an OPC and serves as a major determinant of its net physiological effects. Thus, understanding and controlling the esterase profile of OPC activity and selectivity toward these 4 target enzymes is a significant undertaking. In the present study, we analyzed the inhibitor properties of 52 OPCs against the 4 EOHs, along with pairwise and multitarget selectivities between them, using 2 QSAR approaches: Hansch modeling and Molecular Field Topology Analysis (MFTA). The general formula of the OPCs was (RO)2P(O)X, where R=alkyl, X=- SCH(Hal)COOEt (Hal=Cl, Br), -SCHCl2, -SCH2Br, -OCH(CF3)R(1) (R(1)=C6H5, CF3, COOEt, COOMe). The Hansch model showed that increasing neuropathic potential correlated with rising R hydrophobicity; moreover, OPC binding to scavenger EOHs (BChE and CaE) had different effects on potential acute and delayed neurotoxicity. Predicted protective roles of BChE and CaE against acute toxicity were enhanced with increasing hydrophobicity, but projected protection against OPIDN was decreased. Next, Molecular Field Topology Analysis (MFTA) models were built, considering atomic descriptors, e.g., effective charge, van der Waals radius of environment, and group lipophilicity. Activity/selectivity maps confirmed predictions from Hansch models and revealed other structural factors affecting activity and selectivity. Virtual screening based on multitarget selectivity MFTA models was used to design libraries of OPCs with favorable esterase profiles for potential application as selective inhibitors of CaE without untoward side effects. 23896708 Ovarian Pulmonary-type Small Cell Carcinoma: Case Report and Review of the Literature. Ovarian pulmonary-type small cell carcinoma is a rare and extremely aggressive neoplasm. We report the occurrence of an ovarian small cell carcinoma of pulmonary type in a 54-year-old woman. She underwent a total abdominal hysterectomy with a bilateral salpingo-oophorectomy and infracolic omentectomy. A diagnosis of stage IIIA pulmonary-type small cell carcinoma was rendered. The tumor appeared to be composed of a solid growth of small cells arranged in sheets and closely packed nests with insular arrangements separated by a fibrous stroma. The tumor cells had hyperchromatic nuclei with inconspicuous nucleoli and scanty cytoplasm. Rosette and rosette-like structures were scattered. Immunohistochemical staining showed positivity for synaptophysin, neural cell adhesion molecule (NCAM), and focally for chromogranin. Cytokeratin and neuron-specific enolase (NSE) were also positive. Over 80% of the tumor cells showed strong reactivity for MIB-1. Electron microscopy showed neuroendocrine granules. She was effectively treated with paclitaxel plus carboplatin after the surgery. 23411226 Antioxidant activity and nutritional quality of traditional red-grained rice varieties containing proanthocyanidins. Proanthocyanidin-containing rice varieties have been rarely reported. Antioxidant capacity, major antioxidant components, and nutritional parameters of eight traditional red-grained rice varieties containing proanthocyanidins grown in Sri Lanka were investigated. The tested traditional red varieties, on the average, had over sevenfold higher both total antioxidant capacity and phenolic content than three light brown-grained new-improved rice varieties. Major antioxidant phenolic compounds identified in this study included proanthocyanidins, phenolic acids and γ-oryzanols (ferulic acid derivatives). Proanthocyanidins were detected only in the traditional red varieties, but not found in new-improved ones. Most traditional red varieties also contained significantly higher levels of protein with well balanced amino acids and higher contents of fat, fibre and vitamin E (tocopherols and tocotrienols) than the new-improved ones. Great variations in antioxidant capacity, major phenolics, and nutritional parameters were observed among different rice varieties. These Sri Lankan traditional red-grained rice varieties containing proanthocyanidins may be used as important genetic sources for rice breeding. 23850214 Altering protein conformation to improve fermentative hydrogen production from protein wastewater. One important reason for low hydrogen production from protein wastewater is due to the native folded conformation of protein. In this study the enhancement of bio-hydrogen production from protein wastewater by altering protein conformation via pretreatment was reported. Firstly, the effect of different pretreatment methods (acid, alkali, heat, and ultraviolet) on hydrogen production from synthetic protein wastewater was compared. The hydrogen production from the ultraviolet pretreated wastewater was 111.3 mL/g-protein, which was 3.79-, 3.73-, 3.54-, and 1.36-fold of that from the unpretreated (blank), acid, alkali, and heat pretreated wastewater, respectively. Then, the reasons for ultraviolet pretreatment showing significantly higher hydrogen production than other pretreatments were investigated. It was found that all pretreatments did not cause the cleavage of peptide bond, but the ultraviolet one caused much greater damage of hydrogen bonding networks and unfolding of protein. Thus, during anaerobic fermentation much higher protease activity and protein utilization were observed, which resulted in the bio-hydrogen production being remarkably improved. Further studies indicated that the photo-oxidization of aromatic residues in protein was not the reason for ultraviolet pretreatment remarkably improving bio-hydrogen production. Finally, the application of ultraviolet pretreatment to enhance hydrogen production from real protein wastewater was testified. 23067727 Reduced thickness of anterior cingulate cortex in obsessive-compulsive disorder. Obsessive-compulsive disorder (OCD) is characterized by a pattern of repetitive, intrusive thoughts and behaviours that patients do not want to but feel they have to perform. Functional brain imaging revealed dysfunctional pathways in OCD involving the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and basal ganglia. Structural alterations in OCD have been discussed but analysis tools focussing on specific morphometric aspects such as cortical thickness have rarely been employed. We acquired MRI scans from 101 OCD patients and 95 healthy control subjects. FreeSurfer analysis software was employed to model the individual grey-white and pial surfaces to compute cortical thickness as our target measure. Relative to controls, OCD patients demonstrate cortical thinning in dorsal and subgenual ACC (false discovery rate corrected at p < .001), as well as in several other regions within the fronto-parietal network (false discovery rate corrected at p < .05). Cortical thickness could not be predicted in whole brain analyses from symptom state, but there was a modest correlation of left dorsal ACC thickness with the obsession subscore of the Yale-Brown Obsessive-Compulsive Scale as well as with the Beck Depression Inventory score. The findings confirm and extend previous reports showing that OCD is associated with morphometric alterations. The location of the most robust cortical thinning in ACC regions matches the previously reported topography of functional alterations at resting state and during cognitive task execution. 23707766 Early treatment of chlorine-induced airway hyperresponsiveness and inflammation with corticosteroids. Chlorine (Cl2) is an industrial gas that is highly toxic and irritating when inhaled causing tissue damage and an acute inflammatory response in the airways followed by a long-term airway dysfunction. The aim of this study was to evaluate whether early anti-inflammatory treatment can protect against the delayed symptoms in Cl2-exposed mice. BALB/c mice were exposed by nose-only inhalation using 200ppm Cl2 during 15min. Assessment of airway hyperresponsiveness (AHR), inflammatory cell counts in bronchoalveolar lavage, occurrence of lung edema and lung fibrosis were analyzed 24h or 14days post-exposure. A single dose of the corticosteroid dexamethasone (10 or 100mg/kg) was administered intraperitoneally 1, 3, 6, or 12h following Cl2 exposure. High-dose of dexamethasone reduced the acute inflammation if administered within 6h after exposure but treated animals still displayed a significant lung injury. The effect of dexamethasone administered within 1h was dose-dependent; high-dose significantly reduced acute airway inflammation (100mg/kg) but not treatment with the relatively low-dose (10mg/kg). Both doses reduced AHR 14days later, while lung fibrosis measured as collagen deposition was not significantly reduced. The results point out that the acute inflammation in the lungs due to Cl2 exposure only partly is associated with the long-term AHR. We hypothesize that additional pathogenic mechanisms apart from the inflammatory reactions contribute to the development of long-term airway dysfunction. By using this mouse model, we have validated early administration of corticosteroids in terms of efficacy to prevent acute lung injury and delayed symptoms induced by Cl2 exposure. 23611029 An immunological basis for chronic histiocytic intervillositis in recurrent fetal loss. Chronic histiocytic intervillositis (CHIV) is a rare type of placental pathology that is associated with reproductive loss at all gestational ages. The aim of the study was to investigate the relationship between the severity of CHIV and the outcome of pregnancy and to compare the immune response between CHIV patients and controls to explore an immunological origin of CHIV. Microscopic slides were reviewed and scored according to a previously published grading system in 30 pregnancies of 22 CHIV patients. Partner-specific mixed lymphocyte reactions, cytotoxic T-lymphocyte precursor frequencies (CTLpf), and anti-HLA antibodies were determined in four patients and seven controls. Higher CHIV scores are associated with worse pregnancy outcome. CHIV patients demonstrated a higher CTLpf against their partner compared to non-complicated pregnancies (P = 0.03). The CTLpf was extremely high in 75% of the patients. Antipaternal HLA antibodies were only present in 75% of the CHIV patients compared to none of the controls (P = 0.02). CHIV scores seem to be associated with the severity of adverse pregnancy outcome. High antipaternal cellular (T-cell) and humoral (B-cell) response to partner-specific CTLpf and the presence of anti-HLA antibodies directed to the partner suggest an immunologic origin of CHIV. 23461712 Anatomic fitting of total artificial hearts for in vivo evaluation. Successful anatomic fitting of a total artificial heart (TAH) is vital to achieve optimal pump hemodynamics after device implantation. Although many anatomic fitting studies have been completed in humans prior to clinical trials, few reports exist that detail the experience in animals for in vivo device evaluation. Optimal hemodynamics are crucial throughout the in vivo phase to direct design iterations and ultimately validate device performance prior to pivotal human trials. In vivo evaluation in a sheep model allows a realistically sized representation of a smaller patient, for which smaller third-generation TAHs have the potential to treat. Our study aimed to assess the anatomic fit of a single device rotary TAH in sheep prior to animal trials and to use the data to develop a three-dimensional, computer-aided design (CAD)-operated anatomic fitting tool for future TAH development. Following excision of the native ventricles above the atrio-ventricular groove, a prototype TAH was inserted within the chest cavity of six sheep (28-40 kg). Adjustable rods representing inlet and outlet conduits were oriented toward the center of each atrial chamber and the great vessels, with conduit lengths and angles recorded for future analysis. A three-dimensional, CAD-operated anatomic fitting tool was then developed, based on the results of this study, and used to determine the inflow and outflow conduit orientation of the TAH. The mean diameters of the sheep left atrium, right atrium, aorta, and pulmonary artery were 39, 33, 12, and 11 mm, respectively. The center-to-center distance and outer-edge-to-outer-edge distance between the atria, found to be 39 ± 9 mm and 72 ± 17 mm in this study, were identified as the most critical geometries for successful TAH connection. This geometric constraint restricts the maximum separation allowable between left and right inlet ports of a TAH to ensure successful alignment within the available atrial circumference. 23896354 Neuropsychological functioning in posttraumatic stress disorder following forced displacement in older adults and their offspring. The aim of the present study was to investigate neuropsychological performance in an untried trauma sample of older adults displaced during childhood at the end of World War II (WWII) with and without posttraumatic stress disorder (PTSD) as well as transgenerational effects of trauma and PTSD on their offspring. Displaced older adults with (n=20) and without PTSD (n=24) and nondisplaced healthy individuals (n=11) as well as one of their respective offspring were assessed with a large battery of cognitive tests (primarily targeting memory functioning). No evidence for deficits in neuropsychological performance was found in the aging group of displaced people with PTSD. Moreover, no group difference emerged in the offspring groups. Findings may be interpreted as first evidence for a rather resilient PTSD group of older adults that is available for assessment 60 years after displacement. 23821701 Inpatient characteristics of the child admitted with chronic pain. To define the demographic, diagnostic, procedural, and episode of care characteristics for children admitted with chronic pain. We used the Pediatric Health Information System database to obtain data on demographic characteristics, length of stay, readmission rates, diagnoses, and procedures for children admitted with chronic pain. Patients with sickle cell disease, cancer, burns, cerebral palsy, transplants, and ventilator-dependent children were excluded. A total of 3752 patients with chronic pain were identified from 2004 through 2010. Admissions increased by 831% over this time period. The mean age of these patients was 13.5 years, the most common race was white (79%), and female subjects outnumbered male subjects by 2.41 to 1. The most common admission and principal discharge diagnosis was abdominal pain; comorbid diagnoses were common, with a mean of 10 diagnoses per patient. In total, 65% of patients had a comorbid gastrointestinal diagnosis and 44% had a psychiatric diagnosis. The mean length of stay was 7.32 days, with an expected length of stay of 4.24 days; 12.5% were readmitted at least once within 1 year. They underwent a mean of 3.18 procedures per patient. The average child admitted with chronic pain is a teenaged female with a wide variety of comorbid conditions, many of which are gastrointestinal and psychiatric in nature. Admissions for chronic pain are rising and account for substantial resource utilization. Future studies should further characterize this population, with the overall objective of improving outcomes and optimizing cost-effective care. 23867060 Vaccination of ferrets with a recombinant G glycoprotein subunit vaccine provides protection against Nipah virus disease for over 12 months. Nipah virus (NiV) is a zoonotic virus belonging to the henipavirus genus in the family Paramyxoviridae. Since NiV was first identified in 1999, outbreaks have continued to occur in humans in Bangladesh and India on an almost annual basis with case fatality rates reported between 40% and 100%. Ferrets were vaccinated with 4, 20 or 100 μg HeVsG formulated with the human use approved adjuvant, CpG, in a prime-boost regime. One half of the ferrets were exposed to NiV at 20 days post boost vaccination and the other at 434 days post vaccination. The presence of virus or viral genome was assessed in ferret fluids and tissues using real-time PCR, virus isolation, histopathology, and immunohistochemistry; serology was also carried out. Non-immunised ferrets were also exposed to virus to confirm the pathogenicity of the inoculum. Ferrets exposed to Nipah virus 20 days post vaccination remained clinically healthy. Virus or viral genome was not detected in any tissues or fluids of the vaccinated ferrets; lesions and antigen were not identified on immunohistological examination of tissues; and there was no increase in antibody titre during the observation period, consistent with failure of virus replication. Of the ferrets challenged 434 days post vaccination, all five remained well throughout the study period; viral genome - but not virus - was recovered from nasal secretions of one ferret given 20 μg HeVsG and bronchial lymph nodes of the other. There was no increase in antibody titre during the observation period, consistent with lack of stimulation of a humoral memory response. We have previously shown that ferrets vaccinated with 4, 20 or 100 μg HeVsG formulated with CpG adjuvant, which is currently in several human clinical trials, were protected from HeV disease. Here we show, under similar conditions of use, that the vaccine also provides protection against NiV-induced disease. Such protection persists for at least 12 months post-vaccination, with data supporting only localised and self-limiting virus replication in 2 of 5 animals. These results augur well for acceptability of the vaccine to industry. 23192664 Merkel cell carcinoma: a systematic review of ENT presentations. The aim of this study was to perform a systematic literature review of Merkel cell carcinomas (MCCs) originating exclusively in the ear, nose and throat (ENT) district. An appropriate string was run on PubMed to retrieve articles dealing with ENT presentations of MCC. A double cross-check was performed on citations and full-text articles found using the selected inclusion and exclusion criteria. In total, 43 articles were finally included in the study, describing 51 cases of MCC involving the ENT region: 22/51 (43%) cases involving the ear; 20/51 (39%) cases involving the mucosal sites; 9/51 (18%) cases involving other ENT regions. Patients with mucosal site involvement showed a higher mortality rate from the disease (45%) in comparison with the other two groups, especially when compared with those patients having primary involvement of the ear (22%). The ENT specialist should suspect and consider MCC, especially in elderly patients presenting with a suspicious lesion of the auricular pavilion, so as to avoid misdiagnosis and delayed treatments. 23647887 Improving meat cutters' work: Changes and effects following an intervention. Meat cutters face higher risks of injury and musculoskeletal problems than most other occupational groups. The aims of this paper were to describe ergonomics changes implemented in three meat cutting plants and to evaluate effects related to ergonomics on the individual meat cutters and their work. Data was collected by interviews, observations, document studies and a questionnaire (n = 247), as a post intervention study. The changes implemented consisted of reducing knife work to a maximum of 6 h per day and introducing a job rotation scheme with work periods of equal length. Tasks other than traditional meat cutting were added. A competence development plan for each meat cutter and easy adjustment of workplace height were introduced. The questionnaire showed a reduction in perceived physical work load. In general, the changes were perceived positively. Figures from the company showed a positive trend for injuries and sick leave. 23707171 Roadmap for the international collaborative epidemiologic monitoring of safety and effectiveness of new high priority vaccines. With the advent of new vaccines targeted to highly endemic diseases in low- and middle-income countries (LMIC) and with the expansion of vaccine manufacturing globally, there is an urgent need to establish an infrastructure to evaluate the benefit-risk profiles of vaccines in LMIC. Fortunately the usual decade(s)-long time gap between introduction of new vaccines in high and low income countries is being significantly reduced or eliminated due to initiatives such as the Global Alliance for Vaccines and Immunizations (GAVI) and the Decade of Vaccines for the implementation of the Global Vaccine Action Plan. While hoping for more rapid disease control, this time shift may potentially add risk, unless appropriate capacity for reliable and timely evaluation of vaccine benefit-risk profiles in some LMIC's are developed with external assistance from regional or global level. An ideal vaccine safety and effectiveness monitoring system should be flexible and sustainable, able to quickly detect possible vaccine-associated events, distinguish them from programmatic errors, reliably and quickly evaluate the suspected event and its association with vaccination and, if associated, determine the benefit-risk of vaccines to inform appropriate action. Based upon the demonstrated feasibility of active surveillance in LMIC as shown by the Burkina Faso assessment of meningococcal A conjugate vaccine or that of rotavirus vaccine in Mexico and Brazil, and upon the proof of concept international GBS study, we suggest a sustainable, flexible, affordable and timely international collaborative vaccine safety monitoring approach for vaccines being newly introduced. While this paper discusses only the vaccine component, the same system could also be eventually used for monitoring drug effectiveness (including the use of substandard drugs) and drug safety. 23840022 Insufficient autoantigen presentation and failure of tolerance in a mouse model of rheumatoid arthritis. Objective. In the K/BxN mouse model of rheumatoid arthritis, T cells reactive for the self-antigen glucose-6-phosphate isomerase (GPI) escape negative selection even though GPI expression is ubiquitous. We sought to determine whether insufficient GPI presentation could account for the failure of negative selection and development of arthritis. Methods. To increase the antigen presentation of GPI, we generated transgenic mice expressing a membrane-bound form of GPI (mGPI) and crossed them to the K/BxN mice. A monoclonal antibody specific for the alpha chain of the KRN TCR was generated to follow the fate of GPI-specific T cells. Results. mGPI transgenic mice presented GPI more efficiently and showed a dramatic increase of negative selection and an inhibition of arthritis. Interestingly, thymic negative selection remained incomplete in these mice, and the escaped autoreactive T cells were anergic in the periphery, suggesting that enhanced antigen presentation also induces peripheral tolerance. Despite this apparent tolerance induction towards GPI, these mice did go on to develop a chronic wasting disease, characterized by colonic inflammation with epithelial dysplasia, as well as a dramatic reduction in Treg cells. Conclusion. These data indicate that insufficient autoantigen expression or presentation results in defects of both central and peripheral tolerance in the K/BxN mice. It supports the idea that insufficient autoantigen levels may underlie the development of autoimmunity. © 2013 American College of Rheumatology. 23937441 Effect of the glycemic index of pre-exercise snack bars on substrate utilization during subsequent exercise. Abstract Purpose: To investigate the effect of the glycemic index (GI) of pre-exercise snack bars on substrate utilization during subsequent moderate intensity exercise. Methods: Fourteen male participants (Age: 27 ± 5 yr; BMI: 22.5 ± 2.7 kg m(-2); [Formula: see text]: 48.7 ± 6.1 mL kg(-1 )min(-1)) completed two trials in a randomized and counterbalanced crossover design. Two iso-caloric snack bars with different GI values (20, LGI versus 68, HGI) were provided to the participants. Ninety minutes later, all participants completed 45 minutes of ergometer cycling at 65% [Formula: see text]. Substrate utilization was measured using indirect calorimetry. Results: During exercise, higher fat oxidation and lower carbohydrate (CHO) oxidation were observed in the LGI trial (LGI versus HGI: CHO, 87.3 ± 20.1 versus 99.2 ± 19.0 g, p < 0.05; Fat, 15.0 ± 5.8 versus 9.7 ± 7.0 g, p < 0.05). Conclusion: Compared with an iso-caloric HGI snack bar, pre-exercise LGI snack bar consumption may facilitate a shift of substrate utilization from CHO to fat during subsequent moderate intensity exercise. 23523317 Comprehensive study of ovarian metastases in young women with peritoneal pseudomyxoma: is a preservation of fertility possible? To determine whether ovaries can be preserved in selected young women with peritoneal pseudomyxoma (PMP). The traditional rule is to systematically perform a bilateral oophorectomy. A new policy was developed to preserve the ovaries when they are macroscopically normal in young women with PMP, strongly desiring a future pregnancy. Thirty-three women younger than 41 years were selected after undergoing complete cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for PMP. A normal ovary was preserved in 6 of them, but in 6 of the 14 women who strongly desired a future pregnancy. Subsequently, ovarian preservation was only performed in cases of grade-1 PMP. Ovarian invasion was correlated with the grade (p < 0.05) and with the extent of peritoneal disease (p < 0.01). After a median follow-up of 54 months, none of the 6 women with preserved ovaries has developed an ovarian or a peritoneal recurrence. One woman became pregnant and egg harvesting and cryopreservation were performed for 4 women with a partially normal ovary. This new policy allowed ovarian preservation in 43% of the young women desiring a future pregnancy and has already resulted in one birth. It exclusively concerned low-grade PMP. Recurrence in the preserved ovary was 0% with our selection criteria. 23874573 Personality and dietary intake - findings in the helsinki birth cohort study. Personality traits are associated with health outcomes including non-communicable diseases. This could be partly explained by lifestyle related factors including diet. The personality traits neuroticism, extraversion, openness, agreeableness, and conscientiousness are linked with resilience, meaning adaptability in challenging situations. Resilient people usually comply with favorable health behaviors. Our objective was to explore the associations between food and nutrient intake, personality traits and resilience. A validated semi-quantitative food frequency questionnaire was used to measure diet and the NEO-personality inventory to assess personality in 1681 subjects. Linear regression analysis was used to explore diet-personality associations and cluster analysis to define resilient and non-resilient personality profiles. Adjusting for age, education and energy intake, and applying Bonferroni corrections, openness in men was associated with higher vegetable (14.9 g/d for 1 SD increase in the personality score, PBonf <0.01) and lower confectionery and chocolate (-2.8 g/d, PBonf <0.01) intakes. In women, neuroticism was associated with lower fish (-4.9 g/d, PBonf <0.001) and vegetable (-18.9 g/d, PBonf <0.01) and higher soft drink (19.9 g/d, PBonf <0.001) intakes. Extraversion, in women, associated with higher meat (5.9 g/d, PBonf <0.05) and vegetable (24.8 g/d, PBonf <0.001) intakes, openness with higher vegetable (23.4 g/d, PBonf <0.001) and fruit (29.5 g/d, PBonf <0.01) intakes. Agreeableness was associated with a lower soft drink (-16.2 g/d, PBonf <0.01) and conscientiousness with a higher fruit (32.9 g/d, PBonf<0.01) intake in women. Comparing resilient and non-resilient subjects, we found resilience in women to be associated with higher intakes of vegetables (52.0 g/d, P<0.001), fruits (58.3 g/d, P<0.01), fish (8.6 g/d, P<0.01) and dietary fiber (1.6 g/d, P<0.01). Personality traits are associated with dietary intake and especially subjects with resilient personality profiles had healthier dietary intakes. These associations were stronger in women than in men. 23487534 Heterotopic heart transplantation: where do we stand? Orthotopic heart transplantation (OHT) is a well established and commonly utilized procedure for end-stage heart failure patients. Heterotopic heart transplantation (HHT) is a surgical procedure that allows the graft to be connected to the native heart in a parallel fashion. The main advantage of HHT is to assist the patient's native heart and to maintain circulation in the cases of severe acute rejection. HHT has also been proposed to overcome pulmonary hypertension, to increase the size of the donor pool and to decrease waiting times without increasing morbidity caused by the procedure. However, only a few papers have reported the short- or long-term results of HHT, and most of these studies have included <30 cases. OHT remains the standard technique and is preferable whenever the patient meets the current criteria and a suitable organ is available. HHT is far less useful than in the past because of the major advances in immunosuppression therapy and the development of long-term mechanical circulatory support. This study reviews the origin of HHT and discusses clinical developments, including their advantages and disadvantages. 23740718 Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug-like compounds. Spinal muscular atrophy (SMA) is a neurodegenerative disease that causes progressive muscle weakness, which primarily targets proximal muscles. About 95% of SMA cases are caused by the loss of both copies of the SMN1 gene. SMN2 is a nearly identical copy of SMN1, which expresses much less functional SMN protein. SMN2 is unable to fully compensate for the loss of SMN1 in motor neurons but does provide an excellent target for therapeutic intervention. Increased expression of functional full-length SMN protein from the endogenous SMN2 gene should lessen disease severity. We have developed and implemented a new high-throughput screening assay to identify small molecules that increase the expression of full-length SMN from a SMN2 reporter gene. Here, we characterize two novel compounds that increased SMN protein levels in both reporter cells and SMA fibroblasts and show that one increases lifespan, motor function, and SMN protein levels in a severe mouse model of SMA. 23817334 Severity of Diarrhea and Malnutrition among Under Five-Year-Old Children in Rural Bangladesh. Abstract. Enteric pathogens are commonly associated with diarrhea among malnourished children. This study aimed to determine the association between the severity of diarrheal illnesses and malnutrition among under 5-year-old children. During 2010 and 2011, we studied 2,324 under 5-year-old diarrheal children with mild disease (MD) and moderate-to-severe disease (MSD) attending a hospital in Bangladesh. Children with MSD were more likely to be malnourished compared with children with MD (35% versus 24%, P < 0.001). In multivariate analysis, malnutrition (odds ratio [95% confidence interval] = 1.53 [1.22, 1.92]), age of the child (24-59 months; 1.67 [1.28, 2.19]), fever (1.65 [1.28, 2.12]), abdominal pain (1.87 [1.48, 2.37]), straining (5.93 [4.80, 7.33]), and infection with Shigella (3.26 [2.38, 4.46]) and Vibrio cholerae (2.21 [1.07, 4.58]) were shown to be significantly associated with MSD. Factors significantly associated with malnutrition were disease severity (1.56 [1.24, 1.95]), age (24-59 months; 1.75 [1.38, 2.22]), mother's schooling (1.54 [1.16, 2.04]), and monthly household income (1.71 [1.42, 2.07]). Childhood malnutrition was associated with dysentery and dehydrating diarrhea. 23583883 Motor neuron dysfunction in a mouse model of ALS: Gender-dependent effect of P2X7 antagonism. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative progressive currently untreatable disease, characterized by selective motor neuron degeneration; the incidence and prevalence of ALS are greater in men than in women. Although some important mechanisms that might contribute to the death of motor neurons have been identified, the mechanisms underlying disease pathophysiology are still uncertain. In particular, the mechanisms underlying the role of gender in ALS and whether treatments should take into account sexual dimorphism remain only partially understood. Recently, the P2X7 receptor for ATP was reported to display neurotoxic potential in motor neuron disorders, and antagonism of the receptor has been suggested to be helpful in these disorders. Studying transgenic mice with superoxide dismutase 1 gene mutations, widely used as model for ALS, may provide a better understanding of pathogenic mechanisms and of toxicity towards motor neurons, also possibly helping to understand whether treatments for ALS should take into account sexual dimorphism. The aim of the work was (1) investigating on gender-dependence of disease progression in the standard model for ALS - the transgenic mouse bearing superoxide dismutase 1 gene mutations - and (2) assessing if a P2X7 receptor antagonist treatment should take into account sexual dimorphism. We evaluated if gender affect the disease course, the motor performance, the weight loss and the lifespan in mice overexpressing mutant superoxide dismutase 1. We measured motor impairment, motor strength and coordination by rotarod and grip strength testing. Further, we assessed if a treatment with the P2X7 receptor antagonist Brilliant Blue G - a dye that can cross the blood-brain barrier, has low toxicity, and has exhibited therapeutic effects in animal models of neurodegenerative diseases - impact on the disease progression, in male and female ALS mice. We found that (1) the onset and the disease progression, and the survival were dependent on gender: male performed worst than female, lost body weight and died before; (2) treatment with the P2X7 receptor antagonist Brilliant Blue G ameliorated the disease progression. The treatment effect was gender-dependent: amelioration was greater in male than in female. In conclusions, we suggest that not only pathogenetic mechanism of motor neuron toxicity but also the drug treatment effectiveness may depend on gender; sexual dimorphism should be considered when investigating on ALS treatment efficacy in the ALS animal model. Our findings also point on the potential relevance of P2X7 receptor antagonism for ALS treatment, and highlight the importance of adopting a sex-specific approach to searching for treatment of ALS. 23955239 Foodborne illness incidence rates and food safety risks for populations of low socioeconomic status and minority race/ethnicity: a review of the literature. While foodborne illness is not traditionally tracked by race, ethnicity or income, analyses of reported cases have found increased rates of some foodborne illnesses among minority racial/ethnic populations. In some cases (Listeria, Yersinia) increased rates are due to unique food consumption patterns, in other cases (Salmonella, Shigella, Campylobacter) it is unclear why this health disparity exists. Research on safe food handling knowledge and behaviors among low income and minority consumers suggest that there may be a need to target safe food handling messages to these vulnerable populations. Another possibility is that these populations are receiving food that is less safe at the level of the retail outlet or foodservice facility. Research examining the quality and safety of food available at small markets in the food desert environment indicates that small corner markets face unique challenges which may affect the quality and potential safety of perishable food. Finally, a growing body of research has found that independent ethnic foodservice facilities may present increased risks for foodborne illness. This review of the literature will examine the current state of what is known about foodborne illness among, and food safety risks for, minority and low socioeconomic populations, with an emphasis on the United States and Europe. 23580374 Free radicals: free radical reactions in two dimensions: a case study on photochlorination of graphene (small 8/2013). Graphene is a 2D giant polycyclic aromatic molecule that provides opportunities for studying chemical reactions in two dimensions. H. Peng, Z. Liu, and co-workers have systematically investigated the influence of specific features of 2D molecules, such as their thickness, stacking order, single- and double-side upon graphene's radical reactivity by utilizing a free radical photochlorination as a probe. The result, described on page 1388, can contribute to a deeper understanding of dimensionality effects for the chemistry of 2D graphene. 23060531 A Randomized Comparison of Laparoscopic, Flexible Endoscopic, and Wired and Wireless Magnetic Cameras on Ex Vivo and In Vivo NOTES Surgical Performance. Background. The influence of endoscopic video camera (VC) image quality on surgical performance has not been studied. Flexible endoscopes are used as substitutes for laparoscopes in natural orifice translumenal endoscopic surgery (NOTES), but their optics are originally designed for intralumenal use. Manipulable wired or wireless independent VCs might offer advantages for NOTES but are still under development. Objective. To measure the optical characteristics of 4 VC systems and to compare their impact on the performance of surgical suturing tasks. Methods. VC systems included a laparoscope (Storz 10 mm), a flexible endoscope (Olympus GIF 160), and 2 prototype deployable cameras (magnetic anchoring and guidance system [MAGS] Camera and PillCam). In a randomized fashion, the 4 systems were evaluated regarding standardized optical characteristics and surgical manipulations of previously validated ex vivo (fundamentals of laparoscopic surgery model) and in vivo (live porcine Nissen model) tasks; objective metrics (time and errors/precision) and combined surgeon (n = 2) performance were recorded. Results. Subtle differences were detected for color tests, and field of view was variable (65°-115°). Suitable resolution was detected up to 10 cm for the laparoscope and MAGS camera but only at closer distances for the endoscope and PillCam. Compared with the laparoscope, surgical suturing performances were modestly lower for the MAGS camera and significantly lower for the endoscope (ex vivo) and PillCam (ex vivo and in vivo). Conclusions. This study documented distinct differences in VC systems that may be used for NOTES in terms of both optical characteristics and surgical performance. Additional work is warranted to optimize cameras for NOTES. Deployable systems may be especially well suited for this purpose. 23892354 Final height and insulin-like growth factor-I in adult survivors of Wilms tumour. OBJECTIVE ONE-SIDED NEPHRECTOMY IS FOLLOWED BY INCREASED LEVELS OF INSULIN-LIKE GROWTH FACTOR-I (IGF-I), ASSOCIATED WITH LINEAR GROWTH DURING CHILDHOOD. THE AIM WAS TO EVALUATE FINAL HEIGHT AND IGF-I LEVELS IN NEPHRECTOMIZED WILMS TUMOUR SURVIVORS AS COMPARED TO HEALTHY DUTCH REFERENCES AND SURVIVORS OF OTHER CANCER TYPES.DESIGN CROSS-SECTIONAL RETROSPECTIVE STUDY.METHODS DATA OF 575 ADULT CHILDHOOD CANCER SURVIVORS WAS ANALYZED. MEDIAN FOLLOW-UP TIME WAS 17.8 YEARS (RANGE 5.0-48.8). ANALYSIS OF (CO)VARIANCE WAS PERFORMED TO EVALUATE DIFFERENCES BETWEEN SUBGROUPS: nephrectomized Wilms survivors treated with or without abdominal irradiation (n=41 and n=36); survivors of other cancer types treated with or without irradiation involving the cranium, abdomen or total body (n=149 and n=349). Main outcome measures were IGF-I and height, expressed as standard deviation scores (SDS).Results After adjustment for age at diagnosis, former corticosteroid treatment and renal impairment, height SDS in non-irradiated nephrectomized Wilms survivors was significantly higher than height SDS in non-irradiated survivors of other cancer types (estimated mean SDS -0.09 versus -0.49, p=0.044), abdominal irradiated survivors (SDS -0.70, p=0.015) and other irradiated survivors (SDS -1.47, p<0.001). Non-irradiated nephrectomized Wilms tumour survivors had significantly higher IGF-I SDS than other irradiated survivors (estimated mean SDS -0.05 versus -1.36, p<0.001 and 0.11 versus 1.37 p<0.001), while there was no significant difference with the other two subgroupsConclusions Adult survivors of Wilms tumour showed better attainment of final height and relatively higher IGF-I levels than survivors of other cancer types who had significantly shorter stature and lower IGF-I levels than Dutch references. 23521216 Baeckein E, a new bioactive C-methylated biflavonoid from the roots of Baeckea frutescens. A phytochemical study of Baeckea frutescens afforded a new biflavonoid named as baeckein E (1), along with four known C-methylated flavonols, baeckeins A (2) and B (3), 6-methylquercetin (6) and 6-methylquercetin-4'-O-β-d-glucopyranoside (7), and two known biflavonoids baeckeins C (4) and D (5). The structure of compound 1 was elucidated on the basis of spectroscopic analysis, including HR-ESI-MS, 1D and 2D NMR spectra, and the absolute configurations of C-2 and C-3 for compound 1 were assigned by circular dichroism spectrometry combined with quantum chemical calculations. The antioxidant and cytoprotective activities of compounds 1-7 were also investigated. 23606504 3D Graphene Foams Cross-linked with Pre-encapsulated Fe3 O4 Nanospheres for Enhanced Lithium Storage. Electrostatic assembly between Fe3 O4 nanospheres and graphene oxide, and subsequent hydrothermal assembly with additional graphene sheets, leads to Fe3 O4 nanospheres encapsulated in the graphene shells and interconnected by the graphene networks. Such 3D Fe3 O4 /graphene foams exhibit enhanced lithium storage with excellent cycling performance and rate capability. 23839280 A surfactant-thermal method to prepare four new three-dimensional heterometal-organic frameworks. Here, we report on a surfactant-thermal method to prepare four new 3-D crystalline heterometal-organic frameworks (HMOFs). The results indicate that our new strategy for growing crystalline materials in surfactant media has great potential for the synthesis of novel MOFs with various structures. 23931889 Effect on extrapulmonary sepsis-induced acute lung injury by hemoperfusion with neutral microporous resin column. The aim of this study was to investigate the effect of neutral microporous resin hemoperfusion on oxygenation improvement, removal of inflammatory cytokines in plasma and bronchoalveolar lavage, and mortality in acute lung injury induced by extrapulmonary sepsis. Forty-six patients with acute lung injury induced by extrapulmonary sepsis were randomized to HA type hemoperfusion treatment (N = 25) or standard therapy (N = 21). Those undergoing hemoperfusion treatment received HA330 hemoperfusion. We measured the plasma and bronchoalveolar lavage concentrations of TNF-α and IL-1, and the following parameters were compared between the control group and the hemoperfusion group on days 0, 3 and 7: lung injury measurements (arterial oxygen tension/fractional inspired oxygen ratio, lung injury score, chest X-ray score); interstitial edema of lung (extravascular lung water). Duration of mechanical ventilation, hospital, 28-day, and intensive care unit mortality were also observed. Patients treated with HA hemoperfusion showed a significant removal of plasma and bronchoalveolar lavage TNF-α and IL-1 over time while in the study. Patients in the HA group also demonstrated not only significant improvement of PaO2 /FiO2 , but also decreased Lung Injury Score and chest X-ray score at days 3 and 7. Furthermore, the measurements of the arterial oxygen tension/fractional inspired oxygen ratio, lung injury score and extravascular lung water (EVLWI) significantly correlated with and the concentration of cytokines in the plasma (all P < 0.05). The HA hemoperfusion treatment group had a significant reduction in duration of mechanical ventilation, length of intensive care unit stay, and intensive care unit mortality. Significant removal of inflammatory cytokines from circulation and lung by hemoperfusion treatment using the HA type cartridge may contribute to the improvement of lung injury and intensive care unit outcome in extrapulmonary septic patients. 23872861 Extracellular matrix microenvironment contributes actively to pulmonary fibrosis. The purpose of this review is to describe the contribution of an altered, profibrotic extracellular matrix (ECM) microenvironment to pulmonary fibrosis and how it changes cell behaviour and actively drives disease progression. Idiopathic pulmonary fibrosis is a chronic and fatal disease of unknown cause. It is characterized by proliferation and accumulation of fibroblasts and myofibroblasts in clusters, termed fibroblastic foci, and extensive ECM deposition. Recent evidence from in-vivo and ex-vivo experimental studies has highlighted that the abnormal ECM in fibrotic lungs alters the behaviour of epithelial and mesenchymal cells. This profibrotic ECM microenvironment is characterized by altered biochemical and biomechanical properties and stores abundant amount of growth factors. By this, the 'fibrotic ECM' can drive progressive fibrogenesis in the lungs without any further initiating trigger. These concepts indicate a more complicated dynamic and active role of the fibrotic ECM than previously thought and offer many novel therapeutic targets. The fibrotic ECM microenvironment is an active contributor to the development and progression of pulmonary fibrosis and a promising therapeutic target. 23871966 Mechanisms of HCV-induced liver cancer: What did we learn from in vitro and animal studies? Hepatitis C virus (HCV) is a cause of liver diseases that range from steatohepatitis, to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The challenge of understanding the pathogenesis of HCV-associated liver cancer is difficult as most standard animal models used in biomedical research are not permissive to HCV infection. Herein, we provide an overview of a number of creative in vivo, mostly in the mouse, and in vitro models that have been developed to advance our understanding of the molecular and cellular effects of HCV on the liver, specifically with their relevance to HCC. 23957193 6 strategies for managing value in uncertain times. To maintain their creditworthiness in a volatile market and prepare for changes ahead, middle-market hospitals are: Cutting costs beyond the low-hanging fruit. Preparing for population health management. Integrating with physicians and growing their primary care networks. Expanding outpatient services. Reviewing their merger and acquisition options and affiliating when it makes sense. Investing in IT. 23791771 A practice-based randomised controlled trial of the efficacy of three interventions to reduce dentinal hypersensitivity. The aim of this study was to evaluate the efficacy of three different interventions (non-desensitising toothpaste, desensitising toothpaste and professionally applied dentine bonding agent) in reducing dentinal hypersensitivity over a 2-week, 3-month and 6-month-period in a dental practice setting. This was a randomised controlled, single-blind; parallel-group trial conducted in general dental practice by a single general dental practitioner. Seventy-five subjects were randomly allocated to three groups; non-desensitising toothpaste (NDT), desensitising toothpaste (DT) and professionally applied desensitising agent (DA). Dentinal hypersensitivity was measured using a Visual Analogue Scale (VAS) to record the response from a standardised short blast of air from a triple syringe. Dentinal hypersensitivity was recorded at baseline, two weeks, three months and six months for all groups. Dentinal hypersensitivity reduced significantly (p<0.0001) in both groups DT and DA, in addition the reduction in sensitivity was sustained and continued to improve over a 6-month-period. The greatest reduction in dentinal hypersensitivity was recorded in group DA. The results from this study suggest that application of dentine bonding agents, to teeth diagnosed with dentine hypersensitivity provides the greatest improvement in dentine hypersensitivity at 2 weeks and 6 months. This reduction in dentine hypersensitivity is greater than that achieved by the desensitising toothpaste tested and a non-desensitising toothpaste. 23063559 Neuroimaging in aphasia treatment research: standards for establishing the effects of treatment. The goal of this paper is to discuss experimental design options available for establishing the effects of treatment in studies that aim to examine the neural mechanisms associated with treatment-induced language recovery in aphasia, using functional magnetic resonance imaging (fMRI). We present both group and single-subject experimental or case-series design options for doing this and address advantages and disadvantages of each. We also discuss general components of and requirements for treatment research studies, including operational definitions of variables, criteria for defining behavioral change and treatment efficacy, and reliability of measurement. Important considerations that are unique to neuroimaging-based treatment research are addressed, pertaining to the relation between the selected treatment approach and anticipated changes in language processes/functions and how such changes are hypothesized to map onto the brain. 23261677 Shikonin induces programmed necrosis-like cell death through the formation of receptor interacting protein 1 and 3 complex. An alternative cell demise programmed necrosis has also been proposed when apoptotic machinery is impaired or blocked during tumor necrosis factor alpha (TNFα) stimulation. Shikonin (SKN), an herbal extract from the Chinese plant, has been reported to induce either apoptosis or necrosis depending on cell types or its concentrations. In this presentation, SKN caused cell death of NIH3T3 in a dose-dependent manner. Intriguingly, SKN-mediated cell death was in part protected by necrostatin-1 (Nec-1), a specific inhibitor of programmed necrosis, but not zVAD a pan-caspase inhibitor. SKN directly mediated cell death via receptor interacting protein1 and 3 (RIP1-RIP3) complex formation, which is required for TNFα-mediated programmed necrosis. Additionally, SKN-caused cell death was reversed by a reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) whereas TNFα-mediated necrosis was successfully protected by butylated hydroxyanisole (BHA), implying that ROS may be differentially derived from death inducing agents. Concurrently with the protective effect of the ROS scavenger or Nec-1 on TNFα or SKN, the RIP1-RIP3 complex was significantly affected in the presence of those agents. Here, it is highlighted that SKN as well as TNFα can directly mediate cell death via a pronecrotic complex, but ROS were generated via different routes depending on cell death-inducing agents. 23828071 Total alkaloids of Rubus aleaefolius Poir. inhibit the STAT3 signaling pathway leading to suppression of proliferation and cell cycle arrest in a mouse model of hepatocellular carcinoma. Signal transducer and activator of transcription 3 (STAT3) plays a critical role in cell survival and proliferation and is constitutively activated in many types of human cancers including hepatocellular carcinoma (HCC). Therefore, it is a major focus in the development of anticancer agents. Rubus aleaefolius Poir. has been demonstrated to be effective in the treatment of HCC. However, the precise mechanism of its anticancer activity remains largely unknown. Using HepG2 cells and a HCC mouse xenograft model, in the present study we evaluated the effect of the total alkaloids of Rubus aleaefolius Poir. (TARAP) on tumor growth in vitro and in vivo and investigated the underlying molecular mechanisms. We found that TARAP inhibited the proliferation of HepG2 human HCC cells and blocked G1/S cell cycle progression. In addition, TARAP treatment suppressed STAT3 phosphorylation in tumor tissues. Consequently, the inhibitory effect of TARAP on STAT3 activation resulted in the inhibition of proliferation. Moreover, TARAP altered the expression of several important target genes of the STAT3 signaling pathway, such as decreased expression of cyclinD1, cyclinE, cyclin-dependent kinase (CDK) 4 and CDK2 as well as upregulated p21. These results suggest that suppression of the STAT3 signaling pathway leading to inhibition of proliferation and cell cycle arrest may be one of the mechanisms of the anticancer activity of TARAP against HCC. 23927752 A rare case of primary malignant small cell carcinoma combined with urothelial cell carcinoma in the ureter. Extrapulmonary small cell carcinomas have been reported in a variety of organs, and their incidence in the genitourinary tract is second only to that in the gastrointestinal tract. To date, however, only a few cases of small cell carcinoma of the ureter have been reported. Because the extreme rarity of this type of carcinoma, its clinical behaviour, diagnostic methods, and effective treatment modalities have not yet been determined. A 59-year-old man presented with a 1-month history of painless gross haematuria. Urine cytopathology revealed a urothelial carcinoma and computed tomography revealed left hydronephroureterosis with a distal ureteral stone and a mildly enhanced fungating mass just below the stone-impacted site. The preoperative TNM stage was T2N0M0. The patient underwent simultaneous diagnostic ureterorenoscopy and left laparoscopic nephroureterectomy with bladder cuff resection. Gross examination showed a 3.5 × 3.0 × 0.8 cm white, partly yellow mass in the left distal ureter. Light microscopy showed a small cell carcinoma, overlaid on a urothelial carcinoma in situ, invading the ureter and external lateral resection margins. The small cell carcinoma was diffusely positive for neuron-specific enolase, and exhibited focal positivity for CD 56, synaptophysin, chromogranin and cytokeratin 20. The patient was treated with adjuvant chemotherapy, consisting of cisplatin and etoposide, and radiation therapy, and has been well, without evidence of tumour recurrence or metastasis in the 10 months after surgery. Small cell carcinoma of the ureter is rare. Although its clinical behaviour and diagnostic modalities have not been determined and it has yet to be diagnosed immunohistopathologically, multimodality treatment including surgery, chemotherapy and radiotherapy may improve patient survival. 23665860 Interventional exclusion of iliac artery aneurysms using the flow-diverting multilayer stent. This study was designed to evaluate retrospectively the results of complex iliac artery aneurysm (IAA) exclusion using the Cardiatis-Multilayer-Stent. Between October 2010 and August 2012, ten IAAs were treated in eight males (mean age 75 (59-91) years) using the Multilayer Stent. All IAA exceeded a diameter of 3 cm or were symptomatic. Follow-up (FU) examinations included CT or MR angiography, sonography, and clinical assessment up to 2 years. Primary stent placement was technically successful in eight of ten cases. In two cases, severe stent retraction during deployment necessitated placement of an additional stent. Immediately after stent placement, a marked reduction of flow within the sac was observed in all cases (peri-interventional mortality 0%). During FU, there were two thrombotic stent occlusions, making reintervention necessary (primary patency rate 80%, secondary patency 100%). Four IAA were completely occluded at FU, whereas the original vessel and covered branches (n = 8) were patent. In four IAA, there was still residual perfusion. In one patient, IAA diameter decreased slightly, while it remained constant in seven (mean imaging FU 195 (range 1-695) days). There were no adverse events on clinical FU (mean FU 467 (range 101-695) days). Other studies showed the Cardiatis-Multilayer-Stent to be a technically relatively simple treatment option for complex IAA with inadequate landing zones, especially in patients with multiple comorbidities to avoid ipsilateral IIA obstruction. However, in our series complication rate was high. Incomplete sac exclusion, stent-shortening, and thrombotic occlusion can complicate treatment, making meticulous patient selection necessary. Close imaging surveillance is mandatory especially in the early postinterventional period. 23564317 Prediction of the clinical outcome of cavernous sinus lesions in children. To identify predictive findings in children with nontraumatic acquired cavernous sinus lesions, a retrospective study of the clinical course of 4 of our own patients and 17 more children found in an extensive literature search was performed. Mean age was 8.7 years. Malignancy was found in 11 of 21 children (6 female, 15 male). Of these 21 children, 9 were cured, 8 are either in remission or their course is unknown, and 4 died. Eight of the nine cured patients were diagnosed as having had Tolosa-Hunt syndrome. Of the four deceased children, three had a very short course (1 to 4 months) and were diagnosed with malignant lymphoma (n = 2) and rhabdomyosarcoma (n = 1). One patient died from a brain tumor other than the initially diagnosed T-cell lymphoma in the cavernous sinus after a follow-up of 8 years. MRI should be the preferred imaging technique-even if it is not conclusive in many cases-and every possible diagnostic effort should be made before using corticosteroids. No clinical or radiological signs other than rapid deterioration seem to be predictable of a malignant cavernous sinus lesion with poor outcome. Thus, close follow-up is recommended in children with signs and symptoms indicative of an acquired lesion in the cavernous sinus. 23942085 Intraspecies variation in cotton border cell production: Rhizosphere microbiome implications. • Premise of the study: Border cells, which separate from the root cap, can comprise >90% of carbon-based exudates released into the rhizosphere, but may not provide a general source of nutrients for soil microorganisms. Instead, this population of specialized cells appears to function in defense of the root tip by an extracellular trapping process similar to that of mammalian white blood cells. Border cell production is tightly regulated, and direct tests of their impact on crop production have been hindered by lack of intraspecies variation.• Methods: Border cell number, viability, and clumping were compared among 22 cotton cultivars. Slime layer "extracellular trap" production by border cells in response to copper chloride, an elicitor of plant defenses, was compared in two cultivars with divergent border cell production. Trapping of bacteria by border cells in these lines also was measured.• Key results: Emerging roots of some cultivars produced more than 20000 border cells per root, a 100% increase over previously reported values for this species. No differences in border cell morphology, viability, or clumping were found. Copper chloride-induced extracellular trap formation by border cells from a cultivar that produced 27921 ± 2111 cells per root was similar to that of cells from a cultivar with 10002 ± 614 cells, but bacterial trapping was reduced.• Conclusions: Intraspecific variation in border cell production provides a tool to measure their impact on plant development in the laboratory, greenhouse, and field. Further research is needed to determine the basis for this variation, and its impact on rhizosphere community structure. 23826907 Pfannenstiel laparoendoscopic single-site (LESS) vs conventional multiport laparoscopic live donor nephrectomy: a prospective randomized controlled trial. To present outcomes of a randomized, patient-blinded controlled trial on Pfannenstiel laparoendoscopic single-site (LESS) vs conventional multiport laparoscopic live donor nephrectomy. Patients presenting as left kidney donors between January 2009 and November 2011 were randomized to LESS donor nephrectomy (LESS-DN: n = 15) or conventional laparoscopic donor nephrectomy (LDN: n = 14). Patients were blinded to the surgical approach preoperatively and attempts to continue patient blinding postoperatively were made by applying dressings consistent with multiple conventional laparoscopic incisions for all patients. De-identified data related to the operation, peri-operative course and postoperative follow-up were prospectively collected and compared between the two groups with an intention-to-treat analysis. There were no significant differences between the groups when comparing operating time, estimated blood loss (EBL), i.v. fluid administration, renal allograft warm ischaemia time (WIT), length of hospital stay (LOS) and total inpatient analgesic requirements. Quantitative pain assessment was not significantly different on postoperative day (POD) #0, however, it was significantly lower in the LESS-DN group, beginning on POD #1 (P < 0.05). The changes in haematocrit and serum creatinine in the two groups were not significantly different, and there were no blood transfusions in either group, nor was there a decline in estimated glomerular filtration rate to <60 mL/min per 1.73 m(2) of body surface area in any patients. Two patients in the LESS-DN group were converted to conventional LDN, both because of failure to progress effectively. All allografts were functional at the time of transplantation and revascularization, with no cases of hyperacute rejection. Peri-operative variables including EBL, WIT and LOS were equivalent when comparing Pfannenstiel LESS-DN with conventional LDN. Patient-reported visual analogue pain scale scores were significantly lower in the LESS-DN group beginning on the first postoperative day. 23816877 Aptamer-nanoparticle-based chemiluminescence for p53 protein. A simple colorimetric biosensing technique based on the interaction of gold nanoparticles (AuNPs) with the aptamer was developed for detection of p53, a tumor suppressor protein, in the current study. Aggregation of AuNPs was induced by desorption of the p53 binding RNA aptamer from the surface of AuNPs as a result of the aptamer target interaction leading to the color change of AuNPs from red to purple. The detection limit of p53 protein by the colorimetric approach was 0.1ng/ml after successful optimization of the amount of aptamer, AuNPs, salts, and incubation time. Furthermore, the catalytic activity of the aggregated AuNPs was greatly enhanced by chemiluminescence (CL) reaction, where the detection limit was enhanced to 10pg/ml with a regression coefficient of R(2)=0.9907. Here the sensitivity was increased by 10-fold compared with the AuNP-based colorimetric method. Hence, the sensitivity of detection was increased by employing CL, by using the catalytic activity of aggregated AuNPs, on the luminol-hydrogen peroxide reaction. Thus, the combination of colorimetric and CL-based aptasensor can be of great advantage in increasing the sensitivity of detection for any target analyte. 23698458 Scintigraphy in Ochoa syndrome. The Ochoa or urofacial syndrome is a disease characterized by non-neurogenic bladder dysfunction and unusual facial expressions when smiling or crying. It is an extremely rare disorder with over 150 cases reported in the medical literature. This condition has been determined to be inherited by an autosomal recessive pattern. We present radionuclide renogram and renal scan of a boy with a history of incontinence, frequent infections of the urinary tract, and gene mutations consistent with this syndrome. Nuclear medicine images showed extensive bilateral renal scarring and obstructive pattern in diuretic renogram. 23313796 Profiling of neuraminidase inhibitory polyphenols from the seeds of Paeonia lactiflora. Bacterial neuraminidase (NA) is a lynch pin enzyme in the formation of biofilms. Thus NA continues to be one of the key enzymes targeted by bacterial infection. The purpose of this manuscript is to communicate four new naturally derived inhibitors of neuraminidase (IC50s 3.7-24.4μM). All these active species (1-4) contained a resveratrol chemotype, however resveratrol itself was inactive (IC50>100μM). 1-4 were isolated from the 60% aqueous ethanol extract of seeds of Paeonia lactiflora, which exhibited potent neuraminidase inhibition. Purification of the extracts yielded four chiral polyphenols, suffruticosol A (1), suffruticosol B (2), trans-ε-viniferin (3), and trans-gnetin H (4). Mechanistic analysis of 1-4's inhibition showed that they were all reversible, noncompetitive inhibitors. Trans-ε-viniferin (3) underwent trans-cis isomerization, which led to a reduction in inhibition potency. This correlates with the fact that the cis-isomer is a weaker inhibitor of neuraminidase than the trans-isomer. Importantly, significantly different optical rotations ([α]D) compared to previous reports were found for suffruticosols A (+95 vs -34) and B (+136 vs +13). These two species are the most important standard metabolites in the whole paeoniaceae family and therefore correction of this error is important. 23898785 Crystalline liquid and rubber-like behavior in cu nanowires. Via in situ TEM tensile tests on single crystalline copper nanowires with an advanced tensile device, we report here a crystalline-liquid-rubber-like (CRYS-LIQUE-R) behavior in fracturing crystalline metallic nanowires. A retractable strain of the fractured crystalline Cu nanowires can approach over 35%. This astonishing CRYS-LIQUE-R behavior of the fracturing highly strained single crystalline Cu nanowires originates from an instant release of the stored ultralarge elastic energy in the crystalline nanowires. The release of the ultralarge elastic energy was estimated to generate a huge reverse stress as high as ∼10 GPa. The effective diffusion coefficient (Deff) increased sharply due to the consequent pressure gradient. In addition, due to the release of ultrahigh elastic energy, the estimated concomitant temperature increase was estimated as high as 0.6 Tm (Tm is the melting point of nanocrystalline Cu) on the fractured tip of the nanowires. These factors greatly enhanced the atomic diffusion process. Molecular dynamic simulations revealed that the very high reverse stress triggered dislocation nucleation and exhaustion. 23934489 The microbial content of vacuum cleaner bag dust and emitted bioaerosols: Implications for human exposures indoors. Vacuum cleaners can release large concentrations of particles, both in their exhaust air and from resuspension of settled dust. However, the size, variability and microbial diversity of these emissions are unknown, despite evidence to suggest they may contribute to allergic responses and infection transmission indoors. This study aimed to evaluate bioaerosol emission from various vacuum cleaners. We sampled the air in an experimental flow tunnel where vacuum cleaners were run and their airborne emissions sampled with closed-face cassettes. Dust samples were also collected from the dust bag. Total bacteria, total archaea, Penicillium/Aspergillus and total Clostridium cluster 1 were quantified with specific qPCR protocols and emission rates were calculated. Clostridium botulinum, as well as antibiotic resistance genes were detected in each sample using endpoint PCR. Bacterial diversity was also analyzed using denaturing gel electrophoresis (DGGE), image analysis and band sequencing. We demonstrated that emission of bacteria and moulds (Pen/Asp) can reach values as high as 1E05/min and that those emissions are not related to each other. The bag dust bacterial and mould content was also consistently across the vacuums we assessed, reaching up to 1E07 bacteria or moulds equivalent/g. Antibiotic resistance genes were detected in several samples. No archaea or C. botulinum were detected in any air samples. Diversity analyses showed that most bacteria are from human sources, in keeping with other recent results. These results highlight the potential capability of vacuum cleaners to disseminate appreciable quantities of moulds and human-associated bacteria indoors and their role as a source of exposure to bioaerosols. 23830067 Learning styles and critical thinking relationship in baccalaureate nursing education: A systematic review. Critical thinking is a desirable competency for contemporary nurses although there are growing concerns supporting a disturbing paucity in its achievement. Learning styles reflect habitual behaviors which determine distinct preferences within learning situations. Evidence suggests that critical thinking could evolve through learning processes. Variances in critical thinking achievement by nursing students might therefore be influenced by individual learning preferences. The concepts "learning styles" and "critical thinking" have been independently examined in the nursing literature. No reviews were found however exploring their association in nursing education. To identify the potential relationships between learning styles and critical thinking in baccalaureate nursing students. Systematic review. Eleven electronic databases were utilized without geographical and time publishing filters. Hand-searching journals and scanning references from retrieved studies were also performed. Databases were searched for descriptive correlational studies which considered the relationship between learning styles and critical thinking in baccalaureate nursing students. The authors independently progressed three stage screening. Retrieved articles were reviewed at title, abstract and full text levels according to predetermined criteria. All included studies were quality appraised using a rating tool for descriptive studies. Six studies were finally included. Findings were grouped under four key themes: predominant learning styles, critical thinking scoring, critical thinking evolution across academic progress and learning styles-critical thinking correlations. Learning styles' diversities, weak critical thinking and inconsistent evolution through academic progress were revealed across studies. Critical thinking differed significantly between learning styles. Commonly accepted models in nursing education were lacking in both learning styles and critical thinking. Within studies identical learning styles were found to be positively or negatively related to critical thinking. However comparative findings across studies revealed that all learning styles might be positive determinants toward critical thinking evolution, suggesting that there is a relationship between learning styles and critical thinking. Certain links between learning styles and critical thinking were supported in given settings and given nursing student populations. Further field exploration is required. 23415242 Integrated land use and regional resource management - A cross-disciplinary dialogue on future perspectives for a sustainable development of regional resources. Our paper introduces objectives and ideas of the special issue "Integrated land use and regional resource management - A cross-disciplinary dialogue on future perspectives for a sustainable development of regional resources" and provides an overview on the contributions of the single papers in the special issue to this topic. Furthermore, we discuss and present major challenges and demands on integrated land use and regional resource management and we come up with an analytical framework how to correspond these demands. 23865893 Haem catabolism: a novel modulator of inflammation in Gilbert's syndrome. Moderately elevated unconjugated bilirubin concentrations protect against inflammatory diseases and are present in individuals with Gilbert's syndrome. This study examined the relationship between circulating haem oxygenase catabolites, unconjugated bilirubin, carboxy haemoglobin, iron and inflammatory parameters. Seventy-six matched individuals were allocated to Gilbert's syndrome (GS) or control group (unconjugated bilirubin ≥ or  < 17·1 Î¼M). Iron, carboxy haemoglobin and high-sensitivity C-reactive protein were analysed using routine diagnostic tests. Unconjugated bilirubin and haem were analysed using high-performance liquid chromatography. The cytokines IL-1β, TNF-α and IL-6 were assessed using high-sensitivity enzyme-linked immunosorbent assays. Gilbert's syndrome subjects had significantly greater levels of unconjugated bilirubin (P < 0·05), carboxy haemoglobin (P < 0·05), iron (P < 0·05), IL-1β (P < 0·05), a significantly lower body mass index (P < 0·05) and IL-6 concentrations (P < 0·05) vs. controls. Regression analysis revealed that unconjugated bilirubin mainly explained IL-1β results (16%), and body mass index+IL-6 predicted 26% of the variance in C-reactive protein concentrations. A positive relationship between unconjugated bilirubin and free plasma haem, iron and carboxy haemoglobin indicated a positive feedback loop of haem oxygenase induction possibly mediated by unconjugated bilirubin. Furthermore, reduced body mass index in Gilbert's syndrome individuals was linked to reduced inflammation status, which could be influenced by circulating haem oxygenase catabolites and contribute to reduced risk of noncommunicable diseases in this population. 23718831 Hexavalent chromium-induced alteration of proteomic landscape in human skin fibroblast cells. Hexavalent chromium [Cr(VI)] generated during industrial processes is carcinogenic. Although much is known about the deleterious effects caused by reactive oxygen species generated during the reduction of Cr(VI) after its absorption by biological systems, the precise mechanisms underlying Cr(VI) cytotoxicity remain poorly defined. Here, we analyzed, at the global proteome scale, the perturbation of protein expression in GM00637 human skin fibroblast cells upon exposure to potassium dichromate (K₂Cr₂O₇). We were able to quantify ∼4600 unique proteins, among which ∼400 exhibited significant alterations in expression levels upon a 24-h treatment with 0.5 μM K₂Cr₂O₇. Pathway analysis revealed the Cr(VI)-induced perturbation of cholesterol biosynthesis, G-protein signaling, inflammatory response, and selenoprotein pathways. In particular, we discovered that the K₂Cr₂O₇ treatment led to pronouncedly elevated expression of a large number of enzymes involved in de novo cholesterol biosynthesis. Real-time PCR analysis revealed the increased mRNA expression of selected genes involved in cholesterol biosynthesis. Consistently, K₂Cr₂O₇ treatment resulted in marked increases in cellular cholesterol level in multiple cell lines. Moreover, the Cr(VI)-induced growth inhibition of cultured human cells could be rescued by a cholesterol-lowering drug, lovastatin. Together, we demonstrated, for the first time, that Cr(VI) may exert its cytotoxic effect, at least partly, through the up-regulation of enzymes involved in de novo cholesterol biosynthesis and the resultant increase of cholesterol level in cells. 23940622 A Temporal Signature of Epidermal Growth Factor Signaling Regulates the Differentiation of Germline Cells in Testes of Drosophila melanogaster. Tissue replenishment from stem cells follows a precise cascade of events, during which stem cell daughters first proliferate by mitotic transit amplifying divisions and then enter terminal differentiation. Here we address how stem cell daughters are guided through the early steps of development. In Drosophila testes, somatic cyst cells enclose the proliferating and differentiating germline cells and the units of germline and surrounding cyst cells are commonly referred to as cysts. By characterizing flies with reduced or increased Epidermal Growth Factor (EGF) signaling we show that EGF triggers different responses in the cysts dependent on its dose. In addition to the previously reported requirement for EGF signaling in cyst formation, a low dose of EGF signaling is required for the progression of the germline cells through transit amplifying divisions, and a high dose of EGF signaling promotes terminal differentiation. Terminal differentiation was promoted in testes expressing a constitutively active EGF Receptor (EGFR) and in testes expressing both a secreted EGF and the EGFR in the cyst cells, but not in testes expressing either only EGF or only EGFR. We propose that as the cysts develop, a temporal signature of EGF signaling is created by the coordinated increase of both the production of active ligands by the germline cells and the amount of available receptor molecules on the cyst cells. 23865554 Long-term results of a three arms prospective cohort study on implants in periodontally compromised patients: 10-year data around sandblasted and acid-etched (SLA) surface. The aim of this study was to compare the long-term outcomes of sandblasted and acid-etched (SLA) implants in patients previously treated for periodontitis and in periodontally healthy patients (PHP). One hundred and forty-nine partially edentulous patients were consecutively enrolled in private specialist practice and divided into three groups according to their periodontal condition: PHP, moderately periodontally compromised patients (PCP) and severely PCP. Implants were placed to support fixed prostheses, after successful completion of initial periodontal therapy. At the end of active periodontal treatment (APT), patients were asked to follow an individualized supportive periodontal therapy (SPT) program. Diagnosis and treatment of peri-implant biological complications were performed according to cumulative interceptive supportive therapy (CIST). At 10 years, clinical and radiographic measures were recorded by two calibrated operators, blind to the initial patient classification, on 123 patients, as 26 were lost to follow up. The number of sites treated according to therapy modalities C and D (antibiotics and/or surgery) during the 10 years was registered. Six implants were removed for biological complications. The implant survival rate was 100% for PHP, 96.9% for moderate PCP and 97.1% for severe PCP. Antibiotic and/or surgical therapy was performed in 18.8% of cases in PHP, in 52.2% of cases in moderate PCP and in 66.7% cases in severe PCP, with a statistically significant differences between PHP and both PCP groups. At 10 years, the percentage of implants, with at least one site that presented a PD ≥ 6 mm, was, respectively, 0% for PHP, 9.4% for moderate PCP and 10.8% for severe PCP, with a statistically significant difference between PHP and both PCP groups. This study shows that SLA implants, placed under a strict periodontal control, offer predictable long-term results. Nevertheless, patients with a history of periodontitis, who did not fully adhere to the SPT, presented a statistically significant higher number of sites that required additional surgical and/or antibiotic treatment. Therefore, patients should be informed, from the beginning, of the value of the SPT in enhancing long-term outcomes of implant therapy, particularly those affected by periodontitis. 23933815 Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells. Many cancer entities and their associated cell line models are highly heterogeneous in their responsiveness to apoptosis inducers and, despite a detailed understanding of the underlying signaling networks, cell death susceptibility currently cannot be predicted reliably from protein expression profiles. Here, we demonstrate that an integration of quantitative apoptosis protein expression data with pathway knowledge can predict the cell death responsiveness of melanoma cell lines. By a total of 612 measurements, we determined the absolute expression (nM) of 17 core apoptosis regulators in a panel of 11 melanoma cell lines, and enriched these data with systems-level information on apoptosis pathway topology. By applying multivariate statistical analysis and multi-dimensional pattern recognition algorithms, the responsiveness of individual cell lines to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or dacarbazine (DTIC) could be predicted with very high accuracy (91 and 82% correct predictions), and the most effective treatment option for individual cell lines could be pre-determined in silico. In contrast, cell death responsiveness was poorly predicted when not taking knowledge on protein-protein interactions into account (55 and 36% correct predictions). We also generated mathematical predictions on whether anti-apoptotic Bcl-2 family members or x-linked inhibitor of apoptosis protein (XIAP) can be targeted to enhance TRAIL responsiveness in individual cell lines. Subsequent experiments, making use of pharmacological Bcl-2/Bcl-xL inhibition or siRNA-based XIAP depletion, confirmed the accuracy of these predictions. We therefore demonstrate that cell death responsiveness to TRAIL or DTIC can be predicted reliably in a large number of melanoma cell lines when investigating expression patterns of apoptosis regulators in the context of their network-level interplay. The capacity to predict responsiveness at the cellular level may contribute to personalizing anti-cancer treatments in the future.Cell Death and Differentiation advance online publication, 9 August 2013; doi:10.1038/cdd.2013.106. 23878226 Structural and functional insight into an unexpectedly selective N-methyltransferase involved in plantazolicin biosynthesis. Plantazolicin (PZN), a polyheterocyclic, N(α),N(α)-dimethylarginine-containing antibiotic, harbors remarkably specific bactericidal activity toward strains of Bacillus anthracis, the causative agent of anthrax. Previous studies demonstrated that genetic deletion of the S-adenosyl-l-methionine-dependent methyltransferase from the PZN biosynthetic gene cluster results in the formation of desmethylPZN, which is devoid of antibiotic activity. Here we describe the in vitro reconstitution, mutational analysis, and X-ray crystallographic structure of the PZN methyltransferase. Unlike all other known small molecule methyltransferases, which act upon diverse substrates in vitro, the PZN methyltransferase is uncharacteristically limited in substrate scope and functions only on desmethylPZN and close derivatives. The crystal structures of two related PZN methyltransferases, solved to 1.75 Å (Bacillus amyloliquefaciens) and 2.0 Å (Bacillus pumilus), reveal a deep, narrow cavity, putatively functioning as the binding site for desmethylPZN. The narrowness of this cavity provides a framework for understanding the molecular basis of the extreme substrate selectivity. Analysis of a panel of point mutations to the methyltransferase from B. amyloliquefaciens allowed the identification of residues of structural and catalytic importance. These findings further our understanding of one set of orthologous enzymes involved in thiazole/oxazole-modified microcin biosynthesis, a rapidly growing sector of natural products research. 23902309 Flyingfish feeding ecology in the eastern Pacific: prey partitioning within a speciose epipelagic community. To test the hypothesis that prey partitioning contributes to community stability in flyingfish, the gut contents of 359 flyingfish specimens (representing five genera and eight species within Exocoetidae and Hemiramphidae) were collected at 50 dip-net stations during hour-long night-time fishing in oceanic waters of the eastern tropical Pacific Ocean between August and November 2007. Analyses using multidimensional scaling, and analysis of similarity revealed significant dietary differences among species, and similarity percentages tests helped identify the specific prey taxa responsible for these differences. Six species specialized on copepods (58·3-96·9% by number), but targeted different families. Specifically, the barbel flyingfish Exocoetus monocirrhus (n = 205) focused on euchaetids (51·6%), the banded flyingfish Hirundichthys marginatus (n = 24) fed on pontellids (21·8%), while the tropical two-wing flyingfish Exocoetus volitans (n = 11) and the bigwing halfbeak Oxyporhamphus micropterus (n = 34) ingested calanoids (54·6 and 17·0%). In contrast, the whitetip flyingfish Cheilopogon xenopterus (n = 73) and the mirrorwing flyingfish Hirundichthys speculiger (n = 4) had generalized diets comprising similar proportions of amphipod, copepod, mollusc and larval fish prey. Distinct differences in mean fullness, highly digested material, per cent empty guts and mean numbers of prey per gut were also synthesized, and uncovered a pattern of asynchronous feeding. Altogether, these findings provide valuable descriptive data on the diets of an understudied group of epipelagic teleosts, and, by extension, suggest that prey partitioning (taxa and feeding times) may influence flyingfish feeding ecology by reducing interspecific competition. 23821402 Risk stratification in patients with acute chest pain using three high-sensitivity cardiac troponin assays. Several high-sensitivity cardiac troponin (hs-cTn) assays have recently been developed. It is unknown which hs-cTn provides the most accurate prognostic information and to what extent early changes in hs-cTn predict mortality. In a prospective, international multicentre study, cTn was simultaneously measured with three novel [high-sensitivity cardiac Troponin T (hs-cTnT), Roche Diagnostics; hs-cTnI, Beckman-Coulter; hs-cTnI, Siemens] and a conventional assay (cTnT, Roche Diagnostics) in a blinded fashion in 1117 unselected patients with acute chest pain. Patients were followed up 2 years regarding mortality. Eighty-two (7.3%) patients died during the follow-up. The 2-year prognostic accuracy of hs-cTn was most accurate for hs-cTnT [area under the receivers operating characteristic curve (AUC) 0.78 (95% CI: 0.73-0.83) and outperformed both hs-cTnI (Beckman-Coulter, 0.71 (95% CI: 0.65-0.77; P = 0.001 for comparison), hs-cTnI (Siemens) 0.70 (95% CI: 0.64-0.76; P < 0.001 for comparison)] and cTnT 0.67 (95% CI: 0.61-0.74; P < 0.001 for comparison). Absolute changes of hs-cTnT were more accurate than relative changes in predicting mortality, but inferior to presentation values of hs-cTnT. Combining changes of hs-cTnT within the first 6 h with their presentation values did not further improve prognostic accuracy. Similar results were obtained for both hs-cTnI assays regarding the incremental value of changes. Hs-cTn concentrations remained predictors of death in clinically challenging subgroups such as patients with pre-existing coronary artery disease, impaired renal function, and patients older than 75 years. High-sensitivity cardiac Troponin T is more accurate than hs-cTnI in the prediction of long-term mortality. Changes of hs-cTn do not seem to further improve risk stratification beyond initial presentation values. 23828876 Multiple accessory pathways in a patient with congenitally corrected transposition of the great arteries and severe malformation of the coronary sinus. A 29-year-old patient diagnosed with (S,L,L) congenitally corrected transposition of great arteries (CCTGA) and pre-excitation is presented. We performed a coronary angiogram and it documented multiple coronary sinus rings in both mitral and tricuspid atrioventricular grooves, with multiple branches and right atrium fistulas. Note the venous retour shows a dual coronary venous system, with a remnant of the left superior venacava draining in the 'left' coronary sinus (white arrows) marking the level of the true AV groove, and a prominent 'right' coronary venous system at the 'right' AV groove fistulas (red arrow). Three accessory pathways were ablated. To our knowledge, this severe malformation of the coronary venous system has not been previously described. The full-length version of this report can be viewed at: http://www.escardio.org/communities/EHRA/publications/ep-case-reports/Documents/multiple-accessory-pathways.pdf. 23748104 Heterogeneity of bone microstructure in the femoral head in patients with osteoporosis: An ex vivo HR-pQCT study. Trabecular bone in the femoral head has a complicated and heterogeneous structure with few studies having analyzed heterogeneity in this structure quantitatively. We analyze trabecular bone microstructure in the femoral head with osteoporosis (OP) using high resolution peripheral quantitative CT (HR-pQCT) to investigate its regional characteristics. Fifteen femoral heads extracted from female OP patients with femoral neck fracture (85±7, 67-94years) were scanned by HR-pQCT at 41μmvoxel size. The femoral head was segmented into 15 regions (3 longitudinal regions: superior, center, and inferior, and 5 axial subregions: center, medial, lateral, anterior, posterior). Of these 15 regions, five were excluded due to overlap with the fracture site, leaving a total of 10 regions of cancellous bone microstructures to be quantitatively assessed using the following parameters: bone volume fraction, trabecular thickness, number, separation, connectivity density, structure model index, and degree and orientation of anisotropy. These parameters were compared among each region. Trabecular bone at the center, superior, and supero-posterior regions of the femoral head had higher bone volume, trabecular number, thickness, narrower bone marrow spaces, higher connectivity and anisotropy, and more plate-like structure. This plate-like structure ran supero-inferiorly and antero-posteriorly at the superior and center regions. Bone volume at the anterior, posterior, and medial regions was almost half of the central and superior regions. Significant heterogeneity of the trabecular bone microstructure in the OP femoral head was showed quantitatively in this study. These data offer new insight into bone microstructural anatomy and may prove to provide useful information on clinical medicine such as hip surgeries. 23648805 Evaluating the impact of database heterogeneity on observational study results. Clinical studies that use observational databases to evaluate the effects of medical products have become commonplace. Such studies begin by selecting a particular database, a decision that published papers invariably report but do not discuss. Studies of the same issue in different databases, however, can and do generate different results, sometimes with strikingly different clinical implications. In this paper, we systematically study heterogeneity among databases, holding other study methods constant, by exploring relative risk estimates for 53 drug-outcome pairs and 2 widely used study designs (cohort studies and self-controlled case series) across 10 observational databases. When holding the study design constant, our analysis shows that estimated relative risks range from a statistically significant decreased risk to a statistically significant increased risk in 11 of 53 (21%) of drug-outcome pairs that use a cohort design and 19 of 53 (36%) of drug-outcome pairs that use a self-controlled case series design. This exceeds the proportion of pairs that were consistent across databases in both direction and statistical significance, which was 9 of 53 (17%) for cohort studies and 5 of 53 (9%) for self-controlled case series. Our findings show that clinical studies that use observational databases can be sensitive to the choice of database. More attention is needed to consider how the choice of data source may be affecting results. 23968818 Focal cortical dysplasia type IIIc associates with multiple cerebral cavernomas. The distinction of isolated malformations and combined lesions constitutes a major novelty in the 2011 consensus classification of the International League against Epilepsy (ILAE) for focal cortical dysplasias (FCD). Cortical lamination abnormalities together with vascular lesions are subsumed as FCD IIIc. Little is known regarding frequency and etiology of this entity. Here, we systematically evaluated biopsy specimens from 72 drug-refractory epilepsy patients with cerebral cavernous malformations (CCM) regarding presence of associated FCD. Due to a non-perpendicular orientation of the cortical structures or absence of sufficient cortical tissue adjacent to the vascular lesion 25 samples were not classifiable. In the remaining 47 cases FCD IIIc was rare (4.3%), but significantly increased in patients with multiple CCM (28.6%; p<0.05 vs. single CCM). Association of FCD IIIc with multiple CCM may argue against FCD IIIc as an acquired lesion. 23740645 NEUROTOXICOLOGY OF bis(n)-TACRINES ON Blattella germanica AND Drosophila melanogaster ACETYLCHOLINESTERASE. A series of bis(n)-tacrines were used as pharmacological probes of the acetylcholinesterase (AChE) catalytic and peripheral sites of Blattella germanica and Drosophila melanogaster, which express AChE-1 and AChE-2 isoforms, respectively. In general, the potency of bis(n)-tacrines was greater in D. melanogaster AChE (DmAChE) than in B. germanica AChE (BgAChE). The change in potency with tether length was high in DmAChE and low in BgAChE, associated with 90-fold and 5.2-fold maximal potency gain, respectively, compared to the tacrine monomer. The optimal tether length for Blattella was 8 carbons and for Drosophila was 10 carbons. The two species differed by only about twofold in their sensitivity to tacrine monomer, indicating that differential potency occurred among dimeric bis(n)-tacrines due to structural differences in the peripheral site. Multiple sequence alignment and in silico homology modeling suggest that aromatic residues of DmAChE confer higher affinity binding, and the lack of same at the BgAChE peripheral site may account, at least in part, to the greater overall sensitivity of DmAChE to bis(n)-tacrines, as reflected by in vitro assay data. Topical and injection assays in cockroaches found minimal toxicity of bis(n)-tacrines. Electrophysiological studies on D. melanogaster central nervous system showed that dimeric tacrines do not readily cross the blood brain barrier, explaining the observed nonlethality to insects. Although the bis(n)-tacrines were not good insecticide candidates, the information obtained in this study should aid in the design of selective bivalent ligands targeting insect, pests, and disease vectors. 23874509 Development of a rapid and efficient method for non-lethal DNA sampling and genotyping in scallops. Non-lethal DNA sampling has long appealed to researchers studying population and conservation genetics, as it does not necessitate removing individuals permanently from their natural environment or destroying valuable samples. However, such an approach has not yet been well established in bivalves. In this study, we demonstrate that the gill represents a good source of tissue for non-lethal sampling in scallops. Removal of a few gill filaments caused no noticeable behavioral abnormalities or increased mortality rates in Zhikong scallop (Chlamys farreri) during a three-month period of observation. To facilitate rapid gill-based DNA extraction, six methods (MA-MF) were designed and evaluated, each requiring less than one hour of processing time. The optimal method was identified as MF, in terms of maintaining DNA integrity and genotyping accuracy. Further optimization of MF method by orthogonal experimental design suggested that the utilization of gills could be limited to 2 mg of sample, which is sufficient for performing up to 20,000 PCR reactions. We also demonstrate the excellent cross-species utility of MF in two additional scallop species, Yesso scallop (Patinopecten yessoensis) and bay scallop (Argopecten irradians). Taken together, our study provides a rapid and efficient approach for applying non-lethal DNA sampling in bivalve species, which would serve as a valuable tool for maintaining bivalve populations and conservation genetics, as well as in breeding studies. 23177786 Triazoyl-phenyl linker system enhancing the aqueous solubility of a molecular probe and its efficiency in affinity labeling of a target protein for jasmonate glucoside. In methods employing molecular probes to explore the targets of bioactive small molecules, long or rigid linker moieties are thought to be critical factors for efficient tagging of target protein. We previously reported the synthesis of a jasmonate glucoside probe with a highly rigid linker consisting of a triazoyl-phenyl (TAzP) moiety, and this probe demonstrated effective target tagging. Here we compare the TAzP probe with other rigid or flexible probes with respect to target tagging efficiency, hydrophobic parameters, aqueous solubility, and dihedral angles around the biaryl linkage by a combination of empirical and calculation methods. The rigid biaryl linkage of the TAzP probe has a skewed conformation that influences its aqueous solubility. Such features that include rigidness and good aqueous solubility resulted in highly efficient target tagging. These findings provide a promising guideline toward designing of better linkers for improving molecular probe performance. 23880663 Biophysical and formulation studies of the Schistosoma mansoni TSP-2 extracellular domain recombinant protein, a lead vaccine candidate antigen for intestinal schistosomiasis. A candidate vaccine to prevent human schistosomiasis is under development. The vaccine is comprised of a recombinant 9 kDa antigen protein corresponding to the large extracellular domain of a tetraspanin surface antigen protein of Schistosoma mansoni, Sm-TSP-2. Here, we describe the biophysical profile of the purified, recombinant Sm-TSP-2 produced in the yeast PichiaPink™, which in preclinical studies in mice was shown to be an effective vaccine against intestinal schistosomiasis. Biophysical techniques including circular dichroism, intrinsic and extrinsic fluorescence and light scattering were employed to generate an empirical phase diagram, a color based map of the physical stability of the vaccine antigen over a wide range of temperatures and pH. From these studies a pH range of 6.0-8.0 was determined to be optimal for maintaining the stability and conformation of the protein at temperatures up to 25 °C. Sorbitol, sucrose and trehalose were selected as excipients that prevented physical degradation during storage. The studies described here provide guidance for maximizing the stability of soluble recombinant Sm-TSP-2 in preparation of its further development as a vaccine. 23353737 Anti-hepatitis B virus and anti-cancer activities of novel isoflavone analogs. We have synthesized a series of novel isoflavone analogs and evaluated their anti-HBV and anti-cancer activities in vitro. The bioassays showed that the majority of the resultant compounds exerted inhibitory effects on HBsAg and HBeAg levels, HBV DNA replication, as well as the growth of four human cancer cell lines to various extents, which supported the rationale of the design. In particular, compound 8f showed the highest activity against HBV infection and HBV-related liver cancer. Compound 7l (IC50 = 0.47 μM) also exerted remarkable inhibitory effect on the growth lung cancer cell line A-549. 23639964 A 1.1Mb deletion in distal 13q deletion syndrome region with congenital heart defect and postaxial polydactyly: Additional support for a CHD locus at distal 13q34 region. 13q deletion syndrome is a rare genetic disorder, especially for group 3 deletion (13q33-q34 deletion). Previously we described a patient with congenital heart defect and mental retardation and proposed that a distal 6Mb region might contain the causative gene of congenital heart defect. Here we present a new patient with congenital heart defects (CHD), hand and foot anomalies and mild mental retardation. We identified a 1.1Mb deletion at chromosome 13q34 with high resolution SNP-array BeadChips (HumanOmni1-Quad, Illumina, USA). This chromosome region contains ten annotated genes, including GRK1, TFDP1, RASA3 and GAS6. To our knowledge, this represents the smallest 13q34 deletion identified to date. Our study provides additional support that distal 13q34 deletion region might contain key gene(s) responsible for cardiac development. 23873958 HCV IRES interacts with the 18S rRNA to activate the 40S ribosome for subsequent steps of translation initiation. Previous analyses of complexes of 40S ribosomal subunits with the hepatitis C virus (HCV) internal ribosome entry site (IRES) have revealed contacts made by the IRES with ribosomal proteins. Here, using chemical probing, we show that the HCV IRES also contacts the backbone and bases of the CCC triplet in the 18S ribosomal RNA (rRNA) expansion segment 7. These contacts presumably provide interplay between IRES domain II and the AUG codon close to ribosomal protein S5, which causes a rearrangement of 18S rRNA structure in the vicinity of the universally conserved nucleotide G1639. As a result, G1639 becomes exposed and the corresponding site of the 40S subunit implicated in transfer RNA discrimination can select . These data are the first demonstration at nucleotide resolution of direct IRES-rRNA interactions and how they induce conformational transition in the 40S subunit allowing the HCV IRES to function without AUG recognition initiation factors. 23829643 Magnetism in nanocrystalline gold. While bulk gold is well known to be diamagnetic, there is a growing body of convincing experimental and theoretical work indicating that nanostructured gold can be imparted with unconventional magnetic properties. Bridging the current gap in experimental study of magnetism in bare gold nanomaterials, we report here on magnetism in gold nanocrystalline films produced by cluster deposition in the aggregate form that can be considered as a crossover state between a nanocluster and a continuous film. We demonstrate ferromagnetic-like hysteretic magnetization with temperature dependence indicative of spin-glass-like behavior and find this to be consistent with theoretical predictions, available in the literature, based on first-principles calculations. 23958434 The correlation between self-reported and measured height, weight, and BMI in reproductive age women. This prospective, cross-sectional study of 60 women compares self-reported height, weight, and BMI with measured values. Self-reported BMI (29.0±8.37kg/m(2)) was slightly lower than measured BMI (29.1±8.38kg/m(2)) (p=0.4). Eighty percent of participants reported a BMI in the same category in which their BMI was measured. Pearson's correlation coefficient for height (0.96, p<0.001), weight (0.99, p<0.001), and BMI (0.99, p<0.001) were high. Reproductive age women accurately reported their height and weight. 23829965 Complications and factors associated with severity of influenza in hospitalized children and adults during the pandemic wave of A(H1N1)pdm2009 infections-The Fluco French cohort. The emergence of novel A(H1N1)pdm2009 virus threatened to lead to frequent severe manifestations. To describe the clinical, virological, and biological characteristics of the disease and identify the factors associated with severe presentations. This prospective multicenter study recruited consecutive hospitalized patients with confirmed A(H1N1)pdm2009 disease. Clinical, virological and biological assessments were carried out at inclusion and 30 days post-inclusion. Disease manifestations were assessed by an adjudication committee using pre-identified definitions of complications and severity scores. The study analyzed from November 30th, 2009 to February 8th, 2010, 40 hospitalized patients, 21 children and 19 adults. Eighteen (45%) were considered to have severe presentations. Except age, main characteristics in children and adults did not differ. The majority (18/21) of children and all adults had a respiratory presentation; extra-respiratory manifestations tended to be more frequent in children (12 vs. 6, P=0.10). Two children against 5 adults presented acute respiratory distress syndrome (ARDS, P=0.23), but more children suffered respiratory failure (7 vs. 1, P=0.046) without ARDS. At day 30, one death had occurred in each group. The main factor associated with non-severe presentation was an early (<48h) implementation of oseltamivir treatment (P=0.038). Although the study failed to achieve its main objective, due mainly to the difficulty of carrying a study of this nature in the midst of a pandemic, it allowed the description of a panel of unusual and complicated forms and confirmed the added value of early oseltamivir treatment in limiting severity in hospitalized children and adults. 23439233 Isolation, identification and antimicrobial activity of propolis-associated fungi. Propolis is a natural product widely known for its medicinal properties. In this work, fungi present on propolis samples were isolated, identified and tested for the production of antimicrobial metabolites. Twenty-two fungal isolates were obtained, some of which were identified as Alternaria alternata, Aspergillus flavus, Bipolaris hawaiiensis, Fusarium merismoides, Lasiodiplodia theobromae, Penicillium citrinum, Penicillium crustosum, Penicillium janthinellum, Penicillium purpurogenum, Pestalotiopsis palustris, Tetracoccosporium paxianum and Trichoderma koningii. These fungi were grown in liquid media to obtain crude extracts that were evaluated for their antibiotic activity against pathogenic bacteria, yeast and Cladosporium cladosporioides and A. flavus. The most active extract was obtained from L. theobromae (minimum inhibitory concentration = 64 μg/mL against Listeria monocitogenes). Some extracts showed to be more active than the positive control in the inhibition of Staphylococcus aureus and L. monocitogenes. Therefore, propolis is a promising source of fungi, which produces active agents against relevant food poisoning bacteria and crop-associated fungi. 23444059 Comparison of HPV DNA testing in cervical exfoliated cells and tissue biopsies among HIV-positive women in Kenya. HIV-positive women are infected with human papillomavirus (HPV) (especially with multiple types), and develop cervical intraepithelial neoplasia (CIN) and cervical cancer more frequently than HIV-negative women. We compared HPV DNA prevalence obtained using a GP5+/6+ PCR assay in cervical exfoliated cells to that in biopsies among 468 HIV-positive women from Nairobi, Kenya. HPV prevalence was higher in cells than biopsies and the difference was greatest in 94 women with a combination normal cytology/normal biopsy (prevalence ratio, PR = 3.7; 95% confidence interval, CI: 2.4-5.7). PR diminished with the increase in lesion severity (PR in 58 women with high-grade squamous intraepithelial lesions (HSIL)/CIN2-3 = 1.1; 95% CI: 1.0-1.2). When HPV-positive, cells contained 2.0- to 4.6-fold more multiple infections than biopsies. Complete or partial agreement between cells and biopsies in the detection of individual HPV types was found in 91% of double HPV-positive pairs. The attribution of CIN2/3 to HPV16 and/or 18 would decrease from 37.6%, when the presence of these types in either cells or biopsies was counted, to 20.2% when it was based on the presence of HPV16 and/or 18 (and no other types) in biopsies. In conclusion, testing HPV on biopsies instead of cells results in decreased detection but not elimination of multiple infections in HIV-positive women. The proportion of CIN2/3 attributable to HPV16 and/or 18 among HIV-positive women, which already appeared to be lower than that in HIV-negative, would then further decrease. The meaning of HPV detection in cells and random biopsy from HIV-positive women with no cervical abnormalities remains unclear. 23833129 Draft Genome Sequence of Salinibacillus aidingensis Strain MSP4, an Obligate Halophilic Bacterium Isolated from a Salt Crystallizer of the Rann of Kutch, India. We report the 7.42-Mbp draft whole genome sequence of Salinibacillus aidingensis strain MSP4, an obligate halophilic bacterium, isolated from a salt crystallizer of the Rann of Kutch in India. Analysis of the genome of this organism will lead to a better understanding of the genes and metabolic pathways involved in imparting osmotolerance. 23727283 Molecular cloning, characterization and expression analysis of coagulation factor VII gene in grass carp (Ctenopharyngodon idella). Coagulation factor VII has been studied in several species but, to date, not in grass carp (Ctenopharyngodon idella), a commercially important freshwater fish found in China. In this study, the full-length cDNA of grass carp coagulation factor VII (GcCFVII) was cloned using a RACE-Ready cDNA Kit, grass carp were challenged with a hemorrhagic virus, and temporal expression profiles of GcCFVII in the thymus, gills, liver, spleen, and head kidney were examined at 0 h, 24 h, 48 h, 72 h, 96 h, and 138 h using fluorescence quantitative PCR. The results showed the 1480 bp GcCFVII to contain three conservative motifs: Gla, EGF-CA, and Tryp-SPc, similar to other species. Phylogenetic analysis showed the evolution of GcCFVII gene to be consistent with the evolution of the species. After viral challenge, GcCFVII expression in five tissues of grass carp showed different patterns of fluctuation. These results provide a solid basis for further investigation of GcCFVII and its relationship with grass carp hemorrhage. 23671124 The grasshopper: a novel model for assessing vertebrate brain uptake. The aim of the present study was to develop a blood-brain barrier (BBB) permeability model that is applicable in the drug discovery phase. The BBB ensures proper neural function, but it restricts many drugs from entering the brain, and this complicates the development of new drugs against central nervous system diseases. Many in vitro models have been developed to predict BBB permeability, but the permeability characteristics of the human BBB are notoriously complex and hard to predict. Consequently, one single suitable BBB permeability screening model, which is generally applicable in the early drug discovery phase, does not yet exist. A new refined ex vivo insect-based BBB screening model that uses an intact, viable whole brain under controlled in vitro-like exposure conditions is presented. This model uses intact brains from desert locusts, which are placed in a well containing the compound solubilized in an insect buffer. After a limited time, the brain is removed and the compound concentration in the brain is measured by conventional liquid chromatography-mass spectrometry. The data presented here include 25 known drugs, and the data show that the ex vivo insect model can be used to measure the brain uptake over the hemolymph-brain barrier of drugs and that the brain uptake shows linear correlation with in situ perfusion data obtained in vertebrates. Moreover, this study shows that the insect ex vivo model is able to identify P-glycoprotein (Pgp) substrates, and the model allows differentiation between low-permeability compounds and compounds that are Pgp substrates. 23876414 Activation of glyoxylate pathway without the activation of its related gene in succinate-producing engineered Escherichia coli. For the first time, glyoxylate pathway in the biosynthesis of succinate was activated without the genetic manipulations of any gene related with glyoxylate pathway. Furthermore, the inactivation of succinate biosynthesis by-products genes encoding acetate kinase (ackA) and phosphotransacetylase (pta) was proven to be the key factor to activate glyoxylate pathway in the metabolically engineered Escherichia coli under anaerobic conditions. In order to enhance the succinate biosynthesis specifically, the genes (i.e., ldhA, ptsG, ackA-pta, focA-pflB, adhE) that disrupt by-products biosynthesis pathways were combinatorially deleted, while the E. coli malate dehydrogenase (MDH) was overexpression. The highest succinate production of 150.78mM was obtained with YJ003 (ΔldhA, ptsG, ackA-pta), which were 5-folds higher than that obtained with wild type control strain DY329 (25.13mM). For further understand the metabolic response as a result of several genetic manipulations, an anaerobic stoichiometric model that takes into account the glyoxylate pathway have successfully been implemented to estimate the intracellular fluxes in various recombinant E. coli. The fraction to the glyoxylate pathway from OAA in DY329 was 0 and 31% in YJ003, which indicated that even without the absence of the iclR mutation; the glyoxylate pathway was also activated by deleting the by-products biosynthetic genes, and to be responsible for the higher succinate yields. For further strengthen glyoxylate pathway, a two-stage fed-batch fermentation process was developed by using a 600gl(-1) glucose feed to achieve a cell growth rate of 0.07h(-1) in aerobic fermentation, and using a 750gl(-1) glucose feed to maintain the residual glucose concentration around 40gl(-1) when its residual level decreased to 10gl(-1) in anaerobic fermentation. The best mutant strain YJ003/pTrc99A-mdh produces final succinate concentration of 274mM by fed-batch culture, which was 10-folds higher than that obtained with wild type control strain DY329. This study discovered that glyoxylate pathway could be activated by deleting glyoxylate pathway irrelevant genes (i.e., genes encoding acetate and lactate) and consequently the succinate biosynthesis was effectively improved. This work provides useful information for the modification of metabolic pathway to improve succinate production. 23322767 School connectedness and susceptibility to smoking among adolescents in Canada. Smoking susceptibility in early adolescence is strongly predictive of subsequent smoking behavior in youth. As such, smoking susceptibility represents a key modifiable factor in reducing the onset of smoking in young people. A growing literature has documented a number of factors that influence susceptibility to smoking; however, there is limited amount of research examining associations of susceptibility to smoking and school connectedness. The current study examines whether school connectedness has an independent protective effect on smoking susceptibility among younger adolescents. A nationally representative sample of 12,894 Canadian students in grades 6-8 (11-14 years old), surveyed as part of the 2010-2011 Youth Smoking Survey, was analyzed. Multilevel logistic regression models examined unadjusted and adjusted associations between school connectedness and smoking susceptibility. The impacts of other covariates on smoking susceptibility were also explored. Approximately 29% of never-smokers students in grades 6-8 in Canada were susceptible to future smoking. Logistic regression analysis, controlling for standard covariates, found that school connectedness had strong protective effects on smoking susceptibility (odds ratio [OR] 0.91, 95% CI 0.89-0.94). The finding that school connectedness is protective of smoking susceptibility, together with previous research, provides further evidence that improving school conditions that promote school connectedness could reduce risky behavior in adolescents. While prevention efforts should be directed at youth of all ages, particular attention must be paid to younger adolescents in the formative period of 11-14 years of age. 23574361 Executive function as a mediator in the link between attention-deficit/hyperactivity disorder and social problems. Cognitive processes and mechanisms underlying the strong link between attention-deficit/hyperactivity disorder (ADHD) and social problems remain unclear. Limited knowledge also exists regarding a subgroup of youth with ADHD who do not have social problems. This study investigated the extent to which executive function (EF) mediated the association between ADHD and social problems and compared ADHD symptoms, comorbidities, and EF among ADHD youth with and without social problems and controls. The sample consisted of 279 youth with ADHD and 173 controls without ADHD (11-17 years of age) in Taiwan. Among youth with ADHD, two subgroups were further identified: 70 ADHD youth with social problems and 31 ADHD youth without social problems. EF was assessed with four subtests from the Cambridge Neuropsychological Test Automated Battery (Spatial span, Spatial working memory, Intra-dimensional/extra-dimensional shifts, Stockings of Cambridge). Social problems were assessed by mother and child reports. Executive function measures in working memory and planning mediated the effect of ADHD on social problems, independent of age, gender, and IQ. The two ADHD groups with and without social problems did not differ in ADHD severity or comorbidities; however, ADHD youth without social problems performed better on certain measures of EF such as working memory, planning, and response inhibition. These findings suggest that deficits in some aspects of EF may account for social problems often experienced by youth with ADHD. 23444964 Chronic food administration of Salvia sclarea oil reduces animals' anxious and dominant behavior. Recent studies indicate that an oil extract from Salvia sclarea may provide clinical benefits in various pathological conditions. In comparison to extracts from other Salvia species, S. sclarea oil contains twice as much omega-3 fatty acids, which are involved in eicosanoid synthesis pathways, and has been found to contain significant levels of the psychoactive monoterpane linalool. In the present study, we examined the mood stabilizing and anxiolytic-like effects of chronic food administration of S. sclarea oil extract on behavioral and physiological parameters of mice with prominent dominant and submissive features in behavioral assays used to test mood stabilizing and antidepressant drugs. Experimental animals received oil supplemented food from the age of 4 weeks or from conception via their pregnant dams. Each age group received either S. sclarea oil- or sunflower oil-enriched feed. Dominant animals, whose pregnant mothers received S. sclarea oil-enriched feed from the date of conception, showed a significant reduction of dominant and anxiety-like behavior, in comparison to their sunflower oil-treated counterparts. S. sclarea oil-treated submissive animals exhibited a similar tendency, and showed a significant reduction in blood corticosterone levels. These findings enforce the hypothesis that S. sclarea oil possesses anxiolytic properties. 23829475 Characterization of inflamin, the first member of a new family of snake venom proteins that induces inflammation. Unlike other sea snakes, Aipysurus eydouxii feeds exclusively on fish eggs. This unusual feeding habit prompted us to search for unique transcripts in their venom glands. Here, we expressed a novel cysteine-rich, secretory protein containing 94 amino acid residues that was identified in its cDNA library. As it induced inflammation and writhing in animals, this protein was named as inflamin. It induced two waves of prostanoids production. The first wave peaked at 10 min and 6-keto PGF1α was the major product. The second wave, specifically of 6-keto PGF1α and PGE2, started after 2 h. In RAW264.7 cells, COX-1 activity showed a transient increase at 10 min and is responsible for the first wave, but its expression was unaffected. COX-2 was induced after 3 h and is responsible for the second wave. Using specific inhibitors, we showed that cPLA2, and not sPLA2, iPLA2 or DAG lipase, plays a key role in arachidonate release. The cPLA2 activity showed a transient increase of 62% at 10 min; this increase was due to its phosphorylation and not due to an increase in its expression. Thus, inflamin - the first member of a new family of snake venom proteins, leads to an increase in the cPLA2 and COX-1 activity resulting in inflammation and pain. 23873652 Spontaneous Translocation of Antitumor Oxaliplatin, its Enantiomeric Analogue, and Cisplatin from One Strand to Another in Double-Helical DNA. Oxaliplatin and cisplatin belong to the class of platinum-based anticancer agents. Formation of DNA adducts by these complexes and the consequences for its structure and function, is the mechanistic paradigm by which these drugs exert their antitumor activity. We show that employing short oligonucleotide duplexes containing single, site-specific 1,3-intrastrand cross-links of oxaliplatin, its enantiomeric analogue, or cisplatin and by using gel electrophoresis that under physiological conditions the coordination bonds between platinum and the N7 position of guanine residues involved in the cross-links of the Pt(II) complexes can be cleaved. This cleavage may lead to linkage isomerization reactions between these metallodrugs and double-helical DNA. For instance, approximately 25 % 1,3-intrastrand cross-links of the platinum complexes isomerized after 192 h (at 310 K in 200 mM NaClO4 ). Differential scanning calorimetry of duplexes containing single, site-specific cross-links of oxaliplatin, its enantiomeric analogue, and cisplatin reveals that one of the driving forces that leads to the lability of DNA cross-links of these metallodrugs is a difference between the thermodynamic destabilization induced by the cross-link and by the adduct into which it could isomerize. The rearrangements may proceed in the way that cross-links originally formed in one strand of the DNA can spontaneously translocate from one DNA strand to its complementary counterpart, which may evoke walking of the platinum complex on DNA molecule. In addition, the differences in the kinetics of the rearrangement reactions and the thermodynamic destabilization of DNA observed for adducts of oxaliplatin and its enantiomeric analogue confirm that the chirality at the carrier 1,2-diaminocyclohexane ligand can considerably affect structural and other physical properties of DNA adducts and consequently their biological effects. In aggregate, interesting generalization of the results described in this work might be that the migration of oxaliplatin, its enantiomeric analogue, or cisplatin from one strand to another in double-helical DNA controlled by energetic signatures of these agents might contribute to a better understanding of their cytotoxic and mutagenic potential. 23746753 Incorporation of extruded coils into the third nerve in association with third nerve palsy. The extrusion of the coil complex outside of the aneurysmal dome is thought to be an important mechanism by which the aneurysm neck and fundus recanalize, but the migration of the coil loops and their incorporation inside vital nervous structures has not been clearly described. We reviewed the medical literature on coil extrusion and migration and report a rare case of third nerve palsy due to direct damage caused by coil loop migration that resolved after surgery. A 25-year-old woman presented with subarachnoid hemorrhage and painful left third nerve palsy. The angiogram revealed a supraclinoid internal carotid aneurysm incorporating the origin of the left posterior communicating artery. Her aneurysm was coiled. The 8month follow-up angiogram revealed a major recurrence of her aneurysm. It was decided to surgically clip the aneurysm. At surgery, coil loops were found in the subarachnoid space and embedded into the third nerve. At 1month follow-up she had recovered well, and only had very subtle diplopia upon fatigue. Coil extrusion is a fairly common phenomenon that should be suspected in instances of major aneurysmal recurrence. Surgical treatment is recommended, and special care should be taken when mobilizing the extruded coil mass. 23386596 A case-based approach to the practical application of dexmedetomidine in critically ill adults. Dexmedetomidine is a selective α(2) -adrenoceptor agonist that offers unique sedation because patients are readily awakened while administration continues and the drug does not suppress the respiratory center. Limitations of use include higher acquisition cost, inability to produce deep sedation, and bradycardia and hypotension. Using a case-based approach, the purpose of this review was to qualitatively assess the role of dexmedetomidine in the care of the critically ill and in the management of alcohol withdrawal, and to formulate recommendations regarding its clinical application. Sixty-six studies were identified that investigated dexmedetomidine for the provision of sedation. These studies were heterogeneous in design and patient populations; most investigated patients did not require heavy sedation, and few used propofol as the comparator. In general, though, the aggregate results of all studies demonstrate that dexmedetomidine provides comfort, possibly shortens the duration of mechanical ventilation to facilitate extubation, reduces the occurrence of acute brain dysfunction, and facilitates communication, but the drug is associated with hemodynamic instability and requires the supplemental use of traditional sedative and analgesic agents. These outcomes need to be substantiated in additional studies that include assessments of cost-effectiveness. Dexmedetomidine should be considered when patients require mild to moderate levels of sedation of short to intermediate time frames, and they qualify for daily awakenings with traditional sedative therapies. The data for dexmedetomidine in relation to alcohol withdrawal are limited to 12 retrospective reports representing a total of 127 patients. Its role for this indication requires further study, but it may be considered as adjunctive therapy when clinicians are concerned about respiratory suppression associated with escalating doses of γ-aminobutyric acid agonists. Regardless of the indication for dexmedetomidine, the practitioner must closely monitor patient comfort and the occurrence of hemodynamic deviations with the realization that as-needed administration of traditional sedatives and analgesics will be required and some degree of bradycardia and hypotension expected but intervention rarely required. 23927568 Comparative effects of sitagliptin and metformin in patients with type 2 diabetes mellitus: a meta-analysis. Abstract Background: Sitagliptin has been widely used in the treatment of type 2 diabetes mellitus (T2DM); however, the therapeutic efficacy of sitagliptin remains inconclusive in randomized controlled studies on T2DM in which metformin has served as a control. Objectives: The present meta-analysis aimed to compare the therapeutic efficacy of sitagliptin and metformin in the treatment of T2DM. Methods: We searched the following databases (Medline, Embase, Cochrane databases, Chinese Medical Journal Database, and the Chinese National Knowledge Infrastructure from inception until April 2013), and identified randomized controlled trials (RCTs) involving sitagliptin and metformin for T2DM. Two independent authors determined whether or not these trials met the inclusion criteria. Then, the variance of results from each study was calculated, and I(2) was employed for evaluation of heterogeneity. Results: One hundred twenty-one studies were identified, of which 7 were included for further analysis. For T2DM, the therapeutic efficacy of sitagliptin and metformin was comparable in reducing HbAlc (P = 0.148, SMD=0.13, 95% confidence interval [CI] = -0.05, 0.30), decreasing BMI (P =0.063, SMD=0.26, 95% CI = -0.01,0.54), and improving the homeostasis model assessment (HOMA)-β (P=0.285, SMD=-0.05, 95% CI = -0.15,0.04), but sitagliptin was inferior to metformin in improving HOMA-IR (P =0.003, SMD=0.16, 95% CI = 0.06,0.27). Conclusions:Sitagliptin is similar to metformin in reducing HbAlc, decreasing body weight, and improving the function of beta cells, but is inferior to metformin in improving insulin sensitivity. More RCTs with large sample sizes are required to provide evidence for the rational application of sitagliptin. 23957412 Impact of rearing conditions on the microbiological quality of raw retail poultry meat. There is a gap in knowledge of microbiological quality in raw chicken products produced by nonconventional methods and no studies have reported the microbiological quality of turkeys produced under different rearing environments. Thus, the aim of this study was to compare the microbiological quality of conventionally and organically reared whole chicken and turkey carcasses purchased from 3 retail outlets in Knoxville, Tenn., U.S.A. A total of 100 raw broiler chickens organically (n = 50) and 50 raw turkey carcasses consisting of 3 brands reared either conventionally (n = 25) or organically (n = 25) were evaluated. The FDA BAM protocol for rinsing poultry carcasses was used to enumerate of aerobic bacteria, Campylobacter, and Staphylococcus spp., and for qualitative analysis of Salmonella. Organic chickens from one brand had the highest average counts of aerobic bacteria, Staphylococcus spp. and Campylobacter (4.8, 4.8, and 4.7 Log10 CFU/mL rinsate, respectively) while the other organic brand had the lowest average counts (3.4, 3.3, and 3.1, respectively) of all 4 brands evaluated. The organic turkeys had the highest average counts of these same bacteria (4, 3.9, and 3.8, respectively) compared to the 2 brands of conventional turkeys evaluated. Salmonella (5% prevalence) was isolated only from organic chickens and turkeys. From these data, it appears that the microbiological quality of the raw product was not dependent on rearing conditions and, thus, it cannot be assumed that organic raw poultry is safer than conventionally raised poultry in terms of microbiological quality. 22929928 Creaming enhancement in a liter scale ultrasonic reactor at selected transducer configurations and frequencies. Recent research has shown that high frequency ultrasound (0.4-3 MHz), can enhance milkfat separation in small scale systems able to treat only a few milliliters of sample. In this work, the effect of ultrasonic standing waves on milkfat creaming was studied in a 6L reactor and the influence of different frequencies and transducer configurations in direct contact with the fluid was investigated. A recombined coarse milk emulsion with fat globules stained with oil-red-O dye was selected for the separation trials. Runs were performed with one or two transducers placed in vertical (parallel or perpendicular) and horizontal positions (at the reactor base) at 0.4, 1 and/or 2 MHz (specific energy 8.5 ± 0.6 kJ/kg per transducer). Creaming behavior was assessed by measuring the thickness of the separated cream layer. Other methods supporting this assessment included the measurement of fat content, backscattering, particle size distribution, and microscopy of samples taken at the bottom and top of the reactor. Most efficient creaming was found after treatment at 0.4 MHz in single and double vertical transducer configurations. Among these configurations, a higher separation rate was obtained when sonicating at 0.4 MHz in a vertical perpendicular double transducer setup. The horizontal transducer configuration promoted creaming at 2 MHz only. Fat globule size increase was observed when creaming occurred. This research highlights the potential for enhanced separation of milkfat in larger scale systems from selected transducer configurations in contact with a dairy emulsion, or emulsion splitting in general. 23941675 Influenza virus m2e with additional cysteine residues shows enhanced immunogenicity and protection against lethal virus challenge. Abstract The amino acid sequence of the extracellular domain of matrix protein 2 (M2e) is conserved among all subtypes of influenza A viruses. Therefore, the M2e peptide can be considered as a target antigen for the development of a universal influenza vaccine. We evaluated the effects of adding cysteine residues to a peptide of amino acids 2-24 of M2e. Mice immunized with some of these peptides containing one, two, three, four, or five extra cysteines displayed enhanced antibody titers to M2e. In addition, immunization with a peptide containing three extra cysteines, along with an aluminum adjuvant, protected mice more effectively against a lethal influenza virus challenge than the original M2e peptide. These results indicated that an M2e peptide containing additional cysteine residues could be a universal influenza vaccine candidate even without the addition of strong adjuvants. 23862647 Safety and Pharmacokinetics of 120 mg/kg versus 60 mg/kg Weekly Intravenous Infusions of Alpha-1 Proteinase Inhibitor in Alpha-1 Antitrypsin Deficiency: A Multicenter, Randomized, Double-Blind, Crossover Study (SPARK). Abstract Augmentation therapy with the approved dose of 60 mg/kg weekly intravenous (IV) alpha-1 proteinase inhibitor (alpha1-PI), achieves a trough serum level of 11 Î¼M in individuals with alpha-1 antitrypsin deficiency (AATD), yet this is still below the level observed in healthy individuals. This study assessed the safety and pharmacokinetic profile of weekly infusions of a 120 mg/kg dose of alpha1-PI in 30 adults with AATD. Subjects with symptomatic, genetically determined (genotypes PI*ZZ, PI*Z(null), PI*(null)(null) or PI*(Z)Mmalton) AATD were randomly assigned to weekly infusions of 60 or 120 mg/kg alpha1-PI (Prolastin-C®) for 8 weeks before crossing over to the alternate dose for 8 weeks. Adverse events (AEs) (including exacerbations), vital signs, pulmonary function tests, and laboratory assessments were recorded. Pharmacokinetic measurements included AUC0-7days, Cmax, trough, tmax, and t1/2, based on serum alpha1-PI concentrations. In total for both treatments, 112 AEs were reported, with exacerbation of COPD being the most frequent, consistent with the subjects' diagnoses. Mean steady-state serum alpha1-PI concentrations following 120 mg/kg weekly IV alpha1-PI were higher than with the 60 mg/kg dose and mean trough concentrations were 27.7 versus 17.3 Î¼M, respectively. Dose proportionality was demonstrated for AUC0-7days and Cmax, with low inter-subject variability. The 120 mg/kg alpha1-PI weekly dose was considered to be safe and well tolerated, and provided more favorable physiologic alpha1-PI serum levels than the currently recommended 60 mg/kg dose. The effect of this dosing regimen on slowing and/or preventing emphysema progression in subjects with AATD warrants further investigation. 23563297 The endothelialization and hemocompatibility of the functional multilayer on titanium surface constructed with type IV collagen and heparin. The type IV collagen/heparin (IVCol/Hep) multilayer was developed on amino-silanized titanium (Ti) surface layer by layer self-assembly. Ti, TiOH, TiOHA and TiOHA(HC)3H were characterized by Fourier transform infrared spectroscopy (FTIR), water contact angle measurements and scanning electron microscopy (SEM), respectively. Alcian Blue 8GX staining and immunofluorescence staining were used to characterize the heparin (Hep) and type IV collagen (IVCol), respectively. The blood compatibilities of Ti and the treated Ti were evaluated by platelet adhesion test and clotting time using PRP. Blood compatibility tests reveal that the assembled functional multilayer displayed less platelets adhesion and prolonged APTTs time compared with the controlled Ti. Endothelial cells (ECs) culture results showed more attached and proliferated ECs on the TiOHA(HC)3H than that on Ti, especially compared with that on TiOH and TiOHA. Thus, the assembled Hep and IVCol multilayer can improve the cell compatibility and the blood compatibility. We anticipate that this IVCol/Hep functional multilayer will be beneficial to enhance the biocompatibility of the Ti-based biomaterial devices. 23261671 The uptake and distribution of selenium in three aquatic plants grown in Se(IV) solution. The uptake of Se(IV) by Myriophyllum spicatum, Ceratophyllum demersum and Potamogeton perfoliatus, and the effects of Se(IV) on their physiological and biochemical characteristics were studied. Plants were cultivated outdoors under semi-controlled conditions in water solution containing Na selenite (20 μg Se L(-1) and 10 mg Se L(-1)). The higher concentration of Se lowered the photochemical efficiency of PSII in all species studied, while the lower concentration had no effect on any species. The higher concentration of Se lowered respiratory potential in M. spicatum. The response of M. spicatum and C. demersum to Se(IV) regarding chlorophylls was variable, however in the majority of cases, there was a trend of increasing the amount of chlorophylls, while in P. perfoliatus the amount of chlorophyll a decreased. The concentration of Se in plants cultured in 10 mg Se(IV) L(-1) ranged from 436 to 839 μg Se g(-1) DM in M. spicatum, 319 to 988 μg Se g(-1) DM in C. demersum and 310 to 661 μg Se g(-1) DM in P. perfoliatus. The amount of soluble Se compounds in enzyme extracts of high Se treatment was 27% in M. spicatum, 41% in C. demersum and 35% in P. perfoliatus. Se compounds were determined using HPLC-ICP-MS. It was observed that the applied Se(IV) was mainly transformed to insoluble Se. 23702384 The precise timing of embryo splitting for monozygotic dichorionic diamniotic twins: when does embryo splitting for monozygotic dichorionic diamniotic twins occur? Evidence for splitting at the morula/blastocyst stage from studies of in vitro fertilization. There is a long-held credo, as illustrated in Langman's Medical Embryology (11th ed., Sadler, 2010), that dichorionic diamniotic (DD) twins develop after embryo splitting in the early stages of embryonic development. However, from our clinical experiences of the examination of data from single-embryo transfers in 16 fertility clinics in Japan and from various reports, the majority of occurrences of DD twins have been found in the blastocyst stages. 23910779 Happy eating: The Single Target Implicit Association Test predicts overeating after positive emotions. For many years, questionnaires have been considered the standard when examining emotional eating behavior. However, recently, some controversy has arisen about these questionnaires, and their usefulness in identifying emotional eaters has been questioned. The current study aimed to investigate the Single Target Implicit Association Test (ST-IAT) as a measure of emotional eating. Two ST-IATs (assessing food-positive and food-negative associations respectively) and the Dutch Eating Behaviour Questionnaire (DEBQ) were compared in undergraduate students. A positive, negative or neutral mood was induced by means of a film clip, and milkshake consumption was measured during and after the mood induction. It was hypothesized that participants with strong emotion-food associations on the ST-IATs (i.e., IAT-emotional eaters) would consume more food in the emotion induction condition corresponding to that emotion, as compared to those with weak emotion-food associations as well as to those in the neutral condition. Participants who scored high on both the positive and negative ST-IATs ate more during a positive mood induction than during a negative mood induction. This effect did not extend to milkshake consumption after the mood induction procedure. In addition, IAT-positive emotional eaters consumed more food than IAT-non-emotional eaters. No effects of the DEBQ on milkshake consumption were found. It is concluded that the ST-IAT has potential as a measure of emotional eating. 23266123 Triazole-based inhibitors of geranylgeranyltransferase II. A small set of triazole bisphosphonates has been prepared and tested for the ability to inhibit geranylgeranyltransferase II (GGTase II). The compounds were prepared through use of click chemistry to assemble a central triazole that links a polar head group to a hydrophobic tail. The resulting compounds were tested for their ability to inhibit GGTase II in an in vitro enzyme assay and also were tested for cytotoxic activity in an MTT assay with the human myeloma RPMI-8226 cell line. The most potent enzyme inhibitor was the triazole with a geranylgeranyl tail, which suggests that inhibitors that can access the enzyme region that holds the isoprenoid tail will display greater activity. 23948313 Effectiveness of specific factors in community-based intervention for child-witnesses of interparental violence: A randomized trial. A community-based intervention with specific factors for children and parents exposed to interparental violence (IPV) was compared with a control intervention based on non-specific factors. We hypothesized that participation in an intervention with specific factors, focused on IPV, parenting and coping, would be associated with better recovery. IPV exposed children and parents were group randomized over a specific factors- and control intervention. Baseline, posttest and follow-up measurements of 155 parents and children (aged 6-12 years, 55.5% boys) were fitted in a multilevel model. Outcomes were parent and teacher reported children's internalizing and externalizing problems (CBCL, TRF), child self-reported depressive symptoms (CDI) and parent and child reported children's post-traumatic stress symptoms (TSCYC, TSCC). Based on intention-to-treat and completer analyses, children in the specific factors intervention did not show better recovery than children in the control intervention. Children in both interventions decreased significantly in parent-reported children's internalizing and externalizing problems and post-traumatic stress symptoms. Children reported a decrease in their mean level of depressive and post-traumatic stress symptoms. Teachers reported a decrease in internalizing problems, but not in externalizing problems. No association between time since exposure and level and course of symptoms was found. Treatment differentiation was assessed and both programs were significantly different on hypothesized effective factors. Higher treatment adherence in both programs did not result in a larger difference in recovery. IPV exposed children improve over the course and after participating in a community-based child- and parent program, but specific factors in intervention may not carry additional benefits when implemented in community settings. 23398966 Inter-rater reliability in child sexual abuse diagnosis among expert reviewers. To determine how well experts agree when assessing child sexual abuse cases. A total of twelve physician subjects were recruited and voluntarily enrolled from an existing peer review network. Experts from the network had been chosen for their experience in the field and their affiliation with children's advocacy centers. Each expert submitted three cases of prepubertal female genital examinations clearly demonstrable of the case findings. Submitted cases included demographics, history, physical and genital exam findings, photodocumentation, and diagnosis. Experts reviewed each submitted case and labeled the case negative for physical finding(s), positive for physical finding(s), or indeterminate. Cases were analyzed to determine the level of agreement. Thirty-six cases were submitted for use in this study; one case was excluded prior to starting the review process. After all experts completed their reviews the authors reviewed the cases and results. Two additional cases were excluded, one due to poor quality photodocumentation and one for not meeting the study criteria. Thirty-three cases were used for data analysis. All 12 expert reviewers agreed in 15 of the cases. Overall, in 22 of 33 (67%) cases at least 11 of the 12 reviewers agreed with the original diagnosis. Six of 33 (18%) cases had variable agreement (8-10 reviewers agreed with original diagnosis) among reviewers; 5 of 33 (15%) cases had poor or mixed agreement (7 or less reviewers agreed with original diagnosis). Experts exhibit consensus in cases where the findings clearly are normal and abnormal, but demonstrate much more variability in cases where the diagnostic decisions are less obvious. Most of the diagnostic variability is due to interpretation of the findings as normal, abnormal or indeterminate, not on the perception of the examination findings themselves. More research should be done to develop a national consensus on the accurate interpretation of anogenital examination findings. Photographic image quality plays an important role in this quality review process and universally needs to be improved. 23881480 Group B Streptococcal Meningitis in Infants Beyond the Neonatal Period. To describe the clinico-bacteriological profile, and early outcomes of infants diagnosed with Group B streptococcus (GBS) meningitis. This was a retrospective review of infants (aged 1 mo to 2 y) diagnosed with GBS meningitis in a tertiary care hospital in New Delhi from October 2010 through January 2012. The clinico-bacteriological data and early outcomes of infants with suspected bacterial meningitis and a positive CSF latex agglutination test for GBS were studied. The CSF samples were subjected to PCR for broad spectrum 16s ribosomal DNA and the GBS species specific gene, the scpB. Twenty seven patients (13 boys, and 14 girls) were diagnosed with GBS meningitis during the study period. Broad spectrum 16s ribosomal DNA PCR was performed on 18 of the 27 CSF samples. Sixteen were positive. All these 16 were also positive for the species specific scpB gene. The median duration of hospital stay was 7 d (range 1-72 d). Nine patients died. One patient each developed ventriculitis, optic atrophy and hydrocephalus. Overall, 12 patients had a complete recovery at discharge. GBS must be considered in the etiology of bacterial meningitis in Indian infants. 23957893 A Natural Driven Membrane Process for Brackish and Wastewater Treatment: Photovoltaic Powered ED and FO Hybrid System. In isolated locations, remote areas or islands, potable water is precious due to the lack of drinking water treatment facilities and energy supply. Thus, a robust and reliable water treatment system based on natural energy is needed to reuse wastewater or to desalinate groundwater/seawater for provision of drinking water. In this work, a hybrid membrane system combining electrodialysis (ED) and forward osmosis (FO), driven by renewable energy (solar energy), denoted as EDFORD (ED-FO Renewable energy Desalination), is proposed to produce high quality water (potable) from secondary wastewater effluent or brackish water. In this hybrid membrane system, feed water (secondary wastewater effluent or brackish water) was drawn to the FO draw solution while the organic and inorganic substances (ions, compounds, colloids and particles) were rejected. Then the diluted draw solution was pumped to the solar energy driven ED. In the ED unit, the diluted draw solution was desalted and high quality water was produced; the concentrate was recycled to the FO unit and reused as the draw solution. Results show that the water produced from this system contains a low concentration of total organic carbon (TOC), carbonate and cations derived from the feed water, had a low conductivity and meets potable water standards. The water production cost considering the investment for membranes and solar panel is 3.32 to 4.92 EUR.m-3 (for 300 days of production per year) for a small size potable water production system. 23828447 Unveiling the stereoelectronic properties of a triphenylene-based tris N-heterocyclic carbene. Two rhodium complexes with a triphenylene-based tris-NHC have been fully characterized. DFT and electrochemical studies suggest that the electronic communication between the metals is very weak, and that the electron donating properties of the ligand are very similar to those shown by its benzimidazolylidene analogue. 23707761 Ursolic acid improves domoic acid-induced cognitive deficits in mice. Our previous findings suggest that mitochondrial dysfunction is the mechanism underlying cognitive deficits induced by domoic acid (DA). Ursolic acid (UA), a natural triterpenoid compound, possesses many important biological functions. Evidence shows that UA can activate PI3K/Akt signaling and suppress Forkhead box protein O1 (FoxO1) activity. FoxO1 is an important regulator of mitochondrial function. Here we investigate whether FoxO1 is involved in the oxidative stress-induced mitochondrial dysfunction in DA-treated mice and whether UA inhibits DA-induced mitochondrial dysfunction and cognitive deficits through regulating the PI3K/Akt and FoxO1 signaling pathways. Our results showed that FoxO1 knockdown reversed the mitochondrial abnormalities and cognitive deficits induced by DA in mice through decreasing HO-1 expression. Mechanistically, FoxO1 activation was associated with oxidative stress-induced JNK activation and decrease of Akt phosphorylation. Moreover, UA attenuated the mitochondrial dysfunction and cognitive deficits through promoting Akt phosphorylation and FoxO1 nuclear exclusion in the hippocampus of DA-treated mice. LY294002, an inhibitor of PI3K/Akt signaling, significantly decreased Akt phosphorylation in the hippocampus of DA/UA mice, which weakened UA actions. These results suggest that UA could be recommended as a possible candidate for the prevention and therapy of cognitive deficits in excitotoxic brain disorders. 23908616 Neural pathways mediating cross education of motor function. Cross education is the process whereby training of one limb gives rise to enhancements in the performance of the opposite, untrained limb. Despite interest in this phenomenon having been sustained for more than a century, a comprehensive explanation of the mediating neural mechanisms remains elusive. With new evidence emerging that cross education may have therapeutic utility, the need to provide a principled evidential basis upon which to design interventions becomes ever more pressing. Generally, mechanistic accounts of cross education align with one of two explanatory frameworks. Models of the "cross activation" variety encapsulate the observation that unilateral execution of a movement task gives rise to bilateral increases in corticospinal excitability. The related conjecture is that such distributed activity, when present during unilateral practice, leads to simultaneous adaptations in neural circuits that project to the muscles of the untrained limb, thus facilitating subsequent performance of the task. Alternatively, "bilateral access" models entail that motor engrams formed during unilateral practice, may subsequently be utilized bilaterally-that is, by the neural circuitry that constitutes the control centers for movements of both limbs. At present there is a paucity of direct evidence that allows the corresponding neural processes to be delineated, or their relative contributions in different task contexts to be ascertained. In the current review we seek to synthesize and assimilate the fragmentary information that is available, including consideration of knowledge that has emerged as a result of technological advances in structural and functional brain imaging. An emphasis upon task dependency is maintained throughout, the conviction being that the neural mechanisms that mediate cross education may only be understood in this context. 23778901 Towards the installation of transition metal ions on donor ligand decorated tin sulfide clusters. Decoration of tetrelchalcogenide T-E clusters with chelating donor ligands was achieved to capture transition metal ions on their surfaces. We demonstrate that by covalent linking of bispyridyl ligands to an Sn-S complex, [ZnX](+) units can be trapped and incorporated into the cluster framework. Intermediates that were identified using spectroscopy and/or X-ray diffraction gave insight into the formation processes. 23907594 The Sexual Ethics of HPV Vaccination for Boys. Human papillomavirus (HPV) is one of the most common sexually transmitted infections. It is a leading cause of cervical cancer in women but the virus is increasingly being linked to several other cancers in men and women alike. Since the introduction of safe and effective but also expensive vaccines, many developed countries have implemented selective vaccination programs for girls. Some however argue that these programs should be expanded to include boys, since (1) HPV constitutes non-negligible health risks for boys as well and (2) protected boys will indirectly also protect girls. In this paper we approach this discussion from an ethical perspective. First, on which moral grounds can one justify not reimbursing vaccination for the male sex? We develop an ethical framework to evaluate selective vaccination programs and conclude that, in the case of HPV, efficiency needs to be balanced against non-stigmatization, non-discrimination and justice. Second, if vaccination programs were to be expanded to boys as well, do the latter then also have a moral duty to become immunized? Two arguments in favor of such a moral duty are well known in vaccination ethics: the duty not to harm others and to contribute to the public good of public health. However, we argue that these are not particularly convincing in the context of HPV. In contrast, we believe a third, more powerful but also more controversial argument is possible. In our view, the sexual mode of transmission of HPV constitutes an additional reason to believe that boys in fact may have a moral obligation to accept vaccination. 23705627 Persistent cough associated with osteophyte formation and vagus nerve impingement following cervical spinal surgery. Persistent cough due to irritation of the vagus nerve by osteophytes resulting from cervical spinal surgery is a very rare condition. The authors report the case of a 49-year-old woman who presented with a persistent cough subsequent to cervical spinal surgery. One year after the initial operation, the patient underwent surgery to free the larynx from the prevertebral fascia and cut the pharyngeal plexus, but her symptoms persisted. In order to control the cough, she used a soft cervical collar with padding inserted in the left side so that the larynx would be pushed to the right, a solution she discovered on her own. Without the collar, she coughed uncontrollably. A CT scan was performed and showed an osteophyte that had developed at the level of the prosthesis. Based on these findings, the authors hypothesized that the cough was caused by vagus nerve irritation due to the osteophyte. The osteophyte was resected and the vagus nerve was moved to a position anterior to the carotid artery and was isolated by means of an autogenous tensor fascia lata graft. The patient's symptom disappeared immediately after the surgery. At the most recent follow-up visit, 18 months after surgery, the patient was symptom free and was pursuing regular daily activities without using a cervical collar. 23864381 Regulation of epileptiform discharges in rat neocortex by HCN channels. Hyperpolarization-activated, cyclic-nucleotide gated, non-specific cation (HCN) channels have a well-characterized role in regulation of cellular excitability and network activity. The role of these channels in control of epileptiform discharges is less thoroughly understood. This is especially pertinent given altered HCN channel expression in epilepsy. We hypothesized that inhibition of HCN channels would enhance bicuculline-induced epileptiform discharges. Whole-cell recordings were obtained from layers 2/3 and 5 (L2/3; L5) pyramidal neurons and L1 and L5 GABAergic interneurons. In the presence of bicuculline (10 uM), HCN channel inhibition with ZD7288 (20 uM) significantly increased the magnitude (defined as area) of evoked epileptiform events in both L2/3 and L5 neurons. We recorded activity associated with epileptiform discharges in L1 and L5 interneurons to test the hypothesis that HCN channels regulate excitatory synaptic inputs differently in interneurons versus pyramidal neurons. HCN channel inhibition increased the magnitude of epileptiform events in both L1 and L5 interneurons. The increased magnitude of epileptiform events in both pyramidal cells and interneurons was due to an increase in network activity since holding cells at depolarized potentials under voltage-clamp conditions to minimize HCN channel opening did not prevent enhancement in the presence of ZD7288. In neurons recorded with ZD7288-containing pipettes, bath application of the Ih antagonist still produced increases in epileptiform responses. These results show that epileptiform discharges in disinhibited rat neocortex are modulated by HCN channels. 23459149 Analytical chemistry, toxicology, epidemiology and health impact assessment of melamine in infant formula: Recent progress and developments. This review summarizes the most recent scientific literature and regulations regarding analytical chemistry, toxicology, epidemiology, exposure, and risk assessment of melamine in infant formula. For analyses, enzyme-linked immunosorbent assay, high-performance liquid chromatography, capillary electrophoresis, gas chromatography coupled with mass spectrometry and liquid chromatography coupled with tandem mass spectrometry have commonly been used. Organization of proficiency test programs provided good evidence to facilitate granting laboratories accreditation and to ascertain the measurement reliability of melamine methods. Metabolic studies demonstrated that melamine is predominantly restricted to blood or extracellular fluid and is not extensively distributed to organs and tissues. Studies of human renal histopathology and clinical diagnoses indicated that melamine-related obstructive nephropathy derives from melamine precipitation in the lower urinary tract, with stones that are thought to be melamine-uric acid complexes. Epidemiologic studies showed that the occurrence of melamine-related urolithiasis is related to both the concentration of melamine in ingested milk products and the duration of ingestion. Long-term follow-up cohort studies should be continued to further investigate the epidemic and chronic hazard of melamine-induced nephrotoxicity. The World Health Organization set a tolerable daily intake of 0.2mg/kgbw/day to be applied to "the whole population including infants". Other authorities and research institutes have set/proposed lower values. 23919351 Toxicity and Mutagenicity of Gulf of Mexico Waters During and After the Deepwater Horizon Oil Spill. The Deepwater Horizon oil spill is unparalleled among environmental hydrocarbon releases, because of the tremendous volume of oil, the additional contamination by dispersant, and the oceanic depth at which this release occurred. Here, we present data on general toxicity and mutagenicity of upper water column waters and, to a lesser degree, sediment porewater of the Northeastern Gulf of Mexico (NEGOM) and west Florida shelf (WFS) at the time of the Deepwater Horizon oil spill in 2010 and thereafter. During a research cruise in August 2010, analysis of water collected in the NEGOM indicated that samples of 3 of 14 (21%) stations were toxic to bacteria based on the Microtox assay, 4 of 13 (34%) were toxic to phytoplankton via the QwikLite assay, and 6 of 14 (43%) showed DNA damaging activity using the λ-Microscreen Prophage induction assay. The Microtox and Microscreen assays indicated that the degree of toxicity was correlated to total petroleum hydrocarbon concentration. Long-term monitoring of stations on the NEGOM and the WFS was undertaken by 8 and 6 cruises to these areas, respectively. Microtox toxicity was nearly totally absent by December 2010 in the Northeastern Gulf of Mexico (3 of 8 cruises with one positive station). In contrast, QwikLite toxicity assay yielded positives at each cruise, often at multiple stations or depths, indicating the greater sensitivity of the QwikLite assay to environmental factors. The Microscreen mutagenicity assays indicated that certain water column samples overlying the WFS were mutagenic at least 1.5 years after capping the Macondo well. Similarly, sediment porewater samples taken from 1000, 1200, and 1400 m from the slope off the WFS in June 2011 were also highly genotoxic. Our observations are consistent with a portion of the dispersed oil from the Macondo well area advecting to the southeast and upwelling onto the WFS, although other explanations exist. Organisms in contact with these waters might experience DNA damage that could lead to mutation and heritable alterations to the community pangenome. Such mutagenic interactions might not become apparent in higher organisms for years. 22384983 Adjunctive usage of a non-comedogenic moisturizer with adapalene gel 0.1% improves local tolerance: a randomized, investigator-blinded, split-face study in healthy Asian subjects. Abstract Background: Adapalene gel 0.1% is an efficacious treatment for acne vulgaris in Asians. It is generally well tolerated, but may still cause cutaneous side effects among patients with sensitive skin. Objective: To assess the ability of a moisturizing lotion (Cetaphil®) in improving the local tolerance of adapalene. Methods: In this 4-week, randomized, investigator-blinded, split-face study among 30 healthy volunteers of Chinese origin, adapalene gel was applied once daily to the whole face and the moisturizing lotion was applied once daily to only one side of the face according to the randomization scheme. Results: At each study visit, both investigators and subjects reported better tolerance on the side of moisturizing lotion + adapalene gel than the side of adapalene gel only, with significant differences reported by the subjects during the first 2 weeks (p = 0.039 and 0.013, respectively). Global worst score, defined as the average of worst scores for erythema, desquamation, dryness, stinging/burning and pruritus, was significantly lower for the side of moisturizing lotion + adapalene gel than for the side of adapalene gel alone (0.43 ± 0.34 vs. 0.59 ± 0.44, p = 0.032). Conclusion: The adjunctive usage of an effective moisturizer improves local tolerance of adapalene gel and may contribute to better adherence. 23611119 Students coached for an admission test perform less well throughout a medical course. : Undertaking commercial coaching to improve one's chance of selection into medical school is widespread. Although its effect on selection test performance appears to be relatively minimal, its impact on the predictive validity of the tests is unknown. To examine whether commercial coaching for the Undergraduate Medical and Health Sciences Admissions Test (UMAT) changes its ability to predict the subsequent academic performance of medical students. : The first two cohorts to enrol in a new Australian medical school provided information at the time of their selection interview about whether or not they had undertaken a commercial coaching course to help prepare for the UMAT. Final academic grades for each year of the degree and overall grade point average (GPA) of coached students were compared with those of non-coached students. Moderated regression analyses examined differences in the relationship between UMAT scores and examination results while controlling for entry UMAT scores and past academic performance. : Coached students had a lower GPA than those who were not coached. In cohort 1, coached students performed more poorly than non-coached students in every year of their degree. This effect, while similar, was not statistically significant in cohort 2. : Differences in selection process and learning context between the two cohorts may explain why coaching was only significantly related to the performance of one cohort. Further research is required to ascertain if coached students develop a learning style that hinders ongoing acquisition of knowledge, which might have serious implications for job performance after graduation. 23385031 Phosphodiesterase-5 inhibitor tadalafil attenuates oxidative stress and protects against myocardial ischemia/reperfusion injury in type 2 diabetic mice. Diabetic patients exhibit increased risk for the development of cardiovascular diseases primarily because of impaired nitric oxide (NO) bioavailability. The phosphodiesterase-5 (PDE-5) inhibitor sildenafil restores NO signaling and protects against ischemia/reperfusion (I/R) injury. In this study, we determined the effect of the long-acting PDE-5 inhibitor tadalafil on diabetes-associated complications and its role in attenuating oxidative stress after I/R injury in type 2 diabetic db/db mice. Adult male db/db mice (n=40/group) were randomized to receive dimethyl sulfoxide (10% DMSO, 0.2ml, ip) or tadalafil (1mg/kg in 10% DMSO, ip) for 28 days. After 28 days treatment, the hearts were isolated and subjected to 30min global ischemia followed by 60min reperfusion in the Langendorff mode. Infarct size was measured using computer morphometry of tetrazolium-stained sections. Cardiomyocytes were isolated from a subset of hearts and subjected to 40min simulated ischemia followed by 1h of reoxygenation (SI/RO). Dichlorodihydrofluorescein diacetate and JC-1 staining was used to measure reactive oxygen species (ROS) generation and mitochondrial membrane potential (Δψm), respectively. Another subset of hearts was used for the estimation of lipid peroxidation, glutathione, and the expression of myocardial pRac1, Rac1, gp91(phox), p47(phox), and p67(phox) by Western blot. Tadalafil treatment improved the metabolic status and reduced infarct size compared to the untreated db/db mice (21.2±1.8% vs 45.8±2.8%; p<0.01). The db/db mice showed enhanced oxidative stress in cardiomyocytes as indicated by a significant increase in ROS production. Cardiac NAD(P)H oxidase activity, lipid peroxidation, and oxidized glutathione were also increased in db/db mice compared to nondiabetic control animals. Tadalafil treatment in db/db mice suppressed oxidative stress, attenuated myocardial expression of pRac1 and gp91(phox), and also preserved the loss of Δψm in cardiomyocytes after SI/RO. In conclusion, these results demonstrate that chronic treatment with tadalafil attenuates oxidative stress and improves mitochondrial integrity while providing powerful cardioprotective effects in type 2 diabetes. 23906664 GATA-3 is down-regulated in patients with clear cell renal carcinoma. GATA-3 is a transcription factor involved in human growth and development. Recent studies found its association with breast cancer, however, its expression profile in renal cell carcinoma (RCC) has not been investigated. The study included 35 patients submitted to radical nephrectomy with confirmed pathological diagnosis of RCC. Normal control kidney tissues were obtained from 25 living kidney donors and tissues were biopsied before implantation. The majority of RCC samples were diagnosed as clear cell renal cell carcinoma (94.3%) except for 1 case of papillary RCC and 1 case of collecting duct carcinoma. GATA-3 expression was evaluated by quantitative PCR and Western blotting (WB) in RCC samples and normal kidneys respectively, immunohistochemical staining was performed as well. Meanwhile, the GATA-3 expression in two cancer cell lines (786-O, ACHN) and normal kidney epithelial cells (HK-2) was detected by PCR and WB. In addition, renal cancer cells and HK-2 cells were cultivated and detected by confocal microscopy for the exact intra-cellular localization of GATA-3. Data showed a significant down-regulation of GATA-3 expression present in neoplastic tissues compared with normal tissues; similarly, GATA-3 was significantly attenuated in all renal cancer cell lines compared with normal HK-2 cells. Confocal displayed a strong cytoplasmic immno-fluorescence activity of GATA-3 with peri-nuclear zone in HK-2, whereas the intensity in cancer cells was markedly weaker than that of HK-2. In summary, our present study clarifies that the aberrant expression profile of GATA-3 in human RCC is possibly involved with tumorigenesis, and the complicated mechanism is worthy of further investigation. 23344553 Increased impulsive choice for saccharin during PCP withdrawal in female monkeys: influence of menstrual cycle phase. BACKGROUND: In previous studies with male and female rhesus monkeys, withdrawal of access to oral phencyclidine (PCP) self-administration reduced responding for food under a high fixed-ratio (FR) schedule more in males than females, and with a delay discounting (DD) task with saccharin (SACC) as the reinforcer impulsive choice for SACC increased during PCP withdrawal more in males than females. OBJECTIVES: The goal of the present study was to examine the effect of PCP (0.25 or 0.5 mg/ml) withdrawal on impulsive choice for SACC in females during the follicular and luteal phases of the menstrual cycle. MATERIALS AND METHODS: In component 1, PCP and water were available from two drinking spouts for 1.5 h sessions under concurrent FR 16 schedules. In component 2, a SACC solution was available for 45 min under a DD schedule. Monkeys had a choice of one immediate SACC delivery (0.6 ml) or six delayed SACC deliveries, and the delay was increased by 1 s after a response on the delayed lever and decreased by 1 s after a response on the immediate lever. There was then a 10-day water substitution phase, or PCP withdrawal, that occurred during the mid-follicular phase (days 7-11) or the late luteal phase (days 24-28) of the menstrual cycle. Access to PCP and concurrent water was then restored, and the PCP withdrawal procedure was repeated over several follicular and luteal menstrual phases. RESULTS: PCP deliveries were higher during the luteal (vs follicular) phase. Impulsive choice was greater during the luteal (vs follicular) phase during withdrawal of the higher PCP concentration. CONCLUSIONS: PCP withdrawal was associated with elevated impulsive choice for SACC, especially in the luteal (vs follicular) phase of the menstrual cycle in female monkeys. 23587873 Prevalence and natural history of Graves' orbitopathy in the XXI century. Graves' orbitopathy (GO) is an autoimmune disorder and the main extrathyroidal expression of Graves' disease. There is a spectrum of ocular involvement in Graves' disease, from complete absence of symptoms and signs to sight-threatening conditions. The prevalence of GO varies in different published series of Graves' patients, due to confounding factors (new diagnosis vs. long-lasting disease, way of defining and assessing ocular involvement, treatment of hyperthyroidism with potentially GO-modifying treatments, such as radioiodine). Recent studies, however, suggest that most Graves' patients have mild or no GO at presentation, while moderate-to-severe GO is rare, and sight-threatening GO (mostly due to dysthyroid optic neuropathy) is exceptional in non-tertiary referral centers. The natural course of GO is incompletely defined, particularly in patients with moderate-to12 severe GO, because these patients require prompt and disease-modifying therapies for orbital disease. In patients with mild GO at presentation, progression to severe forms is rare, while partial or complete remission is frequent. Progression of preexisting GO or de novo occurrence of GO is more likely in smokers. There seems to be a trend towards a decline in progression of GO, possibly due to a better control of risk factors (cigarette smoking, thyroid dysfunction, etc.) and a closer interaction between endocrinologists and ophthalmologists allowing an improved integrated management of thyroid and orbital disease. 23756634 Effects of Schedule I drug laws on neuroscience research and treatment innovation. Many psychoactive drugs are used recreationally, particularly by young people. This use and its perceived dangers have led to many different classes of drugs being banned under national laws and international conventions. Indeed, the possession of cannabis, 3,4-methylenedioxy-N-methylamphetamine (MDMA; also known as ecstasy) and psychedelics is stringently regulated. An important and unfortunate outcome of the controls placed on these and other psychoactive drugs is that they make research into their mechanisms of action and potential therapeutic uses - for example, in depression and post-traumatic stress disorder - difficult and in many cases almost impossible. 23845858 Trace metal biogeochemistry in mangrove ecosystems: A comparative assessment of acidified (by acid sulfate soils) and non-acidified sites. The generation of acidity and subsequent mobilization of toxic metals induced by acid sulfate soils (ASSs) are known to cause severe environmental damage to many coastal wetlands and estuaries of Australia and worldwide. Mangrove ecosystems serve to protect coastal environments, but are increasingly threatened from such ASS-induced acidification due to variable hydrological conditions (i.e., inundation-desiccation cycles). However, the impact of such behaviors on trace metal distribution, bio-availability and accumulation in mangrove tissues, i.e., leaves and pneumatophores, are largely unknown. In this study, we examined how ASS-induced acidifications controlled trace metal distribution and bio-availability in gray mangrove (Avicennia marina) soils and in tissues in the Kooragang wetland, New South Wales, Australia. We collected mangrove soils, leaves and pneumatophores from a part of the wetland acidified from ASS (i.e., an affected site) for detailed biogeochemical studies. The results were compared with samples collected from a natural intertidal mangrove forest (i.e., a control site) located within the same wetland. Soil pH (mean: 5.90) indicated acidic conditions in the affected site, whereas pH was near-neutral (mean: 7.17) in the control site. The results did not show statistically significant differences in near-total and bio-available metal concentrations, except for Fe and Mn, between affected and control sites. Iron concentrations were significantly (p values≤0.001) greater in the affected site, whereas Mn concentrations were significantly (p values≤0.001) greater in the control site. However, large proportions of near-total metals were potentially bio-available in control sites. Concentrations of Fe and Ni were significantly (p values≤0.001) greater in leaves and pneumatophores of the affected sites, whereas Mn, Cu, Pb and Zn were greater in control sites. The degree of metal bio-accumulation in leaves and pneumatophores suggest contrasting hydrological behaviors and near-surface geochemical conditions favoring differential metal uptake by mangrove plants in the two sites. 23497872 Chemical composition and antioxidant activity of dried powder formulations of Agaricus blazei and Lentinus edodes. Several mushroom species have been pointed out as sources of antioxidant compounds, in addition to their important nutritional value. Agaricus blazei and Lentinus edodes are among the most studied species all over the world, but those studies focused on their fruiting bodies instead of other presentations, such as powdered preparations, used as supplements. In the present work the chemical composition (nutrients and bioactive compounds) and antioxidant activity (free radical scavenging activity, reducing power and lipid peroxidation inhibition) of dried powder formulations of the mentioned mushroom species (APF and LPF, respectively) were evaluated. Powder formulations of both species revealed the presence of essential nutrients, such as proteins, carbohydrates and unsaturated fatty acids. Furthermore, they present a low fat content (<2g/100g) and can be used in low-calorie diets, just like the mushrooms fruiting bodies. APF showed higher antioxidant activity and higher content of tocopherols and phenolic compounds (124 and 770 μg/100g, respectively) than LPF (32 and 690 μg/100g). Both formulations could be used as antioxidant sources to prevent diseases related to oxidative stress. 23963440 Occurrence of Organochlorine Pesticides in Surface Soils from College School Yards of Xi'an, China. In this study, surface soil samples from 14 representative college school yards in Xi'an, the capital city of Shaanxi province, China, were collected and analyzed for 21 organochlorine pesticides (OCPs). The total concentrations were in the ranges of 0.2-67.0 ng/g. HCHs and DDTs were the most dominant compounds among the 21 OCPs, and their concentrations ranged from 0.1-8.5 to 0.1-56.3 ng/g, respectively. Source identification analysis indicated that the residues of HCHs and DDTs were mostly due to historical use of these chemicals or from other source regions. The quality of all the Xi'an college school yard soils except sample XAUAT was classified as low pollution by OCPs according to the National Environmental Quality Standards for Soils of China (GB15618-1995). 23715717 Information processing bottlenecks in macaque posterior parietal cortex: an attentional blink? When two brief stimuli are presented in rapid succession, our ability to attend and recognize the second stimulus is impaired if our attentional resources are devoted to processing the first. Such inability (termed the "attentional blink" in human studies) arises around 200-500 ms following the onset of the first stimulus. We trained two monkeys on a delayed-match-to-sample task where both the location and orientation of two successively presented grating patches had to be matched. When the delay between the two gratings was varied, monkey's behavioral performance (d') was affected in a way that was analogous to the attentional blink in humans. Furthermore, a subset of neurons in the monkey's lateral intraparietal area, known to be crucial in the control of attention, closely followed the variation in d', even on occasions when d' followed an atypical pattern. Our results provide the first behavioral demonstration of an attentional bottleneck in the macaque of a type similar to the human attentional blink as well as a possible single-neuron correlate of the phenomenon. 22902329 Vitamin E deficiency impairs the somatostatinergic receptor-effector system and leads to phosphotyrosine phosphatase overactivation and cell death in the rat hippocampus. Vitamin E plays an essential role in maintaining the structure and function of the nervous system, and its deficiency, commonly associated with fat malabsorption diseases, may reduce neuronal survival. We previously demonstrated that the somatostatinergic system, implicated in neuronal survival control, can be modulated by α-tocopherol in the rat dentate gyrus, increasing cyclic adenosine monophosphate response element binding protein phosphorylation. To gain a better understanding of the molecular actions of tocopherols and examine the link among vitamin E, somatostatin and neuronal survival, we have investigated the effects of a deficiency and subsequent administration of tocopherol on the somatostatin signaling pathway and neuronal survival in the rat hippocampus. No changes in somatostatin expression were detected in vitamin-E-deficient rats. These rats, however, showed a significant increase in the somatostatin receptor density and dissociation constant, which correlated with a significant increase in the protein levels of somatostatin receptors. Nevertheless, vitamin E deficiency impaired the ability of the somatostatin receptors to couple to the effectors adenylyl cyclase and phosphotyrosine phosphatase by diminishing Gi protein functionality. Furthermore, vitamin E deficiency significantly increased phosphotyrosine phosphatase activity and PTPη expression, as well as PKCδ activation, and decreased extracellular-signal-regulated kinase phosphorylation. All these changes were accompanied by an increase in neuronal cell death. Subsequent α-tocopherol administration partially or completely reversed all these values to control levels. Altogether, our results prove the importance of vitamin E homeostasis in the somatostatin receptor-effector system and suggest a possible mechanism by which this vitamin may regulate the neuronal cell survival in the adult hippocampus. 23430532 Warrior culture, spirituality, and prayer. Research has shown an increase in suicides by military veterans and law enforcement officers in the United States. Etiologic research elucidates warrior culture and subculture as contributing factors of this pathology. This paper examines the idiosyncratic nature and influence of warrior culture and subculture and offers recommendations to promote culture change. Faith-based spirituality and prayer are examined as adjunct modalities for stress management and emotional healing. Further research is recommended to assess the associated hidden cost factors and long-term financial impact of warrior culture on society. 23874840 Osteoprotegerin Inhibits Calcification of Vascular Smooth Muscle Cell via Down Regulation of the Notch1-RBP-Jκ/Msx2 Signaling Pathway. Vascular calcification is a common pathobiological process which occurs among the elder population and in patients with diabetes and chronic kidney disease. Osteoprotegerin, a secreted glycoprotein that regulates bone mass, has recently emerged as an important regulator of the development of vascular calcification. However, the mechanism is not fully understood. The purpose of this study is to explore novel signaling mechanisms of osteoprotegerin in the osteoblastic differentiation in rat aortic vascular smooth muscle cells (VSMCs). VSMCs were isolated from thoracic aorta of Sprague Dawley rats. Osteoblastic differentiation of VSMCs was induced by an osteogenic medium. We confirmed by Von Kossa staining and direct cellular calcium measurement that mineralization was significantly increased in VSMCs cultured in osteogenic medium; consistent with an enhanced alkaline phosphatase activity. This osteoblastic differentiation in VSMCs was significantly reduced by the addition of osteoprotegerin in a dose responsive manner. Moreover, we identified, by real-time qPCR and western blotting, that expression of Notch1 and RBP-Jκ were significantly up-regulated in VSMCs cultured in osteogenic medium at both the mRNA and protein levels, these effects were dose-dependently abolished by the treatment of osteoprotegerin. Furthermore, we identified that Msx2, a downstream target of the Notch1/RBP-Jκ signaling, was markedly down-regulated by the treatment of osteoprotegerin. Osteoprotegerin inhibits vascular calcification through the down regulation of the Notch1-RBP-Jκ signaling pathway. 23955694 Nocturnal Awakening and Sleep Efficiency Estimation using Unobtrusively Measured Ballistocardiogram. Fragmented sleep due to frequent awakenings represents a major cause of impaired daytime performance and adverse health outcomes. Currently, the gold standard for studying and assessing sleep fragmentation is polysomnography. Here, we propose an alternative method for real-time detection of nocturnal awakening via ballistocardiography using an unobtrusive polyvinylidene fluoride (PVDF) film sensor on a bed mattress. From ballistocardiogram, heart rate and body movement information were extracted to develop an algorithm for classifying sleeping and awakening epochs. In total, 10 normal subjects (mean age 38.7 ± 14.6 years) and 10 patients with obstructive sleep apnea (OSA) (mean age 44.2 ± 16.5 years) of varying symptom severity participated in this study. Our study detected awakening epochs with an average sensitivity of 85.3% and 85.2%, specificity of 98.4% and 97.7%, accuracy of 97.4% and 96.5%, and Cohen's Kappa coefficient of 0.83 and 0.81 for normal subjects and OSA patients, respectively. Also, sleep efficiency was estimated using detected awakening epochs and then compared with polysomnography results. Mean absolute errors in sleep efficiency were 1.08% and 1.44% for normal subjects and OSA patients, respectively. The results presented here indicate that our suggested method could be reliably applied to real-time nocturnal awakening detection and sleep efficiency estimation. Furthermore, our method may ultimately be an effective tool for long-term, home monitoring of sleep-wake behavior. 23550970 Epidemiology of Soybean vein necrosis-associated virus. ABSTRACT Soybean vein necrosis-associated virus has been linked to an emerging soybean disease in the United States and Canada. Virus distribution and population structure in major growing areas were evaluated. Data were employed to design and develop sensitive detection protocols, able to detect all virus isolates available in databases. The host range for the virus was assessed and several species were found to sustain virus replication, including ivyleaf morning glory, a common weed species in soybean-growing areas in the United States. Koch's postulates were fulfilled using soybean thrips and transmission efficiency was determined. This article provides significant insight into the biology of the most widespread soybean virus in the United States. 23874335 Vitamin-Mediated Regulation of Intestinal Immunity. The intestine is exposed continuously to complex environments created by numerous injurious and beneficial non-self antigens. The unique mucosal immune system in the intestine maintains the immunologic homeostasis between the host and the external environment. Crosstalk between immunocompetent cells and endogenous (e.g., cytokines and chemokines) as well as exogenous factors (e.g., commensal bacteria and dietary materials) achieves the vast diversity of intestinal immune functions. In addition to their vital roles as nutrients, vitamins now also are known to have immunologically crucial functions, specifically in regulating host immune responses. In this review, we focus on the immunologic functions of vitamins in regulating intestinal immune responses and their roles in moderating the fine balance between physiologic and pathologic conditions of the intestine. 23859712 Oligodeoxynucleotides containing multiple thiophene-modified isomorphic fluorescent nucleosides. 5-(Thien-2-yl)-2'-deoxyuridine, an isomorphic fluorescent nucleoside analogue, was incorporated into multiple positions within single stranded oligodeoxynucleotides. With minimal impact on duplex stability and overall structure, oligonucleotides containing three identical isomorphic fluorescent nucleosides in alternating or neighboring positions display enhanced, sequence-dependent on-signals for either duplex formation or dissociation. 23400867 Intraoperative pre- and post-craniofacial reconstruction intracranial pressure (ICP) monitoring in children with craniosynostosis. One of the goals of cranial vault expansion performed in patients with craniosynostosis (CS) is to reduce the harmful effects associated with elevated intracranial pressure (ICP). Until now, clear guidelines on when cranial vault expansion should take place have not been established except in unacceptable cosmetic deformities. This paper illustrates the potential benefit of ICP monitoring in determining the time of surgery. The ICP of six patients (ranging from 7 months to 8 years) was measured before and after surgery. For the first time, we regulated end-tidal carbon dioxide, the position and movements, the level of sedation and the monitoring site of our patients under anesthesia to report accurate ICP readings. The mean pre- and postoperative ICPs were 14.7 and 4.2 mmHg, respectively. Pressure sensor was placed through a burr hole under general anesthesia and remained through all stages of recording. Though ICP monitoring has been reported before, the physiological fluctuations of ICP and patient's condition affected results. Under our ICP monitoring protocol, the six-patient study represents a suggestion to standardize ICP measurements under certain conditions in order to improve the reproducibility of ICP monitoring and therefore establish the need for optimal timing of cranial vault expansion in pediatrics. Although we cannot clearly define the indications and establish normal pediatric ICP values from the result of this study because of the small number of cases and some other limitations, this is a new approach to define ICP increase as a potential indication for surgery in CS. 23929725 Local translation in neuronal processes - in vivo tests of a 'heretical hypothesis' Intracellular trafficking and localization of mRNA is a fundamental feature of living cells, suggesting that localized mRNA translation should enable subcellular regulation of the proteome. Such localized regulation may be of particular importance in highly polarized cells such as neurons, where the requirement for a specific protein can be at a site far distant from the nucleus. Although dendritic and synaptic protein syntheses are well-established phenomena, the apparent paucity of ribosomes in early studies on mature vertebrate axons generated significant skepticism regarding the possibility of protein synthesis within axons. Here we summarize recent findings in genetically engineered mouse models that support a role for local translation in axonal expression of β-actin and importin β1 in injured adult sensory neurons in vivo. These definitive confirmations of mammalian axonal protein synthesis in both transgenic and subcellular knockout models should direct further attention to the diverse roles suggested for local protein synthesis in axonal physiology. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013. 23901933 Microhemodynamic aberrations created by transfusion of stored blood. Human red blood cells (RBCs) can be stored for up to 42 days under controlled conditions. Physical and chemical changes occur during RBC storage, altering their function. This study links stored cell mechanical changes with hemodynamic functional alterations upon transfusion. Mechanical properties of fresh and stored RBCs were evaluated in vitro. Their transfusion effects were evaluated in vivo using intravital microscopy of the rat's cremaster muscle preparation. Rats were hemodiluted to 30% hematocrit, to mimic an anemic state before transfusion, and then exchange-transfused with fresh or stored cells. In vitro studies on rheology and oxygen affinity of stored cells confirmed previously published results. Storage was found to modify static and dynamic RBC mechanic behavior. After transfusion, systemic hemodynamics were similar for fresh and stored cells; however, microvascular hemodynamics were drastically affected by stored cells. Stored cells reduced blood flow and oxygen delivery. Additionally, the presence of stored cells in circulation affected cell-to-cell and cell-to-wall interactions and affected cell hydrodynamics. Stored cells disrupted the RBC cell-free layer and wall shear stress signals. The reduced cell deformability due to RBC "storage lesions" caused pathologic changes in microvascular hemodynamics, endothelial cell mechanotransduction, and RBC dynamics. Thus, the mechanical changes of blood-banked cells can limit transfusion ability to achieve its intended goal. 23893950 Remotely controlled iridium-catalyzed asymmetric hydrogenation of terminal 1,1-diaryl alkenes. Working together: The presence of a remote directing group on terminal 1,1-diaryl and 1,1-dialkyl alkenes led to high and unprecedented enantioselectivity in iridium-catalyzed asymmetric hydrogenation. This strategy offers efficient synthetic pathways towards valuable enantiomerically enriched 1,1-diaryl and 1,1-dialkyl alkanes. Moreover, the directing group can be further functionalized. 23908239 Sequencing Y chromosomes resolves discrepancy in time to common ancestor of males versus females. The Y chromosome and the mitochondrial genome have been used to estimate when the common patrilineal and matrilineal ancestors of humans lived. We sequenced the genomes of 69 males from nine populations, including two in which we find basal branches of the Y-chromosome tree. We identify ancient phylogenetic structure within African haplogroups and resolve a long-standing ambiguity deep within the tree. Applying equivalent methodologies to the Y chromosome and the mitochondrial genome, we estimate the time to the most recent common ancestor (T(MRCA)) of the Y chromosome to be 120 to 156 thousand years and the mitochondrial genome T(MRCA) to be 99 to 148 thousand years. Our findings suggest that, contrary to previous claims, male lineages do not coalesce significantly more recently than female lineages. 23588257 Effects of isometric handgrip training dose on resting blood pressure and resistance vessel endothelial function in normotensive women. Isometric handgrip (IHG) training lowers resting blood pressure (BP) in both hypertensives and normotensives, yet the effect of training dose on the magnitude of reduction and the mechanisms associated with the hypotensive response are elusive. We investigated, in normotensive women, the effects of two different doses of IHG training on resting BP, and explored improved resistance vessel endothelial function and heart rate variability (HRV) as potential mechanisms of BP reduction. Resting BP, HRV, and resistance vessel endothelial function (venous strain-gauge plethysmography with reactive hyperemia) were assessed in 32 women before and after 4 and 8 weeks of 3×/week (n = 12) or 5×/week (n = 11) IHG training (four, 2-min unilateral contractions at 30 % maximal voluntary contraction), or 0×/week control (n = 9). IHG training decreased systolic BP in the 3×/week (94 ± 6 to 91 ± 6 to 88 ± 5 mmHg, pre- to mid- to post-training; P < 0.01) and 5×/week (97 ± 11 to 90 ± 9 to 91 ± 9 mmHg, P < 0.01) groups, concomitant with increased forearm reactive hyperemic blood flow (26 ± 7 to 30 ± 8 to 36 ± 9 mL/min/100 mL tissue, P < 0.01; and 26 ± 7 to 29 ± 7 to 38 ± 13 mL/min/100 mL tissue, P < 0.01, respectively), yet both remained unchanged in the control group. No changes were observed in diastolic BP, mean arterial BP, or any indices of HRV in any group (all P > 0.05). In conclusion, IHG training lowers resting systolic BP and improves resistance vessel endothelial function independent of training dose in normotensive women. 23820050 Reaction schemes, escape times and geminate recombinations in particle-based spatial simulations of biochemical reactions. Modeling the spatiotemporal dynamics of biochemical reaction systems at single-molecule resolution has become feasible with the increase of computing power and is applied especially to cellular signal transduction. For an association reaction the two molecules have to be in contact. Hence, a physically faithful model of the molecular interaction assumes non-overlapping molecules that interact at their surfaces (boundary scheme). For performance reasons, this model can be replaced by particles that can overlap and react when they are closer than a certain distance with a reaction probability (volume scheme). Here we present an analytical approximation for the reaction probability in the volume scheme and compare the volume- with the boundary scheme. A dissociation reaction, in contrast, creates two molecules next to each other. If the reaction is reversible, these two products can directly re-bind again, leading to an overestimation of the dimerized state in the simulation. We show how the correct recombination rate can be achieved if the products of the dissociation are placed at identical positions, but cannot react for a certain timespan. This refractory time corresponds to the completion of the diffusion-controlled dissociation of the two molecules to their contact distance ri + rj at [Formula: see text] with [Formula: see text] for molecules with radii ri and rj and diffusion coefficients Di and Dj, respectively. 23619607 The role of methyl-CpG binding protein 2 in liver fibrosis. Liver injure is induced by various insults such as alcohol abuse, if insults persistent, may result in the formation of liver fibrosis. Hepatic stellate cell (HSC) activation and transdifferentiation into hepatic myofibroblast, accompanied with potent pro-inflammatory and pro-fibrogenic activities and the down-regulation of anti-inflammatory anti-fibrogenic in gene expression in coordination with epigenetic modifications at the level of the chromatin structure, are pivotal events in liver fibrogenesis. In this review we focus on the role of the methyl-CpG binding protein 2 (MeCP2) transcriptional regulation of different target genes and the interaction MeCP2 with microRNAs (miRNAs) during liver fibrosis. In addition, we address different signaling pathways interacted with MeCP2 regulated HSC activation. Such approaches provide valuable insights into the potential targets of liver fibrosis, and are useful pointers for the development of future therapeutic strategies. 23104378 The crystal structure of human telomeric DNA complexed with berberine: an interesting case of stacked ligand to G-tetrad ratio higher than 1:1. The first crystal structure of human telomeric DNA in complex with the natural alkaloid berberine, produced by different plant families and used in folk medicine for millennia, was solved by X-ray diffraction method. The G-quadruplex unit features all-parallel strands. The overall folding assumed by DNA is the same found in previously reported crystal structures. Similarly to previously reported structures the ligand molecules were found to be stacked onto the external 5' and 3'-end G-tetrads. However, the present crystal structure highlighted for the first time, the presence of two berberine molecules in the two binding sites, directly interacting with each tetrad. As a consequence, our structural data point out a 2:1 ligand to G-tetrad molar ratio, which has never been reported before in a telomeric intramolecular quadruplex structure. 23922674 Morphoproteomic Profiling of the Mammalian Target of Rapamycin (mTOR) Signaling Pathway in Desmoplastic Small Round Cell Tumor (EWS/WT1), Ewing's Sarcoma (EWS/FLI1) and Wilms' Tumor(WT1). Desmoplastic small round cell tumor (DSRCT) is a rare sarcoma in adolescents and young adults. The hallmark of this disease is a EWS-WT1 translocation resulting from apposition of the Ewing's sarcoma (EWS) gene with the Wilms' tumor (WT1) gene. We performed morphoproteomic profiling of DSRCT (EWS-WT1), Ewing's sarcoma (EWS-FLI1) and Wilms' tumor (WT1) to better understand the signaling pathways for selecting future targeted therapies. This pilot study assessed patients with DSRCT, Wilms' tumor and Ewing's sarcoma. Morphoproteomics and immunohistochemical probes were applied to detect: p-mTOR (Ser2448); p-Akt (Ser473); p-ERK1/2 (Thr202/Tyr204); p-STAT3 (Tyr 705); and cell cycle-related analytes along with their negative controls. In DSRCT the PI3K/Akt/mTOR pathway is constitutively activated by p-Akt (Ser 473) expression in the nuclear compartment of the tumor cells and p-mTOR phosphorylated on Ser 2448, suggesting mTORC2 (rictor+mTOR) as the dominant form. Ewing's sarcoma had upregulated p-Akt and p-mTOR, predominantly mTORC2. In Wilm's tumor, the mTOR pathway is also activated with most tumor cells moderately expressing p-mTOR (Ser 2448) in plasmalemmal and cytoplasmic compartments. This coincides with the constitutive activation of one of the downstream effectors of the mTORC1 signaling pathway, namely p-p70S6K (Thr 389). There was constitutive activation of the Ras/Raf/ERK pathway p-ERK 1/2 (Thr202/Tyr204) expression in the Wilms tumor and metastatic Ewing's sarcoma, but not in the DSRCT. MORPHOPROTEOMIC TUMOR ANALYSES REVEALED CONSTITUTIVE ACTIVATION OF THE MTOR PATHWAY AS EVIDENCED BY: (a) expression of phosphorylated (p)-mTOR, p-p70S6K; (b) mTORC 2 in EWS and DSRCT; (c) ERK signaling was seen in the advanced setting indicating these as resistance pathways to IGF1R related therapies. This is the first morphoproteomic study of such pathways in these rare malignancies and may have potential therapeutic implications. Further study using morphoproteomic assessments of these tumors are warranted. 23849048 Resolving breast cancer heterogeneity by searching reliable protein cancer biomarkers in the breast fluid secretome. One of the major goals in cancer research is to find and evaluate the early presence of biomarkers in human fluids and tissues. To resolve the complex cell heterogeneity of a tumor mass, it will be useful to characterize the intricate biomolecular composition of tumor microenvironment (the so called cancer secretome), validating secreted proteins as early biomarkers of cancer initiation and progression. This approach is not broadly applicable because of the paucity of well validated and FDA-approved biomarkers and because most of the candidate biomarkers are mainly organ-specific rather than tumor-specific. For these reasons, there is an urgent need to identify and validate a panel of biomarker combinations for early detection of human tumors. This is especially important for breast cancer, the cancer spread most worldwide among women. It is well known that patients with early diagnosed breast cancer live longer, require less extensive treatment and fare better than patients with more aggressive and/or advanced disease. In the frame of searching breast cancer biomarkers (especially using nipple aspirate fluid mirroring breast microenvironment), studies have highlighted an optimal combination of well-known biomarkers: uPA + PAI-1 + TF. When individually investigated they did not show perfect accuracy in predicting the presence of breast cancer, whereas the triple combination has been demonstrated to be highly predictive of pre-cancer and/or cancerous conditions, approaching 97-100% accuracy. Despite the heterogeneous composition of breast cancer and the difficulties to find specific breast cancer biomolecules, the noninvasive analysis of the nipple aspirate fluid secretome may significantly improve the discovery of promising biomarkers, helping also the differentiation among benign and invasive breast diseases, opening new frontiers in early oncoproteomics. 23644999 Successful surgical repair of complex Christmas-tree pattern tracheo-bronchial anatomy with stenosis. Congenital anomalies of bronchial division are extremely rare. Presence of complete cartilaginous rings in bronchial tree with co-existent bronchial division anomalies make surgical correction more challenging, and needs a well-structured surgical pathway. We report a case of complex airway pattern similar to Christmas-tree appearance with associated stenosis due to complete rings, treated by modified sliding tracheoplasty with a successful outcome. 23929611 Tattoo pigment in axillary lymph node mimicking calcification of breast cancer. A tattoo is defined as the intentional or accidental deposit of pigment into the skin. The phenomenon of skin tattooing is on the rise worldwide and complications of tattooing are increasingly being recognised in diagnostic and clinical medicine. We describe a case of calcification-like changes on mammography resembling that of breast malignancy as a result of tattoo pigment deposition in an axillary lymph node. Recognition of such changes in routine breast screening is crucial to avoid further unnecessary invasive investigations and surgery in such patients. 23077183 Noncanonical suppression of GH-dependent isoforms of cytochrome P450 by the somatostatin analog octreotide. Octreotide is a potent somatostatin analog therapeutically used to treat several conditions including hyper GH secretion in patients with acromegaly. We infused, over 30 s, octreotide into male rats every 12 h for 6 days at levels considerably greater than typical human therapeutic doses. Unexpectedly, resulting circulating GH profile was characterized by pulses of higher amplitudes, longer durations, and greater total content than normal, but still contained an otherwise male-like episodic secretory profiles. In apparent disaccord, the normally elevated masculine expression levels (protein and/or mRNA) of CYP2C11 (accounting for >50% of the total hepatic cytochrome P450 content), CYP3A2, CYP2C7, and IGF1, dependent on the episodic GH profile, were considerably downregulated. We explain this contradiction by proposing that the requisite minimal GH-devoid interpulse durations in the masculine profile that solely regulate expression of at least CYP2C11 and IGF1 may be sufficiently reduced to suppress transcription of the hepatic genes. Alternatively, we observed that octreotide infusion may have acted directly on the hepatocytes to induce expression of immune response factors postulated to suppress CYP transcription and/or upregulate expression of several negative regulators (e.g. phosphatases and SOCS proteins) of the JAK2/STAT5B signaling pathway that normally mediates the upregulation of CYP2C11 and IGF1 by the masculine episodic GH profile. 23968576 Novel Kv1.3 blockers for immunosuppression: W02012155199. A recent patent application from Bionomics/Merck Serono describes novel compounds as blockers of the voltage-gated Kv1.3 ion channel. The blockade of this channel shows great promise as a new therapeutic target for the treatment of autoimmune disorders such as multiple sclerosis, psoriasis, diabetes and rheumatoid arthritis. The generic claim of this patent refers to a new chemotype of Kv1.3 blockers based on an amide core with potent IC50's which are potentially within the nanomolar range. This article briefly reviews the chemistry and biology found in the patent and compares it with previous discoveries in the field. 23771778 Enhanced cardiomyogenic lineage differentiation of adult bone-marrow-derived stem cells grown on cardiogel. The extracellular matrix (ECM) and its components are known to promote growth and cellular differentiation in vitro. Cardiogel, a three-dimensional extracellular matrix derived from cardiac fibroblasts, is evaluated for its cardiomyogenic-differentiation-inducing potential on bone-marrow-derived stem cells (BMSC). BMSC from adult mice were grown on cardiogel and induced to differentiate into specific lineages that were validated by morphological, phenotypic and molecular assays. The data revealed that the cardiogel enhanced cardiomyogenic and adipogenic differentiation and relegated osteogenic differentiation following specific induction. More importantly, increased cardiomyogenic differentiation was also observed following BMSC growth on cardiogel without specific chemical (5-azacytidine) induction. This is the first report of an attempt to use cardiogel as a biomaterial on which to achieve cardiomyogenic differentiation of BMSC without chemical induction. Our study suggests that cardiogel is an efficient extracellular matrix that enhances the cardiomyogenic differentiation of BMSC and that it can therefore be used as a scaffold for cardiac tissue regeneration. 23880197 Effects of ezetimibe, simvastatin and ezetimibe/simvastatin on correlations between apolipoprotein B, LDL cholesterol and non-HDL cholesterol in patients with primary hypercholesterolemia. Apolipoprotein (apo) B is highly predictive of coronary risk, especially in patients with high triglycerides (TG). This post hoc analysis evaluated the effects of lipid-lowering therapy on correlations between apoB and low-density lipoprotein cholesterol (apoB:LDL-C) and non-high-density lipoprotein cholesterol (apoB:non-HDL-C) in patients with TG< and ≥200 mg/dL. This analysis used data from 3 randomized clinical trials in patients with primary hypercholesterolemia receiving placebo, ezetimibe (EZE), simvastatin (SIMVA) or EZE/SIMVA for 12 weeks. Simple linear regression analyses predicted LDL-C and non-HDL-C levels corresponding to apoB values (80 mg/dL) at baseline and Week 12. ApoB correlated with LDL-C (r â‰¥ 0.76) and non-HDL-C (r â‰¥ 0.86) at baseline. The correlations were strengthened with SIMVA and EZE/SIMVA at Week 12 (r â‰¥ 0.88 for LDL-C and r â‰¥ 0.94 for non-HDL-C). The predicted LDL-C and non-HDL-C values were lower following treatment with SIMVA or EZE/SIMVA than for placebo and EZE. For SIMVA and EZE/SIMVA, the predicted LDL-C and non-HDL-C values were closer to more aggressive LDL-C and non-HDL-C levels (i.e., 70 and 100 mg/dL, respectively). The apoB:LDL-C and apoB:non-HDL-C correlations were weaker and the predicted LDL-C values were generally lower in high TG patients than in low TG patients both at baseline and Week 12. In contrast, the predicted non-HDL-C values were generally higher in high versus low TG patients at baseline but less so at Week 12. After treatment with EZE, SIMVA, or EZE/SIMVA, a given apoB value corresponds to lower LDL-C and non-HDL-C levels than those obtained from untreated patients. 23845218 1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazines, a novel class of 11ß-HSD1 inhibitors for the treatment of diabetes. Racemic cis-1,1-dioxo-5,6-dihydro-[4,1,2]oxathiazine derivative 4a was isolated as an impurity in a sample of a hit from a HTS campaign on 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). After separation by chiral chromatography the 4a-S, 8a-R enantiomer of compound 4a was identified as the true, potent enzyme inhibitor. The cocrystal structure of 4a with human and murine 11ß-HSD1 revealed the unique binding mode of the oxathiazine series. SAR elucidation and optimization in regard to metabolic stability led to monocyclic tetramethyloxathiazines as exemplified by compound 21g. 23609961 Design, synthesis and spectroscopic characterisation of a focused library based on the polyandrocarpamine natural product scaffold. A focused library based on the marine natural products polyandrocarpamines A (1) and B (2) has been designed and synthesised using parallel solution-phase chemistry. In silico physicochemical property calculations were performed on synthetic candidates in order to optimise the library for drug discovery and chemical biology. A library of ten 2-aminoimidazolone products (3-12) was prepared by coupling glycocyamidine and a variety of aldehydes using a one-step stereoselective aldol condensation reaction under microwave conditions. All analogues were characterised by NMR, UV, IR and MS. The library was evaluated for cytotoxicity towards the prostate cancer cell lines, LNCaP, PC-3 and 22Rv1. Copyright © 2013 John Wiley & Sons, Ltd. 23225068 Discharge of patients to long-term care from a large acute hospital over a 12-year period. Several factors may be important in determining the discharge of patients to long-term care from the acute hospital. We aimed to look at factors associated with discharge to long-term care from St. James's Hospital, Dublin between 1997 and 2008. Data obtained from a long-term care database within the geriatric service were analysed. This service is responsible for assessing and listing all patients for long-term care within the hospital. 3,107 patients were listed and 2,520 discharged to long-term care during the period. Mean age was 81.7±7.3 years and 64.1% were female. The number listed increased since 1997, but there was no change in age or gender. Median time to discharge was 52 days, but varied by year and was longer for public versus private facilities (mean difference=18 days, P=0.006). Mortality of those awaiting long-term care was 17.0%, but varied significantly by year and ranged form 9.3-29.0%. Mortality was higher in males, in those of older age and during the winter months. Variation in the time to discharge appears to be associated with changes in the provision of publicly funded private nursing home beds. 23606422 Patterns and mutational signatures of tandem base substitutions causing human inherited disease. Tandem base substitutions (TBSs) are multiple mutations that comprise two or more contiguous nucleotide substitutions without any net gain or loss of bases. They have recently become recognized as a distinct category of human genomic variant. However, their role in causing human inherited disease so far has not been studied methodically. Here, using data from the Human Gene Mutation Database (http://www.hgmd.org), we identified 477 events to be TBSs (doublets, 448; triplets, 16; and quadruplets to octuplets, 13). A comprehensive sequence pattern and context analysis implied the likely fundamental importance of translesion synthesis (TLS) DNA polymerases in generating these diverse TBSs but revealed that TLS polymerases may operate differently in generating TBSs of ≤3 bases (bypass of endogenous DNA lesions) than those of ≥4 bases (serial replication slippage). Moreover, GC was found to be the most frequently affected dinucleotide with GC/GC>AA/TT being the most frequent double TBS. Comparison with cancer genome mutational spectra allowed us to conclude that human germline TBSs arise predominantly through the action of endogenous mechanisms of mutagenesis rather than through exposure to exogenous mutagens. Finally, the rates of double and triple TBSs were estimated to be 0.2-1.2 Ã— 10(-10) and 0.8-4.8 Ã— 10(-12) per base per generation, respectively. 23852384 Models of Frequency-dependent Selection with Mutation from Parental Alleles. Frequency-dependent selection (FDS) remains a common heuristic explanation for the maintenance of genetic variation in natural populations. The pairwise-interaction model (PIM) is a well-studied general model of frequency-dependent selection, which assumes that a genotype's fitness is a function of within-population intergenotypic interactions. Previous theoretical work indicated that this type of model is able to sustain large numbers of alleles at a single locus when it incorporates recurrent mutation. These studies, however, have ignored the impact of the distribution of fitness effects of new mutations on the dynamics and end-results of polymorphism construction. We suggest that a natural way to model mutation would be to assume mutant fitness is related to the fitness of the parental allele, i.e., the existing allele from which the mutant arose. Here we examine the numbers and distributions of fitnesses and alleles produced by construction under the PIM with mutation from parental alleles, and the impacts on such measures due to different methods of generating mutant fitnesses. We find that, in comparison with previous results, generating mutants from existing alleles lowers the average number of alleles likely to be observed in a system subject to FDS, but produces polymorphisms that are highly stable and have realistic allele-frequency distributions. 23842844 Imaging reactions of acetone with oxygen adatoms on partially oxidized TiO2(110). Understanding the interaction of O2 with ketones on metal oxide surfaces is important for the photo-oxidation of toxic organic molecules. The consecutive reaction steps of acetone molecules with oxygen adatoms (Oa's) on partially oxidized TiO2(110) surfaces have been studied using high-resolution scanning tunneling microscopy (STM) at 300 K. The sequential isothermal STM images reveal two types of acetone-Oa species as a result of reactions of acetone with an oxygen adatom and a bridging bound oxygen vacancy (VO). One such species is the Ti5c-bound acetone-Oa diolate formed from Ti5c-bound acetone reacting with Oa. The diolate is mobile at 300 K and can assist the diffusion of surface Oa by exchanging the acetone oxygen with the Oa. The second acetone-Oa species is the VO-bound acetone-Oa complex formed from a VO-bound acetone reacting with an Oa located on the neighboring Ti row. The VO-bound complex is stationary at 300 K. This species has not been reported previously. 23949627 Decreasing operating potential for water electrolysis to hydrogen via local confinement of iron-based soft coordination suprapolymers. Currently there is intense interest in decreasing the operating potential for hydrogen evolution in water electrolysis to considerably decrease the energy cost. In this work we report a significant decrease of the operating potential for hydrogen evolution from neutral water mediated by an iron based soft coordination polymer (Fe(III)-SCSP). The creation of a local acidic environment with a thickness in the range of ∼40 nm on the surface of a glassy carbon electrode allows enrichment of H(+) on the GCE, so that the operating potentials were effectively decreased. This strategy thus generates a new paradigm for lowering the operating potential of hydrogen generation from neutral water without the use of additional acids and organic cosolvents. 23953670 Validation of shear wave elastography in skeletal muscle. Skeletal muscle is a very dynamic tissue, thus accurate quantification of skeletal muscle stiffness throughout its functional range is crucial to improve the physical functioning and independence following pathology. Shear wave elastography (SWE) is an ultrasound-based technique that characterizes tissue mechanical properties based on the propagation of remotely induced shear waves. The objective of this study is to validate SWE throughout the functional range of motion of skeletal muscle for three ultrasound transducer orientations. We hypothesized that combining traditional materials testing (MTS) techniques with SWE measurements will show increased stiffness measures with increasing tensile load, and will correlate well with each other for trials in which the transducer is parallel to underlying muscle fibers. To evaluate this hypothesis, we monitored the deformation throughout tensile loading of four porcine brachialis whole-muscle tissue specimens, while simultaneously making SWE measurements of the same specimen. We used regression to examine the correlation between Young's modulus from MTS and shear modulus from SWE for each of the transducer orientations. We applied a generalized linear model to account for repeated testing. Model parameters were estimated via generalized estimating equations. The regression coefficient was 0.1944, with a 95% confidence interval of (0.1463-0.2425) for parallel transducer trials. Shear waves did not propagate well for both the 45° and perpendicular transducer orientations. Both parallel SWE and MTS showed increased stiffness with increasing tensile load. This study provides the necessary first step for additional studies that can evaluate the distribution of stiffness throughout muscle. 23096776 Midstream Modulation in Biotechnology Industry: Redefining What is 'Part of the Job' of Researchers in Industry. In response to an increasing amount of policy papers stressing the need for integrating social and ethical aspects in Research and Development (R&D) practices, science studies scholars have conducted integrative research and experiments with science and innovation actors. One widely employed integration method is Midstream Modulation (MM), in which an 'embedded humanist' interacts in regular meetings with researchers to engage them with the social and ethical aspects of their work. While the possibility of using MM to enhance critical reflection has been demonstrated in academic settings, few attempts have been made to examine its appropriateness in industry. This paper describes the outcomes of a case study aiming to find out firstly whether MM can effectively be deployed to encourage and facilitate researchers to actively include social and ethical aspects in their daily R&D practice, and secondly to what extent the integration activities could form an integral part of the engaged industrial researchers' professional activities. Our data show that after MM, researchers display increased reflexive awareness on the social and ethical aspects of their work and acknowledge the relevance and utility of such aspects on their daily practice. Also, all participants considered actively reflecting on social and ethical aspects to be part of their work. Future research on the role of MM in industrial settings could focus on how to embed social and ethical integration as a regular part of innovation practice. We suggest that one possibility would be through aligning social and ethical aspects with innovation Key Performance Indicators. 23535350 Use of asenapine in clinical practice for the management of bipolar mania. Bipolar disorder is a chronic mental illness associated with high levels of somatic morbidity, comorbidity and mortality. Treatment guidelines for bipolar mania generally recommend initiating first-line therapy with a second-generation antipsychotic or mood stabiliser, either alone or in combination. Asenapine is a second-generation antipsychotic with a unique receptor binding profile, licensed for the treatment of manic episodes in adults with bipolar I disorder. 'Real-world' data are needed to complement evidence from clinical trials, in order to provide clinicians with pragmatic information regarding the likely risks and benefits of using a new agent in clinical practice. Evidence from real-world case reports demonstrates that - as in clinical trials - asenapine is effective in treating mania and mixed episodes associated with bipolar I disorder, whether used as monotherapy or in combination with a mood stabiliser. It has a rapid onset of antimanic effect and an early improvement is associated with treatment outcome. Asenapine also shows promise in controlling depressive symptoms and clinically challenging mixed states. Asenapine has a favourable tolerability profile, compared with other first-line agents, having a minimal impact on weight and metabolic parameters. Asenapine should be considered a first-line treatment option for adults with bipolar I disorder. 23936628 Mechanism of ubiquitin ligation and lysine prioritization by a HECT E3. Ubiquitination by HECT E3 enzymes regulates myriad processes, including tumor suppression, transcription, protein trafficking, and degradation. HECT E3s use a two-step mechanism to ligate ubiquitin to target proteins. The first step is guided by interactions between the catalytic HECT domain and the E2∼ubiquitin intermediate, which promote formation of a transient, thioester-bonded HECT∼ubiquitin intermediate. Here we report that the second step of ligation is mediated by a distinct catalytic architecture established by both the HECT E3 and its covalently linked ubiquitin. The structure of a chemically trapped proxy for an E3∼ubiquitin-substrate intermediate reveals three-way interactions between ubiquitin and the bilobal HECT domain orienting the E3∼ubiquitin thioester bond for ligation, and restricting the location of the substrate-binding domain to prioritize target lysines for ubiquitination. The data allow visualization of an E2-to-E3-to-substrate ubiquitin transfer cascade, and show how HECT-specific ubiquitin interactions driving multiple reactions are repurposed by a major E3 conformational change to promote ligation. DOI:http://dx.doi.org/10.7554/eLife.00828.001. 23544460 Nickel and Cobalt-Catalyzed Coupling of Alkyl Halides with Alkenes via Heck Reactions and Radical Conjugate Addition. Cross-coupling of alkyl halides with alkenes leading to Heck-type and addition products is summarized. The development of Heck reaction with aliphatic halides although has made significant progress in the past decade and particularly recently, it was much less explored in comparison with the aryl halides. The use of Ni- and Co-catalyzed protocols allowed efficient Heck coupling of activated and unactivated alkenes with 1(o), 2(o) and 3(o) alkyl halides. In addition, radical conjugate addition to activated alkenes has become a well-established method that has led to efficient construction of many natural products. The utilization of Ni- and Co-catalyzed strategies would avoid toxic tin reagents, and therefore worth exploring. The recent development of Ni- and Co-catalyzed addition of alkyl halides to alkenes displays much improved reactivity and functional group tolerance. In this mini-review, we also attempt to overview the mechanisms that are proposed in the reactions, aiming at providing insight into the nickel and cobalt-catalyzed coupling of alkyl halides with alkenes. 23461881 Microwave-assisted synthesis and tyrosinase inhibitory activity of chalcone derivatives. A series of chalcones and their derivatives were synthesized, and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed that some of the synthesized compounds exhibited significant inhibitory activity, and four compounds exhibited more potent tyrosinase inhibitory activity than the reference standard inhibitor kojic acid (5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one). Specifically, 1-(-1-(4-methoxyphen- yl)-3-phenylallylidene)thiosemicarbazide (18) exhibited the most potent tyrosinase inhibitory activity with IC₅₀ value of 0.274 μM. The inhibition mechanism analysis of 1-(-1-(2,4-dihydroxyphenyl)-3-phenylallylidene) thiosemicarbazide (16) and 1-(-1-(4-methoxyphenyl)-3-phenylallylidene) thiosemicarbazide (18) demonstrated that the inhibitory effects of the two compounds on the tyrosinase were irreversible. Preliminary structure activity relationships' analysis suggested that further development of such compounds might be of interest. 23830575 Programmable shunt valves for the treatment of hydrocephalus: A systematic review. To evaluate the clinical effectiveness of programmable valves compared with non-programmable valves of hydrocephalus. In this paper, the authors report a systematic review and meta-analysis of complications and revision rate for programmable valves and non-programmable implantation. Randomized or non-randomized controlled trials of hydrocephalus treated by programmable and non-programmable valves were considered for inclusion. Seven published reports of eligible studies involving 1702 participants meet the inclusion criteria. Compared with non-programmable, programmable valves had no significant difference in catheter-related complications [RR = 0.88, 95%CI (0.66,1.19), p = 0.10] and infection rate [RR = 1.25, 95%CI (0.92,1.69), p = 1.00]. There were significant differences in overall complications [RR = 0.80, 95%CI (0.67,0.96), p < 0.01], over-drainage or under-drainage complications [RR = 0.44, 95%CI (0.31,0.63), p < 0.01] and revision rate [RR = 0.56, 95%CI (0.45,0.69), p < 0.01] in favor of programmable valves. Although the studies seem to demonstrate a small advantage for the programmable shunts, the probable bias and the difficulties in patient selection are too important to make a general conclusion. 23881723 Targeting the Gut-Liver Axis in Cirrhosis: Antibiotics and Non-Selective β-Blockers. The gut-liver axis in cirrhosis and portal hypertension is gaining increasing attention as a key pathophysiological mechanism responsible for progression of liver failure and development of complications such as spontaneous infections and hepatocellular carcinoma. Antibiotics and non-selective β-blockers (NSBB) intercept this axis and each drug has proven efficacy in clinical trials. A synergistic effect is a hitherto unproven possibility. There is an increasing body of evidence supporting improved outcome with expanded use of NSBB and antibiotic therapy beyond current indications. This review addresses the issue of pharmacological treatment of cirrhosis and portal hypertension with antibiotics and NSBB. We discuss their mechanism of action and suggest that combining the two treatment modalities could potentially reduce the risk of complications. 23194568 Comparison of consumer perception and acceptability for steaks cooked to different endpoints: validation of photographic approach. Photographs have been used to enhance consumer reporting of preference of meat doneness, however, the use of photographs has not been validated for this purpose. This study used standard cooking methods to produce steaks of five different degrees of doneness (rare medium, medium well, well done and very well done) to study the consumer's perception of doneness, from both the external and internal surface of the cooked steak and also from corresponding photographs of each sample. Consumers evaluated each surface of the cooked steaks in relation to doneness for acceptability, 'just about right' and perception of doneness. Data were analysed using a split plot ANOVA and least significant test. Perception scores (for both external and internal surfaces) between different presentation methods (steak samples and corresponding photos), were not significantly different (p>0.05). The result indicates that photographs can be used as a valid approach for assessing preference for meat doneness. 22086211 Dietary L-glutamine supplementation improves pregnancy outcome in mice infected with type-2 porcine circovirus. Porcine circovirus type 2 (PCV2) causes reproductive failure in swine. As glutamine can enhance immune function in animals, this study was conducted with mice to test the hypothesis that dietary glutamine supplementation will improve pregnancy outcome in PCV2-infected dams. Beginning on day 0 of gestation, mice were fed a standard diet supplemented with 1.0% L-glutamine or 1.22% L-alanine (isonitrogenous control). All mice were infected with PCV2 (2000 TCID50) on day 10 of gestation. On day 17 of gestation, six mice from each group were euthanized to obtain maternal tissues and fetuses for hematology and histopathology tests. The remaining mice continued to receive their respective diets supplemented with 1.0% L-glutamine or 1.22% L-alanine through lactation. The PCV2 virus was present in maternal samples (serum and lung) of most mice in the control group but was not detected in the glutamine-supplemented mice. Dietary glutamine supplementation reduced abortion, decreased fetal deaths, and enhanced neonatal survival. The glutamine treatment also reduced concentrations of interleukin-6, while increasing concentrations of tumor necrosis factor-α and C-reactive protein, in the maternal serum of mice. Furthermore, glutamine supplementation attenuated microscopic lesions in maternal tissues (lung, spleen, and liver). Collectively, these results indicate that dietary glutamine supplementation is beneficial for ameliorating reproductive failure in virus-infected mice. The findings support the notion that gestating dams require adequate amounts of dietary glutamine for the optimal survival and growth of embryos, fetuses, and neonates, and have important implications for nutritional support of mammals (including swine and humans) during gestation and lactation. 23941277 Dispersed Three-Pulse Infrared Photon Echoes of Nitrous Oxide in Water and Octanol. Dispersed IR three-pulse photon echoes due to the antisymmetric (ν3) stretch mode of N2O dissolved in H2O and 1-octanol at room temperature are reported and analyzed. The experimentally determined transition frequency-frequency correlation function (FFCF) in these two solvents is explained in terms of inertial solvent contributions, hydrogen bond network fluctuations and, for octanol, the motions of the alkly chains. The H2O hydrogen bond fluctuations result in 1.5 ps FFCF decay in agreement with relaxation rates determined from photon echo based measurements of other aqueous solutions including salt solutions. In octanol, hydrogen bond fluctuations decay on a slower timescale of 3.3 ps and alkyl chain motions result an inhomogeneous broadening contribution to the ν3 absorption spectrum that decay on a 35 ps timescale. Rotational reorientation of N2O is nearly three times faster in octanol as compared to water. Although the vibrational ν3 N2O absorption line shapes in water and octanol are similar, the line widths result from different coherence loss mechanisms. A hot band contribution in the N2O in octanol solution is found to have a significant effect on the echo spectrum due to its correspondingly stronger transition moment than that of the fundamental transition. The dephasing dynamics of the N2O ν3 stretch mode is of interest as a probe in ultrafast studies of complex or nano-confined systems with both hydrophobic and hydrophilic regions such as phospholipids, nucleic acids and proteins. These results demonstrate the value of the N2O molecule to act as a reporter of equilibrium fluctuations in such complex systems particularly due to its solubility characteristics and long vibrational lifetime. 23746588 Accuracy of genomic prediction for milk production traits in the Chinese Holstein population using a reference population consisting of cows. Genomic selection using dense markers covering the whole genome is a tool for the genetic improvement of livestock and is revolutionizing the breeding system in dairy cattle. Progeny-tested bulls have been used to form reference populations in almost all countries where genomic selection has been implemented. In this study, the accuracy of genomic prediction when cows are used to form the reference population was investigated. The reference population consisted of 3,087 cows. All individuals were genotyped with Illumina BovineSNP50. After genotype imputation and editing, 48,676 single nucleotide polymorphisms were available for analysis. Two methods, genomic BLUP (GBLUP) and BayesB, were used to render genomic estimated breeding values (GEBV) for 5 milk production traits. Accuracies of GEBV were assessed in 3 ways: rGEBV,EBV (the correlation between GEBV and conventional EBV) in 67 progeny-tested bulls, rGEBV,EBV from a 5-fold cross validation in the 3,087 cow reference population, and the theoretical accuracy (for GBLUP) calculated in the same way as for conventional BLUP. The results showed that using GBLUP, the rGEBV,EBV and theoretical accuracy of genomic prediction in Chinese Holstein ranged from 0.59 to 0.76 and 0.70 to 0.80, respectively, which was 0.13 to 0.30 and 0.23 to 0.33 higher than the accuracies of conventional pedigree index, respectively. The results indicate that, as an alternative, genomic selection using cows in the reference population is feasible. 23929302 Glioma-derived galectin-1 regulates innate and adaptive antitumor immunity. Galectin-1 is a glycan-binding protein which is involved in the aggressive nature of glioblastoma (GBM) in part by stimulating angiogenesis. In different cancer models, galectin-1 has been demonstrated to play a pivotal role in tumor-mediated immune evasion especially by modulating cells of the adaptive immune system. It is yet unknown however whether the absence or presence of galectin-1 within the glioma microenvironment also causes qualitative or quantitative differences in innate and/or adaptive antitumor immune responses. All experiments were performed in the orthotopic GL261 mouse high-grade glioma model. Stable galectin-1 knockdown was achieved via transduction of parental GL261 tumor cells with a lentiviral vector encoding a galectin-1-targeting miRNA. We demonstrated that the absence of tumor-derived but not of host-derived galectin-1 significantly prolonged the survival of glioma-bearing mice as such and in combination with dendritic cell (DC)-based immunotherapy. Both flow cytometric and pathological analysis revealed that the silencing of glioma-derived galectin-1 significantly decreased the amount of brain-infiltrating macrophages and myeloid-derived suppressor cells (MDSC) in tumor-bearing mice. Additionally, we revealed a pro-angiogenic role for galectin-1 within the glioma microenvironment. The data provided in this study reveal a pivotal role for glioma-derived galectin-1 in the regulation of myeloid cell accumulation within the glioma microenvironment, the most abundant immune cell population in high-grade gliomas. Furthermore, the prolonged survival observed in untreated and DC-vaccinated glioma-bearing mice upon the silencing of tumor-derived galectin-1 strongly suggest that the in vivo targeting of tumor-derived galectin-1 might offer a promising and realistic adjuvant treatment modality in patients diagnosed with GBM. © 2013 Wiley Periodicals, Inc. 23956025 Breast implants and anaplastic large cell lymphoma: A Danish population-based cohort study. Background:A potential link between breast implants and anaplastic large cell lymphoma (ALCL) has been suggested. Methods:We examined lymphoma occurrence in a nationwide cohort of 19,885 Danish women who underwent breast implant surgery during 1973-2010. Standardized incidence ratios, with 95% confidence intervals (CI), for ALCL and lymphoma overall associated with breast implantation were calculated. Results:: During 179,246 person-years of follow-up, we observed 31 cases of lymphoma among cohort members. No cases of ALCL were identified. SIRs for ALCL and lymphoma overall were 0 (95% CI, 0-10.3) and 1.20 (95% CI, 0.82-1.70), respectively. Conclusions:In our nationwide cohort study, we did not find an increased risk of lymphoma in general, or ALCL in particular, among Danish women who underwent breast implantation. However, our evaluation of ALCL risk was limited by the rarity of the disease. Impact:Our results do not support an association between breast implants and ALCL and are consistent with other studies on cancer-risk and breast implants. 23395549 Mucosa-associated lymphoid tissue lymphoma of the thyroid with abundant IgG4-positive plasma cells. A case of thyroidal mucosa-associated lymphoid tissue (MALT) lymphoma mimicking IgG4-related disease is described. A 54-year-old male presented with acute swelling of the anterior neck. Anaplastic thyroid carcinoma (ATC), malignant lymphoma (ML), or acute deterioration of Hashimoto's thyroiditis were initially suspected, and an emergent tracheostomy was required for progressive airway obstruction; a simultaneous biopsy from the thyroid tissue was performed. Histopathologically, the lesion consisted of sclerotic fibrosis and diffuse and dense infiltration by small lymphoid cells without atypia and plasma cells, many of which were IgG4-positive. Blood examination also revealed high serum IgG4 levels. Riedel's thyroiditis was suspected. However, despite medical treatments, a firm swelling of the thyroid still remained. In an in situ hybridization study, IgG4-negative plasma cells showed immunoglobulin light-chain restriction (κ-monotype), and immunoglobulin heavy (IgH) chain gene monoclonal re-arrangement was detected by polymerase chain reaction. The lesion was finally diagnosed as MALT lymphoma. When IgG4-related disease is suspected, it is important to thoroughly exclude other possibilities. 23180160 Integrated pharmacokinetic-driven approach to screen candidate anticancer drugs for brain tumor chemotherapy. The goal of the study was to develop an effective screening strategy to select new agents for brain tumor chemotherapy from a series of low molecular weight anticancer agents [ON123x] by the combined use of in silico, in vitro cytotoxicity, and in vitro ADME profiling studies. The results of these studies were cast into a pipeline of tier 1 and tier 2 procedures that resulted in the identification of ON123300 as the lead compound. Of the 154 ON123xx compounds, 13 met tier 1 screening criteria based on physicochemical properties [i.e., MW < 450 Da, predicted log P between 2 and 3.5] and in vitro glioma cell cytotoxicity [i.e., IC50 < 10 μM] and were further tested in tier 2 assays. The tier 2 profiling studies consisted of metabolic stability, MDCK-MDR1 cell permeability and plasma and brain protein binding that were combined to globally assess whether favorable pharmacokinetic properties and brain penetration could be achieved in vivo. In vivo cassette dosing studies were conducted in mice for 12 compounds that permitted examination of in vitro/in vivo relationships that confirmed the suitability of the in vitro assays. A parameter derived from the in vitro assays accurately predicted the extent of drug accumulation in the brain based on the area under the drug concentration-time curve in brain measured in the cassette dosing study (r (2) = 0.920). Overall, the current studies demonstrated the value of an integrated pharmacokinetic-driven approach to identify potentially efficacious agents for brain tumor chemotherapy. 23932118 Vena cava filters for management of venous thromboembolism: A clinical review. Venous thromboembolism (VTE) is the common cause of morbidity and mortality. Vena cava filters (VCF) represent an important alternative to anticoagulation for management of VTE. VCF use has increased dramatically with the availability of retrievable filters. Since indiscriminate use of VCF can be associated with net patient harm, knowledge of the risks and benefits of these devices is essential to optimal evidence-based practice. In this review, we will examine the characteristics of available permanent and optional VCF, their efficacy and safety in management of VTE and discuss appropriate, extended and unsubstantiated indications for VCF use. We will also review the clinical outcomes of VCF in alternative placement sites (supra-renal inferior vena cava and superior vena cava) and in specialized patient populations (bariatric surgery, cancer, etc.), recommendations regarding anticoagulation for prevention of thrombosis as well as recommended follow up for patients with VCF. 23044793 Optical imaging techniques for point-of-care diagnostics. Improving access to effective and affordable healthcare has long been a global endeavor. In this quest, the development of cost-effective and easy-to-use medical testing equipment that enables rapid and accurate diagnosis is essential to reduce the time and costs associated with healthcare services. To this end, point-of-care (POC) diagnostics plays a crucial role in healthcare delivery in both developed and developing countries by bringing medical testing to patients, or to sites near patients. As the diagnosis of a wide range of diseases, including various types of cancers and many endemics, relies on optical techniques, numerous compact and cost-effective optical imaging platforms have been developed in recent years for use at the POC. Here, we review the state-of-the-art optical imaging techniques that can have a significant impact on global health by facilitating effective and affordable POC diagnostics. 23822656 Evidence based herbal drug standardization approach in coping with challenges of holistic management of diabetes: a dreadful lifestyle disorder of 21st century. Plants by virtue of its composition of containing multiple constituents developed during its growth under various environmental stresses providing a plethora of chemical families with medicinal utility. Researchers are exploring this wealth and trying to decode its utility for enhancing health standards of human beings. Diabetes is dreadful lifestyle disorder of 21st century caused due to lack of insulin production or insulin physiological unresponsiveness. The chronic impact of untreated diabetes significantly affects vital organs. The allopathic medicines have five classes of drugs, or otherwise insulin in Type I diabetes, targeting insulin secretion, decreasing effect of glucagon, sensitization of receptors for enhanced glucose uptake etc. In addition, diet management, increased food fiber intake, Resistant Starch intake and routine exercise aid in managing such dangerous metabolic disorder. One of the key factors that limit commercial utility of herbal drugs is standardization. Standardization poses numerous challenges related to marker identification, active principle(s), lack of defined regulations, non-availability of universally acceptable technical standards for testing and implementation of quality control/safety standard (toxicological testing). The present study proposed an integrated herbal drug development & standardization model which is an amalgamation of Classical Approach of Ayurvedic Therapeutics, Reverse Pharmacological Approach based on Observational Therapeutics, Technical Standards for complete product cycle, Chemi-informatics, Herbal Qualitative Structure Activity Relationship and Pharmacophore modeling and, Post-Launch Market Analysis. Further studies are warranted to ensure that an effective herbal drug standardization methodology will be developed, backed by a regulatory standard guide the future research endeavors in more focused manner. 23817676 Evaluating hyperglycaemia in the hospitalised patient: towards an improved system for classification and treatment. Hyperglycaemia is common amongst hospitalised patients. Some of this is due to pre-existing diabetes (either previously diagnosed or not), but a proportion is due to stress hyperglycaemia, a transient state of high blood sugars related to the underlying illness. We aimed to estimate the prevalence of hyperglycaemia in an Irish hospital setting, including an assessment of what contribution is made by cases of stress hyperglycaemia. Over a 9-day period, all bedside glucometer-measured point of care blood glucoses performed in medical and surgical wards in University Hospital Galway were examined. Medical case notes and our diabetes computerised database were analysed to identify individuals with pre-existing diabetes. Glycosylated haemoglobin (HbA1c) was measured on the remainder of patients, to differentiate between pre-existing diabetes (HbA1c â‰¥ 48 mmol/mol) and stress hyperglycaemia (HbA1c < 48 mmol/mol). A total of 1,637 glucose readings were performed on 262 in-patients, of which 164 (63 %) were in the hyperglycaemic range. Of the 126 eligible for study inclusion, 92 (73 %) had pre-existing diabetes and 11 (9 %) had previously undiagnosed diabetes. The remaining 20 patients (16 %) had stress hyperglycaemia. We report a high prevalence of hyperglycaemia (including stress hyperglycaemia) in an in-patient cohort in whom testing was undertaken at the discretion of the treating physician. Our data illustrate the utility of HbA1c measurement in this setting to help differentiate between pre-existing diabetes and stress hyperglycaemia. Much work remains to be done on how to best identify and treat in-patient hyperglycaemia. 23696475 Spirocyclic aromatic hydrocarbon-based organic nanosheets for eco-friendly aqueous processed thin-film non-volatile memory devices. Supramolecular steric hindrance designs make pyrene-functionalized spiro[fluorene-9,7'-dibenzo[c,h]acridine]-5'-one (Py-SFDBAO) assemble into 2D nanostructures that facilitate aqueous phase large-area synthesis of high-quality and uniform crystalline thin films. Thin-film diodes using aqueous nanosheets as active layers exhibit a non-volatile bistable electrical switching feature with ON/OFF ratios of 6.0 × 10(4) and photoswitching with conductive gains of 10(2) -10(3) . Organic nanosheets are potentially key components for eco-friendly aqueous dispersed organic nano-inks in the application of printed and flexible electronics. 23853709 Nutrient restriction enhances the proliferative potential of cells lacking the tumor suppressor PTEN in mitotic tissues. How single cells in a mitotic tissue progressively acquire hallmarks of cancer is poorly understood. We exploited mitotic recombination in developing Drosophila imaginal tissues to analyze the behavior of cells devoid of the tumor suppressor PTEN, a negative regulator of PI3K signaling, under varying nutritional conditions. Cells lacking PTEN strongly overproliferated specifically in nutrient restricted larvae. Although the PTEN mutant cells were sensitive to starvation, they successfully competed with neighboring cells by autonomous and non-autonomous mechanisms distinct from cell competition. The overgrowth was strictly dependent on the activity of the downstream components Akt/PKB and TORC1, and a reduction in amino acid uptake by reducing the levels of the amino acid transporter Slimfast caused clones of PTEN mutant cells to collapse. Our findings demonstrate how limiting nutritional conditions impact on cells lacking the tumor suppressor PTEN to cause hyperplastic overgrowth. DOI:http://dx.doi.org/10.7554/eLife.00380.001. 23319076 Spontaneous and experimental intoxication of cattle by Simarouba versicolor A. St.-Hill (Simaroubaceae). This study describes an outbreak of Simarouba versicolor intoxication in cattle from Mato Grosso do Sul, Brazil, and reproduces it experimentally. Clinical signs of the affected animals were weakness, tremors, hind limbs incoordination, reluctance to move, sternal and lateral recumbency and death. The main necropsy findings, observed in the abomasum and in segments of the small and large intestines, were diffuse redness and mucosal and serosal swelling. Histological examination revealed necrosis of lymphoid tissues and necrotizing enterocolitis. One experiment was carried out using 3 male calves to test the toxicity of a single dose of S. versicolor leaves at 15 g/kg, 5 g/kg and 2.5 g/kg. Clinical signs, necropsy findings and histological examination of calves receiving 15 g/kg and 5 g/kg leaves were similar to those of cattle from the intoxication outbreak. The calf fed 2.5 g/kg leaves developed clinical symptoms of poisoning and recovered naturally. In a second experiment, two male calves received daily administration of S. versicolor leaves at 1.5 g/kg and 2.5 g/kg for 10 days. They developed clinical signs of intoxication within 24 h and recovered eight to nine days after the leaves were administered. These findings suggest that S. versicolor was responsible for the outbreak studied, although this plant does not have cumulative intoxication effects on cattle. 22231567 Genetic and epigenetic regulation of the organic cation transporter 3, SLC22A3. Human organic cation transporter 3 (OCT3 and SLC22A3) mediates the uptake of many important endogenous amines and basic drugs in a variety of tissues. OCT3 is identified as one of the important risk loci for prostate cancer, and is markedly underexpressed in aggressive prostate cancers. The goal of this study was to identify genetic and epigenetic factors in the promoter region that influence the expression level of OCT3. Haplotypes that contained the common variants, g.-81G>delGA (rs60515630) (minor allele frequency 11.5% in African American) and g.-2G>A (rs555754) (minor allele frequency>30% in all ethnic groups) showed significant increases in luciferase reporter activities and exhibited stronger transcription factor-binding affinity than the haplotypes that contained the major alleles. Consistent with the reporter assays, OCT3 messenger RNA expression levels were significantly higher in Asian (P<0.001) and Caucasian (P<0.05) liver samples from individuals who were homozygous for g.-2A/A in comparison with those homozygous for the g.-2G/G allele. Studies revealed that the methylation level in the basal promoter region of OCT3 was associated with OCT3 expression level and tumorigenesis capability in various prostate cancer cell lines. The methylation level of the OCT3 promoter was higher in 62% of prostate tumor samples compared with matched normal samples. Our studies demonstrate that genetic polymorphisms in the proximal promoter region of OCT3 alter the transcription rate of the gene and may be associated with altered expression levels of OCT3 in human liver. Aberrant methylation contributes to the reduced expression of OCT3 in prostate cancer. 23845089 Overexpression of Epstein-Barr virus-induced gene 3 protein (EBI3) in MRL/lpr mice suppresses their lupus nephritis by activating regulatory T cells. Abstract To identify the effect of an imbalance of Th1/Th2 cytokines on the development of autoimmune glomerulonephritis (lupus nephritis), we studied the modification of pathological changes in diffuse proliferative glomerulonephritis (DPGN) and membranous glomerulonephritis (MGN) in MRL/lpr mice, which are animal models of systemic lupus erythematosus (SLE). Transgenic MRL/lpr mice (Tg) that overexpressed Epstein--Barr virus-induced gene 3 (EBI3) showed almost normal renal function, which was demonstrated by healing of glomerulonephritis upon renal histology, as compared to the wild-type MRL/lpr (Wt) mice. The levels of anti-dsDNA antibodies and IgE decreased in the Tg mice compared to Wt mice. Quantitative real-time PCR indicated an increase in the mRNA levels of FoxP3, and a decrease in that of IFNγ in the splenocytes of Tg mice as compared to Wt mice. In addition, flow cytometric analysis showed an increase in CD4(+)CD25(+)FoxP3(+)-T cells in the former, as compared to the latter. Our findings suggest that EBI3-overexpression in MRL/lpr mice induces generation of regulatory T cells, which causes suppression of autoimmune and inflammatory reactions by affecting the Th1/Th2 cytokine balance. 23263759 Biosorption of acidic textile dyestuffs from aqueous solution by Paecilomyces sp. isolated from acidic mine drainage. Removal of textile dyestuffs from aqueous solution by biosorption onto a dead fungal biomass isolated from acidic mine drainage in the Çanakkale Region of Turkey was investigated. The fungus was found to be a promising biosorbent and identified as Paecilomyces sp. The optimal conditions for bioremediation were as follows: pH, 2.0; initial dyestuff concentration, 50 mg l(-1) for Reactive Yellow 85 and Reactive Orange 12, and 75 mg l(-1) for Reactive Black 8; biomass dosage, 2 g l(-1) for Reactive Yellow 85, 3 g l(-1) for Reactive Orange 12, 4 g l(-1) for Reactive Black 8; temperature, 25 °C; and agitation rate, 100 rpm. Zeta potential measurements indicated an electrostatic interaction between the binding sites and dye anions. Fourier transform infrared spectroscopy showed that amine, hydroxyl, carbonyl, and amide bonds were involved in the dyestuff biosorption. A toxicity investigation was also carried out before and after the biosorption process. These results showed that the toxicities for the reactive dyestuffs in aqueous solutions after biosorption studies decreased. The Freundlich and Langmuir adsorption models were used for the mathematical description of the biosorption equilibrium, and isotherm constants were evaluated for each dyestuff. Equilibrium data of biosorption of RY85 and RO12 dyestuffs fitted well to both models at the studied concentration and temperature. 23933858 Atypical presentation of postoperative faecal peritonitis in an elderly patient. A 90-year-old Caucasian man was admitted for an elective sigmoid colectomy having been recently diagnosed with colon cancer. He first presented following a 3-month history of per rectal bleeding. Flexible sigmoidoscopy demonstrated a 4 cm lesion in the proximal sigmoid colon. A biopsy confirmed adenocarcinoma. A CT colonoscopy demonstrated no further colonic lesions and staging CT demonstrated no evidence of metastasis. On postoperative day 7, patient had symptoms of nausea and vomiting. On examination, he had a tender right iliac fossa, sluggish bowel sounds but no evidence of guarding or rebound tenderness. He had no fever with a white cell count 5.8×109/L and C reactive protein 58 mg/L. Chest X-ray showed air under the diaphragm. CT abdomen and pelvis was performed on postoperative day 8 showing a moderate amount of abdominal free fluid and air beneath the anterior abdominal wall. Subsequent laparotomy revealed gangrenous anastomotic disruption and faecal peritonitis. Abdominal washout and terminal colostomy performed. Good postoperative recovery was seen. 23950846 Correction: Bin2 Is a Membrane Sculpting N-BAR Protein That Influences Leucocyte Podosomes, Motility and Phagocytosis. [This corrects the article on p. e52401 in vol. 7.]. 23880652 hESC-derived Olig2(+) progenitors generate a subtype of astroglia with protective effects against ischaemic brain injury. Human pluripotent stem cells (hPSCs) have been differentiated to astroglia, but the utilization of hPSC-derived astroglia as cell therapy for neurological diseases has not been well studied. Astroglia are heterogeneous, and not all astroglia are equivalent in promoting neural repair. A prerequisite for cell therapy is to derive defined cell populations with superior therapeutic effects. Here we use an Olig2-GFP human embryonic stem cell (hESC) reporter to demonstrate that hESC-derived Olig2(+) progenitors generate a subtype of previously uncharacterized astroglia (Olig2PC-Astros). These Olig2PC-Astros differ substantially from astroglia differentiated from Olig2-negative hESC-derived neural progenitor cells (NPC-Astros), particularly in their neuroprotective properties. When grafted into brains subjected to global ischaemia, Olig2PC-Astros exhibit superior neuroprotective effects and improved behavioural outcome compared to NPC-Astros. Thus, this new paradigm of human astroglial differentiation is useful for studying the heterogeneity of human astroglia, and the unique Olig2PC-Astros may constitute a new cell therapy for treating cerebral ischaemia and other neurological diseases. 23851274 Integrated hydrolysation and fermentation of the sugar beet pulp to bioethanol. Sugar beet pulp is an abundant industrial waste material which holds a great potential for bioethanol production due to its high content of cellulose, hemicelluloses and pectin. Its structural and chemical robustness limits the yield of fermentable sugars obtained by hydrolysation and represents the main bottleneck for bioethanol production. Physical (ultrasound and thermal) pre-treatment methods were tested and combined with enzymatic hydrolysis by cellulase and pectinase to evaluate the most efficient strategy. The optimized hydrolysis process was combined with a fermentative step using a Saccharomyces cerevisiae strain for ethanol production in a single tank bioreactor. Optimal sugar beet pulp conversion was achieved at a concentration of 60 g/l (39% of dry weight) and a bioreactor stirrer speed of 960 rpm. The maximum ethanol yield was 0.1 g ethanol/g of dry weight (0.25 g ethanol/g total sugar content), the efficiency of ethanol production was 49% and the productivity of the bioprocess was 0.29 g/l·h, respectively. 23936339 New Empirical Equation for the Atomic Form Factor Function in the Momentum Transfer Range, q = 0-50 Å(-1) for the Elements in the Range 1≤ Z ≤30. The importance of Atomic Form Factors (f) is well-known to the scientific community. Tabulated values for f are mostly used in calculating cross-sections and Monte Carlo sampling for the coherent scattering of photons. The uses of these values are subjected to different approximations and interpolation techniques because the available data points for f in the literature for specified momentum-transfer-grids are very limited. In order to make it easier to accurately use the tabulated data, a mathematical expression for f functions would be a great achievement. Therefore, the current study was designed to suggest an empirical expression for the f functions. In the results, an empirical equation for Hubbell's tabulated data for f is created in the momentum transfer range, q = 0-50 Å(-1) for the elements in the range 1≤ Z ≤30. The number of applied parameters was seven. The fitting to f showed that the maximum deviation was within 3%, 4% and 5% for the element having, Z = 1-11, Z = 12-22 and Z = 23-30, respectively, while the average deviations were within 0.3-2.25% for all elements (i.e., Z = 1-30). The values generated by the analytical equation were used in the Monte Carlo code instead of Hubbell's tabulated values. The statistical noise in the Probability Distribution Functions of coherently scattered photons was efficiently removed. Furthermore, it also reduced the dependence on different interpolation techniques and approximations, and on the use of large tabulated data for f with the specified elements. 23382074 A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex. Although many functions and targets have been attributed to the histone and protein deacetylase SIRT1, a comprehensive analysis of SIRT1 binding proteins yielding a high-confidence interaction map has not been established. Using a comparative statistical analysis of binding partners, we have assembled a high-confidence SIRT1 interactome. Employing this method, we identified the deubiquitinating enzyme ubiquitin-specific protease 22 (USP22), a component of the deubiquitinating module (DUBm) of the SAGA transcriptional coactivating complex, as a SIRT1-interacting partner. We found that this interaction is highly specific, requires the ZnF-UBP domain of USP22, and is disrupted by the inactivating H363Y mutation within SIRT1. Moreover, we show that USP22 is acetylated on multiple lysine residues and that alteration of a single lysine (K129) within the ZnF-UBP domain is sufficient to alter interaction of the DUBm with the core SAGA complex. Furthermore, USP22-mediated recruitment of SIRT1 activity promotes the deacetylation of individual SAGA complex components. Our results indicate an important role of SIRT1-mediated deacetylation in regulating the formation of DUBm subcomplexes within the larger SAGA complex. 23411218 Storage stability of hen egg white powders in three protein/water dough model systems. In recent years, due to the specific health benefits associated with bioactive peptides and the reduction of protein allergenicity by enzymatic hydrolysis, the utilisation of protein hydrolysates in the intermediate-moisture food (IMF) market, such as high protein nutrition bars (HPNB), has significantly increased. Currently, no reported study is related to the storage stability of dried hen egg white (DEW) and its hydrolysates (HEW) in an IMF matrix. Therefore, three DEW/HEW dough model systems (100%HEW+0%DEW, 75%HEW+25%DEW and 50%HEW+50%DEW) were established using two commercial spray-dried egg white powders to study the effect of temperature and fraction of HEW on these IMF models (water activity (a(w)): ∼0.8). During storage at three different temperatures (23, 35 and 45°C) for 70 days, the selected physicochemical properties of the dough systems were compared. Overall, kinetic analysis showed an apparent zero-order model fit for the change in the colour (L(∗)), fluorescence intensity (FI) and hardness, as a function of time, for different dough model systems. As expected, the L(∗), FI and hardness increased as a function of time mainly due to the Maillard reaction. The amount of free amino groups decreased, with an increase in rate of loss, as temperature increased in the 100%HEW+0%DEW model. When DEW was substituted for some HEW, the regeneration of the free amino groups after loss was observed as a function of time. Furthermore, when the percentage of HEW was decreased, the incidence of mouldy samples occurred sooner, which indicates that HEW has some antimicrobial ability, especially in the 100%HEW+0%DEW system where mould growth did not occur. 23868563 Being confident without seeing: What subjective measures of visual consciousness are about. Can observers be confident about the accuracy of a discrimination response without a visual experience of the stimulus? In a series of five experiments, observers performed a masked orientation discrimination task, a masked shape discrimination task, or a random-dot motion discrimination task, followed by two subjective ratings after each trial, in which participants reported either their visual experience of the stimulus or their confidence in being correct. We observed that the threshold for ratings of the perception of the stimulus was above the threshold for ratings of a decision, that decision ratings outperformed stimulus ratings in predicting trial accuracy, and that different decision-related scales were more strongly associated with other decision-related scales than with ratings of stimulus clarity. We propose a taxonomy of subjective measures of consciousness that differentiates between subjective measures relating to the percept of the stimulus and measures relating to a discrimination decision and discuss the relation to type II blindsight. 23950758 Evolution of the selfing syndrome in Ipomoea. Plants that are highly selfing typically exhibit a suite of morphological traits termed a "selfing syndrome," including reduced corollas and reproductive structures, loss of corolla pigmentation, little anther-stigma separation, and a lower pollen/ovule (P/O) ratio. While it is typically assumed that these changes are adaptive, few attempts have been made to determine whether they result from the operation of natural selection or genetic drift. In the southeastern United States, Ipomoea lacunosa has evolved a typical selfing syndrome compared to its close relative, Ipomoea cordatotriloba. Microsatellite markers confirmed that selfing rates are substantially higher in I. lacunosa. Furthermore, using a standard QST - FST comparison, we evaluated the relative importance of selection and drift in the evolution of selfing syndrome traits in I. lacunosa. The analysis demonstrated that natural selection is responsible for the evolution of reduced corolla size, anther-stigma distance, and style length in this species. By contrast, leaf characteristics unrelated to selfing were found to have diverged largely by genetic drift. Our study provides one of the first confirmations that natural selection drives the evolution of selfing-syndrome traits. 23818596 LNK genes integrate light and clock signaling networks at the core of the Arabidopsis oscillator. Light signaling pathways and the circadian clock interact to help organisms synchronize physiological and developmental processes with periodic environmental cycles. The plant photoreceptors responsible for clock resetting have been characterized, but signaling components that link the photoreceptors to the clock remain to be identified. Here we describe a family of night light-inducible and clock-regulated genes (LNK) that play a key role linking light regulation of gene expression to the control of daily and seasonal rhythms in Arabidopsis thaliana. A genomewide transcriptome analysis revealed that most light-induced genes respond more strongly to light during the subjective day, which is consistent with the diurnal nature of most physiological processes in plants. However, a handful of genes, including the homologous genes LNK1 and LNK2, are more strongly induced by light in the middle of the night, when the clock is most responsive to this signal. Further analysis revealed that the morning phased LNK1 and LNK2 genes control circadian rhythms, photomorphogenic responses, and photoperiodic dependent flowering, most likely by regulating a subset of clock and flowering time genes in the afternoon. LNK1 and LNK2 themselves are directly repressed by members of the TIMING OF CAB1 EXPRESSION/PSEUDO RESPONSE REGULATOR family of core-clock genes in the afternoon and early night. Thus, LNK1 and LNK2 integrate early light signals with temporal information provided by core oscillator components to control the expression of afternoon genes, allowing plants to keep track of seasonal changes in day length. 23894626 Integration and disruption effects of shape and texture in haptic search. In a search task, where one has to search for the presence of a target among distractors, the target is sometimes easily found, whereas in other searches it is much harder to find. The performance in a search task is influenced by the identity of the target, the identity of the distractors and the differences between the two. In this study, these factors were manipulated by varying the target and distractors in shape (cube or sphere) and roughness (rough or smooth) in a haptic search task. Participants had to grasp a bundle of items and determine as fast as possible whether a predefined target was present or not. It was found that roughness and edges were relatively salient features and the search for the presence of these features was faster than for their absence. If the task was easy, the addition of these features could also disrupt performance, even if they were irrelevant for the search task. Another important finding was that the search for a target that differed in two properties from the distractors was faster than a task with only a single property difference, although this was only found if the two target properties were non-salient. This means that shape and texture can be effectively integrated. Finally, it was found that edges are more beneficial to a search task than disrupting, whereas for roughness this was the other way round. 23839301 Photosynthetic gene expression in higher plants. Within the chloroplasts of higher plants and algae, photosynthesis converts light into biological energy, fueling the assimilation of atmospheric carbon dioxide into biologically useful molecules. Two major steps, photosynthetic electron transport and the Calvin-Benson cycle, require many gene products encoded from chloroplast as well as nuclear genomes. The expression of genes in both cellular compartments is highly dynamic and influenced by a diverse range of factors. Light is the primary environmental determinant of photosynthetic gene expression. Working through photoreceptors such as phytochrome, light regulates photosynthetic genes at transcriptional and posttranscriptional levels. Other processes that affect photosynthetic gene expression include photosynthetic activity, development, and biotic and abiotic stress. Anterograde (from nucleus to chloroplast) and retrograde (from chloroplast to nucleus) signaling insures the highly coordinated expression of the many photosynthetic genes between these different compartments. Anterograde signaling incorporates nuclear-encoded transcriptional and posttranscriptional regulators, such as sigma factors and RNA-binding proteins, respectively. Retrograde signaling utilizes photosynthetic processes such as photosynthetic electron transport and redox signaling to influence the expression of photosynthetic genes in the nucleus. The basic C3 photosynthetic pathway serves as the default form used by most of the plant species on earth. High temperature and water stress associated with arid environments have led to the development of specialized C4 and CAM photosynthesis, which evolved as modifications of the basic default expression program. The goal of this article is to explain and summarize the many gene expression and regulatory processes that work together to support photosynthetic function in plants. 23834703 Circadian adaptation of airline pilots during extended duration operations between the USA and Asia. This study tracked circadian adaptation among airline pilots before, during, and after trips where they flew from Seattle (SEA) or Los Angeles (LAX) to Asia (7--9 time zones westward), spent 7--12 d in Asia, and then flew back to the USA. In Asia, pilots' exposures to local time cues and sleep opportunities were constrained by duty (short-haul flights crossing ≤1 time zone/24 h). Fourteen captains and 16 first officers participated (median age = 56 versus 48 yrs, p.U) < 0.001). Their sleep was monitored (actigraphy, duty/sleep diaries) from 3 d pre-trip to 5 d post-trip. For every flight, Karolinska Sleepiness and Samn-Perelli Fatigue scales and 5-min psychomotor vigilance task (PVT) tests were completed pre-flight and at top of descent (TOD). Participants had ≥3 d free of duty prior to outbound flight(s). From 72--24 h prior to departure (baseline sleep), mean total sleep/24 h (TST) = 7.00 h (SD = 1.18 h) and mean sleep efficiency = 87% (SD = 4.9%). Most pilots (23/30) flew direct to and from Asia, but 7 LAX-based pilots flew via a 1-d layover in Honolulu (HNL). On flights with ≥2 pilots, mean total in-flight sleep varied from 0.40 to 2.09 h outbound and from 0.74 to 1.88 h inbound. Duty patterns in Asia were variable, with ≤2 flights/d (mean flight duration = 3.53 h, SD = 0.53 h). TST on days 1–7 in Asia did not differ from baseline (p.F) = 0.2031). However, mean sleep efficiency was significantly lower than baseline on days 5--7 (p.F) = 0.0041). More pilots were on duty between 20:00 and 24:00 h on days 5–7 (mean = 21%) than on days 2–4 (mean = 14%). Sleep propensity distribution phase markers and chi-square periodogram analyses suggest that adaptation to local time was complete by day 4 in Asia. On pre-flight PVT tests in Asia, the slowest 10% of responses improved for flights departing 14:00--19:59 h (p.F) = 0.0484). At TOD, the slowest 10% of responses improved across days for flights arriving 14:00--19:59 h (p.F) = 0.0349) and 20:00--01:59 h (p.F) = 0.0379). Sleepiness and fatigue ratings pre-flight and at TOD did not change across days in Asia. TST on post-trip day 1 was longer than baseline (estimated mean extension = 1.68 h; adjusted p(t) < 0.0001). On all post-trip days, sleep efficiency was comparable to baseline. Sleep propensity distribution phase markers and chi-square periodogram analyses suggest complete readaptation in 1–2 d. Two opposing influences appeared to affect sleep and PVT performance across days in Asia: progressive circadian adaptation to local time and increasing duty during local night, which displaced sleep from the optimal physiological time. Cumulative sleep restriction across the return flight may explain the large rebound in TST on day 1 post-trip. Thereafter TST, sleep efficiency, and sleep timing suggest that readaptation was complete. Rapid post-trip readaptation may be facilitated by pilots having unconstrained nocturnal sleep opportunities, coupled with stronger patterns of family and social cues than in Asia. 23839787 Plant MicroRNAs Display Differential 3' Truncation and Tailing Modifications That Are ARGONAUTE1 Dependent and Conserved Across Species. Plant small RNAs are 3' methylated by the methyltransferase HUA1 ENHANCER1 (HEN1). In plant hen1 mutants, 3' modifications of small RNAs, including oligo-uridylation (tailing), are associated with accelerated degradation of microRNAs (miRNAs). By sequencing small RNAs of the wild type and hen1 mutants from Arabidopsis thaliana, rice (Oryza sativa), and maize (Zea mays), we found 3' truncation prior to tailing is widespread in these mutants. Moreover, the patterns of miRNA truncation and tailing differ substantially among miRNA families but are conserved across species. The same patterns are also observable in wild-type libraries from a broad range of species, only at lower abundances. ARGONAUTE (AGO1), even with defective slicer activity, can bind these truncated and tailed variants of miRNAs. An ago1 mutation in hen1 suppressed such 3' modifications, indicating that they occur while miRNAs are in association with AGO1, either during or after RNA-induced silencing complex assembly. Our results showed AGO1-bound miRNAs are actively 3' truncated and tailed, possibly reflecting the activity of cofactors acting in conserved patterns in miRNA degradation. 23844019 The cardiac acetyl-lysine proteome. In the heart, lysine acetylation has been implicated in processes ranging from transcriptional control of pathological remodeling, to cardioprotection arising from caloric restriction. Given the emerging importance of this post-translational modification, we used a proteomic approach to investigate the broader role of lysine acetylation in the heart using a guinea pig model. Briefly, hearts were fractionated into myofilament-, mitochondrial- and cytosol-enriched fractions prior to proteolysis and affinity-enrichment of acetylated peptides. LC-MS/MS analysis identified 1075 acetylated peptides, harboring 994 acetylation sites that map to 240 proteins with a global protein false discovery rate <0.8%. Mitochondrial targets account for 59% of identified proteins and 64% of sites. The majority of the acetyl-proteins are enzymes involved in fatty acid metabolism, oxidative phosphorylation or the TCA cycle. Within the cytosolic fraction, the enzymes of glycolysis, fatty acid synthesis and lipid binding are prominent. Nuclear targets included histones and the transcriptional regulators E1A(p300) and CREB binding protein. Comparison of our dataset with three previous global acetylomic studies uniquely revealed 53 lysine-acetylated proteins. Specifically, newly-identified acetyl-proteins include Ca(2+)-handling proteins, RyR2 and SERCA2, and the myofilament proteins, myosin heavy chain, myosin light chains and subunits of the Troponin complex, among others. These observations were confirmed by anti-acetyl-lysine immunoblotting. In summary, cardiac lysine acetylation may play a role in cardiac substrate selection, bioenergetic performance, and maintenance of redox balance. New sites suggest a host of potential mechanisms by which excitation-contraction coupling may also be modulated. 23418073 Engineered nanomaterials in water and soils: A risk quantification based on probabilistic exposure and effect modeling. The production and use of engineered nanomaterials (ENMs) are increasing rapidly, and therefore, the need to assess their environmental exposure and associated risks has become increasingly important. Only a handful of studies have quantified the release and environmental concentrations of ENMs, but much work has been done to investigate the effects of these materials on organisms. The aim of the present study was to quantify probabilistically the environmental risks of ENMs, producing species sensitivity distributions that were then compared with probability distributions of predicted environmental concentrations. Five nanomaterials (nano-Ag, nano-TiO2 , nano-ZnO, carbon nanotubes [CNTs], and fullerenes) and 4 environmental compartments (surface water, sewage treatment plant effluents, soils, and sludge-treated soils) were considered. From 60 ecotoxicological studies, the authors extracted 112 single values to work with (25 values in 13 studies for nano-Ag, 17 values in 10 studies for CNTs, 7 values in 7 studies for fullerenes, 34 values in 23 studies for nano-TiO2 , and 29 values in 17 studies for nano-ZnO). The results indicate there is only a marginal risk for these metal-based nanomaterials in surface water (0.7% risk for nano-Ag and <0.1% for nano-TiO2 ) and some risk in sewage treatment plant effluents (nano-Ag 39.7%, nano-TiO2 18.7%, and nano-ZnO 1.1%). Apart from a marginal value of <0.1% for nano-TiO2 in sludge-treated soils, no risk from the other evaluated ENMs in terrestrial compartments is currently predicted. The discussion of the results considers the influence of the effects of different forms of 1 ENM (coating, agglomeration state, and mineralogy), the test conditions (dissolution and agglomeration), and transformation reactions. Environ Toxicol Chem 2013;32:1278-1287. © 2013 SETAC. 23949101 Screening for substance use disorders in neurodevelopmental disorders: a clinical routine? Evidence suggests that substance use disorders (SUD) tend to be underdiagnosed in psychiatry. The objective of this study was to investigate whether drug and alcohol screening is a clinical routine in the assessment of two prominent neurodevelopmental disorders, namely ADHD and autism spectrum disorder (ASD). We surveyed drug and alcohol screening routines in 34 general child and adolescent (only practice for adolescents, not children, was assessed) and 29 adult psychiatric outpatient departments in Stockholm County, Sweden. Structured telephone interviews mapping SUD screening procedures were conducted with department representatives in charge. Only a minority of child and adolescent departments regularly used SUD screening questionnaires (6 %) in ADHD and ASD assessment, while this was more common in adult psychiatry (55 %). Urine/blood-based toxicology tests were always used in 28 % and sometimes or in case of clinical suspicion in 38 % of the adult units. Such tests were used sometimes or in case of clinical suspicion in 15 % of the child psychiatric departments, but never routinely. Findings reveal that screening for SUD in ADHD and ASD is not an integral part of routine clinical assessments in psychiatry, although increasingly an integral part of many clinical guidelines. Thus, SUD might be underdiagnosed in neurodevelopmental disorders, which could be particularly true for child and adolescent psychiatry settings. 23898163 Phase-resetting mechanism of the circadian clock in Chlamydomonas reinhardtii. Although the circadian clock is a self-sustaining oscillator having a periodicity of nearly 1 d, its period length is not necessarily 24 h. Therefore, daily adjustment of the clock (i.e., resetting) is an essential mechanism for the circadian clock to adapt to daily environmental changes. One of the major cues for this resetting mechanism is light. In the unicellular green alga Chlamydomonas reinhardtii, the circadian clock is reset by blue/green and red light. However, the underlying molecular mechanisms remain largely unknown. In this study, using clock protein-luciferase fusion reporters, we found that the level of RHYTHM OF CHLOROPLAST 15 (ROC15), a clock component in C. reinhardtii, decreased rapidly after light exposure in a circadian-phase-independent manner. Blue, green, and red light were able to induce this process, with red light being the most effective among them. Expression analyses and inhibitor experiments suggested that this process was regulated mainly by a proteasome-dependent protein degradation pathway. In addition, we found that the other clock gene, ROC114, encoding an F-box protein, was involved in this process. Furthermore, we demonstrated that a roc15 mutant showed defects in the phase-resetting of the circadian clock by light. Taken together, these data strongly suggest that the light-induced degradation of ROC15 protein is one of the triggers for resetting the circadian clock in C. reinhardtii. Our data provide not only a basis for understanding the molecular mechanisms of light-induced phase-resetting in C. reinhardtii, but also insights into the phase-resetting mechanisms of circadian clocks in plants. 23961419 Factors associated with compliance to adjuvant hormone therapy in Black and White women with breast cancer. Studies have demonstrated lower rates of breast cancer survival for Black versus White women. Factors implicated include later stages at diagnosis, differences in tumor biology, and lower compliance rates to adjuvant hormone therapy (AHT) among Black women with hormone sensitive breast cancer. We examined factors associated with compliance to AHT among Black and White women with invasive breast cancer. Women with estrogen receptor positive (ER+), non-metastatic breast cancer were identified by the cancer registry at the University of Chicago Hospital and asked to complete a mail-in survey. Compliance was defined by self-reported adherence to AHT ≥80% at the time of the survey plus medical record verification of persistence (completion of 5 years of AHT). Logistic regression was used to determine factors associated with compliance to AHT. 197 (135 White and 62 Black) women were included in the analysis. 97.4% of patients reported adherence to therapy. 87.4% were found to be persistent to therapy. Overall compliance was 87.7% with no statistically significant racial difference seen (87.9% in White and 87.0% in Black, P = 0.87). For both Black and White women, compliance was strongly associated with both perceived importance of AHT (OR =2.1, 95% CI:1.21-3.68,P = 0.009) and the value placed on their doctor's opinion about the importance of AHT (OR = 4.80, 95% CI: 2.03-11.4, P < 0.001). In our cohort of Black and White women, perceived importance of AHT and the degree to which they valued their doctor's opinion correlated with overall compliance. This suggests that Black and White women consider similar factors in their decision to take AHT. 23578620 The impact of catechin and epicatechin, total phenols and PPO activity on the Mal d 1 content in apple fruit. The most important apple allergen in Central Europe and North America is Mal d 1. Apples are a very important source of secondary plant metabolites like polyphenols in human nutrition. It is known that oxidised phenols can bind proteins. These irreversible bindings can lead to a reduced allergenicity. The most important phenols in apple are epicatechin, catechin and their polymeric structures, which have been identified as substrates of the polyphenoloxidase (PPO). The aim of this study was to analyse the influence of naturally occurring catechin and epicatechin contents in apple on the allergenicity of apple fruits. Fruits of the cultivars 'Elstar', 'Diwa' and 'Boskoop' were harvested and stored for 8 and 12weeks in a cold-chamber at 2°C. Mal d 1-, catechin-, epicatechin- and total phenol content as well as the activity of PPO were determined. Correlation analysis showed that naturally occurring catechin as well as epicatechin has no impact on the Mal d 1 content of the tested cultivars: correlation coefficient ranged from -0.203 to 0.501 for the correlation between Mal d 1 and catechin. The results further indicated that the activity of PPO is more important than the content of total phenols to reduce the Mal d 1 level. If there is a high PPO activity, Mal d 1 could be reduced even if the total phenol concentration is low. 23263985 Both CpG methylation and activation-induced deaminase are required for the fragility of the human bcl-2 major breakpoint region: implications for the timing of the breaks in the t(14;18) translocation. The t(14;18) chromosomal translocation typically involves breakage at the bcl-2 major breakpoint region (MBR) to cause human follicular lymphoma. A theory to explain the striking propensity of the MBR breaks at three CpG clusters within the 175-bp MBR region invoked activation-induced deaminase (AID). In a test of that theory, we used here minichromosomal substrates in human pre-B cell lines. Consistent with the essential elements of the theory, we found that the MBR breakage process is indeed highly dependent on DNA methylation at the CpG sites and highly dependent on the AID enzyme to create lesions at peak locations within the MBR. Interestingly, breakage of the phosphodiester bonds at the AID-initiated MBR lesions is RAG dependent, but, unexpectedly, most are also dependent on Artemis. We found that Artemis is capable of nicking small heteroduplex structures and is even able to nick single-base mismatches. This raises the possibility that activated Artemis, derived from the unjoined D to J(H) DNA ends at the IgH locus on chromosome 14, nicks AID-generated TG mismatches at methyl CpG sites, and this would explain why the breaks at the chromosome 18 MBR occur within the same time window as those on chromosome 14. 23940728 AMD-Associated Genes Encoding Stress-Activated MAPK Pathway Constituents Are Identified by Interval-Based Enrichment Analysis. To determine whether common DNA sequence variants within groups of genes encoding elements of stress-activated mitogen-activated protein kinase (MAPK) signaling pathways are, in aggregate, associated with advanced AMD (AAMD). We used meta-regression and exact testing methods to identify AAMD-associated SNPs in 1177 people with AAMD and 1024 AMD-free elderly peers from 3 large-scale genotyping projects on the molecular genetics of AMD. SNPs spanning independent AAMD-associated genomic intervals were examined with a multi-locus-testing method (INRICH) for enrichment within five sets of genes encoding constituents of stress-activated MAPK signaling cascades. Four-of-five pathway gene sets showed enrichment with AAMD-associated SNPs; findings persisted after adjustment for multiple testing in two. Strongest enrichment signals (P = 0.006) existed in a c-Jun N-terminal kinase (JNK)/MAPK cascade (Science Signaling, STKE CMP_10827). In this pathway, seven independent AAMD-associated regions were resident in 6 of 25 genes examined. These included sequence variants in: 1) three MAP kinase kinase kinases (MAP3K4, MAP3K5, MAP3K9) that phosphorylate and activate the MAP kinase kinases MAP2K4 and MAP2K7 (molecules that phosphorylate threonine and tyrosine residues within the activation loop of JNK); 2) a target of MAP2K7 (JNK3A1) that activates complexes involved in transcriptional regulation of stress related genes influencing cell proliferation, apoptosis, motility, metabolism and DNA repair; and 3) NR2C2, a transcription factor activated by JNK1A1 (a drugable molecule influencing retinal cell viability in model systems). We also observed AAMD-related sequence variants resident in genes encoding PPP3CA (a drugable molecule that inactivates MAP3K5), and two genes (TGFB2, TGFBR2) encoding factors involved in MAPK sensing of growth factors/cytokines. Linkage disequilibrium (LD)-independent genomic enrichment analysis yielded associations of AAMD with aggregates of functionally related genes encoding constituents of the JNK MAPK signaling pathway. FDA-approved drugs now exist to target constituents of stress-activated MAPK pathways and may offer reasonable approaches to preventing or treating AAMD. 23969047 Complete Genome Sequence for Lactobacillus helveticus CNRZ 32, an Industrial Cheese Starter and Cheese Flavor Adjunct. Lactobacillus helveticus is a lactic acid bacterium widely used in the manufacture of cheese and for production of bioactive peptides from milk proteins. We present the complete genome sequence for L. helveticus CNRZ 32, a strain particularly recognized for its ability to reduce bitterness and accelerate flavor development in cheese. 23333767 IκB kinase ε (IKKε): a therapeutic target in inflammation and cancer. The innate immune system forms our first line of defense against invading pathogens and relies for a major part on the activation of two transcription factors, NF-κB and IRF3. Signaling pathways that activate these transcription factors are intertwined at the level of the canonical IκB kinases (IKKα, IKKβ) and non-canonical IKK-related kinases (IKKε, TBK1). Recently, significant progress has been made in understanding the function and mechanism of action of IKKε in immune signaling. In addition, IKKε impacts on cell proliferation and transformation, and is thereby also classified as an oncogene. Studies with IKKε knockout mice have illustrated a key role for IKKε in inflammatory and metabolic diseases. In this review we will highlight the mechanisms by which IKKε impacts on signaling pathways involved in disease development and discuss its potential as a novel therapeutic target. 23788253 Mesothelioma and employment in massachusetts: Analysis of cancer registry data 1988-2003. Cancer registries can be used to monitor mesothelioma cases and to identify occupations and industries previously and newly associated with mesothelioma-causing asbestos exposure by using standard registry data on the "usual" occupation and industry of the case. We used the National Institute for Occupational Safety and Health's Standardized Occupational Industry Coding Software to code 564 mesothelioma cases for occupation and 543 for industry of the 1,424 incident mesothelioma in the Massachusetts Cancer Registry from 1988 to 2003. Additionally, we coded the occupation and industry of 80,184 comparison cancer cases (35% of comparison cases in our database). These were used to compute Standardized Morbidity Odds Ratios (SMORs). Seventeen occupations and 11 industries had statistically significant elevated SMORs for mesothelioma. Occupations and industries historically associated with mesothelioma remained elevated in these results. However, we also found statistically significant elevated SMORs for several occupations and industries for which there was previously weak or no association such as chemical engineers, machine operators, and automobile mechanics and machine manufacturing, railroads, and the U.S. Postal Service. Incident cases of mesothelioma do not appear to be declining in Massachusetts, as legacy exposures to asbestos continue to produce cases in individuals involved in shipbuilding and construction. Exposures in occupations and industries not previously associated with mesothelioma also contribute cases. Cancer registries, with improved data collection, should continue to be monitored for mesothelioma cases and asbestos exposures. Am. J. Ind. Med. 56:985-992, 2013. © 2013 Wiley Periodicals, Inc. 22878060 Effect of perfusion temperature on glucose and electrolyte transport during hyperthermic intraperitoneal chemoperfusion (HIPEC) with oxaliplatin. Hyperthermic intraperitoneal chemoperfusion (HIPEC) with oxaliplatin is increasingly used in patients with carcinomatosis from colorectal cancer. For reasons of chemical stability, oxaliplatin can only be administered in a dextrose (D5%) solution, and this causes peroperative glucose and electrolyte shifts. Here, we examined the influence of perfusion temperature on glucose and electrolyte transport, metabolic shifts, and surgical morbidity. Patients with carcinomatosis underwent cytoreduction and HIPEC using oxaliplatin (460 mg/m(2) in D5%, open abdomen) during 30 min at 39°-41 °C. Intraperitoneal (IP) temperature was measured at three locations using thermocouple probes. The area under the temperature versus time curve (AUCt) was calculated using the trapezoid rule. The influence of perfusion temperature on surgical outcome was assessed using linear regression models and the Mann Whitney U test where appropriate. From July 2005 until March 2011, 145 procedures were performed in 139 patients with a diagnosis of CRC (70%), pseudomyxoma peritonei (11%), ovarian cancer (10%), or miscellaneous peritoneal malignancies (9%). Postoperative mortality and major morbidity were 1.4% and 26%, respectively. Higher perfusion temperature was related to more pronounced changes in serum glucose (P = 0.058), sodium (P = 0.017), and lactate (P < 0.001). The median duration of nasogastric drainage was 5 days, and this was unrelated to perfusion temperature (P = 0.76). The GI fistula rate and reoperation rate were 12.4% and 16.5% respectively; neither was related to perfusion temperature. In patients undergoing HIPEC with oxaliplatin, perfusion temperature exacerbates peroperative metabolic shifts but does not affect surgical outcome. 23639947 Zno nanoparticle based highly efficient CdS/CdSe quantum dot-sensitized solar cells. 20 nm ZnO nanoparticles are used to fabricate the mesoporous photoanode of the CdS/CdSe quantum dot-sensitized solar cells by the simple doctor blade method. A maximum power conversion efficiency of 4.46% has been achieved, which indicated exciting prospects for ZnO nanoparticle based quantum dot-sensitized solar cells. 23941439 25 GHz Embedded-Gate Graphene Transistors with High-K Dielectrics on Extremely Flexible Plastic Sheets. Despite the widespread interest in graphene electronics over the past decade, high-performance graphene field-effect transistors (GFETs) on flexible substrates have been rarely achieved, even though this atomic sheet is widely understood to have greater prospects for flexible electronic systems. In this article, we report detailed studies on the electrical and mechanical properties of vapor synthesized high-quality monolayer graphene integrated onto flexible polyimide substrates. Flexible graphene transistors with high-k dielectric afforded intrinsic gain, maximum carrier mobilities of 3900 cm(2)/V·s, and importantly, 25 GHz cutoff frequency, which is more than a factor of 2.5 times higher than prior results. Mechanical studies reveal robust transistor performance under repeated bending, down to 0.7 mm bending radius, whose tensile strain is a factor of 2-5 times higher than in prior studies. In addition, integration of functional coatings such as highly hydrophobic fluoropolymers combined with the self-passivation properties of the polyimide substrate provides water-resistant protection without compromising flexibility, which is an important advancement for the realization of future robust flexible systems based on graphene. 23953741 Pre-vascularization of bone tissue-engineered constructs. Vascularization remains one of the primary obstacles in the repair of bone defects. In the previous issue of Stem Cell Research &Therapy, Pedersen and colleagues show that co-immobilization of endothelial cells and mesenchymal stem cells in a tissue-engineered construct can achieve functional microvascular networks in vivo. These very interesting findings, together with other state-of-the-art research in this field, are presented in this commentary. They highlight the vital role of mesenchymal stem cells as supporting cells to nascent blood vessels. The development of pre-vascularized implants by using clinically relevant cell sources, which could lead to rapid integration into the host tissue, would be of immense interest. 23778228 Environmental quality predicts optimal egg size in the wild. Parents can maximize their reproductive success by balancing the trade-off between investment per offspring and fecundity. According to theory, environmental quality influences the relationship between investment per offspring and offspring fitness, such that well-provisioned offspring fare better when environmental quality is lower. A major prediction of classic theory, then, is that optimal investment per offspring will increase as environmental quality decreases. To test this prediction, we release over 30,000 juvenile Atlantic salmon (Salmo salar) into eight wild stream environments, and we monitor subsequent growth and survival of juveniles. We estimate the shape of the relationship between investment per offspring (egg size) and offspring fitness in each stream. We find that optimal egg size is greater when the quality of the stream environment is lower (as estimated by a composite index of habitat quality). Across streams, the mean size of stream gravel and the mean amount of incident sunlight are the most important individual predictors of optimal egg size. Within streams, juveniles recaptured in stream subsections that featured larger gravels and greater levels of sunlight also grew relatively quickly, an association that complements our cross-stream analyses. This study provides the first empirical verification that environmental quality alters the relationship between investment per offspring and offspring fitness, such that optimal investment per offspring increases as environmental quality decreases. 23867965 Ages and Stages Questionnaires-3 Developmental Screening of Infants and Young Children With Cancer. The Ages and Stages Questionnaires-3® (ASQ-3) for developmental screening in our young oncology patients was pilot tested in children 4 to 48 months of age with newly diagnosed cancer. Subjects were screened within 28 days of diagnosis (baseline), at 6 and 12 months. Twenty-six of 30 enrolled parents (87%) completed all 3 screens. Screens were completed by parents within 15 minutes. ASQ-3 screening identified unsuspected developmental delays as follows: 7 at baseline, 4 at 6 months, and 3 at 12 months. ASQ-3 developmental screening is feasible, identifies early developmental delays in young children with cancer, and helps initiate appropriate referrals. 23657451 NMR assignments and the acid-base characterization of the pomegranate ellagitannin punicalagin in the acidic pH-range. In exploring the capability of nuclear magnetic resonance (NMR) spectroscopy for pomegranate juice analysis, the eight aromatic singlet resonances of α- and β-punicalagin were clearly identified in the (1)H NMR spectra of juice samples. The four downfield resonances were found to be sensitive to small pH changes around pH 3.50 where the NMR spectra of the juice samples were recorded. To understand this unusual behavior, the (1)H and (13)C resonance assignments of the punicalagin anomers were determined in aqueous solution and pH titrations with UV and (1)H NMR detection carried out to characterize the acid-base properties of punicalagin over the pH range 2-8. Simultaneous fitting of all of the pH-sensitive (1)H NMR signals produced similar but significantly different pKa values for the first two deprotonation equilibria of the gallagic acid moiety of the punicalagin α- (pKa1 = 4.57 ± 0.02, pKa2 = 5.63 ± 0.03) and β- (pKa1 = 4.36 ± 0.01, pKa2 = 5.47 ± 0.02) anomers. Equivalent pKa values, (α : 6.64 ± 0.01, β : 6.63± 0.01) were measured for the third deprotonation step involving the ellagic acid group, in good agreement with a prior literature report. The punicalagin anomer equilibrium readjusts in parallel with the proton dissociation steps as the pH is raised such that β-punicalagin becomes the most abundant anomer at neutral pH. The unusual upfield shifts observed for the glucose H3 and H5 resonances with increasing pH along with the shift in the α/β anomer equilibrium are likely the consequence of a conformational rearrangement. 23125001 First-principles calculations of lithium-ion migration at a coherent grain boundary in a cathode material, LiCoO(2). Results of theoretical calculations are reported, examining the effect of a coherent twin boundary on the electrical properties of LiCoO(2) . This study suggests that internal interfaces in LiCoO(2) strongly affect the battery voltage, battery capacity, and power density of this material, which is of particular concern if it is used in all-solid-state Li-ion batteries. 23775562 Human immunodeficiency virus protease inhibitors interact with ATP binding cassette transporter 4/multidrug resistance protein 4: a basis for unanticipated enhanced cytotoxicity. Human immunodeficiency virus (HIV) pharmacotherapy, by combining different drug classes such as nucleoside analogs and HIV protease inhibitors (PIs), has increased HIV-patient life expectancy. Consequently, among these patients, an increase in non-HIV-associated cancers has produced a patient cohort requiring both HIV and cancer chemotherapy. We hypothesized that multidrug resistance protein 4/ATP binding cassette transporter 4 (MRP4/ABCC4), a widely expressed transporter of nucleoside-based antiviral medications as well as cancer therapeutics might interact with PIs. Among the PIs evaluated (nelfinavir, ritonavir, amprenavir, saquinavir, and indinavir), only nelfinavir both effectively stimulated MRP4 ATPase activity and inhibited substrate-stimulated ATPase activity. Saos2 and human embryonic kidney 293 cells engineered to overexpress MRP4 were then used to assess transport and cytotoxicity. MRP4 expression reduced intracellular accumulation of nelfinavir and consequently conferred survival advantage to nelfinavir cytotoxicity. Nelfinavir blocked Mrp4-mediated export, which is consistent with its ability to increase the sensitivity of MRP4-expressing cells to methotrexate. In contrast, targeted inactivation of Abcc4/Mrp4 in mouse cells specifically enhanced nelfinavir and 9-(2-phosphonylmethoxyethyl) adenine cytotoxicity. These results suggest that nelfinavir is both an inhibitor and substrate of MRP4. Because nelfinavir is a new MRP4/ABCC4 substrate, we developed a MRP4/ABCC4 pharmacophore model, which showed that the nelfinavir binding site is shared with chemotherapeutic substrates such as adefovir and methotrexate. Our studies reveal, for the first time, that nelfinavir, a potent and cytotoxic PI, is both a substrate and inhibitor of MRP4. These findings suggest that HIV-infected cancer patients receiving nelfinavir might experience both enhanced antitumor efficacy and unexpected adverse toxicity given the role of MRP4/ABCC4 in exporting nucleoside-based antiretroviral medications and cancer chemotherapeutics. 23912253 ZnO nanostructures directly grown on paper and bacterial cellulose substrates without any surface modification layer. In this report, hierarchical ZnO nano- and microstructures were directly grown for the first time on a bacterial cellulose substrate and on two additional different papers by hydrothermal synthesis without any surface modification layer. Compactness and smoothness of the substrates are two important parameters that allow the growth of oriented structures. 23943729 Do patients with chronic rhinosinusitis with nasal polyps suffer with facial pain? Many patients attribute their symptoms of facial pain or headache to sinus problems. Facial pain is one of the symptoms of rhinosinusitis according to European and American consensus documents. This symptom, however, has been insufficiently studied in the group of patients with chronic rhinosinusitis with nasal polyps (CRSwNP). The aim of this work is to study the symptom of facial pain in patients with CRSwNP. Patients with CRSwNP were prospectively asked to score their facial pain according to the scoring system used in the Sino Nasal Outcome Test 22 (SNOT 22). Fifty patients fulfilled the inclusion criteria. Thirty-one patients had grade II polyps and 19 patients had grade III polyps. Of these patients, 76% had absent or very mild facial pain. Only 16% of patients had moderate or severe facial pain. All patients with severe facial pain had viscid secretions within their sinuses. Significant facial pain is uncommon in patients with CRSwNP. It is important to consider this when counselling patients before surgery. 23831831 Coronary vessel diameters during and after primary percutaneous coronary artery intervention. Primary percutaneous coronary intervention (P-PCI) is the gold standard treatment for acute coronary syndromes. Plasma levels of catecholamines and other vasopressors are elevated during acute myocardial infarction (AMI) and coronary vasoconstriction is frequent. We aimed to compare the reference vessel diameter (RVD) of the infarct-related artery (IRA) during primary PCI and after an average of 3 days. Coronary angiography (CAG) was performed on 58 patients with acute ST-segment elevation myocardial infarction (STEMI) and TIMI 3 flow after P-PCI (43 men, 15 women; mean age, 55.5 ±â€‰10 years). TIMI 3 flow was achieved either by simple balloon dilatation and/or thrombus aspiration. Lesion length, RVD, minimal lumen diameter (MLD), mean vessel diameter (meanD), and area of stenosis were compared during P-PCI and follow-up CAG. RVD, MLD, and meanD values were significantly higher during the follow-up CAG than after P-PCI (RVD 2.7 ±â€‰0.7 mm vs. 2.9 ±â€‰0.7 mm, p = 0.001; MLD 1.5 ±â€‰0.5 mm vs. 1.7 ±â€‰0.4 mm, p = 0.002; meanD 2.2 ±â€‰0.5 mm vs. 2.4 ±â€‰0.5 mm, p = 0.001). Area of stenosis values were significantly lower during the follow-up CAG than after primary PCI (69.5 ±â€‰16.5 % vs. 62.1 ±â€‰15 %, p = 0.001). Lesion lengths were not statistically significant during the follow-up CAG and primary PCI (lesion length 24.0 ±â€‰10.8 mm vs. 22.1 ±â€‰8.8 mm, p > 0.05). This study showed that RVD was higher at the follow-up CAG a few days after AMI in patients who had TIMI 3 flow after P-PCI with simple balloon dilatation and/or thrombus aspiration. A delay of a few days for stent implantation in P-PCI allows for larger-diameter stent use and may help to reduce stent thrombosis and restenosis rates. 23872571 Genetic characterization of atypical enteropathogenic Escherichia coli (EPEC) strains isolated from ewes' milk, sheep farms environment and humans by multilocus sequence typing and pulsed-field gel electrophoresis. A collection of 81 isolates of enteropathogenic Escherichia coli (EPEC) was obtained from samples of bulk tank sheep milk (62 isolates), ovine faeces (4 isolates), sheep farm environment (water, 4 isolates, and air, 1 isolate) and human stool samples (9 isolates). The strains were considered atypical EPEC, carrying the eae gene without harbouring the pEAF plasmid.Multilocus sequence typing (MLST) was carried out with seven housekeeping genes and 19 sequence types (ST) were detected, none of them previously reported for atypical EPEC. The most frequent ST included 41 strains isolated from milk and human stool samples. Genetic typing by pulsed-field gel electrophoresis (PFGE) resulted in 57 patterns which grouped in 24 clusters.Comparison of strains isolated from the different samples showed phylogenetic relationships between milk and human isolates and also between milk and water isolates.The results obtained show a possible risk for humans due to the presence of atypical EPEC in ewes' milk and suggest a possible transmission route for this emerging pathogen through contaminated water. 23743261 Thalamocortical relationships and network synchronization in a new genetic model "in mirror" for absence epilepsy. Electroencephalographic generalized spike and wave discharges (SWD), the hallmark of human absence seizures, are generated in thalamocortical networks. However, the potential alterations in these networks in terms of the efficacy of the reciprocal synaptic activities between the cortex and the thalamus are not known in this pathology. Here, the efficacy of these reciprocal connections is assessed in vitro in thalamocortical slices obtained from BS/Orl mice, which is a new genetic model of absence epilepsy. These mice show spontaneous SWD, and their features can be compared to that of BR/Orl mice, which are free of SWD. In addition, since gap junctions may modulate the efficacy of these connections, their implications in pharmacologically-induced epileptiform discharges were studied in the same slices. The thalamus and neocortex were independently stimulated and the electrically-evoked responses in both structures were recorded from the same slice. The synaptic efficacy of thalamocortical and corticothalamic connections were assessed by measuring the dynamic range of synaptic field potential changes in response to increasing stimulation strengths. The connection efficacy was weaker in epileptic mice however, this decrease in efficacy was more pronounced in thalamocortical afferents, thus introducing an imbalance in the reciprocal connections between the cortex and thalamus. However, short-term facilitation of the thalamocortical responses were increased in epileptic mice compared to non-epileptic animals. These features may favor occurrence of rhythmical activities in thalamocortical networks. In addition, carbenoxolone (a gap junction blocker) decreased the cumulative duration of 4-aminopyridine-induced ictal-like activities, with a slower time course in epileptic mice. However, the 4-aminopyridine-induced GABA-dependent negative potentials, which appeared to trigger the ictal-like activities, remained. Our results show that the balance of the reciprocal connections between the thalamus and cortex is altered in favor of the corticothalamic connections in epileptic mice, and suggest that gap junctions mediate a stronger cortical synchronization in this strain. 23919394 Potential Usefulness of Baculovirus-mediated Sodium-iodide Symporter Reporter Gene as Non-invasively Gene Therapy Monitoring in Liver Cancer Cells: An In vitro Evaluation. Primary liver cancer has one of the highest mortality rates of all cancers, and the main current treatments have a poor prognosis. This study aims to examine the efficiency of baculovirus vectors for transducing target gene into liver cancer cells and to evaluate the feasibility of using baculovirus vectors to deliver the sodium-iodide symporter (NIS) gene as a reporter gene through co-vector administration approach to monitor the expression of the target therapeutic gene in liver cancer gene therapy. We constructed (green fluorescent protein) GFP- and NIS-expressing baculovirus vectors (Bac-GFP and Bac-NIS), and measured the baculovirus transduction efficiency in HepG2 cells and other tumor cells (A549, SW1116 and 8505C), and it showed that the transduction efficiency and target gene expression level rose with increasing viral multiplicity of infection (MOI) in HepG2 cells, and HepG2 cells had a significantly higher transduction efficiency (60.8% at MOI 5 200) than other tumor cells. Moreover, the baculovirus transduction was not cytotoxic to HepG2 cells at a higher MOI (MOI 5 400). We also performed dynamic iodide uptake trials, and found that Bac-NIS-transduced HepG2 cells exhibited efficient iodide uptake which could be inhibited by sodium perchlorate (NaClO4). And we measured the correlation of fluorescent intensities and 125I uptake amount in HepG2 cells after co-vector administration with Bac-NIS and Bac-GFP at different MOIs, and found a high correlation coefficient (r2 5 0.8447), which provides a good basis for successfully evaluating the feasibility of baculovirus-mediated NIS reporter gene monitoring target gene expression in liver cancer therapy. Therefore, this study indicates that baculovirus vector is a potential vehicle for delivering therapeutic genes in studying liver cancer cells. And it is feasible to use a baculovirus vector to deliver NIS gene as a reporter gene to monitor the expression of target genes. It therefore provides an effective approach and a good basis for future baculovirus-mediated therapeutic gene delivering or therapeutic gene expression monitoring in liver cancer cells studies. 23216818 Preoperative patient teaching: the practice and perceptions among surgical ward nurses. To explore the consistency between the perceptions and actual practice of preoperative patient teaching and also the factors affecting the provision of teaching from the perspective of nurses working in surgical wards. Preoperative teaching is beneficial to surgical patients in alleviating their anxiety and promoting their postoperative recovery. Despite the leading role in patient teaching by nurses, sparse studies have been addressed the consistency between nurses' perceptions and their actual practice of preoperative teaching in surgical wards. A cross-sectional survey. Data were collected by using self-reported preoperative teaching questionnaires together with nurse demographic data sheets. Sampling setting was an acute public hospital and all nurses working in surgical wards (n = 100) were approached in the study. A total of 86 nurses returned the questionnaires. 'Details of anaesthesia' was the most prominent preoperative teaching component rated by nurses although their major teaching was pertained to 'preoperative preparation'. In addition, oral explanation was reported as the most prevalent way of information delivery and internet was the least preferred method. Discrepancies between nurses' perceptions and actual practice were found in this study. Moreover, nurses' time availability, language barriers and tight operation schedules were perceived as top factors affecting the provision of preoperative teaching. Furthermore, nurses' satisfaction with such patient teaching was significantly associated with their professional training and their daily workload in the clinical setting. Preoperative patient teaching was not fully achieved by nurses in this study, and the results highlighted the conflicting issues related to the implementation process that could be resolved by means of proper planning and management in clinical practice. Healthcare organisations and nurse managers should periodically review the existing clinical resources so that sufficient preoperative teaching strategies can be provided. Nurses' perceptions and satisfaction towards preoperative teaching can be compared with those of the patients in further studies so that the insights for developing an effective preoperative teaching programme can be more comprehensive. 23562535 Carboxymethyl starch and lecithin complex as matrix for targeted drug delivery: I. Monolithic Mesalamine forms for colon delivery. For drugs expected to act locally in the colon, and for successful treatment, a delivery device is necessary, in order to limit the systemic absorption which decreases effectiveness and causes important side effects. Various delayed release systems are currently commercialized; most of them based on pH-dependent release which is sensitive to gastrointestinal pH variation. This study proposes a novel excipient for colon delivery. This new preparation consists in the complexation between carboxymethyl starch (CMS) and Lecithin (L). As opposed to existing excipients, the new complex is pH-independent, inexpensive, and easy to manufacture and allows a high drug loading. FTIR, X-ray, and SEM structural analysis all support the hypothesis of the formation of a complex. By minor variation of the excipient content within the tablet, it is possible to modulate the release time and delivery at specific sites of the gastrointestinal tract. This study opens the door to a new pH-independent delivery system for mesalamine targeted administration. Our novel formulation fits well with the posology of mesalamine, used in the treatment of Inflammatory Bowel Disease (IBD), which requires repeated administrations (1g orally four times a day) to maintain a good quality of life. 23926439 Cancer-associated thrombosis: clinical presentation and survival. Thromboembolic events are important causes of morbidity and mortality in cancer patients. Clinical presentation in a community-based setting has not been fully clarified. The purpose of this study was to evaluate the incidence, risk factors, role of thrombophilia, and subsequent survival following thrombosis in cancer patients. A retrospective review was undertaken of clinical data for all consecutive patients with histologically confirmed cancer seen by the author at a regional cancer center, with emphasis on cancer-related thrombosis. Between 2005 and 2012, of 1874 cancer patients, 307 (16.4%) developed thrombosis during their lifetime. Of these patients, 37 (2%) had a history of thrombosis, while the remaining 270 (14.4%) patients developed thrombosis 3 months before or any time after diagnosis of cancer, which was considered to be cancer-related. These patients included 230 (12.3%) with venous thrombosis, 28 (1.5%) cases with arterial occlusion, and 12 (0.6%) with combined venous and arterial thrombosis. Patients of Caucasian ancestry were more prone to develop thrombosis, with a higher frequency of multiple genetic thrombophilia compared with other ethnic groups. In regression analysis, only advanced stages of cancer and the presence of atherosclerosis were predictive of thrombosis. There were no significant differences between venous and arterial thrombosis. The worst survival was noted in patients who developed thrombosis 3 months prior to or shortly after their diagnosis of cancer. There has been a recent improved survival outcome following therapy. In addition to venous thrombosis, arterial occlusion with stroke and anginal symptoms is relatively common among cancer patients, especially those of Caucasian ancestry, and is possibly related to genetic predisposition. 23683950 Frequency of takotsubo cardiomyopathy in postmenopausal women presenting with an acute coronary syndrome. Takotsubo cardiomyopathy (TC) may be more common than previously reported in postmenopausal women (PMW) presenting with acute coronary syndrome (ACS). TC often masquerades as an ACS with electrocardiographic changes, elevated troponins, and/or chest discomfort. Its exact incidence in ACS is unknown but most studies suggest it is 1% to 2.2%. As most patients with TC are PMW, it was hypothesized that the incidence would be greater in this population. A prospective evaluation was carried out in all middle-aged and older women (≥45 years of age) presumed to be peri- or postmenopausal with an elevated troponin presenting to a community hospital over a 1-year period (July 2011 to July 2012). Troponin results above the upper limit of normal were screened on a daily basis through a computerized system. The patients' in-hospital charts were reviewed and determined if they fulfilled the criteria for acute myocardial infarction according to the universal definition of myocardial infarction. Prespecified criteria were used to identify all patients with TC. Of the 1,297 PMW screened for positive troponins, 323 patients (24.9%) fulfilled the criteria for acute myocardial infarction and of these, 19 (5.9%) met the prespecified criteria for TC. Three additional patients with TC had acute neurologic events. Most patients (81.8%) had the apical variant. In conclusion, TC may be more common than reported in PMW with clinical and laboratory criteria suggesting acute myocardial infarction. Heightened awareness of TC in this population appears warranted. 22906570 Improved procedures for in vitro skin irritation testing of sticky and greasy natural botanicals. Skin irritation evaluation is an important endpoint for the safety assessment of cosmetic ingredients required by various regulatory authorities for notification and/or import of test substances. The present study was undertaken to investigate possible protocol adaptations of the currently validated in vitro skin irritation test methods based on reconstructed human epidermis (RhE) for the testing of plant extracts and natural botanicals. Due to their specific physico-chemical properties, such as lipophilicity, sticky/buttery-like texture, waxy/creamy foam characteristics, normal washing procedures can lead to an incomplete removal of these materials and/or to mechanical damage to the tissues, resulting in an impaired prediction of the true skin irritation potential of the materials. For this reason different refined washing procedures were evaluated for their ability to ensure appropriate removal of greasy and sticky substances while not altering the normal responses of the validated RhE test method. Amongst the different procedures evaluated, the use of a SDS 0.1% PBS solution to remove the sticky and greasy test material prior to the normal washing procedures was found to be the most suitable adaptation to ensure efficient removal of greasy and sticky in-house controls without affecting the results of the negative control. The predictive capacity of the refined SDS 0.1% washing procedure, was investigated by using twelve oily and viscous compounds having known skin irritation effects supported by raw and/or peer reviewed in vivo data. The normal washing procedure resulted in 8 out of 10 correctly predicted compounds as compared to 9 out of 10 with the refined washing procedures, showing an increase in the predictive ability of the assay. The refined washing procedure allowed to correctly identify all in vivo skin irritant materials showing the same sensitivity as the normal washing procedures, and further increased the specificity of the assay from 5 to 6 correct predictions out of 7 non irritants as compared to the normal washing procedures. In addition, when exposed to non-irritant oily and viscous materials, tissues rinsed with 0.1% SDS generally showed increased viabilities accompanied by decreased variabilities as compared to the normal washing procedures. Similar results were obtained when testing typical in-house natural botanical ingredients. In conclusion, the use of a refined washing procedure making use of SDS 0.1% in PBS was found a suitable procedure to ensure efficient removal of greasy and sticky materials, leading to an increased predictive capacity and decreased variability of the tissue responses while maintaining its sensitivity and not affecting untreated tissues morphology and viability. 23939978 Barkedji virus, a novel mosquito-borne flavivirus identified in Culex perexiguus mosquitoes, Israel, 2011. Barkedji virus, named after the area of its first identification in Senegal, is a newly discovered flavivirus, for which we propose the abbreviation BJV. In the present study, we report the first-time detection of BJV in Culex perexiguus mosquitoes in Israel in 2011 and determination of its almost complete polyprotein gene sequence. We characterized the BJV genome and defined putative mature proteins, conserved structural elements, and potential enzyme motifs along the polyprotein precursor. By comparing polyproteins and individual proteins of BJV with several other flaviviruses, a distant relationship of BJV to Nounane virus, a recently described African flavivirus, is demonstrated. Phylogenetic analysis of 55 selected flaviviral polyprotein gene sequences exhibits two major clusters, one made up of the classical three clades of flaviviruses: mosquito-borne, tick-borne, and such without known vectors. The other cluster exclusively contains so-called 'insect-specific' flaviviruses, which do not replicate in vertebrate cells. Based on our phylogenetic analysis, BJV is related to other members of the mosquito-borne clade with yet unknown vertebrate hosts, such as Nounane virus, Donggang virus, Chaoyang virus, and Lammi virus. However, with a maximum identity of only 54% to Nounane virus BJV represents a distinct new virus species. 23642037 Surface-sensitive two-dimensional magneto-fingerprint in mesoscopic Bi2Se3 channels. Periodic Aharonov-Bohm and Altshuler-Aronov-Spivak oscillations have traditionally been observed in lateral transport through patterned mesoscopic loops of diffusive conductors. However, our studies of perpendicular-to-plane magnetotransport in straight-channel, diffusive devices of epitaxial Bi2Se3 surprisingly reveal signatures of Aharonov-Bohm orbits -- periodic conductance fluctuation magneto-fingerprints -- even though the devices are not explicitly patterned into loops. We show that the length scale of these orbits corresponds to the typical perimeter of triangular terraces found on the surface of these thin film devices, strongly suggesting that the periodic magneto-fingerprint arises from coherent scattering of electron waves from the step-edges. Our interpretation is bolstered by control measurements in devices without such surface morphology which only show a conventional, aperiodic magneto-fingerprint. These results show that lithographically patterned Bi2Se3 devices provide a novel class of mesoscopic physical systems for systematic studies of coherent surface sensitive transport. 23842045 The reliability of HBV core antibody in serological screening for hepatitis B virus. Accurate diagnosis of hepatitis B virus (HBV) infection is essential for infection control, treatment and screening of potential blood, organ and tissue donors. We assessed the sensitivity of the HBsAg and HBcAb as screening assays alone and in combination for detecting HBV infection in a series of Australian patients. The performance of the Architect (Abbott Diagnostics, Germany) and the Elecsys (Roche Diagnostics, Germany) platforms were assessed for detection of HBcAb. There were 2778 blood samples assessed using the COBAS Ampliprep/TaqMan test for HBV DNA, of which 331 sera had concurrent HBV serology testing. This allowed determination of the correlation between HBV DNA and different serological markers. Of the 331 sera, 260 had sufficient residual volume to be retested for HBcAb using both Elecsys and the Architect assays. Of the 331 patients, one (0.3%) was negative by the Architect Anti-HBc II assay, in the presence of HBV DNA and positive HBsAg, consistent with recent infection. Positive HBcAb in the absence of HBV DNA was found in 67 of 331 (20.2%) patients. Of these, 18 of 67 had isolated HBcAb with negative results on all other tests, with 12 of 18 (3.6%) demonstrating low HBcAb signals on chemiluminscent microparticle assay. No cases of detectable HBV DNA in the presence of negative serology were found. When the HBcAb was used as a marker for past exposure or chronic HBV infection, the Architect Anti-HBc II assay demonstrated sensitivity and specificity of 98% and 79.9%, respectively, compared to 90% and 78.9%, respectively, for the Elecsys Anti-HBc assay. The combination of the Architect Anti-HBc II and HBsAg assays, as per conventional solid organ donor and recipient screening protocols, had 90% specificity and 100% sensitivity for determining HBV infection. This study shows that the use of combined HBsAg and HBcAb is sensitive and reliable for screening and predicting HBV nucleic acid test (NAT) positivity, whereas HBcAb alone missed an acute infection in this study population. There were no significant differences detectable between the Architect and the Elecsys HBcAb assays (p = 0.001), suggesting laboratories should assess individual assays in the local population before use as screening tests. 23887034 Is Prolactin Measurement of Value during Inferior Petrosal Sinus Sampling in Patients with ACTH-dependent Cushing's Syndrome? Inferior petrosal sinus sampling (IPSS) is considered the gold standard test to distinguish between Cushing's disease (CD) and ectopic ACTH syndrome (EAS). Anomalous venous drainage, abnormal venous anatomy and lack of expertise can lead to false-negative IPSS results and thereby misclassification of patients with ACTH-dependent Cushing's syndrome. Prolactin measurement during IPSS can improve diagnostic accuracy and decrease false negative results. A baseline prolactin inferior petrosal sinus to peripheral (IPS/P) ratio (ipsilateral to the dominant post-CRH ACTH IPS/P ratio) of 1.8 or more suggests successful catheterization during IPSS. Prolactin-normalized ACTH IPS/P ratios can then be used to differentiate between a pituitary and ectopic source of ACTH. Values ≤ 0.7 are suggestive of EAS and those ≥ 1.3 are indicative of CD but the implication of values between 0.7 and 1.3 remains unclear and needs further investigation. Larger prospective studies are also needed for further evaluation of the role of contralateral prolactin IPS/P ratios, post-CRH prolactin values and prolactin-adjusted ACTH inter-sinus ratios for tumor localization in CD. 23942271 Karyotype-Phenotype Correlation in Partial Trisomies of the Short Arm of Chromosome 6: A Family Case Report and Review of the Literature. The first child (proband) of nonconsanguineous Caucasian parents underwent genetic investigation because she was affected with congenital choanal atresia, heart defects and kidney hyposplasia with mild transient renal insufficiency. The direct DNA sequencing after PCR of the CHD7 gene, which is thought to be responsible for approximately 60-70% of the cases of CHARGE syndrome/association, found no mutations. The cytogenetic analysis (standard GTG banding karyotype) revealed the presence of extrachromosomal material on 10q. The chromosome analysis was completed with array CGH (30 kb resolution), MLPA and FISH, which allowed the identification of three 6p regions (6p.25.3p23 × 3): 2 of these regions are normally located on chromosome 6, and the third region is translocated to the long arm of chromosome 10. The same chromosomal rearrangement was subsequently found in the father, who was affected with congenital ptosis and progressive hearing loss, and in the proband's sister, the second child, who presented at birth with choanal atresia and congenital heart defects. The mutated karyotypes, which were directly inherited, are thought to be responsible for a variable phenotype, including craniofacial dysmorphisms, choanal atresia, congenital ptosis, sensorineural hearing loss, heart defects, developmental delay, and renal dysfunction. Nevertheless, to achieve a complete audiological assessment of the father, he underwent further investigation that revealed an increased level of the coagulation factor XIII (300% increased activity), fluctuating levels of fibrin D-dimer degradation products (from 296 to 1,587 ng/ml) and a homoplasmic mitochondrial DNA mutation: T961G in the MTRNR1 (12S rRNA) gene. He was made a candidate for cochlear implantation. Preoperative high-resolution computed tomography and magnetic resonance imaging of the temporal bone revealed the presence of an Arnold-Chiari malformation type I. To the best of our knowledge, this study is the second report on partial 6p trisomy that involves the 10q terminal region. Furthermore, we report the first case of documented Arnold-Chiari malformation type I and increased factor XIII activity associated with 6p trisomy. We present a comprehensive report of the familial cases and an exhaustive literature review. © 2013 S. Karger AG, Basel. 23451853 Selective functionalization of the internal and the external surfaces of mesoporous silicon by liquid masking. A general approach for selective, differential functionalization of the interior and exterior surfaces of mesoporous Si is reported. The method employs two immiscible liquids, one inert and the other chemically reactive with the porous Si nanostructure. First, a porous Si sample is prepared by electrochemical etch and then it is mildly oxidized, which places a thin layer of silicon oxide at the surface. The inner pore walls of the partially oxidized porous Si film are then infiltrated with an inert liquid (octane). The sample is then immersed in aqueous solution containing hydrogen fluoride (HF), which serves as the reactive liquid. The hydrophobic phase is retained in the interior of the porous nanostructure, and HF(aq) attacks only the exposed surfaces of the oxidized porous Si sample, generating a hydrophobic, hydrogen-terminated (Si-H) outer layer. The reaction is self-limiting due to the immiscibility of octane and water, and the extent of penetration of the Si-H surface into the porous layer is dependent on the time of exposure to HF(aq). The Si-H surface can then be modified by thermal hydrosilylation (1-dodecene or 10-bromo-1-decene) in a subsequent step, resulting in a bifunctional porous Si film containing hydrophobic pore entrances to hydrophilic inner pores. The hydrophobic dodecyl species at the mouths of the pores is found to form a barrier for molecular transport; it decreases the rate of leaching (into water) of a rhodamine test molecule that is preloaded into the sample by >8 fold. 23436475 Production of polymalic acid and malic acid by Aureobasidium pullulans fermentation and acid hydrolysis. Malic acid is a dicarboxylic acid widely used in the food industry and also a potential C4 platform chemical that can be produced from biomass. However, microbial fermentation for direct malic acid production is limited by low product yield, titer, and productivity due to end-product inhibition. In this work, a novel process for malic acid production from polymalic acid (PMA) fermentation followed by acid hydrolysis was developed. First, a PMA-producing Aureobasidium pullulans strain ZX-10 was screened and isolated. This microbe produced PMA as the major fermentation product at a high-titer equivalent to 87.6 g/L of malic acid and high-productivity of 0.61 g/L h in free-cell fermentation in a stirred-tank bioreactor. Fed-batch fermentations with cells immobilized in a fibrous-bed bioreactor (FBB) achieved the highest product titer of 144.2 g/L and productivity of 0.74 g/L h. The fermentation produced PMA was purified by adsorption with IRA-900 anion-exchange resins, achieving a ∼100% purity and a high recovery rate of 84%. Pure malic acid was then produced from PMA by hydrolysis with 2 M sulfuric acid at 85°C, which followed the first-order reaction kinetics. This process provides an efficient and economical way for PMA and malic acid production, and is promising for industrial application. 23970546 Mitochondrial protein BmPAPI modulates the length of mature piRNAs. PIWI proteins and their associated PIWI-interacting RNAs (piRNAs) protect genome integrity by silencing transposons in animal germlines. The molecular mechanisms and components responsible for piRNA biogenesis remain elusive. PIWI proteins contain conserved symmetrical dimethylarginines (sDMAs) that are specifically targeted by TUDOR domain-containing proteins. Here we report that the sDMAs of PIWI proteins play crucial roles in PIWI localization and piRNA biogenesis in Bombyx mori-derived BmN4 cells, which harbor fully functional piRNA biogenesis machinery. Moreover, RNAi screenings for Bombyx genes encoding TUDOR domain-containing proteins identified BmPAPI, a Bombyx homolog of Drosophila PAPI, as a factor modulating the length of mature piRNAs. BmPAPI specifically recognized sDMAs and interacted with PIWI proteins at the surface of the mitochondrial outer membrane. BmPAPI depletion resulted in 3'-terminal extensions of mature piRNAs without affecting the piRNA quantity. These results reveal the BmPAPI-involved piRNA precursor processing mechanism on mitochondrial outer membrane scaffolds. 23578637 Selenium bioaccessibility and speciation in biofortified Pleurotus mushrooms grown on selenium-rich agricultural residues. Cultivation of saprophytic fungi on selenium-rich substrates can be an effective means to produce selenium-fortified food. Pleurotus florida, an edible species of oyster mushrooms, was grown on wheat straw from the seleniferous belt of Punjab (India) and its potential to mobilize and accumulate selenium from the growth substrate was studied. Selenium concentration in biofortified mushrooms was 800 times higher compared with control samples grown on wheat straw from non selenium-rich areas (141 vs 0.17μgSeg(-1) dry weight). Seventy-five percent of the selenium was extracted after in vitro simulated gastrointestinal digestion and investigation of the selenium molecular fractions by size exclusion HPLC-ICP-MS revealed that proteins and any other high molecular weight selenium-containing molecule were hydrolyzed to peptides and low molecular weight selenocompounds. Analysis of the gastrointestinal hydrolysates by anion exchange HPLC-ICP-MS showed that the bioaccessible selenium was mainly present as selenomethionine, a good bioavailable source of selenium, which accounted for 73% of the sum of the detected species. This study demonstrates the feasibility of producing selenium-biofortified edible mushrooms using selenium-rich agricultural by-products as growth substrates. The proposed approach can be used to evaluate whether selenium-contaminated plant waste materials harvested from high-selenium areas may be used to produce selenium-biofortified edible mushrooms based on the concentration, bioaccessibility and speciation of selenium in the mushrooms. 23955449 MS-Based Monitoring of Proteolytic Decay of Synthetic Reporter Peptides for Quality Control of Plasma and Serum Specimens. Objectives: To determine the preanalytical quality of serum and plasma by monitoring the time-dependent ex vivo decay of a synthetic reporter peptide (RP) with liquid chromatography/mass spectrometry (LC/MS). Methods: Serum and plasma specimens were spiked with the RP and proteolytic fragments were monitored with LC/MS at different preanalytical time points ranging from 2 to 24 hours after blood withdrawal. Results: The concentration of fragments changed in a time-dependent manner, and respective peptide profiles were used to classify specimens according to their preanalytical time span. Classification accuracy was high, with values always above 0.89 for areas under receiver operating characteristic curves. Conclusions: This "proteomics degradation clock" can be used to estimate the preanalytical quality of serum and plasma and might have impact on quality control procedures of biobanking repositories. 23566237 Successful treatment of depressed, distensible acne scars using autologous fibroblasts: a multi-site, prospective, double blind, placebo-controlled clinical trial. A previous clinical trial evaluating autologous fibroblasts (human dermal) injections for the treatment of facial contour deformities found significantly greater improvements in wrinkle and acne scar appearance than with placebo treatment. To compare the efficacy and safety of autologous fibroblast treatment of moderate to severe, depressed, distensible facial acne scars with that of vehicle control. This was a randomized multicenter, double-blind, placebo-controlled trial in subjects with bilateral moderate to severe acne scarring; subjects served as their own controls. Skin biopsies were obtained from randomized subjects for fibroblast production. Subjects (n = 99) underwent three intradermal injection sessions with 2 mL of autologous fibroblast suspension (10-20 million cells/mL) on one cheek and vehicle control (cell culture medium) on the other at 14-day intervals. Efficacy was based on the blinded subject's, evaluator's, and independent photographic viewer's (IPR) assessment of acne scarring 1 to 4 months after the last treatment. Autologous fibroblast treatment was associated with significantly greater treatment success than vehicle control for the subject (43% vs 18%), evaluator (59% vs 42%), and IPR assessments. Autologous fibroblast injections were well tolerated, without permanent adverse effects. Autologous fibroblast injections safely and effectively improved the appearance of depressed distensible acne scars. 23631496 A Chemometric Approach to Distribution of Selenium in Medicinal Plants Cultivated in Poland. Abstract The aim of this study was to evaluate the level of selenium (Se) in common raw plant materials (herbs, leaves, flowers, fruits, and roots) obtained from medicinal plants cultivated in Poland. Furthermore, the relationship between the morphological part of a plant and its species was examined, and the concentration of Se in it was measured. Spectrofluorimetric determination of Se in 148 samples of 44 plant species revealed that the majority of the plants contained Se at a level from several to several tens of μg/kg dry weight (d.w.). A relatively high Se concentration, in the order of 50 μg/kg d.w., was found in Majoranae herba, Crataegi fructus, and Lini semen. An especially high Se level, >100 μg/kg d.w., was found in only three plants-Equiseti herba, Farfarae folium, and Cichorii radix. Application of a nonparametric Kruskal-Wallis analysis of variance test indicates that the morphological variable influences the level of Se in the studied groups of raw plant materials. The mean concentration of Se in fruits differs significantly from that found in flowers and roots. However, there was no statistically significant difference between the Se content in herbs and leaves and its levels in fruits, flowers, and roots. Cluster analysis and principal component analysis calculations show that it is possible to relate the Se concentration in plant material to the plant species and botanical family of the medicinal plant in only a few cases. Analysis of average Se levels in the plant species showed that the plants belonging to the Apiaceae and Labiatae are more Se-rich than those belonging to Rosaceae botanical families. 23927361 Organ S values and effective doses for family members exposed to adult patients following I-131 treatment: A Monte Carlo simulation study. Purpose: To calculate organ S values (mGy∕Bq-s) and effective doses per time-integrated activity (mSv∕Bq-s) for pediatric and adult family members exposed to an adult male or female patient treated with I-131 using a series of hybrid computational phantoms coupled with a Monte Carlo radiation transport technique.Methods: A series of pediatric and adult hybrid computational phantoms were employed in the study. Three different exposure scenarios were considered: (1) standing face-to-face exposures between an adult patient and pediatric or adult family phantoms at five different separation distances; (2) an adult female patient holding her newborn child, and (3) a 1-yr-old child standing on the lap of an adult female patient. For the adult patient model, two different thyroid-related diseases were considered: hyperthyroidism and differentiated thyroid cancer (DTC) with corresponding internal distributions of (131)I. A general purpose Monte Carlo code, MCNPX v2.7, was used to perform the Monte Carlo radiation transport.Results: The S values show a strong dependency on age and organ location within the family phantoms at short distances. The S values and effective dose per time-integrated activity from the adult female patient phantom are relatively high at shorter distances and to younger family phantoms. At a distance of 1 m, effective doses per time-integrated activity are lower than those values based on the NRC (Nuclear Regulatory Commission) by a factor of 2 for both adult male and female patient phantoms. The S values to target organs from the hyperthyroid-patient source distribution strongly depend on the height of the exposed family phantom, so that their values rapidly decrease with decreasing height of the family phantom. Active marrow of the 10-yr-old phantom shows the highest S values among family phantoms for the DTC-patient source distribution. In the exposure scenario of mother and baby, S values and effective doses per time-integrated activity to the newborn and 1-yr-old phantoms for a hyperthyroid-patient source are higher than values for a DTC-patient source.Conclusions: The authors performed realistic assessments of (131)I organ S values and effective dose per time-integrated activity from adult patients treated for hyperthyroidism and DTC to family members. In addition, the authors' studies consider Monte Carlo simulated "mother and baby∕child" exposure scenarios for the first time. Based on these results, the authors reconfirm the strong conservatism underlying the point source method recommended by the US NRC. The authors recommend that various factors such as the type of the patient's disease, the age of family members, and the distance∕posture between the patient and family members must be carefully considered to provide realistic dose estimates for patient-to-family exposures. 23890079 Inhibition of transketolase by oxythiamine altered dynamics of protein signals in pancreatic cancer cells. Oxythiamine (OT), an analogue of anti-metabolite, can suppress the nonoxidative synthesis of ribose and induce cell apoptosis by causing a G1 phase arrest in vitro and in vivo. However, the molecular mechanism remains unclear yet. In the present study, a quantitative proteomic analysis using the modified SILAC method (mSILAC) was performed to determine the effect of metabolic inhibition on dynamic changes of protein expression in MIA PaCa-2 cancer cells treated with OT at various doses (0 muM, 5 muM, 50 muM and 500 muM) and time points (0 h, 12 h and 48 h). A total of 52 differential proteins in MIA PaCa-2 cells treated with OT were identified, including 14 phosphorylated proteins. Based on the dynamic expression pattern, these proteins were categorized in three clusters, straight down-regulation (cluster 1, 37% of total proteins), upright "V" shape expression pattern (cluster 2, 47.8% total), and downright "V" shape pattern (cluster 3, 15.2% total). Among them, Annexin A1 expression was significantly down-regulated by OT treatment in time-dependent manner, while no change of this protein was observed in OT dose-dependent fashion. Pathway analysis suggested that inhibition of transketolase resulted in changes of multiple cellular signaling pathways associated with cell apoptosis. The temporal expression patterns of proteins revealed that OT altered dynamics of protein expression in time-dependent fashion by suppressing phosphor kinase expression, resulting in cancer cell apoptosis. Results from this study suggest that interference of single metabolic enzyme activity altered multiple cellular signaling pathways. 23628159 Cortical mapping by magnetic resonance imaging (MRI) and quantitative cytological analysis in the human brain: A feasibility study in the fusiform gyrus. The cerebral cortex is a layered cellular structure that is tangentially organized into a mosaic of anatomically and functionally distinct fields. In spite of centuries of investigation, the precise localization and classification of many areas in the cerebral cortex remain problematic because the relationship between functional specificity and intra-cortical structure has not been firmly established. Furthermore, it is not yet clear how surface landmarks, visible through gross examination and, more recently, using non-invasive magnetic resonance imaging (MRI), relate to underlying microstructural borders and to the topography of functional activation. We have designed a multi-modal neuroimaging protocol that combines MRI and quantitative microscopic analysis in the same individual to clarify the topography of cytoarchitecture underlying gross anatomical landmarks in the cerebral cortex. We tested our approach in the region of the fusiform gyrus (FG) because, in spite of its seemingly smooth appearance on the ventral aspect of both hemispheres, this structure houses many functionally defined areas whose histological borders remain unclear. In practice, we used MRI-based automated segmentation to define the region of interest from which we could then collect quantitative histological data (specifically, neuronal size and density). A modified stereological approach was used to sample the cortex within the FG without a priori assumptions on the location of architectonic boundaries. The results of these analyses illustrate architectonic variations along the FG and demonstrate that it is possible to correlate quantitative histological data to measures that are obtained in the context of large-scale, non-invasive MRI-based population studies. 23858100 Coronary Vasomotor Response to Intracoronary Acetylcholine Injection, Clinical Features, and Long-term Prognosis in 873 Consecutive Patients With Coronary Spasm: Analysis of a Single-Center Study Over 20 Years. The aim of this study was to elucidate the correlation between angiographic coronary vasomotor responses to intracoronary acetylcholine (ACh) injection, clinical features, and long-term prognosis in patients with vasospastic angina (VSA). This is a retrospective, observational, single-center study of 1877 consecutive patients who underwent ACh-provocation test between January 1991 and December 2010. ACh-provoked coronary spasm was observed in 873 of 1637 patients included in the present analysis. ACh-positive patients were more likely to be older male smokers with dyslipidemia, to have a family history of ischemic heart disease, and to have a comorbidity of coronary epicardial stenosis than were ACh-negative patients. ACh-positive patients were divided into 2 groups: those with focal (total or subtotal obstruction, n=511) and those with diffuse (severe diffuse vasoconstriction, n=362) spasm patterns. Multivariable logistic regression analysis identified female sex and low comorbidity of coronary epicardial stenosis to correlate with the ACh-provoked diffuse spasm pattern in patients with VSA. Kaplan-Meier survival curve indicated better 5-year survival rates free from major adverse cardiovascular events in patients with diffuse spasm pattern compared with those with focal spasm pattern (P=0.019). Multivariable Cox hazard regression analysis identified diffuse spasm pattern as a negative predictor of major adverse cardiovascular events in patients with VSA. ACh-induced diffuse coronary spasm was frequently observed in female VSA patients free of severe coronary epicardial stenosis and was associated with better prognosis than focal spasm. These results suggest the need to identify the ACh-provoked coronary spasm subtypes in patients with VSA. 23967316 Unique Features of Two Potassium Channels, OsKAT2 and OsKAT3, Expressed in Rice Guard Cells. Potassium is the most abundant cation and a myriad of transporters regulate K(+) homeostasis in plant. Potassium plays a role as a major osmolyte to regulate stomatal movements that control water utility of land plants. Here we report the characterization of two inward rectifying shaker-like potassium channels, OsKAT2 and OsKAT3, expressed in guard cell of rice plants. While OsKAT2 showed typical potassium channel activity, like that of Arabidopsis KAT1, OsKAT3 did not despite high sequence similarity between the two channel proteins. Interestingly, the two potassium channels physically interacted with each other and such interaction negatively regulated the OsKAT2 channel activity in CHO cell system. Furthermore, deletion of the C-terminal domain recovered the channel activity of OsKAT3, suggesting that the C-terminal region was regulatory domain that inhibited channel activity. Two homologous channels with antagonistic interaction has not been previously reported and presents new information for potassium channel regulation in plants, especially in stomatal regulation. 23851904 GC-MS-Based Quantitative Signatures of Cytochrome P450-Mediated Steroid Oxidation Induced by Rifampicin. Drug-induced cytochrome P450 (CYP) activity affects endocrine function and drug clearance rates, leading to the development of unpredictable pathologic and toxicologic risks. Urinary steroid profiling based on gas chromatography-mass spectrometry (GC-MS) was used for simultaneous quantification of CYP-mediated regioselective hydroxysteroids and their substrates, including 26 androgens, 9 estrogens, 5 progestins, and 7 corticoids. The quantitative data were visualized using a hierarchically clustered heat map to allow identification of CYP-mediated steroid signatures. Twelve healthy subjects were orally administered 600 mg of rifampicin a day for 7 days, and their CYP enzyme activity was evaluated. Using GC-MS, all 47 steroids were well separated with good peak shapes. This assay had good linearity (r > 0.994) in a dynamic range, and the interassay imprecision (% CV) and inaccuracy (% bias) were 3.0%-15.6% and 98.0%-109.2%, respectively. Administration of the CYP3A4 inducer rifampicin produced distinct differences in CYP3A4 and CYP11B1, CYP19A1, HSD11B, and HSD17B, which were indicated by their heat map-visualized steroid signatures. This CYP-mediated steroid signature profile allows simultaneous assessment of CYP1A, CYP1B, CYP2C, CYP3A, CYP11B, CYP17A, CYP19A, and CYP21A in urine samples. This method could therefore be a useful tool for assessing drug efficacy. 23856315 Adsorption and sequential degradation of polybrominated diphenyl ethers with zerovalent iron. The widely used flame retardants, polybrominated diphenyl ethers (PBDEs), have been regulated owing to their persistence and toxicity. However, the high and increasing accumulation amount of PBDEs in the environment raises a big concern for public safety. In this study, the removal processes of decabromodiphenyl ether (BDE-209) and monobromodiphenyl ether (BDE-3) with microscale zerovalent iron (MZVI) were investigated to get better understandings for the removal mechanism based upon adsorption and degradation. The removal kinetics of both compounds was analyzed and revealed two-step kinetics: a fast removal step at the beginning of the reaction and a follow-up slow removal step. By-products generated during the entire process followed a stepwise sequence. The content of brominated compounds on the surface of MZVI was measured. About 10-20% of BDE-209 and 15-30% of BDE-3 were adsorbed on MZVI. The adsorption of BDE-209 and BDE-3 on MZVI was confirmed through the Fourier transform infrared spectroscopy. Surface adsorption of PBDEs on MZVI dominates the removal mechanism in the beginning and further debromination with MZVI was found. Finally, about 70% of BDE-209 and 60% of BDE-3 was degraded by MZVI within about one month. Our findings provide evidences for understanding the removal mechanism of PBDEs with MZVI and its great longevity on the PBDE degradation, which can facilitate the remediation design. 23664637 In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is accompanied by activation of immuno-inflammatory pathways, increased bacterial translocation and autoimmune responses to serotonin (5-HT). Inflammation is known to damage 5-HT neurons while bacterial translocation may drive autoimmune responses. This study has been carried out to examine the autoimmune responses to 5-HT in ME/CFS in relation to inflammation and bacterial translocation. We examined 5-HT antibodies in 117 patients with ME/CFS (diagnosed according to the centers for disease control and prevention criteria, CDC) as compared with 43 patients suffering from chronic fatigue (CF) but not fulfilling the CDC criteria and 35 normal controls. Plasma interleukin-1 (IL-1), tumor necrosis factor (TNF)α, neopterin and the IgA responses to Gram-negative bacteria were measured. Severity of physio-somatic symptoms was measured using the fibromyalgia and chronic fatigue syndrome rating scale (FF scale). The incidence of positive autoimmune activity against 5-HT was significantly higher (p<0.001) in ME/CFS (61.5%) than in patients with CF (13.9%) and controls (5.7%). ME/CFS patients with 5-HT autoimmune activity displayed higher TNFα, IL-1 and neopterin and increased IgA responses against LPS of commensal bacteria than those without 5-HT autoimmune activity. Anti-5-HT antibody positivity was significantly associated with increased scores on hyperalgesia, fatigue, neurocognitive and autonomic symptoms, sadness and a flu-like malaise. The results show that, in ME/CFS, increased 5-HT autoimmune activity is associated with activation of immuno-inflammatory pathways and increased bacterial translocation, factors which are known to play a role in the onset of autoimmune reactions. 5-HT autoimmune activity could play a role in the pathophysiology of ME/CFS and the onset of physio-somatic symptoms. These results provide mechanistic support for the notion that ME/CFS is a neuro-immune disorder. 23694685 Dependence of the LR-115 radon detector calibration factor on track density. The reliability and accuracy of the methodology based on using LR-115 track detectors for radon measurements have been studied by determining the dependence of their calibration factors on radon exposure at levels reaching 13 MBq m(-3) h. This factor results not constant and demonstrated a decreasing exponential trend vs. exposure that has been explained in terms of the saturation effect and verified using a numerical simulation. This dependence does not affect the parameter that normalizes track density vs. film thickness. This parameter results constant and equal to - 0.30±0.02 cm(-2)/µm in the 300-8000 kBq h m(-3) exposure range. 23628328 Short and long term mortality rates after a lower limb amputation. To determine mortality rates after a first lower limb amputation and explore the rates for different subpopulations. Retrospective cohort study of all people who underwent a first amputation at or proximal to transtibial level, in an area of 1.7 million people. Analysis with Kaplan-Meier curves and Log Rank tests for univariate associations of psycho-social and health variables. Logistic regression for odds of death at 30-days, 1-year and 5-years. 299 people were included. Median time to death was 20.3 months (95%CI: 13.1; 27.5). 30-day mortality = 22%; odds of death 2.3 times higher in people with history of cerebrovascular disease (95%CI: 1.2; 4.7, P = 0.016). 1 year mortality = 44%; odds of death 3.5 times higher for people with renal disease (95%CI: 1.8; 7.0, P < 0.001). 5-years mortality = 77%; odds of death 5.4 times higher for people with renal disease (95%CI: 1.8; 16.0,P = 0.003). Variation in mortality rates was most apparent in different age groups; people 75-84 years having better short term outcomes than those younger and older. Mortality rates demonstrated the frailty of this population, with almost one quarter of people dying within 30-days, and almost half at 1 year. People with cerebrovascular had higher odds of death at 30 days, and those with renal disease and 1 and 5 years, respectively. 23603294 Infliximab counteracts tumor necrosis factor-α-enhanced induction of matrix metalloproteinases that degrade claudin and occludin in non-pigmented ciliary epithelium. Infliximab, a monoclonal antibody directed against human tumor necrosis factor-alpha (TNF-α), effectively treats anterior uveitis, which can accompany Behçet's disease. Here, we investigated the underlying mechanism of this action. We examined human, non-pigmented ciliary epithelial cells (HNPCECs), which make up the blood-aqueous barrier (BAB) in the uvea. We measured the expression levels of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs in the presence or absence of TNF-α using quantitative, real-time polymerase chain reaction and enzyme-linked immunosorbent assays. The expression of MMP-1, MMP-3, and MMP-9 increased in the presence of TNF-α, and the addition of infliximab reversed the increase. The TNF-α effects were more attenuated when infliximab was added before than when it was added after TNF-α exposure. Gelatin zymography demonstrated that the protease activity of these MMPs was also increased in the presence of TNF-α and attenuated with infliximab. Immunostaining showed that MMP-1, MMP-3, and MMP-9 degraded claudin-1 and occludin in HNPCECs and in non-pigmented ciliary epithelial cells of the swine ciliary body. In a monolayer of HNPCECs, we found that permeability was significantly increased with MMP treatment. Thus, TNF-α increased levels of MMPs in cells that form the BAB, and MMPs degraded components of the tight junctions in the BAB, which increased permeability through the cellular barrier. Furthermore, infliximab effectively attenuated the TNF-α-induced increases in MMP expression in cells that make up the BAB. These findings might suggest a basis for the clinical prevention of anterior uveitis. 23931060 Neutrophil extracellular traps as a new paradigm in innate immunity: friend or foe? The discovery of neutrophil extracellular traps in 2004 opened a fascinating new chapter in immune-mediated microbial killing. Brinkman et al. demonstrated that neutrophils, when catastrophically stimulated, undergo a novel form of programmed cell death (neutrophil extracellular trap formation) whereby they decondense their entire nuclear chromatin/DNA and release the resulting structure into the cytoplasm to mix with granule-derived antimicrobial peptides before extruding these web-like structures into the extracellular environment. The process requires the activation of the granule enzyme peptidyl arginine deiminase-4, the formation of reactive oxygen species (in particular hypochlorous acid), the neutrophil microtubular system and the actin cytoskeleton. Recent work by Yousefi et al. demonstrated that exposure to different agents for shorter stimulation periods resulted in neutrophil extracellular trap release from viable granulocytes, and that such neutrophil extracellular traps comprised mitochondrial DNA rather than nuclear DNA and were also capable of microbial entrapment and destruction. Deficiency in NADPH-oxidase production (as found in patients with chronic granulomatous disease) results in an inability to produce neutrophil extracellular traps and, along with their failure to produce antimicrobial reactive oxygen species, these patients suffer from severe, and sometimes life-threatening, infections. However, conversely the release of nuclear chromatin into tissues is also potentially autoimmunogenic and is now associated with the generation of anti-citrullinated protein antibodies in seropositive rheumatoid arthritis. Other neutrophil-derived nuclear and cytoplasmic contents are also pathogenic, either through direct effects on tissues or via autoimmune processes (e.g. autoimmune vasculitis). In this review, we discuss the plant origins of a highly conserved innate immune method of microbial killing, the history and biology of neutrophil extracellular traps and their role in defence and in human diseases. We attempt to resolve areas of controversy and propose roles for excess neutrophil extracellular trap release from hyperactive/reactive neutrophils and for the unique peptidyl arginine deiminase enzyme of Porphyromonas gingivalis in the pathogenesis of periodontitis, and subsequently a role for periodontitis/the peptidyl arginine deiminase enzyme of P. gingivalis in the causal pathway of autoimmune diseases such as rheumatoid arthritis. We propose that neutrophil extracellular trap and peptidyl arginine deiminase release may propagate tissue-destructive mechanisms rather than provide protection in susceptible individuals and that release of host-derived DNase may play an important role in the digestion and removal of neutrophil extracellular traps within tissues. 23928078 The essential nature of iron usage and regulation. The facile ability of iron to gain and lose electrons has made iron an important participant in a wide variety of biochemical reactions. Binding of ligands to iron modifies its redox potential, thereby permitting iron to transfer electrons with greater or lesser facility. The ability to transfer electrons, coupled with its abundance, as iron is the fourth most abundant mineral in the earth's crust, have contributed to iron being an element required by almost all species in the six kingdoms of life. Iron became an essential element for both Eubacteria and Archeabacteria in the early oxygen-free stages of the earth's evolution. With the advent of an oxygen-rich environment, the redox properties of iron made it extremely useful, as much of iron utilization in eukaryotes is focused on oxygen metabolism, either as an oxygen carrier or as an electron carrier that can facilitate oxygen-based chemistry. 23868607 H2O2-responsive molecularly engineered polymer nanoparticles as ischemia/reperfusion-targeted nanotherapeutic agents. The main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury is the overproduction of reactive oxygen species (ROS). Hydrogen peroxide (H2O2), the most abundant form of ROS produced during I/R, causes inflammation, apoptosis and subsequent tissue damages. Here, we report H2O2-responsive antioxidant nanoparticles formulated from copolyoxalate containing vanillyl alcohol (VA) (PVAX) as a novel I/R-targeted nanotherapeutic agent. PVAX was designed to incorporate VA and H2O2-responsive peroxalate ester linkages covalently in its backbone. PVAX nanoparticles therefore degrade and release VA, which is able to reduce the generation of ROS, and exert anti-inflammatory and anti-apoptotic activity. In hind-limb I/R and liver I/R models in mice, PVAX nanoparticles specifically reacted with overproduced H2O2 and exerted highly potent anti-inflammatory and anti-apoptotic activities that reduced cellular damages. Therefore, PVAX nanoparticles have tremendous potential as nanotherapeutic agents for I/R injury and H2O2-associated diseases. 23951141 Lateral diffusion of nutrients by Mammalian herbivores in terrestrial ecosystems. Animals translocate nutrients by consuming nutrients at one point and excreting them or dying at another location. Such lateral fluxes may be an important mechanism of nutrient supply in many ecosystems, but lack quantification and a systematic theoretical framework for their evaluation. This paper presents a mathematical framework for quantifying such fluxes in the context of mammalian herbivores. We develop an expression for lateral diffusion of a nutrient, where the diffusivity is a biologically determined parameter depending on the characteristics of mammals occupying the domain, including size-dependent phenomena such as day range, metabolic demand, food passage time, and population size. Three findings stand out: (a) Scaling law-derived estimates of diffusion parameters are comparable to estimates calculated from estimates of each coefficient gathered from primary literature. (b) The diffusion term due to transport of nutrients in dung is orders of magnitude large than the coefficient representing nutrients in bodymass. (c) The scaling coefficients show that large herbivores make a disproportionate contribution to lateral nutrient transfer. We apply the diffusion equation to a case study of Kruger National Park to estimate the conditions under which mammal-driven nutrient transport is comparable in magnitude to other (abiotic) nutrient fluxes (inputs and losses). Finally, a global analysis of mammalian herbivore transport is presented, using a comprehensive database of contemporary animal distributions. We show that continents vary greatly in terms of the importance of animal-driven nutrient fluxes, and also that perturbations to nutrient cycles are potentially quite large if threatened large herbivores are driven to extinction. 23636474 Photo-patternable electroluminescence based on one-way photoisomerization reaction of tetraoxidized triangle terarylenes. Oxidized triangle terarylenes with asymmetric side-aryl units are synthesized, which show photo-induced turn-on yellow luminescence based on photochemical intramolecular ring-cyclization reaction in the solid state. A direct photo-patterning process for organic electroluminescent devices is successfully demonstrated with selective light irradiation through an appropriate mask-pattern. 23529473 Exposure of Bacillus subtilis to mercury induces accumulation of shorter tRNA Cys species. RNA processing is an essential pathway in the regulation of genetic expression in the cell. In this work, Bacillus subtilis was used to understand the effects of mercury on the mechanism of tRNA metabolism. The CVAAS (cold vapor atomic absorption spectroscopy) method revealed that from the addition of HgCl2 (0.75 μg ml(-1)) during the bacterial exponential phase, ca. 48% of the added mercury was taken up by the cells. This led to an immediate reduction in the rate of cell division. During this response, we observed accumulation of species shorter than mature tRNA(Cys) over a 10 h period. We did not observe this accumulation for another five tRNAs analyzed. tRNA processing is largely dependent on RNase R and PNPase in B. subtilis. Thus, when the exonuclease PNPase was absent, we found that the shorter tRNA(Cys) species increased and mature tRNA(Cys) decreased after mercury addition, but this proportion changed during the time analyzed. However, in the absence of RNase R and PNPase the accumulation of the shorter tRNA(Cys) was more pronounced and the mature form was not recovered. In the single rnr mutant strain the shorter tRNA(Cys) was not observed. All together, we provide in vivo evidence that PNPase and RNase R are indispensable in controlling tRNA(Cys) quality in the presence of mercury. 23599124 Spin-polarized transport through single-molecule magnet Mn6 complexes. The coherent transport properties of a device, constructed by sandwiching a Mn6 single-molecule magnet between two gold surfaces, are studied theoretically by using the non-equilibrium Green's function approach combined with density functional theory. Two spin states of such Mn6 complexes are explored, namely the ferromagnetically coupled configuration of the six Mn(III) cations, leading to the S = 12 ground state, and the low S = 4 spin state. For voltages up to 1 volt the S = 12 ground state shows a current one order of magnitude larger than that of the S = 4 state. Furthermore this is almost completely spin-polarized, since the Mn6 frontier molecular orbitals for S = 12 belong to the same spin manifold. As such the high-anisotropy Mn6 molecule appears as a promising candidate for implementing, at the single molecular level, both spin-switches and low-temperature spin-valves. 23843387 Multiple host transfers, but only one successful lineage in a continent-spanning emergent pathogen. Emergence of a new disease in a novel host is thought to be a rare outcome following frequent pathogen transfers between host species. However, few opportunities exist to examine whether disease emergence stems from a single successful pathogen transfer, and whether this successful lineage represents only one of several pathogen transfers between hosts. We examined the successful host transfer and subsequent evolution of the bacterial pathogen Mycoplasma gallisepticum, an emergent pathogen of house finches (Haemorhous (formerly Carpodacus) mexicanus). Our principal goals were to assess whether host transfer has been a repeated event between the original poultry hosts and house finches, whether only a single host transfer was ultimately responsible for the emergence of M. gallisepticum in these finches, and whether the spread of the pathogen from east to west across North America has resulted in spatial structuring in the pathogen. Using a phylogeny of M. gallisepticum based on 107 isolates from domestic poultry, house finches and other songbirds, we infer that the bacterium has repeatedly jumped between these two groups of hosts but with only a single lineage of M. gallisepticum persisting and evolving in house finches; bacterial evolution has produced monophyletic eastern and western North American subclades. 22186637 Cross-racial measurement equivalence of the eyberg child behavior inventory factors among low-income young african american and non-latino white children. This study examined the cross-racial measurement equivalence of the three Eyberg Child Behavior Inventory Intensity Scale factors, found by Stern and Johnson: Oppositional Defiant Behavior, Attention Difficulties, and Conduct Problems. Cross-racial measurement equivalence was examined between 278 low-income African American and 119 non-Latino White children aged 3 to 6 years. Results did not support configural equivalence of the three subscales between groups. Exploratory factor analyses conducted separately for each racial group showed support for a single factor structure in both groups. Convergent validity of the Intensity Scale was found separately for both groups. Findings suggest the three Intensity Scale factors should not be used to screen or compare treatment outcomes of specific externalizing behavior problems among community samples that include low-income non-Latino White and African American preschoolers. 23469757 Folate Conjugation to Polymeric Micelles via Boronic Acid Ester to Deliver Platinum Drugs to Ovarian Cancer Cell Lines. In this study, a novel technique was used for the reversible attachment of folic acid on the surface of polymeric micelles for a tumor-specific drug delivery system. The reversible conjugation is based on the interaction between phenylboronic acid (PBA) and dopamine to form a borate ester. The conjugation is fast and efficient and in vitro experiments via confocal fluorescent microscopy show that the linker is stable in for several hours. Reversible addition-fragmentation chain transfer (RAFT) polymerization was used to synthesize two various sized water-soluble block copolymer of oligoethylene glycol methylether methacylate and methyl acrylic acid (POEGMEMA35-b-PMAA200 and POEGMEMA26-b-PMAA90). The platinum drug, oxoplatin, was then subsequently attached to the polymer via ester formation leading to platinum loading of 12 wt % as determined by TGA. The platinum-induced amphiphilic block copolymers that consequently led to the formation of micelles of sizes 150 and 20 nm in an aqueous environment with the longer PMAA block forming larger micelles. The small micelles were in addition cross-linked using 1,8-diaminooctane to further stabilize their structure. The targeting ability of folate conjugated polymeric micelles was investigated against two types of tumor cell lines: A549 (-FR) and OVCAR-3 (+FR). The cell line growth inhibitory efficacy of material synthesized was evaluated by using SRB method. The results revealed that folate conjugated micelles showed higher activity in FR + OVCAR-3 cells but not in FR - A549 cells. Similar results were obtained for both small and large micelles without the conjugation of folate. Comparing large and small micelles it can be observed that larger micelles are more efficient, which has been attributed to the lower stability of the smaller micelles. Micelle stabilization via cross-linking could indeed increase the toxicity of the drug carrier. 23881382 Aberrant Sphingolipid Metabolism in the Human Fallopian Tube with Ectopic Pregnancy. Sphingosine 1-phosphate (S1P), a product of sphingomyelin metabolism, is generated via phosphorylation of sphingosine by sphingosine kinases (SphK). It acts via a family of G protein-coupled receptors or as an intracellular second messenger for agonists acting through the S1P receptors (S1P1-5). In our study, the expression of SphK1 and S1P1 was identified by immunohistochemistry and immunoblot. The concentration of S1P was measured using ELISA. The spontaneous contraction of isolated fallopian tube strips was determined by tension recording. Our results showed that SphK1 and S1P1 were localized in the fallopian tube epithelial cells. In addition, smooth muscle cells also contained S1P1. Compared with the intrauterine pregnancy group, SPHK1 and S1P1 were overexpressed in ectopic pregnancy. However, the S1P concentration within the human oviduct from ectopic pregnancy subjects was largely reduced than that from normal pregnancy subject. The results from tension recording indicated that exogenous and intracellularly generated S1P can regulate the spontaneous contraction of oviduct isolated from rats and human. In conclusion, the sphingolipid metabolism signal pathway functionally existed in the human fallopian tube. Aberrant sphingolipid metabolism in the human fallopian tube may be involved in ectopic pregnancy. 23867081 A coaxial optrode as multifunction write-read probe for optogenetic studies in non-human primates. Advances in optogenetics have led to first reports of expression of light-gated ion-channels in non-human primates (NHPs). However, a major obstacle preventing effective application of optogenetics in NHPs and translation to optogenetic therapeutics is the absence of compatible multifunction optoelectronic probes for (1) precision light delivery, (2) low-interference electrophysiology, (3) protein fluorescence detection, and (4) repeated insertion with minimal brain trauma. Here we describe a novel brain probe device, a "coaxial optrode", designed to minimize brain tissue damage while microfabricated to perform simultaneous electrophysiology, light delivery and fluorescence measurements in the NHP brain. The device consists of a tapered, gold-coated optical fiber inserted in a polyamide tube. A portion of the gold coating is exposed at the fiber tip to allow electrophysiological recordings in addition to light delivery/collection at the tip. Coaxial optrode performance was demonstrated by experiments in rodents and NHPs, and characterized by computational models. The device mapped opsin expression in the brain and achieved precisely targeted optical stimulation and electrophysiology with minimal cortical damage. Overall, combined electrical, optical and mechanical features of the coaxial optrode allowed a performance for NHP studies which was not possible with previously existing devices. Coaxial optrode is currently being used in two NHP laboratories as a major tool to study brain function by inducing light modulated neural activity and behavior. By virtue of its design, the coaxial optrode can be extended for use as a chronic implant and multisite neural stimulation/recording. 23666244 Efficient Sequencing of Anuran mtDNAs and a Mitogenomic Exploration of the Phylogeny and Evolution of Frogs. Anura (frogs and toads) constitute over 88% of living amphibian diversity but many important questions about their phylogeny and evolution remain unresolved. For this study, we developed an efficient method for sequencing anuran mitochondrial DNAs (mtDNAs) by amplifying the mitochondrial genome in 12 overlapping fragments using frog-specific universal primer sets. Based on this method, we generated 47 nearly complete, new anuran mitochondrial genomes and discovered nine novel gene arrangements. By combining the new data and published anuran mitochondrial genomes, we assembled a large mitogenomic data set (11,007 nt) including 90 frog species, representing 39 of 53 recognized anuran families, to investigate their phylogenetic relationships and evolutionary history. The resulting tree strongly supported a paraphyletic arrangement of archaeobatrachian (=nonneobatrachian) frogs, with Leiopelmatoidea branching first, followed by Discoglossoidea, Pipoidea, and Pelobatoidea. Within Neobatrachia, the South African Heleophrynidae is the sister-taxon to all other neobatrachian frogs and the Seychelles-endemic Sooglossidae is recovered as the sister-taxon to Ranoidea. These phylogenetic relationships agree with many nuclear gene studies. The chronogram derived from two Bayesian relaxed clock methods (MultiDivTime and BEAST) suggests that modern frogs (Anura) originated in the early Triassic about 244 Ma and the appearance of Neobatrachia took place in the late Jurassic about 163 Ma. The initial diversifications of two species-rich superfamilies Hyloidea and Ranoidea commenced 110 and 133 Ma, respectively. These times are older than some other estimates by approximately 30-40 My. Compared with nuclear data, mtDNA produces compatible time estimates for deep nodes (>150 Ma), but apparently older estimates for more shallow nodes. Our study shows that, although it evolves relatively rapidly and behaves much as a single locus, mtDNA performs well for both phylogenetic and divergence time inferences and will provide important reference hypotheses for the phylogeny and evolution of frogs. 23363044 In vitro study of injury on human bronchial epithelial cells caused by gunpowder smog. Smog inhalation is associated with acute respiratory symptoms in exposed victims. However, despite the evidence from cell injury caused by smog, a stable and practical apparatus used to treat cells with smog is necessary. The aim of this study is to develop a cell research platform of smoke inhalation injury. In the smog-generation device, a wireless electromagnetic heater was used to ignite gunpowder and generate smog. The quality of black powder was checked by the black powder burn rate, and experimental smog was indirectly checked by the amount of cell damage. The temperature and humidity were set at 37 °C ± 1 °C and ≥95% in the smog-cells reaction chamber, respectively. Factors including gunpowder dosages, smog-exposure time, the cell density, modes of exposure, volumes of smog, test durations, volumes of the cell culture medium and combustion velocity were measured. Coefficient variation of different batches of gunpowder and smog were less than 4% and 9%, respectively. With larger gunpowder dosage and longer exposure time, cell injury appeared to increase. When cells were cultured in 4 × 10(4)/well density in culture medium (1 mL/well), exposed to more than 10 L smog with filter screens above plates, detected after 24 h culture in cell incubator and gunpowder burned out within 5 s, smog had the best effect on cell injury. In conclusion, the experimental device can produce test smog stably and safely. The apparatus treating cells with smog can induce cell injury effectively, and the injury is positively correlated with smog concentration and exposure time. 23934189 PTRF/cavin-1 neutralizes non-caveolar caveolin-1 microdomains in prostate cancer. Caveolin-1 has a complex role in prostate cancer and has been suggested to be a potential biomarker and therapeutic target. As mature caveolin-1 resides in caveolae, invaginated lipid raft domains at the plasma membrane, caveolae have been suggested as a tumor-promoting signaling platform in prostate cancer. However, caveola formation requires both caveolin-1 and cavin-1 (also known as PTRF; polymerase I and transcript release factor). Here, we examined the expression of cavin-1 in prostate epithelia and stroma using tissue microarray including normal, non-malignant and malignant prostate tissues. We found that caveolin-1 was induced without the presence of cavin-1 in advanced prostate carcinoma, an expression pattern mirrored in the PC-3 cell line. In contrast, normal prostate epithelia expressed neither caveolin-1 nor cavin-1, while prostate stroma highly expressed both caveolin-1 and cavin-1. Utilizing PC-3 cells as a suitable model for caveolin-1-positive advanced prostate cancer, we found that cavin-1 expression in PC-3 cells inhibits anchorage-independent growth, and reduces in vivo tumor growth and metastasis in an orthotopic prostate cancer xenograft mouse model. The expression of α-smooth muscle actin in stroma along with interleukin-6 (IL-6) in cancer cells was also decreased in tumors of mice bearing PC-3-cavin-1 tumor cells. To determine whether cavin-1 acts by neutralizing caveolin-1, we expressed cavin-1 in caveolin-1-negative prostate cancer LNCaP and 22Rv1 cells. Caveolin-1 but not cavin-1 expression increased anchorage-independent growth in LNCaP and 22Rv1 cells. Cavin-1 co-expression reversed caveolin-1 effects in caveolin-1-positive LNCaP cells. Taken together, these results suggest that caveolin-1 in advanced prostate cancer is present outside of caveolae, because of the lack of cavin-1 expression. Cavin-1 expression attenuates the effects of non-caveolar caveolin-1 microdomains partly via reduced IL-6 microenvironmental function. With circulating caveolin-1 as a potential biomarker for advanced prostate cancer, identification of the molecular pathways affected by cavin-1 could provide novel therapeutic targets.Oncogene advance online publication, 12 August 2013; doi:10.1038/onc.2013.315. 23909779 Improved effectiveness of transepithelial PTK versus topography-guided ablation for stromal irregularities masked by epithelial compensation. To demonstrate improved effectiveness of transepithelial phototherapeutic keratectomy (PTK) where topography-guided ablation is degraded by epithelial compensation for localized irregularities. Artemis very high-frequency digital ultrasound (ArcScan Inc., Morrison, CO) scanning was performed on five eyes (four patients) after LASIK in which a truncated nasal flap was created but the ablation was still performed, resulting in irregular astigmatism and double vision. The stromal ablation pattern of a transepithelial PTK ablation was modeled and compared to topography-guided ablation simulations. Artemis-assisted transepithelial PTK procedures were performed in three eyes (two patients). In all cases, Artemis very high-frequency digital ultrasound demonstrated a crevice on the stromal surface caused by ablation on the underside of the flap nasally, which had been compensated for by epithelial thickening, thus masking a significant proportion of the stromal surface irregularity from corneal surface topography. The transepithelial PTK ablation pattern appeared logically to reduce the ridge nasal to the crevice, whereas topography-guided ablation patterns demonstrated poor targeting of the stromal ridge. Artemis-assisted transepithelial PTK greatly reduced the stromal irregularity, resulting in smoother epithelium and topography. In one eye, the epithelium had compensated fully for the irregularity and the patient reported 95% subjective improvement. One patient (two eyes) reported little change in visual symptoms despite significant anatomical regularization due to the partial nature of epithelial compensation, demonstrating that multiple procedures may often be required. Compensatory epithelial remodeling masks stromal irregularities from the corneal surface, meaning that topography-guided (or wavefront-guided) ablations may not provide an adequate treatment option and may potentially worsen the irregularity. The effectiveness of transepithelial PTK will depend on the proportion of epithelial masking due to remodeling, related to the rate of change of curvature of the stromal surface. 23850577 Potentially functional polymorphisms in ATG10 are associated with risk of breast cancer in a Chinese population. Autophagy is a cellular process directed at recycling of cellular proteins and removal of intracellular microorganisms, which is important for balancing sources of energy at critical times in development and in response to nutrient stress. It has been reported to be a critical process in cancer initiation and progression. We hypothesized that genetic variants in critical genes of autophagy may be involve in the development of breast cancer. Thus, we systematically screened 14 potentially functional polymorphisms in six autophagy-related genes (ATG3, ATG5, ATG7, ATG10, and ATG12 and LC3) that are core components in autophagosome formation. We conducted a case-control study including 1064 breast cancer cases and 1073 cancer-free controls to evaluate the associations of these variants with breast cancer risk. We found that rs1864182 and rs10514231 in ATG10 were significantly associated with a decreased risk of breast cancer [odds ratios (OR)=0.77, 95% confidence interval (CI): 0.61-0.96, P=0.023; and OR=0.75, 95% CI: 0.59-0.93, P=0.010, respectively]. Similar protective effects for both loci were observed between subgroups stratified by ages at diagnosis/recruitment, menarche and first live birth, and status of menopause, estrogen receptor (ER) and progesterone receptor (PR). These results suggest that genetic variants in ATG10 may implicate with breast cancer susceptibility in Chinese population. Further large and functional studies are needed to confirm our findings. 23954375 Decisions under risk in Parkinson's disease: Preserved evaluation of probability and magnitude. Unmedicated Parkinson's disease patients tend to be risk-averse while dopaminergic treatment causes a tendency to take risks. While dopamine agonists may result in clinically apparent impulse control disorders, treatment with levodopa also causes shift in behaviour associated with an enhanced response to rewards. Two important determinants in decision-making are how subjects perceive the magnitude and probability of outcomes. Our objective was to determine if patients with Parkinson's disease on or off levodopa showed differences in their perception of value when making decisions under risk. The Vancouver Gambling task presents subjects with a choice between one prospect with larger outcome and a second with higher probability. Eighteen age-matched controls and eighteen patients with Parkinson's disease before and after levodopa were tested. In the Gain Phase subjects chose between one prospect with higher probability and another with larger reward to maximize their gains. In the Loss Phase, subjects play to minimize their losses. Patients with Parkinson's disease, on or off levodopa, were similar to controls when evaluating gains. However, in the Loss Phase before levodopa, they were more likely to avoid the prospect with lower probability but larger loss, as indicated by the steeper slope of their group psychometric function (t(24)=2.21, p=0.04). Modelling with prospect theory suggested that this was attributable to a 28% overestimation of the magnitude of loss, rather than an altered perception of its probability. While pre-medicated patients with Parkinson's disease show risk-aversion for large losses, patients on levodopa have normal perception of magnitude and probability for both loss and gain. The finding of accurate and normally biased decisions under risk in medicated patients with PD is important because it indicates that, if there is indeed anomalous risk-seeking behaviour in such a cohort, it may derive from abnormalities in components of decision making that are separate from evaluations of size and probability. 23701163 Selected pharmaceutical excipient prevent isoniazid and rifampicin induced hepatotoxicity. Background & Aims: The incidence of isoniazid (INH)- and rifampicin (RIF)-induced abnormal liver enzyme activity is 27% but only 19% with INH alone. Cytochrome P450 2E1 (CYP2E1) is thought to contribute to the synergistic effects of RIF and INH. Pharmaceutical excipients are inactive ingredients that are added to a pharmaceutical compound. The purpose of this study was to screen excipients for CYP2E1 inhibition and identify whether the screened excipients prevented INH/RIF-induced hepatotoxicity. Methods: Fifty-five known pharmaceutical excipients were screened for CYP2E1 inhibition. The hepatotoxic doses of INH and RIF were 50 and 100 mg/kg/day, respectively. Hepatotoxicity was assessed by the galactose single point (GSP) method (a US Food and Drug Administration (FDA) recommended quantitative liver function test), liver histopathology, malondialdehyde (MDA) assay, and measurement of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity. We chose the CYP2E1-specific substrate chlorzoxazone to assess CYP2E1 activity in animal and human. Results: Mannitol inhibited CYP2E1 activity by 54% in mice with INH/RIF-induced hepatotoxicity (p < 0.005). Serum AST, ALT and GSP levels were significantly increased 3.8- to 7.8-fold in these mice (p < 0.005), and these levels could be lowered by mannitol. Mannitol significantly alleviated the depletion of hepatic glutathione (GSH) and partially reversed the increase in MDA formation in mice treated with INH/RIF (p < 0.005). Mannitol also decreased CYP2E1 activity by 58% in humans (p < 0.005). Furthermore, an antituberculosis (TB) efficacy assay revealed that mannitol did not affect the anti-TB effects of INH/RIF. Conclusions: Mannitol, an FDA-approved excipient, was found to be a CYP2E1 inhibitor. Mannitol may be a useful adjuvant for drugs that induce hepatotoxicity through CYP2E1, such as INH and RIF. 23737009 Evaluation of the tooth brushing skills in children aged 6-12 years. To evaluate the tooth brushing skills in children aged between 6 and 12 years and its relation with age, type of grip used, duration of brushing and gender. A total of 105 children aged between 6 and 12 years were divided into seven groups and their plaque scores, type of grip used and duration of brushing were assessed. The most preferred grip was the distal oblique (58.1 %). Oblique, distal oblique and power grips were more efficient (plaque reduction up to 70 %). Plaque removal efficacy improved with age (57 % in 6-year-olds and 82 % in 12-year-old children). Plaque reduction was greater when the duration of brushing was longer (82 % plaque reduction when the brushing time was >2.5 min). Overall, the mean duration of tooth brushing in children aged 6-12 years was 1.71 min (103 s). Tooth brushing skills improved with age and the duration of tooth brushing made a significant difference to the oral hygiene status of the child. The type of grip used and gender did not influence tooth brushing ability in this group of children. Tooth brushing skills were low in children younger than 10 years of age. Hence, parental supervision is considered necessary and recommended until 10 years of age. 23434768 A novel approach to systematically implement the universal definition of myocardial infarction: insights from the CHAMPION PLATFORM trial. To reassess the efficacy of cangrelor efficacy using the universal definition of myocardial infarction (MI). We adopted a novel approach to systematically implement the universal definition of MI. Two physicians blinded to treatment allocation reviewed plots of CK-MB and troponin values in relation to time of randomisation and percutaneous coronary intervention (PCI) to identify patients with stable or falling biomarkers pre-PCI (ie, primary cohort), and those with post-PCI CK-MB elevations. The CHAMPION PLATFORM trial. Non-ST-elevation acute coronary syndromes (95%) and stable angina patients (5%). Cangrelor versus placebo. The efficacy of cangrelor compared with placebo using the reclassified events (type 4a MI) and the original clinical events committee-adjudicated (CEC PCI-MI) results was investigated. Of 5295 patients, 3406 (64.4%) were in the primary cohort. Type 4a MI occurred in 4.3% (226 events/5295 patients) while original CEC PCI-MI occurred in 6.5% (344 events/5295 patients), a significant difference (p<0.0001). Using the reclassified MI events, the primary composite endpoint of death, MI, or ischaemia-driven revascularisation through 48 h occurred in 5.4% of patients (4.9% cangrelor, 6.0% placebo; OR 0.80; 95% CI 0.63 to 1.02) as opposed to 7.5% of the primary analyses (7.0% cangrelor, 8.0% placebo; OR 0.87; 95% CI 0.71 to 1.07). Systematic, strict implementation of the universal MI definition with emphasis on baseline assessment may enhance discrimination in detecting PCI-MI and may allow for more rigorous assessment of interventions in patients undergoing early PCI. 23927943 Impaired CD4+ and T-helper 17 cell memory response to Streptococcus pneumoniae is associated with elevated glucose and percent glycated hemoglobin A1c in Mexican Americans with type 2 diabetes mellitus. Individuals with type 2 diabetes are significantly more susceptible to pneumococcal infections than healthy individuals of the same age. Increased susceptibility is the result of impairments in both innate and adaptive immune systems. Given the central role of T-helper 17 (Th17) and T-regulatory (Treg) cells in pneumococcal infection and their altered phenotype in diabetes, this study was designed to analyze the Th17 and Treg cell responses to a whole heat-killed capsular type 2 strain of Streptococcus pneumoniae. Patients with diabetes demonstrated a lower frequency of total CD4+ T cells, which showed a significant inverse association with elevated fasting blood glucose. Measurement of specific subsets indicated that those with diabetes had, low intracellular levels of interleukin (IL)-17, and lower pathogen-specific memory CD4+ and IL-17+ cell numbers. No significant difference was observed in the frequency of CD4+ and Th17 cells between those with and without diabetes. However, stratification of data by obesity indicated a significant increase in frequency of CD4+ and Th17 cells in obese individuals with diabetes compared with nonobese individual with diabetes. The memory CD4+ T-cell response was associated inversely with both fasting blood glucose and percent glycated hemoglobin A1c. This study demonstrated that those with type 2 diabetes have a diminished pathogen-specific memory CD4+ and Th17 response, and low percentages of CD4+ T cells in response to S. pneumoniae stimulation. 23750747 Pulmonary Administration of PEGylated Polylysine Dendrimers: Absorption from the Lung versus Retention within the Lung Is Highly Size-Dependent. The systemic delivery of drugs via the inhaled route is an attractive, needle-free means of improving the systemic exposure of molecules such as peptides and proteins that are poorly absorbed after oral administration. Directed delivery into the lungs also provides a means of increasing drug concentrations at the site of action for lung-specific disease states such as pulmonary infections and lung cancer. The current study has examined the potential utility of PEGylated polylysine dendrimers as pulmonary delivery agents and in particular sought to explore the relationship between dendrimer size and absorption of the intact construct (as a potential systemic delivery mechanism) versus retention within the lungs (as a potential pulmonary depot for controlled local release). Dendrimer absorption from the lungs was inversely correlated with molecular weight, with approximately 20-30% of the dose of relatively small (<22 kDa) dendrimers systemically absorbed compared to only 2% absorption for a larger (78 kDa) PEGylated dendrimer. Increasing the molecular weight of the dendrimers led to slower absorption and more prolonged retention in the lung tissue and bronchoalveolar lavage fluid. Oral administration of the two smaller dendrimers confirmed that oral bioavailability of the PEGylated dendrimers was essentially zero and did not contribute to exposure after pulmonary administration. The smaller PEGylated dendrimers were also degraded in the lungs to low molecular weight products that were subsequently absorbed and excreted via the urine, while the larger constructs showed good stability in the lungs. The data suggest first, that small PEGylated dendrimer-based drug delivery systems may be delivered to the blood via inhalation, providing a more attractive alternative to injections, and second that larger PEGylated dendrimers may be retained in the lungs providing the potential for controlled delivery of medications to the blood or lung tissue. 23716616 Divergent Mechanisms of Interaction of Helicobacter pylori and Campylobacter jejuni with Mucus and Mucins. Helicobacter pylori and Campylobacter jejuni colonize the stomach and intestinal mucus, respectively. Using a combination of mucus-secreting cells, purified mucins, and a novel mucin microarray platform, we examined the interactions of these two organisms with mucus and mucins. H. pylori and C. jejuni bound to distinctly different mucins. C. jejuni displayed a striking tropism for chicken gastrointestinal mucins compared to mucins from other animals and preferentially bound mucins from specific avian intestinal sites (in order of descending preference: the large intestine, proximal small intestine, and cecum). H. pylori bound to a number of animal mucins, including porcine stomach mucin, but with less avidity than that of C. jejuni for chicken mucin. The strengths of interaction of various wild-type strains of H. pylori with different animal mucins were comparable, even though they did not all express the same adhesins. The production of mucus by HT29-MTX-E12 cells promoted higher levels of infection by C. jejuni and H. pylori than those for the non-mucus-producing parental cell lines. Both C. jejuni and H. pylori bound to HT29-MTX-E12 mucus, and while both organisms bound to glycosylated epitopes in the glycolipid fraction of the mucus, only C. jejuni bound to purified mucin. This study highlights the role of mucus in promoting bacterial infection and emphasizes the potential for even closely related bacteria to interact with mucus in different ways to establish successful infections. 23860490 Phylogenetic and Histological Variation in Avipoxviruses Isolated in South Africa. Thirteen novel avipoxviruses have been isolated from birds from different regions of South Africa. These viruses could be divided into six groups, according to gross pathology and pock appearance on chick chorioallantoic membranes (CAMs). Histopathology revealed distinct differences in epidermal and mesodermal cell proliferation as well as immune cell infiltration caused by the different avipoxviruses, even within groups of viruses causing similar CAM gross pathology. In order to determine the genetic relationships between the viruses several conserved poxvirus genetic regions, corresponding to Vaccinia Virus (VACV) A3L (fpv167, VACV P4b), G8R (fpv 126, VLTF-1), H3L (fpv140, VACV H3L) and A11R-A12L (fpv175-176) were analysed phylogenetically. The South African avipoxvirus isolates in this study all grouped in clade A, either in subclade A2 or A3 of the avipoxvirus genus and differ from the commercial fowlpox vaccines (subclade A1) in use in the South African poultry industry. Analysis of different loci resulted in different branching patterns. There was no correlation between gross morphology, histopathology, pock morphology and phylogenetic grouping. Also, there was no correlation between geographical distribution and virus phenotype or genotype. 23824437 Reliability of broadband middle-ear power-reflectance in younger and older adults: Application of Generalizability Theory. To assess the reliability of broadband middle ear power reflectance (BMEPR) and transmittance profiles for chirp and tonal stimuli using Generalizability Theory (GT). In adults without a history of middle-ear disease, we assessed the reliability of BMEPR to chirp and tonal stimuli using a multivariate approach based on an ANOVA model (GT). For comparisons with other published studies, Pearson's Product Moment Correlation Coefficients (Pearson's r) were also used. Based on GT with chirp stimuli, overall BMEPR measures had good reliability; however, the reliability of individual profiles across frequencies and ears was less than optimal. Lower Generalizability coefficients were found when transmittance was evaluated. Test re-test reliability using Pearson's r was better for right vs. left ears and mid-frequencies were generally more reliable than those at either extreme of the frequency range. In contrast, tonal stimuli had higher Generalizibility coefficients and Pearson's r values than chirps for all frequencies tested; Pearson's r values were also higher for right vs. left ears. We extend the use of GT as a preferred way to evaluate reliability of BMEPR and transmittance profiles for chirp and tones since it allows for a more comprehensive evaluation in comparison to "unidimensional" pair-wise correlations. 23707198 Increased symmetrical dimethylarginine in ischemic acute kidney injury as a causative factor of renal L-arginine deficiency. Availability of L-arginine, the exclusive substrate for nitric oxide synthases, plays an important role in kidney ischemia/reperfusion injury. The endogenous L-arginine derivatives asymmetrical dimethylarginine (ADMA) and symmetrical dimethylarginine (SDMA) block cellular L-arginine uptake competitively, thereby inhibiting the production of nitric oxide. ADMA also blocks nitric oxide synthase activity directly. Here, we investigate the pathomechanistic impact of ADMA and SDMA on ischemic acute kidney injury. Rats were subject to bilateral renal ischemia (60 minutes)/reperfusion (24 hours) injury. Impairment of renal function was determined with inulin clearance (glomerular filtration rate) and para-aminohippurate (PAH) clearance (renal plasma flow). L-arginine, ADMA, and SDMA levels were measured by liquid chromatography-tandem mass spectrometry. L-arginine was extracted from renal tissue and analyzed by enzyme-linked immunosorbent assay, and protein and messenger RNA expressions were determined by Western blot and real-time reverse transcription polymerase chain reaction. Renal function deteriorated severely after ischemia/reperfusion injury, as demonstrated by inulin and PAH clearance. Serum ADMA and SDMA increased, but tissue expression of specific ADMA or SDMA synthesizing and metabolizing enzymes (protein arginine methyltransferases and dimethyl arginine dimethylaminohydrolases) did not alter. Serum L-arginine increased as well, whereas intracellular L-arginine concentration diminished. Renal messenger RNA expression of cationic amino acid transporters, which mediate L-arginine uptake, remained unchanged. In serum, the ratio of L-arginine to ADMA did not alter after ischemia/reperfusion injury, whereas the ratios of L-arginine to SDMA and ADMA to SDMA decreased. A marked increase in serum SDMA, especially when accompanied by a diminished L-arginine-to-SDMA ratio, might reflect competitive inhibition of cellular L-arginine uptake by SDMA. As a consequence, a pathologic renal L-arginine deficiency in ischemic acute kidney injury results. 23892662 A new player SETs in myeloid malignancy. Recent studies have identified recurrent mutations in SETBP1, the gene that encodes SET-binding protein 1, in several types of myeloid malignancies, including chronic myeloid and acute myeloid leukemias. The identified mutations frequently target the SKI-homologous domain, although the exact pathogenic mechanisms remain unknown. 23963074 An engineered multidomain fungicidal peptide against plant fungal pathogens. Fungal pathogens represent major problems for human health and agriculture. As eukaryotic organisms, fungi share some important features with mammalian cells. Therefore, current anti-fungal antibiotics often can not distinguish between fungi and mammalian cells, resulting in serious side effects in mammalian cells. Accordingly, there is strong impetus to develop antifungal alternatives that are both safe and effective. The E1 family of colicin are channel-forming bacteriocins produced by Escherichia coli, which are bactericidal only to E. coli and related species. To target the channel-forming domain of colicin to fungal cell membrane, we engineered a sexual mating pheromone of Candida albicans, α-factor pheromone to colicin Ia. A peptide was constructed consisting of an α mating pheromone of C. albicans fused to the channel-forming domain of colicin Ia to create a new fusion protein, pheromonicin-CA (PMC-CA). Indirect immunolabeling showed that the PMC-CA bound to fungal cells and inhibited growth in the laboratory and field. In the field, the protective activity of pheromonicin against rice blast disease was significantly greater, on a molar basis, than that of triazoles, tricyclazole or isoprothiolane. These results suggest that fusion peptides may be of value as fungicidal agents under agricultural conditions. 23622980 Antiproliferative activity of 2,3-disubstituted indoles toward apoptosis-resistant cancers cells. Many types of cancer, including glioma, melanoma, NSCLC, among others, are resistant to apoptosis induction and poorly responsive to current therapies with propaptotic agents. We describe a series of 2,3-disubstituted indoles, which display cytostatic rather than cytotoxic effects in cancer cells, and serve as a new chemical scaffold to develop anticancer agents capable of combating apoptosis-resistant cancers associated with dismal prognoses. 23855976 Photoselective DNA hairpin spin switches. DNA hairpins having both a tethered anthraquinone (Aq) end-capping group and a perylenediimide (PDI) base surrogate were synthesized, wherein Aq and PDI are each separated from a G-C base pair hole trap by A-T and I-C base pairs (G = guanine, A = adenine, T= thymine, C = cytosine, I = inosine). Selective photoexcitation of PDI at 532 nm generates a singlet radical ion pair (RP), (1)(G(+•)-PDI(-•)), while selective photoexcitation of Aq at 355 nm generates the corresponding triplet RP, (3)(G(+•)-Aq(-•)). Subsequent radical pair intersystem crossing within these spin-correlated RPs leads to mixed spin states that exhibit spin-polarized, time-resolved EPR spectra in which the singlet- and triplet-initiated RPs have opposite phases. These results demonstrate that a carefully designed DNA hairpin can serve as a photodriven molecular spin switch based on wavelength-selective formation of the singlet or triplet RP without significant competition from undesired energy transfer processes. 23955936 A Selective Artificial Enzyme Inhibitor Based on Nanoparticle-Enzyme Interactions and Molecular Imprinting. A novel and general strategy is developed to design selective artificial enzyme inhibitors based on nanoparticle-enzyme interactions and molecular imprinting. Due to the creation of specific binding cavities, the resulting artificial inhibitor has high inhibition efficiency for the target enzyme, and shows great target-selectivity over other enzymes of similar function and proteins of comparable molecular weight. 23443488 Multiphase chemistry of atmospheric amines. Heterogeneous reactions of amines have been recently shown to play an important role in the formation and transformation of atmospheric aerosols. This perspective summarizes the latest laboratory progress in the multiphase chemistry of amines. Particular emphasis is given to the contributions of amines to new particle formation, growth of submicron particles, and alteration in the physiochemical properties of pre-existing particles, including hygroscopicity, thermostability, density, phase, and optical properties, from exposure to gaseous amines. The atmospheric implications of the multiphase reactions of amines, including the potential impact on direct and indirect climate forcing of aerosols, and future research directions are discussed. 23798405 Energy-dependent motion of TonB in the Gram-negative bacterial inner membrane. Gram-negative bacteria acquire iron with TonB-dependent uptake systems. The TonB-ExbBD inner membrane complex is hypothesized to transfer energy to outer membrane (OM) iron transporters. Fluorescence microscopic characterization of green fluorescent protein (GFP)-TonB hybrid proteins revealed an unexpected, restricted localization of TonB in the cell envelope. Fluorescence polarization measurements demonstrated motion of TonB in living cells, which likely was rotation. By determining the anisotropy of GFP-TonB in the absence and presence of inhibitors, we saw the dependence of its motion on electrochemical force and on the actions of ExbBD. We observed higher anisotropy for GFP-TonB in energy-depleted cells and lower values in bacteria lacking ExbBD. However, the metabolic inhibitors did not change the anisotropy of GFP-TonB in ΔexbBD cells. These findings demonstrate that TonB undergoes energized motion in the bacterial cell envelope and that ExbBD couples this activity to the electrochemical gradient. The results portray TonB as an energized entity in a regular array underlying the OM bilayer, which promotes metal uptake through OM transporters by a rotational mechanism. 23665398 Hyperuricemia influences tryptophan metabolism via inhibition of multidrug resistance protein 4 (MRP4) and breast cancer resistance protein (BCRP). Hyperuricemia is related to a variety of pathologies, including chronic kidney disease (CKD). However, the pathophysiological mechanisms underlying disease development are not yet fully elucidated. Here, we studied the effect of hyperuricemia on tryptophan metabolism and the potential role herein of two important uric acid efflux transporters, multidrug resistance protein 4 (MRP4) and breast cancer resistance protein (BCRP). Hyperuricemia was induced in mice by treatment with the uricase inhibitor oxonic acid, confirmed by the presence of urate crystals in the urine of treated animals. A transport assay, using membrane vesicles of cells overexpressing the transporters, revealed that uric acid inhibited substrate-specific transport by BCRP at clinically relevant concentrations (calculated IC50 value: 365±13μM), as was previously reported for MRP4. Moreover, we identified kynurenic acid as a novel substrate for MRP4 and BCRP. This finding was corroborated by increased plasma levels of kynurenic acid observed in Mrp4(-/-) (107±19nM; P=0.145) and Bcrp(-/-) mice (133±10nM; P=0.0007) compared to wild type animals (71±11nM). Hyperuricemia was associated with >1.5 fold increase in plasma kynurenine levels in all strains. Moreover, hyperuricemia led to elevated plasma kynurenic acid levels (128±13nM, P=0.005) in wild type mice but did not further increase kynurenic acid levels in knockout mice. Based on our results, we postulate that elevated uric acid levels hamper MRP4 and BCRP functioning, thereby promoting the retention of other potentially toxic substrates, including kynurenic acid, which could contribute to the development of CKD. 23406471 Relationships between maternal novel adipocytokines and bone biomarkers in complicated by gestational hypertensive disorders and normal pregnancies. Abstract Objective: To investigate possible associations of the novel adipocytokines resistin, apelin and visfatin (implicated in the complex control of bone biology) with several biochemical determinants of bone turnover in maternal blood from normal pregnancies and pregnancies complicated by gestational hypertensive disorders (preeclampsia or pregnancy-induced hypertension). Methods: Circulating maternal concentrations of resistin, apelin and visfatin were correlated with circulating markers of bone formation [osteocalcin (OC), bone-specific alkaline phosphatase (BALP)] and resorption [osteoprotegerin (OPG), soluble receptor activator of nuclear factor-κB ligand (sRANKL) and cross-linked N-telopeptide of type I collagen (NTx)] in full-term pregnancies (20 normal and 20 complicated by gestational hypertensive disorders). Results: In normal pregnancies, no correlation was recorded between maternal concentrations of adipocytokines and the above bone biomarkers. In pregnancies with gestational hypertensive disorders, maternal apelin concentrations negatively correlated with NTx ones (r = -0.489, p = 0.034), while maternal visfatin concentrations positively correlated with OPG ones (r = 0.464, p = 0.039). Conclusions: No associations were found between maternal concentrations of all three studied adipocytokines and respective concentrations of bone biomarkers in normal pregnancies. By contrast, in pregnancies with gestational hypertensive disorders, maternal concentrations of apelin and visfatin correlated with respective concentrations of indices of bone turnover. Further prospective studies are needed to clarify these relationships. 23857822 Synthesis, structure, and theoretical study of trifluoromethyl derivatives of c84 (23) fullerene. Trifluoromethylation of a higher fullerene mixture with CF3 I was performed in ampoules at 550 °C. HPLC separation followed by crystal growth and X-ray diffraction study resulted in the structure elucidation of nine CF3 derivatives of D2d -C84 (isomer 23). The molecular structures of C84 (23)(CF3 )4 , C84 (23)(CF3 )8 , C84 (23)(CF3 )10 , C84 (23)(CF3 )12 , two isomers of C84 (23)(CF3 )14 , two isomers of C84 (23)(CF3 )16 , and C84 (23)(CF3 )18 were discussed in terms of their addition patterns and the relative formation energies. Extensive theoretical DFT calculations were performed to identify the most stable molecular structures. It was found that the addition of CF3 groups to the C84 (23) fullerene is governed by two main rules: no additions in positions of triple hexagon junctions and predominantly para additions in C6 (CF3 )2 hexagons on the fullerene cage. The only exception with an isolated CF3 group in C84 (23)(CF3 )12 is discussed in more detail. 23849432 Soluble TWEAK independently predicts atherosclerosis in renal transplant patients. Cardiovascular risk is increased in the early stages of chronic kidney disease (CKD) and also found to be ongoing in renal transplant (Rtx) patients. As a sign of atherosclerosis, increased carotid intima-media thickness (CIMT) has been widely accepted as a strong predictor of cardiovascular disease (CVD) and mortality in CKD patients. A novel markers, soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and neutrophil-to-lymphocyte ratio (NLR) were introduced as potential markers in inflammatory disorders including CKD. The role of Rtx in terms of atherogenesis is still unclear. We aimed to investigate the relationship between sTWEAK, NLR and CIMT in Rtx patients without overt CVD and to compare these results with those obtained from healthy subjects. Cross-sectional analysis in which CIMT measurements, NLR and serum TWEAK levels were assessed in 70 Rtx patients (29 females; mean age, 40.6 ± 12.4 years) and 25 healthy subjects (13 females, mean age; 37.4±8.8 years). sTWEAK levels were significantly decreased (p=0.01) and hs-CRP, NLR and CIMT levels of Rtx patients were significantly increased compared to healthy subjects (p<0.0001, p=0.001, p<0.0001, respectively). sTWEAK was also found to be decreased when eGFR was decreased (p=0.04 between all groups). CIMT was positively correlated with sTWEAK and NLR in Rtx patients (r=0.81, p<0.0001 and r=0.33, p=0.006, respectively). sTWEAK was also positively correlated with NLR (r=0.37, p=0.002). In the multivariate analysis only sTWEAK was found to be an independent variable of increased CIMT. sTWEAK might have a role in the pathogenesis of ongoing atherosclerosis in Rtx patients. 23706772 Meier-Gorlin syndrome and Wolf-Hirschhorn syndrome: Two developmental disorders highlighting the importance of efficient DNA replication for normal development and neurogenesis. Microcephaly represents one of the most obvious clinical manifestations of impaired neurogenesis. Defects in the DNA damage response, in DNA repair, and structural abnormalities in centrosomes, centrioles and the spindle microtubule network have all been demonstrated to cause microcephaly in humans. Work describing novel functional defects in cell lines from individuals with either Meier-Gorlin syndrome or Wolf-Hirschhorn syndrome highlight the significance of optimal DNA replication and S phase progression for normal human development, including neurogenesis. These findings illustrate how different primary defects in processes impacting upon DNA replication potentially influence similar phenotypic outcomes, including growth retardation and microcephaly. Herein, we will describe the nature of the S phase defects uncovered for each of these conditions and highlight some of the overlapping cellular features. 23876612 Duration of immunity to norovirus gastroenteritis. The duration of immunity to norovirus (NoV) gastroenteritis has been believed to be from 6 months to 2 years. However, several observations are inconsistent with this short period. To gain better estimates of the duration of immunity to NoV, we developed a mathematical model of community NoV transmission. The model was parameterized from the literature and also fit to age-specific incidence data from England and Wales by using maximum likelihood. We developed several scenarios to determine the effect of unknowns regarding transmission and immunity on estimates of the duration of immunity. In the various models, duration of immunity to NoV gastroenteritis was estimated at 4.1 (95% CI 3.2-5.1) to 8.7 (95% CI 6.8-11.3) years. Moreover, we calculated that children (<5 years) are much more infectious than older children and adults. If a vaccine can achieve protection for duration of natural immunity indicated by our results, its potential health and economic benefits could be substantial. 23902419 The form of a trade-off determines the response to competition. Understanding how populations and communities respond to competition is a central concern of ecology. A seminal theoretical solution first formalised by Levins (and re-derived in multiple fields) showed that, in theory, the form of a trade-off should determine the outcome of competition. While this has become a central postulate in ecology it has evaded experimental verification, not least because of substantial technical obstacles. We here solve the experimental problems by employing synthetic ecology. We engineer strains of Escherichia coli with fixed resource allocations enabling accurate measurement of trade-off shapes between bacterial survival and multiplication in multiple environments. A mathematical chemostat model predicts different, and experimentally verified, trajectories of gene frequency changes as a function of condition-specific trade-offs. The results support Levins' postulate and demonstrates that otherwise paradoxical alternative outcomes witnessed in subtly different conditions are predictable. 23588836 Synthesis, characterization and organic field effect transistor performance of a diketopyrrolopyrrole-fluorenone copolymer. A diketopyrrolopyrrole (DPP) with fluorenone (FN) based low band gap alternating copolymer (PDPPT-alt-FN) has been synthesized via Suzuki coupling. PDPPT-alt-FN exhibits a deep HOMO level with a lower band gap. Fabricated organic thin film transistors using PDPPT-alt-FN as a channel semiconductor show p-channel behaviour with the highest hole mobility of 0.083 cm(2) V(-1) s(-1) measured in air. 23428385 Medical therapy of coronary artery disease after percutaneous intervention. Medical therapy following percutaneous coronary intervention aims at preventing first, coronary disease progression and its clinical manifestations, and finally, the two main complications of coronary stenting, stent thrombosis and restenosis. Prevention of in-stent restenosis is restricted to local drug delivery in the form of drug eluting stents (DES). Second generation DES have improved their efficacy and safety profile by innovations in drug coating, the polymer drug-delivery system and stent design. The mainstay of stent thrombosis prevention remains dual anti-platelet therapy with acetylsalicylic acid and a platelet ADP-receptor blocker, traditionally clopidogrel. Two new drugs, prasugrel and ticagrelor, provide faster, greater, and more consistent platelet inhibition than clopidogrel, and have been shown to be more efficacious in preventing ischemic events after PCI in acute coronary syndrome patients. 23557930 Safety, tolerability and pharmacokinetics of repeat dosing of the antibiotic GSK1322322, a peptide deformylase inhibitor: a randomized placebo-controlled study. GSK1322322 is a potent inhibitor of peptide deformylase, an essential bacterial enzyme required for protein maturation. In this two-part, double-blind, randomized, placebo-controlled, Phase 1 study (study identifier: PDF112668), the safety, tolerability and pharmacokinetics of single and repeat oral-dose GSK1322322 (500-1500 mg) in healthy adult and elderly volunteers were evaluated. Part A included GSK1322322 doses of 500, 750, 1000 and 1500 mg in healthy adults; Part B evaluated 1000 mg of GSK1322322 in healthy elderly volunteers. Volunteers received a single morning dose of a powder-in-bottle formulation of GSK1322322 or placebo on day 1, no dosing on day 2 and twice-daily dosing on days 3-12. Of 52 enrolled volunteers, 40 and 12 volunteers were treated with GSK1322322 and placebo, respectively. Mean plasma GSK1322322 trough concentration increased with increasing dose and reached steady-state after 2 days of repeat dosing. After single dosing of GSK1322322, maximum plasma concentration and exposure (AUC) were dose proportional from 500 to 1500 mg. However, after repeat dosing, AUC values at steady-state increased slightly more than proportionally, possibly because of a slightly longer terminal elimination t½ after repeat dosing (compared with single-dose t½) at higher doses (1000 and 1500 mg). There was no age effect or diurnal variation in the GSK1322322 pharmacokinetic profile. GSK1322322 was generally well tolerated-all adverse events were mild to moderate in intensity. Repeat oral GSK1322322 (500-1500 mg) for 10 days was well tolerated. These data warrant further clinical investigation of GSK1322322. 23474187 Impaired leukocyte trafficking and skin inflammatory responses in hamsters lacking a functional circadian system. The immune system is under strong circadian control, and circadian desynchrony is a risk factor for metabolic disorders, inflammatory responses and cancer. Signaling pathways that maintain circadian rhythms (CRs) in immune function in vivo, and the mechanisms by which circadian desynchrony impairs immune function, remain to be fully identified. These experiments tested the hypothesis that the hypothalamic circadian pacemaker in the suprachiasmatic nucleus (SCN) drives CRs in the immune system, using a non-invasive model of SCN circadian arrhythmia. Robust CRs in blood leukocyte trafficking, with a peak during the early light phase (ZT4) and nadir in the early dark phase (ZT18), were absent in arrhythmic hamsters, as were CRs in spleen clock gene (per1, bmal1) expression, indicating that a functional pacemaker in the SCN is required for the generation of CRs in leukocyte trafficking and for driving peripheral clocks in secondary lymphoid organs. Pinealectomy was without effect on CRs in leukocyte trafficking, but abolished CRs in spleen clock gene expression, indicating that nocturnal melatonin secretion is necessary for communicating circadian time information to the spleen. CRs in trafficking of antigen presenting cells (CD11c(+) dendritic cells) in the skin were abolished, and antigen-specific delayed-type hypersensitivity skin inflammatory responses were markedly impaired in arrhythmic hamsters. The SCN drives robust CRs in leukocyte trafficking and lymphoid clock gene expression; the latter of which is not expressed in the absence of melatonin. Robust entrainment of the circadian pacemaker provides a signal critical to diurnal rhythms in immunosurveilliance and optimal memory T-cell dependent immune responses. 23335185 Successful rescue of a child with fall-related multi-organ injuries. Fall-related injury is a major cause of accidental death and is rarely reported in children. Even successful treatment of children with multi-organ injuries caused by fall from the extreme height has been rarely reported. We herein report a 2-year-old girl who fell from the 10th floor, had multi-organ injuries, and was successfully rescued. The girl sustained multi-organ injuries, such as head injury, closed abdominal injury, as well as fractures of the left limbs, and successfully recovered after two surgeries and supportive treatment. This case illustrates that a child who falls from extreme heights can occasionally be rescued. Early neuroprotective strategies help to improve neurological recovery. 23831343 Cortical activation during auditory elicitation of fear and disgust: A near-infrared spectroscopy (NIRS) study. This near infrared spectroscopy study investigated whether nonverbal human sounds representing different basic emotions are able to specifically modulate temporo-parietal cortices, involved in auditory processing and attention. Forty-three adults (19 females and 24 males) were presented with sounds from the categories fear, disgust, and neutral. The stimuli were able to elicit the target emotions with sufficient specificity. The listening to fear-relevant sounds (e.g., screams of fear and pain) led to increased activation of the right superior temporal gyrus and the bilateral supramarginal gyrus. The hemodynamic responses to disgusting sounds (e.g., sniffing, diarrhea) were smaller. Our findings point to a differential neuronal sensitivity of the human brain to two basic emotion elicitors in the auditory domain. 23582590 Oral health risk factors for bisphosphonate-associated jaw osteonecrosis. To investigate the role of oral health, including periodontitis, as a risk factor for bisphosphonate-associated jaw osteonecrosis (ONJ). This cross-sectional study compared cases with an ONJ history to controls. All had a history of bisphosphonate treatment for malignancy. Participants underwent oral examination, gingival crevicular fluid (GCF) sampling, and phlebotomy. Serum was analyzed for biochemical parameters, bone markers, and immunoglobulin G titers against 4 periodontitis-associated bacteria. Cytokine levels were determined in GCF using a multiplex assay. Caries development was comparable between groups. Periodontitis was significantly associated with ONJ using the US National Center for Health Statistics periodontitis definition (P = .002), at least 1 site with a probing depth of at least 4 mm (P = .003), and the percentage of sites per participant with a probing depth of 4 to 5 mm (P = .044). Immunoglobulin G titer against Porphyromonas gingivalis and GCF interleukin-1β level were also significantly associated with ONJ (P = .018 and P = .044, respectively). In participants with a history of bisphosphonate treatment for malignancy, periodontitis was associated with ONJ when measured using clinical parameters, serum immunoglobulin G titers against P gingivalis, and GCF interleukin-1β levels, suggesting that periodontitis and associated bacteria are potentially important in ONJ pathophysiology. 23415686 Relations of oxidative stress in freshwater phytoplankton with heavy metals and polycyclic aromatic hydrocarbons. The phytoplankton is the basis of food webs and also, may bioconcentrate different toxic substances. This phenomenon is well documented, but there are few studies on the toxic effects on the phytoplankton community. In the current study the relation of oxidative stress (TBARS, ROOH, RC=O) and antioxidant defenses (activities of SOD, CAT, GPx and GST) of two phytoplankton communities with BCF of heavy metals (Cu, Fe, Mn, Pb, Zn) and of PAHs (naphthalene, pyrene, indenol, benzo[a]pyrene, benzo[a]anthracene, benzo[b]fluoranthene) was tested. Three sampling surveys were conducted bimonthly on the surface and bottom at different sampling points in the lakes Menor and Mayor of the 2nd section of Chapultepec Park. Also negative and positive controls obtained in the laboratory were included. Toxicity relationships were analyzed using the integrated biomarker response (IBR). Both green algae and cyanobacteria dominated. The contents of ROOH and protein oxidation assessed as RC=O were higher in the Lago Menor, a water body that contains ancient sediments. Through the IBR it was demonstrated that these damages were influenced by Pb, indenol and benzo[b]fluoranthene. In contrast, TBARS content was higher in Lago Mayor, which has sediment in formation. Through IBR it was estimated that Cu, Fe, Mn, Pb, indenol and benzo[b]fluoranthene were related to this damage. However, oxidative stress was accompanied by an induction of CAT and SOD, in contrast, GPx and GST had low or null activity. The field data were similar to the positive controls. We demonstrated for the first time that, although the phytoplankton suffers oxidative stress elicited by metals and PAHs, this community is able to counter this damage through antioxidant defenses. The effects of organic or inorganic toxics in phytoplankton depend on their bioavailability that is modulated by the sediment and also by its physicochemical properties and the characteristics of the abiotic medium. 23098994 Converging levels of analysis on a genomic hotspot for psychosis: insights from 22q11.2 deletion syndrome. Schizophrenia is a devastating neurodevelopmental disorder that, despite extensive research, still poses a considerable challenge to attempts to unravel its heterogeneity, and the complex biochemical mechanisms by which it arises. While the majority of cases are of unknown etiology, accumulating evidence suggests that rare genetic mutations, such as 22q11.2 Deletion Syndrome (22qDS), can play a significant role in predisposition to the illness. Up to 25% of individuals with 22qDS eventually develop schizophrenia; conversely, this deletion is estimated to account for 1-2% of schizophrenia cases overall. This locus of Chromosome 22q11.2 contains genes that encode for proteins and enzymes involved in regulating neurotransmission, neuronal development, myelination, microRNA processing, and post-translational protein modifications. As a consequence of the deletion, affected individuals exhibit cognitive dysfunction, structural and functional brain abnormalities, and neurodevelopmental anomalies that parallel many of the phenotypic characteristics of schizophrenia. As an illustration of the value of rare, highly penetrant genetic subtypes for elucidating pathological mechanisms of complex neuropsychiatric disorders, we provide here an overview of the cellular, network, and systems-level anomalies found in 22qDS, and review the intriguing evidence for this disorder's association with schizophrenia. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. 23910425 Thymoquinone ameliorates lead-induced brain damage in Sprague Dawley rats. The present study aims to investigate the protective effects of thymoquinone, the major active ingredient of Nigella sativa seeds, against lead-induced brain damage in Sprague-Dawley rats. In which, 40 rats were divided into four groups (10 rats each). The first group served as control. The second, third and fourth groups received lead acetate, lead acetate and thymoquinone, and thymoquinone only, respectively, for one month. Lead acetate was given in drinking water at a concentration of 0.5g/l (500ppm). Thymoquinone was given daily at a dose of 20mg/kg b.w. in corn oil by gastric tube. Control and thymoquinone-treated rats showed normal brain histology. Treatment of rats with lead acetate was shown to produce degeneration of endothelial lining of brain blood vessels with peri-vascular cuffing of mononuclear cells consistent to lymphocytes, congestion of choroid plexus blood vessels, ischemic brain infarction, chromatolysis and neuronal degeneration, microglial reaction and neuronophagia, degeneration of hippocampal and cerebellar neurons, and axonal demyelination. On the other hand, co-administration of thymoquinone with lead acetate markedly decreased the incidence of lead acetate-induced pathological lesions. Thus the current study shed some light on the beneficial effects of thymoquinone against neurotoxic effects of lead in rats. 23942806 Assessing remedies for missing weekly individual exposure in sport injury studies. In sport injury epidemiology research, the injury incidence rate (IR) is defined as the number of injuries over a given length of participation time (exposure, eg, game hours). However, it is common that individual weekly exposure is missing due to requirements of personnel at every game to record exposure information. Ignoring this issue will lead to an inflated injury rate because the total exposure serves as the denominator of IR, where the number of injury cases were captured accurately. This paper used data collected from a large community cohort study in youth ice hockey as an example, and compared six methods to handle missing weekly exposure of individual players. The six methods to handle missing weekly exposures include available case analysis, last observation carried forward, mean imputation, multiple imputation, bootstrapping and best/worst case analysis. To estimate injury rate ratios (IRRs) between Alberta and Quebec, as in the original study, three statistical models were applied to the imputed datasets: Poisson, zero-inflated Poisson and negative binomial regression models. The final sample for imputation included 2098 players for whom 12.5% of weekly game hours were missing. Estimated IRs and IRRs with CIs from different imputation methods were similar when the proportion of missing was small. Simulations showed that mean and multiple imputations provide the least biased estimates of IRR when the proportion of missing was large. Complicated methods, like multiple imputation or bootstrap, are not superior over the mean imputation, a much simpler method, in handling missing weekly exposure of injury data where exposures were missing at random. 23890767 Viscum album [L.] extract therapy in patients with locally advanced or metastatic pancreatic cancer: A randomised clinical trial on overall survival. The unfavourable side-effects of late-stage pancreatic cancer treatments call for non-toxic and effective therapeutic approaches. We compared the overall survival (OS) of patients receiving an extract of Viscum album [L.] (VaL) or no antineoplastic therapy. This is a prospective, parallel, open label, monocentre, group-sequential, randomised phase III study. Patients with locally advanced or metastatic cancer of the pancreas were stratified according to a binary prognosis index, composed of tumour stage, age and performance status; and were evenly randomised to subcutaneous injections of VaL extracts or no antineoplastic therapy (control). VaL was applied in a dose-escalating manner from 0.01mg up to 10mg three times per week. Patients in both groups received best supportive care. The primary end-point was 12-month OS, assessed in a group-sequential analysis. We present the first interim analysis, including data from 220 patients. Baseline characteristics were well balanced between the study arms. Median OS was 4.8 for VaL and 2.7months for control patients (prognosis-adjusted hazard ratio, HR=0.49; p<0.0001). Within the 'good' prognosis subgroup, median OS was 6.6 versus 3.2months (HR=0.43; p<0.0001), within the 'poor' prognosis subgroup, it was 3.4 versus 2.0months respectively (HR=0.55; p=0.0031). No VaL-related adverse events were observed. VaL therapy showed a significant and clinically relevant prolongation of OS. The study findings suggest VaL to be a non-toxic and effective second-line therapy that offers a prolongation of OS as well as less disease-related symptoms for patients with locally advanced or metastatic pancreatic cancer. 23790938 Ultra-high-performance liquid chromatography-ion trap mass spectrometry characterisation of milk polar lipids from dairy cows fed different diets. Milk polar lipids are an important class of biologically active species for human health and for improving the physical functionality of food ingredients. Milk polar lipids from 144 multiparous Holstein-Friesian dairy cows fed different diets were analysed using ultra-high-performance liquid chromatography-ion trap mass spectrometry (UHPLC-MS(n)). A complex profile of polar lipids, consisting of 7 species of phosphatidylinositol (PI), 12 species of phosphatidylethanolamine (PE), 18 species of phosphatidylcholine (PC) and 13 species of sphingomyelin (SM) were identified from the molecular ions and sequential MS(n) fragmentation. Qualitative assessment of the data suggested that different cow diets influenced the relative amounts of a small number of species in the milk samples, e.g. PE 14:0/18:1, PE 18:0/18:1, PC 15:0/18:1, PC 18:0/18:1, SM d18:1/14:0, SM d18:1/15:0, SM d18:1/22:0 and SM d18:1/23:0. 23665815 Amebic acute appendicitis: systematic review of 174 cases. This study aimed to determine the clinical and demographic features of acute amebic appendicitis by reviewing the reported cases. The PubMed and MEDLINE databases were searched to identify articles related to amebic appendicitis using key words. The search included all articles published between 1935 and 2012 without restricting language, journal, or country. A total of 174 cases of amebic appendicitis reported in 42 articles were analyzed. The mean age of the patients was 23.5 years (range 2 months-83 years). The majority of patients were male (74.0 %), and the majority of cases were reported from countries with high/moderate risk for amebiasis (76.5 %). A history of traveling to a high/moderate-risk country was cited in 64.0 % of the overall cases. The interval between travel and onset of clinical symptoms ranged from months to years. History of or coexisting dysenteric diarrhea was present in only 7.0 and 14.0 % of overall cases, respectively. A preoperative diagnosis of amebiasis was cited for only five cases (3.0 %). Complicated appendicitis was present in 30.7 % of cases, some of which required colon resection. Severe postoperative intraabdominal complications (e.g., liver abscess, abdominal sepsis, gastrointestinal fistula, hemorrhage) occurred in 19.4 % of surgery-treated patients. The overall mortality rate was 3.2 %. Appendectomy specimens should be routinely sent for histopathologic examination. In the case of suspected amebic acute appendicitis, extra precautions-early appendectomy, metronidazole for antibiotic prophylaxis, wet-preparation examination, obtaining a timely pathology result, increasing the awareness of uncommon complications of appendectomy-can hasten appropriate therapeutic intervention and improve outcome. 23909311 Medium Modification of Jet Fragmentation in Au+Au Collisions at sqrt[s_{NN}]=200  GeV Measured in Direct Photon-Hadron Correlations. The jet fragmentation function is measured with direct photon-hadron correlations in p+p and Au+Au collisions at sqrt[s_{NN}]=200  GeV. The p_{T} of the photon is an excellent approximation to the initial p_{T} of the jet and the ratio z_{T}=p_{T}^{h}/p_{T}^{γ} is used as a proxy for the jet fragmentation function. A statistical subtraction is used to extract the direct photon-hadron yields in Au+Au collisions while a photon isolation cut is applied in p+p. I_{AA}, the ratio of hadron yield opposite the photon in Au+Au to that in p+p, indicates modification of the jet fragmentation function. Suppression, most likely due to energy loss in the medium, is seen at high z_{T}. The associated hadron yield at low z_{T} is enhanced at large angles. Such a trend is expected from redistribution of the lost energy into increased production of low-momentum particles. 23843287 Phototriggered Release of a Leaving Group in Ketoprofen Derivatives via a Benzylic Carbanion Pathway, But not via a Biradical Pathway. 2-Acetoxymethyl-2-(3-benzoylphenyl)propionic acid (KP-OAc) was used as a model to elucidate the solvent-mediated photochemistry mechanism of Ketoprofen (KP). In solutions with a low concentration of water, KP-OAc exhibits a benzophenone-like photochemistry, reacting with water molecules through some reaction to form a ketyl radical intermediate. In neutral solutions with a high concentration of water or acidic solutions, KP-OAc undergoes a photodecarboxylation reaction with the assistance of water molecules or with the catalysis of perchloric acid to directly generate a biradical intermediate that cannot induce the phototrigger reaction to release the AcO(-) group. Therefore, the lifetime of the biradical intermediate of KP-OAc is almost same as that of the biradical intermediate formed from KP in the same kinds of solutions. However, the photodecarboxylation of KP-OAc in phosphate buffer solution directly produces the benzylic carbanion intermediate, which can induce the phototrigger reaction to release the AcO(-) group. Therefore, the lifetime of the biradical intermediate of KP-OAc is significantly shorter than the lifetime of the biradical intermediate of KP in phosphate buffer solution. Interestingly, the investigation of the photochemistry of KP-OAc not only verifies the solvent-mediated photochemistry mechanism of KP but also provides some new insight into the potential of using this kind of platform for phototrigger applications. The biradical intermediate is not the key species leading to the phototrigger reaction but the benzylic carbanion species is the key reactive intermediate that can mediate the phototrigger reaction of KP-OAc. Therefore, a change in the pH of the solutions can be utilized to switch on and switch off the photorelease reactions of KP derivative phototrigger compounds. 23970886 Treg inducing adjuvants for therapeutic vaccination against chronic inflammatory diseases. Many existing therapies in autoimmune diseases are based on systemic suppression of inflammation and the observed side effects of these therapies illustrate the pressing need for more specific interventions. Regulatory T-cells (Treg) are pivotal controllers of (auto-aggressive) immune responses and inflammation, and decreased Treg numbers and/or functioning have been associated with autoimmune disease. Therefore, Treg became frequently studied targets for more specific immunotherapy. Especially antigen-specific targeting of Treg would enable local and tailor made interventions, while obviating the negative side effect of general immuno-suppression. Self-antigens that participate in inflammation, irrespective of the etiology of the different autoimmune diseases, are held to be candidate antigens for antigen-specific interventions. Rather than tolerance induction to disease inciting self-antigens, which are frequently unknown, general self-antigens expressed at sites of inflammation would allow targeting of disease independent, but inflammatory-site specific, regulatory mechanisms. Preferably, such self-antigens should be abundantly expressed and up-regulated at the inflammatory-site. In this perspective heat shock proteins (Hsp) have several characteristics that make them highly attractive targets for antigen-specific Treg inducing therapy. The development of an antigen-specific Treg inducing vaccine is a major novel goal in the field of immunotherapy in autoimmune diseases. However, progress is hampered not only by the lack of effective antigens, but also by the fact that other factors such as dose, route, and the presence or absence of an adjuvant, turned out to be critical unknowns, with respect to the effective induction of Treg. In addition, the use of a Treg inducing adjuvant might be required to achieve an effective regulatory response, in the case of ongoing inflammation. Future goals in clinical trials will be the optimization of natural Treg expansion (or the induction of adaptive Treg) without loss of their suppressive function or the concomitant induction of non-regulatory T-cells. Here, we will discuss the potential use of protein/peptide-based vaccines combined with Treg inducing adjuvants for the development of therapeutic vaccines against chronic inflammatory conditions. 23856359 High Prevalence of Osteoporosis in Patients with Chronic Pancreatitis: a Systematic Review and Meta-Analysis. Patients with chronic pancreatitis may be at high risk for osteoporosis and osteopenia. We performed a systematic review and meta-analysis to determine the prevalence of osteoporosis and osteopenia in patients with chronic pancreatitis. We performed a systematic review and meta-analysis of observational studies that reported prevalence rates of osteoporosis and osteopenia. Articles were identified from MEDLINE, EMBASE, and SCOPUS databases (through October 2012) and a manual search of the literature. The primary outcome measure was bone density, measured by dual-energy X-ray absorptiometry (T-score or Z-score). When available, data on the prevalence of osteopenia, bone mineral density, and bone mineral content were also recorded. Ten studies including 513 patients were eligible for inclusion. Based on a random effects model, the pooled prevalence rate for osteoporosis among patients with chronic pancreatitis was 23.4% (95% confidence interval 16.6, 32.0). The pooled prevalence for osteopenia was 39.8% (95% confidence interval 29.1, 51.6). The pooled prevalence rate for either osteoporosis or osteopenia was 65% (95% confidence interval 54.7-74.0). Based on meta-analysis, almost 1 of 4 patients with chronic pancreatitis have osteoporosis, and almost two thirds have either osteoporosis or osteopenia. Osteoporosis and osteopenia are under-appreciated sources of morbidity in patients with chronic pancreatitis. Bone health management guidelines are urgently required in patients with chronic pancreatitis. 23865807 Competition between homodimerization and cholesterol binding to the c99 domain of the amyloid precursor protein. The 99-residue transmembrane C-terminal domain (C99, also known as β-CTF) of the amyloid precursor protein (APP) is the product of the β-secretase cleavage of the full-length APP and is the substrate for γ-secretase cleavage. The latter cleavage releases the amyloid-β polypeptides that are closely associated with Alzheimer's disease. C99 is thought to form homodimers; however, the free energy in favor of dimerization has not previously been quantitated. It was also recently documented that cholesterol forms a 1:1 complex with monomeric C99 in bicelles. Here, the affinities for both homodimerization and cholesterol binding to C99 were measured in bilayered lipid vesicles using both electron paramagnetic resonance (EPR) and Förster resonance energy transfer (FRET) methods. Homodimerization and cholesterol binding were seen to be competitive processes that center on the transmembrane G700XXXG704XXXG708 glycine-zipper motif and adjacent Gly709. On one hand, the observed Kd for cholesterol binding (Kd = 2.7 ± 0.3 mol %) is on the low end of the physiological cholesterol concentration range in mammalian cell membranes. On the other hand, the observed Kd for homodimerization (Kd = 0.47 ± 0.15 mol %) likely exceeds the physiological concentration range for C99. These results suggest that the 1:1 cholesterol/C99 complex will be more highly populated than C99 homodimers under most physiological conditions. These observations are of relevance for understanding the γ-secretase cleavage of C99. 23877978 Sex-Specific Associations of Gestational Glucose Tolerance With Childhood Body Composition. OBJECTIVETo examine the associations of maternal gestational glucose tolerance with offspring body composition in late childhood.RESEARCH DESIGN AND METHODSAmong 958 women in the prebirth cohort Project Viva, glucose tolerance was assessed in the 2nd trimester by nonfasting 50-g 1-h glucose challenge test (GCT), followed if abnormal by fasting 100-g 3-h oral glucose tolerance test (OGTT). We categorized women as normoglycemic (83.3%) if GCT was ≤140 mg/dL, isolated hyperglycemia (9.1%) if GCT was abnormal but OGTT normal, intermediate glucose intolerance (IGI) (3.3%) if there was one abnormal value on OGTT, or gestational diabetes mellitus (GDM) (4.5%) if there were two or more abnormal OGTT values. Using multivariable linear regression, we examined adjusted associations of glucose tolerance with offspring overall (N = 958) and central (N = 760) adiposity and body composition using dual X-ray absorptiometry (DXA) measured at the school-age visit (95 ± 10 months).RESULTSCompared with that in the male offspring of normoglycemic mothers, DXA fat mass was higher in male offspring of GDM mothers (1.89 kg [95% CI 0.33-3.45]) but not in male offspring of mothers with IGI (0.06 kg [-1.45 to 1.57]). DXA trunk-to-peripheral fat mass, a measure of central adiposity, was also somewhat higher in male offspring of GDM mothers (0.04 [-0.01 to 0.09]). In girls, DXA fat mass was higher in offspring of mothers with IGI (2.23 kg [0.12-4.34]) but not GDM (-1.25 kg [-3.13 to 0.63]). We showed no association of gestational glucose tolerance with DXA lean mass.CONCLUSIONSIn this study, only male offspring of GDM mothers manifested increased adiposity, whereas only female offspring of mothers with IGI did so. Sex differences in glycemic sensitivity may explain these findings. 23429061 Metallothionein 1A polymorphisms may influence urine uric acid and N-acetyl-beta-d-glucosaminidase (NAG) excretion in chronic lead-exposed workers. Lead is a renal toxin, and susceptibility to lead varies between individuals. Metallothionein (MT) is known for its metal scavenging role. The aim of the study was to investigate the association of blood lead levels, urinary uric acid (UA) and N-acetyl-beta-d-glucosaminidase (NAG) in chronic occupational lead-exposed workers, and to study whether the association was influenced by MT1A gene polymorphisms. In this cross-sectional study, 412 lead-exposed workers participated. Their annual health examination data and renal function markers were collected after the Institutional Review Broad of Kaohsiung Medical University Hospital approved the study and consent letters were obtained. From the blood samples, DNA was extracted and used for real-time PCR typing of 2 MT1A single nucleotide polymorphisms (SNPs): rs11640851 and rs8052394 on exons 2 and 3. Descriptive analysis, one-way ANOVA, and multiple linear regressions were performed. There was a significant inverted relationship of creatinine-adjusted urine UA concentrations and the time-weighted index of cumulative blood lead levels (TWICL) that may be significantly influenced by the AC genotypes of rs11640851 in exon 2 and rs8052394 in exon 3. After controlling for potential confounding factors, the creatinine-adjusted urine NAG concentrations were shown to be influenced by the GG genotype of rs8052394 in exon 3, and were weakly increased with TWICL. Therefore, we concluded that the variations of MT1A SNPs may influence urine UA and NAG excretion in chronic lead-exposed workers, and urine creatinine-adjusted urine UA as a biomarker of lead toxicity should be considered. 23563293 Simple, rapid and green one-step strategy to synthesis of graphene/carbon nanotubes/chitosan hybrid as solid-phase extraction for square-wave voltammetric detection of methyl parathion. Simple, rapid, green and one-step electrodeposition strategy was first proposed to synthesis of graphene/carbon nanotubes/chitosan (GR/CNTs/CS) hybrid. The one-step electrodeposition approach for the construction of GR-based hybrid is green environmentally, which would not involve the chemical reduction of graphene oxide (GO) and therefore result in no further contamination. The whole procedure is simple and needs only several minutes. Combining the advantages of GR (large surface area, high conductivity and good adsorption ability), CNTs (high surface area, high enrichment capability and good adsorption ability) and CS (good adsorption and excellent film-forming ability), the obtained GR/CNTs/CS composite could be highly efficient to capture organophosphate pesticides (OPs) and used as solid phase extraction (SPE). The GR/CNTs/CS sensor is used for enzymeless detection of OPs, using methyl parathion (MP) as a model analyte. Significant redox response of MP on GR/CNTs/CS sensor is proved. The linear range is wide from 2.0ngmL(-1) to 500ngmL(-1), with a detection limit of 0.5ngmL(-1). Detection limit of the proposed sensor is much lower than those enzyme-based sensors and many other enzymeless sensors. Moreover, the proposed sensor exhibits high reproducibility, long-time storage stability and satisfactory anti-interference ability. This work provides a green and one-step route for the preparation of GR-based hybrid, and also offers a new promising protocol for OPs analysis. 23192980 A novel adipose-specific gene deletion model demonstrates potential pitfalls of existing methods. Adipose-specific gene deletion in mice is crucial in determining gene function in adipocyte homeostasis and the development of obesity. We noted 100% mortality when the Hdac3 gene was conditionally deleted using Fabp4-Cre mice, the most commonly used model of adipose-targeted Cre recombinase. However, this surprising result was not reproduced using other models of adipose targeting of Cre, including a novel Retn-Cre mouse. These findings underscore the need for caution when interpreting data obtained using Fabp4-Cre mice and should encourage the use of additional or alternative adipose-targeting Cre mouse models before drawing conclusions about in vivo adipocyte-specific functions. 23899371 Cognitive Behavioural Therapy for Obsessive-Compulsive Disorder with Comorbid Schizophrenia: A Case Report with Repetitive Measurements. Background: Obsessive-compulsive disorder (OCD) has been observed in a substantial proportion of patients with schizophrenia. Although cognitive-behavioural therapy (CBT) is well documented for OCD, few case studies are available regarding CBT for comorbid OCD in schizophrenia. Aims: The study aims to present a case study to augment the limited knowledge concerning CBT treatment for OCD in patients with schizophrenia. Method: The research adopted a case study approach, with a baseline condition and repeated assessments during the 3-week treatment and 6-month follow-up period. Results: The treatment was successful and the patient achieved clinical significant change in OCD symptoms. The patient had a reduction on the Y-BOCS from 24 to 5 (79%) and from 38 to 10 (73%) on the OCI-R from before treatment to 6 months follow-up. He did not fulfil the criteria for an OCD diagnosis at the end of the 3-week treatment period, or the follow-up at 3- and 6 months. Conclusions: The results strengthen the impressions given by previous case studies suggesting that CBT may be a promising treatment for OCD in patients with schizophrenia. 23887236 Adverse Effects of Hemorrhagic Shock Resuscitation With Stored Blood Are Ameliorated by Inhaled Nitric Oxide in Lambs. Transfusion of stored RBCs is associated with increased morbidity and mortality in trauma patients. Plasma hemoglobin scavenges nitric oxide, which can cause vasoconstriction, induce inflammation, and activate platelets. We hypothesized that transfusion of RBCs stored for prolonged periods would induce adverse effects (pulmonary vasoconstriction, tissue injury, inflammation, and platelet activation) in lambs subjected to severe hemorrhagic shock and that concurrent inhalation of nitric oxide would prevent these adverse effects. Animal study. Research laboratory at the Massachusetts General Hospital, Boston, MA. Seventeen awake Polypay-breed lambs. Lambs were subjected to 2 hours of hemorrhagic shock by acutely withdrawing 50% of their blood volume. Lambs were resuscitated with autologous RBCs stored for 2 hours or less (fresh) or 39 ± 2 (mean ± SD) days (stored). Stored RBCs were administered with or without breathing nitric oxide (80 ppm) during resuscitation and for 21 hours thereafter. We measured hemodynamic and oxygenation variables, markers of tissue injury and inflammation, plasma hemoglobin concentrations, and platelet activation. Peak pulmonary arterial pressure was higher after resuscitation with stored than with fresh RBCs (24 ± 4 vs 14 ± 2 mm Hg, p < 0.001) and correlated with peak plasma hemoglobin concentrations (R = 0.56, p = 0.003). At 21 hours after resuscitation, pulmonary myeloperoxidase activity was higher in lambs resuscitated with stored than with fresh RBCs (11 ± 2 vs 4 ± 1 U/g, p = 0.007). Furthermore, transfusion of stored RBCs increased plasma markers of tissue injury and sensitized platelets to adenosine diphosphate activation. Breathing nitric oxide prevented the pulmonary hypertension and attenuated the pulmonary myeloperoxidase activity, as well as tissue injury and sensitization of platelets to adenosine diphosphate. Our data suggest that resuscitation of lambs from hemorrhagic shock with autologous stored RBCs induces pulmonary hypertension and inflammation, which can be ameliorated by breathing nitric oxide. 23589019 YB-1 stabilizes HIV-1 genomic RNA and enhances viral production. HIV-1 utilizes cellular factors for efficient replication. The viral RNA is different from cellular mRNAs in many aspects, and is prone to attacks by cellular RNA quality control systems. To establish effective infection, the virus has evolved multiple mechanisms to protect its RNA. Here, we show that expression of the Y-box binding protein 1 (YB-1) enhanced the production of HIV-1. Downregulation of endogenous YB-1 in producer cells decreased viral production. YB-1 increased viral protein expression by stabilizing HIV-1 RNAs. The stem loop 2 in the HIV-1 RNA packaging signal was mapped to be the YB-1-responsive element. Taken together, these results indicate that YB-1 stabilizes HIV-1 genomic RNA and thereby enhances HIV-1 gene expression and viral production. 23838478 Early Intervention with Probiotic Lactobacillus paracasei F19 Has No Long-Term Effect on Caries Experience. The aim of the study was to evaluate possible long-term effects of a cereal diet supplemented with Lactobacillus paracasei F19 (LF19) during weaning on caries experience, mutans streptococci (MS) and lactobacilli (LBC) in a group of 9-year-old children. A secondary aim was to evaluate if the intervention resulted in the permanent integration of LF19 as part of the oral microbiota. The study followed up on a double-blind placebo-controlled randomised trial. Among 179 infants that were randomised to a daily diet that included cereals with or without LF19 from 4 to 13 months of age, 56 from the probiotic group and 62 from the placebo group participated in the follow-up at 9 years. Data were collected by oral clinical examination and questionnaires. MS and LBC levels were assessed with conventional cultivation; LF19 was detected by using randomly amplified polymerase chain reactions (RAPD-PCR). At the follow-up, neither decayed, missing and filled surfaces for primary teeth (dmfs) nor decayed, missing and filled surfaces for permanent teeth (DMFS) differed significantly between the probiotic and placebo groups (p > 0.05). MS and LBC levels were similar in both groups (p > 0.05). RAPD-PCR showed no evidence of oral colonisation with LF19 in the study group. It is concluded that an early intervention with LF19 did not affect the frequency of dental caries, MS or LBC. LF19 did not establish itself as a permanent facet of the oral microbiota in any of the subjects included in this study. 23927994 Absolute monocyte count in follicular lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Elevated absolute monocyte counts (AMCs) have been reported to indicate poor prognosis for patients with lymphoproliferative disease, including those with follicular lymphoma (FL) receiving various treatments. We evaluated the prognostic impact of AMC in 150 consecutive FL patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Progression-free survival (PFS) did not differ significantly according to the AMC level. Univariate and multivariate analyses did not indicate a prognostic significance of AMC for PFS. Thus, the AMC is not a prognostic factor for FL patients treated with R-CHOP. However, immunochemotherapy might influence the prognostic impact of AMC. 23466240 Positioning injuries associated with robotic assisted urological surgery. Nerve injury associated with patient positioning during surgery is well documented. With the development of robotic surgery, surgeons are faced with new surgical positioning, requiring attention to ensure patient safety. Published reports that address positioning injury during robotic surgery are sparse and none address the overall incidence. In this study we determine the incidence of positioning injury during robotic assisted urological surgery, identify risk factors and describe the time to resolution of the neurological injury. We reviewed all adult urological cases at our institution that used the da Vinci® Si and da Vinci Standard® Surgical System from January 2010 to December 2011. We characterized risk factors into the 4 domains of positioning, operative, patient specific and anesthesia related. Within these 4 categories we collected data on 13 specific aspects of patient care to determine their association with positioning injury. Of 334 operations 22 positioning injuries (6.6%) were documented. Of these injuries 13 (59.1%) resolved within 1 month, 4 (18.2%) resolved between 1 and 6 months, and 5 (22.7%) persisted beyond 6 months. We found operative time (p <0.0001), in-room time (p <0.0001) and ASA (American Society of Anesthesiologists) class (p = 0.0033) were significantly associated with injury. Positioning injuries are under recognized in robotic assisted urological surgery and may persist beyond 6 months. Consideration must be given to counseling patients about the risks of positioning injuries, especially for long operations. Patients with multiple medical comorbidities (ASA class 4) are particularly at risk for these injuries. 23922434 Managing catatonia in adolescents with psychosis. Catatonia occurs secondary to medical or psychiatric disorder but despite its prevalence, literature investigating the syndrome is scarce. It is a common yet under-recognised and poorly understood clinical neuropsychiatric syndrome especially when it presents in children and adolescents. It presents with a wide range of neurological disturbances associated with dysregulation of GABA, glutamate and dopamine in the brain. The mainstay of treatment remains with benzodiazepines and electroconvulsive therapy, although recent research also indicates NMDA antagonists in treatment. We describe a 17 year old male with ASD, psychosis and catatonia and the dilemma we faced when choosing suitable antipsychotics to treat his psychosis without exacerbating his catatonia. We explain how we investigated for possible medical causes of catatonia and how the development of a cardiac condition affected his treatment. This case report adds to the diagnostic, pharmacological, ethical and legal dilemmas one faces when managing adolescents with catatonia. 23889906 The efficacy of intravenous sodium valproate and phenytoin as the first-line treatment in status epilepticus: a comparison study. Status epilepticus (SE) is a serious neurological condition and requires prompt treatment. Sodium valproate has been used to treat SE successfully but its role as the first-line antiepileptic drug (AED) is still controversial. This study evaluated the efficacy of intravenous sodium valproate to determine if it is non-inferior to intravenous phenytoin in SE treatment. Patients diagnosed as SE during 2003-2010 who were of an age of more than 15 years and received either intravenous sodium valproate or intravenous phenytoin as the first-line treatment were enrolled. Clinical characteristics and outcomes of SE were recorded and analyzed. The differences of outcomes between sodium valproate and phenytoin group were determined by descriptive statistics. During the study period, there were 37 and 17 SE patients who received intravenous phenytoin and intravenous sodium valproate as the first-line treatment, respectively. All patients received diazepam 10 mg intravenously as a rescue medication before starting the antiepileptic agents if uncontrolled except one patient in the sodium valproate group. There were no significant differences between the phenytoin and sodium valproate groups in all outcome variables including numbers of patients with clinically-controlled seizures, non-dependent patients, time to seizure control, and duration of hospitalization, and death. No serious cardiovasculars event such as hypotension occurred in either group. Intravenous sodium valproate is non-inferior to intravenous phenytoin as the first-line treatment in SE with no significant cardiovascular compromises. 23624863 Foraging Behavior Delays Mechanically-Stimulated Escape Responses in Fish. Foraging and the evasion of predators are fundamental for the survival of organisms, but they impose contrasting demands that can influence performance in each behavior. Previous studies suggested that foraging organisms may experience decreased vigilance to attacks by predators; however, little is known about the effect of foraging on escape performance with respect to the kinematics and the timing of the response. This study tested the hypothesis that engaging in foraging activities affected escape performance by comparing fast-start escape responses of silver-spotted sculpins Blepsias cirrhosus under three conditions: (1) control (no foraging involved), (2) while targeting prey, and (3) immediately after capture of prey. Escape response variables (non-locomotor and locomotor) were analyzed from high-speed videos. Responsiveness was lower immediately after capturing a prey item compared with the other two treatments, and latency of performance was higher in the control treatment than in the other two. Locomotor variables such as maximum speed, maximum acceleration, and turning rates did not show statistical differences among the three groups. Our results demonstrate that foraging can negatively affect two fundamental components of the escape response: (1) responsiveness and (2) latency of escape, suggesting that engaging in foraging may decrease an individual's ability to successfully evade predators. 23427854 Exploring the 'follow-through experience': A statewide survey of midwifery students and academics conducted in Victoria, Australia. follow-through experiences (which enable midwifery students to experience continuity of care with individual women through pregnancy, labour and birth and the postnatal period) are a component of midwifery education programmes in Australia and the United Kingdom. Current accreditation standards in Australia require midwifery students to have a total of 20 continuity of care experiences with an average of 20 hours per woman over the duration of their course. There has been limited research regarding students' and academics' experiences of follow-through experiences; and there has been debate regarding the appropriate number of follow-through experiences in midwifery curricula. This study aimed to explore the follow-through experience from the perspective of midwifery students and academics in Victoria, Australia. cross-sectional design using a web-based survey. Victoria, Australia. students (n=401) and academics (n=35) from all seven universities in Victoria that offer accredited midwifery programmes including the Bachelor of Midwifery, Bachelor of Nursing/Bachelor of Midwifery double degree, Postgraduate Diploma of Midwifery and Masters of Midwifery (entry to practice). students and academics were in agreement that continuity of care is important to women. They considered the follow-through experience to be a unique and valuable learning opportunity and agreed that follow-through experiences should be included in midwifery education programmes. However, students and academics raised major concerns about the impact of follow-through experiences on students' capacity to meet university course requirements (such as missing lectures/tutorials and clinical placements), and spending extensive periods of time on-call both within and outside the university semester. Students and academics also reported concerns about the impact of follow-through experiences on students' personal lives, including paid employment and family responsibilities (such as childcare or caring for family members). in settings where continuity of care options for women are relatively limited, prescriptive requirements regarding the number and hours of follow-through experiences can present significant challenges for midwifery students. Midwifery regulatory bodies should consider these findings when developing or revising standards for midwifery education. 23665469 Homocysteine is a novel risk factor for suboptimal response of blood platelets to acetylsalicylic acid in coronary artery disease: A randomized multicenter study. The incomplete inhibition of platelet function by acetylsalicylic acid (ASA), despite the patients are receiving therapeutic doses of the drug ('aspirin-resistance'), is caused by numbers of risk factors. In this study we verified the idea that plasma homocysteine (Hcy) contributes to 'aspirin-resistance' in patients with coronary artery disease (CAD) and with or without type 2 diabetes mellitus (T2DM). A cross-designed randomized controlled intervention study has been performed (126 CAD pts incl. 26 with T2DM) to determine whether increasing ASA dose from 75mg to 150mg daily may result in the increased antiplatelet effect, in the course of four-week treatment. Platelet response to collagen (coll) or arachidonic acid (AA) was monitored with whole blood aggregometry, plasma thromboxane (Tx), and Hcy levels were determined immunochemically. The ASA-mediated reductions in platelet response to coll (by 12±3%) or AA (by 10±3%) and in plasma Tx (by 20±9%; p<0.02 or less) were significantly greater for higher ASA dose and significantly correlated with plasma Hcy, which was significantly lower in "good" ASA responders compared to "poor" responders (p<0.001). Higher plasma Hcy appeared a significant risk factor for blood platelet refractoriness to low ASA dose (OR=1.11; ±95%CI: 1.02-1.20, p<0.02, adjusted to age, sex and CAD risk factors). Hcy diminished in vitro antiplatelet effect of low ASA concentration and augmented platelet aggregation (by up to 62% (p<0.005) for coll and up to 15% (p<0.005) for AA), whereas its acetyl derivative acted oppositely. Otherwise, Hcy intensified antiplatelet action of high ASA. Hyperhomocysteinaemia may be a novel risk factor for the suppressed blood platelet response to ASA, and homocysteine may act as a specific sensitizer of blood platelets to some agonists. While homocysteine per se acts as a proaggregatory agent to blood platelets, its acetylated form is able to reverse this effect. Thus, these findings reveal a possibly new challenging potential of the acetylating properties of ASA therapy. 23899764 Long-Term Follow-Up and Molecular Characterization of a Patient with a RECQL4 Mutation Spectrum Disorder. The follow-up of a man from birth to adulthood, presenting with features both of RAPADILINO and Rothmund-Thomson syndrome (RTS), is described. Molecular studies confirmed the presence of two different mutations, c.2767_2768delTT and c.3061C>T, in the RECQL4 gene. This gene is known to be causative of a spectrum including Baller-Gerold syndrome, RAPADILINO syndrome and RTS. New and rare features such as oral leukoplakia and very prominent hyperkeratotic verrucous papules on both soles are shown. This patient has to date no cancer history despite bearing a truncating mutation at the age of 21 years, which is also unusual. © 2013 S. Karger AG, Basel. 23848070 Charge transfer structure-reactivity dependence of fullerene-single-walled carbon nanotube heterojunctions. Charge transfer at the interface between single-walled carbon nanotubes (SWCNTs) of distinct chiral vectors and fullerenes of various molecular weights is of interest both fundamentally and because of its importance in emerging photovoltaic and optoelectronic devices. One approach for generating isolated, discretized fullerene-SWCNT heterojunctions for spectroscopic investigation is to form an amphiphile, which is able to disperse the latter at the single-SWCNT level in aqueous solution. Herein, we synthesize a series of methanofullerene amphiphiles, including derivatives of C60, C70, and C84, and investigated their electron transfer with SWCNT of specific chirality, generating a structure-reactivity relationship. In the cases of two fullerene derivatives, lipid-C61-polyethylene glycol (PEG) and lipid-C71-PEG, band gap dependent, incomplete quenching was observed across all SWCNT species, indicating that the driving force for electron transfer is small. This is further supported by a variant of Marcus theory, which predicts that the energy offsets between the nanotube conduction bands and the C61 and C71 LUMO levels are less than the exciton binding energy in SWCNT. In contrast, upon interfacing nanotubes with C85 methanofullerene, a complete quenching of all semiconducting SWCNT is observed. This enhancement in quenching efficiency is consistent with the deeper LUMO level of C85 methanofullerene in comparison with the smaller fullerene adducts, and suggests its promise as for SWCNT-fullerene heterojunctions. 23668633 Abdominal computed tomography-a new tool for predicting recurrent stone disease. Abstract Purpose: To evaluate whether CT-identified Randall plaques can be used to foresee the recurrence of stone disease (SD); to define a cut point that could identify a high-risk population. Materials and Methods: A retrospective study of patients attended for SD from January 2004 to December 2009 was conducted. Study population was patients with a first episode of calcium SD that was diagnosed by abdominal CT. Papillae tip attenuation was measured in Hounsfield units (HU) on unenhanced abdominal CT images. Patients with recurrent SD were identified; t test, Pearson correlation, and receiver operating characteristic (ROC) curve analysis were used. Results: A total of 543 patients were evaluated; 187 fulfilled the criteria and were included, and 49 (26.2%) had recurrent SD. Mean follow-up: 5 years (3-7 years). Papillae tip attenuation was significantly higher in the recurrent group (46.2 HU vs 40.1 HU, P=0.01) and correlated well with the possibility of developing SD (R=0.83). Attenuation >43 HU showed a ROC curve area under the curve=0.87 with sensitivity=77% and specificity=84% separating patients with a RR=8.7 of development of recurrent SD. The number of papillae >43 HU correlated with recurrent SD (RR=11.2 for ≥3 papillae vs <3 papillae with density >43 HU). Conclusions: The presence of the Randall plaques can be used as a marker for predicting SD recurrence. A cut point of 43 HU could be used to identify a high-risk population. 23850195 Reproducibility of blood pressure dipping: relation to day-to-day variability in sleep quality. Previous studies of the reproducibility of blood pressure (BP) dipping have yielded inconsistent results. Few have examined factors that may influence day-to-day differences in dipping. Ambulatory BP monitoring was performed on three occasions, approximately 1 week apart, in 115 untreated adult subjects with elevated clinic BPs. The mean ± standard deviation BP dip was 18 ± 7/15 ± 5 mm Hg (sleep/awake BP ratio = 0.87 ± 0.05/0.82 ± 0.06), with a median (interquartile range) day-to-day variation of 5.2 (3.1-8.1)/4.3 (2.8-5.6) mm Hg. There was no decrease in variability with successive measurements. The reproducibility coefficient (5.6 [95% confidence interval, 5.1-6.1] mm Hg) was greater and the intraclass correlation coefficient (0.53 [95% confidence interval, 0.42-0.63]) was smaller for the systolic dip than for 24-hour or awake systolic BPs, suggesting greater day-to-day variability in dipping. Variability in systolic dipping was greater in subjects with higher awake BP, but was not related to age, gender, race, or body mass index. Within individuals, day-to-day variations in dipping were related to variations in the fragmentation index (P < .001), a measure of sleep quality. Although mean 24-hour and awake BPs were relatively stable over repeated monitoring days, our study confirms substantial variability in BP dipping. Day-to-day differences in dipping are related to sleep quality. 23549304 "The Skill Is Using Your Big Head Over Your Little Head": What Black Heterosexual Men Say They Know, Want, and Need to Prevent HIV. Although the disproportionate toll of HIV/AIDS among Black heterosexuals, particularly in low-income U.S. urban areas is well documented, Black heterosexual men are rarely the explicit focus of HIV prevention messages, research, and interventions. We conducted 4 focus groups with 28 Black men, aged 19 to 51 years, who were enrolled in the workforce and fatherhood development program of a local community-based organization to examine (a) the priority and role of HIV/AIDS in their lives and (b) their HIV prevention needs. Although none articulated HIV as a top life priority, respondents nonetheless prioritized educating their children about HIV prevention and protecting their main partners from HIV if they had other sexual partners. Analyses demonstrated that participants said they wanted and needed: to learn how to talk to partners about HIV testing and use condoms when tempted not to do so, and more discussion-oriented educational opportunities to learn and exchange prevention strategies. 23873263 The impact of health insurance programs on out-of-pocket expenditures in Indonesia: an increase or a decrease? We used panel data from the Indonesian Family Life Survey to investigate the impact of health insurance programs on reducing out-of-pocket expenditures. We employed three linear panel data models, two of which accounted for endogeneity: pooled ordinary least squares (OLS), pooled two-stage least squares (2SLS) for instrumental variable (IV), and fixed effects (FE). The study revealed that two health insurance programs had a significantly negative impact on out-of-pocket expenditures by using IV estimates. In the IV model, Askeskin decreased out-of-pocket expenditures by 34% and Askes by 55% compared with non-Askeskin and non-Askes, respectively, while Jamsostek was found to bear a nonsignificant effect on out-of-pocket expenditures. In the FE model, only Askeskin had a significant negative effect with an 11% reduction on out-of-pocket expenditures. This study showed that two large existing health insurance programs in Indonesia, Askeskin and Askes, effectively reduced household out-of-pocket expenditures. The ability of programs to offer financial protection by reducing out-of-pocket expenditures is likely to be a direct function of their benefits package and co-payment policies. 23810502 Similarities of molecular genetic changes in synchronous and metachronous colorectal cancers are limited and related to the cancers' proximities to each other. Synchronous and metachronous colorectal cancers are distinct primary neoplasms diagnosed either simultaneously or sequentially in the same patient. Because they arise in a common genetic and environmental background, they offer a unique opportunity to study molecular genetic changes occurring during carcinogenesis. We evaluated tumors from 50 patients with synchronous and five additional patients with metachronous cancers for loss of heterozygosity of the genes APC and DCC, KRAS and BRAF gene mutations, and microsatellite instability and methylation. Standard PCR methods were used. Approximately two thirds of the synchronous tumors that were informative for each of the five primary molecular genetic changes showed the same results when located in the same colon segment. However, there was less consistency of molecular findings for the synchronous pairs separated by one or more colonic segments, with half or more of these pairs showing different molecular results. Metachronous tumors also showed variation of molecular genetic findings, but this was less when the subsequent tumor was close to the segment of the first tumor. Molecular genetic findings between synchronous and metachronous tumors can be different, even for tumors sharing the same microenvironment of the same colon segment. These findings support the concept that a mutagen might produce different genetic pathways in two proximate tumors. 23949913 Boston type craniosynostosis: Report of a second mutation in MSX2. We describe a family that segregated an autosomal dominant form of craniosynostosis characterized by variable expression and limited extra-cranial features. Linkage analysis and genome sequencing were performed to identify the underlying genetic mutation. A c.443C>T missense mutation in MSX2, which predicts p.Pro148Leu was identified and segregated with the disease in all affected family members. One other family with autosomal dominant craniosynostosis (Boston type) has been reported to have a missense mutation in MSX2. These data confirm that missense mutations altering the proline at codon 148 of MSX2 cause dominantly inherited craniosynostosis. © 2013 Wiley Periodicals, Inc. 23398496 Mexican antidiabetic herbs: valuable sources of inhibitors of α-glucosidases. Type II-diabetes mellitus (TII-DM) has been regarded as one of the most important public health problems in all nations in the 21st century. Although allopathic therapies remain the most important for the initial management of TII-DM, herbal remedies have gained wide acceptance for treating this condition. These alternative therapies are particularly valued in countries such as Mexico, rich in medicinal plants strongly attached to the cultural values of the population. Medicinal plants are prized sources of α-glucosidase inhibitors, which delay the liberation of glucose from complex carbohydrates, retarding glucose absorption, and thus controlling the characteristic hyperglycemia of TII-DM. Among the plant species used for treating diabetes in Mexico only 38 have been analyzed for their inhibitory activity of α-glucosidases. Most of these studies, reviewed in the present work, have focused on the evaluation of different types of extracts on the activity of α-glucosidases from diverse sources. Four species have been thoroughly analyzed in order to discover novel α-glucosidase inhibitors, namely, Hintonia latiflora and Hintonia standleyana (Rubiaceae), Ligusticum porteri (Apiaceae), and Brickellia cavanillesii (Asteraceae). Their ethnomedical uses, pharmacological and toxicological studies, chemical composition, and antihyperglycemic principles with α-glucosidase inhibitory activity are summarized. 23919741 Effect of Mechanical Instability of Polymer Scaffolds on Cell Adhesion. The adhesion of fibroblast on polymer bilayers composed of a glassy polystyrene (PS) prepared on top of a rubbery polyisoprene (PI) was studied. Since the top PS layer is not build on a glassy, or firm, foundation, the system becomes mechanically unstable with decreasing thickness of the PS layer. When the PS film was thinner than 25 nm, the number of cells adhered to the surface decreased and the cells could not spread well. On a parallel experiment, the same cell adhesion behavior was observed on plasma-treated PS/PI bilayer films, where in this case, the surface was more hydrophilic than that of the intact films. In addition, the fluorescence microscopic observations revealed that the formation of F-actin filaments in fibroblasts attached to the thicker PS/PI bilayer films was greater than those using the thinner PS/PI bilayer films. On the other hand, the thickness dependence of the cell adhesion behavior was not observed for the PS monolayer films. Taking into account that the amount of adsorbed protein molecules evaluated by a quartz crystal microbalance method was independent of the PS layer thickness of the bilayer films, our results indicate that cells, unlike protein molecules, could sense a mechanical instability of the scaffold. 23871572 High discordance rates between sub-areolar and peri-tumoural breast lymphoscintigraphy. To test the hypothesis that sub-areolar (SA) lymphoscintigraphy (LSG) identifies the same sentinel node as peri-tumoural (PT) injections. It is commonly believed that all LSG techniques will identify the same sentinel lymph nodes (SLN) draining the breast. Hybrid imaging technology (SPECT/CT) allows accurate identification of the exact location of SLNs. Using SPECT/CT SA and PT LSG techniques were compared. In a multi-centre trial 39 patients sequentially underwent LSG (SA followed by PT) separated by 2-7 days. Patients were referred by 4 surgeons to 3 LSG centres, with standardization of isotope (99mTc-antimony sulfide colloid), LSG and SPECT/CT evaluation techniques. LSG were evaluated for SLN concordance and degree of discordance in the axilla and internal mammary nodes (IMN). 39 eligible patients, median age 62 years, were recruited. Successful axillary SLN mapping for SA and PT injection techniques was 87% and 95% respectively. Successful internal mammary SLN mapping occurred with SA and PT LSG in 5% and 36% respectively. Discordance was identified in the IMN (39%) and axilla (21%), with an overall rate of discordance between SA and PT LSG of 56%. There is a high level of discordance in the localization of SLN by these commonly used LSG injection techniques. This discordance has implications for accuracy of axillary and extra-axillary staging and could impact on patient outcome. 23639199 In vitro effects of extracts and purified tannins of sainfoin (Onobrychis viciifolia) against two cattle nematodes. Sainfoin (Onobrychis viciifolia) is a condensed tannin (CT)-containing legume and has anthelmintic potential against gastrointestinal nematodes of ruminants. This study investigated in vitro effects of acetone/water extracts and derived CT fractions from different types of sainfoin (i.e. accessions) against larvae of Cooperia oncophora and Ostertagia ostertagi by applying the larval feeding inhibition assay (LFIA). Seven sainfoin accessions were extracted and tested with L1 larvae at 10 and 40μg extract/ml. In addition, CT in extracts from 4 accessions were fractionated according to polymer size and tested by LFIA at two concentrations (2 and 10μg CT fraction/ml). All sainfoin extracts caused significant inhibition of L1-feeding of both C. oncophora and O. ostertagi with varying intensity compared to the control (phosphate buffered saline). For both nematode species the in vitro effect was positively correlated with CT content in the extracts, but not with any of the structural CT parameters. In contrast, the 16 CT fractions revealed significant correlations between in vitro effect and CT content, polymer size (mean degree of polymerisation, mDP) and monomeric composition (prodelphinidin percentage, % PD). These differences between crude extracts and purified fractions may stem from the fact that extracts contain complex CT mixtures, which may mask and thus suppress CT structural effects. This study provides the first indication that, apart from CT and % PD content, polymer size also contributes to anthelmintic activity of CTs. The results, therefore, suggest that the inter-accession variability in CT content and composition needs to be taken into account in future plant breeding programmes which seek to enhance the anthelmintic properties of sainfoin. 23859307 Efficacy of laparoscopic radiofrequency ablation for the treatment of patients with small solitary colorectal liver metastasis. Although radiofrequency ablation (RFA) has been incorporated to the treatment algorithm of patients with unresectable colorectal liver metastasis (CLM), its utility in patients with resectable disease has not been well studied. The aims of this study were to define the clinical profile of patients with a solitary CLM who underwent laparoscopic RFA and to analyze their oncologic outcomes. Between 2000 and 2011, 44 patients underwent laparoscopic RFA and 60 patients resection of solitary CLM ≤3 cm. Data were analyzed from a prospectively maintained institutional review board-approved database using Student's t test, Chi-square, and Kaplan-Meier tests. The indications for RFA were patient decision in 61% (n = 27), comorbidities in 34% (n = 15), and intraoperative findings in 5% (n = 2). In comparison with the resection group, RFA patients had a greater American Society of Anesthesiologists score (3.0 ± 0.1 vs 2.6 ± 0.1, respectively; P = .002), more frequent incidence of cardiopulmonary comorbidities (60% vs 38%, respectively; P = .045), and tumors located deeper in the liver parenchyma (39% vs 12%) that would have required a formal lobectomy. The 2 groups were otherwise similar for age, gender, carcinoembrradyogenic antigen, synchronous versus metachronous presentation of CLM, tumor size, and tumor and nodal status of primary colorectal cancer. The local recurrence rate was 18% after RFA and 4% after resection (P = .012). The overall Kaplan-Meier, cancer-specific, 5-year survival was 47% for RFA and 57% for resection (P = .464). Median disease-free survival was 25 months after RFA and 22 months after resection (P = .973). Our results suggest that laparoscopic RFA might spare a number of patients at greater risk with a small solitary CLM the risk of morbidity from a formal liver resection. Furthermore, laparoscopic RFA might also be acceptable as the first line of therapy for patients with tumors that otherwise would have required a formal lobectomy or open resection. Nevertheless, the local recurrence rate of RFA should be kept in mind and the patients followed closely to treat failures promptly. 23860384 Development of a magnetic electrochemical bar code array for point mutation detection in the H5N1 neuraminidase gene. Since its first official detection in the Guangdong province of China in 1996, the highly pathogenic avian influenza virus of H5N1 subtype (HPAI H5N1) has reportedly been the cause of outbreaks in birds in more than 60 countries, 24 of which were European. The main issue is still to develop effective antiviral drugs. In this case, single point mutation in the neuraminidase gene, which causes resistance to antiviral drug and is, therefore, subjected to many studies including ours, was observed. In this study, we developed magnetic electrochemical bar code array for detection of single point mutations (mismatches in up to four nucleotides) in H5N1 neuraminidase gene. Paramagnetic particles Dynabeads® with covalently bound oligo (dT)₂₅ were used as a tool for isolation of complementary H5N1 chains (H5N1 Zhejin, China and Aichi). For detection of H5N1 chains, oligonucleotide chains of lengths of 12 (+5 adenine) or 28 (+5 adenine) bp labeled with quantum dots (CdS, ZnS and/or PbS) were used. Individual probes hybridized to target molecules specifically with efficiency higher than 60%. The obtained signals identified mutations present in the sequence. Suggested experimental procedure allows obtaining further information from the redox signals of nucleic acids. Moreover, the used biosensor exhibits sequence specificity and low limits of detection of subnanogram quantities of target nucleic acids. 23884902 Crystal structure of 3WJ core revealing divalent ion-promoted thermostability and assembly of the Phi29 hexameric motor pRNA. The bacteriophage phi29 DNA packaging motor, one of the strongest biological motors characterized to date, is geared by a packaging RNA (pRNA) ring. When assembled from three RNA fragments, its three-way junction (3WJ) motif is highly thermostable, is resistant to 8 M urea, and remains associated at extremely low concentrations in vitro and in vivo. To elucidate the structural basis for its unusual stability, we solved the crystal structure of this pRNA 3WJ motif at 3.05 Å. The structure revealed two divalent metal ions that coordinate 4 nt of the RNA fragments. Single-molecule fluorescence resonance energy transfer (smFRET) analysis confirmed a structural change of 3WJ upon addition of Mg(2+). The reported pRNA 3WJ conformation is different from a previously published construct that lacks the metal coordination sites. The phi29 DNA packaging motor contains a dodecameric connector at the vertex of the procapsid, with a central pore for DNA translocation. This portal connector serves as the foothold for pRNA binding to procapsid. Subsequent modeling of a connector/pRNA complex suggests that the pRNA of the phi29 DNA packaging motor exists as a hexameric complex serving as a sheath over the connector. The model of hexameric pRNA on the connector agrees with AFM images of the phi29 pRNA hexamer acquired in air and matches all distance parameters obtained from cross-linking, complementary modification, and chemical modification interference. 23752250 In vitro intestinal bioavailability of arsenosugar metabolites and presystemic metabolism of thio-dimethylarsinic acid in Caco-2 cells. Whereas inorganic arsenic is classified as a human carcinogen, risks to human health related to the presence of arsenosugars in marine food are still unclear. Since studies indicate that human inorganic arsenic metabolites contribute to inorganic arsenic induced carcinogenicity, a risk assessment for arsenosugars should also include a toxicological characterization of their respective metabolites. Here we assessed intestinal bioavailability of the human arsenosugar metabolites oxo-DMAA(V), thio-DMAA(V), oxo-DMAE(V), thio-DMAE(V) and thio-DMA(V) in relation to arsenite in the Caco-2 intestinal barrier model. Whereas arsenite and thio-DMA(V) caused barrier disruption at concentrations ≥10 μM, all other metabolites did not cause a barrier leakage, even when applied at 50 times higher concentrations than arsenite and thio-DMA(V). The transfer studies point to a strong intestinal bioavailability of thio-DMA(V) and thio-DMAE(V), whereas oxo-DMAA(V), thio-DMAA(V) and oxo-DMAE(V) passed the in vitro intestinal barrier only to a very small extent. Detailed influx and efflux studies indicate that arsenite and thio-DMA(V) cross the intestinal barrier most likely by passive diffusion (paracellular) and facilitated (transcellular) transport. LC-ICP-QMS based arsenic speciation studies during the transfer experiments demonstrate transfer of thio-DMA(V) itself across the intestinal barrier and suggest metabolism of thio-DMA(V) using the in vitro intestinal barrier model to its oxygen-analogue DMA(V). In the case of arsenite no metabolism was observed. In summary the two arsenosugar metabolites thio-DMA(V) and thio-DMAE(V) showed intestinal bioavailability similar to that of arsenite, and about 10-fold higher than that reported for arsenosugars (Leffers et al., Mol. Nutr. Food Res., 2013, DOI: 10.1002/mnfr.201200821) in the same in vitro model. Thus, a presystemic metabolism of arsenosugars might strongly impact arsenic intestinal bioavailability after arsenosugar intake and should therefore be considered when assessing the risks to human health related to the consumption of arsenosugar-containing food. 23625112 Blood pressure levels and risk of cardiovascular events and mortality in type-2 diabetes: cohort study of 34 009 primary care patients. The optimal blood pressure (BP) in persons with type-2 diabetes is debated. We investigated shapes of the associations of SBP and DBP levels with risk of cardiovascular events and mortality in a large primary care-based sample of diabetic patients. We investigated all 34 009 consecutive cardiovascular disease-free type-2 diabetes patients aged 35 years or older (mean age 64 years) at 84 primary care centers in central Sweden between 1999 and 2008. We followed this cohort until the end of 2009 in national registries for the incidence of major cardiovascular events (a composite endpoint of myocardial infarction, stroke, heart failure, or cardiovascular mortality) or total mortality. During up to 11 years of follow-up, 6344 patients (18.7%) had a first cardiovascular event, and 6235 died (18.3%). The associations of annually updated SBP and DBP with risk of major cardiovascular events were U-shaped. The lowest risk of cardiovascular events was observed at a SBP of 135-139 mmHg and a DBP of 74-76 mmHg, and the lowest mortality risk at a SBP of 142-150 mmHg and a DBP of 78-79 mmHg, in both antihypertensive drug-untreated and drug-treated persons. In a large primary care-based sample of patients with type-2 diabetes, associations of SBP and DBP with risk of major cardiovascular events and mortality were U-shaped. This may have implications for risk stratification of persons with diabetes. 23872619 Association Between Glaucoma, Glaucoma Therapies, and Erectile Dysfunction. To examine the association between (1) glaucoma and erectile dysfunction (ED) and (2) topical β-blocker (BB) use and ED. A comprehensive, province-wide database of physician visits and diagnoses and prescription drug dispensing was used to identify cases of ED (1380) and find corresponding controls (13,800). A conditional logistic regression model was used to estimate rate ratios for 2 main exposures: (1) diagnosis of glaucoma and (2) use of a prescription of a topical BB before the index date. A variety of risk factors were adjusted for. Cases were more likely to have coronary artery disease, chronic obstructive pulmonary disease, and diabetes. A crude rate ratio of the current diagnosis of ED in a population with at least 2 separate diagnoses of glaucoma was 1.34 and when adjusted for a number of variables (including oral BB use), this ratio was 1.37 [95% confidence interval (CI), 1.06-1.76]. Use of topical BB in the 30 days before the diagnosis of ED did not have a significant association with a diagnosis of ED, with crude and adjusted rate ratios of 1.05 and 1.10, respectively (95% CI, 0.61-1.99). Topical ocular prostaglandin use was also not associated with ED, with crude and adjusted rate ratios of 0.96 and 0.93, respectively (95% CI, 0.57-1.53). Our results confirmed an association between ED and glaucoma that cannot be attributed to topical BB use. Given that most cardiovascular and metabolic risk factors were adjusted for, further research in this area will be necessary to elucidate the nature of this association and potential causation. 23722321 Clay: new opportunities for tissue regeneration and biomaterial design. Seminal recent studies that have shed new light on the remarkable properties of clay interactions suggest unexplored opportunities for biomaterial design and regenerative medicine. Here, recent conceptual and technological developments in the science of clay interactions with biomolecules, polymers, and cells are examined, focusing on the implications for tissue engineering and regenerative strategies. Pioneering studies demonstrating the utility of clay for drug-delivery and scaffold design are reviewed and areas for future research and development highlighted. 23901954 The multi-configuration self-consistent field method within a polarizable embedded framework. We present a detailed derivation of Multi-Configuration Self-Consistent Field (MCSCF) optimization and linear response equations within the polarizable embedding scheme: PE-MCSCF. The MCSCF model enables a proper description of multiconfigurational effects in reaction paths, spin systems, excited states, and other properties which cannot be described adequately with current implementations of polarizable embedding in density functional or coupled cluster theories. In the PE-MCSCF scheme the environment surrounding the central quantum mechanical system is represented by distributed multipole moments and anisotropic dipole-dipole polarizabilities. The PE-MCSCF model has been implemented in DALTON. As a preliminary application, the low lying valence states of acetone and uracil in water has been calculated using Complete Active Space Self-Consistent Field (CASSCF) wave functions. The dynamics of the water environment have been simulated using a series of snapshots generated from classical Molecular Dynamics. The calculated shifts from gas-phase to water display between good and excellent correlation with experiment and previous calculations. As an illustration of another area of potential applications we present calculations of electronic transitions in the transition metal complex, [Fe(NO)(CN)5](2 -) in a micro-solvated environment. This system is highly multiconfigurational and the influence of solvation is significant. 23537096 Exploring drug delivery systems for treating osteoporosis. Introduction: Osteoporosis (OP) is a major disease in elderly people; its complications and prevalence are rapidly increasing worldwide. It is associated with high fragility fracture mainly of hip, wrist and spine. With the rising lifespan worldwide, the number of hip fractures throughout globe will rise from 1.66 million in 1990 to 6.26 million by 2050. So there is a major problem in our society related to the bone diseases which needs to be addressed. Areas covered: This review gives knowledge about OP, its symptoms and problems associated with the existing therapies. It gives idea about various drug delivery systems for bone targeting. This review also gives a comprehensive compilation of the various in vitro and in vivo studies conducted till date and US FDA approved drugs for the treatment of OP. Expert opinion: Various drug delivery systems reduce the adverse effects of drugs and increase the availability of drugs to the target site mainly bones. Active researches are going on to improve the OP treatment, whose high prevalence and considerable functional and socioeconomic impact will raise formidable challenges in the near future. We should work on different targets rather than conventional therapies which will improve the overall treatment strategies. 23883978 Physician orders. Echoes from military and religious history. 23712680 Dynamics of revolution time variability in cycling pattern: voluntary intent can alter the long-range autocorrelations. Long-range dependency has been found in most rhythmic motor signals. The origin of this property is unknown and largely debated. There is a controversy on the influence of voluntary control induced by requiring a pre-determined pace such as asking subjects to step to a metronome. We studied the cycle duration variability of 15 men pedaling on an ergometer at free pace and at an imposed pace (60 rpm). Revolution time was determined based on accelerometer signals (sample frequency 512 Hz). Revolution time variability was assessed by coefficient of variation (CV). The presence of long-range autocorrelations was based on scaling properties of the series variability (Hurst exponent) and the shape of the power spectral density (α exponent). Mean revolution time was significantly lower at freely chosen cadence, while values of CV were similar between both sessions. Long-range autocorrelations were highlighted in all series of cycling patterns. However, Hurst and α exponents were significantly lower at imposed cadence. This study demonstrates the presence of long-range autocorrelations during cycling and that voluntary intent can modulate the interdependency between consecutive cycles. Therefore, cycling may constitute a powerful paradigm to investigate the influence of central control mechanisms on the long-range interdependency characterizing rhythmic motor tasks. 23831051 Recent expansions in an emergent novel drug delivery technology: Emulgel. Emulgel is an emerging topical drug delivery system to which if more effort is paid towards its formulation & development with more number of topically effective drugs it will prove a boon for derma care & cosmetology. Emulgels are either emulsion of oil in water or water in oil type, which is gelled by mixing it with gelling agent. Incorporation of emulsion into gel increases its stability & makes it a dual control release system. Due to lack of excess oily bases & insoluble excipients, it shows better drug release as compared to other topical drug delivery system. Presence of gel phase makes it a non greasy & favors good patient compliance. These reviews give knowledge about Emulgel including its properties, advantages, formulation considerations, and its recent advances in research field. All factors such as selection of gelling agent, oil agent, emulsifiers influencing the stability and efficacy of Emulgel are discussed. All justifications are described in accordance with the research work carried out by various scientists. These brief reviews on formulation method have been included. Current research works that carried out on Emulgel are also discussed and highlighted the wide utility of Emulgel in topical drug delivery system. After the vast study, it can be concluded that the Emulgels appear better & effective drug delivery system as compared to other topical drug delivery system. The comprehensive analysis of rheological and release properties will provide an insight into the potential usage of Emulgel formulation as drug delivery system. 23845011 Covalently interconnected three-dimensional graphene oxide solids. The creation of three-dimensionally engineered nanoporous architectures via covalently interconnected nanoscale building blocks remains one of the fundamental challenges in nanotechnology. Here we report the synthesis of ordered, stacked macroscopic three-dimensional (3D) solid scaffolds of graphene oxide (GO) fabricated via chemical cross-linking of two-dimensional GO building blocks. The resulting 3D GO network solids form highly porous interconnected structures, and the controlled reduction of these structures leads to formation of 3D conductive graphene scaffolds. These 3D architectures show promise for potential applications such as gas storage; CO2 gas adsorption measurements carried out under ambient conditions show high sorption capacity, demonstrating the possibility of creating new functional carbon solids starting with two-dimensional carbon layers. 23074026 Perfluorooctane sulfonate (PFOS) affects hormone receptor activity, steroidogenesis, and expression of endocrine-related genes in vitro and in vivo. Perfluorooctane sulfonate (PFOS) is a widespread and persistent chemical in the environment. We investigated the endocrine-disrupting effects of PFOS using a combination of in vitro and in vivo assays. Reporter gene assays were used to detect receptor-mediated (anti-)estrogenic, (anti-)androgenic, and (anti-)thyroid hormone activities. The effect of PFOS on steroidogenesis was assessed both at hormone levels in the supernatant and at expression levels of hormone-induced genes in the H295R cell. A zebrafish-based short-term screening method was developed to detect the effect of PFOS on endocrine function in vivo. The results indicate that PFOS can act as an estrogen receptor agonist and thyroid hormone receptor antagonist. Exposure to PFOS decreased supernatant testosterone (T), increased estradiol (E2) concentrations in H295R cell medium and altered the expression of several genes involved in steroidogenesis. In addition, PFOS increased early thyroid development gene (hhex and pax8) expression in a concentration-dependent manner, decreased steroidogenic enzyme gene (CYP17, CYP19a, CYP19b) expression, and changed the expression pattern of estrogen receptor production genes (esr1, esr2b) after 500 µg/L PFOS treatment in zebrafish embryos. These results indicate that PFOS has the ability to act as an endocrine disruptor both in vitro and in vivo by disrupting the function of nuclear hormone receptors, interfering with steroidogenesis, and altering the expression of endocrine-related genes in zebrafish embryo. 23553654 Trisomies 18 and 13: trends in prevalence and prenatal diagnosis - population based study. The objective of this study was to determine trends in prenatal detection and current estimates of prevalence for trisomies 18 (T18) and 13 (T13) and their implications for screening policy. We conducted a cohort study from a population-based regional anomaly register covering 995 003 births (1995-2009). There were 786 affected cases. Total prevalence of T18 increased from 3.95 in 1995-1999 to 6.94 per 10 000 births in 2005-2009 (annual trend χ(2)  = 25.99, p < 0.001) and live birth prevalence, when adjusted for in utero attrition, increased from 1.47 to 2.30 per 10 000 births over the same time (annual trend χ(2)  = 6.36, p = 0.01). For T18 and T13 combined, the proportion of cases diagnosed by prenatal karyotype or suspected by ultrasound increased from 85.1% (165/194) in 1995-1999 to 95.2% (299/314) in 2005-2009 (p < 0.001). In 2005-2009, 50.3% of prenatal cytogenetic diagnoses for T18 and 38.5% of T13 were made after the discovery of first trimester ultrasound anomalies, and the majority, 56.4% (185/328), of affected pregnancies were karyotyped or had ended before 18 weeks. T18 is increasing in prevalence because of maternal age and earlier surveillance. Prenatal diagnosis occurs mostly in the first trimester, without the intrinsic structures of a formal screening programme. These findings support the extension of first trimester combined screening to include T18 and T13. © 2013 Crown copyright. 22348279 Chemical composition and antifungal activity of Artemisia nilagirica essential oil growing in northern hilly areas of India. Essential oil extracted from aerial parts of Artemisia nilagirica was analysed by gas chromatography-mass spectroscopy. Forty-three constituents amounting to 98.16% of the total essential oil contents were identified. The essential oil contained approximately 79.91% monoterpenoids and 18.25% sesquiterpenoids. α-Thujone (36.35%), β-thujone (9.37%), germacrene D (6.32%), 4-terpineol (6.31%), β-caryophyllene (5.43%), camphene (5.47%) and borneol (4.12%) were identified as the major constituents. The essential oil exhibited significant antifungal activity against Rhizoctonia solani (ED(50), 85.75 mg L(-1)), Sclerotium rolfsii (ED(50), 87.63 mg L(-1)) and Macrophomina phaseolina (ED(50), 93.23 mg L(-1)). This study indicated that A. nilagirica essential oil can be used to control phytopathogenic fungi infesting agricultural crops and commodities. 23932314 Polyacrylamide phantom for self-actuating needle-tissue interaction studies. This study presents a polyacrylamide gel as a phantom material for needle insertion studies specifically developed for self-actuating needles to enhance the precise placement of needles in prostate. Bending of these self-actuating needles within tissue is achieved by Nitinol actuators attached to the needle body; however these actuators usually involve heating that can thermally damage the tissue surrounding the needles. Therefore, to develop and access feasibility of these needles, a polyacrylamide gel has been developed that mimics the thermal damage and mechanical properties of prostate tissue. Mechanical properties of the polyacrylamide gel was controlled by varying the concentrations of acrylamide monomer and N,N-methylene-bisacrylamide (BIS) cross-linker, and thermal sensitivity was achieved by adding bovine serum albumin (BSA) protein. Two polyacrylamide gels with different concentrations were developed to mimic the elastic modulus of the tissue. The two phantoms showed different rupture toughness and different deflection of bevel-tip needle. To study the thermal damage, a Nitinol wire was embedded in the phantom and resistively heated. The measured opaque zone (0.40mm) formed around the wire was close to the estimated damage zone (0.43mm) determined using the cumulative equivalent minutes at 43°C. 23195331 αC helix displacement as a general approach for allosteric modulation of protein kinases. Owing to their crucial role in the modulation of cell pathways, protein kinases are important targets for several human diseases, including but not limited to cancer. The classic approach of targeting the ATP active site has recently come up against selectivity issues, which can be considerably reduced by following an allosteric modulation approach. Being closely related to protein kinase inactivation, allosteric targeting via displacement of the conserved structural αC helix enables a direct and specific modulation mechanism. A structure-based survey of the allosteric regulation of αC helix conformation in various kinase families is provided, highlighting key allosteric pockets and modulation mechanisms that appear to be more broadly conserved than was previously thought. 23909363 Reflection and refraction of flexural waves at geometric boundaries. We present a theory of flexural wave propagation on elastic shells having nontrivial geometry and develop an analogy to geometric optics. The transport of momentum within the shell itself is anisotropic due to the curvature, and as such complex classical effects such as birefringence are generically found. We determine the equations of reflection and refraction of such waves at boundaries between different local geometries, showing that waves are totally internally reflected, especially at boundaries between regions of positive and negative Gaussian curvature. We verify these effects by using finite element simulations and discuss the ramifications of these effects for the statistical mechanics of thin curved materials. 23845730 Measuring strain using digital image correlation of second harmonic generation images. The micromechanical environment of bone is crucial to understanding both bone fracture and mechanobiological responses of osteocytes, yet few techniques exist that are capable of measuring strains on the micrometer scale. A method for measuring micrometer level strains has been developed based on digital image correlation (DIC) of second harmonic generation microscopy (SHGM) images. Bovine tibias milled into thin sections were imaged using SHGM under loads of 0 and 15MPa. Strains were measured using DIC and compared to applied strain values. First and second principal strains decreased in magnitude as the analysis region area increased from 1750µm(2) to 60,920µm(2), converging to 1.23±0.74 and -0.745±0.9816 times the applied strain respectively. A representative sample histogram revealed regions of pure tensile and compressive strain, and that strains were highly heterogeneous ranging from 8410 to -8840 microstrain for an applied 2870 microstrain. Comparison with applied strain measures suggested that analysis sizes of 1750µm(2) and greater were measuring strains on the tissue scale, and higher resolution is required for collagen fibrillar strains. Regions of low SHGM intensity ("dark" regions) were seen which are believed to be lacunar and perilacunar regions of low collagen density. However, no significant differences in strain magnitude were present in dark regions versus regions of high signal intensity. The proposed technique is effective for strains on the size order of bone microarchitecture, and would be useful for studies into the mechanical microenvironment during loading. The technique also has potential for in vivo studies in small animal models. 23233343 An integrated assessment of sediment remediation in a midwestern U.S. stream using sediment chemistry, water quality, bioassessment, and fish biomarkers. A comprehensive biological, sediment, and water quality study of the lower Little Scioto River near Marion, Ohio, USA, was undertaken to evaluate the changes or improvements in biotic measurements following the removal of creosote-contaminated sediment. The study area covered 7.5 river miles (RMs), including a remediated section between RMs 6.0 and 6.8. Fish and macroinvertebrate assemblages, fish biomarkers (i.e., polycyclic aromatic hydrocarbon [PAH] metabolite levels in white sucker [Castostomus commersoni] and common carp [Cyprinus carpio] bile and DNA damage), sediment chemistry, and water quality were assessed at five locations relative to the primary source of historical PAH contamination-upstream (RM 9.2), adjacent (RM 6.5), and downstream (RMs 5.7, 4.4, and 2.7). Overall, the biomarker results were consistent with the sediment PAH results, showing a pattern of low levels of PAH bile metabolites and DNA damage at the upstream (reference or background location), as well as the remediated section, high levels at the two immediate downstream sites, and somewhat lower levels at the furthest downstream site. Results show that remediation was effective in reducing sediment contaminant concentrations and exposure of fish to PAHs and in improving fish assemblages (60% increase in index of biotic integrity scores) in remediated river sections. Additional remedial investigation and potentially further remediation is needed to improve the downstream benthic fish community, which is still heavily exposed to PAH contaminants. 23827342 Demographic characteristics and health-related quality of life of patients with moderate-to-severe psoriasis: The VACAP study. Psoriasis is associated with a deterioration in the health-related quality of life (HRQoL) of affected patients. The aim of this study was to assess the HRQoL of patients with moderate-to-severe psoriasis. A prospective observational study (the VACAP Study) was carried out in 123 centers in Spain with 1217 patients. Patients were evaluated at baseline (visit 1 [V1]) and again four months later (visit 2 [V2]). The severity of psoriasis was determined using the following indices: (i) Psoriasis Area and Severity Index (PASI) (score range 0-72, higher score indicates more severe disease), (ii) the body surface area (BSA) affected, and (iii) the Physicians Global Assessment (PGA) (range 1-7, higher score indicates more severe disease). Four questionnaires were used for the assessment of the HRQoL: (i) the Short-Form 36 quality-of-life questionnaire (SF-36) (score range 0-100, higher score indicates better HRQoL); (ii) Euroqol (EQ-5D) (range from 1 to 3, lower score indicates better HRQoL); (iii) Dermatology Life Quality Index (DLQI) (ranges 0-30; from best to worst HRQoL); and (iv) Psoriasis Disability Index (PDI) (ranges 0-45; higher score indicates better HRQoL). The mean (SD) age of the patients was 45.11 (13.92) years at V1. The mean age at the onset of psoriasis was 26.08 (14.19) years. The majority of patients were female (61%) and were employed (68%). The mean PASI score was 13.24 (9.50) at V1 and 5.07 (6.03) at V2 (P<.001). Scores from the generic HRQoL questionnaires (EQ-5D, SF-36) showed significant improvement between visits in all dimensions measured (P<.001). The disease-specific questionnaires also revealed overall improvements in quality of life over time: the DLQI mean total score was 8.97 (7.28) at V1 and 4.76 (5.72) at V2 (P<.001), and the PDI mean total score was 9.24 (8.76) V1 and 4.88 (6.65) at V2 (P<.001). Multivariate analysis using PDI as the dependent variable showed that the principal factors related to HRQoL were severity of psoriasis as measured by PASI (P<.001), and gender (P=.048). The principal factor related to HRQoL in patients with psoriasis is the severity of the disease. 23298268 Depressive symptoms moderate the effects of a self-discrepancy induction on overgeneral autobiographical memory. According to the CaRFAX model, rumination is one of the key underlying mechanisms of overgeneral autobiographical memory (OGM). The association between rumination and OGM is well established in clinical populations, but this relationship is not robust in nonclinical samples. A series of null findings is reported in the current paper. Additionally we followed up on recent findings suggesting that a state of rumination needs to be active in order to detect a relationship between trait-rumination and OGM. Secondary school students (N= 123) completed questionnaires assessing trait-rumination and depressive symptoms as well as two autobiographical memory tests (AMTs), one before and one after a self-discrepancy induction. This induction should trigger state-rumination, which would subsequently promote the retrieval of general rather than specific memories. Trait-rumination failed to predict increases in OGM. We did find, however, that higher BDI-II scores were positively related to an increase in OGM following the induction. This adds to the growing body of evidence that OGM reactivity might be more important than baseline memory specificity. 23871661 Comparison of dose-escalated, image-guided radiotherapy vs. dose-escalated, high-dose-rate brachytherapy boost in a modern cohort of intermediate-risk prostate cancer patients. We compared outcomes in intermediate-risk prostate cancer patients treated with dose-escalated adaptive image-guided radiation therapy (IGRT) or dose-escalated high-dose-rate brachytherapy boost (HDR-B). Patients with intermediate-risk prostate cancer by National Comprehensive Cancer Network criteria were treated with either CT-based off-line adaptive IGRT (n = 734) or HDR-B (n = 282). IGRT was delivered with 3D-conformal or intensity-modulated radiation therapy with a median dose of 77.4 Gy. For HDR-B, the whole pelvis received a median 46 Gy, and the prostate 2 implants of 9.5 Gy (n = 71), 10.5 Gy (n = 155), or 11.5 Gy (n = 56). Median followup was 3.7 years for IGRT and 8.0 years for HDR-B (p < 0.001). Eight-year biochemical control was 86% for IGRT and 91% for HDR-B (p = 0.22), disease-free survival 67% for IGRT and 79% for HDR-B (p = 0.006), and overall survival 75% for IGRT and 86% for HDR-B (p = 0.009). Cause-specific survival (8-year, 100% vs. 99%), freedom from distant metastases (98% vs. 97%), and freedom from local recurrence (98% vs. 98%) did not differ (p > 0.50 each). A worse prognosis group was defined by percent positive prostate biopsy cores >50%, perineural invasion, or stage T2b-c, encompassing 260 (35%) IGRT and 171 (61%) HDR-B patients. These patients evidenced a 5-year biochemical control of 96% for HDR-B and 87% for IGRT (p = 0.002). Dose-escalated IGRT and HDR-B both yield excellent clinical outcomes for patients with intermediate-risk prostate cancer. Improved biochemical control with HDR-B for patients with worse pretreatment characteristics suggests that a subgroup of intermediate-risk prostate cancer patients may benefit from dual-modality treatment. 23692346 Vitamin D levels during and after resolution of ketoacidosis in children with new onset Type 1 diabetes. To study the effect of ketoacidosis on measured 25-hydroxyvitamin D3 in children with new onset Type 1 diabetes. Measurement of pH and bicarbonate levels was carried out in children with newly diagnosed Type 1 diabetes at presentation with ketoacidosis. 25-hydroxyvitamin D3 estimation was carried out at presentation (timepoint 1) and 1 month later (timepoint 2). There was no significant difference in the mean (±sd) 25-hydroxyvitamin D3 levels [35.39 (±25.79) vs 39.63 (±48.03) nmol/L; P = 0.661) at the two timepoints in the study. Correlation analysis revealed a positive correlation between bicarbonate levels and timepoint 1, i.e. the lower the bicarbonate levels, the lower were the timepoint 1 levels and vice versa (correlation coefficient 0.538, P = 0.001). Timepoint 2 levels also showed a positive correlation with serum bicarbonate levels with a correlation coefficient of 0.379 (P = 0.032). None of the variables other than bicarbonate,.(age, gender, BMI, pH or time), was found to have the predictive ability for timepoint1 levels. Similarly for predicting timepoint 2 levels, BMI was found to have independent predictive ability in addition to bicarbonate. Severe ketoacidosis, as judged by bicarbonate but not pH, may transiently lower 25-hydroxyvitamin D3 levels in children with new onset Type 1 diabetes. Persistence of low 25-hydroxyvitamin D3 levels after resolution of ketoacidosis suggests a state of permanent vitamin D deficiency in our patient population. 23706476 Evaluating biomarkers of neuronal degeneration and neuroinflammation in CSF of patients with multiple sclerosis-osteopontin as a potential marker of clinical severity. Biomarkers capable of predicting the clinical course and the rate of disease progression in multiple sclerosis are currently unavailable. Our objective was to examine if the levels of proteins associated with axonal and neuronal degeneration (Tau, p-Tau and β-amyloid(1-42)) and T-cell-mediated autoimmunity (osteopontin) are altered in the cerebrospinal fluid (CSF) of MS patients, and to assess their potential in reflecting the clinical severity and predicting the progression and clinical evolution of early MS. The CSF samples collected from patients presenting with different clinical forms of MS were evaluated by enzyme-linked immunosorbent assays. The patients were regularly followed-up and their clinical status was re-evaluated 5 years after sampling. The results demonstrated that while CSF levels of Tau, p-Tau and β-amyloid(1-42) did not differ between MS and Control groups, the levels of osteopontin were significantly elevated in MS patients. This increase was associated with the presence of a relapse and correlated with clinical severity, which findings were independent of age and blood-CSF barrier function. However, none of the examined protein levels differed significantly between groups with different clinical evolutions and no positive correlations with clinical progression could be detected. We conclude that Tau, p-Tau and β-amyloid(1-42) are inappropriate as biomarkers in MS. This is the first report on CSF osteopontin as an independent marker of clinical severity in definite MS. 23591481 Fully automatic segmentation of the proximal femur using random forest regression voting. Extraction of bone contours from radiographs plays an important role in disease diagnosis, preoperative planning, and treatment analysis. We present a fully automatic method to accurately segment the proximal femur in anteroposterior pelvic radiographs. A number of candidate positions are produced by a global search with a detector. Each is then refined using a statistical shape model together with local detectors for each model point. Both global and local models use Random Forest regression to vote for the optimal positions, leading to robust and accurate results. The performance of the system is evaluated using a set of 839 images of mixed quality. We show that the local search significantly outperforms a range of alternative matching techniques, and that the fully automated system is able to achieve a mean point-to-curve error of less than 0.9 mm for 99% of all 839 images. To the best of our knowledge, this is the most accurate automatic method for segmenting the proximal femur in radiographs yet reported. 23802672 Endoscopic ultrasonographic evaluation of the esophagus in healthy dogs. To characterize the ultrasonographic appearance of the canine esophagus. 14 healthy Beagles. Endoscopic ultrasonography (EUS) examinations were performed with a radial ultrasonographic gastrovideoscope in anesthetized dogs. Images were obtained at 3-cm intervals along the esophageal length to allow evaluation of the esophageal wall. Images were obtained with the probe in direct contact with the esophageal wall and with a water-filled balloon as a standoff. Images were obtained with (12 dogs) and without (10) the water-filled balloon. Median thickness of the esophageal wall was 2.19 mm (range, 1.03 to 5.62 mm) in the proximal third of the esophagus, 2.15 mm (range, 1.10 to 4.45 mm) in the middle third, and 2.84 mm (range, 1.35 to 5.92 mm) in the distal third. Wall thickness differed significantly between proximal and distal thirds. Results were similar when the water-filled balloon was used. Esophageal wall layers appeared as 5 alternating hyperechoic and hypoechoic bands that could not be consistently identified in all dogs. All layers could be identified in 26 of 198 (13%) images, 3 layers could be identified in 67 of 198 (34%) images, and 105 of 198 (53%) images had no layers. Visual identification of layers in images obtained with and without the balloon did not differ significantly. EUS appeared to be a useful technique for assessing esophageal wall integrity in dogs; however, complete evaluation of all layers could not be accomplished in all instances. Further studies with this technique in dogs are needed. 23880606 Cross-linked glucose oxidase clusters for biofuel cell anode catalysts. The efficient localization of increased levels of active enzymes onto conducting scaffolds is important for the development of enzyme-based biofuel cells. Cross-linked enzyme clusters (CEC) of glucose oxidase (GOx) constrained to functionalized carbon nanotubes (CEC-CNTs) were generated in order to evaluate the potential of using CECs for developing GOx-based bioanodes functioning via direct electron transfer from the GOx active site to the CNT scaffold. CEC-CNTs generated from several weight-to-weight ratios of GOx:CNT were examined for comparable catalytic activity to free GOx into the solution, with CEC-CNTs generated from a 100% GOx solution displaying the greatest enzymatic activity. Scanning transmission electron microscopic analysis of CEC-CNTs generated from 100% GOx to CNT (wt/wt) ratios revealed that CEC clusters of ∼78 µm(2) localized to the CNT surface. Electrochemical analysis indicates that the enzyme is engaged in direct electron transfer, and biofuel cells generated using GOx CEC-CNT bioanodes were observed to have a peak power density of ∼180 µW cm(-2). These data indicate that the generation of nano-to-micro-sized active enzyme clusters is an attractive option for the design of enzyme-specific biofuel cell powered implantable devices. 23899367 A General Approach to Spindle-Assembled Lanthanide Borate Nanocrystals and Their Photoluminescence upon Eu(3+)/Tb(3+) Doping. Uniform-assembled lanthanide borate nanocrystals have been synthesized via a facile self-assembly process under hydrothermal conditions. All of the prepared lanthanide borate assemblies exhibit a spindle-like profile despite the fact that they belong to different crystal systems and have different formulas for composition. Each assembly is composed of small nanocrystals that are tightly attached along with their lateral surfaces. X-ray diffraction, scanning electron microscopy, and transmission electron microscopy have been used to characterize the structure and morphology of these samples. The mechanism responsible for the growth and assembly of these lanthanide borate assemblies is also demonstrated. After Eu(3+) and/or Tb(3+) ions are doped inside these assemblies, strong and multicolor emissions can be realized. Notably, tunable emission and a warm-white color can be achieved in the Eu(3+)/Tb(3+) codoped samples. 23726360 The contribution of chemical bonding to the short- and long-term enamel bond strengths. MDP (10-methacryloyloxydecyl dihydrogenphosphate) has been proven to possess chemical bonding ability to tooth hard tissues, but its contribution to the enamel bond strength has not been recognized. The aim of this study was to investigate the contribution of chemical bonding to the short- and long-term bovine enamel micro-tensile bond strengths (μTBS). The acid-etched enamel surfaces were treated without any primer (control) or with one of three MDP-containing primers (containing different ratio of MDP/HEMA/Bis-GMA, Kuraray Co.) for 5s, water-sprayed and air-dried. Subsequently, the pretreated enamel surfaces were applied with an etch-and-rinse adhesive Durafill Bond (Heraeus Kulzer) and placed with composite resin Durafill VS (Heraeus Kulzer). The specimens were prepared for μTBS tests after 24-h or 1-yr water storage. The etched enamel surfaces treated with or without MDP-containing primers were analyzed by scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). The acid-etched enamel treated with the MDP-primers for a very short time could produce the greater enamel μTBS than the control did (p<0.05), and change enamel micromorphology. No significant different μTBS were found between 24-h and 1-yr water storage (p>0.05). The chemical bonding of MDP on the enamel surfaces was re-confirmed by XPS. The additional chemical bonding of MDP around the enamel crystallites of the etched enamel substrate could significantly increase the short- and long-term enamel μTBS, and their μTBS surpass those of the etch-and-rinse adhesive alone. 23885936 Aneurysmal disease: thoracic aorta. Thoracic aortic aneurysms are clinically significant for their high mortality risk in the face of rupture. This article reviews the natural history and pathophysiology of thoracic and thoracoabdominal aortic aneurysms, discusses the evaluation of these patients, and details the treatment options. Specifically discussed are treatment advances arising from the development of endovascular technology. 22931530 α-Amino-α´-Halomethylketones: Synthetic Methodologies and Pharmaceutical Applications as Serine and Cysteine Protease Inhibitors. α-Amino-α´-halomethylketones are interesting scaffolds bearing (at least) two sequential electrophilic carbons that by interacting with the nucleophilic moieties of several enzymes, represent the ideal candidates for in vivo and in vitro inhibition studies. In this work a summary of their use as optimal inhibitors of physiologically relevant serine and cysteine proteases is given with a particular emphasis on recently established SAR studies. A brief survey of the most relevant synthetic processes for their obtainment and the importance they possess in synthetic medicinal chemistry is reported. 23946344 Vitamin E Secretion by Caco-2 Monolayers to APOA1, But Not to HDL, Is Vitamer Selective. The aim of this study was to characterize the pathways of basolateral secretion of common dietary tocopherols from polarized Caco-2 monolayers, a model of intestinal absorption. Given differences in structure and physical properties, we hypothesized that secretion may differ between different forms of vitamin E, thus potentially contribute to the selectivity seen in vivo. Monolayers were incubated apically and simultaneously with 10 μmol/L α-, γ-, and δ-tocopherol (1:1:1) in lipid micelles. Treatment with the microsomal triglyceride transfer protein inhibitor BMS201038 revealed that the triglyceride-rich particle secretory pathway (apolipoprotein B-dependent pathway) accounted for ∼80% of total tocopherol secretion, without selectivity among the three forms of vitamin E. Apolipoprotein B-independent secretion of tocopherols (and cholesterol) was greatly enhanced by the liver X receptor agonist T0901317. T0901317 induced ATP-binding cassette transporter A1 (ABCA1) protein expression and basolateral secretion of tocopherols to apolipoprotein A1. ABCA1-dependent secretion demonstrated vitamer selectivity such that efficiency of secretion of α- and γ-tocopherols exceeded that of δ-tocopherol. Basal addition of HDL stimulated vitamin E secretion but without selectivity among the three forms, whereas LDL had no effect. Basal addition of scavenger receptor class B member I (SR-BI) blocking antibody, which inhibits the interaction between SR-BI and HDL, increased basal accumulation of all tocopherols, demonstrating a role for SR-BI in cellular re-uptake of secreted vitamin E. These findings demonstrated that vitamin E and cholesterol utilize common pathways of secretion and that secretion via the ABCA1 pathway favors certain forms of vitamin E. 23857112 Bioactive compounds offered in microcapsules to determine the nutritional value of copepods' natural diet. Experiments were performed, feeding Calanus pacificus seston and a food consisting of seston and microcapsules (μ-caps), i.e., protein and lipid μ-caps to test for potential biochemical limitation. Seston was collected off Scripps Pier (La Jolla, CA, USA). Whereas protein μ-caps were too small to be efficiently ingested, lipid μ-caps rich in ω3-highly-unsaturated fatty acids (ω3-HUFA) were ingested similarly to natural seston and lipids were assimilated. However, egg production experiments exhibited that animals fed with lipid μ-caps didn't produce significantly more eggs than with seston of equal carbon concentration and egg production even declined when the diet consisted of 50% lipid μ-caps. Thus, the content of certain ω3-HUFA seemed to have been sufficiently high in seston to prevent limitation. Algal counts revealed that seston consisted mainly of plankton rich in those fatty acids, such as cryptophytes, dinoflagellates, diatoms, and ciliates in the edible size range. This might be characteristic for upwelling systems like the area off Southern California which are known for high trophic transfer efficiency. 23519590 The effects of autobiographic sexual memory recall on the sexual response of sexually functional men. In this experimental study, we investigated how recalling positive, negative, and affectively neutral autobiographic sexual experiences in their personal history affected the current sexual response of sexually functional male volunteers. Based on an attentional-capacity account of sexual arousal, we predicted that affectively charged autobiographic sexual memory recall, both with negative and positive valence, would negatively impact genital arousal, compared to recalling affectively neutral sexual experiences. We expected that subjective sexual arousal would not be differentially affected by emotional memory valence. We measured subjective and genital response to erotic video fragments in sexually functional volunteers (N = 24) in a within-subjects, repeated-measures design. For the memory manipulation, participants received instructions to visualize and mentally re-experience positive, negative, and neutral sexual episodes from autobiographic memory. Memory instructions were found to result in the expected affective states. As predicted, compared to recalling neutral memory, mean genital response was significantly lower during recalling positive and negative memory. However, contrary to prediction, subjective sexual arousal was affected, when multilevel analysis was performed, including a time effect. The implications of the findings were discussed with respect to the advancement of theory and therapeutic intervention. 23467673 Theoretical realization of robust broadband transparency in ultrathin seamless nanostructures by dual blackbodies for near infrared light. We propose a counter-intuitive mechanism of constructing an ultrathin broadband transparent device with two perfect blackbodies. By introducing hybridization of plasmon modes, resonant modes with different symmetries coexist in this system. A broadband transmission spectrum in the near infrared regime is achieved through controlling their coupling strengths, which is governed by the thickness of high refractive index layer. Meanwhile, the transparency bandwidth is found to be tunable in a large range by varying the geometric dimension. More significantly, from the point view of applications, the proposed method of achieving broadband transparency can perfectly tolerate the misalignment and asymmetry of periodic nanoparticles on the top and bottom, which is empowered by the unique dual of coupling-in and coupling-out processes within the pair of blackbodies. Moreover, roughness has little influence on its transmission performance. According to the coupled mode theory, the distinguished transmittance performance is physically interpreted by the radiative decay rate of the entire system. In addition to the feature of uniquely robust broadband transparency, such a ultrathin seamless nanostructure (in the presence of a uniform silver layer) also provides polarization-independent and angle-independent operations. Therefore, it may power up a wide spectrum of exciting applications in thin film protection, touch screen techniques, absorber-emitter transformation, etc. 23665365 Glycemic control and risk of cardiovascular disease hospitalization and all-cause mortality. This study sought to evaluate the relationship between glycemic control and cardiovascular disease (CVD) hospitalizations and all-cause mortality among patients with type 2 diabetes in a real-world setting. Clinical trials have not established that tight glycemic control reduces CVD events and may be associated with increased mortality. Observational studies of specific cohorts have reported increased risk of those outcomes at both high and low glycosylated hemoglobin (HbA1c) levels. Using the mean of all HbA1c measures over a mean follow-up of 6 years, we created categories of HbA1c (<6.0%, 6.0% to 6.4%, 6.5% to 6.9%, 7.0% to 7.4%, 7.5% to 7.9%, 8.0% to 8.4%, 8.5% to 8.9%, and ≥ 9.0%) to estimate the risk of CVD hospitalization and all-cause mortality associated with glycemic control, adjusting for demographic and clinical characteristics among 26,673 members of Kaiser Permanente Northwest with type 2 diabetes. Compared with patients with mean HbA1c levels 7.0% to 7.4%, those with mean HbA1c levels <6.0% had a 68% increased risk of CVD hospitalization (hazard ratio [HR]: 1.68 [95% confidence interval (CI): 1.39 to 2.04], p < 0.001) after adjustment for demographic and clinical characteristics. Those with HbA1c levels 6.0% to 6.4% (HR: 1.18 [95% CI: 1.00 to 1.40], p = 0.048) and 6.5% to 6.9% (HR: 1.18 [95% CI: 1.02 to 1.37], p = 0.031) also had significantly higher risk relative to the reference group of 7.0% to 7.4%, as did patients with HbA1c levels 8.5% to 8.9% (HR: 1.55 [95% CI: 1.24 to 1.94], p < 0.001) and ≥ 9.0% (HR: 1.83 [95% CI: 1.50 to 2.22], p < 0.001). Risk of all-cause mortality was significantly greater than the reference group among HbA1c categories <6.0%, 6.0% to 6.4%, 6.5% to 6.9%, and ≥ 9.0%. The relationship between mean HbA1c and CVD hospitalizations and all-cause mortality was U-shaped, with greater risk at both higher and lower HbA1c levels. 23768477 Spontaneous resolution of macular detachment associated with optic disc coloboma. CASE REPORT: A 24-year-old male presented with visual acuity loss of the right eye. Examination of the right eye fundus showed a serous detachment of the posterior pole associated with optic disc coloboma. The patient refused surgical treatment. After six months an improvement in visual acuity was observed with the disappearance of macular subretinal fluid. DISCUSSION: The macular detachment is a known complication of the optic disc coloboma. Different therapeutic options have been used, although spontaneous re-attachment may also occur as shown in this case. 23519267 Blood flow and stem cells in vascular disease. It is well known that the altered blood flow is related to vascular diseases, including atherosclerosis, restenosis, and arteriosclerosis, which preferentially located at areas with the disturbed blood flow, suggesting that altered biomechanical stress may exert their effect on the vascular disease. Recent evidence indicated the presence of abundant stem/progenitor cells in the vessel wall, in which laminar shear stress can stimulate these cells to differentiate towards endothelial lineage, while cyclic strain results in smooth muscle differentiation. In line with this, it was evidenced that altered biomechanical stress in stented vessels may lead to 'wrong' direction of vascular stem cell differentiation resulting in restenosis. However, the underlying mechanisms are not well understood. In this article, we will give an overview of the effect of the local flow pattern on stem/progenitor cell differentiation and the possible mechanism on how the blood flow influences stem cell behaviours in the development of vascular diseases. 23917400 Graphene interconnects fully encapsulated in layered insulator hexagonal boron nitride. We demonstrate improvements in the electrical performance of graphene interconnects with full encapsulation by lattice-matching layered insulator, hexagonal boron nitride (h-BN). A novel layer-based transfer method is developed to assemble the top passivating layer of h-BN on the graphene surface to construct the h-BN/graphene/h-BN heterostructures. The encapsulated graphene interconnects (EGIs) are characterized and compared with graphene interconnects on either SiO2 or h-BN substrates with no top passivating h-BN layer. We observe significant improvements in both the maximum current density and breakdown voltage in EGIs. Compared with the uncovered structures, EGIs also show an appreciable increase (∼67%) in power density at breakdown. These improvements are achieved without degrading the carrier transport characteristics in graphene wires. In addition, EGIs exhibit a minimal environment impact, showing electrical behavior insensitive to ambient conditions. 23815884 Newborn genetic screening for high risk deafness-associated mutations with a new Tetra-primer ARMS PCR kit. Previous epidemiological studies indicate that GJB2, SLC26A4 or mtDNA 12S rRNA mutations were chiefly responsible for the hearing loss in children. A cost-effective method for screening deafness-associated mutations at early age is needed. This study aimed to develop a simple kit for screening of high risk deafness-associated mutations in newborns using tetra-primer amplification refractory mutation system PCR. The screening kit was designed to detect high risk deafness-associated mutations (GJB2 c.235delC, SLC26A4 c.919-2A>G, mtDNA 12S rRNA mt.1555A>G and mt.1494C>T). The kit was able to amplify both wild-type and mutant alleles with a control fragment. The proposed method was conducted to genotype the above four deafness gene mutations in four PCR reactions. Each mutation was genotyped by a set of four primers, two allele-specific inner primers, and two common outer primers. A mismatch at the penultimate or antepenult nucleotide of the 3' terminus was introduced in order to maximize specificity. The 16 primers were used for the amplification of genomic DNA as a template. Amplified fragments were separated by electrophoresis. We designed and validated the kit with wild and mutant type DNA samples that had been previously been confirmed by Sanger sequencing. Then 1181 newborns were enrolled, and those samples with mutations were further validated with sequencing too. Among 1181 newborns, 29 individuals had one or two mutant alleles, with the carrier rate being 2.46% (29/1181). For GJB2 c.235delC mutation, one case was homozygote and 12 cases were heterozygote carriers. For SLC26A4 c.919-2A>G mutation, 12 cases were heterozygotes carriers, and no homozygotes were found; for mtDNA 12S rRNA mt.1555A>G mutation, one case was identified; three cases of mtDNA 12S rRNA mt.1494C>T mutation were detected. All mutations were detected with high specificity. Mutation samples were confirmed via Sanger sequencing. No false positive was found. A user-friendly screening kit for deafness-associated mutations was successfully developed. It provided rapid, reproducible, and cost-effective detection of deafness gene mutation without special equipment. The kit allowed the detection of the four high risk deafness-associated mutations with only 4 single tube PCR reactions. In the future, the kit could be applied to large population-based epidemiological studies for newborn hearing defects screening. 23826595 Hepatitis C--an update. Chronic hepatitis C (CHC) infection remains a significant health issue. Most patients are asymptomatic, but long term infection may cause liver failure, liver cancer, and death. Projections estimate that these complications will triple by 2020. Chronic hepatitis C infection is curable, and successful viral eradication reduces liver related complications. The landscape of CHC therapy is rapidly changing. This article outlines the incidence, prevalence and natural history of CHC, and provides information that may assist the general practitioner in the assessment and management of CHC patients. Chronic hepatitis C infection is under-diagnosed and may lead to significant morbidity and mortality. Currently, only 1.3% of cases are being treated. The GP plays an important role in diagnosing CHC, and provides a unique opportunity to screen patients with risk factors and refer for treatment. The first direct-acting antivirals have recently been approved, and combination all-oral therapy (interferon free) is expected in 3-5 years. Hence, all patients with CHC should be referred for treatment consideration. 23828573 ifn-γ-dependent secretion of IL-10 from Th1 cells and microglia/macrophages contributes to functional recovery after spinal cord injury. Transfer of type-1 helper T-conditioned (Th1-conditioned) cells promotes functional recovery with enhanced axonal remodeling after spinal cord injury (SCI). This study explored the molecular mechanisms underlying the beneficial effects of pro-inflammatory Th1-conditioned cells after SCI. The effect of Th1-conditioned cells from interferon-γ (ifn-γ) knockout mice (ifn-γ(-/-) Th1 cells) on the recovery after SCI was reduced. Transfer of Th1-conditioned cells led to the activation of microglia (MG) and macrophages (MΦs), with interleukin 10 (IL-10) upregulation. This upregulation of IL-10 was reduced when ifn-γ(-/-) Th1 cells were transferred. Intrathecal neutralization of IL-10 in the spinal cord attenuated the effects of Th1-conditioned cells. Further, IL-10 is robustly secreted from Th1-conditioned cells in an ifn-γ-dependent manner. Th1-conditioned cells from interleukin 10 knockout (il-10(-/-)) mice had no effects on recovery from SCI. These findings demonstrate that ifn-γ-dependent secretion of IL-10 from Th1 cells, as well as native MG/MΦs, is required for the promotion of motor recovery after SCI. 23865846 Expression and functional relevance of UGT1A4 in a cohort of human drug-resistant epileptic brains. Brain drug bioavailability is regulated by the blood-brain barrier (BBB). It was recently suggested that cytochrome P450 (CYP) enzymes could act in concert with multidrug transporter proteins to regulate drug penetration and distribution into the diseased brain. The possibility that phase II metabolic enzymes could be expressed in the epileptic brain has been not evaluated. Phase II enzymes are involved in the metabolism of common antiepileptic drugs (AEDs). Phase II enzyme UGT1A4 brain expression was evaluated in temporal lobe resections from patients with epilepsy. UGT1A4 expression was determined by western blot and immunocytochemistry in primary cultures of human drug-resistant brain endothelial human brain epileptic endothelial cells (EPI-EC)s and commercially available control cells human brain microvascular endothelial cells (HBMECs). Lack of DNA condensation measured by 4',6-diamidino-2-phenylindole (DAPI) was used as a surrogate marker of cell viability and was correlated to UGT1A4 expression high performance liquid chromatography ultraviolet detection (HPLC-UV) was used to quantify lamotrigine metabolism by EPI-EC and HBMEC. The appearance of the specific lamotrigine metabolite, 2-n glucuronide (MET-1), was also evaluated. Lamotrigine and MET-1 levels were measured in selected surgical brain and matched blood samples. UGT1A4 expression was observed in BBB endothelial cells and neurons. Our quantification study revealed variable levels of UGT1A4 expression across the brain specimens analyzed. Neurons devoid of UGT1A4 expression displayed nuclear DAPI condensation, a sign of cellular distress. UGT1A4 overexpression in EPI-EC, as compared to HBMEC, was reflected by a proportional increase in lamotrigine metabolism. The lamotrigine metabolite, MET-1, was formed in vitro by EPI-EC and, to a lesser extent, by HBMEC. HPLC-UV measurements of brain and blood samples obtained from patients receiving lamotrigine prior to surgery revealed the presence of lamotrigine and its metabolites in the brain. These initial results suggest the presence of a phase II enzyme in the epileptic brain. Further studies are required to fully describe the pattern of brain UGT1A4 expression in relation to clinical variables and drug resistance. 23729355 Hispanic ethnicity and acculturation, maternal age and the risk of gastroschisis in the national birth defects prevention study. Studies indicate that gastroschisis is associated with maternal age, ethnicity, and acculturation. This analysis was conducted to further define the associations between gastroschisis and parental Hispanic ethnicity and acculturation, and to determine whether such associations vary by maternal age. This study was based on data from mothers of 753 gastroschisis cases and 6,496 control infants in the National Birth Defects Prevention Study. The relationships between gastroschisis and both parental Hispanic ethnicity and acculturation, within maternal age strata (<20 versus ≥20 years at conception), were assessed using logistic regression and principal component analyses. The risk of gastroschisis in offspring of women <20 years old was not significantly associated with parental Hispanic ethnicity or acculturation. Among mothers ≥20 years old, US-born non-Hispanic white parents had a lower risk of gastroschisis in offspring as compared to either US-born Hispanic (odds ratios [ORs] ranging from 0.55 to 0.60) or English-speaking Hispanic (ORs ranging from 0.58 to 0.65) parents. Further, compared with US born Hispanic women ≥20 years, the risk of gastroschisis was lower for Hispanic women who had lived in the US <5 years (OR=0.35, 95% confidence interval [CI]: 0.17, 0.74) or who migrated to the US at ≥20 years (OR=0.47, 95% CI: 0.25, 0.88). These results provide further evidence that gastroschisis risk is associated with ethnicity and some aspects of acculturation. Additionally, these associations were limited to the offspring of women who are ≥20 at the time of conception. Birth Defects Research (Part A) 97:538-545, 2013. © 2013 Wiley Periodicals, Inc. 23871002 GFAAS determination of mercury in muscle samples of fish from Amazon, Brazil. In the present study, a simple, rapid and sensitive method was developed for the determination of mercury concentrations in the muscle tissue of fish from the Brazilian Amazon using graphite furnace atomic absorption spectrometry (GFAAS) following acid mineralization of the samples in an ultrasonic cold water bath. Using copper nitrate as a chemical modifier in solution and sodium tungstate as permanent modifier, we were able to attain thermal stabilization of the mercury up to the atomisation temperature of 1600°C in the GFAAS assay. The calculated limits of detection (LOD) and quantification (LOQ) were 0.014 and 0.047mgkg(-1), respectively. 23436656 The Overexpression of Hypomethylated miR-663 Induces Chemotherapy Resistance in Human Breast Cancer Cells by Targeting Heparin Sulfate Proteoglycan 2 (HSPG2). MicroRNAs are involved in regulating the biology of cancer cells, but their involvement in chemoresistance is not fully understood. We found that miR-663 was up-regulated in our induced multidrug-resistant MDA-MB-231/ADM cell line and that this up-regulation was closely related to chemosensitivity. In the present study, we aimed to clarify the role of miR-663 in regulating the chemoresistance of breast cancer. MicroRNA microarray and quantitative RT-PCR assays were used to identify differentially expressed microRNAs. Cell apoptosis was evaluated by annexin V/propidium iodide staining, TUNEL, and reactive oxygen species generation analysis. The expression of miR-663 and HSPG2 in breast cancer tissues was detected by in situ hybridization and immunohistochemistry. The potential targets of miR-663 were defined by a luciferase reporter assay. Bisulfite sequencing PCR was used to analyze the methylation status. We found that miR-663 was significantly elevated in MDA-MB-231/ADM cells, and the down-regulation of miR-663 sensitized MDA-MB-231/ADM cells to both cyclophosphamide and docetaxel. The overexpression of miR-663 in breast tumor tissues was associated with chemoresistance; in MDA-MB-231 cells, this chemoresistance was accompanied by the down-regulation of HSPG2, which was identified as a target of miR-663. MDA-MB-231/ADM contained fewer methylated CpG sites than its parental cell line, and miR-663 expression in MDA-MB-231 cells was reactivated by 5-aza-29-deoxycytidine treatment, indicating that DNA methylation may play a functional role in the expression of miR-663. Our findings suggest that the overexpression of hypomethylated miR-663 induced chemoresistance in breast cancer cells by down-regulating HSPG2, thus providing a potential target for the development of an microRNA-based approach for breast cancer therapy. 23127656 Integrating forensic information in a crime intelligence database. Since 2008, intelligence units of six states of the western part of Switzerland have been sharing a common database for the analysis of high volume crimes. On a daily basis, events reported to the police are analysed, filtered and classified to detect crime repetitions and interpret the crime environment. Several forensic outcomes are integrated in the system such as matches of traces with persons, and links between scenes detected by the comparison of forensic case data. Systematic procedures have been settled to integrate links assumed mainly through DNA profiles, shoemarks patterns and images. A statistical outlook on a retrospective dataset of series from 2009 to 2011 of the database informs for instance on the number of repetition detected or confirmed and increased by forensic case data. Time needed to obtain forensic intelligence in regard with the type of marks treated, is seen as a critical issue. Furthermore, the underlying integration process of forensic intelligence into the crime intelligence database raised several difficulties in regards of the acquisition of data and the models used in the forensic databases. Solutions found and adopted operational procedures are described and discussed. This process form the basis to many other researches aimed at developing forensic intelligence models. 23826747 The Spectrum of β-Thalassemia Mutations In Baghdad, Central Iraq. While previous studies from Iraq have focused on β-thalassemia (β-thal) mutations in the northern part of the country, inhabited mainly by Kurds, no study of significance has looked at these mutations in central or southern Iraq, which is inhabited by the Arab majority. For the latter purpose this study was initiated and 103 β-thal carriers from Baghdad at the center of the country were investigated using multiplex polymerase chain reaction (PCR) and reverse hybridization followed by sequencing. The results revealed that a total of 17 mutations were implicated, six of which, IVS-I-110 (G>A), IVS-II-1 (G>A), IVS-I-5 (G>C), codons 8/9 (+G), IVS-I-I (G>A) and codon 44 (-C), constituted 78.0% of the mutations characterized. Among the 17 mutations identified, six are reported for the first time from Iraq and include: IVS-I, 25 bp deletion, IVS-II-848 (C>A), -28 (A>C), IVS-I-130 (G>C), IVS-I-128 (T>G) and codons 41/42 (-TTCT). The findings of the current study clearly illustrate the genetic heterogeneity of the population of central Iraq, as demonstrated by the presence of a combination of Mediterranean, Asian Indian, Kurdish, Iranian, Egyptian, Saudi Arabian and Turkish mutations that is reflective of the historical background of this part of the country. 23790284 A potential tool for high-resolution monitoring of ocean acidification. Current anthropogenic carbon dioxide emissions generate besides global warming unprecedented acidification rates of the oceans. Recent evidence indicates the possibility that ocean acidification and low oceanic pH may be a major reason for several mass extinctions in the past. However, a major bottleneck for research on ocean acidification is long-term monitoring and the collection of consistent high-resolution pH measurements. This study presents a low-power (<1 W) small sample volume (25 μL) semiconductor based fluorescence method for real-time ship-board pH measurements at high temporal and spatial resolution (approximately 15 s and 100 m between samples). A 405 nm light emitting diode and the blue and green channels from a digital camera was used for swift detection of fluorescence from the pH sensitive dye 6,8-Dihydroxypyrene-1,3-disulfonic acid in real-time. Main principles were demonstrated by automated continuous measurements of pH in the surface water across the Baltic Sea and the Kattegat region with a large range in salinity (~3-30) and temperature (~0-25°C). Ship-board precision of salinity and temperature adjusted pH measurements were estimated as low as 0.0001 pH units. 23877320 Medical staff extremity dosimetry in CT fluoroscopy: an anthropomorphic hand voxel phantom study. This work aims to contribute to the study of the radiation dose distribution delivered to the hands of medical staff members during a general computed tomographic (CT) fluoroscopic guided procedure. In this study, both Monte Carlo simulations and measurements were performed. For free-in-air and computed tomography dose index (CTDI) body phantom measurements, a standard pencil ionization chamber (IC) 100 mm long was used. The CT scanner model was implemented using MCNPX (Monte Carlo N-Particle eXtended) and was successfully validated by comparing the simulated results with measurements. Subsequently, CT images of a hand, together with an anthropomorphic phantom, were voxelized and used with the MCNPX code for dose calculations. The hand dose distribution study was performed both by using thermo-luminescent detector measurements and Monte Carlo simulations. The validated simulation tool provides a new perspective for detailed investigations of CT-irradiation scenarios. Simulations show that there is a strong dose gradient, namely the even zones of the hand that are in precise vicinity to the x-ray beam only receive about 4% of the maximum dose delivered to adjacent areas which are directly exposed to the primary x-ray beam. Finally, the scatter contribution of the patient was also studied through MC simulations. The results show that for directly exposed parts of the hand surface, the dose is reduced by the body of the patient (due to the shielding), whereas the dose is increased by scattered radiation from the patient for parts of the skin that receive scattered radiation only. 23683584 Advanced diagnostics applied to fish liver tumours: relating pathology to underlying molecular aetiology. Liver tumours in flatfish have been diagnosed using histopathology for decades in order to monitor the impacts of marine pollution in coastal and estuarine environments. This traditional method has been coupled with molecular analyses of tumours in the liver of the dab, Limanda limanda, in order to elucidate underpinning molecular level aetiology of such disease. A laser capture microdissection technique for molecular investigation of cancer has been applied in fish. The present study provides optimized steps for environmental sample utilisation: a procedure for field sample collection and handling; a method allowing reliable identification of lesions on frozen tissue sections; and, downstream molecular analyses of tumourigenesis markers (retinoblastoma gene) in laser microdissected samples. This approach facilitates the use of wild flatfish as a model of environmentally-induced tumourigenesis, and has wide applicability to any disease pathology for which the underpinning molecular aetiology is required. 23824375 Pasteurella multocida: from zoonosis to cellular microbiology. In a world where most emerging and reemerging infectious diseases are zoonotic in nature and our contacts with both domestic and wild animals abound, there is growing awareness of the potential for human acquisition of animal diseases. Like other Pasteurellaceae, Pasteurella species are highly prevalent among animal populations, where they are often found as part of the normal microbiota of the oral, nasopharyngeal, and upper respiratory tracts. Many Pasteurella species are opportunistic pathogens that can cause endemic disease and are associated increasingly with epizootic outbreaks. Zoonotic transmission to humans usually occurs through animal bites or contact with nasal secretions, with P. multocida being the most prevalent isolate observed in human infections. Here we review recent comparative genomics and molecular pathogenesis studies that have advanced our understanding of the multiple virulence mechanisms employed by Pasteurella species to establish acute and chronic infections. We also summarize efforts being explored to enhance our ability to rapidly and accurately identify and distinguish among clinical isolates and to control pasteurellosis by improved development of new vaccines and treatment regimens. 23969583 Do Additional Recontacts to Increase Response Rate Improve Physician Survey Data Quality? Although response rates for physician surveys have been decreasing, it is not clear whether this trend is associated with an increase in survey nonresponse bias. One means for assessing potential bias is to conduct a level-of-effort analysis that compares data estimates for respondents interviewed during the first recruitment contact to respondents interviewed at later recontact cycles. We compared early and later responders within the Survey of Physician Attitudes Regarding the Care of Cancer Survivors with respect to both demographic characteristics and aggregate survey responses to items on survivor care knowledge, attitudes, and practices. Accumulating additional completions across each of 4 respondent contact attempts improved weighted response rates (35.0%, 46.9%, 52.3%, and 57.6%, respectively). However, the majority of estimates for analyzed variables remained relatively unchanged over additional cycles of recontact. We conclude that additional respondent recontact attempts, especially beyond a single recontact, had little influence on key data distributions, suggesting that these were ineffective in reducing nonresponse bias. Further, the conduct of additional recruitment recontacts was an inefficient means for increasing statistical power. For the conduct of physician surveys, a practice that may in some cases be cost-effective, while also controlling total survey error, is to establish a larger initial sample; to either eliminate nonresponse follow-up or to limit this to one recontact; and to accept a somewhat lower final overall survey response rate. 23525773 Development and validation of potential structure indicators for evaluating antimicrobial stewardship programmes in European hospitals. This study describes the development of structure indicators for hospital antimicrobial stewardship programmes and pilot validation across European hospitals. A multi-disciplinary panel from four European countries developed structure indicators in three steps: identification and listing of indicators, remote ranking of indicators using multi-criteria scoring, selection of indicators in a face-to-face consensus meeting. Additionally, the top-ten indicators were identified as a minimal set of key indicators. A survey was sent to the directors of antimicrobial stewardship programmes in European hospitals. The yes/no answers for the indicators were transformed into numbers in order to calculate the total scores. A list of 58 indicators was selected and categorised into the following topics: antimicrobial stewardship services (12 items), tools (16 items), human resources and mandate (6 items), health care personnel development (4 items), basic diagnostic capabilities (6 items), microbiological rapid tests (2 items), evaluation of microbiological drug resistance data (3 items), antibiotic consumption control (5 items) and drug use monitoring (4 items). The indicator scores, reported by 11 pilot hospitals from five European countries, ranged from 32 to 50 (maximum score = 58) and from 5 to 10 points (maximum score = 10) for, respectively, the complete and the top-ten list. An international panel selected 58 potential structure indicators, among which was a minimal set of ten key structure indicators, that could be useful for assessment of the comprehensiveness and resource-intensity of antimicrobial stewardship programmes. There was significant heterogeneity among participating centres with regard to their score for structural components of effective antimicrobial stewardship. 23831116 Cell cycle genes co-expression in multiple myeloma and plasma cell leukemia. The objective of this study was to describe co-expression correlations of cell cycle regulatory genes in multiple myeloma (MM) and plasma cell leukemia (PCL). Our results highlight the presence of dynamic equilibrium between co-expression of activator and inhibitor gene sets. Moreover inhibitor set is more sensitive to the activator changes, not vice versa. We have shown that CDKN2A expression is associated with short-term survival in newly diagnosed MM patients (survival was 30.3±3.9months for 'low' expressed and 7.5±5.6months for 'high' expressed group, p<0.0001). Moreover low-expression CDKN2A group showed time-to-progression benefit in newly diagnosed patients (remission was 20.8±3.6months for 'low' and 8.4±2.7months for 'high' expressed group, p<0.0001) as well as in whole studied cohort of MM patients (remission was 20.8±2.8months for 'low' and 9.8±1.1months for 'high' expressed group, p<0.0001). The overexpression of inhibitors can be explained as a compensatory reaction to growing "oncogenic stress". 23749259 Oxidation of dimethylplatinum(II) complexes with a peroxyacid. The complexes [PtMe2(NN)], NN = 2,2′-bipyridine = bipy, 1a; NN = di-2-pyridylamine = dpa, 1b; NN = di-2-pyridyl ketone = dpk, 1c, NN = 4,4′-bis(ethoxycarbonyl)-2,2′-bipyridine, bebipy, react with m-chloroperoxybenzoic acid to give the platinum(IV) complexes [Pt(OH)(O2C-3-C6H4Cl)Me2(NN)], NN = bipy, 2, or [Pt(OH)(OH2···O2C-3-C6H4Cl)Me2(NN)], NN = bipy, 3a; dpa, 3b; bebipy, 3d, or [Pt(OH)2Me2(dpkOH)]3[Pt(OH)(OH2)Me2(dpkOH)][H(O2C-3-C6H4Cl)2]·2MeOH, 43·5·2MeOH. The reactions are proposed to occur by a polar oxidative addition mechanism, followed in most cases by the coordination of water. Complex 3a crystallises as a supramolecular polymer, the compound 43·5·2MeOH crystallises as a supramolecular sheet structure, and 3d easily forms a gel, all through strong intermolecular hydrogen bonding. 23760604 Age estimation by multidetector CT images of the sagittal suture. Closure of cranial sutures progresses with age; therefore, macroscopic assessment of cranial sutures has been used as one method of age estimation. Postmortem computed tomography (PMCT), which many forensic medical departments and institutes have begun to adopt, has the potential to simplify the gathering of information from cranial sutures for both surface and cross-sectional evaluation. To examine the feasibility of age estimation by cross-sectional multidetector computed tomography images of the sagittal suture, PMCT findings of 125 subjects of known age and sex were retrospectively reviewed. The sagittal suture was divided into four segments, and 20 cross-sectional slices from each segment were analyzed. These slices were each categorized by visual evaluation into one of the seven stages defined by Harth et al. according to the degree of closure. The mean stage value of 20 slices was calculated for each segment. We were able to evaluate cross-sectional images of the sagittal suture by PMCT, and a positive correlation between age and closure degree was observed. Despite the prediction interval achieved with this method not being superior to traditional macroscopic or flat-panel CT assessment, multidetector CT is a potentially useful tool, in conjunction with other methods, for age estimation, particularly in adult females and in cases where only a skull is the sole remain. 23940718 Properties of local interactions and their potential value in complementing genome-wide association studies. Local interactions between neighbouring SNPs are hypothesized to be able to capture variants missing from genome-wide association studies (GWAS) via haplotype effects but have not been thoroughly explored. We have used a new high-throughput analysis tool to probe this underexplored area through full pair-wise genome scans and conventional GWAS in diastolic and systolic blood pressure and six metabolic traits in the Northern Finland Birth Cohort 1966 (NFBC1966) and the Atherosclerosis Risk in Communities study cohort (ARIC). Genome-wide significant interactions were detected in ARIC for systolic blood pressure between PLEKHA7 (a known GWAS locus for blood pressure) and GPR180 (which plays a role in vascular remodelling), and also for triglycerides as local interactions within the 11q23.3 region (replicated significantly in NFBC1966), which notably harbours several loci (BUD13, ZNF259 and APOA5) contributing to triglyceride levels. Tests of the local interactions within the 11q23.3 region conditional on the top GWAS signal suggested the presence of two independent functional variants, each with supportive evidence for their roles in gene regulation. Local interactions captured 9 additional GWAS loci identified in this study (3 significantly replicated) and 73 from previous GWAS (24 in the eight traits and 49 in related traits). We conclude that the detection of local interactions requires adequate SNP coverage of the genome and that such interactions are only likely to be detectable between SNPs in low linkage disequilibrium. Analysing local interactions is a potentially valuable complement to GWAS and can provide new insights into the biology underlying variation in complex traits. 23932279 Evaluation of Bi-ventricular Coronary Flow Patterns Using High-Frequency Ultrasound in Mice with Transverse Aortic Constriction. Using high-frequency color and pulsed Doppler ultrasound, we evaluated the flow patterns of the left (LCA), septal (SCA) and right (RCA) coronary arteries in mice with and without transverse aortic constriction (TAC). Fifty-two male C57BL/6J mice were subjected to TAC or a corresponding sham operation. At 2 and 8 wk post-surgery, Doppler flow spectra from the three coronary arteries, together with morphologic and functional parameters of the left and right ventricles, were measured. Histology was performed to evaluate myocyte size and neo-angiogenesis in both ventricles. In sham-operated mice, the LCA and SCA both exhibited low-flow waveforms during systole and dominantly higher-flow waveforms during diastole. The RCA exhibited generally lower flow velocity, with similar systolic and diastolic waveforms. TAC significantly increased the systolic flow velocities of all coronary arteries, but enhanced the flow mainly in the LCA and SCA. In the left ventricle, coronary flow reserve was partially preserved 2 wk post-TAC, but decreased at 8 wk, consistent with changes in neo-angiogenesis and systolic function. In contrast, no significant change was found in the coronary flow reserve, structure or function of the right ventricle. This study has established a protocol for evaluating the flow pattern in three principal coronary arteries in mice using Doppler ultrasound and illustrated the difference among three vessels at baseline. In mice with TAC, the difference in the associating pattern of coronary flow dynamics with the myocardial structure and function between the left and right ventricles provides further insights into ventricular remodeling under pressure overload. 23750830 Evaluating the In Vitro Inhibition of UGT1A1, OATP1B1, OATP1B3, MRP2, and BSEP in Predicting Drug-Induced Hyperbilirubinemia. Hyperbilirubinemia may arise due to inadequate clearance of bilirubin from the body. Bilirubin elimination is a multifaceted process consisting of uptake of bilirubin into the hepatocytes facilitated by OATP1B1 and OATP1B3. Once in the hepatocytes, it is extensively glucuronidated by UGT1A1. Eventually, the glucuronide metabolite is excreted into the bile via MRP2. UGT1A1 inhibition has been previously shown to be linked with hyperbilirubinemia. However, because drug transporters also contribute to bilirubin elimination, the purpose of this work was to investigate the in vitro inhibition of OATP1B1, OATP1B3, MRP2, and BSEP of select test drugs known to elicit hyperbilirubinemia. Test drugs investigated in this study were atazanavir and indinavir, which are associated with hyperbilirubinemia and elevations in serum transaminase; ritonavir and nelfinavir, which are not associated with hyperbilirubinemia; and bromfenac, troglitazone, and trovafloxacin, which are associated with severe idiosyncratic hepatotoxicity exhibiting elevations in serum bilirubin and transaminase. Due to limited solubility and poor ionization of bilirubin and its glucuronide, the formation of estradiol 3-glucuronide was used as a surrogate to assess UGT1A1 activity, while the transport of pitavastatin, CDCF, and taurocholate were used as surrogate probe substrates to monitor the function of OATP1B1/OATP1B3, MRP2, and BSEP, respectively. It was assumed that any inhibition of the surrogate probe substrates by test drugs is indicative of the potential impact of test drugs to modulate the function of proteins involved in bilirubin disposition. In vitro inhibition was determined by calculating IC50. Moreover, Cmax and Cmax,free were integrated with IC50 values to calculate R and Rfree, respectively, which represents the ratio of probe drug glucuronidation/transport in the absence and presence of test drugs. Analysis of the data showed that Rfree demonstrated the best correlation to hyperbilirubinemia. Specifically, Rfree was above the 1.1 target threshold against UGT1A1, OATP1B1, and BSEP for atazanavir and indinavir. In contrast, Rfree was below this threshold for ritonavir and nelfinavir as well as for bromfenac, troglitazone, and trovafloxacin. For all test drugs examined, only minor inhibition against OATP1B3 and MRP2 were observed. These data suggest that the proposed surrogate probe substrates to evaluate the in vitro inhibition of UGT1A1, OATP1B1, and BSEP may be suitable to assess bilirubin disposition. For protease inhibitors, inclusion of OATP1B1 and BSEP inhibition may improve the predictability of hyperbilirubinemia. 23907106 Highlights in clinical autonomic neuroscience: how much salt is salubrious? Individuals differ in their preference for, sensitivity to, and physiologic need for, salt. Increasing the dietary intake of salt is considered first line treatment for orthostatic hypotension, orthostatic intolerance, and syncope. Dietary salt intake is also an important contributing cause for hypertension, which is the leading modifiable risk factor for mortality worldwide. Recent research calls into question the assumption that there is one ideal dose of dietary salt appropriate for everyone. Individualized salt recommendations for some patients should take into account orthostatic blood pressure patterns and in the future may also be guided by genetic information. An as yet unanswered question is whether high salt diets helpful in the treatment of orthostatic disorders would, if continued long-term, increase the risk of developing hypertension. 23746808 Structure and conformational variability of the mycobacterium tuberculosis fatty acid synthase multienzyme complex. Antibiotic therapy in response to Mycobacterium tuberculosis infections targets de novo fatty acid biosynthesis, which is orchestrated by a 1.9 MDa type I fatty acid synthase (FAS). Here, we characterize M. tuberculosis FAS by single-particle cryo-electron microscopy and interpret the data by docking the molecular models of yeast and Mycobacterium smegmatis FAS. Our analysis reveals a porous barrel-like structure of considerable conformational variability that is illustrated by the identification of several conformational states with altered topology in the multienzymatic assembly. This demonstrates that the barrel-like structure of M. tuberculosis FAS is not just a static scaffold for the catalytic domains, but may play an active role in coordinating fatty acid synthesis. The conception of M. tuberculosis FAS as a highly dynamic assembly of domains revises the view on bacterial type I fatty acid synthesis and might inspire new strategies for inhibition of de novo fatty acid synthesis in M. tuberculosis. 23622766 Assessment of immediate pain relief with laser treatment in recurrent aphthous stomatitis. To compare immediate pain relief, healing time between minor recurrent aphthous ulcers treated with a single session of carbon dioxide (CO2) laser and a placebo. A prospective clinical study was performed on 25 patients with minor recurrent aphthous stomatitis. Pretreatment pain levels were recorded using a numerical rating scale. Ulcers were randomized to either receive treatment or placebo. Pain levels were assessed immediately after treatment and after 24 h. Healing was assessed on days 3 and 4, and once every 2 days thereafter for 2 weeks. Mean pain scores in the laser group were significantly reduced immediately after treatment (0.68 ± 0.6) compared with pretreatment (8.48 ± 0.71; P < .001). In contrast, the placebo group showed little difference in pain scores between pretreatment (8.08 ± 0.70) and immediately after treatment (7.96 ± 0.84). In the laser group, significant improvements in healing times were observed (4.08 ± 0.81 vs. 7.84 ± 0.90 days; P < .001). CO2 laser therapy in recurrent aphthous stomatitis (RAS) provides immediate pain relief sustained over 24 h, along with accelerated healing time. 23591109 Stability, metal leaching, photoactivity and toxicity in freshwater systems of commercial single wall carbon nanotubes. Carbon nanotubes (CNTs) are exciting new materials that have been intensively researched and are becoming increasingly used in consumer products. With rapid growth in production and use of CNTs in many applications, there is the potential for emissions to the environment and thus research is needed to assess the risks associated with CNTs in the environment. Here we show that commercial CNTs differ in their stability, photoactivity, metal leachate, and toxicity to freshwater algae. The behavior between raw and purified variants of the CNTs differs considerably; for example purified CNTs are generally more photoactive, producing singlet oxygen and superoxide, while raw CNTs show little or no photoactivity. Residual metal catalysts differ based on synthesis method used to prepare CNTs and thus may be comprised of elements with varying degrees of toxic potential. Influenced by pH and other constituents of the natural waters, our work shows that metals can leach out from all the commercial CNTs studied, even purified versions, albeit at different levels in many natural waters. As much as 10% of the total residual nickel leached from a purified CNT after 72 h. Aqueous concentrations of molybdenum leached from a different purified CNT were nearly 0.060 mg L(-1) after 72 h. With little sample preparation, CNTs are dispersible in most freshwaters and stable for several days. Not all tested CNTs were toxic; for those CNTs that did induce toxicity we show that photoactivity, not metal leaching, contributes to the toxicity of commercial CNTs to freshwater algae, with growth rates significantly reduced by as much as 200%. 23688519 P2X7 inhibition in stellate ganglia prevents the increased sympathoexcitatory reflex via sensory-sympathetic coupling induced by myocardial ischemic injury. Purinergic signaling has been found to participate in the regulation of cardiovascular function. In this study, using a rat myocardial ischemic injury model, the sympathoexcitatory reflex mediated by P2X7 receptor via sensory-sympathetic coupling between cervical dorsal root ganglia (DRG) nerves and stellate ganglia (SG) nerves was explored. Our results showed that the systolic blood pressure, heart rate, serum cardiac enzymes concentrations, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) concentrations were increased, and the expression levels of P2X7 mRNA and protein in DRG and SG were up-regulated after myocardial ischemic injury. Administration of brilliant blue G (BBG), a selective P2X7 antagonist, decreased the elevation of systolic blood pressure, heart rate, serum cardiac enzyme, IL-6 and TNF-α, and inhibited the up-regulated expression of P2X7 mRNA and protein in DRG and SG after myocardial ischemic injury. Retrograde tracing test showed that there were calcitonin gene-related peptide sensory nerves and substance P sensory nerves sprouting from DRG to SG, which played an important role in the development of myocardial ischemic injury. The up-regulated P2X7 receptor expression levels on the surface membrane of satellite glial cells contributed to the activation of sensory-sympathetic coupling, which in turn facilitated the sympathoexcitatory reflex. BBG can inhibit the activation of satellite glial cells and interrupt the generation of sensory-sympathetic coupling in the cervical sympathetic ganglia after the myocardial ischemic injury. Taken together, these findings may provide a new therapeutic approach for treating coronary heart disease, hypertension and other cardiovascular diseases. 23599312 Expression in Yeast Links Field Polymorphisms in PfATP6 to in Vitro Artemisinin Resistance and Identifies New Inhibitor Classes. Background. The mechanism of action of artemisinins against malaria is unclear, despite their widespread use in combination therapies and the emergence of resistance. Results. Here, we report expression of PfATP6 (a SERCA pump) in yeast and demonstrate its inhibition by artemisinins. Mutations in PfATP6 identified in field isolates (such as S769N) and in laboratory clones (such as L263E) decrease susceptibility to artemisinins, whereas they increase susceptibility to unrelated inhibitors such as cyclopiazonic acid. As predicted from the yeast model, Plasmodium falciparum with the L263E mutation is also more susceptible to cyclopiazonic acid. An inability to knockout parasite SERCA pumps provides genetic evidence that they are essential in asexual stages of development. Thaperoxides are a new class of potent antimalarial designed to act by inhibiting PfATP6. Results in yeast confirm this inhibition. Conclusions. The identification of inhibitors effective against mutated PfATP6 suggests ways in which artemisinin resistance may be overcome. 23768979 Fate of antibiotics during wastewater treatment and antibiotic distribution in the effluent-receiving waters of the Yellow Sea, northern China. Antibiotics including three β-lactams, two fluoroquinolones and two macrolides, which were the top seven most prescribed antibiotics in Dalian, China, were selected to investigate their occurrence in six municipal wastewater treatment plants (WWTPs) and their distribution in the effluent-receiving waters of the Yellow Sea. Four WWTPs employing different treatment technologies were selected to explore the mechanism of antibiotics elimination during wastewater treatment. Results showed that fluoroquinolones and macrolides were dominant species in both WWTPs effluents and the surveyed coastal waters. Biodegradation was the main pathway for β-lactams removal, however, primary treatment performed better than biological treatment for fluoroquinolones removal. Concentrations of macrolides increased dramatically after the biological treatment, which was probably due to the release of macrolides enclosed in feces particles. In the surveyed coastal waters, reduction of antibiotic concentration with distance was observed. Potential environmental risk caused by the occurrence of these antibiotics should be evaluated in future work. 23708826 Fluorescence quenching of protonated β-carbolines in water and microemulsions: evidence for heavy-atom and electron-transfer mechanisms. The fluorescence quenching of protonated β-carbolines has been investigated in acidic aqueous solutions and in w/o microemulsions using I(-), Br(-), Cu(2+), SCN(-), and Pb(2+) as quenchers. It was found that fluorescence quenching by these compounds is much more efficient in water than in microemulsions since quenching in microemulsions depends on the simultaneous occupancy of the water droplets by both fluorophore and quencher. Linear Stern-Volmer plots were obtained in all cases, leading to quenching rate constants of ca. 10(8)-10(10) M(-1) s(-1) in water and ca. 10(7)-10(8) M(-1) s(-1) in microemulsions. In the case of quenching by SCN(-), ns flash photolysis studies indicate formation of (SCN)2˙(-) showing that at least part of the quenching process involves an electron transfer mechanism. This indicates that the singlet excited states of the protonated β-carbolines can act as relatively strong oxidants (E° > 1.6 V), capable of oxidizing many species, including the biologically relevant DNA base guanine. The observation of the (SCN)2˙(-) transient in microemulsions demonstrates that it is possible to have the protonated β-carboline and at least two thiocyanate ions in the same water pool. 23063876 Assay of vtg, ERs and PPARs as endpoint for the rapid in vitro screening of the harmful effect of Di-(2-ethylhexyl)-phthalate (DEHP) and phthalic acid (PA) in zebrafish primary hepatocyte cultures. In the last years the concern about the negative effects of phthalates on reproduction significantly increased. Considering that, at date data available dealing with the adverse outcome of Di-(2-ethylhexyl)-phthalate (DEHP) on the reproduction of several species are still contrasting, in this study, the effects induced by DEHP (0.05, 0.1, 1, 10 and 100 nM) and its active metabolite, phthalic acid (PA) (0.01, 0.1, 1 and 10 μM), were analyzed in zebrafish, Danio rerio, primary hepatocyte cultures, using target molecules involved in fish reproduction (vitellogenin--vtg and estrogen receptors--ERα, β1 and β2) and metabolism (peroxisome proliferators activated receptors--PPAR α, β, γ). The use of in vitro culture, in fact, has the potential to significantly reduce the number of animals sacrificed for research allowing a precise control of the physical and chemical parameters that is often not possible in vivo. Moreover, since many toxicological studies revealed a sex specific response to toxicants, male and female primary hepatocyte cultures were set up to elucidate the possible gender specific effects of two common environmental phthalates. The increase of vtg levels observed in the culture media of male or female hepatocytes strongly evidenced the phthalates E2-like action. Moreover, the data obtained suggested that the observed different ERs isoforms modulation is otherwise associated with the vtg increase, depending on fish gender. Regarding PPARs, a similar trend of expression was found in both males and females. In conclusion, this study enforces the role of vtg as biomarker for evaluate the presence of environmental doses of DEHP and PA. Considering the similar gender modulation observed for vtg and PPARs, these molecules could be used for the rapid screening of the presence of DEHP and PA. Noteworthy the gender specific modulation observed for ERs opens a debate on the estrogenic mechanism of action of DEHP and PA and their role on vtg induction. 23660231 Ethics and data protection in human biomarker studies in environmental health. Human biomarker studies in environmental health are essential tools to study the relationship between health and environment. They should ultimately contribute to a better understanding of environmentally induced adverse health effects and to appropriate preventive actions. To ensure the protection of the rights and dignity of study participants a complex legal and ethical framework is applied, consisting of several international directives, conventions, and guidelines, whether or not translated in domestic laws. Main characteristics of ethics and data protection in studies using biomarkers in the field of environmental health are summarized and current discussions on related questions and bottlenecks highlighted. In the current regulatory context, dominated by the protection of the individual study participant, difficulties are reported due to the different interpretation and implementation of the regulations of concern within and across borders. Advancement of consistency and compatibility is recommended and efforts are ongoing. An increasing demand for secondary use of data and samples poses additional challenges in finding a right balance between the individual rights of the study participants on the one hand and the common interest of, and potential benefit for the public or community at large on the other. Ethics committees could play a key role in assessing problems originating from the sometimes competing needs at individual and societal level. Building trust in science amongst (potential) study participants and within the community allows the inclusion of arguments from the societal perspective. This requires increased attention for respectful communication efforts. Striving for public participation in decision making processes may promote policy relevant research and the related translation of study results into action. 23278429 Does C-reactive protein independently predict mortality in adult community-acquired bacteremia patients with known sepsis severity? We evaluated whether sepsis severity and C-reactive protein (CRP) level on admission prognostically corroborated or annulled each other in adult patients with incident community-acquired bacteremia (Funen, Denmark, 2000-2008). We used logistic regression and area under the receiver operating characteristic curve (AUC) to evaluate 30-day mortality in four models: (i) age, gender, comorbidity, bacteria, and ward. (ii) Model 1 and sepsis severity. (iii) Model 1 and CRP. (iv) Model 1, sepsis severity, and CRP. Altogether, 416 of 1999 patients died within 30 days. CRP independently predicted 30-day mortality [Model 4, odds ratio (95% CIs) for 100 mg/L: 1.16 (1.06-1.27)], but it did not contribute to the AUC (Model 2 vs Model 4: p = 0.31). In the 963 non-severe sepsis patients, CRP independently predicted 30-day mortality [Model 4: 1.42 (1.20-1.69)] and it increased the AUC (Model 2 vs Model 4: p = 0.06), thus CRP contributed as much as sepsis severity to prognosis. 23177267 Meeting the need: youth and family planning in sub-Saharan Africa. The need for a concerted effort to address the gaps in family planning services for youth in sub-Saharan Africa has been underreported and underexplored. Trends in fertility, childbearing, unmet need for family planning options and contraceptive prevalence (CP) among youth are described with data from six African countries with four consecutive Demographic and Health Surveys. Estimates of exposure to risk of pregnancy and number of new contraceptives users needed to maintain and double CP in 2015 are calculated using current CP and projected youth population size in six African countries. The youth population is expected to range from approximately 3 to 35 million in six African countries by 2015. Accounting for population growth and current estimates of sexual activity among youth, family planning services will need to absorb more than 800,000 and 11.3 million new contraceptive users total to maintain and double CP, respectively, in 2015 in those six African countries alone. Our findings support existing literature that calls for a reorientation of family planning policies and programs, especially improved access to modern contraceptive methods among African youth. 23155064 MetalPDB: a database of metal sites in biological macromolecular structures. We present here MetalPDB (freely accessible at http://metalweb.cerm.unifi.it), a novel resource aimed at conveying the information available on the three-dimensional (3D) structures of metal-binding biological macromolecules in a consistent and effective manner. This is achieved through the systematic and automated representation of metal-binding sites in proteins and nucleic acids by way of Minimal Functional Sites (MFSs). MFSs are 3D templates that describe the local environment around the metal(s) independently of the larger context of the macromolecular structure embedding the site(s), and are the central objects of MetalPDB design. MFSs are grouped into equistructural (broadly defined as sites found in corresponding positions in similar structures) and equivalent sites (equistructural sites that contain the same metals), allowing users to easily analyse similarities and variations in metal-macromolecule interactions, and to link them to functional information. The web interface of MetalPDB allows access to a comprehensive overview of metal-containing biological structures, providing a basis to investigate the basic principles governing the properties of these systems. MetalPDB is updated monthly in an automated manner. 23893077 Participant perspectives from the Indian Health Service Anticoagulation Training Program. Background The Indian Health Service Anticoagulation Training Program serves to improve patient safety through advanced anticoagulation management training. Although post-program evaluations of program content were conducted at the time of program delivery, little is known about translation of these learned skills into clinical practice. Objective This research sought to describe levels of self-reported participant confidence in anticoagulation management; development, implementation, and performance management of both core and supplemental activities of anticoagulation clinics or services; and current anticoagulation clinical practices subsequent to participating in the Anticoagulation Training Program. Setting A federal Indian Health Service healthcare facility in Oklahoma, USA. Methods A cross-sectional, electronic mail survey was designed, pretested, and administered to 267 eligible Anticoagulation Training Program participants from 1999 to 2009. Data were analyzed using descriptive statistics and interpreted to identify areas of strength and opportunities for improvement. Main outcome measures Information about confidence in anticoagulation management skills; development, implementation and improvement of both core and supplemental activities of anticoagulation clinics or services; and current anticoagulation clinical practices was collected. Results After training, over 90 % of participants reported agreement/strong agreement with statements about confidence in performing patient-care related anticoagulation activities. A smaller proportion (83.3-85.4 %) reported agreement/strong agreement with confidence in measuring, analyzing and reporting anticoagulation outcomes. Improvement activities were more common than development or implementation activities (65.4, 31.9 and 35.1 %, respectively). Not having well established reimbursement procedures, lack of dedicated clinic space, and lack of dedicated personnel salaries (47.3, 38.3 and 32.6 %, respectively) were reported as the most common barriers to developing, implementing or improving an anticoagulation clinic. Participants indicated that anticoagulation outcomes tracking was the most common supplemental development, implementation and improvement activity (37.9, 37.0 and 43.8 % respectively). Benchmarking was the least commonly reported outcomes-related activity by participants (33.6 %). Although there was only a modest gain in the number of established anticoagulation clinics after attending the Anticoagulation Training Program, approximately 21 % of participants reported using skills learned to establish other disease state management clinics. Conclusion In general, a majority of participants reported high levels of confidence related to direct patient care activities after attending the Anticoagulation Training Program. However there is a need to raise confidence in performance improvement and outcomes management activities to align with current accreditation standards in anticoagulation management as the Anticoagulation Training Program evolves. 23905716 Construct Validity of the Need to Belong Scale: Mapping the Nomological Network. Nine studies examined the construct validity of the Need to Belong Scale. The desire for acceptance and belonging correlated with, but was distinct from, variables that involve a desire for social contact, such as extraversion and affiliation motivation. Furthermore, need to belong scores were not related to insecure attachment or unfulfilled needs for acceptance. Need to belong was positively correlated with extraversion, agreeableness, and neuroticism and with having an identity that is defined in terms of social attributes. Need to belong was associated with emotional reactions to rejection, values involving interpersonal relationships, and subclinical manifestations of certain personality disorders. 23874488 Neurodegeneration in Drop-Dead Mutant Drosophila melanogaster Is Associated with the Respiratory System but Not with Hypoxia. Mutations in the gene drop-dead (drd) cause diverse phenotypes in adult Drosophila melanogaster including early lethality, neurodegeneration, tracheal defects, gut dysfunction, reduced body mass, and female sterility. Despite the identification of the drd gene itself, the causes of early lethality and neurodegeneration in the mutant flies remain unknown. To determine the pattern of drd expression associated with the neurodegenerative phenotype, knockdown of drd with various Gal4 drivers was performed. Early adult lethality and neurodegeneration were observed upon knockdown of drd in the tracheal system with two independent insertions of the breathless-Gal4 driver and upon knockdown in the tracheal system and elsewhere with the DJ717-Gal4 driver. Surprisingly, rescue of drd expression exclusively in the tracheae in otherwise mutant flies rescued the neurodegenerative phenotype but not adult lethality. Gut dysfunction, as measured by defecation rate, was not rescued in these flies, and gut function appeared normal upon tracheal-specific knockdown of drd. Finally, the hypothesis that tracheal dysfunction in drd mutants results in hypoxia was tested. Hypoxia-sensitive reporter transgenes (LDH-Gal4 and LDH-LacZ) were placed on a drd mutant background, but enhanced expression of these reporters was not observed. In addition, manipulation of drd expression in the tracheae did not affect expression of the hypoxia-induced genes LDH, tango, and similar. Overall, these results indicate that there are at least two causes of adult lethality in drd mutants, that gut dysfunction and neurodegeneration are independent phenotypes, and that neurodegeneration is associated with tracheal expression of drd but not with hypoxia. 23911316 Statistical mechanics of pluripotency. Recent reports using single-cell profiling have indicated a remarkably dynamic view of pluripotent stem cell identity. Here, we argue that the pluripotent state is not well defined at the single-cell level but rather is a statistical property of stem cell populations, amenable to analysis using the tools of statistical mechanics and information theory. 23666802 Increased acylation stimulating protein levels in young obese males is correlated with systemic markers of oxidative stress. As little is known about relationship between acylation stimulating protein (ASP) and oxidative stress, whether there is any link between ASP and oxidative stress in young obese males were investigated. Forty-five obese (median body mass index (BMI) = 36.99 (IQR = 3.65) kg m(-2) ) male subjects (median age = 22 (IQR = 6) years) and 24 age-matched (median age = 22.5 (IQR = 4.8) years) healthy male volunteers (median body mass index (BMI) = 23.67 (IQR = 2.45) kg m(-2) ) were recruited into the study. All obese subjects have BMI > 30 kg m(-2) , while all controls have BMI < 25 kg m(-2) . Fasting plasma ASP, lipid hydroperoxide, high sensitivity C-reactive protein (hs-CRP), fasting insulin, triglyceride, LDL-cholesterol levels and HOMA-IR were higher, whereas the mean HDL-cholesterol levels and glutathione peroxidase (GPx) enzyme activity were significantly lower in obese subjects than controls. The linear regression analysis showed that lipid hydroperoxide was independently associated with only BMI, while ASP was independently associated with BMI and triglyceride. The present data support the concept that obesity occurs under condition of compex interactions by adipokines, insulin, inflammation, and oxidative stress. 23433706 A modified Vancouver Scar Scale linked with TBSA (mVSS-TBSA): Inter-rater reliability of an innovative burn scar assessment method. Current scar assessment methods do not capture variation in scar outcome across the burn scar surface area. A new method (mVSS-TBSA) using a modified Vancouver Scar Scale (mVSS) linked with %TBSA was devised and inter-rater reliability was assessed. Three raters performed scar assessments on thirty patients with burn scars using the mVSS-TBSA. Scoring on pigmentation, vascularity, pliability and height was undertaken for the 'best' and 'worst' areas of each scar. Raters allocated the total body surface area of the scar (%TBSA) to three mVSS categories (<5, 5-10, >10). Intra-class correlation coefficient (ICC) and weighted kappa statistic (kw) were used to assess inter-rater reliability. The data were also analysed for clinically relevant misclassifications between pairs of raters. Total mVSS scores showed 'fair to good' agreement (ICC 0.65-0.73) in the 'best' area of the scar while there was 'excellent' agreement in the 'worst' scar area (ICC 0.85-0.88). The kw of the individual mVSS components ranged from 0.44 to 0.84 and 0.02 to 0.86 for 'best' and 'worst' scar areas, respectively. Determination of scar %TBSA had 'excellent' reliability (ICC 0.91-0.96). Allocation of scar %TBSA to severity category <5 mVSS demonstrated 'good to excellent' reliability (ICC 0.63-0.80) and 'fair to good' reliability (ICC 0.42-0.74) for 5-10 mVSS category. However, misclassifications were observed for the total mVSS score in the 'worst' scar area and the allocation of scar %TBSA in the <5 mVSS category. Inter-rater reliability of mVSS scores depends on the severity of the scar area being assessed. The mVSS-TBSA method of allocation of scar %TBSA to two broad mVSS categories, namely <5 and ≥5 mVSS, has 'good to excellent' reliability. The mVSS-TBSA has demonstrated utility for both clinical and research purposes; however, there is potential to misclassify scar outcome in some cases. 23852911 The role of serum n-terminal pro-brain natriuretic peptide in transient tachypnea of the newborn. BACKGROUND AND OBJECTIVES: Transient tachypnea of the newborn (TTN), also known as wet lung disease, is a common cause of respiratory distress in the newborn. It has been demonstrated that, in alveolar type II cell cultures of the rat, receptors affected by the natriuretic peptides are expressed and that atrial natriuretic peptide (ANP) reduced amiloride-sensitive Na+ transport in these cells with a pattern similar to that in renal tubules, thereby inhibiting Na+ re-absorption in a concentration-dependent manner. Brain natriuretic peptide (BNP) is known to act on these receptors and it is suggested that it may be involved in fluid absorption by the lungs. The present study aimed to investigate the role of BNP in the pathogenesis of transient tachypnea of the newborn. Serum NT-proBNP (N-terminal-proBNP) level measurements of 43 infants diagnosed with transient tachypnea of the newborn were compared to those of 29 healthy neonates. There were no statistically significant differences in NT-proBNP level between the study group and the control group. NT-proBNP has no role in the pathophysiology of transient tachypnea of the newborn. Other factors which may potentially be involved in this etiology should be investigated. 23664558 Three- and 4-year-old children's response tendencies to various interviewers. Unlike young preschoolers, older preschoolers may exhibit a response bias under social pressure from authoritative interviewers. To examine this, 3- and 4-year-old preschoolers were asked yes-no questions about familiar and unfamiliar objects in three conditions. In one condition an adult asked them questions in a live interaction, in a second condition an adult asked questions via video, and in a third condition a robot asked questions via video. The 3-year-olds exhibited a yes bias-a tendency to say "yes"-in nearly all conditions. The only exception was when they were asked questions about unfamiliar objects by the human interviewer via video, where they did not respond in a biased manner. The 4-year-olds exhibited a yes bias in only one condition-when they were questioned by a live human interviewer about both objects. They also exhibited a nay-saying bias when asked questions about unfamiliar objects in both video conditions, and they did not show any response bias in other conditions. The results suggest that the social pressure from an authoritative adult in a live interaction is problematic. 23927231 Level dominance for the detection of changes in level distribution in sound streams. Sound streams were generated by randomly choosing the levels of tone pips from two different distributions, A and B. Of the 18 tone pips, the first nine were drawn from distribution A and the second nine from distribution B, or the opposite. The listeners' task was to indicate order, A-B or B-A. In two conditions the A and B distributions differed in mean (condition 1) or variance (condition 2). In contrast to an ideal observer, listeners' strategies were consistent across the two conditions. Analyses suggest that listeners relied primarily on the more intense tone pips in making their decisions. 23955069 Assembly and organization of poly(3-hexylthiophene) brushes and their potential use as novel anode buffer layers for organic photovoltaics. Buffer layers that control electrochemical reactions and physical interactions at electrode/film interfaces are key components of an organic photovoltaic cell. Here the structure and properties of layers of semi-rigid poly(3-hexylthiophene) (P3HT) chains tethered at a surface are investigated, and these functional systems are applied in an organic photovoltaic device. Areal density of P3HT chains is readily tuned through the choice of polymer molecular weight and annealing conditions, and insights from optical absorption spectroscopy and semiempirical quantum calculation methods suggest that tethering causes intrachain defects that affect co-facial π-stacking of brush chains. Because of their ability to modify oxide surfaces, P3HT brushes are utilized as an anode buffer layer in a P3HT-PCBM (phenyl-C61-butyric acid methyl ester) bulk heterojunction device. Current-voltage characterization shows a significant enhancement in short circuit current, suggesting the potential of these novel nanostructured buffer layers to replace the PEDOT:PSS buffer layer typically applied in traditional P3HT-PCBM solar cells. 23145953 Prisons: the psychiatric institution of last resort? Throughout recorded history, the mentally ill have been living at the fringes of society, frequently alienated, treated inhumanely, and made as scapegoats for the prevailing societal ills. Australia has seen the number of public psychiatric hospital beds fall from 30 000 in the early 1960's to 8000 as of 2006. The Australian population has more than doubled since this time, such phenomena is mirrored in the UK and the USA. As of June 2011, there were 28 964 individuals detained in Australian prisons, this represents a figure close to 70% higher than in comparison to the figure reported in 1996. However, Australia's population has only increased by just over 27% in this time period. Authors and researchers are claiming that a debilitated public psychiatric healthcare system has resulted in large 'trans-migrations' of patients from psychiatric hospital beds to prisons and jails, via an intermediary period in their communities. The World Health Organization declared in 1948 that the enjoyment of the highest individual attainment of health for any person is a fundamental human right. Australia, the UK and the United States all legally ratified this declaration as becoming signatories to their founding treatise with the United Nations. Despite this, there are many conspicuous examples of inequities of public health as found within these nations. One of the more disparate and outrageous examples of inequities in public health has been an insidious trend towards criminalizing mental illness, and the largely unjust treatment of many mentally ill persons. This change has resulted in untold numbers of mentally ill persons being over-represented within the criminal justice system, experiencing higher morbidity, co-morbidity and mortality rates, and having difficulty in surviving in a society frequently dealing with their illness in a persecutory manner. Questions must be raised: that although over the passage of time medical science and technology has changed, but has western societies' attitudes to health equity kept pace? 23964320 Determinants of neural tube defect (NTD)-protective circulating concentrations of folate in women of child-bearing age in the US post-folic acid fortification era. We evaluated folate status of child-bearing age women diagnosed with abnormal pap smear in the US post-folic acid (FA) fortification era and assessed the determinants of NTD-protective and supra-physiologic (SP) concentrations of folate. The distribution of 843 women according to NTD-protective concentrations of RBC folate, plasma folate and SP concentrations of plasma folate were tested in relation to demographic and life-style factors. Logistic regression models specified NTD-protective concentrations of RBC and plasma folate or SP concentrations of plasma folate as dependent variables and demographic and life-style factors as independent predictors of interest. More than 82% reached NTD-protective concentrations of RBC and plasma folate and ~30% reached SP concentrations of plasma folate. FA supplement use was associated with having SP concentrations of plasma folate rather than NTD-protective concentrations of folate. African American (AA) women and smokers were significantly less likely to achieve NTD-protective concentrations of RBC and plasma folate. A large majority of women reached NTD-protective concentrations of folate with the current level of FA fortification without using supplementary FA. Therefore, the remaining disparities in AA women and in smokers should be addressed by targeted individual improvements in folate intake. 23953955 Inadequacy of vitamins and minerals among high-school pupils in Ouarzazate, Morocco. To assess micronutrient intakes and the prevalence of inadequacy in a sample of high-school pupils in Ouarzazate, Morocco. Food records were compiled over three non-consecutive days by pre-trained pupils. Micronutrient intakes were estimated using the DIAL software, adapted to include foods commonly eaten in Morocco. The prevalence of inadequacy was estimated by the proportion of individuals with intakes below the Estimated Average Requirement (EAR) for vitamins B12, A and K, thiamin, riboflavin, niacin, pyridoxine, folate, ascorbic acid, iodine, Ca, Mg and P; below the Adequate Intake (AI) level for pantothenic acid, biotin, Na and K; and using the probability approach for Fe. Data were adjusted for intra-individual variation with exclusion of under-reporters. Ouarzazate, a semi-urban region situated on the southern slopes of the High Atlas with little industrial development but an important tourism sector. A self-selected sample of 312 pupils aged 15-19 years from the five public high schools. After exclusion of under-reporters, 293 remained for analysis. The highest proportions of below-EAR/AI intakes were seen for pantothenic acid (girls 85·1 %, boys 78·0 %), biotin (boys 83·1 %, girls 79·4 %), thiamin (boys 66·9 %), folate (girls 93·1 %, boys 74·6 %), iodine (boys 94·9 %, girls 88·0 %) and Ca (girls 83·4 %, boys 74·6 %). Na intake was generally in excess whereas K intake was below the AI level. In general, girls had better-quality diets than boys, who appeared to consume more 'empty calories'. Our findings suggest that in this population of Moroccan adolescents, nutritional intervention and educational strategies are needed to promote healthy eating habits and correct micronutrient inadequacies. To provide reliable and precise estimates of nutrient intakes, an update of Moroccan food composition databases is urgently needed. We recommend that national authorities address these issues. 23799538 Effect of Cd(ii) and Se(iv) exposure on cellular distribution of both elements and concentration levels of glyoxal and methylglyoxal in Lepidium sativum. In this work, the effect of cadmium (0-5.0 mg L(-1) as cadmium chloride, Cd(ii)) and selenium (0-2.0 mg L(-1) as sodium selenite, Se(iv)) was studied in Lepidium sativum with specific focus on glyoxal (GO) and methylglyoxal (MGO) and on the cellular distribution of both elements under different exposure conditions. The concentrations of two reactive α-ketoaldehydes present as natural metabolites and as by-products of lipid peroxidation, were increased in plants treated with Cd(ii), providng complementary experimental evidence on element phytotoxicity in garden cress, in terms of oxidative damage. Even though for higher than 1.0 mg L(-1) Se in medium similar adverse effect was found, under simultaneous exposure to both elements the changes in GO and MGO concentrations were clearly attenuated as compared to a single stressor treatment. This effect was accompanied by lower uptake of the two elements, significant decrease of their relative distribution in the fraction containing polar compounds and their increase in fraction corresponding to insoluble cell fragments/components, suggesting that the direct in vivo interaction between two element forms might be involved in the favorable effects of simultaneous treatment with Cd(ii) + Se(iv). The fluorescence spectra obtained for biomass extracts corresponding to different exposure conditions suggested possible in vivo formation of CdSe quantum dots; however further studies are needed for ultimate identification and characterization of such nanoparticulate species. 23873079 Asymmetric anti-aldol addition of achiral ketones via chiral N-amino cyclic carbamate hydrazones. The asymmetric anti-aldol addition of ketone-derived donors and aldehyde acceptors is described. Asymmetric induction is achieved through the use of chiral N-amino cyclic carbamate (ACC) auxiliaries. The transformation exhibits essentially perfect anti-diastereoselectivity and enantioselectivity, and has the unusual feature of proceeding via thermodynamic, rather than kinetic control. 23852280 Prevalence of antimicrobial residues in pork meat in Madagascar. Residual antimicrobials in food constitute a risk to human health, but poor knowledge is available about the significance of contaminated meat in developing countries. The purpose of the study was to determine the occurrence of antimicrobial drug residues in pork products in Madagascar. The occurrence of antimicrobial drug residues in pork meat were investigated by the Premi® test (DSM(©)) technique. There was a high incidence rate of drug residues, with 360 (37.2 %) meat samples being contaminated. A significant increase was observed between 2010 and 2011, with 32 and 39%, respectively. Pork meat samples are less contaminated by drug residues when animals are slaughtered in urban abattoirs (34.4%) vs in provincial abattoirs (42.2%), suggesting that animals under treatment (or sick) are sold preferentially in local abattoir. Drug residue levels in pork meats purchased in Madagascar appear to be serious public health problem at the moment. 23518471 Detecting genome-wide gene transcription profiles associated with high pollution burden in the critically endangered European eel. The European eel illustrates an example of a critically endangered fish species strongly affected by human stressors throughout its life cycle, in which pollution is considered to be one of the factors responsible for the decline of the stock. The objective of our study was to better understand the transcriptional response of European eels chronically exposed to pollutants in their natural environment. A total of 42 pre-migrating (silver) female eels from lowly, highly and extremely polluted environments in Belgium and, for comparative purposes, a lowly polluted habitat in Italy were measured for polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and brominated flame retardants (BFRs). Multipollutant level of bioaccumulation was linked to their genome-wide gene transcription using an eel-specific array of 14,913 annotated cDNAs. Shared responses to pollutant exposure were observed when comparing the highly polluted site in Belgium with the relatively clean sites in Belgium and Italy. First, an altered pattern of transcription of genes was associated with detoxification, with a novel European eel CYP3A gene and gluthatione S-transferase transcriptionally up-regulated. Second, an altered pattern of transcription of genes associated with the oxidative phosphorylation pathway, with the following genes involved in the generation of ATP being transcriptionally down-regulated in individuals from the highly polluted site: NADH dehydrogenase, succinate dehydrogenase, ubiquinol-cytochrome c reductase, cytochrome c oxidase and ATP synthase. Although we did not measure metabolism directly, seeing that the transcription level of many genes encoding enzymes involved in the mitochondrial respiratory chain and oxidative phosphorylation were down-regulated in the highly polluted site suggests that pollutants may have a significant effect on energy metabolism in these fish. 23901969 A comparison between state-specific and linear-response formalisms for the calculation of vertical electronic transition energy in solution with the CCSD-PCM method. The calculation of vertical electronic transition energies of molecular systems in solution with accurate quantum mechanical methods requires the use of approximate and yet reliable models to describe the effect of the solvent on the electronic structure of the solute. The polarizable continuum model (PCM) of solvation represents a computationally efficient way to describe this effect, especially when combined with coupled cluster (CC) methods. Two formalisms are available to compute transition energies within the PCM framework: State-Specific (SS) and Linear-Response (LR). The former provides a more complete account of the solute-solvent polarization in the excited states, while the latter is computationally very efficient (i.e., comparable to gas phase) and transition properties are well defined. In this work, I review the theory for the two formalisms within CC theory with a focus on their computational requirements, and present the first implementation of the LR-PCM formalism with the coupled cluster singles and doubles method (CCSD). Transition energies computed with LR- and SS-CCSD-PCM are presented, as well as a comparison between solvation models in the LR approach. The numerical results show that the two formalisms provide different absolute values of transition energy, but similar relative solvatochromic shifts (from nonpolar to polar solvents). The LR formalism may then be used to explore the solvent effect on multiple states and evaluate transition probabilities, while the SS formalism may be used to refine the description of specific states and for the exploration of excited state potential energy surfaces of solvated systems. 23595929 Moving Forward in GME Reform: A 4 + 1 Model of Resident Ambulatory Training. Traditional ambulatory training models have limitations in important domains, including opportunities for residents to learn, fragmentation of care delivery experience, and satisfaction with ambulatory experiences. New models of ambulatory training are needed. To compare the impact of a traditional ambulatory training model with a templated 4 + 1 model. A large university-based internal medicine residency using three different training sites: a patient-centered medical home, a hospital-based ambulatory clinic, and community private practices. Residents, faculty, and administrative staff. Development of a templated 4 + 1 model of residency where trainees do not attend to inpatient and outpatient responsibilities simultaneously. A mixed-methods analysis of survey and nominal group data measuring three primary outcomes: 1) Perception of learning opportunities and quality of faculty teaching; 2) Reported fragmentation of care delivery experience; 3) Satisfaction with ambulatory experiences. Self-reported empanelment was a secondary outcome. Residents' learning opportunities increased (p = 0.007) but quality of faculty teaching was unchanged. Participants reported less fragmentation in the care residents provide patients in the inpatient and outpatient setting (p < 0.0001). Satisfaction with ambulatory training improved (p < 0.0001). Self-reported empanelment also increased (p < 0.0001). Results held true for residents, faculty, and staff at all three ambulatory training sites (p < 0.0001). A 4 + 1 model increased resident time in ambulatory continuity clinic, enhanced learning opportunities, reduced fragmentation of care residents provide, and improved satisfaction with ambulatory experiences. More studies of similar models are needed to evaluate effects on additional trainee and patient outcomes. 23692025 Review article: antitumoural immunity in colorectal cancer - current and potential future implications in clinical practice. Most of the current research in gastrointestinal oncology is focused on biology of cancer itself, but there is growing interest in the patient's immune system response and its relation with cancer cells. To review the impact of the antitumoural immune response on epidemiology, prognosis and treatment of colorectal cancer. Search of the literature published in English using the PubMed database. The role of the immune system in the antitumoural immunosurveillance is clearly supported by the increased incidence of colorectal cancer and adenomatous polyps in immunosuppressed patients. Moreover, the degree of infiltration of the tumours by the immune cells has been shown to be a strong prognostic factor of both disease recurrence and survival. The immune system plays an important role in the chemotherapy-induced cell death. New therapeutic strategies targeting the antitumoural immunity are being currently investigated with promising results. Better knowledge of antitumoural immune system can have a major impact on patients' management in daily clinical practice. Colorectal cancer screening is an important issue in immunosuppressed patients, and recommendations should be refined for selected high-risk patients. The use of an immune score to guide the therapeutic strategies in the adjuvant setting should be supported. Further and larger clinical trials are necessary to accelerate the development of innovative immune therapies. 23786152 Associations Between First-Time Expectant Women's Representations of Attachment and Their Physiological Reactivity to Infant Cry. Associations among 53 primiparous women's Adult Attachment Interview classifications (secure-autonomous vs. insecure-dismissing) and physiological and self-reported responses to infant crying were explored. Heart rate, skin conductance levels, and respiratory sinus arrhythmia (RSA) were recorded continuously. In response to the cry, secure-autonomous women demonstrated RSA declines, consistent with approach-oriented responses. Insecure-dismissing women displayed RSA and electrodermal increases, consistent with behavioral inhibition. Furthermore, insecure-dismissing women rated the cries as more aversive than secure-autonomous women. Nine months postpartum, secure-autonomous women, who prenatally manifested an approach-oriented response to the unfamiliar cry stimulus, were observed as more sensitive when responding to their own distressed infant, whereas women classified prenatally as insecure-dismissing were observed as less sensitive with their own infants. 23607726 Archaeal and bacterial diversity in acidic to circumneutral hot springs in the Philippines. The microbial diversity was investigated in sediments of six acidic to circumneutral hot springs (Temperature: 60-92 °C, pH 3.72-6.58) in the Philippines using an integrated approach that included geochemistry and 16S rRNA gene pyrosequencing. Both bacterial and archaeal abundances were lower in high-temperature springs than in moderate-temperature ones. Overall, the archaeal community consisted of sequence reads that exhibited a high similarity (nucleotide identity > 92%) to phyla Crenarchaeota, Euryarchaeota, and unclassified Archaea. The bacterial community was composed of sequence reads moderately related (nucleotide identity > 90%) to 17 phyla, with Aquificae and Firmicutes being dominant. These phylogenetic groups were correlated with environmental conditions such as temperature, dissolved sulfate and calcium concentrations in spring water, and sediment properties including total nitrogen, pyrite, and elemental sulfur. Based on the phylogenetic inference, sulfur metabolisms appear to be key physiological functions in these hot springs. Sulfobacillus (within phylum Firmicutes) along with members within Sulfolobales were abundant in two high-temperature springs (> 76 °C), and they were hypothesized to play an important role in regulating the sulfur cycling under high-temperature conditions. The results of this study improve our understanding of microbial diversity and community composition in acidic to circumneutral terrestrial hot springs and their relationships with geochemical conditions. 23907489 A national probabilistic study of polybrominated diphenyl ethers in fish from US lakes and reservoirs. Polybrominated diphenyl ethers (PBDEs) are persistent, bioaccumulative, and toxic chemicals that are present in air, water, soil, sediment, and biota (including fish). Most previous studies of PBDEs in fish were spatially focused on targeted waterbodies. National estimates were developed for PBDEs in fish from lakes and reservoirs of the conterminous US (excluding the Laurentian Great Lakes) using an unequal probability design. Predator (fillet) and bottom-dweller (whole-body) composites were collected during 2003 from 166 lakes selected randomly from the target population of 147,343 lakes. Both composite types comprised nationally representative samples that were extrapolated to the sampled population of 76,559 and 46,190 lakes for predators and bottom dwellers, respectively. Fish were analyzed for 34 individual PBDE congeners and six co-eluting congener pairs representing a total of 46 PBDEs. All samples contained detectable levels of PBDEs, and BDE-47 predominated. The maximum aggregated sums of congeners ranged from 38.3 ng/g (predators) to 125 ng/g (bottom dwellers). Maximum concentrations in fish from this national probabilistic study exceeded those reported from recent targeted studies of US inland lakes, but were lower than those from Great Lakes studies. The probabilistic design allowed the development of cumulative distribution functions to quantify PBDE concentrations versus the cumulative number of US lakes from the sampled population. 23239073 Diphones-fr: A French database of diphone positional frequency. The aim of this article is to describe a database of diphone positional frequencies in French. More specifically, we provide frequencies for word-initial, word-internal, and word-final diphones of all words extracted from a subtitle corpus of 50 million words that come from movie and TV series dialogue. We also provide intra- and intersyllable diphone frequencies, as well as interword diphone frequencies. To our knowledge, no other such tool is available to psycholinguists for the study of French sequential probabilities. This database and its new indicators should help researchers conducting new studies on speech segmentation. 23726790 Using next-generation sequencing as a genetic diagnostic tool in rare autosomal recessive neurologic Mendelian disorders. Next-generation sequencing was used to investigate 9 rare Chinese pedigrees with rare autosomal recessive neurologic Mendelian disorders. Five probands with ataxia-telangectasia and 1 proband with chorea-acanthocytosis were analyzed by targeted gene sequencing. Whole-exome sequencing was used to investigate 3 affected individuals with Joubert syndrome, nemaline myopathy, or spastic ataxia Charlevoix-Saguenay type. A list of known and novel candidate variants was identified for each causative gene. All variants were genetically verified by Sanger sequencing or quantitative polymerase chain reaction with the strategy of disease segregation in related pedigrees and healthy controls. The advantages of using next-generation sequencing to diagnose rare autosomal recessive neurologic Mendelian disorders characterized by genetic and phenotypic heterogeneity are demonstrated. A genetic diagnostic strategy combining the use of targeted gene sequencing and whole-exome sequencing with the aid of next-generation sequencing platforms has shown great promise for improving the diagnosis of neurologic Mendelian disorders. 23810424 Acyclic phosph(on)ate inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase. The pathogenic protozoa responsible for malaria lack enzymes for the de novo synthesis of purines and rely on purine salvage from the host. In Plasmodium falciparum (Pf), hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) converts hypoxanthine to inosine monophosphate and is essential for purine salvage making the enzyme an anti-malarial drug target. We have synthesized a number of simple acyclic aza-C-nucleosides and shown that some are potent inhibitors of Pf HGXPRT while showing excellent selectivity for the Pf versus the human enzyme. 23849099 Simultaneously detected parosteal osteoma and osteochondroma in the distal femur of a single patient. Parosteal osteoma arising from long tubular bone is an extremely rare bone tumor and should be distinguished from parosteal osteosarcoma, whereas osteochondroma is a common benign bone tumor showing an outgrowth of medullary and cortical bone with a cartilaginous cap. This report describes simultaneously detected parosteal osteoma and osteochondroma arising from the distal femur in a single patient. 23918195 Use transition between illegal drugs among Brazilian university students. The aim of the present study was to test whether the first use of an illicit drug increases the chance of first use of other illicit drugs. The transitions from the first use of a drug to the first use of another drug were analyzed. Comparisons were made between first drug users and non-users. Survival analysis methods were used to compare the cumulative probability of second drug use after adjusting for socio-demographic covariates and the intermediate use of alcohol and/or tobacco. A total of 12,721 Brazilian university students participated in this study. Inhalants and marijuana were used prior to the use of several other drugs, whereas the opposite pattern was not found. Ecstasy was used before other drugs in several instances. Other well-examined drugs, such as amphetamines, cocaine and hallucinogens, were used both before and after other illicit drugs without any marked predominance for either of the two roles. This study supports the role of the use of marijuana and inhalants almost exclusively before the use of other illicit drugs, whereas the use of ecstasy has an opposite role. These roles could be linked to the prevalence of lifetime use and whether individuals were at an earlier or later age during experimentation. 23843960 Iduronic Acid in chondroitin/dermatan sulfate affects directional migration of aortic smooth muscle cells. Aortic smooth muscle cells produce chondroitin/dermatan sulfate (CS/DS) proteoglycans that regulate extracellular matrix organization and cell behavior in normal and pathological conditions. A unique feature of CS/DS proteoglycans is the presence of iduronic acid (IdoA), catalyzed by two DS epimerases. Functional ablation of DS-epi1, the main epimerase in these cells, resulted in a major reduction of IdoA both on cell surface and in secreted CS/DS proteoglycans. Downregulation of IdoA led to delayed ability to re-populate wounded areas due to loss of directional persistence of migration. DS-epi1-/- aortic smooth muscle cells, however, had not lost the general property of migration showing even increased speed of movement compared to wild type cells. Where the cell membrane adheres to the substratum, stress fibers were denser whereas focal adhesion sites were fewer. Total cellular expression of focal adhesion kinase (FAK) and phospho-FAK (pFAK) was decreased in mutant cells compared to control cells. As many pathological conditions are dependent on migration, modulation of IdoA content may point to therapeutic strategies for diseases such as cancer and atherosclerosis. 23856922 Panax Quinquefolium Saponin Attenuates Ventricular Remodeling After Acute Myocardial Infarction by Inhibiting CHOP-Mediated Apoptosis. Panax quinquefolium saponin (PQS) alleviates hypoxia-reoxygenation injury of cardiomyocytes in vitro by inhibiting excessive endoplasmic reticulum stress (ERS)-related apoptosis. We hypothesized that inhibition of excessive ERS-related apoptosis contributes to cardioprotection in ventricular remodeling following acute myocardial infarction (AMI). Sprague-Dawley (SD) rats subjected to AMI were randomly treated with either water, PQS (50 mg/kg/d, 100 mg/kg/d or 200 mg/kg/d) or taurine (300 mg/kg/d), an ERS inhibitor, for 4 weeks. Left ventricle (LV) fractional shortening (FS), ejection fraction (EF) and structure were then evaluated using echocardiography. Myocardial infarct size was measured by Evans blue and 2, 3, 5-triphenyhetrazolium chloride (TTC) staining. The hydroxyproline level was determined using the colorimetric method. Cardiomyocyte apoptosis was detected using Terminal Deoxynucleotidyl Transferase Mediated dUTP Biotin Nick End Labeling (TUNEL). In addition, expression of ERS molecule in the non-infarcted myocardium was detected using Western blotting. We found that PQS treatment significantly reduced infarct size and LV dilation and improved LV EF and FS in rat hearts. PQS treatment also decreased hydroxyproline level in non-infarcted myocardium. PQS treatment significantly decreased expression of glucose regulating protein 78 (GRP78), calreticulin (CRT), C/EBP homologous protein (CHOP) and Bax protein, as well as increased Bcl-2 protein expression in non-infarcted myocardium. PQS (200 mg/kg/d) treatment mimicked the results achieved from the taurine-treated rats. CHOP expression positively correlated with the apoptosis index of cardiomyocytes in the non-infarcted myocardium (r = 0.797, P<0.01). Taken together, PQS treatment significantly improves AMI-induced LV remodeling, and this may be attributed to inhibiting CHOP-mediated ERS-related apoptosis. 23801758 Targeted therapy of spontaneous murine pancreatic tumors by polymeric micelles prolongs survival and prevents peritoneal metastasis. Nanoscaled drug-loaded carriers are of particular interest for efficient tumor therapy as numerous studies have shown improved targeting and efficacy. Nevertheless, most of these studies have been performed against allograft and xenograft tumor models, which have altered microenvironment features affecting the accumulation and penetration of nanocarriers. Conversely, the evaluation of nanocarriers on genetically engineered mice, which can gradually develop clinically relevant tumors, permits the validation of their design under normal processes of immunity, angiogenesis, and inflammation. Therefore, considering the poor prognosis of pancreatic cancer, we used the elastase 1-promoted luciferase and Simian virus 40 T and t antigens transgenic mice, which develop spontaneous bioluminescent pancreatic carcinoma, and showed that long circulating micellar nanocarriers, incorporating the parent complex of oxaliplatin, inhibited the tumor growth as a result of their efficient accumulation and penetration in the tumors. The reduction of the photon flux from the endogenous tumor by the micelles correlated with the decrease of serum carbohydrate-associated antigen 19-9 marker. Micelles also reduced the incidence of metastasis and ascites, extending the survival of the transgenic mice. 23786731 Scandinavian neuroscience during the Nazi era. Although Scandinavian neuroscience has a proud history, its status during the Nazi era has been overlooked. In fact, prominent neuroscientists in German-occupied Denmark and Norway, as well as in neutral Sweden, were directly affected. Mogens Fog, Poul Thygesen (Denmark) and Haakon Sæthre (Norway) were resistance fighters, tortured by the Gestapo: Thygesen was imprisoned in concentration camps and Sæthre executed. Jan Jansen (Norway), another neuroscientist resistor, escaped to Sweden, returning under disguise to continue fighting. Fritz Buchthal (Denmark) was one of almost 8000 Jews escaping deportation by fleeing from Copenhagen to Sweden. In contrast, Carl Værnet (Denmark) became a collaborator, conducting inhuman experiments in Buchenwald concentration camp, and Herman Lundborg (Sweden) and Thorleif Østrem (Norway) advanced racial hygiene in order to maintain the "superior genetic pool of the Nordic race." Compared to other Nazi-occupied countries, there was a high ratio of resistance fighters to collaborators and victims among the neuroscientists in Scandinavia. 23678010 Implicit representations of luminance and the temporal structure of moving stimuli in multiple regions of human visual cortex revealed by multivariate pattern classification analysis. The generation of a behaviorally relevant cue to the speed of objects around us is critical to our ability to navigate safely within our environment. However, our perception of speed is often distorted by prevailing conditions. For instance, as luminance is reduced, our perception of the speed of fast-moving patterns can be increased by as much as 30%. To investigate how the cortical representation of speed may vary under such conditions, we have measured the functional MRI blood oxygen level-dependent (BOLD) response of visual cortex to drifting sine gratings at two very different luminances. The average BOLD response in all areas was band-pass with respect to speed (or equivalently, temporal frequency) and thus contained no unambiguous speed information. However, a multivariate classifier was able to predict grating speed successfully in all cortical areas measured. Similarly, we find that a multivariate classifier can predict stimulus luminance. No differences in either the mean BOLD response or the multivariate classifier response with respect to speed were found as luminance changed. However, examination of the spatial distribution of speed preferences in the primary visual cortex revealed that perifoveal locations preferred slower speeds than peripheral locations at low but not high luminance. We conclude that although an explicit representation of perceived speed has yet to be demonstrated in the human brain, multiple visual regions encode both the temporal structure of moving stimuli and luminance implicitly. 23299190 Antioxidative, antiapoptotic, and proliferative effect of curcumin on liver regeneration after partial hepatectomy in rats. The aim of the present study was to assess the influence of curcumin on liver regeneration after partial hepatectomy (PH) in rats. A total of 24 male Sprague Dawley rats were divided into three groups: sham-operated (SH), PH, and PH + curcumin; each group contains eight animals. The rats in curcumin-treated groups were given curcumin (in a dose of 100 mg/kg body weight) once a day orally for 7 days, starting 3 days prior to hepatectomy operation. At 7 days after resection, liver samples were collected. The malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels were estimated in liver homogenates. Moreover, histopathological examination, mitotic index (MI), proliferating cell nuclear antigen labeling, proliferation index (PI), transferase-mediated 2'-deoxyuridine, 5'-triphosphate nick end-labeling assay, and apoptotic index (AI) were evaluated at 7 days after hepatectomy. As a result, curcumin significantly increased MI and PI and significantly decreased AI in PH rats. Additionally, curcumin remarkably inhibited MDA elevation, restored impaired antioxidant SOD activity and GSH level and also attenuated hepatic vacuolar degeneration and sinusoidal congestion. These results suggested that curcumin treatment had a beneficial effect on liver regenerative capacity of the remnant liver tissue after hepatectomy, probably due to its antioxidative, antiapoptotic, and proliferative properties. 23763407 Estimating HCV prevalence at the state level: a call to increase and strengthen current surveillance systems. The degree to which case surveillance captures persons ever infected with HCV is unknown. We determined the discrepancy between HCV seroprevalence, estimated from national survey data, among adults in New York State in 2008 (n = 286 262, or 1.95%) and the number of infected persons reported to the state's surveillance hepatitis registries (n = 144 015). Findings suggest the need to strengthen the existing surveillance system. 23965399 Melanotic Neuroectodermal Tumor of Infancy Arising in the Temporal Bone. Melanotic neuroectodermal tumor of infancy is a rare melanin-containing neoplasm with locally aggressive and rapid expansile growth, usually involving the maxilla, skull, and mandible of early infancy. Radical surgery is critical for a long-term outcome. We present a case of 14-month-old girl with rapid-growing subcutaneous mass arising in the right temporal bone and extending intracranially on computed tomographic scan. Radical surgery was performed. A brownish-black tumor composed of large pigmented epithelioid cells, positive for cytokeratins and HMB-45, and nests of small neuroblast-like cells positive for neuron-specific enolase and synaptophysin, was diagnosed as melanotic neuroectodermal tumor of infancy. The patient remained well without evidence of recurrence for 1 year after surgery. Clinicopathological features, management alternatives and outcome were discussed. 23786743 The burden of inpatient neurologic disease in a tropical African hospital. Neurologic disorders represent a major burden of disease globally and the spectrum ranges from noncommunicable disorders like stroke and neurodegenerative disorders to central nervous system infections. The purpose of the study is to assess the burden of neurological diseases in a tropical environment. A one year retrospective survey of neurological diseases seen at the University of Calabar Teaching Hospital, Nigeria, was evaluated using patients' medical record. Neurological diseases constituted 24.2% of all medical conditions seen over a one year period. Stroke was found to be the commonest cause of admissions accounting for 42.1% of the cases followed by peripheral neuropathy (13.8%) and meningoencephalitis (7.2%). The immediate case fatality rate was 33.6%. Fifty two percent were discharged home with various levels of recovery while 12.5% left against medical advice. About 2% were referred to other tertiary health institutions. The pattern of neurologic diseases in the local medical wards was not remarkably different from those observed in Nigeria and elsewhere. Stroke remains the most frequent cause of neurologic admissions and mortality in this region is same as observed elsewhere. 23695305 IRAK4 kinase activity is not required for induction of endotoxin tolerance but contributes to TLR2-mediated tolerance. Prior exposure to LPS induces "endotoxin tolerance" that reprograms TLR4 responses to subsequent LPS challenge by altering expression of inflammatory mediators. Endotoxin tolerance is thought to limit the excessive cytokine storm and prevent tissue damage during sepsis but renders the host immunocompromised and susceptible to secondary infections. Tolerance initiated via one TLR can affect cellular responses to challenge via the same TLR ("homotolerance") or through different TLRs ("heterotolerance"). IRAK4, an essential component of the MyD88-dependent pathway, functions as a kinase and an adapter, activating subsets of divergent signaling pathways. In this study, we addressed mechanistically the role of IRAK4 kinase activity in TLR4- and TLR2-induced tolerance using macrophages from WT versus IRAK4(KDKI) mice. Whereas IRAK4 kinase deficiency decreased LPS signaling, it did not prevent endotoxin tolerance, as endotoxin pretreatment of WT and IRAK4(KDKI) macrophages inhibited LPS-induced MAPK phosphorylation, degradation of IκB-α and recruitment of p65 to the TNF-α promoter, expression of proinflammatory cytokines, and increased levels of A20 and IRAK-M. Pretreatment of WT macrophages with Pam3Cys, a TLR2-TLR1 agonist, ablated p-p38 and p-JNK in response to challenge with Pam3Cys and LPS, whereas IRAK4(KDKI) macrophages exhibited attenuated TLR2-elicited homo- and heterotolerance at the level of MAPK activation. Thus, IRAK4 kinase activity is not required for the induction of endotoxin tolerance but contributes significantly to TLR2-elicited homo- and heterotolerance. 23220178 Epigenetic control of neurotransmitter expression in olfactory bulb interneurons. Defining the molecular mechanisms that underlie development and maintenance of neuronal phenotypic diversity in the CNS is a fundamental challenge in developmental neurobiology. The vast majority of olfactory bulb (OB) interneurons are GABAergic and this neurotransmitter phenotype is specified in migrating neuroblasts by transcription of either or both glutamic acid decarboxylase 1 (Gad1) and Gad2. A subset of OB interneurons also co-express dopamine, but transcriptional repression of tyrosine hydroxylase (Th) suppresses the dopaminergic phenotype until these neurons terminally differentiate. In mature OB interneurons, GABA and dopamine levels are modulated by odorant-induced synaptic activity-dependent regulation of Gad1 and Th transcription. The molecular mechanisms that specify and maintain the GABAergic and dopaminergic phenotypes in the OB are not clearly delineated. In this report, we review previous studies and present novel findings that provide insight into the contribution of epigenetic regulatory mechanisms for controlling expression of these neurotransmitter phenotypes in the OB. We show that HDAC enzymes suppress the dopaminergic phenotype in migrating neuroblasts by repressing Th transcription. In the mature interneurons, both Th and Gad1 transcription levels are modulated by synaptic activity-dependent recruitment of acetylated Histone H3 on both the Th and Gad1 proximal promoters. We also show that HDAC2 has the opposite transcriptional response to odorant-induced synaptic activity when compared to Th and Gad1. These findings suggest that HDAC2 mediates, in part, the activity-dependent chromatin remodeling of the Th and Gad1 proximal promoters in mature OB interneurons. 23849894 PAX8 expression in sporadic hemangioblastoma of the kidney supports a primary renal cell lineage: implications for differential diagnosis. Hemangioblastoma is a benign, morphologically distinctive neoplasm of disputed histogenesis that typically occurs in the central nervous system either in the setting of von Hippel-Lindau disease or more often sporadically. Extraneural hemangioblastoma is exceptional and raises a challenging differential diagnosis. Herein, we report a primary renal hemangioblastoma occurring in 51-year-old woman without stigmata of von Hippel-Lindau disease. Histologically, the tumor was composed of sheets of polygonal epithelioid stromal cells with ample pale or eosinophilic, vacuolated cytoplasm in an arborizing capillary network. Tumor cells showed variable nuclear pleomorphism, intranuclear cytoplasmic invaginations, scattered hyaline globules, and psammoma-like calcifications. Some areas showed branching hemangiopericytoma-like vessels with tumor cells radiating from the wall, while other areas were edematous and hyalinized with sparse stromal cells and abundant reticular vessels. Immunohistochemically, the tumor cells reacted strongly and diffusely with antibodies to PAX8, CD10, α-inhibin, S100 protein, neuron-specific enolase, and vimentin, and they showed focal positivity with antibodies to epithelial membrane antigen and AE1/AE3. Tumor cells were negative for CK7, CK8/18, RCC antigen, synaptophysin, chromogranin, c-kit, D2-40, HMB45, melan-A, cathepsin K, SMA, desmin, CD31, CD34, and estrogen and progesterone receptors. Positive immunoreactivity for PAX8 is unexpected and contrasts to central nervous system (CNS) hemangioblastomas, which are essentially always negative for PAX8. This novel finding adds support to the hypothesis that the immunoprofile of extraneural hemangioblastoma varies with site of origin, perhaps as a result of tumor cell lineage and retention of organ-specific markers or acquisition of site-specific antigens due to local factors. 23128355 Symmetrically reduced stiffness and increased extensibility in compression and tension at the mineralized fibrillar level in rachitic bone. In metabolic bone diseases, the alterations in fibrillar level bone-material quality affecting macroscopic mechanical competence are not well-understood quantitatively. Here, we quantify the fibrillar level deformation in cantilever bending in a mouse model for hereditary rickets (Hpr). Microfocus in-situ synchrotron small-angle X-ray scattering (SAXS) combined with cantilever bending was used to resolve nanoscale fibril strain in tensile- and compressive tissue regions separately, with quantitative backscattered scanning electron microscopy used to measure microscale mineralization. Tissue-level flexural moduli for Hpr mice were significantly (p<0.01) smaller compared to wild-type (~5 to 10-fold reduction). At the fibrillar level, the fibril moduli within the tensile and compressive zones were significantly (p<0.05) lower by ~3- to 5-fold in Hpr mice compared to wild-type mice. Hpr mice have a lower mineral content (24.2±2.1Cawt.% versus 27.4±3.3Ca wt.%) and its distribution was more heterogeneous compared to wild-type animals. However, the average effective fibril modulus did not differ significantly (p>0.05) over ages (4, 7 and 10weeks) between tensile and compressive zones. Our results indicate that incompletely mineralized fibrils in Hpr mice have greater deformability and lower moduli in both compression and tension, and those compressive and tensile zones have similar moduli at the fibrillar level. 23945003 The Bdtf1 gene in Alternaria brassicicola is important in detoxifying brassinin and maintaining virulence on Brassica species. Brassinin is an antifungal compound induced in Brassica plants after microbial infection. Molecular evidence is incomplete, however, in supporting the importance of brassinin in plant resistance to pathogens. To test the importance of brassinin in plant defense, we studied the functions of the gene Bdtf1 in the necrotrophic fungus, Alternaria brassicicola. Several strains of mutants of this gene were weakly virulent on Brassica species, causing lesions 70% smaller in diameter than the wild type on three Brassica species. These mutants, however, were as virulent as the wild type on Arabidopsis thaliana. They were similar to the wild type in spore germination, colony morphology, and mycelial growth in nutrient-rich media, both with and without stress-inducing chemicals. Unlike wild-type A. brassicicola, however, the mutants failed to germinate and their hyphal growth was arrested in the presence of 200 µM brassinin. When grown in a medium containing 100 µM brassinin, wild-type mycelium entirely converted the brassinin into a non-toxic derivative, of which the precise chemical nature was not established. Mutants of the Bdtf1 gene were unable to perform this conversion. Our results support the hypothesis that the ability of A. brassicicola to detoxify brassinin is necessary for successful infection of Brassica species. 23541799 Voxel-based classification of FDG PET in dementia using inter-scanner normalization. Statistical mapping of FDG PET brain images has become a common tool in differential diagnosis of patients with dementia. We present a voxel-based classification system of neurodegenerative dementias based on partial least squares (PLS). Such a classifier relies on image databases of normal controls and dementia cases as training data. Variations in PET image characteristics can be expected between databases, for example due to differences in instrumentation, patient preparation, and image reconstruction. This study evaluates (i) the impact of databases from different scanners on classification accuracy and (ii) a method to improve inter-scanner classification. Brain FDG PET databases from three scanners (A, B, C) at two clinical sites were evaluated. Diagnostic categories included normal controls (NC, nA=26, nB=20, nC=24 for each scanner respectively), Alzheimer's disease (AD, nA=44, nB=11, nC=16), and frontotemporal dementia (FTD, nA=13, nB=13, nC=5). Spatially normalized images were classified as NC, AD, or FTD using partial least squares. Supervised learning was employed to determine classifier parameters, whereby available data is sub-divided into training and test sets. Four different database setups were evaluated: (i) "in-scanner": training and test data from the same scanner, (ii) "x-scanner": training and test data from different scanners, (iii) "train other": train on both x-scanners, and (iv) "train all": train on all scanners. In order to moderate the impact of inter-scanner variations on image evaluation, voxel-by-voxel scaling was applied based on "ratio images". Good classification accuracy of on average 94% was achieved for the in-scanner setups. Accuracy deteriorated for setups with mismatched scanners (79-91%). Ratio-image normalization improved all results with mismatched scanners (85-92%). In conclusion, automatic classification of individual FDG PET in differential diagnosis of dementia is feasible. Accuracy can vary with respect to scanner or acquisition characteristics of the training image data. The adopted approach of ratio-image normalization has been demonstrated to effectively moderate these effects. 23510685 A mucin-rich variant of salivary duct carcinoma with a prominent mucinous component, a tumor that mimics mucinous adenocarcinoma. The mucin-rich variant of salivary duct carcinoma (mSDC) is a rare type of salivary duct carcinoma. mSDC usually has both conventional SDC and mucinous adenocarcinoma-like areas. This article describes a first case of mSDC in which 95% of the tumor consisted of a mucinous area without no solid conventional SDC, so that the tumor mimicked mucinous adenocarcinoma. A 55-year-old man was evaluated for a 14 mm mass in the left submandibular gland. The tumor showed that floating tumor nests in a prominent mucinous lake. Some floating tumor nests had focal cribriform pattern with comedo necrosis, and all tumor cells had immunoreactivity for androgen receptor, gross cystic disease fluid protein 15, and Her-2/neu. A diagnosis of mSDC was rendered. mSDC with prominent mucinous component sometimes resembles mucinous adenocarcinoma. Identifying specific histological and immunohistochemical features of floating tumor nests in the mucinous area are important for the diagnosis. 23313021 Hepatitis B in immunosuppressed cancer patients: pathogenesis, incidence and prophylaxis. Hepatitis B virus (HBV) reactivation in immunosuppressed cancer patients is a serious clinical problem for HBV carriers undergoing chemotherapy, because it may result in severe liver injury and prevent completion of life-saving treatment of the underlying malignant disease. We reviewed the literature on the incidence, pathogenesis and management of hepatitis B in immunosuppressed cancer patients. The role of primary prophylaxis has also been reviewed. Patients with a previous HBV infection (negative for hepatitis B surface antigen [HBsAg], and positive for both hepatitis B core antibody [anti-HBc] and/or hepatitis B surface antibody [HBsAb]) can experience HBV reactivation. All guidelines support screening of patients with cancer who are about to undergo potentially immunosuppressive therapy, even if the ASCO provisional clinical opinion considers the screening for patients at heightened risk for chronic HBV infection or if undergoing highly immunosuppressive therapy, as hematopoietic cell transplantation and regimens including rituximab. Several meta-analyses support the prophylactic role of lamivudine in preventing HBV reactivation. Most of studies evaluated retrospectively or, if prospectively designed, compared the effect of prophylactic antiviral therapy against historical controls. Screening for HBV should be considered before chemotherapy. Prophylaxis with lamivudine can reduce the incidence of HBV reactivation as well as HBV-related morbidity and mortality. Unsolved issues include the role of antiviral agent with higher potency and less resistance, how to monitor patients for reactivation and when to stop prophylaxis. 23970297 Nurses' attitudes toward palliative care in south-east Iran. Background: Nurses are the element of the palliative care team who spend the most time with patients. Nurses' attitudes toward palliative care affect their behaviour toward their patients. Aim: This study sought to examine oncology and intensive care unit (ICU) nurses' attitudes toward palliative care in south-east Iran. Methods: A self-administered questionnaire was used to assess the palliative care attitudes of 140 oncology and ICU nurses from three hospitals supervised by Kerman University of Medical Science. Results: Participants had moderately negative to neutral attitudes toward palliative care (2.99±0.29 out of 5). Among all categories, the highest mean score came from the category of 'patient's preferences' (mean=3.66) and the lowest from the category of 'withholding and withdrawing treatment' (mean=2.42). A significant correlation was found between nurses' attitudes toward palliative care and some demographic characteristics, including marital status, type of ward, palliative care education, personal study about palliative care, level of education, and experience of caring for a dying family member. Conclusions: This study suggests that educational designers should include specific courses about death and palliative care in undergraduate and postgraduate nursing curricula. Educational programmes need to build on the specific experiences of death and dying among nurses and auxiliary nurses. 23844204 Evidence for letter-specific position coding mechanisms. The perceptual matching (same-different judgment) paradigm was used to investigate precision in position coding for strings of letters, digits, and symbols. Reference and target stimuli were 6 characters long and could be identical or differ either by transposing two characters or substituting two characters. The distance separating the two characters was manipulated such that they could either be contiguous, separated by one intervening character, or separated by two intervening characters. Effects of type of character and distance were measured in terms of the difference between the transposition and substitution conditions (transposition cost). Error rates revealed that transposition costs were greater for letters than for digits, which in turn were greater than for symbols. Furthermore, letter stimuli showed a gradual decrease in transposition cost as the distance between the letters increased, whereas the only significant difference for digit and symbol stimuli arose between contiguous and non-contiguous changes, with no effect of distance on the non-contiguous changes. The results are taken as further evidence for letter-specific position coding mechanisms. 23896732 Decision Making in Prostate Cancer Screening Using Decision Aids vs Usual Care: A Randomized Clinical Trial. IMPORTANCE The conflicting recommendations for prostate cancer (PCa) screening and the mixed messages communicated to the public about screening effectiveness make it critical to assist men in making informed decisions. OBJECTIVE To assess the effectiveness of 2 decision aids in helping men make informed PCa screening decisions. DESIGN, SETTING, AND PARTICIPANTS A racially diverse group of male outpatients aged 45 to 70 years from 3 sites were interviewed by telephone at baseline, 1 month, and 13 months, from 2007 through 2011. We conducted intention-to-treat univariate analyses and multivariable linear and logistic regression analyses, adjusting for baseline outcome measures. INTERVENTION Random assignment to print-based decision aid (n = 628), web-based interactive decision aid (n = 625), or usual care (UC) (n = 626). MAIN OUTCOMES AND MEASURES Prostate cancer knowledge, decisional conflict, decisional satisfaction, and whether participants underwent PCa screening. RESULTS Of 4794 eligible men approached, 1893 were randomized. At each follow-up assessment, univariate and multivariable analyses indicated that both decision aids resulted in significantly improved PCa knowledge and reduced decisional conflict compared with UC (all P <.001). At 1 month, the standardized mean difference (Cohen's d) in knowledge for the web group vs UC was 0.74, and in the print group vs UC, 0.73. Decisional conflict was significantly lower for web vs UC (d = 0.33) and print vs UC (d = 0.36). At 13 months, these differences were smaller but remained significant. At 1 month, high satisfaction was reported by significantly more print (60.4%) than web participants (52.2%; P = .009) and significantly more web (P = .001) and print (P = .03) than UC participants (45.5%). At 13 months, differences in the proportion reporting high satisfaction among print (55.7%) compared with UC (49.8%; P = .06) and web participants (50.4%; P = .10) were not significant. Screening rates at 13 months did not differ significantly among groups. CONCLUSIONS AND RELEVANCE Both decision aids improved participants' informed decision making about PCa screening up to 13 months later but did not affect actual screening rates. Dissemination of these decision aids may be a valuable public health tool. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00196807. 23849826 Evidence of epidermal growth factor receptor expression in uveal melanoma: Inhibition of epidermal growth factor-mediated signalling by Gefitinib and Cetuximab triggered antibody-dependent cellular cytotoxicity. Despite advances in surgery and radiotherapy of uveal melanoma (UM), many patients develop distant metastases that poorly respond to therapy. Improved therapies for the metastatic disease are therefore urgently needed. Expression of the epidermal growth factor receptor (EGFR), a target of kinase inhibitors and humanised antibodies in use for several cancers, had been reported. Forty-eight human UMs were analysed by expression profiling. Signalling was tested in three EGFR expressing UM cell lines by Western blotting using phosphorylation specific antibodies for EGFR and the downstream mediators AKT (v-akt murine thymoma viral oncogene homolog) and extracellular signal-regulated kinase (ERK). Evidence for signalling in tumours was obtained through the application of a UM-specific EGF-signature. The EGFR specific kinase inhibitor, Gefitinib and the humanised monoclonal antibody, Cetuximab, were tested for their effect on EGFR signalling. Natural killer cell mediated antibody-dependent cellular cytotoxicity (ADCC) and tumour necrosis factor α (TNF-α) release was analysed for Cetuximab. Fourteen of 48 UMs and three of 14 cell lines (over-)express EGFR, at least in part due to trisomy of the EGFR locus on chromosome 7p12. EGFR and the downstream mediator, AKT, are phosphorylated upon stimulation with EGF in EGFR expressing cell lines. EGFR over-expressing tumours but not EGFR negative tumours show an activated EGF-signature. Gefitinib inhibits EGFR and AKT phosphorylation and Cetuximab induces EGFR phosphorylation but inhibits signalling to AKT induced with EGF. Cetuximab triggers natural killer (NK) cells to lyse EGFR+ cell lines and to release TNF-α. EGFR appears suited as a novel molecular drug target for therapy of uveal melanoma. 23822644 Combined subthreshold dose inhibition of myosin light chain phosphorylation and matrix metalloproteinase-2 activity provides cardioprotection from ischemic/reperfusion injury in isolated rat heart. Phosphorylation and degradation of myosin light chain 1 (MLC1) during myocardial ischemia/reperfusion (I/R) injury is a well-established phenomenon. It has been established that matrix metalloproteinase-2 (MMP-2) is involved in MLC1 degradation and that this degradation is increased when MLC1 is phosphorylated. We hypothesized that simultaneous inhibition of MLC1 phosphorylation and MMP-2 activity will protect hearts from I/R injury. As phosphorylation of MLC1 and MMP-2 activity is important for normal heart function, we used a cocktail consisting combination of low (subthreshold for any protective effect alone) doses of MLC kinase, MMP-2 inhibitors and subthreshold dose of an MLC phosphatase activator. Isolated rat hearts were subjected to 20 minutes of global, no-flow ischemia and 30 minutes reperfusion in the absence and presence of inhibitors of MLC1 phosphorylation and degradation. The recovery of cardiac function was improved in a concentration-dependent manner by the MLC kinase inhibitor, ML-7 (1-5μM), the MLC phosphatase activator, Y-27632 (0.05-1μM), or the MMP inhibitor, doxycycline (Doxy, 1-30μM). Co-administration of subthreshold doses of ML-7 (1μM) and Y-27632 (0.05μM) showed a potential synergistic effect in protecting cardiac contractility and MLC1 levels in I/R hearts. Further combination with a subthreshold concentration of Doxy (1μM) showed additional protection that resulted in full recovery to control levels. The results of this study exemplify a novel low-dose multidrug approach to pharmacological prevention of reperfusion injury that will enable a reduction of unwanted side effects and/or cytotoxicity associated with currently available MMP-2 and kinase inhibiting drugs. 23940370 Dirigent domain-containing protein is part of the machinery required for formation of the lignin-based Casparian strip in the root. The endodermis acts as a "second skin" in plant roots by providing the cellular control necessary for the selective entry of water and solutes into the vascular system. To enable such control, Casparian strips span the cell wall of adjacent endodermal cells to form a tight junction that blocks extracellular diffusion across the endodermis. This junction is composed of lignin that is polymerized by oxidative coupling of monolignols through the action of a NADPH oxidase and peroxidases. Casparian strip domain proteins (CASPs) correctly position this biosynthetic machinery by forming a protein scaffold in the plasma membrane at the site where the Casparian strip forms. Here, we show that the dirigent-domain containing protein, enhanced suberin1 (ESB1), is part of this machinery, playing an essential role in the correct formation of Casparian strips. ESB1 is localized to Casparian strips in a CASP-dependent manner, and in the absence of ESB1, disordered and defective Casparian strips are formed. In addition, loss of ESB1 disrupts the localization of the CASP1 protein at the casparian strip domain, suggesting a reciprocal requirement for both ESB1 and CASPs in forming the casparian strip domain. 23877307 Duration of mechanical ventilation after craniosynostosis Repair reduces over time. Background:Pediatric craniosynostosis repair (CR) involves wide scalp dissections with multiple osteotomies and has been associated with significant morbidity. The aim of this study was to document the impact of perioperative complications on prolonged mechanical ventilation after CR. Methods: Data were collected from the anaesthesia records, Paediatric Intensive Care Unit (PICU) progress notes and discharge summaries. All the patients were transferred from the operating room sedated and on mechanical ventilation to the PICU. To highlight the determinants of prolonged mechanical ventilation we performed a logistic regression analysis.. Results: 54 patientsunderwent CR, but 6 were excluded due to incomplete records.. The main intraoperative complications were: metabolic acidosis (32%), hypotension (20%), dural tears laceration (22%) and altered coagulation (18%). Metabolic acidosis (46%) and relative polycythemia (24%) were detected on arrival to the PICU. All children received intraoperative blood products and 23 (46%) were transfused in the postoperative period too. No infective complications were detected. The only determinant associated significantly with a prolonged mechanical ventilation was to have surgery in the first 5 years of the program (p = 0.05) [95% CI 0.358 - 0.996]. Conclusions: All life-threatening complications were intraoperative whereas only milder ones, such as hypercloremic and lactic acidosis were noticed in PICU. All children are alive without any neurological deficits. Even though we deal on a daily basis with complex surgical cases, only time, hence experience, showed an impact on prolonged mechanical ventilation. 23922218 Flow cytometry-based enumeration and functional characterization of cd8 t regulatory cells in patients with multiple myeloma before and after lenalidomide plus dexamethasone treatment. Multiple myeloma (MM) is a malignancy of plasma cells frequently associated with immune abnormalities. Several studies have confirmed that in MM immune deregulation can be mediated by increased numbers of CD4 T regulatory (Treg) cells, and these cells were also associated with poor outcome. In this study, we aimed to study CD8 Treg cells before and after lenalidomide plus dexamethasone (len-dex) treatment in MM patients. Using flow cytometry, we enumerated and assessed suppressive function of CD8 Treg cells in 16 MM patients before and after len-dex treatment. Numbers of CD8 Treg cells (CD8+CD25hi+FoxP3+) (P < 0.01) were significantly increased in MM patients (before treatment) compared to healthy donors. However, no significant changes were observed in CD4 and CD8 T cells. A significant increase in CD8 Treg cells was observed after len-dex treatment compared to pre-treatment but no significant difference was observed in CD4 and CD8 T cells. Proliferation assay data showed that CD8 Treg cells inhibited proliferation of CD4 T cells and IFN-γ secretion in a concentration dependent manner. Suppressive activity of CD8 Treg cells did not differ significantly between healthy donors, untreated and len-dex treated MM patients. A significant abnormal level of IL-10 was observed from proliferation assays of untreated and len-dex treated MM patients compared to healthy donors (P ≤ 0.03). Using flow cytometry, we have shown that suppressive CD8 Treg cells are increased in MM patients and len-dex treatment is unable to control these suppressive CD8 Treg cells. © 2013 International Clinical Cytometry Society. 23921356 Organ allocation in adults with congenital heart disease listed for heart transplant: Impact of ventricular assist devices. Adults with congenital heart disease (CHD) listed for heart transplantation are rarely supported by ventricular assist devices (VADs). This may be a disadvantage to their priority for organ allocation. We sought to determine the relationship between VAD implantation and successful transplantation among patients listed for heart transplant. Adults with CHD patients (N = 1,250) were identified from the United Network for Organ Sharing (UNOS) database from 1985 to 2010 and compared to patients without congenital etiology for heart failure (N = 59,606). VAD use at listing, listing status, status upgrades and reasons for upgrade prior to transplant were trended at 5-year intervals and appropriate statistical comparisons were made between groups. Since 1985, VAD use prior to transplant has increased significantly in patients without CHD, but not in CHD patients (17% vs 3% in 2006 to 2010, p < 0.0001). CHD patients were more likely to be listed as Status 2, compared to those without (66% vs 40%, p < 0.001 for 2006 to 2010), and less likely to be upgraded to Status 1 after listing (43% vs 55%, p = 0.03). Among those upgraded to Status 1, CHD patients were less likely to have a VAD at transplant than those without (3% vs 18%, p = 0.005). VAD use was more likely to result in death in CHD patients. VAD use is less common in CHD patients than in patients without CHD, both at the time of listing and transplantation. Reduced VAD use appears to contribute to lower listing status and organ allocation. These differences have grown more disparate over time. Separate criteria for organ allocation for CHD patients may be justified. 23845945 Geometric frustration of icosahedron in metallic glasses. Icosahedral order has been suggested as the prevalent atomic motif of supercooled liquids and metallic glasses for more than half a century, because the icosahedron is highly close-packed but is difficult to grow, owing to structure frustration and the lack of translational periodicity. By means of angstrom-beam electron diffraction of single icosahedra, we report experimental observation of local icosahedral order in metallic glasses. All the detected icosahedra were found to be distorted with partially face-centered cubic symmetry, presenting compelling evidence on geometric frustration of local icosahedral order in metallic glasses. 23608630 Towards multiscale modeling of influenza infection. Aided by recent advances in computational power, algorithms, and higher fidelity data, increasingly detailed theoretical models of infection with influenza A virus are being developed. We review single scale models as they describe influenza infection from intracellular to global scales, and, in particular, we consider those models that capture details specific to influenza and can be used to link different scales. We discuss the few multiscale models of influenza infection that have been developed in this emerging field. In addition to discussing modeling approaches, we also survey biological data on influenza infection and transmission that is relevant for constructing influenza infection models. We envision that, in the future, multiscale models that capitalize on technical advances in experimental biology and high performance computing could be used to describe the large spatial scale epidemiology of influenza infection, evolution of the virus, and transmission between hosts more accurately. 23432603 Local redundancy governs infants' spontaneous orienting to visual-temporal sequences. Two experiments demonstrate that 5-month-olds are sensitive to local redundancy in visual-temporal sequences. In Experiment 1, 20 infants saw 2 separate sequences of looming colored shapes that possessed the same elements but contrasting transitional probabilities. One sequence was random whereas the other was based on bigrams. Without any prior exposure, infants looked longer at the random sequence. In Experiment 2, 17 infants looked equally long at bigram- and trigram-based sequences. However, an analysis of local redundancy revealed that in both experiments disengagement from the sequences was governed by local repetitions rather than by global sequence statistics. This finding suggests that a spontaneous sensitivity to stimulus complexity helps orient infants to sequences they can learn from. 23444069 Postpubertal examination after hypospadias repair is necessary to evaluate the success of the primary reconstruction. Introduction Hypospadias is one of the most common congenital anomalies. There are many studies describing successful initial repair, but there are few studies examining long-term result. The aims of this study were to evaluate our patients that have been reconstructed for hypospadias and undergone final clinical examination after puberty and to assess how long clinical follow-up time is warranted after hypospadias repair.Patients and Methods A standard protocol, with visits at ages 7, 10, 13 and a final clinical examination at the age of 16, was followed. To objectify our long-term functional and aesthetic results, Hypospadias Objective Scoring Evaluation (HOSE) was used.Results A total of 114 boys reconstructed between 1989 and 2009 had undergone final clinical examination. Seventy-nine were classified as degree I, 25 as degree II, 6 degree III, 3 as degree IV, and 1 boy could not be classified retrospectively. Sixty-seven boys were operated on in stages according to Byars, 25 according to Mathieu, and 14 according to Scuderi. Only eight patients needed release of chordee and realignment of skin. Ten boys needed closure of fistulas and strictures had to be operated on in four cases. At the concluding visit, 86% of the patients had an excellent result according to the total HOSE score. It was noted that six patients had developed an incurvation between the prepubertal and postpubertal checkup.Conclusion It is important that the boys are followed according to a planned standardized protocol until they have passed puberty as incurvation may occur during puberty. 23918074 Consecutive exotropia: risk factor analysis and management outcomes. Purpose: To report the frequency of risk factors and outcomes of consecutive exotropia (XT) following bimedial rectus recession (BMR) for the treatment of childhood esotropia (ET). Methods: Ninety-eight patients with ET, who underwent only BMR between 1996 and 2007, were included in this study. Predictors of the development of consecutive XT and treatment outcomes were compared between groups (group 1, cases with consecutive XT; group 2, cases without consecutive XT). Results: Mean follow-up time after BMR surgery was 7.23 ± 3.62 years. There was no significant difference between the groups in terms of age, preoperative angle of near deviation, follow-up time, or refraction for both eyes (p>0.05 for all). The differences regarding preoperative angle of distance deviation (p = 0.009), presence of inferior oblique overaction (p = 0.023), amount of BMR (p = 0.028), and postoperative adduction limitation (p<0.0001) between the groups were statistically significant. However, only preoperative angle of distance deviation and presence of postoperative adduction limitation were independent risk factors for the development of consecutive XT (p = 0.043, p = 0.007, respectively). Conclusions: Postoperative adduction limitation should alert physicians to the increased risk of developing consecutive XT in the long-term follow-up after BMR for the treatment of childhood ET. 23504912 Canopy-scale relationships between stomatal conductance and photosynthesis in irrigated rice. Modeling stomatal behavior is critical in research on land-atmosphere interactions and climate change. The most common model uses an existing relationship between photosynthesis and stomatal conductance. However, its parameters have been determined using infrequent and leaf-scale gas-exchange measurements and may not be representative of the whole canopy in time and space. In this study, we used a top-down approach based on a double-source canopy model and eddy flux measurements throughout the growing season. Using this approach, we quantified the canopy-scale relationship between gross photosynthesis and stomatal conductance for 3 years and their relationships with leaf nitrogen content throughout each growing season above a paddy rice canopy in Japan. The canopy-averaged stomatal conductance (gsc ) increased with increasing gross photosynthesis per unit green leaf area (Ag ), as was the case with leaf-scale measurements, and 41-90% of its variation was explained by variations in Ag adjusted to account for the leaf-to-air vapor-pressure deficit and CO2 concentration using the Leuning model. The slope (m) in this model (gsc versus the adjusted Ag ) was almost constant within a 15-day period, but changed seasonally. The m values determined using an ensemble dataset for two mid-growing-season 15-day periods were 30.8 (SE = 0.5), 29.9 (SE = 0.7), and 29.9 (SE = 0.6) in 2004, 2005, and 2006, respectively; the overall mid-season value was 30.3 and did not greatly differ among the 3 years. However, m appeared to be higher during the early and late growing seasons. The ontogenic changes in leaf nitrogen content strongly affected Ag and thus gsc . In addition, we have discussed the agronomic impacts of the interactions between leaf nitrogen content and gsc . Despite limitations in the observations and modeling, our canopy-scale results emphasize the importance of continuous, season-long estimates of stomatal model parameters for crops using top-down approaches. 23913667 Tridimensional quantitative porosity characterization of three set calcium silicate-based repair cements for endodontic use. The aim of the this study was to quantitatively evaluate in three-dimensional (3D), the porosity degree of three improved silicate-based endodontic repair cements (iRoot BP Plus(®) , Biodentine(®) , and Ceramicrete) compared to a gold-standard calcium silicate bioactive cement (Pro Root(®) MTA). From each tested cement, four samples were prepared by a single operator following the manufacturer's instructions in terms of proportion, time, and mixing method, using cylindrical plastic split-ring moulds. The moulds were lubricated and the mixed cements were inserted with the aid of a cement spatula. The samples were scanned using a compact micro-CT device (Skyscan 1174, Bruker micro-CT, Kontich, Belgium) and the projection images were reconstructed into cross-sectional slices (NRecon v.1.6.9, Bruker micro-CT). From the stack of images, 3D models were rendered and the porosity parameters of each tested material were obtained after threshold definition by comparison with standard porosity values of Biodentine(®) . No statistically significant differences in the porosity parameters among the different materials were seen. Regarding total porosity, iRoot BP Plus(®) showed a higher percentage of total porosity (9.58%), followed by Biodentine(®) (7.09%), Pro Root(®) MTA (6.63%), and Ceramicrete (5.91%). Regarding closed porosity, Biodentine(®) presented a slight increase in these numbers compared to the other sealers. No significant difference in porosity between iRoot BP Plus(®) , Biodentine(®) , and Ceramicrete were seen. In addition, no significant difference in porosity between the new calcium silicate-containing repair cements and the gold-standard MTA were found. Microsc. Res. Tech., 2013. © 2013 Wiley Periodicals, Inc. 23889422 Itinerant versus localized heavy-electron magnetism. The nature of the itinerant-localized transition of heavy electrons is clarified for the Kondo-Heisenberg lattice at finite temperatures. The phase diagram and electronic structure are derived by means of the continuous-time quantum Monte Carlo method combined with the dynamical mean-field theory. Around the itinerant-localized transition inside the antiferromagnetic phase, nearly flat bands appear on the Fermi surface with an almost vanishing quasiparticle renormalization factor. At the same time, there emerges a strong local magnetic fluctuation with a minute energy scale. Considering both antiferromagnetic and ferromagnetic Heisenberg interactions, a coherent understanding is achieved on rich phase diagrams observed in CeRh_{1-x}Co_{x}In_{5}, CeRu_{2}(Si_{x}Ge_{1-x})_{2}, UGe_{2}, and CeT_{2}Al_{10} (T=Fe, Ru, Os). 23768349 Using visible or near infrared spectroscopy (NIRS) on cheese to authenticate cow feeding regimes. An experiment was conducted to evaluate the ability of two spectroscopy methods to distinguish between pasture and preserved-forage cheeses. The reflectance spectra of 308 fresh and freeze-dried samples of cow's milk cheeses were recorded at wavelengths in the range of the visible, using a portable MINOLTA CM-2002 spectrophotometer. The reflectance spectra of the same samples were also measured in near infrared range using a non-portable laboratory monochromator NIRSystem 6500. The proportion of cheeses correctly classified by NIRS and visible spectra was respectively 0.96 and 0.91 for pasture samples, and 0.96 and 0.79 for preserved-forage samples. No significant differences were found when fresh and freeze-dried cheeses were compared. We conclude that NIRS is able to classify cheese samples from different regimes (here, pasture vs. preserved-forage). 23562632 Hyaluronic acid / chitosan multilayer coatings on neuronal implants for localized delivery of siRNA nanoplexes. Binding, stabilizing and promoting cellular uptake of siRNA are all critical efforts in creating matrices for the localized delivery of siRNA molecules to target cells. In this study, we describe the generation of chitosan imidazole/siRNA nanoplexes (NPs) embedded in nano scope polyelectrolyte multilayers (PEMs) composed of hyaluronic acid and chitosan for sustained and localized drug delivery. Regular PEM build-up, successful integration of NPs and controlled release under physiological conditions were shown. Biological efficacy was evaluated in neuronal cell culture concerning cell adhesion, viability, NPs uptake and gene silencing. The additionally shown biological functionalization of neuronal implants possesses potential for future applications in the field of regenerative medicine and treatment of spinal cord injuries. 23863078 Development and in vivo quantitative magnetic resonance imaging of polymer micelles targeted to the melanocortin 1 receptor. Recent emphasis has focused on the development of rationally designed polymer-based micelle carriers for drug delivery. The current work tests the hypothesis that target specificity can be enhanced by micelles with cancer-specific ligands. In particular, we describe the synthesis and characterization of a new gadolinium texaphyrin (Gd-Tx) complex encapsulated in an IVECT micellar system, stabilized through Fe(III) cross-linking and targeted with multiple copies of a specific ligand for the melanocortin 1 receptor (MC1R), which has been evaluated as a cell-surface marker for melanoma. On the basis of comparative MRI experiments, we have been able to demonstrate that these Gd-Tx micelles are able to target MC1R-expressing xenograft tumors in vitro and in vivo more effectively than various control systems, including untargeted or un-cross-linked Gd-Tx micelles. Taken in concert, the findings reported herein support the conclusion that appropriately designed micelles are able to deliver contrast agent payloads to tumors expressing the MC1R. 23954967 Autophagy Reduces Neuronal Damage and Promotes Locomotor Recovery via Inhibition of Apoptosis After Spinal Cord Injury in Rats. Autophagy is an intracellular catabolic mechanism that maintains the balance of proteins, lipids and aging organelles. 3-Methyladenine (3-MA) is a selective inhibitor of autophagy, whereas rapamycin, an antifungal agent, is a specific inducer of autophagy, inhibiting the protein mammalian target of rapamycin. In the present study, we examined the role of autophagy, inhibited by 3-MA and enhanced by rapamycin, in a model of acute spinal cord injury in rats. We found that rapamycin could significantly increase the expression of microtubule-associated protein 1 light chain 3 (LC3) and Beclin1 at the injury site. At the same time, the number of neurons and astrocytes with LC3 positive in the spinal cord was upregulated with time. In addition, administration of rapamycin produced an increase in the Basso, Beattie and Bresnahan scores of injured rats, indicating high recovery of locomotor function. Furthermore, expression of the proteins Bcl-2 and Bax was upregulated and downregulated, respectively. By contrast, the results for rats treated with 3-MA, which inhibits autophagy, were the opposite of those seen with the rapamycin-treated rats. These results show that induction of autophagy can produce neuroprotective effects in acute spinal cord injury in rats via inhibition of apoptosis. 23455461 Active silver nanoparticles for wound healing. In this preliminary study, the silver nanoparticle (Ag NP)-based dressing, Acticoat™ Flex 3, has been applied to a 3D fibroblast cell culture in vitro and to a real partial thickness burn patient. The in vitro results show that Ag NPs greatly reduce mitochondrial activity, while cellular staining techniques show that nuclear integrity is maintained, with no signs of cell death. For the first time, transmission electron microscopy (TEM) and inductively coupled plasma mass spectrometry (ICP-MS) analyses were carried out on skin biopsies taken from a single patient during treatment. The results show that Ag NPs are released as aggregates and are localized in the cytoplasm of fibroblasts. No signs of cell death were observed, and the nanoparticles had different distributions within the cells of the upper and lower dermis. Depth profiles of the Ag concentrations were determined along the skin biopsies. In the healed sample, most of the silver remained in the surface layers, whereas in the unhealed sample, the silver penetrated more deeply. The Ag concentrations in the cell cultures were also determined. Clinical observations and experimental data collected here are consistent with previously published articles and support the safety of Ag NP-based dressing in wound treatment. 23368853 Hydrogenated ZnO core-shell nanocables for flexible supercapacitors and self-powered systems. Although MnO2 is a promising material for supercapacitors (SCs) due to its excellent electrochemical performance and natural abundance, its wide application is limited by poor electrical conductivity. Inspired by our results that the electrochemical activity and electrical conductivity of ZnO nanowires were greatly improved after hydrogenation, we designed and fabricated hydrogenated single-crystal ZnO@amorphous ZnO-doped MnO2 core-shell nanocables (HZM) on carbon cloth as SC electrodes, showing excellent performance such as areal capacitance of 138.7 mF/cm(2) and specific capacitance of 1260.9 F/g. Highly flexible all-solid-state SCs were subsequently assembled with these novel HZM electrodes using polyvinyl alcohol/LiCl electrolyte. The working devices achieved very high total areal capacitance of 26 mF/cm(2) and retained 87.5% of the original capacitance even after 10 000 charge/discharge cycles. An integrated power pack incorporating series-wound SCs and dye-sensitized solar cells was demonstrated for stand-alone self-powered systems. 23456244 Parental monitoring, parental warmth, and minority youths' academic outcomes: exploring the integrative model of parenting. Guided by the integrative model of parenting, the present study investigated the relationship between parental monitoring and racial/ethnic minority adolescents' school engagement and academic motivation as a function of parental warmth, and explored whether these associations varied for boys and girls. Participants (60 % female) were 208 sixth through eighth grade students (63 % African American, 19 % Latino, 18 % Multiracial) from an urban middle school in the Midwestern United States. Youth completed an in-school survey with items on parenting (parental monitoring, mothers'/fathers' warmth), cognitive engagement (school self-esteem), behavioral engagement (school trouble), and academic motivation (intrinsic motivation). As hypothesized, mothers' warmth enhanced the association between parental monitoring and youths' engagement and motivation. No gender differences in these associations emerged. Fathers' warmth strengthened the negative association between parental monitoring and school trouble, and this association was stronger for boys. Implications regarding the importance of sustaining a high level of monitoring within the context of warm parent-adolescent relationships to best support academic outcomes among minority youth are discussed. 23897991 Maternal Clinical Findings in Malaria in Pregnancy in a Region of Northwestern Colombia. In malaria-endemic regions of Latin America, little is known about malaria in pregnancy. To characterize the clinical and laboratory findings of maternal infection, we evaluated 166 cases of pregnant women infected with Plasmodium spp. in a prospective study conducted in northwestern Colombia during 2005-2006. A total of 89.8% (149 of 166) had fever or a history of fever in the past 48 hours, 9.0% (15 of 166) had severe malaria, of which 66.7% was caused by Plasmodium vivax and 33.3% by P. falciparum. Hepatic dysfunction was the main complication (9 of 15) observed. The proportion of severe cases was similar for both species (P = 0.41). In malaria-endemic areas of Colombia, malaria in pregnancy has a broad clinical spectrum. In pregnant women, P. vivax infection frequently leads to organ-specific complications. 23666621 Pressure-induced endocytic degradation of the Saccharomyces cerevisiae low-affinity tryptophan permease Tat1 is mediated by Rsp5 ubiquitin ligase and functionally redundant PPxY motif proteins. Cells of Saccharomyces cerevisiae express two tryptophan permeases, Tat1 and Tat2, which have different characteristics in terms of their affinity for tryptophan and intracellular localization. Although the high-affinity permease Tat2 has been well documented in terms of its ubiquitin-dependent degradation, the low-affinity permease Tat1 has not yet been characterized fully. Here we show that a high hydrostatic pressure of 25 MPa triggers a degradation of Tat1 which depends on Rsp5 ubiquitin ligase and the EH domain-containing protein End3. Tat1 was resistant to a 3-h cycloheximide treatment, suggesting that it is highly stable under normal growth conditions. The ubiquitination of Tat1 most likely occurs at N-terminal lysines 29 and 31. Simultaneous substitution of arginine for the two lysines prevented Tat1 degradation, but substitution of either of them alone did not, indicating that the roles of lysines 29 and 31 are redundant. When cells were exposed to high pressure, Tat1-GFP was completely lost from the plasma membrane, while substantial amounts of Tat1(K29R-K31R)-GFP remained. The HPG1-1 (Rsp5(P514T)) and rsp5-ww3 mutations stabilized Tat1 under high pressure, but any one of the rsp5-ww1, rsp5-ww2, and bul1Δ bul2Δ mutations or single deletions of genes encoding arrestin-related trafficking adaptors did not. However, simultaneous loss of 9-arrestins and Bul1/Bul2 prevented Tat1 degradation at 25 MPa. The results suggest that multiple PPxY motif proteins share some essential roles in regulating Tat1 ubiquitination in response to high hydrostatic pressure. 23843488 Genetic Characteristics of CTX-M-Type Extended-Spectrum-β-Lactamase (ESBL)-Producing Enterobacteriaceae Involved in Mastitis Cases on Japanese Dairy Farms, 2007 to 2011. Sixty-five CTX-M-2/15/14 extended-spectrum-β-lactamase-producing Enterobacteriaceae were isolated from 258,888 mastitic milk samples from Japanese dairy farms between 2007 and 2011. CTX-M-2-producing Klebsiella pneumoniae and CTX-M-15-producing Escherichia coli were the predominant strains isolated. There was no predominant clonal type, and clonal diversity was found even in strains isolated from a single farm. 23113895 Lower nutritional status and higher food insufficiency in frail older US adults. Frailty is a state of decreased physical functioning and a significant complication of ageing. We examined frailty, energy and macronutrient intake, biomarkers of nutritional status and food insufficiency in US older adult (age ≥ 60 years) participants of the Third National Health and Nutrition Examination Survey (n 4731). Frailty was defined as meeting ≥ 2 and pre-frailty as meeting one of the following four-item criteria: (1) slow walking; (2) muscular weakness; (3) exhaustion and (4) low physical activity. Intake was assessed by 24 h dietary recall. Food insufficiency was self-reported as 'sometimes' or 'often' not having enough food to eat. Analyses were adjusted for sex, race, age, smoking, education, income, BMI, other co-morbid conditions and complex survey design. Prevalence of frailty was highest among people who were obese (20·8 %), followed by overweight (18·4 %), normal weight (16·1 %) and lowest among people who were underweight (13·8 %). Independent of BMI, daily energy intake was lowest in people who were frail, followed by pre-frail and highest in people who were not frail (6648 (se 130), 6966 (se 79) and 7280 (se 84) kJ, respectively, P< 0·01). Energy-adjusted macronutrient intakes were similar in people with and without frailty. Frail (adjusted OR (AOR) 4·7; 95 % CI 1·7, 12·7) and pre-frail (AOR 2·1; 95 % CI 0·8, 5·8) people were more likely to report being food insufficient than not frail people. Serum albumin, carotenoids and Se levels were lower in frail adults than not frail adults. Research is needed on targeted interventions to improve nutritional status and food insufficiency among frail older adults, while not necessarily increasing BMI. 23360430 Bisphenol A activates the Nrf1/2-antioxidant response element pathway in HEK 293 cells. Bisphenol A (BPA) is used in the production of polycarbonate plastics and epoxy resins for baby bottles, liners of canned food, and many other consumer products. Previously, BPA has been shown to reduce the activity of several antioxidant enzymes, which may contribute to oxidative stress. However, the underlying mechanism of the BPA-mediated effect upon antioxidant enzyme activity is unknown. Antioxidant and phase II metabolizing enzymes protect cells from oxidative stress and are transcriptionally activated by Nrf1 and Nrf2 factors through their cis-regulatory antioxidant response elements (AREs). In this work, we have assessed the effect of BPA on the Nrf1/2-ARE pathway in cultured human embryonic kidney (HEK) 293 cells. Surprisingly, glutathione and reactive oxygen species (ROS) assays revealed that BPA application created a more reduced intracellular environment in cultured HEK 293 cells. Furthermore, BPA increased the transactivation activity of ectopic Nrf1 and Nrf2 and increased the expression of ARE-target genes ho-1 and nqo1 at high (100-200 μM) BPA concentrations only. Our study suggests that BPA activates the Nrf1/2-ARE pathway at high (>10 μM) micromolar concentrations. 23413783 Overexpression of CD147 contributes to the chemoresistance of head and neck squamous cell carcinoma cells. Head and neck cancer is the sixth most common cancer in the world and most of them are squamous cell carcinomas. High frequency of cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) leads to tumor relapse and irresponsiveness to cisplatin-based chemotherapy. However, the mechanisms underlying cisplatin resistance is still largely unrevealed. In this study, we found that CD147 was overexpressed in cisplatin-resistant HNSCC cell lines. Based on the result, CD147 expression was down-regulated in the cisplatin-resistant cell line and we observed that the sensitivity to cisplatin increased, as showed in the results of MTT assay and PI-staining apoptotic detection. Meanwhile, transfection of CD147 expression vector promoted the occurrence of cisplatin resistance in the cisplatin-sensitive cell line. Simultaneously blocking of uPAR with neutralizing antibody would significantly prevent the occurrence of cisplatin resistance induced by CD147 overexpression. In conclusion, our study finds that CD147 is also involved in mediating cisplatin resistance in HNSCC and uPAR serves as a possible candidate that collaborates with CD147 in this process. 23274088 Ptaquiloside reduces NK cell activities by enhancing metallothionein expression, which is prevented by selenium. Pteridium aquilinum, one of the most important poisonous plants in the world, is known to be carcinogenic to animals and humans. Moreover, our previous studies showed that the immunosuppressive effects of ptaquiloside, its main toxic agent, were prevented by selenium in mouse natural killer (NK) cells. We also verified that this immunosuppression facilitated development of cancer. Here, we performed gene expression microarray analysis in splenic NK cells from mice treated for 14 days with ptaquiloside (5.3 mg/kg) and/or selenium (1.3 mg/kg) to identify gene transcripts altered by ptaquiloside that could be linked to the immunosuppression and that would be prevented by selenium. Transcriptome analysis of ptaquiloside samples revealed that 872 transcripts were expressed differentially (fold change>2 and p<0.05), including 77 up-regulated and 795 down-regulated transcripts. Gene ontology analysis mapped these up-regulated transcripts to three main biological processes (cellular ion homeostasis, negative regulation of apoptosis and regulation of transcription). Considering the immunosuppressive effect of ptaquiloside, we hypothesized that two genes involved in cellular ion homeostasis, metallothionein 1 (Mt1) and metallothionein 2 (Mt2), could be implicated because Mt1 and Mt2 are responsible for zinc homeostasis, and a reduction of free intracellular zinc impairs NK functions. We confirm these hypotheses and show increased expression of metallothionein in splenic NK cells and reduction in free intracellular zinc following treatment with ptaquiloside that were completely prevented by selenium co-treatment. These findings could help avoid the higher susceptibility to cancer that is induced by P. aquilinum-mediated immunosuppressive effects. 23769476 Cross-sectional changes in patterns of allostatic load among persons with varying disabilities, NHANES: 2001-2010. Allostatic Load (AL) is a measure of physiological stress that correlates with morbidity and mortality. The purpose of this study was to evaluate patterns of AL among persons with each of eight categories of disability versus persons with no disabilities over the 10-year Healthy People 2010 examination period. The study examined measures of AL from the 2001-2010 National Health and Nutrition Examination Survey (NHANES). The independent variable was Disability Status (hearing, vision, memory, physical-mental-emotional, walking up 10 steps, bending or kneeling, lifting or carrying, assistive devices, no disability). Eight laboratory and one social AL dependent variables included blood pressure, body mass index (BMI), HDL cholesterol, number of friends, and neutrophil percentages. Weighted statistical analyses included one-way ANCOVA with age as the covariate and chi-square tests. Among respondents, 2.3% had hearing disabilities; 14.0% vision disabilities, 4.6% memory disabilities; 1.5% physical, mental, emotional disabilities; 1.3%, 5.9%, and 3.5% various mobility disabilities; and 5.3% used assistive devices. Persons with disabilities had significantly higher BMI, lower HDL cholesterol, higher C-reactive protein, and higher neutrophil levels than persons without disabilities. Systolic and diastolic blood pressures decreased during the decade, but BMI increased. A range of 36.2-61.0% of persons with non-hearing disabilities exceeded BMI obesity thresholds during 2009, and 13.8-29.9% had fewer than three friends during 2009. These findings support previous research linking risks for secondary conditions/morbidity and allostatic load while demonstrating associations between disabilities and AL, especially for persons with mobility disabilities. 23966979 GPCR Heterodimerization in the Reproductive System: Functional Regulation and Implication for Biodiversity. A G protein-coupled receptor (GPCR) functions not only as a monomer or homodimer but also as a heterodimer with another GPCR. GPCR heterodimerization results in the modulation of the molecular functions of the GPCR protomer, including ligand binding affinity, signal transduction, and internalization. There has been a growing body of reports on heterodimerization of multiple GPCRs expressed in the reproductive system and the resultant functional modulation, suggesting that GPCR heterodimerization is closely associated with reproduction including the secretion of hormones and the growth and maturation of follicles and oocytes. Moreover, studies on heterodimerization among paralogs of gonadotropin-releasing hormone (GnRH) receptors of a protochordate, Ciona intestinalis, verified the species-specific regulation of the functions of GPCRs via multiple GnRH receptor pairs. These findings indicate that GPCR heterodimerization is also involved in creating biodiversity. In this review, we provide basic and current knowledge regarding GPCR heterodimers and their functional modulation, and explore the biological significance of GPCR heterodimerization. 23126604 Enhancement on oral absorption of paclitaxel by multifunctional pluronic micelles. The aim of the present study is to synthesize Pluronic F127-polyethylenimine-folate (PF127-PEI-FA) copolymer, construct a mixed micelle system with PF127-PEI-FA copolymer and Pluronic P123 (PP123) and to evaluate the potential of these mixed micelles as an oral drug delivery system for paclitaxel (PTX). The results of intestinal absorption revealed that the PTX-loaded micelles displayed superior permeability across intestinal barrier than free drug and PF127-PEI-FA/PP123 mixed micelles exhibited the strongest permeability across intestinal barrier. These results were also proved by the studies on cytotoxicity and cell uptake tests. The mechanism was demonstrated in connection with inhibition of the efflux mediated by intestinal P-glycoprotein (P-gp) and enhancement of the electrostatic interaction of positive micelles with the negative intestinal epithelial cells, thereby promoting the permeation across the intestinal wall. The presence of verapamil and Pluronic both improved the intestinal absorption of PTX, which further certified the effect of Pluronic on P-gp inhibition. Pharmacokinetic study demonstrated that the area under the plasma concentration-time curve (AUC(0→36 h)) of PTX-loaded micelles was three times greater than the PTX solution (dissolved in a 50/50 (vol/vol) mixture of Cremophore EL/dehydrated ethanol) (p < 0.05). In general PF127-PEI-FA/PP123 mixed micelles were proved to be potential oral drug delivery system for PTX. 23860608 Current national practice patterns for inpatient management of ventral abdominal wall hernia in the United States. The health-care burden related to ventral hernia management is substantial, with more than 3 billion dollars in expenditures annually in the US. Previous studies have suggested that the utilization of laparoscopic repair remains relatively low although national volume estimates have not been reported. We sought to estimate the inpatient national volume of elective ventral hernia surgery and characterize the proportion of laparoscopic versus open operations. We analyzed data from the Nationwide Inpatient Sample to identify adults with a diagnosis of an umbilical, incisional, or ventral hernia who underwent an elective inpatient repair between 2009 and 2010. Cases that involved other major abdominal or pelvic operations were excluded. Covariates included patient demographics, surgical approach, and use of mesh. National surgical volume estimates were generated and length of stay and total hospital charges were compared for laparoscopic versus open repairs. A total of 112,070 ventral hernia repairs were included in the analysis: 72.1 % (n = 80,793) were incisional hernia repairs, while umbilical hernia repairs comprised only 6.9 % (n = 7,788). Laparoscopy was utilized in 26.6 % (n = 29,870) of cases. Mesh was placed in 85.8 % (n = 96,265) of cases, including 49.3 % (n = 3,841) of umbilical hernia repairs and 90.1 % (n = 72,973) of incisional hernia repairs. Length of stay and total hospital charges were significantly lower for laparoscopic umbilical, incisional, and "other" ventral hernia repairs (p values all <0.001). Total hospital charges during this 2-year period approached 4 billion dollars ($746 million for laparoscopic repair; $3 billion for open repair). Utilization of laparoscopy for elective abdominal wall hernia repair remains relatively low in the US despite its excellent outcomes. Given the substantial financial burden associated with these hernias, future research focused on preventing the development and optimizing the surgical treatment of ventral abdominal wall hernias is warranted. 23684883 Heart cycle-related effects on event-related potentials, spectral power changes, and connectivity patterns in the human ECoG. The perception of one's own heartbeat is a fundamental interoceptive process that involves cortical and subcortical structures. Yet, the precise spatiotemporal neuronal activity patterns underlying the cortical information processing have remained largely elusive. Although the high temporal and spatial resolution of electrocorticographic (ECoG) recordings is increasingly being exploited in functional neuroimaging, it has not been used to study heart cycle-related effects. Here, we addressed the capacity of ECoG to characterize neuronal signals within the cardiac cycle, as well as to disentangle them from heart cycle-related artifacts. Based on topographical distribution and latency, we identified a biphasic potential within the primary somatosensory cortex, which likely constitutes a heartbeat-evoked potential (HEP) of neuronal origin. We also found two different types of artifacts: i) oscillatory potential changes with a frequency identical to the heart pulse rate, which probably represent pulsatility artifacts and ii) sharp potentials synchronized to the R-peak, corresponding to the onset of ventricular contraction and the cardiac field artifact (CFA) in EEG. Finally, we show that heart cycle-related effects induce pronounced phase-synchrony patterns in the ECoG and that this kind of correlation patterns, which may confound ECoG connectivity studies, can be reduced by a suitable correction algorithm. The present study is, to our knowledge, the first one to show a focally localized cortical HEP that could be clearly and consistently observed over subjects, suggesting a basic role of primary sensory cortex in processing of heart-related sensory inputs. We also conclude that taking into account and reducing heart cycle-related effects may be advantageous for many ECoG studies, and are of crucial importance, particularly for ECoG-based connectivity studies. Thus, in summary, although ECoG poses new challenges, it opens up new possibilities for the investigation of heartbeat-related viscerosensory processing in the human brain. 23905912 Effect of ethnicity on liver transplant for hepatocellular carcinoma. Renal artery aneurysms are uncommon, and various surgical options to treat renal artery aneurysms have been described. We report 2 cases of renal transplants from donors with renal artery aneurysm, after resection of aneurysm, and ex vivo renal artery reconstruction. Two women, aged 52 and 45 years, had diagnoses of hilar renal artery aneurysms during evaluation for left flank pain and hematuria. In both cases, radiologic interventions were impossible because of anatomical relations. Both patients were informed of the therapeutic options available, including nephrectomy, autotransplant, and kidney donation. The patients and their families decided on a kidney donation. Renal function test results of both patients satisfied the living-donor selection criteria. The left and right kidney of each patient was removed laparoscopically, and ex vivo resection of the aneurysm and reconstruction of the renal artery was performed under a surgical microscope. The repaired kidneys were successfully transplanted to 2 men, aged 36 and 37 years. In cases of renal artery aneurysms that necessitate treatment, a renal allograft transplant should be considered as a treatment option. It provides safety and benefit to the recipient as well the donor. 23734623 Climate change adaptation through urban heat management in atlanta, georgia. This study explores the potential effectiveness of metropolitan land cover change as a climate change adaptation strategy for managing rising temperatures in a large and rapidly warming metropolitan region of the United States. Through the integration of a mesoscale meteorological model with estimated land cover data for the Atlanta, Georgia region in 2010, this study quantifies the influence of extensive land cover change at the periphery of a large metropolitan region on temperature within the city center. The first study to directly model a metropolitan scale heat transfer mechanism, we find both enhanced tree canopy and impervious cover in the suburban zones of the Atlanta region to produce statistically significant cooling and warming effects in the urban core. Based on these findings, we conclude that urban heat island management both within and beyond the central developed core of large cities may provide an effective climate change adaptation strategy for large metropolitan regions. 23886033 Attitude after a mild aortic valve lesion during rheumatic mitral valve surgery. We evaluated whether rheumatic aortic valve disease of mild degree should be treated in patients undergoing mitral valve surgery. From 1992 to 2010, 197 patients (aged 52 [19-82] years, male:female = 60:137) who had rheumatic mitral valve disease and mild aortic valve disease were enrolled. The aortic valve was untreated in 114 patients (no treatment group), repaired in 40 patients (aortic valvuloplasty group), and replaced in 43 patients (aortic valve replacement group). Operative mortality occurred in 4 patients (2.0%). There were no differences in early mortality and postoperative complications among the 3 groups. Overall survival at 5, 10, and 15 years was 96.3%, 92.1%, and 85.7%, respectively. In the no treatment group, progression-free survival in significant aortic valve disease at 5, 10, and 15 years was 98.7%, 91.3%, and 81.1%, respectively. This was not superior in the aortic valvuloplasty group (85.9%, 77.6%, and 69.8%, respectively) than in the no treatment group. Freedom from aortic valve disease was lower in patients with aortic stenosis than in those with aortic regurgitation in univariate and multivariable analyses (P < .001). Reoperation was performed in 19 patients, including 2 aortic valve reoperations. Aortic valve-related event-free survival was similar among the 3 groups. Mild aortic valve disease in patients undergoing rheumatic mitral valve surgery could be left untreated, because preventive aortic valve operation does not result in better clinical and echocardiographic outcomes. 23764268 Treatment trials for post-lyme disease symptoms revisited. The authors of 4 National Institutes of Health-sponsored antibiotic treatment trials of patients with persistent unexplained symptoms despite previous antibiotic treatment of Lyme disease determined that retreatment provides little if any benefit and carries significant risk. Two groups recently provided an independent reassessment of these trials and concluded that prolonged courses of antibiotics are likely to be helpful. We have carefully considered the points raised by these groups, along with our own critical review of the treatment trials. On the basis of this analysis, the conclusion that there is a meaningful clinical benefit to be gained from retreatment of such patients with parenteral antibiotic therapy cannot be justified. 23669534 Directed attention reduces processing of emotional distracters irrespective of valence and arousal level. Emotional stimuli tend to capture attention, and this so-called motivated attention is commonly measured using the early posterior negativity (EPN) and the late positive potential (LPP). We hypothesized that voluntary, directed attention reduces motivated attention more strongly for highly than moderately arousing pleasant or unpleasant pictures. Participants were instructed to direct their attention to either a picture at fixation or the letters flanking the picture. Pictures varied substantially in arousal and valence. When the pictures were attended to, EPN and LPP increased linearly with arousal. When the letters were attended to, these linear effects decreased in the EPN for pleasant and unpleasant pictures and in the LPP for pleasant pictures. Thus, directed attention decreases processing of emotional distracters more strongly for highly than moderately arousing pleasant and unpleasant pictures. These results are consistent with the view that directed attention decreases emotion effects on sensory gain. 23851263 Luminance and contrast in visual perception of time to collision. Many animals avoid dark, approaching objects seen against a lighter background but show no or weaker reactions to stimuli with inverted contrast. We investigated whether human observers would respond differently to such stimuli in terms of estimated time-to-arrival. We varied luminances of an approaching, light or dark disk and a plain, grey background, and for several conditions, continuously adjusted calibrations so as to keep contrast and/or overall lightness constant. Since no effects were found, we conclude that humans are able to discard luminance and contrast for the task at hand. Generally, however, performance was affected by different, consecutive regimes of feedback: Initially, without feedback, observers responded inconsistently and much too late; they improved after correct feedback, and in a third block of trials with pseudo-random feedback, they responded increasingly early without reverting to the initial level of uncertainty. We discuss our findings with regard to implications for neural mechanisms, put them in the context of evolutionary considerations, and propose continuative animal behavioral studies. 23911626 Acoustic sensing of the initial adhesion of chemokine-stimulated cancer cells. Chemokines together with their receptors play important roles in tumor metastasis. Intracellular signals stimulated by chemokines regulate the initial adhesion of cancer cells, which controls the subsequent cell spreading and migration. Until now, the nature of initial cell adhesion has been understood very poorly, since conventional assays are static and could not provide dynamic information. In order to address this issue, we adopt an acoustic sensor, quartz crystal microbalance (QCM), to monitor the attachment of chemokine-stimulated cancer cells in real-time. As a model, the chemokine CXCL12 was used to stimulate three human breast cancer cell lines expressing different levels of its receptor CXCR4, which triggers intracellular signaling pathways that activate integrins across cell membrane. Interaction between cellular integrins and adhesion molecules (CAMs) pre-coated on sensor surfaces were in situ monitored by QCM of which the frequency was sensitive to the mechanical connection of cells to the sensor surface. The ratio of frequency shift under stimulation to that without stimulation indicated the number and strength of integrin-CAM binding stimulated by the chemokine. The cell-surface binding was found to be enhanced by CXCL12, which depends on the CAM type and levels of chemokine and receptor, and was significantly inhibited by a blocker of the chemokine pathway. The binding of integrin with intercellular adhesion molecule was also found to be strong and in good correlated with the chemotactic indexes obtained by the classical Boyden chamber assay. This research suggests that acoustic sensing of initial cell adhesion could provide a dynamic insight into cell interfacial phenomena. 23726418 Genetic diversity of cosaviruses in nonpolio acute flaccid paralysis cases of undefined etiology, Northern India, 2010-2011. No cases of wild poliovirus have been reported for more than one and a half years from India. Cases of acute flaccid paralysis (AFP) of undefined etiology continue to occur in the region. Despite the recent discovery of the human Cosavirus (HCoSV) in the feces of children from developing countries, there have been no studies of cosavirus infection in India. To detect and characterize HCoSVs in stool specimens of nonpolio AFP cases by RT-PCR followed by sequencing. A total of 387 fecal samples collected from AFP cases in Uttar Pradesh, India, between May 2010 and April 2011, tested negative on cell culture according to WHO algorithm, were subjected to 5'-UTR region specific RT-PCR followed by sequencing to detect HCoSV. Molecular characterization of HCoSV strains was done by sequencing followed by phylogenetic analysis. 123 (32%) samples tested positive for cosaviruses and 87 (70.7%) were identified for genetic variants by sequencing a 316-nucleotide interval in the partial 5'-UTR region. Cosavirus strains were characterized as putative species HCoSV-A (n=70; 82%), HCoSV-B (n=7; 8%), HCoSV-C (n=1; 1.1) and HCoSV-D (n=4; 4.5%) while 5 (5%) strains remain uncharacterized. The cosavirus infection appeared highest (63.5%) in younger children, and showed a distinct seasonality, with a late summer peak and winter low. This study demonstrates a diversity of cosavirus strains in circulation, and reports the first investigation of HCoSV infection in children with nonpolio acute flaccid paralysis in India. Currently, this study provides baseline data for further studies of HCoSV infections in children with common enteric infections in India. 23363244 Surfactant adsorption and interfacial tension investigations on cyclopentane hydrate. Gas hydrates represent an unconventional methane resource and a production/safety risk to traditional oil and gas flowlines. In both systems, hydrate may share interfaces with both aqueous and hydrocarbon fluids. To accurately model macroscopic properties, such as relative permeability in unconventional systems or dispersion viscosity in traditional systems, knowledge of hydrate interfacial properties is required. This work presents hydrate cohesive force results measured on a micromechanical force apparatus, and complementary water-hydrocarbon interfacial tension data. By combining a revised cohesive force model with experimental data, two interfacial properties of cyclopentane hydrate were estimated: hydrate-water and hydrate-cyclopentane interfacial tension values at 0.32 ± 0.05 mN/m and 47 ± 5 mN/m, respectively. These fundamental physiochemical properties have not been estimated or measured for cyclopentane hydrate to date. The addition of surfactants in the cyclopentane phase significantly reduced the cyclopentane hydrate cohesive force; we hypothesize this behavior to be the result of surfactant adsorption on the hydrate-oil interface. Surface excess quantities were estimated for hydrate-oil and water-oil interfaces using four carboxylic and sulfonic acids. The results suggest the density of adsorbed surfactant may be 2× larger for the hydrate-oil interface than the water-oil interface. Additionally, hydrate-oil interfacial tension was observed to begin decreasing from the baseline value at significantly lower surfactant concentrations (1-3 orders of magnitude) than those for the water-oil interfacial tension. 23947846 Understanding wetting of immiscible liquids near a solid surface using molecular simulation. We introduce Monte Carlo simulation methods for determining interfacial properties of fluids that exhibit bulk liquid-liquid immiscibility. An interface-potential-based approach, in which the interfacial properties of a system are related to the surface excess free energy of a thin fluid film in contact with a surface, is utilized to deduce the wetting characteristics of these systems. We present a framework for implementing this general method within both the grand canonical and semigrand isobaric-isothermal ensembles. Tracking the evolution of interfacial properties along various thermodynamic paths is also examined. This task is accomplished by implementing variants of the expanded ensemble technique, which enables one to obtain components of the interface potential along a path of interest. We also discuss how these concepts are employed to calculate bulk liquid-liquid coexistence properties in an efficient manner. The computational strategies introduced here are applied to three model Lennard-Jones systems. For each system, we compile the evolution of the liquid-liquid surface tension and contact angle with temperature or pressure. For one of the model systems we compare our results with literature data. We also examine how interfacial properties evolve upon variation of the relative affinity of the fluid components for the substrate. Overall, we find that the approach pursued here is generally applicable and provides an efficient and precise means to calculate the bulk and interfacial properties of fluids that exhibit liquid-liquid immiscibility. 23361104 Intracellular drug concentrations. Many drug targets are intracellular. To access them, a drug molecule must pass through the cell membrane, a process often facilitated or impeded by transporters. Once in the cytoplasm, basic molecules may become concentrated in organelles. To predict the pharmacologic effect accurately, there must be data concerning the concentration at the target, which is difficult to measure. Techniques that combine mass spectrometry and imaging techniques (matrix-assisted laser desorption/ionization, secondary ion mass spectrometry (SIMS), and nanoSIMS) have promise in addressing this problem. 22963396 Clinical and laboratory findings in patients with oliguric and non-oliguric hantavirus haemorrhagic fever with renal syndrome: an analysis of 128 patients. Patients with haemorrhagic fever with renal syndrome (HFRS) may present without significant oliguria. We compared different initial clinical symptoms and laboratory findings in patients who developed oliguric acute renal failure (ARF) with those in patients who did not develop oliguric ARF. Overall, 128 patients with serologically confirmed HFRS were hospitalized at the University Hospital for Infectious Disease, Zagreb, Croatia between January 1999 and December 2010. Clinical signs and laboratory findings were extracted from medical charts, and were assessed for their relationship to the development of oliguric ARF. Puumala virus infection was diagnosed in 101 (79%) patients, and Dobrava-Belgrade virus infection in 27 (21%). Oliguria or anuria developed in 30% of patients. We identified the following risk factors for the development of oliguria and anuria on multivariable analysis: conjunctival hyperaemia or bleeding (relative risk (RR) 1.84, 95% CI 1.09-3.10; p 0.023), diarrhoea (RR 1.45, 95% CI 1.07-1.97; p 0.017), serum sodium of ≤133 mM (RR 2.21, 95% CI 1.34-3.64; p 0.002), and dipstick protein value of >1.5 g/L (RR 1.59, 95% CI 1.09-2.33; p 0.016), as well as hiking in the forest (RR 1.92, 95% CI 1.13-3.26; p 0.016). Our findings may help physicians in the earlier identification of patients with a more severe form of HFRS caused by Puumala and Dobrava-Belgrade viruses. Particular attention should be given to findings such as conjunctival hyperaemia or bleeding, diarrhoea, a low serum sodium level, and proteinuria. 23806855 Endocrinology of number of follicular waves per estrous cycle and contralateral or ipsilateral relationship between corpus luteum and preovulatory follicle in heifers. A 3-d extension of the luteal phase occurs in interovulatory intervals (IOIs) with a contralateral relationship between the corpus luteum (CL) and preovulatory follicle with 3 follicular waves (Contra-3W group). Concentrations of FSH, progesterone, LH, and estradiol-17β for the ipsilateral versus contralateral CL and/or follicle relationship and 2 versus 3 waves per IOI were studied in 14 heifers. Follicular waves and FSH surges were designated 1, 2, or 3, according to order of occurrence in the IOI. The day (day 0 = ovulation) of the FSH peak in surge 2 occurred earlier (P < 0.02) in 3-wave IOIs (day 6.3 ± 0.5) than in 2-wave IOIs (day 8.5 ± 0.5). Mean FSH was higher in 3-wave than in 2-wave IOI on 82% of the days in the IOI. Repeatability or individuality in FSH concentration was indicated by a correlation (r = 0.54, P < 0.04) in FSH concentrations between ovulations at the beginning and at the end of the IOI. Concentrations of LH and estradiol increased (P < 0.05) near the beginning of the luteolytic period in 2-wave IOI regardless of the CL and/or follicle relationship. In the Contra-3W group, LH and estradiol remained at basal concentrations concurrently with FSH surge 3 and extension of the luteal phase. The hypotheses were supported that FSH surge 2 occurs earlier in 3-wave IOIs than in 2-wave IOIs and that the development of 3-wave IOIs occurs in individuals with greater FSH concentrations. Extension of the luteal phase in the Contra-3W group was temporally associated with lower concentrations of LH and estradiol. 23916318 Effect of carbodiimide (EDC) on the bond stability of etch-and-rinse adhesive systems. Recent studies supported the use of protein cross-linking agents during bonding procedures to inactivate endogenous dentin proteases, preventing dentin collagen degradation thus improving bond durability. The aim of this study was to evaluate the effect of a 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)-containing conditioner on the stability of the adhesive interface created by two etch-and-rinse adhesives. Human dentin was etched with 35% phosphoric acid, treated with 0.3M EDC-containing conditioner followed by a three-step or a two-step etch-and-rinse adhesive. Adhesives were applied to control specimens without EDC pre-treatment. Specimens were subjected to microtensile bond strength test and pulled to failure after 24h or 1 year of storage and interfacial nanoleakage expression was evaluated and quantified by light microscopy. Additionally, to investigate endogenous dentin matrix metalloproteinase activity a zymographic assay was performed on protein extracts obtained from phosphoric-acid-etched dentin powder with or without EDC treatment. The use of the EDC-containing conditioner did not affect immediate bond strength to dentin but contributed to preserve the bond strength after 1 year (p<0.05) for both tested adhesives. No difference was found in the interfacial nanoleakage expression that increased after aging irrespective from the treatment. EDC pre-treatment inhibited dentin endogenous MMPs as assayed with the zymography. In conclusion, the results of the study provide proof that EDC can produce long-term inactivation of MMPs in acid-etched dentin matrices contributing to bond strength preservation over time. Future studies are needed to support the use of EDC in vivo. 23549423 Ultrahigh-efficiency photocatalysts based on mesoporous Pt-WO3 nanohybrids. A reliable nanocasting method has been developed to synthesize mesoporous hybrids of platinum (Pt) nanoparticles decorating tungsten trioxide (WO3). The process began with modification of the SBA-15 template with carbon polymers and Pt nanoparticles accompanied by adsorption of W(6+), which was then converted into m-Pt-WO3 composites by heat treatment and subsequent template removal. The synthetic strategy can be easily extended to prepare other mesoporous nanohybrids with metal oxide loaded precious metal composites. Comprehensive characterizations suggest that the as-developed m-Pt-WO3 nanohybrid exhibits unique properties with mesoporous structure, excellent crystalline structure, and high surface area. When the photocatalytic properties of m-Pt-WO3 nanohybrids were systematically investigated, it was revealed that the m-Pt-WO3 nanohybrids showed great promise for degrading the organic dye under visible light irradiation, which shows an excellent photocatalytic activity that far exceeded those of pure phase mesoporous WO3 and commercial TiO2 (P25), and was 10-fold more active than that of the bulk Pt-WO3 catalyst. The as-developed synthetic route opens up a new avenue for designing mesoporous hybrid materials for various applications benefiting from the unique porous structure, high surface area, and synergistic effects among constituents. 23968541 Resuscitation and auto resuscitation by airway reflexes in animals. Various diseases often result in decompensation requiring resuscitation. In infants moderate hypoxia evokes a compensatory augmented breath -- sigh and more severe hypoxia results in a solitary gasp. Progressive asphyxia provokes gasping respiration saving the healthy infant -- autoresuscitation by gasping. A neonate with sudden infant death syndrome, however, usually will not survive. Our systematic research in animals indicated that airway reflexes have similar resuscitation potential as gasping respiration. Nasopharyngeal stimulation in cats and most mammals evokes the aspiration reflex, characterized by spasmodic inspiration followed by passive expiration. On the contrary, expiration reflex from the larynx, or cough reflex from the pharynx and lower airways manifest by a forced expiration, which in cough is preceded by deep inspiration. These reflexes of distinct character activate the brainstem rhythm generators for inspiration and expiration strongly, but differently. They secondarily modulate the control mechanisms of various vital functions of the organism. During severe asphyxia the progressive respiratory insufficiency may induce a life-threatening cardio-respiratory failure. The sniff- and gasp-like aspiration reflex and similar spasmodic inspirations, accompanied by strong sympatho-adrenergic activation, can interrupt a severe asphyxia and reverse the developing dangerous cardiovascular and vasomotor dysfunctions, threatening with imminent loss of consciousness and death. During progressive asphyxia the reversal of gradually developing bradycardia and excessive hypotension by airway reflexes starts with reflex tachycardia and vasoconstriction, resulting in prompt hypertensive reaction, followed by renewal of cortical activity and gradual normalization of breathing. A combination of the aspiration reflex supporting venous return and the expiration or cough reflex increasing the cerebral perfusion by strong expirations, provides a powerful resuscitation and autoresuscitation potential, proved in animal experiments. They represent a simple but unique model tested in animal experiments. 23860327 Effect of genetic variations within the SH2B2 gene on the growth of Chinese cattle. As an adaptor protein, apart from potentiating Janus kinase 2 (JAK2) activation and promoting the insulin signaling pathway, Src homology 2 B 2 (SH2B2) indirectly takes part in the regulation of glucose uptake through the c-Cb1/CAP/TC10 pathway, which can in turn affect growth. In this study, we identified a 4bp indel mutation and three single nucleotide polymorphisms (SNPs) within the SH2B2 gene in 959 individuals from five Chinese cattle breeds by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing. Based on the four variations, 12 haplotypes were identified. Additionally, there was a tendency that in every population pair-wise linkages increased progressively from V1-V2 to V3-V4. By association analysis, positive effects of genotypes CC and CT (snp1220 locus), DI (4bp indel locus), and CC (snp21049 locus) on growth traits were obtained. Furthermore, when combined, individuals with the combination CCDITTCC showed the best performance at an early age. These results were suggestive of an association of snp1220, 4bp indel and snp12049 with growth performance in Nanyang cattle, indicating possibly the candidate role of the SH2B2 gene in marker assisted selection in a beef cattle breeding program. 23906662 The potato tuber, maize endosperm and a chimeric maize-potato ADP-glucose pyrophosphorylase exhibit fundamental differences in Pi inhibition. ADP-glucose pyrophosphorylase (AGPase) is highly regulated by allosteric effectors acting both positively and negatively. Enzymes from various sources differ, however, in the mechanism of allosteric regulation. Here, we determined how the effector, inorganic phosphate (Pi), functions in the presence and absence of saturating amounts of the activator, 3-phosphoglyceric acid (3-PGA). This regulation was examined in the maize endosperm enzyme, the oxidized and reduced forms of the potato tuber enzyme as well as a small subunit chimeric AGPase (MP), which contains both maize endosperm and potato tuber sequences paired with a wild-type maize large subunit. These data, combined with our previous kinetic studies of these enzymes led to a model of Pi inhibition for the various enzymes. The Pi inhibition data suggest that while the maize enzyme contains a single effector site that binds both 3-PGA and Pi, the other enzymes exhibit more complex behavior and most likely have at least two separate interacting binding sites for Pi. The possible physiological implications of the differences in Pi inhibition distinguishing the maize endosperm and potato tuber AGPases are discussed. 23963867 The Economic Burden of Toxicities Associated with Cancer Treatment: Review of the Literature and Analysis of Nausea and Vomiting, Diarrhoea, Oral Mucositis and Fatigue. Side effects or toxicities are frequent, undesirable companions of almost all forms of non-surgical cancer therapy. It is unusual for patients to complete treatment with radiation or chemotherapy without experiencing at least one form of therapy-associated tissue injury or systemic side effect. Often, toxicities do not occur as solitary events; rather, they result in clusters of symptoms that share a common biological aetiology. Like any disease, cancer treatment-related toxicities (CTRTs) vary in their severity. But, in contrast to most diseases in which incidence is described as being present or absent, the current approach to CTRT typically limits reporting to severe cases only. Not only does this dilute the frequency with which CTRTs occur, but it also undermines our ability to determine the full burden of their impact and to accurately assess the cost effectiveness of potential toxicity interventions. In this article, we report the results of a directed literature review for the years 2000-2012, in which we studied and compared three tissue-based toxicities (nausea and vomiting, diarrhoea, and oral mucositis) and one systemic toxicity (fatigue). Our results confirm the heavy burden of resource use and cost associated with CTRTs. The inclusion of fatigue in our analysis provided an opportunity to compare and contrast a toxicity in which there are both acute and chronic consequences. Our findings also demonstrate a number of challenges to, and opportunities for, future study. Among the most obvious are the lack of provider consistency in diagnosis and grading, especially when there is no global agreement on severity scales. Compounding this inconsistency is the disconnect between healthcare providers and patients that exists when describing toxicity severity and impact. In many cases, cancer can be thought of as a chronic disease that requires prolonged but episodic treatment once the acute disease is eradicated. This change reflects increasing treatment successes, but it also implies that the burden of CTRTs will be expanded and prolonged. Creation of hierarchical attribution of costs in the presence of simultaneous CTRTs, accurate coding, and consistent tracking tools for toxicities will be imperative for effective appraisal of the costs associated with cancer treatment regimen toxicities. 23571104 Is complete lymph node dissection after a positive sentinel lymph node biopsy for cutaneous melanoma always necessary? A meta-analysis. The current recommendation for patients with cutaneous melanoma and a positive sentinel lymph node (SLN) biopsy is a complete lymph node dissection (CLND). However, metastatic melanoma is not present in approximately 80% of CLND specimens. A meta-analysis was performed to identify the clinicopathological variables most predictive of non-sentinel node (NSN) metastases when the sentinel node is positive in patients with melanoma. A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents Connect, Cochrane library, Google scholar, Science Direct, and Web of Science. The search identified 54 relevant articles reporting the frequency of NSN metastases in melanoma. Original data was abstracted from each study and used to calculate a pooled odds ratio (OR) and 95% confidence interval (95% CI). The pooled estimates that were found to be significantly associated with the high likelihood of NSN metastases were: ulceration (OR: 1.88, 95% CI: 1.53-2.31), satellitosis (OR: 3.25, 95% CI: 1.86-5.66), neurotropism (OR: 2.51, 95% CI: 1.39-4.53), >1 positive SLN (OR: 1.77, 95% CI: 1.2-2.62), Starz 3 (old) (OR: 1.83, 95% CI: 0.89-3.76), Angiolymphatic invasion (OR: 2.46, 95% CI: 1.34-4.54), extensive location (OR: 2.22, 95% CI: 1.74-2.81), macrometastases >2 mm (OR: 1.95, 95% CI: 1.61-2.35), extranodal extension (OR: 3.38, 95% CI: 1.79-6.40) and capsular involvement (OR: 3.16, 95% CI: 1.37-7.27). There were 3 characteristics not associated with NSN metastases: subcapsular location (OR: 0.51, 95% CI: 0.38-0.67), Rotterdam Criteria <0.1 mm (OR: 0.29, 95% CI: 0.17-0.50) and Starz I (new) (OR: 0.44, 95% CI: 0.22-0.91). Other variables including gender, Breslow thickness 2-4 mm and extremity as primary site were found to be equivocal. This meta-analysis provides evidence that patients with low SLN tumor burden could probably be spared the morbidity associated with CLND. We identified 9 factors predictive of non-SLN metastases that should be recorded and evaluated routinely in SLN databases. However, further studies are needed to confirm the standard criteria for not performing CLND. 22903142 Emergence of zebrafish models in oncology for validating novel anticancer drug targets and nanomaterials. The in vivo zebrafish models have recently attracted great attention in molecular oncology to investigate multiple genetic alterations associated with the development of human cancers and validate novel anticancer drug targets. Particularly, the transparent zebrafish models can be used as a xenotransplantation system to rapidly assess the tumorigenicity and metastatic behavior of cancer stem and/or progenitor cells and their progenies. Moreover, the zebrafish models have emerged as powerful tools for an in vivo testing of novel anticancer agents and nanomaterials for counteracting tumor formation and metastases and improving the efficacy of current radiation and chemotherapeutic treatments against aggressive, metastatic and lethal cancers. 23657908 Circulation of two mumps virus genotypes in an unimmunized population in India. Two separate outbreaks of fever with parotitis were reported from the Apsinga and Pimpla villages in the Osmanabad district of the Maharashtra State, India during February and March 2012. Meningo-encephalitis was noted in two patients resulting in the death of an 11-year male. Samples of blood and throat swabs were collected from patients with fever and parotitis. Serum samples from suspected (n=62) and convalescent (n=19) patients were tested for mumps virus specific IgM and/or IgG antibodies. Mumps virus specific IgM antibodies were detected in 44 of 62 serum samples (71%). Of the 19 convalescent phase sera 16 had both, anti-mumps virus IgM and IgG antibodies. Twenty-eight throat swabs collected from patients with parotitis were tested by RT-PCR for the SH gene. Twenty-three specimens were found to be positive and nucleotide sequencing of the amplified PCR products revealed circulation of two distinct genotypes that were village specific. Mumps virus genotype C (n=18) was detected in Apsinga village and genotype G (n=5) in Pimpla village. Two mumps virus isolates were also obtained using Vero cells. This is the first report from India confirming simultaneous circulation of mumps virus genotype C in one village and the G genotype in another village only 37 km away. 23897262 Tissue response to bovine fetal collagen extracellular matrix in full-thickness skin wounds. Objectives: To present the findings of the biological response and assimilation of bovine fetal collagen (BFC) as observed in biopsy specimens taken after implant. Methods: The biopsy specimens were from 9 patients with full-thickness skin wounds who received the BFC biomaterial in the first stage of a 2-stage reconstruction. Biopsy specimens were taken at the second stage of skin grafting from the wound margins. Results: The response to the BFC included neovascularization and infiltration of the collagen matrix with fibroblasts. The acellular matrix had the tinctural properties of devitalized tissue, which may be mistaken for coagulative necrosis if one is unaware of the biomaterial implant. Conclusions: The characteristics of BFC histology should be recognized by pathologists involved in patients treated for reconstruction and wound care. 23853350 Supervised patient self-testing of warfarin therapy using an online system. Point-of-care international normalized ratio (INR) monitoring devices simplify warfarin management by allowing selected patients to monitor their own therapy in their homes. Patient self-testing (PST) has been shown to improve the clinical outcomes of warfarin therapy compared to usual care. To compare management of warfarin therapy using PST combined with online supervision by physicians via a custom system with usual warfarin management, which involved laboratory testing and physician dosing. Interested patients were recruited via community pharmacies to participate in a warfarin PST training program. Participants were required to have a long-term indication for warfarin, have been taking warfarin for at least 6 months, and have Internet access in their home. The training involved two sessions covering theoretical aspects of warfarin therapy, use of the CoaguChek XS, and the study website. Following training, patients monitored their INR once weekly for up to 3 months. Patients and physicians utilized a secure website to communicate INR values, dosage recommendations, and clinical incidents. Physicians provided a 6-12 month history of INR results for comparison with study results. The percentage of time spent within the therapeutic INR range (TTR) was the primary outcome, with participants acting as their own historical controls. The percentage of INR tests in range and participant satisfaction were secondary outcomes. Sixteen patients completed training requirements. The mean age of participants was 69.8 (SD 10.1) years. TTR improved significantly from 66.4% to 78.4% during PST (P=.01), and the number of tests within the target range also improved significantly (from 66.0% at prior to the study to 75.9% during PST; P=.04). Patients and physicians expressed a high degree of satisfaction with the monitoring strategy and online system. PST supported by an online system for supervision was associated with improved INR control compared to usual care in a small group of elderly patients. Further research is warranted to investigate the clinical outcomes and cost-effectiveness of online systems to support patients monitoring medications and chronic conditions in the home. 23908384 Enhancement of microhomology-mediated genomic rearrangements by transient loss of mouse Bloom syndrome helicase. Bloom syndrome, an autosomal recessive disorder of the BLM gene, confers predisposition to a broad spectrum of early-onset cancers in multiple tissue types. Loss of genomic integrity is a primary hallmark of such human malignancies, but many studies using disease-affected specimens are limited in that they are retrospective and devoid of an appropriate experimental control. To overcome this, we devised an experimental system to recapitulate the early molecular events in genetically engineered mouse embryonic stem cells, in which cells undergoing loss of heterozygosity (LOH) can be enriched after inducible down-regulation of Blm expression, with or without site-directed DNA double-strand break (DSB) induction. Transient loss of BLM increased the rate of LOH, whose breakpoints were distributed along the chromosome. Combined with site-directed DSB induction, loss of BLM synergistically increased the rate of LOH and concentrated the breakpoints around the targeted chromosomal region. We characterized the LOH events using specifically tailored genomic tools, such as high-resolution array comparative genomic hybridization and high-density single nucleotide polymorphism genotyping, revealing that the combination of BLM suppression and DSB induction enhanced genomic rearrangements, including deletions and insertions, whose breakpoints were clustered in genomic inverted repeats and associated with junctional microhomologies. Our experimental approach successfully uncovered the detailed molecular mechanisms of as-yet-uncharacterized loss of heterozygosities and reveals the significant contribution of microhomology-mediated genomic rearrangements, which could be widely applicable to the early steps of cancer formation in general. 23391281 The complete mitochondrial genome of the pen shell Atrina pectinata (Mollusca: Bivalvia: Pinnidae): The first representative from the family Pinnidae. In this study, we described the complete mitochondrial genome of the pen shell Atrina pectinata. It was 16,811 bp in length and consisted of 35 genes including 12 protein-coding genes, 2 ribosomal RNAs, and 21 transfer RNAs (trnS2 and atp8 lacked). All genes were encoded on the same strand. In gene order, there was no completely identical block compared to those of Mytilus edulis, Crassostrea gigas, Chlamys farreri and Venerupis philippinarum. It may be a ground pattern of Pinnidae mitochondrial genomes. 23003338 Nursing power as viewed by nursing professionals. Background:  The concept of nursing power has not been extensively reported in the nursing literature. Power is an extremely abstract concept, making it difficult to define and study. However, when defined as the capacity to achieve goals, power becomes a significant resource in nursing. Aims:  The aim of this study was to describe how nursing professionals perceive the level of nursing group power in public healthcare organizations. Additionally, the connections between the background variables and nursing group power were analysed. Methods:  The participants in the study consisted of 289 Finnish nurses working in the specialist healthcare sector in Finland. The Sieloff-King Assessment of Group Outcome Attainment within Organizations(©) (SKAGOAO) instrument was utilized to assess the level of nursing group power within the selected organizations. Findings:  According to the present study, nursing professionals rated the outcome attainment (mean, 1.93), as well as goals/outcome competency (mean, 2.24), as very good. The position of nursing (mean, 2.55) as part of the healthcare service system was considered fairly respected. The role of nursing (mean, 2.54) was also considered to be at a good level. As regards to the actualization of power or outcome attainment capacity, respondents gave the lowest ratings to controlling the effects of environmental forces (mean, 2.75), resources (mean, 3.48), communication competency (mean, 3.00) and group supervisor's outcome attainment competency (mean, 2.87). Age, education, type of employment and work experience had an impact on how nursing group power was perceived. Conclusions:  The results of the present study indicated that the nurses perceived the lowest levels of group power in relation to the subscales of controlling the effects of environmental forces, resources, communication competency and group supervisor's outcome attainment competency. 23855433 Individual and Combined Effects of CaCl2 and UV-C on the Biosynthesis of Resveratrols in Grape Leaves and Berry Skins. The individual and combined effects of calcium chloride (CaCl2) and ultraviolet C (UV-C) light on the synthesis of resveratrol in grape leaves and berry skins were investigated. Results showed that all treatments could increase leaf resveratrol contents at least about 5 times, but the combination treatment was the most efficient. Moreover, compared with UV-C treatment, the combination treatment delayed the decline of resveratrol contents. The expression levels of phenylalanine ammonia lyase (PAL), cinnamate-4-hydroxylase (C4H), coumaroyl-CoA ligase (4CL), and stilbene synthase (STS) and 3-O-β-glycosyltransferases, which are related to the synthesis of resveratrol, increased in response to these treatments, paralleling the change in resveratrol content. All treatments also induced the biosynthesis of resveratrol in berry skins at room temperature. The berries of these treatments held at room temperature for 1 day were further stored under low temperature (-1 ± 0.5 °C, RH 95%) for 27 days, and the results showed that all treatments continuously increased berry skin resveratrol content, with the combination treatment being most efficient. During cold storage, resveratrol content remained at high levels and reached a maximum (about 247.7 μg/g FW) at 13 days, then showed a slight decline, though it remained high by the end of storage. Berry firmness and total soluble solids content showed slight changes during cold storage, but there were no differences among the treatments. Thus, the combination treatment of CaCl2 and UV-C could be an efficient method for increasing resveratrol content of table grapes during storage under low temperature. This would be potentially beneficial for producing functional fruits. 23017395 Bioefficacy of EPA-DHA from lipids recovered from fish processing wastes through biotechnological approaches. The effect of fish oil recovered from fish visceral waste (FVW-FO) on serum and liver lipids, activity of HMG-CoA reductase in liver microsomes and EPA+DHA incorporation in liver, heart and brain were evaluated. Rats were fed different concentrations of FVW-FO providing 1.25%, 2.50%, 5.0% EPA+DHA recovered by either fermentation or enzymatic hydrolysis for 8weeks. Feeding FVW-FO reduce triacylglycerols (5.96-20.3%), total cholesterol (7.9-21.5%) and LDL (7.39-21.7%) cholesterol levels in serum compared to group fed on a control diet (groundnut oil). The activity of HMG-CoA reductase was reduced (p<0.05) in the FVW-FO fed groups compared to the control. EPA+DHA level in serum, liver, brain and heart increased with increments in dietary EPA+DHA. Results show the hypolipidemic property of FVW-FO and reduced HMG-CoA reductase activity which is proportional to the incorporation of EPA+DHA. Recovery of FVW-FO will address the increasing demand for fish oil and reduce pollution problems. 23609347 The effects of race, ethnicity, and mood/anxiety disorders on the chronic physical health conditions of men from a national sample. Racial/ethnic differences in health are evident among men. Previous work suggests associations between mental and physical health but few studies have examined how mood/anxiety disorders and chronic physical health conditions covary by age, race, and ethnicity among men. Using data from 1,277 African American, 629 Caribbean Black, and 371 non-Hispanic White men from the National Survey of American Life, we examined associations between race/ethnicity and experiencing one or more chronic physical health conditions in logistic regression models stratified by age and 12-month mood/anxiety disorder status. Among men <45 years without mood/anxiety disorders, Caribbean Blacks had lower odds of chronic physical health conditions than Whites. Among men aged 45+ years with mood/anxiety disorders, African Americans had greater odds of chronic physical health conditions than Whites. Future studies should explore the underlying causes of such variation and how studying mental and chronic physical health problems together may help identify mechanisms that underlie racial disparities in life expectancy among men. 23918662 Non-exomic and synonymous variants in ABCA4 are an important cause of Stargardt disease. Mutations in ABCA4 cause Stargardt disease and other blinding autosomal recessive retinal disorders. However, sequencing of the complete coding sequence in patients with clinical features of Stargardt disease sometimes fails to detect one or both mutations. For example, among 208 individuals with clear clinical evidence of ABCA4 disease ascertained at a single institution, 28 had only one disease-causing allele identified in the exons and splice junctions of the primary retinal transcript of the gene. Haplotype analysis of these 28 probands revealed 3 haplotypes shared among ten families, suggesting that 18 of the 28 missing alleles were rare enough to be present only once in the cohort. We hypothesized that mutations near rare alternate splice junctions in ABCA4 might cause disease by increasing the probability of mis-splicing at these sites. Next-generation sequencing of RNA extracted from human donor eyes revealed more than a dozen alternate exons that are occasionally incorporated into the ABCA4 transcript in normal human retina. We sequenced the genomic DNA containing 15 of these minor exons in the 28 one-allele subjects and observed five instances of two different variations in the splice signals of exon 36.1 that were not present in normal individuals (P < 10(-6)). Analysis of RNA obtained from the keratinocytes of patients with these mutations revealed the predicted alternate transcript. This study illustrates the utility of RNA sequence analysis of human donor tissue and patient-derived cell lines to identify mutations that would be undetectable by exome sequencing. 23611834 7-Oxo-cholesterol potentiates pro-inflammatory signaling in human M1 and M2 macrophages. Macrophages, the major cellular components of atherosclerotic plaques, consist of two main subsets: the pro-inflammatory, M1 or classically activated macrophages, and the anti-inflammatory, M2 or alternatively activated macrophages. The molecular and cellular mechanisms that orchestrate the macrophage polarization and activation that may play a role in plaque progression and stability are poorly understood. Recent studies suggest that oxysterols, oxidative stress-mediated cholesterol oxidation products that are abundant in atherosclerotic lesions, may affect macrophage biology. We investigated whether 7-oxo-cholesterol (7oxo-C) affected polarized human M1 and M2 macrophage phenotypes and functions. Monocyte-derived M1 and M2 macrophages were challenged with 7oxo-C and their phenotype analyzed using flow cytometric analysis, and their function via secretome profiling, the presence of endocytosis and matrix metalloproteinase-9 (MMP-9) release. 7oxo-C increased the expression of HLA-DR in M1 macrophages, and CD14 on M2 macrophages. The oxysterol also reduced CD16 expression on M1 macrophages, while reducing their endocytotic capability and increasing MMP-9 secretion in M2 macrophages. Secretome profiling from cultured cell supernatants showed that 7oxo-C stimulated the production of key pro-atherogenic mediators involved in pro-inflammatory, pro-invasive and pro-angiogenic mechanisms both in M1 and M2 cells. Hypoxic conditions potentiated the effects of 7oxo-C on M1 and M2 cells. The ability of 7oxo-C to polarize macrophages toward a pro-inflammatory state represents a potentially novel mechanism by which oxidative stress can contribute to atherosclerotic lesion progression. 23945135 Physics of protein motility and motor proteins. Motor proteins are enzymatic molecules that transform chemical energy into mechanical motion and work. They are critically important for supporting various cellular activities and functions. In the last 15 years significant progress in understanding the functioning of motor proteins has been achieved due to revolutionary breakthroughs in single-molecule experimental techniques and strong advances in theoretical modelling. However, microscopic mechanisms of protein motility are still not well explained, and the collective efforts of many scientists are needed in order to solve these complex problems. In this special section the reader will find the latest advances on the difficult road to mapping motor proteins dynamics in various systems. Recent experimental developments have allowed researchers to monitor and to influence the activity of single motor proteins with a high spatial and temporal resolution. It has stimulated significant theoretical efforts to understand the non-equilibrium nature of protein motility phenomena. The latest results from all these advances are presented and discussed in this special section. We would like to thank the scientists from all over the world who have reported their latest research results for this special section. We are also grateful to the staff and editors of Journal of Physics: Condensed Matter for their invaluable help in handling all the administrative and refereeing activities. The field of motor proteins and protein motility is fast moving, and we hope that this collection of articles will be a useful source of information in this highly interdisciplinary area. Physics of protein motility and motor proteins contents Physics of protein motility and motor proteinsAnatoly B Kolomeisky Identification of unique interactions between the flexible linker and the RecA-like domains of DEAD-box helicase Mss116 Yuan Zhang, Mirkó Palla, Andrew Sun and Jung-Chi Liao The load dependence of the physical properties of a molecular motor Xianchao Meng, Min Yu and Yunxin Zhang Microtubule organization by kinesin motors and microtubule crosslinking protein MAP65 Joshua Pringle, Amutha Muthukumar, Amanda Tan, Laura Crankshaw, Leslie Conway and Jennifer L Ross Backtracking dynamics of RNA polymerase: pausing and error correction Mamata Sahoo and Stefan Klumpp First-passage problems in DNA replication: effects of template tension on stepping and exonuclease activities of a DNA polymerase motor Ajeet K Sharma and Debashish Chowdhury. 23715410 DiGalactosyl-Glycero-Ether Lipid: synthetic approaches and evaluation as SK3 channel inhibitor. The recent discoveries of the involvement of SK3 channel in some cell motility mechanisms occurring in cancer disease have opened up the way to the synthesis of inhibitors that could reduce metastasis formation. On the basis of our recent previous works showing that both lactose-glycero-ether lipid (Ohmline) and some phosphate analogues (GPGEL) were efficient compounds to modulate SK3 channel activity, the present study, which found its inspiration in the structure of the natural glycolipid DiGalactosylDiacylGlycerol (DGDG), reports the incorporation of a digalactosyl moiety (α-galactopyranosyl-(1→6)-β-galactopyranosyl-) as the polar head of a glycero ether lipid. For the construction of the digalactosyl fragment, two synthetic approaches were compared. The standard strategy which is based on the use of the benzyl protecting group to produce 1→6 disaccharide unit, was compared with a second method that made use of the trimethylsilyl moiety as a protecting group. This second strategy, which is applied for the first time to the synthesis of (1→6)-disaccharide unit, presents a net advantage in terms of efficacy (better global yield) and cost. Finally, compound 16, which is characterized by a (1→6) DiGalactosyl unit (DG) as the polar head of the amphiphilic structure, was tested as a modulator of the SK3 channel activity. Patch-clamp experiments have shown that compound 16 reduced SK3 currents (-28.2 ± 2.0% at 5 μM) and cell migration assays performed at 300 nM have shown a reduction of cell migration (SK3 + HEK293T) by 19.6 ± 2.7%. 22324431 Bromotheoynic acid, a brominated acetylenic acid from the marine sponge Theonella swinhoei. A new brominated C(17) acetylenic acid (1) designated as bromotheoynic acid has been isolated from the marine sponge Theonella swinhoei, collected off the coast of Tanegashima, Kagoshima Prefecture, Japan. The structure was determined on the basis of the analysis of its extensive 2D NMR spectroscopic data as well as HRMS. Bromotheoynic acid (1) inhibited maturation of starfish oocytes and cell division of fertilised starfish eggs. Bromotheoynic acid (1) also inhibited proliferation of human leukaemia U937 and HL60 cells, human lung cancer A549 and H1299 cells, and human embryonic kidney 293 (HEK293) cells. 23479733 Crystal Structures of a Glycoside Hydrolase Family 20 Lacto-N-biosidase from Bifidobacterium bifidum. Human milk oligosaccharides contain a large variety of oligosaccharides, of which lacto-N-biose I (Gal-β1,3-GlcNAc; LNB) predominates as a major core structure. A unique metabolic pathway specific for LNB has recently been identified in the human commensal bifidobacteria. Several strains of infant gut-associated bifidobacteria possess lacto-N-biosidase, a membrane-anchored extracellular enzyme, that liberates LNB from the nonreducing end of human milk oligosaccharides and plays a key role in the metabolic pathway of these compounds. Lacto-N-biosidase belongs to the glycoside hydrolase family 20, and its reaction proceeds via a substrate-assisted catalytic mechanism. Several crystal structures of GH20 β-N-acetylhexosaminidases, which release monosaccharide GlcNAc from its substrate, have been determined, but to date, a structure of lacto-N-biosidase is unknown. Here, we have determined the first three-dimensional structures of lacto-N-biosidase from Bifidobacterium bifidum JCM1254 in complex with LNB and LNB-thiazoline (Gal-β1,3-GlcNAc-thiazoline) at 1.8-Å resolution. Lacto-N-biosidase consists of three domains, and the C-terminal domain has a unique β-trefoil-like fold. Compared with other β-N-acetylhexosaminidases, lacto-N-biosidase has a wide substrate-binding pocket with a -2 subsite specific for β-1,3-linked Gal, and the residues responsible for Gal recognition were identified. The bound ligands are recognized by extensive hydrogen bonds at all of their hydroxyls consistent with the enzyme's strict substrate specificity for the LNB moiety. The GlcNAc sugar ring of LNB is in a distorted conformation near (4)E, whereas that of LNB-thiazoline is in a (4)C1 conformation. A possible conformational pathway for the lacto-N-biosidase reaction is discussed. 23861603 Exercise in obese pregnant women: positive impacts and current perceptions. Overweight and obesity have significant implications during pregnancy and childbirth. The objective of this review was to provide a comprehensive overview of the effect of physical activity on pregnancy outcomes, the change of physical activity during pregnancy, and women's perception of being physically active during pregnancy, with a particular focus on women who are overweight or obese. Many studies have investigated the beneficial effect of exercise during pregnancy, including reduced risk of gestational diabetes, preeclampsia, and operative birth, in addition to improved cardiovascular function, overall fitness, psychological well-being, and mood stability. Benefits for the infant include reduced risks of prematurity and improved fetal growth, although there is more limited information about longer-term health benefits for both women and infants. The existing literature examining physical activity patterns during pregnancy has generally focused on women of all body mass index categories, consistently indicating a reduction in activity over the course of pregnancy. However, the available literature evaluating physical activity during pregnancy among women who are overweight or obese is more limited and contradictory. A number of studies identified barriers preventing women from being active during pregnancy, including pregnancy symptoms, lack of time, access to child care, and concerns about their safety and that of their unborn baby. Conversely, significant enablers included positive psychological feelings, family influence, and receiving advice from health professionals. Very few studies have provided insights about perceptions of being active during pregnancy in the overweight and obese population. There is a need for a detailed description of physical activity patterns during pregnancy in women who are overweight or obese, and more randomized trials evaluating exercise interventions for women who are overweight or obese, with a focus on clinical outcomes. 23643966 Photochemical internalization of CD133-targeting immunotoxins efficiently depletes sarcoma cells with stem-like properties and reduces tumorigenicity. The normal stem cell marker CD133 is also a putative marker of cancer stem cells (CSCs) in different types of cancers. Hence, a major challenge when targeting CD133-expressing CSCs is to prevent depletion of the normal stem cell pool. We hypothesized that the site-specific and light-controlled drug delivery method photochemical internalization (PCI) may have the potential to enhance selectivity and endosomal escape of CD133-targeting immunotoxins in stem-like sarcoma cells. We have used a sarcoma model, SW872 cells isolated from xenografts harboring CSCs within a ~2% CD133(high) subpopulation to investigate the potential of PCI of CD133-targeting toxin as a novel strategy to kill CSCs. Model immunotoxins were generated by binding the ribosome-inactivating protein toxin saporin to each of the monoclonal antibodies CD133/1 (AC133) or CD133/2 (293C), specific for individual CD133-epitopes. Cellular targeting, intracellular co-localization with the PCI photosensitizer, disulfonated meso-tetraphenylchlorin (TPCS2a), and cytotoxic efficacy of PCI of the CD133-targeting toxins were evaluated. PCI of CD133-saporin efficiently targets CD133-expressing SW872 and HT1080 sarcoma cells and results in loss of cell viability. Following sub-toxic treatment, surviving SW872 cells, depleted of the CD133-expressing population, display reduced proliferative capacity and attenuated CSC properties, such as reduced colony-forming ability and tumorigenicity. Here we present a proof-of-concept study, where PCI enables light-triggered delivery of CD133-targeting antibody-drug conjugates, resulting in decreased sarcoma tumor-initiating capacity. PCI of CD133-targeting toxins may be used as a minimal invasive strategy in the treatment of sarcomas, and potentially as a therapeutic for other solid tumors expressing CD133. 23866736 Tolerability and safety of artesunate-amodiaquine and artemether-lumefantrine fixed dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria: two open-label, randomized trials in Nimba County, Liberia. Safety surveillance of widely used artemisinin-based combination therapy (ACT) is essential, but tolerability data in the over five years age group are largely anecdotal. Two open-label, randomized trials were conducted in Nimba County, Liberia: i) the main tolerability trial with 1,000 Plasmodium falciparum malaria patients aged over five years (Study-T), and, ii) an efficacy trial with a secondary objective of collecting tolerability data among 300 children age six to 59 months (Study-E). In both studies patients were randomized to fixed-dose artesunate-amodiaquine (ASAQ Winthrop(R)) or artemether-lumefantrine (AL, Coartem(R)), respectively. Clinical- and laboratory-adverse events (AEs) were recorded until day 28. Study-T: most patients experienced at least one AE. Severe AEs were few, primarily asymptomatic blood system disorders or increased liver enzyme values. No treatment or study discontinuation occurred. Mild or moderate fatigue (39.8% vs 16.3%, p & 0.001), vomiting (7.1% vs 1.6%, p & 0.001), nausea (3.2% vs 1.0%, p = 0.01), and anaemia (14.9% vs 9.8%, p = 0.01) were more frequently recorded in the ASAQ versus AL arm. Study-E: mild or moderate AEs were common, including anaemia, fatigue, vomiting or diarrhoea. The few severe events were asymptomatic blood system disorders and four clinical events (pneumonia, malaria, vomiting and stomatitis). Both ASAQ and AL were well tolerated in patients of all age groups. No unexpected AEs occurred. Certain mild or moderate AEs were more frequent in the ASAQ arm. Standardised safety surveillance should continue for all forms of ACT.Trial registration: The protocols were registered with Current Controlled Trials, under the identifier numbers ISRCTN40020296, ISRCTN51688713 (http://www.controlled-trials.com). 23325022 How benign is hematuria? Using genetics to predict prognosis. Hematuria is a common presenting feature of glomerular disease and is sometimes associated with kidney failure later in life. Where isolated microscopic hematuria occurs in children and young adults, an underlying monogenic disorder, such as Alport syndrome or thin basement membrane nephropathy, is frequently responsible. In this review, these and other diseases, which often present with isolated microscopic hematuria, including hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome, IgA nephropathy, and CFHR5 nephropathy, are discussed together with the associated molecular pathology, clinical features, and prognosis. Genetic testing for these conditions used in clinical practice can provide important diagnostic and prognostic information that is relevant to the patient and their family, particularly when kidney transplantation is considered. 23970209 Superiority of targeted neonatal echocardiography for umbilical venous catheter tip localization: accuracy of a clinician performance model. Objectives:To compare targeted neonatal echocardiography (TnECHO) and antero-posterior (AP) chest radiographs in the localization of the umbilical venous catheter (UVC) tip and to determine the accuracy of UVC tip localization by TnECHO when performed by a trained cohort of pediatric housestaff physicians.Study design:Prospective, observational study of consecutive neonates requiring UVC insertion, in a tertiary care center, in an 18-month period. Chest radiographs reporting optimal position of the UVC tip were compared with the TnECHO results of the pediatric cardiologist. The latter was also compared with the results of TnECHO performed by the pediatric housestaff physicians.Result:Thirty neonates with birth weight ranging between 270 and 4490 g and gestational age ranging between 24 and 44 weeks were enrolled. Nine patients (27%) required UVC tip repositioning as the cardiologist performed TnECHO revealed sub-optimal tip position despite optimal position on chest radiography. Among them, four had the UVC tip in the right atrium and five in the left atrium. Compared with the cardiologist, the housestaff physicians had reported TnECHO with a high-accuracy rate (area under the receiver operating characteristic curve=0.81).Conclusion:TnECHO is superior to chest radiography for identifying malpositioned catheters. TnECHO performed by pediatric housestaff physicians with basic training, demonstrated high-accuracy rates.Journal of Perinatology advance online publication, 22 August 2013; doi:10.1038/jp.2013.96. 23855707 Nonconvective mixing of miscible ionic liquids. Ionic liquids (ILs) are ionic compounds that are liquid at room temperature. We studied the spontaneous mixing behavior between two ILs, ethylammonium nitrate (EAN) and 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM][PF6]), and observed notable phenomena. Experimental studies showed that the interface between the two ILs was unusually long-lived, despite the ILs being miscible with one another. Molecular dynamics (MD) simulations supported these findings and provided insight into the micromixing behavior of the ILs. We found that not only did the ions experience slow diffusion as they mix but also exhibited significant ordering into distinct regions. We suspect that this ordering disrupted concentration gradients in the direction normal to the interface, thus hindering diffusion in this direction and allowing the macroscopic interface to remain for long periods of time. Intermolecular interactions responsible for this behavior included the O-NH interaction between the EAN ions and the carbon chain-carbon chain interactions between the [BMIM](+) cations, which associate more strongly in the mixed state than in the pure IL state. 23550687 Diffusion-weighted imaging changes in cerebral watershed distribution following neonatal encephalopathy are not invariably associated with an adverse outcome. Patterns of injury in term-born infants with neonatal encephalopathy following hypoxia-ischaemia are seen earlier and are more conspicuous on diffusion-weighted magnetic resonance imaging (DW-MRI) than on conventional imaging. Although the prognostic value of DW-MRI in infants with basal ganglia and thalamic damage has been established, data in infants in whom there is extensive injury in a watershed distribution are limited. The aim of this study was to assess cognitive and functional motor outcome in a cohort of infants with changes in a predominantly watershed distribution injury on neonatal cerebral MRI, including DWI. DW-MRI findings in infants with neonatal encephalopathy following hypoxia-ischaemia were evaluated retrospectively. Twenty-two infants in whom DWI changes exhibited a predominantly watershed distribution were enrolled in the study (10 males, 12 females; mean birthweight 3337 g, 2830-3900 g; mean gestational age 40.5 wks, 37.9-42.1 wks). Follow-up MRI data at the age of 3 months (n=15) and over the age of 18 months (n=7) were analysed. In survivors, neurodevelopmental outcome was assessed with the Griffiths Mental Development Scales at the age of at least 18 months. Amplitude-integrated electroencephalography was used to score background patterns and the occurrence of epileptiform activity. DW-MRI revealed abnormalities that were bilateral in all infants and symmetrical in 10. The posterior regions were more severely affected in five infants and the anterior regions in three. Watershed injury occurred in isolation in 10 out of 22 infants and was associated with involvement of the basal ganglia and thalami in the other 12, of whom seven died. Cystic evolution, seen on MRI at age 3 months, occurred in three of the 15 surviving infants. Neurodevelopmental assessment of the surviving infants was performed at a median age of 35 months (range 18-48 mo). Of the five survivors with basal ganglia and thalamic involvement, two developed cerebral palsy, one had a developmental quotient of less than 85, and two had a normal outcome. Of the 10 infants with isolated watershed injury, nine had an early normal motor and cognitive outcome. In all infants with a favourable outcome, background recovery was seen on amplitude integrated EEG within 48 hours after birth. Extensive DWI changes in a watershed distribution in term-born neonates are not invariably associated with adverse sequelae, even in the presence of cystic evolution. Associated lesions of the basal ganglia and thalami are a better predictor of adverse sequelae than the extent and severity of the watershed abnormalities seen on DW-MRI. 23526034 Lip augmentation dermal filler reactions, histopathologic features. Instances of perioral and labial foreign body reactions to a variety of injectable dermal fillers were selected from the oral and maxillofacial pathology and dermatopathology archives at Pacific Pathology Laboratory of San Diego with the objective being to engender a compilation of histopathologic characteristics that allow the pathologist to identify the inciting materials. All cases of foreign body reactions located in the lips and perioral regions were reviewed by four pathologists, retaining those cases with a history of injection lip augmentation as well as those with histologic features previously documented to represent dermal filler substances. In selected cases, Alcian blue pH 2.5 with and without hyaluronidase pretreatment was performed. Immunohistochemical markers for macrophages (CD 68), adipocytes (S-100) and keratinocytes (AE1/AE2) were undertaken. All instances presented as single or multiple submucosal plaques, nodules or swellings. Natural polymers including collagen, hyaluronate, hydroxyapatite, poly-L-lactate and synthetic polymers including carboxymethyl cellulose, dimethylpolysiloxane, and polyethyl methacrylate induce histologically unique features that allow for their identification. Host histopathologic responses included nodule without foreign body reaction, nodule with chronic inflammation, granuloma with epithelioid histiocytic and multinucleated giant cell reaction. Dermal filler foreign body host reactions in conjunction with the morphology of the foreign materials themselves are unique and can be differentiated from one another microscopically. 23936376 Using manifold learning for atlas selection in multi-atlas segmentation. Multi-atlas segmentation has been widely used to segment various anatomical structures. The success of this technique partly relies on the selection of atlases that are best mapped to a new target image after registration. Recently, manifold learning has been proposed as a method for atlas selection. Each manifold learning technique seeks to optimize a unique objective function. Therefore, different techniques produce different embeddings even when applied to the same data set. Previous studies used a single technique in their method and gave no reason for the choice of the manifold learning technique employed nor the theoretical grounds for the choice of the manifold parameters. In this study, we compare side-by-side the results given by 3 manifold learning techniques (Isomap, Laplacian Eigenmaps and Locally Linear Embedding) on the same data set. We assess the ability of those 3 different techniques to select the best atlases to combine in the framework of multi-atlas segmentation. First, a leave-one-out experiment is used to optimize our method on a set of 110 manually segmented atlases of hippocampi and find the manifold learning technique and associated manifold parameters that give the best segmentation accuracy. Then, the optimal parameters are used to automatically segment 30 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). For our dataset, the selection of atlases with Locally Linear Embedding gives the best results. Our findings show that selection of atlases with manifold learning leads to segmentation accuracy close to or significantly higher than the state-of-the-art method and that accuracy can be increased by fine tuning the manifold learning process. 23521722 Time-split cross-validation as a method for estimating the goodness of prospective prediction. Cross-validation is a common method to validate a QSAR model. In cross-validation, some compounds are held out as a test set, while the remaining compounds form a training set. A model is built from the training set, and the test set compounds are predicted on that model. The agreement of the predicted and observed activity values of the test set (measured by, say, R(2)) is an estimate of the self-consistency of the model and is sometimes taken as an indication of the predictivity of the model. This estimate of predictivity can be optimistic or pessimistic compared to true prospective prediction, depending how compounds in the test set are selected. Here, we show that time-split selection gives an R(2) that is more like that of true prospective prediction than the R(2) from random selection (too optimistic) or from our analog of leave-class-out selection (too pessimistic). Time-split selection should be used in addition to random selection as a standard for cross-validation in QSAR model building. 23770645 Overcoming recruitment challenges of web-based interventions for tobacco use: The case of web-based acceptance and commitment therapy for smoking cessation. Web-based behavioral interventions for substance use are being developed at a rapid pace, yet there is a dearth of information regarding the most effective methods for recruiting participants into web-based intervention trials. In this paper, we describe our successful recruitment of participants into a pilot trial of web-based Acceptance and Commitment Therapy (ACT) for smoking cessation and compare traditional and web-based methods of recruitment in terms of their effects on baseline participant characteristics, association with study retention and treatment outcome, yield, and cost-effectiveness. Over a 10-week period starting June 15, 2010, we recruited 222 smokers for a web-based smoking cessation study using a variety of recruitment methods. The largest portion of randomized participants were recruited through Google AdWords (36%), followed by medical Internet media (23%), standard media (14%), word of mouth (12%), broadcast emails (11%), and social media (6%). Recruitment source was not related to baseline participant characteristics, 3-month data retention, or 30-day point prevalence smoking abstinence at the 3-month outcome assessment. Cost per randomized participant ranged from $5.27/participant for word of mouth to $172.76/participant for social media, with a mean cost of $42.48/participant. Our diversified approach to recruitment, including both traditional and web-based methods, enabled timely enrollment of participants into the study. Because there was no evidence of a substantive difference in baseline characteristics, retention, or outcomes based on recruitment channel, the yield and cost-effectiveness of recruitment methods may be the more critical considerations in developing a feasible recruitment plan for a web-based smoking cessation intervention study. 23712014 Responses of Hydrilla verticillata (L.f.) Royle to zinc: in situ localization, subcellular distribution and physiological and ultrastructural modifications. Hydrilla verticillata (L.f.) Royle exposed to 15-150 Î¼M Zn for 7 days were analyzed with reference to the ultrastructural localization, subcellular distribution of metal and its influence on photosynthetic efficiency, malondialdehyde (MDA), adenosine triphosphate (ATP) and ultrastructure. Zn grains were found in the cell walls and within nuclei and chloroplasts using the autometallographic technique. Subcellular fractionation of Zn-containing tissues indicated 43-54% of the element was located in the cell wall fraction, followed by cell organelles (24-31%) and the soluble fraction (21-29%). A significant reduction in photosynthetic efficiency was observed in a concentration dependent manner, as indicated by the reduced efficiency of the PS II photochemical system (Fv/Fm). MDA content showed a sharp increase at all Zn concentrations, which indicated oxidative stress. Zn-exposed plants displayed a significant decrease in ATP content. Zn exposure also caused the chloroplasts and nuclei to disintegrate and the vacuolization of mitochondria, all of which suggested that Zn hastened plant senescence. 23278273 Ly6C+ Ly6G- Myeloid-derived suppressor cells play a critical role in the resolution of acute inflammation and the subsequent tissue repair process after spinal cord injury. Acute inflammation is a prominent feature of central nervous system (CNS) insult and is detrimental to the CNS tissue. Although this reaction spontaneously diminishes within a short period of time, the mechanism underlying this inflammatory resolution remains largely unknown. In this study, we demonstrated that an initial infiltration of Ly6C(+) Ly6G(-) immature monocyte fraction exhibited the same characteristics as myeloid-derived suppressor cells (MDSCs), and played a critical role in the resolution of acute inflammation and in the subsequent tissue repair by using mice spinal cord injury (SCI) model. Complete depletion of Ly6C(+) Ly6G(-) fraction prior to injury by anti-Gr-1 antibody (clone: RB6-8C5) treatment significantly exacerbated tissue edema, vessel permeability, and hemorrhage, causing impaired neurological outcomes. Functional recovery was barely impaired when infiltration was allowed for the initial 24 h after injury, suggesting that MDSC infiltration at an early phase is critical to improve the neurological outcome. Moreover, intraspinal transplantation of ex vivo-generated MDSCs at sites of SCI significantly reduced inflammation and promoted tissue regeneration, resulting in better functional recovery. Our findings reveal the crucial role of an Ly6C(+) Ly6G(-) fraction as MDSCs in regulating inflammation and tissue repair after SCI, and also suggests an MDSC-based strategy that can be applied to acute inflammatory diseases. 23585144 Trends in immediate breast reconstruction across insurance groups after enactment of breast cancer legislation. To improve access to breast reconstruction for mastectomy patients, the United States enacted the Women's Health and Cancer Rights Act in January of 1999. The objective of the current study was to evaluate the impact of this legislation on patients with different insurance plans. Women aged ≥18 years who underwent mastectomy for cancer were identified in the Nationwide Inpatient Sample database (2000-2009) and were classified according to their immediate breast reconstruction (IBR) status. Trends in rates of IBR were described for each insurance category. Multivariable logistic regression analysis with adjustment for age, race, estimated household income, and Elixhauser comorbidity index was performed to evaluate the relation between insurance status and IBR. In total, 168,236 patients were identified who underwent a mastectomy during the study interval. Across the 10-year study period, rates of IBR increased 4.2-fold in Medicaid patients, 2.9-fold in Medicare patients, 2.6-fold in privately insured patients, and 2.1-fold in self-pay patients (P < .01). However, after adjustment for confounders, women without private insurance were less likely to undergo IBR compared with women who had private insurance (Medicaid: odds ratio [OR], 0.34; 95% confidence interval [CI], 0.32-0.37; Medicare: OR, 0.53; 95% CI, 0.49-0.58; self-pay: OR, 0.43; 95% CI, 0.37-0.50; other types of nonprivate insurance: OR, 0.64, 95% CI, 0.56-0.73). After the enactment of policy designed to improve access to IBR, Medicaid and Medicare patients experienced the greatest relative increase in rates of IBR. Although policy changes had the most impact on traditionally underserved populations, disparities still exist. Future studies should endeavor to understand why such disparities have persisted. 23579401 Brain regulation of muscle tone in healthy and functionally unstable ankles. Context: Current research into the etiology of joint instability has yielded inconsistent results, limiting our understanding of how to prevent and treat ligamentous injury effectively. Recently, cortical reorganization was demonstrated in patients with ligamentous injury; however, these neural changes have not been assessed relative to joint laxity. Objective: The purpose of the current study was to determine if changes in cortical excitability and inhibition occur in subjects with functional ankle instability, as well as to investigate the relationship between these measures and joint laxity. Design: Posttest only with control group. Setting: University laboratory. Subjects: 12 subjects with no history of ankle sprain (CON) and 12 subjects with a history of unilateral functional ankle instability (UNS). Interventions: Subjects were tested for joint laxity using an instrumented ankle arthrometer. Cortical excitability and inhibition were assessed using transcranial magnetic stimulation (TMS) to obtain motor-evoked potentials and the cortical silent period from the lower leg muscles. Main Outcome Measures: Joint laxity was quantified as peak anterior displacement and inversion rotation. Active motor threshold, slope, and intensity at 50% of peak slope of TMS-derived recruitment curves were used to quantify cortical excitability from lower leg muscles, while the cortical silent period from the peroneus longus was used to represent intracortical inhibition. Results: No significant differences were observed between groups for laxity or cortical measures. CON demonstrated a significant relationship between laxity and tibialis anterior excitability, as well as laxity and silent period, while UNS ankles demonstrated significant relationships between peroneal and soleus excitability and laxity measures. Conclusion: Our results support relationships between laxity and measures of excitability and inhibition that differ between healthy and unstable subjects. Future research should further investigate the mechanisms behind these findings and consider cortical influences when investigating altered joint laxity. 23888071 Serum miR-1290 as a marker of pancreatic cancer - Letter. na. 23709045 Marine-derived Aspergillus species as a source of bioactive secondary metabolites. This report reviews biologically active secondary metabolites from marine-derived members of the fungal genus Aspergillus. Pharmacological activities and biological roles of the secondary metabolites from marine-derived Aspergillus spp. were addressed in respect of pharmaceutical potential. 23793865 Dichloroacetate induces tumor-specific radiosensitivity in vitro but attenuates radiation-induced tumor growth delay in vivo. Inhibition of pyruvate dehydrogenase kinase (PDK) by dichloroacetate (DCA) can shift tumor cell metabolism from anaerobic glycolysis to glucose oxidation, with activation of mitochondrial activity and chemotherapy-dependent apoptosis. In radiotherapy, DCA could thus potentially enhance the frequently moderate apoptotic response of cancer cells that results from their mitochondrial dysfunction. The aim of this study was to investigate tumor-specific radiosensitization by DCA in vitro and in a human tumor xenograft mouse model in vivo. The interaction of DCA with photon beam radiation was investigated in the human tumor cell lines WIDR (colorectal) and LN18 (glioma), as well as in the human normal tissue cell lines HUVEC (endothelial), MRC5 (lung fibroblasts) and TK6 (lymphoblastoid). Apoptosis induction in vitro was assessed by DAPI staining and sub-G1 flow cytometry; cell survival was quantified by clonogenic assay. The effect of DCA in vivo was investigated in WIDR xenograft tumors growing subcutaneously on BALB/c-nu/nu mice, with and without fractionated irradiation. Histological examination included TUNEL and Ki67 staining for apoptosis and proliferation, respectively, as well as pinomidazole labeling for hypoxia. DCA treatment led to decreased clonogenic survival and increased specific apoptosis rates in tumor cell lines (LN18, WIDR) but not in normal tissue cells (HUVEC, MRC5, TK6). However, this significant tumor-specific radiosensitization by DCA in vitro was not reflected by the situation in vivo: The growth suppression of WIDR xenograft tumors after irradiation was reduced upon additional DCA treatment (reflected by Ki67 expression levels), although early tumor cell apoptosis rates were significantly increased by DCA. This apparently paradoxical effect was accompanied by a marked DCA-dependent induction of hypoxia in tumor-tissue. DCA induced tumor-specific radiosensitization in vitro but not in vivo. DCA also induced development of hypoxia in tumor tissue in vivo. Further investigations relating to the interplay between tumor cell metabolism and tumor microenvironment are necessary to explain the limited success of metabolic targeting in radiotherapy. 23867652 Separation and Identification of 1,2,4-Trihydroxynaphthalene-1-O-glucoside in Impatiens glandulifera Royle. Methanolic extract from lyophilized roots of Impatiens glandulifera Royle was analyzed by high performance liquid chromatography using DAD and FLD detection and this revealed one dominant highly fluorescent very unstable substance. The stability of this derivative is strongly dependent on the plant material drying procedure and extraction procedure used. The structure of the substance was established as 1,2,4-trihydroxynaphthalene-1-O-glucoside (THNG) according LC-MS and NMR measurements. When lyophilized plant material was extracted with methanol an almost four times higher amount of THNG was found in the extract, compared to the amount of 2-hydroxy-1,4-naphthoquinone obtained, while in the case of the same lyophilized plant material extracted with water there was no THNG in the extract. The main compounds in this case was 2-hydroxy-1,4-naphthoquinone. In the plant material dried at the laboratory temperature and extracted by methanol there are only traces of THNG. 23685004 Reconstruction of the face and neck with different types of pre-expanded anterior chest flaps: a comprehensive strategy for multiple techniques. For large defects or deformities of the face and neck, the anterior chest area appears to be an excellent donor site that provides well-matched skin colour and texture. Many flap techniques based on the anterior chest area have been reported; however, there are few reports that focus on a treatment strategy for these different flap techniques. A retrospective study was performed to propose a treatment algorithm. A total of 69 cases were reviewed from May 2005 to July 2011, in which different types of anterior chest flaps were performed for face and neck reconstruction. The reconstructive procedures, the defect characteristics and the complications were collected and analysed. Thirty-three pedicled thoracic branch of the supraclavicular artery flaps (the pedicled TBSA flap), 11 pedicled internal mammary artery perforator flaps (the pedicled IMAP flap), 8 free internal mammary artery perforator flaps (the free IMAP flap), 4 supercharged TBSA flaps, 17 prefabricated flaps and 3 supercharged prefabricated flaps were performed. The applications of six types of pre-expanded anterior chest flaps were described in an algorithmic approach. A treatment strategy for face and neck reconstruction using six anterior chest flap techniques is proposed. It recommended a personalised flap planning according to the characteristics of deformities/defects and the regionally dominant vessels of the anterior chest area. 23913273 The BC component of ABC toxins is an RHS-repeat-containing protein encapsulation device. The ABC toxin complexes produced by certain bacteria are of interest owing to their potent insecticidal activity and potential role in human disease. These complexes comprise at least three proteins (A, B and C), which must assemble to be fully toxic. The carboxy-terminal region of the C protein is the main cytotoxic component, and is poorly conserved between different toxin complexes. A general model of action has been proposed, in which the toxin complex binds to the cell surface via the A protein, is endocytosed, and subsequently forms a pH-triggered channel, allowing the translocation of C into the cytoplasm, where it can cause cytoskeletal disruption in both insect and mammalian cells. Toxin complexes have been visualized using single-particle electron microscopy, but no high-resolution structures of the components are available, and the role of the B protein in the mechanism of toxicity remains unknown. Here we report the three-dimensional structure of the complex formed between the B and C proteins, determined to 2.5 Å by X-ray crystallography. These proteins assemble to form an unprecedented, large hollow structure that encapsulates and sequesters the cytotoxic, C-terminal region of the C protein like the shell of an egg. The shell is decorated on one end by a β-propeller domain, which mediates attachment of the B-C heterodimer to the A protein in the native complex. The structure reveals how C auto-proteolyses when folded in complex with B. The C protein is the first example, to our knowledge, of a structure that contains rearrangement hotspot (RHS) repeats, and illustrates a marked structural architecture that is probably conserved across both this widely distributed bacterial protein family and the related eukaryotic tyrosine-aspartate (YD)-repeat-containing protein family, which includes the teneurins. The structure provides the first clues about the function of these protein repeat families, and suggests a generic mechanism for protein encapsulation and delivery. 23562404 Glycophorin A transmembrane domain dimerization in plasma membrane vesicles derived from CHO, HEK 293T, and A431 cells. Membrane protein interactions, which underlie biological function, take place in the complex cellular membrane environment. Plasma membrane derived vesicles are a model system which allows the interactions between membrane proteins to be studied without the need for their extraction, purification, and reconstitution into lipid bilayers. Plasma membrane vesicles can be produced from different cell lines and by different methods, providing a rich variety of native-like model systems. With these choices, however, questions arise as to how the different types of vesicle preparations affect the interactions between membrane proteins. Here we address this question using the glycophorin A transmembrane domain (GpA) as a model system. We compare the dimerization of GpA in six different vesicle preparations derived from Chinese hamster ovary (CHO), Human Embryonic Kidney 293T (HEK 293T) and A431 cells. We accomplish this with the use of a FRET-based method which yields the FRET efficiency, the donor concentration, and the acceptor concentration in each vesicle. We show that the vesicle preparation protocol has no statistically significant effect on GpA dimerization. Based on these results, we propose that any of the six plasma membrane preparations investigated here can be used as a model system for studies of membrane protein interactions. 23479408 Dyslipidemia in type 2 diabetes: prevalence, pathophysiology, and management. Dyslipidemia is one of the key risk factors for cardiovascular disease (CVD) in diabetes mellitus. Despite the mounting clinical trial data, the management of dyslipidemia other than lowering the low density lipoprotein cholesterol (LDL-c) continues to be controversial. The characteristic features of diabetic dyslipidemia are high plasma triglyceride concentration, reduced high density lipoprotein cholesterol (HDL-c) concentration, and increased concentration of small dense LDL particles. These changes are caused by increased free fatty acid flux secondary to insulin resistance and aggravated by increased inflammatory adipokines. The availability of several lipid-lowering drugs and nutritional supplements offers novel and effective options for achieving target lipid levels in people with diabetes. While initiation of drug therapy based on differences in the lipid profile is an option, most practice guidelines recommend statins as first-line therapy. Although the evidence for clinical utility of combination of statins with fibrates or nicotinic acid in reducing cardiovascular events remains inconclusive, the preponderance of evidence suggests that a subgroup who have high triglycerides and low HDL-c levels may benefit from combination therapy of statins and fibrates. The goal of therapy is to achieve at least 30-40 % reduction in LDL-c levels. Preferably the LDL-c should be less than 100 mg/dL in low-risk people and less than 70 mg/dL in those at high risk, including people with established CVD. 23726145 Biogas final digestive byproduct applied to croplands as fertilizer contains high levels of steroid hormones. In this study we evaluate and demonstrate the occurrence of nine natural and one synthetic steroid hormone, including estrogens, androgens and progestagens in biogas final digestate byproduct (digestion liquid) commonly used as an agricultural fertilizer. We investigated two biogas sites that utilize different anaerobic digestion technologies (mesophilic and thermophilic) from swine manure and other organic wastes. Individual hormone concentration levels were observed up to 1478 ng g(-1) dry weight or 22.5 mg kg(-1) N with estrone and progesterone reaching highest concentration levels. Evaluation of the potential environmental burden through the application in agriculture was also assessed on the basis of predicted environmental concentrations. This study indicates that the biogas digestion process does not completely remove steroid hormones from livestock manure and use of final digestate byproduct on croplands contributes to the environmental emission of hormones. 23278435 Effect of medicaid disease management programs on emergency admissions and inpatient costs. To determine the impact of state Medicaid diabetes disease management programs on emergency admissions and inpatient costs. National InPatient Sample sponsored by the Agency for Healthcare Research and Quality Project for the years from 2000 to 2008 using 18 states. A difference-in-difference methodology compares costs and number of emergency admissions for Washington, Texas, and Georgia, which implemented disease management programs between 2000 and 2008, to states that did not undergo the transition to managed care (N = 103). Costs and emergency admissions were extracted for diabetic Medicaid enrollees diagnosed in the reform and non-reform states and collapsed into state and year cells. In the three treatment states, the implementation of disease management programs did not have statistically significant impacts on the outcome variables when compared to the control states. States that implemented disease management programs did not achieve improvements in costs or the number of emergency of admissions; thus, these programs do not appear to be an effective way to reduce the burden of this chronic disease. 23838551 Management of the 'tight orbit' and associated visual loss. To review the most recent literature on the management of the orbit under high pressure (the tight orbit) with threatened visual loss. Definitive management of traumatic optic neuropathy remains unclear, lacking randomized head-to-head treatment option trials. Instead, numerous case series and anecdotal reports show benefit in each of the four treatment modalities currently in use, but a multitude of variables confound cross-study comparison. In contrast, the management of orbital hemorrhage and orbital emphysema is well known. A number of immunomodulatory protocols have recently arisen for the medical suppression of Graves' ophthalmopathy, but when surgical decompression is required, most authors currently favor a combined transconjunctival and endoscopic endonasal approach. This article reviews the anatomy, pathophysiology, diagnosis, and intervention of the 'tight orbit' with associated visual loss. Guidelines for the intervention are given. 23735826 Novel synthetic acridine derivatives as potent DNA-binding and apoptosis-inducing antitumor agents. Acridine derivatives have been explored as DNA-binding anticancer agents. Some derivatives show undesired pharmacokinetic properties and new derivatives need to be explored. In this work, a series of novel acridine analogues were synthesized by modifying previously unexplored linkers between the acridine and benzene groups and their antiproliferative activity and the DNA-binding ability were evaluated. Among these derivatives, compound 5c demonstrated DNA-binding capability and topoisomerase I inhibitory activity. In K562 cell lines, 5c induced apoptosis through mitochondria-dependent intrinsic pathways. These data suggested that compound 5c and other acridine derivatives with modified linkers between the acridine and benzene groups might be potent DNA-binding agents. 23845061 Enhancing molecular shape comparison by weighted gaussian functions. Shape comparing technologies based on Gaussian functions have been widely used in virtual screening of drug discovery. For efficiency, most of them adopt the First Order Gaussian Approximation (FOGA), in which the shape density of a molecule is represented as a simple sum of all individual atomic shape densities. In the current work, the effectiveness and error in shape similarity calculated by such an approximation are carefully analyzed. A new approach, which is called the Weighted Gaussian Algorithm (WEGA), is proposed to improve the accuracy of the first order approximation. The new approach significantly improves the accuracy of molecular volumes and reduces the error of shape similarity calculations by 37% using the hard-sphere model as the reference. The new algorithm also keeps the simplicity and efficiency of the FOGA. A program based on the new method has been implemented for molecular overlay and shape-based virtual screening. With improved accuracy for shape similarity scores, the new algorithm also improves virtual screening results, particularly when a shape-feature combo scoring function is used. 23355539 Lapatinib-mediated cyclooxygenase-2 expression via epidermal growth factor receptor/HuR interaction enhances the aggressiveness of triple-negative breast cancer cells. Lapatinib, a dual epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) kinase inhibitor, showed clinical benefits in advanced HER2-positive breast cancer patients. Because some triple-negative breast cancers (TNBCs) frequently overexpress EGFR, the antitumor activity of lapatinib in such diseases was also tested. However, the results showed a worse event-free survival rate. It remains unknown whether and how lapatinib elicits the aggressiveness of such cancer cells. In this study, our results demonstrated that lapatinib facilitated axillary and lung metastases of triple-negative MDA-MB-231 breast cancer cells without affecting their viability, leading to worse survival in orthotopic xenograft mice. The lapatinib-increased motility was attributed by the elevation of EGFR through the downregulation of microRNA-7 and by the subsequent overexpression of cyclooxygenase-2 (COX-2). Strikingly, independent of its kinase activity, the elevated EGFR at least partly stabilized COX-2 expression by enhancing the binding of HuR to COX-2 mRNA. Our results suggest that lapatinib may increase the migration and invasion of MDA-MB-231 cells by upregulating EGFR and COX-2 through the downregulation of microRNA-7, providing a potential explanation for the worse clinical outcome of TNBC patients who receive lapatinib-based treatment. These findings also shed new light on the molecular mechanism of COX-2 mRNA stabilization by EGFR in a kinase-independent manner. 23874448 Insulin Receptor-Overexpressing β-Cells Ameliorate Hyperglycemia in Diabetic Rats through Wnt Signaling Activation. To investigate the therapeutic efficacy and mechanism of β-cells with insulin receptor (IR) overexpression on diabetes mellitus (DM), rat insulinoma (INS-1) cells were engineered to stably express human insulin receptor (INS-IR cells), and subsequently transplanted into streptozotocin- induced diabetic rats. Compared with INS-1 cells, INS-IR cells showed improved β-cell function, including the increase in glucose utilization, calcium mobilization, and insulin secretion, and exhibited a higher rate of cell proliferation, and maintained lower levels of blood glucose in diabetic rats. These results were attributed to the increase of β-catenin/PPARγ complex bindings to peroxisome proliferator response elements in rat glucokinase (GK) promoter and the prolongation of S-phase of cell cycle by cyclin D1. These events resulted from more rapid and higher phosphorylation levels of insulin-signaling intermediates, including insulin receptor substrate (IRS)-1/IRS-2/phosphotylinositol 3 kinase/v-akt murine thymoma viral oncogene homolog (AKT) 1, and the consequent enhancement of β-catenin nuclear translocation and Wnt responsive genes including GK and cyclin D1. Indeed, the higher functionality and proliferation shown in INS-IR cells were offset by β-catenin, cyclin D1, GK, AKT1, and IRS-2 gene depletion. In addition, the promotion of cell proliferation and insulin secretion by Wnt signaling activation was shown by 100 nM insulin treatment, and to a similar degree, was shown in INS-IR cells. In this regard, this study suggests that transferring INS-IR cells into diabetic animals is an effective and feasible DM treatment. Accordingly, the method might be a promising alternative strategy for treatment of DM given the adverse effects of insulin among patients, including the increased risk of modest weight gain and hypoglycemia. Additionally, this study demonstrates that the novel mechanism of cross-talk between insulin and Wnt signaling plays a primary role in the higher therapeutic efficacy of IR-overexpressing β-cells. 23546876 Structure of Bradyrhizobium japonicum transcription factor FixK2 unveils sites of DNA binding and oxidation. FixK2 is an important regulatory protein that helps activating a large number of genes for the anoxic and microoxic, endosymbiotic and nitrogen-fixing life styles of the α-proteobacterium Bradyrhizobium japonicum. FixK2 belongs to the cyclic AMP receptor protein (CRP) superfamily. While most CRP-family members are co-regulated by effector molecules, the activity of FixK2 is negatively controlled by oxidation of its single cysteine (C183) located next to the DNA binding domain, and possibly also by proteolysis. Here we report the three-dimensional X-ray structure of FixK2, a representative of the FixK subgroup of the CRP superfamily. Crystallization succeeded only (i) when an oxidation- and protease-insensitive protein variant (C183S-FixK2His6) was used, in which C183 was replaced by serine and the C-terminus fused with a hexa-histidine tag, and (ii) when this protein was allowed to form a complex with a 30mer double-strand target DNA. The structure of the FixK2-DNA complex was solved at a resolution of 1.77 Å in which the protein formed a homodimer. The precise protein-DNA contacts were identified which led to an affirmation of the canonical target sequence, the so-called FixK2 box. The C-terminus is surface-exposed which might explain its sensitivity to specific cleavage and degradation. The oxidation-sensitive C183 is also surface-exposed and in close proximity to DNA. Therefore, we propose a mechanism whereby the oxo-acids generated after oxidation of the cysteine thiol cause an electrostatic repulsion, thus preventing specific DNA binding. 23897626 Full Functionalization of the 7-Azaindole Scaffold by Selective Metalation and Sulfoxide/Magnesium Exchange. Filling positions: 7-Azaindoles are important targets in the pharmaceutical industry. All five carbon positions of the azaindole ring system can be functionalized in a predictable manner starting from the appropriately substituted azaindole 1 by directed metalation and halogen/magnesium and sulfoxide/magnesium exchange. The products are fully substituted azaindoles of type 2. 23958272 'Doing the hard yards': carer and provider focus group perspectives of accessing Aboriginal childhood disability services. Despite a high prevalence of disability, Aboriginal Australians access disability services in Australia less than non-Aboriginal Australians with a disability. The needs of Aboriginal children with disability are particularly poorly understood. They can endure long delays in treatment which can impact adversely on development. This study sought to ascertain the factors involved in accessing services and support for Aboriginal children with a disability. Using the focus group method, two community forums, one for health and service providers and one for carers of Aboriginal children with a disability, were held at an Aboriginal Community Controlled Health Service (ACCHS) in the Sydney, metropolitan area of New South Wales, Australia. Framework analysis was applied to qualitative data to elucidate key issues relevant to the dimensions of access framework. Independent coding consistency checks were performed and consensus of analysis verified by the entire research team, several of whom represented the local Aboriginal community. Seventeen health and social service providers representing local area government and non-government-funded health and social service organisations and five carers participated in two separate forums between September and October 2011. Lack of awareness of services and inadequate availability were prominent concerns in both groups despite geographic proximity to a major metropolitan area with significant health infrastructure. Carers noted racism, insufficient or non-existent services, and the need for an enhanced role of ACCHSs and AHWs in disability support services. Providers highlighted logistical barriers and cultural and historical issues that impacted on the effectiveness of mainstream services for Aboriginal people. Despite dedicated disability services in an urban community, geographic proximity does not mitigate lack of awareness and availability of support. This paper has enumerated a number of considerations to address provision of disability services in an urban Australian Aboriginal community including building expertise and specialist capacity within Aboriginal Health Worker positions and services.Increasing awareness of services, facilitating linkages and referrals, eliminating complexities to accessing support, and working with families and Aboriginal community organisations within a framework of resilience and empowerment to ensure a relevant and acceptable model are necessary steps to improving support and care for Aboriginal children with a disability. 23611691 Protein kinase inhibitor design by targeting the Asp-Phe-Gly (DFG) motif: the role of the DFG motif in the design of epidermal growth factor receptor inhibitors. The Asp-Phe-Gly (DFG) motif plays an important role in the regulation of kinase activity. Structure-based drug design was performed to design compounds able to interact with the DFG motif; epidermal growth factor receptor (EGFR) was selected as an example. Structural insights obtained from the EGFR/2a complex suggested that an extension from the meta-position on the phenyl group (ring-5) would improve interactions with the DFG motif. Indeed, introduction of an N,N-dimethylamino tail resulted in 4b, which showed almost 50-fold improvement in inhibition compared to 2a. Structural studies confirmed this N,N-dimethylamino tail moved towards the DFG motif to form a salt bridge with the side chain of Asp831. That the interactions with the DFG motif greatly contribute to the potency of 4b is strongly evidenced by synthesizing and testing compounds 2a, 3g and 4f: when the charge interactions are absent, the inhibitory activity decreased significantly. 23815183 Meta-analysis: rapid infliximab infusions are safe. Infliximab is typically administered intravenously via 2- to 3-h duration infusions. Infusions are time-consuming and costly. Shorter duration infusions are administered at some centres. Limited safety data are available on shorter duration infusions. To determine risk of infusion reaction associated with standard 2- to 3-h infusions vs. rapid infusions in patients receiving infliximab therapy for inflammatory bowel disease (IBD), rheumatoid arthritis, spondylarthopathy and psoriatic disease. MEDLINE, Embase, and Web of Science were searched. Inclusion required human subjects, documentation of number of standard and rapid infliximab infusions and number of incident infusion reactions. Studies of overlapping populations were excluded. Three reviewers independently extracted data. Study quality was assessed. Relative risk (RR) was pooled using random effects models. We identified 10 studies comprising 13 147 standard 2- to 3-h and 8497 â‰¤ 1-h infliximab infusions. Nine studies reported the risk of infusion reaction in standard vs. 1-h infusions, demonstrating decreased RR of infusion reaction with 1-h vs. standard infusions (0.9% vs. 2.2% of infusions; RR = 0.48, P = 0.009). Seven studies limited to IBD also demonstrated decreased risk of reaction (RR = 0.49, P = 0.002). Other comparisons demonstrated no difference in RR of reaction, including concomitant medication use (P = 0.30) or analysis limited to high and medium quality studies (P = 0.07). Rapid infliximab infusions of ≤1-h duration are not associated with increased risk of infusion reaction when compared to standard 2- to 3-h infusions in selected patients who previously tolerated three to four standard infusions. One-hour infusions will conserve health care resources and may lead to improved adherence and quality of life in patients receiving infliximab. 23824257 Acute effects of high-protein versus normal-protein isocaloric meals on satiety and ghrelin. The objective was to compare isocaloric high-protein (HP) test meals with normal-protein (NP) test ones on satiety and ghrelin in human being. Systematic searches were conducted by using PubMed, Cochrane library, EMBASE, and HighWire Press to identify randomized, crossover trials that investigated the acute effects of isocalorically prescribed HP versus NP test meals on satiety and ghrelin. Pooled analyses showed that subjects with HP test meals had a significantly higher acute satiety area under the curve (AUC) than those with NP test meals (P < 0.001). Conversely, the former had a markedly lower level of acute ghrelin at 180 min as well as acute glucose AUC, although they had a notably higher glucose at 180 min (P = 0.008). The meta-analysis showed that the acute consumption of HP did produce more satiety. In addition, relative to NP test meals, HP test ones may be useful in regulating postprandial glucose, whereas a significantly higher preprandial glucose combined with a lower concentration of ghrelin may contribute to the decrease in ad libitum caloric intake. 23913589 Estimation of the effect of interventions that modify the received treatment. Motivated by a study of surgical operating time and post-operative outcomes for lung cancer, we consider the estimation of causal effects of continuous point-exposure treatments. To investigate causality, the standard paradigm postulates a series of treatment-specific counterfactual outcomes and establishes conditions under which we may learn about them from observational study data. While many choices are possible, causal effects are typically defined in terms of variation of the mean of counterfactual outcomes in hypothetical worlds in which specific treatment strategies are 'applied' to all individuals. For example, one might compare two worlds: one where each individual receives some specific dose and a second where each individual receives some other dose. For our motivating study, defining causal effects in this way corresponds to (hypothetical) interventions that could not conceivably be implemented in the real world. In this work, we consider an alternative, complimentary framework that investigates variation in the mean of counterfactual outcomes under hypothetical treatment strategies where each individual receives a treatment dose corresponding to that actually received but modified in some pre-specified way. Quantification of this variation is defined in terms of contrasts for specific interventions as well as in terms of the parameters of a new class of marginal structural mean models. Within this framework, we propose three estimators: an outcome regression estimator, an inverse probability of treatment weighted estimator and a doubly robust estimator. We illustrate the methods with an analysis of the motivating data. Copyright © 2013 John Wiley & Sons, Ltd. 23809729 Lung size mismatch and survival after single and bilateral lung transplantation. A higher predicted total lung capacity (pTLC)-ratio (=pTLC donor/pTLC recipient), suggestive of oversized allografts, is associated with improved survival after lung transplantation. It is unknown whether the pTLC-ratio has a different association with survival in bilateral (BLT) versus single lung transplantation (SLT). The pTLC-ratio was calculated for all adult patients in the United Network of Organ Sharing lung transplant (LTx) registry who underwent first-time LTx in the post lung allocation score era, between May 2005 and April 2010. The LTx recipients were stratified according to procedure (BLT vs SLT). Risk of death at 1 year after LTx was analyzed using Kaplan-Meier survival and Cox proportional hazards models. In the 4,520 BLT patients, each 0.1 increase in pTLC-ratio conferred a 7% decrease in the hazard for death at 1 year (p < 0.001) in univariate analysis. This association remained significant after controlling for diagnosis, comorbidities, acuity, donor, and transplant factors (hazard ratio [HR] 0.93, 95% confidence interval [CI] 0.88 to 0.98, p = 0.01). Additional adjustment by a propensity score to account for biases to oversizing showed similar results (HR 0.94, 95% CI 0.90 to 0.99, p = 0.018). In the 2,477 SLT patients, each 0.1 increase in pTLC-ratio conveyed a 6% decrease in the hazard for death at 1 year (p = 0.002) in univariate analysis, which did not persist in the multivariate model (HR 1.00, p = 0.8). A higher pTLC-ratio, suggestive of an oversized allograft, is associated with improved survival after lung transplantation. This association is primarily evident in BLT patients. 23529638 A single-center cohort of Canadian children with VUR reveals renal phenotypes important for genetic studies. Many genes and loci have been reported in genetic studies of primary vesicoureteral reflux (VUR), but few have been reproduced in independent cohorts, perhaps because of phenotype heterogeneity. We phenotyped children with VUR who attended urology clinics so we could establish criteria to stratify patients based on the presence or absence of a renal malformation. History, chart review, and DNA were obtained for 200 children with VUR from 189 families to determine the grade of VUR, the mode of presentation, and the family history for each child. Kidney length measured on ultrasound (US) and technetium dimercaptosuccinic acid (DMSA) scans at the time of VUR diagnosis were used to establish the presence of a concurrent renal malformation and identify the presence of renal scarring. There was an even distribution of girls and boys, and most patients were diagnosed following a urinary tract infection (UTI). Thirty-four percent of the children had severe VUR, and 25 % had undergone surgical correction. VUR is highly heritable, with 15 % of the families reporting multiple affected members. Most patients had normally formed kidneys as determined by US and DMSA imaging. Of the 93 patients who underwent DMSA imaging, 17 (18 %) showed scarring, 2 (2 %) showed scarring and diffuse reduction in uptake, and 13 (14 %) showed an isolated diffuse reduction in uptake. Prospective long-term studies of patients with primary VUR combined with renal phenotyping using US and DMSA imaging are needed to establish the presence of a renal malformation. The majority of patients in our study had no renal malformation. This cohort is a new resource for genetic studies of children with primary VUR. 23578884 Sleep duration and quality in relation to non-alcoholic fatty liver disease in middle-aged workers and their spouses. Although accumulated evidence implies that short sleep duration and poor sleep quality may lead to an altered metabolic milieu, potentially triggering the development of non-alcoholic fatty liver disease (NAFLD), no studies have explored this association. This study sought to examine whether short sleep duration or poor sleep quality is associated with NAFLD in the general population. We assessed sleep duration and quality using the Pittsburgh Sleep Quality Index in 69,463 middle-aged workers and their spouses and carried out biochemical and anthropometric measurements. The presence of fatty liver was determined using ultrasonographic findings. Logistic regression models were used to evaluate the association of sleep duration and quality with NAFLD, after adjusting for potential confounders. After controlling for the relevant confounding factors (age, alcohol intake, smoking, physical activity, systolic blood pressure, education level, marital status, presence of job, sleep apnea, and loud snoring), the adjusted odds ratio (95% confidence interval) for NAFLD comparing sleep duration ⩽5h to the reference (>7h) was 1.28 (1.13-1.44) in men and 1.71 (1.38-2.13) in women. After further adjustments for BMI, this association was not significant in men (OR: 1.03, 95% CI: 0.90-1.19) but remained significant in women (OR: 1.59, 95% CI: 1.23-2.05). The multivariate-adjusted odds ratio comparing participants with poor sleep quality vs. participants with good sleep quality was 1.10 (95% CI 1.02-1.19) and 1.36 (95% CI 1.17-1.59) in men and women, respectively. In the middle-aged, general population, short sleep duration, and poor sleep quality were significantly associated with an increased risk of NAFLD. Prospective studies are required to confirm this association. 23664065 Immobilization of tetramethylguanidine on mesoporous SBA-15 silica: a heterogeneous basic catalyst for transesterification of soybean oil. An active heterogeneous catalyst, namely 1,1,3,3-tetramethylguanidine (TMG) immobilized on mesoporous SBA-15 silica (SBA-15-pr-TMG), was prepared and the catalytic activity was investigated for transesterification of soybean oil with methanol. The heterogeneous catalysts were characterized using Hammett titration method, Fourier transform infrared spectra, X-ray diffraction, scanning electron microscopy, transmission electron microscopy, N2 adsorption-desorption, and X-ray photoelectron spectroscopy techniques. It is shown that the activity of the catalysts for the transesterification reaction is closely related to their basic properties. By using this catalyst, an environmentally benign process for biodiesel production in a heterogeneous manner was developed. When the reaction was carried out at reflux of methanol, with a molar ratio of methanol to soybean oil of 15:1, a reaction time 12h and a catalyst amount 5 wt%, the oil conversion of 91.7% was achieved. The catalyst could be recovered easily and reused without significant degradation in activity. 23883422 Analytic Solutions for Some Reaction-Diffusion Scenarios. Motivated currently by the problem of coalescence of receptor clusters in mast cells in the general subject of immune reactions, and formerly by the investigation of exciton trapping and sensitized luminescence in molecular systems and aggregates, we present analytic expressions for survival probabilities of moving entities undergoing diffusion and reaction on encounter. Results we provide cover several novel situations in simple 1-d systems as well as higher-dimensional counterparts along with a useful compendium of such expressions in chemical physics and allied fields. We also emphasize the importance of the relationship of discrete sink term analysis to continuum boundary condition studies. 23922909 Evaluation of Nanoparticle Uptake in Co-culture Cancer Models. Co-culture models are currently bridging the gap between classical cultures and in vivo animal models. Exploring this novel approach unlocks the possibility to mimic the tumor microenvironment in vitro, through the establishment of cancer-stroma synergistic interactions. Notably, these organotypic models offer a perfect platform for the development and pre-clinical evaluation of candidate nanocarriers loaded with anti-tumoral drugs in a high throughput screening mode, with lower costs and absence of ethical issues. However, this evaluation was until now limited to co-culture systems established with precise cell ratios, not addressing the natural cell heterogeneity commonly found in different tumors. Therefore, herein the multifunctional nanocarriers efficiency was characterized in various fibroblast-MCF-7 co-culture systems containing different cell ratios, in order to unravel key design parameters that influence nanocarrier performance and the therapeutic outcome. The successful establishment of the co-culture models was confirmed by the tissue-like distribution of the different cells in culture. Nanoparticles incubation in the various co-culture systems reveals that these nanocarriers possess targeting specificity for cancer cells, indicating their suitability for being used in this illness therapy. Additionally, by using different co-culture ratios, different nanoparticle uptake profiles were obtained. These findings are of crucial importance for the future design and optimization of new drug delivery systems, since their real targeting capacity must be addressed in heterogenous cell populations, such as those found in tumors. 23368095 Discriminating the effects of phylogenetic hypothesis, tree resolution and clade age estimates on phylogenetic signal measurements. Understanding how species traits evolved over time is the central question to comprehend assembly rules that govern the phylogenetic structure of communities. The measurement of phylogenetic signal (PS) in ecologically relevant traits is a first step to understand phylogenetically structured community patterns. The different methods available to estimate PS make it difficult to choose which is most appropriate. Furthermore, alternative phylogenetic tree hypotheses, node resolution and clade age estimates might influence PS measurements. In this study, we evaluated to what extent these parameters affect different methods of PS analysis, and discuss advantages and disadvantages when selecting which method to use. We measured fruit/seed traits and flowering/fruiting phenology of endozoochoric species occurring in Southern Brazilian Araucaria forests and evaluated their PS using Mantel regressions, phylogenetic eigenvector regressions (PVR) and K statistic. Mantel regressions always gave less significant results compared to PVR and K statistic in all combinations of phylogenetic trees constructed. Moreover, a better phylogenetic resolution affected PS, independently of the method used to estimate it. Morphological seed traits tended to show higher PS than diaspores traits, while PS in flowering/fruiting phenology depended mostly on the method used to estimate it. This study demonstrates that different PS estimates are obtained depending on the chosen method and the phylogenetic tree resolution. This finding has implications for inferences on phylogenetic niche conservatism or ecological processes determining phylogenetic community structure. 23391424 Different pharmacokinetics of the two structurally similar dammarane sapogenins, protopanaxatriol and protopanaxadiol, in rats. Dammarane Sapogenins (DS), with main ingredients of protopanaxatriol (PPT, 33%) and protopanaxadiol (PPD, 16%), is an alkaline hydrolyzed product of ginsenosides and had significant activities in improving learning and memory and decreasing chemotherapy-induced myelosuppression. In the present study, the pharmacokinetics and oral bioavailabilities of PPT and PPD were investigated when a single dose of DS was administrated orally (75mg/kg) and intravenously (i.v., 30mg/kg) to rats. Their in vitro stabilities in the GI tract were also investigated. PPT and PPD concentrations were measured by LC-MS. The results showed that PPT was eliminated rapidly from the body with an average t1/2, λz value of 0.80h and CL of 4.27l/h/kg after i.v. administration, while PPD was eliminated relatively slowly with a t1/2, λz of 6.25h and CL of 0.98l/h/kg. After oral administration, both PPD and PPT could be absorbed into the body, but their systemic exposures were quite different. PPT was absorbed into the body quickly, with a Tmax of 0.58h and a Cmax of 0.13μg/ml, while PPD was absorbed relatively slowly with a Tmax of 1.82h and a Cmax of 1.04μg/ml. The absolute bioavailabilities of PPT and PPD were estimated as 3.69% and 48.12%, respectively. The stability test found that PPT was instable in the stomach with 40% degradation after 4h incubation at 37°C, both in pH1.2 buffer and in the stomach content solution. The instability in the stomach might be one of the reasons for PPT's poor bioavailability. 23879299 Synthesis and evaluation of novel radioligands for positron emission tomography imaging of the orexin-2 receptor. Orexin receptors (OXRs) in the brain have been implicated in diverse physiological and neuropsychiatric conditions. Here we describe the design, synthesis, and evaluation of OXR ligands related to (1R,2S)-2-(((2-methyl-4-methoxymethylpyrimidin-5-yl)oxy)methyl)-N-(5-fluoropyridin-2-yl)-2-(3-fluorophenyl)cyclopropanecarboxamide (9a) applicable to positron emission tomography (PET) imaging. Structural features were incorporated to increase binding affinity for OXRs, to enable carbon-11 radiolabeling, and to adjust lipophilicity considered optimal for brain penetration and low nonspecific binding. 9a displayed nanomolar affinity for OXRs, and autoradiography using rat brain sections showed that specific binding of [(11)C]9a was distributed primarily to neocortical layer VI and hypothalamus, consistent with reported localizations of orexin-2 receptors (OX2Rs). In vivo PET study of [(11)C]9a demonstrated moderate uptake of radioactivity into rat and monkey brains under deficiency or blockade of P-glycoprotein, and distribution of PET signals in the brain was in agreement with autoradiographic data. Our approach and findings have provided significant information for development of OX2R PET tracers. 23828765 Duration of residence and dementia literacy among Chinese Americans. To investigate whether duration of residence (DOR) impacts dementia literacy in Chinese Americans aged 40-64. A total of 151 Chinese Americans answered a self-administered, true/false survey assessing knowledge of dementia symptoms, treatment, cause and prognosis. Two groups were dichotomized and compared based on DOR in the USA. DOR did not greatly impact the understanding of dementia between respondents with a < 20-year versus a ≥ 20-year DOR. Both groups exhibited deficiencies in recognizing the symptoms of dementia. Gaps in dementia knowledge reflect a stigma surrounding mental illness among Chinese Americans, and impact the seeking of professional care. 23643754 Upregulation of the dorsal raphe nucleus-prefrontal cortex serotonin system by chronic treatment with escitalopram in hyposerotonergic Wistar-Kyoto rats. Wistar-Kyoto (WKY) rats are sensitive to chronic stressors and exhibit depression-like behavior. Dorsal raphe nucleus (DRN) serotonin (5-HT) neurons projecting to the prefrontal cortex (PFC) comprise the important neurocircuitry underlying the pathophysiology of depression. To evaluate the DRN-PFC 5-HT system in WKY rats, we examined the effects of escitalopram (ESCIT) on the extracellular 5-HT level in comparison with Wistar rats using dual-probe microdialysis. The basal levels of 5-HT in the DRN, but not in the PFC, in WKY rats was reduced as low as 30% of Wistar rats. Responses of 5-HT in the DRN and PFC to ESCIT administered systemically and locally were attenuated in WKY rats. Feedback inhibition of DRN 5-HT release induced by ESCIT into the PFC was also attenuated in WKY rats. Chronic ESCIT induced upregulation of the DRN-PFC 5-HT system in WKY rats, with increases in basal 5-HT in the DRN, responsiveness to ESCIT in the DRN and PFC, and feedback inhibition, whereas downregulation of these effects was induced in Wistar rats. Thus, the WKY rat is an animal model of depression with low activity of the DRN-PFC 5HT system. The finding that chronic ESCIT upregulates the 5-HT system in hyposerotonergic WKY rats may contribute to improved understanding of mechanisms of action of antidepressants, especially in depression with 5-HT deficiency. 23931475 Correlation between spectral-domain optical coherence tomography and autofluorescence findings in sclerochoroidal calcification. The purpose of this article is to report the correlation between spectral domain-optical coherence tomography and autofluorescence findings in 3 consecutive cases with sclerochoroidal calcification. Observational case series. The study involved 3 patients with bilateral sclerochoroidal calcification. B-scan ultrasonography, spectral domain-optical coherence tomography, and autofluorescence were performed in each eye. The choroidal vascular thickness and autofluorescence patterns of the calcified plaques were evaluated with spectral domain-optical coherence tomography and autofluorescence, respectively. An important variation of choroidal vascular thickness overlying sclerochoroidal calcification was observed in spectral domain-optical coherence tomography. Autofluorescence showed 2 patterns of autofluorescence closely correlated with changes in choroidal vascular thickness. In those zones where the thicknesses of choriocapillaris complex were reduced, a hyperautofluorescence pattern was observed in autofluorescence. The hypoautofluorescence pattern was observed in outpouching zone of retinal pigment epithelium-choriocapillaris complex seen in spectral domain-optical coherence tomography. The hypoautofluorescence pattern was closely correlated with remarkable reduction of the choriocapillaris complex. There were no significant differences between the patterns of autofluorescence except the extension. Spectral domain-optical coherence tomography and autofluorescence are noninvasive complementary imaging studies that may help to improve our knowledge about sclerochoroidal calcification. Characteristic patterns of autofluorescence were closely correlated with spectral domain-optical coherence tomography findings. More patients need to be evaluated with both complementary studies to establish conclusions related with these findings. 23109229 Sclerostin antibody inhibits skeletal deterioration due to reduced mechanical loading. Sclerostin, a product of the SOST gene produced mainly by osteocytes, is a potent negative regulator of bone formation that appears to be responsive to mechanical loading, with SOST expression increasing following mechanical unloading. We tested the ability of a murine sclerostin antibody (SclAbII) to prevent bone loss in adult mice subjected to hindlimb unloading (HLU) via tail suspension for 21 days. Mice (n = 11-17/group) were assigned to control (CON, normal weight bearing) or HLU and injected with either SclAbII (subcutaneously, 25 mg/kg) or vehicle (VEH) twice weekly. SclAbII completely inhibited the bone deterioration due to disuse, and induced bone formation such that bone properties in HLU-SclAbII were at or above values of CON-VEH mice. For example, hindlimb bone mineral density (BMD) decreased -9.2% ± 1.0% in HLU-VEH, whereas it increased 4.2% ± 0.7%, 13.1% ± 1.0%, and 30.6% ± 3.0% in CON-VEH, HLU-SclAbII, and CON-SclAbII, respectively (p < 0.0001). Trabecular bone volume, assessed by micro-computed tomography (µCT) imaging of the distal femur, was lower in HLU-VEH versus CON-VEH (p < 0.05), and was 2- to 3-fold higher in SclAbII groups versus VEH (p < 0.001). Midshaft femoral strength, assessed by three-point bending, and distal femoral strength, assessed by micro-finite element analysis (µFEA), were significantly higher in SclAbII versus VEH-groups in both loading conditions. Serum sclerostin was higher in HLU-VEH (134 ± 5 pg/mL) compared to CON-VEH (116 ± 6 pg/mL, p < 0.05). Serum osteocalcin was decreased by hindlimb suspension and increased by SclAbII treatment. Interestingly, the anabolic effects of sclerostin inhibition on some bone outcomes appeared to be enhanced by normal mechanical loading. Altogether, these results confirm the ability of SclAbII to abrogate disuse-induced bone loss and demonstrate that sclerostin antibody treatment increases bone mass by increasing bone formation in both normally loaded and underloaded environments. 23609028 Nitrous Oxide Emissions from Yellow Brown Soil as Affected by Incorporation of Crop Residues With Different Carbon-to-Nitrogen Ratios: A Case Study in Central China. To investigate the influence of crop residues decomposition on nitrous oxide (N2O) emission, a field study was performed with application of crop residues with different C:N ratios in a bare yellow brown soil at the experimental station of Zhangjiachong at Zigui, China. We set up six experimental treatments: no crop residue (CK), rapeseed cake (RC), potato stalk (PS), rice straw (RS), wheat straw (WS), and corn straw (CS). The carbon (C) to nitrogen (N) ratios of these crop residues were 7.5, 32.9, 40.4, 65.7, and 90.9, respectively. Nitrous oxide fluxes were measured using a static closed chamber method. N2O emissions were significantly enhanced by incorporation of crop residues. Cumulative N2O emissions negatively correlated with C:N ratio (R (2) = 0.9821) of the crop residue, but they were positively correlated with average concentrations of dissolved organic carbon and microbial biomass carbon. Nitrogen emission fraction, calculated as N2O-N emissions originated from the crop residues N, positively correlated with C:N ratio of the residues (P < 0.05). Soil temperature did, whereas soil moisture did not, control the residue's induced N2O emissions because a significant correlation (P < 0.01) existed between soil temperature and N2O emissions in all treatments except the control. In contrast, a significant relationship between soil moisture and N2O emissions was found in the control only. Furthermore, N2O emission significantly correlated (P < 0.05) with NO3 (-)-N, and NH4 (+)-N contents from all residue treatments. These results indicate that (1) crop residues with distinct carbon and nitrogen contents can significantly alter soil N2O flux rates; and (2) soil biotic as well as abiotic variables are critical in determining soil-atmospheric N2O emissions after crop residue incorporation into soil. 23960053 The epidemiology and management of adult poisonings admitted to the short-stay ward of a large Scottish emergency department. The emergency department of Aberdeen Royal Infirmary receives around 68,000 new adult admissions annually. All poisoning cases are admitted to a 14-bedded short-stay ward, except those admitted to intensive care or immediately discharged. This study aimed to analyse epidemiological trends and management of short-stay ward admissions for poisonings. Adult (>13 years) poisoning presentations admitted to the emergency department short-stay ward of Aberdeen Royal Infirmary from 1 January-31 December 2009 were retrospectively reviewed using patient discharge summaries. During 2009, there were 1062 poisoning cases, of which repeat episodes were responsible for 15%. The mean age of presentation was 33.9 years (SD 14.4) and there was a female preponderance (62%). Almost half of poisonings were polypharmacy, alcohol was involved in 40% of cases and overdoses most commonly involved paracetamol (43%). Management involved basic observations only (66%), N-acetylcysteine (24%), naloxone (4%) and activated charcoal (1%). Liaison psychiatry reviewed 84% presentations and admitted 9% to the psychiatric unit. The short-stay ward is important for acute management of poisonings and the data gained from this study should help to direct patient services appropriately. 23623433 Resource recovery of organic sludge as refuse derived fuel by fry-drying process. The organic sludge and waste oil were collected from the industries of thin film transistor liquid crystal display and the recycled cooking oil. The mixing ratio of waste cooking oil and organic sludge, fry-drying temperatures, fry-drying time, and the characteristics of the organic sludge pellet grain were investigated. After the fry-drying process, the moisture content of the organic sludge pellet grain was lower than 5% within 25 min and waste cooking oil was absorbed on the dry solid. The fry-drying organic sludge pellet grain was easy to handle and odor free. Additionally, it had a higher calorific value than the derived fuel standards and could be processed into organic sludge derived fuels. Thus, the granulation and fry-drying processes of organic sludge with waste cooking oil not only improves the calorific value of organic sludge and becomes more valuable for energy recovery, but also achieves waste material disposal and cost reduction. 23877652 Strontium-89 (Sr-89) chloride in the treatment of various cancer patients with multiple bone metastases. Although the use of Sr-89 chloride in the treatment of patients with prostate and breast cancer has been widely reported, little information is available about its use for other malignancies. Here, we retrospectively analyzed the clinical profile of Sr-89 chloride in various patients with painful bone metastases. Entry criteria were a pathologically proven malignancy, clinically diagnosed multiple bone metastases, and adequate organ function. Sr-89 chloride (Metastron) was given by single intravenous infusion at 2 MBq/kg over 2 min. Self-reported outcome measures were used as a response index, including pain diary data on a 0-10 numeric rating scale (NRS). Fifty-four consecutive patients with painful bone metastases were treated with Sr-89 chloride at the National Cancer Center Hospital East between March 2009 and July 2011, consisting of 26 with breast/prostate cancer and 28 with other malignancies (lung 8, head and neck 6, colorectal 6, others 8). Thirteen (24 %) patients experienced a transient increase in pain, which was categorized as a flare-up response. Grade 3-4 anemia was observed in 6 patients, 3 of whom required blood transfusion. Regarding efficacy, response rates and complete response rates were 71.2 % and 34.6 %, respectively, and time to response from the initiation of treatment was 36 days (range, 13-217). No significant difference in response rates was seen between patients with breast/prostate cancer and other cancers (breast/prostate 69.2 %, other 73.1 %; p = 0.76). As in patients with breast and prostate cancer, Sr-89 chloride is a promising agent for the treatment of painful bone metastases in patients with various other malignancies. 23769654 Synthesis of novel celecoxib analogues by bioisosteric replacement of sulfonamide as potent anti-inflammatory agents and cyclooxygenase inhibitors. Two series of celecoxib analogues having 1,5-diaryl relationship were synthesized. The key strategy of the molecular design was oriented towards exploring bioisosteric modifications of the sulfonamide moiety of celecoxib. First series (2a-2i) of celecoxib analogues bearing cyano functionality in place of sulfonamide moiety was synthesized by the reaction of appropriate trifluoromethyl-β-diketones (5a-5i) with 4-hydrazinylbenzonitrile hydrochloride (4) in ethanol. Cyano moiety of pyrazoles 2 was then converted into corresponding carbothioamides 3 by bubbling H2S gas in the presence of triethylamine. All the synthesized compounds (2a-2i and 3a-3i) were screened for their in vivo anti-inflammatory (AI) activity using carrageenan-induced rat paw edema assay. COX-1 and COX-2 inhibitory potency was evaluated through in vitro cyclooxygenase (COX) assays. Compounds 2a, 2b, 2c, 2e and 3c showed promising AI activity at 3-4h after the carrageenan injection that was comparable to that of the standard drug indomethacin. Although compounds 3d, 3e and 3f exhibited more pronounced COX-2 inhibition but they also inhibit COX-1 effectively thus being less selective against COX-2. Three compounds 2a, 2f and 3a were found to have a COX profile comparable to the reference drug indomethacin. However 2e, 3b, 3c and 3i compounds were the most potent selective COX-2 inhibitors of this study with 3b showing the best COX-2 profile. In order to better rationalize the action and the binding mode of these compounds, docking studies were carried out. These studies were in agreement with the biological data. 23229954 Enantioresolution of chiral derivatives of xanthones on (S,S)-Whelk-O1 and L-phenylglycine stationary phases and chiral recognition mechanism by docking approach for (S,S)-Whelk-O1. The resolution of seven enantiomeric pairs of chiral derivatives of xanthones (CDXs) on (S,S)-Whelk-O1 and L-phenylglycine chiral stationary phases (CSPs) was systematically investigated using multimodal elution conditions (normal-phase, polar-organic, and reversed-phase). The (S,S)-Whelk-O1 CSP, under polar-organic conditions, demonstrated a very good power of resolution for the CDXs possessing an aromatic moiety linked to the stereogenic center with separation factor and resolution factor ranging from 1.91 to 7.55 and from 6.71 to 24.16, respectively. The chiral recognition mechanisms were also investigated for (S,S)-Whelk-O1 CSP by molecular docking technique. Data regarding the CSP-CDX molecular conformations and interactions were retrieved. These results were in accordance with the experimental chromatographic parameters regarding enantioselectivity and enantiomer elution order. The results of the present study fulfilled the initial objectives of enantioselective studies of CDXs and elucidation of intermolecular CSP-CDX interactions. 23218602 Fragment-based discovery of novel and selective mPGES-1 inhibitors Part 1: identification of sulfonamido-1,2,3-triazole-4,5-dicarboxylic acid. Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible prostaglandin E synthase that catalyzes the conversion of prostaglandin PGH(2) to PGE(2) and represents a novel target for therapeutic treatment of inflammatory disorders. It is essential to identify mPGES-1 inhibitor with novel scaffold as new hit or lead compound for the purpose of the next-generation anti-inflammatory drugs. Herein we report the discovery of sulfonamido-1,2,3-triazole-4,5-dicarboxylic derivatives as a novel class of mPGES-1 inhibitors identified through fragment-based virtual screening and in vitro assays on the inhibitory activity of the actual compounds. 1-[2-(N-Phenylbenzenesulfonamido)ethyl]-1H-1,2,3-triazole-4,5-dicarboxylic acid (6f) inhibits human mPGES-1 (IC(50) of 1.1 μM) with high selectivity (ca.1000-fold) over both COX-1 and COX-2 in a cell-free assay. In addition, the activity of compound 6f was again tested at 10 μM concentration in presence of 0.1% Triton X-100 and found to be reduced to 1/4 of its original activity without this detergent. Compared to the complete loss of activity of nuisance inhibitor with the detergent, therefore, compound 6f would be regarded as a partial nuisance inhibitor of mPGES-1 with a novel scaffold for the optimal design of more potent mPGES-1 inhibitors. 23475068 Delineating multiple functions of VEGF-A in the adult brain. Vascular endothelial growth factor-A (abbreviated throughout this review as VEGF) is mostly known for its angiogenic activity, for its activity as a vascular permeability factor, and for its vascular survival activity [1]. There is a growing body of evidence, however, that VEGF fulfills additional less 'traditional' functions in multiple organs, both during development, as well as homeostatic functions in fully developed organs. This review focuses on the multiple roles of VEGF in the adult brain and is less concerned with the roles played by VEGF during brain development, functions described elsewhere in this review series. Most functions of VEGF that are essential for proper brain development are, in fact, dispensable in the adult brain as was clearly demonstrated using a conditional brain-specific VEGF loss-of-function (LOF) approach. Thus, in contrast to VEGF LOF in the developing brain, a process which is detrimental for the growth and survival of blood vessels and leads to massive neuronal apoptosis [2-4], continued signaling by VEGF in the mature brain is no longer required for maintaining already established cerebral vasculature and its inhibition does not cause appreciable vessel regression, hypoxia or apoptosis [4-7]. Yet, VEGF continues to be expressed in the adult brain in a constitutive manner. Moreover, VEGF is expressed in the adult brain in a region-specific manner and in distinctive spatial patterns incompatible with an angiogenic role (see below), strongly suggesting angiogenesis-independent and possibly also perfusion-independent functions. Here we review current knowledge on some of these 'non-traditional', often unexpected homeostatic VEGF functions, including those unrelated to its effects on the brain vasculature. These effects could be mediated directly (on non-vascular cells expressing cognate VEGF receptors) or indirectly (via the endothelium). Experimental approaches aimed at distinguishing between these possibilities for each particular VEGF function will be described. This review is only concerned with homeostatic functions of VEGF in the normal, non-injured brain. The reader is referred elsewhere in this series for a review on VEGF actions in response to various forms of brain injury and/or brain pathology. 22578007 One new antitumour cassane-type diterpene from Caesalpinia crista. 1α-acetoxy-5α, 7β-dihydroxycassa-11,13(15)-diene-16,12-lactone, a new cassane-type diterpene was isolated from Caesalpinia crista. The structure of this compound was elucidated by analysis of NMR spectra, and the relative configuration was established by NOE experiment. The new compound was evaluated for antitumour activity against T47D, DU145 and showed significant inhibitory activities. 23852322 Visual contribution to the high-frequency human angular vestibulo-ocular reflex. The vestibulo-ocular reflex (VOR) acts to maintain images stable on the retina by rotating the eyes in exactly the opposite direction, but with equal magnitude, to head velocity. When viewing a near target, this reflex has an increased response to compensate for the translation of the eyes relative to the target that acts to reduce retinal image slip. Previous studies have shown that retinal velocity error provides an important visual feedback signal to increase the low-frequency (<1 Hz) VOR response during near viewing. We sought to determine whether initial eye position and retinal image position error could provide enough information to substantially increase the high-frequency VOR gain (eye velocity/head velocity) during near viewing. Ten human subjects were tested using the scleral search coil technique during horizontal head impulses under different lighting conditions (constant dark, strobe light at 0.5, 1, 2, 4, 10, 15 Hz, constant light) while viewing near (9.5 ± 1.3 cm) and far (104 cm) targets. Our results showed that the VOR gain increased during near viewing compared to far viewing, even during constant dark. For the near target, there was an increase in VOR gain with increasing strobe frequency from 1.17 ± 0.17 in constant dark to 1.36 ± 0.27 in constant light, a 21 ± 9 % increase. For the far target, strobe frequency had no effect. Presentation order of strobe frequency (i.e. 0.5-15 vs. 15-0.5 Hz) did not affect the gain, but it did affect the vergence angle (angle between the two eye's lines of sight). The VOR gain and vergence angles were constant during each trial. Our findings show that a retinal position error signal helps increase the vergence angle and could be invoking vestibular adaptation mechanisms to increase the high-frequency VOR response during near viewing. This is in contrast to the low-frequency VOR that depends more on retinal velocity error and predictive adaptation mechanisms. 23568325 Hypothalamic Corticotropin-Releasing Factor is Centrally Involved in Learning Under Moderate Stress. The corticotropin-releasing factor (CRF) neuropeptide is found to have a pivotal role in the regulation of the behavioral and neuroendocrine responses to stressful challenges. Here, we studied the involvement of the hypothalamic CRF in learning under stressful conditions. We have used a site-specific viral approach to knockdown (KD) CRF expression in the paraventricular nucleus of the hypothalamus (PVN). The two-way shuttle avoidance (TWSA) task was chosen to assess learning and memory under stressful conditions. Control animals learned to shuttle from one side to the other to avoid electrical foot shock by responding to a tone. Novel object and social recognition tasks were used to assess memory under less stressful conditions. KD of PVN-CRF expression decreased the number of avoidance responses in a TWSA session under moderate (0.8 mA), but not strong (1.5 mA), stimulus intensity compared to control rats. On the other hand, KD of PVN-CRF had no effect on memory performance in the less stressful novel object or social recognition tasks. Interestingly, basal or stress-induced corticosterone levels in CRF KD rats were not significantly different from controls. Taken together, the data suggest that the observed impairment was not a result of alteration in HPA axis activity, but rather due to reduced PVN-CRF activity on other brain areas. We propose that hypothalamic CRF is centrally involved in learning under moderate stressful challenge. Under 'basal' (less stressful) conditions or when the intensity of the stress is more demanding, central CRF ceases to be the determinant factor, as was indicated by performances in the TWSA with higher stimulus intensity or in the less stressful tasks of object and social recognition. 23926435 Results of a randomized and controlled clinical trial evaluating the efficacy and safety of combination therapy with Endostar and S-1 combined with oxaliplatin in advanced gastric cancer. We aimed to evaluate the efficacy and safety of combination therapy of Endostar (recombinant human endostatin) and S-1 combined with oxaliplatin (SOX) in patients with advanced gastric cancer. In this randomized, controlled trial, 165 late-stage gastric cancer patients were assigned to the experimental arm with Endostar in combination with SOX (80 patients) and the control arm with SOX alone (85 patients). The end points of this study included progression-free survival, response rate, and disease-control rate. There was no statistically significant difference in response rate between the experimental arm and the control arm (53.8% vs 42.4%, P=0.188). The difference in disease-control rate was also statistically insignificant between the two arms (85.0% vs 72.9%, P=0.188). Progression-free survival in the experimental arm was significantly higher than that in the control arm (15.0 months vs 12.0 months, P=0.0001). Common adverse events included immunosuppression, gastrointestinal distress, and neuropathy. There was no statistical difference in the incidences of adverse events. Combination therapy of Endostar and SOX provides therapeutic benefits to advanced gastric cancer patients, with tolerable adverse effects. 23490332 Outcomes and patterns of secondary relapse in platinum-sensitive ovarian cancer: implications for tertiary cytoreductive surgery. To evaluate the outcomes and patterns of patients with secondary relapsed ovarian cancer. A retrospective study was conducted. The cases comprised 83 patients who underwent tertiary cytoreductive surgery (TCS) followed by chemotherapy, whereas the controls consisted of 76 patients who received chemotherapy alone. The median survival was 20 months in 159 patients. Patients with microscopic residual disease after TCS had a median survival of 32.9 months compared with 14.6 months in those with macroscopic residual disease [hazard ratio (HR), 2.82; P = 0.001) and 15.0 months in patients with chemotherapy alone (HR, 2.23; P = 0.001). When stratified by a progression-free interval (PFI) after secondary cytoreduction (SCR), TCS showed no benefit in patients with a PFI ≤12 months or a PFI >12 months compared with those with chemotherapy alone. TCS improved survival in patients with recurrent disease in the pelvis compared with those with recurrent disease in the middle or upper abdomen, with a median survival of 34.9 months and 14.6 months, respectively (HR, 2.94; P = 0.010). However, TCS was not a survival determinant by multivariate analysis. A multivariate analysis identified a PFI after SCR (≤12 mos vs. >12 mos; HR, 2.34; 95% CI, 1.29-4.24; P = 0.005), mesenteric lymph node metastasis at SCR (yes vs. no; HR, 4.18; 95% CI, 1.93-9.03; P < 0.001) and treatment arms at secondary relapse (chemotherapy alone vs. TCS; HR, 1.56; 95% CI, 1.03-2.38; P = 0.037) as independent predictors of survival. Limited survival benefit from tertiary cytoreductive surgery was observed in patients with platinum-sensitive secondary relapsed ovarian cancer. 23891668 Recipients of Electric Powered Indoor/outdoor Wheelchairs provided by a National Health Service: a cross sectional study. To describe the characteristics, across all ages, of powered wheelchair users and the assistive technology prescribed by a regional specialist wheelchair service DESIGN: Cross-sectional study SETTING: Regional wheelchair service provided to those fulfilling strict eligibility criteria by a National Health Service serving a population of 3 million. 544 Electric Powered Indoor/outdoor wheelchair (EPIOC) users. Not applicable MAIN OUTCOME MEASURES: Demographic, clinical/diagnostic details of EPIOC recipients including pain, (kypho)scoliosis and ventilators. Technical features including specialised (adaptive) seating (SS), tilt in space (TIS), and modified control systems. Factors were related to age groups: 1 (0-15), 2 (16-24), 3 (25-54), 4 (55-74) and 5 (75+). 262 men mean age 41.7 (range 8-82, sd 20.7) and 282 women mean age 47.2 (range 7-92, sd 19.7) years were studied. Neurological/neuromuscular conditions predominated (81%) with cerebral palsy (CP) (18.9%) and multiple sclerosis (16.4%). Conditions presenting at birth or during childhood constituted 39%. 99 had problematic pain, 83 a (kypho)scoliosis and 11 used ventilators. SS was provided to 169 users (31%), the majority had CP or muscular dystrophy. TIS was used by 258 (53%). Younger people were more likely to receive TIS than older ones. Only 92 had SS and TIS, mean age 29 (range 8-72, sd 17.8) years. 52 used modified control systems. The diversity of EPIOC users across age and diagnostic groups is shown. Their complex interrelationships with these technical features of EPIOC prescription are explored. Younger users were more complex due to age-related changes. This study provides outcomes of the EPIOC prescription for this heterogeneous group of very severely disabled people. 23537946 Supplemental feeding drives endoparasite infection in wild boar in Western Spain. Wildlife population management is thought to destabilize existing host-parasite equilibriums in opposing directions, that is, it may increase parasite success or host resilience once infection takes place. This process is of special importance for species such as the wild boar (Sus scrofa) that are managed for game purposes throughout much of Europe. However, little is known about how this practices influcences either gastrointestinal or pulmonary parasitism in the wild boar. Twelve hunting estates were chosen in order to study the relationship of management measures (feeder density, wild boar abundance, the ratio of wild boar per feeder and the percentage of sclerophyllous vegetation) and host factors (age and sex) with gastrointestinal and pulmonary parasite aggregation, richness, infection probability and intensity of infection. Parasitological analyses from 300 wild boar gastrointestinal and 269 respiratory tracts were performed for this purpose. A set of general linear models with combinations of the explanatory variables was built and the model with the smallest Akaike Information Criterion was selected as the best. The feeder density increased gastrointestinal parasite traits (richness, infection probability and intensity of infection), probably due to the contamination of feeding sites with infective parasite forms. Pulmonary parasite traits, on the other hand, were only influenced by host sex and age class, and parasite aggregation was as expected for a wild population. Managers should be aware of the consequences on parasitism when implementing supplemental feeding in hunting estates. 23636901 Efficient Light Harvesting with Micropatterned 3D Pyramidal Photoanodes in Dye-Sensitized Solar Cells. 3D TiO2 photoanodes in dye-sensitized solar cells (DSCs) are fabricated by the soft lithographic technique for efficient light trapping. An extended strategy to the construction of randomized pyramid structure is developed by the conventional wet-etching of a silicon wafer for low-cost fabrication. Moreover, the futher enhancement of light absorption resulting in photocurrent increase is achieved by combining the 3D photoanode with a conventional scattering layer. 23470146 Overexpression of Cdc25C predicts response to radiotherapy and survival in esophageal squamous cell carcinoma patients treated with radiotherapy followed by surgery. Biomarker identification is crucial for the selection of patients who might benefit from radiotherapy. To explore potential markers for response and prognosis in patients with locally advanced esophageal carcinoma treated with radiotherapy followed by surgery, we evaluated the expression of cell cycle checkpoint-related proteins Chk2, Cdc25C, and Cyclin D1. A total of 56 patients with locally advanced esophageal squamous cell carcinoma were treated with radiotherapy followed by surgery. Pretreatment tumor biopsy specimens were analyzed for Chk2, Cdc25C, and Cyclin D1 expression by immunohistochemistry. High expression of Chk2, Cyclin D1, and Cdc25C was observed in 44 (78.6%), 15 (26.8%), and 27 (48.2%) patients, respectively. The median survival was 16 months (range, 3-154 months), with a 5-year overall survival rate of 19.6%. Overexpression of Chk2 was associated with smoking (P = 0.021), overexpression of Cdc25C was associated with patient age (P = 0.033) and tumor length (P = 0.001), and overexpression of Cdc25C was associated with pathologic complete response (P = 0.038). Univariate analysis demonstrated that overexpression of Cdc25C and pathologic complete response was associated with better survival. In multivariate analysis, Cdc25C was the most significant independent predictor of better survival (P = 0.014) for patients treated with radiotherapy followed by surgery. Overexpression of Cdc25C was significantly associated with pathologic complete response and better survival of patients with locally advanced esophageal cancer treated with radiotherapy followed by surgery. These results suggest that Cdc25C may be a biomarker of treatment response and good prognosis for esophageal carcinoma patients. Thus, immunohistochemical staining of Cdc25C in a pretreatment specimen may be a useful method of identifying optimal treatment for patients with esophageal carcinoma. 23922853 AMPK-Regulated and Akt-Dependent Enhancement of Glucose Uptake Is Essential in Ischemic Preconditioning-Alleviated Reperfusion Injury. Ischemic preconditioning (IPC) is a potent form of endogenous protection. However, IPC-induced cardioprotective effect is significantly blunted in insulin resistance-related diseases and the underlying mechanism is unclear. This study aimed to determine the role of glucose metabolism in IPC-reduced reperfusion injury. Normal or streptozotocin (STZ)-treated diabetic rats subjected to 2 cycles of 5 min ischemia/5 min reperfusion prior to myocardial ischemia (30 min)/reperfusion (3 h). Myocardial glucose uptake was determined by (18)F-fluorodeoxyglucose-positron emission tomography (PET) scan and gamma-counter biodistribution assay. IPC exerted significant cardioprotection and markedly improved myocardial glucose uptake 1 h after reperfusion (P<0.01) as evidenced by PET images and gamma-counter biodistribution assay in ischemia/reperfused rats. Meanwhile, myocardial translocation of glucose transporter 4 (GLUT4) to plasma membrane together with myocardial Akt and AMPK phosphorylation were significantly enhanced in preconditioned hearts. Intramyocardial injection of GLUT4 siRNA markedly decreased GLUT4 expression and blocked the cardioprotection of IPC as evidence by increased myocardial infarct size. Moreover, the PI3K inhibitor wortmannin significantly inhibited activation of Akt and AMPK, reduced GLUT4 translocation, glucose uptake and ultimately, depressed IPC-induced cardioprotection. Furthermore, IPC-afforded antiapoptotic effect was markedly blunted in STZ-treated diabetic rats. Exogenous insulin supplementation significantly improved glucose uptake via co-activation of myocardial AMPK and Akt and alleviated ischemia/reperfusion injury as evidenced by reduced myocardial apoptosis and infarction size in STZ-treated rats (P<0.05). The present study firstly examined the role of myocardial glucose metabolism during reperfusion in IPC using direct genetic modulation in vivo. Augmented glucose uptake via co-activation of myocardial AMPK and Akt in reperfused myocardium is essential to IPC-alleviated reperfusion injury. This intrinsic metabolic modulation and cardioprotective capacity are present in STZ-treated hearts and can be triggered by insulin. 23860790 Impact of preoperative myocardial infarction on surgical outcomes in inpatient orthopaedic surgery. The purpose of this study was to evaluate the impact of a preoperative myocardial infarction (MI) on outcomes of inpatient orthopaedic operations. The National Surgical Quality Improvement Program database was used to identify patients who underwent common orthopaedic operations from 2006 to 2010. Patient demographic data, comorbidities, complications, and lengths of stay were collected. Multivariate logistic regression and linear regression models were used to compare outcomes for patients with and without a history of MI in the six months prior to surgery. Of the 32,462 patients identified, 86 had sustained an MI in the six months prior to surgery. The MI cohort had no cardiac complications but had increased incidences of superficial surgical site infection, unplanned re-intubation, ventilator-assisted respiration for more than 48 hours, pneumonia, sepsis or septic shock, and postoperative mortality within 30 days of surgery, as well as prolonged lengths of stay. Following logistic regression to adjust for baseline differences, a history of MI showed no association with cardiac complications and was significantly associated with superficial surgical site infection (OR 3.6, 95 % CI 1.1-11.8), ventilator dependence for over 48 hours (OR 4.0, 95 % CI 1.1-14.0), and extended length of stay (median with interquartile range 4 [4-4] vs. 5 [5-5] days). A myocardial infarction within six months prior to orthopaedic surgery is not associated with a higher risk of 30-day perioperative cardiac complications; however, it is associated with increased rates of surgical site infection, prolonged ventilator dependence, and longer hospital stay. 23687002 Site-selective functionalization of periodic mesoporous organosilica (PMO) with macrocyclic host for specific and reversible recognition of heavy metal. A novel kind of macrocyclic-host-functionalized periodic mesoporous organosilica (PMO) with excellent and reversible recognition of Pb(II) was developed. The macrocyclic host molecule cis-dicyclohexano[18]crown-6, with strong affinity to Pb(II), was carefully modified as a bridged precursor to build the PMO material. To break down the limit of the functionalization degree for PMOs incorporated with large-sized moieties, a site-selective post-functionalization method was proposed to further decorate the external surface of the PMO material. The selective recognition ability of the upgraded PMO material towards Pb(II) was remarkably enhanced without destroying the mesoporous ordering. Solid-state (13)C and (29)Si NMR spectroscopy, X-ray photoelectron spectroscopy (XPS), XRD, TEM, and nitrogen adsorption-desorption isotherm measurements were utilized for a full characterization of the structure, micromorphology, and surface properties. Reversible binding of Pb(II) was realized in the binding-elution cycle experiments. The mechanism of the supramolecular interaction between the macrocyclic host and metal ion was discussed. The synthetic strategy can be considered a general way to optimize the properties of PMOs as binding materials for practical use while preserving the mesostructure. 23816131 Automated analysis of carbon in powdered geological and environmental samples by Raman spectroscopy. Raman spectroscopy can be used to assess the structure of naturally occurring carbonaceous materials (CM), which exist in a wide range of crystal structures. The sources of these geological and environmental materials include rocks, soils, river sediments, and marine sediment cores, all of which can contain carbonaceous material ranging from highly crystalline graphite to amorphous-like organic compounds. In order to fully characterize a geological sample and its intrinsic heterogeneity, several spectra must be collected and analyzed in a precise and repeatable manner. Here, we describe a suitable processing and analysis technique. We show that short-period ball-mill grinding does not introduce structural changes to semi-graphitized material and allows for easy collection of Raman spectra from the resulting powder. Two automated peak-fitting procedures are defined that allow for rapid processing of large datasets. For very disordered CM, Lorentzian profiles are fitted to five characteristic peaks, for highly graphitized material, three Voigt profiles are fitted. Peak area ratios and peak width measurements are used to classify each spectrum and allow easy comparison between samples. By applying this technique to samples collected in Taiwan after Typhoon Morakot, sources of carbon to offshore sediments have been identified. Carbon eroded from different areas of Taiwan can be seen mixed and deposited in the offshore flood sediments, and both graphite and amorphous-like carbon have been recycled from terrestrial to marine deposits. The practicality of this application illustrates the potential for this technique to be deployed to sediment-sourcing problems in a wide range of geological settings. 23325315 Excitation-emission matrices applied to the study of urban effluent discharges in the Chubut River (Patagonia, Argentina). Natural and contaminated waters of the final reaches of the Chubut River (Patagonia, Argentina) were studied to obtain information about river organic matter and effects of domestic and industrial discharges (fishery effluents and sewages). Fluorescence Excitation-Emission Matrices (EEMs) were obtained from samples only filtered (0.45 Î¼m) and diluted, if necessary, to avoid the inner filter effect. In addition, physicochemical parameters were measured to know the quality of the water and the effluents. Results show that EEMs allow a rapid and simple control of the effluents from fisheries and domestic sewage in Chubut River estuary, necessary to take management decisions. 23970046 The European society of regional anaesthesia and pain therapy (1982-2012): 30 years strong. Inspired by the earlier establishment of the American Society of Regional Anesthesia, but with a structure to accommodate the diverse languages and health care systems of Europe, the European Society of Regional Anaesthesia (ESRA) held its first scientific meeting in 1982. During the following 30 years, ESRA grew from strength to strength and implemented a number of important educational initiatives, the story of these developments being the subject of this review. ESRA's prime function is to publicize the evidence on regional anesthesia and encourage its further development, but it also led the way in democratizing European anesthesia societies by being the first to open its membership to all. A recent revision of the constitution has further increased the society's democratic nature.Educationally, activities grew from a single annual congress to include zonal meetings, cadaver workshops, a major online program, and collaborations (guidelines and conferences) with other societies. Finally, the introduction of a Diploma qualification in regional anesthesia was an entirely novel project. 23451714 Impact of new genomic tools on the practice of clinical genetics in consanguineous populations: the Saudi experience. Consanguinity is practiced by around one tenth of the world population but its global distribution is far from uniform. In countries where consanguinity is common, a corresponding increase in the frequency of autosomal recessive diseases is usually observed owing to increased risk of homozygosity for ancestral haplotypes (autozygosity or identity by descent) that harbor pathogenic alleles. The burden of these diseases becomes more apparent as the healthcare system makes gains in its fight against communicable diseases in these countries. Recent advances in molecular genetics make it possible to leverage the mechanism by which consanguinity predisposes to the occurrence of autosomal recessive diseases in order to uncover the causal mutations at an efficient and cost-effective way compared to outbred populations. The identification of these mutations at an unprecedented scale has the potential to significantly reshape the practice of clinical genetics in these populations and to offer opportunities for innovative public health policies. This review discusses the impact that new genomic tools have had on a sample patient population and how they can inform future public health policies in ways that might be relevant to other consanguineous populations. 23715048 Health-Related Quality of Life After Solid Organ Transplantation: A Prospective, Multiorgan Cohort Study. Short-term posttransplantation survival and health-related quality of life (HRQoL) is exceptionally high for all patients after organ transplantation; however, predictors of the HRQoL outcome are not well understood. Trajectories of patients' perceived benefit/burden ratio associated with the transplant procedure may differ when taking the organ type for transplantation into account. A prospective, single-center cohort study assessed the trajectories of 354 patients after kidney (n=165), liver (n=53), heart (n=24), and lung (n=112) transplantation at 2, 6, 12, and 24 months with respect to psychosocial outcomes (HRQoL, anxiety, depression, social support, and work performance). Mean age was 50±13 years, and 61.6% were male in the overall sample. Demographics differed with respect to organ type. HRQoL measured by the mean SF-36 Physical Component Scale was 36.8 (95% confidence interval, 35.7-37.8) and 48.9 (95% confidence interval, 47.2-49.7) for the Psychosocial Component Scale for the entire sample at 2 months and showed a marginal decrease until 24 months after transplantation. Overall, HRQoL increased for all organ types with differing trajectories. Liver patients reported the lowest HRQoL benefit for the majority of the physical (P≤0.01) and psychosocial (P≤0.01) SF-36 subscales. Anxiety (17.4%) and depression (13.8%) were prevalent in the overall sample. Depression symptoms impaired HRQoL outcomes in both SF-36 components and unemployment impacted the SF-36 psychosocial outcomes. HRQoL improved after transplantation for all four types of transplant, but the trajectories were different. Regular screening for depression symptoms may diminish psychologic disorders and distress after transplantation and thus may further improve outcomes. 23106241 Nitrate-induced early transcriptional changes during imbibition in non-after-ripened Sisymbrium officinale seeds. We have here demonstrated for the first time that nitrate not only accelerates testa rupture of non- AR seeds but also modifies expression pattern of the cell-wall remodeling proteins (mannanases; SoMAN6 and SoMAN7) and key genes belonging to metabolism and signaling of ABA (SoNCED6, SoNCED9, SoCYP707A2 and SoABI5) and GAs (SoGA3ox, SoGA20ox, SoGA2ox and SoRGL2). These results were obtained during Sisymbrium officinale seed imbibition in the absence of endosperm rupture. Exogenous ABA induced a notable inhibition of testa rupture in both absence and presence of nitrate being this effect sharply reversed by GA4+7 . However, nitrate was capable to provoke testa rupture in absence of ABA synthesis. The expression of SoMAN6 and SoMAN7 were positively altered by nitrate. Although ABA synthesis seems apparent at the start of non-AR seed imbibition, taken together the results of SoNCED6, SoNCED9 and SoCYP707A2 expression seem to suggest that nitrate leads to a strong net ABA decrease. Likewise, nitrate positively affected the SoABI5 expression when the SoNCED9 expression was also stimulated. By contrast, at the early and final of imbibition, nitrate clearly inhibited the SoABI5 expression. The expression of SoGA2ox6 and SoGA3ox2 are strongly inhibited by nitrate whereas of SoGA20ox6 was stimulated. On the other hand, SoRGL2 transcript level decreased in the presence of nitrate. Taken together, the results presented here suggest that the nitrate signaling is already operative during the non-AR S. officinale seeds imbibition. The nitrate, in cross-talk with the AR network likely increases the favorable molecular conditions that trigger germination. 23970414 Senescence at a glance. Cellular senescence is a stable proliferation arrest that is associated with extensive cellular remodelling and an altered secretory pathway. Through its numerous inducers that lead to altered gene expression, senescence is able to influence many contrasting functions and pathologies, namely tumour suppression, tumour promotion, wound healing and ageing. As senescence is able to control such important tissue functions, it is now being pinpointed as a possible route for novel therapies. This article and accompanying poster aim to provide a summary of the initiators, pathways and roles of senescence, as well as present examples of senescence and a possible use for senescence in therapy. 23542609 A GLUE uncertainty analysis of a drying model of pharmaceutical granules. A shift from batch processing towards continuous processing is of interest in the pharmaceutical industry. However, this transition requires detailed knowledge and process understanding of all consecutive unit operations in a continuous manufacturing line to design adequate control strategies. This can be facilitated by developing mechanistic models of the multi-phase systems in the process. Since modelling efforts only started recently in this field, uncertainties about the model predictions are generally neglected. However, model predictions have an inherent uncertainty (i.e. prediction uncertainty) originating from uncertainty in input data, model parameters, model structure, boundary conditions and software. In this paper, the model prediction uncertainty is evaluated for a model describing the continuous drying of single pharmaceutical wet granules in a six-segmented fluidized bed drying unit, which is part of the full continuous from-powder-to-tablet manufacturing line (Consigma™, GEA Pharma Systems). A validated model describing the drying behaviour of a single pharmaceutical granule in two consecutive phases is used. First of all, the effect of the assumptions at the particle level on the prediction uncertainty is assessed. Secondly, the paper focuses on the influence of the most sensitive parameters in the model. Finally, a combined analysis (particle level plus most sensitive parameters) is performed and discussed. To propagate the uncertainty originating from the parameter uncertainty to the model output, the Generalized Likelihood Uncertainty Estimation (GLUE) method is used. This method enables a modeller to incorporate the information obtained from the experimental data in the assessment of the uncertain model predictions and to find a balance between model performance and data precision. A detailed evaluation of the obtained uncertainty analysis results is made with respect to the model structure, interactions between parameters and uncertainty boundaries. 23884195 Diffuse ventricular fibrosis is a late outcome of tachycardia-mediated cardiomyopathy after successful ablation. Background- Successful arrhythmia ablation normalizes ejection fraction (EF) in tachycardia-mediated cardiomyopathy, but recurrent heart failure and late sudden death have been reported. The aim of this study was to characterize the left ventricle (LV) of tachycardia-mediated cardiomyopathy patients long after definitive arrhythmia cure. Methods and Results- Thirty-three patients with a history of successfully ablated incessant focal atrial tachycardia 64±36 months prior, and 20 healthy controls were recruited. At ablation, 18 patients had EF<50% (AT-low EF) that recovered within 3 months from 37±12 to 56±4% (P<0.001), whereas 15 patients had EF>55% (AT-normal EF). No subjects had EF of 50% to 55%. Subjects underwent echocardiography with speckle tracking and contrast-enhanced cardiac MRI with ventricular T1 mapping as an index of diffuse fibrosis. Contrast-enhanced cardiac MRI was performed using a clinical 1.5-T scanner and 0.2 mmol/kg gadolinium-diethylene triamine penta-acetic acid for contrast. Subject characteristics were similar across the 3 groups. Compared with AT-normal EF patients and controls, AT-low EF patients had lower EF (60±6 versus 64±4 and 65±4%; P<0.05), greater indexed LV end-diastolic volume (102±34 versus 84±14 and 85±16 mL/m(2); P<0.05), and greater indexed LV end-systolic volume (41±11 versus 31±7 and 30±8 mL/m(2); P<0.01) on contrast-enhanced cardiac MRI. Compared with controls, AT-low EF patients had reduced global LV corrected T1 time (442±53 versus 529±61; P<0.05) consistent with diffuse fibrosis. Conclusions- Tachycardia-mediated cardiomyopathy patients exhibit differences in LV structure and function including diffuse fibrosis long after arrhythmia cure, indicating that recovery is incomplete. 23747381 Group 12 dithiocarbamate complexes: Synthesis, spectral studies and their use as precursors for metal sulfides nanoparticles and nanocomposites. Zn(II), Cd(II) and Hg(II) dithiocarbamate complexes have been synthesized and characterized by elemental analysis, thermogravimetric analysis, UV-Vis, FTIR, (1)H- and (13)C NMR spectroscopy. The complexes were thermolysed at 180°C and used as single molecule precursors for the synthesis of HDA capped ZnS, CdS and HgS nanoparticles and polymethylmethacrylate (PMMA) nanocomposites. The optical and structural properties of the nanoparticles and nanocomposites were studied by UV-Vis, PL, XRD and SEM. The crystallites sizes of the nanoparticles varied between 3.03 and 23.45nm. SEM and EDX analyses of the nanocomposites confirmed the presence of the nanoparticles in the polymer matrix. 23909299 Optimal coherent control to counteract dissipation. We study to what extent the detrimental impact of dissipation on quantum properties can be compensated by suitable coherent dynamics. To this end, we develop a general method to determine the control Hamiltonian that optimally counteracts a given dissipation mechanism, in order to sustain the desired property, and apply it to two exemplary target properties: the coherence of a decaying two-level system and the entanglement of two qubits in the presence of local dissipation. 23629012 Feasibility of operating a solid-liquid bioreactor with used automobile tires as the sequestering phase for the biodegradation of inhibitory compounds. Finding new uses for waste or discarded material is an important environmental goal; being able to use a waste material to treat another waste is an even more attractive objective, and this was the purpose of the present work. We previously showed that used automobile tires have an affinity for a toxic contaminant, dichlorophenol (DCP), absorbing and releasing it based on concentration driving forces. Here we have exploited this phenomenon by using used tires as the sequestering phase in a Two-Phase Partitioning Bioreactor (TPPB) to treat otherwise-toxic levels of DCP, far out-performing single phase operation in a sequencing batch bioreactor. A comprehensive examination of substrate loading, reactor exchange ratio, and tire fraction used, demonstrated that the tire-TPPB system could handle a 40% higher influent substrate loading and an increase of the exchange ratio value from 0.5 (prohibitive for single phase operation) to 0.7. Such improvement was obtained with a tire fraction ≤9%, comparable to that for commercial polymers previously employed in TPPBs. This study has opened the door to the identification of other waste plastics suitable for use in TPPBs for the treatment of recalcitrant organic contaminants. 23773821 Hsp90-targeted miRNA-liposomal formulation for systemic antitumor effect. Chaperone protein Hsp90 maintains functional integrity and maturation of a large number of cellular proteins including transcription factors, kinases, etc. It is often over-expressed in cancer cells for simultaneous maintenance of many non-regulated and/or genetically mutated proteins. Small molecule-based regimens inhibiting over-expressing Hsp90 in cancer cells often plagued with improper targeting leading to non-specific toxicity. Recently using a glucocorticoid receptor (GR)-targeted cationic lipoplex, we observed cancer cell-specific GR-transactivation and transgene expression by utilizing an unprecedentedly compromised chaperone-activity of cancer cell-associated Hsp90. In normal cells, GR is expressed ubiquitously and is highly regulated and chaperoned by Hsp90. This does not allow cancer cell-alike GR-mediated transgene expression. As a novel anticancer strategy, we showed that compromising Hsp90 in cancer cells can be utilized to selectively deplete its own level by delivering a specially designed artificial miRNA-plasmid against Hsp90 (amiR-Hsp90). Practically, GR-mediated delivery of amiR-Hsp90 plasmid in tumor-bearing mice, depleted Hsp90, critically down-regulated levels of Akt, VEGFR2 and other Hsp90-client proteins but up-regulated wild-type p53 in tumor. These enforced apoptosis in angiogenic vessels and in tumor mass and significantly shrunk tumor-volume. The present study describes gene therapy strategy against Hsp90 using a new GR-targeted liposome-amiR-Hsp90 lipoplex formulation for treating cancer. 23943430 Color Matters-Material Ejection and Ion Yields in UV-MALDI Mass Spectrometry as a Function of Laser Wavelength and Laser Fluence. The success of matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) as a widely employed analytical tool in the biomolecular sciences builds strongly on an effective laser-material interaction that is resulting in a soft co-desorption and ionization of matrix and imbedded biomolecules. To obtain a maximized ion yield for the analyte(s) of interest, in general both wavelength and fluence need to be tuned to match the specific optical absorption profile of the used matrix. However, commonly only lasers with fixed emission wavelengths of either 337 or 355 nm are used for MALDI-MS. Here, we employed a wavelength-tunable dye laser and recorded both the neutral material ejection and the MS ion data in a wide wavelength and fluence range between 280 and 377.5 nm. α-Cyano-4-hydroxycinnamic acid (HCCA), 4-chloro-α-cyanocinnamic acid (ClCCA), α-cyano-2,4-difluorocinnamic acid (DiFCCA), and 2,5-dihydroxybenzoic acid (DHB) were investigated as matrices, and several peptides as analytes. Recording of the material ejection was achieved by adopting a photoacoustic approach. Relative ion yields were derived by division of photoacoustic and ion signals. In this way, distinct wavelength/fluence regions can be identified for which maximum ion yields were obtained. For the tested matrices, optimal results were achieved for wavelengths corresponding to areas of high optical absorption of the respective matrix and at fluences about a factor of 2-3 above the matrix- and wavelength-dependent ion detection threshold fluences. The material ejection as probed by the photoacoustic method is excellently fitted by the quasithermal model, while a sigmoidal function allows for an empirical description of the ion signal-fluence relationship. 23821252 Short-term effect of aniline on soil microbial activity: a combined study by isothermal microcalorimetry, glucose analysis, and enzyme assay techniques. The accidents of aniline spill and explosion happened almost every year in China, whereas the toxic effect of aniline on soil microbial activity remained largely unexplored. In this study, isothermal microcalorimetric technique, glucose analysis, and soil enzyme assay techniques were employed to investigate the toxic effect of aniline on microbial activity in Chinese soil for the first time. Soil samples were treated with aniline from 0 to 2.5 mg/g soil to tie in with the fact of aniline spill. Results from microcalorimetric analysis showed that the introduction of aniline had a significant adverse effect on soil microbial activity at the exposure concentrations ≥0.4 mg/g soil (p < 0.05) and ≥0.8 mg/g soil (p < 0.01), and the activity was totally inhibited when the concentration increased to 2.5 mg/g soil. The glucose analysis indicated that aniline significantly decreased the soil microbial respiratory activity at the concentrations ≥0.8 mg/g soil (p < 0.05) and ≥1.5 mg/g soil (p < 0.01). Soil enzyme activities for β-glucosidase, urease, acid-phosphatase, and dehydrogenase revealed that aniline had a significant effect (p < 0.05) on the nutrient cycling of C, N, and P as well as the oxidative capacity of soil microorganisms, respectively. All of these results showed an intensively toxic effect of aniline on soil microbial activity. The proposed methods can provide toxicological information of aniline to soil microbes from the metabolic and biochemical point of views which are consistent with and correlated to each other. 23830911 Guiding cell migration by tugging. The ability of cells to move directionally toward areas of stiffer extracellular matrix (ECM) via a process known as 'durotaxis' is thought to be critical for development and wound healing, but durotaxis can also drive cancer metastasis. Migration is driven by integrin-mediated focal adhesions (FAs), protein assemblies that couple contractile actomyosin bundles to the plasma membrane, transmit force generated by the cytoskeleton to the ECM, and convert the mechanical properties of the microenvironment into biochemical signals. To probe the stiffness of the ECM, motile fibroblasts modulate FA mechanics on the nanoscale and exert forces that are reminiscent of repeated tugging on the ECM. Within a single cell, all FAs tug autonomously and thus act as local rigidity sensors, allowing discernment of differences in the extracellular matrix rigidity at high spatial resolution. In this article, we review current advances that may shed light on the mechanism of traction force fluctuations within FAs. We also examine plausible downstream effectors of tugging forces which may regulate cytoskeletal and FA dynamics to guide cell migration in response to ECM stiffness gradients. 23937411 Intestinal recruiting and activation profiles in peripheral blood mononuclear cells in response to pathogen-associated molecular patterns stimulation in patients with IBS. Immune activation, increased Toll-like Receptors (TLR) expression, and gut epithelial diffusion of bacterial molecules have been reported in irritable bowel syndrome (IBS). Thus, we sought to relate these factors by analyzing gut homing (integrin α4β7), intestinal recruiting (CCR5) and activation (CD28) phenotypes, and the cytokines and chemokines concentration in peripheral blood T-lymphocytes stimulated with TLR-ligands. Twenty-one IBS-Rome II (1 PI-IBS) patients and 19 controls were studied. Isolated peripheral blood mononuclear cells were cultured with and without Escherichia coli lipopolysaccharide (LPS), Staphylococcus aureus peptidoglycan (PGN), and unmethylated cytosine-phosphate-guanine motifs (CpG). Phenotypes were investigated by flow cytometry and supernatant cytokines and chemokines were also measured. After LPS, CCR5 expression in CD4(+) α4β7(+) cells remained unchanged in IBS, but decreased in controls (p = 0.002), to lower levels than in IBS (Mean fluorescence intensity [MFI]: 1590 ± 126.9 vs 2417 ± 88.4, p < 0.001). There were less CD8(+) α4β7(+) CCR5(+) cells (85.7 ± 1.5 vs 90.8 ± 0.9%, p = 0.006) after LPS and CD3(+) α4β7(+) CCR5(+) (40.0 ± 1.7 vs 51.2 ± 4.3%, p = 0.006) after PGN in controls. Also, after LPS, CD28 decreased in CD4(+) α4β7(+) CCR5(+) in IBS (MFI: 2337 ± 47.2 vs 1779 ± 179.2, p < 0.001), but not in controls. Cytokines and chemokines were similar, except for lower IL8/CXCL8 in the unstimulated condition in IBS (4.18, 95% CI: 3.94-4.42 vs 3.77, 3.59-3.95; p = 0.006). Pathogen-associated molecular patterns stimulation of peripheral blood T cells expressing gut homing marker in IBS compared with controls resulted in an unsuccessful down-regulation of the co-expression of intestinal recruiting/residence phenotype and a state of activation. These findings support an interaction between an innate immune predisposition and microbial triggers, which may unleash or exacerbate IBS. 23868466 "Homeostatic Hitchhiking": A Mechanism for the Evolutionary Retention of Complex Adaptations. The complexity of organismal organization channels and accommodates novel genomic and developmental modifications. Here, I extend this perspective to suggest that emergent processes that dominate homeostasis-co-option, re-use, and recombination of accumulated elements-can create configurations and dependencies among these elements that strongly reduce the number of evolutionary steps needed for the evolution of precise novel adaptations. Evolutionary retention and environmental matching of such configurations are further facilitated when they include elements of homeostasis that are responsive to particular environmental cues. I apply this perspective to the study of evolution of sex-biased egg-laying in birds, a phenomenon that combines precision, complexity, context-dependency, and reversibility. I show that homeostatic hitchhiking can overcome the main difficulty in the evolution of this adaptation-the perceived necessity of de novo co-evolution of oogenesis, sex-determination, and order of ovulation in each environmental context-something that would require unrealistic expectations of evolutionary rates and population sizes and is not a desirable outcome for a process that needs to retain substantial environmental sensitivity. First, I explain the rationale behind the homeostatic-hitchhiking hypothesis and outline its predictions specifically for studies of sex-bias in order of egg-laying. Second, I show that a combination of self-regulatory and emergent processes and ubiquitous re-use of conserved growth factors make oogenesis particularly amendable to homeostatic hitchhiking. Third, I review empirical evidence for this mechanism in the rapid evolution of adaptive sex-biased order of egg-laying that accompanied colonization of North America by the house finch (Carpodacus mexicanus). 23375796 Synthesis and antibacterial activity of 9-oxime ether non-ketolides, and novel binding mode of alkylides with bacterial rRNA. We report a series of new 9-oxime ether non-ketolides, including 3-hydroxyl, 3-O-acyl and 3-O-alkyl clarithromycin derivatives, and thiophene-containing ketolides 1b-1d. Unlike previously reported ketolide 1a, none of them is comparable to telithromycin. A molecular modeling study was performed to gain insight into the binding mode of alkylides 17-20 with bacterial rRNA and to rationalize the great disparity of their SAR. The 3-O-sidechains of 19 and 20 point to the so-called hydrophilic side of the macrolide ring, as seen in clarithromycin. In contrast, the 3-O-sidechains of 17 and 18 bend to the backside, the so-called hydrophobic side of the macrolide ring. The results clearly indicated the alkylides with improved antibacterial activity might possess a novel binding mode, which is different from clarithromycin and the alkylides with poor activity. 23305766 Adolescent social stress does not necessarily lead to a compromised adaptive capacity during adulthood: A study on the consequences of social stress in rats. Childhood bullying or social stress in adolescent humans is generally considered to increase the risk of developing behavioral disorders like depression in adulthood. Juveniles are hypothesized to be particularly sensitive to stressors in their environment due to the relatively late maturation of brain areas that are targeted by stress such as the prefrontal cortex and hippocampus. In our study male adolescent rats were subjected to repeated social defeat on postnatal day (PND) 28, 31 and 34 (experiment 1) or to daily social defeats between PND 35 and 42 (experiment 2). Adolescent rats in experiment 1 were socially housed in pairs with a male of similar age during and after the social defeat. In experiment 2 adolescents were housed either alone or with an age-mate for 7days (PND 35-42) next to either a highly aggressive or a non-aggressive adult male neighbor with whom a repeated physical interaction was allowed. In experiment 1 the adolescent defeats affected subsequent play behavior with the cage mate. Socially stressed rats more frequently initiated play behavior but also adopted more frequently submissive postures during the play fights. As adults, they seemed to cope behaviorally and physiologically better with a similar exposure to a residential aggressive male rat than unstressed controls. In experiment 2 acute effects of adolescent social stress were studied on neuroplasticity markers like hippocampal cell proliferation and neurogenesis as well as hippocampal brain-derived neurotrophic factor (BDNF) levels. The 2nd experiment also studied long-term effects of the adolescent stress in the response to an adult social defeat. A few acute but minor changes in brain plasticity markers and behavior were observed but these were transient and no behavioral or physiological effects persisted into adulthood. The results from both experiments support the theory developed in the so-called "match-mismatch hypothesis" which claims that the final consequence of childhood adversity depends on how well the early life environment matches the challenges in later life. Socially stressed adolescents are rather resilient to the lasting behavioral and physiological effects of the stress exposure if they are socially housed afterward and have the ability to recover. 23609131 Prefrontal Hypoactivity Associated with Impaired Inhibition in Stimulant-Dependent Individuals but Evidence for Hyperactivation in their Unaffected Siblings. A neurocognitive endophenotype has been proposed for stimulant dependence, based on behavioral measures of inhibitory response control associated with white matter changes in the frontal cortex. This study investigated the functional neuroimaging correlates of inhibitory response control, as functional activity serves as a more dynamic measure than brain structure, allowing refinement of the suggested endophenotype. Stimulant-dependent individuals (SDIs), their unaffected siblings (SIBs), and healthy controls (CTs) performed the stop-signal task, including stop-signal reaction time (SSRT) as a measure of response inhibition, while undergoing functional magnetic resonance imaging. SDIs had impaired response inhibition accompanied by hypoactivation in the ventrolateral prefrontal cortex (PFC). In addition, they demonstrated hypoactivation in the anterior cingulate when failing to stop. In contrast, no hypoactivations were noted in their unaffected SIBs. Rather, they exhibited increased activation in the dorsomedial PFC relative to controls, together with inhibitory performance that was intermediate between that of the stimulant group and the healthy CT group. Such hyperactivations within the neurocircuitry underlying response inhibition and control are suggestive of compensatory mechanisms that could be protective in nature or could reflect coping with a pre-existing vulnerability, thus expressing potential aspects of resilience. The functional activation associated with response inhibition and error monitoring showed differential patterns of results between SDIs and their unaffected first-degree relatives, suggesting that the proposed endophenotype does not generalize to functional brain activity. 23810029 Telephone follow-up was more expensive but more efficient than postal in a national stroke registry. To compare the efficiency and differential costs of telephone- vs. mail-based assessments of outcome in patients registered in a national clinical quality of care registry, the Australian Stroke Clinical Registry (AuSCR). The participants admitted to hospital with stroke or transient ischemic attack were randomly assigned to complete a health questionnaire by mail or telephone interview at 3-6 months postevent. Response rate, researcher burden, and costs of each method were compared. Compared with the participants in the mail questionnaire arm (n=277; 50% female; mean age: 70 years), those in the telephone arm (n=282; 45% female; mean age: 68 years) required a shorter time to complete the follow-up (mean difference: 24.2 days; 95% confidence interval [CI]: 15.0, 33.5 days). However, the average cost of completing a telephone follow-up was greater (US$20.87 vs. US$13.86) and had a similar overall response to the mail method (absolute difference: 0.57%; 95% CI: -4.8%, 6%). Posthospital stroke outcome data were slower to collect by mail, but the method achieved a similar completion rate and was significantly cheaper to conduct than follow-up telephone interview. Findings are informative for planning outcome data collection in large numbers of patients with acute stroke. 23935948 Haploinsufficiency of akt1 prolongs the lifespan of mice. There is increasing evidence that nutrient-sensing machinery is critically involved in the regulation of aging. The insulin/insulin-like growth factor-1 signaling pathway is the best-characterized pathway with an influence on longevity in a variety of organisms, ranging from yeast to rodents. Reduced expression of the receptor for this pathway has been reported to prolong the lifespan; however, the underlying mechanisms are largely unknown. Here we show that haploinsufficiency of Akt1 leads to an increase of the lifespan in mice. Akt1 (+/-) mice had a lower body weight than their littermates with less fat mass and normal glucose metabolism. Ribosomal biogenesis and the mitochondrial DNA content were significantly reduced in these mice, along with a decrease of oxidative stress. Consistent with the results obtained in mice, inhibition of Akt-1 promoted longevity in nematodes (Caenorhabditis elegans), whereas activation of Akt-1 shortened the lifespan. Inhibition of Akt-1 led to a decrease of ribosomal gene expression and the mitochondrial DNA content in both human cells and nematodes. Moreover, deletion of ribosomal gene expression resulted in a decrease of the mitochondrial DNA content and normalized the lifespan shortened by Akt-1 activation in nematodes. These results suggest that an increase of mitochondrial amount and energy expenditure associated with enhanced protein synthesis accelerates both aging and the onset of age-associated diseases. 23273383 The influence of ethnicity on the characteristics of multiple sclerosis: A local population study between Persians and Arabs. Based on previous studies, Iran is located in a low risk area in terms of multiple sclerosis (MS). The objective of this study was to determine and compare the incidence, prevalence and demographic characteristics of MS in two ethnic groups of Persian and Arab over the period spanning 2009 in the Khuzestan province, in the Southwest of Iran. A cross-sectional case register study was conducted between January and August 2009. All cases in the region whom were referred to the MS society in the city of Ahwaz were participants in the study. The population data from the Iranian Bureau of Statistics were used to calculate the population at risk based on the 1996 and 2006 census data. A total of 696 patients were identified according to the McDonald criteria during the last 12 years of which 569 patients were Persian. In 2009 the total prevalence and incidence rates of MS were 16.28 and 2.20 per 100,000 individuals. Based on these values, the female to male ratios were 3.11. The Persians manifested more sensory signs and symptoms (40.2%) but motor deficits (19.1%) and cerebellar findings (18.2%) were seen as being more manifest in Arab individuals. The main difference was observed in the progressive types of MS in which 24.7% of the Arab patients showed progressive type symptoms as compared to 15.9% of the cases in the Persian population. According to this study the authors conclude that the prevalence and incidence of MS were higher in Persians; however progressive forms of MS with motor and cerebellar signs are more frequent in the Arab ethnic group. 23559142 Reference levels and patient doses in interventional cardiology procedures in Greece. To present a national survey that was performed for the establishment of national reference levels (RLs) for interventional cardiology (IC) procedures and to estimate the effective dose (E) received by the patient during these procedures. Data concerning the fluoroscopy time and air kerma-area product (P KA) during coronary angiography (CA), percutaneous coronary intervention (PCI), pacemaker implantation (PMI) and radiofrequency cardiac ablation (RFCA) from 26 centres were collected. Moreover, measurements concerning the performance of X-ray systems used in IC were performed in order to set system-related reference levels. P KA to E conversion factors were also calculated. The suggested P KA RLs for CA, PCI, PMI and RFCA are 53 Gycm(2), 129 Gycm(2), 36 Gycm(2) and 146 Gycm(2), respectively, and the estimated E to the patient from these procedures is 9.7 mSv, 26.8 mSv, 5.5 mSv and 20.4 mSv, respectively. Reference levels for the fluoroscopic dose rate and dose per frame during image acquisition at the entrance of a water phantom are 29 mGy/min and 0.23 mGy/frame, respectively. The suggested RLs are comparable to those suggested by other studies. Additional information concerning the complexity of the procedures and patient pathology should be collected for future reevaluation of the suggested RLs. • The radiation dose imparted during fluoroscopically guided interventional procedures can be high • Understanding of reference levels might help optimise interventional cardiological procedures • Optimisation by changing the systems' settings seems feasible in some cases • Procedure complexity and the patient's clinical problem should be taken into account. 23835660 Serum leptin and loss of control eating in children and adolescents. Background:Both insufficiency and resistance to the actions of the adipocyte-derived hormone leptin promote hunger, increased food intake and greater body weight. Some studies suggest that adults reporting binge eating have increased serum leptin compared with those without binge eating, even after adjusting for the greater adiposity that characterizes binge eaters. Pediatric binge or loss of control (LOC) eating are prospective risk factors for excessive weight gain and may predict development of metabolic abnormalities, but whether LOC eating is associated with higher leptin among children is unknown. We therefore examined leptin and LOC eating in a pediatric cohort.Methods:A convenience sample of 506 lean and obese youth (7-18 years) was recruited from Washington, DC and its suburbs. Serum leptin was collected after an overnight fast. Adiposity was measured by dual-energy X-ray absorptiometry or air displacement plethysmography. LOC eating was assessed by interview methodology.Results:Leptin was strongly associated with fat mass (r=0.79, P<0.001). However, even after adjusting for adiposity and other relevant covariates, youth with LOC eating had higher serum leptin compared with those without LOC episodes (15.42±1.05 vs 12.36±1.04 ng ml(-1), P<0.001). Neither reported amount of food consumed during a recent LOC episode nor number of LOC episodes in the previous month accounted for differences in leptin (P>0.05). The relationship between LOC eating and leptin appeared to be significant for females only (P=0.002).Conclusions:Reports of LOC eating were associated with higher fasting leptin in youth, beyond the contributions of body weight. Prospective studies are required to elucidate whether LOC eating promotes greater leptin or whether greater leptin resistance may promote LOC eating.International Journal of Obesity advance online publication, 30 July 2013; doi:10.1038/ijo.2013.126. 23121858 Physical co-morbidity among treatment resistant vs. treatment responsive patients with major depressive disorder. Co-morbid physical illness has been suggested to play an important role among the factors contributing to treatment resistance in patients with major depressive disorder. In the current study we compared the rate of physical co-morbidity, defined by ICD-10, among a large multicenter sample of 702 patients with major depressive disorder. A total of 356 of the participants were defined as treatment resistant depression (TRD) patients-having failed two or more adequate antidepressant trials. No significant difference was found between TRD and non-TRD participants in the prevalence of any ICD-10 category. This finding suggests that although physical conditions such as diabetes, thyroid dysfunction, hypertension, ischemic heart disease, and peptic diseases are often accompanied by co-morbid MDD, they do not necessarily have an impact on the course of MDD or the likelihood to respond to treatment. Marginally higher rates of co-morbid breast cancer, migraine and glaucoma were found among TRD participants. Possible explanations for these findings and their possible relation to TRD are discussed. 23630108 Parity and body mass index in US women: A prospective 25-year study. To investigate long-term body mass index (BMI) changes associated with childbearing. Adjusted mean BMI changes were estimated by race-ethnicity, baseline BMI, and parity using longitudinal regression models for 3,943 young females over 10 and 25 year follow-up from the ongoing 1979 National Longitudinal Survey of Youth cohort. Estimated BMI increases varied by group, ranging from a low of 2.1 BMI units for white, non-overweight nulliparas over the first 10 years to a high of 10.1 BMI units for black, overweight multiparas over the full 25-year follow-up. Impacts of parity were strongest among overweight multiparas and primaparas at 10 years, ranges 1.4-1.7 and 0.8-1.3 BMI units, respectively. Among non-overweight women, parity-related gain at 10 years varied by number of births among black and white but not Hispanic women. After 25 years, childbearing significantly increased BMI only among overweight multiparous black women. Childbearing is associated with permanent weight gain in some women, but the relationship differs by maternal BMI in young adulthood, number of births, race-ethnicity, and length of follow-up. Given that overweight black women may be at special risk for accumulation of permanent, long-term weight after childbearing, effective interventions for this group are particularly needed. 23631614 Access to Outreach Specialist Palliative Care Teams among Cancer Patients in Denmark. Abstract Background: Equal access to end-of-life care is important. However, social inequality has been found in relation to place-of-death. The question is whether social and economic factors play a role in access to specialist palliative care services. Objective: The study analyzed the association between access to outreach specialist palliative care teams (SPCTs) and socioeconomic characteristics of Danish cancer patients who died of their cancer. Methods: The study was a population-based, cross-sectional register study. We identified 599 adults who had died of cancer from March 1 to November 30, 2006, in Aarhus County, Denmark. Data from health registers were retrieved and linked based on the unique personal identifier number. Results: Multivariate analysis with adjustment for age, gender, and general practitioner (GP) involvement showed a higher probability of contact with an SPCT among immigrants and descendants of immigrants than among people of Danish origin (prevalence ratio [PR]: 1.55; 95% confidence interval (CI): 1.04;2.31) and among married compared to unmarried patients (PR: 1.25; 95% CI: 1.01;1.54). The trends were most marked among women. Conclusion: We found an association between females, married patients, and female immigrants and their descendants and access to an SPCT in Denmark. However, no association with the examined economic factor was found. Need for specialized health care, which is supposed to be the main reason for access to an SPCT, may be related to economic imbalance; and despite the relative equality found, SPCT access may not be equal for all Danish residents. Further research into social and economic consequences in palliative care services is warranted. 23174265 Cannabinoid agonists increase the interaction between β-Arrestin 2 and ERK1/2 and upregulate β-Arrestin 2 and 5-HT(2A) receptors. We have recently reported that selective cannabinoid 2 (CB(2)) receptor agonists upregulate 5-HT(2A) receptors by enhancing ERK1/2 signaling in prefrontal cortex (PFCx). Increased activity of cortical 5-HT(2A) receptors has been associated with several neuropsychiatric disorders such as anxiety and schizophrenia. Here we examine the mechanisms involved in this enhanced ERK1/2 activation in rat PFCx and in a neuronal cell model. Sprague-Dawley rats treated with a non-selective cannabinoid agonist (CP55940, 50μg/kg, 7 days, i.p.) showed enhanced co-immunoprecipitation of β-Arrestin 2 and ERK1/2, enhanced pERK protein levels, and enhanced expression of β-Arrestin 2 mRNA and protein levels in PFCx. In a neuronal cell line, we found that selective CB(2) receptor agonists upregulate β-Arrestin 2, an effect that was prevented by selective CB(2) receptor antagonist JTE-907 and CB(2) shRNA lentiviral particles. Additionally, inhibition of clathrin-mediated endocytosis, ERK1/2, and the AP-1 transcription factor also prevented the cannabinoid receptor-induced upregulation of β-Arrestin 2. Our results suggest that sustained activation of CB(2) receptors would enhance β-Arrestin 2 expression possibly contributing to its increased interaction with ERK1/2, thereby driving the upregulation of 5-HT(2A) receptors. The CB(2) receptor-mediated upregulation of β-Arrestin 2 would be mediated, at least in part, by an ERK1/2-dependent activation of AP-1. These data could provide the rationale for some of the adverse effects associated with repeated cannabinoid exposure and shed light on some CB(2) receptor agonists that could represent an alternative therapeutic because of their minimal effect on serotonergic neurotransmission. 23743246 Familial adult-onset Alexander disease with a novel mutation (D78N) in the glial fibrillary acidic protein gene with unusual bilateral basal ganglia involvement. In this report, we describe the case of a new Japanese family (32 to 64 years old; 2 females and 1 male) affected by adult-onset Alexander disease. Clinically, one member (age at onset, 56 years old) developed cerebellar ataxia, another (age at onset, 55 years old) showed cerebellar ataxia and pseudobulbar signs, and one member (32 years old) was asymptomatic. Marked atrophy of the medulla oblongata and spinal cord was detected in the two symptomatic patients by magnetic resonance imaging (MRI). However, in the asymptomatic patient, cervicomedullary atrophy was mild. Hyperintensity signals in the medulla oblongata were detected in the two symptomatic patients, but not in the asymptomatic patient. In addition, there are symmetrical hyperintensity signals in the posterior part of the globus pallidus on T2-weighted images in the two symptomatic patients, which are rarely observed in adult-onset Alexander disease. Molecular genetic analysis revealed a novel missense mutation (p. D78N) in the glial fibrillary acidic protein (GFAP) gene in this family. The typical atrophy of the medulla oblongata and upper cervical cord detected by MRI is the diagnostic feature of adult-onset Alexander disease. Genetic analysis of the GFAP gene is recommended for all patients with late-onset progressive ataxia and suspected of having adult-onset Alexander disease on the basis of MRI findings. Additionally, these characteristic MRI patterns might even lead to the identification of asymptomatic cases, as in one of our cases. 23929707 Mesenchymal stem cells alleviate bacteria-induced liver injury in mice by inducing regulatory dendritic cells. Fulminant hepatic failure (FHF) is a clinical syndrome characterized by sudden and severe impairment of liver function. Mesenchymal stem cells (MSCs) have been proposed as a promising therapeutic approach for FHF. In this study, we have used Propionibacterium acnes (P. acnes)-primed, lipopolysaccharide (LPS)-induced liver injury in mice as an animal model of human FHF. We demonstrated that administration of MSCs significantly ameliorated liver injury and improved the survival rates of mice subjected to P. acnes plus LPS-induced FHF. Allogeneic MSCs showed similar treatment efficacy as autologous MSCs did in FHF. Treatment efficacy of MSCs could be attributed to decreased infiltration and activation of CD4(+) T cells in the liver, inhibition of T helper 1 cells, and induction of regulatory T cells (Tregs). Moreover, decreased DNA copies of P. acnes were detected in the liver of MSC-treated mice. Intriguingly, a distinct liver population of CD11c(+) MHCII(hi) CD80(lo) CD86(lo) regulatory dendritic cells (DCs) was induced by MSCs. Moreover, these DCs induced Treg differentiation through transforming growth factor-β production. Further mechanistic studies demonstrated that MSC-derived prostaglandin E2 and one of its receptors, EP4, played essential roles in the differentiation of CD11c(+) B220(-) DC precursors into regulatory DCs in a phosphoinositide 3-kinase-dependent manner. Conclusion: Our findings demonstrated, for the first time, critical regulatory properties of MSCs for induction of regulatory DCs from CD11c(+) B220(-) DC precursors. This study elucidates an immunoregulatory mechanism of MSCs and further lays a solid foundation for application of MSCs in FHF therapy. (Hepatology 2013;). 23902783 Serving a variety of vegetables and fruit as a snack increased intake in preschool children. Although serving a greater variety of food increases intake, this effect has not been well studied as a strategy to encourage consumption of vegetables and fruit in preschool children. This study examined whether providing a variety of familiar vegetables or fruit to preschool children as a snack would lead to increased selection and intake. In a crossover design, 61 children (aged 3-5 y) ate a snack in their childcare facility on 8 afternoons. At 4 snack times, the children were offered vegetables: either a single type (cucumber, sweet pepper, or tomato) or a variety of all 3 types. At 4 other snack times, the children were offered fruit (apple, peach, pineapple, or all 3 types). Uniform-sized pieces were served family style, and children selected and ate as much as they desired. Offering a variety of vegetables or fruit increased the likelihood of selection (P < 0.0001); children chose some pieces in 94% of snacks with variety and in 70% of snacks without variety. Serving a variety also increased consumption of both vegetables and fruit (P < 0.0002); the mean (±SEM) increase was 31 ± 5 g, about one-sixth the recommended daily amount. Independent of the variety effect, children were less likely to select vegetables than fruit (P < 0.0001), and the mean intake was substantially less for vegetables than for fruit (22 ± 1 compared with 84 ± 3 g). Providing a variety of vegetables and fruit as a snack led to increased consumption of both food types in a childcare facility. Serving a variety of vegetables or fruit as a snack could help preschool children meet recommended intakes. This trial was registered at clinicaltrials.gov as NCT01557218. 23894611 Condition-Dependent Effects of Mating on Longevity and Fecundity of Female Medflies: The Interplay between Nutrition and Age of Mating. In various species mating exerts direct and indirect effects on female demographic traits ranging from life span shortening to behavioural shifts. A wealth of data regarding effects of nutrition on longevity and reproduction output also exists. Nonetheless, little is known regarding the interaction between the age of mating and nutrition on female fitness. We studied, the effects of protein deprivation and age of mating on female fitness traits, using a wild population of the Mediterranean fruit fly (medfly). We tested the hypotheses that (a) protein availability increases female lifespan and fecundity, (b) female longevity and egg production are independent of mating and the age of mating, and (c) female mating behaviour is independent of their age and nutritional status. Thus, we recorded the mating success and the copulation characteristics, as well as the egg production and survival of females mated at young or at old age and fed a full or a protein-deprived diet. Mating boosts egg production and reduces longevity of protein-fed females. On the contrary, mating increases the longevity of protein-deprived females. Mortality responses (negative or positive) to mating are expressed after a long lag phase. Old females are more receptive and less selective than young females regardless of the food regime. Our findings suggest that condition (nutritional status and age) defines the positive or negative output of mating in female medflies. These results contribute towards understanding the effects of mating, aging, resource allocation and their interactions on survival and female reproduction. 23914806 Perinatal bisphenol A exposures increase production of pro-inflammatory mediators in bone marrow-derived mast cells of adult mice. Abstract Bisphenol A (BPA) is a widely used monomer of polycarbonate plastics and epoxide resin that has been implicated in asthma pathogenesis when exposure occurs to the developing fetus. However, few studies have examined the relationship between perinatal BPA exposure and asthma pathogenesis in adulthood. This study used an isogenic mouse model to examine the influence of perinatal BPA exposure via maternal diet on inflammatory mediators associated with asthma in 6-month-old adult offspring by measuring bone marrow-derived mast cell (BMMC) production of lipid mediators (cysteinyl leukotrienes and prostaglandin D2), cytokines (interleukin [IL]-4, IL-5, IL-6, IL-13, and tumor necrosis factor [TNF]-α), and histamine. Global DNA methylation levels in BMMCs from adult offspring were determined to elucidate a potential regulatory mechanism linking perinatal exposure to mast cell phenotype later in life. Four BPA exposure doses were tested: low (50 ng BPA/kg diet, n = 5), medium (50 μg BPA/kg diet, n = 4), high (50 mg BPA/kg diet, n = 4), and control (n = 3). Following BMMC activation, increases in cysteinyl leukotriene (p < 0.01) and TNFα (p < 0.05) production were observed in all BPA-exposure groups, and increases in prostaglandin D2 (p < 0.01) and IL-13 (p < 0.01) production were observed in the high exposure group. Additionally, BMMCs from adult mice in all exposure groups displayed a decrease in global DNA methylation compared to control animals. Thus, perinatal BPA exposure displayed a long-term influence on mast cell-mediated production of pro-inflammatory mediators associated with asthma and global DNA methylation levels, suggesting a potential for mast cell dysregulation, which could affect pulmonary inflammation associated with allergic airway disease into adulthood. 23399882 Agmatine attenuates acquisition but not the expression of ethanol conditioned place preference in mice: a role for imidazoline receptors. The present study investigated the effect of agmatine on acquisition and expression of ethanol conditioned place preference (CPP) and its modulation by imidazoline agents. Swiss albino mice were treated intraperitoneally with saline or agmatine (20-40 mg/kg) before injection of ethanol (1.25 mg/kg) during conditioning days or on a test day (20-120 mg/kg), to observe the effect on acquisition or expression of CPP, respectively. Agmatine inhibited the acquisition but not the expression of ethanol CPP. Furthermore, both the I(1) receptor antagonist, efaroxan (9 mg/kg) and the I(2) receptor antagonist, BU224 (5 mg/kg) attenuated the agmatine-induced inhibition of the ethanol CPP acquisition. In contrast, the I(2) receptor agonist, 2-BFI (5 mg/kg) and I(1) receptor agonist, moxonidine (0.4 mg/kg) alone, or a combination of their subeffective doses, significantly attenuated the effect of agmatine (20 mg/kg) on acquisition of ethanol CPP. Agmatine or imidazoline agents alone produced neither place preference nor aversion, and at the doses used in the present study did not affect locomotor activity. Thus, agmatine attenuates the acquisition of ethanol CPP at least in part by imidazoline (I(1) or I(2)) receptors. In future studies, agmatine or agents acting at the imidazoline receptors could be explored for their therapeutic potential in ethanol dependence. 23334943 High-grade prostate cancer and biochemical recurrence after radical prostatectomy among men using 5α-reductase inhibitors and alpha-blockers. BACKGROUND: Two clinical trials have shown that users of 5α-reductase inhibitors finasteride and dutasteride (5-ARIs) have reduced overall prostate cancer risk, while the proportion of high-grade tumors is increased. We studied tumor characteristics, risk of biochemical recurrence and mortality after radical prostatectomy in 5-ARI and alpha-blocker users. METHODS: The study cohort consisted of 1,315 men who underwent radical prostatectomy at the Tampere University Hospital during 1995-2009. Biochemical relapse was defined as serum PSA ≥ 0.2 ng/ml after the operation. Information on mortality and medication purchases was obtained from national registries. Cox proportional regression was used to analyze hazard ratios (HRs) and 95% confidence intervals (95% CI) of biochemical relapse and death. RESULTS: The proportion of high-grade (Gleason 7-10) tumors was significantly elevated among men who had used 5-ARIs for 4 years or longer compared to the non-users (83.3% vs. 53.3%, respectively). Survival curves for biochemical relapse-free survival differed between long-term and short-term 5-ARI users, but the hazard ratio remained statistically non-significant. Risk of biochemical recurrence was elevated among alpha-blocker users (HR 1.68, 95% CI 1.37-2.06), but in sensitivity analyses this was evident only in men using alpha-blockers after prostatectomy. Mortality was not associated with medication usage. CONCLUSIONS: Long-term users of finasteride or dutasteride had more often high-grade prostate cancer. Our results suggest also worse progression-free survival. The association between risk of biochemical recurrence and post-operative alpha-blocker usage suggests that voiding or storage symptoms after prostatectomy may predict biochemical relapse. Prostate © 2013 Wiley Periodicals, Inc. 23879345 An evaluation of meniscal collagenous structure using optical projection tomography. The collagenous structure of menisci is a complex network of circumferentially oriented fascicles and interwoven radially oriented tie-fibres. To date, examination of this micro- architecture has been limited to two-dimensional imaging techniques. The purpose of this study was to evaluate the ability of the three-dimensional imaging technique; optical projection tomography (OPT), to visualize the collagenous structure of the meniscus. If successful, this technique would be the first to visualize the macroscopic orientation of collagen fascicles in 3-D in the meniscus and could further refine load bearing mechanisms in the tissue. OPT is an imaging technique capable of imaging samples on the meso-scale (1-10 mm) at a micro-scale resolution. The technique, similar to computed tomography, takes two-dimensional images of objects from incremental angles around the object and reconstructs them using a back projection algorithm to determine three-dimensional structure. Bovine meniscal samples were imaged from four locations (outer main body, femoral surface, tibial surface and inner main body) to determine the variation in collagen orientation throughout the tissue. Bovine stifles (n = 2) were obtained from a local abattoir and the menisci carefully dissected. Menisci were fixed in methanol and subsequently cut using a custom cutting jig (n = 4 samples per meniscus). Samples were then mounted in agarose, dehydrated in methanol and subsequently cleared using benzyl alcohol benzyl benzoate (BABB) and imaged using OPT. Results indicate circumferential, radial and oblique collagenous orientations at the contact surfaces and in the inner third of the main body of the meniscus. Imaging identified fascicles ranging from 80-420 mum in diameter. Transition zones where fascicles were found to have a woven or braided appearance were also identified. The outer-third of the main body was composed of fascicles oriented predominantly in the circumferential direction. Blood vessels were also visualized using this technique, as their elastin content fluoresces more brightly than collagen at the 425 nm wavelength used by the OPT scanner. OPT was capable of imaging the collagenous structure, as well as blood vessels in the bovine meniscus. Collagenous structure variability, including transition zones between structural regions not previously described in the meniscus, was identified using this novel technique. 23792378 Complete mitochondrial genomes of the Japanese pink coral (Corallium elatius) and the Mediterranean red coral (Corallium rubrum): a reevaluation of the phylogeny of the family Coralliidae based on molecular data. Precious corals are soft corals belonging to the family Coralliidae (Anthozoa: Octocorallia: Alcyonacea) and class Anthozoa, whose skeletal axes are used for jewelry. The family Coralliidae includes ca. 40 species and was originally thought to comprise of the single genus Corallium. In 2003, Corallium was split into two genera, Corallium and Paracorallium, and seven species were moved to this newly identified genus on the bases of morphological features. Previously, we determined the complete mitochondrial genome sequence of two precious corals Paracorallium japonicum and Corallium konojoi, in order to clarify their systematic positions. The two genomes showed high nucleotide sequence identity, but their gene order arrangements were not identical. Here, we determined three complete mitochondrial genome sequences from the one specimen of Mediterranean Corallium rubrum and two specimens of Corallium elatius coming from Kagoshima (South Japan). The circular mitochondrial genomes of C. rubrum and C. elatius are 18,915bp and 18,969-18,970bp in length, respectively, and encode 14 typical octocorallian protein-coding genes (nad1-6, nad4L, cox1-3, cob, atp6, atp8, and mtMutS, which is an octocoral-specific mismatch repair gene homologue), two ribosomal RNA genes (rns and rnl), and one transfer RNA (trnM). The overall nucleotide differences between C. konojoi and each C. elatius haplotype (T2007 and I2011) are only 10 and 11 nucleotides, respectively; this degree of similarity indicates that C. elatius and C. konojoi are very closely related species. Notably, the C. rubrum mitochondrial genome shows more nucleotide sequence identity to P. japonicum (99.5%) than to its congeneric species C. konojoi (95.3%) and C. elatius (95.3%). Moreover, the gene order arrangement of C. rubrum was the same as that of P. japonicum, while that of C. elatius was the same as C. konojoi. Phylogenetic analysis based on three mitochondrial genes from 24 scleraxonian species shows that the family Coralliidae is separated into two distinct groups, recovering Corallium as a paraphyletic genus. Our results indicate that the currently accepted generic classification of Coralliidae should be reconsidered. 23724912 Case of neuro-Behçet's disease successfully maintained a remission using infliximab for 2 years. Behçet's disease is a systemic inflammatory disorder with chronic remissions and relapses. Involvement of the central nervous system, called neuro-Behçet's disease (NBD), is a serious complication. Although corticosteroids and immunosuppressive agents are used, there is no definite standard of treatment with long term-effects for NBD. Here, we report a female case with NBD successfully treated by infliximab and corticosteroids for 2 years. Our report suggests treatment with infliximab may be effective for long-term remission of NBD. 23922875 SAHA Enhances Synaptic Function and Plasticity In Vitro but Has Limited Brain Availability In Vivo and Does Not Impact Cognition. Suberoylanilide hydroxamic acid (SAHA) is an inhibitor of histone deacetylases (HDACs) used for the treatment of cutaneous T cell lymphoma (CTCL) and under consideration for other indications. In vivo studies suggest reducing HDAC function can enhance synaptic function and memory, raising the possibility that SAHA treatment could have neurological benefits. We first examined the impacts of SAHA on synaptic function in vitro using rat organotypic hippocampal brain slices. Following several days of SAHA treatment, basal excitatory but not inhibitory synaptic function was enhanced. Presynaptic release probability and intrinsic neuronal excitability were unaffected suggesting SAHA treatment selectively enhanced postsynaptic excitatory function. In addition, long-term potentiation (LTP) of excitatory synapses was augmented, while long-term depression (LTD) was impaired in SAHA treated slices. Despite the in vitro synaptic enhancements, in vivo SAHA treatment did not rescue memory deficits in the Tg2576 mouse model of Alzheimer's disease (AD). Along with the lack of behavioral impact, pharmacokinetic analysis indicated poor brain availability of SAHA. Broader assessment of in vivo SAHA treatment using high-content phenotypic characterization of C57Bl6 mice failed to demonstrate significant behavioral effects of up to 150 mg/kg SAHA following either acute or chronic injections. Potentially explaining the low brain exposure and lack of behavioral impacts, SAHA was found to be a substrate of the blood brain barrier (BBB) efflux transporters Pgp and Bcrp1. Thus while our in vitro data show that HDAC inhibition can enhance excitatory synaptic strength and potentiation, our in vivo data suggests limited brain availability may contribute to the lack of behavioral impact of SAHA following peripheral delivery. These results do not predict CNS effects of SAHA during clinical use and also emphasize the importance of analyzing brain drug levels when interpreting preclinical behavioral pharmacology. 23462428 Role of biomarkers in the differential diagnosis of acute respiratory failure in the immediate postoperative period of lung transplantation. Lung transplant recipients are at high risk of suffering many complications during the immediate postoperative period, such as primary graft dysfunction, acute graft rejection or infection. The most common symptom is the presence of acute respiratory failure, and the use of biomarkers could be useful for establishing an early diagnosis of these conditions. Different biomarkers have been studied, but none have proven to be the gold standard in the differential diagnosis of acute respiratory failure. This paper offers a review of the different biomarkers that have been studied in this field. 23688671 Alkaline post-treatment for improved sludge anaerobic digestion. Alkaline post-treatment was tested in order to improve sludge anaerobic digestion. Between the 8th and the 12th hour of a 24-h digestion cycle, 5% of sludge was extracted from a semi-continuous digester with a sludge retention time of 20 days. The sludge was then disintegrated with 0.1 mol/L NaOH and returned to the digester after neutralization. The results showed that alkaline post-treatment increased the level of soluble organic substances in the extracted sludge, particularly of volatile fatty acids and polysaccharides. This process resulted in a 33% enhancement of biogas production in comparison with the control. When the ratio of the recycled sludge was further increased to 10% or 15%, the increment of biogas yield was reduced, due to excessive inactivation of anaerobic bacteria in the digester. Alkaline post-treatment had a minimal impact on the dewaterability of digested sludge. 22464639 Alpha-chymotrypcin ameliorates neuroinflammation and apoptosis characterizing Alzheimer's disease-induced in ovarictomized rats. Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Very little is known about the causes of AD, except that its end stages involve extensive neuronal loss and the appearance of distinctive neuropathological features. This study was under taken to investigate the role of α-chymotrypcin (α-ch) in management of AD-induced in ovariectomized rats. Sixty female Sprague Dawley rats were divided into four groups n=15, (1) normal control group (con), (2) group underwent surgery to remove ovaries (ovx control group), (3) ovx group received aluminum chloride in a dose of 17 mg/kg daily for 2 months to induce AD (AD group), (4) AD group treated with α-chymotrypcin (α-ch) at dose (8.1 unit/rat/day) which is equivalent to the recommended human dose (α-ch-treated group) for three months. At the end of the experimental period, rats were sacrificed; brain samples were obtained for different biochemical analyses and histopathological examination. The biochemical analyses included determination of tumor necrosis factor-α (TNF- α), IL-18, monocyte chemo attractant protein-1 MCP-1, FAS, B-cell lymphoma 2 (Bcl2). In comparison with normal control group, the ovx control group recorded significant increase in the brain levels of TNF-α, IL-18, MCP-1 and FAS. On the other hand, the brain level of Bcl2 was significantly decreased. Also, AD group showed a significant increase in TNF-α, IL-18, MCP-1 and FAS levels in brain tissue. In contrast, significant decrease in brain Bcl2 level was detected in AD group as compared to the ovx control group. However, the treatment of AD group with α-chymotrypcin caused an improvement in the most studied biochemical parameters as indicated by decreased brain levels of TNF-α, IL-18, MCP-1 and FAS accompanied with significant increase in the level of Bcl2 compared to AD group. Histopathological investigation of brain tissue of ovx rats administered with aluminum (AD group) showed AD plaques. While, AD group treated with α-chymotrypcin showed great improvement in the brain morphological structure with the disappearance of amyloid plaques. This study revealed that α-chymotrypcin significantly ameliorates the neuroinflammation characterizing Alzheimer's disease in ovariectomized rats due to it's proteolytic activity as well as it's anti-inflammatory effect. 23199994 Identification of high β-glucan oat lines and localization and chemical characterization of their seed kernel β-glucans. Oat, (Avena sativa) is an excellent source of mixed linkage β-glucans ((1→3)(1→4)-β-D-glucan), a dietary fibre with cholesterol lowering properties. Using a mutagenized oat-population we screened 1700 different lines and identified ten lines that displayed β-glucan levels above 6.7% and 10 below 3.6%.The extreme values were 1.8% and 7.5%. We chose six lines with an increased- and four lines with a reduced β-glucan content for further study. By longitudinal- and cross-sections of seeds it was shown that localization of β-glucan varied between the different lines. In addition, β-glucan quality parameters like molecular weight and solubility were also determined. Although the selection was designed for quantitative differences, qualitative differences between the β-glucans from the different lines were found. The high and low β-glucan lines will now be used as a model system to study molecular regulation of β-glucan biosynthesis as well as possible links between fibre quality and biological activity. 23893432 Enhanced glycan nanoprofiling by weak anion exchange preparative chromatography, mild acid desialylation, and nanoliquid chromatography-mass spectrometry with nanofluorescence detection. The structural characterization and quantification of the glycome of cells and glycoproteins is necessary for the understanding of glycan functions in Biology, the development of diagnostics tests, and the monitoring of glycoprotein pharmaceuticals. Classical N-glycan characterization methods involve enzymatic release followed by derivatization with a fluorochrome and separation by normal-phase HPLC. We have recently developed glycan nanoprofiling, a method for the simultaneous quantification and characterization of the N-glycans without the need of external standardization. Although glycan nanoprofiling allows the characterization of both neutral and sialylated glycans within the same chromatographic run, a significant drawback is the coelution of similar glycans when complex glycan mixtures are analyzed. To overcome this problem, we have developed enhanced glycan nanoprofiling. This new method introduces a weak anion-exchange HPLC separation step to fractionate glycans according to their sialic acid content followed by a mild acid desialylation. Glycans are then resolved by nano-LC-coupled ESI-MS with an intercalated nanofluorescence detector. Neutral glycans have a better analytical separation, better ionization profiles, and provide significantly higher MS signals allowing a detailed characterization of rare glycan species. Enhanced glycan nanoprofiling is a powerful approach that provides a fast and sensitive alternative to available N-glycan profiling methods. 23868291 Strand Invasion of DNA Quadruplexes by PNA: Comparison of Homologous and Complementary Hybridization. Molecular recognition of DNA quadruplex structures is envisioned to be a strategy for regulating gene expression at the transcriptional level and for in situ analysis of telomere structure and function. The recognition of DNA quadruplexes by peptide nucleic acid (PNA) oligomers is presented here, with a focus on comparing complementary, heteroduplex-forming and homologous, heteroquadruplex-forming PNAs. Surface plasmon resonance and optical spectroscopy experiments demonstrated that the efficacy of a recognition mode depended strongly on the target. Homologous PNA readily invades a quadruplex derived from the promoter regulatory region found upstream of the MYC proto-oncogene to form a heteroquadruplex at high potassium concentration mimicking the intracellular environment, whereas complementary PNA exhibits virtually no hybridization. In contrast, complementary PNA is superior to the homologous in hybridizing to a quadruplex modeled on the human telomere sequence. The results are discussed in terms of the different structural morphologies of the quadruplex targets and the implications for in vivo recognition of quadruplexes by PNAs. 23880751 Calcific uremic arteriolopathy: overview for the nurse. Calcific uremic arteriolopathy is a little understood diagnosis of increasing prevalence seen predominantly in patients with chronic kidney disease, particularly those who are approaching end-stage renal disease, who are undergoing renal dialysis, and who have secondary hyperparathyroidism. Calcific uremic arteriolopathy affects women more frequently than men, at a ratio of 3:1, and the median age at diagnosis is 48 years. A clear understanding of the pathogenesis and definitive plans of care are lacking. Nurses should be familiar with the clinical picture of calcific uremic arteriolopathy. Early recognition is important to develop optimal treatment plans and to limit progression of this rare but often fatal disease. Nurses have a pivotal role in maintaining the patient's comfort and dignity, while setting realistic goals of care. Calcific uremic arteriolopathy remains a rare and complex clinical condition that requires a multidisciplinary health care team approach to provide the optimal level of care. Nurses have an essential role in the care of patients with the diagnosis of calcific uremic arteriolopathy. 23968705 Survival After Endovascular Therapy in Patients With Type B Aortic Dissection: A Report From the International Registry of Acute Aortic Dissection (IRAD). This study sought to evaluate long-term survival in type B aortic dissection patients treated with thoracic endovascular aortic repair (TEVAR) therapy. Historical data have supported medical therapy in type B acute aortic dissection (TBAAD) patients. Recent advances in TEVAR appear to improve in-hospital mortality. We examined 1,129 consecutive patients with TBAAD enrolled in IRAD (International Registry of Acute Aortic Dissection) between 1995 and 2012 who received medical (n = 853, 75.6%) or TEVAR (n = 276, 24.4%) therapy. Clinical history was similar between groups. TEVAR patients were more likely to present with a pulse deficit (28.3% vs. 13.4%, p < 0.001) and lower extremity ischemia (16.8% vs. 3.6%, p < 0.001), and to characterize their pain as the "worst pain ever" (27.5% vs. 15.7%, p < 0.001). TEVAR patients were also most likely to present with complicated acute aortic dissection, defined as shock, periaortic hematoma, signs of malperfusion, stroke, spinal cord ischemia, mesenteric ischemia, and/or renal failure (61.7% vs. 37.2%). In-hospital mortality was similar in patients managed with endovascular repair (10.9 % vs. 8.7%, p = 0.273) compared with medically managed patients. One-year mortality was also similar in both groups (8.1% endovascular vs. 9.8% medical, p = 0.604). Among adverse events during follow-up, aortic growth/new aneurysm was most common, occurring in 73.3% of patients with medical therapy and in 62.7% of patients after TEVAR, based on 5-year Kaplan-Meier estimates. Kaplan-Meier survival estimates showed that patients undergoing TEVAR had a lower death rate (15.5% vs. 29.0%, p = 0.018) at 5 years. Results from IRAD show that TEVAR is associated with lower mortality over a 5-year period than medical therapy for TBAAD. Further randomized trials with long-term follow-up are needed. 22893351 A significant dose-dependent relationship between mercury exposure from dental amalgams and kidney integrity biomarkers: A further assessment of the Casa Pia children's dental amalgam trial. Dental amalgams are a commonly used dental restorative material. Amalgams are about 50% mercury (Hg), and Hg is known to significantly accumulate in the kidney. It was hypothesized that because Hg accumulates in the proximal tubules (PTs), glutathione-S-transferases (GST)-α (suggestive of kidney damage at the level of PT) would be expected to be more related to Hg exposure than GST-π (suggestive of kidney damage at the level of the distal tubules). Urinary biomarkers of kidney integrity were examined in children of 8-18 years old, with and without dental amalgam fillings, from a completed clinical trial (parent study). Our study determined whether there was a significant dose-dependent correlation between increasing Hg exposure from dental amalgams and GST-α and GST-π as biomarkers of kidney integrity. Overall, the present study, using a different and more sensitive statistical model than the parent study, revealed a statistically significant dose-dependent correlation between cumulative exposure to Hg from dental amalgams and urinary levels of GST-α, after covariate adjustment; where as, a nonsignificant relationship was observed with urinary levels of GST-π. Furthermore, it was observed that urinary GST-α levels increased by about 10% over the 8-year course of the study among individuals with an average exposure to amalgams among the study subjects from the amalgam group, in comparison with study subjects with no exposure to dental amalgams. The results of our study suggest that dental amalgams contribute to ongoing kidney damage at the level of the PTs in a dose-dependent fashion. 23884578 Genetic analysis of ADIPOQ variants and gastric cancer risk: a hospital-based case-control study in China. Single-nucleotide polymorphisms (SNPs) of adiponectin (ADIPOQ), adiponectin receptor 1 (ADIPOR1) and ADIPOR2 genes contribute to the risk and progression of cancers. Here, we investigated the associations between variants of these three genes and the risk of gastric cancer. We genotyped six ADIPOQ SNPs, nine ADIPOR1 SNPs and six ADIPOR2 SNPs using the Sequenom technique in a hospital-based case-control study of patients with gastric cancer and cancer-free controls in the Chinese Han population. We found associations of certain variants with location of gastric cancer. Rs16861205 with the minor allele A in ADIPOQ, rs10773989 with the minor allele C and rs1044471 with the minor allele T in ADIPOR2 presented significant associations with a decreased risk of cardia cancer (P = 0.024, OR 0.605, 95 % CI 0.390-0.938; P = 0.015, OR 0.699, 95 % CI 0.522-0.935; and P = 0.022, OR = 0.703, 95 % CI 0.519-0.951, respectively). ADIPOQ rs16861205 with minor allele A displayed an association with an increased risk of body cancer (P = 0.010, OR 1.821, 95 % CI 1.148-2.890). Further stratified analysis of the patients indicated that there were significant correlations for rs1342387A/G (P = 0.027) and rs16861205A/G (P = 0.000) with tumor location; rs16850799A/G (P = 0.004) and rs2058033C/A (P = 0.003) with invasion depth; rs16850799A/G (P = 0.019) with the tumor-node-metastasis stage; rs16850799A/G (P = 0.016), rs1501299A/C (P = 0.005) and rs1063538C/T (P = 0.017) with alcohol consumption; rs11612414A/G (P = 0.040) and rs12733285T/C (P = 0.005) with salted food; rs1063538C/T (P = 0.043) with family history of gastric cancer; and rs11612414A/G (P = 0.029) with gender. Adiponectin expression significantly correlated with gender (P = 0.014), alcohol consumption (P = 0.037), family history (P = 0.019) and invasion depth of primary tumor (P = 0.024). Our data suggested that variants of ADIPOQ may be genetic markers conferring susceptibility to gastric cancer subtypes. These findings need to be validated in a larger panel of samples from distinct populations. 23915221 In-hospital refractory cardiac arrest treated with extracorporeal membrane oxygenation: A tertiary single center experience. Abstract We retrospectively assessed the experience of our tertiary care center on the use of venous-arterial extracorporeal membrane oxygenation (VA-ECMO) in 16 adult patients with refractory cardiac arrest. Cardiac arrest was due to acute coronary syndrome in 10 patients (62.5%), Takotsubo Syndrome in 1 patient (6.25%), dilated cardiomyopathy in 4 (25%) patients and massive pulmonary embolism in 1 patient (6.25%). The device was implanted in the catheterization laboratory in 14 patients (87.5%), in the operating room in 1 patient (6.25%) and in the emergency department in 1 patient (6.25%). During support, 7 patients were submitted to percutaneous coronary intervention, while coronary artery bypass grafting was performed in 1 patient, and cardiac surgery for repair of left ventricular wall rupture was performed in 1 patient. The device was successfully weaned in 6 patients (37.5%), among whom 2 patients died and 4 patients (25%) were discharged alive. In our institution 2/16 (12.5%) patients treated with VA-ECMO for refractory cardiac arrest survived to hospital discharge neurologically intact, and a good neurological function was observed in 3/16 (18.8%) at six-month follow-up. 23716605 FeoB-Mediated Uptake of Iron by Francisella tularensis. Francisella tularensis, the bacterial cause of tularemia, infects the liver and replicates in hepatocytes in vivo and in vitro. However, the factors that govern adaptation of F. tularensis to the intrahepatocytic niche have not been identified. Using cDNA microarrays, we determined the transcriptional profile of the live vaccine strain (LVS) of F. tularensis grown in the FL83B murine hepatocytic cell line compared to that of F. tularensis cultured in broth. The fslC gene of the fsl operon was the most highly upregulated. Deletion of fslC eliminated the ability of the LVS to produce siderophore, which is involved in uptake of ferric iron, but it did not impair its growth in hepatocytes, A549 epithelial cells, or macrophages. Therefore, we sought an alternative means by which F. tularensis might obtain iron. Deletion of feoB, which encodes a putative ferrous iron transporter, retarded replication of the LVS in iron-restricted media, reduced its growth in hepatocytic and epithelial cells, and impaired its acquisition of iron. Survival of mice infected intradermally with a lethal dose of the LVS was slightly improved by deletion of fslC but was not altered by loss of feoB. However, the ΔfeoB mutant showed diminished ability to colonize the lungs, liver, and spleen of mice that received sublethal inocula. Thus, FeoB represents a previously unidentified mechanism for uptake of iron by F. tularensis. Moreover, failure to produce a mutant strain lacking both feoB and fslC suggests that FeoB and the proteins of the fsl operon are the only major means by which F. tularensis acquires iron. 23889955 The injured elderly: A rising tide. Injury remains a public health challenge despite advances in trauma care. Periodic survey of injury epidemiology is essential to the trauma system's continuous performance improvement. We undertook this study to characterize the changes in Florida injury rates during the past 15 years. Injured patients were identified with the use of a statewide database over 15 years ending in 2010. Population data were obtained from the U.S. Census. Severe injury was defined by International Classification Injury Severity Scores less than 0.85. Injury rates were expressed in discharges per 100,000 residents. Trends were analyzed by linear regression. The 1.5 million patient discharges consisted of 5.2% children, 39.7% adults, and 55.1% elderly. The overall injury rate decreased in children by 18% but increased in adults by 2% and in the elderly by 17% during the study period. The proportion of severe injuries decreased in children and the elderly but did not change in adults. Injury patterns changed in all age groups. Injury in the elderly is increasing at a rate seven times that of adults. In 2010, the elderly accounted for only 17% of the population but 55% of injury-related discharges. These trends have dramatic implications for the design of future trauma systems and health care resource use. 23746457 Transplacental transmission of BTV-8 in sheep: BTV viraemia, antibody responses and vaccine efficacy in lambs infected in utero. Bluetongue virus (BTV) is an insect vector transmitted virus which causes an economically important disease in ruminants. BTV infection during pregnancy can result in infection of the foetus, which may lead to the birth of persistently infected or immunotolerant offspring. Since persistently infected animals continuously produce large amounts of virus they could be a source of infection for the insect vector. This could significantly influence the epidemiology of the virus and hence might require additional measures to control a BTV outbreak. Therefore, we investigated the potential of BTV-8 to induce persistent infection or immunotolerance in lambs in an experimental setting. Infection of eighteen 70-75 days pregnant ewes with wild type BTV-8 led to the birth of 25 out of 44 BTV RNA positive lambs (foetal infected, FI). All 23 FI lambs born alive also had anti BTV antibodies at birth; infectious virus could be recovered from 5 out of 25 FI lambs. Viral RNA loads decreased rapidly after birth; 19 out of 20 FI lambs that remained in the experiment until week 14 after birth, were RNA negative at that time. Since persistence of BTV-8 infection could not be demonstrated, we investigated whether foetal infection had an effect on protection against a field virus infection and on efficacy of vaccination. To this end, 5 FI lambs and 5 foetal non-infected (FNI) lambs were vaccinated with the inactivated Bovilis(®) BTV-8 vaccine, five months after birth. Three weeks after the vaccination, all lambs were infected with wild type BTV-8. The foetal infection did not interfere with vaccination efficacy. In contrast, foetal BTV-8 infection induced an immune response which afforded protection against BTV challenge comparable to the level of protection induced by vaccination. 22833593 Induction of a shorter compression phase is correlated with a deeper chest compression during metronome-guided cardiopulmonary resuscitation: a manikin study. Recent studies have shown that there may be an interaction between duty cycle and other factors related to the quality of chest compression. Duty cycle represents the fraction of compression phase. We aimed to investigate the effect of shorter compression phase on average chest compression depth during metronome-guided cardiopulmonary resuscitation. Senior medical students performed 12 sets of chest compressions following the guiding sounds, with three down-stroke patterns (normal, fast and very fast) and four rates (80, 100, 120 and 140 compressions/min) in random sequence. Repeated-measures analysis of variance was used to compare the average chest compression depth and duty cycle among the trials. The average chest compression depth increased and the duty cycle decreased in a linear fashion as the down-stroke pattern shifted from normal to very fast (p<0.001 for both). Linear increase of average chest compression depth following the increase of the rate of chest compression was observed only with normal down-stroke pattern (p=0.004). Induction of a shorter compression phase is correlated with a deeper chest compression during metronome-guided cardiopulmonary resuscitation. 23660005 Functional activity maps based on significance measures and Independent Component Analysis. The use of functional imaging has been proven very helpful for the process of diagnosis of neurodegenerative diseases, such as Alzheimer's Disease (AD). In many cases, the analysis of these images is performed by manual reorientation and visual interpretation. Therefore, new statistical techniques to perform a more quantitative analysis are needed. In this work, a new statistical approximation to the analysis of functional images, based on significance measures and Independent Component Analysis (ICA) is presented. After the images preprocessing, voxels that allow better separation of the two classes are extracted, using significance measures such as the Mann-Whitney-Wilcoxon U-Test (MWW) and Relative Entropy (RE). After this feature selection step, the voxels vector is modelled by means of ICA, extracting a few independent components which will be used as an input to the classifier. Naive Bayes and Support Vector Machine (SVM) classifiers are used in this work. The proposed system has been applied to two different databases. A 96-subjects Single Photon Emission Computed Tomography (SPECT) database from the "Virgen de las Nieves" Hospital in Granada, Spain, and a 196-subjects Positron Emission Tomography (PET) database from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Values of accuracy up to 96.9% and 91.3% for SPECT and PET databases are achieved by the proposed system, which has yielded many benefits over methods proposed on recent works. 23510510 Dendrimer Driven Self-Assembly of SPR Active Silver-Gold Nanohybrids. A fourth generation PAMAM dendrimer has been successfully employed for the development of a single step synthesis strategy for self-assembled Ag-Au nanohybrid structures. The surface plasmon resonance properties and the degree of self-assembly of the nanohybrid are strongly correlated with the stoichiometry of the metals which gives rise to enhanced plasmonic properties. The enhanced plasmonic response of the nanohybrids is modeled and is validated experimentally in a model HRP (horseradish peroxidise) bioassay carried out on an SPR-based biochip platform. 23601766 Confirmation of initial antiphospholipid antibody positivity depends on the antiphospholipid antibody profile. The revised classification criteria for the antiphospholipid syndrome state that antiphospholipid (aPL) antibodies (lupus anticoagulant [LAC] and/or anticardiolipin [aCL] and/or anti-β2 -glycoprotein I [aβ2 GPI] antibodies) should be detected on two or more occasions at least 12 weeks apart. Consequently, classification of patient risk and adequacy of treatment may be deferred by 3 months. In order to early classify patient risk, we evaluated whether aPL positivity confirmation is related to aPL antibody profiles. Consecutive patients referred to our center who were initially positive in one or more tests exploring the presence of aPL were tested after 3 months. During a 4-year period, 225 patients were initially positive in one or more tests, and 161 were available for confirmation after 3 months. Patients were classified as triple-positive (n = 54: LAC(+) , aCL(+) , aβ2 GPI(+) , same isotype), double-positive (n = 50: LAC(-) , aCL(+) , aβ2 GPI(+) , same isotype) and single-positive (n = 53: LAC or aCL or aβ2 GPI antibodies as the sole positive test). Among subjects with triple positivity at initial testing, 98% (53 of 54) had their aPL profile confirmed after 12 weeks. The double-positive and single-positive groups had data confirmed in 42 of 50 (84%) and 23 of 57 (40%) subjects, respectively. Our results show that high-risk subjects with triple-positive aPL profiles are identified early, at the time of the initial screening tests. 23826956 Phenotype microarray screening of carbon sources used by Vibrio cholerae identifies genes regulated by the cAMP receptor protein. The cyclic AMP receptor protein (CRP) regulates genes involved in carbon source metabolism, iron uptake, and virulence in bacteria. Identifying the carbon sources utilized by bacteria that are regulated by CRP will help elucidate the CRP regulation cascade and associated responses to environmental stimuli. CRP-dependent regulation of carbon source metabolism in Vibrio cholerae is not thoroughly understood. To identify the candidate carbon sources utilized by V. cholerae that are affected by CRP, we used high-throughput screening to compare the metabolic differences between wild-type and CRP mutant strains of V. cholerae O1 El Tor. Phenotype microarray was used for primary screening of the wild-type and mutant strains, followed by minimal media growth assays and quantitative RT-PCR to validate the candidate carbon sources. In total, 24 carbon sources were subject to CRP regulation, 11 of which have not been previously reported in bacteria. The genes known to be involved in the metabolism of 4 of the carbon sources identified were verified by quantitative RT-PCR. In addition, gel shift experiments showed that CRP bound directly to VCA0053 and VC0391 promoters. Overall, this comprehensive analysis of CRP-mediated catabolite control in V. cholerae has identified new candidate carbon sources for in-depth experimental studies. 23744585 CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia. The association between cytomegalovirus (CMV) reactivation and relapse was evaluated in a large cohort of patients with acute myeloid leukemia (AML) (n = 761), acute lymphoblastic leukemia (ALL) (n = 322), chronic myeloid leukemia (CML) (n = 646), lymphoma (n = 254), and myelodysplastic syndrome (MDS) (n = 371) who underwent allogeneic hematopoietic cell transplantation (HCT) between 1995 and 2005. In multivariable models, CMV pp65 antigenemia was associated with a decreased risk of relapse by day 100 among patients with AML (hazard ratio [HR] = 0.56; 95% confidence interval [CI], 0.3-0.9) but not in patients with ALL, lymphoma, CML, or MDS. The effect appeared to be independent of CMV viral load, acute graft-versus-host disease, or ganciclovir-associated neutropenia. At 1 year after HCT, early CMV reactivation was associated with reduced risk of relapse in all patients, but this did not reach significance for any disease subgroup. Furthermore, CMV reactivation was associated with increased nonrelapse mortality (HR = 1.31; 95% CI, 1.1-1.6) and no difference in overall mortality (HR = 1.05; 95% CI, 0.9-1.3). This report demonstrates a modest reduction in early relapse risk after HCT associated with CMV reactivation in a large cohort of patients without a benefit in overall survival. 23738862 Changes in milk proteome and metabolome associated with dry period length, energy balance, and lactation stage in postparturient dairy cows. The early lactation period of dairy cows, which produce high quantities of milk, is normally characterized by an insufficient energy intake to cover milk production and maintenance requirements. Mobilization of body reserves occurs to compensate this negative energy balance (NEB), and probably as a consequence there is a higher susceptibility to diseases and metabolic disorders. There are several diagnostic methods to detect NEB, usually involving ketosis related parameters. Due to the easy availability of milk this is a preferred matrix, but simple and robust predictors of NEB level are missing. To better understand the physiological mechanism of NEB, milk of cows subjected to different dry period lengths, in different energy balance status and lactation stage, were analyzed by untargeted metabolomics and proteomics techniques. Milk of cows in severe NEB showed higher concentrations of acute phase response proteins, unsaturated fatty acids, and galactose-1-phosphate. Improved energy balance (EB) resulted in higher concentration of cholesterol, cholesterol synthesis related proteins, and stomatin. The presence of stomatin and galactose-1-phosphate in milk was strongly dependent on the EB of the cows. These novel and interesting findings warrant more in-depth research to assess their applicability as robust indicators of NEB in milk and to clarify the role of stomatin and galactose-1-phophate in milk of dairy cows in NEB. 23859608 Clinical applications and issues of oxygen saturation level measurements obtained from peripheral sites. Abstract Studies have suggested that the saturated oxygen level within one's arterial blood can provide crucial information about the status of one's cardiopulmonary system. Currently, a popular and convenient approach is to obtain this vital physiological sign through non-invasive measurement on suitable peripheral sites such as a finger, toe or ear lobe. This measurement is known as the SpO2 parameter. It has been increasingly adopted in not only clinical settings but also remote monitoring purposes. In order to measure this optical based parameter, light sources of both the red and infrared wavelengths are required. The most recognized waveform feature is the peripheral pulse or its AC component which is synchronized to each heartbeat. The AC component is superimposed on a constant DC baseline attributed to breathing efforts, sympathetic nervous system activities and thermoregulation. The popularity of the SpO2 parameter may be due to its viable cost, simplicity to build and portability. Moreover, the basic building blocks of a SpO2 based measurement consists of control, filtering and amplification functions that can easily be incorporated with an embedded system. In this review, a brief description of the SpO2 measurement, its normative values and technical issues in its application as a clinical monitor are discussed. 23770703 Structural and Biochemical Characterization of an Active Arylamine N-Acetyltransferase Possessing a Non-canonical Cys-His-Glu Catalytic Triad. Arylamine N-acetyltransferases (NATs), a class of xenobiotic-metabolizing enzymes, catalyze the acetylation of aromatic amine compounds through a strictly conserved Cys-His-Asp catalytic triad. Each residue is essential for catalysis in both prokaryotic and eukaryotic NATs. Indeed, in (HUMAN)NAT2 variants, mutation of the Asp residue to Asn, Gln, or Glu dramatically impairs enzyme activity. However, a putative atypical NAT harboring a catalytic triad Glu residue was recently identified in Bacillus cereus ((BACCR)NAT3) but has not yet been characterized. We report here the crystal structure and functional characterization of this atypical NAT. The overall fold of (BACCR)NAT3 and the geometry of its Cys-His-Glu catalytic triad are similar to those present in functional NATs. Importantly, the enzyme was found to be active and to acetylate prototypic arylamine NAT substrates. In contrast to (HUMAN) NAT2, the presence of a Glu or Asp in the triad of (BACCR)NAT3 did not significantly affect enzyme structure or function. Computational analysis identified differences in residue packing and steric constraints in the active site of (BACCR)NAT3 that allow it to accommodate a Cys-His-Glu triad. These findings overturn the conventional view, demonstrating that the catalytic triad of this family of acetyltransferases is plastic. Moreover, they highlight the need for further study of the evolutionary history of NATs and the functional significance of the predominant Cys-His-Asp triad in both prokaryotic and eukaryotic forms. 23436440 Increased curvature of hollow fiber membranes could up-regulate differential functions of renal tubular cell layers. Tissue engineering devices as in vitro cell culture systems in scaffolds has encountered the bottleneck due to their much lower cell functions than real tissues/organs in vivo. Such situation has been improved in some extent by mimicking the cell microenvironments in vivo from either chemical or physical ways. However, microenvironmental curvature, commonly seen in real tissues/organs, has never been manipulated to regulate the cell performance in vitro. In this regard, this paper fabricated polysulfone membranes with or without polyethylene glycol modification to investigate the impact of curvature on two renal tubular cells. Regardless the varying membrane curvatures among hollow fiber membranes of different diameters and flat membrane of zero curvature, both renal cells could well attach at 4 h of seeding and form similar confluent layers at 6 days on each membrane. Nevertheless, the renal cells on hollow fibers, though showing confluent morphology as those on flat membranes, expressed higher renal functions and, moreover, the renal functions significantly increased with the membrane curvature among hollow fibers. Such upregulation on functions was unassociated with mass transport barrier of hollow fibers, because the cultures on lengthwise cut hollow fibers without mass transfer barrier showed same curvature effect on renal functions as whole hollow fibers. It could be proposed that the curvature of hollow fiber membrane approaching to the large curvature in kidney tubules increased the mechanical stress in the renal cells and thus might up-regulate the renal cell functions. In conclusion, the increase of substrate curvature could up-regulate the cell functions without altering the confluent cell morphology and this finding will facilitate the design of functional tissue engineering devices. 23723062 Deficiency of senescence marker protein 30 exacerbates angiotensin II-induced cardiac remodelling. Ageing is an important risk factor of cardiovascular diseases including heart failure. Senescence marker protein 30 (SMP30), which was originally identified as an important ageing marker protein, is assumed to act as a novel anti-ageing factor in various organs. However, the role of SMP30 in the heart has not been previously explored. In this study, our aim was to elucidate the functional role of SMP30 on cardiac remodelling. SMP30 knockout (KO) mice and wild-type (WT) mice were subjected to continuous angiotensin II (Ang II) infusion. After 14 days, the extent of cardiac hypertrophy and myocardial fibrosis was significantly higher in SMP30-KO mice than in WT mice. Echocardiography revealed that SMP30-KO mice had more severely depressed systolic and diastolic function with left ventricular dilatation compared with WT mice. Generation of reactive oxygen species related with activation of nicotinamide adenine dinucleotide phosphate-oxidase was greater in SMP30-KO mice than in WT mice. The number of deoxynucleotidyl transferase-mediated dUTP nick end-labelling positive nuclei was markedly increased in SMP30-KO mice with activation of caspase-3, increases in the Bax to Bcl-2 ratio and phosphorylation of c-Jun N-terminal kinase compared with WT mice. Furthermore, the number of senescence-associated β-galactosidase-positive cells was significantly increased via up-regulation of p21 gene expression in SMP30-KO mice compared with WT mice. This study demonstrated the first evidence that deficiency of SMP30 exacerbates Ang II-induced cardiac hypertrophy, dysfunction, and remodelling, suggesting that SMP30 has a cardio-protective role in cardiac remodelling with anti-oxidative and anti-apoptotic effects in response to Ang II. 23796839 Evaluation of some compression aids in tableting of roller compacted swellable core drug layer. Swellable core technology (SCT) represents a broadly applicable oral osmotic drug delivery platform for the controlled release of drugs. SCT tablets control drug delivery by using osmosis to regulate the influx of water into the tablet's core. The tablet consists of two layers; drug layer and sweller layer, with a semi-permeable membrane coating and delivery port located in the drug layer side of the tablet. The key component of SCT formulations is polyethylene oxide (PEO), which is typically wet granulated with organic solvents to prevent rapid gel hydration observed during contact with aqueous environments. However, the use of organic solvents has their own environmental and cost considerations which make this form of processing undesirable. To overcome this issue, dry granulation can be employed. However, PEO is a very plastic material and problems may be encountered during the tableting process, when work hardening occurs upon double compression. The addition of compression aids to the drug layer will help to increase the roll force when generating ribbons - reducing fines and segregation potential - while also reducing work hardening effects which impact tablet friability. The five compression aids used in this study were microcrystalline cellulose (MCC), xylitol, di-calcium phosphate (anhydrous), lactose monohydrate and starch. The work undertaken here studies the compression properties of the drug layer blends with different levels of the five compression aids as part of the formulation. Roller compaction properties are also varied to provide granules with differing solid fractions. The results of this study indicate that addition of microcrystalline cellulose in the formulation in levels between 10% and 30% significantly improve the tablet hardness at lower tablet compression forces. Further work is required to investigate the impact on dissolution. 23684549 VEGF and depression: a comprehensive assessment of clinical data. Vascular Endothelial Growth Factor (VEGF), initially identified as an angiogenic mitogen, is believed to play a role in hippocampal neurogenesis and response to stress. It exerts neuroprotective effects and influences synaptic transmission. The possible role of VEGF in depression has been hypothesized in the context of the neurotrophic model of depression, which postulates that stress can lead to decreased level of neurotrophins. Since VEGF has emerged as a potential component in the pathophysiology of stress and stress-related disorders, animal and clinical studies have attempted to delineate its precise role. In this review article we provide a synopsis of basic studies that are of direct relevance to the clinical findings in depression and antidepressant drug action. We have classified the studies on the basis of higher, lower or no different levels of VEGF as compared to control subjects. It became evident that there is conflicting data regarding VEGF levels in depressed patients. The fact that no definitive trend is apparent in the published data is likely attributable to differences in study designs. However, promising leads have emerged in our effort to understand and clarify this wide variation in results. Further study could establish the potential use of VEGF as a biomarker to aid in making a correct diagnosis and a successful treatment plan. Delineating the relationship of VEGF and depression ultimately has the potential to shed light on the still elusive neural mechanisms underlying the pathophysiology of depression and the mechanisms by which antidepressants exert their effects. 23903175 Gold strip gratings with binary supercell. In this Letter, the study of a periodic structure composed of gold strips arranged in double-period unit cells, in a symmetric and asymmetric environment, is reported. The spectral maps show that the formation of the plasmonic bandgap and the extraordinary optical transmission are subjected to the proportion between the strip widths. Moreover, when the asymmetric environment is considered, high-transmittance and high-absorbance states arise. Hence, by controlling the geometrical parameters of the binary-periodic structure, it is possible to tailor the spectral response of the grating enhancing the desired features and exploiting them for different applications. 23448346 Synthesis of novel estrogen receptor antagonists using metal-catalyzed coupling reactions and characterization of their biological activity. Estrogen receptor (ER) antagonists are valuable in the treatment of ER-positive human breast cancer. In this study, we designed and synthesized nine new derivatives of 17β-estradiol (E2) with a bulky side chain attached to its C-7α position, and determined their ER antagonistic activity using in vitro bioassays. Four of the derivatives showed a strong inhibition of ERα transactivation activity in a luciferase reporter assay and blocked ERα interactions with coactivators. Similarly, these derivatives also strongly inhibited the growth of the ERα-positive human breast cancer cells. Computational docking analysis was conducted to model the interaction of these antagonists with the human ERα and showed that they could tightly bind to the ERα in a manner similar to that of ICI-182,780, a pure ER antagonist. These results provide an example that attachment of a bulky side chain to the C-7α position of E2 can produce ER antagonists with ER affinity comparable to that of ICI-182,780. 23664942 Generation of realistic HMPAO SPECT images using a subresolution sandwich phantom. Traditional interpretation of rCBF SPECT data is of a qualitative nature and is dependent on the observer's understanding of the normal distribution of the tracer. The use of a normal database in quantitative regional analysis facilitates the detection of functional abnormality in individual and group studies by accounting for inter-subject variability. The ability to simulate realistic images would allow various important areas related to the use of normal databases to be studied. These include the optimisation of the detection of abnormal blood flow and the portability of normal databases between gamma camera systems. To investigate this further we have constructed a hardware phantom and scanned various configurations of radioactive brain patterns and simulated skull configurations. A subresolution sandwich phantom was constructed with a simulated skull which was assembled using a high-resolution segmented MR scan printed with a (99m)TcO4- mixture and scanned using a double-headed gamma camera with parallel-hole collimators. Various different grey-to-white matter (GM:WM) ratios and aluminium simulated skull configurations were used. A single difference measure between the phantom data and a control database mean image was used for optimisation. The realism of phantom data was assessed using statistical parametric mapping (SPM) and ROI analysis. Optimisation was achieved with a range of WM:GM ratios from 1.9 to 2.4:1 with various simulated skull configurations. The ability to simulate realistic HMPAO SPECT scans has been demonstrated using a subresolution sandwich phantom. Further work, involving scanning the optimised phantom on different gamma camera systems and comparison with camera-specific normal databases should further refine the phantom configuration. 23592272 Bendamustine salvage therapy for T cell neoplasms. Treatment of relapsed/refractory T cell neoplasms represents an unmet medical need. We recorded, retrospectively, data on 20 consecutive adult patients with T cell neoplasms (8 T cell lymphoma not otherwise specified (T-NOS), 4 angioimmunoblastic (AILT), 3 prolymphocytic leukemia (T-PLL), 3 advance-stage mycosis fungoides (MF) or Sézary syndrome (SS), and 2 T cell large granular lymphocytic leukemia (T-LGL)), treated with bendamustine. Partial (PR) and complete response (CR) rates were reached in nine (45 %) and two (10 %) patients, respectively, including three PR in T-NOS, one CR in AILT, three PR in T-PLL, two PR in MF/SS, and one CR and one PR in T-LGL lymphoma. The 6 months estimated progression free and overall survival was 44 and 67 %, respectively. Grade 3-4 neutropenia and thrombocytopenia were registered in 44 and 25 % of cases. Four patients developed major infectious complications. At a median follow-up of 6 months (range 1-18), 13 patients are alive and 7 patients died all because of lymphoma progression. Bendamustine deserves further investigation in patients with T cell neoplasms. 23661063 Fluorescein-guided surgery for grade IV gliomas with a dedicated filter on the surgical microscope: preliminary results in 12 cases. Fluorescein is widely used as a fluorescent tracer for many applications. Its capability to accumulate in cerebral areas with blood-brain barrier damage makes it an ideal dye for intraoperative visualization of malignant gliomas (MG). We report our preliminary experience in fluorescein-guided removal of grade IV gliomas using a dedicated filter on the surgical microscope. In September 2011 we started a prospective phase II trial (FLUOGLIO) to evaluate the safety and obtain initial indications about the efficacy of fluorescein-guided surgery for MG. Patients with suspected MG amenable to complete resection of contrast-enhancing areas were eligible to participate in this study. This report is based on a preliminary analysis of the results of 12 patients with grade IV gliomas out of 15 consecutive cases (age range 48-72 years) enrolled since September 2011. Fluorescein was injected intravenously (i.v.) after intubation (5-10 mg/kg). The tumor was removed using a microsurgical technique and fluorescence visualization by BLU 400 or YELLOW 560 filters on a Pentero microscope (Carl Zeiss, Germany). The study was approved by our ethics committee and registered on the European Regulatory Authorities website (EudraCT no. 2011-002527-18). Histological analysis confirmed grade IV gliomas in 12/15 cases. Median preoperative tumor volume was 33.15 cm(3) (9.6-87.8 cm(3)). No adverse reaction related to the administration of fluorescein was registered. Contrast-enhanced tumor was completely removed in 75 % of the patients. This preliminary analysis suggested that the use of intravenous fluorescein during surgery on grade IV gliomas is safe and allows a high rate of complete resection of contrast-enhanced tumor at the early postoperative MRI. 23880772 Deletion of Selenoprotein M Leads to Obesity Without Cognitive Deficits. Selenium is an essential trace element that is co-translationally incorporated into selenoproteins in the form of the 21st amino acid, selenocysteine. This class of proteins largely functions in oxidation-reduction reactions and is critically involved in maintaining proper redox balance essential to health. Selenoprotein M (SelM) is a thioredoxin-like ER-resident protein that is highly expressed in the brain and possesses neuroprotective properties. In this study, we first assessed the regional pattern of SelM expression in the mouse brain to provide insights into the potential functional implications of this protein in physiology and behavior. Next, we generated transgenic mice with a targeted deletion of the SelM gene and subjected them to a battery of neurobehavioral tests to evaluate motor coordination, locomotion, and cognitive function in comparison to wild-type controls. Finally, these mice were tested for several measures of metabolic function and body composition. Our results show that SelM knockout (KO) mice display no deficits in measures of motor coordination and cognitive function, but exhibit elevated weight gain, increased white adipose tissue deposition, and diminished hypothalamic leptin sensitivity. These findings suggest that SelM plays an important role in the regulation of body weight and energy metabolism. 23271732 Specific conserved C-terminal amino acids of Caenorhabditis elegans HMP-1/α-catenin modulate F-actin binding independently of vinculin. Stable intercellular adhesions formed through the cadherin-catenin complex are important determinants of proper tissue architecture and help maintain tissue integrity during morphogenetic movements in developing embryos. A key regulator of this stability is α-catenin, which connects the cadherin-catenin complex to the actin cytoskeleton. Although the C-terminal F-actin-binding domain of α-catenin has been shown to be crucial for its function, a more detailed in vivo analysis of discrete regions and residues required for actin binding has not been performed. Using Caenorhabditis elegans as a model system, we have characterized mutations in hmp-1/α-catenin that identify HMP-1 residues 687-742 and 826-927, as well as amino acid 802, as critical to the localization of junctional proximal actin during epidermal morphogenesis. We also find that the S823F transition in a hypomorphic allele, hmp-1(fe4), decreases actin binding in vitro. Using hmp-1(fe4) animals in a mutagenesis screen, we were then able to identify 11 intragenic suppressors of hmp-1(fe4) that revert actin binding to wild-type levels. Using homology modeling, we show that these amino acids are positioned at key conserved sites within predicted α-helices in the C terminus. Through the use of transgenic animals, we also demonstrate that HMP-1 residues 315-494, which correspond to a putative mechanotransduction domain that binds vinculin in vertebrate αE-catenin, are not required during epidermal morphogenesis but may aid efficient recruitment of HMP-1 to the junction. Our studies are the first to identify key conserved amino acids in the C terminus of α-catenin that modulate F-actin binding in living embryos of a simple metazoan. 23863855 An Early Underwater Artificial Vision Model in Ocean Investigations via Independent Component Analysis. Underwater vision is one of the dominant senses and has shown great prospects in ocean investigations. In this paper, a hierarchical Independent Component Analysis (ICA) framework has been established to explore and understand the functional roles of the higher order statistical structures towards the visual stimulus in the underwater artificial vision system. The model is inspired by characteristics such as the modality, the redundancy reduction, the sparseness and the independence in the early human vision system, which seems to respectively capture the Gabor-like basis functions, the shape contours or the complicated textures in the multiple layer implementations. The simulation results have shown good performance in the effectiveness and the consistence of the approach proposed for the underwater images collected by autonomous underwater vehicles (AUVs). 23401232 A self-organized anisotropic liquid-crystal plasmonic metamaterial. A composite material that leads to self organization of mesogen-coated gold nanospheres is synthesized and shows enhanced anisotropic optical properties due to synergistic effects of the mesogens intrinsic birefringence and its ability to drive the self-assembly process into highly anisotropic architectures with densely packed nanospheres. Such nanoengineered matter sustains a response beyond that achievable by its individual constituents, i.e., a metamaterial. 23359004 Molecular mechanisms of central leptin resistance in obesity. The rapidly increasing prevalence of obesity confers a huge health burden globally. The hypothalamus plays a central role in the regulation of energy homeostasis by integrating multiple metabolic signals from peripheral organs and modulating feeding behavior and energy metabolism. Leptin, a key appetite-regulating hormone derived from the white adipose tissue, primarily acts on hypothalamic neurons to activate catabolic pathway and inhibit anabolic pathway, which can result in anorexia and weight reduction. Despite striking obesity resulting from leptin deficiency, treatment with this hormone in human obesity has been unsuccessful due to leptin resistance. In this review, we describe recent researches extending our understanding of obesity-associated hypothalamic leptin resistance. 23819470 Reversal of Polarity in Masked o-Benzoquinones: Rapid Access to Unsymmetrical Oxygenated Biaryls. An unprecedented diacetoxyiodobenzene induced direct arylation of guaiacol derivatives and electron-rich arenes using a Lewis acid as an activator furnishes unsymmetrical biaryls without prefunctionalization of both coupling partners. The addition of electron-rich arenes on the α-position of electrophilic masked o-benzoquinones in an anti-Michael addition fashion affords the highly oxygenated unsymmetrical biaryls in good to excellent yields. 23868156 Automated White Matter Total Lesion Volume Segmentation in Diabetes. BACKGROUND AND PURPOSE:WM lesion segmentation is often performed with the use of subjective rating scales because manual methods are laborious and tedious; however, automated methods are now available. We compared the performance of total lesion volume grading computed by use of an automated WM lesion segmentation algorithm with that of subjective rating scales and expert manual segmentation in a cohort of subjects with type 2 diabetes.MATERIALS AND METHODS:Structural T1 and FLAIR MR imaging data from 50 subjects with diabetes (age, 67.7 ± 7.2 years) and 50 nondiabetic sibling pairs (age, 67.5 ± 9.4 years) were evaluated in an institutional review board-approved study. WM lesion segmentation maps and total lesion volume were generated for each subject by means of the Statistical Parametric Mapping (SPM8) Lesion Segmentation Toolbox. Subjective WM lesion grade was determined by means of a 0-9 rating scale by 2 readers. Ground-truth total lesion volume was determined by means of manual segmentation by experienced readers. Correlation analyses compared manual segmentation total lesion volume with automated and subjective evaluation methods.RESULTS:Correlation between average lesion segmentation and ground-truth total lesion volume was 0.84. Maximum correlation between the Lesion Segmentation Toolbox and ground-truth total lesion volume (ρ = 0.87) occurred at the segmentation threshold of k = 0.25, whereas maximum correlation between subjective lesion segmentation and the Lesion Segmentation Toolbox (ρ = 0.73) occurred at k = 0.15. The difference between the 2 correlation estimates with ground-truth was not statistically significant. The lower segmentation threshold (0.15 versus 0.25) suggests that subjective raters overestimate WM lesion burden.CONCLUSIONS:We validate the Lesion Segmentation Toolbox for determining total lesion volume in diabetes-enriched populations and compare it with a common subjective WM lesion rating scale. The Lesion Segmentation Toolbox is a readily available substitute for subjective WM lesion scoring in studies of diabetes and other populations with changes of leukoaraiosis. 23189959 Modulation of glycolysis and the pentose phosphate pathway influences porcine oocyte in vitro maturation. Glycolytic and pentose phosphate pathway (PPP) activities were modulated in porcine cumulus-oocyte complexes (COCs) during in vitro maturation (IVM) by the addition of inhibitors or stimulators of key enzymes of the pathways to elucidate their relative participation in oocyte maturation. The activities of glycolysis and PPP were evaluated by lactate production per COC and by the brilliant cresyl blue test, respectively. Glucose uptake per COC and the oocyte maturation rate were also evaluated. Lactate production, glucose uptake and the percentage of oocytes reaching metaphase II decreased in a dose-dependent manner in the presence of the pharmacological (NaF) or the physiological (ATP) inhibitors of glycolysis (p < 0.05). The addition of the physiological stimulator of glycolysis (AMP) caused no effect on lactate production, glucose uptake or the meiotic maturation rate. The pharmacological (6-AN) and the physiological (NADPH) inhibitors of PPP induced a dose-dependent decrease in the percentage of oocytes with high PPP activity and in the nuclear maturation rate (p < 0.05). The physiological stimulator of PPP (NADP) caused no effect on the percentage of oocytes with high PPP activity. The glycolytic and PPP activities of porcine COCs and maturational competence of oocytes seem to be closely related events. This study shows for the first time the regulatory effect of ATP and NADPH as physiological inhibitors of glycolysis and PPP in porcine COCs, respectively. Besides, these pathways seem to reach their maximum activities in porcine COCs during IVM because no further increases were achieved by the presence of AMP or NADP. 23925205 Oxidation of 2-arylindoles for synthesis of 2-arylbenzoxazinones with oxone as the sole oxidant. A novel and efficient method for the oxidation of 2-arylindoles to synthesize 2-arylbenzoxazinones utilizing oxone as the sole oxidant has been developed. The reaction tolerates a wide range of functional groups and allows quick and atom-economical assembly of a variety of valuable 2-arylbenzoxazinones in high yields. 23852657 Synthesis of Polycyclic Aminocyclobutane Systems by the Rearrangement of N-(ortho-Vinylphenyl) 2-Azabicyclo[3.1.0]hexane Derivatives. The acid-catalysed thermal rearrangements of a family of N-aryl 2-azabicyclo[3.1.0]hexanes is described. These substrates, designed in such a way that the aromatic system is conjugated with an alkene group located at the ortho position relative to the nitrogen atom, have been prepared by using an intramolecular Kulinkovich-de Meijere reaction. The rearrangements can then be conducted either under standard thermal conditions or with microwave activation. Depending on the conditions applied and the substitution pattern, dihydroquinoline or polycyclic aminocyclobutane derivatives can be obtained. A mechanistic discussion is provided, with the proposition of the initial protonation of the aminocyclopropane moiety to give an iminium intermediate. By analogy with related intermolecular reactions, the involvement of electrocyclic reactions among the series of elementary steps that follow is put forward. 23790533 Plant regeneration via somatic embryogenesis and shoot organogenesis from immature cotyledons of Camellia nitidissima Chi. Camellia nitidissima Chi (Theaceae) is a world-famous economic and ornamental plant with golden-yellow flowers. It has been classified as one of the rarest and most endangered plants in China. Our objective was to induce somatic embryogenesis, shoot organogenesis and plant regeneration for C. nitidissima. Three types of callus (whitish, reddish and yellowish) were induced from immature cotyledons on improved woody plant medium (WPM) with different plant growth regulators (PGRs). Among the callus, whitish callus was induced by 4.5μM 2,4-dichlorophenoxyacetic acid (2,4-D) and reddish and yellowish callus were induced by strongly active cytokinins, thidiazuron (TDZ) or 6-benzylaminopurine (BAP), singly or combined with weakly active auxin, α-naphthaleneacetic acid (NAA). The embryogenic callus could differentiate into somatic embryos, nodular embryogenic structures (large embryo-like structures) or adventitious shoots depending on the PGR used in WPM. BAP was best for adventitious buds and zeatin was best for somatic embryogenesis while kinetin (Kt) was best for the formation of nodular embryogenic structures. The three regeneration pathways often occurred in the same embryogenic callus clumps. Most shoots (80.0%) developed roots in WPM supplemented with 24.6μM IBA and 0.3μM NAA while 47.5% of somatic embryos could germinate directly and develop into plantlets on induction medium supplemented with 0.9μM BAP and 0.1μM NAA. The nodular embryogenic structures could be sub-cultured and cyclically developed in one of two differentiation pathways: shoot organogenesis or somatic embryogenesis. Plantlets derived from shoot buds rooted and somatic embryos germinated when transplanted into soil in a greenhouse; 66.7% of plantlets from shoot culture and 78.6% of plantlets from somatic embryos survived after 8 weeks' acclimatization. 23769992 Behavior of printable formulations of loperamide and caffeine on different substrates-Effect of print density in inkjet printing. The primary goal of the current work was to study the applicability of precision inkjet printing in fabrication of personalized doses of active pharmaceutical ingredients (APIs). Loperamide hydrochloride (LOP) and caffeine (CAF) were used as model compounds. Different doses of the drugs in a single dosage unit were produced, using a drop-on-demand inkjet printer by varying printing parameters such as the distance between jetted droplets (drop spacing) and the physical dimensions of the printed dosage forms. The behavior of the formulated printable inks for both APIs was investigated on the model substrates, using different analytical tools. The obtained results showed that printed LOP did not recrystallize on any substrates studied, whereas at least partial recrystallization of printed CAF was observed on all carrier surfaces. Flexible doses of both APIs were easily obtained by adjusting the drop spacing of the depositing inks, and the results were relevant with regards to the theoretical content. Adapting the dose by varying physical dimensions of single dosage units was less successful than the approach in which drop spacing was altered. In conclusion, controlled printing technology, by means of adjusting the distance between jetted droplets, offers a means to fabricate dosage forms with individualized doses. 23968594 Ligation-independent cloning and self-cleaving intein as a tool for high-throughput protein purification. The rapid production of purified recombinant proteins has become increasingly important for countless applications. Many purification methods involve expression of target proteins in fusion to purification tags, which often must be removed from the target proteins after purification. Recently, engineered inteins have been used to create convenient self-cleaving tags for tag removal. Although intein methods can greatly simplify protein purification, commercially available expression vectors still rely on conventional restriction/ligation cloning methods for target gene insertion. We have streamlined this process by introducing Ligation-Independent Cloning (LIC) capability to our intein expression plasmids, which provides a simple method for constructing self-cleaving tag-target gene fusions. In this work, we demonstrate efficient gene insertion via this system, as well as target protein expression and purification consistent with previously reported results. Through this newly developed system, arbitrary protein genes can be rapidly incorporated into self-cleaving tag expression vectors, and their products purified using convenient platform methods. 23011549 Sonographic diagnosis of symptomatic ureteral calculi: usefulness of the twinkling artifact. Our aim was to analyze the value of ultrasound using the twinkling sign in the diagnosis of ureteral stones in patients with renal colic in the emergency setting. Prospective study of 100 patients with suspected renal colic who underwent an US examination, including color Doppler mode. We analyzed sensitivity, specificity, predictive values, and accuracy. We evaluated whether the stone was observed before or after the twinkling artifact, and whether the use of the Doppler color increased the examination time. US including color Doppler detected 76 of the 84 confirmed lithiasis. The sensitivity and specificity were 90 % and 100 %, respectively. The positive predictive value was 100 % and the negative 67 %. The accuracy was 92 %. A total of 59 calculi (78 %) examined by color Doppler sonography showed the twinkling artifact. Seventy percent of the twinkling-positive calculi showed the artifact before the stone itself was detected. Considering the location of the stones the twinkling sign was seen before the stone in 92 % of lithiasis located in the mid lumbar ureter (p = 0.02). The use of the twinkling artifact showed a trend to facilitate the detection of smaller calculi (<10 mm) (p = 0.08). The average examination time was 5.8 min [±4.3] (without differences between the stones detected before or after the twinkling artifact, p = 0.75). Doppler US examination shows good sensitivity and specificity for the diagnosis of symptomatic ureteral stones. The twinkling artifact is useful for the early detection of the calculi, especially in the middle tract of the ureter, usually the most difficult place in sonographic diagnosis. It also seems helpful for the detection of smaller stones. The use of color Doppler does not increase the exploration time. 23832039 (E)-Ethyl 3-(3,4-dihydroxyphenyl)prop-2-enoate: a natural polymorph extracted from Aristotelia chilensis (Maqui). The natural title compound, C11H12O4, extracted from the Chilean native tree Aristotelia chilensis (Maqui), is a polymorph of the synthetic E form reported by Xia, Hu & Rao [Acta Cryst. (2004), E60, o913-o914]. Both rotational conformers are identical from a metrical point of view, and only differ in the orientation of the 3,4-dihydroxyphenyl ring with respect to the rest of the molecule, which leads to completely different crystal structure arrangements and packing efficiencies. The reasons behind both reside in the different hydrogen-bonding interactions. 23913950 Cold exposure increases intestinal paracellular permeability to nutrients in the mouse. In situations of increased energy demand/food intake, animals can often acclimate within several days. The intestine generally responds to elevated digestive demand by increasing in size. However, there is likely a limit to how quickly the intestine can grow to meet the new demand. We investigated the immediate and longer term changes to intestinal properties of the mouse when suddenly exposed to 4°C. We hypothesized that paracellular permeability to nutrients would increase as part of an immediate response to elevated absorptive demand. We measured absorption of L-arabinose, intestinal size, and gene expression of several tight junction proteins (claudin-2, claudin-4, claudin-15, and ZO-1) at 3 timepoints: pre-exposure, 1 d, and 2 wks of cold exposure. Cold exposure increased food intake 62% after 2 wks but intake was not significantly increased after 1 d. Intestinal wet mass was elevated after 1 day and throughout the experiment. Absorption of arabinose rose 20% after 1 day in the cold and was 33% higher after 2 wks. Expression of claudin-2 increased after 1 day of cold exposure, but there were no changes in expression of any claudin genes when normalized to ZO-1 expression. Our results indicate that intestinal mass can respond rapidly to increased energy demand and that increased paracellular permeability is also part of that response. Increased paracellular permeability may be a consequence of enterocyte hyperplasia resulting in more tight junctions across which molecules can absorb. 23475169 Effects of concurrent training on oxidative capacity in rat gastrocnemius muscle. Training for improvement of oxidative capacity of muscle fibers may be attenuated when concurrently training for peak power. However, because of fiber type-specific recruitment, such attenuation may only account for high-oxidative muscle fibers. Here, we investigate the effects of concurrent training on oxidative capacity (as measured by succinate dehydrogenase (SDH) activity) by using task-specific recruitment of the high- and low-oxidative compartment of rat medial gastrocnemius muscle (GM). Forty rats were subjected to 6 wk of peak power training (PT, n = 10), endurance training (ET, n = 10), concurrent peak power and endurance training (PET, n = 10), or no training (control, n = 10). SDH activity, mRNA expression of SDH, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), receptor-interacting protein 140, and BCL2/adenovirus E1B 19 kDa-interacting protein 3 as well as PGC-1α protein levels were analyzed in the low- and high-oxidative region of the GM. In the low-oxidative compartment, PT and PET induced a 30% decrease in SDH activity of Type IIB fibers compared with controls and ET (P < 0.001) without changes in mRNA or protein levels. In the high-oxidative compartment, after ET, SDH mRNA levels were 42% higher and RIP140 mRNA levels 33% lower compared with controls, which did not result in changes in SDH activity. These results indicate that in compartmentalized rat GM, peak power on top of endurance training attenuated transcription of mRNA for mitochondrial proteins in high-oxidative muscle fibers. In low-oxidative Type IIB fibers, peak power training substantially decreased SDH activity, which was not related to lower SDH mRNA levels. It is concluded that PT and PET enhanced mitochondrial degradation in the low-oxidative compartment of rat GM. 23857477 Oral Bisphosphonates and the Risk of Barrett's Esophagus: Case-Control Analysis of US Veterans. OBJECTIVES:This study examined Barrett's esophagus (BE) risk factors in veterans to determine the association between risk of BE and use of oral bisphosphonates.METHODS:We conducted a case-control study among eligible patients scheduled for an elective esophagogastroduodenoscopy (EGD) and a sample of patients eligible for screening colonoscopy recruited from primary care clinics from a single VA Medical Center. Cases with definitive BE were compared with controls; all underwent study EGD. Use of oral bisphosphonates was ascertained by reviewing filled prescriptions in electronic pharmacy records. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs), using multivariate logistic regression modeling while adjusting for sex, age, race, proton-pump inhibitor use, hiatal hernia, waist-to-hip ratio, Helicobacter pylori infection, and gastroesophageal reflux disorder (GERD) symptoms.RESULTS:There were 285 BE cases, 1,122 endoscopy controls, and 496 primary care controls. Alendronate and risedronate were the only oral bisphosphonates prescribed. The proportion of BE cases with filled prescription of oral bisphosphonates (4.6%) was greater than in endoscopy controls (1.6%) or primary care controls (2.9%). In the adjusted analysis, oral bisphosphonate use was significantly associated with BE risk (OR=2.33; 95% CI: 1.11-4.88) compared with the combined control groups. This association remained significant when BE cases were compared with endoscopy controls only (OR=2.74; 95% CI: 1.28-5.87) but was attenuated when compared with primary care controls only (OR=2.60; 95% CI: 0.99-6.84). The association was observed in patients with GERD symptoms (OR=3.29; 95% CI: 1.36-7.97) but not in those without GERD symptoms.CONCLUSION:Oral bisphosphonate use may increase the risk for BE, especially among patients with GERD.Am J Gastroenterol advance online publication, 16 July 2013; doi:10.1038/ajg.2013.222. 23893975 Effect of moderate dietary restriction on visceral organ weight, hepatic oxygen consumption, and metabolic proteins associated with energy balance in mature pregnant beef cows. Twenty-two nonlactating multiparous pregnant beef cows (639 ± 68 kg) were used to investigate the effect of dietary restriction on the abundance of selected proteins regulating cellular energy metabolism. Cows were fed at either 85% (n = 11; LOW) or 140% (n = 11; HIGH) of total NE requirements. The diet consisted of a haylage-based total mixed ration containing 20% wheat straw. Cows were slaughtered by block (predicted date of parturition), beginning 83 d after the initiation of dietary treatments and every week thereafter for 6 wk, such that each block was slaughtered at approximately 250 d of gestation. Tissue samples from liver, kidney, sternomandibularis muscle, ruminal papilli (ventral sac), pancreas, and small intestinal muscosa were collected at slaughter and snap frozen in liquid N2. Western blots were conducted to quantify abundance of proliferating cell nuclear antigen (PCNA), ATP synthase, ubiquitin, and Na/K+ ATPase for all tissues; PPARγ, PPARγ coactivator 1 α (PGC-1α), and 5´-adenosine monophosphate-activated protein kinase (AMPK) and the activated form phosphorylated-AMPK (pAMPK) for liver, muscle, and rumen; phosphoenolpyruvate carboxykinase (PEPCK) for liver and kidney; and uncoupling protein 2 (UCP2) for liver. Statistical analysis was conducted using Proc Mixed in SAS and included the fixed effects of dietary treatment, cow age, block, and the random effect of pen. Dietary treatments resulted in cows fed HIGH having greater (P ≤ 0.04) ADG and final BW than cows fed LOW. Abundance of ubiquitin in muscle was greater (P = 0.009) in cows fed LOW, and PCG-1 α in liver was greater (P = 0.03) in cows fed HIGH. Hepatic O2 consumption was greater in HIGH (P ≤ 0.04). Feed intake can influence the abundance of important metabolic proteins and suggest that protein degradation may increase in muscle from moderately nutrient restricted cows and that energy metabolism in liver increases in cows fed above NE requirements. 23574813 Vertebral artery injury associated with blunt cervical spine trauma: a multivariate regression analysis. Retrospective analysis of prospective registry data. To determine the patient characteristics, risk factors, and fracture patterns associated with vertebral artery injury (VAI) in patients with blunt cervical spine injury. VAI associated with cervical spine trauma has the potential for catastrophical clinical sequelae. The patterns of cervical spine injury and patient characteristics associated with VAI remain to be determined. A retrospective review of prospectively collected data from the American College of Surgeons trauma registries at 3 level-1 trauma centers identified all patients with a cervical spine injury on multidetector computed tomographic scan during a 3-year period (January 1, 2007, to January 1, 2010). Fracture pattern and patient characteristics were recorded. Logistic multivariate regression analysis of independent predictors for VAI and subgroup analysis of neurological events related to VAI was performed. Twenty-one percent of 1204 patients with cervical injuries (n = 253) underwent screening for VAI by multidetector computed tomography angiogram. VAI was diagnosed in 17% (42 of 253), unilateral in 15% (38 of 253), and bilateral in 1.6% (4 of 253) and was associated with a lower Glasgow coma scale (P < 0.001), a higher injury severity score (P < 0.01), and a higher mortality (P < 0.001). VAI was associated with ankylosing spondylitis/diffuse idiopathic skeletal hyperosteosis (crude odds ratio [OR] = 8.04; 95% confidence interval [CI], 1.30-49.68; P= 0.034), and occipitocervical dissociation (P < 0.001) by univariate analysis and fracture displacement into the transverse foramen 1 mm or more (adjusted OR = 3.29; 95% CI, 1.15-9.41; P= 0.026), and basilar skull fracture (adjusted OR = 4.25; 95% CI, 1.25-14.47; P= 0.021), by multivariate regression model. Subgroup analyses of neurological events secondary to VAI occurred in 14% (6 of 42) and the stroke-related mortality rate was 4.8% (2 of 42). Neurological events were associated with male sex (P= 0.024), facet subluxation/dislocation (crude OR = 9.00; 95% CI, 1.51-53.74; P= 0.004) and the diagnosis of ankylosing spondylitis/diffuse idiopathic skeletal hyperosteosis (OR = 40.67; 95% CI, 5.27-313.96; P < 0.001). VAI associated with blunt cervical spine injury is a marker for more severely injured patients. High-risk patients with basilar skull fractures, occipitocervical dissociation, fracture displacement into the transverse foramen more than 1 mm, ankylosing spondylitis/diffuse idiopathic skeletal hyperosteosis, and facet subluxation/dislocation deserve focused consideration for VAI screening.Level of Evidence: 2. 23387292 DNA barcoding commercially important aquatic invertebrates of Turkey. DNA barcoding was used in order to identify aquatic invertebrates sampled from fisheries bycatch and discards. A total of 440 unique cytochrome c oxidase sub unit I (COI) barcodes were generated for 22 species from three important phyla (Arthropoda, Cnidaria, and Mollusca). All the species were sequenced and submitted to GenBank and Barcode of Life Database (BOLD) databases using 654 bp-long fragment of mitochondrial COI gene. Two of them (Pontastacus leptodactylus and Rapana bezoar) were first records of the species for the BOLD database and six of them (Carcinus aestuarii, Loligo vulgaris, Melicertus kerathurus, Nephrops norvegicus, Scyllarides latus, and Scyllarus arctus) were first standard (>648 bp) COI barcode records for the GenBank database. COI barcodes were analyzed for nucleotide composition, nucleotide pair frequencies, and Kimura's two-parameter genetic distance. Mean genetic distance among species was found increasing at higher taxonomic levels. Neighbor-joining trees generated were congruent with morphometric-based taxonomic classification. Findings of this study clearly demonstrate that DNA barcodes could be used as an efficient molecular tool in identification of not only target species from fisheries but also bycatch and discard species, and so it could provide us leverage for a better understanding in monitoring and management of fisheries and biodiversity. 23881722 Use of Pertuzumab for the Treatment of HER2-Positive Metastatic Breast Cancer. Targeting the human epidermal growth factor receptor (HER) family of tyrosine kinase receptors has proven to be effective as a therapeutic strategy for HER type 2 (HER2)-positive breast cancer. Since resistance to trastuzumab occurs relatively frequently, particularly in the metastatic setting, novel anti-HER2 targeted therapies with complementary and/or synergistic mechanisms of action have been under development. Pertuzumab, a HER2-targeted monoclonal antibody that prevents HER2 dimerisation, is the first of a class of promising targeted agents for the treatment of HER2-positive breast cancer. A review of the biomedical literature published prior to February 2013 was conducted in English using PubMed. ClinicalTrials.gov was searched for appropriate clinical trials. The search terms used included breast neoplasm, pertuzumab, dimerisation, and HER2-positive. Abstracts of studies presented at the ASCO and ESMO Annual Meetings, and San Antonio Breast Cancer Symposium were also included. Pertuzumab represents a novel anti-HER2 targeted therapy for HER2-positive breast cancers. In this article, we describe the mechanism of action of pertuzumab, as well as its drug development process and preclinical testing results. Based on the results of ancillary studies, dual inhibition using pertuzumab and trastuzumab was shown to be effective for the management of HER2-positive metastatic breast cancers pre-treated with trastuzumab-based therapy. For the first-line setting, the combination of both pertuzumab and trastuzumab with docetaxel (CLEOPATRA trial; clinical evaluation of pertuzumab and trastuzumab) has changed the paradigm of patient management. Pertuzumab provided a more comprehensive inhibition of HER2-driven signalling pathways. When administered together with trastuzumab, pertuzumab represent a significant advancement for the treatment of HER2-positive metastatic breast cancer patients. 23738801 Antimutagenic properties of affinin isolated from Heliopsis longipes extract. Abstract Context: Heliopsis longipes (A. Gray) Blake (Asteraceae), commonly known in Mexico as "chilcuage" or "chilcuan", is widely used as an analgesic and anesthetic agent. Affinin, the major metabolite of this plant, and the ethanol extract of the plant have shown antinociceptive properties in mice. H. longipes plant produces a complex mixture of antioxidant chlorophylls and polyamines as well as a number of possible antimutagens. Objective: The current study evaluated the potential utilization of the natural product affinin isolated from H. longipes ethanol extract as an antimutagenic and possibly anticarcinogenic agent. Materials and methods: The Ames assay was used to assess the mutagenic properties of affinin (12.5, 25 and 50 µg/plate) that was added to several mutagens with or without S9 metabolic activation in Salmonella typhimurium (TA98, TA100 and TA102 strains). Results: Heliopsis longipes extract and affinin were not toxic as a reduction in the number of His(+) revertant bacteria colonies. Affinin (25 and 50 µg/plate) significantly reduced the frameshift mutations that were generated by 2-aminoanthracene (2AA) (40%) and reduced the oxidative DNA damage generated by norfloxacin (NOR) (37-50%). Affinin possessed antioxidant properties that were able to reduce 2AA- and NOR-induced mutations in S. typhimurium TA98 and TA102, respectively. Discussion and conclusion: Affinin, the principal metabolite of H. longipes, is not mutagenic and possesses antimutagenic activity. These plants are currently used to treat some pain symptoms in Mexico; and antimutagen activity determined could be important to treat some pain symptoms related to antiradical activity. 23904405 Effect of tumor necrosis factor-alpha infusion on the incretin effect in healthy volunteers. Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance, impaired incretin effect, and increased plasma levels of tumor necrosis factor-alpha (TNF-α). Whereas TNF-α infusion at a dose that induces systemic inflammation in healthy volunteers has been demonstrated to induce peripheral insulin resistance, the influence of this cytokine on the incretin effect is unknown. We investigated whether systemic inflammation induced by TNF-α infusion in healthy volunteers alters the incretin hormone response to an oral and intravenous glucose load in a crossover study design with ten healthy male volunteers (mean age 24 years, mean BMI 23.7 kg/m(2) ). DAYS 1 AND 2: Six-hour infusion of saline. Days 3 and 4: Six-hour infusion of TNF-α. Days 1 and 3: Four-hour oral glucose tolerance test (OGTT). Days 2 and 4: Four hour-corresponding intravenous isoglycemic glucose tolerance test (IVGTT). Glucose tolerance tests were initiated after two hours of saline/TNF-α infusion. Plasma concentrations of TNF-α, IL-6, glucose, incretin hormones, cortisol and serum concentrations of C-peptide and insulin were measured throughout the study days. Insulin sensitivity was estimated by the Matsuda index and HOMA-IR. Pre-hepatic insulin secretion rates were calculated. TNF-α infusion induced symptoms of systemic inflammation, increased plasma levels of cortisol, TNF-α, and IL-6, and increased the HOMA-IR. The secretion of incretin hormones as well as the incretin effect remained unchanged. In healthy young male volunteers, acute systemic inflammation induced by infusion of TNF-α is associated with insulin resistance with no change in the incretin effect. This article is protected by copyright. All rights reserved. 23209194 The potential of Sutherlandia frutescens for herb-drug interaction. In Africa, Sutherlandia frutescens is a popular medicinal herb widely consumed by people living with human immunodeficiency virus/AIDS. Concomitant use with antiretroviral drugs has generated concerns of herb-drug interaction (HDI). This study investigated the inhibitory effects of the crude extracts of S. frutescens on the major cytochrome P450 isozymes with the use of pooled human liver microsomes. Its effect on the metabolic clearance of midazolam using cryopreserved hepatocytes was also monitored. The potential of S. frutescens to inhibit human ATP-binding cassette transporters (P-gp and BCRP) and the human organic anion transporting polypeptide (OATP1B1 and OATP1B3) activity was assessed using cell lines overexpressing the transporter proteins. S. frutescens showed inhibitory potency for CYP1A2 (IC(50) = 41.0 µg/ml), CYP2A6 (IC(50) = 160 µg/ml), CYP2B6 (IC(50) = 20.0 µg/ml), CYP2C8 (IC(50) = 22.4 µg/ml), CYP2C9 (IC(50) = 23.0 µg/ml), CYP2C19 (IC(50) = 35.9 µg/ml), and CYP3A4/5 (IC(50) = 17.5 µg/ml [with midazolam1'-hydroxylation]; IC(50) = 28.3 µg/ml [with testosterone 6β-hydroxylation]). Time-dependent (irreversible) inhibition by S. frutescens was observed for CYP3A4/5 (K(I) = 296 µg/ml, k(inact) = 0.063 min(-1)) under the conditions of this study. S. frutescens also delays the production of midazolam metabolites in the hepatocytes, decreasing its clearance by 40%. Furthermore, S. frutescens inhibited P-gp (IC(50) = 324.8 µg/ml), OATP1B1 (IC(50) = 10.4 µg/ml), and OATP1B3 (IC(50) = 6.6 µg/ml). The result indicates the potential for HDI between S. frutescens and the substrates of the affected enzymes, if sufficient in vivo concentration of the extract is attained. 23937752 Biomechanical Evaluation of Anatomical Double-bundle Coracoclavicular Ligament Reconstruction Secured With Knot Fixation Versus Screw Fixation. Methods to reconstruct the coracoclavicular ligaments anatomically have been described. No clear advantage of 1 technique has been elucidated. The authors' hypothesis was that the biomechanical properties of a modified knot fixation technique would be similar to the anatomical double-bundle technique. Sixteen matched cadaveric shoulders were used for this study, and 1 additional shoulder was used in the knot fixation group only. Shoulders were randomly assigned to the anatomical double-bundle coracoclavicular ligament reconstruction technique (n=8) or a knot fixation technique (n=9). The intact coracoclavicular ligaments were tested to failure with superior displacement at a rate of 2 mm/s. Reconstruction was performed using a semitendinosus tendon allograft, and load to failure was repeated for each construct. Ultimate failure load, stiffness, and failure mode were compared using a paired t test (P<.05). No significant difference existed in load to failure between native and reconstructed ligaments or between reconstruction techniques. Stiffness decreased significantly after reconstruction in the double-bundle group (from 32.5 to 22.5 N/mm; P=.035) and in the modified knot fixation group (from 35.5 to 21.9 N/mm; P=.043). No significant difference existed in stiffness between the 2 reconstruction groups. A significant difference (P=.003) existed between failure modes between the 2 reconstruction techniques. Although less stiff than the native ligament, either technique used to reconstruct the coracoclavicular ligament can be performed to yield a load to failure similar to the intact ligament. The majority of failures in the double-bundle group were by means of the graft slipping at the screw-tendon interface at 1 of the clavicular drill holes. The modified knot fixation technique failed the majority of the time by graft elongation. 23219524 Analysis by substituted cysteine scanning mutagenesis of the fourth transmembrane domain of the CXCR4 receptor in its inactive and active state. The chemokine SDF-1 (CXCL12) selectively binds to CXCR4, a member of the G protein-coupled receptor (GPCR) superfamily. In this study, we used the substituted-cysteine accessibility method (SCAM) to identify specific residues of the fourth transmembrane domain (TM4) that contribute to the formation of the binding pocket of CXCR4 in its inactive and active state. We successively substituted each residue from E179((4.68)) to K154((4.43)) with cysteine and expressed the mutants in COS-7 cells. Mutant receptors were then alkylated with methanethiosulfonate-ethylammonium (MTSEA), and binding inhibition was monitored using the CXCR4 antagonist FC131 [cyclo(-D-Tyr(1)-Arg(2)-Arg(3)-Nal(4)-Gly(5)-)], which displays anti-HIV activity. MTSEA treatment resulted in a significant reduction of FC131 binding to D171C((4.60)) and P170C((4.59)). To assess TM4 accessibility in an active state of CXCR4, TM4 cysteine mutants were transposed within the constitutively active mutant N119S((3.35)). MTSEA treatment of TM4 mutants N119S-S178C((4.67)), N119S-V177C((4.66)) and N119S-I173C((4.62)) resulted in a significant reduction in FC131 binding. Protection assays using FC131 prior to MTSEA treatment significantly reduced the alkylation of all MTSEA-sensitive mutants. The accessibility of the D171C((4.60)) and P170C((4.59)) residues suggests that they are oriented towards a water-accessible area of the binding pocket of CXCR4. S178C((4.67)), V177C((4.66)) and I173C((4.62)) showed binding inhibition only in an N119S((3.35)) background. Taken together our results suggest that TM4 and ECL2 undergo conformational changes during CXCR4 activation and also demonstrate how TM4 is an important feature for the binding of anti-HIV compounds. 23826903 Third-party disability in family members of people with aphasia: a systematic review. The WHO's International Classification of Functioning, Disability, and Health (ICF) describes third-party disability as the disability experienced by significant others as a consequence of their family members' health condition (WHO, 2001). A systematic review of the literature was conducted to summarize the current knowledge of third-party disability in aphasia. PubMed, CINAHL and three other databases were searched for peer-reviewed studies reporting on how aphasia affects family members with no date restrictions. Findings from relevant studies that met the inclusion criteria were extracted and mapped to the ICF. This paper summarizes what is known about the experience of family members of people with aphasia, describing negative outcomes in the body functions and activities and participation components of the ICF. However, due to the limited consensus between studies, this review reveals an incomplete understanding of the nature of third-party disability. While current literature suggests there is a broad range of consequences for family members of people with aphasia, the sequelae of disability for family members of people with aphasia are not well understood. Further research is needed to better describe the nature and degree of third-party disability in aphasia. 23831411 Cognitive, motor and tyrosine hydroxylase temporal impairment in a model of parkinsonism induced by reserpine. Studies have suggested that cognitive deficits can precede motor alterations in Parkinson's disease (PD). However, in general, classic animal models are based on severe motor impairment after one single administration of neurotoxins, and thereby do not express the progressive nature of the pathology. A previous study showed that the repeated administration with a low dose (0.1mg/kg) of the monoamine depleting agent reserpine induces a gradual appearance of motor signs of pharmacological parkinsonism in rats. Here, we showed this repeated treatment with reserpine induced a memory impairment (evaluated by the novel object recognition task) before the gradual appearance of the motor signs. Additionally, these alterations were accompanied by decreased tyrosine hydroxylase (TH) striatal levels and reduced number of TH+ cells in substantia nigra pars compacta (SNpc). After 30 days without treatment, reserpine-treated animals showed normal levels of striatal TH, partial recovery of TH+ cells in SNpc, recovery of motor function, but not reversal of the memory impairment. Furthermore, the motor alterations were statistically correlated with decreased TH levels (GD, CA1, PFC and DS) and number of TH+ cells (SNpc and VTA) in the brain. Thus, we extended previous results showing that the gradual appearance of motor impairment induced by repeated treatment with a low dose of reserpine is preceded by short-term memory impairment, as well as accompanied by neurochemical alterations compatible with the pathology of PD. 23851288 Developing a vital sign alert system. This article describes the implementation of a nurse-designed, automated system for enhancing patient monitoring on medical-surgical and step-down nursing units. The system, which is not derived from any of the early warning scoring systems described in nursing literature, was developed and put into place at a large tertiary hospital in eastern Virginia and found to substantially reduce out-of-unit codes without increasing nurses' workload. 23883094 Androgen Response Element of the Glycine N-Methyltransferase Gene is Located in the Coding Region of its First Exon. Androgen plays an important role in the pathogenesis of prostate cancer (PCa). Previously, we identified glycine N-methyltransferase (GNMT) as a tumor susceptibility gene and characterized its promoter region. Besides, its enzymatic product-sarcosine has been recognized as a marker for prognosis of PCa. The goals of this study were to determine whether GNMT is regulated by androgen and to map its androgen response elements (AREs). Real-time PCR analyses showed that R1881, a synthetic AR agonist induced GNMT expression in AR-positive LNCaP cells, but not in AR-negative DU145 cells. In-silico prediction showed that there are 4 putative AREs in GNMT-ARE1, ARE2 and ARE3 are located in the intron 1 and ARE4 is in the intron 2. Consensus ARE motif deduced from published AREs was used to identify the fifth ARE-ARE5 in the coding region of exon 1. Luciferase reporter assay found that only ARE5 mediated the transcriptional activation of R1881. ARE3 overlaps with a Yin Yang 1 motif (CaCCATGTT, +1118/+1126) that was further confirmed by antibody supershift and chromatin immunoprecipitation assays. Electrophoretic mobility shift and chromatin immunoprecipitation assays confirmed that AR interacts with ARE5 in vitro and in vivo. In summary, GNMT is an AR-targeted gene with its functional ARE located at +19/+33 of the first exon. These results are valuable for the study of the influence of androgen on the gene expression of GNMT especially in the pathogenesis of cancer. 23709278 Diagnostic sensitivity of SPECT myocardial perfusion imaging using a pumping cardiac phantom with inserted variable defects. The diagnostic sensitivity of various SPECT MPI procedures was assessed using a pumping cardiac phantom with variable defects inserted in the myocardial wall of the left ventricle. A diagnostic evaluation of 142 myocardial defects was performed. A diagnosis blinded to prior-known conditions was compared to the known defects severity (transmural, subendocardial) and defects position within the myocardial wall of the left ventricle (apical, anterior, inferior) for three body types (average male, large male, large female). Non-attenuation corrected, attenuation corrected and gated SPECT MPI were performed. The diagnostic sensitivity was improved when applying attenuation correction or gating techniques to identify subendocardial defects in the inferior, anterior and apical segments of the myocardial wall of the left ventricle for all three body types. Transmural defects could be identified without any attenuation correction or gating. The diagnostic sensitivity was improved when applying AC or GSPECT techniques. 23913922 Drosophila Gtsf1 is an essential component of the Piwi-mediated transcriptional silencing complex. The PIWI-interacting RNA (piRNA) pathway is a small RNA silencing system that keeps selfish genetic elements such as transposons under control in animal gonads. Several lines of evidence indicate that nuclear PIWI family proteins guide transcriptional silencing of their targets, yet the composition of the underlying silencing complex is unknown. Here we demonstrate that the double CHHC zinc finger protein gametocyte-specific factor 1 (Gtsf1) is an essential factor for Piwi-mediated transcriptional repression in Drosophila. Cells lacking Gtsf1 contain nuclear Piwi loaded with piRNAs, yet Piwi's silencing capacity is ablated. Gtsf1 interacts directly with a small subpool of nuclear Piwi, and loss of Gtsf1 phenocopies loss of Piwi in terms of deregulation of transposons, loss of H3K9 trimethylation (H3K9me3) marks at euchromatic transposon insertions, and deregulation of genes in proximity to repressed transposons. We propose that only a small fraction of nuclear Piwi is actively engaged in target silencing and that Gtsf1 is an essential component of the underlying Piwi-centered silencing complex. 23619413 Context affects nestmate recognition errors in honey bees and stingless bees. Nestmate recognition studies, where a discriminator first recognises and then behaviourally discriminates (accepts/rejects) another individual, have used a variety of methodologies and contexts. This is potentially problematic because recognition errors in discrimination behaviour are predicted to be context-dependent. Here we compare the recognition decisions (accept/reject) of discriminators in two eusocial bees, Apis mellifera and Tetragonisca angustula, under different contexts. These contexts include natural guards at the hive entrance (control); natural guards held in plastic test arenas away from the hive entrance that vary either in the presence or absence of colony odour or the presence or absence of an additional nestmate discriminator; and, for the honey bee, the inside of the nest. For both honey bee and stingless bee guards, total recognition errors of behavioural discrimination made by guards (% nestmates rejected + % non-nestmates accepted) are much lower at the colony entrance (honey bee: 30.9%; stingless bee: 33.3%) than in the test arenas (honey bee: 60-86%; stingless bee: 61-81%; P<0.001 for both). Within the test arenas, the presence of colony odour specifically reduced the total recognition errors in honey bees, although this reduction still fell short of bringing error levels down to what was found at the colony entrance. Lastly, in honey bees, the data show that the in-nest collective behavioural discrimination by ca. 30 workers that contact an intruder is insufficient to achieve error-free recognition and is not as effective as the discrimination by guards at the entrance. Overall, these data demonstrate that context is a significant factor in a discriminators' ability to make appropriate recognition decisions, and should be considered when designing recognition study methodologies. 23696563 Endogenous somatostatin is critical in regulating the acute effects of L-arginine on growth hormone and insulin release in mice. l-arginine (l-Arg) rapidly stimulates GH and insulin release in vivo. It has been hypothesized that l-Arg stimulates GH release by lowering hypothalamic somatostatin (SST) tone. l-Arg may also act directly at the pituitary to stimulate GH release. Moreover, l-Arg has a direct stimulatory effect on β-cells, which is thought to be blunted by the release of SST from pancreatic δ-cells. To confirm the role of endogenous SST on l-Arg-induced GH and insulin release, wild-type (WT) and SST-knockout (SST-KO) mice were injected with l-Arg (ip; 0.8 g/kg), and pre-/post-injection GH, insulin, and glucose levels were measured. In WT mice, l-Arg evoked a 6-fold increase in circulating GH. However, there was only a modest increase in GH levels in WT pituitary cell cultures treated with l-Arg. In contrast, l-Arg failed to increase GH in SST-KO beyond their already elevated levels. These results further support the hypothesis that the primary mechanism by which l-Arg acutely increases GH in vivo is by lowering hypothalamic SST input to the pituitary and not via direct pituitary effects. Additionally, l-Arg induced a clear first-phase insulin secretion in WT mice, but not in SST-KO. However, SST-KO, but not WT mice, displayed a robust and sustained second-phase insulin release. These results further support a role for endogenous SST in regulating l-Arg-mediated insulin release. 23362116 CrbpI regulates mammary retinoic acid homeostasis and the mammary microenvironment. Cellular retinol-binding protein, type I (CrbpI), encoded by retinol-binding protein, type 1 (Rbp1), is a chaperone of vitamin A (retinol) that is epigenetically silenced in ∼25% of human breast cancers. CrbpI delivers vitamin A to enzymes for metabolism into an active metabolite, all-trans retinoic acid (atRA), where atRA is essential to cell proliferation, apoptosis, differentiation, and migration. Here, we show the effect of CrbpI loss on mammary atRA homeostasis using the Rbp1(-/-) mouse model. Rbp1(-/-) mouse mammary tissue has disrupted retinoid homeostasis that results in 40% depleted endogenous atRA. CrbpI loss and atRA depletion precede defects in atRA biosynthesis enzyme expression. Compensation by CrbpIII as a retinoid chaperone does not functionally replace CrbpI. Mammary subcellular fractions isolated from Rbp1(-/-) mice have altered retinol dehydrogenase/reductase (Rdh) enzyme activity that results in 24-42% less atRA production. Rbp1(-/-) mammary tissue has epithelial hyperplasia, stromal hypercellularity, increased collagen, and increased oxidative stress characteristic of atRA deficiency and early tissue dysfunction that precedes tumor formation. Consistent with the findings from the Rbp1(-/-) mouse, tumorigenic epithelial cells lacking CrbpI expression produce 51% less atRA. Together, these data show that CrbpI loss disrupts atRA homeostasis in mammary tissue, resulting in microenvironmental defects similar to those observed at the early stages of tumorigenesis.-Pierzchalski, K., Yu, J., Norman, V., Kane, M. A. CrbpI regulates mammary retinoic acid homeostasis and the mammary microenvironment. 23369157 Individual Beam Sharpening Improves Composite Dose Fall-off Near a Target for Non-isocentric Cyberknife Radiosurgery. Stereotactic radiosurgery (SRS) refers to a high dose of radiation delivered to a focal region of interest while maximizing the steep dose gradient to minimize dose to the surrounding normal tissues. Multiple factors can influence the dose fall-off, and the relative importance of such factors have not yet been characterized for non-isocentric Cyberknife SRS. Our aim was to investigate whether the composite dose fall-off near a target may be enhanced via sharpening the lateral beam profile (or penumbra) of each individual beam. Cyberknife beam profiles were fitted and parameterized to obtain a characteristic penumbra function for each collimator size. Simulated beam profiles with progressively sharper penumbras were then generated, and used to perform simulated treatment planning on seven pediatric intracranial arteriovenous malformations (AVMs) cases. Penumbra size was found to significantly influence the peripheral dose fall-off. Peripheral dose volumes were reduced by 5 to 10% with reductions in penumbra size ranging from 40 to 80%. Dose conformality and homogeneity were not significantly changed with decreasing penumbra size. Therefore, individual beam sharpening provides a straightforward way of improving the composite dose fall-off for non-isocentric Cyberknife SRS. 23441649 Regio- and Stereocontrolled Synthesis of Oligostilbenoids: Theoretical Highlights at the Supramolecular Level. Oligostilbenoids (e.g., ampelopsin F, viniferin, pallidol) result from homogeneous or heterogeneous coupling of monomeric stilbenoid units, leading to various chemical structures. Oligostilbenoid synthesis is regio- and stereocontrolled. To tackle this regio- and stereocontrol, a supramolecular chemistry approach is required that can be achieved by quantum chemistry. The stability of noncovalent π-stacks, formed between two stilbenoid units prior to oxidation, is accurately evaluated with density functional theory (DFT) including dispersive effects (within the DFT-D formalism). These noncovalent arrangements drive the regiocontrol. The rest of the chemical pathway is a succession of dearomatization and rearomatization stages. The thermodynamics and kinetics of the processes are calculated with classical hybrid functionals. This study allows discrimination between the two main possible chemical pathways, namely, radical-neutral and radical-radical reactions. The former appears more likely, thermodynamics and kinetics being in perfect agreement with the experimental 1:2 ratio obtained for ampelopsin F:pallidol analogues, respectively. 23528711 A canine model of human aging and Alzheimer's disease. The aged dog naturally develops cognitive decline in many different domains (including learning and memory) but also exhibits human-like individual variability in the aging process. The neurobiological basis for cognitive dysfunction may be related to structural changes that reflect neurodegeneration. Molecular cascades that contribute to degeneration in the aging dog brain include the progressive accumulation of beta-amyloid (Aβ) in diffuse plaques and in the cerebral vasculature. In addition, neuronal dysfunction occurs as a consequence of mitochondrial dysfunction and cumulative oxidative damage. In combination, the aged dog captures key features of human aging, making them particularly useful for the development of preventive or therapeutic interventions to improve aged brain function. These interventions can then be translated into human clinical trials. This article is part of a Special Issue entitled: Animal Models of Disease. 23913185 Comparison of fetal mesencephalic grafts, AAV-delivered GDNF, and both combined in an MPTP-induced non-human primate Parkinson's model. We combined viral vector delivery of human glial-derived neurotrophic factor (GDNF) with the grafting of dopamine precursor cells from fetal ventral mesencephalon to determine whether these strategies would improve the anti-Parkinson's effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, an animal model for Parkinson's disease. Both strategies have been reported as individually beneficial in animal models of Parkinson's disease, leading to clinical studies. GDNF delivery has also been reported to augment ventral mesencephalic tissue implants but no combined studies have been done in monkeys. Monkeys were treated with MPTP and placed into four balanced treatment groups receiving only rAAV5/huGDNF, only fetal dopamine precursor cells, both together, or a buffered saline solution (control). The combination of fetal precursors with rAAV5/huGDNF showed significantly higher striatal dopamine concentrations compared with the other treatments, but did not lead to greater functional improvement in this study. For the first time under identical conditions in primates, we show that all three treatments lead to improvement compared with control animals.Molecular Therapy (2013); doi:10.1038/mt.2013.180. 23740668 The Angiogenic Peptide Vascular Endothelial Growth Factor-Basic Fibroblast Growth Factor Signaling is Up-Regulated in a Rat Pressure Ulcer Model. The purpose of this study is to investigate the mRNA and protein expression levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in pressure ulcers, and to elucidate the molecular mechanism by which VEGF and bFGF are involved in pressure ulcer formation. A rat model of ischemia-reperfusion pressure ulcer was established by magnetic disk circulating compression method. Real-time fluorescence quantitative PCR and Western blot assays were conducted to detect the mRNA and protein expression of VEGF and bFGF in the tissues of rat I-, II-, and III-degree pressure ulcers, the surrounding tissues, and normal skin. Our study confirmed that the mRNA and protein expression levels of VEGF and bFGF in the tissues of rat I-degree pressure ulcer were significantly higher than that in the II- and III-degree pressure ulcer tissues (P < 0.05). The expression of VEGF and bFGF in the tissues surrounding I- and II-degree pressure ulcers were higher than the rats with normal skin. The expression of VEGF and bFGF in the tissues of rat III-degree pressure ulcer was lower than that in the surrounding tissues and normal skin (P < 0.05). There was a significant positive correlation between change in the VEGF and bFGF. The results showed that with an increase in the degree of pressure ulcers, the expression of VEGF and bFGF in pressure ulcers tissue are decreased. This leads to a reduction in angiogenesis and may be a crucial factor in the formation of pressure ulcers. Anat Rec, 2013. © 2013 Wiley Periodicals, Inc. 23444015 Probing the Metabotropic Glutamate Receptor 5 (mGlu5) Positive Allosteric Modulator (PAM) Binding Pocket: Discovery of Point Mutations That Engender a "Molecular Switch" in PAM Pharmacology. Positive allosteric modulation of metabotropic glutamate receptor subtype 5 (mGlu5) is a promising novel approach for the treatment of schizophrenia and cognitive disorders. Allosteric binding sites are topographically distinct from the endogenous ligand (orthosteric) binding site, allowing for co-occupation of a single receptor with the endogenous ligand and an allosteric modulator. Negative allosteric modulators (NAMs) inhibit and positive allosteric modulators (PAMs) enhance the affinity and/or efficacy of the orthosteric agonist. The molecular determinants that govern mGlu5 modulator affinity versus cooperativity are not well understood. Focusing on the modulators based on the acetylene scaffold, we sought to determine the molecular interactions that contribute to PAM versus NAM pharmacology. Generation of a comparative model of the transmembrane-spanning region of mGlu5 served as a tool to predict and interpret the impact of mutations in this region. Application of an operational model of allosterism allowed for determination of PAM and NAM affinity estimates at receptor constructs that possessed no detectable radioligand binding as well as delineation of effects on affinity versus cooperativity. Novel mutations within the transmembrane domain (TM) regions were identified that had differential effects on acetylene PAMs versus 2-methyl-6-(phenylethynyl)-pyridine, a prototypical NAM. Three conserved amino acids (Y658, T780, and S808) and two nonconserved residues (P654 and A809) were identified as key determinants of PAM activity. Interestingly, we identified two point mutations in TMs 6 and 7 that, when mutated, engender a mode switch in the pharmacology of certain PAMs. 23720754 microRNA-7 Suppresses the Invasive Potential of Breast Cancer Cells and Sensitizes Cells to DNA Damages by Targeting Histone Methyltransferase SET8. SET8 (SET domain containing 8) is a histone H4 lysine 20 (H4K20)-specific monomethyltransferase in higher eukaryotes that exerts diverse functions in transcription regulation, DNA repair, tumor metastasis, and genome integrity. The activity of SET8 is tightly controlled during cell cycle through post-translational modifications, including ubiquitination, phosphorylation, and sumoylation. However, how the expression of SET8 is regulated is not fully understood. Here, we report that microRNA-7 is a negative regulator of SET8. We demonstrated that microRNA-7 inhibits H4K20 monomethylation and suppresses epithelial-mesenchymal transition and the invasive potential of breast cancer cells. We showed that microRNA-7 promotes spontaneous DNA damages and sensitizes cells to induced DNA damages. Our experiments provide a molecular mechanism for the regulation of SET8 and extend the biological function of microRNA-7 to DNA damage response, supporting the pursuit of microRNA-7 as a potential target for breast cancer intervention. 23913522 Transabdominal amnioinfusion for improving fetal outcomes after oligohydramnios secondary to preterm prelabour rupture of membranes before 26 weeks. Preterm prelabour rupture of membranes (PPROM) before 26 weeks can delay lung development and can cause pulmonary hypoplasia, as a result of oligohydramnios. Restoring the amniotic fluid volume by transabdominal amnioinfusion might prevent abnormal lung development and might have a protective effect for neurological complications, fetal deformities and neonatal sepsis. To assess the effectiveness of transabdominal amnioinfusion in improving perinatal outcome in women with oligohydramnios secondary to rupture of fetal membranes before 26 weeks. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 April 2013). All randomised controlled trials comparing transabdominal amnioinfusion with no transabdominal amnioinfusion. Cluster- or quasi-randomised trials were not eligible for inclusion. In cases where only an abstract was available, we attempted to find the full articles. Two review authors assessed trials for inclusion. No eligible trials were identified. There are no included studies. There is currently no evidence to evaluate the use of transabdominal amnioinfusion in women with oligohydramnios secondary to rupture of fetal membranes before 26 weeks for improving perinatal outcome. Further research examining the effects of this intervention is needed. Two randomised controlled trials are ongoing but final data have not yet been published. 23415050 GERICO-03 phase II trial of accelerated and partial breast irradiation in elderly women: feasibility, reproducibility, and impact on functional status. To analyze the feasibility, reproducibility, and impact on functional status of postoperative accelerated and partial breast irradiation (APBI) using interstitial high-dose rate-brachytherapy in women older than 70 years. From July 2004 to April 2008, 46 patients were screened for enrollment in a nationwide prospective Phase II trial. A total of 40 patients were eligible according to the inclusion criteria (aged >70 years, T1-2 <30mm, and pN0). The total delivered dose was 34Gy of 10 fractions for 5 days. Feasibility and reproducibility were evaluated using a Quality Index (QI) defined as (V100%-clinical target volume)/V100%. Skin toxicity was reported using Common Terminology Criteria for Adverse Events version 3.0. ABPI impact on functional dependence was evaluated using the Activity of Daily Living and Instrumental Activity of Daily Living scales. Reproducibility and feasibility were assessed with the optimal two-stage design of Simon. Median age was 74 years (70-87 years). All patients were treated according to the protocol. Median Quality Index calculated for the 40 eligible patients was 13.3% (1-70%). It was considered acceptable, partially acceptable, and nonacceptable in 10, 28, and 2 patients, respectively. Within 12 months after APBI, overall rates of toxicity were 59%, 28%, and 2% for Grade 1, 2, and 3 events, respectively. Twelve months after APBI, 35 patients (87%) achieved excellent/good cosmetic result. Compared with baseline values, Activity of Daily Living and Instrumental Activity of Daily Living scores remained unchanged 6 and 12 months after APBI. APBI by means of high-dose rate-brachytherapy is a feasible/reproducible technique without significant impact on functional dependence in the treatment of elderly women with early breast cancer. 23182061 Factors associated with female pattern hair loss and its prevalence in Taiwanese women: A community-based survey. Although female pattern hair loss (FPHL) has been considered simply the female counterpart of male pattern hair loss in men, the risk factors may differ. We sought to evaluate factors associated with FPHL and to estimate its prevalence in women. In total, 26,226 subjects aged 30 years and older participated in a cross-sectional survey. Ludwig and Norwood classifications were used to assess the degree of hair loss. Information on possible risk factors for FPHL was collected using a questionnaire interview. The prevalence of FPHL (Ludwig grade >I) for all ages was 11.8% (95% CI 11.5%-12.2%), increasing with advancing age. After controlling for age and family history, statistically significant associations were noted between FPHL and high fasting glucose (odds ratio [OR] 1.15, 95% confidence interval [CI] 1.04-1.28), fewer childbirths (OR 1.24, 95% CI 1.12-1.38), breast-feeding (OR 0.88, 95% CI 0.78-0.98), oral contraceptive use (OR 1.21, 95% CI 1.01-1.45), and ultraviolet exposure more than 16 hours per week (OR 1.12, 95% CI 1.02-1.22). The validity and reliability of FPHL classification may be not perfect in this survey and may need to be verified. Information on family history may be still subject to recall bias. Risk factors for FPHL and male androgenic alopecia may differ. 23760770 Prostate apoptosis response-4 is involved in the apoptosis response to docetaxel in MCF-7 breast cancer cells. Experimental evidence indicates that prostate apoptosis response-4 (Par-4, also known as PAWR) is a key regulator of cancer cell survival and may be a target for cancer-selective targeted therapeutics. Par-4 was first identified in prostate cancer cells undergoing apoptosis. Both intracellular and extracellular Par-4 have been implicated in apoptosis. Relatively little is known about the role of Par-4 in breast cancer cell apoptosis. In this study, we sought to investigate the effects of Par-4 expression on cell proliferation, apoptosis and drug sensitivity in breast cancer cells. MCF-7 cells were stably transfected with expression vectors for Par-4, or transiently transfected with siRNA for Par-4 knockdown. Cell proliferation assays were performed using MTT and apoptosis was evaluated using acridine orange staining, fluorescence microscopy and flow cytometry. Par-4 overexpression reduced MCF-7 proliferation rates. Conversely, Par-4 knockdown led to increased MCF-7 proliferation. Par-4 downregulation also led to increased BCL-2 and reduced BID expression. Par-4 overexpression did not affect the cell cycle profile. However, MCF-7 cells with increased Par-4 expression showed reduced ERK phosphorylation, suggesting that the inhibition of cell proliferation promoted by Par-4 may be mediated by the MAPK/ERK1/2 pathway. MCF-7 cells with increased Par-4 expression showed a marginal increase in early apoptotic cells. Importantly, we found that Par-4 expression modulates apoptosis in response to docetaxel in MCF7 breast cancer cells. Par-4 exerts growth inhibitory effects on breast cancer cells and chemosensitizes them to docetaxel. 23668903 Do benzodiazepines moderate the effectiveness of bitemporal electroconvulsive therapy in major depression? Electroconvulsive therapy (ECT) is the most effective treatment for depression. However, the use of concomitant medications during ECT is controversial, especially benzodiazepines, as some past evidence suggests these may reduce the efficacy of ECT. This study analysed the effect of benzodiazepines on treatment outcomes in a group of depressed patients treated with bitemporal (BT) ECT. 90 patients with major depression who received BT ECT were analysed. Clinical, demographic and ECT data were extracted from clinical records. Mood improvement was rated by trained psychiatrists using the Hamilton Depression Rating Scale (HDRS-21) at baseline and after the final ECT treatment. The association between benzodiazepine dose and mood outcomes over the ECT course was examined with regression analyses, controlling for variables that may affect ECT efficacy. Hierarchical multiple regression analysis found only current episode duration (t=-4.77, p<0.001) was a significant predictor of change in HDRS. Benzodiazepine dose was not associated with a change in HDRS (p>0.05, R(2)=0.39). This was a retrospective study. The use of the half-age dosing method for ECT did not permit examination of the effects of benzodiazepines on seizure threshold. Benzodiazepines did not affect the efficacy of BT ECT with the dosing method used. However, these results may not generalise to other forms of ECT, ECT given with other methods of dose determination or to other populations less responsive to ECT. 23824366 Staphylococcal and streptococcal superantigen exotoxins. SUMMARY This review begins with a discussion of the large family of Staphylococcus aureus and beta-hemolytic streptococcal pyrogenic toxin T lymphocyte superantigens from structural and immunobiological perspectives. With this as background, the review then discusses the major known and possible human disease associations with superantigens, including associations with toxic shock syndromes, atopic dermatitis, pneumonia, infective endocarditis, and autoimmune sequelae to streptococcal illnesses. Finally, the review addresses current and possible novel strategies to prevent superantigen production and passive and active immunization strategies. 23810447 A rudimentary tragus in the nasopharynx: case report, literature review, and discussion of embryologic development. We describe the rare case of a nine year-old girl with a several month history of mouth breathing and nasal obstruction due to a rudimentary tragus in the nasopharynx. We focus on the accessory tragus and its origins by describing the embryologic development of the external ear. Based on our review of the medical literature, this is the first report of a nasopharyngeal mass with a pathologic diagnosis of a rudimentary tragus. 23959846 Possible HIV transmission modes among at-risk groups at an early epidemic stage in the Philippines. A concentrated human immunodeficiency virus (HIV) epidemic might have started in the Philippines. A subsequent characterization of viruses was carried out to estimate HIV transmission modes. Most HIV strains from injecting drug users belonged to subtype-B. CRF-01 was a major subtype harbored by three other at-risk populations: male visa applicants who had sex with men, "men who have sex with men," and visa applicants. An HIV phylogeny suggested that two strain groups of injecting drug users and others circulated separately. In contrast, there was substantial genetic overlap between two strain groups from "men who have sex with men" and visa applicants. Mean nucleotide distance within strains was shorter among subtype-B strains harbored by the injecting drug users (0.010) than among CRF-01 strains of the other three populations: male visa applicants who had sex with men (0.034), "men who have sex with men" (0.023), and visa applicants (0.032). Closely related strains of hepatitis C virus were derived from not only HIV-positive but also -negative individuals. These results suggest that there is potential for transmission from visa applicants to "men who have sex with men," and that once HIV occurs in injecting drug users, it spreads rapidly among them. Close contacts of hepatitis C virus carriers composed of HIV-negative and -positive individuals indicated ongoing HIV spread via blood and possible intervention points. Large-scale analysis is needed to provide more precise information on the transmission directions and to help curb the growth of this HIV epidemic in the Philippines. J. Med. Virol. © 2013 Wiley Periodicals, Inc. 23892860 Physicians' knowledge and attitude towards adverse event reporting system and result to intervention - randomized nested trial among Bulgarian physicians. Aim To identify the factors that influence physicians' under-reporting in Bulgaria and their attitude towards adverse event reporting system and to estimate the role of self-education by providing educational materials. Methods A randomized nested trial among physicians-general practitioners and specialists in Bulgaria was conducted by a validated questionnaire in order to evaluate their knowledge and attitude towards adverse event reporting system. One month after the intervention the participants were re-visited and were asked to answer the same questions again in order to estimate the change in their knowledge and attitude towards pharmacovigilance system and to obtain their evaluation for the materials provided. Results The response rate was 91. Fifty seven (46.3%) physicians were not familiar with the pharmacovigilance system. The most common reason for non-reporting adverse drug reactions (ADRs) was uncertainty concerning the relationship between the suspected drug and ADRs, the ADRs were already known and the fact that the physician was not aware where they should report. Although 103 (83.7%) respondents in the entry survey and by 102 (82.9%) of those participating in the exit survey consider ADRs reporting as their obligation (p more than 0.05), only 50 (40.7%) and 31 (25.2%), respectively answered that they had ever reported ADRs; 109 (88.6%) of the surveyed physicians assessed the provided educational materials as useful for them. Conclusion The physicians in Bulgaria have poor knowledge for the pharmacovigilance system; however self-education leads to a better knowledge and positive attitude towards ADRs reporting system. National drug regulatory authority should play a more active role in improving physicians' adherence to the ADRs reporting systems and the developed educational pack can be used in nationwide campaign. Keywords: pharmacovigilance, adverse event reporting, physicians, knowledge. 23905547 The Chinese wild grapevine (Vitis pseudoreticulata) E3 ubiquitin ligase Erysiphe necator-induced RING finger protein 1 (EIRP1) activates plant defense responses by inducing proteolysis of the VpWRKY11 transcription factor. Ubiquitin-mediated regulation responds rapidly to specific stimuli; this rapidity is particularly important for defense responses to pathogen attack. Here, we investigated the role of the E3 ubiquitin ligase Erysiphe necator-induced RING finger protein 1 (EIRP1) in the defense response of Chinese wild grapevine Vitis pseudoreticulata. The regulatory function of E3 ubiquitin ligase EIRP1 was investigated using molecular, genetic and biochemical approaches. EIRP1 encodes a C3HC4-type Really Interesting New Gene (RING) finger protein that harbors E3 ligase activity. This activity requires the conserved RING domain, and VpWRKY11 also interacts with EIRP1 through the RING domain. VpWRKY11 localizes to the nucleus and activates W-box-dependent transcription in planta. EIRP1 targeted VpWRKY11 in vivo, resulting in VpWRKY11 degradation. The expression of EIRP1 and VpWRKY11 responds rapidly to powdery mildew in Vitis pseudoreticulata grapevine; also, overexpression of EIRP1 in Arabidopsis confers enhanced resistance to the pathogens Golovinomyces cichoracearum and Pseudomonas syringae pv tomato DC3000. Our data suggest that the EIRP1 E3 ligase positively regulates plant disease resistance by mediating proteolysis of the negative regulator VpWRKY11 via degradation by the 26S proteasome. 23411254 A rapid determination method for ethylenethiourea in potato and cucumber by modified QuEChERS - high performance liquid chromatography-tandem mass spectrometry. A rapid and sensitive analytical method for the determination of ethylenethiourea (ETU) in potatoes and cucumbers is developed. This method employs modified QuEChERS followed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis. ETU was extracted by alkaline acetonitrile (containing 1%NH(3).H(2)0), separated on a ZIC-pHILIC column, confirmed by multiple reaction monitoring (MRM) mode with electrospray ionisation source. This modified procedure showed satisfactory recovery (90.6-103.5%) fortified at the range of 0.005-0.05 mg kg(-1) with relative standard deviation (RSD)<7%. The limits of detection (LOD) and the limits of quantification (LOQ) were 0.002 mg kg(-1) and 0.005 mg kg(-1), respectively. Matrix effect and HILIC retention mechanism were also evaluated. The method was finally applied to detect ETU in potato and cucumber samples collected at harvest period. Residues of ETU were detected in four cucumber samples with the level lower than LOQ. 23670092 Journey to the skin: Somatosensory peripheral axon guidance and morphogenesis. The peripheral axons of vertebrate tactile somatosensory neurons travel long distances from ganglia just outside the central nervous system to the skin. Once in the skin these axons form elaborate terminals whose organization must be regionally patterned to detect and accurately localize different kinds of touch stimuli. This review describes key studies that identified choice points for somatosensory axon growth cones and the extrinsic molecular cues that function at each of those steps. While much has been learned in the past 20 years about the guidance of these axons, there is still much to be learned about how the peripheral axons of different kinds of somatosensory neurons adopt different trajectories and form specific terminal structures. 23727470 2-Methyl-l-erythritol glycosides from Gardenia jasminoides. Two new glycosides, 2-methyl-l-erythritol-4-O-(6-O-trans-sinapoyl)-β-d-glucopyranoside (1) and 2-methyl-l-erythritol-1-O-(6-O-trans-sinapoyl)-β-d-glucopyranoside (2), along with two known triterpenoids (3-4), four quinic acid derivatives (5-8) and one flavonoid (9) were isolated from the fruit of Gardenia jasminoides. Their structures were elucidated through MS and 2D NMR experiments (HMQC and HMBC). Inhibitory effects of the isolated compounds on nitric oxide production in lipopolysaccharide-activated macrophages were evaluated. Though 2-methyl-d-erythritol and its glycosides have been reported in a few references, this is the first report about 2-methyl-l-erythritol glycosides. Based on this finding, we propose that 2-methyl-l-erythritol might be a new intermediate in the non-mevalonate biosynthesis of terpenoids. 23858442 Cranial irradiation compromises neuronal architecture in the hippocampus. Cranial irradiation is used routinely for the treatment of nearly all brain tumors, but may lead to progressive and debilitating impairments of cognitive function. Changes in synaptic plasticity underlie many neurodegenerative conditions that correlate to specific structural alterations in neurons that are believed to be morphologic determinants of learning and memory. To determine whether changes in dendritic architecture might underlie the neurocognitive sequelae found after irradiation, we investigated the impact of cranial irradiation (1 and 10 Gy) on a range of micromorphometric parameters in mice 10 and 30 d following exposure. Our data revealed significant reductions in dendritic complexity, where dendritic branching, length, and area were routinely reduced (>50%) in a dose-dependent manner. At these same doses and times we found significant reductions in the number (20-35%) and density (40-70%) of dendritic spines on hippocampal neurons of the dentate gyrus. Interestingly, immature filopodia showed the greatest sensitivity to irradiation compared with more mature spine morphologies, with reductions of 43% and 73% found 30 d after 1 and 10 Gy, respectively. Analysis of granule-cell neurons spanning the subfields of the dentate gyrus revealed significant reductions in synaptophysin expression at presynaptic sites in the dentate hilus, and significant increases in postsynaptic density protein (PSD-95) were found along dendrites in the granule cell and molecular layers. These findings are unique in demonstrating dose-responsive changes in dendritic complexity, synaptic protein levels, spine density and morphology, alterations induced in hippocampal neurons by irradiation that persist for at least 1 mo, and that resemble similar types of changes found in many neurodegenerative conditions. 23398134 Associations of perceived neighborhood physical and social environments with physical activity and television viewing in African-American men and women. Few studies have assessed how attributes of neighborhood environments contribute to sedentary, in addition to active, behaviors. This study investigated associations of perceived social and physical aspects of neighborhood environments with television (TV) viewing and physical activity (PA) in African-American adults. Cross-sectional analysis of self-reported survey. Large mega-church in Houston, Texas. A total of 1374 African-American men and women. Outcomes included log-transformed daily TV viewing and participation in medium/high levels of PA, measured by the short version of the International Physical Activity Questionnaire. Neighborhood perceptions were assessed with the Social Cohesion and Trust and the Neighborhood Problems scales. Multivariable models that controlled for clustering within neighborhoods. Reporting more neighborhood problems was significantly associated with greater log-transformed TV viewing in women (β = .017, SE = .006, p = .003), and social cohesion was positively associated with PA in women (odds ratio = 1.06, 95% confidence interval = 1.02, 1.11, p = .006). Concerns about litter and walking after dark and a lack of places to shop were associated with increased TV viewing among women, and concerns about traffic and walking after dark were associated with reduced PA among men. Physical and social neighborhood conditions were associated with TV viewing and PA, particularly in women. Neighborhood-based strategies to reduce sedentary behaviors and enhance PA should include attention to social as well as physical aspects of neighborhood environments. 23406524 Preparation of lipase-coated, stabilized, hydrophobic magnetic particles for reversible conjugation of biomacromolecules. This Communication presents the development of a novel strategy for the easy conjugation of biomolecules to hydrophobic magnetic microparticles via reversible coating with previously functionalized lipase molecules. First, the ability of lipase to be strongly adsorbed onto hydrophobic surfaces was exploited for the stabilization of microparticles in aqueous medium by the creation of a hydrophilic surface. Second, the surface amino acids of lipase can be tailored to suit biomolecule conjugation. This approach has been demonstrated by amino-epoxy activation of lipase, enabling the conjugation of different biomolecules to the magnetic particle's surface. For example, it was possible to immobilize 70% of Escherichia coli proteins on the recovered particles. Furthermore, this strategy could be extended to other lipase chemical modification protocols, enabling fine control of biomolecule coupling. These conjugation techniques constitute a modular methodology that also permits the recycling of the magnetic carrier following use. 23692691 Scanning confocal electron energy-loss microscopy using valence-loss signals. Finding a faster alternative to tilt-series electron tomography is critical for rapidly evolving fields such as the semiconductor industry, where failure analysis could greatly benefit from higher throughput. We present a theoretical and experimental evaluation of scanning confocal electron energy-loss microscopy (SCEELM) using valence-loss signals, which is a promising technique for the reliable reconstruction of materials with sub-10-nm resolution. Such a confocal geometry transfers information from the focused portion of the electron beam and enables rapid three-dimensional (3D) reconstruction by depth sectioning. SCEELM can minimize or eliminate the missing-information cone and the elongation problem that are associated with other depth-sectioning image techniques in a transmission electron microscope. Valence-loss SCEELM data acquisition is an order of magnitude faster and requires little postprocessing compared with tilt-series electron tomography. With postspecimen chromatic aberration (C c) correction, SCEELM signals can be acquired in parallel in the direction of energy dispersion with the aid of a physical pinhole. This increases the efficiency by 10×-100×, and can provide 3D resolved chemical information for multiple core-loss signals simultaneously. 23312981 Femoral vein homograft for neoaortic reconstruction in the Norwood stage 1 operation: A follow-up study. The aim of this study was to analyze our experience with the cryopreserved femoral vein homograft in comparison with standard biomaterials for neoaortic reconstruction in the Norwood stage 1 operation. All patients who underwent the Norwood operation from September 2004 to April 2011 were analyzed retrospectively (n = 107). Patients were grouped into group A (cryopreserved femoral vein homograft; n = 72) or group B (other; n = 35). Intergroup comparisons and dimensional analyses of all available angiograms were performed. Two surgical techniques, "standard homograft cuff" and "homograft tube," were compared. Multivariable Cox regression analysis revealed use of biomaterial other than femoral vein (P = .01; hazard ratio, 3.0; 95% confidence interval [CI], 1.4-6.4), weight less than 2.5 kg at the time of stage 1 (P = .01; hazard ratio, 3.7; 95% CI, 1.7-7.8), and need for extracorporeal membrane oxygenator support after stage 1 (P < .001; hazard ratio, 13.8; 95% CI, 5.9-31.9) as significant independent predictors of overall mortality. Improved late survival at 48 months was seen with the femoral vein homograft compared with other biomaterials when a "homograft tube with end-to-side ascending aortic reimplantation technique" was used (group A [75%] vs group B [44%]; P = .03). With the use of the "homograft cuff technique," survival was similar for femoral vein homografts and other biomaterials (group A [67%] vs group B [61%]; P = .85). Similar neoaortic coarctation rates were seen in both groups (A: 25/59 [42%] vs B: 12/26 [46%]; P = .81). A progressive increase in the diameter of the neoaorta was seen over time in both groups with both technical modifications (tube grafts pre-stage 2 vs pre-stage 3: group A [10.61 mm ± 1.93 vs 13.74 mm ± 3.16] [P < .001] and group B [13.93 mm ± 6.71 vs 17.38 mm ± 5.92] [P = .049]); cuff repair pre-stage 2 to pre-stage 3: group A [13.98 mm ± 2.13 vs 19.09 mm ± 4.18] [P = .002] and group B [16.06 mm ± 3.05 vs 19.73 mm ± 2.93] [P < .001]). The neoaortic Z-scores were generous with the use of homograft cuffs and modest when homograft tubes were used and maintained in range over the follow-up time. Survivals are improved with the use of femoral vein homograft for neoaortic reconstruction for Norwood stage 1 operation, especially when used as a homograft tube with end-to-side aortic reimplantation. Femoral vein homografts have similar recoarctation rates compared with standard biomaterials. Progressive growth/dilation of the neoaorta in proportion to somatic growth is seen with femoral vein tube grafts. 23962668 Systematic review and meta-analysis of psychiatric disorder and the perpetration of partner violence. Backgrounds. The extent to which psychiatric disorders are associated with an increased risk of violence to partners is unclear. This review aimed to establish risk of violence against partners among men and women with diagnosed psychiatric disorders. Methods. Systematic review and meta-analysis. Searches of eleven electronic databases were supplemented by hand searching, reference screening and citation tracking of included articles, and expert recommendations. Results. Seventeen studies were included, reporting on 72 585 participants, but only three reported on past year violence. Pooled risk estimates could not be calculated for past year violence against a partner and the three studies did not consistently report increased risk for any diagnosis. Pooled estimates showed an increased risk of having ever been physically violent towards a partner among men with depression (odds ratio (OR) 2.8, 95% confidence intervals (CI) 2.5-3.3), generalized anxiety disorder (GAD) (OR 3.2, 95% CI 2.3-4.4) and panic disorder (OR 2.5, 95% CI C% 1.7-3.6). Increased risk was also found among women with depression (OR 2.4, 95% CI 2.1-2.8), GAD (OR 2.4, 95% CI 1.9-3.0) and panic disorder (OR 1.9, 95% CI 1.4-2.5). Conclusions. Psychiatric disorders are associated with high prevalence and increased odds of having ever been physically violent against a partner. As history of violence is a predictor of current violence, mental health professionals should ask about previous partner violence when assessing risk. 23731608 Evaluation of the reliability of clinical staging of t2 n0 esophageal cancer: a review of the society of thoracic surgeons database. Clinical staging of esophageal cancer has improved with positron-emission tomography/computed tomography and endoscopic ultrasound imaging. Despite such progress, small single-center studies have questioned the reliability of clinical staging of T2 N0 esophageal cancer. This study broadly examines the adequacy of clinical staging of T2 N0 disease using The Society of Thoracic Surgeons database. We retrospectively studied 810 clinical stage T2 N0 patients from 2002 to 2011, with 58 excluded because of incomplete pathologic staging data. Clinical stage, pathologic stage, and preoperative characteristics were recorded. Logistic regression analysis was used to identify factors associated with upstaging at the time of surgical intervention. Among 752 clinical stage T2 N0 patients, 270 (35.9%) received induction therapy before the operation. Of 482 patients who went directly to surgical intervention, 132 (27.4%) were confirmed as pathologic T2 N0, 125 (25.9%) were downstaged (ie, T0-1 N0), and 225 (46.7%) were upstaged at the operation (T3-4 N0 or Tany N1-3). Exclusive tumor upstaging (ie, pathologic T3-4 N0) accounted for 41 patients (18.2%), whereas exclusive nodal upstaging (ie, pathological T1-2 N1-3) accounted for 100 (44.5%). Combined tumor and nodal upstaging (ie, pathological T3-4 N1-3) accounted for 84 patients (37.3%). Among patients who received induction therapy, 103 (38.1%) were upstaged vs 225 (46.7%) without induction therapy (p = 0.026). Comparing the induction therapy group and the primary surgical group, postoperative 30-day mortality (3.7% vs 3.7%, p > 0.99) and morbidity (46.3% vs 45%, p = 0.76) were similar. Despite advances in staging techniques, clinical staging of T2 N0 esophageal cancer remains unreliable. Recognizing T2 N0 as a threshold for induction therapy in esophageal cancer, many surgeons have opted to treat T2 N0 disease with induction therapy, even though one-quarter of these patients will be pathologic T1 N0. Although this study demonstrated similar perioperative morbidity and mortality with and without induction therapy, further study is needed to examine the effect of upstaging on long-term survival. 23311710 Interventions for women exposed to acute intimate partner violence: emergency professionals' perspective. Aims and objectives.  To examine interventions and practices carried out by the emergency department professionals. Background.  Developing the related practices provides an opportunity for early intervention in women exposed to intimate partner violence who visit the emergency department. Design.  The descriptive, cross-sectional multi-centre designed study with a convenience sample was used to acquire more information to illustrate the situation of intervening in intimate partner violence at Finnish emergency departments. Participants.  A total of 24-hour emergency departments from all over Finland participated in the study. Methods.  Research materials were collected by questionnaires given to emergency department professionals (n = 950) and 51% were returned. Data analysis.  The data were analysed using quantitative methods. Chi-square test was used to test the statistical significance of the data. A p-value of <0·05 was considered to indicate statistical significance of each analysis. Results.  The findings of this study reveal that the emergency department professionals who had common practices and written procedures for handling intimate partner violence reported having helped both women and perpetrators more often than those without. Good cooperation with different help providers, opportunities to consult them and training received facilitated intervention methods. Conclusions.  There is a need for more effective change of information and cooperation with different help providers concerning how to act with women and their family members in intimate partner violence situations. Emergency department professionals do not know enough about the legislation concerning intimate partner violence and their professional duty, e.g. if a child's health and well-being are in danger. Relevance to clinical practice.  This information can be utilised in research, professional education, further training and practical work and when planning the prevention of intimate partner violence. 23924573 Common rs7138803 variant of FAIM2 and obesity in Han Chinese. Obesity causes severe healthcare problem worldwide leading to numerous diseases, such as cardiovascular diseases and diabetes mellitus. Previous Genome-Wide Association Study (GWAS) identified an association between a single nucleotide polymorphism (SNP) rs7138803, on chromosome 12q13 and obesity in European Caucasians. Since the genetic architecture governing the obesity may vary among different populations, we investigate the variant rs7138803 in Chinese population to find out whether it is associated with obesity. A population-based cohort association study was carried out using the High Resolution Melt (HRM) method with 1851 participants. The association between rs7138803 genotypes and body mass index (BMI) was modeled with a general linear model, and a case-control study for the association between rs7138803 genotypes and obesity was performed using Pearson's χ2 test. There was no indication of a deviation from Hardy-Weinberg equilibrium (HWE p value = 0.51) in our sample. No association was detected between SNP rs7138803 and BMI in our Chinese Han population with a P value of 0.51. SNP rs7138803 was found to be not associated with common forms of obesity after adjusting for age and sex in the Chinese population. SNP rs7138803 was not associated with other obesity related traits, including T2DM, hypertension, lipid profiles, and ischemic stroke. Our data suggest that the rs7138803 exerts no significant effect on obesity in Chinese Han population. Larger cohorts may be more appropriate to detect an effect of this SNP on common obesity. 23633167 Kyphosis and decline in physical function over 15 years in older community-dwelling women: the study of osteoporotic fractures. Maintaining physical function is an important prerequisite for preserving independence in later life. Greater degrees of kyphosis in the thoracic spine are prevalent in older persons and accompanied by reduced physical function in multiple cross-sectional studies. It is unknown whether kyphosis predicts worse physical function over time. We retrospectively assessed whether greater magnitude of kyphosis is associated with decline in self-reported and objectively measured physical function over 15 years. Digitized Cobb angle kyphosis (T4-T12) was derived from supine lateral thoracic spine radiographs in a cohort of 1,196 women aged 65 and older (mean = 69.3 years [SD = 4.0]). Using regression models, we evaluated associations of baseline kyphosis with both self-reported functional status and objectively measured gait speed, grip strength, and timed chair stands cross-sectionally and as change assessed over 15 years. In cross-sectional multivariate analyses, with each 10-degree increment of kyphosis, grip strength was 0.24kg lower (p = .02), but there were no significant associations between kyphosis and functional status, gait speed, or timed chair stand, likely reflecting the high functioning study participants. In multivariate longitudinal analysis, with each 10-degree increment in baseline kyphosis, there was 0.07 point additional decline in functional status (p = .09), 0.01 m/s more decline in gait speed (p = .07), and 0.32 s greater decline in time to complete five chair stands (p = .004), but no association with decline in grip strength. Greater magnitude of kyphosis may predict worsening lower extremity function over time in older women. Early recognition and preventative measures against kyphosis progression may help preserve physical function over the long term. 23846063 Obesity, diabetes and periodontitis - a triangular relationship? The global rise of obesity, both adult and childhood, has been paralleled by a rise in type 2 diabetes, a trend predicted to continue for at least the next two decades. The combined effect will create a burden of direct and co-morbidities that will strain the physical and financial resources of all countries. While it is accepted that both type 1 and type 2 diabetes are major risk factors for the development and progression of periodontal disease, there is growing evidence that obesity is both an indirect risk factor because it affects glycaemic control and a direct risk factor because secretion of pro-inflammatory agents by adipose tissue modifies the periodontal reaction to the plaque biofilm. Recent research suggests that periodontitis may adversely affect glycaemic control, which can be improved by periodontal treatment with reduced risk of diabetic co-morbidity, thereby creating a two-way relationship. Furthermore it appears possible that periodontitis may stimulate inflammatory change in adipose tissue, creating a triangular self-generating cycle of morbidity linking obesity, diabetes and periodontal disease. Dentists should recognise these interlinked risk factors and consider including an assessment of glycaemic control and adiposity, possibly by waist-to-hip ratio, when periodontitis is diagnosed and in collaboration with medical practitioners provide treatment to help reduce the development of systemic disease. 23899572 Feasibility of anaerobic co-digestion of poultry blood with maize residues. The potential of anaerobic digestion for the treatment of poultry blood was evaluated in batch assays at laboratory scale and in a mesophilic semi-continuously fed digester. The biodegradability test performed on poultry blood waste showed a strong inhibition. Maize residues were used as co-substrate to overcome inhibition thanks to nitrogen dilution. Under batch operation, increasing the maize concentration from 15% to 70% (volatile solids (VS) basis) provided an increase of biogas from 130±31 to 188±21LCH4/kgVS. In the semi-continuous mesophilic anaerobic digester, the biogas yield was 165±17LCH4/kgVS fed, as a result of strong volatile fatty acid (VFA) accumulation. Although physical modifications of maize particles were observed by Scanning Electron Microscopy (SEM), an incomplete degradation was confirmed from analysis of digestates. Furthermore, Fourier Transform Infrared (FTIR) spectroscopy analysis demonstrated that along with VFA build-up, an accumulation of non-degraded materials took place. 22376270 Three new α-glucosidase inhibitors from guggul, the oleogum resin of Commiphora wightii. Three new compounds; epi-mukulin, (Z)-Δ(1,2) dehydroguggulsterone and Δ(6,7)dehydro-20-hydroxygugglsterone were isolated from the n-hexane-soluble fraction (HSF) of the methanol extract of guggul, the oleogum resin of Commiphora wightii together with six known compounds: diasesartemin, (+)-epi-magnolin, (+)-diayangambin, gugglsterol I, (E)-guggulsterone and (Z)-guggulsterone. Their structures were elucidated on the basis of different spectroscopic data. α-Glucosidase inhibitory effects of HSF and the isolated compounds were evaluated calorimetrically. The HSF showed significant α-glucosidase inhibitory effect [IC(50) value of 140 µg mL(-1) (p < 0.05)]. Under the assay conditions, diasesartemin (IC(50) = 60.6 ± 0.01 µM) was found to be more potent than the positive control, acarbose (IC(50) = 92.94 ± 0.01 µM); a known α-glucosidase inhibitor (p < 0.05). The IC(50) values of epi-mukulin and (Z)-guggulsterone were found to be 159.33 and 132.14 µM, respectively. Other compounds showed weak α-glucosidase inhibitory effects, <30% inhibition of the enzyme activity at 0.1 mg mL(-1). 23161561 A method for assessing causation of field exposure-response relationships. Because associations between agents and environmental effects are not necessarily causal, it is necessary to assess causation before using such relationships in environmental management. The authors adapted epidemiological methods to assess general causal hypotheses. General causation establishes that an agent is capable of causing an effect. The method uses all relevant and good-quality evidence in a weight-of-evidence system. The system is credible due to its explicit a priori criteria. The evidence is organized in terms of six characteristics of causation: co-occurrence, preceding causation, interaction, alteration, sufficiency, and time order. The causal assessment proceeds through six steps that generate, organize, and score evidence to determine whether causation is adequately supported by the body of evidence. 23941519 Attachment of Bacterial Pathogens to a Bacterial Cellulose-Derived Plant Cell Wall Model: A Proof of Concept. Abstract This study aimed to establish, as a proof of concept, whether bacterial cellulose (BC)-derived plant cell wall models could be used to investigate foodborne bacterial pathogen attachment. Attachment of two strains each of Salmonella enterica and Listeria monocytogenes to four BC-derived plant cell wall models (namely, BC, BC-pectin [BCP], BC-xyloglucan [BCX], and BC-pectin-xyloglucan [BCPX]) was investigated. Chemical analysis indicated that the BCPX composite (31% cellulose, 45.6% pectin, 23.4% xyloglucan) had a composition typical of plant cell walls. The Salmonella strains attached in significantly (p<0.05) higher numbers (∼6 log colony-forming units [CFU]/cm(2)) to the composites than the Listeria strains (∼5 log CFU/cm(2)). Strain-specific differences were also apparent with one Salmonella strain, for example, attaching in significantly (p<0.05) higher numbers to the BCX composite than to the other composites. This study highlights the potential usefulness of these composites to understand attachment of foodborne bacteria to fresh produce. 23942375 Coupling an universal primer to SBE combined spectral codification strategy for single nucleotide polymorphism analysis. We previously reported a strategy that combines Förster resonance energy transfer (FRET) based spectral codification with a single base extension (SBE) reaction for single nucleotide sequence discrimination in solution. This strategy is capable of unequivocally detect the allele variants present in solution. To extend the use of this tool to any locus of interest, it would be required the development of an universal approach capable of combining a sequence specific SBE primer to an universal sequence labeled and optimized for spectral codification. Here, we extend this concept to a general strategy by means of a labeled universal oligonucleotide primer (donor), a sequence specific primer that allows for incorporation of the complementary acceptor labeled ddNTP, which allows discrimination the allele variant in the sample via the unambiguous FRET signature of the donor/acceptor pair. 23621521 Small molecule mediated proliferation of primary retinal pigment epithelial cells. Retinal pigment epithelial (RPE) cells form a monolayer adjacent to the retina and play a critical role in the visual light cycle. Degeneration of this layer results in vision loss, causing retinal disorders such as age-related macular degeneration. Cell transplant therapies exist to restore vision loss; however, risks associated with and an inadequate supply of donor cells have limited their therapeutic success. The identification of factors that proliferate RPE cells ex vivo could provide a renewable source of cells for the treatment of such disorders. We show that a small molecule (WS3) can reversibly proliferate primary RPE cells isolated from fetal and adult human donors. Following withdrawal of WS3, RPE cells differentiate into a functional monolayer, as exhibited by their expression of mature RPE genes and phagocytosis of photoreceptor outer segments. Furthermore, chemically expanded RPE cells preserve vision when transplanted into dystrophic Royal College of Surgeons (RCS) rats, a well-established model of retinal degeneration. 22521499 Modulation of pyramidal cell output in the medial prefrontal cortex by mGluR5 interacting with CB1. The medial prefrontal cortex (mPFC) serves executive cognitive functions such as decision-making that are impaired in neuropsychiatric disorders and pain. We showed previously that amygdala-driven abnormal inhibition and decreased output of mPFC pyramidal cells contribute to pain-related impaired decision-making (Ji et al., 2010). Therefore, modulating pyramidal output is desirable therapeutic goal. Targeting metabotropic glutamate receptor subtype mGluR5 has emerged as a cognitive-enhancing strategy in neuropsychiatric disorders, but synaptic and cellular actions of mGluR5 in the mPFC remain to be determined. The present study determined synaptic and cellular actions of mGluR5 to test the hypothesis that increasing mGluR5 function can enhance pyramidal cell output. Whole-cell voltage- and current-clamp recordings were made from visually identified pyramidal neurons in layer V of the mPFC in rat brain slices. Both the prototypical mGluR5 agonist CHPG and a positive allosteric modulator (PAM) for mGluR5 (VU0360172) increased synaptically evoked spiking (E-S coupling) in mPFC pyramidal cells. The facilitatory effects of CHPG and VU0360172 were inhibited by an mGluR5 antagonist (MTEP). CHPG, but not VU0360172, increased neuronal excitability (frequency-current [F-I] function). VU0360172, but not CHPG, increased evoked excitatory synaptic currents (EPSCs) and amplitude, but not frequency, of miniature EPSCs, indicating a postsynaptic action. VU0360172, but not CHPG, decreased evoked inhibitory synaptic currents (IPSCs) through an action that involved cannabinoid receptor CB1, because a CB1 receptor antagonist (AM281) blocked the inhibitory effect of VU0360172 on synaptic inhibition. VU0360172 also increased and prolonged CB1-mediated depolarization-induced suppression of synaptic inhibition (DSI). Activation of CB1 with ACEA decreased inhibitory transmission through a presynaptic mechanism. The results show that increasing mGluR5 function enhances mPFC output. This effect can be accomplished by increasing excitability with an orthosteric agonist (CHPG) or by increasing excitatory synaptic drive and CB1-mediated presynaptic suppression of synaptic inhibition ("dis-inhibition") with a PAM (VU0360172). Therefore, mGluR5 may be a useful target in conditions of impaired mPFC output. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23965976 Homoserine lactones influence the reaction of plants to rhizobia. Bacterial quorum sensing molecules not only grant the communication within bacterial communities, but also influence eukaryotic hosts. N-acyl-homoserine lactones (AHLs) produced by pathogenic or beneficial bacteria were shown to induce diverse reactions in animals and plants. In plants, the reaction to AHLs depends on the length of the lipid side chain. Here we investigated the impact of two bacteria on Arabidopsis thaliana, which usually enter a close symbiosis with plants from the Fabaceae (legumes) family and produce a long-chain AHL (Sinorhizobium meliloti) or a short-chain AHL (Rhizobium etli). We demonstrate that, similarly to the reaction to pure AHL molecules, the impact, which the inoculation with rhizosphere bacteria has on plants, depends on the type of the produced AHL. The inoculation with oxo-C14-HSL-producing S. meliloti strains enhanced plant resistance towards pathogenic bacteria, whereas the inoculation with an AttM lactonase-expressing S. meliloti strain did not. Inoculation with the oxo-C8-HSL-producing R. etli had no impact on the resistance, which is in agreement with our previous hypothesis. In addition, plants seem to influence the availability of AHLs in the rhizosphere. Taken together, this report provides new insights in the role of N-acyl-homoserine lactones in the inter-kingdom communication at the root surface. 22082822 Ventilatory functions in cotton textile workers and the role of some inflammatory cytokines. Exposure to cotton dust in industrial environments causes inflammation in the airways of the exposed workers. This may manifest as respiratory complaints and changes in the respiratory functions after work shift and in the baseline of their ventilatory functions. The study aimed to investigate the effect of occupational exposure to cotton dust on respiratory symptoms, ventilatory functions and pro-inflammatory cytokine levels (tumor necrosis factor α, interleukin 6 and interleukin 1β). The study was conducted on 63 textile workers and 65 nonexposed subjects. Both groups were matched for age, socioeconomic status and smoking habit. The respirable dust measured in the workplace did not exceed the permissible values of the Egyptian law 1994. The bacterial counts detected were within the occupational exposure limits of the industrial settings. The results revealed that the percentage of respiratory symptoms was higher in textile workers. Respiratory complaints were chronic cough (33.2%), chronic bronchitis (39.7%) and dyspnea (23.8%) in textile workers compared to (6.2%, 6.2% and 1.5%), respectively, in controls. There was a marked reduction in the ventilatory functions (forced vital capacity and forced expiratory volume in 1 s) in the textile workers compared to the controls. The additive effect of smoking on the ventilatory functions was not apparent. The ventilatory functions of the workers were significantly positively correlated with the duration of exposure. The cytokines were insignificantly higher in the textile workers compared to their controls. The textile workers with respiratory complaints showed significant decline in ventilatory functions and elevation in the cytokine levels compared to the nonsymtomatizing workers with significant difference in interleukin 1β and interleukin 6. In conclusion, the results supported the fact that exposure to cotton dust deteriorates ventilatory functions and elevates proinflammatory cytokine levels. Analysis of the release of cytokines can be used to evaluate the immune responses to organic dust-induced airway inflammation. 23590343 Modelling C3 photosynthesis from the chloroplast to the ecosystem. Globally, photosynthesis accounts for the largest flux of CO2 from the atmosphere into ecosystems and is the driving process for terrestrial ecosystem function. The importance of accurate predictions of photosynthesis over a range of plant growth conditions led to the development of a C3 photosynthesis model by Farquhar, von Caemmerer & Berry that has become increasingly important as society places greater pressures on vegetation. The photosynthesis model has played a major role in defining the path towards scientific understanding of photosynthetic carbon uptake and the role of photosynthesis on regulating the earth's climate and biogeochemical systems. In this review, we summarize the photosynthesis model, including its continued development and applications. We also review the implications these developments have on quantifying photosynthesis at a wide range of spatial and temporal scales, and discuss the model's role in determining photosynthetic responses to changes in environmental conditions. Finally, the review includes a discussion of the larger-scale modelling and remote-sensing applications that rely on the leaf photosynthesis model and are likely to open new scientific avenues to address the increasing challenges to plant productivity over the next century. 23720272 Writing in dyslexia: product and process. Research on dyslexia has largely centred on reading. The aim of this study was to assess the writing of 13 children with and 28 without dyslexia at age 11 years. A programme for keystroke logging was used to allow recording of typing activity as the children performed a sentence dictation task. Five sentences were read aloud twice each. The task was to type the sentence as correctly as possible, with no time constraints. The data were analysed from a product (spelling, grammar and semantics) and process (transcription fluency and revisions) perspective, using repeated measures ANOVA and t-tests to investigate group differences. Furthermore, the data were correlated with measures of rapid automatic naming and working memory. Results showed that the group with dyslexia revised their texts as much as the typical group, but they used more time, and the result was poorer. Moreover, rapid automatic naming correlated with transcription fluency, and working memory correlated with the number of semantic errors. This shows that dyslexia is generally not an issue of effort and that cognitive skills that are known to be important for reading also affect writing. 23168113 Positive allosteric modulator of alpha 7 nicotinic-acetylcholine receptors, PNU-120596 augments the effects of donepezil on learning and memory in aged rodents and non-human primates. The development of novel therapeutic agents for disorders of cognition such as Alzheimer's disease (AD) is of paramount importance given the ever-increasing elderly population, however; there is also considerable interest in any strategy that might enhance the clinical efficacy of currently available treatments. The purpose of this study was to evaluate an adjunctive treatment strategy to memory enhancement, namely combining the commonly prescribed acetylcholinesterase inhibitor (AChEI) donepezil, with a positive allosteric modulator (PAM) of α7 nicotinic-acetylcholine receptors (α7-nAChRs), PNU-120596. The treatment strategy was evaluated in a (non-spatial) spontaneous novel object recognition (NOR) task in young rats; a water maze spatial learning and recall procedure in aged, cognitively-impaired rats, and a delayed match to sample (working/short term memory) task in aged rhesus monkeys. In all three experiments a similar drug response was observed, namely that donepezil administered alone improved task performance in a dose-dependent manner; that PNU-120596 administered alone was without significant effect, but that the combination of PNU-120596 with a subthreshold dose of donepezil was effective. The positive effect of the drug combination appeared to be α7-nAChR mediated given that it was blocked in the NOR task by the selective α7-nAChR antagonist methyllycaconitine (MLA). Collectively, these data indicate that PNU-120596 increases the effective dose range of donepezil in learning/memory-related tasks in young and age-impaired animal models. The results suggest that α7-nAChR-selective PAMs like PNU-120596 have potential as adjunctive treatments with acetylcholinesterase inhibitors (e.g., donepezil) for age-related illnesses such as AD as well memory disorders not necessarily associated with advanced age. 23485401 Orally bioavailable and brain-penetrant pyridazine and pyridine-derived γ-secretase modulators reduced amyloidogenic Aβ peptides in vivo. Accumulation of amyloid β (Aβ) in brain is a pathological hallmark of Alzheimer's disease (AD). Aβ is generated after sequential cleavage of its parental molecule, amyloid precursor protein (APP), by β- and γ-secretases. Inhibition of γ-secretase activity is an effective approach for the reduction of Aβ levels. Since γ-secretase targets many different substrates, selective inhibition of its cleavage of APP is believed to be critical in order to avoid undesirable side effects. γ-Secretase modulator (GSM) shifts the cleavage site on APP and production of amyloidogenic to non-amyloidogenic Aβ fragments. Since GSMs only modulate and do not block cleavage of γ-secretase substrates, they are believed less likely to produce untoward adverse reactions. Here, we report in vivo Aβ-lowering profiles of a pyridazine and a pyridine-derived GSM: GSM-C (Wan et al., 2011a) and GSM-D (Wan et al., 2011b). Both compounds reduced Aβ40 and Aβ42 productions, increased shorter Aβ fragments, and had little effect on Notch signaling (∼100-fold selective). They had excellent oral bioavailability (97.8% for GSM-C, ∼100% for GSM-D) and good brain permeability (free brain to free blood AUC ratio of 0.41 and 1.10 for GSM-C and GSM-D, respectively). Oral administration of these compounds in both acute and sub-chronic conditions reduced Aβ levels in plasma and brain in rats in a dose- and time-dependent manner. Therefore, GSM-C and GSM-D represent two GSMs that are orally bioavailable and brain-permeable. They could serve as excellent tools in the investigation of the role of Aβ peptides in AD pathogenesis. 23623950 Evolution of cooperation with similarity to an archetype. We use the framework of Colman with a Prisoner's Dilemma game and an evolutionary agent-based algorithm in order to study the evolution of cooperation and discrimination. We assume that players can discriminate on the basis of the phenotypic distance to an archetype, linked itself with a given behaviour in the game. However, we do not impose that the archetype corresponds to a conditionally cooperative behaviour. We show that cooperation can become the norm and discrimination can evolve spontaneously with no other assumption. For some archetypes, cooperation can even evolve faster and with more intensity than in the similarity-based case studied in Colman et al., 2012. 23910014 TNFα regulates sugar transporters in the human intestinal epithelial cell line Caco-2. During intestinal inflammation TNFα levels are increased and as a consequence malabsorption of nutrients may occur. We have previously demonstrated that TNFα inhibits galactose, fructose and leucine intestinal absorption in animal models. In continuation with our work, the purpose of the present study was to investigate in the human intestinal epithelial cell line Caco-2, the effect of TNFα on sugar transport and to identify the intracellular mechanisms involved. Caco-2 cells were grown on culture plates and pre-incubated during different periods with various TNFα concentrations before measuring the apical uptake of galactose, α-methyl-glucoside (MG) or fructose for 15min. To elucidate the signaling pathway implicated, cells were pre-incubated for 30min with the PKA inhibitor H-89 or the PKC inhibitor chelerythrine, before measuring the sugar uptake. The expression in the apical membrane of the transporters implicated in the sugars uptake process (SGLT1 and GLUT5) was determined by Western blot. TNFα inhibited 0.1mM MG uptake after pre-incubation of the cells for 6-48h with the cytokine and in the absence of cytokine pre-incubation. In contrast, 5mM fructose uptake was stimulated by TNFα only after long pre-incubation times (24 and 48h). These effects were mediated by the binding of the cytokine to its specific receptor TNFR1, present in the apical membrane of the Caco-2 cells. Analysis of the expression of the MG and fructose transporters at the brush border membrane of the cells, after 24h pre-incubation with the cytokine, revealed decrease on the amount of SGLT1 and increase on the amount of GLUT5 proteins. Short-term inhibition of MG transport by TNFα was not modified by H-89 but was blocked by chelerythrine. SGLT1 and GLUT5 expression in the plasma membrane is regulated by TNFα in the human epithelial cell line Caco-2 cells, leading to alteration on sugars transport, suggesting that TNFα could be considered as a physiological local regulator of nutrients absorption in response to an intestinal inflammatory status. 23876623 Clavicle and coracoid process drilling technique for truly anatomic coracoclavicular ligament reconstruction. High-grade acromioclavicular (AC) joint separations require surgical treatment, as conservative treatment may result in functional decline or persistent pain. Although many surgical techniques have been described in the literature, there is still no non-controversial gold standard procedure for AC joint dislocation. The different orientation of the two components of the coracoclavicular (CC) ligaments has been proven to account for different functions. However, the majority of the techniques reconstruct the CC ligaments with a single structure. The purposes of this study were to assess the feasibility of truly anatomic coracoclavicular ligament reconstruction (TACCR) and to determine the corresponding drilling parameter. We constructed virtual three-dimensional (3D) models of 105 shoulders from computed tomography (CT) scan data by using SuperImage software. For each model, the attachment sites and footprint dimensions of the conoid and trapezoid ligaments were defined and adjusted according to previously defined anatomic parameters and individual measurement results. Virtual drilling and 3D measurement were carried out in each model separately. Guided by the drilling parameter, we performed TACCR on 24 shoulders from 12 whole cadavers after transecting the AC and CC ligaments. The collinear drilling technique was noted to breach the bone cortex of the clavicle and/or the coracoid process in 95 of 105 virtual models (90.5%). No cortical breach was observed using a non-collinear drilling technique. The anteversion angulation of the conoid-coracoid tunnel ranged from 10° to 15° (mean value 12.4°). The extraversion angulation of the conoid-coracoid tunnel varied from 5° to 10° (mean value 6.8°). The anteversion angulation of the trapezoid-coracoid tunnel ranged from 20° to 30° (mean value 25.2°). There were no failures when performing the non-collinear drilling technique on cadaver models. The collinear drilling technique is not technically feasible for TACCR. For this reason, we recommend the non-collinear drilling technique, which provides the ability to prepare bony tunnels without any risk of cortical breach. Based on this computer and cadaver model study, we have devised a novel drilling technique to restore the CC ligaments anatomically. 23736089 Tracheal intubation in the ice-pick position with video laryngoscopes: A randomised controlled trial in a manikin. Tracheal intubation in nonstandardised positions is associated with a higher risk of tube misplacement and may have deleterious consequences for patients. Video laryngoscopes for tracheal intubation facilitate both glottic view and success rates. However, their use in the ice-pick position has not been evaluated. To evaluate the role of video laryngoscopes for tracheal intubation in the ice-pick position. A randomised, controlled manikin trial. A standardised airway manikin was placed in the corner of a room. Tracheal intubation was only possible from the lower right side of the manikin. In randomised order, participants used a standard Macintosh laryngoscope and GlideScope Ranger, Storz C-MAC, Pentax AWS, Airtraq and McGrath Series5 video laryngoscopes. Statistical analysis was performed using the Wilcoxon signed-rank and McNemar's tests; A P value of less than 0.05 was deemed statistically significant. Twenty anaesthesiologists, all emergency medicine board-certified. Time to first ventilation (primary); time to glottic view and confirmation of tube position (secondary). Successful ventilation was achieved most rapidly with the Macintosh laryngoscope (36.1 ± 13.4 s; reference method), followed by the Airtraq (38.4 ± 36.3 s; P = n.s.), Pentax AWS (51.6 ± 43.3 s; P = n.s.) and Storz C-Mac (62.7 ± 49.7 s; P = n.s.). The use of the GlideScope Ranger (79.8 ± 61.9 s, P = 0.01) and McGrath series5 (79.8 ± 58.5 s, P = 0.023) resulted in significantly longer times. When comparing overall intubation success, the rate of successful tracheal intubation was higher with the Airtraq than with the McGrath Series5 (P = 0.031; all others n.s.). The use of video laryngoscopes did not result in higher success rates or faster tracheal intubation in the ice-pick position when compared with conventional laryngoscopy in this manikin study. www.clinicaltrials.gov, NCT01210105. 23628949 Ethanolic extract of the Goldenseal, Hydrastis canadensis, has demonstrable chemopreventive effects on HeLa cells in vitro: Drug-DNA interaction with calf thymus DNA as target. This study tested chemotherapeutic potential of Hydrastis canadensis (HC) extract in HeLa cells in vitro, with emphasis on its drug-DNA interaction and apoptosis induction ability. Nuclear uptake of HC by DAPI, Ao/Eb staining and internucleosomal DNA damage by comet assay was studied through fluorescence microscopy. Possible changes in MMP and apoptotic signalling events were critically analyzed. Cell cycle progression studied through FACS and fragmented DNA through "TUNEL" assay were critically analyzed. RT-PCR studies were conducted for analyzing Cyt-C and Bax translocation in mitochondrial and cytosolic extracts, and Caspase 3 in whole cell lysate. Role of p53-mediated regulation of NF-κβ and TNF-α was elucidated by Western blot analysis. Data of CD and Tm profile of CT-DNA were analyzed. Overall results indicated anti-cancer potential of HC through its ability to induce apoptosis, and interaction with CT-DNA that changed structural conformation of DNA, proving HC to be a promising candidate for chemoprevention. 23831318 Distribution and concentrations of petroleum hydrocarbons associated with the BP/Deepwater Horizon Oil Spill, Gulf of Mexico. We examined the geographic extent of petroleum hydrocarbon contamination in sediment, seawater, biota, and seafood during/after the BP/Deepwater Horizon Oil Spill (April 20-July 15, 2010; 28.736667°N, -88.386944°W). TPH, PAHs, and 12 compound classes were examined, particularly C1-benzo(a)anthracenes/chrysenes, C-2-/C-4-phenanthrenes/anthracenes, and C3-naphthalenes. Sediment TPH, PAHs, and all classes peaked near Pensacola, Florida, and Galveston, Texas. Seawater TPH peaked off Pensacola; all of the above classes peaked off the Mississippi River, Louisiana and Galveston. Biota TPH and PAHs peaked near the Mississippi River; C-3 napthalenes peaked near the spill site. Seafood TPH peaked near the spill site, with PAHs and all classes peaking near Pensacola. We recommend that oil concentrations continued to be monitored in these media well after the spill has ceased to assist in defining re-opening dates for fisheries; closures should be maintained until hydrocarbon levels are deemed within appropriate limits. 23720016 High sensitivity piezomagnetic force microscopy for quantitative probing of magnetic materials at the nanoscale. Accurate scanning probing of magnetic materials at the nanoscale is essential for developing and characterizing magnetic nanostructures, yet quantitative analysis is difficult using the state of the art magnetic force microscopy, and has limited spatial resolution and sensitivity. In this communication, we develop a novel piezomagnetic force microscopy (PmFM) technique, with the imaging principle based on the detection of magnetostrictive response excited by an external magnetic field. In combination with the dual AC resonance tracking (DART) technique, the contact stiffness and energy dissipation of the samples can be simultaneously mapped along with the PmFM phase and amplitude, enabling quantitative probing of magnetic materials and structures at the nanoscale with high sensitivity and spatial resolution. PmFM has been applied to probe magnetic soft discs and cobalt ferrite thin films, demonstrating it as a powerful tool for a wide range of magnetic materials. 23737474 Apoptotic and proliferative defects characterize ocular development in a microphthalmic BMP model. Vision is critically dependent on ocular size, which is regulated by environmental and genetic factors. Mutation of human Growth and Differentiation Factor 6 (GDF6) or zebrafish gdf6a results in a spectrum of small eye phenotypes (microphthalmia, anophthalmia, and coloboma). However, current models do not explain their etiology fully. As such, analyses of apoptosis and cell cycle regulation were undertaken in a zebrafish gdf6a mutant. Microarray analysis was performed at 2 days after fertilization to uncover novel gdf6a-dependent cell cycle regulators. Altered expression of Gdf6a targets was confirmed by in situ hybridization, and resulting changes in cell proliferation were assessed by phosphohistone H3 immunohistochemistry. Analysis of apoptosis was evaluated through activated Caspase 3 immunohistochemistry and chemical inhibitors of cell death. Reduced numbers of retinal progenitor cells are observed at 24 hours post fertilization (hpf), resulting in microphthalmic eyes in gdf6a(-/-) embryos. At 28 hpf, a wave of apoptosis occurs; however, apoptosis inhibition does not rescue eye size, indicating a limited contribution. Mutants display altered proliferation and expression levels of cell cycle regulators, including members of the forkhead box i (foxi) transcription factor family expressed in the ciliary marginal zone. Notably, inhibition of foxi2 in gdf6a(-/-) embryos further reduces eye size. These data support a model whereby the gdf6a(-/-)-induced microphthalmia is based on early regulation of retinal progenitor cell number, and later by regulation of proliferation in the ciliary marginal zone. Foxi genes represent downstream effectors of Gdf6a function in the CMZ required for eye size determination. 23305400 Current progresses of novel natural products and their derivatives/ analogs as anti-Alzheimer candidates: an update. Alzheimer's disease (AD) is one of the most threatening diseases affecting the aged with high incidence. Though AD has been defined for more than 100 years, it is still incurable. The drugs clinically used for the treatment of this disease, such as acetylcholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonist, can only provide a limited therapeutic effect. The need of effective drugs has stimulated the search for new compounds with potential clinical utility. Natural products are rich and unexplored sources for discovering novel leading compounds. Currently, a great number of natural products have been found possessing anti-AD property counteracting different etiological factors of AD. This review will give an update demonstration on the novel anti-AD natural products and their derivatives/analogues, which have been divided into five subgroups according to their different action mechanisms: AChEIs, antioxidants, neuroprotective agents, monoamine oxidase (MAO) inhibitors, and tau hyperphosphorylation inhibitors. We put special emphasis on the findings in the past 5 years. Besides, the drug design strategy as well as the structure-activity relationship of the relevant compounds is also discussed when it is possible. 22797669 Rectifying behavior of charge transfer complexes of tetrakis(dimethylamino)ethene with acceptor molecules: a theoretical study. The effect of electric field induced electron transfer on the rectification properties of molecular rectifiers based on charge transfer complexes of tetrakis(dimethylamino)ethane (TDAE) with acceptor molecules was explored. The current-voltage curves and the rectification ratios (RR) for two different molecular rectifiers were obtained using a direct ab initio method at M06/LACVP(d) level of theory in the range from -2 to +2 V. The highest RR of 25.7 was determined for the complex of TDAE with 2-nitropyrene-4,5,9,10-tetraone at 0.5 V (D1), while another rectifier [complex of TDAE with 2,7-dimethyl nitropyrene-4,5,9,10-tetraone (D2)] showed a maximum RR of only 2.9 at 0.3 V. The electric field induced electron transfer occurring in D1 creates a one-way conducting channel consisting of two SOMOs involving the entire D1 complex. In the case of D2, no electron transfer occurs at the applied bias voltages due to the relatively high energy difference between HOMO and LUMO. 23967904 Reaction Field Analysis and Lipid Bilayer Location for Lipophilic Fluorophores. Environment polarity can cause changes in absorbance or emission maxima, for a given fluorophore. This is termed solvatochromism. In this study semiempirical models of solvatochromic shifts are used to predict their lipid bilayer location. Four reaction field models are analyzed and compared, to provide the most accurate prediction of fluorophore solvatochromic shifts using a modified version of the Lippert equation. For curcumin, the reaction field of Block and Walker gave the strongest agreement between experimental and predicted values (r = 0.978, p < 0.0001). For aluminum phthalocyanine disulfonic acid (AlPcS2), the reaction field of Wertheim, based on statistical mechanics, gave the best agreement (r = 0.951, p = 0.001) only when dispersion forces and solute polarizability are considered. The results of these models are correlated to the Dimroth-Reichardt ET(30) solvent polarity scale used by Frimer and colleagues. Using the model predicted values, curcumin is estimated to be 1-1.2 nm from the phospholipid-water interface, in the acyl chain region of the lipid bilayer. AlPcS2 is predicted to be 0.7-0.9 nm from the interface, at the fatty acid carbonyl. This investigation provides semiempirical methods to efficiently link fluorophore solvatochromic shifts to a location in the lipid bilayer via reaction field models. 23832918 Evaluation of a tissue-engineered bovine pericardial patch in paediatric patients with congenital cardiac anomalies: initial experience with the ADAPT-treated CardioCel(R) patch. OBJECTIVESThis study evaluated the safety, efficacy and clinical performance of the tissue-engineered ADAPT® bovine pericardial patch (ABPP) in paediatric patients with a range of congenital cardiac anomalies.METHODSIn this single-centre, prospective, non-randomized clinical study, paediatric patients underwent surgery for insertion of the ABPP. Primary efficacy measures included early (<30 day) morbidity; incidence of device-related complications; haemodynamic performance derived from echocardiography assessment at 6- and 12-month follow-up and magnetic resonance imaging findings in 10 randomly selected patients at 12 months. Secondary measures included device-handling characteristics; shape and sizing characteristics and perioperative implant complications. The Aristotle complexity scoring system was used to score the complexity level of all surgical procedures. Patients completing the 12-month study were eligible to enter a long-term evaluation study.RESULTSBetween April 2008 and September 2009, the ABPP was used in 30 paediatric patients. In the 30-day postoperative period, no graft-related morbidity was observed. In total, there were 5 deaths (2 in the 30-day postoperative period and 3 within the first 6 postoperative months). All deaths were deemed due to comorbid non-graft-related events. Echocardiography assessment at 6 and 12 months revealed intact anatomical and haemodynamically stable repairs without any visible calcification of the patch. Magnetic resonance imaging assessment in 10 patients at 12 months revealed no signs of calcification. Fisher's exact test demonstrated that patients undergoing more complex, higher risk surgical repairs (Aristotle complexity score >8) were significantly more likely to die (P = 0.0055, 58% survival compared with 100% survival for less complex surgical repairs). In 19 patients, echocardiographic data were available at 18-36 months with no evidence of device calcification, infection, thromboembolic events or device failure.CONCLUSIONSThis study demonstrates the safety and efficacy of this engineered bovine pericardial patch as a cardiovascular substitute for surgical repair of both simple and more complex congenital cardiac defects. 23665068 Specific detection and identification of [Actinobacillus] muris by PCR using primers targeting the 16S-23S rRNA internal transcribed spacer regions. [Actinobacillus] muris represents along with [Pasteurella] pneumotropica the most prevalent Pasteurellaceae species isolated from the laboratory mouse. Despite the biological and economic importance of Pasteurellaceae in relation to experimental animals, no molecular based methods for the identification of [A.] muris are available. The aim of the present investigation was to develop a PCR method allowing detection and identification of [A.] muris. In this assay, a Pasteurellaceae common forward primer based on a conserved region of the 16S rRNA gene was used in conjunction with two different reverse primers specific for [A.] muris, targeting the 16S-23S internal transcribed spacer sequences. The specificity of the assay was tested against 78 reference and clinical isolates of Pasteurellaceae, including 37 strains of [A.] muris. In addition, eight other mice associated bacterial species which could pose a diagnostic problem were included. The assay showed 100% sensitivity and 97.95% specificity. Identification of the clinical isolates was validated by ITS profiling and when necessary by 16S rRNA sequencing. This multiplex PCR represents the first molecular tool able to detect [A.] muris and may become a reliable alternative to the present diagnostic methods. 22712599 Calf foetal and early life nutrition on grazing conditions: metabolic and endocrine profiles and body composition during the growing phase. The aim of this study was to determine the effect of nutrition during foetal and lactation periods on calf growth and body composition, and their association with changes in metabolic and endocrine profiles during the calf first year of life on purebred (Hereford and Angus) and cross-bred (F1) dam offspring. Forty cross-bred calves and their dams (purebred - PU: Hereford and Angus, and cross-bred - CR: F1) were used in a randomized block design with a factorial arrangement of herbage allowance of native pastures (high: Hi-HA and low: Lo-HA), 4 vs. 2.5 kg dry matter/kg body weight (BW) and dam genotype (PU vs. CR). Calf BW and blood samples were collected monthly from birth to 380 ± 15 days of age, and body composition was estimated by the urea dilution technique at weaning (142 ± 15 days) and 380 days. Calf birthweight did not differ among groups but from birth to 380 days, and BW was reduced (p = 0.046) in Lo-PU offspring. Although Lo-CR calves achieved similar BW than Hi-PU and Hi-CR offspring, they showed an increased fat in detriment of lean tissue deposition. At birth, plasma total protein was less (p = 0.04), while plasma glucose, insulin or IGF-I tended or were greater (p < 0.072) in Hi-HA than Lo-HA calves. Greater (p < 0.03) plasma total protein and/or glucose concentrations during the first months of lactation were observed in CR offspring associated with the greater dam milk production. Although glucose concentrations did not differ among calf groups after weaning, plasma insulin was greater (p = 0.004) in Hi-PU than other groups at 380 days. Consistent with the reduced BW, Lo-PU offspring presented the lowest (p = 0.026) plasma IGF-I from birth to 380 days. Herbage allowance of native grasslands during calf foetal and lactation periods interacted with maternal heterosis to affect, in the short and/or long term, calf BW or body composition, and metabolic and endocrine profiles. 23845977 Surfactant Reduction of Cerebral Infarct Size and Behavioral Deficit in a Rat Model of Cerebrovascular Arterial Gas Embolism. Gas embolism occurs commonly in cardiac and vascular surgery, and decompression sickness. The goals of this study were to develop a new in vivo rat model of cerebrovascular arterial gas embolism and to determine the effects of exogenous surfactants on resultant brain infarct volume and accompanying long term neurological dysfunction using the model. Unilateral cerebral arterial gas embolism was induced in Sprague Dawley rats, including groups receiving intravenous Pluronic F-127 (PF-127) and Oxycyte perflourocarbon surfactant pretreatment. Magnetic resonance imaging was performed at 24 and 72 hours post embolism to determine infarct volume. The elevated body swing test (EBST), limb placement test, proprioception forelimb and hindlimb tests, whisker tactile test and Morris Water Maze test were performed to assess motor behavior, somatosensory deficit, and spatial cognitive function out to 29 days after embolization. A stable stroke model was developed with MRI examination revealing infarction in the ipsilateral cerebral hemisphere. Gas embolized rats had significant cognitive and sensorimotor dysfunction, including ~3-fold increase in Morris Water Maze latency time, ~20% left-sided biasing in EBST performance, 0.5 to 1.5 (mean) point score elevations in the proprioception and whisker tactile tests and 3 point (mean) elevation in the limb placement test, all of which were persistent throughout the postembolic period. Surfactant prophylaxis with either PF-127 or Oxycyte rendered stroke undetectable by MRI scanning and markedly reduced the postembolic deficits in both cognitive and sensorimotor performance in treated rats, with normalization of EBST and whisker tactile tests within 7 days. 22735770 Cognitive enhancement as a treatment for drug addictions. Drug addiction continues to be an important public health problem, with an estimated 22.6 million current illicit drug users in the United States alone. For many addictions, including cocaine, methamphetamine, and marijuana addiction, there are no approved pharmacological treatments. Behavioral treatments are effective but effects vary widely across individuals. Treatments that are effective across multiple addictions are greatly needed, and accumulating evidence suggests that one such approach may be pharmacological or behavioral interventions that enhance executive inhibitory control in addicts. Current evidence indicates that most forms of chronic drug use may be associated with significant cognitive impairments, especially in attention, working memory, and response inhibition functions. In some studies, these impairments predict poor treatment retention and outcome. A number of cognitive enhancing agents, including galantamine, modafinil, atomoxetine, methylphenidate, and guanfacine, have shown promising findings in human studies. Specific behavioral interventions, including cognitive remediation, also show promise. However, whether improvement of selective cognitive functions reduces drug use behavior remains to be determined. Cognitive enhancement to improve treatment outcomes is a novel strategy worthy of future research, as are related questions such as whether these approaches may be broadly beneficial to most addicts or best reserved for substance users with specific demonstrated cognitive impairments. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23942089 The Influence of Early Drinking Contexts on Current Drinking Among Adult Lesbian and Bisexual Women. Differences exist in alcohol-related outcomes across subgroups of sexual minority women. Likewise, stressors associated with coming out and living as lesbian or bisexual are hypothesized to be highly variable. Lesbians' and bisexual women's risks for hazardous drinking are explored in a 2006 NIAAA-funded interview study of women living in the Northeastern United States. The primary objective of the present study is to replicate and extend an earlier analysis of the relationship between early drinking contexts and current drinking outcomes of adult lesbians with a convenience sample that includes a subgroup of self-identified bisexual women. Potential differences in the early drinking contexts of these two groups of self-identified lesbian and bisexual women are also explored. Bivariate and multiple regression analyses are used to examine relationships between early drinking contexts and current drinking of a racially and age-diverse convenience sample of 145 adult lesbian (N = 94) and bisexually identified (N = 51) women. Consistent with previous research, patterns established while coming out have an enduring effect on drinking outcomes of lesbians; findings for bisexual women are inconclusive. Implications for research and practice are discussed. 23954580 Transmission of influenza A/H5N1 viruses in mammals. Highly pathogenic avian H5N1 influenza A viruses occasionally infect humans and cause severe respiratory disease and fatalities. Currently, these viruses are not efficiently transmitted from person to person, although limited human-to-human transmission may have occurred. Nevertheless, further adaptation of avian H5N1 influenza A viruses to humans and/or reassortment with human influenza A viruses may result in aerosol transmissible viruses with pandemic potential. Although the full range of factors that modulate the transmission and replication of influenza A viruses in humans are not yet known, we are beginning to understand some of the molecular changes that may allow H5N1 influenza A viruses to transmit via aerosols or respiratory droplets among mammals. A better understanding of the biological basis and genetic determinants that confer transmissibility to H5N1 influenza A viruses in mammals is important to enhance our pandemic preparedness. 23833292 Introduction to aortic stenosis. Aortic stenosis is perhaps the most common of all valvular heart diseases in the developed nations of the world. Once primarily caused by rheumatic fever, the most common pathogenesis today is an active inflammatory process with some features that are similar to atherosclerosis. Because of this shift, the age at onset of severe obstruction has changed from the sixth decade 50 years ago to the eighth decade in most individuals today. The onset of symptoms remains a key determinant of outcome, although the later age at onset may make it difficult to discern if aortic stenosis or other age-related comorbidities is the cause of the symptoms. Once symptoms of aortic stenosis develop, life expectancy is shortened to ≈3 years unless the mechanical obstruction to left ventricular outflow is relieved by aortic valve replacement. Traditionally performed during cardiac surgery, aortic valve replacement now may be performed safely and effectively using transcatheter techniques, potentially revolutionizing the approach to this potentially fatal disease. 23953956 Factor analysis in predominantly severe COPD: Identification of disease heterogeneity by easily measurable characteristics. The clinical and demographic variables defining the heterogeneity of chronic obstructive pulmonary disease (COPD) are unclear. A post-hoc analysis of five randomised studies in patients with a history of previous exacerbations examined the clinical and demographic characteristics describing moderate-to-very-severe COPD. Factor analysis was performed on all continuous baseline demographic and clinical data, without variable selection. Analyses were based on the full cohort and on stratifications by pack-years smoked, smoking status, gender, and comorbidities; patient exacerbation history was analysed in two of the five studies. 6162 COPD patients were evaluated (70% male; 40% current smokers; mean pre-bronchodilator forced expiratory volume in 1 s [FEV1] 35.2% predicted). Baseline clinical and demographic variables loaded differentially on six factors with minimal overlap, explaining 60.4% of the heterogeneity: 1) symptoms (cough, dyspnoea, sleep disturbance), health status, reliever use; 2) pre-bronchodilator FEV1, FEV1/forced vital capacity, morning peak expiratory flow (PEF), body mass index (BMI); 3) blood pressure; 4) age, months since first COPD symptoms; 5) PEF variability; 6) pulse, FEV1 reversibility. Most factors loaded similarly in stratified and exacerbation analyses. BMI loaded with reversibility in females, and with age and months since first COPD symptoms in ex-smokers. Exacerbations loaded to factor 6. Readily available data can explain ∼60% of COPD heterogeneity in a large dataset of predominantly severe COPD patients. Factors were robust over determinants of disease outcome; gender, smoking status, pack-years smoked, and comorbidities. The main factors were largely unchanged by adding exacerbations. Only BMI loaded to other factors. 23969488 Regional and socioeconomic disparities in the treatment of unruptured cerebral aneurysms in the USA: 2000-2010. The Institute of Medicine called attention to the pervasive differences in treatments and outcomes between ethnic groups. We sought to highlight the geographic and racial disparities in access to treatment for unruptured cerebral aneurysms. We performed a retrospective cohort study involving patients with unruptured cerebral aneurysms from 2000 to 2010, registered in the National Inpatient Sample (NIS) database. Primary outcomes were those patients receiving treatment and the ratio of untreated to treated aneurysms per state. The purpose of this study was to determine if there were geographic and racial disparities in access to treatment of unruptured cerebral aneurysms based on the NIS. Logistic regression and analysis of variance (ANOVA) techniques were used. There were 57 418 patients diagnosed with unruptured aneurysms (mean age 61.4 years, 70.5% females), with 18 231 undergoing treatment. Males (OR 0.67, 95% CI 0.64 to 0.71, p<0.0001), Asian (OR 0.88, 95% CI 0.81 to 0.96, p=0.003), Hispanic (OR 0.76, 95% CI 0.65 to 0.90, p=0.001), African American (OR 0.57, 95% CI 0.53 to 0.62, p<0.0001), and patients without insurance (OR 0.76, 95% CI 0.67 to 0.87, p<0.0001) were associated with decreased chance of treatment. The opposite was true for lower Charlson Comorbidity Index (OR 3.03, 95% CI 2.71 to 3.39, p<0.0001), coverage by Medicaid (OR 1.12, 95% CI 1.03 to 1.23, p=0.012), or private insurance (OR 1.92, 95% CI 1.80 to 2.04, p<0.0001), and lower income (OR 1.22, 95% CI 1.15 to 1.31, p<0.0001). Significant regional variability was observed among the different states (p=0.006, ANOVA), with Maryland being an outlier. Based on the NIS database, the rate of treatment of unruptured cerebral aneurysms varies according to sex, race, and region. 23624282 BSA adsorption on aliphatic and aromatic acid SAMs: investigating the effect of residual surface charge and sublayer nature. In this work, the influence of surface charge and layer rigidity on Bovin Serum Albumin (BSA) adsorption has been investigated. To this aim, Self Assembled Monolayers (SAMs) bearing terminal COOH or COO(-) groups were built on gold surfaces. The rigidity of the acid terminated SAMs was modified using either an aliphatic, mercaptoundecanoic acid (MUA), or an aromatic, mercaptobenzoic acid (MBA) thiol. X-Ray Photoelectron Spectroscopy (XPS), Polarization Modulation Reflection Absorption Infrared Spectroscopy (PM-RAIRS) and contact angle measurements, were used to deeply characterize the so-built layers. The surface charge was successfully modified by varying the pH of the rinsing solution. Indeed, COOH were the dominating species upon rinsing at pH 2 and COO(-) species dominated upon rinsing at pH 11. Rinsing at an intermediate pH, 5.5, led to the coexistence of both carboxylic and carboxylate moieties. The hydrophilic character of the surface was also found to depend on the rinsing pH, with a minimum after rinsing at intermediate pH. Using aromatic or aliphatic thiols did not affect the speciation but led to considerable differences in the hydrophilic character of these surfaces. Eventually, the adsorption of BSA on the acidic layers was investigated using PM-RAIRS. The results showed interesting differences between the charged layers. Thus, for both MUA and MBA -based SAMs, the amount of adsorbed proteins decreased when the amount of COO(-) on the surface increased. Interestingly, these effects were totally annihilated when the adsorption was carried out in PBS buffer. Moreover, for similar surface charges, the aromatic layers were able to bind higher amounts of proteins than the aliphatic ones. This work points out the key role of both surface charge and rigidity on protein adsorption. The influence of additional parameters, such as hydrophilicity and SAMs' rigidity is also established. 23445166 Development of an in vitro dendritic cell-based test for skin sensitizer identification. The sensitizing potential of chemicals is currently assessed using animal models. However, ethical and economic concerns and the recent European legislative framework triggered intensive research efforts in the development and validation of alternative methods. Therefore, the aim of this study was to develop an in vitro predictive test based on the analysis and integration of gene expression and intracellular signaling profiles of chemical-exposed skin-derived dendritic cells. Cells were treated with four known sensitizers and two nonsensitizers, and the effects on the expression of 20 candidate genes and the activation of MAPK, PI3K/Akt, and NF-κB signaling pathways were analyzed by real-time reverse transcription polymerase chain reaction and Western blotting, respectively. Genes Trxr1, Hmox1, Nqo1, and Cxcl10 and the p38 MAPK and JNK signaling pathways were identified as good predictor variables and used to construct a dichotomous classifier. For validation of the model, 12 new chemicals were then analyzed in a blind assay, and from these, 11 were correctly classified. Considering the total of 18 compounds tested here, 17 were correctly classified, representing a concordance of 94%, with a sensitivity of 92% (12 of 13 sensitizers identified) and a specificity of 100% (5 of 5 nonsensitizers identified). Additionally, we tested the ability of our model to discriminate sensitizers from nonallergenic but immunogenic compounds such as lipopolysaccharide (LPS). LPS was correctly classified as a nonsensitizer. Overall, our results indicate that the analysis of proposed gene and signaling pathway signatures in a mouse fetal skin-derived dendritic cell line represents a valuable model to be integrated in a future in vitro test platform. 23721732 Will plant movements keep up with climate change? In the face of anthropogenic climate change, species must acclimate, adapt, move, or die. Although some species are moving already, their ability to keep up with the faster changes expected in the future is unclear. 'Migration lag' is a particular concern with plants, because it could threaten both biodiversity and carbon storage. Plant movements are not realistically represented in models currently used to predict future vegetation and carbon-cycle feedbacks, so there is an urgent need to understand how much of a problem failure to track climate change is likely to be. Therefore, in this review, we compare how fast plants need to move with how fast they can move; that is, the velocity of climate change with the velocity of plant movement. 23727388 Suppression of cytochrome P450 reductase expression promotes astrocytosis in subventricular zone of adult mice. The aim of this study was to determine the role of NADPH-cytochrome P450 reductase (CPR) and CPR-dependent enzymes in neural stem cell (NSC) genesis in the brain. A mouse model with globally suppressed Cpr gene expression (Cpr-low mouse) was studied for this purpose. Cpr-low and wild-type (WT) mice were compared immunohistochemically for the expression of markers of cell proliferation (Ki67), immature neurons (doublecortin, DCX), oligodendrocytes (oligodendrocyte transcription factor 2, OLIG2), and astrocytes (glial fibrillary acidic protein, GFAP) in the SVZ, and for the in vitro capability of their SVZ cells to form neurospheres and differentiate into astrocytes. We found that the abundance of SVZ cells that are positive for Ki67 or GFAP expression, but not the abundance of SVZ cells that are positive for DCX and OLIG2 expression, was significantly increased in Cpr-low mice, at various ages, compared with WT mice. Furthermore, extents of astrocyte differentiation and growth, but not neurosphere formation, from SVZ cells of the Cpr-low mice were significantly increased, compared with WT mice. These results suggest that CPR and CPR-dependent enzymes play a role in suppressing astrocytosis in the SVZ of adult mice. 23549760 The International Per Oral Endoscopic Myotomy Survey (IPOEMS): a snapshot of the global POEM experience. Per oral endoscopic myotomy (POEM) represents a Natural Orifice Transluminal Endoscopic Surgery (NOTES) approach to Heller myotomy. Even though we are now entering an exponential phase of growth with a large number of centers interested in POEM, published data to guide them are limited. As part of the July 2012 NOSCAR meeting, a conference was organized to review POEM and develop a consensus document. Authors SNS and TS who chaired the NOSCAR panel recognized the dearth of published data, which also may lag the rapid developments in POEM. Therefore, they undertook a survey of early POEM adopters around the world to rapidly obtain global, extensive, and current data on POEM. The raw survey data were made available to NOSCAR panel participants to assist with their presentations. We summarize the salient findings of the survey. A comprehensive POEM survey was created and tested. The final survey instrument consisted of 197 questions that covered all aspects of POEM, including operator discipline, prior training, patient selection, setting, technique preference, results, adverse events, regulatory requirements, and perspectives on the future. An automated online response collector was used. The International Per Oral Endoscopic Myotomy Survey (IPOEMS) involved 16 expert centers, 7 in North America, 5 in Asia, 4 in Europe, including all high-volume centers (≥30 POEMs per center), as of July 2012. These centers had performed 841 POEMs. There were modest variations among centers in technique and periprocedural management, but all centers uniformly reported excellent efficacy and safety outcomes. The international POEM survey provides a "global snapshot" of the experience of early adopters. The excellent outcomes over a large cumulative volume of procedures are in line with those of published small series and lend further support to the notion that POEM represents a paradigm shift in the treatment of achalasia. 23266734 On the structure of aspongopusin recently isolated from Aspongopus chinensis. The 2,5-disubstituted oxazole recently proposed for aspongopusin, a natural product isolated from Aspongopus chinensis, was synthesized through an unambiguous route. The synthetic sample showed (1)H and (13)C NMR entirely different from those in the literature, revealing that the initially assigned structure was incorrect. The spectroscopic data for the given structure are thus made available for the first time. 23935411 On a family of multivariate modified humbert polynomials. This paper attempts to present a multivariable extension of generalized Humbert polynomials. The results obtained here include various families of multilinear and multilateral generating functions, miscellaneous properties, and also some special cases for these multivariable polynomials. 23846011 Neurological recovery after out-of-hospital cardiac arrest: hospital admission predictors and one-year survival in an urban cardiac network experience. Aim: The aim of the study was to detect early predictors of neurological recovery and evaluate one year survival related to neurological status at discharge in patients (pts) admitted after out of hospital cardiac arrest (OHCA). Methods: Sixty-three consecutive pts with OHCA from any cardiac cause, admitted to our cardiac intensive care unit, were classified according to survival and cerebral performance category (CPC) scale from 1 to 4 at hospital discharge. Pre-hospital and emergency room (ER) variables were analyzed to identify early predictors of neurological recovery as defined CPC=1-2. Results: Overall in-hospital survival was 60%. Sixty-eight and 32% of survivors were classified as CPC 1-2 and CPC 3-4 respectively. During one year follow-up 96% of patients classified as CPC 1-2 survived and 100% of CPC 3-4 died. Emergency crew witnessing, performance of cardio pulmonary resuscitation (CPR) by witnesses, the call for chest pain, no history of heart disease and a Glasgow coma scale (GCS) of ≥9 on arrival to the ER, were more frequent in patients classified as CPC 1-2 and times from "OHCA to return of spontaneous circulation (ROSC)", from "emergency medical system (EMS) arrival to ROSC" and "first DC shock to ROSC" were also significantly shorter in these patients. The time of first DC shock to ROSC in pts who presented with rhythm in ventricular fibrillation and the time from OHCA to ROSC in pts with witnessed OHCA were an independent predictors of neurological recovery. Conclusion: Forty-one percent of pts admitted to our tertiary centre after OHCA were discharged with CPC 1-2 and at one year follow-up 96% of these were alive, while all pts classified as CPC 3-4 died. Easily documented information such as the time from OHCA to ROSC and the time of first shock to ROSC are early independent predictors of neurological recovery. 23159663 Nano and microparticulate chitosan-based systems for antiviral topical delivery. Acyclovir (ACV) is one of the drugs of choice for the treatment of epidermal, ocular or systemic herpetic infections. Nevertheless, its trans-mucosal limited absorption and the scarce contact time of the formulation with the mucosal surface - especially in the ocular mucosa - constitute a big limitation of the antiviral efficiency. The most effective way to solve these problems is to increase the quantity and the residence time of the drug over the ocular surface. In order to cope with all these requirements, micro-particles (MPs) and nano-particles (NPs) containing ACV have been developed using cross-linked chitosan with tripolyphosphate (TPP) due to the biocompatibility, bio-adhesion ability and the potential power as penetration enhancer of this polymer. Particles were characterized by Fourier-transformed infrared (FTIR) spectroscopy, X-ray diffraction, SEM, Zeta potential and particle size. Encapsulation efficiency and release profiles in flow through diffusion cells were also determined. Besides the Slug Mucosal Irritation (SMI) assay has been applied as an alternative to the Draize test to predict the mucosal irritation of the selected formulation. FTIR and X-ray results suggested an electrostatic interaction ACV-Chitosan that made ACV be molecularly dispersed within the polymer matrix. Encapsulation efficiency was 75% for MP and 16% for NP. Release profiles in flow through diffusion cells were also determined. From the diffusion profiles, it was found that the amounts of ACV effectively diffused in 24h were 30, 430 and 80 μg for the ACV solution, MP and NP respectively. SMI results showed that chitosan-based particles induced moderate irritation and mild tissue damage, what supposes that ACV-MP constitute a promising alternative for further development of an antiviral formulation. 23873916 The effect of low Pbp2b levels on cell morphology and peptidoglycan composition in Streptococcus pneumoniae R6. Streptococcus pneumoniae produces two class B penicillin-binding proteins, Pbp2x and Pbp2b, both of which are essential. It is generally assumed that Pbp2x is specifically involved in septum formation, while Pbp2b is dedicated to peripheral cell wall synthesis. However, little experimental evidence exists to substantiate this belief. In the present study we have obtained evidence that strongly supports the view that Pbp2b is essential for peripheral peptidoglycan synthesis. Depletion of Pbp2b expression gave rise to long chains of cells in which individual cells were compressed in the direction of the long axis and looked lentil shaped. This morphological change is consistent with a role for pneumococcal Pbp2b in the synthesis of the lateral cell wall. Depletion of Pbp2x, on the other hand, resulted in lemon-shaped and some elongated cells with a thickened mid-cell region. Low Pbp2b levels gave rise to changes in the peptidoglycan layer that made pneumococci sensitive to exogenously added LytA during logarithmic growth, and refractory to chain dispersion upon addition of LytB. Interestingly, analysis of the cell wall composition of Pbp2b-depleted pneumococci revealed that they have a higher proportion of branched stem peptides in their peptidoglycan than the corresponding undepleted cells. Furthermore, MurM deficient mutants, i.e. mutants lacking the ability to synthesize branched muropeptides, were found to require much higher levels of Pbp2b to sustain growth than MurM proficient strains. These findings might help explain why increased incorporation of branched muropeptides is required for high-level beta-lactam resistance in S. pneumoniae. 23959426 A model of liver carcinogenesis originating from hepatic progenitor cells with accumulation of genetic alterations. Activation-induced cytidine deaminase (AID) contributes to inflammation-associated carcinogenesis through its mutagenic activity. In the present study, by taking advantage of the ability of AID to induce genetic aberrations, we investigated whether liver cancer originates from hepatic stem/progenitor cells that accumulate stepwise genetic alterations. For this purpose, hepatic progenitor cells enriched from the fetal liver of AID transgenic (Tg) mice were transplanted into recipient "toxin-receptor mediated conditional cell knockout" (TRECK) mice, which have enhanced liver regeneration activity under the condition of diphtheria toxin treatment. Whole exome sequencing was used to determine the landscape of the accumulated genetic alterations in the transplanted progenitor cells during tumorigenesis. Liver tumors developed in 7 of 11 (63.6%) recipient TRECK mice receiving enriched hepatic progenitor cells from AID Tg mice, while no tumorigenesis was observed in TRECK mice receiving hepatic progenitor cells of wild-type mice. Histologic examination revealed that the tumors showed characteristics of hepatocellular carcinoma and partial features of cholangiocarcinoma with expression of the AID transgene. Whole exome sequencing revealed that several dozen genes acquired single nucleotide variants in tumor tissues originating from the transplanted hepatic progenitor cells of AID Tg mice. Microarray analyses revealed that the majority of the mutations (>80%) were present in actively transcribed genes in the liver-lineage cells. These findings provided the evidence suggesting that accumulation of genetic alterations in fetal hepatic progenitor cells progressed to liver cancers, and the selection of mutagenesis depends on active transcription in the liver-lineage cells. © 2013 Wiley Periodicals, Inc. 23918971 Proper gibberellin localization in vascular tissue is required to regulate adventitious root development in tobacco. Bioactive gibberellins (GAs) are involved in many developmental aspects of the life cycle of plants, acting either directly or through interaction with other hormones. Accumulating evidence suggests that GAs have an important effect on root growth; however, there is currently little information on the specific regulatory mechanism of GAs during adventitious root development. A study was conducted on tobacco (Nicotiana tabacum) plants for altered rates of biosynthesis, catabolism, and GA signalling constitutively or in specific tissues using a transgenic approach. In the present study, PtGA20ox, PtGA2ox1, and PtGAI were overexpressed under the control of the 35S promoter, vascular cambium-specific promoter (LMX5), or root meristem-specific promoter (TobRB7), respectively. Evidence is provided that the precise localization of bioactive GA in the stem but not in the roots is required to regulate adventitious root development in tobacco. High levels of GA negatively regulate the early initiation step of root formation through interactions with auxin, while a proper and mobile GA signal is required for the emergence and subsequent long-term elongation of established primordia. The results demonstrated that GAs have an inhibitory effect on adventitious root formation but a stimulatory effect on root elongation. 23896193 Candidate Gene Analysis: Severe Intraventricular Hemorrhage in Inborn Preterm Neonates. Intraventricular hemorrhage (IVH) is a disorder of complex etiology. We analyzed genotypes for 7 genes from 224 inborn preterm neonates treated with antenatal steroids and grade 3-4 IVH and 389 matched controls. Only methylenetetrahydrofolate reductase was more prevalent in cases of IVH, emphasizing the need for more comprehensive genetic strategies. 23239882 Molecular insights into vesicle tethering at the Golgi by the conserved oligomeric Golgi (COG) complex and the golgin TATA element modulatory factor (TMF). Protein sorting between eukaryotic compartments requires vesicular transport, wherein tethering provides the first contact between vesicle and target membranes. Here we map and start to functionally analyze the interaction network of the conserved oligomeric Golgi (COG) complex that mediates retrograde tethering at the Golgi. The interactions of COG subunits with members of transport factor families assign the individual subunits as specific interaction hubs. Functional analysis of selected interactions suggests a mechanistic tethering model. We find that the COG complex interacts with two different Rabs in addition to each end of the golgin "TATA element modulatory factor" (TMF). This allows COG to potentially bridge the distance between the distal end of the golgin and the target membrane thereby promoting tighter docking. Concurrently we show that the central portion of TMF can bind to Golgi membranes that are liberated of their COPI cover. This latter interaction could serve to bring vesicle and target membranes into close apposition prior to fusion. A target selection mechanism, in which a hetero-oligomeric tethering factor organizes Rabs and coiled transport factors to enable protein sorting specificity, could be applicable to vesicle targeting throughout eukaryotic cells. 23415892 ADAM17, shedding, TACE as therapeutic targets. ADAM17 has been molecularly cloned as the enzyme responsible for cleavage of the transmembrane protein TNFα (TNFα converting enzyme, TACE). Later it was realized that ADAM17 was also responsible for the processing of cell adhesion proteins, cytokine and growth factor receptors and many ligands of the EGF receptor. Since TNFα is a target of anti-inflammatory therapies, it was speculated that inhibition of ADAM17 might be a therapeutic strategy in the treatment of inflammation or inflammation associated cancer. Meanwhile it has been recognized that ADAM17 governs many vital functions in the body and loss of ADAM17 leads to severe defects in the skin and to high susceptibility of the intestine to inflammation. Here I summarize data on the physiologic role of ADAM17 and the feasibility of specific blockade of this enzyme. 23821577 Outcomes in children under 12 months of age undergoing adenotonsillectomy for sleep-disordered breathing. To evaluate the incidence, safety, and efficacy of adenotonsillectomy for the treatment of sleep-disordered breathing (SDB) or obstructive sleep apnea (OSA) in infants 12 months of age and younger. Case series study. A retrospective review was performed of pediatric patients, 12 months of age or younger, who underwent adenotonsillectomy between January 1, 2006 and May 18, 2012 at a tertiary-care children's hospital. Only 25 patients were identified. Most of the patients were male, with an average age of 10.6 months. All of the patients were admitted to the pediatric intensive care unit (PICU) postoperatively. The average length of stay was 2.7 days (range, 1-9 days). Twelve patients were otherwise healthy infants, whereas 13 had significant comorbid conditions. Adenotonsillectomy was successful in treating OSA/SDB in all of the otherwise healthy patients and less effective in patients who had comorbid conditions (38.5%) (P = .002). Postoperative complications occurred in three of the 12 otherwise healthy patients, and in four of the 13 patients with comorbid conditions. Adenotonsillectomy in infants under 12 months old is uncommonly performed, but is more effective in treating OSA/SDB in patients who are healthy than in those with comorbid conditions. Postoperative PICU monitoring is recommended given that the risks of postoperative complications in this young age group is high (28%) and often related to perioperative oxygen requirements. Patients should also be counseled about the potential for symptomatic adenoid regrowth, for which revision adenoidectomy may be indicated. 4. Laryngoscope, 2012. 23809979 Bone graft materials in fixation of orthopaedic implants in sheep. Bone graft is widely used within orthopaedic surgery especially in revision joint arthroplasty and spine fusion. The early implant fixation in the revision situation of loose joint prostheses is important for the long-term survival. Bone autograft has been considered as gold standard in many orthopaedic procedures, whereas allograft is the gold standard by replacement of extensive bone loss. However, the use of autograft is associated with donor site morbidity, especially chronic pain. In addition, the limited supply is a significant clinical challenge. Limitations in the use of allograft include the risk of bacterial contamination and disease transmission as well as non-union and poor bone quality. Other bone graft and substitutes have been considered as alternative in order to improve implant fixation. Hydroxyapatite and collagen type I composite (HA/Collagen) have the potential in mimicking skeletal bones. The osteoconductive properties of the composite might be improved by adding bone marrow aspirate (BMA), which can be harvested during surgery. Other alternatives to bone graft are demineralised bone matrix (DBM) and human cancellous bone (CB). DBM is prepared by acid extraction of human bone and includes bone collagen, morphogenetic proteins and growth factors. The combination of DBM with CB and with allograft might improve the healing potential of these grafts around non-cemented orthopaedic implants and thereby the implant fixation. Study I investigates the effect of HA/Collagen composite alone and in combination with BMA on the early fixation of porous coated titanium implants. In addition, the study compares also the effect of autograft with the gold standard allograft. By using a sheep model, the implants were inserted in the trabecular bone of femoral condyles. The test biomaterials were placed in a well defined peri-implant gap. After the observation period, the bone-implant specimens were harvested and evaluated mechanically by a destructive push-out test and analyzed histologically qualitatively and quantitatively. Study II investigates the effect of DBM alone and in combination with CB or allograft. The control group in study I and II was allograft. Study III is a methodological study and investigates the potential systematic bias by applying the traditional sampling method, which includes evaluating the mechanical fixation by using the superficial part and the histological analysis by using the profound part of the implant. The implants in this study were inserted in the proximal humerus and only allograft was used in the peri-implant gap. In study I, the mechanical testing showed failure by the preloading in the composite group with and without BMA. There were no bone ongrowth and sparely bone formation in the gap by the composite group. Adding BMA to the composite has no beneficial effect on implant fixation. No significant difference between autograft and allograft on mechanical fixation, bone ongrowth and bone formation. In study II the combination of DBM with CB or allograft showed no significant differences on the mechanical testing and histological analysis to the control group, whereas DBM alone showed significant low mechanical fixation, low bone ongrowth and low bone formation. Study III showed no significant difference between the sampling methods. In conclusion, HA/Collagen composite alone or in combination with BMA has no effect on the early fixation of porous coated titanium implants. Autograft has comparable effect on allograft with regard to early implant fixation. The combination of DBM with CB may represent an alternative to allograft. In study III, mechanical testing and histological analysis can be applied either from the superficial or the profound part of the implant. By applying the histological analysis from the superficial part and the mechanical testing from the profound part, an extra section is required. 23542040 Anti-inflammatory and antioxidant properties of hydroalcoholic crude extract from Casearia sylvestris Sw. (Salicaceae). ETHNOPHARMACOLOGICAL RELEVANCE: Casearia sylvestris Sw. is widely used in popular medicine to treat inflammatory conditions. AIM OF THE STUDY: To investigate the anti-inflammatory and antioxidant properties of hydroalcoholic crude extract (HCE) taken from Casearia sylvestris Sw. (Salicaceae). METHODS AND RESULTS: The effect of the HCE from this plant (3-300mg/kg) on the reduction of inflammatory response to carrageenan was investigated in pleurisy in rats (intrapleural, 2% in 0.2mL) or paw edema in mice (intraplantar, 300μg/20μL, right hind paw). The plant anti-inflammatory action was assessed by its capability in inhibiting cell migration, enzymatic activity of myeloperoxidase (MPO) and production of nitrite/nitrate or edema. The in vitro antioxidant activity of this extract against lipid peroxidation and damage to proteins was assessed as possible pathways to contribute as anti-inflammatory mechanisms. Carrageenan-induced hind paw edema (739.3±11.9μm) was reduced by HCE (30mg/kg: 462.8±28.38μm) to similar extents as dexametasone (365.1±16.7). In pleurisy, treatment of the animals with HCE (100mg/kg: 0.010±0.001mU/mg of protein) also reduced MPO activity augmented by carrageenan (0.020±0.001mU/mg of protein) as well as leukocytes migration (carrageenan: 17.8890±2.3900leukocytes/mL, HCE 100mg/kg: 7.0880±9631leukocytes/mL). Significant effects were also observed in animals treated with different doses of HCE in biochemical tests for oxidative stress analysis. CONCLUSION: The anti-inflammatory and antioxidant effects of HCE from Casearia sylvestris Sw. suggests a potential therapeutic benefit of this plant in treatment of inflammatory conditions. 23887831 Reperfusion therapy and mortality in octogenarian STEMI patients: results from the Belgian STEMI registry. Treatment strategies and outcome of ST-elevation myocardial infarction (STEMI) have been mainly studied in middle-aged patients. With increasing lifetime expectancy, the proportion of octogenarians will substantially increase. We aimed to evaluate whether the benefit of currently recommended reperfusion strategies is maintained in octogenarians. Reperfusion therapy and in-hospital mortality were evaluated in 1,092 octogenarians and compared with 7,984 STEMI patients <80 years old based on data from the prospective Belgian STEMI registry. The octogenarian STEMI group had more cardiovascular comorbidities, contained more female patients and presented more frequently with cardiac failure (Killip class >1, 40 vs. 20 %) compared with their younger counterparts (all p < 0.05). Although the rate of thrombolysis was similar (9.2 vs. 9.9 %) between both groups, a conservative approach was chosen more frequently (13.8 vs. 4.7 %), while PCI was performed less frequently (76.9 vs. 85.4 %) in octogenarians (p < 0.001). Moreover, ischemic time and door-to-needle/balloon time were longer for octogenarians. In-hospital mortality for octogenarians was 17.8 vs. 5.5 % in the younger group [adjusted OR 2.43(1.92-3.08)]. In haemodynamically stable octogenarians, PCI seemed to improve outcome compared with thrombolysis or conservative treatment (5.7 vs. 12.7 vs. 8.5 %, p = 0.09). In octogenarians with cardiac failure, in-hospital mortality was extremely high independent of the chosen reperfusion therapy (34.6 vs. 31.6 vs. 36.3 %, p = 0.88). In-hospital mortality in octogenarian STEMI patients was high and related to a high prevalence of cardiac failure. Less PCI was performed in the octogenarian group compared with the younger patients, although mortality benefit of PCI was maintained in haemodynamically stable octogenarians. 23887947 The common duct dilates after cholecystectomy and with advancing age: reality or myth? Objectives- To evaluate changes in the common duct diameter on sonography over time in patients with and without cholecystectomy. Methods- We retrospectively evaluated the common duct diameter, central biliary dilatation, and interval change in 1079 patients who underwent sonography at least 2 years apart over a 6-year period. A board-certified radiologist, blinded to clinical and laboratory data, measured the duct diameter. A total of 893 patients (568 female and 325 male) were divided into 3 groups: group 1, remote cholecystectomy before sonography (mean, 9.7 years before sonography; n = 117); group 2, interval cholecystectomy between the first and second sonographic examinations (n = 56); and group 3, no cholecystectomy (n = 720). All groups were stratified by age, and group 3 was also stratified by the absence (n = 528) or presence (n=192) of gallstones. Results- Duct diameters at baseline and follow-up averaged 4.5 and 5.2, 3.6 and 4.9, and 3.5 and 3.9 mm in groups 1, 2, and 3, respectively. Group 1 ducts were larger at baseline than in the other groups (P < .001). At follow-up, group 2 ducts showed a greater interval diameter increase than the other groups (P < .001). In a subanalysis of each group based on age, there was a mild increase in duct size with increasing age, although not clinically significant and within normal limits. In group 3 patients who never had gallstones, there was a significant small increase in duct size over decades (P < .001). The baseline duct sizes for patients with gallstones were not significantly different from those who never had gallstones (P = .15). Conclusions- Patients with remote cholecystectomy have larger common duct diameters than those with no or interval cholecystectomy. Most asymptomatic patients with or without cholecystectomy have a normal common duct diameter. 23117175 Microwave assisted solid phase synthesis of highly functionalized N-alkylated oligobenzamide α-helix mimetics. Protein-protein interactions (PPIs) mediate cellular pathways and are implicated in numerous aberrant conditions. α-Helix mimetics-small molecules that reproduce the spatial projection of key residues from an α-helix involved in a PPI-are attractive generic templates for development of screening libraries, however library syntheses of α-helix mimetics with diverse functionality are less established. This manuscript describes the automated, microwave assisted solid phase synthesis based on one such scaffold; an N-alkylated oligobenzamide. 23272971 Multidisciplinary approach to patient with malignant melanoma. The incidence of melanoma is rapidly increasing worldwide and the prognosis of patients with metastatic disease is still poor, with a median survival of 8-9 months and a 3-year overall survival (OS) rate less than 15% [1,2]. A complete surgical excision is the main treatment for primary cutaneous melanoma [3], but controversies about the extension of excision margins still remain [4]. Sentinel lymph node biopsy (SLNB) provides important prognostic and staging data by the identification of regional node-negative patients who would not benefit from a complete nodal dissection. However, there is no consensus in the definition of melanoma thickness to enforce the execution of the SLNB [5]. To date, Interferon-α (IFN-α)is the only approved adjuvant treatment after surgical excision of high-risk melanoma, but its indication remains still controversial [2,6]. 23838925 Neoadjuvant Chemotherapy with Gemcitabine and S-1 for Resectable and Borderline Pancreatic Ductal Adenocarcinoma: Results from a Prospective Multi-institutional Phase 2 Trial. Surgical resection is the only curative strategy for pancreatic ductal adenocarcinoma (PDAC), but recurrence rates are high even after purported curative resection. First-line treatment with gemcitabine and S-1 (GS) is associated with promising antitumor activity with a high response rate. The aim of this study was to assess the feasibility and efficacy of GS in the neoadjuvant setting. In a multi-institutional single-arm phase 2 study, neoadjuvant chemotherapy (NAC) with gemcitabine and S-1, repeated every 21 days, was administered for two cycles (NAC-GS) to patients with resectable and borderline PDAC. The primary end point was the 2-year survival rate. Secondary end points were feasibility, resection rate, pathological effect, recurrence-free survival, and tumor marker status. Of 36 patients enrolled, 35 were eligible for this clinical trial conducted between 2008 and 2010. The most common toxicity was neutropenia in response to 90 % of the relative dose intensity. Responses to NAC included radiological tumor shrinkage (69 %) and decreases in CA19-9 levels (89 %). R0 resection was performed for 87 % in resection, and the morbidity rate (40 %) was acceptable. The 2-year survival rate of the total cohort was 45.7 %. Patients who underwent resection without metastases after NAC-GS (n = 27) had an increased median overall survival (34.7 months) compared with those who did not undergo resection (P = 0.0017). NAC-GS was well tolerated and safe when used in a multi-institutional setting. The R0 resection rate and the 2-year survival rate analysis are encouraging for patients with resectable and borderline PDAC. 23358196 Integrative Analysis of miRNA and inflammatory gene expression after acute particulate matter exposure. MicroRNAs (miRNAs) are environmentally sensitive inhibitors of gene expression that may mediate the effects of metal-rich particulate matter (PM) and toxic metals on human individuals. Previous environmental miRNA studies have investigated a limited number of candidate miRNAs and have not yet evaluated the functional effects on gene expression. In this study, we wanted to identify PM-sensitive miRNAs using microarray profiling on matched baseline and postexposure RNA from foundry workers with well-characterized exposure to metal-rich PM and to characterize miRNA relations with expression of candidate inflammatory genes. We applied microarray analysis of 847 human miRNAs and real-time PCR analysis of 18 candidate inflammatory genes on matched blood samples collected from foundry workers at baseline and after 3 days of work (postexposure). We identified differentially expressed miRNAs (fold change [FC] > 2 and p < 0.05) and correlated their expression with the inflammatory associated genes. We performed in silico network analysis in MetaCore v6.9 to characterize the biological pathways connecting miRNA-mRNA pairs. Microarray analysis identified four miRNAs that were differentially expressed in postexposure compared with baseline samples, including miR-421 (FC = 2.81, p < 0.001), miR-146a (FC = 2.62, p = 0.007), miR-29a (FC = 2.91, p < 0.001), and let-7g (FC = 2.73, p = 0.019). Using false discovery date adjustment for multiple comparisons, we found 11 miRNA-mRNA correlated pairs involving the 4 differentially expressed miRNAs and candidate inflammatory genes. In silico network analysis with MetaCore database identified biological interactions for all the 11 miRNA-mRNA pairs, which ranged from direct mRNA targeting to complex interactions with multiple intermediates. Acute PM exposure may affect gene regulation through PM-responsive miRNAs that directly or indirectly control inflammatory gene expression. 23861274 Fountain of steroid from an ectopic ACTH-producing tumour. This case is of a 39-year-old Filipino woman who within 2 months developed, Cushing's features she had no known comorbidities and no history of steroid intake. The patient also presented with hyperpigmentation of knuckles and toes, metabolic alkalosis and persistent hypokalaemia noted as proximal muscle weakness. The patient was referred to our institution for acutely worsening behavioural and psychiatric changes. Work-up for endogenous Cushing's syndrome revealed a significant adrenocorticotropic hormone production from an ectopic source. Further imaging was requested to locate the tumour, but the patient eventually succumbed to the drastic complications of hypercortisolism. On autopsy, the patient was found to have an ectopic well-differentiated neuroendocrine tumour located at the pancreatic head with metastasis to the right hepatic lobe. 23628374 Symptom severity predicts prolonged recovery after sport-related concussion, but age and amnesia do not. To identify predictors of prolonged symptoms in athletes who sustain concussions. This was a multicenter prospective cohort study of patients in 2 sport concussion clinics. Possible predictors of prolonged symptoms from concussion were compared in 2 groups, those whose symptoms resolved within 28 days and those whose symptoms persisted beyond 28 days. Candidate predictor variables were entered into a logistic regression model that was used to generate aORs. A total of 182 patients met the inclusion criteria during the study period. The mean patient age was 15.2 ± 3.04 years. More than one-third of the patients (n = 65) underwent computerized neurocognitive testing on their initial visit. On univariate analyses, Post-Concussion Symptom Scale (PCSS) score and all composite scores on computerized neurocognitive testing were apparently associated with prolonged symptom duration. Sex, age, loss of consciousness at time of injury, and amnesia at time of injury were not associated with prolonged symptom duration. After adjusting for potential confounding, only total PCSS score was associated with the odds of suffering prolonged symptoms. Further efforts to develop clinical tools for predicting which athletes will suffer prolonged recoveries after concussion should focus on initial symptom score. 23881223 HIV enteropathy: HAART reduces HIV-induced stem cell hyperproliferation and crypt hypertrophy to normal in jejunal mucosa. To analyse the structural and kinetic response of small intestinal crypt epithelial cells including stem cells to highly active antiretroviral therapy (HAART). Crypt size and proliferative activity of transit and stem cells in jejunal mucosa were quantified using morphometric techniques. Crypt length was measured by counting the number of enterocytes along one side of a number of crypts in each biopsy specimen and the mean crypt length was calculated. Proliferating crypt cells were identified with MIB-1 monoclonal antibody, and the percentage of crypt cells in proliferation was calculated at each cell position along the length of the crypt (proliferation index). Data were obtained from 9 HIV-positive test patients co-infected with microsporidia, 34 HIV-positive patients receiving HAART and 13 control cases. Crypt length was significantly greater in test patients than in controls, but crypt length in patients receiving HAART was normal. The proliferation index was greater in test subjects than in controls in stem and transit cell compartments, and was decreased in patients treated with HAART only in the stem cell region of the crypt. Villous atrophy in HIV enteropathy is attributed to crypt hypertrophy and encroachment of crypt cells onto villi. HAART restores normal crypt structure by inhibition of HIV-driven stem cell hyperproliferation at the crypt bases. 23806577 Mortality in persons with mental disorders is substantially overestimated using inpatient psychiatric diagnoses. Mental disorders are associated with premature mortality, and the magnitudes of risk have commonly been estimated using hospital data. However, psychiatric patients who are hospitalized have more severe illness and do not adequately represent mental disorders in the general population. We conducted a national cohort study using outpatient and inpatient diagnoses for the entire Swedish adult population (N = 7,253,516) to examine the extent to which mortality risks are overestimated using inpatient diagnoses only. Outcomes were all-cause and suicide mortality during 8 years of follow-up (2001-2008). There were 377,339 (5.2%) persons with any inpatient psychiatric diagnosis, vs. 680,596 (9.4%) with any inpatient or outpatient diagnosis, hence 44.6% of diagnoses were missed using inpatient data only. When including and accounting for prevalent psychiatric cases, all-cause mortality risk among persons with any mental disorder was overestimated by 15.3% using only inpatient diagnoses (adjusted hazard ratio [aHR], 5.89; 95% CI, 5.85-5.92) vs. both inpatient and outpatient diagnoses (aHR, 5.11; 95% CI, 5.08-5.14). Suicide risk was overestimated by 18.5% (aHRs, 23.91 vs. 20.18), but this varied widely by specific disorders, from 4.4% for substance use to 49.1% for anxiety disorders. The sole use of inpatient diagnoses resulted in even greater overestimation of all-cause or suicide mortality risks when prevalent cases were unidentified (∼20-30%) or excluded (∼25-40%). However, different methods for handling prevalent cases resulted in only modest variation in risk estimates when using both inpatient and outpatient diagnoses. These findings have important implications for the interpretation of hospital-based studies and the design of future studies. 23410153 Targeting the akt kinase to modulate survival, invasiveness and drug resistance of cancer cells. The deregulation of oncogenic signaling pathways which provide survival advantages to tumor cells is mediated by multiple cellular networks. Among them, the PI3K-Akt-mTOR axis, in particular the serine/threonine kinase Akt, is recognized as a key player. The kinase is hyperactivated due to a variety of mechanisms including loss of PTEN, mutations in the PI3K catalytic subunit, receptor tyrosine kinase and Ras activation. Indeed, inappropriate activation of the Akt kinase is a common event in human tumors and Akt appears to be a critical player in cell survival that may also account for the therapeutic resistance and the invasive phenotype of tumors. Inhibition of Akt signalling results in apoptosis and growth inhibition of tumour cells with elevated Akt activity. A functional role in drug resistance is supported by evidence that tumor cells with acquired resistance to antitumor agents may display increased Akt activation and that treatment with molecularly targeted agents can activate feed-back loops involving Akt. This serine/threonine kinase may therefore represent an amenable target for modulation of sensitivity to compounds with different molecular features due to its pleiotropic role in cell survival. Different types of Akt inhibitors [i.e., ATP mimetics and pleckstrin-homology (PH) domain binders] have been generated and some of them have reached the clinical setting. The present review focuses on the i) mechanisms implicating Akt in increased survival and invasive potential of tumor cells of different tumor types and ii) on the development of Akt inhibitors as modulators of drug resistance. 23831272 A model for intracellular actin waves explored by nonlinear local perturbation analysis. Waves and dynamic patterns in chemical and physical systems have long interested experimentalists and theoreticians alike. Here we investigate a recent example within the context of cell biology, where waves of actin (a major component of the cytoskeleton) and its regulators (nucleation promoting factors, NPFs) are observed experimentally. We describe and analyze a minimal reaction diffusion model depicting the feedback between signalling proteins and filamentous actin (F-actin). Using numerical simulation, we show that this model displays a rich variety of patterning regimes. A relatively recent nonlinear stability method, the Local Perturbation Analysis (LPA), is used to map the parameter space of this model and explain the genesis of patterns in various linear and nonlinear patterning regimes. We compare our model for actin waves to others in the literature, and focus on transitions between static polarization, transient waves, periodic wave trains, and reflecting waves. We show, using LPA, that the spatially distributed model gives rise to dynamics that are absent in the kinetics alone. Finally, we show that the width and speed of the waves depend counter-intuitively on parameters such as rates of NPF activation, negative feedback, and the F-actin time scale. 23503440 A child exposed to primidone not prescribed for her. A 7.5-year-old girl who was treated with phenobarbital (PHB) for epilepsy was admitted with decreased levels of consciousness. She had been known to have high PHB levels of unknown cause, without symptoms. Her PHB levels were very high, as expected, but primidone levels were also detected although she and her parents denied history of primidone administration. We wished to rule out intentional unprescribed use of primidone. Our retrospective review showed 3 other children with high PHB concentrations where primidone was also detected when PHB levels were over 130 μmol/L. Complementary studies confirmed that high-dose PHB can convert to its prodrug primidone, which has not been reported previously. 23935947 The critical period hypothesis in second language acquisition: a statistical critique and a reanalysis. In second language acquisition research, the critical period hypothesis (cph) holds that the function between learners' age and their susceptibility to second language input is non-linear. This paper revisits the indistinctness found in the literature with regard to this hypothesis's scope and predictions. Even when its scope is clearly delineated and its predictions are spelt out, however, empirical studies-with few exceptions-use analytical (statistical) tools that are irrelevant with respect to the predictions made. This paper discusses statistical fallacies common in cph research and illustrates an alternative analytical method (piecewise regression) by means of a reanalysis of two datasets from a 2010 paper purporting to have found cross-linguistic evidence in favour of the cph. This reanalysis reveals that the specific age patterns predicted by the cph are not cross-linguistically robust. Applying the principle of parsimony, it is concluded that age patterns in second language acquisition are not governed by a critical period. To conclude, this paper highlights the role of confirmation bias in the scientific enterprise and appeals to second language acquisition researchers to reanalyse their old datasets using the methods discussed in this paper. The data and R commands that were used for the reanalysis are provided as supplementary materials. 23726515 Resting functional connectivity reveals residual functional activity in Alzheimer's disease. Functional magnetic resonance imaging (fMRI) has great potential for measuring mechanisms of functional changes in Alzheimer's disease (AD) and mild cognitive impairment, but task fMRI studies have produced conflicting results, partly due to failure to account for underlying morphological changes and to variations in patients' ability to perform the tasks. Resting fMRI has potential for assessing brain function independently from a task, but greater understanding of how networks of resting functional connectivity relate to the functioning of the brain is needed. We combined resting fMRI and task fMRI to examine the correspondence between these methods in individuals with cognitive impairment. Eighty elderly (25 control subjects, 25 mild cognitive impairment, 30 AD) underwent a combined multimodal magnetic resonance imaging protocol including task fMRI and resting fMRI. Task fMRI data were acquired during the execution of a memory paradigm designed to account for differences in task performance. Structural and physiological confounds were modeled for both fMRI modalities. Successful recognition was associated with increased task fMRI activation in lateral prefrontal regions in AD relative to control subjects; this overlapped with increased resting fMRI functional connectivity in the same regions. Our results show that task fMRI and resting fMRI are sensitive markers of residual ability over the known changes in brain morphology and cognition occurring in AD and suggest that resting fMRI has a potential to measure the effect of new treatments. 23433547 Compensatory-step training of healthy, mobile people with unilateral, transfemoral or knee disarticulation amputations: A potential intervention for trip-related falls. The purpose of this study was to evaluate the effects of compensatory-step training of healthy, mobile, young-to-middle aged people with unilateral, transfemoral or knee disarticulation amputations. Outcomes of interest included recovery success, reliance on the prosthesis, and the kinematic variables relevant to trip recovery. Over the course of six training sessions, five subjects responded to postural disturbances that necessitated forward compensatory steps to avoid falling. Subjects improved their ability to recover from these postural disturbances without falling or hopping on the non-prosthetic limb. Subjects improved their compensatory stepping response by decreasing trunk flexion and increasing the sagittal plane distance between the body center of mass and the stepping foot. In response to more challenging disturbances, these training-related improvements were not observed for the initial step with the non-prosthetic limb. Regardless of the stepping limb, step length and the change in pelvic height were not responsive to training. This study exhibits the potential benefits of a compensatory-step training program for amputees and informs future improvements to the protocol. 23561132 Characterisation of non-polar dimers formed during thermo-oxidative degradation of β-sitosterol. Thermo-oxidative degradation of sterols at temperature typical for frying leads to the formation of oxidised derivatives, fragmented sterols and oligomers. Recent research on sterol oxidation focuses mainly on the oxysterol derivatives formation to the exclusion of compounds with high molecular mass. The aim of this work was to decipher the chemical structure of non-polar dimers formed during β-sitosterol oxidation at 180°C in the presence of oxygen. The dimer fraction was separated by size-exclusion chromatography (SEC) after pre-fractionation on silica gel. The chemical structure of the dimers was assessed by 1D and 2D NMR, IR, Raman and MS spectroscopies. NMR data confirmed that the predominant non-polar dimer formed during β-sitosterol oxidative degradation has a configuration of 3β,3β'-disitosteryl ether. Data from IR and Raman spectroscopies further proved it chemical structure. Applied analytical techniques also confirmed presence of dimers with different configuration than disteryl ethers. 23889409 Elastic energy flux by flexible polymers in fluid turbulence. We present a study of the energy transfer in the bulk of a turbulent flow with dilute long-chain polymer additives. Based on prior work by Tabor and de Gennes [Europhys. Lett. 2, 519 (1986); Physica (Amsterdam) 140A, 9 (1986)], we propose a theory on the energy flux into the elastic degrees of freedom of the polymer chains. This elastic energy flux, which increases as the length scale decreases, gradually reduces the energy transferred to smaller scales through turbulence cascade and hence suppresses small scale fluctuations. The balance of the elastic energy flux and the turbulence energy cascade gives an elastic length scale, which describes the effect of polymer elasticity on turbulence in the inertial range. Predictions of this new "energy flux balance theory" agree excellently with our experimental results. 23875506 Overcoming 4 common revenue cycle benchmarking myths. Peer group comparisons can help revenue cycle leaders: Review their performance through an external lens. Set targets and motivate their teams. Provide informed answers to questions from the C-suite. 23895096 Role of Cations in the Interaction of Pradimicins with HIV-1 Envelope gp120. Pradimicins (PRM) are a unique class of nonpeptidic carbohydrate-binding agents that inhibit HIV infection by efficiently binding to the HIV-1 envelope gp120 glycans in the obligatory presence of Ca2+. Surface plasmon resonance (SPR) data revealed that addition of EDTA dose-dependently results in lower binding signals of PRM-A to immobilized gp120. Pradimicin derivatives that lack the free carboxylic acid group on the C-18 position failed to bind gp120 and were devoid of significant antiviral activity. Ca2+ was much more efficient for PRM-A binding to gp120 than Cd2+, Ba2+ or Sr2+. Instead, calcium could not be replaced by any other mono- (i.e. K+), di- (i.e. Cu2+, Mg2+, Mn2+, Fe2+, Zn2+) or trivalent (i.e. Al3+, Fe3+) cation without complete loss of gp120 binding. However, Zn2+, Mg2+ and Mn2+ added to a Ca2+-pradimicin mixture, prevented pradimicin from efficient binding to gp120 glycans. These data suggest that these bivalent cations may bind to pradimicins but lead to pradimicin-cation complexes that are unable to further coordinate with the glycans of gp120. Thus, in order to afford antiviral activity, only a few cations can (i) bind to pradimicin to form a dimeric complex and (ii) subsequently coordinate the pradimicin/cation interaction with gp120 glycans. 23395653 Chemical probes of a trisubstituted pyrrole to identify its protein target(s) in Plasmodium sporozoites. Malaria is a disease that has a major impact in many developing nations, especially on the African continent. There is a need to develop new therapeutics and prophylactic treatments against it. A trisubstituted pyrrole was recently found to inhibit infection of mammalian hepatocytes by Plasmodium sporozoites, but the target of this agent is not known. In this study trisubstituted pyrrole derivatives with different substituents on a piperidinyl nitrogen were prepared. We determined if modifications of the piperidinyl nitrogen would accommodate a drug-biotin linking strategy for affinity purification of the trisubstituted pyrrole's target protein(s). 23772073 Succinyl-CoA:3-Sulfinopropionate CoA-Transferase from Variovorax paradoxus Strain TBEA6, a Novel Member of the Class III Coenzyme A (CoA)-Transferase Family. The act gene of Variovorax paradoxus TBEA6 encodes a succinyl-CoA:3-sulfinopropionate coenzyme A (CoA)-transferase, ActTBEA6 (2.8.3.x), which catalyzes the activation of 3-sulfinopropionate (3SP), an intermediate during 3,3'-thiodipropionate (TDP) degradation. In a previous study, accumulation of 3SP was observed in a Tn5::mob-induced mutant defective in growth on TDP. In contrast to the wild type and all other obtained mutants, this mutant showed no growth when 3SP was applied as the sole source of carbon and energy. The transposon Tn5::mob was inserted in a gene showing high homology to class III CoA-transferases. In the present study, analyses of the translation product clearly allocated ActTBEA6 to this protein family. The predicted secondary structure indicates the lack of a C-terminal α-helix. ActTBEA6 was heterologously expressed in Escherichia coli Lemo21(DE3) and was then purified by Ni-nitrilotriacetic acid (NTA) affinity chromatography. Analytical size exclusion chromatography revealed a homodimeric structure with a molecular mass of 96 ± 3 kDa. Enzyme assays identified succinyl-CoA, itaconyl-CoA, and glutaryl-CoA as potential CoA donors and unequivocally verified the conversion of 3SP to 3SP-CoA. Kinetic studies revealed an apparent Vmax of 44.6 μmol min(-1) mg(-1) for succinyl-CoA, which corresponds to a turnover number of 36.0 s(-1) per subunit of ActTBEA6. For 3SP, the apparent Vmax was determined as 46.8 μmol min(-1) mg(-1), which corresponds to a turnover number of 37.7 s(-1) per subunit of ActTBEA6. The apparent Km values were 0.08 mM for succinyl-CoA and 5.9 mM for 3SP. Nonetheless, the V. paradoxus Δact mutant did not reproduce the phenotype of the Tn5::mob-induced mutant. This defined deletion mutant was able to utilize TDP or 3SP as the sole carbon source, like the wild type. Complementation of the Tn5::mob-induced mutant with pBBR1MCS5::acdDPN7 partially restored growth on 3SP, which indicated a polar effect of the Tn5::mob transposon on acdTBEA6, located downstream of actTBEA6. 23238634 Establishment of a survival and toxic cellular model for Parkinson's disease from chicken mesencephalon. Cellular models for Parkinson's disease (PD) represent a fast and efficient tool in the screening for drug candidates and factors involved in the disease pathogenesis. The objective of this study was to establish and characterize a survival and toxic cellular model for PD by culturing dopaminergic neurons from embryonic chicken ventral midbrain. We show that as in rodents, the common neurotrophic factors--brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and fibroblast growth factor 2 (FGF2)--are able to support the survival of chicken midbrain dopaminergic neurons. Furthermore, after treatment with MPP⁺ or rotenone as in vitro models for PD, the number of tyrosine hydroxylase-positive cells decreased drastically. This effect could be significantly rescued by treatment with BDNF or GDNF. Together, our results indicate that mechanisms of neuroprotection of dopaminergic neurons are conserved between chicken and mammals. This supports the use of primary culture from chicken embryonic midbrain as a suitable tool for the study of neuroprotection in vitro. 23895911 Do protected areas and conservation incentives contribute to sustainable livelihoods? A case study of Bardia National Park, Nepal. Effective biodiversity protection and improved human welfare as 'win-win' situations have been the foundation for protected areas and conservation incentives. However, conserving land in this way can become a development issue that restricts agricultural expansion and resource exploitation, with potentially substantial costs to people living in conditions of high social impoverishment and high critical natural capital. This paper investigates whether Nepal's Bardia National Park and conservation incentives have contributed to the sustainable livelihoods of households. Data on household livelihoods and conservation benefits were collected through a questionnaire survey of 358 households and community workshops in three villages. Different impacts on household livelihoods were observed between the villages. It was found that these impacts were dependent on household characteristics, access to prior capital, and the social position of the household within society. Households lacking resources, being poor and belonging to lower castes were least included and also benefited less from development projects. As finance in the form of development projects from organisations continues to flow to the communities, it is important that detailed livelihood planning focussing on alternative regenerative livelihoods and micro-enterprises in the informal sector is included to target those households that are highly dependent on park resources. Livelihood planning must also include a clear linkage between livelihood enhancing activities and the conservation programme so that communities are aware that the benefits they receive are due to the protected area. Appreciation of benefits and their positive impact on livelihoods is important for the sustainability of incentive-based programmes. 23323954 New tetraterpene glycosides from the fruits of Lycium chinense. Two new compounds lyciumtetraterpenic hexaarabinoside (1) and tetraterpenyl hexaarabinoside (2), along with two known compounds, were isolated from the methanol extract of the fruits of Lycium chinense Miller (Solanaceae), and their structures have been elucidated as 6-(1,1,5-trimethyl-5α-hydroxycyclohexanyl)-6'-(1',1',5'-trimethyl-2'β-hydroxycyclohexanyl)-9,13,9',13'-tetramethyloctadec-7,9,11,13,15,7',9',11',13'-nonene-5α-D-arabinopyranosyl(2a → 1b)-β-D-arabinopyranosyl-(2b → 1c)-β-D-arabinopyranosyl-2'-β-D-arabinopyranosyl-(2d → 1e)-α-D-arabinopyranosyl-(2e → 1f)-α-D-arabinopyranoside (1) and 1(6),11(12),13(14),1'(6'),11'(12'),13'(14')-dodecahydro-β-caroten-4β,4'β-diol-4β-L-arabinopyranosyl-(2a → 1b)-β-L-arabinopyranosyl-(2b → 1c)-β-D-arabinopyranosido-4'β-L-arabinopyranosyl-(2d → 1e)-β-L-arabinopyranosyl-(2e → 1f)-β-D-arabinopyranoside (2) on the basis of spectral data analysis and chemical reactions. 23518299 Neuroprotective effect of sulforaphane in 6-hydroxydopamine-lesioned mouse model of Parkinson's disease. Parkinson's disease (PD) is characterized by the selective loss of dopaminergic nigrostriatal neurons, which leads to disabling motor disturbances. Sulforaphane (SFN), found in cruciferous vegetables, is a potent indirect antioxidant and recent advances have shown its neuroprotective activity in various experimental models of neurodegeneration. This study was undertaken to examine the effects of SFN on behavioral changes and dopaminergic neurotoxicity in mice exposed to 6-hydroxydopamine (6-OHDA). For this purpose, mice were treated with SFN (5mg/kg twice a week) for four weeks after the unilateral intrastriatal injection of 6-OHDA. The increase in 6-OHDA-induced rotations and deficits in motor coordination were ameliorated significantly by SFN treatment. In addition, SFN protected 6-OHDA-induced apoptosis via blocking DNA fragmentation and caspase-3 activation. These results were further supported by immunohistochemical findings in the substantia nigra that showed that SFN protected neurons from neurotoxic effects of 6-OHDA. The neuroprotective effect of SFN may be attributed to its ability to enhance glutathione levels and its dependent enzymes (glutathione-S-transferase and glutathione reductase) and to modulate neuronal survival pathways, such as ERK1/2, in the brain of mice. These results suggest that SFN may potentially be effective in slowing down the progression of idiopathic PD by the modulation of oxidative stress and apoptotic machinery. 23819816 Improving implementation of evidence-based practice in mental health service delivery: protocol for a cluster randomised quasi-experimental investigation of staff-focused values interventions. There is growing acceptance that optimal service provision for individuals with severe and recurrent mental illness requires a complementary focus on medical recovery (i.e., symptom management and general functioning) and personal recovery (i.e., having a 'life worth living'). Despite significant research attention and policy-level support, the translation of this vision of healthcare into changed workplace practice continues to elude. Over the past decade, evidence-based training interventions that seek to enhance the knowledge, attitudes, and skills of staff working in the mental health field have been implemented as a primary redress strategy. However, a large body of multi-disciplinary research indicates disappointing rates of training transfer. There is an absence of empirical research that investigates the importance of worker-motivation in the uptake of desired workplace change initiatives. 'Autonomy' is acknowledged as important to human effectiveness and as a correlate of workplace variables like productivity, and wellbeing. To our knowledge, there have been no studies that investigate purposeful and structured use of values-based interventions to facilitate increased autonomy as a means of promoting enhanced implementation of workplace change. This study involves 200 mental health workers across 22 worksites within five community-managed organisations in three Australian states. It involves cluster-randomisation of participants within organisation, by work site, to the experimental (values) condition, or the control (implementation). Both conditions receive two days of training focusing on an evidence-based framework of mental health service delivery. The experimental group receives a third day of values-focused intervention and 12 months of values-focused coaching. Well-validated self-report measures are used to explore variables related to values concordance, autonomy, and self-reported implementation success. Audits of work files and staff work samples are reviewed for each condition to determine the impact of implementation. Self-determination theory and theories of organisational change are used to interpret the data. The research adds to the current knowledge base related to worker motivation and uptake of workplace practice. It describes a structured protocol that aims to enhance worker autonomy for imposed workplace practices. The research will inform how best to measure and conceptualise transfer. These findings will apply particularly to contexts where individuals are not 'volunteers' in requisite change processes. ACTRN12613000353796. 23838653 Pathologic basis of antibody-mediated organ transplant rejection: from pathogenesis to diagnosis. Although antibody-mediated rejection of clinical organ transplants has been recognized more than a half-century ago, our understanding of its pathological/clinical phenotypes has dramatically increased over the past decade. This review highlights the pathological/clinical spectrum of ABMR and discusses its microscopic pathology in relationship with pathogenesis. Newly recognized pathological manifestations of ABMR are: (1) C4d-negative active ABMR, which cannot be definitely diagnosed by current diagnostic systems and often remains underdetected. Novel molecular diagnostic tests can fill this diagnostic gap but these new tests are yet to be prepared for routine application; (2) antibody-mediated vascular rejection, which is misclassified by the current Banff Classification, is therefore inadequately treated and has a high risk for transplant failure; and (3) subclinical (insidious) microvascular inflammation, which can be with or without complement activation, predicts progression to chronic rejection, transplant dysfunction, and failure. A major progress has been made in understanding of ABMR of clinical transplants in the last 5 years. New pathology types of ABMR are not appropriately classified and updates to the Banff diagnostic criteria are required. Better diagnosis would help develop effective antiantibody treatment strategies and improve long-term outcomes for patients. 23873677 Two-week interval optical coherence tomography: Imaging evidence on neointimal coverage completion after implantation of the endeavor zotarolimus-eluting stent. To obtain imaging evidence by 2-week optical coherence tomography (OCT) on the completion of neointimal coverage (NIC; the percentage of stent strut coverage and thickness of the formed neointima) completion after implantation of the Endeavor zotarolimus-eluting stent (E-ZES). Despite the fact that NIC is a cardinal process in the pathomechanism of late stent thrombosis, little imaging information is available on morphological changes thereof on a short-time interval basis. 27 Japanese patients with stable angina pectoris and de novo native coronary artery lesions were enrolled, and 27 lesions (30 implantations) were examined. OCT was performed at weeks 2, 4, 6, 8, and 10 after E-ZES implantation. NIC was examined using cross-sectional OCT images obtained at the 1.0-mm intervals. In total, 621 cross-sectional OCT images, which depicted 7,747 stent struts, were analyzed. The mean percentages of stent strut coverage at weeks 2, 4, 6, 8, and 10 after E-ZES implantation were 12.3, 70.4, 67.9, 86.0, and 99.2%, respectively; a marked increase was found between weeks 2 and 4. The mean thicknesses of the formed neointima were 40.2, 52.1, 48.1, 86.5, and 146.2 μm at respective weeks, with the high-signal and thick neointima (146 µm) at week 10. An intracoronary thrombus was detected in only one stent at week 4. The full circumferential coverage of the vessel wall by the high-signal neointima was found at as early as week 10 after E-ZES implantation, imparting a surrogate index for vascular healing by NIC. © 2013 Wiley Periodicals, Inc. 23928110 Allele frequencies of 19 autosomal STR loci in Manchu population of China with phylogenetic structure among worldwide populations. The aim of this study was to estimate the allelic frequencies of the 19 STR loci with the Goldeneye™ DNA ID system 20A kit in a sample of 150 Manchu individuals from China to be used for forensic purposes and population studies. The observed heterozygosity(HO)values of these 19 STR loci ranged from 0.600 (D3S1358) to 0.914 (D18S51), the expected (HE) ranged from 0.615 (TPOX) to 0.876 (D16S1043). The power of discrimination (PD) values were found to range from 0.793 (TPOX) to 0.950 (D16S1043) and the probability of exclusion (PE) varies between 0.291 (D3S1358) and 0.825 (D18S51 and Penta E). Among all the 19 loci, D16S1043 had the highest polymorphism (PIC=0.860), whereas TPOX had the lowest (PIC=0.550). For the 19 loci, the combined power of discrimination and the combined probability of exclusion are 0.9999999999999999999942 and 0.999999996777, respectively. The phylogenetic tree established among worldwide population shows different populations who say the same language usually have a close genetic relationship with each other across the three language families studied (Sino-Tibetan, Altaic and Arabic). 23898176 Pinpointing genes underlying the quantitative trait loci for root-knot nematode resistance in palaeopolyploid soybean by whole genome resequencing. The objective of this study was to use next-generation sequencing technologies to dissect quantitative trait loci (QTL) for southern root-knot nematode (RKN) resistance into individual genes in soybean. Two hundred forty-six recombinant inbred lines (RIL) derived from a cross between Magellan (susceptible) and PI 438489B (resistant) were evaluated for RKN resistance in a greenhouse and sequenced at an average of 0.19× depth. A sequence analysis pipeline was developed to identify and validate single-nucleotide polymorphisms (SNPs), infer the parental source of each SNP allele, and genotype the RIL population. Based on 109,273 phased SNPs, recombination events in RILs were identified, and a total of 3,509 bins and 3,489 recombination intervals were defined. About 50.8% of bins contain 1 to 10 genes. A linkage map was subsequently constructed by using bins as molecular markers. Three QTL for RKN resistance were identified. Of these, one major QTL was mapped to bin 10 of chromosome 10, which is 29.7 kb in size and harbors three true genes and two pseudogenes. Based on sequence variations and gene-expression analysis, the candidate genes underlying the major QTL for RKN resistance were pinpointed. They are Glyma10g02150 and Glyma10g02160, encoding a pectin methylesterase inhibitor and a pectin methylesterase inhibitor -pectin methylesterase, respectively. This QTL mapping approach not only combines SNP discovery, SNP validation, and genotyping, but also solves the issues caused by genome duplication and repetitive sequences. Hence, it can be widely used in crops with a reference genome to enhance QTL mapping accuracy. 23559465 Expansion and evolution of Streptococcus pneumoniae serotype 19A ST320 clone as compared to its ancestral clone, Taiwan19F-14 (ST236). The Streptococcus pneumoniae serotype 19A sequence type (ST) 320 clone, derived from an international Taiwan(19F)-14 (ST236) clone, has become prevalent in many countries. The dynamics of invasive pneumococcal disease (IPD) were determined using the database of the National Notifiable Disease Surveillance System in Taiwan. The virulence of 19A ST320 and Taiwan(19F)-14 (ST236) were assessed in mice. By constructing an isogenic serotype 19F variant of the 19A ST320 strain (19F ST320), we analyzed the role of capsular type and genetic background on the difference in virulence between 19A ST320 and Taiwan(19F)-14 (ST236). Between 2008 and 2011, IPD due to serotype 19A increased from 2.1 to 10.2 cases per 100 000 population (P < .001); IPD due to any serotype also significantly increased (P = .01). Most serotype 19A isolates belonged to ST320. Using competition experiments in a murine model of colonization, we demonstrated that 19A ST320 outcompeted Taiwan(19F)-14 (ST236; competitive index, 20.3; P = .001). 19F ST320 was 2-fold less competitive than the 19A ST320 parent (competitive index, 0.47; P = .04) but remained 14-fold more competitive than Taiwan(19F)-14 (ST236; competitive index, 14.7; P < .001). Genetic evolution of pneumococcal clones from Taiwan(19F)-14 (ST236) to 19A ST320 has made this pneumococcus better able to colonize of the nasopharynx. This evolution reflects not only a switch in capsular serotype but also changes in other loci. 23883105 Premature senescence and cellular phenotype transformation of mesangial cells induced by TGF-B1. Abstract Background: Transforming growth factor-β1 (TGF-β1) is a polypeptide member of the transforming growth factor β superfamily of cytokines and performs many cellular functions. Its overexpression may lead to renal fibrosis. Aim: This study planed to investigate the effects of TGF-β1 on the cell cycle and phenotype of mesangial cells. Methods: Rat mesangial cells were cultured together with different concentrations (0, 1, 2, 5, and 10 ng/mL) of TGF-β1 for specified times from 0 min to 72 h. 0 ng/mL TGF-β1 and 0 min served as controls. Cell cycles were assessed by flow cytometry and α-smooth muscle actin expression (α-SMA) protein expression by western blot analysis. All data were presented as Mean ± SD. Statistical analysis was performed by using one-way analysis of variance and correlation analysis. Results were considered significant at p < 0.05. Results: After 15 min of co-culture with different concentrations of TGF-β1, the percentage of mesangial cells in G0/G1 phase was significantly elevated compared to the control (p < 0.05). 12 h co-culture induced cell hyperplasia, 24 h co-culture obvious up-regulation of α-SMA (p < 0.01) and one or two cells' myofibroblast phenotype transition, and 36 h co-culture several cells' phenotype transition. Correlation analysis prompted that the TGF-β1-induced premature aging was time-dependent (p < 0.01). Conclusion: TGF-β1 may induce mesangial cells' premature senescence and myofibroblast-like phenotype transformation time-dependently, which may contribute to the development of early stage of glomerulosclerosis. 23750545 In vivo mercury methylation and demethylation in freshwater tilapia quantified by mercury stable isotopes. In vivo methylation and demethylation processes were simultaneously investigated in freshwater tilapia after dietary exposure to mercury ((198)Hg(II) and methyl(200)Hg). During one month dietary exposure followed by two month depuration, both MeHg and THg increased continuously in muscle tissues but decreased in liver during depuration, indicating the inter-organ transportation of MeHg from liver toward muscle. Direct evidence of in vivo net methylation process in freshwater tilapia was observed. Specifically, 0.67-1.60% of the ingested Hg(198)(II) was converted into Me(198)Hg and deposited in fish muscle at the end of depuration. The methylation potential in terms of methylated fraction was elevated at higher temperature and decreased at higher dosage. However, no direct evidence of MeHg demethylation was observed. In contrast to some previous reports of dose-dependent demethylation, the percentage of MeHg in the liver decreased significantly with increasing THg concentrations, likely due to the faster inter-organ MeHg transportation from liver toward muscle. Our study demonstrates the important role of organ- and species-specific biodynamics in understanding mercury transformation and speciation in fish. The observed in vivo methylation process in tilapia was slow, suggesting that the high %MeHg in fish should be mainly derived from MeHg ingestion instead of in vivo transformation. 23092679 New insights in the pathogenesis and treatment of normal tension glaucoma. Increased intraocular pressure (IOP) is a major risk factor for glaucomatous damage and reducing IOP improves prognosis. Nevertheless, there is little doubt that other risk factors besides IOP such as unstable ocular perfusion are involved. Blood flow is unstable if either the IOP fluctuates at a high level (or blood pressure fluctuates at a low level) or if the autoregulation of blood flow disturbed. A common cause for a disturbed OBF autoregulation is a primary vascular dysregulation (PVD) frequently observed in normal tension glaucoma patients. An unstable blood flow leads to recurrent mild reperfusion injury (chronic oxidative stress) affecting particularly the mitochondria of the optic nerve head. OBF regulation can be improved by magnesium, calcium channel blockers as well as with carbonic anhydrase inhibitors. 23884462 Arthroscopic treatment of iliopsoas impingement (IPI) after total hip replacement. The purpose of the study was to present our arthroscopic surgical technique and the results in patient with an iliopsoas impingement (IPI) syndrome after a hip replacement. Between 1999 and 2011, 35 patients with the clinical picture of an IPI after total hip replacement were diagnosed and treated arthroscopically. The age was ranged from 58 to 82 years. All patients underwent conservative treatment for at least 6 months without success. The indication for the arthroscopic procedure was the failure of the conservative therapy as well as typical clinical signs as painful hip flexion, a positive local anesthesia test and radiological evidence of the presence of a prominent anterior acetabular component. The arthroscopic treatment was performed in all patients with anterior capsulotomy and partial capsulectomy of the hip joint. After identification of the pathology an arthroscopic release of the iliopsoas tendon in the region of the proved lesion was performed. The average follow-up period was 3.6 years (6 months to 12 years). In all patients osseous integrated acetabular components were found. In six cases there was a surface replacement, in three cases it was a cementless screw-in cup and in the other three cases it was a cementless modular press-fit cup. 8 out of 12 patients suffered from a hip dysplasia with a secondary osteoarthritis. After establishing an anterior capsular window arthroscopically, the iliopsoas tendon could be visualized in all cases. In addition to multiple local tendinitis all patients already showed mechanical limitation with partial rupture of variable extent in the iliopsoas tendon. During the arthroscopy the lesion was detected at the level of the anterior prominent acetabular component as well as distal to it. 10 out of 12 patients reported immediately after postoperative mobilization that the typical preoperative complaints have disappeared. Two patients still had residual pain. In one of those patients this was relieved by the time of the follow-up examination. Clinically a temporary weakness of hip flexion in the first days of the postoperative period was detected. In the first follow-up 6 weeks later there was no evidence of weakness in any of the patients. An arthroscopic release of the iliopsoas tendon with evidence of iliopsoas impingement after total hip replacement gives predictably good results. A clinically relevant weakness of hip flexion is not expected after the procedure. 23440581 Quality assessment and discrimination of the roots of Cynanchum auriculatum and Cynanchum wilfordii by HPLC-UV analysis. Cynanchum auriculatum and Cynanchum wilfordii are widely used as folk medicine in Eastern Asia. However, the indeterminacy in the authentic original plant material has resulted in the same appellative name being given to the two plants, and they are commonly misused. Therefore, it is necessary to establish an analytical method for discrimination as well as quality control of the two species. This study was to develop HPLC-UV methods for quality assessment of C. auriculatum and C. wilfordii and discrimination between the two species. Two HPLC methods to analyze eight marker compounds were established and validated. The first method analyzed seven marker compounds simultaneously on a reversed-phase column, while the second method analyzed a single marker compound, conduritol F, which exists only in C. wilfordii, on a Si-column. Thirty-nine batches of C. auriculatum and nineteen batches of C. wilfordii that were collected from different geographical regions of South Korea were analyzed by these methods. The constructed data matrix was subjected to principal components analysis and hierarchical cluster analysis in order to classify the samples. The established methods offer a potential strategy for authentication and differentiation of the two species. 22107131 Effect of a simulated soccer match on the functional hamstrings-to-quadriceps ratio in amateur female players. The purpose of this study was to investigate the effect of a simulated soccer test on the functional hamstrings-to-quadriceps ratio (Hecc  : Qcon ) in female soccer players. Fourteen amateur players (age, 26.1 ± 4.6 years; height, 168 ± 12 cm; body mass, 62.7 ± 5.5 kg; body fat, 23.7 ± 2.2%) performed the modified Loughborough Intermittent Shuttle Test (modified LIST). Isokinetic strength assessments of the hamstrings and quadriceps on the dominant and non-dominant legs at 120°/s were performed before and immediately after the modified LIST. Hecc  : Qcon was calculated as the ratio of the peak eccentric torque of the hamstrings to the peak concentric torque of the quadriceps. A two-way univariate analysis of variance was used to assess the effect of time and leg dominance on Hecc  : Qcon . The main results showed that the modified LIST led to a significant decrease in Hecc  : Qcon in the dominant (-14.1%) and non-dominant legs (-8.0%) (P = 0.02). However, this decrease was not significantly different between dominant and non-dominant legs (P = 0.42). These results reflect a greater risk of hamstrings tears and ACL sprains at the end of soccer matches. 23742858 The H(+)/K(+)-ATPase inhibitory activities of Trametenolic acid B from Trametes lactinea (Berk.) Pat, and its effects on gastric cancer cells. Trametenolic acid B (TAB), the bioactive component in the Trametes lactinea (Berk.) Pat, was reported to possess cytotoxic activities and thrombin inhibiting effects. This study was performed to investigate the effects of TAB on H(+)/K(+)-ATPase and gastric cancer. The H(+)/K(+)-ATPase inhibitory activity was determined by gastric parietal cells. Compared to the normal control group, TAB (10, 20, 40 and 80μg/mL) inhibited the H(+)/K(+)-ATPase activity by 15.97, 16.96, 24.86 and 16.25%, respectively. In the study, 36 Kunming mice were randomly divided into six groups: control, model, TAB-L (TAB, 5mg/kg/day, i.g.), TAB-M (TAB, 20mg/kg/day, i.g.), TAB-H (TAB, 40mg/kg/day, i.g.) and omeprazole (OL, 10mg/kg/day, i.g.). All mice except the control group were administrated with anhydrous alcohol (5.0mL/kg, i.g.) for induced gastric-ulcer 1h after the 5th day. At the same time, the control mice were given the same volume of physiological saline. After 4h, TAB was evaluated for H(+)/K(+)-ATPase inhibitory activities of ulcerative gaster, gastric ulcer index and ulcer inhibition. In vitro, the anti-proliferation effect of TAB to gastric cancer cell (HGC-27) in acid environment was detected by MTT, and the apoptosis morphological changes were also observed by Hoechst 33258 dye assay. The results indicated that TAB inhibited moderately H(+)/K(+)-ATPase activity in vitro. Compared to the model group, TAB showed anti-ulcer effects in gastric tissue with the dosages of 20 and 5mg/kg in vivo. Apart from that, TAB could selectively inhibit gastric cancer cell viability and reduce cell apoptosis against HGC-27 cells at low doses in acid environment. 23957645 Performance test of Nano-HA/PLLA composites for interface fixation. Objective: By in situ polymerization of poly-L-lactic acid (PLLA) and nano-hydroxyapatite (Nano-HA), and finding the best proportion of composite, so as to get ideal interface fixation material. Methods: According to a certain ratio (the mass fraction of Nano-HA, respectively, is 0%, 10%, 20%, 30% and 40%), composite PLLA and Nano-HA by in situ polymerization, and test the performance of this kind of new type of interface fixation such as, bending strength,compressive strength, elastic modulus, scanning electron microscopy (SEM) and degradation experiments in vitro. Then observe its mechanical properties, microstructure, the dispersion of Nano-HA in the PLLA and degradation rate of composite materials. Results: 1. Mechanical tests show that with the increase of Nano-HA content, the tensile strength decreases and the elastic modulus increases; with Nano-HA content of 20%, the bending strength of composite materials presents the peak value (156.8 MPa). 2. SEM scan shows the fracture surface of pure PLLA is relatively smooth; with Nano-HA content of 10%, the fracture surface shows a large number of dimples, and is obvious rough; with Nano-HA content of 20%, the fracture surface is uneven, forming a large number of dimples; with Nano-HA content of 30% or more, the fracture surface becomes more flat, and there are some small dimples. 3. Degradation experiments in vitro show the following: as the degradation time goes on, the pH values of degradation liquid is gradually reduced and the mechanical properties of composite materials also gradually have some decay. Conclusion: With Nano-HA content of 20%, the interface fixation material has a better mechanical properties and degradation properties. According to the best ratio, prepare Nano-HA/PLLA composite artificial materials with good performance. 23954482 DNA-based aptamer fails as a simultaneous cancer targeting agent and drug delivery vehicle for a phenanthroline-based platinum(II) complex. The sgc8c aptamer is a 41-base DNA oligonucleotide that binds to leukaemia cells with high affinity and specificity. In this work we examined the utility of this aptamer as both a delivery vehicle and an active targeting agent for an inert platinum complex [(1,10-phenathroline)(ethylenediamine)platinum(II)](2+). The aptamer forms a stem-and-loop confirmation as determined by circular dichroism. This conformation is adopted in both water and phosphate buffered saline solutions. The metal complex binds through intercalation into the aptamer's double helical stem with a binding constant of approximately 4.3×10(4)M(-1). Binding of the metal complex to the aptamer had a significant effect on the aptamer's global conformation, and increased its melting temperature by 28°C possibly through lengthening and stiffening of the aptamer stem. The effect of the aptamer on the metal complex's cytotoxicity and cellular uptake was determined using in vitro assays with the target leukaemia cell line CCRF-CEM and the off-target ovarian cancer cell lines A2780 and A2780cp70. The aptamer has little inherent cytotoxicity and when used to deliver the metal complex results in a significant decrease in the metal complex's cytotoxicity and uptake. The reason(s) for the poor uptake and activity may be due to the change in aptamer conformation which affects its ability to recognise leukaemia cells. 23953278 Chronic Leg Ulceration Associated with Polycythemia Vera Responding to Ruxolitinib (Jakafi(®)). We present the case of a 63-year-old white male with bilateral chronic leg ulcers due to polycythemia vera and hydroxyurea therapy who demonstrated dramatic healing of his wounds in response to ruxolitinib (Jakafi(®), Novartis), a novel Janus kinase-1 and -2 inhibitor. This patient's wound had previously been refractory to multiple surgical interventions and immunosuppression. After the initiation of ruxolitinib, the patient underwent successful split-thickness skin grafting, with resultant healing of his wounds. He was stable without prednisone and other immunosuppressant therapy and had healed at 6 months. Ruxolitinib therapy could represent a novel option for patients who develop persistent inflammatory wounds in the setting of polycythemia vera and hydroxyurea therapy. 23862947 Hard ellipses: Equation of state, structure, and self-diffusion. Despite their fundamental and practical interest, the physical properties of hard ellipses remain largely unknown. In this paper, we present an event-driven molecular dynamics study for hard ellipses and assess the effects of aspect ratio and area fraction on their physical properties. For state points in the plane of aspect ratio (1 ≤ k ≤ 9) and area fraction (0.01 ≤ φ ≤ 0.8), we identify three different phases, including isotropic, plastic, and nematic states. We analyze in detail the thermodynamic, structural, and self-diffusive properties in the formed various phases of hard ellipses. The equation of state (EOS) is shown for a wide range of aspect ratios and is compared with the scaled particle theory (SPT) for the isotropic states. We find that SPT provides a good description of the EOS for the isotropic phase of hard ellipses. At large fixed φ, the reduced pressure p increases with k in both the isotropic and the plastic phases and, interestingly, its dependence on k is rather weak in the nematic phase. We rationalize the thermodynamics of hard ellipses in terms of particle motions. The static structures of hard ellipses are then investigated both positionally and orientationally in the different phases. The plastic crystal is shown to form for aspect ratios up to k = 1.4, while appearance of the stable nematic phase starts approximately at k = 3. We quantitatively determine the locations of the isotropic-plastic (I-P) transition and the isotropic-nematic (I-N) transition by analyzing the bond-orientation correlations and the angular correlations, respectively. As expected, the I-P transition point is found to increase with k, while a larger k leads to a smaller area fraction where the I-N transition takes place. Moreover, our simulations strongly support that the two-dimensional nematic phase in hard ellipses has only quasi-long-range orientational order. The self-diffusion of hard ellipses is further explored and connections are revealed between the structure and the self-diffusion. We discuss the relevance of our results to the glass transition in hard ellipses. Finally, the results of the isodiffusivity lines are evaluated for hard ellipses and we discuss the effect of spatial dimension on the diffusive dynamics of hard ellipsoidal particles. 23022916 Adaptive deep brain stimulation (aDBS) controlled by local field potential oscillations. Despite their proven efficacy in treating neurological disorders, especially Parkinson's disease, deep brain stimulation (DBS) systems could be further optimized to maximize treatment benefits. In particular, because current open-loop DBS strategies based on fixed stimulation settings leave the typical parkinsonian motor fluctuations and rapid symptom variations partly uncontrolled, research has for several years focused on developing novel "closed-loop" or "adaptive" DBS (aDBS) systems. aDBS consists of a simple closed-loop model designed to measure and analyze a control variable reflecting the patient's clinical condition to elaborate new stimulation settings and send them to an "intelligent" implanted stimulator. The major problem in developing an aDBS system is choosing the ideal control variable for feedback. Here we review current evidence on the advantages of neurosignal-controlled aDBS that uses local field potentials (LFPs) as a control variable, and describe the technology already available to create new aDBS systems, and the potential benefits of aDBS for patients with Parkinson's disease. 23864114 Mechanisms other than activation of the iron regulon account for the hyper-resistance to cobalt of a Saccharomyces cerevisiae strain obtained by evolutionary engineering. Cobalt is an important metal ion with magnetic properties that is widely used for several industrial applications. Overexposure to cobalt ions can be highly toxic for the organisms because they usually overwhelm the endogenous physiological system that maintains their homeostasis causing (geno)toxic effects. To gain insight into the mechanism of cobalt toxicity, we characterized at the molecular and genetic levels a cobalt resistant CI25E Saccharomyces cerevisiae strain previously isolated by an in vivo evolutionary engineering strategy, and which was able to grow on 5 to 10 mM CoCl2. This evolved strain showed cross-resistance to other metal ions including iron, manganese, nickel and zinc, but not to copper. Moreover, the cobalt resistant trait was semi-dominant, and linked to more than one gene, as indicated by the absence of 2(+):2(-) segregation of the cobalt resistance. Genome wide transcriptional profiling revealed a constitutive activation of the iron regulon that could be accounted for by a constitutive nuclear localization of the transcriptional activator Aft1. However, the presence of Aft1 in the nucleus was not a prerequisite for hyper-resistance to cobalt, since a mutant defective in nuclear monothiol glutaredoxin encoding GRX3 and GRX4 that also leads to nuclear localization of Aft1 was cobalt hypersensitive. In addition, the loss of AFT1 only partially abolished the cobalt resistance in the evolved strain, and the deletion of COT1 encoding the major vacuolar transporter of cobalt had only a minor effect on this trait. Paradoxically to the activation of iron regulon, the evolved strain was hypersensitive to the iron chelator BPS, and this hypersensitivity was abrogated by cobalt ions. Taken together, this work suggested that cobalt resistance is not merely dependent upon activation of AFT1, but it likely implicates other mechanisms including intracellular reallocation of iron into important compartments whose function is dependent on this metal and adaptation of some cellular proteins to use Co(2+) in place of Fe(2+) for their catalytic activities. 23577590 Neuraxial morphine induced pruritus in two cats and treatment with sub anaesthetic doses of propofol. Two cats were presented for orthopaedic surgery. With the exception of the orthopaedic injuries found, clinical examination showed no abnormality. As part of anaesthetic management, one cat received intrathecal morphine, the other epidural morphine. Following recovery, intense grooming was observed. After ensuring adequate analgesia this behaviour was interpreted as pruritus. In the first cat, pruritus was initially managed with medetomidine constant rate infusion (CRI) at 1 and 1.5 Î¼g kg(-1)  hour(-1) . The lower dose produced sedation and no relief from pruritus, the higher dose ablated pruritus but induced sedation. Two propofol (lipid emulsion formulation) boli of 0.1 mg kg(-1) ablated pruritus without causing sedation. The second cat was successfully treated with four boli of 0.1 mg kg(-1) propofol over 20 minutes. Following treatment with propofol, pruritus did not recur in either cat and both were discharged from the hospital. This is the first clinical report of morphine-induced pruritus in cats and management with low-dose propofol. These cases suggest an antipruritic mechanism for lipid-formulation propofol. 22989615 Morphology and surface topography of the schistosome Bivitellobilharzia nairi from the Asian elephant (Elephas maximus maximus) in Sri Lanka. Bivitellobilharzia nairi was first recorded from an Indian elephant (Elephas maximus) in Berlin. Infections with this parasite have become increasingly important in E. maximus maximus populations in Sri Lanka. The present work is the first morphological description of this schistosome from Sri Lanka. A number of adult worms were recovered from a dead Asian elephant near the elephant orphanage, Pinnawala, in Sri Lanka. The observed clinical features of the infected elephant included emaciation, subventral oedema and anaemia. Post-mortem results indicated that the liver was enlarged and adult schistosomes were found in the blood vessels of the liver parenchyma. The total number of worms recovered from a portion of the liver was 129,870, which is an average of 22 worms per 100 g of liver. The present study uses both light microscopic and scanning electron microscope (SEM) techniques for the morphological and topographical characterization of this parasite and to permit comparison with other species of schistosomes. Morphologically, these worms correspond very well to the description of B. nairi by Dutt & Srivastava (1955). Moreover, it is clear that B. nairi is a distinctive species easily differentiated from other schistosomes. The SEM study of the tegument of male worms shows that the surface of B. nairi is smoother than in other schistosomes. 23764677 Distinct ocular expression in infants and children with down syndrome in cairo, egypt: myopia and heart disease. IMPORTANCE The study establishes the importance of genetic background for the expression of Down syndrome phenotype. OBJECTIVE To define the ocular manifestations of Down syndrome in infants and children in Cairo, Egypt, a historically isolated region, and compare them with systemic features and with findings in other geographic groups. DESIGN AND PARTICIPANTS We prospectively studied the ocular status and systemic features of 90 infants and children with Down syndrome and monitored all patients for 3 years. The complete ophthalmic examinations were performed along with ultrasonography, if media opacities were evident. Thyroid and cardiac status were assessed. An extensive literature search for comparison was performed. SETTING Outpatient clinical genetics department at the National Research Centre in Cairo, Egypt. MAIN OUTCOMES AND MEASURES Ocular and systemic manifestations of Down syndrome in infants and children in Cairo, and comparison of these features with patients with this anomaly from other geographic regions and ethnic populations. RESULTS Fifty-two infants or children (58%) had at least 1 abnormal ocular finding identified at the first visit. Significant refractive errors (in 37 [41%] patients) were the most common. Nasolacrimal duct obstruction, blepharoconjuctivitis, or conjunctivitis was found in 18 (20%), strabismus in 13 (14%), cataract in 5 (6%), nystagmus in 3 (3%), and optic nerve dysplasia in 2 (2%). Brushfield spots were not found. Additional ocular features developed over time. Thirty-six patients (40%) had congenital heart defects, and many (31 [86%]) had associated ocular disorders; a statistically significant correlation with myopia was established. Chromosomal translocations were high. The phenotype in Cairo was distinct. CONCLUSIONS AND RELEVANCE More than half of infants and children with Down syndrome in Cairo had ophthalmic abnormalities; myopia was correlated with congenital heart defects. Comparison of the specific ocular features in our population with those in previous worldwide studies shows differences that may be related to overexpression or polymorphisms of key, modifying genes or other mutations in this historically isolated region along the Nile River. Down syndrome is more common in the highly consanguineous and multiparous Middle Eastern populations, and our Cairo findings underscore regional differences. 23360109 Modulation of cytochrome P450 enzymes in response to continuous or intermittent high-fat diet in pigs. Abstract 1. To date, no information has been available on the modulation of cytochrome P450 enzymes (CYPs) following the administration of a hyperlipidemic diet in pigs. 2. We investigated the potential modulation of xenobiotic-metabolizing CYPs in liver, heart and duodenum of pigs subjected to a high-fat/high-cholesterol diet for 2 months continuously (C-HFD) or on alternate weeks (A-HFD). 3. The administration of the high-fat diet resulted in considerably increased plasma cholesterol levels although the animals were still able to manage the lipid overload efficiently, and no sign of effective tissue inflammation occurred in livers. Plasma lipid profile and liver histology indicated a better adaptive response of the A-HFD pigs compared to the C-HFD group. We showed a post-transcriptional induction of hepatic CYP2E1 activity in C-HFD pigs and a transcriptional induction of hepatic CYP3As - especially in the A-HFD group. No further CYP modulation was observed in either liver or extra-hepatic tissues. 4. In conclusion, the administration of a high-fat diet in pigs resulted in limited effects on the drug metabolism system. The better adaptive response of A-HFD pigs compared to C-HFD pigs is a very interesting observation since the intermittent administration of the diet reflects the mode of human behavior more closely. 23934508 Mechanism for full-length RNA processing of Arabidopsis genes containing intragenic heterochromatin. Genomes of higher eukaryotes contain many transposable elements, which often localize within the transcribed regions of active genes. Although intragenic transposable elements can be silenced to form heterochromatin, the impact of intragenic heterochromatin on transcription and RNA processing remains largely unexplored. Here we show using a flowering plant, Arabidopsis, that full-length transcript formation over intragenic heterochromatin depends on a protein named IBM2 (Increase in Bonsai Methylation 2), which has a Bromo-Adjacent Homology domain and an RNA recognition motif. Mutation of ibm2 triggers premature termination of transcripts with 3' RNA processing around intragenic heterochromatin at loci including the H3K9 demethylase gene IBM1. The need for IBM2 is circumvented in variant alleles that lack the heterochromatic domain. Our results reveal a mechanism that masks deleterious effects of intragenic heterochromatin, providing evolutionary sources for genetic and epigenetic variations. 23969316 Imaging dynamic interactions between spliceosomal proteins and pre-mRNA in living cells. The ability to observe protein dynamics in living cells is critical for the mechanistic understanding of highly flexible biological processes such as pre-mRNA splicing by the spliceosome. Splicing relies on intricate RNA and protein networks that are repeatedly rearranged during spliceosome assembly. Here we describe a method based on fluorescence microscopy that has been used by our and other laboratories to study interaction of spliceosomal proteins with nascent pre-mRNA in living cells. The method involves co-expressing in mammalian cells the target pre-mRNA labeled with one color, and the spliceosomal protein tagged with another color. The diffusion coefficient of the protein as well as its association and dissociation rates with the pre-mRNA are estimated by fluorescence recovery after photobleaching (FRAP) or photoactivation. 23239011 Nutritionally essential amino acids and metabolic signaling in aging. Aging is associated with a gradual decline in skeletal muscle mass and strength leading to increased risk for functional impairments. Although basal rates of protein synthesis and degradation are largely unaffected with age, the sensitivity of older muscle cells to the anabolic actions of essential amino acids appears to decline. The major pathway through which essential amino acids induce anabolic responses involves the mammalian target of rapamycin (mTOR) Complex 1, a signaling pathway that is especially sensitive to regulation by the branched chain amino acid leucine. Recent evidence suggests that muscle of older individuals require increasing concentrations of leucine to maintain robust anabolic responses through the mTOR pathway. While the exact mechanisms for the age-related alterations in nutritional signaling through the mTOR pathway remain elusive, there is increasing evidence that decreased sensitivity to insulin action, reductions in endothelial function, and increased oxidative stress may be underlying factors in this decrease in anabolic sensitivity. Ensuring adequate nutrition, including sources of high quality protein, and promoting regular physical activity will remain among the frontline defenses against the onset of sarcopenia in older individuals. 23963182 Load-dependent assembly of the bacterial flagellar motor. ABSTRACT It is becoming clear that the bacterial flagellar motor output is important not only for bacterial locomotion but also for mediating the transition from liquid to surface living. The output of the flagellar motor changes with the mechanical load placed on it by the external environment: at a higher load, the motor runs more slowly and produces higher torque. Here we show that the number of torque-generating units bound to the flagellar motor also depends on the external mechanical load, with fewer stators at lower loads. Stalled motors contained at least as many stators as rotating motors at high load, indicating that rotation is unnecessary for stator binding. Mutant stators incapable of generating torque could not be detected around the motor. We speculate that a component of the bacterial flagellar motor senses external load and mediates the strength of stator binding to the rest of the motor. IMPORTANCE The transition between liquid living and surface living is important in the life cycles of many bacteria. In this paper, we describe how the flagellar motor, used by bacteria for locomotion through liquid media and across solid surfaces, is capable of adjusting the number of bound stator units to better suit the external load conditions. By stalling motors using external magnetic fields, we also show that rotation is not required for maintenance of stators around the motor; instead, torque production is the essential factor for motor stability. These new results, in addition to previous data, lead us to hypothesize that the motor stators function as mechanosensors as well as functioning as torque-generating units. 23860470 The impact of compulsory drug detention exposure on the avoidance of healthcare among injection drug users in Thailand. Although Thailand has relied on the use of compulsory drug detention centres as a strategy to try to address problematic drug use, little is known about the effects of exposure to these centres on people who inject drugs (IDU). Therefore, we undertook this study to explore whether exposure to compulsory drug detention was associated with avoiding healthcare among Thai IDU. Using Poisson regression analyses, we examined the relationship between compulsory drug detention exposure and avoiding healthcare among participants in the Mitsampan Community Research Project based in Bangkok. 435 IDU participated in this study, including 111 (25.5%) participants who reported avoiding healthcare. In multivariate analyses, avoiding healthcare was positively associated with exposure to compulsory drug detention (adjusted prevalence ratio [APR]=1.60; 95% confidence interval [CI]: 1.16-2.21), having been refused healthcare (APR=3.46; 95% CI: 2.61-4.60), and experiencing shame associated with one's drug use (APR=1.93; 95% CI: 1.21-3.09). Exposure to compulsory drug detention was associated with avoiding healthcare among Thai IDU, suggesting that this system of detention may be contributing to the burden of preventable morbidity among IDU in this setting. Although further research is needed to confirm these findings, the results of this study reinforce previous calls to replace the system of compulsory drug detention with evidence-based public health interventions for IDU. 23341102 Case report of severe bradycardia due to transdermal fentanyl. Background: This case report describes a patient who developed severe bradycardia due to transdermal fentanyl. There have been no prior case reports of this occurring in palliative care, but the frequency of association of fentanyl with bradycardia in the anesthesia setting suggests it may be more common than realized. Palliative care settings often have a policy of not routinely checking vital signs, and symptoms of bradycardia could be misinterpreted as the dying process. Case presentation: A patient with recurrent ovarian cancer was admitted with nausea and abdominal pain due to bowel obstruction and fever from a urinary tract infection. A switch from injectable hydromorphone to transdermal fentanyl resulted in symptomatic severe bradycardia within 36 h, without any other signs of opioid toxicity and with good analgesic effect. Case management: The fentanyl patch was removed. Atropine was not required. Case outcome: The patient made an uneventful recovery. Transdermal buprenorphine was subsequently used satisfactorily for long-term background pain control, with additional hydromorphone when needed. Conclusions: The delayed absorption of fentanyl via the transdermal route makes early identification of fentanyl-induced bradycardia key to prompt reversal. Patients with resting or relative bradycardia may be at higher than average risk. 22494023 Sol-flame synthesis: a general strategy to decorate nanowires with metal oxide/noble metal nanoparticles. The hybrid structure of nanoparticle-decorated nanowires (NP@NW) combines the merits of large specific surface areas for NPs and anisotropic properties for NWs and is a desirable structure for applications including batteries, dye-sensitized solar cells, photoelectrochemical water splitting, and catalysis. Here, we report a novel sol-flame method to synthesize the NP@NW hybrid structure with two unique characteristics: (1) large loading of NPs per NW with the morphology of NP chains fanning radially from the NW core and (2) intimate contact between NPs and NWs. Both features are advantageous for the above applications that involve both surface reactions and charge transport processes. Moreover, the sol-flame method is simple and general, with which we have successfully decorated various NWs with binary/ternary metal oxide and even noble metal NPs. The unique aspects of the sol-flame method arise from the ultrafast heating rate and the high temperature of flame, which enables rapid solvent evaporation and combustion, and the combustion gaseous products blow out NPs as they nucleate, forming the NP chains around NWs. 23849463 Interleukin newcomers creating new numbers in rheumatology: IL-34 to IL-38. The development of innovative technologies is steadily increasing the body of knowledge on molecules involved in physiological functions. Thus, several interleukins (ILs) have been identified and characterized in the past few years. Here, we detail the structural and functional characteristics of IL-34 to IL-38 with special attention to their involvement in inflammatory joint disease. IL-34 chiefly increases osteoclast activation and proliferation and therefore, it plays a direct role in bone destruction as seen in rheumatoid arthritis (RA). Regulatory T-cells (Tregs) express IL-35, which therefore exerts anti-inflammatory effects by restoring Treg suppressive capabilities and by inhibiting the Th17 pathway. IL-37 has anti-inflammatory effects mediated by a negative feedback loop that decreases the release of pro-inflammatory cytokines. IL-36 belongs to the IL-1 family and has three different forms. Although this cytokine has been chiefly studied in psoriasis and psoriatic arthritis, it also exerts pro-inflammatory effects in RA. The specific IL-36 antagonist, IL-36Ra binds to the IL-36 receptor, thereby, preventing signal transduction. Finally, IL-38 is a recently identified cytokine whose effect may resemble that of IL-36Ra as it binds to the IL-36 receptor and inhibits its effects, particularly the Th17-response. Although the exact roles for these cytokines awaits elucidation, the current improvements in our knowledge of the mechanisms that regulate chronic inflammatory conditions, such as RA may lead to the identification of new treatment targets. 23837590 Structure-dependent inhibitory effects of synthetic cannabinoids against 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and skin tumour promotion in mice. Whether and how synthetic cannabinoids affect inflammation and carcinogenesis has not been well studied. The present study was thus conducted to assess effects of synthetic cannabinoids on inflammation and carcinogenesis in vivo in mice. Twenty-three analogues of synthetic cannabinoids were isolated from, and identified as adulterants in, illegal drugs distributed in the Tokyo metropolitan area, and were examined for their inhibitory effects on the induction of oedema in mouse ears by 12-O-tetradecanoylphorbol-13-acetate (TPA). Furthermore, selected cannabinoids, JWH-018, -122 and -210, were studied for their effects on carcinogenesis induced in mouse skin initiated with 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by TPA. Among cannabinoids, naphthoylindoles mostly exhibited superior inhibitory effects against TPA-induced ear oedema and, especially, JWH-018, -122 and -210 showed potent activity with 50% inhibitory dose (ID50) values of 168, 346 and 542 nm, respectively (an activity corresponding to that of indometacin (ID50 = 908 nm)). Furthermore these three compounds also markedly suppressed the tumour-promoting activity of TPA. This is the first report indicating the structure-activity relationships for the anti-inflammatory activity of synthetic cannabinoids on TPA-induced inflammation in mice. Naphthoylindoles, JWH-018, -122 and -210, had the most potent anti-inflammatory activity and also markedly inhibited tumour promotion by TPA in the two-stage mouse skin carcinogenesis model. The present results suggest that synthetic cannabinoids, such as JWH-018, -122 and -210, may be used as cancer chemopreventive agents in the future. 23927299 3D inpatient dose reconstruction from the PET-CT imaging of (90)Y microspheres for metastatic cancer to the liver: Feasibility study. Purpose: The introduction of radioembolization with microspheres represents a significant step forward in the treatment of patients with metastatic disease to the liver. This technique uses semiempirical formulae based on body surface area or liver and target volumes to calculate the required total activity for a given patient. However, this treatment modality lacks extremely important information, which is the three-dimensional (3D) dose delivered by microspheres to different organs after their administration. The absence of this information dramatically limits the clinical efficacy of this modality, specifically the predictive power of the treatment. Therefore, the aim of this study is to develop a 3D dose calculation technique that is based on the PET imaging of the infused microspheres.Methods: The Fluka Monte Carlo code was used to calculate the voxel dose kernel for (90)Y source with voxel size equal to that of the PET scan. The measured PET activity distribution was converted to total activity distribution for the subsequent convolution with the voxel dose kernel to obtain the 3D dose distribution. In addition, dose-volume histograms were generated to analyze the dose to the tumor and critical structures.Results: The 3D inpatient dose distribution can be reconstructed from the PET data of a patient scanned after the infusion of microspheres. A total of seven patients have been analyzed so far using the proposed reconstruction method. Four patients underwent treatment with SIR-Spheres for liver metastases from colorectal cancer and three patients were treated with Therasphere for hepatocellular cancer. A total of 14 target tumors were contoured on post-treatment PET-CT scans for dosimetric evaluation. Mean prescription activity was 1.7 GBq (range: 0.58-3.8 GBq). The resulting mean maximum measured dose to targets was 167 Gy (range: 71-311 Gy). Mean minimum dose to 70% of target (D70) was 68 Gy (range: 25-155 Gy). Mean minimum dose to 90% of target (D90) was 53 Gy (range: 13-125 Gy).Conclusions: A three-dimensional inpatient dose reconstruction method has been developed that is based on the PET/CT data of a patient treated with (90)Y microspheres. It allows for a complete description of the absorbed dose by the tumor and critical structures. It represents the first step in building predictive models for treatment outcomes for patients receiving this therapeutic modality as well as it allows for better analysis of patients' dose response and will ultimately improve future treatment administration. 23603689 A Bioluminescent Assay System for Whole-Cell Determination of Hormones. A bioluminescent-assay system was fabricated for an efficient determination of bioactive small molecules in physiological samples. The following three components were newly created for this assay system: (i) a single-chain probe exerting a 7.2-times stronger optical intensity than conventional ones, (ii) a high throughput assay device uniquely designed for the assay system with ca. one-fourth smaller standard deviation (SD) to samples than without the device, (iii) a buffer cocktail optimized for the assay system. The advantages of the assay system were evaluated by determining (i) the stress hormone levels in human saliva and (ii) multicolor imaging of genomic and nongenomic effects of woman sex hormones. This study guides on how to fabricate an efficient assay system for bioactive small molecules with convenience and high precision. 23686284 Density functional theory investigation of cocaine water complexes. Twenty cocaine-water complexes were studied using density functional theory (DFT) B3LYP/6-311++G** level to understand their geometries, energies, vibrational frequencies, charge transfer and topological parameters. Among the 20 complexes, 12 are neutral and eight are protonated in the cocaine-water complexes. Based on the interaction energy, the protonated complexes are more stable than the neutral complexes. In both complexes, the most stable structure involves the hydrogen bond with water at nitrogen atom in the tropane ring and C = O groups in methyl ester. Carbonyl groups in benzoyl and methyl ester is the most reactive site in both forms and it is responsible for the stability order. The calculated topological results show that the interactions involved in the hydrogen bond are electrostatic dominant. Natural bond orbital (NBO) analysis confirms the presence of hydrogen bond and it supports the stability order. Atoms in molecules (AIM) and NBO analysis confirms the C-H · · · O hydrogen bonds formed between the cocaine-water complexes are blue shifted in nature. 23963180 Emergence of Epidemic Multidrug-Resistant Enterococcus faecium from Animal and Commensal Strains. ABSTRACT Enterococcus faecium, natively a gut commensal organism, emerged as a leading cause of multidrug-resistant hospital-acquired infection in the 1980s. As the living record of its adaptation to changes in habitat, we sequenced the genomes of 51 strains, isolated from various ecological environments, to understand how E. faecium emerged as a leading hospital pathogen. Because of the scale and diversity of the sampled strains, we were able to resolve the lineage responsible for epidemic, multidrug-resistant human infection from other strains and to measure the evolutionary distances between groups. We found that the epidemic hospital-adapted lineage is rapidly evolving and emerged approximately 75 years ago, concomitant with the introduction of antibiotics, from a population that included the majority of animal strains, and not from human commensal lines. We further found that the lineage that included most strains of animal origin diverged from the main human commensal line approximately 3,000 years ago, a time that corresponds to increasing urbanization of humans, development of hygienic practices, and domestication of animals, which we speculate contributed to their ecological separation. Each bifurcation was accompanied by the acquisition of new metabolic capabilities and colonization traits on mobile elements and the loss of function and genome remodeling associated with mobile element insertion and movement. As a result, diversity within the species, in terms of sequence divergence as well as gene content, spans a range usually associated with speciation. IMPORTANCE Enterococci, in particular vancomycin-resistant Enterococcus faecium, recently emerged as a leading cause of hospital-acquired infection worldwide. In this study, we examined genome sequence data to understand the bacterial adaptations that accompanied this transformation from microbes that existed for eons as members of host microbiota. We observed changes in the genomes that paralleled changes in human behavior. An initial bifurcation within the species appears to have occurred at a time that corresponds to the urbanization of humans and domestication of animals, and a more recent bifurcation parallels the introduction of antibiotics in medicine and agriculture. In response to the opportunity to fill niches associated with changes in human activity, a rapidly evolving lineage emerged, a lineage responsible for the vast majority of multidrug-resistant E. faecium infections. 23811151 DNA interaction of [Cu(dmp)(phen-dion)] (dmp=4,7 and 2,9 dimethyl phenanthroline, phen-dion=1,10-phenanthroline-5,6-dion) complexes and DNA-based electrochemical biosensor using chitosan-carbon nanotubes composite film. The interaction of two new water-soluble [Cu(4,7-dmp)(phen-dione)Cl]Cl (1) and [Cu(2,9-dmp)(phen-dione)Cl]Cl (2) which dmp is dimethyl-1,10-phenanthroline and phen-dion represents 1,10-phenanthroline-5,6-dion, with DNA in solution and immobilized DNA on a chitosan-carbon nanotubes composite modified glassy carbon electrode were investigated by cyclic voltammetry and UV-Vis spectroscopy techniques. In solution interactions, spectroscopic and electrochemical evidences indicate outside binding of these complexes. To clarify the binding mode of complexes, it was done competition studies with Hoechst and Neutral red as groove binder and intercalative probes, respectively. All these results indicating that, these two complexes (1) and (2) interact with DNA via groove binding and partially intercalative modes, respectively. The electrochemical characterization experiments showed that the nanocomposite film of chitosan-carbon nanotubes could effectively immobilize DNA and greatly improve the electron-transfer reactions of the electroactive molecules that latter finding is the result of strong interactions between captured DNA and Cu complexes. This result indicates that these complexes could be noble candidates as hybridization indicators in further studies. At the end, these new complexes showed excellent antitumor activity against K562 (human chronic myeloid leukemia) cell lines. 23902459 Visible Light Water Oxidation Using a Co-Catalyst Loaded Anatase-Structured Ti1-(5x/4)NbxO2-y-δNy Compound. The photocatalytic activity of anatase-structured Ti1-(5x/4)NbxO2-y-δNy (x = 0.25, y = 0.02; NbN-25) was examined for water oxidation under UV and visible light irradiation. The semiconductor was prepared by sol-gel processing followed by nitridation in flowing ammonia and exhibits an indirect optical gap of 2.2 eV. Ti1-(5x/4)NbxO2-y-δNy was loaded with RuO2 by an impregnation technique, and optimized conditions reveal that 1 wt % RuO2 generates 16 μmol O2 from water with concomitant IO3(-) reduction after 3 h of illumination under simulated solar radiation at a flux of 600 mW/cm(2) illumination, which corresponds to 6-sun AM1.5G illumination (compared to no detectible O2 without the RuO2 cocatalyst). A series of cut-on filters shows that the catalyst-loaded semiconductor evolves O2 for λ ≤ 515 nm, and a gas-phase mass spectrometry isotope labeling experiment shows that irradiating an iodate solution in H2(18)O in the presence of 1 wt % RuO2 loaded on NbN-25 gives rise to catalytic water oxidation: both (36)O2 and (34)O2 are observed. It is unclear whether (16)O arises from IO3(-) or surface reconstruction on the photocatalyst, but ICP-AES analysis of the postirradiated solution shows no dissolved metal ions. 23139089 Palivizumab immunoprophylaxis effectiveness in children with cystic fibrosis. Evidence on the effectiveness of respiratory syncytial virus (RSV) immunoprophylaxis with palivizumab in children with cystic fibrosis (CF) is lacking. We utilized Medicaid Extract files from 27 states from 1999 to 2006 linked to the National Cystic Fibrosis Registry to establish a cohort of children 0-2 years with CF diagnosis. Eligible children entered the cohort after CF diagnosis and after RSV season onset, and were followed until season end, second birthday, death, or hospitalizations for reasons other then the study outcome. Two outcomes were examined: hospitalization for RSV infections (RSV-ha), or hospitalization for acute respiratory infections (ARI-ha). Palivizumab exposure was defined based on pharmacy or procedure claims as current (claim date plus 30 days), former (day 31-60 after a claim), and no exposure (days before the first or >60 days after any claim). Both outcomes were examined in a Cox regression model, adjusting for RSV risk factors and CF severity via exposure propensity score. The matched cohort included 1,974 infants (2,875 infant seasons), who experienced 32 RSV-ha and 212 ARI-ha (3.9 and 26.2/1,000 season months, respectively). Compared to periods of no use, the adjusted hazard ratio for current use was 0.57 (95% confidence interval [CI]: 0.20-1.60) for RSV-related hospitalization and 0.85 (95% CI: 0.59-1.21) for ARI-related hospitalization. Each month of increasing age reduced the ARI-ha by 5.8%. RSV hospitalization incidence was low suggesting either little contribution of the virus to respiratory infections in patients with CF or lack of RSV testing. Unadjusted and adjusted RSV-hospitalization incidence rates suggested potentially positive effects of palivizumab, but results were inconclusive due to small event rates. Hospitalizations for acute respiratory illness with possible RSV contribution showed no association with palivizumab use, suggesting limited overall effect of palivizumab. Younger age greatly increased infection risk. Pediatr Pulmonol. 2013; 48:874-884. © 2012 Wiley Periodicals, Inc. 23874882 Loss of notch1 disrupts the barrier repair in the corneal epithelium. The corneal epithelium is the outermost layer of the cornea that directly faces the outside environment, hence it plays a critical barrier function. Previously, conditional loss of Notch1 on the ocular surface was found to cause inflammation and keratinization of the corneal epithelium. This was in part attributed to impaired vitamin A metabolism, loss of the meibomian glands and recurrent eyelid trauma. We hypothesized that Notch1 plays an essential role in the corneal epithelial barrier function and is a contributing factor in the pathologic changes in these mice. Notch1 was conditionally deleted in adult Notch1(flox/flox), K14-Cre-ERT(+/-) mice using hydroxy-tamoxifen. The results indicated that conditional deletion of Notch1 on the ocular surface leads to progressive impairment of the epithelial barrier function before the onset of corneal opacification and keratinization. Loss of the barrier was demonstrated both by an increase in in vivo corneal fluorescein staining and by enhanced penetration of a small molecule through the epithelium. Corneal epithelial wounding resulted in significant delay in recovery of the barrier function in conditional Notch1(-/-) mice compared to wild type. Mice with conditional deletion of Notch1 did not demonstrate any evidence of dry eyes based on aqueous tear production and had normal conjunctival goblet cells. In a calcium switch experiment in vitro, Notch1(-/-) cells demonstrated delayed membrane localization of the tight junction protein ZO-1 consistent with a defect in the epithelial tight junction formation. These findings highlight the role of Notch1 in epithelial differentiation and suggest that intrinsic defects in the corneal epithelial barrier recovery after wounding is an important contributing factor to the development of inflammatory keratinization in Notch1(-/-) mice. 23723158 Nuclear phosphatase PPM1G in cellular survival and neural development. Background: PPM1G is a nuclear localized serine/threonine phosphatase implicated to be a regulator of chromatin remodeling, mRNA splicing, and DNA damage. However, its in vivo function is unknown. Results: Here we show that ppm1g expression is highly enriched in the central nervous system during mouse and zebrafish development. ppm1g(-/-) mice were embryonic lethal with incomplete penetrance after E12.5. Rostral defects, including neural tube and craniofacial defects were observed in ppm1g(-/-) embryos associated with increased cell death in the neural epithelium. In zebrafish, loss of ppm1g also led to neural defects with aberrant neural marker gene expression. Primary fibroblasts from ppm1g(-/-) embryos failed to grow without immortalization while immortalized ppm1g(-/-) fibroblasts had increased cell death upon oxidative and genotoxic stress when compared to wild type fibroblasts. Conclusions: Our in vivo and in vitro studies revealed a critical role for PPM1G in normal development and cell survival. Developmental Dynamics 242:1101-1109, 2013. © 2013 Wiley Periodicals, Inc. 23830198 Driver sleepiness and risk of motor vehicle crash injuries: A population-based case control study in Fiji (TRIP 12). Published studies investigating the role of driver sleepiness in road crashes in low and middle-income countries have largely focused on heavy vehicles. We investigated the contribution of driver sleepiness to four-wheel motor vehicle crashes in Fiji, a middle-income Pacific Island country. The population-based case control study included 131 motor vehicles involved in crashes where at least one person died or was hospitalised (cases) and 752 motor vehicles identified in roadside surveys (controls). An interviewer-administered questionnaire completed by drivers or proxies collected information on potential risks for crashes including sleepiness while driving, and factors that may influence the quantity or quality of sleep. Following adjustment for confounders, there was an almost six-fold increase in the odds of injury-involved crashes for vehicles driven by people who were not fully alert or sleepy (OR 5.7, 95%CI: 2.7, 12.3), or those who reported less than 6h of sleep during the previous 24h (OR 5.9, 95%CI: 1.7, 20.9). The population attributable risk for crashes associated with driving while not fully alert or sleepy was 34%, and driving after less than 6h sleep in the previous 24h was 9%. Driving by people reporting symptoms suggestive of obstructive sleep apnoea was not significantly associated with crash risk. Driver sleepiness is an important contributor to injury-involved four-wheel motor vehicle crashes in Fiji, highlighting the need for evidence-based strategies to address this poorly characterised risk factor for car crashes in less resourced settings. 23313795 Flavonoids profiles, antioxidant, acetylcholinesterase inhibition activities of extract from Dryoathyrium boryanum (Willd.) Ching. The profiles and bioactivities of flavonoids extracted from Dryoathyrium boryanum (Willd.) Ching were investigated. The total flavonoids content in extract from D. boryanum is about 145.8mg/g. By means of HPLC-DAD-ESI-MS, the main flavonoids in D. boryanum were tentatively identified as 3-hydroxyphloretin 6'-O-hexoside, quercetin-7-hexoside, apigenin7-O-glucoside, luteolin 7-O-glucoside, apigenin 7-O-galactoside, acacetin 7-O-(α-D-apio-furanosyl) (1→6)-β-d-glucoside, 3-hydroxy phloretin 6-O-hexoside, luteolin-6-C-glucoside. 0.21mg/ml flavonoids extract from D. boryanum showed very strong superoxide anion radical scavenging potential, which is higher than that of rutin (0.25mg/ml). The extract (0.21mg/ml of flavonoids) from D. boryanum exhibited similar DPPH scavenging potential with that of rutin (0.25mg/ml). However, rutin (0.25mg/ml) showed a significantly higher reducing power and ABTS scavenging potential than that of 0.21mg/ml flavonoids extract from D. boryanum. It had no effect on acetylcholinesterase. D. boryanum can be considered as a medicinal plant and the flavonoids from D. boryanum are excellent antioxidants. 23232793 Anxious and non-anxious adolescents' experiences of non-clinical magnetic resonance imaging research. Magnetic resonance imaging (MRI) has become a ubiquitous research tool for developmental neuroscientists interested in brain structure and function in children and adolescents. However, ethical concerns are sometimes raised about using MRI with children and adolescents, especially when participants have anxiety. We asked 17 clinically/sub-clinically anxious and 19 non-anxious adolescents about their experiences of taking part in MRI for research purposes. Although the anxious group reported experiencing more anxiety during the scan, these differences had attenuated by the time participants got home. We found no evidence that anxious adolescents would be less likely to choose to have another scan or would feel more nervous during another scan. There was some evidence that more trait anxious adolescents found the MRI study enjoyable. These findings should give ethics committees, clinicians, and parents confidence that so long as researchers exercise appropriate care, MRI research is acceptable to adolescents, including those with clinical anxiety. 23810965 Thermal stratification patterns in urban ponds and their relationships with vertical nutrient gradients. Ponds that collect and process stormwater have become a prominent feature of urban landscapes, especially in areas recently converted to residential land use in North America. Given their increasing number and their tight hydrological connection to residential catchments, these small aquatic ecosystems could play an important role in urban biogeochemistry. However, some physicochemical aspects of urban ponds remain poorly studied. Here we assessed the frequency and strength of water column stratification, using measurements of vertical water temperature profiles at high spatial and temporal frequency, in 10 shallow urban stormwater management ponds in southern Ontario, Canada. Many of the ponds were well stratified during much of the summer of 2010 as indicated by relatively high estimates of thermal resistance to mixing (RTRM) indices. Patterns of stratification reflected local weather conditions but also varied among ponds depending on their morphometric characteristics such as maximum water depth and surface area to perimeter ratio. We found greater vertical nutrient gradients and more phosphorus accumulation in bottom waters in ponds with strong and persistent stratification, which likely results from limited particle resuspension and more dissolved phosphorus (P) release from sediments. However, subsequent mixing events in the fall diminished vertical P gradients and possibly accelerated internal loading from the sediment-water interface. Our results demonstrate that stormwater ponds can experience unexpectedly long and strong thermal stratification despite their small size and shallow water depth. Strong thermal stratification and episodic mixing in ponds likely alter the quantity and timing of internal nutrient loading, and hence affect water quality and aquatic communities in downstream receiving waters. 23537891 Associations of aortic distensibility and arterial elasticity with long-term visit-to-visit blood pressure variability: the Multi-Ethnic Study of Atherosclerosis (MESA). Although higher visit-to-visit variability (VVV) of blood pressure (BP) is associated with increased cardiovascular disease risk, the physiological basis for VVV of BP is incompletely understood. We examined the associations of aortic distensibility (assessed by magnetic resonance imaging) and artery elasticity indices (determined by radial artery pulse contour analysis) with VVV of BP in 2,640 and 4,560 participants, respectively, from the Multi-Ethnic Study of Atherosclerosis. Arterial measures were obtained at exam 1. BP readings were taken at exam 1 and at 3 follow-up visits at 18-month intervals (exams 2, 3, and 4). VVV was defined as the SD about each participant's mean systolic BP (SBP) across visits. The mean SDs of SBP were inversely associated with aortic distensibility: 7.7, 9.9, 10.9, and 13.2mm Hg for quartiles 4, 3, 2, and 1 of aortic distensibility, respectively (P trend < 0.001). This association remained significant after adjustment for demographics, cardiovascular risk factors, mean SBP, and antihypertensive medication use (P trend < 0.01). In a fully adjusted model, lower quartiles of large artery and small artery elasticity (LAE and SAE) indices were also associated with higher mean SD of SBP (P trend = 0.02 for LAE; P trend < 0.001 for SAE). In this multiethnic cohort, functional alterations of central and peripheral arteries were associated with greater long-term VVV of SBP. 23768831 Correlation between MMP-2 and NF-κ B expression of intracranial aneurysm. To investigate the correlation between expressions of MMP-2 and NF-κ B in the intracranial aneurysm wall, and explore their role in the mechanism of the occurrence, growth and rupture of intracranial aneurysms. RT-PCR was used to detect the expression of MMP-2 and NF-κ B mRNA of 30 cases of intracranial aneurysm tissue and 10 cases of normal intracranial arterial tissue; Immunohistochemical method was used to detect the expression of MMP-2 and NF-κ B protein. The semi-quantitative analysis of MMP-2 and NF-κ B in aneurysms tissues and normal tissues were statistically significant different from each other (P<0 05). Immunohistochemical staining results showed NF-κ B was expressed in different layers. The expression of them were positive in intimal and medial, and the expression sites were located in the nucleus. MMP-2 were expressed in different layers of the aneurysm wall, and the expressions were positive in media and extima. The MMP-2 and NF- κ B-positive expression of aneurysm wall were significantly higher than in normal cerebral arteries (P <0.05). MMP-2 and NF-κ B mRNA expression showed positive correlation in the aneurysm wall tissue (r = 0.689, P = 0.005). The expressions of MMP-2 and NF-κ B in the intracranial aneurysm wall tissue were significantly higher than in the normal intracranial arterial tissues. They have a synergistic effect on the formation of intracranial aneurysms. 23837425 Associations between residency selection strategies and doctor performance: a meta-analysis. The purpose of this study was to use meta-analysis to establish which of the information available to the resident selection committee is associated with resident or doctor performance. Multiple electronic databases were searched to 4 September 2012. Two reviewers independently selected studies that met the present inclusion criteria and extracted data in duplicate; disagreement was resolved by consensus. Risk for bias was assessed using a customised bias assessment tool. Measures of association were converted to a common effect size (Hedges' g). Meta-analysis was performed using the random-effects model for each selection strategy and all outcomes without pooling. Sensitivity analysis for each selection strategy-outcome pair was performed with pooling of effect size. Eighty studies involving a total of 41 704 participants were included in the meta-analysis. Seventeen different selection strategies and 17 outcomes were assessed across these studies. The strongest positive associations referred to examination-based selection strategies, such as the US Medical Licensing Examination (USMLE) Step 1, and examination-based outcomes, such as scores on in-training examinations. Moderate positive associations were present for medical school marks and both examination-based and subjective outcomes. Minimal or no associations were seen for the selection tools represented by interviews, reference letters and deans' letters. Standardised examination performance and medical school grades show the strongest associations with current measures of doctor performance. Deans' letters, reference letters and interviews all show a lower than expected strength of association given the relative value often assigned to them during resident doctor selection. Objective selection strategies are potentially the most useful to residency selection committees based on current evaluative methods. However, reports in the literature of validated long-term doctor performance outcomes are scant. 23868008 Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a γ-secretase inhibitor, in a preclinical colorectal explant model. Background:Dysregulation of the Notch pathway has been identified to play an important role in the development and progression of colorectal cancer (CRC). In this study, we used a patient-derived CRC explant model to investigate the efficacy of the clinical γ-secretase inhibitor (GSI) PF-03084014.Methods:A total of 16 CRC explants were treated with PF-03084014. Knockdown of RBPjκ gene was used to determine the specificity of PF-03084014. Evaluation of the Notch and Wnt pathways in CRC explant tumours was performed by gene array and immunoblotting.Results:We identified a subset of CRC tumours that exhibited elevations of the Notch and Wnt pathways sensitive to PF-03084014. Treatment with the GSI resulted in a significant reduction in cleaved Notch, Axin2 (Wnt-dependent gene) and active β-catenin. In addition, knockdown of the RBPjκ gene showed that PF-03084014 has specificity for the Notch pathway in an HCT116 cell line xenograft model. Finally, an increase in apoptosis was observed in CRC001- and CRC021-sensitive tumours.Conclusion:This study provides evidence that inhibition of γ-secretase may be beneficial in a subset of patients with elevated levels of the Wnt and Notch pathways. 23744502 Long-term survival of the uncemented Balgrist total hip replacement cup. The purpose of this study was to evaluate the long-term clinical and radiographic outcomes of the Balgrist total hip replacement cup. We report the results of a retrospective review of 195 total hip prostheses with Balgrist cup implanted in 178 patients. There were 59 men and 119 women with a mean age at surgery of 52.3 years (range, 19-72). Cox regression was used to determine the influence of independent variables on the survivorship of the prosthesis. There were 117 (66 %) of 178 patients, and 131 (67 %) of 195 hips available for assessment at a mean follow-up of 17.4 years. A total of 21 patients (22 hips) were lost from follow-up (12 %). A total of 25 patients (27 hips) required some type of re-operation during the follow-up period. Eight of 27 re-operations (30 %) were directly caused by the Balgrist cup failure due to fatigue fracture of the metallic shell (n = 5; 19 %), polyethylene wear (n = 2; 7 %) and aseptic loosening (n = 1; 4 %). The mean polyethylene wear rate was 0.068 mm/year (range, 0.008-0.230; SD = 0.043). The risk of re-operation for any reason was decreased with dysplastic hip as a primary diagnosis (hazard ratio; HR = 0.250; 95 % CI 0.086-0.725) and with greater age at the time of surgery (HR = 0.923; 95 % CI 0.880-0.969). The 19-year survivorship with re-operation for any reason was 75.6 % (95 % CI 67.0-84.2). The 19-year survivorship with re-operation for the Balgrist cup failure was 90.5 % (95 % CI 83.4-97.6). The Balgrist cup continues to provide excellent clinical and radiological outcomes. This is associated at least in part with a low polyethylene wear rate. The main reason for the Balgrist cup failure is fatigue fracture of the metallic shell. 23943611 {Mo24 Fe12 } Macrocycles: Anion Templation with Large Polyoxometalate Guests. POM and circumstance: Nanometer-sized polyoxometalates (POMs) bring a new direction to anion-templated supramolecular chemistry. The Keggin- (left) and Dawson-type (right) polyoxoanions direct the assembly of giant metallomacrocycles through an array of weak hydrogen-bonding interactions. The concerted action of multiple hydrogen bonds keeps the templating guests embedded within the hosts, even in the solution state. 23746337 The association of interleukin-18 promoter polymorphisms and serum levels with duodenal ulcer, and their correlations with bacterial CagA and VacA virulence factors. Abstract Background: We analyzed the impact of interleukin (IL)-18 promoter polymorphisms on IL-18 serum levels in Helicobacter pylori-infected duodenal ulcer (DU) patients and healthy asymptomatic (AS) carriers. We also aimed to determine the association of the H. pylori virulence factors CagA and VacA antibodies with serum concentrations of IL-18 in order to elucidate any correlation between them. Methods: Three groups of patients were enrolled: DU patients (67 individuals), AS carriers (48 individuals), and H. pylori-negative subjects (26 individuals). Serum concentrations of IL-18 were determined by ELISA. Patient sera were tested by Western blot method to determine the presence of serum antibodies to bacterial CagA and VacA. Genotyping of IL-18 promoter polymorphisms at positions - 137G/C and - 607C/A were performed by allele-specific primer PCR protocol. Results: Our study revealed that serum IL-18 levels are positively influenced by CagA-positive H. pylori strains, so that maximum levels of IL-18 were detected in DU patients with the CagA(+) phenotype, regardless of the presence of the anti-VacA antibody. Regarding IL-18 promoter polymorphisms, the AA genotype and A allele at position - 607C/A were found to be significantly lower in DU patients than in AS carriers and H. pylori-negative subjects (p = 0.032 and 0.043, respectively). Conclusions: The IL-18 - 607C variant was associated with higher levels of serum IL-18 and an increased risk of DU. Moreover, our findings indicated that serum concentrations of IL-18 were influenced by CagA factor, irrespective of the VacA status, suggesting that high levels of IL-18 in CagA-positive subjects predisposes to susceptibility to DU. 23915295 A novel approach to scavenging anesthetic gases in rodent surgery. Laboratory animal procedures using gas anesthetics may amass elevated waste gas concentrations in operating rooms if controls are not implemented for capturing and removing the vapors. Area sampling using an infrared analyzer indicated isoflurane concentrations likely to exceed occupational exposure guidelines. Our study showed environmental concentrations of oxygen as high as 40% and isoflurane concentrations >100 ppm when no controls or merely passive controls were utilized. These extraneous isoflurane emissions were determined to be originating from the pre-procedural induction process as well as the gas delivery nose cone. A novel waste gas collection cylinder was designed to enclose the gas delivery nose cone and animal head during the administration of anesthetic gases. The vented cylinder utilized a house vacuum to remove the waste anesthetic gases from the surgical field. A commercially available induction chamber designed to be actively and externally exhausted was used to lower concentrations during the induction process. With implementation of local exhaust ventilation controls, waste anesthetic gas concentrations decreased to below recommended occupational exposure levels. In vitro (sham) testing compared favorably to in vivo measurements validating the reduction capability of active ventilation during rodent anesthetic administration. In vivo isoflurane reductions for the induction chamber emissions, the operating room, and the surgeon's breathing zone were 95%, 60%, and 53%, respectively. The same measurements for an in vitro procedure were 98%, 84%, and 87%, respectively. 23471176 Stents are associated with increased risk of respiratory infections in patients undergoing airway interventions for malignant airways disease. Long-term complications of therapeutic bronchoscopy include infections and airway restenosis due to tumor. No studies have compared the incidence rates of infection in patients with stents with those without stents. We hypothesized that patients with stents would have a higher incidence of lower respiratory tract infections than would patients without stents. We conducted a retrospective cohort study, covering the period September 2009 to August 2011, of patients who had therapeutic bronchoscopy for malignant airways disease. Outcomes recorded were lower respiratory tract infection and airway restenosis by tumor. Seventy-two patients had therapeutic bronchoscopy for malignant airways disease. Twenty-four of these patients had one or more stents placed. Twenty-three of the 72 patients (32%) developed lower respiratory tract infections. Stents were associated with an increased risk of infection (hazard ratio [HR], 3.76; 95% CI, 1.57-8.99; P = .003). The incidence rate of lower respiratory tract infection was 0.0057 infections per person-day in patients with stents vs 0.0011 infections per person-day in patients without stents. The incidence rate difference, 0.0046 infections per person-day, was significant (95% CI, 0.0012-0.0081; P = .0002). Restenosis due to tumor overgrowth was associated with more severe obstruction at baseline (obstruction ≥ 50% vs < 50% preprocedure; HR, 13.71; 95% CI, 1.75-107.55; P = .013). Therapeutic bronchoscopy with stent placement is associated with a higher risk of infection than is therapeutic bronchoscopy alone. If ablative techniques reopen the airway and there is a good chance that the tumor may respond to chemotherapy and/or radiation, a strategy of initially holding off on stenting may be warranted. 23628646 Putative drug and vaccine target protein identification using comparative genomic analysis of KEGG annotated metabolic pathways of Mycoplasma hyopneumoniae. In the present study, a computational comparative and subtractive genomic/proteomic analysis aimed at the identification of putative therapeutic target and vaccine candidate proteins from Kyoto Encyclopedia of Genes and Genomes (KEGG) annotated metabolic pathways of Mycoplasma hyopneumoniae was performed for drug design and vaccine production pipelines against M.hyopneumoniae. The employed comparative genomic and metabolic pathway analysis with a predefined computational systemic workflow extracted a total of 41 annotated metabolic pathways from KEGG among which five were unique to M. hyopneumoniae. A total of 234 proteins were identified to be involved in these metabolic pathways. Although 125 non homologous and predicted essential proteins were found from the total that could serve as potential drug targets and vaccine candidates, additional prioritizing parameters characterize 21 proteins as vaccine candidate while druggability of each of the identified proteins evaluated by the DrugBank database prioritized 42 proteins suitable for drug targets. 23879780 Associations between perceptions of school connectedness and adolescent health risk behaviors in South african high school learners. This study investigated the relationship between school connectedness and health risk behaviors, specifically, substance abuse, violence-related behaviors, sexual risk behaviors, and suicidal ideation among school-going adolescents. School connectedness was understood to encompass a range of aspects pertaining to a learner's sense of belonging to the school. We hypothesized that strong perceptions of school connectedness will more likely be associated with lower levels of risk behaviors among school-going adolescents. The study was conducted in 2 neighboring public co-educational schools in Durban, South Africa. Independent measures assessed school connectedness, substance abuse, violence-related behaviors, sexual risk behaviors, and suicidal ideation. Strong negative correlations were found between adolescents' perceptions of school connectedness and the 4 health risk behaviors, particularly suicidal ideation. The relative importance of risk factors was also evidenced in the sample. Adolescents with lower perceptions of school connectedness were more likely to engage in various risk behaviors, supporting the literature that a lack of school connectedness can act as a risk factor for adolescent involvement in clustering of risk behaviors. Further the relative weighting of individual risk factors, it is argued, was an effect of the sociocultural context of the study. 23194523 Determination of herb authenticity by low-field NMR. The safe use of herbal medicines requires prior authentication of the raw materials used to make them. This is an important step, since the ingestion of herbal preparations or extracts can cause serious health problems. Among the different analytical techniques, nuclear magnetic resonance (NMR) spectroscopy has the advantage of being non-invasive and therefore suitable for the characterization of natural products such as medicinal plants. This work presents a characterisation study of the samples of the popular plant Maytenus ilicifolia, obtained from different commercial producers. This plant is used for the treatment of gastrointestinal disorders, as it possesses antitumorigenic, analgesic, anti-inflammatory and antioxidant properties. The differences in the chemical structure and molecular organisation detected by thermogravimetric analysis (TGA), infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (NMR) were also investigated by proton nuclear magnetic resonance relaxometry, in particular by fast field cycling (FFC) relaxometry, and relaxometry in the rotating frame. All results confirmed the similarity between the control sample and only one of the plant investigated. The differences detected between the samples could be related to their non-authenticity, due to the non recognise the plant due to the leaves similarity among plants from the same family and/or contamination, due to addition of similar other plants parts to the commercial ones, as they are mixed together this difficulties the acceptation of the plant. 23906906 Ca2+ imaging in plants using genetically encoded yellow cameleon Ca2+ indicators. Temporally and spatially defined changes in cellular calcium (Ca(2+)) concentration represent stimulus-specific signals and regulate a myriad of biological processes. The development of ratiometric Ca(2+) reporter proteins like Yellow Cameleons (YCs) has greatly advanced our ability to analyze Ca(2+) dynamics in vivo with unprecedented spatial and temporal resolution. In plants, the application of these Ca(2+) reporter proteins has been pioneered for the investigation of Ca(2+) dynamics in guard cells, and recently their use has been extended to other single-cell models like growing pollen tubes and root hairs. However, in plants, the use of YC reporter proteins has largely remained restricted to the investigation of cytoplasmic alterations of Ca(2+) concentrations. Here, we provide an introduction to current methods for imaging Ca(2+) dynamics with increasing sophistication. 23387987 Allograft survival enhancement using doxycycline in alkali-burned mouse corneas. Purpose:  To explore the inhibitory effects of doxycycline on allograft rejection in alkali-burned cornea beds. Methods:  The corneas of BALB/c mice were injured using a 1 mol/l NaOH solution. Following the injury, the corneas from C57BL/6 mice were transplanted into the eyes of BALB/c mice after being randomized into three groups: allogeneic corneal transplantation (group A), topical use of doxycycline after allogeneic corneal transplantation (group B) and syngeneic corneal transplantation (group C). Corneal angiogenesis was examined using whole-mount immunofluorescence, and corneal inflammation was evaluated using inflammation index scoring. The immune rejection of the grafts was examined using a slit lamp. In addition, the expression of vascular endothelial growth factor A and interleukin-1β in the transplanted corneas was examined using a real-time polymerase chain reaction, immunohistochemistry and an enzyme-linked immunosorbent assay. Results:  The outgrowth of the corneal blood vessels in the group A mice was faster than that in the group B and group C mice. The inflammation index levels were highest in the group A mice, intermediate in the group B mice and lowest in the group C mice. Vascular endothelial growth factor and the interleukin-1β protein and mRNA levels decreased dramatically in the group B mice compared with the group A mice (all p-values < 0.01). In addition, the mean survival time in the group B mice (27.00 ± 2.00 days) was significantly longer than that in the group A mice (11.67 ± 1.51 days; p < 0.05). Conclusions:  Doxycycline may have had a significant role in preventing corneal angiogenesis and inflammation in alkali-burned corneal beds, which resulted in higher allograft survival rates. 23953778 Lack of claudin-7 is a strong predictor of regional recurrence in oral and oropharyngeal squamous cell carcinoma. Adequate treatment of oral and oropharyngeal squamous cell carcinoma (OSCC) is dependent on correctly predicting the presence of lymph node metastases. Current methods to diagnose nodal metastases partly result in overtreatment with associated morbidity and undertreatment with decreased disease-free survival. E-cadherin has been studied extensively as potential marker for lymph node metastases. EpCAM and claudin-7 have a functional relationship with E-cadherin, forming a complex that promotes tumourigenicity in vitro. We hypothesize that the co-expression patterns of these related molecules is a better prognostic marker for nodal status and regional recurrences. We constructed separate tissue microarrays of tumour centre and tumour invasive front of 227 OSCC with complete clinicopathological and follow-up data, including HPV status, and performed immunohistochemistry for these molecules. Lack of E-cadherin and presence of cytoplasmic EpCAM expression in the tumour front were predictive for nodal metastasis, but no co-expression pattern was found clinically relevant. Lack of claudin-7 in the tumour centre was highly and independently predictive for shorter regional disease-free survival (HR=0.19; 95%CI: 0.06-0.62) and disease-specific survival (HR=0.43; 95%CI: 0.21-0.87). High-risk HPV was not associated with any marker. The expression of E-cadherin and EpCAM, depending on the specific tumour sublocalization, is predictive for nodal status. However, co-expression did not improve the prediction of nodal status, indicating that the proposed in vitro complex is not functional in clinical samples. Additionally, lack of claudin-7 expression in the tumour centre may be used to identify patients with increased risk for regional recurrence. 23456921 Which density functional is close to CCSD accuracy to describe geometry and interaction energy of small non-covalent dimers? A benchmark study using gaussian09. A benchmark study on all possible density functional theory (DFT) methods in Gaussian09 is done to locate functionals that agree well with CCSD/aug-cc-pVTZ geometry and Ave-CCSD(T)/(Q-T) interaction energy (Eint ) for small non-covalently interacting molecular dimers in "dispersion-dominated" (class 1), "dipole-induced dipole" (class 2), and "dipole-dipole" (class 3) classes. A DFT method is recommended acceptable if the geometry showed close agreement to CCSD result (RMSD < 0.045) and Eint was within 80-120% accuracy. Among 382 tested functionals, 1-46% gave good geometry, 13-44% gave good Eint , while 1-33% satisfied geometry and energy criteria. Further screening to locate the best performing functionals for all the three classes was made by counting the acceptable values of energy and geometry given by each functionals. The meta-generalized gradient approximation (GGA) functional M06L was the best performer with total 14 hits; seven acceptable energies and seven acceptable geometries. This was the only functional "recommended" for at least two dimers in each class. The functionals M05, B2PLYPD, B971, mPW2PLYPD, PBEB95, and CAM-B3LYP gave 11 hits while PBEhB95, PW91B95, Wb97x, BRxVP86, BRxP86, HSE2PBE, HSEh1PBE, PBE1PBE, PBEh1PBE, and PW91TPSS gave 10 hits. Among these, M05, B971, mPW2PLYPD, Wb97x, and PW91TPSS were among the "recommended" list of at least one dimer from each class. Long-range correction (LC) of Hirao and coworkers to exchange-correlation functionals showed massive improvement in geometry and Eint . The best performing LC-functionals were LC-G96KCIS and LC-PKZBPKZB. Our results predict that M06L is the most trustworthy DFT method in Gaussian09 to study small non-covalently interacting systems. © 2013 Wiley Periodicals, Inc. 23925797 Improving the performance of hollow waveguide-based infrared gas sensors via tailored chemometrics. The use of chemometrics in order to improve the molecular selectivity of infrared (IR) spectra has been evaluated using classic least squares (CLS), partial least squares (PLS), science-based calibration (SBC), and multivariate curve resolution-alternate least squares (MCR-ALS) techniques for improving the discriminatory and quantitative performance of infrared hollow waveguide gas sensors. Spectra of mixtures of isobutylene, methane, carbon dioxide, butane, and cyclopropane were recorded, analyzed, and validated for optimizing the prediction of associated concentrations. PLS, CLS, and SBC provided equivalent results in the absence of interferences. After addition of the spectral characteristics of water by humidifying the sample mixtures, CLS and SBC results were similar to those obtained by PLS only if the water spectrum was included in the calibration model. In the presence of an unknown interferant, CLS revealed errors up to six times higher than those obtained by PLS. However, SBC provided similar results compared to PLS by adding a measured noise matrix to the model. Using MCR-ALS provided an excellent estimation of the spectra of the unknown interference. Furthermore, this method also provided a qualitative and quantitative estimation of the components of an unknown set of samples. In summary, using the most suitable chemometrics approach could improve the selectivity and quality of the calibration model derived for a sensor system, and may avoid the need to analyze expensive calibration data sets. The results obtained in the present study demonstrated that (1) if all sample components of the system are known, CLS provides a sufficiently accurate solution; (2) the selection between PLS and SBC methods depends on whether it is easier to measure a calibration data set or a noise matrix; and (3) MCR-ALS appears to be the most suitable method for detecting interferences within a sample. However, the latter approach requires the most extensive calculations and may thus result in limited temporal resolution, if the concentration of a component should be continuously monitored. 23965849 Establishment and Application of a Loop-Mediated Isothermal Amplification Method for Simple, Specific, Sensitive, and Rapid Detection of Toxoplasma gondii. Loop-mediated isothermal amplification (LAMP) method amplifies DNA with high simply, specificity, sensitivity and rapidity. In this study, A LAMP assay with six primers targeting a highly conserved region of the GRA1 gene has been developed to diagnose Toxoplasma gondii. The reaction time of the LAMP assay was shortened to 30 min after optimizing the reaction system. The LAMP assay was found to be highly specific and stable. The detection limit of the LAMP assay was 10 copies, the same as that of the conventional PCR. We used the LAMP assay to develop a real-time fluorogenic protocol to quantitate T. gondii DNA, and generated a log-linear regression plot by plotting the time-to-threshold values against genomic equivalent copies. Furthermore, the LAMP assay was applied to detect T. gondi DNA in 423 blood samples and 380 lymph nodes samples from 10 pig farms. Positive results were 7.8% and 8.2%, anf the result shows LAMP method is some more sensitive than conventional PCR (6.1% and 7.6%). Positive samples obtained from 6 pig farms. The LAMP assay established in this study resulted in simple, specific, sensitive and rapid detection of T. gondii DNA, and is expected to play an important role in the clinical detection. 23448105 How do delivery mode and parity affect pelvic organ prolapse? To determine the association between mode of delivery, parity, and pelvic organ prolapse, as assessed by the pelvic organ prolapse quantification system. Cross-sectional study. Tertiary referral center, Turkey. A total of 1964 women with benign gynecological disorders who presented between October 2009 and July 2011. Evaluation using the pelvic organ prolapse quantification system and questionnaire assessing previous obstetrics and medical history. Difference in pelvic organ prolapse stages between nulliparous and multiparous women, impact of parity and mode of delivery. In the study population, 86.4, 7.2 and 6.4% had pelvic organ prolapse of stages 0-I, II, and III-IV, respectively, and 7.9% had significant prolapse beyond the hymen. The mean age, parity, and number of vaginal deliveries were significantly higher in the prolapse than in the non-prolapse group. Vaginal delivery was associated with an odds ratio of 2.92 (95% confidence interval 1.19-7.17) for prolapse when compared with nulliparity. Each vaginal delivery increased the risk of prolapse (odds ratio 1.23; 95% confidence interval 1.12-1.35) after controlling for all confounding factors. Cesarean delivery had no impact on the odds for prolapse. Vaginal delivery was an independent risk factor for prolapse, and additional vaginal deliveries significantly increased the risk. However, cesarean delivery had no effect on the development of prolapse in this material. 23421818 Peer support for parents of children with chronic disabling conditions: a systematic review of quantitative and qualitative studies. To review the qualitative and quantitative evidence of the benefits of peer support for parents of children with disabling conditions in the context of health, well-being, impact on family, and economic and service implications. We comprehensively searched multiple databases. Eligible studies evaluated parent-to-parent support and reported on the psychological health and experience of giving or receiving support. There were no limits on the child's condition, study design, language, date, or setting. We sought to aggregate quantitative data; findings of qualitative studies were combined using thematic analysis. Qualitative and quantitative data were brought together in a narrative synthesis. Seventeen papers were included: nine qualitative studies, seven quantitative studies, and one mixed-methods evaluation. Four themes were identified from qualitative studies: (1) shared social identity, (2) learning from the experiences of others, (3) personal growth, and (4) supporting others. Some quantitative studies reported a positive effect of peer support on psychological health and other outcomes; however, this was not consistently confirmed. It was not possible to aggregate data across studies. No costing data were identified. Qualitative studies strongly suggest that parents perceive benefit from peer support programmes, an effect seen across different types of support and conditions. However, quantitative studies provide inconsistent evidence of positive effects. Further research should explore whether this dissonance is substantive or an artefact of how outcomes have been measured. 23846012 Aliskiren improves blood pressure control and prevents cardiac damage in high-risk hypertensive subjects. Aim: Longitudinal study aimed to evaluate the antihypertensive efficacy, safety and the effect on cardiac damage of Aliskiren, administered to a group of high-risk hypertensive patients with mild impairment of renal function and uncontrolled blood pressure (BP) despite a two-drug antihypertensive treatment. Methods: One hundred and six patients (56 men and 50 females) aged 61.9±12.7 years, were assigned to receive Aliskiren 150-300 mg once-daily for 12 months. Clinic BP measurements were taken at every follow-up visit (1st, 6th and 12th month), while biochemical tests, estimated glomerular filtration rate (eGFR), 24-hours ambulatory BP measurements (ABMP) and echocardiography were evaluated at baseline and at the end of follow-up. Analysis of variance for repeated measures compared BP, left ventricular mass index (LVMI) and eGFR values changes. Results: A significant reduction (all P<0.0001) of clinic systolic (-28.6 mmHg) and diastolic (-12.8 mmHg) BP values, mean 24h-systolic (-12.3 mmHg) and 24h-diastolic (-6.5 mmHg), day-time systolic (-11.5 mmHg) and diastolic (-6.4 mmHg), night-time systolic (-11.9 mmHg) and diastolic (-7 mmHg) ABPM values and in the use of antihypertensive drugs was observed (3.0±0.9 vs. 2.0±0.7, p=0.01). LVMI was significantly reduced (130.2±36.1 vs. 115.9±33.4 g/m2, P<0.0001); eGFR was steady (75.3±17.3 vs. 73.1±21.5 ml/min/1.73m2, P>0.05). Putative adverse events caused withdrawal of 7 subjects (6 for gastrointestinal disturbances, 1 for alopecia). Conclusion: Aliskiren was effective in decreasing both clinical and ABPM values and in reducing LVMI in both genders without any influence on eGFR. The treatment resulted safe, even in combination with ACE-inhibitors and angiotensin II receptor blockers. A significant reduction in the use of concomitant antihypertensive drugs was observed. 23906013 Increased Protein Oxidation and Loss of Protein-Bound Sialic Acid in Hepatic Tissues of D-galactose Induced Aged Rats. A redox basis of the increased oxidative protein damage and free radical-mediated desialylation have not been fully elucidated in aging. It is well known that the incidence of several liver diseases increase with age. This original research focuses on protein oxidation mechanisms and protein-bound sialic acid levels in liver tissue of the mimetic aging rats. Injection of D-galactose (60 mg/kg/day) for six weeks to male Sprague-Dawley rats (20-week-old) used to establish mimetic aging model. We investigated the tissue levels of various protein oxidation markers such as protein carbonyl groups, suitable advanced oxidation protein products and protein thiol groups. Our study also covered protein-bound sialic acid in liver tissue of D-galactose-induced aging rats. PCO (Protein Carbonyl Groups), P-OOH (Protein Hydroperoxides) and AOPP (Advanced Oxidation Protein Products) levels in aging rats were significantly higher compared to young control groups. On the other hand, P-SH (Protein Thiol Groups) levels were not found to be different between two groups. SA (Sialic Acid) levels in D-galactose-induced aging rats were significantly lower compared to control groups. Our results demonstrated greater susceptibility to hepatic oxidative protein damage and desialylation of hepatocellular proteins in Dgalactose- induced aging rats. These molecular mechanisms may be operative in the many age-related liver diseases, which are pertinent to increased oxidative stress and altered redox homeostasis. 23889375 Secure entanglement distillation for double-server blind quantum computation. Blind quantum computation is a new secure quantum computing protocol where a client, who does not have enough quantum technologies at her disposal, can delegate her quantum computation to a server, who has a fully fledged quantum computer, in such a way that the server cannot learn anything about the client's input, output, and program. If the client interacts with only a single server, the client has to have some minimum quantum power, such as the ability of emitting randomly rotated single-qubit states or the ability of measuring states. If the client interacts with two servers who share Bell pairs but cannot communicate with each other, the client can be completely classical. For such a double-server scheme, two servers have to share clean Bell pairs, and therefore the entanglement distillation is necessary in a realistic noisy environment. In this Letter, we show that it is possible to perform entanglement distillation in the double-server scheme without degrading the security of blind quantum computing. 23462233 Aldehyde oxidase importance in vivo in xenobiotic metabolism: imidacloprid nitroreduction in mice. Aldehyde oxidase (AOX) metabolizes many xenobiotics in vitro, but its importance in vivo is usually unknown relative to cytochrome P450s (CYPs) and other detoxification systems. Currently, the most important insecticides are neonicotinoids, which are metabolized in vitro by AOX on reduction of the nitroimino group and by CYPs via oxidation reactions. The goal of this study was to establish the relative importance of AOX and CYPs in vivo using the mouse model. The procedure was to reduce liver AOX activity by providing tungsten or hydralazine in the drinking water or to use the AOX-deficient DBA/2 mouse strain. None of these approaches reduced CYP activity measured in vitro with an isozyme nonspecific substrate. Liver AOX activity was reduced by 45% with tungsten and 61% with hydralazine and 81% in AOX-deficient mice relative to controls. When mice were treated ip with the major neonicotinoid imidacloprid (IMI), metabolism by CYP oxidation reactions was not appreciably affected, whereas the AOX-generated nitrosoguanidine metabolite was decreased by 30% with tungsten and 56% with hydralazine and 86% in the AOX-deficient mice. The other IMI nitroreduction metabolite, desnitro-IMI, was decreased by 55%, 65%, and 81% with tungsten, hydralazine, and in the AOX-deficient mice, respectively. Thus, decreasing liver AOX activity by three quite different procedures gave a corresponding decrease for in vivo reductive metabolites in the liver of IMI-treated mice. Possible AOX involvement in IMI metabolism in insects was evaluated using AOX-expressing and AOX-deficient Drosophila, but no differences were found in IMI nitroreduction or sensitivity between the two strains. This is the first study to establish the in vivo relevance of AOX in neonicotinoid metabolism in mammals and one of the first for xenobiotics in general. 23883007 Free energy calculations for molecular solids using GROMACS. In this work, we describe a procedure to evaluate the free energy of molecular solids with the GROMACS molecular dynamics package. The free energy is calculated using the Einstein molecule method that can be regarded as a small modification of the Einstein crystal method. Here, the position and orientation of the molecules is fixed by using an Einstein field that binds with harmonic springs at least three non-collinear atoms (or points of the molecule) to their reference positions. The validity of the Einstein field is tested by performing free-energy calculations of methanol, water (ice), and patchy colloids molecular solids. The free energies calculated with GROMACS show a very good agreement with those obtained using Monte Carlo and with previously published results. 23580644 Transgenic Mouse α-and β-Cardiac Myosins Containing the R403Q Mutation Show Isoform Dependent Transient Kinetic Differences. Familial hypertrophic cardiomyopathy (FHC) is a major cause of sudden cardiac death in young athletes. The discovery in 1990 that a point mutation at residue 403 (R403Q) in the β-myosin heavy chain (MHC) caused a severe form of FHC was the first of many demonstrations linking FHC to mutations in muscle proteins. A mouse model for FHC has been widely used to study the mechanochemical properties of mutated cardiac myosin, but mouse hearts express α-MHC, whereas the ventricles of larger mammals express predominantly β-MHC. To address the role of the isoform backbone on function, we generated a transgenic mouse in which the endogenous α-MHC was partially replaced with transgenically encoded β-MHC or α-MHC. A His-tag was cloned at the N-terminus, along with R403Q, to facilitate isolation of myosin subfragment-1 (S1). Stopped-flow kinetics were used to measure the equilibrium constants and rates of nucleotide binding and release for the mouse S1 isoforms bound to actin. For the wildtype isoforms, we found that the affinity of MgADP for α-S1 (100 μM) is ~ 4-fold weaker than for β-S1 (25 μM). Correspondingly, the MgADP release rate for α-S1 (350 s-1) is ~ 3-fold greater than for β-S1 (120 s-1). Introducing the R403Q mutation caused only a minor reduction in kinetics for β-S1, but R403Q in α-S1 caused the ADP release rate to increase by 20% (430 s-1). These transient kinetic studies on mouse cardiac myosins provide strong evidence that the functional impact of an FHC mutation on myosin depends on the isoform backbone. 23415708 The design and rationale of the Australian Cooperative National Registry of Acute Coronary care, Guideline Adherence and Clinical Events (CONCORDANCE). Cardiovascular observational registries characterise patients and describe the manner and use of therapeutic strategies. They facilitate analyses on the quality of care among participating institutions and document variations in clinical practice which can be benchmarked against best practice recommendations. The Cooperative National Registry of Acute Coronary care, Guideline Adherence and Clinical Events (CONCORDANCE) is an Australian observational registry that describes management and outcomes in patients with acute coronary syndromes (ACS) and feeds back both performance and outcome measures to participating hospitals. The CONCORDANCE registry has been designed within a comparative effectiveness research (CER) framework to collect and report data from hospitals located in geographically diverse regions of Australia. Information including patient demographics, presenting characteristics, past medical history, in-hospital management and outcomes at six months and two years are entered into a web-based database using an electronic clinical record form (eCRF). Individual hospital information is returned to the sites in a real time confidential report detailing information on key performance indicator (KPI) process measures and outcomes benchmarked against the aggregated study cohort. Governance rules ensure data security and protect patient and clinician confidentiality. Consistent with a CER framework, additional characteristics of the registry include: (a) the capacity to evaluate associations between the inter and intra hospital systems and the provision of evidence based care and outcomes, (b) ongoing data collection from representative hospitals which allow spatial and temporal analysis of change in practice and the application of treatment modalities in the real world setting and (c) the provision of a data spine for quality improvement strategies and practical clinical trials. The CONCORDANCE registry is a clinician-driven initiative describing clinical care for ACS patients admitted to Australian hospitals. The registry generates high quality data which is fed back to clinicians, and key stakeholders in ACS care. Using a CER approach, the registry describes the translation of randomised trial evidence into practice, and provides insights into strategies that could improve care and ultimately patient outcomes. 22431000 miR-106a is frequently upregulated in gastric cancer and inhibits the extrinsic apoptotic pathway by targeting FAS. Emerging evidence has shown the association of aberrantly expressed miR-106a with cancer development, however, little is known about its potential role in gastric carcinogenesis. In our present study, obviously overexpressed miR-106a was found in gastric cancer tissues compared with their nontumor counterparts. Suppression of miR-106a significantly inhibited gastric cancer cell proliferation and triggered apoptosis. Bioinformatic analysis combining with validation experiments identified FAS as a direct target of miR-106a. Rescue experiments and examination of caspase-8, PARP and caspase-3 further approved that miR-106a could inhibit gastric cancer cell apoptosis through interfering with FAS-mediated apoptotic pathway. Moreover, a significant inverse correlation was found between miR-106a and FAS expression not only in gastric cancer cell lines but also in gastric cancer specimens. Taken together, these findings suggest that ectopicly overexpressed miR-106a may play an oncogenic role in gastric carcinogenesis and impair extrinsic apoptotic pathway through targeting FAS. © 2012 Wiley Periodicals, Inc. 23893948 Stability-Indicating HPLC Method for Determination of Fosamprenavir Calcium. A novel stability-indicating reverse-phase high-performance liquid chromatographic (HPLC) method has been developed for quantitative determination of Fosamprenavir Calcium, HIV-1 protease inhibitor. Chromatographic separation was achieved using an YMC Pack ODS AQ (150 mm × 4.6 mm × 3.0 μm) HPLC column in isocratic mode employing 0.05 M Potassium dihydrogen orthophosphate monohydrate (pH 6.8) buffer and Acetonitrile in the ratio 60:40 (v/v) with a flow rate of 0.8 mL min(-1). Detector wavelength was monitored at 265 nm and column temperature was maintained at 40°C. Fosamprenavir calcium was exposed to thermal, photolytic, humidity, water, acid, base and oxidative stress conditions. Considerable degradation of the drug substance was found to occur under acid, base and oxidative stress conditions. Peak homogeneity data of Fosamprenavir Calcium obtained by photodiode array detection demonstrated the specificity of the method in the presence of degradants. The degradation products were well resolved from the main peak of Fosamprenavir, indicating that the method is specific and stability-indicating. The HPLC method was validated as per International Conference on Harmonization guidelines with respect to specificity, precision, linearity, accuracy and robustness. Regression analysis showed a correlation coefficient value greater than 0.999. The accuracy of the method was established based on the recovery obtained for Fosamprenavir Calcium. 23836459 Sensibility of male rats fertility against olive oil, Nigella sativa oil and pomegranate extract. To clarify the modulatory effects of daily consumption of pomegranate extract (PE), olive oil (OO) and Nagilla sativa oil (NSO) on antioxidant activity, sperm quality and pituitary-testicular axis of adult male wistar rats. Thirty-two adult male Wistar rats were divided into four equal groups, eight rats each. Using rat gastric tubes, 1.0 mL distilled water, 1.0 mL PE, 0.4 mL NSO and 0.4 mL OO were orally administered daily for 6 weeks in the first, second, third and fourth groups, respectively. Reproductive organs, body weight, sperm criteria, testosterone, FSH, LH, inhibin-B, lipid peroxidation, and antioxidant enzyme activities were investigated. At the end of the study protocol, analyses occurred at the same time. Data were analysed by ANOVA test and P<0.05 was considered to be a significant value. In all studied groups, malondialdehyde level was significantly decreased accompanied with an increases in glutathione peroxidase and glutathione. Rats treated with PE showed an increase in catalase activities accompanied with an increase in sperm concentration which was also observed in NSO group. In PE treated group, sperm motility was also increased accompanied with decreased abnormal sperm rate. NSO, OO and PE treated groups shows an insignificant effect on testosterone, inhibin-B, FSH and LH in comparison with control group. These results show that administration of PE, NSO and OO could modify sperm characteristics and antioxidant activity of adult male wistar rats. 23811403 Ankrd1 is a transcriptional repressor for the androgen receptor that is downregulated by testosterone. The ankryn repeat domain proteins, Ankrd1 and Ankrd2, are expressed at the highest levels in skeletal muscle and heart where they are localized to the I band of the sarcomere through binding to titin and myopaladin. Ankrd1 and Ankrd2 migrate from the sarcomere to the nucleus when muscle is stressed, and act as coregulators for a growing number of transcription factors. Expression of Ankrd1 is altered by castration suggesting a link to androgen action. This investigation explored the effects of testosterone on Ankrd1 and Ankrd2 expression and determined whether Ankrd1 or Ankrd2 binds to or regulates the transcriptional activity of the androgen receptor (AR). Incubation of rat L6 myoblasts expressing the human AR (L6.AR) with testosterone reduced mRNA levels for Ankrd1 by approximately 50% and increased those for Ankrd2 by 20-fold. In reporter gene assays conducted with CHO cells co-transfected with an ARE-Luc reporter gene, Ankrd1 blocked the ability of testosterone to increase reporter gene activity while Ankrd2 had no effect. The effect of Ankrd1 and Ankrd2 on repression of the MAFbx promoter by testosterone was also tested in C2C12 cells using an MAFbx-Luc reporter gene (pMAF400-Luc); Ankrd1 blocked repression of pMAF400-Luc by testosterone while Ankrd2 did not. Co-immunoprecipitation studies revealed that Ankrd1 bound to the AR whereas Ankrd2 did not. The effect of Ankrd1 or Ankrd2 on changes in gene expression induced by testosterone in L6.AR cells was also evaluated. Incubation of L6.AR cells with testosterone modestly reduced myogenin mRNA levels but did not significantly alter those for mdm2, MEF2d, TnnI1, TnnI2, or p21. When cells were transfected with Ankrd1, testosterone markedly reduced mRNA levels for MEF2d, myogenin, p21 and TnnI1, increased those for TnnI2, but did not alter those for mdm2. When cells were transfected with Ankrd2, testosterone increased MEF2d and myogenin mRNA levels, having the opposite effect to cells transfected with Ankrd1; Ankrd2 did not change the effects of testosterone on TnnI1, TnnI2, p21, or mdm2 mRNA levels. In conclusion, testosterone regulates the expression of Ankrd1 and Ankrd2; Ankrd1 binds to and directly regulates the transcriptional activity of the AR whereas Ankrd2 does not; expression levels of both Ankrd1 and Ankrd2 modulate effects of testosterone on gene expression in cultured myoblasts. 23746796 Global and regional estimates of preeclampsia and eclampsia: a systematic review. Reduction of maternal mortality is a target within the Millennium Development Goals. Data on the incidence of preeclampsia and eclampsia, one of the main causes of maternal deaths, are required at both national and regional levels to inform policies. We conducted a systematic review of the incidence of hypertensive disorders of pregnancy (HDP) with the objective of evaluating its magnitude globally and in different regions and settings. We selected studies using pre-specified criteria, recorded database characteristics and assessed methodological quality of the eligible studies reporting incidence of any HDP during the period 2002-2010. A logistic model was then developed to estimate the global and regional incidence of HDP using pre-specified predictor variables where empiric data were not available. We found 129 studies meeting the inclusion criteria, from which 74 reports with 78 datasets reporting HDP were analysed. This represents nearly 39 million women from 40 countries. When the model was applied, the overall estimates are 4.6% (95% uncertainty range 2.7-8.2), and 1.4% (95% uncertainty range 1.0-2.0) of all deliveries for preeclampsia and eclampsia respectively, with a wide variation across regions. The figures we obtained give a general idea of the magnitude of the problem and suggest that some regional variations might exist. The absence of data in many countries is of concern, however, and efforts should be made to implement data collection and reporting for substantial statistics. The implementation of large scale surveys conducted during a short period of time could provide more reliable and up-to-date estimations to inform policy. 23924325 Insights into Aurora-A Kinase Activation Using Unnatural Amino Acids Incorporated by Chemical Modification. Most protein kinases are regulated through activation loop phosphorylation, but the contributions of individual sites are largely unresolved due to insufficient control over sample phosphorylation. Aurora-A is a mitotic Ser/Thr protein kinase that has two regulatory phosphorylation sites on its activation loop, T287 and T288. While phosphorylation of T288 is known to activate the kinase, the function of T287 phosphorylation is unclear. We applied site-directed mutagenesis and selective chemical modification to specifically introduce bioisosteres for phospho-threonine and other unnatural amino acids at these positions. Modified Aurora-A proteins were characterized using a biochemical assay measuring substrate phosphorylation. Replacement of T288 with glutamate and aspartate weakly stimulated activity. Phospho-cysteine, installed by chemical synthesis from a corresponding cysteine residue introduced at position 288, showed catalytic activity approaching that of the comparable phospho-serine protein. Unnatural amino acid residues, with longer side chains, inserted at position 288 were autophosphorylated and supported substrate phosphorylation. Aurora-A activity is enhanced by phosphorylation at position 287 alone but is suppressed when position 288 is also phosphorylated. This is rationalized by competition between phosphorylated T287 and T288 for a binding site composed of arginines, based on a structure of Aurora-A in which phospho-T287 occupies this site. This is, to our knowledge, the first example of a Ser/Thr kinase whose activity is controlled by the phosphorylation state of adjacent residues in its activation loop. Overall we demonstrate an approach that combines mutagenesis and selective chemical modification of selected cysteine residues to investigate otherwise impenetrable aspects of kinase regulation. 23798414 Cognitive relevance of the community structure of the human brain functional coactivation network. There is growing interest in the complex topology of human brain functional networks, often measured using resting-state functional MRI (fMRI). Here, we used a meta-analysis of the large primary literature that used fMRI or PET to measure task-related activation (>1,600 studies; 1985-2010). We estimated the similarity (Jaccard index) of the activation patterns across experimental tasks between each pair of 638 brain regions. This continuous coactivation matrix was used to build a weighted graph to characterize network topology. The coactivation network was modular, with occipital, central, and default-mode modules predominantly coactivated by specific cognitive domains (perception, action, and emotion, respectively). It also included a rich club of hub nodes, located in parietal and prefrontal cortex and often connected over long distances, which were coactivated by a diverse range of experimental tasks. Investigating the topological role of edges between a deactivated and an activated node, we found that such competitive interactions were most frequent between nodes in different modules or between an activated rich-club node and a deactivated peripheral node. Many aspects of the coactivation network were convergent with a connectivity network derived from resting state fMRI data (n = 27, healthy volunteers); although the connectivity network was more parsimoniously connected and differed in the anatomical locations of some hubs. We conclude that the community structure of human brain networks is relevant to cognitive function. Deactivations may play a role in flexible reconfiguration of the network according to cognitive demand, varying the integration between modules, and between the periphery and a central rich club. 23838325 The spatio-temporal expression of MHC class I molecules during human hippocampal formation development. In the immune system, the major histocompatibility complex (MHC) class I molecules mediate both the innate and adaptive immune responses in vertebrates. There has been a dogma that the central nervous system (CNS) is immune privileged and healthy neurons do not express MHC class I molecules. However, recent studies have indicated that the expression and non-immunobiologic roles of MHC class I in mammalian CNS. But data referring to humans are scarce. In this study we report the expression and cellular localization of MHC class I in the human fetal, early postnatal and adult hippocampal formation. The expression of MHC class I was very low in the hippocampus at 20 (gestational weeks) GW and slowly increased at 27-33GW. The gradually increased expression in the somata of some granular cells in dentate gyrus (DG) was observed at 30-33GW. Whereas, a rapid increase in MHC class I molecules expression was found in the subiculum and it reached high levels at 31-33GW and maintained at postnatal 55 days. No expression of MHC class I was found in hippocampal formation in adult. MHC class I heavy chain and β2 microglobulin (β2M) showed similar expression in some cells of the hippocampal formation at 30-33GW. Moreover, MHC class I molecules were mainly expressed in neurons and most MHC class I-expressing neurons were glutamatergic. The temporal and spatial patterns of MHC class I expression appeared to follow gradients of pyramidal neurons maturation in the subiculum at prenatal stages and suggested that MHC class I molecules are likely to regulate neuron maturation. This article is part of a Special Issue entitled Priority to Publish. 23668980 Nimodipine nanocrystals for oral bioavailability improvement: preparation, characterization and pharmacokinetic studies. This study intended to develop nimodipine (NMD) nanocrystals with different sizes for oral administration and to investigate the relationship between dissolution and pharmacokinetics for NMD nanocrystals and Nimotop(®). NMD nanocrystals were prepared by combination of microprecipitation and high pressure homogenization and were further lyophilized. The particle size, morphology and aqueous solubility of the NMD nanocrystals were determined. With Nimotop(®) as the control, the dissolution rate was evaluated and the pharmacokinetic study was undertaken in beagle dogs. NMD nanocrystals with mean diameters of about 159.0, 503.0 and 833.3 nm were prepared, respectively. The lyophilization didn't affect the particle sizes of the redispersed nanocrystals. The aqueous solubility was significantly improved and displayed a size-dependent manner. The nanocrystals exhibited lower dissolution patterns than Nimotop(®) under non-sink condition, but bioavailability of the two nanocrystals (159.0 and 833.3 nm) was equivalent, about 2.6-fold higher than Nimotop(®). In conclusion, oral nanocrystal drug delivery system was a promising strategy in improving the oral bioavailability of poorly soluble or insoluble drugs. But we could not establish a favorable in vitro in vivo correlation for NMD nanocrystals and Nimotop(®) and thus the oral absorption mechanism of the NMD nanocrystals required further study. 23835566 Reading performance in patients with glaucoma evaluated using the MNREAD charts. Reading performance in glaucoma patients has yet to be studied. We hypothesized that glaucomatous visual field loss affects reading performance even in patients with good acuity and evaluated their reading performance quantitatively. A cross-sectional, comparative, non-interventional study. Forty-nine patients with early-moderate glaucomatous visual field loss OU with visual acuity better than 1.0 in the better and 0.7 in the worse eye. Reading performance in glaucoma patients was examined by the Japanese version of the Minnesota Reading Acuity Chart (MNREAD) were compared to that of age-matched normal subjects (n = 30). The study subjects consisted of the 21 men and 28 women. The mean age was 53.3 ± 12.6 years. Diagnosis included primary open-angle glaucoma (n = 22), normal-tension glaucoma (n = 22), developmental glaucoma (n = 4) and exfoliation glaucoma (n = 1). Reading parameters of glaucoma patients examined by MNREAD were: maximum reading speed (MRS), 329.9 ± 55.4 characters per min.; critical print size (CPS), 0.24 ± 0.14 logMAR; reading acuity (RA), 0.02 ± 0.12 log MAR, significantly lower than those of normal subjects (MRS 363.0 ± 42.9, CPS 0.09 ± 0.13 logMAR, RA -0.13 ± 0.10 logMAR, P < 0.01 for three parameters by unpaired t test). CPS in glaucoma subjects was negatively correlated with mean deviation of Humphrey Field Analyzer 10-2 and 30-2 programs in the better eye (r = -0.402, P < 0.005; r = -0.304, P < 0.05; respectively, by linear regression analysis). The reading performance deteriorated even in glaucoma patients with good acuity. 23698554 A novel microbial synthesis of catalytically active Ag-alginate biohydrogel and its antimicrobial activity. The green synthesis of supported noble metal nanoparticles is now the most exciting field for various catalytic applications as well as biomedical applications. In this paper we report a novel synthesis method of a polymer consisting of silver nanoparticles (AgNPs) using immobilized microorganisms in alginate beads. Microorganisms present in the polymer reduce aqueous AgNO3 to AgNPs which get trapped in the polymer to form Ag-Alginate (Ag-Alg) biohydrogel. The formed biohydrogel was characterized by UV-visible (UV-Vis) spectroscopy, dynamic light scattering (DLS) spectroscopy, X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), energy dispersive X-ray (EDS), transmission electron microscopy (TEM), and selected area electron diffraction (SAED) analysis. TEM analysis showed that less than 15 nm AgNPs formed in the polymer. The Ag-Alg biohydrogel exhibited efficient heterogeneous catalytic activity in the reduction of 4-nitrophenol to 4-aminophenol in the presence of NaBH4 in aqueous solution with durable reusability. Also this biohydrogel showed excellent antimicrobial activity against pathogenic bacteria (antibiotic resistant) and fungi. The described synthesis method of Ag-Alg biohydrogel can be considered robust, cost effective and eco-friendly. The formed highly catalytic active biohydrogel can be used as catalyst in industries and drinking water purification. 23897386 Delayed presentation of ACE inhibitor-induced angio-oedema. We report two probable cases of delayed presentation of ACE inhibitor (ACEi)-induced angio-oedema. The first patient was on ACEi for more than 10 years while the second one was on it for 7 years. Both the patients presented with initial unilateral swelling of the tongue which progressed further to involve the soft tissues of the oropharynx, head and neck leading to a compromised airway needing awake fibreoptic intubation and were managed successfully in the intensive care unit (ICU). C1 esterase inhibitor and mast cell tryptase level was normal for both patients. Both were treated with intravenous antihistamines and corticosteroids in the ICU. Both patients were successfully extubated within 72 h and transferred to a medical ward. Age above 65 years, atopy and non-steroidal anti-inflammatory drug use may have been the predisposing factors. Both patients made a full recovery with no complications and the ACEi was ceased. 23742975 Roll compaction of mannitol: Compactability study of crystalline and spray-dried grades. Purpose of this project was to investigate the roll compaction behavior of various mannitol grades. Therefore, five spray-dried grades as well as unprocessed β-d-mannitol were roll compacted with different compaction forces. The resulting granules were characterized with regard to their particle size distribution, flow properties, and BET surface area and compressed to tablets. Granules of unprocessed mannitol, even when applying high compaction forces during dry granulation, were characterized by a high amount of fines (about 21%), a small surface area (0.83m(2)/g), and solely fair flowability (ffc=7.2). Tablets revealed either high friability or insufficient disintegration behavior. However, the use of spray-dried mannitol led to better results. Granules showed improved flow properties and a reduced amount of fines. Robust tablets with low friability were produced. Within the various spray-dried grades huge differences concerning the compactability were observed. Large BET surface areas of the granules resulted in advanced tensile strengths of the tablets, but acceptable disintegration behavior was maintained. These findings are relevant for the development of mannitol based drug formulations, in particular (oro)dispersible tablets containing a low dose or poor flowing active pharmaceutical ingredient, where direct compression is inappropriate and a granulation process prior to tableting is mandatory. 23246471 Poly(ethylene glycol)-block-poly(ε-caprolactone) micelles for combination drug delivery: evaluation of paclitaxel, cyclopamine and gossypol in intraperitoneal xenograft models of ovarian cancer. Ovarian cancer is the most lethal gynecological malignancy, characterized by a high rate of chemoresistance. Current treatment strategies for ovarian cancer focus on novel drug combinations of cytotoxic agents and molecular targeted agents or novel drug delivery strategies that often involve intraperitoneal (IP) injection. Poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) micelles were loaded with paclitaxel (cytotoxic agent), cyclopamine (hedgehog inhibitor), and gossypol (Bcl-2 inhibitor). After physicochemical studies focusing on combination drug solubilization, 3-drug PEG-b-PCL micelles were evaluated in vitro in 2-D and 3-D cell culture and in vivo in xenograft models of ovarian cancer, tracking bioluminescence signals from ES-2 and SKOV3 human ovarian cancer cell lines after IP injection. 3-Drug PEG-b-PCL micelles were not significantly more potent in 2-D cell culture in comparison to paclitaxel; however, they disaggregated ES-2 tumor spheroids, whereas single drugs or 2-drug combinations only slowed growth of ES-2 tumor spheroids or had no noticeable effects. In ES-2 and SKOV3 xenograft models, 3-drug PEG-b-PCL micelles had significantly less tumor burden than paclitaxel based on bioluminescence imaging, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET imaging, and overall survival. (18)F-FLT-PET images clearly showed that 3-drug PEG-b-PCL micelles dramatically reduce tumor volumes over paclitaxel and vehicle controls. In summary, PEG-b-PCL micelles enable the IP combination drug delivery of paclitaxel, cyclopamine and gossypol, resulting in tumor growth inhibition and prolonged survival over paclitaxel alone. These results validate a novel treatment strategy for ovarian cancer based on drug combinations of cytotoxic agents and molecular targeted agents, delivered concurrently by a nanoscale drug delivery system, e.g. PEG-b-PCL micelles. 23845527 Renal Trauma after Blunt Abdominal Injury. The kidney is the third most common solid organ injury in blunt abdominal trauma. The preferred treatment of blunt kidney injury varies according to grade of severity, with a preference for non-operative management in most instances. We examine an unusual case of blunt renal trauma. In this case, our patient presented with severe flank pain and hematuria after a game of softball. Our focused abdominal sonography for trauma revealed fluid in the splenorenal recess concerning for intra-abdominal injury, and subsequent abdominal computed tomography confirmed a grade IV kidney laceration. Our patient was managed medically despite his high grade of injury. This article reviews the diagnosis and management of blunt renal trauma and highlights the fact that despite significant injury, a patient can go on to do well with conservative management alone. 23519926 The classic: Epiphyseal coxa vara or displacement of the capital epiphysis of the femur in adolescence. 1926. This Classic Article is a redacted reprint of the original work by J.A. Key, "Epiphyseal coxa vara or displacement of the capital epiphysis of the femur in adolescence." (Note the case reports and associated figures were deleted but are available in the supplemental reprint of the original article available online.) An accompanying biographical sketch of J.A. Key is available at DOI 10.1007/s11999-013-2907-9. The classic article is reprinted courtesy of The Journal of Bone and Joint Surgery from Key JA. J Bone Joint Surg. 1926;8:53-117. 23301830 Formulation study of a patch containing propranolol by design of experiments. Abstract Objective: To evaluate the feasibility of a transdermal patch containing propranolol (PR). Method: Skin penetration enhancers (SPEs) able to improve the skin permeability of PR were selected and a quality by design approach was applied to the development of the patch by a 2(4) full factorial design. The permeation profile of PR from the formulations was assessed in in vitro permeation studies performed by using Franz diffusion cells and human epidermis as membrane. Finally, skin irritation was evaluated by the Draize test. Results: N-methyl pyrrolidone (NMP) resulted as the best SPE: in addition, the critical factors influencing the PR diffusion through the human epidermis when loaded in the patch resulted in the matrix thickness (X(1), p = 0.0957) and PR content (X(3), p = 0.0004) which improved the flux; conversely, NMP lacked its enhancement effect when loaded in the patch and the increase in its concentration (X(4), p = 0.006) affected the drug permeation through human epidermis. The flux of optimal formulation was 12.7 μg/cm(2)/h. On the basis of the steady-state concentration and clearance of PR, the estimated patch surface was 100-120 cm(2), since the activity of PR is related to its Senantiomer and no in vivo bioconversion occurs. Conclusion: A patch containing (S)-PR was prepared and the (S)-PR flux (13.3 μg/cm(2)/h) permitted to confirm the suitability of a transdermal administration of PR. In particular, the use of a 50 μm thick methacrylic matrix containing 8% (S)-PR and 15% NMP can allow to develop a patch non-irritating to the skin, in order to ensure a constant permeation flux of PR over 48 h. 23747004 Intramedullary cysticercosis of the spinal cord: a review of patients evaluated with MRI. Review of cases of intramedullary spinal cord cysticercosis diagnosed with MRI to outline the features and outcome of this overlooked form of presentation of neurocysticercosis. MEDLINE, LILACS, and manual search of case reports or case series of patients with intramedullary cysticercosis evaluated with MRI. Abstracted data included: demographic profile, clinical manifestations, neuroimaging findings, therapy, and follow-up. Forty-three patients were reviewed. Mean age was 36 years, and 65% were men. Most patients (67%) had parasites located at the thoracic spinal cord. All but two patients had a single cyst. The most common form of presentation was a subacute or chronic transverse myelopathy. On MRI, all lesions had signal properties paralleling that of CSF, and most were surrounded by edema and had a "ring-like" pattern of abnormal enhancement. The scolex of the parasite was visualized in 16 (37%) cases. Twenty-nine patients underwent surgical resection of the lesion, and 14 were medically-treated. Follow-up data was available in 20 surgically-treated and 13 medically-treated patients. Twelve (60%) of the 20 surgically-treated patients recovered completely, and the remaining were left with sequelae or did not improve. In contrast, all the 13 medically-treated patients recovered completely after the use of cysticidal drugs plus corticosteroids (11 cases) or corticosteroids alone (two cases). Intramedullary cysticercosis is rare. Clinical and neuroimaging findings may resemble those of other intramedullary lesions, but the visualization of the scolex or the incidental discovery of intracranial lesions provide helpful diagnostic clues. Prognosis is benign provided the correct diagnosis is suspected and patients receive prompt therapy. 23872379 Metabonomic profiling in studying anti-osteoporosis effects of strontium fructose 1,6-diphosphate on estrogen deficiency-induced osteoporosis in rats by GC/TOF-MS. A novel strontium salt compound strontium fructose 1, 6-diphosphate (FDP-Sr) has been proved to have highly effective for bone loss via dual effects of stimulating bone formation and suppressing bone absorption. In the present study, metabolomic approach was used to identify and study potential biomarkers associated with the effect and safety of FDP-Sr. The metabolomic profiles of bone loss induced by estrogen deficiency in a rat model was described to attain a system-level map of the shift on the metabolic response in plasma using GC/TOF-MS, after FDP-Sr was orally administered at the dose of 110mg/kg/day for the prevention and 220mg/kg/day for the treatment. Meanwhile, bone turnover biomarkers and bone mineral density were investigated to identify the specific changes of potential anti-osteoporosis effects of FDP-Sr. The differences in metabolic profiles between osteoporosis rats and FDP-Sr treated rats were well observed by the partial least squares-discriminant analysis (PLS-DA) to the MS spectra. Some metabolites including homocysteine, arachidonic acid, alanine, and hydroxyproline, which significantly changed during osteoporosis progression could be effectively reversed after FDP-Sr therapy. Of course some metabolites such as uric acid, glyceric acid, octadecadienoic acid, docosahexaenoic acid, oleic acid, and hexadecanoic acid were not found to reverse significantly after FDP-Sr administration. These results delineated the FDP-Sr effects-related metabolic alterations in the bone loss rats, suggesting that metabonomic analysis could provide helpful information on the new potential biomarkers relating to the mechanism of anti-osteoporosis action and side effects of FDP-Sr against estrogen deficiency induced bone loss. 23431964 Two new sesquiterpenoids from the rhizomes of Nardostachys jatamansi. Phytochemical investigation of CHCl(3):MeOH (1:1) extract from the rhizomes of Nardostachys jatamansi led to the isolation of two new sesquiterpenoids (5 and 6), along with six known compounds (1-4, 7, and 8). The structures of two new compounds were established using IR, MS, 1D, and 2D NMR techniques. In addition, all the isolates were tested for their cytotoxicities against the A549 (lung cancer), DU-145 (prostate cancer), MCF-7 (breast cancer), and SK-N-SH (neuroblastoma). 23874959 TCW: Transcriptome Computational Workbench. The analysis of transcriptome data involves many steps and various programs, along with organization of large amounts of data and results. Without a methodical approach for storage, analysis and query, the resulting ad hoc analysis can lead to human error, loss of data and results, inefficient use of time, and lack of verifiability, repeatability, and extensibility. The Transcriptome Computational Workbench (TCW) provides Java graphical interfaces for methodical analysis for both single and comparative transcriptome data without the use of a reference genome (e.g. for non-model organisms). The singleTCW interface steps the user through importing transcript sequences (e.g. Illumina) or assembling long sequences (e.g. Sanger, 454, transcripts), annotating the sequences, and performing differential expression analysis using published statistical programs in R. The data, metadata, and results are stored in a MySQL database. The multiTCW interface builds a comparison database by importing sequence and annotation from one or more single TCW databases, executes the ESTscan program to translate the sequences into proteins, and then incorporates one or more clusterings, where the clustering options are to execute the orthoMCL program, compute transitive closure, or import clusters. Both singleTCW and multiTCW allow extensive query and display of the results, where singleTCW displays the alignment of annotation hits to transcript sequences, and multiTCW displays multiple transcript alignments with MUSCLE or pairwise alignments. The query programs can be executed on the desktop for fastest analysis, or from the web for sharing the results. It is now affordable to buy a multi-processor machine, and easy to install Java and MySQL. By simply downloading the TCW, the user can interactively analyze, query and view their data. The TCW allows in-depth data mining of the results, which can lead to a better understanding of the transcriptome. TCW is freely available from www.agcol.arizona.edu/software/tcw. 23810533 Phage-mediated selection on microbiota of a long-lived host. It is increasingly apparent that the dynamic microbial communities of long-lived hosts affect their phenotype, including resistance to disease [1-3]. The host microbiota will change over time due to immigration of new species [4, 5], interaction with the host immune system [6, 7], and selection by bacteriophage viruses (phages) [8], but the relative roles of each process are unclear. Previous metagenomic approaches confirm the presence of phages infecting host microbiota [8, 9], and experimental coevolution of bacteria and phage populations in the laboratory has demonstrated rapid reciprocal change over time [10, 11]. The key challenge is to determine whether phages influence host-associated bacterial communities in nature, in the face of other selection pressures. I use a tree-bacteria-phage system to measure reciprocal changes in phage infectivity and bacterial resistance within microbial communities of tree hosts over one season. An experimental time shift shows that bacterial isolates are most resistant to lytic phages from the prior month and least resistant to those from the future month, providing clear evidence for both phage-mediated selection on bacterial communities and bacterial-mediated selection on phage communities in nature. These reciprocal changes suggest that phages indeed play a key role in shaping the microbiota of their eukaryotic hosts. 23836681 Increased asthma risk and impaired quality of life after bronchiolitis or pneumonia in infancy. Recent studies have revealed that adulthood asthma has its origin in early childhood. The aim of the present study was to evaluate the prevalence of asthma and respiratory health-related quality of life in adults 30 years after hospitalization for bronchiolitis or pneumonia in infancy. Patients who were hospitalized for bronchiolitis or pneumonia at age under 24 months in 1981-1982 have been followed in repeated visits. In 2010, 48 of the 83 former patients with bronchiolitis (57.8%), 22 of the 44 former patients with pneumonia (50.0%), and 138 matched controls participated in the clinical study at the age of 28-31 years. The participants completed a structured questionnaire on respiratory symptoms, the Saint George's Respiratory Questionnaire (SGRQ), and underwent 2-week peak expiratory flow (PEF) monitoring. Asthma was defined as doctor-diagnosed and self-reported asthma based on doctor-prescribed medication for asthma, the presence of asthma-presumptive symptoms, and the results of home PEF monitoring. Both doctor-diagnosed asthma (31.3% vs. 10.9% adjusted P = 0.002) and self-reported asthma (35.4% vs. 14.5% 0.003), as well as repeated on-demand use of bronchodilators (35.4% vs. 14.5% 0.002), and regular use of inhaled corticosteroids (20.8% vs. 8.7% 0.023) were more common in former bronchiolitis patients than in controls. Former bronchiolitis and pneumonia patients had higher total SGRQ scores than controls. The median scores were 5.4 (IQ25-75 0.0-14.7, P < 0.001) in bronchiolitis group, 4.9 (1.3-14.8, 0.012) in pneumonia group compared to controls 1.5 (0.0-6.0). Hospitalization for bronchiolitis in infancy is associated with an increased risk of asthma, and an increased use of asthma medication in adulthood at the age of 28-31 years. Impaired respiratory health-related quality of life in adulthood as measured by the SGRQ is present after bronchiolitis and pneumonia in infancy. Pediatr Pulmonol. © 2013 Wiley Periodicals, Inc. 23907084 Coverage error of commercial skin pigments as compared to human facial skin tones. It is unknown if present-day pigments used for intrinsic colouration of maxillofacial prostheses are representative of human facial skin tones. This study's purpose was to measure L*a*b* values of pigmented elastomers coloured by eleven skin tone pigments and determine coverage error (CE) when the pigments were compared to human facial lip and nose colour data. 11 skin tone pigments were combined at 0.1%, 1% and 10% by weight with A-2186 elastomer (n=3). L*a*b* values were measured with a spectrophotometer and group means were used to calculate ΔE* colour differences with each L*a*b* value obtained for human nose and lip. Pigmented elastomer CEs were calculated for nose and lip. Results were compared to CEs for proposed shade guide colours obtained from clustering analyses of facial skin colours. L* values of pigmented elastomers generally were higher than those measured for nose and lip, whereas a* values were lower. CEs for pigmented elastomers were higher than those obtained from the proposed shade guide obtained from clustered skin measurements. Overall, the current commercial elastomers appeared to be too white and not red enough to adequately match the skin tones of the subject population. Adjustments must be made to the existing pigmenting system in order to adequately match the skin colours of the study population. The creation of a shade guide and a collection of intrinsic pigments representing the realm of human facial skin colours would greatly decrease the time a patient must sit while the clinician is obtaining an acceptable colour match for the silicone to be used for processing the final prosthesis, thereby increasing both patient satisfaction and clinician productivity. 23219219 Phenotypical characterization of α-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young. In the Belgian Fabry Study (BeFaS), the prevalence of Fabry disease was assessed in 1000 young patients presenting with stroke, unexplained white matter lesions or vertebrobasilar dolichoectasia. The results of the BeFaS suggested that Fabry disease may play a role in up to 1% of young patients presenting with cerebrovascular disease. However, the clinical relevance was unclear in all cases. We report on detailed phenotyping in subjects identified with α-galactosidase A (α-Gal A) enzyme deficiency or GLA mutations identified in the BeFaS (n=10), and on the results of family screening in this population. Family screening was performed to identify additional mutation carriers. Biochemical and/or clinical evaluation of all subjects (BeFaS index patients and relatives carrying a GLA mutation) was performed. Genetic family screening revealed 18 additional GLA mutation carriers. Bloodspot α-Gal A enzyme activity was normal in all GLA mutation carriers, even in 2 males with the p.A143T mutation. Plasma Gb3 and lyso-Gb3 levels were normal in all subjects. Elevated Gb3 in urine was detected in 2 subjects. Some classic clinical signs of Fabry disease, like angiokeratoma or cornea verticillata, could not be detected in our population. Cardiac symptoms of Fabry disease were found in 6 out of 10 p.A143T carriers. No signs of cerebrovascular disease were found in the relatives with a GLA mutation. We could not identify mutations causing the classical clinical phenotype of Fabry disease in our cerebrovascular disease population. Enzyme activity analysis in bloodspots and plasma may fail to identify late-onset variants of Fabry disease. We recommend genetic testing when an atypical, late-onset variant of Fabry disease is suspected in a male cerebrovascular disease patient. However, this may lead to the identification of non-disease causing or controversial genetic variants. 23768743 Mycobacterial pseudotumor of the plantar fascia: how common is it? Mycobacterial spindle cell pseudotumor (MSCP) is an extremely rare complication of mycobacterial infections. It has been reported to occur in various sites such as skin, lymph nodes, bone marrow, lungs, and spleen. This tumor-like lesion can be confused clinically as well as radiographically with dermatofibroma, nodular fasciitis, xanthogranuloma, and Kaposi's sarcoma. While this lesion is rare and has been previously reported to occur only in superficial skin, we emphasize its consideration and inclusion in the differential diagnoses when a deep soft tissue mass is complicated by symptoms of deep tissue infection secondary to abscess formation in immunocompromised hosts. Here, we present the clinical and radiologic findings of a case of MSCP involving the deep plantar sheaths. 23906339 Novel statistical methods for integrating genetic and stable isotope data to infer individual-level migratory connectivity. Methods for determining patterns of migratory connectivity in animal ecology have historically been limited due to logistical challenges. Recent progress in studying migratory bird connectivity has been made using genetic and stable-isotope markers to assign migratory individuals to their breeding grounds. Here, we present a novel Bayesian approach to jointly leverage genetic and isotopic markers and we test its utility on two migratory passerine bird species. Our approach represents a principled model-based combination of genetic and isotope data from samples collected on the breeding grounds and is able to achieve levels of assignment accuracy that exceed those of either method alone. When applied at large scale the method can reveal specific migratory connectivity patterns. In Wilson's warblers (Wilsonia pusilla), we detect a subgroup of birds wintering in Baja that uniquely migrate preferentially from the coastal Pacific Northwest. Our approach is implemented in a way that is easily extended to accommodate additional sources of information (e.g. bi-allelic markers, species distribution models, etc.) or adapted to other species or assignment problems. 23813445 Degrading magnesium screws ZEK100: biomechanical testing, degradation analysis and soft-tissue biocompatibility in a rabbit model. Magnesium alloys are promising implant materials for use in orthopaedic applications. In the present study, screws made of the Mg-alloy ZEK100 (n = 12) were implanted in rabbit tibiae for four and six weeks, respectively. For degradation analysis, in vivo µ-computed tomography (µCT), a determination of the weight changes and SEM/EDX examinations of the screws were performed. Screw retention forces were verified by uniaxial pull-out tests. Additionally, soft-tissue biocompatibility was estimated using routine histological methods (H&E staining) and the immunohistological characterization of B- and T-cells. After six weeks, a 7.5% weight reduction occurred and, in dependence of the implant surrounding, the volume loss (µCT) reached 9.6% (screw head) and 5.0% for the part of the thread in the marrow cavity. Pull-out forces significantly decreased to 44.4% in comparison with the origin value directly after implantation. Soft tissue reactions were characterized by macrophage and lymphocyte infiltration, whereas T-cells as well as B-cells could be observed. In comparison to MgCa0.8-screws, the degradation rate and inflammatory tissue response were increased and the screw holding power was decreased after six weeks. In conclusion, ZEK100-screws seem to be inferior to MgCa0.8-screws, although their initial strength was more appropriate. 23875007 Soluble Markers of the Toll-Like Receptor 4 Pathway Differentiate between Active and Latent Tuberculosis and Are Associated with Treatment Responses. Biomarkers to differentiate between active tuberculosis (TB) and latent TB infection (LTBI) and to monitor treatment responses are requested to complement TB diagnostics and control, particularly in patients with multi-drug resistant TB. We have studied soluble markers of the Toll-like-receptor 4 (TLR-4) pathway in various stages of TB disease and during anti-TB treatment. Plasma samples from patients with culture confirmed drug-sensitive TB (n = 19) were collected before and after 2, 8 and 24 weeks of efficient anti-TB treatment and in a LTBI group (n = 6). Soluble (s) CD14 and myeloid differentiation-2 (MD-2) were analyzed by the Enzyme-linked immunosorbent assay (ELISA). Lipopolysaccharide (LPS) was analyzed by the Limulus Amebocyte Lysate colorimetric assay. Nonparametric statistics were applied. Plasma levels of sCD14 (p<0.001), MD-2 (p = 0.036) and LPS (p = 0.069) were elevated at baseline in patients with untreated active TB compared to the LTBI group. MD-2 concentrations decreased after 2 weeks of treatment (p = 0.011), while LPS levels decreased after 8 weeks (p = 0.005). In contrast, sCD14 levels increased after 2 weeks (p = 0.047) with a subsequent modest decrease throughout the treatment period. There was no significant difference in concentrations of any of these markers between patients with pulmonary and extrapulmonary TB or between patients with or without symptoms. Our data suggest that plasma levels of LPS, MD-2 and sCD14 can discriminate between active TB and LTBI. A decline in LPS and MD-2 concentrations was associated with response to anti-TB treatment. The clinical potential of these soluble TLR-4 pathway proteins needs to be further explored. 23887299 Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential therapeutic target in small-cell lung cancer. Small-cell lung cancer (SCLC) comprises about 13-15% of all lung cancers, and more than 29 400 new cases have been diagnosed in the United States in the year 2012. SCLC is a biologically complex tumor typically occurring in heavy smokers. Its medical treatment has almost remained unchanged over the last decades and selected treatment options have not been established so far, mainly due to the lack of targetable genetic alterations. In this study we analyzed a cohort of 307 SCLC samples for fibroblast growth factor receptor 1 (FGFR1) amplification using a dual color FISH probe. FGFR1 status was correlated with clinical data. FGFR1 amplifications were observed in 5.6% of evaluable pulmonary SCLCs. Most of them (93%) fulfilled the criteria for high-level amplification and only one case showed low-level amplification. Amplification patterns were homogenous in the entire tumor area without occurrence of any 'hot spot' areas. FGFR1 amplification status was not associated with age, sex, stage, smoking status or overall survival. FGFR1 amplification analysis by FISH analysis in SCLC is, under respect of certain technical issues, applicable in the routine clinical setting. However, the FGFR1 amplification patterns in SCLC differs strongly from the previously described FGFR1 amplification pattern in squamous cell carcinoma of the lung, as positive SCLC harbor mostly homogeneous high-level amplifications. We provide evidence that an estimated number of 1640 newly diagnosed FGFR1-positive SCLC cases in the United States annually could benefit from targeted therapy. Therefore, we recommend including SCLC in the screening for ongoing clinical trials with FGFR1 inhibitors.Modern Pathology advance online publication, 26 July 2013; doi:10.1038/modpathol.2013.141. 23664014 In vitro inhibition of canine distemper virus by flavonoids and phenolic acids: Implications of structural differences for antiviral design. Infection caused by canine distemper virus (CDV) is a highly contagious disease with high incidence and lethality in the canine population. Antiviral activity of flavonoids quercetin, morin, rutin and hesperidin, and phenolic cinnamic, trans-cinnamic and ferulic acids were evaluated in vitro against the CDV using the time of addition assay to determine which step of the viral replicative cycle was affected. All flavonoids displayed great viral inhibition when they were added at the times 0 (adsorption) and 1h (penetration) of the viral replicative cycle. Both quercetin and hesperidin presented antiviral activity at the time 2h (intracellular). In the other hand, cinnamic acid showed antiviral activity at the times 0 and 2h while trans-cinnamic acid showed antiviral effect at the times -1h (pre-treatment) and 0h. Ferulic acid inhibited CDV replicative cycle at the times 0 and 1h. Our study revealed promising candidates to be considered in the treatment of CDV. Structural differences among compounds and correlation to their antiviral activity were also explored. Our analysis suggest that these compounds could be useful in order to design new antiviral drugs against CDV as well as other viruses of great meaning in veterinary medicine. 23929470 Complete Genome Sequence of Porcine Epidemic Diarrhea Virus Strain USA/Colorado/2013 from the United States. Porcine epidemic diarrhea virus (PEDV) is newly emerging in the United States. PEDV strain USA/Colorado/2013 (CO/13) was obtained from a 7-day-old piglet with severe diarrhea, and the complete genome was sequenced to further study the PEDV outbreak in the United States. 23312793 Seasonal and locational variations in children's play: Implications for wellbeing. Physical activity, through independent outdoor play, has come to the fore as a way to improve children's health through it fostering healthy mental and social as well as physiological development. However, in many high-income countries children's autonomous play opportunities have diminished due to urban intensification and declining parental license. Regardless of this trend, children's play varies across countries, cities, cultures and seasons. This paper offers new insights into the complexities of play as a vital aspect of children's wellbeing. Within the context of New Zealand - whose citizens generally regard themselves as outdoor people - this paper explores why 'play' might resonate differently across localities and seasons. We contrast the play affordances provided by Auckland's central city (dominated by apartment living) with Beach Haven, a suburban area. We employed a multi-method approach and included 20 children and their parents who were recruited through school and summer holiday programs embracing different gender and ethnicities to reflect the general cultural mix of the respective neighbourhoods. We advance two arguments. First, we suggest that the rarity of children playing outdoors unsupervised normalises supervised indoor play and reduces children's opportunities to see outdoor play as an alternative to interior or supervised pastimes. Second, we follow Bourdieu's theory of practice to argue that the regard parents and children have towards outdoor play reflects locally constituted beliefs about what is seasonally 'appropriate' children's activity. We found that extra-curricular activities and supervised excursions are undertaken in the central city all year around and only vary between social groups by the type of destination. In the suburb, independent outdoor play in summer represents children's main business after school in ways that enhance their environmental literacy and potential future health gain. For others these symbolic values were replaced by safety concerns. In contrast, it seems that even in a relatively mild climate winter is the time to relax and stay indoors unless children have an outdoor habitus. We find that the determinants of seasonal outdoor play transcend modifiable barriers such as traffic and unsuitable play spaces as well as the inevitable issue of inclement weather. 23771724 Effect of systemic α1-adrenergic receptor blockade on central blood pressure response during exercise. The aortic pulse pressure (PP), which consists mainly of the incident wave and the reflected wave, has emerged as an important property of systemic blood vessels underlying the pathophysiology of cardiovascular disease. To determine the role of sympathetic nerve activity on the aortic PP response during dynamic exercise, we evaluated aortic hemodynamics during the right-leg knee-extension (40 and 60 % of maximal voluntary contraction) in six young adults with and without the systemic α1-adrenergic receptor blockade using prazosin (1 mg/20 kg body weight). The use of prazosin attenuated the exercise-induced increase in aortic PP (P < 0.05) but not in radial arterial PP. The amplitude of the reflected waves (via augmentation index) significantly decreased with the exercise and decreased more with the use of prazosin. These results suggest that during dynamic exercise the α1-adrenergic-mediated vasoconstrictor tone of the peripheral resistance vessels is manifestly involved in the magnitude of the reflected wave and the modulation of the aortic PP responses. 23860694 A new model using platelet indices to predict liver fibrosis in patients with chronic hepatitis B infection. We aimed to investigate whether mean platelet volume (MPV) and platelet distribution width (PDW) are variables determining the severity of liver fibrosis in patients with chronic HBV infection. Patients were divided into two groups with fibrosis scores of 0-2 and 3-6 (according to Ishac scoring system). Whether MPV and PDW were independent variables determining the severity of liver fibrosis score or not was investigated by comparing these groups. Of the 111 cases, 74 (66.7 %) were male (mean age 37.7 ± 11.6 years). Twenty-two of the cases (19.8 %) were HBeAg-positive. Fibrosis scores of 42 cases (37.8 %) were ≥ 3 and the remaining 69 cases had fibrosis scores < 3 (62.2 %). Independent variables determining the severity of fibrosis score were low levels of albumin and mean platelet volume, and high levels of prothrombin time and PDW (Odds ratio (95 % confidence interval) and p values were 0.105 (0.018-0.605) and 0.012 for albumin, 0.402 (0.234-0.692) and 0.001 for mean platelet volume, 1.529 (1.183-1.975) and 0.001 for PDW, and 0.924 (0.875-0.976) and 0.005 for prothrombin time, respectively). The sensitivity, specificity, positive predictive value and negative predictive value of regression model that is established using above mentioned parameters were 88.1, 75.3, 68.5, and 91.7 %, respectively (AUC = 0.886, p = 0.0001). MPV and PDW are independent variables determining the severity of liver fibrosis, and the regression model that is established using these parameters along with other markers, may give more information about the severity of liver fibrosis. 23314695 Effects of IgM-Enriched Immunoglobulin Therapy in Septic-Shock-Induced Multiple Organ Failure: Pilot Study. Mortality due to septic-shock-induced respiratory failure remains high. A recent meta-analysis suggested that IgM-enriched immunoglobulin treatment may be beneficial in these patients. In this prospective randomised controlled pilot study we investigated the effects of IgM-enriched immunoglobulin treatment in patients with early septic shock accompanied by severe respiratory failure. 33 patients were randomly allocated to receive 5 ml/kg (predicted body weight) IgM-enriched immunoglobulin (16 patients) or placebo (17 patients), respectively, via 8 h IV-infusion for three consecutive days. Daily Multiple Organ Dysfunction Scores (MODS) were calculated. Serum C-reactive protein (CRP) and procalcitonin (PCT) levels were monitored daily. For statistical analysis two-way ANOVA was used. Daily MODS showed ongoing multiple system organ failure without significant resolution during the 8 days. Median length of ICU stay, mechanical ventilation, vasopressor support during the ICU stay and 28-day mortality were nearly identical in the two groups. Serum PCT levels showed no significant difference between the two groups, however, CRP levels were significantly lower in the IgM-enriched immunoglobulin group on days 4, 5 and 6, respectively. In this study the use of IgM-enriched immunoglobulin preparation failed to produce any improvement in the organ dysfunction as compared to standard sepsis therapy. 23411291 Detection of adulteration in honey samples added various sugar syrups with 13C/12C isotope ratio analysis method. Honey can be adulterated in various ways. One of the adulteration methods is the addition of different sugar syrups during or after honey production. Starch-based sugar syrups, high fructose corn syrup (HFCS), glucose syrup (GS) and saccharose syrups (SS), which are produced from beet or canes, can be used for adulterating honey. In this study, adulterated honey samples were prepared with the addition of HFCS, GS and SS (beet sugar) at a ratio of 0%, 10%, 20%, 40% and 50% by weight. (13)C/(12)C analysis was conducted on these adulterated honey samples using an isotope ratio mass spectrometer in combination with an elemental analyser (EA-IRMS). As a result, adulteration using C(4) sugar syrups (HFCS and GS) could be detected to a certain extent while adulteration of honey using C(3) sugar syrups (beet sugar) could not be detected. Adulteration by using SS (beet sugar) still has a serious detection problem, especially in countries in which beet is used in manufacturing sugar. For this reason, practice and analysis methods are needed to meet this deficit and to detect the adulterations precisely in the studies that will be conducted. 23587955 A novel Leishmania major amastigote assay in 96-well format for rapid drug screening and its use for discovery and evaluation of a new class of leishmanicidal quinolinium salts. In most laboratories, the screening for leishmanicidal compounds is carried out with Leishmania promastigotes or axenic amastigotes. However, the best approach to identify leishmanicidal compounds is the use of amastigotes residing in macrophages. Reporter gene-based assays are relatively new tools in the search for drugs against eucaryotic protozoa, permitting the development of faster, more automated assays. In this paper, we report on the establishment of a rapid screening assay in a 96-well format. A luciferase-transgenic (Luc-tg) Leishmania major strain was generated and used to infect bone marrow-derived macrophages (BMDM). Amastigote-infected BMDM were treated with different compound concentrations. Cells were lysed with a luciferin-containing buffer, and the resulting luminescence was measured to determine the half-maximal inhibitory concentration (IC50). To validate this new amastigote screening assay, a library of a new class of quinolinium salts was synthesized and tested for leishmanicidal activity. Some of the quinolinium salts showed very promising activities, with IC50s against intracellular amastigotes (IC50 < 1 μg/ml) and selectivity indices (SI > 20) that match the criteria of World Health Organization (WHO) for hits. Compound 21c (IC50 = 0.03 μg/ml; SI = 358) could become a new lead structure for the development of improved chemotherapeutic drugs against L. major. In summary, we describe the establishment of a new 96-well format assay with Luc-transgenic L. major for the rapid screening of compounds for leishmanicidal activity against intracellular amastigotes and its application to the identification of a new class of quinolinium salts with most promising leishmanicidal activity. 23911400 Regulation of the Hif-system by micro-RNA 17 and 20a - Role during monocyte-to-macrophage differentiation. MiRNAs are a class of endogenous tiny RNAs that act as inhibitors of translation or promote RNA degradation by duplex-formation within the 3'-UTR of target mRNAs. They play an important role during a wide range of cellular processes by fine-tuning of gene expression. The differentiation of monocytes to macrophages plays a pivotal role in physiological as well as pathophysiological processes such as atherosclerosis. Monocytes which can be found in well-oxygenated blood migrate into areas with a high inflammation, such as the atherosclerotic plaque. There, they differentiate into macrophages. Interestingly, macrophages were found mainly at hypoxic sites of the plaque. Key regulators for the adaptation to hypoxia are the hypoxia-inducible factors (Hif). Therefore the aim of the present study was to investigate the regulation of the Hif-system by miRNAs during the process of monocyte differentiation. The present study shows that during the differentiation of monocytes into macrophages a dramatically change in the expression pattern of Hif-1α and Hif-2α took place. This was associated with a downregulation of microRNAs encoded by the miR-17-92 cluster. An in silico analysis of the 3'-UTR of Hif-α subunits for binding sites of miRNAs was performed using different miRNA databases in concert with a secondary structure prediction algorithm. This analysis revealed that both 3'-UTRs contain binding sites for miRNAs of the miR-17-92 cluster. Transfection of HeLa cells with miR-17 and miR-20a led to an inhibition of Hif-1α and -2α mRNA and protein expression and a lowered Hif DNA binding activity. Using a Luciferase-Reporter assay, it could be shown, that both Hif-α subunits are targeted by miR-17 and miR-20a. Furthermore, miR-overexpression in primary human macrophages demonstrates the important role of this microRNA-mediated regulation of the Hif-system for adaption of macrophages to hypoxia. In conclusion, the present study shows that the Hif-system is activated during monocyte-to-macrophage differentiation. This activation is in part mediated by a miRNA-dependent mechanism, which seems to be crucial for the adaption of macrophages to hypoxia. 23682816 Development and systematic oxidative stress of a rat model of chronic bronchitis and emphysema induced by biomass smoke. ABSTRACT Background: Epidemiological research and meta-analyses of published data have shown that biomass smoke (BS) is a risk factor for chronic obstructive pulmonary disease (COPD). However, the link between BS and COPD lacks experimental confirmation. Objectives: To verify whether BS can induce pathologic changes and systemic oxidative stress, which may be relevant to the development of emphysema and chronic bronchitis in rats. Methods: Rats were exposed to BS, cigarette smoke (CS), or clean air (sham) for 14 weeks. During the exposure, the O2, SO2, and CO levels were monitored. Pathological changes in the lungs, systemic oxidative stress, and inflammation biomarkers, together with GSTM1 and GSTP1 mRNA expression in the lung were measured. The glutamate-cysteine ligase catalytic subunit (GCLC) protein expression in the lung was measured using immunohistochemistry and western blotting. Results: The O2, CO, and SO2 levels were 20.31 ± 0.03%, 981.72 ± 64.76, and 2.59 ± 0.26 mg/m(3) for the BS group, respectively, while their levels in the CS group were 20.28 ± 0.15%, 745.56 ± 30.83, and 12.64 ± 0.591 mg/m(3) respectively. As with the rats exposed to CS, the BS rats showed an increased number of inflammatory cells in the bronchoalveolar lavage fluid, an increased pulmonary mean linear intercept and a decreased pulmonary mean alveolar number. Characteristics of chronic bronchitis and peribronchial fibrosis were also found in the BS-exposed rat lungs. Reduced body weight, systemic oxidative stress, and increased GCLC protein expression in the lungs were observed in the rats exposed to BS and CS. Conclusions: BS can cause emphysema and chronic bronchitis similar to that caused by CS, which is accompanied by systemic oxidative stress and inflammation. 23867455 Aminoacylating Urzymes Challenge the RNA World Hypothesis. We present experimental evidence that ancestral peptide catalysts substantially accelerated development of genetic coding. Structurally invariant 120-130 residue Urzymes (Ur = primitive plus enzyme) derived from Class I and Class II aminoacyl-tRNA synthetases (aaRSs) acylate tRNA far faster than the uncatalyzed rate of non-ribosomal peptide bond formation from activated amino acids. These new data allow us to demonstrate statistically indistinguishable catalytic profiles for Class I and II aaRS in both amino acid activation and tRNA acylation, over a time period extending to well before the assembly of full-length enzymes and even further before the Last Universal Common Ancestor. Both Urzymes also exhibit ~60% of the contemporary catalytic proficiencies. Moreover, they are linked by ancestral sense/antisense genetic coding and their evident modularities suggest descent from even simpler ancestors also coded by opposite strands of the same gene. Thus, aaRS Urzymes substantially pre-date modern aaRS but are, nevertheless, highly evolved. Their unexpectedly advanced catalytic repertoires, sense/antisense coding, and ancestral modularities imply considerable prior protein-tRNA co-evolution. Further, unlike ribozymes that motivated the RNA World hypothesis, Class I and II Urzyme:tRNA pairs represent consensus ancestral forms sufficient for codon-directed synthesis of nonrandom peptides. By tracing aaRS catalytic activities back to simpler ancestral peptides, we demonstrate key steps for a simpler and hence more probable Peptide-RNA development of rapid coding systems matching amino acids with anticodon trinucleotides. 23833092 An unusual cause of a haemorrhagic stroke: acquired haemophilia A. An elderly woman presented with extensive bruising and a haemorrhagic stroke. Initial investigations revealed an abnormal clotting screen with a prolonged activated partial thromboplastin time. Further investigations revealed this to be due to antibodies that the patient had developed against clotting factor VIII also known as acquired haemophilia A. 23873831 Thrombin generation and procoagulant phospholipids in patients with essential thrombocythemia and reactive thrombocytosis. Thrombocytosis is a commonly encountered clinical scenario and can be either a secondary process (reactive thrombocytosis), or due to clonal disorder (ie, essential thrombocythemia). This distinction is important as it carries implications for evaluation, prognosis and treatment. In this study we compared procoagulant potential in essential thrombocythemia and reactive thrombocytosis by measuring the thrombin generation and the level of circulating procoagulant phospholipids with functional tests. Twenty nine patients with essential thrombocythemia and 24 with reactive thrombocytosis were studied. Thrombin generation was determined by calibrated automated thrombography. Procoagulant phospholipids were detected by a chronometric standardised method (STA-Procoag-PPL). Patients with reactive thrombocytosis had a longer lag time, higher endogenous thrombin potential, peak of thrombin generation and velocity index than patients with essential thrombocythemia. The level of circulating procoagulant phospholipids was increased in patients with essential thrombocythemia as observed with the procoagulant phospholipids assay. Each parameter was analysed using ROC curves. Highest areas under the curve (AUC) were found for lag time and procoagulant phospholipids ratio (0.817 and 0.853 respectively), associated with high negative predictive value for ET (92.3% and 80 % respectively). In conclusion, patients with essential thrombocythemia and reactive thrombocytosis displayed significant differences in terms of thrombin generation and levels of procoagulant phospholipids. Among these parameters, lag time and procoagulant phospholipids ratio could help to differentiate between reactive thrombocytosis and essential thrombocythemia patients. 23507343 Alcohol consumption among high-risk Thai youth after raising the legal drinking age. Methamphetamine and alcohol are the leading substances abused by Thai youth. In 2008 the government passed laws that limited alcohol availability and increased the legal drinking age from 18 to 20. We assessed whether the law reduced drinking among methamphetamine-using 18-19 year olds in Chiang Mai. The study compares drinking patterns among methamphetamine smokers aged 18-19 years (n=136) collected prior to the legal changes, to a comparable post-law sample (n=142). Statistical tests for differences between the pre- and post-law samples on problem drinking and recent drinking frequency and drunkenness were conducted. Logistic regression modeled the relative odds of frequent drunkenness, controlling for demographic characteristics. A high prevalence of problematic drinking was present in both samples, with no difference detected. The post-law sample reported a significantly higher median days drunk/month (9 vs. 4, p≤0.01); in adjusted analysis, frequent drunkenness (>5.5 days/month) was more common in the post-law compared to pre-law period in the presence of other variables (AOR: 2.2; 95%CI: 1.3, 3.9). Post-law participants demonstrated a low level of knowledge about the law's components. The study suggests that the new laws did not reduce drinking among high-risk, methamphetamine-smoking 18-19 year olds; rather, the post-law period was associated with increased drinking levels. The data indicate that the law is not reaching high-risk under-aged youth who are at risk of a number of deleterious outcomes as a result of their substance use. 23584194 Intimate partner violence outcomes in women with PTSD and substance use: a secondary analysis of NIDA Clinical Trials Network "Women and Trauma" Multi-site Study. Studies have shown strong associations between intimate partner violence (IPV) and both posttraumatic stress disorder (PTSD) and substance use disorders (SUD). Despite these linkages, research on the dual diagnosis of PTSD-SUD and its relationship to IPV is in an early stage, and little is known about how PTSD-SUD treatment might influence IPV outcomes. The current study is a secondary analysis of a larger NIDA Clinical Trials Network study exploring the effectiveness of two behavioral interventions for women with comorbid PTSD-SUD. Participants (n=288) were randomly assigned to Seeking Safety (SS), a cognitive-behavioral treatment that focuses on trauma and substance abuse symptoms, or to Women's Health Education, a psychoeducational group. Logistic regressions were used to examine how treatment condition, identified risk factors and their interactions were related to IPV. Results showed that participants who were abstinent at baseline were significantly less likely to experience IPV over the 12-month follow-up period, whereas participants living with someone with an alcohol problem were significantly more likely to experience IPV over follow-up. Findings also showed that at a trend level participants with recent interpersonal trauma at baseline and higher total of lifetime trauma exposures were more likely to report IPV during follow-up. Although there was no main effect for treatment condition, a significant interaction between treatment condition and baseline abstinence was found. Participants who were abstinent at baseline and in the SS condition were significantly less likely to report IPV over follow-up. These findings indicate that an integrated treatment for PTSD and SUD was associated with significantly better IPV outcomes for a subset of individuals. The possibility that women with PTSD-SUD may differentially benefit from SS has important clinical implications. Further research examining the intersection of PTSD, SUD and IPV, and the impact of treatment on a range of outcomes is needed. 23792656 Simultaneous removal of organic matter and nitrogen by a heterotrophic nitrifying-aerobic denitrifying bacterial strain in a membrane bioreactor. A heterotrophic nitrifying-aerobic denitrifying bacterial strain, Bacillus methylotrophicus L7, was inoculated solely into a submerged membrane bioreactor (MBR) for continuous treatment of artificial sewage. The running conditions were also optimized for improvement of the treatment efficiency. The results indicated that inoculation of this single strain in a single reactor under constant aerobic conditions resulted in simultaneous removal of organic matter and nitrogen, in striking contrast to traditional aerobic nitrification-anaerobic denitrification treatment system and the sequencing batch reactor (SBR) systems. The optimal running conditions for the MBR were dissolved oxygen (DO) 4.5mg/L, pH 7.5, loading ammonia <100mg/L, and C/N ratio 3.5. Under these conditions, the removal percentages of chemical oxygen demand (COD), NH4(+)-N, and TN as high as 96%, 77.5% and 53%, respectively, were achieved without nitrite accumulation. 23642385 Reports on the distribution of aromatic cyanogenic glycosides in Australian tropical rainforest tree species of the Lauraceae and Sapindaceae. The aromatic cyanogenic glycosides taxiphyllin [(R)-4-hydroxymandelonitrile β-D-glucoside] and prunasin [(R)-mandelonitrile β-D-glucoside] were identified as the main cyanogenic compounds in tissues of Australian endemic tropical rainforest tree taxa in the Lauraceae and Sapindaceae families, respectively. The tyrosine-derived taxiphyllin was the main cyanogenic glycoside in foliage of Beilschmiedia collina. This is the first reported cyanogenic compound from the Lauraceae. In addition, substantial quantitative variation in the capacity for cyanogenesis was detected in leaves from 40 individuals, with taxiphyllin concentrations ranging from 23 to 1263 μg CN g(-1) dry wt. No acyanogenic individuals were detected. Concentrations of taxiphyllin were, on average, 2.2-fold greater in young leaves than in old leaves. Prunasin was the dominant cyanogenic compound in tissues of Mischocarpus grandissimus (leaves) and Mischocarpus exangulatus (leaves and seed capsule). Better known for cyanolipids in seed oils, this is the first time a phenylalanine-derived cyanogenic glycoside has been reported in the Sapindaceae. The concentrations of prunasin varied widely, over an order of magnitude, among individuals and different tissue types in these species, with the higher concentrations found in seed capsules and young leaves. 23811101 Selaginella tamariscina (Beauv.) possesses antimetastatic effects on human osteosarcoma cells by decreasing MMP-2 and MMP-9 secretions via p38 and Akt signaling pathways. Selaginella tamariscina is a traditional medicinal plant for treatment of some advanced cancers in the Orient. However, the effect of S. tamariscina on metastasis of osteosarcoma and the underlying mechanism remain unclear. We tested the hypothesis that S. tamariscina suppresses cellular motility, invasion and migration and also investigated its signaling pathways. This study demonstrates that S. tamariscina, at a range of concentrations (from 0 to 50μg/mL), concentration-dependently inhibited the migration/invasion capacities of three osteosarcoma cell lines without cytotoxic effects. Zymographic and western blot analyses revealed that S. tamariscina inhibited the matrix metalloproteinase (MMP)-2 and MMP-9 enzyme activity, as well as protein expression. Western blot analysis also showed that S. tamariscina inhibits phosphorylation of p38 and Akt. Furthermore, SB203580 (p38 inhibitor) and LY294002 (PI3K inhibitor) showed the similar effects as S. tamariscina in U2OS cells. In conclusion, S. tamariscina possesses an antimetastatic activity in osteosarcoma cells by down-regulating MMP-2 and MMP-9 secretions and increasing TIMP-1 and TIMP-2 expressions through p38 and Akt-dependent pathways. S. tamariscina may be a powerful candidate to develop a preventive agent for osteosarcoma metastasis. 23728385 Erythropoietin prevents lymphoid apoptosis but has no effect on survival in experimental sepsis. Background:Lymphoid apoptosis in sepsis is associated with poor outcome, and prevention of apoptosis frequently improves survival in experimental models of sepsis. Recently, erythropoietin (EPO) was shown to protect against lipopolysaccharide (LPS)-induced mortality. As cecal ligation and puncture (CLP) is a clinically more relevant model of sepsis, we evaluated the effect of EPO on CLP-induced lymphoid tissue apoptosis and mortality.Methods:Young Wistar rats were subjected to polymicrobial sepsis by CLP. EPO (5,000 U/kg intraperitoneal) was administered 30 min before CLP and then 1 and 4 h after CLP. Spleen, thymus, and small intestine were harvested at 24 h and assessed for apoptosis by terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) and caspase-3 staining. A separate group of animals was followed up for mortality.Results:Splenic, thymic, and intestinal apoptosis was increased after CLP; administration of EPO significantly decreased apoptosis as determined by TUNEL and caspase-3 staining. Final survival in the CLP mortality study was 30% in both saline and EPO groups.Conclusion:Our results provide the first evidence that EPO attenuates lymphoid apoptosis in the CLP model of sepsis. However, EPO is not associated with a survival benefit in the CLP model of sepsis. 23812238 Age-Associated Cross-reactive Antibody-Dependent Cellular Cytotoxicity Toward 2009 Pandemic Influenza A Virus Subtype H1N1. Background. During the 2009 pandemic of influenza A virus subtype H1N1 (A[H1N1]pdm09) infection, older individuals were partially protected from severe disease. It is not known whether preexisting antibodies with effector functions such as antibody-dependent cellular cytotoxicity (ADCC) contributed to the immunity observed.Methods. We tested serum specimens obtained from 182 individuals aged 1-72 years that were collected either immediately before or after the A(H1N1)pdm09 pandemic for ADCC antibodies to the A(H1N1)pdm09 hemagglutinin (HA) protein.Results. A(H1N1)pdm09 HA-specific ADCC antibodies were detected in almost all individuals aged >45 years (28/31 subjects) before the 2009 A(H1N1) pandemic. Conversely, only approximately half of the individuals aged 1-14 years (11/31) and 15-45 years (17/31) had cross-reactive ADCC antibodies before the 2009 A(H1N1) pandemic. The A(H1N1)pdm09-specific ADCC antibodies were able to efficiently mediate the killing of influenza virus-infected respiratory epithelial cells. Further, subjects >45 years of age had higher ADCC titers to a range of seasonal H1N1 HA proteins, including from the 1918 virus, compared with younger individuals.Conclusions. ADCC antibodies may have contributed to the protection exhibited in older individuals during the 2009 A(H1N1) pandemic. This work has significant implications for improved vaccination strategies for future influenza pandemics. 23683720 Post-mortem MRI versus conventional autopsy in fetuses and children: a prospective validation study. Post-mortem MRI is a potential diagnostic alternative to conventional autopsy, but few large prospective studies have compared its accuracy with that of conventional autopsy. We assessed the accuracy of whole-body, post-mortem MRI for detection of major pathological lesions associated with death in a prospective cohort of fetuses and children. In this prospective validation study, we did pre-autopsy, post-mortem, whole-body MRI at 1·5 T in an unselected population of fetuses (≤24 weeks' or >24 weeks' gestation) and children (aged <16 years) at two UK centres in London between March 1, 2007 and Sept 30, 2011. With conventional autopsy as the diagnostic gold standard, we assessed MRI findings alone, or in conjunction with other minimally invasive post-mortem investigations (minimally invasive autopsy), for accuracy in detection of cause of death or major pathological abnormalities. A radiologist and pathologist who were masked to the autopsy findings indicated whether the minimally invasive autopsy would have been adequate. The primary outcome was concordance rate between minimally invasive and conventional autopsy. We analysed 400 cases, of which 277 (69%) were fetuses and 123 (31%) were children. Cause of death or major pathological lesion detected by minimally invasive autopsy was concordant with conventional autopsy in 357 (89·3%, 95% CI 85·8-91·9) cases: 175 (94·6%, 90·3-97·0) of 185 fetuses at 24 weeks' gestation or less, 88 (95·7%, 89·3-98·3) of 92 fetuses at more than 24 weeks' gestation, 34 (81·0%, 67·7-90·0) of 42 newborns aged 1 month or younger, 45 (84·9%, 72·9-92·1) of 53 infants aged older than 1 month to 1 year or younger, and 15 (53·6%, 35·8-70·5) of 28 children aged older than 1 year to 16 years or younger. The dedicated radiologist or pathologist review of the minimally invasive autopsy showed that in 165 (41%) cases a full autopsy might not have been needed; in these cases, concordance between autopsy and minimally invasive autopsy was 99·4% (96·6-99·9). Minimally invasive autopsy has accuracy similar to that of conventional autopsy for detection of cause of death or major pathological abnormality after death in fetuses, newborns, and infants, but was less accurate in older children. If undertaken jointly by pathologists and radiologists, minimally invasive autopsy could be an acceptable alternative to conventional autopsy in selected cases. Policy research Programme, Department of Health, UK. 23879679 Potassium channel openers and prostacyclin play a crucial role in mediating the vasorelaxant activity of Gynura procumbens. Previous studies of Gynura procumbens (G. procumbens) have shown that partially purified fractions of the leaves are capable of lowering the blood pressure of rats by inhibiting angiotensin-converting enzymic activity and causing vasodilatation. The objectives of this study were therefore to further purify the active compounds that exhibited selective effects on blood vessels, determine the mechanism of actions, and to qualitatively analyse the putative compounds present. The butanolic fraction (BU) of the crude ethanolic extract was purified using column chromatography to obtain several sub-fractions of different polarities. The in vitro effects of BU and the sub-fractions on vascular tension were subsequently determined using isolated rat thoracic aortic rings. The most potent sub-fraction (F1) alone was then investigated for its mechanisms of the vasorelaxant activity. In another experiment, thin-layer chromatography was used to qualitatively analyse the active compounds found in F1. The BU and the sub-fractions ranging from 10-7 to 10-2 g/ml significantly (p < 0.05) inhibited the sustained tonic contractions induced by phenylephrine and potassium chloride in a concentration-dependent manner with various degree of potency. The most potent sub-fraction (F1) antagonised the calcium-induced vasocontractions (1 x 10-4 -- 1 x 10-2 M) in calcium-free with high concentration of potassium as well as in calcium- and potassium-free Krebs-Henseleit solutions. Contractions induced by noradrenaline and caffeine were not affected by F1. The vasorelaxing effect caused by F1 was significantly attenuated with preincubation of potassium channel blockers (glibenclamide and 4-aminopyridine) and prostacyclin inhibitor (indomethacin) while it was not affected by preincubation with tetraethylammonium, l-nitro-arginine methyl esther, propanolol, atropine, oxadiazolo quinoxalin one and methylene blue. The qualitative phytochemical analysis of F1 indicated the presence of flavonoids. These results confirm previous findings that G. procumbens causes vasodilatory effects by blocking calcium channels. In addition, the present study further demonstrates that the vasodilatory effect of G.procumbens may also be due to the opening of potassium channels and the stimulation of prostacyclin production. The putative compounds are probably flavonoids in nature. 23350933 An examination of pay-for-performance in general practice in Australia. This study examines the impact of Australia's pay-for-performance (P4P) program for general practitioners (GPs). The voluntary program pays GPs A$40 and A$100 in addition to fee-for-service payment for providing patients recommended diabetes and asthma treatment over a year, and A$35 for screening women for cervical cancer who have not been screened in 4 years. Three approaches were used to triangulate the program's impact: (1) analysis of trends in national claims for incentivized services pre- and postprogram implementation; (2) fixed effects panel regression models examining the impact of GPs' P4P program participation on provision of incentivized services; and (3) in-depth interviews to explore GPs' perceptions of their own response to the program. There was a short-term increase in diabetes testing and cervical cancer screens after program implementation. The increase, however, was for all GPs. Neither signing onto the program nor claiming incentive payments was associated with increased diabetes testing or cervical cancer screening. GPs reported that the incentive did not influence their behavior, largely due to the modest payment and the complexity of tracking patients and claiming payment. Monitoring and evaluating P4P programs is essential, as programs may not spark the envisioned impact on quality improvement. 23957744 Graphene in Ionic Liquids: Collective Van Der Waals Interaction and Hindrance of Self-Assembly Pathway. Over the past decade, there has been much controversy regarding the microscopic mechanism by which the π-electron riched carbon nanomaterials such as graphene and carbon nanotubes can be dispersed in ionic liquids. Through a combination of a quantum mechanical calculation on the level of density functional theory, an extensive molecular dynamics study on the time scale of microseconds, and a kinetic analysis at the experimental time scale, we have demonstrated that collective van der Waals forces between ionic liquids and graphene are able to describe both the short-ranged cation-π interaction and the long-ranged dispersion interaction and this microscopic interaction drives two graphene plates trapped in their meta-stable state while two graphene plates easily self-assemble into graphite in water. 23693141 Scrambled and fried: Cigarette smoke exposure causes antral follicle destruction and oocyte dysfunction through oxidative stress. Cigarette smoke is a reproductive hazard associated with pre-mature reproductive senescence and reduced clinical pregnancy rates in female smokers. Despite an increased awareness of the adverse effects of cigarette smoke exposure on systemic health, many women remain unaware of the adverse effects of cigarette smoke on female fertility. This issue is compounded by our limited understanding of the molecular mechanisms behind cigarette smoke induced infertility. In this study we used a direct nasal exposure mouse model of cigarette smoke-induced chronic obstructive pulmonary disease to characterise mechanisms of cigarette-smoke induced ovotoxicity. Cigarette smoke exposure caused increased levels of primordial follicle depletion, antral follicle oocyte apoptosis and oxidative stress in exposed ovaries, resulting in fewer follicles available for ovulation. Evidence of oxidative stress also persisted in ovulated oocytes which escaped destruction, with increased levels of mitochondrial ROS and lipid peroxidation resulting in reduced fertilisation potential. Microarray analysis of ovarian tissue correlated these insults with a complex mechanism of ovotoxicity involving genes associated with detoxification, inflammation, follicular activation, immune cell mediated apoptosis and membrane organisation. In particular, the phase I detoxifying enzyme cyp2e1 was found to be significantly up-regulated in developing oocytes; an enzyme known to cause molecular bioactivation resulting in oxidative stress. Our results provide a preliminary model of cigarette smoke induced sub-fertility through cyp2e1 bioactivation and oxidative stress, resulting in developing follicle depletion and oocyte dysfunction. 23944839 Optimization and Stabilization of Electrodeposited Cu2ZnSnS4 Photocathodes for Solar Water Reduction. Cu2ZnSnS4 (CZTS) is a promising p-type semiconductor that has not yet been extensively investigated for solar fuel production via water splitting. Here, we optimize and compare two different electrodeposition routes (simultaneous and sequential) for preparing CZTS electrodes. More consistent results are observed with the simultaneous route. In addition, the effect of etching and the presence of a CdS buffer layer on the photocurrent are investigated. Finally, we demonstrate for the first time the stabilization of these electrodes using protecting overlayers deposited by atomic layer deposition (ALD). Our best performing protected electrodes (Mo/CZTS/CdS/AZO/TiO2/Pt) exhibited a photocurrent of over 1 mA cm(-2) under standard one sun illumination conditions and a significant improvement in stability over unprotected electrodes. 23777678 Epilepsy surgery for hemispheric syndromes in infants: Hemimegalencepahly and hemispheric cortical dysplasia. Objective: Hemimegalencepahly (HME) and Hemispheric Cortical Dysplasia (HCD) are rare congenital diseases that occur with intractable epilepsy. They manifest by early epilepsy, mental retardation, hemianopsia and contralateral hemiplegia. Hemispheric disconnection (mainly anatomical hemispherectomy, peri-insular hemispherotomy, modified lateral hemispherotomy and vertical parasagittal hemispherotomy) have been reported to be efficient on seizures and also to prevent additional cognitive injury and developmental delay. Method: We reviewed literature about clinical presentation, predictors of outcome and expectation about epileptic seizures and cognitive outcome. Results: Clinical presentation and seizures outcome have been described in almost 600 children for the last thirty years. Epilepsy improved in most cases depending on the series and the follow-up duration. Percentage of seizure-free patients with HME or HCD was lower than in other groups (Rasmussen Encephalitis, Vascular Sequellae). Post-operative complications decreased with the hemispherotomy surgical procedures. EEG abnormalities on the "save" hemisphere did not negatively influence postsurgical outcome. Seizure free outcome did not seem to depend on the surgical procedure but the presence of residual insular cortex seemed to be associated with persistent postoperative seizures. Contralateral MRI abnormalities seemed to be associated with poorer prognosis for seizure free outcome and lack of cognitive improvement. Conclusion: Hemispheric disconnection remains the best treatment in order to control epileptic seizures. Hemispheric surgical procedures are safe and can be performed from the first month of life. Prospective studies of cognition are needed to emphasize benefits on long term outcome. 23935952 DNA repair deficiency as a susceptibility marker for spontaneous lymphoma in golden retriever dogs: a case-control study. There is accumulating evidence that an individual's inability to accurately repair DNA damage in a timely fashion may in part dictate a predisposition to cancer. Dogs spontaneously develop lymphoproliferative diseases such as lymphoma, with the golden retriever (GR) breed being at especially high risk. Mechanisms underlying such breed susceptibility are largely unknown; however, studies of heritable cancer predisposition in dogs may be much more straightforward than similar studies in humans, owing to a high degree of inbreeding and more limited genetic heterogeneity. Here, we conducted a pilot study with 21 GR with lymphoma, 20 age-matched healthy GR and 20 age-matched healthy mixed-breed dogs (MBD) to evaluate DNA repair capability following exposure to either ionizing radiation (IR) or the chemical mutagen bleomycin. Inter-individual variation in DNA repair capacity was evaluated in stimulated canine lymphoctyes exposed in vitro utilizing the G2 chromosomal radiosensitivity assay to quantify clastogen-induced chromatid-type aberrations (gaps and breaks). Golden retrievers with lymphoma demonstrated elevated sensitivity to induction of chromosome damage following either challenge compared to either healthy GR or MBD at multiple doses and time points. Using the 75(th) percentile of chromatid breaks per 1,000 chromosomes in the MBD population at 4 hours post 1.0 Gy IR exposure as a benchmark to compare cases and controls, GR with lymphoma were more likely than healthy GR to be classified as "sensitive" (odds ratio = 21.2, 95% confidence interval 2.3-195.8). Furthermore, our preliminary findings imply individual (rather than breed) susceptibility, and suggest that deficiencies in heritable factors related to DNA repair capabilities may be involved in the development of canine lymphoma. These studies set the stage for larger confirmatory studies, as well as candidate-based approaches to probe specific genetic susceptibility factors. 23910146 Giant solitary fibrous tumor of the epicardium causing reversible heart failure. A 68-year-old woman with a 2-year history of dyspnea and fatigue was admitted to our hospital with a massive pericardial effusion. Computed tomography and cardiovascular magnetic resonance imaging revealed a huge (17 cm maximum diameter) intrapericardial mass. After successful tumor resection, a giant solitary fibrous tumour of the epicardium was diagnosed by histology. Histologic features of malignancy were absent, and the patient is alive and well 1 year after the operation, undergoing close follow-up at regular intervals. Recurrences have been exceptionally reported in benign solitary fibrous tumors, and experience with this exceptionally rare and enigmatic cardiac tumor is lacking. 23832623 Safety and feasibility of transulnar catheterization when ipsilateral radial access is not available. We evaluated the safety and feasibility of transulnar approach when ipsilateral radial access was not available. From March 2011 until February 2013, 476 consecutive patients who underwent transulnar catheterization were included in a single center prospective registry of effectiveness and safety. Diagnostic coronary angiography accounted for 42% of cases, percutaneous coronary intervention (PCI) for 38%, and 17% underwent carotid artery stenting. A subgroup analysis was done in 240 patients with documented ipsilateral radial artery occlusion (RAO). Procedural success was 97% with a crossover rate of 3% to transfemoral access. Hand ischemia was not observed in any patient on day 1 after procedure and on 1 month follow-up. None of the patients showed ulnar nerve injury. Two patients developed major forearm hematoma that resolved without clinical consequences. Minor access site hematoma occurred in 8%. Severe clinical spasm occurred in two patients. Asymptomatic ulnar artery occlusion at 1 month follow-up was detected in 3.1%. There was no difference between patients with or without RAO in terms of procedural success and any vascular complication. Transulnar approach is safe and feasible alternative wrist access when performed by experienced radial operators, providing high success rate and low incidence of vascular complications. © 2013 Wiley Periodicals, Inc. 23946203 Field-induced Transition from Room-temperature Ferromagnetism to Diamagnetism in Proton-irradiated Fullerene. Room-temperature ferromagnetism in proton-irradiated C60 fullerene is demonstrated. The ferromagnetism turns into diamagnetism intrinsic to the fullerene as the magnetic field increases above a critical field. 23937323 Aqueous-Phase Linker-Assisted Attachment of Cysteinate(2(-))-Capped CdSe Quantum Dots to TiO2 for Quantum Dot-Sensitized Solar Cells. We have synthesized water-dispersible cysteinate(2(-))-capped CdSe nanocrystals and attached them to TiO2 using one-step linker-assisted assembly. Room-temperature syntheses yielded CdSe magic-sized clusters (MSCs) exhibiting a narrow and intense first excitonic absorption band centered at 422 nm. Syntheses at 80 °C yielded regular CdSe quantum dots (RQDs) with broader and red-shifted first excitonic absorption bands. Cysteinate(2(-))-capped CdSe MSCs and RQDs adsorbed to bare nanocrystalline TiO2 films from aqueous dispersions. CdSe-functionalized TiO2 films were incorporated into working electrodes of quantum dot-sensitized solar cells (QDSSCs). Short-circuit photocurrent action spectra of QDSSCs corresponded closely to absorptance spectra of CdSe-functionalized TiO2 films. Power-conversion efficiencies were (0.43 ± 0.04)% for MSC-functionalized TiO2 and (0.83 ± 0.11)% for RQD-functionalized TiO2. Absorbed photon-to-current efficiencies under white-light illumination were approximately 0.3 for both MSC- and RQD-based QDSSCs, despite the significant differences in the electronic properties of MSCs and RQDs. Cysteinate(2(-)) is an attractive capping group and ligand, as it engenders water-dispersibility of CdSe nanocrystals with a range of photophysical properties, enables facile all-aqueous linker-assisted attachment of nanocrystals to TiO2, and promotes efficient interfacial charge transfer. 23874968 Inhibition of inducible heat shock protein-70 (hsp72) enhances bortezomib-induced cell death in human bladder cancer cells. The proteasome inhibitor bortezomib (Velcade) is a promising new agent for bladder cancer therapy, but inducible cytoprotective mechanisms may limit its potential efficacy. We used whole genome mRNA expression profiling to study the effects of bortezomib on stress-induced gene expression in a panel of human bladder cancer cell lines. Bortezomib induced strong upregulation of the inducible HSP70 isoforms HSPA1A and HSPA1B isoforms of Hsp72 in 253J B-V and SW780 (HSPA1A(high)) cells, but only induced the HSPA1B isoform in UM-UC10 and UM-UC13 (HSPA1A(low)) cells. Bortezomib stimulated the binding of heat shock factor-1 (HSF1) to the HSPA1A promoter in 253JB-V but not in UM-UC13 cells. Methylation-specific PCR revealed that the HSPA1A promoter was methylated in the HSPA1A(low) cell lines (UM-UC10 and UM-UC13), and exposure to the chromatin demethylating agent 5-aza-2'-deoxycytidine restored HSPA1A expression. Overexpression of Hsp72 promoted bortezomib resistance in the UM-UC10 and UM-UC13 cells, whereas transient knockdown of HSPA1B further sensitized these cells to bortezomib, and exposure to the chemical HSF1 inhibitor KNK-437 promoted bortezomib sensitivity in the 253J B-V cells. Finally, shRNA-mediated stable knockdown of Hsp72 in 253J B-V promoted sensitivity to bortezomib in vitro and in tumor xenografts in vivo. Together, our results provide proof-of-concept for using Hsp72 inhibitors to promote bortezomib sensitivity in bladder cancers and suggest that selective targeting of HSPA1B could produce synthetic lethality in tumors that display HSPA1A promoter methylation. 23636656 Diffusion Tensor Imaging (DTI) and its clinical correlates in drug naïve Wilson's disease. The purpose is to evaluate white matter (WM) abnormalities in Wilson's disease (WD) using the technique of diffusion tensor imaging (DTI). The prospective case-control study comprised of 15 drug-naïve patients with WD and 15 controls. The phenotype of subjects was evaluated. The DTI/conventional MRI was acquired (3T MRI): Fractional anisotropy (FA) and mean diffusivity (MD) values were extracted from regions of interest placed in pons, midbrain, bilateral frontal and occipital cerebral white matter, bilateral internal capsules (IC), middle cerebellar peduncles (MCP) and corpus callosum (CC). Six patients showed lobar WM signal changes on T2-Weighted (T2W)/Fluid attenuation inversion recovery (FLAIR) images while remaining had normal appearing WM. MD was significantly increased in the lobar WM, bilateral IC and midbrain of WD patients. FA was decreased in the frontal and occipital WM, bilateral IC, midbrain and pons. Normal-appearing white matter on FLAIR images showed significantly increased MD and decreased FA values in both frontal and occipital lobar WM and IC compared with those in controls. Correlation of clinical scores and DTI metrics revealed positive correlation between neurological symptom score (NSS) and MD of anterior limb of right internal capsule, Chu stage and MD of frontal and occipital WM. Negative correlation was observed between the Modified Schwab and England Activities of Daily Living (MSEADL) score and MD of bilateral frontal and occipital WM and IC. This is the probably the first study to reveal widespread alterations in WM by DTI metrics in drug naïve WD. DTI analysis revealed lobar WM abnormalities which is less frequently noted on conventional MRI and suggests widespread WM abnormalities in WD. It may be valuable in assessing the true extent of involvement and therefore the severity of the illness. 23751100 Low vitamin D serum level is inversely associated with eczema in children and adolescents in Germany. Recent studies have yielded heterogeneous results regarding the relationship between vitamin D and atopic conditions. The aim of this study was to investigate the association between serum vitamin D level and the prevalence of eczema in German children and adolescents. Data were drawn for children aged 1-17 from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS), a nationwide cross-sectional representative survey. 25-hydroxyvitamin D (25(OH)D) serum concentration was measured in 9838 individuals with eczema and categorized into quartiles. We investigated the association of vitamin D level and eczema by means of logistic regression models. Weighted prevalence of eczema was 13.5% (95% confidence interval (CI) 12.6-14.4%). Mean vitamin D level was significantly higher in those with eczema compared with those without (P < 0.0001). Logistic regression revealed an inverse association between low levels of vitamin D and eczema (multivariate OR for quartile 1 vs quartile 2: 0.76 (95% CI 0.61-0.94)). This study suggests that low serum vitamin D level is inversely associated with eczema in German children and adolescents. Prospective studies are required to confirm this result, to discuss a potential opportunity for prevention of eczema. 23865828 Application of RIFLE criteria in patients with multiple myeloma with acute kidney injury: a 15-year retrospective, single center, cohort study. Although there have been numerous studies of patients with multiple myeloma (MM) and acute kidney injury (AKI), the results from these studies have varied greatly because of inconsistent definitions of AKI. The RIFLE criteria, which were designed to standardize the staging of AKI, have been extensively validated worldwide, but rarely in patients with MM. We retrospectively analyzed the natural history of 78 patients with MM and AKI between July 1995 and December 2010. RIFLE criteria, solely on the basis of the serum creatinine standard, were applied to stage the severity of AKI as risk, injury or failure. Among patients at the risk, injury and failure stage, the chemotherapy response rates were 54.5%, 63.6% and 39.3% (p = 0.26), and the renal response rates were 72.7%, 90.9% and 30.4%, respectively (p < 0.001). Severity of AKI predicted renal response but not chemotherapy response. Older age (odds ratio [OR] = 1.04, p = 0.01), hypercalcemia (OR = 2.57, p = 0.01) and reversibility of renal insufficiency (OR = 3.35 for no vs. yes, p < 0.001) were independent prognostic factors associated with survival. Severity of AKI staged by RIFLE class (OR = 2.04, failure stage vs. risk and injury stages. p = 0.06) was associated with marginally better long-term outcome. The RIFLE criteria may play a critical role in the early prevention and management of AKI in this population. 23800733 Inclusivity, exclusivity and limit of detection of commercially available real-time PCR assays for the detection of Salmonella. The traditional cultural detection of Salmonella spp. is both time- and labour-intensive. Salmonella is often a release criterion for the food industry and time to result is therefore an important factor. Storage of finished products and raw materials can be costly and may adversely impact available shelf-life. The application of real-time PCR for the detection of Salmonella spp. in food samples enables a potential time-saving of up to four days. The advancement of real-time PCR coupled with the development of commercially available systems in different formats has made this technology accessible for laboratories in an industrial environment. Ideally these systems are reliable and rapid as well as easy to use. The current study represents a comparative evaluation of seven commercial real-time PCR systems for the detection of Salmonella. Forty-nine target and twenty-nine non-target strains were included in the study to assess inclusivity and exclusivity. The limit of detection for each of the method was determined in four different food products. All systems evaluated were able to correctly identify the 49 Salmonella strains. Nevertheless, false positive results (Citrobacter spp.) were obtained with four of the seven systems. In milk powder and bouillon powder, the limit of detection was similar for all systems, suggesting a minimal matrix effect with these samples. Conversely, for black tea and cocoa powder some systems were prone to inhibition from matrix components. Up to 100% of the samples were inhibited using the proprietary extracts but inhibition could be reduced considerably by application of a DNA clean-up kit. 23791874 Targeted introduction of tissue plasminogen activator (TPA) at the AAVS1 locus in mesenchymal stem cells (MSCs) and its stable and effective expression. Thrombolytic therapy using tissue plasminogen activator (TPA) is an effective method for treating acute myocardial infarction. However, the systemic administration of TPA is associated with the risk of hemorrhage. Mesenchymal stem cells (MSCs) from bone marrow are characterized by low immunogenicity and homing toward damaged tissues and are therefore ideal cell carriers to achieve lesion-targeting medication. In this article, TPA gene was integrated into the AAVS1 of mesenchymal stem cells, which has been confirmed to be a safe chromosomal locus. The targeting efficiency was 83%. The clones with the site-specific integration retained the stem cell traits of MSCs, displayed a normal karyotype and could persistently and effectively express TPA, as demonstrated by an average expression activity of 1.5units/mL (3.4-fold that of the control group). After subculture and subsequent growth for two weeks, the clones showed an average TPA activity of 1.43units/mL and exhibited no significant differences among the individual clones. In summary, the foreign TPA gene can be specifically introduced to the AAVS1 locus, whereby it can be stably and effectively expressed. MSCs can serve as cell carriers for the targeted treatment of a thrombus using TPA. 23867106 Dynamic obstruction of the left main coronary artery ostium by a papillary fibroelastoma. Benign tumours of the heart are usually detected as incidental findings during echocardiography. Most cases are intracardiac tumours, with myxoma being the most frequent entity. We present images of a patient with acute myocardial infarction and a concomitant extracardiac benign tumour in the aortic root. Transesophageal echocardiography, coronary computed tomography angiography, cardiac surgery and histology of the excised tumour were performed. A mobile mass was found in the aortic root obstructing the left main coronary artery ostium during diastole. Coronary CT angiography indicated severe coronary artery disease and the patient underwent bypass surgery and excision of the tumour. The excised tumour was identified as papillary fibroelastoma. Papillary fibroelastoma is the second most benign tumour of the heart. More than other tumours it is prone to embolization. Extracardiac location as in our case is very rare but dangerous since embolization may occur spontaneously or associated with catheterization. 23809700 Genetic and developmental analysis of differences in eye and face morphology between Drosophila simulans and Drosophila mauritiana. Eye and head morphology vary considerably among insects and even between closely related species of Drosophila. Species of the D. melanogaster subgroup, and other Drosophila species, exhibit a negative correlation between eye size and face width (FW); for example, D. mauritiana generally has bigger eyes composed of larger ommatidia and conversely a narrower face than its sibling species. To better understand the evolution of eye and head morphology, we investigated the genetic and developmental basis of differences in eye size and FW between male D. mauritiana and D. simulans. QTL mapping of eye size and FW showed that the major loci responsible for the interspecific variation in these traits are localized to different genomic regions. Introgression of the largest effect QTL underlying the difference in eye size resulted in flies with larger eyes but no significant difference in FW. Moreover,introgression of a QTL region on the third chromosome that contributes to the FW difference between these species affected FW, but not eye size. We also observed that this difference in FW is detectable earlier in the development of the eye‐antennal disc than the difference in the size of the retinal field. Our results suggest that different loci that act at different developmental stages underlie changes in eye size and FW. Therefore, while there is a negative correlation between these traits in Drosophila, we show genetically that they also have the potential to evolve independently and this may help to explain the evolution of these traits in other insects. 23969108 Structural and bioinformatic analysis of the kiwifruit allergen Act d 11, a member of the family of ripening-related proteins. The allergen Act d 11, also known as kirola, is a 17kDa protein expressed in large amounts in ripe green and yellow-fleshed kiwifruit. Ten percent of all kiwifruit-allergic individuals produce IgE specific for the protein. Using X-ray crystallography, we determined the first three-dimensional structures of Act d 11, produced from both recombinant expression in Escherichia coli and from the natural source (kiwifruit). While Act d 11 is immunologically correlated with the birch pollen allergen Bet v 1 and other members of the pathogenesis-related protein family 10 (PR-10), it has low sequence similarity to PR-10 proteins. By sequence Act d 11 appears instead to belong to the major latex/ripening-related (MLP/RRP) family, but analysis of the crystal structures shows that Act d 11 has a fold very similar to that of Bet v 1 and other PR-10 related allergens regardless of the low sequence identity. The structures of both the natural and recombinant protein include an unidentified ligand, which is relatively small (about 250Da by mass spectrometry experiments) and most likely contains an aromatic ring. The ligand-binding cavity in Act d 11 is also significantly smaller than those in PR-10 proteins. The binding of the ligand, which we were not able to unambiguously identify, results in conformational changes in the protein that may have physiological and immunological implications. Interestingly, the residue corresponding to Glu45 in Bet v 1 (Glu46), which is important for IgE binding to the birch pollen allergen, is conserved in Act d 11, even though it is not in other allergens with significantly higher sequence identity to Bet v 1. We suggest that the so-called Gly-rich loop (or P-loop), which is conserved in all PR-10 allergens, may be responsible for IgE cross-reactivity between Bet v 1 and Act d 11. 23619960 A recommendation on the basis of long-term follow-up resultsof our microvascular decompression operation for hemifacial spasm. Microvascular decompression (MVD) for hemifacial spasm (HFS) has been popular, but it may take enough time to master this special operative technique and procedure. This may induce uneven distribution of the number of MVD operations in each institute, possibly resulting in an overall unsatisfactory quality of MVD surgeons. Nakanishi's approach to MVD operations has the feature of using a, "supine, no retractor" technique, which would achieve various benefits for patients and medical professionals. We would like to recommend this approach for MVD surgeons on the basis of our follow-up outcomes. A questionnaire, which was based on the method of evaluation for the long-term results of post-MVD operation as recommended by the Japanese Society of MVD, was sent by mail to the 154 HFS patients who had received Nakanishi's approach at our hospital. Except for 42 patients who had changed their residences, 89 patients (79.5 % of 112) fully answered. The mean postoperative follow-up term was 13.0 years. The 76.4 % of the patients was estimated as excellent. Postoperative deafness was not present. The average value of satisfaction degree for the results of the MVD operation was 87.9 %. This study revealed that Nakanishi's approach produced good results equivalent of other approaches for HFS patients. This approach is considered to have many advantages comparing to the other approaches. Therefore, we would like to recommend that Nakanishi's approach would contribute to overall advancement of the level of MVD surgeons. 23877026 Secondary metabolites of a mangrove endophytic fungus Aspergillus terreus (No. GX7-3B) from the South China Sea. The mangrove endophytic fungus Aspergillus terreus (No. GX7-3B) was cultivated in potato dextrose liquid medium, and one rare thiophene compound (1), together with anhydrojavanicin (2), 8-O-methylbostrycoidin (3), 8-O-methyljavanicin (4), botryosphaerone D (5), 6-ethyl-5-hydroxy-3,7-dimethoxynaphthoquinone (6), 3β,5α-dihydroxy-(22E,24R)-ergosta-7,22-dien-6-one (7), 3β,5α,14α-trihydroxy-(22E,24R)-ergosta-7, 22-dien-6-one (8), NGA0187 (9) and beauvericin (10), were isolated. Their structures were elucidated by analysis of spectroscopic data. This is the first report of a natural origin for compound 6. Moreover, compounds 3, 4, 5, 7, 8 and 10 were obtained from marine microorganism for the first time. In the bioactive assays in vitro, compounds 2, 3, 9 and 10 displayed remarkable inhibiting actions against α-acetylcholinesterase (AChE) with IC50 values 2.01, 6.71, 1.89, and 3.09 μM, respectively. Furthermore, in the cytotoxicity assays, compounds 7 and 10 exhibited strong or moderate cytotoxic activities against MCF-7, A549, Hela and KB cell lines with IC50 values 4.98 and 2.02 (MCF-7), 1.95 and 0.82 (A549), 0.68 and 1.14 (Hela), and 1.50 and 1.10 μM (KB), respectively; compound 8 had weak inhibitory activities against these tumor cell lines; compounds 1, 2, 3, 4, 5, 6 and 9 exhibited no inhibitory activities against them. 23969180 SAMP8 mice have altered hippocampal gene expression in long term potentiation, phosphatidylinositol signaling, and endocytosis pathways. The senescence-accelerated mouse (SAMP8) strain exhibits decreased learning and memory and increased amyloid beta (Aβ) peptide accumulation at 12 months. To detect differences in gene expression in SAMP8 mice, we used a control mouse that was a 50% cross between SAMP8 and CD-1 mice and which showed no memory deficits (50% SAMs). We then compared gene expression in the hippocampus of 4- and 12-month-old SAMP8 and control mice using Affymetrix gene arrays. At 12 months, but not at 4 months, pathway analysis revealed significant differences in the long term potentiation (6 genes), phosphatidylinositol signaling (6 genes), and endocytosis (10 genes) pathways. The changes in long term potentiation included mitogen-activated protein kinase (MAPK) signaling (N-ras, cAMP responsive element binding protein [CREB], protein phosphatase inhibitor 1) and Ca-dependent signaling (inositol triphosphate [ITP] receptors 1 and 2 and phospholipase C). Changes in phosphatidylinositol signaling genes suggested altered signaling through phosphatidylinositol-3-kinase, and Western blotting revealed phosphorylation changes in serine/threonine protein kinase AKT and 70S6K. Changes in the endocytosis pathway involved genes related to clathrin-mediated endocytosis (dynamin and clathrin). Endocytosis is required for receptor recycling, is involved in Aβ metabolism, and is regulated by phosphatidylinositol signaling. In summary, these studies demonstrate altered gene expression in 3 SAMP8 hippocampal pathways associated with memory formation and consolidation. These pathways might provide new therapeutic targets in addition to targeting Aβ metabolism itself. 23708180 Understanding the effect of surface/bulk defects on the photocatalytic activity of TiO2: anatase versus rutile. The sole effect of surface/bulk defects of TiO2 samples on their photocatalytic activity was investigated. Nano-sized anatase and rutile TiO2 were prepared by hydrothermal method and their surface/bulk defects were adjusted simply by calcination at different temperatures, i.e. 400-700 °C. High temperature calcinations induced the growth of crystalline sizes and a decrease in the surface areas, while the crystalline phase and the exposed facets were kept unchanged during calcination, as indicated by the characterization results from XRD, Raman, nitrogen adsorption-desorption, TEM and UV-Vis spectra. The existence of surface/bulk defects in calcined TiO2 samples was confirmed by photoluminescence and XPS spectra, and the surface/bulk defect ratio was quantitatively analyzed according to positron annihilation results. The photocatalytic activity of calcined TiO2 samples was evaluated in the photocatalytic reforming of methanol and the photocatalytic oxidation of α-phenethyl alcohol. Based on the characterization and catalytic results, a direct correlation between the surface specific photocatalytic activity and the surface/bulk defect density ratio could be drawn for both anatase TiO2 and rutile TiO2. The surface defects of TiO2, i.e. oxygen vacancy clusters, could promote the separation of electron-hole pairs under irradiation, and therefore, enhance the activity during photocatalytic reaction. 23830812 Inhibitory effects of polyphenol punicalagin on type-II collagen degradation in vitro and inflammation in vivo. Cartilage destruction is a crucial process in arthritis and is characterized by the degradation of cartilage proteins, proteoglycans, and type II collagen (CII), which are embedded within the extracellular matrix. While proteoglycan loss can be reversed, the degradation of CII is irreversible and has been correlated with an over-expression and over-activation of matrix metalloproteinases (MMPs). Among the various MMPs, the collagenase MMP-13 possesses the greatest catalytic activity for CII degradation. Here we show that the pomegranate-derived polyphenols, punicalagin (PA) and ellagic acid (EA), inhibit MMP-13-mediated degradation of CII in vitro. Surface plasmon resonance studies and molecular docking simulations suggested multiple binding interactions of PA and EA with CII. The effects of PA on bovine cartilage degradation (stimulated with IL-1β) were investigated by assaying proteoglycan and CII release into cartilage culture media. PA inhibited the degradation of both proteins in a concentration-dependent manner. Finally, the anti-inflammatory effects of PA (daily IP delivery at 10 and 50mg/kg for 14days) were tested in an adjuvant-induced arthritis rat model. Disease development was assessed by daily measurements of body weight and paw volume (using the water displacement method). PA had no effect on disease development at the lower dose but inhibited paw volume (P<0.05) at the higher dose. 23965574 Exploring the speed limits of liquid chromatography using shear-driven flows through 45 and 85 nm deep nano-channels. We explored the possibility to perform high speed and high efficiency liquid chromatographic separations in channels with a sub-100 nm depth. The mobile phase flow through these nano-channels was generated using the shear-driven flow principle to generate high speed flows which were the equivalent of a 12 000 bar pressure-driven flow. It was found that the ultra-fast mass transfer kinetics prevailing in this range of small channel depths allow to drastically reduce the C-term contribution to band broadening, at least up to the upper speed limit of our current set-up (7 mm s(-1) mobile phase velocity), leaving the inescapable molecular diffusion (i.e., B-term band broadening) as the sole detectable source of band broadening. Due to the greatly reduced mass transfer limitations, 50 000 to 100 000 theoretical plates could be generated in the span of 1 to 1.5 seconds. This is nearly two orders of magnitude faster than the best performing commercial pressure-driven UHPLC-systems. With the employed channel depths, we appear to have struck a practical lower limit for the channel miniaturization of shear-driven flows. Despite the use of channel substrates with the highest grades of optical flatness, the overall substrate waviness (on the order of some 5 to 10 nm) can no longer be neglected compared to the etched channel depth, which in turn significantly influenced the local retention factor and band broadening. 23664850 Phages bearing affinity peptides to severe acute respiratory syndromes-associated coronavirus differentiate this virus from other viruses. Transmission of SARS-associated coronavirus (SARS-CoV) is now well controlled, nevertheless, it is important to develop effective methods to identify this virus from other pathogens. The purpose of this study was to identify potential ligands and develop a novel diagnostic test to SARS-CoV using phage display technology. The SARS-CoV spike 1 (S1) protein containing the receptor binding region (RBD) was used as an immobilized target followed by incubation with a 12-mer phage display random peptide library. After four rounds of biopanning, 10 monoclonal phages with specific binding activity to the S1-RBD protein were obtained and subjected to binding and diagnostic assays. DNA sequencing showed that two phage displayed peptides HHKTWHPPVMHL (phage-H) and SQWHPRSASYPM (phage-S) that were specific ligands to the S1 protein. Moreover, the selected phage-H and phage-S were capable of differentiating SARS-CoV from other coronaviruses in indirect enzyme-linked immunosorbent assays. The peptides identified in this study are useful reagents for detection of SARS-CoV. 23602091 Acceptability of robotic manipulators in shared working environments through human-like redundancy resolution. Next generation robotic manipulators are expected to resemble a human-like behavior at kinematic level, in order to reach the same level of dexterity of humans in operations like assembly of small pieces. These manipulators are also expected to share the same working environments with humans without artificial barriers. In this work we conjecture that making robots not only kinematically similar but also able to move and act in the same way as humans do, might facilitate their social acceptance. For this the kinematic redundancy of such new generation manipulators can be exploited. An experimental campaign has been organized to assess the physiological comfort/discomfort perceived by humans working side-by-side with robots. For comparison, a human-like and two alternative redundancy resolution strategies have been implemented. The analysis confirmed the hypothesis that a human-like motion of the robot helps in facilitating social acceptance, by reducing the perceived stress by humans in human-robot coexistence. 23919578 Trunk isometric force production parameters during erector spinae muscle vibration at different frequencies. Vibration is known to alter proprioceptive afferents and create a tonic vibration reflex. The control of force and its variability are often considered determinants of motor performance and neuromuscular control. However, the effect of vibration on paraspinal muscle control and force production remains to be determined. Twenty-one healthy adults were asked to perform isometric trunk flexion and extension torque at 60% of their maximal voluntary isometric contraction, under three different vibration conditions: no vibration, vibration frequencies of 30 Hz and 80 Hz. Eighteen isometric contractions were performed under each condition without any feedback. Mechanical vibrations were applied bilaterally over the lumbar erector spinae muscles while participants were in neutral standing position. Time to peak torque (TPT), variable error (VE) as well as constant error (CE) and absolute error (AE) in peak torque were calculated and compared between conditions. The main finding suggests that erector spinae muscle vibration significantly decreases the accuracy in a trunk extension isometric force reproduction task. There was no difference between both vibration frequencies with regard to force production parameters. Antagonist muscles do not seem to be directly affected by vibration stimulation when performing a trunk isometric task. The results suggest that acute erector spinae muscle vibration interferes with torque generation sequence of the trunk by distorting proprioceptive information in healthy participants. 23934154 Myosin II in mechanotransduction: master and commander of cell migration, morphogenesis, and cancer. Mechanotransduction encompasses the role of mechanical forces in controlling cell behavior by activating signal transduction pathways. Most forces at a cellular level are caused by myosin II, which contracts and cross-links actin. Myosin II-dependent forces are transmitted through the actin cytoskeleton to molecular endpoints that promote specific cellular outcomes, e.g., cell proliferation, adhesion, or migration. For example, most adhesive and migratory phenomena are mechanically linked by a molecular clutch comprised of mechanosensitive scaffolds. Myosin II activation and mechanosensitive molecular mechanisms are finely tuned and spatiotemporally integrated to coordinate morphogenetic events during development. Mechanical events dependent on myosin II also participate in tumor cell proliferation, invasion, and metastatic dissemination. Specifically, tumor cells alter the mechanical properties of the microenvironment to create favorable conditions for proliferation and/or dissemination. These observations position myosin II-dependent force generation and mechanotransduction at the crossroads between normal development and cancer. 23707400 Analysis and solution of false-positives when testing CVA16 sera using an antibody assay against the EV71 virus. Hand, foot and mouth disease (HFMD) in humans is caused mainly by Enterovirus 71(EV71) and Coxsackievirus A16 (CVA16). EV71 is associated with severe HFMD cases but not CVA16. Use of IgM-capture enzyme-linked immunosorbent assay (ELISA) is important for the early diagnosis of EV71 infection, but cross-reactivity of the anti-CVA16 IgM antibody with EV71 produces false-positive results. In this report, we designed a new EV71 IgM-capture ELISA method using the EV71 VP1 peptide instead of the EV71 virion as the detectable antigen, and tested sera from patients infected with EV71 or CVA16. The results showed that acute sera from 76 EV71-infected patients had similar sensitivity for virus detection (98.68%) or VP1 detection (97.37%). When acute sera from patients infected with CVA16 were used, significant differences between the two methods were observed. The cross-reactivity rate of the virus detection method was 29.4% (5/17), but no cross-reactivity was observed using the VP1 detection method. Western immunoblotting demonstrated that EV71 VP3 cross-reacted with part of the CVA16 IgM antibody. The results demonstrate that EV71 VP3 is the cross-reactive antigen in the EV71 IgM-capture ELISA when testing CVA16 sera using the virus-antibody detection method. The problem of false-positive results was resolved by using the VP1 peptide as the detectable antigen. 23770616 Effects of chemical agent injections on genotoxicity of wastewater in a microfiltration-reverse osmosis membrane process for wastewater reuse. With combined microfiltration (MF)/ultrafiltration (UF) and reverse osmosis (RO) process being widely used in municipal wastewater reclamation, RO concentrate with high level genotoxicity is becoming a potential risk to water environment. In this study, wastewater genotoxicity in a MF-RO process for municipal wastewater reclamation and also the effects of chemical agent injections were evaluated by SOS/umu genotoxicity test. The genotoxicity of RO concentrate ranged 500-559μg 4-NQO (4-nitroquinoline-1-oxide)/L and 12-22μg 4-NQO/mg DOC, was much higher than that of RO influent. Further research suggested that Kathon biocide was a key chemical agent associated with the genotoxicity increase. Kathon biocide used in RO system was highly genotoxic in vitro and Kathon biocide retained in RO system could contribute to a higher genotoxicity of RO concentrate. Hence, treatments for biocides before discharging are necessary. Chlorination of secondary effluent could significantly decrease the genotoxicity and increasing chlorine dosage could be an efficacious method to decrease the genotoxicity of RO concentrate. According to the result of the experiment, the dosage of chlorine in dual-membrane process could be set to about 2.5mg Cl2/L. The effect of antiscalant (2-phosphomobutane-1,2,4-tricarboxylic acid) was also investigated; it turned out to have no effect on genotoxicity. 23582861 Core-shell nanoparticle controlled hATSCs neurogenesis for neuropathic pain therapy. A stem cell-based strategy for tissue engineering in regenerative medicine is crucial to produce and effective therapeutic replacement of injured or damaged tissues. This type of therapeutic replacement requires interaction with the cells and tissues via the incorporation of a beneficial physical microenvironment and cellular biochemical signals. Recently, we studied a cell-function modifying factor, core-shell nanoparticles consisting of an SPIO (superparamagnetic iron oxide) core covered with a photonic ZnO shell for human adipose tissue-derived stem cells (hATSCs) that regulate various cellular functions: self-renewal, neurogenesis, and dedifferentiation. We proposed an alternative method of stem cell culture that focuses on the use of Zn++ Finger nanoparticles for stem cell expansion and transdifferentiation modulation in vitro and in in vivo spinal cord injury models. Our study showed that treating hATSC cultures with nanoscale particles could lead to active cell proliferation and self-renewal and could promote nuclear Dicer-regulation of several functional molecules, Oct4 and Glutathione peroxidase 3 (GPx3), and the abundance of specific functional proteins that have been observed using biochemical analysis. These biochemical changes in hATSCs induced the functional development of multiple differentiation potencies such as β-cells and neural cells; specifically, the ability to differentiation into GABA-secreting cells was significantly improved in in vitro- and in vivo-induced animal lesions with significantly improved therapeutic modality. 22648665 Screening of venezuelan medicinal plant extracts for cytostatic and cytotoxic activity against tumor cell lines. There are estimated to be more than 20,000 species of plants in Venezuela, of which more than 1500 are used for medicinal purposes by indigenous and local communities. Only a relatively small proportion of these have been evaluated in terms of their potential as antitumor agents. In this study, we screened 308 extracts from 102 species for cytostatic and cytotoxic activity against a panel of six tumor cell lines using a 24-h sulphorhodamine B assay. Extracts from Clavija lancifolia, Hamelia patens, Piper san-vicentense, Physalis cordata, Jacaranda copaia, Heliotropium indicum, and Annona squamosa were the most cytotoxic, whereas other extracts from Calotropis gigantea, Hyptis dilatata, Chromolaena odorata, Siparuna guianensis, Jacaranda obtusifolia, Tapirira guianensis, Xylopia aromatica, Protium heptaphyllum, and Piper arboreum showed the greatest cytostatic activity. These results confirm previous reports on the cytotoxic activities of the abovementioned plants as well as prompting further studies on others such as C. lancifolia and H. dilatata that have not been so extensively studied. Copyright © 2012 John Wiley & Sons, Ltd. 23921204 The management of head-and-neck paragangliomas. Paragangliomas (PGLs) are tumours originating from neural crest-derived cells situated in the region of the autonomic nervous system ganglia. Head-and-neck PGLs (HNPGLs) originate from the sympathetic and parasympathetic paraganglia, most frequently from the carotid bodies and jugular, tympanic and vagal paraganglia, and are usually non-catecholamine secreting. Familial PGLs are considered to be rare, but recently genetic syndromes including multiple PGLs and/or phaeochromocytomas have been more thoroughly characterised. Nowadays, genetic screening for the genes frequently implicated in both familial and sporadic cases is routinely being recommended. HNPGLs are mostly benign, generally slow-growing tumours. Continuous growth leads to the involvement of adjacent neurovascular structures with increased morbidity rates and treatment-related complications. Optimal management mostly depends on tumour location, local involvement of neurovascular structures, estimated malignancy risk, patient age and general health. Surgery is the only treatment option offering the chance of cure but with significant morbidity rates, so a more conservative approach is usually considered, especially in the more difficult cases. Radiotherapy (fractionated or stereotactic radiosurgery) leads to tumour growth arrest and symptomatic improvement in the short term in many cases, but the long-term consequences are unclear. Early detection is essential in order to increase the chance of cure with a lower morbidity rate. The constant improvement in diagnostic imaging, surgical and radiation techniques has led to a safer management of these tumours, but there are still many therapeutic challenges, and no treatment algorithm has been agreed upon until now. The management of HNPGLs requires a multidisciplinary effort addressing the genetic, surgical, radiotherapeutic, oncological, neurological and endocrinological implications. Further progress in the understanding of their pathogenesis will lead to more effective screening and earlier diagnosis, both critical to successful treatment. 23777332 Limbic brain responses in mothers with post-traumatic stress disorder and comorbid dissociation to video clips of their children. Abstract Maternal dissociative symptoms which can be comorbid with interpersonal violence-related post-traumatic stress disorder (IPV-PTSD) have been linked to decreased sensitivity and responsiveness to children's emotional communication. This study examined the influence of dissociation on neural activation independently of IPV-PTSD symptom severity when mothers watch video-stimuli of their children during stressful and non-stressful mother-child interactions. Based on previous observations in related fields, we hypothesized that more severe comorbid dissociation in IPV-PTSD would be associated with lower limbic system activation and greater neural activity in regions of the emotion regulation circuit such as the medial prefrontal cortex and dorsolateral prefrontal cortex (dlPFC). Twenty mothers (of children aged 12-42 months), with and without IPV-PTSD watched epochs showing their child during separation and play while undergoing functional magnetic resonance imaging (fMRI). Multiple regression indicated that when mothers diagnosed with IPV-PTSD watched their children during separation compared to play, dissociative symptom severity was indeed linked to lowered activation within the limbic system, while greater IPV-PTSD symptom severity was associated with heightened limbic activity. Concerning emotion regulation areas, there was activation associated to dissociation in the right dlPFC. Our results are likely a neural correlate of affected mothers' reduced capacity for sensitive responsiveness to their young child following exposure to interpersonal stress, situations that are common in day-to-day parenting. 23022323 Modeling the binding mechanism of Alzheimer's Aβ₁-₄₂ to nicotinic acetylcholine receptors based on similarity with snake α-neurotoxins. For over a decade, it has been known that amyloid β (Aβ) peptides of Alzheimer's disease bind to the nicotinic α7 acetylcholine receptor (AChR) with picomolar affinity, and that snake α-neurotoxins competitively inhibit this binding. Here we propose a model of the binding mechanism of Aβ peptides to α7-AChR at atomic level. The binding mechanism is based on sequence and structure similarities of Aβ residues with functional residues of snake α-neurotoxins (ATX) in complex with AChR. The binding mechanism involves residue (Aβ)K28 (similar to (ATX)R32) which forms cation/π interactions in the acetylcholine binding site, and residues (Aβ)G29-(Aβ)I32 [GAII] (similar to (ATX)G33-(ATX)I36 [GTII]) which form an intermolecular β-sheet with residues (α7)F189-(α7)E191 of AChR. Through these interactions, we propose that the AChR serves as a chaperone for Aβ conformational changes from α- to β-hairpin. The interactions which block channel opening provide fundamental insight into Aβ neurotoxicity and cognition impairment, that could contribute to pathogenic processes in Alzheimer's disease, thus paving the way for structure based therapies. 23402371 A membrane vesicle-based assay to enable prediction of human biliary excretion. Abstract 1. Prediction of biliary excretion is a challenge due to the lack of in vitro assays. Our laboratory previously demonstrated a highly significant correlation between in vitro IC(50) values against mrp2 using rat canalicular liver plasma membrane vesicles and in vivo biliary excretion (Colombo et al., 2012). This study explores the possibility of predicting in vivo biliary excretion in human using membrane vesicles prepared from MDCKII cells transfected with human ABCC2. 2. In vitro MRP2 activity was determined by measuring the ATP-dependent uptake of 5(6)-carboxy-2',7'-dichlorofluorescein (CDCF) in inside-out membrane vesicles isolated from MDCK-ABCC2 cells. CDCF uptake was time- and concentration-dependent (K(m) of 4.0 ± 1.2 µM and a V(max) of 7.8 ± 0.9 pmol/mg/min) and inhibited by benzbromarone and MK-571 with IC(50) values of 1.2 and 7.6 µM, respectively. 3. A significant linear correlation (r(2 )= 0.790) between the in vitro IC(50) values from the described MRP2 assay and in vivo biliary excretion in humans was observed using 11 well-documented drugs covering low to high biliary excretions. 4. This study demonstrates, for the first time, that inhibition of CDCF uptake in MDCKII-ABCC2 vesicles not only provides a screening assay to assess MRP2 drug-drug interaction potential, but is also predictive of human MRP2-mediated biliary excretion. 23314046 Identification of novel antimycobacterial chemical agents through the in silico multi-conformational structure-based drug screening of a large-scale chemical library. The increasing prevalence of drug-resistant tuberculosis, which is resistant to effective multiple antibiotic, presents a major global health threat. The thymidine monophosphate kinase (TMPK) of Mycobacterium tuberculosis (M. tuberculosis), which is an essential enzyme for the maintenance of the thymidine triphosphate pools, is considered an attractive target for the development of effective antibiotics against tuberculosis. In this study, we attempted to identify novel chemical compounds that specifically target the M. tuberculosis TMPK (mtTMPK). We performed in silico structure-based drug screening using the crystal structure data of mtTMPK and a large-scale virtual compound library, which is composed of 6,192,930 chemicals. Through a three-step screening method using the DOCK and GOLD, we identified ten chemical compounds that were predicted to have high binding affinity to the active site cleft of the mtTMPK. We then evaluated the antibiotic effects of these chemical compounds on model mycobacteria strains. As a result, we found that a chemical compound, K10, completely inhibited the growth of Mycobacterium vanbaalenii (M. vanbaalenii) and Mycobacterium smegmatis (M. smegmatis). Moreover, K10 does not exhibit any toxic effects on the growth of enterobacteria and mammalian cells. The structural and experimental information regarding this novel chemical compound, K10, is likely to be useful for the hit-to-lead optimization of new antibiotics for the treatment of tuberculosis. 23615968 Identification of genetic counseling service delivery models in practice: a report from the NSGC Service Delivery Model Task Force. Increasing demand for genetic services has resulted in the need to evaluate current service delivery models (SDMs) and consider approaches that improve access to and efficiency of genetic counseling (GC). This study aimed to describe SDMs currently used by the GC community. The NSGC membership was surveyed regarding the use of four SDMs: in-person GC, telephone GC, group GC, and telegenetics GC. Variables related to access and components of use were also surveyed, including: appointment availability, time-per-patient, number of patients seen, billing, and geographic accessiblity. Seven hundred one usable responses were received. Of these, 54.7 % reported using an in-person SDM exclusively. The remainder (45.3 %) reported using multiple SDMs. Telephone, group and telegenetics GC were used often or always by 8.0 %, 3.2 % and 2.2 % of respondents, respectively. Those using an in-person SDM reported the ability to see the highest number of patients per week (p < 0.0001) and were the most likely to bill in some manner (p < 0.0001). Those using telegenetic and telephone GC served patients who lived the furthest away, with 48.3 % and 35.8 %% respectively providing GC to patients who live >4 h away. This study shows that genetic counselors are incorporating SDMs other than traditional in-person genetic counseling, and are utilizing more than one model. These adaptations show a trend toward shorter wait time and shorter length of appointments. Further study is indicated to analyze benefits and limitations of each individual model and factors influencing the choice to adopt particular models into practice. 23829696 The in vitro antisickling and antioxidant effects of aqueous extracts Zanthoxyllum heitzii on sickle cell disorder. Several plant extracts from Rutaceae family are currently used to the management of sickle cell disorder (SCD) in the African. Few reports have shown that extracts from Zanthoxyllum or Fagara genus demonstrated anti-sickling property. This study investigates the in vitro antisickling and antioxidant properties of extracts from Zanthoxyllum heitzii. The sickling of red blood cells (RBCs) was induced using sodium metabisulfite (2%) followed by treatment with extracts at different concentrations. The osmotic fragility tests permits to explore the effect of Z. heitzii extracts on haemoglobin S solubility and sickle cells membrane stability. For each extract, qualitative phytochemical tests were used to identify the presence of alkaloids, tannins, saponins, flavonoids, glycosides and phenols, while some quantitative methods such as Folin, Ferric Reducing Antioxidant Power (FRAP) and diphenyl 1, 2 picryl hydrazyl (DPPH) were used to determine the antioxidant potential of these extracts. Sodium metabisulphite increased the sickling of RBCs from 29.62 to 55.46% during 2 h. Treatment of sickling cells with extracts at different concentrations showed that a decrease of the percentage of sickling cells was found in both induced and non induced sickling cells. The fruits extract of Z. heitzii demonstrated the best anti-sickling property. The same extract at 250 mug/mL showed the best membrane cell stability compared to others. All the extracts revealed an antioxidant and anti-radical activities although lesser compared to the standard. The fruit extract of Z. Heitzii demonstrated the most significant antisickling effect with a potential for use in the clinical management of SCD. 23876704 Evaluation of glucose variability when converting from insulin infusion to basal-bolus regimen in a surgical-trauma intensive care unit. This study aimed to identify predictive factors resulting in glucose values greater than 200 mg/dL in patients with trauma transitioned from an insulin infusion to a basal-bolus subcutaneous insulin regimen. Thirty-nine patients with trauma on goal enteral nutrition in the intensive care unit receiving an insulin infusion for at least 48 hours and transitioned to a basal-bolus regimen were retrospectively identified. Ten patients had hyperglycemic events after transition. Hyperglycemia was significantly associated with increased age (42 [17] years vs 56 [13] years, P = .02), admission glucose (128 [39] mg/dL vs 214 [91] mg/dL, P = .015), and insulin drip rate 48 hours before transition (87 [38] units/d vs 127 [49] units/d, P = .012). There was no difference between groups with respect to injury severity, demographics, or physiologic parameters. Multiple regression analysis revealed that increased age (odds ratio [OR], 1.215 [1.000-1.477]; P =.05), increased admission blood glucose (OR, 1.053 [1.006-1.101]; P =.025), and higher insulin infusion rates 48 hours before transition (OR, 1.061 [1.009-1.116]; P =.020) predisposed patients to severe hyperglycemic episodes. Older patients with trauma and patients with higher blood glucose on admission are more likely to experience severe hyperglycemia when transitioned to basal-bolus glucose control. Higher insulin infusion rates at 48 hours before transition are also associated with severe hyperglycemia. 23866784 High prevalence of diagnosis of diabetes, depression, anxiety, hypertension, asthma and COPD in the total population of Stockholm, Sweden -- a challenge for public health. There is limited knowledge on the prevalence of disease in total populations. Such studies have historically been difficult to conduct but the development of health data registers has facilitated large-scale studies on recorded diagnoses in entire regions. The aim of this study was to analyze the prevalence of diagnosis of six common diseases in the Swedish capital region. The study population included all living persons who resided in Stockholm County, Sweden, on December 31st 2011 (N = 2 093 717). Information on all consultations between 2007 and 2011 was obtained from primary health care, specialist outpatient care and inpatient care. Prevalence was defined as the proportion of individuals with a recorded diagnosis of diabetes, depression, anxiety disorders, hypertension, asthma and chronic obstructive pulmonary disease during the five year period, respectively. Analyses were done by age and gender. Hypertension had the highest five-year prevalence (12.2%), followed by depression (6.6%), diabetes mellitus (6.2%), asthma (5.9%), anxiety disorders/phobia (4.8%), and COPD (1.8%). Diabetes was more common in men (5.3% of women and 7.1% of men) while depression (8.7% in women and 4.4% in men) and anxiety (6.3% in women and 3.4% in men) were considerably more common in women. Smaller gender differences were also found for hypertension (13.0% in women and 11.4% in men), asthma (6.4% in women and 5.4% in men) and COPD (2.1% in women and 1.6% in men). Diabetes, hypertension and COPD increased markedly with age, whereas anxiety, depression and asthma were fairly constant in individuals above 18 years. During one year of observation, more than half of all patients had only been diagnosed in primary health care, with hypertension being the diagnosis with the largest proportion of patients only identified in primary health care (70.6%). The prevalence of common diseases in the population can be estimated by combining data gathered during consecutive years from primary care, specialist outpatient care and inpatient care. However, accuracy of disease prevalence is highly dependent on the quality of the data. The high prevalence of the six diagnoses analysed in this study calls for preventive action to minimize suffering and costs to society. 23377119 Influence of pesticide exposure on carbonic anhydrase II from sheep stomach. Carbonic anhydrase (CA) is a widely distributed enzyme and has a crucial role in the cells, tissues and organs of living organisms. It is found that CA-II is one of the most abundant CA isoenzymes in the gastrointestinal system. It plays an important role in the gastric acid secretion in stomach. In this study, we purified CA-II isoenzyme from sheep stomach with a 615.2 purification fold, 78% purification yield and 5562.02 specific activity. Moreover, the in vitro effects of some commonly used pesticides including chlorpyrifos, cypermethrin, dichlorvos, glyphosate isopropylamine and lambda cyhalomethrin on the enzyme activity were investigated. Of these compounds, glyphosate isopropylamine and dichlorvos showed an inhibition on CA-II esterase activity. They have IC(50) values of 0.155 µM and 2.690 µM and K(i) values of 0.329 µM and 3.654 µM, respectively. Both glyphosate isopropylamine and dichlorvos inhibited CA-II isoenzyme in a noncompetitive manner. 23668640 Agr function is upregulated by photodynamic therapy for Staphylococcus aureus and is related to resistance to photodynamic therapy. Photodynamic therapy (PDT) has been considered a feasible alternative for antimicrobial therapy of multidrug-resistant pathogens. However, bacterial response mechanisms against PDT-generated photo-oxidative stress remain largely unknown. Herein, it is shown that the accessory gene regulator Agr is involved in Staphylococcus aureus response to photo-oxidative stress generated by laser-induced PDT with the photosensitizer chlorin e6 . Transcriptional profiling revealed that sublethal PDT induces a general stress response and also activates Agr-dependent gene regulation. Moreover, mutant S. aureus lacking Agr function showed hypersusceptibility to two independent PDT conditions with higher energy densities, demonstrating Agr-dependent S. aureus resistance against PDT. 23885035 The Things You Do for Me: Perceptions of a Romantic Partner's Investments Promote Gratitude and Commitment. Although a great deal of attention has been paid to the role of people's own investment in promoting relationship commitment, less research has considered the possible role of the partner's investments. An experiment (Study 1) and two combined daily experience and longitudinal studies (Studies 2 and 3) documented that perceived investments from one partner motivate the other partner to further commit to the relationship. All three studies provided support for gratitude as a mechanism of this effect. These effects held even for individuals who were relatively less satisfied with their relationships. Together, these results suggest that people feel particularly grateful for partners who they perceive to have invested into the relationship, which, in turn, motivates them to further commit to the relationship. Implications for research and theory on gratitude and relationship commitment are discussed. 23872160 Highly sensitive HPLC method for assay of aliskiren in human plasma through derivatization with 1-naphthyl isocyanate using UV detection. A simple and sensitive HPLC method has been developed for the determination of aliskiren in human plasma through derivatization with 1-naphthyl isocyanate. The separation was achieved on a C18 column using a mobile phase consisting of acetonitrile/water/phosphoric acid (45:55:0.01, v/v/v, pH 3.2) in a flow rate of 1mL/min with UV detection at 230nm. Caffeine was used as an internal standard. The factors influencing the derivatization reaction yields were carefully studied and optimized. The method was linear over the concentration range of 5-400ng/mL with a detection limit of 0.5ng/mL and a limit of quantification of 1.0ng/mL. The relative standard deviation was less than 4.2% for both intra-day assay and inter-day assay results. No interferences from endogenous compounds were encountered. The percentage recovery was in the range 97.1-98.6%. The method is suitable for routine therapeutic drug monitoring and for pharmacokinetic studies. 23674352 Sorafenib and HDAC inhibitors synergize with TRAIL to kill tumor cells. The present studies were designed to compare and contrast the abilities of TRAIL (death receptor agonist) and obatoclax (BCL-2 family inhibitor) to enhance sorafenib + HDAC inhibitor toxicity in GI tumor cells. Sorafenib and HDAC inhibitor treatment required expression of CD95 to kill GI tumor cells in vitro and in vivo. In cells lacking CD95 expression, TRAIL treatment, and to a lesser extent obatoclax, enhanced the lethal effects of sorafenib + HDAC inhibitor exposure. In hepatoma cells expressing CD95 a similar data pattern emerged with respect to the actions of TRAIL. Downstream of the death receptor the ability of TRAIL to enhance cell killing correlated with reduced AKT, ERK1/2, p70 S6K, and mTOR activity and enhanced cleavage of pro-caspase 3 and reduced expression of MCL-1 and BCL-XL. Over-expression of BCL-XL or MCL-1 or expression of dominant negative pro-caspase 9 protected cells from drug toxicity. Expression of activated AKT, p70 S6K, mTOR, and to a lesser extent MEK1EE also protected cells that correlated with maintained c-FLIP-s expression, reduced BIM expression, and increased BAD phosphorylation. In vivo sorafenib + HDAC inhibitor toxicity against tumors was increased in a greater than additive fashion by TRAIL. Collectively, our data argue that TRAIL, rather than obatoclax, is the most efficacious agent at promoting sorafenib + HDAC inhibitor lethality. 23754799 Gaseous byproducts from high-temperature thermal conversion elemental analysis of nitrogen- and sulfur-bearing compounds with considerations for δ2H and δ18O analyses. High-temperature, conversion-reduction (HTC) systems convert hydrogen and oxygen in materials into H2 and CO for δ(2)H and δ(18)O measurements by isotope ratio mass spectrometry. HTC of nitrogen- and sulfur-bearing materials produces unintended byproduct gases that could affect isotope analyses by: (1) allowing isotope exchange reactions downstream of the HTC reactor, (2) creating isobaric or co-elution interferences, and (3) causing deterioration of the chromatography. This study characterizes these HTC byproducts. A HTC system (ThermoFinnigan TC/EA) was directly connected to a gas chromatograph/quadrupole mass spectrometer in scan mode (m/z 8 to 88) to identify the volatile products generated by HTC at conversion temperatures of 1350 °C and 1450 °C for a range of nitrogen- and sulfur-bearing solids [keratin powder, horse hair, caffeine, ammonium nitrate, potassium nitrate, ammonium sulfate, urea, and three nitrated organic explosives (PETN, RDX, and TNT)]. The prominent HTC byproduct gases include carbon dioxide, hydrogen cyanide, methane, acetylene, and water for all nitrogen-bearing compounds, as well as carbon disulfide, carbonyl sulfide, and hydrogen sulfide for sulfur-bearing compounds. The 1450 °C reactor temperature reduced the abundance of most byproduct gases, but increased the significant byproduct, hydrogen cyanide. Inclusion of a post-reactor chemical trap containing Ascarite II and Sicapent, in series, eliminated the majority of byproducts. This study identified numerous gaseous HTC byproducts. The potential adverse effects of these gases on isotope ratio analyses are unknown but may be mitigated by higher HTC reactor temperatures and purifying the products with a purge-and-trap system or with chemical traps. 23747276 Ventilatory response to hypoxia of the 1-day old chicken hatchling after prenatal cold-induced hypometabolism. Sustained prenatal hypoxia decreases the growth and metabolic rate of the embryo and causes a blunted hypoxic ventilatory response (HVR) in the newborn. The most likely interpretation is that the sustained hypoxic stimulation may interfere with the normal prenatal development of the chemoreceptors. However, we wanted to consider the possibility that the prolonged hypoxic hypometabolism may be a contributing factor. Chicken embryos were incubated at 35°C (Cold group, N=14), which is known to lower the embryonic oxygen consumption ( [Formula: see text] ) by ∼30% throughout incubation, or at 37.5°C (Controls, N=16). Cold incubation delayed hatching by ∼2 days. The 1-day old hatchlings had normal pulmonary ventilation (V˙E), measured by the barometric technique, and oxygen consumption ( [Formula: see text] ), simultaneously measured by an open flow methodology. During acute hypoxia (∼15% or ∼11% O2) the hyperventilation (increase in [Formula: see text] ), the hyperpnea and the hypometabolism were almost identical between the two groups of hatchlings. We conclude that a sustained decrease in metabolic rate during the embryonic period by itself does not carry obvious consequences on the newborn's resting V˙E and HVR. 23672317 Spermidine promotes adipogenesis of 3T3-L1 cells by preventing interaction of ANP32 with HuR and PP2A. We have shown previously that the polyamine spermidine is indispensable for differentiation of 3T3-L1 preadipocytes. In the present study, we examined the mechanism of spermidine function by using the polyamine biosynthesis inhibitor α-difluoromethylornithine in combination with the metabolically stable polyamine analogues γ-methylspermidine or (R,R)-α,ω-bismethylspermine. At the early phase of differentiation, spermidine-depleted 3T3-L1 cells showed decreased translation of the transcription factor C/EBPβ (CCAAT/enhancer-binding protein β), decreased PP2A (protein phosphatase 2A) activity and increased cytoplasmic localization of the RNA-binding protein HuR (human antigen R). The amount of HuR bound to C/EBPβ mRNA was reduced, whereas the amount of bound CUGBP2, an inhibitor of C/EBPβ translation, was increased. ANP32 (acidic nuclear phosphoprotein 32) proteins, which are known PP2A inhibitors and HuR ligands, bound more PP2A and HuR in spermidine-depleted than in control cells, whereas immunodepletion of ANP32 proteins from the lysate of spermidine-depleted cells restored PP2A activity. Taken together, our data shows that spermidine promotes C/EBPβ translation in differentiating 3T3-L1 cells, and that this process is controlled by the interaction of ANP32 with HuR and PP2A. 23731338 Do Not Hesitate to Use Tversky-and Other Hints for Successful Active Analogue Searches with Feature Count Descriptors. This study is an exhaustive analysis of the neighborhood behavior over a large coherent data set (ChEMBL target/ligand pairs of known Ki, for 165 targets with >50 associated ligands each). It focuses on similarity-based virtual screening (SVS) success defined by the ascertained optimality index. This is a weighted compromise between purity and retrieval rate of active hits in the neighborhood of an active query. One key issue addressed here is the impact of Tversky asymmetric weighing of query vs candidate features (represented as integer-value ISIDA colored fragment/pharmacophore triplet count descriptor vectors). The nearly a 3/4 million independent SVS runs showed that Tversky scores with a strong bias in favor of query-specific features are, by far, the most successful and the least failure-prone out of a set of nine other dissimilarity scores. These include classical Tanimoto, which failed to defend its privileged status in practical SVS applications. Tversky performance is not significantly conditioned by tuning of its bias parameter α. Both initial "guesses" of α = 0.9 and 0.7 were more successful than Tanimoto (at its turn, better than Euclid). Tversky was eventually tested in exhaustive similarity searching within the library of 1.6 M commercial + bioactive molecules at http://infochim.u-strasbg.fr/webserv/VSEngine.html , comparing favorably to Tanimoto in terms of "scaffold hopping" propensity. Therefore, it should be used at least as often as, perhaps in parallel to Tanimoto in SVS. Analysis with respect to query subclasses highlighted relationships of query complexity (simply expressed in terms of pharmacophore pattern counts) and/or target nature vs SVS success likelihood. SVS using more complex queries are more robust with respect to the choice of their operational premises (descriptors, metric). Yet, they are best handled by "pro-query" Tversky scores at α > 0.5. Among simpler queries, one may distinguish between "growable" (allowing for active analogs with additional features), and a few "conservative" queries not allowing any growth. These (typically bioactive amine transporter ligands) form the specific application domain of "pro-candidate" biased Tversky scores at α < 0.5. 23818238 Structural and optical properties of Cu-doped ZnS nanoparticles formed in chitosan/sodium alginate multilayer films. Chitosan/alginate multilayers were fabricated using a spin-coating method, and ZnS:Cu nanoparticles were generated within the network of two natural polysaccharides, chitosan and sodium alginate. The synthesized nanoparticles were characterized using an X-ray diffractometer (XRD), transmission electron microscopy (TEM), energy dispersive spectroscopy (EDS) and atomic force microscopy (AFM). The results showed that cubic zinc blende-structured ZnS:Cu nanoparticles with an average crystal size of ~ 3 nm were uniformly distributed. UV-vis spectra indicate a large quantum size effect and the absorption edge for the ZnS:Cu nanoparticles slightly shifted to longer wavelengths with increasing Cu ion concentrations. The photoluminescence of the Cu-doped ZnS nanoparticles reached a maximum at a 1% doping level. The ZnS:Cu nanoparticles form and are distributed uniformly in the composite multilayer films with a surface average height of 25 nm. Copyright © 2013 John Wiley & Sons, Ltd. 23920037 The effects of lipoplex formulation variables on the protein corona and comparisons with in vitro transfection efficiency. The use of lipoplexes for the intracellular delivery of nucleic acids typically involves the optimization of several parameters that are known to affect delivery. Researchers commonly vary charge ratio, and often incorporate different amounts of helper lipids (e.g., cholesterol) to optimize formulations for transfection in cell culture and in vivo. The results of such experiments are often interpreted in the context of nuclease resistance and cell association, but effects on the protein corona are usually not considered. While many studies have demonstrated that lipoplex structure and function can be dramatically compromised in the presence of serum, little attention has been paid to the adsorption of specific proteins and how this might be affected by formulation parameters. In this study, we characterize changes in the protein corona that occur as DOTAP-based lipoplexes are formulated with different amounts of cholesterol and prepared at different charge ratios. Our results demonstrate a significant effect of lipid composition on both total protein adsorption as well as the individual proteins from fetal calf serum that are associated with lipoplexes. In addition, we show that PEGylation increases protein adsorption with our formulations; effects that depend on the type of PEG conjugate employed in the lipoplex. Attempts to identify a specific protein responsible for enhancing transfection were unsuccessful. 23440057 Light-triggered self-healing and shape-memory polymers. In this review, we highlight the recent progress made in light-controlled self-healing and shape memory polymers. We analyse the materials design, underlying mechanisms and chemistries involved in the different methods developed for these two types of emerging photoresponsive materials. We show that these two seemingly different groups of functional materials are linked by a number of common approaches enabling their optical control, particularly the approaches based on the photothermal effect and photochemical reactions of photoswitching groups incorporated in polymer structures. Possible future developments and perspectives of using light as a unique trigger for polymer self-healing and shape-memory are also discussed. 23291559 Nuclear receptor CAR specifically activates the two-pore K+ channel Kcnk1 gene in male mouse livers, which attenuates phenobarbital-induced hepatic hyperplasia. KCNK1, a member of the family of two-pore K(+) ion channels, is specifically induced in the livers of male mice after phenobarbital treatment. Here, we have determined the molecular mechanism of this male-specific activation of the Kcnk1 gene and characterized KCNK1 as a phenobarbital-inducible antihyperplasia factor. Upon activation by phenobarbital, nuclear receptor CAR binds the 97-bp response element (-2441/-2345) within the Kcnk1 promoter. This binding is observed in the livers of male mice, but not in the livers of female mice and requires the pituitary gland, because hypophysectomy abrogates it. Hyperplasia further progressed in the livers of Kcnk1 ( -/- ) male mice compared with those of Kcnk1 ( +/+ ) males after phenobarbital treatment. Thus, KCNK1 suppresses phenobarbital-induced hyperplasia. These results indicate that phenobarbital treatment induces KCNK1 to elicit a male-specific and growth-suppressing signal. Thus, KCNK1 and Kcnk1 ( -/- ) mice provide an experimental tool for further investigation into the molecular mechanism of CAR-mediated promotion of the development of hepatocellular carcinoma in mice. 23495691 Targeting protein-protein interactions within the cyclic AMP signaling system as a therapeutic strategy for cardiovascular disease. The cAMP signaling system can trigger precise physiological cellular responses that depend on the fidelity of many protein-protein interactions, which act to bring together signaling intermediates at defined locations within cells. In the heart, cAMP participates in the fine control of excitation-contraction coupling, hence, any disregulation of this signaling cascade can lead to cardiac disease. Due to the ubiquitous nature of the cAMP pathway, general inhibitors of cAMP signaling proteins such as PKA, EPAC and PDEs would act non-specifically and universally, increasing the likelihood of serious 'off target' effects. Recent advances in the discovery of peptides and small molecules that disrupt the protein-protein interactions that underpin cellular targeting of cAMP signaling proteins are described and discussed. 23855274 Mammalian target of rapamycin pathway is up-regulated by both acute endurance exercise and chronic muscle contraction in rat skeletal muscle. This study examined changes in the expression of translation initiation regulatory proteins and mRNA following both an acute bout of endurance exercise and chronic muscle contractile activity. Female Sprague Dawley rats ran for 2 h at 15 m·min(-1) followed by an increase in speed of 5 m·min(-1) every 5 min until volitional fatigue. The red gastrocnemius muscle was harvested from nonexercised animals (control; n = 6) and from animals that exercised either immediately after exercise (n = 6) or following 3 h of recovery from exercise (n = 6). Compared with control, ribosomal protein S6 (rpS6) mRNA was elevated (p < 0.05) at both 0 h (+32%) and 3 h (+47%). Both a catalytic subunit of eukaryotic initiation factor 2B (eIF2Bε) (+127%) and mammalian target of rapamycin (mTOR) mRNA (+44%) were increased at 3 h, compared with control. Phosphorylation of mTOR (+40%) and S6 kinase 1 (S6K1) (+266%) were increased immediately after exercise (p < 0.05). Female Sprague Dawley rats also underwent chronic stimulation of the peroneal nerve continuously for 7 days. The red gastrocnemius muscle was removed 24 h after cessation of the stimulation. Chronic muscle stimulation increased (p < 0.05) mTOR protein (+74%), rpS6 (+31%), and eukaryotic initiation factor 2α (+44%, p = 0.069), and this was accompanied by an increase in cytochrome c (+31%). Increased resting phosphorylation was observed for rpS6 (+51%) (p < 0.05) but not for mTOR or eukaryotic initiation factor 4E binding protein 1. These experiments demonstrate that both acute and chronic contractile activity up-regulate the mTOR pathway and mitochondrial content in murine skeletal muscle. This up-regulation of the mTOR pathway may increase translation efficiency and may also represent an important control point in exercise-mediated mitochondrial biogenesis. 23763389 The next chapter of the tobacco wars: unpacking the latest round of constitutional challenges. We have considered the tobacco industry's challenges to legislative attempts to provide more health-related information on retail packaging. The first issue is taking and acquiring the industry's intellectual property in Australia. The second challenge involves the tensions between graphic images and the First Amendment in the United States. We have argued that the Obama administration should take advantage of the current window of opportunity to aggressively restrict the industry's control of its products. 23562062 Arylsulfonamide pyrimidines as VLA-4 antagonists. A series of (S)-2-(2-(diethylamino)-5-(N-alkyl-N-sulfonamido)pyrimidin-4-ylamino)-3-(4-(carbamoyloxy)phenyl)propanoic acid is discovered as orally available VLA-4 antagonists. Representative compounds 11b and 11p showed efficacy in multiple in vivo animal models. The in vitro selectivity of 11p is also described. 23873547 Litter aeration and spread of Salmonella in broilers. Litter quality in the poultry sector is one of the main parameters of health, productivity, and animal welfare. Therefore, innovative management methods have been developed to improve the quality of litter. One of them is litter aeration (LA) by tumbling. However, there is little information related to the effect of this technique on the spreading of pathogens of public health importance such as Salmonella. In this context, the objective of this study was to determine the epidemiology of Salmonella in poultry farms, when serial LA were implemented during the rearing cycle of broilers. For this purpose, an experimental broiler farm with 3 identical rooms was used in the study. Two rooms were assigned to the LA treatment, and the other one served as the control room. Environmental samples were taken in poultry houses after LA in 4 consecutive weeks at the end of the cycle. All samples collected were analyzed according to the standards of the International Organization for Standardization (ISO 6579:2002, Annex D). The results of this study showed that in the control and treated rooms, the percentage of positive samples for Salmonella decreased in the first 3 LA sessions (LA 1, LA 2, and LA 3). However, in the last LA session of rearing (LA 4), the percentage of positive samples increased from 8.2 to 33.2% in the control room instead the treated rooms where the positive samples decreased (P = 0.017). Thus, the aeration of the litter as litter management technique in poultry broiler production does not increase the shedding or the spread of Salmonella throughout broiler houses. In addition, it could be an effective technique to reduce the infective pressure of this bacterium in several areas of the farm or in certain moments of the rearing period with more risk of multiplication and spreading of Salmonella. 23965837 What happens to the medication regimens of older adults during and after an acute hospitalization? Hospitalized elderly patients are at risk for medication errors and nonadherence when discharged home. To describe how older patients' medications change during and after hospitalizations and what patients ultimately take after discharge. We conducted an observational cohort study of 95 patients aged 65 years and older admitted to Johns Hopkins Bayview Medical Center in 2007. Inclusion criteria included admissions longer than 24 hours and discharge to home. Medication lists from three periods were recorded: prehospitalization, day of discharge, and 3 days after discharge. In comparing lists, we characterized: new and discontinued medications, changes in dosage, and changes in frequency. Before admission, patients were taking a total of 701 medications (mean, 7 per patient). Upon discharge, 192 new medicines were started (2.0 per patient), 76 discontinued (0.8 per patient), 67 changed in frequency, (0.7 per patient), and 45 changed in dosage (0.5 per patient). Antibiotics and antihypertensives were the most commonly prescribed new medications. Antihypertensives were also most likely to be discontinued. At day 3 after discharge, patients were adherent with 98% (763/778) of medications. However, 25% of antihypertensives and 88% analgesics discontinued by hospitalists on the day of discharge were reinitiated by patients upon their return home. During hospitalizations, medications of older adults change substantially. Despite clear medication reconciliation efforts in the hospital environment, medication errors occur upon discharge to home. Because current standards are yielding suboptimal results, alternate methodologies for promoting medication adherence should also be considered, developed, and studied for effectiveness. 23924314 Highly Efficient Chemoselective Synthesis of Polysubstituted Pyrroles via Isocyanide-Based Multicomponent Domino Reaction. A multicomponent domino reaction for the chemoselective, catalyst-free synthesis of polysubstituted pyrroles from readily available isocyanides, primary or secondary amines, and gem-diactivated olefins has been developed. Structurally diverse pyrroles were obtained in moderate to good yields under mild conditions. 23384287 The salicylate 1,2-dioxygenase as a model for a conventional gentisate 1,2-dioxygenase: crystal structures of the G106A mutant and its adducts with gentisate and salicylate. The salicylate 1,2-dioxygenase (SDO) from the bacterium Pseudaminobacter salicylatoxidans BN12 is a versatile gentisate 1,2-dioxygenase (GDO) that converts both gentisate (2,5-dihydroxybenzoate) and various monohydroxylated substrates. Several variants of this enzyme were rationally designed based on the previously determined enzyme structure and sequence differences between the SDO and the 'conventional' GDO from Corynebacterium glutamicum. This was undertaken in order to define the structural elements that give the SDO its unique ability to dioxygenolytically cleave (substituted) salicylates. SDO variants M103L, G106A, G111A, R113G, S147R and F159Y were constructed and it was found that G106A oxidized only gentisate; 1-hydroxy-2-naphthoate and salicylate were not converted. This indicated that this enzyme variant behaves like previously known 'conventional' GDOs. Crystals of the G106A SDO variant and its complexes with salicylate and gentisate were obtained under anaerobic conditions, and the structures were solved and analyzed. The amino acid residue Gly106 is located inside the SDO active site cavity but does not directly interact with the substrates. Crystal structures of G106A SDO complexes with gentisate and salicylate showed a different binding mode for salicylate when compared with the wild-type enzyme. Thus, salicylate coordinated in the G106A variant with the catalytically active Fe(II) ion in an unusual and unproductive manner because of the inability of salicylate to displace a hydrogen bond that was formed between Trp104 and Asp174 in the G106A variant. It is proposed that this type of unproductive substrate binding might generally limit the substrate spectrum of 'conventional' GDOs. DATABASE: Structural data are available in the Protein Data Bank databases under the accession numbers 3NST, 3NWA, 3NVC. 23946440 Regulation of long-range planar cell polarity by Fat-Dachsous signaling. Fat (Ft) and Dachsous (Ds) are large cadherins that bind each other and have conserved roles in regulating planar cell polarity (PCP). We quantitatively analyzed Ft-Ds pathway mutant clones for their effects on ommatidial polarity in the Drosophila eye. Our findings suggest that the Ft-Ds pathway regulates PCP propagation independently of asymmetric cellular accumulation of Ft or Ds. We find that the Ft effector Atrophin has a position-specific role in regulating polarity in the eye, and that asymmetric accumulation of the atypical myosin Dachs is not essential for production and propagation of a long-range PCP signal. Our observations suggest that Ft and Ds interact to modulate a secondary signal that regulates long-range polarity, that signaling by the Ds intracellular domain is dependent on Ft, and that ommatidial fate specification is genetically separable from long-range signaling. 23583517 A urinary metabonomics study on biochemical changes in yeast-induced pyrexia rats: a new approach to elucidating the biochemical basis of the febrile response. Fever is a prominent feature of many diseases, such as infection, inflammation and trauma. In the clinic, fever can be easily judged by measuring the body temperature; however, the pathogenesis of fever is still not fully understood. A febrile response is a systemic pathological process that can cause metabolic disorders. Metabonomics can provide powerful tools to reveal the pathological mechanisms for such a systemic disease. Thus, to reveal subtle metabolic changes under the condition of fever and to explore its mechanism, an ultra performance liquid chromatography coupled with a quadrupole time-of-flight mass spectrometry metabonomics approach was employed to investigate the urine biochemical characteristics of yeast-induced pyrexia rats. The acquired data were subjected to principal component analysis for differentiating the pyrexia rats from the control rats. Potential biomarkers were screened by using orthogonal partial least-squares-discriminant analysis and were identified by accurate mass, database, and MS/MS fragment information obtained from the MS(E) technique. Sixteen metabolites in rat urine were identified as potential biomarkers. The relative intensities of the 15 potential biomarkers were calculated. The thermoregulatory circuitry of "endogenous pyrogen (EP) ↑-hypothalamus Na(+)/Ca(2+)-cAMP↑" was partially confirmed in this study. The results suggested that UPLC/MS-based metabolic profiling of rat urine identifies impaired tryptophan metabolism as the mechanism of yeast-induced fever. This research provided informative data that the impaired tryptophan metabolism might be one of the important reasons in elucidating the biochemical basis of the febrile response. 23621523 Two new vinblastine-type N-oxide alkaloids from Catharanthus roseus. Two new vinblastine-type N-oxide alkaloids, 17-desacetoxyvinblastine [Formula: see text]-oxide (1) and 20'-deoxyvinblastine [Formula: see text]-oxide (2), were isolated from the leaves of Catharanthus roseus. The structures of 1 and 2 were established by the analysis of their nuclear magnetic resonance and HR-ESI-MS spectroscopic data. All alkaloids were evaluated for their cytotoxic activities against the human hepatocellular carcinoma (HepG2) cell line, human colorectal carcinoma (Lovo) cell line and human breast carcinoma (MCF-7) cell line by the MTT method in vitro, respectively. The results showed that cytotoxic activities of alkaloids 1 and 2 exhibited moderate inhibitory activity on the proliferation of three cancer cells. 23324856 Is stenting as "a bridge to surgery" an oncologically safe strategy for the management of acute, left-sided, malignant, colonic obstruction? A comparative study with a propensity score analysis. Self-expanding metallic stent (SEMS) insertion has been suggested as a promising alternative to emergency surgery for left-sided malignant colonic obstruction (LMCO). However, the literature on the long-term impact of SEMS as "a bridge to surgery" is limited and contradictory. From January 1998 to June 2011, we retrospectively identified patients operated on for LMCO with curative intent. The primary outcome criterion was overall survival. Short-term secondary endpoints included the technical success rate and overall success rate and long-term secondary endpoints included 5-year overall survival, 5-year cancer-specific mortality, 5-year disease-free survival, the recurrence rate, and mean time to recurrence. Patients treated with SEMS were analyzed on an intention-to-treat basis. Overall survival was analyzed after using a propensity score to correct for selection bias. There were 48 patients in the SEMS group and 39 in the surgery-only group. In the overall population, overall survival (P = 0.001) and 5-year overall survival (P = 0.0003) were significantly lower in the SEMS group than in the surgery-only group, and 5-year cancer-specific mortality was significantly higher in the SEMS group (48% vs 21%, respectively (P = 0.02)). Five-year disease-free survival, the recurrence rate, and the mean time to recurrence were better in the surgery-only group (not significant). For patients with no metastases or perforations at hospital admission, overall survival (P = 0.003) and 5-year overall survival (30% vs 67%, respectively, P = 0.001) were significantly lower in the SEMS group than in the surgery-only group. Our study results suggest worse overall survival of patients with LMCO with SEMS insertion compared with immediate surgery. 23524019 A single-step mixing cloning method for assembly of lentiviral short hairpin RNA expression vectors for gene silencing. Lentiviral expression vectors encoding short hairpin RNA (shRNA) are widely used for RNAi-based gene silencing in mammalian cells. However, current methods for the construction of shRNA expression vectors require multiple steps, which are expensive, time-consuming, and error-prone. Here, we developed a single-step mixing cloning method for the generation of lentiviral shRNA expression vectors. With this method, a pair of short oligonucleotides (∼50 nt) is required and a lentiviral shRNA vector can be constructed with only one step. This method has been used to construct 30 lentiviral shRNA expression vectors successfully. 23504315 LIM-homeodomain Transcription Factor Isl-1 Mediates the Effect of Leptin on Insulin Secretion in Mice. In addition to the well known regulating effects of leptin on energy balance and glucose homeostasis through the central nervous system, circulating leptin has a direct effect on pancreatic islet and insulin secretion through its receptor (OBRb). The LIM-homeodomain transcription factor Isl-1 is expressed in all classes of pancreatic endocrine cells and is involved in regulating both islet development and insulin secretion. Both OBRb and Isl-1 mutations result in obesity-related diabetes. However, the interactions and physiological significance of leptin and Isl-1 in pancreatic islets remain to be established. Here, we show that most of leptin target cells in pancreatic islets and NIT beta cells express Isl-1. Both in vivo and in vitro results demonstrate that leptin suppresses Isl-1 expression and insulin secretion in islet in physiological and pathophysiological conditions, e.g. high fat diet. This effect of leptin on insulin secretion is lost in leptin receptor-defective db/db and Isl-1-inducible knock-out mice. We conclude that the action of leptin on insulin secretion is at least partly mediated by Isl-1. Another new finding of this study is that Isl-1 acts as a direct downstream target of leptin signaling molecule STAT3 to influence the effect of leptin on insulin secretion, whereas inversely, insulin has feedback regulating effects on Isl-1 expression through JAK-STAT3 pathway. These findings are crucial for understanding the mechanisms regulating insulin secretion and metabolism in related diseases, such as obesity and type 2 diabetes. 23455627 Antidepressant drug use and off-label prescribing in children and adolescents in Germany: results from a large population-based cohort study. The off-label use of drugs in children and adolescents is widespread. In Germany, the use of selective serotonin reuptake inhibitors (SSRIs) and other antidepressants (OADs) is not licensed for the treatment of depressive disorders in children and adolescents except for fluoxetine, which was approved in 2006. Against this background, antidepressant drug (ATD) use with a particular focus on off-label prescribing was characterised in a retrospective cohort study including cross-sectional analyses based on claims data of 2,599,685 patients up to 17 years of age. Prevalence of ATD use was 1.84 (95 % CI 1.78-1.90) per 1,000 children in 2004, 1.57 (95 % CI 1.52-1.62) in 2005 and 1.66 (95 % CI 1.61-1.72) in 2006. More than half of all children treated with ATDs (51.29 %) received only one single prescription of an ATD during the study period. Of all prescribed ATDs, 11,172 (42.09 %) were tricyclic antidepressants 9,179 (34.58 %) were SSRIs, 4,371 (16.47 %) were St John's wort preparations and 1,821 (6.86 %) were OADs. Around half of all children and adolescents who were treated with ATDs were diagnosed with depressive disorders (56.30 %). Overall, 13,035 (49.11 %) of all ATDs were prescribed off-label. Off-label use by age (40.18 %) was found to be more common than off-label use by indication (16.63 %) with 7.70 % of off-label use occurring in both categories. Specialist treatment by hospital-based physicians increased the risk (odds ratio: 2.26, 95 % CI 2.05-2.48) of receiving an off-label prescription compared to treatment by general practitioners. In summary, off-label use of ATDs in children and adolescents was substantial in Germany. 23352908 Ultrasonic gene and drug delivery using eLiposomes. eLiposomes are liposomes encapsulating emulsions and therapeutics for targeted delivery. By applying ultrasound to eLiposomes, emulsion droplets can transform from liquid to gas and rupture the lipid bilayer of the eLiposome to release a drug or plasmid. In this study, perfluoropentane (PFC5) emulsions were encapsulated inside folated eLiposomes carrying a model drug (calcein) or a model GFP plasmid to examine the effects of a folate ligand, PFC5 emulsion and various ultrasonic acoustic parameters in drug delivery and gene transfection into HeLa cells. Confocal microscopy was used to quantify drug delivery and the level of plasmid transfection into HeLa cells. The results showed that drug delivery or transfection was minimal without incorporation of internal PFC5 emulsions and folate ligand on the eLiposome surface. It was also shown that application of ultrasound greatly enhanced the drug delivery and plasmid transfection. Delivery of these therapeutics appears to be to the cytosol, indicating that the expansion of the emulsion droplets disrupted both the eLiposomes and the endosomes. 23776208 MIF intersubunit disulfide mutant antagonist supports activation of CD74 by endogenous MIF trimer at physiologic concentrations. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine. In addition to its known receptor-mediated biological activities, MIF possesses a catalytic site of unknown function between subunits of a homotrimer. Each subunit contributes three β-strands to adjacent subunits to form a core seven-stranded β-sheet for each monomer. MIF monomers, dimers, or trimers have been reported, but the active form that binds and activates the MIF receptor (CD74) is still a matter of debate. A cysteine mutant (N110C) that covalently locks MIF into a trimer by forming a disulfide with Cys-80 of an adjacent subunit is used to study this issue. Partial catalytic activity and receptor binding to CD74 are retained by N110C (locked trimer), but there is no cellular signaling. Wild-type MIF-induced cellular signaling, in vivo lung neutrophil accumulation, and alveolar permeability are inhibited with a fivefold excess of N110C. NMR and size-exclusion chromatography with light scattering reveal that N110C can form a higher-order oligomer in equilibrium with a single locked trimer. The X-ray structure confirms a local conformational change that disrupts the subunit interface and results in global changes responsible for the oligomeric form. The structure also confirms these changes are consistent for the partial catalytic and receptor binding activities. The absence of any potential monomer and the retention of partial catalytic and receptor binding activities despite changes in conformation (and dynamics) in the mutant support an endogenous MIF trimer that binds and activates CD74 at nanomolar concentrations. This conclusion has implications for therapeutic development. 23936477 Variation in trans-3'-hydroxycotinine glucuronidation does not alter the nicotine metabolite ratio or nicotine intake. CYP2A6 metabolizes nicotine to its primary metabolite cotinine and also mediates the metabolism of cotinine to trans-3'-hydroxycotinine (3HC). The ratio of 3HC to cotinine (the "nicotine metabolite ratio", NMR) is an in vivo marker for the rate of CYP2A6 mediated nicotine metabolism, and total nicotine clearance, and has been associated with differences in numerous smoking behaviors. The clearance of 3HC, which affects the NMR, occurs via renal excretion and metabolism by UGT2B17, and possibly UGT2B10, to 3HC-glucuronide. We investigated whether slower 3HC glucuronidation alters NMR, altering its ability to predict CYP2A6 activity and reducing its clinical utility. Plasma NMR, three urinary NMRs, three urinary 3HC glucuronidation phenotypes and total nicotine equivalents were examined in 540 African American smokers. The UGT2B17 gene deletion and UGT2B10*2 were genotyped. The UGT2B17 gene deletion, but not UGT2B10*2 genotype, was associated with slower 3HC glucuronidation (indicated by three 3HC-glucuronidation phenotypes), indicating its role in this glucuronidation pathway. However, neither lower rates of 3HC glucuronidation, nor the presence of a UGT2B17 and UGT2B10 reduced function allele, altered plasma or urinary NMRs or levels of smoking. Variation in 3HC glucuronidation activity, including these caused by UGT2B17 gene deletions, did not significantly alter NMR and is therefore unlikely to affect the clinical utility of NMR in smoking behavior and cessation studies. This study demonstrates that NMR is not altered by differences in the rate of 3HC glucuronidation, providing further support that NMR is a reliable indicator of CYP2A6 mediated nicotine metabolism. 23916348 Sex- and age-specific incidence of autoimmune rheumatic diseases in the Chinese population: A Taiwan population-based study. The purpose of this study was to estimate the sex- and age-specific incidence rates of major autoimmune rheumatic diseases (ARDs) in Taiwan using a population longitudinal database. A health insurance database containing the records of 1,000,000 beneficiaries of Taiwan National Health Insurance from 2005 to 2009 was used. Between 2005 and 2009, the overall incidence rate of the major ARDs was 29.8 (95% CI = 28.3-31.3) per 100,000 person-years. Among the ARDs studied, the incidence of rheumatoid arthritis (RA; per 100,000 person-years) was highest (17.2, 95% CI = 16.1-18.4) and was followed by Sjögren's syndrome (11.8, 95% CI = 10.8-12.7), systemic lupus erythematosus (SLE; 7.2, 95% CI = 6.5-8.0), systemic sclerosis (SS; 1.1, 95% CI = 0.8-1.4), vasculitis (1.0, 95% CI = 0.7-1.3), Behçet disease (0.9, 95% CI = 0.6-1.1), dermatomyositis (DM; 0.7, 95% CI = 0.5-1.0), and polymyositis (PM; 0.6, 95% CI = 0.4-0.8). Females had a higher incidence ratio than did males, but a significant female/male incidence ratio was only observed for SLE (8.5, 95% CI = 6.1-12.0), Sjögren's syndrome (6.0, 95% CI = 4.8-7.6), RA (3.0, 95% CI = 2.6-3.5), and SS (2.6, 95% CI = 1.4-4.6). ARDs are three to four times more common among women than among men in the Chinese population of Taiwan. The incidence of RA was the highest, followed by Sjögren's syndrome and SLE, while the incidence of Behçet disease was the lowest in this study. This nationwide, population-based, longitudinal epidemiological study of ARDs in Taiwan provides data for future global comparisons and may provide clues as to the etiology of these diseases. 23541437 Selenium and mercury molar ratios in commercial fish from New Jersey and Illinois: Variation within species and relevance to risk communication. There is an emerging consensus that people consuming large amounts of fish with selenium:mercury ratios below 1 are at higher risk from mercury toxicity. As the relative amount of selenium increases compared to mercury, risk may be lowered, but it is unclear how much excess selenium is required. It would be useful if the selenium:mercury ratio was relatively consistent within a species, but this has not been the case in our studies of wild-caught fish. Since most people in developed countries and urban areas obtain their fish and other seafood commercially, we examined selenium:mercury molar ratios in commercial fish purchased in stores and fish markets in central New Jersey and Chicago. There was substantial interspecific and intraspecific variation in molar ratios. Across species the selenium:mercury molar ratio decreased with increasing mean mercury levels, but selenium variation also contributed to the ratio. Few samples had selenium:mercury molar ratios below 1, but there was a wide range in ratios, complicating the interpretation for use in risk management and communication. Before ratios can be used in risk management, more information is needed on mercury:selenium interactions and mutual bioavailability, and on the relationship between molar ratios and health outcomes. Further, people who are selenium deficient may be more at risk from mercury toxicity than others. 23863573 High Coxiella burnetii DNA load in serum during acute Q fever is associated with progression to a serologic profile indicative of chronic Q fever. PCR is very effective in diagnosing acute Q fever at the early stages of infection, when bacterial DNA is present in the bloodstream but antibodies have not yet developed. The objective of this study was to further analyze the diagnostic value of real-time PCR (qPCR) in diagnosing acute Q fever in an outbreak situation. At the Jeroen Bosch Hospital, in 2009, qPCR for Coxiella burnetii DNA was performed for 2,715 patients suspected of having acute Q fever (positive: n=385; negative: n=2,330). Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the qPCR were calculated for patients with a negative qPCR with a follow-up sample within 14 days (n=305), and qPCR positive patients with at least one follow-up sample (n=369). The correctness of the qPCR was based on immunofluorescence assay results of samples submitted for qPCR and follow-up. Sensitivity of the Q fever qPCR was 92.2%, specificity 98.9%, PPV 99.2%, and NPV 89.8%. Patients who later developed a serologic profile indicative of chronic Q fever infection had during the acute phase a significantly higher C. burnetii DNA load than patients who did not (p<0.001). qPCR is a valuable tool in the diagnosis of acute Q fever and should be used in outbreak situations when onset of symptoms is <15 days. Special attention is needed in the follow-up of patients with high C. burnetii DNA loads during the acute phase, as this might be an indicator for the development of a serologic profile indicative of a chronic infection. 23625817 Multiple Site-Selective Insertions of Noncanonical Amino Acids into Sequence-Repetitive Polypeptides. A simple and efficient method is described for the introduction of noncanonical amino acids at multiple, defined sites within recombinant polypeptide sequences. Escherichia coli MRA30, a bacterial host strain with attenuated activity of release factor 1 (RF1), was assessed for its ability to support incorporation of a diverse range of noncanonical amino acids in response to multiple encoded amber (TAG) codons within genes derived from superfolder GFP and an elastin-mimetic protein polymer. Suppression efficiency and protein yield depended on the identity of the orthogonal aminoacyl-tRNA synthetase/tRNA(CUA) pair and the noncanonical amino acid. Elastin-mimetic protein polymers were prepared in which noncanonical amino acid derivatives were incorporated at up to 22 specific sites within the polypeptide sequence with high substitution efficiency. The identities and positions of the variant residues were confirmed by mass spectrometric analysis of the full-length polypeptides and proteolytic cleavage fragments from thermolysin digestion. The data suggest that this multisite suppression approach permits the preparation of protein-based materials in which novel chemical functionalities can be introduced at precisely defined positions within the polypeptide sequence. 23602693 Long-term outcomes of patients with acute coronary syndrome and nonobstructive coronary artery disease. Patients with acute coronary syndrome (ACS) and nonobstructive coronary artery disease (CAD) have a substantial risk of subsequent coronary events within 1 year. The aim of the present study was to evaluate the prevalence, long-term outcomes, and adherence to oral antiplatelet therapy in patients with ACS and nonobstructive CAD compared with patients with ACS and obstructive CAD who had undergone percutaneous coronary intervention. Nonobstructive CAD was defined as an angiographic finding of <50% diameter stenosis in any major epicardial artery. These patients were further stratified into 2 groups: those with normal coronary arteries (0% angiographic stenosis) and those with mild CAD (0% to 50% angiographic stenosis). Major adverse cardiac events, defined as death, myocardial infarction, ACS leading to hospitalization, and nonfatal stroke, were recorded and compared with a historical control group of patients with ACS and obstructive CAD who had undergone percutaneous coronary intervention. Of 2,438 consecutive patients with ACS undergoing coronary angiography, 318 (13%) had nonobstructive CAD. Of the 318 with nonobstructive CAD, 160 had normal coronary arteries and 158 had mild CAD. Patients with obstructive CAD had experienced greater rates of major adverse cardiac events at 26 ± 16 months (16.6% vs 9.1%, p = 0.001), driven by a greater rate of myocardial infarction compared with those without (5.3% vs 0%, p <0.001). However, the rate of death, ACS leading to hospitalization, and stroke was similar. After adjusting for baseline characteristics, no difference was found in the risk of major adverse cardiac events across the groups. Only 50% of patients with nonobstructive CAD were prescribed dual antiplatelet therapy. In conclusion, patients with ACS and nonobstructive CAD remain at high risk of long-term recurrent ischemic events. 23918709 Quantum rotation and translation of hydrogen molecules encapsulated inside C₆₀: temperature dependence of inelastic neutron scattering spectra. The quantum dynamics of a hydrogen molecule encapsulated inside the cage of a C60 fullerene molecule is investigated using inelastic neutron scattering (INS). The emphasis is on the temperature dependence of the INS spectra which were recorded using time-of-flight spectrometers. The hydrogen endofullerene system is highly quantum mechanical, exhibiting both translational and rotational quantization. The profound influence of the Pauli exclusion principle is revealed through nuclear spin isomerism. INS is shown to be exceptionally able to drive transitions between ortho-hydrogen and para-hydrogen which are spin-forbidden to photon spectroscopies. Spectra in the temperature range 1.6≤T≤280 K are presented, and examples are given which demonstrate how the temperature dependence of the INS peak amplitudes can provide an effective tool for assigning the transitions. It is also shown in a preliminary investigation how the temperature dependence may conceivably be used to probe crystal field effects and inter-fullerene interactions. 23537547 EURObservational Research Programme: regional differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF Pilot). The ESC-HF Pilot survey was aimed to describe clinical epidemiology and 1-year outcomes of outpatients and inpatients with heart failure (HF). The pilot phase was also specifically aimed at validating structure, performance, and quality of the data set for continuing the survey into a permanent Registry. The ESC-HF Pilot study is a prospective, multicentre, observational survey conducted in 136 Cardiology Centres in 12 European countries selected to represent the different health systems across Europe. All outpatients with HF and patients admitted for acute HF on 1 day per week for eight consecutive months were included. From October 2009 to May 2010, 5118 patients were included: 1892 (37%) admitted for acute HF and 3226 (63%) patients with chronic HF. The all-cause mortality rate at 1 year was 17.4% in acute HF and 7.2% in chronic stable HF. One-year hospitalization rates were 43.9% and 31.9%, respectively, in hospitalized acute and chronic HF patients. Major regional differences in 1-year mortality were observed that could be explained by differences in characteristics and treatment of the patients. The ESC-HF Pilot survey confirmed that acute HF is still associated with a very poor medium-term prognosis, while the widespread adoption of evidence-based treatments in patients with chronic HF seems to have improved their outcome profile. Differences across countries may be due to different local medical practice as well to differences in healthcare systems. This pilot study also offered the opportunity to refine the organizational structure for a long-term extended European network. 23747022 Resolution phase lipid mediators of inflammation: agonists of resolution. Lipid mediators are appreciated for their roles in leukocyte traffic required in host defense. With identification of novel resolution phase mediators, resolvins, protectins and maresins, these three families and their aspirin-triggered forms, given their potent stereoselective actions with human cells and animal disease models, are coined specialized pro-resolving mediators (SPM). Stereochemistries of key SPM are established and several groups reported organic synthesis. Given increased availability, this two-year-review period expands their potent pro-resolving and non-redundant actions. Collectively, they support the concept that return of acute inflammation involves active biosynthesis and SPM signaling toward homeostasis. 23529650 Insights into the adsorption and energy transfer of Ag clusters on the AgCl(100) surface. It is fundamental to uncover the real adsorption properties of Ag clusters on an AgCl surface and the energy transfer mechanisms at the interface to understand the highly active photocatalytic performance and the stability of the plasmonic photocatalyst Ag@AgCl. Based on density functional theory calculations we provide valuable insights into the binding nature of Ag clusters on AgCl surface, where the binding between Ag atoms in the cluster and on the surface plays a decisive role in determining the most stable adsorption configurations. Our results demonstrate that there is energy transfer from the plasmonic metals to substrate. The hot holes excited by the decay of surface plasmon resonance on the metals can diffuse into the Cl ions in the outermost two layers of the surface producing highly oxidative Cl atoms. The dipole-dipole interaction between the plasmonic metal clusters and substrate Cl ions can also generate electron-hole pairs in the surface layers. It is deduced that the positively charged nature of adsorbed clusters acting as electron trapping centers and reduction sites plays a crucial role in keeping the stability of the Ag@AgCl system during the photocatalytic process. Finally, the validity of the cluster adsorption model for energy transfer is verified with respect to the nucleation and aggregation process of Ag atoms on the AgCl surface and a detailed description of the formation and evolution of Ag nanoparticles on an AgCl surface is provided. The present study may be helpful for understanding and designing this novel plasmonic photocatalyst and can be useful for investigating other relevant photocatalysts as well. 23864772 Cellular and molecular basis of chronic constipation: Taking the functional/idiopathic label out. In recent years, the improvement of technology and the increase in knowledge have shifted several strongly held paradigms. This is particularly true in gastroenterology, and specifically in the field of the so-called "functional" or "idiopathic" disease, where conditions thought for decades to be based mainly on alterations of visceral perception or aberrant psychosomatic mechanisms have, in fact, be reconducted to an organic basis (or, at the very least, have shown one or more demonstrable abnormalities). This is particularly true, for instance, for irritable bowel syndrome, the prototype entity of "functional" gastrointestinal disorders, where low-grade inflammation of both mucosa and myenteric plexus has been repeatedly demonstrated. Thus, researchers have also investigated other functional/idiopathic gastrointestinal disorders, and found that some organic ground is present, such as abnormal neurotransmission and myenteric plexitis in esophageal achalasia and mucosal immune activation and mild eosinophilia in functional dyspepsia. Here we show evidence, based on our own and other authors' work, that chronic constipation has several abnormalities reconductable to alterations in the enteric nervous system, abnormalities mainly characterized by a constant decrease of enteric glial cells and interstitial cells of Cajal (and, sometimes, of enteric neurons). Thus, we feel that (at least some forms of) chronic constipation should no more be considered as a functional/idiopathic gastrointestinal disorder, but instead as a true enteric neuropathic abnormality. 23788363 Electrochemistry of Single Metalloprotein and DNA-Based Molecules at Au(111) Electrode Surfaces. We have briefly overviewed recent efforts in the electrochemistry of single transition metal complex, redox metalloprotein, and redox-marked oligonucleotide (ON) molecules. We have particularly studied self-assembled molecular monolayers (SAMs) of several 5'-C6-SH single- (ss) and double-strand (ds) ONs immobilized on Au(111) electrode surfaces via AuS bond formation, using a combination of nucleic acid chemistry, electrochemistry and electrochemically controlled scanning tunnelling microscopy (in situ STM). Ds ONs stabilized by multiply charged cations and locked nucleic acid (LNA) monomers have been primary targets, with a view on stabilizing the ds-ONs and improving voltammetric signals of intercalating electrochemical redox probes. Voltammetric signals of the intercalator anthraquinone monosulfonate (AQMS) at ds-DNA/Au(111) surfaces diluted by mercaptohexanol are significantly sharpened and more robust in the presence than in the absence of [Co(NH3 )6 ](3+) . AQMS also displays robust Faradaic voltammetric signals specific to the ds form on binding to similar LNA/Au(111) surfaces, but this signal only evolves after successive voltammetric scanning into negative potential ranges. Triply charged spermidine (Spd) invokes itself a strong voltammetric signal, which is specific to the ds form and fully matched sequences. This signal is of non-Faradaic, capacitive origin but appears in the same potential range as the Faradaic AQMS signal. In situ STM shows that molecular scale structures of the size of Spd-stabilized ds-ONs are densely packed over the Au(111) surface in potential ranges around the capacitive peak potential. 23474343 Neoadjuvant chemotherapy prior to pelvic exenteration in patients with recurrent cervical cancer: single institution experience. The aim of the study is to evaluate the response to neoadjuvant chemotherapy (NACHT) of patients with recurrent cervical cancer who were poor candidates for pelvic exenteration (PE), and the impact on DFS and OS. A retrospective data collection extracted from medical records of 61 patients submitted to pelvic exenteration was performed: 30 underwent up-front exenterative procedure whereas 31 received NACHT. The median tumor size was significantly (P=0.0006) larger in the NACHT group compared to the up-front PE one (43.9 mm vs 28 mm), and a significant (P=0.04) higher percentage of patients (45 vs 20%) had lateral pelvic wall invasion in the NACHT group. No statistically significant difference in early and late complications was observed in the two groups. Median overall survival in study population was 42.9 months (95% CI: 22.2, 180.8). Median overall survival times as well as recurrence free survival times were not significantly different between NACHT (42.9 months and 36.1 months for OS and DFS respectively) vs. No NACHT (111.9 months and 48.1 months for OS and DFS respectively). There was an overall significant difference in DFS between negative and positive margins but the curves were similar for NACHT and up-front PE groups stratified by resection margin status. In our series, though small and retrospective, NACHT prior to PE represents a feasible therapeutic option without intra-operative and early post-operative mortality or worsening of early and late complication rate and with acceptable long-term survival and DFS for recurrent cervical cancer patients who are poor candidates for up-front pelvic exenteration. 23909600 The role of RgpA in the pathogenicity of Porphyromonas gingivalis in the murine periodontitis model. To investigate the in vivo role of gingipains in Porphyromonas gingivalis' virulence, and suggest a possible host mechanisms through which the bacteria cause alveolar bone loss. Mice were orally infected with P. gingivalis wild type, or the gingipains mutants (RgpA(-) , Kgp(-) , RgpA(-) /Kgp(-) ). Mice were analysed for alveolar bone loss using micro-computed tomography. The molecular effects of the proteases were evaluated using the subcutaneous chamber model. Mice were infected with P. gingivalis wild type or mutants. Exudates were analysed for cytokine and leukocytes levels, in vivo phagocytosis, P. gingivalis survival and serum anti-P. gingivalis IgG titres. Only RgpA-expressing bacteria induced significantly alveolar bone loss, and suppressed phagocytosis resulting in increased survival of P. gingivalis in the chamber exudates. In addition, RgpA-expressing bacteria induced higher levels of leukocytes and cytokines 2 h post-infection, and reduced levels of serum anti-P. gingivalis IgG titres 7 days post-infection. Our findings showed that elimination of RgpA from P. gingivalis diminished inflammation, but augmented phagocytosis and antibody titres, coincidental with reduced alveolar bone loss. These findings support the hypothesis that RgpA is a critical virulence factor in the pathogenesis of experimental periodontitis in mice. 23747529 Rapid fluorescent visualization of multiple NAD(P)H oxidoreductases in homogenate, permeabilized cells, and tissue slices. Intracellular NAD(P)H oxidoreductases are a class of diverse enzymes that are the key players in a number of vital processes. The method we present and validate here is based on the ability of many NAD(P)H oxidoreductases to reduce the superoxide probe lucigenin, which is structurally similar to flavins, to its highly fluorescent water-insoluble derivative dimethylbiacridene. Two modifications of the method are proposed: (i) an express method for tissue homogenate and permeabilized cells in suspensions and (ii) a standard procedure for cells in culture and acute thin tissue slices. The method allows one to assess, visualize, and localize, using fluorescent markers of cellular compartments, multiple NADH and NADPH oxidoreductase activities. The application of selective inhibitors (e.g., VAS2870, a NOX2 inhibitor; plumbagin, a NOX4 inhibitor) allows one to distinguish and compare specific NAD(P)H oxidoreductase activities in cells and tissues and to attribute them to known enzymes. The method is simple, rapid, and flexible. It can be easily adapted to a variety of tasks. It will be useful for investigations of the role of various NAD(P)H oxidoreductases in a number of physiological and pathophysiological processes. 23868577 Accurate Estimation of Body Surface Area in Under-5 Children with Non-Edematous Severe Acute Malnutrition. Objective: To determine the accuracy of commonly used body surface area (BSA) equations and to devise a new equation for BSA calculation in non-edematous severe acute malnourished (NE-SAM) children.Methods: Children aged between 2 months and 5 years fulfilling World Health Organization criteria for NE-SAM were included. Seven commonly used equations were used for calculating the BSA. Mean BSA from the equations was used as reference for comparison. A new equation SAM Mosteller modified was also derived.Results: A total of 471 children were included. Of the seven equations, Mosteller had minimum root mean square error (RMSE) value of 2.89. The goodness of SAM Mosteller modified equation was subsequently compared with Mosteller and Boyd in 66 NE-SAM children. The SAM Mosteller modified showed least RMSE (2.65), whereas Boyd had maximum.Conclusions: Among seven equations, Mosteller is useful for BSA calculation in NE-SAM. SAM Mosteller modified equation (164.551 × [Ht × Wt](0.5)) has least error and can serve as best measure of BSA in SAM children. 23955428 ArtR, a novel sRNA of Staphylococcus aureus, regulates α-toxin expression by targeting the 5' UTR of sarT mRNA. Recent studies point to the importance of small-noncoding RNAs (sRNAs) in bacterial virulence control. In Staphylococcus aureus, functional dissections of sRNAs are limited to RNA III, SprD, RsaE, SprA1, and SSR42 only. Here, we report the identification and functional analyses of a novel sRNA, which we have designated ArtR. Our data show that the AgrA protein can bind to the artR promoter and repress artR transcription, suggesting that, after RNA III, ArtR is the second sRNA regulated by AgrA. Furthermore, ArtR is unique in S. aureus and involved in virulence regulation by activating α-toxin expression. ArtR promotes the degradation of sarT mRNA by RNase III and arrests the translation of SarT by direct binding to the 5' untranslated region of the sarT mRNA, suggesting that the activation of ArtR on the α-toxin expression was through SarT. This study reveals another kind of staphylococcal regulatory small RNA that plays a role in virulence control. It also indicates the diversity of small RNA-target mRNA interactions and how these multiple interactions can mediate virulence regulation in this pathogen. 23948105 Epigenetics of cellular reprogramming. Cells are constantly changing their state of equilibrium in response to internal and external stimuli. These changes in cell identity are driven by highly coordinated modulation of gene expression. This coordinated regulation is achieved in large part due to changes in the structure and composition of the chromatin, driven by epigenetic modulators. Recent discoveries in cellular and genomic reprogramming have highlighted the importance of chromatin modifications to reach and uphold the fidelity of target cell states. In this review, we focus on the latest work addressing the mechanisms surrounding the epigenetic regulation of various types of reprogramming, including somatic cell nuclear transfer (SCNT), cell fusion and transcription factor-induced and microRNA-induced pluripotency. The studies covered herein showcase the interplay between these epigenetic pathways, and highlight the importance of furthering our understanding of these connections to form a clearer picture of the mechanisms underlying stable cell fate transitions. 23850600 Impairments in proverb interpretation following focal frontal lobe lesions. The proverb interpretation task (PIT) is often used in clinical settings to evaluate frontal "executive" dysfunction. However, only a relatively small number of studies have investigated the relationship between frontal lobe lesions and performance on the PIT. We compared 52 patients with unselected focal frontal lobe lesions with 52 closely matched healthy controls on a proverb interpretation task. Participants also completed a battery of neuropsychological tests, including a fluid intelligence task (Raven's Advanced Progressive Matrices). Lesions were firstly analysed according to a standard left/right sub-division. Secondly, a finer-grained analysis compared the performance of patients with medial, left lateral and right lateral lesions with healthy controls. Thirdly, a contrast of specific frontal subgroups compared the performance of patients with medial lesions with patients with lateral frontal lesions. The results showed that patients with left frontal lesions were significantly impaired on the PIT, while in patients with right frontal lesions the impairments approached significance. Medial frontal patients were the only frontal subgroup impaired on the PIT, relative to healthy controls and lateral frontal patients. Interestingly, an error analysis indicated that a significantly higher number of concrete responses were found in the left lateral subgroup compared to healthy controls. We found no correlation between scores on the PIT and on the fluid intelligence task. Overall our results suggest that specific regions of the frontal lobes contribute to the performance on the PIT. 23244295 Xyloglucan-derivatized films for the culture of adherent cells and their thermocontrolled detachment: a promising alternative to cells sensitive to protease treatment. By taking advantage of a natural and abundant polymer as well as a straightforward film formation technique, this paper focuses on the conception and use of a new alternative tool for thermo-controlled cell detachment. Thermoresponsive xyloglucan was produced after partial galactose removal by a 24 h reaction with β-galactosidase. The obtained polymer (T24) was then activated by reaction with 4-nitrophenyl chloroformate (NPC) in order to graft a cyclic peptide presenting an arginine-glycine-aspartic acid (RGD) motif. The effect of RGD grafting on the sol-gel transition temperature of T24 is evaluated by rheological measurements. Solvent-casted films of T24-RGD successfully promoted cell adhesion, proliferation, and thermo-controlled detachment. The presented approach is a new alternative for cells sensitive to the proteolytic treatment routinely used for cell detachment. Because the RGD sequence used herein is widely recognized by different cell types, this protocol may be extended to other cells. Besides, the presented chemical route can be applied to different peptide sequences. 23833141 Draft Genome Sequence of Arthrobacter crystallopoietes Strain BAB-32, Revealing Genes for Bioremediation. Arthrobacter crystallopoietes strain BAB-32, a Gram-positive obligate aerobic actinobacterium having potential application in bioremediation and bioreduction of a few metals, was isolated from rhizosphere soil of Gandhinagar, Gujarat, India. The draft genome (4.3 Mb) of the strain revealed a few vital gene clusters involved in the metabolism of aromatic compounds, zinc, and sulfur. 23504029 Biologic disease-modifying anti-rheumatic drugs and the risk of non-vertebral osteoporotic fractures in patients with rheumatoid arthritis aged 50 years and over. Prevention of bone mineral density loss in rheumatoid arthritis (RA) has been associated with use of biologic disease-modifying anti-rheumatic drugs (DMARDs). However, in this study, we could not demonstrate a reduction in the risk of non-vertebral fractures. Additional research is required to clarify the impact of biologic DMARDs on fracture risk in RA. Small studies have suggested biologic DMARDs preserve bone mineral density at 6-12 months. Our objective was to determine the association between biologic DMARD use and the risk of non-vertebral osteoporotic fractures in RA subjects aged ≥50 years. A nested case-control study was conducted using Quebec physician billing and hospital discharge data. RA subjects were identified from International Classification of Disease-9/10 codes in billing and hospitalisation data and followed from cohort entry until the earliest of non-vertebral osteoporotic fracture, death, or end of study period. Controls were matched to cases (4:1 ratio) on age, sex, and date of cohort entry. Biologic DMARD exposure was defined as being on treatment for ≥180 days pre-fracture (index). Conditional logistic regression was used, adjusting for indicators of RA severity, comorbidity, drugs influencing fracture risk, and measures of health care utilisation. Over the study period, 1,515 cases were identified (6,023 controls). The most frequent fracture site was hip/femur (42.3 %). In total, 172 subjects (49 cases and 123 controls) were exposed to biologic DMARDs. The median duration of exposure was 735 (interquartile range (IQR), 564) and 645 (IQR, 903) days in cases and controls, respectively. We were unable to demonstrate an association between biologic DMARDs and fracture risk (odds ratio, 1.03; 95 % confidence interval, 0.42-2.53). RA duration significantly increased the fracture risk. Despite the positive impact of biologic DMARDs on bone remodelling observed in small studies, we were unable to demonstrate a reduction in the risk of non-vertebral osteoporotic fractures in older adults with RA. 23578522 The next generation of novel low-density lipoprotein cholesterol-lowering agents: Proprotein convertase subtilisin/kexin 9 inhibitors. Proprotein convertase subtilisin/kexin 9 (PCSK9) has been shown to degrade hepatic low-density lipoprotein receptors (LDLR). Gain-of-function mutations promote the development of familial hypercholesterolemia, whereas loss-of-function mutations are associated with lower levels of circulating low-density lipoprotein cholesterol (LDL-C) and significant protection against coronary heart disease. The major classes of commonly prescribed lipid-lowering medications, such as statins, increase serum PCSK9 levels, thus PCSK9 inhibition would increase the efficacy of statins on LDL-C lowering. Therefore, PCSK9 is an attractive therapeutic target for the new generation of cholesterol-lowering drugs. Here, we present a brief overview of the development of PCSK9 inhibitors and highlight the effect of currently prescribed LDL-C-lowering drugs on PCSK9, and the strategies that are being explored for its therapeutic inhibition. Current research and clinical trial results indicate that a PCSK9 inhibitor may be an exciting new therapeutic drug for the treatment of dyslipidemia and relevant cardiovascular diseases. 23564015 Synthesis of novel derivatives of murrayafoline A and their inhibitory effect on LPS-stimulated production of pro-inflammatory cytokines in bone marrow-derived dendritic cells. A series of N-substituted-1,2,3-triazole murrayafoline A derivatives were successfully synthesized using click azide-alkyne Huisgen cycloaddition reaction between 1-methoxy-3-methyl-9-(3-azido)-propyl-9H-carbazole and substituted alkynes. Their chemical structures were confirmed by (1)H, (13)C NMR and HR-ESI-MS spectral data. In addition, the interested effects on LPS-stimulated production of pro-inflammatory cytokines in bone marrow-derived dendritic cells of synthetic murrayafoline A derivatives were also investigated. Our results indicated that murrayafoline A derivatives containing 1,2,3-triazole nucleus potentially possessed anti-inflammatory action through inhibiting production of IL-6, IL-12 p40 and TNF-α. 22287617 Protective effect of vitamin E and epicatechin against nicotine-induced oxidative stress in rats. Nicotine is a major pharmacologically active and addictive component of tobacco smoke, which is regarded to be a primary risk factor in the development of cardiovascular and pulmonary diseases. Epicatechin is one of the most potent antioxidants present in the human diet. Particularly high levels of this compound are found in tea, apples and chocolate. It has been reported that tea extracts and/or its constituents have antibacterial, antiviral, antioxidative, antitumor and antimutagenic activities. Vitamin E is a major lipid-soluble antioxidant vitamin and free radical scavenger, presents as an integral component of cellular membranes and has important biological functions. The primary mechanism by which vitamin E is proposed to prevent cancer is through their antioxidant properties. The goal of this study is to evaluate the effect of epicatechin alone or combined with vitamin E in inhibiting the oxidative stress induced by nicotine in rats. Results obtained indicated that there was a significant elevation in the levels of malondialdhyde (MDA) in nicotine injected rats. The combined treatment (epicatechin + Vit E) group showed a potential reduction of these parameters more than individual treatment. The activities of superoxide dismutase, catalase and glutathione peroxidase were found significantly higher in combined treated than untreated rats. In nicotine group, a negative significant correlation between reduced glutathione and MDA (r = -0.92) was observed. In conclusion, these results suggested that the supplementation of diet with epicatechin and vitamin E provided antioxidant defense with strong chemopreventive activity against nicotine-induced carcinogenesis. 23901976 On the electronic structure of the low lying electronic states of vanadium trioxide. The electronic structure of transition metal oxides is frequently studied using density functional theory. Nonetheless, the electronic structure of VO3 has been found to be sensitive to the choice of functional. As a consequence, the basic question of whether or not the ground electronic state exhibits a Jahn-Teller distortion has yet to be resolved. Using basis sets of triple zeta quality and multireference configuration interaction wave functions as large as 700 million configuration state functions, we determine that the ground electronic state of VO3 is a (2)A2 state in C3v symmetry. The first two excited electronic states are also characterized and found to be the components of a degenerate (2)E state, in C3v symmetry, which exhibits a small Jahn-Teller distortion. The Jahn-Teller stabilization energy is only 40 cm(-1) and the barrier to pseudo-rotation is 9 cm(-1). This (2)E state exhibits some unexpected properties. In the vicinity of the minimum energy conical intersection, the local topography appears almost quadratic, rather than linear, in the Jahn-Teller active coordinates. This gives rise to three symmetry-related seams of conical intersections in addition to the symmetry-required seam and results in the suppression of the geometric phase effect. These features, attributable to small linear Jahn-Teller parameters, are usually found in states characterized by e(2) (or e(3)e(')) electron configurations rather than the e(3) configuration found here. In addition to its Jahn-Teller minimum, the first excited state exhibits a second minimum with a structure significantly distorted from C3v. A conical intersection with Cs symmetry connects the two minima and puts an upper limit of 190 cm(-1) on the barrier connecting these minima. 23834568 Near-peer teaching in clinical neuroanatomy. Background:  Near-peer teaching involves students being taught by more senior students and draws on their similar knowledge base and shared experiences. It has been used previously for teaching gross anatomy, but has not yet been reported specifically for neuroanatomy. At the University of Southampton there is no formal neuroanatomy teaching during the clinical years, and so a near-peer teaching programme was developed to support students, learning in between attending their clinical attachments. Methods:  A series of seven sessions were organised and delivered by two medical students throughout the 2010/11 academic year, and each session was evaluated by using participant feedback forms. Results:  Sixty feedback forms were returned by the students, giving an average rating for the overall quality of the sessions of 4.3 out of 5.0. There was an 18 per cent increase in the student's perceived level of knowledge (p < 0.0001) as a result of our near-peer teaching sessions. The most common feedback received from our students related to the availability of handouts and expressions of gratitude. Discussion:  The results from this teaching development support the use of near-peer teaching in neuroanatomy. In this article we provide some evidence to suggest that students feel more confident with neuroanatomy after attending these sessions, and describe some unique advantages of this teaching programme over sessions led by faculty staff. The wider benefits to both faculty staff and student teachers are also considered. 23916686 Gut microbiota limits heavy metals burden caused by chronic oral exposure. Environmental exposure to pollutants such as heavy metal(s) is responsible for various altered physiological functions which are detrimental for health. The gut microbiota is critical for intestinal homeostasis but its role on xenobiotic handling is not fully understood, especially when continuous sub-chronic exposure is addressed. We first confirmed the essential role of the intestinal microbiome to limit heavy metal body burden by using germ-free mice following 6-weeks oral exposure. Significant increases of cadmium and lead absorption and dissemination in blood and target organs were measured in germ-free mice when compared with conventional specific pathogen free (SPF) mice. Besides the "barrier" function of the luminal microbiota, this may involve specific host-genes such as metallothioneins, which are differentially expressed in the gastrointestinal tract of each group of mice. Considering genes relevant for divalent metal transporters and oxidative pathways, significant differences in basal gene expression were measured between control and germ-free mice. Moreover, the magnitude of induction of these genes upon stimulation by heavy metals varied greatly depending on the dose and type of metal as well as the microbial status of the animal. Collectively, these data illustrate the complex host-microbes interplay occurring with environmental pollutants inside the gut. 23871951 Confronting safety gaps across labor and delivery teams. We assessed the occurrence of 4 safety concerns among labor and delivery teams: dangerous shortcuts, missing competencies, disrespect, and performance problems. A total of 3282 participants completed surveys, and 92% of physicians (906 of 985), 93% of midwives (385 of 414), and 98% of nurses (1846 of 1884) observed at least 1 concern within the preceding year. A majority of respondents said these concerns undermined patient safety, harmed patients, or led them to seriously consider transferring or leaving their positions. Only 9% of physicians, 13% of midwives, and 13% of nurses shared their full concerns with the person involved. Organizational silence is evident within labor-and-delivery teams. Improvement will require multiple strategies, used at the personal, social, and structural levels. 23935502 The Late Endosomal HOPS Complex Anchors Active G-Protein Signaling Essential for Pathogenesis in Magnaporthe oryzae. In Magnaporthe oryzae, the causal ascomycete of the devastating rice blast disease, the conidial germ tube tip must sense and respond to a wide array of requisite cues from the host in order to switch from polarized to isotropic growth, ultimately forming the dome-shaped infection cell known as the appressorium. Although the role for G-protein mediated Cyclic AMP signaling in appressorium formation was first identified almost two decades ago, little is known about the spatio-temporal dynamics of the cascade and how the signal is transmitted through the intracellular network during cell growth and morphogenesis. In this study, we demonstrate that the late endosomal compartments, comprising of a PI3P-rich (Phosphatidylinositol 3-phosphate) highly dynamic tubulo-vesicular network, scaffold active MagA/GαS, Rgs1 (a GAP for MagA), Adenylate cyclase and Pth11 (a non-canonical GPCR) in the likely absence of AKAP-like anchors during early pathogenic development in M. oryzae. Loss of HOPS component Vps39 and consequently the late endosomal function caused a disruption of adenylate cyclase localization, cAMP signaling and appressorium formation. Remarkably, exogenous cAMP rescued the appressorium formation defects associated with VPS39 deletion in M. oryzae. We propose that sequestration of key G-protein signaling components on dynamic late endosomes and/or endolysosomes, provides an effective molecular means to compartmentalize and control the spatio-temporal activation and rapid downregulation (likely via vacuolar degradation) of cAMP signaling amidst changing cellular geometry during pathogenic development in M. oryzae. 23846820 Improved efficacy of low dose spironolactone and metformin combination than either drug alone in the management of women with polycystic ovary syndrome (PCOS): a six month, open label randomized study. Context:To improve the treatment outcomes in women with PCOS, various drugs like glitazones, OCP's or anti-androgens have been combined with metformin.Objective:To compare the efficacy of combination of low dose spironolactone and metformin with either drug alone in the management of women with PCOS.Design and Setting:The present study was an open labelled, randomized study conducted at tertiary care referral centre.Patients and Intervention:Out of 204 women who qualified Androgen Excess-PCOS (AE-PCOS) 2006 criteria for PCOS, 198 were randomized into 3 equal groups to receive metformin (1000 mg/day), low dose spironolactone (50 mg/day) or combination of the both drugs for a period of six months. One hundred sixty nine (metformin n=56, spironolactone n=51 and combination n=62) subjects completed the study.Main outcome measures:Menstrual cycle pattern, Ferriman-Gallwey (FG) score, body mass index (BMI), waist-hip ratio, blood pressure (BP), LH, FSH, total T, glucose and insulin sensitivity indices were measured at baseline (0 month), at 3 and 6 months after the intervention. Recording of adverse events and drug compliance was assessed at each of the visits.Results:The three groups had comparable mean age and BMI at baseline. By 6 months, menstrual cycles/year increased whereas FG score, serum total T, AUC-glucose and AUC-insulin decreased significantly (P<0.05) in the combination group as compared to either drug alone. There was no significant change in body weight, BMI, WHR, and BP in any of the three groups. The combination group had better compliance than either drug alone and adverse event rate was not higher.Conclusion:Combination of low dose spironolactone with metformin seems superior to either drug alone in terms of clinical benefits and compliance in women with PCOS. 23899936 Extending the IEEE 802.15.4 Security Suite with a Compact Implementation of the NIST P-192/B-163 Elliptic Curves. Typically, commercial sensor nodes are equipped with MCUsclocked at a low-frequency (i.e., within the 4-12 MHz range). Consequently, executing cryptographic algorithms in those MCUs generally requires a huge amount of time. In this respect, the required energy consumption can be higher than using a separate accelerator based on a Field-programmable Gate Array (FPGA) that is switched on when needed. In this manuscript, we present the design of a cryptographic accelerator suitable for an FPGA-based sensor node and compliant with the IEEE802.15.4 standard. All the embedded resources of the target platform (Xilinx Artix-7) have been maximized in order to provide a cost-effective solution. Moreover, we have added key negotiation capabilities to the IEEE 802.15.4 security suite based on Elliptic Curve Cryptography (ECC). Our results suggest that tailored accelerators based on FPGA can behave better in terms of energy than contemporary software solutions for motes, such as the TinyECC and NanoECC libraries. In this regard, a point multiplication (PM) can be performed between 8.58- and 15.4-times faster, 3.40- to 23.59-times faster (Elliptic Curve Diffie-Hellman, ECDH) and between 5.45- and 34.26-times faster (Elliptic Curve Integrated Encryption Scheme, ECIES). Moreover, the energy consumption was also improved with a factor of 8.96 (PM). 23603315 Blunted HPA axis response to stress is related to a persistent Dysregulation Profile in youth. The Child Behavior Checklist Dysregulation Profile (DP) in youth has been shown to be a predictor of psychopathology later in life. We examined the activity of the hypothalamic pituitary adrenal (HPA) axis in youth with remitted, new, persistent, and no DP. Data from 489 youth (47% boys) participating in a Dutch longitudinal general population study were included (Wave 1 mean age=11.5, Wave 2=14.2). Wave 2 diurnal cortisol patterns and levels in response to a laboratory stress paradigm were compared in youth with DP at Wave 1 only, Wave 2 only, both Waves, and neither Wave. Youth with the DP at Wave 2 only or at both time points showed blunted cortisol responses to stress relative to the other two groups. There were no group or sex differences in diurnal cortisol activity. More research is needed to determine how the association between DP symptoms and HPA axis functioning changes over time. 23775927 Quantitative pixel grey measurement of the "high-risk" sign, darkening of third molar roots: a pilot study. Our aim was to examine the panoramic darkening of the root, which is a "high-risk" sign, using quantitative measurements of pixel grey values to determine different aetiological backgrounds, namely inferior alveolar nerve (IAN) exposure with or without groove formation of the third molar roots or thinning/fenestration of the lingual cortex (LCTF). 38 impacted third molars that had been surgically removed and had darkened roots on panoramic radiographs were included in this retrospective case-control study. 15 IAN exposure cases were selected for the case group, and 23 cases with proven lingual cortical thinning or fenestration were chosen for the control group. The mean pixel grey values of selected areas in the dark band (D) and control areas within the same roots (R) were determined with the ImageTool (University of Texas Health Science Center, San Antonio, TX) software. The differences in pixel values (R-D) of the IAN and LCTF groups were analysed using the Mann-Whitney U-test and Pearson's χ(2) test. The medians of the R-D pixel values were 45.7 in the IAN group and 34.3 in the LCTF group, whereas the interquartile ranges were 12.0 (IAN) and 18.3 (LCTF) (p < 0.001). The R-D critical value at which the outcomes differed significantly was 38. If the differences in pixel grey values (R-D) were higher than 38, the chance of IAN exposure was approximately 32 times higher than the chance of LCTF (χ(2) test, p < 0.001; odds ratio, 32.0; 95% confidence interval, 3.5-293.1). The pre-operative prediction of IAN exposure or lingual cortical thinning in cases with "darkening" is possible based on pixel grey measurements of digital panoramic radiographs. 23921079 Molecular identification and characterization of Type I crustin isoforms from the hemocytes of portunid crabs, Scylla tranquebarica and Portunus pelagicus. Crustins are cationic antimicrobial peptides of ca. 7-14kDa with a characteristic four-disulphide core containing WAP domain, present in the hemocytes of crustaceans. The present study reports the first crustin sequences from two portunid crabs, viz. the mud crab Scylla tranquebarica (St-Crustin, JQ965930) and the blue swimmer crab Portunus pelagicus (Pp-Crustin, JQ753312). St-Crustin and Pp-Crustin represented the complete cDNA sequence of Type I crustin, with an ORF of 336bp encoding 111aa with a predicted molecular weight of 10kDa and a pI of 8. The signal sequence contained 21aa residues, which was followed by a mature peptide with a WAP domain at the C-terminus. Peptide model of St-Crustin and Pp-Crustin indicated a randomly coiled structure enclosing two β-sheets but no helices. St-Crustin and Pp-Crustin shared significant similarities with crustins of portunid crabs (68-95%) and other crabs (60-73%). Phylogenetic analysis showed that St-Crustin and Pp-Crustin possess the same ancestral origin and have a similar evolutionary status like other crustins, which has subsequently diverged at different phases of evolution. St-Crustin and Pp-Crustin were closely related to crab crustins rather than to the crustins of other crustacean groups. The wide distribution of crustins in crustaceans indicates the importance of these AMPs in the innate immunity. Discovery of novel crustins might pave way to the discovery of promising therapeutic/prophylactic agents in health management and disease control in crustacean aquaculture. 23856210 Utilizing commercial microwave for rapid and effective immunostaining. There is an accumulating literature demonstrating the application of microwaves across a wide spectrum of histological techniques. Although exposure to microwaves for short periods resulted in substantial acceleration of all procedures this technique still is not adopted widely. In part, this may be due to concerns over solutions that will avoid induction of thermal damage to the tissue when using standard microwave. Here, we offer a cooling setup that can be used with conventional microwave ovens. We utilized dry ice for effective cooling during microwave irradiation of tissue samples. To prevent overheating, the cups with tissue during exposure to microwaves were surrounded with powdered dry ice. Since the dry ice does not touch the walls of the cups, freezing is prevented. Overheating is avoided by alternating the microwave treatment with 1-2min time periods when the cups are cooled outside of the microwave oven. This technique was used on mouse brain sections that were immunostained with microglia-specific CD68 antiserum and astrocyte labeling GFAP antibody. Both standard and microwave-assisted immonolabeling gave comparable results visualizing cells with fine processes and low background signal. Short incubation time in the microwave requires high concentrations of antibody for tissue immunostaining. We show that by prolonging the microwaving procedure we were able to reduce the antibody concentration to the levels used in standard immunostaining protocol. In summary, our technique gives a possibility to use a conventional microwave for rapid and effective immunolabeling resulting in reduced amount of antibody required for satisfactory immunostaining. 23766266 Cathelicidin LL-37 Induces Angiogenesis via PGE2-EP3 Signaling in Endothelial Cells, In Vivo Inhibition by Aspirin. LL-37, the unique cathelicidin expressed in humans, in addition to acting as an endogenous antibiotic, is an important cell-signaling molecule upregulated in ovarian, breast, and lung tumors. However, the role of LL-37 in tumor microenvironment and its specific actions on the endothelial compartment remain elusive. Prostanoids are key regulators of inflammation, and cyclooxygenases (COXs) display proangiogenic activity in vitro and in vivo, mediated principally through prostaglandin E2 (PGE2). Here, we provide evidence for a novel proangiogenic role of LL-37, exerted via activation of endothelial cells and subsequent PGE2 biosynthesis. LL-37 triggers PGE2 synthesis in endothelial cells in a dose-dependent manner with maximal induction after 4 hours. Endothelial PGE2 biosynthesis was dependent on COX-1, rather than COX-2, as judged by pharmacological inhibition and gene silencing. In vitro matrigel assays supported these findings because LL-37-induced cord formation was abolished by COX-1, but not COX-2, small interfering RNA, and the angiogenic phenotype could be rescued by addition of exogenous PGE2. We find that LL-37 acts on endothelial cells as a potent calcium agonist, inducing phosphorylation and activation of cytosolic phospholipase A2 (cPLA2), promoting a cPLA2→COX-1→PGE2 biosynthetic pathway and subsequent signaling via PGE2 receptor EP3. Moreover, cathelicidin-related antimicrobial peptide, which is the murine ortholog of LL-37, induced prostaglandin-dependent angiogenesis in vivo, which could be blocked by aspirin. Our results identify a novel proangiogenic role of LL-37, suggesting that the axis LL-37/COX-1/PGE2 followed by EP3 signaling is amenable to therapeutic intervention in pathological angiogenesis, for instance by aspirin. 23473581 Molecular interactions in 1-butanol + IL solutions by measuring and modeling activity coefficients. Molecular interactions in 1-butanol + ionic liquid (IL) solutions have been investigated by measuring and modeling activity-coefficient data. The activity coefficients in binary solutions containing 1-butanol and an IL were determined experimentally: the ILs studied were 1-decyl-3-methyl-imidazolium tetracyanoborate ([Im10.1](+)[tcb](-)), 4-decyl-4-methyl-morpholinium tetracyanoborate ([Mo10.1](+)[tcb](-)), 1-decyl-3-methyl-imidazolium bis(trifluoromethylsulfonyl)imide ([Im10.1](+)[ntf2](-)), and 4-decyl-4-methyl-morpholinium bis(trifluoromethylsulfonyl)imide ([Mo10.1](+)[ntf2](-)). The methods used to determine the activity coefficients included vapor-pressure osmometry, headspace-gas chromatography, and gas-liquid chromatography. The results from all of these techniques were combined to obtain activity-coefficient data over the entire IL concentration range, and the ion-specific interactions of the ILs investigated were identified with 1-butanol. The highest (1-butanol)-IL interactions of the ILs considered in this work were found for [Im10.1](+)[tcb](-); thus, [Im10.1](+)[tcb](-) showed the highest affinity for 1-butanol in a binary mixture. The experimental data were modeled with the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). PC-SAFT was able to accurately describe the pure IL and (1-butanol)-IL data. Moreover, the model was shown to be predictive and extrapolative with respect to concentration and temperature. 23910089 Magnetic Resonance Imaging-guided Cryoablation of Recurrent Prostate Cancer After Radical Prostatectomy: Initial Single Institution Experience. To establish the feasibility of magnetic resonance imaging (MRI)-guided cryoablation in patients with previous radical prostatectomy and MRI visualized biopsy-proven local recurrence of prostate adenocarcinoma. Eighteen postprostatectomy patients (mean 67, 57-78 years) were treated with MRI-guided cryoablation for recurrent prostate carcinoma. Patients were found to have a hyperenhancing nodule using multiparametric MRI with endorectal coil followed by a positive transrectal ultrasound-guided biopsy. Of 18 postsurgical patients, 6 had additional salvage external beam radiation with subsequent recurrence. Under general anesthesia and MRI guidance (wide-bore 1.5T MRI), 2-5 cryotherapy probes were placed in or around the recurrence by transperineal approach and cryoablation performed. The patients were stratified into 2 groups: the initial 9 consecutive patients had cryoprobes placed 1 cm apart with 2 freeze-thaw cycles (group 1), and the subsequent 9 patients had cryoprobes placed 0.5 cm apart with 3 freeze-thaw cycles (group 2). In group I, the average preprocedure prostate-specific antigen (PSA) was 1.21 ± 1.12 ng/mL, and 1-3 months postprocedure PSA was 0.14 ± 0.11 ng/mL (P <.01). Sixty-seven percent of patients had PSA â‰¤0.2 ng/mL at 1-3 months follow-up, but only 25% at 4-6 months. No change in impotence or incontinence occurred. In group II, average preprocedure PSA was 2.24 ± 2.71 ng/mL, and 1-3 month postprocedure PSA was 0.08 ± 0.10 ng/mL (P <.05). Eighty-nine percent of patients had PSA â‰¤0.2 ng/mL at 1-3 months follow-up and at 4-6 months. Complications in group 2 included worsening incontinence in 3 patients. MRI-guided salvage cryoablation of postradical prostatectomy prostate cancer recurrence is safe and feasible. Both techniques produce early PSA decrease with more lasting PSA results in the more aggressive group II methodology. 23917912 Prevalence and predictors of compliance with discontinuation of airborne isolation in patients with suspected pulmonary tuberculosis. Objective. Examine the use of airborne isolation by identifying reasons for nontimely discontinuation and predictors of compliance with Centers for Disease Control and Prevention (CDC) guidelines. Compliance with guidelines should result in timely (within 48 hours) discontinuation of isolation in patients without infectious pulmonary tuberculosis (TB). Design. Retrospective, observational study. Setting. A private, university-affiliated, tertiary-care medical center. Patients. All patients in airborne isolation for suspected pulmonary TB from June through December 2011. Method. Chart reviews were performed to identify airborne isolation practices and delayed (greater than 48 hours) or very delayed (greater than 72 hours) discontinuation. We used descriptive statistics and logistic regression to determine independent predictors of nontimely discontinuation of isolation. Results. We identified 113 patients (mean age ± standard deviation, [Formula: see text] years; male sex, 75.2%; white race, 15.9%; mean collection interval ± standard deviation, [Formula: see text] hours). Delayed and very delayed isolation discontinuation was noted in 81% and 49% of patients, respectively. No significant differences in demographic characteristics and clinical characteristics were identified between groups. Predictors of timely (within 48 hours) airborne isolation discontinuation included use of alternate diagnosis for discontinuation of isolation ([Formula: see text]), early infectious diseases (ID) consultation ([Formula: see text]), pulmonary consultation ([Formula: see text]), average sputum collection interval less than 24 hours ([Formula: see text]), and need for more than 1 induced sputum specimen ([Formula: see text]). Adjusting for potential confounders, pulmonary consultation (odds ratio [OR] [95% confidence interval (CI)], 0.14 [0.03-0.58]), alternate diagnosis for discontinuation of isolation (OR [95% CI], 4.5 [1.3-15.8]), and early ID consultation (OR [95% CI], 4.0 [1.1-14.8]) were independently associated with timely discontinuation. Conclusions. Timely airborne isolation discontinuation occurs in only 18.6% of cases and is an opportunity for cost savings, improved efficiency, and potentially patient safety and satisfaction. 23828110 Intracranial Imaging of Uncommon Diseases Is More Frequently Reported in Clinical Publications Than in Radiology Publications. BACKGROUND AND PURPOSE:Descriptions of uncommon diseases with intracranial imaging abnormalities are often difficult to find in the radiology literature. We hypothesized that reported imaging findings of such conditions in the recent literature were more frequent in clinical compared with radiology journals.MATERIALS AND METHODS:PubMed searches from December 1, 2007 to December 1, 2012 were performed for 5 uncommon CNS diseases with intracranial imaging manifestations: 1) Susac syndrome; 2) amyloid β-related angiitis; 3) Parry-Romberg syndrome/en coup de sabre; 4) transient lesion of the splenium of the corpus callosum; and 5) reversible cerebral vasoconstriction syndrome. Articles were classified as a case report, case series, or original research. Journals were categorized as radiology or clinical. The 1- and 5-year Impact Factors of the journals were recorded.RESULTS:Two hundred two articles were identified for the 5 diseases, including 151 (74%) case reports, 26 case series (13%), and 25 original research articles (13%); 179 (89%) were published in nonradiology journals, compared with 23 (11%) in radiology journals. There was no significant difference between the mean 1- and 5-year Impact Factors of the radiology and clinical journals.CONCLUSIONS:Recent reports of the selected uncommon diseases with intracranial manifestations are more frequent in clinical journals when compared with dedicated radiology publications. Most publications are case reports. Radiologists should review both radiology and clinical journals when reviewing imaging features of uncommon diseases affecting the brain. Lack of reporting on such disease in the radiology literature may have significant practice, educational, and research implications for the radiology community. 23721186 Hydroxytyrosol expresses antifungal activity in vitro. Hydroxytyrosol (HT) is a potent antioxidant found in olive oil and leaves. Using several in vitro approaches, we tested antifungal activity of HT. HT showed broad spectrum of antifungal activity against medically important yeasts and dermatophyte strains with MIC values ranging between 97.6 µgml-1 and 6.25 mgml-1. The antimicrobial activity of HT was also tested using the time-kill methodology. Below the MIC value, HT showed potent damage of cell wall of Candida albicans ATCC 10231 using fluorescent dye-exclusion method. At the subinhibitory concentration, HT also influenced dimorphic transition of Candida indicating that HT is inhibitor of germ-tube formation as one of the most important virulence factor of C. albicans. Furthermore, HT showed disturbances in cell surface hydrophobicity (CSH) of C. albicans. The in vitro results indicate that HT caused a significant cell wall damage and changes in CSH as well as inhibition of germ-tube formation as virulence factor of C. albicans. The study indicates that HT has a considerable in vitro antifungal activity against medically important yeasts. 23510119 Systematic review of effectiveness of situated e-learning on medical and nursing education. Because of the complexity of clinical situations, traditional didactic education is limited in providing opportunity for student-patient interaction. Situated e-learning can enhance learners' knowledge and associated abilities through a variety of activities. Healthcare providers who interact with virtual patients in designed situations may avoid unnecessary risks and encounters with real patients. However, the effectiveness of situated e-learning is inconsistent. The purpose of this study is to determine the effectiveness of situated e-learning in prelicensure and postlicensure medical and nursing education. Literature databases of PubMed, Medline, CINAHL, ERIC, and Cochrane Library were searched. The study eligibility criteria included articles published in English, which examined the effectiveness of situated e-learning on the outcomes of knowledge and performance for clinicians or students in medicine and nursing. Effect sizes were calculated with 95% confidence intervals. Fourteen articles were included for meta-analysis. Situated e-learning could effectively enhance learners' knowledge and performance when the control group received no training. Compared to traditional learning, the effectiveness of situated e-learning on performance diminished but still remained significant whereas the effect become insignificant on knowledge. The subgroup analyses indicate the situated e-learning program significantly improved students' clinical performance but not for clinicians. Situated e-learning is an effective method to improve novice learners' performance. The effect of situated e-learning on the improvement of cognitive ability is limited when compared to traditional learning. Situated e-learning is a useful adjunct to traditional learning for medical and nursing students. 23414604 Long term outcome of psychogenic voice disorders. To evaluate different therapy for psychogenic voice disorders. Epidemiological data, organic and psychological symptoms, therapeutic options and outcome were prospectively analyzed in 40 consecutive patients with psychogenic voice disorders. Their voice was evaluated by subjective means and self assessment (voice handicap index) and an organic or functional disorder was excluded by videolaryngostroboscopy. Additionally, a detailed psychological examination and exploration were made. Every patient received intensive voice exercises with biofeedback by a phoniatrician and counseling by a clinical psychologist. Following this, therapy options of psychotherapy or a combination of psychotherapy and voice therapy were given. After an interval (average 16 months) from first contacting our section, every patient was asked to complete a questionnaire about their therapies and quality of voice. Patients had previously received insufficient voice therapy or antibiotics. The psychological examination detected psychological disorders as a basic problem. Overall, in 70% of patients there was either an improvement or resolution of voice problems. For all patients psychotherapy or a combination of voice therapy and psychotherapy was recommended, but only accepted in 37.5%. In all cases, when psychotherapy in combination with speech therapy took place, it was successful, whereas speech therapy alone provided improvement only in 12.5%. Psychogenic voice disorders are often misdiagnosed, leading to inadequate therapy. Psychotherapy (often in combination with voice therapy) was most effective also in the long term, but is often not accepted by patients. Voice therapy alone had a poor success rate. 23950679 Fossils from the Middle Jurassic of China shed light on morphology of Choristopsychidae (Insecta, Mecoptera). Choristopsychidae, established by Martynov in 1937 with a single isolated forewing, is a little known extinct family in Mecoptera. Since then, no new members of this enigmatic family have been described. Based on 23 well-preserved specimens with complete body and wings from the Middle Jurassic of northeastern China, we report one new genus and three new species of Choristopsychidae, two new species of the genus Choristopsyche Martynov, 1937: Choristopsyche perfecta sp. n. and Choristopsyche asticta sp. n.; one new species of Paristopsyche gen. n.: Paristopsyche angelineae sp. n.; and re-describe Choristopsyche tenuinervis Martynov, 1937. In addition, we emend the diagnoses of Choristopsychidae and Choristopsyche. Analyzing the forewing length/width ratios of representative species in Mecoptera, we confirm that choristopsychids have the lowest ratio of forewing length/width, meaning broadest forewings. These findings, the first fossil choristopsychids with well-preserved body structure and the first record of Choristopsychidae in China, shed light on the morphology of these taxa and broaden their distribution from Tajikistan to China, while increasing the diversity of Mesozoic Mecoptera in China. 23408463 Detection of EGFR mutations and EML4-ALK rearrangements in lung adenocarcinomas using archived cytological slides. Although the molecular analysis of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) in archived lung cancer tissues is relatively well established, the genetic testing of cytological material has not yet become a routine. The current study used cell samples that were obtained by bronchial brushing, transthoracic needle aspiration, or biopsy imprint preparation between 1993 and 2008. Islets of malignant cells were visually located on the archived cytological slides, lysed in situ by a drop of sodium dodecyl sulfate-containing buffer, and subjected to the standard DNA and RNA extraction. Examination of paraffin-embedded tissue blocks (resection specimens or biopsy material) from the same patients was performed in parallel. A total of 75 cytological/histological lung adenocarcinoma sample pairs underwent polymerase chain reaction analysis for the EGFR mutation. Two cytological samples and 1 morphological sample failed to produce DNA. Concordance for the wild-type and mutation status was observed in 54 of 72 and 14 of 72 informative pairs, respectively; 3 pairs and 1 pair, respectively, had mutation only in the cytological or histological material. The discrepancies could be explained by the failure to ensure a high percentage of lung cancer cells in the analyzed samples or, alternatively, by the genuine intratumoral molecular heterogeneity of some neoplasms. RNA extraction followed by reverse transcriptase-polymerase chain reaction analysis for the EML4-ALK translocation was performed for 44 EGFR mutation-negative sample pairs; failures were observed for 2 cytological and 6 histological specimens. All informative pairs were concordant either for the norm (32 of 36 pairs) or for the presence of EML4-ALK gene fusion (4 of 36 pairs). Archived cytological slides appear to be well suited both for EGFR and ALK analysis. Cancer (Cancer Cytopathol) 2013;121:370-376. © 2013 American Cancer Society. 22785106 Role of kinesin-1 in the pathogenesis of SPG10, a rare form of hereditary spastic paraplegia. Molecular protein motors play key roles in processes such as intracellular cargo transport and brain wiring, and failure of function can give rise to serious diseases. Kinesin-1, a member of the kinesin superfamily (also known as KIFs) is a two-headed motor protein that uses energy derived from ATP hydrolysis to transport diverse types of intracellular cargo toward the plus-ends of microtubules within axons. Recent studies at the level of a single molecule have provided extensive knowledge on how kinesin-1 moves along microtubules. Further elucidation of kinesin-1 movement may shed light on its influence on axon generation, thereby leading to therapies for diseases such as spastic paraplegia type 10 (SPG10), the subject of this review. SPG10 is an autosomal dominant form of hereditary spastic paraplegia caused by mutations in KIF5A, which encodes one of the isoforms of kinesin-1 (KIF5A, KIF5B, and KIF5C). Although little is known about the cargo of KIF5A, a recent study revealed an axonal transport defect of mitochondria in a KIF5A (-/-) mouse model. This review discusses the consensus moving model of kinesin-1 and the pathogenicity of SPG10 caused by defective KIF5A function. 23159728 Triclosan exposure alters postembryonic development in a Pacific tree frog (Pseudacris regilla) Amphibian Metamorphosis Assay (TREEMA). The Amphibian Metamorphosis Assay (AMA), developed for Xenopus laevis, is designed to identify chemicals that disrupt thyroid hormone (TH)-mediated biological processes. We adapted the AMA for use on an ecologically-relevant North American species, the Pacific tree frog (Pseudacris regilla), and applied molecular endpoints to evaluate the effects of the antibacterial agent, triclosan (TCS). Premetamorphic (Gosner stage 26-28) tadpoles were immersed for 21 days in solvent control, 1.5 μg/L thyroxine (T(4)), 0.3, 3 and 30 μg/L (nominal) TCS, or combined T(4)/TCS treatments. Exposure effects were scored by morphometric (developmental stage, wet weight, and body, snout-vent and hindlimb lengths) and molecular (mRNA abundance using quantitative real time polymerase chain reaction) criteria. T(4) treatment alone accelerated development concomitant with altered levels of TH receptors α and β, proliferating cell nuclear antigen, and gelatinase B mRNAs in the brain and tail. We observed TCS-induced perturbations in all of the molecular and morphological endpoints indicating that TCS exposure disrupts coordination of postembryonic tadpole development. Clear alterations in molecular endpoints were evident at day 2 whereas the earliest morphological effects appeared at day 4 and were most evident at day 21. Although TCS alone (3 and 30 μg/L) was protective against tadpole mortality, this protection was lost in the presence of T(4). The Pacific tree frog is the most sensitive species examined to date displaying disruption of TH-mediated development by a common antimicrobial agent. 23628746 Estradiol increases dendritic length and spine density in CA1 neurons of the hippocampus of spontaneously hypertensive rats: A Golgi impregnation study. Increased neuronal vulnerability has been described in the brain of spontaneously hypertensive rats (SHR), models of primary hypertension. Previous data indicate that estradiol treatment corrects several dysfunctions of the hippocampus and hypothalamus of SHR. Considering this evidence we analyzed the dendritic arborization and spine density of the CA1 subfield in SHR and Wistar-Kyoto (WKY) normotensive rats with and without estradiol treatment. Five month old male SHR and WKY rats received single estradiol or cholesterol pellets (sham treatment) for 2weeks. A substantial rise of circulating estradiol (>25 fold) and testicular atrophy was present in all estradiol-receiving rats. In both SHR and WKY rats, estradiol decreased blood pressure by ~20mmHg; however, a moderate hypertension persisted in SHR (164mmHg). Using a modified Golgi impregnation technique, apical and basal dendrites of the CA1 subfield were subjected to Sholl analysis. Spine density was also statistically analyzed. Apical dendritic length was significantly lower in SHR compared to WKY rats (p<0.01), whereas estradiol treatment increased dendritic length in the SHR group only (SHR vs SHR+estradiol; p<0.01). Apical dendritic length plotted against the shell distances 20-100, 120-200 and 220-300μm, revealed that changes were more pronounced in the range 120-200μm between SHR vs. WKY rats (p<0.05) and SHR vs. SHR+estradiol (p<0.05). Instead, basal dendrites were not significantly modified by hypertension or steroid treatment. Spine density of apical dendrites was lower in SHR than WKY (p<0.05) and was up-regulated in the SHR+estradiol group compared to the SHR group (p<0.001). Similar changes were obtained for basal dendritic spines. These data suggest that changes of neuronal processes in SHR are plastic events restorable by estradiol treatment. In conjunction with previous results, the present data reveal new targets of estradiol neuroprotection in the brain of hypertensive rats. 23296568 Ab initio molecular dynamics simulation on the formation process of He@C₆₀ synthesized by explosion. The applications of endohedral non-metallic fullerenes are limited by their low production rate. Recently, an explosive method developed in our group shows promise to prepare He@C₆₀ at fairly high yield, but the mechanism of He inserting into C₆₀ cage at explosive conditions was not clear. Here, ab initio molecular dynamics analysis has been used to simulate the collision between C₆₀ molecules at high-temperature and high-pressure induced by explosion. The results show that defects formed on the fullerene cage by collidsion can effectively decrease the reaction barrier for the insertion of He into C₆₀, and the self-healing capability of the defects was also observed. 23954851 Antioxidant activity and structural modifications of serum chondroitin sulfate in Graves' disease. Disturbances in the metabolism of proteoglycans/glycosaminoglycans related to free radical overproduction can be detected in Graves' ophthalmopathy. However, it is not evident whether these disorders appear before the clinical manifestation of ophthalmopathy and contribute to the development of nonthyroidal symptoms. They might also reflect the body's defence against the effects of an autoimmune attack, or they merely result from these disorders. Our study conducted in Graves' patients, free of ocular changes at the time of recruitment, is an attempt at explaining these ambiguities. We decided to investigate the relation between the changes in extracellular matrix components, namely the total glycosaminoglycans (GAGs) and chondroitin sulfates (CS), as well as parameters characterising oxidative stress, i.e. the total antioxidant status (TAS), and the thiol group (TG) concentration. GAGs, TAS and TG were quantified in serum samples obtained from 30 healthy subjects and 30 Graves' patients before and after treatment. An increased serum concentration of total GAGs and CS in Graves' patients before and after treatment was observed. Additionally, increased sulfation of CS in both Graves' patient groups was recorded. The serum TG and TAS concentrations in untreated patients were significantly decreased. Subsequent euthyreosis led to the normalisation of TG concentration. We have revealed a significant correlation between changes of extracellular matrix components, especially chondroitin-4-sulfate, thyroid status parameters, and parameters characterising oxidative stress. The structural modifications of serum CS in Graves' patients clinically free of ocular complications are probably the expression of systemic connective tissue remodelling. Simultaneously, these modifications may participate in a defence response to free radical damage underlying this pathology. 23607733 Effect of synchronization of donor cells in early G1-phase using shake-off method on developmental potential of somatic cell nuclear transfer embryos in cattle. In this study, we compared the developmental ability of somatic cell nuclear transfer (SCNT) embryos reconstructed with three bovine somatic cells that had been synchronized in G0-phase (G0-SCNT group) or early G1-phase (eG1-SCNT group). Furthermore, we investigated the production efficiency of cloned offspring for NT embryos derived from these donor cells. The G0-phase and eG1-phase cells were synchronized, respectively, using serum starvation and antimitotic reagent treatment combined with shaking of the plate containing the cells (shake-off method). The fusion rate in the G0-SCNT groups (64.2 ± 1.8%) was significantly higher than that of eG1-SCNT groups (39.2 ± 1.9%) (P < 0.05), but the developmental rates to the blastocyst stage of SCNT embryos per fused oocytes were similar for all groups. The overall production efficiency of the clone offspring in eG1-SCNT groups (12.7%) per recipient cow was higher than that in G0-SCNT groups (3%) (P < 0.05). The mean birth weight of cloned calves and the average calving score in the G0-SCNT groups (48.1 ± 3.4 kg and 3.3 ± 0.3, respectively) was significantly higher (P < 0.05) than those of eG1-SCNT groups (37.2 ± 2.1 kg and 2.3 ± 0.2, respectively). Results of this study indicate that synchronization of donor cells in eG1-phase using the shake-off method improved the overall production efficiency of the clone offspring per transferred embryo. 23864042 Self-healing polymeric materials. Inspired by nature, self-healing materials represent the forefront of recent developments in materials chemistry and engineering. This review outlines the recent advances in the field of self-healing polymers. The first part discusses thermodynamic requirements for self-healing networks in the context of conformation changes that contribute to the Gibbs free energy. The chain flexibility significantly contributes to the entropy changes, whereas the heat of reaction and the external energy input are the main contributors to enthalpy changes. The second part focuses on chemical reactions that lead to self-healing, and the primary classes are the covalent bonding, supramolecular assemblies, ionic interactions, chemo-mechanical self-healing, and shape memory polymers. The third part outlines recent advances using encapsulation, remote self-healing and the role of shape memory polymers. Recent developments in the field of self-healing polymers undeniably indicate that the main challenge will be the designing of high glass transition (Tg) functional materials, which also exhibit stimuli-responsive attributes. Build-in controllable hierarchical heterogeneousness at various length scales capable of remote self-healing by physical and chemical responses will be essential in designing future materials of the 21st century. 23785023 Genome-wide association study for inhibin, luteinizing hormone, insulin-like growth factor 1, testicular size and semen traits in bovine species. The fertility of young bulls impacts on reproduction rates, farm profit and the rate of genetic progress in beef herds. Cattle researchers and industry therefore routinely collect data on the reproductive performance of bulls. Genome-wide association studies were carried out to identify genomic regions and genes associated with reproductive traits measured during the pubertal development of Tropical Composite bulls, from 4 to 24 months of age. Data from 1 085 bulls were collected for seven traits: blood hormone levels of inhibin at 4 months (IN), luteinizing hormone following a gonadotropin releasing hormone challenge at 4 months (LH), insulin-like growth factor 1 at 6 months (IGF1), scrotal circumference at 12 months (SC), sperm motility at 18 months (MOT), percentage of normal spermatozoa at 24 months (PNS) and age at a scrotal circumference of 26 cm (AGE26, or pubertal age). Data from 729 068 single-nucleotide polymorphisms were used in the association analysis. Significant polymorphism associations were discovered for IN, IGF1, SC, AGE26 and PNS. Based on these associations, INHBE, INHBC and HELB are proposed as candidate genes for IN regulation. Polymorphisms associated with IGF1 mapped to the PLAG1 gene region, validating a reported quantitative trait locus on chromosome 14 for IGF1. The X chromosome contained most of the significant associations found for SC, AGE26 and PNS. These findings will contribute to the identification of diagnostic genetic markers and informed genomic selection strategies to assist breeding of cattle with improved fertility. Furthermore, this work provides evidence contributing to gene function annotation in the context of male fertility. 23435674 Fluorescence spectroscopy of PTCDA molecules on the KCl(100) surface in the limit of low coverages: site selection and diffusion. We performed fluorescence (FL) and fluorescence excitation (FLE) spectroscopy on the model molecule perylene-3,4,9,10-tetracarboxyl acid dianhydride (PTCDA) for very low coverages (below 1% of a monolayer) on thin (100) oriented KCl films. Two different states of PTCDA molecules can be distinguished in the spectra: an initial state, which is observed directly after deposition of the molecules onto the cold sample at 20 K, and a final state, which is found after intensive optical excitation or thermal annealing of the sample. The spectrum of the final state is blue-shifted with respect to that of the initial state by 130 ± 15 cm(-1) and exhibits lines with significantly reduced widths. This can be explained by diffusion of molecules from initially populated terrace sites to energetically favoured step edge sites. Polarization dependent spectroscopy reveals the same azimuthal orientation of the molecules on both adsorption sites and leads to a model of the adsorption geometry of PTCDA at the KCl step sites. Our experiment demonstrates how optical spectroscopy can be used to investigate kinetic processes of fluorescent molecules on surfaces. 23634642 Studies on the Himbert Intramolecular Arene/Allene Diels-Alder Cycloaddition. Mechanistic Studies and Expansion of Scope to All-Carbon Tethers. The unusual intramolecular arene/allene cycloaddition described 30 years ago by Himbert permits rapid access to strained polycyclic compounds that offer great potential for the synthesis of complex scaffolds. To more fully understand the mechanism of this cycloaddition reaction, and to guide efforts to extend its scope to new substrates, quantum mechanical computational methods were employed in concert with laboratory experiments. These studies indicated that the cycloadditions likely proceed via concerted processes; a stepwise biradical mechanism was shown to be higher in energy in the cases studied. The original Himbert cycloaddition chemistry is also extended from heterocyclic to carbocyclic systems, with computational guidance used to predict thermodynamically favorable cases. Complex polycyclic scaffolds result from the combination of the cycloaddition and subsequent ring-rearrangement metathesis reactions. 22408003 Effect of chondroitin sulphate C on the in vitro and in vivo chondrogenesis of mesenchymal stem cells in crosslinked type II collagen scaffolds. This study evaluates the crosslinkage effect of chondroitin sulphate C (CSC) and type II collagen (COL II) on chondrogenesis of mesenchymal stem cells (MSCs) in vitro and in vivo. In the in vitro studies, our results show that the weight ratio CSC:COL II that reaches 1.2:100 (CSC1.2/100 -COL II scaffold) can provide an optimal microenvironment for MSC chondrogenesis. When MSCs are cultured in this CSC1.2/100 -COL II scaffold, the chondrogenic gene expression of cultured cells is upregulated, while the osteogenic gene expression of these is downregulated. In addition, MSCs cultivated in the CSC1.2/100 -COL II scaffold are found to express the highest glycosaminoglycans:DNA ratio as compared to those in scaffolds of other CSC:COL II ratios. Histological and immunohistological evidence also supports the result. In the in vivo study, our results show that MSCs cultivated in the CSC1.2/100 -COL II scaffold demonstrate a better repair ability on cartilage lesions than does the COL II scaffold. After 1 month in vivo, the injected MSCs in the CSC1.2/100 -COL II scaffold show lacuna structures and stimulate the formation of type II collagen at the defective sites. Six months after transplantation, the generated cells in the CSC1.2/100 -COL II group show higher gene expressions of type II collagen and aggrecan but lower gene expression of type I collagen at the defective sites than those in the COL II group. The results strongly suggest that CSC1.2/100 -COL II scaffold can serve as a potential candidate for cartilage repair and improve the chondrogenesis of MSCs in general. Copyright © 2012 John Wiley & Sons, Ltd. 23639434 Antecedents and consequences of drug abuse in rats selectively bred for high and low response to novelty. Human genetic and epidemiological studies provide evidence that only a subset of individuals who experiment with potentially addictive drugs become addicts. What renders some individuals susceptible to addiction remains to be determined, but most would agree that there is no single trait underlying the disorder. However, there is evidence in humans that addiction liability has a genetic component, and that certain personality characteristics related to temperament (e.g. the sensation-seeking trait) are associated with individual differences in addiction liability. Consequently, we have used a selective breeding strategy based on locomotor response to a novel environment to generate two lines of rats with distinct behavioral characteristics. We have found that the resulting phenotypes differ on a number of neurobehavioral dimensions relevant to addiction. Relative to bred low-responder (bLR) rats, bred high-responder (bHR) rats exhibit increased exploratory behavior, are more impulsive, more aggressive, seek stimuli associated with rewards, and show a greater tendency to relapse. We therefore utilize this unique animal model to parse the genetic, neural and environmental factors that contribute to addiction liability. Our work shows that the glucocorticoid receptor (GR), dopaminergic molecules, and members of the fibroblast growth factor family are among the neurotransmitters and neuromodulators that play a role in both the initial susceptibility to addiction as well as the altered neural responses that follow chronic drug exposure. Moreover, our findings suggest that the hippocampus plays a major role in mediating vulnerability to addiction. It is hoped that this work will emphasize the importance of personalized treatment strategies and identify novel therapeutic targets for humans suffering from addictive disorders. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. 23381833 Increased Neuronal Apoptosis in Medial Prefrontal Cortex is Accompanied with Changes of Bcl-2 and Bax in a Rat Model of Post-Traumatic Stress Disorder. Post-traumatic stress disorder (PTSD) is an anxiety disorder caused by traumatic experience, which affects a patient's quality of life and social stability. The objective of this study was to determine the apoptosis-related genes B-cell lymphoma 2 (Bcl-2) and BCL2-associated X (Bax) expressions and medial prefrontal cortex (mPFC) neuronal apoptosis after PTSD in rat model and therefore to provide experimental evidence to reveal PTSD pathogenesis. The single-prolonged stress (SPS) method was used to set up the rat PTSD models. Chemiluminescence was used to determine serum corticosterone levels. Neuronal apoptosis was detected using transmission electron microscopy, Hoechst staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Immunohistochemistry, immunofluorescence, RT-PCR, and Western blot were used to detect the expressions of Bcl-2 and Bax protein in mPFC. Our results showed an increased mPFC neuronal apoptosis after SPS stimulation. The number of apoptotic cells peaked on day 7. The expressions of Bcl-2 and Bax peaked on days 4 and 7. The Bcl-2/Bax ratio elevated on days 1 and 4 but decreased markedly on day 7. These results indicated that SPS stimulation increased the number of apoptotic neurons, up-regulated the expressions of Bcl-2 and Bax, and altered the Bcl-2/Bax ratio in the mPFC of PTSD rats. 23709270 Disaster impact across cultural groups: comparison of whites, african americans, and latinos. The current study extends knowledge regarding the differential impact of natural disasters among White, African American, and Latino survivors of Hurricane Ike through its use of a large, regional sample recruited via representative sampling procedures to examine the associations between cultural identification and disaster impact, including loss, damage, and negative mental health outcomes. Consistent with previous research, results indicated disparities between cultural groups with regard to disaster exposure. Additionally, type of disaster impact was differentially associated with PTSD and depression status dependent on cultural group. Specifically, the extent of personal disaster exposure, property damage, and loss of services made significant contributions to PTSD status among White survivors. African-Americans were more likely than White and Latino Ike survivors to endorse post-disaster PTSD and depression and endorsement of depression was predicted by severity of property damage. With respect to Latino respondents, only the extent of personal disaster exposure significantly contributed to both PTSD and depression status. Implications of the current findings are discussed with regard to future disaster preparedness and response efforts and the implementation and evaluation of community-based disaster resources. 23925586 Clinical practice guidelines for treatment of acne vulgaris: a critical appraisal using the AGREE II instrument. A significant number of clinical practice guidelines (CPGs) about the treatment of acne vulgaris in adolescents and adults have been published worldwide. However, little is known about the quality of CPGs in this field. The aim of this study was to appraise the methodological quality of published acne vulgaris CPGs. We performed a systematic review of published CPGs on acne vulgaris therapy from July 2002 to July 2012. Three reviewers independently assessed each CPG using the AGREE II instrument. A standardized score was calculated for each of the six domains. Our search strategy identified 103 citations but just six met our inclusion criteria. Agreement among reviewers was very good: 0.981. The domains that scored better were: "scope and purpose" and "clarity and presentation". Those that scored worse were "stakeholder involvement", "rigor of development", and "applicability". The European and the Malaysian CPGs were the only recommended with no further modifications. In addition, the Mexican, Colombian and the United States guidelines were recommended with provisos, with lower scores regarding stakeholder involvement, rigor of development and applicability. Only two guidelines clearly reported outcome measures for evaluating efficacy or included quality of life outcomes. CPGs varied regarding the consideration of light/laser therapy or consideration of complementary/alternative medicines. None of them included cost considerations of drugs such as systemic isotretinoin. In conclusion, published acne vulgaris CPGs for acne therapy vary in quality with a clear need to improve their methodological rigor. This could be achieved with the adherence to current CPGs development standards. 23850750 Evidence of sugar sensitive genes in the gut of a carnivorous fish species. The ability of intestine to sense glucose in carnivorous animals (consuming minimal carbohydrate) has been partially evaluated to date only in cats. We have evaluated the expression of markers involved in the detection of simple sugars in the intestine of the strict carnivorous fish species rainbow trout (Oncorhynchus mykiss) in response to an oral glucose load and to glucose, galactose and mannose stimulation in vitro. These markers include metabolic (GLUT2 and glucokinase (hexokinase IV, GK)) and electrogenic (SGLT1) sensors, the nuclear receptor nr1h3 and the components of the G-protein-coupled taste receptors (tas1r2-like, tas1r3-like and gnat3-like). For the first time, we show that the gut of rainbow trout can detect simple sugars including glucose, galactose and mannose and respond by changing the expression levels of glucose-sensing proteins. The glucosensing response based on the metabolic and nuclear receptor systems had not been evidenced before in any carnivorous vertebrate species, whereas the responses of markers of the electrogenic mechanism and the taste receptor mechanism were different than those already described in cats. When the responses observed in rainbow trout were compared with those of omnivorous mammals, similar responses were obtained for nr1h3 whereas several differences arise in the responses of the other markers. Intestinal glucose sensing in the rainbow trout appears to be distinct from that reported for other carnivores such as cats and omnivores, revealing a novel glucose sensing mechanism not related entirely to diet in vertebrates and supports the idea that this species constitute a robust model for nutrient sensing study. Since only mRNA abundance is presented, depth studies are needed to fully understand the importance of the present findings. 23829958 Paediatric craniofacial fibrous dysplasia: The Hospital for Sick Children experience and treatment philosophy. Craniofacial fibrous dysplasia is a benign developmental anomaly in which normal bone is replaced by fibro-osseous tissue. The aim of this study was to audit the patient population at a tertiary paediatric centre and report our treatment protocols. A retrospective chart review of all patients with craniofacial fibrous dysplasia treated at the Hospital for Sick Children between 1999 and 2010 was performed. The treatment algorithm used by our centre is presented. A total of 55 patient records were reviewed; 37 patients had sufficient documentation for study; 27 (16 male, 11 female) patients underwent surgery at our institution, of these patients, 26 had post-operative follow up of greater than one year (mean 41 months; median 24 months). Mean age at presentation was 9.9 years (median 10 years) and mean age of surgery was 13 years. Ten patients underwent surgery on the fronto-orbital region, 7 of the calvarium, 2 the skull base and 8 upon tooth-bearing bones. Fourteen cases underwent debulking surgery as their primary therapy whereas 13 patients had complete resection. Nine patients experienced recurrence and all but one case of these occurred in patients that underwent debulking therapy. When age of surgery is considered, total resection and reconstruction or debulking surgery after skeletal maturity has a lower recurrence rate (1/7 cases) than earlier surgery (8/16). Complete resection at any age and debulking surgery once skeletal maturity has been reached may be associated with lower recurrence rates than incomplete resections at an earlier age. Patients with McCune-Albright syndrome may benefit from repeated debulking procedures rather than complex resections and reconstructions. 23769960 A cranial window imaging method for monitoring vascular growth around chronically implanted micro-ECoG devices. Implantable neural micro-electrode arrays have the potential to restore lost sensory or motor function to many different areas of the body. However, the invasiveness of these implants often results in scar tissue formation, which can have detrimental effects on recorded signal quality and longevity. Traditional histological techniques can be employed to study the tissue reaction to implanted micro-electrode arrays, but these techniques require removal of the brain from the skull, often causing damage to the meninges and cortical surface. This is especially unfavorable when studying the tissue response to electrode arrays such as the micro-electrocorticography (micro-ECoG) device, which sits on the surface of the cerebral cortex. In order to better understand the biological changes occurring around these types of devices, a cranial window implantation scheme has been developed, through which the tissue response can be studied in vivo over the entire implantation period. Rats were implanted with epidural micro-ECoG arrays, over which glass coverslips were placed and sealed to the skull, creating cranial windows. Vascular growth around the devices was monitored for one month after implantation. It was found that blood vessels grew through holes in the micro-ECoG substrate, spreading over the top of the device. Micro-hematomas were observed at varying time points after device implantation in every animal, and tissue growth between the micro-ECoG array and the window occurred in several cases. Use of the cranial window imaging technique with these devices enabled the observation of tissue changes that would normally go unnoticed with a standard device implantation scheme. 23861540 Receptor tyrosine kinases fall into distinct classes based on their inferred signaling networks. Although many anticancer drugs that target receptor tyrosine kinases (RTKs) provide clinical benefit, their long-term use is limited by resistance that is often attributed to increased abundance or activation of another RTK that compensates for the inhibited receptor. To uncover common and unique features in the signaling networks of RTKs, we measured time-dependent signaling in six isogenic cell lines, each expressing a different RTK as downstream proteins were systematically perturbed by RNA interference. Network models inferred from the data revealed a conserved set of signaling pathways and RTK-specific features that grouped the RTKs into three distinct classes: (i) an EGFR/FGFR1/c-Met class constituting epidermal growth factor receptor, fibroblast growth factor receptor 1, and the hepatocyte growth factor receptor c-Met; (ii) an IGF-1R/NTRK2 class constituting insulin-like growth factor 1 receptor and neurotrophic tyrosine receptor kinase 2; and (iii) a PDGFRβ class constituting platelet-derived growth factor receptor β. Analysis of cancer cell line data showed that many RTKs of the same class were coexpressed and that increased abundance of an RTK or its cognate ligand frequently correlated with resistance to a drug targeting another RTK of the same class. In contrast, abundance of an RTK or ligand of one class generally did not affect sensitivity to a drug targeting an RTK of a different class. Thus, classifying RTKs by their inferred networks and then therapeutically targeting multiple receptors within a class may delay or prevent the onset of resistance. 23201587 Dysregulated relationship of inflammation and oxidative stress in major depression. Chronic inflammation and oxidative stress have been implicated in the pathophysiology of Major Depressive Disorder (MDD), as well as in a number of chronic medical conditions. The aim of this study was to examine the relationship between peripheral inflammatory and oxidative stress markers in un-medicated subjects with MDD compared to non-depressed healthy controls and compared to subjects with MDD after antidepressant treatment. We examined the relationships between IL-6, IL-10, and the IL-6/IL-10 inflammatory ratio vs. F2-isoprostanes (F2-IsoP), a marker of oxidative stress, in un-medicated MDD patients (n=20) before and after 8 weeks of open-label sertraline treatment (n=17), compared to healthy non-depressed controls (n=20). Among the un-medicated MDD subjects, F2-IsoP concentrations were positively correlated with IL-6 concentrations (p<0.05) and were negatively correlated with IL-10 concentrations (p<0.01). Accordingly, F2-IsoP concentrations were positively correlated with the ratio of IL-6/IL-10 (p<0.01). In contrast, in the control group, there were no significant correlations between F2-IsoPs and either cytokine or their ratio. After MDD subjects were treated with sertraline for 8 weeks, F2-IsoPs were no longer significantly correlated with IL-6, IL-10 or the IL-6/IL-10 ratio. These data suggest oxidative stress and inflammatory processes are positively associated in untreated MDD. Our findings are consistent with the hypothesis that the homeostatic buffering mechanisms regulating oxidation and inflammation in healthy individuals become dysregulated in untreated MDD, and may be improved with antidepressant treatment. These findings may help explain the increased risk of comorbid medical illnesses in MDD. 23740746 Exploration of conformational transition pathways from coarse-grained simulations. A new algorithm to trace conformational transitions in proteins is presented. The method uses discrete molecular dynamics as engine to sample protein conformational space. A multiple minima Go-like potential energy function is used in combination with several enhancing sampling strategies, such as metadynamics, Maxwell Demon molecular dynamics and essential dynamics. The method, which shows an unprecedented computational efficiency, is able to trace a wide range of known experimental transitions. Contrary to simpler methods our strategy does not introduce distortions in the chemical structure of the protein and is able to reproduce well complex non-linear conformational transitions. The method, called GOdMD, can easily introduce additional restraints to the transition (presence of ligand, known intermediate, known maintained contacts, …) and is freely distributed to the community through the Spanish National Bioinformatics Institute (http://mmb.irbbarcelona.org/GOdMD). Freely available on the web at http://mmb.irbbarcelona.org/GOdMD. modesto.orozco@irbbarcelona.org or modesto@mmb.pcb.ub.es Supplementary data are available at Bioinformatics online. 23959307 CYP2J2 and CYP2C19 are the Major Enzymes Responsible for Metabolism of Albendazole and Fenbendazole in Human Liver Microsomes and Recombinant P450 Assay Systems. Albendazole and fenbendazole are broad spectrum anthelmintics that undergo extensive metabolism to form hydroxyl- and sulfoxide-metabolites. Although CYP3A and flavin-containing monooxygenase have been implicated in sulfoxide metabolite formation, the enzymes responsible for hydroxyl metabolite formation have not been identified. In this study, we used human liver microsomes and recombinant cytochrome P450s (P450s) to characterize the enzymes involved in the formation of hydroxyalbendazole and hydroxyfenbendazole from albendazole and fenbendazole, respectively. Of the 10 recombinant P450s, CYP2J2 and/or CYP2C19 were the predominant enzymes catalyzing the hydroxylation of albendazole and fenbendazole. Albendazole hydroxylation to hydroxyalbendazole is mediated primarily by CYP2J2 (0.34 μl/min/pmol P450; 3.9- and 8.1-fold higher than for CYP2C19 and CYP2E1, respectively), whereas CYP2C19 and CYP2J2 contributed to the formation of hydroxyfenbendazole from fenbendazole (2.68 and 1.94 μl/min/pmol P450 for CYP2C19 and CYP2J2, respectively; 11.7- and 8.4-fold higher than that for CYP2D6). Correlation analysis between the known P450 enzyme activities and the rate of hydroxyalbendazole and hydroxyfenbendazole formation in samples from 14 human liver microsomes showed that albendazole hydroxylation correlates with CYP2J2 activity and fenbendazole hydroxylation correlates with CYP2C19 and CYP2J2 activities. These findings were supported by a P450 isoform-selective inhibition study in human liver microsomes. In conclusion, our data for the first time suggest that albendazole hydroxylation is catalyzed primarily by CYP2J2, whereas fenbendazole hydroxylation is preferentially catalyzed by CYP2C19 and CYP2J2. The present data will be useful in understanding the pharmacokinetics and drug interactions of albendazole and fenbendazole in vivo. 23254383 Impact of late preterm birth on neonatal intensive care resources in a tertiary perinatal center. Objective To examine delivery indications, short-term morbidities, and use of resources for late preterm infants admitted to the neonatal intensive care unit (NICU) at a tertiary perinatal center.Study Design Data for 1137 inborn infants 340/7 to 366/7 weeks' gestational age discharged between July 2004 and December 2009 were collected from an electronic NICU database. Birth information was obtained from maternal charts.Results Forty-two percent of late preterm infants were admitted to the NICU. Their mean ( ± standard deviation) birth weight was 2347 ± 569 g; 15.1% were small for gestational age, 35.5% were multiples, and 17.8% had an antenatally diagnosed anomaly. Most births (52%) occurred following spontaneous rupture of membranes or labor. Cesarean section rate was 56.8%. Mortality rate was 1.2%. Most frequent morbidities were transient tachypnea (18.8%), cardiac or other congenital anomaly (16.8%), and respiratory distress syndrome (7.4%). Although 41.5% received ventilatory support, duration was short (1.1 ± 3.1 days). Mean length of NICU stay was 8.1 ± 9.3 days with 38% transferred to community hospitals before discharge.Conclusion For many late preterm infants admitted to the NICU, the duration of intensive therapy was short and some required no interventions. One impact of late preterm birth was bed occupancy. 23878053 Incidental Findings in Children With Blunt Head Trauma Evaluated With Cranial CT Scans. Cranial computed tomography (CT) scans are frequently obtained in the evaluation of blunt head trauma in children. These scans may detect unexpected incidental findings. The objectives of this study were to determine the prevalence and significance of incidental findings on cranial CT scans in children evaluated for blunt head trauma. This was a secondary analysis of a multicenter study of pediatric blunt head trauma. Patients <18 years of age with blunt head trauma were eligible, with those undergoing cranial CT scan included in this substudy. Patients with coagulopathies, ventricular shunts, known previous brain surgery or abnormalities were excluded. We abstracted radiology reports for nontraumatic findings. We reviewed and categorized findings by their clinical urgency. Of the 43 904 head-injured children enrolled in the parent study, 15 831 underwent CT scans, and these latter patients serve as the study cohort. On 670 of these scans, nontraumatic findings were identified, with 16 excluded due to previously known abnormalities or surgeries. The remaining 654 represent a 4% prevalence of incidental findings. Of these, 195 (30%), representing 1% of the overall sample, warranted immediate intervention or outpatient follow-up. A small but important number of children evaluated with CT scans after blunt head trauma had incidental findings. Physicians who order cranial CTs must be prepared to interpret incidental findings, communicate with families, and ensure appropriate follow-up. There are ethical implications and potential health impacts of informing patients about incidental findings. 23291333 Alkyl esters of gallic acid as anticancer agents: a review. The current review presents the antitumoral properties of gallic acid and its ester derivatives. Numerous studies have indicated that the alkyl esters are more effective against tumor cell lines than gallic acid, and that this activity is related to their hydrophobic moiety. All related studies have shown that the antitumor activity is interconnected to the induction of apoptosis by different mechanisms and it depends on the cell type. The results presented in this review may help to emphasize that these compounds could be promising as a new alternative for the treatment of cancer, either alone or in combination with other antitumor drugs to potentiate their effects. 23596978 Macromolecular amplification of binding response in superaptamer hydrogels. It is becoming more important to detect ultralow concentrations of analytes for biomedical, environmental, and national security applications. Equally important is that new methods should be easy to use, inexpensive, portable, and if possible allow detection by the naked eye. By and large, detection of low concentrations of analytes cannot be achieved directly but requires signal amplification by catalysts, macromolecules, metal surfaces, or supramolecular aggregates. The rapidly progressing field of macromolecular signal amplification has been advanced using conjugated polymers, chirality in polymers, solvating polymers, and polymerization/depolymerization strategies. A new type of aptamer-based hydrogel with specific response to target proteins presented in this report demonstrates an additional category of macromolecular signal amplification. This superaptamer assembly provides the first example of using protein-specific aptamers to create volume-changing hydrogels with amplified response to the target protein. A remarkable aspect of these superaptamer hydrogels is that volume shrinking is visible to the naked eye down to femtomolar concentrations of protein. This extraordinary macromolecular amplification is attributed to a complex interplay between protein-aptamer supramolecular cross-links and the consequential reduction of excluded volume in the hydrogel. Specific recognition is even maintained in biological matrices such as urine and tears. Furthermore, the gels can be dried for long-term storage and regenerated for use without loss of activity. In practice, the ease of this biomarker detection method offers an alternative to traditional analytical techniques that require sophisticated instrumentation and highly trained personnel. 23581596 Sacchathridine A, a Prostaglandin Release Inhibitor from Saccharothrix sp. Sacchathridine A (1) was isolated from the fermentation broth of strain Saccharothrix sp. MI559-46F5. The structure was determined as a new naphthoquinone derivative with an acetylhydrazino moiety by a combination of NMR, MS spectral analyses, and chemical degradation. Compound 1 showed inhibitory activity of prostaglandin E2 release in a concentration-dependent manner from human synovial sarcoma cells, SW982, with an IC50 value of 1.0 μM, but had no effect on cell growth up to 30 μM. 23970107 AOSpine thoracolumbar spine injury classification system: Fracture description, neurological status and key modifiers. Study Design: Reliability and agreement study, retrospective case seriesObjective: To develop a widely accepted, comprehensive yet simple classification system with clinically acceptable intra- and inter-observer reliability for use in both clinical practice and research.Summary of Background Data: Although the Magerl classification and Thoracolumbar Injury Classification System (TLICS) are both well known schemes to describe thoracolumbar fractures, no thoracolumbar injury classification system has achieved universal international adoption. This lack of consensus limits communication between clinicians and researchers complicating the study of these injuries and the development of treatment algorithms.Methods: A simple and reproducible classification system of thoracolumbar injuries was developed using a structured international consensus process. This classification system consists of a morphologic classification of the fracture, a grading system for the neurologic status and description of relevant patient-specific modifiers. Forty cases with a broad range of injuries were classified independently twice by group members 1 month apart and analyzed for classification reliability using the Kappa coefficient (κ).Results: The morphologic classification is based on three main injury patterns: A (compression), B (tension band disruption), and C (displacement/translation) type injuries. Reliability in the identification of a morphologic injury type was substantial (κ = 0.72).Conclusion: The AOSpine thoracolumbar injury classification system is clinically relevant according to the consensus agreement of our international team of spine trauma experts. Final evaluation data showed reasonable reliability and accuracy but further clinical validation of the proposed system requires prospective observational data collection documenting use of the classification system, therapeutic decision-making and clinical follow-up evaluation by a large number of surgeons from different countries. 23855320 Genome-wide analysis of short interspersed nuclear elements SINES revealed high sequence conservation, gene association and retrotranspositional activity in wheat. Short interspersed nuclear elements (SINEs) are non-autonomous non-LTR retroelements that are present in most eukaryotic species. While SINEs have been intensively investigated in humans and other animal systems, they are poorly studied in plants, especially in wheat (Triticum aestivum). We used quantitative PCR of various wheat species to determine the copy number of a wheat SINE family, termed Au SINE, combined with computer-assisted analyses of the publicly available 454 pyrosequencing database of T. aestivum. In addition, we utilized site-specific PCR on 57 Au SINE insertions, transposon methylation display and transposon display on newly formed wheat polyploids to assess retrotranspositional activity, epigenetic status and genetic rearrangements in Au SINE, respectively. We retrieved 3706 different insertions of Au SINE from the 454 pyrosequencing database of T. aestivum, and found that most of the elements are inserted in A/T-rich regions, while approximately 38% of the insertions are associated with transcribed regions, including known wheat genes. We observed typical retrotransposition of Au SINE in the second generation of a newly formed wheat allohexaploid, and massive hypermethylation in CCGG sites surrounding Au SINE in the third generation. Finally, we observed huge differences in the copy numbers in diploid Triticum and Aegilops species, and a significant increase in the copy numbers in natural wheat polyploids, but no significant increase in the copy number of Au SINE in the first four generations for two of three newly formed allopolyploid species used in this study. Our data indicate that SINEs may play a prominent role in the genomic evolution of wheat through stress-induced activation. 22946701 Abnormal uterine bleeding and dysfunctional uterine bleeding in pediatric and adolescent gynecology. Abnormal uterine bleeding (AUB), which is defined as excessively heavy, prolonged and/or frequent bleeding of uterine origin, is a frequent cause of visits to the Emergency Department and/or health care provider. While there are many etiologies of AUB, the one most likely among otherwise healthy adolescents is dysfunctional uterine bleeding (DUB), which is characterizing any AUB when all possible underlying pathologic causes have been previously excluded. The most common cause of DUB in adolescence is anovulation, which is very frequent in the first 2-3 post-menarchal years and is associated with immaturity of the hypothalamic - pituitary - ovarian axis. Management of AUB is based on the underlying etiology and the severity of the bleeding and primary goals are prevention of complications, such as anemia and reestablishment of regular cyclical bleeding, while the management of DUB can in part be directed by the amount of flow, the degree of associated anemia, as well as patient and family comfort with different treatment modalities. Treatment options for DUB are: combined oral contraceptives (COCs), progestogens, non steroidal anti inflammatory drugs (NSAIDs), tranexamic acid (anti-fibrinolytic), GnRH analogues, Danazol and Levonorgestrel releasing intra uterine system (LNG IUS). 23891461 Change in symptoms of erectile dysfunction in depressed men initiating buprenorphine therapy. Aims The aim of this study is to describe the change in erectile dysfunction (ED) symptoms in the first 12weeks of outpatient buprenorphine therapy. Erectile dysfunction is highly prevalent in men who use illicit opioids when compared with the general population. To date, no study has examined ED symptoms over time in men initiating buprenorphine therapy for opioid dependence. A randomized, double blind, placebo-controlled trial was conducted to determine whether escitalopram treatment of depressive symptoms begun 1week prior to buprenorphine induction would improve treatment retention. Male patients completed the International Index of Erectile Function scale at baseline prior to induction and monthly thereafter. A score of 25 or less on the erectile function domain (range 1-30) is considered indicative of erectile dysfunction. A total of 111 male subjects enrolled: mean age 38.5 (±9.7) years, 80.1% non-Hispanic Caucasian; 67.3% reported heroin as their opioid of choice. Mean IIEF at baseline was 20.4 (±10.5). At baseline, 44.1% of the entire cohort had erectile dysfunction; among those who identified as sexually active at baseline, 26.1% had ED. Baseline erectile function was inversely and significantly correlated with age (r=-.27, p=.006), but was not associated significantly with race, heroin use, years of opioid use, smoking, or hazardous use of alcohol. Compared to baseline, mean erectile function was significantly improved (p=.001) at 3months, and sexual desire (p=.002) improved significantly at both 2- and 3-month assessments. Erectile dysfunction is highly prevalent in depressed males using illicit opioids. Men who remain in buprenorphine treatment for 3months show improvement in erectile function and sexual desire. 23729737 The Toxoplasma gondii centrosome is the platform for internal daughter budding as revealed by a Nek1 kinase mutant. The pathology and severity of toxoplasmosis results from the rapid replication cycle of the apicomplexan parasite Toxoplasma gondii. The tachyzoites divide asexually through endodyogeny, wherein two daughter cells bud inside the mother cell. Before mitosis is completed, the daughter buds form around the duplicated centrosomes and subsequently elongate to serve as the scaffold for organellogenesis and organelle partitioning. The molecular control mechanism of this process is poorly understood. Here, we characterized a T. gondii NIMA-related kinase (Nek) ortholog that was identified in a chemical mutagenesis screen. A temperature-sensitive mutant, V-A15, possesses a Cys316Arg mutation in TgNek1 (a novel mutant allele in Neks), which is responsible for growth defects at the restrictive temperature. Phenotypic analysis of V-A15 indicated that TgNek1 is essential for centrosome splitting, proper formation of daughter cells and faithful segregation of genetic material. In vitro kinase assays showed that the mutation abolishes the kinase activity of TgNek1. TgNek1 is recruited to the centrosome prior to its duplication and localizes on the duplicated centrosomes facing the spindle poles in a cell-cycle-dependent manner. Mutational analysis of the activation loop suggests that localization and activity are spatio-temporally regulated by differential phosphorylation. Collectively, our results identified a novel temperature-sensitive allele for a Nek kinase and highlight its essential function in centrosome splitting in Toxoplasma. Moreover, these results conclusively show for the first time that Toxoplasma bud assembly is facilitated by the centrosome because defective centrosome splitting results in single daughter cell budding. 23860428 Comparison of synthetic glues and 10-0 nylon in rabbit lamellar keratoplasty. To evaluate changes in mean keratometry and to compare wound repair with corneal lamellar grafts in rabbit eyes using human synthetic tissue adhesives and 10-0 nylon. Corneal grafts were made using a 6.0-mm-diameter trephine and blades in the eyes of 15 New Zealand white rabbits. Human fibrin tissue adhesive (Tisseel) was used in group 1, human fibrin tissue adhesive (Beriplast P) was used in group 2, polyethylene glycol adhesive (Coseal) was used in group 3, and 8 bite sutures with 10-0 nylon were used in group 4 (control) for lamellar keratoplasty. Four bite sutures were made with 10-0 nylon in groups 1, 2, and 3. Slit-lamp microscopy and keratometry were performed at 3 days and 1, 2, and 4 weeks after the surgery. Histopathologic and electromicroscopic examinations were performed 4 weeks after the surgery. No inflammation or corneal toxicity was seen in groups 1 and 2. Histologically, a few inflammatory cells were seen in groups 3 and 4. Groups 1, 2, and 3 showed no statistically significant changes in mean keratometry at 4 weeks postoperatively compared with preoperative mean keratometry (Wilcoxon signed-rank test, P = 0.178, 0.208, and 0.889, respectively). The control group showed significant changes in mean keratometry at 4 weeks postoperatively (Wilcoxon signed-rank test, P = 0.018). Human fibrin tissue adhesives were well tolerated in rabbit eyes, with no apparent corneal toxicity. Polyethylene glycol adhesive showed more inflammation and insufficient wound repair compared with human fibrin tissue adhesives. Therefore, human fibrin tissue adhesives can be used as an alternative to sutures in lamellar keratoplasty. 23560252 Polymerization shrinkage stresses in a premolar restored with different composite resins and different incremental techniques. Purpose: To investigate how the incremental filling technique, elastic modulus, and post-gel shrinkage of different dental composite resins affect residual shrinkage stress in a restored premolar. Materials and Methods: Sixteen composites indicated for restoring posterior teeth were tested. Elastic modulus and Knoop hardness were measured using Knoop indentation tests (n = 10). A strain gauge test was used to measure the post-gel shrinkage (n = 10). Two incremental techniques, horizontal or oblique, were applied in a finite element model of a premolar in combination with the experimentally determined properties to assess the stress conditions along the interface of the restoration and within the material structures. Linear regressions were determined between residual shrinkage stress and the elastic modulus and post-gel shrinkage values. Results: The mechanical properties and the post-gel shrinkage varied significantly among the composites tested. The calculated shrinkage stress showed a strong correlation with post-gel shrinkage and a weaker correlation with elastic modulus. The oblique incremental filling technique resulted in lower residual shrinkage stress in the enamel and dentin and along the enamel/composite interface compared to the horizontal technique. Conclusion: Residual stress varied significantly among the contemporary dental composites indicated for restoring posterior teeth. Shrinkage stress in a restored tooth correlated with post-gel shrinkage. In general, oblique incremental filling resulted in lower residual stresses than did horizontal increments. 23559025 Simultaneous Localization of Lumbar Vertebrae and Intervertebral Discs With SVM-Based MRF. This paper presents a method for localizing and labeling the lumbar vertebrae and intervertebral discs in mid-sagittal MR image slices. The approach is based on a Markov-chain-like graphical model of the ordered discs and vertebrae in the lumbar spine. The graphical model is formulated by combining local image features and semiglobal geometrical information. The local image features are extracted from the image by employing pyramidal histogram of oriented gradients (PHOG) and a novel descriptor that we call image projection descriptor (IPD). These features are trained with support vector machines (SVM) and each pixel in the target image is locally assigned a score. These local scores are combined with the semiglobal geometrical information like the distance ratio and angle between the neighboring structures under the Markov random field (MRF) framework. An exact localization of discs and vertebrae is inferred from the MRF by finding a maximum a posteriori solution efficiently using dynamic programming. As a result of the novel features introduced, our system can scale-invariantly localize discs and vertebra at the same time even in the existence of missing structures. The proposed system is tested and validated on a clinical lumbar spine MR image dataset containing 80 subjects of which 64 have disc- and vertebra-related diseases and abnormalities. The experiments show that our system is successful even in abnormal cases and our results are comparable to the state of the art. 23643485 Impact of ApoB-100 expression on cognition and brain pathology in wild-type and hAPPsl mice. During their lifetime, people are commonly exposed to several vascular risk factors that may affect brain ageing and cognitive function. In the last few years, increasing evidence suggests that pathological plasma lipid profiles contribute to the pathogenesis of late-onset Alzheimer's disease. Importantly, hypercholesterolemia, especially elevated low-density lipoprotein cholesterol values, that is, increased apolipoprotein B-100 (ApoB-100) levels, represents an independent risk factor. In this study, the effects of ApoB-100 overexpression, either alone or in combination with cerebral expression of human amyloid precursor protein (hAPP), on cognitive functions and brain pathology were assessed. Our results show that ApoB-100 overexpression induces memory decline and increases cerebral lipid peroxidation and amyloid beta levels compared to those in wild-type animals. Although double-transgenic ApoBxAPP animals did not develop more distinct behavioral deficits than single-transgenic hAPP littermates, hApoB-100 expression caused additional pathophysiological features, such as high LDL and low HDL-cholesterol levels, increased lipid peroxidation, and pronounced ApoB-100 accumulation in cerebral vessels. Thus, our results indicate that ApoBxAPP mice might better reflect the situation of elderly humans than hAPPsl overexpression alone. 23887659 Detecting and Comparing Non-Coding RNAs in the High-Throughput Era. In recent years there has been a growing interest in the field of non-coding RNA. This surge is a direct consequence of the discovery of a huge number of new non-coding genes and of the finding that many of these transcripts are involved in key cellular functions. In this context, accurately detecting and comparing RNA sequences has become important. Aligning nucleotide sequences is a key requisite when searching for homologous genes. Accurate alignments reveal evolutionary relationships, conserved regions and more generally any biologically relevant pattern. Comparing RNA molecules is, however, a challenging task. The nucleotide alphabet is simpler and therefore less informative than that of amino-acids. Moreover for many non-coding RNAs, evolution is likely to be mostly constrained at the structural level and not at the sequence level. This results in very poor sequence conservation impeding comparison of these molecules. These difficulties define a context where new methods are urgently needed in order to exploit experimental results to their full potential. This review focuses on the comparative genomics of non-coding RNAs in the context of new sequencing technologies and especially dealing with two extremely important and timely research aspects: the development of new methods to align RNAs and the analysis of high-throughput data. 23904581 Association of smokeless tobacco use and smoking in adolescents in the United States: An analysis of data from the Youth Risk Behavior Surveillance System survey, 2011. Using smokeless tobacco and smoking are behaviors that increase the risk of developing oral cancer, soft-tissue lesions, caries, periodontal disease and other oral conditions. The author conducted a study to examine use of smokeless tobacco and smoking by adolescents. The study was a cross-sectional analysis of participants with complete data regarding smoking, smokeless tobacco use and other variables of interest from the 2011 national Youth Risk Behavior Surveillance System survey (n = 9,655). The author performed descriptive analysis and multivariable logistic regression analyses. The unadjusted odds ratio for smokeless tobacco use and smoking was 9.68 (95 percent confidence interval [CI], 7.72-12.13; P < .0001), and the adjusted odds ratio was 3.92 (95 percent CI, 2.89-5.31; P < .0001). Adolescents who used smokeless tobacco were more likely to be male, to smoke and to have engaged in binge drinking. Adolescents who were using smokeless tobacco were more likely to be engaging in concomitant smoking and to be participating in other risk-taking behaviors. Practical Implications. Dentists are involved in helping patients with tobacco-use cessation. The association of smoking with using smokeless tobacco needs to be considered in the design of tobacco-use cessation programs for adolescents. 23629865 US Valuation of the SF-6D. The original SF-6D valuation study collected 3503 standard gambled responses from 611 UK respondents to predict quality-adjusted life year (QALY) values. Using 19,980 paired comparison responses from 666 US respondents and a stacked probit model, the 25 coefficients of the original SF-6D multiattribute utility (MAU) regression were estimated, such that each coefficient represents a QALY decrement. The US QALY predictions were compared with UK predictions using 8428 SF-6D states in the US Medicare Health Outcomes Survey (MHOS), 1998 to 2003. Twenty-two of the 25 decrements in the SF-6D MAU regression are statistically significant. The remaining decrements are insignificant based on US and UK results. The US and UK QALY predictions for the MHOS SF-6D states are remarkably similar given differences in experimental design, format, and sampling (Lin's coefficient of agreement, 0.941; absolute mean difference, 0.043). Limitations. The underlying theoretical framework for the and econometric analysis builds from the episodic random utility model and the concept of QALYs and inherits their limitations. This study enhances the potential for US comparative effectiveness research by translating SF-6D states into US QALYs as well as improves upon discrete choice experiment design and econometric methods for health valuation. 23741007 Loss of endothelial protein C receptors links coagulation and inflammation to parasite sequestration in cerebral malaria in African children. Cerebral malaria (CM) is a major cause of mortality in African children and the mechanisms underlying its development, namely how malaria-infected erythrocytes (IEs) cause disease and why the brain is preferentially affected, remain unclear. Brain microhemorrhages in CM suggest a clotting disorder, but whether this phenomenon is important in pathogenesis is debated. We hypothesized that localized cerebral microvascular thrombosis in CM is caused by a decreased expression of the anticoagulant and protective receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR) and that low constitutive expression of these regulatory molecules in the brain make it particularly vulnerable. Autopsies from Malawian children with CM showed cerebral fibrin clots and loss of EPCR, colocalized with sequestered IEs. Using a novel assay to examine endothelial phenotype ex vivo using subcutaneous microvessels, we demonstrated that loss of EPCR and TM at sites of IE cytoadherence is detectible in nonfatal CM. In contrast, although clotting factor activation was seen in the blood of CM patients, this was compensated and did not disseminate. Because of the pleiotropic nature of EPCR and TM, these data implicate disruption of the endothelial protective properties at vulnerable sites and particularly in the brain, linking coagulation and inflammation with IE sequestration. 23890075 Prevention of cytomegalovirus following solid organ transplantation: A literature review. CMV is the most common opportunistic infection affecting SOT recipients. Although current strategies to prevent both CMV infection and disease have been effective, CMV related complications continue to occur, particularly late-onset CMV disease. This literature review article examines the benefits and disadvantages of different prevention modalities, and presents emerging strategies to better prevent CMV in organ transplant recipients. 23863217 Investigations of the Low-Frequency Spectral Density of Cytochrome c upon Equilibrium Unfolding. The equilibrium unfolding process of ferric horse heart cytochrome c (cyt c), induced by guanidinium hydrochloride (GdHCl), was studied using UV-vis absorption spectroscopy, resonance Raman spectroscopy, and vibrational coherence spectroscopy (VCS). The unfolding process was successfully fit using a three-state model which included the fully folded (N) and unfolded (U) states, along with an intermediate (I) assigned to a Lys bound heme. The VCS spectra revealed for the first time several low-frequency heme modes that are sensitive to cyt c unfolding: γa (∼50 cm(-1)), γb (∼80 cm(-1)), γc (∼100 cm(-1)), and νs(His-Fe-His) at 205 cm(-1). These out-of-plane modes have potential functional relevance and are activated by protein-induced heme distortions. The free energies for the N-I and the I-U transitions at pH 7.0 and 20 °C were found to be 4.6 kcal/M and 11.6 kcal/M, respectively. Imidazole was also introduced to replace the methionine ligand so the unfolding can be modeled as a two-state system. The intensity of the mode γb∼80 cm(-1) remains nearly constant during the unfolding process, while the amplitudes of the other low frequency modes track with spectral changes observed at higher frequency. This confirms that the heme deformation changes are coupled to the protein tertiary structural changes that take place upon unfolding. These studies also reveal that damping of the coherent oscillations depends sensitively on the coupling between heme and the surrounding water solvent. 23913756 Population-specific frequencies for LRRK2 susceptibility variants in the genetic epidemiology of Parkinson's disease (GEO-PD) consortium. Variants within the leucine-rich repeat kinase 2 gene are recognized as the most frequent genetic cause of Parkinson's disease. Leucine-rich repeat kinase 2 variation related to disease susceptibility displays many features that reflect the nature of complex, late-onset sporadic disorders like Parkinson's disease. The Genetic Epidemiology of Parkinson's Disease Consortium recently performed the largest genetic association study for variants in the leucine-rich repeat kinase 2 gene across 23 different sites in 15 countries. Herein, we detail the allele frequencies for the novel risk factors (p.A419V and p.M1646T) and the protective haplotype (p.N551K-R1398H-K1423K) nominated in the original publication. Simple population allele frequencies not only can provide insight into the clinical relevance of specific variants but also can help genetically define patient groups. Establishing individual patient-based genomic susceptibility profiles that incorporate both risk factors and protective factors will determine future diagnostic and treatment strategies. © 2013 Movement Disorder Society. 23838273 Neurophysiological correlates of excitement in schizophrenia. The excitement cluster (excitement, hostility, uncooperativeness and impulsivity) may contribute to the risk of violent behaviour, treatment non-adherence, likelihood of discharge and substance use in psychosis. Evidence suggests involvement of frontal executive mechanisms that may show sex differences in their association with symptom severity. The current study tests the association between excitement and the frontal N200 and P300 components of the auditory event-related potential in schizophrenia as a function of sex. Fourteen men and 14 women with schizophrenia (mean illness duration=20years) completed a novelty oddball and clinical interview. Men showed higher midline N200 and lower novelty P300 amplitude than women. They had more pronounced differences between midline and lateral N200 amplitude, and did not show the same Novel>Target effect for right frontal P300 as did women. Right frontal N200 amplitude to target stimuli was positively associated with excitement in women and inversely associated with excitement in men. Novelty P300 amplitude was inversely associated with excitement, particularly in women and over the right hemisphere. Results suggest that mechanisms underpinning frontal N200 and P300 subcomponents are differentially involved in excitement depending on sex. Understanding these individual differences may have implications for developing personalised treatment. 23167939 Pornography actresses: an assessment of the damaged goods hypothesis. The damaged goods hypothesis posits that female performers in the adult entertainment industry have higher rates of childhood sexual abuse (CSA), psychological problems, and drug use compared to the typical woman. The present study compared the self-reports of 177 porn actresses to a sample of women matched on age, ethnicity, and marital status. Comparisons were conducted on sexual behaviors and attitudes, self-esteem, quality of life, and drug use. Porn actresses were more likely to identify as bisexual, first had sex at an earlier age, had more sexual partners, were more concerned about contracting a sexually transmitted disease (STD), and enjoyed sex more than the matched sample, although there were no differences in incidence of CSA. In terms of psychological characteristics, porn actresses had higher levels of self-esteem, positive feelings, social support, sexual satisfaction, and spirituality compared to the matched group. Last, female performers were more likely to have ever used 10 different types of drugs compared to the comparison group. A discriminant function analysis was able to correctly classify 83% of the participants concerning whether they were a porn actress or member of the matched sample. These findings did not provide support for the damaged goods hypothesis. 23919260 A field-based approach for assessing the impact of treated pulp and paper mill effluent on endogenous metabolites of fathead minnows (Pimephales promelas). A field-based metabolomic study was conducted during a shutdown of a pulp and paper mill (PPM) to assess impacts of treated PPM effluent on endogenous polar metabolites in fathead minnow livers (FHM; Pimephales promelas). Caged male and female FHMs were deployed at a Great Lakes area-of-concern during multiple periods (pre-, during, and post-shutdown) near the outflow for a wastewater treatment plant. Influent to this plant is typically 40% PPM effluent by volume. Additional FHMs were exposed to reference lake water under lab conditions. A bioassay using T47D-KBluc cells showed that estrogenic activity of receiving water near the outflow declined by 46% during the shutdown. We then used 1H-NMR spectroscopy and principal component analysis to profile abundances of hepatic endogenous metabolites for FHMs. Profiles for males deployed pre-shutdown in receiving water were significantly different from those for lab-control males. Profiles were not significantly different for males deployed during the shutdown, but were significant again for those deployed post-shutdown. Impacts of treated effluent from this PPM were sex-specific, as differences among profiles of females were largely nonsignificant. Thus, we demonstrate the potential utility of field-based metabolomics for biologically-based exposure monitoring, and evaluating remediation efforts occurring throughout the Great Lakes and other ecosystems. 23891358 Trimethoprim-Associated Hyponatremia. Hyponatremia associated with diuretic use can be clinically difficult to differentiate from the syndrome of inappropriate antidiuretic hormone secretion (SIADH). We report a case of a 28-year-old man with HIV (human immunodeficiency virus) and Pneumocystis pneumonia who developed hyponatremia while receiving trimethoprim-sulfamethoxazole (TMP/SMX). Serum sodium level on admission was 135 mEq/L (with a history of hyponatremia) and decreased to 117 mEq/L by day 7 of TMP/SMX treatment. In the setting of suspected euvolemia and Pneumocystis pneumonia, he was treated initially for SIADH with fluid restriction and tolvaptan without improvement in serum sodium level. A diagnosis of hyponatremia secondary to the diuretic effect of TMP subsequently was confirmed, with clinical hypovolemia and high renin, aldosterone, and urinary sodium levels. Subsequent therapy with sodium chloride stabilized serum sodium levels in the 126- to 129-mEq/L range. After discontinuation of TMP/SMX treatment, serum sodium, renin, and aldosterone levels normalized. TMP/SMX-related hyponatremia likely is underdiagnosed and often mistaken for SIADH. It should be considered for patients on high-dose TMP/SMX treatment and can be differentiated from SIADH by clinical hypovolemia (confirmed by high renin and aldosterone levels). TMP-associated hyponatremia can be treated with sodium supplementation to offset ongoing urinary losses if the TMP/SMX therapy cannot be discontinued. In this Acid-Base and Electrolyte Teaching Case, a less common cause of hyponatremia is presented, and a stepwise approach to the diagnosis is illustrated. 23485653 The influence of study design and sex-differences on results from developmental neurotoxicity studies of bisphenol A, implications for toxicity testing. Developmental neurotoxicity (DNT) of bisphenol A (BPA) has been investigated in a large number of studies. However, there are discrepancies in the results reported between the studies. The aim of this study was to identify and analyze factors that may contribute to these differences and to assess whether there are sex-differences in the sensitivity of certain endpoints or tests used in DNT-studies. Forty-four DNT studies of BPA were identified from the open literature. Details about study design and results from each study, as well as the criteria for DNT testing according to the standardized OECD test guideline (TG) 426, were collected in a database. This enabled systematic and detailed comparisons between studies as well as to the criteria and recommendations stated in TG 426. Multivariate analyses were also used to investigate how different factors of the study design contributed to differences in study results. The analyses showed behavioral effects were often observed for endpoints that are not required according to OECD TG 426, such as anxiety-related, social and sexual behaviors, especially at very low doses and in female offspring. On the other hand relatively few studies observed any effects on motor activity, which is commonly used in screening for neurotoxic effects in regulatory testing. However, varied and to some extent seemingly contradictory results have been reported in these studies, especially for endpoints related to motor activity and anxiety and exploration. Many studies were also poorly reported, limiting these analyses. No strong conclusions could be drawn from the multivariate analyses. A few factors of study design, such as the size of the dose and number of dose levels used and the use of litter or individual pup as statistical unit seemed to have some influence on study results. In conclusion, this analysis suggests that DNT-studies conducted according to the standardized OECD TG 426 may overlook sensitive effects of BPA, and possibly other potential endocrine disruptors, especially in female offspring. 23804220 The clinical utility of accelerometry in patients with rheumatoid arthritis. Objectives. To assess habitual physical activity levels in patients with RA compared with healthy control participants and to compare these measures with health-related quality of life and disease activity in the RA patients. Methods. Fifty RA patients [age 48 (13) years] and 22 BMI, sex and geographically matched control participants were recruited. Habitual physical activity was measured using an Actical accelerometer worn on the hip for 2 consecutive weeks. Patients completed the Short Form-36 (SF-36) and modified Health Assessment Questionnaires (HAQ-DI). Disease activity was assessed using the Simplified Disease Activity Index (SDAI). RA patients were further categorized as more physically active (n = 25) and less physically active (n = 25) according to their average activity counts. Results. The RA group spent more time in sedentary activity than the control group (71% vs 62% of the day respectively, P = 0.002) and had bimodal decreases in diurnal physical activity compared with the control group in the morning (P < 0.001) and late afternoon (P < 0.001). HAQ-DI, when adjusted for age and disease duration, was negatively correlated with physical activity in the RA group (r = -0.343, P = 0.026). The more physically active patients scored better than the less physically active patients on every component of the SF-36. Conclusion. Patients with RA lead a significantly more sedentary lifestyle than healthy controls and show diurnal differences in physical activity due to morning stiffness and fatigue. Higher levels of habitual physical activity may be protective of functional capacity and are highly associated with improved health-related quality of life in RA patients. 23775237 On the early development of organic dyes for dye-sensitized solar cells. This viewpoint describes the background of the development of organic dyes for dye-sensitized solar cells, the impact of the 2006 ChemComm paper by Sun, Hagfeldt and co-workers regarding the D5 D-π-A-family of dyes, some recent developments and possible future challenges to meet. 23541932 Fishing and knockout of bioactive compounds using a combination of high-speed counter-current chromatography (HSCCC) and preparative HPLC for evaluating the holistic efficacy and interaction of the components of Herba Epimedii. Due to the complex chemical compositions and pharmacological effects of traditional Chinese medicines, we developed a strategy based on fishing and knockout of bioactive compounds using a combination of high-speed counter-current chromatography (HSCCC) and preparative HPLC for evaluating the holistic activity and interaction of the components of Herba Epimedii. First, osteoblast target cell extraction was used for preliminary screening of the potential bioactive compounds of Herba Epimedii. Second, the bioactive compounds identified (epimedin A, epimedin B, epimedin C and icariin) were fished and knocked out using high-speed counter-current chromatography and preparative HPLC. Third, the bioactivity of resulting fractions was assessed by determining their influence on cell proliferation and differentiation, thereby allowing for an evaluation of their interaction.The pharmacodynamic contribution ratio of each bioactive compound to the efficacy of the herbal medicine could then be comprehensively and intuitively determined based on the spectra-activity correlations (VIP values) of the tested compositions using partial least-squares regression (PLS-R), through which the reliability of the screening and isolation of bioactive compounds by the target cell extraction technique were verified. The proposed strategy is a useful approach with potential application in other traditional Chinese medicines. 23328125 Injectable hyaluronic acid-tyramine hydrogels incorporating interferon-α2a for liver cancer therapy. We report an injectable hydrogel system that incorporates interferon-α2a (IFN-α2a) for liver cancer therapy. IFN-α2a was incorporated in hydrogels composed of hyaluronic acid-tyramine (HA-Tyr) conjugates through the oxidative coupling of Tyr moieties with hydrogen peroxide (H2O2) and horseradish peroxidase (HRP). IFN-α2a-incorporated HA-Tyr hydrogels of varying stiffness were formed by changing the H2O2 concentration. The incorporation of IFN-α2a did not affect the rheological properties of the hydrogels. The activity of IFN-α2a was furthermore well-maintained in the hydrogels with lower stiffness. Through the caspase-3/7 pathway in vitro, IFN-α2a released from HA-Tyr hydrogels inhibited the proliferation of liver cancer cells and induced apoptosis. In the study of the pharmacokinetics, a higher concentration of IFN-α2a was shown in the plasma of mice treated with IFN-α2a-incorporated hydrogels after 4h post injection, with a much higher amount of IFN-α2a delivered at the tumor tissue comparing to that of injecting an IFN-α2a solution. The tumor regression study revealed that IFN-α2a-incorporated HA-Tyr hydrogels effectively inhibited tumor growth, while the injection of an IFN-α2a solution did not demonstrate antitumor efficacy. Histological studies confirmed that tumor tissues in mice treated with IFN-α2a-incorporated HA-Tyr hydrogels showed lower cell density, with more apoptotic and less proliferating cells compared with tissues treated with an IFN-α2a solution. In addition, the IFN-α2a-incorporated hydrogel treatment greatly inhibited the angiogenesis of tumor tissues. 23819815 Mercury increases water permeability of a plant aquaporin through a non-cysteine related mechanism. Water transport across cellular membranes is mediated by a family of membrane proteins known as aquaporins (AQP). AQPs were first discovered based on their ability to be inhibited by mercurial compounds, an experiment which has followed the aquaporin field ever since. While mercury inhibition is most common, many AQPs are mercury insensitive. In plants, regulation of AQPs is important in order to cope with environmental changes. Plant plasma membrane aquaporins are known to be gated by phosphorylation, pH and Ca2+. We have previously solved the structure of the spinach AQP SoPIP2;1 in closed and open conformations and proposed a mechanism for how this gating can be achieved. To study the effect of mercury on SoPIP2;1 we solved the structure of the SoPIP2;1-mercury complex and characterized the water transport ability using proteoliposomes. The structure revealed mercury binding to three out of four cysteines. Contrary to what is normally seen for AQPs, mercury increased the water transport rate of SoPIP2;1, an effect which could not be attributed to any of the cysteines. This indicates that other factors might influence the effect of mercury on SoPIP2;1, one of which could be the properties of the lipid bilayer. 22939232 Review: Structure-function and biological properties of the atypical chemokine receptor D6. The atypical chemokine receptor D6 was initially called "silent" on the basis of lack of conventional signaling events that lead to directional cell migration. It has emerged that D6 is able to bind and drive to degradative compartments most inflammatory CC chemokines and that is able to convey G-protein independent signaling events to optimize its scavenging activity. We here summarize the knowledge available today on D6 structural and signaling properties and its essential role for the control of inflammatory cells traffic and proper development of the adaptive immune response. 23848508 Relative intima-media thickening after preterm birth. Preterm infants are at increased risk of early arterial growth arrest and cardiovascular mortality. We assessed intima-media thickness (IMT) - an early marker of accelerated vascular ageing - in very preterm infants. Longitudinal cohort study of 21 very preterm and 29 term infants, all with appropriate birthweights. Intima-media thickness was assessed by M-Mode ultrasound of the aorta and carotid arteries at three occasions during a 6-month period corresponding to the third trimester of pregnancy and ending 3 months after term equivalent age. No differences in absolute aortic or carotid IMT were found. However, in relation to vessel lumen diameter, the IMT switched from being narrower in preterm infants, compared with foetuses at 28 weeks of gestation, to being significantly thicker in both the aorta and carotid artery in older infants born preterm, compared with term controls of equivalent postmenstrual age. Although the aortic and carotid artery diameters increased significantly with postnatal age, IMT did not. In relation to vessel diameter, subjects born preterm show thicker intima-media in the great arteries than infants born at term. It remains to be established whether this relative intima-media thickening persists and may be a risk marker for future cardiovascular disease. 23632107 Significant influence of particular unsaturated fatty acids and pH on the volatile compounds in meat-like model systems. The present study aimed to investigate the effects of particular unsaturated fatty acids and pH on volatile compounds in the meat-like model systems containing 21 amino acids and ribose. We have chosen oleic acid (C18:1n-9), linoleic acid (C18:2n-6) and linolenic acid (C18:3n-3) for the present investigation. The effect on the volatile compounds was evaluated at two different pH 5.5 and 6.2. The addition of C18:2n-6 and C18:3n-3 to the Maillard reaction mixtures inhibited the formation of many Maillard compounds or produced in low amount. Whereas, the addition of C18:1n-9 resulted in an increase in the amount of many Maillard compounds. The thiols and thiophenes were preferentially formed at pH 5.5 whereas pyrazines were preferentially favored at pH 6.2. Based on our results, it is suggested that a high level of C18:2n-6 and C18:3n-3 in meat probably causes an undesirable flavor. The pH value of 5.5 was found to be ideal for the formation of volatile compounds associated with desirable flavor of meat. 23916598 Photoacoustic analysis of the ultrasonic irradiation effect in the photosynthetic activity in aquatic lirium plants. We report, the application of the photoacoustic technique for monitoring the photosynthesis evolution in aquatic lirium (Eichhornia Crassipes), before and after it was exposed to ultrasonic irradiations. We obtained the disappearance of the phototobaric contribution in the PA signal measured for the irradiated samples with ultrasound of 17kHz, and therefore of a possible damage in the centers producing the photosynthesis, due to the irradiation. These results show the utility of the ultrasonic irradiation, as well as, of the photosynthesis monitoring by means of the photoacoustic technique, for the elaboration and establishment of methodologies in the control of this aquatic plant, whose propagation causes many consequences extremely unfavorable for the environment, as well as for the diverse human activities that are developed in the bodies of water in the tropical and sub-tropical regions of the world. 23824306 Caecal absorption of vitexin-2-O-xyloside and its aglycone apigenin, in the rat. The in vivo bioavailability of the flavone-C-glycosides has been little studied compared to their O-glycoside analogues, which are both more common in nature and considered more easily hydrolyzed than C-glycosides, by both enterocytes and gut microbiota. In this study, we used vitexin-2-O-xyloside (VOX), an apigenin-8-C-glucoside-2-O-xyloside, purified from seeds of Swiss chard (Beta vulgaris cicla), to investigate VOX absorption into portal blood compared to its aglycone, apigenin. We used a rat model in which we ligated the ileo- and colo-caecal junctions, then administered apigenin or VOX directly into the caecum. Blood samples were drawn from the portal vein at timed intervals over 40 min. The kinetic profile of appearance in portal blood of the compounds and their metabolites was evaluated by HPLC-ESI-MS. Apigenin was found in portal blood both as the aglycone and as an apigenin-glucuronide derivative. The VOX was found unchanged and as a reduced monoglycoside, which underwent glucuronidation. By collecting the bile, we confirmed that the liver received unchanged VOX, which was returned to the gut by enterohepatic recirculation for reabsorption from the ileum. The amount of apigenin and VOX remaining in the caecum accounted for ∼15% and ∼26%, respectively. These data show for the first time that the C-glycoside VOX is absorbed unchanged and undergoes enterohepatic recirculation in addition to hydrolysis to the monoglycoside, reduction and conjugation to form a bioavailable glucuronide. 23958365 Meningitis. Meningitis is defined as inflammation of the meninges, in almost all cases identified by an abnormal number of white blood cells in the cerebrospinal fluid and specific clinical signs/symptoms. Onset may be acute or chronic, and clinical symptoms of acute disease develop over hours to days. This article reviews the epidemiology, pathophysiology, clinical manifestations, diagnosis, and management of acute meningitis, and provides a list of key points for primary care practitioners. Aseptic and bacterial meningitis vary significantly and are discussed separately. 23918951 Second Allograft for Hematologic Relapse of Acute Leukemia After First Allogeneic Stem-Cell Transplantation From Related and Unrelated Donors: The Role of Donor Change. To evaluate the role of a second allogeneic hematopoietic stem-cell transplantation (HSCT2) given for relapsed acute leukemia (AL) after related or unrelated first hematopoietic stem-cell transplantation (HSCT1) and to analyze the role of donor change for HSCT2 in both settings. We performed a retrospective registry study on 179 HSCT2s given for relapse after HSCT1 from matched related donors (n = 75) or unrelated donors (n = 104), using identical or alternative donors for HSCT2. Separate analyses were performed according to donor at HSCT1. Independent of donor, 74% of patients achieved complete remission after HSCT2, and half of these patients experienced relapse again. Overall survival (OS) at 2 years was 25% ± 4% (39% ± 7% after related HSCT2; 19% ± 4% after unrelated HSCT2). Long-term survivors were observed even after two unrelated HSCT2s. Multivariate analysis for OS from HSCT2 confirmed established risk factors (remission duration after HSCT1: hazard ratio [HR], 2.37; 95% CI, 1.61 to 3.46; P < .001; stage at HSCT2: HR, 0.53; 95% CI, 0.34 to 0.83; P = .006). Outcome of HSCT2 was better after related HSCT1 than after unrelated HSCT1 (2-year OS: 37% ± 6% v 16% ± 4%, respectively; HR, 0.68; 95% CI, 0.47 to 0.98; P = .042, multivariate Cox regression). After both related and unrelated HSCT1, selecting a new donor for HSCT2 did not result in a relevant improvement in OS compared with HSCT2 from the original donor; however, donor change was not detrimental either. After relapse from allogeneic HSCT1, HSCT2 can induce 2-year OS in approximately 25% of patients. Unrelated HSCT2 is feasible after related and unrelated HSCT1. Donor change for HSCT2 is a valid option. However, a clear advantage in terms of OS could not be demonstrated. 23888147 How Mean is the Mean? In this paper we voice concerns about the uncritical manner in which the mean is often used as a summary statistic in psychological research. We identify a number of implicit assumptions underlying the use of the mean and argue that the fragility of these assumptions should be more carefully considered. We examine some of the ways in which the potential violation of these assumptions can lead us into significant theoretical and methodological error. Illustrations of alternative models of research already extant within Psychology are used to explore methods of research less mean-dependent and suggest that a critical assessment of the assumptions underlying its use in research play a more explicit role in the process of study design and review. 23937634 Stabilizing Impact of N-Glycosylation on the WW Domain Depends Strongly on the Asn-GlcNAc Linkage. N-glycans play important roles in many cellular processes and can increase protein conformational stability in specific structural contexts. Glycosylation (with a single GlcNAc) of the reverse turn sequence Phe-Yyy-Asn-Xxx-Thr at Asn stabilizes the Pin 1 WW domain by -0.85 ± 0.12 kcal mol(-1). Alternative methods exist for attaching carbohydrates to proteins; some occur naturally (e.g., the O-linkage), whereas others use chemoselective ligation reactions to mimic the natural N- or O-linkages. Here, we assess the energetic consequences of replacing the Asn linkage in the glycosylated WW domain with a Gln linkage, with two natural O-linkages, with two unnatural triazole linkages, and with an unnatural α-mercaptoacetamide linkage. Of these alternatives, only glycosylation of the triazole linkages stabilizes WW, and by a smaller amount than N-glycosylation, highlighting the need for caution when using triazole- or α-mercaptoacetamide-linked carbohydrates to mimic native N-glycans, especially where the impact of glycosylation on protein conformational stability is important. 23856460 Effect of an investigational CYP17A1 inhibitor, orteronel (TAK-700), on estrogen- and corticoid-synthesis pathways in hypophysectomized female rats and on the serum estradiol levels in female cynomolgus monkeys. Orteronel (TAK-700) is an investigational, non-steroidal inhibitor of CYP17A1 with preferential inhibition of 17,20-lyase in NCI-H295 cells. Estrogen is synthesized from androgen by aromatase activity, and the effect of orteronel on estrogen synthesis was therefore evaluated. First, it was confirmed that orteronel does not directly inhibit aromatase activity. Second, the specific decline of serum estradiol and androgen levels in hypophysectomized female rats by orteronel in comparison with aromatase inhibitor anastrozole was evaluated; orteronel at doses ≥3mg/kg significantly suppressed serum estradiol, testosterone, androstenedione and 17-hydroxyprogesterone levels, and increased progesterone levels in the estrogen-synthesis pathway. Orteronel, at a dose of 300mg/kg, suppressed serum estradiol concentrations to a similar degree as 0.1mg/kg anastrozole. In contrast, in the corticoid-synthesis pathway, serum aldosterone, corticosterone, and progesterone levels did not change significantly following administration of 300mg/kg of orteronel. Third, the effect of multiple oral administration of orteronel on serum estradiol levels in regularly cycling female cynomolgus monkeys was evaluated. Orteronel at 15mg/kg/day (7.5mg/kg/treatment, twice daily [bid]) continued to suppress the estradiol surge prior to the start of luteal phase for 1.5-times the average duration of three consecutive, pre-treatment menstrual cycles, while serum progesterone was maintained at levels almost equal to those in the luteal phase although a certain portion of this increased level of progesterone could be of adrenal-origin. This suppressive effect on estradiol surge was thought to be reversible since serum estradiol levels started to rise immediately after the discontinuation of orteronel. Estradiol surge was not abrogated by treatment with anastrozole 0.2mg/kg/day (0.1mg/kg/treatment, bid). In summary, orteronel can suppress serum estradiol concentrations in hypophysectomized female rats and monkeys through selective inhibition of CYP17A1 activity, suggesting that orteronel might be effective for hormone-dependent breast cancers and estrogen-dependent diseases. 23276824 Prospective study of urinary and serum cross-linked N-telopeptide of type I collagen (NTx) for diagnosis of bone metastasis in patients with lung cancer. Many cancers metastasize to bone, which may cause an increase in bone resorption because of the direct effects of the tumor itself or osteoclastic activation. Levels of urinary cross-linked N-telopeptide of type I collagen (uNTx) and serum cross-linked N-telopeptide of type I collagen (sNTx) were measured in 100 patients with lung cancer and 50 patients with benign respiratory disease using the Osteomark NTx urine and serum assays (Osteomark, Princeton, NJ). Bone metastasis was diagnosed by bone scintigraphy. Receiver operating characteristic (ROC) analysis was used to evaluate the detection of bone metastasis. Sensitivity and specificity to detect bone metastasis were calculated when cutoff points were set to 64 nmol bone collagen equivalents (BCE)/mmol Cr for uNTx and 22 nmol BCE/L for sNTx. Patients with lung cancer and bone metastasis had significantly higher levels of both uNTx and sNTx (uNTx median [range], 61.3 [22.7-593.1] nmol BCE/mmol creatinine [Cr]; sNTx median [range], 19.7 [10.7-97.1] nmol BCE/L) than did patients with lung cancer without bone metastasis (uNTx median [range], 45.2 [19.8-153.0] nmol BCE/mmol Cr; sNTx median [range], 16.7 [11.0-28.4] nmol BCE/L), or patients with benign respiratory diseases (uNTx median [range], 40.6 [15.2-155.9] nmol BCE/mmol Cr; sNTx median [range], 14.8 [9.5-55.5] nmol BCE/L.). There was good correlation between uNTx and sNTx (R = 0.807). Area under the curve (AUC) for ROC was 0.743 for uNTx and 0.712 for sNTx. The sensitivity and specificity for the diagnosis of bone metastasis were 48.0% and 86.0%, respectively, using uNTx, and 40.0% and 87.0%, respectively, using sNTx. This prospective study indicates equivalency between sNTx and uNTx in sensitivity and specificity to detect bone metastasis, and both uNTx and sNTx may have value as aids in the diagnosis of bone metastasis in patients with lung cancer. 23958640 Solid-state fermentation of Jatropha seed cake for optimization of lipase, protease and detoxification of anti-nutrients in Jatropha seed cake using Aspergillus versicolor CJS-98. This study focused on the solid-state fermentation of Jatropha seed cake (JSC), a byproduct generated after biodiesel production. Presence of anti-nutritional compounds and toxins restricts its application in livestock feed. The disposal of the JSC is a major environmental problem in the future, due to the generation of huge quantity of JSC after biodiesel extraction. Hence the JSC was assessed for its suitability as substrate for production and optimization of lipase and protease from Aspergillus versicolor CJS-98 by solid-state fermentation (SSF). The present study was also focused on the biodetoxification of anti-nutrients and toxins in JSC. The SSF parameters were optimized for maximum production of lipase and protease. Under the optimized conditions, the JSC supplemented with maltose and peptone (2%), adjusted to pH 7.0, moisture content 40%, inoculated with 1 Ã— 10(7) spores per 5 g cake and incubated at 25°C, produced maximum lipase, 1288 U/g and protease, 3366 U/g at 96 h. The anti-nutrients like phytic acid (6.08%), tannins (0.37%), trypsin inhibitors (697.5 TIU/g), cyanogenic glucosides (692.5 Î¼g/100 g), and lectins (0.309 mg/ml), were reduced to 1.70%, 0.23%, 12.5 TIU/g, 560.6 Î¼g/100 g and 0.034 mg/ml respectively. The main toxic compound phorbol esters content in the JSC was reduced from 0.083% to 0.015% after SSF. Our results indicate that viability of SSF to utilize the huge amount of seed cake generated after extraction of biodiesel, for production of industrial enzymes and biodetoxification of anti-nutrients, toxins. 23256472 Iodine-129 microdosing for protein and peptide drug development: erythropoietin as a case study. BACKGROUND: Microdosing is a technique for studying the behavior of compounds in vivo at 1/100th of the dose of a test substance calculated, based on animal data, to yield a pharmacologic effect. In microdosing, use is made of accelerator MS (AMS). In this study, we investigated whether (129)I-labeling of proteins with subsequent AMS measurements is a suitable method to perform microdose studies with therapeutic proteins. We used erythropoietin (EPO) as a case study. RESULTS: In an animal study with (129)I-labeled EPO in Han-Wistar rats, an increase of (129)I-EPO is observed after dose administration. The half-life was found to be 2 and 5.5 h for two different EPOs. These results are in accordance with expected values. CoNCLUSION: Although further research is required, (129)I-labeling of proteins seems a feasible method for AMS microdose studies with peptide and protein drugs, such as biosimilars. 23791304 Genetic engineering of multispecies microbial cell factories as an alternative for bioenergy production. There is currently much interest in developing technology to use microlgae or cyanobacteria for the production of bioenergy and biomaterials. Here, we summarize some remarkable achievements in strains improvement by traditional genetic engineering and discuss common drawbacks for further progress. We present general knowledge on natural microalgal-bacterial mutualistic interactions and discuss the potential of recent developments in genetic engineering of multispecies microbial cell factories. This synthetic biology approach would rely on the assembly of complex metabolic networks from optimized metabolic modules such as photosynthetic or nitrogen-fixing parts. 23889243 In vitro induction of functional allergen-specific CD4(+)  CD25(high) Treg cells in horses affected with insect bite hypersensitivity. Insect bite hypersensitivity (IBH) is a recurrent allergic dermatitis of horses with similarities to human atopic eczema, caused by bites of insects of the genus Culicoides. Previous studies suggested a dysregulated T cell tolerance to Culicoides allergen in IBH-affected horses. We have investigated whether the suppressive function of CD4(+)  CD25(high) cells is impaired in IBH-affected horses and possible ways to restore it. CD4(+)  CD25(-) cells sorted from peripheral blood mononuclear cells (PBMC) were stimulated with irradiated autologous PBMC pulsed with Culicoides or tetanus toxoid as control antigen, in the presence of CD4(+)  CD25(high) cells. Furthermore, Culicoides-specific CD4(+)  CD25(high) regulatory cells were expanded or induced from CD4(+)  CD25(-) cells in vitro in the presence of a combination of rIL-2 and rTGF-β1 (rIL-2/rTGF-β1) or of retinoic acid and rapamycin (RetA/Rapa). Proliferation was determined by [(3) H] thymidine incorporation and cytokine production measured by flow cytometry. The ability of Culicoides- but not tetanus-stimulated CD4(+)  CD25(high) cells to suppress proliferation of CD4(+)  CD25(-) cells was significantly lower in IBH-affected horses (28%) than in healthy controls (86%). The decreased suppression in IBH-affected horses was associated with a significantly higher proportion of IL-4(+) cells and a lower percentage of FoxP3(+)  IL-10(+) compared to controls. Addition of rIL-2/rTGF-β1 or of RetA/Rapa to Culicoides-stimulated CD4(+)  CD25(high) cells from IBH-affected horses significantly increased the proportion of FoxP3(+)  IL-10(+) cells. We also found that RetA/Rapa induced a more significant decrease in the frequency of IL-4(+) cells than rIL-2/rTGF-β1. Moreover, the suppressive activity of Culicoides-stimulated CD4(+)  CD25(high) cells was significantly restored by both rIL-2/rTGF-β1and RetA/Rapa, albeit in an antigen-unspecific manner. In contrast, in vitro induced Culicoides-specific CD4(+)  CD25(high) cells suppressed proliferation of CD4(+)  CD25(-) cells in an antigen-specific manner. The in vitro induction of functional allergen-specific Treg cells in IBH-affected horses suggests a potential therapeutic use of these cells in allergy. 23894381 Deciphering bartonella diversity, recombination, and host specificity in a rodent community. Host-specificity is an intrinsic feature of many bacterial pathogens, resulting from a long history of co-adaptation between bacteria and their hosts. Alpha-proteobacteria belonging to the genus Bartonella infect the erythrocytes of a wide range of mammal orders, including rodents. In this study, we performed genetic analysis of Bartonella colonizing a rodent community dominated by bank voles (Myodes glareolus) and wood mice (Apodemus sylvaticus) in a French suburban forest to evaluate their diversity, their capacity to recombine and their level of host specificity. Following the analysis of 550 rodents, we detected 63 distinct genotypes related to B. taylorii, B. grahamii, B. doshiae and a new B. rochalimae-like species. Investigating the most highly represented species, we showed that B. taylorii strain diversity was markedly higher than that of B. grahamii, suggesting a possible severe bottleneck for the latter species. The majority of recovered genotypes presented a strong association with either bank voles or wood mice, with the exception of three B. taylorii genotypes which had a broader host range. Despite the physical barriers created by host specificity, we observed lateral gene transfer between Bartonella genotypes associated with wood mice and Bartonella adapted to bank voles, suggesting that those genotypes might co-habit during their life cycle. 23912275 A novel human TINP1 gene promotes cell proliferation through inhibition of p53 and p21 expression. Transforming growth factor (TGF)-β-inducible nuclear protein 1 (TINP1) is a novel gene, which is localized at chromosome 5q13 where frequent abnormalities in hairy cell leukemia (HCL) occur. The present study investigated the effects of TINP1 knockdown or overexpression on the viability and gene expression of various tumor cell lines. siTINP1 was designed to knock down TINP1 expression. Reverse transcription polymerase chain reaction (RT-PCR) and western blotting were performed to assess gene expression; the cell counting kit-8 (CCK-8) assay was used to detect cell viability, and luciferase and flow cytometry assays were used to determine gene activity. TINP1 was widely expressed in various cell lines. In addition, TINP1 siRNA was able to knock down TINP1 expression in HeLa cells. TINP1 overexpression significantly promoted tumor cell proliferation, which may be associated with the downregulation of p53 expression. Furthermore, TINP1 promoted a number of cell lines to the S phase of the cell cycle. TINP1 promotes cell proliferation and significantly reduces p53 and p21 expression. 23229374 Towards a Richer Debate on Tissue Engineering: A Consideration on the Basis of NEST-Ethics. In their 2007 paper, Swierstra and Rip identify characteristic tropes and patterns of moral argumentation in the debate about the ethics of new and emerging science and technologies (or "NEST-ethics"). Taking their NEST-ethics structure as a starting point, we considered the debate about tissue engineering (TE), and argue what aspects we think ought to be a part of a rich and high-quality debate of TE. The debate surrounding TE seems to be predominantly a debate among experts. When considering the NEST-ethics arguments that deal directly with technology, we can generally conclude that consequentialist arguments are by far the most prominently featured in discussions of TE. In addition, many papers discuss principles, rights and duties relevant to aspects of TE, both in a positive and in a critical sense. Justice arguments are only sporadically made, some "good life" arguments are used, others less so (such as the explicit articulation of perceived limits, or the technology as a technological fix for a social problem). Missing topics in the discussion, at least from the perspective of NEST-ethics, are second "level" arguments-those referring to techno-moral change connected to tissue engineering. Currently, the discussion about tissue engineering mostly focuses on its so-called "hard impacts"-quantifiable risks and benefits of the technology. Its "soft impacts"-effects that cannot easily be quantified, such as changes to experience, habits and perceptions, should receive more attention. 23786476 Bridging developmental systems theory and evolutionary psychology using dynamic optimization. Interactions between evolutionary psychologists and developmental systems theorists have been largely antagonistic. This is unfortunate because potential synergies between the two approaches remain unexplored. This article presents a method that may help to bridge the divide, and that has proven fruitful in biology: dynamic optimization. Dynamic optimization integrates developmental systems theorists' focus on dynamics and contingency with the 'design stance' of evolutionary psychology. It provides a theoretical framework as well as a set of tools for exploring the properties of developmental systems that natural selection might favor, given particular evolutionary ecologies. We also discuss limitations of the approach. 23471537 Breakthrough febrile neutropenia and associated complications among elderly cancer patients receiving myelosuppressive chemotherapy for solid tumors and lymphomas. This study evaluated the prevalence, impact and predictive factors for the occurrence of febrile neutropenia (FN) in elderly patients receiving adjuvant myelosuppressive chemotherapy despite primary prophylaxis with G-CSF (breakthrough FN). This was a single-centre, observational, retrospective cohort study. Elderly cancer patients (≥ 65 years old) who have received adjuvant chemotherapy with primary prophylaxis using G-CSF from Jan 2008 to Aug 2011 were included. Variables identified by the univariate analysis as being associated with FN were included in a multivariable logistic model to investigate the independence of its association with FN. One hundred and forty-five patients and 704 cycles of chemotherapy were analyzed in this study, of which majority were Chinese (79.3 %). The median age of the patients was 69 years old (IQR: 66, 74). Majority of these patients were diagnosed with lymphoma (54.5 %), followed by breast cancer (34.5 %) and small cell lung cancer (8.3 %). In total, 24 patients (16.6 %) manifested at least one episode of FN, of which 41.7 % occurred during the first cycle of treatment. Only a minority of FN patients had clinically significant dose delay or reduction (25.0 % and 12.5 %, respectively). After adjustment with confounders (gender, baseline lymphocyte counts and baseline absolute neutrophil counts), patients with ≥ 2 comorbidities were at higher risk to develop breakthrough FN (AOR = 4.42, 95 %CI: 1.36-14.40, p = 0.014). Breakthrough FN is prevalent among elderly cancer patients receiving adjuvant chemotherapy despite G-CSF support, particularly among patients with more than two comorbidities. 23932431 When love hurts: Assessing the intersectionality of ethnicity, socio-economic status, parental connectedness, child abuse, and gender attitudes in juvenile violent delinquency. Researchers have not yet reached agreement about the validity of several competing explanations that seek to explain ethnic differences in juvenile violent offending. Ethnicity cannot solely explain why boys with an ethnic minority background commit more (violent) crimes. By assessing the intersectionality of structural, cultural and individual considerations, both the independent effects as well as the interplay between different factors can be examined. This study shows that aforementioned factors cumulatively play a role in severe violent offending, with parental connectedness and child abuse having the strongest associations. However, since most variables interact and ethnicity is associated with those specific factors, a conclusion to be drawn is that ethnicity may be relevant as an additional variable predicting severe violent offending although indirectly. 23307232 Warfarin dose prediction in children using pharmacometric bridging-comparison with published pharmacogenetic dosing algorithms. PURPOSE: Numerous studies have investigated causes of warfarin dose variability in adults, whereas studies in children are limited both in numbers and size. Mechanism-based population modelling provides an opportunity to condense and propagate prior knowledge from one population to another. The main objectives with this study were to evaluate the predictive performance of a theoretically bridged adult warfarin model in children, and to compare accuracy in dose prediction relative to published warfarin algorithms for children. METHOD: An adult population pharmacokinetic/pharmacodynamic (PK/PD) model for warfarin, with CYP2C9 and VKORC1 genotype, age and target international normalized ratio (INR) as dose predictors, was bridged to children using allometric scaling methods. Its predictive properties were evaluated in an external data set of children 0-18 years old, including comparison of dose prediction accuracy with three pharmacogenetics-based algorithms for children. RESULTS: Overall, the bridged model predicted INR response well in 64 warfarin-treated Swedish children (median age 4.3 years), but with a tendency to overpredict INR in children ≤2 years old. The bridged model predicted 20 of 49 children (41 %) within ± 20 % of actual maintenance dose (median age 7.2 years). In comparison, the published dosing algorithms predicted 33-41 % of the children within ±20 % of actual dose. Dose optimization with the bridged model based on up to three individual INR observations increased the proportion within ±20 % of actual dose to 70 %. CONCLUSION: A mechanism-based population model developed on adult data provides a promising first step towards more individualized warfarin therapy in children. 23943860 CENTRAL REGION COMPONENT1, a Novel Synaptonemal Complex Component, Is Essential for Meiotic Recombination Initiation in Rice. In meiosis, homologous recombination entails programmed DNA double-strand break (DSB) formation and synaptonemal complex (SC) assembly coupled with the DSB repair. Although SCs display extensive structural conservation among species, their components identified are poorly conserved at the sequence level. Here, we identified a novel SC component, designated CENTRAL REGION COMPONENT1 (CRC1), in rice (Oryza sativa). CRC1 colocalizes with ZEP1, the rice SC transverse filament protein, to the central region of SCs in a mutually dependent fashion. Consistent with this colocalization, CRC1 interacts with ZEP1 in yeast two-hybrid assays. CRC1 is orthologous to Saccharomyces cerevisiae pachytene checkpoint2 (Pch2) and Mus musculus THYROID RECEPTOR-INTERACTING PROTEIN13 (TRIP13) and may be a conserved SC component. Additionally, we provide evidence that CRC1 is essential for meiotic DSB formation. CRC1 interacts with HOMOLOGOUS PAIRING ABERRATION IN RICE MEIOSIS1 (PAIR1) in vitro, suggesting that these proteins act as a complex to promote DSB formation. PAIR2, the rice ortholog of budding yeast homolog pairing1, is required for homologous chromosome pairing. We found that CRC1 is also essential for the recruitment of PAIR2 onto meiotic chromosomes. The roles of CRC1 identified here have not been reported for Pch2 or TRIP13. 23595951 Cyclooxygenase-2-Derived Prostaglandin E2 Promotes Injury-Induced Vascular Neointimal Hyperplasia Through the E-prostanoid 3 Receptor. Rationale: Vascular smooth muscle cell (VSMC) migration and proliferation are the hallmarks of restenosis pathogenesis after angioplasty. Cyclooxygenase (COX)-derived prostaglandin (PG) E2 is implicated in the vascular remodeling response to injury. However, its precise molecular role remains unknown. Objective: This study investigates the impact of COX-2-derived PGE2 on neointima formation after injury. Methods and Results: Vascular remodeling was induced by wire injury in femoral arteries of mice. Both neointima formation and the restenosis ratio were diminished in COX-2 knockout mice as compared with controls, whereas these parameters were enhanced in COX-1>COX-2 mice, in which COX-1 is governed by COX-2 regulatory elements. PG profile analysis revealed that the reduced PGE2 by COX-2 deficiency, but not PGI2, could be rescued by COX-1 replacement, indicating COX-2-derived PGE2 enhanced neointima formation. Through multiple approaches, the EP3 receptor was identified to mediate the VSMC migration response to various stimuli. Disruption of EP3 impaired VSMC polarity for directional migration by decreasing small GTPase activity and restricted vascular neointimal hyperplasia, whereas overexpression of EP3α and EP3β aggravated neointima formation. Inhibition or deletion of EP3α/β, a Gαi protein-coupled receptor, activated the cAMP/protein kinase A pathway and decreased activation of RhoA in VSMCs. PGE2 could stimulate phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase3β signaling in VSMCs through Gβγ subunits on EP3α/β activation. Ablation of EP3 suppressed phosphatidylinositol 3-kinase signaling and reduced GTPase activity in VSMCs and altered cell polarity and directional migration. Conclusions: COX-2-derived PGE2 facilitated the neointimal hyperplasia response to injury through EP3α/β-mediated cAMP/protein kinase A and phosphatidylinositol 3-kinase pathways, indicating EP3 inhibition may be a promising therapeutic strategy for percutaneous transluminal coronary angioplasty. 23660967 Multiple coagulation factor deficiency protein 2 contains the ability to support stem cell self-renewal. Defects in multiple coagulation factor deficiency protein 2 (MCFD2) are a cause of factor V and factor VIII combined deficiency type 2 (F5F8D). MCFD2 was also suggested to play an important role as an autocrine/paracrine factor in maintaining neural stem cell potential. The current work provided direct evidence that both amphibian and human MCFD2 can maintain stem cell pluripotency or stemness of rhesus monkey embryonic stem cells (rESCs) as basic fibroblast growth factor 2 (FGF-2) does. In most cases, MCFD2 had identical effects on stem cells as FGF-2. We investigated the possible mechanism of MCFD2 to support stem cell pluripotency by highlighting the effects of MCFD2 and FGF-2 on several signaling pathways in rESCs, namely MAPK, TGF-β, Wnt, and Akt, and 3 core transcriptional factors (Oct4, Nanog, and Sox2). In addition, some features of signaling pathways (MAPK and Akt), which are different from human embryonic stem cells (hESCs) and mouse embryonic stem cells (mESCs), are found in rESCs, indicating that primate ESCs have unique signaling mechanisms. These results may shed light on the biological roles of MCFD2, the conserved protein family distributed in both vertebrates and invertebrates. The ability to support stem cell self-renewal may be the general function of the conserved protein family.-Liu, H., Zhao, B., Chen, Y., You, D., Liu, R., Rong, M., Ji, W., Zheng, P., Lai, R. Multiple coagulation factor deficiency protein 2 contains the ability to support stem cell self-renewal. 23859434 Real-world rates, predictors, and associated costs of hypoglycemia among patients with type 2 diabetes mellitus treated with insulin glargine: results of a pooled analysis of six retrospective observational studies. Abstract Objective: To evaluate the real-world rates of hypoglycemia and related costs among patients with type 2 diabetes mellitus (T2DM) who initiated insulin glargine with either a disposable pen or vial-and-syringe. Methods: Pooled data were evaluated from six previously published, retrospective, observational studies using US health plan insurance claims databases to investigate adults with T2DM who initiated insulin glargine. The current study evaluated baseline characteristics, hypoglycemic events, and costs during the 6 months prior to and 12 months following insulin glargine initiation. Comparisons were made between patients initiating treatment with a disposable pen (GLA-P) and vial-and-syringe (GLA-V). Multivariate analyses using baseline characteristics as covariates determined predictors of hypoglycemia after initiating insulin glargine. Results: This study included 23,098 patients (GLA-P: 14,911; GLA-V: 8187). Overall annual prevalence of hypoglycemia was low (6.3% overall, 2.2% related to hospital admission or emergency department visit). Prevalence was significantly lower with GLA-P (5.5% vs 7.7%; p < 0.0001). Furthermore, average glycated hemoglobin HbA1c reduction was higher with GLA-P (-1.22% vs -0.86%; p = 0.0012). The average annual hypoglycemia-related cost associated with initiating insulin glargine was $293, with GLA-P being 46% lower than GLA-V ($225 vs $417; p = 0.001). Patients who had already developed microvascular complications at the time of initiating insulin therapy were at higher risk for developing hypoglycemia. Limitations: This study is limited by the use of retrospective data and ICD-9-CM codes, which are subject to coding error. In addition, this pooled analysis used unmatched cohorts, with multivariate regression analyses employed to adjust for between-group differences. Finally, results describe a managed care sample and cannot be generalized to all patients with T2DM. Conclusions: Patients with T2DM initiating insulin glargine treatment showed low rates of hypoglycemia, especially when using a disposable pen device. Hypoglycemia-related costs were low, contributing a very small proportion to overall diabetes-related healthcare costs. 23900904 Artificial antigen synthesis and the development of polyclonal antibody-based immunoassay for citreoviridin determination. Citreoviridin, a mycotoxin produced by Penicillium citreonigrum is a common contaminant of wide range of agri-products and detrimental to human and animal health. Therefore it is important to develop a rapid, sensitive, and specific immunoassay for citreoviridin detection. In this study, polyclonal antibody against citreoviridin was developed. For the preparation of citreoviridin-bovine serum albumin conjugate (CIT-BSA), hydroxyl groups on adjacent carbon atoms were oxidized by sodium periodate, so the product with reactive aldehyde residues was suitable for coupling with amine. Anti-citreoviridin polyclonal antibody was prepared by immunizing mice with CIT-BSA conjugate. The specificity and sensitivity of the polyclonal antibody was determined by indirect competitive ELISA. Results showed that the IC50 value of the polyclonal antibody was 0.56 Î¼g/mL and no cross-reactivity was found between antiserum and other mycotoxins used in the experiment. The citreoviridin recovery rates by this polyclonal antibody were calculated through rice powder spiked by artificial citreoviridin. The recovery rates ranged were found from 70.5 ± 0.08 % to 94.7 ± 0.09 % for inter-assay, and from 77.5 ± 0.04 % to 95.4 ± 0.18 % for intra-assay, which indicated that this polyclonal antibody could detect trace amount of CIT from the tested samples. Consequently, this study provided a specific and sensitive anti-citreoviridin polyclonal antibody, which made the determination of citreoviridin easier, quicker, and more accurate. 23884729 Ultrasonographic evaluation of peritoneal membrane thickness and comparison with the effectiveness and duration of CAPD. The few studies on the morphology and functions of CAPD and peritoneum have tended to use histological and histomorphometrical methods. However, such methods are known to require biopsy, which is an invasive method. The present study aims to determine the morphological changes established by ultrasonography in CAPD patients, as well as achieving a comparison between these changes and the functional properties of peritoneum in CAPD. We aim to determine the effects of the duration of CAPD upon peritoneal thickness. The study included 42 CAPD patients. Twenty-four of them had peritoneal dialysis (PD) duration of less than 24 months (Group 1) and 18 of them had PD duration of longer than 48 months (Group 2). Patients with a history of surgery involving the peritoneum and abdomen and with a history of peritonitis in the last 3 months were excluded. We examined the parietal peritoneum by trans-abdominal ultrasonography. There was a statistically significant positive correlation between PD duration and peritoneal thickness of each quadrant. There was a statistically significant negative correlation between membrane thickness and creatinine clearance (CrCl), peritoneal Kt/V (pKt/V) and normalized protein catabolic rate. There was a positive significant correlation between membrane thickness and dialysate/plasma creatinine ratio. There was a statistically significant difference between the two groups according to their peritoneal membrane thickness. CrCl and pKt/V values were better in Group 1 than in Group 2. Our study revealed that increased PD duration may have a relation with increased peritoneal membrane thickness, and this can be associated with less effective PD. Ultrasound imaging has an important role for evaluating peritoneal membrane thickness without using an invasive method such as biopsy and can be performed easily in dialysis clinics. 23891435 Brain tissue classification based on DTI using an improved Fuzzy C-means algorithm with spatial constraints. We present an effective method for brain tissue classification based on diffusion tensor imaging (DTI) data. The method accounts for two main DTI segmentation obstacles: random noise and magnetic field inhomogeneities. In the proposed method, DTI parametric maps were used to resolve intensity inhomogeneities of brain tissue segmentation because they could provide complementary information for tissues and define accurate tissue maps. An improved fuzzy c-means with spatial constraints proposal was used to enhance the noise and artifact robustness of DTI segmentation. Fuzzy c-means clustering with spatial constraints (FCM_S) could effectively segment images corrupted by noise, outliers, and other imaging artifacts. Its effectiveness contributes not only to the introduction of fuzziness for belongingness of each pixel but also to the exploitation of spatial contextual information. We proposed an improved FCM_S applied on DTI parametric maps, which explores the mean and covariance of the feature spatial information for automated segmentation of DTI. The experiments on synthetic images and real-world datasets showed that our proposed algorithms, especially with new spatial constraints, were more effective. 22396130 Microwave-sintered 3D printed tricalcium phosphate scaffolds for bone tissue engineering. This study reports the manufacturing process of 3D interconnected macroporous tricalcium phosphate (TCP) scaffolds with controlled internal architecture by direct 3D printing (3DP), and high mechanical strength obtained by microwave sintering. TCP scaffolds with 27%, 35% and 41% designed macroporosity with pore sizes of 500 μm, 750 μm and 1000 μm, respectively, were manufactured by direct 3DP. These scaffolds were then sintered at 1150 °C and 1250 °C in conventional electric muffle and microwave furnaces, respectively. Total open porosity between 42% and 63% was obtained in the sintered scaffolds due to the presence of intrinsic micropores along with designed pores. A significant increase in compressive strength between 46% and 69% was achieved by microwave compared to conventional sintering as a result of efficient densification. Maximum compressive strengths of 10.95 ± 1.28 MPa and 6.62 ± 0.67 MPa were achieved for scaffolds with 500 μm designed pores (~ 400 μm after sintering) sintered in microwave and conventional furnaces, respectively. An increase in cell density with a decrease in macropore size was observed during in vitro cell-material interactions using human osteoblast cells. Histomorphological analysis revealed that the presence of both micro- and macropores facilitated osteoid-like new bone formation when tested in femoral defects of Sprague-Dawley rats. Our results show that bioresorbable 3D-printed TCP scaffolds have great potential in tissue engineering applications for bone tissue repair and regeneration. Copyright © 2012 John Wiley & Sons, Ltd. 23651870 Kinase inhibitors: a new tool for the treatment of rheumatoid arthritis. Despite aggressive immunosuppression with biologics and traditional DMARDs, achieving disease remission remains an unmet goal for most rheumatoid arthritis (RA) patients. In this context, there is a demand for novel treatment strategies, with kinase inhibitors expected to enrich the existing therapeutic armamentarium. In RA some kinases participate in the generation of pathogenic signaling cascades. Pharmacologic inhibition of kinases that mediate pathogenic signal transduction heralds a new era for RA therapeutics. Oral inhibitors of JAKs, Syk, PI3Ks, MAPKs and Btk are under development or in clinical trials in patients with RA. In this review, we discuss the scientific rationale for the use of kinase inhibitors in RA and summarize the experience from clinical trials. 23959248 Surface modification of electrospun polyester nanofibers with cyclodextrin polymer for the removal of phenanthrene from aqueous solution. Surface modified electrospun polyester (PET) nanofibers with cyclodextrin polymer (CDP) were produced (PET/CDP). CDP formation onto electrospun PET nanofibers was achieved by polymerization between citric acid (CTR, crosslinking agent) and cyclodextrin (CD). Three different types of native CD (α-CD, β-CD and γ-CD) were used to form CDP. Water-insoluble crosslinked CDP coating was permanently adhered onto the PET nanofibers. SEM imaging indicated that the nanofibrous structure of PET mats was preserved after CDP surface modification process. PET/CDP nanofibers have shown rougher/irregular surface and larger fiber diameter when compared to untreated PET nanofibers. The surface analyses of PET/CDP nanofibers by XPS elucidated that CDP was present on the fiber surface. DMA analyses revealed the enhanced mechanical properties for PET/CDP where PET/CDP nanofibers have shown higher storage modulus and higher glass transition temperature compared to untreated PET nanofibers. The surface area of the PET/CDP nanofibers investigated by BET measurements showed slight decrease due to the presence of CDP coating compared to pristine PET nanofibers. Yet, it was observed that PET/CDP nanofibers were more efficient for the removal of phenanthrene as a model polycyclic aromatic hydrocarbon (PAH) from aqueous solution when compared to pristine PET nanofibers. Our findings suggested that PET/CDP nanofibers can be a very good candidate as a filter material for water purification and waste treatment owing to their very large surface area as well as inclusion complexation capability of surface associated CDP. 23911760 The antimicrobial effects of cinnamon leaf oil against multi-drug resistant Salmonella Newport on organic leafy greens. There is generally no kill-step when preparing salad vegetables, so there is a greater risk for foodborne illness from contaminated vegetables. Some essential oils have antimicrobial activities and could provide a natural way to reduce pathogens on fresh produce. The objective of this study was to investigate the antimicrobial activity of cinnamon oil wash against Salmonella enterica serotype Newport on organic leafy greens. Organic romaine and iceberg lettuce, and organic baby and mature spinach were inoculated with Salmonella Newport and then dip treated in a phosphate buffered saline (PBS) control and 3 different concentrations (0.1, 0.3, and 0.5% v/v) of cinnamon oil. The treatment time varied at either 1 or 2min, and storage temperature varied at either 4 or 8°C. Samples were collected at days 0, 1, and 3. For romaine and iceberg lettuce, S. Newport was not recovered on day 3 for 2min 0.3% and 0.5% cinnamon oil treatments. For mature spinach, S. Newport was not recovered by day 3 for the 2min 0.3% and 0.5% 4°C treatments. For baby spinach, there was no recovery of S. Newport by day 1 for all 0.5% treatments. Overall, the cinnamon oil treatments were concentration and time dependent with higher concentrations and longer treatment times providing the greatest reduction in S. Newport population on leafy greens. In addition, the treatments had a residual effect with the greatest reduction generally seen on the last day of sampling. Storage temperature did not have a significant effect on the reduction of S. Newport. Based on the results of this study, cinnamon oil has the potential to be used as a treatment option for washing organic baby and mature spinach, and iceberg and romaine lettuces. 23807266 Reconstruction of surface potential from Kelvin probe force microscopy images. We present an algorithm for reconstructing a sample surface potential from its Kelvin probe force microscopy (KPFM) image. The measured KPFM image is a weighted average of the surface potential underneath the tip apex due to the long-range electrostatic forces. We model the KPFM measurement by a linear shift-invariant system where the impulse response is the point spread function (PSF). By calculating the PSF of the KPFM probe (tip+cantilever) and using the measured noise statistics, we deconvolve the measured KPFM image to obtain the surface potential of the sample.The reconstruction algorithm is applied to measurements of CdS-PbS nanorods measured in amplitude modulation KPFM (AM-KPFM) and to graphene layers measured in frequency modulation KPFM (FM-KPFM). We show that in the AM-KPFM measurements the averaging effect is substantial, whereas in the FM-KPFM measurements the averaging effect is negligible. 23959591 Tailoring the Window Sizes to Control the Local Concentration and Activity of (salen)Co Catalysts in Plugged Nanochannels of SBA-15 Materials. Ship shape! Chiral (salen)Co(III) complexes (spheres) inside plugged nanochannels of SBA-15 materials is achieved using a ship-in-a-bottle synthesis technique. The local concentration of the metal complexes and the catalytic activity (such as the hydrolytic kinetic resolution of 1,2-epoxyalkanes; see scheme) showed a strong dependence on the size of the window. 23588391 The effects of water molecules on the electronic and structural properties of peptide nanotubes. The self-assembly of short amino acid chains appears to be one of the most promising strategies for the fabrication of nanostructures. Their solubility in water and the possibility of chemical modification by targeting the amino or carboxyl terminus give peptide-based nanostructures several advantages over carbon nanotube nanostructures. However, because these systems are synthesized in aqueous solution, a deeper understanding is needed on the effects of water especially with respect to the electronic, structural and transport properties. In this work, the electronic properties of l-diphenylalanine nanotubes (FF-NTs) have been studied using the Self-Consistent Charge Density-Functional-based Tight-Binding method augmented with dispersion interaction. The presence of water molecules in the central hydrophilic channel and their interaction with the nanostructures are addressed. We demonstrate that the presence of water leads to significant changes in the electronic properties of these systems decreasing the band gap which can lead to an increase in the hopping probability and the conductivity. 23237742 The effect of albumen removal before incubation (embryonic protein under-nutrition) on the post-hatch performance, regulators of protein translation activation and proteolysis in neonatal broilers. Albumen was removed from broiler eggs before the start of incubation to induce prenatal protein under-nutrition in chicken embryos. With this method, the direct effect of protein deficiency was investigated, differing from mammalian models manipulating the maternal diet where indirect, hormonal effects can interfere. Based on the estimated albumen/egg weight ratio, 10 % of albumen was removed with an 18G needle, after making a hole at the sharp end of the egg with another 18G needle. Eggs were taped thereafter. The sham group underwent the same procedure, except that no albumen was removed. Control eggs did not receive any treatment. The removal of albumen decreased both embryonic and post-hatch body weight up to day 7 compared with the control group. On embryonic day 18, embryos from the albumen-deprived group had higher plasma uric acid levels compared with the sham (P= 0·016) and control (P= 0·009) groups. Moreover, a lower plasma amino acid concentration was observed at hatch compared with the sham (P= 0·038) and control (P= 0·152) groups. These findings indicate an altered protein metabolism. At hatch, a higher mRNA expression of muscle ring finger-1 (MuRF1), a gene related to proteolysis, was observed in albumen-deprived chicks compared with the control and sham chicks, together with an up-regulated expression of atrogin-1 (another atrogene) at this time point in the male protein-deficient chicks. These findings suggest that muscle proteolysis is transiently increased by the removal of albumen before the start of incubation. No evidence was found for altered protein synthesis capacity and translational efficiency in albumen-deprived chicks. 23675882 Unmet needs in ovarian cancer: dividing histologic subtypes to exploit novel targets and pathways. Ovarian cancer (OC) carries a poor prognosis; however, accumulating molecular data for the major histologic subtypes may lead to subtype-specific treatment paradigms. The present review discusses what is currently understood about the major molecular and histologic subgroups of OC. Areas specifically addressed include hormonal pathways, tumor protein p53 (TP53) and AT rich interactive domain 1A (SWI-like; ARID1A) mutation, and the breast cancer 1/2, early onset (BRCA1/2) mutation/poly (ADP-ribose) polymerase 1 (PARP1), phosphatidylinositol-4,5-bisphosphate 3- kinase, catalytic subunit alpha (PI3KCA)/v-akt murine thymoma viral oncogene homolog 1 (AKT1)/mechanistic target of rapamycin (MTOR), and mitogen-activated protein kinase kinase 1 and 2 (MAP2K1/2) pathways. This molecular characterization only very recently has impacted clinical research efforts to develop targeted therapies for both common and rare OC subtypes. This targeted strategy is illustrated by ongoing low-grade serous, clear-cell, and mucinous subtypeexclusive clinical trials evaluating agents based on common molecular abnormalities among patients (i.e., PARP1 inhibitors for BRCA1/2 mutation-positive OC). This report also reviews the published clinical trial efficacy data for investigational therapies within specific subgroups, and summarizes the currently active clinical trials evaluating these agents (e.g., temsirolimus, sunitinib, TP53 immunotherapy, olaparib, iniparib, veliparib). Available data suggest that histologic profiles and molecular tumor markers are valuable resources for identifying patients who may benefit from these specific agents, and future research should focus on targeting molecules and signaling pathways that are most commonly altered in each subtype. 23178652 Inhibition of CIP2A determines erlotinib-induced apoptosis in hepatocellular carcinoma. Erlotinib is a small-molecular inhibitor of epidermal growth factor receptor (EGFR). Here, we identify that cancerous inhibitor of protein phosphatase 2A (CIP2A) is a major determinant mediating erlotinib-induced apoptosis in hepatocellular carcinoma (HCC). Erlotinib showed differential effects on apoptosis in 4 human HCC cell lines. Erlotinib induced significant apoptosis in Hep3B and PLC5 cell lines; however, Huh-7 and HA59T cell lines showed resistance to erlotinib-induced apoptosis at all tested doses. Down-regulation of CIP2A, a cellular inhibitor of protein phosphatase 2A (PP2A), mediated the apoptotic effect of erlotinib in HCC. Erlotinib inhibited CIP2A in a dose- and time-dependent manner in all sensitive HCC cells whereas no alterations in CIP2A were found in resistant cells. Overexpression of CIP2A upregulated phospho-Akt and protected Hep3B cells from erlotinib-induced apoptosis. In addition, silencing CIP2A by siRNA restored the effects of erlotinib in Huh-7 cells. Moreover, adding okadaic acid, a PP2A inhibitor, abolished the effects of erlotinib on apoptosis in Hep3B cells; and forskolin, a PP2A agonist enhanced the effect of erlotinib in resistant HA59T cells. Combining Akt inhibitor MK-2206 with erlotinib restored the sensitivity of HA59T cells to erlotinib. Furthermore, in vivo xenograft data showed that erlotinib inhibited the growth of PLC5 tumor but had no effect on Huh-7 tumor. Erlotinib downregulated CIP2A and upregulated PP2A activity in PLC5 tumors, but not in Huh-7 tumors. In conclusion, inhibition of CIP2A determines the effects of erlotinib on apoptosis in HCC. CIP2A may be useful as a therapeutic biomarker for predicting clinical response to erlotinib in HCC treatment. 23962483 Investigation of kinetic interactions between approved oximes and human acetylcholinesterase inhibited by pesticide carbamates. Carbamates are widely used for pest control and act primarily by inhibition of insect and mammalian acetylcholinesterase (AChE). Accidental or intentional uptake of carbamates may result in typical signs and symptoms of cholinergic overstimulation which cannot be discriminated from those of organophosphorus pesticide poisoning. There is an ongoing debate whether standard treatment with atropine and oximes should be recommended for human carbamate poisoning as well, since in vitro and in vivo animal data indicate a deleterious effect of oximes when used in combination with the N-methyl carbamate carbaryl. Therefore, we performed an in vitro kinetic study to investigate the effect of clinically used oximes on carbamoylation and decarbamoylation of human AChE. It became evident that pralidoxime and obidoxime in therapeutic concentrations aggravate the inhibition of AChE by carbaryl and propoxur, with obidoxime being substantially more potent compared to 2-PAM. However, obidoxime had no impact on the decarbamoylation kinetics. Hence, the administration of 2-PAM and especially of obidoxime to severely propoxur and carbaryl poisoned humans cannot be recommended. 23946638 A novel missense mutation in the FERM domain containing 7 (FRMD7) gene causing X-linked idiopathic congenital nystagmus in a Chinese family. Idiopathic congenital nystagmus (ICN) is a genetically heterogeneous disease. Thus far, the disease gene has been identified as the FERM domain containing 7 (FRMD7) gene. The purpose of this study was to elucidate the clinical and genetic characteristics of a four- generation Chinese family with ICN. The clinical data and the genomic DNA of a Chinese ICN family were collected following the provision of informed consent. All coding exons of the FRMD7 gene were amplified by PCR and then sequenced. Affinity GST-p21 activated kinase 2 (PAK2) precipitation was used to investigate whether this novel FRMD7 mutant influenced Rac1 signaling activation in the human embryonic kidney 293 T cells (HEK 293T) cells transiently cotransfected with wild-type or mutant FRMD7 and Rac1. A novel missense mutation (c.635T>C) was identified in all affected members. Obligate female carriers were heterozygous in these mutations and the affected males were homozygous, consistent with X-linked inheritance. This mutation is a substitution of proline for leucine. Function analysis showed that this novel mutant influences Rac1 signaling in human HEK 293T cells. This study widens the mutation spectrum of the FRMD7 gene. This mutant was shown to activate GTPase Rac1 signaling in vitro; however, the quantity of activated Rac1 was obviously decreased compared with the wild type (p<0.05). Taken together, our data strongly support the hypothesis that the identified FRMD7 mutant influences GTPase Rac1 signaling, which regulates neurite development. This mutation may be related to the pathogenesis of X-linked ICN. 23905940 Penile prosthesis insertion for acute priapism. Shunt surgery is not universally successful toward detumescence, may lead to erectile dysfunction, and can make eventual penile prosthesis insertion difficult. Penile prosthesis insertion during a priapistic episode alleviates ischemic pain, allows the patient to resume sexual function sooner, and prevents corporal scarring and shortening that makes subsequent prosthesis implantation difficult. 23899676 Challenging Issues in Tuberculosis in Solid Organ Transplant Recipients. Solid organ transplant recipients (SOT) are at risk for opportunistic infections including tuberculosis (TB). Although guidelines on the management of latent TB infection (LTBI) and active TB are available, there remain a number of clinical areas with limited guidance. We discuss challenges in the diagnosis, management and treatment of LTBI and TB in SOT candidates and recipients who reside in low TB prevalence areas. We discuss the diagnosis of LTBI in SOT candidates/recipients using tuberculin skin tests and interferon-gamma release assays and risk stratification of SOT candidates/recipients that would identify individuals at high risk for LTBI despite negative test results. Through a careful review of post-transplant TB cases, we identify a history of treated TB in SOT recipients as a risk factor for development of post-transplant active TB. Finally, we include comparisons of recommendations by several large transplant organizations and identify areas for future research. 23942078 Ribosomal s6 protein kinase 4: a prognostic factor for renal cell carcinoma. Background:The expression and function of ribosomal s6 protein kinase 4 (RSK4) in renal cell carcinoma (RCC) are unknown.Methods:Immunohistochemistry was used to detect the expression of RSK4 in RCC, and the relationship between RSK4 expression and clinicopathological features as well as prognosis of RCC patients was statistically analysed. Ectopic RSK4 expression in RCC cell lines was performed to determine its effect on cell cycle regulation, tumour invasiveness, and metastatic capability.Results:RSK4 was overexpressed in RCCs (P=0.003), compared with normal tissues, and the expression varied in different RCC subtypes (P=0.021), especially in two subtypes of papillary RCCs (P=0.001). RSK4 expression was positively correlated with high pT stage (P<0.001), high Fuhrman grade (P<0.001), lymph node involvement (P<0.001), and presence of distant metastasis (P=0.039), and could predict poor outcome in RCC patients. Molecular studies showed that overexpression of RSK4 could promote cell cycle progression and enhance the invasive and metastatic capability of RCC cell lines and vice versa.Conclusion:The expression pattern and molecular mechanisms of RSK4 in RCCs indicate that it could be a potential independent prognostic factor and serve as a new potential therapeutic target for RCC patients.British Journal of Cancer advance online publication, 13 August 2013; doi:10.1038/bjc.2013.463 www.bjcancer.com. 23584549 Overexpression of a novel salt stress-induced glycine-rich protein gene from alfalfa causes salt and ABA sensitivity in Arabidopsis. We cloned a novel salt stress-induced glycine-rich protein gene ( MsGRP ) from alfalfa. Its overexpression retards seed germination and seedling growth of transgenic Arabidopsis after salt and ABA treatments. Since soil salinity is one of the most significant abiotic stresses, salt tolerance is required to overcome salinity-induced reductions in crop productivity. Many glycine-rich proteins (GRPs) have been implicated in plant responses to environmental stresses, but the function and importance of some GRPs in stress responses remain largely unknown. Here, we report on a novel salt stress-induced GRP gene (MsGRP) that we isolated from alfalfa. Compared with some glycine-rich RNA-binding proteins, MsGRP contains no RNA recognition motifs and localizes in the cell membrane or cell wall according to the subcellular localization result. MsGRP mRNA is induced by salt, abscisic acid (ABA), and drought stresses in alfalfa seedlings, and its overexpression driven by a constitutive cauliflower mosaic virus-35S promoter in Arabidopsis plants confers salinity and ABA sensitivity compared with WT plants. MsGRP retards seed germination and seedling growth of transgenic Arabidopsis plants after salt and ABA treatments, which implies that MsGRP may affect germination and growth through an ABA-dependent regulation pathway. These results provide indirect evidence that MsGRP plays important roles in seed germination and seedling growth of alfalfa under some abiotic stress conditions. 23939623 Functional determinants of gate-DNA selection and cleavage by bacterial type II topoisomerases. Antibacterial fluoroquinolones trap a cleavage complex of gyrase and topoisomerase (topo) IV inducing site-specific DNA breakage within a bent DNA gate engaged in DNA transport. Despite its importance for drug action and in revealing potential sites of topoisomerase catalysis, the mechanism of DNA selectivity is poorly understood. To explore its functional basis, we generated mutant versions of the strongly cleaved E-site and used a novel competitive assay to examine their gemifloxacin-mediated DNA breakage by Streptococcus pneumoniae topo IV and gyrase. Parallel studies of Ca(2+)-induced cleavage distinguished 'intrinsic recognition' of DNA cleavage sites by topo IV from drug-induced preferences. Analysis revealed strong enzyme-determined requirements for -4G, -2A and -1T bases preceding the breakage site (between -1 and +1) and enzyme-unique or degenerate determinants at -3, plus drug-specific preferences at +2/+3 and for +1 purines associated with drug intercalation. Similar cleavage rules were seen additionally at the novel V-site identified here in ColE1-derived plasmids. In concert with DNA binding data, our results provide functional evidence for DNA, enzyme and drug contributions to DNA cleavage at the gate, suggest a mechanism for DNA discrimination involving enzyme-induced DNA bending/helix distortion and cleavage complex stabilization and advance understanding of fluoroquinolones as important cleavage-enhancing therapeutics. 23302396 Relaxin, Its Receptor (RXFP1), and Insulin-Like Peptide 4 Expression Through Gestation and in Placenta Accreta. This study was designed to show whether placental relaxin (RLN), its receptor (RXFP1), or insulin-like peptide 4 (INSL4) might have altered expression in patients with placenta accreta. The baseline expression of their genes through gestation (n = 34) was quantitated in the placental basal plate (BP) and villous trophoblast (TR), and compared to their expression in placenta accreta (n = 6). The proteins were also immunolocalized and quantitated in the accreta tissues. The messenger RNAs (mRNAs) of matrix metalloproteinase 9, -2, and tissue inhibitors of matrix metalloproteinase (TIMP)-1 were also measured. Results demonstrated that the BP and TR expressed low levels of RLN/RXFP1 and INSL4 through gestation. In accreta, increased RLN gene and protein in BP were associated with antepartum bleeding whereas INSL4 expression decreased throughout the TR. There were no changes in mRNAs for MMPs, but TIMP-1 was increased only in the invasive TR. 23828044 Insights into the pathogenic character of a common NUBPL branch-site mutation associated with mitochondrial disease and complex I deficiency using a yeast model. Complex I deficiencies are the most common causes of mitochondrial disorders. They can result from mutations not only in the structural subunits but also in a growing number of known assembly factors. A branch-site mutation in the human gene encoding assembly factor NUBPL has recently been associated with mitochondrial encephalopathy and complex I deficiency in seven independent cases. Moreover, the mutation is present in 1.2% of European haplotypes. To investigate its pathogenicity, we have reconstructed the altered C-terminus that results from the branch-site mutation and frameshift in the homologous Ind1 protein in the respiratory yeast Yarrowia lipolytica. We demonstrate that the altered sequence did not affect IND1 mRNA stability, yet it led to a decrease in Ind1 protein level. The instability of mutant Ind1 resulted in a strong decrease in complex I activity and caused slow growth, resembling the phenotype of the deletion strain of IND1. The presented data confirms the deleterious impact of the altered C-terminus resulting from the branch-site mutation. Furthermore, our approach demonstrates the great potential of Y. lipolytica as a model to investigate complex I deficiencies, especially in cases with genetic complexity. 23921896 Comparison of CO2 in air versus carbogen for the measurement of cerebrovascular reactivity with magnetic resonance imaging. Measurement of cerebrovascular reactivity (CVR) can give valuable information about existing pathology and the risk of adverse events, such as stroke. A common method of obtaining regional CVR values is by measuring the blood flow response to carbon dioxide (CO2)-enriched air using arterial spin labeling (ASL) or blood oxygen level-dependent (BOLD) imaging. Recently, several studies have used carbogen gas (containing only CO2 and oxygen) as an alternative stimulus. A direct comparison was performed between CVR values acquired by ASL and BOLD imaging using stimuli of (1) 5% CO2 in air and (2) 5% CO2 in oxygen (carbogen-5). Although BOLD and ASL CVR values are shown to be correlated for CO2 in air (mean response 0.11±0.03% BOLD, 4.46±1.80% ASL, n=16 hemispheres), this correlation disappears during a carbogen stimulus (0.36±0.06% BOLD, 4.97±1.30% ASL). It is concluded that BOLD imaging should generally not be used in conjunction with a carbogen stimulus when measuring CVR, and that care must be taken when interpreting CVR as measured by ASL, as values obtained from different stimuli (CO2 in air versus carbogen) are not directly comparable.Journal of Cerebral Blood Flow & Metabolism advance online publication, 7 August 2013; doi:10.1038/jcbfm.2013.131. 23922855 Suppression of cytochrome p450 reductase enhances long-term hematopoietic stem cell repopulation efficiency in mice. Bone marrow microenvironment (niche) plays essential roles in the fate of hematopoietic stem cells (HSCs). Intracellular and extracellular redox metabolic microenvironment is one of the critical factors for the maintenance of the niche. Cytochrome P450 reductase (CPR) is an obligate electron donor to all microsomal cytochrome P450 enzymes (P450 or CYP), and contributes to the redox metabolic process. However, its role in maintaining HSCs is unknown. To examine the effects of low CPR expression on HSCs function using a mouse model of globally suppressed Cpr gene expression (Cpr Low, CL mice). Hematopoietic cell subpopulations in bone marrow (BM) and peripheral blood (PB) from WT and CL mice were examined for their repopulation and differentiation ability upon BM competitive transplantation and enriched HSC (LKS(+)) transplantation. Effects of low CPR expression on hematopoiesis were examined by transplanting normal BM cells into CL recipients. Reactive oxygen species (ROS), cell cycle, and apoptosis in CL mice were analyzed by flow cytometry for DCF-DA fluorescence intensity, Ki67 protein, and Annexin-V, respectively. The levels of ROS in BM cells, HPCs and HSCs were comparable between CL and WT mice. In comparison to WT mice, the number of LT-HSCs or ST-HSCs was lower in CL mice while CMPs, GMPs and MEPs in CL mice were higher than that in WT control. Competitive transplantation assay revealed enhanced repopulation capacity of HSCs with low CPR expression, but no difference in differentiation potential upon in vitro experiments. Furthermore, lymphoid differentiation of donor cells decreased while their myeloid differentiation increased under CL microenvironment although the overall level of donor hematopoietic repopulation was not significantly altered. Our studies demonstrate that suppressing CPR expression enhances the repopulation efficiency of HSCs and a low CPR expression microenvironment favors the differentiation of myeloid over lymphoid lineage cells. 23969187 Metreleptin improves blood glucose in patients with insulin receptor mutations. Context:Rabson-Mendenhall syndrome (RMS) is caused by mutations of the insulin receptor, and results in extreme insulin resistance and dysglycemia. Hyperglycemia in RMS is very difficult to treat, and patients are at risk for early morbidity and mortality from complications of diabetes.Objective:To study one year effects of recombinant human methionyl leptin (metreleptin) in five patients with RMS, and ten year effects in two of these patients.Design:Open-label non-randomized studySetting:National Institutes of HealthPatients:Adolescents with RMS and poorly-controlled diabetesIntervention:Two patients were treated with escalating doses (0.02 up to 0.22 mg/kg/day) of metreleptin for 10 years, including three cycles of metreleptin withdrawal and reinitiation. In all five patients, one-year effects of metreleptin (0.22 mg/kg/day) were studied.Outcome Measures:Hemoglobin A1c and BMI z-scores every 6 months.Results:A1c decreased from 11.4 ± 1.1% at baseline to 9.3 ± 1.9% after 6 months and 9.7 ± 1.6% after 12 months of metreleptin (P=0.007). In patients treated for 10 years, A1c declined with each cycle of metreleptin and rose with each withdrawal. BMI z-scores declined from -1.4 ± 1.8 at baseline, to -2.6 ± 1.6 after 12 months of metreleptin (P=0.0006). Changes in BMI z-score correlated with changes in A1c (P<0.0001).Conclusions:12 month metreleptin treatment was associated with a 1.8% reduction in A1c; part of this improvement was likely mediated via decreased BMI. Metreleptin is a promising treatment option for RMS, but additional therapies are needed to achieve A1c targets. 23872578 Animal models of in utero exposure to a high fat diet: A review. The incidence of metabolic disease, including type 2 diabetes and obesity, has increased to epidemic levels in recent years. A growing body of evidence suggests that the intrauterine environment plays a key role in the development of metabolic disease in offspring. Among other perturbations in early life, alteration in the provision of nutrients has profound and lasting effects on the long term health and well being of offspring. Rodent and non-human primate models provide a means to understand the underlying mechanisms of this programming effect. These different models demonstrate converging effects of a maternal high fat diet on insulin and glucose metabolism, energy balance, cardiovascular function and adiposity in offspring. Furthermore, evidence suggests that the early life environment can result in epigenetic changes that set the stage for alterations in key pathways of metabolism that lead to type 2 diabetes or obesity. Identifying and understanding the causal factors responsible for this metabolic dysregulation is vital to curtailing these epidemics. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. 23883748 On projecting grammatical persons into social neurocognition: A view from linguistics. Though it draws on the grammatical metaphor of person (first, third, second) in terms of representations, Schilbach et al.'s target article does not consider an orthogonal line of evidence for the centrality of interaction to social cognition: the many grammatical phenomena, some widespread cross-linguistically and some only being discovered, which are geared to supporting real-time interaction. My commentary reviews these, and the contribution linguistic evidence can make to a fuller account of social cognition. 23957325 Antifungal efficacy of lasers against dermatophytes and yeasts in vitro. Abstract Purpose: Approximately 2-13% of the world population suffers from onychomycosis. Recently, lasers have been introduced for treatment. However, no effect was found with in vitro laser irradiation of pathogens on agar plates. This study aimed to investigate the efficacy of laser irradiation against fungi using an alternative in vitro approach. Materials and methods: Lasers of 808, 980 and 1064 nm were used to heat cell culture media and a nail clipping. Trichophyton rubrum. T. interdigitale. Microsporum gypseum. Candida albicans. C. parapsilosis, and C. guilliermondii species were subcultured and subjected to laser treatments (808/980 nm: 9-27 J/cm(2), 6 ms, 12 × 12 or 12 × 50 mm and 1064 nm: 50-240 J/cm(2), 90 ms, 5-10 mm). After irradiation, the fungal elements were transferred onto agar plates using conventional and Drigalski spatulas and were incubated for 6 days. Results: The highest increase in temperature was found using a 980-nm laser with a pulse duration of 6 ms and a fluence of 27 J/cm(2). The histology work-up revealed a dissection of the nail plate from the nail bed tissue after laser irradiation. Growth inhibition was only found for C. guilliermondii and T. interdigitale. All other pathogens presented only reduced growth, and C. albicans growth was unaffected. Conclusions: This study demonstrates a clear thermal effect for linear scanning 980-nm and long-pulsed 1064-nm laser systems on either nail clippings or cell culture media. Complete pathogen growth impairment was achieved if temperatures were measured above 50 °C. The results for the 1064-nm system were almost comparable to 980 nm results. 23317432 Study of the scale formation mechanism on gold modified with an alkanethiol monolayer. Scaling is a problem in many industrial processes. To control and minimize it, it is important to understand the dynamics of the scale formation. In this paper, the scale formation was examined on two kinds of gold surfaces. One was a pure metallic gold surface, and the other was a gold surface modified with an alkanethiol self-assembled monolayer. A series of surface characterization experiments were performed to ensure a good understanding of the gold-thiol bond stability in a caustic solution. 23792428 Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles. The protease β-secretase 1 (Bace1) was identified through its critical role in production of amyloid-β peptides (Aβ), the major component of amyloid plaques in Alzheimer's disease. Bace1 is considered a promising target for the treatment of this pathology, but processes additional substrates, among them Neuregulin-1 (Nrg1). Our biochemical analysis indicates that Bace1 processes the Ig-containing β1 Nrg1 (IgNrg1β1) isoform. We find that a graded reduction in IgNrg1 signal strength in vivo results in increasingly severe deficits in formation and maturation of muscle spindles, a proprioceptive organ critical for muscle coordination. Further, we show that Bace1 is required for formation and maturation of the muscle spindle. Finally, pharmacological inhibition and conditional mutagenesis in adult animals demonstrate that Bace1 and Nrg1 are essential to sustain muscle spindles and to maintain motor coordination. Our results assign to Bace1 a role in the control of coordinated movement through its regulation of muscle spindle physiology, and implicate IgNrg1-dependent processing as a molecular mechanism. 23787783 A new series of heteroleptic oxidovanadium(iv) compounds with phenanthroline-derived co-ligands: selective Trypanosoma cruzi growth inhibitors. Searching for prospective metal-based drugs for the treatment of Chagas disease, a new series of ten mixed-ligand oxidovanadium(iv) complexes, [V(IV)O(L-2H)(NN)], where L is a tridentate salicylaldehyde semicarbazone derivative () and NN is either 5-amine-1,10-phenanthroline (aminophen) or 5,6-epoxy-5,6-dihydro-1,10-phenanthroline (epoxyphen), were synthesized. The compounds were characterized in the solid state and in solution. EPR spectroscopy suggests that the NN ligands act as bidentate through both nitrogen donor atoms in an axial-equatorial mode. The stability of the complexes in solution was investigated by EPR and (51)V-nuclear magnetic resonance spectroscopies. The complexes were evaluated in vitro for their activities against Trypanosoma cruzi (T. cruzi), the parasite responsible for the disease, and their selectivity was analyzed using J-774 murine macrophages, as a mammalian model. All the complexes are more active than both the reference drug Nifurtimox and the previously reported [V(IV)O(L-2H)(NN)] complexes. In general they are more active than the corresponding free NN ligands. Complexation led to highly increased selectivities towards the parasite. In addition, the lipophilicity of the compounds was determined and correlated with the observed activity in order to perform a QSAR (quantitative structure-activity relationship) study. A clear quadratic correlation is found. This study also confirms the influence of the structure of the co-ligand on the anti-T. cruzi effect. To get insight into the mechanism of action of the compounds, the changes in biochemical pathways promoted by two of the most active and most selective complexes are studied by analyzing a few of the parasite excreted metabolites by (1)H NMR spectroscopy. The combined information suggests that the mitochondrion could be a target for these complexes. Furthermore, DNA was preliminarily evaluated as a potential target by using atomic force microscopy (AFM), which showed that the complexes display an ability to interact with this biomolecule. 23883874 Rho-Kinase Activation in Patients With Heart Failure. Background: Heart failure (HF) is a complex clinical syndrome, resulting from structural and/or functional cardiac disease. The aim of this study was to determine whether the activity of Rho-kinase, which has been identified as an important therapeutic target of cardiovascular disease, is enhanced in HF patients. Methods and Results: Total and phosphorylated forms of myosin binding subunit (t-MBS and p-MBS), a substrate of Rho-kinase, were measured on western blotting in circulating leukocytes, and the p-MBS/t-MBS ratio was defined as an index of systemic Rho-kinase activity. First, during the time-course of acute HF (n=12), Rho-kinase activity was significantly elevated in the acute phase compared to the chronic phase (1.19±0.06 vs. 0.97±0.04, P<0.05). Next, Rho-kinase activity was examined in 30 controls and 130 chronic HF patients (cardiomyopathy, n=57; valvular heart disease, n=35; ischemic heart disease [IHD], n=33; and others, n=5). As compared with the controls, Rho-kinase activity was significantly elevated in the total HF group (1.14±0.02 vs. 0.77±0.05, P<0.0001) and in each underlying heart disease (P<0.05 each). Importantly, in the high-risk non-IHD group, Rho-kinase activity was significantly associated with plasma brain nutriuretic peptide level. Finally, p-MBS was expressed in myocardial biopsy samples (immunohistochemistry) in chronic HF patients (n=36), independent of Rho-kinase activity in leukocytes. Conclusions: Rho-kinase is activated in HF patients, suggesting that it could be a new therapeutic target of the disorder. 23965061 Private homes should adopt NHS system. A former A&E nurse is calling on the private care home sector to monitor residents' deterioration by adopting the NHS National Early Warning Score. 23814239 The relevance of the radiological signs of acetabular retroversion among patients with femoroacetabular impingement. Orthopaedic surgeons have accepted various radiological signs to be representative of acetabular retroversion, which is the main characteristic of focal over-coverage in patients with femoroacetabular impingement (FAI). Using a validated method for radiological analysis, we assessed the relevance of these signs to predict intra-articular lesions in 93 patients undergoing surgery for FAI. A logistic regression model to predict chondral damage showed that an acetabular retroversion index (ARI) > 20%, a derivative of the well-known cross-over sign, was an independent predictor (p = 0.036). However, ARI was less significant than the Tönnis classification (p = 0.019) and age (p = 0.031) in the same model. ARI was unable to discriminate between grades of chondral lesions, while the type of cam lesion (p = 0.004) and age (p = 0.047) were able to. Other widely recognised signs of acetabular retroversion, such as the ischial spine sign, the posterior wall sign or the cross-over sign were irrelevant according to our analysis. Regardless of its secondary predictive role, an ARI > 20% appears to be the most clinically relevant radiological sign of acetabular retroversion in symptomatic patients with FAI. 23831274 How the microenvironment wires the natural history of chronic lymphocytic leukemia. The investigation on the mechanisms that govern the development and progression of cancer is constantly swaying between "seed" and "soil". Chronic lymphocytic leukemia (CLL) makes no exception. Its natural history, including response to treatment and drug resistance, is determined both by causal and influential genes and by the relationships that leukemic cells entertain with their supportive microenvironments. Therefore dissecting the role of microenvironment may provide new strategies of diagnosis and treatment. CLL, though phenotypically homogeneous, is clinically heterogeneous and despite major therapeutic advances remains incurable. Conceivably the host of new non-genotoxic drugs that operate at the forefront between tumor cells and their milieu will modify the present therapeutic perspective by re-shaping the tumor cell/microenvironment cross talk. 23909511 Strongyloides cebus (Nematoda: Strongyloididae) in Lagothrix cana (Primates: Atelidae) from the Brazilian Amazon: Aspects of clinical presentation, anatomopathology, treatment and parasitic biology. Abstract Seven cases of parasitism by Strongyloides cebus were identified in Lagothrix cana from Brazil. Aspects of the clinical presentation, treatment, pathology and parasitic biology of these infections are described. Moderate to severe disease was observed, requiring hospitalization of three primates, and catarrhal enteritis was the most common clinical sign described. One L. cana individual died, for which ulcerative enteritis was the major finding upon histopathological analysis. The use of ivermectin in these atelids was safe and effective against the parasite. Parallel attempts to experimentally infect gerbils with the parasite failed. L. cana is presented as a new host for S. cebus, and we discuss evidence that Strongyloides infections are common in nonhuman primates under free-living conditions and even more prevalent in captive animals, likely representing a neglected problem. 23089081 Color stability of experimental composites containing different photoinitiators. To evaluate the color stability (ΔE) of experimental composites containing different photoinitiators when submitted to accelerated artificial ageing (AAA). Thirty test specimens were made in a Teflon matrix (8mm×2mm), using an experimental composite (n=10) with the same monomer composition and particle size, but varying photoinitiator used: Group CQ (0.4% Camphorquinone), Group PPD (0.4% 1-Phenyl-1,2 Propanodione) and Group CQ+PPD (0.2% CQ+0.2% PPD). The samples were light activated (QTH - Ultralux - Dabi Atlante - 40s) and polished before performing the initial color readouts (EasyShade - Vita). Next, they were submitted to AAA for 300h, after which final color readouts were made. The results (1-way ANOVA - Tukey - p<0.05) demonstrated that all the groups presented color alteration above the clinically acceptable level (ΔE≥3.3), however, with no statistically significant difference among them (p>0.05). Analysis of Δb demonstrated increase in the values of this coordinate, indicating yellowing in all groups. It was concluded that the type of photoinitiator, which presented a tendency towards yellowing, did not interfere in the color stability of composites submitted to AAA. Alternative photoinitiators have been extensively studied since Camphorquinone presents a yellowish color, which compromises the aesthetic performance of composites, especially the lighter-shade ones. 23895475 Review of the evidence for the potential impact and feasibility of substituting saturated fat in the New Zealand diet. Objective: To estimate the potential impact on cardiovascular health of modifying dietary intake of saturated fat across the New Zealand population, and whether this would be appropriate and feasible. Methods: First, a literature review of meta-analyses was conducted to estimate the magnitude of reduction in risk for cardiovascular events in response to a reduction in dietary saturated fat intake (with or without substitution with other macronutrients). Second, data from the New Zealand Adult Nutrition Survey 2008/09 were used to determine whether a change to the population's dietary fat intake would be warranted and feasible. Results: Five relevant meta-analyses were identified. No significant association between saturated fat intake alone and cardiovascular disease was found. However, the incidence of cardiovascular disease events was less when dietary saturated fats were replaced with polyunsaturated fats, reducing the risk of cardiovascular events by about 10%. Compared with nutritional guidelines, New Zealanders' current saturated fat intake is excessive while polyunsaturated fat intake is inadequate; both would be corrected by a substitution of 5% of daily energy intake. Conclusions: Replacing 5% of daily energy consumed as saturated fat with polyunsaturated fats would be expected to reduce cardiovascular events by about 10%. Implications: In order to achieve the population-wide dietary fat modifications needed to improve cardiovascular health for New Zealanders, a public health strategy (e.g. fiscal, regulatory and/or educational interventions) must be implemented. Further work is needed to establish the cost-effectiveness of the various strategies. 23684518 Variants of hepatic arterial supply in a Caribbean population: a computed tomography based study. To evaluate the spectrum of hepatic arterial variants in unselected patients undergoing computed tomography (CT) of the abdomen at the main regional referral centre in the northern Anglophone Caribbean. Two radiologists independently reviewed 309 CT angiographic studies performed over 2 years between 1 July 2010 and 30 June 2012 at a regional hepatobiliary referral centre for the Northern Caribbean. The anatomical variations were described according to a conventional classification proposed by Michels et al. In this Caribbean population, the majority of patients had conventional Michels' type 1 vascular anatomy (63.4%). However, a statistically significantly greater incidence of Michels' type 2 variations (20.4%) were found than that reported in the international literature and a lower incidence of type 3 (5.2%), type 6 (0.6%), and type 9 (0) patterns than previously reported. One case with variations not previously described in this classification was also encountered. Although 63.4% of persons in a Caribbean population have conventional vascular anatomy, the distribution of anatomical variants is quite different to that seen in North American and European centres. Interventional radiologists and hepatobiliary surgeons practicing in the Caribbean must be cognizant of these differences in order to minimize morbidity and mortality during invasive procedures. 23157633 Transcranial brain stimulation in schizophrenia: targeting cortical excitability, connectivity and plasticity. Transcranial magnetic stimulation (TMS) is a very popular tool used within neuroscience. This and other associated techniques allow the in vivo investigation of cortical excitability, cortical connectivity and cortical plasticity. Schizophrenia is a brain disorder and various theories other than the dopamine hypothesis have been developed to describe its underlying neurobiology. Supported by animal and post mortem studies, findings from TMS studies indicate that schizophrenia is a disease of reduced cortical inhibition and impaired intra- and intercortical connectivity. Further studies using repetitive TMS and other plasticity-inducing techniques have shown that cortical plasticity is altered in schizophrenia patients, supporting the recently discussed plasticity deficiency theory of schizophrenia. This review gives an introduction to the most frequently applied techniques, describes findings in schizophrenia patients and discusses these findings with regard to the neurotransmitters and associated receptors involved. In summary, there is emerging evidence of an important pathophysiological interplay between reduced inhibition, impaired connectivity and reduced plasticity in schizophrenia patients. Gamma-aminobutyric-acid-receptors and glutamtergic N-Methyl-D-aspartic-acid-receptors are most likely to be involved in this complex interplay, which may reflect a disturbed signal-to-noise ratio in schizophrenia patients. This review will discuss this issue with regard to the available treatment options and will give implications for future research and therapeutic strategies regarding disinhibition and neuroplasticity in schizophrenia. 23623260 The sonographic appearances of breast implant rupture. Implant rupture is a common late complication of breast implant procedures. Ruptures are often silent and difficult to diagnose clinically. This review demonstrates normal appearances and sonographic signs of implant rupture. Breast sonologists should be aware of these signs and pitfalls in interpretation when imaging breast implants. 22331665 Prefrontal dopaminergic receptor abnormalities and executive functions in Parkinson's disease. The main pattern of cognitive impairments seen in early to moderate stages of Parkinson's disease (PD) includes deficits of executive functions. These nonmotor complications have a significant impact on the quality of life and day-to-day activities of PD patients and are not effectively managed by current therapies, a problem which is almost certainly due to the fact that the disease extends beyond the nigrostriatal system. To investigate the role of extrastriatal dopamine in executive function in PD, PD patients and a control group were studied with positron-emission-tomography using a high-affinity dopamine D2/D3 receptor tracer, [(11) C]FLB-457. All participants were scanned twice while performing an executive task and a control task. Patients were off medication for at least 12 h. The imaging analysis revealed that parkinsonian patients had lower [(11) C]FLB-457 binding than control group independently of task conditions across different brain regions. Cognitive assessment measures were positively correlated with [(11) C]FLB-457 binding in the bilateral dorsolateral prefrontal cortex and anterior cingulate cortex only in control group, but not in PD patients. Within the control group, during the executive task (as compared to control task), there was evidence of reduced [(11) C]FLB-457 binding (indicative of increased dopamine release) in the right orbitofrontal cortex. In contrast, PD patients did not show any reduction in binding during the executive task (as compared with control task). These findings suggest that PD patients present significant abnormalities in extrastriatal dopamine associated with executive processing. These observations provide important insights on the pathophysiology of cognitive dysfunction in PD. 23925310 Water detection by "turn on" fluorescence of the quinone-containing complexes [Ru(phen)2(1,10-phenanthroline-5,6-dione)(2+)] and [Ru(phenanthroline-5,6-dione)3](2+) Addition of water to the quinone functions in [Ru(phen)2(pdn)](2+) () and [Ru(pdn)3](2+) () (where phen = 1,10-phenanthroline and pdn = 1,10-phenanthroline-5,6-dione) turns on fluorescence at 605 nm, as formation of the geminal diol eliminates the predominant quinone-based non-radiative decay pathway and gives rise to a long-lived (3)MLCT state similar in nature to that seen in [Ru(phen)3](2+). Using NMR, the equilibrium constant for the hydration reaction of in acetonitrile was determined to be 0.0253. From this data and experimental fitting of the luminescent titration data, the equilibrium constant for of 1.62 × 10(-5) and emission yields for hydrated and were determined. Interestingly, all three quinone functions must be hydrated in for luminescence, which is why the equilibrium constants vary so much. The 'turn on' luminescence allows for a very sensitive detection of water in aprotic solvents such as acetonitrile. 23489521 The use of insulin analogues in pregnancy. Excellent glycaemic control is essential in pregnancy to optimise maternal and foetal outcomes. The aim of this review is to assess the efficacy and safety of insulin analogues in pregnancy. Insulin lispro and insulin aspart are safe in pregnancy and may improve post-prandial glycaemic control in women with type 1 diabetes. However, a lack of data indicating improved foetal outcomes would suggest that there is no imperative to switch to a short-acting analogue where the woman's diabetes is well controlled with human insulin. There are no reports of the use of insulin glulisine in pregnancy and so its use cannot be recommended. Most studies of insulin glargine in pregnancy are small, retrospective and include women with pre-existing diabetes and gestational diabetes. There appear to be no major safety concerns and so it seems reasonable to continue insulin glargine if required to achieve excellent glycaemic control. A head-to-head comparison between insulin detemir and NPH insulin in women with type 1 diabetes showed that while foetal outcomes did not differ, fasting plasma glucose improved with insulin detemir without an increased incidence of hypoglycaemia. The greater evidence base supports the use of insulin detemir as the first line long-acting analogue in pregnancy but the lack of definitive foetal benefits means that there is no strong need to switch a woman who is well controlled on NPH insulin. There seems little justification in using long acting insulin analogues in women with gestational diabetes or type 2 diabetes where the risk of hypoglycaemia is low. 23969075 Increased level of interleukin-13, but not interleukin-4 and interferon-γ in chronic rhinosinusitis with nasal polyps. This study was performed to investigate the serum level of interleukin (IL)-13, IL-4, and interferon (IFN)-γ in chronic rhinosinusitis with nasal polyps (CRSwNP) and subsequent inflammation pattern and comorbidities including asthma and aspirin intolerance. A case-control study was conducted on 60 adult patients with CRSwNP with mean age of 37.7±12.7 (ranging from 18 to 70) years, and on 20 healthy controls. Serum levels of IL-13, IL-4, and IFN-γ were assessed, using enzyme-linked immunosorbent assay to be compared between case and control groups. Serum level of total immunoglobulin (Ig) E was also assessed in the patients with CRSwNP. Serum level of IL-13 in the patients with CRSwNP was significantly higher than the controls (0.98±1.56 vs. 0.34±0.16 pg/ml, respectively, p=0.002). IL-4 and IFN-γ did not differ significantly between the two groups. Total IgE level was significantly increased in the patients with CRSwNP, compared to the normal values (301.43±516.54 IU/ml, p=0.033). Among the patients with CRSwNP, 12/60 (20%) had aspirin intolerance and 44/60 (73.3%) had asthma. IgE was also higher in asthmatics than non-asthmatics patients (364.9±586.6 vs. 126.7±135.7, respectively, p=0.015). Patients with aspirin intolerance had higher levels of IFN-γ (4.7±1.4 vs. 4.1±0.6, respectively, p=0.022). IL-13 with high level of total IgE was observed in the patients with CRSwNP, which predisposes them to have concomitant asthma. IFN-γ seems to be down-regulated in the patients with CRSwNP, but could be over-expressed in the presence of aspirin intolerance. 23830323 Dietary Sources of Sodium Intake in Brazil in 2008-2009. Information on the main dietary sources of sodium is essential for developing public health strategies to reduce sodium intake. This study aimed to describe sodium intake according to sex, age, and income and identify the main dietary sources of sodium in Brazil. In total, 34,003 subjects aged 10 years and older participated in the first Brazilian National Dietary Survey, conducted in 2008-2009. Food was classified according to the sodium profile into 31 groups based on a 1-day food record. The daily per capita intake of sodium (mg/day) and sodium density (mg/100 g) were estimated for each food group and stratified by sex, age, and per capita income quartile. The average daily intake of sodium was 3,190 mg/day. The sodium density of the diet increased with age and income (P<0.05). Food groups with the highest densities for both sexes and across all income quartiles included salty preserved meats (997 mg/100 g), processed meats (974 mg/100 g), cheeses (883 mg/100 g), crackers (832 mg/100 g), sandwiches (800 mg/100 g), pizza (729 mg/100 g), and breads (646 mg/100 g), as well as oils, spreads, sauces, and condiments (804 mg/100 g). Altogether, these food groups contributed to 811 mg/day of sodium, which is more than half of the recommended daily sodium intake. Mean sodium intake in Brazil exceeded the tolerable upper intake level of 2,300 mg/day. Processed food contributed to half of the recommended intake and should be targeted by future public health policies aiming at reducing total sodium intake. 23689791 A simple model that identifies potential effects of sea-level rise on estuarine and estuary-ecotone habitat locations for salmonids in Oregon, USA. Diadromous aquatic species that cross a diverse range of habitats (including marine, estuarine, and freshwater) face different effects of climate change in each environment. One such group of species is the anadromous Pacific salmon (Oncorhynchus spp.). Studies of the potential effects of climate change on salmonids have focused on both marine and freshwater environments. Access to a variety of estuarine habitat has been shown to enhance juvenile life-history diversity, thereby contributing to the resilience of many salmonid species. Our study is focused on the effect of sea-level rise on the availability, complexity, and distribution of estuarine, and low-freshwater habitat for Chinook salmon (Oncorhynchus tshawytscha), steelhead (anadromous O. mykiss), and coho salmon (O. kisutch) along the Oregon Coast under future climate change scenarios. Using LiDAR, we modeled the geomorphologies of five Oregon estuaries and estimated a contour associated with the current mean high tide. Contour intervals at 1- and 2-m increments above the current mean high tide were generated, and changes in the estuary morphology were assessed. Because our analysis relied on digital data, we compared three types of digital data in one estuary to assess the utility of different data sets in predicting the changes in estuary shape. For each salmonid species, changes in the amount and complexity of estuarine edge habitats varied by estuary. The simple modeling approach we applied can also be used to identify areas that may be most amenable to pre-emptive restoration actions to mitigate or enhance salmonid habitat under future climatic conditions. 23582237 Performance of Sino-implant (II) in routine service delivery in Madagascar. Sino-implant (II) is a low-cost subdermal contraceptive implant containing levonorgestrel that is currently labeled for 4 years of use. Widely used in China and Indonesia, it has been little studied elsewhere. We conducted a prospective study of Sino-implant (II) use by women in Madagascar. We enrolled a total of 621 women 18 or older who had Sino-implant (II) inserted on day of enrollment, some in fixed clinical sites, and some at outreach sites. Half of the women were scheduled for follow-up visits at 3 months and at 12 months postinsertion (active follow-up cohort); the other half were advised to return if they desired care for any problem, thought they were pregnant or wanted the implants removed (passive surveillance cohort). No insertion complications were reported. A total of 384 women returned for an earlier visit, and 351 returned for a later visit, for a total of 419 woman-years of observation. No postinsertion pregnancies or serious adverse events were observed. Twenty-eight implant removals were reported by 12 months, a cumulative removal probability of 7.3 per 100 women. Acceptability of the implants was very high, as was satisfaction with clinic services. This is the first report on the performance of Sino-implant (II) from outside China and Indonesia and among the first in the English-language literature. These initial data from Madagascar indicate a favorable level of safety, effectiveness and acceptability during the first year of use. 23820975 The role of transforming growth factor β1 in fractional laser resurfacing with a carbon dioxide laser. The aim of this study was to investigate the role of transforming growth factor β1 in mechanisms of cutaneous remodeling induced by fractional carbon dioxide laser treatment. The dorsal skin of Kunming mice was exposed to a single-pass fractional CO2 laser treatment. Biopsies were taken at 1 h and at 1, 3, 7, 14, 21, 28, and 56 days after treatment. Transforming growth factor (TGF) β1 expression in skin samples was evaluated by ELISA, dermal thickness by hematoxylin-eosin staining, collagen and elastic fibers by Ponceau S and Victoria blue double staining, and types I and III collagens by ELISA. The level of TGF β1 in the laser-treated areas of skin was significantly increased compared with that in the control areas on days 1 (p < 0.05), 3 (p < 0.01), and 7 (p < 0.05) and then decreased by day 14 after treatment, at which time it had returned to the baseline level. Dermal thickness and the amount of type I collagen of the skin of the laser-treated areas had increased significantly (p < 0.05) compared with that in control areas on days 28 and 56. Fibroblast proliferation showed a positive correlation with TGF β1 expression during the early stages (r = 0.789, p < 0.01), and there was a negative correlation between the level of TGF β1 and type I collagen in the late stages, after laser treatment (r = -0.546, p < 0.05). TGF β1 appears to be an important factor in fractional laser resurfacing. 23519129 Production, purification and characterization of a novel thermotolerant endoglucanase (CMCase) from Bacillus strain isolated from cow dung. In an attempt to screen out cellulase producing bacteria from herbivorous animal fecal matter it was possible to isolate a potent bacterium from cow dung. The bacterium was identified as Bacillus sp. using 16S rDNA based molecular phylogenetic approach. The effect of different agricultural wastes, paper wastes and carboxymethyl cellulose on endoglucanase production was tested and was found to produce maximally at 8% carboxymethyl cellulose. The endoglucanase was precipitated by ammonium sulfate saturation and purified by DEAE- Sepharose column. The purification was achieved 8.5 fold from the crude extract with a yield of 68.1%. The molecular weight of the protein was determined to be 97 kDa by SDS-PAGE. The enzymatic activity was moderately reduced by detergents (SDS, Tween-80), metal ions (MnCl2, ZnCl2) and EDTA. The endoglucanase was stable between pH 5.0 - 9.0 and temperature between 20-70°C with optimal activity at pH 7.0 and temperature 50°C. The apparent Km value of the enzyme for the substrate carboxymethyl cellulose was recorded to be 0.25 mg/ml. The endoglucanase was stable in the presence of commercial detergents such as Ariel, Surf Excel and Tide, indicated might be of potential applications in detergent industry. The enzyme from this strain could also be applied in bioconversion of lignocellulosic biomass into fermentable sugars. 23881349 A radiological classification system for talocalcaneal coalition based on a multi-planar imaging study using CT and MRI. To develop a radiological classification system for talocalcaneal coalition suitable for adults. A retrospective review was performed on patients diagnosed with talocalcaneal coalition from July 2001 to November 2011. Based on the cartilaginous or bony nature, facet joint orientation and bony structure morphology, we classified talocalcaneal coalitions into four types: I (linear with or without posterior hooking), II (talar overgrowth), III (calcaneal overgrowth) and IV (complete osseous). Seventy feet (59 patients) with talocalcaneal coalition were evaluated by CT (61/70 feet) using multi-planar reformation and/or magnetic resonance imaging (43/70 feet). Type I, II, III and IV coalitions were detected in 45 (64 %), 10 (14 %), 13 (19 %), and 2 feet (3 %), respectively. Fracture fragments were observed in 16 feet (seven Type I and nine Type III coalitions) with hooked or overgrown calcanei and in one foot in the talus (Type I). Eleven patients had bilateral talocalcaneal coalitions; ten patients had coalitions of the same type and one had both Type I and Type III coalitions. Among 48 patients with unilateral involvement, the left and right feet were affected in 26 and 22 patients, respectively. A classification system for talocalcaneal coalition based on multi-planar imaging studies was developed. • A classification system for talocalcaneal coalition based on multi-planar imaging was developed. • The relative frequencies of different talocalcaneal coalition types were determined. • Fracture fragments were easily distinguished and frequently originated from the calcaneus. • Fracture fragments were mostly associated with Type I (linear) with posterior hooking and Type III (calcaneal overgrowth). 23732924 Power generation by packed-bed air-cathode microbial fuel cells. Catalysts and catalyst binders are significant portions of the cost of microbial fuel cell (MFC) cathodes. Many materials have been tested as aqueous cathodes, but air-cathodes are needed to avoid energy demands for water aeration. Packed-bed air-cathodes were constructed without expensive binders or diffusion layers using four inexpensive carbon-based materials. Cathodes made from activated carbon produced the largest maximum power density of 676±93mW/m(2), followed by semi-coke (376±47mW/m(2)), graphite (122±14mW/m(2)) and carbon felt (60±43mW/m(2)). Increasing the mass of activated carbon and semi-coke from 5 to ⩾15g significantly reduced power generation because of a reduction in oxygen transfer due to a thicker water layer in the cathode (∼3 or ∼6cm). These results indicate that a thin packed layer of activated carbon or semi-coke can be used to make inexpensive air-cathodes for MFCs. 23435180 Hepatic and renal Bcrp transporter expression in mice treated with perfluorooctanoic acid. The breast cancer resistance protein (Bcrp) is an efflux transporter that participates in the biliary and renal excretion of drugs and environmental chemicals. Recent evidence suggests that pharmacological activation of the peroxisome proliferator activated receptor alpha (PPARα) can up-regulate the hepatic expression of Bcrp. The current study investigated the regulation of hepatic and renal Bcrp mRNA and protein in mice treated with the PPARα agonist perfluorooctanoic acid (PFOA) and the ability of PFOA to alter human BCRP function in vitro. Bcrp mRNA and protein expression were quantified in the livers and kidneys of male C57BL/6 mice treated with vehicle or PFOA (1 or 3mg/kg/day oral gavage) for 7 days. PFOA treatment increased liver weights as well as the hepatic mRNA and protein expression of the PPARα target gene, cytochrome P450 4a14. Compared to vehicle-treated control mice, PFOA increased hepatic Bcrp mRNA and protein between 1.5- and 3-fold. Immunofluorescent staining confirmed enhanced canalicular Bcrp staining in liver sections from PFOA-treated mice. The kidney expression of cytochrome P450 4a14 mRNA, but not Bcrp, was increased in mice treated with PFOA. Micromolar concentrations of PFOA decreased human BCRP ATPase activity and inhibited BCRP-mediated transport in inverted membrane vesicles. Together, these studies demonstrate that PFOA induces hepatic Bcrp expression in mice and may inhibit human BCRP transporter function at concentrations that exceed levels observed in humans. 23838883 Environmental arsenic exposure, selenium and sputum alpha-1 antitrypsin. Exposure to arsenic in drinking water is associated with increased respiratory disease. Alpha-1 antitrypsin (AAT) protects the lung against tissue destruction. The objective of this study was to determine whether arsenic exposure is associated with changes in airway AAT concentration and whether this relationship is modified by selenium. A total of 55 subjects were evaluated in Ajo and Tucson, Arizona. Tap water and first morning void urine were analyzed for arsenic species, induced sputum for AAT and toenails for selenium and arsenic. Household tap-water arsenic, toenail arsenic and urinary inorganic arsenic and metabolites were significantly higher in Ajo (20.6±3.5 μg/l, 0.54±0.77 μg/g and 27.7±21.2 μg/l, respectively) than in Tucson (3.9±2.5 μg/l, 0.16±0.20 μg/g and 13.0±13.8 μg/l, respectively). In multivariable models, urinary monomethylarsonic acid (MMA) was negatively, and toenail selenium positively associated with sputum AAT (P=0.004 and P=0.002, respectively). In analyses stratified by town, these relationships remained significant only in Ajo, with the higher arsenic exposure. Reduction in AAT may be a means by which arsenic induces respiratory disease, and selenium may protect against this adverse effect.Journal of Exposure Science and Environmental Epidemiology advance online publication, 10 July 2013; doi:10.1038/jes.2013.35. 23828305 Clinical Outcomes of Indwelling Pleural Catheter-Related Pleural Infections: an international multicenter study. Indwelling pleural catheters (IPC) offer effective control of malignant pleural effusion (MPE)s. IPC-related infection is uncommon but remains a major concern. Individual IPC centers see few infections and previous reports lack sufficient numbers and detail. This study combined the experience of 11 centers from North America, Europe and Australia to describe the incidence, microbiology, managements and clinical outcomes of IPC-related pleural infection. A multicenter retrospective review of 1021 patients with IPC; all had confirmed MPE. Only 50 (4.7%) patients developed an IPC-related pleural infection; most (94%) were successfully controlled with antibiotics (62% intravenously). One death (2%) directly resulted from the infection, whilst two (4%) patients had ongoing infectious symptoms when they died of cancer progression (3/1021 = 0.29%). Staphylococcus aureus was the causative organism in 48% of cases. Infections from gram-negative organisms were associated with an increased need for continuous antibiotics or death (60% vs 15% in gram-positive and 25% mixed infections, p=0.02). The infections in the majority (54%) of cases were managed successfully without removing the IPC. Post-infection pleurodesis developed in 31 (62%) patients, especially those infected with Staphylococci (79% vs 45% with non-Staphylococcal infections, p=0.04). The incidence of IPC-related pleural infection was low. The overall mortality risk from pleural infection in IPC-treated patients was only 0.28%. Antibiotics should cover S. aureus and Gram-negative organisms until microbiology is confirmed. Post-infection pleurodesis is common and often allows removal of IPC. Heterogeneity in management is common and future studies to define the optimal treatment strategies are needed. 23825157 Motile sperm organelle morphology examination (MSOME) and sperm head vacuoles: state of the art in 2013. BACKGROUND Approximately 10 years after the first publication introducing the motile sperm organelle morphology examination (MSOME), many questions remained about sperm vacuoles: frequency, size, localization, mode of occurrence, biological significance and impact on male fertility potential. Many studies have tried to characterize sperm vacuoles, to determine the sperm abnormalities possibly associated with vacuoles, to test the diagnostic value of MSOME for male infertility or to question the benefits of intracytoplasmic morphologically selected sperm injection (IMSI). METHODS We searched PubMed for articles in the English language published in 2001-2012 regarding human sperm head vacuoles, MSOME and IMSI. RESULTS A bibliographic analysis revealed consensus for the following findings: (i) sperm vacuoles appeared frequently, often multiple and preferentially anterior; (ii) sperm vacuoles and sperm chromatin immaturity have been associated, particularly in the case of large vacuoles; (iii) teratozoospermia was a preferred indication of MSOME and IMSI. CONCLUSION The high-magnification system appears to be a powerful method to improve our understanding of human spermatozoa. However, its clinical use remains unclear in the fields of male infertility diagnosis and assisted reproduction techniques (ARTs). 23594591 Magnetic resonance imaging-defined areas of microvascular obstruction after acute myocardial infarction represent microvascular destruction and haemorrhage. Lack of gadolinium-contrast wash-in on first-pass perfusion imaging, early gadolinium-enhanced imaging, or late gadolinium-enhanced (LGE) cardiovascular magnetic resonance (CMR) imaging after revascularized ST-elevation myocardial infarction (STEMI) is commonly referred to as microvascular obstruction (MVO). Additionally, T2-weighted imaging allows for the visualization of infarct-related oedema and intramyocardial haemorrhage (IMH) within the infarction. However, the exact histopathological correlate of the contrast-devoid core and its relation to IMH is unknown. In eight Yorkshire swine, the circumflex coronary artery was occluded for 75 min by a balloon catheter. After 7 days, CMR with cine imaging, T2-weighted turbospinecho, and LGE was performed. Cardiovascular magnetic resonance images were compared with histological findings after phosphotungstic acid-haematoxylin and anti-CD31/haematoxylin staining. These findings were compared with CMR findings in 27 consecutive PCI-treated STEMI patients, using the same scanning protocol. In the porcine model, the infarct core contained extensive necrosis and erythrocyte extravasation, without intact vasculature and hence, no MVO. The surrounding-gadolinium-enhanced-area contained granulation tissue, leucocyte infiltration, and necrosis with morphological intact microvessels containing microthrombi, without erythrocyte extravasation. Areas with IMH (median size 1.92 [0.36-5.25] cm(3)) and MVO (median size 2.19 [0.40-4.58] cm(3)) showed close anatomic correlation [intraclass correlation coefficient (ICC) 0.85, r = 0.85, P = 0.03]. Of the 27 STEMI patients, 15 had IMH (median size 6.60 [2.49-9.79] cm(3)) and 16 had MVO (median size 4.31 [1.05-7.57] cm(3)). Again, IMH and MVO showed close anatomic correlation (ICC 0.87, r = 0.93, P < 0.001). The contrast-devoid core of revascularized STEMI contains extensive erythrocyte extravasation with microvascular damage. Attenuating the reperfusion-induced haemorrhage may be a novel target in future adjunctive STEMI treatment. 23288094 Perspectives on the reaction force constant. A synchronous, concerted chemical process is rigorously divided by the reaction force F(R), the negative gradient of V(R), into "reactant" and "product" regions which are dominated by structural changes and an intervening "transition" region which is electronically intensive. The reaction force constant κ(R), the second derivative of V(R), is negative throughout the transition region, not just at the nominal transition state, at which κ(R) has a minimum. This is consistent with experimental evidence that there is a transition region, not simply a specific point. We show graphically that significant nonsynchronicity in the process is associated with the development of a maximum of κ(R) in the transition region, which increases as the process becomes more nonsynchronous. (We speculate that for a nonconcerted process this maximum is actually positive.) Thus, κ(R) can serve as an indicator of the level of nonsynchronicity. 23529629 Magnetic resonance diffusion tensor imaging metrics in perilesional white matter among children with periventricular nodular gray matter heterotopia. Despite pharmacological and surgical interventions, some children with periventricular nodular heterotopia (PNH) remain refractory to treatment, which suggests more diffuse pathology potentially involving perilesional white matter. The purpose of this study was to evaluate MR diffusion tensor imaging (MRDTI) metrics within perilesional white matter in children with PNH. Six children with PNH (four boys; average age 3.2 years, range 2 months to 6 years) were studied with MRDTI at 3 T. Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were quantified within perilesional white matter at distances of 5 mm, 10 mm, 15 mm, and 20 mm from focal areas of PNH and compared to location-matched ROIs in six healthy control patients (two boys, average age 3.3 years, range 2-6 years). Statistical significance was set at an overall level of α = 0.05, corrected for multiple comparisons. Perilesional white matter showed significantly decreased fractional anisotropy and elevated mean and radial diffusivity at all evaluated distances. No significant differences in axial diffusivity were detected at any distance. PNH is associated with microstructural white matter abnormalities as indicated by abnormal perilesional MRDTI metrics detectable at least 20 mm from visible nodular lesions. 23798434 Vibrational imaging of newly synthesized proteins in live cells by stimulated Raman scattering microscopy. Synthesis of new proteins, a key step in the central dogma of molecular biology, has been a major biological process by which cells respond rapidly to environmental cues in both physiological and pathological conditions. However, the selective visualization of a newly synthesized proteome in living systems with subcellular resolution has proven to be rather challenging, despite the extensive efforts along the lines of fluorescence staining, autoradiography, and mass spectrometry. Herein, we report an imaging technique to visualize nascent proteins by harnessing the emerging stimulated Raman scattering (SRS) microscopy coupled with metabolic incorporation of deuterium-labeled amino acids. As a first demonstration, we imaged newly synthesized proteins in live mammalian cells with high spatial-temporal resolution without fixation or staining. Subcellular compartments with fast protein turnover in HeLa and HEK293T cells, and newly grown neurites in differentiating neuron-like N2A cells, are clearly identified via this imaging technique. Technically, incorporation of deuterium-labeled amino acids is minimally perturbative to live cells, whereas SRS imaging of exogenous carbon-deuterium bonds (C-D) in the cell-silent Raman region is highly sensitive, specific, and compatible with living systems. Moreover, coupled with label-free SRS imaging of the total proteome, our method can readily generate spatial maps of the quantitative ratio between new and total proteomes. Thus, this technique of nonlinear vibrational imaging of stable isotope incorporation will be a valuable tool to advance our understanding of the complex spatial and temporal dynamics of newly synthesized proteome in vivo. 23958368 Upper respiratory infections. Upper respiratory infections (URIs) are infections of the mouth, nose, throat, larynx (voice box), and trachea (windpipe). This article outlines the epidemiology, etiology, diagnosis, and management of URIs, including nasopharyngitis (common cold), sinusitis, pharyngitis, laryngitis, and laryngotracheitis. 23877262 Li(+) ion doping: an approach for improving the crystallinity and upconversion emissions of NaYF4:Yb(3+), Tm(3+) nanoparticles. The application of upconversion nanoparticles (UCNPs), especially in vivo, has so far been hampered by their relatively low upconversion efficiency. In this work, a strategy of Li(+) doping was revisited with the aim of enhancing UV to blue UC luminescence of NaYF4:Yb(3+), Tm(3+) nanocrystals. We have demonstrated that the short wavelength UC emission bands were indeed significantly enhanced. Compared to lithium-free NaYF4:Yb(3+), Tm(3+), the UC emission intensities of 452 nm and 479 nm of the NPs co-doped with 7 mol% Li(+) ions were increased by 8 and 5 times, respectively. The mechanism of the enhancement was discussed and the improvement of the nanoparticles' crystallinity and the distortion of the local symmetry around the Tm(3+) ions, when the Li(+) ions were introduced, were confirmed to be the origin of the improvement. 23856996 The applicability of eGFR equations to different populations. The Cockcroft-Gault equation for estimating glomerular filtration rate has been learnt by every generation of medical students over the decades. Since the publication of the Modification of Diet in Renal Disease (MDRD) study equation in 1999, however, the supremacy of the Cockcroft-Gault equation has been relentlessly disputed. More recently, the Chronic Kidney Disease Epidemiology (CKD-EPI) consortium has proposed a group of novel equations for estimating glomerular filtration rate (GFR). The MDRD and CKD-EPI equations were developed following a rigorous process, are expressed in a way in which they can be used with standardized biomarkers of GFR (serum creatinine and/or serum cystatin C) and have been evaluated in different populations of patients. Today, the MDRD Study equation and the CKD-EPI equation based on serum creatinine level have supplanted the Cockcroft-Gault equation. In many regards, these equations are superior to the Cockcroft-Gault equation and are now specifically recommended by international guidelines. With their generalized use, however, it has become apparent that those equations are not infallible and that they fail to provide an accurate estimate of GFR in certain situations frequently encountered in clinical practice. After describing the processes that led to the development of the new GFR-estimating equations, this Review discusses the clinical situations in which the applicability of these equations is questioned. 23624299 Transforming acidic coiled-coil proteins (TACCs) in human cancer. Fine-tuned regulation of the centrosome/microtubule dynamics during mitosis is essential for faithful cell division. Thus, it is not surprising that deregulations in this dynamic network can contribute to genomic instability and tumorigenesis. Indeed, centrosome loss or amplification, spindle multipolarity and aneuploidy are often found in a majority of human malignancies, suggesting that defects in centrosome and associated microtubules may be directly or indirectly linked to cancer. Therefore, future research to identify and characterize genes required for the normal centrosome function and microtubule dynamics may help us gain insight into the complexity of cancer, and further provide new avenues for prognostic, diagnostics and therapeutic interventions. Members of the transforming acidic coiled-coil proteins (TACCs) family are emerging as important players of centrosome and microtubule-associated functions. Growing evidence indicates that TACCs are involved in the progression of certain solid tumors. Here, we will discuss our current understanding of the biological function of TACCs, their relevance to human cancer and possible implications for cancer management. 22943073 Managing potential conflict of interest in journal article publication. The issue of potential conflict of interest and its risk to professional integrity in journal article publication has been strongly debated in medical circles. Most medical journals adhere to international requirements for disclosure of potential conflict of interest. The debate on this issue in nursing, and specifically mental health nursing, has been neither prolific nor strong, despite nursing's potential to influence particular viewpoints about treatment and indeed to prescribe particular treatments; and nursing being a target for pharmaceutical industry marketing. The purpose of this paper is to raise debate about potential conflict of interest in journal article publication and to make recommendations for the management of such potential for this journal. 23880110 Some characteristics of amplified music through hearing aids. Hearing aids are a relatively non-invasive means of reducing the negative effects of hearing loss on an individual who does not require a cochlear implant. Music amplified through hearing aids has some interesting characteristics but high fidelity is not typically one of them. This poses a serious problem for the investigator who wants to perform research on music with hearing impaired individuals who wear hearing aids. If the signal at the tympanic membrane is somewhat distorted then this has consequences for the assessment of music processing when examining both the peripheral and the central auditory system. In this review article on the subject of hearing aids and music, some of the acoustical differences between speech and music will be described. Following this, a discussion about what hearing aids do well and also less well for music as an input will be presented. Finally, some recommendations are made about what can be done for hearing-impaired individuals who wear hearing aids to listen to music. This article is part of a Special Issue entitled . 23915211 Mobile Health in China: A Review of Research and Programs in Medical Care, Health Education, and Public Health. There are nearly 1 billion mobile phone subscribers in China. Health care providers, telecommunications companies, technology firms, and Chinese governmental organizations use existing mobile technology and social networks to improve patient-provider communication, promote health education and awareness, add efficiency to administrative practices, and enhance public health campaigns. This review of mobile health in China summarizes existing clinical research and public health text messaging campaigns while highlighting potential future areas of research and program implementation. Databases and search engines served as the primary means of gathering relevant resources. Included material largely consists of scientific articles and official reports that met predefined inclusion criteria. This review includes 10 reports of controlled studies that assessed the use of mobile technology in health care settings and 17 official reports of public health awareness campaigns that used text messaging. All source material was published between 2006 and 2011. The controlled studies suggested that mobile technology interventions significantly improved an array of health care outcomes. However, additional efforts are needed to refine mobile health research and better understand the applicability of mobile technology in China's health care settings. A vast potential exists for the expansion of mobile health in China, especially as costs decrease and increasingly sophisticated technology becomes more widespread. 23886941 Ligand signature in the membrane dynamics of single TrkA receptor molecules. The neurotrophin receptor TrkA is critically involved in several physio-pathological processes. Still, a clear description of the early steps of ligand-induced TrkA responses at the cell plasma membrane is missing. Here we exploit single particle tracking (SPT) and TIRF microscopy to study TrkA membrane lateral mobility and changes of oligomerization state upon binding of diverse TrkA agonists (NGF, NGF R100E HSANV mutant, proNGF and NT-3). We show that, in the absence of ligands, most of TrkA receptors are fast moving monomers characterized by an average diffusion coefficient of 0.47 µm(2)/s; about 20% TrkA molecules are moving at least an order of magnitude slower and around 4% are almost immobile within regions of about 0.6 µm diameter. Ligand binding results in increased slow and/or immobile populations over the fast one, slowing down of non-immobile trajectories and reduction of confinement areas, observations which are consistent with the formation of receptor dimeric and oligomeric states. We demonstrate that the extent of TrkA lateral mobility modification is strictly ligand-dependent and that each ligand promotes distinct trajectory patterns of TrkA receptors at the cell membrane (ligand "fingerprinting" effect). This ligand-signature of receptor dynamics results from a differential combination of receptor-binding affinity, intracellular effectors recruited in the signalling platforms and formation of signalling/recycling endosome precursors. Thus, our data uncover a close correlation between the initial receptor membrane dynamics triggered upon binding and the specific biological outcomes induced by different ligands for the same receptor. 23761654 Plasma Isoflavone Concentrations Are Not Associated with Gastric Cancer Risk among Japanese Men and Women. The incidence of gastric cancer throughout the world is ∼2-3 times higher in men than in women. Previous research suggested that isoflavones, which are structurally similar to 17β-estradiol, may prevent gastric cancer. Based on a large, population-based, prospective study, we recently reported a null association between dietary isoflavone intake and gastric cancer. However, epidemiologic studies using blood concentrations of isoflavones might better reflect the effect of isoflavones on gastric cancer carcinogenesis than dietary assessment. We therefore conducted a nested case-control study within the Japan Public Health Center-Based Prospective Study. Participants were followed-up from 1990 to 2004. Among 36,745 participants who answered the baseline questionnaire and provided blood samples, 483 gastric cancer cases matched to 483 controls were used in the analysis. ORs and 95% CIs were estimated with a conditional logistic regression model. The overall distribution of plasma isoflavone concentrations was not associated with the development of gastric cancer. Compared with groups with the lowest plasma concentrations (reference groups), the groups with the highest daidzein and genistein concentrations had adjusted ORs and 95% CIs of 1.11 (0.74-1.66; P-trend = 0.6) and 0.96 (0.64-1.44; P-trend = 0.9), respectively. The results did not change when analysis was based on sex, subsite, or histological type. We found no association of plasma isoflavone concentrations with gastric cancer risk. Our data support the previously observed null association between isoflavone intake and gastric cancer risk. 23582567 Human mast cells arise from a common circulating progenitor. Human tissue mast cells (MCs) have the potential to express several neutral granule proteases, which are the most precise markers of the phenotypic heterogeneity of MCs. However, the full extent of such heterogeneity is limited by the fact that MCs containing either tryptase only or tryptase and chymase have long been considered to be the sole MC phenotypes. Moreover, the potential developmental relationship between human MCs of different protease phenotypes has remained a matter of dispute. We attempted to define how human MCs with different protease phenotypes relate to their circulating progenitors. MCs were generated from human peripheral blood-derived CD34(+) progenitors in the presence of kit ligand (KITLG) and the cytokines IL-3, IL-9, and IL-6 under serum-free conditions, or by KITLG alone in the presence or absence of serum. The expression of chymase, carboxypeptidase A3, cathepsin G, granzyme B, and the tryptases derived from the TPSAB1, TPSB2, TPSD1, and TPSG1/PRSS31 genes were determined weekly at the mRNA and/or protein levels. Incubation of CD34(+) progenitors in the presence of KITLG and the cytokines IL-3, IL-9, and IL-6 promoted the development of a single population of MCs with a uniform tryptase(+), chymase(+), CPA3(+), cathepsin G(+), and granzyme B(+) phenotype. Interestingly, the presence of KITLG alone was sufficient to induce the expression of all the above proteases. All circulating human MC progenitors have the potential to differentiate into MCs expressing the complete panel of neutral granule proteases, implying that human MCs originate from a common MC-committed progenitor. 23831681 Lymphocyte-mediated neuroprotection in in vitro models of excitotoxicity involves astrocytic activation and the inhibition of MAP kinase signalling pathways. It is well established that immunosurveillance is active in the CNS and plays a key role in several CNS disorders but the exact role of immune cells remains elusive. Thus, in the present study we investigated whether lymphocytes are protective/detrimental in in vitro models of excitotoxicty. Kainate (KA)-induced neuronal death was significantly reduced following exposure to mixed lymphocytes or purified T lymphocytes containing either activated or non-activated T-lymphocytes. Conditioned media from lymphocyte preparations, but not boiled conditioned media, was protective against KA-induced toxicity indicating soluble mediators underlie the observed neuroprotection with cytokine arrays indicating IL-16 as the likely candidate. A role for astrocytes was established as the neuroprotection was abolished in the presence of the glial toxin, fluoroacetate. Furthermore, lymphocytes inhibited p38 MAPK and ERK signalling pathways with pharmacological inhibition of these pathways mimicking the protective effect of lymphocytes. Similarly, lymphocytes were neuroprotective against oxygen-glucose deprivation (OGD)-induced cell death with the inhibition of p38 MAPK and ERK signalling pathways involved. These data indicate that lymphocytes are neuroprotective under our experimental conditions and we suggest that astrocytic activation and inhibition of MAPK signalling cascades are involved but further studies are required to investigate whether similar mechanisms underlie the actions of lymphocytes in in vivo experimental models of disease. 23955125 Portable music player users: Cultural differences and potential dangers. Many studies have examined the use of portable music players portable listening devices (PLDs) from various ethnic groups. Some findings suggest that there may be differences among ethnic groups that lead to louder or longer listening when using PLD devices. For example, some studies found that Hispanic PLD users listen at higher volume levels while other studies found that African American PLD users listen at higher volume levels. No investigator has explained the reasons for differences among ethnic groups in listening intensity. This paper will address the possible reasons for these differences and offer guidelines for the prevention of noise-induced hearing loss. 23455732 Optimized templates for bottom-up growth of high-performance integrated biomolecular detectors. Electrochemical deposition of metals represents an important approach in the bottom-up fabrication of nanostructures and microstructures. We have used this approach to generate high-performance chip-based biosensors using silicon as a platform for the generation of sensor arrays. Here, we explore the applicability of different materials to support the electrodeposition and identify the parameters that are essential for robust sensor growth. We show that inexpensive materials can be used as templates for electrodeposition, and demonstrate that these low-cost sensors exhibit clinically-relevant levels of sensitivity and specificity. In particular, we prove herein that the glass-based sensors successfully detect E. coli in urine, when present at the 100 cfu μL(-1) levels found typically in samples of patients with urinary tract infections. 23967929 A mechanism study of sound wave-trapping barriers. The performance of a sound barrier is usually degraded if a large reflecting surface is placed on the source side. A wave-trapping barrier (WTB), with its inner surface covered by wedge-shaped structures, has been proposed to confine waves within the area between the barrier and the reflecting surface, and thus improve the performance. In this paper, the deterioration in performance of a conventional sound barrier due to the reflecting surface is first explained in terms of the resonance effect of the trapped modes. At each resonance frequency, a strong and mode-controlled sound field is generated by the noise source both within and in the vicinity outside the region bounded by the sound barrier and the reflecting surface. It is found that the peak sound pressures in the barrier's shadow zone, which correspond to the minimum values in the barrier's insertion loss, are largely determined by the resonance frequencies and by the shapes and losses of the trapped modes. These peak pressures usually result in high sound intensity component impinging normal to the barrier surface near the top. The WTB can alter the sound wave diffraction at the top of the barrier if the wavelengths of the sound wave are comparable or smaller than the dimensions of the wedge. In this case, the modified barrier profile is capable of re-organizing the pressure distribution within the bounded domain and altering the acoustic properties near the top of the sound barrier. 23636270 Rapeseed oil-rich diet alters hepatic mitochondrial membrane lipid composition and disrupts bioenergetics. Diet is directly related with physiological alterations occurring at a cell and subcellular level. However, the role of diet manipulation on mitochondrial physiology is still largely unexplored. Aiming at correlating diet with alterations of mitochondrial membrane composition and bioenergetics, Wistar-Han male rats were fed for 11, 22 and 33 days with a rapeseed oil-based diet and mitochondrial bioenergetics, and membrane composition were compared at each time point with a standard diet group. Considerable differences were noticed in mitochondrial membrane lipid composition, namely in terms of fatty acyl chains and relative proportions of phospholipid classes, the modified diet inducing a decrease in the saturated to unsaturated molar ratio and an increase in the phosphatidylcholine to phosphatidylethanolamine molar ratio. Mass spectrometry lipid analysis showed significant differences in the major species of cardiolipin, with an apparent increased incorporation of oleic acid as a result of exposure to the modified diet. Rats fed the modified diet during 22 days showed decreased hepatic mitochondrial state 3 respiration and were more susceptible to Ca(2+)-induced transition pore opening. Rapeseed oil-enriched diet also appeared to promote a decrease in hydroperoxide production by the respiratory chain, although a simultaneous decrease in vitamin E content was detected. In conclusion, our data indicate that the rapeseed oil diet causes negative alterations on hepatic mitochondrial bioenergetics, which may result from membrane remodeling. Such alterations may have an impact not only on energy supply to the cell, but also on drug-induced hepatic mitochondrial liabilities. 23843410 Ameloblastic fibroma: an uncommon entity. Ameloblastic fibroma is an uncommon mixed odontogenic tumour, which is often confused with ameloblastoma. It exhibits both epithelial and mesenchymal components with absence of any calcified dental structure. This paper presents two cases of this rare entity with detailed review of literature. 23831448 Deep sequencing as a method of typing bluetongue virus isolates. Bluetongue (BT) is an economically important endemic disease of livestock in tropics and subtropics. In addition, its recent spread to temperate regions like North America and Northern Europe is of serious concern. Rapid serotyping and characterization of BT virus (BTV) is an essential step in the identification of origin of the virus and for controlling the disease. Serotyping of BTV is typically performed by serum neutralization, and of late by nucleotide sequencing. This report describes the near complete genome sequencing and typing of two isolates of BTV using Illumina next generation sequencing platform. Two of the BTV RNAs were multiplexed with ten other unknown samples. Viral RNA was isolated and fragmented, reverse transcribed, the cDNA ends were repaired and ligated with a multiplex oligo. The genome library was amplified using primers complementary to the ligated oligo and subjected to single and paired end sequencing. The raw reads were assembled using a de novo method and reference-based assembly was performed based on the contig data. Near complete sequences of all segments of BTV were obtained with more than 20× coverage, and single read sequencing method was sufficient to identify the genotype and serotype of the virus. The two viruses used in this study were typed as BTV-1 and BTV-9E. 23450741 Comparative Binding Energy (COMBINE) Analysis for Understanding the Binding Determinants of Type II Dehydroquinase Inhibitors. Herein we report comparative binding energy (COMBINE) analyses to derive quantitative structure-activity relationship (QSAR) models that help rationalize the determinants of binding affinity for inhibitors of type II dehydroquinase (DHQ2), the third enzyme of the shikimic acid pathway. Independent COMBINE models were derived for Helicobacter pylori and Mycobacterium tuberculosis DHQ2, which is an essential enzyme in both these pathogenic bacteria that has no counterpart in human cells. These studies quantify the importance of the hydrogen bonding interactions between the ligands and the water molecule involved in the DHQ2 reaction mechanism. They also highlight important differences in the ligand interactions with the interface pocket close to the active site that could provide guides for future inhibitor design. 23903844 Preferential HIV infection of CCR6+ Th17 cells is associated with higher virus receptor expression and lack of CCR5 ligands. Th17 cells are enriched in the gut mucosa and play a critical role in maintenance of mucosal barrier and host defense against extracellular bacteria and fungal infections. During chronic HIV infection, Th17 cells were more depleted as compared to Th1 cells, even when the patients had low or undetectable viremia. To investigate the differential effects of HIV infection on Th17 and Th1 cells, a culture system was used in which CCR6+ CD4+ T cells were sorted from healthy human peripheral blood and activated in the presence of IL-1β and IL-23 to drive expansion of Th17 cells, while maintaining Th1 cells. HIV infection of these cultures had minimal effects on Th1 cells, but caused depletion of Th17 cells. Th17 loss correlated with greater levels of virus-infected cells and cell death. In identifying cellular factors contributing to higher susceptibility of Th17 cells to HIV, we compared Th17-enriched CCR6+ versus Th17-depleted CCR6- CD4 T cell cultures and noted that Th17-enriched CCR6+ cells expressed higher levels of α4β7 and bound HIV envelope in an α4β7-dependent manner. The cells also had greater expression of CD4 and CXCR4, but not CCR5. Moreover, unlike Th1 cells, Th17 cells produced little CCR5 ligands, and transfection with one of the CCR5 ligands MIP-1β (CCL4) increased their resistance against HIV. These results indicate that features unique to Th17 cells, including higher expression of HIV receptors and lack of autocrine CCR5 ligands, are associated with enhanced permissiveness of these cells to HIV. 23894515 Fibrinogen Aα Thr312Ala Polymorphism Specifically Contributes to Chronic Thromboembolic Pulmonary Hypertension by Increasing Fibrin Resistance. Polymorphisms are associated with chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary thromboembolism (PTE), but no polymorphism specific to CTEPH but not PTE has yet been reported. Fibrin resistance is associated with CTEPH, but the mechanism has not been elucidated. Polymorphisms were analyzed in 101 CTEPH subjects, 102 PTE subjects and 108 healthy controls by Massarray or restriction fragment length polymorphism (RFLP). Plasmin-mediated cleavage of fibrin was characterized in 69 subjects (29 with CTEPH, 21 with PTE and 19 controls). Genotype frequencies and allele frequencies of fibrinogen Aα Thr312Ala were significantly higher in CTEPH subjects than in controls and PTE subjects, while there was no difference between PTE subjects and controls. The odd ratio (OR 2.037) and 95% confidence interval (95% CI, 1.262-3.289) showed that Thr312Ala polymorphism was a risk factor for CTEPH but not PTE. Fibrin from CTEPH subjects was more resistant to lysis than that from PTE subjects and controls. Fibrin resistance was significantly different between Aα Thr312Ala (A/G) genotypes within CTEPH subjects, and the fibrin with GG genotype was more resistant than that with AA and AG genotype. Fibrinogen Aα Thr312Ala (A/G) polymorphism was associated with CTEPH, but not PTE, suggesting that the fibrinogen Aα Thr312Ala polymorphism may act as a potential biomarker in identifying CTEPH from PTE. GG genotype polymorphism contributes to CTEPH through increasing fibrin resistance, implying that PTE subjects with fibrinogen Aα GG genotype may need long-term anticoagulation therapy. 23689605 Anthelmintic efficacy of Santalum album (Santalaceae) against monogenean infections in goldfish. Dactylogyrus spp. and Gyrodactylus spp. are helminth ectoparasites that are a significant threat to the aquaculture industry. Existing treatments could cause the threats of anthelmintic resistance, risk of residues, environmental contamination, and toxicity to fish. Importantly, there is no report on a treatment against these two parasites. This study explored the possibility of using the extracts of Santalum album to treat Dactylogyrus sp. and Gyrodactylus sp. infections in goldfish. Results showed that among the four extracts (chloroform, methanol, ethyl acetate, and water) of S. album, the chloroform extract is the most effective and 40 mg/L is a safe and the lowest effective dosage. In addition, we found that Gyrodactylus elegans is more sensitive than Dactylogyrus intermedius when exposed to the extract of the medicinal plant. Finally, it is substantiated that bath treatment with long duration and multiple administrations could eliminate a greater proportion of monogenean infections. These findings show the potential for the development of effective and safe therapy to treat Dactylogyrus sp. and Gyrodactylus sp. infections of fishes. 23377648 Recent Advances in SPE-Chiral-HPLC Methods for Enantiomeric Separation of Chiral Drugs in Biological Samples. In medical practices, the determination of enantiomeric ratio of the chiral drugs is very important for their activities, bioavailabilities and biodegradation. Only homochiral medication is safe for humans. The chiral analysis in biological samples is the first and most important step. The present article describes the technical strategies of the enantiomeric resolution of racemic drugs in biological samples. Attempts have been made to describe sample preparation by solid-phase extraction and enantiomeric resolution by chiral high-performance liquid chromatography. Various chiral stationary phases used in chiral separations of racemic drugs have been described. Efforts are also made to discuss the chiral recognition mechanism and future perspectives of chiral analyses in biological samples. 23926315 Global eradication rates for Helicobacter pylori infection: systematic review and meta-analysis of sequential therapy. To do a systematic review and meta-analysis of studies comparing sequential therapy for eradication of Helicobacter pylori with pre-existing and new therapies, thus providing a glimpse of eradication success worldwide. Systematic review and meta-analysis. Medline, Embase, and Cochrane Central Register of Controlled Trials up to May 2013; abstract books of major European, American, and Asian gastroenterological meetings. Randomised controlled trials in previously untreated adults, in which sequential therapy was compared with a pre-existing or new therapy. 46 randomised controlled trials were reviewed and analysed. 5666 patients were randomised to sequential therapy and 7866 to other (established and new) treatments. The overall eradication rate of sequential therapy was 84.3% (95% confidence interval 82.1% to 86.4%). Sequential therapy was superior to seven day triple therapy (relative risk 1.21, 95% confidence interval 1.17 to 1.25; I(2)=29.3%; number needed to treat 6 , 95% confidence interval 5% to 7%), marginally superior to 10 day triple therapy (1.11, 1.04 to 1.19; I(2)= 67.2%; NNT 10, 7 to 15), but not superior to 14 day triple therapy (1.00, 0.94 to 1.06; I(2)=54.3%), bismuth based therapy (1.01, 0.95 to 1.06; I(2)=21.1%), and non-bismuth based therapy (0.99, 0.94 to 1.05; I(2)=52.3%). Data on eradication according to pre-treatment antimicrobial susceptibility testing were available in eight studies, and sequential therapy was able to eradicate 72.8% (61.6% to 82.8%) of the strains resistant to clarithromycin. Eradication rates with pre-existing and new therapies for H pylori are suboptimal. Regional monitoring of resistance rates should help to guide treatment, and new agents for treatment need to be developed. 23857047 Advances in the genetics of Parkinson disease. Parkinson disease (PD) is a multifactorial neurodegenerative disease that was long considered the result of environmental factors. In the past 15 years, however, a genetic aetiology for PD has begun to emerge. Here, we review results from linkage and next-generation sequencing studies of familial parkinsonism, as well as candidate gene and genome-wide association findings in sporadic PD. In these studies, many of the genetic findings overlap, despite different designs and study populations, highlighting novel therapeutic targets. The molecular results delineate a sequence of pathological events whereby deficits in synaptic exocytosis and endocytosis, endosomal trafficking, lysosome-mediated autophagy and mitochondrial maintenance increase susceptibility to PD. These discoveries provide the rationale, molecular insight and research tools to develop neuroprotective and disease-modifying therapies. 23768845 In-situ subaqueous capping of mercury-contaminated sediments in a fresh-water aquatic system, Part I-Bench-scale microcosm study to assess methylmercury production. Bench-scale microcosm experiments were designed to provide a better understanding of the potential for Hg methylation in sediments from an aquatic environment. Experiments were conducted to examine the function of sulfate concentration, lactate concentration, the presence/absence of an aqueous inorganic Hg spike, and the presence/absence of inoculums of Desulfovibrio desulfuricans, a strain of sulfate-reducing bacteria (SRB) commonly found in the natural sediments of aquatic environments. Incubations were analyzed for both the rate and extent of (methylmercury) MeHg production. Methylation rates were estimated by analyzing MeHg and Hg after 2, 7, 14, 28, and 42 days. The production of metabolic byproducts, including dissolved gases as a proxy for metabolic utilization of carbon substrate, was also monitored. In all treatments amended with lactate, sulfate, Hg, and SRB, MeHg was produced (37ng/g-sediment dry weight) after only 48h of incubation and reached a maximum sediment concentration of 127ng/g-sediment dry weight after the 42 day incubation period. Aqueous phase production of MeHg was observed to be 10ng/L after 2 day, reaching a maximum observed concentration of 32.8ng/L after 14 days, and declining to 10.8ng/L at the end of the incubation period (42 day). The results of this study further demonstrates that, in the presence of an organic carbon substrate, sulfate, and the appropriate consortia of microorganisms, sedimentary Hg will be transformed into MeHg through bacterial metabolism. Further, this study provided the basis for evaluation of an in-situ subaqueous capping strategy that may limit (or potentially enhance) MeHg production. 23044488 Amino acid residues at the N- and C-termini are essential for the folding of active human butyrylcholinesterase polypeptide. Human serum butyrylcholinesterase (HuBChE) is currently the most suitable bioscavenger for the prophylaxis of highly toxic organophosphate (OP) nerve agents. A dose of 200mg of HuBChE is envisioned as a prophylactic treatment that can protect humans from an exposure of up to 2×LD50 of soman. The limited availability and administration of multiple doses of this stoichiometric bioscavenger make this pretreatment difficult. Thus, the goal of this study was to produce a smaller enzymatically active HuBChE polypeptide (HBP) that could bind to nerve agents with high affinity thereby reducing the dose of enzyme. Studies have indicated that the three-dimensional structure and the domains of HuBChE (acyl pocket, lip of the active center gorge, and the anionic substrate-binding domain) that are critical for the binding of substrate are also essential for the selectivity and binding of inhibitors including OPs. Therefore, we designed three HBPs by deleting some N- and C-terminal residues of HuBChE by maintaining the folds of the active site core that includes the three active site residues (S198, E325, and H438). HBP-4 that lacks 45 residues from C-terminus but known to have BChE activity was used as a control. The cDNAs for the HBPs containing signal sequences were synthesized, cloned into different mammalian expression vectors, and recombinant polypeptides were transiently expressed in different cell lines. No BChE activity was detected in the culture media of cells transfected with any of the newly designed HBPs, and the inactive polypeptides remained inside the cells. Only enzymatically active HBP-4 was secreted into the culture medium. These results suggest that residues at the N- and C-termini are required for the folding and/or maintenance of HBP into an active stable, conformation. 23776090 Gastrointestinal symbionts of chimpanzees in Cantanhez National Park, guinea-bissau with respect to habitat fragmentation. One of the major factors threatening chimpanzees (Pan troglodytes verus) in Guinea-Bissau is habitat fragmentation. Such fragmentation may cause changes in symbiont dynamics resulting in increased susceptibility to infection, changes in host specificity and virulence. We monitored gastrointestinal symbiotic fauna of three chimpanzee subpopulations living within Cantanhez National Park (CNP) in Guinea Bissau in the areas with different levels of anthropogenic fragmentation. Using standard coproscopical methods (merthiolate-iodine formalin concentration and Sheather's flotation) we examined 102 fecal samples and identified at least 13 different symbiotic genera (Troglodytella abrassarti, Troglocorys cava, Blastocystis spp., Entamoeba spp., Iodamoeba butschlii, Giardia intestinalis, Chilomastix mesnili, Bertiella sp., Probstmayria gombensis, unidentified strongylids, Strongyloides stercoralis, Strongyloides fuelleborni, and Trichuris sp.). The symbiotic fauna of the CNP chimpanzees is comparable to that reported for other wild chimpanzee populations, although CNP chimpanzees have a higher prevalence of Trichuris sp. Symbiont richness was higher in chimpanzee subpopulations living in fragmented forests compared to the community inhabiting continuous forest area. We reported significantly higher prevalence of G. intestinalis in chimpanzees from fragmented areas, which could be attributed to increased contact with humans and livestock. Am. J. Primatol. 75:1032-1041, 2013. © 2013 Wiley Periodicals, Inc. 23768052 The effect of systemic administration of desmopressin on cochlear function in guinea pigs. Systemic desmopressin (dDAVP) administration in guinea pigs for up to 2 weeks induced only minor or no significant changes in cochlear sensitivity, suggesting that other factors may be required to induce the cochlear dysfunction that is usually associated with endolymphatic hydrops. To investigate the effects of chronic systemic administration of dDAVP, a synthetic analog of vasopressin, on cochlear sensitivity in guinea pigs. dDAVP was administered subcutaneously via a mini-osmotic pump, at a rate of 0.2 ng/kg/min (low-dose group) or 2.0 ng/kg/min (high-dose group) for up to 2 weeks. Cochlear responses (compound action potentials) and distortion product otoacoustic emissions (DPOAEs) were measured. Example specimens were scanned using X-ray micro-tomography (micro-CT). Compared with the control group, the low-dose dDAVP group showed a significant threshold increase in response to a 2 kHz tone-burst after 2 weeks of treatment, and also a decrease in the amplitude of the DPOAE after 1 week of treatment. However, individual results were variable and the high-dose dDAVP group showed no significant change compared to the control group. In the micro-CT images, two of four ears in the low-dose group showed mild hydrops, but no hydrops was found in the three ears sampled from the high-dose group. 23966034 Bouillonamide: A Mixed Polyketide-Peptide Cytotoxin from the Marine Cyanobacterium Moorea bouillonii. The tropical marine cyanobacterium, Moorea bouillonii, has gained recent attention as a rich source of bioactive natural products. Continued chemical investigation of this cyanobacterium, collected from New Britain, Papua New Guinea, yielded a novel cytotoxic cyclic depsipeptide, bouillonamide (1), along with previously reported molecules, ulongamide A and apratoxin A. Planar structure of bouillonamide was established by extensive 1D and 2D NMR experiments, including multi-edited HSQC, TOCSY, HBMC, and ROESY experiments. In addition to the presence of α-amino acid residues, compound 1 contained two unique polyketide-derived moieties, namely a 2-methyl-6-methylamino-hex-5-enoic acid (Mmaha) residue and a unit of 3-methyl-5-hydroxy-heptanoic acid (Mhha). Absolute stereochemistry of the α-amino acid units in bouillonamide was determined mainly by Marfey's analysis. Compound 1 exhibited mild toxicity with IC50's of 6.0 µM against the neuron 2a mouse neuroblastoma cells. 23894012 Erythropoietin critically regulates the terminal maturation of murine and human primitive erythroblasts. Primitive erythroid cells, the first red blood cells produced in the mammalian embryo, are necessary for embryonic survival. Erythropoietin and its receptor EpoR, are absolutely required for survival of late-stage definitive erythroid progenitors in the fetal liver and adult bone marrow. Epo- and Epor-null mice die at E13.5 with a lack of definitive erythrocytes, however, the persistence of circulating primitive erythroblasts raises questions about the role of erythropoietin/EpoR in primitive erythropoiesis. Using Epor-null mice and a novel primitive erythroid 2-step culture we find that erythropoietin is not necessary for specification of primitive erythroid progenitors. However, Epor-null embryos develop a progressive, profound anemia by E12.5 as primitive erythroblasts mature as a synchronous cohort. This anemia results from reduced primitive erythroblast proliferation associated with increased p27 expression, from advanced cellular maturation, and from markedly elevated rates of apoptosis associated with an imbalance in pro- and anti-apoptotic gene expression. Both mouse and human primitive erythroblasts cultured without erythropoietin also undergo accelerated maturation and apoptosis at later stages of maturation. We conclude that erythropoietin plays an evolutionarily conserved role in promoting the proliferation, survival, and appropriate timing of terminal maturation of primitive erythroid precursors. 23455494 Chromobacterium violaceum: important insights for virulence and biotechnological potential by exoproteomic studies. Chromobacterium violaceum is a beta-proteobacterium with high biotechnological potential, found in tropical environments. This bacterium causes opportunistic infections in both humans and animals, that can spread throughout several tissues, quickly leading to the death of the host. Genomic studies identified potential mechanisms of pathogenicity but no further studies were done to confirm the expression of these systems. In this study 36 unique protein entries were identified in databank from a two-dimensional profile of C. violaceum secreted proteins. Chromobacterium violaceum exoproteomic preliminary studies confirmed the production of proteins identified as virulence factors (such as a collagenase, flagellum proteins, metallopeptidases, and toxins), allowing us to better understand its pathogenicity mechanisms. Biotechnologically interesting proteins (such as chitinase and chitosanase) were also identified among the secreted proteins, as well as proteins involved in the transport and capture of amino acids, carbohydrates, and oxidative stress protection. Overall, the secreted proteins identified provide us important insights on pathogenicity mechanisms, biotechnological potential, and environment adaptation of C. violaceum. 23790103 Kinetics of reversible reductive carbonylation of heme in human cystathionine β-synthase. Cystathionine β-synthase (CBS) catalyzes the condensation of homocysteine with serine or cysteine to form cystathionine and water or hydrogen sulfide (H2S), respectively. In addition to pyridoxal phosphate, human CBS has a heme cofactor with cysteine and histidine as ligands. While Fe(III)-CBS is inert to exogenous ligands, Fe(II)-CBS can be reversibly inhibited by carbon monoxide (CO) and reoxidized by O2 to yield superoxide radical. In this study, we have examined the kinetics of Fe(II)CO-CBS formation and reoxidation. Reduction of Fe(III)-CBS by dithionite showed a square root dependence on concentration, indicating that the reductant species was the sulfur dioxide radical anion (SO2(•-)) that exists in rapid equilibrium with S2O4(2-). Formation of Fe(II)CO-CBS from Fe(II)-CBS and 1 mM CO occurred with a rate constant of (3.1 ± 0.4) × 10(-3) s(-1) (pH 7.4, 25 °C). The reaction of Fe(III)-CBS with the reduced form of the flavoprotein methionine synthase reductase in the presence of CO and NADPH resulted in its reduction and carbonylation to form Fe(II)CO-CBS. Fe(II)-CBS was formed as an intermediate with a rate constant of (9.3 ± 2.5) × 10(2) M(-1) s(-1). Reoxidation of Fe(II)CO-CBS by O2 was multiphasic. The major phase showed a hyperbolic dependence on O2 concentration. Although H2S is a product of the CBS reaction and a potential heme ligand, we did not find evidence of an effect of exogenous H2S on activity or heme binding. Reversible reduction of CBS by a physiologically relevant oxidoreductase is consistent with a regulatory role for the heme and could constitute a mechanism for cross talk among the CO, H2S, and superoxide signaling pathways. 23841909 Vegetable-based dietary pattern and liver cancer risk: Results from the Shanghai Women's and Men's Health Studies. Although dietary patterns, specific foods, and their constituents have been linked to cancer risk, the role of dietary patterns and specific food groups in liver cancer risk has not been investigated. In the Shanghai Women's Health Study (SWHS) and Shanghai Men's Health Study (SMHS), two cohort studies of 132 837 Chinese women and men, we evaluated the relationship between dietary patterns, food groups, and liver cancer risk. Through in-person interviews, dietary information intake over the preceding year was collected by using a validated food-frequency questionnaire. Cox regression model was used to estimate hazard ratios and 95% confidence intervals with adjustment for potential confounders. During an average follow-up of 10.9 (SWHS) or 5.5 (SMHS) years, 267 incident liver cancer cases were identified after the first 2 years of study enrolment. Three dietary patterns were derived by factor analysis. A vegetable-based dietary pattern was inversely associated with liver cancer; hazard ratios (95% confidence intervals) for the lowest to highest quartiles were: 1.00; 0.98 (0.71-1.35); 0.93 (0.67-1.29); and 0.58 (0.40-0.84); Ptrend  = 0.01. The association was stronger among participants with a history of chronic liver disease. Further analyses showed high intakes of celery, mushrooms, allium vegetables, composite vegetables (including asparagus lettuce and garland chrysanthemum), legumes and legume products were associated with reduced liver cancer risk (all Ptrend  < 0.05). Fruit- and meat-based dietary patterns were not associated with liver cancer risk. Our study suggests that a vegetable-based dietary pattern is associated with reduced liver cancer risk. 23924043 Extracellular matrix determinants and the regulation of cancer cell invasion stratagems. During development, wound repair and disease-related processes, such as cancer, normal, or neoplastic cell types traffic through the extracellular matrix (ECM), the complex composite of collagens, elastin, glycoproteins, proteoglycans, and glycosaminoglycans that dictate tissue architecture. Current evidence suggests that tissue-invasive processes may proceed by protease-dependent or protease-independent strategies whose selection is not only governed by the characteristics of the motile cell population, but also by the structural properties of the intervening ECM. Herein, we review the mechanisms by which ECM dimensionality, elasticity, crosslinking, and pore size impact patterns of cell invasion. This summary should prove useful when designing new experimental approaches for interrogating invasion programs as well as identifying potential cellular targets for next-generation therapeutics. 23822538 NIH classification for chronic graft-versus-host disease (cGvHD) predicts outcome of allo-HSCT after fludarabine-busulfan-ATG conditioning regimen. Abstract In 2005, the National Institute of Health (NIH) proposed standard criteria for diagnosis, organ scoring and global assessment of cGvHD severity. We retrospectively reclassified cGvHD with NIH criteria in a monocentric cohort of 130 consecutive adult patients with hematological malignancies presenting cGvHD after receiving allo-HSCT with Fludarabine-Busulfan-ATG conditioning regimen, among 313 consecutive HSCT recipients. We compared NIH and Seattle classifications to correlate severity and outcome. Median follow-up was 29 months (18-70). Forty-four percent developed Seattle-defined cGvHD (22% limited, 78% extensive forms). Using NIH criteria, there were 23%, 40% and 37% mild, moderate and severe forms respectively, 58%, 32% and 8% classic cGvHD, late acute GvHD and overlap syndrome. Five-year overall survival was 55% (49-61), cumulative incidences of non-relapse mortality (NRM) and relapse/progression at 2 years were 19% (14-23) and 19% (14-24). NIH mild and moderate forms were associated with better survival compared to severe cGvHD (HR = 3.28, 95% CI: 1.38-7.82, p = 0.007), due to higher NRM among patients with severe cGvHD (HR = 3.04, 95% CI: 1.05-8.78, p = 0.04) but comparable relapse risk (p = n.s.). In conclusion, NIH classification appears to be more accurate in predicting outcome mostly by the reclassification of old-defined extensive forms into NIH-defined moderate or severe. 23950938 Increasing Adolescent HIV Prevalence in Eastern Zimbabwe - Evidence of Long-Term Survivors of Mother-to-Child Transmission? Recent data from the Manicaland HIV/STD Prevention Project, a general-population open HIV cohort study, suggested that between 2004 and 2007 HIV prevalence amongst males aged 15-17 years in eastern Zimbabwe increased from 1.20% to 2.23%, and in females remained unchanged at 2.23% to 2.39%, while prevalence continued to decline in the rest of the adult population. We assess whether the more likely source of the increase in adolescent HIV prevalence is recent sexual HIV acquisition, or the aging of long-term survivors of perinatal HIV acquisition that occurred during the early growth of the epidemic. Using data collected between August 2006 and November 2008, we investigated associations between adolescent HIV and (1) maternal orphanhood and maternal HIV status, (2) reported sexual behaviour, and (3) reporting recurring sickness or chronic illness, suggesting infected adolescents might be in a late stage of HIV infection. HIV-infected adolescent males were more likely to be maternal orphans (RR = 2.97, p<0.001) and both HIV-infected adolescent males and females were more likely to be maternal orphans or have an HIV-infected mother (male RR = 1.83, p<0.001; female RR = 16.6, p<0.001). None of 22 HIV-infected adolescent males and only three of 23 HIV-infected females reported ever having had sex. HIV-infected adolescents were 60% more likely to report illness than HIV-infected young adults. Taken together, all three hypotheses suggest that recent increases in adolescent HIV prevalence in eastern Zimbabwe are more likely attributable to long-term survival of mother-to-child transmission rather than increases in risky sexual behaviour. HIV prevalence in adolescents and young adults cannot be used as a surrogate for recent HIV incidence, and health systems should prepare for increasing numbers of long-term infected adolescents. 23280515 Mussel-inspired adhesive binders for high-performance silicon nanoparticle anodes in lithium-ion batteries. Conjugation of mussel-inspired catechol groups to various polymer backbones results in materials suitable as silicon anode binders. The unique wetness-resistant adhesion provided by the catechol groups allows the silicon nanoparticle electrodes to maintain their structure throughout the repeated volume expansion and shrinkage during lithiation cycling, thus facilitating substantially improved specific capacities and cycle lives of lithium-ion batteries. 23435353 Modulation of A-type K(+) channels by the short-chain cobrotoxin through the protein kinase C-delta isoform decreases membrane excitability in dorsal root ganglion neurons. A-type K(+) channels are crucial in controlling neuronal excitability, and their regulation in sensory neurons may alter pain sensation. In this study, we identified the functional role of cobrotoxin, the short-chain α-neurotoxin isolated from Naja atra venom, which acts in the regulation of the transient A-type K(+) currents (IA) and membrane excitability in dorsal root ganglion (DRG) neurons via the activation of the muscarinic M3 receptor (M3R). Our results showed that cobrotoxin increased IA in a concentration-dependent manner, whereas the sustained delayed rectifier K(+) currents (IDR) were not affected. Cobrotoxin did not affect the activation of IA markedly, however, it shifted the inactivation curve significantly in the depolarizing direction. The cobrotoxin-induced IA response was blocked by the M3R-selective antagonists DAU-5884 and 4-DAMP. An siRNA targeting the M3R in small DRG neurons abolished the cobrotoxin-induced IA increase. In addition, dialysis of the cells with the novel protein kinase C-delta isoform (PKC-δ) inhibitor δv1-1 or an siRNA targeting PKC-δ abolished the cobrotoxin-induced IA response, whereas inhibition of PKA or classic PKC activity elicited no such effects. Moreover, we observed a significant decrease in the firing rate of the neuronal action potential induced by M3R activation. Pretreatment of the cells with 4-aminopyridine, a selective blocker of IA, abolished this effect. Taken together, these results suggest that the short-chain cobrotoxin selectively enhances IA via a novel PKC-δ-dependent pathway. This effect occurred via the activation of M3R and might contribute to its neuronal hypoexcitability in small DRG neurons. 23262278 Design, synthesis, inhibition studies, and molecular modeling of pepstatin analogues addressing different secreted aspartic proteinases of Candida albicans. The family of secreted aspartic proteinases is known as an important virulence factor of yeast infections by Candida albicans in particular, which is the most common fungal pathogen for humans with respect to systemic disease. Due to the continuing increase of drug resistant strains, these proteinases are currently considered as promising drug target candidates. Based on the known Sap2-substrate specificity data and X-ray analyses of Sap/inhibitor complexes, three libraries of inhibitors were designed and synthesized by modifying the structure of pepstatin A, a common non-selective aspartic proteinase inhibitor, at the P3, P2, or P2' position. These novel inhibitors showed high inhibitory potencies for the isoenzymes Sap1, Sap3, Sap5 and Sap6. Then, the affinity and selectivity of the peptide ligands were investigated by molecular modeling, highlighting new key structural information for the design of potent and selective anti-virulence agents targeting Candida albicans. 23416216 Pituitary tumor transforming gene and insulin-like growth factor 1 receptor expression and immunohistochemical measurement of Ki-67 as potential prognostic markers of pituitary tumors aggressiveness. The ability to predict recurrence of pituitary adenoma (PA) after surgery may be helpful to determine follow-up frequency and the need for adjuvant treatment. The purpose of this study was to assess the prognostic capacity of pituitary tumor transforming gene (PTTG), insulin-like growth factor 1 receptor (IGF1R), and Ki-67. In this retrospective study, the normalized copy number (NCN) of PTIG and IGF1R mRNA was measured using RT-PCR, and the Ki-67 index was measured by immunohistochemistry in 46 PA samples. Clinical data, histological subtype, and radiographic characteristics were collected to assess associations between variables and tumor behavior. Progression of tumor remnants and its association to markers was also studied in 14 patients with no adjuvant treatment after surgery followed up for 46±36 months. Extrasellar tumors had a lower PTTG expression as compared to sellar tumors (0.065 [1st-3rd quartile: 0.000-0.089] NCN vs. 0.135 [0.105-0.159] NCN, p=0.04). IGF1R expression changed depending on histological subtype (p=0.014), and was greater in tumor with remnant growth greater than 20% during follow-up (10.69±3.84 NCN vs. 5.44±3.55 NCN, p=0.014). Our results suggest that the IGF1R is a more helpful molecular marker than PTTG in PA management. Ki-67 showed no association to tumor behavior. However, the potential of these markers should be established in future studies with standardized methods and on larger samples. 23377760 Acute viral infections of the central nervous system in immunocompetent adults: diagnosis and management. Patients with viral infections of the central nervous system (CNS) may present with a variety of neurological symptoms, most commonly dominated by either encephalitis or meningitis. The aetiological panorama varies in different parts of the world as well as over time. Thus, virological first-line diagnostics must be adapted to the current epidemiological situation and to the individual patient history, including recent travels. This review focuses on the diagnostics and treatment of viral CNS infections in the immunocompetent host from a Northern European perspective. Effective vaccines are available for viruses such as poliovirus and tick-borne encephalitis virus (TBEV) and for the childhood diseases morbilli (measles), rubella (German measles), parotitis (mumps) and varicella (chickenpox). However, cases do appear due to suboptimal immunization rates. In viral CNS infections, epidemiological surveillance is essential for establishing preventive strategies and for detecting emerging viruses. Knowledge of the possibilities and limitations of diagnostic methods for specific viral CNS infections is vital. A positive cerebral spinal fluid (CSF) polymerase chain reaction (PCR) finding is usually reliable for aetiological diagnosis. The demonstration of intrathecal antibody synthesis is useful for confirming the aetiology in a later stage of disease, hitherto sufficiently evaluated in herpes simplex encephalitis (HSE) and tick-borne encephalitis (TBE). Despite improved virological and differential diagnostic methods, aetiology remains unknown in about half of the cases with suspected viral encephalitis. Antiviral treatment is available chiefly for infections caused by herpesviruses, and acyclovir (aciclovir) is the drug of choice for empirical therapy in suspected viral encephalitis. However, randomized, controlled antiviral trials have only been conducted for HSE, while such studies are lacking in other viral CNS infections. Viral cytolysis and immune-mediated mechanisms may contribute to varying extents to neurological damage. Although the brain damage is believed to depend, to a varying degree, on the intrathecal host immune response, the use of corticosteroids in viral CNS infections is scarcely studied, as is specific treatment for neuroinflammation. Improved antiviral and immunomodulating treatment is desirable. Since neurological sequelae are still abundant, follow-up after severe viral CNS disease must include a neuropsychological assessment and an individually adapted rehabilitation plan. 23849115 Manipulation of microRNA expression to improve nitrogen use efficiency. Nitrogen is the key limiting nutrient required for plant growth. The application of nitrogen-based fertilizers to crops has risen dramatically in recent years, resulting in significant yield increases. However, increased production has come at the cost of substantial negative environmental consequences. Higher crop production costs, increased consumption of food and fertilizer, and a growing global population have led to calls for a "second green revolution" using modern genetic manipulation techniques to improve the production, yield, and quality of crops. Considerable research is being directed toward the study and engineering of nitrogen use efficiency in crop plants. The end goal is to reduce the amount of nitrogen-based fertilizer used and thereby reduce production costs and environmental damage while increasing yields. In this review, we present an overview of recent advances in understanding the regulation of nitrogen metabolism by the action of microRNAs with a view toward engineering crops with increased nitrogen use efficiency. 23684916 B cell activating factor-dependent expression of vascular endothelial growth factor in MH7A human synoviocytes stimulated with tumor necrosis factor-α. Angiogenesis in rheumatoid arthritis (RA) is one of the histological hallmarks, which is mediated by expression of vascular endothelial growth factor (VEGF) in RA synovium. VEGF expression is enhanced by TNF-α, the main pro-inflammatory cytokine in RA. B cell activating factor (BAFF) which plays a role in maturation and maintenance of B cells is also associated with autoimmune RA. Here, we investigated whether BAFF could regulate VEGF expression in TNF-α-stimulated synovium using MH7A synovial cells that are established by transfection with the SV40 T antigen. Changes in hBAFF and hVEGF were measured by western blotting, RT-PCR and luciferase promoter assay. When MH7A cells were treated with TNF-α, we observed that TNF-α increased the expression of hBAFF and hVEGF. TNF-α also increased transcriptional activity of hBAFF and hVEGF as judged by luciferase promoter assay. Inhibition of hBAFF expression with BAFF-siRNA decreased transcriptional level and activity of hVEGF. In addition, when c-fos expression was inhibited by the transfection of MH7A cells with c-fos-siRNA, data showed that transcriptional level and activity of both hBAFF and hVEGF were attenuated by the activation with TNF-α. Our results demonstrate for the first time that VEGF-mediated angiogenesis in RA could be controlled by TNF-α-induced BAFF expression through c-Fos. Data suggest that TNF-α-induced BAFF expression and BAFF-mediated VEGF expression in synovium may cooperate to maintain the capacity of such cells to protect B cells from apoptosis and the supply of nutrients and oxygen in inflammatory microenvironments. 23965806 Work-home interference and its prospective relation to major depression and treatment with antidepressants. Few longitudinal studies have investigated if "work-home interference" (WHI), conflicts between work and home demands, predicts depressive disorders. We examined if WHI was prospectively associated with indicators of major depression in a nationally representative sample. We used multiple logistic and Cox regression models to examine if self-reported WHI was related to probable major depression [scoring high on a brief self-report scale based on the (Hopkins) Symptom Checklist] and/or any new antidepressant treatment using the prescribed drug register during a 2-year follow-up. The analytic sample comprised 1576 men and 1678 women, working respondents to the Swedish Longitudinal Occupational Survey of Health (SLOSH), free of major depression and prior purchases of antidepressants at baseline. Altogether, 7% experienced high (very often/the whole time) and 32% moderate (sometimes) WHI. Overall, the analyses indicated prospective associations between especially high WHI and major depression and/or antidepressant treatment also when adjusting for work characteristics (demands, control, support, overtime). However, the estimates for major depression differed by sex. Separate analyses indicated that only women with high WHI were significantly more likely to have subsequent major depression. Analyses further indicated an elevated rate of antidepressant treatment for men in particular, partly explained by work characteristics and that major depression was related to subsequent high WHI. Based on a two-year follow-up, this study indicated that high WHI prospectively predicted major depression and/or antidepressant treatment, though effects appeared to differ to some extent by sex. 23875024 Antiviral responses by Swine primary bronchoepithelial cells are limited compared to human bronchoepithelial cells following influenza virus infection. Swine generate reassortant influenza viruses because they can be simultaneously infected with avian and human influenza; however, the features that restrict influenza reassortment in swine and human hosts are not fully understood. Type I and III interferons (IFNs) act as the first line of defense against influenza virus infection of respiratory epithelium. To determine if human and swine have different capacities to mount an antiviral response the expression of IFN and IFN-stimulated genes (ISG) in normal human bronchial epithelial (NHBE) cells and normal swine bronchial epithelial (NSBE) cells was evaluated following infection with human (H3N2), swine (H1N1), and avian (H5N3, H5N2, H5N1) influenza A viruses. Expression of IFNλ and ISGs were substantially higher in NHBE cells compared to NSBE cells following H5 avian influenza virus infection compared to human or swine influenza virus infection. This effect was associated with reduced H5 avian influenza virus replication in human cells at late times post infection. Further, RIG-I expression was lower in NSBE cells compared to NHBE cells suggesting reduced virus sensing. Together, these studies identify key differences in the antiviral response between human and swine respiratory epithelium alluding to differences that may govern influenza reassortment. 23927133 Adaptation to spectrally-rotated speech. Much recent interest surrounds listeners' abilities to adapt to various transformations that distort speech. An extreme example is spectral rotation, in which the spectrum of low-pass filtered speech is inverted around a center frequency (2 kHz here). Spectral shape and its dynamics are completely altered, rendering speech virtually unintelligible initially. However, intonation, rhythm, and contrasts in periodicity and aperiodicity are largely unaffected. Four normal hearing adults underwent 6 h of training with spectrally-rotated speech using Continuous Discourse Tracking. They and an untrained control group completed pre- and post-training speech perception tests, for which talkers differed from the training talker. Significantly improved recognition of spectrally-rotated sentences was observed for trained, but not untrained, participants. However, there were no significant improvements in the identification of medial vowels in /bVd/ syllables or intervocalic consonants. Additional tests were performed with speech materials manipulated so as to isolate the contribution of various speech features. These showed that preserving intonational contrasts did not contribute to the comprehension of spectrally-rotated speech after training, and suggested that improvements involved adaptation to altered spectral shape and dynamics, rather than just learning to focus on speech features relatively unaffected by the transformation. 23567390 The association of selective serotonin reuptake inhibitors use and stroke in geriatric population. Selective serotonin reuptake inhibitor (SSRI) exposure has controversial results in increasing the stroke risk. With the risk of stroke increased with age, the safety of SSRI use among older adults attracts much concern. We analyzed 28,145 subjects older than 65 years from a subset of a 9-year cohort database from the National Health Insurance Research Database, Taiwan. The survival analysis showed a greater probability of stroke in subjects with SSRI exposure after adjusting other covariates. Compared with other variables, SSRI exposure had the strongest effect (hazard ratio: 2.66, 95% confidence interval: 2.21-3.20). The risk was independent to depression-related stroke risk. The use of SSRIs independently increases the risk of stroke among older patients. SSRIs are still practically safe to most users, providing precautionary measures are taken. 23845680 Atypical hemifacial spasm due to vertebral artery dolichoectasia: rare cause of a rarer clinical entity. A 32-year-old man presented with atypical left hemifacial spasm (HFS) with MRI showing compression of left facial nerve at the root exit zone. HFS rarely presents atypically with onset in orbicularis oris and later spreading upward to involve the orbicularis oculi as was seen in our case. Atypical presentation of hemifacial spasm is rare and vertebral artery dolichoectasia as the underlying aetiology, like in our case is even rarer and has not been described in literature so far. 22868305 A 2-year follow-up of irradiated homologous costal cartilage used as a septal extension graft for the correction of contracted nose in Asians. Septal extension graft is a useful method for the correction of contracted nose. When septal or costal cartilage is not available, irradiated homologous costal cartilage (IHCC) may be an alternative choice. This preliminary study is focused on noninfective absorption and other complications and postoperative changes of nasal length after septal extension graft using IHCC. Thirty patients who could be observed for more than 2 years postoperatively were assessed. All patients had contracted nose deformities with a history of an inflammatory contracture after previous aesthetic surgical procedures. The IHCC was used only as a septal extension graft in each patient. Nasal length was analyzed by comparing preoperative and 2-year postoperative photographs. There was no noticeable graft warping or infective IHCC absorption. However, 3 patients underwent revision: 2 cases of graft avulsion fracture and 1 case of minimal nasal obstruction. Nasal length, which had increased an average of 8.5% after the procedure, was maintained at follow-up 2 years postoperatively. The IHCC has the advantages of avoiding donor-site scars, and also provides the same benefits as autogenous costal cartilage. It can therefore be a reliable alternative material for rhinoplasty. A longer follow-up may be necessary to confirm the structural stability of the IHCC graft in the lengthened caudal septum. 23537893 Patients with type 2 diabetes show a greater decline in muscle mass, muscle strength, and functional capacity with aging. The loss of muscle mass with aging reduces muscle strength, impairs functional capacity, and increases the risk of developing chronic metabolic disease. It has been suggested that the development of type 2 diabetes results in a more rapid decline in muscle mass, strength, and functional capacity. To investigate the impact of type 2 diabetes on muscle mass, strength, and functional capacity in an older population. Muscle mass (DXA and muscle biopsies), strength (1-repetition maximum), functional capacity (sit-to-stand test and handgrip strength), and reaction time performance (computer task) were compared between 60 older men with type 2 diabetes (71 ± 1 years) and 32 age-matched normoglycemic controls (70 ± 1 years). Data were analyzed using ANCOVA to adjust for several potential confounders. Leg lean mass and appendicular skeletal muscle mass were significantly lower in older men with type 2 diabetes (19.1 ± 0.3 and 25.9 ± 0.4 kg, respectively) compared with normoglycemic controls (19.7 ± 0.3 and 26.7 ± 0.5 kg, respectively). Additionally, leg extension strength was significantly lower in the group with type 2 diabetes (84 ± 2 vs 91 ± 2 kg, respectively). In agreement, functional performance was impaired in the men with type 2 diabetes, with longer sit-to-stand time (9.1 ± 0.4 vs 7.8 ± 0.3 seconds) and lower handgrip strength (39.5 ± 5.8 vs 44.6 ± 6.1 kg) when compared with normoglycemic controls. However, muscle fiber size and reaction time performance did not differ between groups. Older patients with type 2 diabetes show an accelerated decline in leg lean mass, muscle strength, and functional capacity when compared with normoglycemic controls. Exercise intervention programs should be individualized to specifically target muscle mass, strength, and functional capacity in the older population with type 2 diabetes. 23806522 Identification of a critical region in the Drosophila ryanodine receptor that confers sensitivity to diamide insecticides. Anthranilic diamides, which include the new commercial insecticide, chlorantraniliprole, are an exciting new class of chemistry that target insect ryanodine receptors. These receptors regulate release of stored intracellular calcium and play a critical role in muscle contraction. As with insects, nematodes express ryanodine receptors and are sensitive to the plant alkaloid, ryanodine. However the plant parasitic nematode, Meloidogyne incognita, is insensitive to anthranilic diamides. Expression of a full-length Drosophila melanogaster ryanodine receptor in an insect cell line confers sensitivity to the receptor agents, caffeine and ryanodine along with nanomolar sensitivity to anthranilic diamides. Replacement of a 46 amino acid segment in a highly divergent region of the Drosophila C-terminus with that from Meloidogyne results in a functional RyR which lack sensitivity to diamide insecticides. These findings indicate that this region is critical to diamide sensitivity in insect ryanodine receptors. Furthermore, this region may contribute to our understanding of the differential selectivity diamides exhibit for insect over mammalian ryanodine receptors. 23399895 Type II EATL (epitheliotropic intestinal T-cell lymphoma): a neoplasm of intra-epithelial T-cells with predominant CD8αα phenotype. In this multicentre study, we examined 60 cases of Type II enteropathy-associated T-cell lymphoma (EATL) from the Asia-Pacific region by histological review, immunohistochemistry and molecular techniques. Patients were mostly adult males (median age: 58 years, male:female 2.6:1), presenting with abdominal pain (60%), intestinal perforation (40%) and weight loss (28%). None had a history of coeliac disease and the median survival was only 7 months. Histologically, these tumours could be divided into (i) central tumour zone comprising a monotonous population of neoplastic lymphocytes, (ii) peripheral zone featuring stunted villi and morphologically atypical lymphocytes showing epitheliotropism, and (iii) distant mucosa with normal villous architecture and cytologically normal intra-epithelial lymphocytes (IELs). Characterized by extensive nuclear expression of Megakaryocyte-associated tyrosine kinase (MATK) (87%) and usually a CD8(+)CD56(+) (88%) cytotoxic phenotype, there was frequent aberrant expression of CD20 (24%). T-cell receptor (TCR) expression was silent or not evaluable in 40% but of the remainder, there was predominant expression of TCRαβ over TCRγδ (1.6:1). In keeping with the normal ratio of IEL subsets, CD8(+) cases showed predominant CD8αα homodimer expression (77%), regardless of TCR lineage. These tumours constitute a distinct entity from classical EATL, and the pathology may reflect tumour progression from IEL precursors, remnants of which are often seen in the distant mucosa. 23886564 A Patient with Nephrotic-Range Proteinuria and Focal Global Glomerulosclerosis. A young male is evaluated for nephrotic-range proteinuria, hypercalciuria, and an elevated serum creatinine. A renal biopsy is performed and shows focal global glomerulosclerosis. The absence of nephrotic syndrome suggest that glomerulosclerosis was a secondary process. Further analysis of the proteinuria showed it to be due mainly to low-molecular weight proteins. The case illustrates the crucial role of electron microscopy as well as evaluation of the identity of the proteinuria that accompanies a biopsy finding of focal and global or focal and segmental glomerulosclerosis. 23440974 Highly Ordered Hollow Oxide Nanostructures: The Kirkendall Effect at the Nanoscale. Highly ordered ultra-long oxide nanotubes are fabricated by a simple two-step strategy involving the growth of copper nanowires on nanopatterned template substrates by magnetron sputtering, followed by thermal annealing in air. The formation of such tubular nanostructures is explained according to the nanoscale Kirkendall effect. The concept of this new fabrication route is also extendable to create periodic zero-dimensional hollow nanostructures. 23742009 Mitochondrial mutations and aging: random drift is insufficient to explain the accumulation of mitochondrial deletion mutants in short-lived animals. Mitochondrial DNA deletions accumulate over the life course in post-mitotic cells of many species and may contribute to aging. Often a single mutant expands clonally and finally replaces the wild-type population of a whole cell. One proposal to explain the driving force behind this accumulation states that random drift alone, without any selection advantage, is sufficient to explain the clonal accumulation of a single mutant. Existing mathematical models show that such a process might indeed work for humans. However, to be a general explanation for the clonal accumulation of mtDNA mutants, it is important to know whether random drift could also explain the accumulation process in short-lived species like rodents. To clarify this issue, we modelled this process mathematically and performed extensive computer simulations to study how different mutation rates affect accumulation time and the resulting degree of heteroplasmy. We show that random drift works for lifespans of around 100 years, but for short-lived animals, the resulting degree of heteroplasmy is incompatible with experimental observations. 23732811 Interaction between a cationic porphyrin and ctDNA investigated by SPR, CV and UV-vis spectroscopy. The interaction between ctDNA and a cationic porphyrin was studied in this work. The binding process was monitored by surface plasmon resonance (SPR) spectroscopy in detail. The association, dissociation rate constants and the binding constants calculated by global analysis were 2.4×10(2)±26.4M(-1)s(-1), 0.011±0.0000056s(-1) and 2.18×10(4)M(-1), respectively. And the results were confirmed by cyclic voltammetry and UV-vis absorption spectroscopy. The binding constants obtained from cyclic voltammetry and UV-vis absorption spectroscopy were 8.28×10(4)M(-1) and 6.73×10(4)M(-1) at 298K, respectively. The covalent immobilization methodology of ctDNA onto gold surface modified with three different compounds was also investigated by SPR. These compounds all contain sulfydryl but with different terminated functional groups. The results indicated that the 11-MUA (HS(CH2)10COOH)-modified gold film is more suitable for studying the DNA-drug interaction. 22846690 Acquired poikiloderma: Proposed classification and diagnostic approach. "Poikiloderma" is a morphologic and descriptive term referring to a combination of cutaneous atrophy, telangiectasia, and varied macular pigmentary changes that result in a mottled skin appearance. Its etiology includes both congenital and acquired causes. Many studies have reported different causes of acquired poikiloderma; however, no single well-defined classification has been explored to date. Herein, we analyze all the possible causes of acquired poikiloderma and propose an etiological classification that, hopefully, will lead to better characterization for this ill-defined condition. Moreover, this study presents a step-by-step approach to the management of patients with acquired poikiloderma and summarizes the key differentiating features for each individual cause, which may help in easy and precise diagnosis of different causes of acquired poikiloderma. 23922994 Woodland dynamics at the northern range periphery: a challenge for protected area management in a changing world. Managers of protected natural areas increasingly are confronted with novel ecological conditions and conflicting objectives to preserve the past while fostering resilience for an uncertain future. This dilemma may be pronounced at range peripheries where rates of change are accelerated and ongoing invasions often are perceived as threats to local ecosystems. We provide an example from City of Rocks National Reserve (CIRO) in southern Idaho, positioned at the northern range periphery of pinyon-juniper (P-J) woodland. Reserve managers are concerned about P-J woodland encroachment into adjacent sagebrush steppe, but the rates and biophysical variability of encroachment are not well documented and management options are not well understood. We quantified the rate and extent of woodland change between 1950 and 2009 based on a random sample of aerial photo interpretation plots distributed across biophysical gradients. Our study revealed that woodland cover remained at approximately 20% of the study area over the 59-year period. In the absence of disturbance, P-J woodlands exhibited the highest rate of increase among vegetation types at 0.37% yr(-1). Overall, late-successional P-J stands increased in area by over 100% through the process of densification (infilling). However, wildfires during the period resulted in a net decrease of woody evergreen vegetation, particularly among early and mid-successional P-J stands. Elevated wildfire risk associated with expanding novel annual grasslands and drought is likely to continue to be a fundamental driver of change in CIRO woodlands. Because P-J woodlands contribute to regional biodiversity and may contract at trailing edges with global warming, CIRO may become important to P-J woodland conservation in the future. Our study provides a widely applicable toolset for assessing woodland ecotone dynamics that can help managers reconcile the competing demands to maintain historical fidelity and contribute meaningfully to the U.S. protected area network in a future with novel, no-analog ecosystems. 23884635 Retrospective serosurveillance of bovine norovirus (GIII.2) and nebovirus in cattle from selected feedlots and a veal calf farm in 1999 to 2001 in the United States. There is a dearth of information on the seroprevalence of bovine norovirus (BoNoV) and nebovirus in cattle of the US. In this retrospective study, serum IgG antibodies to two bovine enteric caliciviruses, GIII.2 BoNoV (Bo/CV186-OH/00/US) and genetically and antigenically distinct nebovirus (Bo/NB/80/US), were evaluated in feedlot and veal calves from different regions of the US during 1999-2001. Three groups of 6- to 7-month-old feedlot calves from New Mexico (NM) (n=103), Arkansas (AR) (n=100) and Ohio (OH) (n=140) and a group of 7- to 10-day-old Ohio veal calves (n=47) were studied. Serum samples were collected pre-arrival or at arrival to the farms for the NM, AR and OH calves and 35 days after arrival for all groups for monitoring seroconversion rates during the period. Virus-like particles of Bo/CV186-OH/00/US and Bo/NB/80/US were expressed using the baculovirus expression system and were used in ELISA to measure antibodies. A high seroprevalence of 94-100 % and 78-100 % was observed for antibodies to GIII.2 BoNoV and nebovirus, respectively, in the feedlot calves tested. In the Ohio veal farm, an antibody seroprevalence of 94-100 % and 40-66 % was found for GIII.2 BoNoV and nebovirus, respectively. Increased seropositive rates of 38-85 % for GIII.2 BoNoV and 26-83 % for nebovirus were observed at 35 days after arrival and commingling on farms for all groups. Infection of calves with either GIII.2 BoNoV or nebovirus, or both viruses, appeared to be common in the regions studied in the US during 1999-2001. These two viruses likely remain endemic because no commercial vaccines are available. 23169597 Sleep disordered breathing in patients with primary ciliary dyskinesia. Upper airway manifestations of primary ciliary dyskinesia (PCD) can cause obstructive sleep apnea syndrome (OSAS). Also abnormalities of lung mechanics and gas exchange may lead to sleep abnormalities in these patients. To determine the rate of OSAS and sleep quality in PCD patients, and whether these are related to upper respiratory system manifestations and severity of lung disease in these patients. Twenty-nine PCD patients and healthy controls were included to the study. Respiratory symptoms within the previous month were separately scored with the severity of the symptoms. Physical examination, pulmonary function tests, and ear-nose-throat assessments were obtained. All patients completed the Turkish version of Pittsburgh Sleep Quality Index (PSQI), sleep questionnaire, and underwent overnight polysomnography. Categorical variables were compared with chi-square and Fisher's exact test while continuous variables were compared with Student's t-test. Eleven PCD patients reported themselves to be "poor" sleepers, compared to only one subject in the control group (P = 0.002). Sixty-five percent of PCD patients had habitual snoring (HS). Fifty-two percent of the PCD patients had OSAS in polysomnography. OSAS rate was higher in PCD patients who snored (P = 0.008). HS and OSAS were more common in PCD patients who had cigarette smoke exposure in their homes (P < 0.001 and P = 0.02, respectively). Patients with PCD have decreased sleep quality and higher rate of sleep disordered breathing compared to controls and higher rate of OSAS compared to population rates. Cigarette smoke exposure is an important risk factor for OSAS in PCD patients. Assessment and treatment of sleep disorders in PCD should be a part of disease management. Pediatr Pulmonol. 2013; 48:897-903. © 2012 Wiley Periodicals, Inc. 23921900 Reference region automatic extraction in dynamic [(11)C]PIB. The positron emission tomography (PET) radiotracer [(11)C]Pittsburgh Compound B (PIB) is a marker of amyloid plaque deposition in brain, and binding potential is usually quantified using the cerebellum as a reference where the specific binding is negligible. The use of the cerebellum as a reference, however, has been questioned by the reported cerebellar [(11)C]PIB retention in familial Alzheimer's disease (AD) subjects. In this work, we developed a supervised clustering procedure for the automatic extraction of a reference region in [(11)C]PIB studies. Supervised clustering models each gray matter voxel as the linear combination of three predefined kinetic classes, normal and lesion gray matter, and blood pool, and extract reference voxels in which the contribution of the normal gray matter class is high. In the validation with idiopathic AD subjects, supervised clustering extracted reference voxels mostly in the cerebellum that indicated little specific [(11)C]PIB binding, and total distribution volumes of the extracted region were lower than those of the cerebellum. Next, the methodology was applied to the familial AD cohort where the cerebellar amyloid load had been demonstrated previously, resulting in higher binding potential compared with that obtained with the cerebellar reference. The supervised clustering method is a useful tool for the accurate quantification of [(11)C]PIB studies.Journal of Cerebral Blood Flow & Metabolism advance online publication, 7 August 2013; doi:10.1038/jcbfm.2013.133. 23949159 Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice. The chronic and systemic administration of rapamycin extends life span in mammals. Rapamycin is a pharmacological inhibitor of mTOR. Metformin also inhibits mTOR signaling but by activating the upstream kinase AMPK. Here we report the effects of chronic and systemic administration of the two mTOR inhibitors, rapamycin and metformin, on adult neural stem cells of the subventricular region and the dendate gyrus of the mouse hippocampus. While rapamycin decreased the number of neural progenitors, metformin-mediated inhibition of mTOR had no such effect. Adult-born neurons are considered important for cognitive and behavioral health, and may contribute to improved health span. Our results demonstrate that distinct approaches of inhibiting mTOR signaling can have significantly different effects on organ function. These results underscore the importance of screening individual mTOR inhibitors on different organs and physiological processes for potential adverse effects that may compromise health span. 23954076 Ceriponols A-K, tremulane sesquitepenes from Ceriporia lacerate HS-ZJUT-C13A, a fungal endophyte of Huperzia serrata. Tremulane sesquiterpenes ceriponols A-K, together with three known ones tremulenediol A, 11,12-dihydroxy-1-tremulen-5-one and conocenol B, were isolated from the cultures of Ceriporia lacerate, a fungal endophyte residing in the stems of the medicinal plant Huperzia serrata. Among these isolates, ceriponol B possessed an unprecedent 12-nortremulane skeleton. The structures of all isolates were elucidated by spectroscopic methods, including MS and NMR (1D and 2D) spectroscopic techniques. The cytotoxic activities of ceriponols A-K were evaluated against three human tumor cell lines (HeLa, HepG2, and SGC 7901). Ceriponols F and K exhibited moderate cytotoxicity against all the tested human cancer cell lines with IC50 values ranging from 32.3±0.4 to 173.2±1.5μM, while ceriponol G showed slightly better cytotoxicity against a HeLa cell line. 23770636 A rapid, accurate and robust UHPLC-MS/MS method for quantitative determination of BMS-927711, a CGRP receptor antagonist, in plasma in support of non-clinical toxicokinetic studies. BMS-927711 is a calcitonin gene-related peptide (CGRP) receptor antagonist that is being developed for the treatment of migraine. A rapid, accurate and robust assay was developed and validated for the quantitation of BMS-927711 in rat, monkey, rabbit and mouse plasma using ultra high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS). A simplified method screening strategy was utilized that included a liquid-liquid extraction (LLE) methodology and eleven LC columns (ten sub-2 μm UHPLC columns and one 2.6 μm HPLC column) for screening with emphasis on the removal of phospholipids, avoidance of metabolite interference and ruggedness of LC conditions. A stable isotope labeled [(13)C2, D4]-BMS-927711 was used as the internal standard, and 50 μL of plasma samples were used for extraction by automated LLE with methyl tert-butyl ether (MTBE) in 96-well format. Chromatographic separation was achieved with an isocratic elution and a gradient column wash on a Waters Acuity UPLC(®) BEH C18 column (2.1 mm × 50 mm, 1.7 μm) with run time of 3.7 min. Positive electrospray ionization was performed using selected reaction monitoring (SRM) with transitions of m/z 535>256 for BMS-927711 and m/z 541>256 for [(13)C2, D4]-BMS-927711. The standard curve, which ranged from 3.00 to 3000 ng/mL for BMS-927711, was fitted to a 1/x(2) weighted linear regression model. The intra-assay precision was within 5.2% CV, inter-assay precision was within 5.9% CV, and the assay accuracy was within ±5.2% deviation (%Dev) of the nominal values in all the species. The stability of an N-carbamoyl glucuronide metabolite was carefully investigated, and the conversion of this metabolite to BMS-927711 was minimal and manageable without a stabilization procedure. The method was successfully applied to multiple non-clinical toxicokinetic studies in different species in support of the investigative new drug (IND) filing. 23827493 Revisiting the tailor's bunion and adductovarus deformity of the fifth digit. Correction of the fifth digit deformity and Tailor's Bunion can be rewarding as well as challenging for a foot and ankle surgeon. Immense care should be taken when performing these reconstructive surgical procedure, especially to avoid and minimize complication rates and mainly to prevent neurovascular damage. Appropriate surgical procedure selection for the fifth digit deformity and Tailor's Bunion is necessary in order to obtain a long term predictable outcome. 23956416 Virus-induced gene silencing unravels multiple transcription factors involved in floral growth and development in Phalaenopsis orchids. Orchidaceae, one of the largest angiosperm families, has significant commercial value. Isolation of genes involved in orchid floral development and morphogenesis, scent production, and colouration will advance knowledge of orchid flower formation and facilitate breeding new varieties to increase the commercial value. With high-throughput virus-induced gene silencing (VIGS), this study identified five transcription factors involved in various aspects of flower morphogenesis in the orchid Phalaenopsis equestris. These genes are PeMADS1, PeMADS7, PeHB, PebHLH, and PeZIP. Silencing PeMADS1 and PebHLH resulted in reduced flower size together with a pelaloid column containing petal-like epidermal cells and alterations of epidermal cell arrangement in lip lateral lobes, respectively. Silencing PeMADS7, PeHB, and PeZIP alone resulted in abortion of the first three fully developed flower buds of an inflorescence, which indicates the roles of the genes in late flower development. Furthermore, double silencing PeMADS1 and PeMADS6, C- and B-class MADS-box genes, respectively, produced a combinatorial phenotype with two genes cloned in separate vectors. Both PeMADS1 and PeMADS6 are required to ensure the normal development of the lip and column as well as the cuticle formation on the floral epidermal cell surface. Thus, VIGS allows for unravelling the interaction between two classes of MADS transcription factors for dictating orchid floral morphogenesis. 23846676 Controversies in the prophylaxis and treatment of postsurgical pericardial syndromes: a critical review with a special emphasis on paediatric age. Postsurgical pericardial syndromes are common complications after cardiac surgery; however, their treatment is not well established yet. We reviewed the accuracy and limits of clinical trials of prophylaxis and treatment of these diseases to identify an evidence-based therapeutic approach. We performed a literature search in the National Library of Medicine using the keywords pericardial effusion, cardiac surgery and paediatric/congenital. The research was then redefined adding separately the keywords postpericardiotomy syndrome, NSAIDs, steroids and colchicine. We found 12 clinical trials (eight for the prophylaxis and four regarding treatment), testing three major agent classes: NSAIDs, corticosteroids and colchicine. Therapy is generally based on NSAID with or without steroids with the adjunct of colchicine for recurrences. Only a few randomized controlled trials (RCTs) in adults support NSAID therapy. Efficacy of steroids has been proved only in small paediatric works, whereas no studies are available for colchicine. Studies furthermore presented some limitations: not univocal endpoints (not allowing for a meta-analysis), a limited sample size, scarce attention to confounders (such as the underlying cardiac disease and diuretic/analgesic regimen). Moreover, different agents were not assessed, nor when to start therapy. More evidence (two wide RCT plus a meta-analysis) supports the role of colchicine for prophylaxis in adults. Prophylaxis with NSAID/corticosteroids instead failed to have significant advantage in children, whereas a few data are available for adults. Evidence for the treatment of postsurgical pericardial syndromes is incomplete, making it difficult to understand when to treat and which agent to employ, especially in children. 23827524 Analysis of hnRNPA1, A2/B1, and A3 genes in patients with amyotrophic lateral sclerosis. Mutations in the prion-like domain (PrLD) of hnRNPA1 and A2/B1 genes were recently identified in 2 families with inclusion body myopathy associated with Paget disease of bone, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis, and in ALS patients. These mutations were shown to increase the propensity of hnRNPA1 and A2/B1 proteins, which are TDP-43-binding partners, to self-aggregate. hnRNPA3 protein contains a similar PrLD and was recently described in the p62-positive/TDP-43-negative inclusions in affected tissues of C9orf72-mutated ALS/FTD patients. We screened hnRNPA1, A2/B1, and A3 genes in a cohort of 113 familial ALS (FALS) individuals without mutations in other known ALS-causative genes. We extended our analysis to 108 FALS with mutations in other ALS-associated genes and to 622 sporadic cases by screening specifically the PrLDs of hnRNPA1, A2/B1, and A3. We failed to find variants in each cohort. Our results suggest that mutations in hnRNPA1, A2/B1, and A3 genes are a rare finding in ALS. 23915412 Drug interactions in Brazilian type 2 diabetes patients. The aim of this paper is to identify the prevalence of the most frequent drug interactions in patients using oral antidiabéticos and their association with capillary glucose and medication adherence. In total, 579 type 2 diabetes mellitus patients from 12 health institutions in Fortaleza, Brazil were interviewed in 2009. A form was applied, including questions on medication use, comorbidities, lifestyle, body mass index and random capillary glucose. Results revealed that 26.7% used five or more different drugs simultaneously and daily. Statistically significant drug interactions occurred between antidiabéticos and diuretics, angiotensin-converting enzyme inhibitors, anti-lipidaemics and corticoids. No significant association was found between polypharmacy, medication adherence and glucose. It is important for nurses, in consensus with other health professionals, to consider the possibility of other drugs that mean less risk for diabetes patients' glucose control or of increased antidiabetics doses. 23629669 Simple and Rapid Synthesis of Magnetite/Hydroxyapatite Composites for Hyperthermia Treatments via a Mechanochemical Route. This paper presents a simple method for the rapid synthesis of magnetite/hydroxyapatite composite particles. In this method, superparamagnetic magnetite nanoparticles are first synthesized by coprecipitation using ferrous chloride and ferric chloride. Immediately following the synthesis, carbonate-substituted (B-type) hydroxyapatite particles are mechanochemically synthesized by wet milling dicalcium phosphate dihydrate and calcium carbonate in a dispersed suspension of magnetite nanoparticles, during which the magnetite nanoparticles are incorporated into the hydroxyapatite matrix. We observed that the resultant magnetite/hydroxyapatite composites possessed a homogeneous dispersion of magnetite nanoparticles, characterized by an absence of large aggregates. When this material was subjected to an alternating magnetic field, the heat generated increased with increasing magnetite concentration. For a magnetite concentration of 30 mass%, a temperature increase greater than 20 K was achieved in less than 50 s. These results suggest that our composites exhibit good hyperthermia properties and are promising candidates for hyperthermia treatments. 23199882 Polymethoxyflavones as agents that prevent formation of cataract: nobiletin congeners show potent growth inhibitory effects in human lens epithelial cells. Posterior capsular opacification (PCO) is the most frequent complication and the primary reason for visual decrease after extracapsular cataract surgery. The proliferation and migration of leftover lens epithelial cells (LECs) after surgery may contribute to the development of PCO. To prevent PCO, a rational approach would be to inhibit both the proliferation and the migration of LECs using nontoxic xenobiotics. Nobiletin, one of the most abundant polymethoxyflavones (PMFs) in citrus peel, and its synthetic congeners displayed a potent inhibition of LEC proliferation. Structural features which enhance anti-proliferative activity have also been discussed. 23810838 Captured streams and springs in combined sewers: A review of the evidence, consequences and opportunities. Captured streams and springs may be flowing in combined sewers, increasing clean baseflow in pipes and wastewater treatment works (WwTWs), reducing pipe capacity and increasing treatment costs. The UK water industry is aware of this in principle, but there has been no explicit discussion of this in the published literature, nor have there been any known attempts to manage it. Instead, the current focus is on the similar intrusion of groundwater infiltration through pipe cracks and joints. We have conducted a thorough review of literature and international case studies to investigate stream and spring capture, finding several examples with convincing evidence that this occurs. We identify three modes of entry: capture by conversion, capture by interception, and direct spring capture. Methods to identify and quantify capture are limited, but the experience in Zurich suggests that it contributed 7-16% of the baseflow reaching WwTWs. There are negative impacts for the water industry in capital and operational expenditure, as well as environmental and social impacts of loss of urban streams. For a typical WwTW (Esholt, Bradford) with 16% of baseflow from captured streams and springs, we conservatively estimate annual costs of £2 million to £7 million. A detailed case study from Zurich is considered that has successfully separated captured baseflow into daylighted streams through the urban area, with multiple economic, environmental and social benefits. We conclude that there is a strong case for the UK water industry to consider captured streams and springs, quantify them, and assess the merits of managing them. 23934073 Development of a dendritic cell vaccine encoding multiple cytotoxic T lymphocyte epitopes targeting hepatitis C virus. The aim of the present study was to develop a dendritic cell (DC) vaccine encoding hepatitis C virus (HCV) multiple cytotoxic T lymphocyte (CTL) epitopes that can stimulate T cell responses in vitro, and can be used for immunization in vivo. DCs were infected with recombinant replication-defective adenoviruses (Ads) expressing 2 HCV sequences fused with green fluorescent protein (GFP) and FLAG tags. One sequence (sequence 1) contained the HCV CTL epitopes, NS4B 1793‑1801 and P7 774-782, as well as the HCV Th epitope, NS3 1248‑1261. A second sequence (sequence 2) was the positive epitope control which contained HCV core 35-44, core 132‑140 and NS3 1248-1261. The efficiency of infection was detected by flow cytometry and the expression of HCV epitopes in the DCs was confirmed by RT-PCR and western blot analysis. Ad infection significantly enhanced DC maturation and interleukin (IL)-12p70 production, resulting in T cell proliferation and increased interferon-γ secretion. The CTLs stimulated by Ad-infected DCs specifically killed Huh7.5 human hepatoma cells. The recombinant Ad-expressing multiple CTL HCV epitopes effectively infected the DCs in vitro and promoted T cell antiviral immune responses, thereby laying the foundation for the development of anti-HCV DC vaccines. 23777694 Estimating health service utilization for treatment of pneumococcal disease: the case of Brazil. Health service utilization (HSU) is an essential component of economic evaluations of health initiatives. Defining HSU for cases of pneumococcal disease (PD) is particularly complex considering the varying clinical manifestations and diverse severity. We describe the process of developing estimates of HSU for PD as part of an economic evaluation of the introduction of pneumococcal conjugate vaccine in Brazil. Nationwide inpatient and outpatient HSU by children under-5 years with meningitis (PM), sepsis (PS), non-meningitis non-sepsis invasive PD (NMNS), pneumonia, and acute otitis media (AOM) was estimated. We assumed that all cases of invasive PD (PM, PS, and NMNS) required hospitalization. The study perspective was the health system, including both the public and private sectors. Data sources were obtained from national health information systems, including the Hospital Information System (SIH/SUS) and the Notifiable Diseases Information System (SINAN); surveys; and community-based and health care facility-based studies. We estimated hospitalization rates of 7.69 per 100,000 children under-5 years for PM (21.4 for children <1 years of age and 4.3 for children aged 1-4 years), 5.89 for PS (20.94 and 2.17), and 4.01 for NMNS (5.5 and 3.64) in 2004, with an overall hospitalization rate of 17.59 for all invasive PD (47.27 and 10.11). The estimated incidence rate of all-cause pneumonia was 93.4 per 1000 children under-5 (142.8 for children <1 years of age and 81.2 for children aged 1-4 years), considering both hospital and outpatient care. Secondary data derived from health information systems and the available literature enabled the development of national HSU estimates for PD in Brazil. Estimating HSU for noninvasive disease was challenging, particularly in the case of outpatient care, for which secondary data are scarce. Information for the private sector is lacking in Brazil, but estimates were possible with data from the public sector and national population surveys. 23907000 Executive deficits: A continuum schizophrenia-bipolar disorder or specific to schizophrenia? Executive dysfunction is a core deficit in schizophrenia (SCH). However, some controversy exists when examining such deficits in studies of bipolar disorder (BD). The aim of the present research was to investigate whether executive deficits were similar or distinct in both illnesses. 148 patients with BD, 262 patients with stable SCH and 108 healthy controls (CT) were recruited for the study. The BD patients were also differentiated according to the clinical subtype (BD subtype I, BDI, or subtype II, BDII) they exhibited and according to whether there was a previous history of psychosis. All subjects completed a broad neuropsychological battery. The influences of other clinical data were also evaluated. Both the BD and SCH patients showed widespread deficits in all executive tasks, with no differences between these two groups of patients. BDII patients only showed some selective deficits, and their scores on planning and inhibitory tasks fell on the continuum between the CT, the BDI and the SCH patients. Psychotic phenotypes did not influence the BD patients' performance on the battery. Other clinical variables related to illness severity did influence deficits in any subgroup of patients. Our results point to the existence of common executive disturbances in both diagnostic categories. Moreover, the inclusion of subclinical phenotypes in research may be helpful in cognitive assessment studies. 23959877 Analysis of Chlamydomonas thiamin metabolism in vivo reveals riboswitch plasticity. Thiamin (vitamin B1) is an essential micronutrient needed as a cofactor for many central metabolic enzymes. Animals must have thiamin in their diet, whereas bacteria, fungi, and plants can biosynthesize it de novo from the condensation of a thiazole and a pyrimidine moiety. Although the routes to biosynthesize these two heterocycles are not conserved in different organisms, in all cases exogenous thiamin represses expression of one or more of the biosynthetic pathway genes. One important mechanism for this control is via thiamin-pyrophosphate (TPP) riboswitches, regions of the mRNA to which TPP can bind directly, thus facilitating fine-tuning to maintain homeostasis. However, there is little information on how modulation of riboswitches affects thiamin metabolism in vivo. Here we use the green alga, Chlamydomonas reinhardtii, which regulates both thiazole and pyrimidine biosynthesis with riboswitches in the THI4 (Thiamin 4) and THIC (Thiamin C) genes, respectively, to investigate this question. Our study reveals that regulation of thiamin metabolism is not the simple dogma of negative feedback control. Specifically, balancing the provision of both of the heterocycles of TPP appears to be an important requirement. Furthermore, we show that the Chlamydomonas THIC riboswitch is controlled by hydroxymethylpyrimidine pyrophosphate, as well as TPP, but with an identical alternative splicing mechanism. Similarly, the THI4 gene is responsive to thiazole. The study not only provides insight into the plasticity of the TPP riboswitches but also shows that their maintenance is likely to be a consequence of evolutionary need as a function of the organisms' environment and the particular pathway used. 23428531 Reliability of a questionnaire for pharmacological treatment appropriateness in patients with multiple chronic conditions. The original Medication Appropriateness Index was validated for elderly and polymedicated patients, both in hospital and outpatient contexts. However, no studies have applied this questionnaire in patients with multiple chronic conditions. The objective of this study is to assess the reliability of a modified Medication Appropriateness Index questionnaire in a population of patients with multiple chronic conditions. We selected patients with multiple chronic conditions who were included in an integrated care project conducted at the Hospital Universitario Virgen del Rocío. To determine inter-observer reliability, each professional (internist or hospital pharmacy specialist) applied the questionnaire under the same conditions and with the same resources. To determine intra-observer reliability, each physician applied the tool at baseline and two months later. We measured inter- and intra-observer reliability using the kappa coefficient. The proportion of overall agreement was also determined. We obtained a weak overall kappa (k=0.38) for inter-observer reliability and moderate (k=0.52) and very good (k=0.84) values for intra-observer reliability of the internist and specialist in hospital pharmacy, respectively. The proportion of overall agreement is very high in all three situations: 96%, 98%, and 99%, respectively. Despite its limitations, the Medication Appropriateness Index questionnaire modified by our group can be used, as a reliable method, to assess the appropriateness of pharmacotherapy in patients with multiple chronic conditions. 23924894 Synthesis and biological evaluation of novel benzyl piperazine derivatives of 5-(5-nitroaryl)-1,3,4-thiadiazoles as Anti-Helicobacter pylori agents. Background and the purpose of the studyHelicobacter pylori is recognized as the main cause of gastritis and gastroduodenal ulcers and classified as class 1 carcinogen pathogen. Different 1,3,4-thiadiazole derivatives bearing 5-nitroaryl moiety have been shown considerable anti- H. pylori activity. In attempt to find new and potent derivatives of described scaffold, a new series of 1-(substituted benzyl)-4-(5-(5-nitroaryl-2-yl)-1,3,4-thiadiazol-2-yl)piperazine derivatives were synthesized and evaluated against three metronidazole-resistant isolates of H. pylori using paper disk diffusion bioassay test. The title compounds were prepared through the reaction of 1-(5-(5-nitroaryl-2-yl)-1,3,4-thiadiazol-2-yl) piperazine 5a-b and substituted benzyl chloride in DMF. The inhibitory activity of the new derivatives 6a-q against three metronidazole-resistant isolates of H. pylori was evaluated by the disc diffusion method and compared with the commercially available standard drug metronidazole. The results of SAR study indicated that the potency and anti-H. pylori activity profile of synthesized derivatives is mainly attributed to the substituted nitroaryl moiety at the C-5 position of 1,3,4-thiadiazole ring. Most of 1,3,4-thiadiazole derivatives bearing 5-nitrofuran moiety at C-5 position of central thiadiazole ring, demonstrated more promising anti-H. pylori than the 5-nitrothiophen counterpart. The most potent nitrofuran derivative containing 3-methoxybenzyl piperazine pendant at the C-2 position of 1,3,4-thiadiazole ring (compound 6i), demonstrated strong anti-H. pylori potential at studied concentrations 100-25 mug/disk (IZD > 20 mm) against all studied metronidazole- resistant isolates of H. pylori. 23820786 The Impact of Long-Term Body Mass Index Patterns on Health-Related Quality of Life: The Doetinchem Cohort Study. Overweight is associated with a reduced health-related quality of life (QOL), but less is known about the impact of long-term body mass index (BMI, calculated as weight (kg)/height (m)(2)) patterns on QOL in adults. In the Dutch Doetinchem Cohort Study (1989-2009) that included 1,677 men and 1,731 women aged 20-66 years, 6 BMI patterns were defined by using 4 measurements over a 15-year period: 1) persistent healthy weight (18.5-24.9, reference pattern); 2) persistent overweight (25.0-29.9); 3) persistent obesity (≥30.0); 4) developing overweight; 5) developing obesity; and 6) switching between BMI categories. For each BMI pattern, adjusted QOL (measured on a 0-100 scale) was estimated at the end of this period. The lowest QOL was observed for persistent obesity of all BMI patterns. It was 5.0 points (P = 0.02) lower for 1 mental dimension in men and 6.2-11.6 points (P < 0.05) lower for 5 (mainly physical) dimensions in women. Developing overweight or obesity scored 1.8-6.3 points (P < 0.05) lower on 2-5 (mainly physical) dimensions. Persistent overweight hardly differed from a persistent healthy weight. In women, switching between BMI categories resulted in a lower QOL on the mental dimensions. Studying long-term BMI patterns over a 15-year period showed that persistent obesity, developing overweight, and developing obesity resulted in a lower QOL-particularly on the physical dimensions-compared with a persistent healthy weight. 23519470 Novel Phosphorylation and Ubiquitination Sites Regulate Reactive Oxygen Species-dependent Degradation of Anti-apoptotic c-FLIP Protein. The cytosolic protein c-FLIP (cellular Fas-associated death domain-like interleukin 1β-converting enzyme inhibitory protein) is an inhibitor of death receptor-mediated apoptosis that is up-regulated in a variety of cancers, contributing to apoptosis resistance. Several compounds found to restore sensitivity of cancer cells to TRAIL, a TNF family death ligand with promising therapeutic potential, act by targeting c-FLIP ubiquitination and degradation by the proteasome. The generation of reactive oxygen species (ROS) has been implicated in c-FLIP protein degradation. However, the mechanism by which ROS post-transcriptionally regulate c-FLIP protein levels is not well understood. We show here that treatment of prostate cancer PPC-1 cells with the superoxide generators menadione, paraquat, or buthionine sulfoximine down-regulates c-FLIP long (c-FLIPL) protein levels, which is prevented by the proteasome inhibitor MG132. Furthermore, pretreatment of PPC-1 cells with a ROS scavenger prevented ubiquitination and loss of c-FLIPL protein induced by menadione or paraquat. We identified lysine 167 as a novel ubiquitination site of c-FLIPL important for ROS-dependent degradation. We also identified threonine 166 as a novel phosphorylation site and demonstrate that Thr-166 phosphorylation is required for ROS-induced Lys-167 ubiquitination. The mutation of either Thr-166 or Lys-167 was sufficient to stabilize c-FLIP protein levels in PPC-1, HEK293T, and HeLa cancer cells treated with menadione or paraquat. Accordingly, expression of c-FLIP T166A or K167R mutants protected cells from ROS-mediated sensitization to TRAIL-induced cell death. Our findings reveal novel ROS-dependent post-translational modifications of the c-FLIP protein that regulate its stability, thus impacting sensitivity of cancer cells to TRAIL. 23703643 Supramolecular complexations of natural products. Complexations of natural products with synthetic receptors as well as the use of natural products as host compounds are reviewed, with an emphasis on possible practical uses or on biomedical significance. Applications such as separation, sensing, enzyme monitoring, and protection of natural drugs are first outlined. We then discuss examples of complexes with all important classes of natural compounds, such as amino acids, peptides, nucleosides/nucleotides, carbohydrates, catecholamines, flavonoids, terpenoids/steroids, alkaloids, antibiotics and toxins. 23801736 The coeruleus/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson's disease. In Parkinson's disease, rapid eye movement sleep behaviour disorder is an early non-dopaminergic syndrome with nocturnal violence and increased muscle tone during rapid eye movement sleep that can precede Parkinsonism by several years. The neuronal origin of rapid eye movement sleep behaviour disorder in Parkinson's disease is not precisely known; however, the locus subcoeruleus in the brainstem has been implicated as this structure blocks muscle tone during normal rapid eye movement sleep in animal models and can be damaged in Parkinson's disease. Here, we studied the integrity of the locus coeruleus/subcoeruleus complex in patients with Parkinson's disease using combined neuromelanin-sensitive, structural and diffusion magnetic resonance imaging approaches. We compared 24 patients with Parkinson's disease and rapid eye movement sleep behaviour disorder, 12 patients without rapid eye movement sleep behaviour disorder and 19 age- and gender-matched healthy volunteers. All subjects underwent clinical examination and characterization of rapid eye movement sleep using video-polysomnography and multimodal imaging at 3 T. Using neuromelanin-sensitive imaging, reduced signal intensity was evident in the locus coeruleus/subcoeruleus area in patients with Parkinson's disease that was more marked in patients with than those without rapid eye movement sleep behaviour disorder. Reduced signal intensity correlated with the percentage of abnormally increased muscle tone during rapid eye movement sleep. The results confirmed that this complex is affected in Parkinson's disease and showed a gradual relationship between damage to this structure, presumably the locus subcoeruleus, and abnormal muscle tone during rapid eye movement sleep, which is the cardinal marker of rapid eye movement sleep behaviour disorder. In longitudinal studies, the technique may also provide early markers of non-dopaminergic Parkinson's disease pathology to predict the occurrence of Parkinson's disease. 22759209 High discordance between punch biopsy and excision in establishing basal cell carcinoma subtype: analysis of 500 cases. Background  Basal cell carcinoma (BCC) is the most frequently occurring cancer in humans. Worldwide incidences rise about 10% each year, increasing the burden on dermatologists, general practitioners and pathologists as well as increasing costs for the health care system. Increasingly non-surgical treatment options are used in the treatment of BCC, without histological confirmation of BCC subtype, potentially resulting in under-treatment. Objective  We evaluated the diagnostic accuracy of a punch biopsy for the BCC histological subytpe in a primary BCC and the prevalence of biopsy-based under-diagnosis of aggressive subtypes. Accuracy of a punch biopsy was defined as concordance of the diagnosis of subtype of BCC at punch biopsy and excision. Methods  A retrospective chart-review was performed of primary BCC, which were proven by punch biopsy and subsequently treated by excision. The first 100 consecutive BCCs per year during the years 2004-2009 were included, yielding a total of 500 evaluated BCCs. Results  The overall accuracy of punch biopsy for BCC subtype at excision was 69%, in single-type BCC 83% (n = 343) and in mixed-type BCC 37% (n = 157). Accuracy varied substantially according to BCC subtype, being highest in the superficial subtype (84%) and subsequently in infiltrative (69%), nodular (63%) and micronodular subtype (38%). In 11% of all cases, an unsuspected more aggressive subtype was present. Conclusion  Punch biopsy has a high accuracy in single-type BCCs and a considerably lower accuracy in mixed-type BCCs for establishing BCC subtype compared to excision. The presence of an unsuspected aggressive subtype could explain therapy failure of non-surgical treatments like imiquimod or photodynamic therapy. 23916451 Epidemiological and molecular characterization of community and hospital acquired Staphylococcus aureus strains prevailing in Shenyang, Northeastern China. In order to obtain adequate information for the treatment of methicillin resistant Staphylococcus aureus (MRSA) infections, it is crucial to identify trends in epidemiological and antimicrobial resistance patterns of local S. aureus strains. Community and hospital acquired S. aureus isolates (n=202) were characterized using staphylococcal cassette chromosome mec (SCCmec) typing, pulse field gel electrophoresis (PFGE) analysis, spa typing and minimal inhibitory concentration (MIC) determination. The prevalence of the Panton-Valentine leukocidine (pvl) and several antibiotic resistance genes among the isolates were also detected by PCR. All of the S. aureus isolates were susceptible to vancomycin, daptomycin and linezolid. Three hospital isolates were resistant to teicoplanin while 14 showed intermediate resistance to teicoplanin. The resistance patterns of community-acquired MRSA (CA-MRSA) isolates to other antimicrobials were similar to those of hospital-acquired MRSA (HA-MRSA) isolates except for clindamycin and gentamicin. There was excellent correlation between phenotypes and genotypes in the determination of S. aureus resistance to erythromycin, gentamicin, and tetracycline. The SCCmec type II and SCCmec type IV were the predominant types detected in hospital and community isolates, respectively. The most frequently encountered spa types were t002 and t030 both in HA- and CA-MRSA isolates. Pulsotype A was the most predominant pulsotype identified among the isolates tested, followed by pulsotype B. Seventy-two hospital isolates (19 HA-MRSA and 53 HA-MSSA) and 10 CA-MRSA were positive for the pvl gene. This study shows that the combination of susceptibility testing and various molecular methods has provided useful information on the antibiotic resistance and molecular diversity of S. aureus in a specific region of China. The high proportion of pvl positive MSSA and MRSA isolates observed in this study indicates that adequate measures are needed to curtail the spread of those MRSA and MSSA clones prevailing both in hospital and the community. 23624182 Age-related changes of neurochemically different subpopulations of cardiac spinal afferent neurons in rats. This study investigated the effect of aging on cardiac spinal afferent neurons in the rat. A patch loaded with retrograde tracer Fast Blue (FB) was applied to all chambers of the rat heart. Morphological and neurochemical characteristics of labeled cardiac spinal afferent neurons were assessed in young (2months) and old (2years) rats using markers for likely unmyelinated (isolectin B4; IB4) and myelinated (neurofilament 200; N52) neurons. The number of cardiac spinal afferent neurons decreased in senescence to 15% of that found in young rats (1604 vs. 248). The size of neuronal soma as well as proportion of IB4+ neurons increased significantly, whereas the proportion of N52+ neurons decreased significantly in senescence. Unlike somatic spinal afferents, neurochemically different populations of cardiac spinal afferent neurons experience morphological and neurochemical changes related to aging. A major decrease in total number of cardiac spinal afferent neurons occurs in senescence. The proportion of N52+ neurons decreased in senescence, but it seems that nociceptive innervation is preserved due to increased proportion and size of IB4+ unmyelinated neurons. 23915403 Investigating nurses' knowledge, attitudes and self-confidence patterns to perform the conscious level assessment: A cluster analysis. By accurately assessing a patient's conscious level, the nurse is able to detect neurological changes in order to improve survival outcomes and minimize long-term sequelae. However, problems are encountered when using the Glasgow Coma Scale (GCS) to assess a patient's conscious level. This study aims to identify the profile of a group of nurse's knowledge, attitudes and self-confidence (KAS) to perform the conscious level assessment using the GCS. A descriptive correlational survey was conducted from January to March 2010 in one acute care hospital in Singapore. A convenience sampling was used, and 114 nursing staff (91.2% response rates) completed a self-reported questionnaire. Four main outcomes: demographic and clinical experiences, and KAS. Two-step cluster analysis yielded two clusters. Cluster A (48.2%) was labelled 'average attitudes, knowledge and self-confidence' group. Cluster B (51.8%) was labelled as 'positive attitudes, good knowledge and high self-confidence' group. Two clusters showed differences in the levels of their KAS. Findings may be used for management to improve support of nurses to ensure accurately assessing patient's conscious level. Management should formulate strategies to encourage nurses to resolve actual problems following training or mentoring and to increase the depth and breadth of nurses' KAS to perform the conscious level assessment using the GCS. 23458149 Ultrasensitive optical shape characterization of gold nanoantennas using second harmonic generation. Second harmonic generation from plasmonic nanoantennas is investigated numerically using a surface integral formulation for the calculation of both the fundamental and the second harmonic electric field. The comparison between a realistic and an idealized gold nanoantenna shows that second harmonic generation is extremely sensitive to asymmetry in the nanostructure shape even in cases where the linear response is barely modified. Interestingly, minute geometry asymmetry and surface roughness are clearly revealed by far-field analysis, demonstrating that second harmonic generation is a promising tool for the sensitive optical characterization of plasmonic nanostructures. Furthermore, defects located where the linear field is strong (e.g., in the antenna gap) do not necessarily have the strongest impact on the second harmonic signal. 22989721 Airway contractility and remodeling: links to asthma symptoms. Respiratory symptoms are largely caused by obstruction of the airways. In asthma, airway narrowing mediated by airway smooth muscle (ASM) contraction contributes significantly to obstruction. The spasmogens produced following exposure to environmental triggers, such as viruses or allergens, are initially responsible for ASM activation. However, the extent of narrowing of the airway lumen due to ASM shortening can be influenced by many factors and it remains a real challenge to decipher the exact role of ASM in causing asthmatic symptoms. Innovative tools, such as the forced oscillation technique, continue to develop and have been proven useful to assess some features of ASM function in vivo. Despite these technologic advances, it is still not clear whether excessive narrowing in asthma is driven by ASM abnormalities, by other alterations in non-muscle factors or simply because of the overexpression of spasmogens. This is because a multitude of forces are acting on the airway wall, and because not only are these forces constantly changing but they are also intricately interconnected. To counteract these limitations, investigators have utilized in vitro and ex vivo systems to assess and compare asthmatic and non-asthmatic ASM contractility. This review describes: 1- some muscle and non-muscle factors that are altered in asthma that may lead to airway narrowing and asthma symptoms; 2- some technologies such as the forced oscillation technique that have the potential to unveil the role of ASM in airway narrowing in vivo; and 3- some data from ex vivo and in vitro methods that probe the possibility that airway hyperresponsiveness is due to the altered environment surrounding the ASM or, alternatively, to a hypercontractile ASM phenotype that can be either innate or acquired. 23164552 Impact of molecular imaging on the diagnostic process in a memory clinic. [(11)C]Pittsburgh compound B ([(11)C]PIB) and [(18)F]-2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) PET measure fibrillar amyloid-β load and glucose metabolism, respectively. We evaluated the impact of these tracers on the diagnostic process in a memory clinic population. One hundred fifty-four patients underwent paired dynamic [(11)C]PIB and static [(18)F]FDG PET scans shortly after completing a standard dementia screening. Two-year clinical follow-up data were available for 39 patients. Parametric PET images were assessed visually and results were reported to the neurologists responsible for the initial diagnosis. Outcome measures were (change in) clinical diagnosis and confidence in that diagnosis before and after disclosing PET results. [(11)C]PIB scans were positive in 40 of 66 (61%) patients with a clinical diagnosis of Alzheimer's disease (AD), 5 of 18 (28%) patients with frontotemporal dementia (FTD), 4 of 5 (80%) patients with Lewy body dementia, and 3 of 10 (30%) patients with other dementias. [(18)F]FDG uptake patterns matched the clinical diagnosis in 38 of 66 (58%) of AD patients, and in 6 of 18 (33%) FTD patients. PET results led to a change in diagnosis in 35 (23%) patients. This only occurred when prior diagnostic certainty was <90%. Diagnostic confidence increased from 71 ± 17% before to 87 ± 16% after PET (p < .001). Two-year clinical follow-up (n = 39) showed that [(11)C]PIB and [(18)F]FDG predicted progression to AD for patients with mild cognitive impairment, and that the diagnosis of dementia established after PET remained unchanged in 96% of patients. In a memory clinic setting, combined [(11)C]PIB and [(18)F]FDG PET are of additional value on top of the standard diagnostic work-up, especially when prior diagnostic confidence is low. 23966116 Differences in Resuscitation in Morbidly Obese Burn Patients May Contribute to High Mortality. The rising number of obese patients poses new challenges for burn care. These may include adjustments in calculations of burn size, resuscitation, ventilator wean, nutritional goals as well as challenges in mobilization. The authors have focused this observational study on resuscitation in the obese patient population in the first 48 hours after burn injury. Previous trauma studies suggest a prolonged time to reach end points of resuscitation in the obese compared to nonobese injured patients. The authors hypothesize that obese patients have worse outcomes after thermal injury and that differences in the response to resuscitation contribute to this disparity. The authors retrospectively analyzed data prospectively collected in a multicenter trial to compare resuscitation and outcomes in patients stratified by NIH/WHO body mass index (BMI) classification (BMI: normal weight, 18.5-24.9; overweight, 25-29.9, obese, 30-39.9; morbidly obese, ≥40). Because of the distribution of body habitus in the obese, total burn size was recalculated for all patients by using the method proposed by Neaman and compared with Lund-Browder estimates. The authors analyzed patients by BMI class for fluids administered and end points of resuscitation at 24 and 48 hours. Multivariate analysis was used to compare morbidity and mortality across BMI groups. The authors identified 296 adult patients with a mean TBSA of 41%. Patient and injury characteristics were similar across BMI categories. No significant differences were observed in burn size calculations by using Neaman vs Lund-Browder formulas. Although resuscitation volumes exceeded the predicted formula in all BMI categories, higher BMI was associated with less fluid administered per actual body weight (P = .001). Base deficit on admission was highest in the morbidly obese group at 24 and 48 hours. Furthermore, these patients did not correct their metabolic acidosis as well as lower BMI groups (P values .04 and .03). Complications and morbidities across BMI groups were similar, although examination of organ failure scores indicated more severe organ dysfunction in the morbidly obese group. Compared with being normal weight, being morbidly obese was an independent risk factor for death (odds ratio = 10.1; confidence interval, 1.94-52.5; P = .006). Morbidly obese patients with severe burns tend to receive closer to predicted fluid resuscitation volumes for their actual weight. However, this patient group has persistent metabolic acidosis during the resuscitation phase and is at risk of developing more severe multiple organ failure. These factors may contribute to higher mortality risk in the morbidly obese burn patient. 23454583 Novel MicroRNAs regulating proliferation and apoptosis in uterine papillary serous carcinomas. MicroRNAs (miRNAs) are endogenous, non-coding RNA transcripts that regulate gene expression. Here, we report 175 putative novel miRNAs identified in uterine cancers profiled by Next Generation Sequencing. Our data indicate that one of these putative miRNAs (BCM-173) is conserved across multiple species and is expressed at levels similar to known human miRNAs. Functionally, this miRNA promotes the growth and migration of uterine cancer cell lines by targeting vinculin and altering the distribution of focal adhesions. These results expand our insight into the repertoire of human miRNAs and identify novel pathways by which dysregulated miRNA expression promotes uterine cancer growth. 23282222 Highly sensitive fluorescent and colorimetric pH sensor based on polyethylenimine-capped silver nanoclusters. Silver nanoclusters capped by hyperbranched polyethylenimine (PEI) have been developed as a highly sensitive fluorescent and colorimetric pH sensor. The probe responds rapidly to pH fluctuations and has such absorption characteristics that the color changes from the colorless or a nearly colorless state to a colored state with increasing acidity, so PEI-capped Ag nanoclusters could be used as a color indicator for colorimetric pH detection. Quantitatively, the fluorescence intensity of PEI-capped Ag nanoclusters exhibits a linear fashion over the pH range of 5.02-7.96 and increases by around 10-fold approximately with greater fluorescence at higher pH values. The repulsion development and conformational change of PEI with decreasing pH induce the aggregation of Ag nanoclusters, leading to an obvious color change and fluorescence quenching of Ag nanoclusters at low pH values. As expected, the pH probe is also sensitive to the different buffer solutions, except for those containing some anions that could react with Ag nanoclusters. Besides, the ionic strength of the buffers has a little influence on the pH-responsive behavior. Our pH sensor with nanoscaled physical dimensions would be a promising candidate in the applications in biological, medical, and pharmaceutical fields. 23938106 Electrocardiogram as a screening tool in the general population: A strategic review. Sudden cardiac death (SCD) is a major public health concern, accounting for 400,000 deaths in the US each year. Clinical and autopsy studies have consistently demonstrated a predominant, common pathophysiology in Western populations, showing that the most common electrophysiological mechanism of SCD is ventricular fibrillation, and the most common pathologic substrate is coronary heart disease (CHD). In about half of SCD cases, death is the first clinical manifestation of CHD. Yet risk factors of SCD early in the natural history of conditions predisposing SCD have not been fully identified, and SCD risk stratification strategy in the general population has not been developed. ECG is an easily available, non-expensive and non-invasive tool, which carries valuable information on electrophysiological properties of the heart. However, traditional analysis of ECG includes very limited assessment of the arrhythmogenic substrate. In this review rationale for development of ECG SCD risk score for screening in the general population is discussed. 23769372 Strain-specific pathogenicity of putative host-adapted and nonadapted strains of Streptococcus uberis in dairy cattle. Streptococcus uberis is an important cause of intramammary infection in dairy cattle. Strains of Strep. uberis appear to differ in their ability to cause disease based on previous epidemiological studies. We explored the pathogenicity of 2 strains of Strep. uberis, where one strain represented a putatively host-adapted type based on its ability to cause persistent infection and to spread from cow to cow in a lactating herd. This type was part of a clonal complex that is commonly associated with bovine mastitis. The other strain, which was isolated from a transient infection in a single animal in the same herd and did not belong to any known clonal complex, was selected as putatively nonadapted type. Cows (6 per strain) were experimentally challenged in a single hind quarter and the adjacent hind quarter was used as mock challenged control quarter. Both strains showed an equal ability to grow in the milk of challenge animals in vitro. All cows that were challenged with the putatively host-adapted strain developed clinical signs of mastitis, including fever and milk yield depression as well as elevated somatic cell count due to influx of polymorphonuclear leucocytes and lymphocytes. The cytokine response followed a specific order, with an increase in IL-1β, IL-6, and IL-8 levels at the time of first SCC elevation, followed by an increase in IL-10, IL-12p40, and tumor necrosis factor-α levels approximately 6h later. In 4 of 6 animals, IL-17A was detected in milk between 57 and 168h postchallenge. The increase in IL-17A levels coincided with inversion of the prechallenge CD4(+)-to-CD8(+) T lymphocyte ratio, which was observed from 96h postchallenge. This was followed by normalization of the CD4(+)-to-CD8(+) ratio due to continued increase of the CD8(+) concentration up to 312h postchallenge. Spontaneous resolution of infection was observed in 5 animals and coincided with a measurable IL-17A response in 4 animals, suggesting that IL-17 may be involved in the resolution of intramammary infection. With the exception of minor elevation of IL-8 levels, no clinical, cytological, or immunological response was detected in quarters challenged with the nonadapted strain. The observed strain-specific pathogenicity was consistent across animals, implying that it is determined by pathogen factors rather than host factors. 23925695 Deep neck infections: risk factors for mediastinal extension. The goal of the study was to find out the risk factors for the development of mediastinitis in patients with deep neck infections (DNI) and describe the differences in symptoms and clinical image between uncomplicated DNI and infections with mediastinal spread. Our study represents the retrospective analysis of 634 patients with DNI. The file was divided into two groups. There were 619 patients (97.6 %) in the first group who had an uncomplicated course of DNI without spread of infection into mediastinum (DNI group). The second group included 15 patients (2.4 %) with descending mediastinitis as a complication of DNI (mediastinitis group). The most frequent comorbidities were cardiac and pulmonary diseases, which were more frequent in the mediastinitis group comparing to DNI group. Dental origin of the infection was more frequent in DNI group than in the mediastinitis group. On the other hand, tonsillar origin of the infection was more frequent in the mediastinitis group than in DNI group. In both mediastinitis and DNI groups, the typical presenting symptoms were pain, oedema and dysphagia. Furthermore, dysphagia, dyspnoea, dysphonia and restriction of neck movements were more significant in the mediastinitis group than in DNI group. The incidence of airway obstruction, sepsis, pneumonia and death was significantly higher in the mediastinitis group than in DNI group. Due to our results, the predisposing factors for mediastinal extension of DNI are cardiovascular and pulmonary diseases. Mediastinitis is associated with higher morbidity and mortality than DNI. The most common complications are airway obstruction, pneumonia and sepsis. 23942624 On the mechanism of iodine oxide particle formation. The formation of atmospherically relevant iodine oxides IxOy (x = 1,…,3, y = 1,…,7) has been studied experimentally using time-of-flight mass spectrometry combined with a soft ionisation source, complemented with ab initio electronic structure calculations of ionisation potentials and bond energies at a high level of theory presented in detail in the accompanying paper (Galvez et al., 2013). For the first time, direct experimental evidence of the I2Oy (y = 1,…,5) molecules in the gas phase has been obtained. These chemical species are observed alongside their precursors (IO and OIO) in experiments where large amounts of aerosol are also generated. The measured relative concentrations of the IxOy molecules and their dependence on ozone concentration have been investigated by using chemical modelling and rate theory calculations. It is concluded that I2O4 is the most plausible candidate to initiate nucleation, while the contribution of I2O5 in the initial steps is likely to be marginal. The absence of large I3Oy (y = 3,…,6) peaks in the mass spectra and the high stability of the I2O4-I2O4 dimer indicate that dimerisation of I2O4 is the key step in iodine oxide particle nucleation. 23229324 A photoinduced charge transfer composite of graphene oxide and ferrocene. We demonstrate the formation of a photoinduced charge transfer composite with graphene oxide (GO) and ferrocene (Fc) molecules. Derived insulating GO was partially reduced to improve the conductivity and modified with the Fc molecules. Transmission electron microscopy (TEM), elemental mapping, X-ray photoelectron and UV-visible spectroscopy studies confirm that the Fc molecules were well grafted to the surface of a GO sheet. Photoresponsivity of the prepared GO-Fc composite was investigated by fabricating a metal/GO-Fc/metal device. The fabricated device shows enhanced current density under light illumination, suggesting a photo-induced charge transfer process in the developed GO-Fc composite. 23962959 An In-vitro Preparation of Isolated Enteric Neurons and Glia from the Myenteric Plexus of the Adult Mouse. The enteric nervous system is a vast network of neurons and glia running the length of the gastrointestinal tract that functionally controls gastrointestinal motility. A procedure for the isolation and culture of a mixed population of neurons and glia from the myenteric plexus is described. The primary cultures can be maintained for over 7 days, with connections developing among the neurons and glia. The longitudinal muscle strip with the attached myenteric plexus is stripped from the underlying circular muscle of the mouse ileum or colon and subjected to enzymatic digestion. In sterile conditions, the isolated neuronal and glia population are preserved within the pellet following centrifugation and plated on coverslips. Within 24-48 hr, neurite outgrowth occurs and neurons can be identified by pan-neuronal markers. After two days in culture, isolated neurons fire action potentials as observed by patch clamp studies. Furthermore, enteric glia can also be identified by GFAP staining. A network of neurons and glia in close apposition forms within 5 - 7 days. Enteric neurons can be individually and directly studied using methods such as immunohistochemistry, electrophysiology, calcium imaging, and single-cell PCR. Furthermore, this procedure can be performed in genetically modified animals. This methodology is simple to perform and inexpensive. Overall, this protocol exposes the components of the enteric nervous system in an easily manipulated manner so that we may better discover the functionality of the ENS in normal and disease states. 23904988 Warming increases the top-down effects and metabolism of a subtidal herbivore. Ecological theory and experiments indicate that warming can increase the relative strength of top-down effects via alterations to metabolic rates in several different systems, thereby resulting in decreased plant biomass at higher temperatures. However, the general influence of increased environmental temperature on top-down effects is not well understood in systems where organisms experience relatively large variation in temperature. Rapid ocean temperature changes are pervasive throughout the Galápagos Islands due to upwelling and downwelling of internal waves, ENSO events and seasonality. We measured the effect of large, but not uncommon, water temperature variation on the metabolism and grazing rate of a common subtidal herbivore and on photosynthesis of their algal prey in the Galápagos Islands in July 2012. We found that green urchin consumption and metabolism were greater at the higher temperature treatment (28°C), resulting in significantly less algal biomass. Our result that warming increased green urchin metabolic rates, even in a highly dynamic system, provides further support for a mechanistic link between environmental temperature and feeding rates. And further, our findings suggest individual response to temperature results in changes in top-down effects. And if this response is maintained over longer-time scales of days to weeks, this could translate to alterations of larger-scale ecological patterns, such as primary producer community composition and structure. 23947313 An Ongoing Lack of Knowledge About Lead Poisoning. Lead poisoning is a serious health problem facing children in the United States. For that reason, the Pediatric Environmental Health Specialty Unit (PEHSU) network was particularly interested in the recent article by Zhang et al. detailing early lead exposure and poorer educational achievement among school children in Detroit, Michigan.(1) (Am J Public Health. Published online ahead of print August 15, 2013: e1-e2. doi:10.2105/AJPH.2013.301499). 23915196 Loss of utility of bone marrow biopsy as a staging evaluation for Hodgkin lymphoma in the positron emission tomography-computed tomography era: a West of Scotland study. Positron emission tomography-computed tomography (PET-CT) scanning has been shown to be more sensitive than bone marrow biopsy (BMB) in detecting bone marrow involvement (BMI) in classical Hodgkin lymphoma (cHL). In this 5-year retrospective series, 93 (54%) of all new cases of cHL were staged using PET-CT and BMB. PET-CT identified focal bone marrow uptake in 17/93 (18.3%), whilst only five of these (29.4%) were confirmed by BMB. Abnormal pelvic uptake was seen on PET-CT in these five cases. The other 12 cases were missed, giving BMB a sensitivity of 29.4% and a specificity of 100%. PET-CT upstaged 9.7% of patients compared to CT alone. BMB upstaged only one patient; however, this patient was already stage IV on PET-CT. BMB did not alter clinical management in any case. Bone positivity on PET-CT appeared to correlate with anemia, raised lactate dehydrogenase (LDH) and B symptoms. BMB has little or nothing to offer staging cHL in the PET-CT era. 23657602 Transcriptome meta-analysis of peripheral lymphomononuclear cells indicates that gestational diabetes is closer to type 1 diabetes than to type 2 diabetes mellitus. We performed a meta-analysis of the transcription profiles of type 1, type 2 and gestational diabetes to evaluate similarities and dissimilarities among these diabetes types. cRNA samples obtained from peripheral blood lymphomononuclear cells (PBMC) of 56 diabetes mellitus patients (type 1 = 19; type 2 = 20; gestational = 17) were hybridized to the same whole human genome oligomicroarray platform, encompassing 44,000 transcripts. The GeneSpring software was used to perform analysis and hierarchical clustering, and the DAVID database was used for gene ontology. The gene expression profiles showed more similarity between gestational and type 1 diabetes rather than between type 2 and gestational diabetes, a finding that was not influenced by patient gender and age. The meta-analysis of the three types of diabetes disclosed 3,747 differentially and significantly expressed genes. A total of 486 genes were characteristic of gestational diabetes, 202 genes of type 1, and 651 genes of type 2 diabetes. 19 known genes were shared by type 1, type 2 and gestational diabetes, highlighting EGF, FAM46C, HBEGF, ID1, SH3BGRL2, VEPH1, and TMEM158 genes. The meta-analysis of PBMC transcription profiles characterized each type of diabetes revealing that gestational and type 1 diabetes were transcriptionally related. 23958456 Factors influencing the demand of the service of community based animal health care in Zimbabwe. This study was done to find out about animal health service providers and factors that determined demand for community based veterinary service delivery in smallholder sector of Zimbabwe. Focus group discussions and a questionnaire was used to collect data on veterinary services providers and socio-economic factors related to animal health from a sample (N=333) smallholder livestock farmers from Gutu district of Masvingo province in Zimbabwe. Analytical techniques used were descriptive statistics, K-mean cluster analysis and Tobit regression model. Results showed that the majority of farmers (45%) obtained services from both Community Based Animal Health Workers (CBAHWs) and Department of Veterinary Service (DVS), 25% DVS only, 20% used CBAHWs while 10% did not seek any services. Further analysis showed that distance to CBAHW, distance to AHMC and employment status were significantly related to demand for CBAHWs with coefficients of -1.5, 0.7 and -10.3, respectively. The study thus concluded that CBAHW is an alternative animal health service delivery approach already practiced in smallholder farming sectors of Zimbabwe. Socio-economic factors significantly influenced the demand for CBAHW services. Given limited resources by state sponsored veterinary services, it is recommended that the CBAHWs approach should be encouraged as supplementary service provider especially in areas further DVS. These community organizations can be empowered by the state to deliver more improved services based on hygiene and modern science at a relatively low cost to farmers. 23764218 Hurdle enhancement of slightly acidic electrolyzed water antimicrobial efficacy on Chinese cabbage, lettuce, sesame leaf and spinach using ultrasonication and water wash. Slightly acidic electrolyzed water (SAEW) is well known as a good sanitizer against foodborne pathogens on fresh vegetables. However, microbial reductions from SAEW treatment are not enough to ensure produce safety. Therefore, it is necessary to improve its antimicrobial efficiency by combining it with other appropriate approaches. This study examined the microbicidal activity of SAEW (pH 5.2-5.5, oxidation reduction potential 500-600 mV, available chlorine concentration 21-22 mg/l) on Chinese cabbage, lettuce, sesame leaf and spinach, four common fresh vegetables in Korea under same laboratory conditions. Subsequently, effects of ultrasonication and water wash to enhance the sanitizing efficacy of SAEW were studied, separately. Finally, an optimized simple and easy approach consisting of simultaneous SAEW treatment with ultrasonication (3 min) followed by water wash (150 rpm, 1 min) was developed (SAEW + US-WW). This newly developed hurdle treatment significantly enhanced the microbial reductions compared to SAEW treatment alone, SAEW treatment with ultrasonication (SAEW + US) and SAEW treatment followed by water wash (SAEW-WW) at room temperature (23 ± 2 °C). Microbial reductions of yeasts and molds, total bacteria count and inoculated Escherichia coli O157:H7 and Listeria monocytogenes were in the range of 1.76-2.8 log cfu/g on different samples using the new hurdle approach. 23712241 Spectroscopic studies of oxo-centered, carboxylate-bridged, trinuclear mixed-valence iron (ІІІ, ІІІ, ІІ) complexes with aromatic hydroxycarboxylic acids. New type of oxo-centered, carboxylate-bridged, trinuclear, mixed-valence iron complexes of the general formula [Fe3O(OOCR)3(OOCR*)3L3] (where R=C13H27 or C15H31 and R*=C6H4(OH), (R'); C6H5CH(OH), (R") or (C6H5)2C(OH), (R''') and L=Methanol) were synthesized by the reaction of [Fe3O(OOCCH3)6(H2O)3] with straight chain carboxylic acids and aromatic hydroxycarboxylic acids. These were characterized by elemental analyses, spectral (electronic, infrared, Mössbauer, FAB mass and powder XRD) studies, conductance and magnetic susceptibility measurements. Infrared spectra suggested bidentate and bridging mode of coordination of both the carboxylate and hydroxycarboxylate anions along with Fe3O vibrations in the complexes. Mössbauer parameters indicated the presence of high-spin Fe(ІІ) (S=2) and high-spin Fe(ІІІ) (S=5/2) centers in the complexes, confirming the valence-localized type of species. An intervalence-transfer band observed at 13,690-13,850 cm(-1) range in the room-temperature electronic spectra of the complexes also suggested the complexes containing iron in mixed-valence state. Trinuclear nature of the complexes was confirmed by their FAB mass spectra. Magnetic moment values displayed octahedral geometry around each iron in the complexes and a net anti-ferromagnetic exchange coupling via μ-oxo atom related to mixed-valence pairs. A plausible structure for these complexes has been established on the basis of spectra and magnetic moment data. 23868288 Audit of rapid access introduction reveals high prevalence of prostate cancer in Western Region. Men with symptoms suggestive of prostate cancer are now directly referred by their general practitioners to rapid access prostate assessment clinics (RAPACs). This service implements recommendations outlined by the National Cancer Control Programme. The RAPAC was introduced at Galway University Hospital, Galway, Ireland in June 2009, aiming to structure GP referral of patients with suspected prostate cancer to a urology service. The aims of this study are to assess our initial experience with particular emphasis on access times, patient demographics, detection rates and treatment outcomes. Data on all patients presenting to the RAPAC during the preliminary 2-year period have been gathered prospectively and analysed using standard parametric analysis methods. A total of 1,106 patients were reviewed at 278 clinic sessions during the initial 2-year period. The average waiting time to first clinic visit was 18 days (12-39 days). The mean age of referral to the clinic is 65 years (44-88 years). The mean PSA is 16.31 g/dL (0.4-845 g/dL). Of the 1106 patients undergoing TRUS biopsies, 503 (45.5 %) patients were diagnosed with prostate cancer. Further analysis patient demographics and cancer grading is presented in the article. Seventy-one patients (14.1 %) underwent radical retropubic prostatectomy. Sixty-seven patients (13.3 %) are being followed on an active monitoring programme, whilst 235 (56.7 %) received primary treatment with external beam radiotherapy and 68 (13.5 %) received brachytherapy. This data highlight the necessity of a RAPAC to streamline the provision of prostate cancer services in the west of Ireland. 23916820 The anti-thrombotic effect of hydrogen sulfide is partly mediated by an upregulation of nitric oxide synthases. Hydrogen sulfide (H2S) known as a gasotransmitter is increasingly recognized for its anti-adhesive, anti-inflammatory and vasoactive properties. Due to these properties, we analysed anti-thrombotic effects of H2S and the participation of the nitric oxide synthase (NOS)-pathway. In individual venules of the ear of hairless SKH1-hr mice, thrombus formation was induced using a phototoxic light/dye-injury model and intravital fluorescence microscopy. Animals were treated intravenously with the H2S donor Na2S or NaCl as control. In a second setting, the NOS inhibitor L-NAME was applied intraperitoneally as a bolus 12h prior to Na2S treatment and thrombus induction. Blood and ear tissue were sampled after microscopy for assessment of plasma concentrations of soluble (s)P-selectin, sE-selectin, sVCAM-1 and sICAM-1 and expression of endothelial (e)NOS and inducible (i)NOS, respectively. When mice were treated with Na2S, venular thrombus formation was significantly delayed versus that in animals of the NaCl-treated control group. While plasma levels of pro-thrombotic adhesion molecules were not affected by Na2S, immunohistochemistry of the vessel walls showed a significant up-regulation of eNOS and iNOS expression within the Na2S-treated group. The delay of thrombus formation in the Na2S-group was partly but significantly reverted by application of L-NAME. The anti-thrombotic efficacy of H2S involves the NOS-pathway and may be of preventive and therapeutic value for clinical disorders with increased risk of thrombotic events. 23473372 Systematic study of the basis set superposition error in core-electron correlation effects. In a recent paper, Xu et al. [J. Phys. Chem. A2012, 116, 11668] emphasized the importance of core-electron correlation effects to describe the Si2H6BH3 complex and related systems properly. Unexpected large energy differences between a frozen core and all electron treatment were observed. In the present study, it will be shown that these energy differences are an artifact of an insufficient choice of basis set and can be attributed to an intramolecular basis set superposition error (BSSE). Although the general problem is known, systematic studies on the effect are scarce. Therefore, the BSSE in related systems is investigated. This study shows that the problem of BSSE for core-electron correlation is quite common if inadequate basis sets are applied and that it amounts to 2 kcal mol(-1) on average in binding energies for the given test set (with a maximum of 5.8 kcal mol(-1)). 23758710 High-Throughput Models for Exposure-Based Chemical Prioritization in the ExpoCast Project. The United States Environmental Protection Agency (U.S. EPA) must characterize potential risks to human health and the environment associated with manufacture and use of thousands of chemicals. High-throughput screening (HTS) for biological activity allows the ToxCast research program to prioritize chemical inventories for potential hazard. Similar capabilities for estimating exposure potential would support rapid risk-based prioritization for chemicals with limited information; here, we propose a framework for high-throughput exposure assessment. To demonstrate application, an analysis was conducted that predicts human exposure potential for chemicals and estimates uncertainty in these predictions by comparison to biomonitoring data. We evaluated 1936 chemicals using far-field mass balance human exposure models (USEtox and RAIDAR) and an indicator for indoor and/or consumer use. These predictions were compared to exposures inferred by Bayesian analysis from urine concentrations for 82 chemicals reported in the National Health and Nutrition Examination Survey (NHANES). Joint regression on all factors provided a calibrated consensus prediction, the variance of which serves as an empirical determination of uncertainty for prioritization on absolute exposure potential. Information on use was found to be most predictive; generally, chemicals above the limit of detection in NHANES had consumer/indoor use. Coupled with hazard HTS, exposure HTS can place risk earlier in decision processes. High-priority chemicals become targets for further data collection. 23865795 Rheological Study of Chitosan/Polyol-phosphate Systems: Influence of the Polyol Part on the Thermo-Induced Gelation Mechanism. Thermo-sensitive gelling systems, like chitosan/polyol-phosphate, are candidates with a high potential for the design of biodegradable drug delivery systems, notably for in situ forming depots. They consist of stable and low viscosity aqueous solutions, liquid at room temperature, which turn into a gel state upon an increase of temperature (e.g., after subcutaneous administration). This technology enables a sustained release of potentially encapsulated active substances. Despite these thermo-gelling solutions being widely studied for the development of parenteral drug delivery systems, most commonly using β-glycerophosphate (β-GP) as gelling agent, the mechanism inducing the gelation and the role of the polyol part in this mechanism has not been clearly elucidated. To investigate the mechanism of the gelation process, comprehensive rheological studies were performed, comparing different chitosan/polyol-phosphate systems varying in the chemical structure of the polyol parts of the gelling agents. As reference, β-GP was compared to glucose-1-phosphate (G1-P) and glucose-6-phosphate (G6-P) and to a polyol-free phosphate salt, Na2HPO4, as well. Frequency sweep experiments at different temperatures or different gelling agent concentrations, temperature, and time sweep tests were performed as complementary experimental approaches. The results disclosed significant trends with widespread implications, establishing a relationship between the chemical structure of the polyol part and the macroscopic gelling behavior of the solutions, that is, transition temperature, gelation time, and gel strength. The new results presented in this study show that increasing the size of the polyol part prevents the interactions between the chitosan chains, strongly influencing the gelling process. 23949476 Robotic Colorectal Surgery. Minimally invasive surgery has many potential benefits, and the application of recently developed robotic technology to patients with colorectal diseases is rapidly gaining popularity. However, the literature evaluating such techniques, including the outcomes, risks, and costs, is limited. In this review, we evaluate and summarize the existing information, calling attention to areas where future investigation should occur. 23334212 Tendon involvement in the feet of patients with gout: a dual-energy CT study. To examine the frequency and patterns of monosodium urate (MSU) crystal deposition in tendons and ligaments in patients with gout using dual-energy CT (DECT). Ninety-two patients with tophaceous gout had DECT scanning of both feet. Two readers scored the DECT scans for MSU crystal deposition at 20 tendon/ligament sites and 42 bone sites (total 1840 tendon/ligament sites and 3864 bone sites). MSU crystal deposition was observed by both readers in 199/1840 (10.8%) tendon/ligament sites and in 399/3864 (10.3%) bone sites (p=0.60). The Achilles tendon was the most commonly involved tendon/ligament site (39.1% of all Achilles tendons), followed by the peroneal tendons (18.1%). Tibialis anterior and the extensor tendons were involved less commonly (7.6-10.3%), and the other flexor tendons, plantar fascia and deltoid ligaments were rarely involved (<5%) (p<0.0001 between sites). Involvement of the enthesis alone was more common in the Achilles tendon (OR (95% CI) 74.5 (4.4 to 1264), p<0.0001), as was any involvement of the enthesis (OR (95% CI) 6.8 (3.6 to 13.0), p<0.0001). Tendons are commonly affected by MSU crystal deposition in patients with tophaceous gout. The patterns of MSU crystal deposition suggest that biomechanical strain or other local factors may contribute to deposition of MSU crystals. 23215012 Surface-scribed transparency-based microplates. Transparency sheets, which are normally associated with use on overhead projectors, offer lowered costs and high amenability for optical diagnostics in microplate instrumentation. An alternative microplate design in which circles are scribed on the surface of the transparency to create the boundaries to hold the drop in place is investigated here. The 3D profile of the scribed regions obtained optically showed strong likelihood of affecting three-phase contact line interactions. During dispensation, the contact angle (≈95°) was larger than the drop advancing state (≈80°) due to a period of nonadhesion, where the contact angle later reduced to the drop advancing state followed by increase in the liquid area coverage on the substrate. It was established that 50 μL was needed to fill the well fully, and the maximum volume retainable before breaching was 190 μL. While the tilt angle needed for displacement reduced significantly from 50 to 95 μL, this was markedly better than nonscribed surfaces, where tilt angles always had to be kept to within 30°. It was found that there was greater ability to fill the well with smaller volumes with dispensation at the center. This was attributed to the growing contact line not meeting the scribed edge in parallel if liquid was dispensed closer to it, wherein pinning reduction in some directions permitted liquid travel along the scribed edge to undergo contact angle hysteresis. Fluorescence measurements conducted showed no performance compromise when using scribed transparency microplates over standard microplates. 23889458 Exploring the Assembly of Supramolecular Polyoxometalate Triangular Morphologies with Johnson Solid Cores: [(Mn(II)(H2O)3)2(K⊂{α-GeW10Mn(II)2O38}3)](19-). A new polyoxometalate (POM) cluster compound is presented which incorporates a trimeric assembly of Keggin-type germanotungstate fragments trapping a Johnson-type solid {Mn8} core. The mixed K-Li salt of the polyanion [(Mn(II)(H2O)3)2(K⊂{α-GeW10Mn(II)2O38}3)](19-) was characterized in the solid state and solution. The correlation of the assembly processes and the observed architecture of the "trinity" family of POMs is discussed. 23123598 Fibroblasts as architects of cancer pathogenesis. Studies of epithelial cancers (i.e., carcinomas) traditionally focused on transformation of the epithelium (i.e., the cancer cells) and how aberrant signaling within the cancer cells modulates the surrounding tissue of origin. In more recent decades, the normal cells, blood vessels, molecules, and extracellular components that surround the tumor cells, collectively known as the "tumor microenvironment" or "stroma", have received increasing attention and are now thought to be key regulators of tumor initiation and progression. Of particular relevance to the work reviewed herein are the fibroblasts, which make up the major cell type within the microenvironment of most carcinomas. Due to their inherent heterogeneity, plasticity, and function, it is perhaps not surprising that fibroblasts are ideal modulators of normal and cancerous epithelium; however, these aspects also present challenges if we are to interrupt their tumor-supportive functions. Here, we review the current body of knowledge and the many questions that still remain about the special entity known as the cancer-associated fibroblast. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. 23843470 What is a clinically relevant change on the HIT-6 questionnaire? An estimation in a primary-care population of migraine patients. To interpret questionnaire scores, clinicians and researchers need to know what change in score reflects a meaningful change in the condition of an individual patient, and what difference reflects a meaningful difference between groups. These values differ between different populations. We determined the within-person minimally important change (MIC) and the between-group minimally important difference (MID) of the Headache Impact Test-6 (HIT-6) questionnaire in a primary-care population of migraine patients. We included 490 patients who participated in a clinical trial on the treatment of migraine in primary care. We compared their change scores on the HIT-6 questionnaire between baseline and at three-months follow-up with the answers to two anchor questions according to the 'mean change approach' and the 'ROC curve approach'. The within-person MIC was estimated to be between -2.5 points (mean change approach) and -6 points (ROC curve approach). The choice for the within-person MIC value depends on the consequences of false positives and false negatives in a particular setting. The between-group MID was estimated at -1.5 points. We determined the within-person MIC and between-group MID for the HIT-6 in a primary-care population of migraine patients. We recommend the use of these values for clinical care and for research. 23870423 Lifestyle factors and reproductive health: taking control of your fertility. Approximately 10 to 15% of couples are impacted by infertility. Recently, the pivotal role that lifestyle factors play in the development of infertility has generated a considerable amount of interest. Lifestyle factors are the modifiable habits and ways of life that can greatly influence overall health and well-being, including fertility. Many lifestyle factors such as the age at which to start a family, nutrition, weight, exercise, psychological stress, environmental and occupational exposures, and others can have substantial effects on fertility; lifestyle factors such as cigarette smoking, illicit drug use, and alcohol and caffeine consumption can negatively influence fertility while others such as preventative care may be beneficial. The present literature review encompasses multiple lifestyle factors and places infertility in context for the couple by focusing on both males and females; it aims to identify the roles that lifestyle factors play in determining reproductive status. The growing interest and amount of research in this field have made it evident that lifestyle factors have a significant impact on fertility. 22988818 Friedelin and lanosterol from Garcinia prainiana stimulated glucose uptake and adipocytes differentiation in 3T3-L1 adipocytes. Friedelin and lanosterol have been isolated from twigs of Garcinia prainiana. Their structures were elucidated by spectroscopic methods. The compounds were examined for their effects on 3T3-L1 adipocytes. In the MTT assay, it was found that the compounds had no cytotoxic effects up to 25 µM. Adipocyte differentiation analysis was carried out by Oil Red O staining method. In the presence of adipogenic cocktail (MDI), it was found that friedelin and lanosterol enhanced intracellular fat accumulation by 2.02 and 2.18-fold, respectively, compared with the vehicle-treated cells. Deoxyglucose uptake assay was used to examine the insulin sensitivity of adipocytes in the presence of the compounds. It was found that friedelin was able to stimulate glucose uptake up to 1.8-fold compared with insulin-treated cells. It was suggested that friedelin and lanosterol may be beneficial to mimic insulin action that would be useful in the treatment of diabetes type 2 patients. 23928083 Invertebrate vision: peripheral adaptation to repeated object motion. Visual systems adapt rapidly to objects moving repeatedly within the visual field, because such objects are likely irrelevant. In the crab, the neural switch for such adaptation has been found to take place at a surprisingly early stage of the visual processing pathway. 23490546 Nested case control study of proteomic biomarkers for interstitial lung disease in Japanese patients with non-small-cell lung cancer treated with erlotinib: a multicenter phase IV study (JO21661). Interstitial lung disease (ILD) is a serious adverse drug reaction associated with epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR TKIs). Its risk factors are yet to be fully elucidated. We sought to identify proteomic biomarkers associated with ILD development in erlotinib-treated Japanese patients with non-small-cell lung cancer (NSCLC) to build predictive models. We conducted a nested case-control study. The participants were patients with NSCLC enrolled in a phase IV study of erlotinib in whom ILD developed within 120 days after erlotinib administration. The controls were randomly selected patients without ILD from the overall study cohort who were also treated with erlotinib. Serum samples were obtained before the first administration of erlotinib and were assayed by liquid chromatography-mass spectroscopy/mass spectroscopy (LC-MS/MS). Logistic regression analysis was performed to identify the peptide and proteins associated with ILD. A total of 645 patients were enrolled in the cohort; 15 case patients and 64 controls were analyzed. When multiplicity was taken into account, we were unable to statistically verify any genuine association between individual markers and ILD. Investigation of the predictive power based on leave-one-out cross-validation (LOOCV) showed that the area under the receiver operating characteristic curve was 0.73 at a maximum. Additional analysis suggested that 3 proteins (C3, C4A/C4B, and APOA1) have a stronger association with ILD than do the other proteins tested. We were unable to demonstrate predictive serum protein markers for ILD development. However, C3, C4A/C4B, and APOA1 are worthy of further investigation. 23817809 A population-based study of low-grade gliomas and mutated isocitrate dehydrogenase 1 (IDH1). Low-grade gliomas (LGG) have a slow growth rate, but transformations into malignant gliomas with a rapid deterioration occur in many patients. The aim of this study was to evaluate clinical prognostic factors in a population-based cohort of patients with LGG. In addition we investigated the expression and prognostic value of the isocitrate dehydrogenase 1 (IDH1) R132H mutation. Seventy-four patients diagnosed between 2005 and 2009 in the Region of Southern Denmark were identified using the Danish Cancer Register and The Danish Pathology Databank. Survival analysis using Cox regression was performed in 52 patients with tumor samples useable for immunohistochemical evaluation of IDH1 status. Patients with a contrast enhancing tumor, neurological deficits, headache, an astrocytic tumor and PS 2-4 had an increased risk of recurrence. In univariate analysis age > 50 years (HR 2.14, 95 % CI 1.08-4.24), having neurological deficit (HR 2.28, 95 % CI 1.15-4.52), receiving post-surgical treatment (HR 2.52, 95 % CI 1.19-5.32), being in performance status 2-4 (HR 1.44, 95 % CI 1.15-1.81), and having an astrocytic tumor (HR 3.79, 95 % CI 1.64-8.73) were associated with poor survival. Mutated IDH1 (mIDH1) was identified in 46 % of the patients and was significantly correlated to a good survival in both univariate (HR 0.24, 95 % CI 0.11-0.53) and in multivariate analysis (HR 0.40, 95 % CI 0.17-0.91). The other clinical variables were not significant when adjusted for the effect of mIDH1 status. We find that young age, the absence of neurologic deficit, PS 0-1 and oligodendroglial histology were associated with better survival. IDH1 status showed independent prognostic information when adjusting for classical prognostic factors, and should be validated in a larger patient population. 23947794 Herbimycins D-F, Ansamycin Analogues from Streptomyces sp. RM-7-15. Bacterial strains belonging to the class actinomycetes were isolated from the soil near a thermal vent of the Ruth Mullins coal fire (Appalachian Mountains of eastern Kentucky). High-resolution electrospray ionization mass spectrometry and ultraviolet absorption profiles of metabolites from one of the isolates (Streptomyces sp. RM-7-15) revealed the presence of a unique set of metabolites ultimately determined to be herbimycins D-F (1-3). In addition, herbimycin A (4), dihydroherbimycin A (TAN 420E) (7), and the structurally distinct antibiotic bicycylomycin were isolated from the crude extract of Streptomyces sp. RM-7-15. Herbimycins A and D-F (1-3) displayed comparable binding affinities to the Hsp90α. While the new analogues were found to be inactive in cancer cell cytotoxicity and antimicrobial assays, they may offer new insights in the context of nontoxic ansamycin-based Hsp90 inhibitors for the treatment of neurodegenerative disease. 23586778 In situ response of the linuron degradation potential to linuron application in an agricultural field. To assess the involvement of the genus Variovorax and the linuron hydrolase gene libA in in situ linuron degradation in agricultural fields, changes in Variovorax community size and composition, in libA abundance and in linuron mineralization capacity were monitored in field soil plots either treated or not with a linuron-containing herbicide mixture. Changes in Variovorax community composition, due to the proliferation of a hereto unknown Variovorax phylotype D, and increases in libA numbers occurred concomitant to increases in linuron mineralization capacity in the plot treated with the herbicide mixture. The observations suggest that Variovorax and libA proliferated as a response to linuron and hence their contribution to in situ linuron degradation. The involvement of Variovorax phylotype D and libA in linuron degradation in the examined soil was supported by laboratory soil microcosm experiments. Attempts to enrich in suspended cultures and isolate the organism corresponding to phylotype D from the soil were unsuccessful as the enrichment resulted in replacement of Variovorax phylotype D by other Variovorax phylotypes. This illustrates that linuron-degrading strains isolated by liquid enrichment cultures are not always representatives of those responsive to linuron in the field, although the genus specificity of linuron degradation was retained. 23811257 Novel quinoxaline 1,4-di-N-oxide derivatives as new potential antichagasic agents. As a continuation of our research and with the aim of obtaining new agents against Chagas disease, an extremely neglected disease which threatens 100 million people, eighteen new quinoxaline 1,4-di-N-oxide derivatives have been synthesized following the Beirut reaction. The synthesis of the new derivatives was optimized through the use of a new and more efficient microwave-assisted organic synthetic method. The new derivatives showed excellent in vitro biological activity against Trypanosoma cruzi. Compound 17, which was substituted with fluoro groups at the 6- and 7-positions of the quinoxaline ring, was the most active and selective in the cytotoxicity assay. The electrochemical study showed that the most active compounds, which were substituted by electron-withdrawing groups, possessed a greater ease of reduction of the N-oxide groups. 23727299 GelClust: a software tool for gel electrophoresis images analysis and dendrogram generation. This paper presents GelClust, a new software that is designed for processing gel electrophoresis images and generating the corresponding phylogenetic trees. Unlike the most of commercial and non-commercial related softwares, we found that GelClust is very user-friendly and guides the user from image toward dendrogram through seven simple steps. Furthermore, the software, which is implemented in C# programming language under Windows operating system, is more accurate than similar software regarding image processing and is the only software able to detect and correct gel 'smile' effects completely automatically. These claims are supported with experiments. 23964963 Detection of dengue viruses using reverse transcription-loop-mediated isothermal amplification. Early and rapid detection of dengue virus (DENV) infection during the febrile period is crucial for proper patient management and prevention of disease spread. An easy to perform and highly sensitive method is needed for routine implementation especially in the resource-limited rural healthcare settings where dengue is endemic. A single-tube reverse transcription-loop-mediated isothermal amplification (RT-LAMP) assay with a set of nine primers was developed for the detection of all four DENV serotypes and their different genotypes. The sensitivity and specificity of the RT-LAMP were evaluated. The clinical applicability of RT-LAMP assay for detection of DENV RNA was assessed in a total of 305 sera of clinically-suspected dengue patients. The test results of RT-LAMP were statistically compared to those of quantitative reverse transcription-polymerase chain reaction (qRT-PCR), IgM- and IgG-capture enzyme-linked immunosorbent assays (ELISA). Acute DENV infection was confirmed in 171 samples (n = 305); 43.3% (74/171) and 46.8% (80/171) of the samples were positive for DENV using RT-LAMP and qRT-PCR, respectively. The combination of RT-LAMP with the dengue IgM and IgG ELISA increased detection of acute DENV infection to 97.7% (167/171), in comparison to only 70.8% (121/171) when dengue IgM and IgG ELISA alone were used. The RT-LAMP assays showed high concordance (kappa = 0.939) with the qRT-PCR. The RT-LAMP assay detected up to 10 copies of virus RNA within an hour but 100% reproducibility (12/12) was achieved with 100 copies. There was no cross reactivity of RT-LAMP with other closely related arboviruses. The RT-LAMP assay developed in this study is sensitive, specific and simple to perform. The assay improved the detection of dengue when used in combination with serological methods. 23844112 Modeling Change in Learning Strategies throughout Higher Education: A Multi-Indicator Latent Growth Perspective. The change in learning strategies during higher education is an important topic of research in the Student Approaches to Learning field. Although the studies on this topic are increasingly longitudinal, analyses have continued to rely primarily on traditional statistical methods. The present research is innovative in the way it uses a multi-indicator latent growth analysis in order to more accurately estimate the general and differential development in learning strategy scales. Moreover, the predictive strength of the latent growth models are estimated. The sample consists of one cohort of Flemish University College students, 245 of whom participated in the three measurement waves by filling out the processing and regulation strategies scales of the Inventory of Learning Styles - Short Versions. Independent-samples t-tests revealed that the longitudinal group is a non-random subset of students starting University College. For each scale, a multi-indicator latent growth model is estimated using Mplus 6.1. Results suggest that, on average, during higher education, students persisting in their studies in a non-delayed manner seem to shift towards high-quality learning and away from undirected and surface-oriented learning. Moreover, students from the longitudinal group are found to vary in their initial levels, while, unexpectedly, not in their change over time. Although the growth models fit the data well, significant residual variances in the latent factors remain. 23141189 Inactivation of Escherichia coli by sonoelectrocatalytic disinfection using TiO2 as electrode. This is the first study to demonstrate sonoelectrocatalytic disinfection using titanium dioxide (TiO(2)) as an anode for effective inactivation of Escherichia coli. In brief, a non-woven TiO(2) fabric used as an anode and a platinum cathode were immersed in an E. coli suspension in which a positive potential was applied to TiO(2) concomitant with ultrasound (US) irradiation. Two control experiments were performed using E. coli suspensions to exhibit the effects of the sonoelectrocatalytic disinfection. One was disinfection by applying a positive potential to a TiO(2) electrode, but without US irradiation (electrochemical disinfection). The other was disinfection without applying a potential, but with US irradiation in the presence of TiO(2) (sonocatalytic disinfection). The cell inactivation rate in sonoelectrocatalytic disinfection was synergistically much more enhanced than the combined inactivation rates in electrochemical disinfection and sonocatalytic disinfection. This synergistically enhanced inactivation rate of E. coli cells was attributable to effective reaction of the sonocatalytically generated OH radicals with E. coli cells at the surface of the TiO(2) anode, which resulted from the electroadsorption of E. coli cells toward the TiO(2) anode. 23574017 Effects of 17α-ethynylestradiol-induced cholestasis on the pharmacokinetics of doxorubicin in rats: reduced biliary excretion and hepatic metabolism of doxorubicin. Abstract 1. Since the prevalent hormonal combination therapy with estrogen analogues in cancer patients has frequency and possibility to induce the cholestasis, the frequent combination therapy with 17α-ethynylestradiol (EE, an oral contraceptive) and doxorubicin (an anticancer drug) might be monitored in aspect of efficacy and safety. Doxorubicin is mainly excreted into the bile via P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2) in hepatobiliary route and metabolized via cytochrome P450 (CYP) 3A subfamily. Also the hepatic Mrp2 (not P-gp) and CYP3A subfamily levels were reduced in EE-induced cholestatic (EEC) rats. Thus, we herein report the pharmacokinetic changes of doxorubicin with respect to the changes in its biliary excretion and hepatic metabolism in EEC rats. 2. The pharmacokinetic study of doxorubicin after intravenous administration of its hydrochloride was conducted along with the investigation of bile flow rate and hepatobiliary excretion of doxorubicin in control and EEC rats. 3. The significantly greater AUC (58.7% increase) of doxorubicin in EEC rats was due to the slower CL (32.9% decrease). The slower CL was due to the reduction of hepatic biliary excretion (67.0% decrease) and hepatic CYP3A subfamily-mediated metabolism (21.9% decrease) of doxorubicin. These results might have broader implications to understand the altered pharmacokinetics and/or pharmacologic effects of doxorubicin via biliary excretion and hepatic metabolism in experimental and clinical estrogen-induced cholestasis. 23529408 Current status of genetics and genomics of reared penaeid shrimp: information relevant to access and benefit sharing. At present, research and progress in shrimp genomics and genetics show significant developments. Shrimp genetics and genomics also show immense potential for an increased production in a way that meets shrimp culture progress goals for the third millennium. This review article aims to provide an overview of its current status and future direction, discusses questions that need focused research to address them, and summarizes areas where genetics and genomics knowledge can make a positive difference to shrimp culture sustainability. Sustainable progress of penaeid shrimps will depend upon feasible solutions for environmental, research, economic, consumer problems, proper development, and planning policy enforcement. It is recommended that increased funding for biotechnology research and progress be directed to expand worldwide commercial shrimp culture and address environmental and public health issues. For any researcher or shrimp company member who has attempted to or whom would like to thoroughly search the literature to gain a complete understanding of the current state of shrimp genetics and genomics, this publication will be an invaluable source of reference materials, some of which is reported here for the first time. 23445204 The role of fecundity and reproductive effort in defining life-history strategies of North American freshwater mussels. Selection is expected to optimize reproductive investment resulting in characteristic trade-offs among traits such as brood size, offspring size, somatic maintenance, and lifespan; relative patterns of energy allocation to these functions are important in defining life-history strategies. Freshwater mussels are a diverse and imperiled component of aquatic ecosystems, but little is known about their life-history strategies, particularly patterns of fecundity and reproductive effort. Because mussels have an unusual life cycle in which larvae (glochidia) are obligate parasites on fishes, differences in host relationships are expected to influence patterns of reproductive output among species. I investigated fecundity and reproductive effort (RE) and their relationships to other life-history traits for a taxonomically broad cross section of North American mussel diversity. Annual fecundity of North American mussel species spans nearly four orders of magnitude, ranging from < 2000 to 10 million, but most species have considerably lower fecundity than previous generalizations, which portrayed the group as having uniformly high fecundity (e.g. > 200000). Estimates of RE also were highly variable, ranging among species from 0.06 to 25.4%. Median fecundity and RE differed among phylogenetic groups, but patterns for these two traits differed in several ways. For example, the tribe Anodontini had relatively low median fecundity but had the highest RE of any group. Within and among species, body size was a strong predictor of fecundity and explained a high percentage of variation in fecundity among species. Fecundity showed little relationship to other life-history traits including glochidial size, lifespan, brooding strategies, or host strategies. The only apparent trade-off evident among these traits was the extraordinarily high fecundity of Leptodea, Margaritifera, and Truncilla, which may come at a cost of greatly reduced glochidial size; there was no relationship between fecundity and glochidial size for the remaining 61 species in the dataset. In contrast to fecundity, RE showed evidence of a strong trade-off with lifespan, which was negatively related to RE. The raw number of glochidia produced may be determined primarily by physical and energetic constraints rather than selection for optimal output based on differences in host strategies or other traits. By integrating traits such as body size, glochidial size, and fecundity, RE appears more useful in defining mussel life-history strategies. Combined with trade-offs between other traits such as growth, lifespan, and age at maturity, differences in RE among species depict a broad continuum of divergent strategies ranging from strongly r-selected species (e.g. tribe Anodontini and some Lampsilini) to K-selected species (e.g. tribes Pleurobemini and Quadrulini; family Margaritiferidae). Future studies of reproductive effort in an environmental and life-history context will be useful for understanding the explosive radiation of this group of animals in North America and will aid in the development of effective conservation strategies. 23866830 Gastroprotective effect of desmosdumotin C isolated from Mitrella kentii against ethanol-induced gastric mucosal hemorrhage in rats: possible involvement of glutathione, heat-shock protein-70, sulfhydryl compounds, nitric oxide, and anti-Helicobacter pylori activity. Mitrella kentii (M.kentii) (Bl.) Miq , is a tree-climbing liana that belongs to the family Annonaceae. The plant is rich with isoquinoline alkaloids, terpenylated dihydrochalcones and benzoic acids and has been reported to possess anti-inflammatory activity. The purpose of this study is to assess the gastroprotective effects of desmosdumotin C (DES), a new isolated bioactive compound from M. kentii ,on gastric ulcer models in rats. DES was isolated from the bark of M. kentii. Experimental rats were orally pretreated with 5, 10 and 20 mg/kg of the isolated compound and were subsequently subjected to absolute ethanol-induced acute gastric ulcer. Gross evaluation, mucus content, gastric acidity and histological gastric lesions were assessed in vivo. The effects of DES on the anti-oxidant system, non-protein sulfhydryl (NP-SH) content, nitric oxide (NO)level, cyclooxygenase-2 (COX-2) enzyme activity, bcl-2-associated X (Bax) protein expression and Helicabacter pylori (H pylori) were also investigated. DES pre-treatment at the administered doses significantly attenuated ethanol-induced gastric ulcer; this was observed by decreased gastric ulcer area, reduced or absence of edema and leucocytes infiltration compared to the ulcer control group. It was found that DES maintained glutathione (GSH) level, decreased malondialdehyde (MDA) level, increased NP-SH content and NO level and inhibited COX-2 activity. The compound up regulated heat shock protein-70 (HSP-70) and down regulated Bax protein expression in the ulcerated tissue. DES showed interesting anti-H pylori effects. The efficacy of DES was accomplished safely without any signs of toxicity. The current study reveals that DES demonstrated gastroprotective effects which could be attributed to its antioxidant effect, activation of HSP-70 protein, intervention with COX-2 inflammatory pathway and potent anti H pylori effect. 23770094 Regulation of miR-17-92a cluster processing by the microRNA binding protein SND1. MicroRNAs are small non-coding RNAs that regulate gene expression. Although all seven members of the miR-17-92a cluster originate from one primary transcript they are differentially expressed suggesting the presence of posttranscriptional regulation. By RNA pulldown and mass spectrometry we identified SND1, a known regulator of edited RNAs, interacting with pre-miR-92a and all mature miR-17-92a members. Hypoxic conditions lead to an elevation of the pri-miR-17-92a transcript and significantly increased levels of the precursors whereas the mature miRs were not significantly changed. SND1 silencing resolved this block in processing and induced an increase in mature miRs. Together, SND1 might be the missing link between hypoxia and the differential regulation of miRNA processing. 23835756 Corneal biomechanics predict the outcome of selective laser trabeculoplasty in medically uncontrolled glaucoma. To evaluate the predictive value of clinical parameters, including biomechanical properties on the outcome of selective laser trabeculoplasty (SLT) in medically uncontrolled open angle glaucoma (OAG). Sixty-eight eyes from 68 patients with OAG and IOP insufficiently regulated by topical medications were enrolled. Patients' follow-up occurred 6 and 12 months after the procedure. The recorded parameters intraocular pressure (IOP), angle characteristics, central corneal thickness (CCT) and biomechanical properties of the eyes, including corneal hysteresis CH and corneal resistance factor CRF measured with the Ocular Responses Analyzer (ORA, Reichert Ophthalmic Instruments) were tested on their predictive value of SLT-induced IOP lowering effect using correlation analyses and regression models. Mean IOP reduction 12 months after SLT was 4.2 ±â€‰5.7 mmHg (23.2 %, from baseline 18.1 ±â€‰5.2 mmHg). The preoperative IOP correlated significantly with IOP reduction (maximum Spearman's correlation r = 0.75, p < 0.001). In linear regression analysis, the corneal biomechanical properties (CH and CRF) together with the baseline IOP revealed good modelling for the IOP lowering effect of SLT (R(2) = 0.64, respectively). In addition to the baseline IOP biomechanical properties (CH and CRF) are significant predictors of SLT induced IOP lowering effect in medically uncontrolled OAG. 23927647 Response to Reshef et al: Colectomy with ileorectal anastomosis has a worse 30-day outcome when performed for colonic inertia than for a neoplastic indication. We read with great interest the article entitled "Colectomy with ileorectal anastomosis has a worse 30-day outcome when performed for colonic inertia than for a neoplastic indication" authored by Reshef et al [1]. As pointed out by the authors, colectomy with ileorectal anastomosis for colonic inertia is associated with high rate of postoperative morbidity compared to patients undergoing the same procedure for neoplastic indication (19%). This is likely to have impacted on the length of stay, as well as the urinary tract infection and postoperative abscess formation that were found to be more frequent in patients with colonic inertia. In this study, the authors did not provide data regarding the patients' outcome 30 days after surgery. This article is protected by copyright. All rights reserved. 23652156 Sequence representation during response preparation in the serial reaction time task. The type of representations involved in implicit learning during the response preparation stage of sequence learning was studied using the response-locked lateralized readiness potential (LRP-R) as an index. Participants performed a modified serial reaction time task on an eight-letter sequence; half were informed to look for patterns in the sequence and half were not. The standard sequence was occasionally replaced by one of two deviant sequences and the LRP-R elicited was analyzed. When comparing across three sequence conditions, namely, a perceptual deviant sequence, a motor deviant sequence, and a standard sequence (as control), the onset latency and the mean amplitude of the LRP-R were similar for all three conditions and for both explicit and implicit learners. The perceptual deviant sequence group showed a longer response preparation time than the motor deviant group and the standard sequence group, but the latter two were not significantly different. The perceptual deviant sequence group showed more negative LRP-R amplitude than the other two groups that did not differ from each other. The finding of similar LRP-R profiles between implicit and explicit learners suggests that stimulus representation (S-S association) is the main form of representation supporting sequence learning in the response preparation stage. 23506002 New selective inhibitors of MMP-13 for inflammatory diseases: a patent evaluation (W02012151158). A series of compounds incorporating an aromatic scaffold based on isoxazolines were prepared in the patent application (WO2012151158). The new compounds from the patent are defined to be biologically active metabolites, prodrugs, isomers, stereoisomers, solvates, hydrates and pharmaceutically acceptable salts, they are claimed to be useful for treating immunological conditions because of their inhibitory activities on matrix metalloproteinase (MMP-13), although no specific MMP-13 inhibition data or other rationale to explain their biological effects is provided. The compounds have a broad potential utility with osteoarthritis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, degenerative joint disease or systemic lupus erythematosus among the likely preferred indications. 23900208 A novel cell-processing method 'AgarCytos' in conjunction with OCT3/4 and PLAP to detect intratubular germ cell neoplasia in non-obstructive azoospermia using remnants of testicular sperm extraction specimens. Can we diagnose intratubular germ cell neoplasia (IGCN) using the immunohistochemical markers placental-like alkaline phosphatase (PLAP) and OCT3/4 using a novel cell-processing method 'AgarCytos', applied to the remnants of testicular sperm extraction (TESE) specimens and what is the prevalence of a testicular germ cell (pre)malignancy in men with a non-obstructive azoospermia (NOA) undergoing TESE for fertility treatment? IGCN can be successfully detected by immunohistochemical evaluation of AgarCytos, made of the remnants of TESE biopsies. The observed prevalence of a germ cell (pre)malignancy in this specific population was found to be 4.4%. Infertile men are at higher risk for testicular cancer than the general population. IGCN can be detected by immunohistochemistry using PLAP and OCT3/4 in standard testicular biopsies and, with less accuracy, in semen. Between January 2011 and April 2012 a prospective cohort study was conducted at a Dutch tertiary care academic training hospital. All males with NOA (n = 182) undergoing a urological work-up followed by a diagnostic TESE for fertility treatment (n = 251) were included. After cryopreservation of sperm, if present, an AgarCyto was made of the remnants of the TESE biopsies. Sections were stained with haematoxylin-eosin for pathological examination as well as PLAP and OCT3/4 for immunohistochemistry to detect IGCN. Eight men (4.4%) were diagnosed with a germ cell (pre)malignancy: six of them had seminoma, two without and four with concomitant IGCN, and two of them had IGCN only. Microscopic evaluation including immunohistochemical analysis of the AgarCytos diagnosed three (1.6%) more cases of a germ cell (pre)malignancy compared with scrotal ultrasound alone (one case of bilateral seminoma with concomitant IGCN and two cases of IGCN alone). No false-positive cytology results were found upon conventional histological evaluation. The main limitation of this study is lack of a simultaneously taken standard testicular biopsy, to compare the results of our novel diagnostic method with. Nevertheless, in all but one of our cases orchidectomy followed and the diagnosis was confirmed by histology. In the remaining case repeat TESE showed similar results. Simultaneous screening for IGCN is highly recommended to men with NOA undergoing TESE, because of the increased incidence of germ cell (pre)malignancies in this specific population. The principal advantage of our new method is that all available testicular tissue can be used for both sperm recovery and pathological evaluation, increasing the yield of spermatozoa as well as the chance to find (pre)malignant cells. In those cases where the disease is still in a premalignant stage, early diagnosis will allow for timely treatment and reduction of morbidity and mortality in this group of patients. This study was (partially) funded by Merck Serono (the Netherlands). There are no conflicting interests to disclose. TRIAL REGISTRATION NUMBER: N/A. 23323627 Folic acid modified cationic γ-cyclodextrin-oligoethylenimine star polymer with bioreducible disulfide linker for efficient targeted gene delivery. For an efficient folate-targeted delivery, while the interaction between the folate on the carriers and the folate receptor (FR) on the cells is necessary, the recovering and recycling of FR to maintain a high density level of FR on the cellular membrane is also important. Herein, we demonstrate a design and synthesis of a new star-shaped cationic polymer containing a γ-cyclodextrin (γ-CD) core and multiple oligoethylenimine (OEI) arms with folic acid (FA) linked by a bioreducible disulfide bond for efficient targeted gene delivery. The newly synthesized cationic polymer, named γ-CD-OEI-SS-FA, could be cleaved efficiently, and FA was readily released under reductive condition similar to intracellular environment. The γ-CD-OEI-SS-FA polymer was well-characterized and studied in terms of its gene delivery properties in FR-positive KB cells and FR-negative A549 cells under various conditions, in comparison with cationic polymers such as high molecular weight branched polyethylenimine (PEI), γ-CD-OEI star-shaped cationic polymer, γ-CD-OEI-FA polymer where FA was directed linked to the star polymer without disulfide linker. Our data have demonstrated that the new γ-CD-OEI-SS-FA gene carrier had low cytotoxicity and possessed capacity to target and deliver DNA to specific tumor cells that overexpress FRs, as well as functions to recover and recycle FRs onto cellular membranes to facilitate continuous FR-mediated endocytosis to achieve very high levels of gene expression. This study has expanded the strategy of FA-targeted delivery by combining the smart FR-recycling function to achieve the significant enhancement of gene expression. The new FA-targeted and bioreducible carrier may be a promising efficient gene delivery system for potential cancer gene therapy. 23607754 Syntenin-a promotes spinal cord regeneration following injury in adult zebrafish. In contrast to mammals, adult zebrafish recover locomotor function after spinal cord injury, in part due to the capacity of the central nervous system to repair severed connections. To identify molecular cues that underlie regeneration, we conducted mRNA expression profiling and found that syntenin-a expression is upregulated in the adult zebrafish spinal cord caudal to the lesion site after injury. Syntenin is a scaffolding protein involved in mammalian cell adhesion and movement, axonal outgrowth, establishment of cell polarity, and protein trafficking. It could thus be expected to be involved in supporting regeneration in fish. Syntenin-a mRNA and protein are expressed in neurons, glia and newly generated neural cells, and upregulated caudal to the lesion site on days 6 and 11 following spinal cord injury. Treatment of spinal cord-injured fish with two different antisense morpholinos to knock down syntenin-a expression resulted in significant inhibition of locomotor recovery at 5 and 6 weeks after injury, when compared to control morpholino-treated fish. Knock-down of syntenin-a reduced regrowth of descending axons from brainstem neurons into the spinal cord caudal to the lesion site. These observations indicate that syntenin-a is involved in regeneration after traumatic insult to the central nervous system of adult zebrafish, potentially leading to novel insights into the cellular and molecular mechanisms that require activation in the regeneration-deficient mammalian central nervous system. 23831979 Investigation of the binding sites and orientation of caffeine on human serum albumin by surface-enhanced Raman scattering and molecular docking. Fluorescence, normal Raman and surface-enhanced Raman scattering (SERS) were introduced to explore the absorptive geometry of caffeine on Human Serum Albumin (HSA) at physiological condition. The molecular docking was also employed to make a better understanding of the interaction between caffeine and HSA as well as to elucidate the detailed information of the major binding site. The results showed that caffeine could bind to HSA via the hydrophobic force of aromatic stacking and the main binding group on caffeine could be the pyrimidine ring. In addition, a consecutive set of changes in the orientation of caffeine molecule had been demonstrated during the process of caffeine binding to HSA, and the primary binding site was considered to be a hydrophobic cavity formed by Leu198, Lys199, Ser202, Phe211, Trp214, Val344, Ser454 and Leu481 in domain II. 23727993 Toxic effects, bioconcentration and depuration of verapamil in the early life stages of common carp (Cyprinus carpio L.). Verapamil is a pharmaceutical that belongs to a group of calcium channel blockers and is mainly used as a treatment of angina pectoris and arterial hypertension. Verapamil has been detected in aquatic environments in concentrations ranging from ng L(-1) to μg L(-1). In the present study, a series of acute toxicity tests of verapamil on various developmental stages of common carp (Cyprinus carpio) were conducted. As a result, 96hLC50 values of verapamil were estimated at 16.4±9.2, 7.3±1.5 and 4.8±0.2mgL(-1) for embryos (E5-E9) and common carp larvae L2 and L5, respectively. Lethal concentrations of verapamil decreased with an increase in the age of the fish. Acute exposure to verapamil significantly reduced the heart rate in the embryos and larvae. In an embryo-larval toxicity test (sub-chronic exposure), the bioconcentration, depuration, and toxic effects of verapamil were assessed in common carp. The fish were exposed to verapamil in a concentration of 0.463 (environmentally relevant), 4.63, 46.3 and 463μgL(-1). Verapamil had no effect on the accumulated mortality, hatching, condition factor, growth or ontogeny of the fish in any of the tested concentrations. In carp exposed to 463 and 46.3μgL(-1) of verapamil, significantly higher occurrences of malformations and edemas were observed compared to the control. The bioconcentration factor of verapamil in whole fish homogenates ranged between 6.6 and 16.6 and was therefore below the critical value for hazard substances (BCF>500). The half-life and the 95% depuration time for the tested compound were estimated to be 10.2±1.6days and 44.2±8.6days, respectively. No effects of verapamil on the studied endpoints were observed at environmentally relevant concentrations. 23915745 Challenges in the treatment of older breast cancer patients. As the population ages, oncologists will be faced with managing an exploding number of older patients with breast cancer. The primary challenge of caring for older cancer patients is providing treatment options that maximize long-term survival while accounting for comorbidities, life expectancy, and effects of treatment. There is a paucity of data from trials on the risks and benefits of effective treatments in elderly breast cancer patients. This article discusses how to evaluate older breast cancer patients and provides guidelines for optimal therapies in the adjuvant and metastatic treatment settings. 23879662 An iterative consensus-building approach to revising a genetics/genomics competency framework for nurse education in the UK. To report a review of a genetics education framework using a consensus approach to agree on a contemporary and comprehensive revised framework. Advances in genomic health care have been significant since the first genetics education framework for nurses was developed in 2003. These, coupled with developments in policy and international efforts to promote nursing competence in genetics, indicated that review was timely. A structured, iterative, primarily qualitative approach, based on a nominal group technique. A meeting convened in 2010 involved stakeholders in UK nursing education, practice and management, including patient representatives (n = 30). A consensus approach was used to solicit participants' views on the individual/family needs identified from real-life stories of people affected by genetic conditions and the nurses' knowledge, skills and attitudes needed to meet those needs. Five groups considered the stories in iterative rounds, reviewing comments from previous groups. Omissions and deficiencies were identified by mapping resulting themes to the original framework. Anonymous voting captured views. Educators at a second meeting developed learning outcomes for the final framework. Deficiencies in relation to Advocacy, Information management and Ongoing care were identified. All competencies of the original framework were revised, adding an eighth competency to make explicit the need for ongoing care of the individual/family. Modifications to the framework reflect individual/family needs and are relevant to the nursing role. The approach promoted engagement in a complex issue and provides a framework to guide nurse education in genetics/genomics; however, nursing leadership is crucial to successful implementation. 23962265 The interrupted V-Y advancement flap for the reconstruction of the vulvovaginal defect. High-quality reconstruction of vulvovaginal defects after tumor excision is critical. Various techniques for vulvovaginal reconstruction have been described. However, these flaps are often bulky, and tip necrosis occasionally occurs. To reduce bulkiness and prevent flap necrosis, we have therefore developed an ideal approach using a fasciocutaneous flap that is advanced in a modified V-Y fashion. The V-Y flap is interrupted in the defect area by a bipedicled flap and therefore termed "the interrupted V-Y advancement flap". We used the interrupted V-Y advancement flap to cover vulvovaginal defects in five patients who underwent surgical treatment for extramammary Paget's disease or carcinoma of the vulva. Each flap survived completely without complications. This flap is easily elevated, not bulky, and reliable because it is supplied by the internal pudendal artery and vein without excessive skeletonization of the vascular pedicle; it also matches the local skin quality. 23269436 Regulatory circuits controlling vascular cell calcification. Vascular calcification is a common feature of chronic kidney disease, cardiovascular disease, and aging. Such abnormal calcium deposition occurs in medial and/or intimal layers of blood vessels as well as in cardiac valves. Once considered a passive and inconsequential finding, the presence of calcium deposits in the vasculature is widely accepted as a predictor of increased morbidity and mortality. Recognition of the importance of vascular calcification in health is driving research into mechanisms that govern its development, progression, and regression. Diverse, but highly interconnected factors, have been implicated, including disturbances in lipid metabolism, oxidative stress, inflammatory cytokines, and mineral and hormonal balances, which can lead to formation of osteoblast-like cells in the artery wall. A tight balance of procalcific and anticalcific regulators dictates the extent of disease. In this review, we focus on the main regulatory circuits modulating vascular cell calcification. 23681342 Phenotypic Conservation in Patients With X-Linked Retinitis Pigmentosa Caused by RPGR Mutations. IMPORTANCE For patients with X-linked retinitis pigmentosa and clinicians alike, phenotypic variability can be challenging because it complicates counseling regarding patients' likely visual prognosis. OBJECTIVE To evaluate the clinical findings from patients with X-linked retinitis pigmentosa with 13 distinct RPGR mutations and assess for phenotypic concordance or variability. DESIGN Retrospective medical record review of data collected from 1985 to 2011. SETTING Kellogg Eye Center, University of Michigan. PATIENTS A total of 42 patients with X-linked retinitis pigmentosa with mutations in RPGR. Age at first visit ranged from 4 to 53 years, with follow-up ranging from 1 to 11 visits (median follow-up time, 5.5 years; range, 1.4-32.7 years, for 23 patients with >1 visit). MAIN OUTCOMES AND MEASURES Clinical data assessed for concordance included visual acuity (VA), Goldmann visual fields (GVFs), and full-field electroretinography (ERG). Electroretinography phenotype (cone-rod vs rod-cone dysfunction) was defined by the extent of photopic vs scotopic abnormality. Qualitative GVF phenotype was determined by the GVF pattern, where central or peripheral loss suggested cone or rod dysfunction, respectively. Goldmann visual fields were also quantified and compared among patients. RESULTS Each mutation was detected in 2 or more related or unrelated patients. Five mutations in 11 patients displayed strong concordance of VA, while 4 mutations in 16 patients revealed moderate concordance of VA. A definitive cone-rod or rod-cone ERG pattern consistent among patients was found in 6 of 13 mutations (46.2%); the remaining mutations were characterized by patients demonstrating both phenotypes or who had limited data or nonrecordable ERG values. Concordant GVF phenotypes (7 rod-cone pattern vs 4 cone-rod pattern) were seen in 11 of 13 mutations (84.6%). All 6 mutations displaying a constant ERG pattern within the mutation group revealed a GVF phenotype consistent with the ERG findings. CONCLUSIONS AND RELEVANCE While VA and ERG phenotypes are concordant in only some patients carrying identical mutations, assessment of GVF phenotypes revealed stronger phenotypic conservation. Phenotypic concordance is important for establishing proper counseling of patients diagnosed as having X-linked retinitis pigmentosa, as well as for establishing accurate patient selection and efficacy monitoring in therapeutic trials. 21763161 Chromosomal imbalances in successive moments of human bladder urothelial carcinoma. To understand developmental characteristics of urinary bladder carcinomas (UBC) by evaluating genomic alterations and p53 protein expression in primary tumors, their recurrences, and in the morphologically normal urothelium of UBC patients. Tumors and their respective recurrences, six low-grade and five high-grade cases, provided 19 samples that were submitted to laser microdissection capture followed by high resolution comparative genomic hybridization (HR-CGH). HR-CGH profiles went through two different analyses-all tumors combined or classified according to their respective histologic grades. In a supplementary analysis, 124 primary urothelial tumors, their recurrences, and normal urothelium biopsied during the period between tumor surgical resection and recurrence, were submitted to immunohistochemical analyses of the p53 protein. During the follow-up of at least 21 patients, urinary bladder washes citologically negative for neoplastic cells were submitted to fluorescence in situ hybridization (FISH) to detect copy number alterations in centromeres 7, 17, and 9p21 region. HR-CGH indicated high frequencies (80%) of gains in 11p12 and losses in 16p12, in line with suggestions that these chromosome regions contain genes critical for urinary bladder carcinogenesis. Within a same patient, tumors and their respective recurrences showed common genomic losses and gains, which implies that the genomic profile acquired by primary tumors was relatively stable. There were exclusive genomic alterations in low and in high grade tumors. Genes mapped in these regions should be investigated on their involvement in the urinary bladder carcinogenesis. Successive tumors from same patient did not present similar levels of protein p53 expression; however, when cases were grouped according to tumor histologic grades, p53 expression was directly proportional to tumor grades. Biopsies taken during the follow-up of patients with history of previously resected UBC revealed that 5/15 patients with no histologic alterations had more than 25% of urothelial cells expressing the p53 protein, suggesting that the apparently normal urothelium was genomically unstable. No numerical alterations of the chromosomes 7, 17, and 9p21 region were found by FISH during the periods "free-of-neoplasia." Our data are informative for further studies to better understand urinary bladder urothelial carcinogenesis. 23645329 Accuracy of multidetector-row CT for restaging after neoadjuvant treatment in patients with oesophageal cancer. To assess the diagnostic accuracy of 64-multidetector CT (MDCT) for restaging of patients with oesophageal cancer undergoing neoadjuvant therapy. Results of pathological staging were correlated with those from 64-MDCT before and after neoadjuvant treatment in 35 patients using the American Joint Committee on Cancer/TNM classification (7th edition). CT response was determined using the Response Evaluation Criteria in Solid Tumours (RECIST) method, modified for one-dimensional tumour diameter measurement. 64-MDCT predicted T stage correctly in 34 % (12/35), overstaged in 49 % (17/35) and understaged in 17 % (6/35). Sensitivity/specificity values were as follows: T0, 20 %/92 %; T1-T2, 31 %/59 %; T3, 60 %/64 %; T4, 100 %/4 %. Negative predictive values for T3/T4 were 80 %/100 %. MDCT accurately predicted complete histopathological response in 20 % (accuracy 74 %) and overstaged in 80 %. Tumour regression grade was predicted correctly in only 8 % (2/25) and underestimated in 68 % (17/25). Accurate N stage was noted in 69 % (24/35). Although MDCT tends to be able to exclude advanced tumour stages (T3, T4) with a higher likelihood, the diagnostic accuracy of high resolution MDCT for restaging oesophageal cancer and assessing the response to neoadjuvant therapy has not improved in comparison to older-generation CT. Therefore, the future assessment of oesophageal tumour response should focus on combined morphologic and metabolic imaging. • Multidetector CT (MDCT) has been beneficial for the evaluation of many tumours. • However diagnostic accuracy for restaging oesophageal cancer has not improved with MDCT. • MDCT tends to be able to exclude advanced tumour stages (T3/T4). • MDCT has a low accuracy for determining lymph node metastasis. • Oesophageal tumour response should be assessed by combined morphological and metabolic imaging. 23873206 Hydrothermal Synthesis of High-Quality Thiol-Stabilized CdTexSe 1-x Alloyed Quantum Dots. Alloyed semiconductor quantum dots (QDs) enriched the synthetic routes for engineering materials with unique structural and optical properties. High-quality thiol-stabilized CdTexSe1-x alloyed QDs were synthesized through a facile and economic hydrothermal method at 120 °C, a relatively low temperature. These water-soluble QDs were prepared using different capping agents including 3-mercaptopropionic acid (MPA) and L-cysteine (L-Cys). The photoluminescence (PL) intensity and stability of L-Cys-capped CdTexSe1-x QDs were found to be higher than that of MPA-stabilized ones. The molar ratios of Se-to-Te upon preparation were adjusted for investigating the effect of composition on the properties of the resulting QDs. We also investigated the effect of the pH value of the reaction solution on the growth kinetics of the alloyed CdTexSe1-x QDs. The resulting CdTexSe1-x QDs were characterized by UV-vis absorbance and PL spectroscopy, powder X-ray diffraction, and transmission electron microscopy. Being coated with a CdS inorganic shell, the PL intensity and stability of the CdTexSe1-x/CdS core-shell QDs were drastically enhanced, accompanied by the red-shift of the PL peak wavelength. Owing to the unique optical properties, the QDs hold great potential for application and have to be further exploited. 23594336 Lectin-like oxidized low-density lipoprotein receptor 1 pathways. The role of lectin-like oxidized low-density lipoprotein receptor (LOX)-1 has been implicated in the pathogenesis of different diseases, including atherosclerosis, hypertension, obesity, diabetes mellitus and metabolic syndrome. To date, several studies aimed at partially investigating the mechanistic role of LOX-1 in these various pathologies. Still, so far, the precise signal transduction pathways involving LOX-1 have not yet been elucidated. The most recent data published by the authors as well as others concerning different pathways involving LOX-1 are collected to formulate the presented updated review. One of the most prominent pathways highlighted in the present review is the relationship of LOX-1 to NADPH oxidase that acts as a major source of harmful free radicals causing oxidative stress in blood vessels. Other pathways involve lipid and glucose metabolism-mediated signal transduction. The modulatory role of LOX-1 on nitric oxide and renin/angiotensin systems as well as on fibrosis, apoptosis and inflammatory pathways is discussed. The current review revisits LOX-1 and its related pathways, implicating LOX-1 as a target for ameliorating various pathological conditions. 23711089 Melatonin reverses tunicamycin-induced endoplasmic reticulum stress in human hepatocellular carcinoma cells and improves cytotoxic response to doxorubicin by increasing CHOP and decreasing Survivin. Chemoresistance in hepatocellular carcinoma (HCC) is associated with multiple cellular responses to environmental stresses, such as nutrient deprivation and hypoxia. Nevertheless, whether ER stress resulting from nutrient deprivation and tumor hypoxia contributes to drug resistance remains unclear. Melatonin increased the efficacy of chemotherapeutic drugs in hepatocellular carcinoma in our previous studies. However, the effects of melatonin on endoplasmic reticulum (ER) stress-induced resistance to chemotherapeutic agents in HCC have not been tested. The effect of the endoplasmic reticulum (ER) stress response during resistance of human hepatocellular carcinoma cells against doxorubicin was investigated in this study. Pretreatment of HepG2 and SMMC-7721 cells (two human hepatocellular carcinoma cell lines) with tunicamycin, an ER stress inducer, drastically decreased the rate of apoptosis generated by doxorubicin. Interestingly, co-pretreatment with tunicamycin and melatonin significantly increased apoptosis induced by doxorubicin. Simultaneously, the expression of phosphorylated AKT (p-AKT) was elevated in HepG2 and SMMC-7721 cells given tunicamycin but reduced in the presence of melatonin. Furthermore, consistent with inhibition of AKT activation by using the PI3K inhibitor LY294002, melatonin elevated the levels of CHOP (C/EBP-homologous protein) and reduced the levels of Survivin (a member of the inhibitor of apoptosis protein family)suggesting that inhibition of the PI3K/AKT pathway by melatonin-reversed ER stress-induced resistance to doxorubicin in human hepatocellular carcinoma cells. These results demonstrate that melatonin attenuates ER stress-induced resistance to doxorubicin in human hepatocellular carcinoma cells by down-regulating the PI3K/AKT pathway, increasing the levels of CHOP and decreasing the levels of Survivin. 23798388 miR-9 is an essential oncogenic microRNA specifically overexpressed in mixed lineage leukemia-rearranged leukemia. MicroRNAs (miRNAs), small noncoding RNAs that regulate target gene mRNAs, are known to contribute to pathogenesis of cancers. Acute myeloid leukemia (AML) is a group of heterogeneous hematopoietic malignancies with various chromosomal and/or molecular abnormalities. AML with chromosomal translocations involving the mixed lineage leukemia (MLL) gene are usually associated with poor survival. In the present study, through a large-scale, genomewide miRNA expression assay, we show that microRNA-9 (miR-9) is the most specifically up-regulated miRNA in MLL-rearranged AML compared with both normal control and non-MLL-rearranged AML. We demonstrate that miR-9 is a direct target of MLL fusion proteins and can be significantly up-regulated in expression by the latter in human and mouse hematopoietic stem/progenitor cells. Depletion of endogenous miR-9 expression by an appropriate antagomiR can significantly inhibit cell growth/viability and promote apoptosis in human MLL-rearranged AML cells, and the opposite is true when expression of miR-9 is forced. Blocking endogenous miR-9 function by anti-miRNA sponge can significantly inhibit, whereas forced expression of miR-9 can significantly promote, MLL fusion-induced immortalization/transformation of normal mouse bone marrow progenitor cells in vitro. Furthermore, forced expression of miR-9 can significantly promote MLL fusion-mediated leukemogenesis in vivo. In addition, a group of putative target genes of miR-9 exhibited a significant inverse correlation of expression with miR-9 in a series of leukemia sample sets, suggesting that they are potential targets of miR-9 in MLL-rearranged AML. Collectively, our data demonstrate that miR-9 is a critical oncomiR in MLL-rearranged AML and can serve as a potential therapeutic target to treat this dismal disease. 23941507 Plasma Klotho Levels Were Inversely Associated with Subclinical Carotid Atherosclerosis in HIV-infected Patients Receiving Combined Antiretroviral Therapy. Combined antiretroviral therapy (cART) has significantly improved the survival rate in HIV-infected individuals, but it contributes to the development of various metabolic complications. Klotho is a novel antiaging gene that encodes a protein with pleiotropic functions, including an emerging role in cardiovascular disease (CVD). The protective effect of higher plasma klotho levels against CVD was recently observed in non HIV-infected adults. We aimed to assess whether plasma secreted α-klotho is associated with subclinical carotid atherosclerosis in HIV-infected patients receiving cART. We prospectively examined the association of circulating plasma α-klotho in 120 HIV-infected patients who had received cART for ≥ 6 months with intima-media thickness (IMT) in the carotid artery and other metabolic variables. The subclinical carotid atherosclerosis was defined as increased mean-IMT level of ≥ 75th percentile for the matched age, sex and race and/or the presence of carotid plaque. Thirty-four (28.3%) of 120 had subclinical carotid atherosclerosis. The higher plasma levels of α-klotho had protective effect against subclinical carotid atherosclerosis (OR 0.006, p = 0.034) in multivariate regression analysis. Plasma α-klotho levels had a significantly negative correlation with fasting glucose levels (r = -0.216, p=0.018) and mean-IMT (r = -0.258, p = 0.004) in multiple stepwise regression analyses. The optimal cutoff values of plasma α-klotho levels for the greatest sensitivity and specificity was calculated as 2.83 log10[pg/mL] (sensitivity, 48.7%; specificity, 90.5%). These results show that plasma klotho levels were inversely associated with subclinical carotid atherosclerosis in HIV-infected patients receiving cART. 22608863 Urban-rural disparities of child health and nutritional status in China from 1989 to 2006. This paper analyzes urban-rural disparities of China's child health and nutritional status using the China Health and Nutrition Survey data from 1989 to 2006. We investigate degrees of health and nutritional disparities between urban and rural children in China as well as how such disparities have changed during the period 1989-2006. The results show that on average urban children have 0.29 higher height-for-age z-scores and 0.19 greater weight-for-age z-scores than rural children. Urban children are approximately 40% less likely to be stunted (OR=0.62; p<0.01) or underweight (OR=0.62; p<0.05) during the period 1989-2006. We also find that the urban-rural health and nutritional disparities have been declining significantly from 1989 to 2006. Both urban and rural children have increased consumption of high protein and fat foods from 1989 to 2006, but the urban-rural difference decreased over time. Moreover, the urban-rural gap in child preventive health care access was also reduced during this period. 23399651 Low 25-OH Vitamin D is Associated with Benign Prostatic Hyperplasia. We tested the hypothesis that low vitamin D is associated with benign prostatic hyperplasia. We also studied whether body composition, sex hormones, serum sex hormone-binding globulin, albumin corrected serum calcium, adiponectin and lipid status are associated with benign prostatic hyperplasia. We investigated 184 representative, randomly selected men 72 to 76 years old enrolled in the Gothenburg arm of the Osteoporotic Fractures in Men Study (MrOS). Men with a history of prostate cancer, prostate operation or medication for benign prostatic hyperplasia were excluded from study, leaving 155 available for analysis. A cross-sectional study was performed in which benign prostatic hyperplasia measured by total prostate volume was related to clinical, anthropometric, endocrine and metabolic factors on univariate and multivariate analyses with regression models. Median prostate volume was 40 ml. In multivariate models only 25-OH vitamin D, albumin corrected serum calcium, serum sex hormone-binding globulin and high density lipoprotein cholesterol were significantly and inversely associated with large prostate glands. The current report adds 4 independent factors associated with benign prostatic hyperplasia, including low 25-OH vitamin D, serum calcium, sex hormone-binding globulin and high density lipoprotein cholesterol. 23935911 Whole Cell Screen for Inhibitors of pH Homeostasis in Mycobacterium tuberculosis. Bacterial pathogens like Mycobacterium tuberculosis (Mtb) encounter acidic microenvironments in the host and must maintain their acid-base homeostasis to survive. A genetic screen identified two Mtb strains that cannot control intrabacterial pH (pHIB) in an acidic environment; infection with either strain led to severe attenuation in mice. To search for additional proteins that Mtb requires to survive at low pH, we introduced a whole-cell screen for compounds that disrupt pHIB, along with counter-screens that identify ionophores and membrane perturbors. Application of these methods to a natural product library identified four compounds of interest, one of which may inhibit novel pathway(s). This approach yields compounds that may lead to the identification of pathways that allow Mtb to survive in acidic environments, a setting in which Mtb is resistant to most of the drugs currently used to treat tuberculosis. 23659619 The activity of valproic Acid in the treatment of refractory hyperleukocytosis in a child with acute lymphoblastic leukemia. Hyperleukocytosis may be associated with an early morbidity and mortality due to leukostasis. Cytoreductive therapies-such as steroids, hydroxiurea, exchange transfusion, and leukapheresis-have been used for the prevention of leukostasis. Herein, the valproic acid used for the treatment of the hyperleukocytosis did not respond to known therapies in a child; lymphoblastic lymphoma developed bone marrow relapse under the treatment is discussed. 23647006 Indications and safety of proton pump inhibitor drug use in patients with cancer. Introduction: Although the exact prevalence of proton pump inhibitor (PPI) use in cancer patients is not known, it is generally perceived to be widespread. PPIs are generally well tolerated and carry an excellent safety profile. However, increasing and longer term PPI use has raised concerns about the risk of pneumonia, bone fractures and enteric infections, and a possible interaction with clopidogrel that could increase the risk of cardiovascular events. Areas covered: We conducted a PubMed search of English language articles addressing the safety and adverse events associated with PPI use with particular emphasis in cancer patients. Expert opinion: PPIs, frequently used in cancer patients, are generally well tolerated and carry an excellent safety profile. PPI-induced acid suppression may increase the risk of Clostridium difficile or other enteric infections, nutritional deficiencies and community acquired pneumonia, all particularly important in cancer patients. The indications for PPI use in cancer patients should be carefully reviewed prior to use. 22888105 Practicability of nitrogen multiple-breath washout measurements in a pediatric cystic fibrosis outpatient setting. Although lung clearance index (LCI) is a sensitive indicator of mild cystic fibrosis (CF) lung disease, it is rarely measured due to lengthy protocols and the commercial unavailability of multiple-breath washout (MBW) setups and tracer gases. We used a newly validated, commercially available nitrogen (N2 ) MBW setup to assess success rate, duration, and variability of LCI within a 20 min timeframe, during clinical routine. We also evaluated the relationship between LCI and other clinical markers of CF lung disease. One hundred thirty six children (83 with CF) between 4 and 16 years were studied in a pediatric CF outpatient setting. One hundred eighteen out of 136 children were naïve to MBW. Within 20 min, each child was trained, N2 MBW was performed, and LCI was analyzed. We assessed intra- and between-test reproducibility in a subgroup of children. At least one LCI was feasible in 123 (90%) children, with a mean (range) of 3.3 (1.2-6.4) min per test. Two or more measurements were feasible in 56 (41%) children. Comparing LCI in CF versus controls, LCI mean (SD) was 12.0 (3.9) versus 6.1 (0.9), and the intra- and inter-test coefficient of repeatability was 1.00 versus 0.81 and 0.96 versus 0.62, respectively. LCI was correlated with spirometry, blood gases, and Pseudomonas aeruginosa infection. Using available N2 MBW equipment, LCI measurements are practical and fast in children. LCI is correlated with markers of CF lung disease. Longer timeframes would be required for triplicate N2 MBW tests in inexperienced children. Pediatr Pulmonol. 2013; 48:739-746. © 2012 Wiley Periodicals, Inc. 23480147 Is a value of over 200 mg/dL in the oral glucose tolerance test, a marker of severity in patients with gestational diabetes mellitus? Abstract Objective: To determine whether blood glucose values of over 200 mg/dL in the oral glucose tolerance test (OGTT) are associated with pregnancy complications and adverse perinatal outcomes in patients with gestational diabetes mellitus (GDM). Methods: A retrospective cohort study was performed comparing patients with GDM A1 (diet controlled) that had at least one value of 200 mg/dL or higher in the OGTT, to those who did not. Patients were treated at the diabetes day care clinic of a tertiary medical center between the years 1999 and 2010. Data were available from the computerized perinatal databases. Results: During the study period, 778 women with GDM were treated at the diabetes day care clinic. Of these, 162 had at least one test value of 200 mg/dL or greater. No significant differences regarding maternal and perinatal complications, such as polyhydramnios, macrosomia (birth-weight above 4 kg), shoulder dystocia, low Apgar scores at 5 min (<7) and cesarean section were noted between the groups. Conclusions: A value of 200 mg/dL or more in the OGTT is not an indicator of perinatal complications. 23848608 Plasmon-Enhanced Photothermoelectric Conversion in Chemical Vapor Deposited Graphene p-n Junctions. Graphene p-n junctions grown by chemical vapor deposition hold great promise for the applications in high-speed, broadband photodetectors and energy conversion devices, where efficient photoelectric conversion can be realized by a hot-carrier-assisted photothermoelectric (PTE) effect and hot-carrier multiplication. However, the overall quantum efficiency is restricted by the low light absorption of single-layer graphene. Here, we present the first experimental demonstration of a plasmon-enhanced PTE conversion in chemical vapor deposited graphene p-n junctions. Surface plasmons of metallic nanostructures placed near the graphene p-n junctions were found to significantly enhance the optical field in the active layer and allow for a 4-fold increase in the photocurrent. Moreover, the utilization of localized plasmon enhancement facilitates the realization of efficient PTE conversion of graphene p-n junction devices under global illumination, which may offer an avenue for practical applications of graphene-based photodetectors and solar cells. 23928571 Coadministration of lapatinib increases exposure to docetaxel but not doxorubicin in the small intestine of mice. Combination therapy is increasingly being utilized for the treatment of metastatic breast cancer. However, coadministration of drugs, particularly agents that are substrates for or inhibitors of p-glycoprotein, can result in increased tissue toxicity. Unfortunately, determination of levels of chemotherapeutics in human tissues is challenging, and plasma drug concentrations are not always indicative of tissue toxicokinetics or toxicodynamics, especially when tissue penetration is altered. The aim of the present work was to determine whether concomitant administration of compounds currently being combined in clinical trials for metastatic breast cancer treatment alters plasma and tissue pharmacokinetics in mice if both agents are p-glycoprotein substrates and/or inhibitors. Accordingly, we investigated the pharmacokinetic interactions of the classic cytotoxics and p-glycoprotein substrates docetaxel and doxorubicin when administered concurrently with the targeted agent and p-glycoprotein inhibitor lapatinib. Our time-course plasma and tissue distribution studies showed that coadministration of lapatinib with doxorubicin did not appreciably alter the pharmacokinetics of this anthracycline in the plasma or six tissues evaluated in mice, presumably because, at doses relevant to human exposure, lapatinib inhibition of p-glycoprotein did not significantly alter doxorubicin transport out of these tissue compartments. However, combining lapatinib with docetaxel significantly increased intestinal exposure to this chemotherapeutic, which has clinical implications for enhancing gastrointestinal toxicity. The significant lapatinib-docetaxel interaction is likely CYP3A4-mediated, suggesting that caution should be exercised when this combination is administered, particularly to patients with compromised CYP3A activity, and recipients should be monitored closely for enhanced toxicity, particularly for adverse effects on the intestine. 23388031 Performance of infrared ear and forehead thermometers: a comparative study in 205 febrile and afebrile children. This study compared readings from two professional-grade, commercially available infrared (IR) thermometers, the ThermoScan(®) PRO 4000 prewarmed tip ear thermometer and the Temporal Scanner(™) TAT-5000 temporal artery thermometer. The repeatability and precision of readings from IR thermometers for professional use were questioned in the past, but in recent years, these types of thermometers have been technologically improved, so their ability to replicate standard temperature readings reliably should be re-examined. Febrile and afebrile children were recruited from the emergency department, overflow treatment areas and the paediatric intensive care unit of a large hospital in Argentina. Each child had a randomised sequence of seven temperature readings, including three from the ear, three from the forehead or behind the ear and one reference oral or rectal reading. Temperature readings were taken with the ThermoScan PRO 4000, the Temporal Scanner TAT-5000 and the monitor mode of SureTemp(®) Plus, a widely used professional-grade contact thermometer, for reference. Of 205 children, 46% were febrile, per reference thermometer readings. While mean ThermoScan PRO 4000 febrile measurements did not differ significantly from reference, mean Temporal Scanner TAT-5000 febrile measurements were significantly lower (by a mean of 0·42 °C) than the reference. Overall bias of the ThermoScan PRO 4000 was significantly lower than that of the Temporal Scanner TAT-5000; repeatability was 1·5 times higher, and overall false-negative rate was about a third that of Temporal Scanner TAT-5000, when compared to the reference. This study indicates that the ThermoScan PRO 4000 provides measurements closer to those of a professional-grade contact thermometer when compared to the Temporal Scanner TAT-5000. The odds of misclassifying a febrile child as non-febrile were about threefold higher with the Temporal Scanner TAT-5000 temporal artery thermometer than with the ThermoScan(®) PRO 4000 ear thermometer. 23804025 A cyclodextrin dimer as a supramolecular reaction platform for aqueous organometallic catalysis. A reaction platform based on a cyclodextrin dimer, which is able to simultaneously include a substrate in one cavity and an organometallic catalyst into the other, proved to be highly efficient for aqueous hydroformylation reaction of higher olefins. 23009567 Post-partum blues among Korean mothers: a structural equation modelling approach. The objective of this study was to propose the post-partum blues (PPB) model and to estimate the effects of self-esteem, social support, antenatal depression, and stressful events during pregnancy on PPB. Data were collected from 249 women post-partum during their stay in the maternity units of three hospitals in Korea using a self-administered questionnaire. A structural equation modelling approach using the Analysis of Moments Structure program was used to identify the direct and indirect effects of the variables on PPB. The full model had a good fit and accounted for 70.3% of the variance of PPB. Antenatal depression and stressful events during pregnancy had strong direct effects on PPB. Household income showed indirect effects on PPB via self-esteem and antenatal depression. Social support indirectly affected PPB via self-esteem, antenatal depression, and stressful events during pregnancy. 23122096 Quantitative determination of fatty acid chain composition in pork meat products by high resolution 1H NMR spectroscopy. High resolution (1)H NMR spectroscopy was proposed for the determination of the fatty acid chain profile of lipids in pork meat products during ripening. Two typical Mediterranean PDO salami produced in Calabria, a region in the Southern Italy, were chosen as a case of study. Quantitative NMR analysis provided the fatty acid chain profiles of total lipid extracts. The transesterification of total lipid extracts furnished FAME mixtures that enabled quantitation of fatty acid acyl chains in the acylglycerol and FFA portions. In all cases, oleyl chains were predominant, and high amounts of polyunsaturated fatty acid chains were observed. The proposed spectroscopic method allowed also the estimation of the most important nutritional parameters of dry fermented meat products. 23148227 Runt-related transcription factor 1 (RUNX1) stimulates tumor suppressor p53 protein in response to DNA damage through complex formation and acetylation. Representative tumor suppressor p53 plays a critical role in the regulation of proper DNA damage response. In this study, we have found for the first time that Runt-related transcription factor 1 (RUNX1) contributes to p53-dependent DNA damage response. Upon adriamycin (ADR) exposure, p53 as well as RUNX1 were strongly induced in p53-proficient HCT116 and U2OS cells, which were closely associated with significant transactivation of p53 target genes, such as p21(WAF)(1), BAX, NOXA, and PUMA. RUNX1 was exclusively expressed in the cell nucleus and formed a complex with p53 in response to ADR. Chromatin immunoprecipitation assay demonstrated that p53 together with RUNX1 are efficiently recruited onto p53 target gene promoters following ADR exposure, indicating that RUNX1 is involved in p53-mediated transcriptional regulation. Indeed, forced expression of RUNX1 stimulated the transcriptional activity of p53 in response to ADR. Consistent with these observations, knockdown of RUNX1 attenuated ADR-mediated induction of p53 target genes and suppressed ADR-dependent apoptosis. Furthermore, RUNX1 was associated with p300 histone acetyltransferase, and ADR-dependent acetylation of p53 at Lys-373/382 was markedly inhibited in RUNX1 knockdown cells. In addition, knockdown of RUNX1 resulted in a significant decrease in the amount of p53-p300 complex following ADR exposure. Taken together, our present results strongly suggest that RUNX1 is required for the stimulation of p53 in response to DNA damage and also provide novel insight into understanding the molecular mechanisms behind p53-dependent DNA damage response. 23908482 Pharmacokinetics of posaconazole within epithelial cells and fungi: Insights into potential mechanisms of action during treatment and prophylaxis. Background. The antifungal posaconazole concentrates within host cells and protects against Aspergillus fumigatus (AF) infection. The specific subcellular location of posaconazole, and mechanism by which cell-associated posaconazole inhibits fungal growth remains uncharacterized.Methods. Posaconazole was conjugated with the fluorophore BOPIDY (BDP-PCZ). A549 pulmonary epithelial cells and AF were exposed to BDP-PCZ individually and in co-culture. BDP-PCZ subcellular localization and trafficking were observed using confocal microscopy and flow cytometry.Results. BDP-PCZ concentrated within A549 cell membranes, and in particular within the endoplasmic reticulum (ER). Epithelial cell-associated BDP-PCZ rapidly transferred to, and concentrated within AF cell membranes upon contact. BDP-PCZ transfer to conidia did not require phagocytosis and was markedly enhanced by the conidial hydrophobin RodA. Within AF, BDP-PCZ also concentrated in membranes including the ER and co-localized with the azole target enzyme CYP51a. Concentration of BDP-PCZ within host and fungal cell membranes persisted for >48 hours and could be competitively inhibited by posaconazole but not voriconazole.Conclusions. Posaconazole concentrates within host cell membranes and rapidly transfers to AF where it accumulates to high concentrations and persists at the site of its target enzyme. These intracellular and intercellular pharmacokinetic properties likely contribute to the efficacy of PCZ. 23328951 Gender differences in Parkinson's disease: focus on plasma alpha-synuclein. Among promising biological markers proposed for Parkinson's disease (PD) and other disorders related to Lewy bodies, plasma alpha-synuclein assay has provided conflicting results mainly owing to the various laboratory assay techniques used and protein forms assayed. In this observational and exploratory cross-sectional study, using an immunoenzymatic technique, we assayed and compared total plasma alpha-synuclein concentrations in 69 patients with PD and 110 age-matched healthy control subjects. Two previously unreported findings concerned gender. First, plasma alpha-synuclein concentrations measured in the more advanced parkinsonian disease stages decreased in men, but not in women. Second, again only in men, plasma alpha-synuclein concentration was associated with cognitive impairments, hallucinations, and sleep disorders. These findings underline the gender-related differences in parkinsonian patients and indicate plasma alpha-synuclein expression as a potential biological marker for PD progression in men. 23922669 Cancer-associated fibroblasts promote proliferation of endometrial cancer cells. Endometrial cancer is the most commonly diagnosed gynecologic malignancy worldwide; yet the tumor microenvironment, especially the fibroblast cells surrounding the cancer cells, is poorly understood. We established four primary cultures of fibroblasts from human endometrial cancer tissues (cancer-associated fibroblasts, CAFs) using antibody-conjugated magnetic bead isolation. These relatively homogenous fibroblast cultures expressed fibroblast markers (CD90, vimentin and alpha-smooth muscle actin) and hormonal (estrogen and progesterone) receptors. Conditioned media collected from CAFs induced a dose-dependent proliferation of both primary cultures and cell lines of endometrial cancer in vitro (175%) when compared to non-treated cells, in contrast to those from normal endometrial fibroblast cell line (51%) (P<0.0001). These effects were not observed in fibroblast culture derived from benign endometrial hyperplasia tissues, indicating the specificity of CAFs in affecting endometrial cancer cell proliferation. To determine the mechanism underlying the differential fibroblast effects, we compared the activation of PI3K/Akt and MAPK/Erk pathways in endometrial cancer cells following treatment with normal fibroblasts- and CAFs-conditioned media. Western blot analysis showed that the expression of both phosphorylated forms of Akt and Erk were significantly down-regulated in normal fibroblasts-treated cells, but were up-regulated/maintained in CAFs-treated cells. Treatment with specific inhibitors LY294002 and U0126 reversed the CAFs-mediated cell proliferation (P<0.0001), suggesting for a role of these pathways in modulating endometrial cancer cell proliferation. Rapamycin, which targets a downstream molecule in PI3K pathway (mTOR), also suppressed CAFs-induced cell proliferation by inducing apoptosis. Cytokine profiling analysis revealed that CAFs secrete higher levels of macrophage chemoattractant protein (MCP)-1, interleukin (IL)-6, IL-8, RANTES and vascular endothelial growth factor (VEGF) than normal fibroblasts. Our data suggests that in contrast to normal fibroblasts, CAFs may exhibit a pro-tumorigenic effect in the progression of endometrial cancer, and PI3K/Akt and MAPK/Erk signaling may represent critical regulators in how endometrial cancer cells respond to their microenvironment. 23848409 Recurrent furunculosis: Efficacy of the CMC regimen - skin disinfection (chlorhexidine), local nasal antibiotic (mupirocin), and systemic antibiotic (clindamycin). Background: The treatment of recurrent furunculosis is poorly documented and represents a public health challenge. The medical care of this disease is often disappointing, especially as the disease evolution is uncertain and relapses occur. We report the efficacy and safety of our CMC regimen: skin disinfection (chlorhexidine), local nasal antibiotic (mupirocin), and systemic antibiotic (clindamycin). Methods: Patients attending our institution during the period 2006-2012 for recurrent furunculosis (≥ 4 episodes/y) were enrolled in the study. Clinical and bacteriological data were collected. Staphylococcus aureus colonization was also investigated in close contacts, and carriers were treated. Patients were treated with the CMC regimen: skin disinfection with chlorhexidine for 21 days, nasal mupirocin ointment for 5 days, and oral clindamycin 1800-2400 mg for 21 days. Results: Nineteen patients were included. Their mean age was 36 ± 14.5 y and the male to female sex ratio was 1.1. Screening swabs from all sites were S. aureus-positive in 63% (n = 12), including 4 methicillin-resistant S. aureus (MRSA). Before the CMC regimen, the median time to relapse was 31 days (mean 52 days). The mean number of recurrences was 5.5 ± 2.4/y. After the CMC regimen, among 16 patients who had a complete follow-up, 14 were healed beyond 9 months. Two recurrences occurred, 1 in an MRSA carrier and 1 in a patient with an insufficiently treated dermatosis. No serious side effect occurred that required the cessation of treatment. Conclusions: There are 2 major routes involved in recurrent furunculosis: risk factors and staphylococcal colonization of close contacts. Our procedure is safe and effective, with 87% remission beyond 9 months. It merits testing on larger numbers of participants. 23866682 Consumption of animal source foods and dietary diversity reduce stunting in children in Cambodia. Malnutrition in children is a major public health concern. This study aimed to determine the association between dietary diversity and stunting, underweight, wasting, and diarrhea and that between consumption of each specific food group and these nutritional and health outcomes among children. A nationally representative household survey of 6209 children aged 12 to 59 months was conducted in Cambodia. We examined the consumption of food in the 24 hours before the survey and stunting, underweight, wasting, and diarrhea that had occurred in the preceding 2 weeks. A food variety score (ranging from 0 to 9) was calculated to represent dietary diversity. Stunting was negatively associated with dietary diversity (adjusted odd ratios [ORadj] 0.95, 95% confident interval [CI] 0.91-0.99, P = 0.013) after adjusting for socioeconomic and geographical factors. Consumption of animal source foods was associated with reduced risk of stunting (ORadj 0.69, 95% CI 0.54-0.89, P = 0.004) and underweight (ORadj 0.74, 95% CI 0.57-0.96, P = 0.025). On the other hand, the higher risk of diarrhea was significantly associated with consumption of milk products (ORadj 1.46, 95% CI 1.10-1.92, P = 0.019) and it was significantly pronounced among children from the poorer households (ORadj 1.85, 95% CI 1.17-2.93, P < 0.01). Consumption of a diverse diet was associated with a reduction in stunting. In addition to dietary diversity, animal source food was a protective factor of stunting and underweight. Consumption of milk products was associated with an increase in the risk of diarrhea, particularly among the poorer households. Both dietary diversity and specific food types are important considerations of dietary recommendation. 23775316 Assessment of pesticide residues in karaboğaz lake from kızılırmak delta, Turkey. Monitoring of pesticide residues in water and sediments was conducted for the coastal shallow Karaboğaz Lake, northern Turkey. During a one-year study period, eight pesticides (malathion, etofenprox, molinate, oxamyl, propamocarb hydrochloride, tebufenozide, linuron, piperonyl butoxide) were detected in water and in sediments, all at μg/L and μg/kg concentrations, respectively. Temporal variation in pesticide concentrations was observed. Highest pesticide concentrations in water and sediment were from tebufenozide and etofenprox, respectively. Aquatic risk assessments revealed that out of eight pesticides detected, three showed unaccaptable risk: malathion, oxamyl and etofenprox. 23777780 Phosphinic acid-based inhibitors of tubulin polyglutamylases. Tubulin is subject to a reversible post-translational modification involving polyglutamylation and deglutamylation of glutamate residues in its C-terminal tail. This process plays key roles in regulating the function of microtubule associated proteins, neuronal development, and metastatic progression. This study describes the synthesis and testing of three phosphinic acid-based inhibitors that have been designed to inhibit both the glutamylating and deglutamylating enzymes. The compounds were tested against the polyglutamylase TTLL7 using tail peptides as substrates (100 μM) and the most potent inhibitor displayed an IC₅₀ value of 150 μM. The incorporation of these compounds into tubulin C-terminal tail peptides may lead to more potent TTLL inhibitors. 23397234 Is living in a border region a risk for a high prevalence of resistance? This study assessed the antimicrobial resistance and population structure of Staphylococcus aureus isolated from general practice (GP) patients and nursing home (NH) residents in the province of Limburg (near the border with Germany and Belgium) in comparison with those obtained in the remaining provinces of the Netherlands. A total of 617 and 418 S. aureus isolates were isolated from 2,691 to 1,351 nasal swabs from GP patients and NH residents, respectively. Quantitative antibiotic susceptibility testing was performed using a microbroth dilution method. Putative methicillin-resistant S. aureus (MRSA) isolates were tested for the presence of the mecA gene and spa typing was performed on all S. aureus isolates. No significant differences in the prevalence of resistance were found between the two groups of GP isolates, but the isolates from the NH residents showed a lower resistance for trimethoprim-sulfamethoxazole (p = 0.003) in Limburg province compared with the remaining provinces in the Netherlands. Among the isolates from NH residents in Limburg province, the prevalence of spa-CC 084 was higher (p = 0.003) and that of spa-CC 002 was lower (p = 0.01) compared with isolates from NHs in the remaining provinces of the Netherlands. We observed no differences in resistance and population structure between S. aureus isolates from GP patients in Limburg and the remaining provinces of the Netherlands, and only a few differences were observed between the NH populations. There was no higher prevalence of resistance among the GP and NH isolates from Limburg compared with the remaining provinces. 23836323 The trefoil factor 1 (TFF1) protein involved in doxorubicin‑induced apoptosis resistance is upregulated by estrogen in breast cancer cells. Trefoil factor 1 (TFF1) is a small secretory protein expressed in various types of carcinomas including breast cancer. The TFF1 gene contains an estrogen response element and its expression can be regulated by estrogen. Previous reports showed that TFF1 could protect cells from induced apoptosis in vitro. In the present study, the effect of estrogen on the promotion of doxorubicin-induced apoptosis resistance and the role of TFF1 in this process was demonstrated using the MCF-7 breast cancer cell model. Stable knockdown of the TFF1 gene in MCF-7 cells was generated and used to test the sensitivity to doxorubicin treatment compared to mock control cells in the presence or absence of 17β-estradiol. The apoptotic cells were measured by flow cytometry. The results showed that with the stimulation of apoptosis by doxorubicin, 17β-estradiol could suppress this process in mock cells but not in TFF1 knockdown cells. Moreover, using a viable cell counting method, it was shown that the anti-TFF1 antibody could reverse the anti-apoptotic effect of estrogen in mock cells and recombinant TFF1 could recover doxorubicin-induced cell death in TFF1 knockdown cells. This process, however, could not be inhibited by fulvestrant, an estrogen antagonist. An apoptosis protein array experiment reflected the role of the anti-oxidative enzyme catalase in estrogen and TFF1-modulated apoptosis and this was confirmed by enzymatic assay. These phenomena determine the role of TFF1 in estrogen-promoted resistance to apoptosis induced by doxorubicin in MCF-7 breast cancer cells. The TFF1 gene may be a target for enhancing the sensitivity to chemotherapy in breast cancer treatment. 23897479 Structural and mechanistic studies of the orf12 gene product from the clavulanic acid biosynthesis pathway. Structural and biochemical studies of the orf12 gene product (ORF12) from the clavulanic acid (CA) biosynthesis gene cluster are described. Sequence and crystallographic analyses reveal two domains: a C-terminal penicillin-binding protein (PBP)/β-lactamase-type fold with highest structural similarity to the class A β-lactamases fused to an N-terminal domain with a fold similar to steroid isomerases and polyketide cyclases. The C-terminal domain of ORF12 did not show β-lactamase or PBP activity for the substrates tested, but did show low-level esterase activity towards 3'-O-acetyl cephalosporins and a thioester substrate. Mutagenesis studies imply that Ser173, which is present in a conserved SXXK motif, acts as a nucleophile in catalysis, consistent with studies of related esterases, β-lactamases and D-Ala carboxypeptidases. Structures of wild-type ORF12 and of catalytic residue variants were obtained in complex with and in the absence of clavulanic acid. The role of ORF12 in clavulanic acid biosynthesis is unknown, but it may be involved in the epimerization of (3S,5S)-clavaminic acid to (3R,5R)-clavulanic acid. 23645194 Engineering the soil bacterium Pseudomonas putida for arsenic methylation. Accumulation of arsenic has potential health risks through consumption of food. Here, we inserted the arsenite [As(III)] S-adenosylmethionine methyltransferase (ArsM) gene into the chromosome of Pseudomonas putida KT2440. Recombinant bacteria methylate inorganic arsenic into less toxic organoarsenicals. This has the potential for bioremediation of environmental arsenic and reducing arsenic contamination in food. 23727611 COPI-mediated blood meal digestion in vector mosquitoes is independent of midgut ARF-GEF and ARF-GAP regulatory activities. We have previously shown that defects in COPI coatomer proteins cause 80% mortality in blood fed Aedes aegypti mosquitoes by 96 h post-feeding. In this study we show that similar deficiencies in COPII and clathrin mediated vesicle transport do not disrupt blood meal digestion and are not lethal, even though both COPII and clathrin functions are required for ovarian development. Since COPI vesicle transport is controlled in mammalian cells by upstream G proteins and associated regulatory factors, we investigated the function of the orthologous ADP-ribosylation factor 1 (ARF1) and ARF4 proteins in mosquito tissues. We found that both ARF1 and ARF4 function upstream of COPI vesicle transport in blood fed mosquitoes given that an ARF1/ARF4 double deficiency is required to phenocopy the feeding-induced mortality observed in COPI coatomer deficient mosquitoes. Small molecule inhibitors of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) are often transitory, and therefore, we investigated the role of five Ae. aegypti ARF-GEF and ARF-GAP proteins in blood meal digestion using RNA interference. Surprisingly, we found that ARF-GEF and ARF-GAP functions are not required for blood meal digestion, even though both vitellogenesis and ovarian development in Ae. aegypti are dependent on GBF1 (ARF-GEF) and GAP1/GAP2 (ARF-GAPs) proteins. Moreover, deficiencies in orthologous COPI regulating genes in Anopheles stephensi mosquitoes had similar phenotypes, indicating conserved functions in these two mosquito species. We propose that based on the need for rapid initiation of protein digestion and peritrophic membrane formation, COPI vesicle transport in midgut epithelial cells is not dependent on ARF-GEF and ARF-GAP regulatory proteins to mediate vesicle recycling within the first 48 h post-feeding. 23339447 MicroRNAs in mantle cell lymphoma. Abstract Mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin lymphoma. New treatment modalities, including intensive induction regimens with immunochemotherapy and autologous stem cell transplant, have improved survival. However, many patients still relapse, and there is a need for novel therapeutic strategies. Recent progress has been made in the understanding of the role of microRNAs (miRNAs) in MCL. Comparisons of tumor samples from patients with MCL with their normal counterparts (naive B-cells) have identified differentially expressed miRNAs with roles in cellular growth and survival pathways, as demonstrated in various biological model systems. In addition, MCL clinico-pathological and prognostic subtypes can be identified using individual miRNAs or miRNA classifiers. miRNA based therapies have now shown efficacy in animal models, and many efforts are currently being made to further develop these drugs for use in patients. Thus, there is hope that specific targeting of pathogenic miRNAs may be used in cases of MCL when conventional therapies fail. Here, we review the current knowledge about the role of miRNAs in MCL, and highlight the perspectives for clinical use. 23968855 Rapid tissue engineering of biomimetic human corneal limbal crypts with 3D niche architecture. Limbal epithelial stem cells are responsible for the maintenance of the human corneal epithelium and these cells reside in a specialised stem cell niche. They are located at the base of limbal crypts, in a physically protected microenvironment in close proximity to a variety of neighbouring niche cells. Design and recreation of elements of various stem cell niches have allowed researchers to simplify aspects of these complex microenvironments for further study in vitro. We have developed a method to rapidly and reproducibly create bioengineered limbal crypts (BLCs) in a collagen construct using a simple one-step method. Liquid is removed from collagen hydrogels using hydrophilic porous absorbers (HPAs) that have custom moulded micro-ridges on the base. The resulting topography on the surface of the thin collagen constructs resembles the dimensions of the stromal crypts of the human limbus. Human limbal epithelial cells seeded onto the surface of the constructs populate these BLCs and form numerous layers with a high proportion of the cells lining the crypts expressing putative stem cell marker, p63α. The HPAs are produced using a moulding process that is flexible and can be adapted depending on the requirements of the end user. Creation of defined topographical features using this process could be applicable to numerous tissue-engineering applications where varied 3-dimensional niche architectures are required. 23193186 Hyperglycemia slows embryonic growth and suppresses cell cycle via cyclin D1 and p21. In pregnant women, the diabetic condition results in a three- to fivefold increased risk for fetal cardiac malformations as a result of elevated glucose concentrations and the resultant osmotic stress in the developing embryo and fetus. Heart development before septation in the chick embryo was studied under two hyperglycemic conditions. Pulsed hyperglycemia induced by daily administration of glucose during 3 days of development caused daily spikes in plasma glucose concentration. In a second model, sustained hyperglycemia was induced with a single injection of glucose into the yolk on day 0. The sustained model raised the average plasma glucose concentration from 70 mg/dL to 180 mg/dL and led to decreased gene expression of glucose transporter GLUT1. Both models of hyperglycemia reduced embryo size, increased mortality, and delayed development. Within the heart outflow tract, reduced proliferation of myocardial and endocardial cells resulted from the sustained hyperglycemia and hyperosmolarity. The cell cycle inhibitor p21 was significantly increased, whereas cyclin D1, a cell cycle promoter, decreased in sustained hyperglycemia compared with controls. The evidence suggests that hyperglycemia-induced developmental delays are associated with slowed cell cycle progression, leading to reduced cellular proliferation. The suppression of critical developmental steps may underlie the cardiac defects observed during late gestation under hyperglycemic conditions. 23837894 Biofilm formation with mixed cultures of Pseudomonas aeruginosa/Escherichia coli on silicone using artificial urine to mimic urinary catheters. In this study, single and dual species biofilms of Pseudomonas aeruginosa and Escherichia coli, two common bacteria associated with urinary tract infections, were formed in silicon coupons immersed in artificial urine medium. In single species experiments, E. coli appeared to form biofilms more easily than P. aeruginosa. In mixed biofilms, both species apparently benefited from the presence of the other, as the average Log total cells cm(-2) of mixed biofilms (7.29 cells cm(-2)) was higher than obtained for single cultures (6.99 cells cm(-2)). However, the use of selective media seemed to indicate that P. aeruginosa was the only microorganism to benefit in mixed biofilms (Log 7 CFU of P. aeruginosa cm(-2), compared to Log 6 CFU cm(-2) obtained in pure cultures). Peptide nucleic acid-fluorescence in situ hybridization combined with confocal laser scanning microscopy confirmed that E. coli was indeed being outnumbered by P. aeruginosa at 48 h. Whereas E. coli is the main causative agent of catheter-associated urinary tract infections, the results from this study indicate that the reason for the higher prevalence of this microorganism is not related to an enhanced ability to form biofilm and outcompete other species that may also be present, but rather to a better ability to form single-species biofilms possibly due to a more frequent access to the catheter surface. 23631402 (De)Lithiation Mechanism of Li/SeSx (x = 0-7) Batteries Determined by In-situ Synchrotron X-ray Diffraction and X-ray Absorption Spectroscopy. Electrical energy storage for transportation has going beyond the limit of converntional lithium-ion batteries currently. New material or new battery system development is an alternative approach to achieve the goal of new high energy storage system with energy densities five times or more greater. A series of SeSx-carbon ( x = 0-7) composite materials has been prepared and evaluated as the positive electrodes in secondary lithium cells with ether-based electrolyte. In-situ synchrotron high energy X-ray diffraction was utilized to investigate the crystalline phase transition during cell cycling. Complementary, in-situ Se K-edge X-ray absorption near edge structure analysis was used to track the evolution of the Se valence state for both crystalline and non-crystalline phases, including amorphous and electrolyte-dissolved phases in the (de)lithiation process. On the basis of these reuslts, a mechanism for the (de)lithiation process is proposed, where Se is reduced to the polyselenides, Li2Sen (n≥4), Li2Se2, and Li2Se sequentially during the lithiation, and Li2Se is oxidized to Se through Li2Sen (n≥4) during the delithiation. In addition, X-ray photoelectron spectroscopy and electrochemical impedance spectroscopy demonstrated the reversibility of the Li/Se system in ether-based electrolyte and the presence of side products in the carbonate-based electrolytes. For Li/SeS2 and Li/SeS7 cells, Li2Se and Li2S are the discharged products with the presence of Se only as the crystalline phase in the end of charge. 23770162 Impact of low flow on the outcome of high-risk patients undergoing transcatheter aortic valve replacement. This study sought to assess the impact of baseline left ventricular (LV) outflow, LV ejection fraction (LVEF), and transvalvular gradient on outcomes following transcatheter aortic valve replacement (TAVR) in patients with severe aortic stenosis (AS). Low flow (i.e., reduced stroke volume index [SVi]) can occur with both reduced and preserved LVEF. Low flow is often associated with low gradient despite severe stenosis and with worse outcomes following surgical aortic valve replacement. However, there are few data about the impact of low flow on outcomes following TAVR. We retrospectively analyzed the clinical, Doppler-echocardiographic, and outcome data prospectively collected in 639 patients who underwent TAVR for symptomatic severe AS in 2 Canadian centers. In this cohort, 334 (52.3%) patients had a low flow (SVi <35 ml/m(2)) and these patients had increased 30-day mortality (11.4 vs. 5.9%, p = 0.01), 2-year all-cause mortality (35.3 vs. 30.9%, p = 0.005), and 2-year cardiovascular mortality (25.7 vs. 16.8%, p = 0.01) compared with patients with normal flow. Reduced flow was an independent predictor of 30-day mortality (odds ratio: 1.94, p = 0.026), cumulative all-cause mortality (hazard ratio: 1.27 per 10 ml/m² SVi decrease, p = 0.016), and cumulative cardiovascular mortality (hazard ratio: 1.29 per 10 ml/m² decrease, p = 0.04). Despite significant association in univariable analyses, low LVEF and low mean gradient were not found to be independent predictors of outcomes in multivariable analyses. Low flow but not low LVEF or low gradient is an independent predictor of early and late mortality following TAVR in high-risk patients with severe AS. SVi should be integrated in the risk stratification process of these patients. 23890675 Virulence, genomic features, and plasticity of Aeromonas salmonicida subsp. salmonicida, the causative agent of fish furunculosis. The bacterium Aeromonas salmonicida subsp. salmonicida is the causative agent of furunculosis, a systemic disease of fish in the salmonid family. Furunculosis is a ubiquitous disease that affects aquaculture operations worldwide and is characterized by high mortality and morbidity. A better understanding of the bacterium is required to find a cure. Thereby, this review centers on A. salmonicida subsp. salmonicida, its major virulence factors, and its genome. The classification and characteristics of A. salmonicida subsp. salmonicida, the virulence factors, such as the A-layer, extracellular molecules, and type three secretion system as well as the characteristics and plasticity of its genome are described. 23955080 A peptide that inhibits function of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) reduces lung cancer metastasis. Myristoylated Alanine-Rich C Kinase Substrate (MARCKS), a substrate of protein kinase C, is a key regulatory molecule controlling mucus granule secretion by airway epithelial cells as well as directed migration of leukocytes, stem cells and fibroblasts. Phosphorylation of MARKCS may be involved in these responses. However, the functionality of MARCKS and its related phosphorylation in lung cancer malignancy have not been characterized. This study demonstrated elevated levels of MARCKS and phospho-MARCKS in highly invasive lung cancer cell lines and lung cancer specimens from non-small-cell lung cancer patients. siRNA knockdown of MARCKS expression in these highly invasive lung cancer cell lines reduced cell migration and suppressed PI3K (phosphatidylinositol 3'-kinase)/Akt phosphorylation and Slug level. Interestingly, treatment with a peptide identical to the MARCKS N-terminus sequence (the MANS peptide) impaired cell migration in vitro and also the metastatic potential of invasive lung cancer cells in vivo. Mechanistically, MANS peptide treatment resulted in a coordination of increase of E-cadherin expression, suppression of MARCKS phosphorylation and AKT/Slug signalling pathway but not the expression of total MARCKS. These results indicate a crucial role for MARCKS, specifically its phosphorylated form, in potentiating lung cancer cell migration/metastasis and suggest a potential use of MARCKS-related peptides in the treatment of lung cancer metastasis.Oncogene advance online publication, 19 August 2013; doi:10.1038/onc.2013.336. 23454149 Inhibition of angiogenesis and invasion by DMBT is mediated by downregulation of VEGF and MMP-9 through Akt pathway in MDA-MB-231 breast cancer cells. Invasion, either directly or via metastasis formation, is the main cause of death in cancer patients, development of efficient anti-invasive agents is an important research challenge. In order to obtain more potent inhibitors, a series of brartemicin analogs were synthesized and evaluated for their inhibitory activity against invasion. Among the synthetic analogs tested, DMBT, 6,6'-bis (2,3-dimethoxybenzoyl)-a,a-d-trehalose, was found to be the most potent anti-invasive agent. But the effects of DMBT on breast cancer cells were not known. In this study, the effects of DMBT on invasion and metastasis in MDA-MB-231 cells were investigated. MTT assay showed that no obvious inhibitory or cytotoxic effect of DMBT was found. DMBT could inhibit invasion, migration and tube formation of HUVECs. Gelatin zymography showed that DMBT inhibited secretion and activity of MMP-9. Western blotting demonstrated that DMBT effectively suppressed the expression of VEGF, p-VEGFR-2, p-EGFR, and p-Akt. These results suggested that DMBT could inhibit invasion and angiogenesis by downregulation of VEGFand MMP-9, resulting from the inhibition of Akt pathway. DMBT might be a promising lead molecule for the anti-metastasis and serve as a therapeutic agent to inhibit breast cancer cell invasion and metastasis. 23679043 Laryngeal spasm after general anaesthesia due to Ascaris lumbricoides. Postoperative upper airway obstruction during recovery from general anaesthesia may have several causes. This is a report of a young girl who developed laryngeal spasm as a result of an ectopic roundworm Ascaris lumbricoides. 23706975 Analysis of bronchoalveolar lavage fluid in a mouse model of bronchial asthma and H1N1 2009 infection. Bronchial asthma is known as a risk factor of admission to the intensive care unit. However, the mechanism by which pandemic 2009 H1N1 (A(H1N1)pdm09) infection increases the severity of symptoms in patients with bronchial asthma is unknown; therefore, we aimed at determining this mechanism. Inflammatory cell levels in the bronchoalveolar lavage (BAL) fluid from the non-asthma/mock, non-asthma/A(H1N1)pdm09, asthma/mock, and asthma/A(H1N1)pdm09 groups were determined using BALB/c mice. Cell infiltration levels, cytokine levels, and viral titers were compared among the groups. Neutrophil, monocyte, interleukin (IL)-5, IL-6, IL-10, IL-13, and tumor necrosis factor (TNF)-α levels were significantly higher in the BAL fluid from the non-asthma/A(H1N1)pdm09 and asthma/A(H1N1)pdm09 groups than in the mock groups (p<0.05 for neutrophils and monocytes; p<0.01 for the rest). The number of eosinophils and CD8(+) lymphocytes and the level of transforming growth factor beta 1 (TGF-β1) in BAL fluid in the asthma/A(H1N1)pdm09 group were significantly higher among all groups (p<0.05 for eosinophils and CD8(+) lymphocytes; p<0.01 for TGF-β1). The levels of IL-6, IL-10, IL-13, and TNF-α were significantly higher in the asthma/A(H1N1)pdm09 group than in the non-asthma/A(H1N1)pdm09 group (p<0.05 for IL-6 and IL-10; p<0.01 for IL-13 and TNF-α). The level of IFN-γ in the asthma/A(H1N1)pdm09 group was significantly lower than that in the non-asthma/A(H1N1)pdm09 group (p<0.05). The viral titers in the BAL fluids were higher in the asthma/A(H1N1)pdm09 group than in the non-asthma/A(H1N1)pdm09 group (p<0.05). Histopathological examination showed more severe infiltration of inflammatory cells and destruction of lung tissue in the asthma/A(H1N1)pdm09 group than in the non-asthma/A(H1N1)pdm09 group. Severe pulmonary inflammation induced by elevated levels of cytokines, combined with increased viral replication due to decreased IFN-γ levels, may contribute to worsening respiratory symptoms in patients with bronchial asthma and A(H1N1)pdm09 infection. 23588255 No inflammatory gene-expression response to acute exercise in human Achilles tendinopathy. Although histology data favour the view of a degenerative nature of tendinopathy, indirect support for inflammatory reactions to loading in affected tendons exists. The purpose of the present study was to elucidate whether inflammatory signalling responses after acute mechanical loading were more pronounced in tendinopathic versus healthy regions of human tendon and if treatment with non-steroidal anti-inflammatory medications (NSAID's) reduces this response. Twenty-seven tendinopathy patients (>6 months) were randomly assigned to a placebo (n = 14) or NSAID (Ibumetin NYCOMED GmbH Plant Oranienburg Germany (600 mg) Ã— 3/day/1 week) group (n = 13) in a double-blinded-fashion. Tendon biopsies were taken from the painful and a healthy region of the same tendon 2 h after 1 h running. Gene-expression of several targets was analysed in the sampled Achilles tendon biopsies. The mRNA for TGF-β, collagen-I and collagen-III were significantly higher expressed, and decorin, CTGF, IL-6 and IL-10 were significantly lower expressed in the tendinopathic versus healthy tendon area. Only IL-10 was lower in expression in experiments with NSAID administration, while all other determined parameters were unaffected by NSAID. All ultrasonographic outcomes were unchanged in response to acute exercise and not influenced by NSAID. The signalling for collagen and TGF-beta was upregulated after acute loading in tendinopathic tendon. In contrast to the hypothesis, inflammatory signalling was not exaggerated in tendinopathic tendon 2 h after acute mechanical loading. 23420300 Peritoneal manifestations of fascioliasis on CT images: a new observation. To describe peritoneal manifestations of fascioliasis on CT. We reviewed CT images in 31 patients with fascioliasis confirmed by enzyme-linked immunosorbent assay (ELISA) (n = 24) or surgery (n = 7). Image analyses were performed to identify hepatic, biliary, and peritoneal abnormalities. Hepatic abnormalities were seen in 28 (90.3 %) of the 31 patients. The most common finding was caves sign, which was present in 25 (80.1 %) patients. Three patients (9.7 %) presented with biliary abnormalities exhibiting dilatation and enhancing wall thickening of the bile duct, wall thickening of the gallbladder, and elongated structures in the bile duct or gallbladder. Peritoneal abnormalities were seen in 14 (45.2 %) of the 31 patients. The most common peritoneal abnormality was mesenteric or omental infiltration, which was seen in 9 (29.0 %) patients. Other peritoneal findings included lymph node enlargement (n = 7), ascites (n = 7), thickening of ligamentum teres (n = 2), and peritoneal mass (n = 2). Peritoneal manifestations of fascioliasis are relatively common, and CT findings include mesenteric or omental infiltration, lymph node enlargement, ascites, thickening of the ligamentum teres, and peritoneal masses. 23458173 Efficacy and safety of leflunomide in treatment of steroid-dependent and steroid-resistant adult onset minimal change disease. To observe the efficacy and safety of leflunomide combined with prednisone therapy (LEF therapy) in the treatment of patients with adult onset steroid-dependent and steroid-resistant minimal change disease (MCD). 16 MCD patients who had been treated with LEF therapy were retrospectively analyzed. 87.5% (14/16) of the patients were steroid-dependent and 12.5% (2/16) of the patients were steroid-resistant. The initial dose of LEF was 10 - 20 mg/day combined with prednisone 0.25 - 1.0 mg/kg/day, gradually tapering after 8 weeks. Clinical and laboratory data at baseline, 2nd, 4th, 8th, 12th, 24th, and 48th week were analyzed compared with initial course of prednisone monotherapy (PRED monotherapy) and cyclophosphamide combined with prednisone therapy (CTX therapy). All the 16 patients achieved different levels of remission in LEF therapy. 93.8% (15/16) of the patients, including the two steroid-resistant patients, achieved complete remission. During the treatment, 8 patients had adverse effects which could be well tolerated. Compared LEF therapy with PRED monotherapy (n = 16), the dose of prednisone to maintain remission was reduced (from median 22.5 mg/day to median 7.5 mg/day, p = 0.041); relapse rate during the follow-up decreased from 100% to 31.3% (p = 0.002); the median time before relapse increased from 20.3 weeks to 32.5 weeks. Compared LEF therapy with CTX therapy (n = 12), the dose of prednisone to maintain remission was reduced significantly (from median 22.5 mg/day to median 5.0 mg/day, p = 0.003); relapse rate during the follow-up decreased from 100% to 31.3% (p = 0.001); the median time before relapse increased from 11.7 weeks to 32.5 weeks. LEF therapy seems to be effective in steroid-resistant and steroiddependent MCD. This therapy may reduce the amount of prednisone to maintain remission and reduce the relapse rate compared with PRED monothrerapy and CTX therapy. LEF therapy was usually well tolerated. 23884241 Amphiphiles in aqueous solution: well beyond a soap bubble. Owing to their "dual" affinity, amphiphiles self-assemble in water to form different kinds of nanoscale multimolecular assemblies ranging from simple micelles and vesicles to highly organized fibers, helices and tubes. In this tutorial review the aggregates formed in water by head/tail amphiphiles are revisited and discussed from the point of view of supramolecular chemistry with a focus on their structure and recognition abilities. Their applications in materials chemistry, as soft templates for inorganic nanostructures, as well as in biological and medicinal chemistry are also illustrated. Special attention is paid to highlight intriguing aspects, for example the control of morphology and chirality, their modulation by experimental parameters and chiral symmetry breaking. 23860860 Design of short membrane selective antimicrobial peptides containing tryptophan and arginine residues for improved activity, salt-resistance, and biocompatibility. Antimicrobial peptides (AMPs) kill microbes by non-specific membrane permeabilization, making them ideal templates for designing novel peptide-based antibiotics that can combat multi-drug resistant pathogens. For maximum efficacy in vivo and in vitro, AMPs must be biocompatible, salt-tolerant and possess broad-spectrum antimicrobial activity. These attributes can be obtained by rational design of peptides guided by good understanding of peptide structure-function. Toward this end, this study investigates the influence of charge and hydrophobicity on the activity of tryptophan and arginine rich decamer peptides engineered from a salt resistant human β-defensin-28 variant. Mechanistic investigations of the decamers with detergents mimicking the composition of bacterial and mammalian membrane, reveal a correlation between improved antibacterial activity and the increase in tryptophan and positive residue content, while keeping hemolysis low. The potent antimicrobial activity and high cell membrane selective behavior of the two most active decamers, D5 and D6, are attributed to an optimum peptide charge to hydrophobic ratio bestowed by systematic arginine and tryptophan substitution. D5 and D6 show surface localization behavior with binding constants of 1.86 × 10(8) and 2.6 × 10(8)  M(-1) , respectively, as determined by isothermal calorimetry measurements. NMR derived structures of D5 and D6 in SDS detergent micelles revealed proximity of Trp and Arg residues in an extended structural scaffold. Such potential cation-π interactions may be critical in cell permeabilization of the AMPs. The fundamental characterization of the engineered decamers provided in this study improves the understanding of structure-activity relationship of short arginine tryptophan rich AMPs, which will pave the way for future de novo design of potent AMPs for therapeutic and biomedical applications. Biotechnol. Bioeng. 2013;9999: 1-13. © 2013 Wiley Periodicals, Inc. 23640662 Electrically driven ultraviolet random lasing from an n-MgZnO/i-ZnO/SiO2/p-Si asymmetric double heterojunction. Electrically pumped lasing action has been realized in ZnO from an n-MgZnO/i-ZnO/SiO2/p-Si asymmetric double heterostructure, an ultralow threshold of 3.9 mA was obtained. The mechanism of the laser is associated with the in-plane random resonator cavities formed in the ZnO films and the elaborate hollow-shaped SiO2 cladding pattern, which prevent the lateral diffusion of injection current and ultimately lower the threshold current of the laser diode. In addition, a waveguide mechanism due to different refractive indices of three epilayers enhances the guided optical field on the ZnO side, resulting in an improved light extraction efficiency. 23871087 In vivo digestion of bovine milk fat globules: Effect of processing and interfacial structural changes. I. Gastric digestion. The aim was to study the in vivo gastric digestion of fat globules in bovine cream from raw, pasteurised or pasteurised and homogenised milk. Fasted rats were gavaged once and chyme samples were collected after 30, 120 and 180min post-gavage. Proteins from raw (RC) and pasteurised (PC) creams appeared to be digested faster and to a greater extent. Free fatty acids (FAs) increased throughout the 3h postprandial period. Short and medium chain FAs were released more rapidly than long chain FAs which were hydrolysed to a greater degree from PC. The size of the fat globules of all creams increased in the stomach. Protein aggregates were observed in pasteurised and homogenised cream chyme. Protrusions, probably caused by the accumulation of insoluble lipolytic products, appeared at the surface of the globules in RC and PC chyme. Overall, PC proteins and lipids appeared to be digested to a greater extent. 23836155 Maqasid al-Shariah as a Complementary Framework to Conventional Bioethics. With the rapid advancements made in biotechnology, bioethical discourse has become increasingly important. Bioethics is a multidisciplinary and interdisciplinary field that goes beyond the realm of natural sciences, and has involved fields in the domain of the social sciences. One of the important areas in bioethical discourse is religion. In a country like Malaysia, where Muslims make up the majority of the population, Islam plays a crucial role in providing the essential guidelines on the permissibility and acceptability of biotechnological applications in various fields such as medicine, agriculture, and food processing. This article looks at the framework of a complementary model of bioethics derived from the perspective of Islam. The framework is based on 'maqasid al-shariah' (purposes or objectives of Islamic law) which aims to protect and preserve mankind's faith, life, intellect, progeny, and property. It is proposed that 'maqasid al-shariah' be used as a pragmatic checklist that can be utilized in tackling bioethical issues and dilemmas. 23479677 Systemic vascular resistance has an impact on the reliability of the Vigileo-FloTrac system in measuring cardiac output and tracking cardiac output changes. /st> The aim of this study was to examine the ability of the Vigileo-FloTrac system to measure cardiac output (CO) and track changes in CO induced by increased vasomotor tone, under different states of systemic vascular resistance (SVR). /st> Forty patients undergoing cardiac surgery were enrolled. Haemodynamic variables including CO measured by the Vigileo-FloTrac system (version 3.02) (APCO), CO measured by a pulmonary artery catheter (ICO), and SVR index (SVRI) were recorded before (T1) and 2 min after (T2) phenylephrine administration (100 μg). Bland and Altman analysis was used to compare ICO and APCO at T1. We used four-quadrant plots and polar plots to compare the trending abilities between ICO and APCO. Patients were divided into three groups according to the SVRI value at T1, with low (<1200 dyn cm(-5) m(2)), normal (1200-2500 dyn cm(-5) m(2)), and high (>2500 dyn cm(-5) m(2)) SVRI states. /st> A total of 155 paired data were collected. The adjusted percentage error was 46.3%, 26.4%, and 61.4%, and the concordance rate between ΔICO and ΔAPCO was 67.5%, 28.8%, and 7.7% in the low, normal, and high SVRI state, respectively. The polar plot analysis showed that the mean angular bias was -22.3°, -46.0°, and -3.51°, and the radial limits of agreement were 70°, 85°, and 87°, in the low, normal, and high SVRI state, respectively. /st> These results indicate that the reliability of the Vigileo-FloTrac system to measure CO and track changes in CO induced by phenylephrine administration was not clinically acceptable. 23864703 Association of Circulating Sclerostin with Bone Mineral Mass, Microstructure, and Turnover Biochemical Markers in Healthy Elderly Men and Women. Context:Sclerostin inhibits bone formation and is involved in the bone response to mechanical loading, but the role and significance of circulating sclerostin is poorly understood.Objective:We assessed the association between serum sclerostin and calcitropic hormones, bone turnover marker levels, bone mineral content/density (BMC/BMD), and microstructure using three different immunoassays.Design, Setting, and Participants:In a cross-sectional study, serum sclerostin was measured in a cohort of 187 healthy subjects (98 women; 89 men) aged 65±1 (x±SD) years.Results:Overall, mean sclerostin (95% CI) was 37.3 (18.0-69.2) ng/l, 1165.8 (464.0-2296.4) ng/l, and 513.5 (250.7-950.9) ng/l with assays I, II and III, respectively. Serum sclerostin was higher in men with assays II and III. In all three assays, sclerostin and PTH were inversely correlated, only after adjustment for whole-body BMC (WB-BMC). After adjustment for sex and WB-BMC, the bone turnover markers P1NP and CTX negatively correlated, only with assay II. In all three assays, sclerostin positively correlated to WB-BMC, distal radius and distal tibia cortical area, cancellous bone volume (BV/TV) and trabecular number, and lumbar spine and proximal femur areal BMD following adjustment for sex.Conclusion:Sclerostin levels are markedly different according to the immunoassay used. Detection of an association with calcitropic hormones or turnover markers relies on the epitope recognized by the immunoassay and adjustment for bone mass. 23850883 Sustained health-economic effects after reorganisation of a Swiss hospital emergency centre: a cost comparison study. Emergency departments (EDs) are increasingly overcrowded by walk-in patients. However, little is known about health-economic consequences resulting from long waiting times and inefficient use of specialised resources. We have evaluated a quality improvement project of a Swiss urban hospital: In 2009, a triage system and a hospital-associated primary care unit with General Practitioners (H-GP-unit) were implemented beside the conventional hospital ED. This resulted in improved medical service provision with reduced process times and more efficient diagnostic testing. We now report on health-economic effects. From the hospital perspective, we performed a cost comparison study analysing treatment costs in the old emergency model (ED, only) versus treatment costs in the new emergency model (triage plus ED plus H-GP-unit) from 2007 to 2011. Hospital cost accounting data were applied. All consecutive outpatient emergency contacts were included for 1 month in each follow-up year. The annual number of outpatient emergency contacts increased from n=10 440 (2007; baseline) to n=16 326 (2011; after intervention), reflecting a general trend. In 2007, mean treatment costs per outpatient were €358 (95% CI 342 to 375). Until 2011, costs increased in the ED (€423 (396 to 454)), but considerably decreased in the H-GP-unit (€235 (221 to 250)). Compared with 2007, the annual local budget spent for treatment of 16 326 patients in 2011 showed cost reductions of €417 600 (27 200 to 493 600) after adjustment for increasing patient numbers. From the health-economic point of view, our new service model shows 'dominance' over the old model: While quality of service provision improved (reduced waiting times; more efficient resource use in the H-GP-unit), treatment costs sustainably decreased against the secular trend of increase. 23605806 Mathematical model approach to describe tumour response in mice after vaccine administration and its applicability to immune-stimulatory cytokine-based strategies. Immunotherapy is a growing therapeutic strategy in oncology based on the stimulation of innate and adaptive immune systems to induce the death of tumour cells. In this paper, we have developed a population semi-mechanistic model able to characterize the mechanisms implied in tumour growth dynamic after the administration of CyaA-E7, a vaccine able to target antigen to dendritic cells, thus triggering a potent immune response. The mathematical model developed presented the following main components: (1) tumour progression in the animals without treatment was described with a linear model, (2) vaccine effects were modelled assuming that vaccine triggers a non-instantaneous immune response inducing cell death. Delayed response was described with a series of two transit compartments, (3) a resistance effect decreasing vaccine efficiency was also incorporated through a regulator compartment dependent upon tumour size, and (4) a mixture model at the level of the elimination of the induced signal vaccine (k 2) to model tumour relapse after treatment, observed in a small percentage of animals (15.6%). The proposed model structure was successfully applied to describe antitumor effect of IL-12, suggesting its applicability to different immune-stimulatory therapies. In addition, a simulation exercise to evaluate in silico the impact on tumour size of possible combination therapies has been shown. This type of mathematical approaches may be helpful to maximize the information obtained from experiments in mice, reducing the number of animals and the cost of developing new antitumor immunotherapies. 23845486 A fragmentation-based method for the differentiation of glutathione conjugates by high-resolution mass spectrometry with electrospray ionization. Idiosyncratic reactions are one of the major causes of drug treatment limitations or market withdrawals, and likely involve the formation of reactive metabolites. Because of their unstable nature, reactive species are usually discovered as stable conjugates by glutathione (GSH) trapping rather than by direct detection. The GSH conjugates are then detected by neutral loss scanning of 129Da or precursor ion scanning at m/z 272, but the conjugation sites can only be identified by comparison with reference standards. In the present study, the fragmentation behaviors of 52 GSH conjugates belonging to five structural classes (aliphatic, aromatic, benzylic, disulfide, and thioester) were investigated in both positive and negative electrospray ionization modes by high-resolution mass spectrometry with suitable collision energies such that the relative abundance of the parent ion was approximately 50% of the most abundant product ion. Several structural-diagnostic fragmentations were identified: aliphatic conjugates gave i/j-type ions upon cleavage of the CS bond between the drug and GSH, and d/k-type ions formed by the cleavage of the cysteinyl CS bond, with approximately equal intensity, in both positive and negative modes, whereas aromatic conjugates only possessed d/k-type ions, and benzylic conjugates primarily yielded i/j-type ions. Disulfide conjugates typically produced dehydrogenated GS(-) fragment ions ([i-2H]-type) in negative mode, and thioester conjugates displayed sequential losses of pyroglutamic acid and water ([e-H2O]-type) in positive mode. A fragmentation-based method was thus established to facilitate the discrimination of these five classes of GSH conjugates, thereby providing insight into the bioactivation mechanisms and supporting lead optimization. 23809449 Rotator cuff tendon repair morphology comparing 2 single-anchor repair techniques. To compare the effect of 2 common rotator cuff repair techniques, for smaller tears limited to the use of a single anchor, on tendon morphology in relation to the footprint. Six matched pairs of human shoulders were dissected, and a standardized 10-mm supraspinatus tendon tear was created. Two single-anchor repairs were performed: simple repair with the anchor on the footprint or inverted-mattress repair with the anchor 1 cm distal-lateral to the footprint. The repaired specimens were frozen in situ with liquid nitrogen. Coronal cross sections through the intact and repaired tendon were made. A digitizer was used to measure variables including tendon area and radius of tendon curvature. Comparing between repairs, we found significantly more gap formation for the simple repair at the repair cross section (3.67 ± 0.32 mm v 0.68 ± 0.10 mm, P = .00050). The simple repair had less tendon area (38.28 ± 2.50 mm(2)v 58.65 ± 4.06 mm(2), P = .0036) and a smaller radius of curvature (8.47 ± 1.39 mm v 32.51 ± 3.94 mm, P = .0046). For the simple repair, there was significantly more gap formation, less tendon area, and a smaller radius of tendon curvature for all repair cross sections compared with the intact cross sections (P < .05). For the inverted-mattress repair, there was more gap formation compared with the intact condition (P < .05), although it was less than 1 mm on average; for tendon area, radius of curvature, and tendon height, the cross section centered on the repair showed no differences compared with the intact control. For rotator cuff tears that are 10 mm or smaller and limited to the use of a single anchor, using a distal-lateral anchor position with tape-type suture can provide better maintenance of native tendon morphology and footprint dimensions when compared with repair that uses standard sutures and places the anchor on the footprint. For smaller tears, the inverted-mattress repair described in this article may provide a relatively improved healing environment compared with a simple repair on the footprint, potentially optimizing the prevention of early tear progression. 23299544 Long-range corrected functionals satisfy Koopmans' theorem: calculation of correlation and relaxation energies. In this article, we show that the long-range-corrected (LC) density functionals LC-BOP and LCgau-BOP reproduce frontier orbital energies and highest-occupied molecular orbital (HOMO)-lowest-unoccupied molecular orbital (LUMO) gaps better than other density functionals. The negative of HOMO and LUMO energies are compared with the vertical ionization potentials (IPs) and electron affinities, respectively, using CCSD(T)/6-311++G(3df,3pd) for 113 molecules, and we found LC functionals to satisfy Koopmans' theorem. We also report that the frontier orbital energies and the HOMO-LUMO gaps of LC-BOP and LCgau-BOP are better than those of recently proposed ωM05-D (Lin et al., J. Chem. Phys. 2012, 136, 154109). We express the exact IP in terms of orbital relaxation, and correlation energies and hence calculate the relaxation and correlation energies for the same set of molecules. It is found that the LC functionals, in general, includes more relaxation effect than Hartree-Fock and more correlation effect than the other density functionals without LC scheme. Finally, we scan μ parameter in LC scheme from 0.1 to 0.6 bohr(-1) for the above test set molecules with LC-BOP functional and found our parameter value, 0.47 bohr(-1), is usefully applicable to our tested systems. 23417348 Age-of-onset of menopause is associated with enhanced painful and non-painful sensitivity in fibromyalgia. Fibromyalgia (FM) is a chronic pain condition characterized by high prevalence in women. In particular, estrogen deficit has been considered as a potentially promoting factor of FM symptoms. This study was aimed to examine the relationship between age-of-onset of menopause and pain sensitivity in FM. For this purpose, pain sensitivity was assessed in 74 FM and 32 pain-free control women. All participants were postmenopausal and underwent a detailed semi-structured clinical interview, including data about menopause transition, previous history of hysterectomy or ovariectomy, and menses time. Participants were divided into two groups depending on age-of-onset of menopause: early menopause [≤49 years] vs. late menopause [>49 years]. Pain and non-pain thresholds were assessed by using cold, heat, mechanical, and electrical stimulation. FM women showed higher overall pain sensitivity as compared with healthy subjects. FM women with early age-of-onset of menopause displayed greater pain and non-pain sensitivity than FM women with late age-of-onset of menopause, whereas no differences were observed in healthy women due to age-of-onset of menopause. These results suggest that an early transition to menopause (shortening the time of exposure to estrogens) may influence pain hypersensitivity and could be related to aggravation of FM symptoms. 23565852 Striatal glutamate induces retrograde excitotoxicity and neuronal degeneration of intralaminar thalamic nuclei: their potential relevance for Parkinson's disease. An over-stimulation of nigral glutamate (GLU) receptors has been proposed as a cause of the progression of the dopamine (DA) cell degeneration (excitotoxicity) which characterizes Parkinson's disease. The possible toxic action of striatal GLU (retrograde excitotoxicity) on these cells, and on other neurons which innervate the striatum and which also degenerate in Parkinson's disease (thalamostriatal cells of the intralaminar thalamic nuclei), is still practically unexplored. The retrograde excitotoxicity of striatal GLU on DAergic mesostriatal and GLUergic thalamostriatal cells was tested here by studying these cells 6 weeks after striatal perfusion of GLU by reverse microdialysis. GLU perfusion induced the striatal denervation of thalamic inputs (as revealed by vesicular glutamate transporter 2) and the remote degeneration of intralaminar neurons. In both centres, these effects were accompanied by microglial activation. Similar responses were not observed for nigrostriatal neurons, which showed no dopaminergic striatal denervation, no microglial activation in the substantia nigra and no changes in the number of dopaminergic cells in the substantia nigra. The inhibition of DAergic transmission increased the extrasynaptic GLU levels in the striatum (evaluated by microdialysis), an effect observed after the local administration of agonists and antagonists of DAergic transmission, and after the peripheral administration of levodopa (which increased the DA and decreased the GLU levels in the striatum of rats with an experimental DAergic denervation of this centre). The data presented show that striatal GLU induced a retrograde excitotoxicity which did not affect all striatal inputs in the same way and which could be involved in the cell degeneration of the intralaminar nuclei of the thalamus generally observed in Parkinson's disease. 23843495 Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). The safety and activity of obinutuzumab (GA101) plus chemotherapy in relapsed/refractory follicular lymphoma was explored in 56 patients. Participants received obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP; every 3 weeks for 6 to 8 cycles) or obinutuzumab plus fludarabine and cyclophosphamide (G-FC; every 4 weeks for 4 to 6 cycles). Patients were randomly assigned to either obinutuzumab 1600 mg on days 1 and 8 of cycle 1 followed by 800 mg on day 1 of subsequent cycles or 400 mg for all doses. Treatment responders were eligible for obinutuzumab maintenance every 3 months for up to 2 years. Grade 1/2 infusion-related reactions (IRRs) were the most common treatment-related adverse event (AE) (all grades: G-CHOP, 68%; G-FC, 82%). Grade 3/4 IRRs were rare (7%) and restricted to the first infusion. All patients received the planned obinutuzumab dose. Neutropenia was the most common treatment-related hematologic AE for G-CHOP (43%) and G-FC (50%). At induction end, 96% (27/28) of patients receiving G-CHOP (complete response [CR], 39% [11/28]) and 93% (26/28) receiving G-FC (CR, 50% [14 of 28]) achieved responses. G-CHOP and G-FC had an acceptable safety profile with no new or unexpected AEs, but G-FC was associated with more AEs than G-CHOP. Obinutuzumab plus chemotherapy resulted in 93% to 96% response rates, supporting phase 3 investigation. This trial was registered at www.clinicaltrials.gov as #NCT00825149. 23675911 New substituted benzimidazole derivatives: a patent review (2010 - 2012). Introduction: Benzimidazole is a heterocyclic aromatic system, which is part of some natural and many synthetic compounds. A large number of benzimidazoles and its derivatives are found to be biologically active against many diseases. Researchers around the world are paying greater attention to and showing increasing interests in this field. Areas covered: Areas covered in this paper include a review of the synthesis, biological effects and mechanisms of benzimidazole derivatives in the past 2 years, based on literature and patents. The patent databases SciFinder and esp@cenet were used to locate patent applications that were published between 2010 to present. Information from articles published is also included. The current state and problems are also discussed. Expert opinion: Benzimidazole derivatives possess a broad spectrum of biological activities, whose scopes of treatment ranging from ordinary antimicrobial activities to world's most deadly diseases. However, challenges such as drug resistance, relatively little knowledge of structure of receptors and rare convenient methods for synthesis of benzimidazoles still exist. 23906598 The sensate fibula osteocutaneous flap: Neurosomal anatomy. Rapid return of oral sensation enhances quality of life following oromandibular reconstruction. For predictable reinnervation of flaps, a detailed knowledge of their nerve supply is required. This study was designed to investigate the cutaneous nerve supply of the fibula osteocutaneous flap. We dissected thirty-seven fresh cadaveric specimens to better understand the cutaneous innervation of the typical fibula flap that would be used in oromandibular reconstruction. In addition, ten volunteers were enlisted for nerve blocks testing the cutaneous innervation of the lateral aspect of the lower leg. The lateral sural cutaneous nerve (LSCN) is generally considered to be sole cutaneous innervation to the lateral aspect of the lower leg; however, our analysis of the cadaveric specimens revealed dual innervation to this region. We identified a previously unnamed distal branch of the superficial peroneal nerve, which we have termed the recurrent superficial peroneal nerve (RSPN). Given the cadaveric findings, both the LSCN and the RSPN were tested using sequential nerve blocks in 10 volunteers. An overlapping pattern of innervation was demonstrated. The lateral aspect of the lower leg has an overlapping innervation from the LSCN and the newly described RSPN. The overlap zone lies in the region of the skin paddle of the fibula flap. The exact position of the neurosomal overlap zone (N.O.Z.E.) may be an important factor in reestablishing sensation in the fibula's skin paddle following free tissue transfer. 23519679 Determination of alachlor residues in pepper and pepper leaf using gas chromatography and confirmed via mass spectrometry with matrix protection. Alachlor residues were determined in pepper and pepper leaf, after 49 days of manufacturer-recommended single- and double-dose application to the soil and plant. The samples were extracted with acetonitrile, partitioned with n-hexane, and purified through solid-phase extraction, and finally detected with a gas chromatography-microelectron capture detector. The linearity of the analytical response across the studied range of concentrations (0.05-4.0 µg/mL) was excellent, obtaining coefficients of determination (r(2) ) of 0.999. Recovery studies were carried out on spiked pepper and pepper leaf samples, at two concentrations levels (0.2 and 1.0 mg/kg), with three replicates performed at each level. Mean recoveries of 73.1-109.0% with relative standard deviations of 1.3-2.3% were obtained. The method was successfully applied to field samples, and alachlor residue was found in pepper (0.02 mg/kg) and pepper leaf (0.03 mg/kg), at levels lower than the maximum residue limits (0.2 mg/kg) set by the Korea Food and Drug Administration. The field-detected residues were further confirmed with gas chromatography-mass spectrometry with the help of pepper leaf matrix protection. 23861220 Hepatitis C virus genotype 4 in Southern and Central Spain does not originate from recent foreign migration waves. Hepatitis C virus genotype 4 (HCV-4) is highly prevalent in Spain, but the information on the molecular characterization of HCV-4 in this region is scarce. Due to this, the molecular characteristics and the evolution of HCV-4 infection in Seville were analyzed (Southern Spain) and compared them with samples from Madrid. HCV genotype was determined by LIPA 2.0 assay and confirmed by sequence analysis of NS5B. Phylogenetic tree was estimated by MEGA 5.10. Bayesian coalescent-based methods were used to estimate the substitution rate and the age of the most recent common ancestor (MRCA). In the phylogenetic analysis of 50 NS5B HCV-4 from Seville and 11 from Madrid, 2 clusters were distinguished: The first cluster (HCV-4a) included 48% of the sequences from Seville and 9% of sequences from Madrid. The second cluster included the remaining sequences belonging to HCV-4d. The mean estimated substitution rate was 2.39 × 10(-3) for HCV-4a and 1.81 × 10(-3) for HCV-4d for Seville and 2.32 × 10(-3) for HCV-4d from Madrid. The date for MRCA was estimated to be around 1981-1984 for HCV-4 from Seville. The dates for MRCA were dated before the recent flow of immigration in Spain. Therefore, the results presented in this study argues against the possibility of a foreign introduction of the HCV-4 from other regions with high prevalence, at least during the last two, decades in which there was a great flow of immigrants. Additionally, an unusual high prevalence of subtype 4a was observed in Seville. J Med. Virol. 85:1734-1740, 2013. © 2013 Wiley Periodicals, Inc. 23539510 Insulin-like Factor 3 promotes wound healing at the ocular surface. Tear fluid is known to contain many different hormones with relevance for ocular surface homeostasis. We studied the presence and functional role of insulin-like factor 3 (INSL3) and its cognate receptor RXFP2 at the ocular surface and in tears. Expression of human INSL3 and RXFP2 was determined in tissues of the ocular surface, lacrimal apparatus, in human corneal (HCE), conjunctival (HCjE), sebaceous (SC) epithelial cell lines and in human tears by RT-PCR and ELISA. We investigated effects of human recombinant (hr)INSL3 on cell proliferation and cell migration and the influence of hrINSL3 on the expression of MMP2, -9, -13 and TIMP1 and -2 was quantified by real-time PCR and ELISA in HCE, HCjE and SC cells. We used a C57BL/6 mouse corneal defect model to elucidate the effect of topical application of hrINSL3 on corneal wound healing. INSL3 and RXFP2 transcripts and INSL3 protein were detected in all tissues and cell lines investigated. Significantly higher concentrations of INSL3 were detected in tears from male vs. female volunteers. Stimulation of HCE, HCjE and SC with hrINSL3 significantly increased cell proliferation in HCjE and SC and migration of HCjE. Treatment with hrINSL3 for 24 h regulated MMP2, TIMP1 and TIMP2 expression. The local application of hrINSL3 onto denuded corneal surface resulted in significantly accelerated corneal wound healing in mice. These findings suggest a novel and gender specific role for INSL3 and cognate receptor RXFP2 signaling in ocular surface homeostasis and determined a novel role for hrINSL3 in corneal wound healing. 23548266 Assessment of renal function by means of cystatin C following standard and fenestrated endovascular aneurysm repair. Cystatin C (Cyst C) is more sensitive marker for early renal injury. However, serum creatinine (sCr) and estimated glomerular filtration rate (eGFR) are still used as the standard renal markers after endovascular aortic aneurysm repair (EVAR). The goal of this study was to compare the efficacy of Cyst C, sCr, and eGFR as markers of renal function after EVAR. This study examined 29 patients (27 men) with a mean age of 76.9 years (range, 55-89 years) undergoing standard (n = 19) and fenestrated (n = 10) EVAR for abdominal aortic aneurysm (AAA) of mean diameter 6.9 cm (range, 5.5-10 cm). Cyst C and sCr were measured and eGFR calculated before and 1 day and 1, 6, and 12 months after EVAR. At 24 hours after procedure, a significant increase in Cyst C (P < 0.005) and sCr (P = 0.028) and significant decrease in eGFR (P = 0.04) were seen. Cyst C continued to increase and was significantly higher at 1 (P < 0.002), 6 (P < 0.005), and 12 (P < 0.005) months compared with baseline. By contrast, sCr and eGFR did not show any significant change at 1, 6, and 12 months from the baseline level. Cyst C increased significantly postoperatively regardless of the baseline renal function. None of the patients required renal replacement therapy. EVAR is associated with a significant increase in Cyst C starting 24 hours after the procedure and is maintained for 12 months. sCr and eGFR only show significant change at 24 hours and therefore may underestimate long-term renal damage after EVAR. 23582662 Phosphodiesterase 7 inhibitor reduced cognitive impairment and pathological hallmarks in a mouse model of Alzheimer's disease. Elevated levels of amyloid beta (Aβ) peptide, hyperphosphorylation of tau protein, and inflammation are pathological hallmarks in Alzheimer's disease (AD). Phosphodiesterase 7 (PDE7) regulates the inflammatory response through the cyclic adenosine monophosphate signaling cascade, and thus plays a central role in AD. The aim of this study was to evaluate the efficacy of an inhibitor of PDE7, named S14, in a mouse model of AD. We report that APP/Ps1 mice treated daily for 4 weeks with S14 show: (1) significant attenuation in behavioral impairment; (2) decreased brain Aβ deposition; (3) enhanced astrocyte-mediated Aβ degradation; and (4) decreased tau phosphorylation. These effects are mediated via the cyclic adenosine monophosphate/cyclic adenosine monophosphate response element-binding protein signaling pathway, and inactivation of glycogen synthase kinase (GSK)3. Our data support the use of PDE7 inhibitors, and specifically S14, as effective therapeutic agents for the prevention and treatment of AD. 23692309 Transfusion in critically ill children: an ongoing dilemma. Transfusion of blood products is a cornerstone in managing many critically ill children. Major improvements in blood product safety have not diminished the need for caution in transfusion practice. In this review, we aim to discuss the interplay between benefits and potential adverse effects of transfusion in critically ill children by including 65 papers, which were evaluated based on previously agreed selection criteria. Current practice on transfusing critically ill children is mainly founded on the basis of adult studies, common practices with cut-off values, and expert opinions, rather than evidence-based medicine. Paediatric patients have explicit physiological challenges and requirements to be addressed. Critically ill children often suffer from anaemia, have substantial iatrogenic blood loss with subsequent transfusions, and are at a higher risk of complications, often due to human errors. Transfusion in children is associated with increased morbidity. A restrictive transfusion strategy is not associated with increased morbidity. Thus, transfusion in paediatrics should be considered a high-risk treatment and requires individual clinical assessment. Current level of evidence support the notion that in most stable cases, despite high severity of illness (cyanotic children and neonates excluded), a restrictive haemoglobin threshold of 70 g/l (4.3 mmol/l) is no more harmful than to transfuse at a liberal trigger, e.g. haemoglobin 95 g/l (5.9 mmol/l). Thus, balanced against potential benefits and often its necessity, a restrictive approach may be appropriate due to the associated risks of transfusion. 23770361 Loading and pre-loading processes generate a distinct siRNA population in Tetrahymena. The various properties of small RNAs, such as length, terminal nucleotide, thermodynamic asymmetry and duplex mismatches, can impact their sorting into different Argonaute proteins in diverse eukaryotes. The developmentally regulated 26- to 32-nt siRNAs (scnRNAs) are loaded to the Argonaute protein Twi1p and display a strong bias for uracil at the 5' end. In this study, we used deep sequencing to analyze loaded and unloaded populations of scnRNAs. We show that the size of the scnRNA is determined during a pre-loading process, whereas their 5' uracil bias is attributed to both pre-loading and loading processes. We also demonstrate that scnRNAs have a strong bias for adenine at the third base from the 3' terminus, suggesting that most scnRNAs are direct Dicer products. Furthermore, we show that the thermodynamic asymmetry of the scnRNA duplex does not affect the guide and passenger strand decision. Finally, we show that scnRNAs frequently have templated uracil at the last base without a strong bias for adenine at the second base indicating non-sequential production of scnRNAs from substrates. These findings provide a biochemical basis for the varying attributes of scnRNAs, which should help improve our understanding of the production and turnover of scnRNAs in vivo. 23824585 DXP Synthase-Catalyzed CN Bond Formation: Nitroso Substrate Specificity Studies Guide Selective Inhibitor Design. 1-Deoxy-D-xylulose 5-phosphate (DXP) synthase catalyzes the first step in the nonmammalian isoprenoid biosynthetic pathway to form DXP from pyruvate and D-glyceraldehyde 3-phosphate (D-GAP) in a thiamin diphosphate-dependent manner. Its unique structure and mechanism distinguish DXP synthase from its homologues and suggest that it should be pursued as an anti-infective drug target. However, few reports describe any development of selective inhibitors of this enzyme. Here, we reveal that DXP synthase catalyzes CN bond formation and exploit aromatic nitroso substrates as active site probes. Substrate specificity studies reveal a high affinity of DXP synthase for aromatic nitroso substrates compared to the related ThDP-dependent enzyme pyruvate dehydrogenase (PDH). Results from inhibition and mutagenesis studies indicate that nitroso substrates bind to E. coli DXP synthase in a manner distinct from that of D-GAP. Our results suggest that the incorporation of aryl acceptor substrate mimics into unnatural bisubstrate analogues will impart selectivity to DXP synthase inhibitors. As a proof of concept, we show selective inhibition of DXP synthase by benzylacetylphosphonate (BnAP). 23842607 Heavy metals contamination in water and three species of most consumed fish sampled from Caspian Sea, 2011. The present study is an attempt to evaluate the heavy metal contamination in the marine environment of the Caspian Sea of Iran. The concentrations of zinc, chromium, cadmium, and lead were measured in water and dorsal muscle of fish sampled from 10 selected stations along Gorgan coast using atomic absorption spectrophotometry during summer of 2011. The average concentrations of lead in water and fish samples (115.29 ±â€‰14.78 and 113.23 ±â€‰27.01 Î¼g/L) were significantly higher than that of cadmium and chromium (P < 0.05). The highest heavy metals content was observed in Cyprinus carpio samples. The heavy metals concentrations in the samples were within the acceptable recommended standards. But, elevating levels of heavy metals in water and fish made a serious concern about ecosystem and food chain contamination. It is recommended that protective authorities should carry out a continual assessment on the levels of pollutants in the sea. 23903664 Rh-catalyzed sulfonic acid group directed ortho C-H olefination of arenes. A Rh-catalyzed ortho C-H olefination of arenes directed by a sulfonic acid group was developed with good yields and a broad reaction scope. Efficient performance of the catalyst caused this electron-poor aromatic C-H to be activated effectively and unactivated alkenes are also suitable for this reaction. 23764745 Neighborhood crime and school climate as predictors of elementary school academic quality: a cross-lagged panel analysis. Past research has found negative relationships between neighborhood structural disadvantage and students' academic outcomes. Comparatively little work has evaluated the associations between characteristics of neighborhoods and schools themselves. This study explored the longitudinal, reciprocal relationships between neighborhood crime and school-level academic achievement within 500 urban schools. Results revealed that higher neighborhood crime (and particularly violent crime) predicted decreases in school academic achievement across time. School climate emerged as one possible mechanism within this relationship, with higher neighborhood crime predicting decreases in socioemotional learning and safety, but not academic rigor. All three dimensions of school climate were predictive of changes in academic achievement. Although this research supports a primarily unidirectional hypothesis of neighborhoods' impacts on embedded settings, additional work is needed to understand these relationships using additional conceptualizations of neighborhood climate. 23935098 Agonist-dependent endocytosis of GABAA receptors revealed by a γ2(R43Q) epilepsy mutation. GABA-gated chloride channels (GABAARs) trafficking is involved in the regulation of fast inhibitory transmission. Here, we took advantage of a γ2(R43Q) subunit mutation linked to epilepsy in humans that considerably reduces the number of GABAARs on the cell surface to better understand trafficking of GABAARs. Using recombinant expression in cultured rat hippocampal neurons and COS-7 cells, we showed that receptors containing γ2(R43Q) were addressed to the cell membrane but underwent clathrin-mediated dynamin-dependent endocytosis. The γ2(R43Q)-dependent endocytosis was reduced by GABAARs antagonists. These data, in addition to a new homology model, suggested that a conformational change in the extracellular domain of γ2(R43Q)-containing GABAARs increased their internalization. This led us to show that endogenous and recombinant wild-type GABAARs endocytosis in both cultured neurons and COS-7 cells can be amplified by their agonists. These findings revealed not only a direct relationship between endocytosis of GABAARs and a genetic neurological disorder but also that trafficking of these receptors can be modulated by their agonist. 23347045 Recombinant Luteinizing Hormone supplementation in poor responders undergoing IVF: a systematic review and meta-analysis. The results of several studies about the effectiveness of recombinant luteinizing hormone (rLH) supplementation in poor responder in vitro fertilization (IVF) patients were conflicting. To evaluate the current available data regarding the efficacy of rLH supplementation in poor responders, a meta-analysis was performed. A systemic search was performed without language limitation but restricted to randomized controlled trial (RCT). We mainly explored MEDLINE, EMBASE, CNKI and Cochrane Library for the relevant studies. Three studies were considered eligible for inclusion. The meta-analysis indicated that rLH supplementation did not increase the ongoing pregnancy rate in poor responders (OR 1.30, 95% CI: 0.80, 2.11). Furthermore, there was no significant difference in the number of oocytes retrieved, total dose of rFSH used, total duration of stimulation, number of retrieved metaphase II oocytes and cycle cancellation rate between the study and control groups. In conclusions, the available evidence does not support the addition of rLH in poor responders treated with rFSH and GnRHa for IVF. It was inconclusive. Future research should be based on strict criteria to define poor responders, and large, well-designed RCTs are necessary to definitively answer the important question of whether there was need to use rLH in poor responders undergoing IVF. 23314054 Fragment-based design, synthesis, and biological evaluation of N-substituted-5-(4-isopropylthiophenol)-2-hydroxynicotinamide derivatives as novel Mcl-1 inhibitors. We have previously reported a nanomolar inhibitor of antiapoptotic Mcl-1 protein, 3-thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1). S1 plays its function by binding to the BH3 groove of Mcl-1. Basing on this spacial structural characteristic, we developed a novel class of Mcl-1 inhibitor using fragment-based drug discovery approach. By dissecting S1, we identified the compound 4 with a 2-hydroxypyridine core as the starting fragment. In the following molecular growth, we used the ligand efficiency evaluation and fit quality score to assess the fragments. A novel potent compound, N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide (12c), which binds Mcl-1 with an IC(50) value of 54 nM was obtained. Compound 12c demonstrated a better aqueous solubility than S1. 23953742 Immunohistochemical determination of estrogen receptor-α in canine vaginal biopsies throughout proestrus, estrus, and early diestrus. The aim of this study was to describe the presence of estrogen receptor-α (ERα) in several vaginal histological compartments in healthy adult bitches throughout three estrous cycle stages (proestrus, estrus, and early diestrus) and to relate ERα presence with serum progesterone and estradiol-17β concentrations. For this purpose, serial blood samples and vaginal biopsies were taken from five bitches every 48 hours, starting at the clinical onset of proestrus, marked by the beginning of serosanguineous vaginal secretion. Serum progesterone and estradiol-17β concentrations were determined by RIA, whereas detection of steroid receptors was carried out through immunohistochemistry. Subjective image analysis was conducted by two independent observers in the following histological compartments: superficial, intermediate, and deep epithelia and superficial (loose) and deep (dense) stroma (connective tissue). Nuclear ERα immunoreactivity was detected in every histological compartment and estrous cycle stage studied. ERα expression varied among histological compartments and during stages of the cycle. Receptor expression was associated with estradiol-17β and progesterone serum profiles. Most relevant cyclic changes were detected in the superficial and deep epithelia and in the dense connective tissue. The highest ERα expression was detected during diestrus, although each compartment had a different pattern throughout the other cycle stages. Thus, vaginal ERα expression in the bitch varied throughout proestrus, estrus, and early diestrus according to the histological compartment involved. 23836065 Amino acids and proteins at ZnO-water interfaces in molecular dynamics simulations. We determine potentials of the mean force for interactions of amino acids with four common surfaces of ZnO in aqueous solutions. The method involves all-atom molecular dynamics simulations combined with the umbrella sampling technique. The profiled nature of the density of water with the strongly adsorbed first layer affects the approach of amino acids to the surface and generates either repulsion or weak binding. The largest binding energy is found for tyrosine interacting with the surface in which the Zn ions are at the top. It is equal to 7 kJ mol(-1) which is comparable to that of the hydrogen bonds in a protein. This makes the adsorption of amino acids onto the ZnO surface much weaker than onto the well studied surface of gold. Under vacuum, binding energies are more than 40 times stronger (for one of the surfaces). The precise manner in which water molecules interact with a given surface influences the binding energies in a way that depends on the surface. Among the four considered surfaces the one with Zn at the top is recognized as binding almost all amino acids with an average binding energy of 2.60 kJ mol(-1). Another (O at the top) is non-binding for most amino acids. For binding situations the average energy is 0.66 kJ mol(-1). The remaining two surfaces bind nearly as many amino acids as they do not and the average binding energies are 1.46 and 1.22 kJ mol(-1). For all of the surfaces the binding energies vary between amino acids significantly: the dispersion in the range of 68-154% of the mean. A small protein is shown to adsorb onto ZnO only intermittently and with only a small deformation. Various adsorption events lead to different patterns in mobilities of amino acids within the protein. 23968757 Surgical Technique Influences HeartMate II Left Ventricular Assist Device Thrombosis. Thrombosis of the HeartMate II (HM2 [Thoratec Corporation, Pleasanton, CA]) is a potentially devastating complication. While attention has been focused on anticoagulation strategies to prevent this complication, the impact of surgical technique has not been assessed. Patients undergoing HM2 implantation at two institutions were reviewed. Pump thrombosis (PT) was defined as a clinical syndrome that included more than 30% elevation in pump power, more than 30% elevation in lactate dehydrogenase, and greater than 20% decrease in hemoglobin with the presence of thrombus in the HM2 stator or rotor, or both, at explant or autopsy. A blinded clinician reviewed dimensions and angles of the HM2 obtained from chest x-ray films. Patients demonstrating PT were compared with patients having normal function. Of the 49 patients reviewed, 11 (22.4%) displayed evidence of PT at a median of 42 days after HM2 implantation. Patient with PT had greater acute angulation of the HM2 inflow cannula immediately postoperatively (48.2 ± 6.8 versus 65.4 ± 9.2 degrees, p < 0.001) and after 30 days (50.1 ± 8.0 versus 65.1 ± 9.9 degrees, p < 0.001). Pump pocket depth was lower in the PT group immediately after HM2 implantation (107.0 ± 41.9 versus 144.3 ± 20.3 cm, p < 0.001) and after 30 days (86.0 ± 39.1 versus 113.1 ± 25.4 cm, p = 0.02). Patients with evidence of PT did not have a decrease in end-diastolic diameter (76 ± 9 versus 70 ± 15 mm, p = 0.24) whereas patients in the normal function group had effective remodeling of the left ventricle (70 ± 10 versus 56 ± 12 mm, p = 0.01). Meticulous surgical technique, which necessitates creating an adequately sized pump pocket and appropriately directing the inflow cannula at the time of operation, may reduce the risk of PT. 23860272 The effect of Amifostine prophylaxis on bone densitometry, biomechanical strength and union in mandibular pathologic fracture repair. Pathologic fractures (Fx) of the mandibles are severely debilitating consequences of radiation (XRT) in the treatment of craniofacial malignancy. We have previously demonstrated Amifostine's effect (AMF) in the remediation of radiation-induced cellular damage. We posit that AMF prophylaxis will preserve bone strength and drastically reverse radiotherapy-induced non-union in a murine mandibular model of pathologic fracture repair. Twenty-nine rats were randomized into 3 groups: Fx, XRT/Fx, and AMF/XRT/Fx. A fractionated human equivalent dose of radiation was delivered to the left hemimandibles of XRT/Fx and AMF/XRT/Fx. AMF/XRT/Fx was pre-treated with AMF. All groups underwent left mandibular osteotomy with external fixation and setting of a 2.1mm fracture gap post-operatively. Utilizing micro-computed tomography and biomechanical testing, the healed fracture was evaluated for strength. All radiomorphometrics and biomechanical properties were significantly diminished in XRT/Fx compared to both Fx and AMF/XRT/Fx. No difference was demonstrated between Fx and AMF/XRT/Fx in both outcomes. Our investigation establishes the significant and substantial capability of AMF prophylaxis to preserve and enhance bone union, quality and strength in the setting of human equivalent radiotherapy. Such novel discoveries establish the true potential to utilize pharmacotherapy to prevent and improve the treatment outcomes of radiation-induced late pathologic fractures. 23920005 T helper subsets in Sjögren's syndrome and IgG4-related dacryoadenitis and sialoadenitis: A critical review. IgG4-related disease (IgG4-RD) is a systemic disease characterized by the elevation of serum IgG4 and infiltration of IgG4-positive plasma cells in multiple target organs, including the pancreas, kidney, biliary tract and salivary glands. In contrast, Mikulicz's disease (MD) has been considered a subtype of Sjögren's syndrome (SS) based on histopathological similarities. However, it is now recognized that MD is an IgG4-RD distinguishable from SS and called as IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS). Regarding immunological aspects, it is generally accepted that CD4+ T helper (Th) cells play a crucial role in the pathogenesis of SS. Since it is well known that IgG4 is induced by Th2 cytokines such as interleukin (IL)-4 and IL-13, IgG4-DS is speculated to be a unique inflammatory disorder characterized by Th2 immune reactions. However, the involvement of Th cells in the pathogenesis of IgG4-DS remains to be clarified. Exploring the role of Th cell subsets in IgG4-DS is a highly promising field of investigation. In this review, we focus on the selective localization and respective functions of Th cell subsets and discuss the differences between SS and IgG4-DS to clarify the pathogenic mechanisms of these diseases. 23721961 The regulation of ApoB metabolism by insulin. The leading cause of death in diabetic patients is cardiovascular disease. Apolipoprotein B (ApoB)-containing lipoprotein particles, which are secreted and cleared by the liver, are essential for the development of atherosclerosis. Insulin plays a key role in the regulation of ApoB. Insulin decreases ApoB secretion by promoting ApoB degradation in the hepatocyte. In parallel, insulin promotes clearance of circulating ApoB particles by the liver via the low-density lipoprotein receptor (LDLR), LDLR-related protein 1 (LRP1), and heparan sulfate proteoglycans (HSPGs). Consequently, the insulin-resistant state of type 2 diabetes (T2D) is associated with increased secretion and decreased clearance of ApoB. Here, we review the mechanisms by which insulin controls the secretion and uptake of ApoB in normal and diabetic livers. 23540608 Methadone in healthy goats - pharmacokinetics, behaviour and blood pressure. The pharmacokinetics and effects of the opioid methadone on behaviour, arterial blood pressure, heart rate and haematocrit were studied in goats. Two goats received methadone (0.2mg/kg) intravenously and the terminal half-life was 88 and 91 min, the volume of distribution 8.4 and 6.1L/kg, and clearance 86 and 123 mL/min/kg. In a crossover study eight goats received methadone (0.6 mg/kg) or 0.15M NaCl subcutaneously (SC). After SC administration bioavailability was complete and the terminal half-life was 215 ± 84 min (mean ± SD), Tmax 31 ± 15 min and Cmax 45 ±11 ng/mL. Blood pressure and haematocrit increased while heart rate did not change. The goats did not ruminate and they climbed, scratched, gnawed and showed tail-flicking after SC methadone in contrast to NaCl administration. The use of methadone in goats may be restricted due to the inhibition of rumination and the rather short half-life. 23921306 Role of small GTPase protein Rac1 in cardiovascular diseases: development of new selective pharmacological inhibitors. A pathway-based genome-wide association analysis has recently identified Rac1 as one of the biologically important gene in coronary heart diseases. The role of the small GTPase Rac1 in cardiac hypertrophy and atherosclerosis has also been documented in clinical studies with the HMG-CoA reductase inhibitors, and in in vitro and in vivo settings using transgenic and knock-out mice. Thus, Rac1 has emerged as a new pharmacological target for the treatment of cardiovascular diseases. The activation state of Rac1 depends on the release of GDP and the binding of GTP. This cycling is regulated by the guanine nucleotide exchange factors (GEFs), as activators, and by the GTPase activating proteins (GAPs). Three categories of selective Rac1 inhibitors have been developed affecting different steps of this pathway: antagonists of Rac1-GEF interaction, allosteric inhibitors of nucleotide binding to Rac1, and antagonists of Rac1-mediated NADPH oxidase activity. These chemical compounds have shown to selectively inhibit Rac1 activation in cultured cell lines without affecting the homologous proteins RhoA and Cdc42. In addition, pioneer studies have been conducted with Rac1 inhibitors in in vivo experimental models of cardiovascular diseases with encouraging results. In the present review it is summarized the current knowledge of the role of Rac1 in cardiovascular diseases and the pharmacological approaches that have been developed in order to selectively inhibit its function. 23466506 Novel treatment of neuroinflammation against low back pain by soluble fullerol nanoparticles. An in vitro study to investigate the anti-inflammatory effects of fullerol on mouse dorsal root ganglia (DRG) under tumor necrosis factor (TNF)-α induction. To evaluate the potential of a free radical scavenger, fullerol nanoparticles, to prevent DRG tissue and neuron inflammatory responses under TNF-α induction in vitro. Low back pain is one of the most common reasons for clinician visits in Western societies. Symptomatic intervertebral disc degeneration is strongly implicated as a cause of low back pain, as it results in DRG inflammation. Increased production of reactive oxygen species (ROS) is associated with DRG inflammation. With or without fullerol treatment, DRG tissue and DRG neurons isolated from wild-type C3H/HeNCrl (Charles River Laboratories, Wilmington, MA) mice were cultured under TNF-α induction. The amount of intracellular ROS was measured with H2DCFDA (Life Technologies Corporation, Grand Island, NY) fluorescence staining. Cellular apoptosis was detected via terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. The expression of inflammatory as well as antioxidative enzyme genes in neurons was analyzed by real-time polymerase chain reaction. In addition, inflammatory cytokine expression in DRG tissue was determined by immunofluorescence staining and enzyme-linked immunosorbent assay. Fluorescence staining results indicated that TNF-α markedly increased the production of intracellular ROS and the number of apoptotic cells. Under fullerol treatment, cellular apoptosis was reduced along with concomitant suppression of ROS. The expression of inflammatory cytokines interleukin 1 β, interleukin 6, cyclooxygenase-2, and prostaglandin E2, was also inhibited by fullerol in a dose-dependent manner. Furthermore, fullerol-treated cells exhibited upregulation of antioxidative enzyme genes superoxide dismutase 2 and catalase. The results obtained from this study clearly suggest that fullerol treatment suppresses the inflammatory responses of DRG and neurons, as well as cellular apoptosis by decreasing the level of ROS and potentially enhancing antioxidative enzyme gene expression. Therefore, fullerol has potential to serve as a novel therapeutic agent for low back pain treatment.Level of Evidence: N/A. 23953961 High Activity Arthroplasty Score has a Lower Ceiling Effect Than Standard Scores After Knee Arthroplasty. The tested hypothesis was following: the High Activity Arthroplasty Score has a significant lower ceiling effect than American Knee Society Score and Oxford Knee Score after total knee arthroplasty. One hundred patients operated on for total knee arthroplasty with more than one-year follow-up have been included. The ceiling effect was 53% for the American Knee Society Score, 33% for the Oxford Knee Score, and 0% for the High Activity Arthroplasty Score. High Activity Arthroplasty Score had a significantly lower ceiling effect than American Knee Society Score and Oxford Knee Score. High Activity Arthroplasty Score has the potential to detect more subtle differences in level of function than standard scoring systems among a non-selected total knee arthroplasty population. 23815352 Photoprotective effects of inclusion complexes of fullerenes with polyvinylpyrrolidone. The outermost surface of the body is covered by the stratum corneum, which is critical for proper skin barrier function. We investigated photoprotective effects of inclusion complexes of fullerenes with polyvinylpyrrolidone (PVP/fullerenes). To examine the cytoprotective activity of PVP/fullerenes against ultraviolet B (UVB) irradiation, we placed a dish with or without PVP/fullerenes on top of dishes containing cultured keratinocytes with or without PVP/fullerenes. Next, we examined the effects of PVP/fullerenes on the ratio of cells with cornified envelopes and transglutaminase-1 expression by real-time polymerase chain reaction and immunohistochemistry. Finally, we examined the barrier recovery effect of PVP/fullerenes solution by measuring transepidermal water loss after tape stripping in humans. UVB irradiation at 40 mJ/cm(2) markedly induced inhibition of keratinocyte proliferation. The inhibition of keratinocyte proliferation was restored only when PVP/fullerenes were present before UVB irradiation in the lower dish with the cells. UVB irradiation decreased the ratio of cells with cornified envelopes and transglutaminase-1 expression; however, the application of PVP/fullerenes reversed this phenomenon. PVP/fullerenes solution significantly promoted the recovery of transepidermal water loss on the second and third days after tape stripping. PVP/fullerenes can be used in cosmetics, especially in those intended to protect photo damage and ameliorate skin barrier perturbations. 23948445 Six years of follow-up after bilateral hand replantation. Replantation is the gold standard surgical treatment of amputations of the upper limb; however, this demanding procedure is not always preformed in bilateral limb amputation. The objective of this study was to analyze, sixyears after surgery, the sensorimotor recovery of both replanted hands. A 21-year-old patient with bilateral hand amputation was benefited from limb replantation. Surgery included debridement of the amputated hands and recipient's stumps, bone fixation, arterial and venous anastomoses, nerve sutures, tendon sutures and skin closure. Rehabilitation program included physiotherapy, electrostimulation and occupational therapy. Sensory and motor evaluation was performed 6years after replantation. At 6years, the patient presented a good/satisfactory recovery of range of motion and strength, better at right hand. The patient was able to perform right thumb opposition. Static two-point discrimination was 20mm, sensitivity to pain and thermal stimuli and ability to sweat were present on both hands. Reinnervation was confirmed by electromyography. Functional recovery was higher at the right hand when compared to the left hand. He was highly satisfied with the result of surgery for right hand and fairly satisfied with the result for left hand. He was able to return to a secretary work 16months after the accident. A proper functional result can be accomplished with bilateral hand replantation. 23801575 Impaired Tethering and Fusion of GLUT4 Vesicles in Insulin-Resistant Human Adipose Cells. Systemic glucose homeostasis is profoundly influenced by adipose cell function. Here we investigated GLUT4 dynamics in living adipose cells from human subjects with varying BMI and insulin sensitivity index (Si) values. Cells were transfected with hemagglutinin (HA)-GLUT4-green fluorescent protein (GFP)/mCherry (red fluorescence), and were imaged live using total internal reflection fluorescence and confocal microscopy. HA-GLUT4-GFP redistribution to the plasma membrane (PM) was quantified by surface-exposed HA epitope. In the basal state, GLUT4 storage vesicle (GSV) trafficking to and fusion with the PM were invariant with donor subject Si, as was total cell-surface GLUT4. In cells from insulin-sensitive subjects, insulin augmented GSV tethering and fusion approximately threefold, resulting in a corresponding increase in total PM GLUT4. However, with decreasing Si, these effects diminished progressively. All insulin-induced effects on GLUT4 redistribution and trafficking correlated strongly with Si and only weakly with BMI. Thus, while basal GLUT4 dynamics and total cell-surface GLUT4 are intact in human adipose cells, independent of donor Si, cells from insulin-resistant donors show markedly impaired GSV tethering and fusion responses to insulin, even after overnight culture. This altered insulin responsiveness is consistent with the hypothesis that adipose cellular dysfunction is a primary contributor to systemic metabolic dysfunction. 23964590 Novel Highly Sensitive, Specific, and Straightforward Strategy for Comprehensive N-Terminal Proteomics Reveals Unknown Substrates of the Mitochondrial Peptidase Icp55. We present a novel straightforward method for enrichment of N-terminal peptides, utilizing charge-based fractional diagonal chromatography (ChaFRADIC). Our method is robust, easy to operate, fast, specific, and more sensitive than existing methods, enabling the differential quantitation of 1459 nonredundant N-terminal peptides between two S. cerevisiae samples within 10 h of LC-MS, starting from only 50 μg of protein per condition and analyzing only 40% of the obtained fractions. Using ChaFRADIC we compared mitochondrial proteins from wild-type and icp55Δ yeast (30 μg each). Icp55 is an intermediate cleaving peptidase, which, following mitochondrial processing peptidase (MPP)-dependent cleavage of signal sequences, removes a single amino acid from a specific set of proteins according to the N-end rule. Using ChaFRADIC we identified 36 icp55 substrates, 14 of which were previously unknown, expanding the set of known icp55 substrates to a total of 52 proteins. Interestingly, a novel substrate, Isa2, is likely processed by Icp55 in two consecutive steps and thus might represent the first example of a triple processing event in a mitochondrial precursor protein. Thus, ChaFRADIC is a powerful and practicable tool for protease and peptidase research, providing the sensitivity to characterize even samples that can be obtained only in small quantities. 23930850 Results of Gamma Knife surgery for Cushing's disease. Object Cushing's disease is a challenging neuroendocrine disorder. Although resection remains the primary treatment option for most patients, the disease persists if there is residual or recurrent tumor. Stereotactic radiosurgery has been used to treat patients with persistent Cushing's disease after a prior resection. The authors report on the long-term risks and benefits of radiosurgery for Cushing's disease. Methods A retrospective review of a prospectively collected database of radiosurgery patients was undertaken at the University of Virginia. All patients with Cushing's disease treated with Gamma Knife surgery (GKS) were identified. Those without at least 12 months of clinical and radiological follow-up were excluded from this analysis. Rates of endocrine remission, tumor control, and adverse events were assessed. Statistical methods were used to identify favorable and unfavorable prognostic factors. Results Ninety-six patients with the required follow-up data were identified. The mean tumor margin dose was 22 Gy. The median follow-up was 48 months (range 12-209.8 months). At the last follow-up, remission of Cushing's disease occurred in 70% of patients. The median time to remission among all patients was 16.6 months (range 1-165.7 months). The median time to remission in those who had temporarily stopped taking ketoconazole at the time of GKS was 12.6 months, whereas it was 21.8 months in those who continued to receive ketoconazole (p < 0.012). Tumor control was achieved in 98% of patients. New loss of pituitary function occurred in 36% of patients. New or worsening cranial neuropathies developed in 5 patients after GKS, with the most common involving cranial nerves II and III. Conclusions Gamma Knife surgery offers a high rate of tumor control and a reasonable rate of endocrine remission in patients with Cushing's disease. The cessation of cortisol-lowering medications around the time of GKS appears to result in a more rapid rate of remission. Delayed hypopituitarism and endocrine recurrence develop in a minority of patients and underscore the need for long-term multidisciplinary follow-up. 22391569 microRNA-125b inhibits tube formation of blood vessels through translational suppression of VE-cadherin. Angiogenesis is controlled positively or negatively by extrinsic and intrinsic molecular cues in endothelial cells (ECs); in the tumor microenvironment, the action of positive regulators exceeds that of negative regulators. Thus, overinduction of negative regulators may inhibit tumor angiogenesis. MicroRNAs (miRNAs or miRs) are endogenous short noncoding RNAs regulating gene expression either through translational inhibition or destabilization of target mRNA. Here, we show that miR-125b expression is transiently induced in ECs on stimulation with vascular endothelial growth factor or by ischemia. miR-125b inhibits translation of vascular endothelial (VE)-cadherin mRNA and in vitro tube formation by ECs. Injection of miR-125b into the tumor inhibited VE-cadherin expression by ECs and induced nonfunctional blood vessel formation, resulting in inhibition of tumor growth. It has been suggested that pro-angiogenic signals in ECs also upregulate anti-angiogenic molecules simultaneously via negative feedback. Because miR-125b induction in ECs is transient after pro-angiogenic stimulation, prolonged overexpression of miR-125b could result in blood vessel regression. Thus, miR-125b may be useful in cancer therapy by causing the collapse of the lumen of ECs. 23474352 Single line source with and without vaginal loading and the impact on target coverage and organ at risk doses for cervix cancer Stages IB, II, and IIIB: treatment planning simulation in patients treated with MRI-guided adaptive brachytherapy in a multicentre study (EMBRACE). Three-dimensional evaluation and comparison of target and organs at risk (OARs) doses from two traditional standard source loading patterns in the frame of MRI-guided cervical cancer brachytherapy for various clinical scenarios based on patient data collected in a multicenter trial setting. Two nonoptimized three-dimensional MRI-based treatment plans, Plan 1 (tandem and vaginal loading) and Plan 2 (tandem loading only), were generated for 134 patients from seven centers participating in the EMBRACE study. Both plans were normalized to point A (Pt. A). Target and OAR doses were evaluated in terms of minimum dose to 90% of the high-risk clinical target volume (HRCTV D90) grouped by tumor stage and minimum dose to the most exposed 2cm³ of the OARs volume. An HRCTV D90 â‰¥ Pt. A was achieved in 82% and 44% of the patients with Plans 1 and 2, respectively. Median HRCTV D90 with Plans 1 and 2 was 120% and 90% of Pt. A dose, respectively. Both plans had optimal dose coverage in 88% of Stage IB tumors; however, the tandem-only plan resulted in about 50% of dose reduction to the vagina and rectum. For Stages IIB and IIIB, Plan 1 had on average 35% better target coverage but with significant doses to OARs. Standard tandem loading alone results in good target coverage in most Stage IB tumors without violating OAR dose constraints. For Stage IIB tumors, standard vaginal loading improves the therapeutic window, however needs optimization to fulfill the dose prescription for target and OAR. In Stage IIIB, even optimized vaginal loading often does not fulfill the needs for dose prescription. The significant dose variation across various clinical scenarios for both target and OARs indicates the need for image-guided brachytherapy for optimal dose adaptation both for limited and advanced diseases. 23570970 Genes encoding FAD-binding proteins in Volvariella volvacea exhibit differential expression in homokaryons and heterokaryons. Flavin adenine dinucleotide (FAD)-binding proteins play a vital role in energy transfer and utilization during fungal growth and mycelia aggregation. We sequenced the genome of Volvariella volvacea, an economically important edible fungus, and discovered 41 genes encoding FAD-binding proteins. Gene expression profiles revealed that the expression levels of four distinctly differentially expressed genes in heterokaryotic strain H1521 were higher than in homokaryotic strains PYd15 and PYd21 combined. These observations were validated by quantitative real-time PCR. The results suggest that the differential expression of FAD-binding proteins may be important in revealing the distinction between homokaryons and heterokaryons on the basis of FAD-binding protein functionality. 23877628 Interaction Between AT1 Receptor and NF-κB in Hypothalamic Paraventricular Nucleus Contributes to Oxidative Stress and Sympathoexcitation by Modulating Neurotransmitters in Heart Failure. Angiotensin II type 1 receptor (AT1-R) and nuclear factor-kappaB (NF-κB) in the paraventricular nucleus (PVN) play important roles in heart failure (HF); however, the central mechanisms by which AT1-R and NF-κB contribute to sympathoexcitation in HF are yet unclear. In this study, we determined whether interaction between AT1-R and NF-κB in the PVN modulates neurotransmitters and contributes to NAD(P)H oxidase-dependent oxidative stress and sympathoexcitation in HF. Rats were implanted with bilateral PVN cannulae and subjected to coronary artery ligation or sham surgery (SHAM). Subsequently, animals were treated for 4 weeks through bilateral PVN infusion with either vehicle or losartan (LOS, 10 Î¼g/h), an AT1-R antagonist; or pyrrolidine dithiocarbamate (PDTC, 5 Î¼g/h), a NF-κB inhibitor via osmotic minipump. Myocardial infarction (MI) rats had higher levels of glutamate (Glu), norepinephrine (NE) and NF-κB p65 activity, lower levels of gamma-aminobutyric acid (GABA), and more positive neurons for phosphorylated IKKβ and gp91(phox) (a subunit of NAD(P)H oxidase) in the PVN when compared to SHAM rats. MI rats also had higher levels of renal sympathetic nerve activity (RSNA) and plasma proinflammatory cytokines (PICs), NE and epinephrine. PVN infusions of LOS or PDTC attenuated the decreases in GABA and the increases in gp91(phox), NF-κB activity, Glu and NE, in the PVN of HF rats. PVN infusions of LOS or PDTC also attenuated the increases in RSNA and plasma PICs, NE and epinephrine in MI rats. These findings suggest that interaction between AT1 receptor and NF-κB in the PVN contributes to oxidative stress and sympathoexcitation by modulating neurotransmitters in heart failure. 23832102 Bacteriophage PRD1 batch experiments to study attachment, detachment and inactivation processes. Knowledge of virus removal in subsurface environments is pivotal for assessing the risk of viral contamination of water resources and developing appropriate protection measures. Columns packed with sand are frequently used to quantify attachment, detachment and inactivation rates of viruses. Since column transport experiments are very laborious, a common alternative is to perform batch experiments where usually one or two measurements are done assuming equilibrium is reached. It is also possible to perform kinetic batch experiments. In that case, however, it is necessary to monitor changes in the concentration with time. This means that kinetic batch experiments will be almost as laborious as column experiments. Moreover, attachment and detachment rate coefficients derived from batch experiments may differ from those determined using column experiments. The aim of this study was to determine the utility of kinetic batch experiments and investigate the effects of different designs of the batch experiments on estimated attachment, detachment and inactivation rate coefficients. The experiments involved various combinations of container size, sand-water ratio, and mixing method (i.e., rolling or tumbling by pivoting the tubes around their horizontal or vertical axes, respectively). Batch experiments were conducted with clean quartz sand, water at pH7 and ionic strength of 20mM, and using the bacteriophage PRD1 as a model virus. Values of attachment, detachment and inactivation rate coefficients were found by fitting an analytical solution of the kinetic model equations to the data. Attachment rate coefficients were found to be systematically higher under tumbling than under rolling conditions because of better mixing and more efficient contact of phages with the surfaces of the sand grains. In both mixing methods, more sand in the container yielded higher attachment rate coefficients. A linear increase in the detachment rate coefficient was observed with increased solid-water ratio using tumbling method. Given the differences in the attachment rate coefficients, and assuming the same sticking efficiencies since chemical conditions of the batch and column experiments were the same, our results show that collision efficiencies of batch experiments are not the same as those of column experiments. Upscaling of the attachment rate from batch to column experiments hence requires proper understanding of the mixing conditions. Because batch experiments, in which the kinetics are monitored, are as laborious as column experiments, there seems to be no major advantage in performing batch instead of column experiments. 23845285 Metabolic flux analysis of recombinant Pichia pastoris growing on different glycerol/methanol mixtures by iterative fitting of NMR-derived (13)C-labelling data from proteinogenic amino acids. The yeast Pichia pastoris has emerged as one of the most promising yeast cell factories for the production of heterologous proteins. The readily available genetic tools and the ease of high-cell density cultivations using methanol or glycerol/methanol mixtures are among the key factors for this development. Previous studies have shown that the use of mixed feeds of glycerol and methanol seem to alleviate the metabolic burden derived from protein production, allowing for higher specific and volumetric process productivities. However, initial studies of glycerol/methanol co-metabolism in P. pastoris by classical metabolic flux analyses using (13)C-derived Metabolic Flux Ratio (METAFoR) constraints were hampered by the reduced labelling information obtained when using C3:C1 substrate mixtures in relation to the conventional C6 substrate, that is, glucose. In this study, carbon flux distributions through the central metabolic pathways in glycerol/methanol co-assimilation conditions have been further characterised using biosynthetically directed fractional (13)C labelling. In particular, metabolic flux distributions were obtained under 3 different glycerol/methanol ratios and growth rates by iterative fitting of NMR-derived (13)C-labelling data from proteinogenic amino acids using the software tool (13)CFlux2. Specifically, cells were grown aerobically in chemostat cultures fed with 80:20, 60:40 and 40:60 (w:w) glycerol/methanol mixtures at two dilutions rates (0.05hour(-1) and 0.16hour(-1)), allowing to obtain additional data (biomass composition and extracellular fluxes) to complement pre-existing datasets. The performed (13)C-MFA reveals a significant redistribution of carbon fluxes in the central carbon metabolism as a result of the shift in the dilution rate, while the ratio of carbon sources has a lower impact on carbon flux distribution in cells growing at the same dilution rate. At low growth rate, the percentage of methanol directly dissimilated to CO2 ranges between 50% and 70%. At high growth rate the methanol is completely dissimilated to CO2 by the direct pathway, in the two conditions of highest methanol content. 23792055 Analysis of KIR gene frequencies and HLA class I genotypes in breast cancer and control group. Breast cancer is the main cause of cancer-related death among women, with a 0.5% increase in incidence per year. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer cell immunoglobulin-like receptors (KIR). The aim of our study was to evaluate the association between the KIR genes and HLA alleles in patients with breast cancer and healthy controls. Two hundred thirty patients with breast cancer and 272 healthy controls were typed for HLA class I and KIR genes by PCR-SSO. When both groups were compared, the presence of inhibitory KIR2DL2 receptors was significantly higher in breast cancer patients than in healthy controls. No significant differences were found for HLA-C2 and HLA-Bw4. However, a higher frequency of HLA-C1 in breast cancer patients was observed. These findings suggest a potential role for the KIR gene system in breast cancer. Further studies to confirm this observation are warranted. 23899129 Detecting 20 nm Wide Defects in Large Area Nanopatterns Using Optical Interferometric Microscopy. Due to the diffraction limited resolution and the presence of speckle noise, visible laser light is generally thought to be impractical for finding deep subwavelength defects in patterned semiconductor wafers. Here, we report on a nondestructive low-noise interferometric imaging method capable of detecting nanoscale defects within a wide field of view using visible light. The method uses a common-path laser interferometer and a combination of digital image processing techniques to produce 70 μm by 27 μm panoramic phase and amplitude images of the test nanopattern. Significant noise reduction and high sensitivity are achieved, which enables successful detection of several different types of sparse defects with sizes on the order of 20 nm wide by 100 nm long by 110 nm tall. 23771794 Traceability of Biopharmaceuticals in Spontaneous Reporting Systems: A Cross-Sectional Study in the FDA Adverse Event Reporting System (FAERS) and EudraVigilance Databases. Adverse drug reactions (ADRs) of biopharmaceuticals can be batch or product specific, resulting from small differences in the manufacturing process. Detailed exposure information should be readily available in systems for postmarketing safety surveillance of biopharmaceuticals, including spontaneous reporting systems (SRSs), in which reports of ADRs are collected. The aim of this study was to explore the current status of traceability of biopharmaceuticals in the US and the EU up to patient level in SRSs. A cross-sectional study was conducted over the period 2004-2010, including ADR reports from two major SRSs: the FDA Adverse Event Reporting System (FAERS) in the US and EudraVigilance (EV) in the EU. The availability of batch numbers was determined for biopharmaceuticals, and compared with small molecule drugs. For biopharmaceuticals for which a biosimilar has been approved for marketing in the EU, the identifiability of the product (i.e. the possibility of distinguishing the biosimilar from the reference biopharmaceutical) was determined. A total of 2,028,600 unique ADR reports were identified in the FAERS, reporting a total of 591,380 biopharmaceuticals (of which 487,065 were suspected). In EV there were 2,108,742 unique ADR reports, reporting a total of 439,971 biopharmaceuticals (356,293 suspected). Overall, for 24.0 % of the suspected biopharmaceuticals in the FAERS and 7.4 % of the suspected small molecule drugs (p < 0.001) batch numbers were available. A similar pattern was seen in EV: for 21.1 % of the suspected biopharmaceuticals batch numbers were available, compared with only 3.6 % of the small molecule drugs (p < 0.001). In both SRSs, consumers were most likely to report a batch number for suspected biologicals (36.3 % in the FAERS and 40.7 % in EV). A total of 13,790 biopharmaceuticals (9,759 suspected) for which a biosimilar has been approved in the EU were identified in EV. For 90.4 % of these biopharmaceuticals and 96.2 % of the suspected biopharmaceuticals the product was clearly identifiable. This study underlines the need for improving traceability of biopharmaceuticals, in particular with respect to individual batches, allowing better identification and monitoring of postmarketing safety issues related to biopharmaceuticals. 23962435 Biological early warning system based on the responses of aquatic organisms to disturbances: A review. Aquatic ecosystems are subject to a number of anthropogenic disturbances, including environmental toxicants. The efficient monitoring of water resources is fundamental for effective management of water quality and aquatic ecosystems. Spot sampling and continuous water quality monitoring based on physicochemical factors are conducted to assess water quality. However, not all contaminants or synergistic and antagonistic toxic effects can be determined by solely analyzing the physicochemical factors. Thus, various biotests have been developed using long-term and automatic observation studies based on the ability of the aquatic organisms to continuously sense a wide range of pollutants. In addition, a biological early warning system (BEWS) has been developed based on the response behaviors of organisms to continuously detect a wide range of pollutants for effective water quality monitoring and management. However, large amounts of data exhibiting non-linearity and individual behavioral variation are continuously accumulated over long-term and continuous behavioral monitoring studies. Thus, appropriate mathematical and computational data analyses are necessary to manage and interpret such large datasets. Here, we review the development and application of BEWS by using various groups of organisms and the computational methods used to process the behavioral monitoring data. 23870403 Analytical chemistry of the persistent organic pollutants identified in the Stockholm Convention: A review. Persistent organic pollutants (POPs) are major environmental concern due to their persistence, long-range transportability, bio-accumulation and potentially adverse effects on living organisms. Analytical chemistry plays an essential role in the measurement of POPs and provides important information on their distribution and environmental transformations. Much effort has been devoted during the last two decades to the development of faster, safer, more reliable and more sensitive analytical techniques for these pollutants. Since the Stockholm Convention (SC) on POPs was adopted 12 years ago, analytical methods have been extensively developed. This review article introduces recent analytical techniques and applications for the determination of POPs in environmental and biota samples, and summarizes the extraction, separation and instrumental analyses of the halogenated POPs. Also, this review covers important aspects for the analyses of SC POPs (e.g. lipid determination and quality assurance/quality control (QA/QC)), and finally discusses future trends for improving the POPs analyses and for potential new POPs. 23830560 Micro-CT evaluation of bone defects: Applications to osteolytic bone metastases, bone cysts, and fracture. Bone defects can occur in various forms and present challenges to performing a standard micro-CT evaluation of bone quality because most measures are suited to homogeneous structures rather than ones with spatially focal abnormalities. Such defects are commonly associated with pain and fragility. Research involving bone defects requires quantitative approaches to be developed if micro-CT is to be employed. In this study, we demonstrate that measures of inter-microarchitectural bone spacing are sensitive to the presence of focal defects in the proximal tibia of two distinctly different mouse models: a burr-hole model for fracture healing research, and a model of osteolytic bone metastases. In these models, the cortical and trabecular bone compartments were both affected by the defect and were, therefore, evaluated as a single unit to avoid splitting the defects into multiple analysis regions. The burr-hole defect increased mean spacing (Sp) by 27.6%, spacing standard deviation (SpSD) by 113%, and maximum spacing (Spmax) by 72.8%. Regression modeling revealed SpSD (β=0.974, p<0.0001) to be a significant predictor of the defect volume (R(2)=0.949) and Spmax (β=0.712, p<0.0001) and SpSD (β=0.271, p=0.022) to be significant predictors of the defect diameter (R(2)=0.954). In the mice with osteolytic bone metastases, spacing parameters followed similar patterns of change as reflected by other imaging technologies, specifically bioluminescence data which is indicative of tumor burden. These data highlight the sensitivity of spacing measurements to bone architectural abnormalities from 3D micro-CT data and provide a tool for quantitative evaluation of defects within a bone. 23554086 Impacts of silver nanoparticles on cellular and transcriptional activity of nitrogen-cycling bacteria. The widespread use of silver nanoparticles (AgNPs) raises the potential for environmental releases that could impact microbial ecosystem services. In the present study, the authors address how the AgNPs and Ag(+) that they release may impact nitrogen-cycling bacteria. The authors studied the cellular and transcriptional response of the denitrifier Pseudomonas stutzeri, the nitrogen fixer Azotobacter vinelandii, and the nitrifier Nitrosomonas europaea exposed to 35 nm (carbon-coated) AgNPs or to Ag(+) (added as AgNO3 ). Based on minimum inhibitory concentrations (MICs), Ag(+) was 20 times to 48 times more toxic to the tested strains than AgNPs (including Ag(+) released during exposure). Exposure to sublethal concentrations of AgNPs or Ag(+) (representing 10% of the respective MIC for AgNO3 ) resulted in no significant effect on the expression of the denitrifying genes narG, napB, nirH, and norB in P. stutzeri or the nitrogen-fixing genes nifD, nifH, vnfD, and anfD in A. vinelandii, whereas nitrifying genes (amoA1 and amoC2) in N. europaea were upregulated (2.1- to 3.3-fold). This stimulatory effect disappeared at higher silver concentrations (60% of the Ag(+) MIC), and toxicity was exerted at concentrations higher than 60% of the Ag(+) MIC. The MIC for N. europaea was 8 times to 24 times lower than for the other strains, indicating higher susceptibility to AgNPs. This was corroborated by the lower half-lethal concentration for N. europaea (87 µg/L) compared with P. stutzeri (124 µg/L) and A. vinelandii (>250 µg/L) when cells were exposed with Ag(+) for 24 h in 1 mM bicarbonate buffer. This suggests that ammonia oxidation would be the most vulnerable nitrogen-cycling process in wastewater treatment plants receiving AgNPs and in agricultural soils amended with biosolids that concentrate them. 23680362 Co-stimulatory molecules as targets for treatment of lupus. Co-stimulatory molecules help to regulate interactions between T cells and antigen-presenting cells and may play an important role in the pathogenesis of lupus. Both work in murine models and some early studies in human lupus support further examination of these molecules as therapeutic targets. Complexities of lupus clinical trial variables may have hampered progress in this area but recent developments in the field may make interventional trials more feasible in the near future. To date biologics which provide direct blockade of interactions between CD40 and CD154, B7RP-1 and ICOS, and CD80 or CD86 with CD28 have been assessed in multicenter clinical trials. These data will be reviewed and critiqued. 23954935 Biodegradation of 4-bromophenol by Arthrobacter chlorophenolicus A6 in batch shake flasks and in a continuously operated packed bed reactor. The present study investigated growth and biodegradation of 4-bromophenol (4-BP) by Arthrobacter chlorophenolicus A6 in batch shake flasks as well as in a continuously operated packed bed reactor (PBR). Batch growth kinetics of A. chlorophenolicus A6 in presence of 4-BP followed substrate inhibition kinetics with the estimated biokinetic parameters value of μ max = 0.246 h(-1), K i = 111 mg L(-1), K s  = 30.77 mg L(-1) and K = 100 mg L(-1). In addition, variations in the observed and theoretical biomass yield coefficient and maintenance energy of the culture were investigated at different initial 4-BP concentration. Results indicates that the toxicity tolerance and the biomass yield of A. chlorophenolicus A6 towards 4-BP was found to be poor as the organism utilized the substrate mainly for its metabolic maintenance energy. Further, 4-BP biodegradation performance by the microorganism was evaluated in a continuously operated PBR by varying the influent concentration and hydraulic retention time in the ranges 400-1,200 mg L(-1) and 24-7.5 h, respectively. Complete removal of 4-BP was achieved in the PBR up to a loading rate of 2,276 mg L(-1) day(-1). 23835521 Forage and tree seedling growth in a soil with an encased swine sludge layer. The closure of swine farms requires decommissioning of lagoons that contain large amounts of swine solids (sludge). Sludge is typically transported and land applied to soils. However, in some cases this process could be economically prohibitive and/or unpractical. An alternative idea is to encase sludge with lagoon soil berms after removing overlying effluent, followed by establishment of forages or short-rotation woody crops on the encased sludge. The objective of this study was to investigate growth potential for several forages and tree species into a pure layer of swine sludge. Alfalfa (Meticago sativa), bermudagrass (Cynodon dactylon), switchgrass (Panicum virgatum), green ash (Fraxinus pennsylvanica), black locust (Robinia pseudoacacia), and sycamore (Platanus occidentalis) were established in 40 cm deep pots consisting of a lagoon berm soil overlaying a sludge layer for 12 w followed by analysis of aboveground and belowground biomass production. "New" and "old" sludge was collected from an active 10 year old lagoon and decommissioned 50 year old lagoon, respectively. A control (soil only) was used. Encased sludge treatments increased forage biomass production. Sycamore and green ash were sensitive to new sludge but not old sludge as these species had less biomass production in new sludge than control and showed tissue trace nutrient deficiencies. While both sludge materials contained adequate nutrients, the new sludge had a salt concentration 1.8 times higher than old sludge as indicated by electrical conductivity (12.4 mS). Thus, the forage crops and black locust were able to thrive in new sludge due to their salt tolerance. 23700148 Dosage effect of a phex mutation in a murine model of x-linked hypophosphatemia. X-linked hypophosphatemia (XLH) is caused by mutations in the PHEX gene, which increase circulating levels of the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Because XLH is a dominant disease, one mutant allele is sufficient for manifestation of the disease. However, the dosage effect of a PHEX mutation in XLH is not completely understood. To examine the effect of Phex genotypes, we compared serum biochemistries and skeletal measures between all five possible genotypes of a new murine model of XLH (Phex (K496X) or Phex (Jrt) ). Compared to sex-matched littermate controls, all Phex mutant mice had hypophosphatemia, mild hypocalcemia, and increased parathyroid hormone and alkaline phosphatase levels. Furthermore, mutant mice had markedly elevated serum Fgf23 levels due to increased Fgf23 expression and reduced cleavage of Fgf23. Although females with a homozygous Phex mutation were slightly more hypocalcemic and hypophosphatemic than heterozygous females, the two groups had comparable intact Fgf23 levels. Similarly, there was no difference in intact Fgf23 or phosphorus concentrations between hemizygous males and heterozygous females. Compared to heterozygous females, homozygous counterparts were significantly smaller and had shorter femurs with reduced bone mineral density, suggesting the existence of dosage effect in the skeletal phenotype of XLH. However, overall phenotypic trends in regards to mineral ion homeostasis were mostly unaffected by the presence of one or two mutant Phex allele(s). The lack of a gene dosage effect on circulating Fgf23 (and thus phosphorus) levels suggests that a Phex mutation may create the lower set point for extracellular phosphate concentrations. 23936479 Associations between Two Genetic Variants in NKX2-5 and Risk of Congenital Heart Disease in Chinese Population: A Meta-Analysis. NKX2-5 is a transcriptional factor, which plays an important role in heart formation and development. Two genetic variants in the coding region of NKX2-5, 63A>G (rs2277923) and 606G>C (rs3729753), have been investigated in the risk of congenital heart disease (CHD), although with inconsistent results. Thus, a meta-analysis was performed to clarify the associations between the two variants and CHD risk in the Chinese population. Relevant studies were identified by searching PubMed, ISI Web of Science and CNKI databases and by reviewing the reference lists of retrieved articles. Then, the data from eligible studies were combined in an allelic model. A total of 7 and 4 studies were ultimately included for 63A>G and 606G>C, respectively. The results of overall meta-analyses showed that significant association was detected for 63A>G (OR = 1.26, 95% CI = 1.02-1.56, P heterogeneity = 0.009, I (2) = 65.1%), but not for 606G>C (OR = 1.22, 95% CI = 0.75-1.96, P heterogeneity = 0.412, I (2) = 0.0%). Regarding 63A>G variant, positive results were also obtained in the subgroups of atrial septal defect and large-sample-size study. Besides, the sensitivity analysis indicated that significant association was still detected after deletion of the individual studies with positive result and striking heterogeneity. Our results revealed that the 63A>G variant in NKX2-5, but not the 606G>C, may contribute to CHD risk for Chinese. 23813584 Symmetry of paraspinal muscle denervation in clinical lumbar spinal stenosis: Support for a hypothesis of posterior primary ramus stretching? Denervation of the paraspinal muscles in spinal disorders is frequently attributed to radiculopathy. Therefore, patients with lumbar spinal stenosis causing asymmetrical symptoms should have asymmetrical paraspinal denervation. Seventy-three patients with clinical lumbar spinal stenosis, aged 55-85 years, completed a pain drawing and underwent masked electrodiagnostic testing, including bilateral paraspinal mapping and testing of 6 muscles on the most symptomatic (or randomly chosen) limb. With the exception of 10 subjects with unilateral thigh pain (P = 0.043), there was no relationship between side of pain and paraspinal mapping score for any subgroups (symmetrical pain, pain into 1 calf only). Among those with positive limb EMG (tested on 1 side), no relationship between side of pain and paraspinal EMG score was found. Evidence suggests that paraspinal denervation in spinal stenosis may not be due to radiculopathy, but rather due to stretch or damage to the posterior primary ramus. Muscle Nerve, 48: 198-203, 2013. 23845200 Manual treatment for cervicogenic headache and active trigger point in the sternocleidomastoid muscle: a pilot randomized clinical trial. The purpose of this preliminary study was to determine feasibility of a clinical trial to measure the effects of manual therapy on sternocleidomastoid active trigger points (TrPs) in patients with cervicogenic headache (CeH). Twenty patients, 7 males and 13 females (mean ± SD age, 39 ± 13 years), with a clinical diagnosis of CeH and active TrPs in the sternocleidomastoid muscle were randomly divided into 2 groups. One group received TrP therapy (manual pressure applied to taut bands and passive stretching), and the other group received simulated TrP therapy (after TrP localization no additional pressure was added, and inclusion of longitudinal stroking but no additional stretching). The primary outcome was headache intensity (numeric pain scale) based on the headaches experienced in the preceding week. Secondary outcomes included neck pain intensity, cervical range of motion (CROM), pressure pain thresholds (PPT) over the upper cervical spine joints and deep cervical flexors motor performance. Outcomes were captured at baseline and 1 week after the treatment. Patients receiving TrP therapy showed greater reduction in headache and neck pain intensity than those receiving the simulation (P < .001). Patients receiving the TrP therapy experienced greater improvements in motor performance of the deep cervical flexors, active CROM, and PPT (all, P < .001) than those receiving the simulation. Between-groups effect sizes were large (all, standardized mean difference, >0.84). This study provides preliminary evidence that a trial of this nature is feasible. The preliminary findings show that manual therapy targeted to active TrPs in the sternocleidomastoid muscle may be effective for reducing headache and neck pain intensity and increasing motor performance of the deep cervical flexors, PPT, and active CROM in individuals with CeH showing active TrPs in this muscle. Studies including greater sample sizes and examining long-term effects are needed. 23484861 Ultrathin 2D Coordination Polymer Nanosheets by Surfactant-Mediated Synthesis. Low-dimensional nanostructures offer a host of intriguing properties which are distinct from those of the bulk material, owing to size-confinement effects and amplified surface areas. Here, we report on the scalable, bottom-up synthesis of ultrathin coordination polymer nanosheets via surfactant-mediated synthesis and subsequent exfoliation. Layers of a two-dimensional (2D) zinc coordination polymer are self-assembled in the interlamellar space of a reverse microemulsion mesophase into stacks of nanosheets interleaved with cethyltrimethylammonium bromide (CTAB) at regular intervals, thus giving rise to a lamellar hybrid mesostructure with a lattice period of ∼8 nm and an underlying highly crystalline substructure. The basic structural motif is composed of 2D acetato-benzimidazolato-zinc layers of tetrahedrally coordinated zinc joined together by anionic acetate and benzimidazolate ligands. The hierarchical structure was studied by PXRD, TEM, EDX, EELS, AFM, and solid-state NMR spectroscopy, revealing a high level of order on both the atomic and mesoscale, suggesting fairly strong interactions along the organic-inorganic hybrid interface. Exfoliation of the hybrid material in organic solvents such as THF and chloroform yields sheet- and belt-like nanostructures with lateral sizes between 10's and 100's of nanometers and a height of about 10 nm measured by AFM, which precisely maps the basal spacing of the lamellar mesostructure; further exfoliation results in nanobelts with minimum sizes around 4 nm. Finally, the sheetlike nanostructures behave as morphological chameleons, transforming into highly regular multiwalled coordination polymer nanotubes upon treatment with organic solvents. 23950799 Correction: The Effects of Sampling Bias and Model Complexity on the Predictive Performance of MaxEnt Species Distribution Models. [This corrects the article on p. e55158 in vol. 8.]. 23893302 Does spicing step affect the quality and drying behaviour of Traditional kaddid: a Tunisian cured meat? The effects of spicing on physicochemical and microbial characteristics and drying behaviour of kaddid, a Tunisian dry-cured meat, are studied. Also, the quality of traditional sun dried and processed convective dried kaddid are compared. Spicing had no significant effect on pH and water activity of brined beef meat at 21% (w/w). Nevertheless, it reduced the product water and salt contents. Effects of spicing on brined meat microbial flora were appearance of sulfito-reducer bacteria, increase in total mesophilic aerobic flora (15%) and staphylococci (26%) and decrease in faecal coliforms (23%). Salted beef meat sorption behaviour was affected by spicing. Besides, spicing increased the kaddid drying rate and allowed a significant decrease (33%) in the drying process time. Traditional and processed kaddid presents comparable microbial characteristics. Both drying methods led to reductions in numbers of the total mesophilic aerobic flora in unspiced and spiced kaddid and of faecal coliforms in spiced kaddid. The study showed that spicing, as a step in kaddid meat processing to enhance the final product flavor, caused changes in salted meat physicochemical and microbial characteristics and accelerated the drying rate of the product. Convective drying at 30°C is recommended to produce kaddid having the same characteristics as a traditional kaddid. 23598167 Evaluation of the APTIMA Combo 2 Assay using self-administered vaginal swabs for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae. We report on the performance of the APTIMA Combo 2 assay for the detection of chlamydial infection and gonorrhea using self-administered vaginal specimens in specimen transport medium and specimen kept dry. The results are compared with the results using the Amplicor assay and the BD ProbeTec assay™. 23839165 Current challenges in travelers' malaria. Travel health providers are often confronted with complex scenarios when advising travelers on malaria prevention. Current challenges in prevention include malaria risk assessment, where a detailed itinerary and knowledge of malaria epidemiology are needed. Up-to-date information on the correct use, limitations, and drug interactions of current priority chemoprophylaxis agents (atovaquone/proguanil, mefloquine, doxycycline) is key. Another challenge is to identify and reach travelers who are most at risk of malaria, such as the traveler visiting friends and relatives. Posttravel, delays in presentation, diagnosis, and inappropriate treatment of malaria are key risk factors leading to death. Treatment of malaria is an emergency requiring expert in-patient management and referral to a center with adequate expertise. Artemisinin combination therapies are the drugs of choice for uncomplicated malaria. Complicated malaria is treated preferably with intravenous artesunate, and the supply and quality of this life-saving antimalarial in some settings can pose one of the most urgent challenges in travelers' malaria. 23892672 Isolation of Sensory Neurons of Aplysia californica for Patch Clamp Recordings of Glutamatergic Currents. The marine gastropod mollusk Aplysia californica has a venerable history as a model of nervous system function, with particular significance in studies of learning and memory. The typical preparations for such studies are ones in which the sensory and motoneurons are left intact in a minimally dissected animal, or a technically elaborate neuronal co-culture of individual sensory and motoneurons. Less common is the isolated neuronal preparation in which small clusters of nominally homogeneous neurons are dissociated into single cells in short term culture. Such isolated cells are useful for the biophysical characterization of ion currents using patch clamp techniques, and targeted modulation of these conductances. A protocol for preparing such cultures is described. The protocol takes advantage of the easily identifiable glutamatergic sensory neurons of the pleural and buccal ganglia, and describes their dissociation and minimal maintenance in culture for several days without serum. 23728614 Current concepts and trends for operative treatment of FAI: hip arthroscopy. There has been an increasing body of literature regarding arthroscopic management of femoroacetabular impingement (FAI). Refinement of arthroscopic techniques has allowed for more complete management of FAI, and meta-analysis and systematic reviews have shown comparable outcomes to surgical hip dislocation with appropriate indications. There are still, however, pathomorphologies that are not accessible or much more challenging to address arthroscopically, and open corrective procedures should be considered in these situations. Extra-articular FAI is receiving increased attention and can be secondary to anterior inferior iliac spine/subspine impingement, trochanteric-pelvic impingement, and ischio-femoral impingement. Femoral and acetabular version and their impact on hip stability as well as the concept of impingement induced instability are being increasingly recognized. Acetabular labral and capsular management and repair techniques have also received increased attention. Finally, 3-dimensional imaging and dynamic software analysis are beginning to emerge as potential tools to better evaluate hip pathomorphology. 23440969 EMLasso: logistic lasso with missing data. In clinical settings, missing data in the covariates occur frequently. For example, some markers are expensive or hard to measure. When this sort of data is used for model selection, the missingness is often resolved through a complete case analysis or a form of single imputation. An alternative sometimes comes in the form of leaving the most damaged covariates out. All these strategies jeopardise the goal of model selection. In earlier work, we have applied the logistic Lasso in combination with multiple imputation to obtain results in such settings, but we only provided heuristic arguments to advocate the method. In this paper, we propose an improved method that builds on firm statistical arguments and that is developed along the lines of the stochastic expectation-maximisation algorithm. We show that our method can be used to handle missing data in both categorical and continuous predictors, as well as in a nonpenalised regression. We demonstrate the method by applying it to data of 273 lung cancer patients. The objective is to select a model for the prediction of acute dysphagia, starting from a large set of potential predictors, including clinical and treatment covariates as well as a set of single-nucleotide polymorphisms. 23248200 Drug-drug interactions between rosuvastatin and oral antidiabetic drugs occurring at the level of OATP1B1. Organic anion-transporting polypeptide 1B1 (OATP1B1) is an important hepatic uptake transporter, of which the polymorphic variant OATP1B1*15 (Asn130Asp and Val174Ala) has been associated with decreased transport activity. Rosuvastatin is an OATP1B1 substrate and often concomitantly prescribed with oral antidiabetics in the clinic. The aim of this study was to investigate possible drug-drug interactions between these drugs at the level of OATP1B1 and OATP1B1*15. We generated human embryonic kidney (HEK)293 cells stably overexpressing OATP1B1 or OATP1B1*15 that showed similar protein expression levels of OATP1B1 and OATP1B1*15 at the cell membrane as measured by liquid chromatography-tandem mass spectrometry. In HEK-OATP1B1*15 cells, the V(max) for OATP1B1-mediated transport of E(2)17β-G (estradiol 17β-d-glucuronide) was decreased >60%, whereas K(m) values (Michaelis constant) were comparable. Uptake of rosuvastatin in HEK-OATP1B1 cells (K(m) 13.1 ± 0.43 μM) was nearly absent in HEK-OATP1B1*15 cells. Interestingly, several oral antidiabetics (glyburide, glimepiride, troglitazone, pioglitazone, glipizide, gliclazide, and tolbutamide), but not metformin, were identified as significant inhibitors of the OATP1B1-mediated transport of rosuvastatin. The IC(50) values for inhibition of E(2)17β-G uptake were similar between OATP1B1 and OATP1B1*15. In conclusion, these studies indicate that several oral antidiabetic drugs affect the OATP1B1-mediated uptake of rosuvastatin in vitro. The next step will be to translate these data to the clinical situation, as it remains to be established whether the studied oral antidiabetics indeed affect the clinical pharmacokinetic profile of rosuvastatin in patients. 23597486 Anosognosia and depression in patients with Alzheimer's dementia. Anosognosia refers to impaired awareness of patients to realize deficits related to a disorder and is a common symptom of dementia. Anosognosia has far-reaching consequences for diagnosis and treatment and is probably associated with unfavorable prognosis. This study examined the relationship between anosognosia and depression in patients with Alzheimer's dementia (AD). Assessment included interviews of patients and their caregivers. Depressive symptoms were evaluated with observer and self-rating instruments: the Geriatric Depression Scale (GDS), and the "mood" subscale of the Nurses Observation Scale for geriatric patients (NOSGER). Anosognosia was evaluated with the Anosognosia Questionnaire for Dementia (AQ-D). For the evaluation of behavioral and neuropsychological symptoms in dementia and the caregiver burden, the neuropsychiatric inventory (NPI) and the Cares of older People in Europe (COPE) Index were administered. A total of 47 patients were enrolled in the study at the department's geriatric psychiatry outpatient clinic. A considerable discrepancy was found between observer- and self-ratings of depressive symptoms. In 74.5% of the participants, caregiver ratings indicated secondary symptoms of depression as opposed to patient ratings. Thus, in AD, anosognosia may affect not only deficits in cognition and everyday functioning but also affective symptoms ("affective anosognosia"). Caregiver rating therefore is particularly important when assessing mood changes in AD patients. 23935425 New sensors and techniques for the structural health monitoring of propulsion systems. The ability to monitor the structural health of the rotating components, especially in the hot sections of turbine engines, is of major interest to aero community in improving engine safety and reliability. The use of instrumentation for these applications remains very challenging. It requires sensors and techniques that are highly accurate, are able to operate in a high temperature environment, and can detect minute changes and hidden flaws before catastrophic events occur. The National Aeronautics and Space Administration (NASA), through the Aviation Safety Program (AVSP), has taken a lead role in the development of new sensor technologies and techniques for the in situ structural health monitoring of gas turbine engines. This paper presents a summary of key results and findings obtained from three different structural health monitoring approaches that have been investigated. This includes evaluating the performance of a novel microwave blade tip clearance sensor; a vibration based crack detection technique using an externally mounted capacitive blade tip clearance sensor; and lastly the results of using data driven anomaly detection algorithms for detecting cracks in a rotating disk. 23764374 Expression of IL-33 in the epidermis: The mechanism of induction by IL-17. Interleukin (IL)-33 is a dual functional, IL-1 family member cytokine, whose exact roles in inflammatory skin diseases are still unknown. IL-17A is a key cytokine in the pathogenesis of psoriasis. We investigated if IL-17A could induce IL-33 in epidermal keratinocytes, and the signaling mechanisms involved. IL-33 levels were evaluated by RT-PCR and western blot in human keratinocytes following IL-17A simulation. IL-33 immunohistochemical staining of psoriatic skin samples was also performed and compared with that of control tissues. The role of signaling pathways downstream of IL-17A was investigated using small molecule inhibitors of EGFR, ERK, p38, and JAK. Adenovirus vector expressing dominant negative STAT1 was also utilized. IL-33 and its receptor, ST2L, were expressed in the psoriatic epidermis, and the associated infiltrating cells. IL-17A induced IL-33 expression at mRNA and protein levels in a time- and concentration-dependent manner. IL-17A caused phosphorylation of EGFR, ERK, p38, and STAT1. IL-17A-induced IL-33 expression was blocked by the addition of EGFR, ERK, p38, and JAK inhibitors, and dominant negative STAT1-expressing adenovirus vector. IL-17A induced IL-33 in NHEKs through EGFR, ERK, p38, and JAK/STAT1 pathways, which were necessary for the induction of IL-33. IL-33, induced by IL-17A in epidermal keratinocytes, may be involved in the pathophysiology of inflammatory skin diseases, including psoriasis. 23897512 Fourier transform infrared imaging analysis in discrimination studies of bladder cancer. Bladder carcinoma represents more than 4% of all cancer diseases in Austria. The histomorphological evaluation is invasive and remains a subjective and time consuming technique. On account of this it is necessary to find novel non-invasive approaches which support the pathologists for histological recognition to identify malignancy at an early stage. In the present study, Fourier transform infrared (FTIR) microscopic imaging was combined with univariate and multivariate data analysis methods to study bladder carcinoma tissue sections in detail. The possibility to collect IR spectra of bladder carcinoma tissue sections employing an optimized analytical protocol is demonstrated. The correlation between FTIR microscopic imaging and the morphological tissue features obtained by histological staining of the sections demonstrated that many histomorphological tissue patterns can be visualized in the colour images. The routine generation of high quality imaging data is enabled because of the combination of FTIR technology and optimized sample preparation techniques. This opens a new quality of spectroscopic analyses of cancerous tissue, allowing exploration of molecular changes associated with the histopathological morphology. 23488569 Self-administration of hospital-based narrowband ultraviolet B (TL-01) phototherapy: a feasibility study in an outpatient setting. Self-administration of narrowband (TL-01) ultraviolet (UV)B phototherapy by patients at home is a safe and effective mode of treatment. Could selected patients self-administer phototherapy in hospital? To assess the feasibility of outpatient self-administration of UVB phototherapy as a potential service development. A total of 20 patients with psoriasis (n = 15) and eczema (n = 5) (13 female, mean age 32 years, range 17-56 years) were included in this pilot project. Patients underwent a training programme over 2 days, which included a minimal erythemal dose test and supervised treatment, prior to commencing self-administration of phototherapy. Questionnaires were used to gather feedback from patients and staff. Treatment data were collected for 18 of the 20 patients. The mean number of exposures was 25 (range 3-45), and the mean cumulative dose was 16 J cm(-2) (range 0·23-41·27 J cm(-2) ). No unexpected adverse effects were noted. These results were similar to those of a sample group of outpatients who had nurse-administered UVB phototherapy, for whom the mean number of exposures was 24 (range 4-49) and the mean cumulative dose was 17 J cm(-2) (range 0·53-71·16 J cm(-2) ). Thirteen patients completed the questionnaires. All concluded that the training programme sufficiently prepared them for self-administering phototherapy, and 12 reported that they would be happy to self-administer treatment in the future. Self-administration of UVB phototherapy is practicable, safe and effective for most selected patients. This mode of treatment provides training and support for patients to gain more control over management of their skin disease, empowering them to take an active role in their treatment. Self-administration of UVB phototherapy by outpatients provides an intermediate level of care between nurse-administered hospital phototherapy and self-administered home phototherapy. 23471538 Impact of oral mucositis on short-term clinical outcomes in paediatric and adolescent patients undergoing chemotherapy. The purpose of this study is to determine the burden of the peak severity of oral mucositis and severity over time on selected clinical outcomes in paediatric and adolescent patients receiving chemotherapy. A multicentre study enrolled 140 patients between the ages of 6 and 18 years, who had been treated with chemotherapy and completed the self-report Mouth and Throat Soreness-related questions of the Oral Mucositis Daily Questionnaire for 14 days. Clinical data were collected from patients' medical records during the first 14 days after starting chemotherapy. Forty-one percent developed oral mucositis. Multiple linear regression analysis revealed that oral mucositis was significantly associated with an increased loss of baseline body weight, after controlling for nausea/vomiting (β = 0.34, p = 0.002). Multiple logistic regression analysis showed that severe mucositis was significantly associated with a higher probability of fluid replacement, after controlling for nausea/vomiting (adjusted OR = 12.8; 95 % CI = 2.7-61.0; p = 0.001). In addition, severe mucositis was significantly associated with a higher probability of fever, after controlling for neutropoenia (adjusted OR = 5.4; 95 % CI = 1.8-15.4; p = 0.002). No difference was observed for oral or systemic infections among the subgroups. About 5 % of the patients with oral mucositis had delays in chemotherapy (≤ 7 days). None of the patients had dose modification or unplanned hospitalization due to oral mucositis. The associations of peak severity and overall oral mucositis with adverse clinical outcomes in paediatric and adolescent patients were equivalent. Oral mucositis is associated with negative effects on clinical outcomes. 23498139 Frontal Lobe γ-Aminobutyric Acid Levels During Adolescence: Associations with Impulsivity and Response Inhibition. The brain undergoes major remodeling during adolescence, resulting in improved cognitive control and decision-making and reduced impulsivity, components of behavior mediated in part by the maturing frontal lobe. γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter system, also matures during adolescence, with frontal lobe GABA receptors reaching adult levels late in adolescence. Thus, the objective of this study was to characterize in vivo developmental differences in brain GABA levels. Proton magnetic resonance spectroscopy was used at 4 T to acquire metabolite data from the anterior cingulate cortex (ACC) and the parieto-occipital cortex (POC) in adolescents (n=30) and emerging adults (n = 20). ACC GABA/creatine (Cr) levels were significantly lower in adolescents relative to emerging adults, whereas no age differences were observed in the POC. Lower ACC GABA/Cr levels were significantly associated with greater impulsivity and worse response inhibition, with relationships being most pronounced for ACC GABA/Cr and No-Go response inhibition in adolescent males. These data provide the first human developmental in vivo evidence confirming frontal lobe GABA maturation, which was linked to impulsiveness and cognitive control. These findings suggest that reduced GABA may be an important neurobiological mechanism in the immature adolescent brain, contributing to the reduced yet rapidly developing ability to inhibit risky behaviors and to make suboptimal decisions, which could compromise adolescent health and safety. 23950927 Estuaries as filters: the role of tidal marshes in trace metal removal. Flux calculations demonstrate that many estuaries are natural filters for trace metals. Yet, the underlying processes are poorly investigated. In the present study, it was hypothesized that intertidal marshes contribute significantly to the contaminant filter function of estuaries. Trace metal concentrations and sediment characteristics were measured along a transect from the subtidal, over an intertidal flat and marsh to a restored marsh with controlled reduced tide. Metal concentrations in the intertidal and restored marsh were found to be a factor two to five higher than values in the subtidal and intertidal flat sediments. High metal concentrations and high accretion rates indicate a high metal accumulation capacity of the intertidal marshes. Overbank sedimentation in the tidal marshes of the entire estuary was calculated to remove 25% to 50% of the riverine metal influx, even though marshes comprise less than 8% of the total surface of the estuary. In addition, the large-scale implementation of planned tidal marsh restoration projects was estimated to almost double the trace metal storage capacity of the present natural tidal marshes in the estuary. 23925707 Variability of the preC/C region of hepatitis B virus genotype A from a South African cohort predominantly infected with HIV. Hepatitis B virus (HBV) is a serious global health problem, and HBV genotype is an important determinant of disease progression and treatment outcome. The aim of this study was to assess variations of the precore/core (preC/C) region in HBV genotype A. Sequencing of the preC/C and surface (S) genes of HBV was performed on plasma samples from 20 HBV/HIV co-infected and 5 HBV mono-infected individuals. All preC/C study sequences clustered with subgenotype A1, except for two which clustered with subgenotype D4 reference strains. The nucleotide and amino acid variability was far higher in the preC/C region than in the S region. Mutations associated with reduction or failure of HBV e-antigen (HBeAg) production were observed, with a preC start codon mutation being common (24%). Other mutations (e.g., P5H/L and I97L) associated with severe liver disease were also noticed, some of which were located in the major histocompatibility restricted sites. PreC/C intergenotype nucleotide divergence was >7%, while subgenotypes differed by 2.5-7%. Several study sequences were highly divergent from other African subgenotype A1 strains. This study showed that HBeAg-negative chronic hepatitis B is underestimated in subgenotype A1, and also highlighted the variant South African A1 strains. The major advantage of preC/C sequencing is that it informs patient management as HBeAg-negative chronic hepatitis B responds poorly to conventional interferon-α therapy, and some guidelines treat HBeAg-negative chronic hepatitis B differently from HBeAg-positive chronic hepatitis B. These data suggest that subgenotype A1 may be more involved in severe HBV-related diseases. J Med. Virol. 85:1883-1892, 2013. © 2013 Wiley Periodicals, Inc. 23414253 Randomized clinical trial examining the incremental efficacy of a 90-minute motivational alcohol intervention as an adjunct to standard batterer intervention for men. The efficacy of batterer intervention programs to reduce intimate partner violence (IPV) is questionable, with individuals with alcohol problems particularly unlikely to benefit. We examined whether adding adjunctive alcohol intervention to batterer intervention reduced the likelihood of substance use and violence relative to batterer intervention alone. Randomized clinical trial. Batterer intervention programs in Rhode Island, USA. A total of 252 hazardous drinking men in batterer intervention programs. Participants were randomized to receive 40 hours of standard batterer program (SBP) or the SBP plus a 90-minute alcohol intervention (SBP + BAI). None withdrew due to adverse effects. Data were collected at baseline, 3-, 6- and 12-month follow-up, with follow-up rates of 95, 89 and 82%, respectively. Substance use was measured with a well-validated calendar-assisted interview. Violence was measured with a validated questionnaire. Arrest records were obtained for all participants. The primary substance use outcome was drinks per drinking day (DPDD) and the primary violence outcome was frequency of any physical IPV. Relative to SBP alone, men receiving SBP + BAI reported consuming fewer DPDD at 3-month follow-up [B = -1.36, 95% confidence interval (CI): -2.65, -0.04, P = 0.04] but not 6- or 12-month follow-up. In secondary analyses, men receiving SBP + BAI reported significantly greater abstinence at 3- (B = 0.09, 95% CI: 0.03, 0.14, P = 0.002) and 6-month (B = 0.06, 95% CI: 0.01, 0.11, P = 0.01) follow-up but not 12-month follow-up. There were no significant differences in physical IPV between men receiving SBP and men receiving SBP + BAI. In secondary analyses, men receiving SBP + BAI reported less severe physical aggression at 3-month (IRR = 0.18, 95% CI: 0.05, 0.65, P = 0.009) but not 6- or 12-month follow-up. Men receiving SBP + BAI reported less severe psychological aggression (B = -1.24, 95% CI: -2.47, -0.02, P = 0.04) and fewer injuries to partners at 3- and 6-month follow-up (IRR = 0.33, 95% CI: 0.12, 0.92, P = 0.03), with differences fading by 12 months. Men with a history of intimate partner violence and hazardous drinking who received a batterer intervention plus an alcohol intervention showed improved alcohol and violence outcomes initially, but improvements faded by 12 months. 23933071 Phylogeography of Beck's Desert Scorpion, Paruroctonus becki, reveals Pliocene diversification in the Eastern California Shear Zone and postglacial expansion in the Great Basin Desert. The distribution of Beck's Desert Scorpion, Paruroctonus becki (Gertsch and Allred, 1965), spans the 'warm' Mojave Desert and the western portion of the 'cold' Great Basin Desert. We used genetic analyses and species distribution modeling to test whether P. becki persisted in the Great Basin Desert during the Last Glacial Maximum (LGM), or colonized the area as glacial conditions retreated and the climate warmed. Phylogenetic and network analyses of mitochondrial cytochrome c oxidase 1 (cox1), 16S rDNA, and nuclear internal transcribed spacer (ITS-2) DNA sequences uncovered five geographically-structured groups in P. becki with varying degrees of statistical support. Molecular clock estimates and the geographical arrangement of three of the groups suggested that Pliocene geological events in the tectonically dynamic Eastern California Shear Zone may have driven diversification by vicariance. Diversification was estimated to have continued through the Pleistocene, during which a group endemic to the western Great Basin diverged from a related group in the eastern Mojave Desert and western Colorado Plateau. Demographic and network analyses suggested that P. becki underwent a recent expansion in the Great Basin. According to a landscape interpolation of genetic distances, this expansion appears to have occurred from the northwest, implying that P. becki may have persisted in part of the Great Basin during the LGM. This prediction is supported by species distribution models which suggest that climate was unsuitable throughout most of the Great Basin during the LGM, but that small patches of suitable climate may have remained in areas of the Lahontan Trough. 23664899 Anxiolytic effects of the GABA(A) receptor partial agonist, L-838,417: impact of age, test context familiarity, and stress. The partial α2,3,5 GABA(A) receptor agonist, L-838,417 has been reported to have anxiolytic effects in adult rodents. Although maturational differences exist for the GABA(A) receptor subunits, the anxiolytic effects of L-838,417 have not been tested in younger animals. The goal of the present experiments was to determine whether L-838,417 reverses anxiety-like behavior induced by either an unfamiliar environment (Experiment 1) or repeated restraint stress (Experiment 2) differentially in adolescent and adult, male and female Sprague-Dawley rats using a modified social interaction test. In Experiment 1, rats were injected with 0, 0.5, 1.0, 2.0, or 4.0 mg/kg L-838,417, i.p. and tested 30 min later in an unfamiliar test context for 10 min. In Experiment 2, rats were exposed to restraint stress (90 min daily for 5 days). Immediately after the last restraint session, animals were injected with L-838,417 and placed alone for 30 min in the test apparatus to familiarize them to this context prior to the 10 min social interaction test. In Experiment 1, L-838,417 produced anxiolytic effects in adults at 1.0 mg/kg, as indexed by a transformation of social avoidance into preference and an increase in social investigation. In adolescents, a dose of 2.0 mg/kg eliminated social avoidance, but had no anxiolytic effects on social investigation. Testing under familiar circumstances (Experiment 2) after repeated restraint stress eliminated age differences in sensitivity to L-838,417, with 0.5 mg/kg reversing the anxiogenic effects of prior stress regardless of age, but with doses ≥ 1 mg/kg decreasing social investigation, an effect possibly due in part to locomotor-impairing effects of this compound. Although locomotor activity was suppressed in both experiments, higher doses of L-838,417 were necessary to suppress locomotor activity in Experiment 1. Thus, anxiolytic effects of L-838,417 were found to be context-, age-, and stress-dependent. 23591043 Pregnancy outcome in women exposed to antiepileptic drugs: teratogenic role of maternal epilepsy and its pharmacologic treatment. Infants born to epileptic women treated with Antiepileptic Drugs (AEDs) have an increased risk of major congenital malformations (MCMs). In order to determine the role of maternal epilepsy we conducted a prospective cohort study on three cohorts of pregnant women: i) 385 epileptic women treated with AEDs, ii) 310 non-epileptic women treated with AEDs, iii) 867 healthy women not exposed to AEDs (control group). The rate of MCMs in the epileptic group (7.7%) was not statistically higher than in the non-epileptic one (3.9%) (p=0.068). The rate in the first group was higher compared to the control group (p=0.001), while the rate in the second one was not (p=0.534). Our data confirm that AEDs therapy is the main cause of the increased risk of malformations in the offspring of epileptic women; however a teratogenic role of the maternal epilepsy itself cannot be excluded. 23425332 Self-assembly of morphology-tunable architectures from tetraarylmethane derivatives for targeted drug delivery. Tetraarylmethane compounds consisting of two pyrogallol and two aniline units, namely, Ar2CAr'2 {Ar = 3,4,5-C6H2(OH)3 and Ar' = 3,5-R2-4-C6H2NH2 [R = Me (1), iPr (2)]} exhibit excellent self-assembly behavior. Compound 1 yields size-tunable hollow nanospheres (HNSs) with a narrow size distribution, and 2 yields various morphologies ranging from microtubules to microrods via self-assembly induced by hydrogen bonding and π-π stacking interactions. On the basis of the experimental results, a plausible mechanism for morphology tunability was proposed. As a means of utilizing the self-assembled HNSs for targeting controlled drug delivery, folic acid (FA) and rhodamine 6G (Rh6G) were grafted onto compound 1 to yield the FA-Rh6G-1 complex. The HNSs fabricated with FA-Rh6G-1 showed low cytotoxicity against human embryonic kidney 293T cells and CT26 colon carcinoma cells and good doxorubicin (DOX) loading capacity (9.6 wt %). The FA receptor-mediated endocytosis of FA-Rh6G-1 HNSs examined by using a confocal laser scanning microscope and a flow cytometer revealed that the uptake of FA-Rh6G-1 HNSs into CT26 cells was induced by FA receptor-mediated endocytosis. In vitro drug delivery tests showed that the DOX molecules were released from the resulting HNSs in a sustainable and pH-dependent manner, demonstrating a potential application for HNSs in targeted drug delivery for cancer therapy. 23868422 Vitamin D Insufficiency in Patients With THA: Prevalence and Effects on Outcome. The consequences of vitamin D insufficiency in the elderly remain controversial. The prevalence and potential effects of its chronic insufficiency on quality of life and physical function in patients undergoing THA have received little attention. We determined (1) prevalence of preoperative vitamin D insufficiency in patients undergoing THA and (2) relationships of insufficiency to patient-perceived outcomes (PPOs) and hip scores. We retrospectively reviewed 62 consecutive patients who underwent 66 primary THAs. We excluded two patients with missing data and the second hip of bilateral THAs, leaving 60 patients (60 hips) for final inclusion. Based on preoperative plasma 25-hydroxyvitamin-D3 levels, patients were retrospectively assigned into a normal or insufficient group. We used two different thresholds (20 and 30 ng/mL) to define insufficiency; groups were set twice. We compared demographics, BMI, American Society of Anesthesiologists score, Charlson Comorbidity Index; albumin, transferrin, calcium levels; and total lymphocyte count between groups. The insufficient group had a higher mean BMI with the 20-ng/mL cutoff but not with the 30-ng/mL cutoff. We compared the 20-ng/mL cutoff groups (adjusting for BMI) and the 30-ng/mL cutoff groups in terms of preoperative and postoperative Quality of Well-being Scale, SF-36, WOMAC, Harris hip, and Merle d'Aubigné-Postel scores. Mean followup was 11 months (range, 3-24 months). The prevalence of vitamin D insufficiency was 30% (using 20 ng/mL) and 65% (using 30 ng/mL). Preoperative and postoperative Harris hip and Merle d'Aubigné-Postel scores were lower in patients with insufficiency using 30 ng/mL. No differences in PPOs or hip scores were found using 20 ng/mL. Hypovitaminosis D was common in patients with THA and associated with lower hip scores. Standardization of the definition of hypovitaminosis D is urgently needed so that further studies can properly evaluate its real prevalence, potential negative effects on function, and therapeutic effects of reversing insufficiency before THA. Level III, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence. 23523617 Risk of gestational trophoblastic neoplasia after hCG normalisation according to hydatidiform mole type. The risk of gestational trophoblastic neoplasia (GTN) after a hydatidiform mole (HM) is well known. However, the risk of GTN after normalisation of hCG in HM is poorly reported. The aim of this study was to evaluate the risk of GTN after normalisation of hCG according to HM types. This prospective cohort study carried out between 2000 and 2010 used the database of the French Trophoblastic Disease Centre (FTDC). A total of 2008 registered patients with ascertained types of HM were analysed. Cases of GTN occurring after normalisation of hCG were analysed. A GTN developed in 239 out of 1980 HMs (12.1%) and 6 out of these 239 post-molar GTN (2.5%) were diagnosed after normalisation of hCG. The risk of GTN after normalisation of hCG was 0.34% (6/1747) following a HM, 0% (0/593) after a partial HM (PHM), 0.36% (4/1122) after a complete HM (CHM), and 9.5% (2/21) after a multiple pregnancy with HM. The risk of post-molar GTN justifies hCG monitoring in all women with HM. However, after normalisation of hCG, monitoring of PHM can be stopped safely while it should be maintained for CHM and more importantly for multiple pregnancies with HM. 23104997 'Permission to participate?' A qualitative study of participation in patients from differing socio-economic backgrounds. Participation in health care is an important element of self-management in chronic illness, and policy emphasises patient's choice. Evidence suggests that this may be inequitable and inadequate, since active participation is strongly associated with socio-demographic variables. This qualitative study explores the perceptions of participation in people with differing socio-economic status with themes related to health literacy and relationship with health-care professionals. Patients perceive participation in different ways, related to their prior expectations of a health-care consultation, cultural expectations and social position. Policies aimed at simply improving 'health literacy' and choice will not be successful if these broader disparities are not addressed. 23568561 Low radiation dose protocol in cardiac CT with 100 kVp: usefulness of display preset optimization. To evaluate the radiation dose and image quality of 100 kVp cardiac CT, and the effects of display setting optimization. We randomly assigned 100 patients undergoing cardiac CT to one of following two protocols. Fifty patients underwent our conventional protocol with 120 kVp, and the other 50 patients underwent our low radiation dose protocol with 100 kVp. We compared effective dose (ED); CT number, image noise, and contrast noise ratio (CNR) of ascending aorta at 120 and 100 kVp protocol. We also performed quantitative analysis and qualitative analysis for bitmap image of 120, 100 kVp, and display preset optimization for 100 kVp images. The estimated ED was 48 % lower with the 100 kVp protocol than the 120 kVp protocol (2.8 vs. 5.5 mSv, p < 0.01). There is no significant difference in the CNR between 100 and 120 kVp protocol (18.5 ± 3.6 vs. 18.6 ± 3.8, p = 0.84). Display preset optimization significantly improved image quality of 100 kVp cardiac CT, and there is no significant difference in qualitative analysis and quantitative analysis between 100 kVp scan with optimized display preset and 120 kVp scan (p > 0.05). The 100 kVp scanning with optimized display preset offers almost same image quality at cardiac CT of thin adults under 48 % decreased radiation dose. 23339967 Characterization of a key aminoglycoside phosphotransferase in gentamicin biosynthesis. Gentamicin is an aminoglycoside antibiotic obtained from cultures of Micromonospora as the important anti-infective agents. Gentamicin which lacks 3'-hydroxyl group can avoid the attack from the modification enzymes of antibiotic-resistant bacteria in clinic. Consequently, C-3' dehydroxylation is the key step in gentamicins biosynthesis. We suppose that there are some enzymes responsible for converting intermediate JI-20A to 3',4'-bisdehydroxylated final product gentamicin C(1a), while phosphorylation of 3'-OH is possibly the first step for C-3' dehydroxylation. The gentamicin biosynthetic gene gntI, encoding an aminoglycoside phosphotransferase, was cloned from Micromonospora echinospora ATCC15835 and overexpressed in Escherichia coli. The resulting phosphotransferase was purified, and the kinetic parameters for Kanamycin A, Kanamycin B, Neomycin B and Amikacin were determined. Elucidation of NMR data of phosphorylated kanamycin B has unambiguously demonstrated a regiospecific phosphorylation of 3'-hydroxyl of the 6-aminohexose ring. The results described here partly confirm that the 3'-dehydroxylation step is preceded by a 3' phosphorylation step. It is predicted that GntI belongs to a new aminoglycoside phosphotransferase group involved with aminoglycoside antibiotics biosynthesis pathway. 23425071 Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers. TNFs are major mediators of inflammation and inflammation-related diseases, hence, the United States Food and Drug Administration (FDA) has approved the use of blockers of the cytokine, TNF-α, for the treatment of osteoarthritis, inflammatory bowel disease, psoriasis and ankylosis. These drugs include the chimeric TNF antibody (infliximab), humanized TNF-α antibody (Humira) and soluble TNF receptor-II (Enbrel) and are associated with a total cumulative market value of more than $20 billion a year. As well as being expensive ($15 000-20 000 per person per year), these drugs have to be injected and have enough adverse effects to be given a black label warning by the FDA. In the current report, we describe an alternative, curcumin (diferuloylmethane), a component of turmeric (Curcuma longa) that is very inexpensive, orally bioavailable and highly safe in humans, yet can block TNF-α action and production in in vitro models, in animal models and in humans. In addition, we provide evidence for curcumin's activities against all of the diseases for which TNF blockers are currently being used. Mechanisms by which curcumin inhibits the production and the cell signalling pathways activated by this cytokine are also discussed. With health-care costs and safety being major issues today, this golden spice may help provide the solution. This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8. 23311604 In vivo effects of two acidic soft drinks on shear bond strength of metal orthodontic brackets with and without resin infiltration treatment. To evaluate the in vivo effects of two acidic soft drinks (Coca-Cola and Sprite) on the shear bond strength of metal orthodontic brackets with and without resin infiltration treatment. In addition, the enamel surface was evaluated, after debonding, using a scanning electron microscope. Sixty noncarious maxillary premolars, scheduled for extraction in 30 orthodontic patients, were used. Patients were randomly divided into two groups according to the soft drink tested (Coca-Cola or Sprite). In each group, application of resin infiltration (Icon. DMG, Hamburg, Germany) was done on one side only before bonding of brackets. Patients were told to rinse their mouth with their respective soft drink at room temperature for 5 minutes, three times a day for 3 months. Shear bond strength was tested with a universal testing machine. After shearing test, a scanning electron microscope was used to evaluate enamel erosion. Statistical analysis was performed by twoway analysis of variance followed by the least significant difference test. The Coca-Cola group without resin infiltration showed the lowest resistance to shearing forces. Scanning electron micrographs of both groups after resin application showed a significant improvement compared with results without resin use, as the enamel appeared smoother and less erosive. Pretreatment with the infiltrating resin has proved to result in a significant improvement in shear bond strength, regardless of the type of soft drink consumed. 23811179 Effects of dilution on the properties of nC60. C60 forms colloidally stable nanoparticles (nC60) via extended mixing or solvent exchange. Many studies on the environmental impacts of nC60 use aliquots from a large batch of nC60 suspension and either dilute them or subject them to other modifications under the assumption that the properties of the parent suspension remain stable over time and are unaltered by these manipulations. In the present study, nC60 produced via stirring in the presence of sodium citrate (cit/nC60) was characterized with respect to particle size, surface charge, and morphology following dilution. Counter-intuitively, the results show that the colloidal properties of diluted cit/nC60 are not fixed despite constant solution chemistry and are dependent upon the ratios of [C60] to [Na(+)] and [citrate]. In some cases, diluted nC60 had significantly different morphology. This study suggests that any experiment involving modifications of stock nC60 suspensions must take the altered colloidal properties of the diluted nC60 into consideration. 23743210 On the impartiality of early British clinical trials. Did the impartiality of clinical trials play any role in their acceptance as regulatory standards for the safety and efficacy of drugs? According to the standard account of early British trials in the 1930s and 1940s, their impartiality was just rhetorical: the public demanded fair tests and statistical devices such as randomization created an appearance of neutrality. In fact, the design of the experiment was difficult to understand and the British authorities took advantage of it to promote their own particular interests. I claim that this account is based on a poorly defined concept of experimental fairness (derived from T. Porter's ideas). I present an alternative approach in which a test would be impartial if it incorporates warrants of non-manipulability. With this concept, I reconstruct the history of British trials showing that they were indeed fair and this fairness played a role in their acceptance as regulatory yardsticks. 22987825 Addressing the challenges of improving primary care quality in Uzbekistan: a qualitative study of Chronic Heart Failure management. Uzbekistan has a well-developed primary care system, with universal access to care, but faces challenges in improving the quality of clinical care provided. This study aimed to identify barriers to quality improvement by focusing on one common condition, Chronic Heart Failure (CHF), for which there are evidence-based international guidelines for management. To identify the challenges to improving the quality of care for CHF in line with such guidelines we took a qualitative approach, interviewing 15 physicians and 30 patients in detail about their experiences of CHF management. Despite recent improvements to the training of primary care physicians, their access to up-to-date information was limited, and they were disproportionately reliant on information from pharmaceutical companies. The main barriers to implementing international standards of care were: reluctance of physicians (and patients) to abandon ineffective interventions; enduring, system-wide incentives for clinically unnecessary hospitalization; and the lack of structural support for evidence-based health services improvement. Patients were in general positive about adherence to medications, but faced some problems in affording drugs and hospital care. Future interventions to strengthen primary care should be implemented with evaluations of their impact on the processes and outcomes of care for chronic conditions. 23601455 Acrophialophora fusispora brain abscess in a patient with acquired immunodeficiency syndrome: a case report and review of the literature. We reported a fatal case of brain abscess caused by Acrophialophora fusispora in a patient with acquired immunodeficiency syndrome. Identification of the fungus was based on microscopic morphology and sequence analyses of the internal transcribed spacer 1 (ITS1) and 2 (ITS2) of ribosomal RNA gene from the isolate recovered from brain abscess. Four published cases were reviewed as well. 23317031 Growth of Pt nanowires by atomic layer deposition on highly ordered pyrolytic graphite. The formation of Pt nanowires (NWs) by atomic layer deposition on highly ordered pyrolytic graphite (HOPG) is investigated. Pt is deposited only at the step edges of HOPG and not on the basal planes, leading to the formation of laterally aligned Pt NWs. A growth model involving a morphological transition from 0-D to 1-D structures via coalescence is presented. The width of the NWs grows at a rate greater than twice the vertical growth rate. This asymmetry is ascribed to the wetting properties of Pt on HOPG as influenced by the formation of graphene oxide. A difference in Pt growth kinetics based on crystallographic orientation may also contribute. 23648697 No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Patients with non-celiac gluten sensitivity (NCGS) do not have celiac disease but their symptoms improve when they are placed on gluten-free diets. We investigated the specific effects of gluten after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates (fermentable, oligo-, di-, monosaccharides, and polyols [FODMAPs]) in subjects believed to have NCGS. We performed a double-blind cross-over trial of 37 subjects (aged 24-61 y, 6 men) with NCGS and irritable bowel syndrome (based on Rome III criteria), but not celiac disease. Participants were randomly assigned to groups given a 2-week diet of reduced FODMAPs, and were then placed on high-gluten (16 g gluten/d), low-gluten (2 g gluten/d and 14 g whey protein/d), or control (16 g whey protein/d) diets for 1 week, followed by a washout period of at least 2 weeks. We assessed serum and fecal markers of intestinal inflammation/injury and immune activation, and indices of fatigue. Twenty-two participants then crossed over to groups given gluten (16 g/d), whey (16 g/d), or control (no additional protein) diets for 3 days. Symptoms were evaluated by visual analogue scales. In all participants, gastrointestinal symptoms consistently and significantly improved during reduced FODMAP intake, but significantly worsened to a similar degree when their diets included gluten or whey protein. Gluten-specific effects were observed in only 8% of participants. There were no diet-specific changes in any biomarker. During the 3-day rechallenge, participants' symptoms increased by similar levels among groups. Gluten-specific gastrointestinal effects were not reproduced. An order effect was observed. In a placebo-controlled, cross-over rechallenge study, we found no evidence of specific or dose-dependent effects of gluten in patients with NCGS placed diets low in FODMAPs. www.anzctr.org.au. ACTRN12610000524099. 23333568 Hibernating squirrel muscle activates the endurance exercise pathway despite prolonged immobilization. Skeletal muscle atrophy is a very common clinical challenge in many disuse conditions. Maintenance of muscle mass is crucial to combat debilitating functional consequences evoked from these clinical conditions. In contrast, hibernation represents a physiological state in which there is natural protection against disuse atrophy despite prolonged periods of immobilization and lack of nutrient intake. Even though peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1-α (PGC-1α) is a central mediator in muscle remodeling pathways, its role in the preservation of skeletal muscle mass during hibernation remains unclear. Since PGC-1α regulates muscle fiber type formation and mitochondrial biogenesis, we analyzed muscles of 13-lined ground squirrels. We find that animals in torpor exhibit a shift to slow-twitch Type I muscle fibers. This switch is accompanied by activation of the PGC-1α-mediated endurance exercise pathway. In addition, we observe increased antioxidant capacity without evidence of oxidative stress, a marked decline in apoptotic susceptibility, and enhanced mitochondrial abundance and metabolism. These results show that activation of the endurance exercise pathway can be achieved in vivo despite prolonged periods of immobilization, and therefore might be an important mechanism for skeletal muscle preservation during hibernation. This PGC-1α regulated pathway may be a potential therapeutic target promoting skeletal muscle homeostasis and oxidative balance to prevent muscle loss in a variety of inherited and acquired neuromuscular disease conditions. 23705905 Current treatments for renal failure due to multiple myeloma. Introduction: Renal impairment (RI) is a common complication of symptomatic myeloma; 20 - 40% of newly diagnosed patients present with moderate or severe RI and 10% of them may require dialysis. Immediate initiation of specific antimyeloma therapy is crucial in order to improve RI. Areas covered: There has been a significant improvement in the outcome of patients with RI over the past 15 years. The authors review current data on the role of antimyeloma therapy on the improvement or resolution of RI and the importance of novel regimens, especially those based on bortezomib. IMiDs-based regimens, conventional chemotherapy and high-dose therapy is also reviewed. The role of extrarenal free light chain removal, by means of plasma exchange or extended hemodialysis with the use of high cutoff dialysis membranes, is also discussed. Expert opinion: Bortezomib/dexamethasone-based regimens are the preferred regimens for most patients with multiple myeloma (MM) who present with RI, especially for newly diagnosed patients; however, other novel agents (thalidomide, lenalidomide) in combination with dexamethasone may also improve RI in several patients. Further investigation is needed for the clarification of the role of plasma exchange or extended high cutoff dialysis. Carfilzomib, which was recently approved, may also be a treatment choice for selected patients with relapsed MM and RI. 23720050 Mapping the stability diagram of a quadrupole mass spectrometer with a static transverse magnetic field applied. Previous experimental and theoretical work identified that the application of a static magnetic (B) field can improve the resolution of a quadrupole mass spectrometer (QMS) and this simple method of performance enhancement offers advantages for field deployment. Presented here are further data showing the effect of the transverse magnetic field upon the QMS performance. For the first time, the asymmetry in QMS operation with B x and B y is considered and explained in terms of operation in the fourth quadrant of the stability diagram. The results may be explained by considering the additional Lorentz force (v x B) experienced by the ion trajectories in each case. Using our numerical approach, we model not only the individual ion trajectories for a transverse B field applied in x and y but also the mass spectra and the effect of the magnetic field upon the stability diagram. Our theoretical findings, confirmed by experiment, show an improvement in resolution and ion transmission by application of magnetic field for certain operating conditions. 23900296 Visible-light photocatalytic degradation performances and thermal stability due to the synergetic effect of TiO2 with conductive copolymers of polyaniline and polypyrrole. Conductive polypyrrole-polyaniline/TiO2 nanocomposites (PPy-PANI/TiO2) were prepared by in situ oxidative copolymerization of pyrrole and aniline monomers in the presence of TiO2. For comparison studies, polypyrrole/TiO2 (PPy/TiO2) and polyaniline/TiO2 (PANI/TiO2) were also prepared. The samples were characterized by X-ray diffraction, transmission electron microscopy, UV-vis diffuse reflectance spectroscopy, zeta potential analysis, Fourier transform infrared spectroscopy, thermogravimetric analysis and photocurrent tests. In contrast to PPy/TiO2 and PANI/TiO2, PPy-PANI/TiO2 exhibits obvious absorption in the visible-light range, and is much superior to PPy/TiO2 and PANI/TiO2 in thermal stability. It is found that PPy-PANI/TiO2 performs well in the visible-light photocatalytic degradation of 4-nitrophenol. The optimized pyrrole : aniline : TiO2 molar ratio for best performance is 0.75 : 0.25 : 100. The efficacy of PPy-PANI/TiO2 is attributed to its conductivity, conjugated structure, as well as to the synergy amidst polypyrrole, polyaniline and TiO2. 23857798 In healthy adults, biological activity of vitamin D, as assessed by serum PTH, is largely independent of DBP concentrations. Vitamin D insufficiency, as measured by 25-hydroxyvitamin D (25[OH]D) levels, has been associated with important health outcomes. The majority of vitamin D in circulation is bound to vitamin D-binding protein (DBP) and albumin, and recent genetic studies have demonstrated that serum DBP is a major determinant of 25(OH)D concentrations in adults. The impact of circulating DBP levels on vitamin D's biologic action, is unclear, but is of particular relevance to vitamin D epidemiology, since a lack of control for DBP levels could strongly influence the association of vitamin D with disease. Serum parathyroid hormone (PTH) levels can act as a biological readout of 25(OH)D activity. We therefore assessed the relationship between serum total and free 25(OH)D and PTH with and without adjusting for DBP, in 2,073 subjects of European descent. Total 25(OH)D levels correlated positively (r = 0.19, P = 1.8 × 10(-17) ) with DBP, whereas the free 25(OH)D correlated negatively (r = - 0.14, P = 5.0 × 10(-12) ). Total and free 25(OH)D levels correlated negatively with PTH (r = - 0.29, P= 1.3 × 10(-39) ; r = - 0.26, P= 1.9 × 10(-33) , respectively). Including age, BMI, sex, estimated glomerular filtration rate, calcium and season of blood draw as covariates, total 25(OH)D levels were significantly associated with lnPTH levels (linear term: β= -0.010, P <0.0001, squared term: β= 0.00004, P <0.0001) and this association was not changed by adjusting for DBP. These findings provide evidence that in a largely vitamin D-sufficient cohort, the biological effect of vitamin D on PTH levels is mainly independent of DBP concentration. Accordingly, this study may provide useful information for studies investigating the relationship between vitamin D, DBP and disease. 23851991 Genome-wide association analyses for growth and feed efficiency traits in beef cattle. A genome-wide association study using the Illumina 50K BeadChip included 38,745 SNP on 29 BTA analyzed on 751 animals, including 33 purebreds and 718 crossbred cattle. Genotypes and 6 production traits: birth weight (BWT), weaning weight (WWT), ADG, DMI, midtest metabolic BW (MMWT), and residual feed intake (RFI), were used to estimate effects of individual SNP on the traits. At the genome-wide level false discovery rate (FDR < 10%), 41 and 5 SNP were found significantly associated with BWT and WWT, respectively. Thirty-three of them were located on BTA6. At a less stringent significance level (P < 0.001), 277 and 27 SNP were in association with single traits and multiple traits, respectively. Seventy-three SNP on BTA6 and were mostly associated with BW-related traits, and heavily located around 30 to 50Mb. Markers that significantly affected multiple traits appeared to impact them in same direction. In terms of the size of SNP effect, the significant SNP (P < 0.001) explained between 0.26 and 8.06% of the phenotypic variation in the traits. Pairs of traits with low genetic correlation, such as ADG vs. RFI or DMI vs. BWT, appeared to be controlled by 2 groups of SNP; 1 of them affected the traits in same direction, the other worked in opposite direction. This study provides useful information to further assist the identification of chromosome regions and subsequently genes affecting growth and feed efficiency traits in beef cattle. 23851074 Crystal structure of the ligand-binding form of nanoRNase from Bacteroides fragilis, a member of the DHH/DHHA1 phosphoesterase family of proteins. NanoRNase (Nrn) specifically degrades nucleoside 3',5'-bisphosphate and the very short RNA, nanoRNA, during the final step of mRNA degradation. The crystal structure of Nrn in complex with a reaction product GMP was determined. The overall structure consists of two domains that are interconnected by a flexible loop and form a cleft. Two Mn(2+) ions are coordinated by conserved residues in the DHH motif of the N-terminal domain. GMP binds near the DHHA1 motif region in the C-terminal domain. Our structure enables us to predict the substrate-bound form of Nrn as well as other DHH/DHHA1 phosphoesterase family proteins. 23358193 Brain hemispheric differences in the neurochemical effects of lead, prenatal stress, and the combination and their amelioration by behavioral experience. Brain lateralization, critical to mediation of cognitive functions and to "multitasking," is disrupted in conditions such as attention deficit disorder and schizophrenia. Both low-level lead (Pb) exposure and prenatal stress (PS) have been associated with mesocorticolimbic system-mediated executive-function cognitive and attention deficits. Mesocorticolimbic systems demonstrate significant laterality. Thus, altered brain lateralization could play a role in this behavioral toxicity. This study examined laterality of mesocorticolimbic monoamines (frontal cortex, nucleus accumbens, striatum, midbrain) and amino acids (frontal cortex) in male and female rats subjected to lifetime Pb exposure (0 or 50 ppm in drinking water), PS (restraint stress on gestational days 16-17), or the combination with and without repeated learning behavioral experience. Control males exhibited prominent laterality, particularly in midbrain and also in frontal cortex and striatum; females exhibited less laterality, and this was primarily striatal. Lateralized Pb ± PS induced neurotransmitter changes were assessed only in males because of limited sample sizes of Pb + PS females. In males, Pb ± PS changes occurred in left hemisphere of frontal cortex and right hemisphere of midbrain. Behavioral experience modified the laterality of Pb ± PS-induced neurotransmitter changes in a region-dependent manner. Notably, behavioral experience eliminated Pb ± PS neurotransmitter changes in males. These findings underscore the critical need to evaluate both sexes and brain hemispheres for the mechanistic understanding of sex-dependent differences in neuro- and behavioral toxicity. Furthermore, assessment of central nervous system mechanisms in the absence of behavioral experience, shown here for males, may constitute less relevant models of human health effects. 23638885 Short-chain Fatty Acid-modified hexosamine for tissue-engineering osteoarthritic cartilage. Inflammation and tissue degeneration play key roles in numerous rheumatic diseases, including osteoarthritis (OA). Efforts to reduce and effectively repair articular cartilage damage in an osteoarthritic environment are limited in their success due to the diseased environment. Treatment strategies focused on both reducing inflammation and increasing tissue production are necessary to effectively treat OA from a tissue-engineering perspective. In this work, we investigated the anti-inflammatory and tissue production capacity of a small molecule 3,4,6-O-tributanoylated-N-acetylglucosamine (3,4,6-O-Bu3GlcNAc) previously shown to inhibit the nuclear factor κB (NFκB) activity, a key transcription factor regulating inflammation. To mimic an inflammatory environment, chondrocytes were stimulated with interleukin-1β (IL-1β), a potent inflammatory cytokine. 3,4,6-O-Bu3GlcNAc exposure decreased the expression of NFκB target genes relevant to OA by IL-1β-stimulated chondrocytes after 24 h of exposure. The capacity of 3,4,6-O-Bu3GlcNAc to stimulate extracellular matrix (ECM) accumulation by IL-1β-stimulated chondrocytes was evaluated in vitro utilizing a three-dimensional hydrogel culturing system. After 21 days, 3,4,6-O-Bu3GlcNAc exposure induced quantifiable increases in both sulfated glycosaminoglycan and total collagen. Histological staining for proteoglycans and type II collagen confirmed these findings. The increased ECM accumulation was not due to the hydrolysis products of the small molecule, n-butyrate and N-acetylglucosamine (GlcNAc), as the isomeric 1,3,4-O-tributanoylated N-acetylglucosamine (1,3,4-O-Bu3GlcNAc) did not elicit a similar response. These findings demonstrate that a novel butanoylated GlcNAc derivative, 3,4,6-O-Bu3GlcNAc, has the potential to stimulate new tissue production and reduce inflammation in IL-1β-induced chondrocytes with utility for OA and other forms of inflammatory arthritis. 23930780 Obstetrical Interventions for Term First Deliveries in the US. Labour induction and caesarean are increasingly done without clinical indication. However, little is known about the prevalence of such interventions, or the characteristics of women who receive them. We used the 2003 revision of the US birth certificates to summarise recorded interventions and to characterise maternal profiles associated with such interventions. We carried out a retrospective study of 2.35 million primiparous women delivering singleton live births at 37-44 weeks in the US from 2005 to 2008. We used the 2003 revision of the birth certificate to define delivery categories: 'indicated' were those with induced labour or pre-labour caesarean for hypertension, diabetes, chorioamnionitis, failed cephalic version at ≥40 weeks, growth restriction (<3rd centile), or post-term (≥42 weeks); those with pre-labour caesarean with breech at ≥39 weeks; or those with caesarean with labour lasting ≥12 h, failed trial of labour, vacuum/forceps extraction, or fetal intolerance to labour. Remaining deliveries with induction/caesarean were classified as 'non-indicated' and all other deliveries 'spontaneous'. Half of all term first births (50%) were delivered after intervention, and half of interventions were non-indicated (26% of all deliveries). Women with interventions were more likely to deliver on a weekday. Non-indicated interventions were more common among socially advantaged women. Nearly a quarter of US term first deliveries had an indicated intervention, and another quarter received intervention without a recorded clinical indication. Both numbers are probably underestimates. 23823873 Benchmark study on the smallest bimolecular nucleophilic substitution reaction: H⁻+CH₄-->CH₄+H⁻. We report here a benchmark study on the bimolecular nucleophilic substitution (S(N)2) reaction between hydride and methane, for which we have obtained reference energies at the coupled cluster toward full configuration-interaction limit (CC-cf/CBS). Several wavefunction (HF, MP2, coupled cluster) and density functional methods are compared for their reliability regarding these reference data. 23820791 Mesh pullout force: comparative study of different deployment techniques in a sheep model. Pullout force of mesh from tissue is one of the important mechanical properties of an implanted mesh to repair pelvic organ prolapse (POP). The EndoFast Reliant™ system kit allows mesh attachment with soft-tissue fasteners. The aim of this study was to compare the pullout force that developed in mesh that was attached by EndoFast Reliant fasteners to mesh that was attached by trocar-based methods (tunnel, pocket) in a sheep model. Six sheep underwent mesh attachment with three methods (EndoFast Reliant, tissue pocket, tissue tunnel), and each method was repeated five times in both thighs of the same sheep. The pullout force was measured at different time intervals from surgery: 0, 3, 7, 15, 30, and 45 days. Statistical analysis was performed by using the appropriate one-way analysis of variance (ANOVA) for each time interval and a general linear model for repeated measures using IBM® SPSS® software version 20.0.0. During the immediate postoperative period (0-3 days), pullout force was significantly higher with EndoFast Reliant than with tissue pocket or tissue tunnel. At day 7, this trend continues without statistical significance. Pullout force increased progressively until day 15, when the force caused the mesh to tear; it was similar in all three groups. ANOVA showed significant effect of time and study group. The EndoFast Reliant system provides significantly stronger attachment in the immediate postoperative period (0-3 days) compared with trocar-based techniques, and this difference disappeared at day 15 postsurgery. 23740222 Perinatal depression: a review of US legislation and law. Accumulating research documenting the prevalence and negative effects of perinatal depression, together with highly publicized tragic critical incidents of suicide and filicide by mothers with postpartum psychosis, have fueled a continuum of legislation. Specialists in perinatal mental health should recognize how their work influences legislative initiatives and penal codes, and take this into consideration when developing perinatal services and research. Yet, without legal expertise, the status of legislative initiatives can be confusing. To address this shortfall, we assembled an interdisciplinary team of academics specializing in law, as well as perinatal mental health, to summarize these issues. This review presents the relevant federal and state legislation and summarizes the criminal codes that governed the court decisions on cases in which a mother committed filicide because of postpartum psychosis. Moreover, the review aims to help researchers and providers who specialize in perinatal depression understand their role in this legal landscape. 23950973 An S-Type Anion Channel SLAC1 Is Involved in Cryptogein-Induced Ion Fluxes and Modulates Hypersensitive Responses in Tobacco BY-2 Cells. Pharmacological evidence suggests that anion channel-mediated plasma membrane anion effluxes are crucial in early defense signaling to induce immune responses and hypersensitive cell death in plants. However, their molecular bases and regulation remain largely unknown. We overexpressed Arabidopsis SLAC1, an S-type anion channel involved in stomatal closure, in cultured tobacco BY-2 cells and analyzed the effect on cryptogein-induced defense responses including fluxes of Cl(-) and other ions, production of reactive oxygen species (ROS), gene expression and hypersensitive responses. The SLAC1-GFP fusion protein was localized at the plasma membrane in BY-2 cells. Overexpression of SLAC1 enhanced cryptogein-induced Cl(-) efflux and extracellular alkalinization as well as rapid/transient and slow/prolonged phases of NADPH oxidase-mediated ROS production, which was suppressed by an anion channel inhibitor, DIDS. The overexpressor also showed enhanced sensitivity to cryptogein to induce downstream immune responses, including the induction of defense marker genes and the hypersensitive cell death. These results suggest that SLAC1 expressed in BY-2 cells mediates cryptogein-induced plasma membrane Cl(-) efflux to positively modulate the elicitor-triggered activation of other ion fluxes, ROS as well as a wide range of defense signaling pathways. These findings shed light on the possible involvement of the SLAC/SLAH family anion channels in cryptogein signaling to trigger the plasma membrane ion channel cascade in the plant defense signal transduction network. 23890157 Prescribing trends of antipsychotics in youth receiving income assistance: results from a retrospective population database study. Prescribing of antipsychotics (AP) to young people has increased in the last decade internationally. We aimed to characterize AP prescribing in a population of low-income youth in Nova Scotia, Canada. We conducted a population database study of AP prescription claims and health services utilization by young people aged 25 years and younger receiving drug benefits through the publicly funded Pharmacare program between October 1, 2000 to September 30, 2007. Four percent (1715/43888) of youth receiving Pharmacare benefits filled AP prescriptions. The use of second generation antipsychotics (SGAs) significantly increased (p < 0.0001) in all age groups except 0-5 year olds, whereas first generation antipsychotic use significantly decreased. Pharmacare beneficiaries aged 21-25 years represented 45.2% of AP users. The majority (66%) of youth filling AP prescriptions had 2 or more psychiatric diagnoses. Most youth (76%) filled prescriptions for only one type of AP during the study period. Psychotic disorders were the most common indication for AP use except with risperidone, in which ADHD was the most likely reason for use. Co-prescribing of psychotropics was prevalent with antidepressants and mood stabilizers prescribed in 42% and 27% of AP users, respectively. General practitioners (GPs) prescribed incident APs most often (72%) followed by psychiatrists (16%). The age- and gender-adjusted rate of death was higher in AP users as compared to the age-matched general population of Nova Scotia. SGA use increased significantly over seven years in a cohort of 0 to 25 years olds receiving Pharmacare benefits. Off-label use of APs was prevalent with ADHD and other non-psychotic disorders being common reasons for AP use. GPs initiated most AP prescriptions. Co-prescribing of other psychotropics, especially antidepressants and mood stabilizers, was prevalent even in younger age strata. This study raises further questions about AP prescribing in those 25 years of age and under, especially given the range of diagnoses and psychotropic co-prescribing. 23874738 Does recall after sleep-dependent memory consolidation reinstate sensitivity to retroactive interference? Previous studies have shown that newly encoded memories are more resistant to retroactive interference when participants are allowed to sleep after learning the original material, suggesting a sleep-related strengthening of memories. In the present study, we investigated delayed, long-term effects of sleep vs. sleep deprivation (SD) on the first post-training night on memory consolidation and resistance to interference. On day 1, participants learned a list of unrelated word pairs (AB), either in the morning or in the evening, then spent the post-training night in a sleep or sleep deprivation condition, in a within-subject paradigm. On day 4, at the same time of day, they learned a novel list of word pairs (AC) in which 50% of the word pairs stemmed with the same word than in the AB list, resulting in retroactive interference. Participants had then to recall items from the AB list upon presentation of the "A" stem. Recall was marginally improved in the evening, as compared to the morning learning group. Most importantly, retroactive interference effects were found in the sleep evening group only, contrary to the hypothesis that sleep exerts a protective role against intrusion by novel but similar learning. We tentatively suggest that these results can be explained in the framework of the memory reconsolidation theory, stating that exposure to similar information sets back consolidated items in a labile form again sensitive to retroactive interference. In this context, sleep might not protect against interference but would promote an update of existing episodic memories while preventing saturation of the memory network due to the accumulation of dual traces. 23836627 Chemical imaging of lignocellulosic biomass by CARS microscopy. Chemical and structural composition of wood biomass is studied by label-free and chemically specific Coherent Anti-Stokes Raman Scattering (CARS) microscopy. A concept developed for assignment and semi-quantitative imaging of sample components; cellulose, hemicellulose, and lignin; by multiplex CARS microspectroscopy and subsequent data analysis is presented. Specific imaging without fluorescence backround is achieved an order of magnitude faster compared with conventional Raman microscopy. Laser polarization control yield information on molecular arrangement in wood fibers. Narrowband CARS excitation of single vibrations allows for three-dimensional volume imaging. Thus, CARS microscopy has potential as an important instrument for characterization of lignocellulosic materials. (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim). 23657724 Treatment of a supernumerary large breast with medial pedicle reduction mammaplasty. Accessory breast tissues including nipples, areolas, and glandular tissue may develop on the chest in addition to two normal breasts. An accessory breast with a complete ductal system, areola, and nipple is termed a "supernumerary breast." Supernumerary nipples are fairly common, but complete supernumerary breasts are rare. This report describes an 18-year-old woman who presented with a complete supernumerary breast including a nipple-areola complex located on the upper outer quadrant of her left breast and causing severe breast asymmetry. She was referred to the authors for aesthetic reasons. Unilateral reduction mammaplasty was performed to remove the supernumerary breast and correct the breast asymmetry. The medial pedicle Wise technique was used for en bloc resection of the ectopic breast, including the nipple-areola complex together with the upper outer breast quadrant. The woman's postoperative course was uneventful. At 8 months after surgery, she was very satisfied with the results. Ectopic breast tissue can be treated by a variety of methods such as liposuction or excision. However, breast deformation because of a complete supernumerary breast is very rare, and research on the treatment of such patients is lacking. No reports describing surgical treatment for this condition were identified in the literature. The authors suggest that unilateral breast reduction is the most appropriate treatment, allowing excision of the accessory tissues, with the best possible cosmetic outcome. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . 23241369 5-Benzylglycinyl-amiloride kills proliferating and nonproliferating malignant glioma cells through caspase-independent necroptosis mediated by apoptosis-inducing factor. 5'-Βenzylglycinyl-amiloride (UCD38B) and glycinyl-amiloride (UCD74A) are cell-permeant and cell-impermeant derivatives of amiloride, respectively, and used here to identify the cellular mechanisms of action underlying their antiglioma effects. UCD38B comparably kills proliferating and nonproliferating gliomas cells when cell cycle progression is arrested either by cyclin D1 siRNA or by acidification. Cell impermeant UCD74A inhibits plasmalemmal urokinase plasminogen activator (uPA) and the type 1 sodium-proton exchanger with potencies analogous to UCD38B, but is cytostatic. In contrast, UCD38B targets intracellular uPA causing mistrafficking of uPA into perinuclear mitochondria, reducing the mitochondrial membrane potential, and followed by the release of apoptotic inducible factor (AIF). AIF nuclear translocation is followed by a caspase-independent necroptotic cell death. Reduction in AIF expression by siRNA reduces the antiglioma cytotoxic effects of UCD38B, while not activating the caspase pathway. Ultrastructural changes shortly following treatment with UCD38B demonstrate dilation of endoplasmic reticulum (ER) and mitochondrial swelling followed by nuclear condensation within hours consistent with a necroptotic cell death differing from apoptosis and from autophagy. These drug mechanism of action studies demonstrate that UCD38B induces a cell cycle-independent, caspase-independent necroptotic glioma cell death that is mediated by AIF and independent of poly (ADP-ribose) polymerase and H2AX activation. 23836695 Accidental injury of the latissimus dorsi flap pedicle during axillae dissection: Types and reconstruction algorithm. The intra-operative latissimus dorsi (LD) pedicle damage during axillary lymph-node dissection by the general surgeon is a rare complication leading to flap failure and poor outcomes. The authors present their experience on this topic and develop a classification of the thoracodorsal (TD) pedicle injuries and reconstruction algorithm. Pedicle damage of LD occurred in five cases, three of which were experienced during immediate breast reconstruction and two observed in patients who underwent prior surgery. In two cases the thoracodorsal vein (TDV) was damaged in its proximal segment, thus end-to-end anastomosis was performed between distal stump of TDV and circumflex scapular vein (CSV). In one case the TDV required simple microsurgical repair while in other two cases the severe damage of vein and artery required more complex surgical strategies in attempt to salvage the flap. Four cases completely survived with one case of rippling phenomenon. One case had partial flap necrosis that required subtotal muscle resection. Based on these cases, the authors have developed a reconstruction algorithm in attempt to repair LD pedicle damage while preserving breast reconstruction. Taking into account its anatomical conformation, TD pedicle injuries are classified in four different types and available options are suggested for all of them according to the anatomical site and to the mechanism and timing of injury. © 2013 Wiley Periodicals, Inc. Microsurgery, 2013. 23927207 Acoustic field characterization of the Duolith: Measurements and modeling of a clinical shock wave therapy device. Extracorporeal shock wave therapy (ESWT) uses acoustic pulses to treat certain musculoskeletal disorders. In this paper the acoustic field of a clinical portable ESWT device (Duolith SD1) was characterized. Field mapping was performed in water for two different standoffs of the electromagnetic head (15 or 30 mm) using a fiber optic probe hydrophone. Peak positive pressures at the focus ranged from 2 to 45 MPa, while peak negative pressures ranged from -2 to -11 MPa. Pulse rise times ranged from 8 to 500 ns; shock formation did not occur for any machine settings. The maximum standard deviation in peak pressure at the focus was 1.2%, indicating that the Duolith SD1 generates stable pulses. The results compare qualitatively, but not quantitatively with manufacturer specifications. Simulations were carried out for the short standoff by matching a Khokhlov-Zabolotskaya-Kuznetzov equation to the measured field at a plane near the source, and then propagating the wave outward. The results of modeling agree well with experimental data. The model was used to analyze the spatial structure of the peak pressures. Predictions from the model suggest that a true shock wave could be obtained in water if the initial pressure output of the device were doubled. 23149877 Impact of type D personality on adherence to oral appliance therapy for sleep-disordered breathing. Type D personality, defined as a combination of social inhibition and negative affectivity, has been associated with poor medication adherence and lower adherence to continuous positive airway pressure in patients with sleep-disordered breathing. Up to this date, the association of patient's personality with adherence with a mandibular advancement device (MAD) has not been studied. The purposes of this study were to examine the association between type D personality and poor adherence to MAD treatment and to examine the impact of type D personality on perceived side effects during this treatment. Eighty-two patients out of 113 patients with a known baseline type D scale who have started MAD treatment between June 2006 and December 2009 were included. Information about side effects and adherence were collected via a postal questionnaire. Thirty-three patients were using a monobloc MAD and 49 patients were using a duobloc MAD. Forty-five percent of type D patients discontinued MAD treatment, whereas only 15 % of non-type D patients reported treatment discontinuation. The odds ratio for treatment discontinuation was 6.03 (95 % confidence interval 1.22-29.81; p = 0.027) for type D personality, adjusted for age, gender, MAD type (monobloc or duobloc), and decrease in apnea severity. In continuing MAD users, no significant difference in perceived side effects was reported between the personality types. This is the first study to examine the relationship between type D personality and adherence to MAD treatment. Type D patients reported a significantly higher discontinuation rate when compared to patients without type D personality. 23899353 The provision of and need for social support among adult and pediatric patients with tuberculosis in Lima, Peru: a qualitative study. Tuberculosis (TB) remains a significant public health problem in Peru, causing an estimated 35,000 new cases each year, 6.7% of whom are co-infected with HIV. Social support mechanisms are key in influencing health-seeking behavior, adherence, and overall patient wellbeing in clinical settings. We examine the types of social support received by TB patients and parents of pediatric patients in peri-urban Lima, Peru, to understand its role in patients' psychosocial wellbeing during treatment. Semi-structured interviews were conducted between August 2004 and May 2005 among 43 individuals: 19 adults with TB, 8 adults with TB/HIV, 13 parents of pediatric TB patients, and 3 parents of pediatric TB/HIV patients. Patients described the need for psychosocial support to mitigate the difficulty of continually going to the clinic to take medications, tending to other family or professional responsibilities while on treatment, and confronting stigma and social isolation within their community. Family members most often contributed to meeting these psychosocial needs, and were also crucial in providing economic support to patients faced with burdensome medical expenses or who were forced to leave their jobs due to being on treatment. Most healthcare personnel were described as key providers of emotional support and encouragement for patients to successfully adhere to treatment, however there were a select few doctors whose "scare tactics" seemingly discouraged patient adherence. During the treatment process, patients described being more socially withdrawn as a result of feeling fatigued from their medications, however most participants also described forming new mutually supportive friendships among their fellow patients. Despite the general reluctance of patients to disclose their disease status, patients received a significant amount of psychosocial support from both family members to whom they disclosed, and from positive interactions with healthcare providers. High levels of depression were reported, with many patients voicing need for improved and more frequent psychological interventions. To improve the Peru TB program, participants suggested extending educational opportunities to patients' families and the wider community, increasing the existing amount of nutritional support, and programmatic provision of vocational activities to increase economic opportunities. 23590870 Systematic review and meta-analysis of the retroperitoneal versus the transperitoneal approach to the abdominal aorta. The aim was to systematically review and meta-analyse the differences between the retroperitoneal (RP) and the transperitoneal (TP) approach to the infrarenal abdominal aorta. Systematic review and meta-analysis. PubMed, the Cochrane library, Embase and ClinicalTrials.gov were searched for all studies on differences in clinical outcomes between the RP and TP approach. Outcomes were selected based on inclusion in two or more studies: Operative (length of procedure, intraoperative blood loss); Post operative complications (paralytic ileus, pneumonia, myocardial infarction (MI), renal failure and wound hernia); Mortality (30 day, 1 year); Post-operative changes in respiratory function (forced expiratory volume in 1 second, forced vital capacity); Length of hospital and Intensive care unit (ICU) stay and Cost. The data were pooled by outcome. Eight randomised and 21 cohort studies involving 3035 patients were included. Meta-analysis showed significantly lower rates of postoperative ileus (Odds ratio (OR) 0.17[95% CI 0.10, 0.32] p < 0.00001), pneumonia (OR 0.42[95% CI 0.26, 0.68] p = 0.0004), ICU stay (standardised mean difference (SMD) 0.67[95% CI 1.28, 0.06] p = 0.03), total hospital stay (SMD 0.88[95% CI 1.32, 0.44] p < 0.0001) and cost (SMD 1.15[95% CI 2.11, 0.19] p = 0.02) for patients undergoing a RP approach. Study quality was generally low, with conflicting results and concerns over publication bias in some cohort studies. The RP approach for open aortic surgery is associated with lower rates of postoperative ileus and pneumonia when compared to the TP approach. 23713823 High-multiplicity natural orbitals in multireference configuration interaction for excited state potential energy surfaces. We have previously proposed the use of natural orbitals obtained from a single reference correlated calculation describing a high-multiplicity state (HMNOs), as a substitute for complete active space self-consistent field (CASSCF) molecular orbitals, in the calculation of singlet excited states using the multi-reference configuration interaction (MRCI) method. In our previous work, we found that the MRCI/HMNO method reliably reproduces vertical excitation energies that can be obtained from the standard MRCI/CASSCF procedure for several representative molecules with an average absolute difference of ca. 0.1 eV. In this paper, we test how the MRCI/HMNO method performs when used to generate excited state potential energy surfaces of three sample systems: ethylene, cyclohexadiene, and uracil. We find that the MRCI/HMNO method gives potential energy surfaces for valence excited states that are in good agreement with those generated with the analogous MRCI/CASSCF method, although there are some cases where special care is needed to avoid discrepancies between the two approaches. 23828589 L-DOPA and graft-induced dyskinesia: Different treatment, same story? One of the well-recognized problems of long-term l-3,4-dihydroxyphenylalanine (l-DOPA) therapy in the treatment of Parkinson's disease is the development of l-DOPA induced dyskinesia. These abnormal movements cause significant disability and narrow the therapeutic window of l-DOPA. Cell transplantation is one of the most promising upcoming therapies for the treatment of Parkinson's disease, and may help alleviate or avoid l-DOPA-induced dyskinesia. However, the more recently acknowledged phenomenon of graft-induced dyskinesia is posing a major obstacle to the success of this treatment. This motor side-effect closely resembles abnormal movements induced by chronic l-DOPA treatment, yet they remain after withdrawal of the medication indicating their origins lie in the transplant. In this review, we compare these two therapy-induced adverse effects, from the way they manifest in patients to the possible mechanisms underlying their development. 23535012 Pubertal height velocity and associations with prepubertal and adult heights in cystic fibrosis. To test the hypothesis that pubertal peak height velocity (PHV) in cystic fibrosis (CF) has improved and is influenced by prepubertal growth and genetic potential. PHV from 1862 children born in 1984-87 and documented in the 1986-2008 US CF Foundation Registry was determined by statistical modeling and classified into normal, delayed (2-SD > average age), attenuated (magnitude <5th percentile), or both delayed and attenuated (D&A). Genetic potential for height was estimated by parental stature. PHV averaged 8.4 cm/year at age 14.0 years in boys and 7.0 cm/year at age 12.1 years in girls, ∼6-month delay and ∼15% reduction compared with healthy children. PHV was normal in 60%, delayed in 9%, attenuated in 21%, and D&A in 5%. Patients with delayed PHV reached similar adult height percentile (boys: 34th, girls: 46th) to those with normal PHV (boys: 33rd, girls: 34th); both were significantly taller than the attenuated (boys: 11th, girls: 19th) and D&A PHV subgroups (boys: 8th, girls: 14th). Pancreatic-sufficient patients had taller prepubertal and adult heights but similar PHV compared with pancreatic-insufficient or meconium ileus patients. Adjusting for genetic potential reduced adult height percentiles more in boys (from 25th to 16th) than girls (from 28th to 24th). Height at age 7 years, PHV age and magnitude, and parental stature significantly predicted adult height. Pubertal PHV has improved in children with CF born after mid-1980s compared with older cohorts but remains below normal. Suboptimal prepubertal and pubertal growth led to adult height below genetic potential in CF. 23404656 Interpretation of optoelectronic transient and charge extraction measurements in dye-sensitized solar cells. Tools that assess the limitations of dye sensitized solar cells (DSSCs) made with new materials are critical for progress. Measuring the transient electrical signals (voltage or current) after optically perturbing a DSSC is an approach which can give information about electron concentration, transport and recombination. Here we describe the theory and practice of this class of optoelectronic measurements, illustrated with numerous examples. The measurements are interpreted with the multiple trapping continuum model which describes electrons in a semiconductor with an exponential distribution of trapping states. We review standard small perturbation photocurrent and photovoltage transients, and introduce the photovoltage time of flight measurement which allows the simultaneous derivation of both effective diffusion and recombination coefficients. We then consider the utility of large perturbation measurements such as charge extraction and the current interrupt technique for finding the internal charge and voltage within a device. Combining these measurements allows differences between DSSCs to be understood in terms such as electron collection efficiency, semiconductor conduction band edge shifts and recombination kinetics. 23932804 Effect of physical exercise on muscle mass and strength in cancer patients during treatment-A systematic review. Cancer treatment and its side effects may cause muscle wasting. Physical exercise has the potential to increase muscle mass and strength and to improve physical function in cancer patients undergoing treatment. A systematic review was conducted to study the effect of physical exercise (aerobic, resistance or a combination of both) on muscle mass and strength in cancer patients with different type and stage of cancer disease. Electronic searches were performed up to January 11th 2012, identifying 16 randomised controlled trials for final data synthesis. The studies demonstrated that aerobic and resistance exercise improves upper and lower body muscle strength more than usual care. Few studies have assessed the effect of exercise on muscle mass. Most studies were performed in patients with early stage breast or prostate cancer. Evidence on the effect of physical exercise on muscle strength and mass in cancer patients with advanced disease is lacking. More exercise studies in patients with advanced cancer and at risk of cancer cachexia are warranted. 23892365 Stochastic effects as a force to increase the complexity of signaling networks. Cellular signaling networks are complex and appear to include many nonfunctional elements. Recently, it was suggested that nonfunctional interactions of proteins cause signaling noise, which, perhaps, shapes the signal transduction mechanism. However, the conditions under which molecular noise influences cellular information processing remain unclear. Here, we explore a large number of simple biological models of varying network sizes to understand the architectural conditions under which the interactions of signaling proteins can exhibit specific stochastic effects-called deviant effects-in which the average behavior of a biological system is substantially altered in the presence of molecular noise. We find that a small fraction of these networks does exhibit deviant effects and shares a common architectural feature whereas most of the networks show only insignificant levels of deviations. Interestingly, addition of seemingly unimportant interactions into protein networks gives rise to deviant effects. 23672591 The role of microparticles in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus. Microparticles (MPs) are small membrane-bound vesicles with potent biological activities that can promote the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus (SLE). These particles contain diverse cellular components and are shed from cells during apoptosis or activation. MPs can drive inflammation and autoimmunity by multiple mechanisms reflecting their content of bioactive molecules and ability to engage multiple receptor systems simultaneously. In the rheumatoid joint, particles can stimulate synovitis via their display of cytokines, chemokines, complement and angiogenesis factors. In SLE, particles can serve as an important source of extracellular nuclear molecules to signal 'danger' and form pathogenic immune complexes. Future studies will define the pathways by which particles promote pathogenesis, strategies to block their activity and their utility as biomarkers to assess disease activity and the response to therapy. 23444110 The fate is not always written in the genes: Epigenomics in epidemiologic studies. Cost-effective, high-throughput epigenomic technologies have begun to emerge, rapidly replacing the candidate gene approach to molecular epidemiology and offering a comprehensive strategy for the study of epigenetics in human subjects. Epigenome-wide association studies (EWAS) provide new opportunities for advancing our understanding of epigenetic changes associated with complex disease states. However, such analyses are complicated by the dynamic nature of DNA methylation. In contrast to genomic studies, where genotype is essentially constant across somatic cells, EWAS present a new set of challenges, largely due to differential DNA methylation across distinct cell types, particularly for studies involving heterogeneous tissue sources, and changes in the epigenetic profile that occur over time. This review describes potential applications of EWAS from the viewpoint of the molecular epidemiologist, along with special considerations and pitfalls involved in the design of such studies. Environ. Mol. Mutagen. 54:533-541, 2013. © 2013 Wiley Periodicals, Inc. 23061396 APP independent and dependent effects on neurite outgrowth are modulated by the receptor associated protein (RAP). Amyloid precursor protein (APP) and its secreted form, sAPP, contribute to the development of neurons in hippocampus, a brain region critical for learning and memory. Full-length APP binds the low-density lipoprotein receptor-related protein (LRP), which stimulates APP endocytosis. LRP also contributes to neurite growth. Furthermore, the receptor associated protein (RAP) binds LRP in a manner that blocks APP-LRP interactions. To elucidate APP contributions to neurite growth for full-length APP and sAPP, we cultured wild type (WT) and APP knockout (KO) neurons in sAPPα and/or RAP and measured neurite outgrowth at 1 day in vitro. Our data reveal that WT neurons had less axonal outgrowth including less axon branching. RAP treatment potentiated the inhibitory effects of APP. KO neurons had significantly more outgrowth and branching, especially in response to RAP, effects which were also associated with ERK2 activation. Our results affirm a major inhibitory role by full-length APP on all aspects of axonal and dendritic outgrowth, and show that RAP-LRP binding stimulated axon growth independently of APP. These findings support a major role for APP as an inhibitor of neurite growth and reveal novel signaling functions for LRP that may be disrupted by Alzheimer's pathology or therapies aimed at APP processing. 23433811 Checkpoint protein Rad9 plays an important role in nucleotide excision repair. Rad9, an evolutionarily conserved checkpoint gene with multiple functions for preserving genomic integrity, has been shown to play important roles in homologous recombination repair, base excision repair and mismatch repair. However, whether Rad9 has an impact on nucleotide excision repair remains unknown. Here we demonstrated that Rad9 was involved in nucleotide excision repair and loss of Rad9 led to defective removal of the UV-derived photoproduct 6-4PP (6,4 pyrimidine-pyrimidone) and the BPDE (anti-benzo(a)pyrene-trans-7,8-dihydrodiol-9,10-epoxide)-DNA adducts in mammalian cells. We also demonstrated that Rad9 could co-localize with XPC in response to local UV irradiation. However, our data showed that Rad9 was not required for the photoproducts recognition step of nucleotide excision repair. Further investigation revealed that reduction of Rad9 reduced the UV-induced transcription of the genes of the nucleotide excision repair factors DDB2, XPC, DDB1 and XPB and DDB2 protein levels in human cells. Interestingly, knockdown of one subunit of DNA damage recognition complex, hHR23B impaired Rad9-loading onto UV-damaged chromatin. Based on these results, we suggest that Rad9 plays an important role in nucleotide excision repair through mechanisms including maintaining DDB2 protein level in human cells. 23770550 Transport of particle-associated elements in two agriculture-dominated boreal river systems. Transport of particulate pollutants in fluvial systems can contribute greatly to total loads. Understanding transport mechanics under different hydrological conditions is key in successful load estimation. This study analysed trace elements and physico-chemical parameters in time-integrated suspended sediment samples, together with dissolved and total concentrations of pollutants, along two agriculture- and peatland-dominated boreal river systems. The samples were taken in a spatially and temporally comprehensive sampling programme during the ice-free seasons of 2010 and 2011. The hydrochemistry and transport of particle-bound elements in the rivers were strongly linked to intense land use and acid sulphate soils in the catchment area, with arable, pasture and peat areas in particular being main diffuse sources. There were significant seasonal and temporal variations in dissolved and particulate fluxes, but spatial variations were small. Continuous measurements of EC, turbidity and discharge proved to be an accurate indicator of dissolved and particulate fluxes. Overall, the results show that transport of particle-bound elements makes a major contribution to total transport fluxes in agriculture-dominated boreal rivers. 23591116 Synthesis and antibacterial evaluation of a novel series of 10-hydroxyl ketolide derivatives. A novel series of 10-hydroxyl ketolide derivatives were synthesized, during which a distinctive intermediate, 3-O-descladinosyl-3-oxo-11-deoxy-10,11-epoxy-6-O-methylerythromycin A, was obtained from 6-O-methylerythromycin A. The structure and stereochemistry of this novel structure were confirmed via NMR and X-ray crystallography. Moreover, antibacterial evaluations were established in order to assess our modifications and acquire a deep understanding of the ketolides' structure-activity relationship (SAR). 23530013 Rapid Improvement of Diabetes After Gastric Bypass Surgery: Is It the Diet or Surgery? OBJECTIVEImprovements in diabetes after Roux-en-Y gastric bypass (RYGB) often occur days after surgery. Surgically induced hormonal changes and the restrictive postoperative diet are proposed mechanisms. We evaluated the contribution of caloric restriction versus surgically induced changes to glucose homeostasis in the immediate postoperative period.RESEARCH DESIGN AND METHODSPatients with type 2 diabetes planning to undergo RYGB participated in a prospective two-period study (each period involved a 10-day inpatient stay and periods were separated by a minimum of 6 weeks of wash-out) in which patients served as their own controls. The presurgery period consisted of diet alone. The postsurgery period was matched in all aspects (daily matched diet) and included RYGB surgery. Glucose measurements were performed every 4 h throughout the study. A mixed meal challenge test was performed before and after each period.RESULTSTen patients completed the study and had the following characteristics: age, 53.2 years (95% CI, 48.0-58.4); BMI, 51.2 kg/m(2) (46.1-56.4); diabetes duration, 7.4 years (4.8-10.0); and HbA1c, 8.52% (7.08-9.96). Patients lost 7.3 kg (8.1-6.5) during the presurgery period versus 4.0 kg (6.2-1.7) during the postsurgery period (P = 0.01 between periods). Daily glycemia in the presurgery period was significantly lower (1,293.58 mg/dL*day [1,096.83-1,490.33) vs. 1,478.80 mg/dL*day [1,277.47-1,680.13]) compared with the postsurgery period (P = 0.02 between periods). The improvements in the fasting and maximum poststimulation glucose and 6-h glucose area under the curve (primary outcome) were similar during both periods.CONCLUSIONSGlucose homeostasis improved in response to a reduced caloric diet, with a greater effect observed in the absence of surgery as compared with after RYGB. These findings suggest that reduced calorie ingestion can explain the marked improvement in diabetes control observed after RYGB. 23827150 Escherichia coli tetracycline efflux determinants in relation to tetracycline residues in chicken. To screen for Escherichia coli (E. coli) resistant to tetracycline, followed by identification of tet efflux genes by polymerase chain reaction (PCR). In addition, detection of tetracycline residues in chicken livers and kidneys were conducted using high performance liquid chromatography-tandem quadrupole mass spectrometry (HPLC-MS-MS). Strains of E. coli were isolated from samples of chicken colon and screened for tetracycline resistance. Tetracycline genes conferring resistance (Tc(r)) were detected by polymerase chain reaction (PCR). Most of the isolates were resistant to tetracycline (97.9%). PCR analysis indicated that Tc(r)E. coli R-plasmids contained tet(A), tet(B) and a combination of both efflux genes. None of the isolates contained other efflux tet genes tet (C, D, E and Y). High performance liquid chromatography-tandem quadrupole mass spectrometry (HPLC-MS-MS), a sensitive technique, was used to detect residues of chlortetracycline (CTC), oxytetracycline (OTC), doxycycline (DC) in chicken livers and kidneys. The samples containing tetracycline residues were at 0.13-0.65 pg/μL levels. Tetracycline and other antibiotics are commonly used in the poultry and meat production industry for prevention of microbial infections. Multiple antibiotic resistant bacteria in Oman have increased to alarming levels, threatening public health, domestic and may have adverse effect on environment. 23899186 Bisanthracene Bis(dicarboxylic imide)s as Potential Photosensitizers in Photodynamic Therapy: A Theoretical Investigation. The electronic structures and spectroscopic properties of four bisanthracene bis(dicarboxylic imide)s (M1-M4) have been investigated theoretically by using density functional theory (DFT) and its time-dependent extension (TDDFT) in view of their potential use as photosensitizers in photodynamic therapy (PDT). The optimized geometries, electronic absorption transitions, singlet-triplet energy gaps, spin-orbit matrix elements, ionization potentials, and electron affinities have been determined in gas phase and in solvent. Both type I and II PDT mechanisms have been considered. In addition, the variation of a series of relevant properties upon heavy atom substitution (Br and I) have been determined and discussed. Results show that only M4 is able to support the type I reaction, and one of its brominated and iodinated derivatives can produce cytotoxic singlet oxygen (type II reaction). 22491023 Actions of Xanthurenic acid, a putative endogenous Group II metabotropic glutamate receptor agonist, on sensory transmission in the thalamus. Xanthurenic acid (XA), a molecule arising from tryptophan metabolism by transamination of 3-hydroxykynurenine, has recently been identified as an endogenous Group II (mGlu2 and mGlu3) metabotropic glutamate (mGlu) receptor ligand in vitro. Impairments in Group II mGlu receptor expression and function have been implicated in the pathophysiology of schizophrenia, as have multiple steps in the kynurenine metabolism pathway. Therefore, we examined XA in vivo to further investigate its potential as a Group II mGlu receptor ligand using a preparation that has been previously demonstrated to efficiently reveal the action of other Group II mGlu receptor ligands in vivo. Extracellular single-neurone recordings were made in the rat ventrobasal thalamus (VB) in conjunction with iontophoresis of agonists, an antagonist and a positive allosteric modulator and/or intravenous (i.v.) injection of XA. We found the XA effect on sensory inhibition, when applied iontophoretically and i.v., was similar to that of other Group II mGlu receptor agonists in reducing inhibition evoked in the VB from the thalamic reticular nucleus upon physiological sensory stimulation. Furthermore, we postulate that XA may be the first potential endogenous allosteric agonist (termed 'endocoid') for the mGlu receptors. As the Group II receptors and kynurenine metabolism pathway have both been heavily implicated in the pathophysiology of schizophrenia, XA could play a pivotal role in antipsychotic research as this potential endocoid represents both a convergence within these two biological parameters and a novel class of Group II mGlu receptor ligand. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23587476 Health service cost associated with percutaneous vertebroplasty in patients with spinal metastases. To ascertain prospectively the health service cost of vertebroplasty in a cohort of consecutive patients with spinal metastases. Percutaneous vertebroplasty was performed under conscious sedation and local anaesthetic in the Interventional Suite with fluoroscopic guidance. Data were collected prospectively on standard forms. Quality of life questionnaires (EQ-5D) were filled out pre-, 6 weeks, and at 6 months post-vertebroplasty. The majority of the procedures were performed on an outpatient basis (8/11). The median duration of the procedure was 60 min (range 40-80 min) with a further 60 min spent in the recovery room (range 10-230 min). Personnel involved included a consultant radiologist, a radiology registrar, four nurses, and two radiographers. The average cost of vertebroplasty per patient, including consumables, capital equipment, hotel/clinic costs, and staffing, was £2213.25 (95% CI £729.95). The mean EQ-5D utility scores increased from 0.421 pre-treatment to 0.5979 post-treatment (p = 0.047). The visual analogue scale (VAS) of perceived health improved from a mean of 41.88 to 63.75 (p = 0.00537). Health service costs for percutaneous vertebroplasty in patients with spinal metastases is significantly lower than previously estimated and is in keeping with that of other palliative radiological procedures. 23953636 Predictive Parameters of CyberKnife Fiducial-less (XSight Lung) Applicability for Treatment of Early Non-Small Cell Lung Cancer: A Single-Center Experience. To determine which parameters allow for CyberKnife fiducial-less tumor tracking in stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer. A total of 133 lung SBRT patients were preselected for direct soft-tissue tracking based on manufacturer recommendations (peripherally located tumors ≥1.5 cm with a dense appearance) and staff experience. Patients underwent a tumor visualization test to verify adequate detection by the tracking system (orthogonal radiographs). An analysis of potential predictors of successful tumor tracking was conducted looking at: tumor stage, size, histology, tumor projection on the vertebral column or mediastinum, distance to the diaphragm, lung-to-soft tissue ratio, and patient body mass index. Tumor visualization was satisfactory for 88 patients (66%) and unsatisfactory for 45 patients (34%). Median time to treatment start was 6 days in the success group (range, 2-18 days) and 15 days (range, 3-63 days) in the failure group. A stage T2 (P=.04), larger tumor size (volume of 15.3 cm(3) vs 6.5 cm(3) in success and failure group, respectively) (P<.0001), and higher tumor density (0.86 g/cm(3) vs 0.79 g/cm(3)) were predictive of adequate detection. There was a 63% decrease in failure risk with every 1-cm increase in maximum tumor dimension (relative risk for failure = 0.37, CI=0.23-0.60, P=.001). A diameter of 3.6 cm predicted a success probability of 80%. Histology, lung-to-soft tissue ratio, distance to diaphragm, patient's body mass index, and tumor projection on vertebral column and mediastinum were not found to be predictive of success. Tumor size, volume, and density were the most predictive factors of a successful XSight Lung tumor tracking. Tumors >3.5 cm have ≥80% chance of being adequately visualized and therefore should all be considered for direct tumor tracking. 23725986 rHDL administration increases reverse cholesterol transport in mice, but is not additive on top of ezetimibe or cholestyramine treatment. Promoting reverse cholesterol transport (RCT) is a major atheroprotective property of HDL. The present study explored the effect of stimulating the first step of RCT (cholesterol efflux from macrophages) alone or in combination with stimulating the last step of RCT (fecal sterol excretion). Reconstituted HDL (rHDL) was injected into wild-type mice either with or without administration of the cholesterol absorption inhibitor ezetimibe or the bile acid sequestrant cholestyramine. Single dose administration of rHDL (100 mg apoA-I/kg) resulted in an early (4 h) increase in plasma free cholesterol levels (p < 0.001), without affecting hepatic cholesterol levels or fecal mass sterol excretion. rHDL injection also increased [(3)H]cholesterol appearance in plasma at an early time-point (4 h) after intraperitoneal administration of [(3)H]cholesterol-labeled mouse macrophage foam cells and fecal radioactivity excretion indicating completed RCT was increased by 26% (p < 0.05). Ezetimibe treatment inhibited intestinal cholesterol absorption by 74% (p < 0.01), but also the bile acid sequestrant cholestyramine decreased cholesterol absorption significantly (24%, p < 0.01). Consequently, ezetimibe increased RCT 2.1-fold (p < 0.001) primarily within fecal neutral sterols, while cholestyramine increased RCT by 3.6-fold (p < 0.001), primarily within bile acids (p < 0.001), but also within neutral sterols (p < 0.001). However, no additive effects of both intestinal sterol uptake inhibitors were observed on top of rHDL administration. These data demonstrate that increasing the first step of RCT by rHDL administration results in transient cholesterol mobilization from macrophages to plasma. This effect is not further enhanced by stimulating the last step of RCT, fecal sterol excretion. 23777221 Electric-field alignment of chitin nanorod-siloxane oligomer reactive suspensions. Uniaxially anisotropic chitin-silica nanocomposite solids have been obtained thanks to the electric field-induced macroscopic alignment of liquid-crystalline reactive cosuspensions. We demonstrate how chitin nanorods (260 nm long, 23 nm thick) can be aligned upon the application of an alternating current (ac) electric field, and within water-ethanol suspensions containing reactive siloxane oligomers (D(h) ∼ 3 nm). The alignment at the millimeter length scale is monitored by in situ small-angle X-ray scattering (SAXS) and polarized light optical microscopy. The composition and state (isotropic, chiral nematic) of the cosuspensions are proven to be determining factors. For nematic phases, the alignment is preserved when the electric field is switched off. Further solvent evaporation induces sol-gel transition, and uniaxially anisotropic chitin-silica nanocomposites are formed after complete drying of the aligned nematic suspensions. Here, the collective response of colloidal mesophases to external electric fields and the subsequent formation of ordered nanocomposite solids would represent a new opportunity for materials design. 23650027 BRAF V600E mutation detection by immunohistochemistry in colorectal carcinoma. The serine/threonine-protein kinase B-raf (BRAF) is an oncogene mutated in various neoplasms, including 5-15% of colorectal carcinomas. The T1799A point mutation, responsible for a large majority of these alterations, results in an amino acid substitution (V600E) causing the constitutive activation of a protein kinase cascade. BRAF V600E in MLH1 deficient tumors implicates somatic tumor-only methylation of the MLH1 promoter region instead of a germline MLH1 mutation. BRAF V600E also predicts poor prognosis in microsatellite stable colorectal cancers and may be a marker of resistance to anti-EGFR therapy in metastatic disease. Currently, only molecular methods are available for assessing BRAF mutational status. An immunohistochemical approach is evaluated here. Colon cancers from 2008 to 2012 tested by pyrosequencing for BRAF V600E mutation were selected. A total of 31 tumors with (n = 14) and without (n = 17) the BRAF V600E mutation were analyzed by immunohistochemistry using a commercially available antibody specific to the V600E-mutated protein. All 14 colorectal carcinomas with the BRAF V600E mutation demonstrated cytoplasmic positivity in tumor cells with the anti-BRAF antibody. In a minority of cases, staining intensity for the mutated tumor samples was weak (n = 2) or heterogeneous (n = 4); however, the majority of cases showed diffuse, strong cytoplasmic positivity (8 of 14 cases). None of the 17 BRAF wild-type colorectal cancers showed immunoreactivity to the antibody. The overall sensitivity and specificity of the immunohistochemical BRAF V600E assay was 100%. Detection of the BRAF V600E mutation in colorectal cancer by immunohistochemistry is a viable alternative to molecular methods. 23852014 Translational repression using BIV Tat peptide-TAR RNA interaction in mammalian cells. We developed a strategy to create novel genetically encoded switches based on translational repression. We illustrated its efficacy by incorporating two copies of an RNA hairpin in the 5'-untranslated region (UTR) of a target mRNA and demonstrating 7-fold translational repression upon expression of a ligand - the BIV Tat peptide. 23964206 Mediodorsal thalamus and cognition in non-human primates. Several recent studies in non-human primates have provided new insights into the role of the medial thalamus in different aspects of cognitive function. The mediodorsal nucleus of the thalamus (MD), by virtue of its connectivity with the frontal cortex, has been implicated in an array of cognitive functions. Rather than serving as an engine or relay for the prefrontal cortex, this area seems to be more specifically involved in regulating plasticity and flexibility of prefrontal-dependent cognitive functions. Focal damage to MD may also exacerbate the effects of damage to other subcortical relays. Thus, a wide range of distributed circuits and cognitive functions may be disrupted from focal damage within the medial thalamus (for example as a consequence of stroke or brain injury). Conversely, this region may make an interesting target for neuromodulation of cognitive function via deep brain stimulation or related methods, in conditions associated with dysfunction of these neural circuits. 23623492 Synthesis and evaluation of Janus type nucleosides as potential HCV NS5B polymerase inhibitors. The synthesis of new ribo and 2'-β-C-methyl ribo Janus type nucleosides J-AA, J-AG and J-AU is reported along with their ability to block HCV and HIV replication. Their toxicity was also assessed in Huh7, human lymphocytes, CEM and Vero cells. 23860200 Defining "The Elderly" Undergoing Major Gastrointestinal Resections: Receiver Operating Characteristic Analysis of a Large ACS-NSQIP Cohort. "The elderly" is an often used but poorly defined descriptor of surgical patients. Investigators have used varying subjectively determined age cutoffs to report outcomes in the elderly. We set out to use objective outcomes data to determine the "at-risk" elderly population. Mortality steadily increases with age. On receiver operating characteristic analysis, there is a nonlinear transition zone (50-75 years of age) flanked by 2 linear zones on either end. The younger linear zone showed a low mortality increase (0.5% per decade). Larger mortality increase with age (5.3% per decade) was observed at the older age end. Similar patterns were observed for large-volume surgical subtypes, with clustering of a "critical age" beyond which mortality increases dramatically at 75 ± 2 years. Receiver operating characteristic analysis identified the "optimum age" for mortality being 68.5 years (area under the curve = 0.72, sensitivity = 66.6%, and specificity = 65.5%). Mortality risk for major gastrointestinal surgical resections starts increasing at 50 years of age, and at 75 years of age, it starts increasing very rapidly. The optimum age of 68.5 years predicts mortality with the best combination of sensitivity and specificity. These ages should be used to standardize outcome data and focus perioperative resources to improve outcomes. 23353656 Pestaloficiols Q-S from the plant endophytic fungus Pestalotiopsis fici. Two new isoprenylated chromone derivatives, pestaloficiols Q (1) and R (2), and one new benzofuran derivative, pestaloficiol S (3), along with three known metabolites, anofinic acid (4), siccayne (5), and pyrenophorol (6) were isolated from solid cultures of the plant endophytic fungus Pestalotiopsis fici. Their structures were elucidated primarily by NMR spectroscopy, and the absolute of the C-6 secondary alcohol in 1 was deduced on the basis of circular dichroism (CD) data. Compound 5 showed cytotoxic activity against the human cancer cell lines, HeLa and HT29, with IC50 values of 48.2 and 33.9μM, respectively. 23860210 Risk factors for maternal and fetal outcome in pregnancy complicated by Ebstein anomaly. The goal of the study was to examine risks in pregnancy in patients with Ebstein anomaly. Data were examined retrospectively for 13 patients (27 pregnancies, 21 live births) with Ebstein anomaly during pregnancy who were treated at our institution from 1985 to 2011. The associated anomalies in these patients were atrial septal defect (ASD) (n = 4) and the Wolff-Parkinson-White syndrome (n = 6). Before pregnancy, 2 patients underwent ASD closure and 1 received tricuspid valve replacement (TVR). In all patients, the cardiothoracic ratio increased from 55.1 at conception to 57.0 during pregnancy and 58.0 postpartum (P < .05). Cesarean sections were performed in 3 cases: 1 with ventricular tachycardia and orthopnea (New York Heart Association [NYHA] III) preterm; at full term, and the third in a patient with a mechanical tricuspid valve who developed maternal cerebellum hemorrhage at 27 weeks. The baby died of prematurity in the third case. In all other cases (20 of 21), neonatal prognoses were good without congenital heart diseases. There were 6 spontaneous abortions. Recurrent paroxysmal supraventricular tachycardia occurred during pregnancy in 2 cases and was treated with adenosine triphosphate or verapamil. In 17 pregnancies, NYHA remained in class I and all had full-term vaginal delivery. Maternal and fetal outcomes are good in patients with Ebstein anomaly and NYHA class I. However, pregnancy in Ebstein anomaly can be complicated with tachyarrhythmia or cardiac failure. In post-TVR cases, meticulous care is required for these complications during pregnancy and delivery. 23779229 Plasma cell-free DNA and its DNA integrity as biomarker to distinguish prostate cancer from benign prostatic hyperplasia in patients with increased serum prostate-specific antigen. To investigate whether plasma cell-free DNA (cfDNA) or its integrity could differentiate prostate cancer from benign prostate hyperplasia (BPH) in patients with serum prostate-specific antigen (PSA) â‰¥ 4 ng/ml. Ninety-six patients with prostate cancer and 112 patients with BPH were enrolled. cfDNA levels in plasma before prostate biopsy were quantified by real-time PCR amplification of ALU gene (product size of 115 bp), and quantitative ratio of ALU (247 bp) to ALU (115 bp) reflected the integrity of cfDNA. In patients with serum PSA â‰¥ 4 ng/ml, there were significant differences in plasma cfDNA or its integrity between the patients with prostate cancer (19.74 ± 4.43, 0.34 ± 0.05) and patients with BPH (7.36 ± 1.58, 0.19 ± 0.03; P < 0.001, P < 0.001). Prostate cancer could be differentiated with a sensitivity of 73.2 % and a specificity of 72.7 % by cfDNA (AUC = 0.864). The integrity of cfDNA had a sensitivity of 81.7 % and a specificity of 78.8 % for the distinguishing prostate cancer from BPH (AUC = 0.910). cfDNA and its integrity could be applied to differentiate prostate cancer from BPH in patients with serum PSA â‰¥ 4 ng/ml. 23588565 Population pharmacokinetics analysis of cyclophosphamide with genetic effects in patients undergoing hematopoietic stem cell transplantation. PURPOSE: To build a population pharmacokinetic (PK) model of cyclophosphamide (CY) and its metabolite, 4-hydroxycyclophosphamide (HCY), in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) and to identify covariates, including genetic polymorphisms, which affect CY and HCY PK parameters. METHOD: The study cohort comprised 21 patients undergoing HSCT who received CY intravenously between 2009 and 2011. Clinical characteristics and CY and HCY concentration data were collected for all patients, and ABCB1, ABCC2, GSTA1, GSTM1, GSTP1, GSTT1, CYP2B6, CYP2C19, and CYP3A5 genotyping was performed. A hypothetical enzyme compartment was conducted using the NONMEM program. RESULTS: A population PK analysis showed that the ABCC2 1249 genotype and aspartate aminotransferase levels significantly affected non-induced clearance (CL UI) and induced clearance (CL I) of CY, respectively. The final estimate of the mean CL UI and CL I of CY was 15.5 and 0.683 L/h, respectively, and the mean volume of distribution (V 1) of CY was 88.0 L. The inter-individual variability for CL UI, CL I, and V 1 of CY was 52.8, 200, and 18.0 %, respectively. Additionally, the CL UI of CY was significantly decreased to approximately 51 % in patients with the 1249 GA heterozygous genotype compared to those with the 1249 GG wild-type genotype (p < 0.05). There were only three heterozygous GA variants of ABCC2 1249 in the study patients. CONCLUSIONS: The population PK model developed in this study implies an influence of genetic factors on the clearance of CY. Clearance was moderately reduced in patients with the ABCC2 1249GA heterozygous genotype. 23876282 Specific Music Therapy Techniques in the Treatment of Primary Headache Disorders in Adolescents: A Randomized Attention-Placebo-Controlled Trial. Migraine and tension-type headache have a high prevalence in children and adolescents. In addition to common pharmacologic and nonpharmacologic interventions, music therapy has been shown to be efficient in the prophylaxis of pediatric migraine. This study aimed to assess the efficacy of specific music therapy techniques in the treatment of adolescents with primary headache (tension-type headache and migraine). A prospective, randomized, attention-placebo-controlled parallel group trial was conducted. Following an 8-week baseline, patients were randomized to either music therapy (n = 40) or a rhythm pedagogic program (n = 38) designed as an "attention placebo" over 6 sessions within 8 weeks. Reduction of both headache frequency and intensity after treatment (8-week postline) as well as 6 months after treatment were taken as the efficacy variables. Treatments were delivered in equal dose and frequency by the same group of therapists. Data analysis of subjects completing the protocol showed that no treatment was superior to the other at any point of measurement (posttreatment and follow-up). Intention-to-treat analysis revealed no impact of drop-out on these results. Both groups showed a moderate mean reduction of headache frequency posttreatment of about 20%, but only small numbers of responders (50% frequency reduction). Follow-up data showed no significant deteriorations or improvements. This article presents a randomized placebo-controlled trial on music therapy in the treatment of adolescents with frequent primary headache. Music therapy is not superior to an attention placebo within this study. These results draw attention to the need of providing adequate controls within therapeutic trials in the treatment of pain. 23532331 Disrupting the scaffold to improve focal adhesion kinase-targeted cancer therapeutics. Focal adhesion kinase (FAK) is emerging as a promising cancer target because it is highly expressed at both the transcriptional and translational level in cancer and is involved in many aspects of tumor growth, invasion, and metastasis. Existing FAK-based therapeutics focus on inhibiting the kinase's catalytic function and not the large scaffold it creates that includes many oncogenic receptor tyrosine kinases and tumor suppressor proteins. Targeting the FAK scaffold is a feasible and promising approach for developing highly specific therapeutics that disrupt FAK signaling pathways in cancer. 23316685 Directed motion of colloidal particles in a galvanic microreactor. The mechanisms leading to the deposition of colloidal particles in a copper-gold galvanic microreactor are investigated. Using in situ current density measurements and particle velocimetry, we establish correlations between the spatial arrangement and the geometry of the electrodes, current density distribution, and particle aggregation behavior. Ionic transport phenomena are responsible for the occurrence of strongly localized high current density at the edges and corners of the copper electrodes at large electrode separation, leading to a preferential aggregation of colloidal particles at the electrode edges. Preferential aggregation appears to be the result of a combination of electrophoretic effects and changes in bulk electrolyte flow patterns. We demonstrate that electrolyte flow is most likely driven by electrochemical potential gradients of reaction products formed during the inhomogeneous copper dissolution. 23417992 Economic and labor market forces matter for worker well-being. In light of recent interest in societal subjective well-being, policies that seek to improve the economy and labor markets need to address the question of whether economic factors matter for worker well-being, specifically job satisfaction. In a worldwide representative poll of 136 nations, economic factors are associated with job satisfaction beyond demographic and job factors. Hierarchical linear modeling showed that higher national GDP and job optimism was associated with job satisfaction, whereas higher unemployment was associated with job dissatisfaction. Mediational analyses revealed that economic variables (GDP and job optimism) were partially mediated by job satisfaction in predicting life satisfaction; full mediation was found for unemployment. In a second study, time series regression of monthly data from a nationally representative poll in the United States from 2008 to 2011 revealed that unemployment rate was significantly associated with job dissatisfaction over time. There was some evidence that prior unemployment rates predicted job satisfaction at a higher level than job satisfaction predicted unemployment rates, suggesting that economic factors lead to job (dis)satisfaction rather than the converse. Theoretical and practical implications are discussed. 23838147 Preliminary mapping of non-conserved epitopes on envelope glycoprotein E2 of Bovine viral diarrhea virus type 1 and 2. Bovine viral diarrhea virus (BVDV) belongs together with Classical swine fever virus (CSFV) and Border disease virus (BDV) to the genus Pestivirus in the Flaviviridae family. BVDV has been subdivided into two different species, BVDV1 and BVDV2 based on phylogenetic analysis. Subsequent characterization of both strains revealed major antigenic differences. Because the envelope glycoprotein E2 is the most immunodominant protein for all pestiviruses, the present study focused on epitope mapping by constructing chimeric BVDV type 1 and 2 E2 genes in expression plasmids. These plasmids with chimeric E2-genes were transfected in SK6 cells and transient expression was studied by immunostaining with a panel of MAbs specific for E2 of BVDV1 or BVDV2, resulting in the localization of type-specific antigenic domains at similar regions. These results indicate that E2 glycoproteins of both BVDV types exhibit a comparable antigenic structure, but with type specific epitopes. In addition, the antigenic resemblance with envelope glycoprotein E2 of Classical swine fever virus is discussed. 23912785 Severe mitral paravalvular leakage: echo-morphologic description of 47 patients from real-time three-dimensional transesophageal echocardiography perspective. Paravalvular leaks (PVLs) commonly occur in mitral prostheses. Real-time 3-dimensional transesophageal echocardiography (RT-3D TEE) may provide invaluable information about complex 3D anatomy of mitral PVLs compared to two-dimensional (2D) TEE findings. We, herein, aimed to evaluate the detailed description of anatomical characteristics of severe mitral PVLs using RT-3D TEE. Patients with diagnosis of severe mitral PVLs were simultaneously examined with 2D transthoracic echocardiography (TTE), 2D TEE, and RT-3D TEE. 3D characteristics of PVLs (localization, number, size, shape, etc.) were recorded and compared to 2D findings. Results were also compared with surgical findings. The study comprised 47 cases (3 bioprosthesis, 44 mechanical) with 61 severe mitral PVLs. The most common PVL localizations were anterolateral commissure, posteromedial commissures and posterolateral region. The mean PVL width measured by 2D TEE was 3.1±1.3 (range; 2-7) mm and the mean width of defect measured by 3D TEE was 3.1±1.1 (range; 2-7) mm (p=0.7). The mean length of defect measured by 3D TEE was 11.1±6.5 mm. The most common defect type was 'oval/round' shaped (n=29; 48%). There were also 19 'crescentic' (31%), 9 'slit like' (15%), and 2 tunnel-like shaped defects. In 22 patients, the site and dimension of the PVLs were all confirmed surgically. RT-3D TEE permits detailed structural evaluation of the prosthesis and description of paravalvular leak morphology compared to 2D TEE. It may provide more accurate information to the clinician in decision making and may contribute to the success of the potential corrective procedures. 23851613 Vanadium oxide-carbon nanotube composite electrodes for energy storage by supercritical fluid deposition: experiment design and device performance. Vanadium pentoxide (V2O5) deposited on porous multiwalled carbon nanotube (MWCNT) buckypaper using supercritical fluid CO2(scCO2) deposition shows excellent performance for electrochemical capacitors. However, the low weight loading of V2O5 is one of the main problems. In this paper, design of experiments and response surface methods were employed to explore strategies for improving the active material loading by increasing the organo-vanadium precursor adsorption. A second-order response surface model was fitted to the designed experiments to predict the loading of the vanadium precursors onto carbon nanotube buckypaper as a function of time, temperature and pressure of CO2, buckypaper functionalization, precursor type, initial precursor mass and stir speed. Operation conditions were identified by employing a model that led to a precursor loading of 19.33%, an increase of 72.28% over the initial screening design. CNTs-V2O5 composite electrodes fabricated from deposited samples using the optimized conditions demonstrated outstanding electrochemical performance (947.1 F g(-1) of V2O5 at a high scan rate 100 mV s(-1)). The model also predicted operation conditions under which light precursor aggregation took place. The V2O5 from aggregated precursor still possessed considerable specific capacitance (311 F g(-1) of V2O5 at a scan rate 100 mV s(-1)), and the significantly higher V2O5 loading (∼81%) contributed to an increase in overall electrode capacitance. 23929481 Draft Genome Sequence of Strain SA_ST125_MupR of Methicillin-Resistant Staphylococcus aureus ST125, a Major Clone in Spain. Here, we report the draft genome sequence of a methicillin-resistant Staphylococcus aureus (MRSA) strain with high-level mupirocin resistance (SA_ST125_MupR), isolated from a patient with recurrent bacteremia. This strain belonged to sequence type ST125, which was responsible for more than 50% of the health care-associated infections caused by MRSA in Spain. 23199228 Physicochemical analysis from real-time imaging of liposome tubulation reveals the characteristics of individual F-BAR domain proteins. The Fer-CIP4 homology-BAR (F-BAR) domain, which was identified as a biological membrane-deforming module, has been reported to transform lipid bilayer membranes into tubules. However, details of the tubulation process, the mechanism, and the properties of the generated tubules remain unknown. Here, we successfully monitored the entire process of tubulation and the behavior of elongated tubules caused by four different F-BAR domain family proteins (FBP17, CIP4, PSTPIP1, and Pacsin2) using direct real-time imaging of giant unilamellar liposomes with dark-field optical microscopy. FBP17 and CIP4 develop many protrusions simultaneously over the entire surface of individual liposomes, whereas PSTPIP1 and Pacsin2 develop only a few protrusions from a narrow restricted part of the surface of individual liposomes. Tubules formed by FBP17 or CIP4 have higher bending rigidities than those formed by PSTPIP1 or Pacsin2. The results provide striking evidence that these four F-BAR domain family proteins should be classified into two groups: one group of FBP17 and CIP4 and another group of PSTPIP1 and Pacsin2. This classification is consistent with the phylogenetic proximity among these proteins and suggests that the nature of the respective tubulation is associated with biological function. These findings aid in the quantitative assessment with respect to manipulating the morphology of lipid bilayers using membrane-deforming proteins. 23811219 20-Hydroxyecdysone-induced transcriptional activity of FoxO upregulates brummer and acid lipase-1 and promotes lipolysis in Bombyx fat body. In a previous study, we have shown that the molting hormone, 20-hydroxyecdysone (20E), reduces insect food consumption resulting in fat body lipolysis during the non-feeding molting and pupation stages, and assumed that the transcription factor FoxO is involved in this process. To verify this hypothesis, we cloned foxO from the silkworm, Bombyx mori. During molting and pupation, FoxO is highly expressed and predominantly localizes in the nuclei of fat body cells. 20E induced foxO mRNA expression and FoxO nuclear localization resulting in an increase of FoxO transcriptional activity. RNAi of foxO prior to the 4th larval molting downregulated two lipase genes - the insect adipose triacylglycerol lipase homologue, brummer, and an acid lipase, acid lipase-1, in the fat body. Overexpression of the constitutively-active form of foxO (foxO(CA)) upregulated brummer and acid lipase-1 in both the fat body and Bombyx Bm-12 cells. Putative FoxO-response elements (FREs) are present in the promoter regions of brummer and acid lipase-1, and mutation of the FREs attenuated their FoxO-induced luciferase activities. ChIP assay revealed that FoxO binds directly to those FREs. Moreover, foxO(CA) overexpression in vivo doubled lipid concentration in the hemolymph, increased total lipase activity, and slightly but significantly reduced lipid content in the fat body. Taken together, we conclude that 20E increases the transcriptional activity of FoxO which, in turn, upregulates brummer and acid lipase-1 and induces lipolysis in the Bombyx fat body during molting and pupation. 23862117 Mediterranean Fever gene analysis in the azeri turk population with familial mediterranean Fever: evidence for new mutations associated with disease. Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent febrile attacks accompanied by serosal and synovial membrane inflammation. FMF is caused by mutations in the MEFV gene and are found usually among Mediterranean populations, Armenians, Turks, Arabs and Jews. The aim of this study was to determine the frequency of MEFV gene mutations among FMF patients in the Azeri Turk population in North-West of Iran. In this descriptive study, 130 FMF patients with Azeri Turk origin were screened for mutations in four exons (2, 3, 5 and10) of MEFV gene. Genomic DNA was extracted from whole blood and entered in ARMS-PCR and PCR-RFLP reactions. When cases were negative in ARMS-PCR and PCR-RFLP, the exons were amplified and subjected to direct sequencing. Our results showed that the most common mutations in this study population was M694V (40.19%) followed by E148Q (17.64%), V726A (13.72%), M680I (12.74%) and M694I (2.94%) mutations. Four new mutations including K618N, K716M, S614F and G136E were identified in our study. The prevalence of five common mutations in our study was highly similar to previous studies analysing the Mediterranean basin populations. Investigation by sequencing also revealed four new variants in the study population. The main genotypephenotype correlation finding was the presence of M694V mutation in homozygote or compound heterozygote state in the patients with renal manifestations. 23934392 Microextraction by packed sorbents combined with surface-enhanced Raman spectroscopy for determination of musk ketone in river water. Microextraction by packed sorbents (MEPS) combined with Surface-enhanced Raman spectroscopy (SERS) was investigated, and applied to the determination of musk ketone (MK) in river water samples. The full MEPS-SERS method includes analyte enrichment by MEPS preconcentration with C18 sorbent followed by SERS detection supported by silver nanoparticles. An eluent drop containing the analyte is deposited directly from the MEPS syringe on a CaF2 glass plate. When the drop has dried, a specific volume of silver nanoparticles solution is added on it before each SERS measurement. Several experimental variables were studied in depth; under the optimum experimental conditions MK can be extracted from a 500 μL sample with recoveries in the range 47-63 %. The limit of detection was 0.02 mg L(-1) and the relative standard deviation 15.2 % (n = 4). Although not investigated in this work, the proposed method might be suitable for in-situ monitoring, because of the portability of the Raman spectrometer used. 23898802 Pretreatment of rice straw with combined process using dilute sulfuric acid and aqueous ammonia. Use of lignocellulosic biomass has received attention lately because it can be converted into various versatile chemical compounds by biological processes. In this study, a two-step pretreatment with dilute sulfuric acid and aqueous ammonia was performed efficiently on rice straw to obtain fermentable sugar. The soaking in aqueous ammonia process was also optimized by a statistical method. Response surface methodology was employed. The determination coefficient (R2) value was found to be 0.9607 and the coefficient of variance was 6.77. The optimal pretreatment conditions were a temperature of 42.75[degree sign]C, an aqueous ammonia concentration of 20.93%, and a reaction time of 48 h. The optimal enzyme concentration for saccharification was 30 filter paper units. The crystallinity index was approximately 60.23% and the Fourier transform infrared results showed the distinct peaks of glucan. Ethanol production using Saccharomyces cerevisiae K35 was performed to verify whether the glucose saccharified from rice straw was fermentable. The combined pretreatment using dilute sulfuric acid and aqueous ammonia on rice straw efficiently yielded fermentable sugar and achieved almost the same crystallinity index as that of alpha-cellulose. 23074145 Multicenter precision of cortical and trabecular bone quality measures assessed by high-resolution peripheral quantitative computed tomography. High-resolution peripheral quantitative computed tomography (HR-pQCT) has recently been introduced as a clinical research tool for in vivo assessment of bone quality. The utility of this technology to address important skeletal health questions requires translation to standardized multicenter data pools. Our goal was to evaluate the feasibility of pooling data in multicenter HR-pQCT imaging trials. Reproducibility imaging experiments were performed using structure and composition-realistic phantoms constructed from cadaveric radii. Single-center precision was determined by repeat scanning over short-term (<72 hours), intermediate-term (3-5 months), and long-term intervals (28 months). Multicenter precision was determined by imaging the phantoms at nine different HR-pQCT centers. Least significant change (LSC) and root mean squared coefficient of variation (RMSCV) for each interval and across centers was calculated for bone density, geometry, microstructure, and biomechanical parameters. Single-center short-term RMSCVs were <1% for all parameters except cortical thickness (Ct.Th) (1.1%), spatial variability in cortical thickness (Ct.Th.SD) (2.6%), standard deviation of trabecular separation (Tb.Sp.SD) (1.8%), and porosity measures (6% to 8%). Intermediate-term RMSCVs were generally not statistically different from short-term values. Long-term variability was significantly greater for all density measures (0.7% to 2.0%; p < 0.05 versus short-term) and several structure measures: cortical thickness (Ct.Th) (3.4%; p < 0.01 versus short-term), cortical porosity (Ct.Po) (15.4%; p < 0.01 versus short-term), and trabecular thickness (Tb.Th) (2.2%; p < 0.01 versus short-term). Multicenter RMSCVs were also significantly higher than short-term values: 2% to 4% for density and micro-finite element analysis (µFE) measures (p < 0.0001), 2.6% to 5.3% for morphometric measures (p < 0.001), whereas Ct.Po was 16.2% (p < 0.001). In the absence of subject motion, multicenter precision errors for HR-pQCT parameters were generally less than 5%. Phantom-based multicenter precision was comparable to previously reported in in vivo single-center precision errors, although this was approximately two to five times worse than ex vivo short-term precision. The data generated from this study will contribute to the future design and validation of standardized procedures that are broadly translatable to multicenter study designs. 23768401 Reducing the sulfur-dioxide binding power of sweet white wines by solid-phase extraction. The high sulfur-dioxide binding power of sweet white wines may be reduced by extracting the naturally present carbonyl compounds from wine that are responsible for carbonyl bisulphites formation. The carbonyl compounds mainly responsible for trapping SO2 are acetaldehyde, pyruvic acid, and 2-oxoglutaric acid. The method employed was selective solid phase extraction, using phenylsulfonylhydrazine as a scavenging agent. The scavenging function was grafted onto a support prepared from raw materials derived from lignin. This approach is more acceptable to winemakers than the polymer media previously reported, as it reduces the possible contamination of wine to molecules already present in the wine making process. 23543653 Novel 4-substituted-2(1H)-phthalazinone derivatives: synthesis, molecular modeling study and their effects on α-receptors. Novel 4-(4-bromophenyl)phthalazine derivatives connected via an alkyl spacer to amine or N-substituted piperazine were designed and synthesized as promising α-adrenoceptor antagonists. The structures of the phthalazine derivatives were established using elemental and spectral analyses. Twelve of the tested compounds displayed significant α-blocking activity. Molecular modeling studies were performed to rationalize the biological results. Among the tested compounds, 7j displayed the best-fitting score and the highest in vitro activity. 23792753 Symptom dimensions in obsessive-compulsive disorder: Differences in distress, interference, appraisals and neutralizing strategies. Cognitive proposals about the mediating role of misinterpretations, emotional reactions, and control strategies in the escalation of obsessional intrusive thoughts (OIT) to clinical obsessions have received only partial support. This study aims to examine these variables, taking into account the obsession/OIT contents and the severity of the Obsessive-Compulsive Disorder (OCD). After identifying their most upsetting OIT/obsession, 61 OCD patients and 61 non-clinical individuals assessed the associated distress, interference and appraisals, and the strategies used to control the obsession/OIT. Compared with the nonclinical subjects, OCD individuals scored higher on all variables. The obsession's severity was associated with high disturbance, interference and dysfunctional appraisals, whereas the compulsion's severity was related to specific control strategies. Different obsessional contents produced similar emotional disturbance and interference. However, obsessional contents influence the amount of adscription to different dysfunctional appraisals and the frequency of use of several control strategies. Our conclusions are limited by the scarce number of patients representing the various obsessive contents, specially order. Overall, superstitious obsessions were more dysfunctionally appraised than the other obsessional contents, inducing both covert and overt neutralizing strategies, whereas contamination obsessions were less dysfunctionally appraised. 23427019 Surface Enhanced Raman Scattering on Non-SERS Active Substrates and In Situ Electrochemical Study based on a Single Gold Microshell. A single gold microshell, which was elaborately fabricated to carry numerous hot spots on its own surface, enabled the acquisition of the SERS spectra from the molecules on non-SERS active substrates such as Si/SiO2 , ITO, and glass. A self-assembled monolayer of 11-mercaptoundecanols on the gold microshell offered an easy and reliable way to electrically insulate from the underlying flat Pt electrode and accomplish in situ monitoring the electrochemical reaction with minimal interference. 22456764 An unusual case of IgA-mediated anti-glomerular basement membrane disease. Anti-glomerular basement membrane (GBM) disease is mediated by circulating autoantibodies, principally IgG, targeted at the type IV collagen of GBM. The IgA variant of anti-GBM disease has rarely been described. We report a 65-year-old man with uremia, undergoing hemodialysis, who was referred because of hemoptysis. A chest X-ray showed diffuse infiltration in the right lung field. Laboratory data were remarkable for renal failure, anemia, and thrombocytopenia. Furthermore, laboratory evidence of microangiopathic hemolytic anemia was present. A kidney biopsy revealed diffuse crescentic glomerulonephritis. Circulating IgA anti-GBM antibody was found, as well as the presence of significant IgA deposition in a linear pattern along the GBM, suggesting an anti-GBM antibody-mediated disease. The patient was treated with plasmapheresis and pulse steroid therapy, which resulted in an immediate improvement in the pulmonary hemorrhage and hematological abnormalities. However, the patient did not regain renal function and remained on hemodialysis. 23778090 Fibroblast activation protein-α promotes ovarian cancer cell proliferation and invasion via extracellular and intracellular signaling mechanisms. Fibroblast activation protein-α (FAPα) is secreted by activated stromal fibroblasts and can promote ovarian cancer cell proliferation, migration and invasion. However, the molecular mechanism by which FAPα promotes tumor cell proliferation and invasion is unknown. The role of the non-enzymatic activities of FAPα in tumor migration and invasion and the intracellular and extracellular signaling mechanisms of FAPα were investigated. In this study, we confirm that FAPα promote ovarian cancer cell proliferation, migration and invasion by extracellular and intracellular signaling mechanisms. These results provide evidence that FAPα, together with integrin α3β1 and the uPAR signaling complex, mediate cancer cell migration in the HO-8910PM cell line via the small GTPase Rac1. FAPα-mediated upregulation of p-ERK occurred in a time-dependent manner. 23929504 Value-Based Insurance Design: Aligning Incentives and Evidence in Pulmonary Medicine. ABSTRACT When consumers are required to pay the same out-of-pocket amount for pulmonary services for which clinical benefits depend on patient characteristics, clinical indication, and provider choice, there is enormous potential for both under- and overutilization. Unlike most current "one size fits all" health plan designs, value-based insurance design (V-BID) explicitly acknowledges clinical heterogeneity across the continuum of care. By adding "clinical nuance" to benefit design, V-BID seeks to align consumer and provider incentives with value, encouraging use of high-value services and discouraging use of low-value interventions. This manuscript further describes the concept of V-BID, creates a framework for its development in pulmonary medicine, and outlines how this concept aligns with research, care delivery, and payment reform initiatives. 23939725 Developing indicators of service integration for child health: Perceptions of service providers and families of young children in a region of high need in New Zealand. Children in many areas of New Zealand have poor health indices; statistics indicate health inequalities. Existing international indicators of child health currently take little account of local context. There are few composite indicators of how child health services are integrated at a community level. This study aimed to explore what local people consider would be useful indicators of better child health. Data for this qualitative study were collected via 24 individual interviews and two focus groups in a rural area of New Zealand. A total of 13 in-depth interviews were conducted with parents/families of small children. Participants were asked about wide-ranging aspects of child health. Also, 11 interviews and two focus groups were conducted with front line health professionals/stakeholders. Key themes from the content thematic analysis: include child health should be measured in multidimensional ways; essential interdependence of family--child health; universal access to culturally appropriate care, free primary care services and parenting education and support is needed; and there is a lack of integration and communication between health, education and social services. There is an important need to measure and monitor communication/integration across existing health, education and social services, provide better parenting support and health education and improve access to culturally appropriate primary care. 23906262 Phylogenetic analyses of vector mosquito basic helix-loop-helix transcription factors. Basic helix-loop-helix (bHLH) transcription factors play critical roles in the regulation of a wide range of developmental processes in higher organisms and have been identified in more than 20 organisms. Mosquitoes are important vectors of certain human diseases. In this study, Aedes aegypti, Anopheles gambiae str. PEST and Culex quinquefasciatus genomes were found to encode 55, 55 and 57 bHLH genes, respectively. Further phylogenetic analyses and OrthoDB and Kyoto encyclopedia of genes and genomes orthology database searches led us to define orthology for all the identified mosquito bHLHs successfully. This provides useful information with which to update annotations to 40 Ae. aegypti, 55 An. gambiae and 38 C. quinquefasciatus bHLH genes in VectorBase. The mosquito lineage has more bHLH genes in the Atonal, neurogenin (Ngn) and Hes-related with YRPW motif (Hey) families than do other insect species, suggesting that mosquitoes have evolved to be more sensitive to vibration, light and chemicals. Mosquito bHLH genes generally have higher evolutionary rates than other insect species. However, no pervasive positive selection occurred in the evolution of insect bHLH genes. Only episodic positive selection was found to affect evolution of bHLH genes in 11 families. Besides, coding regions of several Ae. aegypti bHLH motifs have unusually long introns in which multiple copies of transposable elements have been identified. These data provide a solid basis for further studies on structures and functions of bHLH proteins in the regulation of mosquito development and for prevention and control of mosquito-mediated human diseases. 23599212 Flap infection associated with medicinal leeches in reconstructive surgery: two new drug-resistant organisms. The use of medicinal leeches in reconstructive surgery has proven value for the salvage of flaps with venous congestion but is associated with a risk of leech-acquired infection. The most common leech-associated organism is Aeromonas hydrophila, which antibiotic prophylaxis is typically directed against. The authors describe two new multidrug-resistant organisms acquired from medicinal leech therapy that resulted in flap infection. The evaluation of suspected leech-borne infection and management protocol for this leech-acquired resistant multi-organism infection is presented. 23954231 Hemojuvelin-hepcidin axis modeled and analyzed using Petri nets. Systems biology approach to investigate biological phenomena seems to be very promising because it is capable to capture one of the fundamental properties of living organisms, i.e. their inherent complexity. It allows for analysis biological entities as complex systems of interacting objects. The first and necessary step of such an analysis is building a precise model of the studied biological system. This model is expressed in the language of some branch of mathematics, as for example, differential equations. During the last two decades the theory of Petri nets has appeared to be very well suited for building models of biological systems. The structure of these nets reflects the structure of interacting biological molecules and processes. Moreover, on one hand, Petri nets have intuitive graphical representation being very helpful in understanding the structure of the system and on the other hand, there is a lot of mathematical methods and software tools supporting an analysis of the properties of the nets. In this paper a Petri net based model of the hemojuvelin-hepcidin axis involved in the maintenance of the human body iron homeostasis is presented. The analysis based mainly on T-invariants of the model properties has been made and some biological conclusions have been drawn. 23847209 Pseudophosphatase STYX modulates cell-fate decisions and cell migration by spatiotemporal regulation of ERK1/2. Serine/threonine/tyrosine-interacting protein (STYX) is a catalytically inactive member of the dual-specificity phosphatases (DUSPs) family. Whereas the role of DUSPs in cellular signaling is well explored, the function of STYX is still unknown. Here, we identify STYX as a spatial regulator of ERK signaling. We used predictive-model simulation to test several hypotheses for possible modes of STYX action. We show that STYX localizes to the nucleus, competes with nuclear DUSP4 for binding to ERK, and acts as a nuclear anchor that regulates ERK nuclear export. Depletion of STYX increases ERK activity in both cytosol and nucleus. Importantly, depletion of STYX causes an ERK-dependent fragmentation of the Golgi apparatus and inhibits Golgi polarization and directional cell migration. Finally, we show that overexpression of STYX reduces ERK1/2 activation, thereby blocking PC12 cell differentiation. Overall, our results identify STYX as an important regulator of ERK1/2 signaling critical for cell migration and PC12 cell differentiation. 23955247 Life-prolonging measures for a dead theory? In a recent review article, Selman and colleagues (Trends Ecol Evol 27:570-577, 2012) discuss the status quo of the oxidative stress theory of aging (OSTA) and how it links to life history evolution. They suggest that the OSTA should be tested in wild populations which might show effects masked in laboratory settings. We disagree with their propositions for several reasons. We argue that there is increasing evidence that reactive oxygen species (ROS) are not causally linked with aging and that ROS do not play a straightforward role in shaping life history evolution. We propose that laboratory animals and semi-wild populations rather than wild animals are suited best to test any hypothesized effect of reactive oxygen species. This is because data from controlled manipulative experiments rather than observational correlations are preferred to solve this issue. In addition, nonconventional model organisms will be useful in answering the question how relevant the OSTA could be for life history evolution. 23731865 Development of a larval bioassay using the calanoid copepod, Eurytemora affinis to assess the toxicity of sediment-bound pollutants. Hydrophobic pollutants, in particular sediment-sorbed organic compounds, are widespread in the aquatic environment and could represent a threat to living organisms. Estuarine species, which live in turbulent ecosystems, are particularly exposed to this mode of contamination. For precise evaluation of the toxicity of hydrophobic contaminants desorbed from particles, a new larval assay using nauplii of the estuarine calanoid copepod Eurytemora affinis was developed. It consists of the direct exposure of copepods during naupliar development to elutriates of an unpolluted sediment spiked with different model contaminants. This bioassay measures the toxicity of the bioavailable fraction of particle-sorbed pollutants on the naupliar stage of copepods. Mortality and growth (non-invasive endpoints) in nauplii were analysed after six days of exposure. This approach was validated using six pollutants with different modes of action: benzo[a]pyrene (BaP), dimethylbenzo[a]anthracene (DMBA), phenanthrene (PHE), polychlorinated biphenyls (PCB 126, PCB 153) and 4-nonylphenol (4-NP). All these compounds induced a dose-dependent increase in toxic effects. Lethal effects only occurred at the highest tested concentrations: 58,541 and 6092 ng g(-1) dry weight sediment (dws), for PHE and DMBA, respectively. Sublethal effects (growth inhibition) were observed at lower concentrations for all tested compounds except PCB 153, from 8, 142, 297, 6092 and 8453 ng g(-1) dws for PCB 126, BaP, PHE, DMBA and 4-NP, respectively. 23951168 Sonic hedgehog-induced histone deacetylase activation is required for cerebellar granule precursor hyperplasia in medulloblastoma. Medulloblastoma, the most common pediatric brain tumor, is thought to arise from deregulated proliferation of cerebellar granule precursor (CGP) cells. Sonic hedgehog (Shh) is the primary mitogen that regulates proliferation of CGP cells during the early stages of postnatal cerebellum development. Aberrant activation of Shh signaling during this time has been associated with hyperplasia of CGP cells and eventually may lead to the development of medulloblastoma. The molecular targets of Shh signaling involved in medulloblastoma formation are still not well-understood. Here, we show that Shh regulates sustained activation of histone deacetylases (HDACs) and that this activity is required for continued proliferation of CGP cells. Suppression of HDAC activity not only blocked the Shh-induced CGP proliferation in primary cell cultures, but also ameliorated aberrant CGP proliferation at the external germinal layer (EGL) in a medulloblastoma mouse model. Increased levels of mRNA and protein of several HDAC family members were found in medulloblastoma compared to wild type cerebellum suggesting that HDAC activity is required for the survival/progression of tumor cells. The identification of a role of HDACs in the early steps of medulloblastoma formation suggests there may be a therapeutic potential for HDAC inhibitors in this disease. 23085672 N-acetylcysteine-pretreated human embryonic mesenchymal stem cell administration protects against bleomycin-induced lung injury. The transplantation of mesenchymal stem cells (MSCs) has been reported to be a promising approach in the treatment of acute lung injury. However, the poor efficacy of transplanted MSCs is one of the serious handicaps in the progress of MSC-based therapy. Therefore, the purpose of this study was to investigate whether the pretreatment of human embryonic MSCs (hMSCs) with an antioxidant, namely N-acetylcysteine (NAC), can improve the efficacy of hMSC transplantation in lung injury. In vitro, the antioxidant capacity of NAC-pretreated hMSCs was assessed using intracellular reactive oxygen species (ROS) and glutathione assays and cell adhesion and spreading assays. In vivo, the therapeutic potential of NAC-pretreated hMSCs was assessed in a bleomycin-induced model of lung injury in nude mice. The pretreatment of hMSCs with NAC improved antioxidant capacity to defend against redox imbalances through the elimination of cellular ROS, increasing cellular glutathione levels, and the enhancement of cell adhesion and spreading when exposed to oxidative stresses in vitro. In addition, the administration of NAC-pretreated hMSCs to nude mice with bleomycin-induced lung injury decreased the pathological grade of lung inflammation and fibrosis, hydroxyproline content and numbers of neutrophils and inflammatory cytokines in bronchoalveolar lavage fluid and apoptotic cells, while enhancing the retention and proliferation of hMSCs in injured lung tissue and improving the survival rate of mice compared with results from untreated hMSCs. The pretreatment of hMSCs with NAC could be a promising therapeutic approach to improving cell transplantation and, therefore, the treatment of lung injury. 23568586 Doxycycline prevents acute pulmonary embolism-induced mortality and right ventricular deformation in rats. Acute pulmonary embolism (APE) is a critical cardiopulmonary condition associated with right ventricular (RV) failure and death. While pharmacological inhibition of matrix metalloproteinases (MMPs) attenuated APE-induced hemodynamic alterations, no previous study has evaluated whether this approach decreases APE-induced mortality and RV deformation. We tested this hypothesis in rats. Wistar rats received an intraperitoneal injection of 30 mg/kg doxycycline (or saline) and after 30 min a sterile suspension of 300 Î¼m microsphere (21 mg/kg or saline) was injected into the tail vein. After 24 h, surviving animals were killed and the RVs were collected and used for histological and morphometric analyses. RV samples were also homogenized and assayed by SDS-polyacrilamide gel electrophoresis gelatin zymography to evaluate MMP-2 and MMP-9 activity. In situ zymography was carried out in RV to assess MMP activity and neutrophil accumulation in myocardial tissue was determined by myeloperoxidase activity measurement. Dihydroethidium was used to assess RV reactive oxygen species concentrations. APE caused 72.5 % mortality during the first hour of follow up. Pretreatment with doxycycline was associated with significant decrease in APE-induced mortality rate to 50 % (P < 0.05). Embolized animals showed significant RV dilation, and pretreatment with doxycycline blunted this alteration (P < 0.05). APE increased the number of RV neutrophils and MMP-9 levels (P < 0.05). Pretreatment with doxycycline blunted APE-induced increases in RV myocardial ROS concentrations and MMP gelatinolytic activity (both P < 0.05). These findings show that MMP inhibition with doxycycline protects against APE-induced mortality and RV enlargement. These beneficial effects are probably due to attenuation of APE-induced oxidative stress and increases in ventricular proteolytic activity and suggest that doxycycline may have promising protective effects in patients with APE. 23941357 Local control of cis-peptidyl-prolyl bonds mediated by CH⋅⋅⋅π interactions: The Xaa-Pro-Tyr motif. Compared to generic peptide bonds, the peptidyl-prolyl bond shows a high propensity for the cis-conformer. The presence of a sequence-contiguous aromatic (Aro) residue can further stabilize the cis-conformer, as observed for the Aro-Pro motif. The cis-propensity of the reverse sequence motif, Pro-Aro, is not so well understood, especially the effect of N-capping the Pro-Aro motif with different amino acid residues. From a comparative NMR study on two peptide series with the general sequence, Ac-Xaa-Pro-Tyr-NH2 and Ac-Xaa-Pro-Ala-NH2, we present a relative thermodynamic scale that reflects how the nature of Xaa sidechain influences the cis-propensity of the Xaa-Pro-Tyr motif, with Gly, Pro and Ala at position Xaa exhibiting the highest enhancement of the cis peptidyl-prolyl population. We also show that CH⋅⋅⋅π interaction, operative between Xaa and Tyr is responsible for the enhanced cis-population. However, the mere presence of the CH⋅⋅⋅π interaction does not guarantee that the peptidyl-prolyl bond will have a higher cis-content in Xaa-Pro-Tyr compared to that in Xaa-Pro-Ala. Xaa-dependent intra-molecular interactions present in Xaa-transPro-Tyr can nullify favorable CH⋅⋅⋅π interactions in Xaa-cisPro-Tyr. The relative cis-peptidyl-prolyl stabilizing propensities of Xaa (Xaa-Pro-Tyr) in proteins and in our peptide series show strong linear correlation except when Xaa is aromatic. We also explore the sequence motif Xaa-Pro-Gly-Tyr and show that mediated by a Pro-Tyr CH⋅⋅⋅π interaction, the cis-peptidyl-prolyl bond in the motif is stabilized when Xaa is Pro. 23780343 Effectiveness of Sal Deoiled Seed Cake as an Inducer for Protease Production from Aeromonas sp. S1 for its Application in Kitchen Wastewater Treatment. The present study is an attempt to demonstrate the feasibility of sal (Shorea robusta) deoiled cake-a forest-based industrial by-product-as a cheaper media supplement for augmented protease production from Aeromonas sp. S1 and application of protease in the treatment of kitchen wastewater. Under optimized conditions, protease production could successfully be enhanced to 5.13-fold (527.5 U mL(-1)) on using sal deoiled seed cake extract (SDOCE), as medium additive, compared to an initial production of 102.7 U mL(-1) in its absence. The culture parameters for optimum production of protease were determined to be incubation time (48 h), pH (7.0), SDOCE concentration (3 % (v/v)), inoculum size (0.3-0.6 % (v/v)), and agitation rate (100 rpm). The enzyme was found to have an optimum pH and temperature of 8.0 and 60 °C, respectively. The protease preparation was tested for treatment of organic-laden kitchen wastewater. After 96 h of wastewater treatment under static condition, enzyme preparation was able to reduce 74 % biological oxygen demand, 37 % total suspended solids, and 41 % oil and grease. The higher and improved level of protease obtained using sal deoiled seed cake-based media hence offers a new approach for value addition to this underutilized biomass through industrial enzyme production. The protease produced using this biomass could also be used as pretreatment tool for remediation of organic-rich food wastewater. 23932416 Outcomes of Endovascular Management for Complicated Chronic Type B Aortic Dissection: Effect of the Extent of Stent Graft Coverage and Anatomic Properties of Aortic Dissection. To assess the effect of the extent of stent graft coverage and anatomic properties of aortic dissection on the outcomes of thoracic endovascular aortic repair (TEVAR) for complicated chronic type B aortic dissection (CCBAD) in terms of survival, reintervention, and false lumen thrombosis. A retrospective analysis was performed of 71 patients who underwent TEVAR for CCBAD. Mean patient age was 54.7 years. Distal extent of stent graft coverage was categorized as short (≤ T7) or long (≥ T8) coverage. Indications of reintervention were categorized into three groups: proximal, alongside, and distal according to the anatomic relationship of the culprit lesion and the stent graft. Overall survival, reintervention-free survival, and extent of false lumen thrombosis were compared. The technical success rate was 97.2%. The 1-year, 3-year, and 5-year overall survival rates were 97.1%, 88.9%, and 88.9%, and 1-year, 3-year, and 5-year reintervention-free survival rates were 80.7%, 73.8%, and 60.6%. There were no differences in overall survival, reintervention-free survival rates, and extent of false lumen thrombosis between the groups. In the short coverage group, distal reintervention was more frequent in patients with an abdominal aortic diameter ≥ 37 mm compared with patients with an abdominal aortic diameter < 37 mm (P = .005). TEVAR was effective for CCBAD with a high technical success rate and low mortality. The extent of stent graft coverage did not make a difference in terms of survival and false lumen thrombosis. Reinterventions were more frequently performed in patients with a large baseline abdominal aortic diameter who were treated with short stent graft coverage, and so longer coverage is recommended in such patients. 22566187 Evaluation of food-drug interaction of guava leaf tea. Guava leaf tea (GLT) contains guava leaf polyphenol (Gvpp), which regulates the absorption of dietary carbohydrate from the intestines. Borderline diabetics, who are at high risk of development of diabetes, take GLT to suppress a rapid increase of blood sugar level after meals. However, patients with diabetes in whom diabetic drugs or warfarin as a blood thinner are prescribed also take GLT with the expectation of glycemic control. Therefore, we studied whether GLT had potential for inhibition or induction of cytochrome P450 (CYP) and an influence on the action of warfarin. Extract of guava leaf (GvEx) consists of carbohydrate and polyphenols, which are Gvpp, quercetin, and ellagic acid. These polyphenols, but not GvEx, showed a certain level of inhibition of human-cDNA-expressed CYPs. In a comparison of GLT and grapefruit juice, GLT showed weaker inhibition of CYP activities and of midazolam 1'-hydroxylation than grapefruit juice. Furthermore, neither liver weight nor CYP3A expression in the liver was changed in rats that received GvEx for 90 days compared with the control group. When rats were concomitantly treated with GLT and warfarin, the prolongation of clotting time of blood by warfarin was not influenced. These data suggest that GLT is unlikely to interact with drugs. 23831494 Treating influenza with statins and other immunomodulatory agents. Statins not only reduce levels of LDL-cholesterol, they counteract the inflammatory changes associated with acute coronary syndrome and improve survival. Similarly, in patients hospitalized with laboratory-confirmed seasonal influenza, statin treatment is associated with a 41% reduction in 30-day mortality. Most patients of any age who are at increased risk of influenza mortality have chronic low-grade inflammation characteristic of metabolic syndrome. Moreover, differences in the immune responses of children and adults seem responsible for the low mortality in children and high mortality in adults seen in the 1918 influenza pandemic and in other acute infectious and non-infectious conditions. These differences probably reflect human evolutionary development. Thus the host response to influenza seems to be the major determinant of outcome. Outpatient statins are associated with reductions in hospitalizations and deaths due to sepsis and pneumonia. Inpatient statins are also associated with reductions in short-term pneumonia mortality. Other immunomodulatory agents - ACE inhibitors (ACEIs), angiotensin receptor blockers (ARBs), PPARγ and PPARα agonists (glitazones and fibrates) and AMPK agonists (metformin) - also reduce mortality in patients with pneumonia (ACEIs, ARBs) or in mouse models of influenza (PPAR and AMPK agonists). In experimental studies, treatment has not increased virus replication. Thus effective management of influenza may not always require targeting the virus with vaccines or antiviral agents. Clinical investigators, not systems biologists, have been the first to suggest that immunomodulatory agents might be used to treat influenza patients, but randomized controlled trials will be needed to provide convincing evidence that they work. To guide the choice of which agent(s) to study, we need new types of laboratory research in animal models and clinical and epidemiological research in patients with critical illness. These studies will have crucial implications for global public health. During the 2009 H1N1 influenza pandemic, timely and affordable supplies of vaccines and antiviral agents were unavailable to more than 90% of the world's people. In contrast, statins and other immunomodulatory agents are currently produced as inexpensive generics, global supplies are huge, and they would be available to treat patients in any country with a basic health care system on the first pandemic day. Treatment with statins and other immunomodulatory agents represents a new approach to reducing mortality caused by seasonal and pandemic influenza. This article forms part of a symposium in Antiviral Research on "Treatment of influenza: targeting the virus or the host". 23962633 Lymphoplasmacytic hypophysitis associated with immunoglobulin G4. We present the unusual case of a 33-year-old woman who presented with a 2year history of amenorrhoea and an expanding sellar lesion. Initial MRI revealed a lesion in the pituitary fossa, thought to be a pituitary adenoma. One year later, the lesion had enlarged by 5mm, with associated enhancement of the dura of the planum sphenoidale and pituitary stalk. Histopathology revealed a lymphocytic and plasma cell inflammatory infiltrate suggestive of lymphoplasmacytic hypophysitis associated with immunoglobulin G4. 23755995 Poly(methacrylic acid)-grafted chitosan microspheres via surface-initiated ATRP for enhanced removal of Cd(II) ions from aqueous solution. Cross-linked chitosan (CCS) microspheres tethered with pH-sensitive poly(methacrylic acid) (PMAA) brushes were developed for the efficient removal of Cd(II) ions from aqueous solutions. Functional PMAA brushes containing dense and active carboxyl groups (COOH) were grafted onto the CCS microsphere surface via surface-initiated atom transfer radical polymerization (ATRP). Batch adsorption results showed that solution pH values had a major impact on cadmium adsorption by the PMAA-grafted CCS microspheres with the optimal removal observed above pH 5. The CCS-g-PMAA microsphere was found to achieve the adsorption equilibrium of Cd(II) within 1 h, much faster than about 7 h on the CCS microsphere. At pH 5 and with an initial concentration 0.089-2.49 mmol dm(-3), the maximum adsorption capacity of Cd(II), derived from the Langmuir fitting on the PMAA-grafted microspheres was around 1.3 mmol g(-1). Desorption and adsorption cycle experimental results revealed that the PMAA-grafted CCS microspheres loaded with Cd(II) can be effectively regenerated in a dilute HNO3 solution, and the adsorption capacity remained almost unchanged upon five cycle reuse. 23579475 Comparing audio and video data for rating communication. Video recording has become increasingly popular in nursing research, adding rich nonverbal, contextual, and behavioral information. However, benefits of video over audio data have not been well established. We compared communication ratings of audio versus video data using the Emotional Tone Rating Scale. Twenty raters watched video clips of nursing care and rated staff communication on 12 descriptors that reflect dimensions of person-centered and controlling communication. Another group rated audio-only versions of the same clips. Interrater consistency was high within each group with Interclass Correlation Coefficient (ICC) (2,1) for audio .91, and video = .94. Interrater consistency for both groups combined was also high with ICC (2,1) for audio and video = .95. Communication ratings using audio and video data were highly correlated. The value of video being superior to audio-recorded data should be evaluated in designing studies evaluating nursing care. 23927756 Solvothermal Synthesis of Microporous, Crystalline Covalent Organic Framework Nanofibers and their Colorimetric Nanohybrid Structures. This paper reports a facile solvothermal approach for the design and synthesis of novel crystalline COF nanofibers with amazing properties. An interesting morphological transformation from microsphere to nanofibers was observed, which could be supported by the unique dissolution-recrystallization mechanism due to the reversible nature of dynamic imine bonding. Interestingly, it was also found that the COF nanofibers could epitaxial grow on the aramid microfiber surface. This functional nanocomposite showed an interesting colorimetric humidity-responsive behavior. Our study provides a general methodology for the fabrication of COFs with designated micro-nanostructures and has more implications on their applications in catalyst and sensors. 23358190 Functional profiling discovers the dieldrin organochlorinated pesticide affects leucine availability in yeast. Exposure to organochlorinated pesticides such as dieldrin has been linked to Parkinson's and Alzheimer's diseases, endocrine disruption, and cancer, but the cellular and molecular mechanisms of toxicity behind these effects remain largely unknown. Here we demonstrate, using a functional genomics approach in the model eukaryote Saccharomyces cerevisiae, that dieldrin alters leucine availability. This model is supported by multiple lines of congruent evidence: (1) mutants defective in amino acid signaling or transport are sensitive to dieldrin, which is reversed by the addition of exogenous leucine; (2) dieldrin sensitivity of wild-type or mutant strains is dependent upon leucine concentration in the media; (3) overexpression of proteins that increase intracellular leucine confer resistance to dieldrin; (4) leucine uptake is inhibited in the presence of dieldrin; and (5) dieldrin induces the amino acid starvation response. Additionally, we demonstrate that appropriate negative regulation of the Ras/protein kinase A pathway, along with an intact pyruvate dehydrogenase complex, is required for dieldrin tolerance. Many yeast genes described in this study have human orthologs that may modulate dieldrin toxicity in humans. 23460310 Transfection of Mammalian Cells Using Block Copolypeptide Vesicles. An arginine-leucine block copolypeptide (R60 L20 ) is synthesized, which is capable of forming vesicles with controllable sizes, able to transport hydrophilic cargo across the cell membrane, and exhibit relatively low cytotoxicity. The R60 L20 vesicles also possess the ability to deliver DNA into mammalian cells for transfection. Although the transfection efficiency is lower than that of the commercially available transfection agent Lipofectamine 2000, the R60 L20 vesicles are able to achieve transfection with significantly lower cytotoxicity and immunogenicity. This behavior is potentially due to its stronger interaction with DNA which subsequently provides better protection against anionic heparin. 23902530 The diagnostic role of diffusion tensor imaging in multifocal inflammatory leukoencephalopathy. Multifocal inflammatory leukoencephalopathy (MIL) is a rare syndrome that can occur in patients with colon cancer after chemotherapy with 5-fluorouracil (5-FU) and levamisole. Histologic diagnosis by brain biopsy is most effective, but there can be high surgical risks and technical limitations. Therefore, we introduce a noninvasive diagnostic technique using diffusion tensor imaging (DTI) for patients suspected to have MIL. A 45-year-old woman had been treated for 12 weeks with levamisole and 5-FU for adenocarcinoma of the cecum, when she complained of ataxia, diplopia and left ptosis. Brain MRI showed a nodular enhancing lesion in the left midbrain, using gadolinium enhanced T1-weighted imaging, and scattered multiple white matter lesions throughout the cerebral hemisphere. Instead of a brain biopsy, DTI was performed that revealed reduced fractional anisotropy (FA) and increased radial diffusivity (RD) in the left midbrain lesion compared with the right midbrain denoting demyelination. Levamisole and 5-FU were discontinued, and she received intravenously 1 g of methylprednisolone daily for 5 d. After five weeks, follow-up DTI showed an increased FA and decreased RD, signifying the reversibility. DTI therefore may provide valuable information on diagnosing MIL and assessing the treatment response. 23816249 Does hyperbaric oxygen therapy have the potential to improve salivary gland function in irradiated head and neck cancer patients? Following radiotherapy, many patients with osteoradionecrosis suffer from xerostomia, thereby decreasing their quality of life. Patients can develop problems with speech, eating, increased dental caries, dysphagia, fractured dentition, chronic refractory osteomyelitis and osteoradionecrosis. Symptoms associated with salivary gland dysfunction can be severe enough that patients terminate the course of their radiotherapy prematurely due to the decrease in their quality of life. Currently, the only treatments available to patients are palliative. A definitive treatment has yet to be discovered. Head and neck cancers, which comprise 5% of overall cancer treatments, rank 8th most expensive to treat in the United States today. Hyperbaric oxygen is being considered for the therapy of radiated salivary glands because it has been shown to stimulate capillary angiogenesis and fibroplasia in radiation treated tissues. It has been hypothesized that salivary acinar cells undergo apoptosis following radiation therapy. The purpose of this paper is to discuss the mechanisms of salivary gland injury and evaluate whether hyperbaric oxygen therapy improves salivary gland function in patients who develop xerostomia and osteoradionecrosis following head and neck radiation. 23856784 Binding characteristics of raltegravir to plasma proteins. The objective was to characterize raltegravir (RAL) binding to albumin and alpha-1-acid glycoprotein (AAG). Unbound and bound RAL were separated by ultrafiltration. Association constant (Ka) was estimated from graphical method. In HIV-infected patients, average plasma protein binding is 76%. RAL did not bind to AAG but bound to non-saturable, low-affinity albumin sites with an n.Ka product of 9.8 10(2) L/mol. An increase of 0.2 units in pH led to a 2% increase in bound fraction. 23900719 Distinct Expression of Mas1-Related G-Protein-Coupled Receptor B4 in Dorsal Root and Trigeminal Ganglia-Implications for Altered Behaviors in Acid-Sensing Ion Channel 3-Deficient Mice. Mas1-related G-protein-coupled receptors (Mrgprs), comprising more than 50 distinct members, are specifically expressed in primary sensory neurons. Reflecting the diversity and specificity of stimuli they detect, Mrgprs are involved in pain, touch, and itch-related behaviors. Sensory-neuron-specific acid-sensing ion channel 3 (ASIC3) is essential for touch and inflammatory pain, but mice lacking ASIC3 have complex behavioral alterations in various modalities of pain and touch. To understand whether Mrgprs are involved in complex behavioral alterations found in ASIC3-deficient mice, we examined Mrgpr gene expression in ASIC3(-/-) mice. Only MrgprB4 expression has shown significant change. MrgprB4 expression was increased in ASIC3(-/-) dorsal root ganglia (DRG) but decreased in ASIC3(-/-) trigeminal ganglia. The distinct alterations in DRG and trigeminal ganglia imply that MrgprB4 could have multiple functions. Given that MrgprB4 is expressed in neurons that may detect gentle touch and that ASIC3(-/-) mice have altered sensitivity of mechanoreceptors for light touch, the expression change of MrgprB4 is more likely related to the altered touch behaviors of ASIC3(-/-) mice. 23940805 Mapping sub-antarctic cushion plants using random forests to combine very high resolution satellite imagery and terrain modelling. Monitoring changes in the distribution and density of plant species often requires accurate and high-resolution baseline maps of those species. Detecting such change at the landscape scale is often problematic, particularly in remote areas. We examine a new technique to improve accuracy and objectivity in mapping vegetation, combining species distribution modelling and satellite image classification on a remote sub-Antarctic island. In this study, we combine spectral data from very high resolution WorldView-2 satellite imagery and terrain variables from a high resolution digital elevation model to improve mapping accuracy, in both pixel- and object-based classifications. Random forest classification was used to explore the effectiveness of these approaches on mapping the distribution of the critically endangered cushion plant Azorellamacquariensis Orchard (Apiaceae) on sub-Antarctic Macquarie Island. Both pixel- and object-based classifications of the distribution of Azorella achieved very high overall validation accuracies (91.6-96.3%, κ = 0.849-0.924). Both two-class and three-class classifications were able to accurately and consistently identify the areas where Azorella was absent, indicating that these maps provide a suitable baseline for monitoring expected change in the distribution of the cushion plants. Detecting such change is critical given the threats this species is currently facing under altering environmental conditions. The method presented here has applications to monitoring a range of species, particularly in remote and isolated environments. 23643890 A bacterial monorhamnolipid alters the biophysical properties of phosphatidylethanolamine model membranes. This work presents a biophysical study on the interactions of a monorhamnolipid (monoRL) produced by Pseudomonas aeruginosa MA01 with model dielaidoylphosphatidylethanolamine (DEPE) membranes. Incorporation of monoRL into DEPE shifts the onset temperature of the Lβ-to-Lα and the Lα-to-HII phase transitions toward lower values. Incorporation of monoRL into DEPE indicates the coexistence of lamellar and hexagonal-HII phases in rhamnolipid-containing samples at 60°C, at which pure DEPE is lamellar. Thus, both techniques show that monoRL facilitates formation of the hexagonal-HII phase in DEPE, i.e. it destabilizes the bilayer organization. The phase diagram for the phospholipid component indicates a near-ideal behavior, with better miscibility of monoRL into DEPE in the fluid phase than in the gel phase. The various vibrational mode bands of the acyl chains of DEPE were studied by FTIR spectroscopy, focusing on the CH2 symmetric stretching mode. Incorporation of monoRL into DEPE shifts the frequency of this band to higher wavenumbers, at temperatures both below and above the main gel to liquid-crystalline phase transition. Examination of the CO stretching band of DEPE indicates that monoRL/DEPE interactions result in an overall dehydration effect on the polar headgroup of DEPE. These results are discussed in light of the possible role of rhamnolipids as bilayer stabilizers/destabilizers during cell membrane fluctuation events. 23911933 Epigenetic alterations by NuRD and PRC2 in the neonatal mouse cochlea. Mammalian cochlear supporting cells remain quiescent at postnatal ages and age-dependent changes in supporting cell proliferative capacity are evident. Ectopic Atoh1 expression in neonatal supporting cells converts only a small percentage of these cells into hair cell-like cells. Despite tremendous potential for therapeutics, cellular reprogramming in the mammalian inner ear remains a slow inefficient process that requires weeks, with most cells failing to reprogram. Cellular reprogramming studies in other tissues have shown that epigenetic inhibitors can significantly improve reprogramming efficiency. Very little is known about epigenetic regulation in the mammalian inner ear, and almost nothing is known about the histone modifications. Histone modifications are vital for proper transcriptional regulation, and aberrant histone modifications can cause defects in the regulation of genes required for normal tissue development and maintenance. Our data indicate that cofactors of repressive complexes such as NuRD and PRC2 are present in the neonatal organ of Corti. These NuRD cofactors are present throughout most of the organ of Corti from E18.5 until P4. By P6, these NuRD cofactors are mostly undetectable by immunofluorescence and completely lost by P7, but are detectable again at P8 and continue to be present through P21. The PRC2 enzymatic subunit, EZH2 is also highly present from E18.5 to P0 in the organ of Corti, but lost between P2 and P4. However, EZH2 staining is evident again throughout the organ of Corti by P6 and persists through P21. Our data provide evidence that HDACs, DNA methyltransferases, histone methyltransferases, and histone demethylases are expressed postnatally within the organ of Corti, and may be targets for drug inhibition to increase the capacity, speed, and efficiency of reprogramming a supporting cell into a hair cell. 23718142 Simultaneous thoracic and abdominal transplantation: can we justify two organs for one recipient? Simultaneous thoracic and abdominal (STA) transplantation is controversial because two organs are allocated to a single individual. We studied wait-list urgency, and whether transplantation led to successful outcomes. Candidates and recipients for heart-kidney (SHK), heart-liver (SHLi), lung-liver (SLuLi) and lung-kidney (SLuK) were identified through the United Network for Organ Sharing (UNOS) and outcomes were compared to single-organ transplantation. Since 1987, there were 1801 STA candidates and 836 recipients. Wait-list survival at 1- and 3 years for SHK (67.4%, 40.8%; N = 1420), SHLi (65.7%, 43.6%; N = 218) and SLuLi (65.7%, 41.0%; N = 122), was lower than controls (p < 0.001), whereas for SLuK (65.0%, 51.6%; N = 41) it was comparable (p = 0.34). All STA groups demonstrated similar 1- and 5 years posttransplant survival to thoracic controls. Compared to abdominal controls, 1- and 5 years posttransplant survival in SHK (85.3%, 74.0%; N = 684), SLuLi (75.5%, 59.0%; N= 42) and SLuK (66.7%, 55.6%; N = 18) was decreased (p < 0.01), but SHLi (85.9%, 74.3%; N = 92) was comparable (p = 0.81). In summary, STA candidates had greater risk of wait-list mortality compared to single-organ candidates. STA outcomes were similar to thoracic transplantation; however, outcomes were similar to abdominal transplantation for SHLi only. Although select patients benefit from STA, risk-exposure variables for decreased survival should be identified, aiming to eliminate futile transplantation. 23924950 Modern treatment of short bowel syndrome. Recently, the US Food and Drug Administration and the European Medicines Agency approved the glucagon-like peptide 2 analogue, teduglutide, for the treatment of short bowel syndrome (SBS), and this review describes the physiological basis for its clinical use. By affecting the intestinal neuroendocrine system, hormones may promote the growth of the intestinal mucosa, restore a more normal gastric emptying and secretion, stimulate intestinal blood flow, increase intestinal barrier function, immunity and absorption, and thereby promote structural and functional adaptation following intestinal resection. In a 3-week, phase 2, metabolic balance study, teduglutide increased intestinal wet weight absorption by ∼700 g/day and reduced faecal energy losses by ∼0.8 MJ/day. In two subsequent 24-week, phase 3 studies in SBS patients with intestinal failure (SBS-IF), teduglutide reduced the need for parenteral support in the same magnitude. Teduglutide adds incremental benefit to the limited medical treatment armamentarium in SBS patients. Modern treatments should aim to maximize remnant intestinal absorption, decrease malabsorption and accompanying symptoms, reduce the need, burdens and complications related to parenteral support, and ultimately improve the health-related quality of life in SBS-IF patients. Future research should target and implement other key hormones with similar effects, thereby promoting intestinal adaptation and rehabilitation in SBS patients. 23864155 Platelets and matrix metalloproteinases. Matrix metalloproteinases (MMPs) and their inhibitors essentially contribute to a variety of pathophysiologies by modulating cell migration, tissue degradation and inflammation. Platelet-associated MMP activity appears to play a major role in these processes. First, platelets can concentrate leukocyte-derived MMP activity to sites of vascular injury by leukocyte recruitment. Second, platelets stimulate MMP production in e.g. leukocytes, endothelial cells, or tumour cells by direct receptor interaction or/and by paracrine pathways. Third, platelets synthesise and secrete a variety of MMPs including MMP-1, MMP-2, MMP-3, and MMP-14 (MT1-MMP), and potentially MMP-9 as well as the tissue inhibitors of metalloproteinase (TIMPs). This review focuses on platelet-derived and platelet-induced MMPs and their inhibitors. 23942202 Genetic analysis of the role of Alx4 in the coordination of lower body and external genitalia formation. Although several syndromes include abnormalities of both the ventral body wall and external genitalia, the developmental bases of this correlation are largely unknown. Naturally occurring mutations in Aristaless-like 4 (Alx4, Strong's luxoid: Alx4(Lst)) have ventral body wall and pelvic girdle abnormalities. We sought to determine whether the development of the genital tubercle (GT) and its derivatives, the external genitalia, is affected by this mutation. We thus performed genetic and tissue labeling analyses in mutant mice. Alx4(Lst/Lst) mutants displayed hypoplasia of the dorsal GT and reduced expression of Fibronectin. We analyzed cell migration during GT formation by tissue labeling experiments and discovered that the cells located in the proximal segment of the umbilical cord (infra-umbilical mesenchyme) migrate toward the dorsal part of the GT. The Alx4(Lst/Lst) mutants also displayed augmented expression of Hh signal-related genes. Hence, we analyzed a series of combinatorial mutants for Alx4, Sonic hedgehog (Shh) and GLI-Kruppel family member 3 (Gli3). These phenotype-genotype analyses suggested a genetic interaction between Alx4 and Hh signaling during GT formation. Moreover, Hh gain-of-function mutants phenocopied some of these phenotypes. These observations reveal novel information regarding the pathogenic mechanisms of syndromic lower ventral body malformations, which are largely unknown.European Journal of Human Genetics advance online publication, 14 August 2013; doi:10.1038/ejhg.2013.160. 23952600 The relationship between tirasemtiv serum concentration and functional outcomes in patients with ALS. Tirasemtiv is a fast skeletal muscle activator that increases efficiency of muscle contraction. Both single and repeated dose studies suggested beneficial effects on measures of function, muscle strength and endurance. As the outcomes measured were identical in previous studies and the duration of all studies was 21 days or less, we pooled data from all studies and assessed the relationship between outcomes and plasma tirasemtiv concentration to assess consistency of observations as well as to increase sensitivity. We pooled data for ALSFRS-R, three pulmonary function measures, quantitative muscle strength, and submaximal handgrip endurance. Up to 855 values from 143 patients were plotted against tirasemtiv concentrations. Linear associations between tirasemtiv concentrations and changes from baseline of clinical measures were estimated using a repeated-measures mixed model. Trends toward improvement were noted in all measures except for vital capacity, despite the fact that time was not included as a factor so that any time-related decline acted to reduce the magnitude of any noted trend. In conclusion, tirasemtiv appears to have concentration-dependent beneficial effects on both function and measures of strength and endurance when administered for up to 21 days, even when time is eliminated as a cofactor. These findings further support the development of this agent in ALS. 23945390 Should patients with extrapulmonary small-cell carcinoma receive prophylactic cranial irradiation? Extrapulmonary small-cell carcinoma (EPSCC) is a rare disease. Management is based on small-cell lung carcinoma. Prophylactic cranial irradiation (PCI) is not routinely administered in EPSCC. This study investigates the role of PCI in EPSCC, by analyzing the incidence, treatment, and survival of patients with brain metastases in a national cohort. Disease biology and epidemiology are also investigated. Patients diagnosed with primary EPSCC from the National Cancer Registry of Ireland from 1995 to 2007 were identified. The number of patients who developed brain metastases, their survival, and treatment data were documented. Patients who received PCI were investigated. Patient and disease characteristics, treatment, and survival data were stratified by stage and primary site. Two hundred eighty patients were identified; 141 (50.4%) were men and 139 (49.6%) were women. One hundred eighty six patients (66.4%) had extensive-stage disease, 65 (23.2%) had limited-stage disease, and in 29 patients (10.3%) the stage was unknown. Eighteen patients (6.4%) developed brain metastases, with a median overall survival of 10.1 months. Eleven (61%) received cranial irradiation, and 12 (67%) received palliative chemotherapy. Two patients in the entire cohort (0.17%) received PCI. The most common primary sites included the esophagus (n = 43; 15.4%), cervix uteri (n = 17; 6.0%), bladder (n = 13; 4.6%), and prostate (n = 10; 3.6%). Median overall survival was 15.2 months (10.2-20.6) for limited-stage disease, 2.3 months (1.7-3.1) for extensive-stage EPSCC, and 3.7 months (1.3-8.3) for disease of unknown stage. Brain metastases were uncommon in EPSCC compared with small-cell lung carcinoma. PCI is thus probably not warranted in this disease. 23942968 Novel Quinic Acid Derivative KZ-41 prevents retinal endothelial cell apoptosis without inhibiting retinoblastoma cell death through P38 signaling. Purpose: To determine whether a novel NF-κB inhibitor, KZ-41, can inhibit melphalan's actions on retinal endothelial cells (REC) inflammation and apoptosis, without eliminating the chemotherapeutic efficacy of melphalan on cell death of retinoblastoma cells (Y79). Methods: REC were cultured in M131 medium supplemented with growth factors and antibiotics. Once cells reached confluence, they were treated with or without 10 μM KZ-41, following treatment with 4 μg/ml melphalan. Cell proteins were extracted and analyzed for intracellular adhesion molecule 1 (ICAM-1) levels and cell death ELISA. REC were also transfected with or without NF-κB siRNA or treated with SB202190 (P38 MAPK inhibitor) before melphalan treatment to determine the involvement of NF-κB and P38 MAPK in REC apoptosis and ICAM-1 levels. We also cultured retinoblastoma cells (Y79) in RMPI-1640 medium supplemented with 20% fetal bovine serum and performed a cell death ELISA after melphalan + KZ-41 treatment to determine if the treatments altered melphalan's ability to promote cell death of Y79 cells. Results: KZ-41 inhibited melphalan-stimulation of ICAM-1 levels and REC apoptosis, whereas KZ-41 did not alter melphalan's effects on Y79 cells. KZ-41's protective effects on REC were mediated through P38 MAPK activation. Although KZ-41 blocked both NF-κB- and P38 MAPK-depedent ICAM-1 stimulation; the P38 MAPK/ICAM-1 pathway appears to be the primary pathway involved in melphalan induced REC apoptosis. Conclusions: KZ-41 protects REC against melphalan-induced upregulation of ICAM-1 and apoptosis through P38 MAPK dependent pathways. 23275570 Circularized synthetic oligodeoxynucleotides serve as promoterless RNA polymerase III templates for small RNA generation in human cells. Synthetic RNA formulations and viral vectors are the two main approaches for delivering small therapeutic RNA to human cells. Here we report findings supporting an alternative strategy in which an endogenous human RNA polymerase (RNAP) is harnessed to make RNA hairpin-containing small RNA from synthetic single-stranded DNA oligonucleotides. We report that circularizing a DNA template strand encoding a pre-microRNA hairpin mimic can trigger its circumtranscription by human RNAP III in vitro and in human cells. Sequence and secondary structure preferences that appear to promote productive transcription are described. The circular topology of the template is required for productive transcription, at least in part, to stabilize the template against exonucleases. In contrast to bacteriophage and Escherichia coli RNAPs, human RNAPs do not carry out rolling circle transcription on circularized templates. While transfected DNA circles distribute between the nucleus and cytosol, their transcripts are found mainly in the cytosol. Circularized oligonucleotides are synthetic, free of the hazards of viral vectors and maintain small RNA information in a stable form that RNAP III can access in a cellular context with, in some cases, near promoter-like precision and biologically relevant efficiency. 23780563 Platinum(II) and Gold(III) Allenylidene Complexes: Phosphorescence, Self-Assembled Nanostructures and Cytotoxicity. The bright side of triple double bonds: Two series of stable tridentate cyclometalated Pt(II) and Au(III) allenylidene complexes were found to exhibit many functionalities, such as long-lived excited states, self-assembly into supramolecular nanostructures, DNA and nucleus binding and cellular imaging capabilities. 23353735 Syntheses and anti-allergic activity of 2-((bis(trimethylsilyl)methylthio/methylsulfonyl)methyl)-5-aryl-1,3,4-oxadiazoles. A new class of sila-substituted 1,3,4-oxadiazoles was synthesized by a convenient synthetic method. Both silathio/silasulfonyl acetic acids were efficiently condensed with benzohydrazides in the presence of phosphorus oxychloride to give sila-substituted 1,3,4-oxadiazoles in high yields. The compounds displayed variable extent of anti-allergic activity on IgE/Ag-stimulated RBL-2H3 cells at 50 and 100 μM concentrations. Compounds having sulfonyl moiety with bis(trimethylsilyl)-1,3,4-oxadiazoles (5a-c), exhibited better anti-allergic activities than those of compounds having sulphur moiety with bis(trimethylsilyl)-1,3,4-oxadiazoles (4a-c). 23336257 Spoligotyping of Mycobacterium tuberculosis isolates among pulmonary tuberculosis patients in Amhara Region, Ethiopia. The aim of this study was to characterize Mycobacterium tuberculosis isolates circulating in the Amhara Region of Ethiopia. Sputum samples were collected from new pulmonary tuberculosis (TB) patients in the Region. Genotyping of mycobacterial DNA was performed by spoligotyping and isolates were assigned to families using the SpolDB4 and the model-based program 'Spotclust'. A high level of diversity was found among the 237 isolates. Sixty-five different spoligopatterns were obtained. The T (30.8%), Central Asian (CAS; 21.1%) and U (17.7%) families were the predominant isolates comprising 69.6% of the total strains. Eighty-five per cent of the U lineage belonged to Spoligo-International-Type (SIT) 910 and SIT 1729. Only a few of these strains are included in SpolDB4 to date. Of the total strains, 41 (17.3%) were unique and have not been described in SpolDB4 to date. This study indicated that the TB epidemic in Amhara Region, Ethiopia, is characterized by the circulation of numerous M. tuberculosis strain families. The high proportion of SIT 910 and SIT 1729 strains may indicate an increase in the importance of these lineages in the transmission of TB in the study region. 23888872 ICEA of Mycoplasma agalactiae: a new family of self-transmissible integrative elements that confers conjugative properties to the recipient strain. Horizontal gene transfer (HGT) is a major force of microbial evolution but was long thought to be marginal in mycoplasmas. In silico detection of exchanged regions and of loci encoding putative Integrative Conjugative Elements (ICE) in several mycoplasma genomes challenged this view, raising the prospect of these simple bacteria being able to conjugate. Using the model pathogen Mycoplasma agalactiae, we demonstrated for the first time that one of these elements, ICEA, is indeed self-transmissible. As a hallmark of conjugative processes, ICEA transfers were DNase resistant and required viable cells. ICEA acquisition conferred ICE-negative strains with the new ability to conjugate, allowing the spread of ICEA. Analysis of transfer-deficient mutants indicated that this process requires an ICEA-encoded lipoprotein of unknown function, CDS14. Formation of a circular extrachromosomal intermediate and the subsequent chromosomal integration of ICEA involved CDS22, an ICEA-encoded product distantly related to the ISLre2 transposase family. Remarkably, ICEA has no specific or no preferential integration site, often resulting in gene disruptions. Occurrence of functional mycoplasma ICE offers these bacteria with a means for HGT, a phenomenon with far-reaching implications given their minute-size genome and the number of species that are pathogenic for a broad host-range. 23828233 Auxiliary basis sets for density-fitting second-order Møller-Plesset perturbation theory: Weighted core-valence correlation consistent basis sets for the 4d elements Y-Pd. Auxiliary basis sets (ABS) specifically matched to the cc-pwCVnZ-PP and aug-cc-pwCVnZ-PP orbital basis sets (OBS) have been developed and optimized for the 4d elements Y-Pd at the second-order Møller-Plesset perturbation theory level. Calculation of the core-valence electron correlation energies for small to medium sized transition metal complexes demonstrates that the error due to the use of these new sets in density fitting is three to four orders of magnitude smaller than that due to the OBS incompleteness, and hence is considered negligible. Utilizing the ABSs in the resolution-of-the-identity component of explicitly correlated calculations is also investigated, where it is shown that i-type functions are important to produce well-controlled errors in both integrals and correlation energy. Benchmarking at the explicitly correlated coupled cluster with single, double, and perturbative triple excitations level indicates impressive convergence with respect to basis set size for the spectroscopic constants of 4d monofluorides; explicitly correlated double-ζ calculations produce results close to conventional quadruple-ζ, and triple-ζ is within chemical accuracy of the complete basis set limit. © 2013 Wiley Periodicals, Inc. 23069759 The neurobiological effects of stress on adolescent decision making. Relative to other developmental periods, adolescence is characterized by risky decision making, increased perceived stress and heightened reactivity to acute stress. It is also during this time that individuals undergo significant neurodevelopment in brain regions that process decision making and stress. In this review, we summarize what is currently known about stress during adolescence, how it impacts risky decision-making, and how acute stress may exert neurobiological effects on circuitry that subserves decision-making in the developing brain. We conclude by suggesting future research directions that may help the field gain traction on this important, but relatively understudied, question. 23786788 Pediatric oral burns: a ten-year review of patient characteristics, etiologies and treatment outcomes. To summarize etiologies and treatments of pediatric oropharyngeal burns. Retrospective summary of 75 patients treated from January 1999 to January 2009. Tertiary Children's Hospital. Data collected included demographics, etiology of burn, site of injury, medical and/or surgical treatments, need for endoscopy, duration of hospitalization, and complications. 75 patients were treated with 50 being males (66%). Mean age was 4.3 years (median 2.7 years). The five most common causes were chemical (34.6%), electrical (12.3%), hot liquids (12.3%), food (12.3%) and battery ingestion (9.9%). Ingestion of hair products made up nearly 1/3 of the chemical causes (9/28) and alone made up 12% of the burns in our study. Main sites of injury included buccal mucosa (77.3%), lips (56%), tongue (48%), and palate (22.7%). One-third of the patients' required PICU/Burn unit admissions, 1/3 were admitted to floor, and 1/3 were discharged home from the ED. Average duration of hospitalization was 5 days. Of those admitted, 30% received antibiotics and only 8% received systemic steroids. Patients were made NPO on the first day of admission in 33.3% of patients and allowed to resume normal diet after surgical consultation. Only 9/75 (12%) patients required intubation. Otolaryngology consultation was obtained in 10.7% of cases. Only 18% of all patients required surgical intervention with debridement being most common (>60%). In this group, 20% received esophagogastroduodenoscopies due to ingestion of alkali substance. Complications occurred in less than 6% of all cases. Ingestion of chemicals, including hair dye/relaxer products, as well as overheated liquids and foods, are leading causes of oropharyngeal burns treated at our Children's Hospital Emergency Department over the past decade. 23929145 The impact of Metzembaum septoplasty on nasal and facial growth in children. Several studies have investigated the effects of septoplasty on facial growth in children, with conflicting results. However, just handful of those employed objective measures or evaluated patients after facial growth completion. This study assesses the effects of the Metzenbaum septoplasty, which preserves the perichondrium and growth-related areas on nasal and facial growth in children. We included those children submitted to surgery before the age of 14 and who had 16 years or years of follow up. Sixteen patients were selected. We evaluated the following parameters: clinical satisfaction (nasal patency and aesthetics), anthropometric measurements and cephalometry. Scientific design: cross-sectional historical cohort. The mean age at surgery was 13 years, children were assessed on average 4.3 years after surgery. Only one patient had anthropometric and cephalometric values below normal, but no aesthetics or patency complaints. Four other patients complained about their nasal aesthetics and three had patency complaints. The Metzenbaum septoplasty appears to be a safe technique to correct caudal septum deviations. This technique had no significant impact on facial growth of the patients assessed. 23836583 Ventricular Ectopy and QTc-Interval Prolongation Associated with Dronedarone Therapy. Amiodarone is an effective treatment for atrial and ventricular arrhythmias, but its use is limited by a toxic adverse-effect profile. Although dronedarone has been touted as an antiarrhythmic agent devoid of both solid organ toxicity and proarrhythmic properties, its potential for prolonging ventricular repolarization may augment triggered ectopy. We describe a 66-year-old man who began dronedarone 400 mg twice/day for new-onset paroxysmal atrial fibrillation; he had no left ventricular dysfunction or clinical heart failure. Three months after starting the drug, he complained of malaise, fatigue, and rare palpitations. Twenty four-hour Holter monitoring revealed increased premature ventricular complexes, and the rate-corrected QT (QTc) interval was prolonged (range 525-760 msec). Dronedarone was discontinued and the patient's symptoms gradually resolved over the next 3 weeks. Holter monitoring revealed a marked reduction in ventricular ectopy burden, and the QTc interval decreased to his baseline values. Even in the absence of documented symptomatic torsade de pointes, this case suggests that caution should be exercised when prescribing dronedarone and that serial QTc interval monitoring may be appropriate. In addition, clinicians should have a low threshold to perform Holter monitoring if symptoms develop during dronedarone therapy. 23803696 Innate immunity gene polymorphisms and the risk of colorectal neoplasia. Inherited variation in genes that regulate innate immunity and inflammation may contribute to colorectal neoplasia risk. To evaluate this association, we conducted a nested case-control study of 451 colorectal cancer cases, 694 colorectal advanced adenoma cases and 696 controls of European descent within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. A total of 935 tag single-nucleotide polymorphisms (SNPs) in 98 genes were evaluated. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association with colorectal neoplasia. Sixteen SNPs were associated with colorectal neoplasia risk at P < 0.01, but after adjustment for multiple testing, only rs2838732 (ITGB2) remained suggestively associated with colorectal neoplasia (ORper T allele = 0.68, 95% CI: 0.57-0.83, P = 7.7 × 10(-5), adjusted P = 0.07). ITGB2 codes for the CD18 protein in the integrin beta chain family. The ITGB2 association was stronger for colorectal cancer (ORper T allele = 0.41, 95% CI: 0.30-0.55, P = 2.4 × 10(-) (9)) than for adenoma (ORper T allele = 0.84, 95%CI: 0.69-1.03, P = 0.08), but it did not replicate in the validation study. The ITGB2 rs2838732 association was significantly modified by smoking status (P value for interaction = 0.003). Among never and former smokers, it was inversely associated with colorectal neoplasia (ORper T allele = 0.5, 95% CI: 0.37-0.69 and ORper T allele = 0.72, 95% CI: 0.54-0.95, respectively), but no association was seen among current smokers. Other notable findings were observed for SNPs in BPI/LBP and MYD88. Although the results need to be replicated, our findings suggest that genetic variation in inflammation-related genes may be related to the risk of colorectal neoplasia. 23903479 Enhancing insulin-use safety in hospitals: Practical recommendations from an ASHP Foundation expert consensus panel. Consensus recommendations to help ensure safe insulin use in hospitalized patients are presented. Insulin products are frequently involved in medication errors in hospitals, and insulin is classified as a high-alert medication when used in inpatient settings. In an initiative to promote safer insulin use, the American Society of Health-System Pharmacists (ASHP) Research and Education Foundation convened a 21-member panel representing the fields of pharmacy, medicine, and nursing and consumer advocacy groups for a three-stage consensus-building initiative. The panel's consensus recommendations include the following: development of protocol-driven insulin order sets, elimination of the routine use of correction/sliding-scale insulin doses for management of hyperglycemia, restrictions on the types of insulin products stored in patient care areas, and policies to restrict the preparation of insulin bolus doses and i.v. infusions to the pharmacy department. In addition, the panelists recommended that hospitals better coordinate insulin use with meal intake and glucose testing, prospectively monitor the coordination of insulin delivery and rates of hypoglycemia and hyperglycemia, and provide standardized education and competency assessment for all hospital-based health care professionals responsible for insulin use. A 21-member expert panel convened by the ASHP Foundation identified 10 recommendations for enhancing insulin-use safety across the medication-use process in hospitals. Professional organizations, accrediting bodies, and consumer groups can play a critical role in the translation of these recommendations into practice. Rigorous research studies and program evaluations are needed to study the impact of implementation of these recommendations. 23603682 A novel muconic acid biosynthesis approach by shunting tryptophan biosynthesis via anthranilate. Muconic acid is the synthetic precursor of adipic acid, and the latter is an important platform chemical that can be used for the production of nylon-6,6 and polyurethane. Currently, the production of adipic acid relies mainly on chemical processes utilizing petrochemicals, such as benzene, which are generally considered environmentally unfriendly and nonrenewable, as starting materials. Microbial synthesis from renewable carbon sources provides a promising alternative under the circumstance of petroleum depletion and environment deterioration. Here we devised a novel artificial pathway in Escherichia coli for the biosynthesis of muconic acid, in which anthranilate, the first intermediate in the tryptophan biosynthetic branch, was converted to catechol and muconic acid by anthranilate 1,2-dioxygenase (ADO) and catechol 1,2-dioxygenase (CDO), sequentially and respectively. First, screening for efficient ADO and CDO from different microbial species enabled the production of gram-per-liter level muconic acid from supplemented anthranilate in 5 h. To further achieve the biosynthesis of muconic acid from simple carbon sources, anthranilate overproducers were constructed by overexpressing the key enzymes in the shikimate pathway and blocking tryptophan biosynthesis. In addition, we found that introduction of a strengthened glutamine regeneration system by overexpressing glutamine synthase significantly improved anthranilate production. Finally, the engineered E. coli strain carrying the full pathway produced 389.96 ± 12.46 mg/liter muconic acid from simple carbon sources in shake flask experiments, a result which demonstrates scale-up potential for microbial production of muconic acid. 23929915 Public views on the donation and use of human biological samples in biomedical research: a mixed methods study. A mixed methods study exploring the UK general public's willingness to donate human biosamples (HBSs) for biomedical research. Cross-sectional focus groups followed by an online survey. Twelve focus groups (81 participants) selectively sampled to reflect a range of demographic groups; 1110 survey responders recruited through a stratified sampling method with quotas set on sex, age, geographical location, socioeconomic group and ethnicity. (1) Identify participants' willingness to donate HBSs for biomedical research, (2) explore acceptability towards donating different types of HBSs in various settings and (3) explore preferences regarding use and access to HBSs. 87% of survey participants thought donation of HBSs was important and 75% wanted to be asked to donate in general. Responders who self-reported having some or good knowledge of the medical research process were significantly more likely to want to donate (p<0.001). Reasons why focus group participants saw donation as important included: it was a good way of reciprocating for the medical treatment received; it was an important way of developing drugs and treatments; residual tissue would otherwise go to waste and they or their family members might benefit. The most controversial types of HBSs to donate included: brain post mortem (29% would donate), eyes post mortem (35%), embryos (44%), spare eggs (48%) and sperm (58%). Regarding the use of samples, there were concerns over animal research (34%), research conducted outside the UK (35%), and research conducted by pharmaceutical companies (56%), although education and discussion were found to alleviate such concerns. There is a high level of public support and willingness to donate HBSs for biomedical research. Underlying concerns exist regarding the use of certain types of HBSs and conditions under which they are used. Improved education and more controlled forms of consent for sensitive samples may mitigate such concerns. 23910482 Trait-based tests of coexistence mechanisms. Recent functional trait studies have shown that trait differences may favour certain species (environmental filtering) while simultaneously preventing competitive exclusion (niche partitioning). However, phenomenological trait-dispersion analyses do not identify the mechanisms that generate niche partitioning, preventing trait-based prediction of future changes in biodiversity. We argue that such predictions require linking functional traits with recognised coexistence mechanisms involving spatial or temporal environmental heterogeneity, resource partitioning and natural enemies. We first demonstrate the limitations of phenomenological approaches using simulations, and then (1) propose trait-based tests of coexistence, (2) generate hypotheses about which plant functional traits are likely to interact with particular mechanisms and (3) review the literature for evidence for these hypotheses. Theory and data suggest that all four classes of coexistence mechanisms could act on functional trait variation, but some mechanisms will be stronger and more widespread than others. The highest priority for future research is studies of interactions between environmental heterogeneity and trait variation that measure environmental variables at within-community scales and quantify species' responses to the environment in the absence of competition. Evidence that similar trait-based coexistence mechanisms operate in many ecosystems would simplify biodiversity forecasting and represent a rare victory for generality over contingency in community ecology. 23428346 Atorvastatin withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex. Statins are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting step in cholesterol biosynthesis. Statins effectively prevent and reduce the risk of coronary artery disease through lowering serum cholesterol, and also exert anti-thrombotic, anti-inflammatory and antioxidant effects independently of changes in cholesterol levels. On the other hand, clinical and experimental evidence suggests that abrupt cessation of statin treatment (i.e. statin withdrawal) is associated with a deleterious rebound phenomenon. In fact, statin withdrawal increases the risk of thrombotic vascular events, causes impairment of endothelium-dependent relaxation and facilitates experimental seizures. However, evidence for statin withdrawal-induced detrimental effects to the brain parenchyma is still lacking. In the present study adult male Wistar rats were treated with atorvastatin for seven days (10mg/kg/day) and neurochemical assays were performed in the cerebral cortex 30min (atorvastatin treatment) or 24h (atorvastatin withdrawal) after the last atorvastatin administration. We found that atorvastatin withdrawal decreased levels of nitric oxide and mitochondrial superoxide dismutase activity, whereas increased NADPH oxidase activity and immunoreactivity for the protein nitration marker 3-nitrotyrosine in the cerebral cortex. Catalase, glutathione-S-transferase and xanthine oxidase activities were not altered by atorvastatin treatment or withdrawal, as well as protein carbonyl and 4-hydroxy-2-nonenal immunoreactivity. Immunoprecipitation of mitochondrial SOD followed by analysis of 3-nitrotyrosine revealed increased levels of nitrated mitochondrial SOD, suggesting the mechanism underlying the atorvastatin withdrawal-induced decrease in enzyme activity. Altogether, our results indicate the atorvastatin withdrawal elicits oxidative/nitrosative damage in the rat cerebral cortex, and that changes in NADPH oxidase activity and mitochondrial superoxide dismutase activities may underlie such harmful effects. 23384447 Northern contaminant mixtures induced morphological and functional changes in human coronary artery endothelial cells under culture conditions typifying high fat/sugar diet and ethanol exposure. It has been reported that Northern populations are exposed to mixtures of various environmental contaminants unique to the Arctic (Northern contaminant mixtures - NCM) at a large range of concentrations, depending on their geological location, age, lifestyle and dietary habits. To determine if these contaminants may contribute to a cardiovascular health risk, especially when combined with a high fat and sugar diet and ethanol exposure, we treated human coronary artery endothelial cells (HCAEC) with two mixtures of 4 organic (NCM1) or 22 organic and inorganic (NCM2) chemicals detected in Northerners' blood during 2004-2005 in the presence or absence of low-density lipoprotein (1.5mg/ml), very-low-density lipoprotein (1.0mg/ml) and glucose (10mmol/L) (LVG), and in the absence or presence of 0.1% ethanol. After 24h of exposure, cell morphology and markers of cytotoxicity and endothelial function were examined. NCM1 treatment did not affect cell viability, but increased cell size, disrupted cell membrane integrity, and decreased cell density, uptake of small peptides, release of endothelin-1 (ET-1) and plasminogen activator inhibitor (PAI), while causing no changes in endothelial nitric oxide synthase (eNOS) protein expression and nitric oxide (NO) release. In contrast, NCM2 decreased cell viability, total protein yield, uptake of small peptides, eNOS protein expression, and NO release and caused membrane damage, but caused no changes in the secretion of ET-1, prostacyclin and PAI. The presence of LVG and/or alcohol did or did not influence the effects of NCM1 or NCM2 depending on the endpoint and the mixture examined. These results suggested that the effects of one or one group of contaminants may be altered by the presence of other contaminants, and that with or without the interaction of high fat and sugar diet and/or ethanol exposure, NCMs at the concentrations used caused endothelial dysfunction in vitro. It remains to be investigated if these effects of NCMs also occur in vivo. 23523615 Differential sensitivities of glioblastoma cell lines towards metabolic and signaling pathway inhibitions. In glioblastoma multiforme (GBM), the activation of the phosphatidylinositol 3-kinase (PI3-K) pathway is known to promote aerobic glycolysis. The relative sensitivity of GBM towards PI3-K and metabolic inhibitors was examined in a panel of human GBM lines. We observed differential sensitivities towards oligomycin, an ATP synthase inhibitor that suppresses oxidative phosphorylation (OXPHOS). GBMs that were sensitive to oligomycin have greater intrinsic oxygen consumption. They also failed to undergo adaptive glycolytic switches in response to oligomycin, as reflected in the failure to activate AMPKα. On the other hand, GBM lines that were less sensitive to oligomycin could be rendered non-viable when simultaneously treated with the glycolysis inhibitor, 2-Deoxyglucose (2DG). Furthermore, inhibiting either PI3-K pathway or glycolysis was effective in suppressing cell migration. Inhibiting OXPHOS alone did not have any significant effects on cell motility. However, both oligomycin and 2DG acted synergistically in suppressing cell migration. We conclude that while there was less synergy by the combined inhibition of PI3-K and glycolysis, the simultaneous targeting of glycolysis and OXPHOS is highly effective in blocking GBM tumorigenic phenotypes. 23657000 IL-7 production in murine lymphatic endothelial cells and induction in the setting of peripheral lymphopenia. IL-7 is a required factor for T-cell homeostasis. Because of low expression levels and poor reagent availability, the cellular sources of IL-7 have proven challenging to characterize. In this study, we describe a reporter mouse in which enhanced GFP is expressed from the endogenous Il7 locus. We show that IL-7 is produced by lymphatic endothelial cells (LECs) distributed throughout the systemic lymphatic vasculature as well as by fibroblastic reticular cells, and that phosphorylation of STAT5 in lymphocytes is higher in lymphatics than in blood. Furthermore, in nodes depleted of lymphocytes, Il7 transcription is increased in stromal but not in myeloid subsets. These data support recent findings that lymphocyte homeostasis is influenced by access to secondary lymphoid organs and point to LECs as an important in vivo source of IL-7, bathing trafficking immune cells under both resting and lymphopenic conditions. 23928502 Design and use of synthetic regulatory small RNAs to control gene expression in Escherichia coli. Gene knockout experiments are often essential in functional genomics and metabolic engineering studies. However, repeated multiple gene knockout experiments are laborious, time consuming and sometimes impossible to perform for those genes that are essential for cell function. Small regulatory RNAs (sRNAs) are short noncoding RNAs in prokaryotes that can finely control the expression of target genes in trans at the post-transcriptional level. Here we describe the protocol for synthetic sRNA-based gene expression control, including sRNA design principles. Customized synthetic sRNAs consist of a scaffold and a target-binding sequence, and they can be created by simply replacing an existing target-binding sequence with one that is complementary to the target mRNA to be repressed, while retaining the scaffold. Our plasmid-based synthetic sRNA system does not require chromosomal modifications, and it enables one to perform high-throughput studies on the effects of knockdowns on host cell physiology, and it further allows the simultaneous screening of target genes in different Escherichia coli strains for applications in metabolic engineering and synthetic biology. Once an sRNA scaffold-harboring plasmid is constructed, customized synthetic sRNAs can be made within 3-4 d; after this time, the synthetic sRNAs can be applied to the desired experiments. 23699063 Determination of the attP and attB sites of phage CD27 from Clostridium difficile NCTC 12727. The attP region of the Clostridium difficile phage CD27 was identified, located immediately downstream of the putative recombinase. The phage could integrate into two specific sites (attB) in the C. difficile genome, one of which was in an open reading frame encoding a putative ATPase of an ABC transporter and the other in an open reading frame encoding a putative ATPase of the flagella protein export apparatus. The prophage was capable of excision and formation of a circular molecule and phages were spontaneously released at a low frequency during growth. Infection and lysogeny of a C. difficile strain previously shown to be sensitive to CD27 were demonstrated, leading to a reduction in toxin production. Finally, a putative repressor was identified which is likely to be involved in maintaining lysogeny in these strains. 23831216 High levels of inactive thymidine kinase 1 polypeptide detected in sera from dogs with solid tumours by immunoaffinity methods: Implications for in vitro diagnostics. Determination of serum thymidine kinase 1 (STK1) activity has been used as a proliferation marker for neoplastic diseases in both human and veterinary medicine. The purpose of this study was to determine STK1 activity and enzyme levels in different dog tumours. Serum samples from three dogs with leukaemia, five with lymphoma, 21 with solid tumours and 18 healthy dogs were analyzed for STK1 activity, using an optimized [(3)H]-deoxythymidine (dThd) phosphorylation assay, and for STK1 protein levels using an immunoaffinity/western blot assay. STK1 activity in dogs with haematological tumours was significantly higher than in the solid tumour and healthy dog groups (mean±standard deviation [SD]=65±79, 1.1±0.5, and 1.0±0.4pmol/min/mL, respectively). Serum samples were analyzed after immunoaffinity isolation by western blot and the TK1 26kDa band intensities quantified revealing that concentrations were significantly higher in dogs with haematological tumours and solid tumours compared to healthy dogs (mean±SD=33±12, 30±13, and 10±5ng/mL, respectively). Pre-incubation with the reducing agent dithioerythritol (DTE) showed a decrease in STK1 activity and protein levels in most samples, but an increase of about 20% in sera from healthy dogs and from those with haematological malignancies. Compared to animals with solid tumours, the specific STK1 activity (nmol [(3)H]-deoxythymidine monophosphate (dTMP)/min/mg of TK1 protein of 26kDa) was 30-fold higher in haematological malignancies and 2.5-fold higher in healthy dogs, respectively. The results demonstrate that there is a large fraction of inactive TK1 protein, particularly in sera from dogs with solid tumours. The findings are important in the use of STK1 as a biomarker. 23932941 Effects of recombinant trout leptin in superoxide production and NF-κB/MAPK phosphorylation in blood leukocytes. Studies in mammals indicate that leptin is a multifunctional cytokine involved in regulation of energy metabolism and the modulation of the immune function. However, evidence for an immunomodulatory effect of leptin in fish is still missing. At least in part, this lack of knowledge is due to the absence of materials and models. In this study, we produced trout recombinant leptin (rt-lep) and tested its capacity to trigger cellular pathways, usually active in mammal immune system cells. STAT3, NF-κB, and the three major MAPK cascades (JNK, p38 and ERK), were activated by rt-lep in in vitro incubations with blood leucocytes of the rainbow trout Oncorhynchus mykiss. We also showed that rt-lep causes a decrease in superoxide anion production in trout blood leucocytes. Thus our data indicate that as in mammals also in teleosts leptin plays pleiotropic activities. Importantly, its actions in fishes do not always conform to the picture emerging for mammals. 23860134 Osteosynthesis of unstable intracapsular femoral neck fracture by dynamic locking plate or screw fixation. Early results. The purpose of this study was to compare the postoperative radiologic and clinical outcomes of telescopic femur neck screws and small locking plate device (Targon FN) (Group 1) with multiple cancellous screws (Group 2) for displaced intracapsular femoral neck fractures. Comparison of a prospective collected data to a historical control group (retrospective). One community teaching hospital. Seventy-eight patients (group 1, 31; group 2, 47) underwent reduction and internal fixation of displaced intracapsular femoral neck fractures with either Targon FN device or multiple cancellous screws from March 2000 to July 2010. Their mean age was 53.7 years (SD 16.4) and the mean follow-up period was 28.6 months. Treatment failure was considered to be either a nonunion, osteonecrosis or revision surgery of any type. Treatment was regarded as successful in patients who did not show failure and had at least one year follow-up. One patient in Group 1 (3.2%) and 22 (46.8%) in Group 2 had a nonunion (p = 0.0001). Four Group 1 patients (12.9%) and 16 Group 2 patients (34.0%) underwent revision surgery (p = 0.036). Four patients in Group 1 (12.9%) and four Group 2 patients (8.5%) had osteonecrosis of the femoral head (p = 0.531). Multivariate logistic regression showed that internal fixation by the fixed angle fixation device decreased the odds ratio for overall complication by a factor of 0.23, i.e., by 77% (p = 0.018). Performing internal fixation by a fixed angle fixation device decreased nonunion rates and revision rates. It did not affect the rate of osteonecrosis. 23861255 Integrative effect of defective interfering RNA accumulation and helper virus attenuation is responsible for the persistent infection of Japanese encephalitis virus in BHK-21 cells. Persistence of RNA viruses is often, but not always, associated with the production of defective interfering (DI) particles. To investigate possible roles of DI particles and helper viruses in RNA virus persistence, persistent infection with Japanese encephalitis virus (JEV) was established in baby hamster kidney (BHK-21) cells. At the 6th and 7th serial undiluted passages of JEV on BHK-21 cells, viral persistence was established spontaneously with DI RNA generation. Seven cell clones exhibiting persistent infection were obtained from the initial BHK-21 cell batches exhibiting JEV persistence, and maintained for over 400 days. Most cell clones produced infectious particles (10(1) -10(5)  PFU/ml) continuously, expressed viral proteins, and resisted homologous superinfection. Two helper viruses, chvBS6-3 and chvBS7-1, were isolated from two of the seven cell clones, and characterized to investigate their roles in JEV persistence. While chvBS6-3 was restored to its full cytopathicity in the absence of DI RNA, chvBS7-1 exhibited almost no cytopathicity, regardless of DI RNA co-replication. Attenuation of chvBS7-1 did not appear to be due to inadequate adsorption or genome replication, but due to inefficient egress of the assembled progeny virions, suggesting altered helper virus emergence during JEV persistence in BHK-21 cells. These observations suggest that at least two mechanisms are involved in JEV persistence; a DI RNA-dependent mechanism, where DI RNA co-replication nullifies the helper virus's cytopathicity, or a DI RNA-independent mechanism, where the helper virus is self-attenuated. This study provides a useful in vitro tool for understanding the mechanisms underlying RNA virus persistent infections. J Med. Virol. 85:1990-2000, 2013. © 2013 Wiley Periodicals, Inc. 22974271 Fasting levels of ghrelin covary with the brain response to food pictures. Ghrelin figures prominently in the regulation of appetite in normal-weighed individuals. The apparent failure of this mechanism in eating disorders and the connection to addictive behavior in general demand a deeper understanding of the endogenous central-nervous processes related to ghrelin. Thus, we investigated processing of pictures showing palatable food after overnight fasting and following a standardized caloric intake (i.e. a 75-g oral glucose tolerance test) using functional magnetic resonance imaging and correlated it with blood plasma levels of ghrelin. Twenty-six healthy female and male volunteers viewed food and control pictures in a block design and rated their appetite after each block. Fasting levels of ghrelin correlated positively with food-cue reactivity in a bilateral network of visual processing-, reward- and taste-related regions, including limbic and paralimbic regions. Notably, among those regions were the hypothalamus and the midbrain where ghrelin receptors are densely concentrated. In addition, high fasting ghrelin levels were associated with stronger increases of subjective appetite during the food-cue-reactivity task. In conclusion, brain activation and subjective appetite ratings suggest that ghrelin elevates the hedonic effects of food pictures. Thereby, fasting ghrelin levels may generally enhance subjective craving when confronted with reward cues. 23928144 Utility of Proton MR Spectroscopy for Differentiating Typical and Atypical Primary Central Nervous System Lymphomas from Tumefactive Demyelinating Lesions. BACKGROUND AND PURPOSE:It may be challenging to differentiate primary CNS lymphomas, especially primary CNS lymphomas with atypical MR features, from tumefactive demyelinating lesions by the use of conventional MR. This study aimed to investigate the usefulness of (1)H-MR spectroscopy for making this discrimination.MATERIALS AND METHODS:Forty-four patients with primary CNS lymphomas and 21 with tumefactive demyelinating lesions were enrolled. Single-voxel (TE = 144 ms) (1)H-MR spectroscopy scans with the use of the point-resolved spectroscopy sequence were retrospectively analyzed. The Cho/Cr and Cho/NAA area ratios were calculated. The lipid and/or lactate peak was visually categorized into 5 grades on the basis of comparison with the height of the Cr peak. The (1)H-MR spectroscopy findings were compared in all of the primary CNS lymphomas and the tumefactive demyelinating lesions and in the subgroup of atypical primary CNS lymphomas and tumefactive demyelinating lesions. The thresholds and added value of (1)H-MR spectroscopy to conventional MR were calculated by use of receiver operating characteristic curves.RESULTS:Discrepancies between all of the primary CNS lymphomas and tumefactive demyelinating lesions were found in the Cho/Cr ratio (P = .000), Cho/NAA ratio (P = .000), and the lipid and/or lactate peak grade (P = .000). Lymphoma rather than tumefactive demyelinating lesions was suggested when the Cho/Cr ratio was >2.58, the Cho/NAA ratio was >1.73, and a high lipid and/or lactate peak grade (grade >3) was seen. Higher Cho/Cr ratios, Cho/NAA ratios, and lipid and/or lactate peak grades were found in atypical primary CNS lymphomas when compared with those of tumefactive demyelinating lesions. The area under the receiver operating characteristic curve of conventional MR was improved from 0.827 to 0.870 when Cho/NAA ratio was added in the uncertain cases.CONCLUSIONS:(1)H-MR spectroscopy may be useful for differentiating primary CNS lymphomas from tumefactive demyelinating lesions. Cho/NAA ratio could provide added value to conventional MR imaging. 23963478 Conductance and shot noise in strained bilayer graphene. We explore the effect of trigonal warping and of elastic deformations on the electronic spectrum of bilayer graphene devices, on their ballistic conductance as well as on the shot noise. Uniaxial strain distorts the lattice creating a uniform fictitious gauge field in the electronic Dirac Hamiltonian which ultimately causes a dramatic reconstruction in the trigonally warped electronic spectrum, inducing topological transitions in the Fermi surface. In this paper we present results of ballistic transport in bilayer graphene in the absence and presence of strain, with particular focus on noise and the Fano factor F. The inclusion of trigonal warping preserves the pseudo-diffusive value of F = 1/3 at the Dirac point, as calculated in the absence of trigonal warping terms. However, the range of energies which show pseudo-diffusive transport increases by orders of magnitude compared to the results stemming out of a parabolic spectrum and the applied strain acts to increase this energy range further. 23886362 Availability of resources for patients with wet age-related macular degeneration. Optimal study. The aim of the study was to assess the availability of resources for patients with wet age-related macular degeneration (wAMD) in current clinical practice. Observational, cross-sectional and multicenter study. Eligible subjects were ≥ 18 years old, with primary/secondary active subfoveal AMD-related choroidal neovascularization diagnosed 12-18 months prior to inclusion in the study. A total of 266 patients were included (39 centers). The mean age (SD) was 76.1 (8.1) years, of whom 55.6% were female. According to the investigator assessment a median (Q1-Q3) of 20.0 (10.0-50.0) patients were visited weekly. A mean of 100.0 (45.0-250.0) were currently under treatment mainly performed in operating rooms (61.5%). Centers had 1.0 (1.0-2.0) operating rooms available for treatment 2.0 (2.0-5.0) days/week. In 74.4% they were located on different floors/buildings from ophthalmology services. Waiting time until visit was 40.0 (30.0-60.0) min, and duration of treatment was 20.0 (15.0-50.0) min. The time between request until medical visit was 20.0 (15.0-30.0) days, and from diagnosis to treatment was 7.0 (5.0-10.0) days. Clinicians considered there was insufficient staff for examinations (84.6%), and treatment (46.2%). About 30.8% and 20.5% mentioned lack of diagnostic tools, such as optical coherence tomography and fluorescein angiography. More resources for diagnosis and treatment of wAMD are required. These results, together with the current policy of reducing the budget in the Spanish Health System, could lead to possible delays in the diagnosis and treatment of wAMD. 23872834 Educational challenges in implementing genomic medicine. Clinical medicine is about to embark on an exciting, although harrowing, period of innovation, the result of astonishing advances in genomic science. The current workforce-physicians, nurses, pharmacists, and others-will soon need to adapt to substantial change, driven by genomics, in diagnostic and therapeutic strategies. If errors of omission and commission are to be prevented, sustained efforts in workforce education will be needed on the part of medical schools, training programs, and professional societies. 23805974 Brown adipose tissue: development, metabolism and beyond. Obesity represents a major risk factor for the development of several of our most common medical conditions, including Type 2 diabetes, dyslipidaemia, non-alcoholic fatty liver, cardiovascular disease and even some cancers. Although increased fat mass is the main feature of obesity, not all fat depots are created equal. Adipocytes found in white adipose tissue contain a single large lipid droplet and play well-known roles in energy storage. By contrast, brown adipose tissue is specialized for thermogenic energy expenditure. Owing to its significant capacity to dissipate energy and regulate triacylglycerol (triglyceride) and glucose metabolism, and its demonstrated presence in adult humans, brown fat could be a potential target for the treatment of obesity and metabolic syndrome. Undoubtedly, fundamental knowledge about the formation of brown fat and regulation of its activity is imperatively needed to make such therapeutics possible. In the present review, we integrate the recent advancements on the regulation of brown fat formation and activity by developmental and hormonal signals in relation to its metabolic function. 23848173 Human periodontal ligament fibroblast response to rhPDGF-BB application on periodontally diseased root surfaces-in vitro. Abstract The aim of the present study was to evaluate the influence of recombinant Platelet Derived Growth Factor-BB (rhPDGF-BB) on the cellular proliferation, morphology and adherence of human periodontal ligament fibroblasts (PLFs) to the root surfaces of periodontally diseased and healthy human teeth roots at two different time periods. Primary cell cultures of PLFs were obtained from clinically healthy premolar or mandibular third molar teeth. 11 scaffolds were prepared from healthy teeth for group-1 (Healthy Substrates), 33 scaffolds were prepared from periodontally diseased teeth, which were further divided in Group-2 - Periodontally diseased substrates, Group-3 - Scaled and Root planed (SRP) substrates, Group-4 - SRP + rhPDGF-BB (50 ng/ml). Groups were further subdivided into two groups (n = 5 scaffolds per subgroup) and PLFs were incubated on the scaffolds for three and seven days, topographical assessment was done on the remaining substrate. Cell morphology and counting was assessed under a scanning electron microscope at 350× on day three and seven and statistically compared with the Mann-Whitney U test and the Kruskal-Wallis test. On day three, Group 1 showed least number of cells attached, whereas maximum number of cells were attached on Group 3 (SRP only) substrates. For day 7, Group 1 and Group 4 showed increase in the number of cells from day 3 to 7, while number of cells attached/substrate reduced drastically for Group 2 and 3 substrates. Group 3 and 4 showed better adhesion and proliferation of PLFs as compared to Group 1 and 2. Group-1 and Group-4 showed predominantly spindle cells with flat appearance, Group-3 showed stellate cells and Group-2 showed predominantly distorted spindle shaped cells. The results of this in-vitro study indicates that rhPDGF-BB plays a significant role as an adjunct to periodontal therapy in influencing maturity, attachment and proliferation of PLFs. 23853197 Relapsing fevers and lymphadenopathy in a young woman. A 23-year-old woman presented to the emergency department with severe occipital headache, nausea and fever. She was treated with intravenous antibiotics for suspected meningitis. After a brief period of response, her symptoms relapsed and remained refractory despite continuing intravenous antibiotics for 10 days leading to referral to our centre. Physical examination was significant for tender right cervical lymph node. Initial tests included pancytopenia, elevated C reactive protein, lactate dehydrogenase and unremarkable cerebrospinal fluid. Extensive infectious and rheumatology work-up was negative. Massive posterior cervical, axillary and inguinal lymphadenopathy was revealed on imaging. Excisional biopsy of the deep cervical lymph node showed histiocytic necrotising lymphadenitis suggesting a diagnosis of Kikuchi disease. Her course was complicated by acute renal failure. Her symptoms resolved in about a week with supportive treatment along with improvement in pancytopenia and renal function. She had two additional self-limited recurrences in the next 3 months and remains symptom free thereafter. 23602073 Changes in circulatory FSH of Barbari goats following treatment with high molecular weight inhibin isolated from buffalo follicular fluid. The objective of the present study was to isolate and purify high MW inhibin (∼129kDa) from buffalo ovarian follicular fluid (buFF) and to investigate its biological activity. Throughout the process of purification, the inhibin fractions were evaluated for bioactivity by a specific, sensitive and uniformly reproducible bioassay in mice. The final biological activity of this preparation was tested in normal cycling adult female Barbari goats. Eight animals, randomly divided into two groups, were synchronized for estrus by administering PGF2α twice at an interval of ten days. Following synchronization, the treatment group (n=4) received (i.m.) 0.4ml (240μg protein total dose) of purified inhibin (MW∼129kDa) of buFF in the morning at 08.00h for the four consecutive days of follicular phase, while the control group (n=4) received only saline (0.4ml). Blood samples were collected from jugular vein immediately before the first injection and subsequent collections were made daily in the afternoon until day 8 of the experiment including four days (0, 1, 2, & 3days) of the next cycle. FSH was assayed in all the samples by ELISA. The peripheral FSH concentration sharply declined from 1.854±0.137 to 0.979±0.02 u/l, 8h after the administration of inhibin on the first day. The value in controls was 2.004±0.132 u/l. For the duration of treatment of four consecutive days, the FSH level in experimental group remained significantly low (p<0.05) compared to control group. After cessation of treatment, the FSH level remained low on day 0 and 1 of the next cycle in the experimental and control animals. However, a significant rebound increase in plasma FSH levels occurred on day 2 & 3 (2.73±0.179 & 1.849±0.128u/l) only in the experimental group compared to control animals (P<0.05). This increment might be caused by the rebound surge of FSH from anterior pituitary which further corroborates the effect of inhibin in treated animals. In conclusion, the present study demonstrates that the high MW form of inhibin (∼129kDa) isolated from buFF has comparable biological activity as revealed by 31-32kDa inhibin from other species. 23485359 Mercury speciation driven by seasonal changes in a contaminated estuarine environment. In this study, seasonal changes of mercury (Hg) species in the highly variable estuary of Soča/Isonzo River (northern Adriatic Sea) were investigated. Samplings were performed on a seasonal basis (September 2009, May, August and October 2010) and Hg species (total Hg, methylmercury (MeHg), dissolved gaseous Hg (DGM)) in waters, sediments and pore waters were determined. In addition, a range of ancillary parameters were measured (salinity, nutrients, organic carbon (OC), nitrogen species). Hg values were interpreted using these parameters and hydrological conditions (river flow, wave height) around the time of sampling. There were no significant changes in Hg load from river to the gulf, compared to previous studies. The load was temporarily higher in May 2010 due to higher river flow. Wave height, through changing hydrostatic pressure, was most likely to cause resuspension of already deposited Hg from the bottom (August 2010). The estuary is a net source of DGM to the atmosphere as suggested by DGM profiles, with salinity, redox potential and organic matter as the most probable controls over its production. MeHg is produced in situ in sediment or in water column, rather than transported by river, as indicated by its correlation with OC of the marine origin. Calculated fluxes for THg and MeHg showed sediment as a source for both the water column. In pore waters, OC in part affects partitioning of both THg and MeHg; however other factors (e.g. sulphide and/or oxyhydroxides precipitation and dissolution) are also probably important. 23669275 Residential proximity to major roadways and renal function. Living near major roadways has been associated with increased risk of cardiovascular events, but little is known about its impact on renal function. We calculated the estimated glomerular filtration rate (eGFR) for 1103 consecutive Boston-area patients hospitalised with confirmed acute ischaemic stroke between 1999 and 2004. We used linear regression to evaluate the association between eGFR and categories of residential distance to major roadway (0 to ≤50, >50 to ≤100, >100 to ≤200, >200 to ≤400, >400 to ≤1000 and >1000 m) adjusting for age, sex, race, smoking, comorbid conditions, treatment with ACE inhibitor and neighbourhood-level socioeconomic characteristics. In a second analysis, we considered the log of distance to major roadway as a continuous variable. Patients living closer to a major roadway had lower eGFR than patients living farther away (Ptrend=0.01). Comparing patients living 50 m versus 1000 m from a major roadway was associated with a 3.9 ml/min/1.73 m(2) lower eGFR (95% CI 1.0 to 6.7; p=0.007): a difference comparable in magnitude to the reduction in eGFR observed for a 4-year increase in age in population-based studies. The magnitude of this association did not differ significantly across categories of age, sex, race, history of hypertension, diabetes or socioeconomic status. Living near a major roadway is associated with lower eGFR in a cohort of patients presenting with acute ischaemic stroke. If causal, these results imply that exposures associated with living near a major roadway contribute to reduced renal function, an important risk factor for cardiovascular events. 23891511 History of lung disease and risk of lung cancer in a population with high household fuel combustion exposures in rural China. History of chronic lung diseases and household coal use for heating and cooking are established risk factors of lung cancer; however, few studies have been able to explore these risk factors simultaneously. Xuanwei, China, has some of the highest rates of lung cancer in China and most residents experience substantial in-home coal smoke exposures. Using a population-based case-control study of 498 lung cancer cases and 498 age-matched controls, we evaluated the risk of lung cancer in relation to coal smoke exposure and history of chronic lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, tuberculosis (TB), chronic bronchitis, and emphysema. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by conditional logistic regression adjusting for potential confounders. We observed an increased risk of lung cancer with history of any chronic lung disease among males (OR=14.2; 95%CI=4.3-46.9), females (OR=2.6; 95%CI=1.1-6.3), smokers (OR=12.7; 95%CI=3.5-45.8), and nonsmokers (OR=2.6; 95%CI=1.1-6.4). Specifically, TB (OR=83.7; 95%CI=11.0-634.7), COPD (OR=3.2; 95%CI=1.7-6.0), and emphysema and chronic bronchitis (OR=3.3; 95%CI=1.7-6.4) were associated with increased risks. These findings suggest that history of chronic lung diseases may also increase risk of lung cancer in populations with indoor coal smoke exposures. 23148920 Hydrogen sulfide increases nitric oxide production with calcium-dependent activation of endothelial nitric oxide synthase in endothelial cells. Hydrogen sulfide (H(2)S) was recently discovered to be synthesized in mammalian tissues by several different enzymes. Numerous studies have shown that H(2)S has vasodilator and antihypertensive effects in the cardiovascular system. However, intracellular mechanisms of the H(2)S-induced vasodilation and its interactions with other endothelium-derived relaxing factors, such as nitric oxide (NO), remain unclear. We investigated whether H(2)S directly regulates endothelial NO synthase (eNOS) activity and NO production in endothelial cells. NaHS, a H(2)S donor, dose-dependently increased NO production in cultured endothelial cells. This effect was abolished by a calcium chelator (BAPTA-AM), but not by the absence of extracellular calcium. The NaHS-induced NO production was partially blocked by inhibitors of ryanodine receptor (dantrolene) or inositol 1,4,5-triphosphate receptor (xestospongin C). NaHS significantly increased intracellular calcium concentrations, and this effect was attenuated by dantrolene or xestospongin C. NaHS induced phosphorylation of eNOS at the activating phosphoserine residue 1179. The NaHS-induced eNOS phosphorylation and NO production were not affected by a PI3K/Akt inhibitor (wortmannin). The data of this study suggest that H(2)S directly acts on endothelial cells to induce eNOS activation and NO production by releasing calcium from the intracellular store in endoplasmic reticulum, which may explain one of mechanisms of its vasodilator function. 23942638 Sensing extremely limited H2 contents by Pd nanogap connected to an amorphous InGaZnO thin-film transistor. A palladium (Pd) nanogap-based thin-film has been connected to an electrically stable amorphous InGaZnO thin-film transistor, to form a hydrogen sensor demonstrating a dramatic sensing capability. As a result of the Pd connection to the transistor source, our sensor circuit greatly enhances the hydrogen-induced signal and sensing speed in the sense of output voltage, clearly resolving a minimum hydrogen content of 0.05%. When the nanogap-based Pd thin-film was connected to the transistor gate, an extremely limited hydrogen content of even less than 0.05% was visibly detected through gate voltage shifts. Our results exhibit the most promising and practical ways to sense extremely limited hydrogen contents, originating from two methods: transistor-to-Pd nanogap resistor and transistor-to-Pd nanogap capacitor coupling. 23276895 Early repolarization: innocent or dangerous? : Electrocardiographic (ECG) findings of wide QRS complexes in right precordial leads with saddle ST elevation in patients with polyarthritis, palpitations and family history of syncope urged us to review early repolarization syndrome (ERS). ERS is commonly seen in young men. The main ECG features are as follows: wide spread concave ST-segment elevation, more in the precordial leads (usually V2-V4); notching or irregular contour of J point and prominent concordant T waves with large amplitude. ERS was historically considered as a benign ECG variant. In recent years, it has emerged as a marker for increased risk of sudden cardiac death. The purpose of this review was to describe the ECG manifestations of this syndrome and to review the literature concerning its arrhythmogenic potential. The authors found it important not only discussing the rate of ERS life threatening but also to reemphasize its differences from other syndromes. Some of the last are much more dangerous: acute myocardial infarction and Brugada syndrome. The tables will be helpful for physicians to distinguish ERS from other syndromes in patients with chest pain and ST elevation. 23756178 Meta-analysis confirms a functional polymorphism (5-HTTLPR) in the serotonin transporter gene conferring risk of bipolar disorder in European populations. The serotonin transporter (5-HTT) is a candidate risk gene for bipolar disorder, and a functional polymorphism of 44-bp insertion/deletion (5-HTTLPR) located in the promoter region of this gene has been investigated for the association with the illness extensively among worldwide populations, but overall results were inconsistent and its role in the disorder remains unclear. The present study attempts to find its potential association with bipolar disorder using meta-analyzes that maximize the statistical power. We applied meta-analysis techniques by combining all available case-control studies of 5-HTTLPR and bipolar disorder in samples of European ancestry (with a total of 3778 cases and 4997 controls), and we assessed the evidence for allelic associations, heterogeneity among different studies, influence of each single study, and potential publication bias. The short allele (S allele) of 5-HTTLPR showed a significant association with bipolar disorder in our meta-analysis (odds ratio=1.10, p-value=0.005), suggesting it is likely a risk polymorphism for the illness, and the observed OR is consistent with other susceptibility loci identified through recent large-scale genetic association studies on bipolar disorder, which could be regarded simply as a small but detectable effects. 22776357 F-actin accumulates in the vulva of female Strongyloides venezuelensis. Little is known about the actin cytoskeleton architecture in female Strongyloides venezuelensis and thus to investigate the distribution and concentration of actin, female worms were labelled with phalloidin-rhodamine and visualized under confocal microscopy. Our results demonstrate that filamentous actin accumulates in the vulva and the concentration of F-actin at this site suggests its important role, especially during oviposition, in the life cycle of S. venezuelensis. 23938176 Pharmacological approaches to treating negative symptoms: A review of clinical trials. Clinical trials of pharmacological agents targeting negative symptoms in schizophrenia are reviewed. The focus is on trials that occurred in patients who were stable on an antipsychotic medication at entry to the trial. A small number of trials compared antipsychotics as monotherapy for negative symptoms. Although the data supporting amisulpride for negative symptoms is promising the trials have limitations and it is plausible that the advantages of amisulpride over placebo may result from effects on secondary negative symptoms. Among available agents, antidepressant medications may have effects in negative symptoms. Other promising agents include minocycline, glutamatergic agents, and alpha-7 nicotinic agents. More than 15 active trials are currently underway to evaluate new treatments for negative symptoms. 23870056 Two new ent-kaurane diterpenoids from Pteris semipinnata. In this study, two new compounds and six known compounds were isolated from the aerial parts of Pteris semipinnata. The chemical structures of these two new compounds were elucidated as 6β,11α-dihydroxy-15-oxo-ent-kaur-16-en-19-oic acid (1) and 7α,11α-dihydroxy-15-oxo-ent-kaur-16-en-19-oic acid (2) by the extensive spectral methods including 2D NMR and HR-MS techniques. 22899726 Organochlorine pesticide levels and risk of Alzheimer's disease in north Indian population. Alzheimer's disease (AD) could result from a multifactorial process involving both genetic predisposition and exposure to environmental factors like pesticides. A case control study of 70 patients of AD and 75 controls was done to examine the association between organochlorine pesticides (OCPs) and risk of AD. OCPs (hexachlorocyclohexane (HCH), aldrin, dieldrin, endosulfan, pp'-dichlorodiphenyldichloroethylene (pp'-DDE), op'-DDE, pp'-dichlorodiphenyltrichloroethane (pp'-DDT), op'-DDT, pp'-dichlorodiphenyldichloroethane (pp'-DDD) and op'-DDD) were extracted from blood and quantitatively estimated using gas chromatography. A Mann-Whitney U test revealed significant difference in β-HCH levels (U = 1237.00, W = 4087.00, z = -6.296, p = 0.000, r = -0.71), dieldrin levels (U = 1449.00, W = 4299.00, z = -5.809, p = 0.000, r = -0.68) and pp'-DDE levels (U = 2062.00, W = 4912.00, z = -2.698, p = 0.007, r = -0.59) between AD patients and controls. In conclusion, this study supports epidemiological studies that associate exposure to pesticides with increased risk of AD, and we identified the specific pesticides β-HCH, dieldrin and pp'-DDE that are associated with the risk of AD in the north Indian population. However, further research is needed to establish the potential role of these OCPs as an etiologic agent for AD case. 23966317 Antitumor Efficacy of Doxorubicin-Loaded Laponite/Alginate Hybrid Hydrogels. Degradable hybrid hydrogels with improved stability are prepared by incorporating nanodisks of biocompatible laponite (LP) in alginate (AG) hydrogels using Ca(2+) as a crosslinker. The Dox-loaded hybrid hydrogels give a controlled Dox release at physiological environment in a sustained manner. Under conditions that mimic the tumor environment, both the sustainability in the Dox release (up to 17 d) and the release efficiency from LP/AG-Dox hydrogels are improved. The in situ degradation of these hybrid hydrogels gives rise to nanohybrids that might serve as vehicles for carrying Dox through the cell membrane and diminish the effect of Dox ion-trapping in the acidic extracellular environment of the tumor and/or in the endo-lysosomal cell compartments. 23321615 Mosaic copy number variation in schizophrenia. Recent reports suggest that somatic structural changes occur in the human genome, but how these genomic alterations might contribute to disease is unknown. Using samples collected as part of the International Schizophrenia Consortium (schizophrenia, n=3518; control, n=4238) recruited across multiple university research centers, we assessed single-nucleotide polymorphism genotyping arrays for evidence of chromosomal anomalies. Data from genotyping arrays on each individual were processed using Birdsuite and analyzed with PLINK. We validated potential chromosomal anomalies using custom nanostring probes and quantitative PCR. We estimate chromosomal alterations in the schizophrenia population to be 0.42%, which is not significantly different from controls (0.26%). We identified and validated a set of four extremely large (>10 Mb) chromosomal anomalies in subjects with schizophrenia, including a chromosome 8 trisomy and deletion of the q arm of chromosome 7. These data demonstrate that chromosomal anomalies are present at low frequency in blood cells of both control and schizophrenia subjects. 23541365 Cloning and characterization of a novel cry8Ab1 gene from Bacillus thuringiensis strain B-JJX with specific toxicity to scarabaeid (Coleoptera: Scarabaeidae) larvae. Isolation of Bacillus thuringiensis (Bt) strain or its cry gene encoding insecticidal crystal protein (ICP) with specific toxicity is of great importance to biological control of insect pests. In this study, by screening 66 strains of Bt isolated from soil samples collected in Shandong Province, China, a new cry8-type gene from Bt strain B-JJX was identified via PCR-RFLP method. This novel gene, cry8Ab1, was cloned from the Bt strain B-JJX and expressed in an acrystalliferous mutant strain HD-73(-). The open reading frame of the cry8Ab1 gene consists of 3543bp with a G+C content of 37.99% and encodes a protein of 1180 amino acids with a putative MW of 133.3kDa which was confirmed by SDS-PAGE analysis. The Cry8Ab1 protein was expressed and released as spherical parasporal crystals from Bt acrystalliferous mutant strain HD-73(-) along with the presence of spores. In bioassays, this protein was toxic to 3-day-old larvae of the scarabaeid pests, Holotrichia oblita and H. parallela, with an LC50 of 5.72 and 2.00μgtoxing(-1)soil, respectively. The results are in accordance with the insecticidal activities of the original Bt strain B-JJX, which had an LC50 of 1.72 and 0.96μgtoxing(-1)soil against H. oblita and H. parallela, respectively. 23913629 Hyperbaric oxygen therapy accelerates vascularization in keratinized oral mucosal surgical flaps. Background. Hyperbaric oxygen therapy (HBOT) is thought to promote vascular regeneration in wounds. The aim of this study was to investigate the role of HBOT in advancing vascular regeneration in healing oral mucosal surgical flaps. Methods. A palatine partial-thickness mucosal flap was raised in 10 male specific-pathogen free New Zealand White rabbits. Randomized into two groups of 5 animals each (control and HBOT), functional capillary density was measured preoperatively (baseline), immediately postoperatively until day 21 using sidestream dark-field video microscopy. Ten HBOT sessions were administered over the course of 2 weeks at 2.5 atmospheres (2.5 bar O2 /90 min). Results. Repeated measures ANOVA was used to compare the HBOT and control group on the sequential functional capillary density measurements. A significant interaction effect was present between time and group, F (8, 64) = 9.60, p < 0.0001, resulting from a significant increase in microcirculation in the HBOT group relative to the control group on days 7, 9, and 11. Conclusion. Our results suggest that HBOT is capable of advancing wound vascular regeneration in healing keratinized oral mucosal flaps. Head Neck, 2013. 23789711 Performance of an electrothermal swing adsorption system with postdesorption liquefaction for organic gas capture and recovery. The use of adsorption on activated carbon fiber cloth (ACFC) followed by electrothermal swing adsorption (ESA) and postdesorption pressure and temperature control allows organic gases with boiling points below 0 °C to be captured from air streams and recovered as liquids. This technology has the potential to be a more sustainable abatement technique when compared to thermal oxidation. In this paper, we determine the process performance and energy requirements of a gas recovery system (GRS) using ACFC-ESA for three adsorbates with relative pressures between 8.3 × 10(-5) and 3.4 × 10(-3) and boiling points as low as -26.3 °C. The GRS is able to capture > 99% of the organic gas from the feed air stream, which is comparable to destruction efficiencies for thermal oxidizers. The energy used per liquid mole recovered ranges from 920 to 52,000 kJ/mol and is a function of relative pressure of the adsorbate in the feed gas. Quantifying the performance of the bench-scale gas recovery system in terms of its ability to remove organic gases from the adsorption stream and the energy required to liquefy the recovered organic gases is a critical step in developing new technologies to allow manufacturing to occur in a more sustainable manner. To our knowledge, this is the first time an ACFC-ESA system has been used to capture, recover, and liquefy organic compounds with vapor pressures as low as 8.3 × 10(-5) and the first time such a system has been analyzed for process performance and energy consumption. 23075005 Pharmacokinetics and metabolism of [(14)C]anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in humans. 1. The disposition of anagliptin, an orally active, highly selective dipeptidyl peptidase-4 inhibitor, was investigated after a single oral dose of 100 mg/1.92 MBq [(14)C]anagliptin to six healthy men. Almost all the dose (98.2%) was recovered within 168 h: 73.2% in urine and 25.0% in faeces. 2. Anagliptin was rapidly absorbed, with peak plasma concentrations of unchanged drug attained at a mean time of 1.8-h postdose. Mean fraction of the dose absorbed was >73%. Unchanged drug and a carboxylate metabolite (M1) were the major components in plasma, accounting for 66.0 and 23.4% of total plasma radioactivity area under the curve, respectively. 3. Anagliptin was incompletely metabolized, with about 50% dose eliminated as unchanged drug (46.6% in urine and 4.1% in faeces). Metabolism to M1 accounted for 29.2% of the dose. No other metabolite accounted for >1% dose in excreta or yielded measurable systemic exposure. Terminal half-life of anagliptin and M1 was 4.37 and 9.88 h, respectively. Renal clearance of unbound anagliptin and unbound M1 far exceeded glomerular filtration rate, indicating active renal elimination: that might reflect the fact that anagliptin may be a substrate of OAT1, OAT3, MDR1 and MRP2, and M1 a substrate of OAT3, BCRP, MRP2 and MRP4. 23673278 The non-selective cannabinoid receptor agonist WIN 55,212-2 attenuates responses of C-fiber nociceptors in a murine model of cancer pain. Pain from cancer can be severe, difficult to treat, and greatly diminishes patients' quality of life. It is therefore important to gain new information on the mechanisms of cancer pain and develop new treatment strategies. We have used a murine model of bone cancer pain to investigate underlying peripheral neural mechanisms and novel treatment approaches. In this model, implantation of fibrosarcoma cells into and around the calcaneous bone produces mechanical and thermal hyperalgesia in mice. C-fiber nociceptors in tumor-bearing mice develop spontaneous ongoing activity and sensitization to thermal stimuli. However, it is unclear whether sensitization of nociceptors to mechanical stimuli underlies the mechanical hyperalgesia seen in tumor-bearing mice. We therefore examined responses of C-fiber nociceptors to suprathreshold mechanical stimuli in tumor-bearing mice and found they did not differ from those of C-nociceptors in control mice. Thus, sensitization of C-fiber nociceptors to mechanical stimulation does not appear to underlie tumor-evoked mechanical hyperalgesia in this murine model of bone cancer pain. We also examined the effect of the non-selective cannabinoid receptor agonist, WIN 55,212-2, on spontaneous activity and responses evoked by mechanical stimuli of C-fiber nociceptors innervating the tumor-bearing paw. Selective CB1 and CB2 antagonists were administered to determine the contribution of each receptor subtype to the effects of WIN 55,212-2. Intraplantar administration of WIN 55,212-2 attenuated spontaneous discharge and responses evoked by mechanical stimulation of C-fiber nociceptors. These effects were inhibited by prior intraplantar administration of selective CB1 (AM281) or CB2 (AM630) receptor antagonists but not by vehicle. These results indicate that activation of either CB1 or CB2 receptors reduced the spontaneous activity of C-fiber nociceptors associated with tumor growth as well as their evoked responses. Our results provide further evidence that activation of peripheral cannabinoid receptors may be a useful target for the treatment of cancer pain. 23824731 A mother and daughter with a novel phenotype of hand and foot abnormalities and severe pectus excavatum. A mother and daughter with an overlapping Catel-Manzke and Temtamy preaxial brachydactyly hyperphalangism syndrome phenotype are reported. We describe a phenotype with a previously undescribed genetic basis. © 2013 Wiley Periodicals, Inc. 23841694 Rural and remote early psychosis intervention services: the Gordian knot of early intervention. One of the basic challenges of Early Psychosis Intervention (EPI) programs for rural populations is translating best practice which developed for urban high-population density areas to rural and remote settings. This paper presents data from two different models (hub and spoke and specialist outreach) of rural EPI practice in Ontario, Canada. This cross-sectional study used a convenience sample of clients from two rural EPI programs between 2005 and 2007. Data about client outcomes specific to general functioning, admissions to hospital and emergency room (ER) visits were collected. For all dichotomous variables, chi-square tests were used to test differences between two groups. The total clients served in hub and spoke were 457 compared to 91 in specialist outreach. Although not statistically significant, the hub and spoke group showed better functioning in the community. There was a significant difference between the two groups with regard to hospital admissions. Although not significant, there was a greater percentage (58.3%) of specialist outreach clients who visited the ER in the previous 12 months as compared to clients serviced by the hub and spoke model (34.9%). The observed data from these two rural models suggest that there may be differing outcomes. There are limitations to this study, and this paper does not address why there are differences. Future work needs to continue to further explore why differences exist and whether they persist so we can provide equity and quality care for rural and remote populations. 23625211 Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part II. In part II of this review, we describe the epidemiology and clinical consequences of vascular disease in patients with diabetes, and discuss the efficacy of risk factor modification and antiplatelet treatment. Specifically, evidence-based cardiovascular therapies are discussed through novel clinical insights on management of hyperglycaemia, hypertension, dyslipidaemia as well as platelet dysfunction. Recent trends in the incidence and outcomes of vascular disease in diabetes suggest that timely and effective implementation of therapies is making a favourable impact. 23940054 Control by potassium of the size-distribution of Escherichia coli FtsZ Polymers is independent of GTPase activity. The influence of potassium content (at neutral pH and millimolar Mg2+) on the size-distribution of FtsZ polymers formed in the presence of constantly replenished GTP under steady-state conditions was studied by a combination of biophysical methods. The size of the GTP-FtsZ polymers decreased with lower potassium concentration, in contrast with the increase in the mass of the GDP-FtsZ oligomers, while no effect was observed on FtsZ GTPase activity and critical concentration of polymerization. Remarkably, the concerted formation of a narrow size-distribution of GTP-FtsZ polymers previously observed at high salt concentration is maintained in all KCl concentrations tested. Polymers induced with GMPCPP, a slowly hydrolysable analog of GTP, became larger and polydisperse as potassium concentration decreased. Our results suggest that the potassium dependence of the GTP-FtsZ polymer size may be related with changes in subunit turnover rate that are independent of the GTP hydrolysis rate. The formation of a narrow size distribution of FtsZ polymers under very different solution conditions indicates it is an inherent feature of FtsZ, not observed in other filament forming proteins, and strongly suggests a role in the assembly and constriction process of the Z-ring. 23519740 Quantitative determination of duloxetine and its metabolite in rat plasma by HPLC-MS/MS. The major metabolite of duloxetine is a glucuronide conjugate of 4-hydroxy duloxetine (4-HD). However, interestingly, there have been no reports determining concentrations of 4-HD and no fully validated method has been established for measuring duloxetine and 4-HD in rat plasma. We developed a method for the simultaneous quantification of duloxetine and its metabolite in rat plasma using high-performance liquid chromatography tandem mass spectrometry. Duloxetine and 4-HD were analyzed on a reverse-phase C18 analytical column after protein precipitation of the plasma sample with methanol, using carbamazepine as an internal standard. The isocratic mobile phase of 5 mm ammonium acetate-methanol (4:6, v/v) was eluted at 0.4 mL/min. Quantification was performed on a triple-quadrupole mass spectrometer using electrospray ionization, and the ion transition monitored in selective reaction monitoring mode. The coefficient of variation for assay precision was <18.0%, and the accuracy was 84.0-118.0%. This method was successfully used to measure the concentrations of duloxetine and its metabolite in plasma following the oral administration of a single 40 mg/kg dose in rats. Copyright © 2013 John Wiley & Sons, Ltd. 23884318 Just Blowing Smoke? Social Desirability and Reporting of Intentions to Quit Smoking. Do cigarette smokers really want to quit smoking or do they simply say they do in order to placate others and avoid criticism? In surveys of smokers, stated quit intentions and reports of quit attempts may be biased by social desirability concerns. This makes it difficult to interpret large-scale state and national surveys of smoking behavior that collect data through telephone and face-to-face interviews, methods that tend to evoke high levels of socially desirable responding. The 2007 Health Information National Trends Survey used a dual-frame design to query smokers' quit intentions and past quit attempts in 1 of 2 ways: A self-administered mail survey (low pressure for socially desirable responding; n = 563) or an interviewer-administered telephone survey (high pressure for socially desirable responding; n = 499). Estimates derived from the 2 formats were compared to test for social desirability effects. In both survey modes, approximately two thirds of smokers reported seriously considering quitting in the next 6 months (mail: 64.9%; telephone: 68.9%), and approximately half reported making a quit attempt in the past year (mail: 54.9%; telephone: 52.3%). Neither difference approached significance in logistic regressions controlling for demographics (ps > .24). It appears that a large proportion of smokers in the United States aspire to live smoke-free lives and are not simply responding in a socially desirable manner to deflect criticism in an antismoking social climate. Future research should replicate this study with greater statistical power, examine the possible effects of survey context (e.g., health survey vs. smoking pleasure survey), and explore survey mode effects in specific subpopulations. 23871419 Evaluation of anticancer effects and enhanced doxorubicin cytotoxicity of xanthine derivatives using canine hemangiosarcoma cell lines. Methylxanthine derivatives increase cAMP and are known to have diuretic, cardiac, and central nervous system stimulatory effects. Moreover, caffeine inhibits the development of tumors induced by various carcinogens. The aim of this work was to elucidate the anticancer effects on apoptosis of xanthine derivatives alone and with doxorubicin in canine hemangiosarcoma cells. Xanthine derivatives with or without doxorubicin were administered to cells, and the effects were investigated by measuring tumor cell proliferation, cell death (cytotoxicity) induction, and apoptosis by the expression of annexin V or caspase 3/7. Both caffeine and theophylline induced apoptosis, and the treated cells expressed annexin V and caspase 3/7. Both drugs enhanced doxorubicin-induced cytotoxicity; however, hypoxanthine showed no effect. These results indicate that theophylline is similar to caffeine; both drugs may enhance doxorubicin-induced cytotoxicity by inhibiting ATM/ATR kinases. Our data suggest that caffeine and theophylline have anticancer effects and can improve the treatment effect in canine hemangiosarcoma patients. 23851412 Integrating exercise is medicine® into the care of pregnant women. A majority of women do not meet the recommended levels of physical activity before and during pregnancy. Physically active women experience fewer complications of pregnancy such as gestational diabetes, hypertensive disorders of pregnancy, and low back pain, to name only a few. Exercise is Medicine encourages adults to achieve a minimum of 150 min·wk of moderate-intensity physical activity, and the same is true for women having uncomplicated pregnancies. Prenatal care is an opportune time to counsel women on how to achieve an active lifestyle to support their own health and the health of their developing fetus. 23893165 Assessment of wasted myocardial work - A novel method to quantify energy loss due to un-coordinated left ventricular contractions. Background: Left ventricular (LV) dyssynchrony reduces myocardial efficiency because work performed by one segment is wasted by stretching other segments. We introduce a novel non-invasive clinical method which quantifies wasted energy as the ratio between work consumed during segmental lengthening (wasted work) divided by work during segmental shortening. Methods: The wasted work ratio (WWR) principle was studied in 6 anesthetized dogs with left bundle branch block (LBBB), and in 28 patients with cardiomyopathy, including 12 with LBBB and 10 with cardiac resynchronization therapy (CRT). Twenty healthy individuals served as controls. Myocardial strain was measured by speckle tracking echocardiography (STE), and left ventricular pressure (LVP) by micromanometer and a previously validated non-invasive method. Segmental work was calculated by multiplying strain rate and LVP to get instantaneous power, which was integrated to give work as a function of time. A global WWR was also calculated. Results: In dogs WWR by estimated LVP and strain showed strong correlation (r =0.94) and good agreement with WWR by LV micromanometer and myocardial segment length by sonomicrometry. In patients, non-invasive WWR showed strong correlation (r =0.96) and good agreement with WWR using LV micromanometer. In healthy controls global WWR was 0.09±0.03, in patients with LBBB 0.36±0.16, and in cardiomyopathy patients without LBBB 0.21±0.09. CRT reduced global WWR from 0.36±0.16 to 0.17±0.07, (p<0.001). Conclusions: Energy loss due to in-coordinated contractions can be quantified non-invasively as LV wasted work ratio. This method may be applied to evaluate the mechanical impact of dyssynchrony. 23959709 The relationship between total and regional corpus callosum atrophy, cognitive impairment and fatigue in multiple sclerosis patients. The objective of this paper is to investigate the relationship between total and regional corpus callosum (CC) atrophy, neuropsychological test performance and fatigue in multiple sclerosis (MS) patients. We conducted a cross-sectional study in 113 MS patients: mean age 48±11 years, 75/113 women, 84/113 relapsing-remitting MS, mean disease duration 21±9 years, mean Expanded Disability Status Scale (EDSS) score 3.2±1.7. All patients underwent brain magnetic resonance imaging, standardised neurological assessment and comprehensive cognitive testing including assessments for fatigue and depression. Total and regional CC atrophy was assessed using the corpus callosum index (CCI). CCI correlated more strongly with T2- and T1-lesion volume and whole brain volume than with disease duration or EDSS score. CCI correlated strongly with the verbal fluency test (VFT), Symbol Digit Modalities Test (SDMT) and Paced Auditory Serial Addition Test (PASAT). Multivariate regression analysis revealed that atrophy of the posterior CC segment was significantly associated with poor outcome in the PASAT, VFT and SDMT. In contrast, atrophy of the anterior CC segment was significantly associated with fatigue severity and poor outcome in the long-term memory test. Atrophy of the CC is associated with cognitive impairment and fatigue. Regional CCI results indicate that these associations are partially spatially segregated. 23927863 Proteomic analysis of global protein expression changes in the endothelin-1 rat model for cerebral ischemia: Rescue effect of mild hypothermia. Mild hypothermia is a promising neuroprotective therapy in stroke management. However, little is known about its effects on the global protein expression patterns in brain regions affected by ischemic stroke. We investigated protein expression changes associated with the neuroprotective effects of hypothermia via a functional proteomics approach through the analysis of the core (striatum) and the penumbra (cortex) after an ischemic insult in rats induced by endothelin-1 (Et-1). Functional outcome, infarct volume and related global protein expression changes were assessed 24h after the insult using two-dimensional difference gel electrophoresis. Mild hypothermia, induced 20min after endothelin-1 infusion, improved the neurological outcome, reflected by a 36% reduction in infarct volume and a significantly better neurological deficit score. Hypothermia was typically associated with opposite protein expression changes in the cortex to those induced by stroke under normothermic conditions, but not in the striatum. The main cellular processes rescued by hypothermia and potentially involved in the protection of the cortex are cellular assembly and organization, followed by cell signaling, thereby confirming that hypothermia is neuroprotective through multiple molecular and cellular pathways. 23958246 Gender-related differences in outcome after BMS or DES implantation in patients with ST-segment elevation myocardial infarction treated by primary angioplasty: Insights from the DESERT cooperation. Several studies have found that among patients with ST-segment elevation myocardial infarction (STEMI) treated by thrombolysis, female sex is associated with a worse outcome. However, still controversial is the prognostic impact of gender in primary angioplasty, especially in the era of drug-eluting stents (DES). Therefore, the aim of this study was to investigate sex-related differences in clinical outcome in patients with STEMI treated with primary angioplasty with Bare-Metal Stent (BMS) or DES. Our population is represented by 6298 STEMI patients undergoing primary angioplasty and stent implantation included in the DESERT database. Follow-up data were collected from 3 to 6 years after primary angioplasty. Female gender was observed in 1466 (23.2%) out of 6298 STEMI patients. Women were older (65.3 ± 12.4 vs 59.3 ± 11.4 years, p < 0.001), with higher prevalence of diabetes (18.6% vs 14.5%, p < 0.001), hypertension (52.4% vs 41.4%, p < 0.001), slightly longer ischemia time (272 ± 247 vs 258 ± 220 min, p = 0.06). No difference was observed in terms of angiographic and procedural characteristics. Follow-up data were available at a mean of 1201 ± 441 days. At long-term follow-up female gender was associated with a significantly higher rate of death (11.7% vs 8.5%, HR [95% CI] = 1.45 [1.18-1.78], p < 0.001), while no difference was observed in terms of reinfarction (HR [95% CI] = 1.14 [0.89-1.45], p = 0.3), ST (HR [95% CI] = 1.12 [0.85-1.48], p = 0.4), with similar temporal distribution (acute, subacute, late and very late) between male and female patients, and no difference in TVR (HR [95% CI] = 1.11 [0.95-1.3], p = 0.2, p = 0.2). These results were confirmed in both patients receiving BMS or DES. The impact of female gender on mortality disappeared after correction for baseline confounding factors (HR [95% CI] = 0.88 [0.71-1.09], p = 0.25). This study shows that in patients with STEMI treated by primary angioplasty, female gender is associated with higher mortality rate in comparison with men, and this is mainly due to their higher clinical and angiographic risk profiles. In fact, female sex did not emerge as an independent predictor of mortality. 23621156 Spatial patterns of bacterial and archaeal communities along the Romanche Fracture Zone (tropical Atlantic). The composition of prokaryotic communities was determined in the meso- and bathypelagic waters funneled through the Romanche Fracture Zone (RFZ, 2°7'S, 31°79'W to 0°6'N, 14°33'W) in the tropical Atlantic. Distinct water masses were identified based on their physical and chemical characteristics. The bacterial and archaeal communities were depth-stratified with a total of 116 and 25 operational taxonomic units (OTUs), respectively, distributed among the distinct water masses as revealed by terminal restriction fragment length polymorphism, and cloning and sequencing. The relative abundance of Thaumarchaeota, determined by catalyzed reporter deposition-fluorescence in situ hybridization, was significantly higher in deeper layers (Antarctic Bottom Water, AABW, > 4000 m depth), contributing up to 31% to the total prokaryotic community, than in the mesopelagic and lower euphotic layer. Although the contribution of SAR11 to bacterial abundance did not increase with depth, SAR202, SAR324, SAR406 and Alteromonas did increase with depth. Terminal restriction fragment length polymorphism analysis revealed successional changes in the bacterial and archaeal community composition of the North Atlantic Deep Water (NADW) with a passage time through the RFZ of c. 4 months but not in the under- and overlying water masses. Our results indicate that specific water masses harbor distinct bacterial and archaeal communities and that the prokaryotic community of the NADW undergoes successional changes in this conduit between the western and eastern Atlantic basin. Apparently, in the absence of major input of organic matter to specific deep-water masses, the indigenous prokaryotic community adapts to subtle physical and biogeochemical changes in the water mass within a time frame of weeks, similar to the reported seasonal changes in surface water prokaryotic communities. 23659564 Clinical outcomes after 24 months of insulin therapy in patients with type 2 diabetes in five countries: results from the TREAT study. Abstract Objective: To assess factors associated with insulin regimens at initiation, changes in treatment and metabolic control over 2 years of insulin therapy in patients with type 2 diabetes in five countries. Research design and methods: TREAT was a prospective, 24 month, observational study in patients with type 2 diabetes initiating insulin in clinical practice. Patient characteristics were collected at baseline and metabolic outcomes at 3, 6, 12, 18 and 24 months after initiation. Results: A total of 985 patients were enrolled, 886 assessed at baseline and 734 (82.8%) at 24 months. Baseline characteristics varied between countries: 52.8% of patients were men; mean age was 60.4 years; body mass index, 29.7 kg/m(2); time since diagnosis, 10.1 years; HbA1c, 9.6%. Less than 25% of patients met ADA/IDF targets for blood pressure/LDL cholesterol. Overall, 50.1% of patients were initiated on long/intermediate insulin, 39.3% on mixture and 7.8% on basal-bolus; distribution varied between countries. Patients on long/intermediate were more likely to have lower baseline HbA1c and be intensified to other regimens (19.4%). No oral antidiabetic medication was used for 16.4% initiating on long/intermediate, 47.4% on mixture and 62.3% with basal-bolus. Overall, mean HbA1c decreased from 9.6% to 7.6%, with little difference between regimens at endpoint. The percentage of patients with hypoglycaemia was highest at 6 months and with basal-bolus. Limitations: Sites were not selected at random. Drop-out of patients prior to 24 months may have introduced a bias that favoured responders. Conclusions: Mean baseline HbA1c was high, indicating delayed initiation of insulin treatment. Blood pressure and lipids were suboptimally controlled. Insulin regimens varied between countries, changed little and resulted in similar HbA1c levels after 24 months. 23583636 Cross-reactive antibodies in convalescent SARS patients' sera against the emerging novel human coronavirus EMC (2012) by both immunofluorescent and neutralizing antibody tests. A severe acute respiratory syndrome (SARS)-like disease due to a novel betacoronavirus, human coronavirus EMC (HCoV-EMC), has emerged recently. HCoV-EMC is phylogenetically closely related to Tylonycteris-bat-coronavirus-HKU4 and Pipistrellus-bat-coronavirus-HKU5 in Hong Kong. We conducted a seroprevalence study on archived sera from 94 game-food animal handlers at a wild life market, 28 SARS patients, and 152 healthy blood donors in Southern China to assess the zoonotic potential and evidence for intrusion of HCoV-EMC and related viruses into humans. Anti-HCoV-EMC and anti-SARS-CoV antibodies were detected using screening indirect immunofluorescence (IF) and confirmatory neutralizing antibody tests. Two (2.1%) animal handlers had IF antibody titer of ≥ 1:20 against both HCoV-EMC and SARS-CoV with neutralizing antibody titer of <1:10. No blood donor had antibody against either virus. Surprisingly, 17/28 (60.7%) of SARS patients had significant IF antibody titers with 7/28 (25%) having anti-HCoV-EMC neutralizing antibodies at low titers which significantly correlated with that of HCoV-OC43. Bioinformatics analysis demonstrated a significant B-cell epitope overlapping the heptad repeat-2 region of Spike protein. Virulence of SARS-CoV over other betacoronaviruses may boost cross-reactive neutralizing antibodies against other betacoronaviruses. Convalescent SARS sera may contain cross-reactive antibodies against other betacoronaviruses and confound seroprevalence study for HCoV-EMC. 23728390 NtNAC-R1, a novel NAC transcription factor gene in tobacco roots, responds to mechanical damage of shoot meristem. Topping is the important agronomic measure for flue-cured tobacco, and results in increase of the nicotine content in top leaves. Nicotine content is one of the vitals factors for the quality of tobacco leaves. Nicotine is exclusively synthesized in tobacco roots, and then transported to the leaves through the xylem. To investigate the molecular mechanism of increase in nicotine biosynthesis ability following topping, some responses of tobacco roots to topping were analyzed, and the role of NtNAC-R1 in regulating nicotine synthesis and the development of roots was discussed. The electronic cloning technique combined with RT-PCR was successfully used to clone NtNAC-R1 from tobacco roots. The number of lateral root and nicotine contents in tobacco roots increased following topping. Although spraying MeJA on leaves had no effects on the root phenotype, the nicotine contents and the expression of PMT increased markedly. The miR164 was down-regulated, and NtNAC-R1 was up-regulated in tobacco roots after topping. PMT and ODC were down-regulated in transgenic tobacco with antisense NtNAC-R1, and PMT was up-regulated in transgenic tobacco with over-expressed NtNAC-R1. In conclusion, topping can induce the decrease of miR164 and the increase of IAA content in roots, which up-regulate the expression of NtNAC-R1, resulting in the increase of lateral roots and nicotine contents. Meanwhile, topping is a mechanical wounding which can induce JA signal, and JA can enhance nicotine biosynthesis in tobacco roots. So the increase of nicotine biosynthesis ability would be related to cross-talking of JA and auxin signaling pathway after topping. 23886768 Two Cases of Interferon-Alpha-Induced Sarcoidosis Koebnerized along Venous Drainage Lines: New Pathogenic Insights and Review of the Literature of Interferon-Induced Sarcoidosis. Sarcoidosis is a systemic granulomatous disorder of unknown origin commonly affecting the lung, the lymphoid system and the skin. We report here two cases of cutaneous sarcoidosis in two former intravenous drug users following interferon (IFN)-α and ribavirin therapy for chronic hepatitis C. Both patients developed skin sarcoidosis along venous drainage lines of both forearms, coinciding with the areas of prior drug injections. The unique distribution of the skin lesions suggests that tissue damage induced by repeated percutaneous drug injections represents a trigger for the local skin manifestation of sarcoidosis. Interestingly, skin damage was recently found to induce the local expression IFN-α, a well-known trigger of sarcoidosis in predisposed individuals. Here we review the literature on sarcoidosis elicited in the context of IFN-α therapy and propose a new link between the endogenous expression of IFN-α and the induction of disease manifestations in injured skin. © 2013 S. Karger AG, Basel. 23816558 The impact of both platinum-based chemotherapy and EGFR-TKIs on overall survival of advanced non--small cell lung cancer. Both platinum-based doublet chemotherapy (PBC) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) prolong the survival of patients with advanced non-small cell lung cancer (NSCLC). In early studies, most patients received PBC as first-line treatment, but not all patients could afford EGFR-TKIs as second-line treatment. To understand the impact of PBC and EGFR-TKIs on NSCLC prognosis, we evaluated the correlation between the receipt of both regimens and overall survival. Using MEDLINE and EMBASE, we identified prospective, randomized, controlled phase III clinical trials in advanced NSCLC that met the inclusion criteria: in general population with advanced NSCLC, the percentage of patients receiving both PBC and EGFR-TKIs was available in the trial and overall survival (OS) was reported. After collecting data from the selected trials, we correlated the percentage of patients receiving both PBC and EGFR-TKIs with the reported OS, using a weighted analysis. Fifteen phase III clinical trials--involving 11,456 adult patients in 32 arms--were included in the analysis, including six trials in Asian populations and nine in non-Asian (predominantly Caucasian) populations. The overall survival was positively correlated with the percentage of patients receiving both PBC and EGFR-TKIs (r = 0.797, P <0.001). The correlation was obvious in the trials in Asian populations (r = 0.936, P < 0.001) but was not statistically significant in the trials in predominantly Caucasian populations (r = 0.116, P = 0.588). These results suggest that treatment with PBC and EGFR-TKIs may provide a survival benefit to patients with advanced NSCLC, highlighting the importance of having both modalities available for therapy. 23909675 An exercise prescription primer for people with depression. A substantial body of evidence supports the value of exercise in the treatment of people with depression. The guidelines for exercise prescription, however, are limited, and based on those developed for healthy populations. This article explores the evidence for exercise in the treatment of depression and the role mental health nurses may play in the delivery of this information. A model of exercise prescription is put forward based on the available evidence and taking into account the challenges faced by mental health nurses and people with depression. 23184315 Deep brain stimulation of the subthalamic nucleus, but not dopaminergic medication, improves proactive inhibitory control of movement initiation in Parkinson's disease. Slowness in movement initiation is a cardinal feature of Parkinson's disease (PD) that is still poorly understood and unsuccessfully alleviated by standard therapies. Here, we raise this major clinical issue within the framework of a novel theoretical model that allows a better understanding of the basic mechanisms involved in movement initiation. This model assumes that movement triggering is inhibited by default to prevent automatic responses to unpredictable events. We investigated to which extent the top-down control necessary to release this locking state before initiating actions is impaired in PD and restored by standard therapies. We used a cue-target reaction time task to test both the ability to initiate fast responses to targets and the ability to refrain from reacting to cues. Fourteen patients with dopaminergic (DA) medication and 11 with subthalamic nucleus (STN) stimulation were tested on and off treatment, and compared with 14 healthy controls. We found evidence that patients withdrawn from treatment have trouble voluntarily releasing proactive inhibitory control; while DA medication broadly reduces movement initiation latency, it does not reinstate a normal pattern of movement initiation; and stimulation of the STN specifically re-establishes the efficiency of the top-down control of proactive inhibition. These results suggest that movement initiation disorders that resist DA medication are due to executive, not motor, dysfunctions. This conclusion is discussed with regard to the role the STN may play as an interface between non-DA executive and DA motor systems in cortico-basal ganglia loops. 23934725 Substituent effects on the decomposition of chemiluminescent tricyclic aromatic dioxetanes. Three tricyclic 1,2-dioxetane derivatives, 1a, 2a and 3a were synthesized from their corresponding 1,4-dioxin acenaphthylene compounds, 1, 2 and 3, by reaction with singlet-oxygen ((1) O2 ) in dichloromethane. Evidence for the formation of the dioxetanes 1a, 2a and 3a is provided by the chemiluminescence (CL) that corresponds to the emission from the electronically excited diesters 1b*, 2b* and 3b*, which are decomposed thermally from the dioxetanes 1a, 2a and 3a, respectively. The highly strained 1,2-dioxetane ring decomposes from a twisted geometry by simultaneous cleavages of the O-O and C-C bonds, producing the electronically excited diester that emits CL. It was observed that the CL from compound 2a is red-shifted relative to that of compounds 1a and 3a suggesting a higher degree of stabilization for the excited state by the electron-donating methoxy group. Also, a study of the solvent effect on fluorescence shows a significant red-shift in compound 2b, indicating a more polar excited state. The kinetics of the thermal decomposition of the 1,2-dioxetanes clearly demonstrate that the CL characteristics of compound 2a are quite different from those of compounds, 1a and 3a. These results are consistent with the proposed intramolecular chemically initiated electron exchange luminescence (CIEEL) mechanism which is triggered by the electron-donating group of compound 2a. Copyright © 2013 John Wiley & Sons, Ltd. 23537831 Orientational behaviors of liquid crystals coupled to chitosan-disrupted phospholipid membranes at the aqueous-liquid crystal interface. In this study, we investigated the orientational behavior of liquid crystals (LCs) which is associated with the chitosan-disrupted phospholipid membrane at the aqueous/LC interface. The optical response of LCs changed from dark to bright after the transfer of an aqueous solution of chitosan onto the LC interface decorated with self-assembled monolayers of a negatively charged phospholipid, dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG). The chitosan-lipid interactions induced a rearrangement of the membrane, and thus, resulted in an orientational transition of LCs from a homeotropic to a planar state, thereby triggering a dark-to-bright shift in the optical response. We observed that LCs exhibited a bright-to-dark shift after an aqueous solution of lysozyme was transferred onto the chitosan-disrupted membrane, which implied that an enzymatic reaction between lysozyme and chitosan took place. We found that the addition of bovine serum album (BSA) induced a bright-to-dark change in the optical response; while LCs remained to appear bright after the transfer of chymotrypsin onto the aqueous/LC interface. We then further examined the interactions between other polyelectrolytes and phospholipid membranes. 23935877 Searching for synergies: matrix algebraic approaches for efficient pair screening. Functionally interacting perturbations, such as synergistic drugs pairs or synthetic lethal gene pairs, are of key interest in both pharmacology and functional genomics. However, to find such pairs by traditional screening methods is both time consuming and costly. We present a novel computational-experimental framework for efficient identification of synergistic target pairs, applicable for screening of systems with sizes on the order of current drug, small RNA or SGA (Synthetic Genetic Array) libraries (>1000 targets). This framework exploits the fact that the response of a drug pair in a given system, or a pair of genes' propensity to interact functionally, can be partly predicted by computational means from (i) a small set of experimentally determined target pairs, and (ii) pre-existing data (e.g. gene ontology, PPI) on the similarities between targets. Predictions are obtained by a novel matrix algebraic technique, based on cyclical projections onto convex sets. We demonstrate the efficiency of the proposed method using drug-drug interaction data from seven cancer cell lines and gene-gene interaction data from yeast SGA screens. Our protocol increases the rate of synergism discovery significantly over traditional screening, by up to 7-fold. Our method is easy to implement and could be applied to accelerate pair screening for both animal and microbial systems. 23781842 Flue Gas Recirculation and Enhanced Performance of Waste Incinerators under Waste Uncertainty. Variations in waste quantities and composition affect incinerator operating conditions and performance. Fluegas volumes consititute a dominant environmental and financial consideration for efficient waste incinerator (WI) operation, since they affect the temperature, throughput, air pollution control system (APCS) residence time, and pollutant emissions, when the charging rate or composition of any waste is varying. Fluegas recirculation (FGR) in WI is an effective technique for reducing WI atmospheric pollution, mainly NOx emissions, albeit affecting WI throughput, temperature and destruction/removal efficiency. FGR refers to mass recirculation of a possibly cooled fraction of fluegases and differs substantially from fluegas heat recovery. The present work shows that, besides emission control, suitable manipulation of FGR enhances WI performance under waste uncertainty, enabling higher throughput, at the desired temperature and within the allowed APCS residence time range. A dimensionless parameter related to the uncertain wastes' net enthalpy contribution is isolated, which encompasses heat of reaction and enthalpy outflows from fluegas and solids and which reveals whether throughput is decreasing or increasing with temperature and FGR ratio. Normalized throughput and total fluegas volume isotherms manifest the interdependence and enable manipulation for enhanced environmental and economic performance. 23729009 Molecular modeling of the piezoelectric effect in the ferroelectric polymer poly(vinylidene fluoride) (PVDF). In this work, computational molecular modeling and exploration was applied to study the nature of the negative piezoelectric effect in the ferroelectric polymer polyvinylidene fluoride (PVDF), and the results confirmed by actual nanoscale measurements. First principle calculations were employed, using various quantum-chemical methods (QM), including semi-empirical (PM3) and various density functional theory (DFT) approaches, and in addition combined with molecular mechanics (MM) methods in complex joint approaches (QM/MM). Both PVDF molecular chains and a unit cell of crystalline β-phase PVDF were modeled. This computational molecular exploration clearly shows that the nature of the so-called negative piezo-electric effect in the ferroelectric PVDF polymer has a self-consistent quantum nature, and is related to the redistribution of the electron molecular orbitals (wave functions), leading to the shifting of atomic nuclei and reorganization of all total charges to the new, energetically optimal positions, under an applied electrical field. Molecular modeling and first principles calculations show that the piezoelectric coefficient d 33 has a negative sign, and its average values lies in the range of d 33  ~ -16.6 to -19.2 pC/N (or pm/V) (for dielectric permittivity ε = 5) and in the range of d 33  ~ -33.5 to -38.5 pC/N (or pm/V) (for ε = 10), corresponding to known data, and allowing us to explain the reasons for the negative sign of the piezo-response. We found that when a field is applied perpendicular to the PVDF chain length, as polarization increases the chain also stretches, increasing its length and reducing its height. For computed value of ε ~ 5 we obtained a value of d31 ~ +15.5 pC/N with a positive sign. This computational study is corroborated by measured nanoscale data obtained by atomic force and piezo-response force microscopy (AFM/PFM). This study could be useful as a basis for further insights into other organic and molecular ferroelectrics. 23818216 Weak operator binding enhances simulated lac repressor-mediated DNA looping. The 50(th) anniversary of Biopolymers coincides closely with the like celebration of the discovery of the Escherichia coli (lac) lactose operon, a classic genetic system long used to illustrate the influence of biomolecular structure on function. The looping of DNA induced by the binding of the Lac repressor protein to sequentially distant operator sites on DNA continues to serve as a paradigm for understanding long-range genomic communication. Advances in analyses of DNA structures and in incorporation of proteins in computer simulations of DNA looping allow us to address long-standing questions about the role of protein-mediated DNA loop formation in transcriptional control. Here we report insights gained from studies of the sequence-dependent contributions of the natural lac operators to Lac repressor-mediated DNA looping. Novel superposition of the ensembles of protein-bound operator structures derived from NMR measurements reveals variations in DNA folding missed in conventional structural alignments. The changes in folding affect the predicted ease with which the repressor induces loop formation and the ways that DNA closes between the protein headpieces. The peeling of the auxiliary operators away from the repressor enhances the formation of loops with the 92-bp wildtype spacing and hints of a structural reason behind their weak binding. 23871581 An experience with plasma exhcange treatment of acute lymphoblastic leukemia in a case with fulminant hepatitis related to l-asparaginase. Acute lymphoblastic leukemia (ALL) is a malignant disorder resulting from the clonal proliferation of lymphoid precursors with arrested maturation. l-asparaginase is commonly used in combination chemotherapy of both pediatric and adult acute lymphoblastic leukemias. The most commonly encountered side effects of l-asparaginase are hypersensitivity reactions like pyrexia, urticaria, skin rash, and respiratory distress. There are also other side effects like anaphylaxis, coagulopathy, pancreatitis, thrombosis, and hepatic toxicity. Plasmapheresis can sometimes be appropriate to manage an overdose of drugs that circulate in the plasma compartment. We have reported plasmapheresis treatment of fulminant hepatitis in a patient with ALL after l-asparaginase treatment. 23835654 Single-nucleotide polymorphism associations with preterm delivery: a case-control replication study and meta-analysis. Background:The aim of this study was to replicate single-nucleotide polymorphism (SNP) associations with preterm birth (PTB; birth at <37 completed weeks of gestation) and synthesize currently available evidence using meta-analysis.Methods:Spontaneous PTB cases and controls were selected from an existing cohort. Candidate SNPs were taken from an existing genotype panel. A systematic review was conducted for each SNP in the panel to determine suitability as a PTB candidate. Those with significant associations previously reported in Caucasians were selected for replication. Candidate SNPs were already genotyped in cases and controls and clinical data were accessed from state perinatal and cerebral palsy databases. Association analysis was conducted between each SNP and PTB, and meta-analysis was conducted if there were ≥3 studies in the literature. Maternal and fetal SNPs were considered as separate candidates.Results:A cohort of 170 cases and 583 controls was formed. Eight SNPs from the original panel of genotyped SNPs were selected as PTB candidates and for replication on the basis of systematic literature review results. In our cohort, fetal factor V Leiden (FVL) was significantly associated with PTB (odds ratio (OR): 2.6, 95% confidence interval (CI): 1.31-5.17), and meta-analysis confirmed this association (OR: 2.71, 95% CI: 1.15-6.4).Conclusion:Replication and meta-analysis support an increased risk of PTB in Caucasians with the fetal FVL mutation.Pediatric Research (2013); doi:10.1038/pr.2013.117. 23877112 Functionalized Single-Walled Carbon Nanotube-Based Fuel Cell Benchmarked Against US DOE 2017 Technical Targets. Chemically modified single-walled carbon nanotubes (SWNTs) with varying degrees of functionalization were utilized for the fabrication of SWNT thin film catalyst support layers (CSLs) in polymer electrolyte membrane fuel cells (PEMFCs), which were suitable for benchmarking against the US DOE 2017 targets. Use of the optimum level of SWNT -COOH functionality allowed the construction of a prototype SWNT-based PEMFC with total Pt loading of 0.06 mgPt/cm(2) - well below the value of 0.125 mgPt/cm(2) set as the US DOE 2017 technical target for total Pt group metals (PGM) loading. This prototype PEMFC also approaches the technical target for the total Pt content per kW of power (<0.125 gPGM/kW) at cell potential 0.65 V: a value of 0.15 gPt/kW was achieved at 80°C/22 psig testing conditions, which was further reduced to 0.12 gPt/kW at 35 psig back pressure. 23743719 Cobalt porphyrins as homogeneous catalysts for water oxidation. Three water-soluble cobalt porphyrins have been investigated as water oxidation catalysts via photo-initiation using Ru(II)(bpy)3(2+)/Na2S2O8. The pH dependence of the turnover frequency revealed maximum activity at pH 11. Based on the second order dependence on catalyst concentration for the rate of water oxidation, we suggest a bimolecular radical coupling process as the rate determining step. 23949426 Targeting the ERBB family in cancer: couples therapy. The ERBB family of receptor tyrosine kinases has a central role in the tumorigenesis of many types of solid tumour. Various therapeutics targeting these receptors have been approved for the treatment of several cancers. Considerable preclinical data have shown that the administration of two inhibitors against an individual ERBB family member - particularly epidermal growth factor receptor (EGFR) or ERBB2 - leads to markedly higher antitumour activity than the administration of single agents. This Opinion article describes the preclinical and clinical performance of these dual-targeting approaches, discusses the key mechanisms that mediate their increased efficacy and highlights areas for ongoing investigation. 23884038 Glatiramer acetate-induced acute hepatotoxicity in an adolescent with MS. Glatiramer acetate (GA), a synthetic copolymer, is a frequently used first-line treatment for relapsing-remitting multiple sclerosis (RRMS). Probable autoimmune hepatotoxicity during GA treatment has been reported,(1-4) but GA hepatotoxicity in the absence of positive autoimmune markers has not previously been described. Here, we report GA-induced hepatotoxicity in a pediatric patient with multiple sclerosis (MS). 23841714 Post-transcriptional activation of a diguanylate cyclase by quorum sensing small RNAs promotes biofilm formation in Vibrio cholerae. Biofilms promote attachment of Vibrio cholerae in aquatic ecosystems and aid in transmission. Intracellular c-di-GMP levels that control biofilm development positively correlate with expression of Qrr sRNAs, which are transcribed when quorum sensing (QS) autoinducer levels are low. The Qrr sRNAs base-pair with and repress translation of hapR encoding the QS 'master regulator', hence increased c-di-GMP and biofilm development at low density were believed to be solely a consequence of Qrr/hapR pairing. We show that Qrr sRNAs also base-pair with and activate translation of the mRNA of a diguanylate cyclase (DGC), Vca0939; relieving an inhibitory structure in vca0939 that occludes the ribosome binding site. A nucleotide substitution in vca0939 disrupted sRNA/mRNA base-pairing and prevented vca0939 translation, while a compensating Qrr sRNA substitution restored pairing and Vca0939 levels. Qrr-dependent DGC activation led to c-di-GMP accumulation and biofilm development in V. cholerae. This represents the first description of (1) a DGC post-transcriptionally activated by direct pairing with an Hfq-dependent sRNA, and (2) control of a V. cholerae QS phenotype, independent of HapR. Thus, direct interactions of the same sRNAs with two mRNAs promote c-di-GMP-dependent biofilm formation by complementary mechanisms in V. cholerae; by negatively regulating HapR, and positively regulating the DGC Vca0939. 23557092 Galactose-Based Amphiphilic Block Copolymers: Synthesis, Micellization, and Bioapplication. Redox-responsive amphiphilic diblock copolymers, poly(6-O-methacryloyl-d-galactopyranose-co-2-(N,N-dimethylaminoethyl) methacrylate)-b-poly(pyridyl disulfide ethyl methylacrylate) (P(MAGP-co-DMAEMA)-b-PPDSMA) were obtained by deprotection of poly((6-O-methacryloyl-1,2:3,4-di-O-isopropylidene-d-galactopyranose)-co-DMAEMA)-b-PPDSMA [P(MAlpGP-co-DMAEMA)-b-PPDSMA], which were prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization of PDSMA using P(MAlpGP-co-DMAEMA) as macro-RAFT agent. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) studies showed that diblock copolymers P(MAGP-co-DMAEMA)-b-PPDSMA can self-assemble into micelles. Doxorubicin (DOX) could be encapsulated by P(MAGP-co-DMAEMA)-b-PPDSMA upon micellization and released upon adding glutathione (GSH) into the micelle solution. The galactose functional groups in the PMAGP block had specific interaction with HepG2 cells, and P(MAGP-co-DMAEMA)-b-PPDSMA can act as gene delivery vehicle. So, this kind of polymer has potential applications in hepatoma-targeting drug and gene delivery and biodetection. 23964896 Panx1 regulates neural stem and progenitor cell behaviours associated with cytoskeletal dynamics and interacts with multiple cytoskeletal elements. Pannexins (Panxs) are relatively newly discovered large-pore ion and metabolite permeable channels. Although no proteomics-based interactome has yet been published, Panx1 has been demonstrated to interact with actin in an ectopic expression system. This interaction affects both Panx1 plasma membrane stability as well as cytoskeletal remodelling. The current study builds on our recent discovery of Panx1 expression in ventricular zone (VZ) neural stem and progenitor cells (NSC/NPCs), and on the demonstrated interaction of Panx1 with the cytoskeleton. Here we demonstrate that Panx1 also plays roles in two additional cell behaviours associated with neurogenesis, including cell migration and neurite extension. Furthermore, we confirmed an endogenous interaction between actin and Panx1, and identified a new interaction with actin-related protein 3, an actin cytoskeleton-modulating protein. This study further establishes the importance of Panx1 in the cell biology of NSC/NPCs and strengthens and expands our knowledge of Panx1 interactions with the cytoskeleton. 23902855 Evolving uses of oral reverse transcriptase inhibitors in the HIV-1 epidemic: from treatment to prevention. The HIV epidemic continues unabated, with no highly effective vaccine and no cure. Each new infection has significant economic, social and human costs and prevention efforts are now as great a priority as global antiretroviral therapy (ART) scale up. Reverse transcriptase inhibitors, the first licensed class of ART, have been at the forefront of treatment and prevention of mother to child transmission over the past two decades. Now, their use in adult prevention is being extensively investigated. We describe two approaches: treatment as prevention (TasP) - the use of combination ART (2NRTI and 1NNRTI) following HIV diagnosis to limit transmission and pre-exposure prophylaxis (PrEP) -the use of single or dual oral agents prior to sexual exposure. Prevention of mother-to-child transmission using NRTI has been highly successful, though does not involve sustained use of NRTI to limit transmission. Despite theoretical and preliminary support for TasP and PrEP, data thus far indicate that adherence, retention in care and late diagnosis are the major barriers to their successful, sustained implementation. Future advances in drug technologies will be needed to overcome the issue of drug adherence, through development of drugs that involve both less frequent dosing as well as reduced toxicity, possibly through specific targeting of infected cells. 22607101 Optimization of PLGA nanoparticles formulation containing L-DOPA by applying the central composite design. The aim of this work was to prepare L-DOPA loaded poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles by a modified water-in-oil-in-water (W(1)/O/W(2)) emulsification solvent evaporation method. A central composite design was applied for optimization of the formulation parameters and for studying the effects of three independent variables: PLGA concentration, polyvinyl alcohol (PVA) concentration and organic solvent removal rate on the particle size and the entrapment efficiency (response variables). Second-order models were obtained to adequately describe the influence of the independent variables on the selected responses. The analysis of variance showed that the three independent variables had significant effects (p < 0.05) on the responses. The experimental results were in perfect accordance with the predictions estimated by the models. Using the desirability approach and overlay contour plots, the optimal preparation area can be highlighted. It was found that the optimum values of the responses could be obtained at higher concentration of PLGA (5%, w/v) and PVA (6%, w/v); and faster organic solvent removal rate (700 rpm). The corresponding particle size was 256.2 nm and the entrapment efficiency was 62.19%. FTIR investigation confirmed that the L-DOPA and PLGA polymer maintained its backbone structure in the fabrication of nanoparticles. The scanning electron microscopic images of nanoparticles showed that all particles had spherical shape with porous outer skin. The results suggested that PLGA nanoparticles might represent a promising formulation for brain delivery of L-DOPA. The preparation of L-DOPA loaded PLGA nanoparticles can be optimized by the central composite design. 23362271 Mutations in the putative dimer-dimer interfaces of the measles virus hemagglutinin head domain affect membrane fusion triggering. Measles virus (MV), an enveloped RNA virus belonging to the Paramyxoviridae family, enters the cell through membrane fusion mediated by two viral envelope proteins, an attachment protein hemagglutinin (H) and a fusion (F) protein. The crystal structure of the receptor-binding head domain of MV-H bound to its cellular receptor revealed that the MV-H head domain forms a tetrameric assembly (dimer of dimers), which occurs in two forms (forms I and II). In this study, we show that mutations in the putative dimer-dimer interface of the head domain in either form inhibit the ability of MV-H to support membrane fusion, without greatly affecting its cell surface expression, receptor binding, and interaction with the F protein. Notably, some anti-MV-H neutralizing monoclonal antibodies are directed to the region around the dimer-dimer interface in form I rather than receptor-binding sites. These observations suggest that the dimer-dimer interactions of the MV-H head domain, especially that in form I, contribute to triggering membrane fusion, and that conformational shift of head domain tetramers plays a role in the process. Furthermore, our results indicate that although the stalk and transmembrane regions may be mainly responsible for the tetramer formation of MV-H, the head domain alone can form tetramers, albeit at a low efficiency. 23639869 Method for quantitative measurements of the elastic modulus of biological cells in AFM indentation experiments. Here we overview and further develop a quantitative method to measure mechanics of biological cells in indentation experiments, which is based on the use of atomic force microscopy (AFM). We demonstrate how the elastic modulus of the cell body should be measured when the cellular brush is taken into account. The brush is an essential inelastic part of the cell, which surrounds all eukaryotic (the brush is mostly microvilli and glycocalyx) and gram-negative prokaryotic cells (the brush is polysaccharides). The other main feature of the described method is the use of a relatively dull AFM probe to stay in the linear stress-strain regime. In particular, we show that the elastic modulus (aka the Young's modulus) of cells is independent of the indentation depth up to 10-20% deformation for the eukaryotic cells studied here. Besides the elastic modulus, the method presented allows obtaining the parameters of cellular brush, such as the effective length and grafting density of the brush. Although the method is demonstrated on eukaryotic cells, it is directly applicable for all types of cells, and even non-biological soft materials surrounded by either a brush or any field of long-range forces. 23864782 Cap polyposis: A rare cause of rectal bleeding in children. To evaluate the clinicopathological features and treatment outcomes of cap polyposis in the pediatric population. All pediatric patients with histologically proven diagnosis of cap polyposis were identified from our endoscopy and histology database over a 12 year period from 2000-2012 at our tertiary pediatric center, KK Women's and Children's Hospital in Singapore. The case records of these patients were retrospectively reviewed. The demographics, clinical course, laboratory results, endoscopic and histopathological features, treatments, and outcomes were analyzed. The study protocol was approved by the hospital institutional review board. The histological slides were reviewed by a pediatric histopathologist to confirm the diagnosis of cap polyposis. Eleven patients were diagnosed with cap polyposis. The median patient age was 13 years (range 5-17 years); the sample included 7 males and 4 females. All of the patients presented with bloody stools. Seven patients (63%) had constipation, while 4 patients (36%) had diarrhea. All of the patients underwent colonoscopy and polypectomies (excluding 1 patient who refused polypectomy). The macroscopic findings were of polypoid lesions covered by fibrinopurulent exudates with normal intervening mucosa. The rectum was the most common involvement site (n = 9, 82%), followed by the rectosigmoid colon (n = 3, 18%). Five (45%) patients had fewer than 5 polyps, and 6 patients (65%) had multiple polyps. Histological examination of these polyps showed surface ulcerations with a cap of fibrin inflammatory exudate. Four (80%) patients with fewer than 5 polyps had complete resolution of symptoms following the polypectomy. One patient who did not consent to the polypectomy had resolution of symptoms after being treated with sulphasalazine. All 6 patients with multiple polyps experienced recurrence of bloody stools on follow-up (mean = 28 mo). Cap polyposis is a rare and under-recognised cause of rectal bleeding in children. Our study has characterized the disease phenotype and treatment outcomes in a pediatric cohort. 23860597 Effects of diethylphthalate and di-(2-ethyl)hexylphthalate on the physiology and ultrastructure of cucumber seedlings. Phthalic acid esters (PAEs) are one kind of persistent organic pollutants. This study was conducted to investigate the effects of diethylphthalate (DEP) and di(2-ethyl)hexylphthalate (DEHP) with different concentrations (0, 30, 50, 100, and 200 mg L(-1)) on early seedling growth of Cucumis sativus L. Physiological, biochemical, and ultrastructure of seedling leaves were examined for 7-day exposure. The three antioxidant enzymes' activities was stimulated at low-DEP treatments and decreased under higher levels (>200 mg L(-1)) compared to the controls. Furthermore, MDA and H2O2 gradually enhanced with the elevation of DEP and DEHP concentration. Significant impact on the chloroplast and mitochondrion was visible, possibly as a consequence of free radical generation. DEP induced bigger and more starch grains in chloroplasts than DEHP. This study concluded that the effects of DEP and DEHP on cucumber seedlings represented the adverse impacts of DEP and DEHP on the ecosystem and agricultural production. The environmental harm caused by DEP was severer than DEHP. 23952342 Platform for High-Throughput Testing of the Effect of Soluble Compounds on 3D Cell Cultures. In vitro 3D culture could provide an important model of tissues in vivo, but assessing the effects of chemical compounds on cells in specific regions of 3D culture requires physical isolation of cells and thus currently relies mostly on delicate and low-throughput methods. This paper describes a technique ("cells-in-gels-in-paper", CiGiP) that permits rapid assembly of arrays of 3D cell cultures and convenient isolation of cells from specific regions of these cultures. The 3D cultures were generated by stacking sheets of 200-μm-thick paper, each sheet supporting 96 individual "spots" (thin circular slabs) of hydrogels containing cells, separated by hydrophobic material (wax, PDMS) impermeable to aqueous solutions, and hydrophilic and most hydrophobic solutes. A custom-made 96-well holder isolated the cell-containing zones from each other. Each well contained media to which a different compound could be added. After culture and disassembly of the holder, peeling the layers apart "sectioned" the individual 3D cultures into 200-μm-thick sections which were easy to analyze using 2D imaging (e.g., with a commercial gel scanner). This 96-well holder brings new utilities to high-throughput, cell-based screening, by combining the simplicity of CiGiP with the convenience of a microtiter plate. This work demonstrated the potential of this type of assays by examining the cytotoxic effects of phenylarsine oxide (PAO) and cyclophosphamide (CPA) on human breast cancer cells positioned at different separations from culture media in 3D cultures. 23864204 Self-Similar Anisotropic Texture Analysis: the Hyperbolic Wavelet Transform Contribution. Textures in images can often be well modeled using self-similar processes while they may at the same time display anisotropy. The present contribution thus aims at studying jointly selfsimilarity and anisotropy by focusing on a specific classical class of Gaussian anisotropic selfsimilar processes. It will first be shown that accurate joint estimates of the anisotropy and selfsimilarity parameters are performed by replacing the standard 2D-discrete wavelet transform by the hyperbolic wavelet transform, which permits the use of different dilation factors along the horizontal and vertical axis. Defining anisotropy requires a reference direction that needs not a priori match the horizontal and vertical axes according to which the images are digitized, this discrepancy defines a rotation angle. Second, we show that this rotation angle can be jointly estimated. Third, a non parametric bootstrap based procedure is described, that provides confidence interval in addition to the estimates themselves and enables to construct an isotropy test procedure, that can be applied to a single texture image. Fourth, the robustness and versatility of the proposed analysis is illustrated by being applied to a large variety of different isotropic and anisotropic self-similar fields. As an illustration, we show that a true anisotropy built-in self-similarity can be disentangled from an isotropic self-similarity to which an anisotropic trend has been superimposed. 23747023 Changes in macrophage phenotype as the immune response evolves. Mononuclear phagocytic cells (MPCs), including macrophages and dendritic cells (DCs), are widely distributed throughout our organs where they perform important homeostatic, surveillance and regenerative tasks. In response to infection or injury, the composition and number of MPCs change remarkably, in part due to the recruitment of inflammatory monocytes from bone marrow. In infection or injury, macrophages and DCs perform important innate and adaptive immune roles from the initial insult through repair and regeneration of the tissue and resolution of inflammation. Evidence from mouse models of disease has shown increasing complexity and subtlety to the mononuclear phagocytic system, which will be reviewed here. New studies show that in addition to monocytes, the resident populations of mononuclear phagocytes expand in disease states and play distinct but important roles in the immune response. Finally, new insights into these functionally diverse cells are now translating into therapeutics to treat human disease. 23712205 Defining the threshold for significant versus insignificant prostate cancer. Autopsy studies have shown the presence of a large reservoir of latent prostate cancers in adult men. Serum PSA testing of asymptomatic men leads to the detection of a proportion of these latent prostate cancers. The unequivocal demonstration of a substantial (30-50%) risk of overdiagnosis by the two largest randomized population-based screening trials has led to a growing awareness of this unwanted effect. Unsurprisingly, active surveillance is now becoming the favoured strategy for deferring active treatment in men diagnosed with low-risk prostate cancer and reducing their risk of overtreatment. Almost all eligibility criteria for active surveillance refer to a strict pathological definition of insignificant prostate cancer, based on two landmark studies published about 20 years ago. However, current epidemiological data suggest that this original pathological definition of insignificant prostate cancer is too restrictive. In addition, the International Society of Urological Pathology (ISUP) 2005 modification to the Gleason grading system might have resulted in a marked upgrading of biopsy-diagnosed prostate cancers, reducing the number of men eligible for active surveillance. An updated definition of insignificant prostate cancer should reflect the optimal trade-off between reducing the risk of underestimating a significant prostate cancer and including as many men as possible in active surveillance programmes. 23740037 Associations between fibroblast growth factor 23 and cardiac characteristics in pediatric heart failure. In adults with heart failure, elevated levels of fibroblast growth factor 23 (FGF23) are associated with mortality. Data on FGF23 levels in pediatric heart failure are lacking. We conducted a cross-sectional study of 17 healthy children (mean age 13 years) and 20 pediatric patients with heart failure (mean age 12 years) who underwent echocardiography and for whom the following measurements were taken: plasma FGF23 and parathyroid hormone (PTH) and serum phosphate, creatinine and N-terminal prohormone brain natriuretic peptide (NT-proBNP). Symptom severity was assessed with the New York Heart Association and the Ross classification systems. Of the 20 patients, 11 had dilated cardiomyopathy, four had congenital heart disease, three had hypertrophic cardiomyopathy, one had a failing heart transplant and one had pulmonary hypertension. Mean phosphate levels in these patients were within the reported reference range for healthy children. Median PTH levels were in the normal range in patients and controls. The median FGF23 level was higher in patients versus controls (110.9 vs. 66.4 RU/ml; P = 0.03) and higher in patients on diuretics versus other patients (222.4 vs. 82.1 RU/ml; P = 0.01). Levels of FGF23 and NT-proBNP were directly correlated (r = 0.47, P = 0.04), and patients with greater physical functional impairment had higher FGF23 levels (142.5 in those with moderate-severe limitation vs. 92.8 RU/ml in those with no limitation; P = 0.05). Among patients with dilated cardiomyopathy, higher FGF23 levels were associated with a greater left ventricular end-diastolic diameter (r = 0.63, P = 0.04). FGF23 levels are elevated in children with heart failure and are associated with diuretic use, severity of heart failure and left ventricular dilation. 23361947 Identification of a small-molecule inhibitor of HIV-1 assembly that targets the phosphatidylinositol (4,5)-bisphosphate binding site of the HIV-1 matrix protein. The development of drug resistance remains a critical problem for current HIV-1 antiviral therapies, creating a need for new inhibitors of HIV-1 replication. We previously reported on a novel anti-HIV-1 compound, N(2)-(phenoxyacetyl)-N-[4-(1-piperidinylcarbonyl)benzyl]glycinamide (14), that binds to the highly conserved phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P(2)) binding pocket of the HIV-1 matrix (MA) protein. In this study, we re-evaluate the hits from the virtual screen used to identify compound 14 and test them directly in an HIV-1 replication assay using primary human peripheral blood mononuclear cells. This study resulted in the identification of three new compounds with antiviral activity; 2-(4-{[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]methyl})-1-piperazinyl)-N-(4-methylphenyl)acetamide (7), 3-(2-ethoxyphenyl)-5-[[4-(4-nitrophenyl)piperazin-1-yl]methyl]-1,2,4-oxadiazole (17), and N-[4-ethoxy-3-(1-piperidinylsulfonyl)phenyl]-2-(imidazo[2,1-b][1,3]thiazol-6-yl)acetamide (18), with compound 7 being the most potent of these hits. Mechanistic studies on 7 demonstrated that it directly interacts with and functions through HIV-1 MA. In accordance with our drug target, compound 7 competes with PI(4,5)P(2) for MA binding and, as a result, diminishes the production of new virus. Mutation of residues within the PI(4,5)P(2) binding site of MA decreased the antiviral effect of compound 7. Additionally, compound 7 displays a broadly neutralizing anti-HIV activity, with IC(50) values of 7.5-15.6 μM for the group M isolates tested. Taken together, these results point towards a novel chemical probe that can be used to more closely study the biological role of MA and could, through further optimization, lead to a new class of anti-HIV-1 therapeutics. 23668320 Multifunctional structural supercapacitor composites based on carbon aerogel modified high performance carbon fiber fabric. A novel multifunctional material has been designed to provide excellent mechanical properties while possessing a high electrochemical surface area suitable for electrochemical energy storage: structural carbon fiber fabrics are embedded in a continuous network of carbon aerogel (CAG) to form a coherent but porous monolith. The CAG-modification process was found to be scalable and to be compatible with a range of carbon fiber fabrics with different surface properties. The incorporation of CAG significantly increased the surface area of carbon fiber fabrics, and hence the electrochemical performance, by around 100-fold, resulting in a CAG-normalized specific electrode capacitance of around 62 F g(-1), determined by cyclic voltammetry in an aqueous electrolyte. Using an ionic liquid (IL) electrolyte, the estimated energy density increased from 0.003 to 1 Wh kg(-1), after introducing the CAG into the carbon fiber fabric. 'Proof-of-concept' multifunctional structural supercapacitor devices were fabricated using an IL-modified solid-state polymer electrolyte as a multifunctional matrix to provide both ionic transport and physical support for the primary fibers. Two CAG-impregnated carbon fabrics were sandwiched around an insulating separator to form a functioning structural electrochemical double layer capacitor composite. The CAG-modification not only improved the electrochemical surface area, but also reinforced the polymer matrix surrounding the primary fibers, leading to dramatic improvements in the matrix-dominated composite properties. Increases in in-plane shear strength and modulus, of up to 4.5-fold, were observed, demonstrating that CAG-modified structural carbon fiber fabrics have promise in both pure structural and multifunctional energy storage applications. 23940937 The role of nurses in medicine administration errors. This article explores the commonly held belief that nurses are to blame for the high rate of medication administration errors in health care. The article argues for a need to move away from a culture of blame and to consider changes to medicine and the increasing complexity of administration as potential reasons for error. Medicine administration should be viewed within the wider context of health care rather than as an isolated process in order to develop effective solutions to reduce medicine-related errors. 23524313 Hypocholesterolemic effect of daily fisetin supplementation in high fat fed Sprague-Dawley rats. We aimed to test whether fisetin could modulate cholesterol homeostasis in rats with diet-induced hypercholesterolemia, and further investigated the underlying mechanisms by which fisetin exerts its cholesterol lowering effect. Blood lipid profile, hepatic cholesterol content, as well as gene expressions in cholesterol metabolism were examined. Elevated levels of total cholesterol and LDL-cholesterol, along with hepatic cholesterol content in a high fat group were found to be significantly reduced by fisetin. The high fat diet significantly decreased hepatic mRNA levels of LDLR, SREBP2, HMGCR and PCSK9 in comparison to the control diet, however, fisetin did not further elicit any changes in mRNA levels of the same genes. The high fat diet dramatically increased the transcript levels of CYP7A1, which was subsequently reversed by the fisetin. In HepG2 cells, fisetin was found to increase the levels of a nuclear form of SREBP2 and LDLR. In conclusion, fisetin supplementation displayed hypocholesterolemic effects by modulating the expression of genes associated with cholesterol and bile acid metabolism. 23896663 S-Adenosylmethionine-induced adipogenesis is accompanied by suppression of Wnt/β-catenin and Hedgehog signaling pathways. S-Adenosylmethionine (SAM) plays a crucial role as a methyl donor in various biological processes and has been previously shown to be involved in adipogenesis in skeletal muscle. This study was conducted to explore the mechanism of SAM inducing adipogenesis in skeletal muscle. Adipose precursor cells, 3T3-L1, and C2C12 cells, were induced into adipogenic differentiation by addition of SAM in MDI-differentiation media (0.5 mmol/L isobutylmethylxanthine, 1 Î¼m/L dexamethasone, and 10 Î¼g/mL insulin) to explore the role of SAM in promoting adipogenesis. Subsequently, cells were cultured with a medium containing SAM alone at the beginning of differentiation to test the relationship between SAM-induced adipogenesis and Wnt/β-catenin, and Hedgehog signaling pathways that control the cell commitment to adipogenic- or myogenic-differentiation. We found SAM possessed an additive effect with MDI in promoting adipogenesis of 3T3-L1 and C2C12 cells at the beginning of adipogenic differentiation. SAM could also individually induce cell adipogenesis in a dose-dependent manner. Moreover, the expression of Wnt/β-catenin and Hedgehog signals and their targets were suppressed by SAM (P < 0.05). These results demonstrate that SAM, as an increasingly accepted nutritional supplement, can initiate adipogenesis of adipose precursor cells derived from adipose and muscle tissues, a function at least partly correlated with the suppression of Wnt/β-catenin and Hedgehog pathways. 23175513 Neuropathic cancer pain: Prevalence, severity, analgesics and impact from the European Palliative Care Research Collaborative-Computerised Symptom Assessment study. Background: Neuropathic pain causes greater pain intensity and worse quality of life than nociceptive pain. There are no published data that confirm this in the cancer population. Aim: We hypothesised that patients with neuropathic cancer pain had more intense pain, experienced greater suffering and were treated with more analgesics than those with nociceptive cancer pain, and a neuropathic pain screening tool, painDETECT, would perform as well in those with cancer pain as is reported in those with non-cancer pain. Design: The data were obtained from an international cross-sectional observational study. Setting/Participants: A total of 1051 patients from inpatients and outpatients, with incurable cancer completed a computerised assessment on symptoms, function and quality of life. In all, 17 centres within eight countries participated. Medical data were recorded by physicians. Pain type was a clinical diagnosis recorded on the Edmonton Classification System for Cancer Pain. Results: Of the patients, 670 had pain: 534 with nociceptive pain, 113 with neuropathic pain and 23 were unclassified. Patients with neuropathic cancer pain were significantly more likely to be receiving oncological treatment, strong opioids and adjuvant analgesia and have a reduced performance status. They reported worse physical, cognitive and social function. Sensitivity and specificity of painDETECT for identifying neuropathic cancer pain was less accurate than when used in non-cancer populations. Conclusions: Neuropathic cancer pain is associated with a negative impact on daily living and greater analgesic requirements than nociceptive cancer pain. Validated assessment methods are needed to enable early identification of neuropathic cancer pain, leading to more appropriate treatment and reduced burden on patients. 23898822 Origin of Polytype Formation in VLS-Grown Ge Nanowires through Defect Generation and Nanowire Kinking. We propose layer-by-layer growth mechanisms to account for planar defect generation leading to kinked polytype nanowires. Cs-corrected scanning transmission electron microscopy enabled identification of stacking sequences of distinct polytype bands found in kinked nanowires, and Raman spectroscopy was used to distinguish polytype nanowires from twinned nanowires containing only the 3C diamond cubic phase. The faceting and atomic-scale defect structures of twinned 3C are compared with those of polytype nanowires to develop a common model linking nucleation pinning to nanowire morphology and phase. 23958380 Lipid profiles in brains from sheep with natural scrapie. Prion diseases are fatal neurodegenerative disorders affecting many mammals, ovine scrapie being the archetypal prion disease. Several independent studies in murine and cell-based models of scrapie have highlighted the presence of a link between prion generation and lipid alterations; yet, no data on natural disease are available. In this study we investigated levels of total lipids and cholesterol as well as profiles of fatty acids in brain homogenates from symptomatic and asymptomatic scrapie-infected sheep vs. healthy sheep, all belonging to the same flock. Lipid extracts were analyzed by means of gas chromatography and high performance liquid chromatography. Data of fatty acids were submitted to multivariate statistical analysis to give a picture of the brain lipid profiles of sheep. Interestingly, results revealed abnormalities in the brain fatty acid unsaturation of infected/symptomatic animals. Significant reduction of monoene 18:1 n-9 was detected in brain lipids from infected/symptomatic sheep, as compared to healthy and infected/asymptomatic animals, and this alteration occurred in combination with a significant increase in 18:0 level. The unsupervised Principal Component Analysis showed that infected/symptomatic and healthy sheep samples lie in two different regions of the plot, infected/asymptomatic lie mostly next to healthy. The increase of cerebral saturated fatty acids provides a rough indication of presumed alterations in lipid raft domains of nervous cells during scrapie, suggesting that they may exist in a notable viscous liquid-ordered state. Such physicochemical alteration would have a profound impact on the raft thermodynamic properties, its spatial organization, and signal transduction, all potentially relevant for prion generation. 23545114 Analysis of fatigue properties and failure mechanisms of Ti6Al4V in the very high cycle fatigue regime using ultrasonic technology and 3D laser scanning vibrometry. Accelerated fatigue tests with Ti6Al4V were carried out using a 20kHz ultrasonic testing facility to investigate the cyclic deformation behavior in the Very High Cycle Fatigue (VHCF) regime in detail. Beside parameters like the ultrasonic generator power and the displacement of the specimen, a 3D laser scanning vibrometer was used to characterize the oscillation and fatigue behavior of the Ti-alloy. The course of the S-Nf curve at the stress ratio R=-1 shows a significant decrease of the bearable stress amplitude and a change from surface to subsurface failures in the VHCF regime for more than 10(7) cycles. Microscopic investigations of the distribution of the α- and β-phase of Ti6Al4V indicate that inhomogeneities in the phase distribution are reasons for the internal crack initiation. High resolution vibrometry was used to visualize the eigenmode of the designed VHCF-specimen at 20kHz in the initial state and to indicate local changes in the eigenmodes as a result of progressing fatigue damage. Non-contact strain measurements were realized and used to determine the stress amplitude. The determined stress amplitudes were correlated with strain gauge measurements and finite element analysis. 23940044 Engraftment of a galactose receptor footprint onto adeno-associated viral capsids improves transduction efficiency. New viral strains can be evolved to recognize different host glycans through mutagenesis and experimental adaptation. However, such mutants generally harbor amino acid changes that affect viral binding to a single class of carbohydrate receptors. We describe the rational design and synthesis of novel, chimeric adeno-associated viral (AAV) strains that exploit an orthogonal glycan receptor for transduction. A dual glycan binding AAV strain was first engineered as proof-of-concept by grafting a galactose (Gal) binding footprint from AAV serotype 9 onto the heparan sulfate (HS) binding AAV serotype 2. The resulting chimera, AAV2G9, continues to bind heparin affinity columns, but interchangeably exploits Gal and HS receptors for infection as evidenced by competitive inhibition assays with lectins, glycans and parental AAV strains. While remaining hepatotropic like AAV2, the AAV2G9 chimera mediates rapid onset and higher transgene expression in mice. Similarly, engraftment of the Gal footprint onto the lab-derived strain, AAV2i8 yielded an enhanced AAV2i8G9 chimera. This new strain remains liver-detargeted like AAV2i8, while selectively transducing muscle tissues at high efficiency comparable to AAV9. The AAV2i8G9 chimera is a promising vector candidate for targeted gene therapy of cardiac and musculoskeletal diseases. In addition to demonstrating the modularity of glycan receptor footprints on viral capsids, our approach provides design strategies to expand the AAV vector toolkit. 23457122 Prenatal bisphenol a exposure alters sex-specific estrogen receptor expression in the neonatal rat hypothalamus and amygdala. Bisphenol A (BPA) exposure is ubiquitous, and in laboratory animals, early-life BPA exposure has been shown to alter sex-specific neural organization, neuroendocrine physiology, and behavior. The specific mechanisms underlying these brain-related outcomes, however, remain largely unknown, constraining the capacity to ascertain the potential human relevance of neural effects observed in animal models. In the perinatal rat brain, estrogen is masculinizing, suggesting that BPA-induced perturbation of estrogen receptor (ESR) expression may underpin later in-life neuroendocrine effects. We hypothesized that prenatal BPA exposure alters sex-specific ESR1 (ERα) and ESR2 (ERβ) expression in postnatal limbic nuclei. Sprague Dawley rats were mated and gavaged on gestational days (GDs) 6-21 with vehicle, 2.5 or 25 μg/kg bw/day BPA, or 5 or 10 μg/kg bw/day ethinyl estradiol. An additional group was restrained but not gavaged (naïve control). Offspring were sacrificed the day after birth to quantify ESR gene expression throughout the hypothalamus and amygdala by in situ hybridization. Relative to the vehicle group, significant effects of BPA were observed on ESR1 and ESR2 expression throughout the mediobasal hypothalamus and amygdala in both sexes. Significant differences in ESR expression were also observed in the mediobasal hypothalamus and amygdala of the naïve control group compared with the vehicle group, highlighting the potential for gavage to influence gene expression in the developing brain. These results indicate that ESR expression in the neonatal brain of both sexes can be altered by low-dose prenatal BPA exposure. 23940791 Amelioration of Murine Passive Immune Thrombocytopenia by IVIg and a Therapeutic Monoclonal CD44 Antibody Does Not Require the Myd88 Signaling Pathway. Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by a low platelet count and the production of anti-platelet antibodies. The majority of ITP patients have antibodies to platelet integrin αIIbβ3 (GPIIbIIIa) which can direct platelet phagocytosis by macrophages. One effective treatment for patients with ITP is intravenous immunoglobulin (IVIg) which rapidly reverses thrombocytopenia. The exact mechanism of IVIg action in human patients is unclear, although in mouse models of passive ITP, IVIg can rapidly increase platelet counts in the absence of adaptive immunity. Another antibody therapeutic that can similarly increase platelet counts independent of adaptive immunity are CD44 antibodies. Toll-like receptors (TLRs) are pattern recognition receptors which play a central role in helping direct the innate immune system. Dendritic cells, which are notable for their expression of TLRs, have been directly implicated in IVIg function as an initiator cell, while CD44 can associate with TLR2 and TLR4. We therefore questioned whether IVIg, or the therapeutic CD44 antibody KM114, mediate their ameliorative effects in a manner dependent upon normal TLR function. Here, we demonstrate that the TLR4 agonist LPS does not inhibit IVIg or KM114 amelioration of antibody-induced thrombocytopenia, and that these therapeutics do not ameliorate LPS-induced thrombocytopenia. IVIg was able to significantly ameliorate murine ITP in C3H/HeJ mice which have defective TLR4. All known murine TLRs except TLR3 utilize the Myd88 adapter protein to drive TLR signaling. Employing Myd88 deficient mice, we found that both IVIg and KM114 ameliorate murine ITP in Myd88 deficient mice to the same extent as normal mice. Thus both IVIg and anti-CD44 antibody can mediate their ameliorative effects in murine passive ITP independent of the Myd88 signaling pathway. These data help shed light on the mechanism of action of IVIg and KM114 in the amelioration of murine ITP. 23968913 An innovative sewage sludge reduction by using a combined mesophilic anaerobic and thermophilic aerobic process with thermal-alkaline treatment and sludge recirculation. Lab-scale High Efficiency Digestion (HED) systems containing a Mesophilic Anaerobic Reactor (MAR), Thermophilic Aerobic Reactor (TAR), liquid/solid separation unit, and thermal-alkaline treatment were developed to evaluate the efficiencies of sludge reduction and methane production. The HED process was divided into three phases to examine the influence of sludge pretreatment and pretreated sludge recirculation using TCOD and VSS reduction, COD solubilization, and methane production. The VSS removal with a solid/liquid separation unit, sludge recirculation, and thermal-alkaline treatment drastically increased up to 95% compared to the feed concentration. In addition, the results of COD solubilization and VSS/TSS showed that the solubilization of cells and organic matters by the thermal-alkaline treatment was highly increased, which was also consistent with the SEM images. In particular, the methane production rate increased 24-fold when the feed sludge and recirculated sludge were pretreated together. Collectively, the HED experiments performed with sludge recirculation and thermal-alkaline treatment demonstrated that the HED systems can be successfully employed for highly efficient sewage sludge reduction and methane gas production. 23806039 Biomimetic reagents for the selective free radical and Acid-base chemistry of glycans: application to glycan structure determination by mass spectrometry. Nature excels at breaking down glycans into their components, typically via enzymatic acid-base catalysis to achieve selective cleavage of the glycosidic bond. Noting the importance of proton transfer in the active site of many of these enzymes, we describe a sequestered proton reagent for acid-catalyzed glycan sequencing (PRAGS) that derivatizes the reducing terminus of glycans with a pyridine moiety possessing moderate proton affinity. Gas-phase collisional activation of PRAGS-derivatized glycans predominately generates C1-O glycosidic bond cleavages retaining the charge on the reducing terminus. The resulting systematic PRAGS-directed deconstruction of the glycan can be analyzed to extract glycan composition and sequence. Glycans are also highly susceptible to dissociation by free radicals, mainly reactive oxygen species, which inspired our development of a free radical activated glycan sequencing (FRAGS) reagent, which combines a free radical precursor with a pyridine moiety that can be coupled to the reducing terminus of target glycans. Collisional activation of FRAGS-derivatized glycans generates a free radical that reacts to yield abundant cross-ring cleavages, glycosidic bond cleavages, and combinations of these types of cleavages with retention of charge at the reducing terminus. Branched sites are identified with the FRAGS reagent by the specific fragmentation patterns that are observed only at these locations. Mechanisms of dissociation as well as application of the reagents for both linear and highly branched glycan structure analysis are investigated and discussed. The approach developed here for glycan structure analysis offers unique advantages compared to earlier studies employing mass spectrometry for this purpose. 23897044 Near-infrared photocatalysis of β-NaYF4:Yb(3+),Tm(3+)@ZnO composites. A novel near-infrared (NIR)-responsive photocatalyst, β-NaYF4:Yb(3+),Tm(3+)@ZnO composites, was prepared by a two-step high temperature thermolysis method. In the NIR-responsive photocatalysis, β-NaYF4:Yb,Tm served as a NIR-to-UV upconverter and provided "UV light" or "necessary energy" to the ZnO catalyst. The energy transfer in the composites and the mixtures of β-NaYF4:Yb,Tm and ZnO was studied by using steady-state and dynamic fluorescence spectroscopy. The NIR photocatalytic activities were investigated by the decomposition of Rhodamine B. It was found that the energy transfer processes dominated the overall photocatalytic activities, and the generation of hydroxyl radicals was the origin of organic pollutant decomposition under NIR irradiation. 23292791 Polyethylene Glycol and Polyethylenimine Dual-Functionalized Nano-Graphene Oxide for Photothermally Enhanced Gene Delivery. Graphene oxide (GO) has been extensively explored in nanomedicine for its excellent physiochemical, electrical, and optical properties. Here, polyethylene glycol (PEG) and polyethylenimine (PEI) are covalently conjugated to GO via amide bonds, obtaining a physiologically stable dual-polymer-functionalized nano-GO conjugate (NGO-PEG-PEI) with ultra-small size. Compared with free PEI and the GO-PEI conjugate without PEGylation, NGO-PEG-PEI shows superior gene transfection efficiency without serum interference, as well as reduced cytotoxicity. Utilizing the NIR optical absorbance of NGO, the cellular uptake of NGO-PEG-PEI is shown to be enhanced under a low power NIR laser irradiation, owing to the mild photothermal heating that increases the cell membrane permeability without significantly damaging cells. As the results, remarkably enhanced plasmid DNA transfection efficiencies induced by the NIR laser are achieved using NGO-PEG-PEI as the light-responsive gene carrier. More importantly, it is shown that our NGO-PEG-PEI is able to deliver small interfering RNA (siRNA) into cells under the control of NIR light, resulting in obvious down-regulation of the target gene, Polo-like kinase 1 (Plk1), in the presence of laser irradiation. This study is the first to use photothermally enhanced intracellular trafficking of nanocarriers for light-controllable gene delivery. This work also encourages further explorations of functionalized nano-GO as a photocontrollable nanovector for combined photothermal and gene therapies. 23357977 The association between daily calcium intake and sarcopenia in older, non-obese Korean adults: the fourth Korea national health and nutrition examination survey (KNHANES IV) 2009. Recent data suggest that variations in calcium intake may influence body weight and composition; however, the relationship between daily calcium intake and muscle mass has not been well established. The objective of this study was to assess the relationship between daily calcium intake and sarcopenia. We analyzed data for older adults (over 60 years) from the fourth Korea National Health and Nutrition Examination Survey (KNHANES) conducted in 2009. A total of 1339 Non-Obese (BMI between 18.5 and 25 kg/m(2)), older adults (592 men and 707 women) were enrolled. Dietary variables were assessed using a nutrition survey that used a 24-hour recall method. Daily calcium intake based on the consumption of each food item was calculated. Sarcopenia was defined as an appendicular skeletal muscle mass divided by body weight less than 2 SD below the sex-specific mean for young adults. We found that daily calcium intake was negatively correlated with total body fat percentage and positively correlated with appendicular skeletal mass (p<0.001). Participants with sarcopenia appear to have significantly lower daily calcium intakes than participants without sarcopenia (p<0.001). The unadjusted prevalence of sarcopenia according to daily calcium intake tertiles were 6.3%, 4.3%, and 2.7% in tertiles 1, 2, and 3, respectively. After adjustment for age, sex, BMI, total energy intake, and lifestyle factors, compared with those in the lowest tertile of daily calcium intake, participants in the highest tertile had an odds ratio for sarcopenia of 0.295 (95% confidence interval, 0.087-0.768; p for trend = 0.014). We found that daily calcium intake, corrected for total energy intake and serum 25(OH)D status, was significantly lower in subjects with sarcopenia than in those without. Our results suggest a strong inverse association between daily calcium intake and sarcopenia in non-obese, older Korean adults. 23869624 Complex care needs of patients with late-stage HIV disease: A retrospective study. This retrospective chart review provides a profile of an emerging population of vulnerable HIV patients with complex comorbidities. Data were abstracted from all 83 patients admitted in 2008 to Casey House, a community-based hospital dedicated to supportive and palliative care for persons with HIV in Toronto, Canada. We describe patient characteristics, including medical and psychiatric conditions, and use a Venn diagram and case study to illustrate the frequency and reality of co-occurring conditions that contribute to the complexity of patients' health and health care needs. The mean age at admission was 49.2 years (SD = 10.5). Sixty-seven patients (80.7%) were male. Patients experienced a mean of 5.9 medical comorbidities (SD = 2.3) and 1.9 psychiatric disorders (lifetime Axis I diagnoses). Forty patients (48.2%) experienced cognitive impairment including HIV-associated dementia. Patients were on a mean of 11.5 (SD = 5.3) medications at admission; 74.7% were on antiretroviral medications with 55.0% reporting full adherence. Current alcohol and drug use was common with 50.6% reporting active use at admission. Our Venn diagram illustrates the breadth of complexity in the clients with 8.4% of clients living in unstable housing with three or more medical comorbidities and two or more psychiatric diagnoses. Comprehensive HIV program planning should include interventions that can flexibly adapt to meet the multidimensional and complex needs of this segment of patients. Researchers, policy-makers, and clinicians need to have greater awareness of overlapping medical, psychiatric and psychosocial comorbidities. Inclusion of the needs of these most vulnerable patients in the development of evidence-based guidelines is an important step for effectively treating, preventing, and planning for the future of HIV/AIDS care. 23785185 Roles of voice onset time and f0 in stop consonant voicing perception: effects of masking noise and low-pass filtering. The contributions of voice onset time (VOT) and fundamental frequency (F0) were evaluated for the perception of voicing in syllable-initial stop consonants in words that were low-pass filtered and/or masked by speech-shaped noise. It was expected that listeners would rely less on VOT and more on F0 in these degraded conditions. Twenty young listeners with normal hearing identified modified natural speech tokens that varied by VOT and F0 in several conditions of low-pass filtering and masking noise. Stimuli included /b/-/p/ and /d/-/t/ continua that were presented in separate blocks. Identification results were modeled using mixed-effects logistic regression. When speech was filtered and/or masked by noise, listeners' voicing perceptions were driven less by VOT and more by F0. Speech-shaped masking noise exerted greater effects on the /b/-/p/ contrast, while low-pass filtering exerted greater effects on the /d/-/t/ contrast, consistent with the acoustics of these contrasts. Listeners can adjust their use of acoustic-phonetic cues in a dynamic way that is appropriate for challenging listening conditions; cues that are less influential in ideal conditions can gain priority in challenging conditions. 23936303 Surface acoustic waves enhance neutrophil killing of bacteria. Biofilms are structured communities of bacteria that play a major role in the pathogenicity of bacteria and are the leading cause of antibiotic resistant bacterial infections on indwelling catheters and medical prosthetic devices. Failure to resolve these biofilm infections may necessitate the surgical removal of the prosthetic device which can be debilitating and costly. Recent studies have shown that application of surface acoustic waves to catheter surfaces can reduce the incidence of infections by a mechanism that has not yet been clarified. We report here the effects of surface acoustic waves (SAW) on the capacity of human neutrophils to eradicate S. epidermidis bacteria in a planktonic state and within biofilms. Utilizing a novel fibrin gel system that mimics a tissue-like environment, we show that SAW, at an intensity of 0.3 mW/cm(2), significantly enhances human neutrophil killing of S. epidermidis in a planktonic state and within biofilms by enhancing human neutrophil chemotaxis in response to chemoattractants. In addition, we show that the integrin CD18 plays a significant role in the killing enhancement observed in applying SAW. We propose from out data that this integrin may serve as mechanoreceptor for surface acoustic waves enhancing neutrophil chemotaxis and killing of bacteria. 23591845 Two Common Bean Genotypes with Contrasting Response to Phosphorus Deficiency Show Variations in the microRNA 399-Mediated PvPHO2 Regulation within the PvPHR1 Signaling Pathway. Crop production of the important legume, the common bean (Phaseolus vulgaris), is often limited by low phosphorus (P) in the soil. The genotypes, BAT477 and DOR364, of the common bean have contrasting responses to P starvation. Plants from the BAT477 P deficiency tolerant genotype showed higher phosphate content and root biomass as compared to the DOR364 plants under P starvation. The PvPHR1 transcription factor-signaling pathway plays an essential role in the response to P starvation. PvPHO2, a negative regulator of this pathway, encodes an ubiquitin E2 conjugase that promotes degradation of P-responsive proteins and is the target gene of PvmiR399. PvPHO2 is downregulated in BAT477 plants under P deficiency, while such a response is not observed in P-starved DOR364 plants. Five putative PvmiR399 binding sites were identified in the 5' UTR region in both genotypes. While four sites showed an identical DNA sequence, the fifth (binding site of PvPHO2 one) showed three base changes and higher complementarity scores in DOR364 as compared to BAT477. Modified 5'RACE experiments indicated that PvmiR399 binding and/or processing was affected in DOR364 P-starved plants. We propose that a less efficient cleavage of the PvPHO2 mRNA directed by PvmiR399 would result in a higher PvPHO2-mediated degradation of P-responsive proteins in the DOR364 genotype with decreased P deficiency tolerance. 23824627 Professor Barrie Vernon-Roberts, AO, MD, BSc, PhD, FRCPath, FRCPA, FAOrthA (Hon), FRS.SA. This issue of Inflammopharmacology contains papers that have been submitted to commemorate the life and work of Professor Barrie Vernon-Roberts, an outstanding clinical scientist in the field of bone pathology and its pharmacological regulation. This review briefly summarizes his major works and achievements as well as a list of his publications. 23959840 Is breath acetone a biomarker of diabetes? A historical review on breath acetone measurements. Since the ancient discovery of the 'sweet odor' in human breath gas, pursuits of the breath analysis-based disease diagnostics have never stopped. Actually, the 'smell' of the breath, as one of three key disease diagnostic techniques, has been used in Eastern-Medicine for more than three thousand years. With advancement of measuring technologies in sensitivity and selectivity, more specific breath gas species have been identified and established as a biomarker of a particular disease. Acetone is one of the breath gases and its concentration in exhaled breath can now be determined with high accuracy using various techniques and methods. With the worldwide prevalence of diabetes that is typically diagnosed through blood testing, human desire to achieve non-blood based diabetic diagnostics and monitoring has never been quenched. Questions, such as is breath acetone a biomarker of diabetes and how is the breath acetone related to the blood glucose (BG) level (the golden criterion currently used in clinic for diabetes diagnostic, monitoring, and management), remain to be answered. A majority of current research efforts in breath acetone measurements and its technology developments focus on addressing the first question. The effort to tackle the second question has begun recently. The earliest breath acetone measurement in clearly defined diabetic patients was reported more than 60 years ago. For more than a half-century, as reviewed in this paper, there have been more than 41 independent studies of breath acetone using various techniques and methods, and more than 3211 human subjects, including 1581 healthy people, 242 Type 1 diabetic patients, 384 Type 2 diabetic patients, 174 unspecified diabetic patients, and 830 non-diabetic patients or healthy subjects who are under various physiological conditions, have been used in the studies. The results of the breath acetone measurements collected in this review support that many conditions might cause changes to breath acetone concentrations; however, the results from the six independent studies using clearly-defined Type 1 and Type 2 diabetic patients unanimously support that an elevated mean breath acetone concentration exists in Type 1 diabetes. Note that there is some overlap between the ranges of breath acetone concentration in individual T1D patients and healthy subjects; this reminds one to be careful when using an acetone breath test on T1D diagnostics. Comparatively, it is too early to draw a general conclusion on the relationship between a breath acetone level and a BG level from the very limited data in the literature. 23875883 (99m)Tc-Galacto-RGD2: A Novel (99m)Tc-Labeled Cyclic RGD Peptide Dimer Useful for Tumor Imaging. This study sought to evaluate [(99m)Tc(HYNIC-Galacto-RGD2)(tricine)(TPPTS)] ((99m)Tc-Galacto-RGD2: HYNIC = 6-hydrazinonicotinyl; Galacto-RGD2 = Glu[cyclo[Arg-Gly-Asp-d-Phe-Lys(SAA-PEG2-(1,2,3-triazole)-1-yl-4-methylamide)]]2 (SAA = 7-amino-l-glycero-l-galacto-2,6-anhydro-7-deoxyheptanamide, and PEG2 = 3,6-dioxaoctanoic acid); and TPPTS = trisodium triphenylphosphine-3,3',3″-trisulfonate) as a new radiotracer for tumor imaging. Galacto-RGD2 was prepared via the copper(I)-catalyzed 1,3-dipolar azide-alkyne Huisgen cycloaddition. HYNIC-Galacto-RGD2 was prepared by reacting Galacto-RGD2 with sodium succinimidyl 6-(2-(2-sulfonatobenzaldehyde)hydrazono)nicotinate (HYNIC-OSu) in the presence of diisopropylethylamine, and was evaluated for its integrin αvβ3 binding affinity against (125)I-echistatin bound to U87MG glioma cells. The IC50 value for HYNIC-Galacto-RGD2 was determined to be 20 ± 2 nM. (99m)Tc-Galacto-RGD2 was prepared in high specific activity (∼185 GBq/μmol) and high radiochemical purity (>95%), and was evaluated in athymic nude mice bearing U87MG glioma xenografts for its tumor-targeting capability and biodistribution. The tumor uptake of (99m)Tc-Galacto-RGD2 was 10.30 ± 1.67, 8.37 ± 2.13, 6.86 ± 1.33, and 5.61 ± 1.52%ID/g at 5, 30, 60, and 120 min p.i., respectively, which was in agreement with high integrin αvβ3 expression on glioma cells and neovasculature. Its lower uptake in intestines, lungs, and spleen suggests that (99m)Tc-Galacto-RGD2 has advantages over (99m)Tc-3P-RGD2 ([(99m)Tc(HYNIC-3P-RGD2)(tricine)(TPPTS)]: 3P-RGD2 = PEG4-E[PEG4-c(RGDfK)]2; PEG4 = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) for imaging tumors in the chest and abdominal regions. U87MG tumors were readily detected by SPECT and the tumor uptake of (99m)Tc-Galacto-RGD2 was integrin αvβ3-specific. (99m)Tc-Galacto-RGD2 also had very high metabolic stability. On the basis of results from this study, it was concluded that (99m)Tc-Galacto-RGD2 is an excellent radiotracer for imaging integrin αvβ3-positive tumors and related metastases. 23363083 Computationally assisted assignment of kahalalide Y configuration using an NMR-constrained conformational search. Assignment of the absolute configuration of cyclic peptides frequently yields challenges, leaving one or more stereogenic centers unassigned due to small quantities of sample and the limited utility of Marfey's or other methods for assigning amino or hydroxy acids. Here, we report isolation of kahalalide Y (1) from Bryopsis pennata for the first time; in addition, the application of a combination of molecular modeling and NOE distance constraint calculations was utilized to determine the conformation of 1 and the absolute configuration of the final stereogenic center of 1. Using the Schrödinger suite, the structure of 1 was sketched in Maestro and minimized using the OPLS2005 force field in Macromodel. A conformational search was performed separately for structures having an R or S configuration at C-3 of the beta-hydroxy fatty acid subunit that completes the cyclic scaffold of 1, after which multiple minimizations for all generated conformers were carried out. The lowest energy conformers of R and S stereoisomers were then subjected to B3LYP geometry optimizations including solvent effects. The S stereoisomer was shown to be in excellent agreement with the NOE-derived distance constraints and hydrogen-bonding stability studies. 23906801 A chiral high-performance liquid chromatography-tandem mass spectrometry method for the stereospecific analysis of enoyl-coenzyme A hydratases/isomerases. The enzymes catalyzing the stereospecific hydration of 2-enoyl-CoA into the corresponding S- or R-3-hydroxyacyl-CoA are named enoyl-CoA hydratases (ECH), where the S-specific is called ECH-1 and the R-specific is called ECH-2. Current ECH assays are mostly based on spectrophotometric methods. Amongst many limitations, these methods do not directly measure the 3-hydroxyacyl-CoA produced, neither do they allow determination of its stereospecific configuration. We have developed a chiral HPLC method coupled with tandem mass spectrometry (MS) for the sensitive, direct, stereospecific and quantitative analysis of ECH-1/-2 reaction products, or R-/S-3-hydroxyalkanoates in general. The method is based on the reaction of the 3-hydroxyl group on the chiral carbon with 3,5-dimethylphenyl isocyanate, creating a urethane derivative which is then chirally resolved on a chiral HPLC column having 3,5-dimethylphenyl carbamate-derivatized cellulose as the chiral stationary phase. The resolved urethane derivatives are detected using tandem MS in the multiple reactions monitoring (MRM) negative electrospray ionization mode by monitoring the free hydroxy fatty acid fragment ion liberated from its parent urethane derivative. The method resolves the R-/S-enantiomers of 3-hydroxy fatty acid homologues ranging from C6 to C16. Using this method, the net ECH activity present in clarified cell lysates of the bacterium Pseudomonas aeruginosa cultivated in a rich medium was found to be of both ECH-1 and ECH-2. Interestingly, the clarified cell lysate of Escherichia coli cultivated also in a rich medium displayed mainly an ECH-1 (S-specific) activity. This method will facilitate the quantification and stereospecific characterization of ECHs, as well as the chiral lipid profiling of bacterial secondary metabolites containing hydroxyalkanoic acid moieties. 23454527 Effect of serum on diesel exhaust particles (DEP)-induced apoptosis of airway epithelial cells in vitro. Patients with chronic airway diseases may be more susceptible to adverse effects of air pollutants including diesel exhaust particles (DEP). We investigated effects of foetal calf serum (FCS) on DEP-induced changes in airway epithelial cell apoptosis and inflammation. DEP (50-200 μg/ml) increased A549 cell viability in the absence of FCS. In the presence of 3.3%FCS, DEP (50-400 μg/ml) decreased A549 cell viability. N-acetylcysteine (NAC, 33 mM) and the c-jun N-terminal kinase (JNK) inhibitor (SP600125, 33 μM) further decreased the viability in the presence of DEP (200 μg/ml) and 3.3% FCS. Under serum-free (SF) condition, DEP (50 μg/ml) reduced apoptotic cells; however, when 3.3% FCS added to the culture medium, this effect was abolished. DEP (200 μg/ml) induced mRNA expression of p21(CIP1/WAF1) both in absence or presence of 3.3% FCS and enhanced JNK2 mRNA expression only in the presence of 3.3% FCS. Under SF condition, DEP (50 μg/ml) induced mRNA expression for p27 and p53, whereas cyclin E mRNA expression was inhibited by DEP (50 and 200 μg/ml). Furthermore, DEP (200 μg/ml) decreased the release of interleukin (IL)-8 in the absence of FCS. In conclusion, FCS modulates effects of DEP on cell death, cell cycle and apoptosis regulating proteins, and IL-8 release by activating oxidant stress pathways, JNK and NF-κB. Extravasation of serum, as occurs in the inflamed airways of patients with chronic airway diseases such as asthma and COPD, may render airway epithelial cells more susceptible to the deleterious effects of DEP. 23484668 Diarylheptanoids and Flavonoids from Viscum album Inhibit LPS-Stimulated Production of Pro-inflammatory Cytokines in Bone Marrow-Derived Dendritic Cells. Three new diarylheptanoids, (3S,5R)-3-hydroxy-5-methoxy-1,7-bis(4-hydroxyphenyl)-6E-heptene (1), (3S,5S)-3-hydroxy-5-methoxy-1,7-bis(4-hydroxyphenyl)-6E-heptene (2), and (3S)-3-hydroxy-1,7-bis(4-hydroxyphenyl)-6E-hepten-5-one (3), four new flavonoid glycosides, 3,7,3'-tri-O-methylquercetin-4'-O-β-d-apiofuranosyl-(1→2)-O-β-d-glucopyranoside (4), 7,3'-di-O-methylquercetin-4'-O-β-d-glucopyranosyl-3-O-[6‴-(3-hydroxy-3-methylglutaroyl)]-α-d-glucopyranoside (5), 7,3'-di-O-methylquercetin-4'-O-β-d-glucopyranosyl-3-O-[(6'''''→5'''')-O-1'''''-(sinap-4-yl)-β-d-glucopyranosyl-6‴-(3-hydroxy-3-methylglutaroyl)]-α-d-glucopyranoside (6), and (2S)-5-hydroxy-7,3'-dimethoxyflavanone-4'-O-β-d-apiofuranosyl-(1→5)-O-β-d-apiofuranosyl-(1→2)-O-β-d-glucopyranoside (9), and 17 known compounds were isolated from the leaves and twigs of Viscum album. Compounds 1, 4, and 19 significantly inhibited LPS-stimulated production of TNF-α, IL-6, and IL-12p40 with IC50 values ranging from 0.09 ± 0.01 to 8.96 ± 0.45 μM. (+)-Medioresinol (13) showed inhibitory effects on LPS-stimulated production of IL-12p40 with an IC50 value of 2.00 ± 0.15 μM. 23659725 Peer and professional parenting support on the internet: a systematic review. Abstract The Internet offers many opportunities to provide parenting support. An overview of empirical studies in this domain is lacking, and little is known about the design of web based parenting resources and their evaluations, raising questions about its position in the context of parenting intervention programs. This article is a systematic review of empirical studies (n=75), published between 1998 and 2010, that describe resources of peer and professional online support for parents. These studies generally report positive outcomes of online parenting support. A number of recent experimental studies evaluated effects, including randomized controlled trials and quasi-experimental designs (totaling 1,615 parents and 740 children). A relatively large proportion of the studies in our sample reported a content analysis of e-mails and posts (totaling 15,059 coded messages). The results of this review show that the Internet offers a variety of opportunities for sharing peer support and consulting professionals. The field of study reflects an emphasis on online resources for parents of preschool children, concerning health topics and providing professional support. A range of technologies to facilitate online communication is applied in evaluated Web sites, although the combination of multiple components in one resource is not very common. The first generation of online resources has already changed parenting and parenting support for a large group of parents and professionals. Suggestions for future development and research are discussed. 23956387 Benchmarking various GFP variants in Bacillus subtilis, Streptococcus pneumoniae and Lactococcus lactis for live cell imaging. Green fluorescent protein offers efficient ways of visualizing promoter activity and protein localization in vivo and many different variants are currently available to study bacterial cell biology. Which of these variants are best suited for a certain bacterial strain, goal or experimental condition is not clear. Here, we have designed and constructed two 'superfolder' GFPs with codon adaptation specifically for Bacillus subtilis and Streptococcus pneumoniae and have benchmarked them against five other previously available variants of GFP in B. subtilis, S. pneumoniae and Lactococcus lactis, using promoter-gfp fusions. Surprisingly, the best-performing GFP under our experimental conditions in B. subtilis was the one codon-optimized for S. pneumoniae and vice versa. The data and tools described in this study will be useful for cell biology studies in low GC-rich Gram-positive bacteria. 23829946 DALI: Vitamin D and lifestyle intervention for gestational diabetes mellitus (GDM) prevention: an European multicentre, randomised trial - study protocol. Gestational diabetes mellitus (GDM) is an increasing problem world-wide. Lifestyle interventions and/or vitamin D supplementation might help prevent GDM in some women. Pregnant women at risk of GDM (BMI ≥ 29 (kg/m(2))) from 9 European countries will be invited to participate and consent obtained before 19+6 weeks of gestation. After giving informed consent, women without GDM will be included (based on IADPSG criteria: fasting glucose<5.1 mmol; 1 hour glucose <10.0 mmol; 2 hour glucose <8.5 mmol) and randomized to one of the 8 intervention arms using a 2 × (2 × 2) factorial design: (1) healthy eating (HE), 2) physical activity (PA), 3) HE+PA, 4) control, 5) HE+PA+vitamin D, 6) HE+PA+placebo, 7) vitamin D alone, 8) placebo alone), pre-stratified for each site. In total, 880 women will be included with 110 women allocated to each arm. Between entry and 35 weeks of gestation, women allocated to a lifestyle intervention will receive 5 face-to-face, and 4 telephone coaching sessions, based on the principles of motivational interviewing. The lifestyle intervention includes a discussion about the risks of GDM, a weight gain target <5 kg and either 7 healthy eating 'messages' and/or 5 physical activity 'messages' depending on randomization. Fidelity is monitored by the use of a personal digital assistance (PDA) system. Participants randomized to the vitamin D intervention receive either 1600 IU vitamin D or placebo for daily intake until delivery. Data is collected at baseline measurement, at 24-28 weeks, 35-37 weeks of gestation and after delivery. Primary outcome measures are gestational weight gain, fasting glucose and insulin sensitivity, with a range of obstetric secondary outcome measures including birth weight. DALI is a unique Europe-wide randomised controlled trial, which will gain insight into preventive measures against the development of GDM in overweight and obese women. ISRCTN70595832. 23278857 Role models and the psychological characteristics that buffer low-socioeconomic-status youth from cardiovascular risk. Little is understood about why some youth from low-socioeconomic-status (SES) environments exhibit good health despite adversity. This study tested whether role models and "shift-and-persist" approaches (reframing stressors more benignly while persisting with future optimism) protect low-SES youth from cardiovascular risk. A total of 163 youth, ages 13-16, completed role model interviews and shift-and-persist measures while cholesterol and inflammatory markers, interleukin-6 (IL-6), and C-reactive protein were assessed. Low-SES youth with supportive role models had lower IL-6. Low-SES youth high in shift-and-persist also had lower IL-6. Shift-and-persist partially mediated the interaction of SES and role models on IL-6. Benefits were not found among high-SES youth. Identifying psychological buffers in low-SES youth has implications for health disparities. 23539148 Paraphyseal changes on bone-age studies predict risk of delayed radiation-associated skeletal complications following total body irradiation. Children undergoing total body irradiation (TBI) often develop delayed skeletal complications. Bone-age studies in these children often reveal subtle paraphyseal changes including physeal widening, metaphyseal irregularity and paraphyseal exostoses. To investigate whether paraphyseal changes on a bone-age study following TBI indicate a predisposition toward developing other radiation-associated skeletal complications. We retrospectively reviewed medical records and bone-age studies of 77 children receiving TBI at our institution between 1995 and 2008 who had at least 2 years of clinical follow-up and one bone-age study after TBI. We graded bone-age studies according to the severity of paraphyseal changes. All documented skeletal complications following TBI were tabulated. Kendall's tau-b was used to examine associations between degree of paraphyseal change and development of a skeletal complication. Kendall's tau analyses showed that physeal widening and metaphyseal irregularity/sclerosis (tau = 0.87, P < 0.001) and paraphyseal exostoses (tau = 0.68, P < 0.001) seen on bone-age studies were significantly positively associated with the development of delayed skeletal complications following TBI. Thirty percent of children with no or mild paraphyseal changes developed a delayed skeletal complication, compared with 58% of children with moderate paraphyseal changes and 90% of children with severe paraphyseal changes. Paraphyseal changes identified on a bone-age study correlate positively with the development of delayed skeletal complications elsewhere in the skeleton following TBI. 23958498 Atg24-assisted mitophagy in the foot cells is necessary for proper asexual differentiation in Magnaporthe oryzae. Macroautophagy-mediated glycogen catabolism is required for asexual differentiation in the blast fungus, Magnaporthe oryzae. However, the function(s) of selective subtypes of autophagy has not been studied therein. Here, we report that mitophagy, selective autophagic delivery of mitochondria to the vacuoles for degradation, occurs during early stages of Magnaporthe conidiation. Specifically, mitophagy was evident in the foot cells while being undetectable in aerial hyphae and/or conidiophores. We show that loss of MoAtg24, a sorting nexin related to yeast Snx4, disrupts mitophagy and consequently leads to highly reduced conidiation, suggesting that mitophagy in the foot cells plays an important role during asexual development in Magnaporthe. Ectopic expression of yeast ScATG32 partially suppressed the conidiation initiation defects associated with MoATG24 deletion. MoAtg24 was neither required for pexophagy nor for macroautophagy, or for MoAtg8 localization per se, but directly associated with and likely recruited mitochondria to the autophagic structures during mitophagy. Lastly, MoAtg24 was also required for oxidative stress response in Magnaporthe. 23196664 Extended aortic repair using frozen elephant trunk technique for marfan syndrome with acute aortic dissection. Purpose: The aim of this study was to analyze midterm results of frozen elephant trunk technique for Marfan syndrome with acute aortic dissection.Methods: Between February 1999 and August 2011 we performed arch replacement uisng frozen elephant trunk technique for acute aortic dissection in 8 patients with Marfan syndrome containing two complicated type B dissections and six type A dissections.Five patients compromised annulo-aortic ectasia who performed Bentall operation.Results: No patients died in the initial operation. Fate of false lumen on the stent graft border was expressed by CT scan follow-up that were patent in 0, thrombosis in 5 and absorption in 3 patients. One patient who had new aortic dissection 8 years after initial surgery required the Crawford V operation. Ten-years-survival rate was 100% and ten years-event free rate was 67%.Conclusions: Frozen elephant trunk technique was feasible for Marfan syndrome with acute aortic dissection and might become alternative prophylactic treatment to the downstream aorta for acute aortic dissection. 23052208 In vivo imaging of therapy-induced anti-cancer immune responses in humans. Immunotherapy aims to re-engage and revitalize the immune system in the fight against cancer. Research over the past decades has shown that the relationship between the immune system and human cancer is complex, highly dynamic, and variable between individuals. Considering the complexity, enormous effort and costs involved in optimizing immunotherapeutic approaches, clinically applicable tools to monitor therapy-induced immune responses in vivo are most warranted. However, the development of such tools is complicated by the fact that a developing immune response encompasses several body compartments, e.g., peripheral tissues, lymph nodes, lymphatic and vascular systems, as well as the tumor site itself. Moreover, the cells that comprise the immune system are not static but constantly circulate through the vascular and lymphatic system. Molecular imaging is considered the favorite candidate to fulfill this task. The progress in imaging technologies and modalities has provided a versatile toolbox to address these issues. This review focuses on the detection of therapy-induced anticancer immune responses in vivo and provides a comprehensive overview of clinically available imaging techniques as well as perspectives on future developments. In the discussion, we will focus on issues that specifically relate to imaging of the immune system and we will discuss the strengths and limitations of the current clinical imaging techniques. The last section provides future directions that we envision to be crucial for further development. 23562699 No benefit of a dual coil over a single coil ICD lead: evidence from the Sudden Cardiac Death in Heart Failure Trial. Dual coil implantable cardioverter-defibrillator (ICD) leads with a superior vena cava (SVC) electrode have been considered standard of care despite sparse data suggesting improved ICD defibrillation efficacy. SVC coils increase lead complexity, cost, risk of lead failure, and lead removal. To compare all-cause mortality, sudden cardiac death, implant defibrillation threshold (DFT) test energies, appropriate shock rates, and first shock efficacy for ventricular tachyarrhythmias for dual coil vs single coil leads in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). In SCD-HeFT, 811 patients with heart failure received a single lead transvenous ICD (Medtronic model 7223) and underwent protocol-driven DFT testing. The selection of a dual vs single coil right ventricular (RV) lead was at the physician's discretion. DFT data were available in 717 patients. Dual coil leads were used in 563 and single coil in 246 patients. After 45.5-month follow-up, overall mortality was similar (19.4% for dual coil vs 21.5% for single coil; adjusted hazard ratio 0.95; 95% confidence interval 0.68-1.34; P = .78). Sudden cardiac death was also similar (3.6% for dual coil vs 3.7% for single coil; P = .96). First shock efficacy was 82.2% vs 91.9% (dual coil vs single coil; unadjusted odds ratio 0.41; 95% confidence interval 0.15-1.13; P = .085). Mean DFT was 12.1 ± 4.7 J vs 12.8 ± 4.8 J (dual coil vs single coil; P = .087). In the SCD-HeFT, the addition of an SVC coil for left-sided implants was not associated with improved outcome measures. We advocate returning to single coil RV ICD leads as the standard of care to decrease chronic lead complications. 23729007 Two chromosome 9p21 haplotype blocks distinguish between coronary artery disease and myocardial infarction risk. Background- Variants at the 9p21 locus associate with the risk of coronary artery disease (CAD) or myocardial infarction (MI). However, atherosclerotic plaque deposition is distinct from MI (plaque rupture and thrombosis), and recent studies showed no association between these variants and MI in patients with preexisting CAD. We performed haplotype analysis at the 9p21 locus to test whether haplotypes at distinct linkage disequilibrium blocks predict these phenotypes. Methods and Results- Using 24 single-nucleotide polymorphisms genotyped in white patients without diabetes mellitus, we reconstructed haplotypes at the 9p21 locus. Patients with angiograhic CAD/MI had ≥1 epicardial stenosis >50% (n=2352), whereas controls were asymptomatic and over the age of 60 years (n=2116). For CAD patients, regression models examined the association of haplotypes with initial age of symptomatic CAD, number of diseased vessels, and history of MI. In the case-control study, only haplotypes at 1 block tagged by rs1333049 associated with CAD more so than MI. These haplotypes also associated with early onset of CAD (β=-0.13; P=1.37×10(-4)) and disease severity (β=0.1823; P=0.006) but not with prevalent MI among patients with CAD. In contrast, haplotypes at another block tagged by rs518394 associated with prevalent MI (β=0.239; P=2.05×10(-4)), but remarkably these are inversely associated with disease severity (β=-0.196; P=0.003). This MI association was replicated in the Cleveland Clinic GeneBank premature CAD cohort (n=1385; β=0.207; P=0.019). Conclusions- Variants/haplotypes at 2 blocks are distinguished at 9p21; those at 1 block predispose to atherosclerosis, whereas those at the other predispose to MI among patients with preexisting CAD. 23065140 Ketamine-induced neuronal damage and altered N-methyl-D-aspartate receptor function in rat primary forebrain culture. Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, is frequently used in pediatric general anesthesia. Accumulating evidence from animal experiments has demonstrated that ketamine causes neuronal cell death during the brain growth spurt. To elucidate the underlying mechanisms associated with ketamine-induced neuronal toxicity and search for approaches or agents to prevent ketamine's adverse effects on the developing brain, a primary nerve cell culture system was utilized. Neurons harvested from the forebrain of newborn rats were maintained under normal control conditions or exposed to either ketamine (10 µM) or ketamine plus L-carnitine (an antioxidant; 1-100 µM) for 24h, followed by a 24-h withdrawal period. Ketamine exposure resulted in elevated NMDA receptor (NR1) expression, increased generation of reactive oxygen species (ROS) as indicated by higher levels of 8-oxoguanine production, and enhanced neuronal damage. Coadministration of L-carnitine significantly diminished ROS generation and provided near complete protection of neurons from ketamine-induced cell death. NMDA receptors regulate channels that are highly permeable to calcium, and calcium imaging data demonstrated that neurons exposed to ketamine had a significantly elevated amplitude of calcium influx and higher intracellular free calcium concentrations ([Ca(2+)]i) evoked by NMDA (50 µM), compared with control neurons. These findings suggest that prolonged ketamine exposure produces an increase in NMDA receptor expression (compensatory upregulation), which allows for a higher/toxic influx of calcium into neurons once ketamine is removed from the system, leading to elevated ROS generation and neuronal cell death. L-Carnitine appears to be a promising agent in preventing or reversing ketamine's toxic effects on neurons at an early developmental stage. 23967349 Characterization of GABAergic neurons in the mouse lateral septum: a double fluorescence in situ hybridization and immunohistochemical study using tyramide signal amplification. Gamma-aminobutyric acid (GABA) neurotransmission in the lateral septum (LS) is implicated in modulating various behavioral processes, including emotional reactivity and maternal behavior. However, identifying the phenotype of GABAergic neurons in the CNS has been hampered by the longstanding inability to reliably detect somal immunoreactivity for GABA or glutamic acid decarboxylase (GAD), the enzyme that produces GABA. In this study, we designed unique probes for both GAD65 (GAD2) and GAD67 (GAD1), and used fluorescence in Situ hybridization (FISH) with tyramide signal amplification (TSA) to achieve unequivocal detection of cell bodies of GABAergic neurons by GAD mRNAs. We quantitatively characterized the expression and chemical phenotype of GABAergic neurons across each subdivision of LS and in cingulate cortex (Cg) and medial preoptic area (MPOA) in female mice. Across LS, almost all GAD65 mRNA-expressing neurons were found to contain GAD67 mRNA (approximately 95-98%), while a small proportion of GAD67 mRNA-containing neurons did not express GAD65 mRNA (5-14%). Using the neuronal marker NeuN, almost every neuron in LS (> 90%) was also found to be GABA-positive. Interneuron markers using calcium-binding proteins showed that LS GABAergic neurons displayed immunoreactivity for calbindin (CB) or calretinin (CR), but not parvalbumin (PV); almost all CB- or CR-immunoreactive neurons (98-100%) were GABAergic. The proportion of GABAergic neurons immunoreactive for CB or CR varied depending on the subdivisions examined, with the highest percentage of colocalization in the caudal intermediate LS (LSI) (approximately 58% for CB and 35% for CR). These findings suggest that the vast majority of GABAergic neurons within the LS have the potential for synthesizing GABA via the dual enzyme systems GAD65 and GAD67, and each subtype of GABAergic neurons identified by distinct calcium-binding proteins may exert unique roles in the physiological function and neuronal circuitry of the LS. 23855907 EMG-based pattern recognition approach in post stroke robot-aided rehabilitation: a feasibility study. Several studies investigating the use of electromyographic (EMG) signals in robot-based stroke neuro-rehabilitation to enhance functional recovery. Here we explored whether a classical EMG-based patterns recognition approach could be employed to predict patients' intentions while attempting to generate goal-directed movements in the horizontal plane. Nine right-handed healthy subjects and seven right-handed stroke survivors performed reaching movements in the horizontal plane. EMG signals were recorded and used to identify the intended motion direction of the subjects. To this aim, a standard pattern recognition algorithm (i.e., Support Vector Machine, SVM) was used. Different tests were carried out to understand the role of the inter- and intra-subjects' variability in affecting classifier accuracy. Abnormal muscular spatial patterns generating misclassification were evaluated by means of an assessment index calculated from the results achieved with the PCA, i.e., the so-called Coefficient of Expressiveness (CoE). Processing the EMG signals of the healthy subjects, in most of the cases we were able to build a static functional map of the EMG activation patterns for point-to-point reaching movements on the horizontal plane. On the contrary, when processing the EMG signals of the pathological subjects a good classification was not possible. In particular, patients' aimed movement direction was not predictable with sufficient accuracy either when using the general map extracted from data of normal subjects and when tuning the classifier on the EMG signals recorded from each patient. The experimental findings herein reported show that the use of EMG patterns recognition approach might not be practical to decode movement intention in subjects with neurological injury such as stroke. Rather than estimate motion from EMGs, future scenarios should encourage the utilization of these signals to detect and interpret the normal and abnormal muscle patterns and provide feedback on their correct recruitment. 23838631 Role of κ-Opioid Receptor in Hypoxic Pulmonary Artery Hypertension and Its Underlying Mechanism. The objective of this study were to determine the mechanism of action and role of the κ-opioid receptor (κ-OR) on hypoxic pulmonary artery hypertension (HPH) in the rat and its underlying mechanisms. The effect of U50,488H, a selective κ-OR agonist, on the proliferation of pulmonary arterial smooth muscle cells (PASMCs) under hypoxic conditions were measured by monotetrazolium assay and [H]-thymidine incorporation. Effects of U50,488H and nor-BNI, a highly selective κ-OR antagonist, on expression of κ-ORs were determined by Western blot technique. The results of our study demonstrated that U50,488H significantly lowered both mean pulmonary artery pressure and right ventricular pressure in HPH rats (P < 0.01). Further, this effect was abolished by nor-BNI (P < 0.01). Further, the effect of the agonist U50,488H was abolished by the antagonist nor-BNI (P < 0.01). mean pulmonary artery pressure and right ventricular pressure were both significantly upregulated in HPH rats treated with nor-BNI versus HPH control group rats (P < 0.01). Moreover, U50,488H inhibited proliferation of the PASMCs that were induced by hypoxia, and this inhibition lasted for 48 hours in a dose-dependent manner (P < 0.01). The inhibitory effect that U50,488H exerted on PASMC proliferation was also abolished by nor-BNI. During hypoxia, the expression of κ-ORs increased in the pulmonary artery. This increase of κ-OR expression was both enhanced by U50,488H and abolished by nor-BNI. The results demonstrate that U50,488H attenuates HPH through both the stimulation and upregulation of κ-ORs. 23846955 Phosphorus removal in a sulfur-limestone autotrophic denitrification (SLAD) biofilter. The sulfur-limestone autotrophic denitrification (SLAD) biofilter was able to remove phosphorous from wastewater during autotrophic denitrification. Parameters influencing autotrophic denitrification in the SLAD biofilter, such as hydraulic retention time (HRT), influent nitrate (NO3 (-)), and influent PO4 (3-) concentrations, had significant effects on P removal. P removal was well correlated with total oxidized nitrogen (TON) removed in the SLAD biofilter; the more TON removed, the more efficient P removal was achieved. When treating the synthetic wastewater containing NO3 (-)-N of 30 mg L(-1) and PO4 (3-)-P of 15 mg L(-1), the SLAD biofilter removed phosphorus of 45 % when the HRT was 6 h, in addition with TN removal of nearly 100 %. The optimal phosphorus removal in the SLAD biofilter was around 60 %. For the synthetic wastewater containing a PO4 (3-)-P concentration of 15 mg L(-1), the main mechanism of phosphorus removal was the formation of calcium phosphate precipitates. 23970121 ABIN1 Dysfunction as a Genetic Basis for Lupus Nephritis. The genetic factors underlying the pathogenesis of lupus nephritis associated with systemic lupus erythematosus are largely unknown, although animal studies indicate that nuclear factor (NF)-κB is involved. We reported previously that a knockin mouse expressing an inactive form of ABIN1 (ABIN1[D485N]) develops lupus-like autoimmune disease and demonstrates enhanced activation of NF-κB and mitogen-activated protein kinases in immune cells after toll-like receptor stimulation. In the current study, we show that ABIN1[D485N] mice develop progressive GN similar to class III and IV lupus nephritis in humans. To investigate the clinical relevance of ABIN1 dysfunction, we genotyped five single-nucleotide polymorphisms in the gene encoding ABIN1, TNIP1, in samples from European-American, African American, Asian, Gullah, and Hispanic participants in the Large Lupus Association Study 2. Comparing cases of systemic lupus erythematosus with nephritis and cases of systemic lupus erythematosus without nephritis revealed strong associations with lupus nephritis at rs7708392 in European Americans and rs4958881 in African Americans. Comparing cases of systemic lupus erythematosus with nephritis and healthy controls revealed a stronger association at rs7708392 in European Americans but not at rs4958881 in African Americans. Our data suggest that variants in the TNIP1 gene are associated with the risk for lupus nephritis and could be mechanistically involved in disease development via aberrant regulation of NF-κB and mitogen-activated protein kinase activity. 23965897 A novel local anti-colorectal cancer drug delivery system: negative lipidoid nanoparticles with a passive target via a size-dependent pattern. The nontoxic, targeted and effective delivery of nucleic acid drugs remains an important challenge for clinical development. Here, we describe a novel negative lipidoid nanoparticle delivery system, providing entrapment-based transfection agents for local delivery of siRNA to the colorectal cancer focus. The delivery system was synthesized with lipidoid material 98N12-5(1), mPEG2000-C12/C14 glyceride and cholesterol at a desired molar ratio to realize the anionic surface charge of particles, which could alleviate to a larger degree the inflammatory response and immune stimulation of the organism, embodying dramatic biocompatibility. In particular, mPEG2000-C12/C14 glyceride was selected to ameliorate the stability of the delivery system and protection of nucleic acids by extending the tail length of the carbons, crucial also to neutralize the positive charge of 98N12-5(1) to form a resultant anionic particle. In vivo experiments revealed that a particle size of 90 nm perfectly realized a passive target in a size-dependent manner and did not affect the function of the liver and kidneys by a local delivery method, enema. We clarified that the uptake of negative lipidoid nanoparticles internalized through a lipid raft endocytotic pathway with low cytotoxicity, strong biocompatibility and high efficacy. This study suggests that negative lipidoid nanoparticles with enema delivery costitute, uniquely and appropriately, a local anti-colorectal cancer nucleic acid drug delivery platform, and the application of similar modes may be feasible in other therapeutic settings. 22317828 Toxic effects of some synthetic food colorants and/or flavor additives on male rats. The objective of the present work was to evaluate the broadest toxic effect of some synthetic additives of colorants and/or flavors on different body organs and metabolic aspects in rats. A number of chemical food color and flavor additives are routinely added during processing to improve the aesthetic appearance of the dietary items. However, many of them are toxic after prolonged use. In this experiment, a total of 100 male albino rats of Spargue Dawley strain were divided into 10 groups: G(1) was fed basal diet and served as control, G(2): basal diet + Brilliant blue (blue dye, No. 2, 124 mg/kg diet), G(3): basal diet + carmoisine (red dye, No. 3, 70 mg/kg diet), G(4): basal diet + tartrazine (yellow dye, FD & C yellow No. 5, 75 mg/kg diet), G(5): basal diet + trans-anethole (4.5 g/kg diet) G(6): basal diet + propylene glycol (0.25 g/kg diet), G(7): basal diet + vanillin(1.25 g/kg diet), G(8): basal diet + Brilliant blue + propylene glycol, G(9): basal diet + carmoisine + trans-anethole, G(10): basal diet + tartrazine + vanillin for 42 successive days. All food colorants mixed with or without flavor additives induced a significant decrease in body weight, hemoglobin concentration and red blood cell count. Also there was a significant decrease in reduced glutathione content; glutathione-S-transferase and superoxide dismutase activities in both blood and liver compared to control group. On the other hand, a significant increase in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase activities, bilirubin, urea, creatinine, total protein and albumin were observed in all test groups when compared to control group. Finally, it is advisable to limit the uses of these food colorants and/or food flavor additives especially those used by children. 23557746 Application of Target-Mediated Drug Disposition Model to Small Molecule Heat Shock Protein 90 Inhibitors. Replacement of hydrogen with fluorine within three pairs of structurally similar small molecule inhibitors of heat shock protein 90 (HSP90) resulted in differences in inhibition constants (Ki) in vitro as well as marked differences in rat intravenous pharmacokinetic profiles. The difference in pharmacokinetic profiles between lower and higher affinity inhibitors (LAIs and HAIs, respectively) was characterized by remarkably different estimates for steady-state volumes of distribution (Vss: 1.8 to 2.0 versus 10 to 13 L/kg) with comparable clearance estimates (3.2 to 3.5 L/h/kg). When the observed Vss estimates were compared to the values predicted with the tissue-composition-based model, the observed Vss estimates for HAIs were 4 to 8-fold larger than the predicted values whereas the Vss values for LAIs were comparable each other. Accordingly, a negative relationship between in vitro HSP90 Ki versus in vivo Vss estimates was observed among these inhibitors. We therefore hypothesized that pharmacokinetic profiles of these inhibitors could be characterized by target-mediated drug disposition (TMDD) model. In vivo equilibrium dissociation constant (KD) estimates for HAIs due to target binding by TMDD model with rapid binding approximation were 1 to 6 nM (equivalent to 0.3 to 2 nM free drug), which appeared comparable to the in vitro Ki estimates (2 to 3 nM). In vivo KD values of LAIs were not accurately determined by the TMDD model, likely due to non-specific binding dependent-tissue distribution obscuring TMDD profiles. Overall, these results suggest that the observed large Vss estimates for potent HSP90 inhibitors are likely due to pharmacological target binding. 23790189 Association of IL-10 and CCL5 single nucleotide polymorphisms with tuberculosis in the Sudanese population. To investigate the genetic determinants for developing tuberculosis in Sudan. Case study of 232 patients with tuberculosis and 206 healthy matched controls from Sudan. In the study population, three single nucleotide polymorphisms (SNPs) in the promoter regions of CCL5 and two in the promoter region of IL-10 were genotyped using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). These five SNPs influence the expression of these genes. There were significant differences in allele distribution for CCL5 -28 C/G (rs 2280788) and IL-10 -592 A/C (rs1800872) in patients with tuberculosis compared with healthy controls. This indicates that the genotypes obtained for CCL5 and IL-10 are associated with an increased risk of developing active TB. 23380376 Cinnamic acid derivatives as inhibitors for chorismatases and isochorismatases. Chorismatases and isochorismatases catalyse the hydrolysis of chorismate or isochorismate leading to unsaturated cyclohexenoic acid derivatives. Based on simplification of the physiological substrates, two cinnamic acid-derived compounds, differing in the saturation of the side chain, were developed. In contrast to earlier inhibitor studies, the compounds described here do not have an ether bond and therefore can be synthesised very easily in one or two steps without the need for protective groups. Both substances demonstrate inhibition of the isochorismatase EntB from Escherichia coli and the chorismatases FkbO and Hyg5 from Streptomyces. For chorismatases, the unsaturated compound shows IC(50) values in the millimolar range, while the saturated compound is the better inhibitor with IC(50) values in the micromolar/low millimolar range; for the isochorismatase tested both compounds inhibit in the micromolar range. Further, an analysis of the apparent K(m) values for FkbO and EntB was performed, showing that both inhibitors act in a competitive manner. Due to the ease of modifying these new inhibitors they are a suitable starting point for exploring further functionalised derivatives. 23831260 Advanced optical imaging techniques for neurodevelopment. Over the past decade, developmental neuroscience has been transformed by the widespread application of confocal and two-photon fluorescence microscopy. Even greater progress is imminent, as recent innovations in microscopy now enable imaging with increased depth, speed, and spatial resolution; reduced phototoxicity; and in some cases without external fluorescent probes. We discuss these new techniques and emphasize their dramatic impact on neurobiology, including the ability to image neurons at depths exceeding 1mm, to observe neurodevelopment noninvasively throughout embryogenesis, and to visualize neuronal processes or structures that were previously too small or too difficult to target with conventional microscopy. 23758210 Highlights of the third international conference on immunotherapy in pediatric oncology. The third International Conference on Immunotherapy in Pediatric Oncology was held in Frankfurt/Main, Germany, October 1-2, 2012. Major topics of the conference included (i) cellular therapies using antigen-specific and gene-modified T cells for targeting leukemia and pediatric solid tumors; (ii) overcoming hurdles and barriers with regard to immunogenicity, immune escape, and the role of tumor microenvironment; (iii) vaccine strategies and antigen presentation; (iv) haploidentical transplantation and innate immunity; (v) the role of immune cells in allogeneic transplantation; and (vi) current antibody/immunoconjugate approaches for the treatment of pediatric malignancies. During the past decade, major advances have been made in improving the efficacy of these modalities and regulatory hurdles have been taken. Nevertheless, there is still a long way to go to fully exploit the potential of immunotherapeutic strategies to improve the cure of children and adolescents with malignancies. This and future meetings will support new collaborations and insights for further translational and clinical immunotherapy studies. 23921648 Effect of increased body mass index (BMI) on time to tumour progression (TTP) in unresectable metastatic colorectal cancer (mCRC) patients treated with bevacizumab-based therapy. High BMI is a well-known risk factor for the development and recurrence of several solid tumours, including CRC. Obesity is associated with increased levels of vascular endothelial growth factor (VEGF). Bevacizumab is the main targeted therapy for inhibiting tumour angiogenesis by blocking the VEGF/VEGF receptor pathway. Elevated VEGF in obese patients might provoke resistance to anti-VEGF therapy. We evaluated the efficacy of bevacizumab on TTP among mCRC patients through stratifying them according to their BMI. Patients with mCRC who had been treated with fluoropyrimidine-based combination chemotherapy with bevacizumab were included in the study. Patients were assigned according to their BMI before initiation of therapy (group A: BMI < 25 kg/m(2), group B: BMI ≥ 25 kg/m(2)). Multivariate analysis was performed to evaluate the risk of tumour progression. Between April 2007 and June 2011, 80 patients were treated with chemotherapy and bevacizumab as first-line therapy (n = 37 for group A, n = 43 for group B). Tumours in 56.3 % of the patients in group A (n = 21) and 76.3 % of the patients in group B (n = 33) progressed during a median 10-months (3-57 months) follow-up. The median TTP was 11.7 months in the group A and 6 months in the group B (p = 0.004). In a multivariate analysis, high BMI (≥25 kg/m(2)) was associated with significantly shorter TTP (p = 0.01; HR: 4.37). High BMI among mCRC patients treated with bevacizumab is associated with shorter TTP. Further study in larger databases is warranted for confirming the negative prognostic effect of obesity during treatment with anti-VEGF agents. 23652847 Increase in left liver lobe function after preoperative right portal vein embolisation assessed with gadolinium-EOB-DTPA MRI. To prospectively evaluate the early development of regional liver function after right portal vein embolisation (PVE) with Gd-EOB-DTPA-enhanced MRI in patients scheduled for extended right hemihepatectomy. Ten patients who received a PVE before an extended hemihepatectomy were examined before and 14 days after PVE using Gd-EOB-DTPA-enhanced MRI of the liver. In these sequences representative region of interest measurements were performed in the embolised right (RLL) and the non-embolised left liver lobe (LLL). The volume as well as hepatic uptake index (HUI) was calculated independently for each lobe. Relative enhancement 14 days after PVE decreased in the RLL and increased significantly in the LLL (P < 0.05). Average hepatic uptake index (HUI) for RLL was significantly lower 14 days after PVE than before PVE (P < 0.05) and significantly higher for LLL (P < 0.05). A significant shift of contrast uptake from the right to the left liver lobe can be depicted as early as 14 days after right PVE by using Gd-EOB-DTPA-enhanced MRI, which could reflect the redirected portal venous blood flow and the rapid utilisation of a hepatic functional reserve. • Preoperative portal vein embolisation (PVE) is widely performed before right-sided hepatic resection. • PVE increases intravenous contrast medium uptake in the left lobe of liver. • The hepatic uptake index for the left liver lobe increases rapidly after PVE. • Left liver lobe function increase may be visualised by Gd-EOB-DTPA-enhanced MRI. 23816930 Toll-like receptor 9 (TLR9) gene polymorphisms associated with increased susceptibility of human papillomavirus-16 infection in patients with cervical cancer. To investigate the association between toll-like receptor 9 (TLR9) single nucleotide polymorphisms (SNPs) and human papillomavirus (HPV) infection among Chinese Han women with cervical cancer. TLR9 -1486 and 2848 SNPs were investigated in patients with cervical cancer and controls using polymerase chain reaction (PCR)-restriction fragment length polymorphism. HPV16 E6 and E7 infections were assessed using PCR. Of 120 patients with cervical cancer and 100 controls, there was a significant association between TLR9 2848 SNP and cervical cancer risk, but there was no such association with TLR9 -1486 SNP. Frequency of the TLR9 2848 GA genotype was significantly higher in patients with cervical cancer than in controls. There was no statistically significant between-group difference in presence of HPV16 infection. Presence of HPV infection with TLR9 2848 (rs352140) GA/AA genotype increased the risk of cervical cancer 13.8-fold compared with the GG genotype. The TLR9 2848 G/A polymorphism in Chinese Han women was associated with increased risk of cervical cancer in the presence of HPV16 infection. Further studies are necessary to uncover the functional aspect of this TLR9 2848 polymorphism. 23381061 Anisole hydrolysis in high temperature water. We investigated the hydrolysis of anisole to phenol in high-temperature water with and without water-tolerant Lewis acid catalysis. With no catalyst present, anisole hydrolyzes to phenol in 97% yield after 24 hours at 365 °C, our experimentally determined optimal temperature and time. Experiments with varied water density and analysis of comparable literature data suggest that anisole hydrolysis is almost third order in water, when the S(N)2 mechanism dominates. Of the water-tolerant Lewis acid catalysts studied, In(OTf)(3) offered the best phenol yield. Anisole hydrolysis was first order in catalyst and first order in substrate. Introducing In(OTf)(3) catalysis lowered the activation energy for anisole hydrolysis to 31 ± 1 kcal mol(-1). Anisole hydrolysis in high-temperature water with In(OTf)(3) catalysis is competitive with other techniques in the literature based on rate and yield. In the presence of 5 mol% In(OTf)(3) catalyst, anisole hydrolyzes to phenol in 97% yield after 90 minutes at 300 °C. 23798676 Degradome Products of the Matricellular Protein CCN1 as Modulators of Pathological Angiogenesis in the Retina. CCN1 is a matricellular protein involved in normal vascular development and tissue repair. CCN1 exhibits cell- and context-dependent activities that are reflective of its tetramodular structure phylogenetically linked to four domains found in various matrix proteins. Here, we show that vitreal fluids from patients with proliferative diabetic retinopathy (PDR) were enriched with a two-module form of CCN1 comprising completely or partially the insulin-like growth factor-binding protein (IGFBP) and von Willebrand factor type C (vWC) domains. The two- and three-module forms comprising, in addition to IGFBP and vWC, the thrombospondin type 1 (TSP1) repeats are CCN1 degradome products by matrix metalloproteinase-2 and -14. The functional significance of CCN1 and its truncated variants was determined in the mouse model of oxygen-induced retinopathy, which simulates neovascular growth associated with PDR and assesses treatment outcomes. In this model, lentivirus-mediated expression of either CCN1 or the IGFBP-vWC-TSP1 form reduced ischemia-induced neovascularization, whereas ectopic expression of the IGFBP-vWC variant exacerbated pathological angiogenesis. The IGFBP-vWC form has potent proangiogenic properties promoting retinal endothelial cell growth, migration, and three-dimensional tubular structure formation, whereas the IGFBP-vWC-TSP1 variant suppressed cell growth and angiogenic gene expression. Both IGFBP-vWC and IGFBP-vWC-TSP1 forms exhibited predictable variations of their domain folding that enhanced their functional potential. These data provide new insights into the formation and activities of CCN1-truncated variants and raise the predictive value of the form containing completely or partially the IGFBP and vWC domains as a surrogate marker of CCN1 activity in PDR distinguishing pathological from physiological angiogenesis. 22923703 Evaluation of carotid plaque neovascularization using contrast ultrasound. Contrast-enhanced ultrasound (CEUS) is increasingly used to improve visualization of carotid arteries. However, its reproducibility and utility for clinical research are not well established. The aim of the present study was to assess reproducibility of detection of carotid artery wall neovascularization using CEUS. Complete sequenced CEUS images from 10 individuals were analyzed for the presence of carotid arterial wall neovascularization. The images were acquired using Philips CompactXtreme CX50 ultrasound unit with an L12-3 probe and Bracco SonoVue contrast agent. The carotid wall neovascularization was graded by 2 independent observers with inter-/intraobserver agreement (κ) calculated. Interobserver κ values for intraplaque neovascularization (mean [95% confidence interval]) were 0.67 (0.40-0.94) for the left side. Interobserver κ values for intraplaque neovascularization were 0.65 (0.38-0.92). No study-related complications were observed. The CEUS method although semiquantitative shows moderate-to-strong intra- and interagreement for the results and can be used for clinical research purpose. 23824511 Antifungal Susceptibility, Exoenzyme Production and Cytotoxicity of Novel Oximes against Candida. Novel oximes were synthesized, their in vitro antifungal activity against Candida was evaluated and their cytotoxicity was determined. The procedure used for the synthesis of the oximes is aligned with the current green chemistry trend; water is employed as the solvent in this reaction. The minimum inhibitory and minimum fungicidal concentrations of the oximes were evaluated using the CLSI M27-A3 method. The influence of these compounds on the inhibition of the production of hydrolytic enzymes, phospholipase and proteinase by Candida was also investigated. The compounds showed a good ability to inhibit phospholipase, with a 50 % reduction in most cases. However, the tested compounds did not affect proteinase. The current results showed a substantial reduction in the phospholipase production, which suggests that compounds of this class may interfere with host infection and disease progression. The oximes examined showed lower fungicidal activities than fluconazole but interfered significantly with the expression of phospholipase. Some of the oximes included in this study could be a suitable matrix for the development of novel antifungal compounds. 23731192 Development of thin-film composite forward osmosis hollow fiber membranes using direct sulfonated polyphenylenesulfone (sPPSU) as membrane substrates. This study investigates a new approach to fabricate thin-film composite (TFC) hollow fiber membranes via interfacial polymerization for forward osmosis (FO) applications. Different degrees of sulfonation of polyphenylenesulfone (PPSU) were adopted as membrane substrates to investigate their impact on water flux. It has been established that the degree of sulfonation plays a role in both creating a macrovoid-free structure and inducing hydrophilicity to bring about higher water fluxes. The fabricated membranes exhibit extremely high water fluxes of 30.6 and 82.0 LMH against a pure water feed using 2.0 M NaCl as the draw solution tested under FO and pressure retarded osmosis (PRO) modes, respectively, while maintaining low salt reverse fluxes below 12.7 gMH. The structural parameter (S) displays remarkable decreases of up to 4.5 times as the membrane substrate is switched from a nonsulfonated to sulfonated one. In addition, the newly developed TFC-FO membranes containing 1.5 mol % sPPSU in the substrate achieves a water flux of 22 LMH in seawater desalination using a 3.5 wt % NaCl model solution and 2.0 M NaCl as the draw solution under the PRO mode. To the best of our knowledge, this value is the highest ever reported for seawater desalination using flat and hollow fiber FO membranes. The use of sulfonated materials in the FO process opens up a frontier for sustainable and efficient production of potable water. 23408272 Lupenone from Erica multiflora leaf extract stimulates melanogenesis in B16 murine melanoma cells through the inhibition of ERK1/2 activation. Hypopigmentation diseases are usually managed using UVB light which increases the patients' risk for skin cancer. Here, we evaluated the melanogenesis stimulatory effects of leaf extracts of Erica multiflora, a medicinal plant from the Mediterranean region, and its active component, lup-20(29)-en-3-one, as possible therapeutic agents to address hypopigmentation disorders. B16 murine melanoma cells were treated with E. multiflora extracts or its active component lupenone to evaluate their effects on melanin biosynthesis. The mechanism underlying the observed effects was also determined. Bioactivity-guided fractionation of fifteen ethyl acetate fractions identified fraction 2 to have melanogenesis stimulatory effects due to its ability to decrease mitogen-activated protein kinase phosphorylated extracellular signal-regulated kinases 1 and 2 activation. Preparative TLC of ethyl acetate fraction 2 revealed the presence of lup-20(29)-en-3-one as the major bioactive component. B16 cells treated with lup-20(29)-en-3-one increased melanin content without cytotoxicity. To determine the mechanism for the observed effects of lup-20(29)-en-3-one, the tyrosinase enzyme activity, the tyrosinase protein expression, and the activation of phosphorylated extracellular signal-regulated kinases 1 and 2 were determined. In addition, the expression of the tyrosinase mRNA was quantified using real-time PCR. Results showed that lup-20(29)-en-3-one has no effect on the tyrosinase enzyme activity but can increase tyrosinase expression at both the transcriptional and translational levels. The increase in the tyrosinase mRNA expression was most likely due to the inhibited mitogen-activated protein kinase phosphorylated extracellular signal-regulated kinases 1 and 2 activation. We report for the first time that E. multiflora ethyl acetate extract and its active compound lup-20(29)-en-3-one stimulate melanogenesis by increasing the tyrosinase enzyme expression via mitogen-activated protein kinase phosphorylated extracellular signal-regulated kinases 1 and 2 phosphorylation inhibition, making it a possible treatment for hypopigmentation diseases. 23889594 Spontaneous Particle Transport through a Triple-Fluid Phase Boundary. We investigate the spontaneous transport of a single particle through an air-water-oil triple phase boundary that is formed by placing a thin oil lens at an air-water interface. We find two distinct transition regimes: a particle initially accelerates upon its adsorption to the air-water-oil triple phase boundary from the air-water interface; subsequently, the particle decelerates after spontaneously detaching from the triple phase boundary. In the first stage, which we call the capillarity regime, the difference in the particle attachment energy to the three fluid-fluid interfaces accounts for the observed initial acceleration. Once it detaches from the air-oil interface and resides solely at the oil-water interface, the particle decelerates due to viscous drag; hence, we call this phase the relaxation regime. We show that the shape of oil lens as well as the size of the particles has a significant influence on the dynamics of particle transport through the triple-fluid phase boundary. 23835902 Outcome prediction in heart failure with atrial fibrillation: Relative role of left ventricular ejection fraction and neurohormonal measures. Since atrial fibrillation (AF) impacts the measurement and interpretation of left ventricular ejection fraction (LVEF), we hypothesized that the outcome in heart failure (HF) with AF and LVEF â‰¤ 35% would be more strongly associated with neurohormonal measures than LVEF. Cardiac adverse events [CAE; HF progression (HFP), life-threatening arrhythmia (ARR), and cardiac death (CD)] and all-cause mortality (ACM) were recorded prospectively in 954 patients with HF and LVEF â‰¤ 35%: 852 in sinus rhythm (SR) and 102 in AF. Cox proportional hazard models found that the univariate hazard ratios (HR) for LVEF and the first CAE (primary outcome), HFP, ARR, CD, and ACM were significant in SR (0.933, P < .001, 0.933, P < .001, 0.929, P < .001, 0.916, P < .001, 0.945, P = .001, respectively), but not in AF (1.002, P = .95, 1.060, P = .24, 0.922, P = .15, 0.885, P = .09, 0.932, P = .25). HRs for CAEs and ACM and one or more neurohormonal measures (iodine 123 m-iodobenzylguanidine cardiac parameters, B-type natriuretic peptide, and plasma norepinephrine) were significant in SR and AF. The multivariate models for the first CAE and HFP included neurohormonal measures and LVEF in SR and neurohormonal measures in AF. In HF with LVEF â‰¤ 35% with AF, neurohormonal measures, but not LVEF, were related to outcomes. 23887144 Blood pressure relation to body composition and age: analysis of a nurse-led investigation and consultation program. Blood pressure (BP) increases with age and obesity. We have assessed the relative contribution of age and fatness to BP regulation in a healthy population investigated by nurse practitioners. Preventive investigation and counseling was offered at the entrance hall of the regional authority´s office in the town of Nitra by 2 nursing specialists who investigated 120 men and 276 women. In men the mean body mass index (BMI) was 26.8 kg/m2, mean weight was 84.4 kg, mean fat percentage was 23.3, mean age was 46.1 years, mean systolic BP was 133.1 mmHg, and mean diastolic BP was 82.5 mmHg. In women the mean BMI was 24.8 kg/m2, mean weight was 67.3 kg, mean fat percentage was 29.4, mean age was 45.4 years, mean systolic BP was 127.7 mmHg, and mean diastolic BP was 78.5 mmHg. Correlation analysis was performed and in multiple regression analysis we used BP values as the dependent variable and fat percentage and age as independent variables. Normality of variables distribution was checked and found satisfactorily. Most of the subjects had an untreated component of metabolic syndrome. There was a correlation between BP values, age, and percent body fat. BP was regulated only to a certain degree by fatness and age, with the influence being relatively small. Our results showed that BP was more influenced by fatness than age, and body fatness was more related to higher systolic than to diastolic BP. Age and fatness could explain BP values by only 3-30%, although BP was more influenced by fatness than by age. Nurse practitioners can effectively detect and motivate people with metabolic syndrome. 23289972 Discovery of thiazolidine-2,4-dione/biphenylcarbonitrile hybrid as dual PPAR α/γ modulator with antidiabetic effect: in vitro, in silico and in vivo approaches. A small series of thiazolidine-2,4-dione and barbituric acid derivatives 1-4 was prepared using a short synthetic route, and all compounds were characterized by elemental analysis, mass spectrometry, and NMR ((1)H, (13)C) spectroscopy. Their in vitro relative expression of peroxisome proliferator-activated receptor α and peroxisome proliferator-activated receptor γ was evaluated. Compound 1 showed an increase in the mRNA expression of both peroxisome proliferator-activated receptor isoforms, as well as the GLUT-4 levels. The antidiabetic activity of compound 1 was determined at 50 mg/kg single dose using a non-insulin-dependent diabetes mellitus rat model. The results indicated a significant decrease in plasma glucose levels. Additionally, we performed a molecular docking of compound 1 into the ligand binding pocket of peroxisome proliferator-activated receptor α and peroxisome proliferator-activated receptor γ. In these binding models, compound 1 may bind into the active site of both isoforms showing important short contacts with the peroxisome proliferator-activated receptor γ residues: Tyr 473, His 449, Ser 289, His 323; and peroxisome proliferator-activated receptor α residues: Tyr 464, His 440, Ser 280 and Tyr 314. 23303290 Vertical flow immunoassay (VFA) biosensor for a rapid one-step immunoassay. A highly rapid, one-step immunoassay of high sensitivity C-reactive protein (hsCRP) using a biosensor with a vertical flow immunoassay (VFA) was developed. The VFA biosensor was primarily composed of a sample pad, conjugate pad, FTH film and nitrocellulose (NC) membrane, which were all vertically stacked upon one another. Anti-hsCRP and secondary antibodies were consecutively immobilized on the NC membrane at the position below the holes. Gold nanoparticles (AuNPs) conjugated with another anti-hsCRP antibody were encapsulated in the conjugation pad. Various assay conditions, including the size of the hole and the sample volume, were optimized. Under optimized conditions, hsCRP concentrations from 0.01 to 10 μg mL(-1) were detected within 2 min. In comparison with a lateral flow assay (LFA) system, the VFA sensor showed a gradual increase of signal in a concentration-dependent manner without a hook effect in the tested range. 23457020 Unusual amino acids and monofluoroacetate from Dichapetalum michelsonii (Umutambasha), a toxic plant from Rwanda. In the course of our investigations on Umutambasha in order to identify its convulsant principles, small quantities of monofluoroacetate were observed in stem bark, leaves, and fruits of this plant newly identified as Dichapetalum michelsonii Hauman. Conclusive evidence for a monofluoroacetate presence came from its isolation from the freeze-dried extract of stem bark. Three free unusual amino acids, named N-methyl-α-alanine, N-methyl-β-alanine, and 2,7-diaminooctan-1,8-dioic acid, described for the first time in a plant, and known trigonelline were also isolated from the stem bark of D. michelsonii. Structure elucidations were mainly achieved by spectroscopic methods (1H-NMR, 2D-NMR, MS) and by comparison with authentic references. These unusual amino acids were detected by a fast, reliable TLC analysis in all our batches of Umutambasha, suggesting that they could be used for identification purposes in case of human or livestock intoxications. Finally, EEG recordings and behavioural observations performed in mice suggested that the convulsive patterns produced by Umutambasha are the consequence of monofluoroacetate presence in D. michelsonii. 23532794 Short, fine and WHO asbestos fibers in the lungs of quebec workers with an asbestos-related disease. The possible role of short asbestos fibers in the development of asbestos-related diseases and availability of lung fiber burden data prompted this study on the relationships between fiber characteristics and asbestos-related diseases among compensated workers. Data collected between 1988 and 2007 for compensation purposes were used; lung asbestos fibers content of 123 Quebec workers are described according to socio-demographic characteristics, job histories and diseases (asbestosis, mesothelioma, lung cancer). Most workers (85%) presented chrysotile fibers in their lungs, and respectively 76%, 64%, and 43% had tremolite, amosite, and crocidolite. Half of the total fibers were short, 30% were thin fibers and 20% corresponded to the World Health Organization definition of fibers (length ≥ 5 μm, diameter ≥ 0.2 and <3 μm). Chrysotile fibers were still observed in the lungs of workers 30 years or more after last exposure. Our findings stress the relevance of considering several dimensional criteria to characterize health risks associated with asbestos inhalation. Am. J. Ind. Med. 56:1001-1014, 2013. © 2013 Wiley Periodicals, Inc. 22884520 Oxysterol generation and liver X receptor-dependent reverse cholesterol transport: not all roads lead to Rome. Cell cholesterol metabolism is a tightly regulated process, dependent in part on activation of nuclear liver X receptors (LXRs) to increase expression of genes mediating removal of excess cholesterol from cells in the reverse cholesterol transport pathway. LXRs are thought to be activated predominantly by oxysterols generated enzymatically from cholesterol in different cell organelles. Defects resulting in slowed release of cholesterol from late endosomes and lysosomes or reduction in sterol-27-hydroxylase activity lead to specific blocks in oxysterol production and impaired LXR-dependent gene activation. This block does not appear to be compensated by oxysterol production in other cell compartments. The purpose of this review is to summarize current knowledge about oxysterol-dependent activation by LXR of genes involved in reverse cholesterol transport, and what these defects of cell cholesterol homeostasis can teach us about the critical pathways of oxysterol generation for expression of LXR-dependent genes. 23242988 Phenylephrine infusion improves blood flow to the stomach during oesophagectomy in the presence of a thoracic epidural analgesia. Gastric tube necrosis is a major cause of mortality after oesophagectomy. The construction of the gastric tube used for oesophageal reconstruction involves a division of several arteries leading to a reduction in the blood supply at the fundus, which is used for the oesophageal anastomosis. This study was undertaken to determine the effect of thoracic epidural anaesthesia and intravenous phenylephrine on haemodynamics and blood flow in the tubularized stomach. Ten patients undergoing an oesophagectomy were prospectively studied. Pulmonary artery catheters were used to measure haemodynamic changes, and laser Doppler flow probes were used to measure gastric blood flow. The effects of an intraoperative thoracic epidural and subsequent intravenous phenylephrine infusion were documented. The administration of a thoracic epidural bolus of bupivacaine 0.25% at 0.1 ml kg resulted in a significant reduction in flux at the anastomotic end of the newly formed gastric tube from a median of 57-41 perfusion units (P = 0.003). A subsequent intravenous phenylephrine infusion titrated to restore mean arterial pressure significantly increased the flux at the anastomotic end from a median of 41-66 perfusion units (P = 0.009). An intravenous phenylephrine infusion can reverse the epidural bolus-induced reduction in blood flow at the anastomotic end of the newly formed gastric tube. 23288947 Bone marrow NR4A expression is not a dominant factor in the development of atherosclerosis or macrophage polarization in mice. The formation of the atherosclerotic lesion is a complex process influenced by an array of inflammatory and lipid metabolism pathways. We previously demonstrated that NR4A nuclear receptors are highly induced in macrophages in response to inflammatory stimuli and modulate the expression of genes linked to inflammation in vitro. Here we used mouse genetic models to assess the impact of NR4A expression on atherosclerosis development and macrophage polarization. Transplantation of wild-type, Nur77⁻/⁻, or Nor1⁻/⁻ null hematopoetic precursors into LDL receptor (LDLR)⁻/⁻ recipient mice led to comparable development of atherosclerotic lesions after high-cholesterol diet. We also observed comparable induction of genes linked to M1 and M2 responses in wild-type and Nur77-null macrophages in response to lipopolysaccharides and interleukin (IL)-4, respectively. In contrast, activation of the nuclear receptor liver X receptor (LXR) strongly suppressed M1 responses, and ablation of signal transductor and activator of transcription 6 (STAT6) strongly suppressed M2 responses. Recent studies have suggested that alterations in levels of Ly6C(lo) monocytes may be a contributor to inflammation and atherosclerosis. In our study, loss of Nur77, but not Nor1, was associated with decreased abundance of Ly6C(lo) monocytes, but this change was not correlated with atherosclerotic lesion development. Collectively, our results suggest that alterations in the Ly6C(lo) monocyte population and bone marrow NR4A expression do not play dominant roles in macrophage polarization or the development of atherosclerosis in mice. 23823316 Myeloproliferative neoplasms and thrombosis. Major causes of morbidity and mortality in myeloproliferative neoplasms (MPN) are represented by arterial and venous complications, progression to myelofibrosis and transformation to acute leukemia. The pathogenesis of thrombosis results from a complex interplay of clinical and disease-related factors. Abnormalities of blood cells arising from the clonal proliferation of hematopoietic stem cells involve not only quantitative changes, but also qualitative modifications which characterize the switch of these cells from a resting to a procoagulant phenotype. According to age and previous thrombosis, patients are classified in a "high-risk" or "low-risk". Novel disease-related determinants such as leukocytosis and JAK2V617F mutational status and/or mutational burden are now under active investigation. In low-risk PV patients only phlebotomy and primary antithrombotic prophylaxis with aspirin is recommended, while in high-risk patients cytotoxic therapy is considered. Whether novel drugs targeting the constitutively active JAK2/STAT pathway will improve management of thrombosis is a challenge for future studies. 23906534 Lack of long-lasting effects of mitotane adjuvant therapy in a mouse xenograft model of adrenocortical carcinoma. Mitotane is a widely used drug in the therapy of adrenocortical carcinoma (ACC). It is important to set up preclinical protocols to study the possible synergistic effects of its association with new drugs for ACC therapy. We assessed the efficacy of different routes of administration of mitotane (i.p. and oral) in inhibiting growth of H295R ACC cell xenografts in an adjuvant setting. Both formulations of mitotane could inhibit H295R xenografts growth only at short times after carcinoma cells inoculation, even though plasma mitotane levels approached or fell within the therapeutic range in humans. Our results show that mitotane adjuvant therapy is inadequate to antagonize long-term growth of H295R cancer cells xenografts and that care should then be taken in the design of preclinical protocols to evaluate the performance of new drugs in association with mitotane. 23909343 Critical Terrace Width for Two-Dimensional Nucleation during Si Growth on Si(111)-(7×7) Surface. The critical terrace width λ for 2D island nucleation and growth (2DNG) on large-scale atomically flat terraces of a step-bunched Si(111)-(7×7) surface has been studied by in situ ultrahigh vacuum reflection electron microscopy as a function of the substrate temperature T and Si deposition rate R. The dependence of λ^{2}(R) is characterized by a power law with scaling exponent χ=1.36-1.46, validating an attachment limited (AL) growth kinetics up to 720 °C. At this temperature, the Arrhenius dependencies ln⁡λ^{2}(1/T) change their slope, so that the effective 2DNG activation energy E_{2D} drops from 2.4 eV down to 0.5 eV at T>720 °C. We first show that the E_{2D} change is caused by a transition between AL and DL (diffusion limited) growth kinetics accompanied by a step shape transformation. The AL growth mode is characterized by kinetic length d_{-}∼10^{5}a and the preferential step-down attachment of atoms to steps limited by an energy barrier E_{ES}^{-}≈0.9  eV. 23796008 False-positive Iodine-131 whole-body scan findings in patients with differentiated thyroid carcinoma: Report of 11 cases and review of the literature. Iodine-131 (I-131) whole-body scan (WBS) plays an important role in the management of patients with differentiated thyroid carcinoma (DTC), to detect normal thyroid remnants and recurrent or metastatic disease. A focus of I-131 accumulation outside the thyroid bed and the areas of physiological uptake is strongly suggestive of a distant functioning metastasis. However, many false-positive I-131 WBS findings have been reported in the literature. We describe a series of 11 personal cases of patients with DTC, collected from 1992 to 2011, in whom diagnostic or post-treatment WBS showed false-positive retention of I-131 in various locations. False-positive accumulations of I-131 on WBS may be classified according to the underlying pathophysiological mechanisms: external and internal contaminations by body secretions, ectopic normal thyroid and gastric tissues, inflammatory and infectious diseases, benign and malignant tumors, cysts and effusions of serous cavities, thymic uptake, and other non classified causes. Clinicians must be aware of possible false-positive findings to avoid misinterpretations of the I-131 WBS, which could lead to inappropriate treatments. 23910877 Multidisciplinary approach to fatal dog attacks: A forensic case study. Dog-bite-related injuries and fatalities are increasing in incidence and represent an important public health concern, as dogs are more and more becoming an integral part of human social life. We report the case of a 27-year-old woman who was found dead in her home. Her body was discovered lying face down in a large pool of partially desiccated blood with signs of having been dragged. Site examination revealed the presence of severe injuries on the face, neck and head, which were then traced back to the dog she owned. Death was attributed to exsanguinations due to a neck blood vessel's laceration with fracture of the fifth cervical vertebra. This was uncommon because the dog bites injured the vertebral artery only without any lacerations of the carotid artery. Confirming that the injuries are dog-bite related was based on a multidisciplinary approach including histological findings, odontological examination of bite marks and DNA analysis. 23910709 Doses to carotid arteries after modern radiation therapy for hodgkin lymphoma: is stroke still a late effect of treatment? Hodgkin lymphoma (HL) survivors are at an increased risk of stroke because of carotid artery irradiation. However, for early-stage HL involved node radiation therapy (INRT) reduces the volume of normal tissue exposed to high doses. Here, we evaluate 3-dimensional conformal radiation therapy (3D-CRT), volumetric-modulated arc therapy (VMAT), and proton therapy (PT) delivered as INRT along with the extensive mantle field (MF) by comparing doses to the carotid arteries and corresponding risk estimates. We included a cohort of 46 supradiaphragmatic stage I-II classical HL patients. All patients were initially treated with chemotherapy and INRT delivered as 3D-CRT (30 Gy). For each patient, we simulated MF (36 Gy) and INRT plans using VMAT and PT (30 Gy). Linear dose-response curves for the 20-, 25-, and 30-year risk of stroke were derived from published HL data. Risks of stroke with each technique were calculated for all patients. Statistical analyses were performed with repeated measures analysis of variance. The mean doses to the right and left common carotid artery were significantly lower with modern treatment compared with MF, with substantial patient variability. The estimated excess risk of stroke after 20, 25, and 30 years was 0.6%, 0.86%, and 1.3% for 3D-CRT; 0.67%, 0.96%, and 1.47% for VMAT; 0.61%, 0.96%, and 1.33% for PT; and 1.3%, 1.72%, and 2.61% for MF. INRT reduces the dose delivered to the carotid arteries and corresponding estimated risk of stroke for HL survivors. Even for the subset of patients with lymphoma close to the carotid arteries, the estimated risk is low. 23576027 Simultaneous quantification of paeoniflorin, nobiletin, tangeretin, liquiritigenin, isoliquiritigenin, liquiritin and formononetin from Si-Ni-San extract in rat plasma and tissues by liquid chromatography-tandem mass spectrometry. In this study, a sensitive and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of seven bioactive components including paeoniflorin, nobiletin, tangeretin, liquiritigenin, isoliquiritigenin, liquiritin and formononetin in rat plasma and tissues after oral administration of Si-Ni-San extract using astragaloside IV as internal standard (IS). The plasma and tissue samples were extracted by solid-phase extraction. Chromatographic separation was accomplished on a C18 column with a multiple-step gradient elution. The quantification was obtained by scanning with multiple reaction monitoring via an electrospray ionization source that was operated by switching between the positive and negative modes in two MS/MS scan segments. Full validation of the assay was implemented. In conclusion, this method demonstrated good linearity and specificity. The lower limits of quantification for the analytes were <7.5 ng/mL. Intra- and inter-day precisions (RSD) were <12.5% and accuracy (RE) ranged from -10.2 to 7.3%. The average recoveries of the analytes from rat plasma and tissues were >65.2% and 58.6%, respectively. The validated method was further applied to the determination of actual rat plasma and tissues after oral administration of Si-Ni-San extract. The results provided a meaningful basis for the clinical application of this prescription. Copyright © 2013 John Wiley & Sons, Ltd. 23231448 A systems approach to the policy-level risk assessment of exotic animal diseases: network model and application to classical Swine Fever. Exotic animal diseases (EADs) are characterized by their capacity to spread global distances, causing impacts on animal health and welfare with significant economic consequences. We offer a critique of current import risk analysis approaches employed in the EAD field, focusing on their capacity to assess complex systems at a policy level. To address the shortcomings identified, we propose a novel method providing a systematic analysis of the likelihood of a disease incursion, developed by reference to the multibarrier system employed for the United Kingdom. We apply the network model to a policy-level risk assessment of classical swine fever (CSF), a notifiable animal disease caused by the CSF virus. In doing so, we document and discuss a sequence of analyses that describe system vulnerabilities and reveal the critical control points (CCPs) for intervention, reducing the likelihood of U.K. pig herds being exposed to the CSF virus. 23886225 New insight into the assessment of asthma using xenon ventilation computed tomography. Image analyses include computed tomography (CT), magnetic resonance imaging, and xenon ventilation CT, which is new modality to evaluate pulmonary functional imaging. To examine the usefulness of dual-energy xenon ventilation CT in asthmatic patients. A total of 43 patients 18 years or older who were nonsmokers were included in the study. Xenon CT images in wash-in and wash-out phases were obtained at baseline and after inhalation of methacholine and salbutamol. The degrees of ventilation defects and xenon trappings were evaluated through visual analysis. Ventilation defects and xenon trapping were significantly increased and decreased after methacholine challenge and salbutamol inhalation, respectively (P < .005). The ventilation abnormalities were not significantly related to the percentage of forced expiratory volume in 1 second (FEV1) or the ratio of FEV1 to forced vital capacity. Xenon trappings after salbutamol inhalation were negatively related to the scores of the asthma control test, wheezing, or night symptoms, with statistical significance (P < .05), whereas, FEV1 showed no significant correlation with symptom scores. Baseline FEV1 was significantly lower and dyspnea and wheezing were more severe in the non-full reversal group than in the full reversal group after salbutamol inhalation in xenon CT (P < .05). The degree of ventilation defects were positively correlated with FEV1 improvement after 3 months of treatment (P = .02). The results of this study suggest that xenon ventilation CT can be used as a new method to assess ventilation abnormalities in asthma, and these ventilation abnormalities can be used as novel parameters that reflect the status of asthma control and symptom severity. 23182847 Interactions between transcranial direct current stimulation (tDCS) and pharmacological interventions in the Major Depressive Episode: Findings from a naturalistic study. Transcranial direct current stimulation (tDCS) is a non-invasive, neuromodulatory technique with an emerging role for treating major depression. To investigate the interactions between tDCS and drug therapy in unipolar and bipolar depressed patients who were refractory for at least one pharmacological treatment. This was a naturalistic study using data from 54 female and 28 male patients (mean age of 54 years) that consecutively visited our psychiatric unit. They received active tDCS (five consecutive days, 2mA, anodal stimulation over the left and cathodal over the right dorsolateral prefrontal cortex, twice a day, 20minutes). The outcome variable (mood) was evaluated using the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HDRS). Predictor variables were age, gender, disorder and pharmacological treatment (seven dummy variables). We performed univariate and multivariate analyses as to identify predictors associated to the outcome. After 5 days of treatment, BDI and HDRS scores decreased significantly (29%±36%, 18%±9%, respectively, P<0.01 for both). Benzodiazepine use was independently associated with a worse outcome in both univariate (β=4.92, P<0.01) and multivariate (β=5.8, P<0.01) analyses; whereas use of dual-reuptake inhibitors positively changed tDCS effects in the multivariate model (β=-4.7, P=0.02). A similar trend was observed for tricyclics (β=-4, P=0.06) but not for antipsychotics, non-benzodiazepine anticonvulsants and other drugs. tDCS over the DLPFC acutely improved depressive symptoms. Besides the inherent limitations of our naturalistic design, our results suggest that tDCS effects might vary according to prior pharmacological treatment, notably benzodiazepines and some antidepressant classes. This issue should be further explored in controlled studies. 23394475 Do SLCO1B3 (T334G) and CYP3A5*3 polymorphisms affect response in Egyptian chronic myeloid leukemia patients receiving imatinib therapy? Imatinib has so far been the first-choice treatment in chronic myeloid leukemia (CML) with excellent results. However, only a proportion of patients achieve major molecular response. Hence, the need to find whether there are some factors that affect the response to treatment is essential. This study aimed to investigate the allele and genotype frequencies of single nucleotide polymorphisms (SNPs) of SLCO1B3 (T334G) and CYP3A5*3 in CML patients undergoing imatinib treatment and to determine whether SNPs of these two genes could predict the response of imatinib therapy in CML patients. We investigated SLCO1B3 (T334G) and CYP3A5*3 polymorphisms by Polymerase Chain Reaction-restriction fragment length polymorphism in 86 Philadelphia positive newly diagnosed Egyptian CML patients (78 patients in chronic phase and 8 patients in accelerated phase). All patients received imatinib therapy and were followed for at least one and half years. The response to imatinib therapy was evaluated by recording the hematological response, cytogenetic response, and molecular response according to the European Leukemia Net criteria. This study included 86 Philadelphia positive newly diagnosed CML patients, 78 in the early chronic phase and 8 in the accelerated phase. In the chronic phase patients, no association between SLCO1B3 (T334G) exon 3 polymorphism and response to imatinib therapy was detected (P = 0.938) while CYP3A5*3 gene polymorphism was associated with inferior outcome (P < 0.001). In the group of accelerated phase patients, the SLCO1B3 polymorphic variants (TG) and (GG) were detected equally with none of the patients in this group having the homozygous wild form (TT). The homozygous state for the CYP3A5*3 allele was the most frequent (50%) and the homozygous state for the CYP3A5*1 allele was the least frequent (12.5%) in this group. CYP3A5*3 polymorphism was associated with imatinib efficacy while the SNP SLCO1B3 (T334G) was not associated with the response to imatinib treatment in Egyptian patients with CML in chronic phase. These results prompt us to explore the effect of CYP3A5*3 in CML patients taking imatinib in a larger scale study. 23460374 Comparison of MR and fluoroscopic mucous fistulography in the pre-operative evaluation of infants with anorectal malformation: a pilot study. Anorectal malformations are often associated with rectal pouch fistulas. Surgical correction requires accurate evaluation of the presence and position of such fistulas. Fluoroscopy is currently the chosen modality for the detection of fistulas. The role of MRI is unexplored. To compare the diagnostic accuracy of MR versus fluoroscopic fistulography in the pre-operative evaluation of infants with anorectal malformation. We conducted a pilot study of infants requiring defunctioning colostomy for initial management of anorectal malformation. Dynamic sagittal steady-state free-precession MRI of the pelvis was acquired during introduction of saline into the mucous fistulas. Findings were compared among MR fistulography, fluoroscopic fistulography and intraoperative inspection. Eight children were included. Median age at fistulography was 15 weeks, inter-quartile range 13-20 weeks; all were boys. There was full agreement among MR fistulography, fluoroscopic fistulography and surgical findings. The pilot data suggest that MR fistulography is promising in the pre-operative evaluation of children with anorectal malformation. 23880723 Circulating nitrite and nitrate are associated with job-related fatigue in women, but not in men. A recent study indicated that serum nitrite and nitrate (NOx) is inversely associated with general fatigue. The purpose of this study was to confirm the negative association between nitric oxide (NO) and fatigue and to examine whether NO can prevent fatigue caused by job strain. The subjects, 570 workers (272 men and 298 women), answered self-administered questionnaires and underwent a medical examination. Job strain was measured using the Job Content Questionnaire. Fatigue was evaluated using the Profile of Mood States. Venous blood samples were collected after overnight fasting. Plasma NOx concentration was determined by the ozone-based chemiluminescence assay. Plasma NOx levels were significantly (p < 0.05) negatively associated with fatigue even after adjustment for job strain and potential confounders in women, but not in men. Significant (p < 0.05) interactions showed that, in women, as the level of the job strain worsened, fatigue was exacerbated, but the plasma NOx seemed to buffer the association, even after adjustment for potential confounders and the interaction between job strain and vegetable intake. In women, NO seemed to be inversely associated with fatigue and to buffer the association between job strain and fatigue, but not in men. 22954325 Resting heart rate and outcomes in patients with cardiovascular disease: where do we currently stand? Data from large epidemiological studies suggest that elevated heart rate is independently associated with cardiovascular and all-cause mortality in patients with hypertension and in those with established cardiovascular disease. Clinical trial findings also suggest that the favorable effects of beta-blockers and other heart rate-lowering agents in patients with acute myocardial infarction and congestive heart failure may be, at least in part, due to their heart rate-lowering effects. Contemporary clinical outcome prediction models such as the Global Registry of Acute Coronary Events (GRACE) score include admission heart rate as an independent risk factor. This article critically reviews the key epidemiology concerning heart rate and cardiovascular risk, potential mechanisms through which an elevated resting heart rate may be disadvantageous and evaluates clinical trial outcomes associated with pharmacological reduction in resting heart rate. Prospective randomised data from patients with significant coronary heart disease or heart failure suggest that intervention to reduce heart rate in those with a resting heart rate >70 bpm may reduce cardiovascular risk. Given the established observational data and randomised trial evidence, it now appears appropriate to include reduction of elevated resting heart rate by lifestyle +/- pharmacological therapy as part of a secondary prevention strategy in patients with cardiovascular disease. 23643093 Apoptosis inducing activity of benzophenanthridine-type alkaloids and 2-arylbenzofuran neolignans in HCT116 colon carcinoma cells. Thirteen compounds belonging to different classes of alkaloids (1-9) and lignans (10-13), isolated from the methanol extract of roots of the African medicinal plant Zanthoxylum capense, were assayed for their ability as apoptosis inducers in HCT116 colon carcinoma cells. The cytotoxicity of these compounds was evaluated in HCT116 colon carcinoma cells by the MTS assay. Out of the tested compounds, three benzophenanthridine alkaloids (1, 4, and 7), a dibenzyl butyrolactone lignan (10), and two 2-arylbenzofuran neolignans (12 and 13) displayed significant cytotoxicity to HCT116 cells, confirmed by the Guava ViaCount viability assay. The selected compounds (1, 4, 7, 10, 12, and 13) were further tested for apoptosis induction activity in HCT116 cells, by evaluation of nuclear morphology following Hoechst staining, and by caspase-3 like activity assays. Morphologic evaluation of HCT116 nuclei following Hoechst staining and fluorescence microscopy revealed that compounds 1, 4, 7, 10, 12, and 13 induced apoptosis in HCT116 colon carcinoma cells, producing similar, or higher, apoptosis levels when compared with 5-fluorouracil (5-FU), the cornerstone cytotoxic used in colon cancer treatment for several decades. In fact, HCT116 cells developed morphological changes characteristic of apoptosis, including chromatin condensation, nuclear fragmentation and formation of apoptotic bodies. Importantly, compounds 4 and 13 at 20μM were the most promising in this study, inducing respectively ~11- and 7-fold increases in apoptotic cells as compared to vehicle control, whereas 5-FU increased apoptosis by ~2-fold. Apoptosis induction for compounds 4 and 13 was further confirmed by caspase-3-like activity assays, which showed respectively ~2- and 1.5-fold increases in caspase-3-like activity compared to vehicle control. These results suggested that specific benzophenanthridine alkaloids and 2-arylbenzofuran neolignans isolated from Zanthoxylum capense show strong anticancer activity in HCT116 colon carcinoma cells. 23964210 Finding synchrony in the desynchronized EEG: the history and interpretation of gamma rhythms. Neocortical gamma (30-80 Hz) rhythms correlate with attention, movement and perception and are often disrupted in neurological and psychiatric disorders. Gamma primarily occurs during alert brain states characterized by the so-called "desynchronized" EEG. Is this because gamma rhythms are devoid of synchrony? In this review we take a historical approach to answering this question. Richard Caton and Adolf Beck were the first to report the rhythmic voltage fluctuations in the animal brain. They were limited by the poor amplification of their early galvanometers. Thus when they presented light or other stimuli, they observed a disappearance of the large resting oscillations. Several groups have since shown that visual stimuli lead to low amplitude gamma rhythms and that groups of neurons in the visual cortices fire together during individual gamma cycles. This synchronous firing can more strongly drive downstream neurons. We discuss how gamma-band synchrony can support ongoing communication between brain regions, and highlight an important fact: there is at least local neuronal synchrony during gamma rhythms. Thus, it is best to refer to the low amplitude, high frequency EEG as an "activated", not "desynchronized", EEG. 23804577 Mutation in the SYNJ1 Gene Associated with Autosomal Recessive, Early-Onset Parkinsonism. Autosomal recessive, early-onset Parkinsonism is clinically and genetically heterogeneous. Here, we report the identification, by homozygosity mapping and exome sequencing, of a SYNJ1 homozygous mutation (p.Arg258Gln) segregating with disease in an Italian consanguineous family with Parkinsonism, dystonia, and cognitive deterioration. Response to levodopa was poor, and limited by side effects. Neuroimaging revealed brain atrophy, nigrostriatal dopaminergic defects, and cerebral hypometabolism. SYNJ1 encodes synaptojanin 1, a phosphoinositide phosphatase protein with essential roles in the postendocytic recycling of synaptic vesicles. The mutation is absent in variation databases and in ethnically matched controls, is damaging according to all prediction programs, and replaces an amino acid that is extremely conserved in the synaptojanin 1 homologues and in SAC1-like domains of other proteins. Sequencing the SYNJ1 ORF in unrelated patients revealed another heterozygous mutation (p.Ser1422Arg), predicted as damaging, in a patient who also carries a heterozygous PINK1 truncating mutation. The SYNJ1 gene is a compelling candidate for Parkinsonism; mutations in the functionally linked protein auxilin cause a similar early-onset phenotype, and other findings implicate endosomal dysfunctions in the pathogenesis. Our data delineate a novel form of human Mendelian Parkinsonism, and provide further evidence for abnormal synaptic vesicle recycling as a central theme in the pathogenesis. 23838485 Variations and constancy of mercury and methylmercury accumulation in rice grown at contaminated paddy field sites in three Provinces of China. Many paddy fields have been contaminated by mercury (Hg) in mining areas of China. In this study, twenty-six rice cultivars and three Hg contaminated paddy fields in different geographic regions were selected for field trials and aimed to investigate the variations and similarities in total Hg (THg) and methylmercury (MeHg) accumulations in brown rice (seeds) across sites. Our results revealed widescale cultivar variation in THg (13-52 ng g(-1) at Wanshan) and MeHg (3.5-23 ng g(-1)) accumulation and %MeHg (17.7-89%) in seeds. The ability to translocate is an important factor in the levels of THg and MeHg in seed. Cultivar tended to stability in THg accumulation across sites. Some cultivars accumulated lower concentrations of both THg and MeHg in seeds at fields seriously contaminated by Hg. Present results suggest that appropriate cultivar selection is a possible way to reduce THg and MeHg accumulation in seeds of rice grown in Hg-contaminated regions. 23883586 Synthetic lethal targeting of PTEN-deficient cancer cells using selective disruption of polynucleotide kinase/phosphatase. A recent screen of 6961 siRNAs to discover possible synthetic lethal partners of the DNA repair protein polynucleotide kinase/phosphatase (PNKP) led to the identification of the potent tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Here we have confirmed the PNKP/PTEN synthetic lethal partnership in a variety of different cell lines including the PC3 prostate cancer cell line, which is naturally deficient in PTEN. We provide evidence that co-depletion of PTEN and PNKP induces apoptosis. In HCT116 colon cancer cells the loss of PTEN is accompanied by an increased background level of DNA double strand breaks, which accumulate in the presence of an inhibitor of PNKP DNA 3'-phosphatase activity. Complementation of PC3 cells with several well-characterized mutated PTEN cDNAs indicated that the critical function of PTEN required to prevent toxicity induced by an inhibitor of PNKP is most likely associated with its cytoplasmic lipid phosphatase activity. Finally, we show that modest inhibition of PNKP in a PTEN knockout background enhances cellular radiosensitivity, suggesting that such a "synthetic sickness" approach involving the combination of PNKP inhibition with radiotherapy may be applicable to PTEN-deficient tumors. 23628321 Multiparameter analyses of three-dimensionally cultured tumor spheroids based on respiratory activity and comprehensive gene expression profiles. Multicellular spheroids of human breast cancer cells (MCF-7) formed with two different three-dimensional (3D) culture methods were evaluated in detail on the basis of respiratory activity and high-throughput gene expression analysis. The spheroids formed with poly(dimethylsiloxane) (PDMS) microwell arrays indicated significant restriction of the spheroid size, whereas their respiratory activity was 2-fold greater than that formed with the hanging drop culture method. Fluidigm BioMark dynamic array was used for comprehensive and quantitative real-time polymerase chain reaction (qRT-PCR) analysis on the samples whose respiratory activity had been measured. Genes involved in cellular senescence and glucose metabolism indicated significantly higher values for the PDMS microwell culture method than for the hanging drop culture method (P<0.05). Interestingly, samples formed with the PDMS microwell culture method showed stronger responses for glycolysis than those formed with the hanging drop method. These results illustrate the power of multiparameter analysis to characterize multicellular spheroids cultured in different microenvironments even if they have the same morphology. 23851654 Effects of equid herpesvirus 1 (EHV-1) AR8 and HH1 strains on BALB-c mice. Here, we used a murine model to describe and compare the pathogenic potential of the Argentinean equid herpesvirus 1 (EHV-1) AR8 strain with the Japanese HH1 reference strain. In AR8-inoculated animals, clinical signs began earlier, but the viremic phase was shorter. Virus isolation and DNA detection in the lungs, liver and spleen were positive for both strains at different times postinfection (pi). Infection foci produced by both strains were immunohistochemically detected in lungs from day 1 to day 4 pi. We conclude that whichever EHV-1 strain is selected to experimentally reproduce the disease, it needs appropriate standardization in order to provide valid conclusions. 23602808 Mapping the Spectrum of Conformational States of the DNA- and C-Gates in Bacillus subtilis Gyrase. Type II DNA topoisomerases alter the supercoiling state of DNA in an ATP-dependent fashion that requires large conformational changes. The directionality of DNA strand transfer is controlled by three transient protein interfaces, termed the N-gate, DNA-gate, and C-gate. Bacterial gyrase is a type II DNA topoisomerase of A2B2 composition. The N-gate is formed by the two GyrB subunits and the GyrA subunits form the DNA- and C-gates. In structures of type II topoisomerase fragments, the DNA- and C-gates delimit a cavity for DNA and can be open or closed. However, the conformational space accessible has not yet been mapped. Here, we describe the crystal structure of the Bacillus subtilis DNA gyrase A subunit lacking the C-terminal DNA-wrapping domains. Five dimeric states of the GyrA N-terminal domain are observed, with their DNA- and C-gates either closed, or open to different extents. All of these conformations can in principle accommodate double-stranded DNA in the central cavity but only one conformation has its DNA-gate open wide enough for DNA to enter. The structure thus reflects the lower limit of DNA-gate opening that must occur during gyrase catalysis. The DNA-gate is formed by two flat surfaces, with few interactions. In contrast, the C-gate exhibits a highly undulated surface and forms a large number of interactions. None of the dimers in the crystal structures display an open C-gate that would allow DNA passage, in agreement with a transient opening of this gate during the catalytic cycle of DNA supercoiling. 23601708 2-(1H-Pyrazol-4-yl)acetic acids as CRTh2 antagonists. High throughput screening identified the pyrazole-4-acetic acid substructure as CRTh2 receptor antagonists. Optimisation of the compounds uncovered a tight SAR but also identified some low nanomolar inhibitors. 23683730 Alleged isotretinoin-associated inflammatory bowel disease: Disproportionate reporting by attorneys to the Food and Drug Administration Adverse Event Reporting System. Some studies have purported to link isotretinoin prescribed for acne with the development of inflammatory bowel disease (IBD). We sought to identify existence of disproportionate attorney-initiated reporting of isotretinoin-associated IBD in the Food and Drug Administration Adverse Event Reporting System (FAERS). A total of 3,338,835 cases (2003-2011) were downloaded from the FAERS. These were queried for IBD cases reported with isotretinoin for a usage indication of acne while recording reporter category. Trends were analyzed over time for reports by attorneys for all medications compared with reports of IBD with isotretinoin. Signal inflation factor was calculated to determine the distortion of pharmacovigilance signals for IBD with isotretinoin. There were 2214 cases of IBD resulting from isotretinoin. Attorneys reported 1944 (87.8%) cases whereas physicians reported 132 (6.0%) and consumers reported 112 (5.1%) cases (P value < .01). For the entire FAERS, only 87,905 of the total 2,451,314 (3.6%) reports for all drug reactions during the same time period were reported by attorneys (P value < .01). The signal inflation factor for IBD with isotretinoin for attorney-initiated reports was 5.82, signifying a clear distortion. The accuracy of reports was not ascertained. Attorney-initiated reports inflate the pharmacovigilance signal of isotretinoin-associated IBD in the FAERS. 23495933 Stress ulcer prophylaxis in the intensive care unit: is it indicated? A topical systematic review. Stress ulcer prophylaxis (SUP) is regarded as standard of care in the intensive care unit (ICU). However, recent randomized, clinical trials (RCTs) and meta-analyses have questioned the rationale and level of evidence for this recommendation. The aim of the present systematic review was to evaluate if SUP in the critically ill patients is indicated. Data sources: MEDLINE including MeSH, EMBASE, and the Cochrane Library. Participants: patients in the ICU. Interventions: pharmacological and non-pharmacological SUP. Study appraisal and synthesis methods: Risk of bias was assessed according to Grading of Recommendations Assessment, Development, and Evaluation, and risk of random errors in cumulative meta-analyses was assessed with trial sequential analysis. A total of 57 studies were included in the review. The literature on SUP in the ICU includes limited trial data and methodological weak studies. The reported incidence of gastrointestinal (GI) bleeding varies considerably. Data on the incidence and severity of GI bleeding in general ICUs in the developed world as of today are lacking. The best intervention for SUP is yet to be settled by balancing efficacy and harm. In essence, it is unresolved if intensive care patients benefit overall from SUP. The following clinically research questions are unanswered: (1) What is the incidence of GI bleeding, and which interventions are used for SUP in general ICUs today?; (2) Which criteria are used to prescribe SUP?; (3) What is the best SUP intervention?; (4) Do intensive care patients benefit from SUP with proton pump inhibitors as compared with other SUP interventions? Systematic reviews of possible interventions and well-powered observational studies and RCTs are needed. 23966072 Probing early misfolding events in prion protein mutants by NMR spectroscopy. The post-translational conversion of the ubiquitously expressed cellular form of the prion protein, PrPC, into its misfolded and pathogenic isoform, known as prion or PrPSc, plays a key role in prion diseases. These maladies are denoted transmissible spongiform encephalopathies (TSEs) and affect both humans and animals. A prerequisite for understanding TSEs is unraveling the molecular mechanism leading to the conversion process whereby most α-helical motifs are replaced by β-sheet secondary structures. Importantly, most point mutations linked to inherited prion diseases are clustered in the C-terminal domain region of PrPC and cause spontaneous conversion to PrPSc. Structural studies with PrP variants promise new clues regarding the proposed conversion mechanism and may help identify "hot spots" in PrPC involved in the pathogenic conversion. These investigations may also shed light on the early structural rearrangements occurring in some PrPC epitopes thought to be involved in modulating prion susceptibility. Here we present a detailed overview of our solution-state NMR studies on human prion protein carrying different pathological point mutations and the implications that such findings may have for the future of prion research. 23314540 Comparison of serum calcitonin and procalcitonin in detecting medullary thyroid carcinoma among patients with thyroid nodules. To prospectively evaluate the role of procalcitonin (PCT) in detecting or excluding medullary thyroid carcinoma (MTC) among patients with thyroid nodules and increased calcitonin (CT) levels. Fourteen of 1236 patients referred for thyroid nodules had increased serum CT >10 pg/mL. A stimulation test with pentagastrin was done and both CT and PCT were measured after stimulation. All patients underwent thyroid ultrasound, fine-needle cytology and, if indicated, surgery with histological and immunohistochemical examination of the surgical specimens. After follow-up, two MTCs were found. These two patients had basal CT >100 pg/mL and detectable (>0.1 ng/mL) PCT, with 100% sensitivity. Pentagastrin stimulated CT achieved values above 100 pg/mL in two MTCs and in other two cases with no MTC outcome (50% PPV and 83% NPV). On the contrary, all patients with no MTC had both basal and stimulated undetectable PCT (100% PPV and 100% NPV). The addition of basal PCT measurement in patients with thyroid nodule(s) and increased CT may significantly improve accuracy of CT measurement without needing a PG stimulation test. 23940282 Egress of CD19+CD5+ cells into peripheral blood following treatment with the BTK inhibitor ibrutinib in mantle cell lymphoma patients. Ibrutinib (PCI-32765) is a highly potent, oral Bruton tyrosine kinase (BTK) inhibitor in clinical development for the treatment of B cell lymphoproliferative diseases. Patients with chronic lymphocytic leukemia (CLL) often show marked, transient increases of circulating CLL cells following ibrutinib treatments, as seen with other inhibitors of the B cell receptor (BCR) pathway. In a Phase I study of ibrutinib, we noted similar effects in patients with mantle cell lymphoma (MCL). We here characterize the patterns and phenotypes of cells mobilized among patients with MCL, and further investigate the mechanism of this effect. Peripheral blood CD19(+)CD5(+) cells from MCL patients were found to have significant reduction in the expression of CXCR4, CD38 and Ki67 after 7 days of treatment. In addition, plasma chemokines such as CCL22, CCL4, and CXCL13 were reduced 40-60% after treatment. Mechanistically, ibrutinib inhibited BCR, and chemokine mediated adhesion and chemotaxis of MCL cell lines, and dose-dependently inhibited BCR, stromal cell and CXCL12/CXCL13 stimulations of pBTK, pPLCγ2, pERK or pAKT. Importantly, ibrutinib inhibited migration of MCL cells beneath stromal cells in co-culture. We propose BTK is essential for the homing of MCL cells into lymphoid tissues, and its inhibition results in an egress of malignant cells into peripheral blood. This study is registered at http://clinicaltrials.gov, identifier: NCT00114738. 23900920 Minimally invasive plate osteosynthesis in type B fibular fractures versus open surgery. In traumatology, the search for better surgical access points has led to the increased use of the minimally invasive plate osteosynthesis (MIPO) technique. There are few studies on the treatment of distal fibular fractures with MIPO. Locking compression plates (LCP) for distal fibular fractures is generally applied after open reduction, but may involve complications to the surgical wound. In this study, we compared two groups of patients receiving either ORIF or MIPO, in order to analyse the advantages and disadvantages of the two techniques. Two homogeneous groups of patients (18 + 18) received LCP for distal fractures of the fibula, type B, according to AO. Group A patients underwent open surgery, whereas Group B patients received plates applied with the MIPO technique. Both groups were examined physically and radiographically 1 and 3 months after the two types of procedure and then 1 year later, with functional assessment according to Olerud and Molander. ROM Group A: 5° reduction in tibiotarsal extension in 8 patients and 5° in supination in 1 patient; Group B: 5° reduction in extension in 7 cases. Mean healing time: 3 months (range 2-4) in Group A and 2.9 (range 2-4) in Group B. Dehiscence of the surgical wound was observed in five Group A patients, but none in Group B. Functional assessment according to Olerud and Molander was 87.4 points in Group A (range 80-100) and 95.6 in Group B (range 82-100). We believe that the MIPO technique for distal fractures of the fibula should be used more often, especially if soft tissue is in a critical condition. Healing times should be reduced in the more complex cases. It is important that the learning curve should be improved, to minimize exposure to radioscopy and possible damage to the superficial fibular nerve. 23933126 Mineralogy affects geoavailability, bioaccessibility and bioavailability of zinc. We correlated mineralogical and particle characteristics of Zn-containing particles with Zn geoavailability, bioaccessibility, and bioavailability following gavage and intranasal (IN) administration in rats. We compared samples of Zn/Pb mine waste and five pulverized pure-phase Zn minerals (<38 Î¼m). Particles were neutron-activated to produce radioactive (65)Zn. We assessed geoavailability using sequential extractions and bioaccessibility using in vitro extraction tests simulating various pH and biological conditions. Zn in vivo bioavailability and in vitro bioaccessibility decreased as follows: mine waste > hydrozincite > hemimorphite > zincite â‰ˆ smithsonite > sphalerite. We found significant correlations among geoavailability, bioaccessibility and bioavailability. In particular, Zn bioavailability post-gavage and post-IN was significantly correlated with bioaccessibility in simulated phagolysosomal fluid and gastric fluid. These data indicate that solid phase speciation influences biological uptake of Zn and that in vitro tests can be used to predict Zn bioavailability in exposure assessment and effective remediation design. 23907553 Growth-suppressive effect of the α-amylase inhibitor of Triticum aestivum on stored-product mites varies by the species and type of diet. A naturally occurring α-amylase inhibitor (α-AI) of Triticum aestivum protects wheat grain from gramnivorous arthropod pests. The α-AI (Type-I) was incorporated into carbohydrate and protein diets to test its inhibitory activity on the stored-product mites Acarus siro, Lepidoglyphus destructor and Tyrophagus putrescentiae (Acari: Astigmata). Growth tests of mites fed the various diets were used to compare the suppressive effects. The final population size of mites attained from an initial population of 50 specimens maintained under controlled conditions (85 % relative humidity and 25 °C) was compared after 21 days of cultivation. The results showed that α-AI in the concentration in the range of 0.01-1 mg g(-1) did not suppress the growth of the tested stored-product mites. α-AI at a concentration of 10 mg g(-1) exerted a growth-suppressive effect that depended on the diet and species of the mites. The growth rate of A. siro was affected by the type of diet and was higher on carbohydrate diet than on the protein diet, the suppressive effect of α-AI was on the both diets. The growth-suppressive effect of α-AI on L. destructor and T. putrescentiae was significant when they were fed the protein diet but not when they were fed the carbohydrate diet. The higher resistance of tested mites to α-AI (proteinaceous) compared to non-proteinaceous acarbose corresponds to a powerful proteotolytic system in the mite gut. The results are discussed in terms of the adaptability of mites to utilize the starch from food sources. 23896556 Updated International Consensus Guidelines on the Management of Cytomegalovirus in Solid-Organ Transplantation. Cytomegalovirus (CMV) continues to be one of the most common infections after solid-organ transplantation, resulting in significant morbidity, graft loss, and adverse outcomes. Management of CMV varies considerably among transplant centers but has been become more standardized by publication of consensus guidelines by the Infectious Diseases Section of The Transplantation Society. An international panel of experts was reconvened in October 2012 to revise and expand evidence and expert opinion-based consensus guidelines on CMV management, including diagnostics, immunology, prevention, treatment, drug resistance, and pediatric issues. The following report summarizes the recommendations. 23676772 Short-term intermittent administration of CXCR4 antagonist AMD3100 facilitates myocardial repair in experimental myocardial infarction. The binding of the stromal cell-derived factor-1α (SDF-1α) to the cysteine (C)-X-C motif chemokine receptor 4 (CXCR4) has emerged as a key signal for stem and progenitor cells trafficking to the circulation from the bone marrow. Our aim was to investigate the role of daily intermittent administration of AMD3100 (a specific reversible CXCR4 receptor antagonist) during the healing process after myocardial infarction (MI). Wistar rats were subjected to MI and AMD3100 was injected intraperitoneally after surgery. SDF-1α mRNA expression was measured by real-time polymerase chain reaction. Histology changes were analyzed with immunofluorescence, Masson's trichrome staining, and wheat germ agglutinin. The number of leukocytes in peripheral blood was measured by complete blood cell count analysis. The activities of matrix metalloproteinase-2/9 (MMP-2/9) were determined by gelatin zymography. The expression level of SDF-1α mRNA in the infarcted tissue was enhanced rapidly (6 h), peaked at 24 h, and then declined to the normal level at 7 days post-MI. AMD3100 further enhanced the increase of SDF-1α in infarct area. Increased leukocytes were observed in AMD3100-treated groups. The mobilization of c-kit(+) stem/progenitor cells and enhanced neovascularization were augmented by AMD3100. Additionally, AMD3100 improved ventricular remodeling, which was revealed by the decrease of infarct size, viable cardiomyocyte cross-sectional area and left ventricle (LV) expansion index, and the increase of LV free wall thickness. The activities of MMP-2/9 were up-regulated by AMD3100. In conclusion, short-term intermittent administration of AMD3100 could accelerate the wound healing process in experimental MI and be a potential therapy for the treatment of MI. 23846331 Porphyrin-based ytterbium complexes targeting anionic phospholipid membranes as selective biomarkers for cancer cell imaging. A porphyrin ytterbium complex (Yb-N) showed strong binding to phosphatidylserine and capability to differentiate cancer cells via targeting the anionic phospholipid membrane. 23866072 Epiphyseal Union of the Cervical Vertebral Centra: Its Relationship to Skeletal Age and Maturation of Thoracic Vertebral Centra. Epiphyseal union stages for cervical vertebral centra (ring epiphyses) were documented for 55 individuals (females and males, ages 14-27 years) from the Terry Collection, using the Albert and Maples method 1, to examine both its relationship to age at death and to thoracic data collected from the same individuals using the same method. Results showed a moderate correlation between cervical ring union and age (r = 0.63, p = 0.000), and a fairly low correlation between cervical and thoracic ring union (r = 0.41, p = 0.002). Paired samples t-tests yielded a statistically significant difference between cervical and thoracic union mean values (p = 0.01). Union progressed earlier in cervical vertebrae and in females. Results indicated fairly substantial variation in both sexes. Findings may serve as a basic guideline for estimating a general age range at death for unknown skeletal remains and to corroborate findings from other skeletal age indicators. 23653139 Carbon nanotubes-based label-free affinity sensors for environmental monitoring. Nanostructures, such as nanowires, nanobelts, nanosprings, and nanotubes, are receiving growing interest as transducer elements of bio/chemical sensors as they provide high sensitivity, multiplexing, small size, and portability. Single-walled carbon nanotubes (SWNTs) are one such class of nanostructure materials that exhibit superior sensing behavior due to its large-surface carbon atoms that are highly responsive to surface adsorption events. Further, their compatibility with modern microfabrication technologies and facile functionalization with molecular recognition elements make them promising candidates for bio/chemical sensors applications. Here, we review recent results on nanosensors based on SWNTs modified with biological receptors such as aptamers, antibodies, and binding proteins, to develop highly sensitive, selective, rapid, and cost-effective label-free chemiresistor/field-effect transistor nanobiosensors for applications in environmental monitoring. 23876302 Assay validation and technology transfer: Problems and solutions. In the industry of fine chemicals, including pharmaceutical and agricultural chemicals, analytical tests are performed by production departments or contract research organizations at some stage in the research and development of products. These external organizations are required to maintain the capabilities to perform analytical tests using methods that are equivalent to or better than those specified by analytical method validation. For this reason, transfer of analytical procedures to an alternative site becomes necessary. In this review, the relationship between transfer of analytical procedures and assay validation is introduced, focusing on analytical procedures that include HPLC. 23953478 Animating platelet production adds physiological context. Animating complex biological processes contextualizes them within their underlying physiology, identifies gaps in our mechanistic understanding, affirms the importance of continued research, and provides a bridge between academic scientists and the general public. Here, two videos illustrate the clinical value of and translate state-of-the-art research in platelet production. 23747404 Molecular cloning, expression and antioxidant characterisation of a typical thioredoxin gene (AccTrx2) in Apis cerana cerana. Thioredoxins (Trxs) are a family of small, highly conserved and ubiquitous proteins that are involved in protecting organisms against toxic reactive oxygen species (ROS). In this study, a typical thioredoxin 2 gene was isolated from Apis cerana cerana, AccTrx2. The full-length cDNA sequence of AccTrx2 was composed of 407bp containing a 318bp open reading frame (ORF) that encodes a predicted protein of 105 amino acids, 11.974kDa and an isoelectric point of 4.45. Expression profile of AccTrx2 as determined by a quantitative real-time PCR (qRT-PCR) analysis was higher in brain than in other tissues, with its highest transcript occurring on the 15day post-emergence adult and upregulated by such abiotic stresses as 4°C, 16°C, 25°C, H2O2, cyhalothrin, acaricide, paraquat, phoxime and mercury (HgCl2) treatments. However, AccTrx2 was slightly repressed when exposed to 42°C treatment. Characterisation of the recombinant protein showed that the purified AccTrx2 had insulin disulfide reductase activity and could protect DNA from ROS damage. These results indicate that AccTrx2 functions as an antioxidant that plays an important role in response to oxidative stress. 23619471 Secreted osteoclastogenic factor of activated T cells (SOFAT), a novel osteoclast activator, in chronic periodontitis. A novel activated human T cell-secreted cytokine, referred as secreted osteoclastogenic factor of activated T cells (SOFAT), that induce osteoclastogenesis in a RANKL-independent manner was recently described. This study evaluated the role of SOFAT in periodontal tissues and periodontitis. Gingival biopsies were harvested from systemically healthy non-periodontitis (n=15) and chronic periodontitis patients (n=15). The mRNA and protein levels of SOFAT were measured by qPCR and by enzyme-linked immunosorbent assay, respectively. Moreover, RAW 264.7 cells were cultured with SOFAT or Receptor activator of nuclear factor-kB ligand (RANKL) and stained for tartrate-resistant acid phosphatase (TRAP). Also, mice received a palatal injection between the first and second upper molar of SOFAT (100 ng/ml) or saline solution (0.9%). The upper jaw was removed, histologically processed and stained with hematoxilin and eosin to observe the presence of osteoclast-like cells. The mRNA and protein levels of SOFAT were significantly higher in the gingival tissue of the periodontitis group when compared to non-periodontitis one (p<0.05). In addition, SOFAT potently induced TRAP-positive multinucleated cell formation by RAW 264.7 cells as well as induced the formation of osteoclast-like cells in the periodontal ligament in mice. The present study demonstrated that SOFAT may play an important role in periodontitis. 23928146 Diffusion Measures Indicate Fight Exposure-Related Damage to Cerebral White Matter in Boxers and Mixed Martial Arts Fighters. BACKGROUND AND PURPOSE:Traumatic brain injury is common in fighting athletes such as boxers, given the frequency of blows to the head. Because DTI is sensitive to microstructural changes in white matter, this technique is often used to investigate white matter integrity in patients with traumatic brain injury. We hypothesized that previous fight exposure would predict DTI abnormalities in fighting athletes after controlling for individual variation.MATERIALS AND METHODS:A total of 74 boxers and 81 mixed martial arts fighters were included in the analysis and scanned by use of DTI. Individual information and data on fight exposures, including number of fights and knockouts, were collected. A multiple hierarchical linear regression model was used in region-of-interest analysis to test the hypothesis that fight-related exposure could predict DTI values separately in boxers and mixed martial arts fighters. Age, weight, and years of education were controlled to ensure that these factors would not account for the hypothesized effects.RESULTS:We found that the number of knockouts among boxers predicted increased longitudinal diffusivity and transversal diffusivity in white matter and subcortical gray matter regions, including corpus callosum, isthmus cingulate, pericalcarine, precuneus, and amygdala, leading to increased mean diffusivity and decreased fractional anisotropy in the corresponding regions. The mixed martial arts fighters had increased transversal diffusivity in the posterior cingulate. The number of fights did not predict any DTI measures in either group.CONCLUSIONS:These findings suggest that the history of fight exposure in a fighter population can be used to predict microstructural brain damage. 23963778 Electrophilic and Reactive Oxygen Species Detoxification Potentials of Chalcone Dimers is Mediated by Redox Transcription Factor Nrf-2. Nuclear erythroid related factor-2 (Nrf2), a redox-transcription factor, plays a critical role in the detoxification of electrophilic and reactive oxygen species that halt various biochemical and molecular processes . This makes it a candidate for regulation by polyphenols. This study investigates the capability of chalcone dimers (lophirones B and C) to induce expressions and activities of cytoprotective enzymes. Chalcone dimers administration to rats not only induced the Nrf2, but also suppressed cytoplasmic Kelch-like ECH-associated protein 1 (Keap1) expressions. In addition, the chalcone dimers significantly (p < 0.05) increased the expressions and activities of nicotinamide adenine dinucleotide and reduced quinone oxidoreductase-1, glutathione-S-transferase, epoxide hydrolase and uridyl glucuronosyl transferase in rat liver. Also, activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase in rat liver increased significantly (p < 0.05). Overall, lophirones B and C increased the expressions and activities of cytoprotective proteins in rat liver possibly through the reduction of cytoplasmic Keap1 expression, leading to the nuclear translocation of Nrf2. 23925820 Can Serum Fetuin-A Be Regarded as an Inflammatory Marker Among Patients with Familial Mediterranean Fever? Familial Mediterranean fever (FMF), the most frequent periodic fever syndrome, is an autosomal recessive inherited disease that predominantly affects eastern Mediterranean populations. Fetuin-A is a well known negative acute-phase protein. Studies of this glycoprotein as a marker of inflammation in FMF are limited. We have investigated the relationship between serum levels of fetuin-A and inflammatory markers in patients with FMF before, during, and after FMF attacks. Sixty-seven patients with FMF were enrolled in this study. Serum fetuin-A, seruloplasmin, fibrinogen, C reactive protein (CRP), white blood cell count (WBC), calcium, and erythrocyte sedimentation rate (ESR) were measured three times: during the attack-free period, 12 h after FMF attacks, and 7 days after FMF attacks. Plasma fetuin-A concentration was measured by use of an enzyme-linked immunoassay (ELISA) kit. Correlations and differentiation between the serum fetuin-A and other inflammatory markers in patients with FMF were investigated by use of the paired-samples T test and the Pearson correlation test (p < 0.01). Serum fetuin-A levels of all FMF patients in the attack period were significantly lower than in the attack-free period (p < 0.001). In contrast, serum seruloplasmin (p < 0.05), fibrinogen (p < 0.001), CRP (p < 0.05), WBC (p < 0.05), and ESR (p < 0.05) were all significantly higher than in the attack-free period. Plasma fetuin-A is significantly and inversely highly correlated with the other inflammatory markers. Fetuin-A might be a novel indicator of disease activity in patients with FMF and could be used as an adjunctive marker for differentiation of FMF attacks. The negative correlation between serum fetuin-A and other inflammatory markers may also be indicative of inflammation-dependent downregulation of fetuin-A expression in FMF patients. 23811376 NO adsorption behaviors of the MnOx catalysts in lean-burn atmospheres. NOx emission control of lean-burn engines is one of the great challenges in the world. Herein, the MnOx model catalysts with the different calcination temperatures were synthesized to investigate their NO adsorbability for lean-burn exhausts. The transformation from (β-)MnO2 to (α-)Mn2O3 following the increased calcination temperatures was evidenced from the viewpoint of the local atomic level. Among these samples, the one calcined at 550°C containing the single α-Mn2O3 phase displayed the best NO adsorbability: NO was mainly adsorbed in the forms of NO/nitrites and NO2/nitrates at the low and high temperatures, respectively; the NO oxidation ability displayed the volcano-shape following the increased operating temperatures, and reached the maximum, i.e. 92.4% of the NO-to-NO2 conversion, at 250°C. Moreover, this sample presented the efficiently reversible NO adsorption/desorption performance in alternative lean-burn/fuel-rich atmospheres, due to the weakly bonded NOx on it. The superficial oxygen species plays a critical role for the NO oxidation over α-Mn2O3. The consumed superficial oxygen could be further compensated by the gaseous and lattice oxygen therein. Our findings show that the α-Mn2O3 material is a promising NOx adsorber for lean-burn exhausts even at low operating temperatures. 23887715 Polyphenolic Composition, Antioxidant and Antibacterial Activities for Two Romanian Subspecies of Achillea distans Waldst. et Kit. ex Willd. The aim of this work was to study the chemical composition, antioxidant and antibacterial properties of Achillea distans Waldst. et Kit. subsp. distans and Achillea distans Waldst. et Kit. subsp. alpina Rochel, from the Rodna Mountains (Romania). The identification and quantification of major phenolic compounds was performed by a HPLC-MS method. The total polyphenolic and flavonoid content was determined spectrophotometrically. The antioxidant activity was evaluated using the DPPH bleaching method, trolox equivalent antioxidant capacity assay (TEAC), hemoglobin ascorbate peroxidase activity inhibition (HAPX) assay, and an Electron Paramagnetic Resonance (EPR) spectroscopy method. A data indicated that A. distans subsp. alpina extract has more antioxidant activity than A. distans subsp. distans extract. Luteolin, apigenin, quercetin, caffeic and chlorogenic acids were present in the two extracts of A. distans, but in different amounts. Three flavonoids were detected only in A. distans subsp. alpina. The polyphenol-richer A. distans subsp. alpina extract showed a higher antioxidant activity than A. distans subsp. distans extract. A. distans subsp. distans extract showed inhibitory activity for Gram-positive bacteria, as evaluated with four species. The quantitative and qualitative differences between the two subspecies of Achillea distans could be used as a potential taxonomic marker in order to distinguish the species. 23859720 Using Glycosaminoglycans/Chemokine Interactions for the Long-Term Delivery of 5P12-RANTES in HIV Prevention. 5P12-RANTES is a recently developed chemokine analog that has shown high level protection from SHIV infection in macaques. However, the feasibility of using 5P12-RANTES as a long term HIV prevention agent has not been explored partially due to the lack of available delivery devices that can easily be tuned to meet release rate needs. Glycosaminoglycans (GAGs) have been known for their affinity for various cytokines and chemokines, including native RANTES. In this work, we investigated used of GAGs in generating a chemokine drug delivery device. Initial studies used surface plasmon resonance analysis to characterize and compare the affinities of different GAGs to 5P12-RANTES. These different GAGs were then incorporated into drug delivery hydrogels to engineer controlled release of the chemokines. In vitro release studies of 5P12-RANTES from the resulting hydrogels were performed and we found that 5P12-RANTES release from these hydrogels can be controlled by the amount and type of GAG incorporated. Gels containing GAGs with stronger affinity to 5P12-RANTES resulted in more sustained, and longer term release than did gels containing GAGs with weaker 5P12-RANTES affinity. Similar trends were observed by varying the amount of GAGs incorporated into the delivery system. 5P12-RANTES released from these hydrogels demonstrated good levels of CCR5 blocking activity even after 30 days of incubation. 23959423 Wip1 Phosphatase Involved in Lipopolysaccharide-Induced Neuroinflammation. Wild type p53-induced phosphatase 1 (Wip1) is a phosphatase which belongs to protein phosphatase type 2C family, which have been predominantly linked to cell growth and to cellular stress signaling. Numerous downstream targets of Wip1 have been identified, and genetic studies confirm that some play a part in tumorigenesis. Recent evidence highlights a new role for Wip1 in the regulation of NF-κB p65, which indicated that it might play a critical role in immune system. However, its regulation role in central nervous system (CNS) remains poorly understood. To elaborate whether Wip1 was involved in CNS injury, we performed a neuroinflammatory model by lipopolysaccharide (LPS) lateral-ventral injection in adult rats. Wip1 expression was strongly upregulated in active astrocytes in inflamed brain cortex. In vitro studies indicated that the upregulation of Wip1 may be involved in the subsequent astrocytic activation following LPS exposure, and knockdown of Wip1 in primary astrocytes by siRNA showed that Wip1 inhibited the synthesis of TNF-α. Collectively, these results suggested that Wip1 may be important in host defense in CNS immune response, which might provide a potent therapeutic target of neuroinflammation. 23637063 Upgraded Silicon Nanowires by Metal-Assisted Etching of Metallurgical Silicon: A New Route to Nanostructured Solar-Grade Silicon. Through metal assisted chemical etching (MaCE), superior purification of dirty Si was observed, from 99.74 to 99.9884% for metallurgical Si and from 99.999772 to 99.999899% for upgraded metallurgical Si. Meanwhile, large area of silicon nanowires (SiNW) was fabricated. The purification effect induced ∼35% increase in photocurrent for SiNW based photoelectrochemical cell. 23493259 Yeast Proteome Variations Reveal Different Adaptive Responses to Grape Must Fermentation. Saccharomyces cerevisiae and S. uvarum are two domesticated species of the Saccharomyces sensu stricto clade that diverged around 100 Ma after whole-genome duplication. Both have retained many duplicated genes associated with glucose fermentation and are characterized by the ability to achieve grape must fermentation. Nevertheless, these two species differ for many other traits, indicating that they underwent different evolutionary histories. To determine how the evolutionary histories of S. cerevisiae and S. uvarum are mirrored on the proteome, we analyzed the genetic variability of the proteomes of domesticated strains of these two species by quantitative mass spectrometry. Overall, 445 proteins were quantified. Massive variations of protein abundances were found, that clearly differentiated the two species. Abundance variations in specific metabolic pathways could be related to phenotypic traits known to discriminate the two species. In addition, proteins encoded by duplicated genes were shown to be differently recruited in each species. Comparing the strain differentiation based on the proteome variability to those based on the phenotypic and genetic variations further revealed that the strains of S. uvarum and some strains of S. cerevisiae displayed similar fermentative performances despite strong proteomic and genomic differences. Altogether, these results indicate that the ability of S. cerevisae and S. uvarum to complete grape must fermentation arose through different evolutionary roads, involving different metabolic pathways and duplicated genes. 23962756 Prediction of outcomes for brainstem cavernous malformation. Brainstem cavernous malformation (CM) poses a challenge to neurosurgeons in terms of operability, postoperative complications and unpredictable outcomes. The present study was conducted to analyze the clinical parameters that might predict the outcomes and to summarize our center experience in treatment of brainstem CM. A total 59 patients with radiological and histologically confirmed brainstem CM diagnosed between 2000 and 2012 were retrospectively reviewed. All but five patients were deemed amenable to surgical resection. Complete resection was attempted in all CM and was achieved in 58/59 patients. Modified Rankin scale (mRS) score dichotomized as mRS 0-2 (favorable outcome) or mRS 3-6 (unfavorable outcome) was employed for neurological status assessment. The association of various clinical parameters to the different brainstem location was evaluated. Predictors of the surgical outcomes were analyzed using the univariate and multivaraite regression statistics. Mean age of 32 female and 27 male patients was 34.3 years. The differences in size of cavernoma, conservative treatment and complications were significantly associated with various location of the CM in the brainstem. Clinical parameters including age at presentation (p=0.029, OR=0.061, CI=0.009-0.414), favorable preoperative mRS (p=0.004, OR=0.058, CI=0.009-0.343), pontine location of CM (p=0.018, OR=0.017, CI=0.001-0.495), and early surgical treatment (p=0.05, OR=0.087, CI=0.07-1.03) were independent predictors of favorable surgical outcomes. Mean long-term follow up of 42.9 months was available in 31/59 (52.5%). The mean size of CM was 22.5mm; small size (<10mm) at presentation was associated with favorable outcomes at long-term follow-up (univariate analysis, p=0.041, adjusted R(2)=0.471). Preoperative mRS (p=0.039) and location of the CM (p=0.034) in the brainstem were predictors of good surgical outcomes at long term follow-up. Favorable surgical outcomes can be predicted in brainstem CM patients with early age at presentation, pontine location of the cavernoma, favorable preoperative mRS and those undergoing early surgery. The outcomes at long-term follow-up were associated with location of the CM in the brainstem, size of the CM and the preoperative mRS. 23949641 Angiotensin Converting Enzyme-Inhibitor Reduces Colitis Severity in an IL-10 Knockout Model. We previously demonstrated angiotensin converting enzymes (ACE) over-expression in a dextran-sodium sulfate colitis model; ACE inhibitor (ACE-I) treatment reduced colitis severity in this model. However, ACE-I has not been tested in more immunologically relevant colitis models. We hypothesized that ACE-I would decrease disease severity in an IL-10 knockout (-/-) colitis model. Colitis was induced by giving 10-week old IL-10-/- mice piroxicam (P.O.) for 14 days. The ACE-I enalaprilat was given transanally at a dose of 6.25 mg/kg for 21 days. Prednisolone (PSL) with or without enalaprilat were used as therapeutic, comparative groups. All groups were compared to a placebo treated group. Outcome measures were clinical course, histology, abundance of pro-inflammatory cytokines/chemokines, and epithelial barrier function. Enalaprilat exhibited better survival (91 %) versus other treatment groups (PSL: 85.7 %, PSL + ACE-I: 71.4 %, placebo: 66.6 %). The ACE-I and PSL + ACE-I groups showed significantly better histological scores versus placebo mice. ACE-I and the PSL groups significantly reduced several pro-inflammatory cytokines versus placebo mice. FITC-dextran permeability was reduced in the ACE-I and PSL + ACE-I groups. Blood pressure was not affected in ACE-I treated mice compared to placebo mice. ACE-I was effective in reducing severity of colitis in an IL-10-/- model. The addition of prednisolone minimally augmented this effect. The findings suggest that appropriately dosed ACE-I with or without steroids may be a new therapeutic agent for colitis. 23766377 Involvement of advanced glycation end product-induced asymmetric dimethylarginine generation in endothelial dysfunction. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, plays a role in endothelial dysfunction, an initial step of atherosclerosis. Advanced glycation end products (AGEs) also contribute to accelerated atherosclerosis. However, a pathophysiological crosstalk between ADMA and AGEs remains unclear. In this study, we investigated the relationship between ADMA and AGE level in patients with end-stage renal disease (ESRD) due to diabetic nephropathy. We also examined whether and how AGEs increased ADMA generation by cultured endothelial cells (ECs). Plasma ADMA levels were positively associated with serum AGE level and were inversely correlated with endothelial function determined by flow-mediated vasodilatation. AGEs dose dependently increased reactive oxygen species (ROS) generation in ECs, which was blocked by antisense DNA raised against receptor for AGEs (RAGE). Furthermore, AGEs decreased messenger RNA (mRNA) level of dimethylarginine dimethylaminohydrolase (DDAH)-II, an enzyme for ADMA degradation, reduced its total enzymatic activity and resultantly increased ADMA, all of which were completely blocked by an antioxidant, N-acetylcysteine. These results suggest that the AGE-RAGE-mediated ROS generation could be involved in endothelial dysfunction in diabetic ESRD patients partly by increasing the ADMA generation via suppression of DDAH activity in ECs. 23969506 Concordance Between Current Job and Usual Job in Occupational and Industry Groupings: Assessment of the 2010 National Health Interview Survey. To determine whether current job is a reasonable surrogate for usual job. Data from the 2010 National Health Interview Survey were utilized to determine concordance between current and usual jobs for workers employed within the past year. Concordance was quantitated by kappa values for both simple and detailed industry and occupational groups. Good agreement is considered to be present when kappa values exceed 60. Overall kappa values ± standard errors were 74.5 ± 0.5 for simple industry, 72.4 ± 0.5 for detailed industry, 76.3 ± 0.4 for simple occupation, 73.7 ± 0.5 for detailed occupation, and 80.4 ± 0.6 for very broad occupational class. Sixty-five of 73 detailed industry groups and 78 of 81 detailed occupation groups evaluated had good agreement between current and usual jobs. Current job can often serve as a reliable surrogate for usual job in epidemiologic studies. 23615085 The indusium griseum: anatomic study with potential application to callosotomy. Although the indusium griseum (IG) is often seen by the neurosurgeon, almost nothing exists in the literature regarding its anatomic structure. Some have postulated that this structure is a remnant of the hippocampus, and some have found memory deficits in patients after callosotomy. To further investigate the anatomy of the IG in humans through gross and histological analysis. The IG from 10 adult cadaveric brains underwent microdissection and immunohistochemical analysis. Grossly, the IG was on average 2 cm in width over the body and genu of the corpus callosum (CC) and traveled in intimate contact anteriorly over the lamina terminalis, and posteriorly it was adherent to the splenium of the CC. Histologically, the IG is a thin layer of hypocellular glial tissue interposed between the pia and the CC. Glial cells composed the cellular constituents of the IG, and compared with the underlying CC, the IG was hypomyelinated. The fibers/axons of the IG travel in a perpendicular plane compared with those of the CC, and the IG varied in thickness from one area to the other and was occasionally discontinuous. The IG is a glial membrane with no neuronal content or obvious connections to the hippocampus. Based on this study, transection of this membrane with callosotomy should not be the reason for postoperative memory loss seen in some of these patients. Future studies aimed at elucidating the function of the IG in humans are now warranted. CC, corpus callosumIG, indusium griseum. 23411207 Anti-inflammatory effects of phenolic crude extracts from five fractions of Corchorus Olitorius L. Corchorus olitorius L. is grown in Taiwan during summer. Tender leaves are crushed and washed by running water before eating. Five fractions including crude phenolic extracts (using 80 per cent aqueous acetone) of whole plant, leaf, stem, washed leaf (WL) and dried water washing material (WW) were used in this study. Linoleic acid autoxidation inhibitions on all fractions were higher than that on α-tocopherol. Except for WL and WW, other fractions also showed DPPH radical scavenging efficiency. The effect of all fractions on the regulation of inflammatory responses in lipopolysaccharide (LPS)-stimulated J774A.1 macrophage cells was investigated. All fractions diminished LPS-induced protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2). Nitric oxide (NO) and prostaglandin E2 (PGE(2)), downstream products, were also suppressed in dose-dependent manners, except for WL and WW. Oxidative modification and loss of leaf phenolics after kneading and washing greatly affected DPPH radical scavenging and inflammatory responses. 23743790 The role of family planning in elimination of new pediatric HIV infection. We reviewed recent literature on the role of family planning in eliminating new pediatric HIV infections. Global commitments to eliminate new pediatric HIV infections recognize that preventing unintended pregnancies among women with HIV is essential to achieving this goal. However, substantial shortcomings exist in translating this policy support into widespread practice. Programs to prevent mother-to-child transmission of HIV continue to be implemented and evaluated as a narrow set of interventions that typically begins in antenatal care, after a woman is already pregnant. In addition, data suggest that women living with HIV experience high rates of unmet need for family planning and unintended pregnancies. Evidence is growing that integrating family planning and HIV services is an effective strategy for increasing access to contraception among women with HIV who do not wish to become pregnant. A number of health system obstacles must be resolved to achieve effective, sustained delivery of integrated services at scale. Prevention of unintended pregnancies among women with HIV must be elevated as a programmatic priority. By strengthening family planning programs for all women, and better integrating family planning and HIV services, progress toward ending new pediatric HIV infections will be accelerated. 23874862 Pixels as ROIs (PAR): A Less-Biased and Statistically Powerful Approach for Gleaning Functional Information from Image Stacks. Especially in the last decade or so, there have been dramatic advances in fluorescence-based imaging methods designed to measure a multitude of functions in living cells. Despite this, many of the methods used to analyze the resulting images are limited. Perhaps the most common mode of analysis is the choice of regions of interest (ROIs), followed by quantification of the signal contained therein in comparison with another "control" ROI. While this method has several advantages, such as flexibility and capitalization on the power of human visual recognition capabilities, it has the drawbacks of potential subjectivity and lack of precisely defined criteria for ROI selection. This can lead to analyses which are less precise or accurate than the data might allow for, and generally a regrettable loss of information. Herein, we explore the possibility of abandoning the use of conventional ROIs, and instead propose treating individual pixels as ROIs, such that all information can be extracted systematically with the various statistical cutoffs we discuss. As a test case for this approach, we monitored intracellular pH in cells transfected with the chloride/bicarbonate transporter slc26a3 using the ratiometric dye SNARF-5F under various conditions. We performed a parallel analysis using two different levels of stringency in conventional ROI analysis as well as the pixels-as-ROIs (PAR) approach, and found that pH differences between control and transfected cells were accentuated by ~50-100% by using the PAR approach. We therefore consider this approach worthy of adoption, especially in cases in which higher accuracy and precision are required. 23851579 Predicting Life Expectancy for Community-dwelling Older Adults From Medicare Claims Data. Estimates of life expectancy are useful in assessing whether different prevention strategies are appropriate in different populations. We developed sex-specific Cox proportional-hazard models that use Medicare claims data to predict life expectancy and risk of death at up to 10 years for older adults. We identified a cohort of Medicare beneficiaries 66-90 years of age from the 5% Medicare claims data in 2000 (n = 1,137,311) and tracked each subject's vital status until December 31, 2009. Subjects were split randomly into training and validation samples. Models were developed from the training sample and validated by comparison of predicted to actual survival in the validation sample. The C statistics for the models including predictors of age and Elixhauser comorbidities were 0.76-0.79 for men and women for prediction of death at the 1-, 5-, 7-, and 10-year follow-up periods. More than 80% of subjects with <25% risk of death at 5, 7, and 10 years survived longer than the chosen cutoff years. More than 80% of subjects with ≥75% risk of death at 5, 7, and 10 years died by those cutoff years. The models overestimated the risk of death at 1 year for the high-risk groups. Sex-specific models that use age and Elixhauser comorbidities can accurately predict patient life expectancy and risk of death at 5-10 years. 23867391 Downregulation of EIF4A2 in Non-small-cell Lung Cancer Associates with Poor Prognosis. EIF4A2, which belongs to the eukaryotic initiation factor 4A family, is a highly conserved gene for one of the protein-synthesis initiation factors involved in the binding of messenger RNA to the ribosome. The role of EIF4A2 in some cancers, eg, breast cancer and melanoma, has been studied. However, the clinical significance and biologic role of EIF4A2 in lung cancer remains unknown. A total of 170 patients with non-small-cell lung cancer who were undergoing surgical resection were studied. We applied the tissue microarray by using immunohistochemistry to study the expression of EIF4A2 in patients with non-small-cell lung cancer (NSCLC). We found that the expression rate of EIF4A2 in NSCLC was 87.6%. The expression of EIF4A2 was significantly correlated with the histopathologic classification (P = .049) and tumor grade (P < .019). Moreover, NSCLC patients with low EIF4A2 expression survived shorter than those with high EIF4A2 expression, as indicated by overall survival (P = .023) and disease-free survival (P = .011) assessed by the Kaplan-Meier method. In addition, multivariate analysis suggested EIF4A2 as an independent predictor of disease-free survival (hazard ratio 0.543 [95% CI, 0.329-0.897]; P = .017). Collectively, our study demonstrated that EIF4A2 was remarkably involvement in the development of NSCLC and could be served as a potential prognostic marker for patients with this deadly disease. 23368901 Influence of chain length and double bond on the aqueous behavior of choline carboxylate soaps. In preceding studies, we demonstrated that choline carboxylates ChC(m) with alkyl chain lengths of m = 12 - 18 are highly water-soluble (for m = 12, soluble up to 93 wt % soap and 0 °C). In addition, choline soaps are featured by an extraordinary lyotropic phase behavior. With decreasing water concentration, the following phases were found: micellar phase (L(1)), discontinuous cubic phase (I(1)' and I(1)"), hexagonal phase (H(1)), bicontinuous cubic phase (V(1)), and lamellar phase (L(α)). The present work is also focused on the lyotropic phase behavior of choline soaps but with shorter alkyl chains or different alkyl chain properties. We have investigated the aqueous phase behavior of choline soaps with C(8) and C(10) chain-lengths (choline octanoate and choline decanoate) and with a C(18) chain-length with a cis-double bond (choline oleate). We found that choline decanoate follows the lyotropic phase behavior of the longer-chain homologues mentioned above. Choline octanoate in water shows no discontinuous cubic phases, but an extended, isotropic micellar solution phase. In addition, choline octanoate is at the limit between a surfactant and a hydrotrope. The double bond in choline oleate leads also to a better solubility in water and a decrease of the solubilization temperature. It also influences the Gaussian curvature of the aggregates which results in a loss of discontinuous cubic phases in the binary phase diagram. The different lyotropic mesophases were identified by the penetration scan technique with polarizing light microscope and visual observations. To clarify the structural behavior small (SAXS) and wide (WAXS) angle X-ray scattering were performed. To further characterize the extended, isotropic micellar solution phase in the binary phase diagram of choline octanoate viscosity and conductivity measurements were also carried out. 23500475 A deep-blue OLED-based biochip for protein microarray fluorescence detection. Integrated biochips exploit a multi-disciplinary approach to produce portable point-of-care medical diagnostic systems that uncouple diagnosis from centralized laboratories. These portable devices are cost effective and have several advantages including broader accessibility to health care worldwide. Fluorescence detection of a disease-specific probe excited by an optical source is one of the most diffused methods for quantitative analysis on biochips. Here we designed and characterized a miniaturized biochip based on a novel deep-blue organic light-emitting diode. The molecular design of the diode was optimized to excite a fluorophore-conjugated antibody and tested on a protein microarray configuration with good sensitivity and specificity. These findings will be instrumental for the development of next generation point-of-care biochips. 23786890 Alpha1-antitrypsin deficiency - Diagnostic testing and disease awareness in Germany and Italy. Alpha1-antitrypsin (AAT) deficiency, although largely under-diagnosed, is the underlying cause of approximately 1% of COPD cases. Lack of awareness leads to long delays in diagnostic testing. Subsequently, lifestyle and treatment choices with potentially positive effects on prognosis may be postponed. Data on the testing and diagnostic practices for AAT deficiency were derived from the University of Pavia, Italy, and the University of Marburg, Germany. In addition, a survey of physicians was undertaken to explore their awareness and attitudes toward AAT deficiency. In Pavia and Marburg, 125 and 729 patients, respectively, were identified with severe AAT deficiency between July 2006 and June 2011. The median time interval between the onset of symptoms and diagnosis was 6 years (interquartile range [IQR], 11; range, 0-40) and 7 years (IQR, 13; range, 0-73), respectively. Augmentation therapy was initiated almost immediately in Germany while treatment was delayed by 3 months in Italy (IQR, 5.25; range, 1-118). Survey data (Italy, n = 181; Germany, n = 180) revealed that pulmonologists had greater knowledge of AAT deficiency than internists and general practitioners, however, overall, only 18-25% of physicians tested all COPD patients. One-third of the respondents stated that they "sometimes" offered augmentation therapy to patients diagnosed with AAT deficiency. Major obstacles to AAT deficiency testing are physicians' attitudes and lack of understanding of the condition. A greater adherence to the guidelines that recommend diagnostic testing of all COPD patients, coupled with simpler testing protocols, may decrease delays and positively impact patient outcomes. 23819978 Characteristics of free endoglucanase and glycosidases multienzyme complex from Fusarium verticillioides. A novel multienzyme complex, E1C, and a free endoglucanase, E2 (GH5), from Fusarium verticillioides were purified. The E1C contained two endoglucanases (GH6 and GH10), one cellobiohydrolase (GH7) and one xylanase (GH10). Maximum activity was observed at 80°C for both enzymes and they were thermostable at 50 and 60°C. The activation energies for E1C and E2 were 21.3 and 27.5kJ/mol, respectively. The KM for E1C was 10.25g/L while for E2 was 6.58g/L. Both E1C and E2 were activated by Mn(2+) and CoCl2 while they were inhibited by SDS, CuSO4, FeCl3, AgNO4, ZnSO4 and HgCl2. E1C and E2 presented endo-β-1,3-1,4-glucanase activity. E1C presented crescent activity towards cellopentaose, cellotetraose and cellotriose. E2 hydrolyzed the substrates cellopentaose, cellotetraose and cellotriose with the same efficiency. E1C showed a higher stability and a better hydrolysis performance than E2, suggesting advantages resulting from the physical interaction between proteins. 23956231 Choosing wisely in adult hospital medicine: Five opportunities for improved healthcare value. In an effort to lead physicians in addressing the problem of overuse of medical tests and treatments, the American Board of Internal Medicine Foundation developed the Choosing Wisely campaign. The Society of Hospital Medicine (SHM) joined the initiative to highlight the need to critically appraise resource utilization in hospitals. The SHM employed a staged methodology to develop the adult Choosing Wisely list. This included surveys of the organization's leaders and general membership, a review of the literature, and Delphi panel voting. The 5 recommendations that were subsequently approved by the SHM Board are: (1) Do not place, or leave in place, urinary catheters for incontinence or convenience or monitoring of output for non-critically ill patients (acceptable indications: critical illness, obstruction, hospice, perioperatively for <2 days for urologic procedures; use weights instead to monitor diuresis). (2) Do not prescribe medications for stress ulcer prophylaxis to medical inpatients unless at high risk for gastrointestinal complications. (3) Avoid transfusions of red blood cells for arbitrary hemoglobin or hematocrit thresholds and in the absence of symptoms or active coronary disease, heart failure, or stroke. (4) Do not order continuous telemetry monitoring outside of the intensive care unit without using a protocol that governs continuation. (5) Do not perform repetitive complete blood count and chemistry testing in the face of clinical and lab stability. Hospitalists have many opportunities to impact overutilization of care. The adult hospital medicine Choosing Wisely recommendations offer an explicit starting point for eliminating waste in the hospital. Journal of Hospital Medicine 2013. © 2013 Society of Hospital Medicine. 23418368 The Prevalence of Meeting A1C, Blood Pressure, and LDL Goals Among People With Diabetes, 1988-2010. OBJECTIVETo determine the prevalence of people with diabetes who meet hemoglobin A(1c) (A1C), blood pressure (BP), and LDL cholesterol (ABC) recommendations, and their current statin use, factors associated with goal achievement, and changes in the proportion achieving goals between 1988 and 2010.RESEARCH AND DESIGN METHODSData were cross-sectional from the National Health and Nutrition Examination Surveys (NHANES) from 1988-1994, 1999-2002, 2003-2006, and 2007-2010. Participants were 4,926 adults aged ≥20 years who self-reported a previous diagnosis of diabetes and completed the household interview and physical examination (n = 1,558 for valid LDL levels). Main outcome measures were A1C, BP, and LDL cholesterol, in accordance with the American Diabetes Association recommendations, and current use of statins.RESULTSIn 2007-2010, 52.5% of people with diabetes achieved A1C <7.0% (<53 mmol/mol), 51.1% achieved BP <130/80 mmHg, 56.2% achieved LDL <100 mg/dL, and 18.8% achieved all three ABCs. These levels of control were significant improvements from 1988 to 1994 (all P < 0.05). Statin use significantly increased between 1988-1994 (4.2%) and 2007-2010 (51.4%, P < 0.01). Compared with non-Hispanic whites, Mexican Americans were less likely to meet A1C and LDL goals (P < 0.03), and non-Hispanic blacks were less likely to meet BP and LDL goals (P < 0.02). Compared with non-Hispanic blacks, Mexican Americans were less likely to meet A1C goals (P < 0.01). Younger individuals were less likely to meet A1C and LDL goals.CONCLUSIONSDespite significant improvement during the past decade, achieving the ABC goals remains suboptimal among adults with diabetes, particularly in some minority groups. Substantial opportunity exists to further improve diabetes control and, thus, to reduce diabetes-related morbidity and mortality. 22976768 Molecular characterization of 355 mucopolysaccharidosis patients reveals 104 novel mutations. Mucopolysaccharidosis (MPS) disorders are heterogeneous and caused by deficient lysosomal degradation of glycosaminoglycans, resulting in distinct but sometimes overlapping phenotypes. Molecular analysis was performed for a total of 355 MPS patients with MPSI (n = 15), MPSII (n = 218), MPSIIIA (n = 86), MPSIIIB (n = 20), MPSIVA (n = 6) or MPSVI (n = 10). This analysis revealed 104 previously unreported mutations: seven in IDUA (MPSI), 61 in IDS (MPSII), 19 in SGSH (MPSIIIA), 11 in NAGLU (MPSIIIB), two in GALNS (MPSIVA) and four in ARSB (MPSVI). The intergenic comparison of the mutation data for these disorders has revealed interesting differences. Whereas IDUA, IDS, NAGLU and ARSB demonstrate similar levels of mutation heterogeneity (0.6-0.675 different mutations per total alleles), SGSH and GALNS have lower levels of mutation heterogeneity (0.282 and 0.455, respectively), due to more recurrent mutations. The type of mutation also varies significantly by gene. SGSH, GALNS and ARSB mutations are usually missense (76.5 %, 81.8 % and 85 %), while IDUA has many more nonsense mutations (56 %) than the other genes (≤20%). The mutation spectrum is most diverse for IDS, including intergenic inversions and multi-exon deletions. By testing 102 mothers of MPSII patients, we determined that 22.5 % of IDS mutations are de novo. We report the allele frequency of common mutations for each gene in our patient cohort and the exonic distribution of coding sequence alterations in the IDS, SGSH and NAGLU genes, which reveals several potential "hot-spots". This further molecular characterization of these MPS disorders is expected to assist in the diagnosis and counseling of future patients. 23767773 The relationship between statins and depression: a review of the literature. Introduction: Statins have been widely used in clinical practice; however, the association between statin use and depression is complex as research findings have been mixed. We know that cholesterol plays an important role in the serotonin system, so statins used to lower cholesterol may lead to the occurrence of depression. Areas covered: This article reviews i) cholesterol function in the brain, ii) how low cholesterol can cause depression, iii) a brief introduction of the serotonin system and how low cholesterol can disturb it, iv) neurosteroids and how they may lead to depression, and v) some direct evidence that statins can cause depression as well as contradicting evidence. Preparation of this article included an extensive literature search of statins and depression using PubMed from 1972 to 2012. Expert opinion: This article shows that statins could lead to depression by lowering cholesterol and that we should draw attention to this in clinical application, especially for patients complicated with depressive symptoms or low serum cholesterol levels. 23810545 Modelling CEC variations versus structural iron reduction levels in dioctahedral smectites. Existing approaches, new data and model refinements. A model was developed to describe how the 2:1 layer excess negative charge induced by the reduction of Fe(III) to Fe(II) by sodium dithionite buffered with citrate-bicarbonate is balanced and applied to nontronites. This model is based on new experimental data and extends structural interpretation introduced by a former model [36-38]. The 2:1 layer negative charge increase due to Fe(III) to Fe(II) reduction is balanced by an excess adsorption of cations in the clay interlayers and a specific sorption of H(+) from solution. Prevalence of one compensating mechanism over the other is related to the growing lattice distortion induced by structural Fe(III) reduction. At low reduction levels, cation adsorption dominates and some of the incorporated protons react with structural OH groups, leading to a dehydroxylation of the structure. Starting from a moderate reduction level, other structural changes occur, leading to a reorganisation of the octahedral and tetrahedral lattice: migration or release of cations, intense dehydroxylation and bonding of protons to undersaturated oxygen atoms. Experimental data highlight some particular properties of ferruginous smectites regarding chemical reduction. Contrary to previous assumptions, the negative layer charge of nontronites does not only increase towards a plateau value upon reduction. A peak is observed in the reduction domain. After this peak, the negative layer charge decreases upon extended reduction (>30%). The decrease is so dramatic that the layer charge of highly reduced nontronites can fall below that of its fully oxidised counterpart. Furthermore, the presence of a large amount of tetrahedral Fe seems to promote intense clay structural changes and Fe reducibility. Our newly acquired data clearly show that models currently available in the literature cannot be applied to the whole reduction range of clay structural Fe. Moreover, changes in the model normalising procedure clearly demonstrate that the investigated low tetrahedral bearing nontronites (SWa-1, GAN and NAu-1) all exhibit the same behaviour at low reduction levels. Consequently, we restricted our model to the case of moderate reduction (<30%) in low tetrahedral Fe-bearing nontronites. Our adapted model provides the relative amounts of Na(+) (p) and H(+) (ni) cations incorporated in the structure as a function of the amount of Fe reduction. Two equations enable the investigated systems to be described: p=m/(1+Kr⋅ω⋅mrel) and ni=Kr⋅ω⋅m⋅mrel/(1+Kr⋅ω⋅mrel); where m is the Fe(II) content, mrel, the reduction level (m/mtot), ω, the cation exchange capacity (CEC, and Kr, an empirical constant specific to the system. 23916800 Characterization of the phytochelatin synthase from the human parasitic nematode Ancylostoma ceylanicum. Hookworm disease is a debilitating worm infection that affects hundreds of millions of people. Despite the existence of anthelmintic drugs, reports have testified of a decrease in efficacy of these drugs. Therefore, it is imperative to find new drugs and drug targets for hookworm disease treatment. In this study we identify the gene encoding the phytochelatin synthase in the human hookworm, Ancylostoma ceylanicum (AcePCS). Phytochelatin synthase catalyzes the production of metal chelating peptides, the phytochelatins, from glutathione (GSH). In plants, algae, and fungi phytochelatin production is important for metal tolerance and detoxification. Phytochelatin synthase proteins also function in the elimination of xenobiotics by processing GSH S-conjugates. We found that in vitro AcePCS could both synthesize phytochelatins and hydrolyze a GSH S-conjugate. Interestingly, the enzyme works through a thiol-dependent and, notably, metal-independent mechanism for both transpeptidase (phytochelatin synthesis) and peptidase (hydrolysis of GSH S-conjugates) activities. AcePCS mRNAs are expressed in vivo throughout the life cycle of A. ceylanicum. Mature adult male hookworms isolated from the small intestines of their hosts displayed significantly enhanced expression of AcePCS with transcript levels 5-fold greater than other developmental forms. Although the role of AcePCS in A. ceylanicum biology has yet to be fully investigated the results reported here provide encouraging evidence of the potential that this enzyme holds as a target for new chemotherapeutic intervention. 23161531 Relationship of land use and elevated ionic strength in Appalachian watersheds. Coal mining activities have been implicated as sources that increase stream specific conductance in Central Appalachia. The present study characterized potential sources of elevated ionic strength for small subwatersheds within the Coal, Upper Kanawha, Gauley, and New Rivers in West Virginia. From a large monitoring data set developed by the West Virginia Department of Environmental Protection, 162 < 20-km(2)-watersheds were identified that had detailed land cover information in southwestern West Virginia with at least one water chemistry sample. Scatter plots of specific conductance were generated for nine land cover classifications: open water, agriculture, forest, residential, barren, total mining, valley fill, abandoned mine lands, and mining excluding valley fill and abandoned mine lands. Conductivity was negatively correlated with the percentage of forest area and positively associated with other land uses. In a multiple regression, the percentage of area in valley fill was the strongest contributor to increased ionic strength, followed by percentage of area in urban (residential/buildings) land use and other mining land use. Based on the 10th quantile regression, 300 µS/cm was exceeded at 3.3% of area in valley fill. In most catchments, HCO 3(-) and SO 4(2-) concentrations were greater than Cl(-) concentration. These findings confirm coal mining activities as the primary source of high conductivity waters. Such activities might be redressed with the goal of protecting sources of dilute freshwater in the region. 23223448 Loss of LARGE2 disrupts functional glycosylation of α-dystroglycan in prostate cancer. Dystroglycan (DG) is a cell surface receptor for extracellular matrix proteins and is involved in cell polarity, matrix organization, and mechanical stability of tissues. Previous studies documented loss of DG protein expression and glycosylation in a variety of cancer types, but the underlying mechanisms and the functional consequences with respect to cancer progression remain unclear. Here, we show that the level of expression of the βDG subunit as well as the glycosylation status of the αDG subunit inversely correlate with the Gleason scores of prostate cancers; furthermore, we show that the functional glycosylation of αDG is substantially reduced in prostate cancer metastases. Additionally, we demonstrate that LARGE2 (GYLTL1B), a gene not previously implicated in cancer, regulates functional αDG glycosylation in prostate cancer cell lines; knockdown of LARGE2 resulted in hypoglycosylation of αDG and loss of its ability to bind laminin-111 while overexpression restored ligand binding and diminished growth and migration of an aggressive prostate cancer cell line. Finally, our analysis of LARGE2 expression in human cancer specimens reveals that LARGE2 is significantly down-regulated in the context of prostate cancer, and that its reduction correlates with disease progression. Our results describe a novel molecular mechanism to account for the commonly observed hypoglycosylation of αDG in prostate cancer. 23922643 Correction: Population Differentiation of Southern Indian Male Lineages Correlates with Agricultural Expansions Predating the Caste System. [This corrects the article on p. e50269 in vol. 7.]. 23340199 Relationship of cellular topoisomerase IIα inhibition to cytotoxicity and published genotoxicity of fluoroquinolone antibiotics in V79 cells. Fluoroquinolone (FQ) antibiotics are bacteriocidal through inhibition of the bacterial gyrase and at sufficient concentrations in vitro, they can inhibit the homologous eukaryotic topoisomerase (TOPO) II enzyme. FQ exert a variety of genotoxic effects in mammalian systems through mechanisms not yet established, but which are postulated to involve inhibition of TOPO II enzymes. To assess the relationship of inhibition of cell nuclear TOPO II to cytotoxicity and reported genotoxicity, two FQ, clinafloxacin (CLFX) and lomefloxacin (LOFX), having available genotoxicity data showing substantial differences with CLFX being more potent than LOFX, were selected for study. The relative inhibitory activities of these FQ on nuclear TOPO IIα in cultured Chinese hamster lung fibroblasts (V79 cells) over dose ranges and at equimolar concentrations were assessed by measuring nuclear stabilized cleavage complexes of TOPO IIα-DNA. Cytotoxicity was measured by relative cell counts. Both FQ inhibited V79 cell nuclear TOPO IIα. The lowest-observed-adverse-effect levels for TOPO IIα inhibition were 55μM for CLFX, and 516μM for LOFX. The no-observed-adverse-effect-levels were 41μM for CLFX, and 258μM for LOFX. At equimolar concentrations (175μM), CLFX was more potent than LOFX. Likewise, CLFX was more cytotoxic than LOFX. Thus, the two FQ, inhibited TOPO IIα in intact V79 cells, differed in their potencies and exhibited no-observed-adverse-effect levels. These findings are in concordance with published genotoxicity data and observed cytotoxicity. 23851293 p-Cresyl sulfate induces osteoblast dysfunction through activating JNK and p38 MAPK pathways. Recent data suggest that several uremic toxins may contribute to the development of bone abnormalities in chronic kidney disease. p-Cresyl sulfate (PCS), the sulfate conjugate of p-cresol, is a protein-bound uremic toxin associated with the progression of chronic kidney disease, cardiovascular risk, and mortality. However, the effects of PCS on bone metabolism remain unclear. In the present study, we evaluated the toxic effects of PCS on primary mouse osteoblasts, compared with an extensively studied uremic toxin indoxyl sulfate (IS). Pre-treatment of osteoblasts with PCS at 0.125mM and above significantly decreased parathyroid hormone (PTH)-induced cAMP production in a dose-dependent manner. PCS also induced a significant increase in intracellular production of reactive oxygen species (ROS) at 0.25mM and above, but not at lower concentrations. PCS at 0.125mM (a concentration that did not induce significant ROS increase) decreased cell viability by augmenting DNA fragmentation and reducing cell proliferation. Inhibition of JNK and p38 mitogen-activated protein kinase (MAPK) abolished the PCS-induced increase in DNA fragmentation and decrease in cAMP production in osteoblastic cells. Compared with PCS, IS induced ROS production at 0.05mM but did not reduce cAMP production from 0.05 to 0.5mM. IS induced decrease in cell viability and increase in DNA fragmentation at 0.5mM only. These results suggest that PCS damages osteoblastic cells through not only increasing ROS production but also activating JNK/p38 MAPKs, which is different from the mechanism of injury by IS. These damages of osteoblasts induced by PCS may play a critical role in impairing bone metabolism in patients with chronic kidney disease in whom PCS accumulates. 23656959 Arthroplasty versus fusion in single-level cervical degenerative disc disease: a cochrane review. A systematic review of randomized controlled trials (RCTs). To assess the effects of arthroplasty versus fusion in the treatment of radiculopathy or myelopathy, or both, due to single-level cervical degenerative disc disease. There is ongoing debate about whether fusion or arthroplasty is superior in the treatment of single-level cervical degenerative disc disease. Mainly because the intended advantage of arthroplasty compared with fusion, prevention of symptoms due to adjacent segment degeneration in the long term, is not confirmed yet. Until sufficient long-term results become available, it is important to know whether results of 1 of the 2 treatments are superior to the other in the first 1 to 2 years. We searched electronic databases for randomized controlled trials. We included randomized controlled trials that directly compared any type of cervical fusion with any type of cervical arthroplasty, with at least 1 year of follow-up. Study selection was performed independently by 3 review authors, and "risk of bias" assessment and data extraction were independently performed by 2 review authors. In case of missing data, we contacted the study authors or the study sponsor. We assessed the quality of evidence. Nine studies (2400 participants) were included in this review; 5 of these studies had a low risk of bias. Results for the arthroplasty group were better than the fusion group for all primary comparisons, often statistically significant. For none of the primary outcomes was a clinically relevant difference in effect size shown. Quality of the evidence was low to moderate. There is low to moderate quality evidence that results are consistently in favor of arthroplasty, often statistically significant. However, differences in effect size were invariably small and not clinically relevant for all primary outcomes.Level of Evidence: 1. 23575224 Heterozygous LmnadelK32 mice develop dilated cardiomyopathy through a combined pathomechanism of haploinsufficiency and peptide toxicity. Dilated cardiomyopathy (DCM) associates left ventricular (LV) dilatation and systolic dysfunction and is a major cause of heart failure and cardiac transplantation. LMNA gene encodes lamins A/C, proteins of the nuclear envelope. LMNA mutations cause DCM with conduction and/or rhythm defects. The pathomechanisms linking mutations to DCM remain to be elucidated. We investigated the phenotype and associated pathomechanisms of heterozygous Lmna(ΔK32/+) (Het) knock-in mice, which carry a human mutation. Het mice developed a cardiac-specific phenotype. Two phases, with two different pathomechanisms, could be observed that lead to the development of cardiac dysfunction, DCM and death between 35 and 70 weeks of age. In young Het hearts, there was a clear reduction in lamin A/C level, mainly due to the degradation of toxic ΔK32-lamin. As a side effect, lamin A/C haploinsufficiency probably triggers the cardiac remodelling. In older hearts, when DCM has developed, the lamin A/C level was normalized and associated with increased toxic ΔK32-lamin expression. Crossing our mice with the Ub(G76V)-GFP ubiquitin-proteasome system (UPS) reporter mice revealed a heart-specific UPS impairment in Het. While UPS impairment itself has a clear deleterious effect on engineered heart tissue's force of contraction, it also leads to the nuclear aggregation of viral-mediated expression of ΔK32-lamin. In conclusion, Het mice are the first knock-in Lmna model with cardiac-specific phenotype at the heterozygous state. Altogether, our data provide evidence that Het cardiomyocytes have to deal with major dilemma: mutant lamin A/C degradation or normalization of lamin level to fight the deleterious effect of lamin haploinsufficiency, both leading to DCM. 23766523 CVD risk among men participating in the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2010: differences by sexual minority status. Recent research indicates that sexual minority women are at increased risk for cardiovascular disease (CVD) compared with heterosexual women; however, few studies of CVD risk exist for sexual minority men (SMM). This study aimed to determine whether disparities in CVD risk exist for SMM and if CVD risk is consistent across subgroups of SMM. This study utilised publicly available data from the National Health and Nutrition Examination Survey (NHANES), pooled from 2001 to 2010. CVD risk was calculated using the Framingham General CVD Risk Score and operationalised as the ratio of a participant's vascular and chronological age. Differences in this ratio were examined between heterosexual and SMM as a whole, and within subgroups of SMM. SMM had vascular systems that were, on average, 4% (95% CI -7.5% to -0.4%) younger than their heterosexual counterparts; however, adjustment for education and history of hard drug use rendered this difference statistically insignificant. Analysis of SMM subgroups revealed increased CVD risk for bisexual men and decreased CVD risk for both gay and homosexually experienced heterosexual men when compared with heterosexual men. Differences in CVD risk persisted for only bisexual and homosexually experienced heterosexual men after adjustment for education and history of hard drug use. Subgroups of SMM are at increased risk for CVD compared with heterosexual men, and this increased risk cannot be completely attributed to differences in demographic characteristics or negative health behaviours. 23574378 The recombinant serine protease XAoz1 of Arthrobotrys oligospora exhibits potent nematicidal activity against Caenorhabditis elegans and Haemonchus contortus. The nematophagous fungus Arthrobotrys oligospora is a potential biological agent against parasitic gastrointestinal nematodes. Its subtilisin-like serine proteases play an important role in nematode cuticle breach. In this study, the cDNA of the mature serine protease XAoz1 from A. oligospora XJ-XAo1 was expressed in Pichia pastoris to assess the in vitro nematicidal activity of recombinant XAoz1 (reXAoz1) on Caenorhabditis elegans and Haemonchus contortus. The cDNA sequence of the protease XAoz1 was amplified by reverse transcription polymerase chain reaction (RT-PCR) and inserted into the vector pPIC9K for expression in P.pastoris GS115. Our results show that the reXAoz1 had a molecular mass of 50 kDa after 3 days of 1.5%-methanol induction at 28 °C. The highest specific protease activity was achieved at 12 168 U mg(-1) protein. The reXAoz1 had the highest hydrolytic activity at pH 6.5-9.5 with an optimal pH at 8.5. Moreover, the purified reXAoz1 displayed a highly toxic and biological activity to immobilize C. elegans and H. contortus by degrading their cuticles and inducing death. 23871986 Neonatal treatment with monosodium glutamate lastingly facilitates spreading depression in the rat cortex. Monosodium glutamate (MSG) is a neuroexcitatory amino acid used in human food to enhance flavor. MSG can affect the morphological and electrophysiological organization of the brain. This effect is more severe during brain development. Here, we investigated the electrophysiological and morphological effects of MSG in the developing rat brain by characterizing changes in the excitability-related phenomenon of cortical spreading depression (CSD) and microglial reaction. From postnatal days 1-14, Wistar rat pups received 2 or 4g/kg MSG (groups MSG-2 and MSG-4, respectively; n=9 in each group), saline (n=10) or no treatment (naïve group; n=5) every other day. At 45-60days, CSD was recorded on two cortical points for 4h. The CSD parameters velocity, and amplitude and duration of the negative potential change were calculated. Fixative-perfused brain sections were immunolabeled with anti-IBA-1 antibodies to identify and quantify cortical microglia. MSG-4 rats presented significantly higher velocities (4.59±0.34mm/min) than the controls (saline, 3.84±0.20mm/min; naïve, 3.71±0.8mm/min) and MSG-2 group (3.75±0.10mm/min). The amplitude (8.8±2.2 to 11.2±1.9mV) and duration (58.2±7.1 to 73.6±6.0s) of the negative slow potential shift was similar in all groups. MSG-treatment dose-dependently increased the microglial immunolabeling. The results demonstrate a novel, dose-dependent action of MSG in the developing brain, characterized by acceleration of CSD and significant microglial reaction in the cerebral cortex. The CSD effect indicates that MSG can influence cortical excitability, during brain development, as evaluated by CSD acceleration. Data suggest caution when consuming MSG, especially in developing organisms. 23894361 Unique Gene Expression and MR T2 Relaxometry Patterns Define Chronic Murine Dextran Sodium Sulphate Colitis as a Model for Connective Tissue Changes in Human Crohn's Disease. Chronically relapsing inflammation, tissue remodeling and fibrosis are hallmarks of inflammatory bowel diseases. The aim of this study was to investigate changes in connective tissue in a chronic murine model resulting from repeated cycles of dextran sodium sulphate (DSS) ingestion, to mimic the relapsing nature of the human disease. C57BL/6 mice were exposed to DSS in drinking water for 1 week, followed by a recovery phase of 2 weeks. This cycle of exposure was repeated for up to 3 times (9 weeks in total). Colonic inflammation, fibrosis, extracellular matrix proteins and colonic gene expression were studied. In vivo MRI T 2 relaxometry was studied as a potential non-invasive imaging tool to evaluate bowel wall inflammation and fibrosis. Repeated cycles of DSS resulted in a relapsing and remitting disease course, which induced a chronic segmental, transmural colitis after 2 and 3 cycles of DSS with clear induction of fibrosis and remodeling of the muscular layer. Tenascin expression mirrored its expression in Crohn's colitis. Microarray data identified a gene expression profile different in chronic colitis from that in acute colitis. Additional recovery was associated with upregulation of unique genes, in particular keratins, pointing to activation of molecular pathways for healing and repair. In vivo MRI T2 relaxometry of the colon showed a clear shift towards higher T2 values in the acute stage and a gradual regression of T2 values with increasing cycles of DSS. Repeated cycles of DSS exposure induce fibrosis and connective tissue changes with typical features, as occurring in Crohn's disease. Colonic gene expression analysis revealed unique expression profiles in chronic colitis compared to acute colitis and after additional recovery, pointing to potential new targets to intervene with the induction of fibrosis. In vivo T2 relaxometry is a promising non-invasive assessment of inflammation and fibrosis. 23870251 The effect of the endothelial cell cortex on atomic force microscopy measurements. We examined whether the presence of the cell cortex might explain, in part, why previous studies using atomic force microscopy (AFM) to measure cell modulus (E) gave higher values with sharp tips than for larger spherical tips. We confirmed these AFM findings in human umbilical vein endothelial cells (HUVEC) and Schlemm's canal (SC) endothelial cells with AFM indentation ≤ 400 nm, two cell types with prominent cortices (312 ± 65 nm in HUVEC and 371 ± 91 nm in SC cells). With spherical tips, E (kPa) was 0.71 ± 0.16 in HUVEC and 0.94 ± 0.06 in SC cells. Much higher values of E were measured using sharp tips: 3.23 ± 0.54 in HUVEC and 6.67 ± 1.07 in SC cells. Previous explanations for this difference such as strain hardening or a substrate effect were shown to be inconsistent with our measurements. Finite element modeling studies showed that a stiff cell cortex could explain the results. In both cell types, Latrunculin-A greatly reduced E for sharp and rounded tips, and also reduced the ratio of the values measured with a sharp tip as compared to a rounded tip. Our results suggest that the cell cortex increases the apparent endothelial cell modulus considerably when measured using a sharp AFM tip. 23794194 Pm50: a new powdery mildew resistance gene in common wheat derived from cultivated emmer. Fungal diseases of wheat, including powdery mildew, cause significant crop, yield and quality losses throughout the world. Knowledge of the genetic basis of powdery mildew resistance will greatly support future efforts to develop and cultivate resistant cultivars. Studies were conducted on cultivated emmer-derived wheat line K2 to identify genes involved in powdery mildew resistance at the seedling and adult plant growth stages using a BC1 doubled haploid population derived from a cross between K2 and susceptible cultivar Audace. A single gene was located distal to microsatellite marker Xgwm294 on the long arm of chromosome 2A. Quantitative trait loci (QTL) analysis indicated that the gene was also effective at the adult plant stage, explaining up to 79.0 % of the variation in the progeny. Comparison of genetic maps indicated that the resistance gene in K2 was different from Pm4, the only other formally named resistance gene located on chromosome 2AL, and PmHNK54, a gene derived from Chinese germplasm. The new gene was designated Pm50. 23934245 Small-molecule inhibition of a depalmitoylase enhances Toxoplasma host-cell invasion. Although there have been numerous advances in our understanding of how apicomplexan parasites such as Toxoplasma gondii enter host cells, many of the signaling pathways and enzymes involved in the organization of invasion mediators remain poorly defined. We recently performed a forward chemical-genetic screen in T. gondii and identified compounds that markedly enhanced infectivity. Although molecular dissection of invasion has benefited from the use of small-molecule inhibitors, the mechanisms underlying induction of invasion by small-molecule enhancers have never been described. Here we identify the Toxoplasma ortholog of human APT1, palmitoyl protein thioesterase-1 (TgPPT1), as the target of one class of small-molecule enhancers. Inhibition of this uncharacterized thioesterase triggered secretion of invasion-associated organelles, increased motility and enhanced the invasive capacity of tachyzoites. We demonstrate that TgPPT1 is a bona fide depalmitoylase, thereby establishing an important role for dynamic and reversible palmitoylation in host-cell invasion by T. gondii. 23585769 Deformation of an elastic capsule in a rectangular microfluidic channel. In the present study we investigate computationally the deformation of an elastic capsule in a rectangular microfluidic channel and compare it with that of a droplet. In contrast to the bullet or parachute shape in a square or cylindrical channel where the capsule extends along the flow direction, in a rectangular channel the capsule extends mainly along the less-confined lateral direction of the channel cross-section (i.e. the channel width), obtaining a pebble-like shape. The different shape evolution in these two types of solid channels results from the different tension development on the capsule membrane required for interfacial stability. Furthermore, in asymmetric channel flows, capsules show a different deformation compared to droplets with constant surface tension (which extend mainly along the flow direction) and to vesicles which extend along the more-confined channel height. Therefore, our study highlights the different stability dynamics associated with these three types of interfaces. Our findings suggest that the erythrocyte deformation in asymmetric vessels (which is similar to that of capsules) results from the erythrocyte's inner spectrin skeleton rather than from its outer lipid bilayer. 23468275 GEICO (Spanish Group for Investigation on Ovarian Cancer) treatment guidelines in ovarian cancer 2012. In 2006, under the auspices of The Spanish Research Group for Ovarian Cancer (Spanish initials GEICO), the first "Treatment Guidelines in Ovarian Cancer" were developed and then published in Clinical and Translational Oncology by Poveda Velasco et al. (Clin Transl Oncol 9(5):308-316, 2007). Almost 6 years have elapsed and over this time, we have seen some important developments in the treatment of ovarian cancer. Significant changes were also introduced after the GCIG-sponsored 4th Consensus Conference on Ovarian Cancer by Stuart et al. (Int J Gynecol Cancer 21:750-755, 2011). So we decided to update the treatment guidelines in ovarian cancer and, with this objective, a group of investigators of the GEICO group met in February 2012. This study summarizes the presentations, discussions and evidence that were reviewed during the meeting and during further discussions of the manuscript. 23436258 Pharmacokinetic properties of anti-influenza neuraminidase inhibitors. Neuraminidase inhibitors are the mainstay of anti-influenza treatment. Oseltamivir is the most widely used drug but is currently available only as an oral formulation. Resistance spreads rapidly in seasonal H1N1 influenza A viruses, which were universally resistant in 2008, because of the H275Y mutation in the neuraminidase (NA) gene. Oseltamivir is a prodrug for the active carboxylate metabolite. Ex vivo conversion in blood samples may have confounded early pharmacokinetic studies. Oseltamivir shows dose linear kinetics, and oseltamivir carboxylate has an elimination half-life (t(1/2) β) after oral administration in healthy individuals of approximately 7.7 hours. Oseltamivir carboxylate is eliminated primarily by tubular secretion, and both clearance and tissue distribution are reduced by probenecid. The H275Y mutation in NA confers high-level oseltamivir resistance and intermediate peramivir resistance but does not alter zanamivir susceptibility. Zanamivir is available as a powder for inhalation, and a parenteral form is under development. Zanamivir distributes in an apparent volume of distribution approximating that of extracellular water and is rapidly eliminated (t(1/2) β of approximately 3.0 hours). Peramivir is slowly eliminated (t(1/2) β of 7.7-20.8 hours) and is prescribed as either a once-daily injection or as a single infusion. Laninamivir is a recently developed slowly eliminated compound for administration by inhalation. 23892030 Lactobacillus plantarum reduces Streptococcus pyogenes virulence by modulating the IL-17, IL-23 and Toll-like receptor 2/4 expressions in human epithelial cells. Streptococcus pyogenes is a common colonizer of the mucosal layers in the mouth, nose, and pharynx but it is also a major Gram-positive human pathogen that causes infections ranging from pharyngitis to severe systemic diseases. The lactobacilli colonize the oral tracts and are known to protect against colonization by many pathogens. Epithelial cells participate in the innate host defense by expressing a variety of proinflammatory cytokines and TLRs in the interaction with microorganisms. The potentially probiotic strain Lactobacillus plantarum was investigated for its capacity to influence the innate immune response of HEp-2 and A549 epithelial cells to S. pyogenes infection. In both epithelial cell types, pre-treatment with L. plantarum showed inhibition of S. pyogenes growth and a greater decrease in IL-17 and IL-23 levels compared to the control. Pre-treatment with the anti-TLR2/4 antibody abolished the inhibitory effects of L. plantarum on IL-17 and IL-23 production following S. pyogenes infection, indicating that L. plantarum downregulates TLR2/4-dependent IL-17 and IL-23 production. Overall, our findings suggest that in epithelial cell cultures with S. pyogenes, cytokine responses are modulated by the presence of L. plantarum through the induction of TLR2/TLR4. 23686818 Dendritic development of hippocampal CA1 pyramidal cells in a neonatal hypoxia-ischemia injury model. It is believed that neonatal hypoxia-ischemia (HI) brain injury causes neuron loss and brain functional defects. However, the effect of HI brain injury on dendritic development of the remaining pyramidal cells of the hippocampus and the reaction of contralateral hippocampal neurons require further studies. The Morris water maze and Golgi-Cox staining were used to evaluate the learning and memory and dendritic morphology of pyramidal cells. The results of Golgi-Cox staining showed CA1 pyramidal neurons of HI injury models with fewer bifurcations and shorter dendrite length than the naive control group. The density of dendritic spines of hippocampal CA1 pyramidal neurons was significantly lower in the HI brain injury group than in controls. With respect to hippocampal function, the HI brain injury group presented cognitive deficits in the reference memory task and probe trail. In the HI group, the pyramidal cells of left hippocampus that did not experienced ischemia but did experience hypoxia had more complex dendrites and higher density of spine than the HI injury side and control. The functional implementation of injured hippocampus might depend mainly on the hypertrophy of contralateral hippocampus after HI brain injury. Corticosterone can partially prevent the hippocampal pyramidal cells from HI injury and reduce the difference of the bilateral hippocampus pyramidal cells, but there was no improvement in learning and memory. © 2013 Wiley Periodicals, Inc. 23769480 Tobacco use in Florida: comparisons between adults living with and without disabilities. Florida has the third largest population in the U.S. of persons living with disabilities, making optimizing health outcomes for this population paramount. Though the state has a long-standing and robust program to reduce tobacco use, prevention efforts do not specifically target persons with disabilities. To compare rates of tobacco use behaviors and second hand smoke exposure between adults living with and without disabilities. Secondary analysis of 2007-2009 Florida BRFSS data. The proportions of persons with disabilities who were cigar or cigarette smokers, quit smoking, were exposed to secondhand smoke, or had an interest in calling a Quit Line were compared for persons with and without disabilities. Weighted proportions and accompanying 95% confidence intervals were calculated, with proportions adjusted for age, gender, race, and education. Adult Floridians with a disability were more likely to report being a current cigarette smoker and being exposed to secondhand smoke, yet were also more likely to report quitting smoking for at least one day than were persons without a disability. No differences were found for cigar smoking, age at smoking initiation, or interest in the Quit Line. Findings suggest persons with disability are disproportionately burdened by tobacco use, yet are more likely to attempt to quit, suggesting a need for targeted interventions to assist persons with a disability in smoking cessation and reducing tobacco use and exposure. This has important implications for the future health of a group at greater risk of chronic disease. 23686261 Benz[a]anthracene biotransformation and production of ring fission products by Sphingobium sp. strain KK22. A soil bacterium, designated strain KK22, was isolated from a phenanthrene enrichment culture of a bacterial consortium that grew on diesel fuel, and it was found to biotransform the persistent environmental pollutant and high-molecular-weight polycyclic aromatic hydrocarbon (PAH) benz[a]anthracene. Nearly complete sequencing of the 16S rRNA gene of strain KK22 and phylogenetic analysis revealed that this organism is a new member of the genus Sphingobium. An 8-day time course study that consisted of whole-culture extractions followed by high-performance liquid chromatography (HPLC) analyses with fluorescence detection showed that 80 to 90% biodegradation of 2.5 mg liter(-1) benz[a]anthracene had occurred. Biodegradation assays where benz[a]anthracene was supplied in crystalline form (100 mg liter(-1)) confirmed biodegradation and showed that strain KK22 cells precultured on glucose were equally capable of benz[a]anthracene biotransformation when precultured on glucose plus phenanthrene. Analyses of organic extracts from benz[a]anthracene biodegradation by liquid chromatography negative electrospray ionization tandem mass spectrometry [LC/ESI(-)-MS/MS] revealed 10 products, including two o-hydroxypolyaromatic acids and two hydroxy-naphthoic acids. 1-Hydroxy-2- and 2-hydroxy-3-naphthoic acids were unambiguously identified, and this indicated that oxidation of the benz[a]anthracene molecule occurred via both the linear kata and angular kata ends of the molecule. Other two- and single-aromatic-ring metabolites were also documented, including 3-(2-carboxyvinyl)naphthalene-2-carboxylic acid and salicylic acid, and the proposed pathways for benz[a]anthracene biotransformation by a bacterium were extended. 23821544 The Legionella pneumophila GTPase Activating Protein LepB Accelerates Rab1 Deactivation by a Non-canonical Hydrolytic Mechanism. GTPase activating proteins (GAPs) from pathogenic bacteria and eukaryotic host organisms deactivate Rab GTPases by supplying catalytic arginine and glutamine fingers in trans and utilizing the cis-glutamine in the DXXGQ motif of the GTPase for binding rather than catalysis. Here, we report the transition state mimetic structure of the Legionella pneumophila GAP LepB in complex with Rab1 and describe a comprehensive structure-based mutational analysis of potential catalytic and recognition determinants. The results demonstrate that LepB does not simply mimic other GAPs but instead deploys an expected arginine finger in conjunction with a novel glutamic acid finger, which forms a salt bridge with an indispensible switch II arginine that effectively locks the cis-glutamine in the DXXGQ motif of Rab1 in a catalytically competent though unprecedented transition state configuration. Surprisingly, a heretofore universal transition state interaction with the cis-glutamine is supplanted by an elaborate polar network involving critical P-loop and switch I serines. LepB further employs an unusual tandem domain architecture to clamp a switch I tyrosine in an open conformation that facilitates access of the arginine finger to the hydrolytic site. Intriguingly, the critical P-loop serine corresponds to an oncogenic substitution in Ras and replaces a conserved glycine essential for the canonical transition state stereochemistry. In addition to expanding GTP hydrolytic paradigms, these observations reveal the unconventional dual finger and non-canonical catalytic network mechanisms of Rab GAPs as necessary alternative solutions to a major impediment imposed by substitution of the conserved P-loop glycine. 23470196 Chitosan-thioglycolic Acid as a versatile antimicrobial agent. As functionalized chitosans hold great potential for the development of effective and broad-spectrum antibiotics, representative chitosan derivatives were tested for antimicrobial activity in neutral media: trimethyl chitosan (TMC), carboxy-methyl chitosan (CMC), and chitosan-thioglycolic acid (TGA; medium molecular weight: MMW-TGA; low molecular weight: LMW-TGA). Colony forming assays indicated that LMW-TGA displayed superior antimicrobial activity over the other derivatives tested: a 30 min incubation killed 100% Streptococcus sobrinus (Gram-positive bacteria) and reduced colony counts by 99.99% in Neisseria subflava (Gram-negative bacteria) and 99.97% in Candida albicans (fungi). To elucidate LMW-TGA effects at the cellular level, microscopic studies were performed. Use of fluorescein isothiocyanate (FITC)-labeled chitosan derivates in confocal microscopy showed that LMW-TGA attaches to microbial cell walls, while transmission electron microscopy indicated that this derivative severely affects cell wall integrity and intracellular ultrastructure in all species tested. We therefore propose LMW-TGA as a promising and effective broad-band antimicrobial compound. 23218715 The discovery of potent and selective 4-aminothienopyridines as B-Raf kinase inhibitors. A series of novel, potent 4-aminothienopyridine B-Raf kinase inhibitors was designed and synthesized using knowledge-based design. Compounds 5f, and 6k exhibited not only excellent potency in both enzyme assay (IC(50)=5.1, 16.6 nM) and cellular assay (IC(50)=0.2, 0.2 μM), but also had an outstanding selectivity profile against other kinases. 23855523 Biotransformation and bioconversion of phenolic compounds obtainment: an overview. Abstract Phenolic compounds have recently been recognized for their influence on human metabolism, acting in the prevention of some chronic diseases as well as proving to be important antioxidants in food. Nevertheless, the extraction and concentration processes are usually carried out by organic solvent extraction from natural sources and can generate some drawbacks like phenolic compound degradation, lengthy process times and low yields. As a solution, some eco-friendly technologies, including solid-state fermentation (SSF) or enzymatic-assisted reaction, have been proposed as alternative processes. This article reviews the extraction of phenolic compounds from agro-industrial co-products by solid-state fermentation, even as friendly enzyme-assisted extractions. It also discusses the characteristics of each bioprocess system and the variables that affect product formation, as well as the range of substrates, microorganisms and enzymes that can be useful for the production of bioactive phenolic compounds. 23831725 In vitro characterization of the impact of selected dietary fibers on fecal microbiota composition and short chain fatty acid production. The effects of six dietary fibers [pectin, guar gum, inulin, arabinoxylan, β-glucan, and resistant starch] on the human fecal microbiota during in vitro fermentation were determined. Bifidobacterium increased almost 25% on pectin compared with the control; a significant increase in Bifidobacterium adolescentis type-2 was observed on resistant starch. Bacteroides exhibited a positive correlation with propionate/short chain fatty acid (SCFA) production (r = 0.59, p < 0.01), while Ruminococcaceae and Faecalibacterium displayed positive correlations with butyrate/SCFA production (r = 0.39, 0.54, p < 0.01). A negative correlation was detected between inulin utilization and Subdoligranulum (r = -0.73, p â‰¤ 0.01), while strong positive relationships were found between β-glucan utilization and Firmicutes (r = 0.73, p â‰¤ 0.01) and resistant starch utilization and Blautia wexlerae (r = 0.82, p < 0.01). Dietary fibers have specific and unique impacts on intestinal microbiota composition and metabolism. These findings provide a rationale for the development of functional ingredients targeted towards a targeted modulation of the gut microbiota. 23754561 A Simple Technique of Preparing Stable CLEAs of Phenylalanine Ammonia Lyase Using Co-aggregation with Starch and Bovine Serum Albumin. Cross-linked enzyme aggregates (CLEAs) have been recently proposed as an alternative to conventional immobilization methods on solid carriers. However, the low cross-linking efficiency causes the major activity loss and instability in the conventional protocol for CLEA preparation. Herein, the effects of bovine serum albumin and starch addition on the cross-linking efficiency of CLEAs of phenylalanine ammonia lyase (PAL) from Rhodotorula glutinis were evaluated. A co-aggregation strategy was developed to improve cross-linking efficiency by adding starch and bovine serum albumin (BSA). CLEAs of PAL prepared in the presence of BSA and starch (PSB-CLEAs) retained 36 % activity, whereas CLEAs prepared without BSA and starch (PAL-CLEAs) retained only 8 % activity of the starting enzyme preparation. Compared with PAL-CLEAs, the thermal stability of PSB-CLEAs has improved considerably, maintaining 30 % residual activity after 4 h of incubation at 70 °C, whereas the PAL-CLEAs have only 13 % residual activity. PSB-CLEAs also exhibited the expected increased stability of PAL against hydrophilic organic solvents, superior operability, and higher storage stability. The proposed technique of preparing CLEAs using co-aggregation with starch and BSA would rank among the potential strategies for efficiently preparing robust and highly stable enzyme aggregates. 23794068 Hepatitis E virus: an underestimated opportunistic pathogen in recipients of allogeneic hematopoietic stem cell transplantation. Hepatitis E virus (HEV) is increasingly acknowledged as a cause of hepatitis in healthy individuals as well as immunocompromised patients. Little is known of HEV infection in recipients of allogeneic hematopoietic stem cell transplantation (alloHSCT). Therefore, we set out to study the incidence and sequelae of HEV as a cause of hepatitis in a recent cohort of 328 alloHSCT recipients. HEV RNA was tested in episodes of liver enzyme abnormalities. In addition, HEV RNA and HEV serology were assessed pre- and post-alloHSCT. We found 8 cases (2.4%) of HEV infection, of which 5 had developed chronic HEV infection. Seroprevalence pre-alloHSCT was 13%. Four patients died with HEV viremia, with signs of ongoing hepatitis, having a median time of infection of 4.1 months. The 4 surviving patients cleared HEV after a median period of 6.3 months. One patient was diagnosed with HEV reactivation after a preceding infection prior to alloHSCT. Although the incidence of developing acute HEV post-alloHSCT is relatively low, the probability of developing chronic hepatitis in severely immunocompromised patients is high. Therefore, alloHSCT recipients should be screened pretransplantation by HEV serology and RNA. Furthermore, a differential diagnosis including hepatitis E is mandatory in all alloHSCT patients with severe liver enzyme abnormalities. 23549964 Evaluation of weight loss on a low-calorie meal replacement diet as a potential predictor of weight loss after laparoscopic adjustable gastric banding surgery in adolescents. Predicting weight loss after laparoscopic adjustable gastric banding (LAGB) from preoperative factors has been challenging. This study aimed to determine the relationship between weight loss from a preoperative low-calorie meal replacement diet (LCMRD) and weight loss after LAGB in a cohort of morbidly obese adolescents. Fifty-one subjects (86 % female, 61 % Caucasian, mean age 16 years, mean weight 140.1 kg) received 2 weeks of LCMRD prior to LAGB. We utilized Pearson's correlation coefficients to test the relationship between weight loss on a LCMRD and weight loss at 3, 6, and 12 months after LAGB. Mean weight loss was 5.7 kg (standard deviation (SD) 2.5) during the LCMRD period and 17.4 kg (SD 12.4) at 1 year postoperatively. Having a higher baseline weight (p < 0.01) and losing less weight prior to LCMRD (p < 0.05) was associated with more weight loss during LCMRD. Weight loss during LCMRD was not significantly associated with postoperative weight loss at any time point. Weight loss during LCMRD was not significantly associated with postoperative weight loss in our study. Less variability in adherence, less influence of genetic and biological potential, and more diuresis during a short course of LCMRD compared to in the postoperative period may explain this lack of association. 23906813 Mass balance modeling to elucidate historical and continuing sources of dioxin into an urban estuary. Polychlorinated dibenzo-p-dioxins and dibenzofurans (dioxins) are typically found in sediment, water and tissue as in the case of the Houston Ship Channel and Upper Galveston Bay (HSC-UGB) in Texas studied in this research. While hydrodynamic and fate and transport models are important to understand dioxin distribution in the various media, it is difficult to assimilate modeling results into a decision framework without appropriate tools that can aid in the interpretation of the simulated data. This paper presents the development of a mass-balance modeling tool linked to RMA2 and WASP models of the HSC-UGB system for 2002-2005. The mass-balance tool was used to aggregate modeling results spatially and temporally and estimate the relative contribution of sediments to dioxin loading into the Channel in comparison to runoff, deposition, and permitted effluent discharges. The total sediment associated-dioxin load into the system calculated using the mass balance model was 2.34×10(7)ngd(-1) (almost 86% of the toxic equivalent load), and the re-deposited load to the sediment from the water column was 1.48×10(7)ng-TEQd(-1), such that 8.6×10(6)ng-TEQd(-1) or approximately 69% of the average daily dioxin flux is transported between model segments as sediment. The external loads to the system contribute approximately 3.83×10(6)ng-TEQd(-1), a value that is an order of magnitude smaller when compared to the contribution from sediment. These findings point to the need for sediment remediation strategies that take into account the spatial locations within the system that serve as sediment sources to dioxin in the water column. 23927851 Chronic cough and sputum production are associated with worse clinical outcomes in stable asthma. Chronic cough and sputum production (chronic mucus hypersecretion) is a poorly described clinical feature of asthma. Our objective was to identify clinical, immunological and computed tomography (CT) measures of airway wall dimensions associated with these symptoms in smokers and never smokers with asthma. Cross-sectional data was analysed from 120 smokers and never smokers with asthma. Participants with and without a history of chronic mucus hypersecretion were compared for clinical outcomes, sputum differential cell counts and CT measures of airway dimensions (wall thickness, luminal area and percent wall area). Chronic mucus hypersecretion occurred in a higher proportion of smokers with asthma (56%) than never smokers with asthma (20%), (p < 0.001) and the proportion of patients with these symptoms increased with asthma severity (p = 0.003). Smokers with asthma and chronic mucus hypersecretion had worse current clinical control than smokers without those symptoms [ACQ score 2.3 versus 1.6, p = 0.002]. A greater proportion of never smokers with chronic mucus hypersecretion required short courses of oral corticosteroids in the last year (58% versus 19%, p = 0.011). Sputum neutrophil and eosinophil counts were similar in asthma patients with or without chronic mucus hypersecretion. Of those with severe asthma and chronic mucus hypersecretion, a CT measure of airway lumen area was reduced in smokers compared to never smokers (11.4 mm(2) versus 18.4 mm(2); p = 0.017). Chronic mucus hypersecretion occurs frequently in adults with stable asthma, particularly in smokers with severe disease and is associated with worse current clinical control in smokers and more exacerbations in never smokers. 23052209 Diversity of IL-17-producing T lymphocytes. Interleukin (IL)-17 is a pro-inflammatory cytokine that plays critical roles in host defense against extracellular bacteria and fungi and also in the pathogenesis of autoimmune diseases. While CD4+ TCRαβ+ T helper (Th) 17 cells are the best-described cellular source of IL-17, many innate-like T cells are in fact potent producers of IL-17. Given the increasing interest in therapeutic modulation of the IL-17 axis, it is crucial to better understand the cellular origins of IL-17 in various infection and diseases settings. While the diverse population of IL-17-producing T cells share many common characteristics, notable differences also exist. In this review, we discuss the heterogeneity of IL-17-producing T cell types focusing on their development, regulation, and function. 23908286 Complete Genome Sequence of a Reassortant H14N2 Avian Influenza Virus from California. We report the complete genome sequence of a reassortant H14N2 avian influenza virus isolated in 2011 from a northern shoveler in California. This introduced Eurasian subtype acquired seven segments from North American viruses and circulated in the Pacific Flyway 1 year after its detection in the Mississippi Flyway. 23559470 Characterization of a novel active release coating to prevent biofilm implant-related infections. Biofilm implant-related infections cost the US healthcare system billions of dollars each year. For several decades, device coatings have been developed that actively release antimicrobial compounds in an attempt to prevent these infections from developing. To date, few coatings have been put into clinical use. These have shown limited to no efficacy in clinical trials. Recent data have shown the in vitro and in vivo efficacy of a novel active release coating that may address the limitations of coatings that are used clinically. In this study, the novel active release coating was characterized to gain an understanding of the effects of combining an antimicrobial additive, cationic steroid antimicrobial-13 (CSA-13), to a medical grade polydimethylsiloxane (PDMS) material. Results indicated that the addition of CSA-13 did influence the physical properties of the PDMS, but not with adverse effects to the desired material properties. Furthermore, there was no indication of chemical reactivity. It was shown that CSA-13 was uniformly dispersed as small particles throughout the PDMS matrix. These particles were able to dissolve and elute out of the PDMS within a 30-day period. The results of this work suggested that the PDMS with CSA-13 was thermally, chemically and physically stable when used as a device coating to treat local infection and/or prevent biofilm implant-related infections from developing. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2013. 23881068 Mesenchymal stem cells in joint disease and repair. Osteoarthritis (OA), a prevalent chronic condition with a striking impact on quality of life, represents an enormous societal burden that increases greatly as populations age. Yet no approved pharmacological intervention, biologic therapy or procedure prevents the progressive destruction of the OA joint. Mesenchymal stem cells (MSCs)-multipotent precursors of connective tissue cells that can be isolated from many adult tissues, including those of the diarthrodial joint-have emerged as a potential therapy. Endogenous MSCs contribute to maintenance of healthy tissues by acting as reservoirs of repair cells or as immunomodulatory sentinels to reduce inflammation. The onset of degenerative changes in the joint is associated with aberrant activity or depletion of these cell reservoirs, leading to loss of chondrogenic potential and preponderance of a fibrogenic phenotype. Local delivery of ex vivo cultures of MSCs has produced promising outcomes in preclinical models of joint disease. Mechanistically, paracrine signalling by MSCs might be more important than differentiation in stimulating repair responses; thus, paracrine factors must be assessed as measures of MSC therapeutic potency, to replace traditional assays based on cell-surface markers and differentiation. Several early-stage clinical trials, initiated or underway in 2013, are testing the delivery of MSCs as an intra-articular injection into the knee, but optimal dose and vehicle are yet to be established. 23794392 Solvent- and Achiral-Guest-Triggered Chiral Inversion in a Planar Chiral pseudo[1]Catenane. On the flipside: A planar chiral pseudo- [1]catenane based on pillar[5]arene, in which an alkyl chain is connected to one pillar[5]arene unit, has been synthesized. Capture and release of achiral guests and solvents trigger the inclusion and de-threading of the alkyl chain, which causes the inversion of planar chirality. 23965808 Highly Pathogenic Avian Influenza A(H7N3) Virus in Poultry Workers, Mexico, 2012. We identified 2 poultry workers with conjunctivitis caused by highly pathogenic avian influenza A(H7N3) viruses in Jalisco, Mexico. Genomic and antigenic analyses of 1 isolate indicated relatedness to poultry and wild bird subtype H7N3 viruses from North America. This isolate had a multibasic cleavage site that might have been derived from recombination with host rRNA. 23689425 Identification and Functional Characterization of a Ku-binding Motif in Aprataxin Polynucleotide Kinase/Phosphatase-like Factor (APLF). Aprataxin polynucleotide kinase/phosphatase-like factor (APLF) facilitates nonhomologous end joining (NHEJ) and associates with the core NHEJ components XRCC4-DNA ligase IV and Ku. The APLF forkhead-associated (FHA) domain directs interactions with XRCC4, but the APLF-Ku interaction has not been well characterized. Here we describe an evolutionarily conserved amino acid motif within APLF that is required for mediating the physical interaction between APLF and Ku. This APLF Ku-binding motif possesses a similarity to regions identified in other NHEJ factors, WRN and XLF, which also direct interactions with Ku. Indeed, peptides derived from the Ku-binding region of APLF, WRN, or XLF were sufficient to reconstitute the interaction with Ku in vitro. Although APLF is localized predominantly to the nucleus, it does not possess a nuclear localization signal (NLS). Interestingly, the disruption of the APLF-Ku interaction by substituting key residues in the APLF Ku-binding motif was associated with increased relocalization of APLF to the cytoplasm and reduced association with XRCC4, which was rescued by the introduction of an NLS onto APLF. When human cells stably depleted of APLF were reconstituted with APLF Ku-binding mutants, or with an APLF FHA mutant that is known to disrupt interactions with XRCC4, APLF-dependent NHEJ and the retention of APLF at sites of laser-generated DNA damage were impaired. These data suggest functional requirements for Ku and XRCC4 in APLF-dependent NHEJ and a unique role for Ku as a factor required to facilitate the nuclear retention of APLF. 23841864 Factors associated with high-frequency illicit methadone use among rural Appalachian drug users. Abstract Background: In recent years there has been a sharp increase in the use of illicit methadone as well as methadone-related overdose deaths. Objective: The purpose of this study was to describe factors associated with low- and high-frequency methadone use in a cohort of rural Appalachian drug users. Methods: Interviews assessing sociodemographics, illicit drug use and drug treatment, psychiatric disorders, health and sociometric drug network characteristics were conducted with 503 rural drug users between 2008 and 2010. A two-level mixed effects regression model was utilized to differentiate low- (one use per month or less in the past six months) versus high-frequency (daily or weekly use in the past six months) illicit methadone users. Results: The lifetime prevalence of illicit methadone use in this population was 94.7% (n = 476) and slightly less than half (46.3%) were high-frequency users. In the mixed effects regression model, initiating illicit methadone use at a younger age was associated with high-frequency illicit methadone use. Taking a prescribed medication for a physical problem, undergoing additional weeks of outpatient drug free treatment, daily OxyContin® use in the past month, and having fewer ties and second-order connections in the drug network reduced the odds of high-frequency illicit methadone use. Conclusions: Rates of illicit methadone use and high-frequency illicit methadone use among this sample of rural drug users were considerably higher than those previously reported in the literature. Health practitioners in rural areas should routinely screen for illicit opioid use, including methadone. 23231414 Acute bacterial septic vasculopathy. Objectives  The frequency and clinicopathologic characteristics of cutaneous lesions in sepsis are not well known. This study aimed to analyze cutaneous lesions in bacterial septic vasculopathy. Methods  The study population comprised 32 patients with bacterial sepsis, cutaneous lesions, and skin biopsy-proven septic vasculopathy. The clinical and histologic characteristics of the lesions were analyzed. Findings in non-immunosuppressed patients (NISPs) and immunosuppressed patients (ISPs) were compared. Results  Nine of 32 patients were immunosuppressed. The foci of sepsis were variable; in 17 patients, the focus was not identified. Although Neisseria meningitidis was the most common causal agent, several microorganisms were identified. Cutaneous manifestations were an early event in 90.6% of patients. The most common skin signs were purpuric lesions and petechiae. Overall mortality was 28.1%; 65.5% of patients survived without sequelae. Skin biopsies showed thrombi in 100% of cases. Other common findings were inflammatory infiltrate, blood extravasation, and epidermal involvement. Bacteria within the vascular wall were seen in 21.9% of cases and fibrinoid necrosis in 25%. A comparison of ISPs with NISPs disclosed that meningococcemia was more common in the latter group, and the presence of pustules was more common in the former. Histopathology testing revealed that fibrinoid necrosis and bacterial invasion of the vessel wall were more common in ISPs than in NISPs. Conclusions  Several microorganisms can cause septic vasculopathy. Clinical presentation is variable and does not depend on the microorganism or the pathogenic mechanism. Histopathologically, septic vasculopathy is a thrombo-occlusive vasculopathy with variable morphology. Cutaneous lesions are an early event and allow for rapid diagnosis. 23952708 Time Resolved Electrochemical Quantification of Azanone (HNO) at Low Nanomolar Level. Azanone (HNO, nitroxyl) is a highly reactive and short-lived compound with intriguing but highly relevant properties. It has been proposed to be i) a reaction intermediate in several chemical reactions, ii) an in-vivo endogenous produced key metabolite and/or signaling molecule and iii) its donors have important pharmacological properties. Therefore, given its relevance and elusive nature (it reacts with itself very fast), the development of reliable analytical methods for quantitative HNO detection is in high demand for the advancement of future research in this area. During the last few years several methods were developed, which rely on chemical reactions followed by mass spectrometry, HPLC characterization, UV-Vis or fluorescence trapping based methodologies. In this work our recently developed HNO sensing electrode, based on the covalent attachment of cobalt(II) 5,10,15,20-tetrakis[3-(p-acetylthiopropoxy)phenyl] porphyrin [Co(P)] to a gold electrode, has been thoroughly characterized in terms of sensibility, accuracy, time resolved detection and compatibility with complex biological compatible media. Our results show that the Co(P) electrode: i) Allows time resolved detection, and thus kinetic analysis of the electrode response, and the underlying HNO producing reactions can be characterized, ii) is able to selectively detect and reliably quantify HNO at least in the 1 - 1000 nM range and iii) has good biological media compatibility (including cell culture), displaying a lack of spurious signal due to the presence of O2, NO and other reactive nitrogen and oxygen species. In summary the Co(P) electrode offers to our knowledge the best perspectives to be used in studies looking for HNO related chemical and biological reactions. 23965844 The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. To evaluate the genetic findings, demographic features and clinical presentation of tumour necrosis factor receptor-associated autoinflammatory syndrome (TRAPS) in patients from the Eurofever/EUROTRAPS international registry. A web-based registry collected retrospective data on patients with TNFRSF1A sequence variants and inflammatory symptoms. Participating hospitals included paediatric rheumatology centres and adult centres with a specific interest in autoinflammatory diseases. Cases were independently validated by experts in the disease. Complete information on 158 validated patients was available. The most common TNFRSF1A variant was R92Q (34% of cases), followed by T50M (10%). Cysteine residues were disrupted in 27% of cases, accounting for 39% of sequence variants. A family history was present in 19% of patients with R92Q and 64% of those with other variants. The median age at which symptoms began was 4.3 years but 9.1% of patients presented after 30 years of age. Attacks were recurrent in 88% and the commonest features associated with the pathogenic variants were fever (88%), limb pain (85%), abdominal pain (74%), rash (63%) and eye manifestations (45%). Disease associated with R92Q presented slightly later at a median of 5.7 years with significantly less rash or eye signs and more headaches. Children were more likely than adults to present with lymphadenopathy, periorbital oedema and abdominal pains. AA amyloidosis has developed in 16 (10%) patients at a median age of 43 years. In this, the largest reported case series to date, the genetic heterogeneity of TRAPS is accompanied by a variable phenotype at presentation. Patients had a median 70 symptomatic days a year, with fever, limb and abdominal pain and rash the commonest symptoms. Overall, there is little evidence of a significant effect of age or genotype on disease features at presentation. 23907317 IQGAP1 Expression in Spared CA1 Neurons After an Excitotoxic Lesion in the Mouse Hippocampus. Repeated seizures induce permanent alterations in the hippocampal circuits in experimental models with intractable temporal lobe epilepsy. Sprouting and synaptic reorganization induced by seizures has been well-studied in the mossy fiber pathway. However, studies investigating sprouting and synaptic reorganization beyond the mossy fiber pathway are limited. The present study examined the biochemical changes of CA1 pyramidal neurons undergoing morphological changes after excitotoxicity-induced hippocampal CA3 neuronal death. IQ-domain GTPase-activating proteins (IQGAP1), is an effector of Rac1 and Cdc42 and an actin-binding protein, was upregulated in CA1 pyramidal neurons after kainic acid-induced hippocampal CA3 neuronal degeneration. IQGAP1 + cells were colocalized with Nestin, but not in astrocytes or mature neurons. Furthermore, IQGAP1 did not originate from newly divided local precursors or NG2 + cells. IQGAP1 and adenomatous polyposis coli localized in CA1 pyramidal neurons, and Cdc42 activation was followed by IQGAP1 recruitment. These findings suggest that IQGAP1 is upregulated in pre-existed sparing neurons of the CA1 layer undergoing morphological changes after excitoxicity-induced hippocampal CA3 neuronal death. It demonstrates the utility of IQGAP1 as a possible marker for spared pyramidal neurons, which may contribute to structural and functional alternations responsible for the development of epilepsy. 23928032 The Ihh signal is essential for regulating proliferation and hypertrophy of cultured chicken chondrocytes. The Indian hedgehog (Ihh) signal plays a vital role in regulating proliferation and hypertrophy of chondrocytes. To investigate its function in postnatal chicken (Gallus gallus) chondrocytes, cyclopamine was used to inhibit Ihh signaling. The MTT and ALP assays revealed the downgrade-proliferation and upgrade-differentiation of chondrocytes. To further elucidate the mechanism, the mRNA expression levels of Ihh, parathyroid hormone related protein (PTHrP), Gli-2, Bcl-2, Bone Morphogenetic Protein 6 (BMP-6), type X collagen (Col X) and type II collagen (Col II) were detected by quantitative real-time RT-PCR analysis, and the protein expressions of Ihh, Col X, and Col II were determined using Western blot analysis. After the Ihh signal was blocked, chondrocytes demonstrated high expression levels of PTHrP and Col X and low levels of Gli-2, BMP-6, Bcl-2 and Col II although Ihh expression was increased. Based on these results, the Ihh signal is essential for balancing chicken chondrocyte proliferation and hypertrophy, and the regulatory function of PTHrP acts in an Ihh-dependent manner. Furthermore, BMP-6 and Bcl-2 played roles in maintaining the development of chondrocytes and may be downstream regulatory factors of Ihh signaling. 23835553 Rapamycin and omega-1: mTOR-dependent and -independent Th2 skewing by human dendritic cells. Recent reports have attributed an immunoregulatory role to the mammalian target of rapamycin (mTOR), a key serine/threonine protein kinase integrating input from growth factors and nutrients to promote cell growth and differentiation. In the present study, we investigated the role of the mTOR pathway in Th2 induction by human monocyte-derived dendritic cells (moDCs). Using a co-culture system of human lipopolysaccharide (LPS)-matured moDCs and allogeneic naive CD4(+) T cells, we show that inhibition of mTOR by the immunosuppressive drug rapamycin reduced moDC maturation and promoted Th2 skewing. Next, we investigated whether antigens from helminth parasites, the strongest natural inducers of Th2 responses, modulate moDCs via the mTOR pathway. In contrast to rapamycin, neither Schistosoma mansoni-soluble egg antigens (SEA) nor its major immunomodulatory component omega-1 affected the phosphorylation of S6 kinase (S6K) and 4E-binding protein 1 (4E-BP1), downstream targets of mTORC1. Finally, we found that the effects of rapamycin and SEA/omega-1 on Th2 skewing were additive, suggesting two distinct underlying molecular mechanisms. We conclude that conditioning human moDCs to skew immune responses towards Th2 can be achieved via an mTOR-dependent and -independent pathway triggered by rapamycin and helminth antigens, respectively. 23490274 Cortisol hyporesponsiveness to the low dose ACTH test is a frequent finding in a pediatric population with type 1 diabetes mellitus. In adults with type 1 diabetes mellitus (DM1), a 25% of risk of hypocortisolism has been found through a low dose ACTH test with negative antibodies suggesting other causes of hypothalamic-pituitary-adrenal axis dysfunction. To evaluate adrenal function in pediatric patients with DM1 and correlate the results with the frequency of hypoglycemia and metabolic control. Sixty-nine patients were enrolled, age 12.3 (5.7-18.1); 50 boys and 19 girls. A 20% had additional autoimmune diseases. Mean hemoglobin A1c (HbA1c) was 8.1% and insulin dose was 1.14 U/kg/d. After an overnight fast, a low dose ACTH test (1 µg) was performed. Basal and stimulated cortisol concentrations, DHEAS, and plasma renin activity (PRA) were measured. A cortisol response post-ACTH below 18 µg/dL was considered abnormal. 58% of the tested patients had an abnormal response to ACTH test. These patients also had lower DHEAS concentrations, but were not different in diabetes duration, HbA1C, severe hypoglycemia, ACTH, or PRA concentrations compared to those who had a normal cortisol post-ACTH. One patient out of 59, had a positive anti-21-hydroxylase antibody (21OHA) and presented a poor response to ACTH. We found a significant proportion of our patients having a subnormal cortisol response independent of the presence of anti-adrenal cell antibodies. We did not find a correlation with metabolic control, probably due to the good metabolic control of this group. The absence of 21OHA does not rule out subclinical hypocortisolism in this population. Our results suggest testing adrenal function in children with DM1. 23206854 Impact of smoking and smoking cessation on outcomes in bladder cancer patients treated with radical cystectomy. Cigarette smoking is the best-established risk factor for urothelial carcinoma development. To elucidate the association of pretreatment smoking status, cumulative exposure, and time since smoking cessation on outcomes of patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy (RC). We retrospectively collected clinicopathologic and smoking variables, including smoking status, number of cigarettes per day (CPD), duration in years, and time since smoking cessation, for 1506 patients treated with RC for UCB. Lifetime cumulative smoking exposure was categorized as light short-term (≤20 CPD for ≤20 yr), light long-term (≤20 CPD for >20 yr), heavy short-term (>20 CPD for ≤20 yr), and heavy long-term (>20 CPD for >20 yr). RC and bilateral lymph node (LN) dissection without neoadjuvant chemotherapy. Logistic regression and competing risk analyses assessed the association of smoking with disease recurrence, cancer-specific mortality, and overall mortality. There was no difference in clinicopathologic factors between patients who had never smoked (20%), former smokers (46%), and current smokers (34%). Smoking status was associated with the cumulative incidence of disease recurrence (p=0.004) and cancer-specific mortality (p=0.016) in univariable analyses and with disease recurrence in multivariable analysis (p=0.02); current smokers had the highest cumulative incidences. Among ever smokers, cumulative smoking exposure was associated with advanced tumor stages (p<0.001), LN metastasis (p=0.002), disease recurrence (p<0.001), cancer-specific mortality (p=0.001), and overall mortality (p=0.037) in multivariable analyses that adjusted for standard characteristics; heavy long-term smokers had the worst outcomes, followed by light long-term, heavy short-term, and light short-term smokers. Smoking cessation ≥10 yr mitigated the risk of disease recurrence (hazard ratio [HR]: 0.44; p<0.001), cancer-specific mortality (HR: 0.42; p<0.001), and overall mortality (HR: 0.69; p=0.012) in multivariable analyses. The study is limited by its retrospective nature. Smoking is associated with worse prognosis after RC for UCB. This association seems to be dose-dependent, and its effects are mitigated by >10 yr smoking cessation. Health care practitioners should counsel smokers regarding the detrimental effects of smoking and the benefits of smoking cessation on UCB etiology and prognosis. 23300187 Successful treatment of malakoplakia of the bladder in a kitten. A 4-month-old female kitten presented with chronic lower urinary tract signs and Escherichia coli cystitis, and was diagnosed with urinary bladder malakoplakia based upon histopathology. The kitten was treated with a prolonged antibiotic course and the malakoplakia resolved. Malakoplakia is a chronic granulomatous reaction characterized by the formation of Michaelis-Gutman bodies within von Hansemann macrophages. It is well described in humans, but has never been documented in a living veterinary patient. This case report describes the first successful treatment of malakoplakia in veterinary medicine. 22897602 Pre-ICH warfarin use, not antiplatelets, increased case fatality in spontaneous ICH patients. Anticoagulant and antiplatelets for prevention of ischaemic stroke and cardiovascular diseases may increase the risk of intracerebral hemorrhage (ICH). This study aimed to investigate the influence of pre-ICH use of anticoagulant and antiplatelets on ICH patients. Consecutive patients with acute spontaneous ICH registered in a single-center stroke registry during 2001 to 2010 were analyzed and categorized according to their pre-ICH use of warfarin (Group I), antiplatelets (Group II), or neither (Group III). Survival analysis and the Cox proportional hazard model were used to compare between the three groups and the predictors. Of 2021 ICH patients (male, 63.3%; mean age, 62.6 ± 14.4 years) included, there were 94 (4.7%) in Group I, 232 (11.4%) in Group II, and 1695 (83.9%) in Group III. Warfarin users had larger hematoma volume, more intraventricular extension, higher frequencies of lobar ICH, and higher case fatality than non-warfarin users (Groups II and III). The Cox proportional hazard model showed increased 6-month case fatality in pre-ICH warfarin users (adjusted hazard ratio 2.75, 95% confidence interval 2.04-3.72, P < 0.001), but not in pre-ICH antiplatelet users (adjusted hazard ratio 0.95, 95% confidence interval 0.72-1.26). Intracerebral hemorrhage patients with prior warfarin use, but not antiplatelet use, had significantly higher case fatality at 6 months. 23354293 Broad diversity and newly cultured bacterial isolates from enrichment of pig feces on complex polysaccharides. One of the fascinating functions of mammalian intestinal microbiota is fermentation of plant cell wall components. Eight-week continuous culture enrichments of pig feces with cellulose and xylan/pectin were used to isolate bacteria from this community. A total of 575 bacterial isolates were classified phylogenetically using 16S rRNA gene sequencing. Six phyla were represented in the bacterial isolates: Firmicutes (242), Bacteroidetes (185), Proteobacteria (65), Fusobacteria (55), Actinobacteria (23), and Synergistetes (5). The majority of the bacterial isolates had ≥97 % similarity to cultured bacteria with sequences in the RDP, but 179 isolates represent new species and/or genera. Within the Firmicutes isolates, most were classified in the families of Lachnospiraceae, Enterococcaceae, Staphylococcaceae, and Clostridiaceae I. The majority of the Bacteroidetes were most closely related to Bacteroides thetaiotaomicron, Bacteroides ovatus, and B. xylanisolvens. Many of the Firmicutes and Bacteroidetes isolates were identified as species that possess enzymes that ferment plant cell wall components, and the rest likely support these bacteria. The microbial communities that arose in these enrichment cultures had broad bacterial diversity. With over 30 % of the isolates not represented in culture, there are new opportunities to study genomic and metabolic capacities of these members of the complex intestinal microbiota. 23561216 Combined impact of Bacillus stearothermophilus maltogenic alpha-amylase and surfactants on starch pasting and gelation properties. In baking applications involving starch gelatinisation, surfactants such as sodium stearoyl lactylate (SSL) and monoacylglycerols (MAG) and Bacillus stearothermophilus maltogenic alpha-amylase (BStA) can be used jointly. We here showed that SSL but not MAG delays wheat starch hydrolysis by BStA. The effects were explained in terms of different degrees of adsorption of the surfactants on the starch granule surface, retarded and/or decreased water uptake and delayed availability of gelatinised starch for hydrolysis by BStA. Additional experiments with waxy maize starch led to the conclusion that SSL impacts swelling power and carbohydrate leaching more by covering the starch granule surface than by forming amylose-lipid complexes. SSL postponed starch hydrolysis by BStA, but this did not influence subsequent starch gelation. Finally, when adding SSL or MAG on top of BStA to starch suspensions, the effect of the surfactants on gel strength predominated over that of BStA. 23415831 Addiction: a drug-induced disorder of memory reconsolidation. Persistent maladaptive memories that maintain drug seeking and are resistant to extinction are a hallmark of addiction. As such, disruption of memory reconsolidation after retrieval has received attention for its therapeutic potential. Unrestrained reconsolidation may have the opposite effect, leading to reiterative and cumulative strengthening of memory over long periods of time. Here we review the molecular mechanisms underlying reconsolidation of appetitive and drug-rewarded memories, and discuss how these findings contribute to our understanding of the nature of this process. Finally, we suggest that drug-induced alterations to signal transduction might lead to dysregulation of reconsolidation, causing enhancements of drug-related memory after retrieval, and significantly contribute to the compulsive drug seeking that is a core component of addiction. 23852161 Single KTP nanocrystals as second-harmonic generation biolabels in cortical neurons. We report an efficient colloidal synthesis of KTiOPO4 (KTP) nanocrystals with excellent crystallinity and the direct observation of optical second-harmonic generation (SHG) from discrete KTP nanocrystals in neurons cultured from mammalian brain cortex. Direct internalization and monitoring of these nanoparticles was successfully achieved without limitations from cytotoxicity, bleaching and blinking emission. 23184152 Recent progress in the development and use of organic ionic plastic crystal electrolytes. Significant progress has been made recently in the development of Organic Ionic Plastic Crystals (OIPCs), a unique family of solid state electrolytes with applications in electrochemical devices such as lithium batteries and dye-sensitised solar cells. The negligible volatility of OIPCs renders them more suitable than molecular species for long-term device use, while the high thermal and electrochemical stability of many OIPCs fulfils an essential requirement for solid state electrolytes for many device applications. However, the complex mechanisms of conduction through these materials, both in their pure state and in the presence of a small amount of a second component (such as lithium salts to enable their use in lithium batteries) are still not fully understood. At the same time, the range of anions and cations utilised in the synthesis of plastic crystal phases continues to increase. This perspective concentrates on recent research into both fundamental and device-oriented aspects of these materials. Important fundamental understanding of the physical properties and transport mechanisms of different OIPCs has been achieved through use of techniques including variable temperature solid-state NMR and crystallographic analysis, as well as detailed molecular dynamics simulations. In parallel, the applicability of these materials as electrolytes for dye-sensitised solar cells and lithium batteries is being more widely demonstrated. The possibility of using OIPCs as solid state electrolytes for fuel cells is also discussed. 23494901 The Role of Traditional Chinese Medicines in Osteogenesis and Angiogenesis. The article aims to review various Traditional Chinese Medicines (TCMs) with both osteogenic and angiogenic effects, alone and in combination, and to consider whether these TCMs promote osteogenesis via angiogenesis and vascular endothelial growth factor (VEGF). Each of the TCMs involving in osteogenesis was searched through PubMed and CBMdisc using its Latin name and English name, and keywords such as 'osteogenesis', 'bone', 'osteoblast', 'angiogenesis', 'VEGF' were used. A total of 241 articles were screened from PubMed and CBMdisc. The articles were only chosen if they discussed the relationship of the TCMs with bone formation and/or angiogenesis. Twenty-seven articles were chosen, of which 16 were in English and 11 were in Chinese with English abstract. As a result, the TCMs (Danshen or Salvia miltiorrhiza Bunge, Danggui or Angelica sinensis, Astragalus membranaceus Bunge or Huangqi, and Ge Gan or Puerarin radix) that have a relationship with both osteogenesis and angiogenesis were screened out. It is found that the aforementioned TCMs enhance angiogenesis and osteogenesis. They show a positive effect on bone formation, and the possible mechanisms may be related to their ability to promote angiogenesis via an effect on substances such as VEGF. Copyright © 2013 John Wiley & Sons, Ltd. 23813622 Sensing Chiral Drugs by Using CdSe/ZnS Nanoparticles Capped with N-Acetyl-L-Cysteine Methyl Ester. Chiral quantum dots (QDs), differing in their core or shell size and, consequently, in their optical properties, were synthesized by the treatment of commercially available amine-capped quantum dots with methyl ester N-acetyl-L-cysteine (CysP). Interestingly, their colloidal methanol solutions remain stable for several months. Their NMR and IR spectra were in accordance with CysP binding to the QD surface through two anchoring groups; its thiolate (strongly bound) and the carbonyl group of its ester (weaker bound) group, whereas their circular dichroism (CD) spectra showed a new broad redshifted band, suggesting that the attachment to the QD surface modified the conformational equilibrium towards conformer(s) with optical activity in this region. These QDs were sufficiently fluorescent to perform studies of the chiral recognition of drugs, in particular the aryl propionic acids (APAs) ketoprofen (KP), naproxen (NP), flurbiprofen (FP), and ibuprofen (IP). We used different drug concentration ranges, depending on the QD solubility. All the assayed drugs quenched the QD emission in a concentration-dependent mode. Quenching fluorescence assays with the chiral QDs (CS@CysP) showed their extraordinary capacity for the chiral recognition of KP, NP, and FP, and particularly in the case of KP and FP, a remarkable positive allosteric effect was detected for the R enantiomer. By using a drug/CS@CysP molar ratio of 5000:1 and 2500:1, the changes of intensity and the sign of the CD spectrum of the drug evidenced the dissociation of the drug carboxylic group in the presence of the QD. 23289963 Physical performance tests, self-reported outcomes, and accidental falls before and after total knee arthroplasty: an exploratory study. This longitudinal, observational study explored the relationship between physical performance tests, self-reported outcomes, and accidental falling, before and after total knee arthroplasty (TKA). Thirty-seven patients were randomly selected from a larger study of falling before and after surgery conducted at a UK National Health Service Orthopaedic Unit. Physical performance tests were the Berg Balance Score (BBS), Timed Up and Go (TUG), and Hand Grip Strength (HGS). Self-reported outcomes incorporated the Western Ontario and McMaster's Osteoarthritis Index (WOMAC), Activities Balance Confidence Scale (ABC-UK), Geriatric Depression Scale (GDS), and accidental falls. Paired pre- and postoperative data were available on 22 patients. A total of 22.7% patients fell before and after TKA. Postoperative improvement in BBS and TUG was found in 41% and 50% of patients, respectively, HGS did not change. BBS showed a consistent moderate-to-strong association with other physical tests both before and after surgery; TUG (rs -0.76; rs -0.90), maximal HGS (r 0.49; r 0.48), and self-report measures; ABC-UK (r 0.52; r 0.74), WOMAC stiffness (r -0.53; r -0.48), and WOMAC function (r -0.56; r -0.45). Although self-report questionnaires are an efficient, cost-effective approach to outcome assessment in TKA, there is a growing case for inclusion of physical performance tests. The Berg Balance Score may be a useful addition to outcome assessment in patients with TKA. 23875896 Ecological implications of single and mixed nitrogen nutrition in Arabidopsis thaliana. Ecologists recognize that plants capture nitrogen in many chemical forms that include amino acids. Access to multiple nitrogen types in plant communities has been argued to enhance plant performance, access to nitrogen and alter ecological interactions in ways that may promote species coexistence. However, data supporting these arguments have been limited. While it is known that plants uptake amino acids from soil, long term studies that link amino acid uptake to measures of plant performance and potential reproductive effort are not typically performed. Here, a series of experiments that link uptake of nitrate, glutamine or asparagine with lifetime reproductive effort in Arabidopsis thaliana are reported. Nitrogen was offered either singly or in mixture and at a variety of combinations. Traits related to reproductive output were measured, as was the preference for each type of nitrogen. When plants were supplied with a single nitrogen type at concentrations from 0.1-0.9 mM, the ranking of nitrogen types was nitrate > glutamine > asparagine in terms of the relative performance of plants. When plants were supplied with two types of nitrogen in mixture at ratios between 0.1:0.9-0.9:0.1 mM, again plants performed best when nitrate was present, and poorly when amino acids were mixed. Additionally, stable isotopes revealed that plants preferentially captured nitrogen types matching the hierarchy of nitrate > glutamine > asparagine. Comparing between the two experiments revealed that mixed nitrogen nutrition was a net cost to the plants. Plant performance on mixed nitrogen was less than half the performance on equal amounts of any single nitrogen type. We asked: why did A. thaliana capture amino acids when doing so resulted in a net cost? We argue that available data cannot yet answer this question, but hypothesize that access to lower quality forms of nitrogen may become important when plants compete. 23836555 VAAST 2.0: Improved Variant Classification and Disease-Gene Identification Using a Conservation-Controlled Amino Acid Substitution Matrix. The need for improved algorithmic support for variant prioritization and disease-gene identification in personal genomes data is widely acknowledged. We previously presented the Variant Annotation, Analysis, and Search Tool (VAAST), which employs an aggregative variant association test that combines both amino acid substitution (AAS) and allele frequencies. Here we describe and benchmark VAAST 2.0, which uses a novel conservation-controlled AAS matrix (CASM), to incorporate information about phylogenetic conservation. We show that the CASM approach improves VAAST's variant prioritization accuracy compared to its previous implementation, and compared to SIFT, PolyPhen-2, and MutationTaster. We also show that VAAST 2.0 outperforms KBAC, WSS, SKAT, and variable threshold (VT) using published case-control datasets for Crohn disease (NOD2), hypertriglyceridemia (LPL), and breast cancer (CHEK2). VAAST 2.0 also improves search accuracy on simulated datasets across a wide range of allele frequencies, population-attributable disease risks, and allelic heterogeneity, factors that compromise the accuracies of other aggregative variant association tests. We also demonstrate that, although most aggregative variant association tests are designed for common genetic diseases, these tests can be easily adopted as rare Mendelian disease-gene finders with a simple ranking-by-statistical-significance protocol, and the performance compares very favorably to state-of-art filtering approaches. The latter, despite their popularity, have suboptimal performance especially with the increasing case sample size. 23915472 Investigating the influence of working memory capacity when driving behavior is combined with cognitive load: An LCT study of young novice drivers. Distracted driving has received increasing attention in the literature due to potential adverse safety outcomes. An often posed solution to alleviate distraction while driving is hands-free technology. Interference by distraction can occur however at the sensory input (e.g., visual) level, but also at the cognitive level where hands-free technology induces working memory (WM) load. Active maintenance of goal-directed behavior in the presence of distraction depends on WM capacity (i.e., Lavie's Load theory) which implies that people with higher WM capacity are less susceptible to distractor interference. This study investigated the interaction between verbal WM load and WM capacity on driving performance to determine whether individuals with higher WM capacity were less affected by verbal WM load, leading to a smaller deterioration of driving performance. Driving performance of 46 young novice drivers (17-25 years-old) was measured with the lane change task (LCT). Participants drove without and with verbal WM load of increasing complexity (auditory-verbal response N-back task). Both visuospatial and verbal WM capacity were investigated. Dependent measures were mean deviation in the lane change path (MDEV), lane change initiation (LCI) and percentage of correct lane changes (PCL). Driving experience was included as a covariate. Performance on each dependent measure deteriorated with increasing verbal WM load. Meanwhile, higher WM capacity related to better LCT performance. Finally, for LCI and PCL, participants with higher verbal WM capacity were influenced less by verbal WM load. These findings entail that completely eliminating distraction is necessary to minimize crash risks among young novice drivers. 23686570 Comparing the effects of nanosilver size and coating variations on bioavailability, internalization, and elimination, using Lumbriculus variegatus. As the production and applications of silver nanoparticles (AgNPs) increase, it is essential to characterize fate and effects in environmental systems. Nanosilver materials may settle from suspension; therefore, the authors' objective was to utilize environmentally relevant bioassays and study the impact, bioaccumulation, tissue distribution, uptake, and depuration of AgNPs on a sediment-dwelling invertebrate, Lumbriculus variegatus. Hydrodynamic diameters of uncoated 30-nm, 80-nm, and 1500-nm AgNP powders and a polyvinyl pyrrolidone (PVP) AgNP suspension were measured utilizing dynamic light scattering in freshwater media (0-280 µS/cm). Aggregation for 30 nm, 80 nm, and 1500 nm silver increased with conductivity but was minimal for PVP silver. Lumbriculus variegatus were exposed to AgNPs or silver nitrate (AgNO3 ) spiked into sediment (nominally 100 mg/kg) and water (PVP 30 nm and 70 nm Ag, nominally 5 mg/L). Uptake was assessed through inductively coupled plasma mass spectroscopy (ICP-MS) and hyperspectral imaging. Particle sizes were examined through field flow fractionation-ICP-MS (FFF-ICP-MS) and ICP-MS in single particle mode (SP-ICP-MS). Lumbriculus variegatus were also depurated for 6 h, 8 h, 24 h, and 48 h to determine gut clearance. Bioaccumulation factors of sediment-exposed L. variegatus were similar regardless of particle size or coatings. The FFF-ICP-MS and SP-ICP-MS detected AgNPs for up to 48 h post depuration. The present study provides information on bioaccumulation and interactions of AgNPs within biological systems. Environ Toxicol Chem 2013;32:2069-2077. © 2013 SETAC. 23559163 A missense mutation in the sodium channel β2 subunit reveals SCN2B as a new candidate gene for Brugada syndrome. Brugada Syndrome (BrS) is a familial disease associated with sudden cardiac death. A 20%-25% of BrS patients carry genetic defects that cause loss-of-function of the voltage-gated cardiac sodium channel. Thus, 70%-75% of patients remain without a genetic diagnosis. In this work, we identified a novel missense mutation (p.Asp211Gly) in the sodium β2 subunit encoded by SCN2B, in a woman diagnosed with BrS. We studied the sodium current (INa ) from cells coexpressing Nav 1.5 and wild-type (β2WT) or mutant (β2D211G) β2 subunits. Our electrophysiological analysis showed a 39.4% reduction in INa density when Nav 1.5 was coexpressed with the β2D211G. Single channel analysis showed that the mutation did not affect the Nav 1.5 unitary channel conductance. Instead, protein membrane detection experiments suggested that β2D211G decreases Nav 1.5 cell surface expression. The effect of the mutant β2 subunit on the INa strongly suggests that SCN2B is a new candidate gene associated with BrS. 23943617 Discovery of β-1,4-D-mannosyl-N-acetyl-D-glucosamine phosphorylase involving in the metabolism of N-glycans. A gene cluster involved in N-glycan metabolism was identified in the genome of B. thetaiotaomicron VPI-5482. This gene cluster encodes a major facilitator superfamily transporter, a starch utilization system-like transporter consisting of a TonB-dependent oligosaccharide transporter and an outer membrane lipoprotein, 4 glycoside hydrolases (α-mannosidase, β-N-acetylhexosaminidase, exo-α-sialidase, and endo-β-N-acetylglucosaminidase), and a phosphorylase (BT1033) with unknown function. It was demonstrated that BT1033 catalyzed the reversible phosphorolysis of β-1,4-D-mannosyl-N-acetyl-D-glucosamine in a typical sequential bi-bi mechanism. These results indicate that BT1033 plays a crucial role as a key enzyme in the N-glycan catabolism where β-1,4-D-mannosyl-N-acetyl-D-glucosamine is liberated from N-glycans by sequential glycoside hydrolase-catalyzed reactions, transported into the cell, and intracellularly converted into α-D-mannose 1-phosphate and N-acetyl-D-glucosamine. In addition, intestinal anaerobic bacteria such as B. fragilis, B. helcogenes, B. salanitronis, B. vulgatus, Prevotella denticola, P. dentalis, P. melaninogenica, Parabacteroides distasonis, and Alistipes finegoldii were also suggested to possess the similar metabolic pathway for N-glycans. A notable feature of the new metabolic pathway for N-glycans is the more efficient use of ATP-stored energy, in comparison with the conventional pathway where β-mannosidase and ATP-dependent hexokinase participate, because it is possible to directly phosphorylate the D-mannose residue of β-1,4-D-mannosyl-N-acetyl-D-glucosamine to enter glycolysis. This is the first report of a metabolic pathway for N-glycans that includes a phosphorylase. We propose 4-O-β-D-mannopyranosyl-N-acetyl-D-glucosamine: phosphate α-D-mannosyltransferase as the systematic name and β-1,4-D-mannosyl-N-acetyl-D-glucosamine phosphorylase as the short name for BT1033. 23958462 Sinonasal squamous cell carcinomas: Clinical outcomes and predictive factors. This was a retrospective study of 33 patients treated for sinonasal squamous cell carcinoma between 1995 and 2008. Epidemiological, clinical, histological, and therapeutic aspects of this series of patients were analysed, and their impacts on overall survival and disease-free survival established using the Kaplan-Meier method. A search for prognostic factors was made using a log-rank test. There were 27 men. The average age at diagnosis was 64.7 years. Tobacco-smoking was found to be a risk factor in 24 patients (72.7%). The median follow-up was 66 months (range 0-99 months). Tumours were classified as T1 in 18.3%, T2 in 27.3%, T3 in 6%, and T4 in 48.5% of cases. Disease-free survival rates at 1 and 5 years were 58.5% and 46.1%, respectively, and overall survival rates were 70.3% and 40%, respectively. Overall survival was correlated to tumour status (TNM, American Joint Committee on Cancer) (P=0.010) and involvement of key structures (skull base, dura mater, brain, orbit, cavernous sinus, infratemporal fossa, skin) (P=0.049). Surgery followed by radiotherapy improved overall survival (P=0.005) and disease-free survival (P=0.028) when compared to other treatment modalities. When compared to surgery alone, it improved disease-free survival (P=0.049) regardless of tumour stage. 22631435 Fostering excellence: development of a course to prepare graduate students for research on migration and health. Canada is an immigrant-receiving nation and many graduate students in nursing and other disciplines pursue immigrant health research. As these students often start with inadequate understanding of the policy, theoretical, and research contexts in which their work should be situated, we became concerned that the theses and dissertations were less sophisticated than were both possible and desirable. This led to development of a PhD-level course titled Migration and Health in the Canadian Context. In this study, we provide an analytic overview including course description, objectives, assignments, and specific class topics. Areas of focus include historical and theoretical considerations; determinants of immigrant health; refugee health; cultural competence and cultural safety; research challenges, approaches, and skills; policy-relevant research; and educational imperatives in the health and related disciplines. Salient research is introduced in each of these classes. While Canada is the main focus, comparative data are provided and there is relevance for nurse-researchers in other immigrant-receiving countries. 23477296 Neural antecedents of emotional disorders: a functional magnetic resonance imaging study of subsyndromal emotional symptoms in adolescent girls. Emotional symptoms (ES) emerge forme fruste in adolescence, before manifesting as fully fledged emotional disorders. Studies indicate that subsyndromal ES precede the onset of emotional disorders. We hypothesized that adolescents showing subsyndromal ES will show perturbations in the emotion regulatory frontolimbic network (FLN) during emotion processing. Fifty-eight female adolescents underwent functional magnetic resonance imaging while viewing an image-based emotion-processing task. Within this sample, 33 (56.9%) displayed emotional symptoms and 25 (43.1%) did not. Clinical measures, including assessments of mood and anxiety, were administered and participants were allocated to one of two groups based on the presence (ES+) or absence (ES-) of subsyndromal ES. Group comparisons were used to identify differential patterns of neural engagement and their relationship to clinical variables. Groups displayed emotion-specific differences in FLN activity with increased frontal activity in ES+ girls during positive emotion processing and decreased frontal and limbic activity during negative emotion processing. Trait anxiety was the strongest clinical predictor of group membership (ES+ versus ES-) and displayed a significant negative correlation with hippocampal neural activity during negative emotion processing. In addition, between the groups, the hippocampus displayed a pattern of reverse coupling with the amygdala and insula that was also significantly correlated with trait anxiety. There is divergence in the pattern of FLN neural processing in adolescent female subjects determined by emotional symptoms. Future research is needed to corroborate these findings and to underline their implications longitudinally. 23824168 Hybrid axial and radial Si-GaAs heterostructures in nanowires. Hybrid structures are formed from materials of different families. Traditionally, group IV and III-V semiconductors have not been integrated together in the same device or application. In this work we present a new approach for obtaining Si-GaAs hybrid heterostructures in nanowires based on a combination of molecular beam epitaxy and plasma enhanced chemical vapor deposition. Crystalline Si segments are integrated into GaAs nanowires grown by the Ga-assisted growth method at temperatures as low as 250 °C. We find that one of the most important factors leading to the successful growth of Si segments on GaAs is the silane-hydrogen dilution, which affects the concentration of silicon and hydrogen-based radicals (SiHx with x < 3) in the plasma, and determines if the Si shell is amorphous, polycrystalline or crystalline, and also if the growth takes place in the axial and/or radial directions. This work opens the path for the successful integration of silicon and III-V materials in one single nanowire. 23664949 Mean-based neural coding of voices. The social significance of recognizing the person who talks to us is obvious, but the neural mechanisms that mediate talker identification are unclear. Regions along the bilateral superior temporal sulcus (STS) and the inferior frontal cortex (IFC) of the human brain are selective for voices, and they are sensitive to rapid voice changes. Although it has been proposed that voice recognition is supported by prototype-centered voice representations, the involvement of these category-selective cortical regions in the neural coding of such "mean voices" has not previously been demonstrated. Using fMRI in combination with a voice identity learning paradigm, we show that voice-selective regions are involved in the mean-based coding of voice identities. Voice typicality is encoded on a supra-individual level in the right STS along a stimulus-dependent, identity-independent (i.e., voice-acoustic) dimension, and on an intra-individual level in the right IFC along a stimulus-independent, identity-dependent (i.e., voice identity) dimension. Voice recognition therefore entails at least two anatomically separable stages, each characterized by neural mechanisms that reference the central tendencies of voice categories. 23030309 Pharmacokinetic properties and bioequivalence of candesartan cilexetil in Korean healthy volunteers. Candesartan is a long-acting and selective nonpeptide AT1 subtype angiotensin II receptor antagonist. The aim of this study was to compare the pharmacokinetics and to evaluate the bioequivalence of two candesartan cilexetil 16 mg formulations. Forty healthy volunteers were randomly assigned into two groups. After a single dose of 16 mg candesartan cilexetil oral administration, blood samples were collected at specific time intervals from 0-36 h. The plasma concentrations of candesartan cilexetil were determined by LC-MS/MS. The pharmacokinetic parameters such as AUClast, AUCinf and Cmax were calculated and the 90% confidence intervals of the ratio (test/reference) pharmacokinetic parameters were obtained by analysis of variance on logarithmically transformed data. The mean for AUClast in the reference and the test drug were 1530.1 ± 434.6 and 1315.7 ± 368.6 ng·h/mL. The mean for AUCinf in the reference and the test drug were 1670.0 ± 454.5 and 1441.2 ± 397.8 ng·h/mL. The mean value for Cmax in the reference and the test drug was 142.6 ± 41.0 and 134.9 ± 41.4 ng/mL. The 90% confidence intervals for the AUClast, AUCinf and Cmax were in the range of log 0.81-log 0.91, log 0.81-log 0.91 and log 0.88-log1.01, respectively. No adverse events were reported by subjects or found on analysis of vital signs or laboratory tests. This single dose study found that the test and reference products met the regulatory criteria for bioequivalence in these health volunteers. Both formulations were safe and well tolerated in 16 mg of candesartan cilexetil hydrochloride. 23873779 Unraveling the Interaction between the LPS O-Antigen of Burkholderia anthina and the 5D8 Monoclonal Antibody by Using a Multidisciplinary Chemical Approach, with Synthesis, NMR, and Molecular Modeling Methods. The interaction between the O-chain from the lipopolysaccharide from Burkholderia anthina and a lipopolysaccharide-specific monoclonal antibody (5D8) has been studied at high resolution by NMR spectroscopy. In particular, the 5D8-bound epitope of the saccharide entity has been unraveled by a combination of saturation transfer difference (STD) and transferred NOESY (tr-NOESY) experiments performed on the 5D8/polysaccharide complex. To dissect the fine details of the molecular recognition events, further experiments with simpler carbohydrate ligands were carried out. Thus, experiments were also performed with ad hoc synthesized trisaccharide and hexasaccharide O-antigen repeating units. By using this multidisciplinary approach (chemical synthesis, NMR spectroscopy and molecular dynamics simulation), determination of the binding epitope and the contribution to the binding of the sugar units composing the O-chain have been determined. 23868271 Physical Activity Frequency and Risk of Incident Stroke in a National US Study of Blacks and Whites. Regular physical activity (PA) is an important recommendation for stroke prevention. We compared the associations of self-reported PA with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. REGARDS recruited 30 239 US blacks (42%) and whites, aged ≥45 years with follow-up every 6 months for stroke events. Excluding those with prior stroke, analysis involved 27 348 participants who reported their frequency of moderate to vigorous intensity PA at baseline according to 3 categories: none (physical inactivity), 1 to 3×, and ≥4× per week. Stroke and transient ischemic attack cases were identified during an average of 5.7 years of follow-up. Cox proportional hazards models were constructed to examine whether self-reported PA was associated with risk of incident stroke. Physical inactivity was reported by 33% of participants and was associated with a hazard ratio of 1.20 (95% confidence intervals, 1.02-1.42; P=0.035). Adjustment for demographic and socioeconomic factors did not affect hazard ratio, but further adjustment for traditional stroke risk factors (diabetes mellitus, hypertension, body mass index, alcohol use, and smoking) partially attenuated this risk (hazard ratio, 1.14 [0.95-1.37]; P=0.17). There was no significant association between PA frequency and risk of stroke by sex groups, although there was a trend toward increased risk for men reporting PA 0 to 3× a week compared with ≥4× a week. Self-reported low PA frequency is associated with increased risk of incident stroke. Any effect of PA is likely to be mediated through reducing traditional risk factors. 23918315 Implication of the chemokine CCL2 in trigeminal nociception and traumatic neuropathic orofacial pain. Chemokine (C-C motif) ligand 2 (CCL2) participates in different mechanisms contributing to the spinal cord inflammation and pain development after sciatic nerve injury. Recent data also support its role in orofacial thermal hypersensitivity, although its implication in different phases of trigeminal pain emergence is unclear. We assessed the importance of CCL2 signalling in biochemical and behavioural alterations during the early and late stages following chronic constriction injury of infraorbital nerve (ION-CCI), a model of peripheral traumatic trigeminal pain. After evaluating the consequences of CCL2 intracisternal injection in naïve rats, we determined the expression changes for CCL2, inflammatory and glia activation markers in the somatosensory trigeminal complex (STC) and trigeminal ganglia (TG) after ION-CCI. The role of CCL2 signalling was assessed using pre-emptive or 'curative' intracisternal treatment with specific CCL2 receptor antagonist - INCB3344. Exogenous CCL2 evoked spontaneous behaviour reminiscent of orofacial pain and marked mechanical hypersensitivity, associated with increased expression of proinflammatory cytokines and glial markers in STC and TG. CCL2-evoked changes were prevented by the co-administration of INCB3344. Two weeks after ION-CCI, mRNA for CCL2, glial and inflammatory markers were up-regulated, and CCL2-immunoreactivity accumulated in central and ganglionic tissues. At this time, repeated intracisternal administration of INCB3344 did not attenuate the ION-CCI-associated behavioural nor biochemical changes. By contrast, pre-emptive INCB3344 treatment delayed the emergence of trigeminal mechanical allodynia and associated biochemical alterations. Our data suggest that CCL2 is involved principally in the early events accompanying the ION lesion rather than in long-term alterations and the maintenance of trigeminal mechanical hypersensitivity. 23924262 Vocational rehabilitation services and employment outcomes for adults with cerebral palsy in the United States. The aim of this study was to examine the relationship between vocational rehabilitation services provided and work outcomes among people with cerebral palsy (CP), taking in to account demographic characteristics. From the US Department of Education Rehabilitation Service Administration Case Service Report (RSA-911) database, data from 3162 individuals with CP (1820 males [57.6%] and 1342 females [42.4% age range 16-54y) whose cases were closed in 2009, were used in this study. A total of 1567 cases (49.6%) were closed with clients being categorized as 'successful employment' and 1595 cases (50.4%) were closed with clients being classified as unemployed. Multivariate logistic regression was used to examine the relationship between services provided and work outcomes with regard to demographic characteristics. Males aged between 26 and 54 years old with higher education attainment were more likely to be employed. Individuals receiving disability benefits were less likely to be employed. After controlling for the effect of demographic and work disincentive variables, five vocational rehabilitation services significantly predicted employment outcomes (p<0.05), including (1) on-the-job training; (2) job placement assistance; (3) on-the-job support; (4) maintenance services; and (5) rehabilitation technology. Medical and health professionals need to be aware of vocational rehabilitation agencies as a resource for providing medical, psychological, educational, and vocational interventions for adults with CP to help them maximize their employability, to address their much needed work adjustment skills, to establish independent living, and to eventually reach their full potential in participation in society. 23620130 Sexually violent predators: toward reasonable estimates of recidivism base rates. The sexual recidivism rate of sex offenders is a controversial issue. Perhaps as controversial is the sexual recidivism rate of the select group of sex offenders who are examined pursuant to sexually violent predator (SVP) statutes. At present, reliable estimates of SVP recidivism are unavailable. We propose that reasonable estimates of SVP recidivism can be reached by considering three available pieces of data: (i) a likely recidivism rate of the general population of sex offenders; (ii) procedures typically followed by jurisdictions that civilly commit sex offenders; and (iii) classification accuracy of procedures. Although sexual recidivism rates vary across jurisdictions, the results of our analyses suggest sex offenders referred for examination pursuant to SVP statutes recidivate at substantially higher rates than typical sex offenders. Our results further suggest that sex offenders recommended for commitment as SVPs recidivate at even greater rates than SVP respondents who are not recommended for commitment. We discuss practice and policy implications of these findings. Copyright © 2013 John Wiley & Sons, Ltd. 23963158 Metal array fabrication based on ultrasound-induced self-assembly of metalated dipeptides. Pd- and Pt-bound bis-metalated peptides were synthesised by the condensation of Pd- or Pt-aldimine-complex-bound glutamic acids to afford the four possible metal isomers of bis-Pd and bis-Pt-homometalated dipeptides and PdPt- and PtPd-heterometalated dipeptides without metal disproportionation. Ultrasound-induced self-assembly of these bis-metalated peptides proceeded effectively to afford supramolecular gels that displayed well-ordered metal arrays. The formation of parallel β-sheet type aggregates through interpeptide amide-amide hydrogen bonding was confirmed by IR, scanning electron microscopy (SEM), and synchrotron X-ray diffraction analyses (WAXS and SAXS). The mechanism of the ultrasound-induced self-assembly of the metalated dipeptides was elucidated via kinetic and association experiments by (1)H NMR, in which ultrasound-triggered dissociation of intramolecular hydrogen bonds between the chloride ligands of the Pd- and Pt-complexes and amides initially occurred. This was followed by the formation of intermolecular amide-amide hydrogen bonds, which afforded the corresponding oligomeric peptide self-assembly as the nucleus for supramolecular aggregation. The observed first-order relationship of the gelation rate versus the sonication frequency suggested that the microcavitation generated under sonication conditions acted as a crucial trigger and provided a reaction field for efficient self-assembly. 22633681 Prognostic significance of smoking in patients with acute ischemic stroke within 3 months of onset. Various factors that have been implicated in recovery after the acute phase of stroke have not been well evaluated. To identify prognostic factors affecting outcomes at 90 days after stroke from the viewpoint of recovery patterns, we enrolled 660 patients from the Edaravone and Argatroban Stroke Therapy for Acute Ischemic Stroke study database. Fourteen groups of patients were identified based on an analysis of their recovery patterns according to changes in their National Institutes of Health Stroke Scale scores during the first 21 days. These groups were then divided into 2 groups: favorable recovery trend (patterns 1-3; n = 486) and poor recovery trend (patterns 4-14; n = 174). Patterns with >80% of the patients experiencing a favorable outcome (National Institutes of Health Stroke Scale score of ≤4 at 90 days) were defined as the favorable recovery trend group, whereas patterns that included ≤80% favorable outcomes were defined as the poor recovery trend group. Using the poor recovery trend group, logistic regression analysis found that after controlling for covariates, lower scores at admission, fewer ischemic lesions, and nonsmoking were significant prognostic factors for a favorable outcome at 90 days. Based on a detailed analysis of the relationship between recovery patterns after stroke and clinical outcomes in the chronic stage of stroke, smoking cessation may improve the prognosis of patients after stroke. 23906993 Uncovering the epidemic of HIV among men who have sex with men in Central Asia. Research among people who inject drugs (PWID) in Central Asia has described same sex behavior among male PWID and may be associated with HIV and other infections. Little is known about the population of men who have sex with men (MSM) and the burden of HIV among MSM in Central Asian countries. We conducted a comprehensive search of peer-reviewed publications and gray literature on MSM and HIV in the region. Search strategies included terms for MSM combined with five Central Asian countries and neighbors, including Mongolia, Afghanistan, and Xinjiang Province, China. 230 sources were identified with 43 eligible for inclusion: 12 provided HIV prevalence and population size estimates for MSM, none provided incidence estimates, and no publications for Turkmenistan were identified. National reports estimate HIV prevalence among MSM to range from 1 to 2% in Kazakhstan, Kyrgyzstan, Tajikistan, Uzbekistan, Xinjiang, to 10% in Mongolia. Biobehavioral studies estimated HIV prevalence at 0.4% in Afghanistan and 20.2% in Kazakhstan. Sexual identities and behaviors vary across countries. Injection drug use was relatively low among MSM (<5% for most). Non-injection drugs, alcohol use prior to sex, and binge drinking were more common and potentially associated with violence. Criminalization of homosexuality (Afghanistan, Uzbekistan, and Turkmenistan) and stigma has limited research and HIV prevention. Improved understanding of risks, including potential linkages between sexual exposures and substance use, among MSM are important for response. The little known about HIV among MSM in Central Asia speaks to the urgency of improvements in HIV research, prevention, and care. 23874558 Curve fitting of the corporate recovery rates: the comparison of Beta distribution estimation and kernel density estimation. Recovery rate is essential to the estimation of the portfolio's loss and economic capital. Neglecting the randomness of the distribution of recovery rate may underestimate the risk. The study introduces two kinds of models of distribution, Beta distribution estimation and kernel density distribution estimation, to simulate the distribution of recovery rates of corporate loans and bonds. As is known, models based on Beta distribution are common in daily usage, such as CreditMetrics by J.P. Morgan, Portfolio Manager by KMV and Losscalc by Moody's. However, it has a fatal defect that it can't fit the bimodal or multimodal distributions such as recovery rates of corporate loans and bonds as Moody's new data show. In order to overcome this flaw, the kernel density estimation is introduced and we compare the simulation results by histogram, Beta distribution estimation and kernel density estimation to reach the conclusion that the Gaussian kernel density distribution really better imitates the distribution of the bimodal or multimodal data samples of corporate loans and bonds. Finally, a Chi-square test of the Gaussian kernel density estimation proves that it can fit the curve of recovery rates of loans and bonds. So using the kernel density distribution to precisely delineate the bimodal recovery rates of bonds is optimal in credit risk management. 23723369 A Novel APOB Mutation Identified by Exome Sequencing Cosegregates With Steatosis, Liver Cancer, and Hypocholesterolemia. In familial hypobetalipoproteinemia, fatty liver is a characteristic feature, and there are several reports of associated cirrhosis and hepatocarcinoma. We investigated a large kindred in which low-density lipoprotein cholesterol, fatty liver, and hepatocarcinoma displayed an autosomal dominant pattern of inheritance. The proband was a 25-year-old female with low plasma cholesterol and hepatic steatosis. Low plasma levels of total cholesterol and fatty liver were observed in 10 more family members; 1 member was affected by liver cirrhosis, and 4 more subjects died of either hepatocarcinoma or carcinoma on cirrhosis. To identify the causal mutation in this family, we performed exome sequencing in 2 participants with hypocholesterolemia and fatty liver. Approximately 22 400 single nucleotide variants were identified in each sample. After variant filtering, 300 novel shared variants remained. A nonsense variant, p.K2240X, attributable to an A>T mutation in exon 26 of APOB (c.6718A>T) was identified, and this variant was confirmed by Sanger sequencing. The gentotypic analysis of 16 family members in total showed that this mutation segregated with the low cholesterol trait. In addition, genotyping of the PNPLA3 p.I148M did not show significant frequency differences between carriers and noncarriers of the c.6718A>T APOB gene mutation. We used exome sequencing to discover a novel nonsense mutation in exon 26 of APOB (p.K2240X) responsible for low cholesterol and fatty liver in a large kindred. This mutation may also be responsible for cirrhosis and liver cancer in this family. 23914192 Taxonomy and systematics are key to biological information: Arabidopsis, Eutrema (Thellungiella), Noccaea and Schrenkiella (Brassicaceae) as examples. Taxonomy and systematics provide the names and evolutionary framework for any biological study. Without these names there is no access to a biological context of the evolutionary processes which gave rise to a given taxon: close relatives and sister species (hybridization), more distantly related taxa (ancestral states), for example. This is not only true for the single species a research project is focusing on, but also for its relatives, which might be selected for comparative approaches and future research. Nevertheless, taxonomical and systematic knowledge is rarely fully explored and considered across biological disciplines. One would expect the situation to be more developed with model organisms such as Noccaea, Arabidopsis, Schrenkiella and Eutrema (Thellungiella). However, we show the reverse. Using Arabidopsis halleri and Noccaea caerulescens, two model species among metal accumulating taxa, we summarize and reflect past taxonomy and systematics of Arabidopsis and Noccaea and provide a modern synthesis of taxonomic, systematic and evolutionary perspectives. The same is presented for several species of Eutrema s. l. and Schrenkiella recently appeared as models for studying stress tolerance in plants and widely known under the name Thellungiella. 23934708 Sympathetic Vasomotor Tone Is Associated With Depressive Symptoms in Young Females: A Potential Link Between Depression and Cardiovascular Disease. Although increased sympathetic nervous system (SNS) activity is commonly associated with major depressive disorder (MDD) and cardiovascular disease (CVD), a biomarker linking these two entities remains elusive. We therefore evaluated the relationship between depressive symptoms and cardiovascular modulation by heart rate variability (HRV), brachial blood pressure (BP), ambulatory BP (ABP), and low frequency component of systolic BP variability (LFSBP), a surrogate of sympathetic vasomotor tone. We hypothesized that LFSBP would be the strongest predictor of depressive symptoms compared with HRV and BP measurements. Eighty young healthy female subjects (20.51±2.82 years) were evaluated for depressive symptoms using the Center for Epidemiologic Studies Depression Scale (CES-D). Data collection was conducted after a 10-minute resting period. Beat-to-beat BPs were recorded for 5-minute at baseline (BASE) followed by a 3-minute cold pressor test (CPT). ABP was obtained for 24 hours. Hierarchical multiple regression analyses indicated that LFSBP at BASE was a stronger predictor of CES-D variance than BP and HRV indices, with LFSBP uniquely accounting for 8.1% of variance in CES-D scores during laboratory beat-by-beat BP assessments and 44.7% in ABP assessments. Individuals with acute depression scores (n = 12; CES-D ≥ 16) had significantly higher (P < 0.001) mean LFSBP values (6.66±2.54mm Hg(2)) than the remaining sample (3.32±2.2mm Hg(2)), whereas no other significant differences were detected in any of the other cardiovascular variables. Cardiovascular responses to CPT did not predict CES-D scores. These findings suggest that LFSBP could be a biomarker of neurovascular functioning with potential clinical implications for understanding the interaction between MDD and CVD. 23292906 A fast protocol for infarct quantification in mice. To demonstrate and validate a late gadolinium enhancement (LGE) imaging protocol, optimized for tissue viability assessment in interventional mouse models of myocardial infarction. The method uses an efficient sampling scheme using multiple slices in a single heartbeat interleaving slice packages between alternate TRs. Sampling multiple slices instead of multiple echoes or multiple k-lines achieves higher SNR efficiency, and images covering the whole heart can be obtained in 3 min. Saturation effects are exploited for an optimum compromise between contrast and speed. The images obtained show high hyperenhancement with good contrast-to-noise. It is shown that inversion time optimization can be reliably omitted with this scheme, and that measured infarct sizes correlate well with histological measures. Our protocol offers a new efficient tool for the measurement of infarct size in mouse models of heart disease. J. Magn. Reson. Imaging 2013;38:468-473. © 2012 Wiley Periodicals, Inc. 23928573 Scavenger receptors in homeostasis and immunity. Scavenger receptors were originally identified by their ability to recognize and to remove modified lipoproteins; however, it is now appreciated that they carry out a striking range of functions, including pathogen clearance, lipid transport, the transport of cargo within the cell and even functioning as taste receptors. The large repertoire of ligands recognized by scavenger receptors and their broad range of functions are not only due to the wide range of receptors that constitute this family but also to their ability to partner with various co-receptors. The ability of individual scavenger receptors to associate with different co-receptors makes their responsiveness extremely versatile. This Review highlights recent insights into the structural features that determine the function of scavenger receptors and the emerging role that these receptors have in immune responses, notably in macrophage polarization and in the pathogenesis of diseases such as atherosclerosis and Alzheimer's disease. 23509042 Enhanced Replication of R5 HIV-1 Isolates in vitro by a Small-Molecule Reagent Targeting HIV-1 Protease. Chemical enhancement: Designed to target HIV-1 protease, a novel γ-hydroxyphosphonate has been found to significantly enhance viral replication in a panel of clinically relevant R5 HIV-1 isolates. This unexpected result constitutes the first instance of a small molecule capable of doing this, and it has implications for the preparation and use of R5 isolates in vaccine and drug development. 23906514 The mediation of platelet quiescence by NO-releasing polymers via cGMP-induced serine 239 phosphorylation of vasodilator-stimulated phosphoprotein. Nitric oxide (NO) releasing (NORel) materials have been shown to create localized increases in NO concentration by the release of NO from a diazeniumdiolate-containing or S-nitrosothiol-containing polymer coating and the improvement of extracorporeal circulation (ECC) hemocompatibility. However, the mechanism and, in particular, the platelet upregulation of the NO/cGMP signaling protein, vasodilator-stimulated phosphoprotein phosphorylated at serine 239 (P-VASP (ser 239)), for the improved ECC hemocompatibility via NO release still needs elucidation. In this work, two NORel polymeric coatings were evaluated in a 4 h rabbit thrombogenicity model and the anti-thrombotic mechanism investigated for rabbit platelet P-VASP upregulation. Polymer films containing 25 wt% diazeniumdiolated dibutylhexanediamine (DBHD) or 5 wt% S-nitroso-N-acetylpenicillamine (SNAP) coated on the inner walls of ECC circuits yielded significantly reduced ECC thrombus formation and maintained normal platelet aggregation compared to polymer controls after 4 h of blood exposure. Platelet P-VASP (ser 239), a useful tool to monitor NO/cGMP signaling, was upregulated after 4 h on ECC and markedly increased after ex vivo sodium nitroprusside (SNP) stimulation. Interestingly, in the rabbit platelet, NO did not upregulate the cAMP P-VASP phosphoprotein P-VASP (ser 157) as previously shown in human platelets. These results suggest that NORel polymers preserve rabbit platelet quiescence by sustaining a level of cGMP signaling as monitored by P-VASP (ser 239) upregulation. The upregulation of this NO-mediated platelet signaling mechanism in this rabbit thrombogenicity model indicates the potential for improved thromboresistance of any NORel-coated medical device. 23913861 The challenging environment on board the International Space Station affects endothelial cell function by triggering oxidative stress through thioredoxin interacting protein overexpression: the ESA-SPHINX experiment. Exposure to microgravity generates alterations that are similar to those involved in age-related diseases, such as cardiovascular deconditioning, bone loss, muscle atrophy, and immune response impairment. Endothelial dysfunction is the common denominator. To shed light on the underlying mechanism, we participated in the Progress 40P mission with Spaceflight of Human Umbilical Vein Endothelial Cells (HUVECs): an Integrated Experiment (SPHINX), which consisted of 12 in-flight and 12 ground-based control modules and lasted 10 d. Postflight microarray analysis revealed 1023 significantly modulated genes, the majority of which are involved in cell adhesion, oxidative phosphorylation, stress responses, cell cycle, and apoptosis. Thioredoxin-interacting protein was the most up-regulated (33-fold), heat-shock proteins 70 and 90 the most down-regulated (5.6-fold). Ion channels (TPCN1, KCNG2, KCNJ14, KCNG1, KCNT1, TRPM1, CLCN4, CLCA2), mitochondrial oxidative phosphorylation, and focal adhesion were widely affected. Cytokine detection in the culture media indicated significant increased secretion of interleukin-1α and interleukin-1β. Nitric oxide was found not modulated. Our data suggest that in cultured HUVECs, microgravity affects the same molecular machinery responsible for sensing alterations of flow and generates a prooxidative environment that activates inflammatory responses, alters endothelial behavior, and promotes senescence.-Versari, S., Longinotti, G., Barenghi, L., Maier, J. A. M., Bradamante, S. The challenging environment on board the International Space Station affects endothelial cell function by triggering oxidative stress through thioredoxin-interacting protein overexpression: the ESA-SPHINX experiment. 23582761 Dexmedetomidine ameliorates TNBS-induced colitis by inducing immunomodulator effect. Since sedatives are often administered to immune-compromised and critically ill patients, our understanding of immunomodulation by sedation will be critical. Dexmedetomidine, a selective α2-adrenergic receptor agonist, is often used for sedation and analgesia especially in intensive care units. There are conflicting and little data concerning both the effect and the mechanism of dexmedetomidine on immune response. In our study, we aimed to investigate the effect of dexmedetomidine on immune system at two different doses (5 μg.kg(-1) and 30 μg.kg(-1)) during inflammatory bowel disease by using an experimental model, which resembles both systemic and local inflammation. The effect of dexmedetomidine on the course of inflammatory bowel disease was investigated by measuring macroscopic and microscopic parameters. We investigated pro-inflammatory Th1, Th2, and Th17 cytokine levels in serum samples to analyze systemic immune response. Following this, local immune response was investigated by measuring cytokine levels in the presence of dexmedetomidine in spleen cell culture. Dexmedetomidine administration led to amelioration of all disease associated pathological manifestations. According to our in vitro and in vivo results, dexmedetomidine shows anti-inflammatory effect by increasing IL-4 and IL-10 levels responsible from anti-inflammatory response via Th2 pathway. Moreover, we showed for the first time in the study that dexmedetomidine administration reduces IL-23, which is responsible from initiation of inflammatory response via Th17 pathway. Dexmedetomidine can have beneficial effect on preoperative or postoperative inflammatory bowel disease patients in intensive care units by down-regulating inflammatory immune response not only in systemic circulation but also in tissue-specific manner. 23905984 Bone marrow neoplastic niche in leukemia. Neoplastic niche is a specific microenvironment for growth and proliferation of malignant cells. Here we review the leukemic niche and its constituent stem cells, signaling pathways and essential chemokines. Relevant literature was identified by a PubMed search (2000-2013) of English-language literature using the terms neoplastic niche, chemokines, and leukemia. Leukemia is caused by malignant hematopoietic stem cells and precursors. Important molecules and signals are involved in interactions between leukemic cells and their microenvironment. MicroRNAs (miRNAs) play an important role in expression regulation of oncogenes, transcription factors, signaling molecules and in eventual fate of the cell. It seems necessary to evaluate the relationship between aberrant miRNA expression and malignant transformation of bone marrow niche. Characterizing malignant leukemic cells, activated signaling pathways, and molecules involved in disease progression will result in understanding the causes of drug resistance, relapse factors, and effective treatments. 23769517 Fabrication of superhydrophobic cotton textiles for water-oil separation based on drop-coating route. In the present study, we are so excited to report a simple drop-coating method for fabricating the superhydrophobic cotton textiles which can remove the water in oil (or the oil in water). It is confirmed that the superhydrophobic composite thin film containing modified-ZnO nanoparticles and polystyren (PS) has been successfully fabricated on the cotton textiles surface by a single-step procedure, and the superhydrophobic cotton textiles displays an excellent property in water-oil separation which is rarely put forward and studied. The static water contact angle on the superhydrophobic cotton sample surface arranges from 153° to 155°, and stays almost the same after exposure to ambient air or immersion in the corrosive liquids and oil, indicating the considerable range of potential applications for the superhydrophobic cotton textiles fabricated by this simple method. 23520191 Library construction and biological evaluation of enmein-type diterpenoid analogues as potential anticancer agents. A library of promising enmein-type 14-O-diterpenoid derivatives was constructed from a commercially available kaurene-type oridonin by practical and efficient synthetic methods. These synthetic derivatives were evaluated for their antiproliferative activities against a set of four human cancer cell lines. The IC50 values are similar to or improved over those of the parent molecule and paclitaxel, the latter of which was used as a positive control. Compound 29 was further investigated for its apoptotic properties against human hepatocarcinoma Bel-7402 cells to better understand its mode of action. Moreover, compound 29 was shown to have potent antitumor activity in vivo in studies with a murine model of gastric cancer (MGC-803 mice). These results warrant further preclinical investigations of these diterpenoid-based analogues as potential novel anticancer chemotherapeutics. 23828665 Geodetic imaging with airborne LiDAR: the Earth's surface revealed. The past decade has seen an explosive increase in the number of peer reviewed papers reporting new scientific findings in geomorphology (including fans, channels, floodplains and landscape evolution), geologic mapping, tectonics and faulting, coastal processes, lava flows, hydrology (especially snow and runoff routing), glaciers and geo-archaeology. A common genesis of such findings is often newly available decimeter resolution 'bare Earth' geodetic images, derived from airborne laser swath mapping, a.k.a. airborne LiDAR, observations. In this paper we trace nearly a half century of advances in geodetic science made possible by space age technology, such as the invention of short-pulse-length high-pulse-rate lasers, solid state inertial measurement units, chip-based high speed electronics and the GPS satellite navigation system, that today make it possible to map hundreds of square kilometers of terrain in hours, even in areas covered with dense vegetation or shallow water. To illustrate the impact of the LiDAR observations we present examples of geodetic images that are not only stunning to the eye, but help researchers to develop quantitative models explaining how terrain evolved to its present form, and how it will likely change with time. Airborne LiDAR technology continues to develop quickly, promising ever more scientific discoveries in the years ahead. 23922838 TaCIPK29, a CBL-Interacting Protein Kinase Gene from Wheat, Confers Salt Stress Tolerance in Transgenic Tobacco. Calcineurin B-like protein-interacting protein kinases (CIPKs) have been found to be responsive to abiotic stress. However, their precise functions and the related molecular mechanisms in abiotic stress tolerance are not completely understood, especially in wheat. In the present study, TaCIPK29 was identified as a new member of CIPK gene family in wheat. TaCIPK29 transcript increased after NaCl, cold, methyl viologen (MV), abscisic acid (ABA) and ethylene treatments. Over-expression of TaCIPK29 in tobacco resulted in increased salt tolerance, which was demonstrated by higher germination rates, longer root lengths and better growth status of transgenic tobacco plants compared to controls when both were treated with salt stress. Physiological measurements indicated that transgenic tobacco seedlings retained high K(+)/Na(+) ratios and Ca(2+) content by up-regulating some transporter genes expression and also possessed lower H2O2 levels and reduced membrane injury by increasing the expression and activities of catalase (CAT) and peroxidase (POD) under salt stress. Moreover, transgenic lines conferred tolerance to oxidative stress by increasing the activity and expression of CAT. Finally, TaCIPK29 was located throughout cells and it preferentially interacted with TaCBL2, TaCBL3, NtCBL2, NtCBL3 and NtCAT1. Taken together, our results showed that TaCIPK29 functions as a positive factor under salt stress and is involved in regulating cations and reactive oxygen species (ROS) homeostasis. 23799614 Whole-exome sequencing to identify novel somatic mutations in squamous cell lung cancers. Squamous cell lung cancer is a major histotype of non-small cell lung cancer (NSCLC) that is distinct from lung adenocarcinoma. We used whole-exome sequencing to identify novel non-synonymous somatic mutations in squamous cell lung cancer. We identified 101 single-nucleotide variants (SNVs) including 77 non-synonymous SNVs (67 missense and 10 nonsense mutations) and 11 INDELs causing frameshifts. We also found four SNVs located within splicing sites. We verified 62 of the SNVs (51 missense, 10 nonsense and 1 splicing-site mutation) and 10 of the INDELs as somatic mutations in lung cancer tissue. Sixteen of the mutated genes were also mutated in at least one patient with a different type of lung cancer in the Catalogue of Somatic Mutation in Cancer (COSMIC) database. Four genes (LPHN2, TP53, MYH2 and TGM2) were mutated in approximately 10% of the samples in the COSMIC database. We identified two missense mutations in C10orf137 and MS4A3 that also occurred in other solid-tumor tissues in the COSMIC database. We found another somatic mutation in EP300 that was mutated in 4.2% of the 2,020 solid-tumor samples in the COSMIC database. Taken together, our results implicate TP53, EP300, LPHN2, C10orf137, MYH2, TGM2 and MS4A3 as potential driver genes of squamous cell lung cancer. 23963797 Self-Assembly of Poly-Adenine-Tailed CpG Oligonucleotide-Gold Nanoparticle Nanoconjugates with Immunostimulatory Activity. Synthetic unmethylated cytosine-guanine (CpG) oligodeoxynucleotides (CpG ODNs) possess high immunostimulatory activity and have been widely used as a therapeutic tool for various diseases including infection, allergies, and cancer. A variety of nanocarriers have been developed for intracellular delivery of CpG ODNs that are otherwise nonpermeable through the cellular membrane. For example, previous studies showed that gold nanoparticles (AuNPs) could efficiently deliver synthetic thiolated CpG ODNs into cultured cells and induce expression of proinflammatory cytokines. Nevertheless, the necessity of using thiolated CpG ODNs for the modification of AuNPs inevitably complicates the synthesis of the nanoconjugates and increases the cost. A new approach is demonstrated for facile assembly of AuNP-CpG nanoconjugates for cost-effective drug delivery. It is found that non-thiolated, diblock ODNs containing a CpG motif and a poly-adenine (polyA) tail can readily self-assemble on the surface of AuNPs with controllable and tunable density. Such nanoconjugates are efficiently delivered into RAW264.7 cells and induce immune response in a Toll-like receptor 9 (TLR9)-dependent manner. Under optimal conditions, polyA-CpG-AuNPs show significantly higher immunostimulatory activity than their thiolated counterpart. In addition, the immunostimulatory activity of CpG-AuNPs can be modulated by varying the length of the polyA tail. In vivo induction of immune responses in mice is demonstrated by using polyA-tailed CpG-AuNP nanoconjugates. 22921523 Pharmacological evaluation of SN79, a sigma (σ) receptor ligand, against methamphetamine-induced neurotoxicity in vivo. Methamphetamine is a highly addictive psychostimulant drug of abuse, causing hyperthermia and neurotoxicity at high doses. Currently, there is no clinically proven pharmacotherapy to treat these effects of methamphetamine, necessitating identification of potential novel therapeutic targets. Earlier studies showed that methamphetamine binds to sigma (σ) receptors in the brain at physiologically relevant concentrations, where it "acts in part as an agonist." SN79 (6-acetyl-3-(4-(4-(4-florophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one) was synthesized as a putative σ receptor antagonist with nanomolar affinity and selectivity for σ receptors over 57 other binding sites. SN79 pretreatment afforded protection against methamphetamine-induced hyperthermia and striatal dopaminergic and serotonergic neurotoxicity in male, Swiss Webster mice (measured as depletions in striatal dopamine and serotonin levels, and reductions in striatal dopamine and serotonin transporter expression levels). In contrast, di-o-tolylguanidine (DTG), a well established σ receptor agonist, increased the lethal effects of methamphetamine, although it did not further exacerbate methamphetamine-induced hyperthermia. Together, the data implicate σ receptors in the direct modulation of some effects of methamphetamine such as lethality, while having a modulatory role which can mitigate other methamphetamine-induced effects such as hyperthermia and neurotoxicity. 23968846 Immunomodulatory effects of dexamethasone on gene expression of cytokine and stress hormone receptors in peripheral blood mononuclear cells. Glucocorticoid (GC) such as cortisol in humans is a major stress hormone and can influence immunomodulation through various mechanisms including impact on regulatory T-cell (RTC) elements and changes in Th1/Th2 cytokine balance. In this study, we sought to determine the immunomodulatory effects of GC equivalent dexamethasone (DEX) at various concentrations (10(-7), 10(-8), and 10(-9)M) on gene expression of RTC, cytokine receptors and stress hormone receptors from normal human peripheral blood mononuclear cells (PBMC) in an in vitro stress model in 24h (acute stress) vs 11-day (chronic stress) cultures. Results revealed that the mRNA of forkhead box P3 (FoxP3) was significantly decreased at 24h with 10(-7) and 10(-8)M DEX. After 11days, FoxP3 expression in the 10(-8)M DEX cultures had returned to baseline but was still down-regulated with 10(-7)M DEX. GC receptor (GR) mRNA decreased and β2 adrenergic receptor (β 2AR) mRNA increased significantly after 24h exposure to DEX. These changes had returned to baseline in the 11-day cultures. The IFN-γR/IL-4R ratio, an alternative marker for Th1/Th2 balance, was significantly increased at 24h and decreased after 11-day cultures with 10(-7) and 10(-8)M DEX compared to control cultures. These findings further contribute to our understanding of the mechanisms associated with the effects of acute vs. chronic stress on normal immune balance. 23216601 Optimizing drug development of anti-cancer drugs in children using modelling and simulation. Modelling and simulation (M&S)-based approaches have been proposed to support paediatric drug development in order to design and analyze clinical studies efficiently. Development of anti-cancer drugs in the paediatric population is particularly challenging due to ethical and practical constraints. We aimed to review the application of M&S in the development of anti-cancer drugs in the paediatric population, and to identify where M&S-based approaches could provide additional support in paediatric drug development of anti-cancer drugs. A structured literature search on PubMed was performed. The majority of identified M&S-based studies aimed to use population PK modelling approaches to identify determinants of inter-individual variability, in order to optimize dosing regimens and to develop therapeutic drug monitoring strategies. Prospective applications of M&S approaches for PK-bridging studies have scarcely been reported for paediatric oncology. Based on recent developments of M&S in drug development there are several opportunities where M&S could support more informative bridging between children and adults, and increase efficiency of the design and analysis of paediatric clinical trials, which should ultimately lead to further optimization of drug treatment strategies in this population. 23889828 Acalculous cholecystitis occurring in the context of Plasmodium malariae infection: a case report. Acalculous cholecystitis has been shown to occur in the context of malarial infection with Plasmodium vivax and Plasmodium falciparum and requires prompt diagnosis and treatment to prevent complications. To the best of our knowledge this is the first reported case of the disease occurring in a patient infected with Plasmodium malariae. We report the first case of acalculous cholecystitis associated with Plasmodium malariae in a 59-year-old male Nepalese ex-Gurkha soldier. He presented with fever and vomiting and later developed right upper quadrant pain. Abdominal ultrasound and computed tomography scans confirmed acalculous cholecystitis for which he was treated medically with chloroquine, gentamicin and metronidazole. He made a full recovery. Physicians should be aware that in addition to Plasmodium vivax and Plasmodium falciparum infections, acalculous cholecystitis can occur in the context of Plasmodium malariae infection. Mechanisms for this are discussed but further studies are needed to establish the etiology of this association. 23902672 Epidemiology of Bacteremia in Young Hospitalized Infants in Vientiane, Laos, 2000-2011. As data about the causes of neonatal sepsis in low-income countries are inadequate, we reviewed the etiology and antibiotic susceptibilities of bacteremia in young infants in Laos. As Staphylococcus aureus is the leading cause of bacteremia in Lao infants, we also examined risk factors for this infection, in particular the local practice of warming mothers during the first weeks postpartum with hot coals under their beds (hot beds). Clinical and laboratory data regarding infants aged 0-60 days evaluated for sepsis within 72 h of admission to Mahosot Hospital in Vientiane, Laos, were reviewed, and 85 of 1438 (5.9%) infants' blood cultures grew a clinically significant organism. Most common were S. aureus, Escherichia coli and Klebsiella pneumoniae. Whereas no methicillin-resistant S. aureus was found, only 18% of E. coli isolates were susceptible to ampicillin. A history of sleeping on a hot bed with mother was associated with S. aureus bacteremia (odds ratio 4.8; 95% confidence interval 1.2-19.0). 23951026 Discrimination and other barriers to accessing health care: perspectives of patients with mild and moderate intellectual disability and their carers. People with intellectual disability have a higher prevalence of physical health problems but often experience disparities in accessing health care. In England, a number of legislative changes, policies and recommendations have been introduced to improve health care access for this population. The aim of this qualitative study was to examine the extent to which patients with intellectual disability and their carers experience discrimination or other barriers in accessing health services, and whether health care experiences have improved over the last decade years. Twenty nine participants (14 patient and carer dyads, and one carer) took part in semi-structured interviews. The interviews were audio-taped and transcribed and analysed using thematic analysis. Eight themes were identified. Half the participants thought that the patient had been treated unfairly or had been discriminated against by health services. There were accounts of negative staff attitudes and behaviour, and failure of services to make reasonable adjustments. Other barriers included problems with communication, and accessing services because of lack of knowledge of local services and service eligibility issues; lack of support and involvement of carers; and language problems in participants from minority ethnic groups. Most participants were able to report at least one example of good practice in health care provision. Suggestions for improving services are presented. Despite some improvements to services as a result of health policies and recommendations, more progress is required to ensure that health services make reasonable adjustments to reduce both direct and indirect discrimination of people with intellectual disability. 23688481 Use of pectin-thorium (IV) tungstomolybdate nanocomposite for photocatalytic degradation of methylene blue. Pectin-thorium (IV) tungstomolybdate (Pc/TWM) nanocomposite was prepared by mixing biopolymer pectin with its inorganic counterpart thorium (IV) tungstomolybdate (TWM) using the sol-gel method. The nanocomposite was characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR). Distribution coefficient, thermal stability, pH titrations, elution and concentration behaviour were investigated to explore the ion exchange behaviour of nanocomposite material. Pc/TWM exhibited higher ion exchange capacity (1.10 mequiv/g) than its inorganic counterpart (0.62 mequiv/g). The Pc/TWM nanocomposite ion exchanger was thermally stable as it retained 59% of its ion exchange capacity upto 400°C. The pH titrations study revealed the bifunctional nature of Pc/TWM. In order to explore the environmental applicability of the Pc/TWM nanocomposite material, its antibacterial and photocatalytic activities was investigated. 76% of methylene blue dye was photocatalytically degraded after five hours exposure. It also totally inhibited Escherichia coli at 400 μg/ml concentration of Pc/TWM nanocomposite. 23575741 The Impact of Escitalopram on IL-2-Induced Neuroendocrine, Immune, and Behavioral Changes in Patients with Malignant Melanoma: Preliminary Findings. Interleukin (IL)-2, a T-cell cytokine used to treat malignant melanoma, can induce profound depression. To determine whether pretreatment with the antidepressant escitalopram could reduce IL-2-induced neuroendocrine, immune, and neurobehavioral changes, 20 patients with Stage IV melanoma were randomized to either placebo or the serotonin reuptake inhibitor, escitalopram (ESC) 10-20 mg/day, 2 weeks before, and during IL-2 treatment (720 000 units/kg Q8 h × 5 days (1 cycle) every 3 weeks × 4 cycles). Generalized estimation equations were used to examine HPA axis activity (plasma ACTH and cortisol), immune activation (plasma IL-6), and depressive symptoms (Hamilton Depression Rating Scale (HDRS) score). Tolerance of IL-2 treatment (concomitant medications required) and adherence (number of IL-2 doses received) were also assessed. Both the groups (ESC (n=9), placebo (n=11)) exhibited significant IL-2-induced increases in plasma cortisol, IL-6, and depressive symptoms (p<0.05), as well as a temporal trend for increases in plasma ACTH (p=0.054); the effects of age and treatment were not significant. Higher plasma ACTH concentrations were associated with higher depressive symptoms during cycles 1-3 of IL-2 therapy (p<0.01). Although ESC had no significant effects on ACTH, cortisol, IL-6, tolerance of, or adherence to IL-2, ESC treatment was associated with lower depressive symptoms, ie, a maximal difference of ∼3 points on the HDRS, which, though not statistically significant (in part, due to small sample size), represents a clinically significant difference according to the National Institute for Health and Clinical Excellence guidelines. A larger sample size will establish whether antidepressant pretreatment can prevent IL-2-induced neurobehavioral changes. 23877306 Comparison of Sublingual Midazolam and Dexmedetomidine for Premedication in Children. Background: Premedication in children scheduled for surgery reduces preoperative anxiety and facilitates a smooth induction of anaesthesia. Midazolam is commonly used premedication in children but because of its undesirable effects such as postoperative behaviour changes and cognitive impairment it is not an ideal premedicant. Dexmedetomidine, a highly specific a2-adrenergic receptor agonist, produces sedation which mimics natural stage 2 non-rapid eye movement sleep and helps in early postoperative recovery. The objective of our study was to evaluate the effectiveness of sublingual dexmedetomidine in comparison to sublingual midazolam as premedicant in children Methods: 100 children aged 1 to 12 years belonging to ASA physical status I or II scheduled to undergo inguinal hernia repair, orchidopexy or circumcision, under general anaesthesia were enrolled in this prospective, randomized, double-blind study . The children were randomly allocated into two groups of 50 each. Children in group I were premedicated with sublingual midazolam 0.25 mg/kg while those in group II with sublingual dexmedetomidine 1.5mg/kg. Sedation was assessed using a 6 point sedation score. Behaviour at induction, wake -up behaviour and mask acceptance was evaluated using a 4 point scoring system. Results: The median sedation score at parental separation was 6 in group I as compared to 3.5 in group II (p<0.001). The behaviour score at induction was comparable in both the groups. The median mask acceptance score (p<0.001) and wake up behaviour score (p=0.001) in pre-school children was 2 in group I as compared to 1 in group II.However in school-aged children both the scores were comparable. Conclusion: Sublingual dexmedetomidine provides more effective preoperative sedation as compared to sublingual midazolam across all the age groups and allows a smooth anaesthesia induction and awakening especially in the pre-school children. 23542133 Otopathology in Idiopathic Dandy's Syndrome. Dandy's syndrome, or bilateral vestibular hypofunction and oscillopsia, may cause chronic disequilibrium aggravated by head movement or in the presence of reduced light. It may be secondary to ototoxicity, central nervous system tumors, Ménière's syndrome, infections, or trauma or may be idiopathic. To describe the temporal bone histopathology in one individual with idiopathic Dandy's syndrome. Temporal bones from 1 individual were removed at autopsy and studied using light and Nomarski microscopy. In this case, the otopathology demonstrated vestibular atelectasis of the membranous labyrinth of the superior, lateral, and posterior semicircular canals but not the utricle or saccule bilaterally. The findings also included mild hair cell loss in the cristae of all semicircular canals and of the utricular and saccular maculae and severely reduced neuronal count in Scarpa's ganglion bilaterally. There was also a scattered loss of inner and outer hair cells throughout the cochlea and moderate-to-severe loss of cochlear neurons bilaterally. We have reported the histopathologic findings in a case of idiopathic Dandy's syndrome. Both temporal bones showed vestibular atelectasis of all three semicircular canals, preservation of normal saccule and utricle, and severe reduction of the neuronal population in Scarpa's ganglion bilaterally. Both ears also showed substantial degeneration of the spiral ganglion of the cochleas. Severe Scarpa's ganglion degeneration was also noted in the only other case of idiopathic Dandy's Syndrome in the literature. However, that other case had no evidence of vestibular atelectasis and had normal hearing. 23421805 Functional interactions between matrix metalloproteinases and glycosaminoglycans. Similar to most proteinases, matrix metalloproteinases (MMP) do not recognize a consensus cleavage site. Thus, it is not surprising that, in a defined in vitro reaction, most MMPs can act on a wide range of proteins, including many extracellular matrix proteins. However, the findings obtained from in vivo studies with genetic models have demonstrated that individual MMPs act on just a few extracellular protein substrates, typically not matrix proteins. The limited, precise functions of an MMP imply that mechanisms have evolved to control the specificity of proteinase:substrate interactions. We discuss the possibility that interactions with the glycosaminoglycan chains of proteoglycans may function as allosteric regulators or accessory factors directing MMP catalysis to specific substrates. We propose that understanding how the activity of specific MMPs is confined to discreet compartments and targeted to defined substrates via interactions with other macromolecules may provide a means of blocking potentially deleterious MMP-mediated processes at the same time as sparing any beneficial functions. 23707541 Biomineral repair of abalone shell apertures. The shell of the gastropod mollusc, abalone, is comprised of nacre with an outer prismatic layer that is composed of either calcite or aragonite or both, depending on the species. A striking characteristic of the abalone shell is the row of apertures along the dorsal margin. As the organism and shell grow, new apertures are formed and the preceding ones are filled in. Detailed investigations, using electron backscatter diffraction, of the infill in three species of abalone: Haliotis asinina, Haliotis gigantea and Haliotis rufescens reveals that, like the shell, the infill is composed mainly of nacre with an outer prismatic layer. The infill prismatic layer has identical mineralogy as the original shell prismatic layer. In H. asinina and H. gigantea, the prismatic layer of the shell and infill are made of aragonite while in H. rufescens both are composed of calcite. Abalone builds the infill material with the same high level of biological control, replicating the structure, mineralogy and crystallographic orientation as for the shell. The infill of abalone apertures presents us with insight into what is, effectively, shell repair. 23789744 Enthalpy-Entropy Compensation in Biomolecular Halogen Bonds Measured in DNA Junctions. Interest in noncovalent interactions involving halogens, particularly halogen bonds (X-bonds), has grown dramatically in the past decade, propelled by the use of X-bonding in molecular engineering and drug design. However, it is clear that a complete analysis of the structure-energy relationship must be established in biological systems to fully exploit X-bonds for biomolecular engineering. We present here the first comprehensive experimental study to correlate geometries with their stabilizing potentials for fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) X-bonds in a biological context. For these studies, we determine the single-crystal structures of DNA Holliday junctions containing halogenated uracil bases that compete X-bonds against classic hydrogen bonds (H-bonds), estimate the enthalpic energies of the competing interactions in the crystal system through crystallographic titrations, and compare the enthalpic and entropic energies of bromine and iodine X-bonds in solution by differential scanning calorimetry. The culmination of these studies demonstrates that enthalpic stabilization of X-bonds increases with increasing polarizability from F to Cl to Br to I, which is consistent with the σ-hole theory of X-bonding. Furthermore, an increase in the X-bonding potential is seen to direct the interaction toward a more ideal geometry. However, the entropic contributions to the total free energies must also be considered to determine how each halogen potentially contributes to the overall stability of the interaction. We find that bromine has the optimal balance between enthalpic and entropic energy components, resulting in the lowest free energy for X-bonding in this DNA system. The X-bond formed by iodine is more enthalpically stable, but this comes with an entropic cost, which we attribute to crowding effects. Thus, the overall free energy of an X-bonding interaction balances the stabilizing electrostatic effects of the σ-hole against the competing effects on the local structural dynamics of the system. 23111283 Toosendanin induces apoptosis through suppression of JNK signaling pathway in HL-60 cells. Toosendanin (TSN), a triterpenoid isolated from Melia toosendan Sieb. et Zucc., has been found to suppress proliferation and induce apoptosis in a variety of human cancer cells. However, the mechanism how TSN induces apoptosis remains poorly understood. In this study, we examined the effects of TSN on the growth, cell cycle arrest, induction of apoptosis and the involved signaling pathway in human promyelocytic leukemia HL-60 cells. Proliferation of HL-60 cells was inhibited in a dose-dependent manner with the IC(50 (48 h)) of 28 ng/mL. The growth inhibition was due primarily to the S phase arrest and cell apoptosis. Cell apoptosis induced by TSN was confirmed by Annexin V-FITC/propidium iodide staining. The increase of the pro-apoptotic protein Bax, cleaved PARP and caspase-3, and the decrease of anti-apoptotic protein Bcl-2 were observed. Western blot analysis indicated that TSN inhibits the CDC42/MEKK1/JNK pathway. Taken together, our study suggested, for the first time, that the pro-apoptotic effects of TSN on HL-60 cells were mediated through JNK signaling pathway. 23632905 Clock Gene Expression in the Liver of Streptozotocin-induced and Spontaneous Type 1 Diabetic Rats. Several investigations have shown a relation between diabetes and alterations of the liver circadian clock. We investigated the diurnal expression of clock genes and clock-controlled genes (CCGs) in 3-hour intervals for a 24-h period in the livers of male streptozotocin (STZ)-treated rats, male spontaneous type 1 diabetic LEW.1AR1-iddm (Iddm) rats, and Iddm rats treated for 10 days with insulin. Hepatic mRNA was extracted, and the relative expression of clock genes (Per1, Per2, Bmal1, Clock, Cry1), as well as CCGs (Dbp, E4bp4, RevErbα, Rorα, Pparγ), was analyzed by reverse transcription followed by real-time polymerase chain reaction. Diabetic STZ and Iddm rats, as well as insulin-substituted Iddm rats, exhibited a significant diurnal expression pattern of clock genes as determined by Cosinor analysis; however, the MESOR (midline estimating statistic of rhythm) of Bmal1, Per2, and Clock transcript expression was altered in Iddm and insulin-substituted Iddm rats. The hepatic expression of the CCGs Dbp and RevErbα revealed a diurnal rhythm in all investigated groups. Insulin administration to Iddm rats normalized the enhanced MESOR in the expression of Dbp, RevErbα, and E4bp4 to the levels of normoglycemic controls. Cosinor analysis indicated no diurnal rhythm of Pparγ expression in the livers of diabetic STZ or Iddm rats or in those of insulin-substituted Iddm rats. Also, insulin substitution could not reverse the decreased MESOR of Pparγ expression in Iddm rats. In consequence of the diabetic disease, changes in the expression of clock genes and CCGs suggest alterations in the hepatic peripheral clock mechanism. 23659909 Identification of adenovirus-encoded small RNAs by deep RNA sequencing. Using deep RNA sequencing, we have studied the expression of adenovirus-encoded small RNAs at different times after infection. Nineteen small RNAs which comprised more than 1% of the total pool of small RNAs at least one time point were identified. These small RNAs were between 25 and 35 nucleotides long and mapped in the region of the VA RNAI and RNAII genes. However, the overlap was incomplete and some contained a few extra nucleotides at the 3' end. This finding together with the observation that some of the small RNAs were detected before VA RNA expression had started might indicate that they are derived from other precursors than VA RNAI and II. Interestingly, the small RNAs displayed different expression profiles during the course of the infection suggesting that they have different functions. An effort was made to identify their mRNA targets by using computer prediction and deep cDNA sequencing. The most significant targets for the earliest small RNAs were genes involved in signaling pathways. 23470866 Oroxylin A reverses P-glycoprotein-mediated multidrug resistance of MCF7/ADR cells by G2/M arrest. Oroxylin A is a naturally occurring monoflavonoid isolated from the root of Scutellaria baicalensis Georgi, which has been used in traditional Chinese medicine for its anti-tumor, anti-inflammatory and anti-bacterial properties. The purpose of this study is to investigate the reversal effect and the fundamental mechanisms of oroxylin A in MCF7/ADR cells. Data indicated that oroxylin A showed strong reversal potency in MCF7/ADR cells and the reversal fold (RF) reached 4.68. After treatment with oroxylin A, MCF7/ADR cells displayed reduced functional activity and expression of MDR1 at both the protein and mRNA levels. Meanwhile, oroxylin A induced cells G2/M arrest in a concentration-dependent manner by increasing the expression of p-Chk2 (Thr68). Moreover, western blot and EMSA assays were used to reveal the inhibition of NF-κB in nucleus and the suppression of NF-κB binding activity by oroxylin A. NSC 109555 ditosylate-Chk2 inhibitor partly dismissed G2/M arrest induced by oroxylin A, reversed the increased trend of p-Chk2 and p-P53 (Ser20), inhibited the decreasing effect of oroxylin A on the expression of P-gp and decreased the reversal fold of 90μM oroxylin A from 4.68 fold to 1.73 fold. In conclusion, we suggested that oroxylin A reversed MDR by G2/M arrest and the underlying mechanism attributed to the suppression of P-gp expression via Chk2/P53/NF-κB signaling pathway. 23809967 Endoscopic brush cytology from the biliary duct system is still valuable. The aim of this study was to define sensitivity, specificity and positive and negative predictive values of endoscopic retrograde cholangiopancreatography (ERCP) brush cytology from biliary strictures obtained over a period of 12 years in a county hospital in Denmark. Patients with cytology specimens identified by brushings of the bile duct, pancreatic duct and ampulla of Vater were included. The specimens were reported as unsatisfactory, normal, atypical, suspicious for malignancy or malignant. Our evaluation comprised 75 specimens. For the statistical analysis, an atypical cytology result was considered benign, and a suspicious result was considered malignant. The cytological diagnoses were compared with the final diagnoses which were established either by histopathology (surgery, biopsy or autopsy) or by at least one year of clinical follow-up. Of the 75 specimens included, 40 were diagnosed as cytologically benign (35 normal and five atypical) and 35 as cytologically malignant (22 suspicious for malignancy and 13 malignant). Comparing the cytological diagnosis with the final diagnosis, we found 35 to be true positives, 22 to be true negatives, zero to be false positives and 18 to be false negatives. Of the five atypical specimens, four were false negatives. The operating characteristics were: 66% sensitivity, 100% specificity, 100% positive predictive value and 55% negative predictive value. The diagnostic accuracy was 76%. Suspicion and malignant cytology are reliable with a specificity of 100%. In these cases, we recommend that the patients are considered for surgical or oncological treatment without further histological investigations. not relevant. not relevant. 23853027 A foreign body of the larynx misdiagnosed as vocal cord paralysis. Foreign bodies in the aerodigestive tract continue to be a common problem that contribute significantly to high morbidity and mortality all over the world. Laryngeal foreign bodies may present with less severe symptoms compared with lower respiratory tract foreign bodies, resulting in misdiagnosis, confusion and delay in diagnosis. Rigid endoscopy with forceps removal under general anaesthesia is the preferred management modality. This case is described to show the importance of a detailed history and examination including X-ray neck in children to rule out any radiopaque laryngeal foreign body as a delay in diagnosis and management can lead to life-threatening complications. 23846492 Neonatal hyperglycemia and diminished long-term growth in very low birth weight preterm infants. OBJECTIVE:To investigate the association between early hyperglycemia and growth and development from hospital discharge to 2 years corrected age (CA) in very low birth weight (VLBW) infants.STUDY DESIGN:Blood glucose levels during the first 14 days after birth, weight, length and occipital-frontal circumference (OFC) at birth, hospital discharge and 4, 12 and 24 months CA, Bayley developmental scores at 12 and 24 months CA, and information on multiple clinical variables were recorded on VLBW preterm infants (N=80). The relationships between hyperglycemia, growth and developmental scores were determined using linear mixed effects regression.RESULT:Hyperglycemia was a strong predictor of poor rate of increase in weight, length and OFC until 24 months CA. Hyperglycemia was not associated with lower scores on the Bayley scales.CONCLUSION:Neonatal hyperglycemia was associated with poor physical growth until at least 2 years CA in this cohort of VLBW preterm infants.Journal of Perinatology advance online publication, 11 July 2013; doi:10.1038/jp.2013.77. 23856562 Plant phosphoinositide-dependent phospholipases C: Variations around a canonical theme. Phosphoinositide-specific phospholipase C (PI-PLC) cleaves, in a Ca(2+)-dependent manner, phosphatidylinositol-4,5-bisphosphate (PI-4,5-P2) into diacylglycerol (DAG) and inositol triphosphate (IP3). PI-PLCs are multidomain proteins that are structurally related to the PI-PLCζs, the simplest animal PI-PLCs. Like these animal counterparts, they are only composed of EF-hand, X/Y and C2 domains. However, plant PI-PLCs do not have a conventional EF-hand domain since they are often truncated, while some PI-PLCs have no EF-hand domain at all. Despite this simple structure, plant PI-PLCs are involved in many essential plant processes, either associated with development or in response to environmental stresses. The action of PI-PLCs relies on the mediators they produce. In plants, IP3 does not seem to be the sole active soluble molecule. Inositol pentakisphosphate (IP5) and inositol hexakisphosphate (IP6) also transmit signals, thus highlighting the importance of coupling PI-PLC action with inositol-phosphate kinases and phosphatases. PI-PLCs also produce a lipid molecule, but plant PI-PLC pathways show a peculiarity in that the active lipid does not appear to be DAG but its phosphorylated form, phosphatidic acid (PA). Besides, PI-PLCs can also act by altering their substrate levels. Taken together, plant PI-PLCs show functional differences when compared to their animal counterparts. However, they act on similar general signalling pathways including calcium homeostasis and cell phosphoproteome. Several important questions remain unanswered. The cross-talk between the soluble and lipid mediators generated by plant PI-PLCs is not understood and how the coupling between PI-PLCs and inositol-kinases or DAG-kinases is carried out remains to be established. 23011321 The acute effect of fludrocortisone on basal and hCRH-stimulated hypothalamic-pituitary-adrenal (HPA) axis in humans. Mineralocorticoid receptors (MR) in the hippocampus display an important role in the control of hypothalamic-pituitary-adrenal (HPA)-axis, mediating the "proactive"-feedback of glucocorticoids. Fludrocortisone (FC), a potent MR agonist, has been shown to decrease HPA activity through a mechanism placed at hippocampal level. In order to clarify the effects of MR agonism on HPA function in humans, we studied the effects of FC, in a dose-related manner, on both basal and CRH-stimulated HPA axis during the quiescent phase. 8 young women were studied. ACTH, cortisol and aldosterone levels were evaluated every 15', from 1600 to 2000 hours, in randomized sessions: (1) placebo p.o. + placebo i.v., (2) 0.3 mg FC p.o. + placebo, (3) 0.1 mg FC. + placebo, (4) 0.075 mg FC + placebo, (5) 0.05 mg FC + placebo, (6) placebo + hCRH (2.0 Î¼g/kg iv-bolus), (7) 0.3 mg FC + hCRH, (8) 0.1 mg FC + hCRH, (9) 0.075 mg FC + hCRH, (10) 0.05 mg FC + hCRH. FC induced a dose-related trend toward a further decrease of the ACTH and cortisol levels, while it showed a significant and dose-dependent inhibition of the hormonal response to hCRH (p < 0.05 for the doses of 0.3, 0.1 and 0.075 mg). Conversely, 0.05 mg FC did not modify the CRH-stimulatory effect on both ACTH and cortisol secretion. Aldosterone levels were not modified by FC administration. Fludrocortisone inhibits corticotrope and adrenal response to hCRH in humans, in a dose-dependent manner. The 0.075 mg FC seems the lowest active while 0.05 mg the first neutral dose on HPA activity. These data suggest a possible hypophysial MR-mediated inhibiting effect of FC, although its pituitary glucocorticoid-mediated effect cannot be excluded. The interplay between fludrocortisone and hypophysial glucocorticoid receptors needs to be clarified in order to define better the clinical consequences of the hormonal replacement therapy of patients with primary adrenal insufficiency. 23926093 Grip strength and its determinants among older people in different healthcare settings. low muscle strength is central to geriatric syndromes including sarcopenia and frailty. It is well described in community-dwelling older people, but the epidemiology of grip strength of older people in rehabilitation or long-term care has been little explored. to describe grip strength of older people in rehabilitation and nursing home settings. cross-sectional epidemiological study. three healthcare settings in one town. hundred and one inpatients on a rehabilitation ward, 47 community rehabilitation referrals and 100 nursing home residents. grip strength, age, height, weight, body mass index, number of co-morbidities and medications, Barthel score, Mini-Mental State Examination (MMSE), nutritional status and number of falls in the last year were recorded. grip strength differed substantially between healthcare settings for both men and women (P < 0.0001). Nursing home residents had the lowest age-adjusted mean grip strength and community rehabilitation referrals the highest. Broadly higher grip strength was associated in univariate analyses with younger age, greater height and weight, fewer comorbidities, higher Barthel score, higher MMSE score, better nutritional status and fewer falls. However, after mutual adjustment for these factors, the difference in grip strength between settings remained significant. The Barthel score was the characteristic most strongly associated with grip strength. older people in rehabilitation and care home settings had lower grip strength than reported for those living at home. Furthermore grip strength varied widely between healthcare settings independent of known major influences. Further research is required to ascertain whether grip strength may help identify people at risk of adverse health outcomes within these settings. 23940583 Voting-based cancer module identification by combining topological and data-driven properties. Recently, computational approaches integrating copy number aberrations (CNAs) and gene expression (GE) have been extensively studied to identify cancer-related genes and pathways. In this work, we integrate these two data sets with protein-protein interaction (PPI) information to find cancer-related functional modules. To integrate CNA and GE data, we first built a gene-gene relationship network from a set of seed genes by enumerating all types of pairwise correlations, e.g. GE-GE, CNA-GE, and CNA-CNA, over multiple patients. Next, we propose a voting-based cancer module identification algorithm by combining topological and data-driven properties (VToD algorithm) by using the gene-gene relationship network as a source of data-driven information, and the PPI data as topological information. We applied the VToD algorithm to 266 glioblastoma multiforme (GBM) and 96 ovarian carcinoma (OVC) samples that have both expression and copy number measurements, and identified 22 GBM modules and 23 OVC modules. Among 22 GBM modules, 15, 12, and 20 modules were significantly enriched with cancer-related KEGG, BioCarta pathways, and GO terms, respectively. Among 23 OVC modules, 19, 18, and 23 modules were significantly enriched with cancer-related KEGG, BioCarta pathways, and GO terms, respectively. Similarly, we also observed that 9 and 2 GBM modules and 15 and 18 OVC modules were enriched with cancer gene census (CGC) and specific cancer driver genes, respectively. Our proposed module-detection algorithm significantly outperformed other existing methods in terms of both functional and cancer gene set enrichments. Most of the cancer-related pathways from both cancer data sets found in our algorithm contained more than two types of gene-gene relationships, showing strong positive correlations between the number of different types of relationship and CGC enrichment [Formula: see text]-values (0.64 for GBM and 0.49 for OVC). This study suggests that identified modules containing both expression changes and CNAs can explain cancer-related activities with greater insights. 23435093 From evolution to revolution: miRNAs as pharmacological targets for modulating cholesterol efflux and reverse cholesterol transport. There has been strong evolutionary pressure to ensure that an animal cell maintains levels of cholesterol within tight limits for normal function. Imbalances in cellular cholesterol levels are a major player in the development of different pathologies associated to dietary excess. Although epidemiological studies indicate that elevated levels of high-density lipoprotein (HDL)-cholesterol reduce the risk of cardiovascular disease, recent genetic evidence and pharmacological therapies to raise HDL levels do not support their beneficial effects. Cholesterol efflux as the first and probably the most important step in reverse cholesterol transport is an important biological process relevant to HDL function. Small non-coding RNAs (microRNAs), post-transcriptional control different aspects of cellular cholesterol homeostasis including cholesterol efflux. miRNA families miR-33, miR-758, miR-10b, miR-26 and miR-106b directly modulates cholesterol efflux by targeting the ATP-binding cassette transporter A1 (ABCA1). Pre-clinical studies with anti-miR therapies to inhibit some of these miRNAs have increased cellular cholesterol efflux, reverse cholesterol transport and reduce pathologies associated to dyslipidemia. Although miRNAs as therapy have benefits from existing antisense technology, different obstacles need to be solved before we incorporate such research into clinical care. Here we focus on the clinical potential of miRNAs as therapeutic target to increase cholesterol efflux and reverse cholesterol transport as a new alternative to ameliorate cholesterol-related pathologies. 23830430 Visual and surface plasmon resonance sensor for zirconium based on zirconium-induced aggregation of adenosine triphosphate-stabilized gold nanoparticles. Owing to its high affinity with phosphate, Zr(IV) can induce the aggregation of adenosine 5'-triphosphate (ATP)-stabilized AuNPs, leading to the change of surface plasmon resonance (SPR) absorption spectra and color of ATP-stabilized AuNP solutions. Based on these phenomena, visual and SPR sensors for Zr(IV) have been developed for the first time. The A(660 nm)/A(518 nm) values of ATP-stabilized AuNPs in SPR absorption spectra increase linearly with the concentrations of Zr(IV) from 0.5 μM to 100 μM (r=0.9971) with a detection limit of 95 nM. A visual Zr(IV) detection is achieved with a detection limit of 30 μM. The sensor shows excellent selectivity against other metal ions, such as Cu(2+), Fe(3+), Cd(2+), and Pb(2+). The recoveries for the detection of 5 μM, 10 μM, 25 μM and 75 μM Zr(IV) in lake water samples are 96.0%, 97.0%, 95.6% and 102.4%, respectively. The recoveries of the proposed SPR method are comparable with those of ICP-OES method. 23220587 Retinoic acid biosynthesis catalyzed by retinal dehydrogenases relies on a rate-limiting conformational transition associated with substrate recognition. Retinoic acid (RA), a metabolite of vitamin A, exerts pleiotropic effects throughout life in vertebrate organisms. Thus, RA action must be tightly regulated through the coordinated action of biosynthetic and degrading enzymes. The last step of retinoic acid biosynthesis is irreversibly catalyzed by the NAD-dependent retinal dehydrogenases (RALDH), which are members of the aldehyde dehydrogenase (ALDH) superfamily. Low intracellular retinal concentrations imply efficient substrate molecular recognition to ensure high affinity and specificity of RALDHs for retinal. This study addresses the molecular basis of retinal recognition in human ALDH1A1 (or RALDH1) and rat ALDH1A2 (or RALDH2), through the comparison of the catalytic behavior of retinal analogs and use of the fluorescence properties of retinol. We show that, in contrast to long chain unsaturated substrates, the rate-limiting step of retinal oxidation by RALDHs is associated with acylation. Use of the fluorescence resonance energy transfer upon retinol interaction with RALDHs provides evidence that retinal recognition occurs in two steps: binding into the substrate access channel, and a slower structural reorganization with a rate constant of the same magnitude as the kcat for retinal oxidation: 0.18 vs. 0.07 and 0.25 vs. 0.1 s(-1) for ALDH1A1 and ALDH1A2, respectively. This suggests that the conformational transition of the RALDH-retinal complex significantly contributes to the rate-limiting step that controls the kinetics of retinal oxidation, as a prerequisite for the formation of a catalytically competent Michaelis complex. This conclusion is consistent with the general notion that structural flexibility within the active site of ALDH enzymes has been shown to be an integral component of catalysis. 23885240 Insulin signaling and the regulation of insect diapause. A rich chapter in the history of insect endocrinology has focused on hormonal control of diapause, especially the major roles played by juvenile hormones (JHs), ecdysteroids, and the neuropeptides that govern JH and ecdysteroid synthesis. More recently, experiments with adult diapause in Drosophila melanogaster and the mosquito Culex pipiens, and pupal diapause in the flesh fly Sarcophaga crassipalpis provide strong evidence that insulin signaling is also an important component of the regulatory pathway leading to the diapause phenotype. Insects produce many different insulin-like peptides (ILPs), and not all are involved in the diapause response; ILP-1 appears to be the one most closely linked to diapause in C. pipiens. Many steps in the pathway leading from perception of daylength (the primary environmental cue used to program diapause) to generation of the diapause phenotype remain unknown, but the role for insulin signaling in mosquito diapause appears to be upstream of JH, as evidenced by the fact that application of exogenous JH can rescue the effects of knocking down expression of ILP-1 or the Insulin Receptor. Fat accumulation, enhancement of stress tolerance, and other features of the diapause phenotype are likely linked to the insulin pathway through the action of a key transcription factor, FOXO. This review highlights many parallels for the role of insulin signaling as a regulator in insect diapause and dauer formation in the nematode Caenorhabditis elegans. 23868113 Validating therapeutic targets through human genetics. More than 90% of the compounds that enter clinical trials fail to demonstrate sufficient safety and efficacy to gain regulatory approval. Most of this failure is due to the limited predictive value of preclinical models of disease, and our continued ignorance regarding the consequences of perturbing specific targets over long periods of time in humans. 'Experiments of nature' - naturally occurring mutations in humans that affect the activity of a particular protein target or targets - can be used to estimate the probable efficacy and toxicity of a drug targeting such proteins, as well as to establish causal rather than reactive relationships between targets and outcomes. Here, we describe the concept of dose-response curves derived from experiments of nature, with an emphasis on human genetics as a valuable tool to prioritize molecular targets in drug development. We discuss empirical examples of drug-gene pairs that support the role of human genetics in testing therapeutic hypotheses at the stage of target validation, provide objective criteria to prioritize genetic findings for future drug discovery efforts and highlight the limitations of a target validation approach that is anchored in human genetics. 23924783 Bacterial profiling of White Plague Disease in a comparative coral species framework. Coral reefs are threatened throughout the world. A major factor contributing to their decline is outbreaks and propagation of coral diseases. Due to the complexity of coral-associated microbe communities, little is understood in terms of disease agents, hosts and vectors. It is known that compromised health in corals is correlated with shifts in bacterial assemblages colonizing coral mucus and tissue. However, general disease patterns remain, to a large extent, ambiguous as comparative studies over species, regions, or diseases are scarce. Here, we compare bacterial assemblages of samples from healthy (HH) colonies and such displaying signs of White Plague Disease (WPD) of two different coral species (Pavona duerdeni and Porites lutea) from the same reef in Koh Tao, Thailand, using 16S rRNA gene microarrays. In line with other studies, we found an increase of bacterial diversity in diseased (DD) corals, and a higher abundance of taxa from the families that include known coral pathogens (Alteromonadaceae, Rhodobacteraceae, Vibrionaceae). In our comparative framework analysis, we found differences in microbial assemblages between coral species and coral health states. Notably, patterns of bacterial community structures from HH and DD corals were maintained over species boundaries. Moreover, microbes that differentiated the two coral species did not overlap with microbes that were indicative of HH and DD corals. This suggests that while corals harbor distinct species-specific microbial assemblages, disease-specific bacterial abundance patterns exist that are maintained over coral species boundaries.The ISME Journal advance online publication, 8 August 2013; doi:10.1038/ismej.2013.127. 23606109 Inulin-type fructans with different degrees of polymerization improve lipid metabolism but not glucose metabolism in rats fed a high-fat diet under energy restriction. Inulin-type fructan ameliorates metabolic diseases associated with obesity in animals. However, relatively little information is available on the comparative effects of inulins with different degree of polymerization (DP) on the lipid or glucose metabolism. The objective of this study was to investigate the effect of inulins with various DP on metabolic disorders associated with obesity in rats fed a high-fat diet under food restriction. Rats were fed a high-fat diet supplemented with 5 % inulin-GR (Raftiline GR), inulin-Tokachi (Tokachi), or inulin-HP (Raftiline HP) without cellulose for 28 days at normal energy intakes or 14.5 % energy restriction. Under food restriction, the dietary inulin-Tokachi (mean DP 15) and -HP (mean DP 24), but not -GR (mean DP 10), reduced (p < 0.05) the serum cholesterol and triglyceride levels, and liver triglyceride concentration in rats, compared to the control diet. The cecal neutral steroid, bile acid, and propionate concentrations in the Tokachi and HP groups were higher (p < 0.05) than in the CONT group, and the cecal Bifidobacterium count in the Tokachi group was higher (p < 0.05) than in the other groups. Findings suggest that, depending on DP, dietary supplementation with inulin (DP 15 or DP 24) in rats fed a high-fat diet, regardless of food intake, positively modulates lipid metabolism and fecal microbiota but not glucose metabolism. 22949309 Diagnosis of invasive pulmonary aspergillosis in children with bronchoalveolar lavage galactomannan. Invasive pulmonary aspergillosis (IPA) is a life-threatening complication in immunocompromised patients. Early diagnosis and therapy improves outcome. Assessment of galactomannan (GM) in bronchoalveolar lavage (BAL) fluid is a proposed tool to diagnose IPA. Little is known about the diagnostic value of BAL GM in children. Retrospectively, 72 bronchoscopies were analyzed for GM in patients fulfilling the host factor criteria as defined by the EORTC/MSG. A cut-off index value GM of ≥0.5 was used. Clinical data, results of chest CT-scans and BAL cultures were collected. Sensitivity, specificity, PPV, and NPV of BAL GM for a diagnosis of proven and probable IPA (n = 41) were 82.4%, 87.5%, 82.4%, and 87.5% respectively. A significant relation was found for BAL GM and abnormal chest CT (P = 0.01). No significant relationship was observed between BAL Aspergillus sp. culture and chest CT (n = 47). BAL GM and serum GM correlated significantly. In 9 out of 12 patients classified as possible IPA, antifungal therapy was continued or started, despite a negative BAL GM. BAL GM test had good diagnostic value in children suspected of IPA. However, the decision to continue or start antifungal therapy was mainly determined by the clinical suspicion of IPA based on chest CT-outcome, serum GM index values and failure of antibiotic therapy. Pediatr Pulmonol. 2013; 48:789-796. © 2012 Wiley Periodicals, Inc. 23909609 Identification of Sensory Attributes That Drive Consumer Liking of Commercial Orange Juice Products in Korea. Orange juice is a well-accepted fruit juice, and its consumption increases steadily. Many studies have been conducted to understand the sensory characteristics of orange juice throughout its varying processing steps. Sensory language and consumer likings of food can be influenced by culture. The objective of this study is to evaluate the sensory characteristics of commercially available orange juices in Korea and identify drivers of liking for orange juices in Korea. A quantitative descriptive analysis was conducted using a trained panel (n = 10) to evaluate 7 orange juice samples in triplicates, followed by consumer acceptance tests (n = 103). Univariate and multivariate statistical analyses were conducted for data analysis. The sensory characteristics of commercially available orange juice were documented and grouped: group 1 samples were characterized by high in natural citrus flavors such as orange peel, orange flesh, citrus fruit, and grape fruit, whereas group 2 samples were characterized by processed orange-like flavors such as over-ripe, cooked-orange, and yogurt. Regardless of orange flavor types, a high intensity of orange flavor in orange juice was identified as a driver of liking for orange juices in Korea. Three distinct clusters were segmented by varying sensory attributes that were evaluated by likes and dislikes. Overall, many similarities were noticed between Korean market segment and global orange juice market. By knowing the drivers of liking and understanding the distinct consumer clusters present in the Korean orange juice market, the orange juice industry could improve the strategic marketing of its products in Korea. 23161651 Comparison of gel-based phosphoproteomic approaches to analyse scarce oviductal epithelial cell samples. The reversible change of the phosphorylation state of proteins regulates key cellular processes. In the present study, three different gel-based approaches were compared with regard to their applicability to quantitatively analyse the phosphoproteome of scarce biological material obtained ex vivo. Our results show that the phosphoproteome characterisation of oviductal epithelial cells isolated from the female reproductive tract requires affinity enrichment and pre-electrophoretic labelling using fluorescence dyes. Using this approach, 30 μg of enriched phosphoproteins proved to be sufficient for the phosphoproteome characterisation. In contrast, sequential fluorescence staining of 2D-separated total cell lysates as well as sequential staining in conjunction with a pre-enrichment step led to detection discrepancies and excluded further analysis steps. Information gained from this study provides a successful approach for the phosphoproteome analysis of scarce samples. In addition, the cellular processes taking place in the female reproductive tract can be monitored ex vivo. 23852802 Role of norovirus in acute gastroenteritis in the Northwest of Spain during 2010-2011. A total of 2,643 samples from patients with gastroenteritis in Galicia (NW Spain) were tested for the presence of Norovirus (NoV). NoV genogroup GI was detected in 416 (15.7%) samples, while NoV genogroup GII was detected in 278 (10.5%) samples. Mixed infections of NoV GI and GII were observed in 53 (2%) samples. Total prevalence of NoV in the analyzed samples was 28.3%. Besides NoV diagnosis assay, all the specimens were also submitted to routine clinical bacteriology tests. Cryptosporidium spp. as well as adenovirus (AdV) and rotavirus (RV) were determined on some samples after specific request by hospital units. The results obtained allowed to determine the disease etiology in 14.4% of the patients. Taking into account all the microorganisms studied, the etiological agent was determined for 39.5% of the cases. The results indicated that NoVs are the leading cause of acute gastroenteritis in all age-groups in Northwestern Spain, and that the lack of routine NoV diagnosis contributes to the underestimation of the importance of this virus, not only in outbreaks, but also in sporadic cases of acute gastroenteritis. J Med. Virol. 85:2009-2015, 2013.. © 2013 Wiley Periodicals, Inc. 23965531 A facile solvothermal method to produce ZnS quantum dots-decorated graphene nanosheets with superior photoactivity. Zinc sulfide-graphene (ZnS-GR) nanocomposites with a high degree of dispersion and high coverage of ZnS quantum dots (QDs) have been synthesized by a facile solvothermal method without any dispersant, during which the formation of ZnS nanoparticles and the reduction of graphene oxide (GO) occur simultaneously. ZnS-GR nanocomposites exhibit much higher photoactivity than nanoparticle crystal ZnS (NPC-ZnS) prepared in the absence of graphene (GR), as evaluated by degradation of methylene blue (MB) in the liquid phase under ultraviolet (UV) light. Among them, the ZnS-GR nanocomposite with a 5% mass fraction of GR prepared at 120 ° C has the highest photocatalytic activity. The conversion and mineralization over MB are 96.7% and 57.1% respectively, which is much higher than that of NPC-ZnS. The high photoactivity of ZnS-GR nanocomposites can be ascribed to the integrated effect of an extremely high specific surface area and the excellent electron conductivity of GR and its significant influence on the morphology and structure of the samples. Moreover, it is found that the oxidation of MB is driven mainly by the participation of ⋅OH radicals. Accordingly, a potential photocatalytic mechanism of ZnS-GR nanocomposites in the photocatalytic process has been proposed in this work. It is expected that our work could provide valuable information on the design of metal sulfide decorated GR with excellent properties. 23265876 3'-Modified oligodeoxyribonucleotides for the study of 2-deoxyribose damage in DNA. Well-defined substrates for the study of oxidative processes are important for the elucidation of the role of DNA damage in the etiology of diseases such as cancer. We have synthesized 3'-modified oligodeoxyribonucleotides (ODNs) using 5'→3' 'reverse' DNA synthesis for the study of 2-deoxyribose oxidative damage to DNA. The modified monomers designed for these studies all share a common feature, they lack the naturally occurring 3'-hydroxyl group found in 2-deoxyribonucleosides. Modified H-phosphonates containing 3'-phenyl selenides as well as saturated and unsaturated sugars were obtained and incorporated in ODNs. These ODNs were used to investigate the fate of C3'-dideoxyribonucleotide radicals in DNA. 23949147 Long-Term Safety and Efficacy of Donepezil in Patients with Dementia with Lewy Bodies: Results from a 52-Week, Open-Label, Multicenter Extension Study. Background/Aims: To investigate the safety and efficacy of long-term administration (52 weeks) of donepezil in patients with dementia with Lewy bodies (DLB). Methods: This was a 52-week, multicenter, open-label extension study. Up to 8 weeks after the completion of the preceding randomized, placebo-controlled trial (RCT), patients started treatment with 3 mg of donepezil daily for 2 weeks, followed by 5 mg daily for the remaining 50 weeks. Cognitive function, behavioral and psychiatric symptoms, cognitive fluctuations, and caregiver burden were assessed using the Mini-Mental State Examination, Neuropsychiatric Inventory, Cognitive Fluctuation Inventory, and the Zarit Caregiver Burden Interview, respectively. Safety parameters were monitored throughout. Results: In total, 108 patients were enrolled in the study. Cognitive function and dementia-related behavioral symptoms, including cognitive fluctuations, were improved after the start of donepezil treatment, and improvement was maintained for 52 weeks. Reduction in caregiver burden observed in the preceding RCT returned to the baseline level at 52 weeks. There was no significant imbalance in the incidence of adverse events (AEs) by onset time, and delayed AE onset induced by the long-term administration of donepezil was unlikely to appear. Conclusion: The long-term administration of donepezil at 5 mg/day was well tolerated in patients with DLB and is expected to exhibit lasting effects, improving impaired cognitive function and psychiatric symptoms up to 52 weeks. © 2013 S. Karger AG, Basel. 23302765 Gender difference in sickness absence from work: a multiple mediation analysis of psychosocial factors. Previous research has shown that job characteristics, private life and psychosocial factors partially account for gender difference in work absences because of sickness. Most studies have analysed these factors separately. The aim of the present study was to evaluate whether these explanatory factors act as mediators when they are considered simultaneously. The evaluated data set comprises the merger of two Belgian longitudinal studies, BELSTRESS III and SOMSTRESS. It includes 3821 workers (1541 men) aged 21-66 years, employed in eight organizations. A multiple mediation analysis was performed to explain the higher prevalence among women. Estimated factors were occupational grade, total number of paid working hours per week, job strain, overcommitment, home-work interference and social support at and outside work. Prospective data concerning duration and frequency of medically justified sickness absence (registered by the organizations) were used as outcomes. Overall, the mediating factors partially account for gender difference in sickness absence. The strongest mediator for both outcomes is job strain. In addition, difference in absence duration is mediated by social support at work, whereas difference in frequency is mediated by professional grade and home-work interference. Our results call attention to the necessity to elaborate actual preventive actions aiming at favouring a better positioning of women on the labour market in term of hierarchical level as well as in terms of quality of work for reducing sickness absence in this group. 23805796 State variation in the cortisol awakening response. Abstract The cortisol awakening response (CAR) is a much studied but poorly understood aspect of the circadian pattern of cortisol secretion. A Scopus search of "cortisol" and "awakening" reveals 666 publications in this area since 1997 when it was first identified by Pruessner and colleagues as a "reliable biomarker of adrenocortical activity". The primary focus of the majority of these studies is centered on its utility as a biomarker associated with a range of psychosocial, physical and mental health variables. Such studies typically examine differences in the CAR (studied on 1 or 2 days) between healthy participants and other comparator groups of interest. Fewer studies (25 in our estimation) have examined correlates of day-to-day variation in the CAR in healthy participants, informing its role and regulation within the healthy circadian pattern of cortisol secretion. This is the first review to examine these studies which, although limited in number, offer a relatively coherent emerging story about state factors that influence the CAR and the impact of the CAR on daily functioning. Greater understanding of these issues helps illuminate the utility of the CAR as a promising biomarker in psychophysiological and epidemiological research. The review also highlights areas that require greater clarification and points to potentially fruitful areas of further research. 23845478 Amperometric sensing of norepinephrine at picomolar concentrations using screen printed, high surface area mesoporous carbon. Norepinephrine (NE) is detected amperometrically using the enzyme Phenylethanolamine N-methyl transferase and cofactor S-(5'-Adenosyl)-l-methionine chloride dihydrochloride with disposable screen printed mesoporous carbon electrodes. The role of internal surface area and pore size of the mesoporous carbon is systematically examined using soft-templated, mesoporous silica-carbon powders with highly microporous walls obtained from etching of the silica to produce powders with surface areas ranging from 671-2339m(2)g(-1). As the surface area increases, the sensitivity of the biosensor at very low NE concentrations (0-500pgmL(-1)) in phosphate buffered saline (PBS) increases just as the current signal increases with respect to the NE concentration of 81-1581μAmLng(-1)cm(-2) for the mesoporous carbons. The best performing electrode provides similar sensitivity in whole rabbit blood in comparison to PBS despite no membrane layer to filter the non-desired reactants; the small (<5nm) pore size and large internal surface area acts to minimize non-specific events that decrease sensitivity. 23541671 Synthesis and biological evaluation of prodrugs of 2-fluoro-2-deoxyribose-1-phosphate and 2,2-difluoro-2-deoxyribose-1-phosphate. We report in this Letter the synthesis of prodrugs of 2-fluoro-2-deoxyarabinose-1-phosphate and 2,2-difluoro-2-deoxyribose-1-phosphate. We demonstrate the difficulty of realising a phosphorylation step on the anomeric position of 2-deoxyribose, and we discover that introduction of fluorine atoms on the 2 position of 2-deoxyribose enables the phosphorylation step: in fact, the stability of the prodrugs increases with the degree of 2-fluorination. Stability studies of produgs of 2-fluoro-2-deoxyribose-1-phosphate and 2,2-difluoro-2-deoxyribose-1-phosphate in acidic and neutral conditions were conducted to confirm our observation. Biological evaluation of prodrugs of 2,2-difluoro-2-deoxyribose-1-phosphate for antiviral and cytotoxic activity is reported. 23883100 Synthesis and spectroscopic and spectroelectrochemical characterization of a new family of 44e(-) tris-phosphido-bridged palladium triangles. Triangular clusters containing a [M3(μ-PR2)3](+) core are very common in platinum chemistry but were virtually unknown for M = Pd. Herein we describe the synthesis and characterization of several palladium derivatives belonging to this class. The trinuclear monohalide clusters {Pd3}(CO)2X [{Pd3} = Pd3(μ-PBu(t)2)3; X = Br, I] were prepared by reacting [(n)Bu4N]X or KX with the dinuclear complex [Pd(PBu(t)2H)(μ-PBu(t)2)]2 and H2O under an atmosphere of CO. The reaction of {Pd3}(CO)2I with CNBu(t) leads to the substitution of all the terminal ligands to afford the symmetrical cluster [{Pd3}(CNBu(t))3]I. The latter reacts with TlPF6 (excess) or AgCF3SO3 (1:1 ratio) to give anion metathesis, whereas the addition of a second equivalent of Ag(+) causes cluster oxidation to the thermally stable paramagnetic 43e(-) dication [{Pd3}(CNBu(t))3](2+). The cationic clusters [{Pd3}(CO)2(L)]PF6 (L = NCCH3, Py or CO) were obtained by reacting {Pd3}(CO)2I with TlPF6, under nitrogen in acetonitrile or in pyridine or under 1 atm of carbon monoxide in THF. Finally, {Pd3}(CO)2Cl was achieved by the reaction of [{Pd3}(CO)3]PF6 with [(PPh3)2N]Cl. All clusters have been obtained in good yields and purity and have been characterized by microanalysis and IR and multinuclear NMR spectroscopy. Single crystal X-ray diffraction studies on {Pd3}(CO)2Br and [{Pd3}(CNBu(t))3]CF3SO3 are also reported. The cyclovoltammetric profile exhibited by the palladium clusters prepared in this work is characterized by the presence of two monoelectronic oxidation processes whose reversibility and potentials depend on the nature of the ligands. Moreover, the UV-vis and IR spectroelectrochemical analysis of {Pd3}(CO)2I, [{Pd3}(CO)3]PF6 and [{Pd3}(CNBu(t))3]PF6 allowed the spectroscopical characterization of some electrogenerated oxidized species and provided some detail for the redox-coupled reactions of metastable products. 23743183 Neural systems underlying the influence of sound shape properties of the lexicon on spoken word production: Do fMRI findings predict effects of lesions in aphasia? Previous behavioral work has shown that the phonetic realization of words in spoken word production is influenced by sound shape properties of the lexicon. A recent fMRI study (Peramunage, Blumstein, Myers, Goldrick, & Baese-Berk, 2011) showed that this influence of lexical structure on phonetic implementation recruited a network of areas that included the supramarginal gyrus (SMG) extending into the posterior superior temporal gyrus (pSTG) and the inferior frontal gyrus (IFG). The current study examined whether lesions in these areas result in a concomitant functional deficit. Ten individuals with aphasia and 8 normal controls read words aloud in which half had a voiced stop consonant minimal pair (e.g. tame; dame), and the other half did not (e.g. tooth; (*)dooth). Voice onset time (VOT) analysis of the initial voiceless stop consonant revealed that aphasic participants with lesions including the IFG and/or the SMG behaved as did normals, showing VOT lengthening effects for minimal pair words compared to non-minimal pair words. The failure to show a functional deficit in the production of VOT as a function of the lexical properties of a word with damage in the IFG or SMG suggests that fMRI findings do not always predict effects of lesions on behavioral deficits in aphasia. Nonetheless, the pattern of production errors made by the aphasic participants did reflect properties of the lexicon, supporting the view that the SMG and IFG are part of a lexical network involved in spoken word production. 23649131 Debulking from within: a robotic steerable cannula for intracerebral hemorrhage evacuation. New approaches to intracerebral hemorrhage management are motivated by its high incidence and 40% mortality rate. Surgery is sometimes attempted to decompress the brain, although patient outcomes are similar regardless of whether surgery occurs. We hypothesize that surgical decompression is not more effective because current open surgical techniques disrupt healthy brain tissue to access the clot formed by the hemorrhage, offsetting the benefits of surgery. To address this, we propose a less invasive needle-based approach in which the clot is debulked from within using a superelastic, precurved aspiration cannula that is deployed from a needle. The tip of this aspiration cannula is controlled by coordinated insertion and retraction of the cannula and needle, as well as axial rotation of the cannula. We describe the design of a sterilizable and biocompatible robot that can control the three degrees of freedom of the needle and cannula. Image guidance is achieved by adapting an approach originally developed for brain biopsy. We provide an optimization method for the selection of the precurvatures of one or more sequentially used aspiration cannulas to maximize hemorrhage evacuation, based on preoperative medical image data. In vitro experiments demonstrate the feasibility of evacuating 83-92% of hemorrhage volume, depending on the number of tubes and deployment method used. 23944974 Scalable Synthesis of N-Acylaziridines from N-Tosylaziridines. N-Acylaziridines are important starting materials for the synthesis of chiral amine derivatives. The traditional methods for producing these activated aziridines have significant drawbacks. The gram scale synthesis of N-acylaziridines by deprotection of N-tosylaziridines and reprotection with N-hydroxysuccinimide derivatives is described. Mono- and disubstituted aziridines perform well, with complete retention of stereochemical purity. The consistently moderate yields are linked to the N-tosylaziridine deprotection step, while acylation with N-hydroxysuccinimide derivatives is highly efficient. 23918787 Pseudomonas guangdongensis sp. nov., isolated from an electroactive biofilm, and amended description of the genus Pseudomonas Migula 1894. A Gram-negative, straight to slightly curved rod-shaped and motile with peritrichous flagella bacterium, designated SgZ-6T, was isolated from an electroactive biofilm and was characterized by means of a polyphasic approach. Growth occurred with 0-5.0% (w/v) NaCl (optimum 1%), at pH 6.0-10.0 (optimum pH 7.0) and at 10-42 oC (optimum 30 oC) in trypticase soya broth. The phylogenetic analysis based on 16S rRNA gene and gyrB gene identified the isolate to be a novel Pseudomonas species. Strain SgZ-6T exhibited the highest 16S rRNA gene sequence similarity with 'P. linyingensis' CGMCC 1.10701T (97.5%), followed by P. sagittaria JCM 18195T (97.4%), P. oleovorans subsp. lubricantis DSM 21016T (96.6%), P. tuomuerensis JCM 14085T (96.5%) and P. alcaliphila JCM 10630T (96.4%). Strain SgZ-6T showed the highest gyrB gene sequence similarity of 93.7% with 'P. linyingensis' CGMCC 1.10701T among all the type strains of genus Pseudomonas. DNA-DNA pairing studies showed that strain SgZ-6T displayed 47.1% and 40.3% relatedness values to the type strain of 'P. linyingensis' CGMCC 1.10701T and P. sagittaria JCM 18195T, respectively. The major isoprenoid quinone was ubiquinone-9 (Q-9). The whole-cell fatty acids mainly consisted of C16:1ω6c/C16:1ω7c, C16:0 and C18:1ω6c/C18:1ω7c. G+C content of genomic DNA was 68.1 mol%. On the basis of phenotypic, chemotaxonomic and phylogenetic data, strain SgZ-6T is proposed to represent a novel species of the genus Pseudomonas, for which the name Pseudomonas guangdongensis sp. nov. is proposed. The type strain is SgZ-6T (=CCTCC AB 2012022T =KACC 16606T). 23611176 Inhibition of fear is differentially associated with cycling estrogen levels in women. Although the prevalence of posttraumatic stress disorder (PTSD) is twice as high in women as it is in men, the role of estrogen in the risk for PTSD is not well understood. Deficits in fear inhibition and impaired safety signal learning may be biomarkers for PTSD. We examined menstrual cycle phase and serum estradiol levels in naturally cycling women while they were undergoing a novel conditioned inhibition procedure that measured their ability to discriminate between cues representing danger versus safety and to inhibit fear in the presence of safety cues. Sample 1 included healthy participants in whom we compared inhibition of fearpotentiated startle during the follicular (lower estrogen) and luteal (higher estrogen) phases of the menstrual cycle. We used the same paradigm in a traumatized clinical population (sample 2) in whom we compared low versus high estradiol levels. In both samples, we found that lower estrogen in cycling women was associated with impaired fear inhibition. In the clinical sample, the low estradiol group was on average older than the high estradiol group owing to the random recruitment approach; we did not exclude participants based on hormonal status or menopause. Our results suggest that the lower estrogen state during normal menstrual cycling may contribute to risk for anxiety disorders through dysregulated fear responses. 23968278 Palladium Catalyzed Coupling Reactions for the Functionalization of Si Surfaces: Superior Stability of Alkenyl Monolayers. Palladium catalyzed Suzuki, Heck and Sonogashira coupling reactions were studied as reaction protocols for organic modification of Si surfaces. These synthetically useful protocols allow for surface modification of alkene, alkyne and halide terminated surfaces. Surface oxidation and metal contamination was assessed by X-ray photoelectron spectroscopy. The nature of the primary passivation layer was an important factor in the oxidation resistance of the Si surface during the secondary functionalization. Specifically, the use of alkynes as the primary functionalization layer gave superior stability compared to alkene analogues. The ability to utilize Pd catalyzed coupling chemistries on Si surfaces opens great versatility for potential molecular and nanoscale electronics and sensing/biosensing applications. 23407662 Age-dependent changes in hippocampal synaptic transmission and plasticity in the PLB1Triple Alzheimer mouse. Several genetically engineered models exist that mimic aspects of the pathological and cognitive hallmarks of Alzheimer's disease (AD). Here we report on a novel mouse model generated by targeted knock-in of transgenes containing mutated human amyloid precursor protein (APP) and microtubule-associated protein tau genes, inserted into the HPRT locus and controlled by the CaMKIIα regulatory element. These mice were crossed with an asymptomatic presenilin1A246E overexpressing line to generate PLB1Triple mice. Gene expression analysis and in situ hybridization confirmed stable, forebrain-specific, and gene-dose-dependent transgene expression. Brain tissue harvested from homozygous, heterozygous, and wild-type cohorts aged between 3 and 24 months was analyzed immunohistochemically and electrophysiologically. Homozygous PLB1Triple offspring presented with mostly intracellular cortical and hippocampal human APP/amyloid, first detected reliably at 6 months. Human tau was already uncovered at 3 months (phospho-tau at 6 months) and labeling intensifying progressively with age. Gene-dose dependence was confirmed in age-matched heterozygous females that accumulated less tau and amyloid protein. General excitability of hippocampal neurones was not altered in slices from PLB1Triple mice up to 12 months, but 2-year-old homozygous PLB1Triple mice had smaller synaptically evoked postsynaptic potentials compared with wild types. Synaptic plasticity (paired-pulse depression/facilitation and long-term potentiation) of synaptic CA1 pyramidal cell responses was deficient from 6 months of age. Long-term depression was not affected at any age or in any genotype. Therefore, despite comparatively subtle gene expression and protein build-up, PLB1Triple mice develop age-dependent progressive phenotypes, suggesting that aggressive protein accumulation is not necessary to reconstruct endophenotypes of AD. 23936475 Isolation and Characterization of the New Mosaic Filamentous Phage VFJ Φ of Vibrio cholerae. Filamentous phages have distinguished roles in conferring many pathogenicity and survival related features to Gram-negative bacteria including the medically important Vibrio cholerae, which carries factors such as cholera toxin on phages. A novel filamentous phage, designated VFJΦ, was isolated in this study from an ampicillin and kanamycin-resistant O139 serogroup V. cholerae strain ICDC-4470. The genome of VFJΦ is 8555 nucleotides long, including 12 predicted open reading frames (ORFs), which are organized in a modular structure. VFJΦ was found to be a mosaic of two groups of V. cholerae phages. A large part of the genome is highly similar to that of the fs2 phage, and the remaining 700 bp is homologous to VEJ and VCYΦ. This 700 bp region gave VFJΦ several characteristics that are not found in fs2 and other filamentous phages. In its native host ICDC-4470 and newly-infected strain N16961, VFJΦ was found to exist as a plasmid but did not integrate into the host chromosome. It showed a relatively wide host range but did not infect the classical biotype O1 V. cholerae strains. After infection, the host strains exhibited obvious inhibition of both growth and flagellum formation and had acquired a low level of ampicillin resistance and a high level of kanamycin resistance. The antibiotic resistances were not directly conferred to the hosts by phage-encoded genes and were not related to penicillinase. The discovery of VFJΦ updates our understanding of filamentous phages as well as the evolution and classification of V. cholerae filamentous phage, and the study provides new information on the interaction between phages and their host bacteria. 23628592 Cytotoxic effects of amphetamine mixtures in primary hepatocytes are severely aggravated under hyperthermic conditions. Amphetamine consumers are often, deliberately or not, polydrug abusers. Predicting combination effects based on concentration-response analysis of individual components is a valid strategy for accurate toxicological assessment of mixtures. We previously reported that joint effects of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and three other often co-ingested amphetamines (methamphetamine, 4-methylthyoamphetamine and D-amphetamine) could be predicted by the concentration addition (CA) model in HepG2 cells. We sought to further evaluate the relevance of these findings by extending these studies to a cell model that more closely mimics the in vivo situation. Detailed cytotoxic information of the four individual amphetamines on primary rat hepatocytes was recorded by the MTT assay, at 37°C and 40.5°C, simulating the rise in body temperature that could be induced following amphetamine intake. Mixture expectations were calculated using CA and independent action (IA) models. At 37°C, concentration-dependent cytotoxicity occurred for the drugs individually and combined. Mixture effects were accurately predicted by the CA model, while the IA model underestimated cytotoxicity. At 40.5°C these cytotoxic effects were aggravated. Our findings provide evidence of the increased risks associated with the abuse of amphetamine mixtures, especially during hyperthermia, emphasising the need to increase awareness of misinformed users who believe these drugs are safe. 23880025 Evaluation of transcranial sonographic findings and MIBG cardiac scintigraphy in the diagnosis of idiopathic Parkinson's disease. The diagnosis of idiopathic Parkinson's disease (IPD) is based on clinical criteria. In the last two decades several neuroimaging methods using transcranial sonography (TCS) or radiolabelled tracers such as the myocardial MIBG scintigraphy were applied to support diagnosis of IPD. They have been used independently of each other and their interrelation is not yet clear. In the present study we analyzed the relation between findings of TCS, MIBG scintigraphy, and clinical presentation in 42 patients with IPD who were clinically diagnosed and underwent clinical follow-up over ≥3 years in order to confirm IPD diagnosis throughout the clinical course. The extent of substantia nigra hyperechogenicity (SN+) contralateral to the clinically more affected body side (SNcontra) was compared to myocardial (123)I-MIBG uptake. SNcontra did not correlate with the myocardial MIBG uptake (r = -0.10; p = 0.52). Both myocardial MIBG uptake and TCS did not correlate significantly with Hoehn and Yahr stage (r = -0.03; p = 0.87 and r = -0.10; p = 0.54, respectively). Sensitivity of TCS in the diagnosis of IPD was 79%, of MIBG scintigraphy 81%. The combination of both measurements reached a sensitivity of 95%. TCS and MIBG scintigraphy may disclose complementary aspects of IPD. The combined use of both neuroimaging methods might improve the diagnostic sensitivity regarding IPD. 22610968 The role of diallyl sulfides and dipropyl sulfides in the in vitro antimicrobial activity of the essential oil of garlic, Allium sativum L., and Leek, Allium porrum L. The in vitro antibacterial activity of essential oils (EOs) obtained from fresh bulbs of garlic, Allium sativum L., and leek, Allium porrum L. ( Alliaceae), was studied. A. sativum (garlic) EO showed a good antimicrobial activity against Staphylococcus aureus (inhibition zone 14.8 mm), Pseudomonas aeruginosa (inhibition zone 21.1 mm), and Escherichia coli (inhibition zone 11.0 mm), whereas the EO of A. porrum (leek) had no antimicrobial activity. The main constituents of the garlic EO were diallyl monosulfide, diallyl disulfide (DADS), diallyl trisulfide, and diallyl tetrasulfide. The EO of A. porrum was characterized by the presence of dipropyl disulfide (DPDS), dipropyl trisulfide, and dipropyl tetrasulfide. The antimicrobial activities of the DADS and DPDS were also studied. The results obtained suggest that the presence of the allyl group is fundamental for the antimicrobial activity of these sulfide derivatives when they are present in Allium or in other species (DADS inhibition zone on S. aureus 15.9 mm, P. aeruginosa 21.9 mm, E. coli 11.4 mm). Copyright © 2012 John Wiley & Sons, Ltd. 23772950 HPLC determination of isoflavone levels in osage orange from the midwest and southern United States. The fruit of the Maclura pomifera tree is a sustainable source for the pharmacologically interesting isoflavones, osajin and pomiferin. A reversed-phase HPLC method was developed to identify osage orange samples with high isoflavone content and to determine the optimum conditions for sample preparation. Analytical run time was 8 min at a flow rate of 1 mL/min using a gradient of acetonitrile in H2O (0.1% formic acid) and UV peak detection at 274 nm. The method was validated for specificity, accuracy, precision, and limits of detection and quantitation (LOD/LOQ). The method was applied to determine the levels of osajin and pomiferin in extracts prepared from different samples of osage orange growing in the Midwest and southern United States. Results demonstrated the effect of different variables, such as sample preparation, geographical location, and growth stage, on the levels of osajin and pomiferin in analyzed samples. 23959585 Brief Report: Diminishing Geographic Variability in Autism Spectrum Disorders Over Time? We investigated differences in the geographic distribution of autism spectrum disorders (ASD) over time in central North Carolina with data from the Autism and Developmental Disabilities Monitoring Network. Using generalized additive models and geographic information systems we produced maps of ASD risk in 2002-2004 and 2006-2008. Overall the risk of ASD increased 52.9 % from 2002-2004 to 2006-2008. However, the magnitude of change in risk was not uniform across the study area; while some areas experienced dramatic increases in ASD risk (>400 %), others experienced slight decreases. Generally, areas with the lowest risk in 2002-2004 experienced the greatest increases over time. Education and outreach efforts in North Carolina expanded during this period, possibly contributing to the observed leveling of risk over time. 23970536 Muscle Immobilization and Remobilization Down-regulates PGC-1α Signaling and Mitochondrial Biogenesis Pathway. Prolonged immobilization (IM) results in skeletal muscle atrophy accompanied by increased reactive oxygen species (ROS), inflammation, and protein degradation. In this study, we examined peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) controlled mitochondrial biogenesis pathway and inflammatory response in mice subjected to two weeks of hindlimb IM followed by five days of remobilization (RM). FVB/N mice (age 2 mo) were randomly assigned to either 14 days of IM with capping one of the hindlimbs (N=7), IM followed by 5 day of RM with cap removed (N=7), or control (Con, N=7). Protein contents of PGC-1α and nuclear respiratory factor (NRF)-1 and -2 in tibialis anterior (TA) muscle was reduced by 50% (p<0.01) in IM vs. Con, with no recovery seen during RM. IM suppressed mitochondrial transcription factor A and cytochrome c content by 57% and 63% (P<0.01), respectively and cytochrome c oxidase activity by 58% (P<0.05). Furthermore, mitochondrial DNA content was reduced by 71% (P<0.01) with IM. None of these changes was reversed after RM. With RM, TA muscle showed a 2.3-fold (P<0.05) and 4-fold (P<0.01) higher H2O2 and 8-isoprostane contents, respectively, compared with Con, indicating an oxidative stress. Tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels in TA muscle were 4- and 3-fold higher (P<0.05), respectively, in IM or RM vs. CON, NFκB pathway activation was observed only after RM, but not after IM alone. These data indicate that during the initial phase of muscle RM there is an increase in ROS generation that could activate NFkB pathway and elicit inflammation and oxidative stress. 23777274 Integrated Metabolomics Approach Facilitates Discovery of an Unpredicted Natural Product Suite from Streptomyces coelicolor M145. Natural products exhibit a broad range of biological properties and have been a crucial source of therapeutic agents and novel scaffolds. Although bacterial secondary metabolomes are widely explored, they remain incompletely cataloged by current isolation and characterization strategies. To identify metabolites residing in unexplored chemical space, we have developed an integrated discovery approach that combines bacterial growth perturbation, accurate mass spectrometry, comparative mass spectra data analysis, and fragmentation spectra clustering for the identification of low-abundant, novel compounds from complex biological matrices. In this investigation, we analyzed the secreted metabolome of the extensively studied Actinomycete, Streptomyces coelicolor M145, and discovered a low-abundant suite of 15 trihydroxamate, amphiphilic siderophores. Compounds in this class have primarily been observed in marine microorganisms making their detection in the soil-dwelling S. coelicolor M145 significant. At least 10 of these ferrioxamine-based molecules are not known to be produced by any organism, and none have previously been detected from S. coelicolor M145. In addition, we confirmed the production of ferrioxamine D1, a relatively hydrophilic family member that has not been shown to be biosynthesized by this organism. The identified molecules are part of only a small list of secondary metabolites that have been discovered since sequencing of S. coelicolor M145 revealed that it possessed numerous putative secondary metabolite-producing gene clusters with no known metabolites. Thus, the identified siderophores represent the unexplored metabolic potential of both well-studied and new organisms that could be uncovered with our sensitive and robust approach. 23727044 Discovery of non-LBD inhibitor for androgen receptor by structure-guide design. In this study, we synthesized the BF-3 binding small molecules, a series of pyridazinone-based compounds, as a novel class of non-LBP antiandrogens for treating prostate cancer by inhibiting androgen receptor. The new class compound was discovered to inhibitor the viability of AR-dependent human prostate LNCap cells and AR activity combining with the computational method. It showed a good physicochemical and PK property. 23819682 Perinatal systemic inflammatory responses of growth-restricted preterm newborns. To compare the early post-natal pattern of systemic inflammation in growth-restricted infants born before the 28th week of gestation to that of appropriately grown peers. We measured the concentrations of 25 inflammation-related proteins in blood spots collected from 939 newborns during the first 2 post-natal weeks. We calculated the odds ratios (99% confidence intervals) that concentrations would be in the highest quartile. Severely growth-restricted infants (birth weight Z-score <-2) were not at increased risk of systemic inflammation shortly after birth. On post-natal day 14, however, they were significantly more likely than their peers to have a CRP, IL-1β, IL-6, TNF-α, IL-8, MCP-4, ICAM-1, ICAM-3, E-SEL, MMP-9, VEGF-R2 and/or IGFBP-1 concentration in the highest quartile. These increased risks could not be attributed to delivery indication, bacteremia or duration of ventilation. Growth-restricted preterm newborns appear to be at increased risk of elevated concentrations of inflammation-associated proteins by post-natal day 14. 23855376 Efficacy and cost-effectiveness of a web-based and mobile stress-management intervention for employees: design of a randomized controlled trial. Work-related stress is associated with a variety of mental and emotional problems and can lead to substantial economic costs due to lost productivity, absenteeism or the inability to work. There is a considerable amount of evidence on the effectiveness of traditional face-to-face stress-management interventions for employees; however, they are often costly, time-consuming, and characterized by a high access threshold. Web-based interventions may overcome some of these problems yet the evidence in this field is scarce. This paper describes the protocol for a study that will examine the efficacy and cost-effectiveness of a web-based guided stress-management training which is based on problem solving and emotion regulation and aimed at reducing stress in adult employees. The study will target stressed employees aged 18 and older. A randomized controlled trial (RCT) design will be applied. Based on a power calculation of d=.35 (1-β of 80%, α = .05), 264 participants will be recruited and randomly assigned to either the intervention group or a six-month waitlist control group. Inclusion criteria include an elevated stress level (Cohen's Perceived Stress Scale-10 ≥ 22) and current employment. Exclusion criteria include risk of suicide or previously diagnosed psychosis or dissociative symptoms. The primary outcome will be perceived stress, and secondary outcomes include depression and anxiety. Data will be collected at baseline and seven weeks and six months after randomization. An extended follow up at 12 months is planned for the intervention group. Moreover, a cost-effectiveness analysis will be conducted from a societal perspective and will include both direct and indirect health care costs. Data will be analyzed on an intention-to-treat basis and per protocol. The substantial negative consequences of work-related stress emphasize the necessity for effective stress-management trainings. If the proposed internet intervention proves to be (cost-) effective, a preventative, economical stress-management tool will be conceivable. The strengths and limitations of the present study are discussed. German Register of Clinical Studies (DRKS): DRKS00004749. 22795295 Heterozygosity for lysosomal acid lipase E8SJM mutation and serum lipid concentrations. The complete absence of the lysosomal acid lipase (LAL) enzyme function causes Wolman's Disease that is fatal within the first six months of life. Subtotal defects cause Cholesteryl ester storage disease (CESD), an autosomal recessive disorder leading to hepatic steatosis, fibrosis, micronodular cirrhosis, combined hyperlipidemia with low HDL-cholesterol, increased risk for atherosclerosis, premature death. Since the frequency of the Exon 8 splice junction mutation (c.894 G > A, E8SJM), the CESD leading mutation, is not rare in the general population (allele frequency 0.0025), we investigated the impact of this mutation on serum lipid profile in E8SJM carriers. We collected E8SJM carriers both form genetic study-population analysis and from Outpatient Lipid Clinics and then we assessed their serum lipid profile. We found thirteen individuals heterozygote for E8SJM. Most of them were Germans, three Spanish and two Italian. We found a significant increase in total cholesterol levels in both sexes with E8SJM mutation, leading to a significant increase in LDL cholesterol in males. Our results show that LAL E8SJM carriers have an alteration in lipid profile with a Polygenic Hypercholesterolemia phenotype, leading to an increase in cardiovascular risk profile. References to electronic databases: lysosomal acid lipase; EC 3.1.1.13. 23862958 Numerical simulation of photocurrent generation in bilayer organic solar cells: Comparison of master equation and kinetic Monte Carlo approaches. Numerical approaches can provide useful information about the microscopic processes underlying photocurrent generation in organic solar cells (OSCs). Among them, the Kinetic Monte Carlo (KMC) method is conceptually the simplest, but computationally the most intensive. A less demanding alternative is potentially represented by so-called Master Equation (ME) approaches, where the equations describing particle dynamics rely on the mean-field approximation and their solution is attained numerically, rather than stochastically. The description of charge separation dynamics, the treatment of electrostatic interactions and numerical stability are some of the key issues which have prevented the application of these methods to OSC modelling, despite of their successes in the study of charge transport in disordered system. Here we describe a three-dimensional ME approach to photocurrent generation in OSCs which attempts to deal with these issues. The reliability of the proposed method is tested against reference KMC simulations on bilayer heterojunction solar cells. Comparison of the current-voltage curves shows that the model well approximates the exact result for most devices. The largest deviations in current densities are mainly due to the adoption of the mean-field approximation for electrostatic interactions. The presence of deep traps, in devices characterized by strong energy disorder, may also affect result quality. Comparison of the simulation times reveals that the ME algorithm runs, on the average, one order of magnitude faster than KMC. 23252951 Towards a balanced value business model for personalized medicine: an outlook. Novel targeted drugs, mainly in oncology, have commanded substantial price premiums in the recent past. Consequently, the attention of pharmaceutical companies has shifted away from the traditional low-price and high-volume blockbuster business model to drugs that command high, and sometimes extremely high, prices in limited markets defined by targeted patient populations. This model may have already passed its zenith, as the impact of more and more high-priced drugs coming to market substantially increases their combined burden on payors and public health finances. This article introduces a new 'balanced value' business model for personalized medicine, leveraging the emerging opportunities to reduce drug development cost and time for targeted therapies. This model allows pharmaceutical companies to charge prices for targeted therapy below the likely future thresholds for payors' willingness to pay, at the same time preserving attractive margins for the drug developers. 23511023 Identification of benzofurano[3,2-d]pyrimidin-2-ones, a new series of HIV-1 nucleotide-competing reverse transcriptase inhibitors. Screening of our sample collection led to the identification of a set of benzofurano[3,2-d]pyrimidine-2-one hits acting as nucleotide-competing HIV-1 reverse transcriptase inhibitiors (NcRTI). Significant improvement in antiviral potency was achieved when substituents were introduced at positions N1, C4, C7 and C8 on the benzofuranopyrimidone scaffold. The series was optimized from low micromolar enzymatic activity against HIV-1 RT and no antiviral activity to low nanomolar antiviral potency. Further profiling of inhibitor 30 showed promising overall in vitro properties and also demonstrated that its potency was maintained against viruses resistant to the other major classes of HIV-1 RT inhibitors. 23828375 PNEUMONIC AND NON-PNEUMONIC EXACERBATIONS OF COPD: SYSTEMIC INFLAMMATORY RESPONSE AND CLINICAL CHARACTERISTICS. Community-acquired pneumonia (CAP) is a frequent event in patients with chronic obstructive pulmonary disease (COPD), although it is not currently considered an acute exacerbation (AECOPD). No studies have compared the inflammatory response of COPD patients who develop CAP or AECOPD. The aim of our study was to compare clinical and evolutive manifestations and biological signalling of AECOPD and CAP+COPD. Prospective data were collected from 249 consecutively hospitalized COPD patients. Comparative analyses were performed in AECOPD (n=133) and CAP+COPD patients (n=116). Measures of clinical characteristics, blood biomarkers and evolution were recorded on admission, after 3 and 30 days, and in a follow-up period of 30/90 days/1 year. COPD+CAP patients had higher FEV1 compared to COPD patients without pneumonia. In- hospital and long-term outcomes (1 yr) were similar for both populations. However, AECOPD patients had more readmissions and CAP patients more prior episodes of pneumonia. At day 1 and day 3, CAP+COPD patients had significantly (p<0.001) higher serum levels of C-reactive protein (CRP), procalcitonin (PCT), tumour necrosis factor-alpha (TNF-α) and interleukin (IL) 6. Repetition of the analyses after stratifying patients based on severity of disease, current inhaled pharmacotherapy and noninfectious AECOPD etiology confirmed higher levels of the same biomarkers in patients with CAP+COPD. Chills, pleuritic pain, sputum purulence and CRP levels at day 1 were independent clinical predictors of CAP+COPD. Our study confirms that two different clinical and inflammatory profiles exist in hospitalized COPD patients in response to CAP (stronger response) and AECOPD although with similar short-term and long-term outcomes. 22921313 Functional phenotype of airway myocytes from asthmatic airways. In asthma, the airway smooth muscle (ASM) cell plays a central role in disease pathogenesis through cellular changes which may impact on its microenvironment and alter ASM response and function. The answer to the long debated question of what makes a 'healthy' ASM cell become 'asthmatic' still remains speculative. What is known of an 'asthmatic' ASM cell, is its ability to contribute to the hallmarks of asthma such as bronchoconstriction (contractile phenotype), inflammation (synthetic phenotype) and ASM hyperplasia (proliferative phenotype). The phenotype of healthy or diseased ASM cells or tissue for the most part is determined by expression of key phenotypic markers. ASM is commonly accepted to have different phenotypes: the contractile (differentiated) state versus the synthetic (dedifferentiated) state (with the capacity to synthesize mediators, proliferate and migrate). There is now accumulating evidence that the synthetic functions of ASM in culture derived from asthmatic and non-asthmatic donors differ. Some of these differences include an altered profile and increased production of extracellular matrix proteins, pro-inflammatory mediators and adhesion receptors, collectively suggesting that ASM cells from asthmatic subjects have the capacity to alter their environment, actively participate in repair processes and functionally respond to changes in their microenvironment. 23966453 Modification of Erythrocyte Membrane Proteins, Enzymes and Transport Mechanisms in Chronic Alcoholics: An In vivo and In vitro Study. The aim of the study was to elucidate the molecular mechanisms underlying the alcohol perturbation leading to deleterious effects on erythrocyte membrane transport in chronic alcoholics. Membrane bound enzyme activities such as Na(+), K(+)-ATPase, Ca(2+),Mg(2+)-ATPase and acetylcholine esterase and membrane transport analysis by in vitro and erythrocyte membrane profile analysis in controls and chronic alcoholic red cells were analyzed. It was observed that decreased Na(+), K(+)-ATPase enzyme activity and increased activities of Ca(2+),Mg(2+)-ATPase and acetylcholine esterase in chronic alcoholics compared to controls. The in vitro studies of erythrocytes suggested that there is an increased uptake of glucose through chronic alcoholic red cells. However, glucose utilization by chronic alcoholic red cells was decreased. An increased sensitivity of ouabain for its binding site on Na(+), K(+)-ATPase in chronic alcoholic erythrocyte membrane was evident from this study. Though there appears to be an increased Na(+) influx in chronic alcoholic cells, the status of Na(+) transport is not altered much. However, ouabain caused slight disturbances in the transport of sodium, similar disturbances in the potassium transport resulting in much accumulation of potassium in red cells. It was concluded that chronic alcohol consumption modified certain membrane bound proteins, enzymes and transport mechanisms in chronic alcoholics. 23411264 Molecular and functional properties of gelatin from the skin of unicorn leatherjacket as affected by extracting temperatures. Gelatins extracted from the skin of unicorn leatherjacket at different temperatures (45, 55, 65 and 75°C) in the presence and the absence of soybean trypsin inhibitor (SBTI; 100 units/g pretreated skin) for 12h were characterised. In general, the addition of SBTI resulted in the lower yield, regardless of extraction temperature. Higher yield was obtained when higher extraction temperature was used (P<0.05). Gelatin from skin extracted at 75°C in the absence of SBTI showed the highest yield (10.66 ± 0.41%) (based on dry weight). The highest α-amino group content was observed in gelatin extracted at 55°C without SBTI incorporated. The band intensity of β-chain and α-chains increased as the extraction temperature increased, particularly above 55°C. Gelatin extracted at 65°C with and without SBTI incorporation exhibited the highest gel strength (178.00 ± 7.50 g and 170.47 ± 1.30 g, respectively). FTIR spectra indicated that a greater loss of molecular order of triple helix with a higher degradation was found in gelatin extracted at 55°C in the absence SBTI. Gelatin extracted at 65°C, either with or without SBTI, had the highest EAI and ESI with high foam expansion and stability. Thus, the extraction of gelatin from the skin of unicorn leatherjacket at temperature sufficiently high could render the gelatin with less degradation. 23871384 Morphological and biomechanical features of the temporomandibular joint disc: An overview of recent findings. The temporomandibular joint is a type of synovial joint with unique structure and function. Between the mandibular condyle and the mandibular fossa there is a dense fibrocartilaginous oval articular disc, temporomandibular joint disc. This disc serves as a nonossified bone, thus permitting the complex movements of the joint, and plays a major role in jaw function by providing stress distribution and lubrication in the temporomandibular joint. Pathological mechanical loads are one of the principal causes of temporomandibular joint disc displacement. There is a high frequency of temporomandibular joint disc disorders and treatment options are very limited. For this reason, it is necessary to examine possible alternatives to current treatment options like physiotherapy, drugs, splints or surgical techniques. Recent discoveries in the field of structure and functions of temporomandibular joint disc have created the need for their particular systematization, all in order to create an implant that would be used to replace the damaged disc and be more similar to the natural one. There is a need to more fully meet the morphology and biomechanical properties of the temporomandibular joint disc, and using tissue engineering, make a substitute for it, as faithful as possible, in a case where the natural TMJ disc is damaged so much that the normal function of the joint can be preserved only through implanted disc. Therefore, the aim of this paper was to describe morphology and structure, as well as biomechanical properties of the TMJ disc, in light of the possible applications of this knowledge for the purposes of tissue engineering. 23770641 Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance. Through the use of intravital imaging of the liver, we demonstrate a collaborative role for platelets with Kupffer cells (KCs) in eradicating blood-borne bacterial infection. Under basal conditions, platelets, via the platelet-adhesion receptor GPIb, formed transient 'touch-and-go' interactions with von Willebrand factor (vWF) constitutively expressed on KCs. Bacteria such as Bacillus cereus and methicillin-resistant Staphylococcus aureus (MRSA) were rapidly caught by KCs and triggered platelets to switch from 'touch-and-go' adhesion to sustained GPIIb-mediated adhesion on the KC surface to encase the bacterium. Infected GPIbα-deficient mice had more endothelial and KC damage than did their wild-type counterparts, which led to more fluid leakage, substantial polycythemia and rapid mortality. Our study identifies a previously unknown surveillance mechanism by which platelets survey macrophages that rapidly converts to a critical host response to blood-borne bacteria. 23822588 GABA Receptors, Alcohol Dependence and Criminal Behavior. The aim of this study was to analyze the connection between alcohol dependence and criminal behavior by an integrated genetic-environmental approach. The research, structured as a case-control study, examined 186 alcohol-dependent males; group 1 (N = 47 convicted subjects) was compared with group 2 (N = 139 no previous criminal records). Genetic results were innovative, highlighting differences in genotype distribution (p = 0.0067) in group 1 for single-nucleotide polymorphism rs 3780428, located in the intronic region of subunit 2 of the GABA B receptor gene (GABBR2). Some environmental factors (e.g., grade repetition) were associated with criminal behavior; others (e.g., attendance at Alcoholics Anonymous) were inversely related to convictions. The concomitant presence of the genetic and environmental factors found to be associated with the condition of alcohol-dependent inmate showed a 4-fold increase in the risk of antisocial behavior. The results need to be replicated on a larger population to develop new preventive and therapeutic proposals. 23344039 A Molecular-Modeling Toolbox Aimed at Bridging the Gap between Medicinal Chemistry and Computational Sciences. In the current era of high-throughput drug discovery and development, molecular modeling has become an indispensable tool for identifying, optimizing and prioritizing small-molecule drug candidates. The required background in computational chemistry and the knowledge of how to handle the complex underlying protocols, however, might keep medicinal chemists from routinely using in silico technologies. Our objective is to encourage those researchers to exploit existing modeling technologies more frequently through easy-to-use graphical user interfaces. In this account, we present two innovative tools (which we are prepared to share with academic institutions) facilitating computational tasks commonly utilized in drug discovery and development: (1) the VirtualDesignLab estimates the binding affinity of small molecules by simulating and quantifying their binding to the three-dimensional structure of a target protein; and (2) the MD Client launches molecular dynamics simulations aimed at exploring the time-dependent stability of ligand-protein complexes and provides residue-based interaction energies. This allows medicinal chemists to identify sites of potential improvement in their candidate molecule. As a case study, we present the application of our tools towards the design of novel antagonists for the FimH adhesin. 23932290 Non-invasive monitoring of cell metabolism and lipid production in 3D engineered human adipose tissues using label-free multiphoton microscopy. Non-linear optical microscopy methods can characterize over time multiple functional properties of engineered tissues during development. Here, we demonstrate how the combined use of third-harmonic generation (THG) and two-photon excited fluorescence (2PEF) imaging can provide direct quantitative biomarkers of adipogenic stem cell differentiation and metabolic state, respectively. Specifically, we imaged over nine weeks silk scaffolds embedded with human mesenchymal stem cells and exposed to either propagation (PM) or adipogenic differentiation media (AM). THG was employed to visualize the formation of lipid droplets. 2PEF was used to assess the metabolic state of the cells through the redox ratio defined based on the endogenous FAD and NADH fluorescence. The redox ratio of cells in the AM scaffold was significantly lower than that in the PM scaffold during week 5 and 9, and correlated with significant increases in lipid-to-cell volume ratio, and number and size of lipid droplets in the AM scaffold. These findings indicate that the decrease in redox ratio during adipogenic differentiation is associated with fatty acid synthesis and lipid accumulation. Our methods therefore enabled us to identify and measure dynamic correlations between lipid droplet formation and cell metabolic state, while providing insight on the spatial heterogeneity of the observed signals. 23930771 A systematic review of vitamin D status in populations worldwide. Vitamin D deficiency is associated with osteoporosis and is thought to increase the risk of cancer and CVD. Despite these numerous potential health effects, data on vitamin D status at the population level and within key subgroups are limited. The aims of the present study were to examine patterns of 25-hydroxyvitamin D (25(OH)D) levels worldwide and to assess differences by age, sex and region. In a systematic literature review using the Medline and EMBASE databases, we identified 195 studies conducted in forty-four countries involving more than 168 000 participants. Mean population-level 25(OH)D values varied considerably across the studies (range 4·9-136·2 nmol/l), with 37·3 % of the studies reporting mean values below 50 nmol/l. The highest 25(OH)D values were observed in North America. Although age-related differences were observed in the Asia/Pacific and Middle East/Africa regions, they were not observed elsewhere and sex-related differences were not observed in any region. Substantial heterogeneity between the studies precluded drawing conclusions on overall vitamin D status at the population level. Exploratory analyses, however, suggested that newborns and institutionalised elderly from several regions worldwide appeared to be at a generally higher risk of exhibiting lower 25(OH)D values. Substantial details on worldwide patterns of vitamin D status at the population level and within key subgroups are needed to inform public health policy development to reduce risk for potential health consequences of an inadequate vitamin D status. 22752958 Modified-release prednisone decreases complaints and fatigue compared to standard prednisolone in patients with adrenal insufficiency. Patients with adrenal insufficiency (AI) receive first glucocorticoid replacement dose after waking, resulting in a 3-5 h delay compared to physiological secretion. Impaired quality of life (QoL) and fatigue might be due to this delayed dose scheme. Modified-release glucocorticoid preparations might have therapeutic advantages. Exploratory pilot study including 14 patients with AI was conducted in a single university center. Patients on morning dose prednisolone (5 mg) were included, switched to modified-release prednisone (5 mg) at 10 PM for 3 months, and then switched back on standard prednisolone. 3 standardized questionnaires (GBB-24, MFI, and AddiQoL) investigating complaints and fatigue were completed at baseline, after 3, and 6 months. Data regarding clinical and hormonal parameters were assessed. Modified-release prednisone showed significant improvement in one of 4 scales of GBB-24 and positive trends to better scores in 3 of 4 scales. The global score of discomfort improved significantly. The MFI showed also significant improvement in 3 of 5 scales and positive trend to better scores in 2 scales. Significant changes to better scores were seen in 4 out of 30 items of the AddiQoL. Modified-release prednisone showed decreased complaints and fatigue compared to standard prednisolone indicating importance of glucocorticoid increase in early morning hours before waking. 23914336 Transplantated mesenchymal stem cells derived from embryonic stem cells promote muscle regeneration and accelerate functional recovery of injured skeletal muscle. We previously established that mesenchymal stem cells originating from mouse embryonic stem (ES) cells (E-MSCs) showed markedly higher potential for differentiation into skeletal muscles in vitro than common mesenchymal stem cells (MSCs). Further, the E-MSCs exhibited a low risk for teratoma formation. Here we evaluate the potential of E-MSCs for differentiation into skeletal muscles in vivo and reveal the regeneration and functional recovery of injured muscle by transplantation. E-MSCs were transplanted into the tibialis anterior (TA) muscle 24 h following direct clamping. After transplantation, the myogenic differentiation of E-MSCs, TA muscle regeneration, and re-innervation were morphologically analyzed. In addition, footprints and gaits of each leg under spontaneous walking were measured by CatWalk XT, and motor functions of injured TA muscles were precisely analyzed. Results indicate that >60% of transplanted E-MSCs differentiated into skeletal muscles. The cross-sectional area of the injured TA muscles of E-MSC-transplanted animals increased earlier than that of control animals. E-MSCs also promotes re-innervation of the peripheral nerves of injured muscles. Concerning function of the TA muscles, we reveal that transplantation of E-MSCs promotes the recovery of muscles. This is the first report to demonstrate by analysis of spontaneous walking that transplanted cells can accelerate the functional recovery of injured muscles. Taken together, the results show that E-MSCs have a high potential for differentiation into skeletal muscles in vivo as well as in vitro. The transplantation of E-MSCs facilitated the functional recovery of injured muscles. Therefore, E-MSCs are an efficient cell source in transplantation. 23288676 Removal of Disperse Red dye by bamboo-based activated carbon: optimisation, kinetics and equilibrium. This research involved the use of response surface methodology (RSM) to investigate the adsorption of Disperse Red 167 dye onto the bamboo-based activated carbon activated with H3PO4 (PBAC) in a batch process. F400, a commercially available activated carbon, was used in parallel for comparison. Analysis of variance showed that input variables such as the contact time, temperature, adsorbent dosage and the interaction between the temperature and the contact time had a significant effect on the dye removal for both adsorbents. RSM results show that the optimal contact time, temperature, initial dye concentration and adsorbent dosage for both adsorbents were found to be 15.4 h, 50 °C, 50.0 mg L(-1) and 12.0 g L(-1), respectively. Under these optimal conditions, the removal efficiencies reached 90.23% and 92.13% for PBAC and F400, respectively, with a desirability of 0.937. The validation of the experimental results confirmed the prediction of the models derived from RSM. The adsorption followed a nonlinear pseudo-first-order model and agreed well with the Freundlich and Temkin isotherm as judged by the levels of the AICc and the Akaike weight. Furthermore, the thermodynamics analysis indicated that, for both adsorbents, the adsorption was a physical process that was spontaneous, entropy-increasing and endothermic. 23831468 Radiation-induced nitric oxide mitigates tumor hypoxia and radioresistance in a murine SCCVII tumor model. Tumor hypoxia, which occurs mainly as a result of inadequate tissue perfusion in solid tumors, is a well-known challenge for successful radiotherapy. Recent evidence suggests that ionizing radiation (IR) upregulates nitric oxide (NO) production and that IR-induced NO has the potential to increase intratumoral circulation. However, the kinetics of NO production and the responsible isoforms for NO synthase in tumors exposed to IR remain unclear. In this study, we aimed to elucidate the mechanism by which IR stimulates NO production in tumors and the effect of IR-induced NO on tumor radiosensitivity. Hoechst33342 perfusion assay and electron spin resonance oxymetry showed that IR increased tissue perfusion and pO2 in tumor tissue. Immunohistochemical analysis using two different hypoxic probes showed that IR decreased hypoxic regions in tumors; treatment with a nitric oxide synthase (NOS) inhibitor, L-NAME, abrogated the effects of IR. Moreover, IR increased endothelial NOS (eNOS) activity without affecting its mRNA or protein expression levels in SCCVII-transplanted tumors. Tumor growth delay assay showed that L-NAME decreased the anti-tumor effect of fractionated radiation (10Gy×2). These results suggested that IR increased eNOS activity and subsequent tissue perfusion in tumors. Increases in intratumoral circulation simultaneously decreased tumor hypoxia. As a result, IR-induced NO increased tumor radiosensitivity. Our study provides a new insight into the NO-dependent mechanism for efficient fractionated radiotherapy. 23747732 Oral delivery of an anti-diabetic peptide drug via conjugation and complexation with low molecular weight chitosan. Despite the therapeutic potential of exendin-4 as a glucagon-like peptide-1 (GLP-1) mimetic for the treatment of type 2 diabetes, its utility has so far been limited because of the low level of patient compliance due to the requirement for frequent injections. In this study, an orally available exendin-4 was produced by conjugating it to low molecular weight chitosan (LMWC). Conjugation between the LMWC and cysteinylated exendin-4 was carried out using a cleavable linker system in order to maximize the availability of the active peptide. The LMWC-exendin-4 conjugate formed a nanoparticle structure with a mean particle size of 101±41nm through complexation between the positively charged LMWC backbone and the negatively charged exendin-4 of individual conjugate molecules. The biological activity of the LMWC-exendin-4 conjugate was evaluated in an INS-1 cell line. The LMWC-exendin-4 conjugate stimulated insulin secretion in a dose dependent manner as similar as that of native exendin-4. From the pharmacokinetic study after oral administration of the conjugate, a Cmax value of 344pg/mL and a Tmax of 6h were observed, and the bioavailability, relative to the subcutaneous counterpart, was found to be 6.4%. Furthermore, the absorbed exendin-4 demonstrated a significantly enhanced hypoglycemic effect. These results suggest that the LMWC-exendin-4 conjugate could be used as a potential oral anti-diabetic agent for the treatment of type 2 diabetes. 23560913 Quantitating the Lattice Strain Dependence of Monolayer Pt Shell Activity toward Oxygen Reduction. Lattice strain of Pt-based catalysts reflecting d-band status is the decisive factor of their catalytic activity toward oxygen reduction reaction (ORR). For the newly arisen monolayer Pt system, however, no general strategy to isolate the lattice strain has been achieved due to the short-range ordering structure of monolayer Pt shells on different facets of core nanoparticles. Herein, based on the extended X-ray absorption fine structure of monolayer Pt atoms on various single crystal facets, we propose an effective methodology for evaluating the lattice strain of monolayer Pt shells on core nanoparticles. The quantitative lattice strain establishes a direct correlation to monolayer Pt shell ORR activity. 23432784 TNF-α Upregulates Fgl2 Expression in Rat Myocardial Ischemia/Reperfusion Injury. Proinflammatory cytokine TNF-α during MI/R injury has been studied extensively. However, how TNF-α induces microvascular dysfunction in MI/R is still unclear. This study investigates whether TNF-α regulates fibrinogen-like protein 2 (fgl2) expression, a procoagulant resulting in the formation of fibrin-rich microthrombus in MI/R injury. Microthrombosis, TNF-α and fgl2 expression were assessed in rats with MI/R injury. The effect of TNF-α on fgl2 expression and fgl2 prothrombinase activity was investigated in CMECs, then CMECs were pretreated with selective inhibitors of NF-κB and p38 MAPK pathways. TNF-α and fgl2 expression were both upregulated in MI/R group. When neutralization of TNF-α, fgl2 expression was decreased in vivo. Fgl2 expression was upregulated in CMECs exposed to TNF-α. Accordingly, the ability of thrombin generation was increased in CMECs. Besides, TNF-α-induced fgl2 expression in the cells was suppressed by NF-κB inhibitor PDTC and/or p38 MAPK inhibitor SB203580. TNF-α upregulates fgl2 expression via activation of NF-kB and p38 MAPK in CMECs. TNF-α-induced flg2 in CMECs mediates the formation of fibrin-rich microthrombus, which may be one of the mechanisms of microvascular dysfunction or obstruction due to MI/R injury. 23843135 Formation and Evolution of Chain-Propagating Species Upon Ethylene Polymerization with Neutral Salicylaldiminato Nickel(II) Catalysts. Formation of Ni-polymeryl propagating species upon the interaction of three salicylaldiminato nickel(II) complexes of the type [(N,O)Ni(CH3 )(Py)] (where (N,O)=salicylaldimine ligands, Py=pyridine) with ethylene (C2 H4 /Ni=10:30) has been studied by (1) H and (13) C NMR spectroscopy. Typically, the ethylene/catalyst mixtures in [D8 ]toluene were stored for short periods of time at +60 °C to generate the [(N,O)Ni(polymeryl)] species, then quickly cooled, and the NMR measurements were conducted at -20 °C. At that temperature, the [(N,O)Ni(polymeryl)] species are stable for days; diffusion (1) H NMR measurements provide an estimate of the average length of polymeryl chain (polymeryl=(C2 H4 )n H, n=6-18). At high ethylene consumptions, the [(N,O)Ni(polymeryl)] intermediates decline, releasing free polymer chains and yielding [(N,O)Ni(Et)(Py)] species, which also further decompose to form the ultimate catalyst degradation product, a paramagnetic [(N,O)2 Ni(Py)] complex. In [(N,O)2 Ni(Py)], the pyridine ligand is labile (with activation energy for its dissociation of (12.3±0.5) kcal mol(-1) , ΔH(≠) 298 =(11.7±0.5) kcal mol(-1) , ΔS(≠) 298 =(-7±1) cal K(-1)  mol(-1) ). Upon the addition of nonpolar solvent (pentane), the pyridine ligand is lost completely to yield the crystals of diamagnetic [(N,O)2 Ni] complex. NMR spectroscopic analysis of the polyethylenes formed suggests that the evolution of chain-propagating species ends up with formation of polyethylene with predominately internal and terminal vinylene groups rather than vinyl groups. 23768363 Effects of starch on nitrous acid-induced oxidation of kaempferol and inhibition of α-amylase-catalysed digestion of starch by kaempferol under conditions simulating the stomach and the intestine. Kaempferol glycosides can be hydrolyzed to their aglycone kaempferol during cooking under acidic conditions and in the oral cavity and the intestine by glycosidases. Kaempferol was oxidised by nitrite under acidic conditions (pH 2.0) to produce nitric oxide (NO), and the nitrite-induced oxidation of kaempferol was enhanced and inhibited by 10 and 100mg of starch ml(-1), respectively. The opposite effects of starch were discussed by considering the binding of kaempferol to starch and starch-dependent inhibition of the accessibility of nitrous acid to kaempferol. Kaempferol inhibited α-amylase-catalysed starch digestion by forming starch/kaempferol complexes, and the inhibitory effects increased in the order of amylopectin 18 years, 67.9% women) infected with HIV who were receiving chronic care at the Yaounde Jamot Hospital. Adherence was assessed via self-administered questionnaires using the Community Programs for Clinical Research on AIDS (CPCRA) index and the Center for Adherence Support Evaluation (CASE) index. The prevalence of non-adherence to ART was 22.5% based on the CPCRA index and 34.9% based on the CASE index, with a low agreement between the two indexes [kappa = 0.37 (95% confidence interval 0.31-0.44)]. Independent determinants of CPCRA-diagnosed non-adherence were as follows: being a remunerated employee [odds ratio (95% confidence interval): 1.61 (1.14-2.28)], Pentecostal Christianity [2.18 (1.25-3.80)], alcohol consumption [1.65 (1.16-2.34)] and non-adherence to cotrimoxazole prophylaxis [5.73 (3.92-8.38)]. The equivalents for CASE-diagnosed non-adherence were [1.59 (1.19-2.12)], [1.83 (1.36-2.47)], [1.70 (1.27-2.28)], respectively, in addition to association with changes to the ART regimen [1.61 (1.17-2.20)]. Non-adherence to ART remains high in this population. The careful evaluation of patients for the presence of determinants of non-adherence identified in this study may aid ART optimization. 23932616 Treatment of adolescent pilonidal disease with a new modification to the Limberg flap: Symmetrically rotated rhomboid excision and lateralization of the Limberg flap technique. Pilonidal disease is a common and frustrating problem among adolescents due to its high recurrence rate. The rhomboid excision and Limberg flap techniques promise successful results, but the lower part of the incision left on the intergluteal sulcus is prone to recurrences. Consequently, we have developed a new modification to this technique and have designed a descriptive prospective study to evaluate its efficiency. We conducted this prospective study between March 2011 and March 2012. All of the patients who were operated on for sacrococcygeal pilonidal disease were included in this study. The surgical procedure primarily consisted of symmetrically rotated (clockwise) rhomboid excision and lateralization of the Limberg flap in order to keep the inferior corner of the suture line apart from the intergluteal sulcus. A total of 15 adolescents (8 boys and 7 girls) were included in the study group. Of the patients, 47% were normal, 13% were overweight, and 40% were obese. Five patients were operated on under general anesthesia, and 10 were operated on under spinal anesthesia. The length of the flap margins ranged from 2.5 to 7cm (median=4cm). The median duration of hospitalization was 5days, and the median duration of suction drainage was 4days. The median postoperative follow-up period was 4months (ranging from 1 to 12months), and we did not encounter any wound infection or recurrent disease during this period. Only one patient had wound hematoma as a result of drain breakdown and was treated with wound care without any additional complications. Although the number of patients in this study was small and the follow-up period was short, we obtained satisfactory results without any recurrence by performing a symmetrically rotated rhomboid excision and lateralized Limberg flap procedure. 23843458 Carboxyl Group Footprinting Mass Spectrometry and Molecular Dynamics Identify Key Interactions in the HER2-HER3 Receptor Tyrosine Kinase Interface. The HER2 receptor tyrosine kinase is a driver oncogene in many human cancers, including breast and gastric cancer. Under physiologic levels of expression, HER2 heterodimerizes with other members of the EGFR/HER/ErbB family and the HER2-HER3 dimer forms one of the most potent oncogenic receptor pairs. Prior structural biology studies have individually crystallized the kinase domains of HER2 and HER3, but the HER2-HER3 kinase domain heterodimer structure has yet to be solved. Using a reconstituted membrane system to form HER2-HER3 kinase domain heterodimers and carboxyl group footprinting mass spectrometry (MS), we observed that HER2 and HER3 kinase domains preferentially form asymmetric heterodimers with HER3 and HER2 monomers occupying the donor and acceptor kinase positions, respectively. Conformational changes in the HER2 activation loop (A-loop), as measured by changes in carboxyl group labeling, required both dimerization and nucleotide binding, but did not require A-loop phosphorylation at Y877. Molecular dynamics (MD) simulations on HER2-HER3 kinase dimers identify specific inter- and intramolecular interactions and were in good agreement with MS measurements. Specifically, several intermolecular ionic interactions between HER2 K716-HER3 E909, HER2 E717-HER3 K907, and HER2 D871-HER3 R948 were identified by MD. We also evaluate the effect of the cancer associated mutations HER2 D769H/Y, HER3 E909G and HER3 R948K (also numbered HER3 E928G and R967K) on kinase activity in the context of this new structural model. This study provides valuable insights into the EGFR/HER/ErbB kinase structure and interactions, which can guide the design of future therapies. 23938123 Canaliculops: Clinicopathologic Features and Treatment With Marsupialization. To report the features of the rare and under-recognized condition of canaliculops (or canaliculocele) of the eyelid, which is a dilation of the canaliculus, and to evaluate treatment with marsupialization. Retrospective interventional case series. The records of 2 patients with canaliculops from the Massachusetts Eye and Ear Infirmary were reviewed. Data collected included clinical history, surgical technique, histopathologic analysis, and comparative immunohistochemical analysis of a range of cytokeratins in normal conjunctival epithelium, normal canalicular epithelium, and canaliculops epithelium. Two women, 53 and 66 years of age, experienced chronic, noninflammatory, painless medial eyelid and eyelid margin fluctuant swelling after earlier trauma or eyelid surgery. The external mass was accompanied by a whitish opalescent or bluish discoloration of a palpebral surface bulge. Biopsy revealed multilaminar (up to 12 cells thick), nonkeratinizing, tightly packed small squamous epithelial cells that surmounted a highly regimented basal layer with a picket fence arrangement. No goblet cells or subepithelial inflammation were present. Immunohistochemistry revealed only superficial CK7 immunostaining and positive patchy suprabasilar CK17 staining in the canaliculops epithelium, contrasting with their full-thickness positivity and negativity, respectively, in normal conjunctival epithelium. Marsupialization achieved resolution of the condition in each patient. An improved awareness of the normal canalicular epithelial structure and its immunohistochemical features can definitively separate canaliculops from conjunctival cysts. Previous treatment of canaliculops has involved complete excisions. Canaliculops may, however, be effectively treated with less invasive marsupialization while obtaining an adequate biopsy specimen for histopathologic diagnosis. 23266354 Post-translational translocation into the endoplasmic reticulum. Proteins destined for the endomembrane system of eukaryotic cells are typically translocated into or across the membrane of the endoplasmic reticulum and this process is normally closely coupled to protein synthesis. However, it is becoming increasingly apparent that a significant proportion of proteins are targeted to and inserted into the ER membrane post-translationally, that is after their synthesis is complete. These proteins must be efficiently captured and delivered to the target membrane, and indeed a failure to do so may even disrupt proteostasis resulting in cellular dysfunction and disease. In this review, we discuss the mechanisms by which various protein precursors can be targeted to the ER and either inserted into or translocated across the membrane post-translationally. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum. 23597493 IDE (rs6583817) polymorphism and type 2 diabetes differentially modify executive function in older adults. We tested independent and interactive contributions of a recently noted and promising insulin degrading enzyme polymorphism (IDE; rs6583817) and type 2 diabetes (T2D) to executive function performance, concurrently and longitudinally. Regarding normal neurocognitive decline and Alzheimer's disease, T2D is a known risk factor and this IDE variant might contribute risk or risk reduction via the minor (A) or major (G) allele. We compared normal aging and T2D groups (baseline n = 574; ages 53-95 years) over 2 longitudinal waves (mean interval = 4.4 years). We used confirmatory factor analysis, latent growth curve modeling, and path analysis. A confirmed single-factor model of 4 executive function tasks established the cognitive phenotype. This IDE variant predicted concurrent group differences and differential change in cognitive performance. Furthermore, the IDE major allele reduced risk of cognitive decline. T2D predicted performance only concurrently. Both IDE and T2D are associated with executive function levels in older adults, but only IDE moderated 2-wave change. Previously linked to Alzheimer's disease, this IDE variant should be further explored for its potential influence on cognitive phenotypes of normal aging. 23584686 The distribution of TRPV1 and TRPV2 in the rat pharynx. Immunohistochemistry for two nociceptive transducers, the transient receptor potential cation channel subfamily V members 1 (TRPV1) and 2 (TRPV2), was performed on the pharynx and its adjacent regions. TRPV1-immunoreactivity (IR) was detected in nerve fibers beneath and within the epithelium and/or taste bud-like structure. In the pharynx, these nerve fibers were abundant in the naso-oral part and at the border region of naso-oral and laryngeal parts. They were also numerous on the laryngeal side of the epiglottis and in the soft palate. TRPV2-IR was expressed by dendritic cells in the pharynx and epiglottis, as well as in the root of the tongue and soft palate. These cells were located in the epithelium and lamina propria. TRPV2-immunoreactive (IR) dendritic cells were numerous in the naso-oral part of the pharynx, epiglottis, and tongue. Abundance of TRPV2-IR dendritic processes usually obscured the presence of TRPV2-IR nerve fibers in these portions. However, some TRPV2-IR nerve fibers could be observed in the epithelium of the soft palate. Retrograde tracing method also revealed that sensory neurons which innervate the pharynx or soft palate were abundant in the jugular-petrosal ganglion complex and relatively rare in the nodose ganglion. In the jugular-petrosal ganglion complex, TRPV1- and TRPV2-IR were expressed by one-third of pharyngeal and soft palate neurons. TRPV2-IR was also detected in 11.5 % pharyngeal and 30.9 % soft palate neurons in the complex. Coexpression of TRPV1 and CGRP was frequent among pharyngeal and soft palate neurons. The present study suggests that TRPV1- and TRPV2-IR jugular-petrosal neurons may be associated with the regulation of the swallowing reflex. 23149223 Facial emotion recognition in borderline personality disorder. Emotion dysregulation represents a core symptom of borderline personality disorder (BPD). Deficits in emotion perception are thought to underlie this clinical feature, although studies examining emotion recognition abilities in BPD have yielded inconsistent findings. Method The results of 10 studies contrasting facial emotion recognition in patients with BPD (n = 266) and non-psychiatric controls (n = 255) were quantitatively synthesized using meta-analytic techniques. Patients with BPD were less accurate than controls in recognizing facial displays of anger and disgust, although their most pronounced deficit was in correctly identifying neutral (no emotion) facial expressions. These results could not be accounted for by speed/accuracy in the test-taking approach of BPD patients. Patients with BPD have difficulties recognizing specific negative emotions in faces and may misattribute emotions to faces depicting neutral expressions. The contribution of state-related emotion perception biases to these findings requires further clarification. 23220400 Characterisation of an mGlu8 receptor-selective agonist and antagonist in the lateral and medial perforant path inputs to the dentate gyrus. Since its characterisation in 2001, the mGlu8-selective agonist DCPG has been widely used to explore the potential functional role of this group III mGlu receptor within the central nervous system. This research has implicated mGlu8 receptors in a number of disease states and conditions such as epilepsy and anxiety, suggesting that mGlu8-selective ligands may hold important therapeutic potential. However, there is evidence that DCPG exerts off-target effects at higher concentrations, limiting its use as an mGlu8-selective agonist. Here, we have used field recordings in rat hippocampal slices to investigate the effects of DCPG in the lateral perforant path (LPP), a pathway known to express high levels of mGlu8. We show that DCPG does inhibit excitatory transmission in this pathway, but produces a biphasic concentration-response curve suggesting activation of two distinct receptor types. The putative mGlu8-selective antagonist MDCPG antagonises the high, but not the low, potency component of this concentration-response curve. In addition, higher concentrations of DCPG also depress excitatory transmission in the medial perforant path (MPP), a pathway expressing very low levels of mGlu8 receptors. Experiments in slices from mice lacking mGlu8 receptors indicate that concentrations of DCPG >1 μM produce large non-selective effects in both the LPP and MPP. Further experiments in slices from mGlu2, 4 and 7 knock-out mice, as well as in an mGlu2-deficient substrain of Wistar rat, reveal that these non-selective effects are mediated primarily by mGlu2 receptors. Taken together, our results confirm the mGlu8-selectivity of DCPG at submicromolar concentrations, but suggest that care must be taken when employing higher concentrations of the agonist, which may additionally activate mGlu2 receptors, especially at synapses where their expression is high. MDCPG may be a useful tool in determining whether observable DCPG effects are attributable to mGlu8, versus mGlu2, receptor activation. 23945389 Frequency and type of epidermal growth factor receptor mutations in moroccan patients with lung adenocarcinoma. Epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer predict response to tyrosine kinase inhibitors. The frequency of EGFR mutations is ethnicity-dependent, with a higher proportion in Asian populations than in whites. The prevalence of these mutations among North African patients is unknown. The objective of this study was to report the frequency and spectrum of EGFR mutations in a group of Moroccan patients with lung adenocarcinoma (AC). Tumor specimens from 137 Moroccan patients with lung AC were selected to determine frequency and spectrum of EGFR mutations. Mutation detection techniques were polymerase chain reaction amplification and sequencing of exons 18, 19, 20, and 21. The overall frequency of the EGFR mutation was 21%. Mutations were mainly detected in the exon 19 (69%), followed by exon 21 (21%) and exon 20 (7%), whereas mutations in the exon 18 were rare (3%). EGFR mutation rate was significantly higher in women and in never smokers. Some one fifth of lung AC tumors in Moroccan patients harbor EGFR mutations. This mutation frequency is higher than that found in whites but lower than in Asian population. Further studies, in larger numbers of patients, are needed to confirm these findings. 23932724 The lumbar intervertebral disc: From embryonic development to degeneration. Lumbar intervertebral discs (IVDs) are prone to degeneration upon skeletal maturity. In fact, this process could explain approximately 40% of the cases of low back pain in humans. Despite the efficiency of pain-relieving treatments, the scientific community seeks to develop innovative therapeutic approaches that might limit the use of invasive surgical procedures (e.g., spine fusion and arthroplasty). As a prerequisite to the development of these strategies, we must improve our fundamental knowledge regarding IVD pathophysiology. Recently, several studies have demonstrated that there is a singular phenotype associated with Nucleus pulposus (NP) cells, which is distinct from that of articular chondrocytes. In parallel, recent studies concerning the origin and development of NP cells, as well as their role in intervertebral tissue homeostasis, have yielded new insights into the complex mechanisms involved in disc degeneration. This review summarizes our current understanding of IVD physiology and the complex cell-mediated processes that contribute to IVD degeneration. Collectively, these recent advances could inspire the scientific community to explore new biotherapeutic strategies. 23361137 The impact of diet and lifestyle management strategies for obstructive sleep apnoea in adults: a systematic review and meta-analysis of randomised controlled trials. To systematically evaluate the impact of diet, exercise and lifestyle modification programmes on indices of obesity, Obstructive Sleep Apnoea (OSA) parameters and quality of life (QoL) in adults with OSA. Electronic databases were searched to identify randomised controlled trials published in English with an intervention based on dietary weight loss, exercise and/or lifestyle programme in adults with OSA. Meta-analyses were conducted using random-effects models. Twelve studies met the inclusion criteria with nine comparing similar interventions. Diet and diet plus continuous positive airway pressure (CPAP) therapy were compared in three studies (n = 261), and intensive lifestyle programmes and routine care were compared in six studies (n = 483). Diet with CPAP therapy reduced weight by -2.64 kg (95 % Confidence Interval (CI) -3.98, -1.30, I (2) = 0 %) compared with diet alone. No differences were observed for QoL or Epworth Sleepiness Scale. A significant reduction in weight was seen in participants receiving an intensive lifestyle intervention of -5.65 kg (95 % CI -10.91, -0.40, I (2) = 95.7 %) compared with controls. Reductions were also observed for waist circumference (-5.80 cm, 95 % CI -8.64, -2.96, I(2) = 77.7 %), body mass index (BMI) (-2.33 kg/m(2), 95 % CI -3.41, -1.24, I(2) = 78.8 %) and the Apnoea Hypopnoea Index (AHI) (-4.55 events/h, 95 % CI -7.12, -1.98, I (2) = 54.4 %) but with high levels of heterogeneity. Intensive lifestyle management can significantly reduce obesity indices and improve AHI. Future research is required to investigate this effect due to a limited number of studies identified. 23727629 10 Years after Baby-Friendly Designation: Breastfeeding Rates Continue to Increase in a US Neonatal Intensive Care Unit. Background: Mothers of preterm and sick infants admitted to the neonatal intensive care unit (NICU) often encounter more difficulties with breastfeeding than mothers of healthy term newborns. The extent to which Baby-Friendly designation is associated with breastfeeding rates for NICU infants over time is unknown. Objective: This study aimed to determine the rate of breastfeeding initiation and continuation in a US, inner-city, level 3 NICU 10 years after Baby-Friendly designation. Methods: We compared the rate of breastfeeding initiation and continuation among breastfeeding-eligible mothers with infants admitted to the Boston Medical Center NICU in 1999 and 2009, using chi-square tests. Results: Breastfeeding initiation increased from 74% in 1999 to 85% in 2009 (P = .04). Any breast milk at 2 weeks of age increased from 66% to 80% (P = .05), and exclusive breastfeeding at 2 weeks remained stable between 1999 and 2009. Breastfeeding initiation increased from 68% to 86% among black mothers from 1999 to 2009 (P = .01). Conclusion: Improvement in breastfeeding initiation and any breastfeeding at 2 weeks of age continued 10 years after Baby-Friendly designation among mothers with NICU infants in a US, inner-city, level 3 NICU. 23725985 A study on the discrimination of human skeletons using X-ray fluorescence and chemometric tools in chemical anthropology. Forensic anthropological investigations are often restricted in their outcomes by the resources allocated to them, especially in terms of positively identifying the victims exhumed from commingled mass graves. Commingled mass graves can be defined as those graves that contain a number of disarticulated human remains from different individuals that have been mixed by either natural processes or human interventions. The research developed aimed to apply the technique of non-destructive XRF analysis to test whether there is substantial differentiation within the trace elemental composition and their ratios of individuals to separate them using chemometric analysis. The results of the different atomic spectroscopic analyses combined with the use of multivariate analysis on a set of 5 skeletons produced a series of plots using Principal Component Analysis that helped to separate them with a high percentage of accuracy when two, three or four skeletons needed to be separated. Also, two new elemental ratios, Zn/Fe related to metabolic activities and K/Fe related to blood flow into the bone, have been defined for their use in forensic anthropology for the first time to aid in the separation. 23889732 Primary prevention of dental erosion by calcium and fluoride: a systematic review. Overviews of the current literature only provide summaries of existing relevant preventive strategies for dental erosion. To perform a systematic review according to the quantitative meta-analysis method of the scientific literature on prevention of dental erosion. The focused question will address primary prevention of dental erosion by calcium and fluoride. Randomized clinical trials (RCTs) regarding dental erosion prevention. The search included five databases: Embase, Cochrane database of systematic reviews, PubMed (MEDLINE), FDA publication and Berman medical library of the Hebrew University. The search included data in the English language, with effect on preventing dental erosion always presented as mean enamel loss and measured by profilometer. Statistical meta-analysis was performed by StatsDirect program and PEPI statistical software. Fixed- and random-effect models were used to analyse the data. Heterogeneity tests were employed to validate the fixed-effect model assumption. A total of 475 articles on dental erosion prevention were located. A four-stage selection process was employed, and 10 RCT articles were found to be suitable for meta-analysis. The number of studies on prevention of dental erosion maintaining standards of evidence-based dentistry remains insufficient to reach any definite conclusions. The focused questions of this review cannot be addressed according to the existing literature. 23848168 Redox-Dependent Structural Transformations of the [4Fe-3S] Proximal Cluster in O2-Tolerant Membrane-Bound [NiFe]-Hydrogenase: A DFT Study. Broken-symmetry density functional theory (BS-DFT) has been used to address the redox-dependent structural changes of the proximal [4Fe-3S] cluster, implicated in the O2-tolerance of membrane-bound [NiFe]-hydrogenase (MBH). The recently determined structures of the [4Fe-3S] cluster together with its protein ligands were studied at the reduced [4Fe-3S](3+), oxidized [4Fe-3S](4+), and superoxidized [4Fe-3S](5+) levels in context of their relative energies and protonation states. The observed proximal cluster conformational switch, concomitant with the proton transfer from the cysteine Cys20 backbone amide to the nearby glutamate Glu76 carboxylate, is found to be a single-step process requiring ∼12-17 kcal/mol activation energy at the superoxidized [4Fe-3S](5+) level. At the more reduced [4Fe-3S](4+/3+) oxidation levels, this rearrangement has at least 5 kcal/mol higher activation barriers and prohibitively unfavorable product energies. The reverse transformation of the proximal cluster is a fast unidirectional process with ∼8 kcal/mol activation energy, triggered by one-electron reduction of the superoxidized species. A previously discussed ambiguity of the Glu76 carboxylate and 'special' Fe4 iron positions in the superoxidized cluster is now rationalized as a superposition of two local minima, where Glu76-Fe4 coordination is either present or absent. The calculated 12.3-17.9 MHz (14)N hyperfine coupling (HFC) for the Fe4-bound Cys20 backbone nitrogen is in good agreement with the large 13.0/14.6 MHz (14)N couplings from the latest HYSCORE/ENDOR studies. 23912666 Two-color fluorescent (near-infrared and visible) triphasic perfluorocarbon nanoemuslions. Design and development of a new formulation as a unique assembly of distinct fluorescent reporters with nonoverlapping fluorescence spectra and a F19 magnetic resonance imaging agent into colloidally and optically stable triphasic nanoemulsion are reported. Specifically, a cyanine dye-perfluorocarbon (PFC) conjugate was introduced into the PFC phase of the nanoemulsion and a near-infrared dye was introduced into the hydrocarbon (HC) layer. To the best of our knowledge, this is the first report of a triphasic nanoemulsion system where each oil phase, HC, and PFC are fluorescently labeled and formulated into an optically and colloidally stable nanosystem. Having, each oil phase separately labeled by a fluorescent dye allows for improved correlation between in vivo imaging and histological data. Further, dual fluorescent labeling can improve intracellular tracking of the nanodroplets and help assess the fate of the nanoemulsion in biologically relevant media. The nanoemulsions were produced by high shear processing (microfluidization) and stabilized with biocompatible nonionic surfactants resulting in mono-modal size distribution with average droplet size less than 200 nm. Nanoemulsions demonstrate excellent colloidal stability and only moderate changes in the fluorescence signal for both dyes. Confocal fluorescence microscopy of macrophages exposed to nanoemulsions shows the presence of both fluorescence agents in the cytoplasm. 23965309 "Chemo Brain"--Is Cancer Survivorship Related to Later-Life Cognition? Findings From the Health and Retirement Study. Studies have shown a correlation between cancer and cognition referred to as "chemo brain." This study investigated the relationship between cancer and later-life cognition using nationally representative data. Analysis of the 2006 Health and Retirement Study investigated the (a) effects of cancer survivorship on the total cognition score using linear regression in adults age 65+ (n = 9,814) and (b) the effects of cancer treatment on the total recall index using linear regression in adults age 50+ (n = 657). Total cognition score is not associated with cancer survivorship. The association between long-term cancer survivorship and cognition score was significant (p < .05; b = .276). Total recall index is not associated with chemotherapy. These results support other research suggesting that chemo brain may be biased by expectation as well as favored by research that relies upon self-reported cognitive measures versus cognitive testing. The study was limited by the cross-sectional design. 23562053 The impact of chronic blood-brain barrier breach on intracortical electrode function. Brain-computer interfaces (BCIs) have allowed control of prosthetic limbs in paralyzed patients. Unfortunately, the electrodes of the BCI that interface with the brain only function for a short period of time before the signal quality on these electrodes becomes substantially diminished. To truly realize the potential of BCIs, it is imperative to have electrodes that function chronically. In order to elucidate the physiological determinants of a chronically functional neural interface, we studied the role of the blood-brain barrier (BBB) in electrode function, because it is a key mediator of neuronal hemostasis. We monitored the status of the BBB and the consequences of BBB breach on electrode function using non-invasive imaging, electrophysiology, genomic, and histological analyses. Rats implanted with commercially available intracortical electrodes demonstrated an inverse correlation between electrode performance and BBB breach over a period of 16 weeks. Genomic analysis showed that chronically functional electrodes elicit an enhanced wound healing response. Conversely, in poorly functioning electrodes, chronic BBB breach led to local accumulation of neurotoxic factors and an influx of pro-inflammatory myeloid cells, which negatively affect neuronal health. These findings were further verified in a subset of electrodes with graded electrophysiological performance. In this study, we determine the mechanistic link between intracortical electrode function and failure. Our results indicate that BBB status is a critical physiological determinant of intracortical electrode function and can inform future electrode design and biochemical intervention strategies to enhance the functional longevity of BCIs. 23948807 Risk of fracture in patients with muscular dystrophies. The aim of the study was to determine fracture risk in incident muscular dystrophy (MD) patients. Patients with MD are at a 1.4-fold increased risk of fracture as compared with population-based control patients. Risk further increased among elderly and female patients and among patients exposed to oral glucocorticoids. Muscular dystrophies (MDs) are inherited diseases causing muscle weakness and thereby increase the risk of falling and detrimental effects on bone. Both are recognised risk factors for fracture. Therefore, the aim of this study was to determine the hazard ratio of fracture in patients with MD. We conducted a retrospective cohort study using the UK General Practice Research Database (1987-2012). Each patient with MD was matched by year of birth, sex and practice to up to six patients without a history of MD. Outcome measure was all fractures. As compared with control patients, risk of any fracture was statistically significantly increased in MD patients (adjusted hazard ratio [AHR], 1.40; 95 % confidence interval [CI], 1.14-1.71). An increased risk of fracture was observed among MD patients with female gender (AHR, 1.78; 95 % CI, 1.33-2.40) and an increasing age as compared with control patients. Stratification to Duchenne MD showed no association with fracture, whereas risk of fracture was increased twofold among patients with myotonic dystrophy (AHR, 2.34; 95 % CI, 1.56-3.51). MD patients had an almost tripled risk of fracture when they used oral glucocorticoids in the previous 6 months as compared to non-users with MD. Patients with MD are at a 1.4-fold increased risk of fracture as compared with population-based control patients. Especially in older age groups and female gender, the fracture risk of MD versus non-MD patients is increased, whereas exposure to glucocorticoids further increased fracture risk among MD patients. 23867015 How do anticipated worry and regret predict seasonal influenza vaccination uptake among Chinese adults? To test two hypothesized models of how anticipated affect, cognitive risk estimate and vaccination intention might influence vaccination uptake against seasonal influenza. The study collected baseline and follow-up data during the main influenza seasons (January-March) of 2009 and 2010, respectively, among 507 university students and staff of a university in Hong Kong. Following logistic regression to determine eligible variables, two mediation models of cognitive risk estimate, anticipated affect, vaccination intention and vaccination uptake against seasonal influenza were tested using structural equation modeling. Mediation analyses found that anticipated worry if not vaccinated influenced seasonal influenza vaccination uptake through its effects on either perceived probability of influenza infection (β=0.45) or intention (β=0.45) while anticipated regret if not vaccinated influenced vaccination uptake through its effect on intention (β=0.45) only; anticipated regret if vaccinated impeded vaccination uptake indirectly through its effect on vaccination intention (β=-0.26) or directly (β=-0.20); perceived probability of influenza infection influenced vaccination uptake through its effect on intention (β=0.20) or directly (β=0.22); and finally, intention influenced vaccination uptake directly (β=0.58). The results suggest that anticipated affect seems to drive risk estimates related to seasonal influenza vaccination rather than vice versa and intention remains an important mediator of the associations of anticipated affect and cognitive risk estimate with vaccination uptake against seasonal influenza. 23953079 Identifying, documenting, and examining heterogeneity in systematic reviews of complex interventions. This article describes approaches for planning, dealing, and analyzing heterogeneity in a systematic review of complex interventions. Approaches aim to generate a priori hypotheses of the mechanism of action of a complex intervention to identify the key variables that might contribute to variation among studies and guide statistical analysis. In addition to characteristics related to the population, intervention, and outcomes, we describe study-related variables, such as the way the interventions have been implemented and the context and conduct of studies. These approaches will guide reviewers planning a meta-analysis and provide a rationale for not meta-analyzing data if there is too much variability. Potential difficulties in applying meta-analytical techniques to examine statistical association among study results and sources of potential heterogeneity are described; these include the selection of a fixed or random-effects model, the risk of multiple testing and confounding when studies include different aspects of a complex intervention or different subsamples of the intended participant pool. 23403471 Stimuli-responsive copolymer solution and surface assemblies for biomedical applications. Stimuli-responsive polymeric materials is one of the fastest growing fields of the 21st century, with the annual number of papers published more than quadrupling in the last ten years. The responsiveness of polymer solution assemblies and surfaces to biological stimuli (e.g. pH, reduction-oxidation, enzymes, glucose) and externally applied triggers (e.g. temperature, light, solvent quality) shows particular promise for various biomedical applications including drug delivery, tissue engineering, medical diagnostics, and bioseparations. Furthermore, the integration of copolymer architectures into stimuli-responsive materials design enables exquisite control over the locations of responsive sites within self-assembled nanostructures. The combination of new synthesis techniques and well-defined copolymer self-assembly has facilitated substantial developments in stimuli-responsive materials in recent years. In this tutorial review, we discuss several methods that have been employed to synthesize self-assembling and stimuli-responsive copolymers for biomedical applications, and we identify common themes in the response mechanisms among the targeted stimuli. Additionally, we highlight parallels between the chemistries used for generating solution assemblies and those employed for creating copolymer surfaces. 23855300 Alcoholic liver disease: Pathogenesis, management, and novel targets for therapy. Alcohol use is a leading cause of preventable morbidity and mortality worldwide, with much of its negative impact as the result of alcoholic liver disease (ALD). ALD is a broad term that encompasses a spectrum of phenotypes ranging from simple steatosis to steatohepatitis, progressive fibrosis, cirrhosis, and hepatocellular carcinoma. The mechanisms underlying the development of these different disease stages are incompletely understood. Standard treatment of ALD, which includes abstinence, nutritional support, and corticosteroids, has not changed in the last 40 years despite continued poor outcomes. Novel therapies are therefore urgently needed. The development of such therapies has been hindered by inadequate resources for research and unsuitable animal models. However, recent developments in translational research have allowed for identification of new potential targets for therapy. These targets include: (i) CXC chemokines, (ii) IL-22/STAT3, (iii) TNF receptor superfamily, (iv) osteopontin, (v) gut microbiota and lipopolysaccharide (LPS), (vi) endocannabinoids, and (vii) inflammasomes. We review the natural history, risk factors, pathogenesis, and current treatments for ALD. We further discuss the findings of recent translational studies and potential therapeutic targets. 23935036 Predicting response to bevacizumab in ovarian cancer: a panel of potential biomarkers informing treatment selection. The aim of this study was to identify and validate novel predictive and/or prognostic serum proteomic biomarkers in patients with epithelial ovarian cancer (EOC) treated as part of the phase III international ICON7 clinical trial. Experimental design: ICON7 demonstrated a modest but statistically significant benefit in progression-free survival with the addition of bevacizumab to standard chemotherapy. Serum samples from 10 patients who received bevacizumab (5 responders, 5 non-responders) were analysed by mass spectrometry to identify candidate biomarkers. Initial validation by immunoassay across both arms of the trial was undertaken in an independent cohort of 92 patients, followed by a second independent cohort of 115 patients. Three candidate biomarkers were identified, mesothelin, fms-like tyrosine kinase-4 (FLT4) and 1-acid glycoprotein (AGP). Each showed evidence of independent prognostic potential when adjusting for high risk status in initial (p<0.02) and combined (p<0.01) validation cohorts. In cohort I individual biomarkers were not predictive of bevacizumab benefit; however, when combined with CA-125, a signature was developed that was predictive of bevacizumab response and discriminated benefit attributable to bevacizumab better than clinical characteristics. The signature showed weaker evidence of predictive ability in validation cohort II, but was still strongly predictive considering all samples (p=0.001), with an improvement in median PFS of 5.5 months in signature-positive patients in the experimental arm compared to standard arm. This study demonstrates a discriminatory four protein signature as potentially identifying those patients with EOC more likely to benefit from bevacizumab. These results require validation in further patient cohorts. 23814054 Substrate Specificity of R3 Receptor-like Protein-tyrosine Phosphatase Subfamily toward Receptor Protein-tyrosine Kinases. Receptor-like protein-tyrosine phosphatases (RPTPs) are involved in various aspects of cellular functions, such as proliferation, differentiation, survival, migration, and metabolism. A small number of RPTPs have been reported to regulate activities of some cellular proteins including receptor protein-tyrosine kinases (RPTKs). However, our understanding about the roles of individual RPTPs in the regulation of RPTKs is still limited. The R3 RPTP subfamily reportedly plays pivotal roles in the development of several tissues including the vascular and nervous systems. Here, we examined enzyme-substrate relationships between the four R3 RPTP subfamily members and 21 RPTK members selected from 14 RPTK subfamilies by using a mammalian two-hybrid system with substrate-trapping RPTP mutants. Among the 84 RPTP-RPTK combinations conceivable, we detected 30 positive interactions: 25 of the enzyme-substrate relationships were novel. We randomly chose several RPTKs assumed to be substrates for R3 RPTPs, and validated the results of this screen by in vitro dephosphorylation assays, and by cell-based assays involving overexpression and knock-down experiments. Because their functional relationships were verified without exception, it is probable that the RPTKs identified as potential substrates are actually physiological substrates for the R3 RPTPs. Interestingly, some RPTKs were recognized as substrates by all R3 members, but others were recognized by only one or a few members. The enzyme-substrate relationships identified in the present study will shed light on physiological roles of the R3 RPTP subfamily. 23738912 Spatial risk assessment of alien invasive plants in china. The large-scale distribution patterns of alien invasive plants (AIP) can provide key information and a theoretical basis for management strategies, including the prevention of invasions, the control and eradication of established AIPs, and the identification of areas at high risk of invasion. This study aims to quantify distribution patterns of AIP in China, to develop approaches that measure the social, economic, and ecological impacts, and to identify areas that are at higher risk of plant invasion. Based on published literature, there were 384 AIPs in China, representing 233 genera from 66 families. Climatic factors were among the primary factors determining AIPs' overall distribution patterns. The majority of AIPs were tropically distributed in China, meaning that they were mainly restricted to southern China. Temperate-distributed AIPs, those distributed only or predominantly in northern China, were fewer but had higher average rates of spread than tropically distributed AIPs. Average ecological and economic impact per AIP was negatively correlated with AIP richness, meaning that areas with relatively few AIPs nevertheless have some of the most detrimental ones. Our comparative evaluation showed that the risk of invasion differed among regions of China, with high-risk areas in southern China (Yunnan, Guangxi, and Guangdong) and central coastal areas of eastern China (Shandong, Hebei, and Jiangsu). In the context of climate change, areas around latitudes of 33° N, including Hebei, Shandong, Henan, and Jiangsu, should be given more attention for the control and prevention of plant invasions. Predictions of high-risk areas for future invasions differed depending on the scale of aggregation and the evaluation index, indicating that invasive risk assessments should be based on multiple factors. 23416005 Aza-BODIPY: improved synthesis and interaction with soluble Aβ1-42 oligomers. Dye-binding assays that are used to evaluate anti-aggregation ability of small molecule inhibitors towards amyloids are known to be prone to false-positive effects due to spectral overlaps between the dye and the inhibitor. Aza-BODIPY dye, which has both excitation and emission maxima above 600nm, exhibits a significant increase in its fluorescence intensity in the presence of soluble oligomers of Aβ1-42. These results indicate that aza-BODIPY could serve as a near-IR probe for detecting conformational changes of Aβ1-42 soluble oligomers in vitro, and it should eliminate false-positive effects that are associated with currently utilized thioflavin T-based dyes. In addition, a facile synthesis of aza-BODIPY has been developed, which might further expand the applications of this dye. 23605469 Single dose bioequivalence study of two brands of olanzapine 10 mg tablets in Iranian healthy volunteers. This single dose, randomized, open label, 2-period and crossover study in healthy Iranian adult volunteers was conducted to compare the bioavailability of 2 branded formulations of olanzapine 10 mg tablets. 24 volunteers received one tablet of each olanzapine 10 mg formulation. Drugs were administered after a 12 h overnight fast in each of 2 treatment days which separated by a 2-week washout period. Serial blood samples were collected over a period of 72 h. Plasma was analyzed using a validated high performance liquid chromatography method with ultraviolet detection in the range of 2-24 ng/mL with a lower limit of quantitation of 1.25 ng/mL. A non-compartmental method was employed to determine the pharmacokinetic properties (Cmax, Tmax, AUC0-t, AUC0-∞ and T1/2) to test to bioequivalence. Cmax, AUC0-t and AUC0-∞ were used to test the bioequivalence after log-transformation of plasma data. The mean (SD) Cmax, AUC0-t and AUC0-∞ for the test formulation were 15.82 (3.15) ng/mL, 447.19 (100.64) ng.h/L and 570.75 (130.55) ng.h/L respectively. Corresponding values for the test formulation were 15.72 (4.25) ng/mL, 440.37 (98.75) ng.h/mL and 558.66 (129.57) ng.h/mL. For test formulation vs. the reference formulation, the 90% CIs of the least squares mean test/reference ratios of Cmax, AUC0-t and AUC0-∞ were 97.6-110.0%, 96.4-109.4% and 97.3-109.2%. In these volunteers, based on the FDA regulatory definition, results from the pharmacokinetic analysis suggested that the test and reference formulations of olanzapine 10 mg tablets were bioequivalent. 23782306 Maternal psychological factors and controlled child feeding practices in relation to child body mass index. Abstract Background: The rise of childhood obesity in Western society has focused attention on parental feeding practices. Despite evidence that controlled feeding influences child weight, there is a paucity of research examining predictors of controlled feeding. The aim of this study was to determine whether maternal antenatal and/or concurrent anxiety and depressive symptoms, including stress, predicted controlled feeding and whether maternal controlled feeding practices, in turn, predict child BMI. Methods: In total, 203 mothers participated in a longitudinal follow-up survey. Mothers' self-reported symptoms of anxiety and depression were measured both in pregnancy and at 2-7 years postpartum. Maternal-reported child BMI and maternal use of restriction, pressure to eat, and monitoring were measured at 2-7 years postpartum. Results: Feeding practices were not uniformly predictive of child BMI. Maternal use of restriction and monitoring were partially positively predicted by concurrent maternal stress and negatively partially predicted by concurrent depression. Thus, mothers enduring high stress appeared to employ more controlled feeding patterns, whereas mothers experiencing depression seemingly employed lower levels of controlled feeding. Conclusions: Findings that maternal anxiety and depression affect levels of controlled feeding are of particular interest and broadly supportive of the few existing studies. Given the mixed results linking controlled feeding to child BMI reported in previous research, further work is required to determine the relationships between maternal mood, child feeding practices, and BMI. 23768725 Vitamin E and vitamin E acetate solubilization in mixed micelles: physicochemical basis of bioaccessibility. Vitamin E is an essential micronutrient for humans and animals due to its antioxidant and non-antioxidant biological activities. In this study, an emulsion titration assay was used to quantify the kinetics and extent of vitamin E and vitamin E acetate solubilization in model mixed micelles. The composition of the mixed micelles was designed to mimic those produced during digestion of lipids in the human small intestine: bile salts, phospholipids, and free fatty acids. Initially, the optimum conditions required to form model mixed micelles were established. The solubilization capacities of vitamin E and vitamin E acetate in the mixed micelles were then compared. The solubilization capacity of the mixed micelles for vitamin E was higher than that for vitamin E acetate, which was attributed to differences in the ability of the vitamin molecules to be incorporated into the micelle structure. The solubilization capacities also depended on the composition of the mixed micelles: micelle solubilization of vitamin E was increased by the presence of phospholipid (DOPC), but did not depend strongly on the presence of free fatty acid (octanoic acid or linoleic acid). Overall, this research has important implications for understanding the digestion, absorption, and transportation of vitamin E in the human gastrointestinal tract and for designing suitable delivery systems to increase its bioaccessibility. 23872013 Synthesis, growth and characterization of a nonlinear optical crystal: Bis l-proline hydrogen nitrate. The single crystals of bis l-proline hydrogen nitrate (BLPHN) belonging to non-centrosymmetric space group were successfully grown by the slow evaporation solution growth technique. The BLPHN crystals of size 10×7×3mm(3) were obtained in 35days. Initially, the solubility tests were carried out for two solvents such as deionized water and mixed of deionized water-acetone. Among the two solvents, the solubility of BLPHN was found to be the highest in deionized water, so crystallization of BLPHN was done from its aqueous solution. As grown, crystals were characterized by single crystal X-ray diffraction studies and optical transmission spectral studies. Infrared spectroscopy, thermo gravimetric analysis and differential thermal analysis measurements were performed to study the molecular vibration and thermal behavior of the grown BLPHN crystals. Nonlinear optical (NLO) behavior of BLPHN crystal was studied by Kurtz and Perry powder method. 23659923 Deoxyribonucleic acid damage-associated biomarkers of ionising radiation: current status and future relevance for radiology and radiotherapy. Diagnostic and therapeutic radiation technology has developed dramatically in recent years, and its use has increased significantly, bringing clinical benefit. The use of diagnostic radiology has become widespread in modern society, particularly in paediatrics where the clinical benefit needs to be balanced with the risk of leukaemia and brain cancer increasing after exposure to low doses of radiation. With improving long-term survival rates of radiotherapy patients and the ever-increasing use of diagnostic and interventional radiology procedures, concern has risen over the long-term risks and side effects from such treatments. Biomarker development in radiology and radiotherapy has progressed significantly in recent years to investigate the effects of such use and optimise treatment. Recent biomarker development has focused on improving the limitations of established techniques by the use of automation, increasing sensitivity and developing novel biomarkers capable of quicker results. The effect of low-dose exposure (0-100 mGy) used in radiology, which is increasingly linked to cancer incidences, is being investigated, as some recent research challenges the linear-no-threshold model. Radiotherapy biomarkers are focused on identifying radiosensitive patients, determining the treatment-associated risk and allowing for a tailored and more successful treatment of cancer patients. For biomarkers in any of these areas to be successfully developed, stringent criteria must be applied in techniques and analysis of data to reduce variation among reports and allow data sets to be accurately compared. Newly developed biomarkers can then be used in combination with the established techniques to better understand and quantify the individual biological response to exposures associated with radiology tests and to personalise treatment plans for patients. 23913850 Nitrogen-Containing Microporous Conjugated Polymers via Carbazole-Based Oxidative Coupling Polymerization: Preparation, Porosity, and Gas Uptake. Facile preparation of microporous conjugated polycarbazoles via carbazole-based oxidative coupling polymerization is reported. The process to form the polymer network has cost-effective advantages such as using a cheap catalyst, mild reaction conditions, and requiring a single monomer. Because no other functional groups such as halo groups, boric acid, and alkyne are required for coupling polymerization, properties derived from monomers are likely to be fully retained and structures of final polymers are easier to characterize. A series of microporous conjugated polycarbazoles (CPOP-2-7) with permanent porosity are synthesized using versatile carbazolyl-bearing 2D and 3D conjugated core structures with non-planar rigid conformation as building units. The Brunauer-Emmett-Teller specific surface area values for these porous materials vary between 510 and 1430 m(2) g(-1) . The dominant pore sizes of the polymers based on the different building blocks are located between 0.59 and 0.66 nm. Gas (H2 and CO2 ) adsorption isotherms show that CPOP-7 exhibits the best uptake capacity for hydrogen (1.51 wt% at 1.0 bar and 77 K) and carbon dioxide (13.2 wt% at 1.0 bar and 273 K) among the obtained polymers. Furthermore, its high CH4 /N2 and CO2 /N2 adsorption selectivity gives polymer CPOP-7 potential application in gas separation. 23897666 Mutation of HES7 in a large extended family with spondylocostal dysostosis and dextrocardia with situs inversus. Spondylocostal dysotosis (SCD) is a rare developmental congenital abnormality of the axial skeleton. Mutation of genes in the Notch signaling pathway cause SCD types 1-5. Dextrocardia with situs inversus is a rare congenital malformation in which the thoracic and abdominal organs are mirror images of normal. Such laterality defects are associated with gene mutations in the Nodal signaling pathway or cilia assembly or function. We investigated two distantly related individuals with a rare combination of severe segmental defects of the vertebrae (SDV) and dextrocardia with situs inversus. We found that both individuals were homozygous for the same mutation in HES7, and that this mutation caused a significant reduction of HES7 protein function; HES7 mutation causes SCD4. Two other individuals with SDV from two unrelated families were found to be homozygous for the same mutation. Interestingly, although the penetrance of the vertebral defects was complete, only 3/7 had dextrocardia with situs inversus, suggesting randomization of left-right patterning. Two of the affected individuals presented with neural tube malformations including myelomeningocele, spina bifida occulta and/or Chiari II malformation. Such neural tube phenotypes are shared with the originally identified SCD4 patient, but have not been reported in the other forms of SCD. In conclusion, it appears that mutation of HES7 is uniquely associated with defects in vertebral, heart and neural tube formation, and this observation will help provide a discriminatory diagnostic guide in patients with SCD, as well as inform molecular genetic testing. © 2013 Wiley Periodicals, Inc. 23010104 For whom the bell tolls: Distress signals from long-lived osteocytes and the pathogenesis of metabolic bone diseases. Osteocytes are long-lived and far more numerous than the short-lived osteoblasts and osteoclasts. Immured within the lacunar-canalicular system and mineralized matrix, osteocytes are ideally located throughout the bone to detect the need for, and accordingly choreograph, the bone regeneration process by independently controlling rate limiting steps of bone resorption and formation. Consistent with this role, emerging evidence indicates that signals arising from apoptotic and old/or dysfunctional osteocytes are seminal culprits in the pathogenesis of involutional, post-menopausal, steroid-, and immobilization-induced osteoporosis. Osteocyte-originated signals may also contribute to the increased bone fragility associated with bone matrix disorders like osteogenesis imperfecta, and perhaps the rapid reversal of bone turnover above baseline following discontinuation of anti-resorptive treatments, like denosumab. This article is part of a Special Issue entitled "The Osteocyte". 23825139 Phylogenetic influences on leaf trait integration in Pelargonium (Geraniaceae): Convergence, divergence, and historical adaptation to a rapidly changing climate. • Premise of the study: Trait integration may improve prediction of species and lineage responses to future climate change more than individual traits alone, particularly when analyses incorporate effects of phylogenetic relationships. The South African genus Pelargonium contains divergent major clades that have radiated along the same seasonal aridity gradient, presenting the opportunity to ask whether patterns of evolution in mean leaf trait values are achieved through the same set of coordinated changes among traits in each clade. • Methods: Seven leaf traits were measured on field-collected leaves from one-third of the species (98) of the genus. Trait relationships were examined using phylogenetic regression within major clades. Disparity analysis determined whether the course of trait evolution paralleled historical climate change events. • Key results: Divergence in mean trait values between sister clades A1 and A2 was consistent with expectations for leaves differing in longevity, despite strong similarity between clades in trait interactions. No traits in either clade exhibited significant relationships with multivariate climate axes, with one exception. Species in clades C and A2 included in this study occupied similar environments. These clades had similar values of individual trait means, except for δ(13)C, but they exhibited distinctive patterns of trait integration. • Conclusions: Differing present-day patterns of trait integration are consistent with interpretations of adaptive responses to the prevailing climate at the time of each clade's origin. These differing patterns of integration are likely to exert strong effects on clade-level responses to future climate change in the winter rainfall region of South Africa. 23937436 Glioblastoma: From Molecular Pathology to Targeted Treatment. Glioblastoma (GBM) is one of the most lethal human cancers. Genomic analyses are defining the molecular architecture of GBM, uncovering relevant subsets of patients whose disease may require different treatments. Many pharmacological targets have been revealed, promising to transform patient care through targeted therapies. However, for most patients, clinical responses to targeted inhibitors are either not apparent or not durable. In this review, we address the challenge of developing more effective, molecularly guided approaches for the treatment of GBM patients. We summarize the current state of knowledge regarding molecular classifiers and examine their benefit for stratifying patients for treatment. We survey the molecular landscape of the disease, discussing the challenges raised by acquired drug resistance. Furthermore, we analyze the biochemical features of GBM, suggesting a next generation of drug targets, and we examine the contribution of tumor heterogeneity and its implications. We conclude with an analysis of the experimental approaches and their potential benefit to patients. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 9 is February 28, 2014. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates. 23800583 Adherence to Secondary Prevention Medications and Four-year Outcomes in Outpatients with Atherosclerosis. Although nonadherence with evidence-based secondary prevention medications is common in patients with established atherothrombotic disease, long-term outcomes studies are scant. We assessed the prevalence and long-term outcomes of nonadherence to secondary prevention (antiplatelet agents, statins, and antihypertensive agents) medications in stable outpatients with established atherothrombosis (coronary, cerebrovascular, or peripheral artery disease) enrolled in the international REduction of Atherothrombosis for Continued Health registry. Adherence with these medications in eligible patients at baseline and 1-year follow-up was assessed. The primary outcome was a composite of cardiovascular death, myocardial infarction, or stroke at 4 years. A total of 37,154 patients with established atherothrombotic disease were included. Adherence rates with all evidence-based medications at baseline and 1 year were 46.7% and 48.2%, respectively. Nonadherence with any medication at baseline (hazard ratio, 1.18; 95% confidence interval, 1.11-1.25) and at 1 year (hazard ratio, 1.19; 95% confidence interval, 1.11-1.28) were both significantly associated with an increased risk of the primary end point. The risk of all-cause mortality was similarly elevated. Corresponding numbers needed to treat were 31 and 25 patients for the composite end point and total mortality, respectively. This also was true for each disease-specific subgroup. Patients who were fully adherent at both time points had the lowest incidence of adverse outcomes, whereas patients who were nonadherent at both time points had the worst outcomes (P < .01). Our analysis of a large international registry demonstrates that nonadherence with evidence-based secondary prevention therapies in patients with established atherothrombosis is associated with a significant increase in long-term adverse events, including mortality. 23730946 Three-Dimensional Microfluidic Collagen Hydrogels for Investigating Flow-Mediated Tumor-Endothelial Signaling and Vascular Organization. Hyperpermeable tumor vessels are responsible for elevated interstitial fluid pressure and altered flow patterns within the tumor microenvironment. These aberrant hydrodynamic stresses may enhance tumor development by stimulating the angiogenic activity of endothelial cells lining the tumor vasculature. However, it is currently not known to what extent shear forces affect endothelial organization or paracrine signaling during tumor angiogenesis. The objective of this study was to develop a three-dimensional (3D), in vitro microfluidic tumor vascular model for coculture of tumor and endothelial cells under varying flow shear stress conditions. A central microchannel embedded within a collagen hydrogel functions as a single neovessel through which tumor-relevant hydrodynamic stresses are introduced and quantified using microparticle image velocimetry (μ-PIV). This is the first use of μ-PIV in a tumor representative, 3D collagen matrix comprised of cylindrical microchannels, rather than planar geometries, to experimentally measure flow velocity and shear stress. Results demonstrate that endothelial cells develop a confluent endothelium on the microchannel lumen that maintains integrity under physiological flow shear stresses. Furthermore, this system provides downstream molecular analysis capability, as demonstrated by quantitative RT-PCR, in which, tumor cells significantly increase expression of proangiogenic genes in response to coculture with endothelial cells under low flow conditions. This work demonstrates that the microfluidic in vitro cell culture model can withstand a range of physiological flow rates and permit quantitative measurement of wall shear stress at the fluid-collagen interface using μ-PIV optical flow diagnostics, ultimately serving as a versatile platform for elucidating the role of fluid forces on tumor-endothelial cross talk. 23931678 Bovine Milk Fat Globule Membrane Proteins Are Affected By Centrifugal Washing Processes. The impact of washing on the release of proteins from the milk fat globule membrane (MFGM) was examined by applying washing procedures with different degrees of stringency to milk fat globule (MFG) surfaces in simulated milk ultrafiltrate buffer solution. Three washing methods, M1 (3000g, 5 min, three washes), M2 (3750g, 15 min, one wash), and M3 (15000g, 20 min, three washes) were chosen. MFG ζ-potential increased after M3 washing (P < 0.05), suggesting surface damage. For M1, in which the native MFG surface was least damaged, cluster of differentiation 36 (CD 36) and periodic acid schiff 6/7 proteins were more strongly bound to the MFGM compared with other major membrane proteins. For M3, CD 36 together with fatty acid-binding protein was more strongly bound to the MFGM. Washing by centrifugation and redispersal of the fat globules damaged the MFGM, with release into the aqueous phase of some membrane-associated proteins. The current results show the impact of washing processes on retention of functional MFGM proteins. 23707750 Evaluation of microwave assisted grafted sago starch as controlled release polymeric carrier. In the present investigation an attempt has been made to develop a new co-polymeric material for controlled release tablet formulations. The acrylamide grafting was successfully performed on the backbone of sago starch. The modified starch was tested for acute toxicity and drug-excipient compatibility study. The grafted material was used in making of controlled release tablets of lamivudine. The formulations were evaluated for physical characteristics such as hardness, friability, %drug content and weight variations. The in vitro release study showed that the optimized formulation exhibited highest correlation (R) value in case of Higuchi model and the release mechanism of the optimized formulation predominantly exhibited combination of diffusion and erosion process. There was a significant difference in the pharmacokinetic parameters (Tmax, Cmax, AUC, Vd, T1/2 and MDT) of the optimized formulation as compared to the marketed conventional tablet Lamivir(®) was observed. The pharmacokinetics parameters were showed controlled pattern and better bioavailability. The optimized formulation exhibited good stability and release profile at the accelerated stability conditions. 23595560 Emergency department visits after hours by lung cancer patients in Japan. The aims of this study were to clarify frequency with which Japanese lung cancer patients visited an emergency department (ED) after hours and their final outcome. This is a retrospective and single institutional study. We reviewed medical records of patients who died of lung cancer from January 2008 to June 2012 at Osaka Police Hospital who had been followed up since diagnosis of lung cancer until death. We compared patients who had visited the ED after hours on weekdays, weekends, or holidays over their lives with cancer (ED visitors) and patients who had never visited the ED (non-ED visitors). Overall, 245 patients met the inclusion criteria for analysis. There were 149 after hours ED visits by 106 lung cancer patients. Mean number of ED visits was 0.6 for all patients. Median interval from ED visit to death was 49 days. The most common chief compliant for these patients was respiratory problems (37.6 %). Most patients visited the ED during chemotherapy (32.9 %) or for best supportive care (42.3 %). Directly after ED visits, 56.4 % of ED visitors were finally hospitalized. In a multivariate analysis, performance status (PS) (odds ratio [OR]: 11.2, 95 % confidence interval [CI]: 2.1-59.0, p = 0.004) and cancer stage (OR: 0.003, 95 % CI: 0.0006-0.014, p < 0.001) at diagnosis were statistically associated with ED visits after hours. Japanese patients with lung cancer frequently visit ED after hours. An ED visit is itself an indicator of poor prognosis. 23955124 Pre-enlistment hearing loss and hearing loss disability among US soldiers and marines. Hearing loss is a common condition among US adults, with some evidence of increasing prevalence in young adults. Noise-induced hearing loss attributable to employment is a significant source of preventable morbidity world-wide. The US military population is largely comprised of young adult males serving in a wide variety of occupations, many in high noise-level conditions, at least episodically. To identify accession and service-related risk factors for hearing-related disability, matched case-control study of US military personnel was conducted. Individuals evaluated for hearing loss disability in the US Army and Marine Corps were frequency matched to controls without history of disability evaluation on service and enlistment year. Conditional logistic regression was used to examine the association between accession and service-related factors and hearing-related disability evaluations between October 2002 and September 2010. Individuals with medically disqualifying audiograms or hearing loss diagnoses at application for military service were 8 and 4 times more likely, respectively, to have a disability evaluation related to hearing loss, after controlling for relevant accession, demographic, and service-related factors. Conservative hearing loss thresholds on pre-enlistment audiograms, stricter hearing loss medical waiver policies or qualified baseline audiograms pre-enlistment are needed in the U.S military. Industrial corporations or labor unions may also benefit from identifying individuals with moderate hearing loss at the time of employment to ensure use of personal protective equipment and engineer controls of noise. 23882200 Optic ataxia as a model to investigate the role of the posterior parietal cortex in visually guided action: evidence from studies of patient M.H. Optic ataxia is a neuropsychological disorder that affects the ability to interact with objects presented in the visual modality following either unilateral or bilateral lesions of the posterior parietal cortex (PPC). Patients with optic ataxia fail to reach accurately for objects, particularly when they are presented in peripheral vision. The present review will focus on a series of experiments performed on patient M.H. Following a lesion restricted largely to the left PPC, he developed mis-reaching behavior when using his contralesional right arm for movements directed toward the contralesional (right) visual half-field. Given the clear-cut specificity of this patient's deficit, whereby reaching actions are essentially spared when executed toward his ipsilateral space or when using his left arm, M.H. provides a valuable "experiment of nature" for investigating the role of the PPC in performing different visually guided actions. In order to address this, we used kinematic measurement techniques to investigate M.H.'s reaching and grasping behavior in various tasks. Our experiments support the idea that optic ataxia is highly function-specific: it affects a specific sub-category of visually guided actions (reaching but not grasping), regardless of their specific end goal (both reaching toward an object and reaching to avoid an obstacle); and finally, is independent of the limb used to perform the action (whether the arm or the leg). Critically, these results are congruent with recent functional MRI experiments in neurologically intact subjects which suggest that the PPC is organized in a function-specific, rather than effector-specific, manner with different sub-portions of its mantle devoted to guiding actions according to their specific end-goal (reaching, grasping, or looking), rather than according to the effector used to perform them (leg, arm, hand, or eyes). 23884017 Abdominal Muscle Training Can Enhance Cough After Spinal Cord Injury. . Respiratory complications in people with high-level spinal cord injury (SCI) are a major cause of morbidity and mortality, particularly because of a reduced ability to cough as a result of abdominal muscle paralysis. . We investigated the effect of cough training combined with functional electrical stimulation (FES) over the abdominal muscles for 6 weeks to observe whether training could improve cough strength. . Fifteen SCI subjects (C4-T5) trained for 6 weeks, 5 days per week (5 sets of 10 coughs per day) in a randomized crossover design study. Subjects coughed voluntarily at the same time as a train of electrical stimulation was delivered over the abdominal muscles via posterolaterally positioned electrodes (50 Hz, 3 seconds). Measurements were made of esophageal (Pes) and gastric (Pga) expiratory pressures and the peak expiratory flow (PEFcough) produced at the 3 time points of before, during, and after the training. . During voluntary coughs, FES cough stimulation improved Pga, Pes, and PEFcough acutely, 20-fold, 4-fold, and 50%, respectively. Six weeks of cough training significantly increased Pga (37.1 ± 2.0 to 46.5 ± 2.9 cm H2O), Pes (35.4 ± 2.7 to 48.1 ± 2.9 cm H2O), and PEFcough (3.1 ± 0.1 to 3.6 ± 0.1 L/s). Cough training also improved pressures and flow during voluntary unstimulated coughs. . FES of abdominal muscles acutely increases mechanical output in coughing in high-level SCI subjects. Six weeks of cough training further increases gastric and esophageal cough pressures and expiratory cough flow during stimulated cough maneuvers. 23894377 Cold-induced changes in gene expression in brown adipose tissue, white adipose tissue and liver. Cold exposure imposes a metabolic challenge to mammals that is met by a coordinated response in different tissues to prevent hypothermia. This study reports a transcriptomic analysis in brown adipose tissue (BAT), white adipose (WAT) and liver of mice in response to 24 h cold exposure at 8°C. Expression of 1895 genes were significantly (P<0.05) up- or down-regulated more than two fold by cold exposure in all tissues but only 5 of these genes were shared by all three tissues, and only 19, 14 and 134 genes were common between WAT and BAT, WAT and liver, and BAT and liver, respectively. We confirmed using qRT-PCR, the increased expression of a number of characteristic BAT genes during cold exposure. In both BAT and the liver, the most common direction of change in gene expression was suppression (496 genes in BAT and 590 genes in liver). Gene ontology analysis revealed for the first time significant (P<0.05) down regulation in response to cold, of genes involved in oxidoreductase activity, lipid metabolic processes and protease inhibitor activity, in both BAT and liver, but not WAT. The results reveal an unexpected importance of down regulation of cytochrome P450 gene expression and apolipoprotein, in both BAT and liver, but not WAT, in response to cold exposure. Pathway analysis suggests a model in which down regulation of the nuclear transcription factors HNF4α and PPARα in both BAT and liver may orchestrate the down regulation of genes involved in lipoprotein and steroid metabolism as well as Phase I enzymes belonging to the cytochrome P450 group in response to cold stress in mice. We propose that the response to cold stress involves decreased gene expression in a range of cellular processes in order to maximise pathways involved in heat production. 23914941 Electrical stimulation modulates Wnt signaling and regulates genes for the motor endplate and calcium binding in muscle of rats with spinal cord transection. Spinal cord injury (SCI) results in muscle atrophy and a shift of slow oxidative to fast glycolytic fibers. Electrical stimulation (ES) at least partially restores muscle mass and fiber type distribution. The objective of this study was to was to characterize the early molecular adaptations that occur in rat soleus muscle after initiating isometric resistance exercise by ES for one hour per day for 1, 3 or 7 days when ES was begun 16 weeks after SCI. Additionally, changes in mRNA levels after ES were compared with those induced in soleus at the same time points after gastrocnemius tenotomy (GA). ES increased expression of Hey1 and Pitx2 suggesting increased Notch and Wnt signaling, respectively, but did not normalize RCAN1.4, a measure of calcineurin/NFAT signaling, or PGC-1ss mRNA levels. ES increased PGC-1alpha expression but not that of slow myofibrillar genes. Microarray analysis showed that after ES, genes coding for calcium binding proteins and nicotinic acetylcholine receptors were increased, and the expression of genes involved in blood vessel formation and morphogenesis was altered. Of the 165 genes altered by ES only 16 were also differentially expressed after GA, of which 12 were altered in the same direction by ES and GA. In contrast to ES, GA induced expression of genes related to oxidative phosphorylation. Notch and Wnt signaling may be involved in ES-induced increases in the mass of paralyzed muscle. Molecular adaptations of paralyzed soleus to resistance exercise are delayed or defective compared to normally innervated muscle. 23822149 Age-dependent differences in diabetes and acute hyperglycemia between men and women with ST-elevation myocardial infarction: a cohort study. Both acute hyperglycemia as diabetes results in an impaired prognosis in ST-elevation myocardial infarction (STEMI) patients. It is unknown whether there is a different prevalence of diabetes and acute hyperglycemia in men and women within age-groups. Between 2004 and 2010, 4640 consecutive patients (28% women) with STEMI, were referred for primary PCI. Patients were stratified into two age groups, < 65 years (2447 patients) and ≥65 years (2193 patients). Separate analyses were performed in 3901 patients without diabetes. Diabetes was defined as known diabetes or HbA1c ≥6.5 mmol/l at admission. The prevalence of diabetes was comparable between women and men in the younger age group (14% vs 12%, p = 0.52), whereas in the older age group diabetes was more prevalent in women (25% vs 17% p < 0.001). In patients without diabetes, admission glucose was comparable between both genders in younger patients (8.1 ± 2.0 mmol/l vs 8.0 ± 2.2 mmol/l p = 0.36), but in older patients admission glucose was higher in women than in men (8.7 ± 2.1 mmol/l vs 8.4 ± 2.1 mmol/l p = 0.028). After multivariable analyses, the occurrence of increased admission glucose was comparable between men and women in the younger age group (OR 1.1, 95%CI 0.9-1.5), but increased in women in the older age group (OR 1.3, 95% CI 1.1-1.7). Both diabetes and hyperglycemia were associated with a higher one-year mortality in both men and women. The differences between men and women in hyperglycemia and diabetes in patients with STEMI are age dependent and can only be observed in older patients. This may have implications for medical treatment and should be investigated further. 23666228 Hematological alterations caused by high intensity of L3 larvae of Contracaecum sp Railliet & Henry, 1912 (Nematoda, Anisakidae) in the stomach of Hoplias malabaricus in lakes in Pirassununga, São Paulo. The objective of the present study was to discover the hematological indices of Hoplias malabaricus infected by larvae of Contracaecum sp. A total of 105 fish were collected from two lakes located in the municipal district of Pirassununga, São Paulo, Brazil, of which 95.2 % were infested by L3 larvae of Contracaecum sp., with an average intensity of 348.7 ±â€‰231.55 helminths/fish. A total of 76 fish were analyzed to establish hematological parameters. Following analysis, it was found that there was a significant difference between hematological parameters Hct, erythrocytes (Er), thrombocytopenia (p = 0.01), and Hb (p = 0.02) in lakes A and B, while there was no significant difference for leukocyte (p = 0.68), mean corpuscular volume, mean corpuscular hemoglobin (p = 0.06), and mean corpuscular hemoglobin concentration (p = 0.47). The intensity of infection correlated negatively with Er (r s  = -0.42; p < 0.01) and positively for (r s  = 0.48; p < 0.01). The high intensity of infection by Contracaecum sp. in H. malabaricus did not affect the health of the fish despite causing alterations in hematological variables. 23940722 Exercise-induced blood lactate increase does not change red blood cell deformability in cyclists. The effect of exercise-induced lactate production on red blood cell deformability and other blood rheological changes is controversial, given heavy-exercise induces biochemical processes (e.g., oxidative stress) known to perturb haemorheology. The aim of the present study was to examine the haemorheological response to a short-duration cycling protocol designed to increase blood lactate concentration, but of duration insufficient to induce significant oxidative stress. Male cyclists and triathletes (n = 6; 27±7 yr; body mass index: 23.7±3.0 kg/m(2); peak oxygen uptake 4.02±0.51 L/min) performed unloaded (0 W), moderate-intensity, and heavy-intensity cycling. Blood was sampled at rest and during the final minute of each cycling bout. Blood chemistry, blood viscosity, red blood cell aggregation and red blood cell deformability were measured. Blood lactate concentration increased significantly during heavy-intensity cycling, when compared with all other conditions. Methaemoglobin fraction did not change during any exercise bout when compared with rest. Blood viscosity at native haematocrit increased during heavy-intensity cycling at higher-shear rates when compared with rest, unloaded and moderate-intensity cycling. Heavy-intensity exercise increased the amplitude of red blood cell aggregation in native haematocrit samples when compared with all other conditions. Red blood cell deformability was not changed by exercise. Acute exercise perturbs haemorheology in an intensity dose-response fashion; however, many of the haemorheological effects appear to be secondary to haemoconcentration, rather than increased lactate concentration. 23850389 Social support and self-care behaviors in individuals with heart failure: An integrative review. The purpose of this review is to examine and synthesize recent literature regarding the relationship between social support and self-care behaviors in individuals with heart failure (HF). Self-care is an important factor in maintaining health and well-being for individuals with heart failure. Self-care behaviors are an integral component of self-care, and may be impacted by the disease process of heart failure. However, social support may positively influence an individual's self-care behaviors by assisting with activities associated with symptom management and evaluation, as well as activities associated with maintaining heart failure-related treatment regimens. This review will synthesize the current knowledge related to the influence of social support on heart failure self-care behaviors. Using an integrative review method, a review of current empirical literature was conducted utilizing CINAHL, PsycARTICLES, and PubMed computerized databases for a period of January 2000 to December 2012. Thirteen studies were identified that met the inclusion criteria for review and investigated aspects of social support and heart failure self-care behaviors. Social support appears to have a positive relationship on heart failure self-care behaviors, with an individual's family playing an important role in assisting individuals to maintain positive self-care behaviors. Social support appears to influence both heart failure self-care maintenance and management related behaviors by assisting with maintaining treatment regimens and by participating in the decision-making process related to the management of symptoms, as well as seeking treatment for symptoms of heart failure. All four types of social support (i.e., emotional support, instrumental/tangible support, informational support, and appraisal support) are involved in the interactive process between an individual's social network (i.e., family and peers) and the individual with heart failure to maintain self-care behaviors that enhance health and well-being. However, more research is needed, specifically longitudinal and experimental designs, to determine the effectiveness of social support on self-care behaviors in individuals with heart failure, since this review revealed mostly cross-sectional, correlational studies which limits the ability to infer causality. 23859642 Brain Activation during Masked and Unmasked Semantic Priming: Commonalities and Differences. Using fMRI during a lexical decision task, we investigated the neural correlates of semantic priming under masked and unmasked prime presentation conditions in a repeated measurement design of the same group of 24 participants (14 women). The task was to discriminate between pseudowords and words. Masked and unmasked prime words differed in their degree of semantic relatedness with target stimuli. Neural correlates of priming were defined as significantly different neural activations upon semantically unrelated minus related trials. Left fusiform gyrus, left posterior inferior frontal gyrus, and bilateral pre-SMA showed priming effects independent of the masking condition. By contrast, bilateral superior temporal gyri, superior parietal lobules, and the SMA proper demonstrated greater neural priming in the unmasked compared with the masked condition. The inverted contrast (masked priming minus unmasked priming) did not show significant differences even at lowered thresholds of significance. The conjoint effects of priming in the left fusiform gyrus suggest its involvement as a direct consequence of the neural organization of semantic memory. Activity in brain regions showing significantly more neural priming in the unmasked condition possibly reflected participants' evaluation of the prime-target relationship, presumably in the context of semantic matching. The present results therefore indicate that masked and unmasked semantic priming partially depend on dissociable mechanisms at the neural and most likely also at the functional level. 23121442 Psychometric evaluation of a Swedish Self-Efficacy scale and Recovery Locus of Control scale in the context of minor illness. Reliable and valid instruments are essential when examining the role of self-efficacy and locus of control in the self-care context. The aim of this study was to test the validity and reliability of the Self-Efficacy Scale in Self-Care (SESSC) and the Swedish version of the Recovery Locus of Control scale (RLoC) in the context of minor illness. A descriptive correlational design was used to assess the psychometric characteristics of the scales. The study population was 317 randomly selected Swedish inhabitants aged 18-80. The results from this study showed that the RLoC has limitations in reliability and validity and should not be applied in the context of self-care of minor illness. The SESSC proved to be a reliable and valid instrument in assessing self-efficacy in self-care for minor illness. 23255551 Identification of multiple binding sites for substrate transport in bovine organic anion transporting polypeptide 1a2. Organic anion transporting polypeptides (OATP) have been extensively recognized as key determinants of absorption, distribution, metabolism, and excretion of various drugs because of their broad substrate specificity, wide tissue distribution, and the involvement of drug-drug interaction. As the first cloned human OATP, OATP1A2 has been found to transport a wide spectrum of endogenous and exogenous compounds. Bovine Oapt1a2 shared high homology with the human transporter and is considered as its functional ortholog. In the present study, we expressed bovine Oatp1a2 in human embryonic kidney 293 cells and found that, unlike human OATP1A2, the transport of estrone-3-sulfate (E-3-S) exhibited biphasic saturation kinetics. The K(m) values are 0.25 ± 0.08 and 46.6 ± 18.5 µM, and V(max) values were 24.5 ±4.4 and 375 ± 142 pmol/mg protein/min for high- and low-affinity sites, respectively, suggesting the presence of multiple binding sites. Further study on other Oatp1a2 substrates showed that the high affinity component for E-3-S is responsible for the interaction with taurocholate, bromsulphthalein, and rifampicin and is sensitive to proton concentration change, whereas the low affinity binding site is only involved in the binding of the antitumor drug methotrexate and had no response to change of pH. 22700989 On the relationship between autistic traits and executive functioning in a non-clinical Dutch student population. We examined the association between autistic traits and different aspects of executive functioning (EF), using non-clinical Social Science and Science students as participants. Autistic traits, and associated personality traits, were measured using the Autism Quotient (AQ) and the Temperament and Character Inventory (TCI), respectively. EF was examined by means of a random number generation test and a phonemic fluency test. Using appropriate dependent measures, the following EF components were examined: 1) inhibition of prepotent responding, 2) simple output inhibition, 3) working memory monitoring and updating, and 4) switching. No significant relationship was found between the AQ and each of the four components of EF. However, two TCI subscales were reliably correlated with either the working memory or the shifting component. These results were discussed in view of the concept of an autism spectrum with respect to executive abilities. 23758534 Neuroprotective properties and mechanisms of resveratrol in in vitro and in vivo experimental cerebral stroke models. Resveratrol, a natural stilbene present at relatively high concentrations in grape skin and seeds and red wine, is known for its purported antioxidant activity in the vascular and nervous systems. In contrast to its direct antioxidant role within the central nervous system, recent research supports a protective mechanism through increasing endogenous cellular antioxidant defenses, which triggers a cascade of parallel neuroprotective pathways. A growing body of in vitro and in vivo evidence indicates that resveratrol acts through multiple pathways and reduces ischemic damage in vital organs, such as the heart and the brain, in various rodent models. Most of the protective biological actions of resveratrol have been associated with its antioxidative, anti-inflammatory, and antiapoptotic properties and other indirect pathways. Continued public interest and increasing resveratrol supplements on the market warrant a review of the available in vitro and in vivo science reported in the stroke-related literature. Rigorous clinical trials evaluating the effects of resveratrol in stroke are absent, though the general population consumption appears to be relatively safe. Resveratrol has shown potential for treating stroke in laboratory animals and in vitro human cell studies, yet there is still a need for human research in preclinical settings. This review summarizes many of the findings on the neuroprotective potential of resveratrol in cerebral stroke, focusing on both the in vitro and in vivo experimental models and some proposed mechanisms of action. 23411599 Expression patterns of cell cycle proteins in the livers of rats treated with hepatocarcinogens for 28 days. Some hepatocarcinogens induce cytomegaly, which reflects aberrant cell cycling and increased ploidy, from the early stages of administration to animals. To clarify the regulatory molecular mechanisms behind cell cycle aberrations related to the early stages of hepatocarcinogenesis, we performed gene expression analysis using microarrays and real-time reverse transcription polymerase chain reaction followed by immunohistochemical analysis in the livers of rats treated with the cytomegaly inducing hepatocarcinogens thioacetamide (TAA), fenbendazole, and methyleugenol, the cytomegaly non-inducing hepatocarcinogen piperonyl butoxide (PBO), or the non-carcinogenic hepatotoxicants acetaminophen and α-naphthyl isothiocyanate, for 28 days. Gene expression profiling showed that cell cycle-related genes, especially those of G(2)/M phase, were mostly upregulated after TAA treatment. Immunohistochemical analysis was performed on cell cycle proteins that were upregulated by TAA treatment and on related proteins. All hepatocarcinogens, irrespective of their cytomegaly inducing potential, increased liver cells immunoreactive for p21(Cip1), which acts on cells arrested in G(1) phase, and for Aurora B or Incenp, which is suggestive of an increase in a cell population with chromosomal instability caused by overexpression. PBO did not induce cell proliferation after 28-day treatment. Hepatocarcinogens that induced cell proliferation after 28-day treatment also caused an increase in p53(+) cells in parallel with increased apoptotic cells, as well as increased population of cells expressing M phase-related proteins nuclear Cdc2, phospho-Histone H3, and HP1α. These results suggest that hepatocarcinogens may increase cellular populations arrested in G(1) phase or showing chromosomal instability after 28-day treatment. Hepatocarcinogens that induce cell cycle facilitation may cause M phase arrest accompanied by apoptosis. 23410960 Effects of salinomycin on human bone marrow-derived mesenchymal stem cells in vitro. Various hypotheses on the origin of cancer stem cells (CSCs) exist, including that CSCs develop from transformed human bone marrow mesenchymal stem cells (hBMSC). Since the polyether antibiotic salinomycin selectively kills CSCs, the present study aims to elucidate the effects of salinomycin on normal hBMSC. The immunophenotype of hBMSC after salinomycin exposure was observed by flow cytometry. The multi-differentiation capacity of hBMSC was evaluated by Oil Red O and van Kossa staining. Cytotoxic effects of salinomycin were monitored by the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) assay. Furthermore, spheroid formation and migration capacity were assessed. There were no differences in the immunophenotype and multi-differentiation capacity of hBMSC induced by salinomycin treatment. Cytotoxic effects were observed at concentrations of 30 μM and above. Neither the migration capability nor the ability to form spheroids was affected. Essential functional properties of hBMSC were unaffected by salinomycin. However, dose-dependent cytotoxicity effects could be observed. Overall, low dose salinomycin showed no negative effects on hBMSC. Since mesenchymal stem cells from various sources respond differently, further in vitro studies are needed to clarify the effect of salinomycin on tissue-specific stem cells. 23743568 Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements. Immune-related response criteria (irRC) was developed to adequately assess tumor response to immunotherapy. The irRC are based on bidimensional measurements, as opposed to unidimensional measurements defined by Response Evaluation Criteria in Solid Tumors, which has been widely used in solid tumors. We aimed to compare response assessment by bidimensional versus unidimensional irRC in patients with advanced melanoma treated with ipilimumab. Fifty-seven patients with advanced melanoma treated with ipilimumab in a phase II, expanded access trial were studied. Bidimensional tumor measurement records prospectively conducted during the trial were reviewed to generate a second set of measurements using unidimensional, longest diameter measurements. The percent changes of measurements at follow-up, best overall response, and time-to-progression (TTP) were compared between bidimensional and unidimensional irRC. Interobserver variability for bidimensional and unidimensional measurements was assessed in 25 randomly selected patients. The percent changes at follow-up scans were highly concordant between the 2 criteria (Spearman r: 0.953-0.965, first to fourth follow-up). The best immune-related response was highly concordant between the 2 criteria (κw = 0.881). TTP was similar between the bidimensional and unidimensional assessments (progression-free at 6 months: 70% vs. 81%, respectively). The unidimensional measurements were more reproducible than bidimensional measurements, with the 95% limits of agreement of (-16.1%, 5.8%) versus (-31.3%, 19.7%), respectively. irRC using the unidimensional measurements provided highly concordant response assessment compared with the bidimensional irRC, with less measurement variability. The use of unidimensional irRC is proposed to assess response to immunotherapy in solid tumors, given its simplicity, higher reproducibility, and high concordance with the bidimensional irRC. Clin Cancer Res; 19(14); 3936-43. ©2013 AACR. 23440892 Very small embryonic-like cells: Biology and function of these potential endogenous pluripotent stem cells in adult tissues. Very small embryonic-like cells (VSELs), found in murine bone marrow and other adult tissues, are small, non-hematopoietic cells expressing markers of pluripotent embryonic and primordial germ cells. A similar cell type in humans has begun to be characterized, though with a slightly different phenotype and surface markers. Consistent with expression of pluripotency genes, murine VSELs differentiate into cell types from three germ-layer lineages in vitro, though pluripotency has yet to be shown at the single-cell level or in vivo. VSELs appear to be quiescent under steady state conditions, apparently due to partially erased imprinting and overexpression of cell cycle inhibitory genes. In vivo, VSELs can enter the cell cycle under stress conditions, but which factors regulate quiescence versus proliferation and self-renewal versus differentiation are as yet unknown, and in vitro conditions that induce proliferation and self-renewal have yet to be defined. Future experiments are needed to address whether a VSEL niche actively regulates quiescence in vivo or quiescence is cell autonomous under steady state conditions. Insights into these mechanisms may help to address whether or not VSELs could play a role in regenerative medicine in the future. Mol. Reprod. Dev. 80:677-690, 2013. © 2013 Wiley Periodicals, Inc. 23826842 SABRE 1 (Surgery Against Brachytherapy - a Randomised Evaluation): feasibility randomised controlled trial (RCT) of brachytherapy vs radical prostatectomy in low-intermediate risk clinically localised prostate cancer. To determine the feasibility of a phase III randomised controlled trial of brachytherapy vs radical prostatectomy (RP) in men with low-intermediate risk localised prostate cancer. This parallel, two-group, multicentre, randomised controlled feasibility trial enrolled men with histologically confirmed localised, low-risk prostate cancer and good performance status from five UK hospitals. Participants were randomly allocated (1:1) by remote computer allocation to receive a decision aid (DA) DVD or standard information (control group), followed by a second randomisation (1:1) to brachytherapy or RP. There was no 'blinding' of staff or patients. Primary outcome was feasibility: a recruitment rate of six patients per centre over the last 6 months of recruitment would deem a phase III trial feasible. Between May 2009 and May 2011, 30 patients were randomised (15 in the DA group and 15 in the control group), and four continued to the second treatment randomisation (one from the DA group and three from the control group). One patient was allocated and received brachytherapy and three RP. SABRE 1 closed early due to poor recruitment. All patients were analysed. Screening logbook analysis showed that the main reasons for declining trial entry were a wish to choose treatment or opting for active monitoring. Results from the DA questionnaire (completed by 10 men) showed that four of the men 'felt surgery and radiotherapy had been proven in a high quality trial' and seven felt 'they should make their treatment decision while knowing their doctors opinion'. Recruitment to a RP vs brachytherapy trial in localised prostate cancer was not feasible by the use of this two-step randomisation using a DA and previous trials in early prostate cancer have had similar difficulties in recruitment, with only a few achieving their accrual target. The best treatment method for treating low-risk prostate cancer is still unproven in a head-to-head trial and the increasing number of options will make choices correspondingly more difficulty without good quality comparative research. More sophisticated techniques for recruitment may be more successful in future trials in this patient population. 23929807 The hard Test Your Memory. Evaluation of a short cognitive test to detect mild Alzheimer's disease and amnestic mild cognitive impairment. The aim of this study is the evaluation of a novel cognitive test, the hard Test Your Memory (H-TYM), in the detection of mild Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). This paper uses a prospective study in an outpatient memory clinic. We recruited 97 patients with a diagnosis of mild AD or aMCI aged between 50 and 80 years. All scored 20 or more on the mini mental state examination (MMSE). We recruited 200 controls from a similar background. The patients were given a novel short cognitive test (H-TYM) designed to test recall of newly learnt visual and verbal material together with the Addenbrooke's Cognitive Assessment Revised, MMSE, and TYM test. Alzheimer's disease/aMCI patients completed the H-TYM with an average recall score of 6.69 (SD 3.45); control participants scored an average of 20.4 (SD 4.54). The H-TYM detected 95% of cases of mild AD/aMCI on the basis of an optimum cutoff point. The area under the receiver operating characteristic for the H-TYM ratio was calculated to be 0.989 with a 95% confidence interval of 0.980-0.997. The H-TYM test has an excellent ability to discriminate between AD/aMCI cases and healthy controls. The H-TYM is a useful tool for the detection of mild AD/aMCI, and it detects AD/aMCI in the majority of patients who "pass" the MMSE and Addenbrooke's Cognitive Assessment Revised. Copyright © 2013 John Wiley & Sons, Ltd. 23926217 Humor and Laughter in Persons With Cognitive Impairment and Their Caregivers. Purpose: The purpose of this study was to describe humor and laughter in persons with cognitive impairment (PWCI) and caregivers who were recalling a shared experience in a focus group. Design: Twenty participants attended an Art Engagement Activity at the Andy Warhol Art Museum, which included a guided tour and an art project. All PWCI had medically diagnosed cognitive disorders and all caregiver participants did not. Four focus groups were conducted and transcripts of audio-recorded sessions were transferred to a qualitative software program. Method: Words, phrases, and episodes of humor and laughter were used to construct codes, which were refined during group analysis using constant comparison. Findings: Humor and laughter were present in all four focus groups. Emerging themes of humor included silliness, sarcasm, and commenting about hardships of dementia. Laughter was identified in segments with and without humor. Some PWCI were unable to follow social cues. Conclusions: Humor and laughter played a role in creating a safe social environment. PWCI were able to engage in humor during social interactions, yet some had difficulty recognizing social cues. Further study may reveal roles of humor and laughter in adaptation to cognitive decline and holistic interventions for improved quality of life. 23928270 Application of cetylpyridinium chloride and sodium chloride decontamination method for recovery of Mycobacterium tuberculosis from clinically suspected cases of pulmonary tuberculosis. The study was designed to compare the efficacy of cetylpyridinium chloride (CPC) and sodium chloride (NaCl) decontamination method with N-acetyl L-Cystine (NALC) and sodium hydroxide (NaOH) decontamination (the reference method) method for the recovery of Mycobacterium tuberculosis (MTB) from clinically suspected cases of pulmonary tuberculosis. To evaluate CPC-NaCl and NALC-NaOH decontamination methods, sputum specimens (n = 796) were studied (culturing on Löwenstein-Jensen medium), and the performances were compared. The CPC-NaCl decontamination method demonstrated a sensitivity, specificity, negative predictive value, and positive predictive value of 97.99%, 87.53%, 70.19%, and 99.32%, respectively, when compared to NALC-NaOH decontamination method. In summary, CPC-NaCl decontamination method effectively detected significantly higher number of MTB cases (n = 208) than NALC-NaOH decontamination method (n = 149) particularly in sputum with scanty bacilli and smear-negative cases, indicating the potential of CPC-NaCl decontamination method to preserve paucibacillary cases more efficient than NALC-NaOH decontamination method. 23930023 in-silico analysis suggests alterations in the function of XisA protein as a possible mechanism of butachlor toxicity in the nitrogen fixing cyanobacterium Anabaena sp. PCC 7120. Butachlor, a commonly used herbicide adversely affects the nitrogen fixing capability of Anabaena, an acclaimed nitrogen fixer in the Indian paddy fields. The nitrogen fixation in Anabaena is triggered by the excision of nifD element by xisA gene leading to rearrangement of nifD forming nifHDK operon in the heterocyst of Anabaena sp. PCC7120. Functional elucidation adjudged through in-silico analysis revealed that xisA belongs to integrase family of tyrosine recombinase. The predicted functional partners with XisA protein that have shown cooccurence with this protein in a network are mainly hypothetical proteins with unknown functions except psaK1 whose exact function in photosystem I is not yet known. The focus of this study was to find out the relation between XisA and butachlor using in-silico approaches. The XisA protein was modeled and its active sites were identified. Docking studies revealed that butachlor binds at the active site of XisA protein hampering its excision ability vis-à-vis nif genes in Anabaena sp. PCC7120. This study reveals that butachlor is not directly involved in hampering the nitrogen fixing ability of Anabaena sp. PCC7120 but by arresting the excision ability of XisA protein necessary for the functioning of nif gene and nitrogen fixation. 23817754 Preliminary Results Suggest Tranexamic Acid is Safe and Effective in Arthroplasty Patients with Severe Comorbidities. Tranexamic acid (TXA) reduces blood loss and transfusion after total joint arthroplasty (TJA) but concerns remain that patients with severe medical comorbidities might be at increased risk for thromboembolic complications. Among patients undergoing primary TJA with severe systemic medical disease, (1) was TXA associated with increased symptomatic thromboembolic events; (2) was TXA associated with decreased blood transfusion rates; and (3) were there differences in symptomatic thromboembolism or transfusions in the subset of patients with a history of, or risk factors for; thromboembolic disease? We performed a retrospective review of 1131 primary TJAs in 1002 patients with American Society of Anesthesiologists score III or IV. Of these, 402 had at least one of seven risk factors for thromboembolic events and were designated as high risk; 240 of those patients received TXA. Outcome measures included 30-day postoperative symptomatic thromboembolic events and postoperative transfusion. There were no differences in symptomatic thromboembolic events within 30 days of surgery between patients who received TXA and those who did not (2.5% versus 2.6%, p = 0.97). Fewer patients treated with TXA received transfusions (11% with versus 41% without; p < 0.0001). In high-risk patients, TXA was not associated with an increase in symptomatic thromboembolic events (6.7% with versus 4.3% without; p = 0.27) and was associated with a decrease in transfusion rates (17% with versus 48% without; p = 0.001). Although TXA seemed safe and effective in this database review of patients with severe medical comorbidities, a larger prospective trial is warranted to confirm these results. Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. 23832447 A simple method to evaluate reactivity of acylglucuronides optimized for early stage drug discovery. Drugs containing the carboxylic functional group can be metabolized to form acylglucuronides believed to cause idiosyncratic drug toxicity when the acylglucuronide is unstable. Recent studies have shown that the half-life of an acylglucuronide in phosphate buffer is the best means for classifying acylglucuronides into safe, warning, and withdrawn drugs. However, it is difficult to halt the late stage development of new chemical entities due to the instability of their acylglucuronides. We report an optimized in vitro method for determining the half-lives of acylglucuronides in simple phosphate buffer without the need for authentic standards. The experiment was divided into two incubations. In the first incubation, acylglucuronide was synthesized by human liver microsomes, and in the second incubation, the degradation rate of acylglucuronide in phosphate buffer was determined. The degradation rate constants of acylglucuronides were determined from changes in the LC-MS/MS peak area and the half-lives were calculated. We evaluated the half-lives of 10 drugs: 3 safe drugs (telmisartan, gemfibrozil and flufenamic acid) and 7 withdrawn or warning drugs (zomepirac, diclofenac, furosemide, ibuprofen, S-naproxen, probenecid and tolmetin). The half-lives of the 3 safe drugs were 10.6 hours or longer, whereas the half-lives of the 7 withdrawn or warning drugs were 4.0 hours or shorter. Although authentic acylglucuronide standards were not used, we obtained half-lives of acylglucuronides in phosphate buffer similar to those reported previously. Using this method, the risk of reactivity caused by acylglucuronides can be evaluated in the early stages of drug discovery. 23702522 The use and misuse of prescription stimulants as "cognitive enhancers" by students at one academic health sciences center. Prescription stimulant use as "cognitive enhancers" has been described among undergraduate college students. However, the use of prescription stimulants among future health care professionals is not well characterized. This study was designed to determine the prevalence of prescription stimulant misuse among students at an academic health sciences center. Electronic surveys were e-mailed to 621 medical, pharmacy, and respiratory therapy students at East Tennessee State University for four consecutive weeks in fall 2011. Completing the survey was voluntary and anonymous. Surveys asked about reasons for, frequency of, and side effects of nonprescription misuse of prescription stimulants. Given the sensitive material, an opportunity to win one of ten $50 gift cards was used as an incentive. Three hundred seventy-two (59.9%) students completed the survey from three disciplines (47.6% medical, 70.5% pharmacy, and 57.6% respiratory therapy). Overall, 11.3% of responders admitted to misusing prescription stimulants. There was more misuse by respiratory therapy students, although this was not statistically significant (10.9% medicine, 9.7% pharmacy, 26.3% respiratory therapy; P = .087). Reasons for prescription stimulant misuse included to enhance alertness/energy (65.9%), to improve academic performance (56.7%), to experiment (18.2%), and to use recreationally/get high (4.5%). Prescription stimulant misuse was prevalent among participating students, but further research is needed to describe prevalence among future health care workers more generally. The implications and consequences of such misuse require further study across professions with emphasis on investigating issues of academic dishonesty (e.g., "cognitive enhancement"), educational quality, and patient safety or health care quality. 23947621 ROCK InhibitorPrevents Bleomycin-Induced Injury in Neonatal RatsIndependent of Effects on LungInflammation. Bleomycin-induced lung injury is characterized in the neonatal rat by inflammation dominated by neutrophils and macrophages, inhibited distal airway and vascular development and pulmonary hypertension, similar to human infants with severe bronchopulmonary dysplasia. Rho-kinase (ROCK) is known to mediate lung injury in adult animals via stimulatory effects on inflammation. We therefore hypothesized that inhibition of ROCK may ameliorate bleomycin-induced lung injury in the neonatal rat. Pups received daily i.p. bleomycin or saline from postnatal days 1-14 with or without Y-27632, a ROCK inhibitor. Treatment with Y-27632 prevented bleomycin-induced pulmonary hypertension, as evidenced by normalized pulmonary vascular resistance, decreased right-ventricular hypertrophy and attenuated remodeling of pulmonary resistance arteries. Bleomycin-induced changes in distal lung architecture, including septal thinning, inhibited alveolarization and decreased numbers of peripheral arteries and capillaries, were partially or completely normalized by Y-27632. Treatment with Y-27632 or a CXCR2 antagonist, SB265610, also abrogated tissue neutrophil influx, while having no effect on macrophages. However, treatment with SB265610 did not prevent bleomycin-induced lung injury. Lung content of angiostatic thrombospondin-1 (TSP1) was increased significantly in the lungs of bleomycin-exposed animals and was completely attenuated by treatment with Y-27632. Thrombin-stimulated TSP1 production by primary cultured rat pulmonary artery endothelial cells was also attenuated by Y-27632. Taken together, our findings suggest a preventive effect of Y-27632 on bleomycin-mediated injury by a mechanism unrelated to inflammatory cells. Our data suggests that improvements in lung morphology may have been related to indirect stimulatory effects on angiogenesis via down-regulation of TSP1. 23768326 Coumarins of Matricaria chamomilla L.: aglycones and glycosides. The identity and quantity of coumarin-like compounds in leaves and anthodia of Matricaria chamomilla L. were studied by LC-DAD and NMR. So far, two monosubstituted coumarins, herniarin and umbelliferone, and two herniarin precursors were identified therein. In this paper, two other coumarin glycosides and one aglycone were confirmed. Skimmin (umbelliferone-7-O-β-d-glucoside), daphnin (daphnetin-7-O-β-d-glucoside) and daphnetin (7,8-dihydroxycoumarin) were found for the first time in diploid and tetraploid leaves and anthodia of M. chamomilla L. Daphnetin is known as a strong sensitizer, so this compound and its glycosidic derivative can contribute to the allergic potential of chamomile. Commercial chamomile preparations were tested for their presence. 23934067 Sweeping lymph node micrometastases off their feet: an engineered model to evaluate natural killer cell mediated therapeutic intervention of circulating tumor cells that disseminate to the lymph nodes. Approximately 90% of cancer related deaths are due to metastasis. Cells from the primary tumor can metastasize through either the vascular or lymphatic circulation. Cancer cells in circulation are called circulating tumor cells (CTCs) and it has been shown that bone marrow is a niche for homing of blood borne CTCs from several epithelial tumors. Cancer cells found in bone marrow are termed disseminated tumor cells (DTCs). Likewise, CTCs in the lymphatic circulation are more often seeded in the sentinel lymph nodes (SLN) that drain the tumor. Micrometastases (<2 mm) occur after the arrest and implantation of DTCs in lymph nodes over time. This paper presents a cell culture platform termed microbubbles formed in polydimethylsiloxane (PDMS) from a microfabricated silicon wafer for mimicking lymph node micrometastases. We cultured lymph node seeking cancer cells in microbubbles to evaluate the efficacy of natural killer (NK) mediated therapy for targeting lymph node micrometastasis. The microbubble platform consists of an array of microcavities that provides a unique microenvironment for mimicking the deep cortical unit of the lymph nodes. We show that cancer cells cultured in microbubbles with therapeutic NK cells undergo apoptosis after 24 h in culture. Since lymph node metastases are prevalent across several types of cancer, this platform may be useful for developing improved cancer therapies for targeting lymph node micrometastases. 23561112 Changes in urocanic acid, histamine, putrescine and cadaverine levels in Indian mackerel (Rastrelliger kanagurta) during storage at different temperatures. Histamine, putrescine cadaverine and cis-urocanic acid (UCA) have all been implicated or suggested in scombroid fish poisoning. However, there is little information on UCA especially during storage. Changes in their contents during storage of whole Indian mackerel at 0, 3±1, 10±1 for up to 15days and 23±2°C for up to 2days were monitored. Fresh muscles contained 14.83mg/kg trans-UCA, 2.23mg/kg cis-UCA and 1.86mg/kg cadaverine. Histamine and putrescine were not detected. After 15days at 0 and 3°C, trans-UCA content increased to 52.83 and 189.51mg/kg, respectively, and decreased to <2mg/kg at the other two temperatures. Storage at 10°C also resulted in an increase in trans-UCA after 3days, only to decrease after 6days. The concentration of cis-UCA increased nearly 13-fold after 15days at 0 and 3°C, decreased at 10°C and remained unchanged at 23°C. Histamine, putrescine and cadaverine levels increased significantly (P value<0.05) at all temperatures especially at 23°C. 23959081 Altered topological patterns of large-scale brain functional networks during passive hyperthermia. In this study, we simulated environmental heat exposure to 18 participants, and obtained functional magnetic resonance image (fMRI) data during resting state. Brain functional networks were constructed over a wide range of sparsity threshold according to a prior atlas dividing the whole cerebrum into 90 regions. Results of graph theoretical approaches showed that although brain networks in both normal and hyperthermia conditions exhibited economical small-world property, significant alterations in both global and nodal network metrics were demonstrated during hyperthermia. Specifically, a lower clustering coefficient, maintained shortest path length, a lower small-worldness, a lower mean local efficiency were found, indicating a tendency shift to a randomized network. Additionally, significant alterations in nodal efficiency were found in bilateral gyrus rectus, bilateral parahippocampal gyrus, bilateral insula, right caudate nucleus, bilateral putamen, left temporal pole of middle temporal gyrus, right inferior temporal gyrus. In consideration of physiological system changes, we found that the alterations of normalized clustering coefficient, small-worldness, mean normalized local efficiency were significantly correlated with the rectal temperature alteration, but failed to obtain significant correlations with the weight loss. More importantly, behavioral attention network test (ANT) after MRI scanning showed that the ANT effects were altered and correlated with the alterations of some global metrics (normalized shortest path length and normalized global efficiency) and prefrontal nodal efficiency (right dorsolateral superior frontal gyrus, right middle frontal gyrus and left orbital inferior frontal gyrus), implying behavioral deficits in executive control effects and maintained alerting and orienting effects during passive hyperthermia. The present study provided the first evidence for human brain functional disorder during passive hyperthermia according to graph theoretical analysis using resting-state fMRI. 23956307 You only notice them if you understand them: Geriatric syndromes. No abstract available. 23219002 Parametrisation of the free energy of ATP binding to wild-type and mutant Kir6.2 potassium channels. ATP-sensitive K(+) (K(ATP)) channels, comprised of pore-forming Kir6.x and regulatory SURx subunits, play important roles in many cellular functions; because of their sensitivity to inhibition by intracellular ATP, K(ATP) channels provide a link between cell metabolism and membrane electrical activity. We constructed structural homology models of Kir6.2 and a series of Kir6.2 channels carrying mutations within the putative ATP-binding site. Computational docking was carried out to determine the conformation of ATP in its binding site. The Linear Interaction Energy (LIE) method was used to estimate the free-energy of ATP binding to wild-type and mutant Kir6.2 channels. Comparisons of the theoretical binding free energies for ATP with those determined from mutational experiments enabled the identification of the most probable conformation of ATP bound to the Kir6.2 channel. A set of LIE parameters was defined that may enable prediction of the effects of additional Kir6.2 mutations within the ATP binding site on the affinity for ATP. 23702711 Three-dimensional co-cultures of human endothelial cells and embryonic stem cell-derived pericytes inside a microfluidic device. Organs-on-chips are microengineered in vitro tissue structures that can be used as platforms for physiological and pathological research. They provide tissue-like microenvironments in which different cell types can be co-cultured in a controlled manner to create synthetic organ mimics. Blood vessels are an integral part of all tissues in the human body. Development of vascular structures is therefore an important research topic for advancing the field of organs-on-chips since generated tissues will require a blood or nutrient supply. Here, we have engineered three-dimensional constructs of vascular tissue inside microchannels by injecting a mixture of human umbilical vein endothelial cells, human embryonic stem cell-derived pericytes (the precursors of vascular smooth muscle cells) and rat tail collagen I into a polydimethylsiloxane microfluidic channel with dimensions 500 μm × 120 μm × 1 cm (w × h × l). Over the course of 12 h, the cells organized themselves into a single long tube resembling a blood vessel that followed the contours of the channel. Detailed examination of tube morphology by confocal microscopy revealed a mature endothelial monolayer with complete PECAM-1 staining at cell-cell contacts and pericytes incorporated inside the tubular structures. We also demonstrated that tube formation was disrupted in the presence of a neutralizing antibody against transforming growth factor-beta (TGF-β). The TGF-β signaling pathway is essential for normal vascular development; deletion of any of its components in mouse development results in defective vasculogenesis and angiogenesis and mutations in humans have been linked to multiple vascular genetic diseases. In the engineered microvessels, inhibition of TGF-β signaling resulted in tubes with smaller diameters and higher tortuosity, highly reminiscent of the abnormal vessels observed in patients with one particular vascular disease known as hereditary hemorrhagic telangiectasia (HHT). In summary, we have developed microengineered three-dimensional vascular structures that can be used as a model to test the effects of drugs and study the interaction between different human vascular cell types. In the future, the model may be integrated into larger tissue constructs to advance the development of organs-on-chips. 23561953 Impact of food to microorganism (F/M) ratio and colloidal chemical oxygen demand on nitrification performance of a full-scale membrane bioreactor treating thin film transistor liquid crystal display wastewater. This study investigated impact of food to microorganism (F/M) ratio and colloidal chemical oxygen demand (COD) on nitrification performance in one full-scale membrane bioreactor (MBR) treating monoethanolamine (MEA)/dimethyl sulfoxide (DMSO)-containing thin film transistor liquid crystal display (TFT-LCD) wastewater. Poor nitrification was observed under high organic loading and high colloidal COD conditions, suggesting that high F/M ratio and colloidal COD situations should be avoided to minimize their negative impacts on nitrification. According to the nonmetric multidimensional scaling (NMS) statistical analyses on terminal restriction fragment length polymorphism (T-RFLP) results of ammonia monooxygenase (amoA) gene, the occurrence of Nitrosomonas oligotropha-like ammonia oxidizing bacteria (AOB) was positively related to successful nitrification in the MBR systems, while Nitrosomonas europaea-like AOB was positively linked to nitrification rate, which can be attributed to the high influent total nitrogen condition. Furthermore, Nitrobacter- and Nitrospira-like nitrite oxidizing bacteria (NOB) were both abundant in the MBR systems, but the continuously low nitrite environment is likely to promote the growth of Nitrospira-like NOB. 23884852 Management of injuries of the eye and its adnexa. The face plays the main role in interpersonal communication and in aesthetic perception. What is more, on account of the complex eyelid anatomy required to ensure the functioning of the eye, the treatment of periocular injuries requires a profound knowledge of anatomy and plastic reconstructive surgery, even if a loss of soft tissue is involved. Many methods for the reconstruction of eyelid defects have been described in the current literature. These methods must be guided by the site and extent of the defect on the one hand and by cosmetic requirements on the other to produce best results in terms of form and function. The treatment of injuries in the area of the eyelid involves some peculiarities that must be considered. The management of large defects in particular requires the cooperation of all head surgery disciplines. 23967328 Association Study of Val66Met Polymorphism in Brain-Derived Neurotrophic Factor Gene with Clozapine-Induced Metabolic Syndrome: Preliminary Results. The prevalence of the metabolic syndrome (MetS) is higher among patients receiving atypical antipsychotics (AAPs) treatment, and even among AAPs, treatment with clozapine has been shown to be associated with a higher long-term incidence rate of MetS. Likewise, brain-derived neurotrophic factor (BDNF) deficiency has been reported to result in metabolic traits, such as increased food intake, hyperphagia and obesity, etc. In this study, we hypothesized that a functional polymorphism (Val66Met) in the BDNF gene may confer susceptibility to clozapine-induced MetS, potentially in a sex-specific manner, since an interaction between Val66Met polymorphism and sex was observed in our previous studies. A total of 199 schizophrenia patients being treated with clozapine were divided into two groups, MetS and non-MetS, based on the diagnostic criteria of the National Cholesterol Education Program's Adult Treatment Panel III. We genotyped the Val66Met polymorphism, and measured the serum levels of fasting glucose (GLU), triglyceride (TG) and high density lipoprotein cholesterol (HDL). There was a trend indicating a significant association between the homozygous Met/Met genotype and MetS in male patients (OR = 2.39; 95% CI: 1.05-5.41; p = 0.039; corrected p = 0.078). Among the six risk factors listed in the ATPIII criteria, we found a significant association between fasting GLU levels and Val66Met polymorphism in males (p = 0.005; corrected p = 0.03), but not in females (p = 0.65). Post-hoc analysis in males revealed that the Met/Met carriers had significant higher levels of fasting GLU than those with Val/Val or Val/Met genotypes (p = 0.007; corrected p = 0.042 and p = 0.002; corrected p = 0.012, respectively). In conclusion, we observed a weak association between the Val66Met polymorphism and clozapine-induced MetS in a sex-specific manner. While preliminary, such findings prompt further, large-scale longitudinal studies to replicate these findings. 23608738 Diagnosis of hepatocellular carcinoma in cirrhotic patients: a proof-of-concept study using serum micro-Raman spectroscopy. Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide. The development of novel diagnostic methods is needed to detect tumours at an early stage when patients are eligible for curative treatments. The purpose of this proof-of-concept study was to determine if micro-Raman spectroscopy applied to the sera of cirrhotic patients may be an alternative method for rapidly discriminating patients with and without HCC. Serum samples were collected from 2 groups of patients: cirrhotic patients with HCC (n = 37) and without HCC (n = 34). Two different approaches were used, dried serum drops and freeze-dried serum, and micro-Raman spectra were acquired in the point-mode with a 785 nm laser excitation in the spectral range of 600-1800 cm(-1). Spectra were quality-tested and pre-processed (smoothing, baseline subtraction, vector normalization). Using principal component analysis, the 2 classes, corresponding to cirrhotic patients with and without HCC, could not be differentiated. In contrast, the support vector machine method using the leave-one-out cross validation procedure was able to correctly classify the two groups of patients with an overall rate of accuracy of 84.5% to 90.2% for dried serum drops and 86% to 91.5% for freeze-dried serum. These results are promising and support the concept that serum micro-Raman spectroscopy may become a useful diagnostic tool to detect biomarkers in the field of cancer, as described here for distinguishing between cirrhotic patients with and without HCC. 23488598 High Aminopeptidase N/CD13 Levels Characterize Human Amniotic Mesenchymal Stem Cells and Drive Their Increased Adipogenic Potential in Obese Women. Maternal obesity is associated to increased fetal risk of obesity and other metabolic diseases. Human amniotic mesenchymal stem cells (hA-MSCs) have not been characterized in obese women. The aim of this study was to isolate and compare hA-MSC immunophenotypes from obese (Ob-) and normal weight control (Co-) women, to identify alterations possibly predisposing the fetus to obesity. We enrolled 16 Ob- and 7 Co-women at delivery (mean/SEM prepregnancy body mass index: 40.3/1.8 and 22.4/1.0 kg/m(2), respectively), and 32 not pregnant women. hA-MSCs were phenotyped by flow cytometry; several maternal and newborn clinical and biochemical parameters were also measured. The expression of membrane antigen CD13 was higher on Ob-hA-MSCs than on Co-hA-MSCs (P=0.005). Also, serum levels of CD13 at delivery were higher in Ob- versus Co-pregnant women and correlated with CD13 antigen expression on Ob-hA-MSCs (r(2)=0.84, P<0.0001). Adipogenesis induction experiments revealed that Ob-hA-MSCs had a higher adipogenic potential than Co-hA-MSCs as witnessed by higher peroxisome proliferator-activated receptor gamma and aP2 mRNA levels (P=0.05 and P=0.05, respectively), at postinduction day 14 associated with increased CD13 mRNA levels from baseline to day 4 postinduction (P<0.05). Adipogenesis was similar in the two sets of hA-MSCs after CD13 silencing, whereas it was increased in Co-hA-MSCs after CD13 overexpression. CD13 expression was high also in Ob-h-MSCs from umbilical cords or visceral adipose tissue of not pregnant women. In conclusion, antigen CD13, by influencing the adipogenic potential of hA-MSCs, could be an in utero risk factor for obesity. Our data strengthen the hypothesis that high levels of serum and MSC CD13 are obesity markers. 23427996 Excitons in conjugated polymers: a tale of two particles. Since the discovery of electroluminescence in the phenyl-based conjugated polymers in 1990, the field of polymer optoelectronics has matured to the extent that presently a wide class of devices have been commercialized. These range from both miniature and wide-area light emitting devices to hybrid photovoltaic devices. Similarly, our understanding of the fundamental processes that determine these optoelectronic properties has also progressed. In particular, owing to insights from both experimental and theoretical investigations, the role of the primary excited states, i.e., excitons, is now considerably clearer. This review discusses these primary excited states and explains how the three key roles of electron-electron interactions, electron-nuclear coupling, and disorder determine their properties. We show that the properties of an exciton are more readily understood by decomposing it into two effective particles. First, a relative particle that describes the size and binding energy of the electron-hole pair. Second, a center-of-mass particle that describes the extent of the delocalization of the electron-hole pair. Disorder and coupling to the normal modes localizes the center-of-mass particle and provides a quantitative definition of chromophores in conjugated polymers, paving the way for a first-principles theory of exciton diffusion in these systems. 23864920 Comparative approach to non-traumatic acute abdominal pain between elderly and non-elderly in the emergency department: a study in rural Greece. Acute abdominal pain is one of the most common symptoms that emergency department physicians encounter during their practice. The difficult task of early diagnosis and management of abdominal pain becomes more complicated when it involves elderly patients. The aim of this study was to evaluate the presence of age based differences regarding the management of acute non-traumatic abdominal pain in the Emergency Department. We retrospectively analyzed the medical records of 933 patients with acute non-traumatic abdominal pain in the emergency department of a regional hospital during one year period. There were no differences between native and foreign elder patients regarding the use of imaging studies and discharge status. Although no differences were detected regarding the clinical presentation and management within the Emergency Department, elder patients with abdominal pain had a higher likelihood of being admitted for further hospitalization and were more often submitted to diagnostic examinations. The elder group had a trend towards lower number of cases of non-specific abdominal pain in comparison with the non-elders. Between male and female elders no statistically significant differences were detected. A thorough work-up is essential for all patients. The clinician should always be alerted, since elderly patients may require more tests and they should have a low threshold for hospital admission. 23852586 Polymorphisms in DNA repair genes, recreational physical activity and breast cancer risk. The mechanisms driving the inverse association between recreational physical activity (RPA) and breast cancer risk are complex. While exercise is associated with increased reactive oxygen species production it may also improve damage repair systems, particularly those that operate on single-strand breaks including base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR). Of these repair pathways, the role of MMR in breast carcinogenesis is least investigated. Polymorphisms in MMR or other DNA repair gene variants may modify the association between RPA and breast cancer incidence. We investigated the individual and joint effects of variants in three MMR pathway genes (MSH3, MLH1 and MSH2) on breast cancer occurrence using resources from the Long Island Breast Cancer Study Project. We additionally characterized interactions between RPA and genetic polymorphisms in MMR, BER and NER pathways. We found statistically significant multiplicative interactions (p<0.05) between MSH2 and MLH1, as well as between postmenopausal RPA and four variants in DNA repair (XPC-Ala499Val, XPF-Arg415Gln, XPG-Asp1104His and MLH1-lle219Val). Significant risk reductions were observed among highly active women with the common genotype for XPC (OR=0.54; 95% CI, 0.36-0.81) and XPF (OR=0.62; 95% CI, 0.44-0.87), as well as among active women who carried at least one variant allele in XPG (OR=0.46; 95% CI, 0.29-0.77) and MLH1 (OR=0.46; 95% CI, 0.30-0.71). Our data show that women with minor alleles in both MSH2 and MLH1 could be at increased breast cancer risk. RPA may be modified by genes in the DNA repair pathway, and merit further investigation. © 2013 Wiley Periodicals, Inc. 23954270 Production of human antibodies by in vitro immunization using a fusion protein containing the transcriptional transactivator of HIV-1. Antigen-specific activation of human B cells represents a key step for the production of monoclonal antibodies. Several approaches have been developed over the last thirty years in order to improve the process of lymphocyte activation in vitro. In the present study, we investigated whether the transcriptional transactivator (Tat) of human immunodeficiency virus, which possesses numerous biological activities, is able to trigger antibody secretion when incubated with human peripheral blood mononuclear cells. No such effect was observed when using Tat as a free protein. However, we found a significant IgM antibody production when Tat was previously fused to a double domain, called ZZ, derived from protein A of Staphylococcus aureus. The effect was also observed when the fusion protein, called ZZTat101, was incubated with purified B cells, indicating that the phenomenon does not require T-cell help. Antibody secretion was observed in the absence of cytokines that are usually used during in vitro immunization experiments, indicating that ZZTat101 provides the signals required for the initiation of the immune response. Antibody secretion was observed using a ZZTat mutant, containing only the Tat residues 22 to 57, called ZZTat22-57, indicating that this region is sufficient to initiate the immune response. In contrast, the effect was not found with a ZZTat22-57 mutant devoid of the seven Tat cysteines located between residues 22 and 37, demonstrating that these residues play a crucial role in the phenomenon. Our results pave the way to the development of a new in vitro immunization method based on antigens associated with ZZTat. 23835559 Do modern total knee replacements offer better value for money? A health economic analysis. Cost effectiveness is an increasingly important factor in today's healthcare environment, and selection of arthroplasty implant is not exempt from such concerns. Quality adjusted life years (QALYs) are the typical tool for this type of evaluation. Using this methodology, joint arthroplasty has been shown to be cost effective; however, studies directly comparing differing prostheses are lacking. Data was gathered in a single-centre prospective double-blind randomised controlled trial comparing the outcome of modern and traditional knee implants, using the Short Form 6 dimensional (SF-6D) score and quality adjusted life year (QALY) methodology. There was significant improvement in the SF-6D score for both groups at one year (p < 0.0001). The calculated overall life expectancy for the study cohort was 15.1 years, resulting in an overall QALY gain of 2.144 (95 % CI 1.752-2.507). The modern implant group demonstrated a small improvement in SF-6D score compared to the traditional design at one year (0.141 versus 0.143, p = 0.94). This difference resulted in the modern implant costing £298 less per QALY at one year. This study demonstrates that modern implant technology does not influence the cost-effectiveness of TKA using the SF-6D and QALY methodology. This type of analysis however assesses health status, and is not sensitive to joint specific function. Evolutionary design changes in implant technology are thus unlikely to influence QALY analysis following joint replacement, which has important implications for implant procurement. 23955711 Inhibition of p300 impairs Foxp3(+) T regulatory cell function and promotes antitumor immunity. Forkhead box P3 (Foxp3)(+) T regulatory (Treg) cells maintain immune homeostasis and limit autoimmunity but can also curtail host immune responses to various types of tumors. Foxp3(+) Treg cells are therefore considered promising targets to enhance antitumor immunity, and approaches for their therapeutic modulation are being developed. However, although studies showing that experimentally depleting Foxp3(+) Treg cells can enhance antitumor responses provide proof of principle, these studies lack clear translational potential and have various shortcomings. Histone/protein acetyltransferases (HATs) promote chromatin accessibility, gene transcription and the function of multiple transcription factors and nonhistone proteins. We now report that conditional deletion or pharmacologic inhibition of one HAT, p300 (also known as Ep300 or KAT3B), in Foxp3(+) Treg cells increased T cell receptor-induced apoptosis in Treg cells, impaired Treg cell suppressive function and peripheral Treg cell induction, and limited tumor growth in immunocompetent but not in immunodeficient mice. Our data thereby demonstrate that p300 is important for Foxp3(+) Treg cell function and homeostasis in vivo and in vitro, and identify mechanisms by which appropriate small-molecule inhibitors can diminish Treg cell function without overtly impairing T effector cell responses or inducing autoimmunity. Collectively, these data suggest a new approach for cancer immunotherapy. 23868822 Occupational carbon monoxide fatalities in the US from unintentional non-fire related exposures, 1992-2008. To analyze characteristics of, and trends in, work-related carbon monoxide (CO) fatalities in the US. Records of unintentional, non-fire related fatalities from CO exposure were extracted from the Bureau of Labor Statistics' Census of Fatal Occupational Injuries and the Occupational Safety and Health Administration's Integrated Management Information System for years 1992-2008 and analyzed separately. The average number of annual CO fatalities was 22 (standard deviation = 8). Fatality rates were highest among workers aged ≥65, males, Hispanics, winter months, the Midwest, and the Fishing, Hunting, and Trapping industry subsector. Self-employed workers accounted for 28% of all fatalities. Motor vehicles were the most frequent source of fatal CO exposure, followed by heating systems and generators. CO has been the most frequent cause of occupational fatality due to acute inhalation, and has shown no significant decreasing trend since 1992. The high number of fatalities from motor vehicles warrants further investigation. Am. J. Ind. Med. © 2013 Wiley Periodicals, Inc. 23742752 A robust, sensitive assay for genomic uracil determination by LC/MS/MS reveals lower levels than previously reported. Considerable progress has been made in understanding the origins of genomic uracil and its role in genome stability and host defense; however, the main question concerning the basal level of uracil in DNA remains disputed. Results from assays designed to quantify genomic uracil vary by almost three orders of magnitude. To address the issues leading to this inconsistency, we explored possible shortcomings with existing methods and developed a sensitive LC/MS/MS-based method for the absolute quantification of genomic 2'-deoxyuridine (dUrd). To this end, DNA was enzymatically hydrolyzed to 2'-deoxyribonucleosides and dUrd was purified in a preparative HPLC step and analyzed by LC/MS/MS. The standard curve was linear over four orders of magnitude with a quantification limit of 5fmol dUrd. Control samples demonstrated high inter-experimental accuracy (94.3%) and precision (CV 9.7%). An alternative method that employed UNG2 to excise uracil from DNA for LC/MS/MS analysis gave similar results, but the intra-assay variability was significantly greater. We quantified genomic dUrd in Ung(+/+) and Ung(-/-) mouse embryonic fibroblasts and human lymphoblastoid cell lines carrying UNG mutations. DNA-dUrd is 5-fold higher in Ung(-/-) than in Ung(+/+) fibroblasts and 11-fold higher in UNG2 dysfunctional than in UNG2 functional lymphoblastoid cells. We report approximately 400-600 dUrd per human or murine genome in repair-proficient cells, which is lower than results using other methods and suggests that genomic uracil levels may have previously been overestimated. 23318471 Peroxynitrite mediates testosterone-induced vasodilation of microvascular resistance vessels. Our knowledge of how androgens influence the cardiovascular system is far from complete, and this lack of understanding is especially true of how androgens affect resistance vessels. Our aim was to identify the signaling mechanisms stimulated by testosterone (TES) in microvascular arteries and to understand how these mechanisms mediate TES-induced vasodilation. Mesenteric microvessels were isolated from male Sprague-Dawley rats. Tension studies demonstrated a rapid, concentration-dependent, vasodilatory response to TES that did not involve protein synthesis or aromatization to 17β-estradiol. Dichlorofluorescein fluorescence and nitrotyrosine immunoblot experiments indicated that TES stimulated peroxynitrite formation in microvessels, and functional studies demonstrated that TES-induced vasodilation was inhibited by scavenging peroxynitrite. As predicted, TES enhanced the production of both peroxynitrite precursors (i.e., superoxide and nitic oxide), and xanthine oxidase was identified as the likely source of TES-stimulated superoxide production. Functional and biochemical studies indicated that TES signaling involved activity of the phosphoinositide 3 (PI3) kinase-protein kinase B (Akt) cascade initiated by activation of the androgen receptor and culminated in enhanced production of cGMP and microvascular vasodilation. These findings, derived from a variety of analytical and functional approaches, provide evidence for a novel nongenomic signaling mechanism for androgen action in the microvasculature: TES-stimulated vasodilation mediated primarily by peroxynitrite formed from xanthine oxidase-generated superoxide and NO. This response was associated with activation of the PI3 kinase-Akt signaling cascade initiated by activation of the androgen receptor. We propose this mechanism could account for TES-stimulated cGMP production in microvessels and, ultimately, vasodilation. 23828422 Management of prelabour rupture of membranes (PROM) at term. Abstract Over a 20-month period we identified several cases of neonatal pneumonia associated with prelabour rupture of membranes (PROM) at term. PROM complicates 8%-10% of all pregnancies, yet 60% of cases occur at term. Ascending infection is a contributing factor and the incidence of chorioamnionitis in these patients is relatively high, especially with prolonged membrane rupture. The signs and symptoms NICE recommends patients look out for are not always present as the majority of infections are subclinical, yet associated maternal and neonatal morbidity of chorioamnionitis is potentially devastating. A survey of maternity units in the West Midlands reveals significant variance in management of these cases. Given the lack of consensus and clear evidence on optimal management of PROM at term, we believe early detection of developing infections could be enhanced by using a combination of investigations (at presentation, 12 and 24 h), as well as current advice to self-monitor temperature and vaginal loss. 23876578 Long-term Oral Administration of 5α-reductase Inhibitor Attenuates Erectile Function by Inhibiting Autophagy and Promoting Apoptosis of Smooth Muscle Cells in Corpus Cavernosum of Aged Rats. To investigate the effects and mechanisms of long-term treatment of 5α-reductase inhibitors (5ARIs) on erectile organ structure and function in aged rats. Thirty 16-month-old male rats were assigned to 2 groups: untreated or treated with 5ARIs. After 16 weeks, the erectile function was measured after electrical stimulation of the cavernous nerve. The weights and histopathologic features of the corpus cavernosum were examined. The levels of autophagy, apoptosis, and protein expression were also recorded. In the 5ARI-treatment group, the plasma and intraprostatic dihydrotestosterone concentration was lowered by 52.1% and 57.3%, respectively, and the weight of the corpus cavernosum and prostate had decreased by 22.4% and 35.6%, respectively. The in vivo erectile response to electrical stimulation of the cavernous nerve had decreased significantly in the 5ARI-treatment group (P <.001). Masson's staining, immunohistochemistry, and Western blot all demonstrated decreased smooth muscle and increased collagen deposition and decreased endothelial nitric oxide synthase and LC3-II protein expression in the corpus cavernosum of the 5ARI-treatment group. Using transmission electron microscopy and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling, decreased autophagy, aggravated ultrastructural injury of mitochondria, and increased apoptosis were observed in the cavernous smooth muscle cells from the rats in the 5ARI-treatment group. Long-term 5ARI treatment did attenuate the erectile function of aged rats. The mechanisms might have been the decreased rate of autophagy and an increased rate of apoptosis in the cavernous smooth muscle cells, suggesting a new role for androgen in maintaining the structural and functional integrity of the erectile organ. Additional studies are necessary to demonstrate the mechanisms of dihydrotestosterone in regulating the autophagy and apoptosis of the cavernous smooth muscle cells. 23522793 Mouse DNA polymerase kappa has a functional role in the repair of DNA strand breaks. The Y-family of DNA polymerases support of translesion DNA synthesis (TLS) associated with stalled DNA replication by DNA damage. Recently, a number of studies suggest that some specialized TLS polymerases also support other aspects of DNA metabolism beyond TLS in vivo. Here we show that mouse polymerase kappa (Polκ) could accumulate at laser-induced sites of damage in vivo resembling polymerases eta and iota. The recruitment was mediated through Polκ C-terminus which contains the PCNA-interacting peptide, ubiquitin zinc finger motif 2 and nuclear localization signal. Interestingly, this recruitment was significantly reduced in MSH2-deficient LoVo cells and Rad18-depleted cells. We further observed that Polκ-deficient mouse embryo fibroblasts were abnormally sensitive to H2O2 treatment and displayed defects in both single-strand break repair and double-strand break repair. We speculate that Polκ may have an important role in strand break repair following oxidative stress in vivo. 23161747 Large area resist-free soft lithographic patterning of graphene. Large area low-cost patterning is a challenging problem in graphene research. A resist-free, single-step, large area and cost effective soft lithographic patterning strategy is presented for graphene. The technique is applicable on any arbitrary substrate that needs to be covered with a graphene film and provides a viable route to large-area patterning of graphene for device applications. 23250628 Investigation of N-acyl homoserine lactone (AHL) molecule production in Gram-negative bacteria isolated from cooling tower water and biofilm samples. In this study, 99 Gram-negative rod bacteria were isolated from cooling tower water, and biofilm samples were examined for cell-to-cell signaling systems, N-acyl homoserine lactone (AHL) signal molecule types, and biofilm formation capacity. Four of 39 (10 %) strains isolated from water samples and 14 of 60 (23 %) strains isolated from biofilm samples were found to be producing a variety of AHL signal molecules. It was determined that the AHL signal molecule production ability and the biofilm formation capacity of sessile bacteria is higher than planktonic bacteria, and there was a statistically significant difference between the AHL signal molecule production of these two groups (p < 0.05). In addition, it was found that bacteria belonging to the same species isolated from cooling tower water and biofilm samples produced different types of AHL signal molecules and that there were different types of AHL signal molecules in an AHL extract of bacteria. In the present study, it was observed that different isolates of the same strains did not produce the same AHLs or did not produce AHL molecules, and bacteria known as AHL producers did not produce AHL. These findings suggest that detection of signal molecules in bacteria isolated from cooling towers may contribute to prevention of biofilm formation, elimination of communication among bacteria in water systems, and blockage of quorum-sensing controlled virulence of these bacteria. 23790298 A matrix-assisted laser desorption/ionization tandem mass spectrometry method for direct screening of small molecule mixtures against an aminoglycoside kinase. Aminoglycoside phosphotransferase 3'IIIa (APH3'IIIa) is a bacterial enzyme involved in antibiotic resistance through phosphorylation of aminoglycosides, which can potentially be overcome by co-administration of an APH3'IIIa inhibitor with the antibiotic. Current assay methods for discovery of APH3'IIIa inhibitors suffer from low specificity and high false positive/negative hit rates. Here, we describe a method for screening APH3'IIIa inhibitors based on direct detection of kanamycin A phosphorylation using MALDI-MS/MS, which is more rapid than conventional assays and does not require secondary assays or sample cleanup. The MALDI-MS/MS assay operates at an ionic strength of 45 mM and co-factors can be utilized at near-physiological levels for optimal enzyme activity. Detection via MALDI-MS/MS allowed for improved reproducibility when compared to ESI-MS/MS. Furthermore, the use of MS/MS provided better signal-to-noise ratios relative to MS alone on the MALDI instrument. The assay was validated via generation of Z'-factors, with values of 0.78 and 0.56 in the absence and presence of 0.2% DMSO, respectively. The assay was used to screen a kinase directed library of >200 compounds, assayed as 21 mixtures of 10 compounds each. Five novel synthetic inhibitors were identified following mixture deconvolution. Inhibition constants were obtained for the aforementioned inhibitors using the MALDI-MS/MS assay, revealing several low to mid micromolar "hits", and highlighting the quantitative nature of the assay. 23880109 Sensitive competitive immunoassay of multiple mycotoxins with non-fouling antigen microarray. Various mycotoxins with strong carcinogenesis and toxicity are fatal threats in food safety, and require highly sensitive and high-throughput detections greatly. Herein a fluorescent competitive immunoassay microarray based on a non-fouling polymer brush, poly[(ethylene glycol) methacrylate-co-glycidyl methacrylate] (POEGMA-co-GMA) is explored to sensitively detect multiple mycotoxins with aflatoxin B1 (AFB1), ochratoxin A (OTA) and zearalenone (ZEN) as template targets. Due to uniformly large protein loading and high resistance to nonspecific protein absorption of the POEGMA-co-GMA brush, the optimal microarray exhibits wide dynamic ranges of three orders of magnitudes and low detection limits of 4, 4 and 3pgmL(-1), respectively, which is much better than that obtained with an epoxy-functionalized antigen microarray, and is comparable or even better than the conventional ELISA method. This work offers a powerful high-throughput tool to fast screening of toxins in food quality and environmental monitoring. 23817865 Effects of a comprehensive intervention program, including hot bathing, on physical function in community-dwelling healthy older adults: a pilot randomized controlled trial. To study the effects of a comprehensive intervention program comprising exercise, diet, and hot bathing in community-dwelling older adults by using a randomized controlled trial. The program included 61 community-dwelling healthy older adults (mean [SD] age, 69.9 [5.3] years) who were using a hot bath facility. The participants were randomly assigned to four groups as follows: an exercise, diet, and hot bath intervention group (A); an exercise and diet intervention group (B); a hot bath intervention group (C); and a control group (D). Individuals in groups A and B participated in a comprehensive intervention program (including exercise and diet classes) twice a week for 3 months, and those in groups A and C took hot baths. After 3 months, the participants in groups A and B showed a significantly greater improvement in their timed up and go test and stepping test scores than the participants in groups C and D. However, the participants in groups A and C did not show any dependent or independent effects of hot bathing. Three months after the intervention, a follow-up assessment indicated that the group A participants maintained the effect of the intervention and showed improved lower extremity function and health-related quality of life. The present study suggests that a comprehensive intervention program involving hot bathing may improve lower extremity function and that its effects can be maintained even in healthy older adults. However, the dependent or independent effects of hot bathing may not be expected for healthy older adults. 23706782 The use of femto-second lasers to trigger powerful explosions of gold nanorods to destroy cancer cells. Gold nanorods (AuNRs) with an aspect ratio of 3-4 exhibit large cross sections for single and multi photon light absorption processes in the near infrared region due to surface plasmon resonances. 800 nm laser pulses with the 150 fsec pulse duration (fs laser) can trigger explosions of AuNRs. The fs laser pulses at 20 W/mm(2) equivalent continuous wave (cw) power density blasted AuNRs in QGY human carcinoma cells as confirmed using transmission electron microscopy, while a cw laser at the same power density and dose did not. Cell survival studies further demonstrated that the cw laser at a dose of 15 J/mm(2) resulted in the death of 15% of AuNRs-loaded cells, probably due to a photothermal effect, while the fs laser at only 1.5 J/mm(2) killed more than 90% of AuNRs-loaded cells, indicating that the fs laser-triggered explosions of intracellular AuNRs are powerful enough to instantaneously kill tumour cells. 23910598 Virus-host interaction in feline immunodeficiency virus (FIV) infection. Feline immunodeficiency virus (FIV) infection has been the focus of several studies because this virus exhibits genetic and pathogenic characteristics that are similar to those of the human immunodeficiency virus (HIV). FIV causes acquired immunodeficiency syndrome (AIDS) in cats, nevertheless, a large fraction of infected cats remain asymptomatic throughout life despite of persistent chronic infection. This slow disease progression may be due to the presence of factors that are involved in the natural resistance to infection and the immune response that is mounted by the animals, as well as due to the adaptation of the virus to the host. Therefore, the study of virus-host interaction is essential to the understanding of the different patterns of disease course and the virus persistence in the host, and to help with the development of effective vaccines and perhaps the cure of FIV and HIV infections. 23541312 Diabetes and osteoporosis: Action of gastrointestinal hormones on the bone. A 62-year-old woman consulted for evaluation of treatment for her type 2 diabetes diagnosed four years ago. He had been received treatment with metformin 850mg twice, with no chronic associated complications. She had hypertension and dyslipidemia. She was being treated with candesartan/hydrochlorothiazide 32/12.5mg and atorvastatin 40mg. Her weight was 92kg and height 162cm (BMI, 35.1kg/m(2)). The last analysis showed fasting glucose 168mg/dl and glycated hemoglobin 7.5%, Microalbuminuria was negative. Blood pressure and lipid profile were within the therapeutic range. Two years ago she suffered a nontraumatic Colle's fracture in her left arm for which she was taking a daily calcium and vitamin D supplement and weekly alendronate. In summary, this is an obese female patient with type 2 diabetes mellitus and inadequate metabolic control, She also has a history of fragility fracture. How should this patient be evaluated and treated? 23899023 The effect of a biphasic injectable bone substitute on the interface strength in a rabbit knee prosthesis model. In joint prosthetic surgery, various methods are used to provide implant stability. We used an injectable bone substitute, composed of calcium sulfate/hydroxyapatite, as bone defect filler to stabilize a tibia prosthesis in an experimental rabbit model. The aim of the study was to investigate and compare the stability of prosthetic fixation with and without the use of an injectable bone substitute. Sixteen rabbits were used and the tibia prostheses were implanted bilaterally, one side with the prosthesis alone and the other side with the prosthesis and calcium sulfate/hydroxyapatite (Cerament™). The rabbits were randomly divided into two groups and euthanized after 6 and 12 weeks, respectively. The prosthesis was extracted measuring the pull-out force in an Instron tester, and the bone surrounding the former prosthesis site was analyzed by histology, histomorphometry, and micro-computed tomography. At 6 weeks no difference in maximum pull-out force was found between the prostheses fixed with or without Cerament™. At 12 weeks the maximum pull-out force for the prostheses with Cerament™ was significantly higher than that for the prostheses without Cerament™ (p = 0.04). The maximum pull-out force at 12 weeks was significantly higher than that at 6 weeks for the prostheses fixed with Cerament™ (p = 0.03) but not for the prostheses without. We conclude that early prosthesis-bone interface strength is not influenced by a bone substitute. However, during remodeling, the bone substitute might provide improved mechanical support for the prosthesis. The results support further studies of the use of injectable calcium sulfate/hydroxyapatite in fixation of prosthetic joint implants. 23898809 Forensic Identification of Blood in the Presence of Contaminations Using Raman Microspectroscopy Coupled with Advanced Statistics: Effect of Sand, Dust, and Soil. Body fluid traces recovered at crime scenes are among the most common and important types of forensic evidence. However, the ability to characterize a biological stain at a crime scene nondestructively has not yet been demonstrated. Here, we expand the Raman spectroscopic approach for the identification of dry traces of pure body fluids to address the problem of heterogeneous contamination, which can impair the performance of conventional methods. The concept of multidimensional Raman signatures was utilized for the identification of blood in dry traces contaminated with sand, dust, and soil. Multiple Raman spectra were acquired from the samples via automatic scanning, and the contribution of blood was evaluated through the fitting quality using spectroscopic signature components. The spatial mapping technique allowed for detection of "hot spots" dominated by blood contribution. The proposed method has great potential for blood identification in highly contaminated samples. 23750535 Isolation of Pluripotent Neural Crest-Derived Stem Cells from Adult Human Tissues by Connexin-43 Enrichment. Identification and isolation of pluripotent stem cells in adult tissues represent an important advancement in the fields of stem cell biology and regenerative medicine. For several years, research has been performed on the identification of biomarkers that can isolate stem cells residing in neural crest (NC)-derived adult tissues. The NC is considered a good model in stem cell biology as cells from it migrate extensively and contribute to the formation of diverse tissues in the body during organogenesis. Migration of these cells is modulated, in part, by gap junction communication among the cell sheets. Here we present a study in which, selection of connexin 43 (Cx43) expressing cells from human adult periodontal ligament yields a novel pluripotent stem cell population. Cx43(+) periodontal ligament stem cells express pluripotency-associated transcription factors OCT4, Nanog, and Sox2, as well as NC-specific markers Sox10, p75, and Nestin. When injected in vivo into an immunodeficient mouse model, these cells were capable of generating teratomas with tissues from the three embryological germ layers: endoderm, mesoderm, and ectoderm. Furthermore, the cells formed mature structures of tissues normally arising from the NC during embryogenesis such as eccrine sweat glands of the human skin, muscle, neuronal tissues, cartilage, and bone. Immunohistochemical analysis confirmed the human origin of the neoplastic cells as well as the ectodermal and endodermal nature of some of the structures found in the tumors. These results suggest that Cx43 may be used as a biomarker to select and isolate the remnant NC pluripotent stem cells from adult human tissues arising from this embryological structure. The isolation of these cells through routine medical procedures such as wisdom teeth extraction further enhances their applicability to the regenerative medicine field. 23446959 Reduction in range of cervical motion on serial long-term follow-up in patients undergoing oblique corpectomy for cervical spondylotic myelopathy. To determine whether motion preservation following oblique cervical corpectomy (OCC) for cervical spondylotic myelopathy (CSM) persists with serial follow-up. We included 28 patients with preoperative and at least two serial follow-up neutral and dynamic cervical spine radiographs who underwent OCC for CSM. Patients with an ossified posterior longitudinal ligament (OPLL) were excluded. Changes in sagittal curvature, segmental and whole spine range of motion (ROM) were measured. Nathan's system graded anterior osteophyte formation. Neurological function was measured by Nurick's grade and modified Japanese Orthopedic Association (JOA) scores. The majority (23 patients) had a single or 2-level corpectomy. The average duration of follow-up was 45 months. The Nurick's grade and the JOA scores showed statistically significant improvements after surgery (p < 0.001). 17% of patients with preoperative lordotic spines had a loss of lordosis at last follow-up, but with no clinical worsening. 77% of the whole spine ROM and 62% of segmental ROM was preserved at last follow-up. The whole spine and segmental ROM decreased by 11.2° and 10.9°, respectively (p ≤ 0.001). Patients with a greater range of segmental movement preoperatively had a statistically greater range of movement at follow-up. The analysis of serial radiographs indicated that the range of movement of the whole spine and the range of movement at the segmental spine levels significantly reduced during the follow-up period. Nathan's grade showed increase in osteophytosis in more than two-thirds of the patients (p ≤ 0.01). The whole spine range of movement at follow-up significantly correlated with Nathan's grade. Although the OCC preserves segmental and whole spine ROM, serial measurements show a progressive decrease in ROM albeit without clinical worsening. The reduction in this ROM is probably related to degenerative ossification of spinal ligaments. 23666069 Pluri-energy analysis of livestock systems--a comparison of dairy systems in different territories. This paper introduces a generic assessment method called pluri-energy analysis. It aims to assess the types of energy used in agricultural systems and their conversion efficiencies. Four types of energy are considered: fossil energy, gross energy contained in the biomass, energy from human and animal labor and solar energy. The method was applied to compare smallholder low-input dairy-production systems, which are common in developing countries, to the high-input systems encountered in OECD countries. The pluri-energy method is useful for analyzing the functioning of agricultural systems by highlighting their modes of energy management. Since most dairy systems in South Mali (SM) are low-input systems, they are primarily based on solar and labor energy types and do not require substantial fossil-energy inputs to produce milk. Farms in Poitou-Charentes (PC) and Bretagne (BR) show intermediate values of fossil-energy use for milk production, similar to that found in the literature for typical European systems. However, fossil-energy use for milk production is higher on PC than BR farms because of a higher proportion of maize silage in the forage area; grazing pastures are more common on BR farms. Farms on Reunion Island (RI) require a relatively large amount of fossil energy to produce milk, mainly because the island context limits the amount of arable land. Consequently, milk production is based on large imports of concentrated feed with a high fossil-energy cost. The method also enables assessment of fossil-energy-use efficiency in order to increase the performance of biological processes in agricultural systems. Comparing the low-input systems represented by SM to the high-input systems represented by RI, PC and BR, an increase in solar-energy conversion, and thus land productivity, was observed due to intensification via increased fossil-energy use. Conversely, though fossil-energy use at the herd level increased milk productivity, its effect on gross-energy conversion by the herd was less evident. Partitioning the total on-farm gross energy produced among animal co-products (milk, meat and manure) highlights the major functions of SM herds, which are managed to produce organic crop fertilizers. 23567798 Fibronectin conformation regulates the proangiogenic capability of tumor-associated adipogenic stromal cells. Changes in fibronectin (Fn) matrix remodeling contribute to mammary tumor angiogenesis and are related to altered behavior of adipogenic stromal cells; yet, the underlying mechanisms remain unclear due in part to a lack of reductionist model systems that allow the inherent complexity of cell-derived extracellular matrices (ECMs) to be deciphered. In particular, breast cancer-associated adipogenic stromal cells not only enhance the composition, quantity, and rigidity of deposited Fn, but also partially unfold these matrices. However, the specific effect of Fn conformation on tumor angiogenesis is undefined. Decellularized matrices and a conducting polymer device consisting of poly(3,4-ethylenedioxythiophene) doped with poly(styrenesulfonate) (PEDOT:PSS) were used to examine the effect of Fn conformation on the behavior of 3T3-L1 preadipocytes. Changes in cell adhesion and proangiogenic capability were tested via cell counting and by quantification of vascular endothelial growth factor (VEGF) secretion, respectively. Integrin-blocking antibodies were utilized to examine varied integrin specificity as a potential mechanism. Our findings suggest that tumor-associated partial unfolding of Fn decreases adhesion while enhancing VEGF secretion by breast cancer-associated adipogenic precursor cells, and that altered integrin specificity may underlie these changes. These results not only have important implications for our understanding of tumorigenesis, but also enhance knowledge of cell-ECM interactions that may be harnessed for other applications including advanced tissue engineering approaches. This article is part of a Special Issue entitled Organic Bioelectronics - Novel Applications in Biomedicine. 23795957 Statistical regression model of standard and new laboratory markers and its usefulness in prediction of preeclampsia. Abstract Objective: This study was undertaken to investigate the usefulness of angiogenic markers and standard laboratory parameters measurement after 20th week of pregnancy for the individual prediction of preeclampsia (PE). Methods: A prospective designed study included 34 patients with PE and a control group of 35 uncomplicated pregnancies. Patients were recruited from 20th until 41st week of pregnancy at the Department of Obstetrics and Gynecology, General Hospital Celje, Slovenia. PlGF (placental growth factor), sFlt-1 (soluble fms-like tyrosine kinase 1), erythrocytes, leukocytes, platelets, hemoglobin, hematocrit, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase, alkaline phosphatase, total bilirubin, urea, creatinine, urate, body mass index, body surface area, parity, and age were evaluated to predict the occurrence of PE based on multivariate logistic regression model. Results: When parameters such as PlGF, sFlt-1, and urates were included into logistic regression model, we correctly classified 85% patients. With additional two models which also contained anthropometric parameters, we correctly classified 88% and 91% patients, respectively. Conclusion: Our results demonstrated that angiogenic markers and urates individually and particularly when used as laboratory test panel have significant prognostic value in the prediction of PE. 23816832 γ-Tocotrienol induced cell cycle arrest and apoptosis via activating the Bax-mediated mitochondrial and AMPK signaling pathways in 3T3-L1 adipocytes. This study aimed to examine the anti-proliferative effects of α-, γ- and δ-tocotrienols (αT3, γT3 and δT3), and α-tocopherol on 3T3-L1 adipocytes. Results showed that compared with other vitamin E analogues, γT3 demonstrated the most potent anti-proliferative effect on 3T3-L1 cells. It significantly caused a reduction in mitochondrial membrane potential (Δψm) and an increase in ROS formation, as well as inducing cell apoptosis and cell cycle arrest at S phase. Further studies showed that it down-regulated Bcl-2 and PPAR-γ expression, suppressed Akt and ERK activation and phosphorylation, and caused cytochrome c release from mitochondria to cytosol, whereas it up-regulated CD95 (APO-1/CD95) and Bax expression, and caused caspase-3 and JNK activation, PARP cleavage and AMPK phosphorylation. Pretreatments with caspase-3 (z-DEVD-fmk) and AMPK (CC) inhibitors significantly suppressed the γT3-induced ROS production and cell death. Caspase-3 inhibitor also efficiently blocked CD95 (APO-1/CD95) and Bax expression, caspase-3 activation and PARP cleavage, whereas antioxidant N-acetyl-l-cysteine, AMPK inhibitor and AMPK siRNA effectively blocked the AMPK phosphorylation. Taken together, these results conclude that the potent anti-proliferative and anti-adipogenic effects of γT3 on 3T3-L1 adipocytes could be through the Bax-mediated mitochondrial and AMPK signaling pathways. 23763908 Evaluation of a 3D serious game for advanced life support retraining. Advanced life support (ALS) knowledge and skills decrease in as little as three months, but only a few ALS providers actually attend retraining courses. We assess the effectiveness of a 3D serious game as a new tool for frequent ALS retraining. We developed a 3D serious game for scenario-based ALS retraining. The serious game, called EMSAVE, was designed to promote self-correction while playing. We organized a retraining course in which 40 ALS providers played two cardiac arrest scenarios with EMSAVE and took a test with 38 multiple-choice questions before and after playing. We administered the same test again 3 months later to evaluate retention. Participants also rated EMSAVE and the overall retraining experience. After using EMSAVE, the number of correct answers per participant increased by 4.8 (95%CI +3.4, +6.2, p<0.001) and all but one participant improved. After 3 months, despite an expected decrease in ALS knowledge and skills (-1.9 correct answers, 95%CI -0.6, -3.3, p<0.01), there was a significant retention benefit (+2.9 correct answers per participant, 95%CI +1.5, +4.2, p<0.001). Moreover, all but one participant regarded EMSAVE as a valuable tool to refresh ALS knowledge and skills, and 85% of participants were also willing to devote 1h/month to retrain with the serious game. A 3D serious game for scenario-based retraining proved effective to retrain in ALS and supported retention of acquired knowledge and skills at 3 months. EMSAVE also positively engaged and motivated participants. 23898053 Efficacy of Cisplatin and lipoplatin™ in combined treatment with radiation of a colorectal tumor in nude mouse. Optimal conditions for efficient concomitant chemoradiation treatment of colorectal cancer with cisplatin still need to be better defined. In addition, intolerance of healthy tissue to cisplatin prevents the full exploitation of its radiosensitizing potential. A liposomal formulation of cisplatin, Lipoplatin™, was proposed to overcome its toxicity. Using an animal model of colorectal cancer, we determined the platinum window, defined by studying the pharmacokinetics and time-dependent intracellular distribution of cisplatin and Lipoplatin™. In nude mice bearing HCT116 human colorectal carcinoma treated with cisplatin or Lipoplatin™, the platinum accumulation in blood, serum, different normal tissues, tumor and different tumor cell compartments was measured by inductively coupled plasma mass spectrometry. Radiation treatment (15 Gy) was given 4, 24, and 48 h after drug administration and was correlated to the amount of platinum-DNA adducts in the cancer cells. The resulting tumor growth delay is reported and correlated to apoptosis analysis. The greatest effects and highest apoptosis were observed when radiation was given at 4 h or 48 h after drug injection. These times correspond to the times of maximal platinum binding to tumor DNA. An enhancement factor (ratio of group treated by combined treatment compared to chemotherapy alone) of 13.00 was obtained with Lipoplatin™, and 4.09 for cisplatin when tumor irradiation was performed 48 h after drug administration. The most efficient combination treatment of radiation with cisplatin or Lipoplatin™ was observed when binding of platinum to DNA was highest. These results improve our understanding over the mechanisms of platinum-induced radiosensitization and should have significant impact on the design of more efficient treatment protocols. 23908256 Treatment of distal radius fractures. The American Academy of Orthopaedic Surgeons has developed Appropriate Use Criteria (AUC) for treating distal radius fractures (DRF). Evidence-based information, in conjunction with the clinical expertise of physicians, was used to develop the criteria to improve patient care and obtain best outcomes while considering the subtleties and distinctions necessary in making clinical decisions. The DRF AUC clinical patient scenarios were derived from patient indications that generally accompany a DRF, as well as from current evidence-based clinical practice guidelines and supporting literature. The 216 indications and 10 treatments were developed by the Writing Panel, a group of clinicians who are specialists in this AUC topic. Next, the Review Panel, a separate group of volunteer physicians, independently reviewed these materials to ensure that they were representative of patient scenarios that clinicians are likely to encounter in daily practice. Finally, the multidisciplinary Voting Panel (made up of specialists and nonspecialists) rated the appropriateness of treatment of each patient scenario using a 9-point scale to designate a treatment as Appropriate (median rating, 7 to 9), May Be Appropriate (median rating, 4 to 6), or Rarely Appropriate (median rating, 1 to 3). 23411338 Pesticide residues in market foods in Shaanxi Province of China in 2010. The aim of this study was to investigate the pesticide residues in market vegetables in Shaanxi Province of China. The concentrations of 33 pesticides were determined by gas chromatography (GC) in 285 samples. Ten organophosphorus pesticides (OPs) were found in concentrations ranging from 0.004 to 0.257 mg/kg. The mean levels of omethoate, phorate, chlorpyrifos, methidathion, ethoprophos in vegetables exceeded the maximum residue limits (MRLs) allowed by the Ministry of Health, of China. Other detectable OP pesticide residues levels were below their MRLs. Dicofol were detectable in green pepper and chives samples. Five pyrethroid pesticides (PYRs) were detectable in vegetable samples respectively. The results provide useful information on the current contamination status of a key agricultural area in China, and point to the need for urgent action to control the excessive use of some chemicals. 23836295 FAM9C plays an anti-apoptotic role through activation of the PI3K/Akt pathway in human hepatocellular carcinoma. The function of FAM9C encoding a testis-exclusively expressed and nuclear-localized protein remains unknown. In the present study, we evaluated the role of FAM9C in human hepatocellular carcinoma. We found that among three FAM9 family members, only FAM9C was frequently upregulated in HCC specimens compared with that in corresponding adjacent non-cancer liver tissues. FAM9C was located in the nucleus of HCC cells, as shown by both western blotting and immumofluorescence assays. Significantly, FAM9C overexpression promoted proliferation, clonogenicity in an anchorage-dependent manner, in vivo tumorigenicity of YY-8103, and Huh-7 cells. In contrast, FAM9C knockdown suppressed proliferation, anchorage-dependent colony formation and in vivo tumorigenicity of QGY-7703, and BEL-7404 cells. However, FAM9C had no significant effects on cell cycle progression when FAM9C was stably overexpressed in Huh-7 cells or knocked down in BEL-7404 cells. Most importantly, FAM9C regulated activation of Akt and UV-induced apoptosis in HCC cells. FAM9C overexpression increased the phosphorylation levels of Akt and anti-apoptotic ability of Huh-7 cells, whereas endogenous FAM9C knockdown reduced the phosphorylated levels of Akt and anti-apoptotic ability of BEL-7404 cells. Furthermore, the anti-apoptotic function of FAM9C could be prevented when the PI3K-Akt pathway was in a loss-of-function caused by RNA interference against Akt or PI3K inhibitor LY294002 in HCC cells. Taken together, our data demonstrate that FAM9C as a novel cancer testis gene plays an anti-apoptotic role in human hepatocellular carcinoma through activating the PI3K/Akt signaling pathway, and serves as a promising target for HCC therapy. 23625823 Board of Regents CommentaryQualifications of Pharmacists Who Provide Direct Patient Care: Perspectives on the Need for Residency Training and Board Certification. In 2006, the American College of Clinical Pharmacy (ACCP) released a position statement and a white paper to provide the College's viewpoints on the importance of postgraduate pharmacy residency training as a prerequisite for direct patient care practice and the vision that future clinical pharmacists engaged in direct patient care would be certified by the Board of Pharmacy Specialties (BPS). Since the release of these papers, some members of the pharmacy profession have interpreted ACCP's position as maintaining that all pharmacists-regardless of the focus of their professional practice activities-should complete formal postgraduate residency training and be board-certified specialists. That interpretation is not accurate. In this commentary, ACCP further defines "direct patient care" and states that it believes that clinical pharmacists engaged in direct patient care should be board certified (i.e., and residency-trained or otherwise board eligible) and have established a valid collaborative drug therapy management (CDTM) agreement or have been formally granted clinical privileges. The rationale for this viewpoint is presented in detail. The pharmacy profession has appropriately invested substantial resources to ensure the quality of its accredited residency training programs and board certification processes. ACCP believes that these training and certification programs are essential steps in preparing clinical pharmacists to provide direct patient care. 23782700 Unsaturated Long Chain Free Fatty Acids Are Input Signals of the Salmonella enterica PhoP/PhoQ Regulatory System. The Salmonella enterica serovar Typhimurium PhoP/PhoQ system has largely been studied as a paradigmatic two-component regulatory system not only to dissect structural and functional aspects of signal transduction in bacteria but also to gain knowledge about the versatile devices that have evolved allowing a pathogenic bacterium to adjust to or counteract environmental stressful conditions along its life cycle. Mg(2+) limitation, acidic pH, and the presence of cationic antimicrobial peptides have been identified as cues that the sensor protein PhoQ can monitor to reprogram Salmonella gene expression to cope with extra- or intracellular challenging conditions. In this work, we show for the first time that long chain unsaturated free fatty acids (LCUFAs) present in Salmonella growth medium are signals specifically detected by PhoQ. We demonstrate that LCUFAs inhibit PhoQ autokinase activity, turning off the expression of the PhoP-dependent regulon. We also show that LCUFAs exert their action independently of their cellular uptake and metabolic utilization by means of the β-oxidative pathway. Our findings put forth the complexity of input signals that can converge to finely tune the activity of the PhoP/PhoQ system. In addition, they provide a new potential biochemical platform for the development of antibacterial strategies to fight against Salmonella infections. 23892473 Quantification in magnetic resonance spectroscopy based on semi-parametric approaches. Magnetic resonance spectroscopy (MRS) is a value-added modality to magnetic resonance imaging (MRI) that is often used in diagnosis, treatment and progression monitoring, as well as in non-destructive, non-invasive studies of disease states in humans and model systems in animals. The availability of high magnetic field strengths and use of hyperpolarized nuclei, combined with the possibility of acquiring spectra at very short echo-time, have dramatically increased the potential of MRS. For the last two decades, a challenge has been to quantify short echo-time proton spectra that exhibit many metabolites, and to estimate their concentrations. Quantification of such spectra is challenging. Because the model function describing the acquired MRS signal is incomplete, semi-parametric techniques are required for estimation of the wanted metabolite concentrations. The semi-parametric approaches, QUEST, AQSES, TARQUIN, LCModel and SiToolsFITT, are reviewed and discussed according to handling of macromolecule signal and unknown decay of the metabolite signal (lineshape). Estimation of noise-related errors on model parameters and compromise used in real-world applications are detailed, with emphasis on the bias-variance trade-off. Applications of the semi-parametric methods QUEST and AQSES to quantification of MRS, HRMAS and MRSI data are also provided. 23801064 The role of insulin-like growth factor 1 and its receptor in the formation and development of colorectal carcinoma. To investigate the role of insulin-like growth factor (IGF)-1 and its receptor (IGF1R) in the formation and development of colorectal carcinoma. Colorectal tissue and matching serum samples were collected from patients with adenomatous polyps or carcinoma and healthy control subjects. IGF1R mRNA levels were determined via quantitative real-time reverse transcription-polymerase chain reaction. Serum IGF1 was quantified using enzyme-linked immunosorbent assay. Serum IGF1 concentrations and mucosal IGF1R mRNA levels were significantly higher in patients with adenomatous polyps (n = 24) or carcinoma (n = 13) compared with healthy control subjects (n = 13). There was a significant positive correlation between serum IGF1 and mucosal IGF1R mRNA in patients with adenomatous polyps. High circulating IGF1 concentrations and mucosal IGF1R expression may play important roles in both the formation and development of colorectal carcinoma. IGF1 and its receptor may be activated before carcinogenesis, and may promote the growth and malignant transformation of adenomatous polyps. IGF1 and IGF1R may be useful biomarkers for evaluating the stage and risk of carcinogenesis. 23266504 Influence of drying and cooking process on the phytochemical content, antioxidant and hypoglycaemic properties of two bell Capsicum annum L. cultivars. The present study evaluates the influence of drying and cooking processes on the health properties of two bell Capsicum annuum L. cultivars Roggiano and Senise compared with fresh peppers. The content of phytochemicals decreased in the order fresh>dried>dried frying processes. HPLC analysis was applied to quantify five flavonoids from peppers. Apigenin was identified as main constituent. Its content was affected by drying and dried frying processes. The antioxidant activity was evaluated by DPPH, ABTS, β-carotene bleaching test and Fe-chelating activity assay. A comparable radical scavenging activity was observed for both cultivars. Interestingly, frying process did not influenced this property. Roggiano peppers exhibited the highest antioxidant activity using β-carotene bleaching test with IC(50) values of 38.1 and 24.9 μg/mL for total extract and n-hexane fraction, respectively. GC-MS analysis of lipophilic fraction revealed the presence of fatty acids and vitamin E as major components. In the inhibition of the carbohydrate-hydrolyzing enzymes fresh Senise peppers exerted the strongest activity against α-amylase with an IC(50) value of 55.3 μg/mL. Our results indicate that C. annuum cultivars Roggiano and Senise have an interestingly potential health benefits not influenced by processes that are used before consumption. 23524315 The mycotoxin T-2 inhibits hepatic cytochrome P4503A activity in pigs. Mycotoxins are toxic metabolites produced by fungi that readily colonize crops. After ingestion, these mycotoxins can compromise intestinal health, and once entering the blood stream, even affect the liver and its metabolizing enzymes. It was therefore the aim of the present study to investigate the effect of T-2 toxin, an emerging and potent Fusarium mycotoxin, on the enzymatic activity of cytochrome P4503A (CYP3A) metabolizing enzymes in the liver of pigs. In addition, a yeast-derived feed additive that claims to bind T-2 toxin was included in the study to evaluate its efficacy. Our results demonstrated that a 14-days intake of T-2 toxin contaminated feed at a dose of 903μg/kg feed, whether or not combined with the mycotoxin binder, results in a substantial inhibition of the CYP3A activity in the liver of pigs. This result may be of importance for animal health, the pharmacokinetics and the withdrawal time of drugs that are substrate of CYP3A enzymes, and consequently can be a threat for public health with respect to tissue residues of these drugs. 23357416 Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay: a quantitative method for oxidative stress assessment of nanoparticle-treated cells. No consensus exists on how to address possible toxicity of nanomaterials as they interfere with most in vitro screening tests based on colorimetric and fluorimetric probes such as the dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay for detection of oxidative species. In the present research, nanomaterial interaction with DCFH-DA was studied in relation to its nature and/or assay conditions (cell-based and time exposure) by incubating Rhodamine (Rhd)-labeled 25nm and 50nm silica (SiO2), naked and oleic acid coated magnetite, (Fe3O4) and maghemite (Fe2O3) iron oxide, titanium dioxide (TiO2) and poly(ethylene oxide)-poly(lactide/glycolide) acid (PLGA-PEO) nanoparticles (NPs) with metabolically active rat hepatocytes for 4 and 24-h periods. Data indicated that nanoparticle uptake correlated with quenching of dye fluorescence emission. In spite of their masking effect, the oxidative potential of NPs could be detected at a limited threshold concentration when exposed for periods of time longer than those frequently used for this test. However, changes in the experimental conditions did not systematically result in free radical formation for all nanomaterials tested. Overall data indicate that despite the quenching effect of nanoparticles on DCFH-DA assay, it can be considered as a useful tool for quantitative measurement of NPs-induced oxidative stress by minor modifications of standardized protocols. 23915375 Drug Delivery Interfaces in the 21st Century: From Science Fiction Ideas to Viable Technologies. Early science fiction envisioned the future of drug delivery as targeted micrometer-scale submarines and "cyborg" body parts. Here we describe the progression of the field toward technologies that are now beginning to capture aspects of this early vision. Specifically, we focus on the two most prominent types of systems in drug delivery: the intravascular micro/nano drug carriers for delivery to the site of pathology and drug-loaded implantable devices that facilitate release with the predefined kinetics or in response to a specific cue. We discuss the unmet clinical needs that inspire these designs, the physiological factors that pose difficult challenges for their realization, and viable technologies that promise robust solutions. We also offer a perspective on where drug delivery may be in the next 50 years based on expected advances in material engineering and in the context of future diagnostics. 23212349 A comparison of adolescents engaging in self-injurious behaviors with and without suicidal intent: self-reported experiences of adverse life events and trauma symptoms. Research comparing adolescents engaging in suicidal and non-suicidal self-injury (NSSI), both separately and in combination, is still at an early stage. The purpose of the present study was to examine overlapping and distinguishable features in groups with different types of self-injurious behaviors, using a large community sample of 2,964 (50.6 % female) Swedish adolescents aged 15-17 years. Adolescents were grouped into six categories based on self-reported lifetime prevalence of self-injurious behaviors. Of the total sample, 1,651 (55.7 %) adolescents reported no self-injurious behavior, 630 (21.2 %) reported NSSI 1-4 times, 177 (6.0 %) reported NSSI 5-10 times, 311 (10.5 %) reported NSSI â‰¥ 11 times, 26 (0.9 %) reported lifetime prevalence of suicide attempt and 169 (5.7 %) adolescents reported both NSSI and suicide attempt. After controlling for gender, parental occupation and living conditions, there were significant differences between groups. Pairwise comparisons showed that adolescents with both NSSI and suicide attempt reported significantly more adverse life events and trauma symptoms than adolescents with only NSSI, regardless of NSSI frequency. The largest differences (effect sizes) were found for interpersonal negative events and for symptoms of depression and posttraumatic stress. Adolescents with frequent NSSI reported more adversities and trauma symptoms than those with less frequent NSSI. There were also significant differences between all the NSSI groups and adolescents without any self-injurious behavior. These findings draw attention to the importance of considering the cumulative exposure of different types of adversities and trauma symptoms when describing self-injurious behaviors, with and without suicidal intent. 23603605 67Ga SPECT/CT aids in the diagnosis of occult infected common iliac artery aneurysm. A 56-year-old woman, who had already suffered from systemic sclerosis and primary biliary cirrhosis, was presented with progressive pain at the right lower quadrant of abdomen, lower-grade fever, and leukocytosis for 4 days. Blood cultures did not yield pathogens. Abdominal ultrasonography revealed a right iliac artery aneurysm compressing the right kidney resulting in right hydronephrosis. 67Ga SPECT/CT demonstrated an intense hot area at the right common iliac artery, suggestive of an infected aneurysm. Contrast-enhanced CT showed concordant findings. This case illustrates the value of 67Ga SPECT/CT in discriminating pathologic uptake of the abdomen from physiologic activity of the bowels. 23937210 N-lauroyl chitosan surface-modified PLGA nanoparticles as carrier for adriamycin to overcome cancer drug resistance. Abstract N-lauroyl chitosan (NLCS) conjugates with different degrees of substitution (DS) of lauroyl group were synthesized and used to prepare surface modified poly(lactic-co-glycolic) acid (NLCS-PLGA) nanoparticles via hydrophobic interaction and ionic bond force. NLCS-PLGA nanoparticles had spherical shape with shell-core structure and exhibited the smallest size and narrowest size distribution when DS of lauroyl group of NLCS was 8.5%. Adriamycin (ADR), as a model antitumor drug, was loaded into NLCS-PLGA nanoaprticles and its initial burst release from PLGA nanoparticles was significantly reduced. MTT assay showed that NLCS-2-PLGA nanoaprticles evidently enhanced cytotoxicity of ADR against drug-resistant breast cancer MCF-7/ADR cells, both compared to free ADR and ADR-loaded PLGA nanoparticles. Moreover, cell-live images showed that the cellular uptake and nuclear location of ADR in MCF-7/ADR cells were significantly enhanced by loading of NLCS-2-PLGA nanoparticles. In conclusion, this novel carrier of anticancer drugs has the potential to overcome drug resistance in cancer cells. 23870791 Early diagnosis of myocardial infarction using absolute and relative changes in cardiac troponin concentrations. Absolute changes in high-sensitivity cardiac troponin T (hs-cTnT) seem to have higher diagnostic accuracy in the early diagnosis of acute myocardial infarction compared with relative changes. It is unknown whether the same applies to high-sensitivity cardiac troponin I (hs-cTnI) assays and whether the combination of absolute and relative change might further increase accuracy. In a prospective, international multicenter study, high-sensitivity cardiac troponin (hs-cTn) was measured with 3 novel assays (hs-cTnT, Roche Diagnostics Corp, Indianapolis, Ind; hs-cTnI, Beckman Coulter Inc, Brea, Calif; hs-cTnI, Siemens, Munich, Germany) in a blinded fashion at presentation and after 1 and 2 hours in a blinded fashion in 830 unselected patients with suspected acute myocardial infarction. The final diagnosis was adjudicated by 2 independent cardiologists. The area under the receiver operating characteristic curve for diagnosing acute myocardial infarction was significantly higher for 1- and 2-hour absolute versus relative hs-cTn changes for all 3 assays (P < .001). The area under the receiver operating characteristic curve of the combination of 2-hour absolute and relative change (hs-cTnT 0.98 [95% confidence interval {CI}, 0.97-0.99]; hs-cTnI, Beckman Coulter Inc, 0.97 [95% CI, 0.96-0.99]; hs-cTnI, Siemens, 0.96 [95% CI, 0.93-0.99]) were high and provided some benefit compared with the use of absolute change alone for hs-cTnT, but not for the hs-cTnI assays. Reclassification analysis confirmed the superiority of absolute changes versus relative changes. Absolute changes seem to be the preferred metrics for both hs-cTnT and hs-cTnI in the early diagnosis of acute myocardial infarction. The combination of absolute and relative changes provides a small added value for hs-cTnT, but not for hs-cTnI. 23580152 A statistical approach for analyzing the development of (1)H multiple-quantum coherence in solids. A novel statistical approach for analyzing (1)H multiple-quantum (MQ) spin dynamics in so-called spin-counting solid-state NMR experiments is presented. The statistical approach is based on the percolation theory with Monte Carlo methods and is examined by applying it to the experimental results of three solid samples having unique hydrogen arrangement for 1-3 dimensions: the n-alkane/d-urea inclusion complex as a one-dimensional (1D) system, whose (1)H nuclei align approximately in 1D, and magnesium hydroxide and adamantane as a two-dimensional (2D) and a three-dimensional (3D) system, respectively. Four lattice models, linear, honeycomb, square and cubic, are used to represent the (1)H arrangement of the three samples. It is shown that the MQ dynamics in adamantane is consistent with that calculated using the cubic lattice and that in Mg(OH)2 with that calculated using the honeycomb and the square lattices. For n-C20H42/d-urea, these 4 lattice models fail to express its result. It is shown that a more realistic model representing the (1)H arrangement of n-C20H42/d-urea can describe the result. The present approach can thus be used to determine (1)H arrangement in solids. 23702387 Body composition and reproductive function exert unique influences on indices of bone health in exercising women. Reproductive function, metabolic hormones, and lean mass have been observed to influence bone metabolism and bone mass. It is unclear, however, if reproductive, metabolic and body composition factors play unique roles in the clinical measures of areal bone mineral density (aBMD) and bone geometry in exercising women. This study compares lumbar spine bone mineral apparent density (BMAD) and estimates of femoral neck cross-sectional moment of inertia (CSMI) and cross-sectional area (CSA) between exercising ovulatory (Ov) and amenorrheic (Amen) women. It also explores the respective roles of reproductive function, metabolic status, and body composition on aBMD, lumbar spine BMAD and femoral neck CSMI and CSA, which are surrogate measures of bone strength. Among exercising women aged 18-30years, body composition, aBMD, and estimates of femoral neck CSMI and CSA were assessed by dual-energy x-ray absorptiometry. Lumbar spine BMAD was calculated from bone mineral content and area. Estrone-1-glucuronide (E1G) and pregnanediol glucuronide were measured in daily urine samples collected for one cycle or monitoring period. Fasting blood samples were collected for measurement of leptin and total triiodothyronine. Ov (n=37) and Amen (n=45) women aged 22.3±0.5years did not differ in body mass, body mass index, and lean mass; however, Ov women had significantly higher percent body fat than Amen women. Lumbar spine aBMD and BMAD were significantly lower in Amen women compared to Ov women (p<0.001); however, femoral neck CSA and CSMI were not different between groups. E1G cycle mean and age of menarche were the strongest predictors of lumbar spine aBMD and BMAD, together explaining 25.5% and 22.7% of the variance, respectively. Lean mass was the strongest predictor of total hip and femoral neck aBMD as well as femoral neck CSMI and CSA, explaining 8.5-34.8% of the variance. Upon consideration of several potential osteogenic stimuli, reproductive function appears to play a key role in bone mass at a site composed of primarily trabecular bone. However, lean mass is one of the most influential predictors of bone mass and bone geometry at weight-bearing sites, such as the hip. 23846786 Intra-arterial Therapy for Advanced Intrahepatic Cholangiocarcinoma: A Multi-institutional Analysis. Many patients with intrahepatic cholangiocarcinoma (ICC) present with advanced and inoperable disease. Data on the safety and efficacy of intra-arterial therapy (IAT) for ICC are limited. Between 1992 and 2012, a total of 198 patients with advanced ICC treated with IAT were retrospectively identified from the databases of five major hepatobiliary institutions. Data on clinicopathological factors, morbidity, response rates, and overall survival were collected and analyzed. Median patient age was 61 years. Median tumor size was 8.1 cm, and 47.5 % patients had a solitary lesion. IAT consisted of conventional transarterial chemoembolization (cTACE) (64.7 %), drug-eluting beads (DEB) (5.6 %), bland embolization (TAE) (6.6 %), or yttrium-90 radioembolization (23.2 %). Median number of IAT sessions was 2 (range 1-8). The median time between IAT sessions was 48 days. The periprocedural morbidity was 29.8 %; most complications were minor (n = 43); however, 16 patients had a grade 3-4 complication. Assessment of tumor response revealed complete or partial response in 25.5 % patients, while 61.5 % had stable disease; 13.0 % had progressive disease. Median overall survival was 13.2 months and did not differ on the basis of the type of IAT (cTACE, 13.4 months vs. DEB 10.5 months vs. TAE, 14.3 months vs. yttrium-90, 11.3 months; P = 0.46). IAT response on modified response evaluation criteria in solid tumors (mRECIST; hazard ratio for complete-partial response 0.49, 95 % confidence interval 0.30-0.81; P < 0.001) was independently associated with better survival. IAT for ICC was safe and led to stable disease or partial to complete response in up to three-quarters of patients. Among patients with an IAT response, overall survival was prolonged. The role of IAT therapy for ICC warrants further prospective evaluation in clinical trials. 23818667 Purification and culture of retinal ganglion cells from rodents. Here we describe methods for acute purification of retinal ganglion cells (RGCs) from rodent retina by immunopanning, followed by culture in serum-free medium. Though the method was initially established and verified with rats, we have included modifications for the purification of mouse RGCs. This protocol is written for isolation of cells from one litter of pups. All of the volumes and numbers of panning plates should be scaled according to the number of litters used, particularly for rat RGCs. 23643873 Cloning and expression analysis of grouper (Epinephelus coioides) M-CSFR gene post Cryptocaryon irritans infection and distribution of M-CSFR(+) cells. The M-CSF/M-CSFR system plays a central role in the cell survival, proliferation, differentiation and maturation of the monocyte/macrophage lineage. In present study, we cloned the sequence of the M-CSFR cDNA from the orange-spotted grouper (Epinephelus coioides). Sequence analysis reveals that ten cysteines in the extracellular immunoglobulin-like (Ig-like) domains of EcM-CSFR are conserved in fish and mammals, its nine possible N-glycosylation sites are conserved in fish but not mammals, 7 of 8 identified mammal M-CSFR intracellular autophosphorylation tyrosine sites was found in EcM-CSFR. Real-time PCR showed that the constitutive expression level of EcM-CSFR was the highest in the spleen, less in the gill, kidney, head kidney and liver, least in the blood, skin, gut and thymus. A rabbit anti-EcM-CSFR polyclonal antibody against the recombinant EcM-CSFR extracellular domain was developed and it was efficient in labeling the monocytes and macrophages isolated from the head kidney. Immunochemistry analysis showed that M-CSFR(+) cells located in all tested paraffin-embedded tissues and M-CSFR(+) cell centres with the characteristic of melano-macrophage centres(MMCs) was found in the spleen, head kidney, kidney, gut and liver. All these results indicate the widespread distribution of macrophages in grouper tissues and its importance in fish immune system. In Crytocaryon irritans infected grouper, EcM-CSFR was transient up-regulated and rapidly down-regulated in skin, gill, head kidney and spleen. The possible activation mechanism of macrophage via EcM-CSFR signal transduction in the fish anti-C. irritans infection was discussed. 23531819 Identification and characterisation of a functional aquaporin water channel (Anomala cuprea DRIP) in a coleopteran insect. Water transport across the plasma membrane depends on the presence of the water channel aquaporin (AQP), which mediates the bulk movement of water through osmotic and pressure gradients. In terrestrial insects, which are solid and/or plant feeders, the entrance and exit of water is primarily executed along the alimentary tract, where the hindgut, particularly the rectum, is the major site of water conservation. A cDNA encoding the homologue of the water-specific Drosophila AQP [Drosophila integral protein (DRIP)] was identified through the RT-PCR of RNA isolated from the rectum of the cupreous chafer larvae, Anomala cuprea, a humus and plant root feeder. This gene (Anocu AQP1) has a predicted molecular mass of 26.471 kDa, similar to the DRIP clade of insect AQPs characterised from caterpillars, flies and several liquid-feeding insects. When expressed in Xenopus laevis oocytes, Anocu AQP1 showed the hallmarks of aquaporin-mediated water transport but no glycerol or urea permeability, and the reversible inhibition of elevated water transport through 1 mmol l(-1) HgCl2. This is the first experimental demonstration of the presence of a water-specific AQP, namely DRIP, in the Coleoptera. The genome of the model beetle Tribolium castaneum contains six putative AQP sequences, one of which (Trica-1a, XP_972862) showed the highest similarity to Anocu AQP1 (~60% amino acid identity). Anocu AQP1 is predominantly expressed in the rectum. Using a specific antibody raised against DRIP in the silkworm Bombyx mori (AQP-Bom1), Anocu AQP1 was localised to the apical plasma membrane of rectal epithelial cells, and lacking in the midgut and gastric caecal epithelia. Based on the BeetleBase prediction, there are three putative AQPs (Trica-3a, 3b, 3c: XP_970728, 970912, 970791) that are homologous to B. mori aquaglyceroporin [AQP-Bom2 (GLP)]. The immunocytochemical studies using the specific anti-peptide antibody against AQP-Bom2 revealed the presence of the GLP homologue at the apical plasma membrane of enterocytes in the midgut and gastric caeca. Thus, DRIP (Anocu AQP1) and the putative GLP share epithelial fluid-transporting roles along the alimentary tract in cupreous chafer larvae. 23553767 A comparison of bone quality at the distal radius between Asian and Caucasian adolescents and young adults: An HR-pQCT study. Paradoxically, Asians have lower areal bone mineral density, but their rates of hip and wrist fractures are lower than Caucasians. Therefore, we used high-resolution pQCT (HR-pQCT) to determine whether differences in bone macro- and microstructure, BMD and bone strength at the distal radius are apparent in Asian (n = 91, 53 males, 38 females, 17.3 ± 1.5 yrs) and Caucasian (n = 89, 46 males, 43 females, 18.1 ± 1.8 yrs) adolescents and young adults. HR-pQCT outcomes included total BMD (Tt.BMD), trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), thickness (Tb.Th) and separation (Tb.Sp). We used an automated segmentation algorithm to determine total bone area (Tt.Ar), cortical BMD (Ct.BMD), porosity (Ct.Po) and thickness (Ct.Th), and we applied finite element analysis to HR-pQCT scans to estimate bone strength. We fit sex-specific multivariable regression models to compare bone outcomes between Asians and Caucasians, adjusting for age, age at menarche (girls), lean mass, ulnar length, dietary calcium intake and physical activity. In males, after adjusting for covariates, Asians had 11% greater Tt.BMD, 8% greater Ct.BMD and 25% lower Ct.Po than Caucasians (p < 0.05). Also, Asians had 9% smaller Tt.Ar and 27% greater Ct.Th (p < 0.01). In females, Asians had smaller Tt.Ar than Caucasians (16%, p < 0.001), but this difference was not significant after adjusting for covariates. Asian females had 5% greater Ct.BMD, 12% greater Ct.Th and 11% lower Tb.Sp than Caucasians after adjusting for covariates (p < 0.05). Estimated bone strength did not differ between Asian and Caucasian males or females. Our study supports the notion of compensatory elements of bone structure that sustain bone strength; smaller bones as observed between those of Asian compared with Caucasian origin, have, on average, more dense, less porous and thicker cortices. Longitudinal studies are needed to determine whether ethnic differences in bone structure exist in childhood, persist into old age and whether they influence fracture risk. © 2013 American Society for Bone and Mineral Research. 23727261 Gene transfection efficacy and biocompatibility of polycation/DNA complexes coated with enzyme degradable PEGylated hyaluronic acid. Coating the polycation/DNA binary complexes with PEGylated polyanions can improve long-circulation and biocompatibility in vivo. However, it has been certificated PEG dilemma can reduces gene transfection efficiency because of inhibition in cellular uptake and endosomal escape. Herein, two PEGylated anionic polymers, PEGylated hyaluronic acid (HgP) and PEGylated polyglutamic acid (PGgP) were synthesized to coat the binary complexes of core-shell cationic polycaprolactone-graft-poly (N, N-dimethylaminoethyl methacrylate) nanoparticles/DNA (NP-D). The effects of polyanion structure were evaluated in terms of particle size, zeta potential, cytotoxicity, cellular uptake and transfect efficiency in vitro and in vivo. In vitro study illustrated that HgP coated complexes showed better efficiencies in both cell uptake and transfection than PGgP coated complexes. The coating of HgP on NP-D improved the biocompatibility without reduction in cell uptake and transfection efficacy, and resulted in higher accumulation and gene expression in tumor after IV injection. The success of HgP coating in overcoming PEG dilemma is attributed to the hyaluronic acid (HA)-receptor-mediated endocytosis and outer shell-detachment through the hyaluronidases catalyzed degradation of HA. These results demonstrated that HgP was a promising anionic polymer for coating the polycation/DNA complexes and ternary complexes (HgP coated NP-D) hold promising potential for cancer therapy. 23870088 Identification of the lamin A/C phosphoepitope recognized by the antibody P-STM in mitotic HeLa S3 cells. Lamins A and C, two major structural components of the nuclear lamina that determine nuclear shape and size, are phosphoproteins. Phosphorylation of lamin A/C is cell cycle-dependent and is involved in regulating the assembly-disassembly of lamin filaments during mitosis. We previously reported that P-STM, a phosphoepitope-specific antibody raised against the autophosphorylation site of p21-activated kinase 2, recognizes a number of phosphoproteins, including lamins A and C, in mitotic HeLa cells. Here, using recombinant proteins and synthetic phosphopeptides containing potential lamin A/C phosphorylation sites in conjunction with in vitro phosphorylation assays, we determined the lamin A/C phosphoepitope(s) recognized by P-STM. We found that phosphorylation of Thr-19 is required for generating the P-STM phosphoepitope in lamin A/C and showed that it could be created in vitro by p34cdc2/cyclin B kinase (CDK1)-catalyzed phosphorylation of lamin A/C immunoprecipitated from unsynchronized HeLa S3 cells. To further explore changes in lamin A/C phosphorylation in living cells, we precisely quantified the phosphorylation levels of Thr-19 and other sites in lamin A/C isolated from HeLa S3 cells at interphase and mitosis using the SILAC method and liquid chromatography-tandem mass spectrometry. The results showed that the levels of phosphorylated Thr-19, Ser-22 and Ser-392 in both lamins A and C, and Ser-636 in lamin A only, increased -2- to 6-fold in mitotic HeLa S3 cells. Collectively, our results demonstrate that P-STM is a useful tool for detecting Thr-19-phosphorylated lamin A/C in cells and reveal quantitative changes in the phosphorylation status of major lamin A/C phosphorylation sites during mitosis. 23889231 The Placebo Effect in Clinical Trials for Alcohol Dependence: An Exploratory Analysis of 51 Naltrexone and Acamprosate Studies. The placebo effect often undermines efforts to determine treatment effectiveness in clinical trials. A significant placebo response occurs in alcohol trials, but it is not well understood. The purpose of this study was to characterize the placebo response across multiple naltrexone and acamprosate studies. Fifty-one trials, 3 with a naltrexone and an acamprosate arm, 31 with at least 1 naltrexone arm, and 17 with at least 1 acamprosate arm, were identified from Cochrane reviews and PubMed search. To be included in this study, patients had to be at least 18 years old, abstinent from alcohol before randomization, and meet a diagnosis of alcohol dependence. Pearson correlation coefficients (rp ) and simple linear regression were used to describe the strength of linear relationships between placebo response and treatment effect size. Spearman's rank correlation coefficients (rs ) were used to examine the strength of associations between study characteristics and placebo response. For the end point measures of percent days abstinent and total abstinence, a negative relationship was evident between placebo response and treatment effect size in the naltrexone trials (rp  = -0.55, p < 0.01 and rp  = -0.20, p = 0.35, respectively) as well as in the acamprosate trials (rp  = -0.45, p = 0.09 and rp  = -0.56, p = 0.01, respectively). The placebo response for percent days abstinent was negatively correlated with mean age of participants (rs  = -0.42, p = 0.05) across naltrexone trials and positively correlated with publication year (rs  = 0.57, p = 0.03) across acamprosate trials. However, these 2 study characteristics were not significantly correlated with treatment effect size. The placebo response varied considerably across trials and was negatively correlated with the treatment effect size. Additional studies are required to fully understand the complex nature of the placebo response and to evaluate approaches to minimize its effects. 23579183 Effect of single-session repetitive transcranial magnetic stimulation applied over the hand versus leg motor area on pain after spinal cord injury. . Neuropathic pain often follows spinal cord injury (SCI). . To compare the effect of repetitive transcranial magnetic stimulation (rTMS) applied over different motor cortex targets (hand vs leg area) versus sham stimulation on neuropathic pain and local neurophysiological changes in patients with SCI. . A total of 16 patients with complete or incomplete motor SCI and chronic neuropathic pain participated in a double-blind, cross-over randomized study. Three single sessions of sham or active rTMS (10 Hz, total of 2000 stimuli) were applied in random order over the hand or leg area with a minimal 2-week interval. The were the numeric rating scale for pain sensation and parameters derived from motor mapping of the first dorsal interosseous muscle, including maximal amplitude of evoked response as well as map area, volume, and location. . rTMS applied to either the hand or the leg area, but not sham stimulation, induced a significant but equivalent reduction in pain for the first 48 hours postintervention (P < .05). Participants with an incomplete lesion showed greater analgesia than those with a complete lesion (21% vs 3%, respectively; P < .05). The main change observed for motor map measurements was an increase in corticospinal excitability after stimulation of the hand area (P = .04) but not for the other conditions. . rTMS applied over the hand or leg motor cortex decreased neuropathic pain regardless of any change in cortical excitability, suggesting that the analgesic effect is not associated with local changes at the motor cortex level itself. 23877170 Short-Term Functional Outcomes of First Metatarsophalangeal Total Joint Replacement for Hallux Rigidus. Although metatarsophalangeal (MTP) arthrodesis has been advocated by many authors, implant arthroplasty appears to be successful option in advanced hallux rigidus (HR). The aim of our study was to evaluate the early results of the ToeFit-Plus prosthesis for the treatment of HR. Between December 2007 and January 2011, a total of 26 toes of 24 patients with MTP arthritis of the great toe were treated with ToeFit-Plus implant. The average follow-up time was 29.9 (range: 25 to 62) months. All patients were evaluated clinically and radiographically. Postoperative satisfaction and function were scored according to the American Orthopaedic Foot and Ankle Society (AOFAS) score. Pain was assessed with the use of a visual analogue scale. Mean preoperative AOFAS score improved from 42.7 (range: 36 to 59) to 88.5 (range: 59 to 98) at the final follow-up (P < .01). Preoperative average visual analogue scale pain scores improved from 7.4 preoperatively to 1.9 at the final follow-up (P < .01). The average MTP joint range of motion improved from 25.9 degrees preoperatively to 53.8 degrees at the final follow-up. No radiologic loosening was found, but radiolucency was observed in 2 patients with this implant. No revision was required for any of the patients during the follow-up period. This total first MTP joint prosthesis yielded good functional outcome and high patient satisfaction level with low early complication rate. Preservation of joint movement and good pain relief with early mobilization were the advantages of this procedure. Salvage arthrodesis remains an option if future revisions are indicated. Level IV, retrospective case series. 23428468 Oxysterol-binding proteins: Functions in cell regulation beyond lipid metabolism. Oxysterol-binding (OSBP)-related proteins (ORPs) constitute a family of sterol and phosphoinositide binding/transfer proteins in eukaryotes from yeast to man. While their functions have mainly been addressed in cellular lipid metabolism or sterol transport, increasing evidence points to more versatile regulatory roles in a spectrum of cellular regimes. In fact ORPs do not appear to be robust controllers of lipid homeostasis. Several ORPs localize at membrane contacts sites (MCS), where endoplasmic reticulum (ER) is apposed with other organelle limiting membranes. Apparently, ORPs have the capacity to control the formation of MCS or activity of enzymatic machineries at these sites. Thereby, ORPs most likely affect organelle membrane lipid compositions, with impacts on signaling and vesicle transport, but also cellular lipid metabolism. Moreover, an increasing number of protein interaction partners of ORPs have been identified, connecting these proteins with various aspects of cell regulation. Small molecular anti-proliferative compounds, ORPphilins, were recently found to target two members of the ORP family, OSBP and ORP4, revealing an essential function of ORPs in cancer cell proliferation and survival. Further functions assigned for ORPs include regulation of extracellular signal regulated kinase (ERK) activity (OSBP), control of ER-late endosome MCS and late endosome motility (ORP1L), regulation of β1-integrin activity (ORP3), modulation of hepatocyte insulin signaling and macrophage migration (ORP8), as well as post-Golgi vesicle transport, phosphatidylinositol-4-phosphate and target of rapamycin complex 1 signaling and nitrogen sensing (Saccharomyces cerevisiae Osh4p). These and other recent observations shed light on the ORPs as integrators of lipid signals with an unforeseen variety of vital cellular processes. 23622971 Comparison of follicular fluid and serum anti-Mullerian hormone levels as predictors of the outcome of assisted reproductive treatment. To compare follicular fluid and serum concentrations of anti-Mullerian hormone (AMH) as predictors of the outcome of assisted reproduction. This observational study enrolled 58 women who were undergoing IVF or ICSI treatment with the long stimulation protocol. Patients diagnosed as having PCOS were excluded. Serum and follicular fluid AMH levels were assessed as predictors of clinical pregnancy. Both the serum and follicular fluid AMH levels were higher in the clinical pregnancy group than in the failed group. A significant correlation was found between the serum and follicular fluid AMH levels, but a discrepancy was observed in some patients with elevated AMH levels in the follicular fluid or serum alone. Assisted reproductive treatment resulted in clinical pregnancy in all of the patients with elevated AMH levels in the follicular fluid (>40pM) or in the serum (>10pM). The ROC-AUC for the combination of follicular and serum AMH was 0.772, which was relatively higher than that for either the serum AMH (AUC: 0.691) or follicular fluid AMH (AUC: 0.688) alone. Elevated AMH levels in either the serum or follicular fluid appeared to be predictive of clinical pregnancy, even if AMH levels in other fluids were low. This is a pilot study with preliminary data that need further confirmation. 23732233 Critical evaluation of the anatomical location of the Barrington nucleus: Relevance for deep brain stimulation surgery of pedunculopontine tegmental nucleus. Deep brain stimulation (DBS) has become the standard surgical procedure for advanced Parkinson's disease (PD). Recently, the pedunculopontine tegmental nucleus (PPN) has emerged as a potential target for DBS in patients whose quality of life is compromised by freezing of gait and falls. To date, only a few groups have published their long-term clinical experience with PPN stimulation. Bearing in mind that the Barrington (Bar) nucleus and some adjacent nuclei (also known as the micturition centre) are close to the PPN and may be affected by DBS, the aim of the present study was to review the anatomical location of this structure in human and other species. To this end, the Bar nucleus area was analysed in mouse, monkey and human tissues, paying particular attention to the anatomical position in humans, where it has been largely overlooked. Results confirm that anatomical location renders the Bar nucleus susceptible to influence by the PPN DBS lead or to diffusion of electrical current. This may have an undesirable impact on the quality of life of patients. 23935763 The Organizational Health of Urban Elementary Schools: School Health and Teacher Functioning. This study examined the factor structure of the Organizational Health Inventory-Elementary version (OHI-E; Hoy, Tarter, & Kottkamp, 1991) in a sample of 203 teachers working in 19 high-poverty, urban schools and the association of organizational school health with teacher efficacy, teacher stress, and job satisfaction. Results indicated a similar factor structure of the OHI-E as compared with the population of schools in the original sample (Hoy et al., 1991), and that specific components of organizational health, such as a positive learning environment, are associated with teacher efficacy, stress, and satisfaction. Overall, teachers' relations with their peers, their school leadership, and their students appear especially critical in high-poverty, urban schools. Recommendations for research and practice related to improving high-poverty, urban schools are presented. 23761633 STAT4 and T-bet are required for the plasticity of IFN-γ expression across Th2 ontogeny and influence changes in Ifng promoter DNA methylation. CD4(+) T cells developing toward a Th2 fate express IL-4, IL-5, and IL-13 while inhibiting production of cytokines associated with other Th types, such as the Th1 cytokine IFN- γ. IL-4-producing Th2 effector cells give rise to a long-lived memory population committed to reactivation of the Th2 cytokine gene expression program. However, reactivation of these effector-derived cells under Th1-skewing conditions leads to production of IFN-γ along with IL-4 in the same cell. We now show that this flexibility ("plasticity") of cytokine expression is preceded by a loss of the repressive DNA methylation of the Ifng promoter acquired during Th2 polarization yet requires STAT4 along with T-box expressed in T cells. Surprisingly, loss of either STAT4 or T-box expressed in T cells increased Ifng promoter CpG methylation in both effector and memory Th2 cells. Taken together, our data suggest a model in which the expression of IFN-γ by Th2-derived memory cells involves attenuation of epigenetic repression in memory Th2 cells, combined with Th1-polarizing signals after their recall activation. 23286893 Left ventricular mechanical dyssynchrony in patients with different stages of chronic kidney disease and the effects of hemodialysis. Left ventricular (LV) dyssynchrony is a known cause of mortality in patients with heart failure and may possibly play a similar role in patients with chronic kidney disease (CKD) in whom sudden death is one of the most common and as yet not fully explained cause of death. LV synchronicity and its relationship with increased volume load and various biomarkers was analyzed in 145 patients including 53 patients with CKD stages 3 and 4 and in 92 CKD stage 5 patients undergoing hemodialysis (HD) or peritoneal dialysis (PD) using color tissue Doppler imaging and tissue synchronization imaging. The HD patients were evaluated both before and after a single HD session. LV dyssynchrony was defined as a regional difference in time to peak systolic myocardial velocity, between 12 LV segments > 105 milliseconds. LV dyssynchrony was present in 54% of the patients with no difference between CKD 3 and 4 (58%), HD (48%), and PD (51%). LV dyssynchrony was independently associated with LV mass index and increased estimation of LV end-diastolic pressure. A single HD session resulted in significant changes in LV synchronicity variables-with improvement in 50% of the patients-especially in patients with higher myocardial systolic velocities and lower LV mass index. Abnormalities in LV synchronicity are highly prevalent in CKD patients already prior to dialysis treatment and are associated with LV hypertrophy, LV dysfunction and load conditions, underlining the importance of volume status for LV synchronicity in CKD patients. 23964332 Evidence-based recommendations on colorectal stenting: a report from the stent study group of the korean society of gastrointestinal endoscopy. Recently, placement of self-expandable metallic stents has been used for the treatment of colorectal obstruction. As domestic awareness of colorectal cancer has increased, the number of colorectal stenting procedures performed has also increased. We aimed to provide evidence-based recommendations for colorectal stenting to aid gastroenterologists in making informed decisions regarding the management of patients who present with colorectal obstruction. The working group consisted of eight gastroenterologists who actively practice and conduct research in the field of colorectal stenting and are the members of the Stent Study Group of the Korean Society of Gastrointestinal Endoscopy. A literature search was conducted using the PubMed, Embase, KoreaMed, and the Cochrane Library databases to identify relevant articles published between January 2001 and June 2012. Based on the modified Delphi process, 10 recommendation statements regarding indications, usefulness, methodology and complications of colorectal stenting, and alternative treatments for malignant colorectal obstruction were determined. The contents will be widely distributed, and periodically revised to reflect the latest knowledge. These evidence-based recommendations for colorectal stenting will provide gastroenterologists and patients with appropriate and balanced information, and will improve the quality of care. 23845679 Acute disseminated encephalomyelitis following infectious mononucleosis in a toddler. Symptomatic Epstein-Barr virus (EBV) infection complicated by acute disseminated encephalomyelitis (ADEM) in a toddler is rare. Our patient is a 14 month-old boy who presented with listlessness and reduced eye movements nearly 10 days after a prodromal upper respiratory illness that was accompanied by an amoxicillin rash. On examination, the boy appeared drowsy, had a congested throat and a resolving lower extremity rash, but otherwise had a normal neurological examination. Investigation revealed lymphocytosis, mildly elevated liver enzyme and a positive EBV IgM serology. Cerebrospinal fluid analysis showed pleocytosis. Subsequent brain and spine MRI showed demyelinating disease extending from the cerebral peduncles, across the brain stem and down to the mid-thoracic spinal cord. The patient was treated as a case of ADEM and given intravenous methylprednisolone. On outpatient follow-up his symptoms resolved completely in 6 weeks. 23939795 Photodynamic activity of plant extracts from sarawak, borneo. Photodynamic therapy (PDT) is a medical treatment that involves the irradiation of an administered photosensitizing drug with light of a particular wavelength to activate the photosensitizer to kill abnormal cells. To date, only a small number of photosensitizers have been clinically approved for PDT, and researchers continue to look for new molecules that have more desirable properties for clinical applications. Natural products have long been important sources of pharmaceuticals, and there is a great potential for discovery of novel chemotypes from under-explored biodiversities in the world. The objective of this study is to mine the terrestrial plants in Sarawak, Borneo Island, for new photosensitizers for PDT. In a screening program from 2004 to 2008, we prepared and studied 2,400 extracts from 888 plants for their photosensitizing activities. This report details the bioprospecting process, preparation and testing of extracts, analysis of the active samples, fractionation of four samples, and isolation and characterization of photosensitizers. 23880345 TXNIP interacts with hEcd to increase p53 stability and activity. The p53 protein plays a central role in cell cycle arrest and apoptosis in response to diverse stress stimuli. Human ecdysoneless (hEcd) is known for its role in stabilizing the p53 protein level and increasing p53-mediated transcription. Here, we report that thioredoxin interacting protein (TXNIP), a member of the tumor suppressor family, interacts with hEcd and decreases MDM2-mediated p53 ubiquitination, leading to p53 stabilization and an increase in p53 activity. The ectopic overexpression of both TXNIP and Ecd increased actinomycin D-mediated cell death in MCF-7 cells, whereas knockdown of TXNIP and Ecd decreased cell death. These results show that TXNIP is a new regulator of the Ecd-MDM2-p53 loop. 23952168 Psychosomatics in obstetrics and gynecology - evaluation of a compulsory standardized teaching program. Abstract Objective: This observational study was aimed at assessing the effect of case supervision in small groups over a two-year period as part of a standardized psychosomatic basic training for future obstetrician-gynecologists from the physicians' perspective. Methods: The supervised groups were evaluated by questionnaires distributed to all 128 candidates at the beginning (T1), at half time (T2) and at the end of the course (T3). Aside from a validated battery of questions on self-efficacy, items included self-estimated psychosomatic competence, professional satisfaction as well as a validation of the training program. Results: The training program was associated with a significant increase of self-reported psychosomatic competence (55.0/68.9, p = 0.000) and self-efficacy (2.4/2.8, p = 0.0011). While major changes occurred at the end of the first year of the supervised groups, no further enhancement could be demonstrated throughout the second year. A total of 44 (88%) study participants who answered at T3 considered the training program as helpful. Conclusions: The presented teaching program - more precisely the supervised groups - seemed to be effective in increasing self-estimated psychosomatic competence and self-efficacy in future specialists for obstetrics and gynecology. It may serve as a model for the systematic integration of standardized psychosomatic basic training into the education of obstetrician-gynecologists. 23857725 Effect of electric field on the partitioning behavior of solutes in entropic interaction chromatography. In this study, a novel column design with a round cross-section was proposed to be suitable for a transverse electric field (EF). Additionally, two beads for entropic interaction chromatography (EIC) were prepared by grafting glycidyl methacrylate onto Toyopearl HW-65F (T65F) beads. Solute partitioning was then investigated to elucidate the role of graft polymerization with and without an EF. In a T65F column, solute partitioning was attributed to the distinct pore structure in the beads and was governed by pore flow. Under EF, partition coefficients (Kp ) for solutes decreased with increasing EF strength. In the two EIC columns, a decrease of Kp was also observed without an EF while the fractionation windows were extended. It was more pronounced in the EIC column with a high grafting density (T65F-H). This was explained by the decrease in the effective pore size of solutes caused by the steric hindrance of polymer chains. Under an EF, the solutes showed different partitioning behaviours in the T65F-H column. With increasing EF strength, Kp for vitamin B12 and myoglobin was decreased. In contrast, Kp for large solutes increased as a result of concentration polarization on the bead surface. Both behaviors were related to the modulation of graft polymerization to residual charge on the matrix and the pore size of the solutes. 23523434 Validation of a consensus-based minimal clinically important difference (MCID) threshold using an objective functional external anchor. The minimal clinically important difference (MCID) is defined as the smallest change in an outcome that a patient would perceive as meaningful. The Initiative on Methods, Measurement and Assessment in Clinical Trials (IMMPACT) group proposed defining the MCID as a 30% improvement in self-reported pain or function. However, this MCID threshold has not been validated against an objective physical measure. To test the validity of the IMMPACT-based MCID threshold, using an objective physical measure as an external anchor. Prospective study of chronic disabling occupational lumbar disorder (CDOLD) patients completing a functional restoration program. A consecutive cohort of 743 CDOLD patients. Self-report measures of pain-related function were compared with an objective lifting measure, the progressive isoinertial lifting evaluation (PILE), obtained after treatment. The association between reporting 30% or greater improvement (the IMMPACT's MCID key criterion) and the PILE score after treatment was assessed. A 30% or greater improvement on the self-report measures was significantly associated with improvement in physical function on the PILE task. Despite extensive use of the MCID to evaluate effects of treatment in spinal disorders, this is the first empirical documentation of the validity of the IMMPACT's 30% change criterion compared with an objective physical anchor. 23952425 Role of Oxygen Holes in Li_{x}CoO_{2} Revealed by Soft X-Ray Spectroscopy. The fundamental electronic structure of the widely used battery material Li_{x}CoO_{2} still remains a mystery. Soft x-ray absorption spectroscopy of Li_{x}CoO_{2} reveals that holes with strong O 2p character play an essential role in the electronic conductivity of the Co^{3+}/Co^{4+} mixed valence CoO_{2} layer. The oxygen holes are bound to the Co^{4+} sites and the Li-ion vacancy, suggesting that the Li-ion flow can be stabilized by oxygen hole back flow. Such an oxygen hole state of Li_{x}CoO_{2} is unique among the various oxide-based battery materials and is one of the key ingredients to improving their electronic and Li-ion conductivities. 23848215 Prosthetic joint-associated infections treated with DAIR (debridement, antibiotics, irrigation, and retention). Background and purpose For prosthetic joint-associated infection (PJI), a regimen of debridement, antibiotics, irrigation, and retention of the prosthesis (DAIR) is generally accepted for acute infections. Various risk factors associated with treatment success have been described. The use of local antibiotic carriers (beads and sponges) is relatively unknown. We retrospectively analyzed risk factors in a cohort of patients from 3 hospitals, treated with DAIR for PJI. Patients and methods 91 patients treated with DAIR for hip or knee PJI in 3 Dutch centers between 2004 and 2009 were retrospectively evaluated. The mean follow-up was 3 years. Treatment success was defined as absence of infection after 2 years, with retention of the prosthesis and without the use of suppressive antibiotics. Results 60 patients (66%) were free of infection at follow-up. Factors associated with treatment failure were: a history of rheumatoid arthritis, late infection (> 2 years after arthroplasty), ESR at presentation above 60 mm/h, and infection caused by coagulase-negative Staphylococcus. Symptom duration of less than 1 week was associated with treatment success. The use of gentamicin sponges was statistically significantly higher in the success group, and the use of beads was higher in the failure group in the univariate analysis, but these differences did not reach significance in the logistic regression analysis. Less surgical procedures were performed in the group treated with sponges than in the group treated with beads. Interpretation In the presence of rheumatoid arthritis, duration of symptoms of more than 1 week, ESR above 60 mm/h, late infection (> 2 years after arthroplasty), and coagulase-negative Staphylococcus PJI, the chances of successful DAIR treatment decrease, and other treatment methods should be considered. 23875538 The Worringham and Beringer 'visual field' principle for rotary controls. Worringham and Beringer (1989, 1998) developed a very important principle relating compatibility of movement of horizontally moving translational controls to display movements when the operator's view of the display is in a plane different to that of the control. On the basis of past data of the current authors, it is shown that the visual field principle also applies to the operation of vertically moving translational controls and to rotary controls. These additions make the Worringham and Beringer principle the most powerful design principle available for situations where the operator is viewing a display that is not in the same plane as the control. Practitioner Summary: High compatibility between control input and display output is of great importance in machine design. This paper demonstrates that, for cases where the display is not in the same plane as the control, the visual field principle is operational for vertically moving translational controls and rotary controls as well as for horizontally moving translational controls. 23017673 Therapeutic modulation of intestinal dysbiosis. The human gastrointestinal tract is home to an extremely numerous and diverse collection of microbes, collectively termed the "intestinal microbiota". This microbiota is considered to play a number of key roles in the maintenance of host health, including aiding digestion of otherwise indigestible dietary compounds, synthesis of vitamins and other beneficial metabolites, immune system regulation and enhanced resistance against colonisation by pathogenic microorganisms. Conversely, the intestinal microbiota is also a potent source of antigens and potentially harmful compounds. In health, humans can therefore be considered to exist in a state of natural balance with their microbial inhabitants. A shift in the balance of microbiota composition such that it may become deleterious to host health is termed "dysbiosis". Dysbiosis of the gut microbiota has been implicated in numerous disorders, ranging from intestinal maladies such as inflammatory bowel diseases and colorectal cancer to disorders with more systemic effects such as diabetes, metabolic syndrome and atopy. Given the far reaching influence of the intestinal microbiota on human health a clear future goal must be to develop reliable means to alter the composition of the microbiota and restore a healthy balance of microbial species. While it is clear that much fundamental research remains to be done, potentially important therapeutic options include narrow spectrum antibiotics, novel probiotics, dietary interventions and more radical techniques such as faecal transplantation, all of which aim to suppress clinical dysbiosis, restore intestinal microbiota diversity and improve host health. 23961783 Possible association of hepatitis C virus infection with late-onset psoriasis: A hospital-based observational study. Psoriasis is a chronic inflammatory disease mainly involving the skin and joints, mediated by pro-inflammatory cytokine tumor necrosis factor (TNF)-α. In hepatitis C, continuous inflammation mediated by TNF-α leads to liver cirrhosis and diabetes mellitus. Hence, psoriasis and hepatitis C have pathophysiological factors in common. An epidemiological association between the two conditions has been reported, but no detailed research has yet been performed. Frequency of hepatitis C virus (HCV) infection was assessed in 717 patients with psoriasis and 38 057 with all other dermatological diseases who visited Fukuoka University Hospital in 1998-2011. HCV(+) and HCV(-) psoriatic patients were further compared. Frequency of HCV infection was significantly higher in psoriasis (7.5%) than in controls (3.3%) in overall ages. When stratified by age at the first visit, the frequency was significantly higher in patients with psoriasis than in controls aged in their 60s (11.8% vs 6.6%, respectively, P = 0.0215) and 70s (19.5% vs 7.3%, P < 0.0001). HCV(+) psoriatic patients were significantly older at onset than HCV(-) ones (median, 54 vs 39 years), stronger male predominance (male/female ratio, 4.4:1), similar family history of psoriasis, higher association of diabetes mellitus and hypertension, and significantly lower body mass index (22.4 ± 2.73 vs 24.2 ± 4.61), in age-stratified (≥40 years) analysis. HCV(+) psoriatic patients were less obese, but still had a higher frequency of diabetes mellitus and hypertension, possibly due to chronic inflammation in the liver and other organs. HCV infection may trigger psoriasis, especially late-onset psoriasis, possibly via overproduction of TNF-α, a common mediator of the two conditions. 23969729 Reduced expression of bone morphogenetic protein receptor IA in pancreatic cancer is associated with a poor prognosis. Background:The expression of SMAD4, the central component of the transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signalling pathways, is lost in 50% of pancreatic cancers and is associated with a poor survival. Although the TGF-β pathway has been extensively studied and characterised in pancreatic cancer, there is very limited data on BMP signalling, a well-known tumour-suppressor pathway. BMP signalling can be lost not only at the level of SMAD4 but also at the level of BMP receptors (BMPRs), as has been described in colorectal cancer.Methods:We performed immunohistochemical analysis of the expression levels of BMP signalling components in pancreatic cancer and correlated these with survival. We also manipulated the activity of BMP signalling in vitro.Results:Reduced expression of BMPRIA is associated with a significantly worse survival, primarily in a subset of SMAD4-positive cancers. In vitro inactivation of SMAD4-dependent BMP signalling increases proliferation and invasion of pancreatic cancer cells, whereas inactivation of BMP signalling in SMAD4-negative cell does not change the proliferation and invasion or leads to an opposite effect.Conclusion:Our data suggest that BMPRIA expression is a good prognostic marker and that the BMP pathway is a potential target for future therapeutic interventions in pancreatic cancer.British Journal of Cancer advance online publication, 22 August 2013; doi:10.1038/bjc.2013.486 www.bjcancer.com. 23228849 A naonoporous cell-therapy device with controllable biodegradation for long-term drug release. Herein we describe the development and implementation of a nanoporous cell-therapy device with controllable biodegradation. Dopamine-secreting PC12 cells were housed within newly formulated alginate-glutamine degradable polylysine (A-GD-PLL) microcapsules. The A-GD-PLL microcapsules provided a 3-D microenvironment for good spatial cell growth, viability and proliferation. The microcapsules were subsequently placed within a poly(ethylene glycol) (PEG)-coated poly(ε-caprolactone) (PCL) chamber covered with a PEG-grafted PCL nanoporous membrane formed by phase inversion. To enhance PC12 cell growth and to assist in controlled degradation of both the PC12 cells and the device construct, small PCL capsules containing neural growth factor (PCL-NGF) and a poly(lactic-co-glycolic acid) pellet containing glutamine (PLGA-GLN) were also placed within the PCL chamber. Release of NGF from the PCL-NGF capsules facilitated cell proliferation and viability, while the controlled release of GLN from the PLGA-GLN pellet resulted in A-GD-PLL microcapsule degradation and eventual PC12 cell death following a pre-specified period of time (4 weeks in this study). In vivo, our device was found to be well tolerated and we successfully demonstrated the controlled release of dopamine over a period of four weeks. This integrated biodegradable device holds great promise for the future treatment of a variety of diseases. 23648835 In vivo distribution and ex vivo permeation of cyclosporine A prodrug aqueous formulations for ocular application. Cyclosporine A is a poorly water-soluble, immunosuppressive drug used to treat a variety of ocular diseases. Its limited solubility makes challenging the development of a cyclosporine A-based eye drop for ocular topical application. Based on the prodrug strategy, the practically insoluble cyclosporine A was converted into a freely soluble prodrug. Such a water-soluble prodrug made it possible to develop water-based concentrated eye drops. The prodrug formulations were tested for their ex vivo permeation and in vivo distribution at three concentrations (equivalent to 0.05%, 0.50% and 2.00% w/v cyclosporine A). The ex vivo permeation experiments were performed on corneal and conjunctival epithelia. The in vivo distribution evaluated the total cyclosporine A present in the ocular structures as well as in serum, spleen and cervical lymphatic ganglions. Each prodrug formulation was compared to conventionally used cyclosporine A eye drops at an equivalent concentration. The experimental results showed that the tested eye drops behaved differently. The prodrug formulation was characterized by the following: i) preferential conjunctival penetration, ii) an interesting capacity to create large tissue deposits and iii) a lower risk of systemic complications and immunosuppression. The prodrug aqueous eye drop was demonstrated to be a patient-friendly option for the treatment of ocular diseases requiring high ocular levels of cyclosporine A, pushing the boundaries of the current therapeutic arsenal. 23499299 Metastasis dynamics for non-small-cell lung cancer: effect of patient and tumor-related factors. We studied event dynamics (probability of an event occurring over a specific time interval) in patients undergoing surgery for early-stage non-small-cell lung cancer (NSCLC) according to patient and tumor characteristics. By using a database of 1506 patients who underwent initial surgery for NSCLC, event dynamics, based on a time-specific hazard rate, were evaluated. The event of interest was the development of distant metastases, with or without a local recurrence. The effect of sex, tumor size, nodal involvement, histology, lymphovascular space invasion, pleural invasion, age, and race were studied. The hazard rate for developing distant metastases was not constant over time but was characterized by specific peaks, the first being approximately 9 months after surgery and the second at 18 to 20 months for men and 24 to 26 months for women. For women, the hazard rate peaked considerably in the first year. For men, the hazard rate peaks were smaller but lasted for a longer duration. Pathologic factors associated with a higher risk of recurrence (eg, size, lymph node involvement, pleural invasion) all increased the sex-specific hazard rates. The probability of developing distant metastases after surgery for NSCLC peaks at specific and consistent time intervals after surgery, with specific differences between men and women. A factor-specific modulation of peak heights that ranged from no impact (eg, race) to relevant effects for primary tumor size, nodal involvement, and pleural invasion, possibly related to sex, was also observed. The bimodal distant metastases dynamics may be an intrinsic feature of metastatic progression in NSCLC. 23813782 Heterologous prime-boost immunization regimens using adenovirus vector and virus-like particles induce broadly neutralizing antibodies against H5N1 avian influenza viruses. Highly pathogenic avian influenza (HPAI) H5N1 viruses continue to trigger severe diseases in poultry and humans, prompting efforts to develop an effective vaccine. Toward that goal, we constructed a recombinant adenovirus vector encoding influenza hemagglutin (rAd-HA) and a flagellin-containing virus-like particle (FliC-VLP). Using a murine model, we investigated a heterologous prime-boost vaccination regimen combining these two vectors. Our results indicate that priming with the rAd-HA vector followed by a FliC-VLP booster induced the highest HA-specific total IgG, IgG1and IgG2a. Maximum neutralizing antibody titers against homologous and heterologous clades of H5N1 virus strains and hemagglutination inhibition resulted from the heterologous vaccination strategy. Our results are likely to contribute to the development of more effective H5N1 vaccines. 23503898 The epidemiology of Schmorl's nodes and their correlation to radiographic degeneration in 4,151 subjects. Schmorl's nodes (SNs) are commonly seen in vertebral imaging of the normal adult population referred for different reasons and are duly noted by the radiologist. However, little is known about their etiology: either SNs are perceived as largely inert developmental or congenital herniations of disc tissue into weak areas of the vertebral end-plates, or they are perceived as a common pathological pathway of different adverse and general factors such as malignancy, trauma, infection, osteoporosis, Paget's disease and so forth. A commonly accepted morphological definition of what precisely constitute SNs does not exist, and consequently prevalences vary wildly in the literature. In the present study of 4,151 standardized lateral radiographs of the lumbar spine in an adult, Caucasian population between 22 and 93 years (median age 63 years, M 1,533, W 2,618). We investigated prevalence, distribution and epidemiologic relationships of SNs. SNs occur primarily in the upper part of the lumbar spine, and usually there are multiple lesions in the same individual. We could not establish any significant correlation between SNs and gender, age, BMI, height, weight or occupational exposure for heavy lifting. The overall prevalence was 3.8 %. We did not find any significant correlations between SNs and overall degeneration of the lumbar spine. We found a prevalence of SNs in the lower end of the spectrum than hitherto reported. 23878298 Public availability of results of trials assessing cancer drugs in the United States. To evaluate to what extent results of completed trials of cancer drugs conducted in the United States are publicly available at ClinicalTrials.gov, as required by the Food and Drug Administration Amendments Act (FDAAA), or are published in journals. We searched ClinicalTrials.gov for cancer trials governed by the FDAAA: phase II to IV trials assessing drugs in the United States with a primary completion date between December 26, 2007, and May 31, 2010. For each trial, we also searched PubMed to identify the publication of results. We assessed the cumulative percentages of posted or published results over time by using the Kaplan-Meier method. We identified 646 trials, including 209 randomized controlled trials (RCTs). At 12 months after completion of the trials, the cumulative percentages of trials with results posted at ClinicalTrials.gov, published in journals, and available either at ClinicalTrials.gov or in journals were 9% (95% CI, 7% to 11%), 12% (95% CI, 10% to 15%), and 20% (95% CI, 17% to 23%), respectively, and for RCTs, the percentages were 12% (95% CI, 8% to 16%), 5% (95% CI, 2% to 8%), and 17% (95% CI, 12% to 22%), respectively. At 36 months, these percentages were 31% (95% CI, 28% to 35%), 35% (95% CI, 31% to 39%), and 55% (95% CI, 51% to 59%), respectively, and for RCTs, they were 38% (95% CI, 31% to 45%), 32% (95% CI, 25% to 39%), and 56% (95% CI, 48% to 62%), respectively. Public availability of phase III trials was 15% (95% CI, 7% to 23%) at 12 months, 39% (95% CI, 27% to 49%) at 24 months, and 64% (95% CI, 50% to 73%) at 36 months. Despite the FDAAA, results for nearly half the trials of cancer drugs in the United States were not publicly available 3 years after completion of the trials. 23917081 Endometrial echo complex thickness in postmenopausal endometrial cancer. To determine the preoperative pelvic ultrasonographic characteristics of postmenopausal women diagnosed with endometrial cancer (EC) at our institution. Postmenopausal women with EC who underwent preoperative transvaginal pelvic ultrasound from 1999-2009 were identified from our institutional database. The histologic diagnosis was based on pathologic findings in the hysterectomy specimen. Endometrial echo complex (EEC) thickness was abstracted from ultrasound reports. In all instances, ultrasound preceded the biopsy by a maximum of 3months. Means with standard deviations were calculated for all categorical data. Differences between type 1 and type 2 ECs were determined using Mann-Whitney U tests and Chi squared/Fisher's exact tests, as appropriate. A p-value of <0.05 was considered statistically significant. Among 250 patients with postmenopausal EC, 156 had type 1 EC while 94 had type 2 EC. Thirty-six percent of the cohort had an EEC ≤4mm, including 37% of patients with type 1 EC and 34% of patients with type 2 EC (p=0.63). There were no significant differences between type 1 and type 2 ECs in any demographic characteristic, other than likelihood of postmenopausal bleeding. Current expert opinion recommends no further diagnostic procedure in a woman with postmenopausal bleeding and an EEC ≤4mm. These results indicate that a sizable proportion of women with EC have EECs ≤4mm during their initial evaluation. An EEC ≤4mm does not completely rule out endometrial cancer and cannot supplant histologic evaluation. 23085120 Bis(12)-hupyridone, a novel acetylcholinesterase inhibitor, protects against glutamate-induced neuronal excitotoxicity via activating α7 nicotinic acetylcholine receptor/phosphoinositide 3-kinase/Akt cascade. Bis(12)-hupyridone (B12H), derived from the Chinese medicinal component huperzine A, was originally designed as a novel acetylcholinesterase (AChE) inhibitor. In this paper, we report that B12H (24-h pretreatment) effectively blocked glutamate-induced neuronal excitotoxicity in cerebellar granule neurons (CGNs). However, the huge discrepancy between the EC50 value and IC50 value of B12H, to protect against neuronal toxicity (0.09μM) and to block the NMDA receptor (21.8μM) respectively, suggests that the neuroprotection of B12H might be not primarily due to the blockade of the NMDA receptor. Pretreatment by specific antagonists of alpha7-nicotinic acetylcholine receptor (α7nAChR), but not muscarinic acetylcholine receptor (mAChR) or α4β2nAChR, decreased the neuroprotection of B12H. The neuroprotection of B12H could also be abolished by the pretreatment of specific PI3-K inhibitors. Furthermore, B12H restored the suppressed activation of the Akt pathway caused by glutamate as evidenced by the decreased expressions of pSer473-Akt and pSer9-GSK3β. All these results suggest that B12H substantially protected CGNs against glutamate-induced neuronal excitotoxicity via activating α7nAChR/PI3-K/Akt cascade. 23219342 Ginkgo biloba leaves extract (EGb 761) attenuates lipopolysaccharide-induced acute lung injury via inhibition of oxidative stress and NF-κB-dependent matrix metalloproteinase-9 pathway. Acute lung injury (ALI) presents high mortality and morbidity clinically and by far no effective preventive strategy has been established. Extract of Ginkgo biloba leaves, EGb 761, is a complex mixture that possesses several clinical beneficial effects such as anti-oxidation, anti-inflammation, anti-tumor, and cardioprotective property. With EGb 761 pretreatment, both lipopolysaccharide (LPS)-induced protein leakage and neutrophil infiltration, and LPS-induced inflammatory responses including increased myeloperoxidase (MPO) activity, lipid peroxidation, and metalloproteinase (MMP)-9 activity, were inhibited; LPS-suppressed activation of antioxidative enzymes (AOE) were reversed; and not only the phosphorylation of NF-κB but also the degradation of its inhibitor, IκB, were suppressed. These results suggested that the protection mechanism of EGb 761 is by inhibition of NFκB activation, possibly via the up-regulation of antioxidative enzymes. More studies are needed to further evaluate whether EGb 761 is a suitable candidate as an effective dietary strategy to reduce the incidence of endotoxin-induced ALI. 23160931 The effect of C-vacancy on hydrogen storage and characterization of H2 modes on Ti functionalized C60 fullerene a first principles study. Density functional theory calculations were performed to examine the effect of a C vacancy on the physisorption of H(2) onto Ti-functionalized C(60) fullerene when H(2) is oriented along the x-, y-, and z-axes of the fullerene. The effect of the C vacancy on the physisorption modes of H(2) was investigated as a function of H(2) binding energy within the energy window (-0.2 to -0.6 eV) targeted by the Department of Energy (DOE), and as functions of a variety of other physicochemical properties. The results indicate that the preferential orientations of H(2) in the defect-free (i.e., no C vacancy) C(60)TiH(2) complex are along the x- and y-axes of C(60) (with adsorption energies of -0.23 and -0.21 eV, respectively), making these orientations the most suitable ones for hydrogen storage, in contrast to the results obtained for defect-containing fullerenes. The defect-containing (i.e., containing a C vacancy) C(59)TiH(2) complex do not exhibit adsorption energies within the targeted energy range. Charge transfer occurs from Ti 3d to C 2p of the fullerene. The binding of H(2) is dominated by the pairwise support-metal interaction energy E(i)(Cn...Ti), and the role of the fullerene is not restricted to supporting the metal. The C vacancy enhances the adsorption energy of Ti, in contrast to that of H(2). A significant reduction in the energy gap of the pristine C(60) fullerene is observed when TiH(2) is adsorbed by it. While the C( n ) fullerene readily participates in nucleophilic processes, the adjacent TiH(2) fragment is available for electrophilic processes. 23824956 Icariin: Does It Have An Osteoinductive Potential for Bone Tissue Engineering? Traditional Chinese medicines have been recommended for bone regeneration and repair for thousands of years. Currently, the Herba Epimedii and its multi-component formulation are the attractive native herbs for the treatment of osteoporosis. Icariin, a typical flavonol glycoside, is considered to be the main active ingredient of the Herba Epimedii from which icariin has been successfully extracted. Most interestingly, it has been reported that icariin can be delivered locally by biomaterials and that it has an osteoinductive potential for bone tissue engineering. This review focuses on the performance of icariin in bone tissue engineering and on blending the information from icariin with the current knowledge relevant to molecular mechanisms and signal pathways. The osteoinductive potential of icariin could be attributed to its multiple functions in the musculoskeletal system which is involved in the regulation of multiple signaling pathways in anti-osteoporosis, osteogenesis, anti-osteoclastogenesis, chondrogenesis, angiogenesis, and anti-inflammation. The osteoinductive potential and the low price of icariin make it a very attractive candidate as a substitute of osteoinductive protein-bone morphogenetic proteins (BMPs), or as a promoter for enhancing the therapeutic effects of BMPs. However, the effectiveness of the local delivery of icariin needs to be investigated further. Copyright © 2013 John Wiley & Sons, Ltd. 23927657 Attention HIV: older African American women define sexual risk. Understanding sexual-risk behaviours as defined by a culture presents new challenges for human service professionals. Older African American women constitute the fastest growing group of new cases of HIV in the USA. With heterosexual sex as the primary mode of transmission among this group, there exist minimal programmes that are culture and age-specific in terms of primary and secondary prevention. In an attempt to address this gap in knowledge, this study examined how a group of older African American women defined sexual-risk behaviour. A focus group was conducted with seven women age 45 and older, who were recruited from a community centre. This paper examines the way that sexual-risk behaviour was defined through thematic analysis and conceptualises the locus of sexual risk behaviour as defined by the participants. The major theme of the study was social prescription, how to behave sexually as an ageing adult. Underlying ideas that arose were that unprotected sex occurred out of habit, that impulsivity was associated with risky sex and that older women needed to be aware of warning signs and behaviours of potential mates. Micro- and macro-level implications for human service professionals are discussed. 22824189 Egis-11150: a candidate antipsychotic compound with procognitive efficacy in rodents. Classical antipsychotics, e.g. haloperidol, chlorpromazine, are potent at controlling the positive symptoms of schizophrenia but frequently elicit extrapyramidal motor side-effects. The introduction of atypical antipsychotics such as risperidone, olanzapine and clozapine has obviated this problem, but none of the current drugs seem to improve the cognitive deficits accompanying schizophrenia. Thus there is an unmet need for agents that not only suppress the psychotic symptoms but also ameliorate the impairment of cognition. Here, we report the preclinical properties of a candidate antipsychotic, Egis-11150, that shows marked pro-cognitive efficacy. Egis-11150 displayed high affinity for adrenergic α(1), α(2c), 5-HT(2A) 5-HT₇, moderate affinity for adrenergic α(2a) and D₂ receptors. It was a functional antagonist on all of the above receptors, with the exception of 5-HT₇ receptors, where it was an inverse agonist. Phencyclidine-induced hypermotility in mice and inhibition of conditioned avoidance response in rats were assessed to estimate efficacy against the positive and social withdrawal test in rats was used to predict efficacy against the negative symptoms of schizophrenia. Passive-avoidance learning, novel object recognition and radial maze tests in rats were used to assess pro-cognitive activity, while phencyclidine-induced disruption of prepulse inhibition in mice was examined to test for effects on attention. Egis-11150 (0.01-0.3 mg/kg, ip.) was effective in all of the preclinical models of schizophrenia examined. Moreover, a robust pro-cognitive profile was apparent. In summary, work in preclinical models indicates that Egis-11150 is a potential treatment for controlling the psychosis as well as the cognitive dysfunction in schizophrenia. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23831747 Reduction of sludge generation by the addition of support material in a cyclic activated sludge system for municipal wastewater treatment. An innovative biomass carrier (Biobob®) was tested for municipal wastewater treatment in an activated sludge system to evaluate the pollutant removal performance and the sludge generation for different carrier volumes. The experiment was carried out in a pilot-scale cyclic activated sludge system (CASS®) built with three cylindrical tanks in a series: an anoxic selector (2.1m(3)), an aerobic selector (2.5m(3)) and the main aerobic reactor (25.1m(3)). The results showed that by adding the Biobob® carrier decreased the MLVSS concentration, which consequently reduced the waste sludge production of the system. Having 7% and 18% (v/v) support material in the aerobic reactor, the observed biomass yield decreased 18% and 36%, respectively, relative to the reactor operated with suspended biomass. The addition of media did not affect the system's performance for COD and TSS removal. However, TKN and TN removal were improved by 24% and 14%, respectively, using 18% (v/v) carrier. 23299759 Antibodies against Yariv's reagent for immunolocalization of arabinogalactan-proteins in aerial parts of Echinacea purpurea. Arabinogalactan-proteins are glycoproteins that occur in higher plants and are involved in important processes like cell differentiation and plant growth. In the medicinal plant Echinacea purpurea L., they belong to the putative immunomodulating compounds and are structurally well characterized. For microscopic localization of arabinogalactan-proteins, synthetic (β-D-Glc)3 Yariv phenylglycoside that specifically binds to most plant arabinogalactan-proteins was used to label arabinogalactan-proteins in fresh cut sections of stems and petioles of Echinacea purpurea. Polyclonal antibodies against (β-D-Glc)3 Yariv phenylglycoside were used to detect the arabinogalactan-protein-(β-D-Glc)3 Yariv phenylglycoside complex. After addition of fluorescein isothiocyanate-conjugated secondary antibodies, the sections were analyzed by confocal laser scanning microscopy. Arabinogalactan-proteins are localized mainly in the central cylinder in the collateral vascular bundles, especially in the area of the xylem. In cell walls of fully differentiated vessels and tracheids, arabinogalactan-proteins have been detected mainly at the inner area of the wall close to the cell lumina. Intense labeling occurs around pit canals connecting adjacent vessels. Furthermore, arabinogalactan-proteins are present in the lumina of cells of the sclerenchyma caps and in companion cells of the phloem. 23970857 Neural correlates of auditory temporal predictions during sensorimotor synchronization. Musical ensemble performance requires temporally precise interpersonal action coordination. To play in synchrony, ensemble musicians presumably rely on anticipatory mechanisms that enable them to predict the timing of sounds produced by co-performers. Previous studies have shown that individuals differ in their ability to predict upcoming tempo changes in paced finger-tapping tasks (indexed by cross-correlations between tap timing and pacing events) and that the degree of such prediction influences the accuracy of sensorimotor synchronization (SMS) and interpersonal coordination in dyadic tapping tasks. The current functional magnetic resonance imaging study investigated the neural correlates of auditory temporal predictions during SMS in a within-subject design. Hemodynamic responses were recorded from 18 musicians while they tapped in synchrony with auditory sequences containing gradual tempo changes under conditions of varying cognitive load (achieved by a simultaneous visual n-back working-memory task comprising three levels of difficulty: observation only, 1-back, and 2-back object comparisons). Prediction ability during SMS decreased with increasing cognitive load. Results of a parametric analysis revealed that the generation of auditory temporal predictions during SMS recruits (1) a distributed network of cortico-cerebellar motor-related brain areas (left dorsal premotor and motor cortex, right lateral cerebellum, SMA proper and bilateral inferior parietal cortex) and (2) medial cortical areas (medial prefrontal cortex, posterior cingulate cortex). While the first network is presumably involved in basic sensory prediction, sensorimotor integration, motor timing, and temporal adaptation, activation in the second set of areas may be related to higher-level social-cognitive processes elicited during action coordination with auditory signals that resemble music performed by human agents. 23912602 Malignant transformation of metachronous bilateral Schneiderian inverted papilloma of the lacrimal sac: management considerations and the contentious issue of orbital exenteration. The authors present an unusual case of malignant transformation of metachronous bilateral Schneiderian inverted papilloma (IP) of the lacrimal sac. Such pathology has been sparingly covered in prior published literature, in particular with little formal discussion surrounding its optimal management. We describe the clinical presentation, course and management in a 35-year-old male with histopathological diagnosis of Squamous cell carcinoma (SCC) arising within IP. He underwent radical surgery, including orbital exenteration and medial maxillectomy. Our patient re-presented with IP in the contralateral side and subsequent malignant transformation to SCC with disseminated disease. Unfortunately he succumbed to disease approximately 20 months following initial surgery. This case raises several important questions with regard to appropriate treatment. In particular, we discuss the various management options with special consideration given to the contentious topic of orbital exenteration in such patients. We emphasise two particular controversial issues, namely, oncological efficacy of orbital preservation and the functional compromise that may result in the preserved eye. 23132152 Footfall placement variability and falls in multiple sclerosis. Gait variability (i.e., fluctuations in walking) provides unique information about the control of movement and is associated with falls. This investigation examined the association between gait variability and falls in persons with multiple sclerosis (MS) and healthy controls. Traditional distributional metrics of gait variability (i.e., coefficient of variation (CV)) and a novel metric based on Fourier series analysis of footfall placement variability were determined for 41 individuals with MS and 20 age- and sex-matched controls. Spatiotemporal parameters of gait were collected using a 7.9 m electronic walkway that recorded individual footfalls during steady state comfortable walking. Persons with MS were divided into two groups based on fall history (non-fallers and recurrent fallers). Overall, persons with MS had greater gait variability than controls as indexed by CV and Fourier-based variability (p's < 0.05). Moreover, recurrent fallers with MS had greater Fourier-based variability than non-fallers with MS (p = 0.025), whereas there was no difference in MS groups in traditional gait variability metrics (p > 0.05). These observations highlight that footfall placement variability is related to fall status in MS. Future work determining the sensitivity of footfall placement variability to dysfunction is warranted. 23904250 Annexin 1: A glucocorticoid-inducible protein that modulates inflammatory pain. Annexin 1, a glucocorticoid (GC)-inducible protein, can play an important role via formyl peptide receptor like 1 (FPR2/ALX, also known as FPRL1) in inflammatory pain modulation. The aim of this review is to analyze different lines of evidence for the role of ANXA1 with different mechanisms on inflammatory pain and describe the profile of ANXA1 as a potential analgesic. A Medline (PUBMED) search using the terms 'Annexin 1 distribution OR expression, FPR2/ALX distribution OR expression, Annexin 1 AND pain, Annexin 1 AND FPR2/ALX AND pain' was performed. Articles with a publication date up to Nov. 1st, 2012 were included. The antinociception of ANXA1 has been evaluated in diverse pain models. It has been suggested that ANXA1 may exerts its action via: (1) inhibiting vital cytokines involved in pain transmission, (2) inhibiting neutrophil accumulation through preventing transendothelial migration via an interaction with formyl peptide receptors, (3) facilitating tonic opioid release from neutrophil in inflammatory site, (4) interrupting the peripheral nociceptive transmission by suppressing neuronal excitability. In general, ANXA1 is a potential mediator for anti-nociception and the role with its receptor constitute attractive targets for developing anesthesia and analgesic drugs, and their interaction may prove to be a useful strategy to treat inflammatory pain. 23838043 Peroxyacetyl nitrate (PAN) in the urban atmosphere. Peroxyacetyl nitrate (PAN) in air has been well known as the indicator of photochemical smog due to its frequent occurrences in Seoul metropolitan area. This study was implemented to assess the distribution characteristics of atmospheric PAN in association with relevant parameters measured concurrently. During a full year period in 2011, PAN was continuously measured at hourly intervals at two monitoring sites, Gwang Jin (GJ) and Gang Seo (GS) in the megacity of Seoul, South Korea. The annual mean concentrations of PAN during the study period were 0.64±0.49 and 0.57±0.46ppb, respectively. The seasonal trends of PAN generally exhibited dual peaks in both early spring and fall, regardless of sites. Their diurnal trends were fairly comparable to each other. There was a slight time lag (e.g., 1h) in the peak occurrence pattern between O3 and PAN, as the latter trended to peak after the maximum UV irradiance period (16:00 (GJ) and 17:00 (GS)). The concentrations of PAN generally exhibited strong correlations with particulates. The results of this study suggest that PAN concentrations were affected sensitively by atmospheric stability, the wet deposition of NO2, wind direction, and other factors. 23187157 Factors Predictive of Early Radiographic Failure After Closed Reduction of Gartland Type II Supracondylar Humeral Fractures. Supracondylar humerus fractures are the most common elbow fractures seen in the pediatric population. The American Academy of Orthopedic Surgeons Board of Directors recently published clinical practice guidelines recommending surgical treatment for all displaced fractures. We sought to identify predictive factors to assist the orthopedic surgeon in identifying which type II fractures are more likely to fail closed reduction and immobilization without pinning. This was a retrospective cohort study. This study was conducted at a pediatric medical center in the Midwestern United States. This study analyzed 29 patients who underwent closed reduction and immobilization for significantly displaced, type II supracondylar humerus fractures. We compared the lateral capitellar humeral angle, Baumann angle, and anterior humeral line index at the time of presentation, postreduction, and at final follow-up. Two statistically similar groups were identified based on the amount of initial displacement. Variables were examined between the 2 groups including age, gender, initial displacement, quality of initial reduction, treatment in cast or splint, and position of immobilization. Forty-eight percent of the patients failed closed reduction and immobilization, with an average 71% loss of initial reduction at final follow-up. None of the examined variables were statistically significant or had any predictive value for failure. Our study suggests that type II fractures should be viewed as a spectrum of injury. Our data show that a significantly displaced type II fracture that requires a reduction to obtain satisfactory alignment has a 48% chance of losing that reduction without percutaneous pinning. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. 23410221 Newly observed spontaneous activation of ethephon as a butyrylcholinesterase inhibitor. The plant growth regulator ethephon (2-chloroethylphosphonic acid) inhibits human butyrylcholinesterase (BChE) by making a covalent adduct on the active site serine 198. Our goal was to extend earlier studies on ethephon inhibition. Addition of freshly prepared ethephon to BChE in buffered medium, at pH 7.0 and 22 °C, resulted in no inhibition initially. However, inhibition developed progressively over 60 min of incubation. Preincubation of ethephon in pH 7-9 buffers increased its initial inhibitory potency. These observations indicated that ethephon itself was not the inhibitor. About 3% of the initial ethephon could be trapped as a BChE adduct. Mass spectral analysis of the active site peptide from inhibited BChE showed that the inhibitor added a mass of 108 Da to the active site serine on peptide FGES198AGAAS. This result rules out a previous hypothesis that ethephon adds HPO3 to BChE (added mass of 80 Da). To accommodate these observations, we propose that in aqueous media at neutral to slightly alkaline pH about 3% of the ethephon is converted (t1/2 = 9.9 h at pH 7.0) into a cyclic oxaphosphetane which is the actual BChE inhibitor forming the 2-hydroxyethylphosphonate adduct on BChE at Ser198 while about 97% of the ethephon breaks down to ethylene (t1/2 = 11-48 h at pH 7.0) which is responsible for plant growth regulation. 23820795 Randomized prospective trial of hyperbaric oxygen therapy and intratympanic steroid injection as salvage treatment of sudden sensorineural hearing loss. To compare the effects of hyperbaric oxygen (HBO) and intratympanic (IT) steroid injection on hearing after the failure of primary treatment in patients with idiopathic sudden sensorineural hearing loss (ISSHL). A prospective randomized trial. Tertiary referral center. Fifty patients with failure of primary therapy for ISSHL. After primary treatment with systemic steroids and failure of therapy, defined as less than 10-dB hearing gain, 50 patients were enrolled in the study and received either hyperbaric oxygen or intratympanic steroid treatment. The patients were not matched and not similar. Hearing gain at 0.25, 0.5, 1, 2, and 4 kHz after treatment. There were significant differences between hearing thresholds at all frequencies before and after the HBO treatment. Similarly, there were significant differences between hearing thresholds at most frequencies (except 2 kHz) before and after the treatment in the IT group. The subgroups of patients with pure tone average less than 81 dB and were younger than 60 years had better response to HBO treatment than those with profound deafness and in the elderly. HBO and IT steroid therapy could be successfully used as salvage therapies in patients with sudden deafness. Further study is needed to demonstrate superiority of one of the treatments. 23904340 Investigation of serum bisphenol A, vitamin D, and parathyroid hormone levels in patients with obstructive sleep apnea syndrome. Obstructive sleep apnea syndrome (OSAS) is a common health problem, and associated with obesity, metabolic syndrome (MetS), and diabetes. Growing evidence shows that 25-hydroxyvitamin-D3 (25-OH-D) insufficiency and high parathyroid hormone (PTH) levels may be correlated to glucose intolerance, MetS, obesity, and cardiovascular abnormalities similar to OSAS. Bisphenol A (BPA) is an endocrine disruptor agent which exerts a wide variety of metabolic effects. It has estrogenic activity and its exposure may contribute to weight gain, obesity, impaired glucose metabolism, and the development of diabetes, also similar to OSAS. The aim of this study is to investigate the relationships between OSAS and serum BPA, 25-OH-D, and PTH levels. This study enrolled 128 subjects, with all of the OSAS patients having been diagnosed by polysomnography. The 128 subjects were divided into three groups: a control (n = 43), a moderate OSAS (n = 23) (AHI = 15-30), and a severe OSAS groups (n = 62) (AHI > 30). The serum BPA, 25-OH-D, and PTH levels for each subject were analyzed. 25-OH-D was lower in both OSAS groups, and PTH was higher in the OSAS groups than in the control subjects. The BPA levels were higher in the severe OSAS group than the moderate OSAS and control. There was a positive correlation between the BPA and body mass index, and a negative correlation between the 25-OH-D and BPA levels in all of the individuals. OSAS is related to high BPA and PTH levels, and low vitamin D levels. There is a positive association between BPA levels and OSAS, and the severity of OSAS. These results suggest that the BPA levels may have a role in the pathogenesis of OSAS. 23165591 Development of automated paper-based devices for sequential multistep sandwich enzyme-linked immunosorbent assays using inkjet printing. To the best of our knowledge, this is the first report on paper-based devices for automating the sequential multistep procedures of a sandwich-type enzyme-linked immunosorbent assay (ELISA) that require only a single-step application of the sample solution. The device was based on a piece of nitrocellulose (NC) membrane with specially designed channels, where all the reagents are applied at different locations in order to control the fluid travel to the detection region. The inkjet printing method, a simple and low-cost process, was used to create the flow channel and device barrier patterns. The fabricated barrier was found to be an efficient boundary for the liquid along the printed design in the NC membrane, enabling direct control of the reagent flow time. ELISA results were obtained with a single-step sample application. The developed devices (so-called automated paper-based devices) provided a simple procedure for the sandwich ELISA, while reducing assay time and reagent consumption. Colorimetric results were measured using digital camera imaging with software processing. The capability of the method developed herein was successfully used to determine the levels of human chorionic gonadotropin (hCG) by ELISA. 23670170 Paracetamol, aspirin and indomethacin display endocrine disrupting properties in the adult human testis in vitro. Do mild analgesics affect the endocrine system of the human adult testis? Mild analgesics induce multiple endocrine disturbances in the human adult testis in vitro. Mild analgesics have recently been incriminated as potential endocrine disruptors. Studies of the effects of these widely used molecules on the androgenic status of men are limited and somewhat contradictory. This prompted us to investigate whether these compounds could alter the adult human testicular function. We therefore assessed in parallel the effects of paracetamol, aspirin and indomethacin on organo-cultured adult human testis and on the NCI-H295R steroid-producing human cell line. Adult human testis explants or NCI-H295R adrenocortical human cells were cultured with 10(-4) or 10(-5) M paracetamol, aspirin or indomethacin for 24-48 h. The effect of 10(-5) M ketoconazole, used as an anti-androgenic reference molecule, was also assessed. Testes were obtained from prostate cancer patients, who had not received any hormone therapy. The protocol was approved by the local ethics committee of Rennes, France and informed consent was given by the donors. Only testes displaying spermatogenesis, as assessed by transillumination, were used in this study. Hormone levels in the culture media were determined by radioimmunoassay (testosterone, insulin-like factor 3), Enzyme-Linked Immunosorbent Assay (inhibin B) or Enzyme Immunosorbent Assay [prostaglandin (PG) D2, and PGE2]. Tissues were observed and cells counted using classical immunohistochemical methods. The three mild analgesics caused multiple endocrine disturbances in the adult human testis. This was particularly apparent in the interstitial compartment. Effective doses were in the same range as those measured in blood plasma following standard analgesic treatment. The production of testosterone and insulin-like factor 3 by Leydig cells was altered by exposure to all these drugs. Inhibin B production by Sertoli cells was marginally affected by aspirin only. Our experiments also revealed that mild analgesics display direct anti-PG activity, which varied depending on the drug used, the dose and the duration of exposure. Nevertheless, associations between the alteration of the PG and testosterone profiles were not systematically observed, suggesting that a combination of mechanisms of endocrine disruption is at play. Our studies were performed in vitro. We provide the first evidence that direct exposure to mild analgesics can result in multiple endocrine disturbances in the human adult testis. Caution, concerning the consumption of mild analgesics by men, should be strengthened, particularly in high-risk population subgroups such as elite athletes. 23720421 SPE and purification of DNA using magnetic particles. Superparamagnetic particles have been attractive for molecular diagnostics and analytical chemistry applications due to their unique magnetic properties and their ability to interact with various biomolecules of interest. This paper presents a critical overview of magnetic nano- and microparticles used as a solid phase for extraction and purification of DNAs. The mechanisms of DNA binding to the surface of functionalised magnetic particles are described. The most widely used materials including silica supports, organic polymers and other materials, mostly containing magnetite or paramagnetic metallic elements are reviewed. The main application areas of magnetic particles for DNA separation are briefly described. 23957812 LHRH-targeted nanogels as delivery system for cisplatin to ovarian cancer. Targeted drug delivery using multifunctional polymeric nanocarriers is a modern approach for cancer therapy. Our purpose was to prepare targeted nanogels for selective delivery of chemotherapeutic agent cisplatin to luteinizing hormone-releasing hormone (LHRH) receptor overexpressing tumor in vivo. Building blocks of such delivery systems consisted of innovative soft block copolymer nanogels with ionic cores serving as a reservoir for cisplatin (loading 35%) and a synthetic analog of LHRH conjugated to the nanogels via poly(ethylene glycol) spacer. Covalent attachment of (D-Lys6)-LHRH to nanogels was shown to be possible without loss in either the ligand binding affinity or the ability of nanogels to incorporate the drug. LHRH-nanogel accumulation was specific to the LHRH-receptor positive A2780 ovarian cancer cells and not towards LHRH-receptor negative SKOV-3 cells. The LHRH-nanogel cisplatin formulation was more effective and less toxic than equimolar doses of free cisplatin or untargeted nanogels in the treatment of receptor-positive ovarian cancer xenografts in mice. Collectively, the study indicates that LHRH mediated nanogel-cisplatin delivery is a promising formulation strategy for therapy of tumors that express the LHRH receptor. 23843213 Meeting report: Trends in Bioanalytical Imaging. "Trends in Bioanalytical Imaging" - a DECHEMA event, was organized by leaders in bioanalytical imaging in Germany and took place in Frankfurt am Main on May 27-28, 2013. This meeting report covers the Raman spectroscopy section of the meeting. Image: MSI of barley grain, (©) Karin Gorzolka. 23444300 Light energy collection in a porphyrin-imide-corrole ensemble. An assembly consisting of three units, that is, a meso-substituted corrole (), 1,8 naphthaleneimide (), and a Zn porphyrin (), has been synthesized. NIE is connected to C3 through a 1,3-phenylene bridge and to the ZnP unit through a direct CC bond. The convergent synthetic strategy includes the preparation of a trans-A2 B-corrole possessing the imide unit, followed by Sonogashira coupling with a meso-substituted A3 B-porphyrin. The photophysical processes in the resulting triad are examined and compared with those of the corresponding dyad and the constituent reference models , , and . Excitation of the NIE unit in leads to a fast energy transfer of 98 % efficiency to C3 with a rate ken =7.5×10(10)  s(-1) , whereas excitation of the corrole unit leads to a reactivity of the excited state identical to that of the model , with a deactivation rate to the ground state k=2.5×10(8)  s(-1) . Energy transfer to C3 and to ZnP moieties follows excitation of NIE in the triad . The rates are ken =7.5×10(10)  s(-1) and ken =2.5×10(10)  s(-1) for the sensitization of the C3 and ZnP unit, respectively. The light energy transferred from NIE to Zn porphyrin unit is ultimately funneled to the corrole component, which is the final recipient of the excitation energy absorbed by the different components of the array. The latter process occurs with a rate ken =3.4×10(9)  s(-1) and 89 % efficiency. Energy transfer processes take place in all cases by a Förster (dipole-dipole) mechanism. The theory predicts quite satisfactorily the rate for the ZnP/C3 couple, where components are separated by about 23 Å, but results in calculated rates that are one to two orders of magnitude higher for the couples NIE/ZnP (D/A) and NIE/C3, which are separated by distances of about 14 and 10 Å, respectively. 23967207 Predictors of Raised Viral Load during Antiretroviral Therapy in Patients with and without Prior Antiretroviral Use: A Cross-Sectional Study. In Lagos, Nigeria, Médecins Sans Frontières (MSF) and the Ministry of Health (MoH) commenced free antiretroviral treatment (ART) in a hospital-based clinic. We performed a cross-sectional study to compare factors associated with raised viral load between patients with ("experienced") and without ("naïve") prior antiretroviral (ARV) exposure at commencement of ART at the clinic. We also examined factors influencing ARV adherence in experienced patients prior to clinic entry. We included adult patients receiving ART from MSF who answered a questionnaire about previous antiretroviral use. Multivariate logistic regression was used to estimate odds ratios (OR) for raised viral load (≥1000 copies/mL). 1246 (96%) patients answered: 1075 (86%) reported no, and 171 (14%) some, prior ARV exposure. ARV-naïve patients were more immunosuppressed at baseline: 65% vs 37% (p<0.001) had CD4<200; 17% vs 9% (p = 0.013) were WHO stage 4. Proportionately more experienced than naïve patients had raised viral loads (20% vs 9%, p<0.001) on ART in the MSF/MoH clinic. Raised viral load was associated with prior ARV experience (adjusted OR = 3.74, 95%CI 2.09-6.70, p<0.001) and complete interruption of current ART (adjusted OR = 3.71, 95%CI 2.06-6.68, p<0.001). Higher CD4 at time of VL and a higher self-rated score of recent adherence were associated with lower OR of a raised viral load. Among experienced patients who missed pills before joining MSF/MoH, most common reasons were because ARVS were not affordable (58%) or available (33%), with raised viral load associated with being unsure how to take them (OR = 3.16, 95%CI 1.10-9.12, p = 0.033). Patients previously exposed to ARVs had increased OR of raised viral load. The cost and availability of ARVs were common reasons for missing ARVs before joining the MSF/MoH clinic, and inadequate patient knowledge was associated with raised viral load. 23553771 Autologous uncultured bone marrow-derived mononuclear cells and modified cannulated screw in repair of femoral neck fracture. The purpose of this study was to assess whether autologous uncultured bone marrow-derived mononuclear cells (BMMNCs) combined with modified cannulated screw would accelerate the healing of canine femoral neck fracture. BMMNCs were encapsulated within fibrin glue (FG) and implanted into the fractured femoral neck via modified cannulated screw in experiment group, and the control group was treated by modified cannulated screw. Gross observation, radiological examination, histological analysis, and blood vessel microdensity counting were used to compare bone healing of each group at 1, 2, and 3 months. FG was confirmed as an ideal cell-delivery vehicle for BMMNCs proliferation and differentiation in vitro testing. In vivo animal testing, faster new bone formation and fracture healing were confirmed by gross observation, radiological examination, histological analysis in experimental group than in control group at all times points. The blood vessel microdensity counting increased gradually both in the experimental group and control group, but was more obviously in experimental group at 3 months (p < 0.01). These data suggest that autologous BMMNCs combined with modified cannulated screw treatment is an effective therapy for femoral neck fracture and thus, may be an option for clinical applications. 23861384 Meta-analyses of studies of the human microbiota. Our body habitat-associated microbial communities are of intense research interest because of their influence on human health. Because many studies of the microbiota are based on the same bacterial 16S ribosomal RNA (rRNA) gene target, they can, in principle, be compared to determine the relative importance of different disease/physiologic/developmental states. However, differences in experimental protocols used may produce variation that outweighs biological differences. By comparing 16S rRNA gene sequences generated from diverse studies of the human microbiota using the QIIME database (http://www.microbio.me/qiime/), we found that variation in composition of the microbiota across different body sites was consistently larger than technical variability across studies. However, samples from different studies of the Western adult fecal microbiota generally clustered by study, and the 16S rRNA target region, DNA extraction technique, and sequencing platform produced systematic biases in observed diversity that could obscure biologically meaningful compositional differences. In contrast, systematic compositional differences in the fecal microbiota that occurred with age and between Western and more agrarian cultures were great enough to outweigh technical variation. Furthermore, individuals with ileal Crohn's disease and in their third trimester of pregnancy often resembled infants from different studies more than controls from the same study, indicating parallel compositional attributes of these distinct developmental/physiological/disease states. Together, these results show that cross-study comparisons of human microbiota are valuable when the studied parameter has a large effect size, but studies of more subtle effects on the human microbiota requires carefully selected control populations and standardized protocols. 23765702 Proteomic analysis reveals a proteolytic feedback loop in murine seminal fluid. Matrix metalloproteinase 9 (MMP9) has been implicated in extracellular matrix (ECM) remodelling, angiogenesis and inflammation. However, the targets for proteolysis that lead to these physiological consequences are often undefined as is the regulation of MMP9 itself. Therefore, identification of both the potential direct and indirect targets of MMP9 is critical for further understanding the effects of its proteolytic cascades. To study these cascades on a wider scale, transgenic mouse "knock-out" models and ultra-high performance liquid chromatography mass spectroscopy (UPLC-MS(E) ) were used to elucidate the MMP9 targets, inhibitors, and interactors found in mouse seminal vesicle fluid (SVF). Proteomics analysis of SVF from wild type, mmp9-/- or pn1-/- mice detected differences in serine protease inhibitors (serpins), reproductive proteins, developmental regulators, and cancer proto-oncogenes, including Renin 1/2. Protease nexin 1 (PN1), an ECM-based inhibitor of urokinase, was elevated in the SVF of mmp9-/- mice. We observed that MMP9-mediated N-terminal cleavage of PN1 reduces this serpin's functional activity. Our data also suggest a feedback loop in which inhibition of PN1 is a critical step in permitting greater activity of MMP9. This study extends the degradome of MMP9 and examines components relevant to seminal fluid physiology. PN1 is proposed to be a novel inhibitor of MMP9 activity and a block to collagen cleavage, a frequent antecedent to cancer cell invasion. The interaction of MMP9 with PN1 and other serpins may lead to a better understanding of seminal vesicle function and possible impacts on fertility, as well as provide novel therapeutic targets. Prostate 73: 1427-1440, 2013. © 2013 Wiley Periodicals, Inc. 23335582 Pain Severity and Neuropathic Pain Symptoms in Primary Sjögren's Syndrome: A Comparison Study of Seropositive and Seronegative Sjögren's Syndrome Patients. To compare clinical characteristics and patient-reported outcomes in seropositive versus seronegative primary Sjögren's syndrome (SS) patients and to investigate the effect of serologic status on the prevalence of chronic pain, comorbidity, and health quality. Pain severity and neuropathic pain symptoms, comorbidity, and health status were assessed in 108 primary SS patients. Differences between patient groups were assessed by t-test and chi-square test, as well as adjusted pain-affect associations. The effect of predictor variables on pain severity was examined with multivariate regression. Pain severity was greater (P = 0.003) and physical function (P = 0.023) was reduced in the seronegative patients. Prevalence of neuropathic pain, depression, anxiety, and disability was similar between groups. Chronic pain, defined as daily pain for >3 months, was reported by 65% of seropositive (n = 65) and 75% of seronegative (n = 40) patients. After adjustment for age, sleep quality, and psychological distress, the difference in pain severity between seropositive and seronegative patients remained significant. Chronic pain is pervasive in both seropositive and seronegative primary SS patients, while pain severity and functional impairment are greater in seronegative patients. Neuropathic pain is equally prevalent and is the predominant pain phenotype in patients with moderate to severe pain. Accurate assessment of pain phenotypes is needed for more effective management of chronic pain in primary SS. The focus of future research should be to standardize assessment of pain and to identify the factors contributing to more severe pain in seronegative patients. 23864281 Working memory and insight in verbal problems: analysis of compound remote associates. Problem solving is sometimes accompanied by a sudden feeling of knowing, or insight. The specific cognitive processes that underlie insightful problem solving are a matter of great interest and debate. Although some investigators favor a special-process view, which explains insight in terms of specialized mechanisms that operate outside of conscious awareness, others favor a business-as-usual account, which posits that insightful problem solving involves the same conscious mechanisms-including working memory (WM) and attention-that are implicated in noninsightful problem solving. In the present study, we used an individual-differences approach to explore the contributions of WM and attention to the solution of compound remote associate (CRA) problems. On the basis of self-report insight ratings, we identified CRA problems whose solution was accompanied by a subjective feeling of insight and examined the correlations between problem performance and measures of WM capacity (verbal and spatial) and attention control (Stroop and antisaccade tasks). The results indicated that individual differences in verbal WM and attention significantly explained variation in overall CRA problem solving and, most importantly, in the occurrence of solutions that were accompanied by a feeling of insight. The findings implicated both modality-dependent WM mechanisms and modality-independent attention control mechanisms in this class of insight problems. Comparisons of the accuracy and solution-latency findings for insightfully versus noninsightfully solved CRA problems, and for participants working silently versus in a "think-aloud" condition, provided additional evidence against the special-process view, and reinforcing the business-as-usual account of insight. 23770291 Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Recent studies have indicated that the regulation of innate immunity and energy metabolism are connected together through an antagonistic crosstalk between NF-κB and SIRT1 signaling pathways. NF-κB signaling has a major role in innate immunity defense while SIRT1 regulates the oxidative respiration and cellular survival. However, NF-κB signaling can stimulate glycolytic energy flux during acute inflammation, whereas SIRT1 activation inhibits NF-κB signaling and enhances oxidative metabolism and the resolution of inflammation. SIRT1 inhibits NF-κB signaling directly by deacetylating the p65 subunit of NF-κB complex. SIRT1 stimulates oxidative energy production via the activation of AMPK, PPARα and PGC-1α and simultaneously, these factors inhibit NF-κB signaling and suppress inflammation. On the other hand, NF-κB signaling down-regulates SIRT1 activity through the expression of miR-34a, IFNγ, and reactive oxygen species. The inhibition of SIRT1 disrupts oxidative energy metabolism and stimulates the NF-κB-induced inflammatory responses present in many chronic metabolic and age-related diseases. We will examine the molecular mechanisms of the antagonistic signaling between NF-κB and SIRT1 and describe how this crosstalk controls inflammatory process and energy metabolism. In addition, we will discuss how disturbances in this signaling crosstalk induce the appearance of chronic inflammation in metabolic diseases. 23800196 Cost-effectiveness of personalized plaque control for managing the gingival manifestations of oral lichen planus: a randomized controlled study. To undertake cost-effectiveness and cost-benefit analyses of an intervention to improve oral health in patients presenting with the gingival manifestations of oral lichen planus (OLP). Eighty-two patients were recruited to a 20-week randomized controlled trial. The intervention was personalized plaque control comprising powered tooth brushing and inter-dental cleaning advice. The primary outcome measure was the oral health impact profile (OHIP) with secondary outcomes of pain, plaque index, mucosal disease score and cost-effectiveness. Private cost data and stated willingness-to-pay (WTP) values for treatment were obtained from intervention patients at 20 weeks. Overall, 81% of intervention patients showed improvement in both plaque index and mucosal disease score at 20 weeks compared to 30% of controls that continued with their usual plaque control regimen. All intervention group patients stated a positive WTP value. The mean net value of the treatment was £172 compared to the incremental cost of the treatment estimated at £122.75. The cost-effectiveness analysis resulted in an incremental cost-effectiveness ratio of £13 per OHIP point. The tailored plaque control programme was more effective than control in treating the gingival manifestations of oral lichen planus. The programme is cost effective for modest values placed on a point on the OHIP scale and patients generally valued the treatment in excess of the cost. 23863943 Potential use of synthetic α-galactosyl-containing glycotopes of the parasite Trypanosoma cruzi as diagnostic antigens for Chagas disease. A synthetic glycoarray containing non-reducing α-galactopyranosyl moieties related to mucin O-glycans of the parasite Trypanosoma cruzi was evaluated by a chemiluminescent enzyme-linked immunosorbent assay with sera from patients with chronic Chagas disease. Our data revealed the disaccharide Galα(1,3)Galβ as the immunodominant glycotope, which may eventually be employed as a diagnostic antigen for Chagas disease. 23910961 High-performance liquid chromatography with paired ion electrospray ionization (PIESI) tandem mass spectrometry for the highly sensitive determination of acidic pesticides in water. A novel method based on the paired ion electrospray ionization (PIESI) mass spectrometry has been developed for determination of acidic pesticides at ultratrace levels in surface and ground waters. The proposed approach provides greatly enhanced sensitivity for acidic pesticides and overcomes the drawbacks of the less sensitive negative ion mode ESI-MS. The limits of detection (LODs) of 19 acidic pesticides were evaluated with four types of dicationic ion-pairing reagent (IPR) in both single ion monitoring (SIM) and selected reaction monitoring (SRM) mode. The LOD of 19 pesticides obtained with the use the optimal dicationic ion-pairing reagent ranged from 0.6pg to 19pg, indicating the superior sensitivity provided by this method. The transition pathways for different pesticide-IPR complexes during the collision induced dissociation (CID) were identified. To evaluate and eliminate any matrix effects and further decrease the detection limits, off-line solid-phase extraction (SPE) was performed for DI water and a river water matrix spiked with 2000ngL(-1) and 20ngL(-1) pesticides standards respectively, which showed an average percent recovery of 93%. The chromatographic separation of the acidic pesticides was conducted by high-performance liquid chromatography (HPLC) using a C18 column (250mm×2.1mm) in the reversed phase mode using linear gradient elution. The optimized HPLC-PIESI-MS/MS method was utilized for determination of acidic pesticide at ngL(-1) level in stream/pond water samples. This experimental approach is 1-3 orders of magnitude more sensitive for these analytes than other reported methods performed in the negative ion mode. 23941666 Johan Turi's animal, mineral, vegetable cures and healing practices: an in-depth analysis of Sami (Saami) folk healing one hundred years ago. The healing knowledge of a Sami (Saami) hunter and reindeer herder was surveyed as a window into the concepts of health, healing, and disease in early twentieth-century Sapmi (Northern Sweden). The two books of Johan Turi (1854-1936)--An Account of the Sami (1910) and Lappish Texts (1918-19) were examined to determine the varieties of recorded zootherapeutic, mineral, chemical, and ethnobotanical lore, as well as the therapeutic acts, identified conditions, and veterinary knowledge included. Tabulation of the materials and species mentioned in Turi's descriptions (n = 137) permitted analysis of the relative frequency of differing types of healing in Turi's overall therapeutic repertoire, his relative attention to chronic vs. acute ailments, and the frequency of magic as a component of healing. A qualitative appraisal was made of the degree to which outside influences affected Sami healing of the period. A further assessment of the possible clinical efficacy of the recorded remedies was undertaken. Turi's remedies consist most often of zootherapeutics (31%), followed by physical acts such as massage, moxibustion, or manipulation (22%). Ethnobotanical cures make up a significantly smaller portion of his repertoire (17%), followed by mineral and chemical cures (12%). Magic rituals (including incantations and ritual acts) make up a significant portion of Turi's repertoire, and could be used alone (17%) or in conjunction with other types of healing (38%). Turi's healing aimed primarily at acute ailments (65%), with chronic conditions addressed less often (35%). A literature review revealed that Turi's remedies held a marked frequency of likely efficacy, at least in cases in which it was possible to ascertain the precise species, conditions, or substances described. Although it is possible at times to recognize foreign sources in Turi's repertoire, it is clear that Turi understood all his healing methods as distinctively Sami. The research illustrates the variety and depth of a single informant's healing knowledge, and demonstrates the value of both historical sources and in-depth data collection with single experts as useful means of assessing and characterizing an indigenous population's healing traditions. 23915007 Plasmonic Probe of the Semiconductor to Metal Phase Transition in Vanadium Dioxide. An array of 180 nm diameter gold nanoparticles (NPs) embedded in a thin vanadium dioxide film was used as a nanoscale probe of the thermochromic semiconductor-to-metal transition (SMT) in the VO2. The observed 30% reduction in plasmon dephasing time resulted from the interaction between the localized surface plasmon resonance of the NPs with the 1.4 eV electronic transitions in VO2. The NPs act as nanoantennas probing the SMT; homogeneous broadening of the gold plasmon resonance is observed at the temperatures where electron correlations are strongest in VO2. 23960217 Slow-fast dynamics of a time-delayed electro-optic oscillator. Square-wave oscillations exhibiting different plateau lengths have been observed experimentally by investigating an electro-optic oscillator. In a previous study, we analysed the model delay differential equations and determined an asymptotic approximation of the two plateaus. In this paper, we concentrate on the fast transition layers between plateaus and show how they contribute to the total period. We also investigate the bifurcation diagram of all possible stable solutions. We show that the square waves emerge from the first Hopf bifurcation of the basic steady state and that they may coexist with stable low-frequency periodic oscillations for the same value of the control parameter. 23850619 Off-target effect of the Epac agonist 8-pCPT-2'-O-Me-cAMP on P2Y12 receptors in blood platelets. The primary target of the cAMP analogue 8-pCPT-2'-O-Me-cAMP is exchange protein directly activated by cAMP (Epac). Here we tested potential off-target effects of the Epac activator on blood platelet activation signalling. We found that the Epac analogue 8-pCPT-2'-O-Me-cAMP inhibits agonist-induced-GPCR-stimulated, but not collagen-stimulated, P-selectin surface expression on Epac1 deficient platelets. In human platelets, 8-pCPT-2'-O-Me-cAMP inhibited P-selectin expression elicited by the PKC activator PMA. This effect was abolished in the presence of the extracellular ADP scavenger system CP/CPK. In silico modelling of 8-pCPT-2'O-Me-cAMP binding into the purinergic platelet receptor P2Y12 revealed that the analogue docks similar to the P2Y12 antagonist 2MeSAMP. The 8-pCPT-2'-O-Me-cAMP analogue per se, did not provoke Rap 1 (Rap 1-GTP) activation or phosphorylation on the vasodilator-stimulated phosphoprotein (VASP) at Ser-157. In addition, the protein kinase A (PKA) antagonists Rp-cAMPS and Rp-8-Br-cAMPS failed to block the inhibitory effect of 8-pCPT-2'-O-Me-cAMP on thrombin- and TRAP-induced Rap 1 activation, thus suggesting that PKA is not involved. We conclude that the 8-pCPT-2'-O-Me-cAMP analogue is able to inhibit agonist-induced-GPCR-stimulated P-selectin independent from Epac1; the off-target effect of the analogue appears to be mediated by antagonistic P2Y12 receptor binding. This has implications when using cAMP analogues on specialised system involving such receptors. We found, however that the Epac agonist 8-Br-2'-O-Me-cAMP did not affect platelet activation at similar concentrations. 23547729 Photoinduced and Thermal Denitrogenation of Bulky Triazoline Crystals: Insights into Solid-to-Solid Transformation. The photoinduced and thermal denitrogenation of crystalline triazolines with bulky substituents leads to the quantitative formation of aziridines in clean solid-to-solid reactions despite very large structural changes in the transition from reactant to product. Analysis of the reaction progress by powder X-ray diffraction, solid-state (13)C CPMAS NMR, solid-state FTIR spectroscopy, and thermal analysis has revealed that solid-to-solid reactions proceed either through metastable phases susceptible to amorphization or by mechanisms that involve a reconstructive phase transition that culminates in the formation of the stable phase of the product. While the key for a solid-to-solid transformation is that the reaction occurs below the eutectic temperature of the reactant and product two-component system, experimental evidence suggests that those reactions will undergo a reconstructive phase transition when they take place above the glass transition temperature. 23369734 Evolution of the unfolded protein response. The unfolded protein response (UPR) is a network of signaling pathways that responds to stress in the endoplasmic reticulum (ER). The general output of the UPR is to upregulate genes involved in ER function, thus restoring and/or increasing the capacity of the ER to fold and process proteins. In parallel, many organisms have mechanisms for limiting the load on the ER by attenuating translation or degrading ER-targeted mRNAs. Despite broad conservation of these signaling pathways across eukaryotes, interesting variations demonstrate a variety of mechanisms for managing ER stress. How do early-diverging protozoa respond to stress when they lack traditional transcriptional regulation? What is the role of the ER stress sensor Ire1 in fungal species that are missing its main target? Here I describe how diverse species have optimized the UPR to fit their needs. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum. 23853206 The polysaccharide inulin is characterized by an extensive series of periodic isoforms with varying biological actions. In studying the molecular basis for the potent immune activity of previously described gamma and delta inulin particles and to assist in production of inulin adjuvants under Good Manufacturing Practice, we identified five new inulin isoforms, bringing the total to seven plus the amorphous form. These isoforms comprise the step-wise inulin developmental series amorphous → alpha-1 (AI-1) → alpha-2 (AI-2) → gamma (GI) → delta (DI) → zeta (ZI) → epsilon (EI) → omega (OI) in which each higher isoform can be made either by precipitating dissolved inulin or by direct conversion from its precursor, both cases using regularly increasing temperatures. At higher temperatures, the shorter inulin polymer chains are released from the particle and so the key difference between isoforms is that each higher isoform comprises longer polymer chains than its precursor. An increasing trend of degree of polymerization is confirmed by end-group analysis using (1)H nuclear magnetic resonance spectroscopy. Inulin isoforms were characterized by the critical temperatures of abrupt phase-shifts (solubilizations or precipitations) in water suspensions. Such (aqueous) "melting" or "freezing" points are diagnostic and occur in strikingly periodic steps reflecting quantal increases in noncovalent bonding strength and increments in average polymer lengths. The (dry) melting points as measured by modulated differential scanning calorimetry similarly increase in regular steps. We conclude that the isoforms differ in repeated increments of a precisely repeating structural element. Each isoform has a different spectrum of biological activities and we show the higher inulin isoforms to be more potent alternative complement pathway activators. 23624774 Microfluidics and Raman microscopy: current applications and future challenges. Raman microscopy systems are becoming increasingly widespread and accessible for characterising chemical species. Microfluidic systems are also progressively finding their way into real world applications. Therefore, it is anticipated that the integration of Raman systems with microfluidics will become increasingly attractive and practical. This review aims to provide an overview of Raman microscopy-microfluidics integrated systems for researchers who are actively interested in utilising these tools. The fundamental principles and application strengths of Raman microscopy are discussed in the context of microfluidics. Various configurations of microfluidics that incorporate Raman microscopy methods are presented, with applications highlighted. Data analysis methods are discussed, with a focus on assisting the interpretation of Raman-microfluidics data from complex samples. Finally, possible future directions of Raman-microfluidic systems are presented. 22624955 Flavonoids and saponins from Zizyphus incurva. A new flavonol triglycoside, myricetin-3-O-[β-xylopyranosyl-(1-2)-α-rhamnopyranoside]-4'-O-α -rhamnopyranoside, named as bayarin (1), was isolated from the aerial parts of Zizyphus incurva Roxb. (Rhamnaceae) along with eight known compounds: six flavonoids and two saponins. All of these compounds were isolated for the first time from this plant. Structures of these compounds were elucidated on the basis of spectroscopic data. 23669178 RDFBuilder: a tool to automatically build RDF-based interfaces for MAGE-OM microarray data sources. This paper presents RDFBuilder, a tool that enables RDF-based access to MAGE-ML-compliant microarray databases. We have developed a system that automatically transforms the MAGE-OM model and microarray data stored in the ArrayExpress database into RDF format. Additionally, the system automatically enables a SPARQL endpoint. This allows users to execute SPARQL queries for retrieving microarray data, either from specific experiments or from more than one experiment at a time. Our system optimizes response times by caching and reusing information from previous queries. In this paper, we describe our methods for achieving this transformation. We show that our approach is complementary to other existing initiatives, such as Bio2RDF, for accessing and retrieving data from the ArrayExpress database. 23416846 In silico investigations of potential anabolic treatments in multiple myeloma-induced bone disease. No anabolic drugs are currently approved to treat multiple myeloma (MM)-induced bone disease and the anti-MM agent bortezomib exhibits the anabolic effects in the clinic. In this study, we focus on investigating potential anabolic treatments of MM-induced bone disease using our previously proposed MM-bone model, with the goal for clarifying the underlying molecular/cellular mechanisms. Firstly, a variety of virtual drug treatments are explored by the parametric study to clarify the anabolic-related molecular/cellular mechanisms. The real drug (i.e., bortezomib) treatments are further examined by developing an integrated model with bortezomib to validate the clarified anabolic-related molecular/cellular mechanisms. The simulated responses to the bortezomib treatments that are validated by the clinical data are consistent with the simulated responses to the virtual drug treatments. Our study clarifies that the anabolic effects in the treatment of MM-induced bone disease are associated with promoting the differentiation of bone marrow stromal cells (BMSC) and inhibiting the apoptosis of active osteoblasts, while promoting the differentiation of osteoblast precursors is instead suggested to be associated with the anti-catabolic effects. Compared with the individual anabolic therapies, the anabolic therapies that promote the differentiation of BMSC in combination with the anti-MM/anti-catabolic therapies are found to induce a greater increase in the bone volume, while the anabolic therapies that inhibit the apoptosis of active osteoblasts in combination with the anti-MM/anti-catabolic therapies induce a lower increase in the bone volume. The simulations also suggest that the direct inhibition of bortezomib on the osteoclast activity is probably a redundant mechanism. 23680829 Extracellular signal-regulated kinase inhibition modulates rat annulus fibrosus cell response to interleukin-1. Rat annulus fibrosus (AF) cells were activated with interleukin-1 (IL-1) with or without extracellular signal-regulated kinase (ERK) inhibition. Factors associated with the anabolic/catabolic balance of the disc were determined. To clarify the role of ERK pathway in AF cells response to IL-1. IL-1 plays an important role in intervertebral disc degeneration. ERK is an important inflammatory pathway that plays a crucial role in the expression of inflammatory and catabolic genes induced by IL-1 in chondrocytes. However, the role of the ERK pathway in AF cells response to IL-1 has not been fully investigated. Rat AF cells in monolayer culture were exposed to IL-1, with or without ERK inhibition; ribonucleic acid was isolated for real time polymerase chain reaction analysis of gene expression, conditioned media analyzed for nitrite, prostaglandin E-2, and IL-6, Western blot was performed to detect the changes of protein expression. ERK specific inhibitor U0126 significantly inhibited IL-1-induced ERK activation. IL-1-dependent upregulation of iNOS, IL-6, Cox-2, (MMP)-3, and MMP-13 was significantly reduced by ERK inhibition. The decreased gene expression of collagen I, collagen II, collagen IX, and IGF-1 induced by IL-1 was also reversed by U0126. Gene expression of ADAMTS-4, ADAMTS-5, and TGF-b were not affected by IL-1 or ERK inhibition. IL-1 moderately upregulated aggrecan and TIMP-1 expression, ERK inhibition had no significant effect on aggrecan expression but decreased TIMP-1 expression in the presence of IL-1. ERK inhibition reversed the changes of protein expression of MMP-3, MMP-13, TIMP-1, aggrecan and collagen II induced by IL-1. IL-1-induced nitric oxide, prostaglandin E-2, and IL-6 accumulation were also reduced by ERK inhibition. These results suggest that IL-1 induces an imbalance between anabolic and catabolic events in AF cells, ERK inhibition could provide some protection against the adverse effects of IL-1.Level of Evidence: N/A. 23639115 Indanomycin-related antibiotics from marine Streptomyces antibioticus PTZ0016. Four indanomycin-related antibiotics 2-5 were isolated from the cultured broth of marine Streptomyces antibioticus strain PTZ0016. Their structures were characterised as 16-deethylindanomycin (2), iso-16-deethylindanomycin (3), 16-deethylindanomycin methyl ester (4) and iso-16-deethylindanomycin methyl ester (5) on the basis of NMR, HR-ESI-MS and CD evidences. Compounds 3-5 are new additions to the class of indanomycin antibiotics. All isolated compounds showed in vitro activity against Staphylococcus aureus with minimal inhibitory concentration at 4.0-8.0 μg/ml. 23773773 Incidence and the Clinical Impact of Stent Fractures after Primary Stenting for TASC C and D Femoropopliteal Lesions at 1 Year. The clinical impact of stent fractures is still controversial. This study analyzed the incidence and the clinical impact of stent fractures after stenting of long femoropopliteal lesions. From November 2008 to October 2009, 58 patients (62 limbs) were treated in a single center with a primary nitinol self-expanding stent for Trans-Atlantic Inter-Consensus (TASC) C and D de novo femoropopliteal lesions. Patients were prospectively followed by medical and duplex scan examinations. Stent fractures were assessed by biplane X-rays at 12 months. Logistic regression analysis was performed. At 1 year a complete follow-up was obtained in 42 limbs/90 stents. The median length of the stented segment was 240 ± 180 cm with a mean of 2.1 (1-4) stents per patient. Sixteen stents (17.8%) were fractured: one type I (asymptomatic); seven type II (2 restenosis); five type III (asymptomatic), and three type IV stent fractures (1 restenosis). Stent diameter (p = .04) and stent implantation in the distal part of the superficial femoral artery (p = .05) were positively associated with stent fractures. Stent fracture had no influence on restenosis. This study suggests that the high stent fracture rate associated with endovascular treatment of long femoropopliteal lesions should be balanced with its low clinical impact. 22365313 Aspirin desensitization in patients undergoing planned or urgent coronary stent implantation. A single-center experience. Dual antiplatelet therapy (aspirin and ADP-antagonists) is mandatory after stent implantation in order to avoid stent thrombosis, especially in the era of DES. In fact, a delayed re-endothelization process may enlarge the window of occurrence of stent thrombosis beyond 1-year after implantation. Allergy to acid acetylsalicylic is not a rare event and may influence the use and the choice of coronary stent with an important impact in terms of outcome especially in patients at high risk for in-stent restenosis. The aim of this study was to evaluate the safety and efficacy of a new intravenous rapid desensitization protocol in patients with acetylsalicylic acid sensitivity undergoing coronary stent implantation. Among a total of 1385 patients undergoing coronary angioplasty at our catheterization laboratory from January 2007 to June 2011, a total of 43 patients (3.1%) had history of aspirin sensitivity characterized by respiratory or cutaneous manifestations (none had previous anaphylactic reactions). Twenty-three patients (53.5%) presented with acute coronary syndromes. All patients underwent a novel rapid desensitization procedure before or after cardiac catheterization (in case of ST-elevation myocardial infarctions, n=5). The desensitization procedure was based on intravenous administration of 9 sequential doses of aspirin (1, 2, 4, 8, 16, 32, 64, 128, 250 mg) over 4.5h without the use of corticosteroids or antihistamines. Patients were followed for at least 30 days and up to 12 months to assess compliance with aspirin therapy and adverse events. The desensitization procedure was successful in 42 patients (97.6%). All patients underwent stent implantation (1.6 stents/patient). Drug-eluting stents were used in 36 patients (85.7%). At follow-up, all patients who successfully responded to the desensitization procedure did not develop any allergic reaction. This study showed the safety and efficacy of a new rapid intravenous protocol desensitization for patients with history of aspirin sensitivity undergoing planned or urgent coronary stent implantation. 23942995 Myopia and diabetes mellitus as modificatory factors of glaucomatous optic neuropathy. Myopic deformation of the eye and metabolic alterations of the nerve tissue of patients with diabetes may modify glaucomatous optic neuropathy (GON). Blockage of axonal transport of neurotrophic factors (NTFs) is the event crucial to understanding the factors that affect GON. The primary, but not sole, blockage site is at the lamina cribrosa (LC). Other than this primary site of damage at the LC, 7 other factors may explain atypical nerve fiber layer (NFL) defects and the vulnerability of the nerve fibers in eyes with high myopia and glaucoma: a second point of blockage at the edge of the posterior scleral foramen; ectatic strain on the NFL; ectasia and distortion of the LC; association of a hypoplastic optic disc; thin and weak collagen fibers; peripapillary chorioretinal atrophy; and myopic neuropathy. Among diabetic patients, diabetic neuropathy in the retinal NFL is present initially, and increased resistance to aqueous outflow leads to ocular hypertension. Superimposition of GON on diabetic neuropathy and ocular hypertension in patients with diabetes may enhance their susceptibility to nerve damage. Results of a meta-analysis study suggested a positive association between diabetes mellitus and glaucoma whereas other reports suggested that leakage of vascular endothelial growth factor, a survival mechanism of ischemic neural tissue, and enhanced stiffness of the LC as a result of diabetic glycation may protect neurons from apoptosis. Thus, modification of GON as a result of diabetes remains controversial. 23897234 The role of Ca2+ in the pathophysiology of pancreatitis. Acute pancreatitis is a human disease in which the pancreatic pro-enzymes, packaged into the zymogen granules of the acinar cells, become activated and cause auto-digestion. The main causes of pancreatitis are alcohol abuse and biliary disease. A considerable body of evidence indicates that the primary event initiating the disease process is excessive release of Ca2+ from intracellular stores, followed by excessive entry of Ca2+ from the interstitial fluid. However, Ca2+ release and subsequent entry are also precisely the processes that control physiological secretion of the digestive enzymes in response to stimulation via the vagal nerve or the hormone cholecystokinin. The spatial and temporal Ca2+ signal patterns in physiology and pathology, as well as the contributions from different organelles in the different situations, are therefore critical issues. There has recently been significant progress in our understanding of both physiological stimulus-secretion coupling and the pathophysiology of acute pancreatitis. Very recently, a promising potential therapeutic development has occurred with the demonstration that blockade of Ca2+ release-activated Ca2+ currents in pancreatic acinar cells offers remarkable protection against Ca2+ overload, intracellular protease activation and necrosis evoked by a combination of alcohol and fatty acids, which is a major trigger of acute pancreatitis. 23640180 Three Ubiquitination Sites of Organic Anion Transporter-1 Synergistically Mediate Protein Kinase C-dependent Endocytosis of the Transporter. Organic anion transporter-1 (OAT1) mediates the body disposition of a diverse array of clinically important drugs, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, anti-hypertensives, and anti-inflammatories. Therefore, understanding the regulation of OAT1 has profound clinical significance. We previously established that OAT1 constitutively internalizes from and recycles back to cell surface, and that activation of protein kinase C (PKC) inhibits OAT1 activity by promoting ubiquitination of the transporter, which then leads to an accelerated internalization of the transporter from cell surface to intracellular compartments. In the current study, we demonstrated that PKC isoform PKC-alpha was responsible for OAT1 ubiquitination. To directly address the role of OAT1 ubiquitination, we then generated two OAT1 mutants, each having multiple lysines (K) simultaneously mutated to arginine (R). One mutant K163/297/303/315/321R lost sensitivities to PKC-induced inhibition of transport activity, to PKC-induced ubiquitination, and to PKC-induced acceleration of transporter internalization. Further dissecting each lysine within this mutant, we identified Lys297, Lys303 and Lys315 being the ubiquitin-conjugation sites. Interestingly, mutating any one of the three lysines prevented the ubiquitin-conjugation to the other two lysines, suggesting that Lys297, Lys303 and Lys315 may form an optimal structure to interact with ubiquitination machineries. This is the first demonstration that Lys297, Lys303 and Lys315 play synergistic role in PKC-regulated OAT1 ubiquitination, trafficking and transport activity. 23685735 Lipogels: surface-adherent composite hydrogels assembled from poly(vinyl alcohol) and liposomes. Drug-eluting engineered surface coatings are of paramount importance for many biomedical applications from implantable devices to tissue engineering. Herein, we present the assembly of lipogels, composite physical hydrogels assembled from poly(vinyl alcohol) and liposomes using thiol-disulfide exchange between end group modified PVA and thiocholesterol containing liposomes, and the response of adhering cells to these coatings. We demonstrate the controlled loading of liposomes into the polymer matrix and the preserved mechanical properties of the lipogels. Furthermore, the lipogels are successfully rendered cell adhesive by incorporation of poly(l-lysine) into the PVA polymer matrix or by poly(dopamine) coating of the lipogels. The successful lipid uptake from the lipogels by macrophages, hepatocytes, and myoblasts was monitored by flow cytometry. Finally, the delivery of active cargo, paclitaxel, to adherent myoblasts is shown, thus illustrating the potential of the lipogels as a drug eluting interface for biomedical applications. 23907140 Change in Cognitive Function Over 12 Months Among Patients With an Implantable Cardioverter-Defibrillator. Patients with implantable cardioverter-defibrillators (ICDs) have decreased cognitive function associated with arrhythmic and/or cardiac disorders, such as ischemic cardiomyopathy. Little is known about changes in cognitive function over time among ICD patients. The aim of this study was to evaluate baseline-to-12-month changes in cognitive function in memory (total recall and delayed recall), psychomotor speed, and executive function among ICD patients. In this prospective study, 115 (mean [SD] age, 64.83 [9.06] years, 75% mean) and 77 ICD patients completed baseline and 12-month face-to-face interviews, respectively, which included neuropsychological tests to evaluate cognitive function. Patients who completed baseline and 12-month testing had decreased total and delayed recall memory (all P < .05). No significant changes from baseline to 12 months were observed in psychomotor speed (t = 0.33; P = .74) and executive function (t = -1.12; P = .27). Using 1.0 standard deviation or below the mean as a cutoff criterion, 12% to 22% of ICD patients had poor cognitive function over time. Particularly, at baseline, 17 (15%) and 15 (13%) of the 115 patients had poor memory in total and delayed recall, respectively. At 12 months, 12 (16%) and 9 (12%) of the 77 patients had poor memory in total and delayed recall, respectively. In this sample of patients with ICDs, memory was poor at baseline and decreased over 12 months. Future studies are indicated to determine how this change in memory influences outcomes such as medication adherence. 23582852 Prostate-specific antigen bounce after high-dose-rate monotherapy for prostate cancer. To characterize the magnitude and kinetics of prostate-specific antigen (PSA) bounces after high-dose-rate (HDR) monotherapy and determine relationships between certain clinical factors and PSA bounce. Longitudinal PSA data and various clinical parameters were examined in 157 consecutive patients treated with HDR monotherapy between 1996 and 2005. We used the following definition for PSA bounce: rise in PSA ≥threshold, after which it returns to the prior level or lower. Prostate-specific antigen failure was defined per the Phoenix definition (nadir +2 ng/mL). A PSA bounce was noted in 67 patients (43%). The number of bounces per patient was 1 in 45 cases (67%), 2 in 19 (28%), 3 in 2 (3%), 4 in 0, and 5 in 1 (1%). The median time to maximum PSA bounce was 1.3 years, its median magnitude was 0.7, and its median duration was 0.75 years. Three patients (2%) were noted to have PSA failure. None of the 3 patients who experienced biochemical failure exhibited PSA bounce. In the fully adjusted model for predicting each bounce, patients aged <55 years had a statistically significant higher likelihood of experiencing a bounce (odds ratio 2.22, 95% confidence interval 1.38-3.57, P=.001). There was also a statistically significant higher probability of experiencing a bounce for every unit decrease in Gleason score (odds ratio 1.52, 95% confidence interval 1.01-2.04, P=.045). A PSA bounce occurs in a significant percentage of patients treated with HDR monotherapy, with magnitudes varying from <1 in 28% of cases to ≥1 in 15%. The median duration of bounce is <1 year. More bounces were identified in patients with lower Gleason score and age <55 years. Further investigation using a model to correlate magnitude and frequency of bounces with clinical variables are under way. 23698651 Electronic and optical properties of the triphenylamine-based organic dye sensitized TiO2 semiconductor: insight from first principles calculations. Plausible mechanisms of the ultrafast electron injection and the significant dependence of the power conversion efficiency on the anchor group for the triphenylamine-based dye-sensitized TiO2 solar cells have been explored by the density functional calculations. Calculations show that the ultrafast charge recombination on the surface trap state of the dye-sensitized TiO2 system can be ascribed to the lack of electron density on the carboxyl group of the A3 dye with the rhodanine group anchor. Predicted electronic and optical properties of the A1-3-adsorbed TiO2 system reveal that the direct electron injection arises from the electronic excitation from HOMO-1 of the dye to the conduction band bottom of TiO2. On the basis of the calculations, the electron density distributions of related frontier orbitals and energy bands of dyes and their adsorbed systems have been discussed, which play an important role in electron injection and charge recombination. 23865808 The timing of TGF-β inhibition affects the generation of antigen-specific CD8+ T cells. Transforming growth factor (TGF)-β is a potent immunosuppressive cytokine necessary for cancer growth. Animal and human studies have shown that pharmacologic inhibition of TGF-β slows the growth rate of established tumors and occasionally eradicates them altogether. We observed, paradoxically, that inhibiting TGF-β before exposing animals to tumor cells increases tumor growth kinetics. We hypothesized that TGF-β is necessary for the anti-tumor effects of cytotoxic CD8+ T lymphocytes (CTLs) during the early stages of tumor initiation. BALB/c mice were pretreated with a blocking soluble TGF-β receptor (sTGF-βR, TGF-β-blockade group, n=20) or IgG2a (Control group, n=20) before tumor inoculation. Tumor size was followed for 6 weeks. In vivo lymphocyte assays and depletion experiments were then performed to investigate the immunological basis of our results. Lastly, animals were pretreated with either sTGF-βR (n=6) or IgG2a (n=6) prior to immunization with an adenoviral vector encoding the human papillomavirus E7 gene (Ad.E7). One week later, flow cytometry was utilized to measure the number of splenic E7-specific CD8+ T cells. Inhibition of TGF-β before the injection of tumor cells resulted in significantly larger average tumor volumes on days 11, 17, 22, 26 and 32 post tumor-inoculation (p < 0.05). This effect was due to the inhibition of CTLs, as it was not present in mice with severe combined immunodeficiency (SCID) or those depleted of CD8+ T cells. Furthermore, pretreatment with sTGF-βR inhibited tumor-specific CTL activity in a Winn Assay. Tumors grew to a much larger size when mixed with CD8+ T cells from mice pretreated with sTGF-βR than when mixed with CD8+ T cells from mice in the control group: 96 mm3 vs. 22.5 mm3, respectively (p < 0.05). In addition, fewer CD8+ T cells were generated in Ad.E7-immunized mice pretreated with sTGF-βR than in mice from the control group: 0.6% total CD8+ T cells vs. 1.9%, respectively (p < 0.05). These studies provide the first in vivo evidence that TGF-β may be necessary for anti-tumor immune responses in certain cancers. This finding has important implications for our understanding of anti-tumor immune responses, the role of TGF-β in the immune system, and the future development of TGF-β inhibiting drugs. 23871509 Impact of Attenuated Plaque as Detected by Intravascular Ultrasound on the Occurrence of Microvascular Obstruction After Percutaneous Coronary Intervention in Patients With ST-Segment Elevation Myocardial Infarction. The aim of the study was to investigate whether intravascular ultrasound (IVUS) can predict microvascular obstruction (MVO) as detected by magnetic resonance imaging (MRI) after primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). MVO occurs in a sizable proportion of patients with acute myocardial infarction despite successful PCI and results in poor clinical outcomes. We assessed infarct-related lesions in 68 patients with STEMI by using IVUS before primary PCI. All patients were examined by MRI 1 week after primary PCI. MRI-derived MVO was seen in 23 patients (34%). In the IVUS assessment, the frequency of plaque rupture, echolucent plaque, calcification and positive remodeling, and quantitative geometric data were not different between the MVO group and the no-MVO group. Although the frequency of plaque with ultrasound attenuation was similar between the 2 groups (87% vs. 89%, p = 0.999), the maximum attenuation angle (280° [range: 215° to 360°] vs. 150° [range: 95° to 300°], p = 0.008) and attenuation length (11.3 mm [range: 7.2 to 17.8 mm] vs. 6.8 mm [range: 3.0 to 10.4 mm], p = 0.009) were significantly greater in the MVO group than the no-MVO group. Multivariable logistic regression analysis showed that attenuated plaque with a maximum attenuation angle of >180° and attenuation length of >5 mm was an independent predictor of MVO (odds ratio: 6.07, 95% confidence interval: 1.89 to 19.53, p = 0.002). Attenuated plaque with maximum attenuation angle of >180° and attenuation length of >5 mm was associated with the occurrence of MVO after primary PCI. IVUS might to be a useful tool for risk stratification in STEMI patients undergoing primary PCI. 23878000 Male mice express spermatogenic cell-specific triosephosphate isomerase isozymes. Triosephosphate isomerase 1 (TPI1) is a member of the glycolytic pathway, which is a critical source of energy for motility in mouse sperm. By immunoblotting, we detected two male, germ line-specific TPI1 bands (Mr 33,400 and 30,800) as well as the somatic-type band (Mr 27,700). Although all three bands were observed in spermatogenic cells, somatic-type TPI1 disappeared from sperm during epididymal maturation. In vitro dephosphorylation analysis suggested that the two male, germ line-specific TPI1 bands were not the result of phosphorylation of the 27,700 Mr TPI1 band. The Mr 33,400; 30,800; and 27,700 TPI1 bands corresponded to the respective sizes of the proteins predicted to use the first, second, and third possible initiation codons of the Tpi1 cDNA. We performed immunofluorescence on epididymal sperm and determined that TPI1 specifically localized in the principal piece. The antibody staining was stronger in cauda epididymal sperm than in caput epididymal sperm, a finding consistent with the identification of TPI1 as a cauda epididymal sperm-enriched protein. Immunofluorescence with sodium dodecyl sulfate (SDS)-insoluble flagellar accessory structures showed a strong TPI1 signal only in the principal piece, indicating that TPI1 is a component of the fibrous sheath. Northern blot hybridization detected longer Tpi1 transcripts (1.56 kb) in mouse testis, whereas somatic tissues had shorter transcripts (1.32 kb). As there is only one triosephosphate isomerase gene in the mouse genome, we conclude that the three variants we see in sperm result from the use of alternative translation start codons in spermatogenic cells. Mol. Reprod. Dev. 9999: 1-9, 2013. © 2013 The Authors. Molecular Reproduction and Development. Published by Wiley Periodicals, Inc. 23872609 Synergizing nucleic acid aptamers with 1-dimensional nanostructures as label-free field-effect transistor biosensors. Since the introduction by Gold et al. in 1990, nucleic acid aptamers had evolved to become a true contender in biosensors for protein and cell detections. Aptamers are short strands of synthetically designed DNA or RNA oligonucleotides that can be self-assembled into unique 3-dimensional structures and can bind to different proteins, cells or even small molecules at a high level of specificity and affinity. In recent years, there had been many reports in literature in using aptamers in place of conventional antibodies as capture biomolecules on the surface. This is mainly due to the better thermal stability properties and ease in production. Consequently, also these characteristics allowed the aptamers to find use in field effect transistors (FETs) based upon 1D nanostructured (1D-NS) as label-free biosensing. In terms of designing label-free platforms for biosensors applications, 1D-NS FET had been an attractive option due to reported high sensitivities toward protein targets arising from the large surface area for detection as well as to their label-free nature. Since the first aptamer-based 1D-NS FET biosensor had surfaced in 2005, there had been many more improvements in the overall design and sensitivity in recent years. In this review, the latest developments in synergizing these two interesting areas of research (aptamers and 1D-NS FET) will be discussed for a range of different nanowire types as well as for the detection results. 23945136 Expression of neuroepithelial transforming gene 1 is enhanced in oesophageal cancer and mediates an invasive tumour cell phenotype. Neuroepithelial Transforming Gene 1 (NET1) is a well characterised oncoprotein and a proven marker of an aggressive phenotype in a number of cancers, including gastric adenocarcinoma. We aimed to investigate whether NET1 plays a functional role in oesophageal cancer (OAC) and its pre-malignant phenotype Barrett's oesophagus. Baseline NET1 mRNA levels were determined by qPCR across a panel of six cell lines, including normal oesophageal, Barrett's and OAC derived cells. Quantification of NET1 protein in OAC cells was performed using Western blot and immunofluorescence. NET1 expression was modulated by treating with lysophosphatidic acid (LPA) and NET1-specific siRNA. The functional effects of NET1 knockdown were assessed in vitro using proliferation, migration and invasion assays. NET1 expression was increased in Barrett's and in OAC-derived cells in comparison to normal oesophageal cells. The highest expression was observed in OE33 a Barrett's-related OAC cell line. NET1 protein and mRNA expression was enhanced by LPA treatment in OAC and furthermore LPA treatment caused increased proliferation, migration and invasion in a NET1-dependent manner. NET1 knockdown resulted in reduced OAC cell proliferation and invasion. As found in other malignancies, NET1 expression is elevated in OAC and its pre-malignant phenotype, Barrett's oesophagus. NET1 promotes OAC cell invasion and proliferation and it mediates LPA-induced OAC cell migration. 23864600 Colour cues proved to be more informative for dogs than brightness. The results of early studies on colour vision in dogs led to the conclusion that chromatic cues are unimportant for dogs during their normal activities. Nevertheless, the canine retina possesses two cone types which provide at least the potential for colour vision. Recently, experiments controlling for the brightness information in visual stimuli demonstrated that dogs have the ability to perform chromatic discrimination. Here, we show that for eight previously untrained dogs colour proved to be more informative than brightness when choosing between visual stimuli differing both in brightness and chromaticity. Although brightness could have been used by the dogs in our experiments (unlike previous studies), it was not. Our results demonstrate that under natural photopic lighting conditions colour information may be predominant even for animals that possess only two spectral types of cone photoreceptors. 23837662 Langerhans-type and monocyte-derived human dendritic cells have different susceptibilities to mRNA electroporation with distinct effects on maturation and activation: implications for immunogenicity in dendritic cell-based immunotherapy. mRNA electroporation of dendritic cells (DCs) facilitates processing and presentation of multiple peptides derived from whole antigen, tailored to different HLA molecules. Clinical responses to electroporated moDC vaccines, however, have been suboptimal. Human Langerhans-type DCs (LCs) are the most potent conventional DC subtype for inducing CD8+ cytotoxic T lymphocytes (CTLs) in vitro. We recently demonstrated that Wilms' tumor 1 (WT1) mRNA-electroporated LCs are superior to moDCs as stimulators of tumor antigen-specific CD8+ CTLs, even though they are comparable stimulators of allogeneic T cell proliferative responses. A detailed comparative evaluation of the effects of mRNA electroporation on LCs versus moDCs, however, is needed. Immature and partially-matured human moDCs and LCs electroporated with mRNA were compared for transfection efficiency, phenotypic changes, viability, retention of transgene expression after cryopreservation, and immunogenicity. Student t test was used for each pairwise comparison. One-way analysis of variance was used for multiple group comparisons. Transfection efficiency after electroporation with enhanced green fluorescent protein (eGFP) mRNA was higher for immature than for partially-matured moDCs. In contrast, transfection efficiency was higher for partially-matured than for immature LCs, with the additional benefit that electroporation itself increased maturation and activation of CD83+HLA-DRbright LCs but not moDCs. Electroporation did not impair final maturation and activation of either DC subtype, after which both mRNA-electroporated LCs and moDCs were functionally similar in stimulating allogeneic T cell proliferation, a standard assay of DC immunogenicity. These findings support mRNA electroporation of DCs, and in particular LCs, as an effective non-viral method to stimulate specific, potent CD8+ CTL responses. The differences between LCs and moDCs regarding this form of antigen-loading have important implications for DC-based immunotherapies. 22324400 Chlorogenic acid, rutin and hyperoside content in Fragaria vesca, F. viridis and F. moschata in Lithuania. In Lithuania, two species of the genus Fragaria L. (Rosaceae), F. vesca L. and F. viridis Weston, occur naturally in the wild and two others, F. moschata Weston and F. × ananassa Duchesne ex Rozier are found escaped from cultivation. The main objective of this study was to establish the variation pattern in the content of chlorogenic acid, rutin and hyperoside in leaves and fruits of the native Lithuanian species. In this work, the chemical polymorphisms of different Fragaria species were studied by growing plants side by side under the same cultivated field conditions. F. vesca fruits had the highest rutin (1.38 ± 0.19 mg g(-1) DM), hyperoside (0.69 ± 0.10 mg g(-1) DM) and chlorogenic acid (2.25 ± 0.34 mg g(-1) DM) content, followed by F. viridis and F. moschata. Our results showed that the leaves should be taken into account as important rutin and hyperoside contributors for strawberries. 23899894 Actions of β2-Adrenoceptor Agonist Drug on Neuromuscular Function after Fatigue. The effects of β2-agonists on human skeletal muscle contractile function are unclear, more particularly in the presence of fatigue. Moreover, it remains to be ascertained whether central motor drive during voluntary contractions could counter for eventual contractile alterations induced by β2-agonists. This study explored central and peripheral neuromuscular adjustments of the quadriceps induced by β2-agonist terbutaline following fatiguing exercise. On two days, nine men performed 120 intermittent (5-s contraction/5-s relaxation) submaximal (50% MVC) voluntary contractions, 2 h after having ingested a terbutaline (8 mg) or placebo capsule, in a double-blind randomized order. Isometric knee extension peak torque of single twitch and tetanic (10 and 100 Hz) contractions, and of maximal voluntary contractions (MVC) was recorded before (PRE) and after (POST) the fatiguing exercise. Twitch maximal rate of torque relaxation (-dT/dt) was also calculated. Central motor drive was estimated via quadriceps electromyogram recorded during the submaximal voluntary contractions. In PRE and POST conditions, MVC and twitch peak torque were not modified by terbutaline. PRE twitch -dT/dt was 22% higher in terbutaline compared to placebo (P < 0.005), but it did not differ significantly between treatments at POST. Evoked torque of 10- and 100-Hz tetani were significantly lower in terbutaline compared to placebo, regardless of time (-16% and -17% respectively, P < 0.05). Central motor drive during voluntary exercise did not differ between treatments. These results demonstrate that terbutaline affected the contractile function of the quadriceps muscle during electrically-evoked contractions both before and after fatiguing exercise. However, this did not impair the maximal voluntary force-generating capacity of the knee extensors and did not result in any compensatory adjustments of the central nervous system. 23851226 Monocytes and macrophages as biomarkers for the diagnosis of megalencephalic leukoencephalopathy with subcortical cysts. Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare congenital leukodystrophy characterized by macrocephaly, subcortical cysts and demyelination. The majority of patients harbor mutations in the MLC1 gene encoding for a membrane protein with largely unknown function. Mutations in MLC1 hamper its normal trafficking and distribution in cell membranes, leading to enhanced degradation. MLC1 protein is highly expressed in brain astrocytes and in circulating blood cells, particularly monocytes. We used these easily available cells and monocyte-derived macrophages from healthy donors and MLC1-mutated patients to study MLC1 expression and localization, and to investigate how defective MLC1 mutations may affect macrophage functions. RT-PCR, western blot and immunofluorescence analyses show that MLC1 is expressed in both monocytes and macrophages, and its biosynthesis follows protein trafficking between endoplasmic reticulum and trans-Golgi network and the secretory pathway to the cell surface. MLC1 is transported along the endosomal recycling pathway passing through Rab5+ and Rab11A+vesicles before lysosomal degradation. Alterations in MLC1 trafficking and distribution were observed in macrophages from MLC1-mutated patients, which also showed changes in the expression and localization of several proteins involved in plasma membrane permeability, ion and water homeostasis and ion-regulated exocytosis. As a consequence of these alterations, patient-derived macrophages show abnormal cell morphology and intracellular calcium influx and altered response to hypo-osmotic stress. Our results suggest that blood-derived macrophages may give relevant information on MLC1 function and may be considered as valid biomarkers for MLC diagnosis and for investigating therapeutic strategies aimed to restore MLC1 trafficking in patient cells. 23966912 Perirhinal cortical inactivation impairs object-in-place memory and disrupts task-dependent firing in hippocampal CA1, but not in CA3. Objects and their locations can associatively define an event and a conjoint representation of object-place can form an event memory. Remembering how to respond to a certain object in a spatial context is dependent on both hippocampus and perirhinal cortex (PER). However, the relative functional contributions of the two regions are largely unknown in object-place associative memory. We investigated the PER influence on hippocampal firing in a goal-directed object-place memory task by comparing the firing patterns of CA1 and CA3 of the dorsal hippocampus between conditions of PER muscimol inactivation and vehicle control infusions. Rats were required to choose one of the two objects in a specific spatial context (regardless of the object positions in the context), which was shown to be dependent on both hippocampus and PER. Inactivation of PER with muscimol (MUS) severely disrupted performance of well-trained rats, resulting in response bias (i.e., choosing any object on a particular side). MUS did not significantly alter the baseline firing rates of hippocampal neurons. We measured the similarity in firing patterns between two trial conditions in which the same target objects were chosen on opposite sides within the same arm [object-in-place (O-P) strategy] and compared the results with the similarity in firing between two trial conditions in which the rat chose any object encountered on a particular side [response-in-place (R-P) strategy]. We found that the similarity in firing patterns for O-P trials was significantly reduced with MUS compared to control conditions (CTs). Importantly, this was largely because MUS injections affected the O-P firing patterns in CA1 neurons, but not in CA3. The results suggest that PER is critical for goal-directed organization of object-place associative memory in the hippocampus presumably by influencing how object information is associated with spatial information in CA1 according to task demand. 23623394 Engraftment of retrovirally transduced Bet v 1-GFP expressing bone marrow cells leads to allergen-specific tolerance. Molecular chimerism is a promising strategy to induce tolerance to disease-causing antigens expressed on genetically modified haematopoietic stem cells. The approach was employed successfully in models of autoimmunity and organ transplantation. Recently, we demonstrated that molecular chimerism induces robust and lasting tolerance towards the major grass pollen allergen Phl p 5. Since allergens are a group of antigens differing widely in their function, origin and structure we further examined the effectiveness of molecular chimerism using the Phl p 5-unrelated major birch pollen allergen Bet v 1, co-expressed with the reporter GFP. Besides, inhibition of CD26 was used to promote engraftment of modified stem cells. Retrovirus VSV-Betv1-GFP was generated to transduce 5-FU-mobilized BALB/c hematopoietic cells to express membrane-bound Bet v 1 (VSV-GFP virus was used as control). Myeloablated BALB/c mice received Betv1-GFP or GFP expressing bone marrow cells, pre-treated with a CD26 inhibitor. Chimerism was followed by flow cytometry. Tolerance was assessed by measuring allergen-specific isotype levels in sera, RBL assays and T-cell proliferation assays. Mice transplanted with transduced BMC developed multi-lineage molecular chimerism which remained stable long-term (>8 months). After repeated immunizations with Bet v 1 and Phl p 5 serum levels of Bet v 1-specific antibodies (IgE, IgG1, IgG2a, IgG3 and IgA) remained undetectable in Betv1-GFP chimeras while high levels of Phl p 5-specific antibodies developed. Likewise, basophil degranulation was induced in response to Phl p 5 but not to Bet v 1 and specific non-responsiveness to Bet v 1 was observed in proliferation assays. These data demonstrate successful tolerization towards Bet v 1 by molecular chimerism. Stable long-term chimerism was achieved under inhibition of CD26. These results provide evidence for the broad applicability of molecular chimerism as tolerance strategy in allergy. 23900511 Leukemia-like onset of bone marrow metastasis from anaplastic oligodendroglioma after 17 years of dormancy: an autopsy case report. Extraneural metastases from primary brain tumors are extremely rare. We present an autopsy case that displayed a very late and unique pattern of metastasis from an anaplastic oligodendroglioma. The patient was a 74-year-old woman who was disease free for 17 years after resection of the primary oligodendroglioma. She was subsequently admitted to a hospital for heart failure where her bone marrow was found to be completely infiltrated with tumor cells, eventually resulting in disseminated intravascular coagulation. The onset was like leukemia, but the "blast-like" cells were different from leukemic cells, and the diagnosis was difficult until autopsy. After her death, a review of her past medical history and comprehensive analysis of her primary brain tumor and aspiration biopsy/autopsy bone marrow samples with glial immunohistochemical markers, fluorescence in situ hybridization examination, and immunohistochemical/sequencing analyses of mutant IDH1 revealed the accurate diagnosis. The metastatic tumor in her bone marrow was finally diagnosed as bone metastasis from the primary anaplastic oligodendroglioma. Although metastatic oligodendroglioma is very rare, it should be noted that this condition displays a propensity for bone and bone marrow and can present with features similar to those of leukemia after a long latency period. 23201449 Phyllanthus urinaria suppresses human osteosarcoma cell invasion and migration by transcriptionally inhibiting u-PA via ERK and Akt signaling pathways. Phyllanthus urinaria is widely used as anti-inflammatory, antiviral, antibacterial, and anti-hepatotoxic medicines in almost every tropical country. However, scientific evidence supporting its use in cancer metastasis is limited, particularly osteosarcoma. We investigated the effect of P. urinaria extract (PUE) on cell viability, invasion, and migration in the human osteosarcoma Saos-2 cell line, and looked at the impact of PUE on several relevant proteases and signaling pathways. This study demonstrates that PUE, at a range of concentrations (from 0 to 100 μg/ml), concentration-dependently inhibited the migration/invasion capacities of Saos-2 without cytotoxic effects. Zymographic and western blot analyses revealed that PUE inhibited the urokinase-type plasminogen activator (u-PA) and matrix metalloproteinase-2 (MMP-2) enzyme activity, as well as protein expression. Western blot analysis also showed that PUE inhibits phosphorylation of ERK1/2 and Akt. Testing of mRNA level, quantitative real-time PCR, and promoter assays evaluated the inhibitory effects of PUE on u-PA expression in Saos-2 cells. The chromatin immunoprecipitation (ChIP) assay was reactive to the transcription protein SP-1, which was inhibited by PUE. In conclusion, PUE suppresses human osteosarcoma Saos-2 cell invasion and migration by transcriptionally inhibiting u-PA via ERK and Akt signaling pathways. Therefore, PUE produces anti-metastatic activity in Saos-2 cells. 23925935 Power doppler ultrasound is useful for prediction of re-therapy with rituximab in rheumatoid arthritis. To evaluate the value of grey scale (GS) and power Doppler (PD) ultrasound (US) in detecting inflammatory/destructive changes and for prediction of necessity for re-therapy with Rituximab (RTX) in patients with RA over one year of follow-up. GS/PDUS were performed to assess synovitis, tenosynovitis, and erosions on the clinically dominant hand and forefoot of 20 patients with RA before and after therapy with RTX. US parameters were compared with clinical (DAS28, tender/swollen joints [TJC/SJC], patients' VAS of disease activity) and laboratory parameters (CRP, ESR). Results were compared for patients with and without re-therapy with RTX. Significant decreases in clinical and laboratory parameters were observed after 6 and 12 months. US synovitis scores significantly decreased after 6 and 12 months (each p<0.05). Regarding patients that received a re-therapy between 6 and 9 months after start of therapy (n=9), still a fair therapy response was detectable before re-therapy. In these patients, PD positive synovitis was the only parameter which increased up to the 6 months' examination. All patients negative for RF and ACPA (n=4) were in the group of patients receiving a second course of treatment. Seropositive patients showed better response to treatment with less need for re-therapy. Response to therapy was measurable by clinical and laboratory parameters as well as by US. Since PDUS was able to detect the onset of disease activity before worsening of clinical symptoms occurred, PDUS is most helpful in evaluating disease activity and making earlier therapy decisions. 23877877 Sorghum Extracellular Leucine-Rich Repeat Protein SbLRR2 Mediates Lead Tolerance in Transgenic Arabidopsis. A sorghum pathogen-inducible gene predicted to encode a simple extracellular leucine-rich repeat (LRR) protein SbLRR2 was previously isolated. LRR was the only domain identified in SbLRR2 and its homologous sequences. Phylogenetic analysis revealed that they are distinct from the simple extracellular LRR proteins reported previously. Agrobacterium-mediated transient expression in tobacco leaf cells demonstrated that the SbLRR2-EYFP (enhanced yellow fluorescent protein) fusion protein was targeted to the extracellular space. Transgenic analysis of SbLRR2 revealed its role in enhancing lead [Pb(II)] tolerance in Arabidopsis. Consequently, SbLRR2-overexpressing lines were found to show alleviated Pb(II)-induced root inhibition, lower levels of Pb(II) accumulation and enhanced transcription of AtPDR12 which encodes a plasma membrane ATP-bind cassette (ABC)-type transporter formerly shown to contribute to Pb(II) detoxification. However, all the Pb(II) tolerance responses were abolished when SbLRR2 was overexpressed in an atpdr12 T-DNA insertion line. The extracellular localization of SbLRR2 was also shown to be essential for the Pb(II) phenotypes and AtPDR12 up-regulation. Taken together, SbLRR2 appears to mediate Pb(II) tolerance through the elevation of AtPDR12 expression in transgenic Arabidopsis, thus activating a glutathione-independent mechanism for detoxification. Further investigations revealed the Pb(II)-induced transcriptional activation of SbLRR2 and several highly conserved AtPDR12 homologs in sorghum seedlings, suggesting the possibility of a common molecular mechanism for Pb(II) tolerance in diverse plant species. 23800333 Feasibility, acceptability and preliminary effectiveness of patient advocates for improving asthma outcomes in adults. Abstract Background: Asthmatic adults from low-income urban neighborhoods have inferior health outcomes which in part may be due to barriers accessing care and with patient-provider communication. We adapted a patient advocate (PA) intervention to overcome these barriers. Objective: To conduct a pilot study to assess feasibility, acceptability and preliminary evidence of effectiveness. Methods: A prospective randomized design was employed with mixed methods evaluation. Adults with moderate or severe asthma were randomized to 16 weeks of PA or a minimal intervention (MI) comparison condition. The PA, a non-professional, modeled preparations for a medical visit, attended the visit and confirmed understanding. The PA facilitated scheduling, obtaining insurance coverage and overcoming barriers to implementing medical advice. Outcomes included electronically-monitored inhaled corticosteroid (ICS) adherence, asthma control, quality of life, FEV1, emergency department (ED) visits and hospitalizations. Mixed-effects models guided an intention-to-treat analysis. Results: 100 adults participated: age 47 ± 14 years, 75% female, 71% African-American, 16% white, baseline FEV1 69% ± 18%, 36% experiencing hospitalizations and 56% ED visits for asthma in the prior year. Ninety-three subjects completed all visits; 36 of 53 PA-assigned had a PA visit. Adherence declined significantly in the control (p = 0.001) but not significantly in the PA group (p = 0.30). Both PA and MI groups demonstrated improved asthma control (p = 0.01 in both) and quality of life (p = 0.001, p = 0.004). Hospitalizations and ED visits for asthma did not differ between groups. The observed changes over time tended to favor the PA group, but this study was underpowered to detect differences between groups. Conclusion: The PA intervention was feasible and acceptable and demonstrated potential for improving asthma control and quality of life. 23838914 Surgical Treatment of Pediatric Desmoid Tumors. A 12-Year, Single-Center Experience. Pediatric desmoid tumors (PDTs) represent a group of rare, distinct lesions. While sparse, available literature suggests that PDT are particularly aggressive and difficult to control when compared with their adult counterpart. A retrospective review identified 39 patients who underwent treatment of PDT at St. Jude Children's Research Hospital over a 12-year period. Clinicopathologic and treatment characteristics were analyzed to identify predictors of outcome. A total of 39 patients were treated during the study period, with a total number of 67 resections. Median age was 12.2 years; 49 % of patients were male, and 51 % were female. Median tumor size was 9.8 cm. PDT most commonly arose in the extremities (40 %), thorax (23 %), head and neck (21 %), and trunk (16 %). Also, 18 % of resections had negative margins (R0), 48 % were microscopic positive (R1), and 30 % were macroscopic positive (R2). The 1- and 5-year recurrence-free survival (RFS) was 97.1 and 73.1 %, respectively. Factors associated with worse RFS were patient age >12 years (HR = 5.08, p = 0.038) and tumor size >5 cm (HR = 1.22, p = 0.0597). Margin status did not affect RFS. Selective use of radiation therapy appeared to improve RFS. Our study suggests that margin status alone at the time of extirpation is not a predictor of ultimate cure or likelihood of recurrence. Many patients received adjuvant therapy, with benefits suggested after analysis. For patients with PDT, surgical extirpation should not come at the expense of functional preservation, as overall survival is excellent. 23707885 Sub-unit vaccine against S. aureus-mediated infections: set-up of nano-sized polymeric adjuvant. The aim of this work was the design of a novel adjuvanted system for vaccination against S. aureus-mediated infections: in particular, poly-lactide-co-glycolide (PLGA) nanoparticles were developed in order to efficiently load and boost a sub-unit model vaccine, namely a purified recombinant collagen binding bacterial adhesin fragment (CNA19). At first, the assessment of the actual immunogenicity of free CNA19 via subcutaneous administration was evaluated, in order to consider it as subunit antigen model. Secondly, for the development of CNA19 loaded PLGA nanoparticles, a preliminary study was focused on the production of well-formed nanoparticles by w/o/w double emulsion method exploiting ultrasonication cycles under mild conditions, then the optimization of the freeze-drying conditions and different CNA19 loading methods were considered (encapsulation, adsorption of on blank or CNA19 encapsulated nanoparticles). The set-up preparation method (process yield of about 83%) permitted to obtain CNA19 loaded nanoparticles with spherical shape, narrow size distribution (187.41 ± 51.2 nm), a slightly negative zeta-potential (-2.91 ± 0.64 mV) and to elicit satisfactory protein encapsulation efficiency (75.91 ± 4.22%) and loading capacity (8.59 ± 0.33 μg CNA19/nanoparticles mg). Then, CNA19 loaded PLGA nanoparticles were characterized by (i) an in vitro release test performed at different temperatures, namely 4°C, 25°C and 37°C, testing the antigen integrity (SDS-PAGE) and activity (ELISA); (ii) an in vitro stability study in terms of dimension and surface charge performed in a 21 days period of time. At 37°C there was evidence of a sustained release of the antigen, in active form, for almost 240 h with a burst release of about 20% in the first 2h. At 4°C stability tests and activity assays allowed to identify storage conditions useful to maintain CNA19 activity and easily NP re-suspendability with intact physical characteristics. Furthermore the evaluation of CNA19 loaded nanoparticles cytotoxicity (up to 10.652 mg PLGA/ml) by MTT assay and the study of cellular up-take assessed on human fibroblasts confirmed the feasibility to formulate a dosage form useful for vaccination against S. aureus-mediated infections. 23205707 YopK controls both rate and fidelity of Yop translocation. Yersinia pestis, the causative agent of plague, utilizes a type III secretion system (T3SS) to intoxicate host cells. The injection of T3SS substrates must be carefully controlled, and dysregulation leads to altered infection kinetics and early clearance of Y. pestis. While the sequence of events leading up to cell contact and initiation of translocation has received much attention, the regulatory events that take place after effector translocation is less understood. Here we show that the regulator YopK is required to maintain fidelity of substrate specificity, in addition to controlling translocation rate. YopK was found to interact with YopD within targeted cells during Y. pestis infection, suggesting that YopK's regulatory mechanism involves a direct interaction with the translocation pore. In addition, we identified a single amino acid in YopK that is essential for translocation rate regulation but is dispensable for maintaining fidelity of translocation. Furthermore, we found that expression of YopK within host cells was sufficient to downregulate translocation rate, but it did not affect translocation fidelity. Together, our data support a model in which YopK is a bifunctional protein whose activities are genetically and spatially distinct such that fidelity control occurs within bacteria and rate control occurs within host cells. 23416218 Reliability and concurrent validity of Four Square Step Test scores in subjects with chronic stroke: a pilot study. To establish (1) the intrarater and interrater reliability of Four Square Step Test (FSST) times in persons with chronic stroke; (2) the concurrent validity of FSST times with standing balance and functional mobility measures; and (3) the FSST cutoff score for distinguishing the differences in dynamic balance performance of persons with chronic stroke from healthy control adults. Cross-sectional study. University-based rehabilitation center. Convenience sample of subjects (N=30) consisting of community-dwelling persons with chronic stroke (n=15) and healthy control adults (n=15). Not applicable. FSST scores; balance and functional mobility measured using Berg Balance Scale (BBS) scores; Timed Up & Go (TUG) test scores; and limits of stability (LOS) measured by dynamic posturography. FSST times showed good intrarater reliability, with intraclass correlation coefficients ranging from .82 to .83 and an interrater reliability >.99. An FSST cutoff score of 11 seconds was able to discriminate between healthy adults older than 50 years and persons with stroke (sensitivity, 73.3%; specificity, 93.3%). FSST times were correlated with LOS scores for directional control in the backward direction (r=.64; P=.01). FSST was approaching a significant correlation with TUG scores (r=.59; P=.02) and LOS scores for endpoint excursion in the forward direction (r=-.58; P=.02). However, there was no correlation with BBS scores. FSST is an easy-to-administer clinical test with good intrarater and interrater reliability in persons with chronic stroke to assess dynamic standing balance. FSST times of 11 seconds are able to differentiate between persons with chronic stroke and healthy adults older than 50 years. The correlation of FSST times with standing balance and functional mobility measures requires further research with a larger sample size. 23602152 Genome-wide Analysis Reveals TET- and TDG-Dependent 5-Methylcytosine Oxidation Dynamics. TET dioxygenases successively oxidize 5-methylcytosine (5mC) in mammalian genomes to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). 5fC/5caC can be excised and repaired to regenerate unmodified cytosines by thymine-DNA glycosylase (TDG) and base excision repair (BER) pathway, but it is unclear to what extent and at which part of the genome this active demethylation process takes place. Here, we have generated genome-wide distribution maps of 5hmC/5fC/5caC using modification-specific antibodies in wild-type and Tdg-deficient mouse embryonic stem cells (ESCs). In wild-type mouse ESCs, 5fC/5caC accumulates to detectable levels at major satellite repeats but not at nonrepetitive loci. In contrast, Tdg depletion in mouse ESCs causes marked accumulation of 5fC and 5caC at a large number of proximal and distal gene regulatory elements. Thus, these results reveal the genome-wide view of iterative 5mC oxidation dynamics and indicate that TET/TDG-dependent active DNA demethylation process occurs extensively in the mammalian genome. 23603382 Protective effects of selenium on oxidative damage and oxidative stress related gene expression in rat liver under chronic poisoning of arsenic. Arsenic (As) is a toxic metalloid existing widely in the environment, and chronic exposure to it through contaminated drinking water has become a global problem of public health. The present study focused on the protective effects of selenium on oxidative damage of chronic arsenic poisoning in rat liver. Rats were divided into four groups at random and given designed treatments for 20weeks. The oxidative damage of liver tissue was evaluated by lipid peroxidation and antioxidant enzymes. Oxidative stress related genes were detected to reflect the liver stress state at the molecular level. Compared to the control and Na2SeO3 groups, the MDA content in liver tissue was decreased and the activities of antioxidant enzymes were increased in the Na2SeO3 intervention group. The mRNA levels of SOD1, CAT, GPx and Txnrd1 were increased significantly (P<0.05) in the combined Na2SeO3+NaAsO2 treatment group. The expressions of HSP70 and HO-1 were significantly (P<0.05) increased in the NaAsO2 group and reduced in the combined treatment group. The results indicate that long-term intake of NaAsO2 causes oxidative damage in the rat liver, and Na2SeO3 protects liver cells by adjusting the expression of oxidative stress related genes to improve the activities of antioxidant enzymes. 23441807 Cardiac self-efficacy and its predictors in patients with coronary artery diseases. To investigate cardiac self-efficacy and its predictors among patients with coronary artery diseases. Patients with coronary artery diseases must perform the health behaviour to prevent recurrent cardiac events. It has been already well known that self-efficacy is a vital factor in both initiating and maintaining health behaviours. Descriptive correlational and cross-sectional survey design. Subjects were interviewed using structured study questionnaires. The data collected were statistically analysed by descriptive statistics and inferential statistics including the t-test, anova, Tukey's test, Pearson's correlation and hierarchical multiple regression analysis to determine the predictors of cardiac self-efficacy. A convenience sample of 214 patients with coronary artery diseases was included. The mean age of subjects was 60·71 ± 10·07 years, and three-fourths were men. The overall model significantly explained 15·8% of variance in cardiac self-efficacy. Among predictors, occupation, diagnosis, body mass index, experience of receiving patient education and awareness of risk factors had statistically significant influences on cardiac self-efficacy. Rather than disease knowledge, factors related to subject's perception were more likely to associate with cardiac self-efficacy. These findings might provide a theoretical basis to develop nursing interventions for enhancing cardiac self-efficacy of patients with coronary artery diseases. Clinical nurses taking care of patients with coronary artery diseases should consider the patients' perception on their coronary artery diseases including experience of receiving patient education, and awareness of risk factors in encouraging the cardiac self-efficacy to promote the health behaviours for the secondary prevention of coronary artery diseases. 23937530 Dose-dependent inhibitory effects of Proton pump inhibitors on human osteoclastic and osteoblastic cells activity. Proton pump inhibitors (PPIs), a class of molecules that are used to decrease gastric acid production, might display adverse effects in bone metabolism. The aim of this work was to characterize the concentration- and time-dependent effects of three PPIs (omeprazole, esomeprazole and lansoprazole) on human osteoclast precursor cells isolated from peripheral blood, and on human mesenchymal stem cells (osteoblast precursors). Cell cultures were characterized for total protein content, apoptosis and several osteoclastic/osteoblastic features, and also for the involvement of some intracellular signaling pathways. PPIs caused a dose-dependent decrease in cellular density, which correlated with an increase in the apoptosis rate, effects that became statistically significant at concentrations ≥ 10(-5) M. They also inhibited phenotype-related gene expression and functional parameters. For both cell types, cellular function, i.e. osteoclastic resorption and formation of mineralized deposits by osteoblastic cells, was more affected than proliferation related parameters. The three PPIs showed similar qualitative and quantitative effects, but displayed some differences in the underlying intracellular signaling pathways. Results suggest that PPIs might have a direct deleterious effect on bone cells, with the possibility of decreased bone turnover. This article is protected by copyright. All rights reserved. 23841722 Application of an Efficient Gene Targeting System Linking Secondary Metabolites to their Biosynthetic Genes in Aspergillus terreus. Nonribosomal peptides (NRPs) are natural products biosynthesized by NRP synthetases. A kusA-, pyrG- mutant strain of Aspergillus terreus NIH 2624 was developed that greatly facilitated the gene targeting efficiency in this organism. Application of this tool allowed us to link four major types of NRP-related secondary metabolites to their responsible genes in A. terreus. In addition, an NRP affecting melanin synthesis was also identified in this species. 23884223 Interpretation and clinical significance of small monoclonal peaks in capillary electrophoresis. Background Although the testing mechanism and interpretation criteria for capillary electrophoresis differ from those for gel-based electrophoresis, there are not that many reports on the efficacy of capillary electrophoresis. Materials and Methods We performed a retrospective analysis, using the Laboratory Information System (LIS) to review a total of 163 capillary electrophoresis results from 117 different patients treated in our hospital between March and August 2012. Capillary electrophoresis was performed on capillary2 (Sebia, Lysse, France). Results Among the patients' group, 4 patients presented very small M-peaks in capillary electrophoresis. By using the zoom function in capillary electrophoresis, two of them were confirmed to have monoclonality, but the remaining two required reconfirmation in gel electrophoresis, leading to confirmation of a discrete monoclonal band. Conclusion In this study, we found that small peaks in capillary electrophoresis accompanying a skewed K/L ratio deserve particular attention as they can grow into larger peaks within a few months. We suggest that any trivial M-peak in capillary electrophoresis should not be overlooked and that a combination of platform tests such as gel electrophoresis or FLC assay be implemented in order to confirm monoclonality. 23406484 Raman spectra of interchanging β-lactamase inhibitor intermediates on the millisecond time scale. Rapid mix-rapid freeze is a powerful method to study the mechanisms of enzyme-substrate reactions in solution. Here we report a protocol that combines this method with normal (non-resonance) Raman microscopy to enable us to define molecular details of intermediates at early time points. With this combined method, SHV-1, a class A β-lactamase, and tazobactam, a commercially available β-lactamase inhibitor, were rapidly mixed on the millisecond time scale and then were flash-frozen by injection into an isopentane solution surrounded by liquid nitrogen. The "ice" was finally freeze-dried and characterized by Raman microscopy. We found that the reaction is almost complete in solution at 25 ms, giving rise to a major population composed of the trans-enamine intermediate. Between 25 and 500 ms, minor populations of protonated imine are detected that have previously been postulated to precede enamine intermediates. However, within 1 s, the imines are converted entirely to enamines. Interestingly, with this method, we can measure directly the turnover number of SHV-1 and tazobactam. The enzyme is completely inhibited at 1:4 ratio (enzyme:inhibitor) or greater, a number that agrees with the turnover number derived from steady-state kinetic methods. This application, employing non-intensity-enhanced Raman spectroscopy, provides a general and effective route to study the early events in enzyme-substrate reactions. 23911082 Elucidating the temporal and spatial dynamics of Biomphalaria glabrata genetic diversity in three Brazilian villages. The freshwater snail Biomphalaria glabrata is the principal intermediate host for the parasite Schistosoma mansoni within Brazil. We assessed the potential effects of snail population dynamics on parasite transmission dynamics via population genetics. We sampled snail populations located within the confines of three schistosome-endemic villages in the state of Minas Gerais, Brazil. Snails were collected from individual microhabitats following seasonal periods of flood and drought over the span of 1 year. Snail spatio-temporal genetic diversity and population differentiation of 598 snails from 12 sites were assessed at seven microsatellite loci. Average genetic diversity was relatively low, ranging from 4.29 to 9.43 alleles per locus, and overall, subpopulations tended to exhibit heterozygote deficits. Genetic diversity was highly spatially partitioned among subpopulations, while virtually, no partitioning was observed across temporal sampling. Comparison with previously published parasite genetic diversity data indicated that S. mansoni populations are significantly more variable and less subdivided than those of the B. glabrata intermediate hosts. Within individual Brazilian villages, observed distributions of snail genetic diversity indicate temporal stability and very restricted gene flow. This is contrary to observations of schistosome genetic diversity over the same spatial scale, corroborating the expectation that parasite gene flow at the level of individual villages is likely driven by vertebrate host movement. 23937963 The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy. Antiepileptic drugs may affect the endocrine system. We investigated the effects of valproic acid and topiramate on the levels of insulin, c-peptide and adipocytokines in pre-pubertal patients with idiopathic partial and generalized epilepsy. Forty-one children with epilepsy were included. The patients were divided into two groups (valproic acid; n=21, topiramate; n=20). The weight, height, body mass index and homeostasis model assessment of insulin resistance (HOMA-IR) were recorded and insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin and resistin levels were determined at 0, 6 and 12 months of therapy. In the valproate group, weight and height increased significantly. Seven of 21 patients were overweight at the end of one year. Leptin was higher in the overweight subgroup. Although insulin and HOMA-IR increased (p<0.05), none of the patients showed hyperinsulinism or IR. Resistin had decreased at the 6th and 12th months (p<0.05). In the topiramate group, some statistically nonsignificant changes were demonstrated. The mechanisms behind valproate and topiramate-related weight control are still unclear, especially in children. Valproate and topiramate affect the weight, BMI, and insulin, leptin and adipocytokine levels in prepubertal children. We suggest that further studies including more patients with a long follow-up period are necessary to draw a firm conclusion regarding an association between the treatment with these drugs and the levels of leptin, insulin and adipocytokines. 23720743 The Atypical Guanine Nucleotide Exchange Factor Dock4 Regulates Neurite Differentiation through Modulation of Rac1 GTPase and Actin Dynamics. Precise regulation of neurite growth and differentiation determines accurate formation of synaptic connections, whose disruptions are frequently associated with neurological disorders. Dedicator of cytokinesis 4 (Dock4), an atypical guanine nucleotide exchange factor for Rac1, is found to be associated with neuropsychiatric diseases, including autism and schizophrenia. Nonetheless, the neuronal function of Dock4 is only beginning to be understood. Using mouse neuroblastoma (Neuro-2a) cells as a model, this study identifies that Dock4 is critical for neurite differentiation and extension. This regulation is through activation of Rac1 and modulation of the dynamics of actin-enriched protrusions on the neurites. In cultured hippocampal neurons, Dock4 regulates the establishment of the axon-dendrite polarity and the arborization of dendrites, two critical processes during neural differentiation. Importantly, a microdeletion Dock4 mutant linked to autism and dyslexia that lacks the GEF domain leads to defective neurite outgrowth and neuronal polarization. Further analysis reveals that the SH3 domain-mediated interaction of Dock4 is required for its activity toward neurite differentiation, whereas its proline-rich C terminus is not essential for this regulation. Together, our findings reveal an important role of Dock4 for neurite differentiation during early neuronal development. 23416700 Central administration of angiotensin IV rapidly enhances novel object recognition among mice. Angiotensin IV (Val(1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6)) has demonstrated potential cognitive-enhancing effects. The present investigation assessed and characterized: (1) dose-dependency of angiotensin IV's cognitive enhancement in a C57BL/6J mouse model of novel object recognition, (2) the time-course for these effects, (3) the identity of residues in the hexapeptide important to these effects and (4) the necessity of actions at angiotensin IV receptors for procognitive activity. Assessment of C57BL/6J mice in a novel object recognition task demonstrated that prior administration of angiotensin IV (0.1, 1.0, or 10.0, but not 0.01 nmol, i.c.v.) significantly enhanced novel object recognition in a dose-dependent manner. These effects were time dependent, with improved novel object recognition observed when angiotensin IV (0.1 nmol, i.c.v.) was administered 10 or 20, but not 30 min prior to the onset of the novel object recognition testing. An alanine scan of the angiotensin IV peptide revealed that replacement of the Val(1), Ile(3), His(4), or Phe(6) residues with Ala attenuated peptide-induced improvements in novel object recognition, whereas Tyr(2) or Pro(5) replacement did not significantly affect performance. Administration of the angiotensin IV receptor antagonist, divalinal-Ang IV (20 nmol, i.c.v.), reduced (but did not abolish) novel object recognition; however, this antagonist completely blocked the procognitive effects of angiotensin IV (0.1 nmol, i.c.v.) in this task. Rotorod testing demonstrated no locomotor effects with any angiotensin IV or divalinal-Ang IV dose tested. These data demonstrate that angiotensin IV produces a rapid enhancement of associative learning and memory performance in a mouse model that was dependent on the angiotensin IV receptor. 23921534 Consanguineous marriage and reproductive risk: attitudes and understanding of ethnic groups practising consanguinity in Western society. Consanguineous couples should be adequately informed about their increased reproductive risk and possibilities for genetic counselling. Information may only be effective if it meets the needs of the target group. This study aimed to gain more insight into: (1) attitudes of people belonging to ethnic groups in Western society towards consanguinity and their understanding of risk for offspring; and (2) their attitudes regarding reproductive information targeted at consanguineous couples. Dutch Moroccans and Turks were invited to complete an online questionnaire by snowball sampling and by placing a link on two popular Dutch Moroccan/Turkish forum websites between September and October 2011. The questionnaire was completed by 201 individuals who were, on average, neither positive nor negative towards consanguinity. Respondents with a consanguineous partner were more positive, estimated the risk for the offspring lower and were less positive about the provision of risk information to consanguineous couples when compared with respondents without a consanguineous partner. Participants of Turkish origin had a more negative attitude towards consanguinity and estimated the reproductive risk higher than Moroccan participants. More than half of the respondents thought that information should be given before marriage, whereas only 10% thought it should never be provided. The general practitioner was most often mentioned (54%) as the designated professional to inform people. Information about genetic risks related to consanguinity should be offered early, preferably before marriage. The diversity of the target population requires various strategies to disseminate information and reach consanguineous couples with the offer of genetic counselling.European Journal of Human Genetics advance online publication, 7 August 2013; doi:10.1038/ejhg.2013.167. 23887148 2-Selenouridine triphosphate synthesis and Se-RNA transcription. 2-Selenouridine ((Se)U) is one of the naturally occurring modifications of Se-tRNAs ((Se)U-RNA) at the wobble position of the anticodon loop. Its role in the RNA-RNA interaction, especially during the mRNA decoding, is elusive. To assist the research exploration, herein we report the enzymatic synthesis of the (Se)U-RNA via 2-selenouridine triphosphate ((Se)UTP) synthesis and RNA transcription. Moreover, we have demonstrated that the synthesized (Se)UTP is stable and recognizable by T7 RNA polymerase. Under the optimized conditions, the transcription yield of (Se)U-RNA can reach up to 85% of the corresponding native RNA. Furthermore, the transcribed (Se)U-hammerhead ribozyme has the similar activity as the corresponding native, which suggests usefulness of (Se)U-RNAs in function and structure studies of noncoding RNAs, including the Se-tRNAs. 23645536 Analysis of the inhibitory activity of Abeliophyllum distichum leaf constituents against aldose reductase by using high-speed counter current chromatography. We isolated five phenolic glycosides (acteoside, eutigoside B, isoacteoside, rutin and cornoside) from Abeliophyllum distichum leaves by high-speed counter current chromatography (HSCCC) using a solvent system of ethyl acetate:n-butanol:water (8:0.7:5). We determined the purity of the 5 compounds by high-performance liquid chromatography, and confirmed their chemical structures by using nuclear magnetic resonance data. We examined the inhibitory effect of these compounds on rat lens aldose reductase. Among these compounds, acteoside (1) showed the most potent inhibitory effect, with an IC50 value of 1.39 μM. The inhibitory effect of 1 was 5.0 times greater than that of quercetin (7.05 μM), which was used as a positive control. These results suggest that acteoside may be a promising agent for the prevention or treatment of diabetic complications. Moreover, HSCCC is a promising method for the isolation and purification of biologically active compounds from natural products. 23954008 Cytokine removal on extracorporeal life support for treatment of acute endotoxemia: A randomized controlled animal study. We prospectively evaluated the effectiveness of resin adsorption incorporated in an extracorporeal life support (ELS) circuit in an animal model of sepsis for removal of cytokines and prevention of hemodynamic deterioration during the treatment of septic shock. Twelve female landrace pigs were randomly assigned to two groups, a study group(n=6), treated with high-flow resin adsorption (300mL/min) and ELS, and a control group (n=6), treated only with ELS. Septic shock was induced by intravenous 0.02μg/kg/min infusion was of Escherichia coli lipopolysaccharide (LPS). Measurements were carried out in the study group at baseline, at the end of LPS injection(t0) at 30(t1), 60(t2), 90(t3) and 120min (t4) and 60min after stopping resin-adsorption (t5). In the control group measurements were performed at baseline (t0), t1 and only t2, as no control animal survived beyond this latter experimental timepoint. The final population consisted of 9 animals, five in the study group and 4 in the control group. Plasma values of both tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) were reduced during resin-adsorption (t1-t4) while these mediators increased in controls undergoing ELS only. With a clearance of TNF-α of 15,233pg/min and IL-6 of 10,233pg/min, 79.2% of TNF-α and 95.3% of IL-6 produced were adsorbed. Systemic vascular resistance decreased significantly in both groups at t0. While it further was reduced during the control experiments at t1 and t2, it returned to normal in the study animals. Cardiac output increased at t0, t1 and t2 in the control experiments. In contrast, in study animals after a peak at t0, it returned to the baseline value and did not vary thereafter. Combined resin-adsorption and ELS improved hemodynamics resulting from effective removal of inflammatory mediators in a pig model of septic shock. 23770982 Danthron activates AMP-activated protein kinase and regulates lipid and glucose metabolism in vitro. Aim:To discover the active compound on AMP-activated protein kinase (AMPK) activation and investigate the effects of the active compound 1,8-dihydroxyanthraquinone (danthron) from the traditional Chinese medicine rhubarb on AMPK-mediated lipid and glucose metabolism in vitro.Methods:HepG2 and C2C12 cells were used. Cell viability was determined using MTT assay. Real-time PCR was performed to measure the gene expression. Western blotting assay was applied to investigate the protein phosphorylation level. Enzymatic assay kits were used to detect the total cholesterol (TC), triglyceride (TG) and glucose contents.Results:Danthron (0.1, 1, and 10 μmol/L) dose-dependently promoted the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) in both HepG2 and C2C12 cells. Meanwhile, danthron treatment significantly reduced the lipid synthesis related sterol regulatory element-binding protein 1c (SREBP1c) and fatty acid synthetase (FAS) gene expressions, and the TC and TG levels. In addition, danthron treatment efficiently increased glucose consumption. The actions of danthron on lipid and glucose metabolism were abolished or reversed by co-treatment with the AMPK inhibitor compound C.Conclusion:Danthron effectively reduces intracellular lipid contents and enhanced glucose consumption in vitro via activation of AMPK signaling pathway. 23632031 Radically different phylogeographies and patterns of genetic variation in two European brown frogs, genus Rana. We reconstruct range-wide phylogeographies of two widespread and largely co-occurring Western Palearctic frogs, Rana temporaria and R. dalmatina. Based on tissue or saliva samples of over 1000 individuals, we compare a variety of genetic marker systems, including mitochondrial DNA, single-copy protein-coding nuclear genes, microsatellite loci, and single nucleotide polymorphisms (SNPs) of transcriptomes of both species. The two focal species differ radically in their phylogeographic structure, with R. temporaria being strongly variable among and within populations, and R. dalmatina homogeneous across Europe with a single strongly differentiated population in southern Italy. These differences were observed across the various markers studied, including microsatellites and SNP density, but especially in protein-coding nuclear genes where R. dalmatina had extremely low heterozygosity values across its range, including potential refugial areas. On the contrary, R. temporaria had comparably high range-wide values, including many areas of probable postglacial colonization. A phylogeny of R. temporaria based on various concatenated mtDNA genes revealed that two haplotype clades endemic to Iberia form a paraphyletic group at the base of the cladogram, and all other haplotypes form a monophyletic group, in agreement with an Iberian origin of the species. Demographic analysis suggests that R. temporaria and R. dalmatina have genealogies of roughly the same time to coalescence (TMRCA ~3.5 mya for both species), but R. temporaria might have been characterized by larger ancestral and current effective population sizes than R. dalmatina. The high genetic variation in R. temporaria can therefore be explained by its early range expansion out of Iberia, with subsequent cycles of differentiation in cryptic glacial refugial areas followed by admixture, while the range expansion of R. dalmatina into central Europe is a probably more recent event. 22961094 Increased nuclear thioredoxin-1 potentiates cadmium-induced cytotoxicity. Cadmium (Cd) is a widely dispersed environmental agent that causes oxidative toxicity through mechanisms that are sensitive to thioredoxin-1 (Trx1). Trx1 is a cytoplasmic protein that translocates to nuclei during oxidative stress. Recent research shows that interaction of Trx1 with actin plays a critical role in cell survival and that increased nuclear Trx-1 potentiates proinflammatory signaling and death in cell and mouse models. These observations indicate that oxidative toxicity caused by low-dose Cd could involve disruption of actin-Trx1 interaction, nuclear Trx1 translocation, and potentiation of proinflammatory cell death mechanisms. In this study, we investigated the role of nuclei-localized Trx1 in Cd-induced inflammation and cytotoxicity using in vitro and in vivo models. The results show that Cd stimulated nuclear translocation of Trx1 and p65 of NF-κB. Elevation of Trx1 in nuclei in in vitro cells and kidney of transgenic mice potentiated Cd-stimulated NF-κB activation and cell death. Cd-stimulated Trx1 nuclear translocation and NF-κB activation were inhibited by cytochalasin D, an inhibitor of actin polymerization, suggesting that actin regulates Trx1 nuclear translocation and NF-κB activation by Cd. A nuclear-targeted dominant negative form of Trx1 blocked Cd-stimulated NF-κB activation and decreased cell death. Addition of zinc, known to antagonize Cd toxicity by increasing metallothionein, had no effect on Cd-stimulated nuclear translocation of Trx1 and NF-κB activation. Taken together, the results show that nuclear translocation and accumulation of redox-active Trx1 in nuclei play an important role in Cd-induced inflammation and cell death. 23661050 Perforation of the nasal septum as the first sign of histoplasmosis associated with AIDS and review of published literature. Disseminated histoplasmosis in South America is associated with AIDS in 70-90 % of cases. It is visceral and cutaneous, compromising the oral, pharynx, and laryngeal mucous membranes. The involvement of the nasal mucosa is unusual. Two patients with perforation of the nasal septum as the only sign of their disease were clinically and histopathologically diagnosed as leishmaniasis. The revision of the biopsies and the culture of nasal discharge secretions showed that the pathogens seen were not amastigotes but Histoplasma capsulatum. Other mycotic lesions were not detected, nor there was history of cutaneous leishmaniasis. The leishmanin skin test, available only for the male patient, was negative. The PCR and immunofluorescence antibody titers for Leishmania were negative in both patients. They were HIV positive; in the male, his CD4+ T cell count was 60/mm(3) and in the female 133/mm(3). The nasal ulcer was the only manifestation of histoplasmosis and the first of AIDS in both patients. The male patient recovered with amphotericin B and itraconazole treatment. The female has improved with itraconazole. Both patients received antiretroviral treatment. Nasal mucous membrane ulcers should include histoplasmosis among the differential diagnosis. In conclusion, two patients had perforation of their nasal septum as the only manifestation of histoplasmosis, a diagnosis confirmed by nasal mucosa biopsy and by culture of H. capsulatum, findings which demonstrated that both patients had AIDS. 23902687 A novel PAR-1-binding protein, MTCL1, plays critical roles in organizing microtubules in polarizing epithelial cells. The establishment of epithelial polarity is tightly linked to the dramatic reorganization of microtubules (MTs) from a radial array to a vertical alignment of non-centrosomal MT bundles along the lateral membrane and a meshwork under the apical and basal membranes. However, little is known about the underlying molecular mechanism of this polarity-dependent MT remodeling. The evolutionarily conserved cell polarity-regulating kinase PAR-1, whose activity is essential for maintaining the dynamic state of MTs, plays indispensable roles to promote this process. Here, we identify a novel PAR-1-binding protein, named MTCL1 (Microtubule crosslinking factor 1), which crosslinks MTs through its N-terminal MT-binding region and subsequent coiled-coil motifs. MTCL1 colocalized with the apicobasal MT bundles in epithelial cells, and its knockdown impaired the development of these MT bundles and the epithelial cell specific columnar shape. Rescue experiments revealed that the N-terminal MT-binding region was indispensable for restoring these defects of the knockdown cells. MT regrowth assays indicated that MTCL1 was not required for the initial radial growth of MTs from the apical centrosome, but was essential for the accumulation of non-centrosomal MTs to the sublateral regions. Interestingly, MTCL1 recruited a subpopulation of PAR-1b to the apicobasal MT bundles, and its interaction with PAR-1b was required for MTCL1-dependent development of the apicobasal MT bundles. These results suggest that MTCL1 mediates the epithelial cell-specific reorganization of non-centrosomal MTs through its MT-crosslinking activity, and cooperates with PAR-1b to maintain the correct temporal balance between dynamic and stable MTs within the apicobasal MT bundles. 23969064 Draft Genome Sequence of Holospora undulata Strain HU1, a Micronucleus-Specific Symbiont of the Ciliate Paramecium caudatum. Holospora undulata is a micronucleus-specific symbiont of the ciliate Paramecium caudatum. We report here the draft genome sequence of H. undulata strain HU1. This genome information will contribute to the study of symbiosis between H. undulata and the host P. caudatum. 23926944 A family cluster of giardiasis with variable treatment responses: refractory giardiasis in a family after a trip to India. Persistence of giardiasis after some of the recommended drugs is occurring with increasing frequency. We describe the follow-up of four members of a family with giardiasis through microscopic observation, immunochromatography and PCRs of tpi and β-giardin genes. Three patients did not respond to tinidazole but they were cured after quinacrine. However, PCR became negative at 2 months after negativization of stools in two patients and after 1 year in one patient. In all cases Giardia assemblage B was characterized with high homology between all isolates. Further studies are needed to determine the value of PCR in the diagnosis of Giardia infections. 22727823 GABAergic activity in autism spectrum disorders: an investigation of cortical inhibition via transcranial magnetic stimulation. Mounting evidence suggests a possible role for γ-aminobutyric acid (GABA) in the neuropathophysiology of autism spectrum disorders (ASD), but the extent of this impairment is unclear. A non-invasive, in vivo measure of GABA involves transcranial magnetic stimulation (TMS) of the primary motor cortex to probe cortical inhibition. Individuals diagnosed with ASD (high-functioning autism or Asperger's disorder) (n = 36 [28 male]; mean age: 26.00 years) and a group of healthy individuals (n = 34 [23 male]; mean age: 26.21 years) (matched for age, gender, and cognitive function) were administered motor cortical TMS paradigms putatively measuring activity at GABAA and GABAB receptors (i.e., short and long interval paired pulse TMS, cortical silent period). All cortical inhibition paradigms yielded no difference between ASD and control groups. There was, however, evidence for short interval cortical inhibition (SICI) deficits among those ASD participants who had experienced early language delay, suggesting that GABA may be implicated in an ASD subtype. The current findings do not support a broad role for GABA in the neuropathophysiology of ASD, but provide further indication that GABAA could be involved in ASD where there is a delay in language acquisition. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. 23913309 The Memristive Properties of a Single VO2 Nanowire with Switching Controlled by Self-Heating. A two-terminal memristor memory based on a single VO2 nanowire is reported that can not only provide switchable resistances in a large range of about four orders of magnitude but can also maintain the resistances by a low bias voltage. The phase transition of the single VO2 nanowire was driven by the bias voltage of 0.34 V without using any heat source. The memristive behavior of the single VO2 nanowire was confirmed by observing the switching and non-volatile properties of resistances when voltage pulses and low bias voltage were applied, respectively. Furthermore, multiple retainable resistances in a large range of about four orders of magnitude can be utilized by controlling the number and the amount of voltage pulses under the low bias voltage. This is a key step towards the development of new low-power and two-terminal memory devices for next-generation non-volatile memories. 23904330 A novel test for selection on cis-regulatory elements reveals positive and negative selection acting on mammalian transcriptional enhancers. Measuring natural selection on genomic elements involved in the cis-regulation of gene expression-such as transcriptional enhancers and promoters-is critical for understanding the evolution of genomes, yet it remains a major challenge. Many studies have attempted to detect positive or negative selection in these noncoding elements by searching for those with the fastest or slowest rates of evolution, but this can be problematic. Here we introduce a new approach to this issue, and demonstrate its utility on three mammalian transcriptional enhancers. Using results from saturation mutagenesis studies of these enhancers, we classified all possible point mutations as up-regulating, down-regulating, or silent, and determined which of these mutations have occurred on each branch of a phylogeny. Applying a framework analogous to Ka/Ks in protein-coding genes, we measured the strength of selection on up-regulating and down-regulating mutations, in specific branches as well as entire phylogenies. We discovered distinct modes of selection acting on different enhancers: while all three have experienced negative selection against down-regulating mutations, the selection pressures on up-regulating mutations vary. In one case we detected positive selection for up-regulation, while the other two had no detectable selection on up-regulating mutations. Our methodology is applicable to the growing number of saturation mutagenesis data sets, and provides a detailed picture of the mode and strength of natural selection acting on cis-regulatory elements. 23932735 Administration of aluminium to neonatal mice in vaccine-relevant amounts is associated with adverse long term neurological outcomes. Our previous ecological studies of autism spectrum disorder (ASD) has demonstrated a correlation between increasing ASD rates and aluminium (Al) adjuvants in common use in paediatric vaccines in several Western countries. The correlation between ASD rate and Al adjuvant amounts appears to be dose-dependent and satisfies 8 of 9 Hill criteria for causality. We have now sought to provide an animal model to explore potential behavioural phenotypes and central nervous system (CNS) alterations using s.c. injections of Al hydroxide in early postnatal CD-1 mice of both sexes. Injections of a "high" and "low" Al adjuvant levels were designed to correlate to either the U.S. or Scandinavian paediatric vaccine schedules vs. control saline-injected mice. Both male and female mice in the "high Al" group showed significant weight gains following treatment up to sacrifice at 6months of age. Male mice in the "high Al" group showed significant changes in light-dark box tests and in various measures of behaviour in an open field. Female mice showed significant changes in the light-dark box at both doses, but no significant changes in open field behaviours. These current data implicate Al injected in early postnatal life in some CNS alterations that may be relevant for a better understanding of the aetiology of ASD. 23831847 Effect of acute and chronic bilateral visual deafferentation on c-Fos immunoreactivity in the visual system of adult rats. In our study we examined acute and chronic changes in c-Fos expression patterns in the visual system of the rat after complete visual deafferentation. In 20 male Lewis rats, the retro-bulbar part of the optic nerve was sectioned bilaterally. Ten animals underwent c-Fos immunohistochemistry after 3 days and 10 animals after 3 weeks examining time-dependent changes. The control group consisted of 10 animals, which did not undergo any surgical manipulation. c-Fos expression in the rat visual system experienced significant changes after acute and chronic bilateral complete visual deafferentation. Acute decrease in c-Fos level was observed in the ventral lateral geniculate nucleus, intergeniculate leaflet, superficial gray layer of the superior colliculus and layers IV and V of the primary visual cortex. After chronic deafferentation, c-Fos expression was also found to be decreased in the optic and deep layers of the superior colliculus and layer VI of the primary visual cortex. No change in c-Fos expression was observed in the dorsal lateral geniculate nucleus and layers I, II and III of the primary visual cortex. This work shows that secondary complete blindness does not lead to uniform decrease in c-Fos levels in all subcortical and cortical brain regions related to vision. These findings provide important information concerning expression of the immediate-early gene product c-Fos in secondary blind rodent models. It may further serve as a relevant baseline finding when electrical stimulation of the visual system is performed, aiding the assessment of visual neuroprosthesis using c-Fos as a functional mapping tool when evaluating different stimulus parameters in blind rodent models. 23933311 Transgenic overexpression of the cell adhesion molecule L1 in neurons facilitates recovery after mouse spinal cord injury. It has been shown that the X-chromosome-linked neural cell adhesion molecule L1 plays a beneficial role in regeneration after spinal cord injury (SCI) in young adult rodents when applied in various molecular and cellular forms. In an attempt to further characterize the multiple functions of L1 after severe SCI we analyzed locomotor functions during 6weeks after injury and measured axonal regrowth/sprouting and sparing, glial scarring, and synaptic remodeling at 6weeks after severe spinal cord compression injury at the T7-9 levels of L1-deficient mice (L1-/y) and their wild-type (L1+/y) littermates, as well as mice that overexpress L1 under the control of the neuron-specific Thy-1 promoter (L1tg) and their wild-type littermates (L1+/+). No differences were found in the locomotor scale score and single frame motion analysis between L1-/y and L1+/y mice during 6weeks after SCI, most likely due to the very low expression of L1 in the adult spinal cord of wild-type mice. L1tg mice, however, showed better locomotor recovery than their L1+/+ littermates, being associated with enhanced numbers of catecholaminergic axons in the lumbar spinal cord, but not of cholinergic, GABAergic or glutamatergic terminals around motoneuron cell bodies in the lumbar spinal cord. Additionally, no difference between L1tg and L1+/+ mice was detectable in dieback of corticospinal tract axons. Neuronal L1 overexpression did not influence the size of the glial fibrillary acidic protein-immunoreactive astrocytic scar 6weeks after injury. We conclude that neuronal overexpression of L1 improves functional recovery from SCI by increasing catecholaminergic axonal regrowth/sprouting and/or sparing of severed axons without affecting the glial scar size. 23677847 The relationship between excessive daytime sleepiness and depressive and anxiety disorders in women. Objective: Excessive daytime sleepiness (EDS) is a common clinical symptom that affects women more than men. However, the association of excessive sleepiness with depressive and anxiety disorders in the broader population is unclear. The aim of this study was, therefore, to examine the association between excessive daytime sleepiness as measured by the Epworth Sleepiness Scale, and depressive and anxiety disorders in a population-based sample of women. Methods: Using the Structured Clinical Interview for DSM-IV Disorders (Non-Patient) (SCID-I/NP), 944 women aged 20-97 years (median 49 years, IQR 33-65 years) were assessed for depressive and anxiety disorders as part of the Geelong Osteoporosis Study. EDS was assessed using the Epworth Sleepiness Scale (ESS, cut-off > 10). Lifestyle factors were documented by self-report, height and weight were measured, and socioeconomic status categorised according to the Index of Relative Socio-Economic Advantage and Disadvantage. Results: Overall, 125 (13.2%) of the women were identified with EDS. EDS was associated with an increased likelihood for both current (OR = 2.11, 95% CI 1.10-4.06) and lifetime history (OR = 1.95, 95% CI 1.28-2.97) of depressive disorders, but not anxiety disorders, independent of age and alcohol consumption. These findings were not explained by antidepressant or sedative use, body mass index, physical activity, smoking, or socioeconomic status. Conclusions: These results suggest that excessive daytime sleepiness is associated with current and lifetime depressive, but not anxiety disorders. Clinically, this highlights the need to take into account the possible bidirectional relationship between depressive disorders and excessive sleepiness when assessing mental health issues in patients with EDS. 23874634 Male-Biased Genes in Catfish as Revealed by RNA-Seq Analysis of the Testis Transcriptome. Catfish has a male-heterogametic (XY) sex determination system, but genes involved in gonadogenesis, spermatogenesis, testicular determination, and sex determination are poorly understood. As a first step of understanding the transcriptome of the testis, here, we conducted RNA-Seq analysis using high throughput Illumina sequencing. A total of 269.6 million high quality reads were assembled into 193,462 contigs with a N50 length of 806 bp. Of these contigs, 67,923 contigs had hits to a set of 25,307 unigenes, including 167 unique genes that had not been previously identified in catfish. A meta-analysis of expressed genes in the testis and in the gynogen (double haploid female) allowed the identification of 5,450 genes that are preferentially expressed in the testis, providing a pool of putative male-biased genes. Gene ontology and annotation analysis suggested that many of these male-biased genes were involved in gonadogenesis, spermatogenesis, testicular determination, gametogenesis, gonad differentiation, and possibly sex determination. We provide the first transcriptome-level analysis of the catfish testis. Our analysis would lay the basis for sequential follow-up studies of genes involved in sex determination and differentiation in catfish. 23919395 Performance Evaluations of Demons and Free Form Deformation Algorithms for the Liver Region. We investigated the influence of breathing motion on radiation therapy according to four- dimensional computed tomography (4D-CT) technology and indicated the registration of 4D-CT images was significant. The demons algorithm in two interpolation modes was compared to the FFD model algorithm to register the different phase images of 4D-CT in tumor tracking, using iodipin as verification. Linear interpolation was used in both mode 1 and mode 2. Mode 1 set outside pixels to nearest pixel, while mode 2 set outside pixels to zero. We used normalized mutual information (NMI), sum of squared differences, modified Hausdorff-distance, and registration speed to evaluate the performance of each algorithm. The average NMI after demons registration method in mode 1 improved 1.76% and 4.75% when compared to mode 2 and FFD model algorithm, respectively. Further, the modified Hausdorff-distance was no different between demons modes 1 and 2, but mode 1 was 15.2% lower than FFD. Finally, demons algorithm has the absolute advantage in registration speed. The demons algorithm in mode 1 was therefore found to be much more suitable for the registration of 4D-CT images. The subtractions of floating images and reference image before and after registration by demons further verified that influence of breathing motion cannot be ignored and the demons registration method is feasible. 23893007 Designing a Bio-responsive Robot from DNA Origami. Nucleic acids are astonishingly versatile. In addition to their natural role as storage medium for biological information(1), they can be utilized in parallel computing(2,3) , recognize and bind molecular or cellular targets(4,5) , catalyze chemical reactions(6,7) , and generate calculated responses in a biological system(8,9). Importantly, nucleic acids can be programmed to self-assemble into 2D and 3D structures(10-12), enabling the integration of all these remarkable features in a single robot linking the sensing of biological cues to a preset response in order to exert a desired effect. Creating shapes from nucleic acids was first proposed by Seeman(13), and several variations on this theme have since been realized using various techniques(11,12,14,15) . However, the most significant is perhaps the one proposed by Rothemund, termed scaffolded DNA origami(16). In this technique, the folding of a long (>7,000 bases) single-stranded DNA 'scaffold' is directed to a desired shape by hundreds of short complementary strands termed 'staples'. Folding is carried out by temperature annealing ramp. This technique was successfully demonstrated in the creation of a diverse array of 2D shapes with remarkable precision and robustness. DNA origami was later extended to 3D as well(17,18) . The current paper will focus on the caDNAno 2.0 software(19) developed by Douglas and colleagues. caDNAno is a robust, user-friendly CAD tool enabling the design of 2D and 3D DNA origami shapes with versatile features. The design process relies on a systematic and accurate abstraction scheme for DNA structures, making it relatively straightforward and efficient. In this paper we demonstrate the design of a DNA origami nanorobot that has been recently described(20). This robot is 'robotic' in the sense that it links sensing to actuation, in order to perform a task. We explain how various sensing schemes can be integrated into the structure, and how this can be relayed to a desired effect. Finally we use Cando(21) to simulate the mechanical properties of the designed shape. The concept we discuss can be adapted to multiple tasks and settings. 23925446 Potential efficacy of monthly administrations of spot-on moxidectin 2.5 %/imidacloprid 10 % in the simultaneous prevention of major canine filarioses. Dirofilaria immitis, Dirofilaria repens, and Acanthocheilonema reconditum are the most important canine filariae. These species are expanding their distribution in both endemic regions and in previously free areas, thus enhancing the risk for single and mixed infestations in both dogs and humans. The present study evaluated the potential use of moxidectin in a spot-on formulation in preventing these dog filarioses in a confined area where the three major canine filariae live in sympatry. The trial was performed in a private shelter with a history of mixed infestations. Twenty-nine negative dogs were monthly treated with a spot-on formulation containing moxidectin 2.5 %/imidacloprid 10 % in spring and summer of 2010. The blood of the dogs was examined monthly with classical and molecular assays until December 2011. Twenty-six dogs completed the study, and they scored constantly negative to all diagnostic assays. Three further dogs completed the study in February 2011 until when they were filariae-negative. These results show that monthly treatment with moxidectin may potentially contribute in reducing the spreading of canine filarial diseases. The permanent negativity of treated dogs for the study period is discussed in relation to the potential use of this spot-on formulation in the prevention of single and mixed infestations of major vector-borne canine filariae. 23862933 Phase-field approach to implicit solvation of biomolecules with Coulomb-field approximation. A phase-field variational implicit-solvent approach is developed for the solvation of charged molecules. The starting point of such an approach is the representation of a solute-solvent interface by a phase field that takes one value in the solute region and another in the solvent region, with a smooth transition from one to the other on a small transition layer. The minimization of an effective free-energy functional of all possible phase fields determines the equilibrium conformations and free energies of an underlying molecular system. All the surface energy, the solute-solvent van der Waals interaction, and the electrostatic interaction are coupled together self-consistently through a phase field. The surface energy results from the minimization of a double-well potential and the gradient of a field. The electrostatic interaction is described by the Coulomb-field approximation. Accurate and efficient methods are designed and implemented to numerically relax an underlying charged molecular system. Applications to single ions, a two-plate system, and a two-domain protein reveal that the new theory and methods can capture capillary evaporation in hydrophobic confinement and corresponding multiple equilibrium states as found in molecular dynamics simulations. Comparisons of the phase-field and the original sharp-interface variational approaches are discussed. 23839065 Pleurocidin, a novel antimicrobial peptide, induces human mast cell activation through the FPRL1 receptor. Pleurocidins are a novel family of α-helical cationic antimicrobial peptides (CAPs) that are structurally and functionally similar to cathelicidins, one of the major CAP families. As cathelicidins stimulate mast cell chemotaxis and mediator release, we postulated that pleurocidins similarly activate mast cells. A screen of 20 pleurocidin peptides revealed that some were capable of degranulating the human mast cell line LAD2 (Laboratory of Allergic Diseases 2). Pleurocidin NRC-04 caused LAD2 to adhere, migrate, degranulate, and release cysteinyl leukotrienes and prostaglandin D2. Moreover, pleurocidin increased intracellular Ca(2+) mobilization in mast cells and induced the production of proinflammatory chemokines such as monocyte chemotactic protein-1/C-C motif chemokine ligand 2 (CCL2) and macrophage inflammatory protein-1β/CCL4. Our evaluation of possible cellular mechanisms suggested that G proteins, phosphoinositol-3 kinase (PI3K), phospholipase C (PLC), and phosphokinase C (PKC) were involved in pleurocidin-induced mast cell activation as evidenced by the inhibitory effects of pertussis toxin (G protein inhibitor), wortmanin (PI3K inhibitor), U-73122 (PLC inhibitor), and Ro-31-8220 (PKC inhibitor), respectively. We also found that human mast cells expressed the N-formyl-peptide receptor 1 (FPRL1) receptor and FPRL1-specific inhibitor affected pleurocidin-mediated activation of mast cell. Our finding that the novel CAP pleurocidin activated human mast cell through G protein-coupled receptor signaling suggests that this peptide might have immunomodulatory functions.Mucosal Immunology advance online publication 10 July 2013. doi:10.1038/mi.2013.37. 23843450 Plasmacytoid Dendritic Cells, Interferon Signaling, and FcγR Contribute to Pathogenesis and Therapeutic Response in Childhood Immune Thrombocytopenia. Immune thrombocytopenia (ITP) is an autoimmune disorder of childhood characterized by immune-mediated destruction of platelets. The mechanisms underlying the pathogenesis of ITP and the therapeutic efficacy of intravenous immunoglobulins (IVIG) in this disorder remain unclear. We show that monocytes from patients with ITP have a distinct gene expression profile, with increased expression of type I interferon response (IR) genes. Plasma from ITP patients had increased levels of several cytokines indicative of immune activation, including an increase in interferon-α. ITP patients also had an increase in plasmacytoid dendritic cells (pDCs) compared to healthy donors. Therapy-induced remission of ITP was associated with abrogation of the IR gene signature in monocytes without reduction in the levels of circulating interferon-α itself. IVIG altered the ratio of activating/inhibitory Fcγ receptors (FcγRs) in vivo primarily by reducing FcγRIII (CD16). The engagement of activating FcγRs was required for IVIG-mediated abrogation of monocyte response to exogenous interferon-α in culture. Moreover, plasma from ITP patients led to activation of monocytes and myeloid DCs in culture with an increase in T cell stimulatory capacity; this activation depended on the engagement of activating FcγRs and interferon-α receptor (IFNAR) and was inhibited by antibody-mediated blockade of these pathways. These data point to a central role of type I interferon in the pathogenesis of ITP and suggest targeting pDCs and blockade of IR as potential therapeutic approaches in this disorder. They also provide evidence for the capacity of IVIG to extinguish IR in vivo, which may contribute to its effects in autoimmunity. 23616670 Analysis of the Secretome and Identification of Novel Constituents from Culture Filtrate of Bacillus Calmette-Guerin Using High-resolution Mass Spectrometry. Tuberculosis (TB) is an infectious bacterial disease that causes morbidity and mortality, especially in developing countries. Although its efficacy against TB has displayed a high degree of variability (0%-80%) in different trials, Mycobacterium bovis bacillus Calmette-Guérin (BCG) has been recognized as an important weapon for preventing TB worldwide for over 80 years. Because secreted proteins often play vital roles in the interaction between bacteria and host cells, the secretome of mycobacteria is considered to be an attractive reservoir of potential candidate antigens for the development of novel vaccines and diagnostic reagents. In this study, we performed a proteomic analysis of BCG culture filtrate proteins using SDS-PAGE and high-resolution Fourier transform mass spectrometry. In total, 239 proteins (1555 unique peptides) were identified, including 185 secreted proteins or lipoproteins. Furthermore, 17 novel protein products not annotated in the BCG database were detected and validated by means of RT-PCR at the transcriptional level. Additionally, the translational start sites of 52 proteins were confirmed, and 22 proteins were validated through extension of the translational start sites based on N-terminus-derived peptides. There are 103 secreted proteins that have not been reported in previous studies on the mycobacterial secretome and are unique to our study. The physicochemical characteristics of the secreted proteins were determined. Major components from the culture supernatant, including low-molecular-weight antigens, lipoproteins, Pro-Glu and Pro-Pro-Glu family proteins, and Mce family proteins, are discussed; some components represent potential predominant antigens in the humoral and cellular immune responses. 23688606 Label-free immunosensor for the detection of kanamycin using Ag@Fe₃O₄ nanoparticles and thionine mixed graphene sheet. A highly sensitive label-free immunosensor for the detection of kanamycin had been developed using silver hybridized mesoporous ferroferric oxide nanoparticles (Ag@Fe₃O₄ NPs) and thionine mixed graphene sheet (TH-GS). TH was used as an electron transfer mediator. The electrical signal was greatly improved in the presence of GS due to its good electron-transfer ability. With the advantages of large specific surface area and excellent electrical conductivity, Ag@Fe₃O₄ NPs could immobilize more antibodies of kanamycin and promote the electron transfer. Cyclic voltammetry and square wave voltammetry were used to characterize the recognition of kanamycin. The proposed immunosensor showed good performances such as low detection limit (15 pg mL⁻¹), wide linear range (from 0.050 to 16 ng mL⁻¹), short analysis time (3 min), high stability, and good selectivity in the detection of kanamycin. The immunosensor was evaluated for pork meat sample, receiving satisfactory results. 23939392 Lactate-Induced Release of GABA in the Ventromedial Hypothalamus Contributes to Counterregulatory Failure in Recurrent Hypoglycemia and Diabetes. Suppression of GABAergic neurotransmission in the ventromedial hypothalamus (VMH) is crucial for full activation of counterregulatory responses to hypoglycemia and increased GABA output contributes to counterregulatory failure in recurrently hypoglycemic (RH) and diabetic rats. The goal of this study was to establish whether lactate contributes to raising VMH GABA levels in these two conditions. We used microdialysis to deliver artificial extracellular fluid (aECF) or L-lactate into the VMH and sample for GABA. We then microinjected a GABAA receptor antagonist, an inhibitor of lactate transport (4CIN) or an inhibitor of lactate dehydrogenase, oxamate (OX), into the VMH prior to inducing hypoglycemia. To assess whether lactate contributes to raising GABA in RH and diabetes, we injected 4CIN or OX into the VMH of RH and diabetic rats before inducing hypoglycemia. L-lactate raised VMH GABA levels and suppressed counterregulatory responses to hypoglycemia. While blocking GABAA receptors did not prevent the lactate-induced rise in GABA, inhibition of lactate transport or utilization did, despite the presence of lactate. All three treatments restored the counterregulatory responses, suggesting lactate suppresses these responses by enhancing GABA release. Both RH and diabetic rats had higher baseline GABA levels and were unable to reduce GABA levels sufficiently to fully activate counterregulatory responses during hypoglycemia. 4CIN or OX lowered VMH GABA levels in both RH and diabetic rats and restored the counterregulatory responses. Lactate likely contributes to counterregulatory failure in RH and diabetes by increasing VMH GABA levels. 23930076 Role of leukotrienes in exercise-induced bronchoconstriction before and after a pilot rehabilitation training program. Whatever the initial stimulus for the exercise-induced bronchoconstriction (EIB) observed in asthmatic patients after exercise, the final effect is release of bronchoactive mediators, especially cysteinyl leukotrienes. Exercise rehabilitation training programs have been reported to protect against EIB. The exact mechanism(s) involved are not well understood. However, this protective effect may be related to adaptation and better coordination during exercise, depletion of cysteinyl leukotrienes, and/or a sluggish cysteinyl leukotriene response to exercise. The aim of the present work was to test the hypothesis that improvement in the incidence and severity of post-exercise bronchoconstriction after a rehabilitation training program is related to a change in leukotriene levels in response to exercise. Twenty asthmatic children aged 6-12 years and known to develop EIB were enrolled in an exercise training program for 12 weeks. The severity and incidence of EIB before and after training was assessed. Baseline and post-exercise sputum cysteinyl leukotriene levels were assessed before and after the training program. The training program offered significant protection against EIB with a concomitant decrease in sputum cysteinyl leukotriene levels in response to exercise. A training program can result in depletion and/or a sluggish cysteinyl leukotriene response to exercise and may be responsible for the protective effect of training programs on EIB. It is recommended to use an exercise rehabilitation training program as a complementary tool in the management of bronchial asthma, especially EIB. 23738794 Novel approaches to glioma drug design and drug screening. Introduction: Gliomas are considered the most malignant form of brain tumors, and ranked among the most aggressive human cancers. Despite advance standard therapy the prognosis for patients with gliomas remains poor. Chemotherapy has played an important role as an adjuvant in treating gliomas. The efficacy of the chemotherapeutic drug is limited due to poor drug delivery and the inherent chemo- and radio-resistance. Challenges of the brain cancer therapy in clinical settings are; i) to overcome the chemo- and radio-resistance, ii) to improve drug delivery to tumors and iii) the development of effective drug screening procedures. Areas covered: In this review, the authors discuss clinically important chemotherapeutic agents used for treating malignant gliomas along with novel drug design approaches. The authors, furthermore, discuss the in vitro and in vivo drug screening procedures for the development of novel drug candidates. Expert opinion: The development of novel and highly potent chemotherapeutic agents for both glioma and glioma stem cells (GSCs) is highly important for future brain cancer research. Thus, research efforts should be directed towards developing innovative molecularly targeted antiglioma agents in order to reduce the toxicity and drug resistance which are associated with current forms of therapy. Development of novel pre-clinical drug screening procedures is also very critical for the overall success of brain cancer therapies in clinical settings. 23872525 Dissecting children's observational learning of complex actions through selective video displays. Children can learn how to use complex objects by watching others, yet the relative importance of different elements they may observe, such as the interactions of the individual parts of the apparatus, a model's movements, and desirable outcomes, remains unclear. In total, 140 3-year-olds and 140 5-year-olds participated in a study where they observed a video showing tools being used to extract a reward item from a complex puzzle box. Conditions varied according to the elements that could be seen in the video: (a) the whole display, including the model's hands, the tools, and the box; (b) the tools and the box but not the model's hands; (c) the model's hands and the tools but not the box; (d) only the end state with the box opened; and (e) no demonstration. Children's later attempts at the task were coded to establish whether they imitated the hierarchically organized sequence of the model's actions, the action details, and/or the outcome. Children's successful retrieval of the reward from the box and the replication of hierarchical sequence information were reduced in all but the whole display condition. Only once children had attempted the task and witnessed a second demonstration did the display focused on the tools and box prove to be better for hierarchical sequence information than the display focused on the tools and hands only. 23915776 Parents' physical victimization in childhood and current risk of child maltreatment: The mediator role of psychosomatic symptoms. To test the potential mediation effect of psychosomatic symptoms on the relationship between parents' history of childhood physical victimization and current risk for child physical maltreatment. Data from the Portuguese National Representative Study of Psychosocial Context of Child Abuse and Neglect were used. Nine-hundred and twenty-four parents completed the Childhood History Questionnaire, the Psychosomatic Scale of the Brief Symptom Inventory, and the Child Abuse Potential Inventory. Mediation analysis revealed that the total effect of the childhood physical victimization on child maltreatment risk was significant. The results showed that the direct effect from the parents' history of childhood physical victimization to their current maltreatment risk was still significant once parents' psychosomatic symptoms were added to the model, indicating that the increase in psychosomatic symptomatology mediated in part the increase of parents' current child maltreatment risk. The mediation analysis showed parents' psychosomatic symptomatology as a causal pathway through which parents' childhood history of physical victimization exerts its effect on increased of child maltreatment risk. Somatization-related alterations in stress and emotional regulation are discussed as potential theoretical explanation of our findings. A cumulative risk perspective is also discussed in order to elucidate about the mechanisms that contribute for the intergenerational continuity of child physical maltreatment. 23496341 Pyridone Alkaloids from a Marine-Derived Fungus, Stagonosporopsis cucurbitacearum, and Their Activities against Azole-Resistant Candida albicans. Four new 4-hydroxy-2-pyridone alkaloids, didymellamides A-D (1-4), were isolated from the marine-derived fungus Stagonosporopsis cucurbitacearum. The structures of 1-4 were elucidated from spectroscopic data (NMR, MS, and IR), and the absolute configuration of 1 was determined by X-ray diffraction analysis. Didymellamide A (1) exhibited antifungal activity against azole-resistant Candida albicans. 23948599 Rationale for an experimental treatment of retinitis pigmentosa: 140-Month test of hypothesis with one patient. Numerous mutations in over 100 rod genes are the well-established cause of apoptotic death of these cells and development of night blindness in retinitis pigmentosa (RP). Cone death is either concomitant or follows rod death with resultant loss of critical peripheral and central day vision. As cones are generally not encumbered by genetic mutations, the causes of their death and its prevention are the central problems of RP research. Currently no FDA-approved medications are available for retarding RP progression. It is proposed that cones, which are outnumbered 20:1 by rods, undergo apoptosis as a consequence of neurotrophic factor deficiencies and oxidative stresses accompanying massive rod death: increased retinal oxygen tension; leakage of lipid-peroxidation catalysts from disrupted membranes; reactive oxygen species from active/hyperactive microglia ingesting rod-apoptotic bodies. Accordingly we developed and tested a treatment regimen with a range of antioxidants in combination with the off-label use of deprenyl (1mg/day), a safe antiapoptotic agent, which also upregulates eight neurotrophic factors. Since deprenyl inhibits only one of four mitochondrial apoptotic pathways, we added the antibiotic minocycline (100mg/day) to our protocol at month 76. Minocycline complements deprenyl's therapeutic properties: it inhibits all four apoptotic pathways; inhibits apoptosis-initiating proteins; as phenol exerts powerful antioxidant properties; upregulates three antioxidant enzymes; downregulates oxidative/inflammatory microglia activities. Its safe long-term use for acne and rheumatoid arthritis received FDA approval; it passes the blood/brain and blood/retinal barriers readily; and because of its rapid and complete absorption causes no intestinal disturbances. The National Eye Institute has initiated in 2010 and 2011 clinical trials with minocycline (200mg/day) for diabetic macular edema and retinal branch vein occlusion. The hypothesis was tested for 140months with one RP patient monitored by Humphrey Perimetry, which was quantitated by two parameters: (a) sum of decibel units, (b) number of detected light sources (visual field). Although no decline was observed in these parameters during the first 50months of treatment, they declined by 10-28% during months 50-65. These declines reversed upon introduction of minocycline: over the total 140-month treatment, the right eye visual field showed 0% decline and left eye 13.3% decline. Rate constants for logarithmic decline of visual field measured prior to treatment indicate that visual fields would have decreased by 64% and 70%, respectively by month 140 in the absence of treatment. 23956399 Exoproteome profiles of Clostridium cellulovorans on various carbon sources. The cellulosome is a complex of cellulosomal proteins bound to scaffolding proteins. This complex is considered the most efficient system for cellulose degradation. Clostridium cellulovorans, known to produce cellulosomes, changes the composition of its cellulosomes depending on the growth substrate. However, studies have only investigated cellulosomal proteins; changes in non-cellulosomal proteins have rarely been examined. In this study, we performed a quantitative proteome analysis of the whole exoproteome of C. cellulovorans, including cellulosomal and non-cellulosomal proteins, to illustrate how various substrates are efficiently degraded. C. cellulovorans was cultured with cellobiose, xylan, pectin, or phosphoric acid swollen cellulose (PASC) as the sole carbon source. PASC was used as a cellulose substrate for more accurate quantitative analysis. Using an isobaric tag method and a liquid chromatography mass spectrometer equipped with a long monolithic silica column, 639 proteins were identified and quantified in all 4 samples. Among these, 79 proteins were involved in saccharification, including 35 cellulosomal and 44 non-cellulosomal proteins. We compared protein abundance by spectral count and found that cellulosomal proteins were more abundant than non-cellulosomal proteins. Next, we focused on the fold change of the proteins depending on the growth substrate. Drastic changes were mainly observed among the non-cellulosomal proteins. These results indicate that cellulosomal proteins were primarily produced to efficiently degrade any substrate, and that non-cellulosomal proteins were specifically produced to optimize the degradation of a particular substrate. This study highlights the importance of non-cellulosomal proteins as well as cellulosomes for the efficient degradation of various substrates. 23942706 A simple amino acid dose-response method to quantify amino acid requirements of individual meal-fed pigs. Two experiments were conducted to develop a simplified dose-response technique to estimate the Lys requirement of individual, meal-fed growing pigs. In Exp. 1, we studied adaptation processes that occur during such a dose-response study in meal-fed pigs, and in Exp. 2, we studied the accuracy of this simplified technique to estimate changes in Lys requirement estimates of pigs following changes in energy intake. In Exp. 1, the effect of the Lys supply strategy on the Lys requirement was assessed in 14 barrows fed an increasing (low to high, LH) or decreasing (high to low, HL) total Lys supply, with total Lys levels varying from 0.36 to 1.06 g/MJ DE in 7 equidistant steps of 4 d each. Urinary urea and ammonia excretion and whole body N turnover were measured. In Exp. 2, the accuracy of the dose-response technique to determine a shift in Lys requirement was assessed in 20 barrows fed at either 2.2 (low energy, LE) or 2.7 (high energy, HE) times the energy requirements for maintenance, with total Lys supply decreasing from 1.10 to 0.37 g Lys/MJ DE in 9 equidistant steps of 3 d each. In Exp. 1, a lower increment in protein synthesis, breakdown, and whole body N turnover with increasing dietary Lys supply was observed in LH-pigs than HL-pigs (P < 0.01) and the estimated Lys requirement was 0.06 g/MJ DE greater (P = 0.01) in LH-pigs than HL-pigs. These results indicated that pigs at a decreasing Lys supply strategy require less time for metabolic adaptation to a change in Lys supply than those at an increasing Lys supply. In Exp. 2, the estimated Lys requirement was 2.6 g/d greater (P < 0.001) in HE-pigs than LE-pigs. The variation in AA requirement estimates between individual pigs was low (4.9% in LH-pigs and 3.0% in HL-pigs in Exp. 1, and 8.1% in LE-pigs and 6.0% in HE-pigs in Exp. 2). The present studies indicated that a dose-response technique with a decreasing Lys supply in time and a step length of 3 d with urinary N excretion as response criteria provides a simple, accurate technique to quantitatively estimate a change in AA requirements of individual meal-fed pigs. 23542493 In vitro and in vivo characterization of meloxicam nanoparticles designed for nasal administration. The nasal pathway represents a non-invasive route for delivery of drugs to the systemic circulation. Nanonization of poorly soluble drugs offers a possibility to increase dissolution properties, epithelial permeability or even bioavailability. The aim of the present study was to use in vitro methods to screen formulations which were intended for nasal application, and to perform animal experiments for recognizing the differences in plasmakinetics of intranasal- and oral-administered meloxicam nanoparticles. Due to nanonization the solubility of meloxicam elevated up to 1.2mg/mL, additionally the extent of dissolution also increased, complete dissolution was observed in 15min. Favorable in vitro diffusion profile of meloxicam nanoparticles was observed and their epithelial permeability through human RPMI2650 cells was elevated. The pharmacokinetic parameters were significantly increased when meloxicam was administered as nanoparticles to rats either nasally (increase of Cmax 2.7-fold, AUC 1.5-fold) or orally (increase of Cmax 2.4-fold, AUC 2-fold) as compared to physical mixture of the drug and the excipients. 23299757 Fetal and neonatal outcomes in women reporting ingestion of licorice (Glycyrrhiza uralensis) during pregnancy. Maternal intake of licorice from dietary sources has been associated with adverse maternal and fetal outcomes. We prospectively studied the outcome of 185 singleton pregnancies who took over-the-counter or naturopathic formulations containing licorice during their pregnancy, and 370 age-matched singleton pregnant controls that were not exposed to any potential teratogen. The indication in 56.8% of the women taking licorice was for cough and cold control, with the maximum dose of 2104 mg/day and exposure occurring between the 4th day and 25th week of gestation. The rate of stillbirths was marginally higher among women who took licorice than those who did not (OR = 7.9; 95% CI 0.9-71.5; p = 0.048), and significantly higher when compared to the general population in the Republic of Korea (OR = 13.3; 95% CI 4.9-35.8; p < 0.001). Other fetal outcomes assessed in the study were similar between the two study groups, e.g., the OR of major malformations was 3.9 (95% CI 0.4-43.5; p = 0.27). In conclusion, the present study suggests that licorice is not a major teratogen. However, whether licorice may increase the risk of stillbirths requires careful consideration in further studies with a larger sample size. 23466332 Experience-dependent homeostatic synaptic plasticity in neocortex. The organism's ability to adapt to the changing sensory environment is due in part to the ability of the nervous system to change with experience. Input and synapse specific Hebbian plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), are critical for sculpting the nervous system to wire its circuit in tune with the environment and for storing memories. However, these synaptic plasticity mechanisms are innately unstable and require another mode of plasticity that maintains homeostasis to allow neurons to function within a desired dynamic range. Several modes of homeostatic adaptation are known, some of which work at the synaptic level. This review will focus on the known mechanisms of experience-induced homeostatic synaptic plasticity in the neocortex and their potential function in sensory cortex plasticity. This article is part of a Special Issue entitled 'Homeostatic Plasticity'. 22766107 Role of AMPK in pancreatic beta cell function. Pharmacological activation of AMP activated kinase (AMPK) by metformin has proven to be a beneficial therapeutic approach for the treatment of type II diabetes. Despite improved glucose regulation achieved by administration of small molecule activators of AMPK, the potential negative impact of enhanced AMPK activity on insulin secretion by the pancreatic beta cell is an important consideration. In this review, we discuss our current understanding of the role of AMPK in central functions of the pancreatic beta cell, including glucose-stimulated insulin secretion (GSIS), proliferation, and survival. In addition we discuss the controversy surrounding the role of AMPK in insulin secretion, underscoring the merits and caveats of methods used to date. 23830978 Hypoxia/hepatoma dual specific suicide gene expression plasmid delivery using bio-reducible polymer for hepatocellular carcinoma therapy. Gene therapy is suggested as a promising alternative strategy of hepatocellular carcinoma (HCC, also called hepatoma) therapy. To achieve a successful and safe gene therapy, tight regulation of gene expression is required to minimize side-effects in normal tissues. In this study, we developed a novel hypoxia and hepatoma dual specific gene expression vector. The constructed vectors were transfected into various cell lines using bio-reducible polymer, PAM-ABP. First, pAFPS-Luc or pAFPL-Luc vector was constructed with the alpha-fectoprotein (AFP) promoter and enhancer for hepatoma tissue specific gene expression. Then, pEpo-AFPL-Luc was constructed by insertion of the erythropoietin (Epo) enhancer for hypoxic cancer specific gene expression. In vitro transfection assay showed that pEpo-AFPL-Luc transfected hepatoma cell increased gene expression under hypoxic condition. To confirm the therapeutic effect of dual specific vector, herpes simplex virus thymidine kinase (HSV-TK) gene was introduced for cancer cell killing. The pEpo-AFPL-TK was transfected into hepatoma cell lines in the presence of ganciclovir (GCV) pro-drug. Caspase-3/7, MTT and TUNEL assays elucidated that pEpo-AFPL-TK transfected cells showed significant increasing of death rate in hypoxic hepatoma cells compared to controls. Therefore, the hypoxia/hepatoma dual specific gene expression vector with the Epo enhancer and AFP promoter may be useful for hepatoma specific gene therapy. 23924091 Trusts instigate immediate bans on care pathway. Immediate bans on the use of the Liverpool Care Pathway are being introduced following the announcement that the framework will be phased out over the coming year. 23659970 Tumor heterogeneity and permeability as measured on the CT component of PET/CT predict survival in patients with non-small cell lung cancer. We prospectively examined the role of tumor textural heterogeneity on positron emission tomography/computed tomography (PET/CT) in predicting survival compared with other clinical and imaging parameters in patients with non-small cell lung cancer (NSCLC). The feasibility study consisted of 56 assessed consecutive patients with NSCLC (32 males, 24 females; mean age 67 ± 9.7 years) who underwent combined fluorodeoxyglucose (FDG) PET/CT. The validation study population consisted of 66 prospectively recruited consecutive consenting patients with NSCLC (37 males, 29 females; mean age, 67.5 ± 7.8 years) who successfully underwent combined FDG PET/CT-dynamic contrast-enhanced (DCE) CT. Images were used to derive tumoral PET/CT textural heterogeneity, DCE CT permeability, and FDG uptake (SUVmax). The mean follow-up periods were 22.6 ± 13.3 months and 28.5± 13.2 months for the feasibility and validation studies, respectively. Optimum threshold was determined for clinical stage and each of the above biomarkers (where available) from the feasibility study population. Kaplan-Meier analysis was used to assess the ability of the biomarkers to predict survival in the validation study. Cox regression determined survival factor independence. Univariate analysis revealed that tumor CT-derived heterogeneity (P < 0.001), PET-derived heterogeneity (P = 0.003), CT-derived permeability (P = 0.002), and stage (P < 0.001) were all significant survival predictors. The thresholds used in this study were derived from a previously conducted feasibility study. Tumor SUVmax did not predict survival. Using multivariable analysis, tumor CT textural heterogeneity (P = 0.021), stage (P = 0.001), and permeability (P < 0.001) were independent survival predictors. These predictors were independent of patient treatment. Tumor stage and CT-derived textural heterogeneity were the best predictors of survival in NSCLC. The use of CT-derived textural heterogeneity should assist the management of many patients with NSCLC. 23279752 Evaluation of chewing ability and its relationship with activities of daily living, depression, cognitive status and food intake in the community-dwelling elderly. The aim of this study was to assess chewing ability using color-changeable chewing gum and to show the association between chewing ability and geriatric functions, as well as dietary status in the community-dwelling elderly. The study population consisted of 269 community-dwelling elderly aged ≥ 75 living in Tosa, Japan. Assessment of chewing ability was carried out by a dentist using color-changeable chewing gum. Activities of daily living (ADL), depression and subjective quality of life (QOL) were assessed by questionnaire. Cognitive status was assessed by; Mini-Mental State Examination (MMSE), Hasegawa Dementia Scale-Revised (HDS-R) and Frontal Assessment Battery (FAB) during the check-up. Food diversity was assessed using the 11-item Food Diversity Score Kyoto (FDSK-11). Number of teeth was significantly related to chewing ability (P<0.001). The participants with low chewing ability had significantly lower ADL scores in the items of self-maintenance (P=0.029) and intellectual activity (P=0.021). There was a significant association between low chewing ability and depression (P<0.001). Lower cognitive functions were significantly related to low chewing ability; MMSE (P=0.022), HDSR (P=0.017) and FAB (P=0.002). The participants with low chewing ability had lower food variety (P<0.001), and less frequent intake of beans, vegetables, seaweed and nuts, than the participants with high chewing ability. Low chewing ability evaluated by color-changeable gum was associated with lower ADL, lower cognitive functioning, depression and food insufficiency in the community-dwelling elderly. More attention should be paid to assessing chewing ability of elderly persons in community settings. 23508742 Dammarane-type saponins from heat-processed Gynostemma pentaphyllum show fortified activity against A549 cells. An ethanol extract from heat-processed Gynostemma pentaphyllum showed more potent cytotoxic activity against human lung adenocarcinoma A549 cells than that of raw G. pentaphyllum. Four constituents were isolated from heat-processed G. pentaphyllum using resin HP-20, silica gel and reversed ODS column chromatography. They were identified by mass and NMR spectra as damulin A and damulin B, gypenoside L and gypenoside LI, respectively. To evaluate the efficacy of these four constituents, the MTT cytotoxicity assay was performed using A549 cells. Based on the structure of these four constituents, the results indicate that the hydroxyl group in C-2 and double bond in C20(21) and C20(22) positions are of importance in inhibition of A549 cell proliferation. 23924084 Cross-parent reliability in rating ASD markers in infants. Abstract Objective: To investigate the congruence and discrepancies between mother and father reports of early autism spectrum disorders (ASD) markers. Methods: Mothers (n = 80) and fathers (n = 78) of 12-month-old infants (55% boys) completed the first year inventory (FYI), an ASD norm-referenced screening questionnaire. Mothers also completed the Infant Toddler Social Emotional Assessment (ITSEA). Results: There were significant and moderate intra-class correlations between mother and father reports for most FYI factors. Fathers' median FYI social-communication domain score was almost twice that of mothers. Mann-Whitney tests indicated that fathers rated their child significantly higher than mothers on the four FYI social-communication factors and on the sensory processing factor. Linear weighted kappa analyses indicated poor agreement on gaze-related and reactivity FYI items. FYI social-communication and sensory-regulatory factors showed significant correlations with corresponding ITSEA scores. Conclusions: Social-communication markers pose a greater challenge for consistent report across parents than sensory-regulatory markers. 23274887 Fetal PGC-1α overexpression programs adult pancreatic β-cell dysfunction. Adult β-cell dysfunction, a hallmark of type 2 diabetes, can be programmed by adverse fetal environment. We have shown that fetal glucocorticoids (GCs) participate in this programming through inhibition of β-cell development. Here we have investigated the molecular mechanisms underlying this regulation. We showed that GCs stimulate the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a coregulator of the GCs receptor (GR), and that the overexpression of PGC-1α represses genes important for β-cell development and function. More precisely, PGC-1α inhibited the expression of the key β-cell transcription factor pancreatic duodenal homeobox 1 (Pdx1). This repression required the GR and was mediated through binding of a GR/PGC-1α complex to the Pdx1 promoter. To explore PGC-1α function, we generated mice with inducible β-cell PGC-1α overexpression. Mice overexpressing PGC-1α exhibited at adult age impaired glucose tolerance associated with reduced insulin secretion, decreased β-cell mass, and β-cell hypotrophy. Interestingly, PGC-1α expression in fetal life only was sufficient to impair adult β-cell function whereas β-cell PGC-1α overexpression from adult age had no consequence on β-cell function. Altogether, our results demonstrate that the GR and PGC-1α participate in the fetal programming of adult β-cell function through inhibition of Pdx1 expression. 23965103 Notice board. Courses, events, grants, and awards to progress your career. 23657539 Synthesis of metal selenide colloidal nanocrystals by the hot injection of selenium powder. We describe the synthesis of metal selenide nanocrystals, including CdSe, ZnSe, CuInSe2 and Cu2(Zn,Sn)Se4, by the hot injection of selenium powder dispersed in a carrier solvent. Since this results in a fast and high yield nanocrystal formation, we argue that the approach is well suited for the low cost, large volume production of nanocrystals. 23851040 Influence of temporal relationships between serotonergic and dopaminergic precursors on the regulation of gonadal development in birds. This article is focused on the effect of specific phase relation of serotonergic and dopaminergic oscillations on the gonadal responses of different avian species. These species include (i) summer breeding birds - Red headed bunting (exhibiting post-reproductive absolute photorefractoriness) and Indian Weaver bird (which lacks absolute photorefractoriness), (ii) autumn breeding - Spotted munia and Lal munia (photoperiodic responses of which are distinctly different from that of any long day birds described thus far) and (iii) domesticated Japanese quail (which under natural day length breeds in summer, exhibits relative photorefractoriness, but breeds continuously if maintained in long photoperiod). Previous experiments have shown that daily administration of serotonin precursor 5-hydroxytryptophan and dopamine precursor L-dihydroxyphenylalanine given 8h apart during progressive phase of gonadal cycle can lead to a significant decrease in gonadal activity. However, if given at an interval of 12h it leads to an increase in gonadal activity and the effect of other intervals (0-, 4-, 16- and 20-h) were not different from control. Similar effects were observed during regressive phase of the gonadal cycle of above species except in those which display absolute photorefractory phase in their breeding cycle. This shows that, gonad of such species not only develop post-reproductive photorefractoriness but also becomes insensitive to the stimulatory effects of 5-HTP and L-DOPA when given at the interval of 12h. It is suggested that, temporal phase relation of circadian serotonergic and dopaminergic oscillations is the basis of seasonality in birds and may alter the activity of neuroendocrine-gonadal axis not only under natural day length but also under experimental/different photoperiodic conditions. These results are in agreement with the internal coincidence model of photoperiodic time measurement and indicate that birds can detect specific phase relationship between the two neural oscillations for their reproductive regulations and circadian organization is intricately involved in the regulation of seasonality. 23900768 Genetic evidence does not support an etruscan origin in Anatolia. The debate on the origins of Etruscans, documented in central Italy between the eighth century BC and the first century AD, dates back to antiquity. Herodotus described them as a group of immigrants from Lydia, in Western Anatolia, whereas for Dionysius of Halicarnassus they were an indigenous population. Dionysius' view is shared by most modern archeologists, but the observation of similarities between the (modern) mitochondrial DNAs (mtDNAs) of Turks and Tuscans was interpreted as supporting an Anatolian origin of the Etruscans. However, ancient DNA evidence shows that only some isolates, and not the bulk of the modern Tuscan population, are genetically related to the Etruscans. In this study, we tested alternative models of Etruscan origins by Approximate Bayesian Computation methods, comparing levels of genetic diversity in the mtDNAs of modern and ancient populations with those obtained by millions of computer simulations. The results show that the observed genetic similarities between modern Tuscans and Anatolians cannot be attributed to an immigration wave from the East leading to the onset of the Etruscan culture in Italy. Genetic links between Tuscany and Anatolia do exist, but date back to a remote stage of prehistory, possibly but not necessarily to the spread of farmers during the Neolithic period. Am J Phys Anthropol, 2013. © 2013 Wiley Periodicals, Inc. 23792156 Athlete use and opinion of point of choice nutrition labels at a major international competition. Point of choice (POC) labels may assist individuals to choose food appropriate for their needs when dining away from home. However, limited research exists on the use and opinion of labels by athletes in a large dining hall environment. The aim of this study was to evaluate athletes' utilisation and opinion of POC nutrition labels provided in the athletes village main dining hall at a major competition event (the 2010 Commonwealth Games, New Delhi, India). A questionnaire was distributed to athletes from a range of cultural and sporting backgrounds (n=351) while present within the dining hall during main meal periods throughout the competition event (23rd September-14th October, 2010). While the majority of respondents (79%) reported that it was important/very important to provide POC information for menu items and 59% rated the POC labels as useful/very useful, only 14% of athletes reported using labels all of the time. Athletes from specific regions (India/Sri Lanka, Africa), sports (team and weight category), and those with less education reported using the labels more frequently. Although females rated the importance of providing nutrition information higher than males (p=0.008), there was no gender difference in reported use of POC labels. Athletes believed that POC labels could be improved with the addition of more information, better aesthetic properties, and better positioning in more convenient locations. Further research to identify the most effective POC label for use in this environment, and ultimately the development of a standardised label may assist a broader range of athletes at future competitions. 22422627 Berberine inhibits myofibroblast differentiation in nasal polyp-derived fibroblasts via the p38 pathway. The purposes of this study were to determine whether berberine has any effect on phenotype changes and extracellular matrix (ECM) production in nasal polyp-derived fibroblasts (NPDFs) and to investigate the underlying molecular mechanism. NPDFs were pre-treated with berberine prior to induction by transforming growth factor (TGF)-β1. The expression of α-smooth muscle actin (SMA) and collagen type I mRNA was determined by a reverse transcription-polymerase chain reaction, and the expression of α-SMA protein and collagen type I was determined by western blotting and/or immunofluorescent staining. The total soluble collagen production was analysed by the SirCol collagen assay. The expression of several signaling molecules of the TGF-β1 pathway was evaluated by western blot analysis. In TGF-β1-induced NPDFs, berberine significantly inhibited the expression of α-SMA and collagen type I mRNA and reduced α-SMA and collagen protein levels. Berberine only suppressed the expression of pp38 among the evaluated signaling molecules. SB203580 (a specific inhibitor of p38 kinase) markedly suppressed the increased expression of collagen type I and α-SMA in TGF-β1-induced NPDFs. Berberine exerts suppressive effects on phenotype changes and ECM production in NPDFs via p38 signaling pathway interference. The findings provide new therapeutic options for ECM production in nasal polyps. 23355111 Post-mortem detection of gasoline residues in lung tissue and heart blood of fire victims. The purpose of this study was to determine whether gasoline residues could be detected post-mortem in lung tissue and heart blood of fire victims. The lungs and heart blood were investigated to determine whether they were suitable samples for collection and could be collected without contamination during an autopsy. Three sets of test subjects (pig carcasses) were investigated under two different fire scenarios. Test subjects 1 were anaesthetized following animal ethics approval, inhaled gasoline vapours for a short period and then euthanized. The carcasses were clothed and placed in a house where additional gasoline was poured onto the carcass post-mortem in one fire, but not in the other. Test subjects 2 did not inhale gasoline, were clothed and placed in the house and had gasoline poured onto them in both fires. Test subjects 3 were clothed but had no exposure to gasoline either ante- or post-mortem. Following controlled burns and suppression with water, the carcasses were collected, and their lungs and heart blood were excised at a necropsy. The headspace from the samples was analysed using thermal desorption-gas chromatography-mass spectroscopy. Gasoline was identified in the lungs and heart blood from the subjects that were exposed to gasoline vapours prior to death (test subjects 1). All other samples were negative for gasoline residues. These results suggest that it is useful to analyse for volatile ignitable liquids in lung tissue and blood as it may help to determine whether a victim was alive and inhaling gases at the time of a fire. 23803315 Traumatic brain injury may be an independent risk factor for stroke. To explore whether traumatic brain injury (TBI) may be a risk factor for subsequent ischemic stroke. Patients with any emergency department visit or hospitalization for TBI (exposed group) or non-TBI trauma (control) based on statewide emergency department and inpatient databases in California from 2005 to 2009 were included in a retrospective cohort. TBI was defined using the Centers for Disease Control definition. Our primary outcome was subsequent hospitalization for acute ischemic stroke. The association between TBI and stroke was estimated using Cox proportional hazards modeling adjusting for demographics, vascular risk factors, comorbidities, trauma severity, and trauma mechanism. The cohort included a total of 1,173,353 trauma subjects, 436,630 (37%) with TBI. The patients with TBI were slightly younger than the controls (mean age 49.2 vs 50.3 years), less likely to be female (46.8% vs 49.3%), and had a higher mean injury severity score (4.6 vs 4.1). Subsequent stroke was identified in 1.1% of the TBI group and 0.9% of the control group over a median follow-up period of 28 months (interquartile range 14-44). After adjustment, TBI was independently associated with subsequent ischemic stroke (hazard ratio 1.31, 95% confidence interval 1.25-1.36). In this large cohort, TBI is associated with ischemic stroke, independent of other major predictors. 23936007 Tuning of thioredoxin redox properties by intramolecular hydrogen bonds. Thioredoxin-like proteins contain a characteristic C-x-x-C active site motif and are involved in a large number of biological processes ranging from electron transfer, cellular redox level maintenance, and regulation of cellular processes. The mechanism for deprotonation of the buried C-terminal active site cysteine in thioredoxin, necessary for dissociation of the mixed-disulfide intermediate that occurs under thiol/disulfide mediated electron transfer, is not well understood for all thioredoxin superfamily members. Here we have characterized a 8.7 kD thioredoxin (BC3987) from Bacillus cereus that unlike the typical thioredoxin appears to use the conserved Thr8 side chain near the unusual C-P-P-C active site to increase enzymatic activity by forming a hydrogen bond to the buried cysteine. Our hypothesis is based on biochemical assays and thiolate pKa titrations where the wild type and T8A mutant are compared, phylogenetic analysis of related thioredoxins, and QM/MM calculations with the BC3987 crystal structure as a precursor for modeling of reduced active sites. We suggest that our model applies to other thioredoxin subclasses with similar active site arrangements. 23000076 Cannabinoid CB₁ receptor in the modulation of stress coping behavior in mice: the role of serotonin and different forebrain neuronal subpopulations. The endocannabinoid system (ECS) may either enhance or inhibit responses to aversive stimuli, possibly caused by its modulatory activity on diverse neurotransmitters. The aim of this work was to investigate the involvement of serotonin (5-HT) and catecholamines, as well as the role of glutamatergic and GABAergic cannabinoid type 1 (CB(1)) receptor, in responses to the antidepressant-like doses of the CB(1) receptor agonist Δ(9)-tetrahydrocannabinol (THC) and the antagonist rimonabant in the forced swim test (FST). Mice received acute injections of low doses of THC (0.1 or 0.5 mg/kg) or high dose of rimonabant (3 or 10 mg/kg) after treatment with the 5-HT synthesis inhibitor pCPA (100 mg/kg, 4 days), the 5-HT(1A) receptor antagonist WAY100635 (1 mg/kg, acute) or the non-selective blocker of catecholamine synthesis, AMPT (20 mg/kg, acute). THC and rimonabant were also tested in mutant mice lacking CB(1) receptor in specific forebrain neuronal subpopulations. Both THC and rimonabant induced antidepressant-like effects, quantified as immobility in the FST. However, only THC effects were reversed by pCPA or WAY100635. In contrast, only AMPT could attenuate the rimonabant effect. We also found decreased immobility in mice lacking the CB(1) receptor in glutamatergic cortical neurons, but not in forebrain GABAergic neurons, as compared with wild-type controls. The effect of THC persisted in mutant mice with CB(1) receptor inactivation in GABAergic neurons, whereas rimonabant effects were alleviated in these mutants. Thus, employing both pharmacological and genetic tools, we could show that the ECS regulates stress responses by influencing GABAergic, glutamatergic and monoaminergic transmission. The antidepressant-like action of THC depends on serotonergic neurotransmission, whereas rimonabant effects are mediated by CB(1) receptor on GABAergic neurons and by catecholamine signaling. 23523580 Increased risk of cognitive impairment in cirrhotic patients with bacterial infections. A causal relationship between infection, systemic inflammation, and hepatic encephalopathy (HE) has been suggested in cirrhosis. No study, however, has specifically examined, in cirrhotic patients with infection, the complete pattern of clinical and subclinical cognitive alterations and its reversibility after resolution. Our investigation was aimed at describing the characteristics of cognitive impairment in hospitalized cirrhotic patients, in comparison with patients without liver disease, with and without infection. One hundred and fifty cirrhotic patients were prospectively enrolled. Eighty-one patients without liver disease constituted the control group. Bacterial infections and sepsis were actively searched in all patients independently of their clinical evidence at entry. Neurological and psychometric assessment was performed at admission and in case of nosocomial infection. The patients were re-evaluated after the resolution of the infection and 3months later. Cognitive impairment (overt or subclinical) was recorded in 42% of cirrhotics without infection, in 79% with infection without SIRS and in 90% with sepsis. The impairment was only subclinical in controls and occurred only in patients with sepsis (42%). Multivariate analysis selected infection as the only independent predictor of cognitive impairment (OR 9.5; 95% CI 3.5-26.2; p=0.00001) in cirrhosis. The subclinical alterations detected by psychometric tests were also strongly related to the infectious episode and reversible after its resolution. Infections are associated with a worse cognitive impairment in cirrhotics compared to patients without liver disease. The search and treatment of infections are crucial to ameliorate both clinical and subclinical cognitive impairment of cirrhotic patients. 23905922 Characterization of the Late Endosomal ESCRT Machinery in Trypanosoma brucei. The multivesicular body (MVB) is a specialized Rab7+ late endosome (LE) containing multiple intralumenal vesicles that function in targeting ubiquitinylated cell surface proteins to the lysosome for degradation. African trypanosomes lack a morphologically well-defined MVB, but contain orthologs of the ESCRT (Endosomal Sorting Complex Required for Transport) machinery that mediates MVB formation. We investigate the role of TbVps23, an early ESCRT component, and TbVps4, the terminal ESCRT ATPase, in lysosomal trafficking in bloodstream form trypanosomes. Both localize to the TbRab7+ LE and RNAi silencing of each rapidly blocks growth. TbVps4 silencing results in approximately threefold accumulation of TbVps23 at the LE, consistent with blocking terminal ESCRT disassembly. Trafficking of endocytic and biosynthetic cargo, but not default lysosomal reporters, is also negatively affected. Others reported that TbVps23 mediates ubiquitin-dependent lysosomal degradation of invariant surface glycoproteins (ISG65) (Leung et al., Traffic 2008;9:1698-1716). In contrast, we find that TbVps23 ablation does not affect ISG65 turnover, while TbVps4 silencing markedly enhances lysosomal degradation. We propose several models to accommodate these results, including that the ESCRT machinery actually retrieves ISG65 from the LE to earlier endocytic compartments, and in its absence ISG65 traffics more efficiently to the lysosome. Overall, these results confirm that the ESCRT machinery is essential in Trypanosoma brucei and plays important and novel role(s) in LE function in trypanosomes. 23904246 Does Vitamin D Improve Osteoarthritis of the Knee: A Randomized Controlled Pilot Trial. Animal, epidemiologic, and human clinical studies suggest a putative role for vitamin D in osteoarthritis (OA). Inadequate sunlight exposure and lower serum levels of 25(OH)D appear in some reports to be associated with an increased risk for progression of knee OA. We asked whether treatment with vitamin D would (1) reduce knee pain (WOMAC and VAS), (2) improve function (WOMAC), and (3) change levels of relevant biochemical markers in patients with knee OA with vitamin D insufficiency. This randomized controlled pilot trial prospectively enrolled 107 patients with knee OA with vitamin D insufficiency (25(OH)D â‰¤ 50 nmol/L) to receive oral vitamin D or placebo. The primary outcome measures were pain and function, and the secondary were biochemical markers. At baseline, the two groups were comparable. The patients were followed for 1 year. At 12 months, knee pain had decreased in the vitamin D group by mean -0.26 (95% CI, -2.82 to -1.43) on VAS and -0.55 (95% CI, -0.07 to 1.02) on the WOMAC, whereas in the placebo group, it increased by mean 0.13 (95% CI, -0.03 to 0.29) on the VAS and 1.16 (95% CI, 0.82 to 1.49) on the WOMAC (effect size = 0.37 and 0.78). Likewise knee function improved in the vitamin D group by mean -1.36 (95% CI, -1.87 to -0.85) over the placebo group which had a mean 0.69 (95% CI, -0.03 to 1.41; effect size = 0.06). There were significant biochemical changes in serum total calcium, 25(OH)D and alkaline phosphatase. The results above suggest there is a small but statistically significant clinical benefit to vitamin D treatment in patients with knee OA, although we recommend a long-term study to determine whether these changes are clinically important and whether they will be sustained with time. Further studies with long-term radiologic evaluations are needed. Level I, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence. 23279941 Blood pressure and levels of Fe, Ca, Mg, Zn, Cu, Na and K in the hair of young Bantu men from Tanzania. Mineral imbalance in the body may significantly contribute to the development and course of hypertension. In this paper, blood pressure figures have been linked to the levels of Fe, Ca, Mg, Zn, Cu, Na and K in hair. The research sample was composed of young men (n = 91) aged 13-21, from the town of Mafinga, Iringa District, Tanzania. The data collected included their age, tribal background and weekly diet. Based on body mass index, the participants were categorised into pre-defined subgroups. To examine how the minerals in question affect blood pressure, correlation analysis and multiple ridge regression analysis were performed. Analysis of ridge regression findings for the researched group (n = 91) shows that the minerals under scrutiny account for systolic blood pressure variation in 13 % and in 15 % for diastolic blood pressure variation. After including two additional variables-calendar age and body mass index-in regression analysis, the ultimate coefficient of determination (R (2)) changes for systolic blood pressure and remains the same for diastolic blood pressure (R (2) = 0.194 and R (2) = 0.156, respectively). Nutritional analysis shows that the students included in the study received insufficient calories per day (1,500-2,200 kcal). The group of students with abnormal blood pressure were not aware of their poor health. Research findings may result from progressive environmental changes and poor nutrition in terms of food quantity and quality, which had an impact on the subjects' blood pressure. Hair analysis used to determine mineral content in the body may be an auxiliary tool in identifying the links between factors leading to the development of hypertension. 23864248 Longitudinal dynamics of depressogenic personality and attachment dimensions in adolescence: an examination of associations with changes in depressive symptoms. Depressogenic personality and attachment are two major factors related to the development of adolescents' depressive symptoms. However, no previous longitudinal studies have examined simultaneously both vulnerability factors in relationship to depressive symptoms. The present study examined associations between intra-individual change in adolescents' depressogenic personality orientations (i.e., sociotropy and autonomy), dimensions of mother-adolescent attachment (i.e., anxiety and avoidance), and depressive symptoms. The sample of the present research consisted of 289 high school students (mean age = 12.51 years at Time 1, 66 % female) participating in a 3-wave cohort-sequential design. Latent growth curve modeling revealed no significant intra-individual change in depressogenic personality orientations but significant changes in dimensions of attachment and symptoms of depression. Initial levels of sociotropy were not related significantly to changes in attachment dimensions and depressive symptoms. High initial levels of autonomy were associated with increases in attachment anxiety, attachment avoidance, and depressive symptoms. In addition, results suggested that the association between initial levels of autonomy and increases in depressive symptoms was mediated by increases in attachment anxiety and avoidance. The discussion focuses on the status of depressogenic personality and attachment as risk factors for depression. 23252447 Dynamic or nondynamic? Helical trajectory in hexabenzocoronene nanotubes biased by a detachable chiral auxiliary. When ether vapor was allowed to diffuse into a CH(2)Cl(2) solution of an enantiomer of a hexa-peri-hexabenzocoronene (HBC) derivative carrying a chiral (BINAP)Pt(II)-appended coordination metallacycle (HBC(Py)([(R)-Pt]) or HBC(Py)([(S)-Pt])), screw-sense-selective assembly took place to give optically active nanotubes (NT(Py)([(R)-Pt]) or NT(Py)([(S)-Pt])) with helical chirality, which were enriched in either left-handed (M)-NT(Py)([(R)-Pt]) or right-handed (P)-NT(Py)([(S)-Pt]), depending on the absolute configuration of the (BINAP)Pt(II) pendant. When MeOH was used instead of ether for the vapor-diffusion-induced assembly, nanocoils formed along with the nanotubes. As determined by scanning electron microscopy, the diastereomeric excess of the nanocoils was 60% (80:20 diastereomeric ratio). Removal of the (BINAP)Pt(II) pendants from NT(Py)([(R)-Pt]) or NT(Py)([(S)-Pt]) with ethylenediamine yielded metal-free nanotubes (NT(Py)) that remained optically active even upon heating without any change in the circular dichroism spectral profile. No helical inversion took place when NT(Py) derived from HBC(Py)([(R)-Pt]) or HBC(Py)([(S)-Pt]) was allowed to complex with (BINAP)Pt(II) with an absolute configuration opposite to the original one. 23958489 Passivity-based sliding mode control for a polytopic stochastic differential inclusion system. Passivity-based sliding mode control for a polytopic stochastic differential inclusion (PSDI) system is considered. A control law is designed such that the reachability of sliding motion is guaranteed. Moreover, sufficient conditions for mean square asymptotic stability and passivity of sliding mode dynamics are obtained by linear matrix inequalities (LMIs). Finally, two examples are given to illustrate the effectiveness of the proposed method. 23888907 What Students Experienced: A Narrative Analysis of Essays Written by First-Year Medical Students Participating in a Geriatrics Home Visit. To develop a house call experience for first-year medical students introducing them to challenges that homebound, chronically ill elderly adults face. During the semester, two students were paired with a preceptor to see two to three patients. The house call practices of the Division of Geriatric Medicine at the University of Pennsylvania and the Philadelphia Veterans Affairs Hospital. One hundred sixty-five first-year medical students. Pairs of students worked together to write an essay after the visit. Essays addressed specific areas, as detailed in a provided checklist, including noting patients' functional limitations, identifying community supports available to patients, and writing about general surprises that the students discovered during their visit. These data were then measured using narrative analysis. In all domains, students identified core goals and objectives. In the first domain (meeting challenges of functional limitations), students recognized the importance of family support. In the second domain (mentioning of functional limitation), high levels of compliance were seen. In the third domain (community support), students mentioned specific formal supports. In the fourth domain (surprises during the visit), students identified many important geriatrics concepts. In writing their essays, students demonstrated a high level of recognition of functional impairment and noted the importance of family, social networks, and home environment in enabling homebound, chronically ill elderly adults to stay in their homes. Many students also demonstrated an awareness of the possibilities of independence and happiness despite significant illness and disability. 23297152 Self-reported sexual desire in homosexual men and women predicts preferences for sexually dimorphic facial cues. Recent studies investigating the relationship between self-reported sexual desire and attraction to same- and opposite-sex individuals have found that homosexual men's sexual desire is positively correlated with their self-reported attraction to own-sex individuals only, while homosexual women's sexual desire is positively correlated with their self-reported attraction to both men and women. These data have been interpreted as evidence that sexual desire strengthens men's pre-existing (i.e., dominant) sexual behaviors and strengthens women's sexual behaviors in general. Here we show that homosexual men's (n = 106) scores on the Sexual Desire Inventory-2 (SDI-2) were positively correlated with their preferences for exaggerated sex-typical shape cues in own-sex, but not opposite-sex, faces. Contrary to the hypothesis that sexual desire strengthens women's preferences for sexual dimorphism generally, homosexual women's (n = 83) SDI-2 scores were positively correlated with their preferences for exaggerated sex-typical shape cues in opposite-sex faces only. Together with previous research in heterosexual subjects, our findings support the proposal that sexual desire increases the incidence of existing sexual behaviors in homosexual and heterosexual men, and increases the incidence of sexual responses more generally in heterosexual women, although not necessarily in homosexual women. 23239080 Liver T2-weighted MR imaging: Assessment of a three-dimensional fast spin-echo with extended echo train acquisition sequence at 1.5 Tesla. To retrospectively compare image quality and lesion detectability with two T2-weighted sequences at 1.5 Tesla (T): respiratory-triggered three-dimensional fat sat fast-spin-echo with extended echo-train acquisition (3D FSE-XETA) and respiratory-triggered two-dimensional fat-sat fast recovery fast-spin-echo (2D FRFSE). MR was performed at 1.5T in 53 consecutive patients. Two radiologists blinded to the sequence details reviewed the studies to determine: (i) signal and contrast to noise ratios, (ii) overall image quality, (iii) sensitivity for focal lesion detection. Image assessment scores for the 2D FRFSE sequence were significantly higher than those for the 3D FSE-XETA sequence for overall image quality (P < 0.01) and artifacts (P < 0.001). Sensitivity for liver lesion detection was higher with the 3D FSE-XETA sequence (69.3% versus 57.3%; P < 0.05) compared with the 2D FRFSE sequence. The 3D FSE-XETA sequence improves the reader confidence score (P < 0.01) for liver lesions detection. Inter-observer correlation was higher with the 3D FSE-XETA sequence. For T2-weighted liver imaging at 1.5T, the 3D FSE-XETA sequence improves sensitivity, reader confidence score and interobserver correlation for focal liver lesion detection, but it suffers from a lower overall image quality and higher artifacts. J. Magn. Reson. Imaging 2013;38:336-343. © 2013 Wiley Periodicals, Inc. 23872849 The regulation of 2,3-butanediol synthesis in Klebsiella pneumoniae as revealed by gene over-expressions and metabolic flux analysis. A variety of microorganism species are able naturally to produce 2,3-butanediol (2,3-BDO), although only a few of them are suitable for consideration as having potential for mass production purposes. Klebsiella pneumoniae (K. pneumoniae) is one such strain which has been widely studied and used industrially to produce 2,3-BDO. In the central carbon metabolism of K. pneumoniae, the 2,3-BDO synthesis pathway is dominated by three essential enzymes, namely acetolactate decarboxylase, acetolactate synthase, and butanediol dehydrogenase, which are encoded by the budA, budB, and budC genes, respectively. The mechanisms of the three enzymes have been characterized with regard to their function and roles in 2,3-BDO synthesis and cell growth (Blomqvist et al. in J Bacteriol 175(5):1392-1404, 1993), while a few studies have focused on the cooperative mechanisms of the three enzymes and their mutual interactions. Therefore, the K. pneumoniae KCTC2242::ΔwabG wild-type strain was utilized to reconstruct seven new mutants by single, double, and triple overexpression of the three enzymes key to this study. Subsequently, continuous cultures were performed to obtain steady-state metabolism in the organisms and experimental data were analyzed by metabolic flux analysis (MFA) to determine the regulation mechanisms. The MFA results showed that the seven overexpressed mutants all exhibited enhanced 2,3-BDO production, and the strain overexpressing the budBA gene produced the highest yield. While the enzyme encoded by the budA gene produced branched-chain amino acids which were favorable for cell growth, the budB gene enzyme rapidly enhanced the conversion of acetolactate to acetoin in an oxygen-dependent manner, and the budC gene enzyme catalyzed the reversible conversion of acetoin to 2,3-BDO and regulated the intracellular NAD(+)/NADH balance. 23963316 Relationship Between Cognitive Dysfunction and Behavioural Symptoms in Nigerian Patients with Parkinson's Disease No dementia. Background: There is presently no information on the behavioural symptoms that are related to cognitive dysfunction in African patients with Parkinson's disease. Objectives: This study highlights the behavioral symptoms that are related to global cognitive dysfunction without dementia, as well as the caregivers' distress they create in a population of Nigerians with idiopathic Parkinson's disease. Methods: Fifty patients with idiopathic Parkinson's disease, confirmed using the United Kingdom Parkinson's Disease Society (UKPDS) Brain Bank Clinical Diagnostic Criteria, were cross-sectionally assessed for cognitive functions using the modified Mini-mental State Examination (MMSE), motor symptoms using the Unified Parkinson's disease Rating Scale (UPDRS), as well as neuropsychiatric symptoms and caregivers' distress using the Neuropsychiatric Inventory (NPI). Additional information obtained from all the participants and their caregivers included demographic data, personal history, psychiatric history, medical history and family history. The behavioural, caregivers' distress and motor correlates of cognitive dysfunction were explored. Results: In all, 24.0% of the patients had cognitive dysfunction according to the local norm of the MMSE. Hallucinations (Chi2 = 5.556, p = 0.018) and agitation (Chi2 = 5.556, p = 0.018) were related to cognitive dysfunctions. There was more behaviour related caregivers' distress in those with cognitive dysfunction than those without (Chi2 = 2.208, p = 0.032). The MMSE scores correlated inversely with the score for rigidity (r = -0.506, p = 0.0002), bradykinesia (r = -0.592, p < 0.0001), and the UPDRS total score (r = -0.503, p = 0.0002). Conclusion: The psychotic symptoms of hallucinations and agitations differentiated Parkinson's disease patients with cognitive dysfunction from those with normal cognition. Generally, the presence of behavioural symptom led to more distress in the caregivers of patients with cognitive dysfunction. 23395915 Effect of repeated dosing on rifampin exposure in BALB/c mice. The discovery of novel therapeutics for the treatment of tuberculosis involves routine testing in a mouse model over four weeks of daily dosing with test compounds. In this model, daily oral administration of rifampin (10mg/kg) showed significantly lower plasma exposure on day 5 compared to day 1. The absence of PXR-mediated induction of mouse Cyp3a isoforms was confirmed in the present study by incubating liver microsomes prepared from control and rifampin treated mice with probe substrates of CYP3A. To test whether the reduction in exposure was due to Pgp-mediated efflux, verapamil, a known Pgp inhibitor, was dosed to the rifampin pre-treated mice which led to an increase in exposure to that obtained after a single dose of rifampin, suggesting the role of Pgp induction in reducing exposure to rifampin. To further confirm Pgp induction in rifampin treated mice, digoxin, a known substrate of Pgp, was administered to the rifampin pre-treated mice, and a significant drop in the digoxin exposure was observed compared to the control group. Collectively, our results show that repeated administration of rifampin in mice leads to a reduction in oral exposure due to induction of Pgp-mediated efflux of rifampin, and not via induction of CYP3A isoforms. 23627692 The significance of pretransplant donor-specific antibodies reactive with intact or denatured human leucocyte antigen in kidney transplantation. Antibodies recognizing denatured human leucocyte antigen (HLA) can co-react with epitopes on intact HLA or recognize cryptic epitopes which are normally unaccessible to HLA antibodies. Their specificity cannot be distinguished by single antigen beads (SAB) alone, as they carry a mixture of intact and denatured HLA. In this study, we selected pretransplant sera containing donor-specific HLA class I antibodies (DSA) according to regular SAB analysis from 156 kidney transplant recipients. These sera were analysed using a SAB preparation (iBeads) which is largely devoid of denatured HLA class I, and SAB coated with denatured HLA class I antigens. A total of 241 class I DSA were found by regular SAB analysis, of which 152 (63%) were also found by iBeads, whereas 28 (11%) were caused by reactivity with denatured DNA. Patients with DSA defined either by regular SAB or iBeads showed a significantly lower graft survival rate (P = 0·007) compared to those without HLA class I DSA, whereas reactivity to exclusively denatured HLA was not associated with decreased graft survival. In addition, DSA defined by reactivity to class I SAB or class I iBeads occurred more frequently in female patients and in patients with historic HLA sensitization, whereas reactivity to denatured HLA class I was not associated with any of these parameters. Our data suggest that pretransplant donor-specific antibodies against denatured HLA are clinically irrelevant in patients already sensitized against intact HLA. 23963510 A novel genotoxicity assay of carbon nanotubes using functional macrophage receptor with collagenous structure (MARCO)-expressing chicken B lymphocytes. Although carbon nanotubes (CNTs) are promising nanomaterials, their potential carcinogenicity is a major concern. We previously established a genetic method of analyzing genotoxicity of chemical compounds, where we evaluated their cytotoxic effect on the DT40 lymphoid cell line comparing DNA-repair-deficient isogenic clones with parental wild-type cells. However, application of our DT40 system for the cytotoxic and genotoxic evaluation of nanomaterials seemed to be difficult, because DT40 cells only poorly internalized nanoparticles. To solve this problem, we have constructed a chimeric gene encoding a trans-membrane receptor consisting of the 5' region of the transferrin receptor (TR) gene (to facilitate internalization of nanoparticles) and the 3' region of the macrophage receptor with collagenous structure (MARCO) gene (which is a receptor for environmental particles). We expressed the resulting MARCO-TR chimeric receptor on DNA-repair-proficient wild-type cells and mutants deficient in base excision repair (FEN1 (-/-)) and translesion DNA synthesis (REV3 (-/-)). We demonstrated that the chimera mediates uptake of particles such as fluorescence-tagged polystyrene particles and multi-walled carbon nanotubes (MWCNTs), with very poor uptake of those particles by DT40 cells not expressing the chimera. MWCNTs were cytotoxic and this effect was greater in FEN1 (-/-)and REV3 (-/-) cells than in wild-type cells. Furthermore, MWCNTs induced greater oxidative damage (measured as 8-OH-dG formation) and a larger number of mitotic chromosomal aberrations in repair-deficient cells compared to repair-proficient cells. Taken together, our novel assay system using the chimeric receptor-expressing DT40 cells provides a sensitive method to screen for genotoxicity of CNTs and possibly other nanomaterials. 23847771 Tick vaccines and the control of tick-borne pathogens. Ticks are obligate hematophagous ectoparasites that transmit a wide variety of pathogens to humans and animals. The incidence of tick-borne diseases has increased worldwide in both humans and domestic animals over the past years resulting in greater interest in the study of tick-host-pathogen interactions. Advances in vector and pathogen genomics and proteomics have moved forward our knowledge of the vector-pathogen interactions that take place during the colonization and transmission of arthropod-borne microbes. Tick-borne pathogens adapt from the vector to the mammalian host by differential gene expression thus modulating host processes. In recent years, studies have shown that targeting tick proteins by vaccination can not only reduce tick feeding and reproduction, but also the infection and transmission of pathogens from the tick to the vertebrate host. In this article, we review the tick-protective antigens that have been identified for the formulation of tick vaccines and the effect of these vaccines on the control of tick-borne pathogens. 23688936 Comparison of the effects of extracts from three Vitex plant species on Anopheles gambiae s.s. (Diptera: Culicidae) larvae. Acetone and methanol extracts of different parts of three Vitex species (leaves and stem bark of Vitex trifolia, leaves, stem bark and root bark of Vitex schiliebenii and stem and root bark of Vitex payos) were evaluated for their potential to control Anopheles gambiae Giles s.s. larvae (Diptera: Culicidae). The extracts gave different levels and rate of mortality of the larvae. Some (methanol extract of V. trifolia leaves, acetone extracts of stem bark and leaves of V. schiliebenii, acetone extract of root bark of V. payos) caused 100% mortality at 100 ppm in 72 h, with those of V. schiliebenii and V. payos showing faster rate of mortality (LT₅₀=8 h) than that of V. trifolia (LT₅₀=14 h). At lower doses of these extracts (≤50 ppm), most of the larvae failed to transform to normal pupae but gave larval-pupal intermediates between 4 and 14 days of exposure. Some pupated normally but the adults that emerged appeared to be weak and died within 48 h. Extracts of the stem bark of V. payos showed interesting effects on the larvae. Initially, the larvae were relatively hyperactive compared to those in control treatments. Later, the ones that did not transform to larval-pupal intermediates became stretched and inactive and died and floated in clusters on the surface. These observations suggest some interesting growth-disrupting constituents in the plants, with possible application in the practical control of mosquito larvae in aquatic ecosystems. 23964798 TTFV-Based Molecular Tweezers and Macrocycles as Receptors for Fullerenes. Hybrids of tetrathiafulvalene vinylogues (TTFVs) and planar arenes were synthesized via the click reaction to form tweezer-like and macrocyclic structures. These compounds were investigated as receptors for fullerenes (C60 and C70) by UV-vis absorption and fluorescence spectroscopy. 23477947 The impact of daylight saving time on sleep and related behaviours. Daylight saving time is currently adopted in over 70 countries and imposes a twice yearly 1 h change in local clock time. Relative ease in adjustment of sleep patterns is assumed by the general population but this review suggests that the scientific data challenge a popular understanding of the clock change periods. The start of daylight saving time in the spring is thought to lead to the relatively inconsequential loss of 1 h of sleep on the night of the transition, but data suggests that increased sleep fragmentation and sleep latency present a cumulative effect of sleep loss, at least across the following week, perhaps longer. The autumn transition is often popularised as a gain of 1 h of sleep but there is little evidence of extra sleep on that night. The cumulative effect of five consecutive days of earlier rise times following the autumn change again suggests a net loss of sleep across the week. Indirect evidence of an increase in traffic accident rates, and change in health and regulatory behaviours which may be related to sleep disruption suggest that adjustment to daylight saving time is neither immediate nor without consequence. 23775397 Polarization functions for the modified m6-31G basis sets for atoms Ga through Kr. The 2df polarization functions for the modified m6-31G basis sets of the third-row atoms Ga through Kr (Int J Quantum Chem, 2007, 107, 3028; Int J. Quantum Chem, 2009, 109, 1158) are proposed. The performances of the m6-31G, m6-31G(d,p), and m6-31G(2df,p) basis sets were examined in molecular calculations carried out by the density functional theory (DFT) method with B3LYP hybrid functional, Møller-Plesset perturbation theory of the second order (MP2), quadratic configuration interaction method with single and double substitutions and were compared with those for the known 6-31G basis sets as well as with the other similar 641 and 6-311G basis sets with and without polarization functions. Obtained results have shown that the performances of the m6-31G, m6-31G(d,p), and m6-31G(2df,p) basis sets are better in comparison with the performances of the known 6-31G, 6-31G(d,p) and 6-31G(2df,p) basis sets. These improvements are mainly reached due to better approximations of different electrons belonging to the different atomic shells in the modified basis sets. Applicability of the modified basis sets in thermochemical calculations is also discussed. © 2013 Wiley Periodicals, Inc. 22422724 Neural changes when actions change: adaptation of strong and weak expectations. Repeated experiences with an event create the expectation that subsequent events will expose an analog structure. These spontaneous expectations rely on an internal model of the event that results from learning. But what happens when events change? Do experience-based internal models get adapted instantaneously, or is model adaptation a function of the solidity of, i.e., familiarity with, the corresponding internal model? The present fMRI study investigated the effects of model solidity on model adaptation in an action observation paradigm. Subjects were made acquainted with a set of action movies that displayed an altered script when encountered again in the scanning session. We found model adaptation to result in an attenuation of the premotor-parietal network for action observation. Model solidity was found to modulate activation in the parahippocampal gyrus and the anterior cerebellar lobules, where increased solidity correlated with activity increase. Finally, the comparison between early and late stages of learning indicated an effect of model solidity on adaptation rate. This contrast revealed the involvement of a fronto-mesial network of Brodmann area 10 and the ACC in those states of learning that were signified by high model solidity, no matter if the memorized original or the altered action model was the more solid component. Findings suggest that the revision of an internal model is dependent on its familiarity. Unwarranted adaptations, but also perseverations may thus be prevented. 23707978 An increase in initial shock index is associated with the requirement for massive transfusion in emergency department patients with primary postpartum hemorrhage. The aim of this study was to determine whether initial shock index (SI) was independently associated with the requirement for massive transfusion (MT) in emergency department (ED) patients with primary postpartum hemorrhage (PPH). A retrospective cohort study of ED patients with primary PPH was performed at a university-affiliated, tertiary referral center between January 2004 and May 2012. Patients were classified to two groups: MT group (patients who received ≥10 U of packed red blood cells within 24 h of ED admission) and non-MT group (patients who received <10 U). Variables of the two groups were compared using univariate and multivariate analyses. A total of 126 patients were included in this study. Of these patients, 26 (20.6%) were included in MT group and 100 (79.4%) in non-MT group. Patients in MT group had significantly lower blood pressure and higher heart rate compared with patients in non-MT group (P < 0.01). Initial SI was significantly higher in MT group than in non-MT group (1.3 vs 0.8, P < 0.01). In multivariate logistic regression analysis, initial SI and heart rate were the only variables associated with the requirement for MT, with an odds ratio of 9.47 (95% confidence interval, 1.75-51.28; P < 0.01) and 1.06 (95% confidence interval, 1.02-1.09; P < 0.01), respectively. In conclusion, initial SI was independently associated with the requirement for MT in ED patients with primary PPH. Routine calculation of initial SI can help clinicians to identify patients who may benefit from timely and appropriate use of MT to improve clinical outcomes. 23870167 Empirical assessment of competitive hybridization and noise in ultra high density canine tiling arrays. In addition to probe sequence characteristics, noise in hybridization array data is thought to be influenced by competitive hybridization between probes tiled at high densities. Empirical evaluation of competitive hybridization and an estimation of what other non-sequence related features might affect noisy data is currently lacking. A high density array was designed to a 1.5 megabase region of the canine genome to explore the potential for probe competition to introduce noise. Multivariate assessment of the influence of probe, segment and design characteristics on hybridization intensity demonstrate that whilst increased density significantly depresses fluorescence intensities, this effect is largely consistent when an ultra high density offset is applied. Signal variation not attributable to sequence composition resulted from the reduction in competition when large inter-probe spacing was introduced due to long repetitive elements and when a lower density offset was applied. Tiling of probes immediately adjacent to various classes of repeat elements did not generate noise. Comparison of identical probe sets hybridized with DNA extracted from blood or saliva establishes salivary DNA as a source of noise. This analysis demonstrates the occurrence of competitive hybridization between oligonucleotide probes in high density tiling arrays. It supports that probe competition does not generate random noise when it is maintained across a region. To prevent the introduction of noise from this source, the degree of competition should be regulated by minimizing variation in density across the target region. This finding can make an important contribution to optimizing coverage whilst minimizing sources of noise in the design of high density tiling arrays. 23906958 Prediction of initiation and cessation of breastfeeding from late pregnancy to 16 weeks: the Feeding Your Baby (FYB) cohort study. To derive prediction models for both initiation and cessation of breastfeeding using demographic, psychological and obstetric variables. A prospective cohort study. Women delivering at Ninewells Hospital, Dundee, UK. Demographic data and psychological measures were obtained during pregnancy by questionnaire. Birth details, feeding method at birth and at hospital discharge were obtained from the Ninewells hospital database, Dundee, UK. Breastfeeding women were followed up by text messages every 2 weeks until 16 weeks or until breastfeeding was discontinued to ascertain feeding method and feeding intentions. Pregnant women over 30 weeks gestation aged 16 years and above, living in Dundee, booked to deliver at Ninewells Hospital, Dundee, and able to speak English. Initiation and cessation of breastfeeding. From the total cohort of women at delivery (n=344) 68% (95% CI 63% to 73%) of women had started breastfeeding at discharge. Significant predictors of initiating breastfeeding were older age, parity, greater intention to breastfeed from a Theory of Planned Behaviour (TPB)-based questionnaire, higher Iowa Infant Feeding Assessment Scale (IIFAS) score as well as living with a husband or partner. For the final model, the AUROC was 0.967. For those who initiated breastfeeding (n=233), the strongest predictors of stopping were low intention to breastfeed from TPB, low IIFAS score and non-managerial/professional occupations. The findings from this study will be used to inform the protocol for an intervention study to encourage and support prolonged breastfeeding as intentions appear to be a key intervention focus for initiation. The predictive models could be used to identify women at high risk of not initiating and also women at high risk of stopping for interventions to improve the longevity of breastfeeding. 23248975 Optical and electrical detection of single-molecule translocation through carbon nanotubes. Ion current through a single-walled carbon nanotube (SWCNT) was monitored at the same time as fluorescence was recorded from charged dye molecules translocating through the SWCNT. Fluorescence bursts generally follow ion current peaks with a delay time consistent with diffusion from the end of the SWCNT to the fluorescence collection point. The fluorescence amplitude distribution of the bursts is consistent with single-molecule signals. Thus each peak in the ion current flowing through the SWCNT is associated with the translocation of a single molecule. Ion current peaks (as opposed to blockades) were produced by both positively (Rhodamine 6G) and negatively (Alexa 546) charged molecules, showing that the charge filtering responsible for the current bursts is caused by the molecules themselves. 23889969 Neutral sphingomyelinase 2 modulates cytotoxic effects of protopanaxadiol on different human cancer cells. Some of ginsenosides, root extracts from Panax ginseng, exert cytotoxicity against cancer cells through disruption of membrane subdomains called lipid rafts. Protopanaxadiol (PPD) exhibits the highest cytotoxic effect among 8 ginsenosides which we evaluated for anti-cancer activity. We investigated if PPD disrupts lipid rafts in its cytotoxic effects and also the possible mechanisms. Eight ginsenosides were evaluated using different cancer cells and cell viability assays. The potent ginsenoside, PPD was investigated for its roles in lipid raft disruption and downstream pathways to apoptosis of cancer cells. Anti-cancer effects of PPD was also investigated in vivo using mouse xenograft model. PPD consistently exerts its potent cytotoxicity in 2 cell survival assays using 5 different cancer cell lines. PPD disrupts lipid rafts in different ways from methyl-β-cyclodextrin (MβCD) depleting cholesterol out of the subdomains, since lipid raft proteins were differentially modulated by the saponin. During disruption of lipid rafts, PPD activated neutral sphingomyelinase 2 (nSMase 2) hydrolyzing membrane sphingomyelins into pro-apoptotic intracellular ceramides. Furthermore, PPD demonstrated its anti-cancer activities against K562 tumor cells in mouse xenograft model, confirming its potential as an adjunct or chemotherapeutic agent by itself in vivo. This study demonstrates that neutral sphingomyelinase 2 is responsible for the cytotoxicity of PPD through production of apoptotic ceramides from membrane sphingomyelins. Thus neutral sphingomyelinase 2 and its relevant mechanisms may potentially be employed in cancer chemotherapies. 23847539 A standardized approach to study human variability in isometric thermogenesis during low-intensity physical activity. Limitations of current methods: The assessment of human variability in various compartments of daily energy expenditure (EE) under standardized conditions is well defined at rest [as basal metabolic rate (BMR) and thermic effect of feeding (TEF)], and currently under validation for assessing the energy cost of low-intensity dynamic work. However, because physical activities of daily life consist of a combination of both dynamic and isometric work, there is also a need to develop standardized tests for assessing human variability in the energy cost of low-intensity isometric work. Experimental objectives: Development of an approach to study human variability in isometric thermogenesis by incorporating a protocol of intermittent leg press exercise of varying low-intensity isometric loads with measurements of EE by indirect calorimetry. Results: EE was measured in the seated position with the subject at rest or while intermittently pressing both legs against a press-platform at 5 low-intensity isometric loads (+5, +10, +15, +20, and +25 kg force), each consisting of a succession of 8 cycles of press (30 s) and rest (30 s). EE, integrated over each 8-min period of the intermittent leg press exercise, was found to increase linearly across the 5 isometric loads with a correlation coefficient (r) > 0.9 for each individual. The slope of this EE-Load relationship, which provides the energy cost of this standardized isometric exercise expressed per kg force applied intermittently (30 s in every min), was found to show good repeatability when assessed in subjects who repeated the same experimental protocol on 3 separate days: its low intra-individual coefficient of variation (CV) of ~ 10% contrasted with its much higher inter-individual CV of 35%; the latter being mass-independent but partly explained by height. Conclusion: This standardized approach to study isometric thermogenesis opens up a new avenue for research in EE phenotyping and metabolic predisposition to obesity. 23896424 Association of vaccine-related attitudes and beliefs between parents and health care providers. Health care providers influence parental vaccination decisions. Over 90% of parents report receiving vaccine information from their child's health care provider. The majority of parents of vaccinated children and children exempt from school immunization requirements report their child's primary provider is a good source for vaccine information. The role of health care providers in influencing parents who refuse vaccines has not been fully explored. The objective of the study was to determine the association between vaccine-related attitudes and beliefs of health care providers and parents. We surveyed parents and primary care providers of vaccinated and unvaccinated school age children in four states in 2002-2003 and 2005. We measured key immunization beliefs including perceived risks and benefits of vaccination. Odds ratios for associations between parental and provider responses were calculated using logistic regression. Surveys were completed by 1367 parents (56.1% response rate) and 551 providers (84.3% response rate). Parents with high confidence in vaccine safety were more likely to have providers with similar beliefs, however viewpoints regarding disease susceptibility and severity and vaccine efficacy were not associated. Parents whose providers believed that children get more immunizations than are good for them had 4.6 higher odds of holding that same belief compared to parents whose providers did not have that belief. The beliefs of children's health care providers and parents, including those regarding vaccine safety, are similar. Provider beliefs may contribute to parental decisions to accept, delay or forgo vaccinations. Parents may selectively choose providers who have similar beliefs to their own. 23916753 Tonotopic mapping of human auditory cortex. Since the early days of functional magnetic resonance imaging (fMRI), retinotopic mapping emerged as a powerful and widely-accepted tool, allowing the identification of individual visual cortical fields and furthering the study of visual processing. In contrast, tonotopic mapping in auditory cortex proved more challenging primarily because of the smaller size of auditory cortical fields. The spatial resolution capabilities of fMRI have since advanced, and recent reports from our labs and several others demonstrate the reliability of tonotopic mapping in human auditory cortex. Here we review the wide range of stimulus procedures and analysis methods that have been used to successfully map tonotopy in human auditory cortex. We point out that recent studies provide a remarkably consistent view of human tonotopic organisation, although the interpretation of the maps continues to vary. In particular, there remains controversy over the exact orientation of the primary gradients with respect to Heschl's gyrus, which leads to different predictions about the location of human A1, R, and surrounding fields. We discuss the development of this debate and argue that literature is converging towards an interpretation that core fields A1 and R fold across the rostral and caudal banks of Heschl's gyrus, with tonotopic gradients laid out in a distinctive V-shaped manner. This suggests an organisation that is largely homologous with non-human primates. This article is part of a Special Issue entitled . 23849808 Synthesis and in vitro antitumor activity of novel iridium(III) complexes with enantiopure C2-symmetrical vicinal diamine ligands. Four novel iridium(III) complexes with enantiopure C2-symmetrical vicinal diamine ligands were designed, synthesized, and characterized by FT-IR, NMR, and MS. The cytotoxicities of all of the complexes against the human solid tumor cell lines A2780, A549, KB, and MDA-MB-231 were evaluated. Both R,R-configured complexes (R,R)-5a and (R,R)-5b exhibited more potent or similar activity compared with oxaliplatin, whereas their corresponding (S,S)-isomers (S,S)-5a and (S,S)-5b were found to be mostly inactive. As indicated by the activation of caspase-3, the cleavage of PARP, and the upregulation of p53, the preliminary mechanism studies revealed that the mode of cell death initiated by (R,R)-5a in A2780 cells was predominantly p53-mediated apoptosis. In addition, the structure of (R,R)-5a was unambiguously confirmed through single crystal X-ray structure determination. 23955168 Food Consumption and Nutritional Labeling Among Immigrants to Israel from the Former Soviet Union. Nutritional labeling helps consumers make healthier choices regarding food product purchases. In this study, we examined the difference between immigrants from the former Soviet Union who emigrated to Israel beginning in 1990 (IIFSU) and the general population of Israel regarding food consumption broadly and the use of nutritional labeling specifically. A representative sample of each population (n = 592) was composed and interviewed. According to the findings, compared to the general population, the IIFSU attribute less importance to health factors in purchasing food products and information about the ingredients contained in food products; they tend not to follow nutritional labels; and report less on the need for nutritional integrative labeling. Following from this, in the second part of the study, we investigated which of the socio-economic variables is most dominant in shaping attitudes towards food consumption and nutritional labeling. Only immigration and age were found in correlation with attitudes related to healthy food consumption. In contrast, gender, education and religious observance did not affect food selection. Immigration was recognized as the main factor with more clout than the other variables. In conclusion, it is crucial to clarify immigrants' perceptions of the concept of "health" and "proper nutrition" in formulating health promotion programs. 23852148 Characterization of mycobacterial triacylglycerols and monomeromycolyl diacylglycerols from Mycobacterium smegmatis biofilm by electrospray ionization multiple-stage and high-resolution mass spectrometry. The storage of triacylglycerols (TAGs) is essential for non-replicating persistence relevant to survival and the re-growth of mycobacteria during their exit from non-replicating state stress conditions. However, the detailed structures of this lipid family in mycobacteria largely remain unexplored. In this contribution, we describe a multiple-stage linear ion-trap mass spectrometric approach with high resolution mass spectrometry toward direct structural analysis of the TAGs, including a novel lipid subclass previously defined as monomeromycolyl diacylglycerol (MMDAG) isolated from biofilm of Mycobacterium smegmatis, a rapidly growing, non-pathogenic mycobacterium that has been used as a tool for molecular analysis of mycobacteria. Our results demonstrate that the major isomer in each of the molecular species of TAGs and MMDAGs consists of the common structure in which Δ(9)18:1- and 16:0-fatty acyl substituents are exclusively located at sn-1 and sn-2, respectively. Several isomers were found for most of the molecular species, and thus hundreds of structures are present in this lipid family. More importantly, this study revealed the structures of MMDAG, a novel subclass of TAG that has not been previously reported by direct mass spectrometric approaches. 23436101 Over-the-scope clip (OTSC) represents an effective endoscopic treatment for acute GI bleeding after failure of conventional techniques. Through-the-scope clips are commonly used for endoscopic hemostasis of gastrointestinal (GI) bleeding, but their efficacy can be suboptimal in patients with complex bleeding lesions. The over-the-scope clip (OTSC) could overcome the limitations of through-the-scope clips by allowing compression of larger amounts of tissue, allowing a more efficient hemostasis. We analyzed the use of OTSC in a consecutive case series of patients with acute GI bleeding unresponsive to conventional endoscopic treatment modalities. In a retrospective analysis of prospectively collected data in tertiary referral centers, patients undergoing emergency endoscopy for severe acute nonvariceal GI bleeding were treated with the OTSC after failure of conventional techniques. All patients underwent repeat endoscopy 2-4 days after the procedure. Data analysis included primary hemostasis, complications, and 1-month follow-up clinical outcome. During a 10-month period, 30 patients entered the study consecutively. Bleeding lesions unresponsive to conventional endoscopic treatment (saline/adrenaline injection and through-the-scope clipping) were located in the upper and lower GI tract in 23 and 7 cases, respectively. Primary hemostasis was achieved in 29 of 30 cases (97 %). One patient with bleeding from duodenal bulb ulcer required emergent selective radiological embolization. Rebleeding occurred in two patients 12 and 24 h after the procedure; they were successfully treated with conventional saline/adrenaline endoscopic injection. OTSC is an effective and safe therapeutic option for severe acute GI bleeding when conventional endoscopic treatment modalities fail. 23902185 'Regulators are not here to be liked, but I want the NMC to be respected'. It has been an eventful 18 months for Nursing and Midwifery Council chief executive Jackie Smith. After taking over as acting chief executive in January 2012, she has been the public face of an organisation under intense scrutiny from politicians, the press and nurses themselves. 23915163 Two New Species of Pristionchus (Nematoda: Diplogastridae) Support the Biogeographic Importance of Japan for the Evolution of the Genus Pristionchus and the Model System P. pacificus. Pristionchus pacificus Sommer, Carta, Kim, and Sternberg, 1996 is an important model organism in evolutionary biology that integrates developmental biology with ecology and population genetics. This species is part of a sub-complex of the genus Pristionchus that is considered to have originated in East Asia. Here, we describe two new species of Pristionchus, P. maxplancki and P. quartusdecimus, which were isolated from beetles in Japan, supporting the hypothesis that a region including Japan is the origin of diversification of the P. pacificus species complex. Phytogeny inferred from a partial small subunit rRNA gene and 25 ribosomal protein genes shows P. maxplancki to be the closest known outgroup to a triad of sibling species, including P. pacificus. Pristionchus quartusdecimus is a putative outgroup to the P. pacificus species complex, supporting a more ancient origin of Pristionchus species in the region. Species diagnoses are based on morphological and molecular characters, in addition to reproductive isolation for P. maxplancki. Members of the P. pacificus species complex as well as P. quartusdecimus are distinguished by stegostomatal structures, male genital papilla arrangement, and gubernaculum shape. The discovery of a new member of the P. pacificus species complex allows greater precision in polarizing and reconstructing ancestral states in the comparative model system centering on P. pacificus. Together with previous reports, these findings support an important biogeographic role of Japan in the evolution of the genus Pristionchus and the P. pacificus species complex, especially the associated phenotypic evolution of mouth morphology. 23950907 Immunohistochemical, Ultrastructural and Functional Analysis of Axonal Regeneration through Peripheral Nerve Grafts Containing Schwann Cells Expressing BDNF, CNTF or NT3. We used morphological, immunohistochemical and functional assessments to determine the impact of genetically-modified peripheral nerve (PN) grafts on axonal regeneration after injury. Grafts were assembled from acellular nerve sheaths repopulated ex vivo with Schwann cells (SCs) modified to express brain-derived neurotrophic factor (BDNF), a secretable form of ciliary neurotrophic factor (CNTF), or neurotrophin-3 (NT3). Grafts were used to repair unilateral 1 cm defects in rat peroneal nerves and 10 weeks later outcomes were compared to normal nerves and various controls: autografts, acellular grafts and grafts with unmodified SCs. The number of regenerated βIII-Tubulin positive axons was similar in all grafts with the exception of CNTF, which contained the fewest immunostained axons. There were significantly lower fiber counts in acellular, untransduced SC and NT3 groups using a PanNF antibody, suggesting a paucity of large caliber axons. In addition, NT3 grafts contained the greatest number of sensory fibres, identified with either IB4 or CGRP markers. Examination of semi- and ultra-thin sections revealed heterogeneous graft morphologies, particularly in BDNF and NT3 grafts in which the fascicular organization was pronounced. Unmyelinated axons were loosely organized in numerous Remak bundles in NT3 grafts, while the BDNF graft group displayed the lowest ratio of umyelinated to myelinated axons. Gait analysis revealed that stance width was increased in rats with CNTF and NT3 grafts, and step length involving the injured left hindlimb was significantly greater in NT3 grafted rats, suggesting enhanced sensory sensitivity in these animals. In summary, the selective expression of BDNF, CNTF or NT3 by genetically modified SCs had differential effects on PN graft morphology, the number and type of regenerating axons, myelination, and locomotor function. 23143930 IsoDGR-tagged albumin: a new αvβ3 selective carrier for nanodrug delivery to tumors. A new cyclic peptide containing the isoDGR motif that, after coupling to albumin, selectively binds αvβ3, an integrin overexpressed in the tumor vasculature. IsoDGR-tagged albumin binds tumor vessels and can be exploited as a carrier for the preparation of tumor vasculature-selective nanomedicines, such as gold nanoparticles (Au) carrying tumor necrosis factor α (TNF), a potent vascular damaging agent. 23916190 Adsorptive removal of fluoride from aqueous medium using a fixed bed column packed with Zr(IV) loaded dried orange juice residue. The potential of the adsorbent prepared from DOJR marketed as cattle food in Japan was identified as an efficient and low cost adsorbent for fluoride using fixed bed column. DOJR was loaded with Zr(IV) ions to develop active adsorption sites for fluoride. Fluoride adsorption performance of column packed with Zr(IV) loaded DOJR was assessed under variable operating conditions such as Zr(IV) loading temperature, initial fluoride concentration, bed depth, initial pH, and flow rate. Breakthrough curve modeling showed that Thomas and bed depth service time (BDST) models were in good agreement with the experimental data. Application of adsorbent investigated in this study to the treatment of actual waste plating solution containing fluoride ion showed successful removal below acceptable standard in Japan using a fixed bed column, hence, Zr(IV)-DOJR can be expected to be a promising candidate for the treatment waste water containing trace amount of fluoride ion in fixed bed column. 23643803 Potential impact of the 70-gene signature in the choice of adjuvant systemic treatment for ER positive, HER2 negative tumors: a single institution experience. We investigated in a single institution series of 124 women with operable breast cancer whether tumor clinicopathological features could predict the 70-gene signature (Mammaprint, MP) results, and whether MP results could help to make decisions for the use of chemotherapy (CT) in patients (pts) with ER positive breast cancer beyond recommendations of international guidelines. Among the 68 ER/PgR positive, HER2 negative tumors, Ki-67 ≥ 20% was the only significant predictor of a high risk-MP among standard clinicopathological features. In candidates for endocrine therapy with undetermined benefit from CT according to international guidelines, MP results would have led to different treatment decisions in 13/46 (28%) and in 20/68 (29%) pts according to NCCN and St. Gallen recommendations, respectively. Ki-67 independently predicted high risk-MP in ER/PgR positive, HER2 negative tumors. MP results would have led to discordant treatment recommendations in about 30% of cases, generally increasing indication rate for CT. The results of large randomized trials are warranted in order to understand whether we should rely on multigene assays rather than on standard clinicopathological features for treatment decisions. 23889205 Subcortical and cerebellar volumetric deficits in paediatric sickle cell anaemia. Sickle cell anaemia (SCA) is associated with silent cerebral infarction (SCI), affecting white and cortical grey matter, but there are few data on subcortical volumes. We analysed retrospective magnetic resonance imaging (MRI) data in 26 SCA patients and 20 controls, comparing mean subcortical volumes between three groups: controls, SCA with SCI (n = 13) and SCA without visible abnormality (n = 13). Specific volumetric differences were found in the hippocampus, amygdala, pallidum, caudate, putamen, thalamus, and cerebellum. This is the first study to demonstrate subcortical volume change in SCA, with the most severe volumetric deficits occurring in children with SCI seen on MRI. 23757337 Etiology of viral gastroenteritis in children <5 years of age in the United States, 2008-2009. Background. Although rotavirus and norovirus cause nearly 40% of severe endemic acute gastroenteritis (AGE) in children <5 years of age in the United States, there are limited data on the etiologic role of other enteric viruses in this age group. Methods. We conducted active population-based surveillance in children presenting with AGE to hospitals, emergency departments, and primary care clinics in 3 US counties. Stool specimens from these children and from age-matched healthy controls collected between October 2008 and September 2009 were tested for enteric adenovirus, astrovirus, sapovirus, parechovirus, bocavirus, and aichivirus. Typing was performed by sequencing and phylogenetic analysis. Results. Adenovirus, astrovirus, sapovirus, parechovirus, bocavirus, and aichivirus were detected in the stool specimens of 11.8%, 4.9%, 5.4%, 4.8%, 1.4%, and 0.2% of patients with AGE and 1.8%, 3.0%, 4.2%, 4.4%, 2.4%, and 0% of healthy controls, respectively. Adenovirus (type 41), astrovirus (types 1, 2, 3, 4, and 8), sapovirus (genogroups I and II), parechovirus (types 1, 3, 4, and 5), and bocavirus (types 1, 2, and 3) were found cocirculating. Conclusions. Adenovirus, astrovirus, and sapovirus infections were detected in 22.1% of the specimens from children <5 years of age who had medical visits for AGE and tested negative for rotavirus and norovirus. No causal role for parechovirus and bocavirus was found. 23423679 A refined combined antero-retrograde approach 
for the resolution of a complex ureterovaginal fistula: an endourologic case report. he onset of a ureterovaginal fistula is a not frequent, though it represents a dreaded and disabling complication of the pelvic surgery. The literature suggests to perform ureteroneocystostomy associated, if necessary, with a bladder suspension technique to Psoas muscle, or endoscopic procedures of ureteral stenting as the "gold standard" to repair this condition. We describe an innovative combined anterograde trans-nephrostomic and retrograde trans-ureteral surgical approach successfully carried out for the treatment of a rare ureterovaginal fistula associated with ipsilateral hydroureteronephrosis secondary to a complete obliteration of the ureteral orifice. We believe that this approach could be considered as a minimally invasive surgical option, an alternative to the traditional ones, for the repair of ureterovaginal fistulae complicated by a complete obliteration of the ipsilateral ureteral meatus. 23917594 Effects of the ischemic preconditioning on anastomotic healing in laparoscopic colon operations. Previous experimental studies have repeatedly demonstrated the potential protective effect of remote ischemic preconditioning (IPC) on colon anastomosis. The purpose of this experimental study was to investigate the possible positive effects of IPC by interval insufflations in laparoscopic colon operations. Thirty Wistar-albino rats were randomized into 3 groups. Colonic transsection and anastomosis were performed in the control group. In the laparoscopic colon operation without IPC group, the intra-abdominal pressure was raised to 14 mm Hg for 60 minutes, and then laparotomy and colonic anastomosis were performed. In the IPC group, the intra-abdominal pressure was raised to 14 mm Hg for 5 minutes, followed by desufflation. Laparotomy and colonic anastomosis were performed exactly as in the non-IPC group. On the seventh postoperative day, all animals were killed, and blood and tissue samples were obtained. Anastomotic healing and inflammatory responses were determined by histopathologic examination and by measuring the anastomotic bursting pressure, tissue hydroxyproline level, and tissue and serum nitric oxide, malondialdehyde (MDA), and catalase activity levels. Differences with P-values of <0.05 were considered to be statistically significant. Although the best anastomotic healing was detected in the control group, anastomotic healing was better in the IPC group than that in the non-IPC group. In terms of anastomotic bursting pressure, plasma MDA, serum catalase activity, and tissue nitric oxide levels, the IPC group was superior to the non-IPC group. No significant differences were found between the control and IPC groups, except in the plasma MDA levels. Use of IPC with colon anastomosis had positive effects on wound healing and may serve as a safe method to reduce the adverse effects of ischemia and wound healing in laparoscopic colon operations. 23968719 Development of a single multiplex amplification refractory mutation system PCR for the detection of rifampin-resistant Mycobacterium tuberculosis. A rapid and simple method for the detection of drug-resistant Mycobacterium tuberculosis is critical for the efficient treatment and control of this pathogen in developing country. Here we developed a single multiplex amplification refractory mutation system (M-ARMS) PCR, in which chimeric-primer and temperature switch PCR (TSP) strategy were included. Using this method, we detected rifampin resistance-associated mutations at codons 511, 516, 526 and 531 in the rifampin resistance-determining region of rpoB gene. The performance of M-ARMS-PCR assay was evaluated with 135 cultured isolates of M. tuberculosis. The sensitivity and specificity were 94.2% and 100%, respectively, compared with direct DNA sequencing, and 86.67% and 89.71%, respectively, compared with culture-based phenotypic drug susceptibility testing. Therefore, this newly-developed M-ARMS-PCR method is useful and efficient with an intended application in provincial Centers for Disease Control and Prevention for rapid detection of rifampin resistance-associated mutations. 23702129 The local immune response to intraocular Toxoplasma re-challenge: less pathology and better parasite control through Treg/Th1/Th2 induction. Ocular toxoplasmosis is a major cause of blindness world-wide. Ocular involvement is frequently seen following congenital infection. Many of these infections are quiescent but pose a life-time risk of reactivation. However, the physiopathology of ocular toxoplasmosis reactivation is largely unexplored. We previously developed a Swiss-Webster outbred mouse model for congenital toxoplasmosis by neonatal injection of Toxoplasma gondii cysts. We also used a mouse model of direct intraocular infection to show a deleterious local T helper 17 type response upon primary infection. In the present study, our two models were combined to study intravitreal re-challenge of neonatally infected mice, as an approximate model of reactivation, in comparison with a primary ocular infection. Using BioPlex proteomic assays in aqueous humour and reverse transcription-PCR for T helper cell transcription factors, we observed diminished T helper 17 type reaction in reinfection, compared with primary infection. In contrast, T helper 2 and T regulatory responses were enhanced. Interestingly, this was also true for T helper 1 markers such as IFN-γ, which was paralleled by better parasite control. Secretion of IL-27, a central cytokine for shifting the immune response from T helper 17 to T helper 1, was also greatly enhanced. We observed a similar protective immune reaction pattern in the eye upon reinfection with the virulent RH strain, with the notable exception of IFN-γ. In summary, our results show that the balance is shifted from T helper 17 to a less pathogenic but more effective anti-parasite Treg/T helper 1/T helper 2 pattern in a reactivation setting. 23913692 Structural changes during cysteine desulfurase CsdA and sulfur-acceptor CsdE interactions provide insight into the trans-persulfuration. In Escherichia coli, three cysteine desulfurases (IscS, SufS and CsdA) initiate the delivery of sulfur for various biological processes such as the biogenesis of Fe-S clusters. The sulfur generated as persulfide on a cysteine residue of cysteine desulfurases are further transferred to Fe-S scaffolds (e.g. IscU), or to intermediate cysteine-containing sulfur-acceptors (e.g. TusA, SufE, and CsdE) prior to its utilization. Herein, we report structures of CsdA, and CsdA-CsdE complex, which provide insight into the sulfur transfer mediated by the trans-persulfuration reaction. Analysis of the structures indicates that the conformational flexibility of the active cysteine loop in CsdE is essential for accepting the persulfide from the cysteine of CsdA. Additionally, CsdA and CsdE invoke a different binding mode than those of previously reported cysteine desulfurase (IscS) and sulfur-acceptors (TusA and IscU). Moreover, the conservation of interaction-mediating residues between CsdA/SufS and CsdE/SufE further suggests that the SufS-SufE interface likely resembles that of CsdA and CsdE. 23743147 Tributyltin induces oxidative damage, inflammation and apoptosis via disturbance in blood-brain barrier and metal homeostasis in cerebral cortex of rat brain: An in vivo and in vitro study. Tributyltin (TBT), a member of the organotin family, is primarily used for its biocidal activity. Persistent environmental levels of TBT pose threat to the ecosystem. Since neurotoxic influence of TBT remains elusive, we therefore, studied its effect on cerebral cortex of male Wistar rats. A single oral dose of Tributyltin-Chloride (TBTC) (10, 20, 30mg/kg) was administered and the animals were sacrificed on day 3 and day 7. Blood-brain barrier permeability remained disrupted significantly till day 7 with all the doses of TBTC. Pro-oxidant metal levels (Fe, Cu) were increased with a concomitant decrease in Zn. ROS generation was substantially raised resulting in oxidative damage (increased protein carbonylation and lipid peroxidation) with marked decline in tissue antioxidant status (GSH/GSSG levels). Protein expression studies indicated astrocyte activation, upregulation of inflammatory molecules (IL-6, Cox-2 and NF-κB) and simultaneous elevation in the apoptotic index (Bax/Bcl2). Neurodegeneration was evident by reduced neurofilament expression and increased calpain cleaved Tau levels. The in-vitro study demonstrated involvement of calcium and signaling molecules (p38), with downstream activation of caspase-3 and -8, and apoptotic cell death was evident by nuclear fragmentation, DNA laddering and Annexin V binding experiments. Ca(2+) inhibitors (BAPTA-AM, EGTA, and RR) and free radical scavengers (NAC and biliprotein [C-PC]) increased cell viability (MTT assay), signifying specific roles of Ca(2+) and ROS. Significance of p38 signaling was evaluated on pro-apoptotic proteins by using SB203580, a selective p38 inhibitor. Our data collectively illustrates that TBTC can disrupt BBB, induce oxidative stress, cause cell death and initiate neurodegeneration in rat brain. 23774212 mTOR Signaling Feedback Modulates Mammary Epithelial Differentiation and Restrains Invasion Downstream of PTEN Loss. Oncogenic signaling pathways are tightly regulated by negative feedback circuits and relief of these circuits represents a common mechanism of tumor drug resistance. Although the significance of these feedback pathways for signal transduction is evident, their relevance for cellular differentiation and morphogenesis in a genetically defined context is unclear. In this study, we used isogenic benign mammary organotypic cultures to interrogate the role of mTOR-mediated negative feedback in the specific setting of PTEN inactivation. We found that mTOR signaling promoted basal-like differentiation and repressed nuclear hormone receptor expression after short-term PTEN loss in murine cell cultures analyzed ex vivo. Unexpectedly, we found that PTEN inactivation inhibited growth factor-induced epithelial invasion and that downstream mTOR-mediated signaling feedback was both necessary and sufficient for this effect. Mechanistically, using isogenic MCF10A cells with and without somatic PTEN deletion, we showed that mTOR inhibition promoted EGF-mediated epithelial invasion by derepressing upstream EGF receptor, SRC tyrosine kinase, and phosphoinositide 3-kinase signaling. In addition to offering new signal transduction insights, these results bring to light a number of important and potentially clinically relevant cellular consequences of mTOR inhibition in the specific context of PTEN loss, including modulation of hormone and growth factor responsiveness and promotion of epithelial invasion. Our findings prompt future investigations of the possibility that mTOR inhibitor therapy may not only be ineffective but even deleterious in tumors with PTEN loss. Cancer Res; 73(16); 5218-31. ©2013 AACR. 23720775 Small Oligomers of Ribulose-bisphosphate Carboxylase/Oxygenase (Rubisco) Activase Are Required for Biological Activity. Ribulose-bisphosphate carboxylase/oxygenase (Rubisco) activase uses the energy from ATP hydrolysis to remove tight binding inhibitors from Rubisco, thus playing a key role in regulating photosynthesis in plants. Although several structures have recently added much needed structural information for different Rubisco activase enzymes, the arrangement of these subunits in solution remains unclear. In this study, we use a variety of techniques to show that Rubisco activase forms a wide range of structures in solution, ranging from monomers to much higher order species, and that the distribution of these species is highly dependent on protein concentration. The data support a model in which Rubisco activase forms an open spiraling structure rather than a closed hexameric structure. At protein concentrations of 1 μm, corresponding to the maximal activity of the enzyme, Rubisco activase has an oligomeric state of 2-4 subunits. We propose a model in which Rubisco activase requires at least 1 neighboring subunit for hydrolysis of ATP. 23178655 Boldine protects endothelial function in hyperglycemia-induced oxidative stress through an antioxidant mechanism. Increased oxidative stress is involved in the pathogenesis and progression of diabetes. Antioxidants are therapeutically beneficial for oxidative stress-associated diseases. Boldine ([s]-2,9-dihydroxy-1,10-dimethoxyaporphine) is a major alkaloid present in the leaves and bark of the boldo tree (Peumus boldus Molina), with known an antioxidant activity. This study examined the protective effects of boldine against high glucose-induced oxidative stress in rat aortic endothelial cells (RAEC) and its mechanisms of vasoprotection related to diabetic endothelial dysfunction. In RAEC exposed to high glucose (30 mM) for 48 h, pre-treatment with boldine reduced the elevated ROS and nitrotyrosine formation, and preserved nitric oxide (NO) production. Pre-incubation with β-NAPDH reduced the acetylcholine-induced endothelium-dependent relaxation; this attenuation was reversed by boldine. Compared with control, endothelium-dependent relaxation in the aortas of streptozotocin (STZ)-treated diabetic rats was significantly improved by both acute (1 μM, 30 min) and chronic (20mg/kg/daily, i.p., 7 days) treatment with boldine. Intracellular superoxide and peroxynitrite formation measured by DHE fluorescence or chemiluminescence assay were higher in sections of aortic rings from diabetic rats compared with control. Chronic boldine treatment normalized ROS over-production in the diabetic group and this correlated with reduction of NAD(P)H oxidase subunits, NOX2 and p47(phox). The present study shows that boldine reversed the increased ROS formation in high glucose-treated endothelial cells and restored endothelial function in STZ-induced diabetes by inhibiting oxidative stress and thus increasing NO bioavailability. 23953431 Adjunctive cryotherapy for pigmentary keratitis in dogs: a study of 16 corneas. To assess whether soft cryotherapy (dimethylether, isobutene, and propane) can remove pigmentation of the cornea that has accumulated under different conditions when conventional therapy has been unsuccessful. Nine dogs with unilateral or bilateral corneal pigmentation (16 eyes) were included based on progressive corneal pigmentation that was unresponsive to long-term etiological treatment. The dogs had keratoconjunctivitis sicca or chronic superficial keratitis. A cryogen of 95% dimethylether, 3% isobutane, and 2% propane was applied to the pigmented areas of each cornea under anesthesia. Initial corneal pigmentation and changes were documented over the entire study period using a grading scheme and clinical photographs. Most of the pigment deposits were gone by 5-15 days after cryosurgery. Postoperatively, the dogs showed some corneal edema and corneo-conjunctival inflammation, and three dogs had superficial corneal ulcers; these symptoms had resolved by 1 month after the procedure. Follow-up for more than 90 days was available in five dogs (nine corneas), and we observed total or partial repigmentation when the underlying disease was not controlled. A new cryotherapy procedure was successfully performed in two of these dogs. Given the sensitivity to cold of melanocytes, cryotherapy is a viable adjunctive treatment for refractory severe corneal pigmentation. Etiological treatment remains necessary to prevent pigmentation from rapidly reappearing. Only a few dogs were followed for more than 90 days; further study is necessary to evaluate the long-term safety and efficacy of soft cryotherapy. 23921543 Proteolytic degradation of the flavonoid regulators, TRANSPARENT TESTA8 and TRANSPARENT TESTA GLABRA1, in Arabidopsis is mediated by the ubiquitin/26Sproteasome system. Regulated proteolysis by the ubiquitin/26S proteasome system (UPS) has emerged as a major posttranslational control mechanism regulating transcription factor (TF) activity in plants. Anthocyanin biosynthesis in Arabidopsis is regulated by a ternary complex comprised of basic helix-loop-helix (bHLH), R2R3MYB and WD-repeat (WDR) proteins. The bHLH TF, TRANSPARENT TESTA 8 (TT8), and the WDR protein, TRANSPARENT TESTA GLABRA1 (TTG1), are essential for expression of late flavonoid biosynthesis genes. Previous studies have demonstrated that the turnover of several anthocyanin pathway regulators is controlled by the UPS. Here, we showthatTT8 and TTG1areshort-lived and targeted by the UPS for degradation. Our findings further extend our understanding of the role of the UPS in the regulation of anthocyanin biosynthesis in plants. 23872014 Host-guest inclusion complex of propafenone hydrochloride with α- and β-cyclodextrins: Spectral and molecular modeling studies. Host-guest inclusion complexes of cyclodextrins (CDs) with a potential cardiovascular drug propafenone hydrochloride (PFO), were prepared and characterized using absorption, fluorescence, time-resolved fluorescence, SEM, FT-IR, DSC, (1)H NMR, XRD and PM3 methods. The spectral studies suggested the phenyl ring along with carbonyl group is present inside of CD cavity. Solvent studies revealed that the normal Stokes shifted band originates from the locally excited state and the large Stokes shifted band occurs due to the emission from ICT. Nanosecond time-resolved studies indicated that PFO exhibits biexponential decay in water and triexponential decay in CD, indicating the formation of 1:1 inclusion complex. The results from solid state studies showed important modifications in the physicochemical properties of free PFO. The ΔH, ΔG and ΔS of the complexation process were determined and it was found that the complexation processes were spontaneous. Investigations of thermodynamic and electronic properties confirmed the stability of the inclusion complex. 23106652 Evolution and diversity of Arsenophonus endosymbionts in aphids. Endosymbiotic bacteria are important drivers of insect evolutionary ecology, acting both as partners that contribute to host adaptation and as subtle parasites that manipulate host reproduction. Among them, the genus Arsenophonus is emerging as one of the most widespread lineages. Its biology is, however, entirely unknown in most cases, and it is therefore unclear how infections spread through insect populations. Here we examine the incidence and evolutionary history of Arsenophonus in aphid populations from 86 species, characterizing the processes that shape their diversity. We identify aphids as harbouring an important diversity of Arsenophonus strains. Present in 7% of the sampled species, incidence was especially high in the Aphis genus with more than 31% of the infected species. Phylogenetic investigations revealed that these Arseno-phonus strains do not cluster within an aphid-specific clade but rather exhibit distinct evolutionary origins showing that they undergo repeated horizontal transfers (HT) between distantly related host species. Their diversity pattern strongly suggests that ecological interactions, such as plant mediation and parasitism, are major drivers for Arsenophonus dispersal, dictating global incidence across insect communities. Notably, plants hosting aphids may be important ecological arenas for global exchange of Arsenophonus, serving as reservoirs for HT. 23335441 Nanostructural anisotropy underlies anisotropic electrical bistability. Regular arrays of nanorods having asymmetric cross-sections are fabricated by a combination of electrodeposition and glancing-angle deposition (GLAD). When these nanorods are embedded in a polymer matrix, they give rise to composite materials in which the structural anisotropy at the nanoscale translates into functional anisotropy in the form of direction-dependent electrical bistability. The degree of this directional bistability depends on and can be controlled by the spacing between the nearby nanorods. 23895738 Measurement of baseline toxicity and QSAR analysis of 50 non-polar and 58 polar narcotic chemicals for the alga Pseudokirchneriella subcapitata. In this paper a set of homogenous experimental algal toxicity data was measured for 50 non-polar narcotic chemicals using the alga Pseudokirchneriella subcapitata in a closed test with a growth rate endpoint. Most of the tested compounds are high volume industrial chemicals that so far lacked published REACH-compliant algal growth inhibition values. The test protocol fulfilled the criteria set forth in the OECD guideline 201 and had the same sensitivity as the open test which allowed direct comparison of toxicity values. Baseline QSAR model for non-polar narcotic compounds was established and compared with previous analogous models. Multi-linear QSAR model was derived for the non-polar and 58 previously tested polar (anilines and phenols) narcotic compounds modulating hydrophobicity, molecular size, electronic and molecular stability effects coded in the molecular descriptors. Descriptors in the model were analyzed and applicability domain was assessed providing further guidelines for the in silico prediction purposes in decision support while performing risk assessment. QSAR models in the manuscript are available on-line through QsarDB repository for exploring and prediction services (http://hdl.handle.net/10967/106). 23902709 On the phenomenon of large photoluminescence red shift in GaN nanoparticles. We report on the observation of broad photoluminescence wavelength tunability from n-type gallium nitride nanoparticles (GaN NPs) fabricated using the ultraviolet metal-assisted electroless etching method. Transmission and scanning electron microscopy measurements performed on the nanoparticles revealed large size dispersion ranging from 10 to 100 nm. Nanoparticles with broad tunable emission wavelength from 362 to 440 nm have been achieved by exciting the samples using the excitation power-dependent method. We attribute this large wavelength tunability to the localized potential fluctuations present within the GaN matrix and to vacancy-related surface states. Our results show that GaN NPs fabricated using this technique are promising for tunable-color-temperature white light-emitting diode applications. 23417827 Constraints to cattle production in a semiarid pastoral system in Kenya. Livestock keeping is the mainstay for the pastoral community while also providing social and cultural value. This study ranked main production constraints and cattle diseases that impacted livelihood and estimated herd prevalence, incidence rate, and impact of diseases on production parameters in a semiarid pastoral district of Narok in Kenya. Data collection employed participatory techniques including listing, pairwise ranking, disease incidence scoring, proportional piling, and disease impact matrix scoring and this was disaggregated by gender. Production constraints with high scores for impact on livelihood included scarcity of water (19 %), lack of extension services (15 %), presence of diseases (12 %), lack of market for cattle and their products (10 %), and recurrent cycle of drought (9 %). Diseases with high scores for impact on livelihood were East Coast fever (ECF) (22 %) and foot and mouth disease (FMD) (21 %). High estimated incidence rates were reported for FMD (67 %), trypanosomosis (28 %), and ECF (15 %), while contagious bovine pleuropneumonia (CBPP) had an incidence rate <1 %. Milk yield was affected by FMD, ECF, and trypanosomosis, while ECF was the cause of increased mortality. FMD, ECF, CBPP, and brucellosis caused increased abortion, while effect of gender and location of study was not significant. Despite CBPP being regarded as an important disease affecting cattle production in sub-Sahara Africa, its estimated incidence rate in herds was low. This study indicates what issues should be prioritized by livestock policy for pastoral areas. 23253260 Assessment of the usefulness of the murine cytotoxic T cell line CTLL-2 for immunotoxicity screening by transcriptomics. A toxicogenomics approach was applied to assess the usefulness of the mouse cytotoxic T cell line CTLL-2 for in vitro immunotoxicity testing. CTLL-2 cells were exposed for 6 h to two model immunotoxic compounds: (1) the mycotoxin deoxynivalenol (DON, 1 and 2 μM), a ribotoxic stress inducer, and (2) the organotin compound tributyltin oxide (TBTO, 100 and 200 nM), an endoplasmic reticulum (ER) stress inducer. Effects on whole-genome mRNA expression were assessed by microarray analysis. The biological interpretation of the microarray data indicated that TBTO (200 nM) induced genes involved in T cell activation, ER stress, NFκB activation and apoptosis, which agreed very well with results obtained before on TBTO exposed Jurkat cells and mouse primary thymocytes. Remarkably, DON (2 μM) downregulated genes involved in T cell activation, ER stress and apoptosis, which is opposite to results obtained before for DON-exposed Jurkat cells and mouse primary thymocytes. Furthermore, the results for DON in CTLL-2 cells are also opposite to the results obtained for TBTO in CTLL-2 cells. In agreement with the lack of induction of ER stress and apoptosis, viability assays showed that CTLL-2 cells are much more resistant to the toxicity of DON than Jurkat cells and primary thymocytes. We propose that CTLL-2 cells lack the signal transduction that induces ER stress and apoptosis in response to ribotoxic stress. Based on the results for TBTO and DON, the CTLL-2 cell line does not yield an added value for immunotoxicity compared to the human Jurkat T cell line. 23935400 Which Adverse Events Are Related to Health Care during Hospitalization in Elderly Inpatients? Background: Adverse events result in longer hospital stays and increase costs and mortality. We aimed to assess incidence of adverse events occurring during hospitalization in a post-emergency unit and to describe their characteristics. Methods: All adverse events occurring in patients during their hospitalization in a post-emergency unit in a French university hospital (20 beds) were systematically and consecutively recorded from September 2009 to February 2011. Patients with adverse events were compared to up to three control patients, matched for date of admission +/- age in the same unit. Results: We identified 56 patients with 64 adverse events, giving an incidence of 3.0/100 patients admitted/year. Fifty-one adverse events were drug-related. Patients had a median age of 82.5 years with a male/female ratio of 1/1.4. They presented a median Charlson score of 1 and the median number of medications was 6. The drugs most frequently involved in drug-related events were nervous system drugs (47%) and anti-infectives (22%). In multivariate analysis, a Charlson score ≥ 2 was associated with the occurrence of adverse events (OR 0.4; 95% CI [0.21 - 0.80]). Conclusions: Systematic recording showed that adverse events were not rare in a post-emergency unit. Patients with comorbid conditions were less likely to present an adverse event, possibly because of greater precautions taken by the medical team. 23901238 Impact of being overweight on the surgical outcomes of patients with gastric cancer: A meta-analysis. To investigate the effect of being overweight on the surgical results of patients with gastric cancer. Comprehensive electronic searches of the PubMed, Web of Science, and Cochrane Library databases were conducted. Studies were identified that included patients with surgical complications from gastric cancer who were classified as normal weight [body mass index (BMI) < 25 kg/m(2)] or overweight (BMI ≥ 25 kg/m(2)). The operative time, retrieved lymph nodes, blood loss, and long-term survival were analyzed. A subgroup analysis was conducted based on whether patients received laparoscopic or open gastrectomy procedures. All statistical tests were performed using ReviewerManager 5.1.2 software. This meta-analysis included 23 studies with 20678 patients (15781 with BMI < 25 kg/m(2); 4897 with BMI ≥ 25 kg/m(2)). Overweight patients had significantly increased operation times [MD: -29.14; 95%CI: -38.14-(-20.21); P < 0.00001], blood loss [MD: -194.58; 95%CI: -314.21-(-74.95); P = 0.001], complications (RR: 0.75; 95%CI: 0.66-0.85; P < 0.00001), anastomosis leakages (RR: 0.59; 95%CI: 0.42-0.82; P = 0.002), and pancreatic fistulas (RR: 0.486; 95%CI: 0.34-0.63; P < 0.00001), whereas lymph node retrieval was decreased significantly in the overweight group (MD: 1.69; 95%CI: 0.75-2.62; P < 0.0001). In addition, overweight patients had poorer long-term survival (RR: 1.14; 95%CI: 1.07-1.20; P < 0.0001). No significant difference was detected for the mortality and length of hospital stay. This meta-analysis demonstrates that a high BMI not only increases the surgical difficulty and complications but also impairs the long-term survival of patients with gastric cancer. 23794395 Versatile Eco-friendly Pickering Emulsions Based on Substrate/Native Cyclodextrin Complexes: A Winning Approach for Solvent-Free Oxidations. Solvent-less Pickering emulsions were developed and applied to catalytic oxidation. These systems are stabilized by inclusion complexes between cyclodextrins and substrates, forming a 3D network among the dispersed phase. In the presence of hydrogen peroxide as a green oxidant and [Na]3 [PW12 O40 ] as a catalyst, they provide particularly efficient reaction media for the oxidation of olefins, organosulfurs, and alcohols. The reactions proceed at competitive rates (up to 400 h(-1) ) with straightforward separation of the phases by centrifugation or heating. Moreover, these new eco-friendly systems work at a preparative scale (up to 2.5 M) and are recycled without loss of activity. 23616476 Folate-Conjugated PEG on Single Walled Carbon Nanotubes for Targeting Delivery of Doxorubicin to Cancer Cells. A highly effective drug carrier is constructed by coating folic acid-terminated poly(ethylene glycol) (PEG-FA) on single walled carbon nanotubes (SWNTs) in a facile non-covalent method. The anti-cancer drug, doxorubicin (DOX), is further loaded on the surface of SWNTs at a very high loading efficiency, 149.3 ± 4.1%. The drug system (DOX/PEG-FA/SWNTs) exhibits excellent stability under neutral pH conditions such as serum, but dramatically releases DOX at reduced pH typical of the tumour environment and intracellular lysosomes and endosomes. With the help of FA, DOX/PEG-FA/SWNTs tend to selectively attach onto cancer cells and enter the lysosomes or endosomes by clathrin-mediated endocytosis. This can greatly improve the pharmaceutical efficiency and reduce potential side effects. 23686699 UGT1A1 6/28 polymorphisms could predict irinotecan-induced severe neutropenia not diarrhea in Chinese colorectal cancer patients. The aim of this study was to investigate the associations between UDP-glucuronosyltransferase (UGT) 1A1 polymorphisms and irinotecan-induced toxicities in Chinese advanced colorectal cancer patients. The genotypes of UGT1A1 6 and UGT1A1 28 were analyzed by PCR amplification and Sanger sequencing in 276 advanced colorectal cancer patients receiving irinotecan-containing chemotherapy. The influences of UGT1A1 6/28 polymorphisms on severe diarrhea and neutropenia were analyzed. The overall incidence of UGT1A1 6 and UGT1A1 28 variants was 35.5 % (GA: 28.6 %; AA: 6.9 %) and 21.0 % (TA6/TA7: 19.9 %; TA7/TA7: 1.1 %) in our cohort, respectively. A total of 16 patients (5.8 %, 16/276) had severe diarrhea and 56 patients (20.3 %, 56/276) had severe neutropenia. Neither UGT1A1 6 nor UGT1A1 28 variants were associated with severe diarrhea; however, either UGT1A1 6 (P = 0.001) or UGT1A1 28 (P = 0.029) variants were significantly associated with severe neutropenia. No differences were found between severe toxicities and clinical response in this study. Compared to western countries, Chinese patients had a distinct frequency of UGT1A1 6 or UGT1A1 28 genotypes. Both UGT1A1 6 and UGT1A1 28 variants were closely associated with irinotecan-induced severe neutropenia, but not diarrhea. 23922614 Pneumothorax, music and balloons: A case series. We describe two cases of spontaneous pneumothorax in young healthy adults with no underlying structural lung disease. The onset of pneumothorax was following physical activity including playing musical instruments and blowing of balloons. There is sparse data evaluating the pathophysiology of primary spontaneous pneumothorax in relation to increased mouth pressures. These cases highlight the possible physical effect of valsalva manoeuvre on transpulmonary pressures, and the potential risk of developing pneumothorax in otherwise healthy individuals. This aspect of pneumothorax development is worthy of further exploration, to better elucidate the mechanism and enhance our understanding of this common respiratory presentation. 23280947 Relative importance of direct and trophic uranium exposures in the crayfish Orconectes limosus: Implication for predicting uranium bioaccumulation and its associated toxicity. Pollutants that occur at sublethal concentrations in the environment may lead to chronic exposure in aquatic organisms. If these pollutants bioaccumulate, then organisms higher in the food chain may also be at risk. Increased attention has thus been focused on the relative importance of dietary uptake, but additional knowledge of the cellular distribution of metals after dietary exposure is required to assess the potential toxicity. The authors address concerns relating to increasing uranium (U) concentrations (from 12 µg/L to 2 mg/L) in the freshwater ecosystem caused by anthropogenic activities. The objective of the present study is to compare uranium bioaccumulation levels in tissues and in the subcellular environment. The authors focused on the cytosol fraction and its microlocalization (TEM-EDX) in the gills and the hepatopancreas (HP) of the crayfish Orconectes limosus after 10 d of direct exposure (at concentrations of 20, 100, and 500 µg/L) and five trophic exposure treatments (at concentrations from 1 to 20 µg/g). Results indicated that adsorption of uranium on the cuticle represents the main contribution of total uranium accumulation to the animal. Accumulation in the gills should be considered only as a marker of waterborne uranium exposure. Accumulation in the HP after trophic environmental exposure conditions was higher (18.9 ± 3.8 µg/g) than after direct exposure. Moreover, no significant difference in the subcellular distribution of uranium (50%) in HP was observed between animals that had been exposed to both types of treatment. A potential toxic effect after uranium accumulation could therefore exist after trophic exposure. This confirms the need to focus further studies on the metal (uranium) risk assessment. 23921624 Treatment Costs of Bladder Pain Syndrome/Interstitial Cystitis in Austria: A Pharmacoeconomic Approach Following Current Guidelines. Bladder pain syndrome/interstitial cystitis (BPS/IC) is a chronic disease with a significant impact on quality of life. A broad range of therapies are used to treat this condition, and patients are often excluded from receiving more expensive and more effective therapies because of cost issues. The objective of this study was to assess the mid- and long-term costs (over 1, 5 and 10 years) of various therapies for BPS/IC. Costs in an open-access health system (Austria) for three BPS/IC-specific therapies (intravesical hyaluronan, pentosanpolysulfate and amitriptyline), taken from the American Urological Association guidelines, were evaluated and compared with those of non-specific symptomatic therapies. Response rates for the different therapies were taken from peer-reviewed publications and used to define the need for therapy maintenance with regard to symptom improvement. Despite the highest initial costs, the reduced need for further therapy in patients with long-term symptom remission after hyaluronan therapy resulted in the lowest total treatment costs at all three timepoints. Hyaluronan was cost saving against all alternatives in standard assumptions and in all sensitivity analyses. As a limitation, treatment costs in this study are specific for Austria. However, the template used for calculation of treatment costs can be transferred to all countries by inserting local prices. Disease-specific therapies with high remission rates result in significantly lower long-term costs in BPS/IC. Non-specific symptomatic therapies are most expensive. Long-term cost effectiveness is crucial in the treatment of chronic diseases to limit expenses in individual healthcare systems. 23921968 Towards [NiFe]-hydrogenase biomimetic models that couple H2 binding with functionally relevant intramolecular electron transfers: a quantum chemical study. [FeFe]- and [NiFe]-hydrogenases are dihydrogen-evolving metalloenzymes that share striking structural and functional similarities, despite being phylogenetically unrelated. Most notably, they are able to combine substrate binding and redox functionalities, which has important bearings on their efficiency. Model complexes of [FeFe]-hydrogenases that are able to couple H2 binding with a substrate-dependent intramolecular electron transfer promoting dihydrogen activation were recently shown to reproduce the complex redox chemistry of the all-iron enzyme. Notably, coupling of H2 binding and intramolecular redox events was proposed to have a key role also in [NiFe]-hydrogenases, but this feature is not reproduced in currently available nickel-iron biomimetic compounds. In the present study, we exploit dedicated density functional theory approaches to show that H2 binding and activation on a NiFe core can be favored by the installment of conveniently substituted isocyanoferrocenes, thanks to their ability to undergo intramolecular reduction upon substrate binding. Our results support the concept that a unified view on hydrogenase chemistry is a key element to direct future efforts in the modeling of microbial H2 metabolism. 23770120 Increased hepatic functionality of the human hepatoma cell line HepaRG cultured in the AMC bioreactor. The clinical application of a bioartificial liver (BAL) depends on the availability of a human cell source with high hepatic functionality, such as the human hepatoma cell line HepaRG. This cell line has demonstrated high hepatic functionality, but the effect of BAL culture on its functionality in time is not known. Therefore, we studied the characteristics of the HepaRG-AMC-BAL over time, and compared the functionality of the HepaRG-AMC-BAL with monolayer cultures of HepaRG cells, normalized for protein (bioactive mass) and DNA (cell number). Histological analysis of 14-day-old BALs demonstrated functional heterogeneity similar to that of monolayer cultures. Hepatic functionality of the HepaRG-AMC-BALs increased during 2-3 weeks of culture. The majority of the measured protein-normalized hepatic functions were already higher in day 14 BAL cultures compared to monolayer cultures, including ammonia elimination (3.2-fold), urea production (1.5-fold), conversion of (15)N-ammonia into (15)N-urea (1.4-fold), and cytochrome P450 3A4 activity (7.9-fold). Lactate production in monolayer cultures switched into lactate consumption in the BAL cultures, a hallmark of primary hepatocytes. When normalized for DNA, only cytochrome P450 3A4 activity was 2.5-fold higher in the BAL cultures compared to monolayer cultures and lactate production switched to consumption, whereas urea production and (15)N-urea production were 1.5- to 2-fold lower. The different outcomes for protein and DNA normalized functions probably relate to a smaller cell volume of HepaRG cells when cultured in the AMC-BAL. Cell damage was 4-fold lower in day 14 BAL cultures compared to monolayer cultures. Transcript levels of cytochrome P450 1A2, 2B6, 3A4 and 3A7 genes and of regulatory genes hepatic nuclear factor 4α and pregnane X receptor increased in time in BAL cultures and reached higher levels than in monolayer cultures. Lastly, metabolism of amino acids, particularly the alanine consumption and ornithine production of HepaRG-AMC-BALs more resembled that of primary hepatocytes than monolayer HepaRG cultures. We conclude therefore that BAL culture of HepaRG cells increases its hepatic functionality, particularly when normalized for biomass, both over time, and compared to monolayer, and this is associated with a reduction in cell damage, upregulation of both regulatory and structural hepatic genes, and changes in amino-acid metabolism. These results underline the potential of HepaRG cells for BAL application. 23434930 Functional redundancy of CXCR3/CXCL10 signaling in the recruitment of diabetogenic cytotoxic T lymphocytes to pancreatic islets in a virally induced autoimmune diabetes model. Cytotoxic T lymphocytes (CTLs) constitute a major effector population in pancreatic islets from patients suffering from type 1 diabetes (T1D) and thus represent attractive targets for intervention. Some studies have suggested that blocking the interaction between the chemokine CXCL10 and its receptor CXCR3 on activated CTLs potently inhibits their recruitment and prevents β-cell death. Since recent studies on human pancreata from T1D patients have indicated that both ligand and receptor are abundantly present, we reevaluated whether their interaction constitutes a pivotal node within the chemokine network associated with T1D. Our present data in a viral mouse model challenge the notion that specific blockade of the CXCL10/CXCR3 chemokine axis halts T1D onset and progression. 23877073 Measuring femoral and rotational alignment: EOS system versus computed tomography. Computed tomography (CT) is currently the reference standard for measuring femoral and tibial rotational alignment. The EOS System is a new biplanar low-dose radiographic device that allows 3-dimensional lower-limb modelling with automated measurements of femoral and tibial rotational alignment (torsion). Femoral and tibial torsion measurements provided by the EOS System are equivalent to those obtained using CT. In a retrospective analysis of 43 lower limbs in 30 patients, three senior radiologists measured femoral and tibial torsion on both CT and EOS images. Agreement between CT and EOS values was assessed by computing Pearson's correlation coefficient and interobserver reproducibility by computing the intraclass correlation coefficient (ICC). Femoral torsion was 13.4° by EOS vs. 13.7° by CT (P=0.5) and tibial torsion was 30.8° by EOS vs. 30.3° by CT (P=0.4). Strong associations were found between EOS and CT values for both femoral torsion (P=0.93) and tibial torsion (P=0.89). With EOS, the ICC was 0.93 for femoral torsion and 0.86 for tibial torsion; corresponding values with CT were 0.90 and 0.92. The EOS system is a valid alternative to CT for lower-limb torsion measurement. EOS imaging allows a comprehensive evaluation in all three planes while substantially decreasing patient radiation exposure. Level III, case-control. 23969825 Table of Contents for Online Material in the August 2013 issue. Abstracts or summaries of online content are printed in every issue of Obstetrics & Gynecology in this section. The complete documents can be found on our web site, www.greenjournal.org. The specific URL for the content in this section is printed at the end of the abstract or summary. 23345025 Presence of Anti-proteinase 3 Antineutrophil Cytoplasmic Antibodies (Anti-PR3 ANCA) as Serologic Markers in Inflammatory Bowel Disease. Anti-proteinase 3 anti-neutrophil cytoplasmic antibodies (anti-PR3 ANCA) represent an established serologic marker of active granulomatosis with polyangiitis, but their role as a serologic marker in inflammatory bowel disease (IBD) remains uncertain. This study evaluates the presence of anti-PR3 ANCA and their validity as a serologic marker to aid in the diagnosis of IBD. Retrospectively, 142 serum samples obtained at early stages of the disease were analyzed with a new chemiluminiscent assay for the measurement of anti-PR3 ANCA. The results were correlated to the diagnosis, clinical, and therapeutic data, and ANCA and anti-Saccharomyces cerevisiae antibody (ASCA) measurements available from routine clinical practice. Anti-PR3 ANCA were significantly more prevalent (p < 0.0001) and their titers significantly higher (p < 0.0001) among ulcerative colitis compared with Crohn's disease patients. Receiver operating characteristic curve analysis performed with anti-PR3 ANCA titers to assess the diagnostic accuracy of the assay gave an area under the curve of 0.81 (95 % CI (0.76-0.89); p < 0.0001), with a cut-off titer of 11.8 chemiluminescent units displaying 52.1 % sensitivity and 97.3 % specificity for ulcerative colitis. Combining anti-PR3 ANCA positivity with IgA ASCA negativity as the diagnostic parameter demonstrated highest diagnostic utility, with a sensitivity and specificity of 47.5 % and 98.2 %, respectively. In our cohort, anti-PR3 ANCA was significantly more prevalent in ulcerative colitis than in Crohn's disease patients, which suggests a possible role of anti-PR3 ANCA as a serologic marker to aid in the diagnosis of IBD. 23898057 Combination Chemoprevention with Diclofenac, Calcipotriol and Difluoromethylornithine Inhibits Development of Non-melanoma Skin Cancer in Mice. Background/Aim: With increasing incidence of non-melanoma skin cancer (NMSC), focus on chemoprevention of this disease is growing. The aim of this study was to evaluate topical combination therapies as chemoprevention of UV radiation-induced tumors in a mouse model. A total of 160 SKH-1 mice were randomized to one placebo group and four chemoprevention groups (diclofenac plus difluoromethylornithine; diclofenac plus calcipotriol; difluoromethylornithine plus calcitriol; and diclofenac plus difluoromethylornithine plus calcipotriol). The mice received UVB radiation for 20 weeks followed by 17 weeks with topical application of chemoprevention. The number of mice with tumors, number of tumors per group and tumor area size were compared using a linear regression model. Chemoprevention with diclonefac plus calcipotriol and diclonefac plus difluoromethylornithine had a significant inhibiting effect on the number of tumors per group and the area of tumors. Moreover, diclonefac plus difluoromethylornithine had a significant inhibiting effect on the number of mice with tumors. Potentially, non-melanoma skin cancer in humans may be prevented with these agents with few adverse effects. Therefore, clinical studies are needed to determine their therapeutic/preventive effect and possible adverse effects. 23864372 Dynamic effects of TNF-α on synaptic transmission in mice over time following sciatic nerve chronic constriction injury. Nerve injury-induced central sensitization can manifest as an increase in excitatory synaptic transmission and/or as a decrease in inhibitory synaptic transmission in spinal dorsal horn neurons. Cytokines such as tumor necrosis factor-α (TNF-α) are induced in the spinal cord under various injury conditions and contribute to neuropathic pain. In this study we examined the effect of TNF-α in modulating excitatory and inhibitory synaptic input to spinal substantia gelatinosa (SG) neurons over time in mice following chronic constriction injury (CCI) of the sciatic nerve. Whole-cell patch clamp studies from SG neurons showed that TNF-α enhanced overall excitability of the spinal cord early in time following nerve injury 3 days after CCI compared to that in sham control mice. In contrast the effects of TNF were blunted 14 days after CCI in nerve injured mice compared to sham surgery mice. Immunohistochemical staining showed that the expression of TNF-α receptor 1 (TNFR1) was increased at 3 days but decreased 14 days following CCI in the ipsilateral versus the contralateral spinal cord dorsal horn. These results suggest that TNF-a acting at TNFR1 is important in the development of neuropathic pain by facilitating excitatory synaptic signaling in the acute phases after nerve injury but has a reduced effect on spinal neuron signaling in the later phases of nerve injury induced pain. Failure of the facillatory effects of TNFα on excitatory synaptic signaling in the dorsal horn to resolve following nerve injury may be an important component in the transition between acute and chronic pain conditions. 23894444 Variable Myopathic Presentation in a Single Family with Novel Skeletal RYR1 Mutation. We describe an autosomal recessive heterogeneous congenital myopathy in a large consanguineous family. The disease is characterized by variable severity, progressive course in 3 of 4 patients, myopathic face without ophthalmoplegia and proximal muscle weakness. Absence of cores was noted in all patients. Genome wide linkage analysis revealed a single locus on chromosome 19q13 with Zmax = 3.86 at θ = 0.0 and homozygosity of the polymorphic markers at this locus in patients. Direct sequencing of the main candidate gene within the candidate region, RYR1, was performed. A novel homozygous A to G nucleotide substitution (p.Y3016C) within exon 60 of the RYR1 gene was found in patients. ARMS PCR was used to screen for the mutation in all available family members and in an additional 150 healthy individuals. This procedure confirmed sequence analysis and did not reveal the A to G mutation (p.Y3016C) in 300 chromosomes from healthy individuals. Functional analysis on EBV immortalized cell lines showed no effect of the mutation on RyR1 pharmacological activation or the content of intracellular Ca(2+) stores. Western blot analysis demonstrated a significant reduction of the RyR1 protein in the patient's muscle concomitant with a reduction of the DHPRα1.1 protein. This novel mutation resulting in RyR1 protein decrease causes heterogeneous clinical presentation, including slow progression course and absence of centrally localized cores on muscle biopsy. We suggest that RYR1 related myopathy should be considered in a wide variety of clinical and pathological presentation in childhood myopathies. 23515376 Can patients or clinicians predict the severity or duration of an acute upper respiratory infection? Purpose: Acute upper respiratory infections (URI) are the second most common diagnosis in primary care offices. As treatments have limited effectiveness, patient counseling regarding expectations for the course of the URI is an important aspect of care. It is unknown how accurate patients, clinicians or questionnaires such as the Wisconsin Upper Respiratory Symptom Survey (WURSS) instrument are at predicting URI severity and duration, and whether these predictions should be used to counsel patients. Methods: Seven hundred and nineteen individuals with recent onset cold in community clinic settings participated. Participants and clinicians predicted the severity and duration of the URI and participants completed the WURSS instrument at initial visit. Subsequent URI global severity was calculated as area under the curve using an average of twice-daily WURSS-21 self-reports as the y-axis and illness duration as the x-axis. URI duration was determined by self-report of beginning and end of illness. Linear regression analysis was used to correlate baseline predictions with subsequent outcomes. Analyses by gender, age and income were also performed. Results: There was no significant association between participant and clinician predictions of severity or duration. Initial WURSS values explained 0.119 (95% CI: 0.074-0.163) of the variance in subsequent severity outcomes. There were no significant differences in associations by age, gender or income. Conclusions: Clinicians should not use their predictive assessments or their patients' predictions when advising patients on the expected course of a URI. This study also suggests that the WURSS instrument could give some predictive information, but whether this is clinically useful is uncertain. 23958057 High plasma fibrinogen concentration and platelet count unfavorably impact survival in non-small cell lung cancer patients with brain metastases. High expression of fibrinogen and platelets are often observed in non-small cell lung cancer (NSCLC) patients with local regional or distant metastasis. However, the role of these factors remains unclear. The aims of this study were to evaluate the prognostic significance of plasma fibrinogen concentration and platelet count, as well as to determine the overall survival of NSCLC patients with brain metastases. A total of 275 NSCLC patients with brain metastasis were enrolled into this study. Univariate analysis showed that high plasma fibrinogen concentration was associated with age ≥65 years (P = 0.011), smoking status (P = 0.009), intracranial symptoms (P = 0.022), clinical T category (P = 0.010), clinical N category (P = 0.003), increased partial thromboplastin time (P < 0.001), and platelet count (P < 0.001). Patients with low plasma fibrinogen concentration demonstrated higher overall survival compared with those with high plasma fibrinogen concentration (median, 17.3 months versus 11.1 months; P ≤0.001). A similar result was observed for platelet counts (median, 16.3 months versus 11.4 months; P = 0.004). Multivariate analysis showed that both plasma fibrinogen concentration and platelet count were independent prognostic factors for NSCLC with brain metastases (RR = 1.698, P < 0.001 and RR = 1.699, P < 0.001, respectively). Our results suggest that high plasma fibrinogen concentration and platelet count indicate poor prognosis for NSCLC patients with brain metastases. Thus, these two biomarkers might be independent prognostic predictors for this subgroup of NSCLC patients. 23174754 Deficits in male sexual behavior in adulthood after social instability stress in adolescence in rats. There is increasing evidence that exposure to stressors in adolescence has long-lasting effects on emotional and cognitive behavior, but little is known as to whether reproductive functions are affected. We investigated appetitive and consummatory aspects of sexual behavior in male rats that were exposed to chronic social instability stress (SS, n=24) for 16 days in mid-adolescence compared to control rats (CTL, n=24). Over five sexual behavior test sessions with a receptive female, SS rats made fewer ejaculations (p=0.02) and had longer latencies to ejaculation (p=0.03). When only data from rats that ejaculated in the fifth session were analyzed, SS rats (n=18) had reduced copulatory efficiency (more mounts and intromissions before ejaculation) compared to CTL rats (n=19) (p=0.004), and CTL rats were twice as likely as SS rats to make more than one ejaculation in the fifth session (p=0.05). Further, more CTL (14/24) than SS (5/25) rats ejaculated in four or more sessions (p=0.05). SS rats had lower plasma testosterone concentrations than CTL rats (p=0.05), but did not differ in androgen receptor, estrogen receptor alpha, or Fos immunoreactive cell counts in the medial preoptic area. The groups did not differ in a partner preference test administered between the fourth and fifth sexual behavior session. The results suggest that developmental history contributes to individual differences in reproductive behavior, and that stress exposures in adolescence may be a factor in sexual sluggishness. 23962804 Stability and mobility of vacancy-H complexes in Al. The effect of hydrogen loading on the stability and mobility of vacancy-H complexes in aluminum is determined by applying DFT and the minimum-mode-following method. The binding energy per H-atom within a complex is found to range from -0.36 eV/atom to -0.34 eV/atom for an occupancy of, respectively, a single and eight H-atoms. When eight H-atoms are neighboring the vacancy the total binding energy becomes -2.72 eV. However, already at a load level of two H-atoms the total binding energy reaches -0.70 eV, which fully compensates the vacancy creation energy. It is observed that for complexes with four or more H-atoms the vacancy gets pinned, as the diffusion barrier increases by a factor of two, reaching a value of 1.03 eV or more. The explanation for the increased energy barrier is that at the higher hydrogen load levels the system must traverse an energetically unfavorable configuration where two or more H-atoms are separated from the vacancy. As a possible consequence of the decreased mobility and increased stability, highly loaded vacancy-H complexes are likely to act as nucleation sites for extended defects. 23893247 Swim pacemaker response to bath applied neurotransmitters in the cubozoan Tripedalia cystophora. The four rhopalia of cubomedusae are integrated parts of the central nervous system carrying their many eyes and thought to be the centres of visual information processing. Rhopalial pacemakers control locomotion through a complex neural signal transmitted to the ring nerve and the signal frequency is modulated by the visual input. Since electrical synapses have never been found in the cubozoan nervous system all signals are thought to be transmitted across chemical synapses, and so far information about the neurotransmitters involved are based on immunocytochemical or behavioural data. Here we present the first direct physiological evidence for the types of neurotransmitters involved in sensory information processing in the rhopalial nervous system. FMRFamide, serotonin and dopamine are shown to have inhibitory effect on the pacemaker frequency. There are some indications that the fast acting acetylcholine and glycine have an initial effect and then rapidly desensitise. Other tested neuroactive compounds (GABA, glutamate, and taurine) could not be shown to have a significant effect. 23964250 Predicting musically induced emotions from physiological inputs: linear and neural network models. Listening to music often leads to physiological responses. Do these physiological responses contain sufficient information to infer emotion induced in the listener? The current study explores this question by attempting to predict judgments of "felt" emotion from physiological responses alone using linear and neural network models. We measured five channels of peripheral physiology from 20 participants-heart rate (HR), respiration, galvanic skin response, and activity in corrugator supercilii and zygomaticus major facial muscles. Using valence and arousal (VA) dimensions, participants rated their felt emotion after listening to each of 12 classical music excerpts. After extracting features from the five channels, we examined their correlation with VA ratings, and then performed multiple linear regression to see if a linear relationship between the physiological responses could account for the ratings. Although linear models predicted a significant amount of variance in arousal ratings, they were unable to do so with valence ratings. We then used a neural network to provide a non-linear account of the ratings. The network was trained on the mean ratings of eight of the 12 excerpts and tested on the remainder. Performance of the neural network confirms that physiological responses alone can be used to predict musically induced emotion. The non-linear model derived from the neural network was more accurate than linear models derived from multiple linear regression, particularly along the valence dimension. A secondary analysis allowed us to quantify the relative contributions of inputs to the non-linear model. The study represents a novel approach to understanding the complex relationship between physiological responses and musically induced emotion. 23660128 The plant cytoskeleton controls regulatory volume increase. The ability to adjust cell volume is required for the adaptation to osmotic stress. Plant protoplasts can swell within seconds in response to hypoosmotic shock suggesting that membrane material is released from internal stores. Since the stability of plant membranes depends on submembraneous actin, we asked, whether this regulatory volume control depends on the cytoskeleton. As system we used two cell lines from grapevine which differ in their osmotic tolerance and observed that the cytoskeleton responded differently in these two cell lines. To quantify the ability for regulatory volume control, we used hydraulic conductivity (Lp) as readout and demonstrated a role of the cytoskeleton in protoplast swelling. Chelation of calcium, inhibition of calcium channels, or manipulation of membrane fluidity, did not significantly alter Lp, whereas direct manipulation of the cytoskeleton via specific chemical reagents, or indirectly, through the bacterial elicitor Harpin or activation of phospholipase D, was effective. By optochemical engineering of actin using a caged form of the phytohormone auxin we can break the symmetry of actin organisation resulting in a localised deformation of cell shape indicative of a locally increased Lp. We interpret our findings in terms of a model, where the submembraneous cytoskeleton controls the release of intracellular membrane stores during regulatory volume change. 23790087 Femtosecond electron solvation at the ionic liquid/metal electrode interface. Electron solvation is examined at the interface of a room temperature ionic liquid (RTIL) and an Ag(111) electrode. Femtosecond two-photon photoemission spectroscopy is used to inject an electron into an ultrathin film of RTIL 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide ([Bmpyr](+)[NTf2](-)). While much of current literature highlights slower nanosecond solvation mechanisms in bulk ionic liquids, we observe only a femtosecond response, supporting morphology dependent and interface specific electron solvation mechanisms. The injected excess electron is found to reside in an electron affinity level residing near the metal surface. Population of this state decays back to the metal with a time constant of 400 ± 150 fs. Electron solvation is measured as a dynamic decrease in the energy with a time constant of 350 ± 150 fs. We observe two distinct temperature regimes, with a critical temperature near 250 K. The low temperature regime is characterized by a higher work function of 4.41 eV, while the high temperature regime is characterized by a lower work function of 4.19 eV. The total reorganizational energy of solvation changes above and below the critical temperature. In the high temperature regime, the electron affinity level solvates by 540 meV at 350 K, and below the critical temperature, solvation decreases to 200 meV at 130 K. This study will provide valuable insight to interface specific solvation of room temperature ionic liquids. 23609812 Posterior Condylar Offset Does Not Correlate With Knee Flexion After TKA. Studies of medial and lateral femoral posterior condylar offset have disagreed on whether posterior condylar offset affects maximum knee flexion angle after TKA. We asked whether posterior condylar offset was correlated with knee flexion angle 1 year after surgery in (1) a PCL-retaining meniscal-bearing TKA implant, or in (2) a PCL-substituting mobile-bearing TKA implant. Knee flexion angle was examined preoperatively and 12 months postoperatively in 170 patients who underwent primary TKAs to clarify the effect of PCL-retaining (85 knees) and PCL-substituting (85 knees) prostheses on knee flexion angle. A quasirandomized design was used; patients were assigned to receive one or the other implant using chart numbers. A quantitative three-dimensional technique with CT was used to examine individual changes in medial and lateral posterior condylar offsets. In PCL-retaining meniscal-bearing knees, there were no significant correlations between posterior condylar offset and knee flexion at 1 year. In these knees, the mean (± SD) postoperative differences in medial and lateral posterior condylar offsets were 0.0 ± 3.6 mm and 3.8 ± 3.6 mm, respectively. The postoperative change in maximum knee flexion angle was -5° ± 15°. In PCL-substituting rotating-platform knees, similarly, there were no significant correlations between posterior condylar offset and knee flexion 1 year after surgery. In these knees, the mean postoperative differences in medial and lateral posterior condylar offsets were -0.5 ± 3.3 mm and 3.3 ± 4.2 mm, respectively. The postoperative change in maximum knee flexion angle was -2° ± 18°. Differences in individual posterior condylar offset with current PCL-retaining or PCL-substituting prostheses did not correlate with changes in knee flexion 1 year after TKA. We should recognize that correctly identifying which condyle affects the results of the TKA may be difficult with conventional radiographic techniques. Level II, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. 23881310 The Exocrine Pancreas: The Acinar-Ductal Tango in Physiology and Pathophysiology. There are many reviews of pancreatic acinar cell function and also of pancreatic duct function, but there is an almost total absence of synthetic reviews bringing the integrated functions of these two vitally and mutually interdependent cells together. This is what we have attempted to do in this chapter. In the first part, we review the normal integrated function of the acinar-ductal system, with particular emphasis on how regulation of one type of cell also influences the other cell type. In the second part, we review a range of pathological processes, particularly those involved in acute pancreatitis (AP), an often-fatal human disease in which the pancreas digests itself, in order to explore how malfunction of one of the cell types adversely affects the function of the other. 23631374 X-ray structure analysis of a solid solution of milbemycins A3 and A4. Milbemycins A3 and A4 are pharmaceutically and agriculturally useful macrolides isolated from Streptomyces species. The molecular structures of the title compounds were unambiguously established by a single crystal X-ray analysis of the solid solution of both compounds. The crystals present trigonal system, space group P32 with Z = 3, unit cell dimensions: a = 12.2211(4), c = 17.5372(7) Å; V = 2268.4(1) Å(3), μ = 0.082 mm(- 1); d = 1.183 g cm(- 3). An interesting system of intramolecular hydrogen bonds and weak intermolecular CH…O type hydrogen bond was observed in the solid state. 23731078 IL-17 targeted therapies for psoriasis. Introduction: Psoriasis is a chronic, disabling, inflammatory skin disease whose pathogenesis still remains to be fully elucidated. Genetic and environmental factors induce an immune response mediated by several cytokines and chemokines, including IL-17A. Areas covered: Emerging evidence now suggests that IL-17A is central in the pathogenesis of psoriasis. Three agents neutralizing IL-17 (i.e., secukinumab and ixekizumab) or antagonizing its receptor (i.e., brodalumab) are in development and are being studied in Phase III clinical trials to evaluate their overall efficacy and safety. However, Phase II results of IL-17 blockade with each of these agents has shown a marked improvement of disease severity, thus confirming the pathogenic relevance of IL-17 in mediating crucial inflammatory circuits in psoriasis. Expert opinion: Anti-IL-17 agents are likely to become important future therapeutics in this disease and the may potentially impact on cardiovascular diseases, arthritis and other comorbidities associated with psoriasis. 23948658 An independent validation association study of carcass quality, shear force, intramuscular fat percentage and omega-3 polyunsaturated fatty acid content with gene markers in Australian lamb. Previous association studies revealed several single nucleotide polymorphisms (SNPs) that explained the observed phenotypic variation for meat tenderness and long-chain omega-3 polyunsaturated fatty acid (PUFA) content of Australian lamb. To confirm the validity of these associated SNPs at predicting meat tenderness and omega-3 PUFA content, an independent validation study was designed. The OvineSNP50 genotypes of these animals were used to impute the 192 SNP Meat Quality Research (MQR) panel genotypes on nearly 6200 animals from the Cooperative Research Centre for Sheep Industry Innovation Information Nucleus Flock and Sheep Genomics Falkiner Memorial Field Station flock. Association analysis revealed numerous SNP from the 192 SNP MQR panel that were associated with carcass quality - fat depth at the C-site and eye muscle depth; shear force at day 1 and day 5 after slaughter (SF1 and SF5); and omega-3 PUFA content at P<0.01. However, 1 SNP was independently validated for SF5 (i.e. CAST_101781475). The magnitude of the effect of each significant SNP and the relative allele frequencies across Merino-, Maternal- and Terminal-sired progeny was determined. The independently validated SNP for SF5 and the associated SNP with omega-3 PUFA content will accelerate efforts to improve these phenotypic traits in Australian lamb. 23829555 Shaping legal abortion provision in Ghana: using policy theory to understand provider-related obstacles to policy implementation. Unsafe abortion is a major public health problem in Ghana; despite its liberal abortion law, access to safe, legal abortion in public health facilities is limited. Theory is often neglected as a tool for providing evidence to inform better practice; in this study we investigated the reasons for poor implementation of the policy in Ghana using Lipsky's theory of street-level bureaucracy to better understand how providers shape and implement policy and how provider-level barriers might be overcome. In-depth interviews were conducted with 43 health professionals of different levels (managers, obstetricians, midwives) at three hospitals in Accra, as well as staff from smaller and private sector facilities. Relevant policy and related documents were also analysed. Findings confirm that health providers' views shape provision of safe-abortion services. Most prominently, providers experience conflicts between their religious and moral beliefs about the sanctity of (foetal) life and their duty to provide safe-abortion care. Obstetricians were more exposed to international debates, treaties, and safe-abortion practices and had better awareness of national research on the public health implications of unsafe abortions; these factors tempered their religious views. Midwives were more driven by fundamental religious values condemning abortion as sinful. In addition to personal views and dilemmas, 'social pressures' (perceived views of others concerning abortion) and the actions of facility managers affected providers' decision to (openly) provide abortion services. In order to achieve a workable balance between these pressures and duties, providers use their 'discretion' in deciding if and when to provide abortion services, and develop 'coping mechanisms' which impede implementation of abortion policy. The application of theory confirmed its utility in a lower-middle income setting and expanded its scope by showing that provider values and attitudes (not just resource constraints) modify providers' implementation of policy; moreover their power of modification is constrained by organisational hierarchies and mid-level managers. We also revealed differing responses of 'front line workers' regarding the pressures they face; whilst midwives are seen globally as providers of safe-abortion services, in Ghana the midwife cadre displays more negative attitudes towards them than doctors. These findings allow the identification of recommendations for evidence-based practice. 23743535 Is it necessary to use three mandatory loading doses when commencing therapy for neovascular age-related macular degeneration using bevacizumab? (BeMOc Trial). PurposeTo determine whether a Pro Re Nata (PRN) regimen with three initial mandatory loading doses results in better functional and anatomical outcome compared with a PRN regimen without initial loading when using intravitreal bevacizumab in patients with minimal classic or occult choroidal neovascularisation secondary to age-related macular degeneration.MethodsPatients were randomised (1 : 1) to Loading (LD group) or No Loading (NLD group) and treated with open label intravitreal bevacizumab. In the LD group, patients received two mandatory doses after the baseline dose before entering the PRN phase and in the NLD group, patients did not receive mandatory doses after the baseline dose. Six-weekly evaluations were performed up to week 54 and retreatment was done based on OCT criteria. Visual stability and reduction in central retinal thickness were compared between groups.Results49 patients were in the NLD group and 50 patients were in the LD group. At the 12-month end point, 84% of the patients in the LD group achieved visual stability (<15 letter loss) compared with 67% of the patients in the NLD group (P<0.05). The mean reduction in central macular thickness was 105.35 μm in the LD group and 81.45 μm in the NLD group (P>0.05). There was no significant difference in scores of VFQ-25 questionnaire testing between the two groups and no serious ocular or systemic side effects were observed.ConclusionThe results supported our hypothesis that a loading dose leads to slightly better visual stability in terms of proportions of patients experiencing moderate visual loss, but did not support the hypothesised difference in anatomical outcome. 23948320 Forensic DNA methylation profiling-Potential opportunities and challenges. Investigating the DNA sequence is the most powerful tool that can be employed in forensic genetics for the identification of an individual, or to determine specific ethnic and phenotypic characteristics. However, there are also other heritable changes in gene function or cellular phenotype which are caused by mechanisms other than differences in the DNA sequence itself. Over the last decade it has become evident that epigenetic markers can be of substantial forensic significance. The determination of possible alterations in DNA methylation patterns could aid various forensic investigations, such as differentiating monozygotic twins, identifying the tissue source or determining the age of tissue donors. This review aims to give a brief overview of the possible advantages of forensic DNA methylation profiling and sheds light on the limitations of this approach. 23890278 Clinical review: Glucose control in severely burned patients - current best practice. Tight glucose control changed the way many burn centers practice burn ICU care. However, after the initial impressive data, various clinical trials followed that showed mixed results. The objective of the present review is to discuss recent studies in the area of burn and critical care, and to identify the current best practice for current burn care providers. We reviewed relevant publications from PubMed and selected high-impact publications on tight glycemic control in various patient populations with a focus on burn patients. We conclude that in burns there seems to be a signal that insulin administration to a target range of 130 to 150 mg/dl is beneficial in terms of morbidity and mortality without the risk of hypoglycemia. 23921546 The ultrasound elastography inverse problem and the effective criteria. The elastography (elasticity imaging) is one of the recent state-of-the-art methods for diagnosis of abnormalities in soft tissue. The idea is based on the computation of the tissue elasticity distribution. This leads to the inverse elasticity problem; in that, displacement field and boundary conditions are known, and elasticity distribution of the tissue is aimed for computation. We treat this problem by the Gauss-Newton method. This iterative method results in an ill-posed problem, and therefore, regularization schemes are required to deal with this issue. The impacts of the initial guess for tissue elasticity distribution, contrast ratio between elastic modulus of tumor and normal tissue, and noise level of the input data on the estimated solutions are investigated via two different regularization methods. The numerical results show that the accuracy and speed of convergence vary when different regularization methods are applied. Also, the semi-convergence behavior has been observed and discussed. At the end, we signify the necessity of a clever initial guess and intelligent stopping criteria for the iterations. The main purpose here is to highlight some technical factors that have an influence on elasticity image quality and diagnostic accuracy, and we have tried our best to make this article accessible for a broad audience. 23571022 Intra- and interday reliability of voluntary and electrically stimulated isometric contractions of the quadriceps femoris. The reliability of voluntary and electrically stimulated isometric contractions of m. quadriceps femoris of male participants (n=10; age 30±8years; height 1.79±0.05m; body mass 79.4±8.3kg) was investigated using ratio limits of agreement (LoA) on a time scale common to examine recovery from muscle damaging exercise. No systematic changes in reliability occurred over time (baseline versus 2, 24, 48, and 72h). Maximal voluntary contraction (MVC) and interpolated twitch technique (ITT) showed no mean bias (P>0.05) with 95% LoA of ±12.7 and ±5.4, respectively. Resting twitch and potentiated doublet peak force showed no mean bias (P>0.05). However, 95% LoA were smaller for the doublet (±13.9) than the twitch (±32.0). Twitch and doublet rates showed similar trends. Ratio of low (20Hz) to high (50Hz) frequency forces showed no mean bias (P>0.05) and 95% LoA of (±9.2). However, there was significant mean bias (P<0.05) and wider 95% LoA for peak force, contraction and relaxation parameters of the low and high frequency forces. In conclusion, MVC, ITT, potentiated doublet and the ratio of low to high frequency forces are recommended to most reliably examine functional muscle recovery between 2 and 72h after damaging exercise. 23556438 Rovibrational Energies of the Hydrocarboxyl Radical from a RCCSD(T) Study. A RCCSD(T)/cc-pVQZ potential energy surface is constructed for the HOCO radical in the ground electronic state and used to compute rotation-vibration levels of HOCO and DOCO. Two numerical strategies are employed to study in detail the wave function properties. The importance of stretch-bend coupling, such as ν4/ν5 and ν3/ν4, for the internal dynamics is demonstrated. The rotational constants computed for the vibrational ground state of trans and cis conformers are in good agreement with experimental values. 23839705 Warfarin and Statins are Associated with Hematoma Volume in Primary Infratentorial Intracerebral Hemorrhage. Despite extensive studies of supratentorial intracerebral hemorrhage (ICH), limited data are available on determinants of hematoma volume in infratentorial ICH. We therefore aimed to identify predictors of infratentorial ICH volume and to evaluate whether location specificity exists when comparing cerebellar to brainstem ICH. We undertook a retrospective analysis of 139 consecutive infratentorial ICH cases (95 cerebellar and 44 brainstem ICH) prospectively enrolled in a single-center study of ICH. ICH volume was measured on the CT scan obtained upon presentation to the Emergency Department using an established computer-assisted method. We used linear regression to identify determinants of log-transformed ICH volume and logistic regression to evaluate their role in surgical evacuation. Median ICH volumes for all infratentorial, cerebellar, and brainstem ICH were nine [interquartile range (IQR), 3-23], ten (IQR, 3-25), and eight (IQR, 3-19) milliliters, respectively. Thirty-six patients were on warfarin treatment, 31 underwent surgical evacuation, and 65 died within 90 days. Warfarin was associated with an increase in ICH volume of 86 % [β = 0.86, standard error (SE) = 0.29, p = 0.003] and statin treatment with a decrease of 69 % (β = -69, SE = 0.26, p = 0.008). Among cerebellar ICH subjects, those on warfarin were five times more likely to undergo surgical evacuation (OR = 4.80, 95 % confidence interval 1.63-14.16, p = 0.005). Warfarin exposure increases ICH volume in infratentorial ICH. Further studies will be necessary to confirm the inverse relation observed between statins and ICH volume. 23815351 Good agreement between minimal erythema dose test reactions and objective measurements: an in vivo study of human skin. The erythema resulting from the minimal erythema dose (MED) test is subjectively assessed. The evaluator visually grades erythema on an ordinal scale. Both intra- and interobserver variation have been found for this erythema assessment. We wanted to examine if objective measurements could be used to confirm the subjective finding. One hundred two ultraviolet radiation (UVR)-exposed skin sites on the backs of 17 healthy volunteers were assessed. Erythema was visually graded according to a 5-point scale [0, (+), 1+, 2+, 3+] and objectively measured by a skin reflectance meter. Skin water content was objectively measured by tissue dielectric constant measurements. The relationship between subjective assessments and objective measurements of erythema was found to be linear (R(2)  = 0.482, P < 0.0001). A positive correlation was found between subjective assessments of erythema and objective measurements of water content (Spearman's Rho = 0.414, P < 0.0001). Water content in categories 2+ and 3+ of the subjective erythema assessments differed significantly from the lesser categories (P < 0.0001). A linear relationship was found between the objective measurements of erythema and water content (R(2)  = 0.241, P < 0.0001). Objective measurements of skin erythema and water content after UV exposure were in good agreement with the subjective assessments of erythema, but showed considerable interpersonal variation. 23894513 Plasminogen-Based Capture Combined with Amplification Technology for the Detection of PrP(TSE) in the Pre-Clinical Phase of Infection. Variant Creutzfeldt-Jakob disease (vCJD) is a neurodegenerative infectious disorder, characterized by a prominent accumulation of pathological isoforms of the prion protein (PrP(TSE)) in the brain and lymphoid tissues. Since the publication in the United Kingdom of four apparent vCJD cases following transfusion of red blood cells and one apparent case following treatment with factor VIII, the presence of vCJD infectivity in the blood seems highly probable. For effective blood testing of vCJD individuals in the preclinical or clinical phase of infection, it is considered necessary that assays detect PrP(TSE) concentrations in the femtomolar range. We have developed a three-step assay that firstly captures PrP(TSE) from infected blood using a plasminogen-coated magnetic-nanobead method prior to its serial amplification via protein misfolding cyclic amplification (PMCA) and specific PrP(TSE) detection by western blot. We achieved a PrP(TSE) capture yield of 95% from scrapie-infected material. We demonstrated the possibility of detecting PrP(TSE) in white blood cells, in buffy coat and in plasma isolated from the blood of scrapie-infected sheep collected at the pre-clinical stage of the disease. The test also allowed the detection of PrP(TSE) in human plasma spiked with a 10(-8) dilution of vCJD-infected brain homogenate corresponding to the level of sensitivity (femtogram) required for the detection of the PrP(TSE) in asymptomatic carriers. The 100% specificity of the test was revealed using a blinded panel comprising 96 human plasma samples. We have developed a sensitive and specific amplification assay allowing the detection of PrP(TSE) in the plasma and buffy coat fractions of blood collected at the pre-clinical phase of the disease. This assay represents a good candidate as a confirmatory assay for the presence of PrP(TSE) in blood of patients displaying positivity in large scale screening tests. 23528715 Physiological costs and carry-over effects of avian interspecific brood parasitism influence reproductive tradeoffs. Although models of co-evolution between brood parasites and their hosts primarily focus upon the cost to hosts in the current reproductive bout, the impact of brood parasitism may carry over to future reproductive attempts by altering resource allocation. Glucocorticoid stress hormones help mediate resource allocation to reproduction, yet they have rarely been examined in brood parasitic systems. Here we determined if shifts in parental care and corticosterone had carry-over effects on future reproductive effort in the rufous-and-white wren (Thryophilus rufalbus), a host of the Central American striped cuckoo (Tapera naevia). We found that parasitized parents had significantly higher stress-induced, but not baseline, corticosterone than natural parents during the fledgling stage, which was associated with changes in parental care. The high investment in current reproduction while parasitized may be due to the value of fledged chicks in tropical systems. This maladaptive response by parasitized parents was associated with delayed re-nesting and a reduced likelihood of nesting in the subsequent breeding season. Although a reduction in future reproductive effort can result from a combination of factors, this work suggests that fitness costs of brood parasitism are mediated by changes in corticosterone and parental care behavior that carry over into subsequent breeding seasons. 23968667 Risk Factors for Squamous Cell Carcinoma, A Study by the National Dermatology Centre of Colombia. Nonmelanoma skin cancer is the most common malignancy in white individuals. The risk factors for squamous cell carcinoma, which belongs to the family of nonmelanoma skin cancers, have not been studied in Colombia. To determine the risk factors for squamous cell carcinoma in patients at a national referral center for skin diseases in Colombia. We conducted a case-control study that evaluated sociodemographic, epidemiological, and clinical factors among 332 individuals. Risk was calculated as odds ratio (ORs) using the multivariate conditional logistic regression analysis method. The following risk factors were identified: family history of skin cancer (OR, 6.55; 95% CI, 1.4-28.9), living in a rural area after the age of 30 years (OR, 3.13; 95% CI, 1.3-7.2), a lifetime working outdoors (OR, 2.98; 95% CI, 1.5-5.7), smoking more than 10 cigarettes a day (OR, 2.96; 95% CI, 1.3-6.5), actinic conjunctivitis (OR, 2.68; 95% CI, 1.2-5.9), poikiloderma of Civatte (OR, 3.29; 95% CI, 1.7-6.1), numerous facial actinic keratoses (OR, 9.23; 95% CI, 4.9-17.1), and numerous freckles (OR, 3.68; 95% CI, 1.3-10.1). We have documented clinical characteristics and personal history factors that should guide the physician in making decisions on the preventive and follow-up measures to be adopted for individuals at risk of squamous cell carcinoma. These findings may help guide policy for controlling the disease using local information. 23871558 Preparation of a polyhedral oligomeric silsesquioxane-based perfluorinated monolithic column. A monolithic column with high affinity to fluorous compounds was prepared using a polyhedral oligomeric silsesquioxane (POSS) reagent as the cross-linker and pentadecafluorooctyl methacrylate (PDFOMA) as the functionality monomer. The pore properties and permeability could be tuned by the composition of the polymerization mixture. The characterization and evaluation results revealed that the obtained POSS-PDFOMA hybrid monolith owned the merits of POSS and PDFOMA with good mechanical stability, no residual silanol and high affinity to fluorous compounds. A series of perfluoroalkyl methacrylates were baseline resolved on the optimized monolithic column under isocratic elution of 70% acetonitrile aqueous solution. Such a resolution could not be achieved on a silica-based C18 monolithic column. A column efficiency of 30000N/m was observed. In addition, several perfluoroalkyl sulfonates were also baseline separated on the fluorous monolith applying 0.1% (v/v) acetic acid aqueous solution containing 75% acetonitrile as mobile phase without the addition of ammonium. 23954793 High dose remifentanil increases myocardial oxidative stress and compromises remifentanil infarct-sparing effects in rats. Chronic administration of high dose opioids such as morphine is known to create intracellular oxidative stress via an opioid receptor dependent mechanism and this can interfere with cellular function. This study aimed at examining whether such changes can occur following short term exposure to high concentration of remifentanil, a potent short acting opioid. We conducted a experimental study using rat myocardium and systematically quantified tissue levels of superoxide anions, malondialdehyde (MDA) and nitrotyrosine following exposure to increasing duration (15min, 1 or 2h) or escalating doses of remifentanil (1μg, 5μg, 10μg or 20μg/kg/min). Concurrently the susceptibility of the heart to ischaemia reperfusion injury was assessed under the similar conditions. For any given duration of remifentanil infusion, there was increasing superoxide anions generated as the dose of remifentanil was increased. MDA concentrations were significantly increased when the animal was exposed to 10μg/kg/min for 2h or 20μg/kg/min for any duration. There was a trend towards an increased nitrotyrosine concentration with increasing dose of remifentanil, becoming significant when the dose was 20μg/kg/min. The infarct limiting ability of remifentanil was compromised when the dihydroethidium fluorescence positive cell percentage exceeded 50%, MDA concentration greater than 2nmol/mg of protein and nitrotyrosine content exceeding 1.5μg/mg of protein. Short term high dose opioid exposure can induce oxidative changes seen previously only with chronic opioid use and this high oxidative stress environment corrupts the heart's sensitivity to be preconditioned by opioids. 23313663 Benzo[α]pyrene repressed DNA mismatch repair in human breast cancer cells. DNA mismatch repair (MMR) has been recently implicated to play a significant role in breast cancer progression, however, few studies have examined how various carcinogens affect MMR system in breast cancer cells. The present study employs an in vivo MMR assay developed in our laboratory to assess how prevalent environmental carcinogens such as polycyclic aromatic hydrocarbons (PAHs) affect MMR activity in human breast carcinoma cells. Specifically, we quantitatively measured MMR activity in ZR75-1 cells after they were exposed to benzo[α]pyrene (BaP), a prototypical PAH, at various concentrations. Our findings revealed that BaP exposure at high concentrations of 1 and 5 μM induced significant inhibition of MMR activity in ZR75-1 cells. Further, we also identified that MMR repression induced by 5 μM BaP was mediated through one of the MMR key proteins MSH6 as significant reduction in protein level was detected by western blot. More importantly, ectopic expression of hMSH6 restored MMR activity in the BaP treated cells to the same level as in the control cells. Impaired MMR plays an important role in carcinogenesis. Our findings suggest that BaP induced repression of MMR activity may also contribute to the progression of mutagenesis event. Meanwhile, the present study also for the first demonstrated that our in vivo DNA MMR assay can be applied in the field of environmental toxicology. 23106125 The "Reading the Mind in the Eyes" test: Systematic review of psychometric properties and a validation study in Italy. Introduction. The "Reading the Mind in the Eyes" test (henceforth, Eyes test) is a simple but advanced Theory of Mind test, and it is widely used across different cultures. This study assessed the reliability and construct (convergent and discriminant) validity of the Eyes test in Italy. Methods. A sample of 18- to 32-year-old undergraduate students of both sexes (N=200, males=46%) were invited to fill in the Italian version of the Eyes test, the Empathy Quotient (EQ), the Toronto Alexithymia Scale (TAS), and the Marlowe-Crowne Social Desirability Scale (SDS). Results. Internal consistency (Cronbach's alpha) was .605. Confirmatory factor analysis provided evidence for a unidimensional model, with maximal weighted internal consistency reliability=.719. Test-retest reliability for the Eyes test, as measured by intraclass correlation coefficient, was .833 (95% confidence interval=.745 to .902). Females scored significantly higher than males on both the Eyes test and the EQ, replicating earlier work. Those participants who scored lower than 30 on the EQ (n=10) also scored lower on the Eyes test than those who did not (p<.05). Eyes test scores were not related to social desirability. Conclusions. This study confirms the validity of the Eyes test. Both internal consistency and test-retest stability were good for the Italian version of the Eyes test. 23827217 CCK-8S increases the firing frequency of CCK-positive neurons and facilitates excitatory synaptic transmission in primary rat hippocampal neurons. The neuropeptide cholecystokinin octapeptide (CCK) is involved in a variety of brain functions. In the hippocampus, most CCK is released from CCK-positive (CCK+) neurons, but the effects of CCK on CCK+ neurons are poorly understood. We employed primary hippocampal cultures to explore the modulatory effect of CCK on CCK+ neurons. CCK-8S (0.2μM) was added to the culture medium from day in vitro 2 (DIV-2) to DIV-11. An adenovirus integrated with the CCK promoter was used to label CCK+ neurons. Whole-cell patch clamp recording was carried on to record the electrophysiology properties. The results show that: (1) CCK-8S significantly decreased membrane capacity but increased the membrane resistance (Rm) of CCK+ neurons, (2) CCK-8S increased action potential (AP) firing frequency of CCK+ neurons but did not affect the firing pattern, (3) CCK-8S facilitated CCK+ neuron excitatory synaptic transmission but attenuated inhibitory synaptic transmission, and (4) the expression of postsynaptic density-95 (PSD-95) in cultured hippocampal neurons was elevated by CCK-8S treatment. Our results demonstrate that CCK-8S significantly alters the membrane electrophysiological characteristics and synaptic activity of cultured hippocampal CCK+ neurons. These findings may enhance our understanding of the modulatory effect of CCK in the brain. 23789878 Influence of humic Acid on algal uptake and toxicity of ionic silver. The biogeochemical cycle of silver has been profoundly disturbed by various anthropogenic activities. To better understand the relationship among silver speciation, bioavailability, and toxicity in freshwaters, we have studied the short-term uptake of silver by two species of green algae, Chlamydomonas reinhardtii and Pseudokirchneriella subcapitata, in the presence or absence of a well-characterized humic acid (Suwannee River Humic Acid, SRHA). The free Ag(+) concentrations in the exposure solutions were determined using an equilibrium ion-exchange technique. According to the biotic ligand model, for a given free metal ion concentration, metal uptake should remain the same in the presence or absence of humic acid. However, short-term silver uptake in the presence of SRHA was greater than anticipated on the basis of free Ag(+) concentration. Subsequent determination of silver subcellular distribution revealed that significantly more silver was present in the "cell debris" fraction (known to contain the cell wall and fragmented membranes) in the presence of SRHA than in its absence. Finally, this increase in silver uptake in the presence of humic acid did not result in decreased algal growth. These results suggest that the increase in silver uptake observed in the presence of SRHA is surface-bound, not truly internalized. 23830769 Influence of kinesiologic tape on postoperative swelling, pain and trismus after zygomatico-orbital fractures. Surgical treatment of zygomatico-orbital (ZO) fractures is a common procedure in maxillofacial surgery. Often accompanied by pain, trismus and swelling, postoperative morbidity is a major disadvantage, affecting patients' quality of life. The appliance of kinesiologic tape (KT) improves the blood and lymph flow, removing congestions of lymphatic fluid and haemorrhages. The aim of this study was to find out if the application of kinesiologic tape prevents or improves swelling, pain and trismus after zygomatico-orbital fracture surgery, improving patients' postoperative quality of life. A total of 30 patients were assigned for treatment of zygomatico-orbital fractures and were randomly divided into treatment either with or without kinesiologic tape. Tape was applied directly after surgery and maintained for at least 5 days postoperatively. Facial swelling was quantified using a five-line measurement at six specific time points. Pain and degree of mouth opening was measured. Patient's subjective feeling and satisfaction was queried. The results of this study show that application of kinesiologic tape after zygomatico-orbital surgery significantly reduced the incidence of swelling with an earlier swelling maximum, and decreased the maximum turgidity for more than 60% during the first 2 days after surgery. Although, kinesiologic tape has no significant influence on pain control and trismus, mouth opening increased earlier after operation in the kinesiologic tape group compared to the no-kinesiologic tape group. Furthermore, patients with kinesiologic tape felt significantly lower morbidity than those without kinesiologic tape. Therefore kinesiologic tape is a promising, simple, less traumatic, economical approach, which is free from adverse reaction and improves patients' quality of life. 23279720 Pharmaco-economic analysis of direct medical costs of metastatic colorectal cancer therapy with XELOX or modified FOLFOX-6 regimens: Implications for health-care utilization in Australia. The objective of this economic evaluation, which was based on patients from two randomized controlled clinical trials (NO16966 and NO16967), was to compare direct medical costs to the Australian health-care system of capecitabine plus oxaliplatin (XELOX) and bolus and/or infusional 5-fluorouracil (5-FU) plus folinic acid combined with oxaliplatin (modified [m] FOLFOX-6) in first-line and second-line treatment of advanced or metastatic colorectal cancer (mCRC). Direct medical costs were estimated for five treatment settings from a public and private hospital. The costs included in evaluation were for drug acquisition, preparation (oxaliplatin, bolus and infusional 5-FU), administration and wastage. The cost of drug acquisition was calculated based on dosage data and the mean number of treatment cycles from the pivotal studies NO16966 and NO16967. There were no costs associated with preparing capecitabine and leucovorin. An oncology grouping and costing study was performed to determine the relevant administration costs associated with central venous access devices, their placement, maintenance and removal (for oxaliplatin administration) and the continuous infusion of 5-FU via a continuous ambulatory delivery device pump or infuser. This economic evaluation has shown that treating mCRC patients with XELOX in the first and second-line settings results in average cost savings of $9110 and $7113, respectively, compared with mFOLFOX-6. A multi-way sensitivity analysis demonstrated that the use of XELOX remained cost-saving from an Australian government health budget perspective. The use of XELOX, compared with mFOLFOX-6, for the treatment of mCRC is cost-saving in the Australian government health budget. 23683169 Angiogenin outperforms VEGF, EPCs and CECs in predicting Dukes' and AJCC stage in colorectal cancer. Circulating endothelial cells (CECs), endothelial progenitor cells (EPCs), Willebrand factor (vWf), soluble E-selectin, vascular endothelial growth factor (VEGF) and angiogenin are of interest in cancer vascular biology. However, few studies have looked at more than one in combination. We set out to determine which would be best in predicting the Dukes' and American Joint Committee on Cancer (AJCC) scores in colorectal cancer patients. We recruited 154 patients with colorectal cancer, 29 healthy controls and 26 patients with benign bowel disease. CD34(+) /CD45(-) /CD146(+) CECs and CD34(+) /CD45(-) /CD309[KDR](+) EPCs were measured by flow cytometry, plasma markers by ELISA. All research indices were raised in colorectal cancer (P < 0·05) compared to control groups. Although CECs (P < 0·05), EPCs (P < 0·01) and angiogenin (P < 0·01) increased stepwise across the four Dukes' stages and four AJCC stages, only angiogenin remained significant in multiple regression analysis (P = 0·003 for Dukes, P = 0·01 for AJCC). Angiogenin levels were higher in Dukes' stages C and D compared to stage A, and AJCC stages 4-6 and 7-10 compared to stage 1 (all P < 0·05). Adding a second research marker to angiogenin did not markedly improve this relationship. Although we found disturbances in endotheliod cells and plasma markers of the endothelium and growth factors, only angiogenin levels were independently associated with progression of the Dukes' stage and AJCC stage, with the association with Duke's stage being stronger. We suggest that angiogenin is a potential biomarker in risk stratification for colorectal cancer, and may aid clinical decision making. 23531031 HISTONE DEACETYLASE INHIBITION AFFECTS SODIUM IODIDE SYMPORTER (NIS) EXPRESSION AND INDUCES ¹³¹I CYTOTOXICITY IN ANAPLASTIC THYROID CANCER CELLS. Background: Anaplastic thyroid cancers (ATC) represent only 1-2% of all thyroid tumors, but they account for up to 50% of the mortality. Treatment of differentiated thyroid carcinomas is well standardized and the use of radioiodine represents an essential step; in contrast, there is no standardized therapeutic approach for anaplastic tumors and their prognosis is poor. The resistance of anaplastic thyroid cancer to radioiodine treatment is principally due to the absence of expression of the sodium iodide symporter (NIS), mainly due to epigenetic silencing. The acetylation status of histones is involved in the epigenetic control of gene expression and is usually disrupted in advanced thyroid cancer. Histone deacetylase inhibitors have been demonstrated as potent anticancer drugs with several different effects on cell viability and differentiation. Methods: Stabilized anaplastic thyroid cancer cell lines (BHT-101 and CAL-62) and primary cultures from patients who underwent thyroidectomy for anaplastic thyroid cancer were treated with the histone deacetylase inhibitor LBH589. After treatment, we evaluated the expression and function of NIS. Gene expression was evaluated by real-time PCR (RT-PCR); NIS promoter activity was determined with a luciferase reporter assay; and protein expression was assessed through immunofluorescence. We tested the protein function by 125I uptake and efflux experiments; finally the cytotoxic effect of 131I was determined with a clonogenic assay. Results: Our results demonstrate that treatment with LBH589 leads to NIS RNA expression as shown by RT-PCR and luciferase assay, and to protein expression as determined by immunofluorescence in vitro and by immunohistochemistry in xenograft tumors. Moreover, 125I uptake and efflux experiments show the correct protein function and iodine retention, that translate into cytotoxicity effects, as demonstrated by a clonogenic assay with 131I . Conclusions: This study supplies a new potential strategy for the treatment of ATC by modifying gene expression with the aim of inducing responsiveness towards radioiodine therapy. 22810210 Aortic artery distensibility shows inverse correlation with heart rate variability in elderly non-hypertensive, cardiovascular disease-free individuals: the Ikaria Study. The aim of this study was to evaluate the relation between aortic artery distensibility, expressed by pulse pressure (PP) and autonomic nervous system function expressed by heart rate variability (HRV), among elders. During 2009, 469 individuals (50 % males, mean age 75 ± 6 years old), permanent inhabitants of Ikaria Island, were enrolled. Among several sociodemographic, bioclinical, lifestyle, and dietary characteristics, and biochemical parameters related to cardiovascular risk, a digital, standard, 12-lead electrocardiogram (ECG) and 5-min ECG monitoring were recorded. Smart ECG measurement and interpretation programs were used for the automated measurement and interpretation of ECG intervals. Autonomic nervous system tone was estimated with the HRV-standard deviation of normal to normal intervals (SDNN)-in surface ECG. Pulse pressure was calculated as the difference between systolic and diastolic blood pressures. Pulse pressure showed a positive association with age, systolic blood pressure levels, and presence of diabetes mellitus (all P < 0.001) and an inverse correlation with logSDNN. Multiadjusted logistic regression analysis revealed that 10-unit increase in SDNN values decreases by 26 % the likelihood of having PP above 70 mmHg; when the analysis was stratified according to hypertension status, the relationship remained significant only among non-hypertensive individuals. These data support the hypothesis that cardiac sympathovagal disturbance correlates with impaired elasticity properties of aorta, indicating parallel impairment in cardiac autonomic modulation and mechanical vessel wall properties in elderly non-hypertensive individuals. 23887931 The Evolution of an Academic-Community Partnership in the Design, Implementation, and Evaluation of Experience Corps(R) Baltimore City: A Courtship Model. Experience Corps Baltimore City (EC) is a product of a partnership between the Greater Homewood Community Corporation (GHCC) and the Johns Hopkins Center on Aging and Health (COAH) that began in 1998. EC recruits volunteers aged 55 and older into high-impact mentoring and tutoring roles in public elementary schools that are designed to also benefit the volunteers. We describe the evolution of the GHCC-COAH partnership through the "Courtship Model." We describe how community-based participatory research principals, such as shared governance, were applied at the following stages: (1) partner selection, (2) getting serious, (3) commitment, and (4) leaving a legacy. EC could not have achieved its current level of success without academic-community partnership. In early stages of the "Courtship Model," GHCC and COAH were able to rely on the trust developed between the leadership of the partner organizations. Competing missions from different community and academic funders led to tension in later stages of the "Courtship Model" and necessitated a formal Memorandum of Understanding between the partners as they embarked on a randomized controlled trial. The GHCC-COAH partnership demonstrates how academic-community partnerships can serve as an engine for social innovation. The partnership could serve as a model for other communities seeking multiple funding sources to implement similar public health interventions that are based on national service models. Unified funding mechanisms would assist the formation of academic-community partnerships that could support the design, implementation, and the evaluation of community-based public health interventions. 23835562 Glutathione modified gold nanorods with excellent biocompatibility and weak protein adsorption, targeting imaging and therapy toward tumor cells. The non-specific interaction between the surface of gold nanorods (GNRs) and biomolecules is a significant problem in hyperthermia applications. In this work, a novel surface modification strategy was performed using zwitterionic oxidized glutathione (GSSG) to modify the GNRs through robust Au-S bond formation. The GSSG-GNRs were stable in aqueous solution over a broad range of pH and high ionic strength values. Importantly, the glutathione coating greatly reduced non-specific protein adsorption on GNRs due to zwitterions. In order to target tumor sites, folic acid (FA) and Rhodamine B (RBITC) dye were conjugated to GSSG modified GNRs through the reaction between the activated carboxyl group and the amino group. The targeting of RBITC-FA-GSSG-GNRs in human cervical carcinoma cells (HeLa cells) with high-level folate receptor expression was confirmed using confocal laser scanning microscopy (CLSM) to excite Rhodamine B dye at 488 nm. The targeting photothermal therapy efficacy was monitored in real time with the multi-channel function of a confocal laser scanning microscope coupled with an 808 nm laser. The results indicate that the FA-GSSG-GNR hybrids demonstrate efficient photothermal conversion and excellent targeting hyperthermia, and are therefore suitable for biomedical applications. 23926121 A Validated Specific Stability-Indicating RP-HPLC Assay Method for Ambrisentan and Its Related Substances. A validated specific stability-indicating reverse-phase liquid chromatographic method was developed for the quantitative determination of Ambrisentan as well as its related substances in bulk samples, pharmaceutical dosage forms in the presence of degradation products and its related impurities. Forced degradation studies were performed on bulk samples of Ambrisentan as per the ICH-prescribed stress conditions using acid, base, oxidative, thermal stress and photolytic degradation to show the stability-indicating power of the LC method. Significant degradation in acidic, basic stress conditions was observed and no degradation was observed in other stress conditions. The chromatographic method was optimized using the samples generated from the forced degradation studies and the impurity-spiked solution. Good resolution between the peaks corresponds to Ambrisentan-related impurities and degradation products from the analyte were achieved on a SunFire C18 column using a mobile phase consisting of a mixture of potassium dihydrogen orthophosphate at a pH adjusted to 2.5 with ortho-phosphoric acid in water and a mixture of acetonitrile:methanol using a simple linear gradient. The detection was carried out at 225 nm. The limit of detection and the limit of quantification for the Ambrisentan and its related impurities were established. The stressed test solutions were assayed against the qualified working standard of Ambrisentan and the mass balance in each case was between 98.9 and 100.3%, indicating that the developed LC method was stability indicating. Validation of the developed LC method was carried out as per the ICH requirements. The developed method was found to be suitable to check the quality of bulk samples of Ambrisentan at the time of batch release and also during its storage (long-term and accelerated stability). 23929378 Contrast-Enhanced Ultrasound in Renal Transplants: Applications and Future Directions. The role of contrast-enhanced ultrasound (CEUS) in the detection and characterisation of focal liver lesions is well established 1. The renal applications of ultrasound contrast agents (UCAs) have increased and diversified since their introduction 234567 and recent guidelines have underlined their importance in the renal transplantation 4. Ultrasound contrast agents are simple to use and are well tolerated by patients 8. They can be safely used in renal impairment and obstruction unlike computed tomography (CT) and magnetic resonance (MR) agents. The imaging methods operate in real-time, often allowing a diagnosis to be promptly attained without exposure to ionising radiation, the fear of claustrophobia and at a lower cost than CT or MR imaging. Normally, B-mode and Doppler ultrasonography are the modality of choice for imaging the transplant kidney; excellent at assessing graft vascularity, diagnosing obstruction, detecting peri-nephric collections, focal masses and cysts. B-mode and Doppler ultrasonography have limitations in the assessment of the renal transplant microcirculation, cortical perfusion and deciphering focal masses or complex cysts. Before the introduction of UCAs focal lesions would be further characterised by contrast-enhanced CT and magnetic resonance (MR) imaging and there was no reliable non-invasive method of assessing the microcirculation.The application of CEUS in renal transplants highlights its versatility in immediate problem solving, without recourse to other potentially nephrotoxic agents. In addition CEUS can uniquely provide additional information not available from other modalities about the microcirculation. This is elegantly illustrated in the article by Fernandez et al. 9, where renal cortical necrosis is clearly depicted, allows immediate clinical management and adds to the knowledge in this expanding field.It is important to have a clear understanding of the background, current applications and potential for UCAs in the evaluation of the renal transplant to appreciate the value of CEUS in this domain.Microbubbles 1011 consist of a complex gas (e.g perfluorocarbon gas) stabilized by a phospholipid, or polymer shell and are of the size of a red blood cell, small enough to cross capillary beds but are too large to enter the interstitial fluid and therefore serve as pure intravascular agents. Renal ultrasound contrast agent dynamics differ from CT and MR contrast agents; UCAs remain entirely intravascular, are not excreted by the kidneys and therefore have no nephrographic or excretory phase. Following an intravenous bolus of UCAs the cortical phase (90 % of renal perfusion) begins 10 - 15 s after injection and lasts 20 - 40 s followed by a slower medullary phase lasting 45 - 120 s. The whole CEUS examination lasts about 3 min. CEUS allows imaging of vessels down to 100 μm in diameter which is well below the 1 mm resolution limit of conventional Doppler techniques. Therefore, CEUS is excellent at assessing the vascular complications of renal transplants, can exquisitely image the microcirculation and is very sensitive in the detection of infarction (which shows as a defect on all phases of enhancement). The defect on CEUS appears smaller than on the corresponding Doppler study because of this ability to depict flow in the microcirculation. Perfusion defects appear as focal wedge shaped areas of absent, decreased or delayed contrast enhancement compared with the adjacent renal parenchyma 12. As Fernandez et al. 9 confirm cortical necrosis is rendered more conspicuous by CEUS, making this an exquisite tool for bedside assessment of transplant vascularity.Quantitative methods can be applied to the kidney (native or transplant) using low or high acoustic power techniques 13. Since microbubbles are pure blood pool agents their transit through a region of interest can be followed using a low acoustic power technique. A time intensity curve (TIC) can be generated and a number of indices can be derived such as arrival time, time to peak intensity, area under the curve and rate of washout. Alternatively a high energy reperfusion technique can be used to measure perfusion 14. This may play a role in the assessment of transplant perfusion and the early detection of complications. B-mode ultrasound is poor at discriminating between the important causes of early graft dysfunction, especially acute tubular necrosis, rejection, and drug toxicity: these important distinctions still rely on biopsy. Recent work with UCAs has provided hope that functional data from microbubble contrast agent dynamics might produce useful information for their detection and differentiation, thus directing management and possibly avoiding the need for biopsy. Recent studies using microbubbles to measure renal flow in renal transplants have shown promising results in terms of monitoring graft function and directing anti-rejection therapy 1516171819.CEUS can be helpful in the characterisation of focal tumours in the native and transplant kidney, with typical differential hyper or hypo enhancement compared to the adjacent cortex. Cystic or avascular necrotic components can be distinguished from viable tumour as they appear as conspicuous signal voids. However, current CEUS guidelines 4 indicate that there are no specific patterns which reliably differentiate benign from malignant renal tumours. Although tumours are uncommon in renal transplants, cysts are frequently encountered and the superior spatial and temporal resolution of CEUS, real-time imaging allows visualisation of flow within septa, nodules and cyst wall which cannot be imaged on conventional US techniques, contrast-enhanced CT or contrast-enhanced MR 20212223. A CEUS Bosniak classification is likely more sensitive than a CT classification 23 when adapted for ultrasonography 21, and should be more accurate in the evaluation of cystic structures in the superficially located renal transplant. CEUS is usually unnecessary in the diagnosis of renal artery thrombosis or stenosis but can be used in difficult cases. CEUS is also excellent in assessing venous patency in renal transplants in problem cases and also distinguishing bland from tumour thrombus.In conclusion CEUS is a safe and excellent method for assessing the renal transplant vasculature and can be used in the diagnosis of renal infarction, renal arterial/venous thrombosis, as well as the non-invasive quantification of cortical perfusion and the microcirculation. CEUS provides unique functional data in grafts with promising results in terms of monitoring graft function and directing anti-rejection therapy. CEUS may characterise indeterminate renal lesions, complex cysts and focal inflammatory lesions to rival CT and MR imaging. The possibility of visualising and diagnosing acute cortical necrosis adds to the already formidable armamentarium of the physician who uses CEUS in assessing the renal transplant. All of this without any nephrotoxicity! 23411339 Colour and stability assessment of blue ferric anthocyanin chelates in liquid pectin-stabilised model systems. The formation of blue coloured ferric anthocyanin chelates and their colour stability during storage and thermal treatment were monitored in a pH range relevant to food (3.6-5.0). Liquid model systems were composed of different types of Citrus pectins, juices (J) and the respective phenolic extracts (E) from elderberry (EB), black currant (BC), red cabbage (RC) and purple carrot (PC) in the presence of ferric ions. For EB, BC and PC, pure blue colours devoid of a violet tint were exclusively observed for the phenolic extracts and at pH values ≥ 4.5 in model systems containing high methoxylated and amidated pectins, respectively. Colour and its stability strongly depended on the amount of ferric ions and the plant source; however, colour decay could generally be described as a pseudo-first-order kinetics. Despite optimal colour hues for RC-E and RC-J, storage and heat stabilities were poor. Highest colour intensities and best stabilities were observed for model systems containing PC-E at a molar anthocyanin:ferric ion ratio of 1:2. Ascorbic and lactic acids interfered with ferric ions, thus significantly affecting blue colour evolution and stability. Colour loss strongly depended on heat exposure with activation energies ranging between 60.5 and 78.4 kJ/mol. The comprehensive evaluation of the interrelationship of pigment source, pH conditions and pectin type on chelate formation and stability demonstrated that ferric anthocyanin chelates are promising natural blue food colourants. 23872125 Effects of Bacillus subtilis ANSB060 on growth performance, meat quality and aflatoxin residues in broilers fed moldy peanut meal naturally contaminated with aflatoxins. This study was conducted to investigate the toxic effects of aflatoxins and the efficacy of Bacillus subtilis ANSB060 for the amelioration of aflatoxicosis in broiler chickens. Six replicates of ten broilers each were assigned to one of seven dietary treatments, which were labeled C0 (basal diet); M0 (basal diet containing moldy peanut meal); C500 and C1000 (C0+500 or 1000g/t aflatoxin biodegradation preparations, composed mainly of ANSB060); and M500, M1000 and M2000 (M0+500, 1000 or 2000g/t aflatoxin biodegradation preparations). The concentrations of aflatoxin B1, B2, G1 and G2 in the moldy diets (M0, M500, M100 and M2000) fluctuated around 70.7±1.3, 11.0±1.5, 6.5±0.8 and 2.0±0.3μg/kg, respectively. The results showed that the M0 diet caused a significant decrease in average daily weight gain and increased feed requirements, with a gain ratio increasing from d 8 to 42, deterioration in meat quality and aflatoxin residues in broilers' livers as compared with the C0 diet. The addition of ANSB060 to the aflatoxin-contaminated diets offset these negative effects, leading to the conclusion that ANSB060 has a protective effect on growth performance and meat quality while reducing the amount of aflatoxin residues in the livers of broilers fed naturally moldy peanut meal. 23747422 Cytoplasmic proteasomes are not indispensable for cell growth in Saccharomyces cerevisiae. The 26S proteasome is an essential protease complex responsible for the degradation of ubiquitinated proteins in eukaryotic cells. In rapidly proliferating yeast cells, proteasomes are mainly localized in the nucleus, but the biological significance of the proteasome localization is still unclear. In this study, we investigated the relationship between the proteasome localization and the functions by the anchor-away technique, a ligand-dependent sequestration of a target protein into specific compartment(s). Anchoring of the proteasome to the plasma membrane or the ribosome resulted in conditional depletion of the nuclear proteasomes, whereas anchoring to histone resulted in the proteasome sequestration into the nucleus. We observed that the accumulation of ubiquitinated proteins in all the proteasome-targeted cells, suggesting that both the nuclear and cytoplasmic proteasomes have proteolytic functions and that the ubiquitinated proteins are produced and degraded in each compartment. Consistent with previous studies, the nuclear proteasome-depleted cells exhibited a lethal phenotype. In contrast, the nuclear sequestration of the proteasome resulted only in a mild growth defect, suggesting that the cytoplasmic proteasomes are not basically indispensable for cell growth in rapidly growing yeast cells. 23604799 Teleradiology from the provider's perspective-cost analysis for a mid-size university hospital. Real costs of teleradiology services have not been systematically calculated. Pricing policies are not evidence-based. This study aims to prove the feasibility of performing an original cost analysis for teleradiology services and show break-even points to perform cost-effective practice. Based on the teleradiology services provided by the Greifswald University Hospital in northeastern Germany, a detailed process analysis and an activity-based costing model revealed costs per service unit according to eight examination categories. The Monte Carlo method was used to simulate the cost amplitude and identify pricing thresholds. Twenty-two sub-processes and four staff categories were identified. The average working time for one unit was 55 (x-ray) to 72 min (whole-body CT). Personnel costs were dominant (up to 68 %), representing lower limit costs. The Monte Carlo method showed the cost distribution per category according to the deficiency risk. Avoiding deficient pricing by a likelihood of 90 % increased the cost of a cranial CT almost twofold as compared with the lower limit cost. Original cost analysis is possible when providing teleradiology services with complex statutory requirements in place. Methodology and results provide useful data to help enhance efficiency in hospital management as well as implement realistic reimbursement fees. • Analysis of original costs of teleradiology is possible for a providing hospital • Results discriminate pricing thresholds and lower limit costs to perform cost-effective practice • The study methods represent a managing tool to enhance efficiency in providing facilities • The data are useful to help represent telemedicine services in regular medical fee schedules. 23273219 Synthesis, molecular modeling and evaluation of novel N'-2-(4-benzylpiperidin-/piperazin-1-yl)acylhydrazone derivatives as dual inhibitors for cholinesterases and Aβ aggregation. To develop new drugs for treatment of Alzheimer's disease, a group of N'-2-(4-Benzylpiperidin-/piperazin-1-yl)acylhydrazones was designed, synthesized and tested for their ability to inhibit acetylcholinesterase, butyrylcholinesterase and aggregation of amyloid beta peptides (1-40, 1-42 and 1-40_1-42). The enzyme inhibition assay results indicated that compounds moderately inhibit both acetylcholinesterase and butyrylcholinesterase. β-Amyloid aggregation results showed that all compounds exhibited remarkable Aβ fibril aggregation inhibition activity with a nearly similar potential as the reference compound rifampicin, which makes them promising anti-Alzheimer drug candidates. Docking experiments were carried out with the aim to understand the interactions of the most active compounds with the active site of the cholinesterase enzymes. 23483189 Mechanisms of RAS/β-catenin interactions. Signaling through the WNT/β-catenin and the RAS (rat sarcoma)/MAPK (mitogen-activated protein kinase) pathways plays a key role in the regulation of various physiological cellular processes including proliferation, differentiation, and cell death. Aberrant mutational activation of these signaling pathways is closely linked to the development of cancer in many organs, in humans as well as in laboratory animals. Over the past years, more and more evidence for a close linkage of the two oncogenic signaling cascades has accumulated. Using different experimental approaches, model systems, and experimental conditions, a variety of molecular mechanisms have been identified by which signal transduction through WNT/β-catenin and RAS interact, either in a synergistic or an antagonistic manner. Mechanisms of interaction comprise an upstream crosstalk at the level of pathway-activating ligands and their receptors, interrelations of cytosolic kinases involved in either pathways, as well as interaction in the nucleus related to the joint regulation of target gene transcription. Here, we present a comprehensive review of the current knowledge on the interaction of RAS/MAPK- and WNT/β-catenin-driven signal transduction in mammalian cells. 23646916 The dynamic interaction between eyewitnesses and interviewers: The impact of differences in perspective on memory reports and interviewer behavior. Despite myriad possible differences in perspectives brought to an investigative interview by eyewitnesses and interviewers, little is known about how such differences might affect eyewitness memory reports or interviewer behavior. Two experiments tested the impact of such differences in a dynamic interaction paradigm in which participants served as eyewitnesses and interviewers. In Experiment 1 (N = 38 pairs), reporting goals for eyewitnesses and interviewers were manipulated in a factorial design, with participants instructed to provide or obtain either as much information as possible or only accurate information. Matching interviewer-interviewee instructions promoted accurate reporting, regardless of the actual content of the instructions. In Experiment 2 (N = 45 pairs), access to information about corroborating eyewitness identifications was manipulated in a factorial design. Corroborating information affected interviewers, but not eyewitnesses. When interviewers did not have access to corroborating information, they provided more negative feedback, and there was a trend toward interrupting more and asking more yes/no questions. These experiments indicate that differences in perspective can have effects on both the content of a witness's report and the behavior of an interviewer. The potential for differences in perspective should be considered in research on protocols intended to maximize eyewitness report accuracy. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23943649 Alternative models of cardiac rehabilitation: a systematic review. The traditional hospital-based model of cardiac rehabilitation faces substantial challenges, such as cost and accessibility. These challenges have led to the development of alternative models of cardiac rehabilitation in recent years. The aim of this study was to identify and critique evidence for the effectiveness of these alternative models. A total of 22 databases were searched to identify quantitative studies or systematic reviews of quantitative studies regarding the effectiveness of alternative models of cardiac rehabilitation. Included studies were appraised using a Critical Appraisal Skills Programme tool and the National Health and Medical Research Council's designations for Level of Evidence. The 83 included articles described interventions in the following broad categories of alternative models of care: multifactorial individualized telehealth, internet based, telehealth focused on exercise, telehealth focused on recovery, community- or home-based, and complementary therapies. Multifactorial individualized telehealth and community- or home-based cardiac rehabilitation are effective alternative models of cardiac rehabilitation, as they have produced similar reductions in cardiovascular disease risk factors compared with hospital-based programmes. While further research is required to address the paucity of data available regarding the effectiveness of alternative models of cardiac rehabilitation in rural, remote, and culturally and linguistically diverse populations, our review indicates there is no need to rely on hospital-based strategies alone to deliver effective cardiac rehabilitation. Local healthcare systems should strive to integrate alternative models of cardiac rehabilitation, such as brief telehealth interventions tailored to individual's risk factor profiles as well as community- or home-based programmes, in order to ensure there are choices available for patients that best fit their needs, risk factor profile, and preferences. 23870665 Emerging roles of E3 ubiquitin ligases in autophagy. Autophagy is an evolutionarily conserved intracellular catabolic process that delivers cytoplasmic components to lysosomes for degradation and recycling. Although originally considered to be a non-selective pathway, it is now recognized that autophagy is involved in selective processes, including the turnover of organelles, removal of protein aggregates, and elimination of intracellular pathogens. This specificity implies that cargo recognition and processing by the autophagy machinery are tightly regulated processes. In support of this, various forms of post-translational modification have been implicated in the regulation of autophagy, one of which is the ubiquitin-proteasome system. Here we review current understanding of the role of ubiquitylation in the control of autophagy. 23108805 Molecular cloning of grass carp (Ctenopharyngodon idellus) T-bet and GATA-3, and their expression profiles with IFN-γ in response to grass carp reovirus (GCRV) infection. Both T-bet and GATA-3, Th1/Th2 lineage-specific transcription factors, play important roles in the development of T cells and Th1/Th2 differentiation. In this study, T-bet and GATA-3 genes were cloned from grass carp (Ctenopharyngodon idellus). The putative primary structure of the polypeptide deduced from the cDNA sequence of grass carp T-bet contained 608 aa, which possessed a T-box DNA binding domain. The putative primary structure of the polypeptide deduced from the cDNA sequence of grass carp GATA-3 contained 396 aa, which possessed two consensus zinc finger domains (C-X(2)-C-X(17)-C-X(2)-C). The YxKxHxxxRP motif, KRRLSA and LMEKs/n sequences were also conserved in this GATA-3. Phylogenetic analysis indicated that grass carp T-bet and GATA-3 group with their known counterparts with zebrafish T-bet and GATA-3 as the closest neighbor, respectively. RT-qPCR results showed that grass carp T-bet gene was highly expressed in head kidney, followed by spleen, and low expressed in gill, liver, kidney, and intestine, while GATA-3 gene was highly expressed in intestine, followed by spleen, and low expressed in gill, liver, kidney, and head kidney. Grass carp is one of the "four important domestic fish" in China and often infected by grass carp reovirus (GCRV). As yet, there is no evidence that T-bet and GATA-3 (Th1/Th2 subsets) are involved in anti-virus immune of teleost fish. In this study, by RT-qPCR, we analyzed the expression dynamics of grass carp T-bet and GATA-3 genes with IFN-γ gene in response to GCRV infection for the first time. The expression dynamics showed that three genes might be crucially modulated by in vivo GCRV infection: (1) GCRV mainly induced a T-bet expression profile comparing to the GATA-3 expression, while the higher expression profiles of IFN-γ correlated with the up-regulation of T-bet; (2) T-bet/IFN-γ and GATA-3 expression changes suggest that in GCRV-infected grass carp, the common immune state of head kidney further heightens, whereas the common physiological state of intestine transforms to an anti-virus immune state. From this finding, we realize that GCRV mainly induces a Th1 response, and Th1 cell-mediated recognition mechanisms play very important roles in anti-virus cellular immune of grass carp. 23911833 Ultrasound-based teaching of cardiac anatomy and physiology to undergraduate medical students. Ultrasonography is a non-invasive imaging modality that offers the opportunity to teach living cardiac anatomy and physiology. The objectives of this study were to assess the feasibility of integrating an ultrasound-based course into the conventional undergraduate medical teaching programme and to analyse student and teacher feedback. An ultrasound-based teaching course was implemented and proposed to all second-year medical students (n=348) at the end of the academic year, after all the conventional modules at our faculty. After a brief theoretical and practical demonstration, students were allowed to take the probe and use the ultrasound machine. Students and teachers were asked to complete a survey and were given the opportunity to provide open feedback. Two months were required to implement the entire module; 330 (95%) students (divided into 39 groups) and 37 teachers participated in the course. Student feedback was very positive: 98% of students agreed that the course was useful; 85% and 74% considered that their understanding of cardiac anatomy and physiology, respectively, was improved. The majority of the teachers (97%) felt that the students were interested, 81% agreed that the course was appropriate for second-year medical students and 84% were willing to participate to future sessions. Cardiac anatomy and physiology teaching using ultrasound is feasible for undergraduate medical students and enhances their motivation to improve their knowledge. Student and teacher feedback on the course was very positive. 23292302 Zinc deficiency induced in Swiss 3T3 cells by a low-zinc medium impairs calcium entry and two mechanisms of entry are involved. Zinc deficiency in 3T3 cells induced by the use of diethylenetriaminepentaacetate (DTPA) has been shown to impair calcium entry associated with failure of proliferation when the cells are stimulated with polypeptide growth factors (GF). These functions of zinc have been evaluated here in the same clone of cells by simple depletion using a low-zinc medium (0.05 μmol/L zinc) without chelator. Confluent cells were maintained for 1 day in the low-zinc medium without GF, then loaded with Fluo-4, and stimulated with GF. Calcium entry was measured by the increase in sustained fluorescence. It was preceded by the release of stored calcium as observed in the previous study using DTPA. Zinc deprivation decreased calcium entry when calcium was added at 0 or 0.05 mmol/L but not when 0.1 mmol/L or higher. Cell proliferation reflected similar effects of zinc and calcium concentrations. In a newly acquired clone of 3T3 cells, GF did not induce internal calcium release but thapsigargin (TG) did. When added in a low-calcium medium, both agonists stimulated calcium entry when external calcium was added, suggesting that two different mechanisms of entry were impaired by zinc deficiency. Zinc deficiency produced by DTPA in the newer clones gave similar results, decreasing calcium entry induced by both agonists. The effects of GF and TG were not additive. The results confirm the earlier observation that zinc deficiency impairs calcium entry into 3T3 cells when stimulated by GF and show that the cells can take up calcium by either store-operated or receptor-operated mechanisms. 23959631 Microscale Polymer Bottles Corked with a Phase-Change Material for Temperature-Controlled Release. Keep your wine chilled! Microscale polystyrene (PS) bottles are loaded with dye molecules and then corked with a phase-change material (PCM). When temperature is raised beyond its melting point, the PCM quickly melts and triggers an instant release of the encapsulated dye. The release profiles can be manipulated by using a binary mixture of PCMs with different melting points. 23927236 Communication: Favorable dimensionality scaling of rectangular collocation with adaptable basis functions up to 7 dimensions. We show that by using a rectangular collocation method with a small basis of parameterized functions, it is possible to compute a vibrational spectrum by solving the Schrödinger equation in 7D from a small number of ab initio calculations without a potential surface. The method is ideal for spectra of molecules adsorbed on a surface. In this paper, it is applied to calculate experimentally relevant energy levels of acetic acid adsorbed on the (101) surface of anatase TiO2. In this case, to obtain levels of experimental accuracy, increasing the number of dimensions from 4 to 7 increases the number of required potential points from about 1000 to about 10 000 and the number of basis functions from 126 to 792: the scaling is very attractive. 23886791 Peritonitis due to Burkholderia gladioli. We report a case of continuous ambulatory peritoneal dialysis (CAPD)-related peritonitis. Burkholderia gladioli, as a plant pathogen, were cultured from peritoneal effluent. Peritonitis healed after intraperitoneal cefazolin and gentamicin. This case indicated that CAPD effluent may be contaminated by B. gladioli, causing CAPD-related peritonitis. On the other hand, it can be successfully treated with intraperitoneal antimicrobials without removal of the Tenckhoff catheter. 23813467 High Mobility N-Type Transistors Based on Solution-Sheared Doped 6,13-Bis(triisopropylsilylethynyl)pentacene Thin Films. An N-Type organic thin-film transistor (OTFT) based on doped 6,13-Bis(triisopropylsilylethynyl)pentacene is presented. A transition from p-type to n-type occurrs with increasing doping concentrations, and the highest performing n-channel OTFTs are obtained with 50 mol% dopant. X-ray diffraction, scanning Auger microscopy, and secondary ionization mass spectrometry are used to characterize the morphology of the blends. The high performance of the obtained transistors is attributed to the highly crystalline and aligned nature of the doped thin films. 22820555 Modafinil effects on cognition and emotion in schizophrenia and its neurochemical modulation in the brain. Modafinil is a central nervous system wake promoting agent used for the treatment of excessive daytime sleeping. Its vigilance promoting properties and low abuse potential has intrigued the scientific community and has led to use it as a cognitive enhancer, before its neural functions were understood. Here, we review the effects of modafinil in human cognition and emotion and its specific actions on symptoms in patients with schizophrenia and whether these are consistently effective throughout the literature. We also performed a systematic review on the effects of modafinil on neurotransmitter signalling in different areas of the brain in order to better understand the neuromechanisms of its cognitive and emotional enhancing properties. A review of its effects in schizophrenia suggests that modafinil facilitates cognitive functions, with pro-mnemonic effects and problem solving improvements. Emotional processing also appears to be enhanced by the drug, although to date there are only a limited number of studies. The systematic review on the neurochemical modulation of the modafinil suggests that its mnemonic enhancing properties might be the result of glutamatergic and dopaminergic increased neuronal activation in the hippocampus and in the prefrontal cortex respectively. Other neurotransmitters were also activated by modafinil in various limbic brain areas, suggesting that the drug acts on these brain regions to influence emotional responses. These reviews seek to delineate the neuronal mechanisms by which modafinil affects cognitive and emotional function. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23732796 Exploiting the nano-sized features of microfibrillated cellulose (MFC) for the development of controlled-release packaging. Microfibrillated cellulose (MFC) was used in this study to prepare films containing an active molecule, lysozyme, which is a natural antimicrobial agent. The main goal of this research was to assess the potential for exploiting the nano-sized dimension of cellulose fibrils to slow the release of the antimicrobial molecule, thus avoiding a too-quick release into the surrounding medium, which is a major disadvantage of most release systems. For this purpose, the release kinetics of lysozyme over a 10-day period in two different media (pure water and water/ethanol 10wt.%) were obtained, and the experimental data was fitted with a solution of Fick's second law to quantify the apparent diffusion coefficient (D). The results indicate that the MFC retained lysozyme, presumably due to electrostatic, hydrogen, and ion-dipole interactions, with the largest release of lysozyme-approximately 14%-occurring from the initial amount loaded on the films. As expected, ethanol as a co-solvent slightly decreased the diffusion of lysozyme from the MFC polymer network. The addition of two potential modulating release agents-glycerol and sodium chloride-was also evaluated. Findings from this work suggest that MFC-based films can be considered a suitable candidate for use in controlled-release packaging systems. 23847278 Temporal Risk Profile for Infectious and Noninfectious Complications of Hemodialysis Access. Vascular access complications are a major cause of morbidity in patients undergoing hemodialysis, and determining how the risks of different complications vary over the life of an access may benefit the design of prevention strategies. We used data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) to assess the temporal profiles of risks for infectious and noninfectious complications of fistulas, grafts, and tunneled catheters in incident hemodialysis patients. We used longitudinal data to model time from access placement or successful treatment of a previous complication to subsequent complication and considered multiple accesses per patient and repeated access complications using baseline and time-varying covariates to obtain adjusted estimates. Of the 7769 incident patients identified, 7140 received at least one permanent access. During a median follow-up of 14 months (interquartile range, 7-22 months), 10,452 noninfectious and 1131 infectious events (including 551 hospitalizations for sepsis) occurred in 112,085 patient-months. The hazards for both complication types declined over time in all access types: They were 5-10 times greater in the first 3-6 months than in later periods after access placement or a remedial access-related procedure. The hazards declined more quickly with fistulas than with grafts and catheters (P<0.001; Weibull regression). These data indicate that risks for noninfectious and infectious complications of the hemodialysis access decline over time with all access types and suggest that prevention strategies should target the first 6 months after access placement or a remedial access-related procedure. 23599221 Dual effects of body-weight supported treadmill training on cardiovascular fitness and walking ability early after stroke: a randomized controlled trial. . Body-weight-supported treadmill training (BWSTT) to train both fitness and ambulation has not been investigated. . To compare the effectiveness of BWSTT to dose-equivalent usual care (UC) in improving cardiovascular fitness and walking early after stroke. . Participants were randomly assigned to 1 of 2 interventions: BWSTT + UC or UC. All individuals participated in 60-minute physiotherapy sessions 5 times weekly as inpatients for 6 weeks and 3 times weekly as outpatients for another 6 weeks. Baseline, posttraining, 6-, and 12-month follow-up outcome measures were as follows: primary, fitness (peak oxygen consumption, VO2peak) and walking ability (6-Minute Walk Test [6MWT] and 10-m walk); secondary, Berg Balance Scale (BBS) and motor impairment (Chedoke-McMaster Stages of Recovery [CMSR] Leg and Foot). . In all, 50 individuals (mean age, 60 ± 14 years; mean event-to-randomization, 23 ± 5 days; 29 men) participated. No adverse events occurred. BWSTT improved VO2peak by 30%, which was significantly greater than the 8% improvement observed for UC (P = .004 between groups). Similarly, there were significant Time × Group interactions for 6MWT and CMSR Foot, with BWSTT outperforming UC for gains in distance (P = .15; 48% vs 19%, respectively) and stage (P = .01; 1.0 vs 0.3, respectively). No group effect was seen for 10-m walk speed, BBS, or CMSR Leg, with both groups demonstrating significant gains. In general, gains observed were preserved for 12 months. . BWSTT elicits greater improvements in cardiovascular fitness and walking endurance than UC in the subacute poststroke period. These gains are largely sustained for 1 year. 23812951 Fertility preservation in the male with cancer. This article reviews the current concepts, recommendations, and principles of fertility preservation in men with cancer. Obstacles to sperm banking are addressed, as well as future directions for fertility-preserving technologies. All cancer therapies-chemotherapy, radiation, and surgery-are potential threats to a man's reproductive potential. Additionally, cancer itself can impair spermatogenesis. Thus, sperm cryopreservation prior to initiating life-saving cancer treatment offers men and their families the best chances to father biologically-related children and should be offered to all men with cancer before treatment. Better patient and provider education, as well as deliberate, coordinated strategies at comprehensive cancer care centers, are necessary to make fertility preservation for male cancer patients a priority during pre-treatment planning. 23861538 Intermittent Drug Techniques for Schizophrenia. Intermittent drug techniques refer to the "use of medication only during periods of incipient relapse or symptom exacerbation rather than continuously." The aim is to reduce the risk of adverse effects of antipsychotics by "reducing long-term medication exposure for patients who are receiving maintenance treatment while limiting risk of relapse," with a further goal of improving social functioning resulting from the reduction of antipsychotic-induced side effects. We reviewed the effects of different intermittent drug techniques compared with maintenance treatment in people with schizophrenia or related disorders. We searched The Cochrane Schizophrenia Group Trials Register (April 2012) and supplemented this by contacting relevant study authors and manually searching reference lists. All relevant randomized controlled trials (RCTs) were included.Of 241 records retrieved by the search, 17 trials were included. Homogenous data demonstrated that instances of relapse were significantly higher in people receiving any intermittent drug treatment in the long term (n=436, 7 RCTs, RR=2.46, 95% CI=1.70- to 3.54). Intermittent treatment was shown to be more effective than placebo, however, and demonstrated that significantly less people receiving intermittent antipsychotics experienced full relapse by medium term (n=290, 2 RCTs, RR=0.37, 95% CI=0.24-0.58). Intermittent antipsychotic treatment is not as effective as continuous, maintained antipsychotic therapy for preventing relapse in people with schizophrenia. It does seem, however, significantly better than no treatment. 23837411 Survey on retinopathy of prematurity (ROP) in Italy. This study aims to investigate the incidence and the relative risk factors of retinopathy of prematurity (ROP) and posterior-ROP (P-ROP): ROP in Zone I and posterior Zone II, as well as to analyze the occurrence of surgical treatment of ROP and to evaluate the short term outcome of the disease in Italy. It is a prospective multicenter observational study; all infants with a birth weight (BW) [less than or equal to] 750 g and/ or a gestational age (GA) [less than or equal to]27 weeks born between January 1st 2008 and December 31 st 2009 in 25 III level Italian neonatal intensive care units were eligible for the study. 421 infants were examined: 265 (62.9%) developed ROP and 102 (24.2%) P-ROP. Following the multivariate analysis erythropoietin-therapy (p < 0.0001) and intraventricular hemorrhage (IVH) (p = 0.003) were significantly associated with ROP while gestational age [less than or equal to]24 weeks (p = 0.011) and sepsis (p = 0.002) were associated with the onset of P-ROP. Eighty nine infants (34%) required surgical treatment; following the multivariate analysis PROP was an independent factor associated with the need of surgical treatment ( p < 0.0001). A favorable outcome was reported in 251 (94.7%) newborns affected by ROP. Adverse outcome occurred in 14 patients: all of them underwent surgery and showed P-ROP. P-ROP is the most aggressive type of ROP. It associates with lower GA and sepsis. Obstetricians and Neonatologists must focus on the reduction of severe preterm births and on the prevention of neonatal early and late onset sepsis in order to reduce the incidence of PROP. 23871998 Label-free high-throughput assays to screen and characterize novel lactate dehydrogenase inhibitors. Catalytic turnover of pyruvate to lactate by lactate dehydrogenase (LDH) is critical in maintaining an intracellular nicotinamide adenine dinucleotide (NAD(+)) pool for continuous fueling of the glycolytic pathway. In this article, we describe two label-free high-throughput assays (a kinetic assay detecting the intrinsic reduced nicotinamide adenine dinucleotide (NADH) fluorescence and a mass spectrometric assay monitoring the conversion of pyruvate to lactate) that were designed to effectively identify LDH inhibitors, characterize their different mechanisms of action, and minimize potential false positives from a small molecule compound library screen. Using a fluorescence kinetic image-based reader capable of detecting NADH fluorescence in the ultra-high-throughput screening (uHTS) work flow, the enzyme activity was measured as the rate of NADH conversion to NAD(+). Interference with NADH fluorescence by library compounds was readily identified during the primary screen. The mass spectrometric assay quantitated the lactate and pyruvate levels simultaneously. The multiple reaction monitoring mass spectrometric method accurately detected each of the two small organic acid molecules in the reaction mixture. With robust Z' scores of more than 0.7, these two high-throughput assays for LDH are both label free and complementary to each other in the HTS workflow by monitoring the activities of the compounds on each half of the LDH redox reaction. 23362800 Evidence for metal-surface interactions and their role in stabilizing well-defined immobilized Ru-NHC alkene metathesis catalysts. Secondary interactions are demonstrated to direct the stability of well-defined Ru-NHC-based heterogeneous alkene metathesis catalysts. By providing key stabilization of the active sites, higher catalytic performance is achieved. Specifically, they can be described as interactions between the metal center (active site) and the surface functionality of the support, and they have been detected by surface-enhanced (1)H-(29)Si NMR spectroscopy of the ligand and (31)P solid-state NMR of the catalyst precursor. They are present only when the metal center is attached to the surface via a flexible linker (a propyl group), which allows the active site to either react with the substrate or relax, reversibly, to the surface, thus providing stability. In contrast, the use of a rigid linker (here mesitylphenyl) leads to a well-defined active site far away from the surface, stabilized only by a phosphine ligand which under reaction conditions leaves probably irreversibly, leading to faster decomposition and deactivation of the catalysts. 23540948 Simple rules for ultrasonographic subcategorization of BI-RADS®-US 4 breast masses. To evaluate an objective method for ultrasonographic (US) subcategorization of BI-RADS(®)-US 4 breast masses based on clear and simple rules in order for woman to benefit from a more complete and homogeneous breast mass analysis. In this cross-sectional study, we selected 330 women, with 339 US breast masses, classified as BI-RADS(®)-US 4. Three physicians experienced in breast imaging independently reviewed all US images, assessing mass shape, margins, orientation, echo texture and vascularity. These experts further subdivided the masses into subcategories 4a, 4b and 4c, according to simple US rules. Inter-observer agreement was calculated for US features categories and for final subcategory assessment. We also estimated the positive predictive value (PPV) for BI-RADS(®)-US subcategories 4a, 4b and 4c assigned by each of the three observers. Pathological examination of all masses confirmed 144 (42%) malignant and 195 (58%) benign tumors. Moderate agreement was obtained for mass shape, margins, vascularity and for final BI-RADS(®)-US 4 subcategory. Substantial agreement was obtained for the description of mass orientation and echo texture. The PPV for subcategories 4a, 4b and 4c were, 17%, 45% and 85%, respectively, for the first observer and 20%, 38% and 79% and 17%, 40% and 85% for the other two observers. Standardization of a US subcategorization of BI-RADS(®)-US 4 breast masses seems to be feasible, with substantial inter-observer agreement and progressive increase in the PPV in the subcategories 4a, 4b and 4c, provided that clear and simple classification rules are defined. 23830287 Serum adipocyte fatty acid-binding protein levels are independently associated with sarcopenic obesity. Adipocyte fatty acid-binding protein (A-FABP) plays a key role in obesity-related insulin resistance and inflammation which may be involved in the pathogenesis of sarcopenic obesity (SO). This study examined the association of SO with serum A-FABP levels in Korean adults. Two hundred ninety eight adults aged 20-70 years were examined using dual X-ray absorptiometry and computed tomography and measuring serum A-FABP levels. Sarcopenia was defined as the appendicular skeletal muscle mass (ASM) divided by weight (%) of <1 SD below the mean values of young adults in both sexes. Obesity was defined as visceral fat area (VFA)≥100cm(2). Serum A-FABP levels were higher in groups with SO compared to non-SO groups in both men and women. In the unadjusted model, serum A-FABP levels were positively associated with VFA and negatively associated with ASM/weight. Even after adjusting for possible confounding factors, ASM/weight was found to be independently and negatively associated with serum A-FABP levels. In addition, multiple logistic regression analysis showed that increased serum levels of A-FABP were independently associated with the presence of SO. The present findings indicate that serum A-FABP levels may be valuable markers of the presence of SO. 23893651 Total synthesis and structural revision of viridicatumtoxin b. Will the real viridicatumtoxin B please stand up: The total synthesis of viridicatumtoxin B resulted in its structural revision and opens the way for analogue construction and biological evaluation of this complex tetracycline-like antibiotic. The highly convergent strategy employed allows for swift construction of the entire carbocyclic framework of the molecule. 23952586 A Database for Mycobacterium Secretome Analysis: 'MycoSec' to Accelerate Global Health Research. Abstract Members of the genus Mycobacterium are notorious for their pathogenesis. Investigations from various perspectives have identified the pathogenic strategies employed by these lethal pathogens. Secretomes are believed to play crucial roles in host cell recognition and cross-talks, in cellular attachment, and in triggering other functions related to host pathogen interactions. However, a proper idea of the mycobacterial secretomes and their mechanism of functionality still remains elusive. In the present study, we have developed a comprehensive database of potential mycobacterial secretomes (MycoSec) using pre-existing algorithms for secretome prediction for researchers interested in this particular field. The database provides a platform for retrieval and analysis of identified secretomes in all finished genomes of the family Mycobacteriaceae. The database contains valuable information regarding secretory signal peptides (Sec type), lipoprotein signal peptides (Lipo type), and Twin arginine (RR/KR) signal peptides (TAT type), prevalent in mycobacteria. Information pertaining to COG analysis, codon usage, and gene expression of the predicted secretomes has also been incorporated in the database. MycoSec promises to be a useful repertoire providing a plethora of information regarding mycobacterial secretomes and may well be a platform to speed global health research. MycoSec is freely accessible at http://www.bicnbu.in/mycosec . 23863413 The Effect of Rod Diameter on Correction of Adolescent Idiopathic Scoliosis at Two Years Follow Up. The review of multicenter national pediatric scoliosis database. The purpose of this study was to compare the radiographic outcomes of patients who underwent scoliosis surgery utilizing different rod diameter constructs by the posterior approach. Little attention has specifically been focused on the effect of rod diameter on correction of spinal deformity after posterior spinal instrumentation and fusion in children with adolescent idiopathic scoliosis (AIS). The review of national database comprised of 1125 patients, of which 352 patients had a minimum follow-up of 2 years. Of these, 163 patients received 5.5 mm and 189 patients received 6.35 mm diameter rods for posterior spinal instrumentation. The 6.35 mm rods were used more often for patients who were male, taller, heavier, with larger coronal curves, and more flexible curves. Larger diameter rods were also more likely to be stainless steel, implanted with an increased number of implants per level, and an increased number of pedicle screws used on the concavity of the curve. Univariate analysis of coronal curve showed a significant difference between 5.5 and 6.35 mm rods in correction (67.0% vs. 57.3%) at 2 years. Multivariate analysis revealed that the most significant factors affecting coronal curve correction at 2 years were rod diameter, the patient's preoperative coronal major curve and flexibility, and the implant density. In the sagittal plane, preoperative sagittal curve and rod diameter are the predictors of sagittal correction at 2 years. The study did not support our hypothesis that larger rods would be associated with a greater correction of frontal and sagittal plane in patients with AIS. In addition to rod diameter, implant density and the inherent flexibility and deformity of the patient were found to be influential factors contributing for the correction and maintenance of coronal and sagittal curves in AIS. 23827226 Distraction reduces theta synchronization in emotion regulation during adolescence. We sought to determine if attentional distraction in adolescents can modulate event-related desynchronization or synchronization (ERD or ERS) of the theta band during emotion regulation. Event-related theta oscillations were collected from 48 adolescents and young adults as they performed a distraction (counting) task while viewing affective pictures. Consistent with data from adult participants, positive and negative pictures elicited a larger theta ERS than did neutral pictures within a 100-400ms window, indicating that early theta ERS is indicative of motivated attention to biologically salient stimuli. Counting as a distraction strategy attenuated early affective modulation of theta ERS. Moreover, theta ERS increased with age in the anterior regions of the brain regardless of valence; however, no age differences were found in the posterior regions. These results suggest that distraction depends on a top-down attentional mechanism that disrupts theta ERS for affective pictures at an early stage. Furthermore, adolescents undergo a developmental increase in oscillatory brain reorganization. 22257685 Effects of enalapril in systolic heart failure patients with and without chronic kidney disease: insights from the SOLVD Treatment trial. Angiotensin-converting enzyme inhibitors improve outcomes in systolic heart failure (SHF). However, doubts linger about their effect in SHF patients with chronic kidney disease (CKD). In the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial, 2569 ambulatory chronic HF patients with left ventricular ejection fraction ≤ 35% and serum creatinine level ≤ 2.5mg/dl were randomized to receive either placebo (n=1284) or enalapril (n=1285). Of the 2502 patients with baseline serum creatinine data, 1036 had CKD (estimated glomerular filtration rate <60 ml/min/1.73 m(2)). Overall, during 35 months of median follow-up, all-cause mortality occurred in 40% (502/1252) and 35% (440/1250) of placebo and enalapril patients, respectively (hazard ratio {HR}, 0.84; 95% confidence interval {CI}, 0.74-0.95; p=0.007). All-cause mortality occurred in 45% and 42% of patients with CKD (HR, 0.88; 95% CI, 0.73-1.06; p=0.164), and 36% and 31% of non-CKD patients (HR, 0.82; 95% CI, 0.69-0.98; p=0.028) in the placebo and enalapril groups, respectively (p for interaction=0.615). Enalapril reduced cardiovascular hospitalization in those with CKD (HR, 0.77; 95% CI, 0.66-0.90; p<0.001) and without CKD (HR, 0.80; 95% CI, 0.70-0.91; p<0.001). Among patients in the enalapril group, serum creatinine elevation was significantly higher in those without CKD (0.09 versus 0.04 mg/dl in CKD; p=0.003) during first year of follow-up, but there was no differences in changes in systolic blood pressure (mean drop, 7 mm Hg, both) and serum potassium (mean increase, 0. /L, both). Enalapril reduces mortality and hospitalization in SHF patients without significant heterogeneity between those with and without CKD. 23926293 Listeners' attitudes toward children with voice problems. To investigate the attitudes of school teachers toward children with voice problems in a Chinese population. Methods Three groups of listeners participated in this study: primary school teachers, speech pathology students, and general university students. They were required to make attitude judgments on 12 voice samples using a semantic differential scale with 22 bipolar adjective pairs. The voice samples were collected from six children with normal voices and six children with dysphonic voice. The 22 bipolar adjective pairs were intended to cover non-speech characteristics about the child's personality, social characteristics, and physical appearance. The mean attitude ratings received by children with dysphonic voice were significantly lower (i.e., less favorable) than those received by children with normal voice in all the 22 adjective pairs (all p<0.002). The attitude ratings made by the three groups of listeners were not significantly different from each other (p>0.05). To our knowledge, this is the first study to examine listeners' perception toward children with voice problems in the Chinese population. The results suggest that voice problems in children warrant attention and their impacts on the child should not be under-estimated. The findings also highlight the importance of early identification and intervention for children with voice problems. 23898072 Sonodynamically-induced Anticancer Effects by Functionalized Fullerenes. Functionalized fullerenes, such as polyhydroxy fullerenes (PHF), have attracted particular attention due to their water solubility and their potential application in tumor imaging and therapy as carbon nanomaterials. In this study, the sonodynamically-induced antitumor effect of PHF was investigated. Sonodynamically-induced antitumor effects of PHF in combination with ultrasound were investigated using isolated sarcoma 180 cells and solid tumor from colon 26 carcinoma cells. The cell damage induced by sonication was enhanced by two-fold in the presence of 80 μM PHF. Histidine significantly inhibited this enhancement. This inhibitory effect suggests that the sonodynamically-induced antitumor effect was mediated by sonodynamically-generated reactive oxygen species. The combined treatment of ultrasonic exposure with PHF suppressed the growth of implanted colon 26 tumors. The destruction of tumor tissue was observed with the ultrasonic treatment in combination with PHF, while neither the treatment with PHF alone nor that with ultrasound alone caused necrosis. These results suggest that PHF is a potential sonosensitizer for sonodynamic treatment of solid tumors. 23566715 Dynamic time warping applied to estimate atrial fibrillation temporal organization from the surface electrocardiogram. Atrial fibrillation (AF) is the most commonly diagnosed arrhythmia in clinical practice. However, the mechanisms responsible for its induction and maintenance still are not fully understood. To this respect, analysis of the electrical activity organization within the atria could play an important role in their proper interpretation. Although many algorithms to quantify AF organization from invasive electrograms can be found in the literature, a reduced number of indirect estimators from the standard ECG have been proposed to date. Furthermore, these surface methods can only yield a global AF organization assessment, blurring the possible information that each individual fibrillatory (f) wave may provide. To this respect, the present manuscript proposes a novel method for direct and short-time AF organization estimation from single-lead surface ECG recordings. Through the computation of morphological variations among f waves, the temporal arrhythmia organization is estimated. The f waves are individually extracted and delineated from the atrial activity signal, making use of a dynamic time warping approach. The proposed algorithm was tested on real AF surface recordings in order to discriminate atrial signals with different organization degrees, obtaining a diagnostic accuracy higher than 88%. In addition, its performance was validated by comparison with two temporal organization measures from invasive unipolar electrograms of both atria, providing statistically significant linear correlations between invasive and non-invasive estimates. As a consequence, new standpoints are opened through this work in the non-invasive analysis of AF, where the individualized study of each f wave could assess short-time AF organization, would improve the understanding of AF mechanisms and become useful for its clinical treatment. 23923267 Hydration--the missing part of nutritional care. Dehydration contributes to poor patient outcomes and can lead to avoidable harm. This article analyses incident reports from National Reporting and Learning System (NRLS) relating to hydration and shows that this area of care continues to be frequently neglected. Reasons for this are suggested with recommendations for changing practice to reduce the negative impact this has on patient outcomes. 23894067 A 2.84 Mb deletion at 21q22.11 in a patient clinically diagnosed with marden-walker syndrome. We present a girl with the characteristic clinical picture associated with Marden-Walker syndrome (MWS; OMIM 248700), including mask-like face with blepharophimosis, joint contractures, intellectual disability, a multicystic dysplastic kidney and cerebral dysgenesis. The long-term follow-up allowed us to monitor the evolution of the phenotype in this patient, and among the main findings we highlight the following: demyelination of the pyramidal tract demonstrated by transcranial magnetic stimulation and the involvement of the levator muscles of angle of mouth in fixed facial expression with relative integrity of the rest of the facial expression muscles. A 244 k array comparative genomic hybridization (aCGH) was carried out and showed a de novo interstitial deletion of approximately 2.84 Mb affecting only the cytoband 21q22.11 (genome coordinates chr21:31,874,016-34,711,763). We selected 10 of the most recent published cases with either total or partial deletions of cytoband 21q22.11 that provided good characterization of the genomic size or the genes in the deleted regions. We observed that in nine of the 10 cases the deleted regions included the RUNX1 gene in 21q22.12, which is not affected in the current patient's deletion or in that of Patient 3 from Roberson et al. [2011]. After a comparison of shared deleted genes between cases, and correlation of their potential phenotypes, we concluded that the pattern of defects considered for a diagnosis of MWS may represent part of the phenotypic expression of a partial or total deletion of 21q22.11. © 2013 Wiley Periodicals, Inc. 23636129 Topographically-patterned porous membranes in a microfluidic device as an in vitro model of renal reabsorptive barriers. Models of reabsorptive barriers require both a means to provide realistic physiologic cues to and quantify transport across a layer of cells forming the barrier. Here we have topographically-patterned porous membranes with several user-defined pattern types. To demonstrate the utility of the patterned membranes, we selected one type of pattern and applied it to a membrane to serve as a cell culture support in a microfluidic model of a renal reabsorptive barrier. The topographic cues in the model resemble physiological cues found in vivo while the porous structure allows quantification of transport across the cell layer. Sub-micron surface topography generated via hot-embossing onto a track-etched polycarbonate membrane, fully replicated topographical features and preserved porous architecture. Pore size and shape were analyzed with SEM and image analysis to determine the effect of hot embossing on pore morphology. The membrane was assembled into a bilayer microfluidic device and a human kidney proximal tubule epithelial cell line (HK-2) and primary renal proximal tubule epithelial cells (RPTEC) were cultured to confluency on the membrane. Immunofluorescent staining of both cell types revealed protein expression indicative of the formation of a reabsorptive barrier responsive to mechanical stimulation: ZO-1 (tight junction), paxillin (focal adhesions) and acetylated α-tubulin (primary cilia). HK-2 and RPTEC aligned in the direction of ridge/groove topography of the membrane in the device, evidence that the device has mechanical control over cell response. This topographically-patterned porous membrane provides an in vitro platform on which to model reabsorptive barriers with meaningful applications for understanding biological transport phenomenon, underlying disease mechanisms, and drug toxicity. 23642733 The effect of aerobic exercise intensity on attenuation of postprandial lipemia is dependent on apolipoprotein E genotype. To investigate the effect of aerobic exercise intensity on postprandial lipemia according to allelic variants of the apolipoprotein E gene. Three groups of 10 healthy men each were formed based genotyping of the APOE gene, rested or performed 500 Kcal tests in a random sequence separated by a minimum 48 h interval, as follows: (a) no exercise (control), (b) intense intermittent exercise, (c) moderate continuous exercise. Each test series was completed 30-min before ingestion of a high-fat meal (1 g fat/kg). Venous blood was collected before and at 1, 2, 3 and 4 h after the high-fat meal. Postprandial lipemia was assessed using the area under the curve approach as well as the kinetic profile of mean lipid variables. Statistical significance was adopted at P ≤ 0.05 level. The main results show that, in the moderate continuous exercise, total postprandial cholesterolemia was higher in ɛ4 than in ɛ2 carriers, whereas under intense intermittent exercise, total and LDL cholesterolemia were higher in ɛ4 than in ɛ2 and ɛ3 carriers. There was no difference in the lipemic profile of the subjects across APOE genotypes at baseline. Moderate and intense exercise were effective in attenuating PPL in both ɛ2 and ɛ3 subjects, with ɛ2 subjects being more susceptible to the lipid lowering effect of moderate training than ɛ3 subjects. Carriers of the ɛ4 allele, however, showed no attenuation of postprandial lipemia. 23726822 Medically induced preterm birth and the associations between prenatal care and infant mortality. During the last 30 years, the use of prenatal care, both the proportion of women receiving the recommended number of visits and the average number of visits, has increased substantially. Although infant mortality has decreased, the incidence of preterm birth has increased. We hypothesized that prenatal care may lead to lower infant mortality in part by increasing the detection of obstetrical problems for which the clinical response may be to medically induce preterm birth. We examined whether medically induced preterm birth mediates the association between prenatal care and infant mortality by using newly developed methods for mediation analysis. Data are the cohort version of the national linked birth certificate and infant death data for 2003 births. Analyses were adjusted for maternal sociodemographic, geographic, and health characteristics. Receiving more prenatal care visits than recommended was associated with medically induced preterm birth (odds ratio [OR], 2.44; 95% confidence interval [95% CI], 2.40-2.49) compared with fewer visits than recommended). Medically induced preterm birth was itself associated with greater infant mortality (OR, 5.08; 95% CI, 4.61-5.60) but that association was weaker among women receiving extra prenatal care visits (OR 3.08; 95% CI, 2.88-3.30) compared with women receiving the recommended number of visits or fewer. These analyses suggest that some of the benefit of prenatal care in terms of infant mortality may be in part due to medically induced preterm birth. If so, the use of preterm birth rates as a metric for tracking birth policy and outcomes could be misleading. 23932410 Increased orosomucoid in urine is an independent predictor of cardiovascular and all-cause mortality in patients with type 2 diabetes at 10years of follow-up. To evaluate whether increased urinary orosomucoid excretion rate (UOER) is an independent predictor of cardiovascular and all-cause mortality in type 2 diabetes (T2DM) and type 1 diabetes (T1DM) at 10years of follow-up. We followed 430 patients with T2DM and 148 patients with T1DM until emigration, death or November 2011. We measured UOER levels in overnight urine samples. Descriptive data are given in the article. In patients with T2DM and T1DM, all-cause mortality (log-rank test, p<0.01 for both types) and cardiovascular mortality (log-rank test, p<0.01 for T2DM and p=0.04 for T1DM) were significantly higher in patients with increased UOER. Normoalbuminuric patients with T2DM and increased UOER levels had higher all-cause and cardiovascular mortality (log-rank test, p<0.01 for both types). UOER was independently predictive of all-cause (HR 1.52; 95% CI 1.10-2.09; p=0.01) and cardiovascular (HR 2.31; 95% CI 1.46-3.66; p<0.01) mortality in patients with T2DM, but not in patients with T1DM. UOER is an independent predictor of all-cause and cardiovascular mortality even in normoalbuminuric patients with T2DM at 10years of follow-up. Further studies are needed in order to evaluate the prognostic and clinical relevance. 23448281 Acyclic nucleoside phosphonates containing a second phosphonate group are potent inhibitors of 6-oxopurine phosphoribosyltransferases and have antimalarial activity. Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) 6-oxopurine phosphoribosyltransferases (PRTs). Chemical modifications based on the crystal structure of 2-(phosphonoethoxy)ethylguanine (PEEG) in complex with human HGPRT have led to the design of new ANPs. These novel compounds contain a second phosphonate group attached to the ANP scaffold. {[(2-[(Guanine-9H-yl)methyl]propane-1,3-diyl)bis(oxy)]bis(methylene)}diphosphonic acid (compound 17) exhibited a Ki value of 30 nM for human HGPRT and 70 nM for Pf HGXPRT. The crystal structure of this compound in complex with human HGPRT shows that it fills or partially fills three critical locations in the active site: the binding sites of the purine base, the 5'-phosphate group, and pyrophosphate. This is the first HG(X)PRT inhibitor that has been able to achieve this result. Prodrugs have been synthesized resulting in IC50 values as low as 3.8 μM for Pf grown in cell culture, up to 25-fold lower compared to the parent compounds. 23822145 No exacerbation but impaired anti-viral mechanisms in a rhinovirus-chronic allergic asthma mouse model. Rationale: Severe asthma and viral-induced asthma exacerbations represent a high unmet medical need as no therapy is currently available for these patients. Human rhinovirus is prominently associated with asthma exacerbations in humans. This study aimed to establish a mouse model of severe asthma with additional rhinovirus infection to investigate the interplay between chronic allergic airway inflammation and acute respiratory viral infection. Methods: BALB/c mice were sensitized with HDM extract (25µg in 50µl saline) by intranasal delivery to the lung over 7 weeks. HRV1B inoculation was performed intranasally on the last three days. Therapeutic treatment with fluticasone propionate was performed to assess steroid efficacy. Lung resistance was measured invasively to assess airway hyperresponsiveness (AHR). Bronchoalveolar lavage (BAL) differential cell count, cytokines, lung histology, and the proliferative and cytokine response of mediastinal lymph node cells upon in vitro restimulation were analyzed. Results: Chronic HDM application induced a strong Th2-skewed eosinophilic airway inflammation and AHR, which was not exacerbated by superimposed HRV1B infection. Therapeutic steroid intervention in the chronic HDM model reduced BAL eosinophil cell counts, cytokine levels and AHR, while neutrophil numbers were unaffected. Steroid efficacy against inflammatory readouts was maintained during additional HRV1B infection. Animals with chronic allergic airway inflammation exhibited a diminished immune response towards superimposed HRV1B infection compared with HRV1B alone, as induction of the anti-viral and proinflammatory cytokines IFN-α, IFN-γ, IL-12 was suppressed. Conclusions: Although superimposed HRV1B infection did not provoke asthma exacerbation in this severe model, a deficient anti-viral immune response to HRV1B was present under chronic allergic airway inflammatory conditions. Thus, this model is able to reflect some aspects of the complex interplay of respiratory virus infection in chronic allergic asthma. 23966720 A continuous quality improvement program to focus a college of pharmacy on programmatic advancement. Objective. To enhance the achievement of a college of pharmacy's goals for education, research, and service missions by implementing an excellence program based on the Studer Group model for continuous quality improvement. Methods. The Studer model was combined with university strategic planning for a comprehensive quality-improvement program that was implemented over 5 years. The program included identifying and measuring key performance indicators, establishing specific "pillar" goals, aligning behaviors with goals and values, and training leaders. Results. Assessment of key performance indicators over 5 years demonstrated progress toward achieving college goals for student and faculty satisfaction, research funding, numbers of students seeking formal postgraduate training, and private giving. Conclusions. Implementation of a continuous quality-improvement program based on the Studer program enabled the college to focus on and meet its yearly and strategic goals for all components of its mission. 23109101 Anti-infective properties of bacteriocins: an update. Bacteriocin production is a widespread phenomenon among bacteria. Bacteriocins hold great promise for the treatment of diseases caused by pathogenic bacteria and could be used in the future as alternatives to existing antibiotics. The anti-infective potential of bacteriocins for inhibiting pathogens has been shown in various food matrices including cheese, meat, and vegetables. However, their inhibition of pathogens in vivo remains unclear and needs more investigation, due mainly to difficulties associated with demonstrating their health benefits. Many bacteriocins produced by established or potential probiotic organisms have been evaluated as potential therapeutic agents and interesting findings have been documented in vitro as well as in a few in vivo studies. Some recent in vivo studies point to the efficacy of bacteriocin-based treatments of human and animal infections. While further investigation remains necessary before the possibilities for bacteriocins in clinical practice can be described more fully, this review provides an overview of their potential applications to human and veterinary health. 23462019 An Intersectional Approach to Social Determinants of Stress for African American Men: Men's and Women's Perspectives. Stress is a key factor that helps explain racial and gender differences in health, but few studies have examined gendered stressors that affect men. This study uses an intersectional approach to examine the sources of stress in African American men's lives from the perspectives of African American men and important women in their lives. Phenomenological analysis was used to examine data from 18 exploratory focus groups with 150 African American men, ages 30 years and older, and eight groups with 77 African American women. The two primary sources of stress identified were seeking to fulfill socially and culturally important gender roles and being an African American man in a racially stratified society. A central focus of African American men's daily lives was trying to navigate chronic stressors at home and at work and a lack of time to fulfill roles and responsibilities in different life domains that are traditionally the responsibility of men. Health was rarely mentioned by men as a source of stress, though women noted that men's aging and weathering bodies were a source of stress for men. Because of the intersection of racism and economic and social stressors, men and women reported that the stress that African American men experienced was shaped by the intersection of race, ethnicity, age, marital status, and other factors that combined in unique ways. The intersection of these identities and characteristics led to stressors that were perceived to be of greater quantity and qualitatively different than the stress experienced by men of other races. 23663871 Management of endovenous heat-induced thrombus using a classification system and treatment algorithm following segmental thermal ablation of the small saphenous vein. We evaluated our experience with segmental radiofrequency ablation (RFA) of the small saphenous vein (SSV), a less common procedure than great saphenous vein ablation, and developed a classification system and algorithm for endovenous heat-induced thrombus (EHIT), based on modifications of our prior algorithm of EHIT following great saphenous ablation. Endovenous ablation was performed on symptomatic patients with incompetent SSVs following a minimum of 3 months of compression therapy. Demographic data, risk factors, CEAP classification, procedure details, and follow-up data were recorded. A four-tier classification system and treatment algorithm was developed, based on EHIT proximity to the popliteal vein. Eighty limbs (in 76 patients) were treated with RFA of the SSV between January 2008 and August 2012. Duplex ultrasound was performed between 24 and 72 hours postprocedure in all patients. Ablation was successful in 98.7% (79/80) of procedures. Sixty-eight (85%) patients had level A closures (≥1 mm caudal to popliteal vein) and 10 patients (13%) had level B closures (flush with popliteal vein) and were observed. Two limbs (3%) had EHIT extending into the popliteal vein (level C) and were treated with outpatient low-molecular-weight heparin anticoagulation. Thrombus retracted to the level of the saphenopopliteal junction in both patients following a short course of anticoagulation. No patient developed an occlusive deep vein thrombosis (DVT) (level D). Mean follow-up period was 6.2 months; no patient had small saphenous recanalization, occlusive DVT, or pulmonary embolus. The presence or absence of the Giacomini vein was not predictive of level B and C closure. RFA of the SSV in symptomatic patients has a high success rate with a low risk of DVT. A classification system and treatment protocol based on the level of EHIT in relation to the saphenopopliteal junction is useful in managing patients. The approach to patients with thrombus flush with the popliteal vein or bulging has not been previously defined; our outcomes were excellent, using our treatment algorithm. 23867031 Mobile Health Technology Evaluation: The mHealth Evidence Workshop. Creative use of new mobile and wearable health information and sensing technologies (mHealth) has the potential to reduce the cost of health care and improve well-being in numerous ways. These applications are being developed in a variety of domains, but rigorous research is needed to examine the potential, as well as the challenges, of utilizing mobile technologies to improve health outcomes. Currently, evidence is sparse for the efficacy of mHealth. Although these technologies may be appealing and seemingly innocuous, research is needed to assess when, where, and for whom mHealth devices, apps, and systems are efficacious. In order to outline an approach to evidence generation in the field of mHealth that would ensure research is conducted on a rigorous empirical and theoretic foundation, on August 16, 2011, researchers gathered for the mHealth Evidence Workshop at NIH. The current paper presents the results of the workshop. Although the discussions at the meeting were cross-cutting, the areas covered can be categorized broadly into three areas: (1) evaluating assessments; (2) evaluating interventions; and (3) reshaping evidence generation using mHealth. This paper brings these concepts together to describe current evaluation standards, discuss future possibilities, and set a grand goal for the emerging field of mHealth research. 23782266 Normative data for the Mini-Mental State Examination, the Free and Cued Selective Reminding Test and the Isaacs Set Test for an older adult Mexican population: The Coyoacán Cohort Study. The Mini-Mental State Examination (MMSE), the Free and Cued Selective Reminding Test (FCSRT), and the Isaacs Set Test (IST) are useful instruments in the neuropsychological assessment of older individuals. Several versions of these tests exist in Spanish but normative data specifically set up for Mexican older adult population are missing although Mexico is the country containing the largest population of Spanish speakers and is undergoing a demographic transition with its aging population. Therefore, the aim of the present work was to produce age, educational level, and gender-adjusted normative scores for these tests for the population of older adults living in Mexico. Methods: Data were collected from a sample of 1047 subjects aged 70 years and over who participated in the Coyoacán cohort study, a population-based cohort study conducted in Mexico City. Results: Normative scores, presented in percentiles, were calculated according to age (70-79 and 80 years and over), educational level (0 years of schooling vs. 1-5 years of schooling vs. 6 and more years of schooling), and gender. Conclusion: This work provides norms for the MMSE, the FCSRT, and the IST which should be useful in clinical practice and helpful to better interpret the performances of Mexican older people consulting for memory troubles. 22984862 Brief report: relationships between facets of impulsivity and borderline personality features. Relationships between specific borderline personality disorder (BPD) features and facets of impulsivity (negative and positive urgency, premeditation, perseverance, and sensation seeking) were examined in a sample of 227 undergraduate students, oversampled to include many with elevations on a measure of borderline features. Most facets of impulsivity were positively correlated with borderline features, except for sensation seeking, which showed a mixed pattern of relationships with specific BPD features. In regression models, negative urgency was the strongest predictor of all BPD features scales, including affective instability, identity problems, negative relationships, and self-harm. Premeditation, positive urgency, and sensation seeking demonstrated incremental validity over negative urgency in predicting some BPD features; however, significant beta weights were negative for sensation seeking, suggesting that it may be protective or adaptive for BPD, unlike other forms of impulsivity. This study provides evidence for variation in how types of impulsivity contribute to different BPD features and demonstrates the importance of examining BPD features on the subscale level. 23943314 Z-2-(β-d-glucopyranosyloxy)-3-phenylpropenoic acid, an α-hydroxy acid from rooibos (Aspalathus linearis) with hypoglycemic activity. The rare enolic phenylpyruvic acid-2-O-glucoside, (PPAG:Z-2-(β-d-glucopyranosyloxy)-3-phenylpropenoic acid), is one of the major constituents of fermented rooibos infusions. 3-Phenylpyruvic acid (2-oxo-3-phenylpropanoic acid), without the sugar moiety and with a keto form instead of an enolic arrangement, has been shown to enhance insulin release and glucose uptake in muscle cells. The purpose of this study was to assess if PPAG has similar activity on glucose metabolism. Preliminary in vitro studies confirmed that PPAG, isolated from rooibos, enhanced glucose uptake. A dose-response study in Chang cells showed that PPAG enhanced glucose uptake in the concentration range 1.0-31.6 μM (EC50 = 3.6 μM). In obese insulin-resistant rats, oral administration of PPAG lowered fasting glucose concentrations and improved oral glucose tolerance values; messenger RNA expression of glucokinase, glucose transporter 1 and 2, insulin receptor, peroxisome proliferator-activated receptor alpha, and suppressor of cytokine signaling 3, were increased in the liver. This suggests that the liver is mainly responsible for PPAG bioactivity. This study describes for the first time that PPAG increases in vitro glucose uptake and improves glucose tolerance in an obese insulin-resistant rat model, suggesting that it has potential as a new class of antidiabetic therapeutics that would contribute to the antidiabetic effect of rooibos. 23535146 Monomeric PcrA helicase processively unwinds plasmid lengths of DNA in the presence of the initiator protein RepD. The helicase PcrA unwinds DNA during asymmetric replication of plasmids, acting with an initiator protein, in our case RepD. Detailed kinetics of PcrA activity were measured using bulk solution and a single-molecule imaging technique to investigate the oligomeric state of the active helicase complex, its processivity and the mechanism of unwinding. By tethering either DNA or PcrA to a microscope coverslip surface, unwinding of both linear and natural circular plasmid DNA by PcrA/RepD was followed in real-time using total internal reflection fluorescence microscopy. Visualization was achieved using a fluorescent single-stranded DNA-binding protein. The single-molecule data show that PcrA, in combination with RepD, can unwind plasmid lengths of DNA in a single run, and that PcrA is active as a monomer. Although the average rate of unwinding was similar in single-molecule and bulk solution assays, the single-molecule experiments revealed a wide distribution of unwinding speeds by different molecules. The average rate of unwinding was several-fold slower than the PcrA translocation rate on single-stranded DNA, suggesting that DNA unwinding may proceed via a partially passive mechanism. However, the fastest dsDNA unwinding rates measured in the single-molecule unwinding assays approached the PcrA translocation speed measured on ssDNA. 23970862 Training approach-avoidance of smiling faces affects emotional vulnerability in socially anxious individuals. PREVIOUS RESEARCH REVEALED AN AUTOMATIC BEHAVIORAL BIAS IN HIGH SOCIALLY ANXIOUS INDIVIDUALS (HSAS): although their explicit evaluations of smiling faces are positive, they show automatic avoidance of these faces. This is reflected by faster pushing than pulling of smiling faces in an Approach-Avoidance Task (AAT; Heuer et al., 2007). The current study addressed the causal role of this avoidance bias for social anxiety. To this end, we used the AAT to train HSAs, either to approach smiling faces or to avoid them. We examined whether such an AAT training could change HSAs' automatic avoidance tendencies, and if yes, whether AAT effects would generalize to a new approach task with new facial stimuli, and to mood and anxiety in a social threat situation (a video-recorded self-presentation). We found that HSAs trained to approach smiling faces did indeed approach female faces faster after the training than HSAs trained to avoid smiling faces. Moreover, approach-faces training reduced emotional vulnerability: it led to more positive mood and lower anxiety after the self-presentation than avoid-faces training. These results suggest that automatic approach-avoidance tendencies have a causal role in social anxiety, and that they can be modified by a simple computerized training. This may open new avenues in the therapy of social phobia. 23515338 Cost-effectiveness of a specialized atrial fibrillation clinic vs. usual care in patients with atrial fibrillation. A recent randomized controlled trial demonstrated significant reductions in cardiovascular hospitalizations and deaths with a nurse-led integrated chronic care approach in patients with atrial fibrillation (AF) compared with usual care. The aim of the present study is to assess cost-effectiveness of this nurse-led care programme vs. usual care. A cost-effectiveness analysis was undertaken alongside the randomized controlled trial in which 712 patients were included at the Maastricht University Medical Centre, The Netherlands, and allocated to nurse-led care or usual care. Nurse-led care implied guideline-adherent management, steered by dedicated software, supervised by cardiologists. Usual care was regular outpatient care performed by cardiologists. A cost per life-year and a cost per quality-adjusted life-year (QALY) analysis was performed, both from a hospital perspective. The nurse-led care programme was associated with slightly more life-years and QALYs at a lower cost. Specifically, the nurse-led programme contributed to 0.009 QALY gains with a reduced cost of €1109 per patient and a gain of 0.02 life-years with a reduced cost of €735 per patient. Therefore, the nurse-led programme would be considered dominant. In fact, for all the possible values of willingness to pay for a QALY the nurse-led programme is considered to be more likely cost-effective than the care as usual. The cost-effectiveness analysis in the present study demonstrated that a nurse-led integrated care approach will save costs and improve survival and quality of life, and is therefore a cost-effective management strategy for patients with AF. 23852563 Incidental pineal cysts in children who undergo 3-T MRI. Pineal cysts, both simple and complex, are commonly encountered in children. More cysts are being detected with MR technology; however, nearly all pineal cysts are benign and require no follow-up. To discover the prevalence of pineal cysts in children at our institution who have undergone high-resolution 3-T MRI. We retrospectively reviewed 100 consecutive 3-T brain MRIs in children ages 1 month to 17 years (mean 6.8 ± 5.1 years). We evaluated 3-D volumetric T1-W imaging, axial T2-W imaging, axial T2-W FLAIR (fluid attenuated inversion recovery) and coronal STIR (short tau inversion recovery) sequences. Pineal parenchymal and cyst volumes were measured in three planes. Cysts were analyzed for the presence and degree of complexity. Pineal cysts were present in 57% of children, with a mean maximum linear dimension of 4.2 mm (range 1.5-16 mm). Of these cysts, 24.6% showed thin septations or fluid levels reflecting complexity. None of the cysts demonstrated complete T2/FLAIR signal suppression. No cyst wall thickening or nodularity was present. There was no significant difference between the ages of children with and without cysts. Cysts were more commonly encountered in girls than boys (67% vs. 52%; P = 0.043). There was a slight trend toward increasing pineal gland volume with age. Pineal cysts are often present in children and can be incidentally detected by 3-T MRI. Characteristic-appearing pineal cysts in children are benign, incidental findings, for which follow-up is not required if there are no referable symptoms or excessive size. 23617609 Maternal smoking modulates fatty acid profile of breast milk. We hypothesized that the fatty acid composition of breast milk can be affected by a smoking habit in the mother. Consequently, this study verified whether maternal smoking modulates, and if so to what extent, the breast milk fatty acid profile. The study included 20 postpartum women who declared smoking more than five cigarettes daily throughout a period of pregnancy and lactation, and 136 nonsmoking postpartum women. Breast milk samples were collected between the 17th and the 30th day after delivery. The samples were analysed by means of high-resolution gas chromatography for overall content of saturated, monounsaturated and polyunsaturated fatty acids. Compared with nonsmokers, smokers were characterized by significantly higher relative breast milk contents of fatty acids and monounsaturated fatty acids. Additionally, smokers' breast milk had higher concentrations of selected saturated fatty acids, monounsaturated fatty acids and polyunsaturated fatty acids. Furthermore, smokers were characterized by significantly lower values of linoleic to arachidonic acid ratio and n-6 to n-3 polyunsaturated fatty acids ratio. Aside from its other harmful consequences, smoking modulates the fatty acid profile of human milk. 23642158 Updating the Mitochondrial Free Radical Theory of Aging: An Integrated View, Key Aspects, and Confounding Concepts. Abstract An updated version of the mitochondrial free radical theory of aging (MFRTA) and longevity is reviewed. Key aspects of the theory are emphasized. Another main focus concerns common misconceptions that can mislead investigators from other specialties, even to wrongly discard the theory. Those different issues include (i) the main reactive oxygen species (ROS)-generating site in the respiratory chain in relation to aging and longevity: complex I; (ii) the close vicinity or even contact between that site and the mitochondrial DNA, in relation to the lack of local efficacy of antioxidants and to sub-cellular compartmentation; (iii) the relationship between mitochondrial ROS production and oxygen consumption; (iv) recent criticisms on the MFRTA; (v) the widespread assumption that ROS are simple "by-products" of the mitochondrial respiratory chain; (vi) the unnecessary postulation of "vicious cycle" hypotheses of mitochondrial ROS generation which are not central to the free radical theory of aging; and (vii) the role of DNA repair concerning endogenous versus exogenous damage. After considering the large body of data already available, two general characteristics responsible for the high maintenance degree of long-lived animals emerge: (i) a low generation rate of endogenous damage: and (ii) the possession of tissue macromolecules that are highly resistant to oxidative modification. Antioxid. Redox Signal. 00, 000-000. 23411258 Characterization of 3,4-DHPEA-EDA oxidation products in virgin olive oil by high performance liquid chromatography coupled with mass spectrometry. Secoiridoid derivatives are the most important antioxidants of virgin olive oil (VOO), and their oxidation products could be used as molecular markers of VOO freshness to define the VOO autoxidation state. The aim of this research was to characterise the dialdehydic form of decarboxymethyl elenolic acid linked to hydroxytyrosol (3,4-DHPEA-EDA) oxidation products to find analytical indicators that could be used as early evaluation index of the VOO autoxidation state. 3,4-DHPEA-EDA was oxidised by enzymatic and Fenton reactions. Terpenic structure oxidation products accumulated in VOO during the autoxidation process, thus they may be used as early evaluation index of the VOO autoxidation state before fatty acids oxidation. 23838429 Calmodulin expression distinguishes the smooth muscle cell population of human carotid plaque. Several observations suggest the expansion of a distinct medial smooth muscle cell (SMC) subset in atherosclerosis and restenosis. We characterized the phenotypic features of SMC subsets in cultures derived from human carotid endarterectomy specimens. Specimens comprised an undiseased portion (thin intimal thickening with the underlying media) and a diseased portion (atherosclerotic plaque with the underlying media). From plaque tissues of the diseased portion, only macrophage-derived foam cells were retrieved. From medial tissues, two SMC phenotypes were isolated: large SMCs (flat with a monolayered growth pattern, from the undiseased portion) and small SMCs (fusiform and growing in multilayers, from the undiseased and diseased portions after co-culture with macrophage-derived foam cells). Small SMCs displayed higher proliferative and migratory activities and were less differentiated than large SMCs. Proteomic analysis showed that calmodulin was predominant in small SMCs. Co-culture of large SMCs with macrophage-derived foam cells induced a transition to the small phenotype with increased calmodulin expression. The calmodulin inhibitor W-7 decreased the proliferation of small SMCs and prevented the large to small phenotypic transition. In vivo, calmodulin was markedly expressed in SMCs of atherosclerotic plaques and was barely detectable in the media. Macrophage-derived foam cells promote selective migration from the media of atheroma-prone SMCs characterized by calmodulin overexpression. Further studies of small SMCs could be instrumental in understanding atherosclerosis pathogenesis and in planning therapeutic strategies. 23410041 Development of method for three-point data estimation and SVR-QSAR model to screen anti cancer leads. Present work deals with generation of virtual samples as mathematical modeling of empirical data on the basis of empirical data. The generated samples were used for development of QSAR model. The method deals with extrapolation of sample vector in such a manner that there is conservation of the empirical data distribution. The data distribution has been judged with statistical parameters. The method was implemented with anticancer activity of Gossypol acetic acid against BCL2 target for colorectal cancer. Considering the virtual samples only for model development, model training showed a regression coefficient for leave one out cross validation as 0.996 with 66 virtual samples, and a regression coefficient with external test set data (51 samples) as 0.993. External test set data which were never used in the virtual sample generation showed predicted regression coefficient value of >0.61. On the basis of QSAR model, nine compounds were suggested as anti-BCL2 active compounds. The suggested compounds were further validated by docking study with Gossypol acetic acid and 'Tetrahydroisoquinoline amide substituted phenyl pyrazole' cocrystallized with chimeric BCL2-XL (PDBID: 2W3L) protein. 23921938 Microbial flora of cochlear implants by gene pyrosequencing. To describe the microbial flora associated with cochlear implants (CIs) removed for infectious and noninfectious indications. Prospective, controlled. Academic, tertiary medical center. All patients undergoing CI removal. CIs were removed with aseptic technique and processed for microbial identification. CI microbes were identified with routine culture and speciation and 16s deoxyribonucleic acid 454-pyrosequencing. All CIs had evidence of microbes. Propionibacterium acnes and Acidovorax facilis were more common on noninfected CIs (p = 0.005, 0.031). Staphylococcus aureus was more common on infected CIs (p = 0.003). The microbial profiles associated with CI infection were different from, but overlapped with those of noninfected CIs. Microbial culture with selective media identified pathogens not identified on pyrosequencing. Bacteria are present on all CIs, both with and without evidence of clinical infection, but species differ with clinical status. Empiric therapy for CI infections should include coverage for S. aureus. Gene pyrosequencing and selective culture techniques may yield complementary results that may impact the management of CI infections. 23602987 BDNF-induced local protein synthesis and synaptic plasticity. Brain-derived neurotrophic factor (BDNF) is an important regulator of synaptic transmission and long-term potentiation (LTP) in the hippocampus and in other brain regions, playing a role in the formation of certain forms of memory. The effects of BDNF in LTP are mediated by TrkB (tropomyosin-related kinase B) receptors, which are known to be coupled to the activation of the Ras/ERK, phosphatidylinositol 3-kinase/Akt and phospholipase C-γ (PLC-γ) pathways. The role of BDNF in LTP is best studied in the hippocampus, where the neurotrophin is thought to act at pre- and post-synaptic levels. Recent studies have shown that BDNF regulates the transport of mRNAs along dendrites and their translation at the synapse, by modulating the initiation and elongation phases of protein synthesis, and by acting on specific miRNAs. Furthermore, the effect of BDNF on transcription regulation may further contribute to long-term changes in the synaptic proteome. In this review we discuss the recent progress in understanding the mechanisms contributing to the short- and long-term regulation of the synaptic proteome by BDNF, and the role in synaptic plasticity, which is likely to influence learning and memory formation. This article is part of a Special Issue entitled 'BDNF'. 23877637 Use of analgesic and sedative drugs in VLBW infants in German NICUs from 2003-2010. Very low birth weight (VLBW) infants frequently receive analgesia and/or sedation for painful procedures and mechanical ventilation to avoid negative stress. Yet, concerns remain regarding potential adverse long-term effects of these drugs on VLBW infants' neurocognitive outcome. Recent studies have shown that less invasive surfactant application (LISA) and early nasal CPAP treatment reduce the need for mechanical ventilation and painful procedures. Therefore, these measures might also reduce the application of analgesic and/or sedative drugs in VLBW infants. To evaluate this hypothesis and to identify potential changes in analgesic treatment concepts in recent years, we retrospectively analyzed data on analgesia and sedation, respiratory support, and the method of surfactant application in VLBW infants enrolled in the German Neonatal Network (GNN) trial between 2003 and 2009 (period 1) and compared it with data from infants participating in GNN in 2010 (period 2). In both periods, about one third of all infants were treated with analgesic and/or sedative drugs using a wide variety of substances. The administration of novel drugs such as propofol, sufentanil, or intravenous paracetamol was higher in 2010 (6.7 vs. 12.2 %). Infants who were treated with CPAP only received significantly less analgesic/sedative medication than infants who were mechanically ventilated (12 vs. 65 %, p = <0.001). Similarly, infants treated with LISA received less analgesic or sedative drugs as compared to infants who received surfactant via endotracheal intubation (36 vs. 63 %, p = 0.001). Conclusion: Although both avoidances of mechanical ventilation and less invasive surfactant application are associated with reduced analgesic or sedative treatment, the percentage of VLBW infants who received analgesia and/or sedation remained unchanged in Germany in recent years. 22473789 Androgenic and spermatogenic activity of alkylamide-rich ethanol solution extract of Anacyclus pyrethrum DC. Anacyclus pyrethrum (A. pyrethrum) has been used as Vajikaran Rasayana (aphrodisiac) in traditional Indian ayurvedic medicine to treat male sexual dysfunction, including infertility. Aphrodisiac activity may be due to an increase in the production or effect of androgens, so this study sought to evaluate the androgenic and spermatogenic potential of the alkylamide-rich ethanol solution extract. Male Wistar strain rats weighing between 150 and 180 g were completely randomized divided into five groups. The ethanol solution extract of A. pyrethrum was administered to groups of rats in 50, 100, and 150 mg/kg doses for a period of 28 days, and the action was compared with control and testosterone-treated rats. Thirteen N-alkylamides were detected in the extract by using HPLC/UV/electrospray ionization mass spectrometry method. Extract administration at all the doses produced significant increase in body weight, sperm count, motility, and viability along with serum testosterone, luteinizing hormone, and follicle-stimulating hormone concentrations. Histoarchitecture of testis revealed increased spermatogenic activities. Seminal fructose content was also significantly increased after 28 days of treatment. Our results suggest that the ethanol solution extract of the roots of A. pyrethrum has androgenic potential and may improve male fertility by enhancing spermatogenesis. 23412955 Statistical analysis of heavy metals in Cerastoderma edule glaucum and Venerupis aurea laeta from Ganzirri Lake, Messina (Italy). Our study was carried out on two species of clams, Venerupis aurea laeta and Cerastoderma edule glaucum, from Ganzirri Lake considered as "environmental biomarkers" for their changes in physiology, morphology or distribution under the influence of substances in the environment. The aim of the present study was to conduct a statistical analysis on Venerupis and Cerastoderma to investigate the difference between the two autochthonous clams according to the presence of metals, and to link metal concentrations to the reproductive cycle of clam during 2009-2010. Metal analysis was carried out with inductively coupled plasma mass spectrometry (ICP-MS). Accuracy and precision were assessed by analyzing the certified standard matrix: mussel tissue NIST SRM 2976. The multivariate analysis was made using the SPSS 13.0 software package for Windows (SPSS Inc., Chicago, IL). In this study, the concentrations of some metals found in clam tissues showed seasonal cycles with higher values in summer than in winter. The significances of metal concentrations differences between Venerupis and Cerastoderma samples were estimated with Mann-Whitney U-test. The concentrations of Ag, As, Cd, Mn, Se and Zn show a significant p-level that suggests a difference between the two group samples. Statistical analysis showed that the link of metal concentrations to the reproductive cycles of Venerupis and Cerastoderma was not evident. 23916927 Secretory Phospholipase A2-IIA and Cardiovascular Disease: a Mendelian randomization study. To investigate the role of secretory phospholipase A2-(sPLA2)-IIA in cardiovascular disease. Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase-III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. We conducted a Mendelian randomization meta-analysis of 19 general population studies (8021 incident, 7513 prevalent major vascular events (MVE) in 74,683 individuals) and ten acute coronary syndrome (ACS) cohorts (2520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. PLA2G2A rs11573156 C-allele associated with lower circulating sPLA2-IIA mass (38-44%) and sPLA2 enzyme activity (3-23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C-allele was 1.02(95%CI:0.98,1.06) in general populations and 0.96(95%CI:0.90,1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1 log unit lower sPLA2-IIA mass was 1.04(95%CI:0.96,1.13), and differed from the non-genetic observational estimate (OR0.69;95%CI:0.61,0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events. 23701588 Dietary fat in breast cancer survival. Laboratory evidence suggests a plausible role for dietary fat in breast cancer pathophysiology. We conducted a systematic literature review to assess the epidemiological evidence on the impact of total dietary fat and fat subtypes, measured pre- and/or postcancer diagnosis, in relation to breast cancer-specific and all-cause mortality among breast cancer survivors. Studies were included if they were in English, had a sample size ≥200, and presented the hazard ratio/rate ratio for recurrence, disease-specific mortality, or all-cause mortality (n = 18). Although the results are mixed, most studies suggested that higher saturated fat intake prediagnosis was associated with increased risk of breast cancer-specific and all-cause mortality. Postdiagnostic trans fat intake was associated with a 45% and 78% increased risk of all-cause mortality. Higher monounsaturated fat intake before and after diagnosis was generally associated with increased risk of all-cause and breast cancer-specific mortality, albeit the majority of the studies were statistically nonsignificant. Two studies evaluating omega-3 fat intake suggested an inverse association with all-cause mortality. Although there were too few studies on fat subtypes to draw definitive conclusions, high consumption of saturated fat may exert a detrimental effect on breast cancer-specific and all-cause mortality, whereas omega-3 fat may be beneficial. The inconsistent and limited evidence warrants research to assess the impact of consumption of fat subtypes on breast cancer recurrence and mortality. 23872434 Likelihood-based classification of cryo-EM images using FREALIGN. We describe an implementation of maximum likelihood classification for single particle electron cryo-microscopy that is based on the FREALIGN software. Particle alignment parameters are determined by maximizing a joint likelihood that can include hierarchical priors, while classification is performed by expectation maximization of a marginal likelihood. We test the FREALIGN implementation using a simulated dataset containing computer-generated projection images of three different 70S ribosome structures, as well as a publicly available dataset of 70S ribosomes. The results show that the mixed strategy of the new FREALIGN algorithm yields performance on par with other maximum likelihood implementations, while remaining computationally efficient. 23262271 Characterization of tyrosinase inhibitors in the twigs of Cudrania tricuspidata and their structure-activity relationship study. The twigs of Cudrania tricuspidata were found to show strong tyrosinase inhibitory activity, and further detailed component analysis resulted in the isolation of a new flavanol glucoside, (2S,3S)-2,3-trans-dihydromorin-7-O-β-d-glucoside (1), plus twenty-seven known compounds (2-28). Their structures were elucidated on the basis of ESI-MS and NMR spectral data. Among the isolated compounds, trans-dihydromorin (8), oxyresveratrol (9), and steppogenin (12) were found to exhibit significant tyrosinase inhibition activities. Moreover, the structure-activity relationship of these isolated compounds was also discussed. 23902942 NMDA receptor subunits have different roles in NMDA-induced neurotoxicity in the retina. Loss of retinal ganglion cells (RGCs) is a hallmark of various retinal diseases including glaucoma, retinal ischemia, and diabetic retinopathy. N-methyl-D-aspartate (NMDA)-type glutamate receptor (NMDAR)-mediated excitotoxicity is thought to be an important contributor to RGC death in these diseases. Native NMDARs are heterotetramers that consist of GluN1 and GluN2 subunits, and GluN2 subunits (GluN2A-D) are major determinants of the pharmacological and biophysical properties of NMDARs. All NMDAR subunits are expressed in RGCs in the retina. However, the relative contribution of the different GluN2 subunits to RGC death by excitotoxicity remains unclear. GluN2B- and GluN2D-deficiency protected RGCs from NMDA-induced excitotoxic retinal cell death. Pharmacological inhibition of the GluN2B subunit attenuated RGC loss in glutamate aspartate transporter deficient mice. Our data suggest that GluN2B- and GluN2D-containing NMDARs play a critical role in NMDA-induced excitotoxic retinal cell death and RGC degeneration in glutamate aspartate transporter deficient mice. Inhibition of GluN2B and GluN2D activity is a potential therapeutic strategy for the treatment of several retinal diseases. 23940705 Sarcoptes scabiei Mites Modulate Gene Expression in Human Skin Equivalents. The ectoparasitic mite, Sarcoptes scabiei that burrows in the epidermis of mammalian skin has a long co-evolution with its hosts. Phenotypic studies show that the mites have the ability to modulate cytokine secretion and expression of cell adhesion molecules in cells of the skin and other cells of the innate and adaptive immune systems that may assist the mites to survive in the skin. The purpose of this study was to identify genes in keratinocytes and fibroblasts in human skin equivalents (HSEs) that changed expression in response to the burrowing of live scabies mites. Overall, of the more than 25,800 genes measured, 189 genes were up-regulated >2-fold in response to scabies mite burrowing while 152 genes were down-regulated to the same degree. HSEs differentially expressed large numbers of genes that were related to host protective responses including those involved in immune response, defense response, cytokine activity, taxis, response to other organisms, and cell adhesion. Genes for the expression of interleukin-1α (IL-1α) precursor, IL-1β, granulocyte/macrophage-colony stimulating factor (GM-CSF) precursor, and G-CSF precursor were up-regulated 2.8- to 7.4-fold, paralleling cytokine secretion profiles. A large number of genes involved in epithelium development and keratinization were also differentially expressed in response to live scabies mites. Thus, these skin cells are directly responding as expected in an inflammatory response to products of the mites and the disruption of the skin's protective barrier caused by burrowing. This suggests that in vivo the interplay among these skin cells and other cell types, including Langerhans cells, dendritic cells, lymphocytes and endothelial cells, is responsible for depressing the host's protective response allowing these mites to survive in the skin. 23843961 A Multivariate Surface-Based Analysis of the Putamen in Premature Newborns: Regional Differences within the Ventral Striatum. Many children born preterm exhibit frontal executive dysfunction, behavioral problems including attentional deficit/hyperactivity disorder and attention related learning disabilities. Anomalies in regional specificity of cortico-striato-thalamo-cortical circuits may underlie deficits in these disorders. Nonspecific volumetric deficits of striatal structures have been documented in these subjects, but little is known about surface deformation in these structures. For the first time, here we found regional surface morphological differences in the preterm neonatal ventral striatum. We performed regional group comparisons of the surface anatomy of the striatum (putamen and globus pallidus) between 17 preterm and 19 term-born neonates at term-equivalent age. We reconstructed striatal surfaces from manually segmented brain magnetic resonance images and analyzed them using our in-house conformal mapping program. All surfaces were registered to a template with a new surface fluid registration method. Vertex-based statistical comparisons between the two groups were performed via four methods: univariate and multivariate tensor-based morphometry, the commonly used medial axis distance, and a combination of the last two statistics. We found statistically significant differences in regional morphology between the two groups that are consistent across statistics, but more extensive for multivariate measures. Differences were localized to the ventral aspect of the striatum. In particular, we found abnormalities in the preterm anterior/inferior putamen, which is interconnected with the medial orbital/prefrontal cortex and the midline thalamic nuclei including the medial dorsal nucleus and pulvinar. These findings support the hypothesis that the ventral striatum is vulnerable, within the cortico-stiato-thalamo-cortical neural circuitry, which may underlie the risk for long-term development of frontal executive dysfunction, attention deficit hyperactivity disorder and attention-related learning disabilities in preterm neonates. 23843935 Posttraumatic Stress Disorder and Not Depression Is Associated with Shorter Leukocyte Telomere Length: Findings from 3,000 Participants in the Population-Based KORA F4 Study. A link between severe mental stress and shorter telomere length (TL) has been suggested. We analysed the impact of Posttraumatic Stress Disorder (PTSD) on TL in the general population and postulated a dose-dependent TL association in subjects suffering from partial PTSD compared to full PTSD. Data are derived from the population-based KORA F4 study (2006-2008), located in southern Germany including 3,000 individuals (1,449 men and 1,551 women) with valid and complete TL data. Leukocyte TL was measured using a quantitative PCR-based technique. PTSD was assessed in a structured interview and by applying the Posttraumatic Diagnostic Scale (PDS) and the Impact of Event Scale (IES). A total of 262 (8.7%) subjects qualified for having partial PTSD and 51 (1.7%) for full PTSD. To assess the association of PTSD with the average TL, linear regression analyses with adjustments for potential confounding factors were performed. The multiple model revealed a significant association between partial PTSD and TL (beta = -0.051, p = 0.009) as well as between full PTSD and shorter TL (beta = -0.103, p = 0.014) indicating shorter TL on average for partial and full PTSD. An additional adjustment for depression and depressed mood/exhaustion gave comparable beta estimations. Participants with partial and full PTSD had significantly shorter leukocyte TL than participants without PTSD. The dose-dependent variation in TL of subjects with partial and full PTSD exceeded the chronological age effect, and was equivalent to an estimated 5 years in partial and 10 years in full PTSD of premature aging. 23964022 Molecular diversity subdivides the adult forebrain neural stem cell population. Neural stem cells (NSCs) in the ventricular domain of the subventricular zone (V-SVZ) of rodents produce neurons throughout life while those in humans become largely inactive or may be lost during infancy. Most adult NSCs are quiescent, express glial markers and depend on Notch signaling for their self-renewal and the generation of neurons. Using genetic markers and lineage tracing we identified subpopulations of adult V-SVZ NSCs (Type1, 2 and 3) indicating a striking heterogeneity including activated, brain lipid binding protein (BLBP, FABP7) expressing stem cells. BLBP(+) NSCs are mitotically active components of pinwheel structures in the lateral ventricle walls and persistently generate neurons in adulthood. BLBP(+) NSCs express epidermal growth factor (EGF) receptor, proliferate in response to EGF and are a major clonogenic population in the SVZ. We also find BLBP expressed by proliferative ventricular and subventricular progenitors in the fetal and postnatal human brain. Loss of BLBP(+) stem/progenitor cells correlates with reduced neurogenesis in aging rodents and postnatal humans. These findings of molecular heterogeneity and proliferative differences subdivide the NSC population and have implications for neurogenesis in the forebrain of mammals during aging. Stem Cells 2013. 23763550 The reliability and validity of a research-grade pedometer for children and adolescents with cerebral palsy. The aim of this study was to determine the reliability, validity, and optimal placement of pedometers in children with cerebral palsy (CP) who ambulate without aids. Seventeen participants aged 7 to 17 years with CP (eight males, nine females; mean age 12y 4mo; SD 3y 2mo), who could ambulate without aids, wore four New Lifestyles pedometers (NL-1000) on an elasticized waist belt. Fourteen participants had hemiplegia, two diplegia, and one triplegia; all were classified in Gross Motor Function Classification System (GMFCS) level I (n=8) or II (n=9). Participants completed 3-minute walking and running trials around an indoor course and were videotaped to verify the actual number of steps taken during each trial. Inter-pedometer reliability was determined by comparing pedometer readings using intraclass correlation coefficients (ICCs). Validity was determined by comparing pedometer step counts with video step counts using ICC, t-tests, and Bland-Altman plots. Optimal pedometer placement was determined using Wilcoxon signed-rank tests to compare the percentage error for pedometers positioned on the dominant and non-dominant hips. Excellent reliability (ICC 0.88-0.99) and validity (ICC 0.78-0.95) were demonstrated with no significant difference between the video step counts and pedometer step counts. There was no significant difference between the step counts recorded by pedometers on the dominant and non-dominant hips. This study showed that NL-1000 pedometers have a high degree of reliability and validity in ambulant children with CP in controlled conditions. 23891802 Revealing molecular structure and orientation with Stokes vector resolved second harmonic generation microscopy. We report on measurements and characterization of polarization properties of Second Harmonic (SH) signals using a four-channel photon counting based Stokes polarimeter. In this way, the critical polarization parameters can be obtained concurrently without the need of repeated image acquisition. The critical polarization parameters, including the degree of polarization (DOP), the degree of linear polarization (DOLP), and the degree of circular polarization (DOCP), are extracted from the reconstructed Stokes vector based SH images in a pixel-by-pixel manner. The measurements are further extended by varying the polarization states of the incident light and recording the resulting Stokes parameters of the SH signal. In turn this allows the molecular structure and orientation of the samples to be determined. Use of Stokes polarimetry is critical in determination of the full polarization state of light, and enables discrimination of material properties not possible with conventional crossed-polarized detection schemes. The combination of SHG microscopy and Stokes polarimeter hence makes a powerful tool to investigate the structural order of targeted specimens. 22835042 Fertility and endocrine outcome after robot-assisted laparoscopic myomectomy (RALM). Introduction: Laparoscopic myomectomy has recently gained wide acceptance but this procedure remains technically highly demanding and concerns have been raised about the increased blood loss and an higher risk of postoperative uterine rupture of the pregnant uterus. Objective: The aim of the present study is to evaluate the fertility and endocrine outcome in women underwent robot-assisted laparoscopic myomectomy (RALM). Methods: Data from 48 RALM performed in our department between the years 2007 and 2011 have been collected. Conception rate, abortion rate, incidence of feto-maternal morbidity or severe pregnancy and labor-related complications were reported; FSH and AMH levels and ultrasound valuation of AFC has been made before and 6 months after operation. Number of cesarean sections and vaginal deliveries were described. Results: The average age of the patients was 35 years and median Body Mass Index was 23 kg/m(2) (range 18-35 kg/m(2)). Seven women (13%) became pregnant after RALM with eight pregnancies. One pregnancy is actually on going; there were six deliveries with caesarian section and one spontaneous delivery. No spontaneous abortions. No uterine ruptures occurred. No significant modification of ovarian function was found after myomectomy. Conclusion: RALM seems to have a favorable impact on the reproductive outcome of young patients with no impact on the ovarian function. 22173956 Impact of aqueous doash extract on urinary mutagenicity in rats exposed to heterocyclic amines. Doash (Origanum majorana) is an herbaceous plant found commonly in Saudi Arabia. It is used as a food flavor and a folk remedy to treat a number of diseases. The 2-amino-3-methylimidazo[4,5-f] quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are the most abundant of the heterocyclic amine carcinogens present in cooked food. In the present study, the potential of doash tea to influence carcinogen metabolism was investigated indirectly using heterocyclic amines as model mutagens, IQ and PhIP. Results obtained showed that doash tea had no influence on body weight in both the studies. Rats were treated with different doses of IQ (1, 3, 5 and 10 mg/kg) or PhIP (1, 5, 10 and 20 mg/kg). The selected dosage was 5 mg/kg for both heterocyclic amines. Results obtained revealed that rats treated with doash tea and given a single dose of the heterocyclic amines, whether for 1 day (short-term) or for 1 month (long term), showed a statistically significant decrease in their excretion of indirect mutagens (IQ or PhIP). Following treatment of the rats with a single oral dose of IQ or PhIP, the highest mutagenic activity determined in the presence of an activation system was excreted in the urine after 24 h, with much lower levels of mutagencity being excreted during subsequent elimination from the body. No mutagenicity was observed in the absence of an activation system that is direct-acting mutagenicity using (IQ and PhIP). Statistical analysis revealed that, in comparison with the control group, the aqueous doash extract significantly reduced the mutagenic response after 24 h. It was concluded that doash extract significantly decreased the excretion of mutagens in comparison with the control group (water only). 23878020 Non-operative management of blunt liver injury: a new protocol for selected hemodynamically unstable patients under hypotensive resuscitation. The objective of this study was to evaluate our new protocol for performing non-operative management for selected unstable patients under hypotensive resuscitation using improved diagnostic imaging techniques. This retrospective study included 77 consecutive patients with blunt liver injury. They were divided into two groups: those treated before and those treated after the revision. Under the new protocol, we attempted to manage the patients non-operatively, usually with angioembolization, including those whose shock improved with fluid resuscitation and continuous loading, permitting the maintenance of a target systolic blood pressure of 80 mmHg. The outcomes of the two groups were evaluated and compared. While comparing the groups, although there was no change in the liver-related morbidity and mortality rates, the urgent and overall laparotomy rates and transfusion requirements in 24 h significantly decreased after the protocol revision. While comparing the subgroups of high-grade injury (AAST Grades 3-5), the overall laparotomy rates and transfusion requirements in 24 h significantly decreased after the protocol revision. All the selected unstable patients were successfully managed non-operatively after the protocol revision. The decrease in laparotomy rates and transfusion requirements confirmed the feasibility of our new protocol for these selected patients. 23574575 Altered sleep in Borderline Personality Disorder in relation to the core dimensions of psychopathology. The aim of the study was to review the literature regarding sleep disturbances in Borderline Personality Disorder (BPD) and to relate the reported sleep alterations to the underlying core dimensions of BPD pathology. We present a qualitative and theoretical review regarding the empirical studies that investigated objective and subjective sleep quality in BPD and in different psychiatric conditions showing high co-morbidity with this disorder. We show that disturbed sleep including sleep fragmentation, alterations in Slow Wave Sleep and REM sleep, and dysphoric dreaming are prevalent symptoms in BPD. We provide a framework relating the specific sleep alterations to the core dimensions of BPD pathology in order to clarify the inconsistencies of the different findings. The specific sleep disturbances in BPD seem to be related to different dimensions of psychopathological functioning and may have detrimental consequences on waking affect and cognition. Investigating disturbed sleep in BPD in relation to waking symptoms and underlying neural functioning would shed more light on the nature of this complex disorder. Moreover, a stronger emphasis on sleep disturbances would enrich the treatment protocols of BPD. 23910866 Demonstration of ethyl glucuronide in dental tissue samples by liquid chromatography/electro-spray tandem mass spectrometry. Ethyl glucuronide (EtG) has been studied in various tissues and body fluid for determination of alcohol intake. However, no study, dealing with EtG analysis in dental tissue, was performed so far. In this study, we aimed to demonstrate EtG levels in dental tissue. Michigan Alcohol Screening Test (MAST) was performed to 29 participants. Following the test, cases were divided into three groups as non-hazardous alcohol users, alcohol abusers and 6 controls who verbally declared that they were abstainers. A total of 29 tooth specimens, obtained from participants, was included in the study. These specimens were analyzed using LC/MS/MS. All of the participants included in the study were male. According to the MAST outcomes 14 of the participants were non-hazardous alcohol users, and 9 were alcohol abusers, while 6 patients verbally declared that they were abstainers. Dental tissue analyses revealed EtG levels ranging between EtG0.05) with either outcome when factors including existing calving pattern and heat detection accuracy and efficiency were accounted for. The existing spread in calving pattern, heat detection quality and length of voluntary waiting period were the most influential factors that reduced fertility performance in seasonal-calving herds. 23695436 Contribution of two ζ-carotene desaturases to the poly-cis desaturation pathway in the cyanobacterium Nostoc PCC 7120. The presence of two completely unrelated ζ-carotene desaturases CrtQa and CrtQb in some Nostoc strains is unique. CrtQb is the ζ-carotene desaturase, which was acquired by almost all cyanobacteria. The additional CrtQa can be regarded as an evolutionary relict of the CrtI desaturase present in non-photosynthetic bacteria. By reconstruction of the carotene desaturation pathway, we showed that both enzymes from Nostoc PCC 7120 were active. However, they differed in their preferred utilization of ζ-carotene Z isomers. CrtQa converted ζ-carotene isomers that were poorly metabolized by CrtQb. In this respect, CrtQa complemented the reactions of CrtQb, which is an advantage avoiding dead ends in the poly-cis desaturation pathway. In addition to ζ-carotene desaturation, CrtQa still possesses the Z to E isomerase function of the ancestral desaturase CrtI. Biochemical characterization showed that CrtQb is an enzyme with one molecule of tightly bound FAD and acts as a dehydrogenase transferring hydrogen to oxidized plastoquinone. 23804632 Latent HIV-1 Can Be Reactivated by Cellular Superinfection in a Tat-Dependent Manner, Which Can Lead to the Emergence of Multidrug-Resistant Recombinant Viruses. The HIV-1 latent reservoir represents an important source of genetic diversity that could contribute to viral evolution and multidrug resistance following latent virus reactivation. This could occur by superinfection of a latently infected cell. We asked whether latent viruses might be reactivated when their host cells are superinfected, and if so, whether they could contribute to the generation of recombinant viruses. Using populations of latently infected Jurkat cells, we found that latent viruses were efficiently reactivated upon superinfection. Pathways leading to latent virus reactivation via superinfection might include gp120-CD4/CXCR4-induced signaling, modulation of the cellular environment by Nef, and/or the activity of Tat produced upon superinfection. Using a range of antiviral compounds and genetic approaches, we show that gp120 and Nef are not required for latent virus reactivation by superinfection, but this process depends on production of functional Tat by the superinfecting virus. In a primary cell model of latency in unstimulated CD4 T cells, superinfection also led to latent virus reactivation. Drug-resistant latent viruses were also reactivated following superinfection in Jurkat cells and were able to undergo recombination with the superinfecting virus. Under drug-selective pressure, this generated multidrug-resistant recombinants that were identified by unique restriction digestion band patterns and by population-level sequencing. During conditions of poor drug adherence, treatment interruption or treatment failure, or in drug-impermeable sanctuary sites, reactivation of latent viruses by superinfection or other means could provide for the emergence or spread of replicatively fit viruses in the face of strong selective pressures. 23949058 Tolerance and effectiveness of a new dynamic hand-wrist orthosis in chronic stroke patients. To evaluate tolerance of a new dynamic hand-wrist orthosis and effectiveness on the prevention of progressive wrist contracture and spasticity after stroke. Chronic stroke patients (N = 6) with upper limb spasticity, who had not been able to endure a static orthosis, were provided with a custom-made dynamic orthosis. Tolerance of the orthosis was evaluated by the daily wearing time, and self-reported pain and spasticity. Effectiveness was measured by contracture of wrist and finger flexor muscles, upper limb spasticity and use of spasticity treatment. Outcome measures were collected at time of fitting of the dynamic orthosis (baseline) and after three and six months. Five patients could endure the dynamic orthosis without discomfort for 6 hours daily during the 6-month period. Self-reported spasticity and pain decreased significantly (p < 0.05) compared to wearing the static orthosis. In comparison to baseline, the maximum passive wrist extension increased significantly from -29° to -12° (p < 0.05). Although, no significant change in spasticity was measured, the use of Botulinum Toxin injections decreased for two patients. The majority of the included chronic stroke patients tolerated the new dynamic orthosis for at least 6 hours daily and the use significantly reduced wrist contractures in a 6-month period. 23211426 Liver X Receptors and female reproduction: when cholesterol meets fertility! The role of cholesterol in female reproductive physiology has been suspected for a long time, while the molecular bases were unknown. Cholesterol is the precursor of ovarian steroid biosynthesis and is also essential for fertility. In the uterus, cholesterol is essential to achieve correct contractions at term, but an excessive uterine cholesterol concentration has been associated with contractility defects. Liver X Receptor (LXR) α and LXR β are nuclear receptors activated by oxysterols, oxidized derivatives of cholesterol. Since their discovery, the role of LXR in the control of cholesterol homeostasis has been widely described. Beyond their cholesterol-lowering role, more recent data have linked these nuclear receptors to various physiological processes. In particular, they control ovarian endocrine and exocrine functions, as well as uterine contractility. Their contribution to female reproductive cancers will also be discussed. This review will try to enlighten on the LXR as a molecular link between dietary cholesterol and reproductive diseases in women. In the future, a better comprehension of the various physiological processes regulated by the LXR will help to develop new ligands to prevent or to cure these pathologies in women. 22925550 Acid-induced gelation behavior of soybean protein isolate with high intensity ultrasonic pre-treatments. High intensity ultrasonic (HUS, 20 kHz, 400 W) pre-treatments of soybean protein isolate (SPI) improved the water holding capacity (WHC), gel strength and gel firmness (final elastic moduli) of glucono-δ-lactone induced SPI gels (GISG). Sonication time (0, 5, 20, and 40 min) had a significant effect on the above three properties. 20 min HUS-GISG had the highest WHC (95.53 ± 0.25%), gel strength (60.90 ± 2.87 g) and gel firmness (96340Pa), compared with other samples. Moreover, SH groups and non-covalent interactions of GISG also changed after HUS pre-treatments. The HUS GISG had denser and more uniform microstructures than the untreated GISG. Rheological investments showed that the cooling step (reduce the temperature from 95 to 25 °C at a speed of 2 °C/min) was more important for the HUS GISG network formation while the heat preservation step (keep temperature at 95 for 20 min) was more important for the untreated GISG. HUS reduced the particle size of SPI and Pearson correlation test showed that the particle size of SPI dispersions was negatively correlated with WHC, gel strength and gel firmness. 23925518 Prevalence of Hepatitis B and C Viruses Among Asylum Seekers in Izmir. Hepatitis B and C virus infections are known to be an important health problem all over the World. According to the data from World Health Organization, 350 million people are estimated to have been chronically infected by hepatitis B virus and 180 million people have been infected by hepatitis C virus. Most of the patients are not aware of their illnesses. Hepatitis B and C virus infections are the most common cause of sequel liver disease related to decompensate liver cirrhosis and hepatocellular carcinoma. Many people are obliged to leave their country due to political, economic and social reasons. In Turkey, where there is refugee and asylum seeker problem because of geographical location, we aimed to specify the demographic characteristics of asylum seekers in Izmir and to evaluate the asylum seekers in terms of blood-borne and sexually transmitted diseases such as hepatitis B and C. 23863103 Protein Adsorption at Nanopatterned Surfaces Studied by Quartz Crystal Microbalance with Dissipation and Surface Plasmon Resonance. This paper presents the use of the quartz crystal microbalance with dissipation (QCM-D) combined with surface plasmon resonance (SPR) to probe protein adsorption at nanopatterned surfaces. Three different types of adsorbing materials, representing rigid discrete nanoparticles, dense protein films, and soft low density films have been studied on systematic varied circular nanostructures in the 100-1000 nm size range. Analysis and quantification of the QCM-D response from larger nanostructures could be understood and quantified in the same way as for homogeneous surfaces, while that for nanostructures of 100 and 200 nm diameter was significantly underestimated. Our findings suggest a size limitation of those techniques in analysis of adsorption at nanofeatures. 23307699 Synthesis of a potent antimalarial agent through natural products conjugation. Au naturel! (+)-Usnic acid (green) is a weak antimalarial agent, however, in conjugation with known antimalarial scaffolds and drugs, such as dihydroartemisinin (blue), potent activity against the blood-stage parasite can be seen both in vitro and in vivo. The compound shown exhibits an IC(50) value of 1.4 nM against Plasmodium falciparum in vitro and proved nearly as efficacious as artesunate in a mouse model of infection. 23709367 Pre-therapy Laparoscopic Feeding Jejunostomy is Safe and Effective in Patients Undergoing Minimally Invasive Esophagectomy for Cancer. Laparoscopic feeding jejunostomy is a safe and effective means of providing enteral nutrition in the preoperative phase to esophageal cancer patients. This research is a retrospective case series. This study was conducted in a university tertiary care center. Between August 2007 and April 2012, 153 laparoscopic feeding jejunostomies were performed in patients 10 weeks prior to their definitive minimally invasive esophagectomy. The outcome is measured based on the technique, safety, and feasibility of a laparoscopic feeding jejunostomy in the preoperative phase of esophageal cancer patients. One hundred fifty-three patients underwent a laparoscopic feeding jejunostomy approximately 1 and 10 week(s) prior to the start of their neoadjuvant therapy and definitive minimally invasive esophagectomy, respectively. Median age was 63 years. Of the patients, 75 % were males and 25 % were females. One hundred twenty-seven patients had gastroesophageal junction adenocarcinoma and 26 had squamous cell carcinoma. All patients completed their neoadjuvant chemoradiation therapy. The median operative time was 65 min. We had no intraoperative complications, perforation, postoperative bowel necrosis, bowel torsion, herniation, intraperitoneal leak, or mortality as a result of the laparoscopic feeding jejunostomy. Four patients were noted to have superficial skin infection around the tube, and 11 patients required a tube exchange for dislodgment, clogging, and leaking around the tube. All patients progressed to their definitive surgical esophageal resection. A laparoscopic feeding jejunostomy is technically feasible, safe, and can provide appropriate enteral nutrition in the preoperative phase of esophageal cancer patients. 23847498 Guidelines and quality measures for the diagnosis of optic ataxia. Since the first description of a systematic mis-reaching by Bálint in 1909, a reasonable number of patients showing a similar phenomenology, later termed optic ataxia (OA), has been described. However, there is surprising inconsistency regarding the behavioral measures that are used to detect OA in experimental and clinical reports, if the respective measures are reported at all. A typical screening method that was presumably used by most researchers and clinicians, reaching for a target object in the peripheral visual space, has never been evaluated. We developed a set of instructions and evaluation criteria for the scoring of a semi-standardized version of this reaching task. We tested 36 healthy participants, a group of 52 acute and chronic stroke patients, and 24 patients suffering from cerebellar ataxia. We found a high interrater reliability and a moderate test-retest reliability comparable to other clinical instruments in the stroke sample. The calculation of cut-off thresholds based on healthy control and cerebellar patient data showed an unexpected high number of false positives in these samples due to individual outliers that made a considerable number of errors in peripheral reaching. This study provides first empirical data from large control and patient groups for a screening procedure that seems to be widely used but rarely explicitly reported and prepares the grounds for its use as a standard tool for the description of patients who are included in single case or group studies addressing optic ataxia similar to the use of neglect, extinction, or apraxia screening tools. 23834507 Transcriptional profiling of sweetpotato (Ipomoea batatas) roots indicates down-regulation of lignin biosynthesis and up-regulation of starch biosynthesis at an early stage of storage root formation. The number of fibrous roots that develop into storage roots determines sweetpotato yield. The aim of the present study was to identify the molecular mechanisms involved in the initiation of storage root formation, by performing a detailed transcriptomic analysis of initiating storage roots using next-generation sequencing platforms. A two-step approach was undertaken: (1) generating a database for the sweetpotato root transcriptome using 454-Roche sequencing of a cDNA library created from pooled samples of two root types: fibrous and initiating storage roots; (2) comparing the expression profiles of initiating storage roots and fibrous roots, using the Illumina Genome Analyzer to sequence cDNA libraries of the two root types and map the data onto the root transcriptome database. Use of the 454-Roche platform generated a total of 524,607 reads, 85.6% of which were clustered into 55,296 contigs that matched 40,278 known genes. The reads, generated by the Illumina Genome Analyzer, were found to map to 31,284 contigs out of the 55,296 contigs serving as the database. A total of 8,353 contigs were found to exhibit differential expression between the two root types (at least 2.5-fold change). The Illumina-based differential expression results were validated for nine putative genes using quantitative real-time PCR. The differential expression profiles indicated down-regulation of classical root functions, such as transport, as well as down-regulation of lignin biosynthesis in initiating storage roots, and up-regulation of carbohydrate metabolism and starch biosynthesis. In addition, data indicated delicate control of regulators of meristematic tissue identity and maintenance, associated with the initiation of storage root formation. This study adds a valuable resource of sweetpotato root transcript sequences to available data, facilitating the identification of genes of interest. This resource enabled us to identify genes that are involved in the earliest stage of storage root formation, highlighting the reduction in carbon flow toward phenylpropanoid biosynthesis and its delivery into carbohydrate metabolism and starch biosynthesis, as major events involved in storage root initiation. The novel transcripts related to storage root initiation identified in this study provide a starting point for further investigation into the molecular mechanisms underlying this process. 23821022 Diffusion-weighted MR imaging in primary rectal cancer staging demonstrates but does not characterise lymph nodes. To evaluate the performance of diffusion-weighted MRI (DWI) for the detection of lymph nodes and for differentiating between benign and metastatic nodes during primary rectal cancer staging. Twenty-one patients underwent 1.5-T MRI followed by surgery (± preoperative 5 × 5 Gy). Imaging consisted of T2-weighted MRI, DWI (b0, 500, 1000), and 3DT1-weighted MRI with 1-mm isotropic voxels. The latter was used for accurate detection and per lesion histological validation of nodes. Two independent readers analysed the signal intensity on DWI and measured the mean apparent diffusion coefficient (ADC) for each node (ADCnode) and the ADC of each node relative to the mean tumour ADC (ADCrel). DWI detected 6 % more nodes than T2W-MRI. The signal on DWI was not accurate for the differentiation of metastatic nodes (AUC 0.45-0.50). Interobserver reproducibility for the nodal ADC measurements was excellent (ICC 0.93). Mean ADCnode was higher for benign than for malignant nodes (1.15 ±â€‰0.24 vs. 1.04 ±â€‰0.22 *10(-3) mm(2)/s), though not statistically significant (P = 0.10). Area under the ROC curve/sensitivity/specificity for the assessment of metastatic nodes were 0.64/67 %/60 % for ADCnode and 0.67/75 %/61 % for ADCrel. DWI can facilitate lymph node detection, but alone it is not reliable for differentiating between benign and malignant lymph nodes. • Diffusion-weighted (DW) magnetic resonance imaging (MRI) offers new information in rectal cancer. • DW MRI demonstrates more lymph nodes than standard T2-weighted MRI. • Visual DWI assessment does not discriminate between benign and metastatic nodes. • Apparent diffusion coefficients do not discriminate between benign and metastatic nodes. 23414631 Perceived gender-based barriers to careers in academic surgery. Women represent roughly 50% of US medical students and one third of US surgery residents. Within academic surgery departments, however, women are disproportionately underrepresented, particularly at senior levels. The aim of this study was to test the hypothesis that female surgeons perceive different barriers to academic careers relative to their male colleagues. A modified version of the Career Barriers Inventory-Revised was administered to senior surgical residents and early-career surgical faculty members at 8 academic medical centers using an online survey tool. Likert-type scales were used to measure respondents' agreement with each survey item. Fisher's exact test was used to identify significant differences on the basis of gender. Respondents included 70 women (44 residents, 26 faculty members) and 84 men (41 residents, 43 faculty members). Women anticipated or perceived active discrimination in the form of being treated differently and experiencing negative comments about their sex, findings that differed notably from those for male counterparts. Sex-based negative attitudes inhibited the career aspirations of female surgeons. The presence of overt and implicit bias resulted in a sense that sex is a barrier to female surgeons' career development in academic surgery. No differences were observed between male and female respondents with regard to career preparation or structural barriers. Female academic surgeons experience challenges that are perceived to differ from their male counterparts. Women who participated in this study reported feeling excluded from the dominant culture in departments of surgery. This study may help guide transformative initiatives within academic surgery departments. 23908625 Self-specific stimuli interact differently than non-self-specific stimuli with eyes-open versus eyes-closed spontaneous activity in auditory cortex. Previous studies suggest that there may be a distinct relationship between spontaneous neural activity and subsequent or concurrent self-specific stimulus-induced activity. This study aims to test the impact of spontaneous activity as recorded in an eyes-open (EO) resting state as opposed to eyes-closed (EC) on self-specific versus non-self-specific auditory stimulus-induced activity in fMRI. In our first experiment we used self-specific stimuli comprised of the subject's own name and non-self-specific stimuli comprised of a friend's name and an unknown name, presented during EO versus EC baselines in a 3 name condition × 2 baseline design. In Experiment 2 we directly measured spontaneous activity in the absence of stimuli during EO versus EC to confirm a modulatory effect of the two baseline conditions in the regions found to show an interaction effect in Experiment 1. Spontaneous activity during EO was significantly higher than during EC in bilateral auditory cortex and non-self-specific names yielded stronger signal changes relative to EO baseline than to EC. In contrast, there was no difference in response to self-specific names relative to EO baseline than to EC despite the difference between spontaneous activity levels. These results support an impact of spontaneous activity on stimulus-induced activity, moreover an impact that depends on the high-level stimulus characteristic of self-specificity. 23902515 Laparoscopic donor nephrectomy with Transvaginal extraction: Initial experience of thirty cases. Aim To assess the safety and feasibility of laparoscopic donor nephrectomy with transvaginal extraction and impact of BMI, menopausal status, previous surgery and uterine fibroids. Materials and methods: Five port conventional laparoscopic donor nephrectomy with successful transvaginal extraction of the kidney was performed in 30 donors. The parameters assessed included age, Body mass index (BMI), operative time, estimated blood loss, warm ischemia time, post operative pain score, pre and post operative sexual function, wound complications, hospital stay, return to normal activities, recipient creatinine and other recipient related complications. The data was compared with 30 female donors who had laparoscopic donor nephrectomy and transabdominal extraction Results: The total number of patients consented for the study was 38. In 7 patients intraoperative decision to abort the transvaginal extraction was made due to obesity, pelvic adhesions, large uterine fibroids and uterine artery injury. When compared with transabdominal extraction there was no significant difference in warm ischemia time, mean operating time, estimated blood loss, hospital stay, recipient creatinine and complications. The mean pain score was significantly less on post op day 3 and day 4. There was also an earlier return to normal activities in the transvaginal group. There was no increase in infectious complication in both donors and recipient. Conclusion Based on our initial experience with laparoscopic donor nephrectomy with transvaginal extraction we recommend this procedure for a premenopausal donor, with a BMI less than 30. Our initial cases demonstrate that transvaginal extraction is feasible and safe for the donors. 23836912 Peptide modulation of class I major histocompatibility complex protein molecular flexibility and the implications for immune recognition. T cells use the αβ T cell receptor (TCR) to recognize antigenic peptides presented by class I major histocompatibility complex proteins (pMHCs) on the surfaces of antigen-presenting cells. Flexibility in both TCRs and peptides plays an important role in antigen recognition and discrimination. Less clear is the role of flexibility in the MHC protein; although recent observations have indicated that mobility in the MHC can impact TCR recognition in a peptide-dependent fashion, the extent of this behavior is unknown. Here, using hydrogen/deuterium exchange, fluorescence anisotropy, and structural analyses, we show that the flexibility of the peptide binding groove of the class I MHC protein HLA-A*0201 varies significantly with different peptides. The variations extend throughout the binding groove, impacting regions contacted by TCRs as well as other activating and inhibitory receptors of the immune system. Our results are consistent with statistical mechanical models of protein structure and dynamics, in which the binding of different peptides alters the populations and exchange kinetics of substates in the MHC conformational ensemble. Altered MHC flexibility will influence receptor engagement, impacting conformational adaptations, entropic penalties associated with receptor recognition, and the populations of binding-competent states. Our results highlight a previously unrecognized aspect of the "altered self" mechanism of immune recognition and have implications for specificity, cross-reactivity, and antigenicity in cellular immunity. 23527823 Inhaled dry powder apomorphine (VR040) for 'off ' periods in Parkinson's disease: an in-clinic double-blind dose ranging study. 'Off' periods increase as Parkinson's disease (PD) progresses and the benefits of standard therapy wane. Subcutaneous apomorphine rescues 'off' periods, but patient self-injection and adverse cutaneous effects are sometimes problematic. We assessed safety, tolerability and efficacy of inhaled dry powder apomorphine (VR040) in a double-blind clinic-based Phase II study. Of 48 patients recruited at nine sites, 47 were randomized 2:1 inhaled apomorphine/placebo. Respirable doses (drug predicted to reach the lung), ascending through 1.5, 2.3, 3.0 and 4.0 mg until efficacy was achieved, were administered to patients in a practically defined 'off' state. The primary endpoint was the response in unified PD rating scale Part 3 (UPDRS 3), at the highest dose received by the patient. Secondary endpoints included time to 'on', the proportion of patients converting from 'off' to 'on', and duration of 'on'. In the 47 intent-to-treat patients with PD, mean age 60.6 years, the mean UPDRS 3 improvement was significantly greater for VR040 at 26.8 points (standard deviation 12.0), vs 14.9 (16.3) for placebo (treatment difference 11.6, 95% confidence interval 2.3-20.9, P = 0.016). Rapid apomorphine absorption (2-7 min) translated to rapid (mean 10 min) reversal from the 'off' state. Adverse effects did not differ between VR040 and placebo; no patient discontinued due to an adverse event; one serious adverse event (constipation) in the VR040 group was considered unrelated to trial medication. Inhaled apomorphine shows significant promise as a replacement for intermittent subcutaneous injections; further studies are appropriate to optimize efficacy and tolerability. 23875941 Au-Nanoparticle-Loaded Graphitic Carbon Nitride Nanosheets: Green Photocatalytic Synthesis and Application toward the Degradation of Organic Pollutants. Au nanoparticles (AuNPs) were loaded on graphitic carbon nitride (g-C3N4) nanosheets prepared by ultrasonication-assisted liquid exfoliation of bulk g-C3N4 via green photoreduction of Au(III) under visible light irradiation using g-C3N4 as an effective photocatalyst. The nanohybrids show superior photocatalytic activities for the decomposition of methyl orange under visible-light irradiation to bulk g-C3N4, g-C3N4 nanosheets, and AuNP/bulk g-C3N4 hybrids. 23877875 A superior catalyst with dual redox cycles for the selective reduction of NOx by ammonia. An environmentally benign Cu-Ce-Ti oxide catalyst exhibited excellent NH3-SCR activity, high N2 selectivity and strong resistance against H2O and SO2 with a broad operation temperature window. The dual redox cycles (Cu(2+) + Ce(3+) ↔ Cu(+) + Ce(4+), Cu(2+) + Ti(3+) ↔ Cu(+) + Ti(4+)) play key roles for the superior catalytic deNOx performance. 23886738 Expression of calcium-dependent protein kinase (CDPK) genes under abiotic stress conditions in wild-growing grapevine Vitis amurensis. Calcium-dependent protein kinases (CDPKs), which are important sensors of Ca(2+) flux in plants, are known to play essential roles in plant development and adaptation to abiotic stresses. In the present work, we studied expression of CDPK genes under osmotic and temperature stress treatments in wild-growing grapevine Vitis amurensis Rupr., which is known to possess high adaptive potential and a high level of resistance against adverse environmental conditions. In this study, using RT-PCR with degenerate primers, DNA sequencing and frequency analysis of RT-PCR products, we identified 13 CDPK genes that are actively expressed in healthy V. amurensis cuttings under high salt, high mannitol, desiccation, and temperature stress conditions. 12 CDPKs, namely VaCPK1, VaCPK2, VaCPK3, VaCPK9, VaCPK13, VaCPK16, VaCPK20, VaCPK21, VaCPK25, VaCPK26, VaCPK29 and VaCPK30, were novel for Vitaceae, and their full cDNAs were obtained and described. Quantitative real-time RT-PCR demonstrated that mRNA levels of 10 VaCPK genes were differentially up-regulated under the osmotic and temperature stress treatments, while the abundance of 3 VaCPK transcript variants, VaCPK3a, VaCPK25, and VaCPK30, was not markedly changed. Expression profiling of the VaCPK genes in leaves, leaf petioles, stems, inflorescences, berries, and seeds of V. amurensis revealed that the genes exhibit different organ-specific expression patterns. The stimulatory effect of abiotic stress on the expression of the VaCPK1, 2, 3, 9, 13, 16, 20, 21, 26, and VaCPK29 genes is suggestive of their implication in the grapevine response to osmotic and temperature stresses, while the variability in their organ-specific expression patterns indicates that the enzymes perform distinct biological functions. 23932207 Anticancer drug delivery system based on calcium carbonate particles loaded with a photosensitizer. In photodynamic therapy (PDT), photosensitizers are required to arrive in high concentrations at selective targets like cancer cells avoiding toxicity in healthy tissue. In this work, we propose the application of porous calcium carbonate carriers in the form of polycrystalline vaterite for this task. We investigated the loading efficiency for the photosensitizer Photosens in vaterite micro- and nanocarriers. A possible release mechanism depending on the surrounding pH was studied, showing a fast degradation of the carriers in buffers below pH7. These results hold out the prospect of a novel PDT drug delivery system. Variation of particle size or additional coatings allow custom-design of workload release curves. An intrinsic cancer-sensitivity can be expected from the pH-dependent release in the acidic microenvironment of cancer tissue. 23909885 Analysis of the Impact of the Birmingham OwnHealth Program on Secondary Care Utilization and Cost: A Retrospective Cohort Study. Abstract Background: This study aimed to assess the impact of the Birmingham OwnHealth(®) program (a partnership among the National Health Service [NHS] Birmingham East and North, formerly Birmingham East and North PCT, as the commissioner, Pfizer Health Solutions [Tadworth, United Kingdom] as the primary contractor, and NHS Direct as a subcontractor) on the number of unscheduled secondary care spells and the cost of care for patients with long-term conditions. This article reports a retrospective cohort study conducted at the NHS Birmingham East and North. Subjects and Methods: Adults with at least 1 of 10 defined long-term conditions were eligible for inclusion. Patients in the OwnHealth program were compared with those in a matched comparison group from a population who were eligible but did not enroll in the program. The main outcome measures were the difference in the number of secondary care spells (defined as the experience between hospital admission and discharge) between the OwnHealth group and the comparison group and the difference in the cost of care (calculated from the cost of activities during secondary care spells). Results: The mean number of secondary care spells per person per year in the OwnHealth group was 0.61 (standard deviation [SD] 1.35) compared with 0.84 (SD 1.49) in the comparison group (p<0.0005). This constituted a 27% reduction in secondary care spells per person per year. The mean cost of secondary care spells per person per year in the OwnHealth group was $1,305 (SD $3,138) compared with $1,678 (SD $3,485) in the comparison group (p<0.0005). Discussion: This difference in costs constituted a 27% reduction in utilization and 22% reduction in cost of secondary care with the OwnHealth program. Conclusions: Telehealth intervention can reduce the cost of secondary care of some patients with long-term conditions. 23886007 Linking melanism to brain development: expression of a melanism-related gene in barn owl feather follicles covaries with sleep ontogeny. Intra-specific variation in melanocyte pigmentation, common in the animal kingdom, has caught the eye of naturalists and biologists for centuries. In vertebrates, dark, eumelanin pigmentation is often genetically determined and associated with various behavioral and physiological traits, suggesting that the genes involved in melanism have far reaching pleiotropic effects. The mechanisms linking these traits remain poorly understood, and the potential involvement of developmental processes occurring in the brain early in life has not been investigated. We examined the ontogeny of rapid eye movement (REM) sleep, a state involved in brain development, in a wild population of barn owls (Tyto alba) exhibiting inter-individual variation in melanism and covarying traits. In addition to sleep, we measured melanistic feather spots and the expression of a gene in the feather follicles implicated in melanism (PCSK2). As in mammals, REM sleep declined with age across a period of brain development in owlets. In addition, inter-individual variation in REM sleep around this developmental trajectory was predicted by variation in PCSK2 expression in the feather follicles, with individuals expressing higher levels exhibiting a more precocial pattern characterized by less REM sleep. Finally, PCSK2 expression was positively correlated with feather spotting. We demonstrate that the pace of brain development, as reflected in age-related changes in REM sleep, covaries with the peripheral activation of the melanocortin system. Given its role in brain development, variation in nestling REM sleep may lead to variation in adult brain organization, and thereby contribute to the behavioral and physiological differences observed between adults expressing different degrees of melanism. 23835834 Determination of five active compounds in Artemisia princeps and A. capillaris based on UPLC-DAD and discrimination of two species with multivariate analysis. Five active compounds, chlorogenic acid, 3,5-di-O-caffeoylquinic acid, 4,5-di-O-caffeoylquinic acid, jaceosidin, and eupatilin, in Artemisia princeps (Compositae) were simultaneously determined by ultra-performance liquid chromatography connected to diode array detector. The morphological resemblance between A. princeps and A. capillaris makes it difficult to properly identify species properly. It occasionally leads to misuse or misapplication in Korean traditional medicine. In the study, the discrimination between A. princeps and A. capillaris was optimally performed by the developed validation method, which resulted in definitely a difference between two species. Also, it was developed the most reliable markers contributing to the discrimination of two species by the multivariate analysis methods, such as a principal component analysis and a partial least squares discrimination analysis. 23850272 Annual changes in pulmonary function in combined pulmonary fibrosis and emphysema: Over a 5-year follow-up. Combined pulmonary fibrosis and emphysema (CPFE) is a unique disorder that has been previously described, and the distinct features of CPFE in comparison with chronic obstructive pulmonary disease (COPD) have been reported. However, the yearly dynamics of pulmonary function parameters in CPFE patients compared with those in COPD patients have not yet been reported. We retrospectively enrolled patients with CPFE and COPD who had undergone pulmonary function tests more than five times during a follow-up period of more than five years. The baseline clinical characteristics and the annual changes in pulmonary function during the follow-up period in 16 stable CPFE patients were compared with those in 19 stable COPD patients. Annual changes in pulmonary function were estimated from linear regressions, with assumptions for time-dependency and linearity. We analyzed the time-dependent fluctuations in pulmonary function for the two disorders. Annual decreases in VC and FVC in the CPFE group were significantly higher than those in the COPD group. Annual decrease in FEV1/FVC in the COPD group was significantly higher than in the CPFE group. During the follow-up period, FEV1/FVC in the CPFE group appeared to improve because of annual decrease in FVC. Annual decreases in DLco and DLco/VA in the CPFE group were significantly higher than those in the COPD group. This is the first report showing the yearly dynamics of pulmonary function parameters in CPFE patients compared with those in COPD patients during a follow-up period of more than five years. This study revealed that the physiologic consequences of CPFE including the rate of progression of pulmonary function impairment were different from those of COPD. 23864104 Pure and Part-Solid Pulmonary Ground-Glass Nodules: Measurement Variability of Volume and Mass in Nodules with a Solid Portion Less than or Equal to 5 mm. Purpose:To prospectively assess and compare the measurement variability of volume and mass for pure and part-solid ground-glass nodules (GGNs) with solid portions less than or equal to 5 mm by using a commercially available volumetric software program.Materials and Methods:This prospective study was approved by the institutional review board. Written informed consent was obtained. From November 2011 to June 2012, 73 patients (26 men and 47 women) with 94 GGNs (>5 mm and <20 mm; 72 pure and 22 part-solid GGNs) were prospectively enrolled and underwent two consecutive computed tomographic (CT) examinations. Both the volume and mass of GGNs were measured with volumetric software by two radiologists. Intraobserver, interobserver, and interscan variability were analyzed and compared by using the Bland-Altman method and coefficients of variation. The influence of the solid portion of GGNs and GGN size on interscan variability was investigated with multiple linear regression analysis and analysis of variance.Results:Nodule segmentation was successful in 420 of 438 (95.9%) segmentations. As for volume measurement, interscan variability ranged from -17.3% to 18.5%, while intraobserver and interobserver variability ranged from -7.6% to 8.5% and from -11.7% to 18.1%, respectively. Interscan variability in mass measurement ranged from -17.7% to 18.6%, while intraobserver and interobserver variability ranged from -8.4% to 9.4% and from -17.5% to 11.8%, respectively. In the coefficient of variation comparison, there were no significant differences in volume and mass measurements for intraobserver, interscan, and interobserver variability. Measurement variability of volume and mass was not significantly influenced by the presence of a solid portion, solid portion size, or GGN size.Conclusion:Mass measurement of GGNs showed measurement variability from -17.7% to 18.6% and may be a useful method in the follow-up of GGNs with solid portions less than or equal to 5 mm.© RSNA, 2013. 23915574 Influence of delayed muscle reflexes on spinal stability: Model-based predictions allow alternative interpretations of experimental data. Model-based calculations indicate that reflex delay and reflex gain are both important for spinal stability. Experimental results demonstrate that chronic low back pain is associated with delayed muscle reflex responses of trunk muscles. The aim of the present study was to analyze the influence of such time-delayed reflexes on the stability using a simple biomechanical model. Additionally, we compared the model-based predictions with experimental data from chronic low back pain patients and healthy controls using surface-electromyography. Linear stability methods were applied to the musculoskeletal model, which was extended with a time-delayed reflex model. Lateral external perturbations were simulated around equilibrium to investigate the effects of reflex delay and gain on the stability of the human lumbar spine. The model simulations predicted that increased reflex delays require a reduction of the reflex gain to avoid spinal instability. The experimental data support this dependence for the investigated abdominal muscles in chronic low back pain patients and healthy control subjects. Reflex time-delay and gain dependence showed that a delayed reflex latency could have relevant influence on spinal stability, if subjects do not adapt their reflex amplitudes. Based on the model and the experimental results, the relationship between muscle reflex response latency and the maximum of the reflex amplitude should be considered for evaluation of (patho) physiological data. We recommend that training procedures should focus on speeding up the delayed reflex response as well as on increasing the amplitude of these reflexes. 23503470 Sol-gel nanoglues for an organic binder-free TiO2 nanofiber anode for lithium ion batteries. A TiO2 nanofiber anode is glued using a sol-gel reaction to improve cycle performance and Coulombic efficiencies. The hydrolysis-condensation process produces TiO2 nanoglues consisting of TiO2 nanoparticles, providing strong adhesion between nanofibers and the current collector as well as between nanofibers, rendering favourable transporting properties of electrons and Li ions in the TiO2 nanofiber electrode, and eventually leading to the excellent performance of Li ion batteries exhibiting an excellent initial Coulombic efficiency (~85%), cycle performance up to 100 cycles, and high rate capability (60% at 5 C). 23940218 Histologic and Clinical Characteristics Can Guide Staging Evaluations for Children and Adolescents With Rhabdomyosarcoma: A Report From the Children's Oncology Group Soft Tissue Sarcoma Committee. To simplify the recommended staging evaluation by correlating tumor and clinical features with patterns of distant metastasis in newly diagnosed patients with embryonal rhabdomyosarcoma (ERMS) or alveolar rhabdomyosarcoma (ARMS). Patient data from the Intergroup Rhabdomyosarcoma Study Group and the Children's Oncology Group over two periods were analyzed: 1991 to 1997 and 1999 to 2004. We used recursive partitioning analyses to identify factors (including histology, age, regional nodal and distant metastatic status, tumor size, local invasiveness, and primary site) that divided patients into subsets with the most different rates of metastatic disease. Of the 1,687 patients analyzed, 5.7% had lung metastases, 4.8% had bone involvement, and 6% had bone marrow (BM) involvement. Rhabdomyosarcoma (RMS) without local invasion (T1) had a low rate of metastasis for all distant sites, especially ERMS (0% bone, 0% BM). ARMS with local invasion (T2) had a higher rate of metastasis for all distant sites (13% lung, 18% bone, 23% BM). ERMS, T2 also had a higher rate of metastatic lung involvement (9%). The likelihood of bone or BM involvement increased in the presence of lung metastases (41% with, 6% without). Regional nodal metastases (N1) predicted a high rate of metastasis in all distant sites (14% lung, 14% bone, 18% BM). A staging algorithm was developed. Staging studies in childhood RMS can be tailored to patients' presenting characteristics. Bone marrow aspirate and biopsy and bone scan are unnecessary in at least one third of patients with RMS. 23207322 pH-responsive composite microspheres based on magnetic mesoporous silica nanoparticle for drug delivery. pH-responsive composite microspheres, consisting of a core of Fe3O4 nanoparticle, a sandwiched layer of mesoporous silica and a shell of crosslinked poly (methacrylic acid) (PMAA), were successfully synthesized via distillation precipitation polymerization. The pKa of the composite microsphere increased with the increase in the crosslinking density. Doxorubicin hydrochloride (DOX) was applied as a model drug, and the behavior of drug storage/release was investigated. The cumulative release of DOX-loaded composite microsphere in vitro showed that the drug release rate was much faster below its pKa than that of above its pKa. Because pH of most tumor tissues was lower than that of normal tissues, the pH-responsive composite microspheres are promising drug delivery system especially for cancer therapy. 23528608 Probing the interaction of oppositely charged gold nanoparticles with DPPG and DPPC Langmuir monolayers as cell membrane models. The growing use of nanoparticles in a variety of applications calls for detailed studies of their toxicology, which in turn require understanding the interactions between nanoparticles and living cells. Since simulating the interaction with real cell membranes is rather complex, Langmuir monolayers (LMs) have been used to mimic the first barrier encountered by a nanoparticle as it approaches a biological membrane to assess molecular-level interactions. In this study, we show how oppositely charged gold nanoparticles (Au-NPs) interact with monolayers of the zwitterionic dipalmitoylphosphatidyl choline (DPPC) and negatively charged dipalmitoylphosphatidyl glycerol (DPPG). The monolayers were spread on subphases containing two concentrations of either negatively charged Au-NPs coated with citrate anions or positively charged Au-NPs functionalized with the cationic polyelectrolyte poly(allylamine hydrochloride) (PAH). For DPPG, electrostatic effects dominated which depended strongly on the NPs capping agent, being obviously larger for the positive nanoparticles. The in-plane elasticity for DPPG monolayers within the surface pressure range corresponding to real cell membranes increased with adsorption of positively charged NPs, but decreased with the negative ones. For the zwitterionic DPPC, on the other hand, significant effects only occurred for negatively charged NPs, including a decrease in elasticity. Therefore, it is concluded that the nature, namely the charge of the capping agents, is crucial for the interaction of charged NPs with the cell membrane. 23832952 The value of community-focused interprofessional care in peru for developing cultural competency in health professions students. International immersion experiences for health-care students have increased over the past 10 years. Students and faculty expect these experiences to increase cultural competency; however, research on outcomes of these programs has lacked rigor. Over a 4-year period, groups of nursing and other health professions students spent 3 weeks in Peru providing primary care and health education. Students attended pre-departure seminars addressing personal travel health and safety, culture and health care in Peru, working with interpreters, and ethics of international health care. Student participants (N=77) completed an instrument assessing self-perceived cultural competency before and after the experience. Results of pre- and post-immersion scores showed significant increases in perceived cultural competency and increased self-efficacy in cultural knowledge, skills, and attitudes for four groups of students. Implications and future directions are discussed and recommended. 23938876 Computational study of porphyrin-based dyes with better performance. Using density functional theory (DFT) and time-dependent DFT in different levels, we have systematically studied new porphyrin-based dyes with A-π-D structures focusing on optical absorption, light harvest efficiency, ground state oxidation potential, excited state oxidation potential, and natural transition orbitals. Compared with existing dyes, we find that these new dyes have wide absorption regions (400-1000 nm) with high molar extinction coefficients, and display good energy level alignment for efficient injection of electrons and fast regeneration of the oxidized dyes. 23588078 Blood culture results do not affect treatment in complicated cellulitis. Cellulitis, a frequently encountered complaint in the Emergency Department, is typically managed with antibiotics. There is some debate as to whether obtaining blood cultures and knowing their results would change the management of cellulitis, although most authors argue that information from blood cultures does not change the empirical management of uncomplicated cellulitis. However, for complicated cellulitis (as defined by the presence of significant comorbidity), there is considerable disagreement and lack of evidence as to the utility of blood cultures. Our aim was to determine the role of blood cultures in the management of complicated cellulitis. This retrospective chart review assessed the utility of obtaining blood cultures in complicated cellulitis (as defined by active chemotherapy, dialysis, human immunodeficiency virus/acquired immune deficiency syndrome, diabetes, or organ transplantation) vs. a cohort of individuals without medical comorbidity. Six hundred and thirty-nine patients were identified, 314 of which were deemed cases and 325 controls. Within the cases, 29 of 314 returned as positive blood cultures vs. 17 of 325 positive blood culture controls within the cases (p = 0.05; odds ratio = 1.84; 95% confidence interval 0.99-3.43). A clinically significant change in management (a change in the class of antibiotic) was found in 6 of 314 cases vs. 4 of 325 controls (p = 0.578; odds ratio = 1.5525; 95% confidence interval 0.434-5.5541). Within this cohort of patients with complicated cellulitis, blood cultures rarely changed management from empirical coverage. 23847254 Irreversible Electroporation: Treatment Effect is Susceptible to Local Environment and Tissue Properties. Purpose:To study the effects of the surrounding electrical microenvironment and local tissue parameters on the electrical parameters and outcome of irreversible electroporation (IRE) ablation in porcine muscle, kidney, and liver tissue.Materials and Methods:Animal Care and Use Committee approval was obtained, and National Institutes of Health guidelines were followed. IRE ablation (n = 90) was applied in muscle (n = 44), kidney (n = 28), and liver (n = 18) tissue in 18 pigs. Two electrodes with tip exposure of 1.5-2 cm were used at varying voltages (1500-3000 V), pulse repetitions (n = 70-100), pulse length (70-100 µsec), and electrode spacing (1.5-2 cm). In muscle tissue, electrodes were placed exactly parallel, in plane, or perpendicular to paraspinal muscle fibers; in kidney tissue, in the cortex or adjacent to the renal medulla; and in liver tissue, with and without metallic or plastic plates placed 1-2 cm from electrodes. Ablation zones were determined at gross pathologic (90-120 minutes after IRE) and immunohistopathologic examination (6 hours after) for apoptosis and heat-shock protein markers. Multivariate analysis of variance with multiple comparisons and/or paired t tests and regression analysis were used for analysis.Results:Mean (± standard deviation) ablation zones in muscle were 6.2 cm ± 0.3 × 4.2 cm ± 0.3 for parallel electrodes and 4.2 cm ± 0.8 × 3.0 cm ± 0.5 for in-plane application. Perpendicular orientation resulted in a cross-shaped zone. Orientation significantly affected IRE current applied (28.5-31.7A for parallel, 29.5-39.7A for perpendicular; P = .003). For kidney cortex, ovoid zones of 1.5 cm ± 0.1 × 0.5 cm ± 0.0 to 2.5 cm ± 0.1 × 1.3 cm ± 0.1 were seen. Placement of electrodes less than 5 mm from the medullary pyramids resulted in treatment effect arcing into the collecting system. For liver tissue, symmetric 2.7 cm ± 0.2 × 1.4 cm ± 0.3 coagulation areas were seen without the metallic plate but asymmetric coagulation was seen with the metallic plate.Conclusion:IRE treatment zones are sensitive to varying electrical conductivity in tissues. Electrode location, orientation, and heterogeneities in local environment must be considered in planning ablation treatment.© RSNA, 2013Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122590/-/DC1. 23845781 Dynamic expression of 3' UTRs revealed by Poisson hidden Markov modeling of RNA-Seq: Implications in gene expression profiling. RNA sequencing (RNA-Seq) allows for the identification of novel exon-exon junctions and quantification of gene expression levels. We show that from RNA-Seq data one may also detect utilization of alternative polyadenylation (APA) in 3' untranslated regions (3' UTRs) known to play a critical role in the regulation of mRNA stability, cellular localization and translation efficiency. Given the dynamic nature of APA, it is desirable to examine the APA on a sample by sample basis. We used a Poisson hidden Markov model (PHMM) of RNA-Seq data to identify potential APA in human liver and brain cortex tissues leading to shortened 3' UTRs. Over three hundred transcripts with shortened 3' UTRs were detected with sensitivity >75% and specificity >60%. Tissue-specific 3' UTR shortening was observed for 32 genes with a q-value≤0.1. When compared to alternative isoforms detected by Cufflinks or MISO, our PHMM method agreed on over 100 transcripts with shortened 3' UTRs. Given the increasing usage of RNA-Seq for gene expression profiling, using PHMM to investigate sample-specific 3' UTR shortening could be an added benefit from this emerging technology. 23220749 Apomorphine is a bimodal modulator of TRPA1 channels. Apomorphine is a non-narcotic derivative of morphine, which acts as a dopamine agonist and is clinically used to treat "off-states" in patients suffering from Parkinson's disease. Adverse effects of apomorphine treatment include severe emesis and nausea, and ulceration and pain at the injection site. We wanted to test whether sensory transient receptor potential (TRP) channels are a molecular target for apomorphine. Here, we show that rTRPV1, rTRPV2, rTRPV3, and mTRPV4, as well as hTRPM8, and rTRPM3, which are expressed in dorsal root ganglion neurons, are insensitive toward apomorphine treatment. This also applied to the cellular redox sensor hTRPM2. On the contrary, human TRPA1 could be concentration-dependently modulated by apomorphine. Whereas the addition of apomorphine in the low micromolar range produced an irreversible activation of the channel, application of higher concentrations caused a reversible voltage-dependent inhibition of heterologously expressed TRPA1 channels, resulting from a reduction of single-channel open times. In addition, we provide evidence that apomorphine also acts on endogenous TRPA1 in cultured dorsal root ganglion neurons from rats and in the enterochromaffin model cell line QGP-1, from which serotonin is released upon activation of TRPA1. Our study shows that human TRPA1 is a target for apomorphine, suggesting that an activation of TRPA1 might contribute to adverse side effects such as nausea and painful injections, which can occur during treatment with apomorphine. 23967111 Genetic imprint of vaccination on simian/human immunodeficiency virus type 1 transmitted viral genomes in rhesus macaques. Understanding the genetic, antigenic and structural changes that occur during HIV-1 infection in response to pre-existing immunity will facilitate current efforts to develop an HIV-1 vaccine. Much is known about HIV-1 variation at the population level but little with regard to specific changes occurring in the envelope glycoprotein within a host in response to immune pressure elicited by antibodies. The aim of this study was to track and map specific early genetic changes occurring in the viral envelope gene following vaccination using a highly controlled viral challenge setting in the SHIV macaque model. We generated 449 full-length env sequences from vaccinees, and 63 from the virus inoculum. Analysis revealed a different pattern in the distribution and frequency of mutations in the regions of the envelope gene targeted by the vaccine as well as different patterns of diversification between animals in the naïve control group and vaccinees. Given the high stringency of the model it is remarkable that we were able to identify genetic changes associated with the vaccination. This work provides insight into the characterization of breakthrough viral populations in less than fully efficacious vaccines and illustrates the value of HIV-1 Env SHIV challenge model in macaques to unravel the mechanisms driving HIV-1 envelope genetic diversity in the presence of vaccine induced-responses. 23833038 The effect of blood collection procedure on plasma renin activity (PRA) and concentrations of direct renin (DRC) and aldosterone. Performing measurements of plasma renin activity (PRA) or direct renin concentration (DRC) and aldosterone concentration, we should be well informed about requirements concerning blood sample processing. Forty-seven patients had blood collected in the supine and upright positions. Blood was withdrawn into two EDTA2K tubes and one with clot activator. One EDTA2K tube was cooled at +4°C and centrifuged at +4°C whereas the other was prepared at room temperature. PRA and DRC were measured by radioimmunoassay (RIA) and radioimmunometry (IRMA), respectively, in both cooled and not cooled plasma samples, and aldosterone was measured by RIA in not cooled plasma and in serum. In all the groups, with low, medium, and high values of PRA and direct renin, the temperature of sample processing within 30 minutes had no marked influence on the final result (correlation coefficient for renin was 0.9994, and for PRA, 0.8297). The measured concentrations of aldosterone also showed high correlation (r = 0.9790) but were markedly higher in plasma. The measurements of DRC, and to a lesser extent PRA, were similar regardless of temperature condition during the 20-30 minutes necessary for blood sample processing. Aldosterone concentrations in plasma vs serum samples appeared to be markedly higher. 23926089 Development and validation of the spondyloarthritis radiography module for calibration of readers using the modified stoke ankylosing spine score. Objective. To develop and validate a reference image module aimed at calibration of readers using the modified Stoke Ankylosing Spondylitis Spine Score to assess radiographic progression in spondyloarthritis. Methods. Our working group comprised 6 rheumatologists and 3 musculoskeletal radiologists.. The following developmental steps were conducted: 1. Review of the literature to identify aspects of the mSASSS requiring methodological clarity. 2. Independent assessment of baseline and 2 year radiographs from 25 patients using the mSASSS (pilot exercise). 3. Development of a training module (the SPAR module) that clarifies definitions, rules and scoring methodology, and a set of reference radiographic images. 4. Scoring exercise 1 by 6 readers on 39 patients where baseline and 2 year radiographs were scored blinded to time point. 5. Revision of SPAR module followed by scoring exercise 2 conducted by the same 6 readers on 35 patients. Reliability of status and 2-year change scores was assessed by the intraclass correlation method (ICC). Results. ICC for change scores for the radiologist reader pair improved from 0.46 to 0.62 after minimal calibration with the SPAR module. Recalibration from exercise 1 to exercise 2 with the SPAR module led to substantial improvement in inter-reader reliability for change in mSASSS score from ICC (range) = 0.44 (0.31-0.62) to ICC = 0.62 (0.34-0.84). Simultaneous assessment of AP and lateral lumbar radiographs did not enhance reliability or detection of progression. Conclusion. Calibration according to the SPAR module led to improved reliability in the scoring of the mSASSS even for expert readers. © 2013 American College of Rheumatology. 23821295 Persistent Left Superior Vena Cava in Cardiac Congenital Surgery. Persistent left superior vena cava (LSVC) is a relatively frequent finding in congenital cardiac malformation. The scope of the study was to analyze the timing of diagnosis of persistent LSVC, the timing of diagnosis of associated anomalies of the coronary sinus, and the global impact on morbidity and mortality of persistent LSVC in children with congenital heart disease after cardiac surgery. Retrospective analysis of a cohort of children after cardiac surgery on bypass for congenital heart disease. Three hundred seventy-one patients were included in the study, and their median age was 2.75 years (IQR 0.65-6.63). Forty-seven children had persistent LSVC (12.7 %), and persistent LSVC was identified on echocardiography before surgery in 39 patients (83 %). In three patients (6.4 %) with persistent LSVC, significant inflow obstruction of the left ventricle developed after surgery leading to low output syndrome or secondary pulmonary hypertension. In eight patients (17 %), persistent LSVC was associated with a partially or completely unroofed coronary sinus and in two cases (4 %) with coronary sinus ostial atresia. Duration of mechanical ventilation was significantly shorter in the control group (1.2 vs. 3.0 days, p = 0.04), whereas length of stay in intensive care did not differ. Mortality was also significantly lower in the control group (2.5 vs. 10.6 %, p = 0.004). The results of study show that persistent LSVC in association with congenital cardiac malformation increases the risk of mortality in children with cardiac surgery on cardiopulmonary bypass. Recognition of a persistent LSVC and its associated anomalies is mandatory to avoid complications during or after cardiac surgery. 23873851 Uracil DNA glycosylase expression determines human lung cancer cell sensitivity to pemetrexed. Uracil misincorporation into DNA is a consequence of pemetrexed inhibition of thymidylate synthetase. The base excision repair (BER) enzyme, uracil DNA glycosylase (UNG) is the major glycosylase responsible for removal of misincorporated uracil. We previously illustrated hypersensitivity to pemetrexed in UNG(-/-) human colon cancer cells. Here, we examined the relationship between UNG expression and pemetrexed sensitivity in human lung cancer. We observed a spectrum of UNG expression in human lung cancer cells. Higher levels of UNG are associated with pemetrexed resistance and are present in cell lines derived from pemetrexed-resistant histological subtypes (small cell and squamous cell carcinoma). Acute pemetrexed exposure induces UNG protein and mRNA, consistent with up-regulation of uracil-DNA repair machinery. Chronic exposure of H1299 adenocarcinoma cells to increasing pemetrexed concentrations established drug-resistant sublines. Significant induction of UNG protein confirmed up-regulation of BER as a feature of acquired pemetrexed resistance. Co-treatment with the BER inhibitor, methoxyamine (MX) overrides pemetrexed resistance in chronically exposed cells, underscoring the utility of BER directed therapeutics to offset acquired drug resistance. Expression of UNG-directed siRNA and shRNA enhanced sensitivity in A549 and H1975 cells, and in drug-resistant sublines, confirming that UNG up-regulation is protective. In human lung cancer, UNG deficiency is associated with pemetrexed-induced retention of uracil in DNA that destabilizes DNA replication forks resulting in DNA double strand breaks and cell death. Thus, in experimental models, UNG is a critical mediator of pemetrexed sensitivity that warrants evaluation to determine clinical value. 23809873 Effect of prenatal alcohol exposure on bony craniofacial development: a mouse MicroCT study. Craniofacial bone dysmorphology is an important but under-explored potential diagnostic feature of fetal alcohol spectrum disorders. This study used longitudinal MicroCT 3D imaging to examine the effect of prenatal alcohol exposure on craniofacial bone growth in a mouse model. C57BL/6J dams were divided into 3 groups: alcohol 4.2% v/v in PMI® liquid diet (ALC), 2 weeks prior to and during pregnancy from embryonic (E) days 7-E16; pair-fed controls (PF), isocalorically matched to the ALC group; chow controls (CHOW), given ad libitum chow and water. The MicroCT scans were performed on pups on postnatal days 7 (P7) and P21. The volumes of the neurocranium (volume encased by the frontal, parietal, and occipital bones) and the viscerocranium (volume encased by the mandible and nasal bone), along with total skull bone volume, head size, and head circumference were evaluated using general linear models and discriminant analyses. The pups in the alcohol-treated group, when compared to the chow-fed controls (ALC vs CHOW) and the isocaloric-fed controls (ALC vs PF), showed differences in head size and circumference at P7 and P21, the total skull volume and parietal bone volume at P7, and volume of all the tested bones except nasal at P21. There was a growth trend of ALC < CHOW and ALC < PF. While covarying for gender and head size or circumference, the treatment affected the total skull and mandible at P7 (ALC > CHOW), and the total skull, parietal bone, and occipital bone at P21 (ALC < CHOW, ALC < PF). While covarying for the P7 measures, the treatment affected only the 3 neurocranial bones at P21 (ALC < CHOW, ALC < PF). Discriminant analysis sensitively selected between ALC and CHOW (AUC = 0.967), between ALC and PF (AUC = 0.995), and between PF and CHOW (AUC = 0.805). These results supported our hypothesis that craniofacial bones might be a reliable and sensitive indicator for the diagnosis of prenatal alcohol exposure. Significantly, we found that the neurocranium (upper skull) was more sensitive to alcohol than the viscerocranium (face). 23896191 Tetanus, Diphtheria, Acellular Pertussis Vaccine during Pregnancy: Pregnancy and Infant Health Outcomes. To assess pregnancy and birth outcomes in infants born to women who did or did not receive tetanus, diphtheria, acellular pertussis (Tdap) vaccine during pregnancy. Retrospective cohort. Pregnant women 12-45 years of age who received Tdap at Intermountain Healthcare facilities and their infants were identified and compared with mother-infant pairs without documented Tdap from May 2005 through August 2009. Primary measures included pregnancy outcomes and infant health outcomes at birth through 12 months. From 162 448 pregnancies we identified 138 women (0.08%) with documented Tdap administration during pregnancy (cases); 552 pregnant women without documented Tdap were randomly selected as controls. Of 138 immunized women, 63% received Tdap in the first trimester and 37% after. Tdap was given most commonly as wound prophylaxis. The incidence of spontaneous or elective abortion was no greater in Tdap cases than in controls. There were no significant differences in preterm delivery, gestational age, or birth weight between groups. One or more congenital anomaly was identified in 3.7% (95% CI 1.2%-8.5%) of case infants and 4.4% (95% CI 2.7%-6.5%) of control infants (P = .749). In infants born to women receiving Tdap during pregnancy, 3.6% (0.8%-10.2%) had International Classification of Diseases, Ninth Revision, Clinical Modification diagnoses consistent with complex chronic conditions within 12 months compared with 10.4% (95% CI 7.2%-14.4%) of infants of controls (P = .054). Documented Tdap administration during pregnancy was uncommon and occurred most often in the first trimester as prophylaxis following trauma. No increase in adverse outcomes was identified in infants born to women receiving Tdap compared with infants of controls. 23957651 Review article: small intestinal bacterial overgrowth - prevalence, clinical features, current and developing diagnostic tests, and treatment. The symptoms and signs of small intestinal bacterial overgrowth (SIBO) are often identical to a variety of diseases and can lead to diagnostic confusion. To review the diagnostic options for SIBO and present new investigative options for the condition. A literature search was performed on MEDLINE, EMBASE and Web of Science for English articles and abstracts. Search terms included free text words and combinations of the following terms 'small intestinal bacterial overgrowth', 'small bowel bacterial overgrowth', 'diagnostic tests', 'treatment', 'antibiotics', 'probiotics', 'metabonomics', 'proton nuclear magnetic resonance spectroscopy', 'electronic nose' and 'field asymmetric ion mobility spectrometry'. All of the available methods to test for SIBO have inherent limitations and no 'gold-standard' diagnostic test for the condition exists. Accurate diagnosis of SIBO requires identification of bacterial species growing inappropriately within the small intestine and symptom response to antibiotics. Proton nuclear magnetic resonance spectroscopy, electronic nose technology and/or field asymmetric ion mobility spectrometry may represent better investigative options for the condition. Novel diagnostic options are needed to supplement or replace available tests. 23855770 Evolutionary variation in the mechanics of fiddler crab claws. Fiddler crabs, genus Uca, are classic examples of how intense sexual selection can produce exaggerated male traits. Throughout the genus the enlarged "major" cheliped (claw) of the male fiddler crab is used both as a signal for attracting females and as a weapon for combat with other males. However, the morphology of the major claw is highly variable across the approximately 100 species within the genus. Here we address variation, scaling, and correlated evolution in the mechanics of the major claw by analyzing the morphology and mechanical properties of the claws of 21 species of fiddler crabs from the Pacific, Gulf and Atlantic coasts of the Americas. We find that the mechanics that produce claw closing forces, the sizes of claws and the mechanical strength of the cuticle of claws are all highly variable across the genus. Most variables scale isometrically with body size across species but claw force production scales allometrically with body size. Using phylogenetically independent contrasts, we find that the force that a claw can potentially produce is positively correlated with the strength of the cuticle on the claw where forces are delivered in a fight. There is also a negative correlation between the force that a claw can potentially produce and the size of the claw corrected for the mass of the claw. These relationships suggest that there has been correlated evolution between force production and armoring, and that there is a tradeoff between claw mechanics for signaling and claw mechanics for fighting. 23832808 Quantitative analysis of organophosphorus pesticides in freshwater using an optimized firefly luciferase-based coupled bioluminescent assay. In this paper, a coupled bioluminescent assay, relying on the coupling of the enzymes acetylcholinesterase, S-acetyl-coenzyme A synthetase and firefly luciferase, for the detection and quantitation of organophosphorus pesticides, is presented. Using malathion as a model organophosphorus pesticide, the assay was optimized through statistical experimental design methodology, namely Plackett-Burman and central composite designs. The optimized method requires only 20 μL of sample. The linear range for the assay was 2.5-15 μM of malathion, with limits of detection and quantitation of 1.5 and 5.0 μM, respectively. This simple, fast and robust method allows samples to be analyzed at room temperature and without any pretreatment. Copyright © 2013 John Wiley & Sons, Ltd. 23917645 Optimal Schedule of Preoperative Embolization for Spinal Metastasis Surgery. Study Design. A retrospective study.Objective. To investigate the relationship between intraoperative blood loss during spinal metastasis surgery and the surgical delay after preoperative embolization.Summary of Background Data. Delaying surgery after embolization is believed to diminish its effectiveness because of revascularization, but there has been no scientific study that supports this hypothesis.Methods. We reviewed data from 66 consecutive posterior palliative decompression surgeries for spinal metastasis from thyroid and renal cell carcinoma (39 thyroid and 27 renal) in 58 patients between 2004 and 2012. All patients underwent preoperative angiography. The timing of preoperative embolization was determined on the operating room and interventional radiologist schedules. Excluding one case who did not receive embolization due to lack of hypervascularity, we analyzed 65 cases to compare intraoperative blood loss according to the completeness of embolization and the time lapse between embolization and surgery.Results. Surgeries were performed on the same day of embolization in 21 cases (same day group), and on the next day after embolization in 39 cases (next day group). Five surgeries were performed two days later. The intraoperative blood loss was significantly smaller with complete embolization than with partial embolization (mean ± SD: 809 ± 835 vs. 1210 ± 904 mL, p = 0.03). Among those with complete embolization, the intraoperative blood loss as well as the perioperative transfusion requirement was significantly smaller in the same day group than in the next day group (mean ± SD: blood loss: 433 ± 376 vs. 1012 ± 974 mL, p = 0.01; transfusion requirement: 1.5 ± 1.7 vs. 4.2 ± 4.1 units, p = 0.04).Conclusions. Preoperative embolization showed greater effectiveness in reducing intraoperative blood loss when surgery for spinal metastasis was performed on the same day than when surgery was delayed. Surgery should be performed on the same day of embolization if possible. 23198917 Electronic size effects in three-dimensional nanostructures. We show that bismuth nanostructures form three-dimensional patterns governed by two-dimensional electronic effects. Scanning tunneling microscopy reveals that both the vertical and the lateral dimensions of the structures strongly favor certain values and that the preferred widths are substantially different for each preferred height. First-principles calculations demonstrate that this vertical-lateral correlation is governed by the Fermi surface topology and that this is itself sensitively dependent on the dimensions of the structure. 23632268 A risk stratification model of acute pyelonephritis to indicate hospital admission from the ED. There are no guidelines regarding the hospitalization of female patients with acute pyelonephritis (APN); therefore, we performed a retrospective analysis to construct a clinical prediction model for hospital admission. We conducted a retrospective analysis of a prospective database of women diagnosed as having APN in the emergency department between January 2006 and June 2012. Independent risk factors for admission were determined by multivariable logistic regression analysis in half of the patients in this database. The risk of admission was categorized into 5 groups. The internal and external validations were conducted using the remaining half of the patients and 192 independent patients, respectively. Independent risk factors for admission were age of 65 years or greater (odds ratio [OR], 2.62; 1 point), chill (OR, 2.40; 1 point), and the levels of segmented neutrophils greater than 90% (OR, 2.00; 1 point), serum creatinine greater than 1.5 mg/dL (OR, 2.41; 1 point), C-reactive protein greater than 10 mg/dL (OR, 2.37; 1 point), and serum albumin less than 3.3 g/dL (OR, 7.36; 2 points). The admission risk scores consisted of 5 categories, which were very low (0 points; 5.9%), low (1 point; 10.7%), intermediate (2 points; 20.7%), high (3-4 points; 51.9%), and very high (5-7 points; 82.8%) risk, showing an area under the curve of 0.770. The areas under the curve of the internal and external validation cohorts were 0.743 and 0.725, respectively. This model can provide a guideline to determine the admission of women with APN in the emergency department. 23906249 Meta-analyses: Does Long-term PPI use Increase the Risk of Gastric Premalignant Lesions? Proton pump inhibitors (PPIs) are the most effective agents available for reducing acid secretion. They are used for medical treatment of various acid-related disorders. PPIs are used extensively and for extended periods of time in gastroesophageal reflux disease (GERD). A troublesome issue regarding maintenance therapy has been the propensity of PPI-treated patients to develop chronic atrophic gastritis while on therapy that could theoretically lead to an increased incidence of gastric cancer. In addition, animal studies have raised concern for development of enterochromaffin-like cell hyperplasia and carcinoid tumors in the stomachs of mice receiving high dose PPIs. Current literature does not provide a clear-cut conclusion on the subject and the reports are sometimes contradictory. Therefore, this study is a systematic review of the available literature to address the safety of long-term PPI use and its relation to the development of malignant/premalignant gastric lesions. A literature search of biomedical databases was performed. The reference lists of retrieved articles were reviewed to further identify relevant trials. We hand-searched the abstracts of the American Digestive Disease Week (DDW) and the United European Gastroenterology Week (UEGW) from 1995 to 2013. Only randomized clinical trials (RCTs) that used PPIs as the primary treatment for at least six month versus no treatment, placebo, antacid or anti-reflux surgery (ARS) were included. Two reviewers independently extracted the data. Discrepancies in the interpretation were resolved by consensus. All analyses of outcomes were based on the intention-to-treat principle. We performed statistical analysis using Review Manager software. The effect measure of choice was relative risk (RR) for dichotomous data. Six RCTs with a total of 785 patients met the inclusion criteria. Two multicenter RCTs compared Esomeprazole with placebo. One RCT compared omeprazole with ARS. Two RCTs compared omeprazole with ranitidine and one RCT compared lansoprazole with ranitidine. Four of the included RCTs had moderate risk of bias and two had low risk of bias. The number of patients with increased corporal atrophy score, intestinal metaplasia score and chronic antral inflammation did not statistically differ between the PPI maintenance group and controls. Similar results were found when ECL-cell hyperplasia was assessed between the groups. Maintenance PPIs did not have an association with increased gastric atrophic changes or ECL-cell hyperplasia for at least three years in RCTs. 23870020 Vestibular schwannoma surgery in the elderly: a matched cohort study. Object The authors' objective was 2-fold: 1) to compare outcomes of microsurgical resection for vestibular schwannoma (VS) between patients aged 70 years or older and patients younger than 70 years and 2) to test the hypothesis that symptomatic tumors in elderly patients represent a more aggressive variant of VS than those in younger adults, resulting in increased morbidity and a higher rate of recurrence after subtotal resection (STR). Methods A retrospective matched cohort study was conducted. Patients aged 70 years or older who had undergone microsurgical resection of VS were matched to adult patients younger than 70 years; the matching was performed on the basis of surgical approach, completeness of resection, and tumor size. Associations between clinical, radiographic, and surgical data and postoperative outcome were analyzed using conditional logistic regression. Results Twenty patients aged 70 years or older (mean age ± SD 75.9 ± 5.3, range 70-86 years) were identified and matched to a cohort of younger adult patients (mean age ± SD 55.7 ± 13.8, range 25-69 years). The mean tumor size in both groups was approximately 3 cm. Overall, the elderly patients had a poorer preoperative American Society of Anesthesiology physical status score (p = 0.038), were more likely to report imbalance (OR 9.61, p = 0.016), and more commonly exhibited compromised balance and coordination (OR 9.61, p = 0.016) than patients in the younger cohort. There were no differences between the 2 cohorts in perioperative complications (p = 0.26) or facial nerve function (p > 0.5) at any time. The elderly patients were 13 times more likely to have long-term postoperative imbalance (OR 13.00, p = 0.013) than the younger patients. Overall, 9 tumors recurred among 32 patients undergoing STR; 6 of these patients underwent additional interventions (stereotactic radiosurgery in 5 patients and microsurgery in 1) and showed no evidence of tumor progression at the last follow-up. The median growth rate of the recurrent tumor in the 6 elderly patients was 4.8 mm/year (range 2.1-14.9 mm/year) and, in the 3 control patients, 2.2 mm/year (range 1.9-4.0 mm/year). Overall, the mortality data showed a trend toward statistical significance (p = 0.068) with a higher risk of death in the elderly. Conclusions As the number of elderly patients with VS increases, microsurgical resection will remain an important management option for these patients. Despite a poorer preoperative physical status in elderly patients, their morbidity profiles are similar to those in adult patients younger than 70 years. However, elderly patients may require longer convalescence due to prolonged postoperative imbalance. Not surprisingly, overall diminished functional reserve and advanced comorbidities may increase the mortality risk associated with surgical intervention in the elderly patients. Finally, there was a high risk of further tumor growth following STR in the elderly patients (6 [37.5%] of 16), underscoring the need for close postoperative radiological surveillance and consideration of early stereotactic radiosurgery for the tumor remnant following the STR. 23892465 The analysis of spinopelvic parameters and stability following long fusions with S1, S2 or iliac fixation. The purpose of this study was to analyse changes of spinopelvic parameters and stability in the treatment of degenerative lumbar deformity. A retrospective review was carried out on 70 cases of degenerative lumbar deformity treated by long fusion with uni-cortical S1 fixation alone (US1F group, n = 20), bi-cortical S1 fixation alone (BS1F group, n = 20), additional diagonal S2 fixation (DS2F group, n = 14), and additional iliac fixation (ILF group, n = 16) from July 2003 to April 2010. The sagittal vertical axis (SVA), lumbar lordosis (LL), sacral slope (SS), pelvic tilt (PT), pelvic incidence (PI), and stability were used to evaluate radiologic outcomes. The clinical outcome was evaluated using the Oswestry Disability Index (ODI). In all groups, the LL was significantly increased at three months (p < 0.05). The PI and the SS of ILF patients significantly increased at three months (p < 0.05), while none of these values changed over time in non-ILF patients. The PT did not change postoperatively in any groups. The LL, SS, and PI were significantly greater in the ILF group at three months postoperatively and later (p < 0.05). DS2F and ILF had statistically significant stability compared to US1F and BS1F (p < 0.05). The ODI scores were significantly improved after surgery in all groups compared to before surgery (p < 0.05). Patients who had ILF in long fusion for the treatment of degenerative lumbar deformity had significant restoration of spinopelvic parameters compared to the other groups. In addition, DS2F and ILF provided more stability of distal instruments. 23966134 Supramolecular Helices: Chirality Transfer from Conjugated Molecules to Structures. Different scales of chirality endow a material with many excellent properties and potential applications. In this review, using π-conjugated molecules as functional building blocks, recent progress on supramolecular helices inspired by biological helicity is summarized. First, induced chirality on conjugated polymers and small molecules is introduced. Molecular chirality can be amplified to nanostructures, superstructures, and even macroscopic structures by a self-assembly process. Then, the principles for tuning the helicity of supramolecular chirality, as well as formation of helical heterojunctions, are summarized. Finally, the potential applications of chiral structures in chiral sensing and organic electronic devices are critically reviewed. Due to recent progress in chiral structures, an interdisciplinary area called "chiral electronics" is expected to gain wide popularity in the near future. 23824558 Protein τ-Mediated Effects on Rat Hippocampal Choline Transporters CHT1 and τ-Amyloid β Interactions. It is suggested that intracellular tau protein (Ï„), when released extracellularly upon neuron degeneration, could evoke direct toxic effects on the cholinergic neurotransmitter system through muscarinic receptors and thus contribute to the pathogenesis of Alzheimer's disease. In this study, we evaluated the in vitro effects of six naturally occurring monomeric Ï„ isoforms on rat hippocampal synaptosomal choline transporters CHT1 (large transmembrane proteins associated with high-affinity choline transport and vulnerable to actions of amyloid β peptides (Aβ) applied in vitro or in vivo). Some Ï„ isoforms at nM concentrations inhibited choline transport in a dose- and time-dependent saturable manner (352 = 441 > 410 = 383 > 381 = 412) and effects were associated with changes in the Michaelis constant rather than in maximal velocity. Moreover, the actions of Ï„ 352/441 were not influenced by previous depolarisation of synaptosomes or by previous depletion of membrane cholesterol. Specific binding of [3H]hemicholinium-3 was not significantly altered by Ï„ 352/441 at higher nM concentrations. Results of in vitro tests on CHT1 transporters from cholesterol-depleted synaptosomes supported interactions between Aβ 1-40 and Ï„ 352. In addition, we developed surface plasmon resonance biosensors to monitor complexes of Aβ 1-42 and Ï„ 352 using a sandwich detection format. It seems, therefore, that protein Ï„, similar to Aβ peptides, can contribute to the pathogenesis of Alzheimer's disease through its actions on CHT1 transporters. However, the interaction mechanisms are quite different (Ï„ probably exerts its effects through direct interactions of microtubule binding repeats with extracellular portions of the CHT1 protein without influencing the choline recognition site, Aβ rather through lipid rafts in the surrounding membranes). An N-terminal insert of Ï„ is not necessary but the N-terminal projection domain plays a role. The developed biosensor will be used to detect Aβ-Ï„ complexes in cerebrospinal fluid in order to evaluate them as prospective biomarkers of Alzheimer's disease. 23943035 Management of Papillary Lesions of the Breast: Can Larger Core Needle Biopsy Samples Identify Patients Who May Avoid Surgical Excision? The ability to distinguish benign from atypical/malignant papillary lesions on core needle biopsy is limited by the representative nature of the biopsy method, thus follow-up excision is usually recommended. We aimed to determine if larger samples of tissue obtained by core needle biopsy can more reliably predict the true benign nature of a papilloma. We reviewed the pathology slides and medical records of 51 patients who were diagnosed with benign papillomas on core needle biopsy from 2000 to 2010, who subsequently underwent surgical excision. The characteristics of the core needle biopsy that were associated with retention of benign histology on excision were determined and analyzed. Atypical ductal hyperplasia and carcinoma were identified in 5.8 % (3/51) and 5.8 % (3/51) of papillary lesions, respectively, when excised. Patients whose lesions were diagnosed as benign on excision were significantly distinguished by the area (mm(2)) of tissue sampled by core needle biopsy (mean ± standard deviation (SD): 101.5 ± 106.5) compared with those with atypia or carcinoma on excision (mean ± SD: 41.7 ± 24.0, P = 0.003). All biopsies performed with 12-gauge or larger needles retained benign features on excision. Core needle biopsy tissue samples consisting of ≥7 cores, or measuring >96 mm(2) in aggregate, had a negative predictive value for atypia/malignancy of 100 %. Larger tissue samples significantly improved the predictive value of benign histology on core needle biopsy. A papilloma sampled by a 12-gauge or larger needle, ≥7 cores, or >96 mm(2) retained its benign features upon excision. 23919896 Organ-specific remodeling of the Arabidopsis transcriptome in response to spaceflight. Spaceflight presents a novel environment that is outside the evolutionary experience of terrestrial organisms. Full activation of the International Space Station as a science platform complete with sophisticated plant growth chambers, laboratory benches, and procedures for effective sample return, has enabled a new level of research capability and hypothesis testing in this unique environment. The opportunity to examine the strategies of environmental sensing in spaceflight, which includes the absence of unit gravity, provides a unique insight into the balance of influence among abiotic cues directing plant growth and development: including gravity, light, and touch. The data presented here correlate morphological and transcriptome data from replicated spaceflight experiments. The transcriptome of Arabidopsis thaliana demonstrated organ-specific changes in response to spaceflight, with 480 genes showing significant changes in expression in spaceflight plants compared with ground controls by at least 1.9-fold, and 58 by more than 7-fold. Leaves, hypocotyls, and roots each displayed unique patterns of response, yet many gene functions within the responses are related. Particularly represented across the dataset were genes associated with cell architecture and growth hormone signaling; processes that would not be anticipated to be altered in microgravity yet may correlate with morphological changes observed in spaceflight plants. As examples, differential expression of genes involved with touch, cell wall remodeling, root hairs, and cell expansion may correlate with spaceflight-associated root skewing, while differential expression of auxin-related and other gravity-signaling genes seemingly correlates with the microgravity of spaceflight. Although functionally related genes were differentially represented in leaves, hypocotyls, and roots, the expression of individual genes varied substantially across organ types, indicating that there is no single response to spaceflight. Rather, each organ employed its own response tactics within a shared strategy, largely involving cell wall architecture. Spaceflight appears to initiate cellular remodeling throughout the plant, yet specific strategies of the response are distinct among specific organs of the plant. Further, these data illustrate that in the absence of gravity plants rely on other environmental cues to initiate the morphological responses essential to successful growth and development, and that the basis for that engagement lies in the differential expression of genes in an organ-specific manner that maximizes the utilization of these signals--such as the up-regulation of genes associated with light-sensing in roots. 23537500 NMDA receptor-dependent function and plasticity in inhibitory circuits. NMDA receptors have been known to play a central role in long-term potentiation at glutamatergic synapses in principal cells for thirty years. In contrast, their roles in the development and activity-dependent plasticity of synapses in inhibitory circuits have only recently begun to be understood. Progress has, to a great extent, been hampered by the extensive diversity of GABAergic cell types in the CNS. However, anatomical, immunohistochemical and electrophysiological methods have allowed distinct types to be identified, with the result that consistent patterns of synaptic plasticity have begun to emerge. This review summarizes recent evidence on the role of NMDA receptors in the development and plasticity of GABAergic synapses on principal cells and of glutamatergic synapses on identified interneurons. A major challenge is to understand how NMDA receptors affect the routing of information in healthy inhibitory circuits, and how changes in NMDA receptor function may contribute to altered circuit function in disorders such as schizophrenia. This article is part of a Special Issue entitled "Glutamate receptor-dependent synaptic plasticity". 23947544 Hidden Non-Innocence in an Expanded Porphyrin: Electronic Structure of the Siamese-Twin Porphyrin's Dicopper Complex in Different Oxidation States. The Siamese-twin porphyrin (2H4) is a unique pyrazole-expanded porphyrin providing two adjacent cavities each offering an {N4} binding motif. It was previously found to form stable dicopper(II) or dinickel(II) complexes where both metal ions are nested in a porphyrin-like environment. This work addresses the rich redox chemistry of the dicopper complex 2Cu2 that originates from the redox synergy of two proximate metal ions in combination with the potentially non-innocent expanded porphyrin ligand. Complementing previous X-ray crystallographic and SQUID data for solid material, the electronic structure of parent 2Cu2 in solu-tion was now investigated by MCD and EPR spectroscopy. This allowed the assignment of UV-vis absorptions and confirmed the drastic twist of the molecule with ferromagnetically coupled copper(II) ions. 2Cu2 was found to exhibit multiple redox events in the potential range from -2.4 to +1.7 V versus Fc/Fc+, and singly oxidized [2Cu2]+ as well as doubly oxidized [2Cu2]2+ were character-ized in detail by various analytical and spectroscopic methods. [2Cu2]+ was found by EPR spectroscopy and DFT calculations to have an S = ½ ground state, while [2Cu2]2+ is diamagnetic. Single crystal X-ray crystallography of [2Cu2(acetone)2](BF4)2 revealed that the 2Cu2 core is structurally invariant upon twofold oxidation, while XAS measurements at the Cu K-edge for 2Cu2 and [2Cu2(acetone)2](BF4)2 showed that the copper ions remain in the +2 oxidation state throughout. The combined experimental and computational evidence identified the Siamese-twin porphyrin as a multi-electron redox-active ligand with hidden non-innocence. Each ligand subunit upon oxidation forms a ligand-centered radical, though the spin vanishes because of covalency and strong antiferromagnetic coupling between the ligand radical and the proximate metal ion. Complexes of the Siamese-twin porphyrin may thus serve as a valuable bioinspired platform that combines both metal-ligand and two-metal-ion cooperativities for use in multi-electron processes. 23908469 TLR stimulation initiates a CD39-based autoregulatory mechanism that limits macrophage inflammatory responses. Sepsis is a highly fatal disease caused by an initial hyper-inflammatory response followed by a state of profound immunosuppression. While, it is well-appreciated that the initial production of pro-inflammatory cytokines by macrophages accompanies the onset of sepsis, it remains unclear what causes the transition to an immunosuppressive state. In this study, we reveal that macrophages themselves are key regulators of this transition, and that the surface enzyme CD39 plays a critical role in self-limiting the activation process. We demonstrate that TLR-stimulated macrophages modulate their activation state by increasing the synthesis and secretion of ATP. This endogenous ATP is paradoxically immunosuppressive due to its rapid catabolism into adenosine by CD39. Macrophages lacking CD39 are unable to transition to a regulatory state and consequently continue to produce inflammatory cytokines. The importance of this transition is demonstrated in a mouse model of sepsis, where small numbers of CD39-deficient macrophages were sufficient to induce lethal endotoxic shock. Thus, these data implicate CD39 as a key 'molecular switch' that allows macrophages to self-limit their activation state. We propose that therapeutics targeting the release and hydrolysis of ATP by macrophages may represent new ways to treat inflammatory diseases. 23946915 Structural and thermoelectric properties of TMGa3 (TM = Fe, Co) thin films. Based on chemically synthesized powders of FeGa3, CoGa3, as well as of a Fe0.75Co0.25Ga3 solid solution, thin films (typical thickness 40 nm) were fabricated by flash evaporation onto various substrates held at ambient temperature. In this way, the chemical composition of the powders could be transferred one-to-one to the films as demonstrated by Rutherford backscattering experiments. The relatively low deposition temperature necessary for conserving the composition leads, however, to 'X-ray amorphous' film structures with immediate consequences on their transport properties: A practically temperature-independent electrical resistivity of ρ = 200 μΩ·cm for CoGa3 and an electrical resistivity of about 600 μΩ·cm with a small negative temperature dependence for FeGa3. The observed values and temperature dependencies are typical of high-resistivity metallic glasses. This is especially surprising in the case of FeGa3, which as crystalline bulk material exhibits a semiconducting behavior, though with a small gap of 0.3 eV. Also the thermoelectric performance complies with that of metallic glasses: Small negative Seebeck coefficients of the order of -6 μV/K at 300 K with almost linear temperature dependence in the range 10 K ≤ T ≤ 300 K. 23628128 Inter-laboratory variability in the presence of human papillomavirus in normal and abnormal cervical cytology samples. Treatment of cervical carcinoma is affected by the stage of the disease, being most likely curable with early detection. High-risk human papillomavirus (HPV) infection and persistency are necessary to the development of precancerous and cancerous lesions leaving the possibility to detect in time cells progressing in at risk behaviour. This study documents the proportion of HPV DNA positivity in 906 samples with cytological result negative for intraepithelial lesion and malignancy (NILM), 220 atypical squamous cells of undetermined significance (ASC-US) samples and 211 low grade intraepithelial lesions (LSIL) samples collected from various pathological laboratories in Brussels, Belgium. The proportion of samples harbouring one or more HPV types was 10.8% (95% confidence interval, 95% CI: 8.8-12.8) in NILM, 34.5% (95% CI: 27.6-40.3) in ASC-US, 54.3% (95% CI: 47.5-61.1) in LSIL, with significant variability of HPV proportion in ASC-US and LSIL between laboratories. This study provides an on-site picture, confirming an added value of HPV DNA detection. 23831593 Engraftment of nonintegrating neural stem cells differentially perturbs cortical activity in a dose-dependent manner. Neural stem cell (NSC) therapy represents a potentially powerful approach for gene transfer in the diseased central nervous system. However, transplanted primary, embryonic stem cell- and induced pluripotent stem cell-derived NSCs generate largely undifferentiated progeny. Understanding how physiologically immature cells influence host activity is critical to evaluating the therapeutic utility of NSCs. Earlier inquiries were limited to single-cell recordings and did not address the emergent properties of neuronal ensembles. To interrogate cortical networks post-transplant, we used voltage sensitive dye imaging in mouse neocortical brain slices, which permits high temporal resolution analysis of neural activity. Although moderate NSC engraftment largely preserved host physiology, subtle defects in the activation properties of synaptic inputs were induced. High-density engraftment severely dampened cortical excitability, markedly reducing the amplitude, spatial extent, and velocity of propagating synaptic potentials in layers 2-6. These global effects may be mediated by specific disruptions in excitatory network structure in deep layers. We propose that depletion of endogenous cells in engrafted neocortex contributes to circuit alterations. Our data provide the first evidence that nonintegrating cells cause differential host impairment as a function of engrafted load. Moreover, they emphasize the necessity for efficient differentiation methods and proper controls for engraftment effects that interfere with the benefits of NSC therapy.Molecular Therapy (2013); doi:10.1038/mt.2013.163. 23823152 Eccentric Exercise in Rehabilitation: Safety, Feasibility and Application. This non-exhaustive, mini review reports on the application of eccentric exercise in various rehabilitation populations. The two defining properties of eccentric muscle contractions, a potential for high muscle force production at an energy cost that is uniquely low, are revisited and formatted as exercise countermeasures to muscle atrophy, weakness and deficits in physical function. Following a dual phase implementation, eccentric exercise that induces rehabilitation benefits without muscle damage, thereby making it both safe and feasible in rehabilitation, is described. Clinical considerations, algorithms of exercise progression and suggested modes of eccentric exercise are presented. 23948872 Bandwidth Optimization Design of a Multi Degree of Freedom MEMS Gyroscope. A new robust multi-degree of freedom (multi-DOF) MEMS gyroscope is presented in this paper. The designed gyroscope has its bandwidth and amplification factor of the sense mode adjusted more easily than the previous reported multi-DOF MEMS gyroscopes. Besides, a novel spring system with very small coupling stiffness is proposed, which helps achieve a narrow bandwidth and a high amplification factor for a 2-DOF vibration system. A multi-DOF gyroscope with the proposed weak spring system is designed, and simulations indicate that when the operating frequency is set at 12.59 kHz, the flat frequency response region of the sense mode can be designed as narrow as 80 Hz, and the amplification factor of the sense mode at the operating frequency is up to 91, which not only protects the amplification factor from instability against process and temperature variations, but also sacrifices less performance. An experiment is also carried out to demonstrate the validity of the design. The multi-DOF gyroscope with the proposed weak coupling spring system is capable of achieving a good tradeoff between robustness and the performance. 23122156 Use of viscera extract from hybrid catfish (Clarias macrocephalus × Clarias gariepinus) for the production of protein hydrolysate from toothed ponyfish (Gazza minuta) muscle. Proteolytic activity of viscera extract from hybrid catfish (Clarias macrocephalus × Clarias gariepinus) was studied. The optimal pH and temperature were 9.0 and 50°C, respectively, when toothed ponyfish (Gazza minuta) muscle was used as a substrate. When viscera extract from hybrid catfish was used for the production of protein hydrolysate from toothed ponyfish muscle, extract concentration, reaction time, and fish muscle/buffer ratio affected the hydrolysis and nitrogen recovery (NR) (p<0.05). Optimum conditions for toothed ponyfish muscle hydrolysis were 3.5% hybrid catfish viscera extract, 15 min reaction time and fish muscle/buffer ratio of 1:3 (w/v). High correlation between the degree of hydrolysis (DH) and NR (R(2)=0.974) was observed. Freeze-dried hydrolysate had a high protein content (89.02%, dry weight basis) and it was brownish yellow in colour (L(∗)=63.67, a(∗)=6.33, b(∗)=22.41). The protein hydrolysate contained a high amount of essential amino acids (48.22%) and had arginine and lysine as the dominant amino acids. 23967839 Diet quality from pre-school to school age in Brazilian children: a 4-year follow-up in a randomised control study. A previous study demonstrated that dietary counselling for mothers during the first year of life improved overall diet quality of children at pre-school age in a low-income population. Thus, the objective of the present study was to assess the long-term effect of this intervention on diet quality of children at school age and examine the tracking of dietary intake throughout childhood. The present study was a follow-up of a randomised controlled trial with children who were assessed at 3-4 years (n 345) and 7-8 years (n 307) of age. We collected two 24 h dietary recalls and assessed diet quality using the Healthy Eating Index (HEI). Analyses were performed by group using a paired t test and a Student's t test for independent samples. Diet quality did not differ between the intervention and control groups at 7-8 years of age (HEI score 65·2 (sd 9·5) v. 64·9 (sd 8·5)). Regarding changes in diet quality from pre-school to school age, we observed the tracking of diet quality in the control group and the loss of the intervention effect in the intervention group. In both groups, the score for fruit and milk intake decreased, while that for saturated fat and dietary variety intake increased. The score for the intakes of grains, meat and legumes, and total fat remained constant for all children. The present data provide evidence that diet quality tracks during childhood since the total HEI score did not differ over time in the control group. The decrease in score for some HEI components did not affect the overall diet quality due to the increase in score for other HEI components. 23934910 Enhancing in vivo survival of adipose-derived stromal cells through bcl-2 overexpression using a minicircle vector. Abstract Tissue regeneration using progenitor cell-based therapy has the potential to aid in the healing of a diverse range of pathologies, ranging from short-gut syndrome to spinal cord lesions. However, there are numerous hurdles to be overcome prior to the widespread application of these cells in the clinical setting. One of the primary barriers to effective stem cell therapy is the hostile environment that progenitor cells encounter in the clinical injury wound setting. In order to promote cellular survival, stem cell differentiation, and participation in tissue regeneration, relevant cells and delivery scaffolds must be paired with strategies to prevent cell death to ensure that these cells can survive to form de novo tissue. The Bcl-2 protein is a prosurvival member of a family of proteins that regulate the mitochondrial pathway of apoptosis. Using several strategies to overexpress the Bcl-2 protein, we demonstrated a decrease in the mediators of apoptosis in vitro and in vivo. This was shown through the use of two different clinical tissue repair models. Cells overexpressing Bcl-2 not only survived within the wound environment at a statistically significantly higher rate than control cells, but also increased tissue regeneration. Finally, we used a nonintegrating minicircle technology to achieve this in a potentially clinically applicable strategy for stem cell therapy. 23579166 In vitro toxicological assessment of clays for their use in food packaging applications. Montmorillonite based clays have a wide range of applications that are going to contribute to increase human exposure to these materials. One of the most promising uses of clays is the development of reinforced food contact materials that results in nanocomposites with improved barrier properties. Different organoclays have been developed introducing modifiers in the natural clay which is commercially available. However, the toxicological aspects of these materials have been scarcely studied so far. In the present study, the cytotoxic effects of a non-modified clay (Cloisite® Na+) and an organoclay (Cloisite® 30B) have been investigated in the hepatic cell line HepG2. Only Cloisite® 30B showed cytotoxicity. In order to elucidate the toxic mechanisms underlying these effects, apoptosis, inflammation, oxidative stress and genotoxicity biomarkers were assayed. Moreover, a morphology study with light and electron microscopy was performed. Results showed genotoxic effects and glutathione decrease. The most relevant ultraestructural alterations observed were mitochondrial degeneration, dilated endomembrane systems, heterophagosomes formation, fat droplets appearance and presence of nuclear lipid inclusions. Cloisite® 30B, therefore, induces toxic effects in HepG2 cells. Further research is needed to assess the risk of this clay on the human health. 23818386 Bullying and victimization in early adolescence: Relations to social information processing patterns. There is a gap in the literature on the social information processing (SIP) patterns of adolescents exposed to victimization in school. Therefore, we examine the SIP patterns of young adolescents characterized by their teachers and by their own reports as victims, bullies, bullies/victims, and neither bullies nor victims. The 105 adolescents participating in this study were asked to respond to hypothetical social scenarios in which a protagonist is either rebuffed or provoked by peers. The scenarios were ambiguous in nature and thus could have been processed in different ways. Indeed, distinctive processing patterns were found for each of these groups: victims tended to avoid challenging social situations while expecting others to be purposefully hostile or ignoring; bullies tended to interpret others as purposefully hostile and stated their desire to retaliate; bullies/victims showed patterns more similar to those of the bullies than the victims; and those who were neither victims nor bullies tended to view the same challenging social situations as non hostile and more likely to end well for them. We conclude by discussing the theoretical and practical implications of these findings. Aggr. Behav. 9999:XX-XX, 2013. © 2013 Wiley Periodicals, Inc. 23884844 Production of the Phanerochaete flavido-alba laccase in Aspergillus niger for synthetic dyes decolorization and biotransformation. We investigated the expression of Phanerochaete flavido-alba laccase gene in Aspergillus niger and the physical and biochemical properties of the recombinant enzyme (rLac-LPFA) in order to test it for synthetic dye biotransformation. A. niger was able to produce high levels of active recombinant enzyme (30 mgL(-1)), whose identity was further confirmed by immunodetection using Western blot analysis and N-terminal sequencing. Interestingly, rLac-LPFA exhibited an improved stability at pH (2-9) and organic solvents tested. Furthermore, the percentage of decoloration and biotransformation of synthetic textile dyes, Remazol Brilliant Blue R (RBBR) and Acid Red 299 (NY1), was higher than for the native enzyme. Its high production, simple purification, high activity, stability and ability to transform textile dyes make rLac-LPFA a good candidate for industrial applications. 23240889 Optomechanical Shutter Modulated Broad-Band Cavity-Enhanced Absorption Spectroscopy of Molecular Transients of Astrophysical Interest. We describe a sensitive spectroscopic instrument capable of measuring broad-band absorption spectra through supersonically expanding planar plasma pulses. The instrument utilizes incoherent broad-band cavity-enhanced absorption spectroscopy (IBBCEAS) and incorporates an optomechanical shutter to modulate light from a continuous incoherent light source, enabling measurements of durations as low as ∼400 μs. The plasma expansion is used to mimic conditions in translucent interstellar clouds. The new setup is particularly applicable to test proposed carriers of the diffuse interstellar bands, as it permits swift measurements over a broad spectral range with a resolution comparable to astronomical observations. The sensitivity is estimated to be better than 10 ppm/pass, measured with an effective exposure time of only 1 s. 23395003 Fbxl10/Kdm2b recruits polycomb repressive complex 1 to CpG islands and regulates H2A ubiquitylation. Polycomb repressive complex 1 (PRC1) catalyzes lysine 119 monoubiquitylation on H2A (H2AK119ub1) and regulates pluripotency in embryonic stem cells (ESCs). However, the mechanisms controlling the binding of PRC1 to genomic sites and its catalytic activity are poorly understood. Here, we show that Fbxl10 interacts with Ring1B and Nspc1, forming a noncanonical PRC1 that is required for H2AK119ub1 in mouse ESCs. Genome-wide analyses reveal that Fbxl10 preferentially binds to CpG islands and colocalizes with Ring1B on Polycomb target genes. Notably, Fbxl10 depletion causes a decrease in Ring1B binding to target genes and a major loss of H2AK119ub1. Furthermore, genetic analyses demonstrate that Fbxl10 DNA binding capability and integration into PRC1 are required for H2AK119 ubiquitylation. ESCs lacking Fbxl10, like previously characterized Polycomb mutants, cannot differentiate properly. These results demonstrate that Fbxl10 has a key role in regulating Ring1B recruitment to its target genes and H2AK119 ubiquitylation in ESCs. 23955766 Fabrication of ZIF-8@SiO2 Core-Shell Microspheres as the Stationary Phase for High-Performance Liquid Chromatography. The unique features of high porosity, shape selectivity, and multiple active sites make metal-organic frameworks (MOFs) promising as novel stationary phases for high-performance liquid chromatography (HPLC). However, the wide particle size distribution and irregular shape of conventional MOFs lead to lower column efficiency of such MOF-packed columns. Herein, the fabrication of monodisperse MOF@SiO2 core-shell microspheres as the stationary phase for HPLC to overcome the above-mentioned problems is reported. Zeolitic imidazolate framework 8 (ZIF-8) was used as an example of MOFs due to its permanent porosity, uniform pore size, and exceptional chemical stability. Unique carboxyl-modified silica spheres were used as the support to grow the ZIF-8 shell. The fabricated monodisperse ZIF-8@SiO2 packed columns (5 cm long × 4.6 mm i.d.) show high column efficiency (23 000 plates m(-1) for bisphenol A) for the HPLC separation of endocrine-disrupting chemicals (bisphenol A, β-estradiol, and p-(tert-octyl)phenol) and pesticides (thiamethoxam, hexaflumuron, chlorantraniliprole, and pymetrozine) within 7 min with good relative standard deviations for 11 replicate separations of the analytes (0.01-0.39, 0.65-1.7, 0.70-1.3, and 0.17-0.91 % for retention time, peak area, peak height, and half peak width, respectively). The ZIF-8@SiO2 microspheres combine the advantages of the good column packing properties of the uniform monodisperse silica microspheres and the separation ability of the ZIF-8 crystals. 23727591 In vitro inhibition of vesicular stomatitis virus replication by purified porcine Mx1 protein fused to HIV-1 Tat protein transduction domain (PTD). Vesicular stomatitis virus (VSV) is the causative agent of Vesicular stomatitis (VS), a highly contagious fatal disease of human and pigs. Few effective antiviral drugs are currently available against VSV infection. Mx proteins are interferon (IFN)-induced dynamin-like GTPases present in all vertebrates with a range of antiviral activities. Previous studies have shown that the transfected cell lines expressing either porcine Mx1 or human MxA acquired a high degree of resistance to VSV. To explore the feasibility of taking porcine Mx1 protein expressed in Escherichia coli as an antiviral agent, we applied the pCold system to express this fusion protein (PTD-poMx1), which consisted of an N-terminal HIV-1 Tat protein transduction domain (PTD) and the full-length porcine Mx1, and investigated its effects on the replication of VSV in Vero cells. The results demonstrated that the purified PTD-poMx1 fusion proteins could transduct into cells after incubated for 5h and had no cytotoxic. Furthermore, plaque reduction assay, determination of TCID50, real-time PCR and Western blot analyses were carried out to confirm the antiviral activity of purified fusion proteins in VSV-infected Vero cells. Altogether, these data suggested that PTD-poMx1 fusion proteins might be applicable to inhibit VSV replication as a novel antiviral therapeutic agent. 23885762 In vitro antibacterial and antibiotic-potentiation activities of four edible plants against multidrug-resistant gram-negative species. The present study was designed to investigate the antibacterial activities of the methanol extracts of four Cameroonian edible plants, locally used to treat microbial infections, and their synergistic effects with antibiotics against a panel of twenty nine Gram-negative bacteria including Multi-drug resistant (MDR) phenotypes expressing active efflux pumps. The broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) of the extracts [alone and in the presence of the efflux pumps inhibitor (EPI) Phenylalanine-Arginine β-Naphtylamide (PAβN)], and those of antibiotics in association with the two of the most active ones, Piper nigrum and Telfairia occidentalis. The preliminary phytochemical screening of the extracts was conducted according to the standard phytochemical methods. Phytochemical analysis showed the presence of alkaloids and flavonoids in all studied extracts. Other chemical classes of secondary metabolites were selectively present in the extracts. The results of the MIC determination indicated that the crude extracts from P. nigrum and V. amygdalina were able to inhibit the growth of all the twenty nine studied bacteria within a concentration range of 32 to 1024 μg/mL. At a similar concentration range (32 to 1024 μg/mL) the extract from T. occidentalis inhibited the growth of 93.1% of the tested microorganisms. At MIC/2 and MIC/5, synergistic effects were noted between the extracts from P. nigrum and T. occidentalis and seven of the tested antibiotics on more than 70% of the tested bacteria. The overall results of the present study provide information for the possible use of the studied edible plants extracts in the control of bacterial infections including MDR phenotypes. 23818709 Canadian Pain Society and Canadian Rheumatology Association Recommendations for Rational Care of Persons with Fibromyalgia. A Summary Report. To summarize the development of evidence-based guidelines for the clinical care of persons with fibromyalgia (FM), taking into account advances in understanding of the pathogenesis of FM, new diagnostic criteria, and new treatment options. Recommendations for diagnosis, treatment, and patient followup were drafted according to the classification system of the Oxford Centre for Evidence-Based Medicine, and following review were endorsed by the Canadian Rheumatology Association and the Canadian Pain Society. FM is a polysymptomatic syndrome presenting a spectrum of severity, with a pivotal symptom of body pain. FM is a positive clinical diagnosis, not a diagnosis of exclusion, and not requiring specialist confirmation. There are no confirmatory laboratory tests, although some investigation may be indicated to exclude other conditions. Ideal care is in the primary care setting, incorporating nonpharmacologic and pharmacologic strategies in a multimodal approach with active patient participation. The treatment objective should be reduction of symptoms, but also improved function using a patient-tailored treatment approach that is symptom-based. Self-management strategies combining good lifestyle habits and fostering a strong locus of control are imperative. Medications afford only modest relief, with doses often lower than suggested, and drug combinations used according to clinical judgment. There is a need for continued reassessment of the risk-benefit ratio for any drug treatment. Outcome should be aimed toward functioning within a normal life pattern and any culture of disablement should be discouraged. These guidelines should provide the health community with reassurance for the global care of patients with FM with the aim of improving patient outcome by reducing symptoms and maintaining function. 23830599 FDG-PET/CT characterization of adrenal nodules: diagnostic accuracy and interreader agreement using quantitative and qualitative methods. To determine interreader agreement and diagnostic accuracy across varying levels of reader experience using qualitative and quantitative methods of evaluating adrenal nodules using ((18)F)-fluorodeoxyglucose-positron emission tomography/computed tomography. 132 adrenal nodules (96 adenomas, 36 metastases) were retrospectively identified in 105 patients (49 men and 56 women, mean age 66 years, age range 45-85 years) with a history of lung cancer who underwent ((18)F)-fluorodeoxyglucose-positron emission tomography/computed tomography. For each nodule, three readers independently performed one qualitative and two quantitative measurements: visual assessment, standardized uptake value (SUVmax), and standard uptake ratio (SUVratio). Interreader agreement was calculated using percent agreement with κ statistic for qualitative analysis and intraclass correlation coefficient (ICC) for quantitative analysis. Accuracy, sensitivity, and specificity for distinguishing benign from malignant adrenal nodules were calculated for each method. Percent agreement between readers for visual (qualitative) assessment was 92% to 96% and κ statistic was 0.79 to 0.90 (95% confidence limits 0.66-0.99). ICC for SUVmax was 92% to 99% (95% CL 0.8-1.0), and ICC for SUVratio was 89% to 99% (95% CL 0.74-0.99). For diagnosis of malignancy, mean sensitivity and specificity for visual assessment were 80% and 97%, respectively. Mean sensitivity and specificity for SUVmax were 91% and 81%, respectively; for SUVratio, 90% and 80%. Mean diagnostic accuracy was 93%, 83%, and 84% for visual assessment, SUVmax, and SUVratio, respectively. Excellent interreader agreement is seen for quantitative and qualitative methods of distinguishing benign from malignant adrenal nodules. Qualitative analysis demonstrated higher accuracy but lower sensitivity compared with quantitative analysis. 23749505 Studies of Asymmetric Styrene Cyclopropanation with a Rhodium(II) Metallopeptide Catalyst Developed with a High-Throughput Screen. Dirhodium metallopeptides have been developed as selective catalysts for asymmetric cyclopropanation reactions. A selective ligand sequence has been identified by screening on-bead metallopeptide libraries in a 96-well plate format. Efficient ligand synthesis and screening allows a 200-member library to be created and assayed in less than three weeks. These metallopeptides catalyze efficient cyclopropanation of aryldiazoacetates, providing asymmetric access to cyclopropane products in high diastereoselectivity. Chirality 25:493-497, 2013. © 2013 Wiley Periodicals, Inc. 23901234 Fibroblast growth factor receptor 4 Gly388Arg polymorphism in Chinese gastric cancer patients. To investigate the contribution of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism as a genetic risk factor for gastric cancer (GC) and to investigate any associations between this polymorphism and clinicopathological parameters and survival. Tumors and matched adjacent non-cancer tissues were collected from 304 GC patients, and 5 mL of venous blood was collected from 62 GC patients and 392 age- and sex-matched healthy controls without cancer history from the same ethnic population. DNA was extracted, and direct sequencing analyses were performed to genotype the FGFR4 Gly388Arg polymorphism in all the samples. Differences in the genotype frequencies of the FGFR4 Gly388Arg polymorphism between GC patients and healthy controls were estimated using the χ(2) test. Binary logistic regression was used for all analysis variables to estimate risk as the ORs with 95%CIs. The relationships between the FGFR4 genotype and clinicopathological parameters were tested with the χ(2) test. The Kaplan-Meier product-limit method, the log-rank test, and the Cox regression model were applied to evaluate the effect of the FGFR4 genotype on the overall survival of patients with GC. In the present GC cohort, 118 patients (38.8%) were homozygous for the Gly388 allele, 124 patients (40.8%) were heterozygous, and 62 patients (20.4%) were homozygous for the Arg388 allele. The frequencies of the Gly/Gly, Gly/Arg, and Arg/Arg genotypes in the healthy controls were 33.6%, 48.0%, and 18.4%, respectively. The distributions of genotypes (χ(2) = 3.589, P = 0.166) and alleles (χ(2) = 0.342, P = 0.559) of the FGFR4 Gly388Arg polymorphism were not different between the GC patients and the healthy controls. Although we observed no correlation between the FGFR4 Gly388Arg polymorphism and clinicopathological parameters or survival in the total cohort of GC patients, the presence of the Arg388 allele was associated with shorter survival time in patients with GC if the tumor was small (log rank χ(2) = 5.449, P = 0.020), well differentiated (log rank χ(2) = 12.798, P = 0.000), T1 or T2 stage (log rank χ(2) = 4.745, P = 0.029), without lymph node involvement (log rank χ(2) = 6.647, P= 0.010), and at an early clinical stage (log rank χ(2) = 4.615, P = 0.032). Our results suggest that the FGFR4 Gly388Arg polymorphism is not a risk factor for GC cancer initiation but that it is a useful prognostic marker for GC patients when the tumor is relatively small, well differentiated, or at an early clinical stage. 23872021 Evaluation of MidIR fibre optic reflectance: Detection limit, reproducibility and binary mixture discrimination. MidIR fibre optic reflectance (MidIR-FORS) is a promising analytical technique in the field of science conservation, especially because it is non-destructive. Another advantage of MidIR-FORS is that the obtained information is representative, as a large amount of spectral data can be collected. Although the technique has a high potential and is almost routinely applied, its quality parameters have not been thoroughly studied in the specific application of analysis of artistic materials. The objective of this study is to evaluate the instrumental capabilities of MidIR-FORS for the analysis of artwork materials in terms of detection limit, reproducibility, and mixture characterisation. The study has been focused on oil easel painting and several paints of known composition have been analysed. Paint layers include blue pigments not only because of their important role along art history, but also because their physical and spectroscopic characteristics allow a better evaluation of the MidIR-FORS capabilities. The results of the analysis indicate that MidIR-FORS supplies a signal affected by different factors, such as the optical, morphological and physical properties of the surface, in addition to the composition of materials analysed. Consequently, the detection limits established are relatively high for artistic objects (Prussian blue - PB 2.1-6.5%; Phthalocyanine blue - Pht 6.3-10.2%; synthetic Ultramarine blue - UM 12.1%) and may therefore lead to an incomplete description of the artwork. Reproducibility of the technique over time and across surface has been determined. The results show that the major sources of dispersion are the heterogeneity of the pigments distribution, physical features, and band shape distortions. The total dispersion is around 4% for the most intense bands (oil) and increases up to 26% when weak or overlapped bands are considered (PB, Pht, UM). The application of different pre-treatments (cutoff of fibres absorption, Savizky-Golay smoothing algorithm, polynomial baseline offset, Standard Normal Variate algorithm - SNV) to the raw spectra allows improving these results to maximum values of 15%. Finally, the capabilities of PCA and MidIR-FORS to discriminate between binary mixtures were tested. The results demonstrate that it is possible to differentiate mixtures depending on the range of concentration of their components, within specific limits of detection. 23873968 The influence of ethnicity and gender on caregiver health in older new zealanders. Objectives. We examined the interrelationships between ethnicity, gender, and caregiving on the health of older New Zealanders. We hypothesized that those providing higher levels of care and more care across time would have poorer health outcomes and that these relationships would be moderated by ethnicity and gender. Method. A representative sample of participants (N = 2,155) aged 54-70 years from the first 2 waves of the New Zealand Health, Work and Retirement study completed postal surveys in 2006 and 2008. Caregiving questions were adapted from the Australian Women's Health study, and health measures were derived from the SF36 Health Survey. Women and Māori (indigenous New Zealanders) were more likely to provide care than men and non-Māori. Respondents providing higher levels of care reported poorer mental health and this was particularly true of Māori and female caregivers. Male Māori caregivers providing the highest level of care reported the poorest mental health. Level of care was unrelated to physical health. There was minimal evidence for changes in health over time based on caregiver status. Discussion. The poorer health of caregivers supports previous findings on the detrimental health effects of caregiving. Caregiving may have more detrimental effects on Māori health outcomes due to existing inequalities in health, barriers to formal support services, and the multiple roles of elder Māori. 23702696 Plus disease in retinopathy of prematurity: qualitative analysis of diagnostic process by experts. IMPORTANCE Plus disease is the most important parameter that characterizes severe treatment-requiring retinopathy of prematurity, yet diagnostic agreement among experts is imperfect and the precise factors involved in clinical diagnosis are unclear. This study is designed to address these gaps in knowledge by analyzing cognitive aspects of the plus disease diagnostic process by experts. OBJECTIVE To examine the diagnostic reasoning process of experts for plus disease in retinopathy of prematurity using qualitative research techniques. DESIGN Cognitive walk-through, with qualitative analysis of videotaped expert responses and quantitative analysis of expert diagnoses. SETTING Experimental setting in which experts were videotaped while reviewing study data. PARTICIPANTS A panel of international retinopathy of prematurity experts who had the experience of using qualitative retinal features as their primary basis for clinical diagnosis. INTERVENTION Six experts were video recorded while independently reviewing 7 wide-angle retinal images from infants with retinopathy of prematurity. Experts were asked to explain their diagnostic process in detail (think-aloud protocol), mark findings relevant to their reasoning, and diagnose each image (plus vs pre-plus vs neither). Subsequently, each expert viewed the images again while being asked to examine arteries and veins in isolation and answer specific questions. Video recordings were transcribed and reviewed. Diagnostic process of experts was analyzed using a published cognitive model. MAIN OUTCOME AND MEASURES Interexpert and intraexpert agreement. RESULTS Based on the think-aloud protocol, 5 of 6 experts agreed on the same diagnosis in 3 study images and 3 of 6 experts agreed in 3 images. When experts were asked to rank images in order of severity, the mean correlation coefficient between pairs of experts was 0.33 (range, -0.04 to 0.75). All experts considered arterial tortuosity and venous dilation while reviewing each image. Some considered venous tortuosity, arterial dilation, peripheral retinal features, and other factors. When experts were asked to rereview images to diagnose plus disease based strictly on definitions of sufficient arterial tortuosity and venous dilation, all but 1 expert changed their diagnosis compared with the think-aloud protocol. CONCLUSIONS AND RELEVANCE Diagnostic consistency in plus disease is imperfect. Experts differ in their reasoning process, retinal features that they focus on, and interpretations of the same features. Understanding these factors may improve diagnosis and education. Future research defining more precise diagnostic criteria may be warranted. 23847428 Evidence for the benefit of exercise therapy in patients with type 2 diabetes. Exercise interventions are recommended in most guidelines for the treatment of type 2 diabetes. Although most guidelines suggest a combination of both aerobic and resistance training, the exact benefits of these interventions remain unclear. Although either modality alone or in combination seems to have an identical impact on glycated hemoglobin levels, resistance training and aerobic training have independent effects on other parameters of cardio-metabolic risk. This review examines the current evidence for aerobic and resistance training on glycemic control, lipid profile, body composition, vascular health, and mental health in patients with type 2 diabetes. The uncertainties surrounding exercise modality, volume and intensity are also addressed. 23812957 Are explanatory trials ethical? Shifting the burden of justification in clinical trial design. Most phase III clinical trials today are explanatory. Because explanatory, or efficacy, trials test hypotheses under "ideal" conditions, they are not well suited to providing guidance on decisions made in most clinical care contexts. Pragmatic trials, which test hypotheses under "usual" conditions, are often better suited to this task. Yet, pragmatic, or effectiveness, trials are infrequently carried out. This mismatch between the design of clinical trials and the needs of health care professionals is frustrating for everyone involved, and explains some of the challenges inherent in attempts to enhance knowledge translation and encourage evidence-based practice. The situation is more than simply frustrating, however; it is potentially unethical. Clinical trials must be socially valuable in order to (1) warrant the risks they impose on human research subjects and (2) fairly and efficiently assess new clinical interventions. Most bioethicists would agree that trials that have no social value, for instance, because their results do not have the potential to advance clinical care, should not be performed. What is less widely appreciated is that given limited research resources, trials that are more socially valuable should be preferred to trials that are less socially valuable when all else is equal. With respect to clinical trial design, I argue that while explanatory trials often have some social value, many have less social value than their pragmatic counterparts. On the basis of this general ethical assessment, I provide a preliminary defense of the position that clinical researchers should aim to conduct pragmatic trials, that is, that researchers face a burden of justification related to any idealizing elements added to trial designs. 22917842 High multivitamin intakes during pregnancy and postweaning obesogenic diets interact to affect the relationship between expression of PPAR genes and glucose regulation in the offspring. High multivitamin intake (HV) during pregnancy increases body fat and weight and alters glucose and fatty acid metabolism in Wistar rat offspring. This study investigated the expression of peroxisome-proliferator activated receptors (PPARs) genes involved in regulation of glucose and fatty acid metabolism in their tissues. Dams received the AIN-93G diet with either the regular (RV) or 10-fold multivitamins (HV) during pregnancy. Male offspring were weaned to either the RV diet (RV-RV and HV-RV) or an obesogenic diet (RV-Ob and HV-Ob). Gene expression of PPARs in tissues was analyzed by real-time reverse transcriptase polymerase chain reaction. Gestational diet (GD) did not affect PPARs gene expression in offspring at either birth or weaning. In liver, at 14 weeks postweaning, PPAR-γ was 30% lower in the HV-RV and 30% higher in HV-Ob than in the RV-RV group [GD P=.76, postweaning diet (PD) P=.19, interaction P=.02, by two-way analysis of variance]. In muscle, PPAR-α expression was affected by GD and PD (GD P=.05, PD P<.01, interaction P=.07). In adipose tissue, PPAR-α expression was higher in all groups compared to RV-RV (GD P=.25, PD P=.85, interaction P=.03). PPAR-γ mRNA levels correlated with abdominal fat (r=0.45, P<.05) and insulin resistance index (r=0.39, P<.05). In liver, PPAR-γ expression correlated with insulin resistance index in offspring from RV (r=-0.62, P<.05), but not in those from HV dams (r=0.13, P>.05). In conclusion, the HV diet during pregnancy interacts with postweaning diets in determining the expression of PPARs genes in a tissue- and age-dependent manner and uncouples the relationship between these genes and glucose regulation and fat mass in the rat offspring. 23504764 Vulnerability of terrestrial island vertebrates to projected sea-level rise. Sea-level rise (SLR) from global warming may have severe consequences for biodiversity; however, a baseline, broad-scale assessment of the potential consequences of SLR for island biodiversity is lacking. Here, we quantify area loss for over 12 900 islands and over 3000 terrestrial vertebrates in the Pacific and Southeast Asia under three different SLR scenarios (1 m, 3 m and 6 m). We used very fine-grained elevation information, which offered >100 times greater spatial detail than previous analyses and allowed us to evaluate thousands of hitherto not assessed small islands. Depending on the SLR scenario, we estimate that 15-62% of islands in our study region will be completely inundated and 19-24% will lose 50-99% of their area. Overall, we project that between 1% and 9% of the total island area in our study region may be lost. We find that Pacific species are 2-3 times more vulnerable than those in the Indomalayan or Australasian region and risk losing 4-22% of range area (1-6 m SLR). Species already listed as threatened by IUCN are particularly vulnerable compared with non-threatened species. Under a simple area loss-species loss proportionality assumption, we estimate that 37 island group endemic species in this region risk complete inundation of their current global distribution in the 1 m SLR scenario that is widely anticipated for this century (and 118 species under 3 m SLR). Our analysis provides a first, broad-scale estimate of the potential consequences of SLR for island biodiversity and our findings confirm that islands are extremely vulnerable to sea-level rise even within this century. 23418775 Two new triterpenoids from the fungus Perenniporia maackiae. Two new triterpenoids, 3β-(2-methoxy-oxalyloxy)-24-methylene-lanost-8-en-21-oic acid (1) and 3β-(2-methoxy-oxalyloxy)-15α-hydroxy-24-methylene-lanost-8-en-21-oic acid (2), were isolated from cultures of the fungus Perenniporia maackiae, together with two previously known triterpenoids (3 and 4). Their structures were determined by spectroscopic methods, including 1D and 2D NMR, and MS analyses. All compounds were evaluated for their cytotoxic activities on five tumor cell lines. 23884095 Boosting innate immunity: Development and validation of a cell-based screening assay to identify LL-37 inducers. Innate immunity, the front line of our defence against pathogens, relies, to a great extent, on the production of antimicrobial peptides (AMPs). These peptides exhibit antimicrobial activity and immunomodulatory properties. In humans, AMPs include the defensins (α- and β-families) and the cathelicidin, LL-37. Bacterial resistance against antibiotics is a growing concern, and novel antimicrobial strategies are needed urgently. Hence, the concept of strengthening immune defences against infectious microbes by inducing AMP expression may represent novel or complementary pharmaceutical interventions in the treatment or prevention of infections. We have developed and validated a robust cell-based reporter assay for LL-37 expression, which serves as a marker for a healthy epithelial barrier. This reporter assay can be a powerful tool for high-throughput screenings. We first employed our assay to screen a panel of histone deacetylase inhibitors and derivatives, and then the Prestwick Chemical Library of Food and Drug Administration-approved compounds. After hit confirmation and independent validation in the parental cell line we identified five novel inducers of LL-37. This reporter assay will help to identify novel drug candidates for the treatment and prevention of infections. Importantly, the pattern of hits obtained may suggest cellular pathways and key mediators involved in the regulation of AMP expression. 23858059 Parkin-dependent degradation of the f-box protein fbw7β promotes neuronal survival in response to oxidative stress by stabilizing mcl-1. Parkinson's disease (PD) is characterized by progressive loss of midbrain dopaminergic neurons resulting in motor dysfunction. While most PD is sporadic in nature, a significant subset can be linked to either dominant or recessive germ line mutations. PARK2, encoding the ubiquitin ligase parkin, is the most frequently mutated gene in hereditary Parkinson's disease. Here, we present evidence for a neuronal ubiquitin ligase cascade involving parkin and the multisubunit ubiquitin ligase SCF(Fbw7β). Specifically, parkin targets the SCF substrate adapter Fbw7β for proteasomal degradation. Furthermore, we show that the physiological role of parkin-mediated regulation of Fbw7β levels is the stabilization of the mitochondrial prosurvival factor Mcl-1, an SCF(Fbw7β) target in neurons. We show that neurons depleted of parkin become acutely sensitive to oxidative stress due to an inability to maintain adequate levels of Mcl-1. Therefore, loss of parkin function through biallelic mutation of PARK2 may lead to death of dopaminergic neurons through unregulated SCF(Fbw7β)-mediated ubiquitylation-dependent proteolysis of Mcl-1. 23908142 Comparison of benign lesion regression following vocal fold steroid injection and vocal hygiene education. This study intends to objectively quantify and compare the regression rates of vocal lesions in patients receiving either vocal fold steroid injection (VFSI) or vocal hygiene education (VHE). Potential influence of occupational vocal demands on the treatment outcome was also investigated. Retrospective case series. This study enrolled 176 patients of vocal nodules and vocal polyps. Ninety-two patients received VFSI, while 84 patients received VHE. We measured the lesion area with correction by the length of vocal fold, according to videolaryngoscopic examinations before, 1, and 2 months after treatments. VFSI was associated with a higher lesion reduction rate than VHE at 1 and 2 months (p<0.05). In vocal nodules and patients with ordinary occupational vocal demands, VFSI achieved a higher lesion regression rate than VHE at 1 month (p<0.05), while both modalities resulted in similar lesion reduction rates at 2 month (p>0.05). In vocal polyps, the lesion reduction rate after VFSI was higher than that following VHE at 1 and 2 months (p<0.01). In patients with high occupational vocal dependence, the lesion sizes decreased significantly at 1 and 2 months following VFSI (p<0.01), but not for those receiving VHE (p>0.05). VHE remains the fundamental strategy for all dysphonic patients, while VFSI can be applied alternatively. Both VFSI and VHE are effective for vocal nodules and patients with ordinary occupational vocal demands, but VFSI achieves lesion regression earlier than VHE. VFSI is preferred over VHE for vocal polyps and patients with high occupational vocal demands. 4 Laryngoscope, 2013. 23858044 HMGB1 Levels Are Increased in Patients with Juvenile Idiopathic Arthritis, Correlate with Early Onset of Disease, and Are Independent of Disease Duration. High mobility group box chromosomal protein 1 (HMGB1) has been implicated as a mediator of inflammation in rheumatoid arthritis (RA), while its role in juvenile idiopathic arthritis (JIA) has not been described. To evaluate the role of HMGB1 in the inflammatory process in JIA and its potential as a therapeutic target, we investigated whether extracellular HMGB1 is detectable in JIA and if so, to correlate the levels with established inflammatory markers and clinical measures. Matching samples of blood and synovial fluid (SF) were collected from 23 patients with JIA. Levels of HMGB1, soluble receptor for advanced glycation endproducts, S100A12, myeloid-related protein 8/14, and other inflammatory mediators were analyzed. Significantly increased HMGB1 levels were recorded in SF compared to blood samples from patients with JIA. The amount of HMGB1 was highest in patients with early disease onset irrespective of disease duration. In contrast, the proinflammatory S100 protein and interleukin 8 were highest in patients in early phases of disease. Matrix metalloproteinase-3, a marker of cartilage destruction, was higher in patients with late disease onset, indicating similarities with RA in that patient subgroup. Levels of extracellular HMGB1 are increased in the inflamed joints of patients with JIA. This warrants further studies of HMGB1 as a mediator of JIA pathogenesis as well as a biomarker for inflammatory activity and as a target for therapy. The variation in levels of HMGB1 and S100 proteins in relation to disease onset indicates a difference in inflammatory phenotype during disease progression. 23970910 The Neurobiological Basis of Adolescent-onset Borderline Personality Disorder. Over the past two decades, neurobiological studies in adult onset borderline personality disorder have made important strides, but inquiry into adolescent-onset BPD is still in its infancy and our understanding of the neurobiology of adolescent BPD remains highly tentative. This paper highlights recent findings in genetics, neuroendocrinology and neuroimaging for adult and adolescent-onset BPD. Neurobiological studies of adolescent-onset BPD to date have focused mainly on volumetric studies of various brain regions and measurements of HPA axis components, with comparatively few publications on brain functioning. Such information is essential to developing more effective screening, treatment and preventive strategies. Abstract available from the publisher. 23869536 Two new antioxidant diarylheptanoids from the fruits of Alpinia oxyphylla. Two new diarylheptanoids, 1-(3',5'-dihydroxy-4'-methoxyphenyl)-7-phenyl-3-heptanone (1) and 1-(2',4'-dihydroxy-3'-methoxyphenyl)-7-(4″-methoxyphenyl)-3-heptanone (2), along with known diarylheptanoid yakuchinone A (3), and five flavanoids, tectochrysin (4), chrysin (5), izalpinin (6), kaempferol 7, 4'-dimethyl ether (7), and kaempferide (8) were isolated from the fruits of Alpinia oxyphylla Miq. Their structures were determined by means of spectroscopic methods. Antioxidant activities of all the isolated compounds were evaluated using a 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. Compounds 1-3 and 6-8 exhibited potent antioxidant activities in the DPPH assay. 23707208 In vitro and in vivo hepatoprotective and antioxidant activity of ethanolic extract from Meconopsis integrifolia (Maxim.) Franch. Meconopsis integrifolia (Maxim.) Franch is a high mountain endemic species used as a traditional Tibetan and Mongolian herb to treat hepatitis, pneumonia, and edema. This study aims to investigate the hepatoprotective and antioxidant effects of Meconopsis integrifolia ethanolic extract (MIE) in vitro and in vivo. The in vitro antioxidant property of MIE was investigated by employing various established systems. Rats with carbon tetrachloride (CCl4)-induced liver injury were used to assess the hepatoprotective and antioxidant effect of MIE in vivo. The level or activity of alkaline phosphatase (ALP), glutamate pyruvate transaminase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) in the blood serum and thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) in the liver and kidney of the rats were assayed using standard procedures. MIE exhibited strong antioxidant ability in vitro. In the rats with CCl4-induced liver injury, the groups treated with MIE and silymarin showed significantly lower levels of ALT, AST, ALP, and TB. MIE demonstrated good antioxidant activities in both the liver and kidney of the rats in vivo. MIE exhibits excellent hepatoprotective effects and antioxidant activities in vitro and in vivo, supporting the traditional use of Meconopsis integrifolia in the treatment of hepatitis. 23858098 53BP1 is limiting for nonhomologous end-joining in ATM-deficient cells subjected to oncogenic stress or radiation. DNA Damage Response (DDR) factors Ataxia Telangiectasia Mutated (ATM) and p53 Binding Protein 1 (53BP1) function as tumor suppressors in humans and mice, but the significance of their mutual interaction to the suppression of oncogenic translocations in vivo has not been investigated. To address this question, we have examined here phenotypes of mice lacking 53BP1 and ATM (Trp53bp1-/-/Atm-/-), relative to single mutants. These analyses reveal that loss of 53BP1 markedly decreases the latency of T lineage lymphomas driven by RAG-dependent oncogenic translocations in Atm-/- mice (average survival, 23 and 14 weeks for Atm-/- and Trp53bp1-/-/Atm-/- mice, respectively). Mechanistically, 53BP1 deficiency aggravates the deleterious effect of ATM deficiency on nonhomologous end-joining (NHEJ)-mediated double-strand break (DSB) repair. Analysis of V(D)J recombinase-mediated coding joints (CJs) and signal joints (SJs) in Trp53bp1-/-/Atm-/- primary thymocytes is, however, consistent with canonical NHEJ-mediated repair. Together, these findings indicate that the greater NHEJ defect in double mutants results from a decrease in the efficiency of rejoining rather than a switch to alternative NHEJ-mediated repair. Complementary analyses of irradiated primary cells indicate that defects in cell cycle checkpoints subsequently function to amplify the NHEJ defect, resulting in more frequent chromosomal breaks and translocations in double mutants cells throughout the cell cycle. Finally, we find that 53BP1 is dispensable for the formation of RAG-mediated hybrid joints (HJs) in Atm-/- thymocytes, but is required to suppress large deletions in a subset of HJs. Collectively, these results uncover novel ATM-independent functions for 53BP1 in the suppression of oncogenic translocations and in radioprotection. 23400749 Correlation between carbapenem consumption and antimicrobial resistance rates of Acinetobacter baumannii in a university-affiliated hospital in China. To investigate the correlation between carbapenem consumption and rates of antimicrobial resistance in Acinetobacter baumannii, carbapenem consumption was expressed as defined daily dose based on the World Health Organization (WHO) anatomical therapeutic chemical classification index. Clinical isolates from 2001-2009 were collected and analyzed using WHONET 5.4 software. Results show that the consumption of imipenem/cilastatin, meropenem, and total carbapenem is significantly correlated with imipenem resistance in A baumannii (r = 0.818, P = .007; r = 0.817, P = .007; r = 0.827, P = .006). Furthermore, total carbapenem consumption is significantly correlated with meropenem resistance in A baumannii (r = 0.900, P = .037). In addition, consumption of imipenem/cilastatin, meropenem, and total carbapenem is associated with A baumannii resistance to piperacillin-tazobactam, ceftazidime, cefepime, amikacin, and levofloxacin. These drugs are mainly β-lactams, aminoglycosides, and fluoroquinolones. The imipenem and meropenem resistance rates are significantly correlated with resistance rates to numerous antimicrobial drugs (eg, β-lactams, aminoglycosides, and fluoroquinolones) in A baumannii. Therefore, increased consumption of carbapenem may contribute to the development of resistance in A baumannii to imipenem, meropenem, and other antimicrobial drugs. Cross-resistance possibly occurs among imipenem/cilastatin and meropenem, as well as with β-lactams, aminoglycosides, and fluoroquinolones. 23919219 Reduced esophageal cancer incidence in statin users, particularly with cyclo-oxygenase inhibition. To examine the association between statin use and the development of esophageal cancer We performed a systematic review and meta-analysis. Multiple databases (Pubmed, EMBASE, Cochrane Library, Web of Science, Wiley Interscience and Google Scholar) were systematically searched for studies reporting the association of statin use and the development of esophageal cancer. Literature searching and data abstraction were performed independently by two separate researchers. The quality of studies reviewed was evaluated using the Newcastle-Ottawa Quality assessment scale. Meta-analysis on the relationship between statin use and cancer incidence was performed. The effect of the combination of statin plus a cyclo-oxygenase inhibitor was also examined. Eleven studies met eligibility criteria, 9 high and 2 medium quality. All were observational studies. Studies examining adenocarcinoma development in Barrett's esophagus included 317 cancers and 1999 controls, population-based studies examining all esophageal cancers included 371203 cancers and 6083150 controls. In the Barrett's population the use of statins (OR = 0.57; 95%CI: 0.43-0.75) and cyclo-oxygenase inhibitors (OR = 0.59; 95%CI: 0.45-0.77) were independently associated with a reduced incidence of adenocarcinoma. Combined use of a statin plus cyclo-oxygenase inhibitor was associated with an even lower adenocarcinoma incidence (OR = 0.26; 95%CI: 0.1-0.68). There was more heterogeneity in the population-based studies but pooled adjusted data showed that statin use was associated with a lower incidence of all combined esophageal cancers (OR = 0.81; 95%CI: 0.75-0.88). Statin use in patients with Barrett's oesophagus is associated with a significantly lower incidence of adenocarcinoma. The chemopreventive actions of statins, especially combined with cyclo-oxygenase inhibitors deserve further exploration. 22960442 Methamphetamine-induced nitric oxide promotes vesicular transport in blood-brain barrier endothelial cells. Methamphetamine's (METH) neurotoxicity is thought to be in part due to its ability to induce blood-brain barrier (BBB) dysfunction. Here, we investigated the effect of METH on barrier properties of cultured rat primary brain microvascular endothelial cells (BMVECs). Transendothelial flux doubled in response to METH, irrespective of the size of tracer used. At the same time, transendothelial electrical resistance was unchanged as was the ultrastructural appearance of inter-endothelial junctions and the distribution of key junction proteins, suggesting that METH promoted vesicular but not junctional transport. Indeed, METH significantly increased uptake of horseradish peroxidase into vesicular structures. METH also enhanced transendothelial migration of lymphocytes indicating that the endothelial barrier against both molecules and cells was compromised. Barrier breakdown was only observed in response to METH at low micromolar concentrations, with enhanced vesicular uptake peaking at 1 μM METH. The BMVEC response to METH also involved rapid activation of endothelial nitric oxide synthase and its inhibition abrogated METH-induced permeability and lymphocyte migration, indicating that nitric oxide was a key mediator of BBB disruption in response to METH. This study underlines the key role of nitric oxide in BBB function and describes a novel mechanism of drug-induced fluid-phase transcytosis at the BBB. 23238353 Associations between social support, prevalent symptoms and health-related quality of life in Chinese women undergoing treatment for breast cancer: a cross-sectional study using structural equation modelling. There is little in the literature exploring the inter-relationship of social support, prevalent symptoms and health-related quality of life (HRQoL) among breast cancer patients. This study examines the inter-relationships among the three variables using the 'Theory of Unpleasant Symptoms' as a framework. 279 Chinese breast cancer patients undergoing treatment were recruited for face-to-face interviews. The instruments used were Chinese versions of the Brief Fatigue Inventory, Brief Pain Inventory, Hospital Anxiety and Depression Scales, Medical Outcomes Study Social Support Survey and Functional Assessment of Cancer Therapy for Breast Cancer. Goodness-of-fit and misfit indices were obtained for the final model (SRMR = 0.034, robust RMSEA = 0.051 and robust CFI = 0.981), and the results showed that social support had large total effects on social/family (total effect = 0.704, P < 0.05) and functional well-being (total effect = 0.450, P < 0.05), but a minimal effect on the breast cancer scale (total effect = 0.036, P > 0.05). The inter-relationships among the three variables give us a better understanding of breast cancer patients' experience and provide guidance for developing effective strategies to improve their HRQoL and relieving unpleasant symptoms. 23751125 Efficiency assessment and pH effect in removing nitrogen and phosphorus by algae-bacteria combined system of Chlorella vulgaris and Bacillus licheniformis. To achieve better removal of NH4(+) and TP in wastewater, a new algae-bacteria combined system of Chlorella vulgaris and Bacillus licheniformis was investigated in a 6-d experiment. The results showed that 78% of NH4(+) could be removed in the combined system, while 29% in single algae system and only 1% in single bacteria system. Approximately 92% of TP was removed in the combined system, compared with 55% and 78% in single algae and bacteria system, respectively. B. licheniformis was proven to be a growth-promoting bacterium for C. vulgaris by comparing Chl a concentrations in the single and combined systems. In the removal process, pH of the combined system was observed to reduce significantly from 7.0 to 3.5. Whereas with pH regulated to 7.0, higher removal efficiencies of NH4(+) (86%) and TP (93%) were achieved along with the recovery of algal cells and the increase of Chl a. These results suggest that nutrients in wastewater can be removed efficiently by the algae-bacteria combined system and pH control is crucial in the process. 23856047 Tetrazole and triazole as bioisosteres of carboxylic acid: Discovery of diketo tetrazoles and diketo triazoles as anti-HCV agents. A series of diketo tetrazoles and diketo triazoles were designed and synthesized as bioisosteres of α,γ-diketo acid, the active site inhibitor of HCV (Hepatitis C virus) polymerase NS5B. Among the synthesized compounds, 4-(4-fluorobenzyloxy)phenyl diketo triazole (30) exhibited anti-HCV activity with an EC50 value of 3.9μM and an SI value more than 128. The reduction of viral protein and mRNA levels were also validated, supporting the anti-HCV activity of compound 30. These results provide convincing evidence that the diketo tetrazoles and diketo triazoles can be developed as bioisosteres of α,γ-diketo acid to exhibit potent inhibitory activity against HCV. 22677456 In vitro characterization of organophosphorus compound hydrolysis by native and recombinant human prolidase. Human prolidase is a binuclear metalloenzyme, which can potentially function as a catalytic bioscavenger for organophosphorus (OP) nerve agents. Although the biochemical properties of native prolidase purified from human erythrocytes, liver, kidney, and fibroblast cells are well known, it is very poorly characterized with regard to its OP hydrolyzing activity. Also, the high cost of purification of large quantities of native enzyme limits its use as a bioscavenger. Thus, recombinant human prolidase with similar biochemical properties to those of native enzyme would be more suitable as a catalytic bioscavenger. In this study, we established an Escherichia coli expression system, which produced a large amount of tagged human liver prolidase that was purified to over 95% purity from the soluble fraction of cell lysate by affinity chromatography on Streptavidin-agarose resin. The catalytic properties of the recombinant enzyme were compared in vitro with those of highly purified prolidase I isolated from human erythrocytes. The catalytic properties of recombinant prolidase overlap with those of the erythrocyte-derived native enzyme. Both enzymes efficiently hydrolyzed diisopropylfluorophosphate, sarin, soman, tabun and cyclosarin, but were much less efficient at hydrolyzing paraoxon and methyl paraoxon. These results suggest that human prolidase expressed in E. coli is suitable for further development as a catalytic bioscavenger for OP nerve agents. 23736878 Immunotherapy of sarcomas. To describe the current advances in immunotherapy and how they can be applied to sarcoma. This review will discuss the recent literature and selected clinical trials. Evidence supporting treatment with immunotherapy alone in sarcoma will be reviewed, as will the potential incorporation of immunotherapy into treatment for sarcoma. Sarcoma, cancer of the connective tissues, frequently strikes young people, comprising a large percentage of cancer in children and young adults, but may occur at any age. Although molecularly targeted inhibitors are of great interest in treating sarcoma patients, immunotherapy is emerging as a plausible therapeutic modality because of the recent advances in other cancer types that may be translated to sarcoma. The licensing of ipilimumab and sipuleucel-T for cancer, and the remarkable success of immunotherapy for some childhood cancers, suggest a role for immunotherapy in the treatment of tumors like sarcoma. Sarcoma is a disease for which new treatments are needed. Immunotherapies have different mechanisms of action from most current therapies and could work in concert with them. Recent advances in sarcoma biology and cancer immunotherapy suggest that our knowledge of the immune system has reached the point where it can be used to augment both targeted and multimodality therapy for sarcoma. 23897659 Transcatheter PFO closure with GORE® SEPTAL OCCLUDER: early and mid-term clinical results. Background: Transcatheter closure of patent foramen ovale (PFO) is a widespread procedure. However the "quest" for the ideal device is still ongoing. Here we present the procedural and early results of transcatheter closure of PFO with the GORE® Septal Occluder. Methods: Three Italian centers participated in a registry and collected data from 122 consecutive patients undergoing PFO closure by using GSO device. Indication for closure was previous stroke or TIA in 110 and migraine in 12 subjects. Results: The procedure was successful in all patients. The procedure was performed under general anesthesia, fluoroscopic and trans-esophageal echocardiographic imaging in 80 subjects while it was performed with local anesthesia, fluoroscopic and intracardiac echocardiographic monitoring in 42 subjects. Twenty patients received a 20 mm device, 70 patients received a 25 mm device, and 32 received a 30 mm device. Procedure and fluoroscopy times were 30±20 and 5±4 minutes, respectively. In 3 cases the implanted device was retrieved because of unsatisfactory position. Four subjects (2.5%) experienced vascular complications. During a median follow-up of 9 months (range 1-18 months) seven patients experienced atrial arrhythmias and 4 of them required medical treatment. At six months follow-up, at chest x-ray in two cases there was evidence of fracture of two wires of the device. Devices were stable and no treatment was required. Moderate residual shunting was found in two patients at 6 and 12 months follow-up. No other complication occurred. Conclusion: GORE® Septal Occluder is an easy, safe and effective device in closing PFO. © 2013 Wiley Periodicals, Inc. 23632339 Safety of thromboembolic chemoprophylaxis in spinal trauma patients requiring surgical stabilization. Retrospective review. To determine the incidence of thromboembolic events, bleeding complications such as epidural hematomas, and wound complications in patients with spinal trauma requiring surgical stabilization. Literature addressing the safety and efficacy of chemoprophylactic agents in postoperative patients with spinal trauma is sparse. As a result, significant variability exists regarding administration of thromboembolic chemoprophylaxis in this population. The risk of bleeding complications is particularly concerning. Patients with spinal trauma who underwent surgical stabilization in 2009 and 2010 at a single level 1 trauma center were retrospectively reviewed. Exclusion criteria included patients who underwent solely decompressive procedures, noninstrumented fusions, kyphoplasty, or had incomplete medical records. Patients who received chemoprophylaxis were compared with patients who did not. Demographical information and injury data were collected. Primary outcome measures were prevalence of thromboembolic events, epidural hematomas, and persistent wound drainage requiring irrigation and debridement. Two hundred twenty-seven of 373 patients were included (56 in the untreated group, 171 in the treated group). Eight patients in the untreated group (14.3%) and 12 patients in the treated group (7%) developed postoperative thromboembolism (P = 0.096). There was 1 pulmonary embolism in the untreated group (1.8%), and 4 pulmonary embolisms in the treated group (2.3%). Surgical irrigation and debridement for wound drainage was required for 1.8% of patients in the untreated group and for 5.3% of patients in the treated group. No epidural hematomas were noted in either group. The treated group had more spinal levels fused (P = 0.46), higher injury severity scores (0.001), and longer hospitalizations (0.018). Patients who developed postoperative thromboembolism had significantly higher body mass indexes (P = 0.01), injury severity scores (0.001), number of spinal levels fused (P = 0.004), incidence of neurological deficits (0.001), and longer hospitalizations (0.16) compared with those who did not. The use of chemoprophylaxis appears to be safe in at-risk patients in the immediate postoperative period after spinal trauma surgery. No epidural hematomas occurred, and the risk of wound drainage is small. Body mass index, injury severity score, presence of neurological deficits, and number of spinal levels fused should be considered when determining which patients should receive chemoprophylaxis after surgical stabilization.Level of Evidence: 3. 23488809 Channel Size Conversion of Phi29 DNA-Packaging Nanomotor for Discrimination of Single- and Double-Stranded Nucleic Acids. Nanopores have been utilized to detect the conformation and dynamics of polymers, including DNA and RNA. Biological pores are extremely reproducible at the atomic level with uniform channel sizes. The channel of the bacterial virus phi29 DNA-packaging motor is a natural conduit for the transportation of double-stranded DNA (dsDNA) and has the largest diameter among the well-studied biological channels. The larger channel facilitates translocation of dsDNA and offers more space for further channel modification and conjugation. Interestingly, the relatively large wild-type channel, which translocates dsDNA, cannot detect single-stranded nucleic acids (ssDNA or ssRNA) under the current experimental conditions. Herein, we reengineered this motor channel by removing the internal loop segment of the channel. The modification resulted in two classes of channels. One class was the same size as the wild-type channel, while the other class had a cross-sectional area about 60% of the wild-type. This smaller channel was able to detect the real-time translocation of single-stranded nucleic acids at single-molecule level. While the wild-type connector exhibited a one-way traffic property with respect to dsDNA translocation, the loop-deleted connector was able to translocate ssDNA and ssRNA with equal competencies from both termini. This finding of size alterations in reengineered motor channels expands the potential application of the phi29 DNA-packaging motor in nanomedicine, nanobiotechnology, and high-throughput single-pore DNA sequencing. 23832187 Enhanced Resveratrol Production in Vitis vinifera Cell Suspension Cultures by Heavy Metals Without Loss of Cell Viability. The effects of heavy metal ions (Co(2+), Ag(+), Cd(2+)) on cell viability and secondary metabolite production, particularly anthocyanins and phenolic acids in Vitis vinifera cell suspension cultures, were investigated. Of these, Co at all three used concentrations (5.0, 25, and 50 Î¼M), Ag, and Cd at low concentration (5.0 Î¼M) were most effective to stimulate the phenolic acid production, increasing the 3-O-glucosyl-resveratrol up to 1.6-fold of the control level (250.5 versus 152.4 Î¼mol/g), 4 h after the treatments. Meanwhile, the elicitors at effective concentrations did not suppress cell growth, while the cell viability maintained. In contrast, Ag and Cd at high concentrations (25 and 50 Î¼M) remarkably reduced the cell viability, decreasing the cell viability up to about 15 % of the control level, 24 h after the treatments. The heavy metal ions did not affect the anthocyanin production. These observations show how, in a single system, different groups of secondary products can show distinct differences in their responses to potential elicitors. The 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity, peroxidase activity, medium pH value, and conductivity were only slightly elevated by the heavy metal ions. The results suggest that some of the secondary metabolites production was stimulated by the used elicitors, but there was not a stress response of the cells. 23712510 Aptamer-based turn-on detection of thrombin in biological fluids based on efficient phosphorescence energy transfer from Mn-doped ZnS quantum dots to carbon nanodots. This paper presents the first example of a sensitive, selective, and stable phosphorescent sensor based on phosphorescence energy transfer (PET) for thrombin that functions through thrombin-aptamer recognition events. In this work, an efficient PET donor-acceptor pair using Mn-doped ZnS quantum dots labeled with thrombin-binding aptamers (TBA QDs) as donors, and carbon nanodots (CNDs) as acceptors has been constructed. Due to the π-π stacking interaction between aptamer and CNDs, the energy donor and acceptor are taken into close proximity, leading to the phosphorescence quenching of donors, TBA QDs. A maximum phosphorescence quenching efficiency as high as 95.9% is acquired. With the introduction of thrombin to the "off state" of the TBA-QDs-CNDs system, the phosphorescence is "turned on" due to the formation of quadruplex-thrombin complexes, which releases the energy acceptor CNDs from the energy donors. Based on the restored phosphorescence, an aptamer-based turn-on thrombin biosensor has been demonstrated by using the phosphorescence as a signal transduction method. The sensor displays a linear range of 0-40 nM for thrombin, with a detection limit as low as 0.013 nM in pure buffers. The proposed aptasensor has also been used to monitor thrombin in complex biological fluids, including serum and plasma, with satisfactory recovery ranging from 96.8 to 104.3%. This is the first time that Mn-doped ZnS quantum dots and CNDs have been employed as a donor-acceptor pair to construct PET-based biosensors, which combines both the photophysical merits of phosphorescence QDs and the superquenching ability of CNDs and thus affords excellent analytical performance. We believe this proposed method could pave the way to a new design of biosensors using PET systems. 23788118 A Monte Carlo investigation of lung brachytherapy treatment planning. Iodine-125 ((125)I) and Caesium-131 ((131)Cs) brachytherapy have been used in conjunction with sublobar resection to reduce the local recurrence of stage I non-small cell lung cancer compared with resection alone. Treatment planning for this procedure is typically performed using only a seed activity nomogram or look-up table to determine seed strand spacing for the implanted mesh. Since the post-implant seed geometry is difficult to predict, the nomogram is calculated using the TG-43 formalism for seeds in a planar geometry. In this work, the EGSnrc user-code BrachyDose is used to recalculate nomograms using a variety of tissue models for (125)I and (131)Cs seeds. Calculated prescription doses are compared to those calculated using TG-43. Additionally, patient CT and contour data are used to generate virtual implants to study the effects that post-implant deformation and patient-specific tissue heterogeneity have on perturbing nomogram-derived dose distributions. Differences of up to 25% in calculated prescription dose are found between TG-43 and Monte Carlo calculations with the TG-43 formalism underestimating prescription doses in general. Differences between the TG-43 formalism and Monte Carlo calculated prescription doses are greater for (125)I than for (131)Cs seeds. Dose distributions are found to change significantly based on implant deformation and tissues surrounding implants for patient-specific virtual implants. Results suggest that accounting for seed grid deformation and the effects of non-water media, at least approximately, are likely required to reliably predict dose distributions in lung brachytherapy patients. 23458445 Cellulose-ethylenediaminetetraacetic Acid conjugates protect Mammalian cells from bacterial cells. Cellulose-ethylenediaminetetraacetic acid (EDTA) conjugates were synthesized by the esterification of cellulose with ethylenediaminetetraacetic dianhydride (EDTAD). The new materials provided potent antimicrobial activities against Staphylococcus aureus (S. aureus, Gram-positive bacteria) and Pseudomonas aeruginosa (P. aeruginosa, Gram-negative bacteria), and inhibited the formation of bacterial biofilms. The biocompatibility of the new cellulose-EDTA conjugates was evaluated with mouse skin fibroblasts for up to 14 days. SEM observation and DNA content analysis suggested that the new materials sustained the viability of fibroblast cells. Moreover, in mouse skin fibroblast-bacteria co-culture systems, the new cellulose-EDTA conjugates prevented bacterial biofilm formation and protected the mammalian cells from the bacterial cells for at least one day. 23805784 Nanoparticle Assemblies via Coordination with a Tetrakis(terpyridine) Linker Bearing a Rigid Tetrahedral Core. Controlling particle-particle interactions is a major challenge in achieving the programmable assembly of nanoparticles, which shows great potential for device fabrication and detection systems. We present here a simple chemical method that allows the formation of Pd nanoparticle assemblies using a tetrakis(terpyridine) linker with a rigid tetrahedral core. 23581876 Metabolism of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) atropisomers in tissue slices from phenobarbital or dexamethasone-induced rats is sex-dependent. Abstract 1. Chiral polychlorinated biphenyls (PCBs) such as PCB 136 enantioselectively sensitize the ryanodine receptor (RyR). In light of recent evidence that PCBs cause developmental neurotoxicity via RyR-dependent mechanisms, this suggests that enantioselective PCB metabolism may influence the developmental neurotoxicity of chiral PCBs. However, enantioselective disposition of PCBs has not been fully characterized. 2. The effect of sex and cytochrome P450 (P450) enzyme induction on the enantioselective metabolism of PCB 136 was studied using liver tissue slices prepared from naïve control (CTL), phenobarbital (PB; CYP2B inducer) or dexamethasone (DEX; CYP3A inducer) pretreated adult Sprague-Dawley rats. PCB 136 metabolism was also examined in hippocampal slices derived from untreated rat pups. 3. In liver tissue slices, hydroxylated PCB (OH-PCB) profiles depended on sex and inducer pretreatment, and OH-PCB levels followed the rank orders male > female and PB > DEX > CTL. In contrast, the enantiomeric enrichment of PCB 136 and its metabolites was independent of sex and inducer pretreatment. Only small amounts of PCB 136 partitioned into hippocampal tissue slices and no OH-PCB metabolites were detected. 4. Our results suggest that enantioselective metabolism, sex and induction status of P450 enzymes in the liver may modulate the neurotoxic outcomes of developmental exposure to chiral PCBs. 23920248 Acute and sub-chronic toxicity of HPLC fingerprinted extract of Conyza sumatrensis (Retz.) E.H. Walker in rodents. Conyza sumatrensis (CS) is an extensively used medicinal herb in the tropics for varied ailments related to pain, inflammation and malaria. Though in constant folkloric use, scientific validations are proving valuable. Evaluate the safety profile of methanol extract from CS in mice and rats through acute and sub-chronic toxicity studies respectively. Acute toxicity study involved the single oral administration of CS at 1000, 2000 and 3000mg/kg in mice, while the sub chronic toxicity was carried upon in rats at doses 250, 500 and 1000mg/kg/day for 28 days. Besides body weight, general behaviour and mortality, serum biochemical parameters and liver histology were assessed after 7 and 28 days for acute and sub-chronic study respectively. The parameters were again checked on days 14 and 56 in order to assess the recovery from damage, if any. HPLC fingerprinting of the aqueous and methanol extract was performed through C18 column using water: acetonitrile as mobile phase with observations at 240nm. In the acute toxicity test, single oral dose of 1000, 2000 and 3000mg/kg of CS did not result in any behavioural changes or mortality, indicating non toxicity. In sub-chronic toxicity studies in rats, no mortality was observed at 250, 500 and 1000mg/kg/day when administered orally for a period of 28 days. Except Serum Glutamate Pyruvate Transaminase (SGPT) level in acute study and Alkaline Phosphatase (ALP), SGPT and Serum Glutamate Oxaloacetate Transaminase (SGOT) level in sub-chronic study, all the observational, haematological and biochemical parameters studied showed non-significant changes. Histological examination of liver did not reveal any treatment-related effects in any of the studies. Moreover, haematological and biochemical changes orchestrated by CS got normalised after 14 and 56 days post-treatment in acute and sub-chronic toxicity respectively. The HPLC fingerprint could resolve 11 and 28 peaks from aqueous and methanol extracts respectively. The experiments indicate the methanol extract to be safe even at high and repeated doses in pre-clinical studies even though the constituents are more than in aqueous extract. 23919733 Outcomes of fetal listed patients awaiting heart transplantation. HTx in neonates is mainstay therapy for those with severe cardiomyopathies and congenital heart disease. Fetal listing for HTx has been proposed as a way to increase the potential window for a donor with outcomes predicted to be similar to the neonatal population. Data from the PHTS, a prospective multicenter study, were used to examine the outcomes of fetuses listed between 1993 and 2009. Four thousand three hundred and sixty-five children were listed for HTx during this period. Fetuses comprised 1% and neonates 19.8% of listed patients. In those patients listed as fetus and transplanted, the median wait time from listing to HTx was 55 days (range 4-255), with a median of 25 days (range 0-233) after birth. By six months post-listing, a higher proportion of fetal listed patients had undergone HTx with a lower waitlist mortality when compared with neonate. There was no significant difference in survival following HTx between the two group (p = 0.4). While the results of this study may be less applicable to current practice due to changes in referrals for fetal listing, they do indicate that fetal listing can be a reasonable option. These results are of particular interest at the present time given the ongoing public discourse on the proposed elimination of fetal listing within UNOS. 23752892 Investigation into the mechanical properties of single-walled carbon nanotube heterojunctions. The mechanical properties of finite-length (6,0)/(8,0) single-walled carbon nanotube (SWCNT) heterojunctions with respect to different kinds of connection segments, either coaxial or bias, are investigated using molecular dynamics simulation calculations. It is found that the resulting significant deformation of structure and significant drop of stress under yielding strain is due to the strain localization. Moreover, the deformation is occurred below the heptagon ring in the thinner segment of the heterojunctions under tension at different temperatures, whereas under compression it occurs on the heptagon ring. The computed atomic bond number distribution and radius distribution function are applied to determine the deformed atomic structure. Finally, with increasing temperature, the yielding stresses decrease for both coaxial and bias heterojunctions under tension and compression, while the dependence of temperature on the Young's modulus of the heterojunctions is only observed in the case of tension. 23939127 61 Gbits/s direct-detection optical OFDM based on blockwise signal phase switching with signal-to-signal beat noise cancellation. We propose a scheme for a direct-detection optical orthogonal frequency-division multiplexing (OFDM) system based on blockwise signal-phase-switching (SPS). Experimental demonstration of 61  Gbits/s SPS direct-detection optical OFDM signal transmission over 80 km standard single-mode-fiber was successfully achieved with single polarization and a single photodetector. 23848222 Megakaryopoiesis through the ages: from the twinkle in the eye to the fully grown adult. The development of the human haematopoietic system during embryogenesis, then the foetal in utero period and after birth has been fascinating scientists and clinicians alike for some time. "Primitive" haematopoiesis first arises in the yolk sack and is followed by the emergence of "definitive" haematopoietic stem cells in the aorta-gonado-mesonephros (AGM) region, the colonization of the foetal liver by the haematopoietic system and finally, in the late stage of foetal development, the emergence of the bone marrow as the principal site of haematopoiesis[1]. The red cell lineage is the haematopoietic system where each of these transitions are best documented because they are accompanied by a switch in the type of haemoglobin (Hb) chains produced in the red cells. This article is protected by copyright. All rights reserved. 23940674 Prognostic Value of CD166 Expression in Cancers of the Digestive System: A Systematic Review and Meta-Analysis. Many studies have reported the prognostic predictive value of CD166 as a cancer stem cell marker in cancers of the digestive system; however, its predictive value remains controversial. Here, we investigate the correlation between CD166 positivity in digestive system cancers and clinicopathological features using meta-analysis. A comprehensive search in PubMed and ISI Web of Science through March of 2013 was performed. Only articles containing CD166 antigen immunohistochemical staining in cancers of the digestive system were included,including pancreatic cancer, esophageal cancer, gastric cancer and colorectal cancer. Data comparing 3- and 5-year overall survival along with other clinicopathological features were collected. Nine studies with 2553 patients who met the inclusion criteria were included for the analysis. The median rate of CD166 immunohistochemical staining expression was 56% (25.4%-76.3%). In colorectal cancer specifically, the results of a fixed-effects model indicated that CD166-positive expression was an independent marker associated with a smaller tumor burden (T category; RR = 0.93, 95%, CI: 0.88-0.98) but worse spread to nearby lymph nodes (N category; RR = 1.17, 95% CI: 1.05-1.30). The 5-year overall survival rate was showed relationship with cytoplasmic positive staining of CD166 (RR = 1.47 95% 1.21-1.79), but no significant association was found in the pool or any other stratified analysis with 3- or 5- year overall survival rate. Based on the published studies, different cellular location of CD166 has distinct prognostic value and cytoplasmic positive expression is associated with worse prognosis outcome. Besides, our results also find CD166 expression indicate advanced T category and N-positive status in colorectal cancer specifically. 22930532 Abusive Supervision and Workload Demands from Supervisors: Exploring Two Types of Supervisor-related Stressors and their Association with Strain. Our study aimed to identify two types of stressors from supervisors: abusive supervision (AS) and workload demands from supervisors (WDS). AS reflects the relationship dimension of supervisor-related stressors, and WDS reflects the task dimension of supervisor-related stressors. In Study 1, we attempted to distinguish between AS and WDS. The results of confirmatory factor analysis showed that AS and WDS are two distinct dimensions of supervisor-related stressors. In Study 2, we utilized job demands-resources model and investigated whether AS and WDS can uniquely predict subordinates' emotional exhaustion (EE). We also explored whether perceived job characteristics (PJCs) have differential moderating effects on the relationships between the two dimensions of supervisor-related stressors (AS and WDS) and EE. Consistent with our predictions, the results showed that both AS and WDS have incremental predictive effects on EE after controlling for the effect of the other. The results also revealed that PJCs weaken the WDS-EE relationship, not the AS-EE relationship. We discussed the theoretical and practical implications at the end. Copyright © 2012 John Wiley & Sons, Ltd. 23961958 Proteomic analysis of extremely severe hand, foot and mouth disease infected by enterovirus 71. To clarify the molecular mechanisms that participate in the severe hand, foot and mouth disease (HFMD) infected by Enterovirus 71 and to detect any related protein biomarkers, we performed proteomic analysis of protein extracts from 5 extremely severe HFMD children and 5 healthy children. The protein profiles of them were compared using two-dimensional electrophoresis. Differentially expressed proteins were identified using mass spectrometry. Functional classifications of these proteins were based on the PANTHER. The interaction network of the differentially expressed protein was generated with Pathway Studio. A total of 38 differentially expressed proteins were identified. Functional classifications of these proteins indicated a series of altered cellular processes as a consequence of the severe HFMD. These results provided not only new insights into the pathogenesis of severe HFMD, but also implications of potential therapeutic designs. Our results suggested the possible pathways that could be the potential targets for novel therapy: viral protection, complement system and peroxide elimination. 23844761 Tracking of tuning effects in bis-cyclometalated iridium complexes: a combined time resolved infrared spectroscopy, electrochemical, and computational study. Electronic structure and photophysical properties have been investigated for a new series of fluorinated iridium complexes with the parent [Ir(ppy)2(deeb)](PF6) (deeb is 4,4'-diethylester-2,2'-bipyridine). Time resolved infrared spectroscopy (TRIR) has been used to observe the long-lived triplet excited state of each complex confirming its mixed charge transfer character. Supplementary evidence of charge transfer in the triplet state is provided via emission spectroscopy, transient absorption spectroscopy, and density functional theory (DFT) calculations. Both computational and spectroscopic assignments reveal consistency in the first excitation throughout the series of complexes. Electrochemical measurements meanwhile show that increasing fluorination still induces expected shifting of frontier orbitals. Excited states beyond the lowest lying triplet are probed for the complexes via UV-vis spectroscopy which reveals three distinct features. These features are assigned via time-dependent DFT (TD-DFT) to build a broader understanding of electronic structure. 23147869 Extraction of sediment-associated polycyclic aromatic hydrocarbons with granular activated carbon. Addition of activated carbon (AC) to sediments has been proposed as a method to reduce ecotoxicological risks of sediment-bound contaminants. The present study explores the effectiveness of granular AC (GAC) in extracting polycyclic aromatic hydrocarbon (PAH) from highly contaminated sediments. Four candidate GAC materials were screened in terms of PAH extraction efficiency using single-step 24-h GAC extractions, with traditional 24-h Tenax extraction as a reference. Subsequently, sorption of native PAHs to the best performing GAC 1240W (0.45-1.70 mm) was studied for sediment only and for GAC-sediment mixtures at different GAC-sediment weight ratios, using 76-µm polyoxymethylene (POM) passive samplers. Granular AC sorption parameters for PAHs were determined by subtracting the contribution of PAH sorption to sediment from PAH sorption to the GAC-sediment mixture. It appears that the binding of PAHs and the effectiveness of GAC to reduce sediment porewater concentrations were highly dependent on the GAC-sediment mixing ratio and hydrophobicity of the PAH. Despite the considerable fouling of GAC by organic matter and oil, 50 to 90% of the most available PAH was extracted by the GAC during a 28-d contact time, at a dose as low as 4%, which also is a feasible dose in field-scale applications aimed at cleaning the sediment by GAC addition and removal. 23903194 Phosphorylation of RNA polymerase II is independent of P-TEFb in the C. elegans germline. RNA polymerase II (Pol II) elongation in metazoans is thought to require phosphorylation of serine 2 (Ser2-P) of the Pol II C-terminal domain (CTD) by the P-TEFb complex, CDK-9/cyclin T. Another Ser2 kinase complex, CDK-12/cyclin K, which requires upstream CDK-9 activity has been identified in Drosophila and human cells. We show that regulation of Ser2-P in C. elegans soma is similar to other metazoan systems, but Ser2-P in the germline is independent of CDK-9, and largely requires only CDK-12. The observed differences are not due to differential tissue expression as both kinases and their cyclin partners are ubiquitously expressed. Surprisingly, loss of CDK-9 from germ cells has little effect on Ser2-P, yet CDK-9 is essential for germline development. By contrast, loss of CDK-12 and Ser2-P specifically from germ cells has little impact on germline development or function, although significant loss of co-transcriptional H3K36 trimethylation is observed. These results show a reduced requirement for Pol II Ser2-P in germline development and suggest that generating Ser2-P is not the essential role of CDK-9 in these cells. Transcriptional elongation in the C. elegans germline thus appears to be uniquely regulated, which may be a novel facet of germline identity. 23220105 In vivo biocompatibility, sustained-release and stability of triptorelin formulations based on a liquid, degradable polymer. Hexylsubstituted poly(lactic acid) (hexPLA) is a viscous polymer, which degrades in the presence of water similar to the structure related poly(lactic acid). With hydrophilic active compounds, like Triptorelin acetate, the lipophilic polymer was formulated in form of parenterally injectable suspensions. This first in vivo study toward the biocompatibility of hexPLA implants in rats over 3 months in comparison to in situ forming poly(lactic-co-glycolic acid) (PLGA) formulations is presented here. The hexPLA implants showed only a mild acute inflammation at the injection site after application, which continuously regressed. In contrast to the PLGA formulations, hexPLA did not provoke an encapsulation of the implant with extracellular matrix. Prior to the formulation application, the stability of Triptorelin inside the hexPLA matrix was assessed under different storage conditions and in the presence of buffer to simulate a peptide degrading environment. At 5°C Triptorelin showed a stability of 98% inside the polymer for at least 6 months. The stability was still 78% at an elevated temperature of 40°C. HexPLA protected the incorporated peptide from the surrounding aqueous environment, which resulted in 20% less degradation inside the polymer compared to the solution. This protection effect supports the use of Triptorelin-hexPLA formulations for parenteral sustained-release formulations. In a second in vivo evaluation in Wistar Hannover rats, formulations containing 5% and 10% Triptorelin in the polymeric matrix released the active compound continuously for 6 months. The formulations showed a higher release during the initial 7 days, which is necessary for the clinical use to down-regulate all GnRH-receptors. Afterwards, a zero order drug release was observed over the first 3 months. After 3 months, the plasma levels decreased slowly but remained at effective concentrations for the total of 6 months. Furthermore, a qualitative in vitro-in vivo correlation was observed, possibly facilitating future optimization of the Triptorelin-hexPLA sustained-release formulations. 23674254 Early Enteral Nutrition Prevents Intra-abdominal Hypertension and Reduces the Severity of Severe Acute Pancreatitis Compared with Delayed Enteral Nutrition: A Prospective Pilot Study. To investigate the effects of early enteral nutrition (EEN) on intra-abdominal pressure (IAP) and disease severity in patients with severe acute pancreatitis (SAP). Enteral nutrition (EN) was started within 48 h after admission in the EEN group and from the 8th day in the delayed enteral nutrition (DEN) group. The IAP and intra-abdominal hypertension (IAH) incidence were recorded for 2 weeks. The caloric intake and feeding intolerance (FI) incidence were recorded daily after EN was started. The severity markers and clinical outcome variables were also recorded. Sixty patients were enrolled to this study. No difference about IAP was found. The IAH incidence of the EEN group was significantly lower than that of the DEN group from the 9th day (8/30 versus 18/30; P = 0.009) after admission. The FI incidence of the EEN group was higher than that of the DEN group during the initial 3 days of feeding (25/30 versus 12/30; P = 0.001; 22/30 versus 9/30; P = 0.001; 15/30 versus 4/30; P = 0.002). Patients with an IAP <15 mmHg had lower FI incidence than those with an IAP ≥15 mmHg on the 1st day (20/22 versus 17/38; P < 0.001), the 3rd day (11/13 versus 8/47; P < 0.001), and the 7th day (3/5 versus 3/55; P = 0.005) of feeding. The severity markers and clinical outcome variables of the EEN group were significantly improved. Early enteral nutrition did not increase IAP. In contrast, it might prevent the development of IAH. In addition, EEN might be not appropriate during the initial 3-4 days of SAP onset. Moreover, EN might be of benefit to patients with an IAP <15 mmHg. Early enteral nutrition could improve disease severity and clinical outcome, but did not decrease mortality of SAP. 23597598 Saccade adaptation as a model of flexible and general motor learning. The rapid point-to-point movements of the eyes called saccades are the most commonly made movement by humans, yet differ from nearly every other type of motor output in that they are completed too quickly to be adjusted during their execution by visual feedback. Saccadic accuracy remains quite high over a lifetime despite inevitable changes to the physical structures controlling the eyes, indicating that the oculomotor system actively monitors and adjusts motor commands to achieve consistent behavioral production. Indeed, it seems that beyond the ability to compensate for slow, age-related bodily changes, saccades can be modified following traumatic injury or pathology that affects their production, or in response to more short-term systematic alterations to post-saccadic visual feedback in a laboratory setting. These forms of plasticity rely on the visual detection of accuracy errors by a unified set of mechanisms that support the process known as saccade adaptation. Saccade adaptation has been mostly studied as a phenomenon in its own right, outside of motor learning in general. Here, we highlight the commonalities between eye and arm movement adaptation by reviewing the literature across these fields wherever there are compelling overlapping theories or data. Recent exciting findings are challenging previous interpretations of the underlying mechanisms of saccade adaptation with the incorporation of concepts including prediction, reinforcement and contextual learning. We review the emerging ideas and evidence with particular emphasis on the important contributions made by Josh Wallman in this sphere over the past 15 years. 22902506 2'-Behenoyl-paclitaxel conjugate containing lipid nanoparticles for the treatment of metastatic breast cancer. The aim of these studies was to develop a novel 2'-behenoyl-paclitaxel (C22-PX) conjugate nanoparticle (NP) formulation for the treatment of metastatic breast cancer. A lipophilic paclitaxel derivative C22-PX was synthesized and incorporated into lipid-based NPs. Free C22-PX and its NP formulation were evaluated in a series of in vitro and in vivo studies. The results demonstrated that C22-PX NPs were much better tolerated and had significantly higher plasma and tumor AUCs compared to Taxol at the maximum tolerated dose (MTD) in a subcutaneous 4T1 mouse mammary carcinoma model. These benefits resulted in significantly improved antitumor efficacy with the NP-based formulation. 23601697 Disease duration-related differences in non-motor symptoms: a study of 616 Chinese Parkinson's disease patients. The differences in non-motor symptoms (NMS) along with the duration of Parkinson's disease (PD) in Chinese populations remain largely unknown. A total of 616 PD patients consisting of 189 patients with disease duration of less than 2years, 239 patients with duration between 2 and 5years, 122 patients with duration between 5 and 10years, and 66 patients with duration more than 10years from Southwest China were studied. Each patient was assessed using the non-motor symptoms scale (NMSS). The mean affected number of NMS was 8.8±5.8, and the mean total NMSS score was 36.3±33.2. The mean affected number of NMS and the mean total NMSS score increased with the disease progression. The following symptoms became more common and severe with the disease duration: falls due to fainting, fatigue, difficulty falling asleep, restless legs, perceptual problem/hallucination domain (i.e., "hallucinations," "delusions," and "double vision"), gastrointestinal domain (i.e., "dribbling saliva," "swallowing," and "constipation"), urinary domain (i.e., "urgency," "frequency," and "nocturia"), and miscellaneous domain (i.e., "excessive sweating"). However, some symptoms such as mood/apathy pleasure, sexual dysfunction, and others remained stable. NMS are prevalent in all disease duration of the Chinese PD patients. Although the mean affected number of NMS and NMMS score increased with the disease duration, NMS progression is symptom specific. 23481437 Estradiol as a Mechanism for Sex Differences in the Development of an Addicted Phenotype following Extended Access Cocaine Self-Administration. Women progress more rapidly after initial cocaine use to addiction as compared with men. Similarly, female rats appear to require less cocaine exposure before developing an addicted phenotype with evidence implicating estradiol as a potential mechanism. The goals of this study were to determine whether there are sex differences in the magnitude of the addicted phenotype under optimized conditions that induce its development in both males and females and to determine the role of estradiol in this effect. Following acquisition, intact male and intact and ovariectomized (OVX) female rats with and without estradiol replacement were given access to cocaine (1.5 mg/kg per infusion) under either extended access (ExA; discrete trial procedure, 4 trials/h, 24 h/day, 10 days) or short access (ShA) conditions (20 infusions maximum/day, 3 days). Motivation to obtain cocaine (0.5 mg/kg/infusion), as assessed under a progressive-ratio schedule, was then examined following a 2-week abstinence period. Results showed that following ExA self-administration, both males and females developed an addicted phenotype, with 9 of 11 males and 8 of 10 females showing a greater than 15% increase in levels of motivation to obtain cocaine as compared with ShA controls. In contrast, within the OVX groups, responding was enhanced from control levels after ExA self-administration in estradiol-replaced rats only. These results suggest that while females may have an enhanced vulnerability to developing an addicted phenotype, they may be similar to males once addiction has developed. These results also suggest that estradiol is critically involved in the development of an addicted phenotype in females. 23455540 Color Doppler ultrasound (CDU) in the diagnosis of obstructive hydronephrosis in pregnant women. Color Doppler ultrasound (CDU) accuracy of kidneys and bladder in the diagnosis and treatment of hydronephrosis and/or renal colic in pregnancies was evaluated. Between January 2010 and September 2012, 234 pregnant women asymptomatic in 204 cases and with unilateral renal colic in 30 (median 26 years) were evaluated. A CDU of the urinary tract was performed using a sonograph GE Logiq 500 PRO with a multifrequency (3-5 MHz) convex probe. The following parameters were evaluated: resistive index (RI) of the arciform arteries of both kidneys and bilateral ureteric jets. A renal RI > 0.70 and/or a 10 % difference between the kidneys and an asymmetric and/or reduced ureteric jet from the ureteric orifices were considered as diagnostic of obstructive uropathy. Overall incidence of hydronephrosis was equal to 27 % (63 out 234 cases); the incidence of hydronephrosis, RI > 0.70 and abnormal ureteric jet in asymptomatic vs symptomatic pregnant women was equal to 30.9 vs 50 %, 16.1 vs 50 %, 3 vs 60 % (p < 0.05), respectively. In the 63 pregnancies with asymptomatic hydronephrosis RI and ureteric jet evaluation were abnormal in 39 (19.1 %) and 6 cases (3 %), respectively. In the 30 pregnancies with renal colic conventional ultrasound vs CDU, findings were abnormal in 15 (50 %) vs 20 (66.7 %) (p = 0.015) cases, respectively. Color Doppler ultrasound in pregnancies with hydronephrosis and/or renal colic improves conventional ultrasound accuracy; in fact, CDU adds a functional evaluation of the urinary tract when combined with clinical findings allows performing the appropriate management. 22456940 Beetroot red (betanin) inhibits vinyl carbamate- and benzo(a)pyrene-induced lung tumorigenesis through apoptosis. Betanin, also called beetroot red, has been extensively used as a food colorant. In this study, the chemopreventive activity of betanin by oral consumption was investigated in two mouse lung tumor models. Vinyl carbamate (VC) and benzo(a)pyrene (B(a)P) were used to induce lung tumors, and female A/J mice were treated with betanin in drinking water. Betanin significantly decreased tumor multiplicity and tumor load induced by both carcinogens. Tumor multiplicity and tumor load were decreased by 20% and 39% in the VC lung model, and by 46% and 65% in the B(a)P lung model, respectively. Betanin reduced the number of CD31+ endothelial microvessels and increased the expression of caspase-3, suggesting that the lung tumor inhibitory effects were through induction of apoptosis and inhibition of angiogenesis. Betanin also induced apoptosis through activated caspase-3, -7, -9, and PARP in human lung cancer cell lines. Our data show that betanin significantly inhibits lung tumorigenesis in A/J mice and merits investigation as a chemopreventive agent for human lung cancer. © 2012 Wiley Periodicals, Inc. 23378625 Glycation Gap Is Associated With Macroproteinuria but Not With Other Complications in Patients With Type 2 Diabetes. OBJECTIVEWe investigated whether glycation gap (G-Gap), an index of intracellular glycation of proteins, was associated with diabetes complications.RESEARCH DESIGN AND METHODSWe measured concomitantly HbA(1c) and fructosamine in 925 patients with type 2 diabetes to calculate the G-Gap, defined as the difference between measured HbA(1c), and fructosamine-based predicted HbA(1c). Patients were explored for retinopathy, nephropathy, peripheral neuropathy, cardiac autonomic neuropathy (n = 512), and silent myocardial ischemia (n = 506).RESULTSMacroproteinuria was the only complication that was associated with G-Gap (prevalence in the first, second, and third tertile of G-Gap: 2.9, 6.2, and 11.0%, respectively; P < 0.001). The G-Gap was higher in patients with macroproteinuria than in those without (1.06 ± 1.62 vs. 0.03 ± 1.30%; P < 0.0001). Because HbA(1c) was associated with both G-Gap (HbA(1c) 7.0 ± 1.4, 7.9 ± 1.4, and 10.1 ± 1.8% in the first, second, and third G-Gap tertile, respectively; P < 0.0001) and macroproteinuria (HbA(1c) 8.8 ± 2.2% if macroproteinuria, 8.3 ± 2.0% if none; P < 0.05), and because it could have been a confounder, we matched 54 patients with macroproteinuria and 200 patients without for HbA(1c). Because macroproteinuria was associated with lower serum albumin and fructosamine levels, which might account for higher G-Gap, we calculated in this subpopulation albumin-indexed fructosamine and G-Gap; macroproteinuria was independently associated with male gender (odds ratio [OR], 3.2; 95% CI, 1.5-6.7; P < 0.01), hypertension (2.9; [1.1-7.5]; P < 0.05), and the third tertile of albumin-indexed G-Gap (2.3; [1.1-4.4]; P < 0.05) in multivariate analysis.CONCLUSIONIn type 2 diabetic patients, G-Gap was associated with macroproteinuria, independently of HbA(1c), albumin levels, and confounding factors, suggesting a specific role of intracellular glycation susceptibility on kidney glomerular changes. 23871716 Inhibition of glycogen synthase kinase-3β by lithium chloride suppresses 6-hydroxydopamine-induced inflammatory response in primary cultured astrocytes. An increasing amount of evidence has emerged to suggest that neuroinflammatory process is involved in the pathogenesis of Parkinson's disease (PD). Activated microglia and astrocytes are found in the substantia nigra (SN) of Parkinson's disease brains as well as in animal models of Parkinson's disease. Although reactive astrocytes are involved in the progression of PD, the role of reactive astrocytes in neuroinflammation of PD has received limited attention to date. Recently, Glycogen synthase kinase-3β (GSK-3β) was identified as a crucial regulator of the inflammatory response. The purpose of this study was to explore the mechanism by which 6-hydroxydopamine (6-OHDA) induces inflammatory response in astrocytes and observe the anti-inflammatory effect of lithium chloride (LiCl) on 6-OHDA-treated astrocytes. In the present study, we found that glial fibrillary acidic protein (GFAP) was markedly upregulated in the presence of 6-OHDA. Moreover, our results revealed that proinflammatory molecules including inducible nitric oxide synthase (iNOS), nitric oxide (NO), cyclooxygenase-2(COX-2), prostaglandins E2 (PGE2), and tumor necrosis factor-α (TNF-α) were obviously increased in astrocytes exposed to 6-OHDA. Western blot analysis revealed that 6-OHDA significantly increased dephosphorylation/activation of GSK-3β as well as the nuclear translocation of nuclear factor-κB (NF-κB) p65. Besides, GSK-3β inhibitor LiCl and SB415286 inhibited the GSK-3β/NF-κB signaling pathway, leading to the reduction of proinflammatory molecules in 6-OHDA-activated astrocytes. These results confirmed that GSK-3β inhibitor LiCl and SB415286 provide protection against neuroinflammation in 6-OHDA-treated astrocytes. Therefore, GSK-3β may be a potential therapeutic target for the treatment of PD. 23300011 Clinical correlations and prognostic relevance of Fn14 expression in breast carcinoma. The aim of the present study was to clarify the expression of fibroblast growth factor-inducible 14 (Fn14), a type I transmembrane protein, in breast carcinoma and its correlation with clinicopathological features. We examined the expression of Fn14 in normal breast epithelial cells as well as in breast carcinoma cells, and in 12 cases of breast carcinoma tissues and the paired normal breast tissues by RT-PCR and Western blot analysis. In addition, we analyzed Fn14 protein expression in 171 clinicopathologically characterized breast carcinoma cases by immunohistochemistry. Statistical analyses were applied to test for prognostic and diagnostic associations. The results show that the level of Fn14 mRNA and protein were higher in the cancer cell lines and most cancer tissues than in normal control tissues. Immunohistochemistry showed that Fn14 was expressed in 148 of 171 cases (86.5%). Statistical analysis of cases showed that there was a significant difference of Fn14 expression in patients categorized according to HER-2 expression, lymph node metastasis and clinical stage. Our results suggest that Fn14 protein is a valuable marker of breast carcinoma progression. Fn14 might be used as a valuable prognostic marker for breast carcinoma patients. 23922362 JHPPL Workshop on Medicaid Fiscal and Governance Issues: Objectives and Themes. At a November 2012 workshop, state health policy officials, other Medicaid and insurance exchange practitioners, and health policy researchers discussed issues surrounding the implementation and sustainability of Medicaid expansion and insurance exchange coordination under the Patient Protection and Affordable Care Act (PPACA). Foremost were concerns about (1) intergovernmental relations (states experiencing uncertain information, lack of coordination among federal agencies, and limited resources to take on new responsibilities under the PPACA), and (2) policy design (new issues such as Medicaid exchange coordination on top of preexisting Medicaid challenges). JHPPL has proposed the creation of a research network to develop policy options and share strategies and best practices. 23894282 Quantitative Assessment of 2q35-rs13387042 Polymorphism and Hormone Receptor Status with Breast Cancer Risk. The association between rs13387042 polymorphism on 2q35 and breast cancer (BC) has been widely evaluated since it was first identified through genome-wide association approach. However, the results have been inconclusive. To investigate this inconsistency, we performed a meta-analysis of all available studies dealing with the relationship between the 2q35-rs13387042 polymorphism and BC. Databases including MEDLINE, PubMed, EMBASE, ISI web of science and CNKI (China National Knowledge Infrastructure) were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. The random-effects model was applied, addressing heterogeneity and publication bias. A total of 24 articles involving 99,772 cases and 164,985 controls were included. In a combined analysis, the summary per-allele odds ratio (OR) for BC of 2q35-rs13387042 polymorphism was 1.13 (95% CI: 1.11-1.16; P<10(-5)). Significant associations were also detected under co-dominant, dominant and recessive genetic models. In the subgroup analysis by ethnicity, significantly increased risks were found in Asians, Caucasians and Hispanic whites for the polymorphism in all comparisons; whereas no significant associations were found among Africans. In addition, we find 2q35-rs13387042 polymorphism conferred significantly risks for both ER-positive and ER-negative tumors. Furthermore, significant associations were also detected both in PR-positive and PR-negative cancer. Our findings demonstrated that rs13387042-A allele is a risk-conferring factors for the development of BC, especially in Asians, Caucasians and Hispanic whites. 23584016 Profiling the venom gland transcriptome of Tetramorium bicarinatum (Hymenoptera: Formicidae): The first transcriptome analysis of an ant species. Animal venoms are complex mixtures containing a range of bioactive elements with potential pharmacological and therapeutic use. Even though ants account among the most diverse zoological group, little information is available regarding their venom composition. To initiate the characterization of the transcriptomic venom gland expression of the ant species Tetramorium bicarinatum, 400 randomly selected clones from cDNA library were sequenced and a total of 364 high quality expressed sequence tags (ESTs) were generated. Based on the results of BLAST searches, these sequences were clustered and assembled into 83 contigs (22 multiple sequences) and 61 singletons. About 74% (267) of the contigs matched BLASTx hits with an interesting diversity together with an unusual abundance of cellular transcripts related to gene expression regulation (29% of the total library) reflecting the specialization of this tissue. About eighteen per cent of the ESTs were categorized as Hymenoptera venom compounds, the major part represented by allergens (62% of the total venom compounds). In addition, a high number of sequences (26%) had no similarity to any known sequences. This study provides a first insight of the gene expression scenario of the venom gland of T. bicarinatum which might contribute to acquiring a more comprehensive view on the origin and functional diversity of venom proteins among ants and more broadly among Hymenopteran insects. 23867117 Associations between polymorphisms in sex steroid related genes and autistic-like traits. Sex differences in psychiatric disorders are common, which is particularly striking in autism spectrum disorders (ASDs) that are four times more prevalent in boys. High levels of testosterone during early development have been hypothesized to be a risk factor for ASDs, supported by several studies showing fetal testosterone levels, as well as indirect measures of prenatal androgenization, to be associated with ASDs and autistic-like traits (ALTs). Further, the importance of sex steroid related genes in ASDs is supported by studies reporting associations between polymorphisms in genes involved in sex steroid synthesis/metabolism and ASDs and ALTs. The aim of the present study was to investigate possible associations between 29 single nucleotide polymorphisms (SNPs) in eight genes related to sex steroids and autistic features. Individuals included in the study belong to a subset (n=1771) from The Child and Adolescent Twin Study in Sweden (CATSS), which are all assessed for ALTs. For two SNPs, rs2747648 located in the 3'-UTR of ESR1 encoding the estrogen receptor alpha and rs523349 (Leu89Val) located in SRD5A2 encoding 5-alpha-reductase, type 2, highly significant associations with ALTs were found in boys and girls, respectively. The results of the present study suggest that SNPs in sex steroid related genes, known to affect gene expression (rs2747648 in ESR1) and enzymatic activity (Leu89Val in SRD5A2), seem to be associated with ALTs in a general population. In conclusion, the current findings provide further support for a role of sex steroids in the pathophysiology of ASDs. 23842117 Computed Tomography Angiography of Situs Inversus, Portosystemic Shunt and Multiple Vena Cava Anomalies in a Dog. A 5-year-old Shih Tzu was presented with intermittent vomiting and anorexia. Microhepatica and reversed position of the abdominal organs were observed on radiography. Ultrasonographically, portosystemic shunt (PSS) was tentatively diagnosed. On computed tomography (CT), the distended portal vein drained into the left hepatic vein. The caudal vena cava (CdVC) splited postrenally and converged at the renal level. Cranial to this, the azygos continuation of the CdVC was confirmed. On thorax, persistent left cranial vena cava (CrVC) along with right CrVC was found. This is first report of dog with persistent left CrVC in accordance with multiple abdominal malformations. CT angiography was useful to evaluate the characteristics of each vascular anomaly and determine the surgical correction in this complex case. 23851578 Lack of association between occupational exposure to diesel exhaust and risk of pancreatic cancer: a systematic evaluation of available data. To review epidemiologic studies on risk of pancreatic cancer and occupational exposure to diesel exhaust. A literature search was conducted, and data were abstracted in a systematic fashion. Comparable results were combined using a random-effects meta-analysis. Twenty-six studies were included in the review, including five studies based on routine statistics, 11 case-control studies [meta-relative risk (RR) of three estimates for diesel exhaust exposure 0.9; 95 % confidence interval (CI) 0.5, 1.6] and ten cohort studies (meta-RR of their results: 1.03; 95 % CI 0.93, 1.13). Few studies reported results according to duration of exposure or other quantitative measures; no consistent pattern emerged. The overall evidence from studies on occupational exposure to diesel exhaust and risk of pancreatic cancer leads to the conclusion of the absence of such association. 23836937 DETECTION OF CIRCULATING TUMOR CELLS IN PATIENTS WITH ADRENOCORTICAL CARCINOMA: A MONOCENTRIC PRELIMINARY STUDY. Context:Adrenocortical carcinoma (ACC) is a rare malignancy, the prognosis of which is mainly dependent on stage at diagnosis. The identification of disease-associated markers for early diagnosis and drug monitoring is mandatory. Circulating tumor cells (CTC) are released into the bloodstream from primary tumor/metastasis. CTC detection in blood samples may have enormous potential for assisting diagnosis of malignancy, estimating prognosis and monitoring the disease.Objective:To investigate the presence of CTC in blood samples of patients with ACC or benign adrenocortical adenoma (ACA).Setting:University Hospital.Patients:14 ACC and 10 ACA.Intervention:CTC analysis performed in blood samples from 14 ACC and 10 ACA patients. CTC isolated on the basis of cell size by filtration through ScreenCell® devices, followed by identification according to validated morphometric criteria and immunocytochemistry.Main outcome measure:Difference in CTC detection between ACC and ACA.Results:CTC were detected in all ACC but not in ACA samples. Immunocytochemistry confirmed the adrenocortical origin. When ACC patients were stratified according to the median value of tumor diameter and metastatic condition, a statistically significant difference was found in the number of CTC detected after surgery. A significant correlation between the number of CTC in post-surgical samples and clinical parameters was found for tumor diameter alone.Conclusions:Our findings provide the first evidence for adrenocortical tumors that CTC may represent a useful marker to support differential diagnosis between ACC and ACA. The correlation with some clinical parameters suggests a possible relevance of CTC analysis for prognosis and non-invasive monitoring of disease progression and drug response. 23607659 Exposure to anthrax toxin alters human leucocyte expression of anthrax toxin receptor 1. Anthrax is a toxin-mediated disease, the lethal effects of which are initiated by the binding of protective antigen (PA) with one of three reported cell surface toxin receptors (ANTXR). Receptor binding has been shown to influence host susceptibility to the toxins. Despite this crucial role for ANTXR in the outcome of disease, and the reported immunomodulatory consequence of the anthrax toxins during infection, little is known about ANTXR expression on human leucocytes. We characterized the expression levels of ANTXR1 (TEM8) on human leucocytes using flow cytometry. In order to assess the effect of prior toxin exposure on ANTXR1 expression levels, leucocytes from individuals with no known exposure, those exposed to toxin through vaccination and convalescent individuals were analysed. Donors could be defined as either 'low' or 'high' expressers based on the percentage of ANTXR1-positive monocytes detected. Previous exposure to toxins appears to modulate ANTXR1 expression, exposure through active infection being associated with lower receptor expression. A significant correlation between low receptor expression and high anthrax toxin-specific interferon (IFN)-γ responses was observed in previously infected individuals. We propose that there is an attenuation of ANTXR1 expression post-infection which may be a protective mechanism that has evolved to prevent reinfection. 23896173 A Gene Expression Signature of Epithelial Tubulogenesis and a Role for ASPM in Pancreatic Tumor Progression. & Aims: Many patients with pancreatic ductal adenocarcinoma (PDAC) develop recurrent or metastatic diseases following surgery, so it is important to identify those most likely to benefit from aggressive therapy. Disruption of tissue microarchitecture is an early step in pancreatic tumorigenesis and a parameter used in pathology grading of glandular tumors. We investigated whether changes in gene expression during pancreatic epithelial morphogenesis were associated with outcomes of patients with PDAC after surgery. We generated architectures of human pancreatic duct epithelial (HPDE) cells in a 3-dimensional basement membrane matrix. We identified gene expression profiles of the cells during different stages of tubular morphogenesis (tubulogenesis) and of PANC-1 cells during spheroid formation. Differential expression of genes was confirmed by immunoblot analysis. We compared the gene expression profile associated with pancreatic epithelial tubulogenesis with that of PDAC samples from 27 patients, as well as with their outcomes after surgery. We identified a gene expression profile associated with tubulogenesis that resembled the profile of human pancreatic tissue with differentiated morphology and exocrine function. Patients with PDACs with this profile fared well following surgery. Based on this profile, we established a 6-28 gene tubulogenesis-specific signature that accurately determined the prognosis of independent cohorts of patients with PDAC (total n = 128; accuracy = 81.2%-95.0%). One gene ASPM, was downregulated during tubulogenesis, but upregulated in human PDAC cell lines and tumor samples; upregulation correlated with patient outcome (Cox regression P = .0028). Bioinformatic, genetic, biochemical, functional, and clinical correlative studies showed that ASPM promotes aggressiveness of PDAC by maintaining Wnt-β-catenin signaling and stem cell features of PDAC cells. We identified a gene expression profile associated with pancreatic epithelial tubulogenesis and a tissue architecture-specific signature of PDAC cells that is associated with patient outcome following surgery. 23589195 Investigating the role of the corpus callosum in regulating motor overflow in multiple sclerosis. The corpus callosum (CC) is commonly affected in multiple sclerosis (MS), however, sensitive behavioral measures of MS-related CC pathology are lacking. The CC is considered a key structure in the mediation of a type of involuntary movement known as motor overflow. In this study, we sought to characterize the impact of CC damage on motor overflow in MS. Twenty MS participants and 20 controls performed a unilateral force production task. Motor overflow (involuntary force) in the non-active hand was measured while the active hand performed the task. CC volume and lesion load were calculated for MS participants using T2-weighted MRI. We found no group differences in motor overflow; however, motor overflow correlated significantly with MS disease severity [Expanded disability status scale (EDSS)]. CC damage (lesions and decreased volume) did not correlate with motor overflow. This study suggests that CC damage may not directly lead to changes in the regulation of motor overflow. Rather, findings support the notion that a wider network of structures may mediate the production and suppression of motor overflow. 23965842 Functional responses and molecular mechanisms involved in histone-mediated platelet activation. Histones are highly alkaline proteins found in cell nuclei and they can be released by either dying or inflammatory cells. The recent observations that histones are major components of neutrophil extracellular traps and promote platelet aggregation and platelet-dependent thrombin generation have shown that these proteins are potent prothrombotic molecules. Because the mechanism(s) of platelet activation by histones are not completely understood, we explored the ability of individual recombinant human histones H1, H2A, H2B, H3 and H4 to induce platelet activation as well as the possible molecular mechanisms involved. All histones were substrates for platelet adhesion and spreading and triggered fibrinogen binding, aggregation, von Willebrand factor release, P-selectin and phosphatidylserine (PS) exposure and the formation of platelet-leukocyte aggregates; however, H4 was the most potent. Histone-mediated fibrinogen binding, P-selectin and PS exposure and the formation of mixed aggregates were potentiated by thrombin. Histones induced the activation of ERK, Akt, p38 and NFκB. Accordingly, histone-induced platelet activation was significantly impaired by pretreatment of platelets with inhibitors of ERK (U 0126), PI3K/Akt (Ly 294002), p38 (SB 203580) and NFκB (BAY 11-7082 and Ro 106-9920). Preincubation of platelets with either aspirin or dexamethasone markedly decreased fibrinogen binding and the adhesion mediated by histones without affecting P-selectin exposure. Functional platelet responses induced by H3 and H4, but not H1, H2A and H2B, were partially mediated through interaction with Toll-like receptors -2 and -4. Our data identify histones as important triggers of haemostatic and proinflammatory platelet responses, and only haemostatic responses are partially inhibited by anti-inflammatory drugs. 23781925 Sarcopenia is an independent prognostic factor in elderly patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Approximately 25-35% of patients with diffuse large B-cell lymphoma (DLBCL) are older than 70 years. The aim of this study was to investigate the prognostic impact of depletion of skeletal muscle (sarcopenia) in elderly patients with DLBCL. This retrospective analysis included 82 patients with DLBCL older than 70 years and treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, Oncovin, prednisone) or R-miniCHOP. Sarcopenia was measured by the analysis of stored computed tomography (CT) images at the L3 level at baseline. The surface of the muscular tissues was selected according to the CT Hounsfield unit. This value was normalized for stature in order to calculate the lumbar L3 skeletal muscle index (LSMI, in cm(2)/m(2)). The mean age of the population was 78 years. According to the defined cut-offs for LSMI, 45 patients with DLBCL were considered sarcopenic. Sarcopenic patients displayed a higher revised International Prognostic Index (R-IPI) compared with patients without sarcopenia, and were older, with a mean age of 80 years and 77 years, respectively (p = 0.006). With a median follow-up of 39 months, the 2-year overall survival in the sarcopenic population was 46% compared with 84% in the non-sarcopenic group (HR = 3.22; 95% CI = 1.73-5.98; p = 0.0002). In a multivariate analysis, sarcopenia remained predictive of outcome (p = 0.005). Sarcopenia is a relevant and predictive factor in elderly patients with DLBCL treated with rituximab plus chemotherapy. 23849094 Comparative study of clinical courses, gross lesions, acute phase response and coagulation disorders in sheep inoculated with bluetongue virus serotype 1 and 8. Bluetongue virus serotypes 1 (BTV-1) and 8 (BTV-8) have been described as the most prevalent in Europe during recent outbreaks displaying intense virulence, sheep being among the most severely affected livestock species. However, BTV pathogenesis is still unclear. This study sought to elucidate differences in the pathogenetic mechanisms of BTV-1 and -8 in sheep. For this purpose, a time-course study was carried out, with sequential sacrifices in order to relate pathological lesions to changes in a range of virological and serological parameters. A greater virulence of BTV-1 was probed. BTV-1 infected sheep showed a longer clinical course, with a significant increase of clinical signs and more severe gross lesions than BTV-8 infected sheep. These differences appear not to be attributable to greater virus replication, suggesting viral loads did not influence in the pathogenicity of these serotypes. While both groups displayed an early, intense antibody response, they still developed clinical signs and lesions characteristic of bluetongue, indicating a lack of correlation between antibody levels and protection against the disease. Both acute phase response (APR) and thrombocytopenia induced by BTV-1 in sheep were more intense. Furthermore, an association between acute phase proteins (APPs) concentrations and the evolution of clinical signs and gross lesions was also observed, suggesting the existence of a direct link between the pathogenicity of BTV serotypes, the severity of vascular lesions and the serum concentrations of APPs. To our knowledge, this is the first verification of a measurable APR in sheep with both experimental and naturally occurring bluetongue. 23835851 A new set of differentially expressed signaling genes is early expressed in coffee leaf rust race II incompatible interaction. New races of coffee rust are overcoming resistance genes available in germplasm and cultivated cultivars and bringing recently some coffee-producing countries in severe economic challenge. The objective of this study was to identify the genes that are linked to host resistance to the major coffee rust race II. In our study, we have identified and studied a segregating population that has a single monogenic resistant gene to coffee rust. Coffee leaves of parents, resistant, and susceptible genotypes of the F2 generation plants were inoculated with pathogen spores. A differential analysis was performed by combined cDNA-AFLP and bulk segregant analysis (BSA) in pooled samples collected 48 and 72 h postinoculation, increasing the selectiveness for differential gene expression. Of 108 differential expressed genes, between 33,000 gene fragments analyzed, 108 differential expressed genes were identified in resistant plants. About 20 and 22 % of these resistant-correlated genes are related to signaling and defense genes, respectively. Between signaling genes, the major subclass corresponds to receptor and resistant homolog genes, like nucleotide-binding site leucine-rich repeat (NBS-LRR), Pto-like, RLKs, Bger, and RGH1A, all not previously described in coffee rust responses. The second major subclass included kinases, where two mitogen-activated kinases (MAPK) are identified. Further gene expression analysis was performed for 21 selected genes by real-time PCR gene expression analysis at 0, 12, 24, 48, and 72 h postinoculation. The expression of genes involved in signaling and defense was higher at 24 and 72 h after inoculation, respectively. The NBS-LRR was the more differentially expressed gene between the signaling genes (four times more expressed in the resistant genotype), and thraumatin (PR5) was the more expressed between all genes (six times more expressed). Multivariate analysis reinforces the significance of the temporal separation of identified signaling and defense genes: early expression of signaling genes support the hypothesis that higher expression of the signaling components up regulates the defense genes identified. Additionally the increased gene expression of these two gene sets is associated with a single monogenic resistance trait to to leaf coffee rust in the interaction characterized here. 23122125 Dietary Monascus adlay supplements facilitate suppression of cigarette smoke-induced pulmonary endoplasmic reticulum stress, autophagy, apoptosis and emphysema-related PLGF in the rat. Cigarette smoke (CS) exposure may cause oxidative stress in the lung, leading to cell death and long-term injury. Monascus adlay (MA) with antioxidant components produced by inoculating adlay (Cois lachrymal-jobi L. var. ma-yuen Stapf) with Monascus purpureus may protect lung against CS-induced lung injuries in rats. MA and lovastatin had higher antioxidant activities than either M. purpureus or adlay. CS exposure caused significant lung damage, as evidenced by higher levels of reactive oxygen species (ROS), neutrophil infiltration, dityrosine and 4-HNE, as well as lower levels of Mn-superoxide dismutase and catalase expression. Lung tissues with CS exposure had higher levels of ER stress, apoptosis, autophagy and emphysema-related placenta growth factor (PlGF) expressions. All CS-induced injuries were significantly suppressed by MA supplements. MA would be a beneficial nutritional therapy to ameliorate CS-induced lung injury via preserving antioxidant defense mechanisms, decreasing oxidative stress and inhibiting ER stress, autophagy, apoptosis and emphysema-related risk factor. 23934264 A great option for elderly patients with locally invasive bladder cancer, BOAI-CDDP-radiation (OMC regimen). We have developed a novel bladder preservation therapy, balloon-occluded arterial infusion (BOAI) of cisplatin/gemcitabine, concomitantly with hemodialysis, along with concurrent irradiation [the so-called 'OMC (Osaka Medical College) regimen']. The OMC regimen delivers an extremely high concentration of anticancer agent to the site of a tumor without systemic adverse effects, since more than 95% of free Pt was efficiently eliminated by hemodialysis, which enables short hospital stay. In this study, we investigated the efficiency of OMC regimen in patients aged over 70 years with muscle‑invasive bladder cancer without metastasis. A total of 134 such patients were assigned to receive either the OMC regimen (n=89) or cystectomy (n=45). OMC regimen patients who failed to achieve CR underwent cystectomy, or secondary BOAI with gemcitabine (1,600 mg). The OMC regimen, which delivers an extremely high concentration of anticancer agent to the tumor site without systemic adverse effects, yielded CR in >91% (81/89) of patients. More than 96% (78/81) of the CR patients survived without recurrence with intact bladder after a mean follow-up of 164 (range 16-818) weeks. The 5- and 10-year bladder intact survival rates were 87.2 and 69.8%, and overall survival rates were 88.4 and 70.7% (vs. 59.9 and 33.3% for cystectomy, p=0.0002), respectively, although the median age in the OMC regimen group was significantly greater than in the cystectomy group (median, range = 77, 70-98 vs. 74, 70-89; p=0.0003). No patients suffered grade II or more severe toxicities; the oldest patient, aged 91 years, successfully completed this therapy. In conclusion, the OMC regimen is a useful bladder preservation strategy for elderly patients with locally invasive bladder cancer, not only in those for whom cystectomy is indicated, but also in patients whose condition is not amenable to curative treatment and for whom palliation would otherwise seem the only option. 23892008 Focal malformations of cortical development: New vistas for molecular pathogenesis. Focal malformations of cortical development (FMCD) are highly associated with several neurological disorders including intractable epilepsy and neurocognitive disabilities. Over the past decade, several FMCD subtypes have been linked to hyperactivation of the mammalian target of rapamycin (mTOR) signaling cascade. In view of the roles that mTOR plays in cell proliferation, size, motility, and stem cell phenotype, many of the features of FMCD such as cytomegaly, disorganized lamination, and expression of stem cell markers can be explained by enhanced mTOR signaling. FMCD result from several distinct and fascinating molecular mechanisms including biallelic gene inactivation, somatic mutation, and potentially, viral infection. These mechanisms have been directly linked to mTOR activation. Perhaps most compelling, pharmacological inhibition of mTOR has been implemented successfully in clinical trials for select FMCD and provides a new vista for treatment. 23945600 Separacenes A-D, Novel Polyene Polyols from the Marine Actinomycete, Streptomyces sp. Separacenes A-D (1-4), novel polyene polyols, were isolated from Streptomyces sp. collected from the southern area of Jeju Island, Korea. The chemical structures of 1-4 were established by NMR, mass, UV, and IR spectroscopy as well as the modified Mosher's method. Separacenes A-B (1-2), which share an identical planar structure but possess different relative configurations, bear tetraene units flanked by two diol moieties, whereas the stereoisomeric separacenes C-D (3-4) possess a triene moiety between two diol substructures. Separacenes A-D each contain a terminal olefinic methylene. Separacene A displayed inhibitory activity against Candida albicans isocitrate lyase and weak cytotoxicity against both the colon carcinoma cell line HCT-116 and the lung cancer cell line A549. 23951300 Dynamic Contrast-Enhanced MR Imaging Predicts Local Control in Oropharyngeal or Hypopharyngeal Squamous Cell Carcinoma Treated with Chemoradiotherapy. The role of pretreatment dynamic contrast-enhanced perfusion MR imaging (DCE-PWI) and diffusion-weighted MR imaging (DWI) in predicting the treatment response of oropharyngeal or hypopharyngeal squamous cell carcinoma (OHSCC) to chemoradiation remains unclear. We prospectively investigated the ability of pharmacokinetic parameters derived from pretreatment DCE-PWI and DWI to predict the local control of OHSCC patients treated with chemoradiation. Between August, 2010 and March, 2012, patients with untreated OHSCC scheduled for chemoradiation were eligible for this prospective study. DCE-PWI and DWI were performed in addition to conventional MRI. The relationship of local control with the following clinical and imaging variables was analyzed: the hemoglobin level, T-stage, tumor location, gross tumor volume, maximum standardized uptake value, metabolic tumor volume and total lesion glycolysis on FDG PET/CT, transfer constant (K (trans) ), volume of blood plasma and volume of extracellular extravascular space on DCE-PWI, and apparent diffusion coefficient on DWI of the primary tumor. The patients were also divided into a local control group and a local failure group, and their clinical and imaging parameters were compared. There were 58 patients (29 with oropharynx squamous cell carcinoma [SCC] and 29 with hypopharynx SCC) with successful pretreatment DCE-PWI and DWI available for analysis. After a median follow-up of 18.2 months, 17 (29.3%) participants had local failure, whereas the remaining 41 patients achieved local control. Univariate analysis revealed that only the K (trans) value was significantly associated with local control (P = 0.03). When the local control and local failure groups were compared, significant differences were observed in K (trans) and the tumor location (P = 0.01 and P = 0.04, respectively). In the multivariable analysis, only K (trans) was statistically significant (P = 0.04). Our results suggest that pretreatment K (trans) may help predict the local control in OHSCC patients treated with chemoradiation. 23595923 An evaluation of internal medicine residency continuity clinic redesign to a 50/50 outpatient-inpatient model. There have been recent calls for improved internal medicine outpatient training, yet assessment of clinical and educational variables within existing models is lacking. To assess the impact of clinic redesign from a traditional weekly clinic model to a 50/50 outpatient-inpatient model on clinical and educational outcomes. Pre-intervention and post-intervention study intervals, comparing the 2009-2010 and 2010-2011 academic years. Ninety-six residents in a Primary Care Internal Medicine site of a large academic internal medicine residency program who provide care for > 13,000 patients. Continuity clinic redesign from a traditional weekly clinic model to a 50/50 model characterized by 50 % outpatient and 50 % inpatient experiences scheduled in alternating 1 month blocks, with twice weekly continuity clinic during outpatient months and no clinic during inpatient months. 1) Clinical outcomes (panel size, patient visits, adherence with chronic disease and preventive service guidelines, continuity of care, patient satisfaction, and perceived safety/teamwork in clinic); 2) Educational outcomes (attendance at teaching conference, resident and faculty satisfaction, faculty assessment of resident clinic performance, and residents' perceived preparedness for outpatient management). Redesign was associated with increased mean panel size (120 vs. 137.6; p ≤ 0.001), decreased continuity of care (63 % vs. 48 % from provider perspective; 61 % vs. 51 % from patient perspective; p ≤  0.001 for both; team continuity was preserved), decreased missed appointments (12.5 % vs. 10.9 %; p ≤  0.01), improved perceived safety and teamwork (3.6 vs. 4.1 on 5-point scale; p ≤  0.001), improved mean teaching conference attendance (57.1 vs. 64.4; p ≤  0.001), improved resident clinic performance (3.6 vs. 3.9 on 5-point scale; p ≤  0.001), and little change in other outcomes. Although this model requires further study in other settings, these results suggest that a 50/50 model may allow residents to manage more patients while enhancing the climate of teamwork and safety in the continuity clinic, compared to traditional models. Future work should explore ways to preserve continuity of care within this model. 23475530 Combined non-invasive functional and anatomical diagnostic work-up in clinical practice: the magnetic resonance and computed tomography in suspected coronary artery disease (MARCC) study. The combined use of cardiac computed tomography (CT) coronary angiography (CTCA) and myocardial perfusion imaging allows the non-invasive evaluation of coronary morphology and function. Cardiovascular magnetic resonance (CMR) imaging has several advantages: it can simultaneously assess myocardial perfusion, ventricular and valvular function, cardiomyopathy, and aortic disease and does not involve any additional ionizing radiation. We investigated the combined use of cardiac CT and CMR for the diagnostic evaluation of patients with suspected coronary artery disease (CAD) in clinical practice. A total of 192 patients with low or intermediate pre-test probability of CAD underwent CTCA and CMR. All patients with obstructive CAD on CTCA and/or myocardial ischaemia on CMR were referred for invasive coronary angiography (ICA). Fractional flow reserve was measured in case of intermediate lesions (30-70% diameter stenosis) on ICA. Additional cardiac and extra-cardiac findings by CTCA and CMR were registered. The combination of CTCA and CMR significantly improved specificity and overall accuracy (94 and 91%) for the detection of significant CAD compared with their use as a single technique (CTCA 39 and 57%, P < 0.0001; CMR 82 and 83%, P = 0.016). No events were recorded during follow-up (18 ± 6 months) in 104 patients who did not undergo ICA. Furthermore, the combined strategy provided an alternative diagnosis in 19 patients. The combined use of CTCA and CMR significantly improved specificity and overall diagnostic accuracy for the detection of significant CAD and allowed the detection of alternative (extra-)cardiac disease in patients without significant CAD. 23734976 Outbreak of acute respiratory disease caused by human adenovirus type 7 in a military training camp in Shaanxi, China. Outbreaks of ARD associated with HAdV have been reported in military populations in many countries. Here, we report an ARD outbreak caused by HAdV-7 in a military training camp in Shaanxi Province, China, from February to March of 2012. Epidemic data and samples from the patients were collected, and viral nucleotides from samples and viral isolations were detected and sequenced. IgG and IgA antibodies against HAdV, and the neutralization antibodies against the viral strain isolated in this outbreak, were detected. Epidemiological study showed that all personnel affected were males with an average age of 19.1 years. Two peaks appeared on the epicurve and there was an 8-day interval between peaks. Laboratory results of viral nucleotide detection carried out with clinical specimens were positive for HAdV (83.33%, 15/18). Further study through serum antibody assay, virus isolation and phylogenetic analysis showed that HAdV-7 was the etiological agent responsible for the outbreak. IgA antibody began to appear on the 4th day after the onset and showed 100% positivity on the 8th day. The virus strain in the present outbreak was highly similar to the virus isolated in Hanzhong Shaanxi in 2009. We conclude that HAdV-7 was the pathogen corresponding to the outbreak, and this is the first report of an ARD outbreak caused by HAdV-7 in military persons in China. Vaccine development, as well as enhanced epidemiological and virological surveillance of HAdV infections in China should be emphasized. 23822584 A Single Channel Mutation Alters Agonist Efficacy at 5-HT3 A and 5-HT3 AB Receptors. 5-HT3 receptors are composed of 5-HT3 A subunits (homomeric receptors), or combinations of 5-HT3 A and other 5-HT3 receptor subunits (heteromeric receptors, the best studied of which are 5-HT3 AB receptors). Here we explore the effects of partial agonists at 5-HT3 A and 5-HT3 AB receptors, and the importance of a channel-lining residue in determining the efficacy of activation. Wild type and mutant 5-HT3 A and 5-HT3 AB receptors were expressed in Xenopus oocytes and examined using two-electrode voltage-clamp, or expressed in HEK293 cells and examined using [(3) H]granisetron binding. Dopamine, quipazine and VUF10166 were partial agonists at wild type 5-HT3 A and 5-HT3 AB receptors, with quipazine and VUF10166 causing a long-lived (>20 min) inhibition of subsequent agonist responses. At 5-HT3 A receptors, mCPBG was a partial agonist, but was a super-agonist at 5-HT3 AB receptors, a sit produced a response 2.6x greater that that of 5-HT. A T6'S substitution in the 5-HT3A subunit decreased EC50 and increased Rmax of dopamine and quipazine at both homomeric and heteromeric receptors. The greatest changes were seen with VUF10166 at 5-HT3 AT6'S B receptors, where it became a full agonist (EC50 = 7 nM) with an EC50 58-fold less than 5-HT (EC50 = 0.4 μM) and no longer caused inhibition of subsequent agonist responses. These results indicate that a mutation in the pore lining domain in both 5-HT3 A and 5-HT3 AB receptors changes the relative efficacy of a series of agonists, changing some (e.g. quipazine) from effectively antagonists to potent and efficacious agonists. 23876140 Sorption of ferrous and ferric iron by extracellular polymeric substances (eps) from acidophilic bacteria. The sorption of Fe(II) and Fe(III) by extracellular polymeric substances (EPS) of acidophilic bacteria Acidiphilium 3.2Sup(5) and Acidithiobacillus ferrooxidans, harvested from the ecosystem of the Tinto River (Huelva, Spain), was investigated. EPS from mixed cultures of both bacteria (EPSmixed) and pure cultures of A. 3.2Sup(5) (EPSpure) were extracted with ethylenediamine tetraacetic acid (EDTA) and were characterized by Fourier-transform infrared (FTIR), electron photoemission (XPS), x-ray diffraction (DRX), and energy dispersive x-ray (EDX) spectroscopy and scanning electron microscopy (SEM). EPS pure were loaded, in sorption tests, with Fe(II) and Fe(III). The results obtained indicate that the biochemical composition and structure of EPSmixed was very similar to that of EPSpure. Besides, results indicate that EPSmixed adsorbed Fe(II) and Fe(III) by preferential interaction with the carboxyl group, which favored the formation of Fe(II)/Fe(III) oxalates. These species were also formed in EPSpure loaded with Fe(II)/Fe(III). All this behavior suggested that the sorption of iron by EPSmixed was similar to sorption of EPSpure, which fitted the Freundlich model. Thus, the iron uptake of EPSmixed reached 516.7 ± 23.4 mg Fe/g-EPS at an initial concentration of 2.0 g/L of Fetotal and Fe(II)/Fe(III) ratio of 1.0. 23948501 Enzymatic conversion of d-galactose to d-tagatose: Cloning, overexpression and characterization of l-arabinose isomerase from Pediococcus pentosaceus PC-5. The gene encoding l-arabinose isomerase from food-grade strain Pediococcus pentosaceus PC-5 was cloned and overexpressed in Escherichia coli. The recombinant protein was purified and characterized. It was optimally active at 50°C and pH 6.0. Furthermore, this enzyme exhibited a weak requirement for metallic ions for its maximal activity evaluated at 0.6mM Mn(2+) or 0.8mM Co(2+). Interestingly, this enzyme was distinguished from other l-AIs, it could not use l-arabinose as its substrate. In addition, a three-dimensional structure of l-AI was built by homology modeling and l-arabinose and d-galactose were docked into the active site pocket of PPAI model to explain the interaction between l-AI and its substrate. The purified P. pentosaceus PC-5 l-AI converted d-galactose into d-tagatose with a high conversion rate of 52% after 24h at 50°C, suggesting its excellent potential in d-tagatose production. 23820108 A 26-Gene Hypoxia Signature Predicts Benefit from Hypoxia-Modifying Therapy in Laryngeal Cancer but Not Bladder Cancer. Tumor hypoxia is associated with a poor prognosis, hypoxia modification improves outcome, and hypoxic status predicts benefit from treatment. Yet, there is no universal measure of clinical hypoxia. The aim of this study was to investigate whether a 26-gene hypoxia signature predicted benefit from hypoxia-modifying treatment in both cancer types.EXPERIMENTAL DESIGN: Samples were available from 157 T2-T4 laryngeal cancer and 185 T1-T4a bladder cancer patients enrolled on the accelerated radiotherapy with carbogen and nicotinamide (ARCON) and bladder carbogen nicotinamide (BCON) phase III randomized trials of radiotherapy alone or with carbogen and nicotinamide (CON) respectively. Customized TaqMan low density arrays (TLDA) were used to assess expression of the 26-gene signature using quantitative real-time PCR. The median expression of the 26 genes was used to derive a hypoxia score (HS). Patients were categorized as TLDA-HS low (≤median) or TLDA-HS high (>median). The primary outcome measures were regional control (RC; ARCON) and overall survival (BCON).RESULTS: Laryngeal tumors categorized as TLDA-HS high showed greater benefit from ARCON than TLDA-HS low tumors. Five-year RC was 81% (radiotherapy alone) versus 100% (CON) for TLDA-HS high (P = 0.009). For TLDA-HS low, 5-year RC was 91% (radiotherapy alone) versus 90% (CON; P = 0.90). TLDA-HS did not predict benefit from CON in bladder cancer.CONCLUSION: The 26-gene hypoxia signature predicts benefit from hypoxia-modifying treatment in laryngeal cancer. These findings will be evaluated in a prospective clinical trial. Clin Cancer Res; 1-10. ©2013 AACR. 23050672 Differential expression of the P2X7 receptor in ovarian surface epithelium during the oestrous cycle in the mouse. Purinergic signalling has been proposed as an intraovarian regulatory mechanism. Of the receptors responsible for purinergic transmission, the P2X7 receptor is an ATP-gated cationic channel that displays a broad spectrum of cellular functions ranging from apoptosis to cell proliferation and tumourigenesis. In the present study, we investigated the functional expression of P2X7 receptors in ovarian surface epithelium (OSE). P2X7 protein was detected in the OSE layer of the mouse, both in situ and in primary cultures. In cultures, 2'(3')-O-(4-Benzoylbenzoyl)adenosine-5'-triphosphate (BzATP) activation of P2X7 receptors increased [Ca(2+)]i and induced apoptosis. The functionality of the P2X7 receptor was investigated in situ by intrabursal injection of BzATP on each day of the oestrous cycle and evaluation of apoptosis 24h using the terminal deoxyribonucleotidyl transferase-mediated dUTP-fluorescein nick end-labelling (TUNEL) assay. Maximum effects of BzATP were observed during pro-oestrus, with the effects being blocked by A438079, a specific P2X7 receptor antagonist. Immunofluorescence staining for P2X7 protein revealed more robust expression during pro-oestrus and in OSE regions behind the antral follicles, strongly supporting the notion that the differences in apoptosis can be explained by increased receptor expression, which is regulated during the oestrous cycle. Finally, P2X7 receptor expression was detected in the OSE layer of human ovaries, with receptor expression maintained in human ovaries diagnosed with cancer, as well as in the human ovarian carcinoma SKOV3 cell line. 23702390 Prognostic factors in 105 Japanese cases of mycosis fungoides and Sézary syndrome: Clusterin expression as a novel prognostic factor. The analysis of prognostic factors in Japanese cases of cutaneous T-cell lymphoma (CTCL) is scarce. Clusterin is a ubiquitous 80kDa heterodimeric glycoprotein expressed on tumor cells of systemic and primary cutaneous anaplastic large cell lymphoma. The expression of clusterin in mycosis fungoides (MF) and Sézary syndrome (SS) has only been sporadically reported in a small number of cases. To determine the long-term prognosis of Japanese patients with MF and SS, to identify clinical and pathological factors predictive of survival, and to evaluate the prognostic significance of the International Society for Cutaneous Lymphomas (ISCL) revised staging system (2007). We performed a retrospective cohort study of 105 Japanese patients with MF and SS managed at the Department of Dermatology Asahikawa Medical University from 1976 to 2011. Formalin-fixed, paraffin-embedded sections of MF and SS were immunostained for clusterin, CD30, and Ki-67. No statistically significant difference in survival was found between stages IA-IIA and IIIA patients. The significant prognostic factors in the univariate analysis were higher age, TNMB classification, clinical staging, performance status, increased serum LDH level, dermal Ki-67-positive cells, and clusterin expression. In the multivariate analysis, T classification, extracutaneous disease, increased serum LDH level, clusterin expression, and performance status were the significant independent prognostic factors. Japanese stage IIIA MF/SS patients contain a subpopulation with a favorable prognosis. The most significant prognostic factor for survival of MF and SS was the presence of extracutaneous disease. Clusterin expression was shown to be a novel unfavorable prognostic factor. 23223401 Effectiveness and response predictive factors of erlotinib in a non-small cell lung cancer unselected European population previously treated: A retrospective, observational, multicentric study. Aims and background: Erlotinib approval was supported by the positive results of a large multicentric phase III trial (BR.21 study) that included 10% Asiatic patients and the remaining were North-American Caucasian. It is well-known that the efficacy of tyrosine kinase inhibitors is strongly influenced by ethnicity and other genetic factors. It is, therefore, relevant to establish whether the same profile of efficacy is seen in an unselected population and whether the results of BR.21 can be generalized to other patient populations, such as that described here. In this retrospective, observational, multicentric study, we assessed effectiveness and potentially response predictive factors in 222 unselected Italian patients, with stage IIIB/IV non-small-cell lung cancer, with performance status from 0 to 3, who had received at least one line of chemotherapy, treated with the standard dose of erlotinib (150 mg once daily) until disease progression or unacceptable toxicity. The disease control rate was 60.9% (135 patients). Median progression-free survival and overall survival times were 3.1 months and 7.97 months, respectively. The characteristics of non-smoker, female gender, performance status 0 or 1 were associated with a significantly better prognosis in terms of disease control rate and were also predictive of longer overall survival and progression-free survival. The 1-year survival rate was 38.79%. Even though Italian patients baseline characteristics were strongly different to those reported in pivotal BR.21 trial in terms of age, performance status, line treatment and ethnic group, our study confirms the favorable effectiveness profile in real clinical practice of erlotinib according to results from the pivotal study BR.21. Today, we know that epidermal growth factor receptor (EGFR) status assessment is mandatory before starting first-line therapy and that the presence of only certain clinical characteristics initially associated with sensitivity to EGFR-tyrosine kinase inhibitors, as reported in this study, is not sufficient in selecting patients candidates to such treatments. 23808462 Accuracy and false-positive rate of the cytologic diagnosis of follicular cervicitis: observations from the College of American Pathologists Pap Educational Program. Follicular cervicitis is usually easily identifiable on Papanicolaou (Pap) tests; however, historically, follicular cervicitis is reported to lead to false-positive diagnoses of epithelial cell abnormalities. To assess participant responses in the College of American Pathologists (CAP) Pap educational program (CAP-PAP) to determine the accuracy and false-positive rate of follicular cervicitis cases. Design.-We performed a retrospective review of 4914 participant responses for gynecologic cytology challenges with the reference diagnosis of follicular cervicitis during 11 years (2000-2010) from CAP-PAP. Reference diagnosis category, false-positive rates by participant type (laboratory, cytotechnologist, pathologist), and preparation type (conventional smears, ThinPrep) were analyzed. Of the total 4914 general category responses, 4368 (88.9%) were benign while 546 (11.1%) responses were epithelial cell abnormalities (false positives). Of benign responses, only 2026 (46.4%) were an exact match to follicular cervicitis. Adenocarcinoma and high-grade squamous intraepithelial lesion were the most common diagnoses chosen as a false-positive interpretation (42.3% and 20.1%, respectively). Participant type was significantly associated with false-positive interpretations (laboratory: 19.2%; cytotechnologist: 11.1%; pathologist: 7.9%; P < .001). ThinPrep was also significantly associated with false-positive results as compared to conventional smears (12.2% versus 3.6%; P < .001). In an interlaboratory comparison educational program, follicular cervicitis is difficult to interpret accurately and represents an important cause of false-positive responses. Follicular cervicitis may mimic adenocarcinoma or high-grade squamous intraepithelial lesion, particularly in liquid-based preparations. The diagnostic difficulty most likely arises from the lymphocytes being less conspicuous in the background as well as their tendency to aggregate in ThinPrep as compared to conventional smears. 23921993 The effect of FTO variation on increased osteoarthritis risk is mediated through body mass index: a mendelian randomisation study. Variation in the fat mass and obesity-associated (FTO) gene influences susceptibility to obesity. A variant in the FTO gene has been implicated in genetic risk to osteoarthritis (OA). We examined the role of the FTO polymorphism rs8044769 in risk of knee and hip OA in cases and controls incorporating body mass index (BMI) information. 5409 knee OA patients, 4355 hip OA patients and up to 5362 healthy controls from 7 independent cohorts from the UK and Australia were genotyped for rs8044769. The association of the FTO variant with OA was investigated in case/control analyses with and without BMI adjustment and in analyses matched for BMI category. A mendelian randomisation approach was employed using the FTO variant as the instrumental variable to evaluate the role of overweight on OA. In the meta-analysis of all overweight (BMI≥25) samples versus normal-weight controls irrespective of OA status the association of rs8044769 with overweight is highly significant (OR[CIs] for allele G=1.14 [01.08 to 1.19], p=7.5×10(-7)). A significant association with knee OA is present in the analysis without BMI adjustment (OR[CIs]=1.08[1.02 to 1.14], p=0.009) but the signal fully attenuates after BMI adjustment (OR[CIs]=0.99[0.93 to 1.05], p=0.666). We observe no evidence for association in the BMI-matched meta-analyses. Using mendelian randomisation approaches we confirm the causal role of overweight on OA. Our data highlight the contribution of genetic risk to overweight in defining risk to OA but the association is exclusively mediated by the effect on BMI. This is consistent with what is known of the biology of the FTO gene and supports the causative role of high BMI in OA. 23090712 Lanthanum (III) regulates the nitrogen assimilation in soybean seedlings under ultraviolet-B radiation. Ultraviolet-B (UV-B, 280-320 nm) radiation has seriously affected the growth of plants. Finding the technology/method to alleviate the damage of UV-B radiation has become a frontal topic in the field of environmental science. The pretreatment with rare earth elements (REEs) is an effective method, but the regulation mechanism of REEs is unknown. Here, the regulation effects of lanthanum (La(III)) on nitrogen assimilation in soybean seedlings (Glycine max L.) under ultraviolet-B radiation were investigated to elucidate the regulation mechanism of REEs on plants under UV-B radiation. UV-B radiation led to the inhibition in the activities of the key enzymes (nitrate reductase, glutamine synthetase, glutamate synthase) in the nitrogen assimilation, the decrease in the contents of nitrate and soluble proteins, as well as the increase in the content of amino acid in soybean seedlings. The change degree of UV-B radiation at the high level (0.45 W m(-2)) was higher than that of UV-B radiation at the low level (0.15 W m(-2)). The pretreatment with 20 mg L(-1) La(III) could alleviate the effects of UV-B radiation on the activities of nitrate reductase, glutamine synthetase, glutamate synthase, and glutamate dehydrogenase, promoting amino acid conversion and protein synthesis in soybean seedlings. The regulation effect of La(III) under UV-B radiation at the low level was better than that of UV-B radiation at the high level. The results indicated that the pretreatment with 20 mg L(-1) La(III) could alleviate the inhibition of UV-B radiation on nitrogen assimilation in soybean seedlings. 23429976 Renal function in heart failure: a disparity between estimating function and predicting mortality risk. To compare the predictive value of estimated renal function calculated by the Chronic Kidney Disease Epidemiology Collaboration (eGFR(CKD-EPI)), four-variable Modification of Diet in Renal Disease (eGFR(MDRD-4)), and Cockcroft-Gault [estimated creatinine clearance (eCcr)] equation in terms of all-cause mortality in heart failure. Renal function is an important prognostic factor in heart failure. Established methods of estimating renal function are known to under-/overestimate true function in certain settings. A total of 800 systolic heart failure outpatients (mean age 57 ± 11.5 years, 82% male) were studied over a median follow-up of 121 (Q1-Q3: 110-130) months. The highest systematic difference was seen between eCcr and eGFR(MDRD-4) [+12.33 points (mean), 95% limits of agreement -22.35 to 47.01; generalized kappa = 0.36]. eGFR(MDRD-4) and eGFR(CKD-EPI) were the most similar [-4.16 points (mean), 95% limits of agreement -11.56 to 3.25; generalized kappa = 0.74]. Up to 35.4% of patients were reclassified into different estimated glomerular filtration rate (eGFR) categories when comparing eGFR(CKD-EPI) with eCcr and eGFR(MDRD-4). eGFR(CKD-EPI) performed marginally better in terms of predicting all-cause mortality than eGFR(MDRD-4), as univariate areas under the time-dependent receiver operating characteristic curves (AUC), marginal and partial proportions of explained variation (PEV), net reclassification improvement (NRI), and the integrated discrimination improvement (IDI) for 5 years of follow-up were significantly higher for eGFR(CKD-EPI) than for eGFR(MDRD-4). In this cohort of heart failure patients, eGFR(CKD-EPI) was marginally better in predicting all-cause mortality than eGFR(MDRD-4). Estimated function differed widely between equations and is likely to have an effect on therapy choice. 23684898 Non-invasive brain stimulation and the autonomic nervous system. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are non-invasive methods of brain stimulation (NIBS) that can induce significant effects on cortical and subcortical neural networks. Both methods are relatively safe if appropriate guidelines are followed, and both can exert neuromodulatory effects that may be applied to the investigation of the autonomic nervous system (ANS). In addition, ANS measures can shed important light onto the neurobiologic mechanisms of NIBS. Here we present a systematic review on studies testing NIBS and ANS simultaneously. We structure our findings into four broad (not mutually exclusive) categories: (i) studies in which ANS function was modified by NIBS versus those in which it was not; (ii) studies in which NIBS was used to understand ANS function, (iii) studies in which ANS was used to understand NIBS mechanisms and (iv) NIBS/ANS studies conducted in healthy subjects versus those in patients with neuropsychiatric diseases. Forty-four articles were identified and no conclusive evidence of the effects of NIBS on ANS was observed, mainly because of the heterogeneity of included studies. Based on a comprehensive summary of this literature we propose how NIBS might be further developed to enhance our understanding of the cortical mechanisms of autonomic regulation and perhaps to modulate autonomic activity for therapeutic purposes. 23773833 New proposed conceptual mathematical models for biomass viability and membrane fouling of membrane bioreactor. The production and accumulation of soluble microbial products (SMP), extracellular polymeric substances (EPS) and colloidal inert compounds within a membrane bioreactor (MBR) may greatly affect the biomass viability and subsequently the permeability of the membrane. This paper aims at presenting new mathematical models of biomass viability and membrane fouling that has been conceptually developed through establishing links between these biomass parameters and operating parameters of the MBR. The proposed models can be used to predict the biomass viability and membrane fouling at any state of operation of MBR. Meanwhile, easily measurable parameters of the proposed model can also serve to estimate SMP/EPS concentration in the supernatant of MBR without the tedious and expensive measurement. 23964249 From resilience to vulnerability: mechanistic insights into the effects of stress on transitions in critical period plasticity. While early experiences are proposed to be important for the emergence of anxiety and other mental health problems, there is little empirical research examining the impact of such experiences on the development of emotional learning. Of the research that has been performed in this area, however, a complex picture has emerged in which the maturation of emotion circuits is influenced by the early experiences of the animal. For example, under typical laboratory rearing conditions infant rats rapidly forget learned fear associations (infantile amnesia) and express a form of extinction learning which is relapse-resistant (i.e., extinction in infant rats may be due to fear erasure). In contrast, adult rats exhibit very long-lasting memories of past learned fear associations, and express a form of extinction learning that is relapse-prone (i.e., the fear returns in a number of situations). However, when rats are reared under stressful conditions then they exhibit adult-like fear retention and extinction behaviors at an earlier stage of development (i.e., good retention of learned fear and relapse-prone extinction learning). In other words, under typical rearing conditions infant rats appear to be protected from exhibiting anxiety whereas after adverse rearing fear learning appears to make those infants more vulnerable to the later development of anxiety. While the effects of different experiences on infant rats' fear retention and extinction are becoming better documented, the mechanisms which mediate the early transition seen following stress remain unclear. Here we suggest that rearing stress may lead to an early maturation of the molecular and cellular signals shown to be involved in the closure of critical period plasticity in sensory modalities (e.g., maturation of GABAergic neurons, development of perineuronal nets), and speculate that these signals could be manipulated in adulthood to reopen infant forms of emotional learning (i.e., those that favor resilience). 23503780 Gas-phase structures and thermochemistry of neutral histidine and its conjugated acid and base. Extensive exploration of the conformational space of neutral, protonated and deprotonated histidine has been conducted at the G4MP2 level. Theoretical protonation and deprotonation thermochemistry as well as heats of formation of gaseous histidine and its ionized forms have been calculated at the G4 level considering either the most stable conformers or an equilibrium population of conformers at 298 K. These theoretical results were compared to evaluated experimental determinations. Recommended proton affinity and protonation entropy deduced from these comparisons are PA(His) = 980 kJ mol(-1) and ΔpS(His) ∼ 0 J mol(-1) K(-1), thus leading to a gas-phase basicity value of GB(His) = 947.5 kJ mol(-1). Similarly, gas phase acidity parameters are ΔacidH(o)(His) = 1373 kJ mol(-1), ΔacidS(His) ∼ 10 J mol(-1) K(-1) and ΔacidG(o)(His) = 1343 kJ mol(-1). Computed G4 heats of formation values are equal to -290, 265 and -451 kJ mol(-1) for gaseous neutral histidine and its protonated and deprotonated forms, respectively. The present computational data correct, and complete, previous thermochemical parameter estimates proposed for gas-phase histidine and its acido-basic properties. 23851147 Citrinin-induced fluidization of the plasma membrane of the fission yeast Schizosaccharomyces pombe. Citrinin (CTN) is a toxic fungal metabolite that is a hazardous contaminant of foods and feeds. In the present study, its acute toxicity and effects on the plasma membrane of Schizosaccharomyces pombe were investigated. The minimum inhibitory concentration of CTN against the yeast cells proved to be 500μM. Treatment with 0, 250, 500 or 1000μM CTN for 60min resulted in a 0%, 2%, 21% or 100% decrease, respectively, in the survival rate of the cell population. Treatment of cells with 0, 100, 500 or 1000μM CTN for 20min induced decrease in the phase-transition temperature of the 5-doxylstearic acid-labeled plasma membrane to 16.51, 16.04, 14.18 or 13.98°C, respectively as measured by electron paramagnetic resonance spectroscopy. This perturbation was accompanied by the efflux of essential K(+) from the cells. The existence of an interaction between CTN and glutathione was detected for the first time by spectrofluorometry. Our observations may suggest a direct interaction of CTN with the free sulfhydryl groups of the integral proteins of the plasma membrane, leading to dose-dependent membrane fluidization. The change in fluidity disturbed the ionic homeostasis, contributing to the death of the cells, which is a novel aspect of CTN cytotoxicity. 23884942 Survivin Is a Transcriptional Target of STAT3 Critical to Estradiol Neuroprotection in Global Ischemia. Transient global ischemia causes selective, delayed death of hippocampal CA1 pyramidal neurons in humans and animals. It is well established that estrogens ameliorate neuronal death in animal models of focal and global ischemia. However, the role of signal transducer and activator of transcription-3 (STAT3) and its target genes in estradiol neuroprotection in global ischemia remains unclear. Here we show that a single intracerebral injection of 17β-estradiol to ovariectomized female rats immediately after ischemia rescues CA1 neurons destined to die. Ischemia promotes activation of STAT3 signaling, association of STAT3 with the promoters of target genes, and STAT3-dependent mRNA and protein expression of prosurvival proteins in the selectively vulnerable CA1. In animals subjected to ischemia, acute postischemic estradiol further enhances activation and nuclear translocation of STAT3 and STAT3-dependent transcription of target genes. Importantly, we show that STAT3 is critical to estradiol neuroprotection, as evidenced by the ability of STAT3 inhibitor peptide and STAT3 shRNA delivered directly into the CA1 of living animals to abolish neuroprotection. In addition, we identify survivin, a member of the inhibitor-of-apoptosis family of proteins and known gene target of STAT3, as essential to estradiol neuroprotection, as evidenced by the ability of shRNA to survivin to reverse neuroprotection. These findings indicate that ischemia and estradiol act synergistically to promote activation of STAT3 and STAT3-dependent transcription of survivin in insulted CA1 neurons and identify STAT3 and survivin as potentially important therapeutic targets in an in vivo model of global ischemia. 23886437 Performance and utility of a rapid diagnostic test for cholera: notes from Haiti. The present study details work done at the National Public Health Laboratory in Haiti (LNSP), comparing the results of a cholera rapid diagnostic test (RDT) with culture-based methods. As of October 21, 2011, 644 specimens were tested by both RDT and culture-based method at the LNSP. The sensitivity and specificity of RDT were 95% and 80%, respectively, with a positive predictive value of 89% and negative predictive value of 91%. In resource-limited settings, the RDT has good utility and should be considered as part of the laboratory testing algorithm. 23547003 Transcriptome profiling of gill tissue in regionally bred and globally farmed rainbow trout strains reveals different strategies for coping with thermal stress. Thermal stress can pose a major challenge to salmonid fish. A 4x44K oligonucleotide microarray approach was used to screen for genetically determined variations of a temperature stress response during acclimation in fish gills, a highly specialized and complex organ responsible for gas and electrolyte exchange as well as excretion. The comparison addressed transcriptional changes in the local breeding strain BORN and imported (TCO) rainbow trout after graded 2-week acclimation to 8 and 23 °C. Besides well-characterized mediators of thermoregulation such as genes encoding cold-inducible RNA-binding protein and heat shock proteins, the present microarray study suggests several new candidate genes commonly regulated in gills of the two trout lines. Having identified the differential expression of thermoregulated genes as duplicated paralogues, they were subsequently validated in a gill cell model. Moreover, the comparison of transcriptome profiles provides evidence for distinctively employed expression patterns. The induction of genes encoding factors of the early innate immunity in BORN trout upon warming contrasts with the increased expression of adaptive immune genes in import trout. Cold acclimation induced genes assigned to the functional categories "cell death" and "ion channel activity" in import trout, but repressed "lipid metabolism." This manuscript provides an overview of the genes of the multifunctional gills in rainbow trout that are mandated after temperature change, suggesting links between the different temperature-dependent pathways and gene networks. 22849867 A story about a word: does narrative presentation promote learning of a spatial preposition in German two-year-olds? ABSTRACT We trained forty German-speaking children aged 1;8-2;0 in their comprehension of UNTER [UNDER]. The target word was presented within semantically organized input in the form of a 'narrative' to the experimental group and within 'unconnected speech' to the control group. We tested children's learning by asking them to perform an UNDER-relation before, immediately after, and again one day after the training using familiarized and unfamiliarized materials. Compared to controls, the experimental group learned better and retained more. Children with advanced expressive lexicons in particular were aided in generalizing to unfamiliarized materials by the narrative presentation. This study extends our understanding of how narrations scaffold young children's enrichment of nascent word knowledge. 23887140 An application of Pavlovian principles to the problems of obesity and cognitive decline. An enormous amount of research has been aimed at identifying biological and environmental factors that are contributing to the current global obesity pandemic. The present paper reviews recent findings which suggest that obesity is attributable, at least in part, to a disruption of the Pavlovian control of energy regulation. Within our framework, this disruption occurs when (a) consumption of sweet-tasting, but low calorie or noncaloric, foods and beverages reduces the ability of sweet tastes to predict the postingestive caloric consequences of intake and (b) consuming diets high in saturated fat and sugar (a.k.a., Western diet) impairs hippocampal-dependent learning and memory processes that are involved with the use of interoceptive "satiety" signals to anticipate when food and eating are not followed by appetitive postingestive outcomes. The paper concludes with discussion of a "vicious-cycle" model which links obesity to cognitive decline. 23962403 Relation of parenting styles, feeding styles and feeding practices to child overweight and obesity. Direct and moderated effects. The purpose of this study was to evaluate the direct and interacting relations of parenting styles, feeding styles, and feeding practices to child overweight and obesity. Participants were 144 mothers and children under 6years of age. Mothers completed questionnaires about parenting and feeding styles and feeding practices. Researchers weighed and measured mothers and children or obtained measurements from a recent health report. Feeding practices were not directly related to child weight status. Compared to the uninvolved feeding style, authoritative and authoritarian feeding style categories were linked to lower odds of overweight. Feeding practices interacted with authoritative and authoritarian parenting styles to predict obesity: (1) healthful modeling was associated with 61% (OR=0.39) reduced odds of obesity in children of authoritative mothers but with 55% (OR=1.55) increased odds in children of non-authoritative mothers and (2) covert control was linked to 156% (OR=2.56) increased odds of obesity in children of authoritarian mothers but with 51% (OR=0.49) decreased odds in children of non-authoritarian mothers. Healthful modeling interacted with feeding style demandingness to predict overweight and with responsiveness to predict obesity. Findings suggest the need for research and interventions on mechanisms mediating between feeding practices and obesity in families characterized by non-authoritative parenting styles. 23731522 Oestrogen and immunomodulation: new mechanisms that impact on peripheral and central immunity. The regulation of the immune response to infection or tissue damage is a complex interplay of multiple factors, but it has long been recognised that steroid hormones can exert powerful modulatory effects at all levels of the innate and adaptive immune systems. Although most attention has been paid to glucocorticoids given their widespread clinical use, it is becoming increasingly clear that sex steroid hormones, and in particular the principle female sex steroid oestrogen, exerts potent effects upon the immune response. In this review, we will discuss the latest findings on the impact of oestrogen upon various cellular components of the immune system, and how this hormone can offer new opportunities to pharmacologically harness the immune response. 23794708 Optimal targeting of HER2-PI3K signaling in breast cancer: mechanistic insights and clinical implications. The combination of a PI3K inhibitor with trastuzumab has been shown to be effective at overcoming trastuzumab resistance in models of HER2(+) breast cancer by inhibiting HER2-PI3K-FOXO-survivin signaling. In this review the potential clinical implications of these findings are discussed. 23511008 Gene and protein localisation of tumour necrosis factor (TNF)-α converting enzyme in gingival tissues from periodontitis patients with drug-induced gingival overgrowth. It is known that tumour necrosis factor (TNF)-α converting enzyme (TACE) plays a crucial role in fibrotic inflammatory diseases, and is specifically inhibited by tissue inhibitor of metalloproteinase (TIMP)-3. Fibrotic drug-induced gingival overgrowth (GO) is often combined with periodontitis. However, neither TACE nor TIMP-3 has been thoroughly examined in periodontal tissues to date. The aim of the present study was to analyse mRNA expression of TACE and TIMP-3, and protein localisation of TACE in gingival tissues removed from drug-(calcium-channel blocker) induced GO and periodontitis. A total of 30 gingival tissue samples were taken from 15 GO and 15 periodontitis patients. The mRNA expression levels were analysed by quantitative reverse transcription polymerase chain-reaction (qRT-PCR) and the protein localisation was investigated by immunohistochemistry. Statistical analysis was performed using the Mann-Whitney U-test. TACE and TIMP-3 mRNA levels were significantly higher in GO compared to the periodontitis groups, as revealed by qRT-PCR (p<0.05). TACE-producing cells were immunohistochemically detected among monocytes/macrophages, plasma cells and some epithelial cells. TACE immunoreactivity was shown to be more intense in GO than in periodontitis-gingival tissue. We have demonstrated TACE expression in cells such as macrophages, plasma cells and epithelial cells, and its predominant expression in GO tissues. This data suggests that TACE expression in GO-gingiva could be involved in the pathogenesis of disease. 23910473 Surgical innovations. This article reviews the evidence behind surgical innovations and effect on treatment-related morbidity to examine how they may be integrated into modern management strategies for oral cavity and oropharyngeal squamous cell carcinoma (SCC). Technologic advances, including transoral laser microsurgery and transoral robotic surgery, along with the application of sentinel lymph node biopsy for oral cavity and oropharyngeal SCC are discussed. 23523425 Structure of the Polycomb Group Protein PCGF1 in Complex with BCOR Reveals Basis for Binding Selectivity of PCGF Homologs. Polycomb-group RING finger homologs (PCGF1, PCGF2, PCGF3, PCGF4, PCGF5, and PCGF6) are critical components in the assembly of distinct Polycomb repression complex 1 (PRC1)-related complexes. Here, we identify a protein interaction domain in BCL6 corepressor, BCOR, which binds the RING finger- and WD40-associated ubiquitin-like (RAWUL) domain of PCGF1 (NSPC1) and PCGF3 but not of PCGF2 (MEL18) or PCGF4 (BMI1). Because of the selective binding, we have named this domain PCGF Ub-like fold discriminator (PUFD). The structure of BCOR PUFD bound to PCGF1 reveals that (1) PUFD binds to the same surfaces as observed for a different Polycomb group RAWUL domain and (2) the ability of PUFD to discriminate among RAWULs stems from the identity of specific residues within these interaction surfaces. These data show the molecular basis for determining the binding preference for a PCGF homolog, which ultimately helps determine the identity of the larger PRC1-like assembly. 23212242 A prior cesarean section and incidence of obstetric anal sphincter injury. Obstetric anal sphincter injury (OASIS) following birth may have serious, long-term effects on affected women, including fecal incontinence, despite primary repair. This was a retrospective population-based register study. Women with OASIS grouped by order of vaginal delivery and prior cesarean section (CS) were compared separately with women without OASIS using logistic regression analysis. The aim was to assess an association between prior CS and incidence of OASIS across groups of women categorized according to singleton first, second, and third vaginal deliveries between 1997 and 2007 in Finland. The incidence of OASIS was 1.8 % at a first vaginal delivery after a prior CS compared with 1.0 % at a first vaginal delivery without prior CS. After adjustment prior CS was associated with a 1.42-fold risk of OASIS only at the first vaginal delivery, with no further significant risk after one or two previous vaginal deliveries. One centimeter increase in maternal height was associated with a 2 % decrease in OASIS incidence at the first vaginal delivery. Prior CS is a significant risk factor for OASIS at the first vaginal delivery. This suggests that relative fetopelvic disproportion leading to CS for a first delivery also predisposes to OASIS at a first vaginal delivery since 40 % of the increased incidence of OASIS risk was explained by birthweight and 4 % by maternal height. 23016694 Obesity and addiction: neurobiological overlaps. Drug addiction and obesity appear to share several properties. Both can be defined as disorders in which the saliency of a specific type of reward (food or drug) becomes exaggerated relative to, and at the expense of others rewards. Both drugs and food have powerful reinforcing effects, which are in part mediated by abrupt dopamine increases in the brain reward centres. The abrupt dopamine increases, in vulnerable individuals, can override the brain's homeostatic control mechanisms. These parallels have generated interest in understanding the shared vulnerabilities between addiction and obesity. Predictably, they also engendered a heated debate. Specifically, brain imaging studies are beginning to uncover common features between these two conditions and delineate some of the overlapping brain circuits whose dysfunctions may underlie the observed deficits. The combined results suggest that both obese and drug-addicted individuals suffer from impairments in dopaminergic pathways that regulate neuronal systems associated not only with reward sensitivity and incentive motivation, but also with conditioning, self-control, stress reactivity and interoceptive awareness. In parallel, studies are also delineating differences between them that centre on the key role that peripheral signals involved with homeostatic control exert on food intake. Here, we focus on the shared neurobiological substrates of obesity and addiction. 23891713 Sex and menstrual cycle phase at encoding influence emotional memory for gist and detail. Sex influences on emotional memory have received increasing interest over the past decade. However, only a subset of this previous work explored the influence of sex on memory for central information (gist) and peripheral detail in emotional versus neutral contexts. Here we examined the influence of sex and menstrual cycle phase at encoding on memory for either an emotional or neutral story, specifically with respect to the retention of gist and peripheral detail. Healthy naturally cycling women and men viewed a brief, narrated, three-phase story containing neutral or emotionally arousing elements. One week later, participants received a surprise free recall test for story elements. The results indicate that naturally cycling women in the luteal (high hormone) phase of the menstrual cycle at encoding show enhanced memory for peripheral details, but not gist, when in the emotional compared with neutral stories (p<.05). In contrast, naturally cycling women in the follicular (low hormone) phase of the menstrual cycle at encoding did not show enhanced memory for gist or peripheral details in the emotional compared with neutral stories. Men show enhanced memory for gist, but not peripheral details, in the emotional versus neutral stories (p<.05). In addition, these sex influences on memory cannot be attributed to differences in attention or arousal; luteal women, follicular women, and men performed similarly on measures of attention (fixation time percentage) and arousal (pupil diameter changes) during the most arousing phase of the emotional story. These findings suggest that sex and menstrual cycle phase at encoding influence long term memory for different types of emotional information. 23864073 Difficult encounters with a hemophilic patient: the inner perspective of physicians. This study aimed at exploring the hematologists' internal representation of a difficult encounter with a hemophilic patient, using a written open format. Narrations were analyzed with Interpretative Phenomenological Analysis. Three main issues were identified, each with sub-issues: (1) Inside the relationship: to tell or not to tell, the balance between a normal life and a deviant medical condition, the guilt; (2) The borders of the professional role: professional values, the "do-it-all" doctor; and (3) The existential confrontation. This study reveals the deep involvement of physicians with their patients, at a professional level and, strongly, at a personal level. The experience of being so deeply involved should be considered in the continuing medical programs for physicians dealing with hemophilia. 23895646 Orthoformimycin, a Selective Inhibitor of Bacterial Translation Elongation from Streptomyces Containing an Unusual Orthoformate. Upon high throughput screening of 6700 microbial fermentation extracts, we discovered a compound, designated orthoformimycin, capable of inhibiting protein synthesis in vitro with high efficiency. The molecule, whose structure was elucidated by chemical, spectrometric, and spectroscopic methods, contains an unusual orthoformate moiety (hence the name) and belongs to a novel class of translation inhibitors. This antibiotic does not affect any function of the 30S ribosomal subunit but binds to the 50S subunit causing inhibition of translation elongation and yielding polypeptide products of reduced length. Analysis by fluorescence stopped flow kinetics revealed that EF-G-dependent mRNA translocation is inhibited by orthoformimycin, whereas, surprisingly, translocation of the aminoacyl-tRNA seems to be unaffected. 23734664 Bioconcentration of perfluorinated alkyl acids: how important is specific binding? Perfluorinated alkyl acids (PFAAs) are important global pollutants with unique pharmacokinetics. Evidence is accumulating that their behavior within organisms is affected by interaction with a number of proteins. In mammals, serum albumin, fatty acid binding proteins (FABPs) and organic anion transporters (OATs) have been identified as important to the tissue distribution, species-specific accumulation, and species- and gender-specific elimination rates of perfluoroalkyl carboxylates and perfluoroalkane sulfonates. Similar pharmacokinetics has been identified in fish. Yet, no mechanistic model exists for the bioaccumulation of PFAAs in fish that explicitly considers protein interactions. In this work, we present the first mechanistic protein-binding bioconcentration model for PFAAs in fish. Our model considers PFAA uptake via passive diffusion at the gills, association with serum albumin in the circulatory and extracellular spaces, association with FABP in the liver, and renal elimination and reabsorption facilitated by OAT proteins. The model is evaluated using measured bioconcentration and tissue distribution data collected in two previous studies of rainbow trout (Oncorhynchus mykiss) and common carp (Cyprinus carpio). Comparing our model with previous attempts to describe PFAA bioconcentration using a nonspecific (partitioning-type) approach shows that inclusion of protein interactions is key to accurately predicting tissue-specific PFAA distribution and bioconcentration. 23759382 A superparamagnetic Fe3O4-loaded polymeric nanocarrier for targeted delivery of evodiamine with enhanced antitumor efficacy. The aim of this study was to design and synthesize a polymeric nanocarrier system loaded with both superparamagnetic iron oxide nanoparticles (SPIONs) and the anticancer drug evodiamine through a solvent evaporation technique. The hydrodynamic diameter of the prepared SPION-evodiamine-loaded nanocarrier was approximately 261nm, and the drug-loading content and encapsulation efficiency were 8.61±0.73% and 40.36±3.42%, respectively. The nanocarrier exhibited good superparamagnetism and an iron content of approximately 9.34%. In vitro drug release experiments showed a sustained release profile over 70h. Staining with Prussian blue confirmed that the nanocarrier could be effectively internalized into HeLa cells. MTT assays indicated that the SPION-evodiamine-loaded nanocarrier showed cytotoxicity comparable to that of free evodiamine. If an external magnetic field was applied, the SPION-loaded nanocarrier accumulated at the targeted sites and demonstrated a magnetic force-mediated targeting property with the aid of a magnetic field. Furthermore, the SPION-evodiamine-loaded nanocarrier exhibited a much higher in vivo antitumor efficacy than free evodiamine. Together, these results indicate that the SPION-evodiamine-loaded nanocarrier could effectively inhibit tumor growth both in vitro and in vivo with reduced toxicity, and therefore is a promising candidate to achieve enhanced therapeutic efficacy for clinical development. 23825037 Combination of radiofrequency ablation and sequential cellular immunotherapy improves progression-free survival for patients with hepatocellular carcinoma. Hepatocellular carcinoma (HCC) recurs frequently after minimally invasive therapy. The aim of our study was to observe the efficiency and safety of the combined treatment of radiofrequency ablation (RFA) with cellular immunotherapy (CIT) for HCC patients. In our study, 62 patients with HCC who were treated with radical RFA were divided into two groups: RFA alone (32 patients) and RFA/CIT (30 patients). Autologous mononuclear cells were collected from the peripheral blood and separated by apheresis, and then induced into natural killer (NK) cells, γδT cells and cytokine-induced killer (CIK) cells. These cells were identified by flow cytometry with their specific antibodies and then were infused intravenously to RFA/CIT patients for three or six courses. The tumor recurrent status of these patients was evaluated with computed tomography or magnetic resonance imaging every 3 months after RFA. Progression-free survival (PFS), liver function, viral load and adverse effects were examined. The results implied that PFS was higher in RFA/CIT group than that in RFA group. In RFA/CIT group, six courses had better survival prognosis than three courses. Viral load of hepatitis C was decreased in two of three patients without antiviral therapy in RFA/CIT group, but was increased in RFA group. No significant adverse reaction was found in the patients with CIT. In summary, these preliminary results suggest that combination of sequential CIT with RFA for HCC patients was efficient and safe, and may be helpful in the prevention of the recurrence for the patients with HCC after RFA. 23240691 FINDSITE(comb): a threading/structure-based, proteomic-scale virtual ligand screening approach. Virtual ligand screening is an integral part of the modern drug discovery process. Traditional ligand-based, virtual screening approaches are fast but require a set of structurally diverse ligands known to bind to the target. Traditional structure-based approaches require high-resolution target protein structures and are computationally demanding. In contrast, the recently developed threading/structure-based FINDSITE-based approaches have the advantage that they are as fast as traditional ligand-based approaches and yet overcome the limitations of traditional ligand- or structure-based approaches. These new methods can use predicted low-resolution structures and infer the likelihood of a ligand binding to a target by utilizing ligand information excised from the target's remote or close homologous proteins and/or libraries of ligand binding databases. Here, we develop an improved version of FINDSITE, FINDSITE(filt), that filters out false positive ligands in threading identified templates by a better binding site detection procedure that includes information about the binding site amino acid similarity. We then combine FINDSITE(filt) with FINDSITE(X) that uses publicly available binding databases ChEMBL and DrugBank for virtual ligand screening. The combined approach, FINDSITE(comb), is compared to two traditional docking methods, AUTODOCK Vina and DOCK 6, on the DUD benchmark set. It is shown to be significantly better in terms of enrichment factor, dependence on target structure quality, and speed. FINDSITE(comb) is then tested for virtual ligand screening on a large set of 3576 generic targets from the DrugBank database as well as a set of 168 Human GPCRs. Excluding close homologues, FINDSITE(comb) gives an average enrichment factor of 52.1 for generic targets and 22.3 for GPCRs within the top 1% of the screened compound library. Around 65% of the targets have better than random enrichment factors. The performance is insensitive to target structure quality, as long as it has a TM-score ≥ 0.4 to native. Thus, FINDSITE(comb) makes the screening of millions of compounds across entire proteomes feasible. The FINDSITE(comb) web service is freely available for academic users at http://cssb.biology.gatech.edu/skolnick/webservice/FINDSITE-COMB/index.html. 23746472 Synthesis and acrosin inhibitory activities of 5-phenyl-1H-pyrazole-3-carboxylic acid amide derivatives. A series of novel 5-phenyl-1H-pyrazole-3-carboxylic acid amide derivatives were designed, synthesized, and their acrosin inhibitory activities in vitro were evaluated. The results of the acrosin inhibitory activity showed that all target compounds were more potent than control TLCK. Compounds AQ-A1, AQ-D3, AQ-D4, AQ-E4 and AQ-E5 exhibited stronger acrosin inhibitory activities than control ISO-1. Especially, compound AQ-E5 displayed the most potent acrosin inhibitory activity in all the compounds, with an IC50 of 0.01μmol/mL. This study provided a new structural class for the development of novel acrosin inhibitory agents. 23942617 Thrombospondin-4 expression is activated during the stromal response to invasive breast cancer. The thromobospondins are a family of extracellular glycoproteins that are activated during tissue remodeling processes such as embryogenesis, wound healing and cancer. Thrombospondin-4 (THBS4) is known to have roles in cellular migration, adhesion and attachment, as well as proliferation in different contexts. Data to support a role in cancer biology is increasing, including for gastrointestinal and prostate tumours. Here, using a combination of immunohistochemistry, immunofluorescence and analysis of publicly available genomic and expression data, we present the first study describing the pattern of expression of THBS4 in normal breast and breast cancer. THBS4 was located to the basement membrane of large ducts and vessels in normal breast tissue, but was absent from epithelium and extracellular matrix. There was a significant induction in expression in cancer-associated stroma relative to normal stroma (P = 0.0033), neoplastic epithelium (P < 0.0001) and normal epithelium (P < 0.0001). There was no difference in stromal expression of THBS4 between invasive ductal carcinomas (IDC) and invasive lobular carcinomas (ILC). The THBS4 mRNA levels were variable yet were generally highest in tumours typically rich in stromal content (ILC, ER positive low grade IDC; luminal A and normal-like subtypes). Genomic alterations of the THBS4 gene (somatic mutations and gene copy number) are rare suggesting this dramatic activation in expression is most likely dynamically regulated through the interaction between invading tumour cells and stromal fibroblasts in the local microenvironment. In summary, THBS4 expression in breast cancer-associated extracellular matrix contributes to the activated stromal response exhibited during tumour progression and this may facilitate invasion of tumour cells. 23963401 Tissue Engineering of a Human 3D in vitro Tumor Test System. Cancer is one of the leading causes of death worldwide. Current therapeutic strategies are predominantly developed in 2D culture systems, which inadequately reflect physiological conditions in vivo. Biological 3D matrices provide cells an environment in which cells can self-organize, allowing the study of tissue organization and cell differentiation. Such scaffolds can be seeded with a mixture of different cell types to study direct 3D cell-cell-interactions. To mimic the 3D complexity of cancer tumors, our group has developed a 3D in vitro tumor test system. Our 3D tissue test system models the in vivo situation of malignant peripheral nerve sheath tumors (MPNSTs), which we established with our decellularized porcine jejunal segment derived biological vascularized scaffold (BioVaSc). In our model, we reseeded a modified BioVaSc matrix with primary fibroblasts, microvascular endothelial cells (mvECs) and the S462 tumor cell line. For static culture, the vascular structure of the BioVaSc is removed and the remaining scaffold is cut open on one side (Small Intestinal Submucosa SIS-Muc). The resulting matrix is then fixed between two metal rings (cell crowns). Another option is to culture the cell-seeded SIS-Muc in a flow bioreactor system that exposes the cells to shear stress. Here, the bioreactor is connected to a peristaltic pump in a self-constructed incubator. A computer regulates the arterial oxygen and nutrient supply via parameters such as blood pressure, temperature, and flow rate. This setup allows for a dynamic culture with either pressure-regulated pulsatile or constant flow. In this study, we could successfully establish both a static and dynamic 3D culture system for MPNSTs. The ability to model cancer tumors in a more natural 3D environment will enable the discovery, testing, and validation of future pharmaceuticals in a human-like model. 23887533 Summary of: Ethnic disparities in the oral health of three- to four-year-old children in East London. Aim To report ethnic differences related to caries experience among three- to four-year-old children living in three of the most deprived boroughs in the UK in Inner North East London: Tower Hamlets, Hackney and Newham.Methods This cross-sectional survey used a cluster sampling study design following the British Association for the Study of Community Dentistry protocol. Twenty nurseries from each borough were randomly selected and all three- to four-year-old children in selected nurseries were invited to participate (n = 2,434). Calibrated dentists examined children. Demographic information was obtained from schools.Results One thousand, two hundred and eighty-five children were examined in 60 nurseries (response rate = 52.8%). Twenty-four percent of three- to four-year-old children had caries experience (mean dmft = 0.92). Few children (2.1%) had filled teeth. Children living in Hackney had significantly lower dmft scores (mean = 0.63) than children living in Newham (mean = 1.06) and Tower Hamlets (mean = 1.06). White European (mean = 1.91), Bangladeshi (mean = 1.05) and Pakistani (mean = 1.11) children had a significantly higher number of untreated carious teeth than White British children (mean = 0.56).Conclusion Preschool children from a White Eastern European, Bangladeshi and Pakistani background are likely to experience significantly poorer oral health than their White British counterparts. These findings have profound implications for commissioning dental services and oral health promotion. 23672398 ATP-dependent regulation of actin monomer-filament equilibrium by cyclase-associated protein and ADF/cofilin. CAP (cyclase-associated protein) is a conserved regulator of actin filament dynamics. In the nematode Caenorhabditis elegans, CAS-1 is an isoform of CAP that is expressed in striated muscle and regulates sarcomeric actin assembly. In the present study, we report that CAS-2, a second CAP isoform in C. elegans, attenuates the actin-monomer-sequestering effect of ADF (actin depolymerizing factor)/cofilin to increase the steady-state levels of actin filaments in an ATP-dependent manner. CAS-2 binds to actin monomers without a strong preference for either ATP- or ADP-actin. CAS-2 strongly enhances the exchange of actin-bound nucleotides even in the presence of UNC-60A, a C. elegans ADF/cofilin that inhibits nucleotide exchange. UNC-60A induces the depolymerization of actin filaments and sequesters actin monomers, whereas CAS-2 reverses the monomer-sequestering effect of UNC-60A in the presence of ATP, but not in the presence of only ADP or the absence of ATP or ADP. A 1:100 molar ratio of CAS-2 to UNC-60A is sufficient to increase actin filaments. CAS-2 has two independent actin-binding sites in its N- and C-terminal halves, and the C-terminal half is necessary and sufficient for the observed activities of the full-length CAS-2. These results suggest that CAS-2 (CAP) and UNC-60A (ADF/cofilin) are important in the ATP-dependent regulation of the actin monomer-filament equilibrium. 23827210 Triglycerides-diabetes association in healthy middle-aged men: Modified by physical fitness?: A long term follow-up of 1962 Norwegian men in the Oslo Ischemia Study. To examine the impact of physical fitness (PF) on the association between fasting serum triglycerides (FTG) and diabetes risk and whether temporal changes in FTG predict diabetes risk in healthy middle-aged men. FTG and PF (bicycle exercise test) were measured in 1962 men aged 40-59 years in 1972-1975 (Survey 1) and repeated in 1387 still healthy men on average 7.3 years later (Survey 2). Diabetes was diagnosed according to WHO 1985-criteria. During 35 years follow-up 202/1962 (10.3%) men developed diabetes. Compared with the lowest, the upper FTG tertile had a 2.58-fold (95% CI: 1.81-3.74) diabetes risk adjusted for age, fasting blood glucose and maternal diabetes, and a 2.29-fold (95%CI: 1.60-3.33) when also adjusting for PF. Compared with unchanged (±25%) FTG levels (n=664), FTG reduction of more than 25% (n=261) was associated with 56% lower (0.44; 95% CI: 0.24-0.75) diabetes risk, while FTG increase of more than 25% (n=462) was associated with similar risk. These associations were unchanged when adjusted for PF and PF change. High FTG-levels predicted long-term diabetes risk in healthy middle-aged men, and the association was only modestly weakened when adjusted for PF. A reduction in FTG was associated with decreased diabetes risk. 23716405 Monoclonal Antibody-Based Immunofluorescence Microscopy for the Rapid Identification of Burkholderia pseudomallei in Clinical Specimens. Abstract. The diagnosis of melioidosis depends on the culture of Burkholderia pseudomallei, which takes at least 48 hours. We used a polyclonal-FITC-based immunofluorescence microscopic assay (Pab-IFA) on clinical samples to provide a rapid presumptive diagnosis. This has limitations including photobleaching and batch-to-batch variability. This study evaluated an IFA based on a monoclonal antibody specific to B. pseudomallei (Mab-IFA) and Alexa Fluor 488. A diagnostic evaluation was performed on a prospective cohort of 951 consecutive patients with suspected melioidosis. A total of 1,407 samples were tested. Test accuracy was defined against culture as the gold standard, and was also compared against Pab-IFA. A total of 88 samples from 64 patients were culture positive for B. pseudomallei. The diagnostic sensitivity and specificity of the Mab-IFA was comparable to the Pab-IFA (48.4% versus 45.3% for sensitivity, and 99.8% versus 98.8% for specificity). We have incorporated the Mab-IFA into our routine practice. 23811995 Blood pressure levels and brain volume reduction: a systematic review and meta-analysis. High blood pressure (BP) levels may be associated with brain volume reduction and may contribute to brain atrophy in key brain regions involved in cognition and susceptible to neurodegeneration in Alzheimer's disease. The purpose of this work was to systematically review and quantitatively synthesize the association of BP levels with brain volume reduction in humans. An English Medline, Cochrane Library and PsycINFO search was conducted in June 2012 using the Medical Subject Heading terms 'Blood pressure', 'Hypertension', 'Brain mapping' and 'Brain atrophy'. Of the 609 screened abstracts, 28 studies (4.6%) were included in the qualitative analysis. Twenty-six studies (92.9%) showed a significant association of higher BP levels and/or hypertension with total and/or regional brain volume reduction, the frontal and temporal lobes being particularly affected. In addition, four other studies reported an association between lower BP levels and brain volume reduction. Due to the heterogeneity of methodology and outcomes, random-effects meta-analyses of the mean difference of brain volume could be performed on only seven studies, with a total of 709 cases with hypertension and 1001 controls without hypertension. The findings showed no between-group difference regarding the whole-gray matter volume (summary mean difference = 2.42 cm [95% confidence interval (CI): -2.13 to 6.96]). Conversely, cases with hypertension exhibited lower hippocampus volume compared with controls [summary mean difference = -0.10 cm (95% CI: -0.17 to -0.02)]. These findings provide evidence that high BP levels lead to brain volume reduction, specifically in hippocampus, and may be an important factor that contributes to neurodegeneration in Alzheimer's disease. 23901826 Assessing the Impact of Electronic and Steric Tuning of the Ligand in the Spin State and Catalytic Oxidation Ability of the Fe(II)(Pytacn) Family of Complexes. A family of iron complexes with the general formula [Fe(II)((R,R)'Pytacn)(X)2](n+) is described, where (R)(,)(R)'Pytacn is the tetradentate ligand 1-[(4-R'-6-R-2-pyridyl)methyl]-4,7-dimethyl-1,4,7-triazacyclononane, R refers to the group at the α-position of the pyridine, R' corresponds to the group at the γ-position, and X denotes CH3CN or CF3SO3. Herein, we study the influence of the pyridine substituents R and R' on the electronic properties of the coordinated iron center by a combination of structural and spectroscopic characterization using X-ray diffraction, (1)H NMR and UV-vis spectroscopies, and magnetic susceptibility measurements. The electronic properties of the substituent in the γ-position of the pyridine ring (R') modulate the strength of the ligand field, as shown by magnetic susceptibility measurements in CD3CN solution, which provide a direct indication of the population of the magnetically active high-spin S = 2 ferrous state. Indeed, a series of complexes [Fe(II)((H,R)'Pytacn)(CD3CN)2](2+) exist as mixtures of high-spin (S = 2) and low-spin (S = 0) complexes, and their effective magnetic moment directly correlates with the electron-releasing ability of R'. On the other hand, the substitution of the hydrogen atom in the α-position of the pyridine by a methyl, chlorine, or fluorine group favors the high-spin state. The whole family of complexes has been assayed in catalytic C-H and C═C oxidation reactions with H2O2. These catalysts exhibit excellent efficiency in the stereospecific hydroxylation of alkanes and in the oxidation of olefins. Remarkably, R'-substituents have little influence on the efficiency and chemoselectivity of the catalytic activity of the complexes, but the selectivity toward olefin cis-dihydroxylation is enhanced for complexes with R = Me, F, or Cl. Isotopic labeling studies in the epoxidation and cis-dihydroxylation reactions show that R has a definitive role in dictating the origin of the oxygen atom that is transferred in the epoxidation reaction. 23910750 The biological family from the perspective of kinship fostered adolescents. Background: Previous studies emphasise the importance of the biological family to the welfare of fostered adolescents. However, the majority of these studies only take into consideration the viewpoints of the professionals, foster parents and biological parents, not those of the adolescents themselves. For this reason little is known about the perceptions the adolescents have and the needs they express. Method: This study has gathered data from 57 adolescents in kinship family foster care in Spain (AFE). The study applied qualitative reseach, using focus groups to gather data, and the Atlas.ti programme to analyse the data. The qualitative data give us a more profound understanding of how the fostered adolescents relate to their biological families. Results: The results highlight the specific needs of these adolescents with regard to: a) understanding of their family history, b) the impact of visits from and relationship with their biological family, and c) the relationship between the biological family and the foster family. Conclusions: These findings reveal implications to consider when creating support programmes aimed at this group. 23912968 Ocular Morbidity among the Children of Squatter Settlements in Kathmandu. To determine the prevalence of ocular morbidity and refractive error among the children of the squatter settlements in Kathmandu. A cross-sectional study was carried out at five squatter settlement areas at Kathmandu, including 366 children younger than 16 years. Detailed eye examination included the visual acuity testing, cycloplegic refraction, binocular vision assessment, anterior segment examination, and posterior segment examination. Variations in age, sex, and ethnic distribution of the study population were analyzed through analysis of variance. Pearson χ test with Yate correction was used to analyze different types of ocular morbidity. Pearson correlation coefficient test was performed to correlate refractive error in the right eye and the left eye. Majority of children (28.9%) belonged to the age group 8 to 10 years, and most of them belonged to the Manohara settlement area (40.2%). Male-female ratio was 0.7. Uncorrected and best-corrected visual acuity of better than or equal to 6/9 in at least one eye was found in 87.9% and 99.0% children, respectively. Total ocular morbidity was observed in 33.7%. The common type of ocular morbidity was conjunctivitis (11.2%), refractive error (9.0%), and blepharitis (5.4%). Ocular morbidity was common in infants (57.9%; p = 0.043; odds ratio, 2.8) and 14- to 15-year-old children (52.8%; p = 0.002; odds ratio, 2.5). Ocular infection and refractive error represent the common ocular morbidity in children living in squatter settlements. 23827178 Resonance light scattering technique as a new tool to determine the binding mode of anticancer drug oridonin to DNA. In this study, a sensitive and reliable assay has been developed to determine the binding mode of oridonin to DNA in vitro using resonance light scattering (RLS) technique. The binding mode of ORI with DNA has been confirmed by measuring the changes of RLS intensity under different pH and ionic strength. It is the ORI that is intercalated into the double helix DNA to destroy its template function and inhibit the synthesis of DNA. Moreover, the RLS assay result was validated by seasoned vitro methods. The proposed RLS assay is not only an unprecedented one for primarily determine the binding mode of oridonin to DNA, but also a simple, sensitive, objective and straightforward method for the detection of ORI. 23801315 Feasibility and efficacy of argon plasma coagulation for early esophageal squamous cell neoplasia. We present 19 cases in which argon plasma coagulation (APC) was used as curative initial treatment for 5 low-grade esophageal squamous intraepithelial neoplasias (ESINs), 12 high-grade ESINs, and 2 early esophageal squamous cell carcinomas (ESCCs). Complete response was defined as the absence of tumor from any biopsy taken from the ablated lesion. At follow-up endoscopy 2 - 4 months after APC, 94.7 % of patients had achieved complete response in a single treatment session. Only one patient with high-grade ESIN showed local recurrence. This patient underwent additional APC and showed complete response at 12 months after initial APC. At the 12-month follow-up endoscopy, again 94.7 % had a complete response. The exception was one patient with local recurrence, who underwent additional APC. After the 12-month follow-up endoscopy, no patient showed local recurrence during a median follow-up of 22 months. No stricture requiring endoscopic dilation occurred after the procedure. This study suggests that APC is a feasible and effective treatment modality for ESIN and early ESCC. 23411261 Effects of Azocompost and urea on the herbage yield and contents and compositions of essential oils from two genotypes of dragonhead (Dracocephalum moldavica L.) in two regions of Iran. Dragonhead is an annual, herbaceous, balm-scented and spicy aromatic member of the family Lamiaceae. We examined effects of different sources of nitrogen on the content and composition of essential oils in two genotypes of dragonhead in two regions of Iran. The sources of nitrogen used were 100% urea (70 kg N ha(-1)), 75% urea (52.5 kg N ha(-1))+25% Azocompost (3.85 tonha(-1)), 50% urea (35 kg N ha(-1))+50% Azocompost (7.77 tonha(-1)), 25% urea (17.5 kg N ha(-1))+75% Azocompost (11.55 tonha(-1)), and 100% Azocompost (15.55 tonha(-1)). Optimal yield and content of essential oil at both locations for both genotypes were obtained by applying 50% urea+50% Azocompost. Geraniol, geranial, and geranyl acetate were the most abundant compounds. For both genotypes and both locations, application of 50% urea+50% Azocompost increased levels of geraniol and geranial, and application of Azocompost alone increased levels of geranyl acetate. Overall, we conclude that the application of 50% urea with 50% Azocompost is recommended for optimising the content and composition of essential oils in dragonhead. 23955655 Identification of a possible respiratory arsenate reductase in Denitrovibrio acetiphilus, a member of the phylum Deferribacteres. Denitrovibrio acetiphilus N2460(T) is one of the few members of the phylum Deferribacteres with a sequenced genome. N2460(T) was capable of growing with dimethyl sulfoxide, selenate, or arsenate provided as a terminal electron acceptor, and we identified 15 genes that could possibly encode respiratory reductases for these compounds. The protein encoded by one of these genes, YP_003504839, clustered with respiratory arsenate reductases on a phylogenetic tree. Transcription of the gene for YP_003504839, Dacet_2121, was highly induced when arsenate was provided as a terminal electron acceptor. Dacet_2121 exists in a possible operon that is distinct from the previously characterized respiratory arsenate reductase operon in Shewanella sp. ANA-3. 23483584 Use of hydrodistillation and headspace solid-phase microextraction to characterize the volatile composition of different hop cultivars. Hop cones, the immature inflorescences of the female plant of Humulus lupulus L., have been used for centuries to improve the flavor of beer and can be also used for a great variety of other products. Four samples of hop, belonging to three different cultivars (Nugget, Saaz and Perle), were studied in the present work. Headspace solid-phase microextraction and hydrodistillation techniques were used to obtain the volatile profiles of the samples. Independent of the technique employed, over 40 volatile compounds were detected in the hop pellet samples (esters, monoterpenes, monoterpenoids, sesquiterpenes and sesquiterpenoids). Sesquiterpenes and sesquiterpenoids represented the majority of the total aromatic compounds. The main compounds for all cultivars were myrcene, β-caryophyllene and humulene, but the presence of high amounts of β-farnesene in Saaz cultivar was highlighted. Both techniques were suitable for studying qualitatively the volatile composition of hop pellets, but some differences were shown when studying the proportion of the main constituents of the volatile profiles. Understanding these differences may help researchers design future studies to advise the industry how to exploit the potential of each hop cultivar. 23178557 Adaptation of bifidobacteria to the gastrointestinal tract and functional consequences. Members of the genus Bifidobacterium are considered to be important constituents of the microbiota of animals, from insects to mammals. They are gut commensals extensively used by the food industry as probiotic microorganisms, since some strains have been shown to have specific beneficial effects. However, the molecular processes underlying their functional capacities to promote a healthy status in the host, as well as those involved in survival, colonization and persistence of bifidobacteria in the gut, are far from being completely understood. This review summarizes the current knowledge on the mechanisms used by bifidobacteria to cope with gastrointestinal factors and to adapt to them, and discusses the advantages of the adaptive traits acquired by these microorganisms as a consequence of their interactions with the gastrointestinal tract environment, as well as the impact of such adaptations in the functional characteristics of bifidobacteria. 23936573 Association between Ocular Bacterial Carriage and Follicular Trachoma Following Mass Azithromycin Distribution in The Gambia. Trachoma, caused by ocular Chlamydia trachomatis infection, is the leading infectious cause of blindess, but its prevalence is now falling in many countries. As the prevalence falls, an increasing proportion of individuals with clinical signs of follicular trachoma (TF) is not infected with C. trachomatis. A recent study in Tanzania suggested that other bacteria may play a role in the persistence of these clinical signs. We examined associations between clinical signs of TF and ocular colonization with four pathogens commonly found in the nasopharnyx, three years after the initiation of mass azithromycin distribution. Children aged 0 to 5 years were randomly selected from 16 Gambian communitites. Both eyes of each child were examined and graded for trachoma according to the World Health Organization (WHO) simplified system. Two swabs were taken from the right eye: one swab was processed for polymerase chain reaction (PCR) using the Amplicor test for detection of C. trachomatis DNA and the second swab was processed by routine bacteriology to assay for the presence of viable Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus and Moraxella catarrhalis. Prevalence of TF was 6.2% (96/1538) while prevalence of ocular C. trachomatis infection was 1.0% (16/1538). After adjustment, increased odds of TF were observed in the presence of C. trachomatis (OR = 10.4, 95%CI 1.32-81.2, p = 0.03), S. pneumoniae (OR = 2.14, 95%CI 1.03-4.44, p = 0.04) and H. influenzae (OR = 4.72, 95% CI 1.53-14.5, p = 0.01). Clinical signs of TF can persist in communities even when ocular C. trachomatis infection has been controlled through mass azithromycin distribution. In these settings, TF may be associated with ocular colonization with bacteria commonly carried in the nasopharnyx. This may affect the interpretation of impact surveys and the determinations of thresholds for discontinuing mass drug administration. 23899934 Dynamic sensor interrogation using wavelength-swept laser with a polygon-scanner-based wavelength filter. We report a high-speed (~2 kHz) dynamic multiplexed fiber Bragg grating (FBG) sensor interrogation using a wavelength-swept laser (WSL) with a polygon-scanner-based wavelength filter. The scanning frequency of the WSL is 18 kHz, and the 10 dB scanning bandwidth is more than 90 nm around a center wavelength of 1,540 nm. The output from the WSL is coupled into the multiplexed FBG array, which consists of five FBGs. The reflected Bragg wavelengths of the FBGs are 1,532.02 nm, 1,537.84 nm, 1,543.48 nm, 1,547.98 nm, and 1,553.06 nm, respectively. A dynamic periodic strain ranging from 500 Hz to 2 kHz is applied to one of the multiplexed FBGs, which is fixed on the stage of the piezoelectric transducer stack. Good dynamic performance of the FBGs and recording of their fast Fourier transform spectra have been successfully achieved with a measuring speed of 18 kHz. The signal-to-noise ratio and the bandwidth over the whole frequency span are determined to be more than 30 dB and around 10 Hz, respectively. We successfully obtained a real-time measurement of the abrupt change of the periodic strain. The dynamic FBG sensor interrogation system can be read out with a WSL for high-speed and high-sensitivity real-time measurement. 23417542 Trends in otolaryngologic utilization of computed tomography for sinonasal disorders. Determine temporal trends in otolaryngologists' utilization of computed tomography (CT) in the diagnosis of sinonasal disorders. Cross-sectional analysis of national health-care database. The National Ambulatory Medical Care Survey was examined from 2005 to 2010, and all visits to otolaryngologists with a chronic sinonasal diagnosis code (e.g., chronic sinusitis, chronic rhinitis, allergic rhinitis, and septal deviation) were extracted. The demographics and proportion of otolaryngology visits at which a CT scan was ordered were determined for each calendar year, and trends were determined for the 6-year period. An estimated 31.1±2.8 million otolaryngology visits with sinonasal diagnoses were extracted (unweighted N=2,099). The average patient age was 43.2±0.6 years, with a female predominance (57.1%±1.8%). The most common diagnoses were chronic rhinosinusitis (10.9 million visits, unweighted N=819) and allergic rhinitis (10.7 million visits, unweighted N=639). Overall, 10.4%±2.2% of sinonasal diagnosis visits involved CT (unweighted N=232), ranging from 8.4%±3.0% in 2007 to 12.3%±2.6% in 2008; in 2010, 11.7%±2.9% of visits included CT. There was no statistically significant difference in CT rates over the course of these 6 calendar years (P=.798). Despite widespread availability of imaging and a strong prevalence of sinonasal diagnoses, otolaryngologists' CT ordering patterns have not resulted in increased utilization over the past 6 years. This suggests that otolaryngologists are remaining consistent in their ordering patterns for sinonasal CT. 2c. Laryngoscope, 123:1837-1839, 2013. 23835877 Verbal Ability and Language Outcome Following Traumatic Brain Injury in Early Childhood. To investigate language outcomes of TBI in preschool-aged children. Competent early language skills are pivotal for the future development of literacy skills. While previous research has reported that traumatic brain injury (TBI) places children at risk of language impairments, the majority of these studies have been conducted with school-aged children. Royal Children's Hospital, Melbourne, Australia. Children aged 4 to 6 years who had sustained a mild (N = 19) or moderate/severe (N = 16) TBI prior to 3 years of age and a control group (N = 20) of typically developing children matched for age, gender, and socioeconomic status. The Wechsler Preschool and Primary School Scale of Intelligence, Third Edition, measured Verbal IQ. The Clinical Evaluation of Language Fundamentals-Preschool version and the Bus Story Test measured language skills. More severely injured children displayed greater impairments in verbal intellectual abilities and language skills compared with children with mild TBI and uninjured children. Children with mild TBI performed similarly to children in the control group. Language appears vulnerable to TBI and should be investigated as a matter of course in clinical assessments of TBI recovery. 23806478 Left ventricular dysfunction and outcome at two-year follow-up in patients with type 2 diabetes: The DYDA study. Left ventricular dysfunction (LVD) in type 2 diabetes mellitus (DM) (DYDA) study is a prospective investigation enrolling 960 with DM without overt cardiac disease. At baseline, a high prevalence of LVD was detected by analysing midwall shortening. We report here the incidence of clinical events in DYDA patients after 2-year follow-up and the frequency of LVD detected at baseline and 2-year evaluation. Systolic LVD was defined as midwall shortening ≤15%, diastolic LVD as any condition different from "normal diastolic function" identified as E/A ratio on Doppler mitral flow between 0.75 and 1.5 and deceleration time of E wave >140ms. Major outcome was a composite of major events, including all-causes death and hospital admissions. During the study period, any systolic/diastolic LVD was found in 616 of 699 patients (88.1%) in whom LVD function could be measured at baseline or at 2 years. Older age and high HbA1c predicted the occurrence of LVD. During the follow-up 15 patients died (1.6%), 3 for cardiovascular causes, 139 were hospitalized (14.5%, 43 of them for cardiovascular causes, 20 for a new cancer). During a 2-year follow-up any LVD is detectable in a large majority of patients with DM without overt cardiac disease. Older age and higher HbA1c predict LVD. All-cause death or hospitalization occurred in 15% of patients, cardiovascular cause was uncommon. Independent predictors of events were older age, pathologic lipid profile, high HbA1c, claudicatio and repaglinide therapy. Echo-assessed LVD at baseline was not prognosticator of events. 23109429 Piccolo NuA4-catalyzed acetylation of nucleosomal histones: critical roles of an Esa1 Tudor/chromo barrel loop and an Epl1 enhancer of polycomb A (EPcA) basic region. Piccolo NuA4 is an essential yeast histone acetyltransferase (HAT) complex that targets histones H4 and H2A in nucleosome substrates. While Piccolo NuA4's catalytic subunit Esa1 alone is unable to acetylate nucleosomal histones, its accessory subunits, Yng2 and Epl1, enable Esa1 to bind to and to act on nucleosomes. We previously determined that the Tudor domain of Esa1 and the EPcA homology domain of Epl1 play critical roles in Piccolo NuA4's ability to act on the nucleosome. In this work, we pinpoint a loop within the Esa1 Tudor domain and a short basic region at the N terminus of the Epl1 EPcA domain as necessary for this nucleosomal HAT activity. We also show that this Esa1 Tudor domain loop region is positioned close to nucleosomal DNA and that the Epl1 EPcA basic region is in proximity to the N-terminal histone H2A tail, the globular region of histone H4, and also to nucleosomal DNA when Piccolo NuA4 interacts with the nucleosome. Since neither region identified is required for Piccolo NuA4 to bind to nucleosomes and yet both are needed to acetylate nucleosomes, these regions may function after the enzyme binds nucleosomes to disengage substrate histone tails from nucleosomal DNA. 23122080 Toona sinensis and its major bioactive compound gallic acid inhibit LPS-induced inflammation in nuclear factor-κB transgenic mice as evaluated by in vivo bioluminescence imaging. In the present study, we investigated the anti-inflammatory effects of a nutritious vegetable Toona sinensis (leaf extracts, TS) and its major bioactive compound gallic acid (GA) by analysing LPS-induced NF-κB activation in transgenic mice, using bioluminescence imaging. Mice were challenged intraperitoneally with LPS (1mg/kg) and treated orally with TS or GA (100 or 5mg/kg, respectively). In vivo and ex vivo imaging showed that LPS increased NF-κB luminescence in the abdominal region, which was significantly inhibited by TS or GA. Immunohistochemical and ELISA analyses confirmed that TS and GA inhibited LPS-induced NF-κB, interleukin-1β, and tumour necrosis factor-α expression. Microarray analysis revealed that biological pathways associated with metabolism and the immune responses were affected by TS or GA. Particularly, LPS-induced thioredoxin-like 4B (TXNL4B) 2 expression in the small intestine, and TXNL4B, iNOS, and COX-2 expression in RAW 264.7 cells were significantly inhibited by TS or GA. Thus, the anti-inflammatory potential of TS was mediated by the downregulation of NF-κB pathway. 23123257 Reduced in vitro and in vivo toxicity of siRNA-lipoplexes with addition of polyglutamate. We previously designed a new siRNA vector that efficiently silences genes in vitro and in vivo. The vector originality is based on the fact that, in addition to the siRNA molecule, it contains two components: 1) a cationic liposome that auto-associates with the siRNA to form particles called "lipoplexes" and, 2) an anionic polymer which enhances the lipoplex's efficiency. This anionic polymer can be a nucleic acid, a polypeptide or a polysaccharide. We show here how the nature of the added anionic polymer into our siRNA delivery system impacts the toxic effects induced by siRNA lipoplexes. We first observed that: (i) siRNA lipoplexes-induced toxicity was cell line dependent, tumoral cell lines being the more sensitive; and (ii) plasmid DNA-containing siRNA lipoplexes were more toxic than polyglutamate-containing ones or cationic liposomes. We next determined that the toxicity induced by plasmid-containing lipoplexes is a long-lasting effect that decreased cell survival capacity for several generations. We also found that treated cells underwent death following apoptosis pathway. Systemic injection to mice of siRNA lipoplexes, rather than of cationic liposome, triggered a production of several cytokines in mice and replacement of plasmid by polyglutamate reduced the elevation of all assayed cytokines. In order to enhance siRNA lipoplexes efficiency, the addition of polyglutamate as anionic polymer should be preferred to plasmid DNA as far as in vitro as well as in vivo toxicity is concerned. 23682039 Seasonal variation in semen quality in China. In this study, we assessed the effect of seasonal variation on the semen quality in Chinese by using the average highest temperature (AHT) of the ejaculation day for partitioning season periods. A total of 13 635 semen samples were collected and analysed according to the AHT of the ejaculation day. Semen volume, sperm concentration and the percentage of spermatozoa with normal morphology in midsummer (AHT > 30 °C) were significantly lower than those in other periods of the year. Sperm motility with AHT 10-20 °C in winter and spring was significantly higher than that in other seasons. The percentage of head defects spermatozoa with AHT < 10 °C in winter was significantly lower than that in other periods. We observed that there was a significant effect of season on the semen parameters. Highest environment temperature of the day may be a determining factor for the seasonal variations in semen quality. 23614455 Efficient cell and cell-sheet harvesting based on smart surfaces coated with a multifunctional and self-organizing Elastin-Like Recombinamer. A wide range of smart surfaces with novel properties relevant for biomedical applications have been developed recently. Herein we focus on thermoresponsive surfaces that switch between cell-adherent and non-adherent states, and their applications for cell harvesting. These smart surfaces are obtained by covalently coupling a tailored Elastin-Like Recombinamer onto glass surfaces by means of the well-known and widely applied Click Chemistry methodology. The resulting recombinamer-functionalized surfaces have been characterized by means of water contact angle measurements, XPS and TOF-SIMS. A cell-based analysis of these surfaces with human fibroblasts showed a high degree of adhesion to the surface in its adherent state (37ºC), thus promoting cell viability and proliferation. A temperature decrease triggers reorganization of the recombinamer, thus markedly increasing the number of non-adherent domains and masking the adherent ones. This process allows a specific and efficient temporal control of cell adhesion and cell detachment. After determination of the properties required for a suitable cell-harvesting system, optimization of the process allows single cells or cell sheets from at least two types of cells (HFF-1 and ADSCs) to be rapidly harvested. 23722705 Peripheral fatigue limits endurance exercise via a sensory feedback-mediated reduction in spinal motoneuronal output. This study sought to determine whether afferent feedback associated with peripheral muscle fatigue inhibits central motor drive (CMD) and thereby limits endurance exercise performance. On two separate days, eight men performed constant-load, single-leg knee extensor exercise to exhaustion (85% of peak power) with each leg (Leg1 and Leg2). On another day, the performance test was repeated with one leg (Leg1) and consecutively (within 10 s) with the other/contralateral leg (Leg2-post). Exercise-induced quadriceps fatigue was assessed by reductions in potentiated quadriceps twitch-force from pre- to postexercise (ΔQtw,pot) in response to supramaximal magnetic femoral nerve stimulation. The output from spinal motoneurons, estimated from quadriceps electromyography (iEMG), was used to reflect changes in CMD. Rating of perceived exertion (RPE) was recorded during exercise. Time to exhaustion (∼9.3 min) and exercise-induced ΔQtw,pot (∼51%) were similar in Leg1 and Leg2 (P > 0.5). In the consecutive leg trial, endurance performance of the first leg was similar to that observed during the initial trial (∼9.3 min; P = 0.8); however, time to exhaustion of the consecutively exercising contralateral leg (Leg2-post) was shorter than the initial Leg2 trial (4.7 ± 0.6 vs. 9.2 ± 0.4 min; P < 0.01). Additionally, ΔQtw,pot following Leg2-post was less than Leg2 (33 ± 3 vs 52 ± 3%; P < 0.01). Although the slope of iEMG was similar during Leg2 and Leg2-post, end-exercise iEMG following Leg2-post was 26% lower compared with Leg2 (P < 0.05). Despite a similar rate of rise, RPE was consistently ∼28% higher throughout Leg2-post vs. Leg2 (P < 0.05). In conclusion, this study provides evidence that peripheral fatigue and associated afferent feedback limits the development of peripheral fatigue and compromises endurance exercise performance by inhibiting CMD. 23333028 Heart failure and anti tumor necrosis factor-alpha in systemic chronic inflammatory diseases. Tumor necrosis factor alpha (TNF-alpha) antagonists have emerged as an effective therapy for patients with diseases as Crohn's disease, rheumatoid arthritis, and other chronic systemic inflammatory diseases. In the last years, there has been a growing interest in the role that inflammatory cytokines, which sustain the pathogenesis of these diseases, plays in regulating cardiac structure and function, particularly in the progression of chronic heart failure. In fact there is an increase of anti-TNF alpha levels in advanced heart failure but the treatment with anti-TNF alpha has been shown to worsen the prognosis of heart failure in randomized controlled trials. Patients with rheumatoid arthritis have an increased risk for cardiovascular disease and anti-TNF alpha therapy seems to be beneficial on the risk of cardiovascular disease. In Crohn's disease the increased risk of cardiovascular disease is controversial and therefore it is impossible to demonstrate an effect in reduction of the risk; however, heart failure in patients treated with anti-TNF alpha, despite in a small proportion, has been observed. On the basis of this observation, anti-TNF alpha therapy is contraindicated in patients with Crohn's disease and III-IV New York Heart Association heart failure class. 23894486 Exploring Early Micronutrient Deficiencies in Rainbow Trout (Oncorhynchus mykiss) by Next-Generation Sequencing Technology - From Black Box to Functional Genomics. This work studies final nutritional status and transcriptional responses of rainbow trout (Oncorhynchus mykiss Walbaum 1792) (28 g) after a 10 week feeding experiment designed to elucidate the effect of adding a vitamin and mineral premix on growth, health, and nutritional endpoints. Juvenile fish were fed a either a diet supplemented with a vitamin and mineral premix (Diet S) or the same diet without premix supplementation (Diet U). The analyzed micronutrient composition of diets differed accordingly. Pooled livers from 15 fish from each dietary group were used to create suppression subtractive hybridization (SSH) cDNA libraries that were sequenced with 454 FLX GS Titanium Technology. In total 552 812 reads were sequenced from the two cDNA libraries. Ingenuity pathway analysis (IPA) was then used to characterize the hepatic transcriptome of the two dietary groups of rainbow trout. In the present communication we discuss how selected micronutrients may affect the transcriptome at suboptimal status by directly impacting the cellular metabolism, functions, and structures, and by introducing respective compensatory mechanisms. Processes related to lipid metabolism, peptide hydrolysis, oxygen transportation, and growth development were mostly affected. Considering the transcriptomics data relative to changes in nutritional status from the feeding study and the background phenotypic outcome of growth performance and gill histopathology, the outcome of the transcriptional profiling are suggested to be mainly related to suboptimal pantothenic acid and vitamin C nutrition. 23778299 Morphological weighted penalized least squares for background correction. Backgrounds existing in the analytical signal always impair the effectiveness of signals and compromise selectivity and sensitivity of analytical methods. In order to perform further qualitative or quantitative analysis, the background should be corrected with a reasonable method. For this purpose, a new automatic method for background correction, which is based on morphological operations and weighted penalized least squares (MPLS), has been developed in this paper. It requires neither prior knowledge about the background nor an iteration procedure or manual selection of a suitable local minimum value. The method has been successfully applied to simulated datasets as well as experimental datasets from different instruments. The results show that the method is quite flexible and could handle different kinds of backgrounds. The proposed MPLS method is implemented and available as an open source package at . 23855268 Caffeine and glucose homeostasis during rest and exercise in diabetes mellitus. Caffeine is a substance that has been used in our society for generations, primarily for its effects on the central nervous system that causes wakefulness. Caffeine supplementation has become increasingly more popular as an ergogenic aid for athletes and considerable scientific evidence supports its effectiveness. Because of their potential to alter energy metabolism, the effects of coffee and caffeine on glucose metabolism in diabetes have also been studied both epidemiologically and experimentally. Predominantly targeting the adenosine receptors, caffeine causes alterations in glucose homeostasis by decreasing glucose uptake into skeletal muscle, thereby causing elevations in blood glucose concentration. Caffeine intake has also been proposed to increase symptomatic warning signs of hypoglycemia in patients with type 1 diabetes and elevate blood glucose levels in patients with type 2 diabetes. Other effects include potential increases in glucose counterregulatory hormones such as epinephrine, which can also decrease peripheral glucose disposal. Despite these established physiological effects, increased coffee intake has been associated with reduced risk of developing type 2 diabetes in large-scale epidemiological studies. This review paper highlights the known effects of caffeine on glucose homeostasis and diabetes metabolism during rest and exercise. 23911624 Uptake and accumulation of four PPCP/EDCs in two leafy vegetables. Many pharmaceutical and personal care products (PPCPs) and endocrine-disrupting chemicals (EDCs) are present in reclaimed water, leading to concerns of human health risks from the consumption of food crops irrigated with reclaimed water. This study evaluated the potential for plant uptake and accumulation of four commonly occurring PPCP/EDCs, i.e., bisphenol A (BPA), diclofenac sodium (DCL), naproxen (NPX), and 4-nonylphenol (NP), by lettuce (Lactuca sativa) and collards (Brassica oleracea) in hydroponic culture, using (14)C-labeled compounds. In both plant species, plant accumulation followed the order of BPA > NP > DCL > NPX and accumulation in roots was much greater than in leaves and stems. Concentrations of (14)C-PPCP/EDCs in plant tissues ranged from 0.22 ± 0.03 to 927 ± 213 ng/g, but nearly all (14)C-residue was non-extractable. PPCP/EDCs, particularly BPA and NP, were also extensively transformed in the nutrient solution. Dietary uptake of these PPCP/EDCs by humans was predicted to be negligible. 23924122 Militant Lactivism? Attachment Parenting and Intensive Motherhood in the UK and FranceMilitant Lactivism? Attachment Parenting and Intensive Motherhood in the UK and France. After a mother in a café in Bristol was asked to stop breastfeeding in public, militant lactivists took to the streets. They view long-term breastfeeding as inherent to their maternal identities and attachment. Some are pictured on the book's cover. 23466546 Preparation of poly(hydroxyethyl methacrylate) cryogels containing L-histidine for insulin recognition. In the present study, affinity adsorption technique was studied for insulin adsorption. Firstly, insulin-imprinted supermacroporous cryogel was prepared for the insulin adsorption. N-methacryloyl-(L)-histidine methyl ester (MAH) was chosen as the monomer. Insulin was complexed with MAH, and insulin-imprinted p(HEMA-MAH) [insulin-(MIP)] cryogel was prepared by free radical polymerization with 2-hydroxyethyl methacrylate (HEMA), N,N,N',N'-tetramethylethylenediamine (TEMED) and ammonium persulfate (APS) in an ice bath. Then, insulin was removed from the cryogel by using 0.1 M glycine-HCl buffer (pH: 3.5). The characterization of the cryogel was carried out by using scanning electron microscopy (SEM) and swelling test. The equilibrium swelling ratios of the cryogels were found to be 8.56±0.42 g H2O/g polymer for p(HEMA) and 7.20±0.36 g H2O/g polymer for insulin-p(HEMA-MAH). Insulin adsorption experiments were performed under different conditions, such as flow rate, medium pH, initial insulin concentration and ionic strength. It was observed that insulin could be repeatedly adsorbed and desorbed with MIP cryogel without any significant decrease in the adsorption capacity. 23912256 The meaning of interior tomography. The classic imaging geometry for computed tomography is for the collection of un-truncated projections and the reconstruction of a global image, with the Fourier transform as the theoretical foundation that is intrinsically non-local. Recently, interior tomography research has led to theoretically exact relationships between localities in the projection and image spaces and practically promising reconstruction algorithms. Initially, interior tomography was developed for x-ray computed tomography. Then, it was elevated to have the status of a general imaging principle. Finally, a novel framework known as 'omni-tomography' is being developed for a grand fusion of multiple imaging modalities, allowing tomographic synchrony of diversified features. 23870182 Bridging the clinical gaps: genetic, epigenetic and transcriptomic biomarkers for the early detection of lung cancer in the post-National Lung Screening Trial era. Lung cancer is the leading cause of cancer death worldwide in part due to our inability to identify which smokers are at highest risk and the lack of effective tools to detect the disease at its earliest and potentially curable stage. Recent results from the National Lung Screening Trial have shown that annual screening of high-risk smokers with low-dose helical computed tomography of the chest can reduce lung cancer mortality. However, molecular biomarkers are needed to identify which current and former smokers would benefit most from annual computed tomography scan screening in order to reduce the costs and morbidity associated with this procedure. Additionally, there is an urgent clinical need to develop biomarkers that can distinguish benign from malignant lesions found on computed tomography of the chest given its very high false positive rate. This review highlights recent genetic, transcriptomic and epigenomic biomarkers that are emerging as tools for the early detection of lung cancer both in the diagnostic and screening setting. 23819818 Live anatomy of the perineal body in patients with 3rd degree rectocele. In many pelvic floor disorders, the perineal body is damaged or destroyed. There is still a considerable variation in anatomical descriptions of the perineal body and even more debate in regards to its attachments and relationships. Cadaveric dissections do not always reflect the functional behaviour of structures in the pelvis and description of live anatomy on imaging studies is not always reliable. The study aimed to define the anatomy of the perineal body in patients with rectocele during live dissection required for minimally invasive surgical repair. From January 2007 to December 2009, consecutive patients requiring surgery for 3(rd) degree rectocele and obstructed defecation symptoms were recruited. Participants underwent dissection of the perineal body, rectum, and vagina preliminary to Tissue Fixation System, an operation which inserts a tensioned tape to repair the perineal body. 30 caucasian patients, mean age 61 (range 47-87) years, mean parity 2.6 (range 1-5), were included. Live dissection demonstrated that the perineal body was divided into two parts, joined by a stretched central part, anchored laterally by the deep transverse perineii muscle to the descending ramus of the pubic bone. The mean longitudinal length of the perineal body was 4.5 (3.5-5.5) cm, accounting for 50% of the posterior vaginal support. In females with low rectocele, the perineal body appears divided into two parts, severely displaced behind the ischial tuberosities. This article is protected by copyright. All rights reserved. 23962581 Association between TLR3 rs3775291 and resistance to HIV among highly exposed Caucasian intravenous drug users. TLR3 recognizes dsRNA and triggers immune responses against RNA and DNA viruses. A polymorphism in TLR3, rs3775291 (Leu412Phe), has been associated with the increased susceptibility to enteroviral myocarditis, protection against tick-borne encephalitis virus and HIV-1 infection. We investigated Caucasian intravenous drug users (IDUs) and blood donors in order to evaluate the associations between TLR3 genotypes and susceptibility to HIV infection. A total of 345 Caucasian IDUs were recruited, 50% of them were HIV positive, 89% HCV and 77% HBV positive. Based on their history of needle sharing, 20 of the HIV negative IDUs were classified as highly exposed HIV seronegatives (HESNs), 68 as non-HESNs and 85 as unexposed. The control group consisting of 497 blood donors tested negative for all three viruses. TLR3 rs3775291 were determined by using TaqMan Allelic Discrimination Assay. The TLR3 rs3775291 T allele frequency was similar among the HIV negative and HIV positive IDUs and blood donors - 36%, 31% and 34%, respectively. The frequency of persons possessing at least one TLR3 rs3775291 T allele was significantly higher in HESNs compared with blood donors and HIV positive IDUs (80% vs. 55%; p=0.037 and 80% vs. 53%; p=0.031, respectively). In the univariate analysis, persons who possessed at least one T allele had reduced odds of being HIV seropositive (OR=0.29, 95% CI=0.09-0.90). This association remained significant (OR=0.25, 95% CI=0.07-0.87) after the adjustment for other co-variates (HCV, HBV serostatus and duration of intravenous drug use). The TLR3 rs3775291 T allele has a protective effect against HIV infection among HESNs IDUs. 23849659 Brief report: Early adolescents' value development at war time. Values are considered relatively stable individual characteristics, and there is little research to date on the conditions that underlie value-priorities change. This small-scale short-term longitudinal study tested whether a major life event of war changes the priority that early adolescents assign to values. Thirty-nine Israeli adolescents completed the Schwartz Values Survey on four occasions-at the beginning, middle, and end of the 2006 Israeli-Lebanese war during which their hometown was bombed. As hypothesized, anxiety-based values of tradition, power, and security increased in importance, while conformity values decreased in importance. Anxiety-free values of benevolence, universalism, self-direction, stimulation, and hedonism decreased in importance. Achievement values decreased and then increased in importance. Despite methodological limitations, the findings demonstrate that value development, at least during early adolescence, can take place rather quickly under circumstances of major traumatic events such as war. 23594175 West Nile virus in Europe: emergence, epidemiology, diagnosis, treatment, and prevention. West Nile virus (WNV), a mosquito-borne flavivirus in the Japanese encephalitis antigenic group, has caused sporadic outbreaks in humans, horses and birds throughout many of the warmer regions of Europe for at least 20 years. Occasional cases of West Nile encephalitis have also been associated with infected blood transfusions and organ donations. Currently, WNV appears to be expanding its geographical range in Europe and causing increasing numbers of epidemics/outbreaks associated with human morbidity and mortality. This brief review reports on the current epidemic situation regarding WNV in Europe, highlighting the clinical, diagnostic and preventive measures available for controlling this apparently emerging human pathogen. 23668684 How does rate of smoking cessation vary by age, gender and social grade? Findings from a population survey in England. To assess the incidence of long-term smoking cessation as a function of age, gender, social grade and their interactions. Cross-sectional surveys of population representative samples of smokers in England. A total of 24 094 ever smokers (≥21 and ≤60 years of age) participating in household surveys between November 2006 and February 2011. The ratio of long-term (>1 year) ex-smokers to ever-smokers was calculated for each age. Regression analyses were used to model the association between age and quit ratio, with the change in quit ratio by year of age n years versus all years up to n-1 years, yielding an estimate of the quitting incidence at that age. Analyses were conducted for the entire sample and then for the sample stratified by gender and social grade, and interactions assessed between these variables. A cubic trend was needed to fit the data. The estimated quitting incidence between ages 21 and 30 was 1.5% (95% CI: 1.0%-2.0%), between 31 and 50 it was 0.3% (95% CI: 0.2%-0.5%) and between 51 and 60 it was 1.2% (95% CI: 0.7%-1.7%). Age interacted with gender and social grade: women and smokers from higher social grades had a higher incidence of quitting than men and those from lower social grades specifically in young adulthood. CONCLUSIONS : The incidence of smoking cessation in England appears to be greater in young and old adults compared with those in middle age. Women and higher social grade smokers show a greater incidence of quitting than men and those from lower social grades specifically in young adulthood. 23782207 Vitamin d measurement in the intensive care unit: methodology, clinical relevance and interpretation of a random value. Vitamin D deficiency, as measured by a random level of 25-hydroxyvitamin D is very prevalent in critically ill patients admitted to the ICU and is associated with adverse outcomes. Both 25(OH)vitamin D and 1α,25(OH)2D3 are difficult to analyse because of their lipophilic nature, affinity for VDBP and small concentrations. Also, the various tests used to estimate vitamin D levels show significant inter- and intra-assay variability, which significantly affect the veracity of the results obtained and confound their interpretation. The two main types of assays include those that directly estimate vitamin D levels (HPLC, LC-MS/MS) and competitive binding assays (RIA, EIA). The former methods require skilled operators, with prolonged assay times and increased cost, whereas the latter are cheaper and easy to perform, but with decreased accuracy. The direct assays are not affected by lipophilic substances in plasma and heterophile antibodies, but may overestimate vitamin D levels by measuring the 3-epimers. These problems can be eliminated by adequate standardization of the test using SRMs provided by NIST, as well as participating in proficiency schemes like DEQAS. It is therefore important to consider the test employed as well as laboratory quality control, while interpreting vitamin D results. A single random measurement may not be reflective of the vitamin D status in ICU patients because of changes with fluid administration, and intra-day variation in 25-hydroxyvitamin D levels. 1α,25(OH)2D3 may behave differently to 25-hydroxyvitamin D, both in plasma and at tissue level, in inflammatory states. Measurement of tissue 1α,25(OH)2D3 levels may provide the true estimate of vitamin D activity. 23952564 A Diastereo- and Enantioselective Three-Component Coupling Approach to Highly Substituted Pyrrolidines. The enantioselective synthesis of substituted pyrrolidines through a mild Lewis-acid catalyzed three-component coupling reaction between picolinaldehyde, amino acids, and activated olefins is reported. The reaction uses low catalyst loadings of commercially available chiral diamines and copper triflate proposed to self-assemble in conjunction with the chelating aldehydes; 4-substituted-2-picolinaldehydes and 4-methylthiazole-2-carboxaldehyde to generate a catalyst complex. A model is provided to explain how this complex directs enantioselectivity. This work represents a significant advance in the ease, scope, and cost of producing highly substituted, enantioenriched pyrrolidines. 23701228 Endockscope: Using Mobile Technology to Create Global Point of Service Endoscopy. Abstract Background and Purpose: Recent advances and the widespread availability of smartphones have ushered in a new wave of innovations in healthcare. We present our initial experience with Endockscope, a new docking system that optimizes the coupling of the iPhone 4S with modern endoscopes. Materials and Methods: Using the United States Air Force resolution target, we compared the image resolution (line pairs/mm) of a flexible cystoscope coupled to the Endockscope+iPhone to the Storz high definition (HD) camera (H3-Z Versatile). We then used the Munsell ColorChecker chart to compare the color resolution with a 0° laparoscope. Furthermore, 12 expert endoscopists blindly compared and evaluated images from a porcine model using a cystoscope and ureteroscope for both systems. Finally, we also compared the cost (average of two company listed prices) and weight (lb) of the two systems. Results: Overall, the image resolution allowed by the Endockscope was identical to the traditional HD camera (4.49 vs 4.49 lp/mm). Red (ΔE=9.26 vs 9.69) demonstrated better color resolution for iPhone, but green (ΔE=7.76 vs 10.95), and blue (ΔE=12.35 vs 14.66) revealed better color resolution with the Storz HD camera. Expert reviews of cystoscopic images acquired with the HD camera were superior in image, color, and overall quality (P=0.002, 0.042, and 0.003). In contrast, the ureteroscopic reviews yielded no statistical difference in image, color, and overall (P=1, 0.203, and 0.120) quality. The overall cost of the Endockscope+iPhone was $154 compared with $46,623 for a standard HD system. The weight of the mobile-coupled system was 0.47 lb and 1.01 lb for the Storz HD camera. Conclusion: Endockscope demonstrated feasibility of coupling endoscopes to a smartphone. The lighter and inexpensive Endockscope acquired images of the same resolution and acceptable color resolution. When evaluated by expert endoscopists, the quality of the images overall were equivalent for flexible ureteroscopy and somewhat inferior, but still acceptable for flexible cystoscopy. 23454202 Curcumin loaded solid lipid nanoparticles: An efficient formulation approach for cerebral ischemic reperfusion injury in rats. SCOPE: To evaluate curcumin loaded solid lipid nanoparticles (C-SLNs) in the experimental paradigm of cerebral ischemia (BCCAO model) in rats. METHODS AND RESULTS: Oral administration of free curcumin and C-SLNs (25 and 50mg/kg) was started 5days prior and continued for 3days after BCCAO. Alleviation in behavioral, oxidative and nitrosative stress, acetylcholinesterase, mitochondrial enzyme complexes, and physiological parameters were assessed. Confirmation of effective brain delivery of C-SLNs (p.o) was done using biodistribution studies in mice and confocal microscopy of rat brain section. There was an improvement of 90% in cognition and 52% inhibition of acetylcholinesterase versus cerebral ischemic group (I/R). Neurological scoring improved by 79%. Levels of superoxide dismutase, catalase, glutathione, and mitochondrial complex enzyme activities were significantly increased, while lipid peroxidation, nitrite, and acetylcholinesterase levels decreased (p<0.05) after C-SLNs administration. It is noteworthy to report the restoration of SOD, GSH, catalase, and mitochondrial complex enzyme levels equivalent to sham control values. Gamma-scintigraphic studies show 16.4 and 30 times improvement in brain bioavailability (AUC) upon oral and i.v administration of C-SLNs versus solubilized curcumin (C-S). CONCLUSIONS: Study indicates protective role of curcumin against cerebral ischemic insult; provided it is packaged suitably for improved brain delivery. 23942757 Evanescent field excited plasmonic nano-antenna for improving SERS signal. The purpose of this work is to develop a high-performance surface-enhanced Raman scattering (SERS) substrate with high light harvesting and SERS emitting efficiencies based on the principle of a plasmonic nano-antenna. A prism/Ag nanowell array was designed and constructed based on the Kretschmann configuration. Almost 100% of the incident light can be absorbed at the resonance angle. A strong electromagnetic (EM) field is generated in the near field along the rim and at the center of the nanowells by means of the localized energy of surface plasmons (SPs), resulting in the electric field being enhanced 300 times at the Ag surface. The co-enhancement of localized SPs and propagating SPs was achieved in this substrate. The plasmonic nano-antenna structure can also redirect the SERS, which benefits the SERS collection. The SERS sensitivity on this configuration was improved by about 40 times compared with that on a conventional Kretschmann configuration with a flat Ag film. This SERS substrate design with full consideration on the tuning of the EM field in the near field and SERS space distribution in the far field could give insight into the design of a new generation of SERS substrates. 23941971 Scanning Electron Microscopy Studies of Neoformations on Stony Materials of Modern Building Works. The built environment is subjected to several pollutants under variable environmental conditions defined by diverse geochemical systems. These geochemical systems promote the occurrence of neoformations that can have a detrimental effect on surfaces of the building materials. Hence, the study of neoformations helps in the understanding of weathering processes that affect built structures. In the present paper we present a scanning electron microscopy study of macroscopic manifestations of neoformations detected during an extensive visual survey of several modern architectural works in urban areas of northern and central Portugal. The studies performed suggest that cementitious materials play an important role as a source of pollutants for the most common neoformations such as carbonate rich stains and coatings, as well as salt efflorescences of alkaline sulphates and carbonates. There are also indications of contributions from organic sources for alkaline nitrates and atmospheric pollution for gypsum-rich black crusts. Other less common neoformations include phosphate aggregates and silica stains that represent interesting indicators of the geochemical systems in built environments. In the case of carbonate-rich coatings, indications of recurrence related to the circulation of carbonate forming solutions relevant to the maintenance of built surfaces were detected. 23339181 Assessment of emerging biomarkers of liver injury in human subjects. Hepatotoxicity remains a major challenge in drug development. Although alanine aminotransferase (ALT) remains the gold standard biomarker of liver injury, alternative biomarker strategies to better predict the potential for severe drug-induced liver injury (DILI) are essential. In this study, we evaluated the utility of glutamate dehydrogenase (GLDH), purine nucleoside phosphorylase (PNP), malate dehydrogenase (MDH), and paraxonase 1 (PON1) as indicators of liver injury in cohorts of human subjects, including healthy subjects across age and gender, subjects with a variety of liver impairments, and several cases of acetaminophen poisoning. In the healthy subjects, levels of GLDH and MDH were not affected by age or gender. Reference ranges for GLDH and MDH in healthy subjects were 1-10 and 79-176U/L, respectively. In contrast, the levels of PON1 and PNP were not consistent across cohorts of healthy subjects. Furthermore, GLDH and MDH had a strong correlation with elevated ALT levels and possessed a high predictive power for liver injury, as determined by ROC analysis. In contrast, PON1 and PNP did not detect liver injury in our study. Finally, evaluation of patients with acetaminophen-induced liver injury provided evidence that both GLDH and MDH might have utility as biomarkers of DILI in humans. This study is the first to evaluate GLDH, MDH, PON1, and PNP in a large number of human subjects and, and it provides an impetus for prospective clinical studies to fully evaluate the diagnostic value of GLDH and MDH for detection of liver injury. 23731203 Mechanisms of lactone hydrolysis in acidic conditions. The acid-catalyzed hydrolysis of linear esters and lactones was studied using a hybrid supermolecule-polarizable continuum model (PCM) approach including up to six water molecules. The compounds studied included two linear esters, four β-lactones, two γ-lactones, and one δ-lactone: ethyl acetate, methyl formate, β-propiolactone, β-butyrolactone, β-isovalerolactone, diketene (4-methyleneoxetan-2-one), γ-butyrolactone, 2(5H)-furanone, and δ-valerolactone. The theoretical results are in good quantitative agreement with the experimental measurements reported in the literature and also in excellent qualitative agreement with long-held views regarding the nature of the hydrolysis mechanisms at molecular level. The present results help to understand the balance between the unimolecular (AAC1) and bimolecular (AAC2) reaction pathways. In contrast to the experimental setting, where one of the two branches is often occluded by the requirement of rather extreme experimental conditions, we have been able to estimate both contributions for all the compounds studied and found that a transition from AAC2 to AAC1 hydrolysis takes place as acidity increases. A parallel work addresses the neutral and base-catalyzed hydrolysis of lactones. 23922997 Expression Analysis of Combinatorial Genes Using a Bi-Cistronic T2A Expression System in Porcine Fibroblasts. In pig-to-primate xenotransplantation, multiple transgenic pigs are required to overcome a series of transplant rejections. The generation of multiple transgenic pigs either by breeding or the introduction of several mono-cistronic vectors has been hampered by the differential expression patterns of the target genes. To achieve simultaneous expression of multiple genes, a poly-cistronic expression system using the 2A peptide derived from the Thosea asigna virus (T2A) can be considered an alternative choice. Before applying T2A expression system to pig generation, the expression patterns of multiple genes in this system should be precisely evaluated. In this study, we constructed several bi-cistronic T2A expression vectors, which combine target genes that are frequently used in the xenotransplantation field, and introduced them into porcine fibroblasts. The proteins targeted to the same or different subcellular regions were efficiently expressed without affecting the localization or expression levels of the other protein. However, when a gene with low expression efficiency was inserted into the upstream region of the T2A sequences, the expression level of the downstream gene was significantly decreased compared with the expression efficiency without the insertion. A small interfering RNA targeting one gene in this system resulted in the significant downregulation of both the target gene and the other gene, indicating that multiple genes combined into a T2A expression vector can be considered as a single gene in terms of transcription and translation. In summary, the efficient expression of a downstream gene can be achieved if the expression of the upstream gene is efficient. 23914476 Play@home in practice: health visitors' views of perceived facilitators and barriers to programme implementation. Health visitors in Scotland gift 'play@home', a book-based early intervention programme, to parents as part of the universal health visiting service. The provision of health improvement information to parents is recognised as a core function of health visiting and yet evidence shows that not every family receives the play@home resources. This paper discusses the perceived facilitators and barriers to implementing this programme through exploring the views of ten health visitors and four health visiting managers in two health board areas in Scotland. The findings conclude that increasingly vulnerable families, supported by fewer qualified health visitors, present challenges to the health visiting service. The play@home programme is valued by health visitors as a flexible tool with which to engage with families. Collaborative working with other services enhances provision and play@home does become embedded in practice over time. Strategic policy links to raise the profile of play@home are improving. 23900662 Lead versus lag-time trade-off variants: does it make any difference? The traditional time trade-off (TTO) method has some problems in the valuation of health states considered worse than dead. The aim of our study is to compare two TTO variants that address this issue: lead-time and lag-time TTO. Quota sampling was undertaken in June 2011 in Buenos Aires as part of the EQ-5D-5L Multinational Pilot Study. Respondents were randomly assigned to one of the TTO variants with two blocks of five EQ-5D-5L health states. Tasks were administered using a web-based digital aid (EQ-VT) administered in a group interview. A total of 387 participants were included [mean age 38.85 (SD: 13.97); 53.14 % females]. The mean observed values ranged from 0.44 (0.59) for state 21111 to 0.02 (0.76) for state 53555 in the lead-time group and between 0.53 (0.52) and 0.08 (0.76) in the lag-time group. There were no statistically significant differences in the values between TTO variants, except for a significant difference of 0.19 for state 33133. In both variants, marked peaks were observed around the value 0 across all states, with a higher percentage of 0 responses in the last state valued, suggesting ordering effects. No important differences were found between TTO variants regarding values for EQ-5D-5L health states, suggesting that they could be equivalent variants. However, differences between the two methods may have been obscured by other aspects of the study design affecting the characteristics of the data. 23963779 Diazepam treatment blocks the elevation of hippocampal activity and the accelerated proliferation of hippocampal neural stem cells after focal cerebral ischemia in mice. Hippocampal neurogenesis is accelerated during the elevation of hippocampal neural activities under both physiological and pathophysiological conditions. One of these conditions, middle cerebral artery occlusion (MCAO), induces both the hyperactivities of hippocampal network and the elevation of neural stem cell (NSC) proliferation. However, the causal relationship between the elevated activity and the elevation of NSC proliferation is still unclear. In this study, to block the elevation of hippocampal activity after MCAO in mice, we utilized a typical γ-aminobutyric acid type A (GABAA ) receptor active modulator, diazepam. With MCAO mice treated with diazepam, we observed complete disappearance of the elevation of hippocampal activity. Additionally, the diazepam treatment blocked the elevation of NSC proliferation after MCAO. From this result, it is speculated that the increased NSC proliferation is blocked by the suppression of elevated neural activity. However, diazepam might have effects other than the suppression of hippocampal activity, so we performed additional experiment and found that diazepam did not affect the number of bromodeoxyuridine-positive cells under the normal condition, whereas the GABA agonist pentobarbital stimulated NSC/neural progenitor cell proliferation and differentiation. Next, we evaluated the expression of the diazepam-binding inhibitor (DBI) protein and found that the cells expressed DBI in soma and on the surface of cell membrane. From these observations, we can propose that diazepam blocks the elevation of hippocampal activity and also NSC proliferation after MCAO. © 2013 Wiley Periodicals, Inc. 23620371 A systematic capillary electrophoresis study on the effect of the buffer composition on the reactivity of the anticancer drug cisplatin to the DNA model 2'-deoxyguanosine 5'-monophosphate (dGMP). The development of DNA-targeted next-generation platinum-based anticancer chemotherapeutics is often accompanied by studies on the reactivity to DNA models. However, the incubation conditions used in literature vary widely, and some of the buffer/salts used are known to form complexes with Pt. Such coordination can influence the binding process and also the adducts formed. In a systematic approach, studies on the binding of cisplatin (1 mM) to dGMP (2 mM) in a series of different incubation solutions of relevance to biological systems are reported, employing capillary zone electrophoresis (CZE) with UV/vis and electrospray ionization-mass spectrometric (ESI-MS) detectors. Kinetic experiments performed with CZE-UV showed a high reactivity of dGMP to cisplatin in pure water (Ï„ 1/2 = 4.1 ±â€‰0.7 h) but a significantly slowed down in a solution containing a carbonate/phosphate buffer supplemented with NaCl, resulting in a half-life of dGMP of 25 ±â€‰3 h. Especially carbonate had a major impact on the binding, though no coordination to the metal center was detectable with the methods used. The only adducts containing buffer components were (phosphate)Pt and tris(ammine)Pt species, as identified by means of CZE-ESI-MS, in addition to the main adduct [Pt(NH3)2(dGMP)2 - 4H(+)](2-) and other less abundant Pt-containing species. 23751317 In vivo anti-radiation activities of the Ulva pertusa polysaccharides and polysaccharide-iron(III) complex. Polysaccharides with different molecular weights were extracted from Ulva pertusa and fractionated by ultrafiltration. Iron(III) complex of the low molecular-weight U. pertusa polysaccharides were synthesized. Atomic absorption spectrum showed that the iron content of iron(III)-polysaccharide complex was 27.4%. The comparison between U. pertusa polysaccharides and their iron(III) complex showed that iron chelating altered the structural characteristics of the polysaccharides. The bioactivity analysis showed that polysaccharide with low molecular weight was more effective than polysaccharide with high molecular weight in protecting mice from radiation induced damages on bone marrow cells and immune system. Results also proved that the anti-radiation and anti-oxidative activity of iron(III) complex of low molecular-weight polysaccharides were not less than that of low molecular-weight polysaccharides. 23902008 Adsorption of hydrogen on the surface and sub-surface of Cu(111). The interaction of atomic hydrogen with the Cu(111) surface was studied by a combined experimental-theoretical approach, using infrared reflection absorption spectroscopy, temperature programmed desorption, and density functional theory (DFT). Adsorption of atomic hydrogen at 160 K is characterized by an anti-absorption mode at 754 cm(-1) and a broadband absorption in the IRRA spectra, related to adsorption of hydrogen on three-fold hollow surface sites and sub-surface sites, and the appearance of a sharp vibrational band at 1151 cm(-1) at high coverage, which is also associated with hydrogen adsorption on the surface. Annealing the hydrogen covered surface up to 200 K results in the disappearance of this vibrational band. Thermal desorption is characterized by a single feature at ∼295 K, with the leading edge at ∼250 K. The disappearance of the sharp Cu-H vibrational band suggests that with increasing temperature the surface hydrogen migrates to sub-surface sites prior to desorption from the surface. The presence of sub-surface hydrogen after annealing to 200 K is further demonstrated by using CO as a surface probe. Changes in the Cu-H vibration intensity are observed when cooling the adsorbed hydrogen at 180 K to 110 K, implying the migration of hydrogen. DFT calculations show that the most stable position for hydrogen adsorption on Cu(111) is on hollow surface sites, but that hydrogen can be trapped in the second sub-surface layer. 23603479 Cognitive effects of variations in pubertal timing: Is puberty a period of brain organization for human sex-typed cognition? There is considerable interest in the organizational effects of pubertal sex hormones on human sex-related characteristics. Recent evidence from rodents suggests that there is a decreasing window of sensitivity to sex hormones throughout adolescence. If adolescence also represents a period of brain organization in human beings, then the timing of exposure to sex-typical hormones at puberty should have long-term effects on sex-typed characteristics: individuals with early timing should be more sex-typed than individuals with late timing. We tested this hypothesis in 320 young adults by relating their pubertal timing (retrospective comparison to peers) to cognitive abilities that show sex differences. Results provide partial support for the hypothesis. For men, pubertal timing was inversely related to scores on a test of three-dimensional mental rotations. Effects do not appear to be due to duration of hormone exposure (time since puberty), but other potential influences need further study. 23764024 A Zn-doped etch-and-rinse adhesive may improve the mechanical properties and the integrity at the bonded-dentin interface. The objective of the study was to determine if zinc-doped etch-and-rinse dentin adhesive may induce therapeutic effects within the resin-dentin interface. Human acid-etched dentin was infiltrated with Adper™ Single Bond Plus (SB, 3M ESPE, St. Paul, MN, USA), SB doped with 10wt.% ZnO nanoparticles (ZnO-SB) or SB doped with 2wt.% ZnCl2 (ZnCl2-SB). AFM/nanoindentation analysis was performed on fully hydrated specimens to evaluate the nanomechanical properties (Hi: hardness; Ei: modulus of elasticity) across the resin-dentin interface after different SBF storage periods (24h, 1m, 3m). Confocal laser microscopy (CLSM) was used to evaluate the ultramorphology and micropermeability at 24h and 3m of SBF storage. SB control specimens exhibited a decrease in Hi in the hybrid layer (HL) and bottom of the hybrid layer (BHL) and a decrease in Ei in the HL after 3m of SBF storage, indicating that severe degradation occurred in the control interface. ZnO-SB bonded specimens preserved the initial Hi and Ei at the HL and BHL subsequent SBF storage; ZnCl2-SB bonded specimens showed a decrease in Ei, in the HL over time. CLSM analysis confirmed that both Zn-doped adhesives were able to preserve the integrity of the HL. Specific formulation of Zn-doped etch-and-rinse adhesives may offer the possibility to maintain the nano-mechanical properties along the dentin-bonded interface by inhibiting dentin MMPs and by protective mineral crystals formation within the resin-dentin interface. Clinical advantages may be expected by preserving and improving the integrity of the hybrid layer when Zn-doped adhesives are employed. 23830435 Investigations into the feasibility of routine ultra high performance liquid chromatography-tandem mass spectrometry analysis of equine hair samples for detecting the misuse of anabolic steroids, anabolic steroid esters and related compounds. The detection of the abuse of anabolic steroids in equine sport is complicated by the endogenous nature of some of the abused steroids, such as testosterone and nandrolone. These steroids are commonly administered as intramuscular injections of esterified forms of the steroid, which prolongs their effects and improves bioavailability over oral dosing. The successful detection of an intact anabolic steroid ester therefore provides unequivocal proof of an illegal administration, as esterified forms are not found endogenously. Detection of intact anabolic steroid esters is possible in plasma samples but not, to date, in the traditional doping control matrix of urine. The analysis of equine mane hair for the detection of anabolic steroid esters has the potential to greatly extend the time period over which detection of abuse can be monitored. Equine mane hair samples were incubated in 0.1M phosphate buffer (pH 9.5) before anabolic steroids (testosterone, nandrolone, boldenone, trenbolone and stanozolol), anabolic steroid esters (esters of testosterone, nandrolone, boldenone and trenbolone) and associated compounds (fluticasone propionate and esters of hydroxyprogesterone) were extracted by liquid-liquid extraction with a mix of hexane and ethyl acetate (7:3, v:v). Further sample clean up by solid phase extraction was followed by derivatisation with methoxylamine HCL and analysis by UHPLC-MS/MS. Initial method development was performed on a representative suite of four testosterone esters (propionate, phenylpropionate, isocaproate and decanoate) and the method was later extended to include a further 18 compounds. The applicability of the method was demonstrated by the analysis of mane hair samples collected following the intramuscular administration of 500 mg of Durateston(®) (mixed testosterone esters) to a Thoroughbred mare (560 kg). The method was subsequently used to successfully detect boldenone undecylenate and stanozolol in hair samples collected following suspicious screening findings from post-race urine samples. The use of segmental analysis to potentially provide additional information on the timing of administration was also investigated. 23921674 Self-Determination Theory and Romantic Relationship Processes. Self-determination theory can be viewed as a theory of optimal relationship development and functioning. We examine the concept of self that is employed in self-determination theory and explain how its unique definition allows an important and novel characterization of investing one's "self" in romantic relationships. A self-determined perspective on romantic relationships integrates several theories on romantic relationship development, but also goes beyond them by explicitly articulating the personality, developmental, and situational factors that facilitate optimal self-investment and relational functioning. Self-determination promotes openness rather than defensiveness and facilitates perspective-taking, authenticity, and support of close others. The dyadic context of romantic relationships affords great opportunity for theoretical development and integration of self-determination theory with current theories of interdependence and relational well-being. 23872184 Spatiotemporal distribution of (137)Cs in the sea surrounding Japanese Islands in the decades before the disaster at the Fukushima Daiichi Nuclear Power Plant in 2011. The historic spatiotemporal distribution of (137)Cs in the seawaters and sea-floor sediments adjacent to nuclear power plants in Japan are summarized, using data obtained over a period of time more than 20years prior to the disaster at the Fukushima Daiichi Nuclear Power Plant in 2011. Relatively uniform distributions of (137)Cs were observed both in the surface seawaters (1m in depth) and in deeper seawaters (10 to 30m above the seabed and ranging from tens to hundreds of meters in depth) independent of the geographical position, although lower concentrations were observed in significantly deeper bottom seawaters. Conversely, there were wide variations in (137)Cs levels between sediments, such that higher (137)Cs concentrations were observed in the deeper sampling locations. A mathematical model describing the successive transfer of (137)Cs from surface waters through deeper waters to sediments suggested that the transfer rate of (137)Cs from deep water to the sediments, and the loss rate from bottom sediments, were both greater than the transfer rate from surface water to deeper water. It was found that the calculated regression lines for (137)Cs depletion rates over time for surface waters, deeper waters, and sediments were approximately parallel when plotted on a semi-logarithmic coordinate system, regardless of the sampling location. A radionuclide depletion half-life was calculated to be 4months to 16years with the geometric mean of 2.22y for the sediments in the Fukushima region, suggesting that nuclear contamination will be remediated over time through sediment redistribution processes such as remobilization, bioturbation, and migration due to sea currents. 23880161 Evaluation of genital self-sampling methods for HPV detection in males. There are no population-based HPV prevalence estimates in males because optimal sampling methods are unclear. To evaluate the acceptability, feasibility, and validity of different male genital self-sampling methods for HPV detection. A total of 450 males, 14-59 years old, were randomly assigned to one of three genital sampling methods: (1) dry polyester-tipped swab; (2) dry foam swab; and (3) emery paper and wetted polyester-tipped swab. Samples were both self-collected and collected by a clinician. Subjects were queried on the acceptability of sampling methods. HPV was genotyped using an L1 consensus PCR assay. Specimen adequacy (92-96%, p=0.28) and HPV detection (44-49%, p=0.68) were comparable across the three methods. Concordance for HPV detection was observed between self- and clinician-collected specimen pairs for all methods (κ=0.70-0.80). The collection procedure was reported to be very easy by 69% of dry polyester-tipped swab users and 64% of dry foam swab users compared to 48% of emery-wet swab users (p=0.004). Similarly, 43-44% of dry swab and foam users reported the collection to be very comfortable compared to 24% of emery-wet swab users (p=0.002). Pain was reported by 10% of emery-wet swab users compared to 3% and 5% of dry swab and foam users, respectively (p=0.03). Self-collection by the emery-wet swab method required an average of 6min compared to 3.3-3.5min for the two dry methods (p<0.0001). The dry collection methods are optimal for use in large epidemiologic studies or surveillance efforts based on their acceptability and feasibility. 23370970 Coinfection in acute gastroenteritis predicts a more severe clinical course in children. The objectives of this study were to determine the incidence of enteric pathogens causing acute gastroenteritis (AGE) among hospitalized children in a large Italian hospital, to measure the incidence of coinfections, and to compare the clinical characteristics of those infected with one versus multiple agents. A prospective study was conducted from March 2010 to April 2011 at the Bambino Gesù Pediatric Hospital in Rome, Italy. All patients between 1 month and 16 years of age admitted to the Pediatric Department with a diagnosis of AGE were eligible for enrollment. Two stool samples for each patient were tested for gastrointestinal pathogens. We summarized the clinical severity of episodes, describing the duration of diarrhea, duration and frequency of vomiting, fever, and severity of dehydration. All the patients underwent medical evaluation with estimation of dehydration. One or more etiological agents were detected in 151 out of 232 patients (65.1%), while we did not detect any etiological agent in 81 (34.9%). Rotavirus was detected in 96 (63.6%), adenovirus in 17 (11.2%), norovirus in 7 (4.6%), toxin-producing Clostridium difficile in 23 (15.2%), Salmonella spp. in 15 (9.9%, B group in 12/15 and D group in 3/15), C. perfringens in 12 (7.9%), Campylobacter spp. in 6 (4%), and verotoxigenic Escherichia coli (VTEC) in 2 (1.3%). In 27 children out of 151 (17.9%), we found evidence of coinfection. Coinfection with rotavirus and toxin-producing C. difficile was the most common (63%). Children with coinfection had a more severe clinical presentation and had a higher probability to be severely dehydrated, independently of age and living community type. 23206862 Identification of a novel benzimidazole derivative as a highly potent NPY Y5 receptor antagonist with an anti-obesity profile. Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study. Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain. 23891684 Bayesian area-age-period-cohort model with carcinogenesis age effects in estimating cancer mortality. Objective: Area-age-period-cohort (AAPC) model has been widely used in studying the spatial and temporal pattern of disease incidence and mortality rates. However, lack of biological plausibility and ease of interpretability on temporal components especially for age effects are generally the weakness of AAPC models. We develop a Bayesian AAPC model where carcinogenesis age effect is incorporated to explain age effects from the underlying disease process. An autoregressive prior structure and an arbitrary linear constraint are used to solve the nonidentifiability issues. Methods: Two multistage carcinogenesis models are employed to derive the hazard functions to substitute the age effects in the AAPC models. The Iowa county-wide lung cancer mortality data are used for the model fitting and Deviance Information Criteria (DIC) is used for model comparison. Results: Our study shows that conventional AAPC model (DIC=19,231.30), AAPC model with Armitage-Doll age effect (DIC=19,233.00) and with two-stage clonal expansion (TSCE) age effect (DIC=19,234.70) achieved the similar DIC values which indicated consistent model fitting among three models. The spatial pattern shows that the high spatial effects are clustered in the south of Iowa and also in largely populated areas. The lung cancer mortality rate is continuously declining by birth cohorts while increasing by the calendar period until 2000-2004. The age effects show an increasing pattern over time which can be easily explained by Armitage-Doll carcinogenesis model since we assume a log-linear relationship between age and hazard function. Conclusions: Our finding suggests that the proposed Bayesian AAPC model can be used to replace the conventional AAPC model without affecting model performance while providing a more biological sound approach from the underlining disease process. 23368987 Characterization of phenolic compounds, carotenoids, vitamins and antioxidant activities of selected Malaysian wild edible plants. This study was carried out to characterize phenolic compounds, carotenoids, vitamins and the antioxidant activity of selected wild edible plants. Plant extracts were purified, and phenolic compounds comprising 11 phenolic acids (hydroxybenzoic acid and hydrocinnamic acid) and 33 flavonoids (including catechin, glycosides and aglycones) were analysed using High Performance Liquid Chromatography - Diode Array Detector (HPLC-DAD). Furthermore, the contents of ascorbic acid and tocopherol ((α and γ tocopherol) and carotenoids (lutein and β-carotene) were also determined. The major phenolics identified consisted of glycosides of flavones (apigenin and luteolin) and flavonols (kaempferol and quercetin). Among the phenolic acids identified after hydrolysis, coumaric acid was the predominant phenolic acid in all the extracts of wild plants. Ascorbic acid [53.8 mg/100 g fresh weight (FW)] and β-carotene (656.5 mg/100 g FW) showed the highest content in the leaf of Heckeria umbellatum. In conclusion, the leaves of H. umbellatum, Aniseia martinicensis and Gonostegia hirta have excellent potential in the future to emerge as functional ingredients. 23807798 Delocalized and localized states of eg electrons in half-doped manganites. We have studied the magnetic behaviour of half-doped manganite Y0.5Ca0.5MnO3 in an extended range of temperatures by means of magnetic susceptibility, χ(T), and electron spin resonance (ESR) experiments. At high temperature the system crystallizes in an orthorhombic structure. The resistivity value, ρ ≃ 0.05 Ω cm at 500 K, indicates a metallic behaviour, while the Curie-Weiss dependence of χ(T) and the thermal evolution of the ESR parameters are very well described by a model that considers a system conformed by localized Mn(4+) cores, [Formula: see text], and itinerant, eg, electrons. The strong coupling between t2g and eg electrons results in an enhanced Curie constant and an FM Curie-Weiss temperature that overcomes the AFM interactions between the [Formula: see text] cores. A transition to a more distorted phase is observed at T ≈ 500 K and signatures of localization of the eg electrons appear in the χ(T) behaviour below 300 K. A new Curie-Weiss regime is observed, where the Curie-constant value is consistent with dimer formation. Based on mean-field calculations, the dimer formation is predicted as a function of the interaction strength between the t2g and eg electrons. 23719366 Spondyloarthritis in China. Although scientists in China have generated a considerable amount of new information about spondyloarthritis (SpA) in recent years, part of it was published in Chinese. The aim of this review is to summarize all SpA articles for the benefit of English readers. In the field of epidemiology, prevalence of SpA in China has been updated, especially with regard to psoriatic arthritis (PsA). In the field of genetics, Chinese scientists have discovered new single-nucleotide polymorphism (SNP) sites association with ankylosing spondylitis (AS) in Han Chinese. In the field of treatment, tumour necrosis factor-alpha (TNF-α) antagonists are wildly used almost as a routine. The usefulness of certain Chinese traditional medicine is undergoing vigorous testing. In the field of diagnosis, ultrasound has been incorporated into the testing tools. In the field of monitoring of disease activity, Ankylosing Spondylitis Disease Activity Scores (ASDAS) has been validated in a cohort of Chinese SpA patients. Chinese scientists are using cutting-edge technology in the fields of research, diagnosis and management in SpA. What is needed are new approaches that can accommodate the large variations in socioeconomic status of various localities in the vast Chinese continent. 23517069 Therapeutic Agents Triggering Nonapoptotic Cancer Cell Death. It is widely recognized that the evasion of apoptotic cell death is one of the hallmarks of cancer. For many years cytotoxic agents have been developed to target apoptotic cell death as a main method of treating cancer. However, the occurrence of cellular defects involving the apoptotic machinery in many cancers has resulted in an acquired resistance to apoptotic cell death, undermining the effectiveness of chemotherapeutic agents. Over the past decade, research has revealed a growing number of cell death pathways that are not dependent on apoptosis. In addition, compounds specifically triggering these alternative cell death pathways have been identified and explored as novel cancer treatment options. These novel anticancer agents are critically discussed by the authors, and therefore, the current Perspective represents a resource for a practicing medicinal chemist looking for new opportunities to combat cancers resistant to the established proapoptotic therapeutic agents. 23685254 Rab3Gap1 mediates exocytosis of Claudin-1 and tight junction formation during epidermal barrier acquisition. Epidermal barrier acquisition during late murine gestation is accompanied by an increase in Akt kinase activity and cJun dephosphorlyation. The latter is directed by the Ppp2r2a regulatory subunit of the Pp2a phosphatase. This was accompanied by a change of Claudin-1 localisation to the cell surface and interaction between Occludin and Claudin-1 which are thought to be required for tight junction formation. The aim of this study was to determine the nature of the barrier defect caused by the loss of AKT/Ppp2r2a function. There was a paracellular barrier defect in rat epidermal keratinocytes expressing a Ppp2r2a siRNA. In Ppp2r2a knockdown cells, Claudin-1 was located to the cytoplasm and its expression was increased. Inhibiting cJun phosphorylation restored barrier function and plasma membrane localisation of Claudin-1. Expression of the Rab3 GTPase activating protein, Rab3Gap1, was restored in Ppp2r2a siRNA cells when cJun phosphorylation was inhibited. During normal mouse epidermal development, Claudin-1 plasma membrane localisation and Rab3Gap1 cell surface expression were co-incident with Akt activation in mouse epidermis, strongly suggesting a role of Rab3Gap1 in epidermal barrier acquisition. Supporting this hypothesis, siRNA knockdown of Rab3Gap1 prevented plasma membrane Claudin-1 expression and the formation of a barrier competent epithelium. Replacing Rab3Gap1 in Ppp2r2a knockdown cells was sufficient to rescue Claudin-1 transport to the cell surface. Therefore these data suggest Rab3Gap1 mediated exocytosis of Claudin-1 is an important component of epidermal barrier acquisition during epidermal development. 23855750 Assessing Racial/Ethnic Disparities in Treatment across Episodes of Mental Health Care. To investigate disparities in mental health care episodes, aligning our analyses with decisions to start or drop treatment, and choices made during treatment. We analyzed whites, blacks, and Latinos with probable mental illness from Panels 9-13 of the Medical Expenditure Panel Survey, assessing disparities at the beginning, middle, and end of episodes of care (initiation, adequate care, having an episode with only psychotropic drug fills, intensity of care, the mixture of primary care provider (PCP) and specialist visits, use of acute psychiatric care, and termination). Compared with whites, blacks and Latinos had less initiation and adequacy of care. Black and Latino episodes were shorter and had fewer psychotropic drug fills. Black episodes had a greater proportion of specialist visits and Latino episodes had a greater proportion of PCP visits. Blacks were more likely to have an episode with acute psychiatric care. Disparities in adequate care were driven by initiation disparities, reinforcing the need for policies that improve access. Many episodes were characterized only by psychotropic drug fills, suggesting inadequate medication guidance. Blacks' higher rate of specialist use contradicts previous studies and deserves future investigation. Blacks' greater acute mental health care use raises concerns over monitoring of their treatment. 23892418 Surface Structure Dependent Electrocatalytic Activity of Co3O4 Anchored on Graphene Sheets toward Oxygen Reduction Reaction. Catalytic activity is primarily a surface phenomenon, however, little is known about Co3O4 nanocrystals in terms of the relationship between the oxygen reduction reaction (ORR) catalytic activity and surface structure, especially when dispersed on a highly conducting support to improve the electrical conductivity and so to enhance the catalytic activity. Herein, we report a controllable synthesis of Co3O4 nanorods (NR), nanocubes (NC) and nano-octahedrons (OC) with the different exposed nanocrystalline surfaces ({110}, {100}, and {111}), uniformly anchored on graphene sheets, which has allowed us to investigate the effects of the surface structure on the ORR activity. Results show that the catalytically active sites for ORR should be the surface Co(2+) ions, whereas the surface Co(3+) ions catalyze CO oxidation, and the catalytic ability is closely related to the density of the catalytically active sites. These results underscore the importance of morphological control in the design of highly efficient ORR catalysts. 23834827 Control of total GFP expression by alterations to the 3' region nucleotide sequence. Previously, we distinguished the Escherichia coli type II cytoplasmic membrane translocation pathways of Tat, Yid, and Sec for unfolded and folded soluble target proteins. The translocation of folded protein to the periplasm for soluble expression via the Tat pathway was controlled by an N-terminal hydrophilic leader sequence. In this study, we investigated the effect of the hydrophilic C-terminal end and its nucleotide sequence on total and soluble protein expression. The native hydrophilic C-terminal end of GFP was obtained by deleting the C-terminal peptide LeuGlu-6×His, derived from pET22b(+). The corresponding clones induced total and soluble GFP expression that was either slightly increased or dramatically reduced, apparently through reconstruction of the nucleotide sequence around the stop codon in the 3' region. In the expression-induced clones, the hydrophilic C-terminus showed increased Tat pathway specificity for soluble expression. However, in the expression-reduced clone, after analyzing the role of the 5' poly(A) coding sequence with a substituted synonymous codon, we proved that the longer 5' poly(A) coding sequence interacted with the reconstructed 3' region nucleotide sequence to create a new mRNA tertiary structure between the 5' and 3' regions, which resulted in reduced total GFP expression. Further, to recover the reduced expression by changing the 3' nucleotide sequence, after replacing selected C-terminal 5' codons and the stop codon in the ORF with synonymous codons, total GFP expression in most of the clones was recovered to the undeleted control level. The insertion of trinucleotides after the stop codon in the 3'-UTR recovered or reduced total GFP expression. RT-PCR revealed that the level of total protein expression was controlled by changes in translational or transcriptional regulation, which were induced or reduced by the substitution or insertion of 3' region nucleotides. We found that the hydrophilic C-terminal end of GFP increased Tat pathway specificity and that the 3' nucleotide sequence played an important role in total protein expression through translational and transcriptional regulation. These findings may be useful for efficiently producing recombinant proteins as well as for potentially controlling the expression level of specific genes in the body for therapeutic purposes. 23294348 Fragment-based discovery of new highly substituted 1H-pyrrolo[2,3-b]- and 3H-imidazolo[4,5-b]-pyridines as focal adhesion kinase inhibitors. Focal adhesion kinase (FAK) is considered as an attractive target for oncology, and small-molecule inhibitors are reported to be in clinical testing. In a surface plasmon resonance (SPR)-mediated fragment screening campaign, we discovered bicyclic scaffolds like 1H-pyrazolo[3,4-d]pyrimidines binding to the hinge region of FAK. By an accelerated knowledge-based fragment growing approach, essential pharmacophores were added. The establishment of highly substituted unprecedented 1H-pyrrolo[2,3-b]pyridine derivatizations provided compounds with submicromolar cellular FAK inhibition potential. The combination of substituents on the bicyclic templates and the nature of the core structure itself have a significant impact on the compounds FAK selectivity. Structural analysis revealed that the appropriately substituted pyrrolo[2,3-b]pyridine induced a rare helical DFG-loop conformation. The discovered synthetic route to introduce three different substituents independently paves the way for versatile applications of the 7-azaindole core. 23069375 Rosiglitazone disrupts endosteal bone formation during distraction osteogenesis by local adipocytic infiltration. Rosiglitazone (Rosi) is a drug in the thiazolidinedione class for treatment of type 2 diabetes mellitus (T2DM), which binds and activates PPARγ nuclear receptor in fat cells, sensitizing them to insulin. Despite proven antidiabetic efficacy, Rosi therapy may be associated with trabecular bone loss and an increased risk of fractures. To examine the potential side effects of Rosi treatment on bone formation, we delivered Rosi to mice using a combined model of distraction osteogenesis (DO) and type 2 diabetes mellitus (T2DM). DO provides a unique method to isolate the sequence of intramembranous bone formation, an important component of both fracture healing and bone homeostasis. Four groups of n=6 mice were used to compare the effects of Rosi on bone formation and cellular composition in both diabetic (Avy/a strain) and non-diabetic mice (a/a strain). New bone formation was examined by high resolution radiographs, micro-computed tomography, and histology. Precursor cells in the distraction gap were quantitated using immunohistochemical stains for proliferating cell nuclear antigen. Committed osteoblasts and adipocytes in the gap were identified and quantitated by immunostaining for osteocalcin and FABP4/aP2, respectively. The diabetic model developed obesity, hyperglycemia, hyperinsulinemia and insulin resistance, while the control littermates remained lean, normoglycemic and insulin sensitive. Rosi treatment decreased levels of non-fasted glucose and insulin and improved insulin sensitivity in the A(vy)/a mice, but had no effect in a/a mice, indicating antidiabetic efficacy of Rosi at the tested dose. Despite the diabetic, obese mice having twice the number of fat cells in their marrow than the non-diabetic mice, bone formation using DO was not adversely affected by the diabetes itself. However, Rosi treatment significantly diminished intramembranous endosteal bone formation, while increasing adipogenesis in and adjacent to the distraction gap up to 3.5- to 3.8-fold in both diabetic and non-diabetic models. This effect was independent of the anti-diabetic therapeutic response. These results raise the question of whether osteoblast precursors are inhibited in their development or actually converted to adipocytic phenotypes, possibly via marrow fat PPARγ nuclear receptor. 23703295 Nutrition and reproduction: links to epigenetics and metabolic syndrome in offspring. Inappropriate exposure of gametes and/or products of conception to nutritional imbalance alters critical metabolic set points in the offspring and increases propensity to disease. This review will focus on recent findings highlighting clear links to epigenetic modifications in response to dietary manipulations as well as nutritional strategies with the potential to mitigate the effects of an otherwise poor nutritional environment. Maternal nutritional imbalance, either through global nutritional manipulation or deficiencies in select nutrients, predisposes the offspring to metabolic disease. Disease susceptibility is linked to global and/or specific modifications of the epigenome at key metabolic regulatory genes. Paternal nutritional imbalance also increases the likelihood of metabolic disease in offspring through similar epigenetic mechanisms. Finally, dietary intervention with select nutrients has been shown to ameliorate postnatal disease phenotypes in offspring, although the exact molecular mechanisms have not been elucidated. Select nutrients, such as amino acids and vitamins, not only serve as building blocks for growth but also mediate a myriad of physiological functions, including providing substrates for DNA synthesis. These nutrients hold great promise as intervention strategies to combat a suboptimal developmental environment. 23763609 Autonomy versus automation: perceptions of nonmydriatic camera choice for teleretinal screening in an urban safety net clinic. Abstract Objective: Teleretinal screening with nonmydriatic cameras has been presented as a means of increasing the number of patients assessed for diabetic retinopathy in urban safety net clinics. It has been hypothesized that automated nonmydriatic cameras may improve screening rates by reducing the learning curve for camera use. In this article, we examine the impact of introducing automated nonmydriatic cameras to urban safety net clinics whose photographers had previously used manual cameras. Materials and Methods: We evaluated the impact of manual and automated digital nonmydriatic cameras on teleretinal screening using a quantitative analysis of readers' image quality ratings as well as a qualitative analysis, through in-depth interviews, of photographers' experiences. Results: With the manual camera, 68% of images were rated "adequate" or better, including 24% rated "good" and 20% rated "excellent." With the automated camera, 61% were rated "adequate" or better, including 9% rated "good" and 0% rated "excellent." Photographers expressed frustration with their inability to control image-taking settings with the automated camera, which led to unexpected delays. Conclusions: For safety net clinics in which medical assistants are already trained to take photographs for diabetic retinopathy screening with a manual camera, the introduction of automated cameras may lead to frustration and paradoxically contribute to increased patient wait times. When photographers have achieved a high degree of aptitude with manual cameras and value the control they have over camera features, the introduction of automated cameras should be approached with caution and may require extensive training to increase user acceptability. 23892244 Enterotoxigenic Escherichia coli: Orchestrated host engagement. The enterotoxigenic Escherichia coli are a pervasive cause of serious diarrheal illness in developing countries. Presently, there is no vaccine to prevent these infections, and many features of the basic pathogenesis of these organisms remain poorly understood. Until very recently most pathogenesis studies had focused almost exclusively on a small subset of known "classical" virulence genes, namely fimbrial colonization factors and the heat-labile (LT) and heat stable (ST) enterotoxins. However, recent investigations of pathogen-host interactions reveal a surprisingly complex and intricately orchestrated engagement involving the interplay of classical, and "novel" virulence genes, as well as participation of genes highly conserved in the E. coli species. These studies may inform further rational approaches to vaccine development for these important pathogens. 23896715 Interobserver agreement in the reporting of cervical biopsy specimens obtained from women screened by visual inspection with acetic Acid and hybrid capture 2. Visual inspection with acetic acid (VIA) and human papillomavirus detection have sensitivity higher than cytology but lower specificity. The high false-positive rate of either test poses a challenge to the colposcopists who obtain biopsies from the innocuous changes and to the pathologists who have to interpret large numbers of specimens that are either normal or have low-grade abnormalities. Interobserver variation in histopathologic interpretations of cervical punch biopsy specimens is high, specially for the lower-grade abnormalities. Use of the modified Bethesda system to report histology in place of the cervical intraepithelial neoplasia (CIN) system has the potential to reduce such variability as there are fewer categories. The present study aimed to assess the interobserver agreement to interpret cervical punch biopsies when both pathologists followed the modified Bethesda classification system and also when one pathologist followed the modified Bethesda classification system and the other followed the CIN classification system. Colposcopy-directed punch biopsies were obtained from VIA and/or Hybrid Capture 2-positive women. The Institute pathologist interpreted the slides using the CIN system. Blinded review was done by 2 external pathologists who independently interpreted cervical punch biopsies using the Bethesda system. The Institute pathologist's diagnoses based on CIN system were converted post hoc into categories belonging to the Bethesda system for comparison. The overall agreement was poor (κ=0.36). The lowest agreement was observed in the low-grade squamous intraepithelial lesion category (κ=0.23) and the highest in the squamous cell carcinoma category (κ=0.76). The agreement between the reviewers, both of whom used the Bethesda system, was substantial. 23956024 Efficacy of a text message-based smoking cessation intervention for young people: a cluster randomized controlled trial. Smoking prevalence remains high, particularly among adolescents and young adults with lower educational levels, posing a serious public health problem. There is limited evidence of effective smoking cessation interventions in this population. To test the efficacy of an individually tailored, fully automated text messaging (short message service, SMS)-based intervention for smoking cessation in young people. A 2-arm cluster randomized controlled trial, using school class as the randomization unit, was conducted to test the efficacy of the SMS text messaging intervention compared to an assessment-only control group. Students who smoked were proactively recruited via online screening in vocational school classes. Text messages, tailored to demographic and smoking-related variables, were sent to the participants of the intervention group at least 3 times per week over a period of 3 months. A follow-up assessment was performed 6 months after study inclusion. The primary outcome measure was 7-day smoking abstinence. Secondary outcomes were 4-week smoking abstinence, cigarette consumption, stage of change, and attempts to quit smoking. We used regression models controlling for baseline differences between the study groups to test the efficacy of the intervention. Both complete-case analyses (CCA) and intention-to-treat analyses (ITT) were performed. Subgroup analyses were conducted for occasional and daily smokers. A total of 2638 students in 178 vocational school classes in Switzerland participated in the online screening. Overall, 1012 persons met the inclusion criteria for study participation, and 755 persons (74.6%) participated in the study (intervention: n=372; control: n=383). Of the 372 program participants, 9 (2.4%) unsubscribed from the program during the intervention period. Six-month follow-up data were obtained for 559 study participants (74.0%). The 7-day smoking abstinence rate at follow-up was 12.5% in the intervention group and 9.6% in the control group (ITT: P=.92). No differences between the study groups were observed in 4-week point prevalence abstinence rates. The decrease in the mean number of cigarettes smoked per day from baseline to follow-up was higher in the intervention group than in the control group (ITT: P=.002). No differences between the groups were observed in stage of change (ITT: P=.82) and quit attempts (ITT: P=.38). The subgroup analyses revealed lower cigarette consumption in both occasional and daily smokers in the intervention group compared to the control group. Occasional smokers in the intervention group made more attempts to quit smoking than occasional smokers in the control group. This study demonstrated the potential of an SMS text message-based intervention to reach a high proportion of young smokers with low education levels. The intervention did not have statistically significant short-term effects on smoking cessation; however, it resulted in statistically significant lower cigarette consumption. Additionally, it resulted in statistically significant more attempts to quit smoking in occasional smokers. International Standard Randomized Controlled Trial Number (ISRCTN): 19739792; http://www.controlled-trials.com/ISRCTN19739792 (Archived by WebCite at http://webcitation.org/6IGETTHmr). 23821765 Arterial stiffness measured by carotid femoral pulse wave velocity is associated with disease severity in chronic obstructive pulmonary disease. Patients with chronic obstructive pulmonary disease (COPD) face an increased risk of cardiovascular disease and increased cardiac mortality. Carotid femoral pulse wave velocity (cf-PWV) is a validated measure of arterial stiffness, a wellrecognized predictor of adverse cardiovascular outcomes, and offers higher predictive value than classical cardiovascular risk factors. In this study, we investigated the association between COPD and arterial stiffness using cf-PWV as a non-invasive technique. This clinical study was prospective, observational and cross-sectional. Sixty-two patients with stable COPD and 22 healthy controls were enrolled. Physical examinations, chest x-rays, pulmonary function tests, arterial blood gas analysis and 6 minute walking test were performed on each participant, and cf-PWV was measured via a validated tonometry system. Patients with COPD exhibited increased arterial stiffness as compared to the control subjects. These differences were associated with decreases in forced expiratory volume in 1 second (FEV1), partial pressure of oxygen in arterial blood, and oxygen saturation during the 6 minute walking test. We observed higher cf-PWV values in COPD patients with more severe disease forms as compared to patients with mild and moderate disease forms. According to linear regression analyses, only FEV1 was an independent predictor of cf-PWV in our study population. Our results suggest that cf-PWV, a measure of arterial stiffness, is increased in patients with more severe and advanced COPD as compared to those with mild and moderate forms. Airflow limitation and hypoxemia may induce increased arterial stiffness in COPD patients. 23910559 Long-term Functional Outcomes in Patients With a W-shaped Ileal Orthotopic Neobladder With No Antireflux Mechanism. To evaluate the long-term renal function, continence, and voiding function in 64 patients, surviving for 5 or more years after W-shaped ileal neobladder with a short afferent limb and refluxing ureterointestinal anastomoses. Kidney morphology and function were evaluated using nuclear renography, creatinine, and glomerular filtration rate. Continence and voiding function were evaluated with a diary on frequency, voided volumes, number of pads, and with the incontinence severity index (ISI) questionnaire, the American Urological Association-Symptom Index (AUA-SI), and the American Urological Association-Symptom Problem Index. The renal scan showed a dilatation of the upper urinary tract in 4.8% of renoureteral units. Of the patients, 12.5% voided with intermittent or permanent catheterization. The remaining 87.5% voided spontaneously; 75% did not use pads, 12.5% used protection for safety, 7.1% 1 pad, and 5.4% more than 1 pad, during the day; during night, 55.3% did not use pads, 23.2% used protection for safety, and 12.6% and 8.9% 1 or more than 1 pad. The ISI questionnaire showed that 35.7% were fully continent, whereas 41%, 12.5%, and 10.8% had slight, moderate, and severe incontinence. The AUA-SI showed that 50% had mild, 39.3% moderate, and 10.7% severe lower urinary tract symptoms. Urinary incontinence, daytime frequency, and nocturia correlated positively with the age of patients at follow-up and negatively with voided volume. Long-term detrimental effect on renal function of orthotopic neobladder with no antireflux anastomoses is limited. Long-term continence and voiding function results are satisfactory. The ISI questionnaire might be useful to evaluate and grade incontinence in patients with orthotopic neobladder, whereas the AUA-SI has many limitations. 23937979 Discovery of N-(2,3,5-triazoyl)mycophenolic amide and mycophenolic epoxyketone as novel inhibitors of human IMPDH. Syntheses of ten derivatives of mycophenolic acid (MPA) at C-6' position, and structure-activity relationship study among these derivatives, MPA and mycophenolic hydroxamic acid (MPHA) led to discovery of N-(2,3,5-triazolyl)mycophenolic amide 4, (7'S) mycophenolic epoxyketone 9 and (7'R) mycophenolic epoxyketone 10 having potent inhibitory activity against human inosine-5'-monophosphate dehydrogenase (IMPDH) type I and II as well as antiproliferative activity on human leukemia K562 cells. Compounds 4, 9, and 10 showed induction activity of erythroid differentiation in K562 cells. Inhibitory effects of 4 and 10 against IMPDH were attenuated by supplemental guanosine in K562 cells. In contrast, attenuation effect by supplemental guanosine was not significant in the case of 9. Compound 9 weakly inhibited the enzyme activity of HDAC in the nuclear lysate of K562 cells at 10μM. These observations suggest that the primary target of 4, 9, and 10 is IMPDH, whereas compound 9 partially inhibits a certain type of HDAC. 23948185 Immigrant women's experience of maternity services in Canada: A meta-ethnography. to synthesise data on immigrant women's experiences of maternity services in Canada. a qualitative systematic literature review using a meta-ethnographic approach METHODS: a comprehensive search strategy of multiple databases was employed in consultation with an information librarian, to identify qualitative research studies published in English or French between 1990 and December 2011 on maternity care experiences of immigrant women in Canada. A modified version of Noblit and Hare's meta-ethnographic theoretical approach was undertaken to develop an inductive and interpretive form of knowledge synthesis. The seven-phase process involved comparative textual analysis of published qualitative studies, including the translation of key concepts and meanings from one study to another to derive second and third-order concepts encompassing more than that offered by any individual study. ATLAS.ti qualitative data analysis software was used to store and manage the studies and synthesise their findings. the literature search identified 393 papers, of which 22 met the inclusion criteria and were synthesised. The literature contained seven key concepts related to maternity service experiences including social (professional and informal) support, communication, socio-economic barriers, organisational environment, knowledge about maternity services and health care, cultural beliefs and practices, and different expectations between health care staff and immigrant women. Three second-order interpretations served as the foundation for two third-order interpretations. Societal positioning of immigrant women resulted in difficulties receiving high quality maternity health care. Maternity services were an experience in which cultural knowledge and beliefs, and religious and traditional preferences were highly relevant as well but often overlooked in Canadian maternity settings. in order to implement woman-centered care, to enhance access to maternity services, and to promote immigrant women's health, it is important to consider these women's social position, cultural knowledge and beliefs, and traditional customs in the health care. 22956046 Foot drop after ethanol embolization of calf vascular malformation: a lesson on nerve injury. Ethanol is often used in sclerotherapy to treat vascular malformations. Nerve injury is a known complication of this procedure. However, the management of this complication is not well described in literature. This case describes a 10-year-old boy with a slow flow vascular malformation in the right calf who underwent transarterial ethanol embolization following prior unsuccessful direct percutaneous sclerotherapy. The development of a dense foot drop that subsequently recovered is described, and the management of this uncommon but distressful complication is discussed. 23890535 The association between growth response to growth hormone and baseline body composition of children with growth hormone deficiency. We wanted to examine the relationship between initial growth response to recombinant human Growth Hormone (rhGH) treatment and body composition in children with growth hormone deficiency (GHD). Forty-two patients (21 boys and 21 girls) aged between 5.7-15.5years (mean age: 10.8±2.6years) with isolated GHD. The auxological and laboratory data (GH and IGF-I levels) and results of bioelectrical impedance analyses were evaluated. Children with GHD were followed up for 12months and categorized according to growth response to rhGH into good and poor responders (change in height of >0.7 SDS or <0.7 SDS over one year respectively). Mean doses of rhGH per kg of fat free mass (FFM) were calculated. Forty-eight percent of patients showed a good growth response to rhGH therapy. At study entry, mean age, height SDS, weight SDS, serum IGF-1 SDS, IGFBP-3 SDS, growth velocity prior to rhGH therapy, GH after clonidine and l-dopa were similar in the two groups. At baseline, BMI SDS and waist-hip ratio were significantly higher in good responders (p=0.02 and p=0.006, respectively). Good responders had lower percentages of FFM (73.4±8.9 vs. 83.1±5.9) and total body water (TBW) (56.5±5.3 vs. 63.1±4.4), compared to poor responders (p<0.05). There were significant correlations between changes in height SDS over one year and baseline body composition in children with GHD on rhGH treatment (r=-0.617 for percentage of FFM, r=-0.629 for percentage of TBW, p<0.001). A correlation between BMI SDS, waist-hip ratio, mean rhGH dose per FFM and growth response was observed only in prepubertal subjects. Baseline body composition data in children with GHD can be used to predict the growth response to rhGH treatment. A management strategy that involves titrating rhGH dose according to FFM as a means of optimizing the growth response to intervention requires further study. 23912016 Autism spectrum disorders and prematurity: a review across gestational age subgroups. Autism spectrum disorders (ASDs) are increasingly recognized as a public health problem. According to the Centers for Disease Control and Prevention, the prevalence for ASD is now 1 in 88. The prevalence of ASDs in children has increased over the past 2 decades, nearly doubling the prevalence since the Centers for Disease Control and Prevention began tracking these numbers. Infants are defined as premature when birth takes place before 37 weeks' gestation (259 days from the first day of the mother's last menstrual period). More than 4 million live births occur in the United States each year. Preterm births account for approximately half a million of those births. The rate of premature birth has increased by more than 20% between 1990 and 2006. Cognitive impairment and atypical brain development are thought to be sequelae of preterm delivery. Low birth weight and preterm birth place these infants at higher risk for disturbances in social interaction, communication, and other psychoaffective disorders in adulthood. Major advances in the field of early autism detection include validated screening tools to facilitate early screening for children with ASD as well as those considered to be at high risk for the disorder. Given the significant maternal and neonatal morbidities that are often coupled with prematurity, understanding the prevalence and risk factors that are implicated in changes in the fetal brain may provide researchers with vital links to autism in this population. 23856195 The microsporidian Enterocytozoon hepatopenaei is not the cause of white feces syndrome in whiteleg shrimp Penaeus (Litopenaeus) vannamei. The microsporidian Enterocytozoon hepatopenaei was first described from Thailand in 2009 in farmed, indigenous giant tiger shrimp Penaeus (Penaeus) monodon. The natural reservoir for the parasite is still unknown. More recently, a microsporidian closely resembling it in morphology and tissue preference was found in Thai-farmed, exotic, whiteleg shrimp Penaeus (Litopenaeus) vannamei exhibiting white feces syndrome (WFS). Our objective was to compare the newly found pathogen with E. hepatopenaei and to determine its causal relationship with WFS. Generic primers used to amplify a fragment of the small subunit ribosomal RNA (ssu rRNA) gene for cloning and sequencing revealed that the new parasite from WFS ponds had 99% sequence identity to that of E. hepatopenaei, suggesting it was conspecific. Normal histological analysis using tissue sections stained with hematoxylin and eosin (H&E) revealed that relatively few tubule epithelial cells exhibited spores, suggesting that the infections were light. However, the H&E results were deceptive since nested PCR and in situ hybridization analysis based on the cloned ssu rRNA gene fragment revealed very heavy infections in tubule epithelial cells in the central region of the hepatopancreas in the absence of spores. Despite these results, high prevalence of E. hepatopenaei in shrimp from ponds not exhibiting WFS and a pond that had recovered from WFS indicated no direct causal association between these infections and WFS. This was supported by laboratory oral challenge trials that revealed direct horizontal transmission to uninfected shrimp but no signs of WFS. The microsporidian newly found in P. vannamei is conspecific with previously described E. hepatopenaei and it is not causally associated with WFS. However, the deceptive severity of infections (much greater than previously reported in P. monodon) would undoubtedly have a negative effect on whiteleg shrimp growth and production efficiency and this could be exacerbated by the possibility of horizontal transmission revealed by laboratory challenge tests. Thus, it is recommended that the PCR and in situ hybridization methods developed herein be used to identify the natural reservoir species so they can be eliminated from the shrimp rearing system. 23955344 Preexistent Asymmetry in the Human Cyclooxygenase-2 Sequence Homodimer. Prostaglandin endoperoxide H synthase-2 (PGHS-2) also known as cyclooxygenase-2 (COX-2) is a sequence homodimer. However, the enzyme exhibits half-sites heme and inhibitor binding and functions as a conformational heterodimer having a catalytic subunit (Ecat) with heme bound and an allosteric subunit (Eallo) lacking heme. Some recombinant heterodimers comprised of a COX-deficient mutant subunit and a native subunit (i.e. Mutant/Native PGHS-2) have COX activities similar to native PGHS-2. This suggests that the presence of heme plus substrate leads to the subunits becoming lodged in a semi-stable Eallo-Mutant/Ecat-Native~heme form during catalysis. We examined this concept using human PGHS-2 dimers comprised of combinations of Tyr385Phe, Arg120Gln, Arg120Ala, Ser530Ala mutant or native subunits. With some heterodimers (e.g. Y385F/Native PGHS-2) heme binds with significantly higher affinity to the native subunit. This correlates with near native COX activity for the heterodimer. With other heterodimers (e.g. S530A/Native PGHS-2) heme binds with similar affinities to both subunits, and the COX activity approximates that expected for an enzyme in which each monomer contributes equally to the net COX activity. With or without heme, aspirin acetylates one half of the subunits of the native PGHS-2 dimer--the Ecat subunits. Subunits having a Ser530Ala mutation are refractory to acetylation. Curiously, aspirin acetylates only one quarter of the monomers of S530A/Native PGHS-2 with or without heme. This implies that there are comparable amounts of two non-interchangeable species of apo-enzymes: Eallo-S530A/Ecat-Native and Eallo-Native/Ecat-S530A. These results suggest that native PGHS-2 assumes a reasonably stable, asymmetric Eallo/Ecat form during its folding and processing. 23945954 Cortical Folding Defects as Markers of Poor Treatment Response in First-Episode Psychosis. IMPORTANCE At present, no reliable predictors exist to distinguish future responders from nonresponders to treatment during the first episode of psychosis. Among potential neuroimaging predictors of treatment response, gyrification represents an important marker of the integrity of normal cortical development that may characterize, already at illness onset, a subgroup of patients with particularly poor outcome. OBJECTIVE To determine whether patients with first-episode psychosis who do not respond to 12 weeks of antipsychotic treatment already have significant gyrification defects at illness onset. DESIGN Case-control study with 12 weeks' longitudinal follow-up to determine treatment response. SETTING Secondary psychiatric services in an inner-city area (South London, England). PARTICIPANTS A total of 126 subjects, including 80 patients presenting with first-episode psychosis and 46 healthy controls. Patients were scanned at the outset and received various antipsychotic medications in a naturalistic clinical setting. They were followed up for 12 weeks and classified as responders or nonresponders if they reached criteria for symptom remission, evaluated with the Psychiatric and Personal History Schedule. OBSERVATION Patients were exposed to naturalistic antipsychotic treatment for 12 weeks following a magnetic resonance imaging scan. MAIN OUTCOMES AND MEASURES Cortical gyrification was assessed using local gyrification index in a vertexwise fashion across the entire cortical surface with correction for multiple testing using permutation analysis. Differences in local gyrification index were assessed between responders, nonresponders, and healthy controls. The effect of diagnosis (affective vs nonaffective psychosis) on the local gyrification index was also investigated in responders and nonresponders. RESULTS Patients with first-episode psychosis showed a significant reduction in gyrification (hypogyria) across multiple brain regions compared with healthy controls. Interestingly, nonresponders showed prominent hypogyria at bilateral insular, left frontal, and right temporal regions when compared with responders (all clusters significant at P < .05). These effects were present for both affective and nonaffective psychoses. CONCLUSIONS AND RELEVANCE Gyrification appears to be a useful predictor of antipsychotic treatment response. Early neurodevelopmental aberrations may predict unfavorable prognosis in psychosis, irrespective of the existing diagnostic boundaries. 23576690 Early diagnostic biomarkers for esophageal adenocarcinoma--the current state of play. Esophageal adenocarcinoma (EAC) is one of the two most common types of esophageal cancer with alarming increase in incidence and very poor prognosis. Aiming to detect EAC early, currently high-risk patients are monitored using an endoscopic-biopsy approach. However, this approach is prone to sampling error and interobserver variability. Diagnostic tissue biomarkers related to genomic and cell-cycle abnormalities have shown promising results, although with current technology these tests are difficult to implement in the screening of high-risk patients for early neoplastic changes. Differential miRNA profiles and aberrant protein glycosylation in tissue samples have been reported to improve performance of existing tissue-based diagnostic biomarkers. In contrast to tissue biomarkers, circulating biomarkers are more amenable to population-screening strategies, due to the ease and low cost of testing. Studies have already shown altered circulating glycans and DNA methylation in BE/EAC, whereas disease-associated changes in circulating miRNA remain to be determined. Future research should focus on identification and validation of these circulating biomarkers in large-scale trials to develop in vitro diagnostic tools to screen population at risk for EAC development. 23874808 Intrinsic TNF/TNFR2 Interactions Fine-Tune the CD8 T Cell Response to Respiratory Influenza Virus Infection in Mice. TNF is an important inflammatory mediator and a target for intervention. TNF is produced by many cell types and is involved in innate inflammation as well as adaptive immune responses. CD8 T cells produce TNF and can also respond to TNF. Deficiency of TNF or TNFR2 has been shown to affect anti-viral immunity. However, as the complete knockout of TNF or its receptors has effects on multiple cell types as well as on lymphoid architecture, it has been difficult to assess the role of TNF directly on T cells during viral infection. Here we have addressed this issue by analyzing the effect of CD8 T cell intrinsic TNF/TNFR2 interactions during respiratory influenza infection in mice, using an adoptive transfer model in which only the T cells lack TNF or TNFR2. During a mild influenza infection, the capacity of the responding CD8 T cells to produce TNF increases from day 6 through day 12, beyond the time of viral clearance. Although T cell intrinsic TNF is dispensable for initial expansion of CD8 T cells up to day 9 post infection, intrinsic TNF/TNFR2 interactions potentiate contraction of the CD8 T cell response in the lung between day 9 and 12 post infection. On the other hand, TNF or TNFR2-deficient CD8 T cells in the lung express lower levels of IFN-γ and CD107a per cell than their wild type counterparts. Comparison of TNF levels on the TNFR2 positive and negative T cells is consistent with TNF/TNFR2 interactions inducing feedback downregulation of TNF production by T cells, with greater effects in the lung compared to spleen. Thus CD8 T cell intrinsic TNF/TNFR2 interactions fine-tune the response to influenza virus in the lung by modestly enhancing effector functions, but at the same time potentiating the contraction of the CD8 T cell response post-viral clearance. 23174017 Assessing the potential effectiveness of food and beverage taxes and subsidies for improving public health: a systematic review of prices, demand and body weight outcomes. Taxes and subsidies are increasingly being considered as potential policy instruments to incentivize consumers to improve their food and beverage consumption patterns and related health outcomes. This study provided a systematic review of recent U.S. studies on the price elasticity of demand for sugar-sweetened beverages (SSBs), fast food, and fruits and vegetables, as well as the direct associations of prices/taxes with body weight outcomes. Based on the recent literature, the price elasticity of demand for SSBs, fast food, fruits and vegetables was estimated to be -1.21, -0.52, -0.49 and -0.48, respectively. The studies that linked soda taxes to weight outcomes showed minimal impacts on weight; however, they were based on existing state-level sales taxes that were relatively low. Higher fast-food prices were associated with lower weight outcomes particularly among adolescents, suggesting that raising prices would potentially impact weight outcomes. Lower fruit and vegetable prices were generally found to be associated with lower body weight outcomes among both low-income children and adults, suggesting that subsidies that would reduce the cost of fruits and vegetables for lower-socioeconomic populations may be effective in reducing obesity. Pricing instruments should continue to be considered and evaluated as potential policy instruments to address public health risks. 23747467 Solidification/stabilization of toxic metals in calcium aluminate cement matrices. The ability of calcium aluminate cement (CAC) to encapsulate toxic metals (Pb, Zn and Cu) was assessed under two curing conditions. Changes in the consistency and in the setting time were found upon the addition of the nitrates of the target metals. Both Pb and Cu caused a delay in CAC hydration, while Zn accelerated the stiffening of the mortar. Compressive strengths of the metal-doped mortars, when initially cured at 60°C/100% RH, were comparable with that of the free-metal mortar. Three different pore size distribution patterns were identified and related to the compounds identified by XRD and SEM. Sorbent capacities of CAC for the toxic metals were excellent: a total uptake was achieved for up to 3wt.% loading of the three metals. In this way, CAC mortars were perfectly able to encapsulate the toxic metals, allowing the use of CAC for waste management as proved by the leaching tests. 23411500 A comprehensive, national survey of spirometry in Spain: current bottlenecks and future directions in primary and secondary care. We aimed to evaluate the availability and practice of spirometry, training of technicians, and spirometer features and maintenance in Spain in both primary care (PC) and secondary care (SC) centers. We used a nationwide, cross-sectional, 36-item telephone survey of health-care centers in Spain to target the technician in charge of conducting spirometries in PC and SC centers where outpatient respiratory patients are routinely evaluated. The questions surveyed for resources, training, spirometer use, bronchodilator tests, and spirometer features and maintenance. Of a total of 1,259 centers screened, 605 PC centers (21.2% of the PC centers in Spain) and 200 SC centers (24.9% of the SC centers in Spain) were surveyed. The response rate was 85.4% for PC centers and 75.1% for SC centers. All together, 19% of screened centers did not have a spirometer or were not using it. The number of spirometers per center and spirometries conducted per week was higher in SC centers than in PC centers (P < .001). Most centers received training for conducting spirometries, but this was periodically done in < 40%. Most centers used two inhalations of salbutamol for the bronchodilator test, but the international criteria of a positive test was considered only in 55.8% of PC and 52.8% of SC centers. Calibration of the spirometer was never done in 10.5% of PC and 3.1% of SC centers. This survey maps for the first time, to our knowledge, the current situation of spirometry in Spain, identifying bottlenecks and suggesting future directions applicable in both PC and SC centers and elsewhere. 23643185 Recruitment of Th1 effector cells in human tuberculosis: hierarchy of chemokine receptor(s) and their ligands. Selective recruitment of IFN-γ biased Th1 effector cells at the pathologic site(s) determines the local immunity of tuberculosis (TB). We observed the enrichment of CXCR3, CCR5 and CD11a(high) T cells in the peripheral blood, pleural fluid and bronchoalveolar lavage of TB pleural effusion (TB-PE) and miliary tuberculosis (MTB) patients respectively. CXCR3(+)CCR5(+) T cells were significantly high at the local disease site(s) in both the forms of TB and their frequency was highest among activated lymphocytes in TB-PE. Interestingly, all CCR5(+) cells were invariably positive for CXCR3 but all CXCR3(+) cells did not co-express CCR5 in pleural fluid whereas the situation was reverse in bronchoalveolar lavage. These CXCR3(+)CCR5(+) cells dominantly produced IFN-γ in response to Mycobacterium tuberculosis antigen. In vitro chemotaxis assay indicates dominant role of RANTES and IP-10 in the selective recruitment of CXCR3(+)CCR5(+)cells at the tubercular pathologic sites. 23958862 Regulating the redox gatekeeper: vacuolar sequestration puts glutathione disulfide in its place. Oxidative stress signaling is an important player in plant responses to the environment, and is the subject of ever-intensifying interest in relation to processes such as phytohormone regulation. One well documented biochemical response to intracellular oxidation is accumulation of the disulfide form of glutathione, GSSG. In addition to its potential usefulness as a stress marker, this response may be of functional importance, given emerging evidence that glutathione status is important in oxidative stress signaling. Within this context, we present a novel view of the role of compartmentalization of glutathione in the signaling processes, highlighting and discussing the implications of recent studies revealing that oxidative stress can drive changes in the subcellular distribution of GSSG, with a focus on vacuolar transport and the proteins that could be involved. 23819724 Discontinuation rates and inter-injection interval for repeated intravesical botulinum toxin type A injections for detrusor overactivity. To report discontinuation rates, inter-injection interval and complication rates after repeated intravesical botulinum toxin type A for the treatment of detrusor overactivity. Patients with urodyamically proven detrusor overactivity who had two or more botulinum toxin type A injections in the period 2004-2011 at Freeman Hospital, Newcastle Upon Tyne, UK, were considered for the present study. Discontinuation rates, complication rates and interval between botulinum toxin type A treatments were retrospectively analyzed. Overall, 125 patients (median age 53 years, range 19-83 years) were included in the analysis. The female-to-male ratio was 2.4:1 and median follow up was 38 months. A total of 96 patients had idiopathic detrusor overactivity, whereas 29 had neurogenic detrusor overactivity. A total of 667 injections were carried out, with 125 patients receiving two injections, 60 receiving three injections, 28 receiving four injections, 14 receiving five injections, three receiving six injections, three receiving seven injections and two receiving eight injections. The mean interval (±standard deviation) between the first and second injection (n = 125) was 17.6 months (±10.4), between the second and third (n = 60) was 15.7 ± 7.4 months, between the third and fourth (n = 28) was 15.4 ± 8.6 months, and between the fourth and subsequent injections (n = 22) was 11.6 ± 4.5 months. A total of 26% required intermittent catheterization, and 18% developed recurrent urinary tract infections. There was a discontinuation rate of 25% at 60 months. Repeated botulinum toxin type A injections represent a safe and effective method for managing patients with idiopathic detrusor overactivity and neurogenic detrusor overactivity. We have shown that the inter-injection interval remains unchanged up to five injections. 23660407 Solvent isotope and viscosity effects on the steady-state kinetics of the flavoprotein nitroalkane oxidase. The flavoprotein nitroalkane oxidase catalyzes the oxidative denitrification of a broad range of primary and secondary nitroalkanes to yield the respective aldehydes or ketones, hydrogen peroxide and nitrite. With nitroethane as substrate the (D2O)(kcat/KM) value is 0.6 and the (D2O)kcat value is 2.4. The kcat proton inventory is consistent with a single exchangeable proton in flight, while the kcat/KM is consistent with either a single proton in flight in the transition state or a medium effect. Increasing the solvent viscosity did not affect the kcat or kcat/KM value significantly, establishing that nitroethane binding is at equilibrium and that product release does not limit kcat. 23949119 Type of hematological malignancy is crucial for the return to work prognosis: a register-based cohort study. The aims of this study were to determine the proportion of return to work (RTW) among sick-listed patients diagnosed with one of eight subtypes of hematological malignancies; to evaluate the influence of type of hematological malignancy, comorbidity, use of anxiolytics and antidepressants, socioeconomic and demographic factors on RTW; and to investigate if these associations differ between genders. We combined data from national registers on all Danish patients diagnosed with hematological malignancies between 2000 and 2007. A total of 1,741 patients on long-term sick leave were followed until RTW, emigration, permanent withdrawal from the labor market, death, or February 2012, whichever came first. A total of 1,140 (65 %) patients returned to work. A strong association was found between type of diagnosis and RTW (p < 0.001), and the proportion of RTW was lowest for patients with multiple myeloma or acute leukemia compared to patients with Hodgkin lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, chronic myeloid leukemia, and chronic lymphoid leukemia. Use of antidepressants or anxiolytics after diagnosis, gender, age, and educational level were also associated with RTW. Surprisingly, comorbidity was not associated with RTW (p = 0.94); gender only modified the association between age and RTW. Two thirds of patients with hematological malignancies on sick leave RTW. A number of factors seem to lead to a poor prognosis, the hematological diagnosis being the most important, and these should be taken into account when performing studies on work outcome for patients with hematological malignancies. Knowledge in this area should assist in identification of hematological cancer patients at risk of not returning to work so that early targeted rehabilitation interventions can be initiated. 23874649 Single-row or double-row fixation technique for full-thickness rotator cuff tears: a meta-analysis. The single-row and double-row fixation techniques have been widely used for rotator cuff tears. However, whether the double-row technique produces superior clinical or anatomic outcomes is still considered controversial. This study aims to use meta-analysis to compare the clinical and anatomical outcomes between the two techniques. The Pubmed, Embase, and Cochrane library databases were searched for relevant studies published before November 1, 2012. Studies clearly reporting a comparison of the single-row and double-row techniques were selected. The Constant, ASES, and UCLA scale systems and the rotator cuff integrity rate were evaluated. The weighted mean differences and relative risks were calculated using a fixed-effects or random-effects model. Eight studies were included in this meta-analysis. The weighted mean differences of the ASES (-0.84; P = 0.04; I(2) = 0%) and UCLA (-0.75; P = 0.007; I(2) = 0%) scales were significantly low in the single-row group for full-thickness rotator cuff tears. For tear sizes smaller than 3 cm, no significant difference was found between the groups no matter in Constant (P = 0.95; I(2) = 0%), ASES (P = 0.77; I(2) = 0%), or UCLA (P = 0.24; I(2) = 13%) scales. For tear sizes larger than 3 cm, the ASES (-1.95; P = 0.001; I(2) = 49%) and UCLA (-1.17; P = 0.006; I(2) = 0%) scales were markedly lower in the single-row group. The integrity of the rotator cuff (0.81; P = 0.0004; I(2) = 10%) was greater and the partial thickness retear rate (1.93; P = 0.007; I(2) = 10%) was less in the double-row group. Full-thickness retears showed no difference between the groups (P = 0.15; I(2) = 0%). The meta-analysis suggests that the double-row fixation technique increases post-operative rotator cuff integrity and improves the clinical outcomes, especially for full-thickness rotator cuff tears larger than 3 cm. For tear sizes smaller than 3 cm, there was no difference in the clinical outcomes between the two techniques. Level I. 23856095 The Role of a Low-Dose Ketamine-Midazolam Regimen in the Management of Severe Painful Crisis in Patients With Sickle Cell Disease. Acute pain is one of the main causes of hospital admission in sickle cell disease, with variable intensity and unpredictable onset and duration. We studied the role of a low-dose intravenous (IV) ketamine-midazolam combination in the management of severe painful sickle cell crisis. A retrospective analysis was performed with data from nine adult patients who were admitted to the intensive care unit with severe painful sickle cell crises not responding to high doses of IV morphine and other adjuvant analgesics. A ketamine-midazolam regimen was added to the ongoing opioids as an initial bolus of ketamine 0.25mg/kg, followed by infusion of 0.2-0.25mg/kg/h. A midazolam bolus of 1mg followed by infusion of 0.5-1mg/h was added to reduce ketamine emergence reactions. Reduction in morphine daily requirements and improvement in pain scores were the determinants of ketamine-midazolam effect. The t-tests were used for statistical analysis. Nine patients were assessed, with mean age of 27±11 years. Morphine requirement was significantly lower after adding the IV ketamine-midazolam regimen. The mean±SD IV morphine requirement (milligram/day) in the pre-ketamine day (D0) was 145.6±16.5, and it was 112±12.2 on Day 1 (D1) of ketamine treatment (P=0.007). The Numeric Rating Scale scores on D0 ranged from eight to ten (mean 9.1), but improved to range from five to seven (mean 5.7) on D1. There was a significant improvement in pain scores after adding ketamine-midazolam regimen (P=0.01). Low-dose ketamine-midazolam IV infusion might be effective in reducing pain and opioid requirements in patients with sickle cell disease with severe painful crisis. Further controlled studies are required to prove this effect. 23882241 Dissociating compatibility effects and distractor costs in the additional singleton paradigm. The interpretation of identity compatibility effects associated with irrelevant items outside the nominal focus of attention has fueled much of the debate over early versus late selection and perceptual load theory. However, compatibility effects have also played a role in the debate over the extent to which the involuntary allocation of spatial attention (i.e., attentional capture) is completely stimulus-driven or whether it is contingent on top-down control settings. For example, in the context of the additional singleton paradigm, irrelevant color singletons have been found to produce not only an overall cost in search performance but also significant compatibility effects. This combination of search costs and compatibility effects has been taken as evidence that spatial attention is indeed allocated in a bottom-up fashion to the salient but irrelevant singletons. However, it is possible that compatibility effects in the additional singleton paradigm reflect parallel processing of identity associated with low perceptual load rather than an involuntary shift of spatial attention. In the present experiments, manipulations of load were incorporated into the traditional additional singleton paradigm. Under low-load conditions, both search costs and compatibility effects were obtained, replicating previous studies. Under high-load conditions, search costs were still present, but compatibility effects were eliminated. This dissociation suggests that the costs associated with irrelevant singletons may reflect filtering processes rather than the allocation of spatial attention. 23948733 Oral, Esophageal and Cutaneous Lichen Ruber Planus Controlled with Alitretinoin: Case Report and Review of the Literature. Background: Therapy-resistant lichen planus (LP) can be a challenging condition for dermatologists. There are some case reports about successful treatments with alitretinoin of cutaneous and oral, but not of esophageal LP. Objective: We present the unique case of a patient with cutaneous, oral and esophageal LP which was refractory to classical treatment options (topical clobetasol propionate and pimecrolimus, intramuscular triamcinolone acetonide); because of systemic side effects the patient did not tolerate systemic acitretin dosed up to 25 mg daily. Methods: Oral alitretinoin was used at a dose of 30 mg daily. Results: Both oral and skin changes as well as dysphagia completely resolved within 4 weeks without any severe side effects and the drug was used for 6 months. No papules, intraoral striae or dysphagia recurred during the 6 months of treatment. After 4 months the patient relapsed with mucosal patches so that a second cycle was initiated for 6 months where oral LP lesions resolved after 4 weeks also (with sporadic mild headache). Conclusion: Further studies are needed to better understand the impact of alitretinoin in LP. Our observation suggests alitretinoin as a new, well-tolerated treatment option for esophageal LP after failed response to conventional treatments. © 2013 S. Karger AG, Basel. 23426369 Acyl-CoA Synthetase 1 Is Induced by Gram-negative Bacteria and Lipopolysaccharide and Is Required for Phospholipid Turnover in Stimulated Macrophages. The enzyme acyl-CoA synthetase 1 (ACSL1) is induced by peroxisome proliferator-activated receptor α (PPARα) and PPARγ in insulin target tissues, such as skeletal muscle and adipose tissue, and plays an important role in β-oxidation in these tissues. In macrophages, however, ACSL1 mediates inflammatory effects without significant effects on β-oxidation. Thus, the function of ACSL1 varies in different tissues. We therefore investigated the signals and signal transduction pathways resulting in ACSL1 induction in macrophages as well as the consequences of ACSL1 deficiency for phospholipid turnover in LPS-activated macrophages. LPS, Gram-negative bacteria, IFN-γ, and TNFα all induce ACSL1 expression in macrophages, whereas PPAR agonists do not. LPS-induced ACSL1 expression is dependent on Toll-like receptor 4 (TLR4) and its adaptor protein TRIF (Toll-like receptor adaptor molecule 1) but does not require the MyD88 (myeloid differentiation primary response gene 88) arm of TLR4 signaling; nor does it require STAT1 (signal transducer and activator of transcription 1) for maximal induction. Furthermore, ACSL1 deletion attenuates phospholipid turnover in LPS-stimulated macrophages. Thus, the regulation and biological function of ACSL1 in macrophages differ markedly from that in insulin target tissues. These results suggest that ACSL1 may have an important role in the innate immune response. Further, these findings illustrate an interesting paradigm in which the same enzyme, ACSL1, confers distinct biological effects in different cell types, and these disparate functions are paralleled by differences in the pathways that regulate its expression. 23924397 "Tunneling Two-Level Systems" Model of the Low-Temperature Properties of Glasses: Are "Smoking-Gun" Tests Possible? Following a brief review of the "two-level (tunneling) systems" model of the low-temperature properties of amorphous solids ("glasses"), we ask whether it is in fact the unique explanation of these properties as is usually assumed, concluding that this is not necessarily the case. We point out that (a) one specific form of the model is already experimentally refuted and (b) that a definitive test of the model in its most general form, while not yet carried out, would appear to be now experimentally feasible. 23530541 Rapid Expansion of KPC-2-Producing Klebsiella pneumoniae Isolates in Two Texas Hospitals due to Clonal Spread of ST258 and ST307 Lineages. Abstract During 2007 to 2010, 23 carbapenem-resistant Enterobacteriaceae strains were recovered in two hospitals in Texas among three institutions surveyed. Eighteen (2.0% overall) strains carried blaKPC-2 and were collected in 2008 (3/150; 2.0%) and 2010 (15/289; 5.1%). Clonality was noted within hospitals and ten isolates belonged to ST258. All strains carried blaKPC-2 on plasmids and 14 had this gene embedded in Tn4401a. Tn3 transposase was detected upstream of blaKPC-2 in two isolates and another strain had two adjacent copies of blaKPC. Surveillance in prior years shows sporadic detection of KPC-producers in Texas, however, a recent increase in carbapenem-resistant Enterobacteriaceae in this state was due to the spread of KPC-producing Klebsiella pneumoniae, including isolates from ST258. 23881675 An evaluation of circulating bovine viral diarrhea virus type 2 maternal antibody level and response to vaccination in Angus calves. Vaccination against viruses has been shown to help prevent bovine respiratory disease in cattle. However, both passively acquired maternal antibody concentration and calf age have been shown to impact the ability of the immune system of a calf to respond to vaccination. The objectives of this study were to identify and evaluate environmental and management factors that affect 1) passively acquired bovine viral diarrhea virus (BVDV) type 2 antibody level, 2) decay rate of passively acquired BVDV type 2 antibody level, and 3) responses to BVDV type 2 vaccinations. A 2-shot modified live vaccine was administered to 1,004 Angus calves that were weaned at either the initial vaccination (n = 508) or the booster vaccination (n = 496). Calves weaned at the initial vaccination averaged 139 d whereas calves weaned at booster vaccination averaged 128 d of age. Bovine viral diarrhea virus type 2 antibodies were measured in 3 approximately 21-d intervals, serially collected serum samples to quantify antibody levels at initiation and end of vaccination protocol in addition to responses to initial, booster, and overall vaccination protocol. Amount of passively transferred antibody in the calf increased as dam age increased from 2 to 6 yr (P < 0.05) with no differences after dams reached 6 yr (P > 0.05). Calf age nested within birth year-season and dam age affected both initial and final antibody level, initial response, booster response, and overall antibody response to vaccination. The level of circulating, passively acquired maternal antibodies present at the time of vaccination had a significant (P < 0.05) negative effect on antibody responses to vaccination (initial response, booster response, and overall response). Calves that were weaned at the time of initial vaccination had significantly (P < 0.05) greater final antibody level, initial response, and overall response to vaccination than animals weaned at booster vaccination. In order for a calf to mount an overall antibody response to vaccination, maternal antibodies in circulation need to be less than 3.12 titers. However, the age at which a calf reached this antibody threshold was dependent on dam age. This information will help cattle managers and consultants design vaccination protocols to successfully mount an antibody response to vaccination. 23720725 Natural variation in the heparan sulfate binding domain of the eastern equine encephalitis virus e2 glycoprotein alters interactions with cell surfaces and virulence in mice. Recently, we compared amino acid sequences of the E2 glycoprotein of natural North American eastern equine encephalitis virus (NA-EEEV) isolates and demonstrated that naturally circulating viruses interact with heparan sulfate (HS) and that this interaction contributes to the extreme neurovirulence of EEEV (C. L. Gardner, G. D. Ebel, K. D. Ryman, and W. B. Klimstra, Proc. Natl. Acad. Sci. U. S. A., 108:16026-16031, 2011). In the current study, we have examined the contribution to HS binding of each of three lysine residues in the E2 71-to-77 region that comprise the primary HS binding site of wild-type (WT) NA-EEEV viruses. We also report that the original sequence comparison identified five virus isolates, each with one of three amino acid differences in the E2 71-to-77 region, including mutations in residues critical for HS binding by the WT virus. The natural variant viruses, which possessed either a mutation from lysine to glutamine at E2 71, a mutation from lysine to threonine at E2 71, or a mutation from threonine to lysine at E2 72, exhibited altered interactions with heparan sulfate and cell surfaces and altered virulence in a mouse model of EEEV disease. An electrostatic map of the EEEV E1/E2 heterotrimer based upon the recent Chikungunya virus crystal structure (J. E. Voss, M. C. Vaney, S. Duquerroy, C. Vonrhein, C. Girard-Blanc, E. Crublet, A. Thompson, G. Bricogne, and F. A. Rey, Nature, 468:709-712, 2010) showed the HS binding site to be at the apical surface of E2, with variants affecting the electrochemical nature of the binding site. Together, these results suggest that natural variation in the EEEV HS binding domain may arise during EEEV sylvatic cycles and that this variation may influence receptor interaction and the severity of EEEV disease. 23508295 Differential tolerance to copper, but no evidence of population-level genetic differences in a widely-dispersing native barnacle. Despite many estuaries having high levels of metal pollution, species are found to persist in these stressful environments. Populations of estuarine invertebrates exposed to toxic concentrations of such metals may be under selection. However, in species with a wide-dispersal potential, any short-term results of localized selection may be counteracted by external recruitment from populations not under selection. The barnacle Amphibalanus variegatus is found in nearshore coastal environments as well as sheltered embayments and estuaries, including metal-impacted estuaries, from New South Wales, Australia to Western Australia. The fertilised eggs of A. variegatus are brooded internally and released as larvae (nauplii), which remain in the water-column for ~14 days before settling. Hence the species has a considerable dispersal capacity. The purpose of this study was to examine whether populations of A. variegatus from metal-impacted sites, displayed a greater tolerance to a toxicant (copper) than reference populations. Adult barnacles where collected from twenty sites within two metal-impacted and fourteen sites within two reference estuaries. Within 24 h, adults were induced to spawn and the offspring were exposed to copper in a laboratory assay. Larvae collected from the metal-impacted estuaries demonstrated a greater tolerance to copper compared to those from reference sites. To determine if selection/localised in the metal impacted sites was occurring, the genetic structure of populations at three sites was examined using an AFLP methodology. No evidence of unique population identity and or selection (outlier loci) was detected suggesting that: (1) the tolerance displayed in the assay was derived from acclimation during development; and/or (2) that the populations are open preventing the fixation of any unique alleles. 23891998 Effects of highland land-use over lowlands of the Brazilian Pantanal. Human activities in the highlands alter the usual ecohydrological dynamics of the Pantanal wetland in the lowlands. These alterations can be noted by historical observation and identification of key processes that change the normal ecohydrology in the highlands and lowlands. Depending on land-use scenarios in the near future, the ongoing changes in the highlands may have positive or deleterious effects on the Pantanal's carrying capacity and resilience for providing ecosystem services such as nutrient retention and recycling, water purification, fish stocks, among others. This article seeks to summarize recent information to clarify, guide and provide support for the pursuit of realistic scenarios and induce scientific research and government policies that reconcile sustainable development in the highlands and lowlands, in line with the conservation of the Pantanal wetland. 23935577 Dorsolateral prefrontal transcranial magnetic stimulation in patients with major depression locally affects alpha power of REM sleep. Sleep alterations are among the most important disabling manifestation symptoms of Major Depression Disorder (MDD). A critical role of sleep importance is also underlined by the fact that its adjustment has been proposed as an objective marker of clinical remission in MDD. Repetitive transcranial magnetic stimulation (rTMS) represents a relatively novel therapeutic tool for the treatment of drug-resistant depression. Nevertheless, besides clinical evaluation of the mood improvement after rTMS, we have no clear understanding of what are the neurophysiological correlates of such treatment. One possible marker underlying the clinical outcome of rTMS in MDD could be cortical changes on wakefulness and sleep activity. The aim of this open-label study was to evaluate the efficacy of a sequential bilateral rTMS treatment over the dorsolateral prefrontal cortex (DLPFC) to improve the mood in MDD patients, and to determine if rTMS can induce changes on the sleep structure, and if those changes can be used as a surrogate marker of the clinical state of the patient. Ten drug-resistant depressed patients participated to ten daily sessions of sequential bilateral rTMS with a low-frequency TMS (1 Hz) over right-DLPFC and a subsequent high-frequency (10 Hz) TMS over left-DLPFC. The clinical and neurophysiological effects induced by rTMS were evaluated, respectively by means of the Hamilton Depression Rating Scale (HDRS), and by comparing the sleep pattern modulations and the spatial changes of EEG frequency bands during both NREM and REM sleep, before and after the real rTMS treatment. The sequential bilateral rTMS treatment over the DLPFC induced topographical-specific decrease of the alpha activity during REM sleep over left-DLPFC, which is significantly associated to the clinical outcome. In line with the notion of a left frontal hypoactivation in MDD patients, the observed local decrease of alpha activity after rTMS treatment during the REM sleep suggests that alpha frequency reduction could be considered as a marker of up-regulation of cortical activity induced by rTMS, as well as a surrogate neurophysiological correlate of the clinical outcome. 23849598 Blunted cortisol response to stress is associated with higher body mass index in low-income preschool-aged children. No known studies have tested the hypothesis that a blunted pattern of cortisol reactivity to stress, which is often found following exposure to chronic life stressors, is associated with a higher body mass index (BMI) in very young children. Low-income children (n=218, mean age 56.6 (range: 38.1-78.5; SD 7.0) months, 49.1% male, 56.4% white, 16.1% black, 11.5% Hispanic/Latino) participated in a series of behavioral tasks designed to elicit stress. Cortisol was sampled in saliva 5 times during the protocol, and area under the curve (AUC), representing total cortisol output during stress elicitation, was calculated. Children were weighed and height measured and body mass index (BMI) z-score was calculated. Linear regression was used to evaluate the association between cortisol AUC and BMI z-score, controlling for child age, sex, and race/ethnicity (non-Hispanic white vs. not); primary caregiver weight status (overweight, defined as BMI≥25 vs. not); and family income-to-needs ratio. Mean child BMI z-score was 0.88 (SD=1.03). Mean cortisol AUC was 6.11μg/dL/min (SD=10.44). In the fully adjusted model, for each 1-standard deviation unit decrease in cortisol AUC, the child's BMI z-score increased by 0.17 (SE 0.07) standard deviation units (p<0.02). A blunted cortisol response to stress, as is often seen following chronic stress exposure, is associated with increased BMI z-score in very young children. Further work is needed to understand how associations between stress, cortisol, and elevated body mass index may develop very early in the lifespan. 23954088 Analytic and Clinical Validation of a Prostate Cancer-Enhanced Messenger RNA Detection Assay in Whole Blood as a Prognostic Biomarker for Survival. Biomarkers based on detecting prostate cancer (PCa)-specific transcripts in blood are associated with inferior outcomes, but their validation in a clinical context is lacking. To determine whether detecting enhanced transcripts for PCa in whole blood using an analytically valid assay has prognostic significance relative to circulating tumor cell (CTC) enumeration. The detection of KLK3, KLK2, HOXB13, GRHL2, and FOXA1 in whole blood by reverse transcription polymerase chain reaction (RT-PCR) was studied in 97 men with metastatic castration-resistant PCa (mCRPC) as a prognostic factor for overall survival. The 2.5ml of blood was collected in PAXgene tubes for total RNA extraction and 7.5ml for CTC enumeration from patients with progressive mCRPC. PCa-enriched genes were detected using a sensitive RT-PCR assay in whole blood from patients with mCRPC. Analytical validity of the assay was established in a clinical laboratory environment. The frequency of detecting transcripts was compared to CTC enumeration using CellSearch in an independent data set and survival associations were explored by concordance probability estimate (CPE). Two or more genes were detected by PCR in 53% of patients (51 of 97; 95% confidence interval [CI], 43-63%), and unfavorable CTC counts (five of more cells) were seen in 46% (45 of 97; 95% CI, 36-56%). Importantly, transcripts were detectable in 11 of 52 patients with favorable CTC counts (21%; 95% CI, 8-35%). Transcript detection predicted overall survival in a proportional hazards model. Significantly, the predictive accuracy of RT-PCR detection in combination with CTC enumeration had a CPE of 0.752 (standard error: 0.038), although this was limited by the number of patients evaluated. This validated RT-PCR assay detecting prostate-specific RNA in whole blood is prognostic for survival and may assess patient risk in tandem with CellSearch CTC enumeration. Its clinical utility is being prospectively explored. 23592449 Galectin-3 negatively regulates the frequency and function of CD4(+) CD25(+) Foxp3(+) regulatory T cells and influences the course of Leishmania major infection. Galectin-3, an endogenous glycan-binding protein, plays essential roles during microbial infection by modulating innate and adaptive immunity. However, the role of galectin-3 within the CD4(+) CD25(+) Foxp3(+) T regulatory (TREG ) cell compartment has not yet been explored. Here, we found, in a model of Leishmania major infection, that galectin-3 deficiency increases the frequency of peripheral TREG cells both in draining lymph nodes (LNs) and sites of infection. These observations correlated with an increased severity of the disease, as shown by increased footpad swelling and parasite burden. Galectin-3-deficient (Lgals3(-/-) ) TREG cells displayed higher CD103 expression, showed greater suppressive capacity, and synthesized higher amounts of IL-10 compared with their wild-type (WT) counterpart. Furthermore, both TREG cells and T effector (TEFF ) cells from Lgals3(-/-) mice showed higher expression of Notch1 and the Notch target gene Hes-1. Interestingly, Notch signaling components were also altered in both TREG and TEFF cells from uninfected Lgals3(-/-) mice. Thus, endogenous galectin-3 regulates the frequency and function of CD4(+) CD25(+) Foxp3(+) TREG cells and alters the course of L. major infection. 23833040 Frequent Somatic TERT Promoter Mutations in Thyroid Cancer: Higher Prevalence in Advanced Forms of the Disease. Background:TERT encodes the reverse transcriptase component of telomerase, which adds telomere repeats to chromosome ends, thus enabling cell replication. Telomerase activity is required for cell immortalization. Somatic TERT promoter mutations modifying key transcriptional response elements were recently reported in several cancers, such as melanomas and gliomas.Objectives:The objectives of the study were: 1) to determine the prevalence of TERT promoter mutations C228T and C250T in different thyroid cancer histological types and cell lines; and 2) to establish the possible association of TERT mutations with mutations of BRAF, RAS, or RET/PTC.Methods:TERT promoter was PCR-amplified and sequenced in 42 thyroid cancer cell lines and 183 tumors: 80 papillary thyroid cancers (PTCs), 58 poorly differentiated thyroid cancers (PDTCs), 20 anaplastic thyroid cancers (ATCs), and 25 Hurthle cell cancers (HCCs).Results:TERT promoter mutations were found in 98 of 225 (44%) specimens. TERT promoters C228T and C250T were mutually exclusive. Mutations were present in 18 of 80 PTCs (22.5%), in 40 of 78 (51%) advanced thyroid cancers (ATC + PDTC) (P < 3 × 10(-4) vs PTC), and in widely invasive HCCs (4 of 17), but not in minimally invasive HCCs (0 of 8). TERT promoter mutations were seen more frequently in advanced cancers with BRAF/RAS mutations compared to those that were BRAF/RAS wild-type (ATC + PDTC, 67.3 vs 24.1%; P < 10(-4)), whereas BRAF-mutant PTCs were less likely to have TERT promoter mutations than BRAF wild-type tumors (11.8 vs 50.0%; P = .04).Conclusions:TERT promoter mutations are highly prevalent in advanced thyroid cancers, particularly those harboring BRAF or RAS mutations, whereas PTCs with BRAF or RAS mutations are most often TERT promoter wild type. Acquisition of a TERT promoter mutation could extend survival of BRAF- or RAS-driven clones and enable accumulation of additional genetic defects leading to disease progression. 23820957 An optimal cardiothoracic ratio cut-off to predict clinical outcomes in patients with acute myocardial infarction. The traditional cut-off for the cardiothoracic ratio (CTR) by chest X-ray was not originally proposed as a prognostic variable. We investigated an optimal CTR cut-off that could predict clinical outcomes in patients with acute myocardial infarction (AMI). A total of 3,083 AMI patients (65.2 ± 12.0 years, 2,091 males) who underwent successful percutaneous coronary intervention were divided into two groups by use of a CTR of 0.42 as determined by receiver-operating characteristic curve analysis (group I: CTR â‰¤ 0.42, group II: CTR > 0.42). We compared the incidences of in-hospital death and major adverse cardiac events (MACEs), including cardiac death, reinfarction, coronary artery bypass grafting, and target lesion revascularization, during 12 months between the groups. The patients in group II were older than those in group I and included more women. The patients in group II were more likely to have hypertension and multivessel disease and had a higher Killip class, higher troponin, higher N-terminal pro-brain natriuretic peptide, and lower ejection fraction than did those in group I. The in-hospital death rate was higher in group II (1.9 vs. 4.8 %, p < 0.001). The incidences of cardiac death and composite of MACEs during 12 months of follow-up were significantly higher in group II than in group I (2.4 vs. 5.7 %, p < 0.001, and 16.0 vs. 19.8 %, p = 0.007, respectively). Multivariable logistic regression analysis revealed that CTR greater than 0.42 was an independent predictor of MACEs (relative risk: 1.361, 95 % CI 1.014-1.827, p = 0.040). A CTR greater than 0.42, although within the traditional normal range, was associated with worse in-hospital and long-term clinical outcome in AMI patients. 23922840 GABA Transporter-1 Deficiency Confers Schizophrenia-Like Behavioral Phenotypes. The mechanism underlying the pathogenesis of schizophrenia remains poorly understood. The hyper-dopamine and hypo-NMDA receptor hypotheses have been the most enduring ideas. Recently, emerging evidence implicates alterations of the major inhibitory system, GABAergic neurotransmission in the schizophrenic patients. However, the pathophysiological role of GABAergic system in schizophrenia still remains dubious. In this study, we took advantage of GABA transporter 1 (GAT1) knockout (KO) mouse, a unique animal model with elevated ambient GABA, to study the schizophrenia-related behavioral abnormalities. We found that GAT1 KO mice displayed multiple behavioral abnormalities related to schizophrenic positive, negative and cognitive symptoms. Moreover, GAT1 deficiency did not change the striatal dopamine levels, but significantly enhanced the tonic GABA currents in prefrontal cortex. The GABAA receptor antagonist picrotoxin could effectively ameliorate several behavioral defects of GAT1 KO mice. These results identified a novel function of GAT1, and indicated that the elevated ambient GABA contributed critically to the pathogenesis of schizophrenia. Furthermore, several commonly used antipsychotic drugs were effective in treating the locomotor hyperactivity in GAT1 KO mice, suggesting the utility of GAT1 KO mice as an alternative animal model for studying schizophrenia pathogenesis and developing new antipsychotic drugs. 23707523 Mammalian target of rapamycin-independent S6K1 and 4E-BP1 phosphorylation during contraction in rat skeletal muscle. Muscle protein synthesis rates decrease during contraction/exercise, but rapidly increase post-exercise. Previous studies mainly focused on signaling pathways that control protein synthesis during post-exercise recovery, such as mTOR and its downstream targets S6K1 and 4E-BP1. In this study, we investigated the effect of high-frequency electrical stimulation on the phosphorylation state of signaling components controlling protein synthesis in rat skeletal muscle. Electrical stimulation increased S6K1 Thr389 phosphorylation, which was unaffected by Torin1, a selective mTOR inhibitor, suggesting that S6K1 phosphorylation by contraction was mTOR-independent. Phosphorylation of eIF4B Ser422 was also increased during electrical stimulation, which was abrogated by inhibition of MEK/ERK/RSK1 activation. Moreover, although phosphorylation of conventional mTOR sites in 4E-BP1 decreased during contraction, mTOR-independent phosphorylation was also apparent, which was associated with the release of 4E-BP1 from eIF4E. The results indicate mTOR-independent phosphorylation of S6K1 and 4E-BP1 and suggest MEK/ERK/RSK1-dependent phosphorylation of eIF4B during skeletal muscle contraction. These phosphorylation events would keep the translation initiation machinery "primed" in an active state so that protein synthesis could quickly resume post-exercise. 23722413 In vitro interactions between rat bone marrow-derived endothelial progenitor cells and hepatic stellate cells : Interaction between EPCs and HSCs. Transplantation of bone marrow (BM)-derived endothelial progenitor cells (EPCs) has been reported to improve liver fibrosis, but there is no direct evidence for the mechanism of improvement. We investigated the mechanism in vitro by coculturing BM-derived EPCs with activated hepatic stellate cells (HSCs) to mimic the hepatic environment. EPCs and HSCs were cultured alone and indirectly cocultured at a 1:1 ratio in a Transwell system. The characteristics of HSCs and EPCs were examined at different time points. An invasion assay showed the time-dependent effect on degradation of the extracellular matrix (ECM) layer in EPCs cultured alone. Real-time PCR and enzyme-linked immunosorbent assay analysis revealed that EPCs served as a source of matrix metalloproteinase-9 (MMP-9), and MMP-9 expression levels significantly increased during the 2 d of coculture. CFSE labeling showed that EPCs inhibited proliferation of HSCs. Annexin-V/PI staining, erminal deoxynucleotidyl transferase X-dUTP nick end labeling analysis, and (cleaved) caspase-3 activity revealed that EPCs promoted HSC apoptosis. However, the proliferation and apoptosis of EPCs were unaffected by cocultured HSCs. Coculturing increased the expression of inducible nitric oxide synthase, vascular endothelial growth factor, and hepatocyte growth factor (HGF) in EPCs, promoted differentiation of EPCs, and reduced the expression of types I and III collagens and transforming growth factor beta 1. Knockdown of HGF expression attenuated EPC-induced activation of HSC apoptosis and profibrotic ability. These findings demonstrated that BM-derived EPCs could degrade ECM, promoting activated HSC apoptosis, suppressing proliferation and profibrotic ability of activated HSCs. HGF secretion by EPCs plays a key role in inducing activated HSC apoptosis and HSC profibrotic ability. 23965035 4-[(18)F]fluoro-m-hydroxyphenethylguanidine: A Radiopharmaceutical for Quantifying Regional Cardiac Sympathetic Nerve Density with Positron Emission Tomography. 4-[(18)F]fluoro-m-hydroxyphenethylguanidine ([(18)F]4F-MHPG, [(18)F]1) is a new cardiac sympathetic nerve radiotracer with kinetic properties favorable for quantifying regional nerve density with PET and tracer kinetic analysis. An automated synthesis of [(18)F]1 was developed in which the intermediate 4-[(18)F]fluoro-m-tyramine ([(18)F]16) was prepared using a diaryliodonium salt precursor for nucleophilic aromatic [(18)F]fluorination. In PET imaging studies in rhesus macaque monkeys, [(18)F]1 demonstrated high quality cardiac images with low uptake in lungs and liver. Compartmental modeling of [(18)F]1 kinetics provided 'net uptake rate' constants Ki (mL/min/g wet) and Patlak graphical analysis of [(18)F]1 kinetics provided Patlak slopes Kp (mL/min/g). In pharmacological blocking studies with the norepinephrine transporter inhibitor desipramine (DMI), each of these quantitative measures declined in a dose-dependent manner with increasing DMI doses. These initial results strongly suggest that [(18)F]1 can provide quantitative measures of regional cardiac sympathetic nerve density in human hearts using PET. 23968975 Validity of using annual mean particulate matter concentrations as measured at fixed site in assessing personal exposure: An exposure assessment study in Japan. From 2003 through 2005, we compared annual mean particulate matter (PM) and nitrogen dioxide (NO2) concentrations as measured at fixed-site monitoring stations in 6 Japanese cities with those measured inside and outside subject residences and during personal monitoring. A total of 65 households participated in indoor and outdoor residential exposure monitoring. In summer and autumn, we also performed personal monitoring of one resident of each household. On each day, personal samplers were used to collect 24-h samples of PM and NO2 simultaneously from the fixed sites, indoor and outdoor, and from those undergoing personal monitoring. We found good correlations between the fixed-site and outdoor measurements for annual mean (average of 7-day×4-season) concentrations of PM2.5, PM10-2.5, PM10 and NO2 (Spearman's rank correlation coefficients (ρ)≥0.75). However, the correlations between the fixed-site and indoor measurements were moderate to low. In summer and autumn, the correlations between the fixed-site and personal mean concentrations of PM2.5 (ρ=0.62), PM10 (ρ=0.58), and NO2 (ρ=0.70) were acceptable. However, because people spend most of their time indoors, these correlations for annual mean concentrations were not estimated to be high. Our results are important in allowing researchers to estimate the effects of resulting measurement errors of PM and NO2. 23558692 Anabolic resistance of muscle protein synthesis with aging. Aging has been associated with a reduced muscle protein synthetic response to protein intake, termed "anabolic resistance." Physical activity performed before protein intake increases the use of protein-derived amino acids for postprandial muscle protein accretion in senescent muscle. Thus, the level of habitual physical activity may be fundamental to maintain the anabolic responsiveness to protein intake with aging. 23872288 Association of work-related stress with mental health problems in a special police force unit. Law and order enforcement tasks may expose special force police officers to significant psychosocial risk factors. The aim of this work is to investigate the relationship between job stress and the presence of mental health symptoms while controlling sociodemographical, occupational and personality variables in special force police officers. At different time points, 292 of 294 members of the 'VI Reparto Mobile', a special police force engaged exclusively in the enforcement of law and order, responded to our invitation to complete questionnaires for the assessment of personality traits, work-related stress (using the Demand-Control-Support (DCS) and the Effort-Reward-Imbalance (ERI) models) and mental health problems such as depression, anxiety and burnout. Regression analyses showed that lower levels of support and reward and higher levels of effort and overcommitment were associated with higher levels of mental health symptoms. Psychological screening revealed 21 (7.3%) likely cases of mild depression (Beck Depression Inventory, BDI≥10). Officers who had experienced a discrepancy between work effort and rewards showed a marked increase in the risk of depression (OR 7.89, 95% CI 2.32 to 26.82) when compared with their counterparts who did not perceive themselves to be in a condition of distress. The findings of this study suggest that work-related stress may play a role in the development of mental health problems in police officers. The prevalence of mental health symptoms in the cohort investigated here was low, but not negligible in the case of depression. Since special forces police officers have to perform sensitive tasks for which a healthy psychological functioning is needed, the results of this study suggest that steps should be taken to prevent distress and improve the mental well-being of these workers. 23713078 Dissecting the Heat Stress Response in Chlamydomonas by Pharmaceutical and RNAi Approaches Reveals Conserved and Novel Aspects. To study how conserved fundamental concepts of the heat stress response (HSR) are in photosynthetic eukaryotes, we applied pharmaceutical and antisense/amiRNA approaches to the unicellular green alga Chlamydomonas reinhardtii. The Chlamydomonas HSR appears to be triggered by the accumulation of unfolded proteins, as it was induced at ambient temperatures by feeding cells with the arginine analog canavanine. The protein kinase inhibitor staurosporine strongly retarded the HSR, demonstrating the importance of phosphorylation during activation of the HSR also in Chlamydomonas. While the removal of extracellular calcium by the application of EGTA and BAPTA inhibited the HSR in moss and higher plants, only the addition of BAPTA, but not of EGTA, retarded the HSR and impaired thermotolerance in Chlamydomonas. The addition of cycloheximide, an inhibitor of cytosolic protein synthesis, abolished the attenuation of the HSR, indicating that protein synthesis is necessary to restore proteostasis. HSP90 inhibitors induced a stress response when added at ambient conditions and retarded attenuation of the HSR at elevated temperatures. In addition, we detected a direct physical interaction between cytosolic HSP90A/HSP70A and heat shock factor 1, but surprisingly this interaction persisted after the onset of stress. Finally, the expression of antisense constructs targeting chloroplast HSP70B resulted in a delay of the cell's entire HSR, thus suggesting the existence of a retrograde stress signaling cascade that is desensitized in HSP70B-antisense strains. 23861275 Aspiration of a speaking valve. Foreign body aspiration (FBA) is a relatively common and serious condition that can result in a spectrum of presentations ranging from incidental to acutely life-threatening. Described here is a case of aspiration of a tracheo-oesophageal speaking valve through a permanent tracheostomy that went unnoticed for a number of years, and an overview of the technique used for its removal. A 70-year-old ex-heavy smoker with a permanent tracheo-oesophageal fistula presented with a relatively recent history of increasing shortness of breath, sputum purulence and haemoptysis. Further investigation with a CT scan and bronchoscopy revealed the presence of a foreign body within his right lower lobe bronchus which was later removed by advancing a flexible bronchoscope over a rigid one. 23861321 Increased Bioplastic Production with an RNA Polymerase Sigma Factor SigE during Nitrogen Starvation in Synechocystis sp. PCC 6803. Because cyanobacteria directly harvest CO2 and light energy, their carbon metabolism is important for both basic and applied sciences. Here, we show that overexpression of the sigma factor sigE in Synechocystis sp. PCC 6803 widely changes sugar catabolism and increases production of the biodegradable polyester polyhydroxybutyrate (PHB) during nitrogen starvation. sigE overexpression elevates the levels of proteins implicated in glycogen catabolism, the oxidative pentose phosphate pathway, and polyhydroxyalkanoate biosynthesis. PHB accumulation is enhanced by sigE overexpression under nitrogen-limited conditions, yet the molecular weights of PHBs synthesized by the parental glucose-tolerant and sigE overexpression strain are similar. Although gene expression induced by nitrogen starvation is changed and other metabolites (such as GDP-mannose and citrate) accumulate under sigE overexpression, genetic engineering of this sigma factor altered the metabolic pathway from glycogen to PHB during nitrogen starvation. 23647948 Prevalence and spread of extended-spectrum β-lactamase-producing Enterobacteriaceae in Ngaoundere, Cameroon. During April 2010 and June 2010, 334 Enterobacteriaceae isolates from 590 participants (outpatients, inpatients, inpatient carers, hospital workers and members of their households) were collected from faecal samples. Based on β-lactamase pattern, origin of strains and the relationship between participants, 44 isolates of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae were selected from 44 participants (in Ngaoundere Protestant Hospital and Ngaoundere Regional Hospital, Cameroon). To determine the relatedness of bacterial strains, these isolates were fingerprinted using the automated, repetitive-sequenced-based PCR-based DiversiLab system. Subsequently, E. coli isolates that had undergone DiversiLab analysis were examined with respect to their phylogenetic group and detection of the ST131 clone to shed light on the epidemiology of these isolates in the Ngaoundere hospitals. The prevalence of faecal carriage of ESBL-producing Enterobacteriaceae among the study participants was 54.06%. According to participant groups, the prevalence of faecal carriage was also high (outpatients 45%; inpatients 67%; inpatient carers 57%; hospital workers 44%; and members of their households 46%). Analysis of the molecular epidemiology of ESBL-producing E. coli and K. pneumoniae showed a close relationship of the isolates between related and non-related individuals. In addition, DiversiLab results of E. coli identified four related isolates (4/22) from cluster III belonging to the epidemiologically important clone ST131. Our results highlight the importance of outpatients, inpatients, their carers, hospital workers and their families as reservoirs of ESBL-producing Enterobacteriaceae. 23944965 Limits of the Linear Accumulation Regime of DGT Sensors. A key question for the practical application of DGT (Diffusive Gradients in Thin films) as dynamic sensors in the environmental monitoring of trace metals is the influence of pH and dissolved ligands over the linear accumulation regime. Protons compete with metal ions for the binding to the DGT resin sites at relatively low pH, whereas high affinity dissolved ligands compete with resin sites for the binding of metals. Any of the two phenomena can lead to a departure from the linear accumulation regime and an underestimation of the actual species concentration in solution. These effects are studied here through numerical simulation of the diffusion-reaction processes in both gel and resin domains using a detailed chemical model of metal ions and protons interacting with resin sites. Results were tested successfully against experimental data of the Cd-NTA representative system. Charts to delimitate the range of experimental conditions (pH, ligand concentration and strength) where the linear accumulation regime prevails, can be helpful for designing sampling strategies in field conditions. For example, it is foreseen that perturbations of linear regime within 10 h of deployment are negligible above pH 5 and weak complexation (log K' < 0) or above pH 7 and strong complexation (log K' < 3), where K' is the effective stability constant. These plots can also be approximately used for partially labile systems whenever the time is replaced with the product lability degree times t. 23830177 Presence of auto-antibody against two placental proteins, annexin A1 and vitamin D binding protein, in sera of women with pre-eclampsia. Pre-eclampsia (PE) is one of the most complex and life-threatening pregnancy disorders. PE is characterized by maternal hypertension and proteinuria. There is much evidence to support an immunological etiology for PE and auto-immunity is considered a predisposing factor for PE. The aim of the present study was the investigation of placental proteins as targets for auto-antibodies in PE patients. 2D-PAGE technique was used for separation of the total human placental proteins. After separation, protein spots were transferred to the PVDF membranes and blotted with sera from 20 PE patients and compared with membranes blotted with 20 sera from normal women. MALDI TOF/TOF mass spectrometry technique was used for identification of differentially blotted spots. Moreover, the results of mass analysis were confirmed using western blot with commercial mAbs and RT-PCR technique. The results indicated that two placental proteins, annexin A1 and vitamin D binding protein (DBP), might be targeted by PE sera. The expression of annexin A1 and DBP was also confirmed at RNA level using the RT-PCR technique. Furthermore, the mass results were confirmed by western blotting with commercial mAbs against two targeted proteins. The data of the present study suggest two new placental proteins, annexin A1 and DBP, as placental immune targets. Considering the relation among vitamin D deficiency, increased risk of PE, and the role of annexin A1 in the resolution of inflammation, production of antibody against annexin A1 and DBP may be considered a new auto-immune hypothesis in pre-eclampsia that calls for further investigation in future work. 23859631 Culmination of low-dose pesticide effects. Pesticides applied in agriculture can affect the structure and function of nontarget populations at lower doses and for longer timespans than predicted by the current risk assessment frameworks. We identified a mechanism for this observation. The populations of an aquatic invertebrate (Culex pipiens) exposed over several generations to repeated pulses of low concentrations of the neonicotinoid insecticide (thiacloprid) continuously declined and did not recover in the presence of a less sensitive competing species (Daphnia magna). By contrast, in the absence of a competitor, insecticide effects on the more sensitive species were only observed at concentrations 1 order of magnitude higher, and the species recovered more rapidly after a contamination event. The underlying processes are experimentally identified and reconstructed using a simulation model. We conclude that repeated toxicant pulse of populations that are challenged with interspecific competition may result in a multigenerational culmination of low-dose effects. 23876510 A unique technique for intentional occlusion of an abdominal aortic aneurysm. We report the case of a 78-year-old man with coronary artery disease, chronic obstructive pulmonary disease, and chronic renal insufficiency with an enlarging 6.7-cm infrarenal abdominal aortic aneurysm. He also had a 4-cm right common iliac artery aneurysm, and right external iliac artery occlusion. The patient had a history of an axillobifemoral bypass graft placed 10 years prior for aortoiliac occlusive disease. We describe the use of an infrarenal aorto-uni-iliac graft and subsequent intentional graft occlusion as an endovascular solution to treat aneurysmal disease in this sick patient. He remains asymptomatic after surgery, with demonstrated occlusion of his aneurysms. 23159664 A novel permeation enhancer: N-succinyl chitosan on the intranasal absorption of isosorbide dinitrate in rats. The purpose of this paper is to study the potential of N-succinyl chitosan as a novel permeation enhancer for the intranasal absorption of isosorbide dinitrate (ISDN). A series of N-succinyl chitosan (NSCS) with different degree of succinylation (DS) and molecular weight were synthesized. An in situ nasal perfusion technique in rats was utilized to investigate the effect of NSCS substitution degree, NSCS molecular weight and concentration on the intranasal absorption of ISDN. The absorption enhancing effect of NSCS was compared with that of chitosan. It was found that all the NSCS investigated improved the intranasal absorption of ISDN remarkably. Better promoting effect was observed for 0.1% NSCS 50 (63) compared with 0.5% chitosan 50. In nasal ciliotoxicity test, both NSCS and chitosan investigated showed good safety profiles. Thereafter, in vivo studies of the selected formulations were carried out in rats and the pharmacokinetic parameters were calculated and compared with that of intravenous injection. Both in situ and in vivo studies demonstrated that NSCS is more effective than chitosan in promoting intranasal absorption of ISDN. Taking both absorption enhancing and safety reason into account, we suggest NSCS is a promising intranasal absorption enhancer. 23937438 Origin and Pathogenesis of Pelvic (Ovarian, Tubal, and Primary Peritoneal) Serous Carcinoma. A new paradigm for the pathogenesis of female pelvic cancer helps explain persistent problems in describing the development and diverse morphology of these neoplasms. This paradigm incorporates recent advances in the molecular pathogenesis of epithelial ovarian cancer (EOC) with new insights into the origin of these tumors. Correlated clinicopathologic and molecular genetic studies gave rise to a dualistic model that divides the various histologic types of EOCs into two broad categories designated type I and type II. Because serous carcinomas are the most common EOC and account for the vast majority of deaths, they form the subject of this review. Recent studies indicate that the precursor of ovarian high-grade serous carcinoma appears to develop from an occult intraepithelial carcinoma in the fimbria of the fallopian tube and involves the ovary secondarily. Another possible mechanism is implantation of normal fimbrial epithelium on the denuded ovarian surface at the site of rupture when ovulation occurs, causing the development of cortical inclusion cysts. The dualistic model serves as a framework for the study of ovarian cancer and can help investigators organize this complex group of neoplasms. It also facilitates the development of novel approaches to prevention, screening, and treatment of this devastating disease. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 9 is February 28, 2014. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates. 22772603 Multiple coronary plaque ruptures in a patient with a recent ST-elevation acute myocardial infarction causing recurrent coronary instability. Multiple plaque instability has been reported in about one-third of patients with ST elevation acute myocardial infarction (STEMI) and could be responsible for early recurrent instability after STEMI. Optical coherence tomography (OCT) is a high-resolution imaging technique that may help in detection and characterization of unstable coronary plaques. We present a case of multiple coronary instability in a patient with anterior STEMI where OCT has tailored an optimal diagnosis and treatment. 23893771 Prediction of noncovalent Drug/DNA interaction using computational docking models: Studies with over 1350 launched drugs. Noncovalent chemical/DNA interactions, for example, intercalation and groove-binding, may be more important to genomic integrity than previously appreciated, and there may very well be genotoxic consequences of that binding. It is of importance, then, to develop methods allowing a determination or prediction of such interactions. This would have particular utility in the pharmaceutical industry where genotoxicity is, for the most part, disallowed in new drug entities. We have previously used DNA docking simulations to assess if molecules had structure and charge characteristics which could accommodate noncovalent binding via, for example, electrostatic/hydrogen bonding. We here extend those earlier studies by examining a series of over 1,350 "launched" drugs for ability to noncovalently bind 10 different DNA sequences using two computational programs: Autodock and Surflex. These drugs were also evaluated for binding to the crystallographic ATP-binding site of human topoisomerase II. The results obtained clearly demonstrate multiple series of noncovalent DNA binding structure activity relationships which would not have been predicted based on cursory structural examination. Many drugs within these series are genotoxic although not via any commonly recognized structural covalent alerts. The present studies confirm previously implicated features such as N-dialkyl groups and specific N-aryl ketones as potential genotoxic chemical moieties acting through noncovalent mechanisms. These initial studies provide considerable evidence that DNA intercalation may be an important, largely overlooked, source of drug-induced genotoxicity and further suggest involvement of topoisomerase in that genotoxicity. Environ. Mol. Mutagen., 2013. © 2013 Wiley Periodicals, Inc. 23290997 Physiological and molecular determinants of embryo implantation. Embryo implantation involves the intimate interaction between an implantation-competent blastocyst and a receptive uterus, which occurs in a limited time period known as the window of implantation. Emerging evidence shows that defects originating during embryo implantation induce ripple effects with adverse consequences on later gestation events, highlighting the significance of this event for pregnancy success. Although a multitude of cellular events and molecular pathways involved in embryo-uterine crosstalk during implantation have been identified through gene expression studies and genetically engineered mouse models, a comprehensive understanding of the nature of embryo implantation is still missing. This review focuses on recent progress with particular attention to physiological and molecular determinants of blastocyst activation, uterine receptivity, blastocyst attachment and uterine decidualization. A better understanding of underlying mechanisms governing embryo implantation should generate new strategies to rectify implantation failure and improve pregnancy rates in women. 23847518 Intellectual development in autism spectrum disorders: new insights from longitudinal studies. The presence/absence of Intellectual Disability (ID) is considered to be the most critical factor affecting outcomes in individuals with Autism Spectrum Disorders (ASD). However, the question of the specific nature of ID in ASD has received little attention, with the current view being that ID is a comorbid condition (i.e., one that is unrelated in etiology and causality from the ASD itself). Recent advances in developmental neuroscience, highlighting the importance of early exposure to social experiences for cognitive development, support an alternative view; that ID in ASD might emerge as a consequence of severe social-communication deficits on the experience-dependent mechanisms underlying neurocognitive development. We tested this prediction in two independent samples of young children with ASD (Ns = 23 and 60), finding that children with greater ASD severity at an initial assessment were more likely to present with poorer cognitive outcomes at a later assessment, irrespective of initial cognitive level. The results of this proof of principle study suggest that ASD symptom severity contributes to the extent to which the environmental input required to support "typical" brain development can be processed by the individual, so that the risk of developing ID increases as the number and severity of ASD social-communicative impairments increase. 23925063 Periocular fat grafting: indications and techniques. Autologous fat transfer (AFT) is gaining popularity in periorbital and facial rejuvenation as well as structural reconstruction because of the advantages of fat over other fillers and implants. As the technique and instruments were refined over the years, the incidence of AFT morbidity decreased; however, there is still no consensus on the standardization of the procedure. Several studies have failed to demonstrate superiority of any routine technique; however, various suggestions provided by these investigations have had significant impact on the outcome of surgery. New insights are mainly focused on improving the survival of the grafted tissue, mainly through enhancing cell differentiation and angiogenesis. Clinical applications of adipose-derived stem cell (ADSC) transfer with or without other enhancers were proven to be successful; however, there is not enough human research on this topic yet. Experts made a clear distinction between AFT and ADSC transfer, and the details can be found in this report. Management of hard-to-treat maxillofacial conditions including orbital disorders evolved from AFT techniques, the so-called structural fat grafting. Harvesting methods to obtain stem cells have proven helpful in many studies. The future of fat grafting relies on the basic research that includes using additive agents, enhancers, or scaffolds to fat for increased survival of the graft. 23681145 miR-21 Contributes to Xenon-conferred Amelioration of Renal Ischemia-Reperfusion Injury in Mice. MicroRNAs participate in the regulation of numerous physiological and disease processes. The in vivo role of microRNAs in anesthetics-conferred organoprotection is unknown. Mice were exposed for 2 h to either 70% xenon, or 70% nitrogen, 24 h before the induction of renal ischemia-reperfusion injury. The role of microRNA, miR-21, in renal protection conferred by the delayed xenon preconditioning was examined using in vivo knockdown of miR-21 and analysis of miR-21 target pathways. Xenon preconditioning provided morphologic and functional protection against renal ischemia-reperfusion injury (n = 6), characterized by attenuation of renal tubular damage, apoptosis, and oxidative stress. Xenon preconditioning significantly increased the expression of miR-21 in the mouse kidney. A locked nucleic acid-modified anti-miR-21, given before xenon preconditioning, knocked down miR-21 effectively, and exacerbated subsequent renal ischemia-reperfusion injury. Mice treated with anti-miR-21 and ischemia-reperfusion injury showed significantly higher serum creatinine than antiscrambled oligonucleotides-treated mice, 24 h after ischemia-reperfusion (1.37 ± 0.28 vs. 0.81 ± 0.14 mg/dl; n = 5; P < 0.05). Knockdown of miR-21 induced significant up-regulation of programmed cell death protein 4 and phosphatase and tensin homolog deleted on chromosome 10, two proapoptotic target effectors of miR-21, and resulted in significant down-regulation of phosphorylated protein kinase B and increased tubular cell apoptosis. In addition, xenon preconditioning up-regulated hypoxia-inducible factor-1α and its downstream effector vascular endothelial growth factor in a time-dependent manner. Knockdown of miR-21 resulted in a significant decrease of hypoxia-inducible factor-1α. These results indicate that miR-21 contributes to the renoprotective effect of xenon preconditioning. 23740279 Time to reach a new steady state after changes of positive end expiratory pressure. To assess the time interval required to reach a new steady state of oxygenation-, ventilation-, respiratory mechanics- and hemodynamics-related variables after decreasing/increasing positive end expiratory pressure (PEEP). In 23 patients (group 1) with acute respiratory distress syndrome (ARDS), PEEP was decreased from 10 to 5 cmH2O and, after 60', it was increased from 5 to 15 cmH2O. In 21 other ARDS patients (group 2), PEEP was increased from 10 to 15 cmH2O and, after 60', decreased from 15 to 5 cmH2O. Oxygenation, ventilation, respiratory mechanics and hemodynamic variables were recorded at time 5', 15', 30' and 60' after each PEEP change. When PEEP was decreased, PaO2, PaO2/FiO2, venous admixture and arterial oxygen saturation reached their equilibrium after 5'. In contrast, when PEEP was increased, the equilibrium was not reached even after 60'. The ventilation-related variables did not change significantly with PEEP. The respiratory system compliance, when PEEP was decreased, significantly worsened only after 60'. Hemodynamics did not change significantly with PEEP. In the individual patients the change of oxygenation-related variables and of respiratory system compliance observed after 5' could predict the changes recorded after 60'. This was not possible for PaCO2. We could not find a unique equilibration time for all the considered variables. However, in general, a decremental PEEP test requires far lower equilibrium time than an incremental PEEP test, suggesting a different time course for derecruitment and recruitment patterns. 23931350 Testing the MOND Paradigm of Modified Dynamics with Galaxy-Galaxy Gravitational Lensing. The MOND paradigm of modified dynamics predicts that the asymptotic gravitational potential of an isolated, bounded (baryonic) mass, M, is ϕ(r)=(MGa_{0})^{1/2}ln⁡(r). Relativistic MOND theories predict that the lensing effects of M are dictated by ϕ(r) as general-relativity lensing is dictated by the Newtonian potential. Thus MOND predicts that the asymptotic Newtonian potential deduced from galaxy-galaxy gravitational lensing will have (1) a logarithmic r dependence, and (2) a normalization (parametrized standardly as 2σ^{2}) that depends only on M: σ=(MGa_{0}/4)^{1/4}. I compare these predictions with recent results of galaxy-galaxy lensing, and find agreement on all counts. For the "blue"-lenses subsample ("spiral" galaxies) MOND reproduces the observations well with an r^{'}-band M/L_{r^{'}}∼(1-3)(M/L)_{⊙}, and for "red" lenses ("elliptical" galaxies) with M/L_{r^{'}}∼(3-6)(M/L)_{⊙}, both consistent with baryons only. In contradistinction, Newtonian analysis requires, typically, M/L_{r^{'}}∼130(M/L)_{⊙}, bespeaking a mass discrepancy of a factor ∼40. Compared with the staple, rotation-curve tests, MOND is here tested in a wider population of galaxies, through a different phenomenon, using relativistic test objects, and is probed to several-times-lower accelerations-as low as a few percent of a_{0}. 23828132 Ecstasy intoxication as an unusual cause of epileptic seizures in young children. In light of the widespread use of ecstasy, it is surprising that only few cases of intoxicated young children have been reported. Patients almost invariably present with convulsions accompanied by sympathetic signs and symptoms such as hyperthermia. Two new cases of toddlers intoxicated with ecstasy are described. The first patient, a 19-month-old boy, presented with convulsions but no sympathetic signs. The pediatrician's suspicion was raised because of the absence of a postictal state. The second patient, a 20-month-old girl, had a more typical presentation with convulsions and hyperthermia. Her story illustrates the fact that immunoassays for toxicological screening can easily miss traces of additional illicit drugs present in the urine such as cocaine. The presence of other illicit drugs provides clues to the child's risky environment and should lead to further investigation. Finally, we review the available literature on ecstasy intoxication to summarize the key presenting manifestations. 22976840 Physiological and behavioral engagement in social contexts as predictors of adolescent depressive symptoms. Depressive symptoms are considered to have evolutionary social functions to reduce social risks with peers and family members. However, social processes and their relationship to depressive symptoms have been understudied in adolescent boys. Low engagement in social contexts may predict depressive symptoms in adolescent boys, as it may signify efforts to reduce social risks. To address these issues, this study focused on 160 boys at risk for affective problems based on low socioeconomic status. We evaluated how behavioral and physiological engagement in peer and family contexts, respectively, in late childhood predicted depressive symptoms at age 12 and age 15. Social withdrawal was measured across late childhood (ages 9-12) in a camp setting using a latent variable of teacher ratings of withdrawn behavior, peer nominations of withdrawn behavior, and camp counselor ratings of withdrawn behavior. Physiological reactivity was measured during a provocative parent-child conversation using respiratory sinus arrhythmia (RSA) at age 12. Social withdrawal in late childhood predicted depressive symptoms at age 12. The combination of high levels of social withdrawal with peers from ages 9-12 and low RSA reactivity with a parent at age 12 predicted higher depressive symptoms at age 15. Withdrawal in multiple social contexts may place boys at risk for depressive symptoms during the vulnerable period of adolescence. 23506214 Comprehensive Experimental and Computational Analysis of Binding Energy Hot Spots at the NF-κB Essential Modulator/IKKβ Protein-Protein Interface. We report a comprehensive analysis of binding energy hot spots at the protein-protein interaction (PPI) interface between nuclear factor kappa B (NF-κB) essential modulator (NEMO) and IκB kinase subunit β (IKKβ), an interaction that is critical for NF-κB pathway signaling, using experimental alanine scanning mutagenesis and also the FTMap method for computational fragment screening. The experimental results confirm that the previously identified NEMO binding domain (NBD) region of IKKβ contains the highest concentration of hot-spot residues, the strongest of which are W739, W741, and L742 (ΔΔG = 4.3, 3.5, and 3.2 kcal/mol, respectively). The region occupied by these residues defines a potentially druggable binding site on NEMO that extends for ∼16 Å to additionally include the regions that bind IKKβ L737 and F734. NBD residues D738 and S740 are also important for binding but do not make direct contact with NEMO, instead likely acting to stabilize the active conformation of surrounding residues. We additionally found two previously unknown hot-spot regions centered on IKKβ residues L708/V709 and L719/I723. The computational approach successfully identified all three hot-spot regions on IKKβ. Moreover, the method was able to accurately quantify the energetic importance of all hot-spot residues involving direct contact with NEMO. Our results provide new information to guide the discovery of small-molecule inhibitors that target the NEMO/IKKβ interaction. They additionally clarify the structural and energetic complementarity between "pocket-forming" and "pocket-occupying" hot-spot residues, and further validate computational fragment mapping as a method for identifying hot spots at PPI interfaces. 23584247 Los Angeles County Department of Public Health's Health Hazard Assessment: Putting the "Health" Into Hazard Assessment. A ll communities, explicitly or implicitly, assess and prepare for the natural and manmade hazards that they know could impact their community. The commonality of hazard-based threats in most all communities does not usually result in standard or evidence-based preparedness practice and outcomes across those communities. Without specific efforts to build a shared perspective and prioritization, "all-hazards" preparedness can result in a random hodgepodge of priorities and preparedness strategies, resulting in diminished emergency response capabilities. Traditional risk assessments, with a focus on physical infrastructure, do not present the potential health and medical impacts of specific hazards and threats. With the implementation of Centers for Disease Control and Prevention's capability-based planning, there is broad recognition that a health-focused hazard assessment process-that engages the "Whole of Community"-is needed. Los Angeles County's Health Hazard Assessment and Prioritization tool provides a practical and innovative approach to enhance existing planning capacities. Successful utilization of this tool can provide a way for local and state health agencies and officials to more effectively identify the health consequences related to hazard-specific threats and risk, determine priorities, and develop improved and better coordinated agency planning, including community engagement in prioritization. 23867797 Susceptibility of Podocytes to Palmitic Acid Is Regulated by Stearoyl-CoA Desaturases 1 and 2. Type 2 diabetes mellitus is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are highly susceptible to saturated FFAs but not to protective, monounsaturated FFAs. We report that patients with diabetic nephropathy develop alterations in glomerular gene expression of enzymes involved in fatty acid metabolism, including induction of stearoyl-CoA desaturase (SCD)-1, which converts saturated to monounsaturated FFAs. By IHC of human renal biopsy specimens, glomerular SCD-1 induction was observed in podocytes of patients with diabetic nephropathy. Functionally, the liver X receptor agonists TO901317 and GW3965, two known inducers of SCD, increased Scd-1 and Scd-2 expression in cultured podocytes and reduced palmitic acid-induced cell death. Similarly, overexpression of Scd-1 attenuated palmitic acid-induced cell death. The protective effect of TO901317 was associated with a reduction of endoplasmic reticulum stress. It was lost after gene silencing of Scd-1/-2, thereby confirming that the protective effect of TO901317 is mediated by Scd-1/-2. TO901317 also shifted palmitic acid-derived FFAs into biologically inactive triglycerides. In summary, SCD-1 up-regulation in diabetic nephropathy may be part of a protective mechanism against saturated FFA-derived toxic metabolites that drive endoplasmic reticulum stress and podocyte death. 23968398 A Metabolomic Study to Identify New Globotriaosylceramide-Related Biomarkers in the Plasma of Fabry Disease Patients. Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme alpha-galactosidase A which results in the progressive accumulation of glycosphingolipids. In addition to the two biomarkers, globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) which are routinely used for detection and high-risk screening of Fabry disease patients, novel urinary Gb3 related isoforms/analogs, as well as newly defined lyso-Gb3 analogs in plasma and urine from Fabry patients have recently been described by our group. The aim of this study was to, using a mass spectrometry metabolomic approach, extend our recent analyses to identify and evaluate new potential Gb3-related biomarkers in the plasma of untreated male Fabry disease patients. A multivariate statistical analysis revealed five Gb3 related novel biomarkers in the plasma of male Fabry patients. Three of these new biomarkers correspond to Gb3 having an extra double bond on the sphingosine with C16:0, C18:0 and C22:1 fatty acid chains. The fourth biomarker corresponds to a mixture of two structural isomers, the first with a d16:1 sphingosine and a C16:0 fatty acid and the other with a d18:0 sphingosine and a C14:0 fatty acid. To our knowledge, it is the first time that a Gb3 analog with a d16:1 sphingosine moiety has been reported. In addition, this Gb3 analog was also present in its methylated form. These biomarkers are part of a metabolic profile which may provide insight into the pathophysiology of Fabry disease. 23826704 Simultaneous analysis of noble gases, sulfur hexafluoride, and other dissolved gases in water. We developed an analytical method for the simultaneous measurement of dissolved He, Ne, Ar, Kr, Xe, SF6, N2, and O2 concentrations in a single water sample. The gases are extracted from the water using a head space technique and are transferred into a vacuum system for purification and separation into different fractions using a series of cold traps. Helium is analyzed using a quadrupole mass spectrometer (QMS). The remaining gas species are analyzed using a gas chromatograph equipped with a mass spectrometer (GC-MS) for analysis of Ne, Ar, Kr, Xe, N2, and O2 and an electron capture detector (GC-ECD) for SF6 analysis. Standard errors of the gas concentrations are approximately 8% for He and 2-5% for the remaining gas species. The method can be extended to also measure concentrations of chlorofluorocarbons (CFCs). Tests of the method in Lake Lucerne (Switzerland) showed that dissolved gas concentrations agree with measurements from other methods and concentrations of air saturated water. In a small artificial pond, we observed systematic gas supersaturations, which seem to be linked to adsorption of solar irradiation in the pond and to water circulation through a gravel bed. 23355480 Efficient stacking on protein amide fragments. The less polar π-surface of protein amide groups is exposed in many receptor binding sites, either as part of the backbone or in Gln/Asn side chains. Using quantum chemical calculations and Protein Data Bank (PDB) searches on model systems, we investigate the energetics and geometric preferences for the stacking on amide groups of a large number of heteroarenes that are relevant to medicinal chemistry. From this study, we discern that the stacking energy of an aromatic ligand substituent can be improved by: 1) orienting the fragment dipole vector such that it is aligned in an antiparallel fashion with the dipole of the interacting protein amide group, 2) increasing its dipole moment, and 3) decreasing its π-electron density. These guidelines should be helpful to more rationally exploit this interaction type in future structure-based drug design. 23057501 The impact of Prader-Willi syndrome on the family's quality of life and caregiving, and the unaffected siblings' psychosocial adjustment. Prader-Willi syndrome (PWS), a complex multisystem genetic disorder, is characterised by developmental abnormalities leading to somatic and psychological symptoms. Symptoms of PWS include infantile hypotonia and failure-to-thrive, followed by life-long hyperphagia, developmental delays and moderate-to-severe behavioural problems and several physical problems that impact health. This study examined the effects of caring for a child diagnosed with PWS on the mothers and unaffected siblings. We assessed overall family functioning, the mothers' psychological health, the psychosocial and behavioural functioning of siblings, and the quality of life of siblings. Participants included 12 mothers and 13 siblings of a child with genetically confirmed PWS. Self-report measures administered to the mothers evaluated overall family functioning (PedsQL - Family Impact Module), the mothers' psychological health (Brief Symptom Inventory), and the mothers' perception of the sibling's quality of life (PedsQL - Parent Proxy). Self-report measures administered to the siblings evaluated their perceived quality of life (PedsQL) and symptoms of post-traumatic stress disorder (PTSD) (UCLA PTSD Index). Families/mothers/siblings with children with PWS showed poorer perceived quality of life compared with general inpatient and outpatient samples of children with complex health conditions. Families/mothers/siblings with children with PWS reported difficulties in family functioning, communication problems, and an increased number of conflicts. They appeared to be experiencing significant behavioural distress symptoms, with higher than average levels of depression and feelings of isolation, anger and worry. Ninety-two per cent of the siblings indicated moderate-to-severe symptoms of PTSD. Compared with normative populations, siblings demonstrated poorer quality of life, with mothers perceiving more significant deficits in the sibling. This study reaffirms that PWS affects the entire family system. Mothers and siblings would benefit from psychosocial support due to the multiple challenges of living with and caring for a child/young adult with PWS. 23534031 Resin-Dentin Bonds of Etch-and-Rinse Adhesives to Alcohol-saturated Acid-etched Dentin. Purpose: To evaluate the effect of the alcohol wet-bonding technique on bond performance of the adhesive interface produced by two-step etch-and-rinse adhesive systems. Materials and Methods: Composite buildups were bonded to sectioned human third molars using Adper Single Bond 2 (SB) bonded to acid-etched dentin saturated with water (control) or ethanol, or XP Bond (XP) bonded to acid-etched dentin saturated with water (control) or tert-butanol. A simplified dentin dehydration protocol was performed using 100% ethanol or 99.5% tert-butanol directly applied to dentin for 60 s. Specimens were cut into nontrimming dentin-composite beams that were divided equally in two subgroups: immediately tested and after immersion in 10% NaOCl solution for 1 h. Specimens were tested in tension at a crosshead speed of 1 mm/ min until failure, and the failure mode was evaluated. Data were statistically analyzed with three-way ANOVA and Tukey's test (α = 0.05). Additional dentin disks were bonded using the same groups tested and examined for leakage under light microscopy after immersion in ammoniacal silver nitrate solution. Results: The SB control group showed significantly higher bond strength values than did SB used on ethanolsaturated dentin (p < 0.05); this tendency was confirmed by the silver nitrate deposition. The use of tert-butanol did not influence XP bond strength values (p > 0.05) or silver nitrate penetration. NaOCl solution significantly reduced the bond strength of all groups tested (p < 0.05) and also increased the interfacial silver nitrate penetration. Conclusion: The simplified alcohol wet-bonding technique used in the present study was not able to improve resin/dentin bond performance for simplified etch-and-rinse adhesive systems. 22887463 A crown-ether loop-derivatized oligothiophene doubly attached on gold surface as cation-binding switchable molecular junction. A crown-ether dithiol quaterthiophene is synthesized and immobilized on gold surface by double covalent fixation. UV-vis spectroscopy and cyclic voltammetry show that the corresponding dithioester precursor can complex Pb(2+) in solution and that this property is maintained for monolayers of the dithiol on gold. Current-voltage measurements by eutectic GaIn drop contact on the monolayer show a significant increase (up to 1.6 × 10(3) times) of the current at low bias after Pb(2+) complexation. 23874892 Conditional VHL Gene Deletion Causes Hypoglycemic Death Associated with Disproportionately Increased Glucose Uptake by Hepatocytes through an Upregulated IGF-I Receptor. Our conditional VHL knockout (VHL-KO) mice, having VHL gene deletion induced by tamoxifen, developed severe hypoglycemia associated with disproportionately increased storage of PAS-positive substances in the liver and resulted in the death of these mice. This hypoglycemic state was neither due to impaired insulin secretion nor insulin receptor hypersensitivity. By focusing on insulin-like growth factor I (IGF-I), which has a similar effect on glucose metabolism as the insulin receptor, we demonstrated that IGF-I receptor (IGF-IR) protein expression in the liver was upregulated in VHL-KO mice compared to that in the mice without VHL deletion, as was the expression of glucose transporter (GLUT) 1. The interaction of the receptor for activated C kinase (RACK) 1, which predominantly binds to VHL, was enhanced in VHL-KO livers with IGF-IR, because VHL deletion increased free RACK1 and facilitated the IGF-IR-RACKI interaction. An IGF-IR antagonist retarded hypoglycemic progression and sustained an euglycemic state. These IGF-IR antagonist effects on restoring blood glucose levels also attenuated PAS-positive substance storage in the liver. Because the effect of IGF-I on HIF-1α protein synthesis is mediated by IGF-IR, our results indicated that VHL inactivation accelerated hepatic glucose storage through the upregulation of IGF-IR and GLUT1 and that IGF-IR was a key regulator in VHL-deficient hepatocytes. 23826622 Epigallocatechin gallate effectively ameliorates fluoride-induced oxidative stress and DNA damage in the liver of rats. Environmental exposure to sodium fluoride (NaF) compounds is a worldwide health concern. Epigallocatechin gallate (EGCG) is a green tea catechin found in a variety of green tea preparations. The intention of this study was to investigate the hepatoprotective role of EGCG in NaF-intoxicated rats. Rats were orally treated with NaF alone (25 mg·(kg body mass)(-1)·day(-1)) or plus EGCG at different doses (20, 40, and 80 mg·(kg body mass)(-1)·day(-1)) for 4 weeks. Hepatotoxicity of NaF was determined by increased levels of serum hepatospecific markers and total bilirubin, along with increased levels of thiobarbituric acid reactive substances, lipid hydroperoxides, protein carbonyl content, and conjugated dienes. The hepatotoxic nature of NaF was further evidenced by the decreased activity of enzymatic and nonenzymatic antioxidant levels in liver. NaF-treated rats also showed increased DNA damage and fragmentation in hepatocytes. Administration of EGCG (40 mg·(kg body mass)(-1)) to NaF-intoxicated rats significantly recuperated the distorted biochemical indices, DNA damage, and pathological changes in the liver tissue. Thus, the results of the present study clearly demonstrate that EGCG has strong free radical scavenging, antioxidant, and antigenotoxic properties that protect against NaF-induced oxidative hepatic injury in rats. 23707310 Cortical excitability changes after high-frequency repetitive transcranial magnetic stimulation for central poststroke pain. Central poststroke pain (CPSP) is one of the most refractory chronic pain syndromes. Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex has been demonstrated to provide moderate pain relief for CPSP. However, the mechanism underlying the pain relief remains unclear. The objective of this study was to assess changes in cortical excitability in patients with intractable CPSP before and after rTMS of the primary motor cortex. Subjects were 21 patients with CPSP of the hand who underwent rTMS. The resting motor threshold, the amplitude of the motor evoked potential, duration of the cortical silent period, short interval intracortical inhibition, and intracortical facilitation were measured as parameters of cortical excitability before and after navigation-guided 5 Hz rTMS of the primary motor cortex corresponding to the painful hand. Pain reduction from rTMS was assessed with a visual analog scale. The same parameters were measured in both hemispheres of 8 healthy controls. Eight of 21 patients experienced ≥ 30% pain reduction after rTMS (responders). The resting motor threshold in the patients was higher than those in the controls at baseline (P=.035). Intracortical facilitation in the responders was lower than in the controls and the nonresponders at baseline (P=.035 and P=.019), and significantly increased after rTMS (P=.039). There were no significant differences or changes in the other parameters. Our findings suggest that restoration of abnormal cortical excitability might be one of the mechanisms underlying pain relief as a result of rTMS in CPSP. 23885789 Economic analysis of complementary, alternative, and integrative medicine: considerations raised by an expert panel. An international panel of experts was convened to examine the challenges faced in conducting economic analyses of Complementary, Alternative and Integrative Medicine (CAIM). A one and a half-day panel of experts was convened in early 2011 to discuss what was needed to bring about robust economic analysis of CAIM. The goals of the expert panel were to review the current state of the science of economic evaluations in health, and to discuss the issues involved in applying these methods to CAIM, recognizing its unique characteristics. The panel proceedings were audiotaped and a thematic analysis was conducted independently by two researchers. The results were then discussed and differences resolved. This manuscript summarizes the discussions held by the panel members on each theme. The panel identified seven major themes regarding economic evaluation that are particularly salient to determining the economics of CAIM: standardization (in order to compare CAIM with conventional therapies, the same basic economic evaluation methods and framework must be used); identifying the question being asked, the audience targeted for the results and whose perspective is being used (e.g., the patient perspective is especially relevant to CAIM because of the high level of self-referral and out-of-pocket payment); the analytic methods to be used (e.g., the importance of treatment description and fidelity); the outcomes to be measured (e.g., it is important to consider a broad range of outcomes, particularly for CAIM therapies, which often treat the whole person rather than a specific symptom or disease); costs (e.g., again because of treating the whole person, the impact of CAIM on overall healthcare costs, rather than only disease-specific costs, should be measured); implementation (e.g., highlighting studies where CAIM allows cost savings may help offset its image as an "add on" cost); and generalizability (e.g., proper reporting can enable study results to be useful beyond the study sample). The business case for CAIM depends on economic analysis and standard methods for conducting such economic evaluations exist. The challenge for CAIM lies in appropriately applying these methods. The deliberations of this panel provide a list of factors to be considered in meeting that challenge. 23968842 Altered EEG lagged coherence during rest in obsessive-compulsive disorder. Functional magnetic resonance imaging (fMRI) studies found alterations of functional connectivity in obsessive compulsive disorder (OCD). However, there is little knowledge about region of interest (ROI) based electroencephalogram (EEG) connectivity, i.e. lagged non-linear and linear coherence in OCD. Goal of this study was to compare these EEG measures during rest and at different vigilance stages between patients and healthy controls (HC). A 15min resting-state EEG was recorded in 30 unmedicated patients and 30 matched HC. Intracortical lagged non-linear coherence of the main EEG-frequency bands within a set of frontal ROIs and within the default mode network (DMN) were computed and compared using intracortical exact low resolution electromagnetic tomography (eLORETA) software. Lagged non-linear but not linear coherence was significantly decreased for patients in comparison to HC for the beta 2 frequency between frontal brain areas but not within the DMN. When analysing separate EEG-vigilance stages, only high vigilance stages yielded decreased frontal phase synchronisation at beta and theta frequencies. The results underline an altered neuronal communication within frontal brain areas during rest in OCD. These findings encourage further research on connectivity measures as possible biomarkers for physiological homogeneous subgroups. 23406313 High genetic diversity and novelty in planktonic protists inhabiting inland and coastal high salinity water bodies. We analyzed the genetic diversity (18S rRNA gene) of planktonic microbial eukaryotes in 34 different coastal and inland saline ponds. A wide range of environmental conditions was covered with up to 30-fold differences in salinity concentrations (12.5-384 g L(-1)), and in situ temperatures (1.3-37.5 °C), and three orders of magnitude in the trophic status (i.e. chlorophyll a < 0.1 to >50 mg L(-1)). Geographically distant sites were studied with contrasting salt origins, and different temporal patterns of wetting and drying. The genetic diversity was high, far beyond the few groups traditionally considered as high salinity-adapted, with sequences spread throughout eight high-rank taxonomic groups and 27 eukaryal classes. The novelty level was extremely high, with 10% of the whole dataset showing < 90% identity to any previously reported sequence in GenBank. Opisthokonta and Rhizaria contained the highest novelty and Chlorophyta and Alveolata the lowest. Low identity sequences were observed both in coastal and inland sites and at lower and at higher salinities, although the degree of novelty was higher in the hypersaline waters (> 6.5% salinity). Overall, this study shows important gaps in the current knowledge about protists inhabiting continental (hyper)saline water bodies, highlighting the need for future, more detailed investigations. 23686868 Evaluation of revised IPSS cytogenetic risk stratification and prognostic impact of monosomal karyotype in 783 patients with primary myelodysplastic syndromes. Cytogenetic classification by the revised international prognostic scoring system (IPSS-R) and the prognostic value of monosomal karyotype (MK) were assessed in 783 patients with primary myelodysplastic syndromes (MDS). At 22 months median follow-up, 562 (72%) deaths were recorded. Percentages of patients with IPSS-R "very good," "good," "intermediate," "poor," and "very poor" cytogenetic categories was 5, 63, 18, 4, and 10%, respectively. The corresponding median survivals were 21, 40, 24, 18, and 6.5 months and the inter-group differences (good vs. very good/intermediate/poor vs. very poor; P < 0.01) or similarities (very good vs. intermediate vs. poor; P = 0.79) were not significantly modified in multivariable analysis. Results were similar when analysis was restricted to 602 patients managed by supportive care. MK adversely affected survival in both poor and very poor karyotype groups (P < 0.01). In conclusion, we were unable to confirm the prognostic superiority of IPSS-R-very good karyotype or prognostically distinguish between very good, intermediate and poor karyotypes. Furthermore, we show additional prognostic information from MK in poor/very poor karyotype. Am. J. Hematol. 88:690-693, 2013. © 2013 Wiley Periodicals, Inc. 22823948 Molecular characterization of the horse isolate of Echinococcus granulosus in Turkey. Cystic echinococcosis is one of the most important helminthozoonoses, affecting various species of intermediate hosts and humans. In this report, we present Echinococcus granulosus infection in a horse and its molecular characterization. Polymerase chain reaction (PCR) amplification of mitochondrial 12S rRNA (mt-12S rRNA) and partial sequencing of mitochondrial cytochrome c oxidase subunit 1 (mt-CO1) genes were performed. According to the mt-12S rRNA-PCR result, the horse isolate was grouped with E. granulosus sensu stricto (G1-G3) and the partial mt-CO1 sequence corresponded to the G1 strain. This is the first study of the molecular characterization of the horse isolate of E. granulosus in Turkey. 23221636 An in vitro network of intermolecular interactions between viral RNA segments of an avian H5N2 influenza A virus: comparison with a human H3N2 virus. The genome of influenza A viruses (IAV) is split into eight viral RNAs (vRNAs) that are encapsidated as viral ribonucleoproteins. The existence of a segment-specific packaging mechanism is well established, but the molecular basis of this mechanism remains to be deciphered. Selective packaging could be mediated by direct interaction between the vRNA packaging regions, but such interactions have never been demonstrated in virions. Recently, we showed that the eight vRNAs of a human H3N2 IAV form a single interaction network in vitro that involves regions of the vRNAs known to contain packaging signals in the case of H1N1 IAV strains. Here, we show that the eight vRNAs of an avian H5N2 IAV also form a single network of interactions in vitro, but, interestingly, the interactions and the regions of the vRNAs they involve differ from those described for the human H3N2 virus. We identified the vRNA sequences involved in five of these interactions at the nucleotide level, and in two cases, we validated the existence of the interaction using compensatory mutations in the interacting sequences. Electron tomography also revealed significant differences in the interactions taking place between viral ribonucleoproteins in H5N2 and H3N2 virions, despite their canonical '7 + 1' arrangement. 23969043 Frequency power and coherence of electroencephalography are correlated with the severity of Alzheimer's disease: A multicenter analysis in Taiwan. Slowing of average electroencephalography (EEG) frequency in Alzheimer's disease (AD) is well established, but whether EEG changes are able to reflect the severity of AD is uncertain. We attempt to establish quantitative EEG parameters that are suitable for evaluating AD in clinical practice. Ninety-five patients with newly diagnosed AD at different stages from four neurologic institutes were enrolled for the study. Standard scalp resting EEG data were collected for quantitative analysis. Global band power ratio and interhemispheric alpha band coherence were calculated. Patients with advanced AD had a greater slow-to-fast wave power ratio. Among several power ratio parameters, global theta and delta to alpha and beta band power ratio showed the best correlation with stages of AD (p < 0.05 between any two patient groups). Patients with advanced AD had decreased coherence in multiple brain regions. The phenomenon was most prominent in the centroparietal region (p < 0.05 between any two patient groups). Increased global slow-to-fast power ratio and decreased centroparietal interhemispheric alpha band coherence are strongly correlated with disease progress in AD patients. These two quantitative EEG parameters may help evaluate AD patients in daily clinical practice. Global power ratio changes may suggest a shift of dominant frequency, and decreased interhemispheric alpha band coherence may suggest functional disconnection and corpus callosum abnormalities in AD patients. 23320865 Inflammation and cancer revisited: An hypothesis on the oncogenic potential of the apoptotic tumor cell. It is well known that an important property of apoptosis is the prevention of cancer. However, it is becoming increasingly clear that apoptotic cells have the capacity to activate reparative and regenerative responses, which have the potential to make significant impact on pathological processes underlying autoimmune disease and cancer. Those properties of apoptotic cells that influence their immediate microenvironment are reviewed here in the context of cancer progression and treatment. 23689369 The Lectin Domain of the Polypeptide GalNAc Transferase Family of Glycosyltransferases (ppGalNAc Ts) Acts as a Switch Directing Glycopeptide Substrate Glycosylation in an N- or C-terminal Direction, Further Controlling Mucin Type O-Glycosylation. Mucin type O-glycosylation is initiated by a large family of polypeptide GalNAc transferases (ppGalNAc Ts) that add α-GalNAc to the Ser and Thr residues of peptides. Of the 20 human isoforms, all but one are composed of two globular domains linked by a short flexible linker: a catalytic domain and a ricin-like lectin carbohydrate binding domain. Presently, the roles of the catalytic and lectin domains in peptide and glycopeptide recognition and specificity remain unclear. To systematically study the role of the lectin domain in ppGalNAc T glycopeptide substrate utilization, we have developed a series of novel random glycopeptide substrates containing a single GalNAc-O-Thr residue placed near either the N or C terminus of the glycopeptide substrate. Our results reveal that the presence and N- or C-terminal placement of the GalNAc-O-Thr can be important determinants of overall catalytic activity and specificity that differ between transferase isoforms. For example, ppGalNAc T1, T2, and T14 prefer C-terminally placed GalNAc-O-Thr, whereas ppGalNAc T3 and T6 prefer N-terminally placed GalNAc-O-Thr. Several transferase isoforms, ppGalNAc T5, T13, and T16, display equally enhanced N- or C-terminal activities relative to the nonglycosylated control peptides. This N- and/or C-terminal selectivity is presumably due to weak glycopeptide binding to the lectin domain, whose orientation relative to the catalytic domain is dynamic and isoform-dependent. Such N- or C-terminal glycopeptide selectivity provides an additional level of control or fidelity for the O-glycosylation of biologically significant sites and suggests that O-glycosylation may in some instances be exquisitely controlled. 23869585 The use of berberine for women with polycystic ovary syndrome undergoing IVF treatment. Previous studies have indicated that berberine is an effective insulin sensitizer with comparable activity to metformin (Diabetes 2006, 55, 2256). Reduced insulin sensitivity is reportedly a factor adversely affecting the outcome of IVF in patients with polycystic ovary syndrome (PCOS) (Human Reproduction 2006, 21, 1416). Our objective was to evaluate the clinical, metabolic and endocrine effects of berberine vs metformin in PCOS women scheduled for IVF treatment and to explore the potential benefits to the IVF process. We performed a prospective study in 150 infertile women with PCOS undergoing IVF treatment. Patients were randomized to receive berberine, metformin or placebo tablets for 3 months before ovarian stimulation. The clinical, endocrine, metabolic parameters and the outcome of IVF. Compared with placebo, greater reductions in total testosterone, free androgen index, fasting glucose, fasting insulin and HOMA-IR, and increases in SHBG, were observed in the berberine and metformin groups. Three months of treatment with berberine or metformin before the IVF cycle increased the pregnancy rate and reduced the incidence of severe ovarian hyperstimulation syndrome. Furthermore, treatment with berberine, in comparison with metformin, was associated with decreases in BMI, lipid parameters and total FSH requirement, and an increase in live birth rate with fewer gastrointestinal adverse events. Berberine and metformin treatments prior to IVF improved the pregnancy outcome by normalizing the clinical, endocrine and metabolic parameters in PCOS women. Berberine has a more pronounced therapeutic effect and achieved more live births with fewer side effects than metformin. 23313711 Detoxification of aldehydes by histidine-containing dipeptides: from chemistry to clinical implications. Aldehydes are generated by oxidized lipids and carbohydrates at increased levels under conditions of metabolic imbalance and oxidative stress during atherosclerosis, myocardial and cerebral ischemia, diabetes, neurodegenerative diseases and trauma. In most tissues, aldehydes are detoxified by oxidoreductases that catalyze the oxidation or the reduction of aldehydes or enzymatic and nonenzymatic conjugation with low molecular weight thiols and amines, such as glutathione and histidine dipeptides. Histidine dipeptides are present in micromolar to millimolar range in the tissues of vertebrates, where they are involved in a variety of physiological functions such as pH buffering, metal chelation, oxidant and aldehyde scavenging. Histidine dipeptides such as carnosine form Michael adducts with lipid-derived unsaturated aldehydes, and react with carbohydrate-derived oxo- and hydroxy-aldehydes forming products of unknown structure. Although these peptides react with electrophilic molecules at lower rate than glutathione, they can protect glutathione from modification by oxidant and they may be important for aldehyde quenching in glutathione-depleted cells or extracellular space where glutathione is scarce. Consistent with in vitro findings, treatment with carnosine has been shown to diminish ischemic injury, improve glucose control, ameliorate the development of complications in animal models of diabetes and obesity, promote wound healing and decrease atherosclerosis. The protective effects of carnosine have been linked to its anti-oxidant properties, its ability to promote glycolysis, detoxify reactive aldehydes and enhance histamine levels. Thus, treatment with carnosine and related histidine dipeptides may be a promising strategy for the prevention and treatment of diseases associated with high carbonyl load. 23664275 Endothelial PDGF-BB produced ex vivo correlates with relevant hemodynamic parameters in patients affected by chronic venous disease. Surgical specimens of vein were obtained from the tertiary venous network and/or saphenous vein from patients (n=20) affected by chronic venous disease (CVD). Into the venous segments, which subsequently were surgically ablated, the following hemodynamic parameters were assessed by echo-color-doppler (ECD): peak systolic velocity, end diastolic velocity, whose combination allowed the calculation of the resistance index (RI) and the reflux time (RT). Highly purified venous endothelial cell (VEC) cultures derived from venous segments of these CVD patients were then characterized for the profile of cytokines and chemokines released in the culture supernatants. Among the 27 cytokines and chemokines examined, we found a positive and significant correlation (R=0.5; p=0.03) only between the spontaneous release of PDGF-BB by VEC cultures and the RT values of the patients from which the VEC were isolates. In addition, the release of PDGF-BB in the VEC culture supernatants was significantly (p<0.01) increased upon in vitro treatment with recombinant TNF-α. By using pharmacological inhibitors, specific for the main pathways, NF-kB, ERK1/2 and p38 MAPK, activated by exposure of endothelial cells to TNF-α, we found that only NF-kB appeared to be significantly involved in mediating the PDGF-BB induction by TNF-α. Of interest, the release of PDGF-BB in response to the in vitro inflammatory stimulation, maintained a positive and significant correlation with RT (R=0.6; p=0.01), while showing a negative correlation with RI (R=-0.5; p=0.03). The potential implications of our findings for the pathophysiology of CVD are discussed. 23949264 Challenges of Respondent Driven Sampling to Assess Sexual Behaviour and Estimate the Prevalence of Human Immunodeficiency Virus (HIV) and Syphilis in Men Who Have Sex with Men (MSM) in Singapore. There is a lack of representative samples to provide reliable and accurate seroprevalence of sexually transmitted infections (STIs) and human immunodeficiency virus (HIV) as well as behavioural information among men who have sex with men (MSM) in Singapore. We used respondent driven sampling (RDS) to recruit MSM. Participants completed a survey used by Asian Internet MSM Sex Survey (AIMSS) and were tested for HIV and syphilis. We compared the characteristics of the RDS participants with STI diagnosis against those who did not have any STI diagnosis in the past 6 months. We compared RDS participants with AIMSS participants. Of 72 MSM recruited, 1 was positive for HIV (1.3%) and 4 (5.5%) tested positive for syphilis. Median age was 30 years and majority was Chinese (69.4%). RDS participants who had any STI diagnosis reported to have more use of recreational drugs (P = 0.006), and lower condom use (P = 0.054). Comparing RDS participants (n = 72) with the AIMSS participants (n = 2075), RDS respondents had ≥1 male partner in the past 6 months (P = 0.003), more casual sex partners (P = 0.012) and more STI symptoms (P = 0.019). There was no difference in terms of HIV testing and recreational drug use. The HIV and syphilis seroprevalence rates from our study are similar to previous reports conducted in high-risk MSM. In contrast to other settings, RDS did not work well among MSM in Singapore. The public health implications of our study highlight the challenges in obtaining data for HIV surveillance in assessing prevalence and risk behaviours among MSM. 23452431 Synthetic Approaches to RBC Mimicry and Oxygen Carrier Systems. Whole blood or red blood cell (RBC) transfusions are highly significant, clinically, for blood replacement therapies in traumatic injuries, presurgical conditions, and anemias. However, natural RBC-based products suffer from limited shelf life due to pathological contamination and also present risks of refractoriness, graft-versus-host disease, immunosuppression, and acute lung injury. These issues can be only partially resolved by pathogen reduction technologies, serological blood testing, leukoreduction, and specialized storage; hence, they severely affect the efficacy and safety of the blood products. Consequently, there is a significant interest in synthetic RBC analogues that can mimic its oxygen-transport properties while allowing convenient manufacture, reproducibility, long shelf life, and reduced biological risks. To this end, the current Review provides a comprehensive description and discussion of the various research approaches and current state-of-the-art in synthetically mimicking RBC's oxygen-carrying biochemical properties, as well as the biophysical parameters (shape, size and mechanical modulus) that influence RBCs' hemodynamic transport properties in blood flow. 23890360 Radiologic response to transcatheter hepatic arterial chemoembolization and clinical outcomes in patients with hepatocellular carcinoma. The current study analysed the association between radiologic tumour response and survival times of patients with hepatocellular carcinoma (HCC) who were treated with transcatheter hepatic arterial chemoembolization (TACE). Among 493 consecutive patients presenting to our institution between July 2002 and June 2010 with radiologically (n = 398) or histologically (n = 95) confirmed HCC, 368 patients who met inclusion criteria, underwent TACE and had confirmed survival data were retrospectively reviewed. The radiologic response was assessed using RECIST 1.1, EASL and mRECIST criteria at 1 month after the initial TACE. By univariate analysis, higher Child-Turcotte-Pugh (CTP) score, bilobar and multifocal distribution of tumours, larger tumour size (>5 cm), higher serum alpha-foetoprotein (AFP) level (>200 ng/ml), no subsequent radiofrequency ablation, advanced ECOG, UNOS and BCLC staging, absence of complete necrosis and non-responder (SD or PD) in RECIST 1.1, EASL and mRECIST response assessment were significantly associated with shorter overall survival times. By Cox proportional hazards model, advanced age, presence of ascites, higher MELD score, advanced BCLC staging, absence of complete necrosis and non-responder by RECIST 1.1, EASL and mRECIST criteria were independent and significant prognosticators for overall survival times in patients with HCC who underwent TACE. By time-dependent ROC curve analysis, mRECIST response criteria showed greatest accuracy in predicting survival (AUROC = 0.8676), followed by EASL (AUROC = 0.8471) and RECIST 1.1 (AUROC = 0.7986). mRECIST and EASL criteria for assessing radiologic response 1 month after initial TACE more consistently predict the differences in overall survival between responders and non-responders than conventional RECIST 1.1 criteria. 23770737 Detection of ligand-receptor binding using microfluidic frontal affinity chromatography on proteoliposomes derived directly from native cell membranes. A method for characterization of ligand binding to membrane receptors in their native cell membrane is presented. The methodology is based on microfluidic frontal affinity chromatography coupled to mass spectrometry (FAC-MS). Proteoliposomes with receptor of interest are prepared directly from cell membranes and serve as a stationary phase in a microfluidic flow cell for frontal analysis. The G-Protein-Coupled Receptor (GPCR) Ste2 involved in the pheromone-induced yeast mating pathway is used as a model receptor for proof of principle characterization. The ligand affinity of the natural pheromone peptide, the α-factor, is compared to a set of pheromone analogs having different receptor affinities. With short preparation time, preserved lipid composition and the ability to immobilize proteoliposomes from any cell membrane, we propose that our methodology with immobilized proteoliposomes together with microfluidics FAC-MS can be an important improvement for ligand-receptor studies in native membranes. 23695173 Glycemia-dependent Nuclear Factor κB Activation Contributes to Mechanical Allodynia in Rats with Chronic Postischemia Pain. Ischemia-reperfusion injury causes chronic postischemia pain (CPIP), and rats with higher glycemia during ischemia-reperfusion injury exhibit increased allodynia. Glycemia-induced elevation of nuclear factor κB (NFκB) may contribute to increased allodynia. Glycemia during a 3-h ischemia-reperfusion injury was manipulated by: normal feeding; or normal feeding with administration of insulin; dextrose; or insulin/dextrose. In these groups, NFκB was measured in ipsilateral hind paw muscle and spinal dorsal horn by enzyme-linked immunosorbent assay (ELISA), and SN50, an NFκB inhibitor, was administered to determine its differential antiallodynic effects depending on glycemia. CPIP fed/insulin rats (12.03 ± 4.9 g, N = 6) had less allodynia than fed, fed/insulin/dextrose, and fed/dextrose rats (6.29 ± 3.37 g, N = 7; 4.57 ± 3.03 g, N = 6; 2.95 ± 1.10 g, N = 9), respectively. Compared with fed rats (0.209 ± 0.022 AU, N = 7), NFκB in ipsilateral plantar muscles was significantly lower for fed/insulin rats, and significantly higher for fed/dextrose rats (0.152 ± 0.053 AU, N = 6; 0.240 ± 0.057 AU, N = 7, respectively). Furthermore, NFκB in the dorsal horn of fed, fed/insulin/dextrose, and fed/dextrose rats (0.293 ± 0.049 AU; 0.267 ± 0.037 AU; 0.315 ± 0.015 AU, respectively, N = 6 for each) was significantly higher than in fed/insulin animals (0.267 ± 0.037 AU, N = 6). The antiallodynic SN50 dose-response curves of CPIP rats in the fed/insulin/dextrose, fed/dextrose, and fed conditions exhibited a rightward shift compared with the fed/insulin group. The threshold SN50 dose of CPIP fed/dextrose, fed/insulin/dextrose, and fed rats (328.94 ± 92.4 ng, 77.80 ± 44.50 ng, and 24.89 ± 17.20 ng, respectively) was higher than that for fed/insulin rats (4.06 ± 7.04 ng). NFκB was activated in a glycemia-dependent manner in CPIP rats. Hypoglycemic rats were more sensitive to SN50 than rats with higher glycemia. The finding that SN50 reduces mechanical allodynia suggests that NFκB inhibitors might be useful for treating postischemia pain. 23567019 Species history and divergence times of viviparous and oviparous Chinese toad-headed sand lizards (Phrynocephalus) on the Qinghai-Tibetan Plateau. The Qinghai-Tibetan Plateau (QTP) is an important biogeographical area and has recently become a focus for biodiversity studies. Phyrnocephalus lizards form a widespread Eurasian group with oviparous and viviparous reproductive modes, but two previous mtDNA studies of species from around the QTP have provided different phylogenetic hypotheses. We analysed three loci (mtDNA, RAG-1, AME) from all recognised Chinese Phrynocephalus species to reconstruct the speciation history of the group and to estimate species divergence times. The effects of mtDNA partitioning strategy on phylogenetic inference were examined. Bayes factor comparisons of marginal likelihoods (mLs) estimated using stepping-stone sampling revealed that partitioning strategy had a major impact on mL. Nevertheless, it had a negligible effect on the inferred tree topology. The impact of hard-bound uniform or equivalent soft-bound gamma speciation time calibration priors as well as the use of a fixed topology (as opposed to integration over all possible species histories) on divergence time estimation were also assessed, and found to have little impact on posterior estimates. All three gene trees and the species tree supported the hypothesis that the Chinese species form oviparous and viviparous sister clades. This was in agreement with an early mtDNA study but differed from a subsequent reanalysis of the mtDNA data. Inclusion of mtDNA from more widely distributed Phrynocephalus (from previous studies) indicates that the oviparous P. interscapularis from Central Asia lies outside the clade of Chinese viviparous and oviparous species, but that other Asian oviparous species lie within the Chinese oviparous clade. The median of the posterior on the divergence time of Chinese oviparous and viviparous species was 9.7 Ma ago (95% interval: 7.2-13.0 Ma ago), which coincides with major uplifting of the QTP and indicates that viviparity evolved when this clade became restricted to regions of high elevation. We also found that cladogenesis within the viviparous clade began around 5 Ma ago whereas those in the oviparous clade began around 8.6 Ma ago. We establish more robust estimates of divergence times and relationships within this important group and so provide improved insights into the origins of Phrynocephalus diversity across the QTP. 23949284 Liquid-liquid extraction of neodymium(iii) by dialkylphosphate ionic liquids from acidic medium: the importance of the ionic liquid cation. The ionic liquids 1-hexyl-3-methylimidazolium bis(2-ethylhexyl)phosphate, [C6mim][DEHP], 1-hexyl-1-methylpyrrolidinium bis(2-ethylhexyl)phosphate, [C6mpyr][DEHP], and tetrabutylammonium bis(2-ethylhexyl)phosphate, [N4444][DEHP], were prepared and characterized using (1)H and (13)C NMR spectroscopy. The extraction behavior of neodymium(iii) from nitrate medium by these ionic liquids, diluted with the room temperature ionic liquids 1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [C6mim][NTf2], 1-hexyl-3-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide, [C6mpyr][NTf2], and tributylmethylammonium bis(trifluoromethylsulfonyl)imide, [N1444][NTf2], was studied. The distribution ratio of neodymium(iii) was measured as a function of various parameters, such as pH, concentration of the ionic liquid extractant, nature of diluents, concentration of ionic liquid cations and nitrate anions in the aqueous phase. The extraction behavior was compared with that obtained for a solution of the molecular extractant bis(2-ethylhexyl)phosphoric acid (DEHPA) in an ionic liquid diluent. The extraction of neodymium(iii) in the ionic liquids [C6mim][DEHP] and [C6mpyr][DEHP] showed markedly different extraction properties in comparison with that of the quaternary ammonium analogue [N4444][DEHP], especially concerning the pH dependence of the extraction process. These results show that the extraction process can be tuned by the selection of the ionic liquid cation. The extraction experiments also included the trivalent rare-earth ions lanthanum(iii), cerium(iii), praseodymium(iii), ytterbium(iii) and yttrium(iii). Studies of the stripping behavior and the reusability of the ionic liquids were carried out, which indicate that the ionic liquids can be reused with no loss in activity. 23768784 Autographa californica multiple nucleopolyhedrovirus PK-1 is essential for nucleocapsid assembly. PK-1 (Ac10) is a baculovirus-encoded serine/threonine kinase and its function is unclear. Our results showed that a pk-1 knockout AcMNPV failed to produce infectious progeny, while the pk-1 repair virus could rescue this defect. qPCR analysis demonstrated that pk-1 deletion did not affect viral DNA replication. Analysis of the repaired recombinants with truncated pk-1 mutants demonstrated that the catalytic domain of protein kinases of PK-1 was essential to viral infectivity. Moreover, those PK-1 mutants that could rescue the infectious BV production defect exhibited kinase activity in vitro. Therefore, it is suggested that the kinase activity of PK-1 is essential in regulating viral propagation. Electron microscopy revealed that pk-1 deletion affected the formation of normal nucleocapsids. Masses of electron-lucent tubular structures were present in cell transfected with pk-1 knockout bacmid. Therefore, PK-1 appears to phosphorylate some viral or cellular proteins that are essential for DNA packaging to regulate nucleocapsid assembly. 23917442 Influence of ambient air pollution on global DNA methylation in healthy adults: A seasonal follow-up. DNA methylation changes are potential pathways of environmentally induced health effects. We investigated whether exposure to ambient concentrations of NO2, PM10, PM2.5 and O3 and traffic parameters were associated with global DNA methylation in blood of healthy adults. 48 non-smoking adults (25 males) with a median age of 39years were sampled in winter and summer. Global DNA methylation in whole blood (% 5-methyl-2'-deoxycytidine, %5mdC) was analyzed with HPLC. Exposure to air pollutants at the home address was assessed using interpolated NO2, PM10, PM2.5 and O3 concentrations for various exposure windows (60- to 1-day moving average exposures and yearly averages) and GIS-based traffic parameters. Associations between pollutants and %5mdC were tested with multiple mixed effects regression models. Average %5mdC (SD) was 4.30 (0.08) in winter and 4.29 (0.08) in summer. Men had higher %5mdC compared to women both in winter (4.32 vs. 4.26) and summer (4.31 vs. 4.27). When winter and summer data were analyzed together, various NO2, PM10 and PM2.5 moving average exposures were associated with changes in %5mdC (95% CI) ranging from -0.04 (-0.09 to 0.00) to -0.14 (-0.28 to 0.00) per IQR increase in pollutant. NO2, PM10, PM2.5 and O3 moving average exposures were associated with decreased %5mdC (95% CI) varying between -0.01 (-0.03 to 0.00) and -0.17 (-0.27 to -0.06) per IQR increase in pollutant in summer but not in winter. Decreased global DNA methylation in whole blood was associated with exposure to NO2, PM10, PM2.5 and O3 at the home addresses of non- adults. Most effects were observed for the 5- to 30-day moving average exposures. 23842667 Global population variability in Promega PowerPlex CS7, D6S1043, and Penta B STRs. Supplementary short tandem repeats (STRs) can be added to forensic DNA analyses when core markers fail to provide sufficient discrimination power in identity and relationship testing. We combined D6S1043 and Penta B with Promega's PowerPlex CS7 supplementary STR kit, comprising Pentas D and E plus LPL, F13A01, FES/FPS, F13B, and Penta C. The nine STRs were typed in 941 individuals from 51 diverse populations of the CEPH Human Genome Diversity Panel (HGDP-CEPH), and we report allele frequency estimates plus rare alleles identified. Both Penta B and D6S1043 show highly informative variation in all populations, exceeding most CS7 STRs and raising cumulative random match probabilities by at least two orders of magnitude. However, Penta B genotype distributions show an excess of homozygotes across all HGDP-CEPH population groups indicating likely allele dropout from uncharted SNP or Indel variation at the primer sites chosen to type this STR. The first sequence analysis of common regular and rare intermediate D6S1043 alleles is reported. D6S1043 .3 intermediate alleles were found to occur at a high frequency in Native Americans, providing scope for differentiation of this group. 23748044 Pre-attentive auditory processing of non-scale pitch in absolute pitch possessors. Absolute pitch (AP) refers to the ability to identify the pitch of sound without reference. To clarify the neurophysiological characteristics of AP, we compared mismatch negativity (MMN) elicited by scale and non-scale notes between AP possessors and non-AP individuals. Eight individuals who were able to identify pitch with perfect accuracy were defined as AP possessors. Eighteen participants who failed to achieve perfect accuracy were included in the non-AP group. We presented participants with two tone pairs, in a scale condition and a non-scale condition. The frequency ratios of the two pairs were the same. MMN over the frontal region in the non-scale condition was larger in the AP group than the non-AP group. In contrast, no such difference was observed between the two groups in the scale condition. The results suggest that pre-attentive processing of non-scale note sounds in the auditory cortex is a salient neurophysiological characteristic of AP. 23873566 Impact of 6 different intestinal bacteria on broiler breeder sperm motility in vitro. Male fertility is often evaluated by measuring sperm parameters, including concentration, viability, and motility. This is important because after copulation occurs, sperm must overcome many barriers in the female reproductive tract to fertilize the ovum. In mammalian species, sperm have been shown to have reduced motility when bacteria are present. In male broiler breeders, bacteria have been associated with spermatozoa, but their effect on motility has not been investigated. The sperm quality index is a modern rapid method of evaluating avian sperm motility. Therefore, the objective of this study was to use the sperm quality index to determine if broiler breeder sperm motility is reduced when semen is exposed to various bacteria. In this experiment, semen was collected from 20 broiler breeders to obtain a pooled neat semen sample. Six different intestinal bacteria, Salmonella enterica, Escherichia coli, Campylobacter jejuni, Clostridium bifermentans, Lactobacillus acidophilus, and Bifidobacterium animalis were cultured overnight. For each bacterium, 50 µL of semen was diluted in 450 µL of saline, sterile broth, or the overnight culture, creating 3 treatments. The experiment was repeated twice. In each treatment, 3 replicates were evaluated at 0 and 10 min postinoculation, creating a completely randomized design with a split plot over time. Also, the pH was measured for each treatment at 0 and 10 min. The results indicated that all broths containing bacteria immediately reduced broiler breeder sperm motility when compared with the controls (P < 0.0001), but broths containing Bifidobacterium or Lactobacillus virtually made sperm immotile. Although broth containing Salmonella, Campylobacter, and Bifidobacterium immediately reduced sperm motility, the reduction did not change over time. Broths containing E. coli, Clostridium, and Lactobacillus reduced sperm motility immediately, but over time motility continued to decrease. However, pH was increased when semen was exposed to the E. coli and Campylobacter treatment, but when semen was exposed to Bifidobacterium and Lactobacillus treatments, pH was reduced. In conclusion, the results indicate that bacteria can reduce broiler breeder sperm motility upon exposure. 23607415 Mosquito-borne disease surveillance by the European Centre for Disease Prevention and Control. For a few years, a series of traditionally tropical mosquito-borne diseases, such as chikungunya fever and dengue, have posed challenges to national public health authorities in the European region. Other diseases have re-emerged, e.g. malaria in Greece, or spread to other countries, e.g. West Nile fever. These diseases are reportable within the European Union (EU), and the European Centre for Disease Prevention and Control collects information in various ways to provide EU member states with topical assessments of disease threats, risks and trends for prompt and appropriate public health action. Using disease-specific expert networks, the European Surveillance System (TESSy) collects standardized comparable information on all statutory communicable diseases in a database. In addition, the event-based surveillance aims to detect potential public health threats early, and to allow timely response and support to blood deferral decisions for pathogens that can be transmitted through blood donation. Laboratory capacity for early detection is implemented through external quality assessments. Other activities include the development of guidelines for the surveillance of mosquito vectors, and the production of regularly updated maps on the currently known occurrence of mosquito vector species. 23665646 Contamination risk of 100% autologous serum eye drops in management of ocular surface diseases. To evaluate the sterility and safety of 100% nonpreserved, autologous, serum eye drop treatment in patients with ocular surface diseases. A total of 147 autologous serum bottles (294 samples) from 21 patients with ocular surface diseases were included. Seven bottles with autologous serum were prepared for each patient, and each bottle was used for only 1 day, then discarded. Two samples from each bottle were taken (before use and after 24 hours of use) and then cultured in standard media. The culture plates were held for at least 6 weeks or until no growth could be confirmed. To monitor safety, all patients were admitted and evaluated for the occurrence of infection. In the pretreatment group, 4 samples from 4 patients (1.36%) were positive for bacteria and 7 samples from 7 patients (2.38%) were positive for fungi. In the 24-hour-after-treatment group, 1 culture (0.34%) was positive for bacteria, and 6 samples (2.04%) from 6 patients were positive for fungi. Aspergillus spp and Fonsecaea spp were the most common organisms identified in any of the cultures. Neither clinical nor microbiological evidence of infection was demonstrated in any patient during the treatment or follow-up periods. Although no ocular surface infection was observed, the patients under 100% autologous serum eye drops therapy should be closely monitored for clinical evidence of fungal and bacterial infections. 23763482 Myopia, contact lens use and self-esteem. To evaluate whether contact lens (CL) use was associated with self-esteem in myopic children originally enrolled in the Correction of Myopia Evaluation Trial (COMET), that after 5 years continued as an observational study of myopia progression with CL use permitted. Usable data at the 6-year visit, one year after CL use was allowed (n = 423/469, age 12-17 years), included questions on CL use, refractive error measurements and self-reported self-esteem in several areas (scholastic/athletic competence, physical appearance, social acceptance, behavioural conduct and global self-worth). Self-esteem, scored from 1 (low) to 4 (high), was measured by the Self-Perception Profile for Children in participants under 14 years or the Self-Perception Profile for Adolescents, in those 14 years and older. Multiple regression analyses were used to evaluate associations between self-esteem and relevant factors identified by univariate analyses (e.g., CL use, gender, ethnicity), while adjusting for baseline self-esteem prior to CL use. Mean (±S.D.) self-esteem scores at the 6-year visit (mean age = 15.3 ± 1.3 years; mean refractive error = -4.6 ± 1.5 D) ranged from 2.74 (± 0.76) on athletic competence to 3.33 (± 0.53) on global self-worth. CL wearers (n = 224) compared to eyeglass wearers (n = 199) were more likely to be female (p < 0.0001). Those who chose to wear CLs had higher social acceptance, athletic competence and behavioural conduct scores (p < 0.05) at baseline compared to eyeglass users. CL users continued to report higher social acceptance scores at the 6-year visit (p = 0.03), after adjusting for baseline scores and other covariates. Ethnicity was also independently associated with social acceptance in the multivariable analyses (p = 0.011); African-Americans had higher scores than Asians, Whites and Hispanics. Age and refractive error were not associated with self-esteem or CL use. COMET participants who chose to wear CLs after 5 years of eyeglass use had higher self-esteem compared to those who remained in glasses both preceding and following CL use. This suggests that self-esteem may influence the decision to wear CLs and that CLs in turn are associated with higher self-esteem in individuals most likely to wear them. 23404064 Anatomical connection strength predicts dopaminergic drug effects on fronto-striatal function. RATIONALE: The neurotransmitter dopamine plays a key role in cognitive functions that are associated with fronto-striatal circuitry and has been implicated in many neuropsychiatric disorders. However, there is a large variability in the direction and extent of dopaminergic drug effects across individuals. OBJECTIVES: We investigated whether individual differences in dopaminergic drug effects on human fronto-striatal functioning are associated with individual differences in white matter tracts. METHODS: The effects of the dopamine receptor agonist bromocriptine were assessed using functional magnetic resonance imaging in 22 healthy volunteers in a placebo-controlled, double-blind, within-subject design. Human psychopharmacology and functional neuroimaging were combined with functional connectivity analyses and structural connectivity analyses to establish a link between dopaminergic drug effects on fronto-striatal function and fronto-striatal anatomy. RESULTS: We demonstrate that bromocriptine alters functional signals associated with attention switching in the basal ganglia. Crucially, individual differences in the drug's effect on these signals could be predicted from individual differences in fronto-striato-thalamic white matter tracts, as indexed by diffusion tensor imaging. Anatomical fronto-striatal connectivity also predicted drug effects on switch-related functional connectivity between the basal ganglia and the prefrontal cortex. CONCLUSIONS: These data reinforce the link between dopamine, cognition and the basal ganglia and have implications for the individual tailoring of dopaminergic drug therapy based on anatomical fronto-striatal connection strength. 23895234 Endophthalmitis Caused by Alcaligenes Faecalis: A Case Series. Abstract Purpose: To profile the etiology, clinical outcomes and drug sensitivity patterns in endophthalmitis caused by Alcaligenes faecalis. Methods: Retrospective analysis of all the cases of A. faecalis endophthalmitis presenting to tertiary referral care ophthalmic hospital in Eastern India from January 2009 to December 2012 was done. Results: A total of five cases were included in the study. Out of the five cases, one was of endogenous origin and the rest were post cataract surgery. All but one case underwent vitreo-retinal surgical intervention followed by intravitreal antibiotics. Alcaligenes faecalis was isolated in all the cases. Sensitivity to ceftazidime, aminoglycosides and ciprofloxacin was 20%, 60% and 80%, respectively. Two patients attained a final visual acuity of 6/24. One eye became phthisical in due course. Conclusion. Alcaligenes faecalis is a very rare cause of endophthalmitis. Aminoglycosides and fluroquinolones can be considered as main line of treatment. 23485046 Synergistic interactions of epigallocatechin gallate and oxytetracycline against various drug resistant Staphylococcus aureus strains in vitro. Epigallocatechin gallate (EGCG), the major catechin contained in tea leaves, is known to possess the synergistic anti-staphylococcal activity in combination with various β-lactam antibiotics and tetracycline. In the present study, we explored the in vitro combinatory effect of EGCG in combination with oxytetracycline against eight standard strains and clinical isolates of Staphylococcus aureus, including erythromycin, methicillin and tetracycline resistant strains. The minimum inhibitory concentrations were determined by the broth microdilution assay and the data were evaluated according to the sum of fractional inhibitory concentrations (∑FIC). Our results showed synergistic and additive interactions against all S. aureus strains tested (∑FIC 0.288-0.631), two of which were multidrug resistant. According to our best knowledge, it is the first report on the EGCG synergy with oxytetracycline. Considering its significant synergistic antimicrobial effect and low toxicity, we suggest EGCG as a promising compound for the development of new anti-staphylococcal formulations. 23879202 Clinical Value of Magnetic Resonance Imaging and Other Baseline Testing for Conjunctival Mucosa-Associated Lymphoid Tissue Lymphoma. Abstract The objective of this study was to assess the value of magnetic resonance imaging (MRI) of orbit for conjunctival MALT lymphoma. The yield of other staging tests at baselin were also evaluated. 21 consecutive patients treated for conjunctival MALT lymphoma were retrospectively studied. Lymphoma was staged both according to the Ann Arbor staging and the 7th edition of the AJCC. Findings on MRI of orbit, whole body PET/CT, CT of chest/abdomen/pelvis, bone marrow (BM) biopsy, and gastrointestinal (GI) endoscopy were recorded. 17 patients had an orbital MRI. Fourteen of 17 patients (82%) with obvious conjunctival MALT lymphoma on clinical examination had a negative MRI. Only 3 patients had subtle conjunctival enhancement on orbital MRI. Ann Arbor stage at presentation was as follows: Stage IE (15 patients), stage IIE (2 patients), and stage IV (4 patients). Eighteen of 21 patients had total body PET/CT; four patients (22%) had hypermetabolic activity evident on the PET scan. All 21 patients had bilateral BM biopsies. Fifteen of 21 patients (71%) had GI endoscopy. None of the patients had a positive BM biopsy or findings on GI endoscopy. Our data suggest that orbital MRI has very low yield for identification of conjunctival MALT lymphoma. Clinical exam is critical in diagnosing and assessing treatment response for conjunctival MALT lymphoma. The yield for GI endoscopy and BM biopsy also maybe low in staging of conjunctival MALT lymphoma. 23868197 Restrictive eating behaviors are a nonweight-based marker of severity in anorexia nervosa. The purpose of this study was to compare the type and frequency of restrictive eating behaviors across the two subtypes of anorexia nervosa (AN; restricting [ANr] and binge eating/purging [ANbp]) using ecological momentary assessment (EMA) and to determine whether subtype differences in restrictive eating behaviors were attributable to severity of the disorder or the frequency of binge eating. Participants (N = 118) were women at least 18 years of age with full (n = 59) or subthreshold (n = 59) AN who participated in a two week (EMA) protocol. General estimating equations revealed that individuals with ANbp generally reported more frequent restrictive eating behaviors than individuals with ANr. These differences were mostly accounted for by greater severity of eating psychopathology, indicating that the presence and frequency of restrictive eating behaviors in AN may be nonweight-based markers of severity. Binge eating frequency did not account for these findings. The present findings are especially interesting in light of the weight-based severity rating in the DSM-5. © 2013 Wiley Periodicals, Inc. (Int J Eat Disord 2013). 23146748 Decreased levels of AKR1B1 and AKR1B10 in cancerous endometrium compared to adjacent non-cancerous tissue. Endometrial cancer is associated with enhanced cell proliferation due to high concentrations of estrogens, and decreased cell differentiation due to low levels of progesterone and retinoic acid. It is also associated with aberrant inflammatory responses and concomitant increased production of prostaglandins. The human members of the aldo-keto reductase 1B (AKR1B) subfamily, AKR1B1 and AKR1B10, have roles in these processes and can thus be implicated in endometrial cancer. To date, there have been no reports on the expression of AKR1B1 in endometrial cancer, while AKR1B10 has only been studied at the cellular level. To evaluate the roles of these AKR1B enzymes, we investigated expression of AKR1B1 and AKR1B10 in 47 paired samples of cancerous and adjacent control endometrium at the mRNA and protein levels, by quantitative PCR, Western blotting and immunohistochemistry staining. There were significantly lower mRNA and protein levels of AKR1B1 in cancerous tissues compared to adjacent endometrium. The gene expression of AKR1B10 at the mRNA level was significantly increased, while there were significantly decreased protein levels. Immunohistochemistry revealed that both of these enzymes were present in all of the samples, and are located in epithelial cells of cancerous and control endometrial glands. Elevated levels in adjacent non-cancerous tissues imply that these enzymes are more important in the initiation of endometrial cancer than in its progression. To the best of our knowledge, this is the first report on the expression of AKR1B1 and AKR1B10 in endometrial cancer. Further studies are needed to define the precise roles of these enzymes in the pathogenesis of endometrial cancer. 23918903 Supramolecular ferric porphyrins and a cyclodextrin dimer as antidotes for cyanide poisoning. Objectives:This study aimed to evaluate the antidotal effect of a newly developed supramolecular complex, ferric porphyrins and a cyclodextrin dimer (Fe(III)PIm3CD), that possess a higher binding constant and quicker binding rate to cyanide ions than those of hydroxocobalamin (OHCbl) in the presence of serum protein.Methods:First, in vitro cytochrome activity and cell viability were evaluated in murine fibroblast cells cultured with various doses of Fe(III)PIm3CD and potassium cyanide (KCN). Next, BALB/c mice were pretreated with intravenous OHCbl (0.23 mmol/kg), Fe(III)PIm3CD (0.23 mmol/kg), or saline and then received KCN (lethal dose 100% (LD100): 0.23 mmol/kg) through a stomach tube. Finally, as a resuscitation model, KCN-induced apnea was treated with a bolus injection of an equimolar dose of antidotes followed by a slow infusion of the same reagent.Results:Fe(III)PIm3CD showed dose-dependent antidotal effects in vitro. Pretreatment with Fe(III) PIm3CD prevented KCN-induced apnea significantly better than OHCbl. Resuscitation with Fe(III)PIm3CD resulted in an earlier resumption of respiration than that seen with OHCbl. However, 24-h survival was similar among the treatments (Fe(III)PIm3CD, nine of nine mice; OHCbl, eight of nine mice).Conclusion:Fe(III)PIm3CD exerted significant antidotal effects on cyanide toxicity in vitro and in vivo, with a potency equal in the mortality of cyanide-poisoned mice or superior in the respiratory status during an acute phase to those of OHCbl. 23894535 Involvement of the Same TNFR1 Residue in Mendelian and Multifactorial Inflammatory Disorders. TNFRSF1A is involved in an autosomal dominant autoinflammatory disorder called TNFR-associated periodic syndrome (TRAPS). Most TNFRSF1A mutations are missense changes and, apart from those affecting conserved cysteines, their deleterious effect remains often questionable. This is especially true for the frequent R92Q mutation, which might not be responsible for TRAPS per se but represents a susceptibility factor to multifactorial inflammatory disorders. This study investigates TRAPS pathophysiology in a family exceptional by its size (13 members) and compares the consequences of several mutations affecting arginine 92. TNFRSF1A screening was performed by PCR-sequencing. Comparison of the 3-dimensional structure and electrostatic properties of wild-type and mutated TNFR1 proteins was performed by in silico homology modeling. TNFR1 expression was assessed by FACS analysis, western blotting and ELISA in lysates and supernatants of HEK293T cells transiently expressing wild-type and mutated TNFR1. A TNFRSF1A heterozygous missense mutation, R92W (c.361C>T), was shown to perfectly segregate with typical TRAPS manifestations within the family investigated (p<5.10(-4)). It was associated with very high disease penetrance (0.9). Prediction of its impact on the protein structure revealed local conformational changes and alterations of the receptor electrostatic properties. R92W also impairs the TNFR1 expression at the cell surface and the levels of soluble receptor. Similar results were obtained with R92P, another mutation previously identified in a very small familial form with incomplete penetrance and variable expressivity. In contrast, TNFR1-R92Q behaves like the wild-type receptor. These data demonstrate the pathogenicity of a mutation affecting arginine 92, a residue whose involvement in inflammatory disorders is deeply debated. Combined with previous reports on arginine 92 mutations, this study discloses an unusual situation in which different amino acid substitutions at the same position in the protein are associated with a clinical spectrum bridging Mendelian to multifactorial conditions. 23395916 Mini-review: Foldosome regulation of androgen receptor action in prostate cancer. Steroid hormone receptors play diverse roles in many aspects of human physiology including cell division, apoptosis and homeostasis, tissue differentiation, sexual development and response to stress. These ligand-activated transcription factors require the functional activity of numerous chaperone and chaperone-associated proteins, collectively termed the foldosome, at the crucial step of ligand recognition and binding. Since the initial isolation of foldosome components and pioneering research by Pratt, Toft and colleagues we understand much regarding cytosolic receptor function. The classical view, that the role of foldosome components is restricted to the cytosol, has been modified over recent years by research highlighting additional roles of chaperone proteins in nuclear translocation and target gene expression. Further, dysregulation of chaperone activity and expression has been implicated in various cancers, including breast and prostate cancer. Consequently, the foldosome provides an attractive therapeutic target in steroid hormone receptor-driven malignancies. This review summarises current knowledge of how the foldosome impacts upon androgen receptor signalling, which is the key therapeutic target on prostate cancer, and how foldosome components may be used as biomarkers or therapeutic targets in this disease. 23589255 Photoelectro-Fenton mineralization of phenol through optimization of ferrous regeneration. The degradation of phenol in acidic solution at pH 3 has been investigated under various photo- and electrochemical conditions. A laboratory-scale reactor on which were mounted net electrodes (RuO2/IrO2-coated Ti anodes (DSA) and stainless steel cathodes) and 254 nm UV lamps was established to effectively reduce ferric reagents. The experimental results of the photoelectron-chemical reaction suggested that the current efficiency of reducing ferric ion was improved by increasing the number of electrodes used, and the UV lamps were important to inducing the reduction of ferric carboxylates, which were the major intermediates that were formed upon a particular degree of phenol oxidation. Accordingly, the addition of an initial concentration of 400 ppm ferrous salt and 10,200 ppm hydrogen peroxide (in a continuous mode) resulted in the removal of over 92 % of TOC (initial phenol = 2,000 ppm, TOC = 1,532 ppm) by 4 h of the photoelectro-Fenton and the sequential 2 h of the photo-Fenton processes. HPLC was utilized to monitor the formation of aromatic and carboxylate byproducts, and revealed that the aid of photo irradiation eliminated most of the oxalate residue from the final solution, which would have contributed to the 25 % of the TOC that was inactive in the electrolytic system. 23637074 High-Performance Vertical Organic Transistors. Vertical organic thin-film transistors (VOTFTs) are promising devices to overcome the transconductance and cut-off frequency restrictions of horizontal organic thin-film transistors. The basic physical mechanisms of VOTFT operation, however, are not well understood and VOTFTs often require complex patterning techniques using self-assembly processes which impedes a future large-area production. In this contribution, high-performance vertical organic transistors comprising pentacene for p-type operation and C60 for n-type operation are presented. The static current-voltage behavior as well as the fundamental scaling laws of such transistors are studied, disclosing a remarkable transistor operation with a behavior limited by injection of charge carriers. The transistors are manufactured by photolithography, in contrast to other VOTFT concepts using self-assembled source electrodes. Fluorinated photoresist and solvent compounds allow for photolithographical patterning directly and strongly onto the organic materials, simplifying the fabrication protocol and making VOTFTs a prospective candidate for future high-performance applications of organic transistors. 23416363 17β-Estradiol and steady-state concentrations of H2O2: antiapoptotic effect in endometrial cells from patients with endometriosis. Increased levels of hydrogen peroxide (H2O2) can initiate protective responses to limit or repair oxidative damage. However, H2O2 signals also fine-tune responses to growth factors and cytokines controlling cell division, differentiation, and proliferation. Because 17β-estradiol (E2) also plays important roles in these processes, and is considered a major risk factor in the development and progression of endometriosis, this study evaluated whether E2 has an antiapoptotic effect on oxidative stress in endometrial cells in combination with steady-state H2O2 levels ([H2O2]ss). Endometrial stromal cells were prepared from the eutopic endometrium of 18 women with and without endometriosis to produce primary cells. These cells were stimulated with E2 for 20h, exposed to [H2O2]ss, and examined for cell viability, proliferation, and apoptosis. The endometrial cells from women with endometriosis maintained the steady state for 120min at high H2O2 concentrations. When they were pretreated with E2 and exposed to [H2O2]ss, a decrease in apoptosis level was observed compared to the control cells (p<0.01). The endometrial cells from patients with endometriosis subjected to both E2 and [H2O2]ss showed increased ERK phosphorylation. These findings suggested that H2O2 is a signaling molecule that downregulates apoptosis in endometrial cells, supporting the fact that endometriosis, albeit a benign disease, shares some features with cancer such as decreased catalase levels. These results link the E2 effects on [H2O2]ss to resistance to apoptosis and progression of endometriosis. 23864031 Mapping mammalian synaptic connectivity. Mapping mammalian synaptic connectivity has long been an important goal of neuroscientists since it is considered crucial for explaining human perception and behavior. Yet, despite enormous efforts, the overwhelming complexity of the neural circuitry and the lack of appropriate techniques to unravel it have limited the success of efforts to map connectivity. However, recent technological advances designed to overcome the limitations of conventional methods for connectivity mapping may bring about a turning point. Here, we address the promises and pitfalls of these new mapping technologies. 23948602 Evolutionary hypothesis for Chiari type I malformation. Chiari I malformation (CM-I) is classically defined as a cerebellar tonsillar herniation (⩾5mm) through the foramen magnum. A decreased posterior fossa volume, mainly due to basioccipital hypoplasia and sometimes platybasia, leads to posterior fossa overcrowding and consequently cerebellar herniation. Regardless of radiological findings, embryological genetic hypothesis or any other postulations, the real cause behind this malformation is yet not well-elucidated and remains largely unknown. The aim of this paper is to approach CM-I under a broader and new perspective, conjoining anthropology, genetics and neurosurgery, with special focus on the substantial changes that have occurred in the posterior cranial base through human evolution. Important evolutionary allometric changes occurred during brain expansion and genetics studies of human evolution demonstrated an unexpected high rate of gene flow interchange and possibly interbreeding during this process. Based upon this review we hypothesize that CM-I may be the result of an evolutionary anthropological imprint, caused by evolving species populations that eventually met each other and mingled in the last 1.7million years. 23845208 Intrauterine contraception: impact of provider training on participant knowledge and provision. In California's Medicaid family planning expansion, the Family Planning, Access, Care and Treatment (Family PACT) Program, only 1.9% of contracepting women received intrauterine contraception (IUC) in 2006. Ten skills-based IUC provider trainings were offered from 2007 to 2010. The objective was to evaluate the impact of these trainings on participant knowledge of the broad range of appropriate IUC candidates and measure changes in IUC provision following training. We evaluated changes in provider knowledge using a nine-item IUC Candidate Selection Scale on pre- and posttraining surveys. Changes in provision of IUC following the training were measured using Family PACT claims data. We compared changes in insertions posttraining to pretraining levels as well as to matched comparison sites that did not send trainees. Most participants at the training were advanced practice clinicians (70%) specializing in general primary care (77%) and practicing at community clinics (45%). Training participants increased their understanding of appropriate candidates (mean change in raw summary score=8.6, p<.001), from an average of 58% correct responses to 81%. Provider sites that participated in training provided a mean of 4.6 more women with IUC following training than during baseline (p<.01), an increase of 25% compared to only 7% increase among comparison sites. The impact of the training differed by practice size such that the largest and smallest clinics both changed IUC provision the most and had the largest differences over comparison sites. This study shows that skills-based training is an important strategy for the increase of IUC provision. 23869021 Applications of acceptorless dehydrogenation and related transformations in chemical synthesis. Conventional oxidations of organic compounds formally transfer hydrogen atoms from the substrate to an acceptor molecule such as oxygen, a metal oxide, or a sacrificial olefin. In acceptorless dehydrogenation (AD) reactions, catalytic scission of C-H, N-H, and/or O-H bonds liberates hydrogen gas with no need for a stoichiometric oxidant, thereby providing efficient, nonpolluting activation of substrates. In addition, the hydrogen gas is valuable in itself as a high-energy, clean fuel. Here, we review AD reactions selectively catalyzed by transition metal complexes, as well as related transformations that rely on intermediates derived from reversible dehydrogenation. We delineate the methodologies evolving from this recent concept and highlight the effect of these reactions on chemical synthesis. 23947839 Decomposition-order effects of time integrator on ensemble averages for the Nosé-Hoover thermostat. Decomposition-order dependence of time development integrator on ensemble averages for the Nosé-Hoover dynamics is discussed. Six integrators were employed for comparison, which were extensions of the velocity-Verlet or position-Verlet algorithm. Molecular dynamics simulations by these integrators were performed for liquid-argon systems with several different time steps and system sizes. The obtained ensemble averages of temperature and potential energy were shifted from correct values depending on the integrators. These shifts increased in proportion to the square of the time step. Furthermore, the shifts could not be removed by increasing the number of argon atoms. We show the origin of these ensemble-average shifts analytically. Our discussion can be applied not only to the liquid-argon system but also to all MD simulations with the Nosé-Hoover thermostat. Our recommended integrators among the six integrators are presented to obtain correct ensemble averages. 23943629 An FP-CIT PET comparison of the difference in dopaminergic neuronal loss in subtypes of early Parkinson's disease. Patients with tremor-dominant Parkinson's disease (PD) have slower disease progression, show less cognitive decline, and have more favorable outcomes than patients with non-tremor PD. However, the pathophysiology of PD tremor remains unclear. Whether there are differences in nigrostriatal dopaminergic dysfunction between the two PD subtypes is unknown. To evaluate the differences in regional dopamine transporter (DAT) density in the brain between different subtypes of early PD using FP-CIT PET/CT. We recruited 43 patients with PD (21 tremor-dominant PD [TP] and 22 non-tremor-dominant PD [NTP]) and 18 age-matched healthy controls. All patients with PD underwent FP-CIT PET/CT imaging and evaluated Parkinsonian motor severity by using the Hoehn and Yahr stage and Part III of the Unified Parkinson's Disease Rating Scale (UPDRS). We also compared tremor and non-tremor symptoms with motor phenotype scores between two subtypes of PD. All patients with PD demonstrated a significantly decreased FP-CIT uptake in the putamen compared to healthy controls. Differences in putamen FP-CIT uptake versus caudate nucleus FP-CIT uptake in PD showed putamen uptake was significantly more impaired than that in the caudate nucleus. However, there was no significant difference in FP-CIT uptake in the striatum between both PD groups at the same early stage of disease. We suggest that differential of DAT uptake in the striatum did not allow for a reliable separation of subtypes into tremor-dominant and non-tremor-dominant, especially in the early stages of PD. Therefore, we assumed that many systems besides the nigrostriatal dopaminergic system are involved in the generation of tremors in PD. 23540731 Copper-catalyzed diastereoselective arylation of tryptophan derivatives: total synthesis of (+)-naseseazines a and B. A copper-catalyzed arylation of tryptophan derivatives is reported. The reaction proceeds with high site- and diastereoselectivity to provide aryl pyrroloindoline products in one step from simple starting materials. The utility of this transformation is highlighted in the five-step syntheses of the natural products (+)-naseseazine A and B. 23291240 Cerebral and extracerebral cholesterol metabolism and CSF markers of Alzheimer's disease. The disturbances of the cholesterol synthesis and metabolism described in Alzheimer's disease (AD) may be both a consequence of the neurodegenerative process and a contributor to the pathogenesis. These putative relationships and their underlying mechanisms are not well understood. The aim of this study was to evaluate the relationship between the cerebral and extracerebral cholesterol synthesis and metabolism, and the AD pathology as reflected by CSF markers in humans. We evaluated the relationships between the plasma and the cerebrospinal fluid (CSF) concentrations of cholesterol, the cholesterol precursors lanosterol, lathosterol and desmosterol, and the cholesterol elimination products 24S-hydroxycholesterol and 27-hydroxycholesterol, and the CSF markers for AD pathology Aβ1-42 and p-tau181 in 86 subjects with normal cognition and in 107 AD patients. CSF desmosterol, cholesterol and 24S-hydroxycholesterol in the AD group, and CSF 24S-hydroxycholesterol in the control group correlated with the p-tau181 levels. Neither CSF nor plasma concentrations of the included compounds correlated with the CSF Aβ1-42 levels. In multivariate regression tests including age, gender, albumin ratio, number of the APOEɛ4 alleles, and diagnosis, p-tau181 levels independently predicted the CSF desmosterol, cholesterol and 24S-hydroxycholesterol concentrations. The associations remained significant for CSF cholesterol and 24S-hydroxycholesterol when analyses were separately performed in the AD group. The results suggest that alterations of CNS cholesterol de novo genesis and metabolism are related to neurodegeneration and in particular to the cerebral accumulation of phosphorylated tau. 23592609 Technical communication: the effect of the double mask on anesthetic waste gas levels during pediatric mask inductions in dental offices. A significant portion of office-based general anesthesia for pediatric patients is performed in dental offices and involves mask inductions with inhaled drugs. This can lead to significant pollution with waste gases. We assessed occupational exposure to anesthetic drugs during pediatric general anesthesia in dental offices and assessed the effectiveness of the "double mask." Nine freestanding dental offices had measurements of anesthetic waste gas levels taken before and immediately after implementation of a double-mask system. Levels of nitrous oxide decreased from a median of 40.0 parts per million (ppm; interquartile range [IQR] = 23.0-46.0 ppm, n = 9) to 3.0 ppm, (IQR = 2.3-4.7 ppm, n = 9, P = 0.0055) and exceeded 25 ppm in 0% of the 9 offices (upper 95% confidence limit 34%) when using the double mask. Levels of sevoflurane decreased from a median of 4.60 ppm (IQR = 3.10-7.00 ppm, n = 9) to 0 ppm (IQR = 0-0.39 ppm, n = 9, P = 0.0024) and exceeded 2 ppm in 0% of the 9 offices (upper 95% confidence limit 34%) when using the double mask. We demonstrated in our study that the double-mask system, when used with dental "high-volumes" suctions (high-volume evacuators producing approximately 12 m(3)/h) in freestanding dental offices, was sufficient to decrease the exposure to anesthetic waste gas during pediatric mask induction in at least two thirds of offices when compared with the traditional mask. 23815273 Modeling the public health impact of malaria vaccines for developers and policymakers. Efforts to develop malaria vaccines show promise. Mathematical model-based estimates of the potential demand, public health impact, and cost and financing requirements can be used to inform investment and adoption decisions by vaccine developers and policymakers on the use of malaria vaccines as complements to existing interventions. However, the complexity of such models may make their outputs inaccessible to non-modeling specialists. This paper describes a Malaria Vaccine Model (MVM) developed to address the specific needs of developers and policymakers, who need to access sophisticated modeling results and to test various scenarios in a user-friendly interface. The model's functionality is demonstrated through a hypothetical vaccine. The MVM has three modules: supply and demand forecast; public health impact; and implementation cost and financing requirements. These modules include pre-entered reference data and also allow for user-defined inputs. The model includes an integrated sensitivity analysis function. Model functionality was demonstrated by estimating the public health impact of a hypothetical pre-erythrocytic malaria vaccine with 85% efficacy against uncomplicated disease and a vaccine efficacy decay rate of four years, based on internationally-established targets. Demand for this hypothetical vaccine was estimated based on historical vaccine implementation rates for routine infant immunization in 40 African countries over a 10-year period. Assumed purchase price was $5 per dose and injection equipment and delivery costs were $0.40 per dose. The model projects the number of doses needed, uncomplicated and severe cases averted, deaths and disability-adjusted life years (DALYs) averted, and cost to avert each. In the demonstration scenario, based on a projected demand of 532 million doses, the MVM estimated that 150 million uncomplicated cases of malaria and 1.1 million deaths would be averted over 10 years. This is equivalent to 943 uncomplicated cases and 7 deaths averted per 1,000 vaccinees. In discounted 2011 US dollars, this represents $11 per uncomplicated case averted and $1,482 per death averted. If vaccine efficacy were reduced to 75%, the estimated uncomplicated cases and deaths averted over 10 years would decrease by 14% and 19%, respectively. The MVM can provide valuable information to assist decision-making by vaccine developers and policymakers, information which will be refined and strengthened as field studies progress allowing further validation of modeling assumptions. 23871725 Olfactory bulbectomy induces neuronal rearrangement in the entorhinal cortex in the rat. In humans, depression has been associated with disturbances in olfactory circuitry. Symptoms of depression can be mimicked in animals after olfactory bulbectomy (OBX). Animal models of depression-like behavior produce similar neuronal rearrangements in various brain regions as seen in patients affected by depression. We have recently observed that OBX produces neuronal hypotrophy in the piriform cortex (PirC) and CA1 hippocampus as well as decreased adult cell proliferation in the dentate gyrus (DG) of hippocampus. Thus we further evaluated the effects of OBX in neuronal arborization and spine density in brain regions involved in the control of circadian circle, emotion and memory processing such as the prefrontal cortex (PFC), nucleus accumbens (NAcc), infralimbic cortex (ILC), orbitolateral cortex (OLC) and entorhinal cortex (EC). Our present results show that along with severe behavioral deficits observed in these animals, OBX considerably decreased dendritic branching and the total dendritic length in the EC, a major interface of the hippocampus and neocortical regions. The remaining cortices and NAcc were not affected by OBX. Thus, we propose that the lack of input from the olfactory bulbs resulted in serial neuronal rearrangements in the PirC, EC, and hippocampus leading, at least partially, to behavioral deficits in emotion and memory processes. 23498852 Biphasic finite element contact analysis of the knee joint using an augmented Lagrangian method. Biphasic contact analysis is essential to obtain a more complete understanding of soft tissue biomechanics; however, only a limited number of studies have addressed these types of problems. In this paper, a theoretically consistent biphasic finite element solution of the 2D axisymmetric human knee was developed, and an augmented Lagrangian method was used to enforce the biphasic continuity across the contact interface. The interaction between the fluid and solid matrices of the soft tissues of the knee joint, the stress and strain distributions within the meniscus, and the changes in stress and strain distributions in the articular cartilage of the femur and tibia after complete meniscectomy were investigated. It was found that (i) the fluid phase carries more than 60% of the load, which reinforces the need for the biphasic model for knee biomechanics; (ii) the inner third and outer two-thirds of the meniscus had different strain distributions; and (iii) the distributions of both maximum shear stress and maximum principal strain in articular cartilage changed after complete meniscectomy - with peak values increasing by over 350%. 23381796 A decision-analysis tool for benefit-risk assessment of nonprescription drugs. A decision analysis tool is proposed for regulatory assessment of nonprescription drugs. The tool is based on evaluation of each of the drug's potential benefit and risk attributes identified using a value-tree framework. The decision tool is designed as two-factor, two-stage instrument. Each attribute is independently assessed based on both the frequency of occurrence and clinical impact of the attribute. Frequency and clinical impact are scored on a 0-3 scale where a 0 score means no occurrence or no clinical impact, and a 3 means high frequency of occurrence or high clinical impact. The tool is initially used early in drug development to facilitate communication amongst stakeholders and to identify important data gaps. After new data are generated during the development program the tool is used again across the same attributes to yield a final benefit-risk assessment. In both the early assessment and subsequent evaluation use of the Group-Delphi technique and a benefit-risk trade-off heuristic may yield more consistent and coherent outputs. The tool allows regulators to maintain flexibility with respect to how final decisions are made, yet allows specificity and transparency during the evaluation. Further modifications can be incorporated to address drug-specific requirements or regulatory preferences. 23561083 Distribution, antioxidant and characterisation of phenolic compounds in soybeans, flaxseed and olives. The distribution of free and bound phenolic compounds present in soybean, flaxseed and olive were investigated. The phenolic compounds were fractionated on the basis on their solubility characteristics in water, alcohol, dilute base and dilute acid. Reversed phase high pressure liquid chromatography (RP-HPLC) and mass spectrometry (MS) were used for identification of individual components of phenolic compounds. Antioxidant activity (AA%) of free and bound phenolic compounds was measured using the linoleic acid/β-carotene assay. The water-soluble phenolic compound fractions represented 68-81%, 50-72% and 46-56% of the total phenolic compounds measured in full-fat soybean, olive and flaxseed, respectively. Methanolic extraction of free phenolic compounds without heat, solubilised 21-56%, 42-62% and 34-51% of the total phenolic compounds measured in soybean, olive and flaxseed, respectively; methanol extraction of free phenolic compounds with heat solubilised a further 24-34%, 31-37% and 36-37% of phenolic compounds from soybean, olive and flaxseed, respectively. Further dilute alkali and dilute acid solubilised the remaining 10-40%, 1-21% and 12-29% of the total phenolic compounds from soybean, olive and flaxseed, respectively. Results indicated that the full-fat meals of soybean, flaxseed and olive showed higher antioxidant activity compared to defatted meals. RP-HPLC and LC-MS/MS profil1 for soybean, flaxseed and olive indicate two classes of phenolic compounds designated as free and bound phenolic compounds. 23739309 Fish Oil Increases Muscle Protein Mass and Modulates Akt/FOXO, TLR4, and NOD Signaling in Weanling Piglets After Lipopolysaccharide Challenge. Proinflammatory cytokines play a key role in the pathophysiology of muscle atrophy. In addition, n3 polyunsaturated fatty acids (PUFAs) exert an inhibitory effect on proinflammatory cytokines affecting many inflammatory diseases. We hypothesized that dietary supplementation of fish oil could attenuate lipopolysaccharide (LPS)-induced muscle atrophy. Weanling pigs were used in a 2 × 2 factorial design and the main factors included diet (5% corn oil or 5% fish oil) and immunological challenge (LPS or saline). After 21 d of treatment with either fish oil or corn oil, pigs received an i.p. injection of either saline or LPS. At 4 h postinjection, blood and muscle samples were obtained. Fish oil led to enrichment of eicosapentaenoic acid, docosahexaenoic acid, and total n3 PUFAs in muscles. Fish oil increased muscle protein mass, indicated by a higher protein:DNA ratio in gastrocnemius and longissimus dorsi (LD) muscles. In addition, fish oil increased Akt1 mRNA abundance and decreased Forkhead Box O (FOXO) 1 and FOXO4 mRNA abundance. Fish oil also increased phosphorylation of Akt and FOXO1 in gastrocnemius and LD muscles. Fish oil decreased the mRNA abundance of muscle atrophy F-box (MAFbx) and muscle RING finger 1 in gastrocnemius and LD muscles. Moreover, fish oil reduced the plasma tumor necrosis factor (TNF) α, muscle TNFα, and prostaglandin E2 concentrations, and muscle TNFα and cyclooxygenase 2 (COX2) mRNA abundance. Finally, fish oil downregulated the mRNA abundance of muscle toll-like receptor (TLR4) and its downstream signaling molecules [myeloid differentiation factor 88 (MyD88), TNFα receptor-associated factor 6 (TRAF6), and NF-κB p65], and nucleotide-binding oligomerization domain protein (NOD1), NOD2, and their adaptor molecule [receptor-interacting serine/threonine-protein kinase 2 (RIPK2)]. These results indicate fish oil may suppress muscle proinflammatory cytokine production via regulation of TLR and NOD signaling pathways and therefore improve muscle protein mass, possibly through maintenance of Akt/FOXO signaling. 23821124 Novel 3D-CT evaluation of carotid stent volume: greater chronological expansion of stents in patients with vulnerable plaques. Although self-expanding carotid stents may dilate gradually, the degrees of residual stenosis have been quantified by the NASCET criteria, which is too simple to reflect the configuration of the stented artery. We measured the volumes of the stent lumens chronologically by 3D-CT in patients after carotid artery stenting (CAS), and analyzed the correlations between the volume change and medical factors. Fourteen patients with carotid artery stenosis were treated using self-expanding, open-cell stents. All patients underwent preoperative plaque MRI (magnetization-prepared rapid acquisition gradient-echo, MPRAGE) and chronological 3D-CT examinations of their stents immediately after their placement and 1 day, 1 week, and 1 month after the procedure. The volume of the stent lumen was measured using a 3D workstation. The correlations between stent volume and various factors including the presence of underlying diseases, plaque characteristics, and the results of the CAS procedure were analyzed. Stent volume gradually increased in each case and had increased by 1.04-1.55 (mean, 1.25)-fold at 1 postoperative month. The presence of underlying medical diseases, plaque length, the degree of residual stenosis immediately after CAS, and plaque calcification did not have an impact on the change in stent volume. On the other hand, the stent volume increase was significantly larger in the patients with vulnerable plaques that demonstrated high MPRAGE signal intensity (P < 0.05). A 3D-CT examination is useful for precisely measuring stent volume. Self-expanding stents in carotid arteries containing vulnerable plaques expand significantly more than those without such plaques in a follow-up period. 23313864 Omitting chest tube drainage after thoracoscopic major lung resection. Absorbable mesh and fibrin glue applied to prevent alveolar air leakage contribute to reducing the length of chest tube drainage, length of hospitalization and the rate of pulmonary complications. This study investigated the feasibility of omitting chest tube drainage in selected patients undergoing thoracoscopic major lung resection. Intraoperative air leakages were sealed with fibrin glue and absorbable mesh in patients undergoing thoracoscopic major lung resection. The chest tube was removed just after tracheal extubation if no air leakages were detected in a suction-induced air leakage test, which is an original technique to confirm pneumostasis. Patients with bleeding tendency or extensive thoracic adhesions were excluded. Chest tube drainage was omitted in 29 (58%) of 50 eligible patients and was used in 21 (42%) on the basis of suction-induced air leakage test results. Male gender and compromised pulmonary function were significantly associated with the failure to omit chest tube drainage (both, P < 0.05). Regardless of omitting the chest tube drainage, there were no adverse events during hospitalization, such as subcutaneous emphysema, pneumothorax, pleural effusion or haemothorax, requiring subsequent drainage. Furthermore, there was no prolonged air leakage in any patients: The mean length of chest tube drainage was only 0.9 days. Omitting the chest tube drainage was associated with reduced pain on the day of the operation (P = 0.046). The refined strategy for pneumostasis allowed the omission of chest tube drainage in the majority of patients undergoing thoracoscopic major lung resection without increasing the risk of adverse events, which may contribute to a fast-track surgery. 23532151 Enzyme immobilisation in biocatalysis: why, what and how. In this tutorial review, an overview of the why, what and how of enzyme immobilisation for use in biocatalysis is presented. The importance of biocatalysis in the context of green and sustainable chemicals manufacture is discussed and the necessity for immobilisation of enzymes as a key enabling technology for practical and commercial viability is emphasised. The underlying reasons for immobilisation are the need to improve the stability and recyclability of the biocatalyst compared to the free enzyme. The lower risk of product contamination with enzyme residues and low or no allergenicity are further advantages of immobilised enzymes. Methods for immobilisation are divided into three categories: adsorption on a carrier (support), encapsulation in a carrier, and cross-linking (carrier-free). General considerations regarding immobilisation, regardless of the method used, are immobilisation yield, immobilisation efficiency, activity recovery, enzyme loading (wt% in the biocatalyst) and the physical properties, e.g. particle size and density, hydrophobicity and mechanical robustness of the immobilisate, i.e. the immobilised enzyme as a whole (enzyme + support). The choice of immobilisate is also strongly dependent on the reactor configuration used, e.g. stirred tank, fixed bed, fluidised bed, and the mode of downstream processing. Emphasis is placed on relatively recent developments, such as the use of novel supports such as mesoporous silicas, hydrogels, and smart polymers, and cross-linked enzyme aggregates (CLEAs). 23912122 An automatic recording system for the study of escape from fear in rats. Escape from fear (EFF) is an active response to a conditioned stimulus (CS) previously paired with an unconditioned fearful stimulus (US), which typically leads to the termination of the CS. In this paradigm, animals acquire two distinct associations: S-S [CS-US] and R-O [response-outcome] through Pavlovian and instrumental conditioning, respectively. The present study describes a computer controlled automatic recording system that captures the development of EFF and allows the determination of the respective roles of S-S and R-O associations in this process. We validated this system by showing that only rats subjected to a simultaneous CS-US conditioning (i.e., CS and US occur together at the beginning of each trial) acquired EFF, not those subjected to an unpaired CS-US conditioning. Paired rats had a progressively increased number of EFF and significantly shorter escape latencies than unpaired rats across the 5-trial blocks on the test day. However, during the conditioning phase, the unpaired rats emitted more 22kHz ultrasonic vocalizations, a validated measure of conditioned reactive fear responses. Our results demonstrate that the acquisition of EFF is contingent upon pairing of the CS with the US, not simply the consequence of a high level of generalized fear. Because this commercially available system is capable of examining both conditioned active and reactive fear responses in a single setup, it could be used to determine the relative roles of S-S and R-O associations in EFF, the neurobiology of conditioned active fear response and neuropharmacology of psychotherapeutic drugs. 23820002 Trends in revision circumcision at pediatric hospitals. Background. We sought to determine the incidence of revision circumcision at freestanding children's hospitals, and examine trends over time. Methods. We searched the Pediatric Health Information Systems database to identify boys undergoing revision circumcision (RC), primary non-newborn circumcision (PC), or lysis of penile adhesions (LPA) from 2004 to 2009. Rates of RC procedures were calculated by dividing the incidence of procedures by the total male ambulatory surgical volume. Results. We identified 34 568 patients of whom 5632 underwent RC, 25 768 PC, and 3168 LPA. The rate of RC increased 119%, which was significantly more than PC (19%; P < .001) or LPA (37%; P < .001). Urologists performed 76% of RC and 12% were performed with other genitourinary procedures. Boys undergoing RC were predominately white (60%) and publicly insured (61%). Conclusions. There was a disproportionate increased rate of RC performed at Pediatric Health Information Systems hospitals compared with PC or LPA. Wide variation exists in rate increases among hospitals. 23686473 High levels of glucose induces a dose-dependent apoptosis in human periodontal ligament fibroblasts by activating caspase-3 signaling pathway. Periodontitis is one of the main complications of diabetes mellitus and many researches have been done on the relationship between periodontitis and diabetes mellitus, but too much are still unclear, especially the mechanisms by which high glucose induces damage of periodontal ligament fibroblasts. So in this study, we investigated the effects of different concentration of high glucose on apoptosis in human periodontal ligament fibroblasts and the possible mechanisms involved. Human periodontal ligament fibroblasts were cultured and subjected to glucose of different concentration (5.5, 15, 25, and 35 mM) for 24 h. Apoptosis was studied by flow cytometry, caspase assays, fluorescent real-time PCR and Western blot. We also determined Fas/FasL expression was by Western blot. The application of different concentration of high glucose induced a concentration-dependent increase of apoptosis and the activity of caspase-3 in cultured human periodontal ligament fibroblasts. Furthermore, inhibitor of caspase-3 could prevent the high-glucose-induced apoptosis in human periodontal ligament fibroblasts. Protein levels of Fas and FasL remained unchanged. These data indicate that high glucose induces a concentration- and caspase-3-dependent increase of apoptosis in cultured human periodontal ligament fibroblasts in vitro. Activation of caspase-3 caused by high glucose is independent of Fas/FasL signaling pathways system. These results suggest a novel mechanism for the regulation of human periodontal ligament fibroblasts apoptosis by high glucose. 23869207 Computer Simulation of Assembly and Co-operativity of Hexameric AAA ATPases. AAA ATPases form a functionally diverse superfamily of proteins. Most members form homo-hexameric ring complexes, are catalytically active only in the fully assembled state, and show co-operativity among the six subunits. The mutual dependence among the subunits is clearly evidenced by the fact that incorporation of mutated, inactive subunits can decrease the activity of the remaining wild type subunits. For the first time, we develop here models to describe this form of allostery, evaluate them in a simulation study, and test them on experimental data. We show that it is important to consider the assembly reactions in the kinetic model, and to define a formal inhibition scheme. We simulate three inhibition scenarios explicitly, and demonstrate that they result in differing outcomes. Finally, we deduce fitting formulas, and test them on real and simulated data. A non-competitive inhibition formula fitted experimental and simulated data best. To our knowledge, our study is the first one that derives and tests formal allosteric schemes to explain the inhibitory effects of mutant subunits on oligomeric enzymes. 23955378 Effectiveness of one dose of mumps vaccine against clinically diagnosed mumps in Guangzhou, China, 2006-2012. Although mumps-containing vaccines were introduced in China in 1990s, mumps continues to be a public health concern due to the lack of decline in reported mumps cases. To assess the mumps vaccine effectiveness (VE) in Guangzhou, China, we performed a 1:1 matched case-control study. Among children in Guangzhou aged 8 mo to 12 y during 2006 to 2012, we matched one healthy child to each child with clinically diagnosed mumps. Cases with clinically diagnosed mumps were identified from surveillance sites system and healthy controls were randomly sampled from the Children's Expanded Programmed Immunization Administrative Computerized System in Guangzhou. Conditional logistic regression was used to calculate VE. We analyzed the vaccination information for 1983 mumps case subjects and 1983 matched controls and found that the overall VE for 1 dose of mumps vaccine, irrespective of the manufacture, was 53.6% (95% confidence interval [CI], 41.0-63.5%) to children aged 8 mo to 12 y. This post-marketing mumps VE study found that immunization with one dose of the mumps vaccine confers partial protection against mumps disease. Evaluation of the VE for the current mumps vaccines, introduction of a second dose of mumps vaccine, and assessment of modifications to childhood immunization schedules is essential. 23747448 Production of partially phosphorylated myo-inositol phosphates using phytases immobilised on magnetic nanoparticles. Phytases of different origin were covalently bound onto Fe3O4 magnetic nanoparticles (12nm). Binding efficiencies of all three phytases were well above 70% relative to the number of aldehyde groups available on the surface of the magnetic nanoparticles. Temperature stability for all three phytases was enhanced as a consequence of immobilisation, whereas pH dependence of enzyme activity was not affected. Maximum catalytic activity of the immobilised phytases was found at 60°C (rye), 65°C (Aspergillus niger) and 70°C (Escherichia albertii). The immobilised enzymes exhibited the same excellent substrate specificities and unique myo-inositol phosphate phosphatase activities as their soluble counterparts. However, the catalytic turnover number dropped drastically for the immobilised phytases. The amount of the desired partially phosphorylated myo-inositol phosphate isomer could be easily controlled by the contact time of substrate solution and immobilised enzymes. The immobilised phytases showed a high operational stability by retaining almost full activity even after fifty uses. 23519077 Loss of Survivin influences liver regeneration and is associated with impaired Aurora B function. The chromosomal passenger complex (CPC) acts as a key regulator of mitosis, preventing asymmetric segregation of chromosomal material into daughter cells. The CPC is composed of three non-enzymatic components termed Survivin, the inner centromere protein (INCENP) and Borealin, and an enzymatic component, Aurora B kinase. Survivin is necessary for the appropriate separation of sister chromatids during mitosis and is involved in liver regeneration, but its role in regenerative processes is incompletely elucidated. Whether Survivin, which is classified as an inhibitor of apoptosis protein (IAP) based on domain composition, also has a role in apoptosis is controversial. The present study examined the in vivo effects of Survivin ablation in the liver and during liver regeneration after 70% hepatectomy in a hepatocyte-specific knockout mouse model. The absence of Survivin caused a reduction in the number of hepatocytes in the liver, together with an increase in cell volume, macronucleation and polyploidy, but no changes in apoptosis. During liver regeneration, mitosis of hepatocytes was associated with mislocalization of the members of the CPC, which were no longer detectable at the centromere despite an unchanged protein amount. Furthermore, the loss of survivin in regenerating hepatocytes was associated with reduced levels of phosphorylated Histone H3 at serine 28 and abolished phosphorylation of CENP-A and Hec1 at serine 55, which is a consequence of decreased Aurora B kinase activity. These data indicate that Survivin expression determines hepatocyte number during liver development and liver regeneration. Lack of Survivin causes mislocalization of the CPC members in combination with reduced Aurora B activity, leading to impaired phosphorylation of its centromeric target proteins and inappropriate cytokinesis. 23787723 Organization of heart failure management in European Society of Cardiology member countries: survey of the Heart Failure Association of the European Society of Cardiology in collaboration with the Heart Failure National Societies/Working Groups. The aim of this document was to obtain a real-life contemporary analysis of the demographics and heart failure (HF) statistics, as well as the organization and major activities of the Heart Failure National Societies (HFNS) in European Society of Cardiology (ESC) member countries. Data from 33 countries were collected from HFNS presidents/representatives during the first Heart Failure Association HFNS Summit (Belgrade, Serbia, 29 October 2011). Data on incidence and/or prevalence of HF were available for 22 countries, and the prevalence of HF ranged between 1% and 3%. In five European and one non-European ESC country, heart transplantation was reported as not available. Natriuretic peptides and echocardiography are routinely applied in the management of acute HF in the median of 80% and 90% of centres, respectively. Eastern European and Mediterranean countries have lower availability of natriuretic peptide testing for acute HF patients, compared with other European countries. Almost all countries have organizations dealing specifically with HF. HFNS societies for HF patients exist in only 12, while in 16 countries HF patient education programmes are active. Most HFNS reported that no national HF registry exists in their country. Fifteen HFNS produced national HF guidelines, while 19 have translated the ESC HF guidelines. Most HFNS (n = 23) participated in the organization of the European HF Awareness Day. This document demonstrated significant heterogeneity in the organization of HF management, and activities of the national HF working groups/associations. High availability of natriuretic peptide and echocardiographic measurements was revealed, with differences between developed countries and countries in transition. 23829337 Interaction of 2-APB, dantrolene, and TDMT with IP3R and RyR modulates ER stress-induced programmed cell death I and II in neuron-like PC12 cells: an experimental and computational investigation. Ca(2+) is an essential second messenger, playing a fundamental role in maintaining cell viability and neuronal activity. Two specific endoplasmic reticulum calcium channels, ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs) play an important role in Ca(2+) regulation. In the present study, we provided a 3D structure of RyR and IP3R by homology modeling, and we predicted their interactions with a known neuroprotective compound, 3-thiomethyl-5,6-(dimethoxyphenyl)-1,2,4-triazine (TDMT), as well as two inhibitors, dantrolene and 2-aminoethoxydiphenyl borate (2-APB). Interestingly, we found that dantrolene and 2-APB can bind to the IP3-binding domain of IP3R and RyR, while TDMT may directly block both channels by interacting with the putative resident domains in the pore. Cell culture experiments showed that these compounds could protect PC12 cells against H2O2-induced apoptosis and activate autophagic pathways. Collectively, our computational (in silico) and cell culture studies suggest that RyR and IP3R are novel and promising targets to be used against neurodegenerative diseases. 23314899 Air pollution and multiple acute respiratory outcomes. Short-term effects of air pollutants on respiratory mortality and morbidity have been consistently reported but usually studied separately. To more completely assess air pollution effects, we studied hospitalisations for respiratory diseases together with out-of-hospital respiratory deaths. A time-stratified case-crossover study was carried out in six Italian cities from 2001 to 2005. Daily particulate matter (particles with a 50% cut-off aerodynamic diameter of 10 μm (PM10)) and nitrogen dioxide (NO2) associations with hospitalisations for respiratory diseases (n = 100 690), chronic obstructive pulmonary disease (COPD) (n = 38 577), lower respiratory tract infections (LRTI) among COPD patients (n = 9886) and out-of-hospital respiratory deaths (n = 5490) were estimated for residents aged ≥35 years. For an increase of 10 μg·m(-3) in PM10, we found an immediate 0.59% (lag 0-1 days) increase in hospitalisations for respiratory diseases and a 0.67% increase for COPD; the 1.91% increase in LRTI hospitalisations lasted longer (lag 0-3 days) and the 3.95% increase in respiratory mortality lasted 6 days. Effects of NO2 were stronger and lasted longer (lag 0-5 days). Age, sex and previous ischaemic heart disease acted as effect modifiers for different outcomes. Analysing multiple rather than single respiratory events shows stronger air pollution effects. The temporal relationship between the pollutant increases and hospitalisations or mortality for respiratory diseases differs. 23890642 Evaluation of post-mortem heart blood culture in a Chinese population. Post-mortem blood cultures have been used in a wide variety of research studies. However, their significance is still a matter of dispute among medico-legal experts. This study was aimed to determine the factors which influenced post-mortem blood culture results and to assess their value in determining the cause of death. We retrospectively investigated 76 post-mortem cases with suspected infection and correlated pathological findings with heart blood culture results. We found that survival time after onset of illness was significantly associated with positive heart blood cultures (P=0.014). Blood culture results were not influenced by age, gender, prior antibiotic therapy, interval time from death to store or interval time from death to autopsy (P>0.05). In those who had heart blood cultures taken, 49 cases (64.5%) including four cases with mixed growth, showed positive results, and approximately one-third of blood cultures were sterile. The positive predictive value (PPV) was 77.6% (38/49) including two cases with mixed growth; most were genuine pathogens according to the clinical and pathological findings. However, the negative predictive value (NPV) was 59.3% (16/27). Escherichia coli, Streptococcus spp., Staphylococcus aureus, Streptococcus pneumoniae and Klebsiella spp. were isolated most often. These findings suggest that the results of post-mortem heart blood cultures, when combined with clinical and pathological findings, strengthen the understanding of the cause of death. 23262663 FluidFM as a lithography tool in liquid: spatially controlled deposition of fluorescent nanoparticles. The atomic force microscope (AFM) is a powerful instrument for nanolithography, which is well characterized in air where the deposition process is steered by capillary action. In contrast, AFM patterning has been seldom achieved in liquid, mostly via electrochemical deposition. This study investigates the pressure-controlled local deposition of nanoparticles in a liquid environment using a FluidFM. Fluorescent 25 nm polystyrene nanospheres were chosen as nanoobjects to be dispensed because they enable both the in situ monitoring of the process by optical microscopy and the ex situ high-resolution characterization of the pattern by e.g. scanning electron microscopy. The FluidFM microchannel was filled with an aqueous solution of negatively charged nanoparticles to be delivered onto a glass surface coated with a polycation. An overpressure in the internal fluidic circuit leads to the deposition of nanoparticle dots and lines under the tip, while the force control regulates the contact between the probe and the surface. The nanoparticle adsorption process depends both on applied pressure and contact time (respectively tip velocity) and can be described using the Langmuir approximation for the random sequential adsorption model. Moreover, we observed that the force setpoint, which does not influence the capillary-driven mechanism in air, indeed affects the hydrodynamic resistance at the tip aperture and therefore the volumetric flow. The described method demonstrates the potential of FluidFM in depositing nano-sized objects in liquid with nanometre precision. 23873894 Inferring gene networks from discrete expression data. The modeling of gene networks from transcriptional expression data is an important tool in biomedical research to reveal signaling pathways and to identify treatment targets. Current gene network modeling is primarily based on the use of Gaussian graphical models applied to continuous data, which give a closed-form marginal likelihood. In this paper, we extend network modeling to discrete data, specifically data from serial analysis of gene expression, and RNA-sequencing experiments, both of which generate counts of mRNA transcripts in cell samples. We propose a generalized linear model to fit the discrete gene expression data and assume that the log ratios of the mean expression levels follow a Gaussian distribution. We restrict the gene network structures to decomposable graphs and derive the graphs by selecting the covariance matrix of the Gaussian distribution with the hyper-inverse Wishart priors. Furthermore, we incorporate prior network models based on gene ontology information, which avails existing biological information on the genes of interest. We conduct simulation studies to examine the performance of our discrete graphical model and apply the method to two real datasets for gene network inference. 23957912 Comparing the genomes of Helicobacter pylori clinical strain UM032 and Mice-adapted derivatives. Helicobacter pylori is a Gram-negative bacterium that persistently infects the human stomach inducing chronic inflammation. The exact mechanisms of pathogenesis are still not completely understood. Although not a natural host for H. pylori, mouse infection models play an important role in establishing the immunology and pathogenicity of H. pylori. In this study, for the first time, the genome sequences of clinical H. pylori strain UM032 and mice-adapted derivatives, 298 and 299, were sequenced using the PacBio Single Molecule, Real-Time (SMRT) technology.Result: Here, we described the single contig which was achieved for UM032 (1,599,441 bp), 298 (1,604,216 bp) and 299 (1,601,149 bp). Preliminary analysis suggested that methylation of H. pylori genome through its restriction modification system may be determinative of its host specificity and adaptation. Availability of these genomic sequences will aid in enhancing our current level of understanding the host specificity of H. pylori. 23879768 The use of a new indirect method to estimate ethnic-group fertility rates for subnational projections for England. To project the ethnic-group populations of local authorities in England to 2051, estimates of ethnic-specific fertility rates were needed. In the absence of ethnic information on birth records, we developed indirect estimation methods that use a combination of vital statistics, the census (both microdata and aggregate tables), and survey data (Labour Force Survey). We estimated age-specific and total fertility rates successively for five broad ethnic groups encompassed by all data-sets, and for eight ethnic groups encompassed by the 1991 and 2001 Censuses for England. We then used census data to disaggregate the estimates to the 16 ethnic groups required for the subnational projections and the Hadwiger function to estimate single-year-of-age estimates. We estimated the uncertainty around the fertility estimates and used a logistic model to project rates to 2021, after which we assumed rates would remain constant. 23779196 A gene encoding a new cold-active lipase from an Antarctic isolate of Penicillium expansum. Cold-active lipases are of significant interest as biocatalysts in industrial processes. We have identified a lipase that displayed activity towards long carbon-chain-p-nitrophenyl substrates (C12-C18) at 25 °C from the culture supernatant of an Antarctic Penicillium expansum strain assigned P. expansum SM3. Zymography revealed a protein band of around 30 kDa with activity towards olive oil. DNA fragments of a lipase gene designated as lipPE were isolated from the genomic DNA of P. expansum SM3 by genomic walking PCR. Subsequently, the complete genomic lipPE gene was amplified using gene-specific primers designed from the 5'- and 3'-regions. Reverse transcription PCR was used to amplify the lipPE cDNA. The deduced amino acid sequence consisted of 285 residues that included a predicted signal peptide. Three peptides identified by LC/MS/MS analysis of the proteins in the culture supernatant of P. expansum were also present in the deduced amino acid sequence of the lipPE gene suggesting that this gene encoded the lipase identified by initial zymogram activity analysis. Full analysis of the nucleotide and the deduced amino acid sequences indicated that the lipPE gene encodes a novel P. expansum lipase. The lipPE gene was expressed in E. coli for further characterization of the enzyme with a view of assessing its suitability for industrial applications. 23913473 Markus Kalesse. The best advice I have ever been given is "Don't panic!" I can never resist good food. 23967092 IVIg Treatment Reduces Catalytic Antibody Titers of Renal Transplanted Patients. Catalytic antibodies are immunoglobulins endowed with enzymatic activity. Catalytic IgG has been reported in several human autoimmune and inflammatory diseases. In particular, low levels of catalytic IgG have been proposed as a prognostic marker for chronic allograft rejection in patients undergoing kidney transplant. Kidney allograft is a treatment of choice for patients with end-stage renal failure. Intravenous immunoglobulins, a therapeutic pool of human IgG, is used in patients with donor-specific antibodies, alone or in conjunction with other immunosuppressive treatments, to desensitize the patients and prevent the development of acute graft rejection. Here, we followed for a period of 24 months the levels of catalytic IgG towards the synthetic peptide Pro-Phe-Arg-methylcoumarinimide in a large cohort of patients undergoing kidney transplantation. Twenty-four percent of the patients received IVIg at the time of transplantation. Our results demonstrate a marked reduction in levels of catalytic antibodies in all patients three months following kidney transplant. The decrease was significantly pronounced in patients receiving adjunct IVIg therapy. The results suggests that prevention of acute graft rejection using intravenous immunoglobulins induces a transient reduction in the levels of catalytic IgG, thus potentially jeopardizing the use of levels of catalytic antibodies as a prognosis marker for chronic allograft nephropathy. 23142737 Protective effects of erythropoietin on astrocytic swelling after oxygen-glucose deprivation and reoxygenation: mediation through AQP4 expression and MAPK pathway. Recent in vivo studies have shown that erythropoietin (EPO) offers strong protection against brain edema. However, the intracellular and molecular mechanisms behind this beneficial effect have not been specified. The aim of this study was to determine whether human erythropoietin (rhEPO) reduces the astrocytic swelling created by oxygen-glucose deprivation followed by reoxygenation (OGD/Reox) in vitro and whether this effect can be mediated through the modulation of aquaporin4 (AQP4) expression in the plasma membrane (PM) and phosphorylation of the mitogen-activated protein kinase pathway (MAPK) pathway. Our results showed that OGD/Reox produced increase in cell volume, morphological swelling, and mitochondrial swelling. These changes were associated with the up-regulation of AQP4 in PM and the over-activation of MAPK. Silencing AQP4 expression using small interfering ribonucleic acid for AQP4 was found to block astrocytic swelling. Inhibition of the over-activation of MAPK mitigated the PM AQP4 overabundance and cellular swelling. As expected, treatment with rhEPO significantly reduced the OGD/Reox-induced increase in cell volume, morphological swelling, and mitochondrial swelling as well as the up-regulation of AQP4 in PM. In addition, cultures treated with the neutralizing anti-EPO antibody worsened the PM AQP4 abundance and cellular swelling, abolishing the protective effects mediated by rhEPO treatment. Furthermore, the over-activation of these MAPK after OGD/Reox was attenuated by rhEPO treatment significantly. In conclusion, our data strongly suggest that rhEPO can protect astrocytes from swelling caused by ischemia and reperfusion-like injury. This neuroprotective capacity is partially mediated by diminishing the MAPK-activity-dependent overabundance of AQP4 in PM. 23872330 The N-BAR domain protein, Bin3, regulates Rac1- and Cdc42-dependent processes in myogenesis. Actin dynamics are necessary at multiple steps in the formation of multinucleated muscle cells. BAR domain proteins can regulate actin dynamics in several cell types, but have been little studied in skeletal muscle. Here, we identify novel functions for the N-BAR domain protein, Bridging integrator 3 (Bin3), during myogenesis in mice. Bin3 plays an important role in regulating myofiber size in vitro and in vivo. During early myogenesis, Bin3 promotes migration of differentiated muscle cells, where it colocalizes with F-actin in lamellipodia. In addition, Bin3 forms a complex with Rac1 and Cdc42, Rho GTPases involved in actin polymerization, which are known to be essential for myotube formation. Importantly, a Bin3-dependent pathway is a major regulator of Rac1 and Cdc42 activity in differentiated muscle cells. Overall, these data classify N-BAR domain proteins as novel regulators of actin-dependent processes in myogenesis, and further implicate BAR domain proteins in muscle growth and repair. 23496027 Coenzyme Q10 Ameliorates the Reduction in GLUT4 Transporter Expression Induced by Simvastatin in 3T3-L1 Adipocytes. Abstract Background: Statins significantly reduce cardiovascular events in a broad population of patients with hyperlipidemia. However, a small, but significant risk of new-onset diabetes has been reported in patients treated with statins. The mechanism by which statins cause diabetes has not been elucidated and therefore preventive strategies have yet to be defined. Method: Our goal was to study the differing effects of a lipophilic (simvastatin) statin, hydrophilic (pravastatin) statin, and ezetimibe on glucose transporter-4 (GLUT4) protein expression in 3T3-L1 adipocytes. We hypothesized that the reductions in GLUT4 protein secondary to statin treatment would be prevented when cells were co-incubated with coenzyme Q10 (CoQ10). GLUT4 protein expression was determined using the In-Cell Western technique. Confluent adipocytes were differentiated using a hormonal cocktail for 3 days; followed by treatment with simvastatin, pravastatin, ezetimibe and CoQ10. Cell morphology was observed after treatment using phase-contrast microscopy. Results: Treatment with simvastatin (P<0.001) and simvastatin plus ezetimibe (P<0.001) significantly decreased GLUT4 protein expression in the adipocytes compared to control conditions. GLUT4 protein levels were similar to control after treatment with ezetimibe alone (P=0.52) or pravastatin (P=0.32). There was no significant difference (P=0.098) in GLUT4 protein levels after co-treatment with CoQ10 between any of the treatments and control conditions. Conclusion: Our studies have shown that lipophilic statins (simvastatin) reduce the GLUT4 protein levels in adipocytes, whereas hydrophilic statins (pravastatin) or ezetimibe do not. Co-treatment with CoQ10 appears to prevent the reduction in GLUT4 protein levels caused by simvastatin. 23928147 Preparation, characterization, biodistribution and antitumor efficacy of hydroxycamptothecin nanosuspensions. Hydroxycamptothecin (HCPT) has shown activity against a broad spectrum of cancers, but its therapeutic efficacy is impaired by its poor solubility and delivery challenges. In this study, HCPT nanosuspensions were prepared with precipitation-combined ultrasonication and characterized by dynamic light scattering (DLS), scanning electron microscopy (SEM) and X-ray powder diffraction (XRD). The HCPT nanosuspensions were spherical with a smooth surface and a small size of 150-200nm. The lyophilized powders for the HCPT nanosuspensions were amorphous and displayed sustained release in vitro. Compared to commercial HCPT injection, in vivo experiments with HCPT nanosuspensions showed significantly increased HCPT concentrations in the blood and all tissues of the tested as well as improved tumor targetability and liver targetability. Meanwhile, nanosuspensions displayed better anticancer efficacy than injection on H22 bearing mice (81.20% vs. 56.39%, in tumor inhibition rate). Therefore, HCPT nanosuspensions seem very promising for the treatment of hepatic cancer. 23820819 Relationship between respiratory sinus arrhythmia, heart period, and caregiver-reported language and cognitive delays in children with autism spectrum disorders. The present study examines the relationship between autonomic activity and cognitive/language delays in children with autism spectrum disorder (ASD). Baseline levels of respiratory sinus arrhythmia (RSA) and heart period (HP) were assessed in 23 4-7-year old children diagnosed with ASD. The relationship between RSA, HP, and ASD behavioral symptoms was examined. Similar to prior studies on typically developing children, lower basal RSA was related to more caregiver-reported language and cognitive delays, and to the lack of language. 23587845 Multiply-constrained semantic search in the Remote Associates Test. Many important problems require consideration of multiple constraints, such as choosing a job based on salary, location, and responsibilities. We used the Remote Associates Test to study how people solve such multiply-constrained problems by asking participants to make guesses as they came to mind. We evaluated how people generated these guesses by using Latent Semantic Analysis to measure the similarity between the guesses, cues, and answers. We found that people use two systematic strategies to solve multiply-constrained problems: (a) people produce guesses primarily on the basis of just one of the three cues at a time; and (b) people adopt a local search strategy--they make new guesses based in part on their previous guesses. These results inform how people combine constraints to search through and retrieve semantic information from memory. 23962018 Prevalence and patterns of multimorbidity among tuberculosis patients in Brazil: a cross-sectional study. The number of subjects with tuberculosis (TB) presenting with co-occurrence of multiple chronic medical conditions, or multimorbidity (MM) is increasing in Brazil. This manuscript aimed to characterize subjects with TB, according to their MM status and to analyse factors associated with TB treatment outcomes. This is a cross-sectional study that included 39,881 TB subjects reported in Brazil, in 2011. MM were defined as any (two or more) occurrence of chronic medical conditions in a TB patient (TB--MM). Data analysis was performed by hierarchical logistic regression models comparing TBMM with those with only TB. Of the reported TB cases in 2011, 454 (1.14%) had MM. The subjects in the age group 40--59 years (OR: 17.89; 95% CI, 5.71-56.03) and those >= 60 years (OR: 44.11; 95% CI, 14.09-138.06) were more likely to develop TB--MM. The TB--MM subjects were less likely to be male (OR: 0.63; 95% CI, 0.52-0.76), institutionalized (OR: 0.59; 95% CI, 0.23-0.80) and live in rural areas (OR: 0.63; 95% CI, 0.42-0.95). Death from others causes than TB was higher among TB--MM subjects (OR: 1.76; 95% CI, 1.36-2.28). Of 454 TB--MM subjects 302 (66.5%) were cured and 152 (33.5%) were not cured. The odds of not being cured was 1.55 (95% CI, 1.04-2.32) among males, 2.85 (95% CI, 1.12-7.28) among institutionalized subjects, and 3.93 (IC 95%, 1.86-8.30) among those who were infected with HIV. TB retreatment after previous abandonment (OR: 7.53; 95% CI, 2.58-21.97) and transfer from a treatment site (OR: 2.76; 95% CI, 1.20-6.38) were higher for subjects not cured compared to those who were cured. While TB is well recognized to be a disease engendered by social inequity, we found that even among TB patients, those who have MM have greater inequity in terms of socioeconomic status and adverse clinical outcomes. Addressing the problem of TB and TB--MM requires a multisectorial approach that includes health and social service organizations. 23861142 Smad-interacting protein 1 affects acute and tonic, but not chronic pain. Smad-interacting protein 1 (also named Zeb2 and Zfhx1b) is a transcription factor that plays an important role in neuronal development and, when mutated, causes Mowat-Wilson syndrome (MWS). A corresponding mouse model carrying a heterozygous Zeb2 deletion was comprehensively analysed in the German Mouse Clinic. The most prominent phenotype was the reduced pain sensitivity. In this study, we investigated the role of Zeb2 in inflammatory and neuropathic pain. For this, we tested mutant Zeb2 animals in different models of inflammatory pain like abdominal constriction, formalin and carrageenan test. Furthermore, we studied the pain reactivity of the mice after peripheral nerve ligation. To examine the nociceptive transmission of primary sensory dorsal root ganglia (DRG) neurons, we determined the neuronal activity in the spinal dorsal horn after the formalin test using staining of c-Fos. Next, we characterized the neuronal cell population in the DRGs and in the sciatic nerve to study the effect of the Zeb2 mutation on peripheral nerve morphology. The present data show that Zeb2 is involved in the development of primary sensory DRG neurons, especially of C- and Aδ fibres. These alterations contribute to a hypoalgesic phenotype in inflammatory but not in neuropathic pain in these Zeb2(+/-) mice. Our data suggest that the under-reaction to pain observed in MWS patients results from a reduced responsivity to nociceptive stimulation rather than an inability to communicate discomfort. 23941255 Changes in sub-cellular localisation of trophoblast and inner cell mass specific transcription factors during bovine preimplantation development. Preimplantation bovine development is emerging as an attractive experimental model, yet little is known about the mechanisms underlying trophoblast (TE)/inner cell mass (ICM) segregation in cattle. To gain an insight into these processes we have studied protein and mRNA distribution during the crucial stages of bovine development. Protein distribution of lineage specific markers OCT4, NANOG, CDX2 were analysed in 5-cell, 8-16 cell, morula and blastocyst stage embryos. ICM/TE mRNA levels were compared in hatched blastocysts and included: OCT4, NANOG, FN-1, KLF4, c-MYC, REX1, CDX2, KRT-18 and GATA6. At the mRNA level the observed distribution patterns agree with the mouse model. CDX2 and OCT4 proteins were first detected in 5-cell stage embryos. NANOG appeared at the morula stage and was located in the cytoplasm forming characteristic rings around the nuclei. Changes in sub-cellular localisation of OCT4, NANOG and CDX2 were noted from the 8-16 cell onwards. CDX2 initially co-localised with OCT4, but at the blastocyst stage a clear lineage segregation could be observed. Interestingly, we have observed in a small proportion of embryos (2%) that CDX2 immunolabelling overlapped with mitotic chromosomes. Cell fate specification in cattle become evident earlier than presently anticipated - around the time of bovine embryonic genome activation. There is an intriguing possibility that for proper lineage determination certain transcription factors (such as CDX2) may need to occupy specific regions of chromatin prior to its activation in the interphase nucleus. Our observation suggests a possible role of CDX2 in the process of epigenetic regulation of embryonic cell fate. 23766353 Erratum. The following article was published in the March 2013 issue of Behavior Modification and was inadvertently published again on OnlineFirst. The duplicate publication is hereby withdrawn. Below is the citation for the original publication. Schare, M.L. & Wyatt K.P. (2013). On the evolving nature of exposure therapy. Behavior Modification, 37, 243-256. (doi. 10.1177/01454455134774**21). 23943826 The Globalization of Health Care: Implications of Medical Tourism for the ID Clinician. Travel abroad for health care has increased rapidly; interventions include organ transplantation, cardiac surgery, reproductive care, and joint, cosmetic, dental procedures. Individuals who receive medical care abroad are a vulnerable, sentinel population, who sample the local environment and can carry home unusual and resistant infections, documented in many reports. Medical tourists are at risk for hospital-associated and procedure-related infections as well as for locally endemic infections. Patients may not volunteer details about care abroad, so clinicians must inquire about medical procedures abroad as well as recent travel. Special infection control measures may be warranted. Health care abroad is associated with diverse financial, legal, ethical and health-related issues. We focus on problems the infectious disease clinician may encounter and provide a framework for evaluating returned medical tourists with suspected infections. A better system is needed to ensure broad access to high quality health services, continuity of care, and surveillance for complications. 23879957 Semantically assessing the reliability of protein interactions. Protein-protein interactions (PPIs) play very important roles in many cellular processes, and provide rich information for discovering biological facts and knowledge. Although various experimental approaches have been developed to generate large amounts of PPI data for different organisms, high-throughput experimental data usually suffers from high error rates, and as a consequence, the biological knowledge discovered from this data is distorted or incorrect. Therefore, it is vital to assess the quality of protein interaction data and extract reliable protein interactions from the high-throughput experimental data. In this paper, we propose a new Semantic Reliability (SR) method to assess the reliability of each protein interaction and identify potential false-positive protein interactions in a dataset. For each pair of target interacting proteins, the SR method takes into account the semantic influence between proteins that interact with the target proteins, and the semantic influence between the target proteins themselves when assessing the interaction reliability. Evaluations on real protein interaction datasets demonstrated that our method outperformed other existing methods in terms of extracting more reliable interactions from original protein interaction datasets. 23561207 The potential of solvent-minimized extraction methods in the determination of polycyclic aromatic hydrocarbons in fish oils. Fish oil has been identified as one of the most important contributors to the level of Persistent Organic Pollutants (POPs) in feed products. The determination of polycyclic aromatic hydrocarbons (PAHs) in fish oils is complicated due to the fat matrix, which affects both extraction efficiency and analytical quality. This article reviews and addresses two of the most relevant analytical methods for determining 11 mutagenic and carcinogenic PAHs, as well as two EPA indicator PAHs in fish oils. We discuss and critically evaluate two different extraction procedures, such as ultrasound-assisted solvent extraction (USAE) and ultrasound-assisted emulsification-microextraction (USAEME). Clean-up of extracts was performed by solid-phase extraction using C18 and glass columns containing silica gel and florisil for USAE or only C18 for USAEME. Detection of the selected PAHs was carried out by high-performance liquid chromatography coupled with fluorescence detection for determination. Optimization of the variables affecting extraction by the selected extraction techniques was conducted and recoveries ranged from 70% to 100% by USAE and from 70% to 108% by USAEME with estimated quantification limits between 0.020 and 2.6μg/kg were achieved. Moreover, the applicability of the selected methods was evaluated by the analysis of real samples. To our knowledge, this is the first time that USAEME has been applied to the determination of PAHs in food matrices, such as oil fish samples. The methods proposed were applied to the determination of the target PAHs in fish samples from different countries, and it was found that the low PAH contamination of the selected fish oils could mainly occur by atmospheric sources. 23273517 Synthesis and biological evaluation of analogues of the kinase inhibitor nilotinib as Abl and Kit inhibitors. The importance of the trifluoromethyl group in the polypharmacological profile of nilotinib was investigated. Molecular editing of nilotinib led to the design, synthesis and biological evaluation of analogues where the trifluoromethyl group was replaced by a proton, fluorine and a methyl group. While these analogues were less active than nilotinib toward Abl, their activity toward Kit was comparable, with the monofluorinated analogue being the most active. Docking of nilotinib and of analogues 2a-c to the binding pocket of Abl and of Kit showed that the lack of shape complementarity in Kit is compensated by the stabilizing effect from its juxtamembrane region. 23719574 Paradoxical surrogate markers of dental injury-induced pain in the mouse. Dental pain, including toothache, is one of the most prevalent types of orofacial pain, causing severe, persistent pain that has a significant negative effect on quality of life, including eating disturbances, mood changes, and sleep disruption. As the primary cause of toothache pain is injury to the uniquely innervated dental pulp, rodent models of this injury provide the opportunity to study neurobiological mechanisms of tissue injury-induced persistent pain. Here we evaluated behavioral changes in mice with a dental pulp injury (DPI) produced by mechanically exposing the pulp to the oral environment. We monitored the daily life behaviors of mice with DPI, including measures of eating, drinking, and movement. During the first 48 hours, the only parameter affected by DPI was locomotion, which was reduced. There was also a significant short-term decrease in the amount of weight gained by DPI animals that was not related to food consumption. As cold allodynia is frequently observed in individuals experiencing toothache pain, we tested whether mice with DPI demonstrate an aversion to drinking cold liquids using a cold-sucrose consumption test. Surprisingly, mice with DPI increased their consumption of sucrose solution, to over 150% of baseline, regardless of temperature. Both the weight loss and increased sucrose intake in the first 2 days of injury were reversed by administration of indomethacin. These findings indicate that enhanced sucrose consumption may be a reliable measure of orofacial pain in rodents, and suggest that alterations in energy expenditure and motivational behaviors are under-recognized outcomes of tooth injury. 23276136 Melanocortins as innovative drugs for ischemic diseases and neurodegenerative disorders: established data and perspectives. Ischemic insults and neurodegenerative diseases are by far the leading cause of mortality and disability. Whole-body hypoperfusion, as it occurs in polytraumatic and hemorrhagic shock, is alike an increasingly frequent condition, especially due to traffic accidents, wars and acts of terrorism. It is now clearly established that inflammatory processes play a fundamental role in the pathophysiology of both hypoperfusion/ischemia damage (be it generalized to the whole body, as in the case of shock, or limited to individual organs) and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis). On the other hand, concurrent animal and human data show that melanocortin peptides with agonist activity at melanocortin MC3/MC4 receptors are highly effective in different shock conditions as well as in conditions of ischemia/ischemia-reperfusion of individual organs (heart, brain, intestine, kidney, etc.), and accumulating evidence indicates that such effects of melanocortins are mostly due to quite peculiar antiinflammatory mechanisms. Melanocortins have also long been known (i) to exert important neurotrophic effects, not only during fetal development but also in adulthood, in different animal models of brain lesions; (ii) to reduce the morphological correlates of brain aging; (iii) to retard the behavioral deficits that develop during the aging process. Moreover, recent data from different laboratories show that after brain ischemic episodes melanocortins activate the transcription of neurotrophins and their receptors in the cerebral cortex and in the hippocampus, and increase the proliferation of progenitor neuron cells. The above arguments support the view that pharmacokinetically suitable agonists at MC3/MC4 melanocortin receptors may represent a completely innovative class of drugs for an effective treatment of both ischemic and neurodegenerative diseases. 23806103 Strategies for Stabilization of Electrodeposited Metal Particles in Electropolymerized Films for H2O Oxidation and H(+) Reduction. Metal particles were electrodeposited on a variety of conducting substrates, and their electrocatalytic activity toward H2O oxidation to O2 and H(+) reduction to H2 was evaluated. Co, Ni, Cu, Pd, Ag, and Pt were all electrodeposited on fluorine-doped tin oxide (FTO) electrodes. Particularly active were Pd and Pt for H(+) reduction and Co and Ag for H2O oxidation. When cycled reductively in 0.1 M HClO4, FTO electrodes derivatized with Pt and Pd reached current densities for hydrogen evolution of 18.3 and 13.2 mA/cm(2), respectively, at -0.6 V vs normal hydrogen electrode (NHE). FTO electrodes with electrodeposited Co or Ag were cycled oxidatively in H2O buffered to pH 7 with phosphate buffer. Current densities of 10.5 and 8.70 mA/cm(2), respectively, were reached at +1.8 V vs NHE with H2O oxidation onsets at +1.3 and +1.4 V, respectively. The impacts on catalytic stability and performance of electrodeposited metals in/on an electrically conductive polymer support were also investigated. Films of poly-[Fe(vbpy)3](PF6)2 (vbpy is 4-methyl-4'-vinyl-2,2'-bipyridine) were generated on FTO by reductive electropolymerization. Significant improvements to the long-term stability of electrodeposited Ag and Pt particles were observed in the poly-[Fe(vbpy)3](PF6)2 support. Films of poly-[M(vbpy)3](PF6)2 with M = Co(II) or Cu(II) were also prepared and evaluated as electrocatalysts for H2O oxidation. Films containing Co(II) reached current densities of 6.0 mA/cm(2) at +1.8 V vs NHE in H2O. 23688411 Delineation of malignant glioma by turbo spin echo multislice motion-sensitized driven-equilibrium (TSE-MSDE) with gadolinium-based contrast media: A case report. T1-weighted images by turbo spin echo multislice motion-sensitized driven-equilibrium with gadolinium-based contrast media clearly delineated the brainstem invasion of a malignant glioma in an 80-year-old woman compared with other magnetic resonance imaging sequences. 23759098 Arabidopsis thaliana nicotianamine synthase 4 is required for proper response to iron deficiency and to cadmium exposure. The nicotianamine synthase (NAS) enzymes catalyze the formation of nicotianamine (NA), a non-proteinogenic amino acid involved in iron homeostasis. We undertook the functional characterization of AtNAS4, the fourth member of the Arabidopsis thaliana NAS gene family. A mutant carrying a T-DNA insertion in AtNAS4 (atnas4), as well as lines overexpressing AtNAS4 both in the atnas4 and the wild-type genetic backgrounds, were used to decipher the role of AtNAS4 in NA synthesis, iron homeostasis and the plant response to iron deficiency or cadmium supply. We showed that AtNAS4 is an important source for NA. Whereas atnas4 had normal growth in iron-sufficient medium, it displayed a reduced accumulation of ferritins and exhibited a hypersensitivity to iron deficiency. This phenotype was rescued in the complemented lines. Under iron deficiency, atnas4 displayed a lower expression of the iron uptake-related genes IRT1 and FRO2 as well as a reduced ferric reductase activity. Atnas4 plants also showed an enhanced sensitivity to cadmium while the transgenic plants overexpressing AtNAS4 were more tolerant. Collectively, our data, together with recent studies, support the hypothesis that AtNAS4 displays an important role in iron distribution and is required for proper response to iron deficiency and to cadmium supply. 23822855 The impact of a dedicated training program for oral examiners at a medical school in Germany: a survey among participants from operative and non-operative disciplines. Oral examinations have been a crucial format in ancient and modern assessment to evaluate and guarantee quality of medical education and thereby to secure patient safety. To achieve a high level of quality in the oral part of the final examination of medical students, a training program for oral examiners at the Medical Faculty of Ulm (Germany) has been established since 2007.However, little is known about the attitude of the examiners in regard to the impact of this training program and of oral examinations as instruments to ensure patient safety. All 367 academic clinicians from operative and non-operative disciplines, attending the one-day examiner training program at the University of Ulm between 2007 and 2012 have been asked to answer an online survey (EvaSys 5.0). Focus of the survey was to find out in which respect the examiners profited from the trainings, if the training effects were discipline-dependent, and to which degree the oral examinations could contribute to patient safety. Statistical analysis was performed using the t-test for independent samples. Results were considered statistically significant when p < 0.05. A total of 63 participants answered the survey, but in 4 cases the questionnaire was not fully completed (with single items missing). More than half of the study participants (n = 34/59; 58%) have experienced (at least sometimes or rarely) candidates that they deemed incompetent and perhaps even dangerous to the patients' health who nevertheless passed the oral exam successfully. The majority of participants were convinced that oral examinations using concrete clinical cases could significantly contribute to patient safety, if grading is based on clear criteria and if examinations as well as grading are performed more critically. The impact of the training program was rated significantly stronger by surgeons than by non-surgeons in several categories. These categories included "strengths and weaknesses of oral examinations", "reliability", "validity", "competence in grading", "critical grading", and "departmental improvements" concerning oral examinations. In respect to patient safety, it seems crucial to prevent incompetent candidates from passing the oral examination. The present study indicates the importance to continue and to develop our examiner trainings, with main emphasis on concrete clinical problems and a criteria-based critical grading system for oral examinations. Since the impact of the training was particularly high for colleagues from the operative disciplines, the training program should be offered especially in surgical departments. 23874825 Testing the accuracy of different a-axis types for measuring the orientation of bones in the archaeological and paleontological record. Orientation of archaeological and paleontological materials plays a prominent role in the interpretation of site formation processes. Allochthony and authochthony are frequently assumed from orientation patterns or lack thereof. Although it is still debated to what extent orientation of items can be produced in original depositional contexts, the recent use of GIS tools to measure orientations has highlighted several ways of reproducing A-axes with which to address these taphonomic issues. In the present study, the three most relevant A-axis types are compared to test their accuracy in reproducing water current direction. Although results may be similar in specific bone shapes, differences are important in other shapes. As known in engineering working with wind and fluid mechanics (developing shape optimization), longitudinal symmetrical axes (LSA) are the one that best orient structures against or in the same direction of wind and water. The present work shows that this is also the case for bones (regardless of shape), since LSA produce the most accurate estimates of flow direction. This has important consequences for the interpretation of orientation patterns at sites, since this type of axis is still not properly reproduced by GIS available tools. 23934680 Low Fructose and Low Salt Diets Increase Mitochondrial DNA in White Blood Cells of Overweight Subjects. To evaluate the effect of sodium and fructose restriction on mitochondrial DNA (mtDNA) content and systemic oxidative stress in a sample of overweight and pre hypertensive subjects.Data and blood samples were collected from 36 overweight and pre hypertensive patients randomly assigned to either an isocaloric (with respect to baseline) low sodium-fructose diet or an isocaloric low sodium diet. Patients were followed for 8 weeks. We measured mitochondrial DNA (mtDNA) content from peripheral blood white cells by Real-time PCR and plasma malondialdehyde (MDA) and 2,4-dinitrophenylhydrazine (DNPH) as markers of reactive oxigen species (ROS).Compared to baseline, at week 8 there was a continued and significant increase in mtDNA in both the low sodium diet group [2.4 vs. 13.1 (relative copy number), p<0.05] and the low sodium diet-fructose group (1.9 vs. 147.2, p<0.05). By week 8 there was a continued decrease in plasma DNPH levels in the low sodium diet group (4.6 vs. 2.6, p<0.05) and in the low sodium diet-fructose group (5.8 vs. 2.2, p<0.05). No significant differences were found with MDA.Our studies suggest that simple dietary measures such as reducing salt with or without restricting fructose can increase mtDNA and improve markers of oxidative stress. 23929899 Inferior vena caval and right atrial thrombus complicating amoebic liver abscess. We present the result of right atrial thrombectomy in a paediatric patient suffering from a right atrial thrombus due to amoebic liver abscess under total circulatory arrest. A 2-year old boy with amoebic liver abscess complicated by inferior vena cava (IVC) thrombus extending up to the right atrium (RA) was operated on in our institute. During the surgery, the thrombus was removed from the IVC and the RA under deep hypothermic circulatory arrest. After chest closure, open drainage of the abscess was performed. Metronidazole was given postoperatively for 2 weeks. The postoperative period was uneventful. There was rapid convalescence with complete resolution of the abscess. Anticoagulation with warfarin was started on the day following surgery and continued for 6 weeks. There was no recurrence of thrombosis or embolic events in the follow-up period. Extension of thrombus into the right atrium mandates an aggressive surgical approach which may prove life saving. It is crucial in the prevention of pulmonary embolism or Budd-Chiari syndrome, which may have an overall poor outcome. 23202249 Chronic exposure to paclobutrazol causes hepatic steatosis in male rockfish Sebastiscus marmoratus and the mechanism involved. Paclobutrazol (PBZ) is a triazole-containing fungicide which is widely used in agriculture. Acute toxicity can follow its extensive use but it is generally weaker than traditional pesticides such as organochlorine and organophosphorus. However, its adverse effects on aquatic organisms need to be investigated. This study was conducted to investigate the effect of PBZ exposure on the hepatic lipid metabolism of Sebastiscus marmoratus. After PBZ exposure for 50 days, hepatic lipid droplets were enlarged and the hepatic total lipid, triglyceride, total cholesterol and free fatty acid content had increased in a dose dependent manner compared to the control. The mRNA expression of lipid metabolism associated genes such as peroxisome proliferator-activated receptors (PPARs), androgen receptor, acetyl-CoA carboxylase 1, fatty acid synthesis, fatty acid bing protein 4, liver X receptor α (LXRα) and stearoyl-CoA desaturase were up-regulated by PBZ exposure. These results indicated that triazole-containing fungicides might affect the metabolism and health of fish via the multi-signal pathways of nuclear receptors such as PPARs and LXR. 23945108 miRNA Profiling Identifies Candidate miRNAs for Bladder Cancer Diagnosis and Clinical Outcome. Bladder cancer is a common cancer in the Western world. The current prognosticators such as tumor grade, stage, size, and multifocality do not accurately reflect the clinical outcome. It is of clinical interest to identify biomarkers that could improve diagnostic and/or prognostic predictions. The objectives of this study were to identify deregulated miRNAs in bladder cancer samples and evaluate their potential as diagnostic and prognostic biomarkers. We screened 723 miRNAs by microarray and selected a subset of 15 distinctively deregulated miRNAs for further validation by real-time quantitative RT-(q)PCR. Seven miRNAs (miR-20a, miR-106b, miR-130b, miR-141, miR-200a, miR-200a*, and miR-205) were found to be up-regulated and eight miRNAs (miR-100, miR-125b, miR-130a, miR-139-5p, miR-145*, miR-199a-3p, miR-214, and miR-222) were found to be down-regulated in malignant bladder tissue samples compared to healthy tissue. Four miRNAs that have already been described in the literature (miR-141, miR-199a-3p, miR-205, and miR-214) were significantly differentially expressed between nonmuscle-invasive and muscle-invasive bladder cancer. Furthermore, real-time RT-qPCR of all miRNAs provided high overall correct classification (>75%) of bladder cancer diagnosis. Two miRNAs (miR-141 and miR-205) were associated with overall survival time. The verification of tumor-specific miRNA expression profile, together with the observed association of miR-141 and miR-205 expression with overall survival, underline the potential of miRNAs to function as diagnostic and/or prognostic markers of bladder cancer. 23205561 Shear modulus property characterization of nanorods. We demonstrate an innovative technique for the direct measurement on the shear modulus of an individual nanorod. This measurement is based on atomic force microscopy (AFM) and microfabrication techniques. A nanorod is first aligned along the edge of a small trench in a silicon substrate, and then one end of the nanorod is fixed on the substrate. When an AFM tip scans over the nanorod in contact mode, the nanorod will be twisted by the comprehensive action from the force of the AFM tip, confinement from the trench edge and the fixing end. The shear deformation and the corresponding force that caused the deformation can be retrieved from topography and lateral force image, respectively. By small-angle approximation, the shear modulus of the ZnO NR, which has a radius of 166 nm and a length of 4 μm, is measured to be 8.1 ± 1.9 GPa. This method can be applied directly to characterize the shear modulus of any nanowire/nanorod that possesses a polygon cross section. 23877034 A model of postural coordination dynamics. Prior research has shown that voluntary postural movement is characterized by stable in-phase and antiphase hip-ankle coordination modes. Prior modeling of coordination dynamics does not capture the stable fixed-points, phase transitions and hysteresis found in hip-ankle coordination. In this article a model was created to capture the dynamics of hip-ankle postural coordination. The present model follows the synergetic approach and uses two nonlinear oscillators to capture the dynamics of hip-ankle coordination. Terms for symmetry breaking and additive stochastic noise are included in the model. The model captures phase transitions from in-phase to antiphase coordination as movement frequency is scaled up and from antiphase to in-phase coordination as movement frequency is scaled down. The model also exhibits hysteresis, with phase transitions occurring at different movement frequencies as the control parameter is scaled up and down. 23508266 A genome-wide association study of bronchodilator response in asthmatics. Reversibility of airway obstruction in response to β2-agonists is highly variable among asthmatics, which is partially attributed to genetic factors. In a genome-wide association study of acute bronchodilator response (BDR) to inhaled albuterol, 534 290 single-nucleotide polymorphisms (SNPs) were tested in 403 white trios from the Childhood Asthma Management Program using five statistical models to determine the most robust genetic associations. The primary replication phase included 1397 polymorphisms in three asthma trials (pooled n=764). The second replication phase tested 13 SNPs in three additional asthma populations (n=241, n=215 and n=592). An intergenic SNP on chromosome 10, rs11252394, proximal to several excellent biological candidates, significantly replicated (P=1.98 × 10(-7)) in the primary replication trials. An intronic SNP (rs6988229) in the collagen (COL22A1) locus also provided strong replication signals (P=8.51 × 10(-6)). This study applied a robust approach for testing the genetic basis of BDR and identified novel loci associated with this drug response in asthmatics.The Pharmacogenomics Journal advance online publication, 19 March 2013; doi:10.1038/tpj.2013.5. 23908169 Parents' responses to stress in the neonatal intensive care unit. Background Parents' stress resulting from hospitalization of their infant in the neonatal intensive care unit (NICU) produces emotional and behavioral responses. The National Institutes of Health-sponsored Patient Reported Outcomes Measurement Information System (PROMIS) offers a valid and efficient means of assessing parents' responses. Objective To examine the relationship of stress to anxiety, depression, fatigue, and sleep disruption among parents of infants hospitalized in the NICU. Methods Thirty parents completed the Parental Stressor Scale (PSS:NICU) containing subscales for NICU Sights and Sounds, Infant Behavior and Appearance, and Parental Role Alteration, and the PROMIS anxiety, depression, fatigue, and sleep disturbance short-form instruments. Results PSS total score was significantly correlated with anxiety (r = 0.61), depression (r = 0.36), and sleep disturbance (r = 0.60). Scores for NICU Sights and Sounds were not significantly correlated with parents' outcomes; however, scores for Alteration in Parenting Role were correlated with all 4 outcomes, and scores for Infant Appearance were correlated with all except fatigue. Conclusion Stress experienced by parents of NICU infants is associated with a concerning constellation of physical and emotional outcomes comprising anxiety, depression, fatigue, and sleep disruption. 23818133 Networks involved in olfaction and their dynamics using independent component analysis and unified structural equation modeling. The study of human olfaction is complicated by the myriad of processing demands in conscious perceptual and emotional experiences of odors. Combining functional magnetic resonance imaging with convergent multivariate network analyses, we examined the spatiotemporal behavior of olfactory-generated blood-oxygenated-level-dependent signal in healthy adults. The experimental functional magnetic resonance imaging (fMRI) paradigm was found to offset the limitations of olfactory habituation effects and permitted the identification of five functional networks. Analysis delineated separable neuronal circuits that were spatially centered in the primary olfactory cortex, striatum, dorsolateral prefrontal cortex, rostral prefrontal cortex/anterior cingulate, and parietal-occipital junction. We hypothesize that these functional networks subserve primary perceptual, affective/motivational, and higher order olfactory-related cognitive processes. Results provided direct evidence for the existence of parallel networks with top-down modulation for olfactory processing and clearly distinguished brain activations that were sniffing-related versus odor-related. A comprehensive neurocognitive model for olfaction is presented that may be applied to broader translational studies of olfactory function, aging, and neurological disease. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc. 23871303 Occupational Radiation Exposure During Endovascular Aortic Procedures. To measure the radiation exposure of the operating team during endovascular aortic procedures, and to determine factors that predict high exposures. Electronic dosimeters placed over and under protective lead garments, were used to prospectively record radiation exposure during endovascular aortic repairs performed in a designated interventional radiology suite. Univariate and multivariate linear regression analyses of predictors of radiation exposure were performed. A total of 26 infra-renal and 10 thoracic endovascular cases were studied. Median (IQR) patient age and body mass index were 76.0 (70.0-81.8) years and 26.2 (23.9-28.9) kg/m(2) respectively. Over-lead exposure to the operator was higher for thoracic than for infra-renal procedures (421.0 [233.8-597.8] Î¼Sv vs. 52.5 [27.8-179.8] Î¼Sv, p = .0003), reflecting a significant exposure to unprotected parts of the body. Under-lead exposures for operator and assistant were 5.5 (2.0-14.2) Î¼Sv and 1.0 (0.0-2.3) Î¼Sv respectively, which for an average caseload would comply with total body effective dose limits. Type of case and percentage of digital subtraction angiography (DSA) time in left anterior oblique angulations predicted dose to the operator (p < .0001). Thoracic procedures, DSA runs and obliquity of the C-arm are strong predictors of radiation exposure during endovascular aortic repairs. Understanding scatter radiation dynamics and instigating measures to minimise radiation exposure should be mandatory. 23727957 Circular code motifs in transfer RNAs. In 1996, a trinucleotide circular code X is identified in genes of prokaryotes and eukaryotes (Arquès and Michel, 1996). In 2012, X motifs are identified in the transfer RNA (tRNA) Phe and 16S ribosomal RNA (Michel, 2012). A statistical analysis of X motifs in all available tRNAs of prokaryotes and eukaryotes in the genomic tRNA database (September 2012, http://lowelab.ucsc.edu/GtRNAdb/, Lowe and Eddy, 1997) is carried out here. For this purpose, a search algorithm of X motifs in a DNA sequence is developed. Two definitions allow to determine the occurrence probabilities of X motifs and the circular codes X, X1=P(X) and X2=P(2)(X) (P being a circular permutation map applied on X) in a population of tRNAs. This approach identifies X motifs in the 5' and/or 3' regions of 16 isoaccepting tRNAs (except for the tRNAs Arg, His, Ser and Trp). The statistical analyses are performed on different and large tRNA populations according to the taxonomy (prokaryotes and eukaryotes), tRNA length and tRNA score. Finally, a circular code property observed in genes of prokaryotes and eukaryotes is identified in the 3' regions of 19 isoaccepting tRNAs of prokaryotes and eukaryotes (except for the tRNA Leu). The identification of X motifs and a gene circular code property in tRNAs strengthens the concept proposed in Michel (2012) of a possible translation (framing) code based on a circular code. 23852994 Conformational Isomerism in Monomeric, Low-Coordinate Group 12 Complexes Stabilized by a Naphthyl-Substituted m-Terphenyl Ligand. The synthesis and characterization of the first series of low-coordinate bis(terphenyl) complexes of the Group 12 metals, [Zn(2,6-Naph2 C6 H3 )2 ] (1), [Cd(OEt2 )(2,6-Naph2 C6 H3 )2 ] (2) and [Hg(OEt2 )(2,6-Naph2 C6 H3 )2 ] (3) (Naph=1-C10 H7 ) are described. The naphthyl substituents of the terphenyl ligands confer considerable steric bulk, and as a result of limited flexibility introduce multiple conformations to these unusual systems. In the solid state, complex 1 features a two-coordinate Zn centre with the ligands oriented in a syn/anti conformation, whereas the three-coordinate distorted T-shaped complexes 2 and 3 feature the ligands in the syn/syn configurations. The results of DFT calculations are in good agreement with the solid-state configurations for these complexes and support the spectroscopic measurements, which indicate several conformers in solution. 23870935 Effects of flavonoids from Rosa laevigata Michx fruit against high-fat diet-induced non-alcoholic fatty liver disease in rats. The effects and mechanisms of the total flavonoids (TFs) from Rosa laevigata Michx fruit on high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) were investigated in this study. Gavage administration of the TFs significantly decreased the relative liver weight, serum AST and ALT activities, the levels of serum lipid, LDL, blood glucose and insulin, suppressed lipid accumulation in liver, and increased serum HDL level. Moreover, the natural product significantly enhanced SOD activity, increased GSH-Px and GSH contents and decreased the concentration of MDA and CYP2E1 expression as well as prevented mitochondrial membrane potential dysfunctions and ultrastructural alterations. Further mechanism investigation indicated that the TFs inhibited hepatic lipid accumulation by suppressing the expressions of some key molecules in fatty acid synthesis pathway and promoting fatty acid β-oxidation, while not by inhibiting cholesterol synthesis. On the base of these, the TFs should be developed as a new drug for treatment of NAFLD. 23640900 Enhanced expression of MYF5 and MYOD1 in fibroblast cells via the forced expression of bos taurus MYF5. The formation of vertebrate skeletal muscles widely thought to be under the control of hierarchy of regulatory genes. MYF5 is one of the myogenic determination gene expressed in the developing mouse dermomyotome which control skeletal muscle differentiation. In the current work, we had obtained the cDNA sequence including the full coding region of the bos taurus myogenic factor MYF5 by reverse transcription polymerase chain reaction. Furthermore, we examined whether fibroblast cell derived from mouse and bos taurus can be transduced using plasmid vectors carrying bos taurus MYF5. Bos taurus MYF5 activates MYF5 and MYOD1 expression after 1 day culture. The concerted upregulation of the myogenic regulatory factors enhanced myosin (skeletal fast) expression. These observation show that MYF5 is essential for myogenic differentiation and provides candidates for regulation bos taurus skeletal muscle development. 23940818 ERManI Is a Target of miR-125b and Promotes Transformation Phenotypes in Hepatocellular Carcinoma (HCC). The MAN1B1 gene product, designated ER alpha-1, 2-mannosidase (ERManI), is an enzyme localized in the Golgi complex of mammalian cells. By functioning as a "gate keeper" to prevent the inappropriate secretion of misfolded glycoproteins, it plays a critical role in maintaining protein homeostasis in the mammalian secretory pathway. In the present study, we identified that a conserved motif within the 3'UTR of ERManI is a target of miR-125b, a microRNA frequently down-regulated in numerous types of cancers, including hepatocellular carcinoma (HCC). As predicted, the expression of ERManI is significantly elevated in HCC, as measured by immunohistochemistry in a liver spectrum tissue microarray. Additional analyses using several hepatoma cell lines demonstrated that the elevated ERManI inversely correlates with a diminished intracellular concentration of miR-125b. Moreover, functional studies indicated that RNAi-mediated knock-down of endogenous ERManI was sufficient to inhibit proliferation, migration, and invasion of hepatoma cells. These phenotypical changes occurred in the absence of alterations in global glycoprotein secretion or ER-stress status. Together, these results revealed a novel post-transcriptional regulatory mechanism for ERManI and implied that this molecule contributes to the regulation of carcinogenesis in HCC independent of its function in glycoprotein quality control. 23398786 Daily physical activity assessment with accelerometers: new insights and validation studies. The field of application of accelerometry is diverse and ever expanding. Because by definition all physical activities lead to energy expenditure, the doubly labelled water (DLW) method as gold standard to assess total energy expenditure over longer periods of time is the method of choice to validate accelerometers in their ability to assess daily physical activities. The aim of this paper was to provide a systematic overview of all recent (2007-2011) accelerometer validation studies using DLW as the reference. The PubMed Central database was searched using the following keywords: doubly or double labelled or labeled water in combination with accelerometer, accelerometry, motion sensor, or activity monitor. Limits were set to include articles from 2007 to 2011, as earlier publications were covered in a previous review. In total, 38 articles were identified, of which 25 were selected to contain sufficient new data. Eighteen different accelerometers were validated. There was a large variability in accelerometer output and their validity to assess daily physical activity. Activity type recognition has great potential to improve the assessment of physical activity-related health outcomes. So far, there is little evidence that adding other physiological measures such as heart rate significantly improves the estimation of energy expenditure. 23623922 eIF3c: a potential therapeutic target for cancer. Cancer cells are rapidly evolving due to their unstable genome, which contributes to the development of new cancer clones with different gene expression profile (GEP). Manipulating the expression of the genes vital for the progression of the disease is essential to overcome its heterogeneity. However, targeting overexpressed genes, retrieved from GEP analysis, would be efficient for a specific kind of a malignancy. Alternatively, manipulating the expression of genes that are part of a fundamental mechanism in the cell would be effective against a wide range of malignancies. To test this hypothesis we characterized, using RNAi approaches, the therapeutic potential of the housekeeping eIF3c gene in five different cancer cell lines NCI-ADR/RES (NAR), HeLa, MCF7, HCT116 and B16F10. eIF3c is one of the core subunit of the eukaryote translation initiation factor (eIF) 3 complex, which has a crucial role in the translation initiation process. In this study, we demonstrated that eIF3c is vital to translation initiation in vivo, as its downregulation decreases the global protein synthesis and causes a polysome run-off. In addition, reducing the expression of eIF3c mediates G0/G1 or G2/M arrest in a tissue dependent manner, which leads to a reduction in cell proliferation and eventually to cell death. Moreover, we demonstrated the efficiency of the hyaluronan (HA)-coated lipid-based nanoparticles (LNPs) platform to deliver eIF3c-siRNAs to mouse melanoma cells. Taking together, our results emphasize the importance of seeking ubiquitously expressed housekeeping genes such as eIF3c rather than tumor associated overexpressed genes as therapeutic targets for the heterogeneous malignancies. 23334808 Speech Preference is Associated with Autistic-Like Behavior in 18-Months-Olds at Risk for Autism Spectrum Disorder. We examined whether infants' preference for speech at 12 months is associated with autistic-like behaviors at 18 months in infants who are at increased risk for autism spectrum disorder (ASD) because they have an older sibling diagnosed with ASD and in low-risk infants. Only low-risk infants listened significantly longer to speech than to nonspeech at 12 months. In both groups, relative preference for speech correlated positively with general cognitive ability at 12 months. However, in high-risk infants only, preference for speech was associated with autistic-like behavior at 18 months, while in low-risk infants, preference for speech correlated with language abilities. This suggests that in children at risk for ASD an atypical species-specific bias for speech may underlie atypical social development. 23244296 Anion-π interactions: generality, binding strength, and structure. Anion-π interactions have been systematically studied using tetraoxacalix[2]arene[2]triazine 1, an electron-deficient and cavity self-tunable macrocyclic host, as an electron-neutral molecular probe. As revealed by electrospray ionization mass spectrometry (ESI-MS), fluorescence titration and X-ray crystallography, tetraoxacalix[2]arene[2]triazine has been found to form 1:1 complexes with four typical polyatomic anions of different geometries and shapes in the gaseous phase, in solution, and in the solid state. The association constants for the formation of anion-π complexes in acetonitrile are in the range of 239 to 16950 M(-1), following the order of 1·NO(3)(-) > 1·BF(4)(-) > 1·PF(6)(-) > 1·SCN(-). X-ray molecular structures of the complexes showed that two opposing triazine rings of tetraoxacalix[2]arene[2]triazine act as a pair of tweezers to interact with the included anions through cooperative anion-π and lone-pair electron-π interactions. The generality of anion-π interactions and diverse anion-π interaction motifs can provide a new dimension in the study of molecular recognition and self-assembly. Moreover, this study potentiates the effect of anion-π interactions in chemical and biological systems, especially those involving anion and electron-deficient aromatic species. 23966575 Successful stent for a pseudoaneurysm after the patent ductus arteriosus closure procedure. We describe the case of a large pseudoaneurysm after transcatheter closure of patent ductus arteriosus in a 42-year old male who developed back pain and dyspnoea 6 months subsequent to the first procedure. The patient's pseudoaneurysm was successfully treated using Talent prostheses (Medtronic AVE, Santa Rosa, CA, USA), though the postoperative course was without incident. 23897081 Complementary or alternative medicine in cancer care-myths and realities. Complementary therapies are adjuncts to mainstream care, used primarily for symptom control and to enhance physical and emotional strength during and after mainstream cancer treatment. These therapies are rational, noninvasive and evidence-based that have been subjected to study to determine their value, document the problems they aim to ameliorate and define the circumstances under which they are beneficial. By contrast, 'alternative' therapies are generally promoted as such-for use as actual antitumour treatments. Typically they lack biological plausibility and scientific evidence of safety and efficacy, and many are outright fraudulent. Combining the helpful complementary therapies with mainstream oncology care to address patients' physical, psychological and spiritual needs constitutes the practice of integrative oncology. By providing patients' nonpharmacological treatment modalities that reduce symptom burden and improve quality of life, physicians enable patients to have an active role in their care, which in turn improves the physician-patient relationship, the quality of cancer care and the well-being of patients and their families. 23946262 Identification of differentially expressed proteins by treatment with PUGNAc in 3T3-L1 adipocytes through analysis of ATP-binding proteome. O-GlcNAc, an important modification for cellular processes, is catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). O-(2-acetamido-2-deoxy-D-glucopyranosylidene) amino-N-phenylcarbamate (PUGNAc) is a non-selective inhibitor of OGA, which increases the level of protein O-GlcNAcylation and is known to induce insulin-resistance in adipose cells due to uncharacterized targets of this inhibitor. In this study, using ATP affinity chromatography, we applied a targeted proteomic approach for identification of proteins induced by treatment with PUGNAc. For optimization of proteomic methods using ATP affinity chromatography, comparison of two cell lines (3T3-L1 adipocytes and C2C12 myotubes) and two different digestion steps was performed using four different structures of immobilized ATP-bound resins. Using this approach, based on DNA sequence homologies, we found that the identified proteins covered almost half of ATP binding protein families classified by PROSITE. The optimized ATP affinity chromatography approach was applied for identification of proteins that were differentially expressed in 3T3-L1 adipocytes following treatment with PUGNAc. For label-free quantitation, a gel-assisted method was used for digestion of the eluted proteins, and analysis was performed using two different MS modes, data-independent (671 proteins identified) and data-dependent (533 proteins identified) analyses. Among identified proteins, 261 proteins belong to nucleotide binding proteins and we focused on some nucleotide binding proteins, ubiquitin-activation enzyme 1 (E1), heat shock protein 70 (Hsp70), vasolin-containing protein (Vcp), and heat shock protein 90 (Hsp90), involved in ubiquitin-proteasome degradation and insulin signaling pathways. In addition, we found that treatment with PUGNAc resulted in increased ubiquitination of proteins in a time-dependent manner, and a decrease in both the amount of Akt and the level of phosphorylation of Akt, a key component in insulin signaling, through down-regulation of Hsp90. In this study, based on a targeted proteomic approach using ATP affinity chromatography, we found four proteins related to ubiquitination and insulin signaling pathways that were induced by treatment with PUGNAc. This result would provide insight into understanding functions of PUGNAc in 3T3-L1 cells. This article is protected by copyright. All rights reserved. 23728814 Engineering the meso-Diaminopimelate Dehydrogenase from Symbiobacterium thermophilum by Site Saturation Mutagenesis for D-Phenylalanine Synthesis. In order to enlarge the substrate binding pocket of the meso-diaminopimelate dehydrogenase from Symbiobacterium thermophilum to accommodate larger 2-keto acids, four amino acid residues (Phe146, Thr171, Arg181, and His227) were targeted for site saturation mutagenesis. Among all mutants, the single mutant H227V had a specific activity of 2.39 ± 0.06 U · mg(-1), which was 35.1-fold enhancement over the wild-type enzyme. 23685637 Milrinone therapy for enterovirus 71-induced pulmonary edema and/or neurogenic shock in children: a randomized controlled trial. Enterovirus 71-induced brainstem encephalitis with pulmonary edema and/or neurogenic shock (stage 3B) is associated with rapid mortality in children. In a small pilot study, we found that milrinone reduced early mortality compared with historical controls. This prospective, randomized control trial was designed to provide more definitive evidence of the ability of milrinone to reduce the 1-week mortality of stage 3B enterovirus 71 infections. Prospective, unicenter, open-label, randomized, controlled study. Inpatient ward of a large tertiary teaching hospital in Ho Chi Minh City, Vietnam. Children (≤ 18 yr old) admitted with proven enterovirus 71-induced pulmonary edema and/or neurogenic shock. Patients were randomly assigned to receive intravenous milrinone (0.5 μg/kg/min) (n = 22) or conventional management (n = 19). Both groups received dopamine or dobutamine and intravenous immunoglobulin. The primary endpoint was 1-week mortality. The secondary endpoints included length of ventilator dependence and hospital stay and adverse events. The median age was 2 years with a predominance of boys in both groups. The 1-week mortality was significantly lower, 18.2% (4/22) in the milrinone compared with 57.9% (11/19) in the conventional management group (relative risk = 0.314 [95% CI, 0.12-0.83], p = 0.01). The median duration of ventilator-free days was longer in the milrinone treatment group (p = 0.01). There was no apparent neurologic sequela in the survivors in either group, and no drug-related adverse events were documented. Milrinone significantly reduced the 1-week mortality of enterovirus 71-induced pulmonary edema and/or neurogenic shock without adverse effects. Further studies are needed to determine whether milrinone might be useful to prevent progression of earlier stages of brainstem encephalitis. 23625157 The EKZ/AMC childhood cancer survivor cohort: methodology, clinical characteristics, and data availability. Childhood cancer survivors are at high risk of late adverse effects of cancer treatment, but there are still many gaps in evidence about these late effects. We described the methodology, clinical characteristics, data availability, and outcomes of our cohort study of childhood cancer survivors. The Emma Children's Hospital/Academic Medical Center (EKZ/AMC) childhood cancer survivor cohort is an ongoing single-center cohort study of ≥5-year childhood cancer survivors, which started in 1996 simultaneously with regular structured medical outcome assessments at our outpatient clinic. From 1966 to 2003, 3,183 eligible children received primary cancer treatment in the EKZ/AMC, of which 1,822 (57.2 %) survived ≥5 years since diagnosis. Follow-up time ranged from 5.0 to 42.5 years (median, 17.7). Baseline primary cancer treatment characteristics were complete for 1,781 (97.7 %) survivors, and 1,452 (79.7 %) survivors visited our outpatient clinic. Baseline characteristics of survivors who visited the clinic did not differ from those without follow-up. Within our cohort, 54 studies have been conducted studying a wide range of late treatment-related effects. The EKZ/AMC childhood cancer survivor cohort provides a strong structure for ongoing research on the late effects of childhood cancer treatment and will continuously contribute in reducing evidence gaps concerning risks and risk groups within this vulnerable population. Our large cohort study of childhood cancer survivors with complete baseline characteristics and unique, long-term medical follow-up decreases gaps in evidence about specific risks of late effects and high-risk groups, with the ultimate goal of improving the quality of care for childhood cancer survivors. 23890062 Dendritic-cell-based therapeutic cancer vaccines. The past decade has seen tremendous developments in novel cancer therapies through the targeting of tumor-cell-intrinsic pathways whose activity is linked to genetic alterations and the targeting of tumor-cell-extrinsic factors, such as growth factors. Furthermore, immunotherapies are entering the clinic at an unprecedented speed after the demonstration that T cells can efficiently reject tumors and that their antitumor activity can be enhanced with antibodies against immune-regulatory molecules (checkpoint blockade). Current immunotherapy strategies include monoclonal antibodies against tumor cells or immune-regulatory molecules, cell-based therapies such as adoptive transfer of ex-vivo-activated T cells and natural killer cells, and cancer vaccines. Herein, we discuss the immunological basis for therapeutic cancer vaccines and how the current understanding of dendritic cell and T cell biology might enable the development of next-generation curative therapies for individuals with cancer. 23417972 BaSnO3 perovskite nanoparticles for high efficiency dye-sensitized solar cells. The synthesis of highly crystalline perovskite BaSnO3 nanoparticles for use as photoanode materials in dye-sensitized solar cells (DSSCs) is reported, and the photovoltaic properties of DSSCs based on BaSnO3 nanoparticles (BaSnO3 cells) are demonstrated. The resulting DSSCs exhibit remarkably rapid charge collection and a DSSC fabricated with a BaSnO3 film thickness of 43 µm leads to a high energy conversion efficiency of 5.2 %, which is one of the highest reported for ternary oxide-based DSSCs. More importantly, the BaSnO3 cells show superior charge collection in nanoparticle films compared to TiO2 cells and could offer a breakthrough in the efficiencies of DSSCs. 23884031 Diffuse alveolar hemorrhage as a manifestation of Behçet disease. Diffuse alveolar hemorrhage (DAH) is a rare life-threatening condition which refers to the presence of red blood cells within alveoli deriving from hemorrhage originating in the pulmonary microvasculature. It differs from alveolar filling, in which blood cells derive from localized bleeding, usually of bronchial origin. DAH may be part of diffuse alveolar injury of any origin. DAH should be considered a medical emergency due to the significant morbidity and mortality associated with respiratory failure, when secondary to impaired oxygen uptake from alveoli filled with erythrocytes. Patients with alveolar hemorrhage present with non-specific symptoms like dyspnea, cough and hemoptysis, which is not always present. They may develop acutely or insidiously over a few days. We present a case of a patient with probable Behçet's disease complicated by pulmonary capillaritis and DAH resulting in refractory respiratory failure and death. 23867554 Oscillatory correlates of memory in non-human primates. The ability to navigate through our environment, explore with our senses, track the passage of time, and integrate these various components to form the experiences which make up our lives is shared among humans and animals. The use of animal models to study memory, coupled with electrophysiological techniques that permit the direct measurement of neural activity as memories are formed and retrieved, has provided a wealth of knowledge about these mechanisms. Here, we discuss current knowledge regarding the specific role of neural oscillations in memory, with particular emphasis on findings derived from non-human primates. Some of these findings provide evidence for the existence in the primate brain of mechanisms previously identified only in rodents and other lower mammals, while other findings suggest parallels between memory-related activity and processes observed in other cognitive modalities, including attention and sensory perception. Taken together, these results provide insight into how network activity may be organized to promote memory formation, and suggest that key aspects of this activity are similar across species, providing important information about the organization of human memory. 23721747 Advances in NMR structures of integral membrane proteins. Integral membrane proteins (IMPs) play a central role in cell communication with the environment. Their structures are essential for our understanding of the molecular mechanisms of signaling and for drug design, yet they remain badly underrepresented in the protein structure databank. Solution NMR is, aside from X-ray crystallography, the major tool in structural biology. Here we review recently reported solution NMR structures of polytopic IMPs and discuss the new approaches, which were developed in the course of these studies to overcome barriers in the field. Advances in cell-free protein expression, combinatorial isotope labeling, resonance assignment, and collection of structural data greatly accelerated IMP structure determination by solution NMR. In addition, novel membrane-mimicking media made possible determination of solution NMR structures of IMPs in a native-like lipid environment. 23844758 High temperature thermoelectric properties of strontium titanate thin films with oxygen vacancy and niobium doping. We report the evolution of high temperature thermoelectric properties of SrTiO3 thin films doped with Nb and oxygen vacancies. Structure-property relations in this important thermoelectric oxide are elucidated and the variation of transport properties with dopant concentrations is discussed. Oxygen vacancies are incorporated during growth or annealing in Ar/H2 above 800 K. An increase in lattice constant due to the inclusion of Nb and oxygen vacancies is found to result in an increase in carrier density and electrical conductivity with simultaneous decrease in carrier effective mass and Seebeck coefficient. The lattice thermal conductivity at 300 K is found to be 2.22 W m(-1) K(-1), and the estimated figure of merit is 0.29 at 1000 K. 22928530 The effect of post-natal mental distress amongst Indian and Pakistani mothers living in England on children's behavioural outcomes. Low socio-economic status (SES), post-natal mental distress and parenting impact child mental health and future well-being. There are unexplained differences in child mental health between South Asian ethnic minority groups living in the UK that may be due to variation in, and differential mediation of, these factors. We used multivariate multiple regression analysis of the effect of symptoms of mental distress, socio-demographic variables and warmth of parenting on child internalizing and externalizing scores at age seven (measured in 2010) in a population cohort of English children whose mothers were of Indian (n = 211) and Pakistani (n = 260) origin. In the fully adjusted models the legacy of mental distress was visible for both internalizing (β coefficient 1.52, P = 0.04) and externalizing (1.68, P = 0.01) behaviour in the Pakistani children, and on the Indian children's internalizing (2.08, P = 0.008) but not externalizing (0.84, P = 0.204) behaviour. Lower SES was associated with worse behavioural scores for the Pakistani children, and warmth of parenting on Indian children's externalizing scores. Symptoms of post-natal mental distress are associated with Indian and Pakistani child outcomes at age seven. The finding that warmth of parenting had a stronger association on Indian children's externalizing scores than mental distress might be explained by differences in the expression of SES on family characteristics and functioning between the two ethnic groups. 23595946 Lies tell the truth about cognitive dysfunction in essential tremor: an experimental deception study with the guilty knowledge task. Research conducted in the past decade challenges the traditional view that essential tremor (ET) is characterised exclusively by movement disorder, and increasingly shows that these patients have deficits in cognitive and behavioural functioning. The available evidence suggests that this impairment might arise from dysfunction in either the fronto-subcortical or cortico-cerebellar circuits. Although abnormalities in the fronto-subcortical circuits could imply difficulty in lying, no study has investigated deception in patients with ET. To examine the cognitive functions regulating deception in patients with ET, we used a computerised task, the Guilty Knowledge Task (GKT). We also tested a group of patients with Parkinson's disease (PD), a disease associated with a known difficulty in lie production, and a group of healthy subjects (HS). In the GKT for deception, patients with ET responded less accurately than HS (p=0.014) but similarly to patients with PD (p=0.955). No differences between groups were found in truthful responses (p=0.488). Besides confirming impaired deception in patients with PD, our results show a lie production deficit in patients with ET also. These findings suggest that difficulty in lying is an aspecific cognitive feature in movement disorders characterised by fronto-subcortical circuit dysfunction, such as PD and ET. Current knowledge along with our new findings in patients with ET-possibly arising from individually unrecognised extremely mild, cognitive difficulties-should help in designing specific rehabilitative programmes to improve cognitive and behavioural disturbances in patients. 23891173 Lens fiber orientation during phaco chop: Clinical sign to identify appropriate nucleus depth. Phaco chop is the preferred technique for many phaco surgeons. A critical step in chopping is the surgeon's ability to impale the nucleus in the middle of the core endonucleus, which can be challenging. We describe a clinical sign in the phaco chop technique to help surgeons identify the center of the endonucleus without estimating the nucleus thickness. This technique uses the morphological structure of the lens and the lens fiber orientation to precisely gauge the depth at which the surgeon should impale and hold the nucleus for effective chopping. No author has a financial or proprietary interest in any material or method mentioned. 23909361 Manipulating the orbital angular momentum of light at the micron scale with nematic disclinations in a liquid crystal film. We report on the experimental manipulation of the orbital angular momentum of light by exploiting a kind of topological defects that spontaneously appear in nematics-disclinations-as microscopic optical spin-orbit interfaces whose operating wavelength can be controlled electrically. Using six different kinds of disclinations, we demonstrate the efficient generation of both scalar and vectorial singular light beams with a broad topological diversity from a fundamental Gaussian beam. 23371491 Impaired social behavior in chicks exposed to sodium valproate during the last week of embryogenesis. RATIONALE AND OBJECTIVES: To evaluate direct exposure to sodium valproate (VPA) during embryogenesis, we administered VPA to chick embryos and examined their social behaviors after hatching. METHODS AND RESULTS: Embryos treated with VPA (35 μmol/egg) on day 14 were similar to controls for hatching date (day 21) and hatchlings' abilities, such as motor, imprinting, and surface righting. However, these VPA chicks on posthatching day 3 scored significantly low in the chick's social separation stress (SSS) test as follows. Aggregation test evaluated the speed of four chicks, individually isolated by a cardboard in a box, to aggregate upon removal of the cardboards. Belongingness test evaluated the speed of a chick isolated at a corner to join the group of three chicks placed at the opposite corner. Vocalization test for each chick was performed in an isolated corner by using a sound level meter. The results demonstrated that compared with controls, VPA chicks were significantly slow in aggregation (12.7 ± 2.5 s vs. 2.9 ± 0.9 s, p = 0.006) and belongingness (3.6 ± 0.28 s/40 cm vs. 2.6 ± 0.14 s/40 cm, P = 0.003) and weak in vocalization (13.4 ± 2.8 dB/30 s vs. 26.7 ± 1.3 dB/30 s, P = 0.001), respectively. Weight of cerebellum of VAP chick was 15 % lighter than controls (P = 0.004). CONCLUSIONS: Chick embryos exposed to VPA during the last week of embryogenesis had impaired social behaviors in spite of normal mortar and imprinting ability. The present method will be a useful animal model for assessing the effects of environment during embryogenesis on social behaviors in later life. 23947742 Transcranial pulsed electromagnetic fields for multiple chemical sensitivity: study protocol for a randomized, double-blind, placebo-controlled trial. Multiple chemical sensitivity (MCS) is a chronic condition of unknown etiology. MCS is characterized by recurrent nonspecific symptoms from multiple organ systems in response to chemical exposures in concentrations that are normally tolerated by the majority of the population. The symptoms may have severe impact on patients' lives, but an evidence-based treatment for the condition is nonexisting. The pathophysiology is unclarified, but several indicators point towards abnormal processing of sensory signals in the central nervous system. Pulsed electromagnetic fields (PEMF) offer a promising new treatment for refractory depression and can be targeted at the brain, thereby activating biochemical cell processes. In a parallel, randomized, double-blind, placebo-controlled trial conducted at the Danish Research Centre for Chemical Sensitivities, the effects of PEMF in MCS patients will be assessed using the Re5 Independent System. Based on sample size estimation, 40 participants will be randomized to either PEMF therapy or placebo. The allocation sequence will be generated by computer. All involved parties (that is, participants, investigators, the research nurse, and the statistician) will be blinded to group allocation. The participants will receive PEMF therapy or placebo applied transcranially 30 minutes twice a day for 7 days a week over 6 consecutive weeks. Outcomes will be measured at baseline, once weekly during treatment, post treatment, and at 2.5-month and 4.5-month follow-up according to a predefined timetable. The primary outcome will be a measurement of the impact of MCS on everyday life. The secondary outcomes will be measurements of MCS symptoms, psychological distress (stress, anxiety or depressive symptoms), capsaicin-induced secondary punctate hyperalgesia, immunological markers in serum, and quality of life. This trial will assess the effects of PEMF therapy for MCS. Currently, there is no treatment with a documented effect on MCS, and in terms of healthcare there is very little to offer these patients. There is thus a great need for well-conducted randomized trials aimed at assessing possible treatment effects. A positive outcome will pave the way for improved healthcare and understanding of this very disabling and overlooked condition. ClinicalTrials.gov, NCT01834781. 23764105 First rapid eye movement sleep periods and sleep-onset rapid eye movement periods in sleep-stage sequencing of hypersomnias. Discrimination between narcolepsy, idiopathic hypersomnia, and behavior-induced inadequate sleep syndrome (BIISS) is based on clinical features and on specific nocturnal polysomnography (NPSG) and multiple sleep latency test (MSLT) results. However, previous studies have cast doubt on the specificity and sensitivity of these diagnostic tools. Eleven variables of the NPSG were analyzed in 101 patients who were retrospectively diagnosed with narcolepsy with cataplexy (N+C) (n=24), narcolepsy without cataplexy (N-C) (n=38), idiopathic hypersomnia with long sleep period (IHL) (n=21), and BIISS (n=18). Fifteen out of 24 N+C and 8 out of 38 N-C entered the first rapid eye movement (REM) sleep period (FREMP) from sleep stage 1 (N1) or wake (W), though this sleep-stage sequence did not arise in the other patient groups. FREMP stage sequence was a function of REM sleep latency (REML) for both N+C and N-C groups. FREMP stage sequence was not associated with mean sleep latency (MSL) in N+C but was associated in N-C, which implies heterogeneity within the N-C group. REML also was a useful discriminator. Depending on the cutoff period, REML had a sensitivity and specificity of up to 85.5% and 97.4%, respectively. The FREMP stage sequence may be a useful tool in the diagnosis of narcolepsy, particularly in conjunction with sleep-stage sequence analysis of sleep-onset REM periods (SOREMPs) in the MSLT; it also may provide a helpful intermediate phenotype in the clarification of heterogeneity in the N-C diagnostic group. However, larger prospective studies are necessary to confirm these findings. 23741022 A 10 year surveillance for antimicrobial susceptibility of Escherichia coli and Klebsiella pneumoniae in community- and hospital-associated intra-abdominal infections in China. The objective of this study was to investigate the susceptibility of hospital-associated (HA) and community-associated (CA) Escherichia coli and Klebsiella pneumoniae isolated from patients with intra-abdominal infections (IAIs) in China. From 2002 to 2011, the minimum inhibitory concentrations (MICs) of 12 antibiotics against 3074 E. coli and 1025 K. pneumoniae from 23 centres located in 16 cities were determined by the broth microdilution method. During the 10 year study period, ertapenem, imipenem, amikacin and piperacillin-tazobactam retained high and stable activity against E. coli and K. pneumoniae isolates regardless of whether their source was HA or CA and regardless of their extended-spectrum beta-lactamase (ESBL) production. However, the susceptibility of E. coli to cephalosporins and ampicillin-sulbactam decreased dramatically during the 10 years, especially for the CA isolates. Fluoroquinolones showed low activity against E. coli. During the whole study period, the ESBL rates for E. coli isolates from IAIs increased from 36.1 % in 2002-2003 to 68.1 % in 2010-2011 (P<0.001). Correspondingly, the ESBL rates in HA isolates increased from 52.2 % in 2002-2003 to 70.0 % in 2010-2011 (P = 0.001), and in CA isolates from 19.1 % in 2002-2003 to 61.6 % in 2010-2011 (P<0.001). The ESBL-positive rate in K. pneumoniae remained between 30.1 and 39.3 % of the total isolates with no significant change during the 10 years. In conclusion, carbapenems retained the highest susceptibility rates against HA and CA E. coli and K. pneumoniae. High prevalence of ESBL in HA E. coli and fast-growing resistance in CA E. coli severely limit the empirical use of the third- and fourth-generation cephalosporins in the therapy of IAIs. 23725997 Concurrent Stereotactic Radiosurgery and Bevacizumab in Recurrent Malignant Gliomas: A Prospective Trial. Virtually all patients with malignant glioma (MG) eventually recur. This study evaluates the safety of concurrent stereotactic radiosurgery (SRS) and bevacizumab (BVZ), an antiangiogenic agent, in treatment of recurrent MG. Fifteen patients with recurrent MG, treated at initial diagnosis with surgery and adjuvant radiation therapy/temozolomide and then at least 1 salvage chemotherapy regimen, were enrolled in this prospective trial. Lesions <3 cm in diameter were treated in a single fraction, whereas those 3 to 5 cm in diameter received 5 5-Gy fractions. BVZ was administered immediately before SRS and 2 weeks later. Neurocognitive testing (Mini-Mental Status Exam, Trail Making Test A/B), Functional Assessment of Cancer Therapy-Brain (FACT-Br) quality-of-life assessment, physical exam, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed immediately before SRS and 1 week and 2 months following completion of SRS. The primary endpoint was central nervous system (CNS) toxicity. Secondary endpoints included survival, quality of life, microvascular properties as measured by DCE-MRI, steroid usage, and performance status. One grade 3 (severe headache) and 2 grade 2 CNS toxicities were observed. No patients experienced grade 4 to 5 toxicity or intracranial hemorrhage. Neurocognition, quality of life, and Karnofsky performance status did not change significantly with treatment. DCE-MRI results suggest a significant decline in tumor perfusion and permeability 1 week after SRS and further decline by 2 months. Treatment of recurrent MG with concurrent SRS and BVZ was not associated with excessive toxicity in this prospective trial. A randomized trial of concurrent SRS/BVZ versus conventional salvage therapy is needed to establish the efficacy of this approach. 23673285 Interleukin-1beta stimulates platelet-activating factor production in U-937 cells modulating both its biosynthetic and catabolic enzymes. Interleukin-1beta (IL-1β) is a potent agonist of platelet-activating factor (PAF) synthesis. The monocyte-derived PAF may amplify the inflammatory and thrombotic processes. The IL-1β-induced enzymatic alterations leading to increased PAF synthesis are ill-defined. In the present study the last enzymatic activities of the remodeling (acetyl-CoA:lyso-PAF acetyltransferase) and de novo (DTT-insensitive CDP-choline:1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase) biosynthetic routes of PAF and its main catabolic enzyme, PAF acetylhydrolase, along with the intracellular and extracellular PAF levels were determined in homogenates and medium of U-937 after their stimulation with recombinant IL-1β. IL-1β at 2.5ng/mL induced an early (0.5-3h) and a late (12h) elevation of intracellular PAF levels (2-fold). Only a small portion of intracellular PAF (∼10%) was released to the extracellular medium. IL-1β increased lyso-PAF acetyltrasnferase activity which was peaked at 3h and kept elevated till 12h. A rapid 1.5-fold increase of cholinephosphotransferase activity was observed in IL-1β stimulated cells. Finally, a transient stimulation of intracellular PAF-AH was induced by IL-1β at 3h while incubation of U-937 with the PAF acetylhydrolase inhibitor pefabloc in the presence or absence of IL-1β led to a strong sustained increase of intracellular PAF levels. In conclusion, both biosynthetic routes of PAF, along with its degradation can be modulated by IL-1β in a time-specific manner. The inhibition of PAF acetylhydrolase strongly augments PAF's intracellular levels implying its crucial role for the regulation of cellular PAF. The regulation of PAF's enzymatic machinery under inflammatory conditions is more complicated than we thought to be. 23542209 Oxidative stress mediates apoptotic effects of ascorbate and dehydroascorbate in human Myelodysplasia cells in vitro. The Myelodysplastic Syndromes are stem cell heterogeneous disorders characterized by peripheral cytopenias and hypercellular bone marrow, which can evolute to acute leukaemia. Vitamin C can act as an antioxidant, ascorbic acid (AA) donates two electrons and becomes oxidized to dehydroascorbic acid (DHA). Under physiological conditions, vitamin C predominantly exists in its reduced (AA) form but also exists in trace quantities in the oxidized form (DHA). This study evaluates the therapeutic potential of vitamin C in Myelodysplastic Syndromes (MDSs). F36P cells (MDS cell line) were treated with ascorbate and dehydroascorbate alone and in combination with cytarabine. Cell proliferation and viability were assessed by trypan blue assay and cell death was evaluated by optical microscopy and flow cytometry. The role of reactive oxygen species, mitochondrial membrane potential, BAX, BCL-2 and cytochrome C were also assessed. Vitamin C decreases cell proliferation and viability in a concentration, time and administration dependent-manner inducing cell death by apoptosis, which was shown to be associated to an increased in superoxide production, mitochondrial membrane depolarization. These compounds modulate BCL-2, BAX and cytochrome C release. These results suggest that vitamin C induces cell death trough apoptosis in F36P cells and may be a new therapeutic approach in Myelodysplasia. 23893551 Assessing Child Care Providers' Knowledge and Attitudes Regarding Support of Breastfeeding in a Region with Low Breastfeeding Prevalence. Background:Working mothers who place their infants into out-of-home child care face many challenges to sustaining breastfeeding. Child care providers, who are in frequent close contact with young families, may be potential resources for promoting breastfeeding.Objectives:This study focused on identifying child care providers' attitudes toward and knowledge about breastfeeding as well as providers' perceptions about strategies to increase breastfeeding rates among mothers of infants in child care centers.Methods:Seventy-five providers from 11 child care centers in the Baton Rouge, Louisiana, area were surveyed using paper and pencil questionnaires. Self-reported demographics, attitudes, knowledge, and perceptions about breastfeeding were collected.Results:Responses demonstrated a generally positive attitude toward breastfeeding among child care providers but a knowledge deficit in terms of the health impacts and proper handling of breast milk. A minority of providers reported that their center's staff currently receives breastfeeding education, but most providers believed that measures to promote the use of breast milk in their center should target parents rather than the center staff.Conclusion:Child care providers need resources about the benefits of human milk, proper handling of expressed milk, and ways to make centers more breastfeeding friendly. Many providers feel ineffective in supporting breastfeeding and are unaware of the role they may play in mothers' infant feeding decisions. Though child care providers do not appear to believe they can influence parents' decisions about breastfeeding, educating and empowering them could play an important role in increasing breastfeeding rates. 23714210 Mechanical behavior of cells in microinjection: a minimum potential energy study. Microinjection is a widely used technique to deliver foreign materials into biological cells. We propose a mathematical model to study the mechanical behavior of a cell in microinjection. Firstly, a cell is modeled by a hyperelastic membrane and interior cytoplasm. Then, based on the fact that the equilibrium configuration of a cell would minimize the potential energy, the energy function during microinjection is analyzed. With Lagrange multiplier and Rayleigh-Ritz technique, we successfully minimize the potential energy and obtain the equilibrium configuration. Upon this model, the injection force, the injection distance, the radius of the microinjector and the membrane stress are studied. The analysis demonstrates that the microinjector radius has a significant influence on the cell mechanical behavior: (1) the larger radius generates larger injection force and larger interior pressure at the same injection distance; (2) the radius determines the place where the membrane is most likely to rupture by governing the membrane stress distribution. For a fine microinjector with radius less than 20% of the cell radius, the most likely rupture point located at the edge of the contact area between the microinjector and the membrane; however, it may move to the middle of the equilibrium configuration as the radius increases. To verify our model, some experiments were conducted on zebrafish egg cells. The results show that the computational analysis agrees with the experimental data, which supports the findings from the theoretical model. 23790305 Surface-enhanced Raman scattering molecular sentinel nanoprobes for viral infection diagnostics. In this paper, we describe a surface-enhanced Raman scattering (SERS)-based detection approach, referred to as "molecular sentinel" (MS) plasmonic nanoprobes, to detect an RNA target related to viral infection. The MS method is essentially a label-free technique incorporating the SERS effect modulation scheme associated with silver nanoparticles and Raman dye-labeled DNA hairpin probes. Hybridization with target sequences opens the hairpin and spatially separates the Raman label from the silver surface thus reducing the SERS signal of the label. Herein, we have developed a MS nanoprobe to detect the human radical S-adenosyl methionine domain containing 2 (RSAD2) RNA target as a model system for method demonstration. The human RSAD2 gene has recently emerged as a novel host-response biomarker for diagnosis of respiratory infections. Our results showed that the RSAD2 MS nanoprobes exhibits high specificity and can detect as low as 1 nM target sequences. With the use of a portable Raman spectrometer and total RNA samples, we have also demonstrated for the first time the potential of the MS nanoprobe technology for detection of host-response RNA biomarkers for infectious disease diagnostics. 23844208 Calcium-Binding Capacity of Centrin2 Is Required for Linear POC5 Assembly but Not for Nucleotide Excision Repair. Centrosomes, the principal microtubule-organising centres in animal cells, contain centrins, small, conserved calcium-binding proteins unique to eukaryotes. Centrin2 binds to xeroderma pigmentosum group C protein (XPC), stabilising it, and its presence slightly increases nucleotide excision repair (NER) activity in vitro. In previous work, we deleted all three centrin isoforms present in chicken DT40 cells and observed delayed repair of UV-induced DNA lesions, but no centrosome abnormalities. Here, we explore how centrin2 controls NER. In the centrin null cells, we expressed centrin2 mutants that cannot bind calcium or that lack sites for phosphorylation by regulatory kinases. Expression of any of these mutants restored the UV sensitivity of centrin null cells to normal as effectively as expression of wild-type centrin. However, calcium-binding-deficient and T118A mutants showed greatly compromised localisation to centrosomes. XPC recruitment to laser-induced UV-like lesions was only slightly slower in centrin-deficient cells than in controls, and levels of XPC and its partner HRAD23B were unaffected by centrin deficiency. Interestingly, we found that overexpression of the centrin interactor POC5 leads to the assembly of linear, centrin-dependent structures that recruit other centrosomal proteins such as PCM-1 and NEDD1. Together, these observations suggest that assembly of centrins into complex structures requires calcium binding capacity, but that such assembly is not required for centrin activity in NER. 23884090 Flight loss linked to faster molecular evolution in insects. The loss of flight ability has occurred thousands of times independently during insect evolution. Flight loss may be linked to higher molecular evolutionary rates because of reductions in effective population sizes (Ne) and relaxed selective constraints. Reduced dispersal ability increases population subdivision, may decrease geographical range size and increases (sub)population extinction risk, thus leading to an expected reduction in Ne. Additionally, flight loss in birds has been linked to higher molecular rates of energy-related genes, probably owing to relaxed selective constraints on energy metabolism. We tested for an association between insect flight loss and molecular rates through comparative analysis in 49 phylogenetically independent transitions spanning multiple taxa, including moths, flies, beetles, mayflies, stick insects, stoneflies, scorpionflies and caddisflies, using available nuclear and mitochondrial protein-coding DNA sequences. We estimated the rate of molecular evolution of flightless (FL) and related flight-capable lineages by ratios of non-synonymous-to-synonymous substitutions (dN/dS) and overall substitution rates (OSRs). Across multiple instances of flight loss, we show a significant pattern of higher dN/dS ratios and OSRs in FL lineages in mitochondrial but not nuclear genes. These patterns may be explained by relaxed selective constraints in FL ectotherms relating to energy metabolism, possibly in combination with reduced Ne. 23632230 Subthalamic deep brain stimulation versus best medical therapy for L-dopa responsive pain in Parkinson's disease. Pain is a frequently observed non-motor symptom of patients with Parkinson's disease. In some patients, Parkinson's-related pain responds to dopaminergic treatment. In the present study, we aimed to elucidate whether subthalamic deep brain stimulation has a similar beneficial effect on pain in Parkinson's disease, and whether this effect can be predicted by a pre-operative l-dopa challenge test assessing pain severity. We prospectively analyzed 14 consecutive Parkinson's patients with severe pain who underwent subthalamic deep brain stimulation. In 8 of these patients, pain severity decreased markedly with high doses of l-dopa, irrespective of the type and localization of the pain symptoms. In these patients, subthalamic deep brain stimulation provided an even higher reduction of pain severity than did dopaminergic treatment, and the majority of this group was pain-free after surgery. This effect lasted for up to 41 months. In the remaining 6 patients, pain was not improved by dopaminergic treatment nor by deep brain stimulation. Thus, we conclude that pain relief following subthalamic deep brain stimulation is superior to that following dopaminergic treatment, and that the response of pain symptoms to deep brain stimulation can be predicted by l-dopa challenge tests assessing pain severity. This diagnostic procedure could contribute to the decision on whether or not a Parkinson's patient with severe pain should undergo deep brain stimulation for potential pain relief. 23631878 Dopamine D2-like receptor signaling suppresses human osteoclastogenesis. Dopamine, a major neurotransmitter, transmits signals via five different seven-transmembrane G protein-coupled receptors termed D1 to D5. Although the relevance of neuroendocrine system to bone metabolism has been emerging, the precise effects of dopaminergic signaling upon osteoclastogenesis remain unknown. Here, we demonstrate that human monocyte-derived osteoclast precursor cells express all dopamine-receptor subtypes. Dopamine and dopamine D2-like receptor agonists such as pramipexole and quinpirole reduced the formation of TRAP-positive multi-nucleated cells, cathepsin K mRNA expression, and pit formation area in vitro. These inhibitory effects were reversed by pre-treatment with a D2-like receptor antagonist haloperidol or a Gαi inhibitor pertussis toxin, but not with the D1-like receptor antagonist SCH-23390. Dopamine and dopamine D2-like receptor agonists, but not a D1-like receptor agonist, suppressed intracellular cAMP concentration as well as RANKL-meditated induction of c-Fos and NFATc1 mRNA expression in human osteoclast precursor cells. Finally, the dopamine D2-like receptor agonist suppressed LPS-induced osteoclast formation in murine bone marrow culture ex vivo. These findings indicate that dopaminergic signaling plays an important role in bone homeostasis via direct effects upon osteoclast differentiation and further suggest that the clinical use of neuroleptics is likely to affect bone mass. 23639941 MEK1/2 inhibition decreases lactate in BRAF-driven human cancer cells. The RAS/BRAF/MEK/ERK signaling pathway is a central driver in cancer with many BRAF and MEK inhibitors being evaluated in clinical trials. Identifying noninvasive biomarkers of early pharmacodynamic responses is important for development of these targeted drugs. As increased aerobic glycolysis is often observed in cancer, we hypothesized that MEK1/2 (MAP2K1/MAP2K2) inhibitors may reduce lactate levels as detected by magnetic resonance spectroscopy (MRS), as a metabolic biomarker for the pharmacodynamic response. MRS was used to monitor intracellular and extracellular levels of lactate in human cancer cells in vitro and in melanoma tumors ex vivo. In addition, we used (1)H MRS and a fluorescent glucose analog to evaluate the effect of MEK inhibition on glucose uptake. MEK1/2 signaling inhibition reduced extracellular lactate levels in BRAF-dependent cells but not BRAF-independent cells. The reduction in extracellular lactate in BRAF-driven melanoma cells was time-dependent and associated with reduced expression of hexokinase-II driven by c-Myc depletion. Taken together, these results reveal how MEK1/2 inhibition affects cancer cell metabolism in the context of BRAF oncogene addiction. Furthermore, they offer a preclinical proof-of-concept for the use of MRS to measure lactate as a noninvasive metabolic biomarker for pharmacodynamic response to MEK1/2 inhibition in BRAF-driven cancers. 23950537 Cleavage of fibrinogen by proteinases elicits allergic responses through Toll-like receptor 4. Proteinases and the innate immune receptor Toll-like receptor 4 (TLR4) are essential for expression of allergic inflammation and diseases such as asthma. A mechanism that links these inflammatory mediators is essential for explaining the fundamental basis of allergic disease but has been elusive. Here, we demonstrate that TLR4 is activated by airway proteinase activity to initiate both allergic airway disease and antifungal immunity. These outcomes were induced by proteinase cleavage of the clotting protein fibrinogen, yielding fibrinogen cleavage products that acted as TLR4 ligands on airway epithelial cells and macrophages. Thus, allergic airway inflammation represents an antifungal defensive strategy that is driven by fibrinogen cleavage and TLR4 activation. These findings clarify the molecular basis of allergic disease and suggest new therapeutic strategies. 23929538 Sleep-disordered-breathing in Ehlers-Danlos Syndrome (a genetic model of obstructive sleep apnea). Investigation of the presence of sleep-disordered-breathing (SDB) in patients with Ehlers-Danlos(ED) Syndrome. ED is a genetic disorder characterized by cartilaginous defects, including nasal-maxillary cartilages. A retrospective series of 34 ED patients presenting to clinic with complaints of fatigue and poor sleep were evaluated via clinical history, physical examination, polysomnography (PSG) and in some cases with anterior rhinomanometry. Additionally, a prospective clinical investigation of 9 ED patients was performed in a specialized medical ED clinic. All ED patients evaluated had SDB on PSG. In addition to apneas and hypopneas, SDB included flow limitation. With increasing age, flow limitation decreased in favor of apnea and hypopnea events, but clinical complaints were similar independent of the type of PSG finding. In the subgroup of patients who underwent nasal rhinometry, increased nasal resistance was increased relative to normative values. Nasal CPAP improved patient symptoms. ED patients in medical clinic presented with symptoms and clinical signs of SDB, but they never were referred for evaluation of SDB. In ED patients, abnormal breathing during sleep is commonly unrecognized and is responsible for daytime fatigue and poor sleep. ED patients are at particular risk for SDB due to genetically related cartilage defects that lead to the development of facial structures known to cause SDB. ED may be a genetic model for obstructive sleep apnea because of abnormalities of oral-facial growth. Early recognition of SDB may allow treatment with orthodontics and myofacial reeducation. 23530057 Structural basis for activation of ZAP-70 by phosphorylation of the SH2-kinase linker. Serial activation of the tyrosine kinases Lck and ZAP-70 initiates signaling downstream of the T-cell receptor. We had previously reported the structure of an autoinhibited ZAP-70 variant in which two regulatory tyrosine residues (315 and 319) in the SH2-kinase linker were replaced by phenylalanine. We now present the crystal structure of ZAP-70 in which Tyr 315 and Tyr 319 are not mutated, leading to the recognition of a five-residue sequence register error in the SH2-kinase linker of the original crystallographic model. The revised model identifies distinct roles for these two tyrosines. As seen in a recently reported structure of the related tyrosine kinase Syk, Tyr 315 of ZAP-70 is part of a hydrophobic interface between the regulatory apparatus and the kinase domain, and the integrity of this interface would be lost upon engagement of doubly-phosphorylated peptides by the SH2 domains. Tyr 319 is not necessarily dislodged by SH2 engagement, which activates ZAP-70 by only ∼5-fold in vitro. In contrast, phosphorylation by Lck activates ZAP-70 by ∼100-fold. This difference is due to the ability of Tyr 319 to suppress ZAP-70 activity even when the SH2 domains are dislodged from the kinase domain, providing stringent control of ZAP-70 activity downstream of Lck. 23676564 Improved HPLC purification strategy for [11C]raclopride and [11C]DASB leading to high radiochemical yields and more practical high quality radiopharmaceutical formulations. A downscaled analytical HPLC purification strategy for [(11)C]raclopride and [(11)C]DASB was proposed to obtain a straightforward produced injectable solution with a substantially reduced volume. Both tracers were radiosynthesized using [(11)C]methyl triflate, and several analytical columns, in combination with ethanol containing eluents, were examined to optimize the chromatographic resolution. This resulted in a 5 mL solution of [(11)C]raclopride, obtained after 6 min, and a 7 mL solution of [(11)C]DASB, obtained after 10 min, using a C16-alkylamide and CN column respectively. 23786546 Combination treatment of photodynamic therapy with verteporfin and intravitreal ranibizumab in patients with retinal angiomatous proliferation. Purpose:  To investigate the efficacy and safety of initial photodynamic therapy (PDT) with a ranibizumab loading dose of three monthly intravitreal injections and a subsequent PRN ranibizumab regimen in the treatment of retinal angiomatous proliferation (RAP). Methods:  In this 12-month prospective case series, 15 patients underwent PDT followed by 3 intravitreal ranibizumab injections at monthly intervals. At monthly follow-up examinations, further single ranibizumab injections were given in case of any intra- or subretinal fluid on optical coherence tomography (OCT), visual loss ≥5 letters or signs of activity on fluorescein or indocyanine green angiography. Results:  Best-corrected visual acuity (BCVA) improved from 58.1 ± 13.2 at baseline by 9.2 letters (SD ± 8.5; p = 0.004) at 6 months and by 8.7 letters (SD ± 11.4; p = 0.017) at 12 months. Neither at 6 nor at 12 months, any patient had lost ≥15 letters. The mean number of injections per patient was 4.8 (SD ± 1.4) in the first year of therapy after PDT. The average time to first retreatment was 3.7 months (range 1-7 months). No serious adverse events, such as endophthalmitis or retinal detachment, were noted. Conclusion:  PDT with 3 ranibizumab loading injections and subsequent ranibizumab as needed resulted in a significant gain of 8.7 ± 11.4 letters at month 12. This regimen is safe and efficacious, but even in a population of mostly early stages of RAP, retreatment rates remained high. 23824509 Enhanced hybrid search algorithm for protein structure prediction using the 3D-HP lattice model. The problem of protein structure prediction in the hydrophobic-polar (HP) lattice model is the prediction of protein tertiary structure. This problem is usually referred to as the protein folding problem. This paper presents a method for the application of an enhanced hybrid search algorithm to the problem of protein folding prediction, using the three dimensional (3D) HP lattice model. The enhanced hybrid search algorithm is a combination of the particle swarm optimizer (PSO) and tabu search (TS) algorithms. Since the PSO algorithm entraps local minimum in later evolution extremely easily, we combined PSO with the TS algorithm, which has properties of global optimization. Since the technologies of crossover and mutation are applied many times to PSO and TS algorithms, so enhanced hybrid search algorithm is called the MCMPSO-TS (multiple crossover and mutation PSO-TS) algorithm. Experimental results show that the MCMPSO-TS algorithm can find the best solutions so far for the listed benchmarks, which will help comparison with any future paper approach. Moreover, real protein sequences and Fibonacci sequences are verified in the 3D HP lattice model for the first time. Compared with the previous evolutionary algorithms, the new hybrid search algorithm is novel, and can be used effectively to predict 3D protein folding structure. With continuous development and changes in amino acids sequences, the new algorithm will also make a contribution to the study of new protein sequences. 23651943 From soil to leaves - Aluminum fractionation by single step extraction procedures in polluted and protected areas. The paper presents the fractionation of aluminum in the samples of soil and plants of different species using a selective single-step extraction method. The study was conducted in the area located near a chemical plant, which for many years served as a post-crystallization leachate disposal site storing chemical waste (sector I), and in the area around the site: in Wielkopolski National Park, Rogalin Landscape Park and toward the infiltration ponds at the "DÄ™bina" groundwater well-field for the city of PoznaÅ„ (Poland) (sector II). The results of aluminum fractionation in samples of soil, leaves and plants showed heavy pollution with aluminum, especially in the water soluble aluminum fraction - Alsw (maximum concentration of aluminum in soil extract was 234.8 ± 4.8 mg kg(-1), in the leaves of Betula pendula it was 107.4 ± 1.8 mg kg(-1) and in the plants of Artemisia vulgaris (root) and Medicago sativa (leaves) it amounted to 464.7 ± 10.7 mg kg(-1)and 146.8 ± 1.2 mg kg(-1) respectively). In addition, the paper presents the problem of organic aluminum fractionation in biological samples and it shows the relationship between aluminum concentration in soil and the analysed woody and herbaceous species. 23807371 Exploratory analysis of the effect of intravitreal ranibizumab or triamcinolone on worsening of diabetic retinopathy in a randomized clinical trial. IMPORTANCE The standard care for proliferative diabetic retinopathy (PDR) usually is panretinal photocoagulation, an inherently destructive treatment that can cause iatrogenic vision loss. Therefore, evaluating the effects of therapies for diabetic macular edema on development or worsening of PDR might lead to new therapies for PDR. OBJECTIVE To evaluate the effects of intravitreal ranibizumab or triamcinolone acetonide, administered to treat diabetic macular edema, on worsening of diabetic retinopathy. DESIGN Exploratory analysis was performed on worsening of retinopathy, defined as 1 or more of the following: (1) worsening from no PDR to PDR, (2) worsening of 2 or more severity levels on reading center assessment of fundus photographs in eyes without PDR at baseline, (3) having panretinal photocoagulation, (4) experiencing vitreous hemorrhage, or (5) undergoing vitrectomy for the treatment of PDR. SETTING Community- and university-based ophthalmology practices. PARTICIPANTS Individuals with central-involved diabetic macular edema causing visual acuity impairment. INTERVENTIONS Eyes were assigned randomly to sham with prompt focal/grid laser, 0.5 mg of intravitreal ranibizumab with prompt or deferred (≥24 weeks) laser, or 4 mg of intravitreal triamcinolone acetonide with prompt laser. MAIN OUTCOMES AND MEASURES Three-year cumulative probabilities for retinopathy worsening. RESULTS For eyes without PDR at baseline, the 3-year cumulative probabilities for retinopathy worsening (P value comparison with sham with prompt laser) were 23% using sham with prompt laser, 18% with ranibizumab with prompt laser (P = .25), 7% with ranibizumab with deferred laser (P = .001), and 37% with triamcinolone with prompt laser (P = .10). For eyes with PDR at baseline, the 3-year cumulative probabilities for retinopathy worsening were 40%, 21% (P = .05), 18% (P = .02), and 12% (P < .001), respectively. CONCLUSIONS AND RELEVANCE Intravitreal ranibizumab appears to be associated with a reduced risk of diabetic retinopathy worsening in eyes with or without PDR. Intravitreal triamcinolone also appears to be associated with a reduced risk of PDR worsening. These findings suggest that use of these drugs to prevent worsening of diabetic retinopathy may be feasible. Given the exploratory nature of these analyses, the risk of endophthalmitis following intravitreal injections, and the fact that intravitreal triamcinolone can cause cataract or glaucoma, use of these treatments to reduce the rates of worsening of retinopathy, with or without PDR, does not seem warranted at this time. 23934313 Long-term efficacy and safety of pre-emptive maintenance therapy with rituximab in granulomatosis with polyangiitis: results from a single centre. Objective. Rituximab (RTX) is an anti-CD20 antibody used successfully in granulomatosis with polyangiitis (GPA) for induction and maintenance of remission. Our study aims to evaluate the long-term efficacy and safety of chronic pre-emptive RTX therapy in GPA.Methods. Retrospective study of 35 GPA patients treated with RTX between April 2004 and September 2011 for active disease and maintenance. RTX was initiated as two 1 g infusions 2 weeks apart and thereafter 2 g of RTX was readministered annually. Patients were followed for 47 (2-88) months. They received a median RTX dose of 8 g (2-13) over 5 (1-10) rounds.Results. All patients had a clinical response, but nine relapses were recorded (flare rate of 6.6/100 patient-years). At last visit, 13 patients (37%) had discontinued RTX mainly due to hypogammaglobulinaemia (57%). Nine patients (26%) had severe infections (infection rate of 6.6/100 patient-years) and 10 patients (29%) had chronic infections. Risks factors for severe infections are a high cumulative dose of CYC, low CD4 cell count and a significant drop in total immunoglobulins after the first RTX round. Risks factors for chronic infections are low IgG level during RTX maintenance and possibly the cumulative RTX dose.Conclusion. Long-term pre-emptive RTX maintenance was efficacious in reducing the risk for relapse but was discontinued in one-third of the patients. The patients' net state of immunodeficiency under RTX changes over time as low immunoglobulin serum levels increased the risk for infections. 23591632 Maternal coding variants in complement receptor 1 and spontaneous idiopathic preterm birth. Preterm birth (PTB) is a major global public health concern. However, little is known about the pathophysiology of spontaneous idiopathic PTB. We tested the hypothesis that rare variants in families would target specific genes and pathways that contribute to PTB risk in the general population. Whole-exome sequencing was performed on 10 PTB mothers from densely affected families including two mother-daughter pairs. We identified novel variants shared between the two mother-daughter pairs when compared to a 1000 Genomes Project background exome file and investigated these genes for pathway aggregation using the Kyoto Encyclopedia of Genes and Genomes (KEGG). Genes in enriched pathways were then surveyed in the other six PTB exomes and tested for association in a larger number of nuclear families. The KEGG complement and coagulation cascade was one of the most enriched pathways in our two mother-daughter pairs. When the six genes found in this pathway (CFH, CR1, F13B, F5, CR2, and C4BPA) were examined for novel missense variants, half of all the exomes harbored at least one. Association analysis of variants in these six gene regions in nuclear families from Finland (237 cases and 328 controls) found statistically significant associations after multiple test corrections in three CR1 SNPs; the strongest in an exonic missense SNP, rs6691117, p value = 6.91e-5, OR = 1.71. Our results demonstrate the importance of the complement and coagulation cascades in the pathophysiology of PTB, and suggest potential screening and intervention approaches to prevent prematurity that target this pathway. 23576475 Theoretical Investigation of Generator-Collector Microwell Arrays for Improving Electroanalytical Selectivity: Application to Selective Dopamine Detection in the Presence of Ascorbic Acid. Recessed generator-collector assemblies consisting of an array of recessed disks (generator electrodes) with a gold layer (collector electrode) deposited over the top-plane insulator reportedly allow increased selectivity and sensitivity during electrochemical detection of dopamine (DA) in the presence of ascorbic acid (AA), a situation which is frequently encountered. In sensor design, the potential of the disk electrodes is set to the wave plateau of DA, whereas the plane electrode is biased at the irreversible wave plateau of AA before the onset of the DA oxidation wave. Thus, AA is scavenged but DA is allowed to enter the nanocavities to be oxidized at the disk electrodes, and its signal is further amplified by redox cycling between disk and plane electrodes. Several different theoretical approaches are elaborated herein to analyze the behavior of the system, and their conclusions are successfully tested by experiments. This reveals the crucial role of the plane-electrode area which screens access to the recessed disks (i.e. acts as a diffusional Faraday cage) and simultaneously contributes to amplification of the analyte signal through positive feedback, as occurs in interdigitated arrays and scanning electrochemical microscopy. Simulations also allow for the evaluation of the benefits of different geometries inspired by the above design and different operating modes for increasing the sensor performance. 23615896 Orthogonal bis(terpyridine)-Fe(ii) metal complex oligomer wires on a tripodal scaffold: rapid electron transport. The present work reports a tripodal scaffold for bis(terpyridine)-Fe(ii) oligomer wires on an Au(111) surface: the tripodal scaffold realised both orthogonality of the oligomer wires, and fast interfacial electron transfer through the oligomer wires. 23969623 Sex Differences in Succumbing to Sexual Temptations: A Function of Impulse or Control? Men succumb to sexual temptations (e.g., infidelity, mate poaching) more than women. Explanations for this effect vary; some researchers propose that men and women differ in sexual impulse strength, whereas others posit a difference in sexual self-control. These studies are the first to test such underlying mechanisms. In Study 1, participants reported on their impulses and intentional control exertion when they encountered a real-life tempting but forbidden potential partner. Study 2 required participants to perform a reaction-time task in which they accepted/rejected potential partners, and we used process dissociation to separate the effects of impulse and control. In both studies, men succumbed to the sexual temptations more than women, and this sex difference emerged because men experienced stronger impulses, not because they exerted less intentional control. Implications for the integration of evolutionary and self-regulatory perspectives on sex differences are discussed. 23925735 Giant Bullae Emphysema. Bullous lung disease, a variant of the emphysematous process, can come in different forms and presentations, both histologically and radiographically. Giant bulla (GB) is the rarest form of bullous lung disease. Onset of disease to duration to symptoms is unclear. Presenting symptoms include cough, chest pain, and progressive dyspnea. Differentiating between other cystic lung diseases or developmental/congenital anomalies is vital. While most patients with bullous lung disease can be managed medically, those with giant bulla should be referred for careful surgical evaluation. The authors describe GB, highlight the role of imaging, and discuss the evaluation and pathophysiology of this rare presentation. 23912116 Alcohol dehydrogenases from Scheffersomyces stipitis involved in the detoxification of aldehyde inhibitors derived from lignocellulosic biomass conversion. Aldehyde inhibitors such as furfural and 5-hydroxymethylfurfural (HMF) are generated from biomass pretreatment. Scheffersomyces stipitis is able to reduce furfural and HMF to less toxic furanmethanol and furan-2,5-dimethanol; however, the enzymes involved in the reductive reaction still remain unknown. In this study, transcription responses of two known and five putative alcohol dehydrogenase genes from S. stipitis were analyzed under furfural and HMF stress conditions. All the seven alcohol dehydrogenase genes were also cloned and overexpressed for their activity analyses. Our results indicate that transcriptions of SsADH4 and SsADH6 were highly induced under furfural and HMF stress conditions, and the proteins encoded by them exhibited NADH- and/or NADPH-dependent activities for furfural and HMF reduction, respectively. For furfural reduction, NADH-dependent activity was also observed in SsAdh1p and NAD(P)H-dependent activities were also observed in SsAdh5p and SsAdh7p. For HMF reduction, NADPH-dependent activities were also observed in SsAdh5p and SsAdh7p. SsAdh4p displayed the highest NADPH-dependent specific activity and catalytic efficiency for reduction of both furfural and HMF among the seven alcohol dehydrogenases. Enzyme activities of all SsADH proteins were more stable under acidic condition. For most SsADH proteins, the optimum temperature for enzyme activities was 30 °C and more than 50 % enzyme activities remained at 60 °C. Reduction activities of formaldehyde, acetaldehyde, isovaleraldehyde, benzaldehyde, and phenylacetaldehyde were also observed in some SsADH proteins. Our results indicate that multiple alcohol dehydrogenases in S. stipitis are involved in the detoxification of aldehyde inhibitors derived from lignocellulosic biomass conversion. 22982770 A modern in vivo pharmacokinetic paradigm: combining snapshot, rapid and full PK approaches to optimize and expedite early drug discovery. Successful drug discovery relies on the selection of drug candidates with good in vivo pharmacokinetic (PK) properties as well as appropriate preclinical efficacy and safety profiles. In vivo PK profiling is often a bottleneck in the discovery process. In this review, we focus on the tiered in vivo PK approaches implemented at the Genomics Institute of the Novartis Research Foundation (GNF), which includes snapshot PK, rapid PK and full PK studies. These in vivo PK approaches are well integrated within discovery research, allow tremendous flexibility and are highly efficient in supporting the diverse needs and increasing demand for in vivo profiling. The tiered in vivo PK studies expedite compound profiling and help guide the selection of more desirable compounds into efficacy models and for progression into development. 23821484 A one-year prospective study on the antibiotic resistance of E. coli strains isolated in urinary specimens of children hospitalized at the University Pediatric Medical Center in Novi Sad, Serbia. Urinary tract infections (UTIs), the most common serious bacterial infections in children, are frequently caused by Escherichia coli. The purpose of this study was to investigate E. coli resistance/multidrug resistance to antibiotics most frequently used for UTIs. Children 0-18 years of age, hospitalized at the University Pediatric Hospital in Novi Sad, Serbia, were included in a 1-year observational prospective study. The microbiological analysis was performed using the standard Kirby-Bauer disk diffusion method. The results were analyzed using WHONET 5.4 software. E. coli was isolated from 61.7 % of positive urine specimens. In general, higher average E. coli antibiotic resistance was found in infants and toddlers compared to children and adolescents (33.4 vs. 25.0 %) (p < 0.0001). Furthermore, it was observed that the average resistance to all the tested antibiotics was higher in boys than in girls (37.0 vs. 25.1 %) (p < 0.0001). E. coli was highly susceptible to piperacillin/tazobactam (>93.1 %), amikacin (86.3 %), quinolones (>75.0 %), and penems (>96.6 %). The prevalence of multiresistant E. coli strains was significantly higher in infants and toddlers (72.3 vs. 36.8 %) (p < 0.0001). E. coli, a common cause of UTIs in children admitted to pediatric hospitals, is highly resistant/multidrug-resistant to commonly used antibiotics. Higher average resistance is found in infants and toddlers than in children and adolescents, as well as in boys compared to girls. These findings are important for the regional empiric therapy of UTIs and call for actions to decrease E. coli antibiotic resistance. 23411170 Net analyte signal standard addition method for simultaneous determination of sulphadiazine and trimethoprim in bovine milk and veterinary medicines. Net analyte signal standard addition method has been used for the simultaneous determination of sulphadiazine and trimethoprim by spectrophotometry in some bovine milk and veterinary medicines. The method combines the advantages of standard addition method with the net analyte signal concept which enables the extraction of information concerning a certain analyte from spectra of multi-component mixtures. This method has some advantages such as the use of a full spectrum realisation, therefore it does not require calibration and prediction step and only a few measurements require for the determination. Cloud point extraction based on the phenomenon of solubilisation used for extraction of sulphadiazine and trimethoprim in bovine milk. It is based on the induction of micellar organised media by using Triton X-100 as an extraction solvent. At the optimum conditions, the norm of NAS vectors increased linearly with concentrations in the range of 1.0-150.0 μmolL(-1) for both sulphadiazine and trimethoprim. The limits of detection (LOD) for sulphadiazine and trimethoprim were 0.86 and 0.92 μmolL(-1), respectively. 23293134 Occupational hazards control of hazardous substances in clean room of semiconductor manufacturing plant using CFD analysis. The manufacturing processes in chip industries are complex, and many kinds of raw materials and solvents of different nature are used, most of which are highly toxic and dangerous. During the machine preventive maintenance period, these toxic and harmful substances will escape from the sealed reaction chamber to the clean workshop environment and endanger the health of the workers on-site, resulting in occupational diseases. From the perspective of prevention, the spread and prediction of hydrochloric acid (HCl) that escaped from the metal-etching chamber during maintenance were studied in this article. The computational fluid dynamics technology was used for a three-dimensional numerical simulation of the indoor air velocity field and the HCl concentration field, and the simulation results were then compared with the on-site monitoring data to verify the correctness and feasibility. The occupational hazards and control measures were analyzed based on the numerical simulation, and the optimal control measure was obtained. In this article, using the method of ambient air to analyze the occupational exposure can provide a new idea to the field of occupational health research in the integrated circuit industry and had theoretical and practical significance. 23638848 Molecular typing of Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) isolated from animals and retail meat in North Dakota, United States. The objective of this study was to determine the prevalence and molecular typing of methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) in food-producing animals and retail meat in Fargo, North Dakota. A two-step enrichment followed by culture methods were used to isolate S. aureus from 167 nasal swabs from animals, 145 samples of retail raw meat, and 46 samples of deli meat. Positive isolates were subjected to multiplex polymerase chain reaction in order to identify the genes 16S rRNA, mecA, and Panton-Valentine Leukocidin. Pulsed-field gel electrophoresis and multilocus sequence typing were used for molecular typing of S. aureus strains. Antimicrobial susceptibility testing was carried out using the broth microdilution method. The overall prevalence of S. aureus was 37.2% (n=133), with 34.7% (n=58) of the animals positive for the organism, and the highest prevalence observed in pigs (50.0%) and sheep (40.6%) (p<0.05); 47.6% (n=69) of raw meat samples were positive, with the highest prevalence in chicken (67.6%) and pork (49.3%) (p<0.05); and 13.0% (n=6) of deli meat was positive. Five pork samples (7.0%) were positive for MRSA, of which three were ST398 and two were ST5. All exhibited penicillin resistance and four were multidrug resistant (MDR). The Panton-Valentine Leukocidin gene was not detected in any sample by multiplex polymerase chain reaction. The most common clones in sheep were ST398 and ST133, in pigs and pork both ST398 and ST9, and in chicken ST5. Most susceptible S. aureus strains were ST5 isolated from chicken. The MDR isolates were found in pigs, pork, and sheep. The presence of MRSA, MDR, and the subtype ST398 in the meat production chain and the genetic similarity between strains of porcine origin (meat and animals) suggest the possible contamination of meat during slaughtering and its potential transmission to humans. 23617585 Structural identification of (1→6)-α-D-glucan, a key responsible for the health benefits of longan, and evaluation of anticancer activity. Longan is a delicious subtropical fruit with great health-beneficial effects. It has been utilised for disease prevention and health care since ancient age. To explore the chemicals responsible for the health benefits, water-soluble polysaccharides were extracted from longan flesh in this work. A pure polysaccharide (LPS1) was obtained through column purification. Analysis by gas chromatography showed LPS1 was a homopolysaccharide of glucose with glycosidic linkage of →6)-D-Glc-(1→. Nuclear magnetic resonance (NMR ) spectra indicated that the configuration of anomeric carbon in glucose residual was α-form. The polysaccharide structure was further confirmed to be (1→6)-α-D-glucan by chemcial shift of C6. The molecular weight of LPS1 was calculated to be 108 kDa, which had 661 glucose residuals. Anticancer assay showed that LPS1 had anticancer activity against the growth of HepG2 cells to a certain extent. However, it did not show any cytotoxicity against MCF-7 breast cancer cells. 23594303 Bacteriolysis by vancomycin-conjugated acryl nanoparticles and morphological component analysis. Abstract Nanoparticles are currently attracting considerable attention because of their ability to conjugate to various substances. As such, these nanoparticles can assist the transfer of the conjugated substance to target tissues where they are gradually released. In this study, vancomycin-conjugated nanoparticles (VCM NPs) were prepared. The antibacterial activity of VCM NPs was compared with that of VCM alone by exposure to vancomycin-resistant enterococci (VRE). The morphology of the cells was then analyzed by electron microscopy. VCM NPs were found to have more potent antibacterial activity against VRE compared to VCM alone, but the activity against vancomycin-sensitive enterococci (VSE) remained the same. The antibacterial activity of nanoparticles alone was the same against VSE and VRE. The nanoparticles were found to induce characteristic morphological changes in the bacteria based on scanning and transmission electron microscopy. The results suggest that the strong antibacterial activity of VCM NPs against VRE may be attributable not only to the well-known control release carrier property of the nanoparticles but to an additional mechanism that involves VCM NPs avoiding the drug resistant mechanism of VRE. 23745516 Mixed treatment comparison of efficacy and tolerability of biologic agents in patients with rheumatoid arthritis. Abstract Objective: To determine the comparative efficacy and tolerability of abatacept and tumor necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) and inadequate response to conventional disease modifying anti-rheumatic drugs (DMARDs). Research design and methods: A systematic review identified RCTs in RA patients who responded inadequately to conventional DMARDs and were treated with one of the following biologic agents: abatacept, adalimumab, etanercept, infliximab, certolizumab pegol, or golimumab. Bayesian hierarchical models were used to compare efficacy and tolerability outcomes of abatacept and combined TNFi at 6 months and 1 year. Results: In this mixed treatment comparison (MTC), the likelihood of achieving ACR response was comparable between abatacept and combined TNFi at 6 months for ACR20, 50, and 70: (odds ratio [OR] = 0.98 [95% confidence interval (CI): 0.73, 1.27], 0.99 [0.73, 1.31], and 0.91 [0.62, 1.27], respectively); and at 12 months for ACR20 (OR = 1.27 [0.92, 1.71]) and ACR50 (1.21 [0.82, 1.68]), with a higher likelihood of achieving an ACR70 response at 12 months (1.41 [1.02, 1.82]). Odds of DAS28 remission at 12 months was greater for abatacept than the combined TNFi (OR = 2.03 [1.04, 3.58]). Abatacept had better tolerability, defined as a lower likelihood of withdrawal due to adverse events, at both 6 and 12 months (OR = 0.38 [0.10, 0.88] and 0.51 [0.27, 0.86], respectively). These analyses include indirect comparisons across clinical trials and are not a replacement for head-to-head data. While all TNFi have been grouped into one class, there may be some differences between the individual TNFi that are not captured in our study. Conclusions: In this MTC, abatacept demonstrated similar efficacy at 6 months, a higher likelihood of achieving ACR70 response and DAS28 remission at 12 months and better tolerability relative to the combined TNFi in patients with RA who had an inadequate response to conventional DMARDs. 23642731 Food sources of sodium, saturated fat and added sugar in the Spanish hypertensive and diabetic population. Previous research has shown that the diet of hypertensive and diabetic patients has a low accordance with the main nutritional recommendations, mostly due to the high intake of sodium, saturated fat and added sugars. This is the first study to identify the main food sources of these nutrients in these patients. Cross-sectional study conducted in 2008-2010 in a representative sample of the Spanish adult population, including 2323 patients with hypertension and 635 with diabetes. The habitual diet was assessed using a validated diet history. The intake of sodium, saturated fat and added sugars was estimated with Spanish food composition tables. The hypertensive and diabetic population showed, respectively, an intake of 2.9 and 3.1 g/day of sodium, 26 and 26 g/day of saturated fat, and 33 and 24 g/day of added sugar. In hypertensive and diabetic patients, respectively, most sodium intake came from bread (35%, 34%), raw-cured sausages (15%, 15%), cooked sausages (6%, 7%), and soup (5%, 6%). The main sources of saturated fat were cured cheese (13%, 13%), bakery products (12%, 11%), red meat (10%, 11%), raw-cured sausages (8%, 9%) and whole milk (4%, 4%). The food groups that most contributed to added sugar intake were sugar directly added to coffee and other beverages (27%, 19%), bakery products (15%, 19%), sugary soft drinks (10%, 13%), and whole yogurt (9%, 12%). The main food sources of nutrients were similar in all sex and age groups. In patients with hypertension and diabetes, the intake of sodium, saturated fat and added sugar can be substantially reduced by prioritizing low-salt varieties of bread, reducing the consumption of bakery products and sausages, replacing cured cheese and other whole dairy products by low-fat products, using non-sugary sweeteners, and substituting sugar-free soft drinks, or plain water, for sugary sodas. 23969941 Style in science communication. There is little doubt that during the past few decades science communication efforts aimed at non-expert audiences have increased in quantity and intensity on a global scale. Public engagement and outreach activities have now become a routine - when not a prominent - feature for several research institutions in Europe. However, it would be difficult for both scholars and those involved in science communication to agree on the impact of these activities, on the long-term implications of the 'science communication movement' and on the indicators we should develop and employ in order to assess impact. The paper argues that quality is a relevant issue and challenge for contemporary science communication. Style is relevant to addressing that challenge, insofar as it relates to discussions about how to strengthen the quality of science communication, suggesting a different perspective other than the traditional normative/prescriptive framework. The notion of style also fruitfully connects the debate on science communication with a rich tradition of studies in the history and sociology of science. 23486524 Decline in 20-year mortality after myocardial infarction in patients with chronic kidney disease: evolution from the prethrombolysis to the percutaneous coronary intervention era. Cardiovascular disease is the main cause of death in patients with chronic kidney disease (CKD). Here we measured temporal trends in treatment and mortality after myocardial infarction (MI) depending on kidney function at presentation in 12,087 patients admitted for MI to a coronary care unit from 1985 to 2008. The patients were categorized into those with normal kidney function (estimated glomerular filtration rate over 90 ml/min per 1.73 m(2)), and those with CKD as defined by Kidney Foundation practice guidelines, with 8632 patients (71%) at CKD stages 2-5. Use of evidence-based care increased over time in all CKD stages. Mortality rates fell over the entire time period. When comparing data from 2000-2008 to that from 1985-1990, adjusted 30-day mortality fell both in patients with CKD stages 4-5 (adjusted odds 0.33, 95% confidence interval 0.18-0.60) and in those without kidney impairment (adjusted odds 0.21, 95% confidence interval 0.10-0.42). This mortality decrease was sustained during long-term follow-up. There was no significant interaction between kidney function and decade of admission. Overall, median survival was over 20, 15, 8, and 1.8 years for patients with normal kidney function, stage 2, stage 3, and stage 4-5 CKD, respectively. Thus, during the past 25 years, treatment of patients with a MI improved substantially with a concomitant decline in mortality. Although our findings were similar for all stages of kidney function, the prognosis remains poor for patients with stage 4-5 CKD. 22512662 A new triterpenoid from the rhizomes of Nelumbo nucifera. A new triterpenoid, 2α,24-diacetoxy-3β-hydroxyolean-12-en-28-oic acid (1), was characterised from the rhizomes of Nelumbo nucifera Gaertn by spectroscopic and chemical methods along with four known compounds, hyptatic acid-A (2α,3β,24-trihydroxyolean-12-en-28-oic acid) (2), maslinic acid (2α,3β-dihydroxyoleane-12-ene-28-oic acid), betulin and lupeol. 23878350 Cancer Incidence Trends Among Asian American Populations in the United States, 1990-2008. National cancer incidence trends are presented for eight Asian American groups: Asian Indians/Pakistanis, Chinese, Filipinos, Japanese, Kampucheans, Koreans, Laotians, and Vietnamese. Cancer incidence data from 1990 through 2008 were obtained from 13 Surveillance, Epidemiology, End Results (SEER) registries. Incidence rates from 1990 through 2008 and average percentage change were computed using SEER*Stat and Joinpoint software. The annual percentage change (APC) in incidence rates was estimated with 95% confidence intervals (95% CIs) calculated for both the rate and APC estimates. Rates for non-Hispanic whites are presented for comparison. Prostate cancer was the most common malignancy among most groups, followed by lung, colorectal, liver, and stomach cancers. Breast cancer was generally the most common cancer in women, followed by colorectal and lung cancers; liver, cervix, thyroid, and stomach cancers also ranked highly. Among men, increasing trends were observed for prostate (Asian Indians and Pakistanis: APC 1990-2003 = 2.2, 95% CI = 0.3 to 4.1; Filipinos: APC 1990-1994 = 19.0, 95% CI = 4.5 to 35.4; Koreans: APC 1990-2008 = 2.9, 95% CI = 1.8 to 4.0), colorectal (Koreans: APC 1990-2008 = 2.2, 95% CI = 0.9 to 3.5), and liver cancers (Filipinos: APC 1990-2008 = 1.6, 95% CI = 0.4 to 2.7; Koreans: APC 1990-2006 = 2.1, 95% CI = 0.4 to 3.7; Vietnamese: APC 1990-2008 = 1.6, 95% CI = 0.3 to 2.8), whereas lung and stomach cancers generally remained stable or decreased. Among women, increases were observed for uterine cancer (Asian Indians: APC 1990-2008 = 3.0, 95% CI = 0.3 to 5.8; Chinese: APC 2004-2008 = 7.0, 95% CI = 1.4 to 12.9; Filipina: APC 1990-2008 = 3.0, 95% CI = 2.4 to 3.7; Japanese: APC 1990-2008 = 1.1, 95% CI = 0.1 to 2.0), colorectal cancer (Koreans: APC 1990-2008 = 2.8, 95% CI = 1.7 to 3.9; Laotians: APC: 1990-2008 = 5.9, 95% CI = 4.0 to 7.7), lung cancer (Filipinas: APC 1990-2008 = 2.1, 95% CI = 1.4 to 2.8; Koreans: APC 1990-2008 = 2.1, 95% CI = 0.6 to 3.6), thyroid cancer (Filipinas: APC 1990-2008 = 2.5, 95% CI = 1.7 to 3.3), and breast cancer in most groups (APC 1990-2008 from 1.2 among Vietnamese and Chinese to 4.7 among Koreans). Decreases were observed for stomach (Chinese and Japanese), colorectal (Chinese), and cervical cancers (Laotians and Vietnamese). These data fill a critical knowledge gap concerning the cancer experience of Asian American groups and highlight where increased preventive, screening, and surveillance efforts are needed-in particular, lung cancer among Filipina and Korean women and Asian Indian/Pakistani men, breast cancer among all women, and liver cancer among Vietnamese, Laotian, and Kampuchean women and Filipino, Kampuchean, and Vietnamese men. 23453156 Asleep-awake-asleep craniotomy: A comparison with general anesthesia for resection of supratentorial tumors. The anesthetic plan for patients undergoing awake craniotomy, when compared to craniotomy under general anesthesia, is different, in that it requires changes in states of consciousness during the procedure. This retrospective review compares patients undergoing an asleep-awake-asleep technique for craniotomy (group AW: n=101) to patients undergoing craniotomy under general anesthesia (group AS: n=77). Episodes of desaturation (AW=31% versus AS=1%, p<0.0001), although temporary, and hypercarbia (AW=43.75mmHg versus AS=32.75mmHg, p<0.001) were more common in the AW group. The mean arterial pressure during application of head clamp pins and emergence was significantly lower in AW patients compared to AS patients (pinning 91.47mmHg versus 102.9mmHg, p<0.05 and emergence 84.85mmHg versus 105mmHg, p<0.05). Patients in the AW group required less vasopressors intraoperatively (AW=43% versus AS=69%, p<0.01). Intraoperative fluids were comparable between the two groups. The post anesthesia care unit (PACU) administered significantly fewer intravenous opioids in the AW group. The length of stay in the PACU and hospital was comparable in both groups. Thus, asleep-awake-asleep craniotomies with propofol-dexmedetomidine infusion had less hemodynamic response to pinning and emergence, and less overall narcotic use compared to general anesthesia. Despite a higher incidence of temporary episodes of desaturation and hypoventilation, no adverse clinical consequences were seen. 23842482 State of Emergency Medicine in Switzerland: a national profile of emergency departments in 2006. Emergency departments (EDs) are an essential component of any developed health care system. There is, however, no national description of EDs in Switzerland. Our objective was to establish the number and location of EDs, patient visits and flow, medical staff and organization, and capabilities in 2006, as a benchmark before emergency medicine became a subspecialty in Switzerland. In 2007, we started to create an inventory of all hospital-based EDs with a preliminary list from the Swiss Society of Emergency and Rescue Medicine that was improved with input from ED physicians nationwide. EDs were eligible if they offered acute care 24 h per day, 7 days per week. Our goal was to have 2006 data from at least 80% of all EDs. The survey was initiated in 2007 and the 80% threshold reached in 2012. In 2006, Switzerland had a total of 138 hospital-based EDs. The number of ED visits was 1.475 million visits or 20 visits per 100 inhabitants. The median number of visits was 8,806 per year; 25% of EDs admitted 5,000 patients or less, 31% 5,001-10,000 patients, 26% 10,001-20,000 patients, and 17% >20,000 patients per year. Crowding was reported by 84% of EDs with >20,000 visits/year. Residents with limited experience provided care for 77% of visits. Imaging was not immediately available for all patients: standard X-ray within 15 min (70%), non-contrast head CT scan within 15 min (38%), and focused sonography for trauma (70%); 67% of EDs had an intensive care unit within the hospital, and 87% had an operating room always available. Swiss EDs were significant providers of health care in 2006. Crowding, physicians with limited experience, and the heterogeneity of emergency care capabilities were likely threats to the ubiquitous and consistent delivery of quality emergency care, particularly for time-sensitive conditions. Our survey establishes a benchmark to better understand future improvements in Swiss emergency care. 23638965 MtQRRS1, an R-locus required for Medicago truncatula quantitative resistance to Ralstonia solanacearum. Ralstonia solanacearum is a major soilborne pathogen that attacks > 200 plant species, including major crops. To characterize MtQRRS1, a major quantitative trait locus (QTL) for resistance towards this bacterium in the model legume Medicago truncatula, genetic and functional approaches were combined. QTL analyses together with disease scoring of heterogeneous inbred families were used to define the locus. The candidate region was studied by physical mapping using a bacterial artificial chromosome (BAC) library of the resistant line, and sequencing. In planta bacterial growth measurements, grafting experiments and gene expression analysis were performed to investigate the mechanisms by which this locus confers resistance to R. solanacearum. The MtQRRS1 locus was localized to the same position in two recombinant inbred line populations and was narrowed down to a 64 kb region. Comparison of parental line sequences revealed 15 candidate genes with sequence polymorphisms, but no evidence of differential gene expression upon infection. A role for the hypocotyl in resistance establishment was shown. These data indicate that the quantitative resistance to bacterial wilt conferred by MtQRRS1, which contains a cluster of seven R genes, is shared by different accessions and may act through intralocus interactions to promote resistance. 23949858 Contrasting patterns of within-species morphological variation in two cactophilic Drosophila species (Diptera: drosophilidae). In this work, we investigated the morphological variation of the intromittent male copulatory organ (aedeagus) of specimens from natural populations of two cactophilic Drosophila species distributed in the southeast region of Brazil, Drosophila gouveai Tidon-Sklorz & Sene and Drosophila antonietae Tidon-Sklorz & Sene. It was explored how the within-species variability is arranged for both species, considering their historical and ecological features. Our results showed two distinct aedeagal morphologies for these species, and differences within species were observed only in D. gouveai as specimens could be distinguished by their population origin. In contrast, after size discrepancies correction, this feature was not detected in D. antonietae. The contrasting patterns of intraspecific variation, together with the other features exhibited by these two species, are most likely to be explained by differences in the historical host plant association and distribution and in demographic events, which determined the evolutionary history of these two South American cactophilic Drosophila species. 23858067 Predictors of Depressive Symptoms Among Hispanic Women in South Florida. U.S. Hispanics, especially women, experience a disproportionate amount of disease burden for depression. This disparity among Hispanic women necessitates examination of factors associated with depression. The objective of this study was to use an adaptation of the Stress Process Model to test whether self-esteem mediated the relationship between Hispanic stress and depressive symptoms. Data for this secondary analysis were from a previous randomized-control HIV prevention trial.  Participants were 548 Hispanic women (19-52 years). Data collection measures included the Center for Epidemiological Studies-Depression Scale, Rosenberg Self-Esteem Scale, and Hispanic Stress Scale. The bootstrap method in Mplus 6 was used to test mediation. Results indicated that self-esteem was inversely related to depression, and Hispanic stress was found to be positively related to depression. Self-esteem partially mediated the relationship between stress and depression. Strategies to improve/maintain self-esteem should be considered in future interventions for Hispanic women with depression. 23186320 Development and validation of Chinese Health Literacy Scale for Diabetes. To develop and to test the psychometric properties of the Chinese Health Literacy Scale for Diabetes. Patients with diabetes encounter many challenges when making health decisions in their daily lives, as they have access to many different kinds of health information. Health literacy issues are new topics in Chinese society. Without a valid and reliable instrument in Chinese, it is difficult to measure the level of health literacy and promote the concept of health literacy in Chinese societies. A methodological study with a sample of 137 patients with type 2 diabetes aged 65 years or older. Chinese Health Literacy Scale for Diabetes was developed with reference to the revised Bloom's taxonomy model. Psychometric tests (content validity, item analysis, construct validity, discriminative ability and test-retest reliability) were conducted. Correlations between Chinese Health Literacy Scale for Diabetes and four relevant measures were tested. Cronbach's alpha and alpha if item deleted were calculated to assess internal consistency. Cronbach's alpha for Chinese Health Literacy Scale for Diabetes and its four subscales (remembering, understanding, applying and analysing) were 0·884, 0·885, 0·667, 0·654 and 0·717, respectively. The Chinese Health Literacy Scale for Diabetes was significantly correlated with the Diabetic Knowledge Scale (r = 0·398, p < 0·001), the Diabetic Management Self-Efficacy Scale (r = 0·257, p < 0·001), the Preschool and Primary Chinese Literacy Scale (r = 0·822, p < 0·001) and the Chinese Value of Learning Scale (r = 0·303, p < 0·001). It took an average of seven minutes to complete this 34-item instrument. The findings of this study support the Chinese Health Literacy Scale for Diabetes as a reliable and valid instrument for measuring the health literacy of Chinese patients with diabetes. We recommend that clinicians use this tool to assess patients' health literacy before conducting any kind of health promotion. 23937827 Radiological approach to a child with hip pain. Hip pain in a child can be a diagnostic challenge partly because of barriers to communication in the paediatric age group. Pain or limp may result from infective, inflammatory, traumatic, neoplastic, or developmental causes. A meticulous history and detailed clinical examination guide the radiological investigation in the appropriate direction. The age of the child further helps to narrow the differential as certain diseases are more common in certain age groups. In most patients plain radiograph and/or ultrasound is adequate. Ultrasound has the added advantage of being real time and can be used to guide aspiration. Magnetic resonance imaging (MRI) and bone scintigraphy can be used for problem solving, looking for multifocal disease, and staging. Computed tomography (CT) has a limited role to play because of the risks associated with ionizing radiation. In this review we discuss the approach to imaging a child who presents with pain in the hip or with a limp. The various common and rare, but important, diseases are illustrated with examples from our clinical practice. 23727000 Protection against avian necrotic enteritis after immunisation with NetB genetic or formaldehyde toxoids. NetB (necrotic enteritis toxin B) is a recently identified β-pore-forming toxin produced by Clostridium perfringens. This toxin has been shown to play a major role in avian necrotic enteritis. In recent years, a dramatic increase in necrotic enteritis has been observed, especially in countries where the use of antimicrobial growth promoters in animal feedstuffs has been banned. The aim of this work was to determine whether immunisation with a NetB toxoid would provide protection against necrotic enteritis. The immunisation of poultry with a formaldehyde NetB toxoid or with a NetB genetic toxoid (W262A) resulted in the induction of antibody responses against NetB and provided partial protection against disease. 23860697 Unmeasured anions are associated with short-term mortality in patients with hypoxic hepatitis. Hypoxic hepatitis is a common cause of hepatic impairment in critically ill patients and is an independent risk factor for mortality. An elevated level of unmeasured anions is another unfavourable prognostic marker in many disease entities. While the biochemical nature of unmeasured anions is unknown, data suggest that they may be released from the liver. Therefore, the purpose of this study was to determine whether the strong ion gap-the gold standard for estimation of unmeasured anions-is elevated and associated with outcome in patients with hypoxic hepatitis. One hundred and five consecutive patients with hypoxic hepatitis admitted to the (intensive care unit) ICU of a university hospital were prospectively included in the study and compared with 15 healthy controls. Compared with the controls, patients with hypoxic hepatitis had an elevated strong ion gap (4.0 ±â€‰2.6 vs. 7.8 ±â€‰4.0 mmol/L; p = 0.0002) that contributed to metabolic acidosis. Patients dying within 5 days had a larger strong ion gap upon admission than did patients surviving beyond 5 days. The mean strong ion gap (SIG) over the course of the first 5 days after admission to the ICU was 1.3 mmol/L (0.3-2.3 mmol/L) larger in patients who died compared with patients who survived, p = 0.008. In multivariate Cox-regression, larger strong ion gaps were associated with shorter survival time. The SIG correlated positively with both AST and ALT. Unmeasured anions are elevated in patients with hypoxic hepatitis, contribute to metabolic acidosis and are associated with mortality. The liver is a possible source of the unmeasured anions, which may represent markers of tissue damage in hypoxic hepatitis. 23562061 Ostreol A: A new cytotoxic compound isolated from the epiphytic dinoflagellate Ostreopsis cf. ovata from the coastal waters of Jeju Island, Korea. Ostreol A was isolated from cultures of the epiphytic dinoflagellate Ostreopsis cf. ovata from the coastal waters of Jeju Island, Korea. The compound, a non-palytoxin derivative, has a polyhydroxy chain ending with the primary amino group and contains an amide bond, along with two tetrahydropyran rings in the chain. Its chemical structure was elucidated by nuclear magnetic resonance (NMR) spectroscopy methods and confirmed by mass analysis. The compound exhibited significant cytotoxicity in the brine shrimp lethality test at a concentration of 0.9μg/mL. 23831459 Genetic, morphological, geographical and ecological approaches reveal phylogenetic relationships in complex groups, an example of recently diverged pinyon pine species (Subsection Cembroides). Elucidating phylogenetic relationships and species boundaries within complex taxonomic groups is challenging for intrinsic and extrinsic (i.e., technical) reasons. Mexican pinyon pines are a complex group whose phylogenetic relationships and species boundaries have been widely studied but poorly resolved, partly due to intrinsic ecological and evolutionary features such as low morphological and genetic differentiation caused by recent divergence, hybridization and introgression. Extrinsic factors such as limited sampling and difficulty in selecting informative molecular markers have also impeded progress. Some of the Mexican pinyon pines are of conservation concern but others may remain unprotected because the species boundaries have not been established. In this study we combined approaches to resolve the phylogenetic relationships in this complex group and to establish species boundaries in four recently diverged taxa: P. discolor, P. johannis, P. culminicola and P. cembroides. We performed phylogenetic analyses using the chloroplast markers matK and psbA-trnH as well as complete and partial chloroplast genomes of species of Subsection Cembroides. Additionally, we performed a phylogeographic analysis combining genetic data (18 chloroplast markers), morphological data and geographical data to define species boundaries in four recently diverged taxa. Ecological divergence was supported by differences in climate among localities for distinct genetic lineages. Whereas the phylogenetic analysis inferred with matK and psbA-trnH was unable to resolve the relationships in this complex group, we obtained a resolved phylogeny with the use of the chloroplast genomes. The resolved phylogeny was concordant with a haplotype network obtained using chloroplast markers. In species with potential for recent divergence, hybridization or introgression, nonhierarchical network-based approaches are probably more appropriate to protect against misclassification due to incomplete lineage sorting. The boundaries among genetic lineages were delimited by the inclusion of morphological, geographical and ecological data in the haplotype network. These multiple lines of evidence help to assign species boundaries in this complex group. P. johannis, P. discolor, P. culminicola and P. cembroides are different species based on their genetic, morphological and ecological niche differences. We suggest a reevaluation of the conservation status of these species considering the information generated in this study. 23859131 Measuring recovery: Validity of the "Recovery Process Inventory" and the "Recovery Attitudes Questionnaire" Considerable lack of publications and inconsistent results on construct validity make it difficult to choose an appropriate instrument to measure recovery. The aim of the present study was to evaluate additional psychometric aspects of two established measures of personal recovery with differing focusses. Bivariate associations of the recovery measures with personal, clinical and subjective factors were conducted as indicators of concurrent (convergent and divergent) validity. The scales were also tested concerning internal consistency. The sample comprised of 81 inpatients on an acute psychiatric ward (main diagnoses: 27% substance-related disorders, 27% schizophrenic disorders, 25% affective disorders, 10% neurotic or stress-related disorders, and 11% personality disorders). The "Recovery Attitudes Questionnaire (RAQ)" has to be reevaluated before further administration due to serious psychometric shortcomings concerning internal consistency and concurrent validity. The "Recovery Process Inventory (RPI)" total scale showed acceptable concurrent and within-scale validity and can be recommended in order to measure the personal recovery process for clinical and scientific purposes. 23824468 Monitoring in clinical trials: benefit or bias? Monitoring ongoing clinical trials for early signs of effectiveness is an option for improving cost-effectiveness of trials that is becoming increasingly common. Alongside the obvious advantages made possible by monitoring, however, there are some downsides. In particular, there is growing concern in the medical community that trials stopped early for benefit tend to overestimate treatment effect. In this paper, I examine this problem from the point of view of statistical methodology, starting from the observation that the overestimation is caused by the statistical method adopted. Consequently, I argue that some modifications can and should be made to the present statistical framework in order not to miss the advantages the possibility of monitoring can grant. 23933641 Inhaled epoprostenol to support the severely hypoxemic patient with acute respiratory distress syndrome. This article presents a case study demonstrating various rescue therapies considered in the care of a patient with severe, refractory hypoxemia secondary to acute respiratory distress syndrome. In particular, inhaled epoprostenol (Flolan) is becoming an increasingly common alternative to nitric oxide in the treatment of severe, refractory hypoxemia. Research comparing the 2 inhaled vasodilators suggests that epoprostenol is equally efficacious, easier to administer, less costly, and has fewer adverse effects. This article, using a case study approach, discusses the practical implications of this emerging therapy. 23944227 Stereoselective Synthesis of Dienyl Phosphonates via Extended Tethered Ring-Closing Metathesis. Allylphosphonates of allylic alcohols were converted to conjugated dienyl phosphonates in a one-flask reaction, comprising a ring-closing metathesis (RCM), a base-induced ring-opening, and an alkylation. The ring-opening proceeds with very high diastereoselectivity, giving exclusively the (1Z,3E)-configured dienes. Single diastereomers and mixtures of diastereomers can be used as starting materials without noticeable effect on the diastereoselectivity of the sequence. 23726148 Prevalence of Ambler class A β-lactamases and ampC expression in cephalosporin-resistant isolates of Acinetobacter baumannii. We examined the prevalence of various cephalosporins' resistance mechanisms in Acinetobacter baumannii clinical isolates. Phenotypic and molecular detection of Ambler classes A, B and D β-lactamases was performed on 75 isolates. Clonal relatedness was defined using Repetitive Extragenic Palindromic PCR. PCR mapping was used to examine the linkage of insertion sequences and the ampC gene, and ampC expression was analyzed by TaqMan reverse transcriptase-PCR. Twenty-six (37%) isolates carried at least one of the blaPER-1 or blaTEM-1. Sixty-nine (98.5%) out of 70 cephalosporin-resistant isolates had insertions upstream of the ampC gene, of which 48 (69%) and 6 (8%) were identified as ISAba1and ISAba125, respectively. Higher level of expression was obtained in resistant isolates lacking ISAba1/ampC combination in comparison with that in positive ones. The ability to up-regulate the expression of ampC gene in association with different insertion elements has become an important factor in A. baumannii resistance to cephalosporins. 23826562 Comparison of the accuracy of noninvasive hemoglobin sensor (NBM-200) and portable hemoglobinometer (HemoCue) with an automated hematology analyzer (LH500) in blood donor screening. The Hb levels of prospective blood donors are usually determined using a finger prick test. A new noninvasive Hb device has the advantage of not causing any sampling pain. The purpose of this study was to evaluate the accuracy of the noninvasive Hb sensor and to compare its measurements with those of a currently used portable hemoglobinometer. Hb was measured using a noninvasive Hb sensor (NBM-200; OrSense, Israel), a portable hemoglobinometer (HemoCue; HemoCue AB, Sweden), and an automated hematology analyzer (LH500; Beckman Coulter, USA). The correlations between Hb measurements taken by the NBM-200 and HemoCue with those by an automated hematology analyzer were assessed using intraclass correlation coefficients (ICCs). Hb measurements were compared among 3 different Hb level groups. The mean Hb values of 506 blood donors were 14.1 g/dL by the NBM-200, 14.0 g/dL by the LH500, and 14.3 g/dL by the HemoCue. The correlation between the LH500 and the NBM-200 was substantial (ICC=0.69), while that between the LH500 and the HemoCue agreed almost perfectly (ICC=0.86). The possibility to judge to be eligible for donors who are ineligible to donate was substantial when using NBM-200. Even though the NBM-200 has the apparent advantage of noninvasiveness, its use in pre-screening should be given meticulous attention. Since pre-donation testing is crucial to protecting donors' health, complete evaluation of the instrument should be performed prior to use. 23747028 Opportunistic microorganisms in individuals with lesions of denture stomatitis. The aim of this study was to isolate, quantify, identify, and compare opportunistic microorganisms (Candida and Staphylococcus genera and Enterobacteriaceae/Pseudomonadaceae families) from prosthesis-fitting surfaces, the hard palate, and mouth rinses of individuals wearing removable maxillary prosthesis with (50) and without (50) lesions of denture stomatitis (DS). The strains were collected and identified using phenotypic, biochemical and molecular tests. The counts of microorganisms were significantly higher in the group of individuals with DS (P < 0.05). C. albicans was the most frequently isolated yeast species in both groups, following by C. tropicalis and C. glabrata. Six isolates were identified as C. dubliniensis. S. aureus and S. epidermidis were the most frequent Staphylococcus species in both groups. Klebsiella pneumoniae was the predominant species in both groups. The association between Candida spp. and bacteria isolated in this study with DS suggests that these microorganisms may play important roles in the establishment and persistence of this disease. 23921708 Robotics in Keyhole Transcranial Endoscope-assisted Microsurgery: A Critical Review of Existing Systems and Proposed Specifications for New Robotic Platforms. Over the last decade, advances in image guidance, endoscopy and tube-shaft instruments have allowed for the development of keyhole transcranial endoscope-assisted microsurgery, utilizing smaller craniotomies, and minimizing exposure and manipulation of unaffected brain tissue. Although such approaches offer the possibility of shorter operating times, reduced morbidity and mortality, and improved long-term outcomes, the technical skills required to perform such surgery are inevitably greater than for traditional open surgical techniques, and they have not been widely adopted by neurosurgeons. Surgical robotics, which has the ability to improve visualization and increase dexterity, therefore has the potential to enhance surgical performance. To evaluate the role of surgical robots in keyhole transcranial endoscope-assisted microsurgery. The technical challenges faced by surgeons utilizing keyhole craniotomies were reviewed, and a thorough appraisal of presently available robotic systems was carried out. Surgical robotic systems have the potential to incorporate advances in augmented reality, stereo-endoscopy, and jointed-wrist instruments, and therefore significantly impact on the field of keyhole neurosurgery. To date, over 30 robotic systems have been applied to neurosurgical procedures. The vast majority of these robots are best described as supervisory-controlled, and are designed for stereotactic or image-guided surgery. Few telesurgical robots are suitable for keyhole neurosurgical approaches, and none are in widespread clinical use in the field. New robotic platforms in minimally invasive neurosurgery must possess clear and unambiguous advantages over conventional approaches if they are to achieve significant clinical penetration. 23944712 Antiangiogenic approach in soft-tissue sarcomas. Soft-tissue sarcomas (STS) are a group of more than 50 malignancies characterized by their rarity. The most effective treatments available only achieve a response rate (RR) of around 20%. Therefore, new therapeutic strategies are needed. Neoangiogenesis is one of the most fundamental mechanisms in cancer and many studies suggest that it also plays a crucial role in STS. Positive results from two Phase III trials in STS with drugs that target angiogenesis have recently been reported, showing an increase in progression-free survival. These data, although promising, are still insufficient and further investigations are needed. STS are unusual among solid tumors, in which single agent angiogenesis inhibitors produce a significant benefit. Unfortunately, we are currently not able to reliably define according to the histological subtype who are the patients that may benefit from this strategy. Moreover, it is clear that single agent treatment is insufficient, hence the current focus is on combination studies. 23883617 Clinical neuropathology practice guide 5-2013: markers of neuronal maturation. This review surveys immunocytochemical and histochemical markers of neuronal lineage for application to tissue sections of fetal and neonatal brain. They determine maturation of individual nerve cells as the tissue progresses to mature architecture. From a developmental perspective, neuronal markers are all about timing. These diverse cellular labels may be classified in two ways: 1) time of onset of expression (early; intermediate; late); 2) labeling of subcellular structures or metabolic functions (nucleoproteins; synaptic vesicle proteins; enolases; cytoskeletal elements; calcium-binding; nucleic acids; mitochondria). Apart from these positive markers of maturation, other negative markers are expressed in primitive neuroepithelial cells and early stages of neuroblast maturation, but no longer are demonstrated after initial stages of maturation. These examinations are relevant for studies of normal neuroembryology at the cellular level. In fetal and perinatal neuropathology they provide control criteria for application to malformations of the brain, inborn metabolic disorders and acquired fetal insults in which neuroblastic maturation may be altered. Disorders, in which cells differentiate abnormally, as in tuberous sclerosis and hemimegalencephaly, pose another yet aspect of mixed cellular lineage. The measurement in living patients, especially neonates, of serum and CSF levels of enolases, chromogranins and S-100 proteins as biomarkers of brain damage may potentially be correlated with their corresponding tissue markers at autopsy in infants who do not survive. The neuropathological markers here described can be performed in ordinary hospital laboratories, not just research facilities, and offer another dimension of diagnostic precision in interpreting abnormally developed fetal and postnatal brains. 23900586 Qing Hua Chang Yin exerts therapeutic effects against ulcerative colitis through the inhibition of the TLR4/NF‑κB pathway. The activation of the Toll‑like receptor 4 (TLR4)/nuclear factor‑κB (NF‑κB) pathway has been implicated as a key mediator in the pathogenesis of ulcerative colitis (UC); therefore, it has become an attractive target for the treatment of UC. Qing Hua Chang Yin (QHCY) is a traditional Chinese formula, which has been used for many years to clinically treat conditions associated with inflammatory bowel diseases, such as UC. However, the precise mechanisms behind its anti‑inflammatory effects remain largely unknown. In this study, using the dextran sulfate sodium (DSS)‑induced colitis mouse model, we evaluated the therapeutic effects of QHCY against UC and elucidated the possible underlying molecular mechanisms. We found that the administration of QHCY profoundly ameliorated DSS‑induced clinical manifestations, colon shortening and histological damage in the mice with colitis. In addition, treatment with QHCY significantly decreased the DSS‑induced secretion of serum amylase. Moreover, QHCY significantly inhibited the DSS‑induced expression of TLR4 and myeloid differentiation primary response gene 88 (MyD88), the phosphorylation of IκB and the nuclear translocation of NF‑κB. Taken together, our findings suggest that the suppression of the TLR4/NF‑κB signaling pathway may be one of the mechanisms involved in the therapeutic effects of QHCY against UC. 23892170 Extractive fixed-site polymer sorbent for selective boron removal from natural water. Water contamination by boron is a widespread environmental problem. The World Health Organization (WHO) recommends maximum boron concentration of 2.4mgL(-1) for drinking water. The paper presents a simple method for preparation of functionalized sheet sorbent for selective extraction of boron from natural water. The pores of commercially available poly(propylene) membrane were functionalized by room temperature in situ crosslinking of poly(vinylbenzyl chloride) with a cyclic diamine piperazine. The precursor membranes were chemically modified with N-methyl d-glucamine which is selective for boron. Characterization of membrane was carried out using scanning electron microscopy (SEM) and attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) techniques. The functionalized membrane has been characterized in terms of parameters that influence the sorption of boron from aqueous streams like pH, uptake capacity, contact time, effects of competing ions and reusability. The maximum boron sorption capacity determined experimentally was 28mgg(-1). The studies showed that trace concentrations of boron were quantitatively removed from water at neutral pH. The developed fixed site polymer sorbent exhibited high sorption capacity and fast kinetics as compared to various sorbents reported in literature. It was successfully applied for the removal of boron from ground water and seawater samples in presence of high concentration of interfering ions. 23899040 Food Safety: Importance of Composition for Assessing Genetically Modified Cassava ( Manihot esculenta Crantz). The importance of food composition in safety assessments of genetically modified (GM) food is described for cassava ( Manihot esculenta Crantz) that naturally contains significantly high levels of cyanogenic glycoside (CG) toxicants in roots and leaves. The assessment of the safety of GM cassava would logically require comparison with a non-GM crop with a proven "history of safe use". This study investigates this statement for cassava. A non-GM comparator that qualifies would be a processed product with CG level below the approved maximum level in food and that also satisfies a "worst case" of total dietary consumption. Although acute and chronic toxicity benchmark CG values for humans have been determined, intake data are scarce. Therefore, the non-GM cassava comparator is defined on the "best available knowledge". We consider nutritional values for cassava and conclude that CG residues in food should be a priority topic for research. 23830581 Direct measurement of matrix metalloproteinase activity in 3D cellular microenvironments using a fluorogenic peptide substrate. Incorporation of degradable moieties into synthetic hydrogels has greatly increased the utility of these three-dimensional matrices for in vitro cell culture as well as tissue engineering applications. A common method for introducing degradability is the inclusion of oligopeptides sensitive to cleavage by matrix metalloproteinases (MMPs), enabling cell-mediated remodeling and migration within the material. While this strategy has been effective, characterization and measurement of cell-mediated degradation in these materials has remained challenging. There are 20+ MMP family members whose activity is regulated in space and time by a number of biochemical and biophysical cues. Thus, the typical approach of characterizing cleavage of degradable moieties in solution with recombinant enzymes does not easily translate to three-dimensional cell-mediated matrix remodeling. To address this challenge, we report here the synthesis of a cell-laden hydrogel matrix functionalized with a fluorogenic peptide substrate to provide real-time, quantitative monitoring of global MMP activity. Using this system, stimulation of MMP activity was observed with growth factor treatment in mammary epithelial cells and compared to classical zymography results. Further, the effect of biophysical cues on MMP activity of human mesenchymal stem cells was also investigated where more rigid hydrogels were observed to increase MMP activity. The regulation of MMP activity by these biochemical and biophysical cues highlights the need for in situ, real-time measurement of hydrogel degradation, and use of these functionalized hydrogels will aid in future rational design of degradable synthetic hydrogels for in vitro cell studies and tissue engineering applications. 23940083 Overcoming resistance to sonic hedgehog inhibition by targeting p90 ribosomal S6 kinase in pediatric medulloblastoma. Molecular subtyping has allowed for the beginning of personalized treatment in children suffering from medulloblastoma (MB). However, resistance inevitably emerges against these therapies, particularly in the Sonic Hedgehog (SHH) subtype. We found that children with SHH subtype have the worst outcome underscoring the need to identify new therapeutic targets. High content screening of a 129 compound library identified agents that inhibited SHH MB growth. Lead molecular target levels, p90 ribosomal S6 kinase (RSK) were characterized by immunoblotting and qRT-PCR. Comparisons were made to human neural stem cells (hNSC). Impact of inhibiting RSK with the small molecule BI-D1870 or siRNA was assessed in growth assays (monolayer, neurosphere, and soft agar). NanoString was used to detect RSK in a cohort of 66 patients with MB. To determine BI-D1870 pharmacokinetics/pharmacodynamics, 100 mg/kg was I.P. injected into mice and tissues were collected at various time points. Daoy, ONS76, UW228, and UW426 MB cells were exquisitely sensitive to BI-D1870 but unresponsive to SHH inhibitors. Anti-tumor growth corresponded with inactivation of RSK in MB cells. BI-D1870 had no effect on hNSCs. Inhibiting RSK with siRNA or BI-D1870 suppressed growth, induced apoptosis, and sensitized cells to SHH agents. Notably, RSK expression is correlated with SHH patients. In mice, BI-D1870 was well-tolerated and crossed the blood-brain barrier (BBB). RSK inhibitors are promising because they target RSK which is correlated with SHH patients as well as cause high levels of apoptosis to only MB cells. Importantly, BI-D1870 crosses the BBB, acting as a scaffold for development of more long-lived RSK inhibitors. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc. 23436706 A concise synthesis of pyrazole analogues of combretastatin A1 as potent anti-tubulin agents. Combretastatin A1 (CA1) binds to the β-subunit at the colchicine binding site of tubulin and inhibits polymerization. As such, it is both an antitumor agent and a vascular disrupting agent. It has been shown to be at least tenfold more potent than combretastatin A4 (CA4) in terms of vascular shutdown, which correlates with its metabolism to reactive ortho-quinone species that are assumed to be directly cytotoxic in tumor cells. A series of 3,4-diarylpyrazoles were concisely synthesized, one of which, 3-methoxy-6-[4-(3,4,5-trimethoxyphenyl)-1H-pyrazol-3-yl]benzene-1,2-diol (27), proved to be a cytotoxic anti-tubulin agent with low nanomolar potency. We also report that combretastatins, including CA1, CA4, and 27, are effective against mesothelioma cell lines and therefore have significant clinical promise. Metabolism experiments demonstrate that 27 retains the ability to form ortho-quinone species, while the pyrazole ring shows high metabolic stability, suggesting that this compound might result in better pharmacokinetic profiles than CA1, with similar pharmacodynamic properties and clinical potential. 23821223 Research review trends of food analysis in Latvia: major and trace element content. The current paper involves overview of several studies concerning quantitative major and trace element analysis of different food samples, such as products of plant origin, e.g., locally grown vegetables (carrots, onions, potatoes) and products of animal origin derived with or without processing (cottage cheese, eggs, honey). Food samples were collected over the territory of Latvia in the time period 2009-2012. Sample pre-treatment was chosen according to the product specifics but mostly wet mineralization with concentrated nitric acid was applied. Analysis of major elements (e.g., Ca, Fe, K, Mg, Na) and trace elements (e.g., As, Cd, Co, Cr, Cu, Ni, Pb, Se, Zn) was performed by appropriate quantitative analytical technique: atomic absorption spectrometry, inductively coupled plasma mass spectrometry or total reflection X-ray fluorescence spectrometry. Not only the influence of environmental factors (e.g., geographical or seasonal impact) was detected in element dissemination in food, also botanical origin (if applicable) and applied agricultural praxis, product processing and storage specifics were found to be important. Possible food contamination by potentially toxic elements can be associated mostly with the consequences of anthropogenic activities. The studies revealed the significance of food research in the context of environmental science. 23460242 Nutrient composition, antioxidant properties, and anti-proliferative activity of Lignosus rhinocerus Cooke sclerotium. Lignosus rhinocerus (tiger milk mushroom) is an important medicinal mushroom used in Southeast Asia and China, and its sclerotium can be developed into functional food/nutraceuticals. The nutrient composition, antioxidant properties, and anti-proliferative activity of wild type and a cultivated strain of L. rhinocerus sclerotia were investigated. The sclerotial powder has high carbohydrate but low fat content. Interestingly, the cultivated strain contains higher amounts of protein and water-soluble substances than the wild type. Phenolic content of hot-water, cold-water, and methanol extracts of the sclerotial powders ranged from 19.32 to 29.42 mg gallic acid equivalents g(-1) extract, while the ferric reducing antioxidant power values ranged from 0.006 to 0.016 mmol min(-1)  g(-1) extract. The DPPH(•) , ABTS(•+) , and superoxide anion radical scavenging activities of the extracts ranged from 0.52 to 1.12, 0.05 to 0.20, and -0.98 to 11.23 mmol Trolox equivalents g(-1) extract, respectively. Both strains exhibited strong superoxide anion radical scavenging activity comparable to rutin. The cold-water extracts exhibited anti-proliferative activity against human breast carcinoma (MCF-7) cells, with IC50 values of 206 µg mL(-1) and 90 µg mL(-1) for the wild type and cultivated strains, respectively. The cultivated L. rhinocerus sclerotium has the potential to be developed into functional food/nutraceuticals. © 2013 Society of Chemical Industry. 23374416 A performance improvement prescribing guideline reduces opioid prescriptions for emergency department dental pain patients. In an effort to reduce prescription opioid abuse originating from our institution, we implement and measure the effect of a prescribing guideline on the rate of emergency department (ED) opioid prescriptions written for patients presenting with dental pain, a complaint previously associated with drug-seeking behavior. After implementing a departmental guideline on controlled substance prescriptions, we performed a structured before-and-after chart review of dental pain patients aged 16 and older. Before the guideline, the rate of opioid prescription was 59% (302/515). After implementation, the rate was 42% (65/153). The absolute decrease in rates was 17% (95% confidence interval 7% to 25%). Additionally, in comparing the 12-month period before and after implementation, the dental pain visit rate decreased from 26 to 21 per 1,000 ED visits (95% confidence interval of decrease 2 to 9 visits/1,000). A performance improvement program involving a departmental prescribing guideline was associated with a reduction in the rate of opioid prescriptions and visits for ED patients presenting with dental pain. 23810300 Radiation exposure to operating room personnel and patients during endovascular procedures. To characterize radiation exposure to patients and operating room personnel during fluoroscopic procedures. Patient dose information was collected from the imaging equipment. Real-time dosimetry was used to measure doses to the operators, scrub nurse, radiologic technologist (RT), and anesthesiologist in 39 cases of endovascular thoracoabdominal aortic aneurysm repair using fenestrated endografts. Overall equivalent doses and dose rates at time points of interest were noted and compared with the corresponding patient doses. The dosimeter on the anesthesia equipment received 143 μSv (38-247) more radiation per case than the average operator, and the scrub nurse and RT received 106 μSv (66-146) and 100 μSv (55-145) less, respectively. Adjusting for protective lead aprons by the Webster methodology, the average operator received an effective dose of 38 μSv. Except for the RT, personnel doses were well correlated with patient dose as measured by kerma area product (KAP) (r = .82 for average operator, r = .85 for scrub nurse, and r = .86 for anesthesia; all P < .001) but less well correlated with fluoroscopy time or cumulative air kerma (CAK). When preoperative cone beam computed tomography was performed, the equivalent dose to the RT was 1.1 μSv (0.6-1.5) when using shielding and 37 μSv (22-53) when unshielded. Digital subtraction acquisitions accounted for a large fraction of all individuals' doses. Decreasing field size (and thus, increasing magnification) was associated with decreased KAP (r = .47; P < .001) and increased CAK (r = -.56; P < .001). The square of the field size correlated strongly with the KAP/CAK ratio (r = .99; P < .001). Increased lateral angulation of the C-arm increased both CAK and KAP (at field size, 22 cm; r = .54 and r = .44; both P < .001) and the average dose rate to an operator was 1.78 (1.37-2.31) times as high in a lateral projection as in a posterior-anterior projection. Personnel doses were best correlated with KAP and less well correlated with fluoroscopy time or CAK. The dosimeter on the anesthesia equipment recorded the highest doses attributable to ineffective shielding. Operators can reduce the effective dose to themselves, the patient, and other personnel by minimizing the use of digital subtraction acquisitions, avoiding lateral angulation, using higher magnification levels when possible, and being diligent about the use of shielding during fluoroscopy cases. 23913602 Preclinical evaluation of second-generation everolimus- and zotarolimus-eluting coronary stents. This study was designed to evaluate the pharmacokinetic and vascular healing of a second-generation everolimus-eluting stent (EES) and slow-release zotarolimus-eluting stent (R-ZES). Second-generation DESs have alleviated the safety concerns of late stent thrombosis by addressing issues of polymer biocompatibility and stent design, and optimizing drug loads and release kinetics. No preclinical comparison study exists between these stents. Rabbit iliac artery stent implantation was performed using Xience Prime EES and Resolute R-ZES. Histomorphometric evaluation was performed at 28 and 60 days after implantation in an induced atheroma model. Endothelial coverage and maturation were assessed by scanning electron microscopy and immuno-labeling at 14 and 28 days following deployment. For pharmacokinetic studies, arterial tissue and stents were retrieved at 3, 14, 28, and 90 days, and blood samples were obtained during the first 24 hours. Vascular remodeling (percent stenosis, neointimal thickness) was similar in arteries implanted with either stent group. At 28 days, inflammation was significantly less in the EES group as compared to the R-ZES group (inflammation score: 1.59 ± 0.52 vs 2.22 ± 0.69, respectively; P=.044), with no differences observed at 60 days. Endothelial coverage was similar between both groups; however, endothelial maturation above stent struts was significantly higher in the EES group vs R-ZES group at 28 days (33 ± 20% vs 22 ± 21%, respectively; P=.040). Arterial drug level concentrations were also shown to be significantly less in the EES group vs the R-ZES group (P<.0001). Overall, EES and R-ZES displayed similar remodeling properties with lower arterial drug levels observed in the EES group vs the R-ZES group, which may have led to more rapid endothelial maturation. 23906883 Will regenerative medicine replace transplantation? Recent groundbreaking advances in organ bioengineering and regeneration have provided evidence that regenerative medicine holds promise to dramatically improve the approach to organ transplantation. The two fields, however, share a common heritage. Alexis Carrel can be considered the father of both regenerative medicine and organ transplantation, and it is now clear that his legacy is equally applicable for the present and future generations of transplant and regenerative medicine investigators. In this review, we will briefly illustrate the interplay that should be established between these two complementary disciplines of health sciences. Although regenerative medicine has shown to the transplant field its potential, transplantation is destined to align with regenerative medicine and foster further progress probably more than either discipline alone. Organ bioengineering and regeneration technologies hold the promise to meet at the same time the two most urgent needs in organ transplantation, namely, the identification of a new, potentially inexhaustible source of organs and immunosuppression-free transplantation of tissues and organs. 23851964 Teriflunomide effect on immune response to influenza vaccine in patients with multiple sclerosis. To investigate the effect of teriflunomide on the efficacy and safety of seasonal influenza vaccine. The 2011/2012 seasonal influenza vaccine (containing H1N1, H3N2, and B strains) was administered to patients with relapsing forms of multiple sclerosis (RMS) treated for ≥6 months with teriflunomide 7 mg (n = 41) or 14 mg (n = 41), or interferon-β-1 (IFN-β-1; n = 46). The primary endpoint was the proportion of patients with influenza strain-specific antibody titers ≥40, 28 days postvaccination. More than 90% of patients achieved postvaccination antibody titers ≥40 for H1N1 and B in all groups. For H3N2, titers ≥40 were achieved in ≥90% of patients in the 7 mg and IFN-β-1 groups, and in 77% of the 14-mg group, respectively. A high proportion of patients already had detectable antibodies for each influenza strain at baseline. Geometric mean titer ratios (post/prevaccination) were ≥2.5 for all groups and strains, except for H1N1 in the 14-mg group (2.3). The proportion of patients with a prevaccination titer <40 achieving seroprotection was ≥61% across the 3 treatment groups and 3 influenza strains. However, fewer patients in the 14-mg than the 7-mg or IFN-β-1 groups exhibited seroprotection to H3N2 (61% vs 78% and 82%, respectively). Teriflunomide-treated patients generally mounted effective immune responses to seasonal influenza vaccination, consistent with preservation of protective immune responses. This study provides Class II evidence that teriflunomide generally does not adversely impact the ability of patients with RMS to mount immune responses to influenza vaccination. 23742173 Relaxin improves multiple markers of wound healing and ameliorates the disturbed healing pattern of genetically diabetic mice. Diabetic mice are characterized by a disrupted expression pattern of VEGF (vascular endothelial growth factor), and impaired vasculogenesis during healing. Experimental evidence suggests that RLX (relaxin) can improve several parameters associated with wound healing. Therefore we investigated the effects of porcine-derived RLX in diabetes-related wound-healing defects in genetically diabetic mice. An incisional wound model was produced on the back of female diabetic C57BL/KsJ-m+/+Leptdb (db+/db+) mice and their normal littermates (db+/+m). Animals were treated daily with porcine RLX (25 Î¼g/mouse per day, subcutaneously) or its vehicle. Mice were killed on 3, 6 and 12 days after skin injury for measurements of VEGF mRNA and protein synthesis, SDF-1α (stromal cell-derived factor-1α) mRNA and eNOS (endothelial NO synthase) expression. Furthermore, we evaluated wound-breaking strength, histological changes, angiogenesis and vasculogenesis at day 12. Diabetic animals showed a reduced expression of VEGF, eNOS and SDF-1α compared with non-diabetic animals. At day 6, RLX administration resulted in an increase in VEGF mRNA expression and protein wound content, in eNOS expression and in SDF-1α mRNA. Furthermore, the histological evaluation indicated that RLX improved the impaired wound healing, enhanced the staining of MMP-11 (matrix metalloproteinase-11) and increased wound-breaking strength at day 12 in diabetic mice. Immunohistochemistry showed that RLX in diabetic animals augmented new vessel formation by stimulating both angiogenesis and vasculogenesis. RLX significantly reduced the time to complete skin normalization and this effect was abrogated by a concomitant treatment with antibodies against VEGF and CXCR4 (CXC chemokine receptor 4), the SDF-1α receptor. These data strongly suggest that RLX may have a potential application in diabetes-related wound disorders. 23812749 Maturation, not initiation, is the major roadblock during reprogramming toward pluripotency from human fibroblasts. Pluripotency can be induced in somatic cells by forced expression of POU domain, class 5, transcription factor 1 (OCT3/4), sex determining region Y-box 2 (SOX2), Kruppel-like factor 4 (KLF4), myelocytomatosis oncogene (c-MYC) (OSKM). However, factor-mediated direct reprogramming is generally regarded as an inefficient and stochastic event. Contrary to this notion, we herein demonstrate that most human adult dermal fibroblasts initiated the reprogramming process on receiving the OSKM transgenes. Within 7 d, ∼20% of these transduced cells became positive for the TRA-1-60 antigen, one of the most specific markers of human pluripotent stem cells. However, only a small portion (∼1%) of these nascent reprogrammed cells resulted in colonies of induced pluripotent stem cells after replating. We found that many of the TRA-1-60-positive cells turned back to be negative again during the subsequent culture. Among the factors that have previously been reported to enhance direct reprogramming, LIN28, but not Nanog homeobox (NANOG), Cyclin D1, or p53 shRNA, significantly inhibited the reversion of reprogramming. These data demonstrate that maturation, and not initiation, is the limiting step during the direct reprogramming of human fibroblasts toward pluripotency and that each proreprogramming factor has a different mode of action. 23947802 Spatial and Temporal Effects in Protein Post-translational Modification Distributions in the Developing Mouse Brain. Protein post-translational modification (PTM) is a powerful way to modify the behavior of cellular proteins and thereby cellular behavior. Multiple recent studies of evolutionary trends have shown that certain pairs of protein post-translational modifications tend to occur closer to each other than expected at random. This type of observation may form the basis of a proposed "PTM code", whereby protein function is controlled by complex patterns of multiple PTMs. This code could provide an additional, powerful level of regulatory control for protein function and is a plausible explanation for observations of increasingly frequent and diverse protein modification in cell biology. In this study, we use mass spectrometry and proteomic strategies to present biological data showing spatiotemporal PTM co-localization across multiple PTM categories, which display changes over development of the brain. This may be an indication of the existence of a PTM-based functional coding mechanism, which would significantly expand our view of the ways in which cells use protein PTMs in complex signaling networks. 22500979 Prevalence of oral mucosal lesions in an elderly population in the city of Valparaiso, Chile. doi: 10.1111/j.1741-2358.2012.00663.x Prevalence of oral mucosal lesions in an elderly population in the city of Valparaiso, Chile Objective:  Chilean population is ageing, which means an increase in the prevalence of multiple pathologies, including those located in the oral cavity. Aim:  To measure the prevalence and distribution of oral mucosal lesions and to identify associated risk factors in elderly patients in the city of Valparaiso. Material and methods:  This study includes 126 patients over 60 years. The sample was calculated with a sampling error of 3.7% from a population size of 6000 file cards. Frequency and contingency tables were made together with odds ratios, with a confidence interval of 95%. Finally, we built a predictive model based on a binary logistic regression. Results:  From the whole sample, 85 patients (67.5%) had some oral mucosal lesion. The most frequent lesions were denture-induced stomatitis (37.1%). It was noted that there is a statistically significant association between the use of denture and the presence of oral candidiasis. The consumption of drugs and the use of denture increase the likelihood of having oral mucosal lesions. Conclusion:  There is a high prevalence of oral lesions in the elderly patients of Valparaiso. The use of drugs and /or denture increases significantly the likelihood that a person over 60 years presents lesions in the oral mucosa. 23922876 Notch1 signaling regulates the proliferation and self-renewal of human dental follicle cells by modulating the g1/s phase transition and telomerase activity. Multipotent human dental follicle cells (HDFCs) have been intensively studied in periodontal regeneration research, yet the role of Notch1 in HDFCs has not been fully understood. The aim of the current study is to explore the role of Notch1 signaling in HDFCs self-renewal and proliferation. HDFCs were obtained from the extracted wisdom teeth from adolescent patients. Regulation of Notch1 signaling in the HDFCs was achieved by overexpressing the exogenous intracellular domain of Notch1 (ICN1) or silencing Notch1 by shRNA. The regulatory effects of Notch1 on HDFC proliferation, cell cycle distribution and the expression of cell cycle regulators were investigated through various molecular technologies, including plasmid construction, retrovirus preparation and infection, qRT-PCR, western blot, RBP-Jk luciferase reporter and cell proliferation assay. Our data clearly show that constitutively activation of Notch1 stimulates the HDFCs proliferation while inhibition of the Notch1 suppresses their proliferation in vitro. In addition, the HDFCs proliferation is associated with the increased expression of cell cycle regulators, e.g. cyclin D1, cyclin D2, cyclin D3, cyclin E1, CDK2, CDK4, CDK6, and SKP2 and the decreased expression of p27 (kip1). Moreover, our data show that the G1/S phase transition (indicating proliferation) and telomerase activity (indicating self-renewal) can be enhanced by overexpression of ICN1 but halted by inhibition of Notch1. Together, the current study provides evidence for the first time that Notch1 signaling regulates the proliferation and self-renewal capacity of HDFCs through modulation of the G1/S phase transition and the telomerase activity. 23239267 Evaluation of safety and efficacy of radiation-sterilized bone allografts in reconstructive oral surgery. Bone grafting allows reconstruction of the atrophied or destroyed alveolar process. In orthopaedics and traumatology allogeneic grafting has been used to restore defects of osseous tissue for over 60 years. In order to improve safety of the graft recipient, sterilized allogeneic grafts have been use. The aim of the study was to assess the direct and long-term outcomes following augmentation of atrophied alveolar processes with the use of radiation-sterilized allogeneic bone grafts. Sixty-eight patients were surgically treated between 2004 and 2011: 29 underwent open sinus floor elevation, post-extraction alveoli augmentation was performed in 16 subjects and 23 underwent reconstruction of the atrophied alveolar process. Augmentation of bone defects used bone granulate in 63 patients and bone blocks stabilized with titanium screws in 5 patients. PRF membranes collected from the patient's blood were also used in all the procedures. In each of the cases optimal dimensions of the alveolar process were obtained allowing embedment of BIOMET 3I dental implant/-s. In all the patients the defects were successfully restored with implant-supported prostheses. Radiation-sterilized allogeneic bone grafts proved to be safe and effective for the patients and manageable for the surgeon constituting a good alternative to autogeneic material. 23382012 Latitude gradients for lymphoid neoplasm subtypes in Australia support an association with ultraviolet radiation exposure. Given the uncertainty surrounding solar ultraviolet radiation (UVR) exposure and risk of lymphoid neoplasms, we performed an ecological analysis of national Australian data for incident cases diagnosed between 2002 and 2006. Subtype-specific incidence was examined by latitude band (<29°S, 29-36°S, ≥37°S), a proxy for ambient UVR exposure, using multiple Poisson regression, adjusted for sex, age-group and calendar year. Incidence increased with distance from the equator for several mature B-cell non-Hodgkin lymphomas, including diffuse large B-cell [incidence rate ratio (IRR) = 1.37; 95% confidence interval (CI): 1.16-1.61 for latitude ≥37°S relative to <29°S], lymphoplasmacytic (IRR = 1.34; 95% CI: 1.12-1.61), mucosa-associated lymphoid tissue (IRR = 1.32; 95% CI: 0.97-1.80) and mantle cell lymphoma (IRR = 1.29; 95% CI: 1.05-1.58), as well as plasmacytoma (IRR = 1.52; 95% CI: 1.09-2.11) and plasma cell myeloma (IRR = 1.15; 95% CI: 1.03-1.27). A similar pattern was observed for several mature cutaneous T-cell neoplasms, including primary cutaneous anaplastic large cell lymphoma (IRR = 4.26; 95% CI: 1.85-9.84), mycosis fungoides/Sézary syndrome (IRR = 1.72; 95% CI: 1.20-2.46), and peripheral T-cell lymphoma not otherwise specified (NOS) (IRR = 1.53; 95% CI: 1.17-2.00). Incidence of mixed cellularity/lymphocyte-depleted (IRR = 1.60; 95% CI: 1.16-2.20) and nodular sclerosis Hodgkin lymphoma (IRR = 1.57; 95% CI: 1.33-1.85) also increased with distance from the equator. Many of these subtypes have a known association with infection or immune dysregulation. Our findings support a possible protective effect of UVR exposure on the risk of several lymphoid neoplasms, possibly through vitamin D-related immune modulation critical in lymphomagenesis. 23600682 The Chemical constituents of the twigs of Ammopiptanthus nanus. Two new isoflavone glycosides, ammopiptanosides A and B, have been isolated from the 95% EtOH extract of the twigs of Ammopiptanthus nanus (M.Pop.) Cheng f., together with six known compounds, and their structures were characterized by spectroscopic methods and compared with the data in the literature. 23850193 Pneumococcal pneumonia - are the new severity scores more accurate in predicting adverse outcomes? The site-of-care decision is one of the most important factors in the management of patients with community-acquired pneumonia. The severity scores are validated prognostic tools for community-acquired pneumonia mortality and treatment site decision. The aim of this paper was to compare the discriminatory power of four scores - the classic PSI and CURB65 ant the most recent SCAP and SMART-COP - in predicting major adverse events: death, ICU admission, need for invasive mechanical ventilation or vasopressor support in patients admitted with pneumococcal pneumonia. A five year retrospective study of patients admitted for pneumococcal pneumonia. Patients were stratified based on admission data and assigned to low-, intermediate-, and high-risk classes for each score. Results were obtained comparing low versus non-low risk classes. We studied 142 episodes of hospitalization with 2 deaths and 10 patients needing mechanical ventilation and vasopressor support. The majority of patients were classified as low risk by all scores - we found high negative predictive values for all adverse events studied, the most negative value corresponding to the SCAP score. The more recent scores showed better accuracy for predicting ICU admission and need for ventilation or vasopressor support (mostly for the SCAP score with higher AUC values for all adverse events). The rate of all adverse outcomes increased directly with increasing risk class in all scores. The new gravity scores appear to have a higher discriminatory power in all adverse events in our study, particularly, the SCAP score. 23956205 Evidence for replicative mechanism in a CHD7 rearrangement in a patient with CHARGE syndrome. Haploinsufficiency of CHD7 (OMIM# 608892) is known to cause CHARGE syndrome (OMIM# 214800). Molecular testing supports a definitive diagnosis in approximately 65-70% of cases. Most CHD7 mutations arise de novo, and no mutations affecting exon-7 have been reported to date. We report on an 8-year-old girl diagnosed with CHARGE syndrome that was referred to our laboratory for comprehensive CHD7 gene screening. Genomic DNA from the subject with a suspected diagnosis of CHARGE was isolated from peripheral blood lymphocytes and comprehensive Sanger sequencing, along with deletion/duplication analysis of the CHD7 gene using multiplex ligation-dependent probe amplification (MLPA), was performed. MLPA analysis identified a reduced single probe signal for exon-7 of the CHD7 gene consistent with potential heterozygous deletion. Long-range PCR breakpoint analysis identified a complex genomic rearrangement (CGR) leading to the deletion of exon-7 and breakpoints consistent with a replicative mechanism such as fork stalling and template switching (FoSTeS) or microhomology-mediated break-induced replication (MMBIR). Taken together this represents the first evidence for a CHD7 intragenic CGR in a patient with CHARGE syndrome leading to what appears to be also the first report of a mutation specifically disrupting exon-7. Although likely rare, CGR may represent an overlooked mechanism in subjects with CHARGE syndrome that can be missed by current sequencing and dosage assays. © 2013 Wiley Periodicals, Inc. 23229135 Dynamic bioavailability of copper in soil estimated by uptake and elimination kinetics in the springtail Folsomia candida. This study aimed to assess the bioavailability of copper in soil, by measuring its uptake kinetics into a representative soil invertebrate, the collembolan Folsomia candida. The animals were exposed to 25 or 100 μg Cu g(-1) dry LUFA 2.2 soil at nominal pH(CaCl2) 4.5, 5.5, or 6.5 during 14 days after which they were transferred to clean soil for 14 days elimination. Uptake and elimination rate constants were calculated based on total and extractable soil concentrations and porewater concentrations using one-compartment first-order kinetics modelling. Copper was present in the animals at a basal physiological level of 40-90 μg g(-1)dry weight, on top of this uptake and elimination kinetics were observed. Uptake rates constants varied between 0.02 and 0.17 g(soil) g(animal)(-1) day(-1), being higher at lower exposure level, but did not differ significantly between different soil pH levels. Elimination rate constants ranged between 0.04 and 0.20 day(-1) and were negligible (k(2) < 0.001 day(-1)) at pH 4.5 and 6.5. Multiple linear regressions showed that the pH effect on copper uptake was only significant when taking into account cation exchange capacity, or calcium and dissolved organic carbon levels in the pore water. Copper concentrations in the animals however, never were higher than 185 μg g(-1) dry weight, independent of exposure level and pH, suggesting homeostatic regulation. These results show that the chemical composition of the pore water does affect bioavailability of copper in soil, but that copper uptake in collembolans is dominated by homeostatic regulation rather than by soil properties like pH. 23903151 Wavelength-sensitive-function controlled reflectance reconstruction. Spectral reflectance is defined as the "fingerprint" of an object and is illumination invariant. It has many applications in color reproduction, imaging, computer vision, and computer graphics. In previous reflectance reconstruction methods, spectral reflectance has been treated equally over the whole wavelength. However, human eyes or sensors in an imaging device usually have different weights over different wavelengths. We propose a novel method to reconstruct reflectance, considering a wavelength-sensitive function (WSF) that is constructed from sensor-sensitive functions (or color matching functions). Our main idea is to achieve more accurate reconstruction at wavelengths where sensors have high sensitivities. This more accurate reconstruction can achieve better imaging or color reproduction performance. In our method, we generate a matrix through the Hadamard product of the reflectance matrix and the WSF matrix. We then obtain reconstructed reflectance by applying the singular value decomposition on the generated matrix. The experimental results show that our method can reduce 47% mean-square error and 55% Lab error compared with the classical principal component analysis method. 23826953 Isolation of Burkholderia cepacia JB12 from lead- and cadmium-contaminated soil and its potential in promoting phytoremediation with tall fescue and red clover. Phytoremediation combined with suitable microorganisms and biodegradable chelating agents can be a means of reclaiming lands contaminated by toxic heavy metals. We investigated the ability of a lead- and cadmium-resistant bacterial strain (JB12) and the biodegradable chelator ethylenediamine-N,N'-disuccinic acid (EDDS) to improve absorption of these metals from soil by tall fescue and red clover. Strain JB12 was isolated from contaminated soil samples, analysed for lead and cadmium resistance, and identified as Burkholderia cepacia. Tall fescue and red clover were grown in pots to which we added JB12, (S,S)-EDDS, combined JB12 and EDDS, or water only. Compared with untreated plants, the biomass of plants treated with JB12 was significantly increased. Concentrations of lead and cadmium in JB12-treated plants increased significantly, with few exceptions. Plants treated with EDDS responded variably, but in those treated with combined EDDS and JB12, heavy metal concentrations increased significantly in tall fescue and in the aboveground parts of red clover. We conclude that JB12 is resistant to lead and cadmium. Its application to the soil improved the net uptake of these heavy metals by experimental plants. The potential for viable phytoremediation of lead- and cadmium-polluted soils with tall fescue and red clover combined with JB12 was further enhanced by the addition of EDDS. 23893368 Management of Pediatric Obesity: A Lifestyle Modification Approach. Over the last decades, pediatric obesity has become a global epidemic with worldwide estimates as high as 43 million children and adolescents affected, and this number is rising at an exponential rate. With pediatric obesity comes a host of co-morbidities including impaired glucose tolerance, dyslipidemia, hypertension, and impaired liver function. Treatment of this population has proven to be challenging for many reasons. For patients, a new baseline exists consisting of an increasingly sedentary lifestyle as well as a lack of availability of affordable healthy alternatives. In addition, there is an overwhelming presence of energy-dense foods. For physicians, there are many issues including lack of time, training, and reimbursement. The most efficacious and reliable way to treat this population and its co-morbidities is with a healthy, balanced lifestyle consisting of a realistic diet plan and exercise regimen. The is the cornerstone of therapy in the Center for Obesity And its Complications in Health (COACH) clinic which is Children's Medical Center's (Dallas, TX) strategy to combat and treat pediatric overweight and obesity. Lifestyle changes of diet and exercise plans are tailored to each individual's interests and metabolic needs in COACH which is a multi-disciplinary clinic. Additionally, co-morbidities are screened for and treated aggressively to help prevent long-term complications of overweight and obesity. If others do similar interventions in their communities, this global epidemic has the possibility of more positive outcomes than those currently projected. 23909558 Characterizing O-Linked Glycopeptides by Electron Transfer Dissociation: Fragmentation Rules and Applications in Data Analysis. Studying protein O-glycosylation remains an analytical challenge. Different from N-linked glycans, the O-glycosylation site is not within a known consensus sequence. Additionally, O-glycans are heterogeneous with numerous potential modification sites. Electron transfer dissociation (ETD) is the method of choice in analyzing these glycopeptides since the glycan side chain remains intact in ETD, and the glycosylation site can be localized on the basis of the c and z fragment ions. Nonetheless, new software is necessary for interpreting O-glycopeptide ETD spectra in order to expedite the analysis workflow. To address the urgent need, we studied the fragmentation of O-glycopeptides in ETD and found useful rules that facilitate their identification. By implementing the rules into an algorithm to score potential assignments against ETD-MS/MS data, we applied the method to glycopeptides generated from various O-glycosylated proteins including mucin, erythropoietin, fetuin, and an HIV envelope protein, 1086.C gp120. The site-specific O-glycopeptide composition was correctly assigned in every case, proving the merits of our method in analyzing glycopeptide ETD data. The algorithm described herein can be easily incorporated into other automated glycomics tools. 23942881 Patient-specific total knee arthroplasty: the importance of planning by the surgeon. The purpose of the study was to evaluate the accuracy of the planning of the patient-specific pin guides in total knee arthroplasty (TKA). This planning was performed primarily by a technician of the company and offered to the surgeon. All parameters of the implantation can either be modified or accepted by the surgeon. The hypothesis was that the plan needs preoperative intervention by the surgeon. A prospective study in 50 patients was carried out. All patients received the same posterior-stabilised implant with patient-specific instrumentation. All surgical parameters (coronal, sagittal, rotational alignment, femoral and tibial resection levels and implant sizes) were checked by the orthopaedic surgeon and changed if necessary. Preoperatively, the femoral size was changed in 8 patients (16 %), the femoral flexion in 23 patients (46 %), the femoral shift in 34 patients (68 %), the tibial size in 24 patients (48 %) and the tibial rotation in all patients. The epicondylar axis was accepted in 47 patients (94 %) in the technician plan. Mean planning time was 8 ± 4 min. Intraoperatively, the femoral anterior-posterior size was in 50 patients (100 %) the same as in the surgeon and in 42 patients (84 %) the same as in the technician plan (p = 0.003). The tibial component implanted was in 42 patients (84 %) the same as in the surgeon and in 19 patients (38 %) the same as in the technician plan (p < 0.0001). A femoral distal recut was necessary in 31 patients (62 %) and a change of the tibial proximal cut in 17 patients (34 %) during surgery. Intraoperatively, no changes of the femoral and tibial alignment, the femoral anterior-posterior size, the femoral flexion, the femoral shift, the femoral and tibial rotation were necessary. Postoperatively, the coronal mechanical overall axis was within ±3° in 47 patients (94 %) with a maximum deviation of 5.6°. Significant changes of the technician plan were necessary to get an accurate preoperative plan. Intraoperative changes were significant less compared to the surgeon than to the technician plan. No major changes (alignment, femoral anterior-posterior size and rotation) of the surgeon plan were necessary. Surgeons using patient-specific pin guides in TKA may verify the default plan provided by the technician. A blind reply on the technician plan may be not recommended. Therapeutic study, Level III. 23544670 Acute preconditioning of cardiac progenitor cells with hydrogen peroxide enhances angiogenic pathways following ischemia-reperfusion injury. There are a limited number of therapies available to prevent heart failure following myocardial infarction. One novel therapy that is currently being pursued is the implantation of cardiac progenitor cells (CPCs); however, their responses to oxidative stress during differentiation have yet to be elucidated. The objective of this study was to determine the effect of hydrogen peroxide (H2O2) treatment on CPC differentiation in vitro, as well as the effect of H2O2 preconditioning before implantation following ischemia-reperfusion (I/R) injury. CPCs were isolated and cloned from adult rat hearts, and then cultured in the absence or presence of H2O2 for 2 or 5 days. CPC survival was assessed with Annexin V, and cellular differentiation was evaluated through mRNA expression for cardiogenic genes. We found that 100 μM H2O2 decreased serum withdrawal-induced apoptosis by at least 45% following both 2 and 5 days of treatment. Moreover, 100 μM H2O2 treatment for 2 days significantly increased endothelial and smooth muscle markers compared to time-matched untreated CPCs. However, continued H2O2 treatment significantly decreased these markers. Left ventricular cardiac function was assessed 28 days after I/R and I/R with the implantation of Luciferase/GFP(+) CPCs, which were preconditioned with 100 μM H2O2 for 2 days. Hearts implanted with Luciferase/GFP(+) CPCs had significant improvement in both positive and negative dP/dT over I/R. Furthermore, cardiac fibrosis was significantly decreased in the preconditioned cells versus both I/R alone and I/R with control cells. We also observed a significant increase in endothelial cell density in the preconditioned CPC hearts compared to untreated CPC hearts, which also coincided with a higher density of Luciferase(+) vessels. These findings suggest that preconditioning of CPCs with H2O2 for 2 days stimulates neoangiogenesis in the peri-infarct area following I/R injury and could be a viable therapeutic option to prevent heart failure. 23932774 Effects of fatiguing treadmill running on sensorimotor control in athletes with and without functional ankle instability. Sensorimotor control is permanently impaired following functional ankle instability and temporarily decreased following fatigue. Little is known on potential interactions between both conditions. The purpose was to investigate the effect of fatiguing exercise on sensorimotor control in athletes with and without (coper, controls) functional ankle instability. 19 individuals with functional ankle instability, 19 ankle sprain copers, and 19 non-injured controls participated in this cohort study. Maximum reach distance in the star excursion balance test, unilateral jump landing stabilization time, center of pressure sway velocity in single-leg-stance, and passive ankle joint position sense were assessed before and immediately after fatiguing treadmill running. A three factorial linear mixed model was specified for each outcome to evaluate the effects of group, exhausting exercise (fatigue) and their interactions (group by fatigue). Effect sizes were calculated as Cohen's d. Maximum reach distance in the star excursion balance test, jump stabilization time and sway velocity, but not joint position sense, were negatively affected by fatigue in all groups. Effect sizes were moderate, ranging from 0.27 to 0.68. No significant group by fatigue interactions were found except for one measure. Copers showed significantly larger prefatigue to postfatigue reductions in anterior reach direction (P≤0.001; d=-0.55) compared to the ankle instability (P=0.007) and control group (P=0.052). Fatiguing exercise negatively affected postural control but not proprioception. Ankle status did not appear to have an effect on fatigue-induced sensorimotor control impairments. 23757308 Absolute pitch may not be so absolute. Most people cannot name the musical note that corresponds to a particular pitch without being provided a reference note, but those people with absolute pitch (AP) can do this accurately. Early experience during a developmental period is often thought to convey identity and stability of the note categories in people with AP, but the plasticity of these categories has not been investigated. Here we provide the first evidence that the note categories of adults with AP can change with listening experience. Participants with AP showed shifts in perception in direct accord with prior exposure to music detuned by a fraction of a semitone. This suggests that the apparent stability of AP categories is conferred not by early experience but rather by the cultural norms adopted for tuning music. 23340650 Metabolic profiles of brain metastases. Metastasis to the brain is a feared complication of systemic cancer, associated with significant morbidity and poor prognosis. A better understanding of the tumor metabolism might help us meet the challenges in controlling brain metastases. The study aims to characterize the metabolic profile of brain metastases of different origin using high resolution magic angle spinning (HR-MAS) magnetic resonance spectroscopy (MRS) to correlate the metabolic profiles to clinical and pathological information. Biopsy samples of human brain metastases (n = 49) were investigated. A significant correlation between lipid signals and necrosis in brain metastases was observed (p < 0.01), irrespective of their primary origin. The principal component analysis (PCA) showed that brain metastases from malignant melanomas cluster together, while lung carcinomas were metabolically heterogeneous and overlap with other subtypes. Metastatic melanomas have higher amounts of glycerophosphocholine than other brain metastases. A significant correlation between microscopically visible lipid droplets estimated by Nile Red staining and MR visible lipid signals was observed in metastatic lung carcinomas (p = 0.01), indicating that the proton MR visible lipid signals arise from cytoplasmic lipid droplets. MRS-based metabolomic profiling is a useful tool for exploring the metabolic profiles of metastatic brain tumors. 23211868 Halting metastasis through CXCR4 inhibition. Metastasis occurs when cancer cells leave the primary tumor site and migrate to distant parts of the body. The CXCR4-SDF-1 pathway facilitates this migration, and its expression has become the hallmark of several metastatic cancers. Targeted approaches are currently being developed to inhibit this pathway, and several candidates are now in clinical trials. Continued exploration of CXCR4 inhibitors will generate compounds that have improved activity over current candidates. 23792159 Structural evidence for native state stabilization of a conformationally labile amyloidogenic transthyretin variant by fibrillogenesis inhibitors. Several classes of chemicals are able to bind to the thyroxine binding sites of transthyretin (TTR), stabilizing its native state and inhibiting in vitro the amyloidogenic process. The amyloidogenic I84S TTR variant undergoes a large conformational change at moderately acidic pH. Structural evidence has been obtained by X-ray analysis for the native state stabilization of I84S TTR by two chemically distinct fibrillogenesis inhibitors. In fact, they fully prevent the acidic pH-induced protein conformational change as a result of a long-range stabilizing effect. This study provides further support to the therapeutic strategy based on the use of TTR stabilizers as anti-amyloidogenic drugs. TTR and TTRbind by x-ray crystallography (View interaction). 23959963 Concussion Symptoms and Neurocognitive Performance of High School and College Athletes Who Incur Multiple Concussions. BACKGROUND:Multiple concussions have been associated with prolonged symptoms, recovery time, and risk for future concussions. However, very few studies have examined the effect of multiple concussions on neurocognitive performance and the recently revised symptom clusters using a large database. PURPOSE:To examine concussed athletes with a history of 0, 1, 2, or ≥3 concussions on neurocognitive performance and the recently revised symptom clusters. STUDY DESIGN:Cohort study (prognosis); Level of evidence, 2. METHODS:The independent variables were concussion group (0, 1, 2, and ≥3 concussions) and time (baseline, 3 days, and 8 days). The dependent variables were neurocognitive test scores as measured by the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) neurocognitive test battery (verbal and visual memory, processing speed, and reaction time) and 4 concussion symptom clusters (migraine-cognitive-fatigue, affective, somatic, and sleep). All concussed athletes (n = 596) were administered the ImPACT test at a mean 2.67 ± 1.98 and 7.95 ± 4.46 days after injury. A series of 4 (concussion group) × 3 (time) repeated-measures analyses of covariance (age = covariate) were performed on ImPACT composite scores and symptom clusters. RESULTS:Concussed athletes with ≥3 concussions were still impaired 8 days after a concussion compared with baseline scores on verbal memory (P < .001), reaction time (P < .001), and migraine-cognitive-fatigue symptoms (P < .001). There were no significant findings on the remaining dependent variables. CONCLUSION:Concussed athletes with a history of ≥3 concussions take longer to recover than athletes with 1 or no previous concussion. Future research should concentrate on validating the new symptom clusters on multiple concussed athletes, examining longer recovery times (ie, >8 days) among athletes with multiple concussions. 23936078 Effects of mild cold shock (25°c) followed by warming up at 37°c on the cellular stress response. Temperature variations in cells, tissues and organs may occur in a number of circumstances. We report here that reducing temperature of cells in culture to 25°C for 5 days followed by a rewarming to 37°C affects cell biology and induces a cellular stress response. Cell proliferation was almost arrested during mild hypothermia and not restored upon returning to 37°C. The expression of cold shock genes, CIRBP and RBM3, was increased at 25°C and returned to basal level upon rewarming while that of heat shock protein HSP70 was inversely regulated. An activation of pro-apoptotic pathways was evidenced by FACS analysis and increased Bax/Bcl2 and BclXS/L ratios. Concomitant increased expression of the autophagosome-associated protein LC3II and AKT phosphorylation suggested a simultaneous activation of autophagy and pro-survival pathways. However, a large proportion of cells were dying 24 hours after rewarming. The occurrence of DNA damage was evidenced by the increased phosphorylation of p53 and H2AX, a hallmark of DNA breaks. The latter process, as well as apoptosis, was strongly reduced by the radical oxygen species (ROS) scavenger, N-acetylcysteine, indicating a causal relationship between ROS, DNA damage and cell death during mild cold shock and rewarming. These data bring new insights into the potential deleterious effects of mild hypothermia and rewarming used in various research and therapeutical fields. 23279916 Peripartum cardiomyopathy in a previously asymptomatic carrier of duchenne muscular dystrophy. A 40 year-old woman presented to hospital with 12h of progressive shortness of breath. She was 11days postpartum, having delivered a full-term male infant. She was discharged on antibiotics for presumed pneumonia, but represented two days later with NYHA class IV symptoms and in acute decompensated heart failure confirmed on clinical examination and chest X-ray. Echocardiography showed a left ventricular ejection fraction (LVEF) of 20%. She was treated for peripartum cardiomyopathy (PPCM) with angiotensin converting enzyme inhibitors (ACEi), beta-blockers and diuretics with normalisation of her cardiac function within six months. Four years later, her son was diagnosed with Duchenne muscular dystrophy (DMD) and she tested positive as a carrier of the mutant gene. It is unclear whether the DMD carrier state alone is associated with increased susceptibility to PPCM or if this is merely the first expression of cardiomyopathy in a previously asymptomatic carrier. 23831669 Demonstration of a novel laser-driven light source for broadband spectroscopy between 170 nm and 2.1 μm. Combining broadband light sources with optical cavities is a well established approach to sensitive monitoring of trace species in both gas and liquid phases. Here we investigate for the first time the potential of a novel source based on laser-driven xenon plasma technology for spectroscopic studies of gaseous species over the 170-2100 nm spectral range. 23845042 Burrowing dragonfly larvae as biosentinels of methylmercury in freshwater food webs. We assessed the utility of larval burrowing dragonflies (Odonata: Anisoptera: Gomphidae) as biosentinels of methylmercury (MeHg) contamination. Gomphids were the most abundant family of dragonflies sampled during 2008-2010 from 17 lakes in four national parks of the northwestern Laurentian Great Lakes region. Ten species of burrowing gomphids were sampled; 13 lakes contained 3 or more species, and 2 species of Gomphus co-occurred in 12 lakes. Most of the total Hg (THg) in whole, late-instar larvae was MeHg, with mean percent MeHg exceeding 60% in 16 lakes. Mean MeHg in larvae of a given species varied greatly among lakes, ranging from 4 to 109 ng g(-1) dry weight. Methylmercury levels in larvae, however, were much less variable within a given lake and species. The mean concentration of MeHg in burrowing gomphids was positively correlated with mean MeHg concentration in unfiltered lake water. Mean concentrations of THg and MeHg in multispecies assemblages of Gomphus were also positively correlated with mean THg in coexisting prey fish and game fishes. We recommend-and provide guidance on-the application of burrowing gomphids as biosentinels of MeHg contamination, which can extend the bioassessment of MeHg to fishless fresh waters. 23609927 Does gender influence outcomes from a multidisciplinary intervention for quality of life designed for patients with advanced cancer? Cancer treatment can profoundly impact the patient's quality of life (QOL). It has been well documented that there are gender differences in the symptoms associated with cancer treatment. This study explores the impact of gender on QOL for patients with newly diagnosed advanced cancer. A randomized, controlled clinical trial in patients receiving radiotherapy for advanced cancer demonstrated maintenance of QOL with a six session multidisciplinary structured intervention compared to controls. This current study reports the gender differences in that trial. Outcome measures included the functional assessment of cancer therapy-general (FACT-G), linear analog self-assessment (LASA), and profile of mood states (POMS) at baseline and weeks 4, 27, and 52. Kruskal-Wallis was used to compare QOL scores. One hundred thirty-one patients (45 women and 86 men, mean age 58.7) participated in the clinical trial. At week 4 postintervention, women in the intervention group had statistically significant improvement in their FACT-G score, FACT-G physical well-being subscale, LASA fatigue, POMS total score, POMS fatigue-inertia subscale, and POMS confusion-bewilderment subscale (p < 0.05). Men receiving the intervention had a smaller decrease in FACT-G score compared to controls (p = 0.048) and also worsened on the LASA financial (p = 0.02). At week 27, the only gender difference was that intervention group men had more POMS anger-hostility (p = 0.009). By week 52, there were no statistically significant gender differences in any of the QOL measures. Gender-based differences appear to play a role in the early, but not late, response to a multidisciplinary intervention to improve QOL for patients with advanced cancer, suggesting that early interventions can be tailored for each gender. 23845504 Daptomycin: The role of high-dose and combination therapy for Gram-positive infections. Daptomycin, a cyclic lipopeptide with rapid bactericidal activity, is approved at doses of 4mg/kg and 6mg/kg for the treatment of its respective indications [i.e. complicated skin and soft-tissue infections (cSSTIs) caused by Gram-positive bacteria; and Staphylococcus aureus bacteraemia associated with right-sided infective endocarditis (RIE) or cSSTIs, or RIE due to S. aureus]. Higher doses and combination therapy strategies have been investigated in some difficult-to-treat infections in order to: enhance clinical success rates; treat pathogens that may be non-susceptible to standard doses; and minimise the risk of resistance development in patients, particularly those who may need an extended treatment duration, who may have had suboptimal surgical management and/or who may have not responded to prior antibiotic therapy. Although clinical trial data of daptomycin doses >6mg/kg and of daptomycin in combination with other antibiotics are limited, clinical experience reported to date suggests that daptomycin is effective and well tolerated at higher doses and in combination. In this review, the rationale both for high-dose and combination therapy strategies with daptomycin is explored and the available evidence is presented by indication and evaluated from a clinical perspective. Safety and efficacy are discussed from prospective and retrospective clinical studies, together with case reports for a variety of infections, including bacteraemia, endocarditis, cSSTIs and osteomyelitis, and expert recommendations are provided in summary of the evidence. The use of high-dose daptomycin, alone or in combination, may be useful for difficult-to-treat Gram-positive infections and further evaluation of these strategies is warranted. 23265875 Design and synthesis of tricyclic cores for kinase inhibition. Interest in therapeutic kinase inhibitors continues to grow beyond success in oncology. To date, ATP-mimetic kinase inhibitors have focused primarily on monocyclic and bicyclic heterocyclic cores. We sought to expand on the repertoire of potential cores for kinase inhibition by exploring tricyclic variants of classical bicyclic hinge binding motifs such as pyrrolopyridine and pyrrolopyrazine. Herein we describe the syntheses of eight alternative tricyclic cores as well as in vitro screening results for representative kinases of potential therapeutic interest. 23741968 Thyrotropin receptor autoantibodies and early miscarriages in patients with Hashimoto thyroiditis: a case-control study. We have previously hypothesized that early miscarriage in women with Hashimoto thyroiditis might be the result of a cross-reactivity process, in which blocking autoantibodies against thyrotropin receptor (TSHr-Ab) antagonize hCG action on its receptor on the corpus luteum. To test this hypothesis from the clinical perspective, we investigated the presence of TSHr-Ab in Hashimoto thyroiditis patients with apparently unexplained, first-trimester recurrent miscarriages compared to that in Hashimoto thyroiditis patients with documented normal fertility. A total of 86 subjects (43 cases and 43 age-matched controls) were finally included in a case-control study. No difference in the prevalence of TSHr-Ab positivity was detected between cases and controls (Fisher's exact test, p value = 1.00). In patients with recurrent miscarriages, TSHr-Ab concentrations did not predict the number of miscarriages (univariate linear regression, p value = 0.08). These results were robust in sensitivity analyses, including only cases with full investigation or those with three or more miscarriages. We conclude that no role could be advocated for TSHr-Ab in the aetiology of recurrent miscarriages in women with Hashimoto thyroiditis. 23934180 Motivational interviewing with primary care populations: a systematic review and meta-analysis. This meta-analysis synthesized the findings from randomized controlled trials (RCTs) of motivational interviewing (MI) for health behavior outcomes within primary care populations. Published and unpublished RCTs were identified using databases and online listservs. Studies were synthesized by outcome subgroup and meta-regression analyses were conducted to determine potential moderators accounting for heterogeneity within samples. Mean effect sizes ranged from .07 to .47; significant effect sizes were found for the adherence subgroup of studies (p = .04) and all outcomes combined (p = .02). Professional credentials of intervention deliverer were found to significantly moderate the association between MI and effect size in substance use subgroup (p = .0005) and all outcomes combined (p = .004). Mean effect sizes were largest in outcomes related to weight loss, blood pressure, and substance use. MI appears to be useful in clinical settings and as few as 1 MI session may be effective in enhancing readiness to change and action directed towards reaching health behavior-change goals. 23379829 Safety of cupping during bevacizumab therapy. Abstract Objectives: This study reports on the safety of the complementary and alternative medicine (CAM) practice of cupping in a patient undergoing concomitant therapy with bevacizumab for advanced non-small-cell lung cancer (NSCLC), and raises awareness of the need for improved communication between CAM practitioners and oncologists during the care of patients with cancer. The practice of cupping generates local hyperemia, disrupts superficial vasculature in the dermis, and leads to cutaneous lesions including circular erythema, edema, and subsequently ecchymosis. There are no data on the safety of cupping in patients being treated with bevacizumab. Design: This is a single-institution case report. Settings/location: The setting for this study was a tertiary-care academic medical center. Conclusions: A patient with advanced NSCLC received four cycles of carboplatin AUC 6, paclitaxel 200 mg/m(2), and bevacizumab 15 mg/kg, and was continued on every-3-week maintenance bevacizumab 15 mg/kg. The patient underwent glass dry cupping during cycle six of maintenance bevacizumab treatment without overt cutaneous adverse events or bleeding. The patient did not realize he should have communicated his cupping plans or recent bevacizumab treatment with his providers. 23657527 Proteolytic processing of the Yersinia pestis YapG autotransporter by the omptin protease Pla and the contribution of YapG to murine plague pathogenesis. Autotransporter protein secretion represents one of the simplest forms of secretion across Gram-negative bacterial membranes. Once secreted, autotransporter proteins either remain tethered to the bacterial surface or are released following proteolytic cleavage. Autotransporters possess a diverse array of virulence-associated functions such as motility, cytotoxicity, adherence and autoaggregation. To better understand the role of autotransporters in disease, our research focused on the autotransporters of Yersinia pestis, the aetiological agent of plague. Y. pestis strain CO92 has nine functional conventional autotransporters, referred to as Yaps for Yersinia autotransporter proteins. Three Yaps have been directly implicated in virulence using established mouse models of plague infection (YapE, YapJ and YapK). Whilst previous studies from our laboratory have shown that most of the CO92 Yaps are cell associated, YapE and YapG are processed and released by the omptin protease Pla. In this study, we identified the Pla cleavage sites in YapG that result in many released forms of YapG in Y. pestis, but not in the evolutionarily related gastrointestinal pathogen, Yersinia pseudotuberculosis, which lacks Pla. Furthermore, we showed that YapG does not contribute to Y. pestis virulence in established mouse models of bubonic and pneumonic infection. As Y. pestis has a complex life cycle involving a wide range of mammalian hosts and a flea vector for transmission, it remains to be elucidated whether YapG has a measurable role in any other stage of plague disease. 23708708 The effect of familiarity of conversation partners on conversation turns contributed by augmented and typical speakers. The purpose of this current research was to determine the effect of familiarity of conversation partners on contributed conversation turns to dyadic conversation between individuals who use AAC and typically speaking conversation partners. Three groups (G1-G3) participated in this study. Each group contained seven participants, including an individual who used a speech-generating device (SGD) and familiar and unfamiliar conversation partners. Each 20-min dyadic conversation was video-recorded for analysis of contributed conversation turns. The findings of the current study showed that the asymmetries of contributed conversation turns exist in both familiar and unfamiliar dyadic conversation between AAC users and typically speaking conversation partners. In addition, the asymmetry in the familiar dyadic conversation did not differ from that in the unfamiliar dyadic conversation. 23857366 FCRL3 promotes TLR9-induced B-cell activation and suppresses plasma cell differentiation. Fc receptor-like (FCRL) molecules are preferentially expressed by B lymphocytes and possess tyrosine-based immunoregulatory function. Although they generally inhibit B-cell receptor signaling, their influence on other activation pathways remains largely unexplored. In humans, FCRL3 encodes a type I transmembrane protein harboring both cytoplasmic ITAM and ITIM elements that can repress B-cell receptor activation. Despite this inhibitory property, mounting associations for FCRL3 with autoimmune and lympho-proliferative disorders imply a role for it in promoting B-cell pathogenesis. Here, we explore the influence of FCRL3 on B-cell responses to innate TLR9 stimulation. A detailed survey of blood B-cell populations found that FCRL3 expression increased as a function of differentiation and was higher among memory subsets with innate-like features. FCRL3 ligation augmented CpG oligodeoxynucleotide TLR9-mediated B-cell proliferation, activation, and survival, but surprisingly, abrogated plasma cell differentiation and antibody production. Although FCRL3 amplified the NF-κB and mitogen-activated protein kinase signaling cascades, it halted CpG triggered BLIMP1 induction in an ERK-dependent fashion. These findings indicate that FCRL3 differentially modulates innate signaling in B cells and provide new insight into the potential of this disease-associated receptor to counter-regulate adaptive and innate immunity. 23444125 Foreign body giant cells and osteoclasts are TRAP positive, have podosome-belts and both require OC-STAMP for cell fusion. Macrophages have the ability to fuse and form multinucleated giant cells such as Osteoclast (OCs) and FBGCs. Osteoclast stimulatory transmembrane protein (OC-STAMP) is an important cell surface protein involved in the formation of OCs. This study sought to determine if OC-STAMP also regulates formation of FBGCs using expression analysis and subsequent inhibition studies. qPCR and Western blot analysis showed that OC-STAMP expression is significantly higher in FBGCs compared to control monocytes (P < 0.05). Four days following cell culture, OCs were positive for TRAP and F-actin ring formation, but FBGCs were not. In contrast, FBGCs were positive for TRAP and showed podosome belts comprised of F-actin on Day 8. FBGCs were subsequently plated onto dentine, but despite presenting some morphologic features of OCs (OC-STAMP expression, TRAP reactivity, and podosome belts) they failed to resorb bone. To evaluate a role for OC-STAMP in FBGCs, we inhibited this cell surface protein with anti-OC-STAMP antibody and observed that cell fusion and podosome belt formation was inhibited in both OCs and FBGCs. Our data support the hypothesis that OC-STAMP is a regulatory molecule for FBGCs; and that they are functionally distinct from OCs, despite similarities in gene expression profile, podosome belt formation, and TRAP expression. 23134598 Long-term outcomes of a new model of anatomical hydroxyapatite-coated hip prosthesis. This prospective study was designed to evaluate 196 Anatomique Benoist Giraud (ABG II) total hip arthroplasties which were implanted between September 1999 and December 2000. A minimum 11 years follow up was completed in 183 cases. The bearing surfaces were polyethylene-zirconia in 84 cases, polyethylene-metal in 42 and ceramic-ceramic in 57. Changes in the femoral stem design, in relation to the previous ABG I model, have led to a significant improvement in stress-shielding. Polyethylene wear rate was lower by more than 50% compared with non-crosslinked polyethylene. Excellent and good results were obtained in 90.32% of cases, and implant survival was 98.39% at the end of follow-up. 23824041 Low-cost fabrication of centimetre-scale periodic arrays of single plasmid DNA molecules. We report the development of a low-cost method to generate a centimetre-scale periodic array of single plasmid DNA molecules of 11 kilobase pairs. The arrayed DNA molecules are amenable to enzymatic and physical manipulations. 23875623 Combining Naltrexone and Prazosin in a Single Oral Medication Decreases Alcohol Drinking More Effectively Than Does Either Drug Alone. Naltrexone (NTX) is underutilized in clinical treatment settings because its efficacy is modest, and it is not effective for all alcoholics and, when it is effective, a significant number of alcoholics fail to maintain initial treatment gains and subsequently relapse to heavy drinking. This has slowed acceptance of NTX by the treatment community, and there is a clear need for additional treatments for alcoholism and alcohol use disorders. Given that NTX and prazosin can each reduce alcohol drinking in rats selectively bred for alcohol preference and high voluntary alcohol drinking (alcohol-preferring "P" rats), we tested whether a combination of NTX + prazosin is more effective in decreasing alcohol drinking than is either drug alone. P rats were given access to a 15% (v/v) alcohol solution for 2 hours daily. Rats were fed NTX and prazosin, alone or in combination, prior to onset of the daily 2-hour alcohol access period for 4 weeks and the effect of drug treatment on alcohol and water intake was assessed. During the first week of treatment, neither a low dose of NTX, nor prazosin, was effective in decreasing alcohol intake when each drug was administered alone, but combining the 2 drugs in a single medication significantly reduced alcohol intake. The combination was as effective as was a higher dose of NTX. Using a low dose of NTX in combination with prazosin may reduce the potential for undesirable side effects early in treatment which, in turn, may improve patient compliance and result in a more successful outcome when NTX is used for treating alcoholism and alcohol use disorders. Combining low-dose NTX and prazosin in a single medication may be more useful than is either drug alone for treating both inpatient and outpatient alcoholics and heavy drinkers early in the treatment process. 23966680 Effects of cerebellar lesions on working memory interacting with motor tasks of different complexities. We examined the influence of focal cerebellar lesions on working memory (n-back task), gait and on the interaction between working memory and different gait tasks in a dual-task paradigm. The analysis included 17 young patients with chronic focal lesions after cerebellar tumor resection and 17 age-matched controls. Patients have shown mild to moderate ataxia. Lesion sites were examined based on structural magnetic resonance imaging. N-back tasks were executed with different levels of difficulty (n=1-4) during sitting (baseline), treadmill walking and treadmill tandem walking (dual-task conditions). Patients exhibited decreased n-back performance particularly at difficult n-back levels and in dual-task conditions. Voxel-based lesion-symptom mapping revealed that decreased baseline n-back performance was associated with lesions of the posterolateral cerebellar hemisphere and the dentate nucleus. By contrast, decreased n-back performance in dual-task conditions was more associated with motor-related areas including dorsal portions of the dentate and the interposed nucleus suggesting a prioritization of the motor task. During baseline walking, increased gait variability was associated with lesions in medial and intermediate regions, whereas for baseline tandem gait lesions in the posterolateral hemispheres and the dentate nucleus became important. Posterolateral regions overlapped with regions related to baseline n-back performance. Consistently, we observed increased tandem gait variability with growing n-back difficulty in the dual task condition. These findings suggest that dual-task effects in cerebellar patients are at least partially caused by a common involvement of posterolateral cerebellar regions in working memory and complex motor tasks. 23554006 Role of melatonin receptor MT2 and quinone reductase II in the regulation of the redox status of 3T3-L1 preadipocytes in vitro. We have examined the role of melatonin receptor MT2 and quinone reductase II in the regulation of the redox status of preadipocytes (3T3-L1) in vitro. 3T3-L1 cells were treated with melatonin at a physiological concentration (10(-9)  mol/L) and a supraphysiological (pharmacological) concentration (10(-3)  mol/L) for 24 h. Luzindole (10(-4)  mol/L), an antagonist of MT2 receptor, and prazosin (10(-5)  mol/L), an inhibitor of quinone reductase II, were added 30 min before subsequent exposure of the cells to melatonin. The level of oxidative stress was determined by the analysis of activities of enzymes neutralising reactive oxygen species, and determination of the malondialdehyde (MDA) content. Melatonin increased activities of manganese and copper-zinc superoxide dismutase (MnSOD, Cu/ZnSOD) and catalase (CAT) at both a physiological concentration (10(-9)  mol/L) and a pharmacological concentration (10(-3)  mol/L). MDA content was unchanged, whereas activities of glutathione peroxidase (GSH-Px) and glutathione reductase (GSSG-Rd) were increased only by the physiological concentration. Both effects were partially inhibited by luzindole, but not prazosin. These observations suggest that melatonin, acting at least partially via MT2 receptors, can increase antioxidant enzymes activities in 3T3-L1 preadipocytes. 23829619 Genetically modified T lymphocytes: more than just direct effectors. Evaluation of: Russo V, Pilla L, Lunghi F et al. Clinical and immunologic responses in melanoma patients vaccinated with MAGE-A3-genetically modified lymphocytes. Int. J. Cancer 132(11), 2557-2566 (2012). When one mentions T lymphocytes, one easily recognizes the effective and antigen-specific manner by which T lymphocytes execute cellular immune responses towards pathogen-infected or cancerous cells. Russo and coworkers recognized the other side of the coin and exploited the potency of T cells to act as a cellular vaccine, to which end they used T cells transduced with the cancer-testis antigen MAGE-A3. Twenty-three patients with MAGE-A3-expressing melanoma were treated and six patients developed MAGE-A3-specific immune responses and showed clinical benefit, whereas patients without a MAGE-A3-specific immune response did not show clinical benefit. This report includes and extends on results from a pilot study including ten patients, of which three developed MAGE-A3-specific immune responses. The present study further explores a potential beneficial application of the observed immunogenicity of genetically modified T cells. 23923057 Learning of multi-modal stimuli in hawkmoths. The hawkmoth, Manduca sexta, uses both colour and odour to find flowers when foraging for nectar. In the present study we investigated how vision and olfaction interact during learning. Manduca sexta were equally attracted to a scented blue coloured feeding target (multimodal stimulus) as to one that does not carry any scent (unimodal stimulus; visual) or to an invisible scented target (unimodal stimulus; odour). This naive attraction to multimodal as well as to unimodal stimuli could be manipulated through training. Moths trained to feed from a blue, scented multimodal feeding target will, when tested in a set-up containing all three feeding targets, select the multimodal target as well as the scented, unimodal target, but ignore the visual target. Interestingly, moths trained to feed from a blue, unimodal visual feeding target will select the visual target as well as the scented, multimodal target, but ignore the unimodal odour target. Our results indicate that a multimodal target is perceived as two separate modalities, colour and odour, rather than as a unique fused target. These findings differ from earlier studies of desert ants that perceive combined visual and odour signals as a unique fused stimulus following learning trials. 23918985 Soluble CD80 Restores T Cell Activation and Overcomes Tumor Cell Programmed Death Ligand 1-Mediated Immune Suppression. Many tumor cells escape anti-tumor immunity through their expression of programmed death ligand-1 (PDL1 or B7-H1), which interacts with T cell-expressed PD1 and results in T cell apoptosis. We previously reported that transfection of human tumor cells with a membrane-bound form of the human costimulatory molecule CD80 prevented PD1 binding and restored T cell activation. We now report that a membrane-bound form of murine CD80 similarly reduces PDL1-PD1-mediated suppression by mouse tumor cells and that a soluble protein consisting of the extracellular domains of human or mouse CD80 fused to the Fc domain of IgG1 (CD80-Fc) overcomes PDL1-mediated suppression by human and mouse tumor cells, respectively. T cell activation experiments with human and mouse tumor cells indicate that CD80-Fc facilitates T cell activation by binding to PDL1 to inhibit PDL1-PD1 interactions and by costimulating through CD28. CD80-Fc is more effective in preventing PD1-PDL1-mediated suppression and restoring T cell activation compared with treatment with mAb to either PD1 or PDL1. These studies identify CD80-Fc as an alternative and potentially more efficacious therapeutic agent for overcoming PDL1-induced immune suppression and facilitating tumor-specific immunity. 23391716 Cytosine deaminase-expressing human neural stem cells inhibit tumor growth in prostate cancer-bearing mice. Prostate cancer is the most common malignancy among men. Prostate cancer-related deaths are largely attributable to the development of hormone resistance in the tumor. No effective chemotherapy has yet been developed for advanced prostate cancer. It is desirable if a drug can be delivered directly and specifically to prostate cancer cells. Stem cells have selective migration ability toward cancer cells and therapeutic genes can be easily transduced into stem cells. In one form of gene therapy for cancer, the stem cells carry a gene encoding an enzyme that transforms an inert prodrug into a toxic product. Cytosine deaminase (CD) transforms the pro-drug 5-fluorocytosine into highly cytotoxic 5-fluorouracil (5-FU). The migration of the genetically modified stem cells was monitored by molecular magnetic resonance imaging, after labeling the stem cells with fluorescent magnetic nanoparticles (MNPs). Human neural stem cells encoding CD (HB1.F3.CD) were prepared and labeled with MNP. In tumor-bearing C57B mice, systemically transplanted HB1.F3.CD stem cells migrated toward the tumor and in combination with prodrug 5-FC, the volume of tumor implant was significantly reduced. These findings may contribute to development of a new selective chemotherapeutic strategy against prostate cancer. 23913929 Chronic Kidney Disease Defined by Cystatin C Predicts Mobility Disability and Changes in Gait Speed: The Framingham Offspring Study. As creatinine-based estimates of renal function are inaccurate in older adults, an alternative is an estimated glomerular filtration rate (eGFRcys) based on cystatin C. We examined the prospective association between chronic kidney disease (CKDcys) as determined by eGFRcys with the primary outcome of incident mobility disability and the secondary outcome of change in gait speed. Framingham Offspring Study participants older than 60 years and free of mobility disability at baseline (1998-2001) were eligible. Baseline CKDcys was defined as eGFRcys less than 60 mL/min/1.73 m(2). At follow-up (2005-2008), the outcomes of mobility disability, defined as self-reported inability to walk 1/2 mile and/or climb a flight of stairs, and gait speed were measured. Logistic and linear regression models were adjusted for age, sex, body mass index, smoking, diabetes, C reactive protein, and physical activity. Of 1,226 participants, 230 (19%) had CKDcys at baseline. After a mean follow-up of 6.6 years, 185 (15%) developed mobility disability. Of those with CKDcys, 60 (26%) developed mobility disability. Those with CKDcys had greater odds of mobility disability in the age- and sex-adjusted (odds ratio [OR] 1.91, 95% CI 1.32, 2.75) and fully adjusted (OR 1.55, 95% CI 1.05, 2.31) models compared with those without CKDcys. In fully adjusted models, participants with CKDcys had greater gait speed declines than those without CKDcys (β = 0.07 [SE 0.02], p = .0022). CKDcys was associated with higher odds of incident mobility disability and greater decline in gait speed, highlighting the loss of physical independence in elders with CKD. 23953135 On sitting and doing: Ethnography as action in global health. Contemporary discussions within the arenas of medical anthropology and global health are often restricted by the driving imperatives to "do something" about a particular health problem. Drawing on ethnographic fieldwork conducted in Nepal in 1997, which sought to follow the translation of AIDS prevention policies into local awareness, this paper addresses the need to revitalize theories of ethnography for an understanding of global health goals. The Nepal example underscores how the path toward decisions is never entirely clear, nor is it always obvious who benefits or loses from different approaches, even as public health discourse seeks to set a strict agenda around what the problem is and what should be done about it. Ethnography shows that definitions of what matters as well as understandings of why certain things matter are formulated from specific social locations. The paper therefore advocates for a practice of patient ethnographic "sitting" as a means to understanding, as a form of critical reflexivity, and as a diagnostic of the politics of relevance. 23812985 Minimum curvilinearity to enhance topological prediction of protein interactions by network embedding. Most functions within the cell emerge thanks to protein-protein interactions (PPIs), yet experimental determination of PPIs is both expensive and time-consuming. PPI networks present significant levels of noise and incompleteness. Predicting interactions using only PPI-network topology (topological prediction) is difficult but essential when prior biological knowledge is absent or unreliable. Network embedding emphasizes the relations between network proteins embedded in a low-dimensional space, in which protein pairs that are closer to each other represent good candidate interactions. To achieve network denoising, which boosts prediction performance, we first applied minimum curvilinear embedding (MCE), and then adopted shortest path (SP) in the reduced space to assign likelihood scores to candidate interactions. Furthermore, we introduce (i) a new valid variation of MCE, named non-centred MCE (ncMCE); (ii) two automatic strategies for selecting the appropriate embedding dimension; and (iii) two new randomized procedures for evaluating predictions. We compared our method against several unsupervised and supervisedly tuned embedding approaches and node neighbourhood techniques. Despite its computational simplicity, ncMCE-SP was the overall leader, outperforming the current methods in topological link prediction. Conclusion: Minimum curvilinearity is a valuable non-linear framework that we successfully applied to the embedding of protein networks for the unsupervised prediction of novel PPIs. The rationale for our approach is that biological and evolutionary information is imprinted in the non-linear patterns hidden behind the protein network topology, and can be exploited for predicting new protein links. The predicted PPIs represent good candidates for testing in high-throughput experiments or for exploitation in systems biology tools such as those used for network-based inference and prediction of disease-related functional modules. https://sites.google.com/site/carlovittoriocannistraci/home. Supplementary data are available at Bioinformatics online. 23643872 A complementary LC-ESI-MS and MALDI-TOF approach for screening antibacterial proteomic signature of farmed European Sea bass mucus. Antibacterial protection in the mucus is provided by antimicrobial compounds and till now few numbers of AMP and proteins were identified. Herein, mass spectral profiling of fresh mucus from farmed sea bass (Dicentrarchus labrax) using Matrix-assisted laser desorption/ionization-time-of-flight mass spectrometer (MALDI-TOF) and liquid chromatography mass spectrometry is investigated in order to survey the infective/healthy status of the mucus. We identify AMP peptides of 2891.7, 2919.45 and 2286.6 Da molecular weight respectively and characterize Chrysophsins in the mucus of Dicentrarchus labrax. These peptides display broad-spectrum bactericidal activity against Gram-negative (Minimum Inhibitory Concentrations namely MICs < 0.5 μM) and Gram-positive bacteria (MICs < 0.5 μM) including Escherichia coli and Bacillus subtilis. Furthermore, sensitivity to yeast Candida albicans is reported for the first time and shows interesting MICs of less than 2 μM. We also demonstrate that the fish pathogen Aeromonas salmonoicida is sensitive to Chrysophsins (MICs ranging between 5 and 14 μM). Our mucus molecular mass mapping developed approach allows for fast exploration of immune status. Our data provides evidence that Chrysophsins are secreted by immune cells and are released in mucus of non-challenged farmed European sea bass. These results suggest that Chrysophsins, secreted by gills of red sea bream, are an important widespread component of Teleostei defense against disease. 23600476 Three-dimensional plasmonic chiral tetramers assembled by DNA origami. Molecular chemistry offers a unique toolkit to draw inspiration for the design of artificial metamolecules. For a long time, optical circular dichroism has been exclusively the terrain of natural chiral molecules, which exhibit optical activity mainly in the UV spectral range, thus greatly hindering their significance for a broad range of applications. Here we demonstrate that circular dichroism can be generated with artificial plasmonic chiral nanostructures composed of the minimum number of spherical gold nanoparticles required for three-dimensional (3D) chirality. We utilize a rigid addressable DNA origami template to precisely organize four nominally identical gold nanoparticles into a three-dimensional asymmetric tetramer. Because of the chiral structural symmetry and the strong plasmonic resonant coupling between the gold nanoparticles, the 3D plasmonic assemblies undergo different interactions with left and right circularly polarized light, leading to pronounced circular dichroism. Our experimental results agree well with theoretical predictions. The simplicity of our structure geometry and, most importantly, the concept of resorting on biology to produce artificial photonic functionalities open a new pathway to designing smart artificial plasmonic nanostructures for large-scale production of optically active metamaterials. 23447657 Assessment of the global trigger tool to measure, monitor and evaluate patient safety in cancer patients: reliability concerns are raised. Countries around the world are currently aiming to improve patient safety by means of the Institute for Healthcare Improvement global trigger tool (GTT), which is considered a valid tool for evaluating and measuring patient safety within organisations. So far, only few data on the measurement properties and utility of the GTT have been published. To determine and evaluate the effect of interrater variation between review teams on the standard outcome measures of the GTT and to assess and quantify measurement error of the GTT. Retrospective chart reviews were conducted on identical charts by two independent review teams in 2010 at a department of oncology in a university hospital. Standard GTT outcome measurements were obtained and compared between teams using statistical process control (SPC) charts. A Bland-Altman plot assessed measurement error and limits of agreement. Only 31% of adverse events (AE) were identified by both teams, and further differences in categorisation of identical events was found. Moderate interrater agreement (κ=0.45) between teams gave rise to different conclusions on the patient safety process when monitoring using SPC charts. The Bland-Altman plot suggests little systematic error but large random error. Review teams may identify different AE and reach different conclusions on the safety process when using the GTT on identical charts. Tracking true change in the safety level is difficult due to measurement error of the GTT. The results do not encourage further use of the GTT until additional evaluation studies on the measurement properties of the GTT have been conducted. 23868511 Impairments of cells and genomic DNA by environmentally transformed engineered nanomaterials. Enormous increase in the production of nanomaterials and their growing applications in the device technology, biotechnology and biomedical areas suggest the need for developing models for predicting the environmental health and safety (EHS) risks posed by such nanomaterials. We hypothesize that CdSe quantum dots (QDs) and ZnO nanoparticles (NPs) encompassed in liposomes or not and transformed by simulated solar UV light can be model systems for studying the environmental toxicity of engineered nanomaterials. In this study, human lung epithelial adenocarcinoma cells (H1650) are exposed to photoirradiated CdSe QDs or ZnO nanopowder included or not in liposomes. The release of cadmium and zinc ions from the nanomaterials exposed to solar simulated UV radiation is detected and quantified by measuring the steady-state and time resolved fluorescence of the metal ion sensor tetracarboxyphenylporphyrin (TCPP) or the commercial Measure iT Pd/Cd sensor. Viability of cells treated with nanomaterials exposed to solar simulated UV radiation for different durations is measured by MTT assay. Enhanced etching of the nanoparticles exposed to solar simulated UV radiation results in the release of toxic levels of heavy metal ions, which considerably lower the viability of H1650 cells is due to the deactivation of DNA repair enzymes as evidenced by the pinching off of nuclear DNA in comet assays and DNA samples in electrophoresis. Results from this study highlight the need to obtain not only quantitative information about the environmental risks posed by engineered nanomaterials but also environment friendly nanomaterials for practical applications. 23937349 Integrative Mechanisms of Oriented Neuronal Migration in the Developing Brain. The emergence of functional neuronal connectivity in the developing cerebral cortex depends on neuronal migration. This process enables appropriate positioning of neurons and the emergence of neuronal identity so that the correct patterns of functional synaptic connectivity between the right types and numbers of neurons can emerge. Delineating the complexities of neuronal migration is critical to our understanding of normal cerebral cortical formation and neurodevelopmental disorders resulting from neuronal migration defects. For the most part, the integrated cell biological basis of the complex behavior of oriented neuronal migration within the developing mammalian cerebral cortex remains an enigma. This review aims to analyze the integrative mechanisms that enable neurons to sense environmental guidance cues and translate them into oriented patterns of migration toward defined areas of the cerebral cortex. We discuss how signals emanating from different domains of neurons get integrated to control distinct aspects of migratory behavior and how different types of cortical neurons coordinate their migratory activities within the developing cerebral cortex to produce functionally critical laminar organization. Expected final online publication date for the Annual Review of Cell and Developmental Biology Volume 29 is October 06, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates. 23807622 DNA interaction of Cu(II), Ni(II) and Zn(II) functionalized salphen complexes: studies by linear dichroism, gel electrophoresis and PCR. The interaction of salphen-type Ni(II), Cu(II) and Zn(II) complexes with native DNA was investigated by exploiting linear dichroism experiments. The Ni(II) complex behaves as a typical intercalator, binding strongly and stiffening and unwinding the DNA. The strength of the DNA interaction is slightly weaker for the copper complex and much weaker for the zinc complex. Plasmid-DNA gel electrophoresis experiments indicated that while Cu(II) and Zn(II) complexes do not induce the unwinding of supercoiled DNA, the Ni(II) complex has a nuclease activity without the addition of external agents. On the other hand, as shown in the PCR assays, we demonstrate that, at the used concentrations, only the Cu(II) complex is able to inhibit the DNA amplification mediated by Taq DNA polymerase. In this paper we have also reported a detailed characterization of the three compounds including 2D-NMR and ESI-mass experiments and X-ray single crystal structure of the copper and nickel compounds. 23936480 Separating drought effects from roof artifacts on ecosystem processes in a grassland drought experiment. 1: Given the predictions of increased drought probabilities under various climate change scenarios, there have been numerous experimental field studies simulating drought using transparent roofs in different ecosystems and regions. Such roofs may, however, have unknown side effects, called artifacts, on the measured variables potentially confounding the experimental results. A roofed control allows the quantification of potential artifacts, which is lacking in most experiments. 2: We conducted a drought experiment in experimental grasslands to study artifacts of transparent roofs and the resulting effects of artifacts on ecosystems relative to drought on three response variables (aboveground biomass, litter decomposition and plant metabolite profiles). We established three drought treatments, using (1) transparent roofs to exclude rainfall, (2) an unroofed control treatment receiving natural rainfall and (3) a roofed control, nested in the drought treatment but with rain water reapplied according to ambient conditions. 3: Roofs had a slight impact on air (+0.14°C during night) and soil temperatures (-0.45°C on warm days, +0.25°C on cold nights), while photosynthetically active radiation was decreased significantly (-16%). Aboveground plant community biomass was reduced in the drought treatment (-41%), but there was no significant difference between the roofed and unroofed control, i.e., there were no measurable roof artifact effects. 4: Compared to the unroofed control, litter decomposition was decreased significantly both in the drought treatment (-26%) and in the roofed control treatment (-18%), suggesting artifact effects of the transparent roofs. Moreover, aboveground metabolite profiles in the model plant species Medicago x varia were different from the unroofed control in both the drought and roofed control treatments, and roof artifact effects were of comparable magnitude as drought effects. 5: Our results stress the need for roofed control treatments when using transparent roofs for studying drought effects, because roofs can cause significant side effects. 23773959 Early childhood predictors of early onset of smoking: A birth prospective study. Early onset of smoking is associated with subsequent abuse of other substances and development of negative health outcomes. This study aimed to examine early life predictors of onset of smoking in an Australian young cohort. Data were from the Mater Hospital and University of Queensland Study of Pregnancy (MUSP), a population-based prospective birth cohort study (1981-2012). The present study is based on a cohort of 3714 young adults who self-reported smoking status and age of onset of smoking at the 21-year follow-up. Of these, data were available for 3039 on early childhood factors collected between the baseline and 14-year follow-up of the study. Of 3714 young adults, 49.6% (49.9% males and 49.3% females) reported having ever smoked cigarettes. For those who had ever smoked, mean and median ages at first smoke were 15.5 and 16.0years, respectively. In multivariate Cox proportional hazard analysis mother's education, change in maternal marital status, maternal cigarette smoking and alcohol consumption, maternal depression and child externalizing when the child was 5years statistically significantly predicted early onset of smoking. The data suggest that individuals exposed to personal and environmental risk factors during the early stage of childhood are at increased risk of initiation to cigarette smoking at an earlier age. Identification of the pathways of association between these early life factors and initiation to cigarette smoking may help reduce risk of tobacco smoking in adolescents and its adverse consequences. 23921678 Adolescent Dosing and Labeling Since the Food and Drug Administration Amendments Act of 2007. IMPORTANCE During pediatric drug development, dedicated pharmacokinetic studies are generally performed in all relevant age groups to support dose selection for subsequent efficacy trials. To our knowledge, no previous assessments regarding the need for an intensive pharmacokinetic study in adolescents have been performed. OBJECTIVES To compare US Food and Drug Administration (FDA)-approved adult and adolescent drug dosing and to assess the utility of allometric scaling for the prediction of drug clearance in the adolescent population. DESIGN Adult and adolescent dosing and drug clearance data were obtained from FDA-approved drug labels and publicly available databases containing reviews of pediatric trials submitted to the FDA. Dosing information was compared for products with concordant indications for adolescent and adult patients. Adolescent drug clearance was predicted from adult pharmacokinetic data by using allometric scaling and compared with observed values. MAIN OUTCOMES AND MEASURES Adolescent and adult dosing information and drug clearance. RESULTS There were 126 unique products with pediatric studies submitted to the FDA since the FDA Amendments Act of 2007, of which 92 had at least 1 adolescent indication concordant with an adult indication. Of these 92 products, 87 (94.5%) have equivalent dosing for adults and adolescent patients. For 18 of these 92 products, a minimum weight or body surface area threshold is recommended for adolescents to receive adult dosing. Allometric scaling predicted adolescent drug clearance with an overall mean absolute percentage error of 17.0%. CONCLUSIONS AND RELEVANCE Approved adult and adolescent drug dosing is equivalent for 94.5% of products with an adolescent indication studied since the FDA Amendments Act of 2007. Allometric scaling may be a useful tool to avoid unnecessary dedicated pharmacokinetic studies in the adolescent population during pediatric drug development, although each development program in adolescents requires a full discussion of drug dosing with the FDA. 23321616 Rapid degradation of an active formylglycine generating enzyme variant leads to a late infantile severe form of multiple sulfatase deficiency. Multiple sulfatase deficiency (MSD) is a rare inborn error of metabolism affecting posttranslational activation of sulfatases by the formylglycine generating enzyme (FGE). Due to mutations in the encoding SUMF1 gene, FGE's catalytic capacity is impaired resulting in reduced cellular sulfatase activities. Both, FGE protein stability and residual activity determine disease severity and have previously been correlated with the clinical MSD phenotype. Here, we report a patient with a late infantile severe course of disease. The patient is compound heterozygous for two so far undescribed SUMF1 mutations, c.156delC (p.C52fsX57) and c.390A>T (p.E130D). In patient fibroblasts, mRNA of the frameshift allele is undetectable. In contrast, the allele encoding FGE-E130D is expressed. FGE-E130D correctly localizes to the endoplasmic reticulum and has a very high residual molecular activity in vitro (55% of wildtype FGE); however, it is rapidly degraded. Thus, despite substantial residual enzyme activity, protein instability determines disease severity, which highlights that potential MSD treatment approaches should target protein folding and stabilization mechanisms. 23746756 Antinociceptive effects of oxymatrine from Sophora flavescens, through regulation of NR2B-containing NMDA receptor-ERK/CREB signaling in a mice model of neuropathic pain. In this study we investigated antinociceptive effects of oxymatrine through regulation of NR2B-containing NMDA receptor-ERK/CREB signaling in a chronic neuropathic pain model induced by chronic constrictive injury (CCI) of the sciatic nerve. The von Frey and plantar tests were performed to assess the degree of mechanical and thermal changes respectively. Immunohistochemistry assay was used to evaluate the expressions of NR2B. Western blotting assay were used to evaluate the expressions of NR2B, tERK, p-ERK, tCREB and p-CREB. The intraperitoneal administration of OMT (160, 80mg/kg) could prevent the development of mechanical allodynia, thermal hyperalgesia induced by CCI. Intraperitoneal administration of OMT decreased the mean IOD of NR2B in the dorsal horn and expression of NR2B, p-ERK and p-CREB protein. Regulation of NMDA NR2B receptor-ERK/CREB signaling maybe the targets for the antinociceptive effects of OMT on a chronic neuropathic pain model induced by chronic constrictive injury of the sciatic nerve. 23624809 Effects of intravenous nicotine on prepulse inhibition in smokers and non-smokers: relationship with familial smoking. RATIONALE: The reinforcing properties of nicotine may be, in part, derived from its ability to enhance certain forms of cognitive processing. Several animal and human studies have shown that nicotine increases prepulse inhibition (PPI) of the startle reflex. However, it remains unclear whether these effects are related to smoking susceptibility. OBJECTIVES: The current study examined the effects of intravenously delivered nicotine on PPI in smokers and non-smokers, as well as its association with a quantitative index of familial smoking. METHODS: The sample consisted of 30 non-smokers and 16 smokers, who completed an initial assessment, followed on a separate day by a laboratory assessment of PPI prior to and following each of two intravenous nicotine infusions. Separate doses were used in smoker and non-smoker samples. RESULTS: Analyses indicated that both nicotine infusions acutely enhanced PPI among non-smokers, and this enhancement was positively related to the degree of smoking among first and second-degree relatives. Smokers also displayed PPI enhancement after receiving the first infusion, but this effect was unrelated to familial smoking. CONCLUSIONS: These data suggest that the PPI paradigm may have utility as an endophenotype for cognitive processes which contribute to smoking risk. 23884611 Microvascular decompression for neurovascular conflicts in the cerebello-pontine angle: which role for endoscopy? Microvascular decompression (MVD) is the surgical intervention designed to resolve neurovascular conflicts (NCs) in the cerebellopontine angle (CPA). Today, endoscopy is commonly used in many neurosurgical procedures. This study aims to retrospectively assess the usefulness of endoscopy during MVD, focusing on microscopic endoscopic-assisted (MEA) MVD. Between January 2010 and December 2012, 141 patients underwent MVD procedures: 119 (84.5 %) were affected by idiopathic trigeminal neuralgia (TN), 20 (14 %) by hemifacial spasm (HFS), 1 by glossopharyngeal neuralgia (GN) and 1 by TN and GN simultaneously; 128 (91 %) MVD were first time procedures, while 13 (9 %) were recurrences (10 TN, 3 HFS). Visualization techniques used were: pure microscopic in 89 (63 %) cases, fully endoscopic in 12 (8.5 %) and MEA in 40 (28.5 %). The MEA technique was used when the conflict was not clearly identified under microscopic view or it was not certainly resolved. Overall, a NC was found in 130 (92 %) cases, while 11 patients had no intraoperative evidence of NC. Considering specifically the 40 MEA cases, 12 (8.5 % overall) conflicts not clearly visible with the microscope were revealed and solved, a complete conflict resolution was confirmed in 13 (9 % overall) cases, while an incomplete conflict resolution was shown in four cases (3 % overall). Pure microscopic MVD remains the technique of choice. The endoscope is a useful adjunctive imaging tool in confirming NCs identified by the microscope, revealing conflicts missed by the microscopic survey alone and verifying adequate nerve decompression. 23969528 Neuroprotein Dynamics in the Cerebrospinal Fluid: Intraindividual Concomitant Ventricular and Lumbar Measurements. Objective: The measurement of neuromarker/neuroproteins in the cerebrospinal fluid (CSF) is gaining increased popularity. However, insufficient information is available on the rostrocaudal distribution of neuroproteins in the CSF to guarantee an appropriate interpretation of ventricular versus lumbar concentrations. Methods: In 10 patients treated with both an external ventricular and a lumbar CSF drain, we collected concomitant CSF samples. We measured CSF concentrations of the glial S100B protein, the neuron-specific enolase (Cobas e411®; Roche Diagnostics), the leptomeningeal β-trace protein (BN Pro Spec®; Dade Behring/Siemens), and the blood-derived albumin (Immage; Beckman Coulter). Statistical analysis was performed with a paired Wilcoxon signed ranks test. Results: In patients with a free CSF circulation without any recent neurosurgical procedure, S100B and neuron-specific enolase concentrations did not differ between the ventricular and lumbar CSF while β-trace and albumin levels were significantly higher in the lumbar than in the ventricular CSF (p = 0.008 and p = 0.005). Following posterior fossa tumor surgery, all proteins accumulate in the lumbar CSF. Conclusion: For brain-derived proteins, we could not confirm a rostrocaudal CSF gradient while lepto-meningeal and blood-derived proteins accumulate in the lumbar CSF. We conclude that for the interpretation of protein CSF concentrations, the source of the sample is of crucial importance. 23640547 Seawater-driven magnesium based Janus micromotors for environmental remediation. We describe the use of seawater as fuel to propel Janus micromotors. The new micromotors consist of biodegradable and environmentally friendly magnesium microparticles and a nickel-gold bilayer patch for magnetic guidance and surface modification. Such seawater-driven micromotors, which utilize macrogalvanic corrosion and chloride pitting corrosion processes, eliminate the need for external fuels to offer efficient and prolonged propulsion towards diverse applications in aquatic environments. 23906714 Mammalian transcription-coupled excision repair. Transcriptional arrest caused by DNA damage is detrimental for cells and organisms as it impinges on gene expression and thereby on cell growth and survival. To alleviate transcriptional arrest, cells trigger a transcription-dependent genome surveillance pathway, termed transcription-coupled nucleotide excision repair (TC-NER) that ensures rapid removal of such transcription-impeding DNA lesions and prevents persistent stalling of transcription. Defective TC-NER is causatively linked to Cockayne syndrome, a rare severe genetic disorder with multisystem abnormalities that results in patients' death in early adulthood. Here we review recent data on how damage-arrested transcription is actively coupled to TC-NER in mammals and discuss new emerging models concerning the role of TC-NER-specific factors in this process. 23822173 Behavioral response of Caenorhabditis elegans to localized thermal stimuli. Nociception evokes a rapid withdrawal behavior designed to protect the animal from potential danger. C. elegans performs a reflexive reversal or forward locomotory response when presented with noxious stimuli at the head or tail, respectively. Here, we have developed an assay with precise spatial and temporal control of an infrared laser stimulus that targets one-fifth of the worm's body and quantifies multiple aspects of the worm's escape response. When stimulated at the head, we found that the escape response can be elicited by changes in temperature as small as a fraction of a degree Celsius, and that aspects of the escape behavior such as the response latency and the escape direction change advantageously as the amplitude of the noxious stimulus increases. We have mapped the behavioral receptive field of thermal nociception along the entire body of the worm, and show a midbody avoidance behavior distinct from the head and tail responses. At the midbody, the worm is sensitive to a change in the stimulus location as small as 80 mum. This midbody response is probabilistic, producing either a backward, forward or pause state after the stimulus. The distribution of these states shifts from reverse-biased to forward-biased as the location of the stimulus moves from the middle towards the anterior or posterior of the worm, respectively. We identified PVD as the thermal nociceptor for the midbody response using calcium imaging, genetic ablation and laser ablation. Analyses of mutants suggest the possibility that TRPV channels and glutamate are involved in facilitating the midbody noxious response. Through high resolution quantitative behavioral analysis, we have comprehensively characterized the C. elegans escape response to noxious thermal stimuli applied along its body, and found a novel midbody response. We further identified the nociceptor PVD as required to sense noxious heat at the midbody and can spatially differentiate localized thermal stimuli. 23873402 Assessment of Mitral Valve Adaptation with Gated Cardiac Computed Tomography: Validation with Three-Dimensional Echocardiography and Mechanistic Insight to Functional Mitral Regurgitation. -Mitral valve (MV) enlargement is a compensatory mechanism capable of preventing functional mitral regurgitation (FMR) in dilated ventricles. Total leaflet area and its relation with closure area measured by 3D-echocardiography have been related to FMR. Whether these parameters can be assessed with other imaging modalities is not known. Our objectives are to compare cardiac CT-based measurements of MV leaflets with 3D-echocardiography and determine the relationship of these metrics to the presence of FMR. -We used two cohorts of patients who had cardiac CT to measure MV total leaflet, closure and annulus areas. In cohort 1 (26 patients), we validated these CT metrics to 3D-echocardiography. In cohort 2 (66 patients), we assessed the relation of MV size with the presence of FMR in three populations: heart failure with FMR, heart failure without FMR, and normal controls. Cardiac CT and 3D-echocardiography produced similar results for total leaflet (R(2)=0.97), closure (R(2)=0.89) and annulus areas (R(2)=0.84). MV size was largest in heart failure without FMR compared with controls and FMR patients (9.1±1.7 vs 7.5±1.0 vs 8.1±0.9 cm(2)/m(2), p<0.01). FMR patients had reduced ratios of total leaflet:closure areas and total leaflet:annulus areas when compared to patients without FMR (p<0.01). -MV size measured by CT is comparable to 3D-echocardiography. MV enlargement in cardiomyopathy suggests leaflet adaptation. Patients with FMR have inadequate adaptation as reflected by decreased ratios of leaflet area and areas determined by ventricle size (annulus and closure areas). These measurements provide additional insight into the mechanism of FMR. 23123646 Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia. ATP-sensitive potassium (K(ATP)) channels are weak, inward rectifiers that couple metabolic status to cell membrane electrical activity, thus modulating many cellular functions. An increase in the ADP/ATP ratio opens K(ATP) channels, leading to membrane hyperpolarization. K(ATP) channels are ubiquitously expressed in neurons located in different regions of the brain, including the hippocampus and cortex. Brief hypoxia triggers membrane hyperpolarization in these central neurons. In vivo animal studies confirmed that knocking out the Kir6.2 subunit of the K(ATP) channels increases ischemic infarction, and overexpression of the Kir6.2 subunit reduces neuronal injury from ischemic insults. These findings provide the basis for a practical strategy whereby activation of endogenous K(ATP) channels reduces cellular damage resulting from cerebral ischemic stroke. K(ATP) channel modulators may prove to be clinically useful as part of a combination therapy for stroke management in the future. 23901998 Ferroelectric mechanism of croconic acid: A first-principles and Monte Carlo study. The ferroelectric mechanism of croconic acid in terms of the electronic structure and the molecular structure was studied by first principles using the density functional theory with the generalized gradient approximation. The spontaneous polarization (Ps) was simulated by the Berry phase method. It is found that the large polarization originates from charge transfer due to the strong "push-pull" effect of electron-releasing and -withdrawing groups along the hydrogen bond. According to the characteristics of polarization of croconic acid, we constructed a one-dimensional ferroelectric Hamiltonian model to describe the ferroelectric properties of croconic acid. Based on the Hamiltonian model, the thermal properties of the ferroelectricity of croconic acid were studied by Monte Carlo method. The simulated Curie temperature is 756 K, and the spontaneous polarization keeps well temperature range stability up to 400 K. These results are in good agreement with the experimental data. 23962453 ACE2 - from the Renin Angiotensin System to Gut Microbiota and Malnutrition. The renin-angiotensin system (RAS) is a complex network that regulates blood pressure, electrolyte and fluid homeostasis, as well as the function of several organs. Angiotensin-converting enzyme 2 (ACE2) was identified as an enzyme that negatively regulates the RAS by converting Ang II, the main bioactive molecule of the RAS, to Ang 1-7. Thus, ACE2 counteracts the role of angiotensin-converting enzyme (ACE) which generates Ang II from Ang I. ACE and ACE2 have been implicated in several pathologies such as cardiovascular and renal disease or acute lung injury. In addition, ACE2 has functions independent of the RAS: ACE2 is the receptor for the SARS coronavirus and ACE2 is essential for expression of neutral amino acid transporters in the gut. In this context, ACE2 modulates innate immunity and influences the composition of the gut microbiota, which can explain diarrhea and intestinal inflammation observed in Hartnup disorder, Pellagra, or under conditions of severe malnutrition. Here we review and discuss the diverse functions of ACE2 and its relevance to human pathologies. 23841504 Health care utilization and risk of infection and bleeding among MDS patients with/without transfusions, and with/without active therapy. Abstract This study utilized claims data from a national US commercial health insurer to examine rates of cytopenia-related complications (significant bleeding, infection) and health care utilization (emergency room visits, inpatient hospitalizations) among MDS patients within pre-defined periods of transfusion activity and active therapy. Periods with no transfusions, regardless of relationship to treatment intervention, were associated with lower rates of cytopenia-related complications. These data suggest that eliminating or reducing the need for transfusions may help to reduce MDS-related medical problems and treatment towards that goal should be considered in MDS patients needing transfusions. 23949299 Faecal carriage of ESBL-producing Enterobacteriaceae and carbapenem-resistant Gram-negative bacilli in community settings. The aim of this study was to determine the prevalence of intestinal carriage of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and carbapenem-resistant Gram-negative bacilli in the community in Buenos Aires, Argentina. Faecal samples from 164 non-hospitalized patients were cultured on CHROMagar KPC and CHROMagar ESBL plates. Isolates resistant to third-generation cephalosporins or carbapenems were selected for further study. The minimal inhibitory concentration (MIC) of the isolates was determined using the E-test method. The phenotypic detection of ESBLs and carbapenemases was performed using the double-disc synergy test. The rate of faecal carriage of Enterobacteriaceae resistant to third-generation cephalosporins was 26.8%. Escherichia coli represented a large majority (75%) of the isolates recovered. Thirty-three ESBL-producing isolates were detected from 31 faecal samples (18.9% of the collected specimens). Eight carbapenem-resistant Gram-negative bacilli were recovered from eight specimens (4.9%). This study revealed a high prevalence of faecal carriage of multidrug-resistant Gram-negative bacteria, including ESBLs, in Buenos Aires. Therefore, the use of surveillance cultures will be helpful for tracking and monitoring the spread of ESBL-producing Enterobacteriaceae within community settings. 23380309 Developing a theoretical framework to illustrate associations among patient satisfaction, body image and quality of life for women undergoing breast reconstruction. Within the field of breast reconstruction there is increasing focus on patient-reported outcomes related to satisfaction, body image, and quality of life. These outcomes are deemed highly relevant because the primary goal of breast reconstruction is to recreate the appearance of a breast (or breasts) that is satisfying to the patient. Prominent researchers have suggested the need to develop improved standards for outcome evaluation which can ultimately benefit patients as well as physicians. The purpose of this article is to summarize key findings in the area of patient-reported outcomes for breast reconstruction and introduce a theoretical framework for advancing research in this field. We conducted an extensive literature review of outcome studies for breast reconstruction focusing on patient-reported results. We developed a theoretical framework illustrating core patient-reported outcomes related to breast reconstruction and factors associated with these outcomes. Our theoretical model highlights domains and distinguishing features of patient satisfaction, body image, and quality of life outcomes for women undergoing breast reconstruction. This model further identifies a broad range of variables (e.g., historical/premorbid influences, disease and treatment-related factors) that have been found to influence patient-reported outcomes and need to be taken into consideration when designing future research in this area. Additional attention is given to examining the relationship between patient reported outcomes and outside evaluation of breast reconstruction. Our proposed theoretical framework suggests key opportunities to expand research in this area with the goal of optimizing body image adjustment, satisfaction, and psychosocial outcomes for the individual patient. 23706331 Constitutive and tumor necrosis factor-α-induced activation of nuclear factor-κB in adenomyosis and its inhibition by andrographolide. To investigate the action of nuclear factor (NF)-κB in adenomyosis and evaluate the potential therapeutic effect of andrographolide on tumor necrosis factor (TNF)-α-induced expression of NF-κB-mediated genes cyclooxygease-2 (COX-2), vascular endothelial growth factor (VEGF), and tissue factor (TF) in adenomyotic stromal cells. Laboratory study using human tissues. Academic hospital. Twenty-nine patients (cases) with histologically confirmed adenomyosis and 14 (controls) without adenomyosis or endometriosis. Endometrial stromal cells derived from tissue samples harvested from both cases and controls were subjected to electrophoretic mobility shift assay, and gene and protein expression analyses. The NF-κB DNA-binding activity and protein levels of NF-κB subunits p50 and p65 and the messenger RNA (mRNA) and protein levels of NF-κB-mediated genes COX-2, VEGF, and TF in cases and controls, and their changes after stimulation with TNF-α and treatment with andrographolide. The constitutive NF-κB DNA-binding activity and protein expression levels of p50 and p65, and mRNA and protein levels of COX-2, VEGF, and TF in cases were significantly higher than that of controls. The binding activity level correlated positively with dysmenorrhea severity in cases. The TNF-α stimulation further increased the binding activity, and the mRNA and protein levels of COX-2, VEGF, and TF, but treatment with andrographolide significantly reduced them. NF-κB may be a pivotal transcription factor involved in the development of adenomyosis. Targeting NF-κB with inhibitors, like andrographolide, may hold promises of treating adenomyosis. 23788241 Parasite Antigen in Serum Predicts the Presence of Viable Brain Parasites in Patients With Apparently Calcified Cysticercosis Only. Background. Computed tomography (CT) remains the standard neuroimaging screening exam for neurocysticercosis, and residual brain calcifications are the commonest finding. Magnetic resonance imaging (MRI) is more sensitive than CT but is rarely available in endemic regions. Enzyme-linked immunoelectrotransfer blot (EITB) assay uses antibody detection for diagnosis confirmation; by contrast, enzyme-linked immunosorbent assay (ELISA) antigen detection (Ag-ELISA) detects circulating parasite antigen. This study evaluated whether these assays predict undetected viable cysts in patients with only calcified lesions on brain CT. Methods. Serum samples from 39 patients with calcified neurocysticercosis and no viable parasites on CT were processed by Ag-ELISA and EITB. MRI was performed for each patient within 2 months of serologic testing. Conservatively high ELISA and EITB cutoffs were used to predict the finding of viable brain cysts on MRI. Results. Using receiver operating characteristic-optimized cutoffs, 7 patients were Ag-ELISA positive, and 8 had strong antibody reactions on EITB. MRI showed viable brain cysts in 7 (18.0%) patients. Patients with positive Ag-ELISA were more likely to have viable cysts than Ag-ELISA negatives (6/7 vs 1/32; odds ratio, 186 [95% confidence interval, 1-34 470.0], P < .001; sensitivity 85.7%, specificity 96.9%, positive likelihood ratio of 27 to detect viable cysts). Similar but weaker associations were also found between a strong antibody reaction on EITB and undetected viable brain cysts. Conclusions. Antigen detection, and in a lesser degree strong antibody reactions, can predict viable neurocysticercosis. Serological diagnostic methods could identify viable lesions missed by CT in patients with apparently only calcified cysticercosis and could be considered for diagnosis workup and further therapy. 23832628 The Natural PPAR Agonist Linoleic Acid Stimulated Insulin Release in Rat Pancreas. Free fatty acids play an important role in regulating animal insulin secretion response. Acute elevated free fatty acids increased animal insulin secretion and glucose-stimulated insulin secretion. In the present study, we perfused rat pancreas to explore the effect of unsaturated fatty acids on insulin secretion. The results showed that linoleic acid, γ-linolenic acid, and arachidonic acid significantly stimulated insulin secretion. Glucose (10 mM) alone induced a biphasic insulin secretion response. The peak effluent insulin concentrations over the baseline were 444% and 800% increase in the first and second insulin secretion phase, respectively. By comparing the percentage increases, arachidonic acid, γ-linolenic acid, or linoleic acid increased glucose-induced insulin release by 555% and 934%, 522% and 995% and 463% and 1,105% in the first and second insulin secretion phase, respectively. However, the percentage increases of insulin secretion were significantly decreased to 402% and 564% in the first and second phase in the rat fed with high-fat diet for 13 weeks. Linoleic acid alone stimulated a 391% increase of the baseline in the peak insulin concentration in the rat fed with a normal diet. The peak insulin concentration was significantly decreased to183% in the rats fed with a long-term high-fat diet. All the results suggested that unsaturated fatty acids stimulated insulin secretion and additively increased glucose-induced insulin secretion in the perfused rat pancreas. However, the rat fed with a high fat diet decreased linoleic acid-induced insulin secretion response. 23864210 Prospective registration, bias risk and outcome-reporting bias in randomised clinical trials of traditional Chinese medicine: an empirical methodological study. Clinical trials on Traditional Chinese Medicine (TCM) should be registered in a publicly accessible international trial register and report on all outcomes. We systematically assessed and evaluated TCM trials in registries with their subsequent publications. To describe the characteristics of TCM trials, estimate bias risk and outcome-reporting bias in clinical trials. Fifteen trial registries were searched from their inception to July 2012 to identify randomised trials on TCM including Chinese herbs, acupuncture and/or moxibustion, cupping, tuina, qigong, etc. We extracted data including TCM specialty and treated disease/conditions from the registries and searched for subsequent publications in PubMed and Chinese databases. We compared information in the registries of completed trials with any publications focusing on study design, sample size, randomisation, bias risk including reporting bias from the register protocol. 1096 registered randomised trials were identified evaluating TCM, of which 505 were completed studies (46.1%). The most frequent conditions were pain (13.3%), musculoskeletal (11.7%), nervous (8.7%), digestive (7.1%), circulatory (6.5%), respiratory (6.3%), mental and behavioural disorders (6.2%) and cancer (6.0%). The trial register data identified parallel, phase II/III randomised trials with sample size estimations and blinding, but limited information about randomisation (sequence generation and allocation concealment). Comparing trial registration data of 115 completed trials (22.8%) with their subsequent 136 publications, inconsistencies were identified in one or more of the following: sample size (11%), outcome assessor blinding (37.5%), primary outcomes (29%) and safety (28%) reporting. Increasing numbers of clinical trials investigating a variety of TCM interventions have been registered in international trial registries. The study design of registered TCM trials has improved in estimating sample size, use of blinding and placebos. However, selective outcome reporting is widespread and similar to conventional medicine and therefore study conclusions should be interpreted with caution. 23504585 Biliary tract cancer incidence in the United States-Demographic and temporal variations by anatomic site. We evaluated incidence patterns of biliary tract cancers (gallbladder, extrahepatic bile duct, ampulla of Vater and not otherwise specified) to provide potential insight into the etiology of these cancers. Data were obtained from the population-based Surveillance, Epidemiology and End Results program. Rates for cases diagnosed during 1992-2009 were calculated by racial/ethnic, gender and age groups. Temporal trends during 1974-2009 and annual percentage changes (APC) during 1992-2009 were estimated. Age-adjusted rates by site were higher among American Indian/Alaska Natives, Hispanics (white) and Asian/Pacific Islanders (Asian/PI) and lower among whites and blacks. Gallbladder cancer was more common among women in all ethnic groups (female-to-male incidence rate ratio [IRR] ranged from 1.24 to 2.86), but bile duct and ampulla of Vater cancers were more common among men (female-to-male IRR 0.57 to 0.82). Gallbladder cancer rates declined among all racial/ethnic and gender groups except blacks (APC -0.4% to -3.9%). In contrast, extrahepatic bile duct cancer rates rose significantly in most female racial/ethnic groups; the APCs among whites were 0.8 among females and 1.3 among males, both significant. Rates for ampulla of Vater cancer decreased among Asian/PI females (APC -2.7%) but remained stable for the other groups. In addition to confirming that biliary tract cancer incidence patterns differ by gender and site and that the gallbladder cancer incidence rates have been declining, our study provides novel evidence that extrahepatic bile duct cancer rates are rising. These observations may help guide future etiologic studies. 23687346 Metformin Decreases Glucose Oxidation and Increases the Dependency of Prostate Cancer Cells on Reductive Glutamine Metabolism. Metformin inhibits cancer cell proliferation, and epidemiology studies suggest an association with increased survival in patients with cancer taking metformin; however, the mechanism by which metformin improves cancer outcomes remains controversial. To explore how metformin might directly affect cancer cells, we analyzed how metformin altered the metabolism of prostate cancer cells and tumors. We found that metformin decreased glucose oxidation and increased dependency on reductive glutamine metabolism in both cancer cell lines and in a mouse model of prostate cancer. Inhibition of glutamine anaplerosis in the presence of metformin further attenuated proliferation, whereas increasing glutamine metabolism rescued the proliferative defect induced by metformin. These data suggest that interfering with glutamine may synergize with metformin to improve outcomes in patients with prostate cancer. Cancer Res; 73(14); 4429-38. ©2013 AACR. 23021933 Guilt and depression: Two different factors in individuals with negative symptoms of schizophrenia. Depression is common among schizophrenia patients and constitutes a major risk factor for suicide. Calgary Depression Scale (CDSS) is the most widely used instrument for measuring depression in schizophrenia. CDSS has never been examined in patients with predominant negative symptoms, thus possibly hindering both accurate assessment and understanding of the underlying mechanisms. The current study is the first to examine CDSS' structure in this population. We conducted Principal Component Analysis (n=184) for the CDSS items. Thereafter, we correlated emerging factors with psychopathological, demographic and side effect variables. We assessed internal consistency and reliability of the emerging factors, as well as demographic correlations. The analysis yielded two factors: depression-hopelessness and guilt. Factors distinctly correlated with separate variables. Removal of item #7 (early waking) improved internal consistency. The depression-hopelessness factor had an inverse correlation with negative symptoms, and positive correlation with neuroleptic side effects. CDSS structure indicated of two separate factors, i.e., depression-hopelessness and guilt, suggesting separate underlying processes. The validity of the scale might benefit from a two-fold structure and the removal/replacement of item #7 (early waking). A noteworthy inverse correlation was found between the depression factor and negative symptoms, as well as a positive correlation between depression factor and neuroleptic side effects. 23622566 Outcomes of corneal transplantation for irreversible corneal decompensation secondary to corneal endotheliitis in asian eyes. To describe outcomes of corneal transplantation for irreversible corneal decompensation from corneal endotheliitis in Asian eyes. Retrospective, observational case series. We reviewed consecutive patients with corneal endotheliitis (32 eyes of 31 subjects) who underwent keratoplasty (January 1, 2008-December 1, 2009). All eyes had preoperative aqueous polymerase chain reaction (PCR) analysis for viruses, including cytomegalovirus (CMV). CMV-positive patients were treated preoperatively with topical corticosteroids and anti-CMV treatment (oral valganciclovir 900 mg twice daily, topical ganciclovir 0.15% 5 applications per day, for 6 weeks) with complete resolution of ocular inflammation, and quiescence for at least 6 months before corneal transplantation. Our main outcome measure was recurrence of endotheliitis within 1 year after corneal transplantation. Five eyes were CMV positive; the remaining 27 eyes were negative for all viruses on PCR analysis. CMV-positive patients had a higher rate of recurrence of endotheliitis within 1 year after corneal transplantation, compared with CMV-negative eyes (60% vs 7.4%, P = .01). The CMV-positive eyes had recurrent endotheliitis at a median of 10 months (range 3-11 months) after corneal transplantation. After successful anti-CMV treatment, all 5 CMV-positive eyes then continued to have clear grafts for a median duration of 21 months (range 13-44 months). Our study suggests that Asian patients with corneal endotheliitis may benefit from preoperative aqueous PCR analysis before corneal transplantation. Such patients were more likely to have a recurrence of endothelial inflammation if they were CMV positive preoperatively, despite successful anti-CMV treatment before surgery. 23906244 Hypothermia for pediatric refractory status epilepticus. Refractory status epilepticus (RSE) is a life-threatening emergency, demonstrating, by definition, significant pharmacoresistance. We describe five cases of pediatric RSE treated with mild hypothermia. Retrospective chart review was performed of records of children who received hypothermia for RSE at two tertiary-care pediatric hospitals between 2009 and 2012. Five children with RSE received mild hypothermia (32-35°C). Hypothermia reduced seizure burden during and after treatment in all cases. Prior to initiation of hypothermia, four children (80%) received pentobarbital infusions to treat RSE, but relapsed after pentobarbital discontinuation. No child relapsed after treatment with hypothermia. One child died after redirection of care. Remaining four children were discharged. This is the largest pediatric case series reporting treatment of RSE with mild hypothermia. Hypothermia decreased seizure burden during and after pediatric RSE and may prevent RSE relapse. 23837915 A continuum model of solvation energies including electrostatic, dispersion, and cavity contributions. Physically accurate continuum solvent models that can calculate solvation energies are crucial to explain and predict the behavior of solute particles in water. Here, we present such a model applied to small spherical ions and neutral atoms. It improves upon a basic Born electrostatic model by including a standard cavity energy and adding a dispersion component, consistent with the Born electrostatic energy and using the same cavity size parameter. We show that the well-known, puzzling differences between the solvation energies of ions of the same size is attributable to the neglected dispersion contribution. This depends on dynamic polarizability as well as size. Generally, a large cancellation exists between the cavity and dispersion contributions. This explains the surprising success of the Born model. The model accurately reproduces the solvation energies of the alkali halide ions, as well as the silver(I) and copper(I) ions with an error of 12 kJ mol(-1) (±3%). The solvation energy of the noble gases is also reproduced with an error of 2.6 kJ mol(-1) (±30%). No arbitrary fitting parameters are needed to achieve this. This model significantly improves our understanding of ionic solvation and forms a solid basis for the investigation of other ion-specific effects using a continuum solvent model. 23828024 Origin of the Spinocerebellar Ataxia Type 7 Gene Mutation in Mexican Population. Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder characterized by progressive cerebellar ataxia associated with macular degeneration that leads, in the majority of patients, to loss of autonomy and blindness. The cause of the disease has been identified as (CAG) n repeat expansion in the coding sequence of the ATXN7 gene on chromosome 3p21.1. SCA7 is one of the least common genetically verified autosomal dominant cerebellar ataxias found worldwide; however, we previously identified the Mexican population showing high prevalence of SCA7, suggesting the occurrence of a common founder effect. In this study, haplotype analysis using four SCA7 gene-linked markers revealed that all 72 SCA7 carriers studied share a common haplotype, A-254-82-98, for the intragenic marker 3145G/A and centromeric markers D3S1287, D3S1228, and D3S3635, respectively. This multiloci combination is uncommon in healthy relatives and Mexican general population, suggesting that a single ancestral mutation is responsible for all SCA7 cases in this population. Furthermore, genotyping using 17 short tandem repeat markers from the non-recombining region of the Y chromosome and further phylogenetic relationship analysis revealed that Mexican patients possess the Western European ancestry, which might trace the SCA7 ancestral mutation to that world region. 23843347 Unusual tubulin-clustering ability of specifically c7-modified colchicine analogues. Highly cytotoxic C7-modified colchicine analogues, exemplified by tubuloclustin, promote microtubule disassembly followed by the formation of very stable tubulin clusters, both in vitro and in cells. The proposed mechanism of action of tubuloclustin and its analogues, beyond that of colchicine, includes additional specific interactions with the α-tubulin subunit. 23506959 Effects of rumen-escape starch and coarseness of ingredients in pelleted concentrates on performance and rumen wall characteristics of rosé veal calves. The objective was to study the effect of rumen-escape starch and coarseness of ingredients in pelleted concentrates on performance, carcass quality and rumen wall characteristics in rosé veal calf production. Two alternative concentrates (Coarse and Slow) were compared with a traditional (Control) concentrate. Control was based on finely ground ingredients, whereas in Coarse, the same ingredients were coarsely ground resulting in a mean particle size before pelleting of 1.5 in Coarse and 0.6 mm in Control. Slow compared with Control and Coarse contained finely ground sorghum and corn instead of barley and wheat which increased the amount of rumen-escape starch to 59 compared with 22 g/kg in Control and Coarse. All concentrates had the same total starch (362 g/kg), NDF (168 g/kg), CP (154 g/kg) and DE (15.5 MJ/kg DM) content and a pellet diameter of 3.5 to 4 mm. Use of an 'indicator of starch digestibility' method gave a value of 98.6% for Control and Coarse and 91.1% for Slow (P < 0.001). A total of 57 Holstein bull calves (n = 19 per treatment) were offered one of the three concentrates ad libitum from weaning (2½ months of age) to slaughter (<10 months of age). Concentrate intake was recorded individually. Barley straw was available ad libitum but intake was not recorded. Average daily gain (1.43 kg/day), concentrate conversion efficiency (3.7 kg DM concentrate/kg gain), LW at slaughter (386 kg), carcass weight (194 kg) and EUROP conformation (3.9) were not affected by type of concentrate (P > 0.05). Papillae length and shape evaluated in atrium ruminis and the cranial part of the ventral rumen sac at slaughter were not affected by type of concentrate (P > 0.05). Rumen wall characteristics showed degrees of plaque formation (i.e., papillary aggregation), hyperaemia and necrotic areas in all treatment groups, but with no general difference between type of concentrate (P > 0.05). Incidence of liver abscesses (LAs, 16%) was not affected by type of concentrate (P > 0.05). There were no differences in performance or rumen wall characteristics between liver-abscessed and non-abscessed calves. The results show a high level of production performance with the three types of pelleted concentrates and indicates that neither the more coarse ingredients nor the additional rumen-escape starch tested, when fed ad libitum, could improve rumen wall characteristics or reduce LAs of rosé veal calves. 23512500 Diarylheptanoids from Alnus glutinosa Bark and Their Chemoprotective Effect on Human Lymphocytes DNA. A study of secondary metabolites from the bark of Alnus glutinosa led to the isolation of fourteen diarylheptanoids: oregonin (1), platyphylloside (2), rubranoside A (3), rubranoside B (4), hirsutanonol (5), hirsutenone (6), hirsutanonol-5-O-β-D-glucopyranoside (7), platyphyllonol-5-O-β-D-xylopyranoside (8), aceroside VII (9), alnuside A (10), alnuside B (11), 1,7-bis-(3,4-dihydoxyphenyl)-5-hydroxy-heptane-3-O-β-D-xylopyranoside (12), (5S)-1-(4-hydroxyphenyl)-7-(3,4-dihydroxyphenyl)-5-O-β-D-glucopyranosyl-heptan-3-one (13), and (5S)-1,7-bis-(3,4-dihydroxyphenyl)-5-O-β-D-[6-(3,4-dimethoxycinnamoylglucopyranosyl)]-heptan-3-one (14). All of the diarylheptanoids, except 1 and 5, were found in A. glutinosa for the first time, while 13 and 14 were new compounds. The structures were determined by spectroscopic techniques: 1D and 2D NMR, HR-ESI-MS, FTIR, UV, and CD. All isolated compounds were analyzed for an in vitro protective effect on chromosome aberrations in peripheral human lymphocytes using the cytokinesis-block micronucleus assay. The majority of them, including the new compounds 13 and 14, exerted a pronounced effect in decreasing DNA damage in human lymphocytes. Diarylheptanoids 1, 2, 5, 13, and 14 at a concentration of 1 µg/mL decreased the frequency of micronuclei by 52.8 %, 43.8 %, 63.6 %, 44.4 %, and 56.0 %, respectively, exerting a much stronger effect than the synthetic protector amifostine (17.2 %, c = 1 µg/mL). 23846226 DAX-1, as an androgen-target gene, inhibits aromatase expression: a novel mechanism blocking estrogen-dependent breast cancer cell proliferation. Sexual hormones, estrogens and androgens, determine biological response in a tissue- and gender-specific manner and have a pivotal role in endocrine-mediated tumorigenesis. In situ estrogen production by aromatase is a critical determinant for breast cancer growth and progression. On the contrary, clinical and in vitro studies indicate that androgens have a protective role in mammary carcinogenesis. Here, we demonstrated, in hormone-dependent breast cancer cells, the existence of a functional interplay between the androgen receptor (AR), the orphan nuclear receptor DAX-1 and the aromatase enzyme involved in the inhibition of the estrogen-dependent breast cancer cell proliferation exerted by androgen signaling. Indeed, our results revealed, in MCF-7 cells, that ligand-activated AR induces the expression of the orphan nuclear receptor DAX-1 by direct binding to a newly identified androgen-response-element within the DAX-1 proximal promoter. In turn, androgen-induced DAX-1 is recruited, in association with the corepressor N-CoR, within the SF-1/LRH-1 containing region of the aromatase promoter, thereby repressing aromatase expression and activity. In elucidating a novel mechanism by which androgens, through DAX-1, inhibit aromatase expression in breast cancer cell lines, these findings reinforce the theory of androgen- opposing estrogen-action, opening new avenues for therapeutic intervention in estrogen-dependent breast tumors. 23515494 Involvement of serotonin mechanism in methamphetamine-induced chronic pulmonary toxicity in rats. The widest distribution and the highest uptake of methamphetamine (MA) in the human body occurred in the lungs, so that more and more attention should be paid to MA-induced pulmonary toxicity. MA induces the release of serotonin, which is an important mediator in pulmonary disease. The purpose of this study is to investigate the chronic response of the lung to MA and its potential mechanism in rats. Models of the chronic toxicity of MA were established with MA of 5 mg/kg and 10 mg/kg (intraperitoneally, twice per day) for 5 weeks. It was found that the high dose of MA induced rat pulmonary toxicity: crowded lung parenchyma, thickened septum, reduced number of alveolar sacs, inflammatory cell infiltration, and pulmonary arteriolar remodeling. In addition, MA resulted in a significant increase in the lung serotonin concentration and the marked upregulation of tryptophan hydroxylase 1, vesicular monoamine transporter 2, serotonin transporter, and downregulation of monoamine oxidase-A. These findings suggest that MA induced chronic pulmonary toxicity, which is concerned with the elevated serotonin concentration in rat lungs by increased synthesis, reduced metabolism, augmented accumulation, and promoted release of serotonin. 23330546 Nuclear receptors in bile acid metabolism. Bile acids are signaling molecules that activate nuclear receptors, such as farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, and vitamin D receptor, and play a critical role in the regulation of lipid, glucose, energy, and drug metabolism. These xenobiotic/endobiotic-sensing nuclear receptors regulate phase I oxidation, phase II conjugation, and phase III transport in bile acid and drug metabolism in the digestive system. Integration of bile acid metabolism with drug metabolism controls absorption, transport, and metabolism of nutrients and drugs to maintain metabolic homeostasis and also protects against liver injury, inflammation, and related metabolic diseases, such as nonalcoholic fatty liver disease, diabetes, and obesity. Bile-acid-based drugs targeting nuclear receptors are in clinical trials for treating cholestatic liver diseases and fatty liver disease. 23379624 Interleukin-10 controls the protective effects of circulating microparticles from patients with septic shock on tissue-engineered vascular media. During sepsis, inflammation can be orchestrated by the interaction between circulating and vascular cells that, under activation, release MPs (microparticles). Previously, we reported that increased circulating MPs in patients with sepsis play a pivotal role in ex vivo vascular function suggesting that they are protective against vascular hyporeactivity. The present study was designed to investigate the effects of MPs from patients with sepsis on the contractile response of TEVM (tissue-engineered vascular media). TEVM that were composed only of a media layer were produced by tissue engineering from human arterial SMCs (smooth muscle cells) isolated from umbilical cords. TEVM was incubated with MPs isolated from whole blood of 16 patients with sepsis. TEVM were incubated for 24 h with MPs and used for the study of vascular contraction, direct measurements of NO and O2- (superoxide anion) production by EPR and quantification of mRNA cytokine expression. MPs from patients with sepsis increased contraction induced by histamine in TEVM. This effect was not associated with inflammation, neither linked to the activation of NF-κB (nuclear factor κB) pathway nor to the increase in iNOS (inducible NO synthase) and COX (cyclo-oxygenase)-2 expression. In contrast, mRNA expression of IL (interleukin)-10 was enhanced. Then, we investigated the effect of IL-10 on vascular hyporeactivity induced by LPS (lipopolysaccharide). Although IL-10 treatment did not modify the contractile response in TEVM by itself, this interleukin restored contraction in LPS-treated TEVM. In addition, IL-10 treatment both prevented vascular hyporeactivity induced by LPS injection in mice and improved survival of LPS-injected mice. These findings show an association between the capacity of MPs from patients with sepsis to restore vascular hyporeactivity induced by LPS and their ability to increase IL-10 in the tissue-engineered blood vessel model. 23759875 Getting tubed: mechanical bond in endohedral derivatives of carbon nanotubes? We present a brief overview of some of the most prominent examples of encapsulation of molecules inside carbon nanotubes. We then relate them to mechanically interlocked molecules, and in particular rotaxanes, by examining the most prominent features of the mechanical bond (topology, dynamic properties, and stability) and comparing them to those of endohedral derivatives of nanotubes. Our analysis shows that there is a surprisingly clear link between these two apparently disparate species. 23848524 Engineered biochar reclaiming phosphate from aqueous solutions: mechanisms and potential application as a slow-release fertilizer. This work explored the potential application of an engineered biochar prepared from Mg-enriched tomato tissues to reclaim and reuse phosphate (P) from aqueous solution. Findings from batch sorption experiments suggested that, although sorption of P on the biochar was controlled by relatively slow kinetics, the maximum P sorption capacity of the biochar could reach >100 mg·g(-1). Mathematical modeling and postsorption characterization results indicated that the sorption was mainly controlled by two mechanisms: precipitation of P through chemical reaction with Mg particles and surface deposition of P on Mg crystals on biochar surfaces. Most of the P retained in the engineered biochar was bioavailable and could be released equally at multiple successive extractions. In addition, the P-laden biochar significantly stimulated grass seed germination and growth. These results suggested the postsorption biochar can be cycled back directly to soils as an effective slow-release P-fertilizer. 23965292 Blood Synthetic Cannabinoid Concentrations in Cases of Suspected Impaired Driving. Twelve cases of suspected impaired driving are discussed in which the drivers who subsequently tested positive for synthetic cannabinoid drugs underwent a psychophysical assessment. The attitude of the drivers was described as cooperative and relaxed, speech was slow and slurred and coordination was poor. Pulse and blood pressure were generally elevated. Horizontal gaze nystagmus was assessed in nine of the subjects, but was present in only two. The most consistent indicator was a marked lack of convergence. In all cases where a Drug Recognition Expert (DRE) officer evaluated and documented impairment (10 cases), it was attributed to the DRE cannabis category. Performance in field sobriety tests was variable, ranging from poor to minimal observable effect. Synthetic cannabinoid testing was performed by LC-MS-MS. Positive results included: JWH-018 (n = 4), 0.1-1.1 ng/mL; JWH-081 (n = 2) qualitative only; JWH-122 (n = 3), 2.5 ng/mL; JWH-210 (n = 4), 0.1 ng/mL; JWH-250 (n = 1), 0.38 ng/mL and AM-2201 (n = 6), 0.43-4.0 ng/mL. While there is good evidence of psychophysical impairment in these subjects, further structured data collection is needed to fully assess the relationship between synthetic cannabinoid use and psychomotor and cognitive impairment. 23502661 Comparison of Analgesic Effect of Direct Breastfeeding, Oral 25% Dextrose Solution and Placebo during 1st DPT Vaccination in Healthy Term Infants: A Randomized, Placebo Controlled Trial. To compare analgesic effect of direct breast feeding, 25% dextrose solution and placebo as we give 1st intramuscular whole cell DPT injection to 6week - 3month old infants. Randomized, placebo controlled trial. Immunization clinic of Department of Pediatrics, LLRM Medical College. Infants coming for their 1st DPT vaccination were randomized in to three groups of 40 each. Outcome measures: The primary outcome variable was the duration of cry after vaccination. Secondary outcome variables were Modified Facial Coding Score (MFCS) and latency of onset of cry. 120 babies were equally enrolled in breast feed group, 25% dextrose fed group and distilled water fed group. Median (interquartile range) of duration of cry was significantly lower in breast fed (33.5 (17-54) seconds) and 25% dextrose fed babies (47.5 (31-67.5) seconds) as compared to babies given distilled water (80.5 (33.5-119.5) seconds) (P<0.001). MFCS at 1 min and 3 min was significantly lower in direct breast fed and dextrose fed babies. Direct breastfeeding and 25% dextrose act as analgesic in young infants undergoing DPT vaccination in young infants less than 3 month of age. 23289951 Discovery of the rare HLA-B*39:77 allele in an unrelated Taiwanese bone marrow stem cell donor using the sequence-based typing method. We detected a rare HLA-B locus allele, B*39:77, in a Taiwanese unrelated marrow stem cell donor in our routine HLA sequence-based typing (SBT) exercise for a possible haematopoietic stem cell donation. In exons 2, 3 and 4, the DNA sequence of B*39:77 is identical to the sequence of B*39:01:01:01 except one nucleotide at nucleotide position 733 (G->A) in exon 4. The nucleotide variation caused one amino acid alteration at residue 221 (Gly->Ser). B*39:77 was probably derived from a nucleotide substitution event involving B*39:01:01:01. The probable HLA-A, -B, -C, -DRB1 and -DQB1 haplotype in association with B*39:77 may be deduced as A*02:01-B*39:77-C*07:02-DRB1*08:03-DQB1*06:01. Our discovery of B*39:77 in Taiwanese adds further polymorphism of B*39 variants in Taiwanese population. 23605691 Cytochrome p450-mediated changes in oxycodone pharmacokinetics/pharmacodynamics and their clinical implications. In recent years the use of the opioid oxycodone has increased markedly and replacing morphine as the first-line choice of opioid in several countries. There are formulations for oral immediate, oral extended release and intravenous use. The bioavailability is higher than for morphine and less variable. Oxycodone is primarily metabolized in the liver by the cytochrome P450 (CYP) enzymes with CYP3A as the major metabolic pathway and CYP2D6 as the minor metabolic pathway to noroxycodone, oxymorphone and noroxymorphone. Oxycodone exerts its analgesic effect via the µ-opioid receptor. The metabolism of CYP2D6 substrates varies to a large degree between individuals as a result of allele functionality. Poor metabolizers (PM) have two non-functional alleles, extensive metabolizers (EM) are homozygous with two functional alleles or heterozygous with one functional allele and ultrarapid metabolizers (UM) have more than two functional alleles. There are pronounced interethnic differences in the allele distribution. On the basis of studies performed thus far, oxycodone concentrations in comparison with EM are similar in PM and reduced in UM. The pharmacokinetics in UM are insufficiently investigated. Simultaneous inhibition of both CYP3A and CYP2D6 results in increased oxycodone concentrations and such a combination should be avoided. A similar effect is to be expected with use of a CYP3A inhibitor in CYP2D6 PM. Concomitant use of enzyme inducers such as rifampicin, St John's wort and carbamazepine should be avoided because of the risk of subtherapeutic concentrations of oxycodone. When the dosage of morphine may result in unpredictable bioavailability, like in patients with severe hepatic cirrhosis, oxycodone might be beneficial because it has higher and less variability in bioavailability between patients than morphine. 23847351 Scanning for clues to better use selective estrogen receptor modulators. Summary: Ingle and colleagues present timely findings identifying genetic variants associated with response to selective estrogen receptor modulator therapy that when substantiated in follow-up may represent an important step toward understanding estrogen-dependent induction of BRCA1 expression and advancing individualized preventive medicine in women at high risk for developing breast cancer. Cancer Discov; 3(7); 728-9. ©2013 AACR. 23800845 A microporous metal-organic open framework containing uncoordinated carbonyl groups as postsynthetic modification sites for cation exchange and Tb(3+) sensing. A novel 3D microporous compound [Zn3(Httca)2(4,4'-bpy)(H2O)2]n (MOF-COOH) containing uncoordinated carbonyl groups pointing to the pores was prepared. The uncoordinated carbonyl groups in the channels can act as postsynthetic modification sites for cation exchange. The MOF-COOH compound can effectively and selectively serve as an antenna for sensitizing the visible-emitting Tb(3+) cation. 23199056 Fatal respiratory distress syndrome due to coronavirus infection in a child with severe combined immunodeficiency. Please cite this paper as: Szczawinska-Poplonyk et al. (2012) Fatal respiratory distress syndrome due to coronavirus infection in a child with severe combined immunodeficiency. Influenza and Other Respiratory Viruses DOI: 10.1111/irv.12059. Coronaviruses have been demonstrated to contribute substantially to respiratory tract infections among the child population. Though infected children commonly present mild upper airway symptoms, in high-risk patients with underlying conditions, particularly in immunocompromised children these pathogens may lead to severe lung infection and extrapulmonary disorders. In this paper, we provide the first report of the case of a 15-month-old child with severe combined immunodeficiency and coronavirus HKU1-related pneumonia with fatal respiratory distress syndrome. 22594571 A new triterpenoid saponin from Glinus oppositifolius with α-glucosidase inhibitory activity. Evaluation of α-glucosidase inhibitory activity led to the isolation of six triterpene saponins from the aerial parts of Glinus oppositifolius including one new and five known constituents. The structure of the new saponin, glinoside C (1), was established as 16-O-(β-D-glucopyranosyl)-3β,12β,16β,21α,22-pentahydroxy hopane by extensive use of 1-D, 2-D NMR and mass spectral techniques. The other constituents identified were 3-O-(β-D-xylopyranosyl)-spergulagenin A (2), spergulacin (3), spergulin A (4), spergulacin A (5) and spergulin B (6). Compound 1 exhibited the greatest inhibition of the enzyme with IC50 of 127 ± 30 µM. Kinetics study for the compound 1 demonstrated mixed type of inhibition (Ki = 157.9 µM). 23722045 A disposable electrochemiluminescence device for ultrasensitive monitoring of K562 leukemia cells based on aptamers and ZnO@carbon quantum dots. We developed a new electrochemiluminescence (ECL) platform for ultrasensitive and selective detection of leukemia cells. In order to construct the platform, the nonporous gold with controllable three-dimensional porosity and good conductivity was used to modify the screen-printed carbon electrode. The carbon quantum dots (CQDs) coated ZnO nanosphere (ZnO@CQDs) were used as good ECL label with low cytotoxicity and good biocompatibility. Structure characterization was obtained by means of transmission electron microscopy and scanning electron microscopy images. The aptamer was used for cell capture and the concanavalin A conjugated ZnO@CQDs was used for selective recognition of the cell surface carbohydrate. The proposed method showed a good analytical performance for the detection of K562 cells ranging from 1.0×10(2) to 2.0×10(7)cellsmL(-1) with a detection limit of 46cellsmL(-1). The as-proposed device has the advantages of high sensitivity, nice specificity and good stability and could offer great promise for sensitive detection of leukemia cells in response to therapy. 23949963 Umeclidinium in patients with COPD: a randomised, placebo-controlled study. Efficacy and safety of umeclidinium (UMEC) administered in a dry power inhaler were evaluated in moderate-to-very-severe COPD patients.Randomised, placebo-controlled study assessing once-daily UMEC 62.5 and 125 mcg over 12 weeks. Primary end-point: change from baseline in trough FEV1 on day 85. Secondary end-points: 0-6 h weighted mean (wm) and serial FEV1. Other end-points: Transitional Dyspnoea Index (TDI), health outcomes (St. George's Respiratory Questionnaire [SGRQ]), pharmacokinetics and safety.246 patients enrolled; 168 completed study. On day 85, UMEC 62.5 and 125 mcg significantly improved LSM change from baseline in trough FEV1 (127 and 152 mL, respectively; p<0.001) compared with placebo. On day 84, UMEC 62.5 and 125 mcg significantly improved LSM change from baseline in 0-6 h wm (166 and 191 mL, respectively; p<0.001) and serial FEV1 at each time point (p≤0.003). Significant improvement in LSM TDI focal score (1.0 and 1.3 units, respectively; p≤0.05) and change from baseline SGRQ total score (-7.9 and -10.87 units, respectively; p<0.001) were noted compared with placebo at week 12. The incidence of adverse events was low and similar across treatments.UMEC 62.5 and 125 mcg significantly improved lung function, dyspnoea and health status compared with placebo and were well tolerated in COPD patients over 12 weeks. 23869961 Practical Considerations for the Interpretation of Microbial Testing Results Based on Small Numbers of Samples. Abstract While adequate, statistically designed sampling plans should be used whenever feasible, inference about the presence of pathogens in food occasionally has to be made based on smaller numbers of samples. To help the interpretation of such results, we reviewed the impact of small sample sizes on pathogen detection and prevalence estimation. In particular, we evaluated four situations commonly encountered in practice. The first two examples evaluate the combined impact of sample size and pathogen prevalence (i.e., fraction of contaminated food items in a given lot) on pathogen detection and prevalence estimation. The latter two examples extend the previous example to consider the impact of pathogen concentration and imperfect test sensitivity. The provided examples highlight the difficulties of making inference based on small numbers of samples, and emphasize the importance of using appropriate statistical sampling designs whenever possible. 23882088 Effects of various analgesics on the level of prostaglandin E2 during orthodontic tooth movement. AIM:The aim of this double-blind, randomized, placebo-controlled clinical study was to evaluate the analgesic effects of preoperative/postoperative ibuprofen and acetaminophen use after bonding and to find a relation between the pain level and the amount of prostaglandin released.MATERIALS AND METHODS:Forty-eight patients were included and randomly divided to three equal groups that received either ibuprofen, acetaminophen or placebo for pain relief. The pain levels were measured before bonding, after bonding, at first, second, third, and seventh days on a 100mm visual analogue scale (VAS) and gingival crevicular fluid (GCF) samples were collected at the same time intervals to measure the amount of prostaglandin E2 (PGE2) released. PGE2 levels were determined with ELISA test. The results were evaluated with Wilcoxon and Kruskal-Wallis tests with Bonferroni correction.RESULTS:Acetaminophen and placebo groups showed similar pain levels during the first 2 days, whereas ibuprofen group showed lower pain levels during the first day after bonding. PGE2 levels did not show statistically significant difference in time within the analgesic groups. No significant relation between the pain perceived and PGE2 released was found.LIMITATIONS:The biggest limitation of this study is the subjective nature of pain and its method of evaluation.CONCLUSIONS:The perception of pain by patients taking ibuprofen and acetaminophen at pre/post appliance placement was not different from patients taking placebo. No time-related differences in PGE2 level were found between the groups and no significant correlation was found between the perception of pain and PGE2 levels. 23729363 Spinophilin loss correlates with poor patient prognosis in advanced stages of colon carcinoma. The genomic region 17q21 is frequently associated with microsatellite instability and LOH in cancer, including gastric and colorectal carcinomas. This region contains several putative tumor suppressor genes, including Brca1, NM23, prohibitin, and spinophilin (Spn, PPP1R9B, neurabin II). The scaffold protein Spn is one of the regulatory subunits of phosphatase-1 (PP1) that targets PP1 to distinct subcellular locations and couples PP1 to its target. Thus, Spn may alter cell-cycle progression via the regulation of the phosphorylation status of the retinoblastoma protein, a direct target of PP1. Therefore, we analyzed whether Spn levels were reduced in colorectal carcinomas and whether Spn levels correlated with prognosis or response to therapy. By means of immunohistochemistry or quantitative PCR, we studied the levels of Spn in stages II, III, and IV colorectal carcinoma tumors and correlated to other clinicopathologic features as well as prognosis or response to therapy. Spn was lost in a percentage of human gastric, small intestine, and colorectal carcinomas. In patients with colorectal carcinoma, tumoral Spn downregulation correlated with a more aggressive histologic phenotype (poorer tumor differentiation and higher proliferative Ki67 index). Consistent with this observation, lower Spn protein expression levels were associated with faster relapse and poorer survival in patients with stage III colorectal carcinoma, particularly among those receiving adjuvant fluoropyrimidine therapy. We validated this result in an independent cohort of patients with metastatic colorectal carcinoma treated with standard chemotherapy. Although patients that achieved an objective tumor response exhibited Spn levels similar to nontumoral tissue, nonresponding patients showed a significant reduction in Spn mRNA levels. Our data suggest that Spn downregulation contributes to a more aggressive biologic behavior, induces chemoresistance, and is associated with a poorer survival in patients with advanced stages of colorectal carcinoma. Clin Cancer Res; 19(14); 3925-35. ©2013 AACR. 23094687 In Vitro Investigation of the Effect of Ambient Humidity on Regional Delivered Dose with Solution and Suspension MDIs. Abstract Background: Existing literature has shown that high relative humidity (RH) affects in vitro aerosol drug delivery of nebulizer and pressurized metered dose inhaler (pMDI) formulations. The aim of this study is to investigate in vitro mouth-throat deposition and lung delivery of selected solution and suspension pMDI formulations, under a range of RH, temperature, and flow rate conditions. Methods: The Alberta Idealized Throat was connected to a collection filter and placed in an environmental control chamber. The formulations selected were beclomethasone dipropionate (BDP) in 13% w/w ethanol/1.3% w/w glycerol and HFA-134a propellant solution ("BDP HFA134a"), BDP in 13% w/w ethanol and HFA-227 propellant solution ("BDP HFA227"), and Flixotide Evohaler (fluticasone propionate 250 μg/dose in HFA-134a suspension). Each of these pMDI formulations was dispersed into the mouth-throat and filter assembly in triplicate, according to an experimental matrix consisting of the following conditions: air flow rates of 28.3, 60, and 90 L/min; 0%, 35%, and 80% RH; operating temperatures of 20°C and 40°C. Results: There was a general increase in mouth-throat deposition and corresponding decrease in filter deposition (representing lung dose fraction), with increasing RH for both BDP HFA134a and Flixotide pMDIs. Increasing temperature from 20°C to 40°C resulted in decreased mouth-throat deposition and increased lung dose fraction for the solution pMDIs, but generally no effect for the suspension pMDI. Conclusions: Not only is the dose delivery of pMDI formulations affected by environmental conditions (in some cases causing up to 50% reduction in lung delivery), but solution and suspension formulations also behave differently in response to these conditions. These results have implications during dosage form design, testing, and for usage patient use. 23943276 A Novel Colorectal and Cervical Cancer Education Program: Findings from the Community Network for Cancer Prevention Forum Theater Program. Medically underserved populations continue to be disproportionately burdened by cancer. The exact reason for this disparity has not been fully elucidated, but likely involves multiple factors. We explored the potential utility of a novel community-based cancer education program called Forum Theater (FT), aimed at raising awareness about colorectal (CRC) and cervical cancer (CxC) screening among African-American, Hispanic, and Vietnamese populations. We also determined audience likelihood of obtaining CRC and CxC screening in the 6 months following performances. Thirty FT performances were held between September 2011 and July 2012. A brief survey was administered at each performance, eliciting responses on key CRC and CxC screening questions. A total of 662 community residents (316 Hispanic, 165 African-American, and 181 Vietnamese; overall mean age 50.3 ±â€‰16.4) participated in performances. The survey response rate was 71.1 %. After seeing FT performances, the majority responded correctly (>70 %) on CRC and CxC screening questions. In comparison to Hispanic and Vietnamese participants, African-Americans were less likely to report that CRC and CxC are preventable (p < 0.05), that timely and regular screening saves lives (p = 0.05), and that CxC screening should begin at age 21 for most women (p < 0.05). Our findings suggest that FT may be an effective strategy to disseminate cancer screening information. Lack of awareness that CRC/CxC screening saves lives and that CRC/CxC is preventable, as reported by African-Americans, may not stem from lack of knowledge or misconceptions alone, but may be influenced by a sense of fatalism regarding cancer outcomes in this population. 23353745 (E)-4-Aryl-4-oxo-2-butenoic acid amides, chalcone-aroylacrylic acid chimeras: Design, antiproliferative activity and inhibition of tubulin polymerization. Antiproliferative activity of twenty-nine (E)-4-aryl-4-oxo-2-butenoic acid amides against three human tumor cell lines (HeLa, FemX, and K562) is reported. Compounds showed antiproliferative activity in one-digit micromolar to submicromolar concentrations. The most active derivatives toward all the cell lines tested bear alkyl substituents on the aroyl moiety of the molecules. Fourteen compounds showed tubulin assembly inhibition at concentrations <20 μM. The most potent inhibitor of tubulin assembly was unsubstituted compound 1, with IC50 = 2.9 μM. Compound 23 had an oral LD50in vivo of 45 mg/kg in mice. Cell cycle analysis on K562 cells showed that compounds 1, 2 and 23 caused accumulation of cells in the G2/M phase, but inhibition of microtubule polymerization is not the principal mode of action of the compounds. Nevertheless, they may be useful leads for the design of a new class of antitubulin agents. 23873629 Raman microspectroscopic discrimination of TCam-2 cultures reveals the presence of two sub-populations of cells. TCam-2 cells are the main in vitro model for investigations into seminomatous tumors. However, despite their widespread use, questions remain regarding the cells' homogeneity and consequently how representative they are of seminomas. We assess the TCam-2 cell line using routine and novel authentication methods to determine its homogeneity, identify any cellular sub-populations and resolve whether any changes could be due to generational differentiation. TCam-2, embryonal carcinoma cells (2102EP) and breast cancer cell (MCF7) lines were assessed using qRT-PCR, immunocytochemistry, flow cytometry and short tandem repeat analyses. Raman maps of individual cells (minimum of 10) and single scan spectra from 200 cells per culture were obtained. TCam-2s displayed the characteristic marker gene expression pattern for seminoma, were uniform in size and granularity and short tandem repeat analysis showed no contamination. However, based only on physical parameters, flowcytometry was unable to differentiate between TCam-2 and 2102EPs. Raman maps of TCam-2s comprised three equally distributed, distinct spectral patterns displaying large intercellular single spectral variation. All other cells showed little variation. Principal component, cluster and local spectral angle analyses indicated that the TCam-2s contained two different types of cells, one of which comprised two subgroups and was similar to some 2102EP cells. Protein expression corroborated the presence of different cells and generational differences. The detailed characterization provided by the Raman spectra, augmented by the routine methods, provide substantiation to the long-held suspicion that TCam-2 are not homogeneous but comprise differing cell populations, one of which may be embryonal carcinoma in origin. 23386703 Investigating the enteroenteric recirculation of apixaban, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats. The study described here investigated the impact of intestinal excretion (IE; excretion of drug directly from circulation to intestinal lumen), enteroenteric recirculation (EER), and renal tubule recirculation (RTR) on apixaban pharmacokinetics and disposition. The experimental approaches involve integrating apixaban elimination pathways with pharmacokinetic profiles obtained from bile duct-cannulated (BDC) rats and dogs receiving i.v. doses together with oral administration of activated charcoal (AC). Additionally, the role of P-gp (P-glycoprotein; abcb1) and BCRP (breast cancer resistance protein; abcg2) in apixaban disposition was evaluated in experiments using transporter inhibitors and transporter knockout (KO) rats. Approximately 20-50% of an apixaban i.v. dose was found in feces of BDC rats and dogs, suggesting IE leading to fecal elimination and intestinal clearance (IC). The fecal elimination, IC, and systemic clearance of apixaban were increased upon AC administration in both BDC rats and dogs and were decreased in BDC rats dosed with GF-120918, a dual BCRP and P-gp inhibitor). BCRP appeared to play a more important role for absorption and intestinal and renal elimination of apixaban than P-gp in transporter-KO rats after oral and i.v. dosing, which led to a higher level of active renal excretion in rat than other species. These data demonstrate that apixaban undergoes IE, EER, and RTR that are facilitated by efflux transporters. Intestinal reabsorption of apixaban could be interrupted by AC even at 3 hours post-drug dose in dogs (late charcoal effect). This study demonstrates that the intestine is an organ for direct clearance and redistribution of apixaban. The IE, EER, and RTR contribute to overall pharmacokinetic profiles of apixaban. IE as a clearance pathway, balanced with metabolism and renal excretion, helps decrease the impacts of intrinsic (renal or hepatic impairment) and extrinsic (drug-drug interactions) factors on apixaban disposition. 23924747 Exploring new practice models delivering orthopedic care: can we significantly decrease delivery costs and improve quality? Health care delivery models are undergoing rapid transformation in response to market, regulatory, and demographic trends. Many of the new models of delivery are centrally planned structures with attributes dictated by statute. An understanding of these models is essential if physicians wish to retain an influential voice in patient care. Accountable Care Organizations, Medical Homes, Bundled Payment, and Episode of Care are terms even sports medicine physicians must become familiar with to positively affect the delivery of health care in the near future. By embracing both the clinical and economic aspects of health care, surgeons will be in a better position to make health care reform responsive to actual patient needs. 23594314 Ingestion toxicity of three Lamiaceae essential oils incorporated in protein baits against the olive fruit fly, Bactrocera oleae (Rossi) (Diptera Tephritidae). The ingestion toxicity of three Lamiaceae essential oils (EOs) - Hyptis suaveolens, Rosmarinus officinalis and Lavandula angustifolia - incorporated in protein baits was evaluated against Bactrocera oleae, a worldwide pest of olive fruits. In laboratory conditions, all the tested EOs showed dose-dependent toxicity on B. oleae, with mortality rates ranging from 12% (EO concentration: 0.01% w:v) to 100% (EO concentration: 1.75% w:v). Semi-field results highlighted the toxicity of L. angustifolia and H. suaveolens EOs, which exerted more than 60% of flies mortality at a concentration of 1.75% (w:v). Gas Chromatography-Electron Impact Mass Spectrometry analyses of the three EOs showed that H. suaveolens EO was dominated by monoterpene and sesquiterpene hydrocarbons. Oxygenated monoterpenes were the main chemical class in R. officinalis and L. angustifolia EOs. Further research is needed to evaluate the efficacy of these EOs plus food bait against the olive fruit fly in the open field. 23952531 Oxidative Stress in Acute Pancreatitis: Lost in Translation? Abstract Oxidative stress has been implicated in the pathogenesis of acute pancreatitis, a severe and debilitating inflammation of the pancreas that carries a significant mortality, and which imposes a considerable financial burden on the health system due to patient care. Although extensive efforts have been directed towards the elucidation of critical underlying mechanisms and the identification of novel therapeutic targets, the disease remains without a specific therapy. In experimental animal models of acute pancreatitis increased oxidative stress and decreased antioxidant defences have been observed, changes also detected in patients clinically. However, despite the promise of studies evaluating the effects of antioxidants in these model systems, translation to the clinic has thus far been disappointing. This may reflect many factors involved in the design of both preclinical and clinical evaluations of antioxidant therapy, not least the fact that most experimental studies have focussed on pre-treatment rather than post-injury assessment. This review has examined evidence relating to the involvement of oxidative stress in the pathophysiology of acute pancreatitis, focussing on experimental models and the clinical experience, including the experimental techniques employed and potential of antioxidant therapy. 23963734 Long-term efficacy of low-dose all-trans retinoic acid plus minimal chemotherapy induction followed by the addition of intravenous arsenic trioxide post-remission therapy in newly diagnosed acute promyelocytic leukaemia. We evaluated the efficacy of low-dose all-trans retinoic acid (ATRA) plus minimal chemotherapy for induction in newly diagnosed acute promyelocytic leukaemia (APL). Furthermore, we compared its long-term outcome with or without the addition of intravenous arsenic trioxide (ATO) in post-remission therapy. From January 2004 to September 2011, a total of 109 patients with a median age of 41 years (range 14-73) were enrolled in the study. Two arms were assigned according to post-remission protocols: ATO group cases were subsequently treated with intravenous ATO, standard chemotherapy, and ATRA. No-ATO group cases were subsequently treated with chemotherapy and ATRA only. Patients were monitored of minimal residual disease (MRD) by reverse-transcriptase polymerase chain reaction. The haematologic complete remission (CR) rate was 96.3%. The early death rate was 0.9%. At a median follow-up of 49 months (range 8-102 months), the Kaplan-Meier estimates of 5-year relapse-free survival were significantly better for patients in the ATO group than in the no-ATO group, 94.4% vs 54.8% (p = 0.0001), and the 5-year overall survival rate was 95.7% vs 64.1%, in the two groups (p = 0.003). Our data show that low-dose ATRA plus minimal chemotherapy exhibits efficacy in induction therapy for untreated APL and suggest that the addition of ATO to post-remission therapy significantly improves the long-term outcome. Copyright © 2013 John Wiley & Sons, Ltd. 23664959 Increased SMA-M1 coherence in Parkinson's disease - Pathophysiology or compensation? Parkinson's disease (PD) is a common neurodegenerative disorder owing to loss of dopaminergic cells. Akinesia - one of the core symptoms of PD - is associated with exaggerated oscillations at beta frequency (13-30Hz) within the subthalamic nucleus (STN). Thus, enhanced oscillations below 30Hz are assumed to represent a pathophysiological marker of PD. However, recent data suggest that OFF medication exaggerated beta oscillations within basal ganglia (BG) cortical networks may serve for the compensation of BG dysfunctions. The STN is functionally connected to mesial prefrontal areas like the supplementary motor area (SMA). But, it is still not fully understood how enhanced beta oscillations within the BG exert dominance over the primary motor cortex (M1) thereby yielding motor impairment. The present study, therefore, investigates the effect of dopaminergic state on SMA-M1 functional connectivity using Magnetoencephalography (MEG). MEG data were recorded in 7 patients suffering from PD with preponderance of akinesia during isometric contraction of the right forearm and during rest. Coherence as a measure of functional connectivity between M1 and SMA was calculated OFF and ON medication and correlated with the motor part of the Unified Parkinson's Disease Rating Scale (UPDRS III) and with disease duration. During rest a significant positive correlation between disease duration and SMA-M1 coherence was found ON but not OFF medication. Conversely, during isometric contraction SMA-M1 coherence and UPDRS III were inversely correlated OFF but not ON medication explaining more than 80% of variance. The results favor the hypothesis that OFF medication exaggerated cortical coherence at beta frequency represents a compensatory mechanism rather than a pathophysiological marker per se. 23970084 QTL mapping and correlation analysis for 1000-grain weight and percentage of grains with chalkiness in rice. The study of 1000-grain weight (TGW) and percentage of grains with chalkiness (PGWC) is very important in rice. In this study, a set of introgression lines (ILs), derived from Sasanishiki/Habataki with Sasanishiki as the recurrent parent, were used to detect correlations and quantitative trait loci (QTL) on TGW and PGWC in two different environments. Phenotypic correlation analysis showed that there was no significant correlation between TGW and PGWC in both environments, which indicated that the linkage of TGW and PGWC traits could be broken via suitable population. A total of 20 QTL were detected in both environments, nine QTL for 1000-paddy-grain weight (PTGW), five QTL for 1000-brown-grain weight (BTGW) and six QTL for percentage of grains with chalkiness (PGWC). Moreover, five QTL, qPTGW3, qPTGW8.2, qPTGW11.1 for PTGW and qPGWC1.1, qPGWC1.2 for PGWC, were stably expressed in both environments. Phenotypic values were significantly different (P < 0.01) between the introgression lines carrying these five QTL alleles and the genetic background parent, Sasanishiki. The introgression lines carrying these QTL also represent a useful genetic resource in the context of rice yield and quality improvement via a design-breeding approach. 23644225 SKUP3 randomised controlled trial: polysomnographic results after uvulopalatopharyngoplasty in selected patients with obstructive sleep apnoea. To assess the 6-month efficacy of uvulopalatopharyngoplasty (UPPP) compared with expectancy in selected patients with obstructive sleep apnoea syndrome (OSAS). A prospective single-centre randomised controlled trial with two parallel arms stratified by Friedman stage and body mass index (BMI). 65 consecutive patients with moderate to severe OSAS (apnoea-hypopnoea index (AHI) ≥15 events/h sleep), BMI <36 kg/m(2), Epworth sleepiness scale ≥8, Friedman stage I or II. Surgical treatment with UPPP. The control group underwent UPPP after a delay of 6 months. Changes in AHI and other polysomnography parameters at baseline compared with the 6-month follow-up. All patients (32 in the intervention group and 33 in the control group) completed the trial. The mean (SD) AHI in the intervention group decreased significantly (p<0.001) by 60% from 53.3 (19.7) events/h to 21.1 (16.7) events/h . In the control group the mean AHI decreased by 11% from 52.6 (21.7) events/h to 46.8 (22.8) events/h, with a significant difference between the groups (p<0.001). The mean time in the supine position and the BMI were unchanged in both groups. Subgroup analyses for Friedman stage, BMI group and tonsil size all showed significant reductions in AHI in the intervention group compared with controls. There were no severe complications after surgery. This trial demonstrates the efficacy of UPPP in treating selected patients with OSAS with a mean reduction in AHI of 60% compared with 11% in controls, a highly significant and clinically relevant difference between the groups. NCT01659671. 23811404 G-actin sequestering protein thymosin-β4 regulates the activity of myocardin-related transcription factor. Myocardin-related transcription factors (MRTFs) are robust coactivators of serum response factor (SRF). MRTFs contain three copies of the RPEL motif at their N-terminus, and they bind to monomeric globular actin (G-actin). Previous studies illustrate that G-actin binding inhibits MRTF activity by preventing the MRTFs nuclear accumulation. In the living cells, the majority of G-actin is sequestered by G-actin binding proteins that prevent spontaneous actin polymerization. Here, we demonstrate that the most abundant G-actin sequestering protein thymosin-β4 (Tβ4) was involved in the regulation of subcellular localization and activity of MRTF-A. Tβ4 competed with MRTF-A for G-actin binding; thus, interfering with G-actin-MRTF-A complex formation. Tβ4 overexpression induced the MRTF-A nuclear accumulation and activation of MRTF-SRF signaling. The activation rate of MRTF-A by the Tβ4 mutant L17A, whose affinity for G-actin is very low, was lower than that by wild-type Tβ4. In contrast, the β-actin mutant 3DA, which has a lower affinity for Tβ4, more effectively suppressed MRTF-A activity than wild-type β-actin. Furthermore, ectopic Tβ4 increased the endogenous expression of SRF-dependent actin cytoskeletal genes. Thus, Tβ4 is an important MRTF regulator that controls the G-actin-MRTFs interaction. 23891629 The impact of uterine leiomyomas: a national survey of affected women. We sought to characterize the impact of uterine leiomyomas (fibroids) in a racially diverse sample of women in the United States. A total of 968 women (573 white, 268 African American, 127 other races) aged 29-59 years with self-reported symptomatic uterine leiomyomas participated in a national survey. We assessed diagnosis, information seeking, attitudes about fertility, impact on work, and treatment preferences. Frequencies and percentages were summarized. The χ(2) test was used to compare age groups. Women waited an average of 3.6 years before seeking treatment for leiomyomas, and 41% saw ≥2 health care providers for diagnosis. Almost a third of employed respondents (28%) reported missing work due to leiomyoma symptoms, and 24% believed that their symptoms prevented them from reaching their career potential. Women expressed desire for treatments that do not involve invasive surgery (79%), preserve the uterus (51%), and preserve fertility (43% of women aged <40 years). Uterine leiomyomas cause significant morbidity. When considering treatment, women are most concerned about surgical options, especially women aged <40 years who want to preserve fertility. 23720368 Development of an Enzyme-Linked Immunosorbent Assay Using a Recombinant LigA Fragment Comprising Repeat Domains 4 to 7.5 as an Antigen for Diagnosis of Equine Leptospirosis. Leptospira immunoglobulin (Ig)-like (Lig) proteins are a novel family of surface-associated proteins in which the N-terminal 630 amino acids are conserved. In this study, we truncated the LigA conserved region into 7 fragments comprising the 1st to 3rd (LigACon1-3), 4th to 7.5th (LigACon4-7.5), 4th (LigACon4), 4.5th to 5.5th (LigACon4.5-5.5), 5.5th to 6.5th (LigACon5.5-6.5), 4th to 5th (LigACon4-5), and 6th to 7.5th (LigACon6-7.5) repeat domains. All 7 recombinant Lig proteins were screened using a slot-shaped dot blot assay for the diagnosis of equine leptospirosis. Our results showed that LigACon4-7.5 is the best candidate diagnostic antigen in a slot-shaped dot blot assay. LigACon4-7.5 was further evaluated as an indirect enzyme-linked immunosorbent assay (ELISA) antigen for the detection of Leptospira antibodies in equine sera. This assay was evaluated with equine sera (n = 60) that were microscopic agglutination test (MAT) negative and sera (n = 220) that were MAT positive to the 5 serovars that most commonly cause equine leptospirosis. The indirect ELISA results showed that at a single serum dilution of 1:250, the sensitivity and specificity of ELISA were 80.0% and 87.2%, respectively, compared to those of MAT. In conclusion, an indirect ELISA was developed utilizing a recombinant LigA fragment comprising the 4th to 7.5th repeat domain (LigACon4-7.5) as a diagnostic antigen for equine leptospirosis. This ELISA was found to be sensitive and specific, and it yielded results that concurred with those of the standard MAT. 23486649 Pediatric insecticide chalk exposures reported to Texas poison centers. The pesticide Miraculous Insecticide Chalk(TM) is illegal in the United States but can be obtained through a variety of sources. Because it is a stick similar in appearance to common blackboard chalk, children might play with it and put it in their mouths. All Miraculous Insecticide Chalk exposures involving children 5 years or younger reported to Texas poison centers during 2000-2010 were identified. The distribution by selected demographic and clinical factors was calculated. Of the total 188 exposures, the mean age was 1.5 years (range 6 months-5 years) and 60.6% were male. Ingestions were reported in 97.3% of the exposures, and these were reported to involve at most one stick of the chalk. The lowest exposure rates per 100,000 population of 5 years or younger were reported in the Public Health Regions in northern and eastern Texas (0.00-2.30) and the highest rates in the Public Health Regions in southern and western Texas (19.08-39.50). Of the 187 exposures not involving other substances, 96.8% were known or expected to result in at most minor effects, and 71.1% were managed on site (at residence). 23886285 A clinical audit of postoperative urinary retention in the postanesthesia care unit. Postoperative urinary retention (PUR) is a common postsurgical complication. Early detection and management of PUR is of particular concern to nurses working in the postanesthesia care unit (PACU) because a single episode of bladder distention may result in permanent bladder damage. A clinical audit (CA) was conducted that examined the risk factors that may contribute to the development of PUR in the PACU. The CA was conducted over a 1-week time period and used a data collection tool that was developed from the current literature. A total of 34 patients met the inclusion criteria for the CA, and a prevalence rate of 20.6% was reported, which was consistent with prevalence rates reported by larger research studies. Despite the small sample size of this CA, results suggested that PUR should be of concern to nurses in the PACU. Recommendations included the development and implementation of a guideline relating to bladder scanning in the PACU and modification of existing PACU discharge criteria to include bladder management. 23954677 More surprises lying ahead. The endocannabinoids keep us guessing. The objective of this review is to point out some important facts that we don't know about endogenous cannabinoids - lipid-derived signaling molecules that activate CB1 cannabinoid receptors and play key roles in motivation, emotion and energy balance. The first endocannabinoid substance to be discovered, anandamide, was isolated from brain tissue in 1992. Research has shown that this molecule is a bona fide brain neurotransmitter involved in the regulation of stress responses and pain, but the molecular mechanisms that govern its formation and the neural pathways in which it is employed are still unknown. There is a general consensus that enzyme-mediated cleavage, catalyzed by fatty acid amide hydrolase (FAAH), terminates the biological actions of anandamide, but there are many reasons to believe that other as-yet-unidentified proteins are also involved in this process. We have made significant headway in understanding the second arrived in the endocannabinoid family, 2-arachidonoyl-sn-glycerol (2-AG), which was discovered three years after anandamide. Researchers have established some of the key molecular players involved in 2-AG formation and deactivation, localized them to specific synaptic components, and showed that their assembly into a multi-molecular protein complex (termed the '2-AG signalosome') allows 2-AG to act as a retrograde messenger at excitatory synapses of the brain. Basic questions that remain to be answered pertain to the exact molecular composition of the 2-AG signalosome, its regulation by neural activity and its potential role in the actions of drugs of abuse such as Δ(9)-THC and cocaine. 23826999 Effective combination of human bone marrow mesenchymal stem cells and minocycline in experimental autoimmune encephalomyelitis mice. Multiple sclerosis (MS) is the most common inflammatory demyelinating disorder of the central nervous system (CNS). Minocycline ameliorates the clinical severity of MS and exhibits antiinflammatory, neuroprotective activities, and good tolerance for long-term use, whereas it is toxic to the CNS. Recently, the immunomodulation and neuroprotection capabilities of human bone marrow mesenchymal stem cells (hBM-MSCs) were shown in experimental autoimmune encephalomyelitis (EAE). In this study, we evaluated whether the combination of hBM-MSCs and a low-dose minocycline could produce beneficial effects in EAE mice. The sensitivity of hBM-MSCs to minocycline was determined by an established cell-viability assay. Minocycline-treated hBM-MSCs were also characterized with flow cytometry by using MSC surface markers and analyzed for their multiple differentiation capacities. EAE was induced in C57BL/6 mice by using immunization with MOG35-55. Immunopathology assays were used to detect the inflammatory cells, demyelination, and neuroprotection. Interferon gamma (IFN-γ)/tumor necrosis factor alpha (TNF-α) and interleukin-4 (IL-4)/interleukin-10 (IL-10), the hallmark cytokines that direct Th1 and Th2 development, were detected with enzyme-linked immunosorbent assay (ELISA). terminal dUTP nick-end labeling (TUNEL) staining was performed to elucidate the cell apoptosis in the spinal cords of EAE mice. Minocycline did not affect the viability, surface phenotypes, or differentiation capacity of hBM-MSCs, while minocycline affected the viability of astrocytes at a high dose. In vivo efficacy experiments showed that combined treatment, compared to the use of minocycline or hBM-MSCs alone, resulted in a significant reduction in clinical scores, along with attenuation of inflammation, demyelination, and neurodegeneration. Moreover, the combined treatment with hBM-MSCs and minocycline enhanced the immunomodulatory effects, which suppressed proinflammatory cytokines (IFN-γ, TNF-α) and conversely increased anti-inflammatory cytokines (IL-4, IL-10). In addition, TUNEL staining also demonstrated a significant decrease of the number of apoptotic cells in the combined treatment compared with either treatment alone. The combination of hBM-MSCs and minocycline provides a novel experimental protocol to enhance the therapeutic effects in MS. 23959266 ZRX1, the first EGFR inhibitor-capecitabine based combi-molecule, requires carboxylesterase-mediated hydrolysis for optimal activity. Capecitabine, an orally available prodrug of 5-FU, requires activation by carboxylesterase (CES) enzymes present in the liver to generate 5'-deoxy-5-flurocytidine ribose (5'-DFCR). The deamination of the latter by cytidine deaminase gives 5'-deoxy-5-fluorouridine ribose (5'-DFUR). Finally, the conversion of 5'-DFUR to the cytotoxic drug 5-FU, occurs primarily in the tumour and is catalyzed by thymidine phosphorylase (TP). Accordingly, it was surmised that events associated with an increase of TP levels should enhance the potency of capecitabine and its metabolites. EGFR inhibition was found to be one such event. The observed synergy between gefitinib and 5'-DFUR has inspired the design of single molecules capable of acting as prodrugs of both an EGFR inhibitor and 5-FU. Here, we report on the synthesis and characterization of one such molecule, ZRX1, that consists of an acetylated 5'-DFCR moiety linked to a quinazoline inhibitor of EGFR through an alkyl dicarbamate spacer that requires CES activation to generate the two active metabolites. Our results showed that ZRX1 was ineffective as an intact molecule. However, when CES was present, ZRX1 induced an increase in EGFR inhibition, TP expression, DNA damage and apoptosis. ZRX1 was, at least, 3-fold more potent than capecitabine and 5'-DFUR and recapitulated the effects of the combination treatments. LC-MS analysis showed that in the presence of CES, ZRX1 is metabolized into a mixture of bioactive quinazoline derivatives and 5'-DFCR derived metabolites. Our results in toto, suggest that capecitabine-based EGFR targeting combi-molecules of the same type than ZRX1, have the potential to induce stronger growth inhibitory potency than capecitabine, 5'-DFUR or single EGFR inhibitors and equivalent potency when compared with combinations of EGFR inhibitors + 5'-DFUR. 23902577 Debating Deposits: An Interobserver Variability Study of Lymph Nodes and Pericolonic Tumor Deposits in Colonic Adenocarcinoma. Context.- The American Joint Committee on Cancer's Cancer Staging Manual 7th edition defines pericolonic tumor deposits (TDs) as discrete tumor foci in pericolic fat showing no evidence of residual lymph node (LN). This definition relies on subjective features rather than size (5th edition) or shape (6th edition) and introduced the category N1c. Although typically straightforward, metastases are encountered for which the distinction between LNs and TDs is unclear. For data to be meaningful, agreement on distinguishing features between positive LNs and TDs is needed. Objectives.-To assess agreement among gastrointestinal pathologists evaluating difficult metastases and to report the distinguishing features they found helpful. Design.-Twenty-five tumor metastases from right-sided colonic adenocarcinomas were selected in which the distinction between positive LNs and TDs was challenging. Virtual slides were reviewed by 7 gastrointestinal pathologists. A list of features potentially helpful in differentiating positive LNs and TDs was ranked for usefulness by each pathologist. Every metastasis was diagnosed as positive LN or TD. For each case diagnosed as positive LN, reviewers were asked to list every feature used in diagnosis. Results.-Complete agreement was found for 11 of 25 metastases, 5 positive LNs and 6 TDs (κ statistic, 0.48; 95% confidence interval, 0.28-0.67). Top-ranked features included round shape, peripheral lymphocyte rim, peripheral lymphoid follicles, possible subcapsular sinus, residual LN in surrounding fibroadipose tissue, and thick capsule. The top used features were similar among reviewers. Conclusions.-Significant agreement on positive LNs and TDs in difficult colonic adenocarcinoma metastases was found among evaluators, but inconsistency remains. Round shape, peripheral lymphocyte rim, peripheral lymphoid follicles, possible subcapsular sinus, residual LN in surrounding fibroadipose tissue, and thick capsule were most often used to aid in diagnosis. 23954163 Additive Genetic Variation in Schizophrenia Risk Is Shared by Populations of African and European Descent. To investigate the extent to which the proportion of schizophrenia's additive genetic variation tagged by SNPs is shared by populations of European and African descent, we analyzed the largest combined African descent (AD [n = 2,142]) and European descent (ED [n = 4,990]) schizophrenia case-control genome-wide association study (GWAS) data set available, the Molecular Genetics of Schizophrenia (MGS) data set. We show how a method that uses genomic similarities at measured SNPs to estimate the additive genetic correlation (SNP correlation [SNP-rg]) between traits can be extended to estimate SNP-rg for the same trait between ethnicities. We estimated SNP-rg for schizophrenia between the MGS ED and MGS AD samples to be 0.66 (SE = 0.23), which is significantly different from 0 (p(SNP-rg = 0) = 0.0003), but not 1 (p(SNP-rg = 1) = 0.26). We re-estimated SNP-rg between an independent ED data set (n = 6,665) and the MGS AD sample to be 0.61 (SE = 0.21, p(SNP-rg = 0) = 0.0003, p(SNP-rg = 1) = 0.16). These results suggest that many schizophrenia risk alleles are shared across ethnic groups and predate African-European divergence. 23237840 Synthesis and antimycobacterial evaluation of pyrazinamide derivatives with benzylamino substitution. A series of 19 new compounds related to pyrazinamide were synthesized, characterized with analytical data and screened for in vitro whole cell antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium kansasii and two types of Mycobacterium avium. The series consisted of 3-(benzylamino)-5-cyanopyrazine-2-carboxamides and 3-(benzylamino)pyrazine-2,5-dicarbonitriles with various substituents on the phenyl ring. RP-HPLC method was used to determine the lipophilicity of the prepared compounds. Nine compounds exerted similar or better activity against Mycobacterium tuberculosis compared to pyrazinamide (MIC=6.25-12.5 μg/mL). 3-(Benzylamino)pyrazine-2,5-dicarbonitrile inhibited all of the tested mycobacterial strains with MIC within the range 12.5-25 μg/mL. Although not the most active, 4-NH(2) substituted compounds possessed the lowest in vitro cytotoxicity (hepatotoxicity), leading to selectivity index SI=5.5 and SI >21. 23888999 Altered Neural Processing of Threat in Alcohol-Dependent Men. Stress-response biological systems are altered in alcohol-dependent individuals and are reported to predict future relapse. This study was designed to assess neural disruptions in alcohol-dependent participants when exposed to a conditioned stimulus (CS) warning of the impending onset of a universal, nonpersonalized stressor. Fifteen alcohol-dependent men abstinent for 3 to 5 weeks and 15 age- and race-similar healthy controls were studied. Anticipatory anxiety was induced by a CS paired with an uncertain, physically painful unconditioned stressor. Neural response was assessed using functional magnetic resonance imaging. Both groups experienced significant, similar levels of anticipatory anxiety in response to the high-threat relative to the low-threat CS. Whereas control participants markedly increased the blood oxygen level-dependent (BOLD) amplitude in cortical-limbic-striatal regions during the high-threat, relative to low-threat, stimulus, alcohol-dependent participants decreased BOLD amplitude in the pregenual anterior cingulate cortex (pgACC), medial prefrontal cortex (mPFC), medial orbitofrontal cortex, posterior cingulate cortex (PCC), bilateral parietal/occipital cortex, and right hippocampus. Alcohol-dependent participants significantly deactivated pgACC/mPFC and PCC clusters, relative to controls, during the high- versus low-threat stimulus. This difference was due to a decrease in %BOLD amplitude during the high-threat stimulus in the alcohol-dependent, but not the control, participants. Alcohol-dependent men show cortical-limbic-striatal deactivation during anticipatory anxiety, particularly in regions associated with emotional regulation. These findings suggest a lack of engagement of affective regulatory mechanisms during high-stress situations in alcohol-dependent men. 23468072 Vitamin D and the cardiovascular system. Vitamin D, a secosteroid hormone, affects multiple biological pathways via both genomic and nongenomic signalling. Several pathways have potential benefit to cardiovascular health, including effects on parathyroid hormone, the renin-angiotensin-aldosterone system, vascular endothelial growth factor and cytokine production, as well as direct effects on endothelial cell function and myocyte calcium influx. Observational data supports a link between low vitamin D metabolite levels and cardiovascular health. Cross-sectional data shows associations between low 25-hydroxyvitamin D levels and stroke, myocardial infarction, diabetes mellitus, hypertension, and heart failure. Longitudinal data also suggests a relationship with incident hypertension and new cardiovascular events. However, these associations are potentially confounded by reverse causality and by the effects that other cardiovascular risk factors have on vitamin D metabolite levels. Intervention studies to date suggest a modest antihypertensive effect of vitamin D, no effect on serum lipids, a small positive effect on insulin resistance and fasting glucose, and equivocal actions on arterial stiffness and endothelial function. Analysis of cardiovascular event data collected from osteoporosis trials does not currently show a clear signal for reduced cardiovascular events with vitamin D supplementation, but results may be confounded by the coadministration of calcium, and by the secondary nature of the analyses. Despite mechanistic and observational data that suggest a protective role for vitamin D in cardiovascular disease, intervention studies to date are less promising. Large trials using cardiovascular events as a primary outcome are needed before vitamin D can be recommended as a therapy for cardiovascular disease. 23914932 Optimizing strength training for running and cycling endurance performance: A review. Here we report on the effect of combining endurance training with heavy or explosive strength training on endurance performance in endurance-trained runners and cyclists. Running economy is improved by performing combined endurance training with either heavy or explosive strength training. However, heavy strength training is recommended for improving cycling economy. Equivocal findings exist regarding the effects on power output or velocity at the lactate threshold. Concurrent endurance and heavy strength training can increase running speed and power output at VO2max (Vmax and Wmax , respectively) or time to exhaustion at Vmax and Wmax . Combining endurance training with either explosive or heavy strength training can improve running performance, while there is most compelling evidence of an additive effect on cycling performance when heavy strength training is used. It is suggested that the improved endurance performance may relate to delayed activation of less efficient type II fibers, improved neuromuscular efficiency, conversion of fast-twitch type IIX fibers into more fatigue-resistant type IIA fibers, or improved musculo-tendinous stiffness. 23644410 Cardiac rehabilitation and mortality reduction after myocardial infarction: the emperor's new clothes? Evidence in favour of cardiac rehabilitation. This piece highlights the strength of evidence in favour of cardiac rehabilitation (CR) and postulates that the emperor is indeed well dressed. The reason why a single negative trial, in the UK, has caused such hullabaloo in the literature and clinical practice is examined against overwhelming evidence from over 40 positive randomised controlled trials. The lack of motivation to promote lifestyle change and the role of patients in determining outcome is also explored. To conclude, we set the scene for the final chapter of this story by outlining what needs to be done to answer the question about the real-world effectiveness of CR. 23832857 A Chain-Based 2 D Cobalt(II) Coordination Polymer with a "Crab-Like" Flexible Dicarboxylate Ligand: A Weak Ferromagnetic Single-Chain Magnet. Chain gang: A chain-based 2D Co(II) coordination polymer was prepared by hydrothermal reaction of Co(NO3 )2 ⋅6 H2 O, H2 L and bpa in the presence of sodium hydroxide. Magnetic investigation revealed canted antiferromagnetism, magnetic hysteresis, and slow magnetic relaxation. Thus, this complex could be considered as a new homospin weak ferromagnetic single-chain magnet. 23918936 Cryo-electron tomography: The challenge of doing structural biology in situ. Electron microscopy played a key role in establishing cell biology as a discipline, by producing fundamental insights into cellular organization and ultrastructure. Many seminal discoveries were made possible by the development of new sample preparation methods and imaging modalities. Recent technical advances include sample vitrification that faithfully preserves molecular structures, three-dimensional imaging by electron tomography, and improved image-processing methods. These new techniques have enabled the extraction of high fidelity structural information and are beginning to reveal the macromolecular organization of unperturbed cellular environments. 23947858 Plasmon hybridization model generalized to conductively bridged nanoparticle dimers. Charge transfer introduced by a conductive junction bridging a nanoparticle dimer can have a pronounced effect on the optical properties of the system. We have extended the plasmon hybridization model to include conductive junctions and charge transfer effects. From our model, we are able to derive all the plasmon resonances of the bridged dimer, including the charge transfer plasmon (CTP), and predict their trends when system parameters are varied. In particular, we find that CTP is a result of a sufficiently narrow monopole mode interacting with multipolar (including dipolar) modes. The screening arising from charge transfer induces a blueshift of the hybridized bonding dimer modes and decreases the electric field in the junction. Our model may serve as an important guide for optical properties of bridged nanoparticle aggregates. 23559329 Neural conduction abnormality in the brain stem and prevalence of the abnormality in late preterm infants with perinatal problems. Neurodevelopment in late preterm infants has recently attracted considerable interest. The prevalence of brain stem conduction abnormality remains unknown. We examined maximum length sequence brain stem auditory evoked response in 163 infants, born at 33-36 weeks gestation, who had various perinatal problems. Compared with 49 normal term infants without problems, the late preterm infants showed a significant increase in III-V and I-V interpeak intervals at all 91-910/s clicks, particularly at 455 and 910/s (p < 0.01-0.001). The I-III interval was slightly increased, without statistically significant difference from the controls at any click rates. These results suggest that neural conduction along the, mainly more central or rostral part of, auditory brain stem is abnormal in late preterm infants with perinatal problems. Of the 163 late preterm infant, the number (and percentage rate) of infants with abnormal I-V interval at 91, 227, 455, and 910/s clicks was, respectively, 11 (6.5 %), 17 (10.2 %), 37 (22.3 %), and 31 (18.7 %). The number (and percentage rate) of infants with abnormal III-V interval at these rates was, respectively, 10 (6.0 %), 17 (10.2 %), 28 (16.9), and 36 (21.2 %). Apparently, the abnormal rates were much higher at 455 and 910/s clicks than at lower rates 91 and 227/s. In total, 42 (25.8 %) infants showed abnormal I-V and/or III-V intervals. Conclusion: Conduction in, mainly in the more central part, the brain stem is abnormal in late preterm infants with perinatal problems. The abnormality is more detectable at high- than at low-rate sensory stimulation. A quarter of late preterm infants with perinatal problems have brain stem conduction abnormality. 23896256 Severe plantar hyperhidrosis: an effective surgical solution. Severe palmoplantar hyperhidrosis both affects activities of daily living and diminishes quality of life. This study evaluated overall safety and efficacy of endoscopic lumbar sympathectomy (ELS) using a clamping method in a large series of consecutive patients. Patient data were routinely entered into a prospectively designed database. Plantar sweating was graded as cured, improved, or unchanged. ELS (using 5-mm titanium clips) was performed in 154 patients, 68.2 per cent at the third lumbar vertebrae and 31.8 per cent at the fourth lumbar vertebrae. Follow-up averaged 15 months and ranged up to 4.7 years. Anhidrosis was achieved in 97.4 per cent of patients with the remainder reporting major reduction in symptoms. All patients were discharged home within 24 hours of surgery, requiring only oral analgesics, if any. There were two surgical complications (lymphatic leak and misidentification of genitofemoral nerve for sympathetic nerve). Six early patients required conversion to an open surgical procedure. Partial recurrence, usually mild, occurred in 4.5 per cent with 2.6 per cent requiring revision surgery. Severe plantar hyperhidrosis can be safely and effectively treated by endoscopic lumbar sympathectomy using the clamping method. It can be accomplished on an outpatient basis with low morbidity, complete resolution of symptoms, and a significant improvement in quality of life. 23561167 Aluminium and other elements in selected herbal tea plant species and their infusions. The determination of Al, B, Cu, Fe, Mn, Ni, P, Zn and Ca, K, Mg by inductively coupled plasma optical emission spectrometry (ICP-OES) and flame atomic absorption spectroscopy (FAAS), respectively, in digests and infusions of Hibiscus sabdariffa (petals), Rosa canina (receptacles), Ginkgo biloba (leaves), Cymbopogon citratus (leaves), Aloe vera (leaves) and Panax ginseng (roots) was carried out in this study. Particular attention has been given to Al and heavy metals for the identification of possible raw material contaminants, their transformation into the infusion and for predicting their eventual role in the human diet during daily consumption. Additionally, Ion Chromatography (IC) speciation of Al in the leachates was carried out. In dry herbs, hibiscus and ginkgo appeared to contain the greatest contents of Al, Fe, K, Mn, Ni, Zn and B, Mg, P, respectively. A. vera contained the highest amount of Ca and highest values of Cu and P were observed in ginseng. In infusions, the topmost concentrations of Al, B, Cu, Fe, P, K, Mn, Ni, Zn were detected in those prepared from hibiscus petals, Ca from aloe leaves and Mg from leaves of ginkgo. According to a possible daily consumption exceeding 1L, hibiscus decoction was identified as potentially dietetically significant in the content of certain elements. It seems to be possibly one of the top contributors of B from food (up to 5.5±0.2mg/L). The Mg contained in the infusion (up to 106±5mg/L) may be a contributor in the attenuation of blood pressure. A high amount of accessible Mn (up to 17.4±1.1mg/L) can probably have an adverse effect in humans. The total Al allowance (up to 1.2±0.1mg/L) suggests that no more than 1L of the hibiscus infusion should be consumed per day by sensitive individuals including pregnant women and should be completely excluded from the diet of children under 6months of age and children with chronic renal failure. 23561162 Monitoring green leaf tea quality parameters of different TV clones grown in northeast India using satellite data. This study tries to quantify the effects of green leaf tea parameters that influence tea quality in Northeast India. The study is to identify the different parameters that have a significant influence on tea quality through the use of remote sensing. It investigates the methods for estimating tea quality based on remotely sensed Normalized Difference Vegetation Index (NDVI) data. Attention focused on high yielding TV clones (TV1, TV18, TV22, TV23, TV25 and TV26). NDVI was obtained from ASTER images. Statistical analysis shows that NDVI has a strong significant effect on the caffeine content followed by epicatechin (EC), epigallocatechin (EGC) and to some extent in other chemical parameters. Relationships therefore exist between quality parameters and remote sensing in particular for the TV clones. This leads to the conclusion that NDVI has a large potential to be used for monitoring tea quality of individual cultivars in the future. 23773123 Synergistic hybrid organic-inorganic aerogels. A class of inorganic-organic hybrid mesoporous aerogel structure was synthesized by growing gel in a gel. In Type 1, silica gels were grown inside the macropores of thermoreversible syndiotactic polystyrene (sPS) gel, while Type 2 hybrid aerogels were obtained by thermoreversible gelation of sPS chains in the mesopores of preformed silica gel. The hybrid gels were converted into aerogels by exchanging the solvent with liquid carbon dioxide followed by supercritical drying. The hybrid aerogels presented cocontinuous networks of pearl-necklace silica particles and crystalline strands of sPS and exhibited the "petal effect" due to the presence of superhydrophobic sPS and hygroscopic silica. The compressive modulus and compressive strain show large enhancements over sPS and silica aerogels indicating synergy, although Type 1 hybrid aerogels were found to be more robust. The hybrid aerogels showed fast absorption and high absorption capacity for a representative hydrocarbon liquid. 23765209 Residues of (14)c-ethion along the extraction and refining process of maize oil, and the bioavailability of bound residues in the cake for experimental animals. Maize seeds obtained from (14)C-ethion treated plants contained about 0.01 % of the originally applied radioactivity 1 month following the last pesticide application. Hexane and methanol extracts of the seeds accounted for 35 % and 22.5 % of the radioactive residues, respectively, with 40 % remaining in the seed cake. Commercial processing procedures resulted in a gradual decrease in the total amount of (14)C-residues in oils with aged residues. The refined oil contained (14)C-residues that amounted to about 30 % of the amount that was originally present. The major residues in processed oil are ethion monooxon, O,O-diethyl phosphorothioate and O,O-diethyl S-hydroxymethyl phosphorodithioate, in addition to one unknown compound. After feeding rats with the cake containing ethion bound residues, a substantial amount (71 %) of (14)C-residues was eliminated in the urine, while about 12 % was excreted in the feces. About 5 % of the radioactive residues were distributed among various organs. The bound residue was quite readily bioavailable to the rats. 23639801 A selective antagonist reveals a potential role of G protein-coupled receptor 55 in platelet and endothelial cell function. The G protein coupled receptor 55 (GPR55) is a lysophosphatidylinositol (LPI) receptor that is also responsive to certain cannabinoids. Although GPR55 has been implicated in several (patho)physiological functions, its role is still enigmatic mainly owing to the lack of selective GPR55 antagonists. Here we show that the compound CID16020046 ((4-[4-(3-hydroxyphenyl)-3-(4-methylphenyl)-6-oxo-1H,4H,5H,6H-pyrrolo [3,4-c] pyrazol-5-yl] benzoic acid) is a selective GPR55 antagonist. In yeast cells expressing human GPR55, CID16020046 antagonized agonist-induced receptor activation. In HEK293 cells stably expressing human GPR55 (HEK-GPR55), the compound behaved as an antagonist on LPI-mediated Ca2+ release and extracellular signal-regulated kinases (ERK1/2) activation, but not in HEK293 cells expressing cannabinoid receptor 1 or 2 (CB1 or CB2). CID16020046 concentration-dependently inhibited LPI-induced activation of nuclear factor of activated T-cells (NFAT), nuclear factor kappa of activated B cells (NF-κB) and serum response element (SRE), translocation of NFAT and NF-κB, and GPR55 internalization. It reduced LPI-induced wound healing in primary human lung microvascular endothelial cells (HMVEC-L) and reversed LPI-inhibited platelet aggregation, suggesting a novel role for GPR55 in platelet and endothelial cell function. CID16020046 is therefore a valuable tool to study GPR55-mediated mechanisms in primary cells and tissues. 23767891 Surgery for low-grade glioma infiltrating the central cerebral region: location as a predictive factor for neurological deficit, epileptological outcome, and quality of life. Object A main concern with regard to surgery for low-grade glioma (LGG, WHO Grade II) is maintenance of the patient's functional integrity. This concern is particularly relevant for gliomas in the central region, where damage can have grave repercussions. The authors evaluated postsurgical outcomes with regard to neurological deficits, seizures, and quality of life. Methods Outcomes were compared for 33 patients with central LGG (central cohort) and a control cohort of 31 patients with frontal LGG (frontal cohort), all of whom had had medically intractable seizures before undergoing surgery with mapping while awake. All surgeries were performed in the period from February 2007 through April 2010 at the same institution. Results For the central cohort, the median extent of resection was 92% (range 80%-97%), and for the frontal cohort, the median extent of resection was 93% (range 83%-98%; p = 1.0). Although the rate of mild neurological deficits was similar for both groups, seizure freedom (Engel Class I) was achieved for only 4 (12.1%) of 33 patients in the central cohort compared with 26 (83.9%) of 31 patients in the frontal cohort (p < 0.0001). The rate of return to work was lower for patients in the central cohort (4 [12.1%] of 33) than for the patients in the frontal cohort (28 [90.3%] of 31; p < 0.0001). Conclusions Resection of central LGG is feasible and safe when appropriate intraoperative mapping is used. However, seizure control for these patients remains poor, a finding that contrasts markedly with seizure control for patients in the frontal cohort and with that reported in the literature. For patients with central LGG, poor seizure control ultimately determines quality of life because most will not be able to return to work. 23911281 Therapeutic strategy for advanced EGFR mutant non-small-cell lung carcinoma. Activating mutation in exons 19 or 21 of epidermal growth factor receptor (EGFR) in non-small-cell lung cancers (NSCLC) are associated with increased sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib. Cancer patients harboring activating EGFR mutations benefit from first-line TKI therapy. Yet 10% of patients present a primary TKI resistance, while 50% of the others develop a secondary resistance within 9-12 months after starting TKI. The RECIST's definition of progression appears flawed when applied to EGFR-mutated NSCLC patients. Most often, tumor volume shrinking widely exceeds 30% during TKI response and kinetics of growth is low during relapse. At present, secondary resistance mechanisms associated with progression are better known: clonal selection of EGFR resistance mutation (T790M mutation in exon 20), amplification of transmembrane receptors for other growth factors (c-met, HER family, IGF1R, or AXL), downstream molecular alterations in EGFR signaling pathway (PI3K or PTEN), and epithelial-mesenchymal transition or transdifferentiation to small-cell cancer. The best strategy for secondary resistance is not well-defined: maintaining TKI therapy, switching to chemotherapy, combining both treatments, or using new therapies targeting other signaling pathways. 23885765 Detecting, quantifying and adjusting for publication bias in meta-analyses: protocol of a systematic review on methods. Health professionals and policymakers aspire to make healthcare decisions based on the entire relevant research evidence. This, however, can rarely be achieved because a considerable amount of research findings are not published, especially in case of 'negative' results - a phenomenon widely recognized as publication bias. Different methods of detecting, quantifying and adjusting for publication bias in meta-analyses have been described in the literature, such as graphical approaches and formal statistical tests to detect publication bias, and statistical approaches to modify effect sizes to adjust a pooled estimate when the presence of publication bias is suspected. An up-to-date systematic review of the existing methods is lacking. The objectives of this systematic review are as follows:• To systematically review methodological articles which focus on non-publication of studies and to describe methods of detecting and/or quantifying and/or adjusting for publication bias in meta-analyses.• To appraise strengths and weaknesses of methods, the resources they require, and the conditions under which the method could be used, based on findings of included studies.We will systematically search Web of Science, Medline, and the Cochrane Library for methodological articles that describe at least one method of detecting and/or quantifying and/or adjusting for publication bias in meta-analyses. A dedicated data extraction form is developed and pilot-tested. Working in teams of two, we will independently extract relevant information from each eligible article. As this will be a qualitative systematic review, data reporting will involve a descriptive summary. Results are expected to be publicly available in mid 2013. This systematic review together with the results of other systematic reviews of the OPEN project (To Overcome Failure to Publish Negative Findings) will serve as a basis for the development of future policies and guidelines regarding the assessment and handling of publication bias in meta-analyses. 23754331 HPLC column-switching technique for sample preparation and fluorescence determination of propranolol in urine using fused-core columns in both dimensions. A new and fast high-performance liquid chromatography (HPLC) column-switching method using fused-core columns in both dimensions for sample preconcentration and determination of propranolol in human urine has been developed. On-line sample pretreatment and propranolol preconcentration were performed on an Ascentis Express RP-C-18 guard column (5 × 4.6 mm), particle size, 2.7 Î¼m, with mobile phase acetonitrile/water (5:95, v/v) at a flow rate of 2.0 mL min(-1) and at a temperature of 50 °C. Valve switch from pretreatment column to analytical column was set at 4.0 min in a back-flush mode. Separation of propranolol from other endogenous urine compounds was achieved on the fused-core column Ascentis Express RP-Amide (100 × 4.6 mm), particle size, 2.7 Î¼m, with mobile phase acetonitrile/water solution of 0.5 % triethylamine, pH adjusted to 4.5 by means of glacial acetic acid (25:75, v/v), at a flow rate of 1.0 mL min(-1) and at a temperature of 50 °C. Fluorescence excitation/emission detection wavelengths were set at 229/338 nm. A volume of 1,500 Î¼L of filtered urine sample solution was injected directly into the column-switching HPLC system. The total analysis time including on-line sample pretreatment was less than 8 min. The experimentally determined limit of detection of the method was found to be 0.015 ng mL(-1). 23922919 Yeast one-hybrid gγ recruitment system for identification of protein lipidation motifs. Fatty acids and isoprenoids can be covalently attached to a variety of proteins. These lipid modifications regulate protein structure, localization and function. Here, we describe a yeast one-hybrid approach based on the Gγ recruitment system that is useful for identifying sequence motifs those influence lipid modification to recruit proteins to the plasma membrane. Our approach facilitates the isolation of yeast cells expressing lipid-modified proteins via a simple and easy growth selection assay utilizing G-protein signaling that induces diploid formation. In the current study, we selected the N-terminal sequence of Gα subunits as a model case to investigate dual lipid modification, i.e., myristoylation and palmitoylation, a modification that is widely conserved from yeast to higher eukaryotes. Our results suggest that both lipid modifications are required for restoration of G-protein signaling. Although we could not differentiate between myristoylation and palmitoylation, N-terminal position 7 and 8 play some critical role. Moreover, we tested the preference for specific amino-acid residues at position 7 and 8 using library-based screening. This new approach will be useful to explore protein-lipid associations and to determine the corresponding sequence motifs. 23318553 Ordered mesoporous boron-doped carbons as metal-free electrocatalysts for the oxygen reduction reaction in alkaline solution. Ordered mesoporous boron-doped carbons (BOMCs) were prepared by co-impregnation and carbonization of sucrose and 4-hydroxyphenylboronic acid into SBA-15 silica template. Nitrogen sorption, small angle X-ray diffraction (XRD), and transmission electron microscopy (TEM) reveals that BOMCs possess highly ordered mesoporous structure, uniform pore size distribution, and high surface area. X-ray photoelectron spectroscopy (XPS) analysis demonstrates that B atoms can be successfully doped into the framework of OMCs. Due to the desirable characteristics of BOMCs, BOMCs are highly active, cheap, and selective metal-free electrocatalysts for the oxygen reduction reaction (ORR) in alkaline solution. Although B content is a key factor in determining ORR activity, the ORR activity of BOMCs is also dependent on the surface area. The high surface area of BOMCs facilitates the exposure of the active sites for ORR. BOMCs may be further exploited as potentially efficient and inexpensive metal-free ORR catalysts with good long-term stability in alkaline solution. 23889850 Discovery of cashmere goat (Capra hircus) microRNAs in skin and hair follicles by Solexa sequencing. MicroRNAs (miRNAs) are a large family of endogenous, non-coding RNAs, about 22 nucleotides long, which regulate gene expression through sequence-specific base pairing with target mRNAs. Extensive studies have shown that miRNA expression in the skin changes remarkably during distinct stages of the hair cycle in humans, mice, goats and sheep. In this study, the skin tissues were harvested from the three stages of hair follicle cycling (anagen, catagen and telogen) in a fibre-producing goat breed. In total, 63,109,004 raw reads were obtained by Solexa sequencing and 61,125,752 clean reads remained for the small RNA digitalisation analysis. This resulted in the identification of 399 conserved miRNAs; among these, 326 miRNAs were expressed in all three follicular cycling stages, whereas 3, 12 and 11 miRNAs were specifically expressed in anagen, catagen, and telogen, respectively. We also identified 172 potential novel miRNAs by Mireap, 36 miRNAs were expressed in all three cycling stages, whereas 23, 29 and 44 miRNAs were specifically expressed in anagen, catagen, and telogen, respectively. The expression level of five arbitrarily selected miRNAs was analyzed by quantitative PCR, and the results indicated that the expression patterns were consistent with the Solexa sequencing results. Gene Ontology and KEGG pathway analyses indicated that five major biological pathways (Metabolic pathways, Pathways in cancer, MAPK signalling pathway, Endocytosis and Focal adhesion) accounted for 23.08% of target genes among 278 biological functions, indicating that these pathways are likely to play significant roles during hair cycling. During all hair cycle stages of cashmere goats, a large number of conserved and novel miRNAs were identified through a high-throughput sequencing approach. This study enriches the Capra hircus miRNA databases and provides a comprehensive miRNA transcriptome profile in the skin of goats during the hair follicle cycle. 23615713 Stromal cell-derived factor-1 (SDF-1) enhances cells invasion by αvβ6 integrin-mediated signaling in ovarian cancer. Ovarian carcinoma is a common gynecological malignancy and a great threat to health as a result of metastasis. The chemokine stromal-derived factor (SDF-1) plays multiple roles in tumor pathogenesis. However, the precise molecular mechanism underlying SDF-1-induced ovarian cancer cell invasion is still undefined. αvβ6 integrin is an important factor in tumor progression. Therefore, we speculate that SDF-1-enhanced ovarian cancer cell invasion is related to αvβ6 integrin-mediated signaling. After culturing with SDF-1, an obvious time- and dose-dependent increase in αvβ6 integrin was demonstrated. Furthermore, CXC receptor 4 (CXCR4) was responsible for SDF-1-induced αvβ6 integrin expression. Simultaneously, SDF-1 was found to dramatically enhance extracellular matrix degradation via urokinase-type plasminogen activator (uPA) expression and cell invasion by αvβ6 integrin expression; these reinforce failed to be increased when pretreatment was performed with the CXCR4 inhibitor AMD3100 or anti-αvβ6 integrin antibody, respectively. In addition, αvβ6 integrin induced the phosphorylation of p38 MAPK and PI3 K/Akt, contributing to the up-regulation of uPA, as treatment with the specific inhibitor for p38 mitogen-activated protein kinases (MAPK) (SB203580) or phosphatidylinositol 3-kinase (PI3 K)/Akt (LY294002) strikingly abrogated uPA expression. Taken together, these results demonstrated that SDF-1 enhanced ovarian cancer cell invasion through αvβ6 integrin-mediated uPA expression via the p38 MAPK and PI3 K/Akt pathway. Consequently, our findings will provide a new explanation about how SDF-1 aggravates the pathogenesis of ovarian cancer. 23215439 Self-assembled pH-sensitive cholesteryl pullulan nanogel as a protein delivery vehicle. A self-assembled nanogel, derived from an acid-labile cholesteryl-modified pullulan (acL-CHP), was prepared by grafting vinyl ether-cholesterol substituents onto a 100 kD pullulan main chain polymer backbone. Stable nanogels are formed by acL-CHP self-assemblies at neutral pH. The hydrodynamic radius of the nanogels, observed to be 26.5 ± 5.1 nm at pH 7.0, increased by ~135% upon acidification of the solution to pH 4.0. SEC analysis of the acL-CHP nanogel at pH 4.0 showed that the grafts were nearly 80% degraded after 24 h, whereas little or no degradation was observed over the same time period for a pH stable analog (acS-CHP) at pH 4.0 or the acL-CHP at pH 7.0. Complexation of BSA with the acL-CHP nanogel was observed at pH 7.0 with subsequent release of the protein upon acidification. These findings suggest that stimuli-responsive, self-assembled nanogels can release protein cargo in a manner that is controlled by the degradation rate of the cholesterol-pullulan grafting moiety. 23871984 Synthesis and spectroscopic characterization of 3,4-difluoroacetophenone-thiosemicarbazone and its palladium(II) complex: Evaluation of antimicrobial and antitumour activity. A new cis-palladium(II)diaqua(3,4-difluoroacetophenonethiosemicarbazone complex (Pd(II) complex) is synthesized using 3,4-difluoroacetophenonethiosemicarbazone(L). The L and its Pd(II) complex are characterized and confirmed by elemental analyses, electrochemical analyses, FT-IR, FT-Raman, UV-Vis, HRMS and LC-MS techniques. Ligand L is further characterized by (1)H, (13)C and (19)F NMR spectroscopy. The crystal structure of L is unambiguously characterized by single X-ray crystallography. The ligand (L) belongs to monoclinic system with P2(1)/C space group and the unit cell parameters are a(Å)=9.1144(7), b(Å)=13.7928(7), c(Å)=8.4174(5), α(°)=90, β(°)=100.715, γ(°)=90 and volume V(A(3))=1039.73(11). The Raman bands observed for the L and its Pd(II) complex are in good agreement with the FT-IR spectral data. The Pd(II) complex is found to be highly efficient in inhibiting the growth of human pathogens like Salmonella typhimurium and Klebsiella pneumonia with MIC value 10.0μg/mL whose inhibition zones are almost comparable with the standard antibiotic. The synthesized compounds have shown antiproliferative activity against the human breast cancer cell lines MDA-MB231 by intermitting the regular pathway of ribonucleotidereductase. 23796963 A life history view of mutualistic viral symbioses: quantity or quality for cooperation? Mutualistic symbioses between viruses and their hosts do not employ a straightforward rule by viral genome characteristics, transmission mechanisms or host genotypes. In this review we propose that reproduction rates and environmental carrying capacity of hosts may play a major role in maintaining the mutualism. Depending on how host life history shifts following establishment of the symbiosis, a symbiosis can be classified as quality-selected mutualism or quantity-selected mutualism. Quality-selected mutualism is described with modified Lotka-Volterra models. Both our models and previous empirical examples support the hypothesis that quality-selected mutualism can reach stable equilibrium under certain conditions. Quantity-selected mutualism is rare and is not supported by our model. With increasing attention to mutualistic viral ecology, we will have a better understanding of how viruses drive evolution. 23968228 Traits of fear resistance and susceptibility in an advanced intercross line. Genetic variability in the strength and precision of fear memory is hypothesised to contribute to the etiology of anxiety disorders, including post-traumatic stress disorder. We generated fear-susceptible (F-S) or fear-resistant (F-R) phenotypes from an F8 advanced intercross line (AIL) of C57BL/6J and DBA/2J inbred mice by selective breeding. We identified specific traits underlying individual variability in Pavlovian conditioned fear learning and memory. Offspring of selected lines differed in the acquisition of conditioned fear. Furthermore, F-S mice showed greater cued fear memory and generalised fear in response to a novel context than F-R mice. F-S mice showed greater basal corticosterone levels and hypothalamic corticotrophin-releasing hormone (CRH) mRNA levels than F-R mice, consistent with higher hypothalamic-pituitary-adrenal (HPA) axis drive. Hypothalamic mineralocorticoid receptor and CRH receptor 1 mRNA levels were decreased in F-S mice as compared with F-R mice. Manganese-enhanced magnetic resonance imaging (MEMRI) was used to investigate basal levels of brain activity. MEMRI identified a pattern of increased brain activity in F-S mice that was driven primarily by the hippocampus and amygdala, indicating excessive limbic circuit activity in F-S mice as compared with F-R mice. Thus, selection pressure applied to the AIL population leads to the accumulation of heritable trait-relevant characteristics within each line, whereas non-behaviorally relevant traits remain distributed. Selected lines therefore minimise false-positive associations between behavioral phenotypes and physiology. We demonstrate that intrinsic differences in HPA axis function and limbic excitability contribute to phenotypic differences in the acquisition and consolidation of associative fear memory. Identification of system-wide traits predisposing to variability in fear memory may help in the direction of more targeted and efficacious treatments for fear-related pathology. 23640814 A Highly Crystalline Manganese-Doped Iron Oxide Nanocontainer with Predesigned Void Volume and Shape for Theranostic Applications. Hollow Mn-doped iron oxide nanocontainers, formed by a novel one-pot synthetic process, fulfill the dual requirements of delivering an effective dose of an anticancer drug to tumor tissue and enabling image-contrast monitoring of the nanocontainer fate through T2 -weighted magnetic resonance imaging, thereby determining the optimal balance between diagnostic and therapeutic moieties in an all-in-one theranostic nanoplatform. 23850087 Folic acid stimulates proliferation of transplanted neural stem cells after focal cerebral ischemia in rats. Folic acid (FA) stimulates neural stem cell (NSC) proliferation in vitro and enhances hippocampal neurogenesis in rats after middle cerebral artery occlusion (MCAO). The effect of FA supplementation on exogenous NSCs transplanted in MCAO rats was observed to determine if FA can stimulate NSC replacement after focal cerebral ischemia. Rats were randomly assigned to 3 groups: MCAO; MCAO and exogenous NSC transplantation (MCAO+NSCs); and MCAO, NSC transplantation and FA (MCAO+NSCs+FA). FA (0.8 mg/kg) or vehicle was administered by gavage daily for 28 days before MCAO and 23 days afterward. NSCs were labeled with superparamagnetic iron oxide (SPIO) and bromodeoxyuridine (BrdU) prior to transplantation into the striatum, contralateral to the ischemic zone, at 2 days post-MCAO. Magnetic resonance imaging tracking and fluorescent immunohistochemistry, as well as measurement of serum folate concentration, were performed at intervals up to 21 days after transplantation. FA supplementation caused sustained increases of 400-600% in serum folate concentration. Magnetic resonance images indicated that SPIO-labeled NSCs were more abundant at the transplantation and ischemic brain sites in MCAO+NSCs+FA rats than in MCAO+NSCs rats. Similarly, immunohistochemistry showed that the numbers of Sox-2/BrdU double positive cells at the transplantation and ischemic sites were higher in the rats that received FA. In conclusion, after focal cerebral ischemia, FA supplementation stimulates transplanted NSCs to proliferate and migrate to ischemic sites. 23824677 Population Pharmacokinetics of Intermittent Vancomycin in Children with Cystic Fibrosis. Vancomycin is the drug-of-choice for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in children with cystic fibrosis. However, no studies have characterized the pharmacokinetic profile of vancomycin among pediatric cystic fibrosis patients. To evaluate the pharmacokinetics of intermittent vancomycin administration in children with cystic fibrosis and identify covariates that significantly influence vancomycin efficacy and safety. Therapeutic drug monitoring data were obtained from two cystic fibrosis care centers that identified children < 18 years who received vancomycin treatment for an acute pulmonary exacerbation from 2005 to 2010. Trough and peak serum concentrations were determined before and after the third or fourth dose. Nonlinear mixed effects models were developed to evaluate the population pharmacokinetics of vancomycin. Among the 67 children (mean age 12.1 ± 5.3 years), the mean vancomycin dose was 17.4 ± 4.4 mg/kg. The mean trough concentration (Cmin ) was 10.3 ± 3.8 mg/L. The mean daily area under the serum concentration time curve (AUC24 ) was 282.5 ± 816.9 mg·hour/L. A one-compartment model with first-order elimination best described the data. Weight significantly influenced vancomycin clearance (p<0.001). In the final model, clearance was estimated as 5.57 L/hour/70 kg, and the volume of distribution was 44.1 L/70 kg. The between subject variability for clearance and volume of distribution were 27% and 40%, respectively. Using a one-compartment model to evaluate the pharmacokinetic properties of vancomycin in children with cystic fibrosis, clearance increased with body weight. Pharmacodynamic studies are needed to establish an optimal vancomycin dosing regimen for the treatment of pediatric exacerbations of cystic fibrosis. 23725596 Vestibular stimulation attenuates unrealistic optimism. Unrealistic optimism refers to the pervasive tendency of healthy individuals to underestimate their likelihood of future misfortune, including illness. The phenomenon shares a qualitative resemblance with anosognosia, a neurological disorder characterized by a deficient appreciation of manifest current illness or impairment. Unrealistic optimism and anosognosia have been independently associated with a region of right inferior frontal gyrus, the pars opercularis. Moreover, anosognosia is temporarily abolished by vestibular stimulation, particularly by irrigation of the left (but not right) ear with cold water, a procedure known to activate the right inferior frontal region. We therefore hypothesized that left caloric stimulation would attenuate unrealistic optimism in healthy participants. Thirty-one healthy right-handed adults underwent cold-water caloric vestibular stimulation of both ears in succession. During each stimulation episode, and at baseline, participants estimated their own relative risk of contracting a series of illnesses in the future. Compared to baseline, average risk estimates were significantly higher during left-ear stimulation, whereas they remained unchanged during right-ear stimulation. Unrealistic optimism was thus reduced selectively during cold caloric stimulation of the left ear. Our results point to a unitary mechanism underlying both anosognosia and unrealistic optimism, and suggest that unrealistic optimism is a form of subclinical anosognosia for prospective symptoms. 23473032 In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Hypoxic and VHL-deficient cells use glutamine to generate citrate and lipids through reductive carboxylation (RC) of α-ketoglutarate. To gain insights into the role of HIF and the molecular mechanisms underlying RC, we took advantage of a panel of disease-associated VHL mutants and showed that HIF expression is necessary and sufficient for the induction of RC in human renal cell carcinoma (RCC) cells. HIF expression drastically reduced intracellular citrate levels. Feeding VHL-deficient RCC cells with acetate or citrate or knocking down PDK-1 and ACLY restored citrate levels and suppressed RC. These data suggest that HIF-induced low intracellular citrate levels promote the reductive flux by mass action to maintain lipogenesis. Using [(1-13)C]glutamine, we demonstrated in vivo RC activity in VHL-deficient tumors growing as xenografts in mice. Lastly, HIF rendered VHL-deficient cells sensitive to glutamine deprivation in vitro, and systemic administration of glutaminase inhibitors suppressed the growth of RCC cells as mice xenografts. 23556439 Assessment of cervical length by transvaginal ultrasonography to predict preterm delivery in twin pregnancy. Abstract Objective: In singleton pregnancy, short cervix is associated with the risk of spontaneous preterm delivery (SPD). On the other hand, twin pregnancy increases rate of preterm delivery, so this study was designed to evaluate the transvaginal sonographic (TVS) measurement of cervical length (CL) to predict preterm birth in twin pregnancy. Methods: This prospective cohort study was performed on 80 twin pregnant women whom the length and funneling of their cervix were evaluated between 22-24 gestational weeks by (TVS). They referred to us at the early signs of labor. Then the gestational age at delivery was recorded. The Fisher exact test and the odds-ratio was used to determine the association between CL and SPD. Results: Thirty-four (42.5%) women had SPD. Cervical funneling happened in 7.5% of cases and SPD occurred in all women with funneling. There was a significant correlation between CL ≤ 30 mm and SPD (66.7% versus 35.5%, p = 0.029) Also, the risk of SPD was enhanced 3.6 times with CL ≤30 mm, CI 95% (1.1-11). Conclusion: We recommend TVS for assessment of CL between 22-24 weeks for prediction of SPD in twin pregnancy. 23704052 Contributing determinants of overall and wealth-related inequality in under-5 mortality in 13 African countries. To investigate and compare the main determinants of overall inequality and wealth-related inequality in under-5 mortality in 13 African countries. Data from Demographic and Health Surveys conducted in 2007-2010 in African countries were used. The study assessed the contribution of determinants to (1) overall inequality in under-5 mortality measured by the Gini index and (2) wealth-related inequality in under-5 mortality measured by the concentration index. Techniques used were multivariate logistic regression and decomposition of Gini and concentration indexes. Birth order and interval and region contributed the most to overall inequality in under-5 mortality in a majority of countries. A significant wealth-related inequality was observed in five countries: DRCongo, Egypt, Madagascar, Nigeria and Sao Tome & Principe. Overall, household wealth, father's occupation and mother's education contributed the most to this inequality, though the ranking of the most important determinants differed across countries. Assessing the contribution of determinants to overall inequality and to wealth-related inequality in under-5 mortality help in prioritising interventions aiming at improving child survival and equity. 23825404 Spatial stream segregation by auditory cortical neurons. In a complex auditory scene, a "cocktail party" for example, listeners can disentangle multiple competing sequences of sounds. A recent psychophysical study in our laboratory demonstrated a robust spatial component of stream segregation showing ∼8° acuity. Here, we recorded single- and multiple-neuron responses from the primary auditory cortex of anesthetized cats while presenting interleaved sound sequences that human listeners would experience as segregated streams. Sequences of broadband sounds alternated between pairs of locations. Neurons synchronized preferentially to sounds from one or the other location, thereby segregating competing sound sequences. Neurons favoring one source location or the other tended to aggregate within the cortex, suggestive of modular organization. The spatial acuity of stream segregation was as narrow as ∼10°, markedly sharper than the broad spatial tuning for single sources that is well known in the literature. Spatial sensitivity was sharpest among neurons having high characteristic frequencies. Neural stream segregation was predicted well by a parameter-free model that incorporated single-source spatial sensitivity and a measured forward-suppression term. We found that the forward suppression was not due to post discharge adaptation in the cortex and, therefore, must have arisen in the subcortical pathway or at the level of thalamocortical synapses. A linear-classifier analysis of single-neuron responses to rhythmic stimuli like those used in our psychophysical study yielded thresholds overlapping those of human listeners. Overall, the results indicate that the ascending auditory system does the work of segregating auditory streams, bringing them to discrete modules in the cortex for selection by top-down processes. 23931339 Effect of mood stabilizers on DNA methylation in human neuroblastoma cells. Unraveling the epigenetic status of neuronal cells in the brain is critical to our understanding of the pathophysiology of psychiatric disorders, which may reflect a complex interaction between genetic and environmental factors. Several epigenetic studies of mood disorders have been conducted with postmortem brains. However, proper interpretation of the results is hampered by our scant understanding of the effects of mood stabilizers on the epigenetic status of neuronal cells. We performed both comprehensive and gene-specific analyses to examine DNA methylation in human neuroblastoma SK-N-SH cells treated with three mood stabilizers: lithium, valproate and carbamazepine. Measurement of the level of DNA methylation of about 27 000 CpG sites revealed a profound epigenetic effect of lithium, compared with the two other mood stabilizers. In addition, we found that the mood stabilizers have common epigenetic targets and a propensity to increase DNA methylation. Gene-specific analysis involved detailed analysis of the methylation of promoter regions of SLC6A4 and BDNF, both of which have been reported to show altered DNA methylation in bipolar disorder patients or suicide victims, by extensive bisulfite sequencing. We did not observe significant changes in DNA methylation at BDNF promoter IV. However, we found that CpG sites of SLC6A4, which were hypermethylated in patients with bipolar disorder, were hypomethylated in the neuroblastoma cells treated with mood stabilizers. Our results will contribute to a better understanding of the epigenetic changes associated with mood disorders, and they also provide new insight into the mechanisms of action of mood stabilizers. 23336565 5-Hydroxytryptamine type 7 receptor neuroprotection against NMDA-induced excitotoxicity is PDGFβ receptor dependent. The serotonin (5-HT) type 7 receptor is expressed throughout the CNS including the hippocampus. Long-term (2-24 h) activation of 5-HT7 receptors regulates growth factor receptor expression, including the expression of platelet-derived growth factor (PDGF) β receptors. Direct activation of PDGFβ receptors in primary hippocampal and cortical neurons inhibits NMDA receptor activity and attenuates NMDA receptor-induced neurotoxicity. Our objective was to investigate whether the 5-HT7 receptor-induced increase in PDGFβ receptor expression would be similarly neuroprotective. We demonstrate that 5-HT7 receptor agonist treatment in primary hippocampal neurons also increases the expression of phospholipase C (PLC) γ, a downstream effector of PDGFβ receptors associated with the inhibition of NMDA receptor activity. To determine if the up-regulation of PDGFβ receptors is neuroprotective, primary hippocampal neurons were incubated with the 5-HT7 receptor agonist, LP 12, for 24 h. Indeed, LP 12 treatment prevented NMDA-induced neurotoxicity and this effect was dependent on PDGFβ receptor kinase activity. Treatment of primary neurons with LP 12 also differentially altered NMDA receptor subunit expression, reducing the expression of NR1 and NR2B, but not NR2A. These findings demonstrate the potential for providing growth factor receptor-dependent neuroprotective effects using small-molecule ligands of G protein-coupled receptors. 23559483 Synthesis and Cytostatic and Antiviral Activities of 2'-Deoxy-2',2'-difluororibo- and 2'-Deoxy-2'-fluororibonucleosides Derived from 7-(Het)aryl-7-deazaadenines. A series of sugar-modified derivatives of cytostatic 7-heteroaryl-7-deazaadenosines (2'-deoxy-2'-fluororibo- and 2'-deoxy-2',2'-difluororibonucleosides) bearing an aryl or heteroaryl group at position 7 was prepared and screened for biological activity. The difluororibonucleosides were prepared by non- stereoselective glycosidation of 6-chloro-7-deazapurine with benzoyl-protected 2-deoxy-2,2-difluoro-D-erythro-pentofuranosyl-1-mesylate, followed by amination and aqueous Suzuki cross-couplings with (het)arylboronic acids. The fluororibo derivatives were prepared by aqueous palladium-catalyzed cross-coupling reactions of the corresponding 7-iodo-7-deazaadenine 2'-deoxy-2'-fluororibonucleoside 20 with (het)arylboronic acids. The key intermediate 20 was prepared by a six-step sequence from the corresponding arabinonucleoside by selective protection of 3'- and 5'-hydroxy groups with acid-labile groups, followed by stereoselective SN 2 fluorination and deprotection. Some of the title nucleosides and 7-iodo-7-deazaadenine intermediates showed micromolar cytostatic or anti-HCV activity. The most active were 7-iodo and 7-ethynyl derivatives. The corresponding 2'-deoxy-2',2'-difluororibonucleoside 5'-O-triphosphates were found to be good substrates for bacterial DNA polymerases, but are inhibitors of human polymerase α. 23692306 Bacille Calmette-Guérin/DNAhsp65 prime-boost is protective against diabetes in non-obese diabetic mice but not in the streptozotocin model of type 1 diabetes. Type I diabetes is a disease caused by autoimmune destruction of the beta cells in the pancreas that leads to a deficiency in insulin production. The aim of this study was to evaluate the prophylactic potential of a prime-boost strategy involving bacille Calmette-Guérin (BCG) and the pVAXhsp65 vaccine (BCG/DNAhsp65) in diabetes induced by streptozotocin (STZ) in C57BL/6 mice and also in spontaneous type 1 diabetes in non-obese diabetic (NOD) mice. BCG/DNAhsp65 vaccination in NOD mice determined weight gain, protection against hyperglycaemia, decreased islet inflammation, higher levels of cytokine production by the spleen and a reduced number of regulatory T cells in the spleen compared with non-immunized NOD mice. In the STZ model, however, there was no significant difference in the clinical parameters. Although this vaccination strategy did not protect mice in the STZ model, it was very effective in NOD mice. This is the first report demonstrating that a prime-boost strategy could be explored as an immunomodulatory procedure in autoimmune diseases. 23746608 Parsing the peanut panic: the social life of a contested food allergy epidemic. As medical reports over the last decade indicate that food allergies among children are on the rise, peanut allergies in particular have become a topic of intense social debate. While peanut allergies are potentially fatal, they affect very few children at the population level. Yet, peanut allergies are characterized in medical and popular literature as a rising "epidemic," and myriad and broad-based social responses have emerged to address peanut allergy risk in public spaces. This analysis compares medical literature to other textual sources, including media reports, legislation, and advocacy between 1980 and 2010 in order to examine how peanut allergies transformed from a rare medical malady into a contemporary public health problem. I argue that the peanut allergy epidemic was co-constructed through interactions between experts, publics, biomedical categories, and institutions, while social reactions to the putative epidemic expanded the sphere of surveillance and awareness of peanut allergy risk. The characterization of the peanut allergy problem as an epidemic was shaped by mobility across social sites, with both discursive and material effects. 23900287 Mobilization of a plant transposon by expression of the transposon-encoded anti-silencing factor. Transposable elements (TEs) have a major impact on genome evolution, but they are potentially deleterious, and most of them are silenced by epigenetic mechanisms, such as DNA methylation. Here, we report the characterization of a TE encoding an activity to counteract epigenetic silencing by the host. In Arabidopsis thaliana, we identified a mobile copy of the Mutator-like element (MULE) with degenerated terminal inverted repeats (TIRs). This TE, named Hiun (Hi), is silent in wild-type plants, but it transposes when DNA methylation is abolished. When a Hi transgene was introduced into the wild-type background, it induced excision of the endogenous Hi copy, suggesting that Hi is the autonomously mobile copy. In addition, the transgene induced loss of DNA methylation and transcriptional activation of the endogenous Hi. Most importantly, the trans-activation of Hi depends on a Hi-encoded protein different from the conserved transposase. Proteins related to this anti-silencing factor, which we named VANC, are widespread in the non-TIR MULEs and may have contributed to the recent success of these TEs in natural Arabidopsis populations. 23263988 Quantitative analysis of chromosome condensation in fission yeast. Chromosomes undergo extensive conformational rearrangements in preparation for their segregation during cell divisions. Insights into the molecular mechanisms behind this still poorly understood condensation process require the development of new approaches to quantitatively assess chromosome formation in vivo. In this study, we present a live-cell microscopy-based chromosome condensation assay in the fission yeast Schizosaccharomyces pombe. By automatically tracking the three-dimensional distance changes between fluorescently marked chromosome loci at high temporal and spatial resolution, we analyze chromosome condensation during mitosis and meiosis and deduct defined parameters to describe condensation dynamics. We demonstrate that this method can determine the contributions of condensin, topoisomerase II, and Aurora kinase to mitotic chromosome condensation. We furthermore show that the assay can identify proteins required for mitotic chromosome formation de novo by isolating mutants in condensin, DNA polymerase ε, and F-box DNA helicase I that are specifically defective in pro-/metaphase condensation. Thus, the chromosome condensation assay provides a direct and sensitive system for the discovery and characterization of components of the chromosome condensation machinery in a genetically tractable eukaryote. 23885879 Microtubule motors: a new hope for Kinesin-5 inhibitors? A new study demonstrates that two microtubule plus end-directed kinesins can oppose each other. The cause of this apparent contradiction is the specific orientation of microtubules on which each motor exerts its force. 23629602 CT With Hepatic Arterioportography as a Pretreatment Examination for Hepatocellular Carcinoma Patients: A Randomized Controlled Trial. The combination of computed tomography with hepatic arteriography and arterial portography (CTHA/CTAP) can detect additional hepatocellular carcinoma (HCC) nodules undetected by conventional dynamic CT. In this single-center, randomized, open-label, controlled trial, we randomly assigned 280 patients who were diagnosed as having HCC by conventional dynamic CT, and eligible for radiofrequency ablation (RFA), to undergo CTHA/CTAP before treatment, or to the control group. Newly detected HCC nodules by CTHA/CTAP were intended to be ablated completely. The primary end point was recurrence-free survival and the key secondary end point was overall survival. The analysis was conducted on an intention-to-treat basis. Those with nonablated nodules were treated as for recurrence. A total of 75 nodules were newly diagnosed as HCC by CTHA/CTAP in 45 patients. Three patients (one in the CTHA/CTAP group and two in the control group) who refused treatment were excluded from all analyses. The cumulative recurrence-free survival rates at 1, 2, and 3 years were 60.1, 29.0, and 18.9% in the CTHA/CTAP group and 52.2, 29.7, and 23.1% in the control group, respectively (P=0.66 by log-rank test; hazard ratio, 0.94 for CTHA/CTAP vs. control; 95% confidence interval (CI), 0.73-1.22). The cumulative overall survival rates at 3 and 5 years were 79.7 and 56.4% in the CTHA/CTAP group and 86.8 and 60.1% in the control group, respectively (P=0.50; hazard ratio, 1.15, 95% CI, 0.77-1.71). CTHA/CTAP may detect recurrent lesions earlier. However, CTHA/CTAP before RFA did not improve cumulative recurrence-free survival or overall survival. 23846233 Modeling highly pathogenic avian influenza transmission in wild birds and poultry in West Bengal, India. Wild birds are suspected to have played a role in highly pathogenic avian influenza (HPAI) H5N1 outbreaks in West Bengal. Cluster analysis showed that H5N1 was introduced in West Bengal at least 3 times between 2008 and 2010. We simulated the introduction of H5N1 by wild birds and their contact with poultry through a stochastic continuous-time mathematical model. Results showed that reducing contact between wild birds and domestic poultry, and increasing the culling rate of infected domestic poultry communities will reduce the probability of outbreaks. Poultry communities that shared habitat with wild birds or those indistricts with previous outbreaks were more likely to suffer an outbreak. These results indicate that wild birds can introduce HPAI to domestic poultry and that limiting their contact at shared habitats together with swift culling of infected domestic poultry can greatly reduce the likelihood of HPAI outbreaks. 23743185 Triglyceride-coated nanoparticles: Skin toxicity and effect of UV/IR irradiation on them. Triglyceride (TG) is an important compound on the skin, produced by sebaceous glands, and may change cytotoxicity of different nanoparticles. To date, there is no report about toxicity of nanoparticles coated with TG. On the other hand, the use of ultraviolet (UV) and infrared (IR) with nanoparticles changes nanoparticle cytotoxicity. The combination of nanoparticles with UV or IR is applicable, because it may be used for treatment or detection of local cancers, surface microbial infections and other skin diseases. In this study, different nanoparticles including titanium dioxide, zinc oxide, magnesium oxide, silver, gold, and TG-coated form of these nanoparticles, were added to suspensions of Balb/c skin cells, and then incubated for 24h at 37°C. Additionally, TG-coated nanoparticles were treated with UV and IR irradiation for 1h. Different methods were applied for evaluation of cytotoxicity, including 5-diphenyl-tetrazolium bromide assay, lactate dehydrogenase (LDH) assay, cell metabolic assay, ATP assay, and reactive oxygen species (ROS) generation assay. This research showed that TG-coated nanoparticles had less LDH release and ROS generation with higher cell viability, cell metabolic activity, and ATP level, compared with pristine nanoparticles. In contrast, the combination of UV and IR with TG-coated nanoparticles led to higher LDH release and ROS generation with less cell viability, cell metabolic activity, and ATP level, in comparison with pristine nanoparticles. Overall, pristine metal nanoparticles without irradiation had higher cytotoxicity than metal oxide nanoparticles. 23897481 Structural basis of intersubunit recognition in elongin BC-cullin 5-SOCS box ubiquitin-protein ligase complexes. The cullin-RING ubiquitin ligases are multisubunit complexes that ubiquitinate various proteins. Six different cullins encoded by the human genome selectively pair with different adaptors and substrate receptors. It is presently poorly understood how cullin-2 (Cul2) and cullin-5 (Cul5) associate specifically with their adaptor elongin BC and a SOCS-box-containing substrate receptor. Here, crystallographic and mutational analyses of a quaternary complex between the N-terminal half of Cul5, elongin BC and SOCS2 are reported. Cul5 interacts extensively with elongin BC via residues that are highly conserved in Cul2 but not in other cullins. Cul5 also interacts with SOCS2, but via only two residues, Pro184 and Arg186, which are located in the C-terminal part of the SOCS box called the Cul5 box. Pro184 makes a ring-to-ring interaction with Trp53 of Cul5, which is substituted by alanine in Cul2. This interaction is shown to contribute significantly to the overall binding affinity between Cul5 and SOCS2-elongin BC. This study provides structural bases underlying the specificity of Cul5 and Cul2 for elongin BC and their preferential association with Cul5 or Cul2 box-containing substrate receptors. 23949959 Severely reduced diffusion capacity in idiopathic pulmonary arterial hypertension - patient characteristics and treatment responses. A subgroup of patients with idiopathic pulmonary arterial hypertension (IPAH) has severely reduced diffusion capacity for carbon monoxide (DL,CO) and poor prognosis. Their characteristics are currently unknown. The aim of this study is to contrast clinical characteristics and treatment responses of IPAH-patients with a severely reduced and more preserved DL,CO.Retrospectively, 166 IPAH-patients were included and grouped based on a DL,CO cut-off value of 45% of predicted (IPAH<45% and IPAH≥45%). Clinical characteristics, treatment responses and survival were compared.IPAH<45% were older, more often male, had a more frequent history of coronary disease and a higher tobacco exposure. FEV1, FEV1/FVC, TLC and alveolar volume-values were slightly lower and CT scan abnormalities more prevalent in patients with a low DL,CO. Age and number of pack years were independently associated with DL,CO <45%. IPAH<45% showed no different hemodynamic profile, yet worse exercise performance and a worse survival, which were both related to age, gender and the presence of coronary disease.To conclude, a severely reduced DL,CO in IPAH is associated with advanced age and a greater tobacco exposure. These patients have a worse exercise performance despite a similar hemodynamic profile. We confirm the decreased survival in this patient group and now show that this poor outcome is related to age, gender and the presence of coronary disease. 23857714 Enantiomeric separation of proton pump inhibitors on new generation chiral columns using LC and supercritical fluid chromatography. The enantioselectivity of proton pump inhibitors, namely, omeprazole, lansoprazole, rabeprazole, pantoprazole, tenatoprazole, and ilaprazole were studied using new generation chiral packing materials: CHIRALPAK IA, CHIRALPAK IB, and CHIRALPAK IC. Two versatile techniques, HPLC and supercritical fluid chromatography (SFC) were used in this study. CHIRALPAK IC has shown superior selectivity under both LC and SFC conditions, whereas CHIRALPAK IA has shown good selectivity in SFC when compared to LC under primary screening conditions. The chiral recognition ability in LC and SFC modes were found to be in the order CHIRALPAK IC > CHIRALPAK IA > CHIRALPAK IB. In addition to diode array detection, chiral detection was carried out using a laser polarimeter and the elution orders were found to be the same in both LC and SFC elution modes. Mobile phase modifiers and column temperature effects were also studied. In SFC, modifiers (cosolvent) elution strength was found to be in the order ethanol > methanol > 2-propanol > acetonitrile. In both LC and SFC, a decrease in retention and increase in resolution with an increase in temperature was noticed for all the proton pump inhibitors. 23907727 The role of GSTs in the tolerance of Rhizobium leguminosarum to cadmium. A high intraspecific difference in cadmium (Cd) tolerance exits among Rhizobium leguminosarum strains. The higher tolerance to Cd appeared to be related to the efficiency of the glutathione (GSH)-Cd chelation mechanism, but it is not known how efficiency is influenced. Thus, in this work it was intended to investigate the traits behind the efficiency of intracellular Cd chelation by GSH. Glutathione-S-transferases (GST; EC 2.5.1.18) are a family of multi-functional dimeric proteins, found in both prokaryotes and eukaryotes, which are implicated in a variety of stress conditions. The common feature of these enzymes is to catalyze the conjugation of the sulfur atom of GSH with a large variety of hydrophobic toxic compounds of both endogenous and exogenous origin. Taking into account the reactions catalyzed by GSTs, it was hypothesized that they could be involved in the GSH-Cd complex formation in R. leguminosarum. Differences in GSTs activity between strains could explain variation in Cd chelation efficiency detected among strains and, consequently, discrepancy in tolerance to Cd. Thus, GST isoforms of R. leguminosarum strains with distinct tolerances to Cd were purified and their activity investigated. The relationship between chelation efficiency and enzymatic activity of GSTs was demonstrated, supporting the hypothesis that GSTs, in particular one isoform, was involved in the formation of GSH-Cd complexes and in the tolerance of Rhizobium to Cd. 23108716 The hypothalamus-adipose axis is a key target of developmental programming by maternal nutritional manipulation. Epidemiological studies initially demonstrated that maternal undernutrition leading to low birth weight may predispose for energy balance disorders throughout life. High birth weight due to maternal obesity or diabetes, inappropriate early post-natal nutrition and rapid catch-up growth may also sensitise to increased risk of obesity. As stated by the Developmental Origin of Health and Disease concept, the perinatal perturbation of foetus/neonate nutrient supply might be a crucial determinant of individual programming of body weight set point. The hypothalamus-adipose axis plays a pivotal role in the maintenance of energy homoeostasis controlling the nutritional status and energy storage level. The perinatal period largely corresponds to the period of brain maturation, neuronal differentiation and active adipogenesis in rodents. Numerous dams and/or foetus/neonate dietary manipulation models were developed to investigate the mechanisms underlying perinatal programming in rodents. These models showed several common offspring hypothalamic consequences such as impaired neurogenesis, neuronal functionality, nuclei structural organisation and feeding circuitry hardwiring. These alterations led to a persistent reprogrammed appetite system that favoured the orexigenic pathways, leptin/insulin resistance and hyperphagia. Impaired hypothalamic sympathetic outflow to adipose tissue and/or reduced innervation may also account for modified fat cell metabolism. Thus, enhanced adipogenesis and/or lipogenesis capacities may predispose the offspring to fat accumulation. Abnormal hypothalamus-adipose axis circadian rhythms were also evidenced. This review mainly focuses on studies in rodents. It highlights hormonal and epigenetic mechanisms responsible for long-lasting programming of energy balance in the offspring. Dietary supplementation may provide a therapeutic option using a specific regimen for reversing adverse programming outcomes in humans. 23937529 Texturing formulations for uranium skin decontamination. Abstract Context: Since no specific treatment exists in case of cutaneous contamination by radionuclides such as uranium, a nanoemulsion comprising calixarene molecules, known for their good chelation properties, was previously designed. However, this fluid topical form may be not suitable for optimal application on the skin or wounds. Objective: To develop a texturing pharmaceutical form for the treatment of wounded skins contaminated by uranium. Materials and methods: The formulations consisted in oil-in-water (O/W) nanoemulsions, loaded with calixarene molecules. The external phase of the initial liquid nanoemulsion was modified with a combination of thermosensitive gelifying polymers: Poloxamer and HydroxyPropylMethylcellulose (HPMC) or methylcellulose (MC). These new formulations were characterized then tested by ex vivo experiments on Franz cells to prevent uranyl ions diffusion through excoriated pig ear skin explants. Results: Despite strong changes in rheological properties, the physico-chemical characteristics of the new nanoemulsions, such as the size and the zeta potential as well as macroscopic aspect were preserved. In addition, on wounded skin, diffusion of uranyl ions, measured by ICP-MS, was limited to less than 5% for both HPMC and MC nanoemulsions. Conclusions: These results demonstrated that a hybrid formulation of nanoemulsion in hydrogel is efficient to treat uranium skin contamination. 23850500 Molecular phylogenetics of geographically restricted Acropora species: Implications for threatened species conservation. To better understand the underlying causes of rarity and extinction risk in Acropora (staghorn coral), we contrast the minimum divergence ages and nucleotide diversity of an array of species with different range sizes and levels of threat. Time-calibrated Bayesian analyses based upon concatenated nuclear and mitochondrial sequence data implied contemporary range size and vulnerability are linked to species age. However, contrary to previous hypotheses that suggest geographically restricted Acropora species evolved in the Plio-Pleistocene, the molecular phylogeny depicts some Indo-Australian species have greater antiquity, diverging in the Miocene. Species age is not related to range size as a simple positive linear function and interpreting the precise tempo of evolution in this genus is greatly complicated by morphological homoplasy and a sparse fossil record. Our phylogenetic reconstructions provide new examples of how morphology conceals cryptic evolutionary relationships in this keystone genus, and offers limited support for the species groupings currently used in Acropora systematics. We hypothesize that in addition to age, other mechanisms (such as a reticulate ancestry) delimit the contemporary range of some Acropora species, as evidenced by the complex patterns of allele sharing and paraphyly we uncover. Overall, both new and ancient evolutionary information may be lost if geographically restricted and threatened Acropora species are forced to extinction. In order to protect coral biodiversity and resolve the evolutionary history of staghorn coral, further analyses based on comprehensive and heterogeneous morphological and molecular data utilizing reticulate models of evolution are needed. 23871205 Complex metabolic interactions between benzo(a)pyrene and tributyltin in presence of dichlorodiphenyltrichloroethane in South American catfish Rhamdia quelen. In an attempt to explore complex metabolic interactions between toxicants present in polluted freshwater, hepatic metabolism of benzo(a)pyrene (BaP) and tributyltin (TBT) in fish was investigated when these compounds were administrated alone, mixed together and along with dichlorodiphenyltrichloroethane (DDT). Ten Rhamdia quelen per group were treated with a single intra-peritoneal (IP) dose (5-day experiment) or three successive doses (15-day experiment) either containing BaP (0.3; 3 or 30mgkg(-1)) or TBT (0.03; 0.3 or 3mgkg(-1)) or a combination of BaP+TBT, BaP+DDT, TBT+DDT and BaP+TBT+DDT under their respective lower doses, with DDT dose kept at 0.03mgkg(-1). Tetrahydroxy-benzo(a)pyrene (BaP-tetrol-I), and dibutyltin (DBT) and monobutyltin (MBT) were analyzed to assess BaP and TBT hepatic metabolism, respectively. A significant difference in BaP-tetrol-I concentration was observed in liver and bile between the lowest and the highest doses of BaP in both 5 and 15-day experiments. In the 15-day experiment, the presence of TBT with BaP reduced the amount of BaP-tetrol-I in bile compared to the BaP alone. The time of exposure and the number of doses affected BaP-tetrol-I concentration in the bile of fish exposed to BaP 0.3mgkg(-1) and BaP+DDT. TBT and its metabolites concentrations showed a dose-dependent increase in the liver in both experiments and in the bile in the 5-day experiment. TBT at its lowest dose was completely metabolized into DBT and MBT in the liver in the 15-day experiment. No TBT metabolites were detected in the bile of fish exposed to the mixtures in the 5-day experiment, except for a small MBT amount found in BaP+TBT+DDT. This study strengthens the hypothesis of a metabolic interaction between BaP and TBT in fish and suggests DDT as an important third player when present in the mixture. 23714223 Estimation of wall properties and wall strength of aortic aneurysms using modern imaging techniques. One more step towards a patient-specific assessment of aneurysm rupture risk. Abdominal aortic aneurysmal disease is a major health problem with rupture representing its main complication accompanied by great mortality. Elective repair is currently performed with mortality rates <3%, based upon size or expansion rate, with a recommended threshold of 5.5 cm maximum diameter or >1cm/year enlargement. It is well established that even small AAAs without indication for surgical repair can experience rupture with catastrophic outcomes whereas larger aneurysms often remain intact for a long period. It is recognized, therefore, that the currently used, maximum diameter criterion can not accurately predict AAAs evolution. There is increasing interest in the role of patient-specific biomechanical profiling of AAA development and rupture. Biomechanically, rupture of a vessel occurs when intravascular forces exceed vessel wall structural endurance. Peak Wall Stress (PWS) has been previously shown to better identify AAAs prone to rupture than maximum diameter, but currently stress analysis takes into account several assumptions that influence results to a large extent and limit their use. Moreover stress represents only one of two determinants of rupture risk according to the biomechanical perspective. Wall strength and mechanical properties on the other hand cannot be assessed in vivo but only ex vivo through mechanical studies with mean values of these parameters taken into account for rupture risk estimations. New possibilities in the field of aortic imaging offer promising tools for the validation and advancement of stress analysis and the in vivo evaluation of AAAs' wall properties and wall strength. Documentation of aortic wall motion during cardiac cycle is now feasible through ECG-gated multi-detector CT imaging offering new possibilities towards an individualized method for rupture risk and expansion-rate predictions based on data acquired in vivo. 23962313 Does coping mediate the relationship between familism and caregiver outcomes? Objectives: The sociocultural model of stress and coping, which despite receiving support from several studies conducted with diverse ethnic groups, has yet to be tested longitudinally or used within the context of positive caregiver outcomes. The aim of the current study was to test a specific component of the model, which posits that caregiver coping will be influenced by the cultural value of familism (feelings of solidarity and loyalty among family members), which will in turn affect caregiver outcomes. Method: A questionnaire was completed by 123 family caregivers in the UK assessing familism, use of coping strategies, caregiver gains, anxiety and depression at three time points over nine months. Results: Mediation analysis followed guidelines proposed by Baron and Kenny. Religious coping and positive reframing at time 2 (T2) were found to significantly mediate between familism values at time 1 (T1) and caregiver gains at time 3 (T3). Behavioural disengagement at T2 was found to mediate between familism at T1 and caregiver depression atT3. Additionally familism was found to be positively associated with both negative and positive aspects of caregiving. Conclusion: Our longitudinal findings suggest that interventions and services acknowledging caregiver values and the associated coping responses may prove beneficial. 23895306 c-fos down-regulation inhibits testosterone-dependent male sexual behavior and the associated learning. Environmental stimulation results in an increased expression of transcription factors called immediate early genes (IEGs) in specific neuronal populations. In male Japanese quail, copulation with a female increases the expression of the IEGs zenk and c-fos in the medial pre-optic nucleus (POM), a key nucleus controlling male sexual behavior. The functional significance of this increased IEG expression that follows performance of copulatory behavior is unknown. We addressed this question by repeatedly quantifying the performance of appetitive (learned social proximity response) and consummatory (actual copulation) sexual behavior in castrated, testosterone-treated males that received daily intra-cerebroventricular injection of an antisense oligodeoxynucleotide targeting c-fos or control vehicle. Daily antisense injections significantly inhibited the expression of copulatory behavior as well as the acquisition of the learned social proximity response. A strong reduction of the proximity response was still observed in antisense-treated birds that copulated with a female, ruling out the indirect effect of the absence of interactions with females on the learning process. After a 2-day interruption of behavioral testing but not of antisense injections, birds were submitted to a final copulatory test that confirmed the behavioral inhibition in antisense-injected birds. Brains were collected at 90 min after the behavioral testing for quantification of c-fos-immunoreactive cells. A significant reduction of the number of c-fos-positive cells in the POM but not in other brain regions was observed following antisense injection. Taken together, the data suggest that c-fos expression in the POM modulates copulatory behavior and sexual learning in male quail. 23782859 Clinical features and virological analysis of a case of Middle East respiratory syndrome coronavirus infection. The Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging virus involved in cases and case clusters of severe acute respiratory infection in the Arabian Peninsula, Tunisia, Morocco, France, Italy, Germany, and the UK. We provide a full description of a fatal case of MERS-CoV infection and associated phylogenetic analyses. We report data for a patient who was admitted to the Klinikum Schwabing (Munich, Germany) for severe acute respiratory infection. We did diagnostic RT-PCR and indirect immunofluorescence. From time of diagnosis, respiratory, faecal, and urine samples were obtained for virus quantification. We constructed a maximum likelihood tree of the five available complete MERS-CoV genomes. A 73-year-old man from Abu Dhabi, United Arab Emirates, was transferred to Klinikum Schwabing on March 19, 2013, on day 11 of illness. He had been diagnosed with multiple myeloma in 2008, and had received several lines of treatment. The patient died on day 18, due to septic shock. MERS-CoV was detected in two samples of bronchoalveolar fluid. Viral loads were highest in samples from the lower respiratory tract (up to 1·2 × 10(6) copies per mL). Maximum virus concentration in urine samples was 2691 RNA copies per mL on day 13; the virus was not present in the urine after renal failure on day 14. Stool samples obtained on days 12 and 16 contained the virus, with up to 1031 RNA copies per g (close to the lowest detection limit of the assay). One of two oronasal swabs obtained on day 16 were positive, but yielded little viral RNA (5370 copies per mL). No virus was detected in blood. The full virus genome was combined with four other available full genome sequences in a maximum likelihood phylogeny, correlating branch lengths with dates of isolation. The time of the common ancestor was halfway through 2011. Addition of novel genome data from an unlinked case treated 6 months previously in Essen, Germany, showed a clustering of viruses derived from Qatar and the United Arab Emirates. We have provided the first complete viral load profile in a case of MERS-CoV infection. MERS-CoV might have shedding patterns that are different from those of severe acute respiratory syndrome and so might need alternative diagnostic approaches. European Union; German Centre for Infection Research; German Research Council; and German Ministry for Education and Research. 23397510 Prolactin and sex steroids levels in congenital lifetime isolated GH deficiency. Growth hormone (GH) and prolactin share similarities in structure and function. We have previously shown that women with congenital isolated GH deficiency (IGHD) caused by a homozygous mutation in the GHRH receptor gene (GHRHR) (MUT/MUT) have a short reproductive life, with anticipated climacteric. At climacteric, they have lower prolactin levels than normal controls (N/N). Because they are able to breast feed, we hypothesized that this prolactin reduction is limited to climacteric, as result of lower estradiol exposure of the lactotrophs. The purposes of this work were to assess prolactin levels in broader age adults homozygous and heterozygous (MUT/N) for the mutation and in normal controls (N/N), and to correlate them to sex steroids levels. We enrolled 24 GH-naïve MUT/MUT (12 female), 25 MUT/N (14 female), and 25 N/N (11 female) subjects, aged 25-65 years. Anthropometric data and serum prolactin, estradiol, total testosterone, and sex hormone binding globulin (SHBG) were measured. Free testosterone was calculated. Prolactin levels were similar in the three groups. In males, testosterone and SHBG levels were higher in MUT/MUT in comparison to N/N. There was no difference in free testosterone among groups. In all 74 individuals, prolactin correlated inversely with age (p < 0.0001) and directly with serum estradiol (p = 0.018). Prolactin levels in subjects with IGHD due to a homozygous GHRHR mutation are similar to heterozygous and normal homozygous, but total testosterone and SHBG are higher in male MUT/MUT, with no difference in free testosterone. The reduced prolactin level is limited to climacteric period, possibly due to reduced estrogen exposure. 23732849 Purification, characterization and functional analysis of a novel β-1, 3-glucan binding protein from green tiger shrimp Penaeus semisulcatus. A β-1, 3-Glucan binding protein (β-GBP) was isolated from green tiger shrimp Penaeus semisulcatus and purified using laminarin precipitation and affinity chromatography on laminarin-Sepharose 6B column respectively. P. semisulcatus β-GBP exhibits a single band with a molecular weight of 112 kDa on SDS-PAGE and pI of 5.9 in isoelectric focusing (IEF). Negative staining of P. semisulcatus β-GBP showed large aggregates with crystalline surface when viewed by Electron Microscopy. Circular dichroism spectra of P. semisulcatus β-GBP showed broad negative minimum wavelength extending from 200 to 250 nm can be attributed to the presence of β-sheets in its secondary structure. P. semisulcatus β-GBP comprises the specific binding affinity with the polysaccharide β-1, 3-glucans (laminarin), this recognition and binding leads to the activation of prophenoloxidase cascade. Interestingly, P. semisulcatus β-GBP also involved in the agglutination of baker's yeast, bacteria, erythrocytes (RBCs) and enhances the PO activity. Herein, we have investigated the importance of β-GBP in innate immune response of P. semisulcatus and they implicate the evolutionary link with similar proteins found in other invertebrates. 23712819 Comparison of in vitro-in vivo extrapolation of biliary clearance using an empirical scaling factor versus transport-based scaling factors in sandwich-cultured rat hepatocytes. Biliary clearance (CLb ) is often underestimated by in vitro-in vivo extrapolation from sandwich-cultured hepatocytes (SCHs). The objective of this study was to compare the performance of a universal correction factor with transporter-based correction factors in correcting underestimation of CLb . The apparent in vitro CLb of a training set of 21 compounds was determined using the SCH model and extrapolated to apparent in vivo CLb (CLb, app ). A universal correction factor (10.2) was obtained by a linear regression of the predicted CLb, app and observed in vivo CLb of training set compounds and applied to an independent test set (n = 20); the corrected CLb predictions of 13 compounds were within twofold error of observed values. Furthermore, two transporter-based correction factors (Organic anion transporting polypeptides/multidrug-resistance-related protein 2 and diffusion/P-glycoprotein) were estimated by linear regression analysis of training set compounds. The applications of the two correction factors to the test set resulted in improved prediction precision. In conclusion, both the universal correction factor and transporter-based correction factors provided reasonable corrections of CLb values, which are often underestimated by the SCH model. The use of transporter-based correction factors resulted in an even greater improvement of predictions for compounds with intermediate-to-high CLb values. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2837-2850, 2013. 23072715 Depression and pain among inpatients with spinal cord injury and spinal cord disease: differences in symptoms and neurological function. To examine the relationship between depression and pain severity during inpatient rehabilitation for those with new onset of spinal cord injury or spinal cord disease (SCI/D), along with patient characteristics, neurological function and etiology. This cross-sectional study reviewed medical records of 100 adults with SCI/D including their admission scores on the Patient Health Questionnaire 9 (PHQ-9), a measure of depression, and pain ratings collected at admission and discharge. Upon admission, 28% reported moderate-to-severe symptoms of depression and 69% reported pain. PHQ-9 scores were associated with pain only among those with the least severe impairments, for whom higher scores were associated with greater pain. While depression levels did not differ by etiology, those with traumatic injuries had higher pain ratings. In general, depressive symptoms were not associated with pain severity in this sample. Etiology was associated with pain, those with traumatic SCI reporting more pain at admission. Among demographic characteristics, age was related to pain, with younger subjects reporting higher levels. These findings suggest that certain characteristics may predispose patients to pain and depression upon admission to rehabilitation. By determining who is at risk for these symptoms, clinicians can adopt treatments that prevent these from becoming chronic conditions. 23870220 Outcomes of hepatectomy for hepatolithiasis based on 3-dimensional reconstruction technique. The aim of our study was to evaluate the perioperative and long-term outcomes of hepatectomy based on 3-dimensional reconstruction technique for hepatolithiasis by comparing it with traditional hepatectomy. From December 2005 to September 2012, 56 consecutive patients underwent hepatectomy based on 3-dimensional reconstruction technique for hepatolithiasis in our hospital (group A). During the same period, 42 patients with hepatolithiasis who met the inclusion criteria for hepatectomy were selected for traditional hepatectomy (group B). All operations were performed by the authors. There was no significant difference in preoperative data between the 2 groups statistically. Compared with patients in group B, those in group A had a significantly lower stone residual rate (intermediate rate, 3.6% vs 19.0%; final rate, 0% vs 9.5%) and stone recurrence rate (3.6% vs 23.8%), a lower intrahepatic duct stricture residual rate (1.8% vs 14.3%), and a faster operating time (218.8 ± 55.5 minutes vs 254.7 ± 65.6 minutes). Intraoperative blood transfusion, intraoperative blood loss, postoperative hospital stay, and recurrent cholangitis rate were similar. No significant dominance was found in group A with respect to serum aminotransferase level, serum bilirubin level, serum albumin level, and prothrombin time. There was a significant dominance in group A for serum hemoglobin level (116.3 ± 16.0 g/L vs 108.0 ± 13.9 g/L; p < 0.05). Twenty-two complications occurred, 10 in group A and 12 in group B. Neither group had any perioperative mortality. Hepatectomy for hepatolithiasis based on 3-dimensional reconstruction technique is feasible and safe in selected patients. Compared with traditional hepatectomy, it is more effective for diagnosis and treatment of hepatolithiasis. 23676422 Effect of serum folate status on total folate and 5-methyltetrahydrofolate in human skin. It has been suggested that human skin color adapts to balance the need for vitamin D synthesis in comparison with the protection of DNA and folate from photodegradation. However, the folate content of human skin is unknown and may affect the effectiveness of the antifolate methotrexate for the treatment of psoriasis. We examined whether total folate and 5-methyl-(6S)-tetrahydrofolate (5-MTHF) in human skin can be predicted by serum concentrations and whether there are differences in the proportion of 5-MTHF in dermis compared with epidermis. Total folate (by using a microbiological assay) and 5-MTHF (by using high-pressure liquid chromatography) were measured in fasting serum and fresh skin obtained at surgery by using a recovery validated extraction method. Total folate in human epidermis was shown to be low compared with in many other tissues, and dermal folate was an order-of-magnitude even lower. These concentrations were directly and linearly linked to serum folate status. Although the percentage of 5-MTHF of the total in the dermis was similar to that in other organs, it was especially high in the epidermis and increased to >65% as serum folate decreased. The high proportion of 5-MTHF in the epidermis, which is further emphasized in subjects with a lower (10-20-nmol/L) serum folate status, points to a special role for this form of folate in skin, perhaps as a protectant from ultraviolet-induced photosensitization reactions. 5-MTHF may also maintain methylation reactions that influence the proliferative activity. These results may help to individualize the treatment of psoriasis patients with methotrexate and folate. 23874753 Super Resolution Microscopy Reveals that Caveolin-1 Is Required for Spatial Organization of CRFB1 and Subsequent Antiviral Signaling in Zebrafish. Understanding spatial distribution and dynamics of receptors within unperturbed membranes is essential for elucidating their role in antiviral signaling, but conventional studies of detergent-resistant membrane fractions cannot provide this information. Caveolae are integral to numerous signaling pathways and these membrane domains have been previously implicated in viral entry but not antiviral defense. This study shows, for the first time, the importance of spatio-temporal regulation of signaling receptors and the importance of the regulation of clustering for downstream signaling. A novel mechanism for virus evasion of host cell defenses is demonstrated through disruption of clusters of signaling molecules organized within caveolin-rich domains. Viral infection leads to a downregulation in Caveolin-1b (Cav-1b), disrupting clusters of CRFB1, a zebrafish type I interferon receptor (-R) subunit. Super-resolution microscopy has enabled the first single-molecule imaging of CRFB1 association with cav-1b-containing membrane domains. Strikingly, downregulation of Cav-1b, the major protein component of caveolae, caused CRFB1 clusters to disperse. Dispersal of CRFB1 clusters led to a suppressed antiviral immune response both in vitro and in vivo, through abrogation of downstream signaling. This response strongly suggests that CRFB1 organization within cav-1b-containing membrane domains is critical for IFN-mediated antiviral defense and presents a previously undescribed antiviral evasion strategy to alter IFN signaling and the antiviral immune response. 23583438 Impact of weight change and weight cycling on risk of different subtypes of endometrial cancer. Obesity is an established risk factor for endometrial cancer. Associations tend to be stronger for the endometrioid subtype. The role of adult weight change and weight cycling is uncertain. Our study aimed to determine whether there is an association between different adult weight trajectories, weight cycling and risk of endometrial cancer overall, and by subtype. We analysed data from the Australian National Endometrial Cancer study, a population-based case-control study that collected self-reported information on height, weight at three time points (age 20, maximum and 1year prior to diagnosis [recent]), intentional weight loss/regain (weight cycling) from 1398 women with endometrial cancer and 1538 controls. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression analysis. Relative to women who maintained a stable weight during adulthood, greater weight gain after the age of 20 was associated with increased risk of endometrial cancer (OR for gain 40+kg all subtypes 5.3, 95% CI 3.9-7.3; endometrioid 6.5, 95% CI 4.7-9.0). The strongest associations were observed among women who were continually overweight from the age of 20 (all subtypes OR 3.6, 95% CI 2.6-5.0). Weight cycling was associated with increased risk, particularly among women who had ever been obese (OR 2.9 95% CI 1.8-4.7), with ∼3-fold risks seen for both endometrioid and non-endometrioid tumour subtypes. Women who had intentionally lost weight and maintained that weight loss were not at increased risk. These results suggest that higher adult weight gain, and perhaps weight cycling, independently increase the risk of endometrial cancer, however women who lost weight and kept that weight off were not at increased risk. 23828033 Is Routine Postoperative Gastrografin Study Needed After Laparoscopic Sleeve Gastrectomy? Experience of 712 Cases. The current standard of care is to perform a postoperative gastrografin study following laparoscopic sleeve gastrectomy (LSG) to detect leakage or obstruction. This study evaluated the usefulness of this routine procedure. A retrospective chart review was performed in December 2012. All patients had routine intraoperative methylene blue testing to check for possible leakage from the staple line, and any leaking points were oversewn. We also performed postoperative contrast study (gastrografin) routinely in the first 24-48 h for all patients. From June 2007 to December 2012, 712 cases underwent LSG during the study period. Patients included in this study were 556 women (78.1 %) and 156 men (21.9 %). The mean age was 35 years. The mean BMI was 48 kg/m(2). The operative time was 107 ±â€‰29 min, and there were no conversions to open surgery. Intraoperative methylene blue test detected leakage in 28 cases (3.93 %). Postoperative contrast study (gastrografin) was negative for leakage in all cases. Computed tomography (CT) scan with oral contrast study detected leakage in 1.4 % (ten cases); none of these cases were detected by regular contrast study. Our study showed that intraoperative methylene blue test for leakage is a very sensitive and effective method for detecting leakage during sleeve gastrectomy and should be done routinely in all cases. Routine postoperative contrast study is not needed to detect leakage unless clinically indicated in selected cases, and in such cases contrast-enhanced CT scans are the modality of choice. 23870324 Continuous renal replacement therapy in children after cardiac surgery. The objective was to study the clinical course of children requiring continuous renal replacement therapy (CRRT) after cardiac surgery and to analyze the factors associated with mortality. A prospective observational study was performed that included all children requiring CRRT after cardiac surgery, comparing these patients with other critically ill children requiring CRRT. Univariate and multivariate analyses were performed to determine the influence of each factor on mortality. Eighty-one (4.9%) of 1650 children undergoing cardiac surgery required CRRT; 65 of them (80.2%) presented multiorgan failure. Children starting CRRT after cardiac surgery had lower mean arterial pressure and lower urea and creatinine levels, and were more likely to require mechanical ventilation than other children on CRRT. The incidence of complications was similar. Cardiac surgery increased the probability of requiring CRRT for more than 14 days. Mortality was 43% in children receiving CRRT after cardiac surgery and 29% in other children (P = .05). Factors associated with mortality in the univariate analysis were age less than 12 months, weight less than 10 kg, higher Pediatric Risk of Mortality Score, hypotension, lower urea and creatinine on starting CRRT, and use of hemofiltration. In the multivariate analysis, the only factor associated with mortality was hypotension on starting CRRT (hazard ratio, 4.01; 95% confidence interval, 1.2-13.4; P = .024). Although only a small percentage of children undergoing cardiac surgery required CRRT, mortality in these patients was high. Hypotension at the time of starting the technique was the only factor associated with a higher mortality. 23249274 Interactions of NO2 with Zr-based MOF: effects of the size of organic linkers on NO2 adsorption at ambient conditions. Zirconium-based metal organic framework (Zr-MOF), UiO-66 and UiO-67, were synthesized and used as adsorbents of NO(2) at ambient temperatures in either dry or moist conditions. The samples were characterized before and after exposure to NO(2) by X-ray diffraction, scanning electron microscopy, N(2)-adsorption at 77 K, thermal analysis, and infrared spectroscopy. The results indicate the important effect of a ligand size on the adsorption of NO(2) on Zr-MOF materials. While the large size of the 4,4-benzenebiphenyldicarboxylic acid (BDPC) ligand has a positive impact on the adsorption of NO(2) on UiO-67 in moist conditions, the opposite effect is found in dry conditions. The large pore volume of UiO-67 enhances the adsorption of moisture and formation of nitric and nitrous acids. The small pore sizes of UiO-66 favor the NO(2) removal in dry conditions via dispersive forces. Upon interaction of NO(2) molecules with the Zr-MOF in dry conditions, the bond between the organic linker and metallic oxide center is broken, leading to the formation of nitrate and nitrite species. Moreover, organic ligands also contribute to the NO(2) reactive adsorption via nitration reaction. 23775260 Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study. Pulmonary hypertension caused by systolic left ventricular dysfunction is associated with significant morbidity and mortality; however, no treatment is approved for this indication. We hypothesized that riociguat, a novel soluble guanylate cyclase stimulator, would have beneficial hemodynamic effects in patients with pulmonary hypertension caused by systolic left ventricular dysfunction. Overall, 201 patients with heart failure resulting from pulmonary hypertension caused by systolic left ventricular dysfunction were randomized to double-blind treatment with oral placebo or riociguat (0.5, 1, or 2 mg 3 times daily) for 16 weeks in 4 parallel arms. The primary outcome was the placebo-corrected change from baseline at week 16 in mean pulmonary artery pressure. Although the decrease in mean pulmonary artery pressure in the riociguat 2 mg group (-6.1±1.3 mm Hg; P<0.0001 versus baseline) was not significantly different from placebo (P=0.10), cardiac index (0.4 L·min(-1)·m(-2); 95% confidence interval, 0.2-0.5; P=0.0001) and stroke volume index (5.2 mL·m(-2); 95% confidence interval, 2.0-8.4; P=0.0018) were significantly increased without changes in heart rate or systemic blood pressure compared with placebo. Both pulmonary (-46.6 dynes·s(-1)·cm(-5); 95% confidence interval, -89.4 to -3.8; P=0.03) and systemic vascular resistance (-239.3 dynes·s(-1)·cm(-5); 95% confidence interval, -363.4 to -115.3; P=0.0002) were significantly reduced with riociguat 2 mg. Riociguat reduced the Minnesota Living With Heart Failure score (P=0.0002). Discontinuation of treatment was similar between treatment groups. Although the primary end point of the study was not met, riociguat was well tolerated in patients with pulmonary hypertension caused by systolic left ventricular dysfunction and improved cardiac index and pulmonary and systemic vascular resistance. http://www.clinicaltrials.gov. Unique identifier: NCT01065454. 23916911 Unstimulated cortisol secretory activity in everyday life and its relationship with fatigue and chronic fatigue syndrome: A systematic review and subset meta-analysis. The hypothalamic-pituitary-adrenal (HPA) axis is a psychoneuroendocrine regulator of the stress response and immune system, and dysfunctions have been associated with outcomes in several physical health conditions. Its end product, cortisol, is relevant to fatigue due to its role in energy metabolism. The systematic review examined the relationship between different markers of unstimulated salivary cortisol activity in everyday life in chronic fatigue syndrome (CFS) and fatigue assessed in other clinical and general populations. Search terms for the review related to salivary cortisol assessments, everyday life contexts, and fatigue. All eligible studies (n=19) were reviewed narratively in terms of associations between fatigue and assessed cortisol markers, including the cortisol awakening response (CAR), circadian profile (CP) output, and diurnal cortisol slope (DCS). Subset meta-analyses were conducted of case-control CFS studies examining group differences in three cortisol outcomes: CAR output; CAR increase; and CP output. Meta-analyses revealed an attenuation of the CAR increase within CFS compared to controls (d=-.34) but no statistically significant differences between groups for other markers. In the narrative review, total cortisol output (CAR or CP) was rarely associated with fatigue in any population; CAR increase and DCS were most relevant. Outcomes reflecting within-day change in cortisol levels (CAR increase; DCS) may be the most relevant to fatigue experience, and future research in this area should report at least one such marker. Results should be considered with caution due to heterogeneity in one meta-analysis and the small number of studies. 23857638 Micafungin for empirical antifungal therapy in patients with febrile neutropenia: multicenter phase 2 study. Empirical antifungal therapy is the current standard of care for patients with febrile neutropenia unresponsive to broad-spectrum antimicrobials. Although a number of antifungal agents are currently available, the need remains for effective but less toxic alternatives for this indication. We therefore conducted a phase 2 study of micafungin for 80 patients with hematologic diseases who were suffering from persistent or recurrent fever after at least 96 h of antibacterial therapy. The patients were treated with micafungin at a fixed dose of 150 mg/day. Of the 78 evaluable patients, 54 (69 %) achieved defervescence by the time of neutrophil recovery, and 56 (72 %) completed the treatment in accordance with the provision of the protocol. Four patients developed invasive fungal infection, nine changed antifungal therapy because of lack of efficacy, and three discontinued micafungin because of drug-related adverse events. Based on the composite end point taking account of these, the overall treatment success rate was 60 %, with the lower limit of a 90 % confidence interval (50.3 %) exceeding the predefined threshold success rate (50 %). These findings show the efficacy and safety of micafungin for empirical antifungal therapy in patients with persistent or recurrent febrile neutropenia, warranting further investigation of this drug in a phase 3 study. 23917943 The Anatomy of a Community Health Center System-Level Intervention for Intimate Partner Violence. The US Preventive Services Task Force (USPSTF) now recommends screening for intimate partner violence (IPV) as part of routine preventive services for women. However, there is a lack of clarity as to the most effective methods of screening and referral. We conducted a 3-year community-based mixed-method participatory research project involving four community health centers that serve as safety net medical providers for a predominately indigent urban population. The project involved preparatory work, a multifaceted systems-level demonstration project, and a sustainability period with provider/staff debriefing. The goal was to determine if a low-tech system-level intervention would result in an increase in IPV detection and response in an urban community health center. Results highlight the challenges, but also the opportunities, for implementing the new USPSTF guidelines to screen all women of childbearing years for intimate partner violence in resource-limited primary care settings. 23951109 The GPVI - Fc Fusion Protein Revacept Reduces Thrombus Formation and Improves Vascular Dysfunction in Atherosclerosis without Any Impact on Bleeding Times. Glycoprotein VI (GPVI) is a key platelet receptor which mediates plaque-induced platelet activation and consecutive atherothrombosis, but GPVI is also involved in platelet-mediated atheroprogression. Therefore, interference in GPVI-mediated platelet activation has the potential to combine short-term and long-term beneficial effects, specificity and safety especially regarding bleeding complications. We investigated the effects of the soluble dimeric GPVI receptor fusion protein, Revacept, an antagonist of collagen-mediated platelet activation, in an animal model of atherosclerosis: twenty week old rabbits, which had been fed on a cholesterol-rich diet for 8 weeks, received Revacept (8 mg/kg) or control twice weekly for 4 weeks. Pharmacokinetics indicated a slight accumulation of the drug in the serum after repeated dosing of Revacept for 3 weeks. A significant improvement of endothelial dysfunction after 0.06 and 0.6 µg/min acetylcholine and a significant decrease of vessel wall thickening were found after Revacept treatment. Accordingly, aortic vessel weight was reduced, and plaque sizes, macrophage and T-cell invasion tended to be reduced in histological evaluations. Bleeding time was determined after tail clipping in mice. Revacept alone or in combination with widely used anti-platelet drugs revealed a high safety margin with no prolongation of bleeding times. Repeated doses of Revacept led to a significant improvement of endothelial dysfunction and vascular morphology in atherosclerotic rabbits. Furthermore, no influence of Revacept on bleeding time alone or in combinations with various anti-platelet drugs was found in mice. Thus, the inhibition of collagen-mediated platelet interaction with the atherosclerotic endothelium by Revacept exerts beneficial effects on morphology and vascular function in vivo and seems to have a wide therapeutic window without influencing the bleeding time. 23957842 Evaluation of Inhibitory Effect of phlorotannins from Ecklonia cava on Triglyceride Accumulation in Adipocyte. In the present study, methanolic extract of Ecklonia cava and its solvent-partitioned fractions were evaluated for their antiadipogenic effect in 3T3-L1 adipocytes. One of them, n-BuOH fraction, effectively reduced lipid accumulation and glucose consumption. In addition, the presence of n-BuOH fraction in adipocytes suppressed the regulations of adipogenic transcription factors, PPARγ and SREBP1c and adipogenic specific genes, FABP4, FABP1, FAS, LPL, HSL and ACS1. Further purification of n-BuOH fractions led to the isolation of six phlorotannins (1-6). The six phlorotannins effectively suppressed triglyceride accumulation Comparative analysis showed that lipid accumulation in adipocytes was dramatically attenuated in the presence of eckstolonol (4). 23534340 Anesthetic considerations in patients with mitochondrial defects. Mitochondrial disease, once thought to be a rare clinical entity, is now recognized as an important cause of a wide range of neurologic, cardiac, muscle, and endocrine disorders . The incidence of disorders of the respiratory chain alone is estimated to be about 1 per 4-5000 live births, similar to that of more well-known neurologic diseases . High-energy requiring tissues are uniquely dependent on the energy delivered by mitochondria and therefore have the lowest threshold for displaying symptoms of mitochondrial disease. Thus, mitochondrial dysfunction most commonly affects function of the central nervous system, the heart and the muscular system . Mutations in mitochondrial proteins cause striking clinical features in those tissues types, including encephalopathies, seizures, cerebellar ataxias, cardiomyopathies, myopathies, as well as gastrointestinal and hepatic disease. Our knowledge of the contribution of mitochondria in causing disease or influencing aging is expanding rapidly . As diagnosis and treatment improve for children with mitochondrial diseases, it has become increasingly common for them to undergo surgeries for their long-term care. In addition, often a muscle biopsy or other tests needing anesthesia are required for diagnosis. Mitochondrial disease represents probably hundreds of different defects, both genetic and environmental in origin, and is thus difficult to characterize. The specter of possible delayed complications in patients caused by inhibition of metabolism by anesthetics, by remaining in a biochemically stressed state such as fasting/catabolism, or by prolonged exposure to pain is a constant worry to physicians caring for these patients. Here, we review the considerations when caring for a patient with mitochondrial disease. 23909808 Emergent Properties of Nanosensor Arrays: Applications for Monitoring IgG Affinity Distributions, Weakly Affined Hypermannosylation, and Colony Selection for Biomanufacturing. It is widely recognized that an array of addressable sensors can be multiplexed for the label-free detection of a library of analytes. However, such arrays have useful properties that emerge from the ensemble, even when monofunctionalized. As examples, we show that an array of nanosensors can estimate the mean and variance of the observed dissociation constant (KD), using three different examples of binding IgG with Protein A as the recognition site, including polyclonal human IgG (KD μ = 19 μM, σ(2) = 1000 mM(2)), murine IgG (KD μ = 4.3 nM, σ(2) = 3 μM(2)), and human IgG from CHO cells (KD μ = 2.5 nM, σ(2) = 0.01 μM(2)). Second, we show that an array of nanosensors can uniquely monitor weakly affined analyte interactions via the increased number of observed interactions. One application involves monitoring the metabolically induced hypermannosylation of human IgG from CHO using PSA-lectin conjugated sensor arrays where temporal glycosylation patterns are measured and compared. Finally, the array of sensors can also spatially map the local production of an analyte from cellular biosynthesis. As an example, we rank productivity of IgG-producing HEK colonies cultured directly on the array of nanosensors itself. 23715728 Osteocyte-derived insulin-like growth factor I is essential for determining bone mechanosensitivity. This study sought to determine whether deficient Igf1 expression in osteocytes would affect loading-induced osteogenic response. Tibias of osteocyte Igf1 conditional knockout (KO) mice (generated by cross-breeding Igf1 floxed mice with Dmp1-Cre transgenic mice) and wild-type (WT) littermates were subjected to four-point bending for 2 wk. Microcomputed tomography confirmed that the size of tibias of conditional mutants was smaller. Loading with an equivalent loading strain increased periosteal woven bone and endosteal lamellar bone formation in WT mice but not in conditional KO mice. Consistent with the lack of an osteogenic response, the loading failed to upregulate expression of early mechanoresponsive genes (Igf1, Cox-2, c-fos) or osteogenic genes (Cbfa-1, and osteocalcin) in conditional KO bones. The lack of osteogenic response was not due to reduced osteocyte density or insufficient loading strain. Deficient osteocyte Igf1 expression reduced the loading-induced upregulation of expression of canonical Wnt signaling genes (Wnt10b, Lrp5, Dkk1, sFrp2). The loading also reduced (by 40%) Sost expression in WT mice, but the loading not only did not reduce but upregulated (∼1.5-fold) Sost expression in conditional KO mice. Conditional disruption of Igf1 in osteocytes also abolished the loading-induced increase in the bone β-catenin protein level. These findings suggest an impaired response in the loading-induced upregulation of the Wnt signaling in conditional KO mice. In summary, conditional disruption of Igf1 in osteocytes abolished the loading-induced activation of the Wnt signaling and the corresponding osteogenic response. In conclusion, osteocyte-derived IGF-I plays a key determining role in bone mechanosensitivity. 23851196 (-)-Epigallocatechin gallate amplifies interleukin-1-stimulated interleukin-6 synthesis in osteoblast-like MC3T3-E1 cells. We previously reported that interleukin-1 (IL-1), a potent bone resorptive cytokine, stimulates the synthesis of interleukin-6 (IL-6) via activation of p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase in osteoblast-like MC3T3-E1 cells, and that AMP-activated protein kinase (AMPK) negatively regulates the IL-1-induced IL-6 synthesis through the inhibitor of κB (IκB)/nuclear factor-κB (NF-κB) pathway. On the other hand, it is recognized that catechin possesses a beneficial property for bone metabolism. Among them, (-)-epigallocatechin gallate (EGCG) is an abundant and major bioactive component. In the present study, we investigated the effect of EGCG on the IL-1 stimulated IL-6 synthesis in osteoblast-like MC3T3-E1 cells. EGCG significantly enhanced the IL-1-stimulated IL-6 synthesis in a dose-dependent manner in the range between 50 and 100 Î¼M. EGCG increased the mRNA levels of IL-6 stimulated by IL-1. IL-1-induced phosphorylation of IκB and NF-κB were suppressed by EGCG. On the other hand, EGCG failed to affect the IL-1-induced phosphorylation of p44/p42 MAP kinase, p38 MAP kinase and AMPK. These results strongly suggest that EGCG enhances IL-1-stimulated IL-6 synthesis through inhibiting the AMPK-IκB/NF-κB pathway at the point between AMPK and IκB/NF-κB in osteoblasts. 23957696 Current intravesical therapy for non-muscle invasive bladder cancer. Introduction: Transurethral resection of the bladder tumour (TURBT) is still the standard initial treatment for non-muscle invasive bladder cancer (NMIBC). However, even after a radical resection, recurrence (30 - 80%) and progression (1 - 45%) are commonly seen. Intravesical therapy provides direct contact of the agent with the bladder mucosa and clearly has improved the outcome, especially in high-risk disease. Areas covered: The role of a good initial TURBT is emphasized. Risk assessment tools are discussed. Different intravesical therapies are enumerated according to the latest literature, with the emphasis on Bacillus Calmette-Guérin (BCG), including the discussion on the optimal dose and schedule. New developments are mentioned. Expert opinion: A radical TURBT is essential for good prognosis. For optimal visualisation of tumours, fluorescence techniques should be used with low threshold, especially in case of suspicion of carcinoma in situ (CIS). Increased completeness of the resection will lead to less persisting disease and less need for adjuvant treatment. A re-TURBT should be done when in doubt of radical resection (judged by the pathologist or the surgeon). Risk assessment is essential, but the available tools are outdated. A single post-operative instillation (SPI) with chemotherapy is only indicated in low-risk disease. BCG is the treatment of choice for high-grade disease. BCG should be given as maintenance. Awareness of deterioration of the prognosis after progression is of great importance. In BCG failures, cystectomy should be strongly advised. Chemotherapy in combination with hyperthermia seems to be a new promising treatment. 23964979 Tensor Hypercontraction Equation-of-Motion Second-Order Approximate Coupled Cluster: Electronic Excitation Energies in O(N(4)) Time. The tensor hypercontraction (THC) approximation is applied to equation-of-motion second-order approximate coupled cluster singles and doubles (EOM-CC2). The resulting method, THC-EOM-CC2, is shown to scale as O(N^4), a reduction of one order from the formal O(N^5) scaling of EOM-CC2. Numerical tests for a variety of molecules show that errors of less than 0.02 eV are introduced into the excitation energies. 23940810 Serum levels of fibroblast growth factor 19 are inversely associated with coronary artery disease in chinese individuals. The fibroblast growth factor 19 (FGF19) has been implicated in recent studies as a potential regulator of glucose and lipid metabolism, which may lead to atherosclerosis. Here, we investigated the association of FGF19 with the presence and severity of coronary artery disease (CAD) in a Chinese population. A total of 315 patients with suspected or established CAD, including 205 males and 110 postmenopausal females, were enrolled and assessed by coronary angiography. CAD severity was determined by the Gensini score. Serum FGF19 was measured by quantitative sandwich ELISA. FGF19 levels were not significantly different between male and female patients (median [interquartile range], 143.40 [87.96-250.80] vs. 141.60 [87.13-226.32] pg/mL, P = 0.773). CAD patients had lower levels of FGF19 than those without CAD (128.20 [80.62-226.58] vs. 188.00 [105.10-284.70] pg/mL, P = 0.007). FGF19 was negatively correlated with 2hPG (r = -0.150, P = 0.008), FINS (r = -0.169, P = 0.004), HOMA-IR (r = -0.171, P = 0.004), and the Gensini score (r = -0.141, P = 0.012), but positively correlated with HDL-c (r = 0.116, P = 0.041) and adiponectin (r = 0.128, P = 0.024). Moreover, FGF19 was found to be independently correlated with 2hPG (β = -0.146, P = 0.022) and adiponectin (β = 0.154, P = 0.016). After adjusting for other CAD risk factors, FGF19 was demonstrated to be an independent factor for Gensini score (β = -0.140, P = 0.019) and the presence of CAD (β = -1.248, P = 0.036). Serum FGF19 is associated with the presence and severity of CAD in a Chinese population. 23315416 Flavobacterium cutihirudinis sp. nov., isolated from the skin of the medical leech Hirudo verbana. A Gram-staining-negative, non-endospore-forming, yellow-pigmented strain (E89(T)) was isolated from the skin of the medical leech Hirudo verbana obtained from a leech farm located in Biebertal, Germany. 16S rRNA gene sequencing analysis showed that the isolate was grouped in the genus Flavobacterium. Strain E89(T) was most closely related to Flavobacterium chilense LM-09-Fp(T) (98.2 %), Flavobacterium chungangense CJ7(T) (98.1 %), and Flavobacterium oncorhynchi 631-08(T) (98.1 %). 16S rRNA gene sequence similarities to all other species of the genus Flavobacterium were ≤97.4 %. A menaquinone of the type MK-6 was found to be the predominant respiratory quinone and the polar lipid profile consisted of the major compounds phosphatidylethanolamine, phosphatidylserine, two unidentified aminolipids, one unknown phospholipid and two unknown lipids. The fatty acid profile was composed of iso-C15 : 0, C15 : 0, summed feature 3 (C16 : 1ω7c and/or iso-C15 : 0 2-OH) found in major amounts and several hydroxylated fatty acids in smaller amounts, among them iso-C15 : 0 3-OH and iso-C17 : 0 3-OH. All these data support the allocation of the isolate in the genus Flavobacterium. Physiological/biochemical characterization and DNA-DNA hybridizations with the type strains of the most closely related species allowed a clear phenotypic and genotypic differentiation of the strain. Based on these data, strain E89(T) represents a novel species of the genus Flavobacterium, for which the name Flavobacterium cutihirudinis sp. nov. is proposed. The type strain is E89(T) ( = DSM 25795(T) = LMG 26922(T) = CIP 110374(T)). 23406315 A genetically encoded and gate for cell-targeted metabolic labeling of proteins. We describe a genetic AND gate for cell-targeted metabolic labeling and proteomic analysis in complex cellular systems. The centerpiece of the AND gate is a bisected methionyl-tRNA synthetase (MetRS) that charges the Met surrogate azidonorleucine (Anl) to tRNA(Met). Cellular protein labeling occurs only upon activation of two different promoters that drive expression of the N- and C-terminal fragments of the bisected MetRS. Anl-labeled proteins can be tagged with fluorescent dyes or affinity reagents via either copper-catalyzed or strain-promoted azide-alkyne cycloaddition. Protein labeling is apparent within 5 min after addition of Anl to bacterial cells in which the AND gate has been activated. This method allows spatial and temporal control of proteomic labeling and identification of proteins made in specific cellular subpopulations. The approach is demonstrated by selective labeling of proteins in bacterial cells immobilized in the center of a laminar-flow microfluidic channel, where they are exposed to overlapping, opposed gradients of inducers of the N- and C-terminal MetRS fragments. The observed labeling profile is predicted accurately from the strengths of the individual input signals. 23908393 Host range and in vitro lysis of Listeria monocytogenes seafood isolates by bacteriophages. Listeria-infecting bacteriophages (listeriaphages) can be used to control Listeria monocytogenes in the food industry. However, the sensitivity of many of seafood-borne Listeria strains to phages has not been reported. This research investigated the host ranges of three listeriaphages (FWLLm1, FWLLm3 and FWLLm5) by the formation of lytic zones and plaques on host lawns and in vitro lysis kinetics of listeriaphage FWLLm3. The study also predicted the phage titres required to lyse host cells. The host ranges of the phages were determined using 50 L. monocytogenes strains, of which 48 were isolated from the seafood industry and two from clinical cases. Of the 50 strains, 36 were tested at 25 and 30  and the remainder (14) at 15 and 25 . Based on the formation of either discrete plaques or lytic zones (host kill zones), the host ranges of FWLLm1, FWLLm3 and FWLLm5 were about 87%, 81% and 87%, respectively, at 25 . Six L. monocytogenes strains from the seafood environment were insensitive to all three phages, while the other seafood strains (42) were phage-sensitive. The adsorption rate constant (k value) of listeriaphage FWLLm3 was between 1.2 × 10(-9) and 1.6 × 10(-9 )ml/min across four host strains in tryptic soy broth at 25 . The cultures (at 3-4 log colony-forming unit (CFU/ml) were completely lysed (<1 log CFU/ml) when cultures were infected with FWLLm3 at > 8.7 log phage-forming units (PFU/ml) for 30 min. Re-growth of phage-infected cultures was not detected after 24 h. The effective empirical phage titre was similar to the calculated titre using a kinetic model. Results indicate the potential use of the three phages for controlling L. monocytogenes strains in seafood processing environments. 23485431 Respiratory syncytial virus infection is strongly correlated with decreased mean platelet volume. To date, infections have usually been associated with elevations of the mean platelet volume. We correlated infection with respiratory syncytial virus (RSV) with changes in mean platelet volume (MPV). A consecutive series of patients with positive and negative rapid RSV assays and viral cultures, as well as children under 10 years of age with bronchoscopy for pneumonia or airway obstruction, were compared. The MPV was significantly lower in patients with positive versus negative rapid RSV assays (9.7±0.8 vs. 10.5±0.9 fl, p<0.001), as well as viral cultures (9.9±1.0 vs. 10.5±1.0 fl, p<0.001). Children with RSV undergoing bronchoscopy (n=7) also had significantly lower MPV than children without RSV (n=79) (8.8±1.0 vs. 10.2±1.1 fl, p<0.004). An MPV <8.9 fl had a sensitivity of 71% and specificity of 49% for RSV in children undergoing bronchoscopy. We conclude that infection with RSV is associated with decreased MPV and this may be clinically useful in children undergoing bronchoscopy. 23263989 The conserved PHD1-PHD2 domain of ZFP-1/AF10 is a discrete functional module essential for viability in Caenorhabditis elegans. Plant homeodomain (PHD)-type zinc fingers play an important role in recognizing chromatin modifications and recruiting regulatory proteins to specific genes. A specific module containing a conventional PHD finger followed by an extended PHD finger exists in the mammalian AF10 protein, among a few others. AF10 has mostly been studied in the context of the leukemic MLL-AF10 fusion protein, which lacks the N-terminal PHD fingers of AF10. Although this domain of AF10 is the most conserved region of the protein, its biological significance has not been elucidated. In this study, we used genetic and biochemical approaches to examine the PHD1-PHD2 region of the Caenorhabditis elegans ortholog of AF10, zinc finger protein 1 (ZFP-1). We demonstrate that the PHD1-PHD2 region is essential for viability and that the first PHD finger contributes to the preferred binding of PHD1-PHD2 to lysine 4-methylated histone H3 tails. Moreover, we show that ZFP-1 localization peaks overlap with H3K4 methylation-enriched promoters of actively expressed genes genomewide and that H3K4 methylation is important for ZFP-1 localization to promoters in the embryo. We predict that the essential biological role of the PHD1-PHD2 module of ZFP-1/AF10 is connected to the regulation of actively expressed genes during early development. 23891380 Quantitative analysis of conjugated and free estrogens in swine manure: Solutions to overcome analytical problems due to matrix effects. Although animal manure is an important source for environmental estrogens, quantitative analysis of estrogens in manure is complicated due to matrix interference. In the present study, chromatographic methods have been developed for quantification of conjugated and free estrogens in manure samples collected from pig farms. The whole manure samples, immediately after collection, were stored at 4°C, acidified (pH≈2.0) and spiked with (i) (13)C-labeled internal standards to account for possible storage related degradation and (ii) deuterium labeled internal standards for calibration and quantitative analysis. The liquid samples were extracted with ethyl acetate for separating conjugated and free estrogens. The solid samples were eluted with water for desorbing conjugated hormones followed by methanol for desorbing free hormones. The water and extracts were further purified using hydrophilic-lipophilic balance and/or aminopropyl cartridges. The conjugated estrogens were analyzed using high-performance liquid chromatograph-mass spectrometer, while the free estrogens were analyzed using gas chromatograph-mass spectrometer. The extraction and calibration methods used in the present study yielded excellent sensitivity, reproducibility and >85% recovery of both free and conjugated estrogens that was independent of the manure matrix. In general, the total estrogen loads in liquid and solid samples were 5.1mg/l and 4.93mg/kg, respectively. This may represent the hormonal load of approximately 2.3tons estrogen per day. 23749987 DMEAS: DNA methylation entropy analysis software. DMEAS is the first user-friendly tool dedicated to analyze the distribution of DNA methylation patterns for the quantification of epigenetic heterogeneity. It supports the analysis of both locus-specific and genome-wide bisulfite sequencing data. DMEAS progressively scans the mapping results of bisulfite sequencing reads to extract DNA methylation patterns for contiguous CpG dinucleotides. It determines the DNA methylation level and calculates methylation entropy for genomic segments to enable the quantitative assessment of DNA methylation variations observed in cell populations. Availability and implementation: DMEAS program, user guide and all the testing data are freely available from http://sourceforge.net/projects/dmeas/files/ davidxie@vt.edu Supplementary Information: Supplementary data are available at Bioinformatics online. 23857455 The effect of bisphosphonate acidity on the activity of a thymidylyltransferase. Thymidylyltransferases (thymidine diphospho pyrophosphorylases) are nucleotidylyltransferases that play key roles in the biosynthesis of carbohydrate components within bacterial cell walls and in the biosynthesis of glycosylated natural products. They catalyze the formation of sugar nucleotides concomitant with the release of pyrophosphate. Protein engineering of thymidylyltransferases has been an approach for the production of a variety of non-physiological sugar nucleotides. In this work, we have explored chemical approaches towards modifying the activity of the thymidylyltransferase (Cps2L) cloned from S. pneumoniae, through the use of chemically synthesized 'activated' nucleoside triphosphates with enhanced leaving groups, or by switching the metal ion co-factor specificity. Within a series of phosphonate-containing nucleoside triphosphate analogues, thymidylyltransferase activity is enhanced based on the acidity of the leaving group and a Brønsted-type analysis indicated that leaving group departure is rate limiting. We have also determined IC50 values for a series of bisphosphonates as inhibitors of thymidylyltransferases. No correlation between the acidity of the inhibitors (pKa) and the magnitude of enzyme inhibition was found. 23760100 Step-edge induced ordered growth: targeting to assemble super long horizontal nanowire alignment in large-scale. Nowadays, the development of nano-synthesis has turned to controllable design for specific demands in micro-nano device application, to be integrated into functional units more conveniently with low-cost and efficiency principles. In this case, an appropriate approach for directly obtaining horizontally aligned nanowires in a large scale would be of great significance in future micro-nano device integration. Here, on the HOPG surface, we managed to achieve this. The approach is versatile to various kinds of materials. Horizontally aligned nanowires of Al-C based materials, such as Al4C3 and Al4O4C, were achieved. All of the nanowires exhibit a high degree ordered alignments and possess super aspect ratios with uniform widths of about 100 nm and lengths on the millimeter level. We believe the assembly mechanism lies in a step-edge induced ordered growth process, through which quaternary Al-Si-O-C nanoball alignment could also be obtained. It is expected that this method could be beneficial to adjust many useful materials for micro device integration in the future. 23935093 A meta-analysis of cognitive-based behaviour change techniques as interventions to improve medication adherence. To describe and evaluate the use of cognitive-based behaviour change techniques as interventions to improve medication adherence. Systematic review and meta-analysis of interventions to improve medication adherence. Search of the MEDLINE, EMBASE, PsycINFO, CINAHL and The Cochrane Library databases from the earliest year to April 2013 without language restriction. References of included studies were also screened to identify further relevant articles. We used predefined criteria to select randomised controlled trials describing a medication adherence intervention that used Motivational Interviewing (MI) or other cognitive-based techniques. Data were extracted and risk of bias was assessed by two independent reviewers. We conducted the meta-analysis using a random effects model and Hedges' g as the measure of effect size. We included 26 studies (5216 participants) in the meta-analysis. Interventions most commonly used MI, but many used techniques such as aiming to increase the patient's confidence and sense of self-efficacy, encouraging support-seeking behaviours and challenging negative thoughts, which were not specifically categorised. Interventions were most commonly delivered from community-based settings by routine healthcare providers such as general practitioners and nurses. An effect size (95% CI) of 0.34 (0.23 to 0.46) was calculated and was statistically significant (p < 0.001). Heterogeneity was high with an I(2) value of 68%. Adjustment for publication bias generated a more conservative estimate of summary effect size of 0.21 (0.08 to 0.33). The majority of subgroup analyses produced statistically non-significant results. Cognitive-based behaviour change techniques are effective interventions eliciting improvements in medication adherence that are likely to be greater than the behavioural and educational interventions largely used in current practice. Subgroup analyses suggest that these interventions are amenable to use across different populations and in differing manners without loss of efficacy. These factors may facilitate incorporation of these techniques into routine care. 23885717 Genomic amplification is not a frequent event in uveal melanomas. This Correspondence relates to the article by Lake et al that reported copy number and genotyping analysis on formalin-fixed, paraffin-embedded samples using genome-wide SNP arrays version 6.0. 23340897 25-Hydroxyvitamin D in Obese Youth Across the Spectrum of Glucose Tolerance From Normal to Prediabetes to Type 2 Diabetes. OBJECTIVETo 1) determine if plasma 25-hydroxyvitamin D (25[OH]D) concentrations differ among obese youth with normal glucose tolerance (NGT) versus prediabetes versus type 2 diabetes, and 2) assess the relationships between 25(OH)D and in vivo insulin sensitivity and β-cell function in this cohort.RESEARCH DESIGN AND METHODSPlasma 25(OH)D concentrations were examined in banked specimens in 9- to 20-year-old obese youth (n = 175; male 42.3%, black 46.3%) (NGT, n = 105; impaired glucose tolerance [IGT], n = 43; type 2 diabetes, n = 27) who had in vivo insulin sensitivity and secretion measured by hyperinsulinemic-euglycemic and hyperglycemic clamp techniques and had an assessment of total body composition and abdominal adiposity.RESULTSThe mean age and BMI of the subjects were 14.3 ± 2.1 years and 35.7 ± 5.6 kg/m(2), respectively. BMI, plasma 25(OH)D, and the proportion of vitamin D-deficient and -insufficient children did not differ across the three groups. Furthermore, there was no association between 25(OH)D and in vivo insulin sensitivity or β-cell function relative to insulin sensitivity (disposition index) in all groups combined or in each group separately.CONCLUSIONSOur data in obese youth show 1) no differences in plasma 25(OH)D concentrations across the glucose tolerance groups, and 2) no relationship between 25(OH)D and in vivo insulin sensitivity and β-cell function relative to insulin sensitivity in any of the groups. It remains uncertain if enhancement of the vitamin D status could improve pathophysiological mechanisms of prediabetes and type 2 diabetes in obese youth. 23313730 The effect of manganese on dopamine toxicity and dopamine transporter (DAT) in control and DAT transfected HEK cells. Chronic exposure to Mn results in the development of a neurological disorder known as manganism characterized by neurological deficits resembling that seen in Parkinsonism. Although dopaminergic neurons within the nigrostriatal pathway appear intact, Mn-induced irregularities in DA transmission have been observed including decreased amphetamine-induced DA release and loss of the dopamine transporter (DAT). Results of studies to evaluate the effect of Mn and DA on cell viability in control and DAT-transfected HEK cells reveal that Mn is equally toxic to both cell lines whereas DA was only toxic to cells containing DAT. DA toxicity was saturable suggesting that transport may be rate limiting. When Mn and DA were added simultaneously to the media, cell toxicity was similar to that produced by Mn alone suggesting that Mn may suppress DA uptake in the DAT containing cells. Preincubation of DA prior to the addition of Mn resulted in cell death which was essentially additive with that produced independently by the two agents. Mn was also shown to decrease DA uptake and amphetamine-induced DA efflux in DAT containing cells. Time-lapsed confocal microscopy indicates that Mn can promote trafficking of cell surface DAT into intracellular compartments which may account for the decrease in DA uptake and DA efflux in these cells. Mn-induced internalization of DAT may provide an explanation for disruption in DA transmission previously reported in the striatum. 23852270 Cyclophilins as modulators of viral replication. Cyclophilins are peptidyl-prolyl cis/trans isomerases important in the proper folding of certain proteins. Mounting evidence supports varied roles of cyclophilins, either positive or negative, in the life cycles of diverse viruses, but the nature and mechanisms of these roles are yet to be defined. The potential for cyclophilins to serve as a drug target for antiviral therapy is evidenced by the success of non-immunosuppressive cyclophilin inhibitors (CPIs), including Alisporivir, in clinical trials targeting hepatitis C virus infection. In addition, as cyclophilins are implicated in the predisposition to, or severity of, various diseases, the ability to specifically and effectively modulate their function will prove increasingly useful for disease intervention. In this review, we will summarize the evidence of cyclophilins as key mediators of viral infection and prospective drug targets. 23881840 Triage of women with minor abnormal cervical cytology: Meta-analysis of the accuracy of an assay targeting messenger ribonucleic acid of 5 high-risk human papillomavirus types. High-risk human papillomavirus (hrHPV) DNA detection is generally accepted for the triage of women with a cytologic diagnosis of atypical squamous cells of undetermined significance (ASC-US). However, no consensus has been reached on the optimal management of low-grade squamous intraepithelial lesions (LSIL). In this meta-analysis, the diagnostic accuracy of nucleic acid sequence-based amplification (NASBA) detection of messenger ribonucleic acid (mRNA) of 5 hrHPV types (the PreTect HPV-Proofer and NucliSENS EasyQ tests) for detecting grade 2 cervical intraepithelial neoplasia or worse (CIN2+) and CIN3+ was assessed in women who had a diagnosis of ASC-US and LSIL. The results were compared with the Hybrid Capture-2 (HC2) assay, which detects the DNA of 13 hrHPV types. A bivariate random-effect model that incorporated the intrinsic correlation between the true-positive and false-positive rates was used for a pooled meta-analysis. Considering underlying CIN2+, the pooled absolute sensitivity of the 10 included studies was 75.4% (95% confidence interval [CI], 68.1%-82.7%) and 76.2% (95% CI, 68.3%-76.9%) for the triage of ASC-US and LSIL, respectively. The pooled absolute specificity to exclude CIN2+ was 77.9% (95% CI, 70.1%-85.7%) and 74.2% (95% CI, 69.5%-78.8%) in women with ASC-US and LSIL, respectively. Five studies allowed direct comparison of the mRNA assays with HC2. Considering CIN2+ in women with ASC-US and LSIL, mRNA testing was substantially more specific than the HC2 assay (ratio: 1.98 and 3.36, respectively; P < .001) but was less sensitive (ratio: 0.80 and 0.74, respectively; P < .001). HPV assays for detecting the mRNA of 5 hrHPV types may reduce the over-diagnosis of women who have minor cytologic abnormalities. However, given the lower sensitivity, women with negative mRNA test results cannot be considered free of CIN2+ and require further surveillance. Cancer (Cancer Cytopathol) 2013. © 2013 American Cancer Society. 23842493 Sequential deposition as a route to high-performance perovskite-sensitized solar cells. Following pioneering work, solution-processable organic-inorganic hybrid perovskites-such as CH3NH3PbX3 (X = Cl, Br, I)-have attracted attention as light-harvesting materials for mesoscopic solar cells. So far, the perovskite pigment has been deposited in a single step onto mesoporous metal oxide films using a mixture of PbX2 and CH3NH3X in a common solvent. However, the uncontrolled precipitation of the perovskite produces large morphological variations, resulting in a wide spread of photovoltaic performance in the resulting devices, which hampers the prospects for practical applications. Here we describe a sequential deposition method for the formation of the perovskite pigment within the porous metal oxide film. PbI2 is first introduced from solution into a nanoporous titanium dioxide film and subsequently transformed into the perovskite by exposing it to a solution of CH3NH3I. We find that the conversion occurs within the nanoporous host as soon as the two components come into contact, permitting much better control over the perovskite morphology than is possible with the previously employed route. Using this technique for the fabrication of solid-state mesoscopic solar cells greatly increases the reproducibility of their performance and allows us to achieve a power conversion efficiency of approximately 15 per cent (measured under standard AM1.5G test conditions on solar zenith angle, solar light intensity and cell temperature). This two-step method should provide new opportunities for the fabrication of solution-processed photovoltaic cells with unprecedented power conversion efficiencies and high stability equal to or even greater than those of today's best thin-film photovoltaic devices. 23727352 p38 MAP kinase activation does not stimulate serotonin transport in rat brain: Implications for sickness behaviour mechanisms. Several studies suggested an association between dysregulation of immune mediators and behavioural, neuroendocrine and neurochemical features of depression. Available data showed that cytokines affect the serotonin transporter (SERT) activity through p38 MAP kinase (MAPK)-dependent mechanisms in some cell lines and mice neurons (Zhu et al., Neuropsychopharmacology, 2006; 31:2121-31). The aim of this study was to investigate the interaction of Interleukin-1β (IL-1β) or p38 MAPK with SERT activity in rat brain and cell lines. Synaptosomes or cells were treated with IL-1β or the p38 MAPK activator anisomycin at different concentrations and end-points and the modulation of SERT activity as Km and Vmax was evaluated. Treatments with IL-1β or anisomycin did not affect serotonin uptake and p38 MAPK activation in rat synaptosomes, in contrast to reports in mice (Zhu et al., Neuropsychopharmacology, 2010; 35:2510-20). The same treatments activated p38 MAPK phosphorylation in HeLa cells used as positive controls. Similarly, no changes after anisomycin treatment could be detected in [(3)H]serotonin uptake rate in LLC-PK cells expressing human SERT, although phosphorylated p38 MAPK levels augmented significantly. Direct cytokine release in brain was induced by intracerebroventricular administration of bacterial lipopolysaccaride. Although pro-inflammatory cytokines, such as IL-1ß, IL6, and Tumor Necrosis Factor α, showed significant increases in brain cortex, modulation of SERT activity in term of Km and Vmax was not detected. These results imply that the stimulation of serotonin uptake by cytokines may not be a unique and fundamental mechanism in the pathology of depression induced by altered immune response. 23371536 Intraoperative recurrent laryngeal nerve monitoring in revision thyroidectomy. Recurrent laryngeal nerve (RLN) palsy is one of the most important complications after thyroid and parathyroid surgery. There is controversy in the literature regarding whether or not intraoperative nerve monitoring decreases the risk of injury. We report our experience using Nerve Integrity Monitoring (NIM) system in cases of revision thyroidectomy, providing clear indications for its use. A series of 97 patients who underwent revision thyroidectomy with and without intraoperative NIM alternately was evaluated. There were 121 RLN patients at risk. Use of NIM during revision thyroidectomy was not statistically significant compared to revision operation without monitoring (p value = 0.059). Furthermore, comparison of operative times either with or without NIM showed that use of NIM led to statistically significant prolonged operation time (p value <0.001). There is no strict indication to use RLN monitoring during thyroid surgery, especially as there is no statistical evidence that the use of this technique decreases the incidence of RLN palsy, although there is a trend especially in difficult revision cases. 23906062 Motors and MAPs Collaborate to Size Up Microtubules. Midzone microtubules keep chromosomes apart after segregation and provide a platform for cytokinesis factors. Reporting recently in Cell, Subramanian et al. (2013) describe how the motor protein kinesin-4 and the microtubule-associated protein PRC1 work together to mark microtubule ends for incorporation into the midzone in a length-dependent manner. 22676342 Two new phenolic glycosides from Inula cappa DC. Two new phenolic glycosides were isolated from the ethanol extract of the roots of Inula cappa DC. Their structures were defined as 4-[(6-O-(E)-caffeoyl)-β-D-glucopyranosyl]vanillic acid (1) and 3-O-[β-D-apiofurarnosyl-(1-6)-β-D-glucopyranoxy]-6-hydroxy-p-cymene (2) on the basis of spectral analysis. 23877308 Postoperative hemoglobin levels and its association with myocardial ischemia in non-cardiac surgical patients. Background: Low hemoglobin (Hb) levels as well as cardiac complications are common conditions in postoperative surgical patients and both are associated with poor outcome. The aim of this study was to determine the influence of postoperative Hb levels on myocardial ischemia in high-risk patients who underwent non-cardiac surgery. Methods: In this retrospective observational cohort study, we evaluated 3638 consecutive patients admitted to the 24-hour postoperative anesthesia care unit between 2006 and 2010. 273 (8%) high-risk patients, defined as three or more cardiac risk factors, were selected for analyses. Postoperative Hb levels were divided into tertiles (low, intermediate and high). The endpoint of this study was myocardial ischemia which was defined as new electrocardiographic abnormalities and/or elevated levels of troponin-T. The relationship between postoperative Hb levels and myocardial ischemia was assessed using logistic regression analyses stratified by gender. Results: Postoperative myocardial ischemia was present in 73 (27%) of the 273 patients. After adjustment for significant pre-, intra- and postoperative risk factors, 4 independent risk factors remained for postoperative myocardial ischemia in male patients: age (OR 1.1; 95% CI: 1.0 - 1.1), a history of ischemic heart diseases (OR 4.2; 95% CI: 1.0 - 17.8), renal failure (OR 5.4; 95% CI: 2.1 - 13.9) and postoperative Hb levels: intermediate tertile (10.3-11.6 g/dL) (OR 5.8; 95% CI: 1.6 - 20.9) and lowest tertile (7.9-10.2 g/dL) (OR 12.9; 95% CI: 3.0 - 55.5). Conclusion: Postoperative Hb levels are independently associated with postoperative myocardial ischemia in high-risk patients undergoing non-cardiac surgery. 23442787 Marine drugs best paper award 2013. To recognize the most outstanding papers in the area of research, development and production of drugs from the sea, including marine natural product chemistry, that have been published in Marine Drugs, we would like to start an annual "Best Paper Award". 23474269 Neutralization of Apis mellifera bee venom activities by suramin. In this work we evaluated the ability of suramin, a polysulfonated naphthylurea derivative, to antagonize the cytotoxic and enzymatic effects of the crude venom of Apis mellifera. Suramin was efficient to decrease the lethality in a dose-dependent way. The hemoconcentration caused by lethal dose injection of bee venom was abolished by suramin (30 μg/g). The edematogenic activity of the venom (0.3 μg/g) was antagonized by suramin (10 μg/g) in all treatment protocols. The changes in the vascular permeability caused by A. mellifera (1 μg/g) venom were inhibited by suramin (30 μg/g) in the pre- and posttreatment as well as when the venom was preincubated with suramin. In addition, suramin also inhibited cultured endothelial cell lesion, as well as in vitro myotoxicity, evaluated in mouse extensor digitorumlongus muscle, which was inhibited by suramin (10 and 25 μM), decreasing the rate of CK release, showing that suramin protected the sarcolemma against damage induced by components of bee venom (2.5 μg/mL). Moreover, suramin inhibited the in vivo myotoxicity induced by i.m. injection of A. mellifera venom in mice (0.5 μg/g). The analysis of the area under the plasma CK vs. time curve showed that preincubation, pre- and posttreatment with suramin (30 μg/g) inhibited bee venom myotoxic activity in mice by about 89%, 45% and 40%, respectively. Suramin markedly inhibited the PLA2 activity in a concentration-dependent way (1-30 μM). Being suramin a polyanion molecule, the effects observed may be due to the interaction of its charges with the polycation components present in A. mellifera bee venom. 23861759 Prenatal loud music and noise: differential impact on physiological arousal, hippocampal synaptogenesis and spatial behavior in one day-old chicks. Prenatal auditory stimulation in chicks with species-specific sound and music at 65 dB facilitates spatial orientation and learning and is associated with significant morphological and biochemical changes in the hippocampus and brainstem auditory nuclei. Increased noradrenaline level due to physiological arousal is suggested as a possible mediator for the observed beneficial effects following patterned and rhythmic sound exposure. However, studies regarding the effects of prenatal high decibel sound (110 dB; music and noise) exposure on the plasma noradrenaline level, synaptic protein expression in the hippocampus and spatial behavior of neonatal chicks remained unexplored. Here, we report that high decibel music stimulation moderately increases plasma noradrenaline level and positively modulates spatial orientation, learning and memory of one day-old chicks. In contrast, noise at the same sound pressure level results in excessive increase of plasma noradrenaline level and impairs the spatial behavior. Further, to assess the changes at the molecular level, we have quantified the expression of functional synapse markers: synaptophysin and PSD-95 in the hippocampus. Compared to the controls, both proteins show significantly increased expressions in the music stimulated group but decrease in expressions in the noise group. We propose that the differential increase of plasma noradrenaline level and altered expression of synaptic proteins in the hippocampus are responsible for the observed behavioral consequences following prenatal 110 dB music and noise stimulation. 23915671 The gold standard of dental care for the adult performance horse. This article discusses the primary odontogenic problems of the mature performance horse, including wolf teeth; hooks; overbite, overjet, underjet, and wry bite; equine odontoclastic tooth resorption and hypercementosis; infundibular caries; and secondary oral problems. It outlines the author's methods of taking the history, oral examination, and use of diagnostic nerve blocks. 23943000 Degradation pathways of low-ethoxylated nonylphenols by isolated bacteria using an improved method. Nonylphenol ethoxylates (NPEOs) with low ethoxylation degree (NPav2EO; containing two ethoxy units on average) and estrogenic properties are the intermediate products of nonionic surfactant NPEOs. To better understand the environmental fate of low-ethoxylated NPEOs, phylogenetically diverse low-ethoxylated NPEO-degrading bacteria were isolated from activated sludge using gellan gum as the gelling reagent. Four isolates belonging to four genera, i.e., Pseudomonas sp. NP522b in γ-Proteobacteria, Variovorax sp. NP427b and Ralstonia sp. NP47a in β-Proteobacteria, and Sphingomonas sp. NP42a in α-Proteobacteria were acquired. Ralstonia sp. NP47a or Sphingomonas sp. NP42a, have not been reported for the degradation of low-ethoxylated NPEOs previously. The biotransformation pathways of these isolates were investigated. The first three strains (NP522b, NP427b, and NP47a) exhibited high NPav2EO oxidation ability by oxidizing the polyethoxy (EO) chain to form low-ethoxylated nonylphenoxy carboxylates, and then further oxidizing the alkyl chain to form carboxyalkylphenol polyethoxycarboxylates. Furthermore, Sphingomonas sp. NP42a degraded NPav2EO through a nonoxidative pathway with nonylphenol monoethoxylate as the dominant product. 23334320 Post-mortem imaging in traffic fatalities: from autopsy to reconstruction of the scene using freely available software. CT scan coupled with autopsy is the gold standard for the forensic investigation of fatal road traffic accidents. The objective of the present paper is to demonstrate that from this, it is possible to reconstruct elements of an accident with minimal human and material resources using basic knowledge of three-dimensional imaging software. This is illustrated by a case implicating a pedestrian and a motor vehicle in which the impact areas were matched using freely available computer-aided design software. Such an approach aims to improve the visualisation of forensic elements, which is crucial for the understanding of all parties involved in the legal implications of such accidents and which could become the standard practice in many institutes. 23906767 The activation of adenosine monophosphate-activated protein kinase in rat hippocampus contributes to the rapid antidepressant effect of ketamine. Recent studies have shown a rapid, robust, and lasting antidepressant effect of ketamine that makes ketamine a promising antidepressant drug. However, the mechanisms underlying this rapid antidepressant effect remain incompletely understood. The goal of the present study was to determine whether adenosine monophosphate-activated protein kinase (AMPK) was involved in ketamine's rapid antidepressant effect during the forced swimming test (FST). In the first stage of experiment, a lower level of phosphorylated form of AMPK (p-AMPK) in the hippocampus and a longer immobility time were observed in the depressed rats during FST; whereas ketamine reversed these changes at 30min after the administration. In the second stage of experiment, we observed that, ketamine up-regulated the levels of p-AMPK and brain-derived neurotrophic factor (BDNF) in the hippocampus of the depressed rats. Moreover, AMPK agonist strengthened the antidepressant effect of ketamine with an up-regulation of BDNF, while AMPK antagonist attenuated the antidepressant effect of ketamine with a down-regulation of BDNF. In conclusion, our results suggest that the activation of AMPK in rat hippocampus is involved in the procedure of ketamine exerting rapid antidepressant effect through the up-regulation of BDNF. 23825218 Knockouts of Physcomitrella patens CHX1 and CHX2 Transporters Reveal High Complexity of Potassium Homeostasis. This study aims to increase our understanding of the functions of CHX transporters in plant cells using the model plant Physcomitrella patens, in which four CHX genes have been identified, PpCHX1-PpCHX4. Two of these genes, PpCHX1 and PpCHX2, are expressed at approximately the same level as the PpACT5 gene, but the other two genes show an extremely low expression. PpCHX1 and PpCHX2 restored growth of Escherichia coli mutants on low K(+)-containing media, suggesting that they mediated K(+) uptake that may be energized by symport with H(+). In contrast, these genes suppressed the defect associated with the kha1 mutation in Saccharomyces cerevisiae, which suggests that they might mediate K(+)/H(+) antiport. PpCHX1-green fluorescent protein (GFP) fusion protein transiently expressed in P. patens protoplasts co-localized with a Golgi marker. In similar experiments, the PpCHX2-GFP protein appeared to localize to tonoplast and plasma membrane. We constructed the ΔPpchx1 and ΔPpchx2 single mutant lines, and the ΔPpchx2 ΔPphak1 double mutant. Single mutant plants grew normally under all the conditions tested and exhibited normal K(+) and Rb(+) influxes; the ΔPpchx2 mutation did not increase the defect of ΔPphak1 plants. In long-term experiments, ΔPpchx2 plants showed slightly higher Rb(+) retention than wild-type plants, which suggests that PpCHX2 mediates the transfer of Rb(+) either from the vacuole to the cytosol or from the cytosol to the external medium in parallel with other transporters. The distinction between these two possibilities is technically difficult. We suggest that K(+) transporters of several families are involved in the pH homeostasis of organelles by mediating either K(+)/H(+) antiport or K(+)-H(+) symport. 23620059 A novel mechanism regulating insulin secretion involving Herpud1 in mice. Type 2 diabetes results from beta cell dysfunction after prolonged physiological stress, which causes oversecretion of insulin. We recently found that insulin hypersecretion is mediated by at least two genes. Among mouse models of type 2 diabetes, the DBA/2 mouse strain is more susceptible to diabetes than is the C57BL/6J (B6J) strain. One distinctive feature of the DBA/2 mouse is that it hypersecretes insulin, independent of changes in insulin sensitivity; we identified Nnt as a gene responsible for this trait. To identify the other gene(s) affecting insulin hypersecretion, we tested a panel of recombinant inbred BXD strains, which have different combinations of B6 and DBA/2 alleles. We found that 25% of the BXD strains hypersecreted insulin in response to glucose. Microarray profiling of islets from high- and low-secretor strains showed that at least four genes were differentially expressed. One gene was consistently underexpressed in islets from both DBA/2 and the high-secretor BXD strains. This gene (Herpud1 or Herp) encodes the 54 kDa endoplasmic reticulum stress-inducible protein (HERP) that resides in the integral endoplasmic reticulum membrane. To test directly whether Herpud1 can interact with Nnt, Herpud1 was either knocked down or overexpressed in MIN6 cells. These results showed that when Herpud1 was suppressed, Nnt expression was reduced, while overexpression of Herpud1 led to increased Nnt expression. Furthermore, Herpud1 suppression resulted in significantly decreased glucose-stimulated insulin secretion in the DBA/2 islets but not B6J islets. We conclude that Herpud1 regulates insulin secretion via control of Nnt expression. 23899834 Ab Initio Calculations of Possible γ-Gauche Effects in the 13C-NMR for Methine and Carbonyl Carbons in Precise Polyethylene Acrylic Acid Copolymers. The impacts of local polymer chain conformations on the methine and carbonyl 13C-NMR chemical shifts for polyethylene acrylic acid p(E-AA) copolymers were predicted using ab initio methods. Using small molecular cluster models, the magnitude and sign of the γ-gauche torsional angle effect, along with the impact of local tetrahedral structure distortions near the carbonyl group, on the 13C-NMR chemical shifts were determined. These 13C-NMR chemical shift variations were compared to the experimental trends observed for precise p(E-AA) copolymers as a function acid group spacing and degree of zinc-neutralization in the corresponding p(E-AA) ionomers. These ab initio calculations address the future ability of 13C-NMR chemical shift variations to provide information about the local chain conformations in p(E-AA) copolymer materials. 23481577 Lecithin/sphingomyelin ratio and lamellar body count for fetal lung maturity: a meta-analysis. To determine and compare the diagnostic accuracy of the lecithin/sphingomyelin (L/S) ratio and lamellar body count (LBC) in the prediction of neonatal respiratory distress syndrome (RDS). A systematic review was performed to identify studies comparing either the L/S ratio or the LBC with the occurrence of RDS published between January 1999 and February 2009. Two independent reviewers performed study selection and data extraction. For each study sensitivity and specificity were calculated. Summary receiver-operating characteristics (ROC) curves, assessing the diagnostic performance of both tests, were constructed. A subgroup analysis was performed to estimate the sensitivity and specificity of the various cut-off values. 13 studies were included. The ROC curves of the collected data illustrate that the LBC and L/S ratio perform equally well in the prediction of RDS. Comparison of the two summary ROC curves of each test indicates that the diagnostic performance of LBC might even have a slight advantage over L/S ratio. Due to the wide cut-off range it was not possible to define specific cut-off values with the best accuracy. We recommend replacing the L/S ratio as gold standard with the lamellar body count since the LBC is easy to perform, rapid, inexpensive, and available to all hospitals 24h per day. 23914865 Carotid artery stenting in patients with acute coronary syndrome: a possible primary therapy for symptomatic carotid stenosis. Purpose : To report the results of carotid artery stenting (CAS) in symptomatic patients (stroke/transient ischemic attack) after recent percutaneous transluminal coronary angioplasty (PTCA) for acute coronary syndrome (ACS). Methods : Between January 2009 and July 2011, 28 consecutive patients (18 women; mean age 66 years, range 42-82) underwent protected CAS for symptomatic carotid stenosis following recent PTCA that included bare or drug-eluting stents requiring uninterrupted dual antiplatelet therapy. Primary technical success, neurological complications, major adverse cardiovascular events, and death were evaluated at 30 days and over midterm follow-up. Results : Technical success was 96%; 1 patient suffered a nonfatal major stroke (3.5% 30-day stroke rate) during the procedure. During a median 21.6-month follow-up, 4 (14%) patients died of myocardial infarction (all diabetic smokers with ejection fractions <40%), but there were no new neurological events. Estimated survival was 89.3% at 2 years. Further coronary interventions were performed in 2 diabetic patients with a body mass index >34 kg/m(2). Conclusion : This preliminary experience demonstrated that CAS is a reasonable, safe, and effective treatment for patients with symptomatic carotid artery stenosis who were recently treated with coronary stents requiring uninterrupted dual antiplatelet therapy. 23146697 Answers to critics: Why there is a long term toxicity due to a Roundup-tolerant genetically modified maize and to a Roundup herbicide. Our recent work (Séralini et al., 2012) remains to date the most detailed study involving the life-long consumption of an agricultural genetically modified organism (GMO). This is true especially for NK603 maize for which only a 90-day test for commercial release was previously conducted using the same rat strain (Hammond et al., 2004). It is also the first long term detailed research on mammals exposed to a highly diluted pesticide in its total formulation with adjuvants. This may explain why 75% of our first criticisms arising within a week, among publishing authors, come from plant biologists, some developing patents on GMOs, even if it was a toxicological paper on mammals, and from Monsanto Company who owns both the NK603 GM maize and Roundup herbicide (R). Our study has limits like any one, and here we carefully answer to all criticisms from agencies, consultants and scientists, that were sent to the Editor or to ourselves. At this level, a full debate is biased if the toxicity tests on mammals of NK603 and R obtained by Monsanto Company remain confidential and thus unavailable in an electronic format for the whole scientific community to conduct independent scrutiny of the raw data. In our article, the conclusions of long-term NK603 and Roundup toxicities came from the statistically highly discriminant findings at the biochemical level in treated groups in comparison to controls, because these findings do correspond in an blinded analysis to the pathologies observed in organs, that were in turn linked to the deaths by anatomopathologists. GM NK603 and R cannot be regarded as safe to date. 23895691 Synthesis, Structure-Activity Relationship and Biological Activity of Acridine Derivatives as Potent MDR-reversing Agents. Multidrug resistance (MDR) mediated by P-glycoprotein is one of the best characterized transporter-mediated barriers to successful cancer chemotherapy. In an attempt to find MDR-reversing agents, a series of novel acridine derivatives were synthesized and evaluated for their in vitro antiproliferative activities against K562 and K562/ADM cells. Some of these compounds showed superior MDR-reversing activities than Amsacrine, the reference compound. Structure-activity relationships (SAR) of these compounds indicated that the N, N-diethylamine moiety had an affect on the in vitro antiproliferative activity. Interestingly, the compounds bearing N, N-diethylamine moiety showed higher growth-inhibitory activity against K562/ADM cells than K562 cells. The high duplex DNA binding affinity and inhibition of topoisomerase of these acridine compounds are maintained which were confirmed by fluorescent quenching and DNA topoisomerase II cleavage assay, respectively. Moreover, several compounds were examined for their ability to increase the accumulation of rhodamine 123 in K562 and K562/ADM cells, and the result suggested that they may be inhibitors for P-glycoprotein. Our study suggested that acridine framework is a potentially interesting scaffold for developing novel MDR-reversing agents. 23883949 Analysing photonic structures in plants. The outer layers of a range of plant tissues, including flower petals, leaves and fruits, exhibit an intriguing variation of microscopic structures. Some of these structures include ordered periodic multilayers and diffraction gratings that give rise to interesting optical appearances. The colour arising from such structures is generally brighter than pigment-based colour. Here, we describe the main types of photonic structures found in plants and discuss the experimental approaches that can be used to analyse them. These experimental approaches allow identification of the physical mechanisms producing structural colours with a high degree of confidence. 23933389 Quantitative versus qualitative data: The numerical dimensions of drug action. The application of detailed quantitative analyses of the concentration dependence of the biological responses mediated by endogenous hormones and other mediators, drugs, and compounds, has been the foundation of pharmacology for the past century or more. This approach has been remarkably successful in identifying the specific molecular targets for these mediators and drugs, in establishing the mechanisms for those effects at both the cellular and whole organismal levels, and in the development of new chemical entities (NCEs) with great selectivity for individual molecular targets. The availability of such compounds has unfortunately led to a mindset that detailed quantitative analyses are no longer necessary to use such compounds in understanding biological system function and to draw valid conclusions in regard to the utility of NCEs selective for putative drug targets in the potential treatment of human disease states. This lack of appreciation for quantitative approaches has contrubuted significantly to the all-too-frequent failures of new drug candidates in early stage clinical trials. The present article reviews basic drug target/receptor concepts together with the mathematical relationships that underlie the quantitative analysis of dose-response and concentration-effect relationships for individual compounds and for more complex systems, such as the comparative analysis of multiple compounds at a single receptor. A thorough understanding of these concepts and their associated analyses, along with their proper and rigorous application in all pre-clinical drug development studies, is an essential component of an integrated approach toward improving drug development. 23777424 A Functional Insertion/Deletion Polymorphism in the Promoter of PDCD6IP Is Associated with the Susceptibility of Hepatocellular Carcinoma in a Chinese Population. Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Apart from environmental factors such as hepatitis B virus (HBV) or hepatitis C virus, alcohol abuse, and exposure to dietary aflatoxin, genetic factors are also involved in the pathogenesis of HCC. By analyzing 390 HCC cases and 431 healthy controls in a Chinese population, we used a candidate gene approach to evaluate the association between a 15-bp insertion/deletion (indel) polymorphism (rs28381975) in the promoter region of the programmed cell death 6 interacting protein (PDCD6IP) gene and HCC susceptibility. Logistic regression analysis demonstrated that subjects carrying ins/del or ins/ins genotypes had significantly increased risk for HCC than individuals carrying del/del genotypes (adjusted odds ratio=1.39, 95% confidence interval=1.01-1.91, p=0.033]. Carrying the 15-bp insertion allele was associated with a 1.26-fold risk for HCC (95% CI=1.04-1.54, p=0.018). Moreover, significant differences were observed within HCC patients concerning genotypic frequencies of rs28381975 after stratifying by tumor stages and HBV infection. Computational modeling suggests that rs28381975 could disrupt the binding patterns of c-rel, a key subunit of nuclear factor-kappaB transcription factor. Further luciferase-based transient transfection assays revealed that rs28381975 can affect the promoter activity of PDCD6IP, indicating its possible functional significance. Taken together, our data suggest that common genetic variations in PDCD6IP may influence HCC risk, possibly through promoter activity-mediated regulation. Replication of our studies in other populations and further functional analysis will strengthen our understanding of this association. 23492758 Levels of TNF-Related Apoptosis-Inducing Ligand (TRAIL) Show a Long-term Stability in the Breast Milk of Mothers of Preterm Infants. Background: The immune modulator TNF-related apoptosis-inducing ligand (TRAIL) has been found at extremely high levels in human milk of women with normal gestation at day 5 after delivery. Objective: To investigate the presence and the levels of soluble TRAIL in human milk of women with preterm delivery at different time points post-partum (32, 34, and 36 weeks from conception). Methods: The levels of soluble TRAIL were analyzed by ELISA in the breast milk of a group of 25 women with preterm delivery at different gestational ages. Results: Soluble TRAIL was present at high levels in human milk since early post-conceptional ages (32 weeks). No significant differences in TRAIL levels were noticed with respect to different gestational ages, or with respect to time of collection when comparing, in a selected group of patients, samples obtained between 15 and 26 days with those obtained 27 and 40 days after birth. Conclusion: Due to the key immunoregulatory role of human soluble TRAIL, the presence of high levels of TRAIL in the milk of women with preterm delivery and its maintenance at high levels up to 72 days after birth support the importance of breastfeeding the preterm newborn. 23199414 Calcium, magnesium and potassium intake and mortality in women with heart failure: the Women's Health Initiative. Although diet is thought to affect the natural history of heart failure (HF), nutrient intake in HF patients has not been well studied. Based on prior research linking high intake of Ca, Mg and K to improved cardiovascular health, we hypothesised that these nutrients would be inversely associated with mortality in people with HF. Of the 161 808 participants in the Women's Health Initiative (WHI), we studied 3340 who experienced a HF hospitalisation. These participants were followed for post-hospitalisation all-cause mortality. Intake was assessed using questionnaires on food and supplement intake. Hazard ratios (HR) and 95 % CI were calculated using Cox proportional hazards models adjusted for demographics, physical function, co-morbidities and dietary covariates. Over a median of 4·6 years of follow-up, 1433 (42·9 %) of the women died. HR across quartiles of dietary Ca intake were 1·00 (referent), 0·86 (95 % CI 0·73, 1·00), 0·88 (95 % CI 0·75, 1·04) and 0·92 (95 % CI 0·76, 1·11) (P for trend = 0·63). Corresponding HR were 1·00 (referent), 0·86 (95 % CI 0·71, 1·04), 0·88 (95 % CI 0·69, 1·11) and 0·84 (95 % CI 0·63, 1·12) (P for trend = 0·29), across quartiles of dietary Mg intake, and 1·00 (referent), 1·20 (95 % CI 1·01, 1·43), 1·06 (95 % CI 0·86, 1·32) and 1·16 (95 % CI 0·90, 1·51) (P for trend = 0·35), across quartiles of dietary K intake. Results were similar when total (dietary plus supplemental) nutrient intakes were examined. In summary, among WHI participants with incident HF hospitalisation, intakes of Ca, Mg and K were not significantly associated with subsequent mortality. 23754547 Prognosis in women with breast cancer and private extra insurance coverage. Many women covered by the Spanish public health system also have an extra private insurance policy for gynecological examinations and routine annual mammography. We retrospectively analyzed the long-term survival rates in these patients when diagnosed with breast cancer. We analyzed the survival and prognostic factors in patients diagnosed with breast cancer who were referred to a medical oncology unit for multidisciplinary treatment covered by private health insurance. Between 1994 and 2009, a total of 434 patients with breast tumor were analyzed: 33 in situ and 401 infiltrating. Among the infiltrating carcinomas, 38 were stage IV and 363 were stage I, II, or III. With a median follow-up of 62 months, the 5-year global survival rate was 91 %: 97 % for stage I, 94 % for stage II, and 77 % for stage III tumors. In the patients diagnosed by routine mammography, the 5-year survival rate was 96 %, compared with 86 % in those consulting their gynecologist after breast self-examination or for other symptoms (p = 0.0159). Seventy-four percent were treated conservatively and experienced better survival than the 26 % who underwent mastectomy (p = 0.0024). Patients with disease with positive hormone receptors had a better survival rate (p = 0.0264); hormone receptor status was the only independent prognostic factor in the Cox multivariate analysis. Postmenopausal patients who received adjuvant tamoxifen plus exemestane had a better prognosis than those who received tamoxifen alone (p = 0.0203). Long-term survival rate was high in breast cancer patients with extra private insurance coverage. This is probably because disease was diagnosed at an early stage. 23850404 Blood pressure regulation, autonomic control and sleep disordered breathing in children. Sleep disordered breathing (SDB) ranges in severity from primary snoring (PS) to obstructive sleep apnoea (OSA). In adults, SDB is associated with adverse cardiovascular consequences which are mediated, in part, by autonomic dysfunction. Although SDB is common in children, fewer paediatric studies have investigated these cardiovascular effects. Initial research focused on those with OSA, indeed children with PS were occasionally utilised as the comparison control group. However, it is essential to understand the ramifications of this disorder in all its severities, as currently the milder forms of SDB are often untreated. Methodologies used to assess autonomic function in children with SDB include blood pressure (BP), BP variability, baroreflex sensitivity, heart rate variability, peripheral arterial tonometry and catecholamine assays. The aim of this review was to summarise the findings of paediatric studies to date and explore the relationship between autonomic dysfunction and SDB in children, paying particular attention to the roles of disease severity and/or age. This review found evidence of autonomic dysfunction in children with SDB during both wakefulness and sleep. BP dysregulation, elevated generalised sympathetic activity and impairment of autonomic reflexes occur in school-aged children and adolescents with SDB. The adverse effects of SDB seem somewhat less in young children, although more studies are needed. There is mounting evidence that the cardiovascular and autonomic consequences of SDB are not limited to those with OSA, but are also evident in children with PS. The severity of disease and age of onset of autonomic consequences may be important guides for the treatment of SDB. 23711196 Deceased Organ Donor Screening for HIV, Hepatitis B, and Hepatitis C Viruses: A Survey of Organ Procurement Organization Practices. Although Organ Procurement and Transplantation Network (OPTN) policy requires that all potential deceased organ donors are screened for human immunodeficiency (HIV), hepatitis B (HBV) and hepatitis C (HCV) viruses by serology, no current policy requires the use of nucleic acid testing (NAT) for organ donor screening. An electronic survey was sent to 58 organ procurement organizations (OPO) in the United States to assess current screening practices of potential deceased organ donors. Fifty-seven responses were collected for data analysis; not all respondents answered all questions. All OPOs performed required HIV, HBV and HCV serology screening and 48 (84%) performed confirmatory testing for seropositive donors. Ninety-eight percent, 75% and 97% of OPOs performed prospective HIV, HBV and HCV NAT, respectively. Fifty-two percent and 47% used a transcription-mediated amplification assay for HIV and HCV NAT, respectively. Of the 56 respondents that performed HIV NAT and 55 respondents that performed HCV NAT, 39 tested all donors. Seventeen (32%) OPOs performed confirmatory testing for all HIV-positive NAT results, and 15 (27%) OPOs performed confirmatory testing for all HCV-positive NAT results. Since 2008, the number of OPOs performing NAT has increased and more OPOs are testing all donors. 23638698 Functional and morphological characterization of glutamate transporters in the rat locus coeruleus. Excitatory amino acid transporters (EAATs) in the CNS contribute to the clearance of glutamate released during neurotransmission. The aim of this study was to explore the role of EAATs in the regulation of locus coeruleus (LC) neurons by glutamate. We measured the effect of different EAAT subtype inhibitors/enhancers on glutamate- and KCl-induced activation of LC neurons in rat slices. EAAT2-3 expression in the LC was also characterized by immunohistochemistry. The EAAT2-5 inhibitor DL-threo-β-benzyloxaspartic acid (100 μM), but not the EAAT2, 4, 5 inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (100 μM) or the EAAT2 inhibitor dihydrokainic acid (DHK; 100 μM), enhanced the glutamate- and KCl-induced activation of the firing rate of LC neurons. These effects were blocked by ionotropic, but not metabotrobic, glutamate receptor antagonists. DHK (100 μM) was the only EAAT inhibitor that increased the spontaneous firing rate of LC cells, an effect that was due to inhibition of EAAT2 and subsequent AMPA receptor activation. Chronic treatment with ceftriaxone (200 mg·kg(-1) i.p., once daily, 7 days), an EAAT2 expression enhancer, increased the actions of glutamate and DHK, suggesting a functional impact of EAAT2 up-regulation on the glutamatergic system. Immuhistochemical data revealed the presence of EAAT2 and EAAT3 surrounding noradrenergic neurons and EAAT2 on glial cells in the LC. These results remark the importance of EAAT2 and EAAT3 in the regulation of rat LC by glutamate. Neuronal EAAT3 would be responsible for terminating the action of synaptically released glutamate, whereas glial EAAT2 would regulate tonic glutamate concentrations in this nucleus. 23884265 Uterine rupture after prior conservative management of placenta accreta. There is little evidence for counseling patients who seek uterine conservation in the setting of placenta accreta. We report the case of a 37-year-old woman with retained placenta accreta after vaginal delivery. Attempts at transvaginal removal failed, and the placenta was removed through a fundal hysterotomy with bilateral uterine artery ligations performed to control blood loss. She conceived a second pregnancy 11 months later and sustained spontaneous fundal uterine rupture at 26.5 weeks of gestation with a recurrent accreta found at the rupture site. The newborn survived but has residual musculoskeletal morbidity and developmental delay at 1 year of age. Patients undergoing conservative treatment of placenta accreta in the setting of a fundal hysterotomy should be cautioned about recurrent accreta and uterine rupture. 23952569 CuCl2 for the Isolation of a Broad Array of Endohedral Fullerenes Containing Metallic, Metallic Carbide, Metallic Nitride, and Metallic Oxide Clusters, and Separation of Their Structural Isomers. A typical arc-synthesis generates many types of fullerenes and endohedrals. Resulting soot extracts contain a complex mixture of >50 types of fullerenes, metallofullerenes, and their structural isomers. Prior to application development, novel separation methods are required to fractionate this rich array of metallic, metallic carbide, metallic nitride, and metallic oxide endohedrals, all of which can be present in a single, soot extract. Herein, we report the discovery of CuCl2 as a Lewis acid that will selectively precipitate only the more reactive members of each of these endohedral families. The more reactive Sc4O2@Ih-C80, Sc3C2@Ih-C80, and Sc3N@D3h-C78 endohedrals are quickly removed from extracts to greatly decrease the number of endohedrals present in a sample. Experiments indicate that enrichment factors of several orders of magnitude can be achieved within minutes of reaction time. CuCl2 also has sufficient selectivity to resolve and separate structural isomers, as demonstrated with Er2@C82 (isomer I, Cs(6)-C82 versus isomer III). The selective complexation of CuCl2 with fullerenes can be correlated to their first oxidation potential. We estimate a significantly lower threshold of precipitation for CuCl2 (<0.19 V) compared to stronger Lewis acids. Fullerenes and metallofullerenes having first oxidation potentials above 0.19 V tend to remain unreacted in solution. In contrast, species with first oxidation potentials below 0.19 V (vs Fc/Fc(+)) precipitate via complexation, and are easily decomplexed. CuCl2 is compared to Lewis acids having higher precipitation thresholds (e.g., FeCl3) in our goal to predict a priori which endohedrals would remain in solution versus which endohedral species would complex and precipitate. The ability to predict endohedral precipitation a priori is beneficial to the design of purification strategies for metallofullerenes. 23884398 Threshing efficiency as an incentive for rapid domestication of emmer wheat. Background and Aims The harvesting method of wild and cultivated cereals has long been recognized as an important factor in the emergence of domesticated non-shattering ear genotypes. This study aimed to quantify the effects of spike brittleness and threshability on threshing time and efficiency in emmer wheat, and to evaluate the implications of post-harvest processes on domestication of cereals in the Near East. Methods A diverse collection of tetraploid wheat genotypes, consisting of Triticum turgidum ssp. dicoccoides - the wild progenitor of domesticated wheat - traditional landraces, modern cultivars (T. turgidum ssp. durum) and 150 recombinant (wild × modern) inbred lines, was used in replicated controlled threshing experiments to quantify the effects of spike brittleness and threshability on threshing time and efficiency. Key Results The transition from a brittle hulled wild phenotype to non-brittle hulled phenotype (landraces) was associated with an approx. 30 % reduction in threshing time, whereas the transition from the latter to non-brittle free-threshing cultivars was associated with an approx. 85 % reduction in threshing time. Similar trends were obtained with groups of recombinant inbred lines showing extreme phenotypes of brittleness and threshability. Conclusions In tetraploid wheat, both non-brittle spike and free-threshing are labour-saving traits that increase the efficiency of post-harvest processing, which could have been an incentive for rapid domestication of the Near Eastern cereals, thus refuting the recently proposed hypothesis regarding extra labour associated with the domesticated phenotype (non-brittle spike) and its presumed role in extending the domestication episode time frame. 23707727 Inpatient procedures in elderly women: An analysis over time. To describe inpatient surgical and diagnostic/therapeutic procedures in women ≥65 years old and assess procedure trends over time. Procedure data for all women ≥65 years was collected using the National Hospital Discharge Survey, a federal dataset drawn from a representative sampling of U.S. inpatient hospitals which includes patient and hospital demographics and ICD-9-CM diagnosis and procedure codes for admissions from 1979 to 2006. Age-adjusted rates (AAR) per 1000 women were created using 1990 U.S. Census data to compare trends over time. Over 96 million procedures were performed in women age≥65 years from 1979 to 2006. Women age≥65 years constituted 17% of women with ≥1 inpatient procedure in 1979, rising to 32% in 2006. The most common surgical procedures were lower extremity joint replacement, open reduction internal fixation, and cholecystectomy. The most common concurrent diagnosis was femoral neck fracture. Women with femoral neck fracture were more likely to undergo open reduction internal fixation compared to joint replacement. AARs for ORIF fell from 4.3 to 3.2 (p=.02) from 1979 to 2006, while AARs for joint replacement increased from 0.2 to 3.4 (p≤.001, 1979-1988; p=.14, 1990-2006). The rate of women age≥65 years undergoing inpatient procedures has increased dramatically in the last 30 years. Hip fracture was the most common diagnosis for elderly women, highlighting the impact of osteoporosis and falls and the importance of prevention strategies and optimization of peri-operative care in this population. Further comparative study of hip fracture treatment strategies in this population is needed. 23945122 Teriparatide (rhPTH) treatment in children with syndromic hypoparathyroidism. Abstract Background: Subcutaneous recombinant human parathormone [rhPTH (1-34)] has been introduced for hypoparathyroidism treatment, allowing avoidance of vitamin D and calcium side effects. Objective: Our objective was to evaluate rhPTH (1-34) safety and efficacy in pediatric patients with genetically proved syndromic hypoparathyroidism. Methods: The study was a 2.5-year self-controlled trial on six pediatric patients (four males, two females, age 9.8±5.1 years) with syndromic hypoparathyroidism including three with autoimmune polyendocrinopathy candidiasis ectodermal dysplasia (APECED) syndrome, two with DiGeorge syndrome, and one with hypoparathyroidism-deafness-renal dysplasia syndrome. We compared patients' clinical and biochemical outcome of conventional treatment based on oral administration of calcium (1-1.5 g/day in three doses) plus oral calcitriol (6.5-33 ng/kg per day in two to three doses) with the outcome obtained with rhPTH (1-34) (teriparatide, 12.5 μg bid). Therapy shift was conducted introducing rhPTH (1-34) while progressively withdrawing calcium and vitamin D. Blood calcium, phosphorus, alkaline phosphatase, and urinary calcium-to-creatinine ratio (mg/mg) before and during rhPTH therapy were compared. Results: rhPTH treatment allowed complete calcium and vitamin D withdrawal in two patients, calcium withdrawal in three and reduction of vitamin D dose in two. During rhPTH (1-34), mean blood calcium, phosphorus, and alkaline phosphatase were not significantly modified, whereas significant reduction of the calciuria-to-creatininuria ratio (0.55±0.31 vs. 0.1±0.1, p=0.02) was obtained. The number of tetanic episodes was reduced in four patients during teriparatide treatment compared to conventional treatment. Conclusion: In children with syndromic hypoparathyroidism, substitutive treatment with rhPTH (1-34) maintains adequate blood calcium levels and allows prompt normalization of urinary calcium excretion, through direct action on the kidney and through calcium and vitamin D therapy layoff. 23339855 Medical aspects of bio-terrorism. INTRODUCTION: Bioterrorism is a terrorist action involving the intentional release or dissemination of a biological warfare agent (BWA), which includes some bacteria, viruses, rickettsiae, fungi or biological toxins. BWA is a naturally occurring or human-modified form that may kill or incapacitate humans, animals or plants as an act of war or terrorism. BWA is a weapon of choice for mass destruction and terrorism, because of the incubation period, less effective amount than chemical warfare agents, easily distribution, odorless, colorless, difficult to detect, no need of specialized equipment for production and naturally distribution which can easily be obtained. BWA may be disseminating as an aerosol, spray, explosive device, and by food or water. CLASSIFICATION: Based on the risk for human health, BWAs have been prioritized into three categories of A, B and C. Category A includes microorganisms or toxins that easily spread, leading to intoxication with high death rates such as Anthrax, Botulism, Plague, Smallpox, Tularemia and Viral hemorrhagic fevers. Category B has lower toxicity with wider range, including Staphylococcal Entrotoxin type B (SEB), Epsilon toxin of Clostridium perfringens, Ricin, Saxotoxins, Abrin and Trichothecene mycotoxins. The C category includes emerging pathogens that could also be engineered for mass spread such as Hanta viruses, multidrug-resistant tuberculosis, Nipah virus, the tick-borne encephalitis viruses, hemorrhagic fever viruses and yellow fever. CLINICAL MANIFESTATIONS OF BIOTOXINS IN HUMAN: Clinical features and severity of intoxication depend on the agent and exposed dose, route of entry, individual variation and environmental factors. Onset of symptoms varies from 2-24 h in Ricin to 24-96 h in Botulism. Clinical manifestations also vary from irritation of the eyes, skin and mucus membranes in T(2) toxin to an acute flaccid paralysis of bilateral cranial nerve impairment of descending manner in botulism. Most of the pyrogenic toxins such as SEB produce the same signs and symptoms as toxic shock syndrome including a rapid drop in blood pressure, elevated temperature, and multiple organ failure. MANAGEMENT: There is no specific antidote or effective treatment for most of the biotoxins. The clinical management is thus more supportive and symptomatic. Fortunately vaccines are now available for most of BWA. Therefore, immunization of personnel at risk of exposure is recommended. CONCLUSION: Biotoxins are very wide and bioterrorism is a heath and security threat that may induce national and international problems. Therefore, the security authorities, health professional and even public should be aware of bioterrorism. 23411834 End-faced waveguide mediated optical propulsion of microspheres and single cells in a microfluidic device. Single cell transport in microfluidic devices is a topic of interest as their utility is becoming appreciated by cell and molecular biologist. Cell transport should minimize mechanical stress due to friction or pressure gradients. Optical forces have the advantage of applying their forces across the cell volume and not only at the cell membrane and are thus preferable. Optical pushing by scattering force is a suitable candidate so highly dependent on the photon irradiance field inside the propagation capillary which in turn is determined by the waveguide properties delivering the radiation pressure. Here we present a numerical approach to predict the optical scattering force, speed and trajectory of cells as a function of waveguide and propagation capillary geometry. Experimental verification of the simulation approach is demonstrated using polystyrene microspheres and leukemia cells. Effects of optical fibre to waveguide alignment, capillary wall angle and temperature on the dynamic viscosity on speed and position of the microspheres and cells inside the propagation capillary are demonstrated. 23625345 The role of radiation therapy in small cell lung cancer. Radiotherapy (RT) is fundamental to the care of patients diagnosed with small-cell lung cancer (SCLC). In the setting of limited stage disease (LS-SCLC), the addition of thoracic RT to chemotherapy (CHT) improves survival and local control, as demonstrated in decades-worth of randomized clinical trials and subsequent meta-analyses. In extensive stage disease (ES-SCLC), thoracic RT is invaluable in the palliation of chest symptoms but there are suggestions that its use in selected patients may potentially improve overall survival . Prophylactic cranial irradiation (PCI) also improves outcomes in SCLC. For LS-SCLC patients, it reduces brain metastases rates by half and improves overall survival with minimal impact on quality-of-life. Recently, favorable results for PCI with respect to survival and prevention of symptomatic brain disease have been observed for ES-SCLC patients with any response to CHT. Current phase III trials in SCLC RT include studies looking at the optimal dose and target for limited disease and the role of thoracic RT in extensive disease. 23017422 Effects of solvent and alkaline earth metals on the heat-induced precipitation process of sodium caseinate. The precipitation temperatures of sodium caseinate in H(2)O and D(2)O in the presence of Mg(2+), Ca(2+), Sr(2+) and Ba(2+) were investigated through fluorescence, turbidity and conductivity experiments. As for the ability of the divalent cations (1-17.5mM) to induce the precipitation process in H(2)O, the sequence Ba(2+) ≥ Ca(2+)>Mg(2+)>Sr(2+) was found. Remarkably, while at low salt concentrations (<10mM) precipitation temperatures (T(Ps)) were found to change significantly depending on the specific cation, at higher concentrations (>10mM) the differences among the different cations were greatly reduced. By fitting these results with a modified Jones-Dole equation, we confirmed that the less hydrated ions possess a greater capacity to induce precipitation. In D(2)O, the order of ion ability to induce caseinate precipitation was Ba(2+)>Ca(2+)>Sr(2+)>Mg(2+). The different hydrophobicity between D(2)O and H(2)O was shown to affect significantly the T(Ps) of caseinate in the presence of calcium, strontium and barium. 23474802 Acute gut GVHD in children: does skin involvement matter? Gut GVHD (G-GVHD) is frequently the most severe and difficult to treat compared with skin GVHD. It is unknown if skin involvement with G-GVHD has prognostic significance. To compare the prognosis of acute isolated G-GVHD vs acute gut and skin GVHD (GS-GVHD) in children following allo-SCT. Allo-SCT recipients from Jan 2000-Dec 2009 were included and patients who underwent endoscopy and gut biopsy for G-GVHD were identified. Four hundred and fifty children (0-18 years) underwent allo-SCT during the study period. Seventy-nine (17.5%) patients underwent endoscopy and biopsy. At least stage II was required for skin involvement. Forty nine patients had G-GVHD and 30 had combined, GS-GVHD. The majority of patients received CsA and MTX for GVHD prophylaxis. Sixty-seven percent of patients with GS-GVHD had grade III-IV while only 31% had grade III-IV in the G-GVHD group. Median follow-up was 6.3 years (range 3.6-11.9 years). Relapse rate was similar in both the groups. However, children with G-GVHD had a significantly higher risk of dying from GVHD related complications (37% vs 16%) resulting in superior survival for those with skin involvement (79% vs 49% P=0.02). Extension of G-GVHD to the skin may suggest a better outcome. 23880648 Imaging for evaluation of cholesteatoma: current concepts and future directions. To examine the rationale and utility of imaging in patients with known or suspected cholesteatoma, with emphasis on high-resolution computed tomography (HRCT) and diffusion-weighted MRI (DW-MRI). The initial diagnosis of cholesteatoma is largely based on patient history and clinical findings. HRCT scan can be a useful adjunct to define the presence of pathologic soft tissue in the temporal bone, and the extent of bony erosion, and inform the otologic surgeon about expected findings at the time of surgery. Although MRI has not traditionally been used in the evaluation of cholesteatoma given its poor resolution of bone anatomy, recent advances in DW-MRI sequences allow for high sensitivity and specificity in identifying the presence of cholesteatoma. More specifically, non-echo-planar DW-MRI is superior in the detection of residual or recurrent cholesteatoma compared to delayed-contrast MRI and echo-planar DW-MRI. HRCT and DW-MRI offer complementary anatomic information that can be used effectively in the management of cholesteatoma. DW-MRI imaging has proven to be a reliable method for detecting residual or recurrent cholesteatomas down to 3 mm in size, and allows radiologic differentiation between cholesteatoma and other soft tissue. As more centers implement DW-MRI imaging for detecting residual or recurrent cholesteatoma, there will likely be less need for second-look surgery, thereby potentially decreasing associated morbidity and surgical costs. 23749459 Estimation of isotropic nuclear magnetic shieldings in the CCSD(T) and MP2 complete basis set limit using affordable correlation calculations. A linear correlation between isotropic nuclear magnetic shielding constants for seven model molecules (CH2 O, H2 O, HF, F2 , HCN, SiH4 and H2 S) calculated with 37 methods (34 density functionals, RHF, MP2 and CCSD(T)), with affordable pcS-2 basis set and corresponding complete basis set results, estimated from calculations with the family of polarization-consistent pcS-n basis sets is reported. This dependence was also supported by inspection of profiles of deviation between CBS estimated nuclear shieldings and shieldings obtained with the significantly smaller basis sets pcS-2 and aug-cc-pVTZ-J for the selected set of 37 calculation methods. It was possible to formulate a practical approach of estimating the values of isotropic nuclear magnetic shielding constants at the CCSD(T)/CBS and MP2/CBS levels from affordable CCSD(T)/pcS-2, MP2/pcS-2 and DFT/CBS calculations with pcS-n basis sets. The proposed method leads to a fairly accurate estimation of nuclear magnetic shieldings and considerable saving of computational efforts. Copyright © 2013 John Wiley & Sons, Ltd. 23917102 Optic neuritis and the evaluation of visual impairment in multiple sclerosis. Purpose of Review: This review covers causes of visual impairment in multiple sclerosis (MS), differential diagnosis, and treatment. Emerging technologies are sometimes used in assessing the visual system and may require a neurologist's familiarity. The most common causes are emphasized and discussed in detail, including illustrative cases.Recent Findings: The use of optical coherence tomography as both a clinical and research tool has advanced our understanding of how the afferent visual system is affected by MS.Summary: Optic neuritis remains one of the most common initial manifestations of MS, although a number of other causes of visual impairment are possible even in the patient with known MS. Some causes of visual impairment are consequences or complications of MS treatment and are particularly important to recognize. Low-contrast letter acuity and optical coherence tomography are techniques or tests emerging from the research arena that may inform care of the patient with MS and are important for the neurologist to be aware of. 23945251 Dolutegravir Pharmacokinetics in the Genital Tract and Colorectum of HIV-Negative Men After Single and Multiple Dosing. To describe first-dose and steady state pharmacokinetics (PKs) of dolutegravir (DTG) in blood plasma (BP), seminal fluid (SF), colorectal tissue (RT), and rectal mucosal fluid (RF) of healthy HIV-negative men. A phase 1, open-label, PK study that enrolled 12 healthy men taking 50 mg DTG daily for 8 days. Eleven paired BP samples and 3 SF and RF samples were collected over 24 hours after first (PK1) and multiple (PK2) dosing. RT biopsies were collected at 1 of 6 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analyzed by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). Noncompartmental PK analysis was conducted with Phoenix WinNonlin v6.3, and Spearman rank correlations were determined using SAS v9.3. BP area under the concentration-time curves (AUCs) were similar to previous reports, and concentrations at 24 hours (C24 h) were 6- to 34-fold greater than the protein-adjusted concentration required for 90% viral inhibition (PA-IC90) of 64 ng/mL. SF exposures were <7% of BP and below the PA-IC90. RT exposures were 17% of BP and ∼2-fold greater than the PA-IC90. RF AUCs were ∼2%-5% of RT and did not correlate with RT (rho = 0.43, P = 0.17). Accumulation of DTG with multiple dosing was observed in BP, SF, and RT. DTG BP PKs were consistent with previously published values. SF concentrations were <7% BP, with SF C24 h below the PA-IC90. However, SF protein binding was not measured. Although the AUC of DTG in RT was <20% BP, RT C24 h remained ∼2-fold higher than the PA-IC90. RF was not a strong surrogate for RT concentrations. 23258482 Prediction of (TiO2)x(Cu2O)y alloys for efficient photoelectrochemical water splitting. The formation of (TiO(2))(x)(Cu(2)O)(y) solid-solutions is investigated using a global optimization evolutionary algorithm. First-principles calculations based on density functional theory are then used to gain insight into the electronic properties of these alloys. We find that: (i) Ti and Cu in (TiO(2))(x)(Cu(2)O)(y) alloys have similar local environments as in bulk TiO(2) and Cu(2)O except for (TiO(2))(Cu(2)O) which has some trigonal-planar Cu ions. (ii) The predicted optical band gaps are around 2.1 eV (590 nm), thus having much better performance in the absorption of visible light compared with both binary oxides. (iii) (TiO(2))(2)(Cu(2)O) has the lowest formation energy amongst all studied alloys and the positions of its band edges are found to be suitable for solar-driven water splitting applications. 23821039 Withdrawal symptoms and rebound syndromes associated with switching and discontinuing atypical antipsychotics: theoretical background and practical recommendations. With the widespread use of atypical or second-generation antipsychotics, switching treatment has become current practice and more complicated, as the pharmacological profiles of these agents differ substantially despite their similarity in being 'atypical'. All share the ability to block dopamine D2 receptors, and most of them also block serotonin 5-HT2A receptors. Apart from these common features, some atypical antipsychotics are also able to block or stimulate other dopamine or serotonin receptors, as well as histaminergic, muscarinergic or adrenergic receptors. As a result of the varying receptor affinities, in switching or discontinuing compounds several possible pitfalls have to be considered, including the occurrence of withdrawal and rebound syndromes. This article reviews the pharmacological background of functional blockade or stimulation of receptors of interest in regard to atypical antipsychotics and the implicated potential withdrawal and rebound phenomena. A MEDLINE search was carried out to identify information on withdrawal or rebound syndromes occurring after discontinuation of atypical antipsychotics. Using the resulting literature, we first discuss the theoretical background to the functional consequences of atypical antipsychotic-induced blockade or stimulation of neurotransmitter receptors and, secondly, we highlight the clinical consequences of this. We then review the available clinical literature on switching between atypical antipsychotics, with respect to the occurrence of withdrawal or rebound symptoms. Finally, we offer practical recommendations based on the reviewed findings. The systematic evaluation of withdrawal or rebound phenomena using randomized controlled trials is still understudied. Knowledge of pharmacological receptor-binding profiles may help clinicians in choosing adequate switching or discontinuation strategies for each agent. Results from large switching trials indicate that switching atypical antipsychotics can be performed in a safe manner. Treatment-emergent adverse events during or after switching are not always considered to be, at least in part, associated with the pre-switch antipsychotic. Further studies are needed to substantiate the evidence gained so far on different switching strategies. The use of concomitant medication, e.g., benzodiazepines or anticholinergic drugs, may help to minimize symptoms arising from the discontinuation or switching of antipsychotic treatment. 23903185 Modification of oil palm mesocarp fiber characteristics using superheated steam treatment. In this study, oil palm mesocarp fiber (OPMF) was treated with superheated steam (SHS) in order to modify its characteristics for biocomposite applications. Treatment was conducted at temperatures 190-230 °C for 1, 2 and 3 h. SHS-treated OPMF was evaluated for its chemical composition, thermal stability, morphology and crystallinity. OPMF treated at 230 °C exhibited lower hemicellulose content (9%) compared to the untreated OPMF (33%). Improved thermal stability of OPMF was found after the SHS treatment. Moreover, SEM and ICP analyses of SHS-treated OPMF showed that silica bodies were removed from OPMF after the SHS treatment. XRD results exhibited that OPMF crystallinity increased after SHS treatment, indicating tougher fiber properties. Hemicellulose removal makes the fiber surface more hydrophobic, whereby silica removal increases the surface roughness of the fiber. Overall, the results obtained herewith suggested that SHS is an effective treatment method for surface modification and subsequently improving the characteristics of the natural fiber. Most importantly, the use of novel, eco-friendly SHS may contribute to the green and sustainable treatment for surface modification of natural fiber. 23869966 Ernie Mazzaferri: The Breadth of His Influence. NA. 23802738 Long term results of a phase 2 study of vincristine sulfate liposome injection (Marqibo(®) ) substituted for non-liposomal vincristine in cyclophosphamide, doxorubicin, vincristine, prednisone with or without rituximab for patients with untreated aggressive non-Hodgkin lymphomas. Vincristine sulfate liposome injection (VSLI; Marqibo(®) ; M) is active in relapsed and refractory lymphomas, and approved in the United States for relapsed and refractory adult acute lymphocytic leukaemia. We evaluated VSLI (2·0 mg/m(2) without dose cap) substituted for non-liposomal vincristine (VCR) in a cyclophosphamide, doxorubicin, vincristine, prednisone ± ritiximab (CHOP±R) regimen, creating CHMP±R in 72 untreated, aggressive non-Hodgkin lymphoma patients, including 60 with diffuse large B-cell lymphoma (DLBCL). The overall response rate was 96% (69/72) including complete response (CR) in 65 (90%) and unconfirmed CR in 2 (3%). Median progression-free survival (PFS) and overall survival (OS) were not reached at median follow-up of 8 and 10·2 years, respectively. The 5- and 10-year PFS and OS were 75%, 63%, 87%, and 77%, respectively. Despite VSLI exposure of up to 35 mg, the safety profile of CHMP±R was comparable to that reported for CHOP±R. Grade 3 peripheral neuropathy was reported in 2 (3%) patients; there was no reported Grade 3/4 constipation. CHMP±R was highly active, generally well tolerated, and compared favourably to historical trials with R-CHOP in DLBCL. This enhanced activity probably reflects VCR dose intensification, pharmacokinetic optimization, and enhanced delivery afforded by VSLI. A Phase 3 trial of R-CHMP versus R-CHOP in elderly patients with untreated DLBCL is ongoing. 23877106 Development of an integrated population pharmacokinetic model for oral levetiracetam in populations of various ages and ethnicities. Levetiracetam [E Keppra(®)] is a second generation antiepileptic drug for different types of epilepsy in adults and children ≥1 month. The objective is to develop a population pharmacokinetic model to describe the pharmacokinetics of levetiracetam in Japanese children and adults as well as North American children, the purpose being to explore potential dosing recommendations in Japanese children. Levetiracetam plasma concentration-time data were obtained from Japanese adult and paediatric clinical studies. The data were analysed through non-linear mixed effects modelling. The model was used to perform simulations and compare the exposure in Japanese children and adults. It was subsequently extended to North American children through an external validation. A one-compartment model with first-order absorption and first-order elimination adequately described the data. The exposure parameters determined based on the simulations in children were well within the adult range. The external validation against historical data from North American children was successful. The integrated population pharmacokinetic model provided a good description of the data, confirming the similarity of levetiracetam pharmacokinetics in these various populations. In Japanese children, a target dose of 10 to 30 mg/kg twice daily ensures the same exposure as the recommended dose in Japanese adults of 500 to 1500 mg twice daily. 23417437 Physiological and biochemical defense reactions of Vicia faba L.-Rhizobium symbiosis face to chronic exposure to cyanobacterial bloom extract containing microcystins. The presence of cyanotoxins, mainly microcystins (MCs), in surface freshwater represents a serious health risk to aquatic organisms living in the water body, as well as terrestrial animals and plants that are in contact with contaminated water. Consequently, the use of MCs contaminated water for irrigation represents a hazard for cultivated plants and could induce severe economical losses due to crops' yield reduction. The experimental approach undertaken in this work was exposing Vicia faba seedlings (inoculated with a Rhizobium strain resistant to MCs), to water supplemented with cyanobacterial crude extract containing total microcystins at a concentration of 50 and 100 Î¼g/L (environmental relevant concentrations of MCs dissolved in the raw irrigation water from Lalla Takerkoust Lake-Marrakesh region). After chronic MCs exposure (2 months), biological and physiological parameters (plant growth, nitrogen uptake, mineral assimilation, and oxidative defense mechanisms) were evaluated. The results obtained showed evidence that chronic exposure to cyanobacterial bloom extract containing MCs strongly affected the physiological and biological plants activities; reduction of dry matter, photosynthetic activity, nodule number, and nitrogen assimilation. At the same time, an increase of oxidative stress was observed, as deduced from a significant increase of the activities of peroxidase, catalase, polyphenoloxidase, and phenylalanine ammonia lyase in leaves, roots, and nodules of faba bean plants exposed to cyanotoxins, especially at 100 Î¼g/L of MCs. This experimentation constitutes a simulation of the situation related to cyanotoxins chronic exposure of seedlings-plants via the contaminated irrigation water. For this reason, once should take into consideration the possibility of contamination of agricultural crops and the quality of irrigation water should be by the way monitored for cyanotoxins biohazard. 23932583 Calcium and vitamin D supplementation and loss of bone mineral density in women undergoing breast cancer therapy. An unintended consequence of breast cancer therapies is an increased risk of osteoporosis due to accelerated bone loss. We conducted a systematic review of calcium and/or vitamin D (Ca±D) supplementation trials for maintaining bone mineral density (BMD) in women with breast cancer using the "before-after" data from the Ca±D supplemented comparison group of trials evaluating the effect of drugs such as bisphosphonates on BMD. Whether Ca±D supplements increase BMD in women undergoing breast cancer therapy has never been tested against an unsupplemented control group. However, results from 16 trials indicate that the Ca±D doses tested (500-1500mg calcium; 200-1000IU vitamin D) were inadequate to prevent BMD loss in these women. Cardiovascular disease is the main cause of mortality in women with breast cancer. Because calcium supplements may increase cardiovascular disease risk, future trials should evaluate the safety and efficacy of Ca±D supplementation in women undergoing breast cancer therapy. 23876095 Evaluation of effect of low-level laser therapy on adolescents with temporomandibular disorder: study protocol for a randomized controlled trial. A number of problems involving the temporomandibular joint (TMJ) and associated structures can lead to temporomandibular disorder (TMD). The aim of the proposed study is to assess the effect of low-level laser therapy on occlusal contacts, mandibular movements, electromyography activity in the muscles of mastication and pain in adolescents with TMD. A randomized, controlled, double-blind, clinical trial will be carried out involving 85 male and female adolescents between 15 and 18 years of age. The research diagnostic criteria for TMD will be used to assess all individuals who agree to participate. All participants will be submitted to a clinical examination and electromyographic analysis of the masseter muscles and anterior bundle of the temporal muscles bilaterally, to determine TMD. Based on the clinical findings, the participants will be classified as having or not having TMD. Those with TMD will be divided into four groups, three of which will receive low-level laser therapy and one of which will receive a placebo treatment. The treatments will involve the TMJ region alone, the masseter and temporal muscles alone, or both these regions together. The data will be submitted to descriptive statistical analysis. The chi-square test and Fisher's exact test will be used to determine associations among the categorical variables. The Student's t test and analysis of variance will be used for the comparison of mean electromyographic signals. Pearson's correlation coefficients will be calculated for the analysis of correlations among the continuous variables. The protocol for this study has been submitted to Clinical Trials - registration number NCT01846000. 23936402 A Handheld Point-of-Care Genomic Diagnostic System. The rapid detection and identification of infectious disease pathogens is a critical need for healthcare in both developed and developing countries. As we gain more insight into the genomic basis of pathogen infectivity and drug resistance, point-of-care nucleic acid testing will likely become an important tool for global health. In this paper, we present an inexpensive, handheld, battery-powered instrument designed to enable pathogen genotyping in the developing world. Our Microfluidic Biomolecular Amplification Reader (µBAR) represents the convergence of molecular biology, microfluidics, optics, and electronics technology. The µBAR is capable of carrying out isothermal nucleic acid amplification assays with real-time fluorescence readout at a fraction of the cost of conventional benchtop thermocyclers. Additionally, the µBAR features cell phone data connectivity and GPS sample geotagging which can enable epidemiological surveying and remote healthcare delivery. The µBAR controls assay temperature through an integrated resistive heater and monitors real-time fluorescence signals from 60 individual reaction chambers using LEDs and phototransistors. Assays are carried out on PDMS disposable microfluidic cartridges which require no external power for sample loading. We characterize the fluorescence detection limits, heater uniformity, and battery life of the instrument. As a proof-of-principle, we demonstrate the detection of the HIV-1 integrase gene with the µBAR using the Loop-Mediated Isothermal Amplification (LAMP) assay. Although we focus on the detection of purified DNA here, LAMP has previously been demonstrated with a range of clinical samples, and our eventual goal is to develop a microfluidic device which includes on-chip sample preparation from raw samples. The µBAR is based entirely around open source hardware and software, and in the accompanying online supplement we present a full set of schematics, bill of materials, PCB layouts, CAD drawings, and source code for the µBAR instrument with the goal of spurring further innovation toward low-cost genetic diagnostics. 20594058 Functional load in oblique bicortical implants: parasinusal implants and palatine implants. The history of intraosseous implantology, as a whole, begins with the introduction of the Formiggini screw. Single-piece implants were subsequently derived from titanium bars. The intrinsic function of the emerging stump was immediate loading. The great stability of the implant in the bone thus demanded was eventually achieved by means of the self-tapping screw and bicortical support. Oblique implants were subsequently adopted to make the best use of the bone available and to avoid zones at risk, such as the maxillary sinus and the inferior alveolar nerve. Angled stumps on osseointegrated 2-stage implants were also described in the literature. There has since been a switch from sunken to single-stage implants in view of the usefulness of immediate loading. Recent articles have illustrated the use of inclined, nonbicortical implants; these are still placed in the spongy bone. 23743979 Size Ratio Can Highly Predict Rupture Risk in Intracranial Small (<5 mm) Aneurysms. Management strategies for unruptured intracranial aneurysms (UIAs) are controversial. This study aimed to identify surrogate parameters that highly predict the rupture risk of small (<5 mm) UIAs. Radiological data were collected from 854 patients with aneurysmal subarachnoid hemorrhages who were enrolled in the Sapporo SAH Study. They had a total of 854 ruptured intracranial aneurysms and 180 UIAs. The size, aneurysm-to-vessel size ratio, and distribution were precisely compared between ruptured intracranial aneurysms and UIAs. For all aneurysms, the size was significantly larger in ruptured intracranial aneurysms (7.0±1.3 mm) than in the UIAs (3.7±1.2 mm; P<0.001). Size ratio was also significantly higher in ruptured intracranial aneurysms (4.3±1.9) than in the UIAs (2.2±1.6; P<0.001). Multivariate logistic analysis showed that size and size ratio were correlated with aneurysm rupture. However, in small aneurysms, multivariate logistic regression revealed that only size ratio was associated with ruptured aneurysms (P=0.008; odds ratio, 9.1). There were no significant differences in size or aneurysm location. A receiver operating characteristic analysis was performed for size ratio in small aneurysms, and the threshold separating ruptured and unruptured groups was 3.12 and the area under the curve was 0.801. This study revealed that the size ratio, and not the absolute size, may highly predict the risk of rupture in small UIAs. Size ratio measurements are very simple and provide useful information for determining treatment and follow-up strategies for patients with small UIAs. 23669251 Significance of obesity markers and adipocytokines in high grade and high stage prostate cancer in North Indian men - a cross-sectional study. Prostate cancer (CaP) in India is the 10th most common malignancy affecting men. CaP incidence in India is low, but rising like other countries. The reasons for this racial disparity are uncertain. The foremost reasons that may underlie regional/ethnic differences are genetic polymorphisms, altered hormonal status, socioeconomic status, and obesity. This study aimed at investigating the role of adipocytokines in stimulating the promotion and progression of CaP. A cross-sectional study on histopathologically proven prostate cancer (N=95) and benign prostatic hyperplasia (N=95) patients was undertaken. CaP patients were classified into high-grade (N=62) and low-grade (N=33), and high stage (N=31) and low stage (N=64) groups. The level of body mass index (BMI), waste to hip ratio (WHR), interleukin-6 (IL-6), leptin, and adiponectin were compared between BPH and CaP groups and between grades and stages of prostate cancer. The level of BMI was significantly (p<0.001) higher in CaP patients (26.58±4.76) in comparison to BPH (22.15±2.90). Similarly, WHR was significantly (p<0.0001) higher in the CaP patients (1.08±0.37) in comparison to BPH (0.86±0.15). Leptin (BPH: 25.60, CaP: 56.00) and II-6 levels (BPH: 9.90, CaP: 32.30) were significantly higher, but adiponectin was significantly lower in CaP patients as compared to BPH. High grade CaP patients had significantly higher BMI and WHR in comparison to low grade, and WHR was also higher in high stage CaP. Leptin and IL-6 level were higher in high stage and high grade, but adiponectin was low in high stage and high grade groups in comparison to low stage and low grade groups. Higher BMI and WHR correlate with prostate cancer independently, suggesting obesity to be a promoter of poor prostate health. Leptin and IL-6 appear to have stimulating effect on prostate cancer cells inducing the promotion and progression of CaP, but adiponectin appears to be protective against prostate cancer. 23875790 Novel copper-catalyzed multicomponent cascade synthesis of iminocoumarin aryl methyl ethers. A copper(I)-catalyzed one-pot synthesis of iminocoumarin aryl methyl ethers has been developed from ynal, phenol, and sulfonyl azide at ambient conditions via a cascade [3 + 2]-cycloaddition, 1,3-pseudopericyclic ketenimine rearrangement, 1,4-conjugate addition, and aldol-type condensation. This protocol provides a potential route for the construction of a library of iminocoumarin aryl methyl ethers in good yields. 23774627 Structural barriers to receiving health care services for female sex workers in Russia. Female sex workers in Russia have been particularly vulnerable to recent social, political, and economic changes. In this article, we describe the facilitators and barriers for sex workers receiving health care services in St. Petersburg, Russia. We conducted observations at medical institutions and nongovernmental organizations and in-depth interviews with 29 female sex workers. We identified the following barriers: poverty, not having documents, lack of anonymity in testing, and the official registration system. We identified the following facilitators: intervention by family members, social connections within the health care system, and referral services from a nongovernmental organization. Our findings indicate a need for reassessing policies and designing programs that better facilitate the use of health care services for the most vulnerable populations. This should include the expansion of support systems and outreach services designed to help female sex workers navigate the health care system. 23712538 Silver-containing mesoporous bioactive glass with improved antibacterial properties. The aim of the present work is the study of the bacteriostatic/bactericidal effect of a silver-containing mesoporous bioactive glass obtained by evaporation-induced self-assembly and successive thermal stabilization. Samples of the manufactured mesophase were characterized by means of transmission electron microscopy and N2 adsorption/desorption at 77 K, revealing structural and textural properties similar to SBA-15 mesoporous silica. Glass samples used for bioactivity experiments were put in contact with a standardized, commercially available cell culture medium instead of lab-produced simulated body fluid, and were then characterized by means of X-ray diffraction, field emission scanning electron microscopy and Fourier transform infrared spectroscopy. All these analyses confirmed the development of a hydroxyl carbonate apatite layer on glass particles. Moreover, the investigated mesostructure showed a very good antibacterial effect against S. aureus strain, with a strong evidence of bactericidal activity already registered at 0.5 mg/mL of glass concentration. A hypothesis about the mechanism by which Ag affects the bacterial viability, based on the intermediate formation of crystalline AgCl, was also taken into account. With respect to what already reported in the literature, these findings claim a deeper insight into the possible use of silver-containing bioactive glasses as multifunctional ceramic coatings for orthopedic devices. 23220196 Treating epilepsy in Italy between XIX and XX century. Epilepsy is a neurological disorder which has been recognized since antiquity. This paper evaluates the prophylactic and therapeutic remedies used by folk medicine to cure epilepsy in Italy. The data has been collected by reviewing written sources of physicians, ethnographers, folklorists between the late nineteenth and mid twentieth century. This approach leads to unearthing of 78 heterogeneous healing methods that have been divided into 16 (20%) magical, 20 (26%) religious and 42 (54%) natural remedies. The latter has been subdivided into 18 (43%) animal remedies, 17 (40%) plant remedies and 7 (17%) other remedies. Religious and magical remedies were used with the conviction that they would be able to provide recovery from epilepsy and to ward off evil spirits which had taken possession of the sick. Interestingly, the herbal remedies highlighted 12 (70%) plants that play or might play an important role with respect to the mechanisms that generate the epileptic seizures. This leads us to reconsider the historical significance of folk medicine, too often it is underestimated owing to its use of ineffective remedies, born of incompetence and superstition. 23896179 Mobility of polyaromatic hydrocarbons (PAHs) in soil in the presence of carbon nanotubes. Being a potential risk to the environment, a fate study of carbon nanotube (CNT) in the environment is urgently needed. A study of CNT impacts on the bioavailability of other conventional contaminants in a terrestrial system is particularly rare. This study explored PAH leaching behaviors in the presence of CNTs with column leaching tests. Four PAHs (Naphthalene, fluorene, phenanthrene, and pyrene), three CNTs (f-SWNTs, MWNTs, f-MWNTs), and a sandy loam soil were involved in this study. We found that at a concentration of 5mg/g, CNTs could significantly retain PAHs in soil. Such a strong PAH retention was caused by low mobilities of CNTs and their strong PAH sorption capacities. This study illustrated that the properties of both sorbents (e.g. available surface area and micropore volume) and sorbates (e.g. hydrophobicity and molecular volume) influenced the mobility of PAHs in soil. 23807237 Intact emotion-cognition interaction in schizophrenia patients and first-degree relatives: Evidence from an emotional antisaccade task. Schizophrenia patients have deficits in cognitive control as well as in a number of emotional domains. The antisaccade task is a measure of cognitive control that requires the inhibition of a reflex-like eye movement to a peripheral stimulus. Antisaccade performance has been shown to be modulated by the emotional content of the peripheral stimuli, with emotional stimuli leading to higher error rates than neutral stimuli, reflecting an implicit emotion processing effect. The aim of the present study was to investigate the impact on antisaccade performance of threat-related emotional facial stimuli in schizophrenia patients, first-degree relatives of schizophrenia patients and healthy controls. Fifteen patients, 22 relatives and 26 controls, matched for gender, age and verbal intelligence, carried out an antisaccade task with pictures of faces displaying disgusted, fearful and neutral expressions as peripheral stimuli. We observed higher antisaccade error rates in schizophrenia patients compared to first-degree relatives and controls. Relatives and controls did not differ significantly from each other. Antisaccade error rate was influenced by the emotional nature of the stimuli: participants had higher antisaccade error rates in response to fearful faces compared to neutral and disgusted faces. As this emotional influence on cognitive control did not differ between groups we conclude that implicit processing of emotional faces is intact in patients with schizophrenia and those at risk for the illness. 23729391 Repetitive differential finger motion increases shear strain between the flexor tendon and subsynovial connective tissue. Non-inflammatory fibrosis and thickening of the subsynovial connective tissue (SSCT) are characteristic in carpal tunnel syndrome (CTS) patients. These pathological changes have been linked to repetitive hand tasks that create shear forces between the flexor tendons and SSCT. We measured the relative motion of the flexor digitorum superficialis tendon and SSCT during two repetitive finger tasks using color Doppler ultrasound. Twelve participants performed flexion-extension cycles for 30 min with the long finger alone (differential movement) and with all four fingers together (concurrent movement). Shear strain index (SSI, a relative measure of excursion in flexion and extension) and maximum velocity ratio (MVR, the ratio of SSCT versus tendon during flexion and extension) were used to represent shear. A linear effect of exertion time was significant and corresponded with larger tendon shear in differential motion. The flexion SSI increased 20.4% from the first to the 30th minute, while MVR decreased 8.9% in flexion and 8.7% in extension. No significant changes were found during concurrent motion. These results suggest that exposure to repetitive differential finger tasks may increase the risk of shear injury in the carpal tunnel. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1533-1539, 2013. 23869238 Berberine Targets AP-2/hTERT, NF-κB/COX-2, HIF-1α/VEGF and Cytochrome-c/Caspase Signaling to Suppress Human Cancer Cell Growth. Berberine (BBR), an isoquinoline derivative alkaloid isolated from Chinese herbs, has a long history of uses for the treatment of multiple diseases, including cancers. However, the precise mechanisms of actions of BBR in human lung cancer cells remain unclear. In this study, we investigated the molecular mechanisms by which BBR inhibits cell growth in human non-small-cell lung cancer (NSCLC) cells. Treatment with BBR promoted cell morphology change, inhibited cell migration, proliferation and colony formation, and induced cell apoptosis. Further molecular mechanism study showed that BBR simultaneously targeted multiple cell signaling pathways to inhibit NSCLC cell growth. Treatment with BBR inhibited AP-2α and AP-2β expression and abrogated their binding on hTERT promoters, thereby inhibiting hTERT expression. Knockdown of AP-2α and AP-2β by siRNA considerably augmented the BBR-mediated inhibition of cell growth. BBR also suppressed the nuclear translocation of p50/p65 NF-κB proteins and their binding to COX-2 promoter, causing inhibition of COX-2. BBR also downregulated HIF-1α and VEGF expression and inhibited Akt and ERK phosphorylation. Knockdown of HIF-1α by siRNA considerably augmented the BBR-mediated inhibition of cell growth. Moreover, BBR treatment triggered cytochrome-c release from mitochondrial inter-membrane space into cytosol, promoted cleavage of caspase and PARP, and affected expression of BAX and Bcl-2, thereby activating apoptotic pathway. Taken together, these results demonstrated that BBR inhibited NSCLC cell growth by simultaneously targeting AP-2/hTERT, NF-κB/COX-2, HIF-1α/VEGF, PI3K/AKT, Raf/MEK/ERK and cytochrome-c/caspase signaling pathways. Our findings provide new insights into understanding the anticancer mechanisms of BBR in human lung cancer therapy. 23924182 The influence of knowing someone with HIV/AIDS on preventive behaviors in Italy. The influence of knowing someone with HIV/AIDS on HIV preventive behaviors has become increasingly relevant in the literature, with controversial findings. The aim of this study was to investigate the relationship between knowing someone with HIV/AIDS and preventive behaviors in a representative sample of the Italian adult population. Drawing on two sociocognitive models, perceived threat and HIV/AIDS knowledge were proposed as mediators of this relationship. Results from 1969 telephone interviews were analyzed. Questions included sociodemographic information, knowing someone with HIV/AIDS, past sexual behaviors, HIV/AIDS knowledge, HIV/AIDS perceived threat (susceptibility and severity), and preventive behaviors (HIV testing and condom use). The results of mediation models showed that knowing someone with HIV/AIDS had an indirect effect on condom use through HIV-perceived susceptibility. Knowing someone with HIV/AIDS showed a direct and an indirect effect through HIV/AIDS knowledge on HIV testing. 23890659 Driving under the influence with blood alcohol concentrations over 0.4g%. The aim of this study was to evaluate the characteristics of traffic offenders with unusually high blood-alcohol concentrations (BAC>0.4g%) when arrested. The BAC that kills one person might be easily tolerated by another, depending on, among other things, the person's age, pattern of drinking, and the development of tolerance. The archives of two forensic laboratories, one in Sweden and the other in Wisconsin (USA), were searched to find traffic offenders with BACs>0.4g%. The results were compared in relation to the person's age and gender, mean BAC and the weekday and time of day of the arrest. The mean age (±standard deviation) of N=158 Swedish offenders was 45±9.0y, which was not significantly different from the 43±9.4y in N=233 Wisconsin drivers (p>0.05). Overall there were more men (78%) than women (22%) arrested with BAC's>0.4g%, although the proportion of women in Wisconsin (35%) was higher than in Sweden (9%) (p<0.001). The mean (median) and highest BAC did not differ between jurisdictions; 0.429g% (0.422) and 0.546g% in Sweden and 0.428g% (0.421g%) and 0.526g% in Wisconsin. In Sweden 40% of the arrests occurred on Fridays and Saturdays, whereas in Wisconsin the arrests of people with such high BAC's were more evenly distributed throughout the week. Forty eight percent of the arrests in Sweden were made between 12 noon and 6pm compared with 37% in Wisconsin. Neither the mean age of offenders nor their mean BAC seemed to depend on the weekday or time of day of the arrest. Attempting to drive with a BAC above 0.4g% verifies the development of an appreciable tolerance to ethanol-induced cognitive and psychomotor impairment. Reaching such a high BAC probably requires continuous heavy drinking over several days as opposed to an evening's binge drinking. 23712370 Microfluidic redox battery. A miniaturized microfluidic battery is proposed, which is the first membraneless redox battery demonstrated to date. This unique concept capitalizes on dual-pass flow-through porous electrodes combined with stratified, co-laminar flow to generate electrical power on-chip. The fluidic design is symmetric to allow for both charging and discharging operations in forward, reverse, and recirculation modes. The proof-of-concept device fabricated using low-cost materials integrated in a microfluidic chip is shown to produce competitive power levels when operated on a vanadium redox electrolyte. A complete charge/discharge cycle is performed to demonstrate its operation as a rechargeable battery, which is an important step towards providing sustainable power to lab-on-a-chip and microelectronic applications. 23756538 A semi-automated tool for treatment plan-quality evaluation and clinical trial quality assurance. The goal of this work is to develop a plan-quality evaluation program for clinical routine and multi-institutional clinical trials so that the overall evaluation efficiency is improved. In multi-institutional clinical trials evaluating the plan quality is a time-consuming and labor-intensive process. In this note, we present a semi-automated plan-quality evaluation program which combines MIMVista, Java/MATLAB, and extensible markup language (XML). More specifically, MIMVista is used for data visualization; Java and its powerful function library are implemented for calculating dosimetry parameters; and to improve the clarity of the index definitions, XML is applied. The accuracy and the efficiency of the program were evaluated by comparing the results of the program with the manually recorded results in two RTOG trials. A slight difference of about 0.2% in volume or 0.6 Gy in dose between the semi-automated program and manual recording was observed. According to the criteria of indices, there are minimal differences between the two methods. The evaluation time is reduced from 10-20 min to 2 min by applying the semi-automated plan-quality evaluation program. 23771884 Id proteins are critical downstream effectors of BMP signaling in human pulmonary arterial smooth muscle cells. Bone morphogenetic protein type II receptor (BMPR-II) mutations are responsible for over 70% of cases of heritable pulmonary arterial hypertension (PAH). Loss of BMP signaling promotes pulmonary vascular remodeling via modulation of pulmonary artery smooth muscle cell (PASMC) proliferation. Id proteins (Id1-4) are major downstream transcriptional targets of BMP signaling. However, the impact of BMPR-II mutation on the expression of the range of Id proteins and the contribution of individual Id proteins to abnormal PASMC function remain unclear. Human PASMCs were used to determine the expression of Id proteins (Id1-4) by real-time PCR and immunoblotting. The BMP responses in control cells were compared with PASMCs harboring BMPR-II mutations and cells in which BMPR-II was knocked down by siRNA transfection. Id3 expression in pulmonary vessels was also investigated in BMPR-II mutant mice and in patients with heritable PAH. BMP4 and BMP6, but not BMP9, induced mRNA expression of Id1, Id2, and Id3. The BMP-stimulated induction of Id1 and Id3 was markedly reduced in BMPR-II mutant PASMCs and in control PASMCs following siRNA silencing of BMPR-II. Pulmonary arteries in BMPR-II mutant mice and patients with heritable PAH demonstrated reduced levels of Id3 compared with control subjects. Lentiviral overexpression of Id3 reduced cell cycle progression and inhibited proliferation of PASMCs. Lipopolysaccharide further reduced Id3 expression in mutant PASMCs. In conclusion, Id proteins, and particularly Id1 and Id3, are critical downstream effectors of BMP signaling in PASMCs. Loss of BMPR-II function reduces the induction of Id genes in PASMCs, Id1, and Id3 regulate the proliferation of PASMCs via cell cycle inhibition, an effect that may be exacerbated by inflammatory stimuli. 23942331 Supporting a distributed execution of clinical guidelines. Clinical guidelines (GL) play an important role in medical practice: the one of optimizing the quality of patient care on the basis of evidence based medicine. In order to achieve this goal, the interaction between different agents, who cooperate in the execution of the same GL, is a crucial issue. As a matter of fact, in many cases (e.g. in chronic disorders) the GL execution requires that patient treatment is not performed/completed in the hospital, but is continued in different contexts (e.g. at home, or in the general practitioner's ambulatory), under the responsibility of different agents. In this situation, the correct interaction and communication between the agents themselves is critical for the quality of care, and human resources coordination is a key issue to be addressed by the managers of the involved healthcare services. In this paper we describe how GLARE (Guideline Acquisition, Representation, and Execution), a computerized GL management system, has been extended in order to support such a need. In particular, we have provided: (i) an extension to GL actions representation languages, (ii) proper scheduling and (iii) querying services. By means of these enhancements we aimed at guaranteeing (1) treatment continuity and (2) responsibility assignment support in the various steps of a coordinated and distributed patient care process. We illustrate our approach by means of a practical case study. 23222639 HLA-DO acts as a substrate mimic to inhibit HLA-DM by a competitive mechanism. Mammalian class II major histocompatibility (MHCII) proteins bind peptide antigens in endosomal compartments of antigen-presenting cells. The nonclassical MHCII protein HLA-DM chaperones peptide-free MHCII, protecting it against inactivation, and catalyzes peptide exchange on loaded MHCII. Another nonclassical MHCII protein, HLA-DO, binds HLA-DM and influences the repertoire of peptides presented by MHCII proteins. However, the mechanism by which HLA-DO functions is unclear. Here we have used X-ray crystallography, enzyme kinetics and mutagenesis approaches to investigate human HLA-DO structure and function. In complex with HLA-DM, HLA-DO adopts a classical MHCII structure, with alterations near the α subunit's 3₁₀ helix. HLA-DO binds to HLA-DM at the same sites implicated in MHCII interaction, and kinetic analysis showed that HLA-DO acts as a competitive inhibitor. These results show that HLA-DO inhibits HLA-DM function by acting as a substrate mimic, and the findings also limit the possible functional roles for HLA-DO in antigen presentation. 23843602 The inverse problem in magnetic force microscopy-inferring sample magnetization from MFM images. Nanomagnetic structures have the potential to surpass silicon's scaling limitations both as elements in hybrid CMOS logic and as novel computational elements. Magnetic force microscopy (MFM) offers a convenient characterization technique for use in the design of such nanomagnetic structures. MFM measures the magnetic field and not the sample's magnetization. As such the question of the uniqueness of the relationship between an external magnetic field and a magnetization distribution is a relevant one. To study this problem we present a simple algorithm which searches for magnetization distributions consistent with an external magnetic field and solutions to the micromagnetic equations' qualitative features. The algorithm is not computationally intensive and is found to be effective for our test cases. On the basis of our results we propose a systematic approach for interpreting MFM measurements. 23850710 Systems pharmacology strategies for Drug Discovery and Combination with applications to CVD. Multi-target therapeutics is a promising paradigm for drug discovery which is expected to produce greater levels of efficacy with fewer adverse effects and toxicity than monotherapies. Medical herbs featuring multi-components and multi-targets may serve as valuable resources for network-based multi-target drug discovery. In this study, we report an integrated systems pharmacology platform for drug discovery and combination, with a typical example applied to herbal medicines in the treatment of cardiovascular diseases. Firstly, a disease-specific drug-target network was constructed and examined at systems level to capture the key disease-relevant biology for discovery of multi-targeted agents. Secondly, considering an integration of disease complexity and multilevel connectivity, a comprehensive database of literature-reported associations, chemicals and pharmacology for herbal medicines was designed. Thirdly, a large-scale systematic analysis combining pharmacokinetcs, chemogenomics, pharmacology and systems biology data through computational methods was performed and validated experimentally, which results in a superior output of information for systematic drug design strategies for complex diseases. This strategy integrating different types of technologies is expected to help create new opportunities for drug discovery and combination. 23850526 Organs-on-a-chip for drug discovery. The current drug discovery process is arduous and costly, and a majority of the drug candidates entering clinical trials fail to make it to the marketplace. The standard static well culture approaches, although useful, do not fully capture the intricate in vivo environment. By merging the advances in microfluidics with microfabrication technologies, novel platforms are being introduced that lead to the creation of organ functions on a single chip. Within these platforms, microengineering enables precise control over the cellular microenvironment, whereas microfluidics provides an ability to perfuse the constructs on a chip and to connect individual sections with each other. This approach results in microsystems that may better represent the in vivo environment. These organ-on-a-chip platforms can be utilized for developing disease models as well as for conducting drug testing studies. In this article, we highlight several key developments in these microscale platforms for drug discovery applications. 23876111 Number of women requiring care at a tertiary hospital equipped with a neonatal intensive care unit at night in an area with a population of 2 million. Women with imminent premature labor (IPL) are transported to a tertiary hospital equipped with neonatal intensive care unit (NICU) even during the night. However, there have been no extensive studies of the occurrence rate of night IPL. The aim of this study was to determine the occurrence rate of night IPL in an area with a population of 2 million. A retrospective analysis was conducted using data collected by the Sapporo Obstetric System for Emergency Patients launched in October 2008, in which women, physicians, and ambulance staff who sought appropriate obstetric/gynecological facilities available in the night (19.00-06.00 hours) were informed of candidate hospitals by coordinators through telephone consultation. This system covered the Sapporo area, which has a population of 2 000 000 and 17 000 births annually. Approximately 14% and 86% of women received antenatal care at six and 35 obstetric facilities with and without NICU, respectively, in this area. Night IPL was defined as a threatened premature labor and transport to one of six tertiary hospitals with NICU between 19.00 and 06.00 hours the next morning. During a 4-year period from 1 October 2008 to 30 September 2012, the Sapporo Obstetric System for Emergency Patients received 158 ± 23 (mean ± standard deviation) monthly telephone consultations (range 114-218 per month). The monthly number of patients with night IPL was 3.0 ± 2.2 (range 0-9 per month). The monthly number of cases of night IPL was around three among women who received antenatal care at obstetrics facilities without NICU in an area with a population of 2 000 000. 23647074 HPV-genotypes in high-grade intraepithelial cervical lesions in Danish women. A study was undertaken to assess the distribution of high-risk HPV-genotypes in high-grade cervical intraepithelial neoplastic lesions in Danish women. Observational, cross-sectional. Danish data from a multi-centre study undertaken in 13 European countries. 290 archived fixed biopsies with high-grade cervical lesions from the Departments of Pathology at the University Hospitals in Hvidovre and Odense, Denmark. Relevant histological samples were anonymized and shipped to a central laboratory for histopathology review and PCR-testing for HPV-DNA. A standardised HPV-test methodology was utilised to enable comparison of HPV-genotype distribution. Of 290 Danish cervical samples, 276 were evaluated as histologically adequate and all of these were HPV-positive (HPV(+) ). Of the HPV(+) samples 77.9% were diagnosed with a single HPV-type, with cervical intraepithelial neoplasia (CIN)3 diagnosed in 82.3% and CIN2, CIN2/3, adenocarcinoma in situ (AIS) and AIS(+) other high-grade lesion diagnosed in the remaining 17.7%. The most prevalent HPV-types were: HPV16 (54.0%), HPV33 (13.5%), HPV31 (10.7%), HPV18 (7.9%) and HPV52 (4.7%). Of the HPV(+) samples, 21.4% were diagnosed with multiple HPV-types, with CIN3 diagnosed in 79.6% and CIN2, CIN2/3, AIS and AIS(+) other high-grade lesion diagnosed in the remaining 20.4%. The most prevalent HPV-types were: HPV16 (49.2%), HPV31 (30.5%), HPV52 (27.1%), HPV51 (20.3%), HPV18 (16.9%), HPV33 (13.6%), HPV45 (11.9%), with 0.7% unknown types. HPV16 and HPV18 were detected in approximately 75% of high-grade intraepithelial cervical lesions in a Danish population (single or multiple infections); these two genotypes are considered causative in at least 61.9% of the high-grade intraepithelial lesions (single infection). 23860712 Trp358 is a key residue for the multiple catalytic activities of multifunctional amylase OPMA-N from Bacillus sp. ZW2531-1. The oligosaccharide-producing multifunctional amylase-N (OPMA-N) is a novel multifunctional amylase and exhibits both hydrolytic and transglycosyl activities, but the molecular mechanism for its multiple catalytic activities is still unknown. Our research investigates the possible catalytic roles of a Trp residue in OPMA-N (Trp358) which is not only near the catalytic site Glu356 but also highly conserved in glycoside hydrolase subfamily 20 (the neopullulanase subfamily). Site-directed mutageneses at this site reveal that the size and charge of the occupying amino acid directly affect substrate binding, orientation of other crucial catalytic residues, the catalytic specificity, the oligomer formation, as well as the thermal stability of the enzyme. These findings may be useful in elucidating the different mechanisms of the multiple catalytic activities of multifunctional amylase OPMA-N and hence for developing an improved multifunctional amylase for the preparation of isomaltooligosaccharides. 23010389 Development of histopathological indices in a commercial marine bivalve (Ruditapes decussatus) to determine environmental quality. Bivalve histopathology is an acknowledged tool in environmental toxicology studies, however geographically restricted, limited to a few species and still lacking the degree of detail needed to develop effective (semi)quantitative approaches. A first-time detailed histopathological screening was performed on grooved carpet shell clams collected from commercial shellfish beds in distinct coastal ecosystems of the Southern Portuguese coast: two parted sites within an impacted estuary (S(1) and S(2)), an inlet channel of a fish farm at a considered pristine estuary (site M) and a site allocated in a clean coastal lagoon (A). A total of thirty histopathological lesions and alterations were analysed in the gills and digestive glands following a weighted condition indices approach, including inflammation-related responses, necrosis, neoplastic diseases and parasites. Digestive glands were consistently more damaged than gills, except for animals collected from site M, where the most severe lesions were found in both organs, immediately followed by S(2). Clams from sites S(1) and A were overall the least damaged. Neoplastic diseases were infrequent in all cases. Inflammation-related traits were some of the most common alterations progressing in animals enduring severe lesions such as digestive tubule (diverticula) and intertubular tissue necrosis. Some alterations, such as lipofuscin aggregates within digestive tubule cells, did not relate to histological lesions. Granulocytomas only occurred in heavily infected tissues. Animals from M and A presented the highest infections in the digestive gland, especially by protozoa. Gill infections were more similar between sites. Still, the level of infection does not account for all histopathological lesions in either organ. Overall, the results are in accordance with environmental parameters, such as distance to pollution sources, sediment type and hydrodynamics, and show that the combination of multiple histopathological features in these clams provides good sensitivity for inter-site distinction even when low or moderate anthropogenic impacts are at stake. 23769730 Metastable postural coordination dynamics. The present study examined the coordination dynamics of the head and center of mass (COM) using accelerometry in quiet 1 and 2 leg stance with and without vision. The root mean square jerk of effectors was greater in 1 leg stance and without vision, and was greater for the head in 2 leg stance and greater at the COM for 1 leg stance. The coordination of the COM and head was more variable in 1 leg stance with vision than in the other stance and vision combinations. Both grouped and individual participant data showed metastable coordination dynamics with the presence of ghost attractors on both axes of motion that varied with the task. The findings indicated that stance and visual information conditions acted as control parameters, with increments in task difficulty increasing relative phase variability until a bifurcation in the metastable dynamics occurred in 1 leg stance without vision. 23905907 Development of food allergies in patients with Gastroesophageal Reflux Disease treated with gastric acid suppressive medications. The prevalence of food allergy has steadily increased, especially in children. Reflux disease, a very common problem in children, is often treated with gastric acid suppressive (GAS) medications which may alter the processing of food allergens, thereby affecting oral mucosal tolerance. The purpose of this study was to determine if use of GAS medications is associated with the occurrence of food allergies in children. Using a large national commercial insurance database, we identified 4724 children aged 0-18 yrs who were diagnosed with Gastroesophageal Reflux Disease (GERD) and treated with GAS medications between January 1, 2008 and September 30, 2009. We then matched 4724 children with GERD not treated with GAS medications and 4724 children without GERD and not treated with GAS medications, at a 1:1 ratio, on age, gender and number of atopic risk factors. Patients were followed for 12 months. In comparison to the referent (children without GERD who received no GAS medications), children with GERD who were treated with GAS were more likely to be diagnosed with a food allergy (Hazard ratio (HR): 3.67, 95% CI 2.15-6.27), as were children with GERD diagnosis but who were not treated with GAS medications (HR: 2.15, 95% CI: 1.21-3.81). A direct comparison of the two GERD cohorts showed that children with GERD who were treated with GAS had a greater risk of food allergy than those with GERD who were untreated (HR, 1.68, 95%CI, 1.15-2.46). Treatment with GAS medications is associated with the occurrence of food allergy, an effect not apparently related to a diagnosis of GERD alone. 23064031 Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells. Naphtho[1,2-b]furan-4,5-dione (NFD), a bioactive component of Avicennia marina, has been demonstrated to display anti-cancer activity. Activation of epidermal growth factor receptor (EGFR)-induced signaling pathway has been correlated with cancer metastasis in various tumors, including breast carcinoma. We use EGF as a metastatic inducer of MDA-MB-231 cells to investigate the effect of NFD on cell migration and invasion. NFD suppressed EGF-mediated protein levels of c-Jun and c-Fos, and reduced MMP-9 expression and activity, concomitantly with a marked inhibition on cell migration and invasion without obvious cellular cytotoxicity. NFD abrogated EGF-induced phosphorylation of EGF receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt. The specific PI3K inhibitor, wortmannin, blocked significantly EGF-induced cell migration and invasion. Furthermore, the EGFR inhibitor AG1478 inhibited EGF-induced MMP-9 expression, cell migration and invasion, as well as the activation of PI3K/Akt, suggesting that PI3K/Akt activation occur downstream of EGFR activation. These findings suggest that NFD inhibited the EGF-induced invasion and migration of MDA-MB-231 cells via EGFR-dependent PI3K/Akt signaling, leading to the down-regulation of MMP-9 expression. These results provide a novel mechanism to explain the role of NFD as a potent anti-metastatic agent in MDA-MB-231 cells. 23960201 Anticipatory Planning Reveals Segmentation of Cortical Motor Output During Action Observation. It has been argued that the variation in brain activity that occurs when observing another person reflects a representation of actions that is indivisible, and which plays out in full once the intent of the actor can be discerned. We used transcranial magnetic stimulation to probe the excitability of corticospinal projections to 2 intrinsic hand muscles while motions to reach and grasp an object were observed. A symbolic cue either faithfully indicated the required final orientation of the object and thus the nature of the grasp that was required, or was in conflict with the movement subsequently displayed. When the cue was veridical, modulation of excitability was in accordance with the functional role of the muscles in the action observed. If however the cue had indicated that the alternative grasp would be required, modulation of output to first dorsal interosseus was consistent with the action specified, rather than the action observed-until the terminal phase of the motion sequence during which the object was seen lifted. Modulation of corticospinal output during observation is thus segmented-it progresses initially in accordance with the action anticipated, and if discrepancies are revealed by visual input, coincides thereafter with that of the action seen. 23849753 Current EU-27 technical potential of organic waste streams for biogas and energy production. Anaerobic digestion of organic waste generated by households, businesses, agriculture, and industry is an important approach as method of waste treatment - especially with regard to its potential as an alternative energy source and its cost-effectiveness. Separate collection of biowaste from households or vegetal waste from public green spaces is already established in some EU-27 countries. The material recovery in composting plants is common for biowaste and vegetal waste. Brewery waste fractions generated by beer production are often used for animal feeding after a suitable preparation. Waste streams from paper industry generated by pulp and paper production such as black liquor or paper sludge are often highly contaminated with toxic substances. Recovery of chemicals and the use in thermal processes like incineration, pyrolysis, and gasification are typical utilization paths. The current utilization of organic waste from households and institutions (without agricultural waste) was investigated for EU-27 countries with Germany as an in-depth example. Besides of biowaste little is known about the suitability of waste streams from brewery and paper industry for anaerobic digestion. Therefore, an evaluation of the most important biogas process parameters for different substrates was carried out, in order to calculate the biogas utilization potential of these waste quantities. Furthermore, a calculation of biogas energy potentials was carried out for defined waste fractions which are most suitable for anaerobic digestion. Up to 1% of the primary energy demand can be covered by the calculated total biogas energy potential. By using a "best-practice-scenario" for separately collected biowaste, the coverage of primary energy demand may be increased above 2% for several countries. By using sector-specific waste streams, for example the German paper industry could cover up to 4.7% and the German brewery industry up to 71.2% of its total energy demand. 23787345 Stacked autoencoders for unsupervised feature learning and multiple organ detection in a pilot study using 4D patient data. Medical image analysis remains a challenging application area for artificial intelligence. When applying machine learning, obtaining ground-truth labels for supervised learning is more difficult than in many more common applications of machine learning. This is especially so for datasets with abnormalities, as tissue types and the shapes of the organs in these datasets differ widely. However, organ detection in such an abnormal dataset may have many promising potential real-world applications, such as automatic diagnosis, automated radiotherapy planning, and medical image retrieval, where new multimodal medical images provide more information about the imaged tissues for diagnosis. Here, we test the application of deep learning methods to organ identification in magnetic resonance medical images, with visual and temporal hierarchical features learned to categorize object classes from an unlabeled multimodal DCE-MRI dataset so that only a weakly supervised training is required for a classifier. A probabilistic patch-based method was employed for multiple organ detection, with the features learned from the deep learning model. This shows the potential of the deep learning model for application to medical images, despite the difficulty of obtaining libraries of correctly labeled training datasets and despite the intrinsic abnormalities present in patient datasets. 23938878 Danger and disease: Electrocortical responses to threat- and disgust-eliciting images. Previous research suggests facilitated processing of evolutionarily significant stimuli (e.g., depictions of erotica, mutilation, threat), as reflected by augmented event-related potentials (ERPs), including the early posterior negativity (EPN) and late positive potential (LPP). Evolutionary models suggest that images that evoke disgust should be high in motivational salience, but the evidence that the EPN and LPP are enhanced by disgusting images is lacking. Prior studies have employed only a small number of disgusting images that were limited in the types of content depicted. In the current study, participants viewed larger sets of disgusting, threatening, and neutral images with more varied content while electroencephalography (EEG) was recorded. Results showed that disgusting and threatening images elicited equivalent LPPs, which were both significantly increased relative to LPPs elicited by neutral images. EPN amplitudes were augmented for both disgusting and threatening relative to neutral images, though significantly more for disgust. These findings offer initial evidence that the EPN and the LPP are sensitive to disgust-eliciting pictures and that these pictures may receive processing that is at least on par with that of threatening images. Limitations of the current study and implications for future research are discussed. 23211362 Pharmacological characterization of 1-nitrosocyclohexyl acetate, a long-acting nitroxyl donor that shows vasorelaxant and antiaggregatory effects. Nitroxyl (HNO) donors have potential benefit in the treatment of heart failure and other cardiovascular diseases. 1-Nitrosocyclohexyl acetate (NCA), a new HNO donor, in contrast to the classic HNO donors Angeli's salt and isopropylamine NONOate, predominantly releases HNO and has a longer half-life. This study investigated the vasodilatative properties of NCA in isolated aortic rings and human platelets and its mechanism of action. NCA was applied on aortic rings isolated from wild-type mice and apolipoprotein E-deficient mice and in endothelial-denuded aortae. The mechanism of action of HNO was examined by applying NCA in the absence and presence of the HNO scavenger glutathione (GSH) and inhibitors of soluble guanylyl cyclase (sGC), adenylyl cyclase (AC), calcitonin gene-related peptide receptor (CGRP), and K(+) channels. NCA induced a concentration-dependent relaxation (EC(50), 4.4 µM). This response did not differ between all groups, indicating an endothelium-independent relaxation effect. The concentration-response was markedly decreased in the presence of excess GSH; the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide had no effect. Inhibitors of sGC, CGRP, and voltage-dependent K(+) channels each significantly impaired the vasodilator response to NCA. In contrast, inhibitors of AC, ATP-sensitive K(+) channels, or high-conductance Ca(2+)-activated K(+) channels did not change the effects of NCA. NCA significantly reduced contractile response and platelet aggregation mediated by the thromboxane A(2) mimetic 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F(2)(α) in a cGMP-dependent manner. In summary, NCA shows vasoprotective effects and may have a promising profile as a therapeutic agent in vascular dysfunction, warranting further evaluation. 23901060 Test-Retest Reliability of Portable Metabolic Monitoring After Disabling Stroke. . Impaired economy of gait, prevalent in chronic stroke secondary to residual gait deficits, is associated with intolerance for performing activities of daily living. Gait economy/efficiency is traditionally assessed by determining the rate of oxygen consumption during submaximal treadmill walking. However, the mechanics and energetics of treadmill versus overground walking are very different in stroke survivors with ambulatory deficits. Clearly, overground cardiopulmonary measures are needed to accurately profile movement economy after stroke. An obstacle to obtaining such measures after stroke has been the absence of reliable portable metabolic monitoring equipment. The purpose of this study was to establish the test-retest reliability of a portable metabolic monitoring device during overground walking in hemiparetic stroke survivors. . Twenty-three chronic hemiparetic stroke survivors underwent two 6-minute walk tests while wearing a COSMED K4b(2) portable metabolic measurement system. Intraclass correlations coefficients (ICC) were calculated for both cardiopulmonary parameters and distance covered to determine test-retest reliability. An ICC of ≥0.85 was considered reliable. . ICCs for relative Vo2 (0.90), absolute Vo2 (0.93), Vco2 (0.93), and minute ventilation (0.95) demonstrated high reliability, but not for heart rate (0.76) or respiratory exchange ratio (0.64). There was no significant difference in the distance each participant walked between the first and second tests, eliminating distance as a potential confounder of our analyses (ICC = 0.99). . Our results strongly support the reliability of the K4b(2) for quantifying overground gait efficiency after stroke. Use of this device may enable researchers to study how varying poststroke rehabilitation interventions affect this central measure of health and function. 23954766 In vitro - in vivo correlations for endocrine activity of a mixture of currently used pesticides. Two pesticide mixtures were investigated for potential endocrine activity. Mix 3 consisted of bitertanol, propiconazole, and cypermethrin, and Mix 5 included malathion and terbuthylazine in addition to the three pesticides in Mix 3. All five single pesticides and the two mixtures were investigated for their ability to affect steroidogenesis in vitro in H295R cells. The pesticides alone and both mixtures affected steroidogenesis with both mixtures causing increase in progesterone and decrease in testosterone. For Mix 5 an increase in estradiol was seen as well, indicating increased aromatase activity. The two mixtures were also investigated in pregnant rats dosed from gestational day 7 to 21, followed by examination of dams and fetuses. Decreased estradiol and reduced placental testosterone was seen in dams exposed to Mix 5. Also a significant increase in aromatase mRNA-levels in female adrenal glands was found for Mix5. However, either of the two mixtures showed any effects on fetal hormone levels in plasma or testis, or on anogenital distance. Overall, potential aromatase induction was found for Mix 5 both in vitro and in vivo, but not for Mix 3, an effect likely owed to terbuthylazine in Mix 5. However, the hormonal responses in vitro were only partly reflected in vivo, probably due to some toxicokinetic issues, as the pesticide levels in the amniotic fluid also were found to be negatively affected by the number of compounds present in the mixtures. Nonetheless, the H295R assay gives hints on conceivable interference with steroidogenesis, thus generating hypotheses on in vivo effects. 23877074 Flooding tolerance in interspecific introgression lines containing chromosome segments from teosinte (Zea nicaraguensis) in maize (Zea mays subsp. mays). Background and AimsNicaraguan teosinte (Zea nicaraguensis), a species found in frequently flooded areas, provides useful germplasm for breeding flooding-tolerant maize (Z. mays subsp. mays). The objective of this study was to select flooding-tolerant lines using a library of introgression lines (ILs), each containing a chromosome segment from Z. nicaraguensis in the maize inbred line Mi29.MethodsTo produce the ILs, a single F1 plant derived from a cross between maize Mi29 and Z. nicaraguensis was backcrossed to Mi29 three times, self-pollinated four times and genotyped using simple sequence repeat markers. Flooding tolerance was evaluated at the seedling stage under reducing soil conditions.Key ResultsBy backcrossing and selfing, a series of 45 ILs were developed covering nearly the entire maize genome. Five flooding-tolerant lines were identified from among the ILs by evaluating leaf injury. Among these, line IL#18, containing a Z. nicaraguensis chromosome segment on the long arm of chromosome 4, showed the greatest tolerance to flooding, suggesting the presence of a major quantitative trait locus (QTL) in that region. The presence of the QTL was verified by examining flooding tolerance in a population segregating for the candidate region of chromosome 4. There was no significant relationship between the capacity to form constitutive aerenchyma and flooding tolerance in the ILs, indicating the presence of other factors related to flooding tolerance under reducing soil conditions.ConclusionsA flooding-tolerant genotype, IL#18, was identified; this genotype should be useful for maize breeding. In addition, because the chromosome segments of Z. nicaraguensis in the ILs cover nearly the entire genome and Z. nicaraguensis possesses several unique traits related to flooding tolerance, the ILs should be valuable material for additional QTL detection and the development of flooding-tolerant maize lines. 23794250 Further delineation of genotype-phenotype correlation in homozygous 2p21 deletion syndromes: First description of patients without cystinuria. Homozygous contiguous gene deletion syndromes are rare. On 2p21, however, several overlapping homozygous gene deletion syndromes have been described, all presenting with cystinuria but otherwise distinct phenotypes. Hypotonia-cystinuria syndrome (HCS, OMIM606407) is characterized by infantile hypotonia, poor feeding, and growth hormone deficiency. Affected individuals carry homozygous deletions including the cystinuria gene SLC3A1 and the adjacent PREPL gene. Larger homozygous deletions in this region encompassing the PPM1B, SLC3A1, PREPL, and C2orf34 (CAMKMT) genes result in a more severe phenotype, the 2p21 deletion syndrome. A phenotype intermediate to HCS and the 2p21 deletion syndrome is termed atypical HCS and is caused by deletion of SLC3A1, PREPL, and C2orf34 (CAMKMT). Using high resolution SNP array molecular karyotyping we identified two siblings with a homozygous deletion of 83 kb partially encompassing the genes PREPL and C2orf34 (CAMKMT), but not the SLC3A1 gene. The affected siblings display a recognizable phenotype which is similar to atypical HCS with regard to growth failure and neuro-muscular features, but is characterized by lack of cystinuria. The patients also exhibit features which have not been reported to date such as cleft palate and genital abnormalities. In conclusion, we report the first patients with a homozygous 2p21 deletion syndrome without cystinuria and further delineate the complex genotype-phenotype correlations of homozygous microdeletion syndromes of this region. © 2013 Wiley Periodicals, Inc. 23903356 Identification of HKDC1 and BACE2 as Genes Influencing Glycemic Traits During Pregnancy Through Genome-Wide Association Studies. Maternal metabolism during pregnancy impacts the developing fetus, affecting offspring birth weight and adiposity. This has important implications for metabolic health later in life (e.g., offspring of mothers with pre-existing or gestational diabetes mellitus have an increased risk of metabolic disorders in childhood). To identify genetic loci associated with measures of maternal metabolism obtained during an oral glucose tolerance test at ∼28 weeks' gestation, we performed a genome-wide association study of 4,437 pregnant mothers of European (n = 1,367), Thai (n = 1,178), Afro-Caribbean (n = 1,075), and Hispanic (n = 817) ancestry, along with replication of top signals in three additional European ancestry cohorts. In addition to identifying associations with genes previously implicated with measures of glucose metabolism in nonpregnant populations, we identified two novel genome-wide significant associations: 2-h plasma glucose and HKDC1, and fasting C-peptide and BACE2. These results suggest that the genetic architecture underlying glucose metabolism may differ, in part, in pregnancy. 23944374 Memory B cells: a proposed new immunological correlate for protective efficacy of Japanese encephalitis vaccine. Evaluation of: Larena M, Prow NA, Hall RA, Petrovsky N, Lobigs M. JE-ADVAX Vaccine protection against Japanese encephalitis virus mediated by memory B cells in the absence of CD8(+) T cells and pre-exposure neutralizing antibody. J. Virol. 87(8), 4395-4402 (2013). Japanese encephalitis (JE) virus requires dissemination within the host via the circulation for disease development. Thus, a serum-neutralizing antibody is an effective factor to protect against disease. Current licensed JE vaccines induce neutralizing antibodies and titers of 1:10 or higher are the recommended immunological correlate of protection. In this paper, the authors demonstrated, using a highly susceptible knockout mouse model, that memory B cells are required for disease protection and that detectable neutralizing antibodies at the time of challenge are dispensable. The authors proposes that the extent of memory B cells would be an alternative and better immunological correlate for evaluating the efficacy of JE vaccine candidates in clinical trials. 23578514 Phytotoxic effects of the cyanobacterial neurotoxin anatoxin-a: Morphological, physiological and biochemical responses in aquatic macrophyte, Ceratophyllum demersum. Anatoxin-a is one of the common and major cyanobacterial neurotoxins acting as a powerful agonist at nicotinic acetylcholine receptors (nAChR). In recent years, the toxin has become the focus of public attention, due to the mass development of cyanobacteria (cyanobacterial blooms) in freshwater bodies triggered by eutrophication and climate change. Anatoxin-a is suspected to have a distinct toxic mechanism depending on physiological and nervous systems in exposed organisms. The numerous researches have been actively conducted with respect to the toxic effects of anatoxin-a on mammals; however, little research has aimed at its possible effects on aquatic plants, wherein well-structured nervous system is absent with the lack of various components of the acetylcholine mechanism. In this study, submerged macrophyte Ceratophyllum demersum (C. demersum) was adopted to examine the effects of anatoxin-a on morphological (growth), physiological (photosynthetic pigment contents) and biochemical (hydrogen peroxide level, biotransformation and antioxidative enzymes) responses in the aquatic plant at environmentally relevant concentrations (0.005, 0.05, 0.5, 5 and 50 μg/L). The significant elevation of antioxidative enzymes in parallel with increased formation of hydrogen peroxide appeared from 0.5 μg/L of anatoxin-a. In the measurement of photosynthetic pigments, the decrease in chlorophyll a content was detected at 5 and 50 μg/L, whereas the increase in carotenoids/total chlorophyll was observed from 0.05 μg/L. Accordingly, the alteration in growth was manifested in the presence of 5 and 50 μg/L of anatoxin-a. The results clearly indicate that anatoxin-a can disrupt homeostasis of C. demersum through induction of oxidative stress; furthermore this aquatic plant possesses effective defense mechanisms to cope with low concentrations of anatoxin-a. 23731798 Memb-roller: an effective way of making membrane rolls for pathological examination and studies of human placenta. For the pathological evaluation of the chorioamniotic membranes, a membrane roll is made to give an orientation to the sections and to cover more extended planes. We designed a new instrument, Annie's memb-roller, for easy preparation of membrane rolls. Annie's memb-roller has two non-toothed arms which are 2 mm wide, 1 mm thick, and 8 cm long. To test its effectiveness in making a membrane roll, the placentas obtained from pregnant women (n = 10) with various obstetrical conditions were used. Preparation of the membrane rolls using Annie's memb-roller was easy and successful in all cases tested. The lengths of the membranes measured from fresh placentas and paraffin sections showed a very good correlation (p < 0.001; r = 0.941). Application of the memb-roller would be very helpful in the semi-quantitative analysis of the chorioamniotic membranes and the standardization of placental pathology and research practice. 23718729 Thioredoxin-Interacting Protein Expression Is Required for VEGF-Mediated Angiogenic Signal in Endothelial Cells. Abstract Aims: Thioredoxin-interacting protein (TXNIP) contributes to cellular redox-state homeostasis via binding and inhibiting thioredoxin (TRX). Increasing evidence suggests that cellular redox homeostasis regulates vascular endothelial growth factor (VEGF)-mediated signaling. This study aims to examine the redox-dependant role of TXNIP in regulating VEGF-mediated S-glutathionylation and angiogenic signaling. TXNIP-knockout mice (TKO) or wild-type (WT) treated with the reduced glutathione (GSH)-precursor, N-acetyl cysteine (WT-NAC, 500 mg/kg) were compared to WT using hypoxia-induced neovascularization model. Results: In response to hypoxia, retinas from TKO and WT-NAC mice showed significant decreases in reparative revascularization and pathological neovascularization with similar VEGF expression compared with WT. VEGF failed to stimulate vascular sprouting from aortic rings of TKO compared to WT mice. TKO mice or WT+NAC experienced reductive stress as indicated by twofold increase in TRX reductase activity and fourfold increase in reduced-GSH levels compared with WT. In human microvascular endothelial (HME) cells, VEGF stimulated co-precipitation between vascular endothelial growth factor receptor 2 (VEGFR2) with low molecular weight protein tyrosine phosphatase (LMW-PTP). Silencing TXNIP expression blunted VEGF-induced oxidation of GSH and S-glutathionylation of the LMW-PTP in HME cells. These effects were associated with impaired VEGFR2 phosphorylation that culminated in inhibiting cell migration and tube formation. Overexpression of TXNIP restored VEGFR2 phosphorylation and cell migration in TKO-endothelial cells. Innovation: TXNIP expression is required for VEGF-mediated VEGFR2 activation and angiogenic response in vivo and in vitro. TXNIP expression regulates VEGFR-2 phosphorylation via S-glutathionylation of LMW-PTP in endothelial cells. Conclusion: Our results provide novel mechanistic insight into modulating TXNIP expression as a potential therapeutic target in diseases characterized by aberrant angiogenesis. Antioxid. Redox Signal. 00, 000-000. 23969996 Constructional Apraxia as a Distinctive Cognitive and Structural Brain Feature of Pre-Senile Alzheimer's Disease. Constructional apraxia (CA) is often, but not always, observed in patients with Alzheimer's disease (AD). CA is usually explained by impairment of either basic perceptual and motor abilities, or of executive functions. This study aims to evaluate the structural correlates of CA in AD. Forty-eight patients with AD and 20 healthy age-matched controls underwent a thorough neuropsychological investigation and an MRI scan to collect high-resolution T1-weighted data. Patients were classified as having (ADca) or not having (ADnonca) CA based on performance on the Freehand copying of drawings task. T1-weighted volumes were processed according the voxel-based morphometry protocol, to assess the presence of significant differences in local grey matter volume in patients compared to controls and in ADca compared to ADnonca. Post-hoc, the mean grey matter volume of clusters that resulted significantly different between groups was regressed against the neuropsychological scores in which the two patient groups performed differently. A pre-senile disease onset was significantly more frequent in patients with CA compared to ADnonca. ADca patients also showed worse performances than patients with ADnonca at some tests requiring the processing of visuo-spatial data and testing working memory. They also showed widespread reductions in grey matter volume, mainly located in areas known to be implicated in object recognition and localization, and in maintenance and re-orienting of spatial attention. These findings suggest that the occurrence of CA in AD is often associated with a peculiar clinical onset (i.e., pre-senile), neuropsychological profile, and distribution of grey matter atrophy. 23792085 Infant dietary exposure to dioxins and dioxin-like compounds in Greece. The dietary exposure of infants to polychlorinated dibenzo dioxins and furans (PCDD/Fs) and dioxin like polychlorinated biphenyls (dl-PCBs) is an issue of great social impact. We investigated for the first time the dietary intake of these compounds in infants living in Greece. We included in our study two age groups: 0-6months, when infants are fed exclusively by human milk and/or formula milk, and 6 to 12months, when solid food is introduced to nutrition. We took into consideration analytical results for PCDD/Fs and dl-PCBs concentrations in the most popular infant formulae in the Greek market, previous data for mother milk concentrations of PCDD/Fs and dl-PCBs from Greece, and finally analytical data for fat-containing food products from the Greek market. In the first study group, it was found than in infants exclusively fed by breast milk, the calculated sum of PCDD/Fs and dioxin-like PCBs (60.3-80.4TEQpg/kg body weight) was significantly higher than that of infants that consume a combination of human milk and formula (31.2-41.6TEQpg/kg body weight). In the second study group, separate daily intake estimations were performed for babies receiving human milk (estimated total daily intake 19.76-24.95TEQpg/kg body weight) and formula milk (estimated total daily intake 1.60-2.24TEQpg/kg body weight). The risks of this exposure should not be overestimated because nursing is restricted to a limited period of human life and besides, the potential consumption of higher levels of dioxin-like compounds is fully compensated by the significant benefits of breast-feeding. 23838487 Carotid sheath lipoma: first case report in the English literature. Lipomas are the most commonly encountered benign mesenchymal tumour, arising in any location where fat is normally present. Lipomas in the head and neck are rare in all age groups. Cases of vascular sheath lipomas in the femoral region have only been reported in adults. In children, vascular sheath lipomas have not been described to date. We report the first case of a carotid sheath lipoma in a seven-year-old boy. He had a non-tender soft mass with ill defined borders occupying the left upper part of the neck. Magnetic resonance imaging showed a mass at the bifurcation of the left common carotid artery without involving the same. The mass was hyperintense on T1 and T2 weighted sequences, suggestive of a lipoma. The lipoma was enucleated after incising the carotid sheath, safeguarding its contents. Histopathology confirmed it as a lipoma. 23949948 Deoxynivalenol affects the composition of the basement membrane proteins and influences en route the migration of CD16(+) cells into the intestinal epithelium. The numerous pores in the basement membrane (BM) of the intestinal villi are essential for the communication of enterocytes with cells in the lamina propria, an important mechanism for the induction of intestinal immune responses. The intestinal epithelial barrier is affected by the mycotoxin deoxynivalenol (DON) from both the apical (luminal) and basolateral (serosal) side. The pig is the most susceptible species to the anorectic and immune-modulating effects of DON, which is most prevalent in crops. We analysed in pigs the effect of DON-contaminated feed on the composition and perforation of the BM and the presence of CD16(+) cells or their dendrites in the epithelium. In addition to in vivo experiments, in vitro studies were carried out. Using microarray analyses, the effects of DON on IPEC-J2 cells were studied with the focus on the BM. Our in vivo results showed in the control pigs: (1) a significant increased pore number (p ≤ 0.001) in the jejunum in comparison to ileum, (2) no difference in the pore size, and (3) comparable frequency of intraepithelial CD16(+) cells/dendrites in the jejunum and ileum. There was a marked trend that DON feeding increases: (1) the pore number in jejunum, and (2) the number of CD16(+) cells/dendrites in the epithelium (Tukey-Kramer; p = 0.055 and p = 0.067, respectively). The in vivo results were extended with microarray analyses of epithelial cell (IPEC-J2 cells). The down-regulation of genes like syndecan, fibulin 6 and BM-40 was observed. These proteins are important factors in the BM composition and in formation of pores. Our results provide evidence that already low basolateral concentrations of DON (50 ng/mL) influence the production of the BM protein laminin by epithelial cells. Thus, DON affects the composition of the BM. 23104429 Arsenic increases Pi-mediated vascular calcification and induces premature senescence in vascular smooth muscle cells. Several mechanisms have been proposed to explain the vascular toxicity of arsenic. Some of them are described in this work, such as stress-induced premature senescence (SIPS), dedifferentiation, and medial vascular calcification, and they all affect vascular smooth muscle cells (VSMC). Rat aortic VSMC were treated with 1-100 µM of either sodium arsenate (As(V)), sodium arsenite (As(III)), monomethylarsonic acid, or dimethylarsinic acid. None of the treatments induced VSMC calcification in the presence of 1mM inorganic phosphate (Pi), but 1 µM As(III) did increase calcification when induced with 2.5mM Pi. A lactate dehydrogenase assay revealed that this increase was explained by a rise in cytotoxicity due to simultaneous incubation with 1 µM As(III) and 2.5mM Pi. This calcification increase was also observed in the aortas of a vascular calcification model: 5/6 nephrectomized rats fed with a high Pi diet and treated with vitamin D(3). Several known mechanisms that might explain arsenic toxicity in our experimental model were discarded: apoptosis, oxidative stress, and inflammasome activation. Nevertheless, both senescence-associated β-galactosidase activity and p21 expression were increased by As(III), which reveals the induction of SIPS. As(III) also caused dedifferentiation of VSMC, as shown by the reduced expression of the VSMC markers SM22α and calponin. Senescence and gene expression were also observed in the aortas of healthy rats treated with 50 ppm As(V) in drinking water for 1 month. In conclusion, both premature senescence in aortic VSMC with phenotypic dedifferentiation and the increase of Pi-induced calcification are novel mechanisms of arsenic vasculotoxicity. 23963630 Altered brain reward circuits in eating disorders: chicken or egg? The eating disorders anorexia nervosa (AN) and bulimia nervosa (BN) are severe psychiatric disorders with high mortality. Our knowledge about the neurobiology of eating disorders is very limited, and the question remains whether alterations in brain structure or function in eating disorders are state related, remnants of the illness or premorbid traits. The brain reward system is a relatively well-characterized brain circuitry that plays a central role in the drive to eat and individuals with current or past eating disorders showed alterations in those pathways compared to controls. Here we propose that structural and functional alterations in the insula and frontal cortex, including orbitofrontal and cingulate regions, areas that contribute to reward and anxiety processing, could predispose to developing an eating disorder and that adaptive changes in those circuits in response to malnutrition or repeated binge eating and purging could further promote illness behavior, hinder recovery and contribute to relapse. 23849544 Casbane diterpenoids from the roots of Euphorbia pekinensis. Four casbane diterpenoids, together with three known related compounds were isolated from the roots of Euphorbia pekinensis. Their structures were elucidated on the basis of spectroscopic studies and comparison with the known related compounds. In addition, the absolute configuration of three compounds was determined by the modified Mosher's method. The isolated compounds were evaluated for their cytotoxic activity against seven human cancer cell lines by a WST-8 assay. 23935194 Death Receptor-Independent Activation-Induced Cell Death in Human Melanoma Antigen-Specific MHC Class I-Restricted TCR-Engineered CD4 T Cells. Engaging CD4 T cells in antitumor immunity has been quite challenging, especially in an Ag-specific manner, because most human solid tumors usually do not express MHC class II molecules. We have recently shown that human CD4 T cells engineered to express a human melanoma-associated antigenic epitope, MART-127-35, specific MHC class I-restricted transgenic TCR function as polyfunctional effectors that can exhibit a helper as well as cytolytic effector function, in an epitope-specific and MHC class I-restricted manner (Chhabra et al. 2008. J. Immunol. 181: 1063-1070; Ray et al. 2010. Clin. Immunol. 136: 338-347). TCR-engineered (TCReng) CD4 T cells therefore have translational potential, and clinical trials with MHC class I TCReng CD4 T cells are under way. In this study, we show that although TCReng CD4 T cells could be useful in cancer immunotherapy, they are also susceptible to epitope-specific activation-induced cell death (AICD). We also show that the AICD in TCReng CD4 T cells is a death receptor-independent process and that JNK and p53 play critical roles in this process as pharmacological inhibitors targeting JNK activation and p-53-mediated transcription-independent mitochondria-centric death cascade rescued a significant fraction of TCReng CD4 T cells from undergoing AICD without affecting their effector function. Our data offer novel insights toward AICD in TCReng CD4 T cells and identify several potential targets to interfere with this process. 23929036 Genetic modification of corneal neovascularization in Dstn (corn1) mice. Mutations in the gene for destrin (Dstn), an actin depolymerizing factor, lead to corneal abnormalities in mice. A null mutation in Dstn, termed Dstn (corn1) , isolated and maintained in the A.BY background (A.BY Dstn (corn1) ), results in corneal epithelial hyperproliferation, inflammation, and neovascularization. We previously reported that neovascularization in the cornea of Dstn (corn1) mice on the C57BL/6 background (B6.A.BY-Dstn (corn1) ) is significantly reduced when compared to A.BY Dstn (corn1) mice, suggesting the existence of genetic modifier(s). The purpose of this study is to identify the genetic basis of the difference in corneal neovascularization between A.BY Dstn (corn1) and B6.A.BY-Dstn (corn1) mice. We generated N2 mice for a whole-genome scan by backcrossing F1 progeny (A.BY Dstn (corn1) × B6.A.BY-Dstn (corn1) ) to B6.A.BY-Dstn (corn1) mice. N2 progeny were quantitatively phenotyped for the extent of corneal neovascularization and genotyped for markers across the mouse genome. We identified significant association of variability in corneal neovascularization with a locus on chromosome 3 (Chr3). The validity of the identified quantitative trait locus (QTL) was tested using B6 consomic mice carrying Chr3 from A/J mice. Dstn (corn1) mice from F1 and F2 intercrosses (B6.A.BY-Dstn (corn1)  Ã— C57BL/6J-Chr3(A/J)/NaJ) were phenotyped for the extent of corneal neovascularization. This analysis showed that mice carrying the A/J allele at the QTL show significantly increased neovascularization. Our results indicate the existence of a modifier that genetically interacts with the Dstn gene. This modifier demonstrates allelic differences between C57BL6 and A.BY or A/J. The modifier is sufficient to increase neovascularization in Dstn (corn1) mice. 23203002 Extracellular vesicles as an emerging mechanism of cell-to-cell communication. The concept that extracellular vesicles may act as paracrine/endocrine effectors is based on the evidence that they are able to transport bioactive molecules between cells, either within a defined microenvironment or remotely, by entering the biologic fluids. Extracellular vesicles, including exosomes and microvesicles, may deliver lipids and various functional transcripts, released from the cell of origin, to target cells. Since extracellular vesicles contain defined patterns of mRNA, microRNA, long non-coding RNA, and occasionally genomic DNA, they may transfer genetic information which induces transient or persistent phenotypic changes in recipient cells. In this review, we will discuss potential physiologic and pathological implications of extracellular vesicles, as well as the diagnostic and therapeutic opportunities that they may provide. 23590116 Free-Standing Polyelectrolyte Membranes Made of Chitosan and Alginate. Free-standing films have increasing applications in the biomedical field as drug delivery systems for wound healing and tissue engineering. Here, we prepared free-standing membranes by the layer-by-layer assembly of chitosan and alginate, two widely used biomaterials. Our aim was to produce a thick membrane and to study the permeation of model drugs and the adhesion of muscle cells. We first defined the optimal growth conditions in terms of pH and alginate concentration. The membranes could be easily detached from polystyrene or polypropylene substrate without any postprocessing step. The dry thickness was varied over a large range from 4 to 35 μm. A 2-fold swelling was observed by confocal microscopy when they were immersed in PBS. In addition, we quantified the permeation of model drugs (fluorescent dextrans) through the free-standing membrane, which depended on the dextran molecular weight. Finally, we showed that myoblast cells exhibited a preferential adhesion on the alginate-ending membrane as compared to the chitosan-ending membrane or to the substrate side. 23524199 Mechanisms of pelvic organ crosstalk: 1. Peripheral modulation of bladder inhibition by colorectal distention in rats. Bladder activity can be inhibited by afferent input from the colorectum (inhibitory rectovesical reflex). We evaluated the functional response of the rat bladder to nonnoxious and noxious colorectal distention, and investigated the mechanical and pharmacological peripheral modulation of this response. In 70 female Sprague-Dawley® rats we evaluated the effect of nonnoxious (20 mm Hg) and noxious (40 and 60 mm Hg) colorectal distention on the micturition volume threshold and on bladder activity in a filled bladder. We also studied the effect of rectal balloon size (1.5 vs 3.5 cm long), and rectal administration of 2% lidocaine jelly or 1 mM allyl isothiocyanate solution on the inhibitory rectovesical reflex. Colorectal distention at 60 mm Hg increased the micturition volume threshold (mean ± SE 0.640 ± 0.056 vs 0.448 ± 0.035 ml in controls, p <0.001). Bladder contraction frequency was significantly decreased by 40 and 60 mm Hg colorectal distention vs controls (mean 0.62 ± 0.06 and 0.33 ± 0.05 per minute, respectively, vs 0.77 ± 0.03, each p <0.001). These effects were reversible and pressure dependent (p <0.001), and more pronounced using a large rectal balloon (mean 40 vs 60 mm Hg colorectal distention 0.35 ± 0.12 vs 0.07 ± 0.04 per minute, p = 0.004). We noted no significant graded inhibition of bladder contraction amplitude or duration. The inhibitory rectovesical reflex was reversibly abolished by intrarectal lidocaine administration. Intrarectal allyl isothiocyanate administration significantly increased the effect of noxious colorectal distention on bladder contraction frequency. Only noxious levels of colorectal distention initiated the inhibitory rectovesical reflex. The effect increased with rectal balloon size and with intrarectal administration of allyl isothiocyanate. It was reversibly abolished by lidocaine. Results suggest that spinal interneurons are the mechanism behind the inhibitory rectovesical reflex. 23849178 Fingertip rapid point-of-care test in adult case-finding in coeliac disease. Coeliac disease (CD), due to its protean clinical manifestation, is still very under diagnosed in adults and delays in diagnosis may take years and even decades. Simple tools to find cases in primary care may help to identify patients for further diagnostic tests. We have evaluated the usefulness of an on site rapid fingertip whole blood point-of-care test (POCT) for such a purpose. As CD is known to run within families, we tested 148 healthy relatives of 70 Romanian index cases with biopsy-proven CD (87% of all first-degree family members, median age 36 years) for the presence of circulating autoantibodies. In addition to performing the POCT (which measures blood erythrocyte self-TG2-autoantibody complexes) on site, blood was drawn for later evaluations of serum IgA-class endomysial antibodies (EMA). EMA-positive sera were further tested for transglutaminase 2 antibodies (TG2-IgA). All serological parameters were analyzed blindly in a centralized laboratory that had no knowledge of the on site POCT result. Endoscopic small intestinal biopsies was recommended for all POCT- or EMA-test positive subjects. In on site testing the POCT was positive in 12/148 first-degree relatives (8%) and all these subjects were also serum EMA-positive. A positive EMA test was found only in one other subject. All remaining 135 healthy first-degree relatives were negative for both POCT and EMA. Four subjects positive for both POCT and EMA were negative for TG2-IgA. Ten out of thirteen of the antibody-positive subjects agreed to undergo endoscopy. The POCT was found to be positive in 8/9 first-degree relatives having coeliac-type mucosal lesions of grade Marsh 2 (n = 3) or Marsh 3 (n = 6). The three POCT-positive subjects not agreeing to undergo endoscopy were also both EMA- and TG2-IgA-positive. The fingertip whole blood rapid POCT might fulfill the unmet need for a simple and cheap case-finding biomarker for early detection and presumptive diagnosis of CD. Confirmatory studies are warranted in adult case-finding in specialized outpatient clinics and in primary care. 23563892 Seventeen years' follow-up of the tension-free vaginal tape procedure for female stress urinary incontinence. The minimally invasive tension-free vaginal tape (TVT) operation has become the "gold standard" of incontinence surgery. The aim of the present study was to evaluate the long-term effect of the tape material and to assess the continence status 17 years after surgery A cohort of 90 women operated upon with the TVT procedure at three Nordic centers has been prospectively followed for 17 years. All of the women alive according to national registries were contacted and invited to visit the clinics for evaluation. Pelvic examination was performed to reveal any adverse effects of the tape material. Objective and subjective continence status were assessed by a cough stress test and the patients' global impression of improvement as well as by condition-specific quality of life questionnaires. Seventy-eight percent of the potentially assessable women were evaluated either by a clinic visit or by a telephone interview. One case of a minimal, symptom-free tape extrusion was seen. No other tape complications occurred. Over 90 % of the women were objectively continent. Eighty-seven per cent were subjectively cured or significantly improved. The TVT operation is durable for 17 years, with a high satisfaction rate and no serious long-term tape-induced adverse effects. 22927123 Blood oxygenation level-dependent (BOLD)-based techniques for the quantification of brain hemodynamic and metabolic properties - theoretical models and experimental approaches. The quantitative evaluation of brain hemodynamics and metabolism, particularly the relationship between brain function and oxygen utilization, is important for the understanding of normal human brain operation, as well as the pathophysiology of neurological disorders. It can also be of great importance for the evaluation of hypoxia within tumors of the brain and other organs. A fundamental discovery by Ogawa and coworkers of the blood oxygenation level-dependent (BOLD) contrast opened up the possibility to use this effect to study brain hemodynamic and metabolic properties by means of MRI measurements. Such measurements require the development of theoretical models connecting the MRI signal to brain structure and function, and the design of experimental techniques allowing MR measurements to be made of the salient features of theoretical models. In this review, we discuss several such theoretical models and experimental methods for the quantification of brain hemodynamic and metabolic properties. The review's main focus is on methods for the evaluation of the oxygen extraction fraction (OEF) based on the measurement of the blood oxygenation level. A combination of the measurement of OEF and the cerebral blood flow (CBF) allows an evaluation to be made of the cerebral metabolic rate of oxygen consumption (CMRO2 ). We first consider in detail the magnetic properties of blood - magnetic susceptibility, MR relaxation and theoretical models of the intravascular contribution to the MR signal under different experimental conditions. We then describe a 'through-space' effect - the influence of inhomogeneous magnetic fields, created in the extravascular space by intravascular deoxygenated blood, on the formation of the MR signal. Further, we describe several experimental techniques taking advantage of these theoretical models. Some of these techniques - MR susceptometry and T2 -based quantification of OEF - utilize the intravascular MR signal. Another technique - quantitative BOLD - evaluates OEF by making use of through-space effects. In this review, we target both scientists just entering the MR field and more experienced MR researchers interested in the application of advanced BOLD-based techniques to the study of the brain in health and disease. Copyright © 2012 John Wiley & Sons, Ltd. 23892148 Dye removal of activated carbons prepared from NaOH-pretreated rice husks by low-temperature solution-processed carbonization and H3PO4 activation. A coupling of low-temperature sulfuric acid-assisted carbonization and H3PO4 activation was employed to convert NaOH-pretreated rice husks into activated carbons with extremely high surface area (2028m(2)g(-1)) and integrated characteristics. The influences of the activation temperature and impregnation ratio on the surface area, pore volume of activated carbons were thoroughly investigated. The morphology and surface chemistry of activated carbons were characterized using N2 sorption, FTIR, XPS, SEM, TEM, etc. The adsorption capacity of resulting carbons obtained under optimum preparation conditions was systematically evaluated using methylene blue under various simulated conditions. The adsorption process can be well described by both Langmuir isotherm model and the pseudo-second order kinetics models; and the maximum monolayer capacity of methylene blue was ca. 578mgg(-1). 23828410 Magnetic particle imaging scanner with 10-kHz drive-field frequency. Abstract Magnetic particle imaging (MPI) can be used as a fast diagnostic method for obtaining three-dimensional images from inside the body of small animals by the use of functionalized magnetic nanoparticles as tracer. Here, we present our scanner setup working at 10-kHz drive-field frequency to sample a field of view of 22×22×15 mm3 with up to 32 volume images per second. A resolution of about 1×2×1 mm3is achieved with iron oxide nanoparticles (Resovist). We discuss the properties of the complete system for application in imaging small animals such as mice. 23835228 Impact and progress in small and wide angle X-ray scattering (SAXS and WAXS). The advances made in small and wide angle X-ray scattering over the past decades have had a large impact on structural biology. Many new insights into challenging biological probes including large and transient complexes, flexible macromolecules as well as other exciting objects of various sizes were gained with this low resolution technique. Here, we review the recent developments in the experimental setups and in software for data collection and analysis, specifically for hybrid approaches. These progresses have allowed scientists to address a number of intriguing questions which could not be answered with other structural methods alone. 23531719 Intergenerational transmission of drinking motives and how they relate to young adults' alcohol use. This study examined whether parental drinking motives are associated with young adults' drinking motives, and their association with young adults' drinking behaviors. The sample consisted of 290 18-year-old and 289 20-year-old drinking young adults and their parents. For the younger group, stronger maternal coping motives were related to stronger social and enhancement motives, while stronger paternal coping motives were associated with stronger young adult coping motives. For the older group, stronger maternal coping motives were related to stronger social motives and stronger paternal enhancement motives were associated with stronger overall young adult drinking motives. For the younger group, both enhancement and conformity motives were predictive of their alcohol use. For the older group, only higher social motives were predictive of higher alcohol use. Both groups' higher coping and enhancement motives were associated with more drinking problems. While, concerning content, there are some differences due to parent gender and adolescent age, stronger parental drinking motives are indeed associated with stronger adolescent drinking motives, which in turn are quite consistently related to more adolescent alcohol use and alcohol-related problems. 23879223 Surgical Treatment of Retinal Detachment Associated with Degenerative Retinoschisis. Abstract Purpose: Although degenerative retinoschisis is almost always asymptomatic, retinal detachment occurs in some patients with outer layer breaks (OLBs). The purpose of this study is to evaluate the different surgical techniques used for the treatment of this condition. Methods: Retrospective interventional case series. The patients underwent either a Scleral-Buckling procedure (SB) or a 3-port pars plana vitrectomy (V). Pre-, intra-, and post-operative data were analyzed for the two groups. Results: Thirty eyes of 30 consecutive patients were included in the analysis. There was a statistically significant difference (0.5 ± 0.48 LogMAR units for the SB group, 1.37 ± 1.4 LogMAR units for the V group, p = 0.027) in final BCVA when the two groups were compared, whereas there was no statistically significant difference in the baseline BCVA between the two groups (p = 0.38). The proportion of cases that were successfully attached with one operation was slightly lower in the V group (62% versus 76%). Conversely, the proportion of cases that were successfully attached with more than one operation was similar in both groups (23% and 24%, respectively). Conclusion: The present study highlights that retinoschisis-associated RD is a demanding situation to treat and remains a challenge for vitreoretinal surgeons. Scleral buckle procedure was found to be successful in eyes that have peripheral OLBs and not extensive RDs, and PPV should be considered for treating symptomatic, rather extensive schisis-RDs, especially in cases with large or posterior outer layer breaks. 23910632 Postsurgical Comparison of Pulsatile Hemodynamics in Five Unique Total Cavopulmonary Connections: Identifying Ideal Connection Strategies. Appropriate choice of Fontan pathway requires keen preoperative examination of angiographic anatomy. We hypothesize that surgical choices may be better informed by lessons learned from postoperative hemodynamic evaluation in different Fontan connection strategies. High-performance computational fluid dynamics is employed to evaluate hemodynamics in five unique Fontan anatomies. Our cohort included one lateral tunnel, extracardiac conduit, intraatrial conduit, intra/extracardiac conduit, and direct cavopulmonary connection (DCPC) Fontan pathway. Theoretical cardiac cycle-averaged power loss (Eloss) and hepatic flow distribution (HFD) were compared after modeling identical physiologic pulsatile caval flow and time-resolved pulmonary artery flow distribution. The Eloss was also evaluated at instants of peak inferior vena cava flow and peak superior vena cava flow to study caval anastomosis shape sensitivity on hemodynamics. Quantitative examination of Eloss and HFD revealed minimum cycle-averaged Eloss in the extracardiac conduit Fontan; however, at the cost of the poorest HFD (left pulmonary artery/right pulmonary artery = 84.5%/15.5%). In contrast, DCPC Fontan was found to have the best trade-off between mean Eloss (5.87 mW, 2.44%) and HFD (left pulmonary artery/right pulmonary artery = 38.9%/61.1%). Except for intraatrial conduit, the instantaneous superior vena cava and inferior vena cava peak flow Eloss exceeded the cycle average Eloss. The peak inferior vena cava flow Eloss of DCPC Fontan nearly equaled its cycle-averaged Eloss (∼5.69 mW). Considering cycle-averaged Eloss, HFD, and peak inferior vena cava flow Eloss, DCPC had the best hemodynamic performance. Intraatrial conduit Fontan is an efficient modification of lateral tunnel Fontan that offers possibility for excellent streamlining of inferior vena cava and superior vena cava with the pulmonary arteries. 23960240 The Cellular Source and Target of IL-21 in K/BxN Autoimmune Arthritis. IL-21 is a pluripotent cytokine that regulates B cell and plasma cell differentiation and is thought be an autocrine factor for follicular helper T cell (TFH) and Th17 differentiation. Although IL-21 has been implicated in autoimmune diseases, its relevant cellular source and target cells have not been well characterized. We investigated this issue in the K/BxN mouse model of autoimmune arthritis. Adoptive transfer of KRN-transgenic CD4(+) T cells into appropriate hosts drives germinal center (GC) formation and autoantibody production against glucose-6-phosphate isomerase, leading to joint inflammation and destruction. By comparing transfer of T or B cells deficient in IL-21 or IL-21R, we were able to dissect the contribution of each cell type. T cells deficient in IL-21 did not induce GC formation or autoantibody production, but they went through normal TFH differentiation. However, T cells lacking IL-21R induced Ab titers, GC B cell frequency, and arthritis development similar to wild-type T cells, suggesting that IL-21 is not required for TFH differentiation and function. IL-21 acts on B cells, because IL-21R expression on B cells was required to induce disease. In contrast, Th17 cells, a T cell subset that also produces IL-21 and can provide help to B cells, are not required for the GC response and arthritis. These data have implications in developing effective therapies for rheumatoid arthritis and other Ab-mediated autoimmune diseases. 23810928 Effects of self-controlled feedback on learning of a throwing task in children with spastic hemiplegic cerebral palsy. The purpose of this study was to examine the effect of self-controlled feedback on learning a throwing task in children with spastic hemiplegic cerebral palsy (SHCP). In order to achieve the research objectives, using a semi-experimental method, 20 children with SHCP (7-12 years old) were selected from special schools in Tehran, Iran. After showing the participants how to do the throwing task, a pre-test with 10 trials was conducted to homogenize the participants. Then, they were randomly assigned to two groups (self-control group and yoked group) to be examined in acquisition, retention, and transfer phases. Children in self-control group requested feedback when necessary during the acquisition phase. In contrast, participants in yoked-group replicated the feedback schedules of their counterparts in self-control group without any choice. A multivariate analysis of variance (MANOVA) was performed to analyze the data. Based on the results, a significant difference was not found between the self-control and yoked-group in acquisition phase (F=.538, p<.473). However, there was a significant difference between the two groups in retention (F=11.72, p<.003) and transfer (F=6.74, p<.018) phases. Thus, based on the better results obtained in the self-control condition, this type of feedback can be used in physiotherapy programs related to children with CP to improve their motor skills and independence movements. 23927188 Spatial patterning of endothelial cells and vascular network formation using ultrasound standing wave fields. The spatial organization of cells is essential for proper tissue assembly and organ function. Thus, successful engineering of complex tissues and organs requires methods to control cell organization in three dimensions. In particular, technologies that facilitate endothelial cell alignment and vascular network formation in three-dimensional tissue constructs would provide a means to supply essential oxygen and nutrients to newly forming tissue. Acoustic radiation forces associated with ultrasound standing wave fields can rapidly and non-invasively organize cells into distinct multicellular planar bands within three-dimensional collagen gels. Results presented herein demonstrate that the spatial pattern of endothelial cells within three-dimensional collagen gels can be controlled by design of acoustic parameters of the sound field. Different ultrasound standing wave field exposure parameters were used to organize endothelial cells into either loosely aggregated or densely packed planar bands. The rate of vessel formation and the morphology of the resulting endothelial cell networks were affected by the initial density of the ultrasound-induced planar bands of cells. Ultrasound standing wave fields provide a rapid, non-invasive approach to pattern cells in three-dimensions and direct vascular network formation and morphology within engineered tissue constructs. 23899715 Temperature differentially regulates the two kisspeptin systems in the brain of zebrafish. Kisspeptins encoded by the kiss1 and kiss2 genes play an important role in reproduction through the stimulation of gonadotropin-releasing hormone (GnRH) secretion by activating their receptors (KissR1 EU047918 and KissR2 EU047917). To understand the mechanism through which temperature affects reproduction, we examined kiss1 and kiss2 and their respective receptor (kissr1 and kissr2) gene expression in the brain of male zebrafish exposed to a low temperature (15°C), normal temperature (27°C), and high temperature (35°C) for 7-days. kiss1 mRNA levels in the brain were significantly increased (2.9-fold) in the low temperature compared to the control (27°C), while no noticeable change was observed in the high temperature conditions. Similarly, kissr1 mRNA levels were significantly increased (1.5-2.2-folds) in the low temperature conditions in the habenula, the nucleus of the medial longitudinal fascicle, oculomotor nucleus, and the interpeduncular nucleus. kiss2 mRNA levels were significantly decreased (0.5-fold) in the low and high temperature conditions, concomitant with kissr2 mRNA levels (0.5-fold) in the caudal zone of the periventricular hypothalamus and the posterior tuberal nucleus. gnrh3 but not gnrh2 mRNA levels were also decreased (0.5-fold) in the low and high temperature conditions. These findings suggest that while the kiss1/kissr1 system is sensitive to low temperature, the kiss2/kissr2 system is sensitive to both extremes of temperature, which leads to failure in reproduction. 23804404 The archaeal exosome: identification and quantification of site-specific motions that correlate with cap and RNA binding. Big and unexpectedly flexible: The 173 kDa exosome core is unexpectedly dynamic in solution. The kinetic and thermodynamic properties connected with the identified exchange process were quantified. Both cap protein and RNA substrate binding significantly alter the identified motions, suggesting that these interactions occur through conformational selection. 23943384 Therapeutic Options for Adult T-Cell Leukemia/Lymphoma. Adult T-cell leukemia/lymphoma (ATL) is the first human malignancy associated with a retroviral infection and occurs in approximately 5 % of the 15 million to 20 million people infected by human T-cell lymphotropic virus 1. In general, ATL is resistant to chemotherapy, and while awaiting new therapeutics, patients commonly face a detrimental progress of the disease and death. The viral oncoprotein Tax is a key player in the cause of ATL and acts by interfering with DNA repair, cell cycle, apoptosis, and proliferative cellular programs. The Shimoyama classification describes four different subtypes (acute, lymphoma, chronic, and smoldering) associated with different outcomes, and that require different treatment strategies tailored to the clinical presentation. In aggressive ATL (acute and lymphoma subtypes), clinical trials, mostly from Japan, have demonstrated that combinations of chemotherapy can induce acceptable response rates, especially in the lymphoma subtype. However, the overall outcome remains extremely poor owing to a high rate of relapse. Similarly, the so-called indolent forms (smoldering and chronic subtypes) have a poor outcome whether they are managed with watching and waiting or treated with chemotherapy. We recently realized a worldwide meta-analysis and showed that the combination of zidovudine and interferon alpha is highly effective in the leukemic subtypes of ATL and should be considered as standard first-line therapy in that setting. This combination has changed the natural history of the disease through achievement of significantly improved long-term survival in patients with smoldering and chronic ATL as well as a subset of patients with acute ATL. Patients with lymphoma-type ATL still benefit from chemotherapy induction with concurrent or sequential antiretroviral therapy with zidovudine and interferon alpha. Allogeneic stem cell transplantation is a promising option but has several barriers. New drugs such as the new antibody anti-CXCR4 show promising results. Prospective trials testing maintenance therapy in order to avoid relapse are warranted when the patient cannot undergo allogeneic stem cell transplantation. 23606373 Morphological Change and Mobility Enhancement in PEDOT:PSS by Adding Co-solvents. Adding ethylene glycol (EG) to poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) solution improves the crystallinity of the PEDOT and the ordering of the PEDOT nanocrystals in solid films. The carrier-mobility enhancement is confirmed by using ion-gel transistors combined with in situ UV-vis-NIR spectroscopy. 23334753 Microfluidic chemostat for measuring single cell dynamics in bacteria. We designed a microfluidic chemostat consisting of 600 sub-micron trapping/growth channels connected to two feeding channels. The microchemostat traps E. coli cells and forces them to grow in lines for over 50 generations. Excess cells, including the mother cells captured at the start of the process, are removed from both ends of the growth channels by the media flow. With the aid of time-lapse microscopy, we have monitored dynamic properties such as growth rate and GFP expression at the single-cell level for many generations while maintaining a population of bacteria of similar age. We also use the microchemostat to show how the population responds to dynamic changes in the environment. Since more than 100 individual bacterial cells are aligned and immobilized in a single field of view, the microchemostat is an ideal platform for high-throughput intracellular measurements. We demonstrate this capability by tracking with sub-diffraction resolution the movements of fluorescently tagged loci in more than one thousand cells on a single device. The device yields results comparable to conventional agar microscopy experiments with substantial increases in throughput and ease of analysis. 23889250 IgE binding to peanut components by four different techniques: Ara h 2 is the most relevant in peanut allergic children and adults. Several studies have analysed the diagnostic value of specific IgE (sIgE) for individual peanut allergens. However, little is known about the concordance between different techniques available in both children and adults. To evaluate the value of individual peanut allergens by different techniques, i.e. multi-plexed microarray, single-plexed IgE assay, skin prick test (SPT) and immunoblot in both peanut allergic adults and children. Sensitization patterns to peanut allergens Ara h 1, 2, 3, and 8 were evaluated using four different techniques: multi-plexed microarray immunoassay, single-plexed IgE assay, SPT and immunoblot. Twenty-two peanut allergic adults and 15 children scored on clinical severity according to double-blind, placebo-controlled food challenges and 27 atopic control patients were included. Comparable sensitivity values were found between all four techniques in adults, with the highest sensitivity for Ara h 2 (76.2-95.5%, compared to 100% with all techniques in children). The multi-plexed assay to Ara h 1 (93.3%) demonstrated a higher sensitivity compared with the other three techniques (P = 0.04) in children, but absolute values were perfectly correlated. There were no differences between adults and children. The area under the receiver operating characteristic curve (AUC) of sIgE to Ara h 1 was higher with the multi-plexed assay compared with the single-plexed assay (0.91 vs. 0.75). In adults, sIgE to Ara h 1, 2, and 3 was correlated with clinical severity. No such correlation was found in children. In conclusion, the single- and multi-plexed assay, SPT and immunoblot perform equally in both peanut allergic adults and children, with Ara h 2 being most often recognized with all techniques. Specific IgE to Ara h 1, 2, and 3 in adults was correlated with severity. 23790464 Isolation and characterization of alkane degrading bacteria from petroleum reservoir waste water in Iran (Kerman and Tehran provenances). Petroleum products spill and leakage have become two major environmental challenges in Iran. Sampling was performed in the petroleum reservoir waste water of Tehran and Kerman Provinces of Iran. Alkane degrading bacteria were isolated by enrichment in a Bushnel-Hass medium, with hexadecane as sole source of carbon and energy. The isolated strains were identified by amplification of 16S rDNA gene and sequencing. Specific primers were used for identification of alkane hydroxylase gene. Fifteen alkane degrading bacteria were isolated and 8 strains were selected as powerful degradative bacteria. These 8 strains relate to Rhodococcus jostii, Stenotrophomonas maltophilia, Achromobacter piechaudii, Tsukamurella tyrosinosolvens, Pseudomonas fluorescens, Rhodococcus erythropolis, Stenotrophomonas maltophilia, Pseudomonas aeruginosa genera. The optimum concentration of hexadecane that allowed high growth was 2.5%. Gas chromatography results show that all strains can degrade approximately half of hexadecane in one week of incubation. All of the strains have alkane hydroxylase gene which are important for biodegradation. As a result, this study indicates that there is a high diversity of degradative bacteria in petroleum reservoir waste water in Iran. 23870996 The hydroxycinnamic acid content of barley and brewers' spent grain (BSG) and the potential to incorporate phenolic extracts of BSG as antioxidants into fruit beverages. The hydroxycinnamic acid (HA) content of starting barley for brewers' spent grains (BSG), whole BSG and phenolic extracts from BSG was measured using high performance liquid chromatography (HPLC) and correlated with antioxidant potential. The effect of BSG phenolic extracts on antioxidant activity of fruit beverages was also assessed (using the total phenolic content (TPC), 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays). The concentration of HA present in barley extract and BSG was in the order of ferulic acid (FA), p-coumaric acid (p-CA) derivatives, FA derivatives, p-CA, caffeic acid (CA) and CA derivatives. Results suggested that brewing and roasting decreased the HA content. Antioxidant activity was significantly (P<0.05) correlated with caffeic acid (R(2)=0.8309) and total HA (R(2)=0.3942) concentrations. Addition of extracts to fruit beverages resulted in a significant (P<0.05) increase in antioxidant activity of cranberry juice, measured by the FRAP assay. In vitro digestion significantly (P<0.05) reduced TPC, DPPH and FRAP activity of the fruit beverages. 23891982 Increased plasticity of the stiffness of melanoma cells correlates with their acquisition of metastatic properties. The stiffness of tumor cells varies during cancer progression. In particular, metastatic carcinoma cells analyzed by Atomic Force Microscopy (AFM) appear softer than non-invasive and normal cells. Here we examined by AFM how the stiffness of melanoma cells varies during progression from non-invasive Radial Growth Phase (RGP) to invasive Vertical Growth Phase (VGP) and to metastatic tumors. We show that transformation of melanocytes to RGP and to VGP cells is characterized by decreased cell stiffness. However, further progression to metastatic melanoma is accompanied by increased cell stiffness and the acquisition of higher plasticity by tumor cells, which is manifested by their ability to greatly augment or reduce their stiffness in response to diverse adhesion conditions. We conclude that increased plasticity, rather than decreased stiffness as suggested for other tumor types, is a marker of melanoma malignancy. These findings advise caution about the potential use of AFM for melanoma diagnosis. 23930077 The hospital educational environment and performance of residents in the General Medicine In-Training Examination: a multicenter study in Japan. It is believed that the type of educational environment in teaching hospitals may affect the performance of medical knowledge base among residents, but this has not yet been proven. We aimed to investigate the association between the hospital educational environment and the performance of the medical knowledge base among resident physicians in Japanese teaching hospitals. To assess the knowledge base of medicine, we conducted the General Medicine InTraining Examination (GM-ITE) for second-year residents in the last month of their residency. The items of the exam were developed based on the outcomes designated by the Japanese Ministry of Health, Labor, and Welfare. The educational environment was evaluated using the Postgraduate Hospital Educational Environment Measure (PHEEM) score, which was assessed by a mailed survey 2 years prior to the exam. A mixed-effects linear regression model was employed for the analysis of variables associated with a higher score. Twenty-one teaching hospitals participated in the study and a total of 206 residents (67 women) participated and completed the exam. There were no residents who declined to participate in the exam. The mean GM-ITE score was 58 (standard deviation 8.4). The mixed-effects linear regression analysis showed that a higher PHEEM score was associated with a higher GM-ITE score (P = 0.02). Having a department of general medicine, and hospital location in a provincial community (versus an urban setting), were also shown to have a significant relationship with the higher score (P = 0.03, and P = 0.02, respectively). We found that the performance of the medical knowledge base of resident physicians was significantly associated with the educational environment of their hospitals. Improvement of the educational environment in teaching hospitals might be crucial for enhancing the performance of resident physicians in Japan. 23921212 Frequency and nature of testicular and paratesticular lesions in forensic autopsies. The aim of our study was to determine the frequency and nature of testicular and paratesticular lesions in forensic autopsies. A retrospective study was carried out on 495 adult male cases that underwent forensic autopsy from January 2008 to December 2011 in our Department. For each case, the following parameters were reported: age, body mass index, nature of testicular and paratesticular lesions, associated lesions in external genitalia, testicle weight, cause of death, manner of death, resuscitation attempts and prior medical history. Mean age of the studied population was 47.8 years (range 18-96). Mean body mass index was 25.3 kg/m(2) (range 15-46.2). Testicular lesions and/or paratesticular were found in 16.4% of the cases (n = 81). The most frequent lesions were, respectively, testicular atrophy (n = 38) and trauma (n = 28). In three cases showing traumatic lesions, associated traumatic lesions were found in external genitalia. Most frequent cause of death was blunt trauma (19.9% of the cases). Manner of death most frequently associated with testicular trauma was, respectively, road traffic accident (n = 11) and suicidal fall (n = 6). Mean testicular weight was, respectively, 17.9 g for the right and 20.8 g for the left (range 2-38). Atrophy was associated with testicular weight less than 10 g. A significant association between testicular atrophy and age was found, the risk of atrophy increasing quite linearly with age. No significant statistical link between prior medical history and testicular pathology was found. There was also no influence of body mass index. Resuscitation attempts were not statistically associated with testicular traumatic lesions. 23876551 Peripherally inserted central catheters: use at a tertiary care pediatric center. To examine the use of peripherally inserted central catheters (PICCs) in a tertiary care pediatric setting. An observational study of use and referral practices for PICCs in a tertiary care pediatric setting was performed with three distinct approaches: (i) in an institutional overview of trends, data from 2001 to 2012 were initially analyzed to identify high-level trends; (ii) an in-depth analysis of PICC referrals during 1 year was performed to determine details of referral patterns and clinical practices; and (iii) an electronic survey of the perception and understanding of referring clinical staff was conducted. During the past decade, there has been a steady increase in the number of PICC insertions and a decrease in median PICC dwell times. Discrepancies were identified between the anticipated versus actual dwell times. A large proportion of patients was found to have multiple PICC insertions, short dwell times, and premature PICC removals, potentially resulting in increasing risks of short- and long-term complications. Large percentages of the staff respondents valued the role of PICCs and had a good understanding of short-term complications, but underestimated the scale of the PICC service (numbers placed, resources involved) and several long-term complications associated with PICCs. The number of PICCs inserted in children is increasing while PICC dwell times are decreasing. Better postprocedure care is important to minimize premature removals and avoid repeat insertions. Associated complications are not fully appreciated by the referring pediatricians. Further education and guidelines are needed. 23649498 Is montgomery tracheal safe-T-tube clinical failure induced by biofilm? Objectives Montgomery Safe-T-Tube deterioration and early biofilm colonization may explain the discomfort claimed by many patients and clinical failures. The aim of the study was to analyze the deterioration of Montgomery Safe-T-Tube morphological and mechanical properties in vivo in 16 patients by using microbiological methods, optical and electron microscopy, and engineering tests. Study Design Prospective controlled study at a single medical center. Setting University hospital. Subjects and Methods The study, conducted from April 2007 to February 2012 at the "Sapienza" University of Rome, was designed to collect 2 Montgomery Safe-T-Tubes from each patient. The first was removed 3 to 15 days after insertion (group A) and the second at least 90 days after (group B). Specimens underwent microbiologic assays, electron microscopic analysis, immunocytologic analysis, and mechanical tests. Results Microorganisms were not isolated in 2 group A cases (12%), whereas they were in all group B cases. Biofilm was identified in 11 of 16 (69%) group A samples and in 16 of 16 (100%) group B samples (P = .0149) using scanning electron microscopy. Immunohistochemistry showed monocyte-granulocyte line cells producing interleukin-1β on the external surfaces of Montgomery Safe-T-Tubes. The tensile test showed that the wear related to the longer period of use makes Montgomery Safe-T-Tubes more rigid than newer ones. Conclusion Early biofilm colonization takes place in Montgomery Safe-T-Tubes in most cases. The mechanical decay could be justified in part by the destructive biofilm activity and by the release of inflammatory effectors and enzymes. 23939374 Characterization of a new class of androgen receptor antagonists with potential therapeutic application in advanced prostate cancer. The human androgen receptor (AR) plays a major role in the development and progression of prostate cancer (PCa) and represents a well-established drug target. All clinically approved AR antagonists possess similar chemical structures and exhibit the same mode of action on the AR. While initially effective, resistance to these AR antagonists usually develops and the cancer quickly progresses to castration-resistant and metastatic states. Yet even in these late-stage patients, the AR is critical for the progression of the disease. Thus, there is a continuing need for novel chemical classes of AR antagonists that could help overcome the problem of resistance. In this study, we implemented and utilized the synergetic combination of virtual and experimental screening to discover a number of new 10-benzylidene-10H-anthracen-9-ones that not only effectively inhibit AR transcriptional activity, but also induce almost complete degradation of the AR. Of these 10-benzylidene-10H-anthracen-9-one analogues, a lead compound (VPC-3033) was identified that demonstrated strong androgen displacement potency, effectively inhibited AR transcriptional activity, and possesses a profound ability to cause degradation of AR. Notably, VPC-3033 exhibited significant activity against PCa cells that have already developed resistance to the second-generation antiandrogen Enzalutamide (formerly known as MDV3100). VPC-3033 also demonstrated strong anti-AR activity in the LNCaP in vivo xenograft model. These results provide a foundation for the development of a new class of AR antagonists that can help address the problem of antiandrogen resistance in PCa. 23811053 Apo States of Calmodulin and CaBP1 Control CaV1 Voltage-Gated Calcium Channel Function through Direct Competition for the IQ Domain. In neurons, binding of calmodulin (CaM) or calcium-binding protein 1 (CaBP1) to the CaV1 (L-type) voltage-gated calcium channel IQ domain endows the channel with diametrically opposed properties. CaM causes calcium-dependent inactivation and limits calcium entry, whereas CaBP1 blocks calcium-dependent inactivation (CDI) and allows sustained calcium influx. Here, we combine isothermal titration calorimetry with cell-based functional measurements and mathematical modeling to show that these calcium sensors behave in a competitive manner that is explained quantitatively by their apo-state binding affinities for the IQ domain. This competition can be completely blocked by covalent tethering of CaM to the channel. Further, we show that Ca(2+)/CaM has a sub-picomolar affinity for the IQ domain that is achieved without drastic alteration of calcium-binding properties. The observation that the apo forms of CaM and CaBP1 compete with each other demonstrates a simple mechanism for direct modulation of CaV1 function and suggests a means by which excitable cells may dynamically tune CaV activity. 23869062 Estrogen Replacement and Skeletal Muscle: Mechanisms and Population Health. There is a growing body of information supporting the beneficial effects of estrogen and estrogen based hormone therapy (HT) on maintenance and enhancement of muscle mass, strength and connective tissue. These effects are also evident in enhanced recovery from muscle atrophy or damage and have significant implications particularly for the muscular health of post-menopausal women. Evidence suggests that HT will also help maintain or increase muscle mass, improve post-atrophy muscle recovery and enhance muscle strength in aged females. This is important because this population in particular is at risk for a rapid onset of frailty. The potential benefits of estrogen and HT relative to skeletal muscle function and composition combined with other health-related enhancements associated with reduced risk of cardiovascular events, overall mortality and metabolic disfunction and enhanced , cognition, and bone health cumulate in a strong argument for more widespread and prolonged consideration of HT if started proximal to menopausal onset in most women.. Earlier reports of increased health risks with HT use in post-menopausal women had lead to a decline in HT use. However, recent re-evaluation regarding the health effects of HT indicates a general lack of risks and a number of significant health benefits of HT use when initiated at the onset of menopause. Although further research is still needed to fully delineate its mechanisms of action, the general use of HT by post-menopausal women, to enhance muscle mass and strength as well as overall health, with initiation soon after the onset of menopause should be considered. 23757211 Self-assembly of a halogenated molecule on oxide-passivated cu(110). The supramolecular self-assembly of brominated molecules was investigated and compared on Cu(110) and Cu(110)O(2×1) surfaces under ultrahigh vacuum. By using scanning tunnelling microscopy, we show that brominated molecules form a disordered structure on Cu(110), whereas a well-ordered supramolecular network is observed on the Cu(110)O(2×1) surface. The different adsorption behaviors of these two surfaces are described in terms of weakened molecule-substrate interactions on Cu(110)O(2×1) as opposed to bare Cu(110). The effect of oxygen-passivation is to suppress debromination and it can be a convenient approach for investigating other self-assembly processes on copper-based substrates. 23060633 Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis. The broadest pattern of tuberculosis (TB) drug resistance for which a consensus definition exists is extensively drug-resistant (XDR)-TB. It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance in order to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR alone and three nonmutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) and capreomycin and kanamycin/amikacin (XDR+2sli) XDR plus resistance to second-line injectables and to more than one group 4 drug, i.e. ethionamide/protionamide, cycloserine/terizidone or para-aminosalicylic acid (XDR+sliG4) and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR alone, 68 XDR+2sli, 48 XDR+sliG4 and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted OR 0.4, 95% CI 0.2-0.8) compared to XDR alone, while odds of failure and death were higher in all XDR patients with additional resistance (adjusted OR 2.6-2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current drug susceptibility testing methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB. 23833138 Novel human papillomavirus type 174 from a cutaneous squamous cell carcinoma. We report the cloning and characterization of a novel human papillomavirus (HPV), now officially recognized as HPV-174, isolated from a cutaneous squamous cell carcinoma. HPV-174 has a genome organization characteristic of cutaneous HPV types, clusters to the genus Betapapillomavirus, species β2, and is most closely related to HPV-145. 23684540 Generation of Functional Thymic Epithelium from Human Embryonic Stem Cells that Supports Host T Cell Development. Inducing immune tolerance to prevent rejection is a key step toward successful engraftment of stem-cell-derived tissue in a clinical setting. Using human pluripotent stem cells to generate thymic epithelial cells (TECs) capable of supporting T cell development represents a promising approach to reach this goal; however, progress toward generating functional TECs has been limited. Here, we describe a robust in vitro method to direct differentiation of human embryonic stem cells (hESCs) into thymic epithelial progenitors (TEPs) by precise regulation of TGFβ, BMP4, RA, Wnt, Shh, and FGF signaling. The hESC-derived TEPs further mature into functional TECs that support T cell development upon transplantation into thymus-deficient mice. Importantly, the engrafted TEPs produce T cells capable of in vitro proliferation as well as in vivo immune responses. Thus, hESC-derived TEP grafts may have broad applications for enhancing engraftment in cell-based therapies as well as restoring age- and stress-related thymic decline. 23452502 Diabetes, perioperative ischaemia and volatile anaesthetics: consequences of derangements in myocardial substrate metabolism. Volatile anaesthetics exert protective effects on the heart against perioperative ischaemic injury. However, there is growing evidence that these cardioprotective properties are reduced in case of type 2 diabetes mellitus. A strong predictor of postoperative cardiac function is myocardial substrate metabolism. In the type 2 diabetic heart, substrate metabolism is shifted from glucose utilisation to fatty acid oxidation, resulting in metabolic inflexibility and cardiac dysfunction. The ischaemic heart also loses its metabolic flexibility and can switch to glucose or fatty acid oxidation as its preferential state, which may deteriorate cardiac function even further in case of type 2 diabetes mellitus.Recent experimental studies suggest that the cardioprotective properties of volatile anaesthetics partly rely on changing myocardial substrate metabolism. Interventions that target at restoration of metabolic derangements, like lifestyle and pharmacological interventions, may therefore be an interesting candidate to reduce perioperative complications. This review will focus on the current knowledge regarding myocardial substrate metabolism during volatile anaesthesia in the obese and type 2 diabetic heart during perioperative ischaemia. 23461679 Controlling spontaneous emission with plasmonic optical patch antennas. We experimentally demonstrate the control of the spontaneous emission rate and the radiation pattern of colloidal quantum dots deterministically positioned in a plasmonic patch antenna. The antenna consists of a thin gold microdisk separated from a planar gold layer by a few tens of nanometers thick dielectric layer. The emitters are shown to radiate through the entire patch antenna in a highly directional and vertical radiation pattern. Strong acceleration of spontaneous emission is observed, depending on the antenna geometry. Considering the double dipole structure of the emitters, this corresponds to a Purcell factor up to 80 for dipoles perpendicular to the disk. 23558089 The regulatory role of NF-κB in autophagy-like cell death after focal cerebral ischemia in mice. Autophagy may contribute to ischemia-induced cell death in the brain, but the regulation of autophagic cell death is largely unknown. Nuclear factor kappa B (NF-κB) is a regulator of apoptosis in cerebral ischemia. We examined the hypothesis that autophagy-like cell death could contribute to ischemia-induced brain damage and the process was regulated by NF-κB. In adult wild-type (WT) and NF-κB p50 knockout (p50(-/-)) mice, focal ischemia in the barrel cortex was induced by ligation of distal branches of the middle cerebral artery. Twelve to 24h later, autophagic activity increased as indicated by enhanced expression of Beclin-1 and LC3 in the ischemic core and/or penumbra regions. This increased autophagy contributed to cell injury, evidenced by terminal deoxynucleotidyltransferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) co-staining and a protective effect achieved by the autophagy inhibitor 3-methyladenine. The number of Beclin-1/TUNEL-positive cells was significantly more in p50(-/-) mice than in WT mice. Neuronal and vascular cell death, as determined by TUNEL-positive cells co-staining with NeuN or Collagen IV, was more abundant in p50(-/-) mice. Immunostaining of the endothelial cell tight junction marker occludin revealed more damage to the blood-brain barrier in p50(-/-) mice. Western blotting of the peri-infarct tissue showed a reduction of Akt-the mammalian target of rapamycin (mTOR) signaling in p50(-/-) mice after ischemia. These findings provide the first evidence that cerebral ischemia induced autophagy-like injury is regulated by the NF-κB pathway, which may suggest potential treatments for ischemic stroke. 23422214 IL-17A inhibits airway reactivity induced by respiratory syncytial virus infection during allergic airway inflammation. Viral infections are the most frequent cause of asthma exacerbations and are linked to increased airway reactivity (AR) and inflammation. Mice infected with respiratory syncytial virus (RSV) during ovalbumin (OVA)-induced allergic airway inflammation (OVA/RSV) had increased AR compared with OVA or RSV mice alone. Furthermore, interleukin 17A (IL-17A) was only increased in OVA/RSV mice. To determine whether IL-17A increases AR and inflammation in the OVA/RSV model. Wild-type (WT) BALB/c and IL-17A knockout (KO) mice underwent mock, RSV, OVA or OVA/RSV protocols. Lungs, bronchoalveolar lavage (BAL) fluid and/or mediastinal lymph nodes (MLNs) were harvested after infection. Cytokine expression was determined by ELISA in the lungs or BAL fluid. MLNs were restimulated with either OVA (323-229) peptide or RSV M2 (127-135) peptide and IL-17A protein expression was analysed. AR was determined by methacholine challenge. RSV increased IL-17A protein expression by OVA-specific T cells 6 days after infection. OVA/RSV mice had decreased interferon-β protein expression compared with RSV mice. OVA/RSV mice had increased IL-23p19 mRNA expression in lung homogenates compared with mock, OVA or RSV mice. Unexpectedly, IL-17A KO OVA/RSV mice had increased AR compared with WT OVA/RSV mice. Furthermore, IL-17A KO OVA/RSV mice had increased eosinophils, lymphocytes and IL-13 protein expression in BAL fluid compared with WT OVA/RSV mice. IL-17A negatively regulated AR and airway inflammation in OVA/RSV mice. This finding is important because IL-17A has been identified as a potential therapeutic target in asthma, and inhibiting IL-17A in the setting of virally-induced asthma exacerbations may have adverse consequences. 23580340 Structural awareness mitigates the effect of delay in human causal learning. Many studies have demonstrated that reinforcement delays exert a detrimental influence on human judgments of causality. In a free-operant procedure, the trial structure is usually only implicit, and delays are typically manipulated via trial duration, with longer trials tending to produce both longer experienced delays and also lower objective contingencies. If, however, a learner can become aware of this trial structure, this may mitigate the effects of delay on causal judgments. Here we tested this "structural-awareness" hypothesis by manipulating whether response-outcome contingencies were clearly identifiable as such, providing structural information in real time using an auditory tone to delineate consecutive trials. A first experiment demonstrated that providing cues to indicate trial structure, but without an explicit indication of their meaning, significantly increased the accuracy of causal judgments in the presence of delays. This effect was not mediated by changes in response frequency or timing, and a second experiment demonstrated that it cannot be attributed to the alternative explanation of enhanced outcome salience. In a third experiment, making trial structure explicit and unambiguous, by telling participants that the tones indicated trial structure, completely abolished the effect of delays. We concluded that, with sufficient information, a continuous stream of causes and effects can be perceived as a series of discrete trials, the contingency nature of the input may be exploited, and the effects of delay may be eliminated. These results have important implications for human contingency learning and in the characterization of temporal influences on causal inference. 22511564 Topical antiinflammatory activity of essential oil of Lippia sidoides cham: possible mechanism of action. This work reports the chemical composition of the essential oil of Lippia sidoides (EOLS) and evaluation of the topical effect of EOLS and thymol against different irritant agents in vivo. The essential oil was obtained by hydrodistillation, and gas chromatography/mass spectrometry analysis identified the main constituents: thymol (84.9%) and p-cymene (5.33%). The antiinflammatory activity was evaluated using the mouse models of acute ear inflammation induced by croton oil, arachidonic acid, phenol or histamine, and chronic inflammation induced by croton oil. The topical application of EOLS or thymol at a dose of 2 mg/ear significantly reduced (p < 0.001) ear edema induced with arachidonic acid by 45.1% and 47.4% and reduced ear edema induced with phenol by 33.2% (p < 0.05) and 54.7% (p < 0.01) in acute ear edema. However, a proinflammatory effect of EOLS and thymol was evidenced when it was applied for more than 1 day. There were no statistical differences in antiedematogenic activity between EOLS and thymol. In conclusion, the results indicate that thymol is the constituent responsible for the topical antiinflammatory activity of EOLS. Thus, these findings could justify the popular use of L. sidoides by alternative medicine, but chronic use has an inflammatory effect. 23252580 Chemical Modification of Lysozyme, Glucose 6-Phosphate Dehydrogenase, and Bovine Eye Lens Proteins Induced by Peroxyl Radicals: Role of Oxidizable Amino Acid Residues. Chemical and structural alterations to lysozyme (LYSO), glucose 6-phosphate dehydrogenase (G6PD), and bovine eye lens proteins (BLP) promoted by peroxyl radicals generated by the thermal decomposition of 2,2'-azobis(2-amidinopropane) hydrochloride (AAPH) under aerobic conditions were investigated. SDS-PAGE analysis of the AAPH-treated proteins revealed the occurrence of protein aggregation, cross-linking, and fragmentation; BLP, which are naturally organized in globular assemblies, were the most affected proteins. Transmission electron microscopy (TEM) analysis of BLP shows the formation of complex protein aggregates after treatment with AAPH. These structural modifications were accompanied by the formation of protein carbonyl groups and protein hydroperoxides. The yield of carbonyls was lower than that for protein hydroperoxide generation and was unrelated to protein fragmentation. The oxidized proteins were also characterized by significant oxidation of Met, Trp, and Tyr (but not other) residues, and low levels of dityrosine. As the dityrosine yield is too low to account for the observed cross-linking, we propose that aggregation is associated with tryptophan oxidation and Trp-derived cross-links. It is also proposed that Trp oxidation products play a fundamental role in nonrandom fragmentation and carbonyl group formation particularly for LYSO and G6PD. These data point to a complex mechanism of peroxyl-radical mediated modification of proteins with monomeric (LYSO), dimeric (G6PD), and multimeric (BLP) structural organization, which not only results in oxidation of protein side chains but also gives rise to radical-mediated protein cross-links and fragmentation, with Trp species being critical intermediates. 23818039 The Effectiveness and Safety of Landiolol Hydrochloride, an Ultra-Short-Acting β1-Blocker, in Postoperative Patients with Supraventricular Tachyarrhythmias: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study. Persistent postoperative supraventricular tachyarrhythmias (SVTs) increase cardiac burden and aggravate cardiac hemodynamics. Therefore, for patients in unstable conditions after surgery, prompt and sustained control of heart rate is essential. The importance of β-adrenoceptor antagonists (β-blockers) in controlling such postoperative atrial fibrillation or atrial flutter has been established, and the usefulness of ultra-short-acting β1-blockers with high β1 selectivity has been suggested based on their safety and efficacy under such circumstances. Our objectives were to evaluate the effectiveness and safety of landiolol hydrochloride, an ultra-short-acting β1-selective blocker, in the treatment of postoperative SVT in patients with a high risk of myocardial ischemia, or in patients after highly invasive surgery, in a multicenter, randomized, double-blind, placebo-controlled, group-comparative study. A total of 165 patients were randomly allocated to three groups and received LM or MH doses of landiolol hydrochloride or placebo. LM group: dose L (1-min loading dose at a rate of 0.03 mg/kg/min, followed by a 10-min infusion at 0.01 mg/kg/min) followed by dose M (1-min loading at a rate of 0.06 mg/kg/min, followed by a 10-min infusion at 0.02 mg/kg/min); MH group: dose M followed by dose H (1-min loading dose at a rate of 0.125 mg/kg/min, followed by a 10-min infusion at 0.04 mg/kg/min); placebo (PP) group: dose P (1-min loading dose at a rate of 0 mg/kg/min, followed by a 10-min infusion at 0 mg/kg/min) followed by another round of dose P. If the targeted heart-rate reduction was not obtained at the end of the first 10-min infusion, the higher dose was started. The primary endpoint was the percentage of patients who met the heart-rate reduction criteria (≥20 % reduction and <100 beats/min). The safety endpoint was the incidence of adverse events in each of the three groups. The percentages of patients who met the heart-rate reduction criteria (≥20 % reduction and <100 beats/min) were 0.0, 60.4, and 42.0 % in the PP, LM, and MH groups, respectively. There were significant differences in the LM and MH groups relative to the PP group, but there was no significant difference between the LM and MH groups. No significant difference was observed in the incidence of adverse events among the three groups: 29.6 % in the PP group, 45.5 % in the LM group, and 43.1 % in the MH group. Landiolol hydrochloride is effective and safe for patients with postoperative SVT. 23770546 Organohalogenated contaminants (OHCs) in human serum of mothers and children from Pakistan with urban and rural residential settings. This study aimed to provide first data on the concentrations of different classes of organohalogenated contaminants (OHCs) in human serum from Pakistan, an area with limited information on environmental pollution. Serum samples (N=85) were collected from mothers (N=34; age ranged 23-51years), their children (N=34; age 3-10years) and general group (N=17; age 13-65years) with rural and urban residential settings. The concentrations of studied OHCs in serum decreased as follows: organochlorinated pesticides (OCPs)>polychlorinated biphenyls (PCBs)>polybrominated diphenyl ethers (PBDEs). Novel brominated flame retardants (NBFRs) were not detected, except for 1,2-bis(2,4,6-tribromophenoxy)-ethane (BTBPE)<0.2-8ng/g lipid weight (lw). Low levels of HO-PCBs (<0.2-20ng/glw) were detected, while HO-PBDEs were <0.2ng/glw. ∑PCBs (2-105ng/glw) together with ∑PBDEs (0.2-6.7ng/glw) contributed ~5% of the total OHCs body burden. The concentration(s) of major contributors (>80%) of OCPs ranged from <1-3645ng/glw for 1,1'-bis-(4-chlorophenyl)-2,2-dichloroethene (p,p'-DDE), <1-445ng/glw for β-hexachlorocyclohexane (β-HCH) and from 5 to 200ng/glw for pentachlorophenol (PCP). p,p'-DDE, the major OHC, was significantly higher (p<0.05) in rural children than in all other groups. In serum of rural children, the major OHCs were significantly higher (p<0.05) than the mothers. The current study indicates continuous exposure to humans with already regulated OHCs and highlights the need for further monitoring of these OHCs in the region. 23611722 A novel mutation of anti-Mullerian hormone gene in Persistent Mullerian Duct Syndrome presented with bilateral cryptorchidism: a case report. We report a novel mutation in a case of Persistent Mullerian Duct Syndrome (PMDS). PMDS is characterized by the persistence of female reproductive organs derivatives in a 46,XY subject due to the failure of the Mullerian duct to regress in utero. To date, 53 different mutations of the anti-Mullerian hormone (AMH) gene, including the present one, have been identified. A 2-week-old male presented with bilateral cryptorchidism and normal male external genitalia. His karyotype was 46,XY. hCG stimulation test was normal. At age 1 year and 4 months, he underwent laparoscopic surgery which revealed a uterus and fallopian tubes. The anti-Mullerian hormone (AMH) level was undetectable (<0.01 ng/mL). Diagnosis of Persistent Mullerian Duct Syndrome, probably due to an AMH mutation, was made. A unique homozygous T to G base substitution was found at position 2219, near the middle of the exon 5, changing codon CTG to CGG in anti-Mullerian hormone (AMH) gene. This mutation causes leucine to be converted to arginine at position 426 belonging to a (L)RA(L)LLLKALQ highly conserved sequence in the AMH gene. Both parents are heterozygous for the mutation. Persistent Mullerian Duct Syndrome (PMDS) is a rare cause of bilateral cryptorchidism, when in doubt the existence of Mullerian derivatives should be explored by laparoscopy. Assay of serum AMH helps to distinguish between mutations of AMH and AMH receptor. If serum AMH is very low or undetectable, sequencing of the AMH gene usually confirms the presence of a mutation. 23652626 Failure of collateral blood flow is associated with infarct growth in ischemic stroke. Changes in collateral blood flow, which sustains brain viability distal to arterial occlusion, may impact infarct evolution but have not previously been demonstrated in humans. We correlated leptomeningeal collateral flow, assessed using novel perfusion magnetic resonance imaging (MRI) processing at baseline and 3 to 5 days, with simultaneous assessment of perfusion parameters. Perfusion raw data were averaged across three consecutive slices to increase leptomeningeal collateral vessel continuity after subtraction of baseline signal analogous to digital subtraction angiography. Changes in collateral quality, Tmax hypoperfusion severity, and infarct growth were assessed between baseline and days 3 to 5 perfusion-diffusion MRI. Acute MRI was analysed for 88 patients imaged 3 to 6 hours after ischemic stroke onset. Better collateral flow at baseline was associated with larger perfusion-diffusion mismatch (Spearman's Rho 0.51, P<0.001) and smaller baseline diffusion lesion volume (Rho -0.70, P<0.001). In 30 patients without reperfusion at day 3 to 5, deterioration in collateral quality between baseline and subacute imaging was strongly associated with absolute (P=0.02) and relative (P<0.001) infarct growth. The deterioration in collateral grade correlated with increased mean Tmax hypoperfusion severity (Rho -0.68, P<0.001). Deterioration in Tmax hypoperfusion severity was also significantly associated with absolute (P=0.003) and relative (P=0.002) infarct growth. Collateral flow is dynamic and failure is associated with infarct growth. 23904846 Antiphospholipid syndrome complicated by unilateral pleural effusion. Antiphospholipid syndrome (APS) with pleural effusion is extremely rare. A 75-year-old man was admitted to our hospital for spreading erythema on his trunk and extremities, as well as dyspnea. One year before admission, he had visited us with a 1-year history of erythema and purpura on his legs and occasional fever. Given the diagnosis of APS, we initiated a combination therapy of aspirin and warfarin, but the skin lesions had gradually worsened. A biopsy specimen revealed marked thrombosis in the dermal and subcutaneous small vessels. In addition, chest X-ray and computed tomography demonstrated a large pleural effusion in the left lung. He underwent repeated drainage of the pleural effusion but the effusion recurred. We added oral prednisolone 30 mg daily to his prior anticoagulant therapy. The skin lesions and pleural effusion rapidly improved and disappeared without any complication. Corticosteroids might be a choice of treatment for intractable pleural effusion in APS patients. 22893354 Emergency Do Not Consume/do Not Use concentrations for potassium permanganate in drinking water. Over the past decade, regulatory authorities and water purveyors have become increasingly concerned with accidental or intentional adulteration of municipal drinking water. Emergency response guidelines, such as the 'Do Not Consume' or use concentration limits derived herein, can be used to notify the public in such cases. Potassium permanganate (KMnO(4)) is used to control iron concentrations and to reduce the levels of nuisance materials that affect odor or taste of finished drinking water. Manganese (Mn) is recognized an essential nutrient, permanganate (MnO4 (-)) and manganous (Mn(+2)) ions are caustic, and the acute toxicity of KMnO(4) is defined by its oxidant/irritant properties and by the toxicity of Mn. Ingestion of small amounts (4-20 mg/kg) of aqueous KMnO(4) solutions that are above 200 mg/L causes gastrointestinal distress, while bolus ingestion has caused respiratory arrest following coagulative necrosis and hemorrhage in the esophagus, stomach, or liver. Dilute KMnO(4) solutions (1-100 mg/L) are used as a topical antiseptics and astringents, but >1:5000 (200 mg/L) dilutions can irritate or discolor sensitive mucous membranes and direct skin or ocular contact with concentrated KMnO(4) can perforate tissues. Based on clinical experience with 200 mg/L KMnO(4), a Do Not Consume concentration of 7 mg/L KMnO(4) (equivalent to 2 mg Mn/L) is recommended. Recognizing limited empirical data from which to calculate an ocular reference value, a skin contact 'Do Not Use' concentration of 30 mg Mn/L is recommended based on the skin irritation in some patients after a 10-min contact with 100 mg KMnO4/L. 23927689 Screening ability of faecal haemoglobin concentration for excluding colorectal diseases: statistical validity of the receiver operating characteristic curve analysis. McDonald et al. reported a validation study on the exclusion of four significant colorectal diseases by the faecal haemoglobin (Hb) concentration [1]. They analysed the data of 280 subjects who underwent the faecal immunochemical test (FIT) for Hb and subsequent endoscopy. The patients ranged in age from 18 to 84 years, with a median age of 63 years, and were composed of 113 men and 167 women. This article is protected by copyright. All rights reserved. 23937766 Improving practice in community-based settings: a randomized trial of supervision - study protocol. Evidence-based treatments for child mental health problems are not consistently available in public mental health settings. Expanding availability requires workforce training. However, research has demonstrated that training alone is not sufficient for changing provider behavior, suggesting that ongoing intervention-specific supervision or consultation is required. Supervision is notably under-investigated, particularly as provided in public mental health. The degree to which supervision in this setting includes 'gold standard' supervision elements from efficacy trials (e.g., session review, model fidelity, outcome monitoring, skill-building) is unknown. The current federally-funded investigation leverages the Washington State Trauma-focused Cognitive Behavioral Therapy Initiative to describe usual supervision practices and test the impact of systematic implementation of gold standard supervision strategies on treatment fidelity and clinical outcomes. The study has two phases. We will conduct an initial descriptive study (Phase I) of supervision practices within public mental health in Washington State followed by a randomized controlled trial of gold standard supervision strategies (Phase II), with randomization at the clinician level (i.e., supervisors provide both conditions). Study participants will be 35 supervisors and 130 clinicians in community mental health centers. We will enroll one child per clinician in Phase I (N = 130) and three children per clinician in Phase II (N = 390). We use a multi-level mixed within- and between-subjects longitudinal design. Audio recordings of supervision and therapy sessions will be collected and coded throughout both phases. Child outcome data will be collected at the beginning of treatment and at three and six months into treatment. This study will provide insight into how supervisors can optimally support clinicians delivering evidence-based treatments. Phase I will provide descriptive information, currently unavailable in the literature, about commonly used supervision strategies in community mental health. The Phase II randomized controlled trial of gold standard supervision strategies is, to our knowledge, the first experimental study of gold standard supervision strategies in community mental health and will yield needed information about how to leverage supervision to improve clinician fidelity and client outcomes. ClinicalTrials.gov NCT01800266. 23507869 HSV activates Akt to trigger calcium release and promote viral entry: novel candidate target for treatment and suppression. HSV triggers intracellular calcium release to promote viral entry. We hypothesized that Akt signaling induces the calcium responses and contributes to HSV entry. Exposure of human cervical and primary genital tract epithelial, neuronal, or keratinocyte cells to HSV serotype 2 resulted in rapid phosphorylation of Akt. Silencing of Akt with small interfering RNA prevented the calcium responses, blocked viral entry, and inhibited plaque formation by 90% compared to control siRNA. Susceptibility to infection was partially restored if Akt was reintroduced into silenced cells with an Akt-expressing plasmid. HSV-2 variants deleted in glycoproteins B or D failed to induce Akt phosphorylation, and coimmunoprecipitation studies indicated that Akt interacts with glycoprotein B. Cell-surface expression of Akt was rapidly induced in response to HSV exposure. Miltefosine (50 μM), a licensed drug that blocks Akt phosphorylation, inhibited HSV-induced calcium release, viral entry, and plaque formation following infection with acyclovir-sensitive and resistant clinical isolates. Miltefosine blocked amplification of HSV from explanted ganglia to epithelial cells; viral yields were significantly less in miltefosine compared to control-treated cocultures (P<0.01). Together, these findings identify a novel role for Akt in viral entry, link Akt and calcium signaling, and suggest a new target for HSV treatment and suppression. 23912811 Molecular diversity of arbuscular mycorrhizal fungi associated with two co-occurring perennial plant species on a Tibetan altitudinal gradient. Plant communities on Mount Segrila on the Tibetan Plateau show distinct changes at different altitudes, but little information is available on belowground communities of arbuscular mycorrhizal fungi (AMF). Root samples of two co-occurring species, Pennisetum centrasiaticum and Kobresia sp., growing in open grasslands at eight altitudes (3,446-4,556 m) were analyzed for diversity of AMF by PCR, cloning, and sequencing. Dominant plants were well colonized by AMF even at higher altitudes where spore density in rhizospheres decreased dramatically. A total of 29 operational taxonomic units (OTUs) of AMF were detected, and some novel sequence types were found. Acaulosporaceae and Glomeraceae were the dominant families. There was no significant difference in OTU richness along elevational gradients in Kobresia sp., but OTU richness in P. centrasiaticum was higher at intermediate elevations. Elevation, host plant species, and soil variables (pH, soil organic matter, and available P and N) were found to have significant effects on the overall AMF community across all elevations. Fungal community composition differed significantly between the two plant species at each elevation, and the similarity was generally higher at the intermediate elevations. No significant difference in compositional similarity was observed for Kobresia sp. with increasing elevation, but the dissimilarity increased significantly for P. centrasiaticum. These results suggest that host identity is an important determinant for the structure of the AMF communities along the elevational gradients in high altitude environments. 20545541 Minimal iliac bone harvesting in sinus lift surgery. For sinus grafting, the authors propose a minimal posterior iliac bone harvesting, with local anesthesia. Autogenous bone grafting continues to be considered the gold standard for sinus grafting. The classic harvesting sites are calvarial, anterior iliac, and tibial, and harvesting is usually practiced under general anesthesia. We performed this technique in 7 patients under local anesthesia. In the posterior iliac crest, with a specific trocar for bone puncture biopsy, bone was harvested. We performed 1 cm longer for 5-mm diameter of bone. Three bone biopsies were harvested on each side. The harvested cancellous bone (5 cm(3)) was mixed with triphosphocalcic (TCP) material (2 cm(3)), and blood (1 cm(3)). A classic sinus lift was realized. After 6 months, the success rate of bone grafting was 100%. Each of the 7 patients could be implanted by an average of 4 dental implants by superior maxillary. For sinus lift, this simple posterior iliac-bone biopsy harvesting under local anesthesia is very comfortable for the patient and also safe. It provides enough marrow bone to be mixed with TCP for a sinus lift. 23868937 Insulin Resistance Is Associated With Significant Clinical Atherosclerosis in Nondiabetic Patients With Acute Myocardial Infarction. The prevalence of insulin resistance (IR) is increasing worldwide because of increasing age, obesity, and physical inactivity. Emerging evidence supports a direct proatherogenic effect of IR on the coronary vasculature, but the relation between IR and angiographic atherosclerosis in a real-world clinical setting is uncertain. In this work, we assessed whether IR is independently associated with clinically significant angiographic atherosclerosis in nondiabetic individuals. We examined the association between IR and the extent of coronary atherosclerosis determined by angiography in 1073 nondiabetic patients surviving acute myocardial infarction. Patients were divided into quartiles on the basis of the homeostasis model assessment grading of IR, and associations between IR and multivessel coronary artery disease, defined as ≥2 arteries with ≥70% stenosis (or ≥50% left main stenosis), were analyzed in bivariate and multivariable modeling. Overall, the cohort had a median age of 56 years; 28.9% women and 21.8% nonwhite. The crude prevalence of multivessel coronary artery disease was 37.8%, 42.3%, 47.2%, and 48.0% for homeostasis model assessment grading of IR quartiles 1, 2, 3, and 4, respectively (Ptrend=0.009). In multivariable modeling, compared with quartile 1, both quartile 3 (relative risk [95% confidence interval], 1.31 [1.07-1.60]) and quartile 4 (1.29 [1.03-1.60]) were independently associated with multivessel coronary artery disease. Covariates in the model included patient demographic and clinical characteristics and metabolic factors (low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, triglyceride, glycosylated hemoglobin, and high-sensitivity C-reactive protein). We demonstrate an independent association between IR and multivessel coronary artery disease in nondiabetic postmyocardial infarction patients. Our findings strengthen the experimental evidence for a direct atherogenic effect of IR independent of glucose control and other components of the metabolic syndrome. 23411745 Rural-urban, sex variations, and time trend of primary liver cancer incidence in China, 1988-2005. To investigate the incidence rate of primary liver cancer (PLC) in China in recent decades. Cancer registration data from 1988 to 2005 were used to analyze the incidence trends of PLC in 11 cities and counties in China. We estimated crude, age-specific, and age-standardized incidence rates of PLC. We also analyzed the annual percent change of incidence rate. From 1988 to 2005, a total of 97 462 liver cancer patients, among whom 75% were men, were diagnosed in the covered areas. The crude and age-standardized incidence rates in the combined population were 24.27/100 000 and 18.55/100 000, respectively. The age-standardized incidence rate was 28.15/100 000 for men and 9.31/100 000 for women. A decreasing trend was observed in the age-standardized incidence rate, with an annual percent change of -1.44% (P<0.05). Analysis on the basis of geographic location showed that the incidence rate was higher in rural areas than in urban areas. The crude and age-standardized incidence rates were 35.78/100 000 and 34.34/100 000 for rural areas and 21.64/100 000 and 15.72/100 000 for urban areas, respectively. During the past 18 years, the overall incidence rate of PLC had been decreasing gradually in 11 covered areas in China. Further studies are required to identify the risk factors influencing the incidence trend of liver cancer. 23916320 Clinical and pharmacological aspects of bath salt use: A review of the literature and case reports. Bath salts are designer drugs with stimulant properties that are a growing medical and psychiatric concern due to their widespread availability and use. Although the chemical compounds in the mixtures referred to as "bath salts" vary, many are derivatives of cathinone, a monoamine alkaloid. Cathinones have an affinity for dopamine, serotonin, and norepinephrine synapses in the brain. Because of the strong selection for these neurotransmitters, these drugs induce stimulating effects similar to those of methamphetamines, cocaine, and 3,4-methylenedioxy-N-methylamphetamine (MDMA). Much of the emerging information about bath salts is from emergency department evaluation and treatment of severe medical and neuropsychiatric adverse outcomes. This review consists of a compilation of case reports and describes the emergent literature that illustrates the chemical composition of bath salts, patterns of use, administration methods, medical and neuropsychiatric effects, and treatments of patients with bath salt toxicity. 23619143 Childhood passive smoke exposure is associated with adult head and neck cancer. Passive smoke is carcinogenic but its association with head and neck squamous cell carcinoma (HNSCC) is uncertain. We conducted a case-control study of childhood passive smoke exposure (CPSE) and HNSCC in 858 cases and 806 frequency-matched controls using an interviewer-administered questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated with logistic regression controlling for adult smoking in the total study population, and in never-smokers only (184 cases and 415 controls). CPSE was also studied in oropharyngeal separately from other HNSCC using polytomous logistic regression. CPSE was associated with HNSCC (OR, 1.28; 95% CI, 1.01-1.63) after controlling for adult smoking and other factors. This association was similar in magnitude, although not statistically significant, among subjects who never smoked as adults (OR, 1.19, 95% CI, 0.80-1.76). CPSE was associated more strongly with oropharyngeal cancer (a HNSCC subtype commonly associated with human papillomavirus (HPV) infection) than with HNSCC at non-oropharyngeal sites (OR, 2.02; 95% CI, 1.01-4.06, N=52 cases vs. OR, 1.04; 95% CI, 0.68-1.60, N=132 cases; P-for-heterogeneity=0.08). Data from this large US-based case control study suggest a role for CPSE in HNSCC etiology. 23352613 Reconfiguration of the upper extremity relative to the pushrim affects load distribution during wheelchair propulsion. Repetitive loading during manual wheelchair propulsion (WCP) is associated with overuse injury to the upper extremity (UE). The aim of this study was to determine how RF redirection and load distribution are affected by changes upper extremity kinematic modifications associated with modifications in seat positions during a WCP task. The aim of this study was to determine how RF redirection and load distribution are affected by upper extremity kinematic changes associated with seat position adjustment during a WCP task. Dynamic simulations using an experiment-based multi-link inverse dynamics model were used to generate solutions for redistributing UE mechanical load in different seating positions without decrements in WCP task performance. Experimental RF and kinematic data were collected for one subject propelling at a self-selected speed and used as input into the model. Shoulder/axle distance, wrist angular position, and RF direction were systematically modified to simulate how the mechanical demand imposed on the upper extremity (elbow and shoulder net joint moments (NJMs) and net joint forces) may vary. Load distribution depended on UE orientation relative to the wheel. At peak force, lower shoulder/axle distances and more anterior wrist positions on the pushrim allowed for more extended elbow positions and reduced total NJM load. Simulation results incorporating subject-specific data may provide mechanically based information to guide clinical interventions that aim to maintain WCP performance and redistribute load by modifying RF direction, seat configuration and hand/rim interaction. 23554071 A Mineral Extract from red Algae Ameliorates Chronic Spontaneous Colitis in IL-10 Deficient Mice in a Mouse Strain Dependent Manner. Inflammatory bowel disease is an urgent public health problem with a high incidence in developed countries. Alterations of lifestyle or dietary interventions may attenuate the disease progression and increase the efficacy of current therapies. Here we tested the effect of chronic supplementation with a mineral extract from red marine algae - rich in calcium (34%), magnesium, phosphorus, selenium and other trace minerals - in a clinically relevant model of spontaneous enterocolitis, interleukin (IL)-10(-/-) mice. The mineral extract was administered in the drinking water of Il10(-/-) mice on C57BL/6 J and BALB/c strain backgrounds for 25 weeks commencing from 3 to 4 weeks of age. The mineral extract ameliorated the spontaneous development of colitis and severity of disease in Il10(-/-) mice on a C57BL/6 J background. Mineral extract-treated Il10(-/-) C57BL/6 J strain mice had significantly reduced mortality, circulating levels of serum Amyloid A and reduced colonic tissue damage. In contrast, comparable treatment of Il10(-/-) mice on a BALB/c background with the mineral extract did not alter the course of colitis. These data demonstrate that chronic supplementation with a natural mineral extract selectively ameliorates spontaneous mild-moderate colitis in Il10(-/-) mice on a C57BL/6 J, but does not attenuate more moderate-severe colitis in BALB/c strain animals. Copyright © 2013 John Wiley & Sons, Ltd. 22713807 A variant in the carboxyl-terminus of connexin 40 alters GAP junctions and increases risk for tetralogy of Fallot. GJA5 gene (MIM no. 121013), localized at 1q21.1, encodes for the cardiac gap junction protein connexin 40. In humans, copy number variants of chromosome 1q21.1 have been associated with variable phenotypes comprising congenital heart disease (CHD), including isolated TOF. In mice, the deletion of Gja5 can cause a variety of complex CHDs, in particular of the cardiac outflow tract, corresponding to TOF in many cases. In the present study, we screened for mutations in the GJA5 gene 178 unrelated probands with isolated TOF. A heterozygous nucleotide change (c.793C>T) in exon 2 of the gene leading to the p.Pro265Ser variant at the carboxyl-terminus of the protein was found in two unrelated sporadic patients, one with classic anatomy and one with pulmonary atresia. This GJA5 missense substitution was not observed in 1568 ethnically-matched control chromosomes. Immunofluorescent staining and confocal microscopy revealed that cells expressing the mutant protein form sparse or no visible gap-junction plaques in the region of cell-cell contact. Moreover, analysis of the transfer of the gap junction permanent tracer lucifer yellow showed that cells expressing the mutant protein have a reduced rate of dye transfer compared with wild-type cells. Finally, use of a zebrafish model revealed that microinjection of the GJA5-p.Pro265Ser mutant disrupts overall morphology of the heart tube in the 37% (22/60) of embryos, compared with the 6% (4/66) of the GJA5 wild-type-injected embryos. These findings implicate GJA5 gene as a novel susceptibility gene for TOF. 23698295 Full conversion of the hemagglutinin-neuraminidase specificity of the parainfluenza virus 5 fusion protein by replacement of 21 amino acids in its head region with those of the simian virus 41 fusion protein. For most parainfluenza viruses, a virus type-specific interaction between the hemagglutinin-neuraminidase (HN) and fusion (F) proteins is a prerequisite for mediating virus-cell fusion and cell-cell fusion. The molecular basis of this functional interaction is still obscure partly because it is unknown which region of the F protein is responsible for the physical interaction with the HN protein. Our previous cell-cell fusion assay using the chimeric F proteins of parainfluenza virus 5 (PIV5) and simian virus 41 (SV41) indicated that replacement of two domains in the head region of the PIV5 F protein with the SV41 F counterparts bestowed on the PIV5 F protein the ability to induce cell-cell fusion on coexpression with the SV41 HN protein while retaining its ability to induce fusion with the PIV5 HN protein. In the study presented here, we furthered the chimeric analysis of the F proteins of PIV5 and SV41, finding that the PIV5 F protein could be converted to an SV41 HN-specific chimeric F protein by replacing five domains in the head region with the SV41 F counterparts. The five SV41 F-protein-derived domains of this chimera were then divided into 16 segments; 9 out of 16 proved to be not involved in determining its specificity for the SV41 HN protein. Finally, mutational analyses of a chimeric F protein, which harbored seven SV41 F-protein-derived segments, revealed that replacement of at most 21 amino acids of the PIV5 F protein with the SV41 F-protein counterparts was enough to convert its HN protein specificity. 23943570 DNA Modification under Mild Conditions by Suzuki-Miyaura Cross-Coupling for the Generation of Functional Probes. Quick and clean: A method for Pd-catalyzed Suzuki-Miyaura cross-coupling to iododeoxyuridine (IdU) in DNA is described. Key to the reactivity is the choice of the ligand and the buffer. A covalent [Pd]-DNA intermediate was isolated and characterized. Photocrosslinking probes were generated to trap proteins that bind to epigenetic DNA modifications. 23944371 Serum paraoxonase 1 activity in dogs: preanalytical and analytical factors and correlation with C-reactive protein and alpha-2-globulin. Serum activity of paraoxonase (PON1) decreases during inflammation in many species. Little information is available on paraoxon-based tests and the possible role of PON1 in dogs. The objectives of the study were to validate an automated paraoxon-based assay to measure PON1 activity in canine serum, to determine its stability under different storage conditions, to determine a reference interval (RI) in healthy dogs, and to assess whether PON1 is of comparable diagnostic value as C-reactive protein (CRP) and α2 -globulins. Intra-assay and inter-assay imprecision, linearity under dilution (LUD), interference, and storage artifacts were evaluated. A PON1 RI was determined for healthy dogs, and PON1 activity, sensitivity, and specificity were compared with CRP and α2 -globulins. Intra- and inter-assay CVs were below 1.6% and 7.8%, respectively. The LUD test fitted the linear model. PON1 activity measurements were increased after addition of hemolysates and lipids, and after storage for 12 hours at room temperature, 72 hours at 4°C, and 6 months at -20°C. PON1 activity and CRP or α2 -globulins did not correlate well. PON1 activity decreased significantly only in dogs with very high CRP concentrations. In contrast to CRP and α2 -globulins, PON1 activity was not significantly different between dogs with and without inflammation. The automated paraoxon-based method to assess serum canine PON1 activity was accurate and precise, but it was influenced by hemolysis, lipemia, and standard storage conditions. In this study, contrarily to CRP and α2 -globulins, PON1 activity did not provide diagnostic value as a negative acute phase protein in dogs. 22722318 Information technology strategy and alignment issues in health care organizations. Information technology (IT) plays a key role in public health care management because it could improve quality, efficiency, and patient care. Researchers and practitioners repeatedly contend that a health care organization's information systems strategy should be aligned with its objectives and strategies, a notion commonly known as IT alignment. Actor-related IT alignment issues in health care institutions were explored in this study. More specifically, it explores the possibility of moving beyond the current IT alignment perspective and, in so doing, explores whether IT alignment-as currently conceptualized in the dominant body of research-is sufficient for attaining improved quality, efficiency, and patient care in health care organizations. The findings are based on a qualitative and longitudinal study of six health care organizations in the Stockholm metropolitan area. The empirical data were gathered over the 2005-2011 period from interviews, a focus group, observations, and archival material. The data suggest recurrent misalignments between IT strategy and organizational strategy and operations due to the failure to deconstruct the IT artifact and to the existence of various levels of IT maturity. A more complex picture of IT alignment in health care that goes beyond the current perspective is being offered by this study. It argues that the previously common way of handling IT as a single artifact and applying one IT strategy to the entire organizational system is obsolete. MANAGERIAL IMPLICATIONS: The article suggests that considerable benefits can be gained by assessing IT maturity and its impact on IT alignment. The article also shows that there are different kinds of IT in medical care that requires diverse decisions, investments, prioritizations, and implementation approaches. 23876529 Photoswitchable fluorescent proteins: ten years of colorful chemistry and exciting applications. Reversibly photoswitchable fluorescent proteins (RSFPs) are fluorescent proteins whose fluorescence, upon excitation at a certain wavelength, can be switched on or off by light in a reversible manner. In the last 10 years, many new RSFPs have been developed and novel applications in cell imaging discovered that rely on their photoswitching properties. This review will describe research on the mechanisms of reversible photoswitching and recent applications using RSFPs. While cis-trans isomerization of the chromophore is believed to be the general mechanism for most RSFPs, structural studies reveal diversity in the details of photoswitching mechanisms, including different effects of protonation, chromophore planarity, and pocket flexibility. Applications of RSFPs include new types of live-cell superresolution imaging, tracking of protein movements and interactions, information storage, and optical control of protein activity. 23876242 Relationship between excitability, plasticity and thickness of the motor cortex in older adults. The relationship between brain structure, cortical physiology, and learning ability in older adults is of particular interest in understanding mechanisms of age-related cognitive decline. Only a few studies addressed this issue so far, yielding mixed results. Here, we used comprehensive multiple regression analyses to investigate associations between brain structure on the one hand, i.e., cortical thickness (CT), fractional anisotropy (FA) of the pyramidal tract and individual coil-to-cortex distance, and cortical physiology on the other hand, i.e. motor cortex excitability and long-term potentiation (LTP)-like cortical plasticity, in healthy older adults (mean age 64years, 14 women). Additional exploratory analyses assessed correlations between cortical physiology and learning ability in the verbal domain. In the regression models, we found that cortical excitability could be best predicted by CT of the hand knob of the primary motor cortex (CT-M1HAND) and individual coil-to-cortex distance, while LTP-like cortical plasticity was predicted by CT-M1HAND and FA of the pyramidal tract. Exploratory analyses revealed a significant inverse correlation between cortical excitability and learning ability. In conclusion, higher cortical excitability was associated with lower CT and lower learning ability in a cohort of healthy older adults, in line with previous reports of increased cortical excitability in patients with cortical atrophy and cognitive deficits due to Alzheimer's Disease. Cortical excitability may thus be a parameter to identify individuals at risk for cognitive decline and gray matter atrophy, a hypothesis to be explored in future longitudinal studies. 23867521 The carotenoid lycopene protects rats against DNA damage induced by Ochratoxin A. Ochratoxin A (OTA), one of the most prevalent mycotoxins in the world, has nephrotoxic and hepatotoxic properties. Lycopene is an important carotenoid and has a high singlet-oxygen and free-radical scavenging capacity. This study was designed to investigate the possible protective effects of lycopene against the genotoxicity of OTA in rat tissues using the alkaline comet assay. Male Sprague-Dawley rats were used in the experiments. OTA (0.5 mg/kg b.w./day) was administered by gavage for 14 days, whereas lycopene was applied on the last 7 days or for 14 days of the feeding period, with OTA treatment. OTA caused marked increases in tail length, tail moment, and tail intensity vs. control both in the kidney and liver cells, but not in the lymphocytes. Lycopene administration alone for 7 and 14 days did not provide any significant change in DNA damage of the lymphocytes, renal and hepatic cells vs. controls. However, lycopene for both 7 and 14 days, with OTA exposure in renal and hepatic cells, supplied significant decreases in tail length, tail moment, and tail intensity vs. OTA-exposed rats. The effect of 14 days supplementation seemed to be more protective, particularly against hepatic cells. These results suggest that lycopene may protect hepatic and renal tissue from OTA-induced DNA damage. 23567631 Facile synthesis of polydopamine-coated molecularly imprinted silica nanoparticles for protein recognition and separation. Surface imprinting over nanostructured matrices is an effective solution to overcome template removal and achieve high binding capacity. In this work, a facile method was developed for synthesis of polydopamine-coated molecularly imprinted silica nanoparticles (PDA-coated MIP silica NPs) based on self-polymerization of dopamine (DA) on the surface of silica NPs in the presence of template protein. Transmission electronic microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR) and thermogravimetric analysis (TGA) showed that PDA layers were successfully attached on the surface of silica NPs and the corresponding thickness was about 5nm, which enabled the MIP silica NPs to have fast binding kinetics and high binding capacity. Under the aqueous media, the imprinted silica NPs showed much higher binding affinity toward template than non-imprinted (NIP) silica NPs. The protein recognition properties were examined by single-protein or competitive batch rebinding experiments and rebinding kinetics study, validating that the imprinted silica NPs have high selectivity for the template. The resultant BHb-MIP silica NPs could not only selectively separate BHb from the protein mixture, but also specifically deplete high-abundance BHb from cattle whole blood. In addition, the stability and regeneration were also investigated, which indicated that the imprinted silica NPs had excellent reusability. 23446441 Proteinuria in systemic sclerosis: reversal by ACE inhibition. In systemic sclerosis (SSc), kidney damage is a major clinical problem which can lead to a deleterious outcome. Recently, in diabetes mellitus, early detection of proteinuria and treatment with angiotensin-converting enzyme (ACE) inhibitors has been shown to slow progression of kidney disease and to improve prognosis. In this study, we investigated the spontaneous course of proteinuria in SSc and the effects of ACE inhibitor therapy. Proteinuria was determined in SSc patients with urine protein electrophoresis. SSc patients with proteinuria (n = 31) were followed over a median of 12 months. Of all 31 patients with pathologic urine protein electrophoresis investigated in this study, 9 patients (29 %) had additional microalbuminuria and 4 patients (12.9 %) showed increased total urinary protein. ACE inhibitor treatment was subsequently given to 23 patients. A total of 8 patients remained untreated for various reasons. Proteinuria resolved in 74 % of patients treated with ACE inhibitors, whereas in the untreated group, remission was observed only in 25 % (p = 0.014). Improvement of proteinuria was predominantly achieved in patients with recently diagnosed proteinuria and short disease duration. In patients with SSc and proteinuria, initiation of ACE inhibitor therapy resulted in a significant decrease in proteinuria. 23571428 Ion Mobility Spectrometry-Mass Spectrometry Analysis for the Site of Aromatic Hydroxylation. Hydroxylated metabolites often retain the pharmacological activity of parent compound, and the position of hydroxylation determines the formation of chemically reactive intermediates such as quinones and analogues from para- and/or ortho-hydroxylation of phenols or arylamines. Therefore, the identification of exact position of hydroxylation is often required at the early development stage of new drug candidates. In many cases, liquid chromatography-tandem mass spectrometry (LC-MS/MS) provides identical MS/MS spectra among isomeric hydroxylated metabolites, and therefore, it alone cannot unequivocally identify the exact position(s) of hydroxylation. Ion mobility spectrometry (IMS), integrated with LC-MS/MS, recently demonstrates the capability of separating isomeric species based on differences in their drift times from IMS, which are linearly proportional to the collision cross-section (CCS) reflecting physical size and shape. In the present study, a chemical derivatization of isomeric hydroxylated metabolites with 2-fluoro-N-methyl pyridinium p-toluenesulfonate was found to confer distinct theoretical CCS value on each isomer by forming corresponding N-methyl pyridine (NMP) derivative. The regression lines established by the comparison between theoretical CCS values and observed drift times from IMS for each set of parent compound (labetalol, ezetimibe, atorvastatin and warfarin) and its MS/MS product ions accurately and selectively projected the actual drift times of NMP derivatives of corresponding aromatic or isomeric hydroxylated metabolites. The established method was used for the accurate assignment of predominant formation of 2-hydroxylated metabolite from imipramine in NADPH- fortified human liver microsomes. The present application expands the versatility of LC-IMS-MS technique to the structure identification of isomeric hydroxylated metabolites at the early stage for drug development. 23678895 The decline and rise of coronary heart disease: understanding public health catastrophism. The decline of coronary heart disease mortality in the United States and Western Europe is one of the great accomplishments of modern public health and medicine. Cardiologists and cardiovascular epidemiologists have devoted significant effort to disease surveillance and epidemiological modeling to understand its causes. One unanticipated outcome of these efforts has been the detection of early warnings that the decline had slowed, plateaued, or even reversed. These subtle signs have been interpreted as evidence of an impending public health catastrophe. This article traces the history of research on coronary heart disease decline and resurgence and situates it in broader narratives of public health catastrophism. Juxtaposing the coronary heart disease literature alongside the narratives of emerging and reemerging infectious disease helps to identify patterns in how public health researchers create data and craft them into powerful narratives of progress or pessimism. These narratives, in turn, shape public health policy. 23793420 Nanoimprint lithography with a focused laser beam for the fabrication of nanopatterned microchannel molds. We present a process based on nanoimprint lithography for the fabrication of a microchannel mold having nanopatterns formed at the bottoms of its microchannels. A focused laser beam selectively cures the resist in the micrometer scale during nanoimprint lithography. Nanopatterns within the microchannels may be used to control microfluidic behavior. 23893820 Adaptive phenotype of microglial cells during the normal postnatal development of the somatosensory "Barrel" cortex. Accumulative evidence indicates that microglial cells influence the normal development of central nervous system (CNS) synapses. Yet, the functional properties of microglia in relation with synapse development remain unclear. We recently showed that in layer 4 of the whisker-related barrel field of the mouse somatosensory cortex, microglial cells are recruited only after postnatal day (P)5 in the center of the barrels where thalamo-cortical synapses are concentrated and begin their maturation. In the present study, we analyzed the phenotype of microglia during this developmental process. We show that between P5 and P7 microglial cells acquire a more ramified morphology with a smaller soma, they express classical markers of microglia (Iba1, CD11b, and CD68) but never markers of activation (Mac-2 and MHCII) and rarely the proliferation marker Ki67. Electrophysiological recordings in acute cortical slices showed that at P5 a proportion of layer 4 microglia transiently express voltage-dependant potassium currents of the delayed rectifier family, mostly mediated by Kv1.3 subunits, which are usually expressed by activated microglia under pathological conditions. This proportion of cells with rectifying properties doubles between P5 and P6, in concomitance with the beginning of microglia invasion of the barrel centers. Finally, analysis of the responses mediated by purinergic receptors indicated that a higher percentage of rectifying microglia expressed functional P2Y6 and P2Y12 receptors, as compared with nonrectifying cells, whereas all cells expressed functional P2X7 receptors. Our results indicate that during normal cortical development distinct microglia properties mature differentially, some of them being exquisitely influenced by the local environment of the maturating neuronal network.GLIA 2013;61:1582-1594. 23810041 Evaluation of 3 retention protocols using the American Board of Orthodontics cast and radiograph evaluation. The purpose of this study was to quantify tooth movement among different retention protocols after the orthodontic appliances were removed. A total of 90 patients were evaluated using the American Board of Orthodontics discrepancy index and the cast and radiograph evaluation at debond and the 1-year recall. These patients were equally divided into 3 retention protocols: upper Hawley/lower Hawley, upper Hawley/lower bonded, and upper Essix/lower bonded. The patients were then equally grouped by extraction or nonextraction treatment and case complexity. Paired t tests were used to compare the paired sample means. Analysis of variance tests were used to compare the means for more than 2 groups. A 2-sided 0.05 alpha level was used to define statistical significance. The upper Hawley/lower bonded showed the greatest amount of settling, and the upper Essix/lower bonded had the least settling, but these differences were statistically insignificant. The differences between the extraction and nonextraction treatments were not significant. The group with low discrepancy index scores showed significantly more settling than did the group with high discrepancy index scores. The cast and radiograph evaluation variables that improved overall were marginal ridges, overjet, occlusal contacts, interproximal contacts, root angulation, and total cast and radiograph score. The cast and radiograph evaluation variables that worsened were alignment/rotation, buccolingual inclination, and occlusal relationship. Extraction or nonextraction treatment led to no real difference in settling. The discrepancy index, or initial case complexity, was the greatest factor in determining the improvement of occlusion or settling during the retention phase. 23941865 Acute Uterine Irritation Provokes Colonic Motility via Transient Receptor Potential A1-dependent Spinal NR2B Phosphorylation in Rats. Patients with inflammatory gynecological/obstetrical problems often complain of irritable bowel syndrome. The authors examined whether acute uterus irritation reflexively provokes colonic motility in rat preparations. A modified colon manometry and striated abdominal muscle electromyogram activity in response to mustard oil (MO) instillation into the uterine horn were continuously recorded in anesthetized rats. The lumbosacral (L6-S1) dorsal horn was dissected to assess the level and the cellular location of phosphorylated NR2B subunit using Western blotting and immunofluorescence analysis, respectively. Finally, the uterine transient receptor potential A1 or spinal NR2B subunit was pharmacologically blocked to elucidate its roles. MO (0.1%, 0.2 ml) injected into the lower uterine horn dramatically provoked colonic hypermotility characterized by rhythmic colonic contractions (about 3-4 contractions per 10 min, n = 7) accompanied by synchronized electromyogram firing in the abdominal muscle (about 4-5 folds of control, n = 7). In addition to provoking colonic hypermotility, MO administration also up-regulated phosphorylated (about 2-3 folds of control, n = 7), but not total, NR2B expression in the dorsal horn neurons. Both intrathecal Ro 25-6981 (a selective NR2B subunit antagonist; 10 μM, 10 μl) and intrauterine HC-030031 (a selective transient receptor potential A1 receptor antagonist; 30 mg/kg, 0.2 ml) injected before the MO instillation attenuated the MO-induced colonic hypermotility and spinal NR2B phosphorylation. The comorbidity of gynecological/obstetrical and gastrointestinal problems is not coincidental but rather causal in nature, and clinicians should investigate for gynecological/urological diseases in the setting of bowel problems with no known pathological etiology. 23207251 Understanding the interactions between metabolites isolated from Achyrocline satureioides in relation to its antibacterial activity. As part of our ongoing research on the antibacterial activity of Achyrocline satureioides, this study seeks to better understand the interactions between the metabolites isolated from this plant. For this purpose, the combined effect of 23-methyl-6-O-desmethylauricepyrone (1), quercetin (2) and 3-O-methylquercetin (3), obtained through bioguided fractionation from A. satureioides ethanol extract, was evaluated against Staphylococcus aureus and Escherichia coli. In first place, the antibacterial effect of the combination of flavonols 2 and 3 was assessed, as these showed individual effectiveness lower than or equal to that of the fraction from which they were obtained. When the flavonols were applied together at concentrations below their minimum inhibitory concentration (MIC) values, a synergistic effect (FICI<0.30) against S. aureus was observed. In addition, compounds 2 and 3 in combination reduced 1000 times the MIC of compound 1, showing a clear synergistic interaction (FICI<0.15) in treatments against the Gram (+) bacterium. The most active combination against E. coli showed an additive interaction (FICI<0.62) between the three assayed compounds 1-3. These results indicated the existence of concerted action between these metabolites, evidence of the importance of the synergistic interactions between the components of plant-derived extracts for the control of pathogenic bacteria. 23432360 Effects of individual and combined dietary weight loss and exercise interventions in postmenopausal women on adiponectin and leptin levels. Excess body weight and a sedentary lifestyle are associated with the development of several diseases, including cardiovascular disease, diabetes and cancer in women. One proposed mechanism linking obesity to chronic diseases is an alteration in adipose-derived adiponectin and leptin levels. We investigated the effects of 12-month reduced calorie, weight loss and exercise interventions on adiponectin and leptin concentrations. Overweight/obese postmenopausal women (n = 439) were randomized as follows: (i) a reduced calorie, weight-loss diet (diet; N = 118), (ii) moderate-to-vigorous intensity aerobic exercise (exercise; N = 117), (iii) a combination of a reduced calorie, weight-loss diet and moderate-to-vigorous intensity aerobic exercise (diet + exercise; N = 117), and (iv) control (N = 87). The reduced calorie diet had a 10% weight-loss goal. The exercise intervention consisted of 45 min of moderate-to-vigorous aerobic activity 5 days per week. Adiponectin and leptin levels were measured at baseline and after 12 months of intervention using a radioimmunoassay. Adiponectin increased by 9.5% in the diet group and 6.6% in the diet + exercise group (both P â‰¤ 0.0001 vs. control). Compared with controls, leptin decreased with all interventions (diet + exercise, -40.1%, P < 0.0001; diet, -27.1%, P < 0.0001; exercise, -12.7%, P = 0.005). The results were not influenced by the baseline body mass index (BMI). The degree of weight loss was inversely associated with concentrations of adiponectin (diet, P-trend = 0.0002; diet + exercise, P-trend = 0.0005) and directly associated with leptin (diet, P-trend < 0.0001; diet + exercise, P-trend < 0.0001). Weight loss through diet or diet + exercise increased adiponectin concentrations. Leptin concentrations decreased in all of the intervention groups, but the greatest reduction occurred with diet + exercise. Weight loss and exercise exerted some beneficial effects on chronic diseases via effects on adiponectin and leptin. 23764172 A large scale finite element study of a cementless osseointegrated tibial tray. The aim of this study was to investigate the performance of a cementless osseointegrated tibial tray (P.F.C. ® Sigma®, Depuy® Inc, USA) in a general population using finite element (FE) analysis. Computational testing of total knee replacements (TKRs) typically only use a model of a single patient and assume the results can be extrapolated to the general population. In this study, two statistical models (SMs) were used; one of the shape and elastic modulus of the tibia, and one of the tibiofemoral joint loads over a gait cycle, to generate a population of FE models. A method was developed to automatically size, position and implant the tibial tray in each tibia, and 328 models were successfully implanted and analysed. The peak strain in the bone of the resected surface was examined and the percentage surface area of bone above yield strain (PSAY) was used to determine the risk of failure of a model. Using an arbitrary threshold of 10% PSAY, the models were divided into two groups ('higher risk' and 'lower risk') in order to explore factors that may influence potential failure. In this study, 17% of models were in the 'higher risk' group and it was found that these models had a lower elastic modulus (mean 275.7MPa), a higher weight (mean 85.3kg), and larger peak loads, of which the axial force was the most significant. This study showed the mean peak strain of the resected surface and PSAY were not significantly different between implant sizes. 23898068 The Role of p66shc in Taxol- and Dichloroacetic Acid-dependent Renal Toxicity. Background/Aim: Taxol and dichloroacetic acid (DCA) are anticancer agents with potential renal toxicity. Previously, we have shown that the Ser36-phosphorylated p66shc adaptor protein mediates renal toxicity of selected anticancer modalities through increasing production of intracellular reactive oxygen species and consequent mitochondrial depolarization. Here, we analyzed whether p66shc plays a role in potential renal toxicity of Taxol and DCA. Cultured renal proximal tubule cells (TKPTS) were used. ROS production, mitochondrial depolarization (JC-1), cell injury [lactate dehydrogenase (LDH) release] and Ser36 phosphorylation of p66shc were determined after treatment with Taxol and DCA. Involvement of p66shc in adverse effects of these drugs was determined in p66shc knockdown, Ser36 phosphorylation (S36A) and cytochrome c-binding (W134F)- deficient cells. Both Taxol and DCA increased ROS production, mitochondrial depolarization, injury and Ser36 phosphorylation of p66shc in TKPTS cells. We showed that ROS production is responsible for mitochondrial depolarization and consequent injury. Knockdown of p66shc, mutation of its Ser36 (S36A) or cytochrome c binding site (W134F) attenuated adverse effects of the two drugs. Taxol and DCA are potentially nephrotoxic owing their adverse effects on activation of p66shc. Manipulation of expression or activity of p66shc may provide a means of ameliorating nephrotoxicity of these agents. 23828092 Evolving Role of Neoadjuvant Therapy in Rectal Cancer. Management of locally advanced rectal cancer is complex because curative treatment routinely involves administration of surgery, chemotherapy, and radiation. Optimal treatment delivery sequencing and timing are challenging, and moreover, there is considerable heterogeneity in risk based on rectal tumor location, extent, and nodal involvement. The goal in rectal cancer treatment is to optimize disease-free and overall survival while minimizing the risk of local recurrence and toxicity from both radiation and systemic therapy. Currently, the standard approach to management of locally advanced (T3 or T2) rectal cancer involves careful staging with a pelvic MRI and proctoscopic evaluation by a surgeon experienced in total mesorectal excision. MRI can help to distinguish between patients in low-, intermediate-, and high-risk categories. Low-risk tumors have no evidence of either extramural spread or nodal involvement and proximal location in the rectum. For such patients, R0 resection is almost always possible and immediate surgery often is reasonable. In the minority of cases where unanticipated lymph node involvement is detected at surgical pathology, postoperative radiation can be administered. Patients who opt for up-front rectal surgery need to understand that although there is a chance that radiation can be avoided, if it is necessary, it is less well tolerated when administered postoperatively. Initial surgical treatment should be reserved for low-risk patients for whom imaging indicates and multidisciplinary team members feel is able to undergo an R0 resection with low chance for regional spread of disease. For patients with high-risk disease based on distal tumor location requiring an APR, threatened radial margins, or T4 tumors, preoperative chemoradiation is essential. Indeed, this approach increases the likelihood of complete surgical resection with negative margins. For some high-risk patients, for example those with T4 or bulky nodal disease, preoperative systemic therapy followed by preoperative chemoradiation and then surgery may be optimal. The feasibility of this approach is well established based on nonrandomized trials, but it has not been evaluated in a randomized study. Preoperative administration of systemic therapy can achieve clinical downstaging, optimize rates of sphincter preservation, and establish tumor responsiveness, which may be valuable for incorporation into future treatment decisions. For patients with intermediate-risk T3 rectal cancers, for example, a cT3N1 tumor 7 cm from the anal verge with two to three regional lymph nodes in the 7-mm range, we encourage participation in the PROSPECT randomized trial, which is now open and accruing at numerous centers in North America, and shortly in Europe and South America as well. This study will determine in the era of optimal imaging, surgical technique, and better systemic chemotherapy, whether pelvic radiation remains an essential component of curative treatment. The PROSPECT study uses chemoradiation selectively rather than automatically and customizes subsequent treatment based on response to neoadjuvant FOLFOX. Clinical trials with interventions that tailor treatment to more precisely defined clinical subgroups based on both initial features and tumor responsiveness are expected to become the norm. Although this trend is likely to make clinical trial design more complex, customized treatment strategies are likely to achieve the optimal balance between under- and overtreatment and will address the heterogeneity of both tumor biology and disease presentation. For now, treatment for a patient with clinical T3N1 tumor in the mid rectum consists of the following components: Neoadjvuant chemoradiation with either 5-fluorouracil or capecitabine as sensitizing therapy. Low anterior resection with total mesorectal excision. Typically a temporary diverting ostomy is required. Postoperative administration of adjuvant systemic therapy, 8 cycles of FOLFOX is appropriate, although oxaliplatin should be omitted for early signs of peripheral neuropathy or on the basis of age/comorbidity. Although this is the current care standard, there is concern that such extensive treatment is not necessary for all patients to prevent local recurrence and to optimize cure. To determine if therapy can be streamlined, participation in PROSPECT or other clinical trials asking compelling clinical questions is a priority. 23867346 Myelodysplastic syndrome and associated coagulopathy: a case report and review. Myelodysplastic syndrome (MDS) is a primary bone marrow disorder whose hallmark is the development of peripheral cytopenias and a predilection toward the development of acute myeloid leukemia (AML). Patients often have hypercellular bone marrows with dysplastic features that may involve multiple lineages. An increased awareness of MDS has led to the reporting of a number of associated autoimmune and paraneoplastic conditions in the medical literature. We present the case of an elderly man who was transferred to our institution with persistent, refractory bleeding several weeks after the resection of a sebaceous cyst. Despite reoperation, treatment with topical and intravenous hemostatic agents, and transfusion of blood products, the patient's bleeding persisted. A comprehensive evaluation for the cause of his coagulopathy was undertaken. Bone marrow evaluation was consistent with MDS. A paraneoplastic consumptive coagulopathy or fibrinolytic process in conjunction with MDS-related platelet dysfunction was felt to be the most likely etiology of the patient's bleeding. 23601909 Conjunctival goblet cells density and preservative-free tafluprost therapy for glaucoma: an in vivo confocal microscopy and impression cytology study. Purpose:  To evaluate the density of conjunctival goblet cells (GCs) in glaucomatous patients treated with preservative-free (PF) tafluprost, using laser scanning confocal microscopy (LSCM) and impression cytology (IC). Methods:  Thirty glaucomatous patients (30 eyes) naive for therapy and thirty healthy subjects (30 eyes) were enrolled. Conjunctiva was examined by means of Heidelberg Retina Tomography/Rostock cornea module. Afterwards, the specimens for IC were obtained. Patients were randomized to PF-tafluprost (Group 1) or preserved latanoprost (Group 2) and controls to the vehicle of latanoprost (Group 3) or physiological buffered saline solution (Group 4). Both LSCM and IC were performed at baseline, and after the 1st and 6th months of therapy, GC density (GCD) (cells/mm(2) ) was the main outcome measurement. Results:  Baseline. Mean GCD was 240.69 ± 25.43 and 232.65 ± 23.52, for LSCM, and 162.10 ± 23.44 and 164.71 ± 21.03 for IC in Group 1 and 2, respectively. GC density values were not significantly different in Group 3 and 4 (p > 0.05%). Month one. Mean GCD increased to 284.16 ± 43.88 and 230.62 ± 48.32 in Group 1 (p < 0.001) and to 297.86 ± 26.87 and 221.78 ± 43.02 in Group 2 (p < 0.05), measured with LSCM and IC, respectively. In Group 3, GCD decreased to 205.88 ± 25.04 and 139.54 ± 17.37 measured with LSCM and IC, respectively (p < 0.05). Month six. Mean GCD did not change in Group 1 (p > 0.05) whereas it decreased in Group 2 (p < 0.05), compared to month 1. In Group 3, GCD further decreased to 166.32 ± 22.31 and 120.76 ± 11.66, measured with LSCM and IC, respectively (p < 0.05); in Group 4, mean GCD did not change during the study period (p > 0.05). Conclusions:  Treatment with PF tafluprost was associated with an increase in conjunctival GCD in glaucomatous eyes naïve for therapy. Further studies are mandatory to verify this finding because its validation may have important consequences in the medical management of glaucoma. 23876182 Description of a double centrifugation tube method for concentrating canine platelets. To evaluate the efficiency of platelet-rich plasma preparations by means of a double centrifugation tube method to obtain platelet-rich canine plasma at a concentration at least 4 times higher than the baseline value and a concentration of white blood cells not exceeding twice the reference range. A complete blood count was carried out for each sample and each concentrate. Whole blood samples were collected from 12 clinically healthy dogs (consenting blood donors). Blood was processed by a double centrifugation tube method to obtain platelet concentrates, which were then analyzed by a flow cytometry haematology system for haemogram. Platelet concentration and white blood cell count were determined in all samples. Platelet concentration at least 4 times higher than the baseline value and a white blood cell count not exceeding twice the reference range were obtained respectively in 10 cases out of 12 (83.3%) and 11 cases out of 12 (91.6%). This double centrifugation tube method is a relatively simple and inexpensive method for obtaining platelet-rich canine plasma, potentially available for therapeutic use to improve the healing process. 23857370 A retrospective review of cytogenetic studies on methyl isocyanate with special reference to the Bhopal gas tragedy: Is the next generation also at risk? The world's worst industrial disaster, at Union Carbide, Bhopal, India, took place on 2-3 December 1984, leading to the leakage of poisonous methyl-isocyanate into the environment, causing thousands of deaths, pregnancy loss and for some, incapacitation for life. More than a quarter of a century later, the Indian Council of Medical Research undertook to redefine the abysmal consequences of the toxic gas exposure on the exposed population. This invigorated the interest of scientific community in the evaluation of the long-term effects, with reference to cytogenetic parameters. The thrust area was identified in terms of genetic disorders, low birth weight, developmental/growth disorders and congenital malformations. Also the impact on epigenetic factors, which may have contributed to variations in the functional expression of genes, was not negated, stimulating intense scientific research on in utero exposure and the progeny of the exposed population. To accomplish this mammoth task, molecular cytogenetic investigations must be undertaken in conjunction with conventional cytogenetics, using techniques such as FISH, Immuno-FISH, SKY and SNP analysis, to build up a cytogenetic database of the surviving population. 23927220 Influence of preparation time and pitch separation in switching of auditory attention between streams. The ability to consciously switch attention between speakers of interest is necessary for communication in many environments, especially when multiple talkers speak simultaneously. Segregating sounds of interest from the background, which is necessary for selective attention, depends on stimulus acoustics such as differences in spectrotemporal properties of the target and masker. However, the relationship between top-down attention control and bottom-up stimulus segregation is not well understood. Here, two experiments were conducted to examine the time necessary for listeners to switch auditory attention, and how the ability to switch attention relates to the pitch separation cue available for bottom-up stream segregation. 23898178 Interferon-induced RIP1/RIP3-mediated necrosis requires PKR and is licensed by FADD and caspases. Interferons (IFNs) are cytokines with powerful immunomodulatory and antiviral properties, but less is known about how they induce cell death. Here, we show that both type I (α/β) and type II (γ) IFNs induce precipitous receptor-interacting protein (RIP)1/RIP3 kinase-mediated necrosis when the adaptor protein Fas-associated death domain (FADD) is lost or disabled by phosphorylation, or when caspases (e.g., caspase 8) are inactivated. IFN-induced necrosis proceeds via progressive assembly of a RIP1-RIP3 "necrosome" complex that requires Jak1/STAT1-dependent transcription, but does not need the kinase activity of RIP1. Instead, IFNs transcriptionally activate the RNA-responsive protein kinase PKR, which then interacts with RIP1 to initiate necrosome formation and trigger necrosis. Although IFNs are powerful activators of necrosis when FADD is absent, these cytokines are likely not the dominant inducers of RIP kinase-driven embryonic lethality in FADD-deficient mice. We also identify phosphorylation on serine 191 as a mechanism that disables FADD and collaborates with caspase inactivation to allow IFN-activated necrosis. Collectively, these findings outline a mechanism of IFN-induced RIP kinase-dependent necrotic cell death and identify FADD and caspases as negative regulators of this process. 22770610 Evaluation of potential Myt1 kinase inhibitors by TR-FRET based binding assay. In the human cell cycle, the Myt1 kinase is a crucial regulator of the G2/M transition. Because this membrane-associated kinase is hard to obtain and assay, there is a distinct lack of data so far. Here we report the derivatization of a glycoglycerolipid which was shown previously to be active in a Myt1 activity assay. These compounds were tested in a binding assay together with a set of common kinase inhibitors against a full-length Myt1 expressed in a human cell line. Dasatinib exhibited nanomolar affinity whereas broad coverage inhibitors such as sunitinib and staurosporine derivatives did not show any effect. We also carried out docking studies for the most potent compounds allowing further insights into the inhibitor interaction of this kinase. The glycoglycerolipids showed no significant effects in the binding assay, endorsing the idea of a mechanism of action distant from the active site. 23968099 The quantum nature of the OH stretching mode in ice and water probed by neutron scattering experiments. The OH stretching vibrational spectrum of water was measured in a wide range of temperatures across the triple point, 269 K  large intestine > lung > liver > kidney > spleen > heart > brain. Only 0.005-0.006% of schisandrin was recovered in feces and was not detected in urine. Copyright © 2013 John Wiley & Sons, Ltd. 23327841 Lifestyle and osteoporosis in middle-aged and elderly women: Chiba bone survey. Osteoporosis causes an enormous health and economic impact in Japan. We investigated the relation between lifestyle and bone fracture in middle-aged and elderly women. This was a population-based, multicenter, cross-sectional survey for postmenopausal osteoporosis in Chiba City, Japan (Chiba bone survey). This survey included 64,809 Japanese women aged > 40 years. All participants underwent anthropometric measurements including bone mineral density (BMD) and completed a structured, nurse-assisted, self-administered questionnaire also including patient lifestyle. Bone fracture during the recent 5 years was observed in 5.3%, and the fracture group had significantly higher age, BMI, and number of births, family histories of kyphosis and hip fracture, diabetes mellitus (DM), dyslipidemia, kidney disease, exercise, fall, and osteoporosis, and had significantly lower BMD and proportion of menstruating participants. Logistic regression analysis revealed that bone fracture was closely associated with not only low bone mass but also age, fall, family histories of kyphosis and hip fracture, DM, kidney disease, menopause, and lifestyle factors of dieting, exercise, and alcohol. Women's health care focusing on lifestyle-related fracture risks such as dieting, exercise, and alcohol appears necessary to prevent bone fracture in postmenopausal osteoporosis. 23842996 Should acellular pertussis vaccine be recommended to healthcare professionals? The aim of this study was to describe recent changes in the epidemiology of pertussis and existing policies regarding recommended and mandatory occupational vaccinations for healthcare professionals (HCPs). The authors carried out an extensive review of references on the PubMed and SciELO databases and the official sites of the World Health Organization, Pan American Health Organization, Centers for Disease Control and Prevention, and Brazilian Ministry of Health, using the keywords pertussis, vaccines and healthcare professionals. Vaccination against pertussis is recommended for HCPs in the United States, Canada, nine European countries, Australia, Hong Kong, Singapore, Costa Rica, Argentina and Uruguay, and in some countries it is compulsory. In Brazil, only one publication discussing the risk of pertussis among HCPs was found. Considering the reemergence of pertussis and the great number of associated hospitalizations and deaths registered in 2011, it is necessary to review public policies regarding HCP pertussis vaccination, particularly among workers in frequent contact with young babies. 23900198 The complete chloroplast genome sequence of Mahonia bealei (Berberidaceae) reveals a significant expansion of the inverted repeat and phylogenetic relationship with other angiosperms. Mahonia bealei (Berberidaceae) is a frequently-used traditional Chinese medicinal plant with efficient anti-inflammatory ability. This plant is one of the sources of berberine, a new cholesterol-lowering drug with anti-diabetic activity. We have sequenced the complete nucleotide sequence of the chloroplast (cp) genome of M. bealei. The complete cp genome of M. bealei is 164,792bp in length, and has a typical structure with large (LSC 73,052bp) and small (SSC 18,591bp) single-copy regions separated by a pair of inverted repeats (IRs 36,501bp) of large size. The Mahonia cp genome contains 111 unique genes and 39 genes are duplicated in the IR regions. The gene order and content of M. bealei are almost unarranged which is consistent with the hypothesis that large IRs stabilize cp genome and reduce gene loss-and-gain probabilities during evolutionary process. A large IR expansion of over 12kb has occurred in M. bealei, 15 genes (rps19, rpl22, rps3, rpl16, rpl14, rps8, infA, rpl36, rps11, petD, petB, psbH, psbN, psbT and psbB) have expanded to have an additional copy in the IRs. The IR expansion rearrangement occurred via a double-strand DNA break and subsequence repair, which is different from the ordinary gene conversion mechanism. Repeat analysis identified 39 direct/inverted repeats 30bp or longer with a sequence identity ≥90%. Analysis also revealed 75 simple sequence repeat (SSR) loci and almost all are composed of A or T, contributing to a distinct bias in base composition. Comparison of protein-coding sequences with ESTs reveals 9 putative RNA edits and 5 of them resulted in non-synonymous modifications in rpoC1, rps2, rps19 and ycf1. Phylogenetic analysis using maximum parsimony (MP) and maximum likelihood (ML) was performed on a dataset composed of 65 protein-coding genes from 25 taxa, which yields an identical tree topology as previous plastid-based trees, and provides strong support for the sister relationship between Ranunculaceae and Berberidaceae. Molecular dating analyses suggest that Ranunculaceae and Berberidaceae diverged between 90 and 84mya, which is congruent with the fossil records and with recent estimates of the divergence time of these two taxa. 23628763 Cuf2 boosts the transcription of APC/C activator Fzr1 to terminate the meiotic division cycle. The number of nuclear divisions in meiosis is strictly limited to two. Although the precise mechanism remains unknown, this seems to be achieved by adjusting the anaphase-promoting complex/cyclosome (APC/C) activity to degrade cyclin. Here, we describe a fission yeast cuf2 mutant that enters into a third nuclear division cycle, represented by ectopic spindle assembly and abnormal chromosome segregation. Cuf2 is a meiotic transcription factor, and its critical target is fzr1(+)/mfr1(+), which encodes a meiotic APC/C activator. fzr1Δ also enters a third nuclear division. Thus, Cuf2 ensures termination of the M-phase cycle by boosting Fzr1 expression to generate functional gametes. 23615512 Molecular sensing: modulating molecular conduction through intermolecular interactions. We observe changes in the molecular conductivity of individual oligophenylene-vinylene (OPV) molecules due to interactions with small aromatic molecules. Fluorescence experiments were correlated with scanning tunneling microscopy measurements in order to determine the origin of the observed effect. Both nitrobenzene and 1,4-dinitrobenzene decreased fluorescence intensity and molecular conductivity, while toluene had no effect. The observed changes in the fluorescence and conduction of OPV correlate well with the electron withdrawing ability of the interacting aromatic molecules. These results demonstrate the potential usefulness of OPV as a sensor for aromatic compounds containing electron withdrawing groups. 23817496 Translational examination of changes in baroreflex function after renal denervation in hypertensive rats and humans. Renal denervation has shown promise in the treatment of resistant hypertension, although the mechanisms underlying the blood pressure (BP) reduction remain unclear. In a translational study of spontaneously hypertensive rats (n=7, surgical denervation) and resistant hypertensive human patients (n=8; 5 men, 33-71 years), we examined the relationship among changes in BP, sympathetic nerve activity, and cardiac and sympathetic baroreflex function after renal denervation. In humans, mean systolic BP (SBP; sphygmomanometry) and muscle sympathetic nerve activity (microneurography) were unchanged at 1 and 6 months after renal denervation (P<0.05). Interestingly, 4 of 8 patients showed a 10% decrease in SBP at 6 months, but sympathetic activity did not necessarily change in parallel with SBP. In contrast, all rats showed significant and immediate decreases in telemetric SBP and lumbar sympathetic activity (P<0.05), 7 days after denervation. Despite no change in SBP, human cardiac and sympathetic baroreflex function (sequence and threshold techniques) showed improvements at 1 and 6 months after denervation, particularly through increased sympathetic baroreflex sensitivity to falling BP. This was mirrored in spontaneously hypertensive rats; cardiac and sympathetic baroreflex sensitivity (spontaneous sequence and the Oxford technique) improved 7 days after denervation. The more consistent results in rats may be because of a more complete (>90% reduction in renal norepinephrine content) denervation. We conclude that (1) renal denervation improves BP in some patients, but sympathetic activity does not always change in parallel, and (2) baroreflex sensitivity is consistently improved in animals and humans, even when SBP has not decreased. Determining procedural success will be crucial in advancing this treatment modality. 23916480 CB1 cannabinoid receptor-mediated aggressive behavior. This study examined the role of cannabinoid CB1 receptors (CB1r) in aggressive behavior. Social encounters took place in grouped and isolated mice lacking CB1r (CB1KO) and in wild-type (WT) littermates. Cognitive impulsivity was evaluated in the delayed reinforcement task (DRT). Gene expression analyses of monoaminooxidase-A (MAO-A), catechol-o-methyl-transferase (COMT), 5-hydroxytriptamine transporter (5-HTT) and 5-HT1B serotonergic receptor (5HT1Br) in the median and dorsal raphe nuclei (MnR and DR, respectively) and in the amygdala (AMY) were performed by real time-PCR. Double immunohistochemistry studies evaluated COMT and CB1r co-localization in the raphe nuclei and in the cortical (ACo), basomedian (BMA) and basolateral (BLA) amygdaloid nuclei. The behavioral effects of the CB1r agonist ACEA (1 and 2 mg/kg) on aggression were also evaluated in isolated OF1 mice. CB1KO mice housed in groups showed higher levels of offensive aggression. Isolation increased aggressive behavior only in WT. In grouped CB1KO mice COMT gene expression was significantly higher in the MnR and DR, while MAO-A gene expression was lower in the MnR. Gene expression of 5HT1Br, COMT and MAO-A was higher in the amygdala of CB1KO mice. CB1r double-immunohistochemistry revealed cytoplasmic-labeled COMT-ir cells in the raphe nuclei and in the ACo, BMA and BLA. CB1r immunolabeling was observed only in ACo, BMA and BLA, where it was localized in axons and buttons. The density of labeled processes increased in BLA. Acute administration of the CB1 agonist ACEA (2 mg/kg) significantly decreased the aggression levels of OF1 mice. These results suggest that CB1r plays an important role in social interaction and aggressive behavior. 23085367 Xanthohumol induces phase II enzymes via Nrf2 in human hepatocytes in vitro. The aim of this study was to investigate whether xanthohumol may exert chemoprotective activity through the modulation of the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway in immortalized normal THLE-2 hepatocytes and a hepatocellular carcinoma HepG2 cell line. Cells were incubated in the presence of xanthohumol and the activation of Nrf2 and expression of genes controlled by this transcription factor were evaluated. Additionally, p53 level was assessed. Xanthohumol increased the expression and led to the activation of Nrf2 in both cell lines. However, in contrast to normal cells the expression of genes controlled by this transcription factor was not affected in HepG2 cells, except for GSTA and GSTP. Xanthohumol, beside the induction of GSTs and HO-1, significantly elevated NQO1 expression in concert with p53 level in normal hepatocytes. The activation of Nrf2 pathway and subsequently phase II enzymes in concert with p53 induction in normal hepatocytes may account for the molecular mechanism of the chemopreventive activity of xanthohumol. On the other hand its cytotoxicity towards HCC cells shown in this study indicates that it may also be considered as potentially chemotherapeutic. 23807488 Autohydrolysis of tropical agricultural residues by compressed liquid hot water pretreatment. Pretreatment is an essential step in biorefineries for improving digestibility of recalcitrant agricultural feedstocks prior to enzymatic hydrolysis to composite sugars, which can be further converted to fuels and chemicals. In this study, autohydrolysis by compressed liquid hot water (LHW) pretreatment of various tropical agricultural residues including sugarcane bagasse (BG), rice straw (RS), corn stover (CS), and empty palm fruit bunch (EPFB) was investigated. It was found that LHW pretreatment at 200 °C for 5-20 min resulted in high levels of hemicellulose solubilization into the liquid phase and marked improvement on enzymatic digestibility of the solid cellulose-enriched residues. The maximal yields of glucose and pentose were 409.8-482.7 mg/g and 81.1-174.0 mg/g of pretreated substrates, respectively. Comparative analysis based on severity factor showed varying susceptibility of biomass to LHW in the order of BG> RS> CS> EPFB. Structural analysis revealed surface modification of the pretreated biomass along with an increase in crystallinity index. Overall, 75.7-82.3 % yield of glucose and 27.4-42.4 % yield of pentose from the dried native biomass was recovered in the pretreated solid residues, while 18.3-29.7 % of pentoses were recovered in the liquid phase with dehydration by-product concentration under the threshold for ethanologens. The results suggest the potential of LHW as an efficient pretreatment strategy for implementation in biorefineries operated using various seasonal agricultural feedstocks. 23360143 Therapeutic potential of targeting lipid aldehydes and lipoxidation end-products in the treatment of ocular disease. Lipoxidation reactions and the subsequent accumulation of advanced lipoxidation end products (ALEs) have been implicated in the pathogenesis of many of the leading causes of visual impairment. Here, we begin by outlining some of the major lipid aldehydes produced through lipoxidation reactions, the ALEs formed upon their reaction with proteins, and the endogenous aldehyde metabolizing enzymes involved in protecting cells against lipoxidation mediated damage. Discussions are subsequently focused on the clinical and experimental evidence supporting the contribution of lipid aldehydes and ALEs in the development of ocular diseases. From these discussions, it is clear that inhibition of lipoxidation reactions and ALE formation could represent a new therapeutic avenue for the treatment of a broad range of ocular disorders. Current and emerging pharmacological strategies to prevent or neutralize the effects of lipid aldehydes and ALEs are therefore considered, with particular emphasis on the potential of these drugs for treatment of diseases of the eye. 23867753 Adaptation of the health literacy universal precautions toolkit for rheumatology and cardiology - Applications for pharmacy professionals to improve self-management and outcomes in patients with chronic disease. Over a decade of research in health literacy has provided evidence of strong links between literacy skills of patients and health outcomes. At the same time, numerous studies have yielded insight into efficacious action that health providers can take to mitigate the negative effects of limited literacy. This small study focuses on the adaptation, review and use of two new health literacy toolkits for health professionals who work with patients with two of the most prevalent chronic conditions, arthritis and cardiovascular disease. Pharmacists have a key role in communicating with patients and caregivers about various aspects of disease self-management, which frequently includes appropriate use of medications. Participating pharmacists and staff offered suggestions that helped shape revisions and reported positive experiences with brown bag events, suggestions for approaches with patients managing chronic diseases, and with concrete examples related to several medicines [such as Warfarin(©)] as well as to common problems [such as inability to afford needed medicine]. Although not yet tested in community pharmacy sites, these publically available toolkits can inform professionals and staff and offer insights for communication improvement. 23406428 Palm oil and palmitic acid: a review on cardiovascular effects and carcinogenicity. We reviewed the scientific literature on the evidence of the relationship between palm oil and adverse effects on human health. Few studies have investigated the effects of palm oil per se, and the main reason why it has been associated with negative health effects is the relatively high content of saturated fatty acids (SFAs), particularly palmitic acid, which in turn have been associated with increased risk of coronary heart disease and some tumours. However, more recent investigations on the topic seem to have reconsidered the negative role of the dietary SFAs as a risk factor for cardiovascular diseases and show that not only the type of fat, but also that the triglyceride structure plays a role in cholesterolaemia. As regards to a role in cancer, specific studies on dietary palmitic acid or palm oil and the risk of cancer development are scanty, and the evidence is not convincing. 23875561 Screening of antidiabetic and antihyperlipidemic potential of oil from Piper longum and piperine with their possible mechanism. Background: Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia and other symptoms like polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger) which ultimately causes various other complications like retinopathy, neuropathy, nephropathy and microangiopathy. Objectives: The antidiabetic and antihyperlipidemic potential of oil from Piper longum (PLO) and piperine was investigated with their possible mechanism using α-glucosidase, aldose reductase (AR), and pancreatic lipase inhibitory activity. Methods: The biochemical parameters, viz. glucose level, insulin level, liver glycogen content, glycosylated hemoglobin, total plasma cholesterol, triglyceride, and antioxidant parameters, were estimated for all treated groups in acute and chronic antihyperglycemic animal models. Results: PLO (100 and 200 mg/kg), piperine (25 and 50 mg/kg), and glibenclamide (0.6 mg/kg) in respective groups of diabetic animals administered for 28 days reduced the blood glucose level in streptozotocin-induced diabetic rats. There was significant increase in body weight, liver glycogen content, plasma insulin, and high-density lipoprotein and decrease in glycosylated hemoglobin, triglyceride, and total plasma cholesterol in PLO-administered groups as compared to control group. The IC50 value of PLO for α-glucosidase, AR, and pancreatic lipase was found to be 150 ± 2.5, 120 ± 1.2, and 175 ± 1.2 μg/ml, respectively, which was found comparable with the standard drugs acarbose (90 ± 2.3 μg/ml), quercetin (80 ± 2.3 μg/ml), and orlistat (25 ± 0.5 μg/ml), respectively. Conclusion: The investigation done reveals that PLO has significant antidiabetic and antihyperlipidemic activity. 23650121 Controlled fabrication of intermolecular junctions of single-walled carbon nanotube/graphene nanoribbon. Intramolecular junctions can be formed in single-walled carbon nanotubes (SWNTs) by introducing a pentagon and/or heptagon into the hexagonal carbon lattice. The realization of these carbon-based molecular electronics is still quite challenging. Here, it is reported that nickel or cobalt catalyzed etching can be applied to partially unzip an SWNT into an intermolecular junction of SWNT/graphene nanoribbon, directly confirmed by atomic force microscopy and Raman spectroscopy. 23962579 A description of the ICU liaison nurse role in Argentina. Recognising and responding to clinical deterioration in hospital patients has been promoted by many western countries to improve patient safety. In non-western and developing countries it is likely to be even more important to focus on strategies of patient safety. This paper reflects the services provided by Intensive Care Unit Liaison Nurses (ICULN) in the first year of their work, July 2010-June 2011, in an Argentinean hospital. This practice audit aimed to describe the ICULN patient care activities performed for patients discharged from the ICU and ward patients with complex care needs, and to identify education activities carried with ward nursing staff caring for these patients. Experienced critical care nurses, with strong communication and education skills were appointed as ICULNs. They were asked to assess ward patients transferred from ICU once per shift and ward patients as requested by staff. They had to provide patient complex care if necessary and education to ward nurses caring for these patients. A total of 387 patients were followed by ICULNs. The median age of patients was 49 (IQR 26) years (range 15-89). A total of 369 (95.3%) of the patients were discharged from ICU and 18 (4.7%) were ward patients who required complex care. The most frequent conditions patients had were surgery, neurologic conditions, trauma and sepsis. Thirty four (9.2%) of 369 patients who were initially in ICU, were readmitted during the same hospitalisation. During the study period ICULNs performed 5973 patient care and 1709 staff education activities. ICULNs provide advanced assessment and surveillance of ICU discharged and complex ward patients, and facilitate ICU-ward transition assisting and educating ward staff. Further evaluation is necessary to better describe the role in Argentina and the effect of ICULN service on patient outcomes and on staff. 23728925 Is the connection between religiosity and psychological functioning due to religion's social value? A failure to replicate. Increasingly, religion and spirituality has been tied to well-being. However, the mediators are likely multifold, contextually dependent, and remain unclear. A recent report suggested that this is due to religion's social value and presented results indicating that religiosity was more strongly related to psychological adjustment within countries with higher mean religiosity. Effect sizes were small, and given previous research suggesting other more proximal mediators, it was my hypothesis that these findings would not be replicated. Analysis of data from the European Social Survey revealed no significant interactions between country-level religiosity and individual religiosity in predicting psychological well-being. These conflicting findings point to the nuanced nature of the religion-health relationship and suggest that this correlation is unlikely to be due to social valuation. Studies using cursory measures are likely to explain only a small proportion of the variance, yield contradictory findings, and fail to significantly enhance theory in this domain. 23935945 Decreased Expression of AZGP1 Is Associated with Poor Prognosis in Primary Gastric Cancer. 2-Zinc-glycoprotein 1 (AZGP1) is a multidisciplinary protein that participates in many important functions in the human body, including fertilization, immunoregulation and lipid mobilization. Recently, it has been shown that AZGP1 is also involved in carcinogenesis and tumor differentiation. In this study, we investigated the expression levels and prognostic value of AZGP1 in primary gastric cancers. We examined the expression of AZGP1 in 35 paired cancerous and matched adjacent noncancerous gastric mucosa tissues by real-time quantitative RT-PCR (qRT-PCR) and western blotting. Furthermore, we analyzed AZGP1 expression in 248 patients who underwent resection procedures between 2005 and 2007 using immunohistochemistry. The relationships between the AZGP1 expression levels, the clinicopathological factors, and patient survival were investigated. AZGP1 expression was significantly reduced at both the mRNA (P = 0.023) and protein levels (P = 0.019) in tumor tissue samples, compared with expression in matched adjacent non-tumor tissue samples. The immunohistochemical staining data showed that AZGP1 expression was significantly decreased in 52.8% (131/248) of gastric adenocarcinoma cases. Clinicopathological analysis showed that the reduced expression of AZGP1 was significantly correlated with tumor location (P = 0.011), histological grade (P = 0.005) and T stage (P = 0.008). Kaplan-Meier survival curves revealed that the reduced expression of AZGP1 was associated with a poor prognosis in gastric adenocarcinoma patients (P = 0.009). Multivariate Cox analysis identified AZGP1 expression was an independent prognostic factor for overall survival of gastric adenocarcinoma patients (HR = 1.681, 95% CI = 1.134-2.494, P = 0.011). Our study suggests that AZGP1 might serve as a candidate tumor suppressor and a potential prognostic biomarker in gastric carcinogenesis. 23955977 Spontaneous adrenal haemorrhage in early pregnancy. A 32-year-old primigravida presented at our emergency room at 6 weeks of gestation with acute severe right upper quadrant abdominal pain, radiating to the right flank. Vital signs were stable. Abdominal ultrasound showed a round inhomogeneous mass of 10 cm diameter behind the right kidney, suspected for adrenal haemorrhage. The patient was admitted for observation. An MRI showed some right-sided pleural effusion and a round mass in the adrenal region with no recognisable adrenal gland, therefore most likely originating from the right adrenal. After 10 days the patient was discharged with no change in size of the haematoma. MRI was carried out every 2 months which showed a decrease in size of the haematoma, with no other abnormalities. Based on stable MRI and the patient's preference, a vaginal delivery mode was chosen. At 37 weeks of gestation labour was induced, followed by an uncomplicated delivery. 23519575 multifraction separation in countercurrent chromatography (MCSGP). The multicolumn countercurrent solvent gradient purification (MCSGP) process is a continuous countercurrent multicolumn chromatography process capable of performing three fraction separations while applying a linear gradient of some modifier. This process can then be used either for the purification of a single species from a multicomponent mixture or to separate a three component mixture in one single operation. In this work, this process is extended to the separation of multifractions, in principle with no limitation. To achieve this goal the MCSGP standard process is extended by introducing one extra separation section per extra fraction to be isolated. Such an extra separation section is realized in this work through a single additional column, so that a n fraction MCSGP process can be realized using a minimum of n columns. Two separation processes were considered to experimentally demonstrate the possibility of realizing a four-fraction MCSGP unit able to purify two intermediate products in a given multicomponent mixture. The first one was a model mixture containing four different proteins. The two proteins eluting in the center of the chromatogram were purified with yields equal to 95% for the early eluting and 92% for the later eluting one. The corresponding purities were 94% and 97%, respectively. Such performance was well superior to that of the batch operation with the same modifier gradient which for the same purity values could not achieve yields larger than 67% and 81%, respectively. Similar performance improvements were found for the second separation where two out of seven charge variants which constitute the mAb Cetuximab currently available on the market have been purified in one single operation using a four-fraction MCSGP unit. In this case, yields of 81% and 65% were obtained with purities of 90% and 89%, respectively. These data compare well with the corresponding data from batch chromatography where with the same gradient and for the same purities, yield values not larger than 49% and 34%, respectively, could be achieved. Biotechnol. Bioeng. 2013; 110:2436-2444. © 2013 Wiley Periodicals, Inc. 23354517 Downregulation of cell-free miR-198 as a diagnostic biomarker for lung adenocarcinoma-associated malignant pleural effusion. Circulating cell-free microRNAs (miRNAs) are potential cancer biomarkers. The aim of this study was to identify miRNAs that are differentially expressed between benign pleural effusion (BPE) and lung adenocarcinoma-associated malignant pleural effusion (LA-MPE). The expression level of cell-free miRNA was investigated in 107 patients with pleural effusion. Microarrays were used to screen 160 miRNAs in a discovery set comprising 20 effusion samples (ten BPEs and ten LA-MPEs). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate the profiling results obtained for the discovery set and those obtained for a validation set comprising 42 BPEs and 45 LA-MPEs. The area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic performance of the identified miRNAs and other common tumor markers, such as carcinoembryonic antigen (CEA) and cytokeratin fragment (CYFRA) 21-1. Microarray profiling showed that miR-198 was significantly downregulated in LA-MPE compared with BPE (p = 0.002). The miRNA microarray analysis results were confirmed by qRT-PCR (p < 0.001) using the validation set. The AUCs for miR-198, CEA and CYFRA 21-1 in the validation set were 0.887, 0.898 and 0.836, respectively. The diagnostic performance of miR-198 was comparable with that of CEA, but better than that of CYFRA 21-1. The AUC for all three markers combined was 0.926 (95% confidence interval, 0.843-0.973) with a sensitivity of 89.2% and a specificity of 85.0%. The present study suggests that cell-free miR-198 from patients with pleural effusion might have diagnostic potential for differentiating LA-MPE from BPE. 23838078 Moist dressing coverage supports proliferation and migration of transplanted skin micrografts in full-thickness porcine wounds. Transplantation of skin micrografts in a 1:100 ratio regenerate the epidermis of full-thickness wounds in pigs within 14 days in a wet environment. The aim of the current study was to combine micrografts and commercially available moist dressings. We hypothesized that micrografts regenerate the epidermis when covered with a moist dressing. 5cm×5cm and 10cm×10cm full-thickness wounds were created on the backs of pigs. Wounds were transplanted with 0.8mm×0.8mm micrografts created from a split-thickness skin graft in a 1:100 ratio. 5cm×5cm wounds were treated with wound chambers, moist dressings or dry gauze (non-transplanted control group). 10cm×10cm wounds were compared to non-transplanted wounds, both covered with moist dressings. Reepithelialization was assessed in biopsies from day 10, 14 and 18 post-transplantation. 5cm×5cm transplanted wounds covered with moist dressings showed 69.5±20.6% reepithelialization by day 14 and 90.5±10.4% by day 18, similar to wounds covered with a wound chamber (63.9±16.7 and 86.2±11.9%, respectively). 18 days post-transplantation, 10cm×10cm transplanted wounds covered with moist dressings showed 66.1±10.3% reepithelialization, whereas nontransplanted wounds covered with moist dressings were 40.6±6.6% reepithelialized. We conclude that micrografts combined with clinically available moist dressings regenerate the epidermis of full-thickness wounds. 23962375 Aerobic Oxidation of Methanol to Formic Acid on Au8(‒): Benchmark Analysis Based on Completely Renormalized Coupled-Cluster and Density Functional Theory Calculations. The left-eigenstate completely renormalized coupled-cluster (CC) method with singles, doubles, and non-iterative triples (CR-CC(2,3)) and a few representative density functional theory (DFT) approaches are applied to methanol oxidation to formic acid on Au8‒ cluster, which is a model for aerobic oxidations on gold nanoparticles. It is demonstrated that CR-CC(2,3) supports the previous exothermic reaction mechanism, placing the initial rate-determining transition state, which corresponds to hydrogen transfer from the methoxy species to the molecular oxygen, at about 20 kcal/mol above the reactants, less than 40 kcal/mol above the O2 and CH3O‒ species co-adsorbed on Au8‒, and considerably above the remaining two transition states along the reaction pathway. The DFT calculations using the previously exploited M06 hybrid functional show reasonable agreement with CR-CC(2,3), but B3LYP offers additional improvements in the description of the relevant activation energies. Pure functionals, including M06-L, BP86, and TPSS, do not work well, significantly underestimating the activation barriers, but dispersion corrections, as in B97-D, bring the results closer to the M06 accuracy level. 23623832 A multiplex methylation-specific PCR assay for the detection of early-stage ovarian cancer using cell-free serum DNA. Epithelial ovarian cancer (EOC) remains the most lethal disease among gynecological malignancies. Prompt diagnosis is challenging because of the non-specific symptoms exhibited during the early stage of the disease. As a result, there is an urgent need for improved detection methods. In this study, we established a multiplex methylation-specific PCR (MSP) assay to improve the early detection of ovarian cancer, via identification of the methylation status of cell-free serum DNA. After screening, we chose seven candidate genes (APC, RASSF1A, CDH1, RUNX3, TFPI2, SFRP5 and OPCML) with a high frequency of methylation to construct the multiplex-MSP assay. When methylation of at least one of the seven genes was observed, the multiplex-MSP assay was considered positive. We performed retrospective and screening studies to verify the specificity and sensitivity of the assay in the detection of EOC. The methylation status of cell-free serum DNA was examined in the preoperative serum of 202 patients, including 87 EOC patients (stage I, n=41; stage II-IV, n=46), 53 patients with benign ovarian tumors and 62 healthy controls. As expected, the multiplex MSP assay achieved a sensitivity of 85.3% and a specificity of 90.5% in stageI EOC, strikingly higher rates compared with a single CA125, which produced a sensitivity of 56.1% at 64.15% specificity [P=0.0036]. A multiplex MSP assay that analyzes the methylation status of cell-free serum DNA is a suitable and reliable approach to improve the early detection of ovarian cancer, potentially benefiting a broad range of applications in clinical oncology. 23528178 African lessons on climate change risks for agriculture. Climate change impact assessments on agriculture are subject to large uncertainties, as demonstrated in the present review of recent studies for Africa. There are multiple reasons for differences in projections, including uncertainties in greenhouse gas emissions and patterns of climate change; assumptions on future management, aggregation, and spatial extent; and methodological differences. Still, all projections agree that climate change poses a significant risk to African agriculture. Most projections also see the possibility of increasing agricultural production under climate change, especially if suitable adaptation measures are assumed. Climate change is not the only projected pressure on African agriculture, which struggles to meet demand today and may need to feed an additional one billion individuals by 2050. Development strategies are urgently needed, but they will need to consider future climate change and its inherent uncertainties. Science needs to show how existing synergies between climate change adaptation and development can be exploited. 23949914 Role of DNMT3A, TET2, and IDH1/2 mutations in pre-leukemic stem cells in acute myeloid leukemia. Aberrant changes in the epigenome are now recognized to be important in driving the development of multiple human cancers including acute myeloid leukemia. Recent advances in sequencing technologies have led to the identification of recurrent mutations in genes that regulate DNA methylation including DNA methyltransferase 3A (DNMT3A), ten-eleven translocation 2 (TET2), and isocitrate dehydrogenase 1 (IDH1) and IDH2. These mutations have been shown to promote self-renewal and block differentiation of hematopoietic stem/progenitor cells. Acquisition of these mutations in hematopoietic stem cells can lead to their clonal expansion resulting in a pre-leukemic stem cell (pre-LSC) population. Pre-LSCs retain the ability to differentiate into the full spectrum of mature daughter cells but can become fully transformed with the acquisition of additional driver mutations. Here, we review the effects of mutations in DNMT3A, TET2, and IDH1/2 on mouse and human hematopoiesis, the current understanding of their role in pre-LSCs, and therapeutic strategies to eliminate this population which may serve as a cellular reservoir for relapse. 23727058 Mono-PEGylated radix ophiopogonis polysaccharide for the treatment of myocardial ischemia. This work aimed to improve the clinical application of Radix Ophiopogonis polysaccharide (ROP), a natural anti-myocardial ischemic fructan with Mw of 4.80kDa, by mono-PEGylation. Three mono-PEGylated ROPs were prepared by a moderate coupling reaction between amino-terminated methoxy-PEG (20-, 30-, or 40-kDa) and excessive hydroxyl-activated ROP. After being fully characterized by proton nuclear magnetic resonance as well as high-performance gel permeation chromatography and anthrone-sulfuric acid colorimetry coupled assay, they were evaluated for pharmacokinetics and anti-myocardial ischemic activities in rats with coronary artery ligation. The results showed that mono-PEGylated ROPs were successfully and effectively prepared. Compared with ROP, the three mono-PEGylated ROPs showed approximately 32-, 85-, and 100-fold prolonged retention in systemic circulation with plasma half-lives reaching 16.1, 42.4, and 49.8h, respectively. Studies on anti-myocardial ischemic effects of the conjugates showed that administrated at the same molar dose of 4μmol/kg per injection as ROP, they could achieve comparable or even better therapeutic effects although their administration intervals were 2- to 6-fold longer than that of ROP. These findings confirm that PEGylation would be a promising approach to markedly reducing the injection-administered frequency of ROP and hence patient compliance without sacrifice of the therapeutic efficacy by significantly improving its pharmacokinetics. 23749969 Has the bacterial biphenyl catabolic pathway evolved primarily to degrade biphenyl? The diphenylmethane case. In this work, we have compared the ability of Pandoraea pnomenusa B356 and of Burkholderia xenovorans LB400 to metabolize diphenylmethane and benzophenone, two biphenyl analogs in which the phenyl rings are bonded to a single carbon. Both chemicals are of environmental concern. P. pnomenusa B356 grew well on diphenylmethane. On the basis of growth kinetics analyses, diphenylmethane and biphenyl were shown to induce the same catabolic pathway. The profile of metabolites produced during growth of strain B356 on diphenylmethane was the same as the one produced by isolated enzymes of the biphenyl catabolic pathway acting individually or in coupled reactions. The biphenyl dioxygenase oxidizes diphenylmethane to 3-benzylcyclohexa-3,5-diene-1,2-diol very efficiently, and ultimately this metabolite is transformed to phenylacetic acid, which is further metabolized by a lower pathway. Strain B356 was also able to cometabolize benzophenone through its biphenyl pathway, although in this case, this substrate was unable to induce the biphenyl catabolic pathway and the degradation was incomplete, with accumulation of 2-hydroxy-6,7-dioxo-7-phenylheptanoic acid. Unlike strain B356, B. xenovorans LB400 did not grow on diphenylmethane. Its biphenyl pathway enzymes metabolized diphenylmethane, but they poorly metabolize benzophenone. The fact that the biphenyl catabolic pathway of strain B356 metabolized diphenylmethane and benzophenone more efficiently than that of strain LB400 brings us to postulate that in strain B356, this pathway evolved divergently to serve other functions not related to biphenyl degradation. 23898781 Multifunctional Role of Rare Earth Doping in Optical Materials: Nonaqueous Sol-Gel Synthesis of Stabilized Cubic HfO2 Luminescent Nanoparticles. In this work a strategy for the control of structure and optical properties of inorganic luminescent oxide-based nanoparticles is presented. The nonaqueous sol-gel route is found to be suitable for the synthesis of hafnia nanoparticles and their doping with rare earths (RE) ions, which gives rise to their luminescence either under UV and X-ray irradiation. Moreover, we have revealed the capability of the technique to achieve the low-temperature stabilization of the cubic phase through the effective incorporation of trivalent RE ions into the crystal lattice. Particular attention has been paid to doping with europium, causing a red luminescence, and with lutetium. Structure and morphology characterization by XRD, TEM/SEM, elemental analysis, and Raman/IR vibrational spectroscopies have confirmed the occurrence of the HfO2 cubic polymorph for dopant concentrations exceeding a threshold value of nominal 5 mol %, for either Lu(3+) or Eu(3+). The optical properties of the nanopowders were investigated by room temperature radio- and photoluminescence experiments. Specific features of Eu(3+) luminescence sensitive to the local crystal field were employed for probing the lattice modifications at the atomic scale. Moreover, we detected an intrinsic blue emission, allowing for a luminescence color switch depending on excitation wavelength in the UV region. We also demonstrate the possibility of changing the emission spectrum by multiple RE doping in minor concentration, while deputing the cubic phase stabilization to a larger concentration of optically inactive Lu(3+) ions. The peculiar properties arising from the solvothermal nonaqueous synthesis here used are described through the comparison with thermally treated powders. 23800796 Clinical and laboratory studies of 17 patients with acute myeloid leukemia harboring t(7;11)(p15;p15) translocation. The cellular and molecular genetic aberrations of hematopoietic and lymphoid tissues are increasingly important in leukemia classification and are prognostically significant. Although some recurrent molecular cytogenetic abnormalities in AML have been extensively studied, others including t(7;11)(p15;p15) have not been well characterized. In this paper, seventeen AML patients with t(7;11)(p15;p15) were retrospectively reviewed for cell morphology, immuno-phenotype, cytogenetics as well as clinical features and prognosis. Among them, thirteen were female; nine were AML-M2. Six patients who were newly diagnosed were alive, one was lost for followed up and ten died. The median survival was 8 months. Taking together, AML with t(7;11)(p15;p15) is a rare and distinct disease. Most patients with this translocation are female at younger age and have special clinical and hematological characteristics such as M2-subtype of AML, easy to relapse and poor prognosis. 22587951 Human renal cancer stem cells. Cancer stem cells (CSCs), isolated in renal carcinomas, exhibit tumor-initiating capabilities and pluripotency. No specific CSC markers have been identified so far; therefore, their characterization is mainly based on functional studies. As they are resistant to chemo and radio therapy, renal CSCs may have a relevant role in tumor establishment, progression, and recurrence. CSCs were also shown to contribute to intra-tumor vasculogenesis through an endothelial differentiation and to favor the generation of the pre-metastatic niche through the release of exosomes/microvesicles. 23362206 Multifarious roles of intrinsic disorder in proteins illustrate its broad impact on plant biology. Intrinsically disordered proteins (IDPs) are highly abundant in eukaryotic proteomes. Plant IDPs play critical roles in plant biology and often act as integrators of signals from multiple plant regulatory and environmental inputs. Binding promiscuity and plasticity allow IDPs to interact with multiple partners in protein interaction networks and provide important functional advantages in molecular recognition through transient protein-protein interactions. Short interaction-prone segments within IDPs, termed molecular recognition features, represent potential binding sites that can undergo disorder-to-order transition upon binding to their partners. In this review, we summarize the evidence for the importance of IDPs in plant biology and evaluate the functions associated with intrinsic disorder in five different types of plant protein families experimentally confirmed as IDPs. Functional studies of these proteins illustrate the broad impact of disorder on many areas of plant biology, including abiotic stress, transcriptional regulation, light perception, and development. Based on the roles of disorder in the protein-protein interactions, we propose various modes of action for plant IDPs that may provide insight for future experimental approaches aimed at understanding the molecular basis of protein function within important plant pathways. 23815323 The complete mitochondrial genome sequence of Xenocypris davidi (Bleeker). Abstract Xenocypris davidi is a member of Cyprindae and widely distributed in China. To understand the systematic status of this species, we sequenced the whole mitochondrial genome of Xenocypris davidi. The complete mitochondrial genome is 16,630 bp in length including the typical structure of 22 tRNA, 2 rRNA, 13 protein-coding genes and the non-coding region. The major non-coding sequence which is the control region containing 6 CSBs (CSB-1, CSB-2, CSB-3, CSB-D, CSB-E and CSB-F). The second non-coding sequence is the origin of light-strand replication (OL). This region has the potential to fold in a step-loop secondary structure. The mitochondrial genomic sequence will help us to study the conservation genetic and evolution of Xenocypris. 23922264 Synthesis of Small Combinatorial Libraries of Natural Products: Identification and Quantification of New Long-chain 3-Methyl-2-alkanones from the Root Essential Oil of Inula helenium L. (Asteraceae). Recently, a potent anti-staphylococcal activity of Inula helenium L. (Asteraceae) root essential oil was reported. Also, bioassay guided fractionation of the oil pointed to eudesmane sesquiterpene lactones and a series of unidentified constituents as the main carriers of the observed activity. To identify nine new constituents (long-chain 3-methyl-2-alkanones) from a fraction of this root essential oil with a low minimum inhibitory concentration value (0.8 µg/mL) by employing a synthetic methodology that leads to the formation of a small combinatorial library of these compounds. The identity of these constituents was inferred from mass spectral fragmentation patterns and GC retention data. A library of 3-methyl-2-alkanones (C11 -C19 homologous series) was synthesised in three steps starting from methyl acetoacetate and the corresponding alkyl halides. The synthetic library was also screened for in vitro anti-microbial activity. Gas chromatographic analyses of I. helenium essential oil samples with spiked compounds from the synthesised library corroborated the tentative identifications of the long-chain 3-methyl-2-alkanones. The availability of these anti-microbial compounds from this library made it possible to construct GC/FID calibration curves and determine their content in the plant material: 0.08 - 24.2 mg/100 g of dry roots. The small combinatorial library approach enabled the first unequivocal identification of long-chain 3-methyl-2-alkanones as plant secondary metabolites, and, also, allowed determination of not only a single compound and biological properties, but those of a group of structurally related compounds. Copyright © 2013 John Wiley & Sons, Ltd. 23379989 Vitamin D status in professional ballet dancers: Winter vs. summer. Serum 25-hydroxyvitamin D is produced by the exposure of the skin to sunlight. Therefore athletes who train indoors, such as dancers, are vulnerable to vitamin D deficiency. The purpose of the study was to evaluate the serum 25-hydroxyvitamin D status in UK professional dancers during periods of reduced and increased sunlight exposure (i.e., winter vs. summer), and to assess the impact on bone metabolism and risk of injury. Cohort study. 19 elite classical ballet dancers (age 26±8.86yr; height 1.66±8.84m; mass 54.3±10.47kg) were monitored over a 6 month period for 25-hydroxyvitamin D, PTH and blood serum bone turnover markers (CTX and PINP) along with injury data. Repeated measure ANOVA and Wilcoxon and Chi-square analyses were used and significance was set at p≤0.05. Significant changes were noted between the winter and summer test dates for 25-hydroxyvitamin D (14.9ng/ml vs. 23.9ng/ml; p<0.001), PTH (38.7pg/ml vs. 26.3pg/ml; p<0.001) and PINP (89.9ng/ml vs. 67.6ng/ml; p<0.01). The oral contraceptive had a significant effect on serum 25-hydroxyvitamin D, PTH and CTX. Soft tissue injuries were significantly lower in summer compared to winter period (winter=24, summer=13; p<0.05). Professional ballerinas characterized by a high incidence of low serum 25-hydroxyvitamin D levels which improve marginally in the summer. These dancers also demonstrate a higher injury incidence in the winter. Oral contraception seems to increase serum 25-hydroxyvitamin D levels and has a positive effect on bone metabolism. 23870554 Sample size calculation for multicentre efficacy trials of blood-stage malaria antigens. Sample size has increasingly become a prerequisite for grant approval. Study size calculations for multicentre trials are more complicated because these sites present different assumptions on incidence of disease expected in the control group; this then changes the mechanism of sample size determination. This paper suggested an alternative approach to estimating study size in multicentre vaccine efficacy trials. The approach suggested in this paper was to determine the expected number of events for a given sample size under set of different assumptions. The power was then calculated given the expected number of events under the set of assumptions so as to assess the sensitivity of the sample size. The approach was then illustrated assuming a malaria vaccine efficacy trial planned in four centres. The approach showed that by assuming 30% cumulative incidence of malaria in three of the centres and 10% cumulative incidence in the other centre, a sample size of 460 children in each centre (total 1,840) corresponding to a total of 339 events gives 90% power to detect vaccine efficacy of 30% at 5% level of significance, allowing for 15% loss to follow-up. However, if the incidence is lower than anticipated or a centre drops out altogether the power will be low. But this would not have much effect if it were a low incidence centre. Rather, it might have major effect if it were a high incidence centre. Decision on recruitment depends on whether separate estimates of efficacy in each transmission level are reasonable. If not, equal numbers can be recruited, which then gives safety data for each site and overall efficacy. Recruiting all or most subjects in the highest transmission site can minimize sample size but may be better to spread the risk due to uncertainty about incidence due to year to year variation and also the possibility of a site dropping due to political or other unforeseen problems. The approach demonstrated the potential of estimating the expected number of events required to give a specified power for multicentre efficacy trails of blood stage malaria antigens. 23733347 An Emerging Functional Natural Silk Biomaterial from the only Domesticated Non-mulberry Silkworm Samia ricini. Mulberry silk fibroin is a widely used biomaterial and recent work on non-mulberry silk fibroin also suggests it may have similar uses. We expect silk fibroin from the only domesticated non-mulberry eri silkworm, Samia ricini, to possess useful properties as a biomaterial. Eri silk gland fibroin is a heterodimeric protein of approximately 450 kDa. Cytocompatibility evaluation with fibroblasts and osteoblast-like cells shows good cell attachment, viability and proliferation. The matrices, which have high thermal stability and good swellability, are also haemocompatible. Eri silk production is cost effective as no agronomic practices are required for their host plant cultivation. This fibroin provide new opportunities as an alternative natural functional biomaterial in various biomedical applications. 23968136 Small-Angle Neutron Scattering Study of Structure and Interaction of Nanoparticle, Protein and Surfactant Complexes. Small-angle neutron scattering (SANS) measurements have been carried out from the multi-component system of Ludox HS40 silica nanoparticle, bovine serum albumin (BSA) protein and sodium dodecyl sulphate (SDS) surfactant in aqueous system under the solution condition all the components are negatively charged. In spite of the components being similarly charged, strong structural evolutions amongst them have been observed. The complexes of different components in pairs (nanoparticle-protein, nanoparticle-surfactant and protein-surfactant) have been examined to correlate the role of each component in the three-component naoparticle-protein-surfactant system. The nanoparticle-protein system shows depletion interaction induced aggregation of nanoparticles in presence of protein. Both nanoparticle and surfactant coexist individually in nanoparticle-surfactant system. In the case of protein-surfactant system, the cooperative binding of surfactant with protein leads to micelle-like clusters of surfactant formed along the unfolded protein chain. The structure of three-component (naoparticle-protein-surfactant) system is found to be governed by the synergetic effect of nanoparticle-protein and protein-surfactant interactions. The nanoparticle aggregates coexist with the structures of protein-surfactant complex in the three-component system. The nanoparticle aggregation as well as unfolding of protein is enhanced in this system as compared to the corresponding two-component systems. 23889363 The placebo and nocebo effects on peak minute power during incremental arm crank ergometry. Abstract This investigation aimed to explore the effects of inert sugar-free drinks described as either 'performance enhancing' (placebo) or 'fatigue inducing' (nocebo) on peak minute power (PMP;W) during incremental arm crank ergometry (ACE). Twelve healthy, non-specifically trained individuals volunteered to take part. A single-blind randomised controlled trial with repeated measures was used to assess for differences in PMP;W, oxygen uptake, heart rate (HR), minute ventilation, respiratory exchange ratio (RER) and subjective reports of local ratings of perceived exertion (LRPE) and central ratings of perceived exertion (CRPE), between three separate, but identical ACE tests. Participants were required to drink either 500 ml of a 'sports performance' drink (placebo), a 'fatigue-inducing' drink (nocebo) or water prior to exercise. The placebo caused a significant increase in PMP;W, and a significant decrease in LRPE compared to the nocebo (p=0.01; p=0.001) and water trials (p=0.01). No significant differences in PMP;W between the nocebo and water were found. However, the nocebo drink did cause a significant increase in LRPE (p=0.01). These results suggest that the time has come to broaden our understanding of the placebo and nocebo effects and their potential to impact sports performance. 23856204 Local recurrence after surgery for non-small cell lung cancer: A recursive partitioning analysis of multi-institutional data. To define subgroups at high risk of local recurrence (LR) after surgery for non-small cell lung cancer using a recursive partitioning analysis (RPA). This Institutional Review Board-approved study included patients who underwent upfront surgery for I-IIIA non-small cell lung cancer at Duke Cancer Institute (primary set) or at other participating institutions (validation set). The 2 data sets were analyzed separately and identically. Disease recurrence at the surgical margin, ipsilateral hilum, and/or mediastinum was considered an LR. Recursive partitioning was used to build regression trees for the prediction of local recurrence-free survival (LRFS) from standard clinical and pathological factors. LRFS distributions were estimated with the Kaplan-Meier method. The 1411 patients in the primary set had a 5-year LRFS rate of 77% (95% confidence interval [CI], 0.74-0.81), and the 889 patients in the validation set had a 5-year LRFS rate of 76% (95% CI, 0.72-0.80). The RPA of the primary data set identified 3 terminal nodes based on stage and histology. These nodes and their 5-year LRFS rates were as follows: (1) stage I/adenocarcinoma, 87% (95% CI, 0.83-0.90); (2) stage I/squamous or large cell, 72% (95% CI, 0.65-0.79); and (3) stage II-IIIA, 62% (95% CI, 0.55-0.69). The validation RPA identified 3 terminal nodes based on lymphovascular invasion (LVI) and stage: (1) no LVI/stage IA, 82% (95% CI, 0.76-0.88); (2) no LVI/stage IB-IIIA, 73% (95% CI, 0.69-0.80); and (3) LVI, 58% (95% CI, 0.47-0.69). The risk of LR was similar in the primary and validation patient data sets. There was discordance between the 2 data sets regarding the clinical factors that best segregate patients into risk groups. 23810549 Bifid nose - a mild degree of frontonasal dysplasia. A case report. Frontonasal dysplasia is an unusual congenital condition with a wide phenotypic range. Because of this, only a small number of cases and their management have been reported in the literature. The ideal surgical procedures to correct mild cases of frontonasal dysplasia, and the time to perform them, are still controversial. The case of a 9-month-old girl with a mild form of this condition (a congenital bifid nose and a duplicated frenulum), and its surgical management, is presented. The surgery achieved an early improvement of the patient's appearance and she had no complications. In the future, it is probable that she will need secondary rhinoplasty to aid in the projection of the tip and refine the shape of the nose. 23907115 Antiapoptotic activity of argon and xenon. Although chemically non-reactive, inert noble gases may influence multiple physiological and pathological processes via hitherto uncharacterized physical effects. Here we report a cell-based detection system for assessing the effects of pre-defined gas mixtures on the induction of apoptotic cell death. In this setting, the conventional atmosphere for cell culture was substituted with gas combinations, including the same amount of oxygen (20%) and carbon dioxide (5%) but 75% helium, neon, argon, krypton, or xenon instead of nitrogen. The replacement of nitrogen with noble gases per se had no effects on the viability of cultured human osteosarcoma cells in vitro. Conversely, argon and xenon (but not helium, neon, and krypton) significantly limited cell loss induced by the broad-spectrum tyrosine kinase inhibitor staurosporine, the DNA-damaging agent mitoxantrone and several mitochondrial toxins. Such cytoprotective effects were coupled to the maintenance of mitochondrial integrity, as demonstrated by means of a mitochondrial transmembrane potential-sensitive dye and by assessing the release of cytochrome c into the cytosol. In line with this notion, argon and xenon inhibited the apoptotic activation of caspase-3, as determined by immunofluorescence microscopy coupled to automated image analysis. The antiapoptotic activity of argon and xenon may explain their clinically relevant cytoprotective effects. 23829959 The relation between the blood glucose level and the FDG uptake of tissues at normal PET examinations. The influence of the blood glucose level on the tracer uptake of normal tissues at [18F]-2-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) was retrospectively studied in examinations in clinical patients. Five hundred examinations were evaluated in retrospect. The inclusion criteria were studies with a normal or near-normal FDG distribution. Patients who had been subjected to chemotherapy (including GSF treatment) or radiotherapy <4 weeks prior to the examination were excluded; we cannot exclude, however, that in a very few patients the available information might have been incomplete. Otherwise, patients were included regardless of concurrent diseases and/or therapy. In one evaluation, the mean standardized uptake value of the liver, spleen, lungs, peripheral blood, selected muscles and bone marrow of all 500 individuals was correlated to the blood glucose level. In another evaluation, a subgroup of 62 patients with increased blood glucose levels (≥7.0 mmol/l) was compared with another subgroup of 62 patients paired with regard to age and gender with blood glucose levels within normal range (≤6.0 mmol/l). There was a weak positive correlation between the blood glucose level and the muscular uptake of FDG, while there was no correlation with the tracer uptake of the liver, spleen, lungs, peripheral blood or bone marrow. The patient group with increased blood glucose levels showed a slightly, but significantly, higher muscular FDG uptake compared with the matched subgroup of patients with normal blood glucose levels. When comparing the other assessed tissues/organs, there were no differences between these two patient groups. The effect of hyperglycaemia at FDG PET on the studied normal tissues is restricted to a slightly increased muscular uptake. The effect of the blood glucose level on the blood activity at the time of examination is negligible. 23337516 Lower physical activity is a risk factor for a clustering of metabolic risk factors in non-obese and obese Japanese subjects: The Takahata study. In several countries including Japan, people without obesity but with a clustering of metabolic risk factors (MetRFs) were not considered to have the metabolic syndrome (MetS). Here, we examined whether lifestyle characteristics differed between non-obese and obese subjects with or without a clustering of MetRFs. From a population-based cross-sectional study of Japanese subjects aged ≥ 40 years, 1,601 subjects (age: 61.9 ± 10.3 years; 710/891 men/women) were recruited. Physical activity status and daily nutritional intake were estimated using questionnaires. A clustering of MetRFs was defined based on the presence of at least two non-essential risk factors for the diagnosis of the MetS in Japan. Energy intake was not higher in subjects with a clustering of MetRFs compared with those without. Among men, energy expenditure at work was significantly lower in non-obese (9.0 ± 8.2 vs. 11.3 ± 9.3 METs (metabolic equivalents), P = .025) and obese (9.0 ± 7.9 vs. 11.6 ± 9.4 METs, P = .017) subjects with a clustering of MetRFs than in those without. Multiple logistic regression analysis showed that energy expenditure at work was significantly associated with a clustering of MetRFs after adjusting for possible confounding factors including total energy intake. The ORs (per 1 MET (metabolic equivalent)) were 0.970 (95% CI, 0.944-0.997; P = .032) in non-obese men and 0.962 (0.926-0.999; P = .043) in obese men. Similar associations were not observed in women. In Japanese males, lower physical activity, but not excessive energy intake, is a risk factor for a clustering of MetRFs independent of their obesity status. 23858459 Export of submicron particulate organic matter to mesopelagic depth in an oligotrophic gyre. Sixty percent of the world ocean by area is contained in oligotrophic gyres [Longhurst A (1995) Prog Oceanog 36:77-16], the biomass of which is dominated by picophytoplankton, including cyanobacteria and picoeukaryotic algae, as well as picoheterotrophs. Despite their recognized importance in carbon cycling in the surface ocean, the role of small cells and their detrital remains in the transfer of particulate organic matter (POM) to the deep ocean remains disputed. Because oligotrophic marine conditions are projected to expand under current climate trends, a better understanding of the role of small particles in the global carbon cycle is a timely goal. Here we use the lipid profiles, radiocarbon, and stable carbon isotopic signatures of lipids from the North Pacific Subtropical Gyre to show that in the surface ocean, lipids from submicron POM (here called extra-small POM) are distinct from larger classes of suspended POM. Remarkably, this distinct extra-small POM signature dominates the total lipids collected at mesopelagic depth, suggesting that the lipid component of mesopelagic POM primarily contains the exported remains of small particles. Transfer of submicron material to mesopelagic depths in this location is consistent with model results that claim the biological origin of exported carbon should be proportional to the distribution of cell types in the surface community, irrespective of cell size [Richardson TL, Jackson GA (2007) Science 315:838-840]. Our data suggest that the submicron component of exported POM is an important contributor to the global biological pump, especially in oligotrophic waters. 22344318 Is ADHD a risk factor independent of conduct disorder for illicit substance use? A meta-analysis and metaregression investigation. Objective: To investigate meta-analytically if the association between ADHD and illicit substance use (ISU) is maintained when controlling for conduct disorder/oppositional-defiant disorder (CD/ODD). Method: A systematic literature review was conducted through Medline from 1980 to 2008. Data extracted and selections made by one author were reviewed by another. Results: Fifteen articles presented odds ratios (ORs) for the development of ISU in individuals with ADHD controlling for CD/ODD. In total, the study covered results for more than 1,000 individuals. The combined OR for studies that included in their analysis exclusively ISU was 1.35 (0.90-2.03), p = .15, heterogeneity = 55%. Lack of control for socioeconomic status was related with a weaker association between ADHD and ISU. Conclusion: The existing data do not indicate that ADHD increases the risk of ISU beyond the effects of CD/ODD. However, the combination of all existing data is limited in power to detect a small increase in chance. 23306521 Age estimation of immature human skeletal remains using the post-natal development of the occipital bone. Whenever age cannot be estimated from dental formation in immature human skeletal remains, other methods are required. In the post-natal period, development of the skeleton provides alternative age indicators, namely, those associated with skeletal maturity of the cranium. This study wishes to document the age at which the various ossification centres in the occipital bone fuse and provide readily available developmental probabilistic information for use in age estimation. A sample of 64 identified immature skeletons between birth and 8 years of age from the Lisbon collection was used (females = 29, males = 35). Results show that fusion occurs first in the posterior intra-occipital synchondrosis and between the jugular and condylar limbs of the lateral occipital to form the hypoglossal canal (1-4 years), followed by the anterior intra-occipital (3-7 years). Fusion of the post-natal occipital does not show differences in timing between males and females. Relative to other published sources, this study documents first and last ages of fusion of several ossification centres and the posterior probabilities of age given a certain stage of fusion. Given the least amount of overlap in stages of fusion, the closure of the hypoglossal canal provides the narrowest estimated age with the highest probability of age. 23653179 Morphology and biomechanics of the pinniped jaw: mandibular evolution without mastication. Pinnipeds (seals, sea lions, and walruses) underwent a shift in jaw function away from typical carnivoran mastication to more novel marine behaviors during the terrestrial-aquatic transition. Here we test the effect of aquatic prey capture and male-male combat on the morphological evolution of a mammal jaw that does not masticate. Nine three-dimensional landmarks were taken along the mandible for 25 species (N = 83), and corpus and symphysis external and cortical breadths for a subset of five species (N = 33). Principal components analysis was performed on size-corrected landmark data to assess variation in overall jaw morphology across pinnipeds. Corpus breadths were input to a beam model to calculate strength properties and estimated bite force of specific species with contrasting behaviors (filter feeding, suction feeding, grip-and-tear feeding, and male-male combat). Results indicate that, although phylogenetic signal in jaw shape is strong, function is also important in determining morphology. Filter feeders display an elongate symphysis and a long toothrow that may play a role in filtering krill. Grip-and-tear feeders have a long jaw and large estimated bite force relative to non-biting species. However, the largest estimated bite forces were observed in males of male-male combative species, likely due to the high selection pressure associated with male success in highly polygynous species. The suction feeding jaw is weak in biting but has a different morphology in the two suction feeding taxa. In conclusion, familial patterns of pinniped jaw shape due to phylogenetic relatedness have been modified by adaptations to specialized behavior of individual taxa. 23665119 Automated home cage assessment shows behavioral changes in a transgenic mouse model of spinocerebellar ataxia type 17. Spinocerebellar Ataxia type 17 (SCA17) is an autosomal dominantly inherited, neurodegenerative disease characterized by ataxia, involuntary movements, and dementia. A novel SCA17 mouse model having a 71 polyglutamine repeat expansion in the TATA-binding protein (TBP) has shown age related motor deficit using a classic motor test, yet concomitant weight increase might be a confounding factor for this measurement. In this study we used an automated home cage system to test several motor readouts for this same model to confirm pathological behavior results and evaluate benefits of automated home cage in behavior phenotyping. Our results confirm motor deficits in the Tbp/Q71 mice and present previously unrecognized behavioral characteristics obtained from the automated home cage, indicating its use for high-throughput screening and testing, e.g. of therapeutic compounds. 23643891 Insertion of TAT peptide and perturbation of negatively charged model phospholipid bilayer revealed by neutron diffraction. TAT peptide is one of the best-characterized cell penetrating peptides derived from the transactivator of transcription protein from the human immunodeficiency virus 1. The aim of this study was to investigate the interaction between TAT peptide and partially negatively-charged phospholipid bilayer by using lamellar neutron diffraction. The main findings are the existence of a contiguous water channel across the bilayer in the presence of TAT peptide. Taken in combination with other observations, including thinning of the lipid bilayer, this unambiguously locates the peptide within the lipid bilayer. The interaction of TAT peptide with anionic lipid bilayer, composed of an 80:20 mixture of DOPC and DOPS, takes place at two locations. One is in the peripheral aqueous phase between adjacent bilayers and the second is below the glycerol backbone region of bilayer. A membrane thinning above a peptide concentration threshold (1mol%) was found, as was a contiguous transbilayer water channel at the highest peptide concentration (10mol%). This evidence leads to the suggestion that the toroidal pore model might be involved in the transmembrane of TAT peptide. We interpret the surface peptide distribution in the peripheral aqueous phase to be a massive exclusion of TAT peptide from its intrinsic location below the glycerol backbone region of the bilayer, due to the electrostatic attraction between the negatively-charged headgroups of phospholipids and the positively charged TAT peptides. Finally, we propose that the role that negatively-charged headgroups of DOPS lipids play in the transmembrane of TAT peptide is less important than previously thought. 23873165 DIURNAL VARIATION IN CHOROIDAL THICKNESS IN RELATION TO SEX, AXIAL LENGTH, AND BASELINE CHOROIDAL THICKNESS IN HEALTHY KOREAN SUBJECTS. To investigate diurnal variations in choroidal thickness (CT) in relation to various factors in healthy Korean subjects using spectral-domain optical coherence tomography. A prospective study was conducted on 100 healthy volunteers who each underwent measurements of CT in the same subfoveal area using an enhanced depth imaging technique with spectral-domain optical coherence tomography at 8 AM, 11 AM, 2 PM, and 5 PM. Possible correlations between the diurnal variation of CT and other factors, such as sex, axial length (AL), baseline CT (8 AM), blood pressure, and intraocular pressure, were evaluated. One hundred volunteers with a mean age of 30.1 years were scanned. A significant pattern of diurnal variation was observed, with a mean CT of 278.28 ± 91.78 μm at 8 AM, 271.57 ± 89.08 μm at 11 AM, 266.39 ± 86.18 μm at 2 PM, and 264.92 ± 87.10 μm at 5 PM in a right eye. Right eye and left eye had a similar trend of diurnal cycle. Based on sex, AL, and baseline CT, the pattern of diurnal variation was greater and the amplitude significantly was greater in men, AL ≤ 24 mm and baseline CT ≥ 300 μm (men vs. women: P = 0.048, AL ≤ 24 mm vs. AL > 24 mm: P = 0.036, baseline CT ≥ 300 μm vs. baseline CT < 200 μm: P = 0.002, baseline CT ≥ 300 μm vs. 200 μm ≤ baseline CT < 300 μm: P = 0.008). There were no significant correlations between the diurnal variation of CT and systolic blood pressure, diastolic blood pressure, or intraocular pressure. In men as well as in those with a shorter AL and thick baseline CT, a greater pattern of diurnal variation with significantly greater amplitude was observed. 23845998 Phosphorus-based fatty acid methyl esters. With the aim of designing novel transformable fatty acid diesters, various strategies for introducing phosphorus arms to the fatty backbone have been examined. While lithiated phosphine reacts classically to brominated fatty esters to afford the mono-addition product, the synthesis of phosphorylated diesters was found to be difficult, a fact related to the bulkiness of fatty acids and phosphine reagents. A base-induced dehydrochlorination reaction using ArPCl2 and hydroxy-terminated fatty esters resulted in metastable diester for which hydrolytic cleavage undergo phosphine oxidation and expulsion of one fatty chain. Alternatively, ArPOCl2 alleviates this drawback and provides stable, phosphorylated fatty acid diesters. 23685321 Long-term loss of dopamine release mediated by CRF-1 receptors in the rat lateral septum after repeated cocaine administration. The lateral septum (LS) is a brain nucleus associated to stress and drug addiction. Here we show that dopamine extracellular levels in the lateral septum are under the control of corticotrophin releasing factor (CRF). Reverse dialysis of 1μM stressin-1, a type 1 CRF receptor (CRF-R1) agonist, induced a significant increase of LS dopamine extracellular levels in saline-treated rats that was blocked by the co-perfusion of stressin-1 with CP-154526, a specific CRF-R1 antagonist. Repeated cocaine administration (15mg/kg; twice daily for 14 days) suppressed the increase in LS dopamine extracellular levels induced by CRF-R1 activation. This suppression was observed 24h, as well as 21 days after withdrawal from repeated cocaine administration. In addition, depolarization-induced dopamine release in the LS was significantly higher in cocaine-compared to saline-treated rats. Thus, our results show that the activation of CRF-R1 in the LS induces a significant increase in dopamine extracellular levels. Interestingly, repeated cocaine administration induces a long-term suppression of the CRF-R1 mediated dopamine release and a transient increase in dopamine releasability in the LS. 23890047 Protocol for assessing the hypotensive effect of evening administration of acetylsalicylic acid: study protocol for a randomized, cross-over controlled trial. The objective of this study is to evaluate the antihypertensive effect of bedtime administration of low doses of aspirin in patients with treated hypertension and high cardiovascular risk on low-dose aspirin for secondary prevention, in order to optimize their usual treatment and reduce their cardiovascular risk. This is a prospective phase IV multicentre, randomised, triple-blind, placebo-controlled, cross-over clinical trial. We will include 258 individuals with hypertension treated with low-dose aspirin for secondary prevention. These patients will be randomly recruited, by approximately 40 primary care physicians collaborating in the study, mainly in the Guipúzcoa West, Bilbao and Barcelona areas. The 258 patients will be randomly allocated to treatments to create two comparable groups. In the first period, the intervention group will take aspirin at night and placebo in the morning, while the control group will take their aspirin in the morning and placebo in the evening for 2 months. After a washout period of 15 to 30 days, there will be a second 2-month period for which groups will swap treatments. Participants will undergo ambulatory blood pressure monitoring at baseline, at the end of first period and then again at the beginning and end of the second period. The main outcome measure is the change in mean blood pressure over 24 h, and as secondary outcomes we will also assess changes in systolic and diastolic blood pressure, during the day and night, and the relationship between them. Lastly, we will explore whether non-dipper patients convert into dippers with the intervention. The goal of this research is to provide the scientific basis for indicating a change in the time of aspirin administration from morning to evening, by primary health practitioners, to improve the patient control of blood pressure and more effectively reduce their cardiovascular risk, by combining this hypotensive effect with the well-known anti-platelet effect of low-dose aspirin. ClinicalTrials.gov NCT01741922. 23726233 Utility of a microwave surgical instrument in sealing lymphatic vessels. This study assessed the ability of a novel microwave coagulation surgical instrument (MWCX) to seal lymphatic vessels when compared with LigaSure (Valleylab, Boulder, CO), the Harmonic Scalpel (HS; Ethicon Endo-Surgery, Cincinnati, OH), and electric cautery. The burst pressure of pig inguinal lymphatic vessels was assessed after the sealing of vessels with each surgical instrument. The rate of lymphorrhea from pig mesenteric lymphatic vessels was also investigated using indocyanine green and visualized with the Photodynamic Eye system (Hamamatsu Hotoniks, Hamamatsu, Japan). Burst pressures were higher with MWCX (average, 300 mm Hg), LigaSure (average, 290 mm Hg), and HS (average, 253 mm Hg) when compared with electric cautery (average, 152.3 mm Hg; vs MWCX: P = .002, vs LigaSure: P = .002, vs HS: P = .004). The rate of lymphorrhea was significantly lower with LigaSure (13.3%), HS (18.8%), and MWCX (13.3%) when compared with electric cautery (77.3%; vs LigaSure: P < .001, vs HS: P < .001, vs MWCX: P < .001). MWCX was equivalent to LigaSure and HS in terms of the ability to seal lymphatic vessels. 23906773 Detection of synergistic combinations of Baccharis extracts with Terbinafine against Trichophyton rubrum with high throughput screening synergy assay (HTSS) followed by 3D graphs. Behavior of some of their components. Forty four extracts from nine Baccharis spp. from the Caulopterae section were tested in combination with terbinafine against Trichophyton rubrum with the HTSS assay at six different ratios with the aim of detecting those mixtures that produced a ≥50% statistically significant enhancement of growth inhibition. Since an enhanced effect of a combination respective of its components, does not necessarily indicate synergism, three-dimensional (3D) dose-response surfaces were constructed for each selected pair of extract/antifungal drug with the aid of CombiTool software. Ten extracts showed synergistic or additive combinations which constitutes a 22% hit rate of the extracts submitted to evaluation. Four flavonoids and three ent-clerodanes were detected in the active Baccharis extracts with HPLC/UV/ESI-MS methodology, all of which were tested in combination with terbinafine. Results showed that ent-clerodanes but not flavonoids showed synergistic or additive effects. Among them, bacchotricuneatin A followed by bacrispine showed synergistic effects while hawtriwaic acid showed additive effects. 23449501 Ca2+-dependent protein kinase11 and 24 modulate the activity of the inward rectifying K+ channels in Arabidopsis pollen tubes. Potassium (K(+)) influx into pollen tubes via K(+) transporters is essential for pollen tube growth; however, the mechanism by which K(+) transporters are regulated in pollen tubes remains unknown. Here, we report that Arabidopsis thaliana Ca(2+)-dependent protein kinase11 (CPK11) and CPK24 are involved in Ca(2+)-dependent regulation of the inward K(+) (K(+)in) channels in pollen tubes. Using patch-clamp analysis, we demonstrated that K(+)in currents of pollen tube protoplasts were inhibited by elevated [Ca(2+)]cyt. However, disruption of CPK11 or CPK24 completely impaired the Ca(2+)-dependent inhibition of K(+)in currents and enhanced pollen tube growth. Moreover, the cpk11 cpk24 double mutant exhibited similar phenotypes as the corresponding single mutants, suggesting that these two CDPKs function in the same signaling pathway. Bimolecular fluorescence complementation and coimmunoprecipitation experiments showed that CPK11 could interact with CPK24 in vivo. Furthermore, CPK11 phosphorylated the N terminus of CPK24 in vitro, suggesting that these two CDPKs work together as part of a kinase cascade. Electrophysiological assays demonstrated that the Shaker pollen K(+)in channel is the main contributor to pollen tube K(+)in currents and acts as the downstream target of the CPK11-CPK24 pathway. We conclude that CPK11 and CPK24 together mediate the Ca(2+)-dependent inhibition of K(+)in channels and participate in the regulation of pollen tube growth in Arabidopsis. 23628625 Plant bioassay to assess the effects of allelochemicals on the metabolome of the target species Aegilops geniculata by an NMR-based approach. A metabolomic-based approach for the study of allelopathic interactions in the Mediterranean area is proposed using Aegilops geniculata Roth (Poaceae), a Mediterranean herbaceous plant, as test species. Its metabolome has been elucidated by 1D and 2D NMR experiments. Hydroponic plant cultures of A. geniculata were treated with specific compounds of known allelopathic potential: catechol, coumarin, p-coumaric acid, p-hydroxybenzoic acid, ferulic acid and juglone. The metabolic variations due to the presence of allelochemicals have been analyzed and measured. All of the compounds showed the strongest effects at the highest concentration, with coumarin and juglone as the most active compounds, causing an increase of several metabolites. The metabolome changes in test plants confirmed the allelochemicals' reported modes of action. The results demonstrated that the proposed method is a promising tool. It can be applied to plant extracts, making it possible to evidence the metabolites responsible for the activity, as well as their mechanisms of action. 23838560 Soliton driven relaxation dynamics and protein collapse in the villin headpiece. Protein collapse from a random chain to the native state involves a dynamical phase transition. During the process, new scales and collective variables become excited while old ones recede and fade away. The presence of different phases and many scales causes formidable computational bottle-necks in approaches that are based on full atomic scale scrutiny. Here we propose a way to describe the folding and unfolding processes effectively, using only the biologically relevant time and distance scales. We merge a coarse grained Landau theory that models the static collapsed protein in the low-temperature limit with a Glauber protocol that describes finite-temperature relaxation dynamics in a statistical system which is out of thermal equilibrium. As an example we inspect the collapse of a HP35 chicken villin headpiece subdomain, a paradigm specimen in protein folding studies. We simulate the folding and unfolding process by repeated heating and cooling cycles between a given low-temperature, i.e. bad solvent, environment where the protein is collapsed and various different high-temperature, i.e. good solvent, environments. We find that as long as the high temperature value stays below a value in the range that separates the random walk phase from the self-avoiding walk phase, we consistently recover the native state upon cooling. But, when heated to sufficiently high temperatures, the native state practically never recurs. Our result confirms Anfinsen's thermodynamical hypothesis and estimates a temperature range for its validity, in the case of villin. 23736745 CuI-catalyzed and air promoted oxidative cyclization for one-pot synthesis of polyarylated oxazoles. A facile CuI-catalyzed and air promoted oxidative cyclization was developed for the synthesis of polyarylated oxazoles. By virtue of this method, a variety of arylated oxazoles could be easily synthesized from readily available starting materials at room temperature in air. 23888317 Fish oil decreases C-reactive protein/albumin ratio improving nutritional prognosis and plasma Fatty Acid profile in colorectal cancer patients. Previous studies have shown that n-3 polyunsaturated fatty acids n-3 (n-3 PUFA) have several anticancer effects, especially attributed to their ability to modulate a variety of genomic and immune responses. In this context, this randomized, prospective, controlled clinical trial was conducted in order to check whether supplementation of 2 g/day of fish oil for 9 weeks alters the production of inflammatory markers, the plasma fatty acid profile and the nutritional status in patients with colorectal cancer (CRC). Eleven adults with CRC in chemotherapy were randomized into two groups: (a) supplemented (SG) daily with 2 g/day of encapsulated fish oil [providing 600 mg/day of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] for 9 weeks (n = 6), and (b) control (CG) (n = 5). All outcomes were evaluated on the day before the first chemotherapy session and 9 weeks later. Plasma TNF-α, IL-1β, IL-10 and IL-17A, the pro/anti-inflammatory balance (ratio TNF-α/IL-10 and IL-1β/IL10) and serum albumin, showed no significant changes between times and study groups (p > 0.05). C-reactive protein (CRP) and the CRP/albumin ratio showed opposite behavior in groups, significantly reducing their values in SG (p < 0.05). Plasma proportions of EPA and DHA increased 1.8 and 1.4 times, respectively, while the ARA reduced approximately 0.6 times with the supplementation (9 weeks vs baseline, p < 0.05). Patients from SG gained 1.2 kg (median) while the CG lost -0.5 kg (median) during the 9 weeks of chemotherapy (p = 0.72). These results demonstrate that 2 g/day of fish oil for 9 weeks of chemotherapy improves CRP values, CRP/albumin status, plasma fatty acid profile and potentially prevents weight loss during treatment. 23611870 Tumor necrosis factor in traumatic brain injury: effects of genetic deletion of p55 or p75 receptor. The role of tumor necrosis factor (TNF) and its receptors after traumatic brain injury (TBI) remains unclear. We evaluated the effects of genetic deletion of either p55 or p75 TNF receptor on neurobehavioral outcome, histopathology, DNA damage and apoptosis-related cell death/survival gene expression (bcl-2/bax), and microglia/macrophage (M/M) activation in wild-type (WT) and knockout mice after TBI. Injured p55 (-/-) mice showed a significant attenuation while p75 (-/-) mice showed a significant worsening of sensorimotor deficits compared with WT mice over 4 weeks postinjury. At the same time point, contusion volume in p55 (-/-) mice (11.1±3.3 mm(3)) was significantly reduced compared with WT (19.7±3.4 mm(3)) and p75 (-/-) mice (20.9±3.2 mm(3)). At 4 hours postinjury, bcl-2/bax ratio mRNA expression was increased in p55 (-/-) compared with p75 (-/-) mice and was associated with reduced DNA damage terminal deoxynucleotidyl transferaseYmediated dUTP nick end labeling (TUNEL-positivity), reduced CD11b expression and increased Ym1 expression at 24 hours postinjury in p55 (-/-) compared with p75 (-/-) mice, indicative of a protective M/M response. These data suggest that TNF may exacerbate neurobehavioral deficits and tissue damage via p55 TNF receptor whose inhibition may represent a specific therapeutic target after TBI. 23797223 Detection of meningioma metastasis to liver and lung using somatostatin receptor scintigraphy. Extracranial meningioma metastasis is rare. We report a case of a 74-year-old Caucasian man with intracranial recurrence of atypical meningioma treated with a combination of surgical resection and gamma knife radiotherapy over a 4-year period. Somatostatin receptor scintigraphy using In pentreotide for surveillance of tumor recurrence showed multiple pulmonary and hepatic metastases. 23707414 Human T-lymphotropic virus type 1 infective dermatitis in central Australia. The Human T-Lymphotropic Virus type 1 (HTLV-1) is a single-stranded RNA retrovirus that preferentially infects CD4+ T cells. The spectrum of diseases that are associated with the most frequent genotype, the HTLV-1 cosmopolitan subtype A, has been well described. In contrast, very few cases of HTLV-1 related diseases have been reported for the HTLV-1 subtype C variant, which is endemic to Australia and the nearby islands of Melanesia. Here we describe the first case of infective dermatitis associated with the HTLV-1 Australo-Melanesian subtype C. This was complicated by repeated episodes of invasive infection with Staphylococcus aureus and illustrates the life-threatening nature of infective dermatitis among HTLV-1 carriers who live in conditions of social disadvantage. 23830120 Oxidative stress in the kidney injury of mice following exposure to lanthanides trichloride. Environmental pollution from lanthanides (Ln) has been recognized as a major problem due to a grab exploitation of Ln mine in China. Exposure to Ln has been demonstrated to cause the nephrotoxicity, very little is known about the mechanism of oxidative damage to kidney in animals. In order to understand Ln-induced nephrotoxicity, various biochemical and chemical parameters were assayed in mouse kidney. Intragastric exposures of LaCl3, CeCl3, and NdCl3 at doses of 2, 5, and 10mgkg(-1) BW for 90 consecutive days caused nephritis or epithelial cell necrosis and oxidative stress to kidney. An increase in coefficients of the kidney, La, Ce, and Nd accumulation and histopathological changes in the kidney could be observed, followed by increased reactive oxygen species production and peroxidation levels of lipid, protein and DNA, and decreased activities of superoxide dismutase, catalase, glutathione-S-transferase and glutathione reductase as well as antioxidants such as glutathione, ascorbic acid and thiol contents. Furthermore, La, Ce, and Nd significantly suppressed expression of genes and proteins of these antioxidative enzymes in mouse kidney. In addition, kidney functions were disrupted, including an increase of the creatinine, and reductions of uric acid, urea nitrogen, calcium and phosphonium. These findings suggest that nephritis generation or epithelial cell necrosis in mice following exposure to Ln is closely associated with oxidative stress. Of these damages, the most severe was in the Ce(3+)-exposed kidneys, next in the Nd(3+)-exposed kidneys, and the least in the La(3+)-exposed kidneys, which may be attributed to the 4f electron of Ln. 23796961 Over-activation in bilateral superior temporal gyrus correlated with subsequent forgetting effect of Chinese words. We evaluated the subsequent memory and forgotten effects for Chinese using event-related fMRI. Sixteen normal subjects were recruited and performing incidental memory tasks where semantic decision was required during memory encoding. Consistent with previous studies, our results showed bilateral frontal regions as the main locus for the subsequent memory effect. However, contrast between miss and hit responses revealed larger activation in bilateral superior temporal gyrus. We proposed that larger activation in the superior temporal gyrus may reflect alteration of self-monitoring process which resulted in unsuccessful memory encoding for the miss items. 23197374 Selenium (Se) seed priming induced growth and biochemical changes in wheat under water deficit conditions. Insufficient stand establishment at early growth stages in wheat (Triticum aestivum L.) due to drought stress is a major problem that limits overall efficiency and yield of crop. Priming of seed is an effective method for raising seed performance and improving tolerance of crops to abiotic stresses especially drought. The seeds of two local wheat cultivars (Kohistan-97 and Pasban-90) were soaked in distilled water or sodium selenate solutions of 25, 50, 75, and 100 μM for 1/2 or 1 h at 25 °C and later re-dried to their original moisture levels before sowing. One-hour priming significantly increased root length stress tolerance index, dry matter stress tolerance index, and total biomass of seedlings; however, no significant effect of changing duration of Se seed priming was observed on plant height stress tolerance index and shoot/root ratio. Among cultivars, Kohistan-97 was found to be more responsive to Se seed treatment as 1 h priming at 100 μM significantly increased its total biomass by 43 % as compared to control treatment. Although biomass of seedlings was not affected with Se seed priming under normal conditions, but it increased significantly with increase in rates of Se under drought stress conditions. One-hour priming at 75 μM increased the total sugar content and total free amino acids in both wheat cultivars. A more significant decrease in soluble proteins of seedlings was observed by 1 h priming than 1/2 h priming under drought stress conditions. 23777986 The Hsp90 inhibitor SNX-2112, induces apoptosis in multidrug resistant K562/ADR cells through suppression of Akt/NF-κB and disruption of mitochondria-dependent pathways. Heat shock protein 90 (Hsp90) serves as an ATP-dependent molecular chaperone for numerous cell signaling proteins, including many oncogenes and clinically validated cancer targets that are involved in cell proliferation and survival. Recent studies have shown that the Hsp90 inhibitor, SNX-2112, effectively inhibits tumor cell growth and angiogenesis in hematological and solid tumors. However, little is known about the effects of SNX-2112 on leukemias that are resistant to chemotherapy, which is emerging as a major clinical problem. In this study, the effects of SNX-2112 on the multidrug-resistant human chronic myeloid leukemia (CML) K562/ADR cell line were investigated. We observed that SNX-2112 exhibited dose- and time-dependent inhibitory activities against K562/ADR cells. These effects included the induction of apoptosis and secondary necrosis in addition to cell cycle arrest at the G1 and G2 phases. Furthermore, SNX-2112-induced apoptosis was predominantly mediated by the mitochondrial pathway, initiated by the release of cytochrome c and the participation of Bcl-2 family proteins. SNX-2112 also induced the activation of the caspase-3, -8 and -9 cascade and the subsequent cleavage of PARP in K562/ADR cells. Moreover, the inactivation of the Akt and NF-κB signaling pathways may be involved in SNX-2112-induced apoptosis. The expression levels of P-glycoprotein (P-gp) and several chaperons related to drug resistance and apoptosis were also shown to be inhibited, including the Grp78 and Hsp90 isoforms, Grp94 and Trap1. Taken together, these results provide a possible molecular mechanism for the anti-cancer effect of SNX-2112 on K562/ADR cells and provide new insights into the future application of SNX-2112 as a therapeutic agent for anti-multidrug-resistant leukemias. 23377169 Klinefelter's Syndrome and Venous Thrombosis. : Klinefelter's syndrome is the most common cause of primary testicular failure. Previous reports have associated Klinefelter's syndrome with increased risk of thrombosis. The exact cause for this association is unknown, but hypoandrogenism affecting fibrinolysis has been implicated. The authors described a unique patient with Klinefelter's syndrome who presented with deep vein thrombosis of the leg and underlying mutations of MTHFR gene, increased factor VIII coagulant activity and an elevated anticardiolipin antibody. To the authors' knowledge, this combination of hypercoagulability risk factors in such a patient has not been previously reported. The authors also reviewed previously published reports of similar patients and discuss potential genetic mutations that may in part predispose this group of patients to venous thrombosis. 23841690 An immunodominant La/SSB autoantibody proteome derives from public clonotypes. The La/SSB autoantigen is a major target of long-term humoral autoimmunity in primary Sjögren's Syndrome (SS) and systemic lupus erythematosis. A majority of patients with linked anti-Ro60/Ro52/La responses target an NH2-terminal epitope designated LaA that is expressed on Ro/La ribonucleoprotein complexes and the surface membrane of apoptotic cells. In this study, we used high resolution Orbitrap mass spectrometry to determine the clonality, isotype and V-region sequences of LaA-specific autoantibodies in 7 patients with primary SS. Anti-LaA IgGs purified from polyclonal sera by epitope-specific affinity chromatography were analysed by combined database and de novo mass spectrometric sequencing. Autoantibody responses comprised two heavily mutated IgG1 kappa-restricted monoclonal species that were shared (public) across unrelated patients; one clonotype was specified by an IGHV3-30 heavy chain paired with IGKV3-15 light chain and the second by an IGHV3-43/IGKV3-20 pairing. Shared amino acid replacement mutations were also seen within heavy and light chain complementarity-determining regions, consistent with a common breach of B cell tolerance followed by antigen-driven clonal selection. The discovery of public clonotypic autoantibodies directed against an immunodominant epitope on La, taken together with recent findings for the linked Ro52 and Ro60 autoantigens, supports a model of systemic autoimmunity in which humoral responses against protein-RNA complexes are mediated by public sets of autoreactive B cell clonotypes. 23566650 High glucose, insulin and free fatty acid concentrations synergistically enhance perilipin 3 expression and lipid accumulation in macrophages. OBJECTIVE: Perilipin (PLIN) 3, an intracellular lipid droplet (LD)-associated protein, is implicated in foam cell formation. Since metabolic derangements found in metabolic syndrome, such as high serum levels of glucose, insulin and free fatty acids (FFAs), are major risk factors promoting atherosclerosis, we investigated whether PLIN3 expression is affected by glucose, insulin and oleic acid (OA) using RAW264.7 cells. METHODS: Real-time PCR and Western blotting were performed to detect PLIN3 or PLIN2 expression. Oil-red O staining and Lipid Analysis were employed to measure cellular content of triacylglycerides (TAG) and cholesterol. RESULTS: PLIN3 mRNA was stimulated by high glucose or insulin concentrations individually, but not by OA. A combination of any two factors did not enhance PLIN3 expression any more than that evoked by glucose alone at 24h. Interestingly, however, simultaneous addition of all three factors synergistically enhanced the PLIN3 expression. This synergistic effect was not apparent for PLIN2 mRNA expression. Inhibitors of Src family tyrosine kinase and/or phosphatidylinositol 3-kinase, both of which are activated by insulin and FFA signaling, partially suppressed PLIN3 expression induced by the combination of the three factors. While simultaneous addition of glucose, insulin and OA remarkably increased the cellular content of TAG and cholesterol, knocking-down of PLIN3 predominantly reduced TAG content. CONCLUSIONS: These results indicate that PLIN3 expression is synergistically stimulated by high glucose, insulin and FFA concentrations, in parallel with TAG accumulation in macrophages. This finding raises new evidence of PLIN3 involvement in conversion of macrophages into foam cells. 23744592 Comparative proteomics analysis reveals roles for FADD in the regulation of energy metabolism and proteolysis pathway in mouse embryonic fibroblast. Fas-associated death domain-containing protein (FADD) is a classical apoptotic pathway adaptor. Further studies revealed that it also plays essential roles in nonapoptotic processes, which is assumed to be regulated by its phosphorylation. However, the exact mechanisms are still poorly understood. To study the nonapoptotic effects of FADD, a comprehensive strategy of proteomics identification combined with bioinformatic analysis was undertaken to identify proteins differentially expressed in three cell lines containing FADD and its mutant, FADD-A and FADD-D. The cell lines were thought to bear wild-type FADD, unphosphorylated FADD mimic and constitutive phosphorylated FADD mimic, respectively. A total of 47 proteins were identified to be significantly changed due to FADD phosphorylation. Network analysis using MetaCore(TM) identified a number of changed proteins that were involved in cellular metabolic process, including lipid metabolism, fatty acid metabolism, glycolysis, and oxidative phosphorylation. The finding that FADD-D cell line showed an increase in fatty acid oxidation argues that it could contribute to the leaner phenotype of FADD-D mice as reported previously. In addition, six proteins related to the ubiquitin-proteasome pathway were also specifically overexpressed in FADD-D cell line. Finally, the c-Myc gene represents a convergent hub lying at the center of dysregulated pathways, and was upregulated in FADD-D cells. Taken together, these studies allowed us to conclude that impaired mitochondrial function and proteolysis might play pivotal roles in the dysfunction associated with FADD phosphorylation-induced disorders. 22738031 Beyond interference control impairment in ADHD: Evidence from increased intraindividual variability in the color-stroop test. The present study investigates intraindividual variability (IIV) in the Color-Stroop test and in a simple reaction time (SRT) task. Performance level and variability in reaction times (RTs)-quantified with different measures such as individual standard deviation (ISD) and coefficient of variation (ICV), as well as ex-Gaussian parameters (mu, sigma, tau)-were analyzed in 24 children with attention deficit/hyperactivity disorder (ADHD) and 24 typically developing children (TDC). Children with ADHD and TDC presented equivalent Color-Stroop interference effects when mean RTs were considered, and the two groups did not differ in the SRT task. Interestingly, compared to TDC, children with ADHD were more variable in their responses, showing increased ISD and ICV in the Color-Stroop interference condition and in the SRT task. Moreover, children with ADHD exhibited higher tau values-that is, more frequent abnormally long RTs-in the Color-Stroop interference condition than did the TDC, but comparable tau values in the SRT, suggesting more variable responses. These results speak in favor of a general deficit in more basic and central processes that only secondarily may affect the efficiency of inhibitory processes in children with ADHD. Overall the present findings confirm the role of IIV as a cornerstone in the ADHD cognitive profile and support the search for fine-grained analysis of performance fluctuations. 23875716 Lung Function and Respiratory Symptoms in Association with Mortality: The HUNT Study. Abstract Whether respiratory symptoms are associated with mortality independent of lung function is unclear. The authors explored the association of the exposures i) lung function, ii) respiratory symptoms, and iii) lung function and respiratory symptoms combined, with the outcomes all-cause and cardiovascular mortality. The study included 10,491 adults who participated in the Nord-Trøndelag Health Study (HUNT) Lung Study in 1995-1997 and were followed through 2009. Cox regression was used to calculate adjusted hazard ratios (HRs) with 95% confidence intervals for all-cause and cardiovascular mortality associated with pre-bronchodilator% predicted forced expiratory volume in 1 second (ppFEV1), chronic obstructive pulmonary disease (COPD) grades, and respiratory symptoms (chronic bronchitis, wheeze, and levels of dyspnoea). Lung function was inversely associated with all-cause mortality. Compared to ppFEV1 ≥100, ppFEV1 <50 increased the HR to 6.85 (4.46-10.52) in women and 3.88 (2.60-5.79) in men. Correspondingly, compared to normal airflow, COPD grade 3 or 4 increased the HR to 6.50 (4.33-9.75) in women and 3.57 (2.60-4.91) in men. Of the respiratory symptoms, only dyspnoea when walking remained associated with all-cause mortality after controlling for lung function (HR 1.73 [1.04-2.89] in women and 1.57 [1.04-2.36] in men). Analyses of lung function and dyspnoea when walking as a combined exposure further supported this finding. Overall, associations between lung function and cardiovascular mortality were weaker, and respiratory symptoms were not associated with cardiovascular mortality. In conclusion, lung function was inversely associated with all-cause and cardiovascular mortality, and dyspnoea when walking was associated with all-cause mortality independent of lung function. 23772963 Bioconcentration and Biotransformation of Selenite versus Selenate Exposed Periphyton and Subsequent Toxicity to the Mayfly Centroptilum triangulifer. Little is known about the bioaccumulation dynamics, biotransformation processes, or subsequent toxicity to consumers of dissolved selenite (SeO3) versus selenate (SeO4) uptake into aquatic primary producer communities. To address these data gaps, we examined SeO3 and SeO4 bioconcentration into complex freshwater periphyton communities under static and static-renewal conditions. Further, we explored periphyton biotransformation of Se species using X-ray absorption near edge structure (XANES) spectroscopy analysis and changes in the periphyton associated microbial consortium using denaturing gradient gel electrophoresis (DGGE). Last, we fed differentially treated periphyton to the mayfly Centroptilum triangulifer in full life cycle exposures to assess toxicity. Selenite exposed periphyton readily bioconcentrated Se while, in contrast, initial periphyton uptake of SeO4 was negligible, but over time periphyton [Se] increased steadily in conjunction with the formation of dissolved SeO3. XANES analyses revealed that both SeO3 and SeO4 treated periphyton biotransformed Se similarly with speciation dominated by organo-selenide (∼61%). Mayfly survival, secondary production, and time to emergence were similar in both SeO3 and SeO4 treated periphyton exposures with significant adverse effects at 12.8 μg g(-1) ((d.w.) secondary production) and 36 μg g(-1) ((d.w.) survival and development time). Overall, dissolved selenium speciation, residence time, and organisms at the base of aquatic food webs appear to be the principal determinants of Se bioaccumulation and toxicity. 23893617 Acute suppurative thyroiditis following fine-needle aspiration biopsy in an immunocompetent patient. The thyroid gland is remarkably resistant to infectious agents owing to several protective mechanisms. Acute suppurative thyroiditis after fine-needle aspiration (FNA) in an immunocompetent patient is very rare. We report the case of a 50-year-old immunocompetent male patient who presented with painful cervical swelling, fever, and chills after an FNA of the thyroid. His physical and laboratory examination suggested an acute suppurative thyroiditis. Repeat FNA results were consistent with thyroid abscess. Physicians should be aware of the probability of acute bacterial thyroiditis after FNA. © 2013 Wiley Periodicals, Inc. J Clin Ultrasound, 2013. 23874124 Perception on prevention of mother-to-child-transmission (PMTCT) of HIV among women of reproductive age group in Osogbo, Southwestern Nigeria. The fastest growing group of adults living with human immunodeficiency virus (HIV), is women. As more women contract the virus, the number of children infected in utero, intra-partum, and during breastfeeding has been growing. This study assessed the knowledge and attitude of women of child bearing age towards the prevention of mother-to-child-transmission (PMTCT) of HIV. This is a descriptive cross sectional survey of 420 women of the reproductive age group (15-49 years) selected using a multistage sampling technique. Data were obtained using interviewer-administered, pretested, semistructured questionnaires. The data were analyzed using the Statistical Package for Social Sciences (SPSS) software version 15. A high level of awareness about HIV/acquired immunodeficiency syndrome (AIDS) was observed among the respondents (99.8%). The knowledge about MTCT and PMTCT of HIV was high, 92.1% and 91.4%, respectively. However, a significant portion (71.27%) of the study population had poor attitudes towards PMTCT of HIV. Despite the high level of awareness of HIV/AIDS, and good knowledge about MTCT and PMTCT of HIV/AIDS among the respondents, the attitude towards PMTCT is poor. There is need for the involvement of the stakeholders in bridging the gap between knowledge and attitude of prevention of MTCT of HIV among women. 23874399 Gonadotrope-specific expression and regulation of ovine follicle stimulating hormone Beta: transgenic and adenoviral approaches using primary murine gonadotropes. The beta subunit of follicle stimulating hormone (FSHB) is expressed specifically in pituitary gonadotropes in vertebrates. Transgenic mouse studies have shown that enhancers in the proximal promoter between -172/-1 bp of the ovine FSHB gene are required for gonadotrope expression of ovine FSHB. These enhancers are associated with regulation by activins and gonadotropin releasing hormone (GnRH). Additional distal promoter sequence between -4741/-750 bp is also required for expression. New transgenic studies presented here focus on this distal region and narrow it to 1116 bp between -1866/-750 bp. In addition, adenoviral constructs were produced to identify these critical distal sequences using purified primary mouse gonadotropes as an in vitro model system. The adenoviral constructs contained -2871 bp, -750 bp or -232 bp of the ovine FSHB promoter. They all showed gonadotrope-specific regulation since they were induced only in purified primary gonadotropes by activin A (50 ng/ml) and inhibited by GnRH (100 nM) in the presence of activin (except -232FSHBLuc). However, basal expression of all three viral constructs (in the presence of follistatin to block cellular induction by activin) was relatively high in pituitary non-gonadotropes as well as gonadotropes. Thus, gonadotrope-specific regulation associated with the proximal promoter was observed as expected, but the model was blind to distal promoter elements between -2871/-750 necessary for gonadotrope-specific expression of ovine FSHB in vivo. The new adenoviral-based in vitro technique did detect, however, a novel GnRH response element between -750 bp and -232 bp of the ovine FSHB promoter. We conclude that adenoviral-based studies in primary gonadotropes can adequately recognize regulatory elements on the ovine FSHB promoter associated with gonadotrope-specific regulation/expression, but that more physiologically based techniques, such as transgenic studies, will be needed to identify sequences between -1866/-750 bp of the ovine FSHB promoter that are also required for tissue/cell specific expression in vivo. 23872300 IL-6 is a predictive biomarker for stroke associated infection and future mortality in the elderly after an ischemic stroke. Stroke associated infection (within the first seven days) occurs in approximately half of stroke patients and is associated with a worse prognosis, especially in the elderly. It is uncertain what factors predict stroke associated infection, yet identification of a suitable biomarker for infection may allow early and appropriate intervention with antibiotics. The aims of this study were to: a) identify independent risk factors for stroke associated infection, and b) test relationships between these risk factors and mortality at 2years. Eight-two elderly patients were assessed within 72h of stroke. Data on stroke severity (Barthel Index), stroke associated infection and mortality at 2years were collected. Inflammatory biomarkers at baseline and 6months were measured by ELISA. Logistic regression was used to identify risk factors for stroke associated infection and death. Patients with stroke associated infection, especially pneumonia, had increased IL-6, more severe strokes, and higher mortality. IL-6 was independently associated with stroke associated infection (OR=19.2, [95%CI 3.68, 100], p<0.001), after adjustment for other risk factors and cytokines. IL-6 was also independently associated with 2year mortality (OR=9.2, [1.0, 85.1], p=0.031). These data suggest that IL-6 may be a key biomarker for predicting stroke associated infection and mortality in the first two years post stroke. 23426640 CYP2C8*3 polymorphism and donor age are associated with allograft dysfunction in kidney transplant recipients treated with calcineurin inhibitors. Epoxieicosatrienoic acids (EETs) play a protective role against damaging processes in the kidney. We have assessed the effect of polymorphisms in EETs-producing enzymes (CYP2C8 and CYP2J2) and other proteins involved in calcineurin inhibitors (CNIs) disposition (CYP3A4, CYP3A5, and ABCB1) on graft function and clinical outcome in 166 renal transplant recipients treated with CNIs. Both CYP2C8*3 and donor age greater than 48 years were associated to a higher incidence of delayed graft function (DGF) [OR = 2.01 (1.1-4.1), P = .04 and 5.14 (2.4-10.9), P < .0001; respectively] and worse creatinine clearance 1 year after grafting (P < .05 and P < .001, respectively). In addition, carrying 4-6 variants in the 3 ABCB1 loci and older donor age were individually associated to higher incidence of calcineurin-inhibitor-induced nephrotoxicity [OR = 2.38 (1.1-5.4), P = .03 and OR = 1.03 (1.01-1.06), P = .038]. Regression analyses confirmed the relevant effect of both CYP2C8*3 and donor age on graft dysfunction. Carrying the 2C8*3 allele and having a donor older than 48 years was defined as a high-risk status and observed to be highly related to DGF [OR = 3.91 (1.46-10.48), P < .01] and worse creatinine clearance (P = .033). Our results show that genetic and clinical parameters can be combined to identify risk factors for allograft dysfunction in renal transplant recipients. 23739132 Neuropilin-1 biases dendrite polarization in the retina. The majority of neurons in the nervous system exhibit a polarized morphology, with multiple short dendrites and a single long axon. It is clear that multiple factors govern polarization in developing neurons, and the biased accumulation of intrinsic determinants to one side of the cell, coupled with responses to asymmetrically localized extrinsic factors, appears to be crucial. A number of intrinsic factors have been identified, but surprisingly little is known about the identity of the extrinsic signals. Here, we show in vivo that neuropilin-1 (Nrp1) and its co-receptor plexinA1 (Plxna1) are necessary to bias the extension of the dendrites of retinal ganglion cells to the apical side of the cell, and ectopically expressed class III semaphorins (Sema3s) disrupt this process. Importantly, the requirement for Nrp1 and Plxna1 in dendrite polarization occurs at a developmental time point after the cells have already extended their basally directed axon. Thus, we propose a novel mechanism whereby an extrinsic factor, probably a Sema3, acts through Nrp1 and Plxna1 to promote the asymmetric outgrowth of dendrites independently of axon polarization. 23738871 Pressure induced structure formation in Langmuir monolayers of amphiphilic metallocene diblock copolymers. We present in situ structural investigations of a metal-containing diblock copolymer on a water surface. Monolayers of poly(vinylferrocene-b-(2-vinylpyridine)) (PVFc-b-P2VP) block copolymers are studied in a wide range of compositions by varying molar masses of P2VP with two different molecular weights of PVFc. We focus on the role of the respective block partners, PVFc and P2VP, when compressing the layer on the water surface. Compression isotherms are presented and interpreted in terms of the classical gaseous, expanded, and condensed phases. We calculate isothermal compressibilities, which reveal a minimum value independent of the molar masses of the respective block partners. We find the isotherms to be dominated by P2VP while PVFc barely contribute to the compression behavior due to its rather compact coil structure. We consider the diblock copolymer monolayers as a two-dimensional model system, which is reflected by two-dimensional scaling behavior in the semi dilute and condensed regime. By X-ray reflectometry (XR), we monitor in situ the monolayer structure change with increasing surface pressure Π and observe the PVFc-b-P2VP separation at high Π. 23947345 Interferon induction and function at the mucosal surface. Interferons (IFNs) are produced in response to virus infection and induce an antiviral state in virtually all cell types. In addition to upregulating the transcription of genes that inhibit virus replication, type I (or -α/β) IFNs also act to orchestrate the adaptive immune response to virus infection. Recently a new family of antiviral cytokines, the type III (or -λ) IFNs, has been identified that activate the same antiviral pathways via a distinct receptor. Although the identical transcription factor, IFN-stimulated gene factor 3 is activated by either IFN-α/β or IFN-λ signaling, differences in the induction and action of these two cytokine families are beginning to be appreciated. In this article, we review this emerging body of literature on the differing roles these cytokines play in host defense of the mucosal surface. Although many viruses enter the body through the respiratory and gastrointestinal tracts, we have focused the discussion on influenza A virus, respiratory syncytial virus, and rotavirus, three ubiquitous human pathogens that target the epithelial lining and are associated with a major disease burden. 23503441 Systematic review of population pharmacokinetic analyses of imatinib and relationships with treatment outcomes. Several population pharmacokinetic (PPK) analyses of the anticancer drug imatinib have been performed to investigate different patient populations and covariate effects. The present analysis offers a systematic qualitative and quantitative summary and comparison of those. Its primary objective was to provide useful information for evaluating the expectedness of imatinib plasma concentration measurements in the frame of therapeutic drug monitoring. The secondary objective was to review clinically important concentration-effect relationships to provide help in evaluating the potential suitability of plasma concentration values. Nine PPK models describing total imatinib plasma concentration were identified. Parameter estimates were standardized to common covariate values whenever possible. Predicted median exposure (C min) was derived by simulations and ranged between models from 555 to 1388 ng/mL (grand median: 870 ng/mL and interquartile "reference" range: 520-1390 ng/mL). Covariates of potential clinical importance (up to 30% change in pharmacokinetic predicted by at least 1 model) included body weight, albumin, α1 acid glycoprotein, and white blood cell count. Various other covariates were included but were statistically not significant or seemed clinically less important or physiologically controversial. Concentration-response relationships had more importance below the average reference range and concentration-toxicity relationships above. Therapeutic drug monitoring-guided dosage adjustment seems justified for imatinib, but a formal predictive therapeutic range remains difficult to propose in the absence of prospective target concentration intervention trials. To evaluate the expectedness of a drug concentration measurement in practice, this review allows comparison of the measurement either to the average reference range or to a specific range accounting for individual patient characteristics. For future research, external PPK model validation or meta-model development should be considered. 23905540 Propionibacterium acnes: an update on its role in the pathogenesis of acne. In recent years, significant progress has been made in the understanding of the pathophysiological mechanisms of acne and the role of Propionibacterium acnes. With this review, the authors aim to provide an update on the current understanding of the role of P. acnes in the development of acne lesions and analysing the potential implications for future treatments. A total of 188 articles published between January 1980 and March 2013 were searched using key words such as acne, P. acnes, microbiology, Corynebacterium acnes, acne vulgaris, pathogenesis, antibiotic, vaccination and a combination of those key words. From those articles, 77 were analysed in depth. Recent data confirm that P. acnes has a strong proinflammatory activity and targets molecules involved in the innate cutaneous immunity, keratinocytes and sebaceous glands of the pilosebaceous follicle and leads to the development of comedones. Furthermore, the profile of its different strains may differ between healthy subjects and acne patients. The better understanding of the role of P. acnes may allow for new perspectives in the treatment of acne. Novel therapies should target molecules implicated in the activation of innate immunity, including toll-like receptors, protease-activated receptors and topical antimicrobial peptides; the latter may be an alternative to topical antibiotics and thus a solution for limiting bacterial resistance induced by topical macrolides. Vaccines may also be promising. However, the most appropriate candidate remains to be selected. 23528654 Delay in performing ERCP and adverse events increase the 30-day readmission risk in patients with acute cholangitis. Readmission to the hospital within 30 days of discharge (30-day readmission rate) is used as a quality measure. To investigate the incidence and factors that contribute to readmissions in patients with acute cholangitis. Retrospective cohort study. Tertiary-care referral center. Retrospective analysis of consecutive patients admitted to our center for acute cholangitis and ERCP. Incidence and variables associated with 30-day readmission and 1-year mortality. ERCP was successful in 98.8% of patients during the index admission. The 30-day readmission rate was 22.0%. Recurrence of cholangitis was the most common etiology for readmissions (37.8%). Readmission within 30 days was independently associated with failed ERCP or ERCP delayed for >48 hours (odds ratio [OR] 2.47; 95% confidence interval [CI], 1.01-6.07), development of any after-ERCP adverse event (OR 11.0; 95% CI, 3.06-39.30), and the etiology of cholangitis (etiologies not related to stones) (OR 3.3; 95% CI, 1.17-9.18). Every 1-point increase in the Charlson Comorbidity Index score (OR, 1.33; 95% CI, 1.05-1.69) was associated significantly with 1-year mortality. In unadjusted analysis, 30-day readmission after ERCP was associated significantly with 1-year mortality (OR, 2.86; 95% CI, 1.16-7.07). This association, however, was not present after adjustment for other covariates. Retrospective study. Delays in performing ERCP during the index admission, development of after-ERCP adverse events, and etiology of cholangitis not related to stones increased the risk of 30-day readmissions. 23953939 Thought-based interaction with the physical world. Operating a brain-computer interface (BCI) is a skill that individuals must learn. A recent study demonstrated that successful skill acquisition enables human individuals to control telepresence robotic devices in three-dimensional physical space using the non-invasive electroencephalogram (EEG). Although the results are very promising, there is room for improvement in the future. 23688288 Analysing the visible conformational substates of the FK506-binding protein FKBP12. The 1H-15N 2D NMR correlation spectrum of the widely studied FK506-binding protein FKBP12 (FK506-binding protein of 12 kDa) contains previously unreported peak doublings for at least 31 residues that arise from a minor conformational state (12% of total) which exchanges with the major conformation with a time constant of 3.0 s at 43°C. The largest differences in chemical shift occur for the 80's loop that forms critical recognition interactions with many of the protein partners for the FKBP family. The residues exhibiting doubling extend into the adjacent strands of the β-sheet, across the active site to the α-helix and into the 50's loop. Each of the seven proline residues adopts a trans-peptide linkage in both the major and minor conformations, indicating that this slow transition is not the result of prolyl isomerization. Many of the residues exhibiting resonance doubling also participate in conformational line-broadening transition(s) that occur ~105-fold more rapidly, proposed previously to arise from a single global process. The 1.70 Ã… (1 Ã…=0.1 nm) resolution X-ray structure of the H87V variant is strikingly similar to that of FKBP12, yet this substitution quenches the slow conformational transition throughout the protein while quenching the line-broadening transition for residues near the 80's loop. Line-broadening was also decreased for the residues in the α-helix and 50's loop, whereas line-broadening in the 40's loop was unaffected. The K44V mutation selectively reduces the line-broadening in the 40's loop, verifying that at least three distinct conformational transitions underlie the line-broadening processes of FKBP12. 23673006 Systematic analysis of palladium-graphene nanocomposites and their catalytic applications in Sonogashira reaction. Graphene has been modified with palladium nanoparticles (Pd NPs) to develop high performance catalysts for the Sonogashira cross coupling reaction. In this research, graphite oxide (GO) sheets exfoliated from graphite were impregnated with Pd(OAc)2 to prepare Pd(2+)/GO. Thermal treatments of the Pd(2+)/GO in H2 flow at 100°C produced Pd/graphene (Pd/G) nanocomposites. TEM images show that Pd NPs were distributed quite uniformly on the graphene sheet without obvious aggregation, and the mean size of Pd NPs was determined to be less than 2 nm in diameter. Morphological and chemical structures of the GO, Pd(2+)/GO, and Pd/G were investigated using FT-IR, XRD, XPS, and XAFS. The resulting Pd/G showed excellent catalytic efficiency in the Sonogashira reaction and offers significant advantages over inorganic supported catalysts such as simple recovery and recycling. Finally, deactivation process of the Pd/G in recycling was investigated. We believe that the remarkable reactivity of the Pd/G catalyst toward the Sonogashira reaction is attributed to the high degree of the Pd NP dispersion and thus the increased low coordination numbers of smaller Pd NPs. 23891645 A piece of the action: Modulation of sensory-motor regions by action idioms and metaphors. The idea that the conceptual system draws on sensory and motor systems has received considerable experimental support in recent years. Whether the tight coupling between sensory-motor and conceptual systems is modulated by factors such as context or task demands is a matter of controversy. Here, we tested the context sensitivity of this coupling by using action verbs in three different types of sentences in an fMRI study: literal action, apt but non-idiomatic action metaphors, and action idioms. Abstract sentences served as a baseline. The result showed involvement of sensory-motor areas for literal and metaphoric action sentences, but not for idiomatic ones. A trend of increasing sensory-motor activation from abstract to idiomatic to metaphoric to literal sentences was seen. These results support a gradual abstraction process whereby the reliance on sensory-motor systems is reduced as the abstractness of meaning as well as conventionalization is increased, highlighting the context sensitive nature of semantic processing. 23871756 Evaluation of a new rapid test kit to detect hepatitis C virus infection. This study investigated the performance characteristics and diagnostic usefulness of a new rapid device test (RDT) for HCV (SD Bioline, Korea). A total of 200 specimens were used in this study and to assess cross-reactivity, five hepatitis B surface antigen (HBsAg) positive, five anti-hepatitis B surface antibody (anti-HBs) positive, five rheumatoid factor (RF) positive, and six samples from multiple myeloma patients were tested. The early detection capability of the test was assessed using seroconversion panels. Sensitivity and specificity were calculated compared with a recombinant immunoblot assay (RIBA). Sixty-six cases were positive by the RIBA, while 52 cases were positive using the new RDT. The sensitivity and specificity of the new RDT were 78.8% (95% CI: 71.2-86.8%) and 100%, respectively. The kappa value for the agreement between the new RDT and RIBA results was 0.831 (95% CI: 0.746-0.916). The early detection capability of the new RDT and a HCV EIA were similar, with the same window period. The new RDT did not cross-react with HBsAg, anti-HBs, RF and immunoglobulins. In conclusion, the SD Bioline HCV RDT has superior sensitivity and specificity than the GENEDIA(®) HCV Rapid LF that is used in Korea. This assay can be used for HCV screening, especially in small hospitals, without the financial burden of expensive equipment. 23307788 Combined inhibition of mTORC1 and mTORC2 signaling pathways is a promising therapeutic option in inhibiting pheochromocytoma tumor growth: in vitro and in vivo studies in female athymic nude mice. Several lines of evidence, including the recent discovery of novel susceptibility genes, point out an important role for the mammalian target of rapamycin (mTOR) signaling pathway in the development of pheochromocytoma. Analyzing a set of pheochromocytomas from patients with different genetic backgrounds, we observed and confirmed a significant overexpression of key mTOR complex (mTORC) signaling mediators. Using selective ATP-competitive inhibitors targeting both mTORC1 and mTORC2, we significantly arrested the in vitro cell proliferation and blocked migration of pheochromocytoma cells as a result of the pharmacological suppression of the Akt/mTOR signaling pathway. Moreover, AZD8055, a selective ATP-competitive dual mTORC1/2 small molecular inhibitor, significantly reduced the tumor burden in a model of metastatic pheochromocytoma using female athymic nude mice. This study suggests that targeting both mTORC1 and mTORC2 is a potentially rewarding strategy and supports the application of selective inhibitors in combinatorial drug regimens for metastatic pheochromocytoma. 23450039 Detection of infectious bronchitis virus serotypes by reverse transcription polymerase chain reaction in broiler chickens. Infectious bronchitis (IB) is a highly contagious disease of the respiratory and urogenital tract of chickens, caused by infectious bronchitis virus (IBV), a member of the family Coronaviridae. The disease is common throughout the world where chickens are produced commercially. PCR on reverse transcribed RNA is a potent technique for the detection of IBV. In comparison with classical detection methods, PCR-based techniques are both sensitive and fast. Dozens of serotypes and genotypes of IBV have been detected, and many more will surely be reported in future. This research was conducted to identify the infectious bronchitis virus with group specific primers of avian Coronaviruses in Zabol, southeast of Iran. Tracheal swabs were collected from eleven commercial broiler flocks and these swabs were used for RNA extraction. General primers included XCE2+ and XCE2- that amplify all IBV serotypes were used. Primers MCE1+, BCE1+ and DCE1+ was used to amplifying the specific nucleotide sequence of Massachusetts, 4/91 and D274 serotypes, respectively. The results of this study showed that 36.36% of the sampled flocks were positive to IBV by RT-PCR. Moreover, the Massachusetts was the identified serotype of infectious bronchitis virus. The results provide the first molecular evidence for the presence of infectious bronchitis virus and Massachusetts serotype in Zabol. 23283634 Bilateral total knee arthroplasty guidelines: are we there yet? The proportion of bilateral total knee replacements (BTKR) to unilateral total knee replacement (UTKR) in the United States is increasing. From 1990 to 2004, the use of BTKRs more than doubled for the entire civilian population and almost tripled among the female population. BTKRs can be performed in a single-stage or a staged procedure. Supporters of single-stage BTKR point out its low complication rates, high patient satisfaction, and cost-effectiveness. Others strongly believe that BTKR performed during the same anesthetic session is associated with increased morbidity and mortality. Single-stage BTKR surgery aims at reducing the exposure to repeated anesthesia, total hospitalization and recovery time, and cost, while maintaining patient safety and reducing the negative clinical and functional outcomes observed in patients undergoing UTKR or staged BTKR. This article presents the current concepts and controversies around BTKR surgery based on the authors' body of research and a review of the literature. We also present our institutional guidelines for candidates for single-stage BTKR. 23686092 Low temperature Raman study of a liquid crystalline system 4-decyloxy benzoic acid (4DBA). The Raman spectra of a liquid crystalline system, 4-Decyloxy benzoic acid (4DBA) have been recorded at different temperatures within the interval 300-78 K in order to identify the structural changes in crystalline state of a nematogen and to understand the molecular alignment therein. The earlier predicted dimer structure of 4DBA was optimized with DFT method and the theoretical Raman spectra of dimer as well as monomer have been calculated for comparison with the experimental spectra. The mode specific quartic coupling coefficient; A(i,ω) and phonon frequency; ωi have been calculated using temperature dependent anharmonic perturbation theory. The precise band shape analysis of Raman bands at ~807, ~881, ~1255, ~1282, ~1436, ~1576, ~1604, ~2881 and ~3081cm(-1) gives signature of temperature induced slow crystal modification. The structural changes leading to crystal modification have been discussed. 23869949 Differential responses of migratory locusts to systemic RNA interference via double-stranded RNA injection and feeding. The migratory locust, Locusta migratoria, is one of the most destructive agricultural pests and has been widely used as a model system for insect physiology, neurobiology and behavioural research. In the present study, we investigated the effects of RNA interference (RNAi) using two delivery methods for double-stranded RNA (dsRNA) molecules, namely, injection and feeding, to develop a potential new pest control strategy. Our results showed that locusts have a sensitive and systemic response to the injection of dsRNAs in a dose-dependent manner, but do not respond to the feeding of dsRNAs. Further experiments suggested that the ineffectiveness of dsRNA feeding was attributable to the rapid degradation of dsRNA, which was probably induced by nuclease enzymes in the locust midgut. Moreover, we identified almost all the homologous genes involved in the endocytosis-mediated dsRNA uptake from the locust genome, which provided possible clues regarding the dsRNA uptake mechanisms from the intestine to the midgut epithelium. These findings reveal the differential response models of fourth instar locust nymphs to dsRNA delivery methods, contribute to the current understanding of insect RNAi mechanisms and provide important information for the further application of RNAi as a genetic tool and pest control strategy. 23668915 It may be possible to delay the onset of neurodegenerative diseases with an immunosuppressive drug (rapamycin). Rapamycin might have beneficial effects, some of them acting via autophagy, in several cellular, fly and mouse models of degenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and dominant spinocerebellar atrophy (SCA). Other more sophisticated mechanisms have been described such as intervention in cell signaling and cell transcription particularly related to PD. Yet AD, PD, HD and SCA3 are chronic degenerative diseases, and chronic administration of rapamycin at advanced clinical stages may result in deleterious systemic effects due to chronic inhibition of mammalian target of rapamycin (mTOR). Studies are needed to uncover more specific inhibitors of particular mTOR signaling pathways, and to establish realistic guidelines for treatment at early stages of neurodegenerative processes. 23703865 A reductionist mechanistic model for bioconcentration of neutral and weakly polar organic compounds in fish. The bioconcentration factor (BCF) of neutral and weakly polar organic chemicals in fish is modeled using independently calibrated models of chemical partitioning (freely dissolved fraction of chemical in the aqueous phase [φsys ] and wet-weight fish-water partition coefficient [KFW ]), respiratory exchange (respiratory update rate constant [k1 ], and respiratory elimination rate constant [k2  = k1 /KFW ]), and biotransformation (whole-body biotransformation rate constant [kM ]) as BCF = φsys KFW /(1 + kM /k2 ). Existing k1 models tend to overestimate for chemicals with log KOW  < 3.5, which constituted 30% to 50% of the examined chemicals. A revised k1 model covering a wider log KOW range (0-8.5) is presented k1  = (5.46 × 10(-6) MW + 0.261/KOW )(-1) , where MW is the molecular weight. The biotransformation rate constant kM is modeled using biota internal partitioning and Abraham parameters as reactivity descriptors. The reductionist model was tested using 3 different BCF data sets (US Environmental Protection Agency's Estimation Programs Interface [EPI], n = 548; Hertfordshire, n = 210; Arnot-Gobas, n = 1855) and compared with the following 3 state-of-the-art models: 1) the EPI Suite BCFBAF module, 2) the European Commision's Computer Assisted Evaluation of industrial chemical Substances According to Regulations (CAESAR), and 3) the EPI/Arnot mechanistic kinetic model. The reductionist model performed comparably with the alternative models (root mean square errors [RMSEs] = 0.72-0.77), with only 5 fitting parameters and no training against experimental BCFs. Respiratory elimination and biotransformation dominate the total depuration (i.e., [k2  + kM ]/kT  ≥ 0.8) for approximately 98% of the data entries, thus validating the reductionist approximation. Mechanistic models provide greater insights into bioaccumulation and are more sensitive to biological variation. All three BCF data sets and relevant properties and checkpoint values necessary for reproducing predictions of the reductionist model have been documented. The present study shows that a streamlined mechanistic model of BCF is possible for assessment purposes. Environ Toxicol Chem 2013;32:2089-2099. © 2013 SETAC. 23669864 A micro-rheological method for determination of blood type. The measurement of time and distance can be used for determining agglutination in small (nL) samples of liquid. We demonstrate the use of this new scheme of detection in typing and subtyping blood in a simple microfluidic system that monitors the speed of flow of microdroplets. The system (i) accepts small samples of liquids deposited directly onto the chip, (ii) forms droplets on demand from these samples, (iii) merges the droplets, and (iv) measures their speed in a microchannel. A sequence of measurements on different combinations of blood and antibodies can thus be used to determine blood type with the estimated probability of mistyping being less than 1 in a million tests. In addition, in the agglutinated samples, red blood cells concentrate at the rear of the droplets yielding an additional vista for detection and suggesting a possible mechanism for separations. 23857727 Gabapentin-induced pharmacodynamic effects in the spinal nerve ligation model of neuropathic pain. The function of brain networks can be changed in a maladaptive manner in response to chronic neuropathic pain. Analgesics can reduce pain by acting on such networks via direct or indirect (peripheral or spinal) mechanisms. This investigation aimed to map gabapentin's pharmacodynamics (PD) in the rodent brain following induction of neuropathic pain in order to further understand its PD profile. Pharmacological magnetic resonance imaging (phMRI) and a novel functional connectivity analysis procedure were performed following vehicle or gabapentin treatment in the rat spinal nerve ligation (SNL) model of neuropathic pain as well as sham animals. phMRI performed in SNL animals revealed robust gabapentin-induced responses throughout the hippocampal formation, yet significant (p < 0.05, corrected for multiple comparisons) responses were also measured in other limbic structures and the sensorimotor system. In comparison, sham animals displayed weaker and less widespread phMRI signal changes subsequent to gabapentin treatment. Next, communities of networks possessing strong functional connectivity were elucidated in vehicle-treated SNL and sham animals. We observed that SNL and sham animals possessed distinct functional connectivity signatures. When measuring how gabapentin altered the behaviour of the discovered networks, a decrease in functional connectivity driven by gabapentin was not only observed, but the magnitude of this PD effect was greater in SNL animals. Using phMRI and functional connectivity analysis approaches, the PD effects of gabapentin in a preclinical neuropathic pain state were characterized. Furthermore, the current results offer insights on which brain systems gabapentin directly or indirectly acts upon. 23369154 Acute Radiation Esophagitis Caused by High-dose Involved Field Radiotherapy with Concurrent Cisplatin and Vinorelbine for Stage III Non-small Cell Lung Cancer. Purpose of this study is to obtain dose-volume histogram (DVH) predictors and threshold values for radiation esophagitis caused by high-dose involved field radiotherapy (IFRT) with concurrent chemotherapy in patients with stage III non-small cell lung cancer (NSCLC). Thirty-two patients treated by 66 Gy/33 Fr, 72 Gy/36 Fr, and 78 Gy/39 Fr thoracic radiotherapy without elective nodal irradiation plus concurrent cisplatin and vinorelvine were reviewed. Acute radiation esophagitis was evaluated according to common terminology criteria for adverse events version 4.0, and correlations between grade 2 or worse radiation esophagitis and DVH parameters were investigated. Grade 0-1, 2, 3, and 4-5 of radiation esophagitis were seen in 11 (34.4%), 20 (62.5%), 1 (3.1%), and 0 (0%) of the patients, respectively. Multivariate analysis revealed that whole esophagus V35 is a predictor of radiation esophagitis (OR = 0.74 [95%CI; 0.60-0.91], p = 0.006). There is a significant difference (38.4% vs. 89.4%, p = 0.027) in the cumulative rates of acute esophagitis according to V35 values of more than 20% versus less. As compared with other factors concerning patient and tumor and treatment factors, V35 ≤ 20% of the esophagus was an independent predictor (HR 5 0.29 [95%CI; 0.09-0.85], p 5 0.025). In conclusion, whole esophagus V35 < 20% is proposed in high-dose IFRT with concurrent chemotherapy for stage III NSCLC patients. 23157626 Recent developments in neurochemical imaging in schizophrenia: an update. The advent of neurochemical brain imaging methods has provided an opportunity to study the neurochemistry of the human brain in normal and abnormal development. The aim of this article is to provide an update on recent major developments in neurochemical imaging in schizophrenia research. In this concise review, we discuss the major findings on three neurotransmitters, namely dopamine, serotonin and glutamate. The most promising radioligand for D(2)/D(3) neuroreceptor imaging is the agonist [(11)C]PHNO, with higher in vivo affinity for D(3) than D(2) receptors, which can be used to measure amphetamine-induced release of dopamine, and therefore a potential model of dopaminergic alterations in schizophrenia. Recent development of selective radiotracers allow imaging of the serotonin transporter (SERT) using positron emission tomography (PET) with selective tracers such as [(11)C]DASB. Additionally, the glutamatergic hypothesis has evolved from theory to phase III clinical trials of newer agents with novel mechanisms. With the development of newer radioligands and the in vivo application of magnetic resonance spectroscopy (MRS) at relatively high magnetic field strengths, there is ample scope for further neuroimaging advances. 23643845 Synthetic pathway to 22,23-dioxocholestanic chain derivatives and their usefulness for obtaining brassinosteroid analogues. Recognizing the functionality of the pentacyclic steroidal derivative 7a as important synthon to obtain new brassinosteroid analogs, we have accomplished the derivatization of hecogenin, a sapogenin from the 25R serie containing a carbonyl group at C-12, to a 22,23-dioxocholestanic chain derivative. Starting from hecogenin acetate (5a) or hecogenin tosylate (5b), we obtained two pentacyclic derivatives (7a and 7b) which were subjected to an oxidation reaction on the double bond at C-12(23) to obtain a 22,23-dioxocholestanic chain, with the regeneration of the carbonyl group at C-12. Reduction of the carbonyl groups lead to the 20-epi-12,23-dihydroxy-22-oxo system 11a-b. The absolute configuration of compound 11a was established by X-ray diffraction analysis. 23706356 Clinical course of asymmetric motor performance and deformational plagiocephaly in very preterm infants. To describe the clinical courses of positional preference and deformational plagiocephaly up to 6 months corrected age (CA) in infants born at gestational age <30 weeks or birth weight <1000 g, and to explore predictive factors for the persistence of these phenomena. A total of 120 infants were examined 3 times each. The presence of deformational plagiocephaly and a score of 0-6 on an asymmetry performance scale served as outcome measures at 6 months CA. Predictive factors were determined using regression analysis. The prevalence of a positional preference of the head was 65.8% (79 of 120) at term-equivalent age (TEA) and 36.7% (44 of 120) at 3 months CA and that of deformational plagiocephaly was 30% (36 of 120) at TEA and 50% (60 of 120) at 3 months CA. At 6 months CA, 15.8% of the infants (19 of 120) scored ≥2 of a possible 6 on the asymmetry performance scale and 23.3% (28 of 120) had deformational plagiocephaly. Sleeping in the supine position was predictive of an asymmetric motor performance at 6 months CA. Chronic lung disease and/or slow gross motor maturation at 3 months CA predicted the persistence of deformational plagiocephaly. Infants born very preterm may develop deformational plagiocephaly. A positional preference of the head at TEA seems to be a normal aspect of these infants' motor repertoire, with limited ability to predict persistence of an asymmetric motor performance. The decreased prevalence of deformational plagiocephaly between 3 and 6 months CA indicates an optimistic course. Infants with a history of chronic lung disease and/or slow gross motor maturation merit timely intervention. 22886740 The effect of methylmercury exposure on behavior and cerebellar granule cell physiology in aged mice. Epidemiology studies have clearly documented that the central nervous system is highly susceptible to methylmercury toxicity, and exposure to this neurotoxicant in humans primarily results from consumption of contaminated fish. While the effects of methylmercury exposure have been studied in great detail, comparatively little is known about the effects of moderate to low dose methylmercury toxicity in the aging central nervous system. We examined the toxic effects of a moderate dose of methylmercury on the aging mouse cerebellum. Male and female C57BL/6 mice at 16-20 months of age were exposed to methylmercury by feeding a total dose of 5.0 mg kg(-1) body weight and assessed using four behavioral tests. Methylmercury-treated aged mice performed significantly worse in open field, footprint analysis and the vertical pole test compared with age-matched control mice. Isolated cerebellar granule cells from methylmercury-treated aged mice exhibited higher levels of reactive oxygen species and reduced mitochondrial membrane potentials, but no differences in basal intracellular calcium ion levels compared with age-matched control mice. When aged mice were exposed to a moderate dose of methylmercury, they exhibited a similar degree of impairment when compared with young adult mice exposed to the same moderate dose of methylmercury, as reported in earlier studies from this laboratory. Thus, at least in mice, exposure of the aged brain to moderate concentrations methylmercury does not pose greater risk compared with the young adult brain exposed to similar concentrations of methylmercury. Copyright © 2012 John Wiley & Sons, Ltd. 23926118 Phosphoproteomics Study Based on In Vivo Inhibition Reveals Sites of Calmodulin-Dependent Protein Kinase II Regulation in the Heart. The multifunctional Ca(2+)- and calmodulin-dependent protein kinase II (CaMKII) is a crucial mediator of cardiac physiology and pathology. Increased expression and activation of CaMKII has been linked to elevated risk for arrhythmic events and is a hallmark of human heart failure. A useful approach to determining CaMKII's role therein is large-scale analysis of phosphorylation events by mass spectrometry. However, current large-scale phosphoproteomics approaches have proved inadequate for high-fidelity identification of kinase-specific roles. The purpose of this study was to develop a phosphoproteomics approach to specifically identify CaMKII's downstream effects in cardiac tissue. To identify putative downstream CaMKII targets in cardiac tissue, animals with myocardial-delimited expression of the specific peptide inhibitor of CaMKII (AC3-I) or an inactive control (AC3-C) were compared using quantitative phosphoproteomics. The hearts were isolated after isoproterenol injection to induce CaMKII activation downstream of β-adrenergic receptor agonist stimulation. Enriched phosphopeptides from AC3-I and AC3-C mice were differentially quantified using stable isotope dimethyl labeling, strong cation exchange chromatography and high-resolution LC-MS/MS. Phosphorylation levels of several hundred sites could be profiled, including 39 phosphoproteins noticeably affected by AC3-I-mediated CaMKII inhibition. Our data set included known CaMKII substrates, as well as several new candidate proteins involved in functions not previously implicated in CaMKII signaling. 23711247 Abide with me: religious group identification among older adults promotes health and well-being by maintaining multiple group memberships. Objectives: Aging is associated with deterioration in health and well-being, but previous research suggests that this can be attenuated by maintaining group memberships and the valued social identities associated with them. In this regard, religious identification may be especially beneficial in helping individuals withstand the challenges of aging, partly because religious identity serves as a basis for a wider social network of other group memberships. This paper aims to examine relationships between religion (identification and group membership) and well-being among older adults. The contribution of having and maintaining multiple group memberships in mediating these relationships is assessed, and also compared to patterns associated with other group memberships (social and exercise). Method: Study 1 (N = 42) surveyed older adults living in residential care homes in Canada, who completed measures of religious identity, other group memberships, and depression. Study 2 (N = 7021) longitudinally assessed older adults in the UK on similar measures, but with the addition of perceived physical health. Results: In Study 1, religious identification was associated with fewer depressive symptoms, and membership in multiple groups mediated that relationship. However, no relationships between social or exercise groups and mental health were evident. Study 2 replicated these patterns, but additionally, maintaining multiple group memberships over time partially mediated the relationship between religious group membership and physical health. Conclusion: Together these findings suggest that religious social networks are an especially valuable source of social capital among older adults, supporting well-being directly and by promoting additional group memberships (including those that are non-religious). 23855638 Obstetrical complications associated with first-trimester screening markers in twin pregnancies. The aim of this retrospective study was to investigate the relation between perinatal complications in twin pregnancies and the combination of first-trimester maternal serum pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotrophin (β-hCG) levels. The study was conducted at the Perinatology Department of Baskent University between January 2005 and December 2011. In total, 104 patients with twin pregnancies were recruited. The association of first-trimester maternal serum-screening markers with perinatal complications was investigated for small-for-gestational-age (SGA) fetuses or intrauterine growth restriction (IUGR), preterm delivery (before 34 weeks of gestation), pregnancy-induced hypertension (PIH), and growth discordance between fetuses. Low serum PAPP-A (below 10th percentile) levels were not correlated with preterm labor, PIH, or IUGR in twin gestations. Elevated free β-hCG levels (>90th percentile) were linked to increased rates of PIH and small-for-gestational-age fetuses or IUGR. Elevated first-trimester free β-hCG was related to adverse pregnancy outcomes in twin pregnancies, whereas low PAPP-A levels were not linked to adverse pregnancy outcomes. 23681315 Design and synthesis of Pd-MnO2 nanolamella-graphene composite as a high-performance multifunctional electrocatalyst towards formic acid and methanol oxidation. One great challenge in the development of portable fuel cell systems is to explore novel electrocatalysts with better performance and lower costs. Here we report a facile strategy to fabricate a ternary nanocomposite based on Pd/MnO2 nanolamella-graphene sheets (Pd/MNL/GS) and demonstrate its application as a multifunctional catalyst for both the direct formic acid fuel cell (DFAFC) and direct methanol fuel cell (DMFC). The developed route rationally utilizes graphene as both a green reducing agent in the synthesis of MnO2 nanolamella and a superior supporting material for growing and supporting Pd nanoparticles (NPs). Whether for formic acid oxidation or methanol oxidation, the as-prepared Pd/MNL/GS hybrid has extremely large electrochemically active surface area (ECSA) values and exhibits significantly high forward peak current densities, both of which are nearly 3 times greater than those of the Pd/GS catalyst and 6 times the Pd/Vulcan XC-72 catalyst, revealing that metal Pd can be effectively utilized in the presence of promoter components (MNL and GS). Therefore, such a ternary composite with a sophisticated 2D configuration may bring new design opportunities of high-performance energy conversion devices in the future. 22669006 Candida fermentati: a rare yeast involved in fungal keratitis. The aim of this study was to report a rare case of fungal keratitis from Eastern India. This is a case report. A 52-year-old man with a history of minor trauma presented with a total corneal ulcer and hypopyon in the left eye. Microbiologic examination of corneal scrapings showed yeast cells in direct smear and typical yeast colonies on multiple solid agar media. Identification of the organism isolated in the culture was performed using the D1/D2 region of the large subunit (LSU 28S rDNA)-based molecular technique. Polymerase chain reaction amplified a band with a sequence that was 100% homologous with that of Candida fermentati. The organism was susceptible to amphotericin B and anidulafungin and demonstrated resistance to voriconazole, itraconazole, and fluconazole. Therapeutic keratoplasty was performed, followed by the recurrence of the infection in the graft, which was controlled with topical and intracameral amphotericin B. At the end of 3 months, the affected eye had developed phthisis bulbi. This is the first report of isolation of C. fermentati, a species closely related to Candida guilliermondii, from keratitis. Molecular diagnostic techniques are helpful in the accurate identification of this organism, which is clinically important in view of an antifungal susceptibility pattern that differs from that of other yeasts and for selection of appropriate therapy. 23606621 Virological and immunological mechanisms in the pathogenesis of human T-cell leukemia virus type 1. Human T-cell leukemia virus type 1 (HTLV-1) was the first retrovirus shown to cause human disease, such as adult T-cell leukemia and HTLV-1 associated myelopathy/tropic spastic paraparesis. HTLV-1 mainly infects CD4 T cells and deregulates their differentiation, function and homeostasis, which should contribute to the pathogenesis of HTLV-1, for example, inducing transformation of infected CD4 T cells and chronic inflammatory diseases. Therefore, not only virological approach but also immunological approach regarding CD4 T cells are required to understand how HTLV-1 causes related human diseases. This review focuses on recent advances in our understanding of the interaction between HTLV-1 and the main host cell, CD4 T cells, which should provide us some clue to the mechanisms of HTLV-1 mediated pathogenesis. Copyright © 2013 John Wiley & Sons, Ltd. 22995722 Importance of atrial surface area and refractory period in sustaining atrial fibrillation: Testing the critical mass hypothesis. The critical mass hypothesis for atrial fibrillation (AF) was proposed in 1914; however, there have been few studies defining the relationship between atrial surface area and AF. This study evaluated the effect of tissue area and effective refractory period (ERP) on the probability of sustaining AF in an in vivo model. Domestic pigs (n = 9) underwent median sternotomy. Epicardial activation maps were constructed from bipolar electrograms recorded from form-fitting electrode templates placed on the atria. Baseline ERPs were determined. ERP was lowered with a continuous infusion of acetylcholine (0.005-0.04 mg/Kg/min) until AF could be sustained after burst pacing. The atria were sequentially partitioned using bipolar radiofrequency ablation. ERPs were lowered using acetylcholine until AF could be sustained in each subdivision of atrial tissue. Each subdivision was further divided until AF was no longer inducible. At study completion, the heart was excised and the surface area of each section was measured. Over a range of ERPs from 75 to 250 ms, the probability of AF was correlated with increasing tissue area (range, 19.5-105 cm(2)) and decreasing ERP. Logistic regression analysis identified shorter ERP (P < .001) and larger area (P = .006) as factors predictive of an increased probability of sustained AF (area under the curve of the receiver-operator characteristic = 0.878). The probability of sustained AF was significantly associated with increasing tissue area and decreasing ERP. These data may lead to a greater understanding of the mechanism of AF and help to design better interventional procedures. 23880194 Critical limb ischaemia is characterised by an increased production of whole blood reactive oxygen species and expression of TREM-1 on neutrophils. Atherosclerosis is a chronic inflammatory process involving polymorphonuclear neutrophils (PMN) and formation of reactive oxygen species (ROS). The aim of the present study was to investigate the phenotype of inflammatory cells in regard to the expression of triggering receptor expressed on myeloid cells (TREM)-1 and its soluble form (sTREM-1) as well as its relationship with oxidative stress in peripheral artery disease (PAD) patients. In total 90 patients with PAD (N = 30 intermittent claudication (IC) > 300 m absolute walking distance, N = 30 IC < 300 m absolute walking distance, N = 30 critical limb ischaemia (CLI)) and 30 control persons were included. ROS formation was measured at basal or stimulated conditions using the luminol analogue L-012 chemiluminescence. Peripheral blood leucocytes were analysed from whole blood by flow cytometry using different gating strategies to identify PMN and monocytes and analyse TREM-1 expression. CLI patients showed a significant higher ROS production at basal levels (p < 0.05) and upon stimulation with PDBu (p < 0.0001), LPS (p < 0.05) and zymosan A (p < 0.0001). TREM-1 was expressed significantly more on PMN of CLI patients (p < 0.01) in comparison to all other groups, whereas monocytic expression of TREM-1 was similar between all 4 groups. The serum concentration of its soluble form sTREM-1 however was increased in CLI and IC < 300 m patients (p < 0.0001). sTREM-1 concentrations correlated with basal ROS levels as wells with ROS production upon stimulation. Furthermore, we found the walking distance of IC patients to inversely correlate with sTREM-1 (rs = - 0.29; p = 0.03). We found an increased oxidative stress as well as an increased expression of TREM-1 and serum levels of sTREM-1 in patients with CLI. IC < 300 m patients showed a similar patter in regard to oxidative stress, TREM-1 expression and sTREM-1 concentration. Thus, sTREM-1 might represent a potential inflammatory biomarker to evaluate the severity of PAD. Whether this implies the potential for therapeutic recommendations, i.e. conservative vs. interventional/operative treatment, or a possibility to monitor the efficacy of interventions, requires further studies. 23397230 Butyric acid retention in gingival tissue induces oxidative stress in jugular blood mitochondria. Butyric acid (BA) is a major extracellular metabolite produced by anaerobic periodontopathic bacteria and is commonly deposited in the gingival tissue. BA induces mitochondrial oxidative stress in vitro; however, its effects in vivo were never elucidated. Here, we determined the effects of butyric acid retention in the gingival tissues on oxidative stress induction in the jugular blood mitochondria. We established that BA injected in the rat gingival tissue has prolonged retention in gingival tissues. Blood taken at 0, 60, and 180 min after BA injection was used for further analysis. We isolated blood mitochondria, verified its purity, and measured hydrogen peroxide (H2O2), heme, superoxide (SOD), and catalase (CAT) to determine BA effects. We found that H2O2, heme, SOD, and CAT levels all increased after BA injection. This would insinuate that mitochondrial oxidative stress was induced ascribable to BA. 23291215 Clinical outcome of early glottic carcinoma in Serbia. Proposed methods for treating early glottic carcinoma are cordectomy through laryngofissure, laser cordectomy, and radiotherapy. The aim of the study was to conduct comprehensive study to evaluate oncological and functional results of different treatment modalities for Tis and T1 glottic carcinoma, identify prognostic factors for the outcome of treatment and decide where we stand in applying worldwide standards of early glottic carcinoma treatment. Prospective study was conducted on 221 patients treated with Tis and T1 glottic carcinoma from 1998 to 2003 (72 patients were treated endoscopically with CO2 laser, 75 patients with cordectomy through laryngofissure and 74 with radiotherapy), with follow-up period from 38 to 107 months. Important demographic and clinical variables were analyzed. Voice quality after the treatment was assessed using multidimensional voice analysis. Comparing oncological results of three modalities of treatment, there were no significant differences. Functional results of treatment were better after laser cordectomy and primary radiotherapy than following the open cordectomy. Five-year survival rate was almost identical in all three groups of patients, and important prognostic factors for survival were age and histological grade of the tumor. Considering that the choice of treatment in our country is also greatly influenced by other paramedical factors, such as distance from treatment facility, reliability of follow-up, significant time delay of radiotherapy because of small number of radiology centers and strong patients' surgeon and treatment preference, we consider endoscopic laser surgery highly efficient and preferred choice of treatment for early glottic carcinoma. 23793336 Molecular characterization of Ascaridia galli infecting native chickens in Egypt. Family: Ascaridae as a whole is distributed among Africa and adjacent regions and in many areas of the world. The nematode Ascaridia galli is one of the most pathogenic and economically important parasites of poultry. The adult affect the small intestine of the hosts feeding on digested food materials. Its control costs million dollars annually. The genomic DNA was extracted from nematode parasites, A. galli, from specific host, native chickens. The polymerase chain reaction (PCR) was applied to ensure that the DNA content aids in the further studies. Two primers were used in the PCR reactions. The two primers were screened, only the second primer gave total amplified fragment markers 818 bp. The gene sequences obtained from Egyptian A. galli was compared with another one of accession number (AY587609) showing that the sequence was similar in some points from 346 to 1244 sequence, to make a phylogenetic relationships of A. galli with other nematodes on the data base showing that it was to some extent similar to Heterorhabditis spp. 23528746 Validation of a novel semi-automated method for three-dimensional surface rendering of condyles using cone beam computed tomography data. Morphological changes of the condyles are often observed following orthognathic surgery. In addition to clinical assessment, radiographic evaluation of the condyles is required to distinguish the physiological condylar remodelling from pathological condylar resorption. The low contrast resolution and distortion of greyscale values in cone beam computed tomography (CBCT) scans have impeded an accurate three-dimensional (3D) rendering of the condyles. The current study proposes a novel semi-automated method for 3D rendering of condyles using CBCT datasets, and provides a clinical validation of this method. Ten patients were scanned using a standard CBCT scanning protocol. After defining the volume of interest, a greyscale cut-off value was selected to allow an automatic reconstruction of the condylar outline. The condylar contour was further enhanced manually by two independent observers to correct for the under- and over-contoured voxels. Volumetric measurements and surface distance maps of the condyles were computed. The mean within-observer and between-observer differences in condylar volume were 8.62 mm(3) and 6.13 mm(3), respectively. The mean discrepancy between intra- and inter-observer distance maps of the condylar surface was 0.22 mm and 0.13 mm, respectively. This novel method provides a reproducible tool for the 3D rendering of condyles, allowing longitudinal follow-up and quantitative analysis of condylar changes following orthognathic surgery. 22887850 Changes in estimated right ventricular systolic pressure predict mortality and pulmonary hypertension in a cohort of scleroderma patients. Annual echocardiography screening is widely used in scleroderma, but the utility of longitudinal assessment is unknown. We evaluated whether change in right ventricular systolic pressure (RVSP) was a risk factor for mortality and development of pulmonary arterial hypertension (PAH) in a cohort of scleroderma patients. The study population consisted of scleroderma patients who had at least three echocardiograms and pulmonary function tests (PFTs) over ≥1 year as part of routine care. The annual rate of change in RVSP was determined for each subject. Cox proportional hazards regression was performed to assess the association between PAH and mortality and change in RVSP/year, adjusted for relevant covariates. 613 scleroderma patients with 3244 echocardiograms were studied. The adjusted relative hazards of PAH and mortality were 1.08 (95% CI 1.05-1.11) and 1.12 (95% CI 1.08-1.15) per 1 mm Hg increase in RVSP/year, respectively. Compared with patients with a stable RVSP, the relative hazards for the development of PAH were 1.90 (95% CI 0.91-3.96), 5.09 (95% CI 2.53-10.26) and 6.15 (95% CI 3.58-10.56) for subjects whose RVSP increased at rates of 1-1.99, 2-2.99 and 3+ mm Hg/year. Compared with the same reference group, the relative hazards for death were 0.92 (95% CI 0.48-1.73), 2.16 (95% CI 1.16-4.01) and 5.05 (95% CI 3.47-7.34) for subjects whose RVSP increased at rates of 1-1.99, 2-2.99 and 3+ mm Hg/year. In a population of scleroderma patients, the rate of increase in RVSP is a risk factor for mortality and PAH even after adjustment for clinical characteristics and longitudinal PFT data. 23722499 A Series of New Medium-Bandgap Conjugated Polymers Based on Naphtho[1,2-c:5,6-c]bis(2-octyl-[1,2,3]triazole) for High-Performance Polymer Solar Cells. A series of novel conjugated copolymers based on naphtho[1,2-c:5,6-c]bis(2-octyl-[1,2,3]triazole) (TZNT) are synthesized. These copolymers exhibit medium bandgaps of ≈1.9 eV. One of them demonstrates a high performance of up to 6.10% power conversion efficiency in a bulk-heterojunction (BHJ) solar-cell device. The performance can be further enhanced to 7.11% when applied in an inverted device architecture, using PF3 N-OX as an interfacial modifier. 23894189 Protection against type 1 diabetes upon Coxsackievirus B4 infection and iNKT cell stimulation: role of suppressive macrophages. iNKT cells belong to the innate immune system and exercise a dual role as potent regulators of autoimmunity and also participants in responses against different pathogens. They have been shown to prevent type 1 diabetes development and promote antiviral responses. Many studies on the implication of environmental factors on the etiology of type 1 diabetes have suggested a link between enteroviral infections and the development of this disease. Our study using the pancreatropic enterovirus Coxsackievirus B4 (CVB4) shows that while infection accelerated type 1 diabetes development in a subset of pro-insulin 2 deficient (Pro-ins2(-/-)) NOD mice, the activation of iNKT cells by a specific agonist, α-Galactosylceramide (αGalCer), at the time of infection, inhibited the disease. Diabetes development was associated with the infiltration of pancreatic islets by inflammatory macrophages producing high levels of IL-1β, IL-6 and TNF-α and activation of anti-islet T cells. On the contrary, macrophages infiltrating the islets after CVB4 infection and iNKT cell stimulation expressed a number of suppressive enzymes, among which IDO was sufficient to inhibit anti-islet T cell response and prevent diabetes. Our study highlights the critical interaction between virus and the immune system in the acceleration or prevention of type 1 diabetes. 23495872 Identification of Transglutaminase Substrates from Porcine Nucleus Pulposus as Potential Amplifiers in Cross-Linking Cell Scaffolds. Nucleus pulposus from the porcine intervertebral disc was separated chromatographically to discover substrates of microbial transglutaminase. Highly purified proteins were prepared, among them type II collagen, the major protein of the nucleus pulposus. Determination of substrates was performed by transglutaminase-mediated incorporation of biotinylated probes displaying several glutamine and lysine donor proteins. Type II collagen was only labeled if smaller nucleus pulposus proteins were present. One of the modulating proteins was serotransferrin, a lysine donor substrate of bacterial transglutaminase. An additional substrate was the carboxy-terminal propeptide of type II collagen, chondrocalcin. Chondrocalcin, a regulator of type II collagen fibrillogenesis, occurs abundantly in juvenile cartilage and nucleus pulposus. Accordingly, the protein may be regarded as an excellent additive for the preparation of injectable stem cells in nucleus pulposus-like matrices cross-linked by microbial transglutaminase. 23918812 LuciPHOr: algorithm for phosphorylation site localization with false localization rate estimation using target-decoy approach. Localization of phosphorylation sites in peptide sequences is a challenging problem in large-scale phospho-proteomics analysis. The intense neutral loss peaks and co-existence of multiple serine/threonine and/or tyrosine residues are limiting factors for objectively scoring site patterns across thousands of peptides. Various computational approaches for phosphorylation site localization have been proposed including Ascore, Mascot Delta score (MD-Score), and ProteinProspector, yet few address direct estimation of the false localization rate (FLR) in each experiment. Here we propose LuciPHOr, a modified target-decoy based approach that uses mass accuracy and peak intensities for site localization scoring and FLR estimation. Accurate estimation of FLR is a difficult task at the individual site level because the degree of uncertainty in localization varies significantly across different peptides. LuciPHOr carries out simultaneous localization on all candidate sites in each peptide and estimates the FLR based on the target-decoy framework, where decoy phospho-peptides generated by placing artificial phosphorylation(s) on non-candidate residues compete with the non-decoy phospho-peptides. LuciPHOr also reports approximate site-level confidence scores for all candidate sites as a means to localize additional sites from multi-phosphorylated peptides in which localization can be partially achieved. Unlike the existing tools, LuciPHOr is compatible with any search engine output processed through the Trans-Proteomic Pipeline. We evaluated the performance of LuciPHOr in terms of sensitivity and accuracy of FLR estimates using two synthetic phospho-peptide libraries and a phospho-proteomic dataset generated from complex mouse brain samples. 23836256 Age-dependent effects of high fat-diet on murine left ventricles: role of palmitate. Obesity-associated heart disease results in myocardial lipid accumulation leading to lipotoxicity. However, recent studies are suggestive of protective effects of high-fat diets (HFD). To determine whether age results in differential changes in diet-induced obesity, we fed young and old (3 and 18 months) male C57Bl/6 mice control diet, low-fat diet (both 10 kcal% fat) or HFD (45 kcal% fat) for 16 weeks, after which we analyzed LV function, mitochondrial changes, and potential modifiers of myocardial structure. HFD or age did not change LV systolic function, although a mildly increased BNP was observed in all old mice. This was associated with increased myocardial collagen, triglyceride, diacylglycerol, and ceramide content as well as higher caspase 3 activation in old mice with highest levels in old HFD mice. Pyruvate-dependent respiration and mitochondrial biogenesis were reduced in all old mice and in young HFD mice. Activation of AMPK, a strong inducer of mitochondrial biogenesis, was reduced in both HFD groups and in old control or LFD mice. Cardiomyocytes from old rats demonstrated significantly reduced AMPK activation, impaired mitochondrial biogenesis, higher ceramide content, and reduced viability after palmitate (C16:0) in vitro, while no major deleterious effects were observed in young cardiomyocytes. Aged but not young cardiomyocytes were unable to respond to higher palmitate with increased fatty acid oxidation. Thus, HFD results in cardiac structural alterations and accumulation of lipid intermediates predominantly in old mice, possibly due to the inability of old cardiomyocytes to adapt to high-fatty acid load. 23629859 Self-supervised online metric learning with low rank constraint for scene categorization. Conventional visual recognition systems usually train an image classifier in a bath mode with all training data provided in advance. However, in many practical applications, only a small amount of training samples are available in the beginning and many more would come sequentially during online recognition. Because the image data characteristics could change over time, it is important for the classifier to adapt to the new data incrementally. In this paper, we present an online metric learning method to address the online scene recognition problem via adaptive similarity measurement. Given a number of labeled data followed by a sequential input of unseen testing samples, the similarity metric is learned to maximize the margin of the distance among different classes of samples. By considering the low rank constraint, our online metric learning model not only can provide competitive performance compared with the state-of-the-art methods, but also guarantees convergence. A bi-linear graph is also defined to model the pair-wise similarity, and an unseen sample is labeled depending on the graph-based label propagation, while the model can also self-update using the more confident new samples. With the ability of online learning, our methodology can well handle the large-scale streaming video data with the ability of incremental self-updating. We evaluate our model to online scene categorization and experiments on various benchmark datasets and comparisons with state-of-the-art methods demonstrate the effectiveness and efficiency of our algorithm. 23865938 Analysis of single-case data: Randomisation tests for measures of effect size. Single-case experiments can be used to evaluate the effect of an intervention or treatment for a single entity. The internal validity and statistical conclusion validity of single-case experiments can be improved by incorporating randomisation in their design. In this article, we explain how to design randomised single-case phase and alternation studies as well as randomised simultaneous and sequential replication studies, and how to conduct randomisation tests for these designs. Advantages and limitations of randomisation tests are discussed. In order to not only determine the (non)randomness of an intervention effect, but also the magnitude of this effect, we propose to use an effect size index as a test statistic for the randomisation test. We illustrate this combination for the design and analysis of an ABAB phase study, using a free software package. 23849804 Potent l-lactic acid assimilation of the fermentative and heterothallic haploid yeast Saccharomyces cerevisiae NAM34-4C. We screened an industrial thermotolerant Saccharomyces cerevisiae strain, KF7, as a potent lactic-acid-assimilating yeast. Heterothallic haploid strains KF7-5C and KF7-4B were obtained from the tetrads of the homothallic yeast strain KF7. The inefficient sporulation and poor spore viability of the haploid strains were improved by two strategies. The first strategy was as follows: (i) the KF7-5C was crossed with the laboratory strain SH6710; (ii) the progenies were backcrossed with KF7-5C three times; and (iii) the progenies were inbred three times to maintain a genetic background close to that of KF7. The NAM12 diploid between the cross of the resultant two strains, NAM11-9C and NAM11-13A, showed efficient sporulation and exhibited excellent growth in YPD medium (pH 3.5) at 35°C with 1.4-h generation time, indicating thermotolerance and acid tolerance. The second strategy was successive intrastrain crosses. The resultant two strains, KFG4-6B and KFG4-4B, showed excellent mating capacity. A spontaneous mutant of KFG4-6B, KFG4-6BD, showed a high growth rate with a generation time of 1.1 h in YPD medium (pH 3.0) at 35°C. The KFG4-6BD strain produced ascospores, which were crossed with NAM11-2C and its progeny to produce tetrads. These tetrads were crossed with KFG4-4B to produce NAM26-14A and NAM26-15A. The latter strain had a generation time of 1.6 h at 35°C in pH 2.5, thus exhibiting further thermotolerance and acid tolerance. A progeny from a cross of NAM26-14A and NAM26-15A yielded the strain NAM34-4C, which showed potent lactic acid assimilation and high transformation efficiency, better than those of a standard laboratory strain. 23726411 Long-chain triazolyl acids as inhibitors of osteoclastogenesis. Saturated fatty acids (e.g., palmitic acid) are known to moderately inhibit the development of osteoclasts in vitro. In pursuit of more effective inhibitors of osteoclastogenesis we explored two new classes of palmitic acid analogues containing either an ether or triazolyl group at various positions along the chain. The compounds were evaluated for their ability to inhibit the formation of osteoclasts in primary mouse bone marrow cultures. The oxyacids were generally prepared by condensation of the appropriate alkyl halides and diols, followed by Jones oxidation. The triazolyl acids were prepared by copper-catalysed click chemistry between alkyl azides and acetylenic acids, or with the appropriately-protected azides and alkynes, followed by deprotection and oxidation. The oxyacids were little more effective than palmitic acid, but the triazolyl analogues were much more effective osteoclastogenesis inhibitors, especially when the triazole was distant from the acid unit. 23740474 Quantified High-Throughput Screening of Escherichia coli Producing Poly(3-hydroxybutyrate) Based on FACS. Here, we report on a highly sensitive method for the detection of P(3HB) accumulation in Escherichia coli cells based on the automated flow cytometry system using fluorescent dyes. E. coli containing P(3HB) were stained with either BODIPY or Nile red fluorescent dye, and their staining properties were analyzed under a variety of conditions. Compared with Nile red, BODIPY was much more sensitive in staining P(3HB) and overall demonstrated a more rapid staining of cells, a greater resistance to photobleaching, and greater cell viability. In addition, we also successfully monitored heterogeneity in P(3HB) accumulation within a cell population using BODIPY staining and flow cytometry. We believe this optimized staining method using BODIPY in combination with screening by high-speed flow cytometer will be helpful in the engineering of host cells toward an enhanced production of bioplastics. 23890471 Subjective satiety and other experiences of a Paleolithic diet compared to a diabetes diet in patients with type 2 diabetes. We found marked improvement of glycemic control and several cardiovascular risk factors in patients with type 2 diabetes given advice to follow a Paleolithic diet, as compared to a diabetes diet. We now report findings on subjective ratings of satiety at meal times and participants' other experiences of the two diets from the same study. In a randomized cross-over study, 13 patients with type 2 diabetes (3 women and 10 men), were instructed to eat a Paleolithic diet based on lean meat, fish, fruits, vegetables, root vegetables, eggs and nuts, and a diabetes diet designed in accordance with dietary guidelines, during two consecutive 3-month periods. In parallel with a four-day weighed food record, the participants recorded their subjective rating of satiety. Satiety quotients were calculated as the intra-meal quotient of change in satiety during a meal and consumed energy or weight of food and drink for that specific meal. All participants answered the same three open-ended questions in a survey following each diet: "What thoughts do you have about this diet?", "Describe your positive and negative experiences with this diet" and "How do you think this diet has affected your health?". The participants were equally satiated on both diets. The Paleolithic diet resulted in greater satiety quotients for energy per meal (p = 0.004), energy density per meal (p = 0.01) and glycemic load per meal (p = 0.02). The distribution of positive and negative comments from the survey did not differ between the two diets, and the comments were mostly positive. Among comments relating to recurring topics, there was no difference in distribution between the two diets for comments relating to tastelessness, but there was a trend towards more comments on the Paleolithic diet being satiating and improving blood sugar values, and significantly more comments on weight loss and difficulty adhering to the Paleolithic diet. A Paleolithic diet is more satiating per calorie than a diabetes diet in patients with type 2 diabetes. The Paleolithic diet was seen as instrumental in weight loss, albeit it was difficult to adhere to. 23434640 Synthesis and cytotoxicity of 3-aryl acrylic amide derivatives of the simplified saframycin-ecteinascidin skeleton prepared from l-dopa. Twenty four compounds with diversified 3-aryl acrylic amide side chains of the simplified saframycin-ecteinascidin pentacyclic skeleton were synthesized via a 14-step stereospecific route starting from l-dopa. The cytotoxicities of these compounds were tested against eight human tumor cell lines including HCT-8, BEL-7402, BGC-803, A549, A2780, MCF-7, MX-1, and MDA-MB-231. Most of these compounds exhibited potent antitumor activity, and a preliminary structure-activity relationship (SAR) was discussed. Compound 28 with 3-thiophenyl acrylic amide side chain exhibited selective cytotoxicity against MDA-MB-231 cell line with the IC50 value of 50 nM. 23725671 Protein export in malaria parasites: many membranes to cross. The continuous multiplication of Plasmodium parasites in red blood cells leads to a rapid increase in parasite numbers and is responsible for the disease symptoms of malaria. Survival and virulence of the parasite are linked to parasite-induced changes of the host red blood cells. These alterations require export of a large number of parasite proteins that are trafficked across multiple membranes to reach the host cell. Two classes of exported proteins are known, those with a conserved Plasmodium export element (PEXEL/HT) or those without this motif (PNEPs). Recent work has revealed new aspects of the determinants required for export of these 2 protein classes, shedding new light on the mode of trafficking during the different transport steps en route to the host cell. 23725788 Arousal from sleep pathways are affected by the prone sleeping position and preterm birth: Preterm birth, prone sleeping and arousal from sleep. Preterm infants exhibit depressed arousability from sleep when compared with term infants. As the final cortical element of the arousal process may be the most critical for survival, we hypothesized that the increased vulnerability of preterm infants to the Sudden Infant Death Syndrome (SIDS) could be explained by depressed cortical arousal (CA) responses. We evaluated the effects of preterm birth on stimulus-induced arousal processes in both the prone and supine sleeping positions. 10 healthy preterm infants were studied with daytime polysomnography, in both supine and prone sleeping positions, at 36weeks gestational age, 2-4weeks, 2-3months and 5-6months post-term corrected age. Sub-cortical activations and cortical arousals (CA) were expressed as proportions of total arousal responses. Preterm data were compared with data from 13 healthy term infants studied at the same corrected ages. In preterm infants increased CAs were observed in the prone position at all ages studied. Compared to term infants, preterm infants had significantly fewer CAs in QS when prone at 2-3months of age and more CAs when prone at 2-4weeks in AS. There were no differences in either sleep state when infants slept supine. Prone sleeping promoted CA responses in healthy preterm infants throughout the first six months of post-term age. We have previously suggested that in term infants enhanced CA represents a critical protection against a potentially harmful situation; we speculate that for preterm-born infants the need for this protection is greater than in term infants. 23870338 Ultrashort time-to-echo MRI of the cartilaginous endplate: Technique and association with intervertebral disc degeneration. The purpose of this study was to report the feasibility of the ultrashort time-to-echo (UTE) MRI technique to assess cartilaginous endplate (CEP) defects in humans in vivo and to assess their relationship with intervertebral disc (IVD) degeneration. Nine volunteer subjects (mean age = 43.9 years; range = 22-61 years) were recruited, representing 54 IVDs and 108 CEPs. The subjects underwent T2-weighted and UTE MRI to assess for the presence and severity of IVD degeneration, and for the presence of CEP defects, respectively, from T12 to S1. IVD degeneration was graded according to the Schneiderman et al. classification on T2-weighted MRI. CEP defects were defined on UTE MRI as discontinuity of high signal over four consecutive images and were independently assessed by two observers. Thirty-seven out of 108 (34.3%) CEPs had defects, which mainly occurred at T12/L1, L1/L2 and L4/L5 (P = 0.008). Multivariate logistic regression revealed that lower body mass index (P = 0.009) and younger (P = 0.034) individuals had a decreased likelihood of having CEP defects. A statistically significant association was found to exist between the presence of CEP defects and IVD degeneration (P = 0.036). A higher prevalence of degenerated IVDs with CEP defects was found at L4/5 and L5/S1, while degenerated IVDs with no CEP defects were found throughout the whole lumbar region. Mean IVD degeneration scores of the L4/5 and L5/S1 levels with CEP defects were higher in comparison with those with no CEP defects. Our study demonstrates the feasibility of using UTE MRI in humans in vivo to assess the integrity of the CEP. A statistically significant association was found to exist between the presence of CEP defects and IVD degeneration. In the lower lumbar region, more severe degeneration was found to occur in the IVDs with CEP defects than in those without defects. 23895376 Psychoactive substances use and associated factors among Axum University students, Axum Town, North Ethiopia. The use of substances such as alcohol, khat leaves and tobacco have long been recognized as one of the leading causes of human suffering and become one of the rising major public health and socio-economic problems worldwide. Even though substances use occurs in all segments of all societies, it is more spreading in an alarming rate among the young generation. This study aimed to establish the prevalence and associated factors of substances use among undergraduate students in Axum University. Institution based quantitative cross sectional study design was conducted among Axum University students in April 2012. A sample of 764 students was selected by using multi- stage sampling technique. Data were collected using pre- tested self- administered questionnaires. The data were cleaned, coded, entered into EPI-INFO version 3.5.1 and transferred and analysed using SPSS computer soft ware package version 20. The lifetime prevalence of khat chewing, alcohol drinking and cigarette smoking among the study participants were 28.7%, 34.5% and 9.5% respectively. Similarly, the current prevalence of khat chewing, alcohol drinking and cigarette smoking were 27.9%, 32.8% and 9.3% respectively. The commonest reasons for khat, alcohol and cigarette using were to keep alert while reading 40.6%, for relaxation 65.5% and to relief stress 37.7% respectively. Having peer friends who chew khat was strongly and positively associated with khat use [AOR: 10.18, 95%CI: (5.59, 18.54)].Family members and peer friends alcohol use were strongly associated with alcohol drinking [AOR: 2.61, 95%CI: (1.56, 4.34) and [AOR: 14, 95%CI: (8.09, 24.24)] respectively. Ever alcohol use was strongly associated with cigarette smoking [AOR: 6.54, 95%CI: (2.66, 16.05)]. This study revealed that psychoactive substances use became an urgent problem among undergraduate university students. Universities need to monitor and teach their students with special focus on fresh man students, about the health risks and socioeconomic problems associated with psychoactive substances use. 23707469 Circadian variation of Valproic acid pharmacokinetics in mice. Valproic acid (VPA) is currently one of the most commonly used antiepileptic drugs. This study aims to investigate whether VPA pharmacokinetics varied according to circadian dosing-time. A single dose of VPA (350mgkg(-1)) was administered by intraperitonally (i.p.) route to a total of 132 mice synchronized for 3weeks to 12h light (rest span) and 12h dark (activity span). Four different circadian times (1, 7, 13 and 19 HALO) of drug injection were used (33 mice/circadian time). At each circadian time, blood samples were withdrawn at (0h) and at 0.083, 0.166, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2 and 3h after VPA injection. Plasma VPA concentrations were determined by an EMIT method. There were no significant differences in Tmax of VPA whatever the circadian-time of injections (Tmax=0.166h). However, there were relevant differences in Cmax between the four circadian groups (p<0.005), it varied between 386±30.86mgL(-1) in mice treated at 7 HALO and 824±39.85mgL(-1) in mice treated at 19 HALO. The AUC0-∞ was significantly two times higher when VPA was administered at 19 HALO as compared to the injection at 7 HALO. Drug dosing at 7 HALO resulted in highest ClT value: 0.405±0.006Lh(-1)kg(-1), whereas ClT was significantly slower when VPA was administered at 19 HALO (0.157±0.009Lh(-1)kg(-1)) (p<0.0001). The AUC0-∞ was significantly 2-fold higher when VPA was administered at 19 HALO (2216.65±138.91mgh(-1)L(-1)) as compared to the injection at 7 HALO (864.09±16.82mgh(-1)L(-1)) (p<0.0001). Cosinor analysis showed circadian rhythm in different pharmacokinetic parameters. Cmax and AUC0-∞ have a significant circadian rhythm with an acrophase located at 20.16 HALO±0.16h (the middle of the active span) (p<0.001), whereas ClT and Vd showed a significant circadian rhythm with an acrophase located respectively at 7.86 HALO±0.57h and 6.13 HALO±0.07h (the middle of the rest span) (p<0.001). The large circadian variation of VPA pharmacokinetic processes might be involved in the mechanisms of circadian rhythm in murine toxicity since the optimal tolerance corresponded to the time which induces lowest Cmax and AUC values. 23293834 Plasmon dynamics in colloidal Au₂Cd alloy-CdSe core/shell nanocrystals. Metal-semiconductor nanocrystal heterostructures are model systems for understanding the interplay between the localized surface plasmon resonances in the metal domain and the relaxation of the excited carriers in the semiconductor domain. Here we report the synthesis of colloidal Au₂Cd (core)/CdSe (shell) nanocrystal heterostructures, which were characterized extensively with several structural and optical techniques, including time-resolved fluorescence and broad-band transient absorption spectroscopy (both below and above the CdSe band gap). The dynamics of the transient plasmon peak was dominated by the relaxation of hot carriers in the metal core, its spectral shape was independent of the pump wavelength, and the bleaching lifetime was about half a picosecond, comparable with the value found in the AuCd seeds used for the synthesis. 23947323 The Health of Sexual Minorities: A New Frontier. For the past three decades public health research among sexual minority communities focused on HIV/AIDS. This focus ignored many other health disparities that impact sexual minority communities across the life span as well as contextual and structural interventions that can lessen these disparities. However, the public health community continues to expand its lens to recognize the broader concerns that influence the health and well-being of sexual minorities in the United States, including, increasingly, the transgender population. This broader approach is reflected in several articles in this issue of the Journal. (Am J Public Health. Published online ahead of print August 15, 2013: e1. doi:10.2105/AJPH.2013.301568). 23940795 Phosphorylation of the Actin Binding Protein Drebrin at S647 Is Regulated by Neuronal Activity and PTEN. Defects in actin dynamics affect activity-dependent modulation of synaptic transmission and neuronal plasticity, and can cause cognitive impairment. A salient candidate actin-binding protein linking synaptic dysfunction to cognitive deficits is Drebrin (DBN). However, the specific mode of how DBN is regulated at the central synapse is largely unknown. In this study we identify and characterize the interaction of the PTEN tumor suppressor with DBN. Our results demonstrate that PTEN binds DBN and that this interaction results in the dephosphorylation of a site present in the DBN C-terminus - serine 647. PTEN and pS647-DBN segregate into distinct and complimentary compartments in neurons, supporting the idea that PTEN negatively regulates DBN phosphorylation at this site. We further demonstrate that neuronal activity increases phosphorylation of DBN at S647 in hippocampal neurons in vitro and in ex vivo hippocampus slices exhibiting seizure activity, potentially by inducing rapid dissociation of the PTEN:DBN complex. Our results identify a novel mechanism by which PTEN is required to maintain DBN phosphorylation at dynamic range and signifies an unusual regulation of an actin-binding protein linked to cognitive decline and degenerative conditions at the CNS synapse. 23628426 Adhesion awareness: a nationwide survey of gynaecologists. Adhesions and related complications lead to substantially increased morbidity and mortality which increase medical costs. We investigated the awareness of adhesions among Dutch gynaecologists and gynaecology residents. A survey, assessing knowledge and opinion about adhesions, was sent to a randomly selected group of 381 gynaecologists and 256 residents. In addition, the informed consent process and application of anti-adhesive agents were questioned. The response rate was 56.9%. Complications due to adhesions were highly underestimated, leading to low knowledge scores (mean score 35.1%). Of all respondents 73.8% agreed that adhesions exert a clinically relevant and negative effect, but only 51.2% expressed a positive opinion on adhesion prevention. This correlated with a stronger belief in the clinically relevant and negative effects of adhesions and the opinion that adhesion prevention belongs to standard care (ρ=0.212, p<0.001; ρ=0.495, p<0.001). Of all respondents 31.4% expressed a positive attitude towards anti-adhesive agents and 19.8% expressed a negative one. A negative attitude correlated with a negative view in terms of cost-benefits (ρ=0.245, p<0.001). Although 43.5% had used anti-adhesive agents in the past year, 20.9% had used them before but stopped using agents in the past year. Only 5.2% routinely included adhesions or related morbidity in the informed consent. Awareness of adhesions is limited and informed consent is provided inadequately. Implementing adhesion prevention is related with awareness of adhesions. These findings underline the need to embed adhesions, related morbidity and prevention in educational programmes. 23832232 Novel solid-phase extractor based on functionalization of multi-walled carbon nano tubes with 5-aminosalicylic acid for preconcentration of Pb(II) in water samples prior to determination by ICP-OES. New solid-phase extractor (MWCNTs-5-ASA) was synthesized via covalent immobilization of 5-aminsalicylic acid onto multi-walled carbon nanotubes (MWCNs). The success of the functionalization process was confirmed using Fourier transform infrared spectroscopy, scanning electron microscope, and surface coverage determination. Batch experiments were conducted as a function of pH to explore MWCNTs-5-ASA efficiency to extract several metal ions viz., Cr(III), Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Cd(II) and Pb(II). It was found that Pb(II) exhibits the highest extraction percentage with maximum adsorption capacity 32.75 mg g(-1). Its binding performance was well fitted with Langmuir sorption isotherm. On the other hand, the selective separation and preconcentration of trace Pb(II) under dynamic conditions prior to determination by inductively coupled plasma-optical emission spectrometry was investigated under different parameters. These included the rate of flow and volume of sample solution, in addition to the type of the eluate, its volume and concentration. The effect of a variety of foreign ions on the recovery percentage was also evaluated. Trace Pb(II) ions present in 500 mL aqueous solution adjusted to pH 4.0 were retained on 50 mg of MWCNTs-5-ASA and completely eluted using 4.0 mL of 2 M HNO3. The limit of detection and the precision of the method were 0.25 ng mL(-1) and 2.8 %, respectively (N = 5). This methodology has been applied for the determination of Pb(II) in water samples with good results. 23561108 Antioxidant capacity, polyphenolic content and tandem HPLC-DAD-ESI/MS profiling of phenolic compounds from the South American berries Luma apiculata and L. chequén. Native Myrtaceae fruits were gathered by South American Amerindians as a food source. At present, there is still some regional consume of the small berries from trees belonging to genus Luma that occurs in southern Chile and Argentina. The aerial parts and berries from Luma apiculata and Luma chequen were investigated for phenolic constituents and antioxidant capacity. A high performance electrospray ionisation mass spectrometry method was developed for the rapid identification of phenolics in polar extracts from both species. Thirty-one phenolic compounds were detected and 27 were identified or tentatively characterised based on photodiode array UV-vis spectra (DAD), ESI-MS-MS spectrometric data and spiking experiments with authentic standards. Twelve phenolic compounds were detected in L. apiculata fruits and 12 in the aerial parts while L. chequen yielded 10 compounds in fruits and 16 in aerial parts, respectively. From the compounds occurring in both Luma species, seven were identified as tannins or their monomers, 15 were flavonol derivatives and five were anthocyanins. The whole berry and aerial parts extracts presented high antioxidant capacity in the DPPH assay (IC50 of 10.41±0.02 and 2.44±0.03μg/mL for L. apiculata, 12.89±0.05 and 3.22±0.05 for L. chequen, respectively), which can be related to the diverse range of phenolics detected. The antioxidant capacity together with the high polyphenolic contents and compounds identified can support at least in part, their use as botanical drugs. From the compounds identified in both species, 3-O-(6″-O-galloyl)-hexose derivatives of myricetin, quercetin, laricitrin and isorhamnetin are reported for the first time for the genus Luma. 23595773 Palbinone from Paeonia suffruticosa Protects Hepatic Cells via Up-regulation of Heme Oxygenase-1. Paeonia suffruticosa has been traditionally employed for vitalizing blood circulation and alleviating liver and inflammatory diseases. The pathways by which palbinone (PB) isolated from P. suffruticosa mediates heme oxygenase-1 (HO-1) induction were investigated using the specific inhibitors for PI3K and mitogen activated protein kinases pathways. The effect of PB-treatment on Nrf2 translocalization and HO-1-antioxidant response element (ARE) regulation was examined employing Western blot and luciferase assays. PB induced HO-1 expression via the activation of Nrf2 in the hepatic cells, and ARE-dependent genes were stimulated via the PB-mediated Nrf2 activation. PB-mediated HO-1 expression could be involved with PI3K/Akt and ERK1/2 pathways. Our study suggests the mechanism by which PB induces HO-1 expression in the hepatic cells. This might substantiate the traditional applications of P. suffruticosa for the treatment of oxidative stress-related diseases including oxidant and inflammatory-mediated vascular and liver diseases. Copyright © 2013 John Wiley & Sons, Ltd. 23301860 Single-walled carbon nanotube surface control of complement recognition and activation. Carbon nanotubes (CNTs) are receiving considerable attention in site-specific drug and nucleic acid delivery, photodynamic therapy, and photoacoustic molecular imaging. Despite these advances, nanotubes may activate the complement system (an integral part of innate immunity), which can induce clinically significant anaphylaxis. We demonstrate that single-walled CNTs coated with human serum albumin activate the complement system through C1q-mediated classical and the alternative pathways. Surface coating with methoxypoly(ethylene glycol)-based amphiphiles, which confers solubility and prolongs circulation profiles of CNTs, activates the complement system differently, depending on the amphiphile structure. CNTs with linear poly(ethylene glycol) amphiphiles trigger the lectin pathway of the complement through both L-ficolin and mannan-binding lectin recognition. The lectin pathway activation, however, did not trigger the amplification loop of the alternative pathway. An amphiphile with branched poly(ethylene glycol) architecture also activated the lectin pathway but only through L-ficolin recognition. Importantly, this mode of activation neither generated anaphylatoxins nor induced triggering of the effector arm of the complement system. These observations provide a major step toward nanomaterial surface modification with polymers that have the properties to significantly improve innate immunocompatibility by limiting the formation of complement C3 and C5 convertases. 23847335 Endometrial tumors divide into four subtypes. A comprehensive analysis of endometrial cancer from The Cancer Genome Atlas Research Network suggests that tumors can be divided into 4 distinct subtypes based on their molecular profiles, potentially leading to more accurate diagnosis and better-informed treatment choices. 23887178 Design and generation of recombinant rabies virus vectors. Rabies viruses, negative-strand RNA viruses, infect neurons through axon terminals and spread trans-synaptically in a retrograde direction between neurons. Rabies viruses whose glycoprotein (G) gene is deleted from the genome cannot spread across synapses. Complementation of G in trans, however, enables trans-synaptic spreading of G-deleted rabies viruses to directly connected, presynaptic neurons. Recombinant rabies viruses can encode genes of interest for labeling cells, controlling gene expression and monitoring or manipulating neural activity. Cre-dependent or bridge protein-mediated transduction and single-cell electroporation via the EnvA-TVA or EnvB-TVB (envelope glycoprotein and its specific receptor for avian sarcoma leukosis virus subgroup A or B) system allow cell type-specific or single cell-specific targeting. These rabies virus-based approaches permit the linking of connectivity to cell morphology and circuit function for particular cell types or single cells. Here we describe methods for construction of rabies viral vectors, recovery of G-deleted rabies viruses from cDNA, amplification of the viruses, pseudotyping them with EnvA or EnvB and concentration and titration of the viruses. The entire protocol takes 6-8 weeks. 23869554 Evaluating the efficacy of treatments for haemorrhoids: time for a standardised definition of recurrence? We read with interest the systematic review by Pucher et al [1] concerning the safety and efficacy of doppler-guided haemorrhoidal artery ligation. They are to be congratulated on their thorough review which demonstrates the large number of studies that have been published since the last such paper by Giordano et al [2]. The increasingly wide range of options available to surgeons for the treatment of haemorrhoids differ considerably in terms of invasiveness, post-operative pain, convalescence time and, most importantly for the patient and the NHS, recurrence. This article is protected by copyright. All rights reserved. 23865536 Enzyme inhibition-based determination of pesticide residues in vegetable and soil in centrifugal microfluidic devices. Pesticide residue is of concern as an environmental pollutant when present at medium to high concentrations. Such residue was quantified in both vegetable and soil samples by an enzyme inhibition technique. The multistep reactions were integrated into centrifugal microfluidic devices allowing automated simultaneous analysis of several samples or of replicates. The small sample size inherent to microfluidic devices allowed for less reagent to be used including less of the expensive enzyme which is key to this method. Liquid-solid magnetically actuated extraction, filtration, sedimentation, and detection were all integrated on the same device. Several parameters were optimized including the concentration of enzyme, substrate, chromatic agent, and reaction time. In this environmental application of centrifugal microfluidics, the percent inhibition of enzyme activity is logarithmically proportional to the demonstration pesticide concentration (in this case carbofuran). This meant that as the pesticide concentration increased in the samples, the reaction was more inhibited and the final product absorbed less light at 525 nm. Two versions of the centrifugal microfluidic devices were made. One version was designed for the analysis of vegetable samples (cabbage) and the other for the analysis of soil samples. Each version provided results that were statistically similar to the conventional benchtop method with a carbofuran limit of detection of 0.1 ppm or 0.1 μg g(-1) (5 ng absolute limit of detection). 23916723 Structure and rheology of colloidal particle gels: Insight from computer simulation. A particle gel is a network of aggregated colloidal particles with soft solid-like mechanical properties. Its structural and rheological properties, and the kinetics of its formation, are dependent on the sizes and shapes of the constituent particles, the volume fraction of the particles, and the nature of the interactions between the particles before, during and after gelation. Particle gels may be permanent or transient depending on whether the colloidal forces between the aggregating particles lead to irreversible bonding or weak reversible interactions. With short-range reversible interactions, network formation is typically associated with phase separation or kinetic arrest due to particle crowding. Much existing knowledge has been derived from computer simulations of idealized model systems containing spherical particles interacting with well-defined pair potentials. The status of current progress is reviewed here by summarizing the underlying methodology and key findings from a range of simulation approaches: Monte Carlo, molecular dynamics, Brownian dynamics, Stokesian dynamics, dissipative particle dynamics, multiparticle collision dynamics, and fluid particle dynamics. Then it is described how the technique of Brownian dynamics simulation, in particular, has provided detailed insight into how different kinds of bonding and weak reversible interactions can affect the aggregate fractal structure, the percolation behaviour, and the small-deformation rheological properties of network-forming colloidal systems. A significant ongoing development has been the establishment and testing of efficient algorithms that are able to capture the subtle dynamic structuring effects that arise from effects of interparticle hydrodynamic interactions. This has led to an appreciation recently of the potentially important role of these particle-particle hydrodynamic effects in controlling the evolving morphology of simulated colloidal aggregates and in defining the location of the sol-gel phase boundary. 23337524 Call to action: finding solutions for the drug shortage crisis in the United States. In their article in this issue of CPT, Woodcock and Wosinska are the first to clearly outline the quality and manufacturing problems causing drug shortages of generic injectables. These authors have focused on the main issue, namely, that manufacturing problems and the lack of incentives for quality products are the primary reasons for most recent shortages of generic injectable drugs. 23841675 Crystallization and Transformation of Polymorphic Forms of Trioleoyl Glycerol and 1,2-Dioleoyl-3-rac-linoleoyl Glycerol. This study examined the influence of different thermal treatments on the crystallization and transformation of trioleoyl glycerol (OOO) and 1,2-dioleoyl-3-rac-linoleoyl glycerol (OOL). Two triacylglycerol (TAG) samples were cooled at 0.5-15 °C·min(-1) and heated at 2 and 15 °C·min(-1). The polymorphic characteristics of the two TAGs were analyzed in situ using differential scanning calorimetry, Raman spectroscopy, and synchrotron radiation X-ray diffraction. Multiple polymorphic forms were identified in OOO (α, β'2, β'1, β2, and β1) and OOL (α, β'2, and β'1). Larger quantities of more stable forms (e.g., β2 and β1 of OOO and β'1 of OOL) were obtained when the samples were slowly cooled and heated. In contrast, less stable polymorphs were obtained with increased cooling and heating rates. Polymorphic transformations occurred in either solid-state or melt-mediation and were influenced by heating rates. The results were analyzed by considering the activation energies for crystallization and transformation of stable and less stable polymorphic forms in comparison with previous studies on 1,3-dipalmitoyl-2-oleoyl-glycerol and 1, 3-dioleoyl-2-palmitoyl-glycerol. 23270871 Study of the potential oxidative stress induced by six solvents in the rat brain. The mechanisms of action involved in the neurotoxicity of solvents are poorly understood. In vitro studies have suggested that the effects of some solvents might be due to the formation of reactive oxygen species (ROS). This study assesses hydroxyl radical (OH) generation and measures malondialdehyde (MDA) levels in the cerebral tissue of rats exposed to six solvents (n-hexane, n-octane, toluene, n-butylbenzene, cyclohexane and 1,2,4-trimethylcyclohexane). Three of these solvents have been shown to generate ROS in studies carried out in vitro on granular cell cultures from rat cerebellum. We assessed OH production by quantifying the rate of formation of 3,4-dihydroxybenzoic acid using a trapping agent, 4-hydroxybenzoic acid, infused via the microdialysis probe, into the prefrontal cortex of rats exposed intraperitoneally to the solvents. Extracellular MDA was quantified in microdialysates collected from the prefrontal cortex of rats exposed, 6h/day for ten days, to 1000ppm of the solvents (except for n-butylbenzene, generated at 830ppm) in inhalation chambers. Tissue levels of free and total MDA were measured in different brain structures for rats acutely (intraperitoneal route) and sub-acutely (inhalation) exposed to solvents. None of the six solvents studied increased the production of hydroxyl radicals in the prefrontal cortex after acute administration. Nor did they increase extracellular or tissue levels of MDA after 10 days' inhalation exposure. On the other hand, a decrease in the concentrations of free MDA in brain structures was observed after acute administration of n-hexane, 1,2,4-trimethylcyclohexane, toluene and n-butylbenzene. Therefore, data of this study carried out in vivo did not confirm observations made in vitro on cell cultures. 23734825 Adaptation of a commonly used, chemically defined medium for human embryonic stem cells to stable isotope labeling with amino acids in cell culture. Metabolic labeling with stable isotopes is a prominent technique for comparative quantitative proteomics, and stable isotope labeling with amino acids in cell culture (SILAC) is the most commonly used approach. SILAC is, however, traditionally limited to simple tissue culture regimens and only rarely employed in the context of complex culturing conditions as those required for human embryonic stem cells (hESCs). Classic hESC culture is based on the use of mouse embryonic fibroblasts (MEFs) as a feeder layer, and as a result, possible xenogeneic contamination, contribution of unlabeled amino acids by the feeders, interlaboratory variability of MEF preparation, and the overall complexity of the culture system are all of concern in conjunction with SILAC. We demonstrate a feeder-free SILAC culture system based on a customized version of a commonly used, chemically defined hESC medium developed by Ludwig et al. and commercially available as mTeSR1 [mTeSR1 is a trade mark of WiCell (Madison, WI) licensed to STEMCELL Technologies (Vancouver, Canada)]. This medium, together with adjustments to the culturing protocol, facilitates reproducible labeling that is easily scalable to the protein amounts required by proteomic work flows. It greatly enhances the usability of quantitative proteomics as a tool for the study of mechanisms underlying hESCs differentiation and self-renewal. Associated data have been deposited to the ProteomeXchange with the identifier PXD000151. 23477486 Sensing of biologically important cations such as na(+), k(+), ca(2+), cu(2+), and fe(3+) using magnetic nanoemulsions. We report a simple approach to the ultrasensitive detection of biologically important metal ions using a magnetic nanoemulsion. The nanoemulsion used in our study was an oil-in-water emulsion droplet of average size ∼190 nm containing ferrimagnetic iron oxide nanoparticles of average size ∼10 nm. In a static magnetic field, the emulsion droplets self-assemble into a nanoarray with distinct interdroplet spacing. In the presence of cations in the solution, the nanofluid array shows a large blue shift in the diffracted Bragg peak and a visually perceivable color change due to changes in the electrical double layer upon the diffusion of cations. The colloidal force-distance measurements in the presence of cations show large variations at the onset of repulsion in the presence of cations. The sensor shows good selectivity to Na(+), K(+), Ca(2+), Cu(2+), and Fe(3+) ions and offers a rapid response compared to conventional techniques. This approach can be useful for the recognition of biologically important cations. 23542147 Ethanol extract of Adiantum capillus-veneris L. suppresses the production of inflammatory mediators by inhibiting NF-κB activation. ETHNOPHARMACOLOGICAL RELEVANCE: Adiantum capillus-veneris L. is a wildly distributed plant species and has been extensively used in south of China as traditional folk medicine for the treatment of inflammatory diseases. AIM OF THE STUDY: To investigate the anti-inflammatory effect of ethanolic extracts of Adiantum capillus-veneris L. and the involvement of NF-κB signaling in the regulation of inflammation. MATERIALS AND METHODS: The plant ethanolic extracts were initially tested against lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) production in RAW264.7 mouse macrophages, and interleukin 6 (IL-6) and tumor necrosis factor (TNF) production in human U937 monocytes. The effect of the plant extracts on the transcription factor nuclear factor kappa B (NF-κB) pathway was evaluated in TNF-α stimulated HepG2 cells by luciferase gene reporter assay and Western blotting at the transcriptional and translational levels. Subsequently, the inhibition of NF-κB downstream gene expression (IL-8 and ICAM-1) by the plant extracts was assessed via quantitative real time polymerase chain reaction (qPCR). Lastly, the anti-inflammatory activities of the plant extracts in vivo were evaluated by testing spleen index and NF-κB related protein expression in LPS-stimulated CD1 mice. RESULTS: The plant ethanolic extracts effectively suppressed PGE2, IL-6 and TNF release with an IC50 less than 50μg/ml. Moreover, luciferase expression could be specifically blocked in HepG2 cells, not in HEK293 cells, showing that the plant extracts displayed a cell-specific pattern on NF-κB gene transcription. The assayed biological activity also depended on the order of adding TNF-α and the plant extracts because the plant extracts could only block the NF-κB activation if added earlier but were unable to stop the signal when added after TNF-α. However, the plant extracts did not exert any effect on ubiquitination which regulates several steps in the NF-κB pathway. Additionally, the plant extracts down-regulated phosphorylation of IKKα/β at S176/180, p38 at T180/Y182 and p65 at S536, but not p65 at S276. This was confirmed by their ability to selectively abrogate the induction of IL-8 transcription, whereas the ICAM-1 gene, which is not transcribed selectively by an NF-κB complex containing a form of p65 phosphorylated on Ser536, did not change. Finally, the plant extracts at 200μg/mg could normalize the LPS-induced elevation of spleen index as well as NF-κB and p38 activations in CD1 mice. CONCLUSION: The present studies presents the potential utilization of this plant extracts, as a natural resources for the development of an anti-inflammatory medicine. 23842957 Suppression on Your Own Terms: Internally Generated Displays of Craving Suppression Predict Rebound Effects. Research on emotion suppression has shown a rebound effect, in which expression of the targeted emotion increases following a suppression attempt. In prior investigations, participants have been explicitly instructed to suppress their responses, which has drawn the act of suppression into metaconsciousness. Yet emerging research emphasizes the importance of nonconscious approaches to emotion regulation. This study is the first in which a craving rebound effect was evaluated without simultaneously raising awareness about suppression. We aimed to link spontaneously occurring attempts to suppress cigarette craving to increased smoking motivation assessed immediately thereafter. Smokers (n = 66) received a robust cued smoking-craving manipulation while their facial responses were videotaped and coded using the Facial Action Coding System. Following smoking-cue exposure, participants completed a behavioral choice task previously found to index smoking motivation. Participants evincing suppression-related facial expressions during cue exposure subsequently valued smoking more than did those not displaying these expressions, which suggests that internally generated suppression can exert powerful rebound effects. 22943152 Short-term incubation of equine laminar veins with cortisol and insulin alters contractility in vitro: possible implications for the pathogenesis of equine laminitis. This study investigated the effects of cortisol and insulin, hormones that affect both glycaemic status and vascular function, on the in vitro contractility of isolated healthy equine small laminar veins. Small veins (150-500 μm) draining the digital laminae from healthy horses or ponies were investigated by wire myography. Concentration response curves were constructed for noradrenaline (NA), phenylephrine (PE), endothelin-1 (ET-1) and 5-hydroxytryptamine (5-HT) in the presence of either cortisol (10(-6 ) m) or insulin (1000 μIU/mL). Cortisol significantly increased the maximum contractility of laminar veins to the vasoconstrictors NA and 5-HT but decreased the maximal contraction to ET-1. Insulin decreased the contractility of vessels to PE and ET-1. It is possible that short-term cortisol excess could enhance venoconstrictor responses to 5-HT and NA in laminar veins in vivo, thereby predisposing to laminitis. Additionally, a reduction in the ability of insulin to counteract alpha-adrenoreceptor and ET-1-mediated contraction, likely to occur in subjects with insulin resistance, may further exacerbate venoconstriction in animals prone to laminitis. These mechanisms may also predispose horses with disorders such as equine Cushing's disease and equine metabolic syndrome to laminitis. 23910501 Hypercoagulation following brain death cannot be reversed by the neutralization of systemic tissue factor. Cerebral injury and brain death is associated with apparent hypercoagulation and poor organ outcome. This experimental study challenges the hypotheses that i) brain death causes hypercoagulation and microvascular thrombosis and that ii) neutralizing systemic tissue factor (TF) by in vitro addition of a TF inhibitor (recombinant active site-inhibited factor VIIa (ASIS)) can reverse the hypercoagulable profile. Using a validated pig model of intracranial hemorrhage and brain death, 20 pigs were randomized to either control or brain death. The primary endpoints were coagulation parameters measured with whole blood thromboelastometry (ROTEM), thrombin generation and a porcine TF-sensitive plasma clotting time assay. In vitro spiking experiments with ASIS were performed in parallel with the latter two assessments. The kidneys were examined histologically for microvascular thromboses. Brain death induced hypercoagulation, as demonstrated with ROTEM, thrombin generation, and reduced TF-sensitive plasma clotting time. In vitro inhibition of TF with ASIS did not reverse the hypercoagulation. No microvascular thromboses were found in the kidneys. Brain death causes hypercoagulation; however, inhibition of TF does not reverse the coagulopathy. Thus, TF release does not seem to be the primary cause of this hypercoagulation. Minor changes in the levels of protein C suggest that the protein C pathway may be linked to the observed coagulopathy. 22622782 Stress distribution inside bone after suture anchor insertion: simulation using a three-dimensional finite element method. To define stress distribution patterns inside a bone around suture anchors inserted at different angles using a three-dimensional finite element (FE) method. An isotropic cube model (Young's modulus, 1,380 MPa; Poisson's ratio, 0.3) was designed on a computer to standardize analysis conditions. A virtual Twinfix anchor was inserted into the cube at two different angles (45° and 90°) against the top surface. A traction force (100 N) was applied to the anchor at six different angles (15°, 30°, 45°, 60°, 75° and 90°) against the top surface. Elastic analysis was performed, and the distribution of the von Mises equivalent stress inside the cube was calculated. The highest value of the equivalent stress at each traction angle was compared between the 45° and 90° anchor insertion settings. Stress concentration was most evident around proximal anchor threads, particularly on the traction side. Interestingly, stress gradually declined with an increase in traction angle only for the 90° insertion setting. At 15° and 90° traction angles, the equivalent stress was lower for the 45° insertion setting than for the 90° insertion setting. In contrast, the 90° insertion setting exhibited lower equivalent stress than the 45° insertion setting at 30°, 45° and 60° traction angles. Insertion of an anchor at 90° might reduce the stress concentration around the proximal anchor threads on the traction side and provide lower equivalent stress in the middle range of traction angles (30°-60°) than insertion at 45°. This could avoid early postoperative anchor failure. 23801065 Inhibitory effect of geraniol in combination with gemcitabine on proliferation of BXPC-3 human pancreatic cancer cells. To investigate the inhibitory effect of geraniol alone, or in combination with gemcitabine, on the proliferation of BXPC-3 pancreatic cancer cells. BXPC-3 cells were treated under different conditions: with geraniol at 10, 20, 40, 80 and 160 µmol/l each for 24 h, 48 h or 72 h; with 20 µmol/l geraniol for 24 h or 0 h before 20 µmol/l gemcitabine for 24 h; with 20 µmol/l geraniol for 24 h, 48 h and 72 h following 20 µmol/l gemcitabine for 24 h; or with 20 µmol/l gemcitabine alone as a control. Cell proliferation was assessed and changes in cell morphology were assessed by light and fluorescence microscopy. Apoptosis was detected using flow cytometry. Geraniol inhibited BXPC-3 cell proliferation in a time- and dosa-dependent manner. Geraniol alone or combined with gemcitabine induced BXPC-3 cell apoptosis. BXPC-3 inhibition rates with combined treatment were 55.24%, 50.69%, 49.83%, 41.85% and 45.27% following treatment with 20 µmol/l geraniol for 24 h or 0 h before 20 µmol/l gemcitabine for 24 h, or 20 µmol/l geraniol for 24 h, 48 h and 72 h, following 20 µmol/l gemcitabine for 24 h, respectively. Geraniol inhibited the proliferation of BXPC-3 cells. Geraniol significantly increased the antiproliferative and apoptosis-inducing effects of gemcitabine on BXPC-3 cells. Maximum inhibition of BXPC-3 cells was achieved with geraniol treatment for 24 h before gemcitabine treatment. 23955044 Three-dimensional phase-contrast X-ray microtomography with scanning-imaging X-ray microscope optics. A three-dimensional (3D) X-ray tomographic micro-imaging system has been developed. The optical system is based on a scanning-imaging X-ray microscope (SIXM) optics, which is a hybrid system consisting of a scanning microscope optics with a one-dimensional (1D) focusing (line-focusing) device and an imaging microscope optics with a 1D objective. In the SIXM system, each 1D dataset of a two-dimensional (2D) image is recorded independently. An object is illuminated with a line-focused beam. Positional information of the region illuminated by the line-focused beam is recorded with the 1D imaging microscope optics as line-profile data. By scanning the object with the line focus, 2D image data are obtained. In the same manner as for a scanning microscope optics with a multi-pixel detector, imaging modes such as phase contrast and absorption contrast can be arbitrarily configured after the image data acquisition. By combining a tomographic scan method and the SIXM system, quantitative 3D imaging is performed. Results of a feasibility study of the SIXM for 3D imaging are shown. 23908977 The association between serum 25-hydroxyvitamin d concentration and consumption frequencies of vitamin d food sources in korean adolescents. The objectives of this study were to investigate the status of vitamin D in Korean adolescents and to determine the association between serum 25-hydroxyvitamin D (25(OH)D) concentration and consumption frequencies of vitamin D food sources by season (June to November and December to May). The subjects were 1,579 adolescents aged 12-18 years participating in the 2008-2009 Korean National Health and Nutrition Examination Survey (KNHANES). Consumption frequencies of vitamin D food sources were estimated by using a qualitative food frequency questionnaire (FFQ). Thirteen food items were selected as vitamin D food sources including beef, egg, mackerel, tuna, yellow corvine, pollack, anchovy, mushroom, milk, yoghurt, ice cream, all fish and dairy products from the FFQ based on previous research. The data was analyzed using proc survey procedures. The deficiency (5.25-12 ng/mL), inadequacy (12-20 ng/mL) and sufficiency (> 20 ng/mL) proportions of serum 25(OH)D from June to November and December to May were 9.9%, 51.4%, 38.7%, and 39.4%, 51.4%, 9.2%, respectively. Mean serum 25(OH)D concentration was positively related to the consumption frequencies of mackerel, anchovy, all fish and milk. These results suggest high proportion (> 61%) of Korean adolescents were vitamin D deficiency or inadequacy, and serum 25(OH)D was associated with the consumption of vitamin D food sources including fish and milk. 23899067 Hirschsprung disease and use of calretinin in inadequate rectal suction biopsies. Context.-Up to 17% of all rectal suction biopsies performed in the evaluation of Hirschsprung disease are considered inadequate. In most instances, inadequate biopsies contain too little submucosa or are taken within the anal transition zone. Objectives.-To examine the utility of calretinin stain in the workup of inadequate biopsies for patients with clinical suspicion of Hirschsprung disease. Design.-A retrospective analysis was conducted of all rectal suction biopsies performed in the evaluation of Hirschsprung disease during the previous 12 years that were considered "inadequate." Seventeen cases were identified, and Hirschsprung disease status was determined by clinical or surgical follow-up. Immunohistochemistry for calretinin was performed for all cases containing columnar mucosa, which were evaluated without knowledge of clinical course. Results.-All 12 patients without Hirschsprung disease had calretinin-positive nerve fibers in the lamina propria or muscularis mucosae, and all 5 patients with Hirschsprung disease had no calretinin staining of nerves. Conclusions.-In this retrospective series, calretinin immunohistochemistry correctly predicted outcome in all instances. Although the gold standard for the diagnosis of Hirschsprung disease in rectal suction biopsies remains the evaluation of ganglion cells in a hematoxylin-eosin staining with sufficient submucosa, calretinin immunohistochemistry is quite helpful in triaging further workup based on clinical suspicion. 23914942 Reaction of Dimethyl Ether with Hydroxyl Radicals: Kinetic Isotope Effect and Prereactive Complex Formation. The kinetic isotope effect of the reactions OH + CH3OCH3 (DME) and OH + CD3OCD3 (DME-d6) was experimentally and theoretically studied. Experiments were carried out in a slow-flow reactor at pressures between 5 and 21 bar (helium as bath gas) with production of OH by laser flash photolysis of HNO3 and time-resolved detection of OH by laser-induced fluorescence. The temperature dependences of the rate coefficients obtained can be described by the following modified Arrhenius expressions: kOH+DME = (4.5 ± 1.3) × 10(-16) (T/K)(1.48) exp(66.6 K/T) cm(3) s(-1) (T = 292-650 K, P = 5.9-20.9 bar) and kOH+DME-d6 = (7.3 ± 2.2) × 10(-23) (T/K)(3.57) exp(759.8 K/T) cm(3) s(-1) (T = 387-554 K, P = 13.0-20.4 bar). A pressure dependence of the rate coefficients was not observed. The agreement of our experimental results for kOH+DME with values from other authors is very good, and from a fit to all available literature data, we derived the following modified Arrhenius expression, which reproduces the values obtained in the temperature range T = 230-1500 K at pressures between 30 mbar and 21 bar to better than within ±20%: kOH+DME = 8.45 × 10(-18) (T/K)(2.07) exp(262.2 K/T) cm(3) s(-1). For kOH+DME-d6, to the best of our knowledge, this is the first experimental study. For the analysis of the reaction pathway and the kinetic isotope effect, potential energy diagrams were calculated by using three different quantum chemical methods: (I) CCSD(T)/cc-pV(T,Q)Z//MP2/6-311G(d,p), (II) CCSD(T)/cc-pV(T,Q)Z//CCSD/cc-pVDZ, and (III) CBS-QB3. In all three cases, the reaction is predicted to proceed via a prereaction OH-ether complex with subsequent intramolecular hydrogen abstraction and dissociation to give the methoxymethyl radical and water. Overall rate coefficients were calculated by assuming a thermal equilibrium between the reactants and the prereaction complex and by calculating the rate coefficients of the hydrogen abstraction step from canonical transition state theory. The results based on the molecular data from methods (I) and (II) showed a satisfactory agreement with the experimental values, which indicates that the pre-equilibrium assumption is reasonable under our conditions. In the case of method (III), the isotope effect was significantly underpredicted. The reason for this discrepancy was identified in a fundamentally differing reaction coordinate. Obviously, the B3LYP functional applied in method (III) for geometry and frequency calculations is inadequate to describe such systems, which is in line with earlier findings of other authors. 23842035 Repeated Heat Exposure Impairs Nigrostriatal Dopaminergic Neurons in Mice. Environmental heat stress is associated with physical stress responses, including changes in monoamines, protein expression, and neuronal circuits and damage to neurons in the brain. This study determined the effects of heat stress on the nigrostriatal dopaminergic system based on behavioral, histological, and neurochemical analyses. To evaluate behavioral changes after heat exposure, we subjected mice to the pole and open field tests. The data suggested that heat stress for 7 days significantly impaired movement. Then, we conducted a histological analysis using tyrosine hydroxylase (TH) immunoreactivity in the striatum and substantia nigra (SN). Heat stress induced a significant deficit in TH-positive fibers and cells after 14- and 21-day exposure, respectively. We also measured the striatal dopamine (DA), 4-hydroxy-3-methoxy-phenylacetic acid, and 3,4-dihydroxyphenylacetic acid levels. The data suggested that DA turnover rate increased with heat exposure in a time-dependent manner, resulting in the significant decrease of DA after 28 days. Moreover, the expression of heat shock protein 70 (HSP70) was increased in the mouse SN with up to 14-day heat exposure, but decreased after 21 days of the stress. And glucose-regulated protein 78 (GRP78) was gradually increased in the mouse SN with 28-day heat exposure. The caspase-3 activity was also increased after 14-day heat exposure. These findings are the first evidence that repeated heat stress impairs nigrostriatal dopaminergic neurons, motor function, and DA availability with changes of HSP70 and GRP78 expressions and caspase-3 activity in mice. 23868109 Influence of seasonal variation on blood pressure measurements in children, adolescents and young adults. Seasonal fluctuations in outdoor temperature have been shown to affect blood pressure in adults. The aim of our study was to determine whether blood pressure measurements in children and adolescents in Central Europe undergo seasonal variation or are influenced by outdoor temperature. The blood pressure of 6,714 subjects (3,497 boys, 3,237 girls) aged 3 to 21 (median age 10.6) years was routinely measured. The study cohort comprised both healthy and sick children and adolescents visiting outpatient clinics and during hospitalisation. Cross-sectional analysis showed a significant seasonal variation in blood pressure measurements. The mean increase of systolic/diastolic blood pressure was 4.45/2.42 mmHg during the winter. A significant correlation between average outdoor temperature and systolic blood pressure was found (ρ = -0.074 p < 0.001). However, the effect was only detectable at an average temperature below 0 °C/32 °F and above 10 °C/50 °F. For each 1 °C increase in average outdoor temperature, the systolic blood pressure fell by 0.12 mmHg. Blood pressure measurements in children and adolescents, even in a temperate climate, are influenced by temperature and subject to seasonal variation. Considering seasonal variations in blood pressure could be of clinical interest. 23871240 Passive Joint Forces Are Tuned to Limb Use in Insects and Drive Movements without Motor Activity. Limb movements are generally driven by active muscular contractions working with and against passive forces arising in muscles and other structures. In relatively heavy limbs, the effects of gravity and inertia predominate, whereas in lighter limbs, passive forces intrinsic to the limb are of greater consequence. The roles of passive forces generated by muscles and tendons are well understood, but there has been little recognition that forces originating within joints themselves may also be important, and less still that these joint forces may be adapted through evolution to complement active muscle forces acting at the same joint. We examined the roles of passive joint forces in insect legs with different arrangements of antagonist muscles. We first show that passive forces modify actively generated movements of a joint across its working range, and that they can be sufficiently strong to generate completely passive movements that are faster than active movements observed in natural behaviors. We further demonstrate that some of these forces originate within the joint itself. In legs of different species adapted to different uses (walking, jumping), these passive joint forces complement the balance of strength of the antagonist muscles acting on the joint. We show that passive joint forces are stronger where they assist the weaker of two antagonist muscles. In limbs where the dictates of a key behavior produce asymmetry in muscle forces, passive joint forces can be coadapted to provide the balance needed for the effective generation of other behaviors. 23955710 Inducible expression of p50 from TMV for increased resistance to bacterial crown gall disease in tobacco. The dominant tobacco mosaic virus (TMV) resistance gene N induces a hypersensitive response upon TMV infection and protects tobacco against systemic spread of the virus. It has been proposed to change disease resistance specificity by reprogramming the expression of resistance genes or their corresponding avirulence genes. To reprogramme the resistance response of N towards bacterial pathogens, the helicase domain (p50) of the TMV replicase, the avirulence gene of N, was linked to synthetic promoters 4D and 2S2D harbouring elicitor-responsive cis-elements. These promoter::p50 constructs induce local necrotic lesions on NN tobacco plants in an Agrobacterium tumefaciens infiltration assay. A tobacco genotype void of N (nn) was transformed with the promoter::p50 constructs and subsequently crossed to NN plants. Nn F1 offspring selected for the T-DNA develop normally under sterile conditions. After transfer to soil, some of the F1 plants expressing the 2S2D::p50 constructs develop spontaneous necrosis. Transgenic Nn F1 plants with 4D::p50 and 2S2D::p50 expressing constructs upregulate p50 transcription and induce local necrotic leasions in an A. tumefaciens infiltration assay. When leaves and stems of Nn F1 offspring harbouring promoter::p50 constructs are infected with oncogenic A. tumefaciens C58, transgenic lines harbouring the 2S2D::p50 construct induce necrosis and completely lack tumor development. These results demonstrate a successful reprogramming of the viral N gene response against bacterial crown gall disease and highlight the importance of achieving tight regulation of avirulence gene expression and the control of necrosis in the presence of the corresponding resistance gene. 23782694 Comparative Characterization of Two Marine Alginate Lyases from Zobellia galactanivorans Reveals Distinct Modes of Action and Exquisite Adaptation to Their Natural Substrate. Cell walls of brown algae are complex supramolecular assemblies containing various original, sulfated, and carboxylated polysaccharides. Among these, the major marine polysaccharide component, alginate, represents an important biomass that is successfully turned over by the heterotrophic marine bacteria. In the marine flavobacterium Zobellia galactanivorans, the catabolism and uptake of alginate are encoded by operon structures that resemble the typical Bacteroidetes polysaccharide utilization locus. The genome of Z. galactanivorans contains seven putative alginate lyase genes, five of which are localized within two clusters comprising additional carbohydrate-related genes. This study reports on the detailed biochemical and structural characterization of two of these. We demonstrate here that AlyA1PL7 is an endolytic guluronate lyase, and AlyA5 cleaves unsaturated units, α-l-guluronate or β-d-manuronate residues, at the nonreducing end of oligo-alginates in an exolytic fashion. Despite a common jelly roll-fold, these striking differences of the mode of action are explained by a distinct active site topology, an open cleft in AlyA1PL7, whereas AlyA5 displays a pocket topology due to the presence of additional loops partially obstructing the catalytic groove. Finally, in contrast to PL7 alginate lyases from terrestrial bacteria, both enzymes proceed according to a calcium-dependent mechanism suggesting an exquisite adaptation to their natural substrate in the context of brown algal cell walls. 23864189 Risk factors for thirty-day morbidity and mortality following knee arthroscopy: a review of 12,271 patients from the national surgical quality improvement program database. Knee arthroscopy is among the most common orthopaedic surgical procedures. However, the incidence and risk factors for postsurgical morbidity and mortality remain poorly defined. The American College of Surgeons National Surgical Quality Improvement Program prospectively collects thirty-day morbidity and mortality data from more than 258 hospitals around the United States. We used Current Procedural Terminology codes to retrospectively query the database and identified 12,271 cases of elective knee arthroscopy performed from January 1, 2005, to December 31, 2010. Postoperative complications were divided into categories of minor morbidity, major morbidity or mortality, or any complication. The potential risk factors for complications were analyzed with use of univariate and multivariate analyses. The overall incidence of any complication was 1.6% (199 patients). The major morbidity was 0.76% (ninety-three patients), which included one patient death (0.008%), and the minor morbidity was 0.86% (106 patients). The most frequent major complication was a return to the operating room. The most common minor complication was deep venous thrombosis or thrombophlebitis. The risk factors identified in the univariate analysis for any complication included black race, prior operation within thirty days, American Society of Anesthesiologists class, and operative time of >1.5 hours as compared with ≤1.5 hours (p < 0.05 for each). The independent risk factors identified in the multivariate analysis for any complication included black race (odds ratio, 1.81 [95% confidence interval, 1.13 to 2.89]), prior operation within thirty days (odds ratio, 6.33 [95% confidence interval, 1.45 to 27.66]), operative time of >1.5 hours (odds ratio, 1.84 [95% confidence interval, 1.21 to 2.78]), and age of forty to sixty-five years (odds ratio, 1.46 [95% confidence interval, 1.01 to 2.11]). The incidence of complication following elective knee arthroscopy is low. The data presented here should be useful for providing prognostic information to patients during informed consent. Surgeons should be encouraged to minimize operative time whenever possible, and may wish to delay elective arthroscopy in patients who have had other recent surgical procedures. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. 23934574 Inhibition of NF-κB transcriptional activation in HepG2 cells by diterpenoids from the soft coral Sinularia maxima. Anti-inflammatory transcriptional effects of nineteen compounds (1-19) from the soft coral Sinularia maxima were evaluated using NF-κB luciferase and reverse transcriptase polymerase chain reaction. Compounds 1, 2, 4, 8, 15, 17, and 18 significantly inhibited TNFα-induced NF-κB transcriptional activity in HepG2 cells in a dose-dependent manner, with IC50 values ranging from 15.81 ± 2.29 to 29.10 ± 1.54 Î¼M. Furthermore, the transcriptional inhibitory function of these compounds was confirmed by a decrease in intercellular adhesion molecule-1 and inducible nitric oxide synthase gene expression levels in HepG2 cells. These results provide a scientific rationale for the use of the soft coral S. maxima warrant further studies to develop new agents for the prevention and treatment of inflammatory. 23380478 Carbon monoxide protects against ovariectomy-induced bone loss by inhibiting osteoclastogenesis. Carbon monoxide (CO) has been shown to have remarkable therapeutic value at low dosage by suppressing inflammation via inhibitory effects on macrophages, which are also precursors of osteoclasts (OC). The objective of the present study was to determine whether CO limits bone loss through its effects on osteoclastogenesis. Intraperitoneal injection of CO-releasing molecule 2 (CORM2) into mice with reduced bone mass due to ovariectomy (OVX) resulted in significantly elevated bone mass. Increased serum levels of collagen-type I fragments, tartrate-resistant acid phosphatase 5b, and reactive oxygen species (ROS) due to OVX were also decreased when treated with CORM2. In vitro, CORM2 inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced OC formation without affecting bone resorption. CORM2 reduced long-lasting ROS levels and nuclear factor-κB (NF-κB) activation in response to RANKL. Inhibition of NADPH oxidase partially reduced the inhibitory effect of CO. CO induced increase of peroxiredoxin 1 (PRX1) in BMM. Down-regulation of PRX1 reduced the inhibitory effect of CO on OC formation and sustained the ROS levels induced by RANKL, suggesting that CO reduces generation of ROS and scavenges ROS to inhibit osteoclastogenesis. These data suggest that the inhibitory effect of CO on osteoclastogenesis is caused by impaired RANKL signaling through defective NF-κB activation and reduced levels of long-lasting ROS. These changes result in decreased bone loss. Our data highlight the potential utility of CO for ameliorating bone loss induced by loss of ovarian function. 23541215 Synergistic effects of diosmetin with erythromycin against ABC transporter over-expressed methicillin-resistant Staphylococcus aureus (MRSA) RN4220/pUL5054 and inhibition of MRSA pyruvate kinase. Increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) worldwide with limited therapeutic options is a growing public health concern. Natural products have been shown to possess antibacterial actions against MRSA. Flavonoids from natural products have been shown to possess antibacterial actions against MRSA by antagonizing its resistance mechanisms. Diosmin and diosmetin are natural flavonoids found in a variety of citrus fruits. The aim of this study was to investigate whether diosmin and diosmetin could inhibit the growth of MRSA and the in vitro enzymatic activity of a newly discovered MRSA drug target, pyruvate kinase (PK). By using a panel of MRSA strains with known resistant mechanisms, neither diosmin nor diosmetin was shown to possess direct antibacterial activities against all tested MRSA strains. However, in checkerboard assay, we found that diosmetin together with erythromycin, could synergistically inhibit the growth of ABC-pump overexpressed MRSA-RN4220/pUL5054, and time kill assay also showed that the antibacterial activities of diosmetin with erythromycin were bactericidal. Diosmetin was further shown to significantly suppress the MRSA PK activities in a dose dependent manner. In conclusion, the inhibition of MRSA PK by diosmetin could lead to a deficiency of ATP and affect the bacterial efflux pump which might contribute to the antibacterial actions of diosmetin against MRSA. 23961811 Surgical portosystemic shunts in the era of TIPS and liver transplantation are still relevant. The surgical portosystemic shunts (PSS) are a time-proven modality for treating portal hypertension. Recently, in the era of liver transplantation and the transjugular intrahepatic portosystemic shunts (TIPS), use of the PSS has declined. This study was conducted to evaluate changes in practice, referral patterns, and short- and longterm outcomes of the use of the surgical PSS before and after the introduction of the Model for End-stage Liver Disease (MELD). A retrospective analysis of 47 patients undergoing PSS between 1996 and 2011 in a single university hospital was conducted. Subgroups of patients with cirrhosis (53%), Budd-Chiari syndrome (13%), portal vein thrombosis (PVT) (26%), and other pathologies (9%) differed significantly with respect to shunt type, Child-Pugh class, MELD score and perioperative mortality. Perioperative mortality at 60 days was 15%. Five-year survival was 68% (median: 70 months); 5-year shunt patency was 97%. Survival was best in patients with PVT and worst in those with Budd-Chiari syndrome compared to other subgroups. Patency was better in the subgroups of patients with cirrhosis and other pathologies compared with the PVT subgroup. Substantial changes in referral patterns coincided with the adoption of the MELD in 2002, with decreases in the incidence of cirrhosis and variceal bleeding, and increases in non-cirrhotics and hypercoagulopathy. Although the spectrum of diseases benefiting from surgical PSS has changed, surgical shunts continue to constitute an important addition to the surgical armamentarium. Selected subgroups with variceal bleeding in well-compensated cirrhosis and PVT benefit from the excellent longterm patency offered by the surgical PSS. 23914185 Controls on bacterial and archaeal community structure and greenhouse gas production in natural, mined, and restored Canadian peatlands. Northern peatlands are important global C reservoirs, largely because of their slow rates of microbial C mineralization. Particularly in sites that are heavily influenced by anthropogenic disturbances, there is scant information about microbial ecology and whether or not microbial community structure influences greenhouse gas production. This work characterized communities of bacteria and archaea using terminal restriction fragment length polymorphism (T-RFLP) and sequence analysis of 16S rRNA and functional genes across eight natural, mined, or restored peatlands in two locations in eastern Canada. Correlations were explored among chemical properties of peat, bacterial and archaeal community structure, and carbon dioxide (CO2) and methane (CH4) production rates under oxic and anoxic conditions. Bacteria and archaea similar to those found in other peat soil environments were detected. In contrast to other reports, methanogen diversity was low in our study, with only 2 groups of known or suspected methanogens. Although mining and restoration affected substrate availability and microbial activity, these land-uses did not consistently affect bacterial or archaeal community composition. In fact, larger differences were observed between the two locations and between oxic and anoxic peat samples than between natural, mined, and restored sites, with anoxic samples characterized by less detectable bacterial diversity and stronger dominance by members of the phylum Acidobacteria. There were also no apparent strong linkages between prokaryote community structure and CH4 or CO2 production, suggesting that different organisms exhibit functional redundancy and/or that the same taxa function at very different rates when exposed to different peat substrates. In contrast to other earlier work focusing on fungal communities across similar mined and restored peatlands, bacterial and archaeal communities appeared to be more resistant or resilient to peat substrate changes brought about by these land uses. 23674552 Body size and endometriosis: results from 20 years of follow-up within the Nurses' Health Study II prospective cohort. Is there a relationship between body mass index (BMI), body shape and endometriosis? Endometriosis is inversely associated with early adult BMI and may correlate with a peripheral body fat distribution. The literature suggests an inverse relation between endometriosis and BMI, although few studies have specifically explored this association in depth. Prospective cohort study using data collected from 116 430 female nurses from September 1989 to June 2011 as part of the Nurses' Health Study II cohort. PARTICIPANTS/MATERIALS, METHODS AND SETTING: Cases were restricted to laparoscopically confirmed endometriosis. Weight at age 18 and height were reported at baseline, and current weight was updated every 2 years. Waist and hip measurements were first taken in 1993 and updated in 2005. Rate ratios (RR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models with time-varying covariates. A total of 5504 incident cases of endometriosis were reported during 1 299 349 woman-years (incidence rate = 385 per 100 000 woman-years). BMI at age 18 and current BMI were each significantly inversely associated with endometriosis (P-value, test for linear trend <0.0001). Both associations were stronger among infertile women. Obese infertile women with current BMIs of 35-39.9 kg/m(2) and ≥ 40 kg/m(2) had a 55% (95% CI 0.30-0.67) and a 62% (95% CI 0.23-0.62) lower risk of endometriosis, respectively, compared with the low-normal BMI referent (18.5-22.4 kg/m(2)). Rates of endometriosis were nearly 3-fold higher in women with waist-to-hip ratios <0.60 (RR = 2.78, 95% CI 1.38-5.60) compared with those with waist-to-hip ratios between 0.70 and 0.79, although the sample size for this category was very small. Although women with undiagnosed endometriosis certainly remain in the comparison population even in this prospective cohort study, the community prevalence of endometriosis in an asymptomatic population is very low. Moreover, the characteristics of this small proportion of undiagnosed cases are diluted among the >90 000 women accurately defined as being endometriosis-free and are, therefore, unlikely to impact on effect estimation. Although geographically diverse, the NHS II cohort is overwhelmingly Caucasian, which may limit generalizability to more ethnically diverse populations. WIDER IMPLICATIONS OF THE STUDY: The results of this study suggest that endometriosis is inversely associated with early adult BMI and may correlate with a peripheral body fat distribution. 22907766 Uncommon presentations of parathyroid adenoma. Patients with parathyroid adenomas (PAs) are commonly encountered in otolaryngology and may present with asymptomatic hypercalcemia. Retropharyngeal hematoma and recurrent laryngeal nerve (RLN) paralysis are less commonly encountered presentations and may be harbingers of a malignant process. We present 2 patients with rare presentations of parathyroid adenoma. The first is a 57-year-old man with retropharyngeal hemorrhage and progressive airway compromise. The second is a 51-year-old woman presenting with dysphonia who was found to have RLN paralysis. Both of these patients were found to have benign disease. Although most patients with PA present with asymptomatic hypercalcemia, this disease entity must be considered in patients with other unusual presentations including hemorrhagic neck masses and dysphonia. The importance of a broad differential diagnosis and thorough workup is emphasized. © 2012 Wiley Periodicals, Inc. Head Neck, 2013. 23425114 Antinociceptive effect of 7-methoxyflavone isolated from Zornia brasiliensis. In this study, we investigated the antinociceptive effect of 7-methoxyflavone (7MF) in mice using the following tests: acetic acid-induced writhing, glutamate- and formalin-induced nociception and hotplate. 7MF (30, 50, 100 and 300 μmol/kg, i.p.) reduced the number of writhes, with ID(50) = 82.5 ± 11.7 μmol/kg and E (max) = 58.4%. 7MF treatment (100 μmol/kg, i.p.) inhibited paw-licking time in the neurogenic phase of the formalin pain response (65.6%) and did not decrease the nociceptive response in the inflammatory phase. In addition, in glutamate-induced nociception, 7MF inhibited 26% of the nociceptive answer. On the other hand, 7MF did not increase the latency time of the animals in the hotplate test. These results suggest that 7MF has peripheral antinociceptive activity. 23499889 Identification and impact of hepatitis B virus DNA and antigens in pancreatic cancer tissues and adjacent non-cancerous tissues. Increasing evidence suggests that a link exists between hepatitis B virus (HBV) serum markers and pancreatic cancer (PC). In this study, HBsAg and HBcAg were expressed in 21.0% (34/162) of PC and 29.0% (47/162) of non-tumor pancreatic tissues, and they were significantly associated with chronic pancreatitis (P=0.000). The HBV S, C and X genes were identified in 20% (6/30) of PC and 26.9% (7/26) of non-tumor tissues by PCR. A serological survey revealed that the prevalence of HBV DNA and anti-HBc was significantly increased in PC patients compared with healthy controls. Our data suggest that HBV infection in the pancreas may play an etiologic role in PC. 23711475 Computational modeling of MR flow imaging by the lattice Boltzmann method and Bloch equation. In this work, a computational model of magnetic resonance (MR) flow imaging is proposed. The first model component provides fluid dynamics maps by applying the lattice Boltzmann method. The second one uses the flow maps and couples MR imaging (MRI) modeling with a new magnetization transport algorithm based on the Eulerian coordinate approach. MRI modeling is based on the discrete time solution of the Bloch equation by analytical local magnetization transformations (exponential scaling and rotations). Model is validated by comparison of experimental and simulated MR images in two three-dimensional geometries (straight and U-bend tubes) with steady flow under comparable conditions. Two-dimensional geometries, presented in literature, were also tested. In both cases, a good agreement is observed. Quantitative analysis shows in detail the model accuracy. Computational time is noticeably lower to prior works. These results demonstrate that the discrete time solution of Bloch equation coupled with the new magnetization transport algorithm naturally incorporates flow influence in MRI modeling. As a result, in the proposed model, no additional mechanism (unlike in prior works) is needed to consider flow artifacts, which implies its easy extensibility. In combination with its low computational complexity and efficient implementation, the model could have a potential application in study of flow disturbances (in MRI) in various conditions and in different geometries. 23904404 Modular 32-channel transceiver coil array for cardiac MRI at 7.0T. To design and evaluate a modular transceiver coil array with 32 independent channels for cardiac MRI at 7.0T. The modular coil array comprises eight independent building blocks, each containing four transceiver loop elements. Numerical simulations were used for B1 (+) field homogenization and radiofrequency (RF) safety validation. RF characteristics were examined in a phantom study. The array's suitability for accelerated high spatial resolution two-dimensional (2D) FLASH CINE imaging of the heart was examined in a volunteer study. Transmission field adjustments and RF characteristics were found to be suitable for the volunteer study. The signal-to-noise intrinsic to 7.0T together with the coil performance afforded a spatial resolution of 1.1 × 1.1 × 2.5 mm(3) for 2D CINE FLASH MRI, which is by a factor of 6 superior to standardized CINE protocols used in clinical practice at 1.5T. The 32-channel transceiver array supports one-dimensional acceleration factors of up to R = 4 without impairing image quality significantly. The modular 32-channel transceiver cardiac array supports accelerated and high spatial resolution cardiac MRI. The array is compatible with multichannel transmission and provides a technological basis for future clinical assessment of parallel transmission techniques at 7.0T. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc. 23404255 Introduction of selective intersubunit disulfide bonds into self-assembly protein scaffold to enhance an artificial multienzyme complex's activity. In nature, many enzymes participating in multienzyme reactions are often assembled to enhance efficiencies of multiple reactions. Therefore, much attention has been focused on self-assembly of multiple enzymes fused with a protein/peptide that interacts with a specific protein to enhance artificial multienzyme reactions. Sulfolobus solfataricus proliferating cell nuclear antigen (PCNA) is a ring-shaped symmetric heterotrimer consisting of PCNA1, PCNA2 and PCNA3. Multiple enzymes can be co-localized on the PCNA ring by fusing them to the C-termini of the three PCNA subunits. However, an advantage of the specific non-covalent complex formation is inextricably associated with the disadvantage of its concentration-dependent dissociation. In this study, disulfide bonds were introduced between the PCNA subunits by Cys substitution at the sites neighboring the interface for heterotrimerization. Selective intersubunit disulfide bond formation between PCNA1 and PCNA3 and between PCNA2 and PCNA3 by a natural oxidizing reagent successfully stabilized an artificial multienzyme complex, which is composed of a bacterial cytochrome P450 and its two redox partner proteins. The covalent stabilization of the multienzyme complex enhanced its cytochrome P450 activity because of the absence of inactive dissociated components. 23967322 Extrauterine listeriosis in the gravid mouse influences embryonic growth and development. Gravid mice and other rodents inoculated with Listeria monocytogenes typically fail to clear an intrauterine infection and either succumb or expel their intrauterine contents. We took advantage of this property to investigate the effects of an extrauterine infection on parameters of pregnancy success. Pregnant mice were selected for our study if they showed no clinical signs of listeriosis following oral inoculation at 7.5 gestational days (gd), and had no detectable intrauterine colony forming units (cfu) at near term (18.5 gd). The range of oral doses employed was 10(6)-10(8) cfu per mouse for two listerial serotype strains (4nonb and 1/2a). At all doses, inoculation resulted in a decrease in average near-term (18.5 gd) fetal weight per litter compared to sham inoculated controls. Additionally, embryonic death (indicated by intrauterine resorptions) was exhibited by some inoculated mice but was absent in all sham inoculated animals. In parallel experiments designed to detect possible loss of placental function, gravid uteruses were examined histopathologically and microbiologically 96 h after oral inoculation. Placental lesions were associated with high (> 10(6)), but not low (< 10(2)) or absent intrauterine cfu. In vitro, mouse embryonic trophoblasts were indistinguishable from mouse enterocytes in terms of their sensitivity to listerial exposure. A model consistent with our observations is one in which products (host or bacterial) generated during an acute infection enter embryos transplacentally and influences embryonic survival and slows normal growth in utero. 23928892 Narrow-band imaging and white light endoscopy for detection of missed colorectal polyps - randomized study. INTRODUCTION Narrow-band imaging (NBI) is a new, promising technology that might be helpful in finding colorectal polyps. OBJECTIVES The aim of the study was to determine the usefulness of NBI for detection of missed polyps during second-look colonoscopy, as well as in the distribution of the missed colon polyps. PATIENTS AND METHODS This was a randomised controlled trial. Double colonoscopies with polypectomies with the first look in white light (WLE) and the other in WLE or NBI were performed on adult patients who were referred for a screening or a diagnostic colonoscopy. The miss rate of adenomas and hyperplastic polyps in WLE and NBI were noted. RESULTS Two hundred fifty-three total patients were included: 126 in the WLE group and 127 in the NBI group. Overall, 38 polyps (11 adenomas) in the WLE group and 48 polyps (19 adenomas) in the NBI group were found in the second-look colonoscopy. No significant difference was found between the WLE and NBI in the detection of all polyps, adenomas and hyperplastic polyps (38 vs. 48, P < 0.2051; 11 vs. 19, P < 0.12; 27 vs. 29, P < 0.4647 for WLE and NBI respectively). Fifty percent (15/30) of all missed adenomas were found in the cecum and the ascending colon. CONCLUSIONS WLE and NBI seem to be equally effective in finding missed adenomas and hyperplastic polyps during colonoscopy. A second look endoscopy of the cecum and the ascending colon may substantially improve adenoma detection, which necessitates further study. 23948474 Physiological control of bioluminescence in a deep-sea planktonic worm,Tomopteris helgolandica Greeff, 1879. Tomopteris helgolandica Greeff 1879 (Tomopteridae) is a transparent holoplanktonic polychaete that can emit a bright light. In this work, we investigated the emission pattern and control of this deep-sea worm's luminescence. Potassium chloride depolarisation applied on anesthetised specimens triggered a maximal yellow light emission from specific parapodial sites, suggesting that a nervous control pathway was involved. A pharmacological screening revealed a sensitivity to carbachol, which was confirmed by a dose-light response associated with a change in the light emission pattern, where physiological carbachol concentrations induced flashes and higher concentrations induced glows. The light response induced by its hydrolysable agonist, acetylcholine, was significantly weaker but was facilitated by eserine pretreatment. In addition, a specific inhibitory effect of tubocurarine was observed on carbachol-induced emission. Lastly, KCl- and carbachol-induced light responses were significantly reduced when preparations were pre-incubated in Ca2+-free artificial sea water or in different calcium channel blockers (verapamil, diltiazem) and calmodulin inhibitor (trifluoperazine) solutions. All of these results strongly suggest that T. helgolandica produces its light flashes via activating nicotinic cholinergic receptors and a calcium-dependent intracellular mechanism involving L-type calcium channels. 23871723 Imprinted Chromatin around DIRAS3 Regulates Alternative Splicing of GNG12-AS1, a Long Noncoding RNA. Imprinted gene clusters are regulated by long noncoding RNAs (lncRNAs), CCCTC binding factor (CTCF)-mediated boundaries, and DNA methylation. DIRAS3 (also known as ARH1 or NOEY1) is an imprinted gene encoding a protein belonging to the RAS superfamily of GTPases and is located within an intron of a lncRNA called GNG12-AS1. In this study, we investigated whether GNG12-AS1 is imprinted and coregulated with DIRAS3. We report that GNG12-AS1 is coexpressed with DIRAS3 in several tissues and coordinately downregulated with DIRAS3 in breast cancers. GNG12-AS1 has several splice variants, all of which initiate from a single transcription start site. In placenta tissue and normal cell lines, GNG12-AS1 is biallelically expressed but some isoforms are allele-specifically spliced. Cohesin plays a role in allele-specific splicing of GNG12-AS1. In breast cancer cell lines with loss of DIRAS3 imprinting, DIRAS3 and GNG12-AS1 are silenced in cis and the remaining GNG12-AS1 transcripts are predominantly monoallelic. The GNG12-AS1 locus, which includes DIRAS3, provides an example of imprinted cotranscriptional splicing and a potential model system for studying the long-range effects of CTCF-cohesin binding on splicing and transcriptional interference. 23889679 In Situ Microscopy for In-line Monitoring of the Enzymatic Hydrolysis of Cellulose. A new in-line method for the monitoring of enzymatic hydrolysis of cellulose is described. Using a new in situ microscope prototype, the noninvasive determination of particle size distributions was possible. For the automated analysis of the acquired images, a new processing algorithm called CelluloseAnalyzer was developed. It enabled tracking of the number of particles and moreover allowed monitoring of the proportions of particle size fractions during the course of enzymatic hydrolysis reactions. Using this technique, significant differences between hydrolysis with endoglucanases and cellulase mixtures were observed. Furthermore, the in situ microscopy results were compared with results from off-line measurements with laser diffraction spectroscopy and gel permeation chromatography. 23664883 Transgenic indica rice lines, expressing Brassica juncea Nonexpressor of pathogenesis-related genes 1 (BjNPR1), exhibit enhanced resistance to major pathogens. Brassica juncea Nonexpressor of pathogenesis-related genes 1 (BjNPR1) has been introduced into commercial indica rice varieties by Agrobacterium-mediated genetic transformation. Transgenic rice plants were regenerated from the phosphinothricin-resistant calli obtained after co-cultivation with Agrobacterium strain LBA4404 harbouring Ti plasmid pSB111-bar-BjNPR1. Molecular analyses confirmed the stable integration and expression of BjNPR1 in various transgenic rice lines. Transgenes NPR1 and bar were stably inherited and disclosed co-segregation in subsequent generations in a Mendelian fashion. Homozygous transgenic rice lines expressing BjNPR1 protein displayed enhanced resistance to rice blast, sheath blight and bacterial leaf blight diseases. Rice transformants with higher levels of NPR1 revealed notable increases in plant height, panicle length, flag-leaf length, number of seeds/panicle and seed yield/plant as compared to the untransformed plants. The overall results amply demonstrate the profound impact of BjNPR1 in imparting resistance against major pathogens of rice. The multipotent BjNPR1, as such, seems promising as a prime candidate gene to fortify crop plants with durable resistance against various pathogens. 23968777 Empowering change: Realist evaluation of a Scottish Government programme to support normal birth. midwife-led care has consistently been found to be safe and effective in reducing routine childbirth interventions and improving women's experience of care. Despite consistent UK policy support for maximising the role of the midwife as the lead care provider for women with healthy pregnancies, implementation has been inconsistent and the persistent use of routine interventions in labour has given rise to concern. In response the Scottish Government initiated Keeping Childbirth Natural and Dynamic (KCND), a maternity care programme that aimed to support normal birth by implementing multiprofessional care pathways and making midwife-led care for healthy pregnant women the national norm. the evaluation was informed by realist evaluation. It aimed to explore and explain the ways in which the KCND programme worked or did not work in different maternity care contexts. the evaluation was conducted in three phases. In phase one semi-structured interviews and focus groups were conducted with key informants to elicit the programme theory. At phase two, this theory was tested using a multiple case study approach. Semi-structured interviews and focus groups were conducted and a case record audit was undertaken. In the final phase the programme theory was refined through analyses and interpretation of the data. the setting for the evaluation was NHS Scotland. In phase one, 12 national programme stakeholders and 13 consultant midwives participated. In phase two case studies were undertaken in three health boards; overall 73 participants took part in interviews or focus groups. A case record audit was undertaken of all births in Scotland during one week in two consecutive years before and after pathway implementation. government and health board level commitment to, and support of, the programme signalled its importance and facilitated change. Consultant midwives tailored change strategies, using different approaches in response to the culture of care and inter-professional relationships within contexts. In contexts where practice was already changing KCND was seen as validating and facilitating. In areas where a more medical culture existed there was strong resistance to change from midwives and medical staff and robust implementation strategies were required. Overall the pathways appeared to enable midwives to achieve change. our study highlighted the importance of those involved in a change programme working across levels of hierarchy within an organisation and from the macro-context of national policy and institutions to the meso-context of regional health service delivery and the micro-context of practitioner's experiences of providing care. The assumptions and propositions that inform programmes of change, which are often left at a tacit level and unexamined by those charged with implementing them, were made explicit. This examination illuminated the roles of the three key change mechanisms adopted in the KCND programme - appointment of consultant midwives as programme champions, multidisciplinary care pathways, and midwife-led care. It revealed the role of the commitment mechanism, which built on the appointment of the local change champions. The analysis indicated that the process of change, despite these clear mechanisms, needed to be adapted to local contexts and responses to the implementation of KCND. initial formative evaluation should be conducted prior to development of complex healthcare programmes to ensure that (1) the interventions will address the changes required, (2) key stakeholders who may support or resist change are identified, and (3) appropriate facilitation strategies are developed tailored to context. 23904608 Tyrosine Phosphorylation of GABAA Receptor γ2-Subunit Regulates Tonic and Phasic Inhibition in the Thalamus. GABA-mediated tonic and phasic inhibition of thalamic relay neurons of the dorsal lateral geniculate nucleus (dLGN) was studied after ablating tyrosine (Y) phosphorylation of receptor γ2-subunits. As phosphorylation of γ2 Y365 and Y367 reduces receptor internalization, to understand their importance for inhibition we created a knock-in mouse in which these residues are replaced by phenylalanines. On comparing wild-type (WT) and γ2(Y365/367F)+/- (HT) animals (homozygotes are not viable in utero), the expression levels of GABAA receptor α4-subunits were increased in the thalamus of female, but not male mice. Raised δ-subunit expression levels were also observed in female γ2(Y365/367F) +/- thalamus. Electrophysiological analyses revealed no difference in the level of inhibition in male WT and HT dLGN, while both the spontaneous inhibitory postsynaptic activity and the tonic current were significantly augmented in female HT relay cells. The sensitivity of tonic currents to the δ-subunit superagonist THIP, and the blocker Zn(2+), were higher in female HT relay cells. This is consistent with upregulation of extrasynaptic GABAA receptors containing α4- and δ-subunits to enhance tonic inhibition. In contrast, the sensitivity of GABAA receptors mediating inhibition in the female γ2(Y356/367F) +/- to neurosteroids was markedly reduced compared with WT. We conclude that disrupting tyrosine phosphorylation of the γ2-subunit activates a sex-specific increase in tonic inhibition, and this most likely reflects a genomic-based compensation mechanism for the reduced neurosteroid sensitivity of inhibition measured in female HT relay neurons. 23520041 Sodium thiosulfate therapy for calcific uremic arteriolopathy. Calcific uremic arteriolopathy (CUA) is an often fatal condition with no effective treatment. Multiple case reports and case series have described intravenous sodium thiosulfate (STS) administration in CUA, but no studies have systematically evaluated this treatment. This study included 172 patients undergoing maintenance hemodialysis who had CUA and were treated with STS between August 2006 and June 2009 at Fresenius Medical Care North America. Of these, 85% completed STS therapy. Clinical, laboratory, and mortality data were abstracted from clinical information systems. Responses to survey questionnaires sent to treating physicians regarding patient-level outcomes were available for 53 patients. Effect on CUA lesions and mortality were summarized as CUA outcomes. Relevant laboratory measures, weight (using pairwise comparisons of values before, during, and after STS), and adverse events were summarized as safety parameters. Mean age of the cohort was 55 years, and 74% of patients were women. Median STS dose was 25 g, and median number of doses was 38. Among surveyed patients, CUA completely resolved in 26.4%, markedly improved in 18.9%, improved in 28.3%, and did not improve in 5.7%; in the remaining patients (20.8%), the response was unknown. One-year mortality in patients treated with STS was 35%. Adverse events, laboratory abnormalities, and weight-related changes were mild. Significant reductions in serum phosphorous (P=0.02) and parathyroid hormone (P=0.01) were noted during STS treatment in patients who completed the therapy. Although conclusive evidence regarding its efficacy is lacking, a majority of patients who received STS demonstrated clinical improvement in this study. 23422352 Recombinant streptavidin-C3bot for delivery of proteins into macrophages. We demonstrated previously that monocytes and macrophages are target cells for the Rho-modifying Clostridium botulinum C3 ADP-ribosyltransferase. Here, we report the construction, expression and characterization of a recombinant streptavidin-C3 fusion protein which allows for delivery of biotin-labelled molecules into the cytosol of macrophages via enzymatically inactive C3bot1E174Q. The enzyme domain of diphtheria toxin was used as cargo to demonstrate proof of principle. This transport system could represent an attractive tool for experimental monocyte/macrophage pharmacology. 23954969 Genome-wide Association Studies in Alzheimer's Disease: A Review. Over the past decade, research aiming to disentangle the genetic underpinnings of late-onset Alzheimer's disease has mostly focused on the identification of common variants through genome-wide association studies. The identification of several new susceptibility genes through these efforts has reinforced the importance of amyloid precursor protein and tau metabolism in the cause of the disease and has implicated immune response, inflammation, lipid metabolism, endocytosis/intracellular trafficking, and cell migration in the cause of the disease. Ongoing and future large-scale genome-wide association studies, translational studies, and next-generation whole genome or whole exome sequencing efforts, hold the promise to map the specific causative variants in these genes, to identify several additional risk variants, including rare and structural variants, and to identify novel targets for genetic testing, prevention, and treatment. 23938254 Nobiletin and tangeretin ameliorate scratching behavior in mice by inhibiting the action of histamine and the activation of NF-κB, AP-1 and p38. Nobiletin and tangeretin are polymethoxy flavonoids that are abundantly present in the pericarp of Citrus unshiu (family Rutaceae) and the fruit of Citrus depressa (family Rutaceae). They exhibit various biological activities, including anti-inflammatory and anti-asthmatic effects. To evaluate the anti-allergic effects of nobiletin and tangeretin, we measured their inhibitory effects in histamine- or compound 48/80-induced scratching behavioral mice. Nobiletin and tangeretin potently inhibited scratching behavior, as well as histamine-induced vascular permeability. Furthermore, they inhibited the expression of the allergic cytokines, IL-4 and TNF-α as well as the activation of their transcription factors NF-κB, AP-1 and p38 in histamine-stimulated skin tissues. They also inhibited the expression of IL-4 and TNF-α and the activation of NF-κB and c-jun in PMA-stimulated RBL-2H3 cells. Furthermore, nobiletin and tangeretin inhibited protein kinase C (PKC) activity and the IgE-induced degranulation of RBL-2H3 cells. These agents showed potent anti-histamine effect through the Magnus test when guinea pig ileum was used. Based on these results, nobiletin and tangeretin may ameliorate scratching behavioral reactions by inhibiting the action of histamine as well as the activation of the transcription factors NF-κB and AP-1 via PKC. 23910680 Orthopaedic surgeon's nightmare: iatrogenic fractures of talus and medial malleolus following tibial nailing. Intramedullary interlocking nailing is the gold standard for treatment of tibial shaft fractures. The growing use of intramedullary nailing has resulted in an increased number of tibial nailing in daily clinical practice. Despite adequate surgeon experience, tibial nailing is not without complications if proper techniques are not followed. A case of iatrogenic talar neck and medial malleolus fractures during intramedullary nailing of tibia in a 24-year-old male is reported. It is believed to be caused by forceful hammering of insertion zig with foot dorsiflexed. To the best of our knowledge, no such case has been reported in the literature. It is possible to reduce the risk of this complication by adoption of preventive measures. 23352074 Analysis of the spectrum and antibiotic resistance of uropathogens in vitro: results based on a retrospective study from a tertiary hospital. Antibiotic resistance of uropathogens in urinary tract infections (UTIs) is increasing worldwide. This study aimed to compare the spectrum and antimicrobial resistance of uropathogens in community-acquired UTIs (CAUTIs) and nosocomial-acquired UTIs (NAUTIs) at a tertiary hospital in China. Retrospective analysis of uropathogens from UTI patients was performed at Zhong Da Hospital. A total of 1129 strains was isolated from 653 community-acquired and 476 nosocomial-acquired infections. Escherichia coli was the most common uropathogen, accounting for 55.9% of the CAUTIs and 27.1% of the NAUTIs. Among the CAUTIs, Escherichia coli was followed in prevalence by Enterococcus spp (12.9%) and Proteus mirabilis (3.7%). Among the NAUTIs, Escherichia coli was followed by Enterococcus spp (15.3%) and Klebsiella pneumoniae (6.9%). The proportion of fungi in the NAUTIs (23.7%) was higher than that in the CAUTIs (3.1%) (P < .05). Extended-spectrum β-lactamase-producing strains of E coli accounted for 70.6% of the NAUTIs and 47.3% of the CAUTIs. Carbapenems, amikacin, and nitrofurantoin were active agents against E coli. The resistance rates of E coli to cephalosporins, ampicillin, ampicillin/sulbactam, quinolones, and gentamicin were higher in the NAUTIs than in the CAUTIs (P < .05). The distribution of species was different between CAUTIs and NAUTIs. Higher antibiotic resistance rates were observed in the NAUTIs than in the CAUTIs. 23736116 Electronic excited states of guanine-cytosine hairpins and duplexes studied by fluorescence spectroscopy. Guanine-cytosine hairpins, containing a hexaethylene glycol bridge, are studied by steady-state fluorescence spectroscopy and time-correlated single photon counting; their properties are compared to those of duplexes with the same sequence. It is shown that, both in hairpins and in duplexes, base pairing induces quenching of the ππ* fluorescence, the quantum yield decreasing by at least two orders of magnitude. When the size of the systems increases from two to ten base pairs, a fluorescent component decaying on the nanosecond time-scale appears at energy higher than that stemming from the bright states of non-interacting mono-nucleotides (ca. 330 nm). For ten base pairs, this new fluorescence forms a well-defined band peaking at 305 nm. Its intensity is about 20% higher for the hairpin compared to the duplex. Its position (red-shifted by 1600 cm(-1)) and width (broader by 1800 cm(-1) FWHM) differ from those observed for large duplexes containing 1000 base pairs, suggesting the involvement of electronic coupling. Fluorescence anisotropy reveals that the excited states responsible for high energy emission are not populated directly upon photon absorption but are reached during a relaxation process. They are assigned to charge transfer states. According to the emerging picture, the amplitude of conformational motions determines whether instantaneous deactivation to the ground state or emission from charge transfer states will take place, while ππ* fluorescence is associated to imperfect base-pairing. 23193324 Constrained blind source extraction of readiness potentials from EEG. One of the changes seen in electroencephalography (EEG) data preceding human voluntary movement is a cortical potential called readiness potential (RP). Detection of this potential can benefit researchers in clinical neurosciences for rehabilitation of malfunctioning brain and those working on brain-computer interfacing to develop a suitable mechanism to detect the intention of movement. Here, a constrained blind source extraction (CBSE) is attempted for detection of RP. A suitable constraint is defined and applied. The results are also compared with those of the traditional blind source separation in terms of true positive rate, false positive rate, and computation time. The results show that the CBSE approach in overall has superior performance. 23786601 Copper-catalyzed intramolecular N-s bond formation by oxidative dehydrogenative cyclization. Copper-catalyzed synthesis of benzo[d]isothiazol-3(2H)-ones and N-acyl-benzothiazetidine by intramolecular dehydrogenative cyclization is described. In this reaction, a new nitrogen-sulfur (N-S) bond is formed by N-H/S-H coupling. The present reaction has high functional group tolerance and gives products in gram scale. This method promotes double cyclization, allowing for synthesis of a drug intermediate. 23841757 Cage versus Prism: Electronic Energies of the Water Hexamer. Recent experiments show that the cage isomer of the water hexamer is lower in energy than the prism isomer near 0 K, and yet state-of-the-art electronic structure calculations predict the prism to be lower in energy than the cage at 0 K. Here, we study the relative energies of the water hexamers from the parametric two-electron reduced density matrix (2-RDM) method in which the 2-RDM rather than the wave function is the basic variable of the calculations. In agreement with experiment and in contrast with traditional wave function methods, the 2-RDM calculations predict the cage to be more stable than the prism after vibrational zero-point correction. Multiple configurations from the hydrogen bonding are captured by the method. More generally, the results are consistent with our previous 2-RDM applications in that they reveal how multireference correlation in molecular systems is important for resolving small energy differences from hydrogen bonding as well as other types of intermolecular forces, even in systems that are not conventionally considered strongly correlated. 23893739 Identification of Pedigree Relationship from Genome Sharing. Determination of degree of relationship has traditionally been undertaken using genotypic data on individual loci, typically assumed to be independent. With dense marker data as now available it is possible to identify the regions of the genome shared identical by descent (ibd). This information can be used to determine pedigree relationship (R), e.g. cousins vs second cousins and also distinguish pedigrees which have the same Wright's relationship (R) such as half-sibs and uncle nephew. We use simulation to investigate the accuracy with which pedigree relationship can be inferred from genome sharing for uniparental relatives (a common ancestor on only one side of their pedigree), specifically the number, position (whether or not at chromosome ends) and length of shared regions ibd on each chromosome. Moments of the distribution of the likelihood ratio (including its expectation, the Kullback-Leibler distance) for alternative relationships are estimated for model human genomes, with the ratio of the mean to the standard deviation of the likelihood ratio providing a useful reference point. Two relationships differing in R can readily be distinguished provided at least one has high R, e.g. ca. 98.5% correct assignment of cousins and half cousins, but only about 75% for second cousins once removed and third cousins. Two relationships with the same R can be distinguished only if R is high, e.g. half sibs and uncle-nephew, with probability of correct assignment about 5/6. 22965296 A photochemical mechanism for homochirogenesis. Part 2. A theoretical investigation of the photochemistry of racemic compounds with circularly polarized light was undertaken. The exact solutions of the differential equations by numerical integration to the approximate solutions used in an earlier article were compared. The exact solutions showed that sequential reactions yield enhanced optical activities in the products. For irreversible reactions, all enantiomeric excesses are lost if the reactions are carried to completion, but appreciable resolution occurs in many cases for partial conversion. For reversible reactions, significant enantiomeric excesses are found at the photostationary state. 23964694 Guanidination of Tryptic Peptides without Desalting for MALDI-TOF MS Analysis. Derivatizations that enhance mass spectral quality often require desalting which presents as a bottleneck in MALDI-TOF MS-proteomics. Guanidination, which converts lysine to homoarginine, an arginine analog, can increase detection of those peptides 5-15-fold. Our aim was to improve guanidination by using a novel reagent, O-methylisourea-freebase. In a simple reaction, interfering salts were removed prior to guanidination. Freebase preparation took about 30 min and could be applied to samples all at once as opposed to desalting samples one-by-one for 5 min each. For freebase guanidinated BSA tryptic peptides, more than 6-times the peptides were observed relative to tryptic peptides or those guanidinated with the conventional reagent, O-methylisourea hemisulfate. Peptide signals increased more than 10-fold relative to those from guanidination with the conventional reagent and were equivalent to those from conventional guanidination with desalting. In addition, freebase guanidination allowed for a lower limit of detection when combined with another derivatization, N-terminal sulfonation, as evidenced by MS/MS fragmentation analysis of in-gel digests of cytochrome c. Freebase guanidination of rat lung proteins after 2-D gel electrophoresis allowed for identification of all tested protein spots regardless of protein characteristics (MW or pI) or abundance. Co-derivatization with N-terminal sulfonation confirmed the identity of low abundance proteins in 2-D gel spots that contained more than one protein. The freebase guanidination reagent is simple to prepare and to implement. Desalting is not needed prior to MALDI-TOF MS. Freebase guanidination effectively increases the dynamic range of detection of lysine-containing peptides while decreasing the work needed for sample preparation. 23732774 Equal efficacy of endoscopic and surgical cystogastrostomy for pancreatic pseudocyst drainage in a randomized trial. Although surgery is the standard technique for drainage of pancreatic pseudocysts, use of endoscopic methods is increasing. We performed a single-center, open-label, randomized trial to compare endoscopic and surgical cystogastrostomy for pancreatic pseudocyst drainage. Patients with pancreatic pseudocysts underwent endoscopic (n = 20) or surgical cystogastrostomy (n = 20). The primary end point was pseudocyst recurrence after a 24-month follow-up period. Secondary end points were treatment success or failure, complications, re-interventions, length of hospital stay, physical and mental health scores, and total costs. At the end of the follow-up period, none of the patients who received endoscopic therapy had a pseudocyst recurrence, compared with 1 patient treated surgically. There were no differences in treatment successes, complications, or re-interventions between the groups. However, the length of hospital stay was shorter for patients who underwent endoscopic cystogastrostomy (median, 2 days, vs 6 days in the surgery group; P < .001). Although there were no differences in physical component scores and mental health component scores (MCS) between groups at baseline on the Medical Outcomes Study 36-Item Short-Form General Survey questionnaire, longitudinal analysis showed significantly better physical component scores (P = .019) and mental health component scores (P = .025) for the endoscopy treatment group. The total mean cost was lower for patients managed by endoscopy than surgery ($7011 vs $15,052; P = .003). In a randomized trial comparing endoscopic and surgical cystogastrostomy for pancreatic pseudocyst drainage, none of the patients in the endoscopy group had pseudocyst recurrence during the follow-up period, therefore there is no evidence that surgical cystogastrostomy is superior. However, endoscopic treatment was associated with shorter hospital stays, better physical and mental health of patients, and lower cost. Trial Registration: ClinicalTrials.gov: NCT00826501. 23857440 Comparison of Three High Flow Oxygen Therapy Delivery Devices: A Clinical Physiological Cross-over Study. Background: High-flow-oxygen-therapy is provided by various techniques and patient interfaces, resulting in various inspired-fraction of oxygen (FiO2) and airway-pressure levels. However, tracheal measurements have never been performed Methods: Three oxygen-delivery-devices were evaluated: 1) standard-high-flow-oxygen-facemask with reservoir-bag, 2) Optiflow™-high-flow-nasal-cannulae and 3) Boussignac™-oxygen-therapy-system. Main judgment criteria were airway-pressure and FiO2 measured in the trachea. The three devices were randomly evaluated in cross-over in 10 Intensive-Care-Unit patients using three oxygen flow-rates (15, 30 and 45 L/min) and two airway-tightness conditions (open and closed mouth). Airwaypressures and FiO2 were measured by a tracheal-catheter inserted through the hole of a tracheotomy tube. Comfort was evaluated by self-reporting. Data are presented as median [25-75th]. Results: 1) Regarding oxygen-delivery devices, Boussignac™ provided the highest mean tracheal pressure (13.9 [10.4-14.5] cmH20) compared to Optiflow™ (2.0 [1.0-2.3] cmH2O, p<0.001). Boussignac™ provided both positive inspiratory and expiratory airway-pressures, whereas OptiflowTM provided only positive expiratory airway-pressure. Reservoir-bag-facemask provided airway pressure close to zero. For FiO2, highest value was obtained for both Optiflow™ and facemask (90%) compared to Boussignac™ (80%), p<0.01. 2) Regarding oxygen-flow, airway-pressure and FiO2 systematically increased with oxygen-flow with the three devices except airway-pressure for the facemask. 3) Regarding the open-mouth position, mean airway-pressure decreased with Optiflow™ only (2.0 [1.2-3.3] vs. 0.6 [0.3-1.0] cmH2O, p< 0.001). Opening the mouth had little impact on FiO2. 4) Finally, discomfort-intensities were low for both Optiflow™ and reservoir-bag-facemask compared to Boussignac™, p<0.01. Conclusions: On one hand, Boussignac™ is the only device that generates a relevant positive-airwaypressure during both inspiration-and-expiration, independently of mouth-position. OptiflowTM provides a low positive-airway-pressure (<4cmH2O), highly dependent of mouth-closing. The reservoir-bag-facemask provides no positive-airway-pressure. On the other hand, FiO2 are slightly but significantly higher for Optiflow™ and reservoir-bag-facemask than for Boussignac™. Discomfort was lesser for Optiflow™ and reservoir-bag-facemask. 23070662 pHEMA-nHA Encapsulation and Delivery of Vancomycin and rhBMP-2 Enhances its Role as a Bone Graft Substitute. Bone grafts are widely used in orthopaedic procedures. Autografts are limited by donor site morbidity while allografts are known for considerable infection and failure rates. A synthetic composite bone graft substitute poly(2-hydroxyethyl methacrylate)-nanocrystalline hydroxyapatite (pHEMA-nHA) was previously developed to stably press-fit in and functionally repair critical-sized rat femoral segmental defects when it was preabsorbed with a single low dose of 300 ng recombinant human bone morphogenetic protein-2/7 (rhBMP-2/7). To facilitate clinical translation of pHEMA-nHA as a synthetic structural bone graft substitute, we examined its ability to encapsulate and release rhBMP-2 and the antibiotic vancomycin. We analyzed the compressive behavior and microstructure of pHEMA-nHA as a function of vancomycin incorporation doses using a dynamic mechanical analyzer and a scanning electron microscope. In vitro release of vancomycin was monitored by ultraviolet-visible spectroscopy. Release of rhBMP-2 from pHEMA-nHA-vancomycin was determined by ELISA. Bioactivity of the released vancomycin and rhBMP-2 was examined by bacterial inhibition and osteogenic transdifferentiation capabilities in cell culture, respectively. Up to 4.8 wt% of vancomycin was incorporated into pHEMA-nHA without compromising its structural integrity and compressive modulus. Encapsulated vancomycin was released in a dose-dependent and sustained manner in phosphate-buffered saline over 2 weeks, and the released vancomycin inhibited Escherichia coli culture. The pHEMA-nHA-vancomycin composite released preabsorbed rhBMP-2 in a sustained manner over 8 days and locally induced osteogenic transdifferentiation of C2C12 cells in culture. pHEMA-nHA can encapsulate and deliver vancomycin and rhBMP-2 in a sustained and localized manner with reduced loading doses. The elasticity, osteoconductivity, and rhBMP-2/vancomycin delivery characteristics of pHEMA-nHA may benefit orthopaedic reconstructions or fusions with enhanced safety and efficiency and reduced infection risk. 23754661 Actinopolyspora righensis sp. nov., a novel halophilic actinomycete isolated from Saharan soil in Algeria. A novel halophilic actinomycete strain, H23(T), was isolated from a Saharan soil sample collected in Djamâa (Oued Righ region), El-Oued province, South Algeria. Strain H23(T) was identified as a member of the genus Actinopolyspora by a polyphasic approach. Phylogenetic analysis showed that strain H23(T) had 16S rRNA gene sequence similarities ranging from 97.8 % (Actinopolyspora xinjiangensis TRM 40136(T)) to 94.8 % (Actinopolyspora mortivallis DSM 44261(T)). The strain grew optimally at pH 6.0-7.0, 28-32 °C and in the presence of 15-25 % (w/v) NaCl. The substrate mycelium was well developed and fragmented with age. The aerial mycelium produced long, straight or flexuous spore chains with non-motile, smooth-surfaced and rod-shaped spores. Strain H23(T) had MK-10 (H4) and MK-9 (H4) as the predominant menaquinones. The whole micro-organism hydrolysates mainly consisted of meso-diaminopimelic acid, galactose and arabinose. The diagnostic phospholipid detected was phosphatidylcholine. The major cellular fatty acids were anteiso-C17:0 (37.4 %), iso-C17:0 (14.8 %), iso-C15:0 (14.2 %), and iso-C16:0 (13.9 %). The genotypic and phenotypic data show that the strain represents a novel species of the genus Actinopolyspora, for which the name Actinopolyspora righensis sp. nov. is proposed, with the type strain H23(T) (=DSM 45501(T) = CCUG 63368(T) = MTCC 11562(T)). 23842645 The DREAM complex: master coordinator of cell cycle-dependent gene expression. The dimerization partner, RB-like, E2F and multi-vulval class B (DREAM) complex provides a previously unsuspected unifying role in the cell cycle by directly linking p130, p107, E2F, BMYB and forkhead box protein M1. DREAM mediates gene repression during the G0 phase and coordinates periodic gene expression with peaks during the G1/S and G2/M phases. Perturbations in DREAM complex regulation shift the balance from quiescence towards proliferation and contribute to the increased mitotic gene expression levels that are frequently observed in cancers with a poor prognosis. 23620429 Methods and reproducibility of grading optimized digital color fundus photographs in the Age-Related Eye Disease Study 2 (AREDS2 Report Number 2). To establish continuity with the grading procedures and outcomes from the historical data of the Age-Related Eye Disease Study (AREDS), color photographic imaging and evaluation procedures for the assessment of age-related macular degeneration (AMD) were modified for digital imaging in the AREDS2. The reproducibility of the grading of index AMD lesion components and for the AREDS severity scale was tested at the AREDS2 reading center. Digital color stereoscopic fundus photographs from 4203 AREDS2 subjects collected at baseline and annual follow-up visits were optimized for tonal balance and graded according to a standard protocol slightly modified from AREDS. The reproducibility of digital grading of AREDS2 images was assessed by reproducibility exercises, temporal drift (regrading a subset of baseline annually, n = 88), and contemporaneous masked regrading (ongoing, monthly regrade on 5% of submissions, n = 1335 eyes). In AREDS2, 91% and 96% of images received replicate grades within two steps of the baseline value on the AREDS severity scale for temporal drift and contemporaneous assessment, respectively (weighted Kappa of 0.73 and 0.76). Historical data for temporal drift in replicate gradings on the AREDS film-based images were 88% within two steps (weighted Kappa = 0.88). There was no difference in AREDS2-AREDS concordance for temporal drift (exact P = 0.57). Digital color grading has nearly the same reproducibility as historical film grading. There is substantial agreement for testing the predictive utility of the AREDS severity scale in AREDS2 as a clinical trial outcome. (ClinicalTrials.gov number, NCT00345176.) 23843193 I finally see what you see: Parkinson's disease visual hallucinations captured with functional neuroimaging. Functional neuroimaging studies have described alterations in neural activation in PD patients with chronic hallucinations. These studies have not, however, captured neural activation patterns during an actual hallucinatory event. The objective of this work was to investigate neuroanatomical substrates active during visual hallucinations in a patient with Parkinson's disease (PD). We conducted an event-related functional magnetic resonance imaging (fMRI) case-study examination of a 66-year-old male PD patient with stereotypic, chronic, and frequent visual hallucinations. The patient reported 16 hallucinations during the fMRI scan. Increased activation during hallucinations was found in the cingulate, insula, frontal lobe, thalamus, and brain stem. Decreased activation was found in the lingual and fusiform gyri, inferior occipital gyrus, and middle frontal and superior temporal lobes. To our knowledge, this report is the first published case documenting the cortical activation patterns using fMRI techniques in a PD patient during active hallucinations. Our results suggest that during a visual hallucination, a marked desynchronization occurs between posterior and anterior cortical areas involved in visual processing. © 2013 Movement Disorder Society. 23608484 Dendritic spine remodeling induced by hindlimb unloading in adult rat sensorimotor cortex. A sensorimotor restriction, for instance in patients confined to bed, induces an impairment in motor function, which could be due to structural and functional reorganization of the sensorimotor cortex. Hindlimb unloading (HU) is a rodent model used to reproduce the chronic weightless bearing and reduction in hindlimb movement. In this study, we determined whether a 14-day period of HU in adult rats leads to dendritic spine plasticity. For this purpose, we visualized a large number of spines on pyramidal neurons located in superficial and deep layers of the cortex within the hindpaw representation area, by means of confocal microscopy. Spines were classified according to their shape, as stubby, thin, mushroom, or filopodium. Spine density was increased (+26%) after HU. The increase concerned mainly filopodium spines (+82%) and mushrooms (+33%), whereas no change was noticed for stubby and thin spines. Spine length was decreased, whatever their shape. Head diameter evolved differently depending on the layer: it was increased in superficial layers and decreased in deeper ones. These results indicate that morphological changes accompany functional reorganization of motor cortex in response to a decrease in sensorimotor function during adulthood. 23474327 Prospective Evaluation of Patients with Early-/Intermediate-stage Hepatocellular Carcinoma with Disease Progression Following Arterial Locoregional Therapy: Candidacy for Systemic Treatment or Clinical Trials. During the course of cancer treatment, patients whose disease progresses despite therapy are offered alternative options. Similarly, patients with hepatocellular carcinoma (HCC) whose disease progresses following arterial locoregional therapies (LRTs) cross over to undergo systemic therapies or participate in clinical trials. Per current guidelines, patients must meet inclusion criteria (most importantly Child-Pugh class A status) to qualify for systemic options. The present study analyzed the candidacy for systemic agents or clinical trials of patients whose disease progresses despite LRTs. A total of 245 patients with HCC were treated with LRTs (chemoembolization, n = 123; yttrium-90 [(90)Y] radioembolization, n = 122) as part of a previously published comparative effectiveness study; 96 patients exhibiting disease progression were followed prospectively. Modes of progression (cancer stage, Child-Pugh class) were analyzed to determine candidacy for systemic therapy or clinical trials, as well as assess ultimate treatment(s) received. Among the 96 patients with disease progression, 52% and 48% had Child-Pugh class A and class B/C disease, respectively, thereby substantially limiting the latter group's eligibility for systemic therapy and/or clinical trials. Of those whose disease progressed who had advanced-stage HCC, 63% had Child-Pugh class B/C disease. By size and necrosis criteria, the local disease progression rate was higher with chemoembolization than with (90)Y radioembolization (P = .006 and P = .016, respectively). Of the 96 patients with disease progression, only 13 (13%) ultimately received systemic agents or entered clinical trials. Most patients with advanced HCC that progresses following LRTs were not candidates for clinical trials or systemic agents. There is a need for future research efforts directed at treatment options or novel trial designs that will permit inclusion of patients with progressive liver disease and suboptimal liver function. 23740515 Expression of Hsp27 correlated with rat detrusor contraction after acute urinary retention. Heat shock protein 27 (Hsp27) can regulate actin cytoskeleton dynamics and contractile protein activation. This study investigates whether Hsp27 expression is related to bladder contractile dysfunction after acute urinary retention (AUR). Female rats were randomized either to AUR by urethral ligation or to normal control group. Bladder and smooth muscle strip contraction at time points from 0 h to 7 days after AUR were estimated by cystometric and organ bath studies. Hsp27 expression in bladder tissue at each time point was detected with immunofluorescence, Western blots, and real-time PCR. Expression of the three phosphorylated forms of Hsp27 was detected by Western blots. Smooth muscle ultrastructure was observed by transmission electron microscopy. Data suggest that maximum detrusor pressure and both carbachol-induced and spontaneous detrusor strip contraction amplitude decreased gradually for the duration from 0 to 6 h, and then increased gradually to near-normal values at 24 h. Treatment of muscle strips with the p38MAK inhibitor, SB203580, inhibited carbachol-induced contractions. Smooth muscle ultrastructure damage was the highest at 6 h after AUR, and then lessened gradually during next 7 days, and ultrastructure was close to normal. Expressions of Hsp27 mRNA and protein and the proteins of the three phosphorylated forms were higher at 0 h, decreased to lower levels up to 6 h, and then gradually increased. Therefore, we conclude that rat bladder contractile function after AUR worsens during 0-6 h, and then gradually recovers. The findings of the current study suggest that Hsp27 modulates bladder smooth muscle contraction after AUR, and that phosphorylation of Hsp27 may be an important pathway modulating actin cytoskeleton dynamics in bladder smooth muscle contraction and reconstruction after injury. 23215035 Alpha-heteroatom derivatized analogues of 3-(acetylhydroxyamino)propyl phosphonic acid (FR900098) as antimalarials. To explore the hitherto successful derivatization of the α-carbon of fosmidomycin, a series of new α-substituted analogues was prepared. This was done by introduction of a heteroatom (N or O) in α-position to the phosphonate and using the resultant OH and NH₂ groups as a handle for appending a variety of substituents by means of several functional groups such as ether, amide, urea, and 1,4-triazole. The synthesized molecules, as a racemic mixture, were assayed for their EcDXR inhibitory potency. Both the α-azido-analogue and the α-hydroxylated analogue proved most promising, and docking experiments were performed. Although several compounds showed high potency when assayed against Plasmodium falciparum K1 in human erythrocytes, a clear correlation between the enzyme inhibition constants and P. falciparum inhibition concentrations could not be found. 23872012 Chitosans for delivery of nucleic acids. Alternatives to efficient viral vectors in gene therapy are desired because of their poor safety profiles. Chitosan is a promising non-viral nucleotide delivery vector because of its biocompatibility, biodegradability, low immunogenicity and ease of manufacturing. Since the transfection efficiency of chitosan polyplexes is relatively low compared to viral counterparts, there is an impetus to gain a better understanding of the structure-performance relationship. Recent progress in preparation and characterisation has enabled coupling analysis of chitosans structural parameters that has led to increased TE by tailoring of chitosan's structure. In this review, we summarize the recent advances that have lead to a more rational design of chitosan polyplexes. We present an integrated review of all major areas of chitosan-based transfection, including preparation, chitosan and polyplexes physicochemical characterisation, in vitro and in vivo assessment. In each, we present the obstacles to efficient transfection and the strategies adopted over time to surmount these impediments. 23917259 A survey on temperature-aware routing protocols in wireless body sensor networks. The rapid growth of the elderly population in the world and the rising cost of healthcare impose big issues for healthcare and medical monitoring. A Wireless Body Sensor Network (WBSN) is comprised of small sensor nodes attached inside, on or around a human body, the main purpose of which is to monitor the functions and surroundings of the human body. However, the heat generated by the node's circuitry and antenna could cause damage to the human tissue. Therefore, in designing a routing protocol for WBSNs, it is important to reduce the heat by incorporating temperature into the routing metric. The main contribution of this paper is to survey existing temperature-aware routing protocols that have been proposed for WBSNs. In this paper, we present a brief overview of WBSNs, review the existing routing protocols comparatively and discuss challenging open issues in the design of routing protocols. 23839316 A comparative study of the efficacy of Pediatric Airtraq® with conventional laryngoscope in children. Background:Management of pediatric airway may pose a challenge to anesthesiologists. Many modifications in maneuvers and equipments have been made overtime to overcome the problem. Pediatric optical laryngoscope (Airtraq®) is one of the newer equipments for managing simple and difficult pediatric airway. Here we have evaluated the comparative efficacy of pediatric Airtraq® optical laryngoscope with conventional laryngoscope in children scheduled for routine surgeries. Method:After written informed consent from the parents/ guardian of the children, they were allocated into two groups of 17 patients each using the pediatric Airtraq® in one and a conventional laryngoscope in the other. Airtraq intubation patients were those in which pediatric Airtraq® was used to intubate whereas the patients who wereì intubated with conventional laryngoscope were labelled as conventional intubation group. The primary outcome measure was time needed for successful intubation whereas secondary outcome measures were number of attempts to intubate, POGO (percentage of glottic opening) scoring and complications like airway trauma and esophageal intubation. Results:It took significantly shorter time to intubate in Airtraq intubation group of patients as compared to Conventional intubation group of patients (P <0.05). Similarly the POGO scoring was significantly better in Airtraq intubation compared to Conventional intubation (P <0.001). Number of attempts to intubate and complications like airway trauma and esophageal intubation using Airtraq® was less frequent compared to conventional laryngoscopy but the difference was statistically insignificant. CONCLUSION:Pediatric Airtraq® provides better intubating conditions in children compared to conventional laryngoscopewith less frequent complications. 23884802 Trabecular Metal in Total Knee Arthroplasty Associated with Higher Knee Scores: A Randomized Controlled Trial. Porous tantalum is an option of cementless fixation for TKA, but there is no randomized comparison with a cemented implant in a mid-term followup. We asked whether a tibial component fixed by a porous tantalum system might achieve (1) better clinical outcome as reflected by the Knee Society Score (KSS) and WOMAC Osteoarthritis Index, (2) fewer complications and reoperations, and (3) improved radiographic results with respect to aseptic loosening compared with a conventional cemented implant. We randomized 145 patients into two groups, either a porous tantalum cementless tibial component group (Group 1) or cemented conventional tibial component in posterior cruciate retaining TKA group (Group 2). Patients were evaluated preoperatively and 15 days, 6 months, and 5 years after surgery, using the KSS and the WOMAC index. Complications, reoperations, and radiographic failures were tallied. At 5-year followup the KSS mean was 90.4 (range, 68-100; 95% CI, ± 1.6) for Group 1, and 86.5 (range, 56-99; 95% CI, ± 2.4) for Group 2. The effect size, at 95% CI for the difference between means, was 3.88 ± 2.87. The WOMAC mean was 15.1 (range, 0-51; 95% CI, ± 2.6) for the Group 1, and 19.1 (range, 4-61; 95% CI, ± 2.9) for Group 2. The effect size for WOMAC was -4.0 ± 3.9. There were no differences in the frequency of complications or in aseptic loosening between the two groups. Our data suggest there are small differences between the uncemented porous tantalum tibial component and the conventional cemented tibial component. It currently is undetermined whether the differences outweigh the cost of the implant and the results of their long-term performance. Level I, therapeutic study. See Instructions to Authors for a complete description of levels of evidence. 23827825 Mutational analysis of the 5' non-coding region of GJB1 in a Taiwanese cohort with Charcot-Marie-Tooth neuropathy. Mutations in the 5' non-coding region of GJB1 are rarely reported in patients with Charcot-Marie-Tooth disease (CMT). We therefore aimed to assess the frequency and identities of the GJB1 5' non-coding region mutations in a cohort of CMT. We analyzed the 5' non-coding region of GJB1 (including the promoter P2 and exon 1b) in 91 unrelated CMT patients without an identified genetic cause. Two mutations, c.-529T>C, and c.-459C>T, were identified in one patient each. One polymorphism, c.-713G>A, was also identified in 53 patients and 73 of the 100 control subjects. The luciferase reporter assays showed that c.-459C>T significantly reduced the luciferase expression with or without SOX10 activation, whereas c.-529T>C impaired the expression only with SOX10 co-expression. c.-713G>A had no apparent functional effect. Mutations in the 5' non-coding region of GJB1 account for 0.8% (2 of 251) of CMT and 2.2% (2 of 91) of genetically unassigned CMT in a Taiwanese cohort. As previously demonstrated, c.-459C>T and c.-529T>C may cause CMT through compromising GJB1 expression whereas c.-713G>A is a benign variant. This study highlights the pathogenic role of the GJB1 5' non-coding region mutations in CMT, and suggests that their identification should be considered for CMT patients without commonly observed mutations. 23919468 Industry Update: The latest developments in therapeutic delivery. This article covers the period between 1-31 May 2013. During this period, Takeda bolstered its presence in the field of vaccines with the acquisition of the viral vaccine manufacturer, Inviragen, while Valeant dramatically expanded its eye healthcare offering with the purchase of Bausch & Lomb. Product choice for those suffering from growth hormone deficiency in the EU looks set to increase as the Committee for Medicinal Products for Human Use of the European Medicines Agency has given the green light to Biopartners GmbH microparticulate-based, once weekly, subcutaneous injection of recombinant somatotropin. If given approval by the EU commission (anticipated middle of Q3 2013), the product will be the only sustained release growth hormone injection on the European market. As ever, the Industry Update is based mainly on information from press releases and company websites. 23647788 Beyond pregnancy - the neglected burden of mortality in young women of reproductive age in Bangladesh: a prospective cohort study. To describe proportionate mortality and causes of death unrelated to pregnancy. Prospective cohort study. Rural northwest Bangladesh. A cohort of 133 617 married women of reproductive age. Verbal autopsies were conducted for women who died whilst under surveillance in the cohort trial. Physician-assigned causes of death based on verbal autopsies were used to categorise deaths. The proportion of deaths due to non-communicable diseases, infectious diseases, injury or pregnancy. Of the 1107 deaths occurring among women between 2001 and 2007, 48% were attributed to non-communicable diseases, 22% to pregnancy, 17% to infections, 9% to injury and 4% to other causes. Although focus on pregnancy-related mortality remains important, more attention is warranted on non-communicable diseases among women of reproductive age. 23818545 Multi-parameter single-cell profiling of human CD4+FOXP3+ regulatory T cell populations in homeostatic conditions and during graft-versus-host disease. Understanding the heterogeneity of human CD4(+)FOXP3(+) regulatory T cells (Treg) and their potential for lineage-reprogramming is of critical importance for moving Treg therapy into the clinics. Using multi-parameter single-cell analysis techniques we explored the heterogeneity and functional diversity of human Treg in healthy donors and in patients after allogeneic hematopoietic stem cell transplantation (alloHSCT). Human Treg displayed a level of complexity similar to conventional CD4(+) effector T cells with respect to the expression of transcription factors, homing receptors and inflammatory cytokines. Single-cell profiling of the rare Treg producing IL-17A or IFN-γ showed an overlap of gene expression signatures of Th17 or Th1 cells and of Treg. To assess if Treg homeostasis is affected by an inflammatory and lymphopenic environment, we characterized the Treg compartment in patients early after alloHSCT. This analysis suggested a marked depletion of Treg with a naïve phenotype in patients developing acute graft-versus-host disease, compared to tolerant patients. However, single-cell profiling showed that CD4(+)FOXP3(+) T cells maintain the Treg gene expression signature and Treg suppressive activity was preserved. Our study establishes that heterogeneity at the single-cell level, rather than lineage-reprogramming of CD4(+)FOXP3(+) T cells, explains the remarkable complexity and functional diversity of human Treg. 23914756 An amyotrophic lateral sclerosis-like syndrome revealing an amyloid polyneuropathy associated with a novel transthyretin mutation. Abstract Objective: Familial amyloid polyneuropathy (FAP) is typically a predominantly sensory and autonomic neuropathy with progressive and late motor involvement leading to death within 10 years. Recently, prognosis was transformed with liver transplantation. Methods: We report an atypical sporadic pure motor and bulbar neuropathy initially mistaken for amyotrophic lateral sclerosis (ALS) in a 50-year-old Malian man. Results: The diagnostic procedure of this clinical purely motor and bulbar neuropathy disclosed amyloid deposits on nerve biopsy which led to the identification of a new Val93Met mutation of transthyretin. This case was also remarkable by its slow progression. Conclusions: This report confirms the motor phenotype of TTR-FAP. That should be considered in the differential diagnosis of motor neuron diseases in order to start accurate therapy. 23891505 Comparative studies of perceived vibration strength for commercial mobile phones. A mobile phone, also known as cell phone or hand phone, is among the most popular electrical devices used by people all over the world. The present study examines the vibration perception of mobile phones by co-relating the relevant design parameters such as excitation frequency, and size and mass of mobile phones to the vibration perception survey by volunteers. Five popular commercially available mobile phone models were tested. The main findings for the perception surveys were that higher vibration frequency and amplitude of the peak acceleration would result in stronger vibration perception of the mobile phones. A larger contact surface area with the palms and figures, higher peak acceleration and the associated larger peak inertia force may be the main factors for the relatively higher vibration perception. The future design for the vibration alert of the mobile phones is likely to follow this trend. 23417978 Prompt administration of antibiotics is associated with improved outcomes in febrile neutropenia in children with cancer. Time-to-antibiotic (TTA) administration is a widely used quality-of-care measure for children with cancer and febrile neutropenia (FN). We sought to determine whether TTA is associated with outcomes of FN. A single-center, retrospective cohort study was conducted of 1,628 FN admissions from 653 patients from 2001 to 2009. Outcome variables included (1) an adverse event (AE) composite of in-hospital mortality, pediatric intensive care unit (PICU) admission within 24 hours of presentation, and/or fluid resuscitation ≥ 40 ml/kg within 24 hours of presentation and (2) length of stay (LOS). TTA was measured as a continuous variable and in 60-minute intervals. Mixed regression models were constructed to evaluate associations of TTA with the outcome variables after adjusting for relevant covariates including cancer diagnosis, degree of myelosuppression, and presence of bacteremia. The composite AE outcome occurred in 11.1% of admissions including 0.7% in-hospital mortality, 4.7% PICU admission, and 10.1% fluid resuscitation. In univariate analysis, TTA was associated with the composite AE outcome (Odds Ratio [OR] 1.29, 95% CI 1.02-1.64) but not LOS. In multivariate analysis, after adjustment for relevant covariates, 60-minute TTA intervals were associated with the composite AE outcome (61-120 minutes vs. ≤ 60 minutes, OR 1.81, 95% CI 1.01-3.26). Unexpectedly, admission from the emergency department (ED) was also independently associated with the composite AE outcome (ED vs. clinic, OR 3.15, 95% CI 1.95-5.09). TTA and presentation to the ED are independently associated with poor outcomes of FN. 23774830 Ketamine-derived designer drug methoxetamine: metabolism including isoenzyme kinetics and toxicological detectability using GC-MS and LC-(HR-)MSn. Methoxetamine (MXE; 2-(3-methoxyphenyl)-2-(N-ethylamino)-cyclohexanone), a ketamine analog, is a new designer drug and synthesized for its longer lasting and favorable pharmacological effects over ketamine. The aims of the presented study were to identify the phases I and II metabolites of MXE in rat and human urine by GC-MS and LC-high-resolution (HR)-MS(n) and to evaluate their detectability by GC-MS and LC-MS(n) using authors' standard urine screening approaches (SUSAs). Furthermore, human cytochrome P450 (CYP) enzymes were identified to be involved in the initial metabolic steps of MXE in vitro, and respective enzyme kinetic studies using the metabolite formation and substrate depletion approach were conducted. Finally, human urine samples from forensic cases, where the ingestion of MXE was suspected, were analyzed. Eight metabolites were identified in rat and different human urines allowing postulation of the following metabolic pathways: N-deethylation, O-demethylation, hydroxylation, and combinations as well as glucuronidation or sulfation. The enzyme kinetic studies showed that the initial metabolic step in humans, the N-deethylation, was catalyzed by CYP2B6 and CYP3A4. Both SUSAs using GC-MS or LC-MS(n) allowed monitoring an MXE intake in urine. 23774204 Treatment of pediatric femur fractures with the pavlik harness: multiyear clinical and radiographic outcomes. Femur fractures account for 1.4% to 1.7% of all pediatric fractures. The use of the Pavlik harness has been described for infants; however, previous reports have included only short-term follow-up. This study describes the multiyear clinical and radiographic results from patients younger than 6 months of age treated with a Pavlik harness. The clinical and radiographic records were reviewed for all children under the age of 6 months who were treated with a Pavlik harness for an isolated femoral shaft fracture at a level 1 pediatric trauma center. Radiographs were obtained at final follow-up, as well as a standing full-length anteroposterior scanogram. Clinical examination was completed and inquiry regarding patient activity limitations, complications of treatment, and overall parent/provider satisfaction was made. Ten patients with 10 fractures met inclusion criteria. The average age of the patients at the time of injury was 2.2 months. The average duration of Pavlik harness treatment was 43 days (range, 31 to 54 d). The average age at final follow-up was 5.2 years (range, 2.6 to 7.3 y). At final follow-up, average angulation was 3 degrees valgus (range, 0 to 8 degrees) and 5 degrees procurvatum (range, 0 to 24 degrees). Only 1 patient had a measurable leg-length discrepancy of 7 mm at final follow-up. There were no complications noted. It is felt that pediatric patients have a significant potential for bone remodeling and that any angulation at the time of fracture union will remodel. Our study supports this notion as the final angulation at follow-up averaged 3 degrees valgus and 5 degrees procurvatum. In the patient group presenting with >20 degrees of angulation at the time of injury, final angulation averaged 5 degrees valgus and 11 degrees procurvatum. Treatment with the Pavlik harness provides for excellent clinical outcomes with a minimal complication rate. However, some patients, especially those presenting with a high degree of angulation, may have some degree of persistent radiographic angulation. Level IV (case series). 23879546 The role of cardiorenal biomarkers for risk stratification in the early follow-up after hospitalisation for acute heart failure. Abstract Context: Cardiorenal biomarkers (CBs) predict outcome in acute heart failure (AHF). Objective: To evaluate CBs in early follow-up prognostication. Methods: In 124 AHF patients, levels of CystatinC, NT-proBNP and TroponinI measured five weeks from admission (W5) and relative change from day 2 (D2) were assessed for 6-month prognosis (mortality/HF hospitalization). Results: The combined end-point occurred in 33 patients (27%). D2-, W5-cystatin≥ median, and lack of ≥30%decrease in NT-proBNP were independent predictors of outcome. Additionally, a risk score established from W5 CBs identified patients with very high event rate. Conclusions: CBs at early follow-up of AHF may guide risk stratification. 23713076 A New β-Estradiol-Inducible Vector Set that Facilitates Easy Construction and Efficient Expression of Transgenes Reveals CBL3-Dependent Cytoplasm to Tonoplast Translocation of CIPK5. Transient and stable expression of transgenes is central to many investigations in plant biology research. Chemical regulation of expression can circumvent problems of plant lethality caused by constitutive overexpression or allow inducible knock (out/down) approaches. Several chemically inducible or repressible systems have been described and successfully applied. However, cloning and application-specific modification of most available inducible expression systems have been limited and remained complicated due to restricted cloning options. Here we describe a new set of 57 vectors that enable transgene expression in transiently or stably transformed cells. All vectors harbor a synthetically optimized XVE expression cassette, allowing β-estradiol mediated protein expression. Plasmids are equipped with the reporter genes GUS, GFP, mCherry, or with HA and StrepII epitope tags and harbor an optimized multiple cloning site for flexible and simple cloning strategies. Moreover, the vector design allows simple substitution of the driving promoter to achieve tissue-specificity or to modulate expression ranges of inducible transgene expression. We report details of the kinetics and dose-dependence of expression induction in Arabidopsis leaf mesophyll protoplasts, transiently transformed Nicotiana benthamiana leaves, and stably transformed Arabidopsis plants. Using these vectors, we investigated the influence of CBL (Calcineurin B-like) protein expression on the subcellular localization of CIPKs (Calcineurin B-like interacting protein kinases). These analyses uncovered that induced co-expression of CBL3 is fully sufficient for dynamic translocation of CIPK5 from the cytoplasm to the tonoplast. Thus, the vector system presented here facilitates a broad range of research applications. 23903596 Notes from the field: use of electronic messaging and the news media to increase case finding during a cyclospora outbreak - iowa, july 2013. On Friday, June 28, 2013, the Iowa Department of Public Health (IDPH) routinely reported two cases of cyclosporiasis in its weekly electronic newsletter, the EPI Update. The newsletter's primary audience consists of Iowa's public health officials and health-care providers, but readers also include members of the news media. 23782954 Does the threshold for reporting musculoskeletal pain or the probability of attributing work-relatedness vary by socioeconomic position or sex? To examine the effect of sex and socioeconomic position (SEP) on individuals' perceptions of pain and its work-relatedness. We compared self-reported pain in neck-shoulder or arm with clinical diagnoses and workers' judgments of work-relatedness with physicians' assessments based on specific criteria, between sexes and high- and low-SEP participants in the Oslo Health Study (n = 217). Clinical diagnoses were more frequent in low-SEP subjects than high-SEP subjects with pain and generally higher in women than in men. Pain attributed to work was more frequently assessed as work-related by the physicians in low-SEP subjects than high-SEP subjects and in men than in women of low SEP. The threshold for reporting pain seemed higher in low-SEP subjects and among women. Physicians were more likely to agree with low-SEP workers about work-relatedness. 23609882 Morbidity and mortality after massive transfusion in patients undergoing non-cardiac surgery. Massive transfusion is associated with high morbidity and mortality, yet existing reports of massive transfusion are limited. Our primary aim was to determine the incidence of complications and 30-day mortality among patients who received massive transfusions and to explore risk factors associated with 30-day mortality. We evaluated 971,455 patients from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database. We assessed the associations between 30-day mortality and baseline, intraoperative, and postoperative factors among 5,143 patients who received massive transfusions and for whom complete data were available. The crude 30-day postoperative mortality of the non-transfused, low transfusion (1-4 units), and massive transfusion (≥ 5 units) patients in the NSQIP was 1.2%, 8.9%, and 21.5%, respectively. Of the 5,143 massive transfusion patients with non-missing covariable data, 17% (95% confidence interval [CI] 16% to 18%) died within 30 days of surgery, while 54% (95% CI 53% to 56%) had at least one non-fatal major complication. The following baseline and intraoperative variables were independently associated with 30-day mortality after adjusting for multiple testing: age, American Society of Anesthesiologists (ASA) physical status, emergency case, surgical types, coma > 24 hr before surgery, systemic sepsis, preoperative international normalized ratio of prothrombin time, the number of intraoperative transfusions, and requirement of postoperative transfusion. Massive transfusion is associated with substantial risk for respiratory and infectious complications and for mortality. Patients who died within 30 days of a massive perioperative transfusion were generally older, more likely to have vascular surgical procedure and abnormal international normalized ratio of prothrombin time, higher ASA physical status, preoperative coma and sepsis, and higher postoperative bleeding requiring transfusion, and they were likely given more intraoperative red cell units. 23820579 Homoeologous chromosomes of Xenopus laevis are highly conserved after whole-genome duplication. It has been suggested that whole-genome duplication (WGD) occurred twice during the evolutionary process of vertebrates around 450 and 500 million years ago, which contributed to an increase in the genomic and phenotypic complexities of vertebrates. However, little is still known about the evolutionary process of homoeologous chromosomes after WGD because many duplicate genes have been lost. Therefore, Xenopus laevis (2n=36) and Xenopus (Silurana) tropicalis (2n=20) are good animal models for studying the process of genomic and chromosomal reorganization after WGD because X. laevis is an allotetraploid species that resulted from WGD after the interspecific hybridization of diploid species closely related to X. tropicalis. We constructed a comparative cytogenetic map of X. laevis using 60 complimentary DNA clones that covered the entire chromosomal regions of 10 pairs of X. tropicalis chromosomes. We consequently identified all nine homoeologous chromosome groups of X. laevis. Hybridization signals on two pairs of X. laevis homoeologous chromosomes were detected for 50 of 60 (83%) genes, and the genetic linkage is highly conserved between X. tropicalis and X. laevis chromosomes except for one fusion and one inversion and also between X. laevis homoeologous chromosomes except for two inversions. These results indicate that the loss of duplicated genes and inter- and/or intrachromosomal rearrangements occurred much less frequently in this lineage, suggesting that these events were not essential for diploidization of the allotetraploid genome in X. laevis after WGD.Heredity advance online publication, 3 July 2013; doi:10.1038/hdy.2013.65. 23674368 Methylation-specific digital karyotyping of HPV16E6E7-expressing human keratinocytes identifies novel methylation events in cervical carcinogenesis. Transformation of epithelial cells by high-risk human papillomavirus (hrHPV) types can lead to anogenital carcinomas, particularly cervical cancer, and oropharyngeal cancers. This process is associated with DNA methylation alterations, often affecting tumour suppressor gene expression. This study aimed to comprehensively unravel genome-wide DNA methylation events linked to a transforming hrHPV-infection, which is driven by deregulated expression of the viral oncogenes E6 and E7 in dividing cells. Primary human keratinocytes transduced with HPV16E6E7 and their untransduced counterparts were subjected to methylation-specific digital karyotyping (MSDK) to screen for genome-wide DNA-methylation changes at different stages of HPV-induced transformation. Integration of the obtained methylation profiles with genome-wide gene expression patterns of cervical carcinomas identified 34 genes with increased methylation in HPV-transformed cells and reduced expression in cervical carcinomas. For 12 genes (CLIC3, CREB3L1, FAM19A4, LFNG, LHX1, MRC2, NKX2-8, NPTX-1, PHACTR3, PRDM14, SOST and TNFSF13) specific methylation in HPV-containing cell lines was confirmed by semi-quantitative methylation-specific PCR. Subsequent analysis of FAM19A4, LHX1, NKX2-8, NPTX-1, PHACTR3 and PRDM14 in cervical tissue specimens showed increasing methylation levels for all genes with disease progression. All six genes were frequently methylated in cervical carcinomas, with highest frequencies (up to 100%) seen for FAM19A4, PHACTR3 and PRDM14. Analysis of hrHPV-positive cervical scrapes revealed significantly increased methylation levels of the latter three genes in women with high-grade cervical disease compared to controls. In conclusion, MSDK analysis of HPV16-transduced keratinocytes at different stages of HPV-induced transformation resulted in the identification of novel DNA methylation events, involving FAM19A4, LHX1, NKX2-8, PHACTR3 and PRDM14 genes in cervical carcinogenesis. These genes may provide promising triage markers to assess the presence of (pre)cancerous cervical lesions in hrHPV-positive women. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 23826646 Effect of non-Surgical Periodontal Therapy on Serum Ferritin Levels: an Interventional Study. Background: Ferritin, an acute phase reactant, has been found to be elevated in many chronic inflammation- related diseases. The aim of the present study was to investigate differences in concentrations of serum ferritin in patients with and without periodontal disease before and after non surgical periodontal therapy and correlate these values with clinical variables associated with periodontal disease. Methods: Forty two individuals were included in this study; 20 with chronic periodontitis (CP) and 22 without periodontitis classified as periodontally healthy (CG). Serum ferritin concentration, hemoglobin levels and periodontal parameters (probing pocket depth, clinical attachment level, gingival index, bleeding on probing, plaque index) were recorded at baseline and 3 months after non surgical periodontal therapy. Results: Patients with chronic periodontitis showed higher concentration of serum ferritin compared with periodontally healthy controls (p<0.01). After adjusting for confounder, a positive and significant correlation was observed between serum ferritin levels with the number of sites with probing pocket depth ≥6 mm at baseline (p< 0.01). Regression analyses revealed association between deep pockets and serum ferritin levels at baseline (R(2)=0.823) Significant reduction in serum ferritin levels were observed at the three month assessment after periodontal treatment (p<0.01) and the post-treatment serum ferritin values reached comparable to CG (p>0.05). Furthermore post treatment degree of change in the serum ferritin level was positively and significantly associated with improvement in probing pocket depth ((R(2)= 0.213, p<0.05). Conclusions: Serum ferritin levels are raised in patients with chronic periodontitis and are reduced to control group levels post-treatment. 23885004 A case of nonsuppurative encephalomyelitis in a calf in Japan and the isolation of Japanese encephalitis virus genotype 1 from the affected calf. Japanese encephalitis virus (JEV) was isolated from the cerebrum of a calf which showed severe neurological symptoms in late September 2009, and the JEV isolate was revealed to be genotype 1. This is the first report describing the isolation of JEV genotype 1 from cattle. 23597080 Kinase Scaffold Repurposing for Neglected Disease Drug Discovery: Discovery of an Efficacious, Lapatanib-Derived Lead Compound for Trypanosomiasis. Human African trypanosomiasis (HAT) is a neglected tropical disease caused by the protozoan parasite Trypanosoma brucei . Because drugs in use against HAT are toxic and require intravenous dosing, new drugs are needed. Initiating lead discovery campaigns by using chemical scaffolds from drugs approved for other indications can speed up drug discovery for neglected diseases. We demonstrated recently that the 4-anilinoquinazolines lapatinib (GW572016, 1) and canertinib (CI-1033) kill T. brucei with low micromolar EC50 values. We now report promising activity of analogues of 1, which provided an excellent starting point for optimization of the chemotype. Our compound optimization that has led to synthesis of several potent 4-anilinoquinazolines, including NEU617, 23a, a highly potent, orally bioavailable inhibitor of trypanosome replication. At the cellular level, 23a blocks duplication of the kinetoplast and arrests cytokinesis, making it a new chemical tool for studying regulation of the trypanosome cell cycle. 23830695 Structure-activity relationship studies of Niemann-Pick type C1-like 1 (NPC1L1) ligands identified by screening assay monitoring pharmacological chaperone effect. A number of hereditary diseases are caused by defective protein trafficking due to a folding defect resulting from point mutations in proteins. Ligands that bind to the folding intermediates of such mutant proteins and rescue their trafficking defects, known as pharmacological chaperones, have promise for the treatment of certain genetic diseases, including Fabry disease, cystic fibrosis, and Niemann-Pick disease type C. Here we show that this pharmacological chaperone effect can be used for ligand screening, that is, binding of candidate ligands can be detected by monitoring the ligand-mediated correction of a localization defect caused by artificially introduced point mutations of the protein of interest. Using this method, we discovered novel steroidal ligands of Niemann-Pick type C1-like 1 (NPC1L1), an intestinal cholesterol transporter that is the target of the cholesterol absorption inhibitor ezetimibe, and conducted structure-activity relationship studies. We also present data indicating that the binding site of the new ligands is distinct from both the N-terminal sterol-binding domain and the ezetimibe-binding site. 23821650 An integrative approach to understanding the combinatorial histone code at functional elements. The rapid advancement of genomic technology has revealed the enormous complexity and combinatorial nature of chromatin modifications. To facilitate interpretation of the combinatorial nature of chromatin, we have developed a novel method to integrate all chromatin datasets into distinct nucleosome types (nucleosome alphabet). We have applied this approach to Saccharomyces cerevisiae, generating a nucleosome alphabet, which forms chromatin motifs when mapped back to the genome. By applying novel chromatin alignment and global word search approaches, we have defined distinctive chromatin motifs for introns, origins of replication, tRNAs, antisense transcripts, double-strand-break hotspots and DNase hypersensitive sites, and can distinguish genes by expression level. We have also uncovered strong associations between transcription factor binding and specific types of nucleosomes. Our results demonstrate the uses and functionality of defining a chromatin alphabet and provide a unique and novel framework for exploring chromatin architecture. mjbuck@buffalo.edu Supplementary data are available at Bioinformatics online. 23756654 Effects of dietary weight loss and exercise on insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in postmenopausal women: a randomized controlled trial. High levels of insulin-like growth factor (IGF)-I may increase the risk of common cancers in humans. We hypothesized that weight loss induced by diet and/or exercise would reduce IGF-I in postmenopausal women. Four hundred and thirty nine overweight or obese [body mass index (BMI) ≥ 25 kg/m(2)] women (50-75 years) were randomly assigned to: (i) exercise (N = 117), (ii) dietary weight loss (N = 118), (iii) diet + exercise (N = 117), or (iv) control (N = 87). The diet intervention was a group-based program with a 10% weight loss goal. The exercise intervention was 45 minutes/day, 5 days/week of moderate-to-vigorous intensity activity. Fasting serum IGF-I and IGF-binding protein (IGFBP)-3 were measured at baseline and 12 months by radioimmunoassay. Higher baseline BMI was associated with lower IGF-I and IGF-I/IGFBP-3 molar ratio. Although no significant changes in either IGF-I or IGFBP-3 were detected in any intervention arm compared with control, the IGF-I/IGFBP-3 ratio increased significantly in the diet (+5.0%, P < 0.01) and diet + exercise (+5.4%, P < 0.01) groups compared with control. Greater weight loss was positively associated with change in both IGF-I (Ptrend = 0.017) and IGF-I/IGFBP-3 ratio (Ptrend < 0.001) in the diet group, but inversely with change in IGFBP-3 in the diet + exercise group (Ptrend = 0.01). No consistent interaction effects with baseline BMI were detected. Modified IGF-I bioavailability is unlikely to be a mechanism through which caloric restriction reduces cancer risk in postmenopausal women. Cancer Epidemiol Biomarkers Prev; 22(8); 1457-63. ©2013 AACR. 23640987 Integrated approach of in vivo and in vitro evaluation of the involvement of hepatic uptake organic anion transporters in the drug disposition in rats using rifampicin as an inhibitor. Cumulative studies describe the importance of drug transporters as one of the key determinants of pharmacokinetics that necessitate investigation and assessment of the involvement of drug transporters in drug discovery and development. The present study investigated an integrated in vivo and in vitro approach to determine the involvement of organic anion transporting polypeptides (Oatps) in the disposition of drugs in rats using rifampicin as an inhibitor. When bromosulfophthalein (BSP) and HMG-CoA reductase inhibitors (statins), which were used as model substrates for Oatps, were administered intravenously (3 and 1 mg/kg, respectively) to rats pretreated with rifampicin orally (30 mg/kg), the total plasma clearance of BSP and statins was attenuated compared with that in control rats, suggesting the involvement of Oatps in the disposition of these drugs in vivo. On the other hand, the pharmacokinetics of midazolam, used as a model substrate of cytochrome P450 3a (Cyp3a), was unchanged between control rats and rifampicin-pretreated rats. The involvement of Oatps in the disposition of statins observed in vivo was further clarified by employing an in vitro hepatic uptake study and media-loss assay in the presence or absence of 100 μM rifampicin. Hepatic intrinsic clearance was reduced in the presence of rifampicin in both the media-loss assay and hepatocyte uptake study. The present study suggests in vivo investigations in rats using rifampicin together with in vitro investigations with a media-loss assay and/or uptake assay using rat hepatocytes can help determine whether a clinical drug-drug interaction study is necessary in drug development. 23871698 Glycosylated Hemoglobin for Diagnosis of Prediabetes in Acute Ischemic Stroke Patients. Prediabetes (PD) is an independent risk factor for stroke. The American Diabetes Association (ADA) has recently published new guidelines recommending glycosylated hemoglobin A1c (HbA1c) as a marker to diagnose diabetes and PD. Diagnosis of diabetes Mellitus (DM) is often made at the time of hospitalization for stroke. Less is known about identifying PD in acute ischemic stroke (AIS) patients. We aim to investigate the frequency of new-onset PD in the hospitalized AIS patients using the new ADA guidelines. We retrospectively studied 362 AIS patients from our local database. Stroke risk factors, type of stroke, and white matter hyperintensities (WMHs) were all collected. Based on the 2010 ADA guidelines, patients were classified as prediabetics, with HbA1c levels of 5.7%-6.4%; diabetics, with HbA1c levels more than 6.5%; and normoglycemic, HbA1c levels less than 5.7%. We used SAS 9.3 for analysis. On admission, 279 (78%) AIS patients had HbA1c values collected. Stratifying by HbA1c, 113 (31%) AIS patients were given the diagnosis of DM and 109 (30%) were given the diagnosis of PD. From the 166 patients with no DM history, 53% had PD and 15% had DM. Patients with DM and PD were more likely to have hypertension (P < .001) and hyperlipidemia (P = .05). The likelihood of new-onset PD increased with age (P < .01). No differences were found by the type of stroke or WMH. Diabetes and PD are highly prevalent in the hospitalized ischemic stroke (IS) patients. Our results suggest a need for routine HbA1c testing in all patients with IS. Further larger studies need to confirm these findings. 23859890 Colonize, evade, flourish: How glyco-conjugates promote virulence of Helicobacter pylori. Helicobacter pylori is an adapted gastric pathogen that colonizes the human stomach, causing severe gastritis and gastric cancer. A hallmark of infection is the ability of this organism to evade detection by the human immune system. H. pylori has evolved a number of features to achieve this, many of which involve glyco-conjugates including the lipopolysaccharide, peptidoglycan layer, glycoproteins, and glucosylated cholesterol. These major bacterial components possess unique features from those of other gram-negative organisms, including differences in structure, assembly, and modification. These defining characteristics of H. pylori glycobiology help the pathogen establish a long-lived infection by providing camouflage, modulating the host immune response, and promoting virulence mechanisms. In this way, glyco-conjugates are essential for H. pylori pathogenicity and survival, allowing it to carve out a niche in the formidable environment of the human stomach. 23934030 Persistent Structural Disease Is the Most Common Cause of Repeat Hip Preservation Surgery. Hip preservation surgery has become more commonplace, yet when it fails, it is unclear why it does so. Understanding failed procedures should lead to improved surgical results. The purposes of this study were to (1) characterize patients undergoing hip preservation surgery after prior procedures; (2) compare demographics, hip pain, and function in patients with prior procedures with those undergoing primary surgery; (3) determine the types of previous procedures and the reasons for secondary surgery; and (4) report the procedure profile of the secondary surgeries. A prospective, multicenter hip preservation database of 2263 patients (2386 surgery cases) was reviewed to identify 352 patients (359 hips, 15% of the total) who had prior surgery. Patient demographics, type of previous surgery, diagnostic categories, clinical scores, and type of secondary procedure were recorded. For patients undergoing secondary surgery, the average age was 23 years and 70% were female. Hip pain and function were similar between patients undergoing primary and secondary surgery. The previous surgical approaches were open in 52% and hip arthroscopy in 48%. In the femoroacetabular impingement and adult acetabular dysplasia subgroups, hip arthroscopy was the most common previous surgical approach (86% and 64%, respectively). Inadequately corrected structural disease was the most common reason for secondary surgery. Femoral osteochondroplasty and acetabular reorientation were the most common secondary procedures. Inadequately corrected structural disease (femoroacetabular impingement or acetabular dysplasia) was commonly associated with the need for secondary hip preservation surgery. Although we do not have data to identify other technical failures, the available data suggest primary treatments should encompass comprehensive deformity correction when indicated. Level III, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. 23938469 Regulation of stress-inducible phosphoprotein 1 nuclear retention by PIAS1. Stress-inducible phosphoprotein 1 (STI1), a co-chaperone for Hsp90, has been shown to regulate multiple pathways in astrocytes, but its contributions to cellular stress responses are not fully understood. We show that in response to irradiation-mediated DNA damage stress STI1 accumulates in the nucleus of astrocytes. Also, STI1 haploinsufficiency decreases astrocyte survival after irradiation. Using yeast two-hybrid screenings we identified several nuclear proteins as STI1 interactors. Overexpression of one of these interactors, PIAS1, seems to be specifically involved in STI1 nuclear retention and in directing STI1 and Hsp90 to specific sub-nuclear regions. PIAS1 and STI1 co-immunoprecipitate and PIAS1 can function as an E3 SUMO ligase for STI. Using mass spectrometry we identified 5 SUMOylation sites in STI1. A STI1 mutant lacking these 5 sites is not SUMOylated, but still accumulates in the nucleus in response to increased expression of PIAS1, suggesting the possibility that a direct interaction with PIAS1 could be responsible for STI1 nuclear retention. To test this possibility, we mapped the interaction sites between PIAS1 and STI1 using yeast-two hybrid assays and surface plasmon resonance and found that a large domain in the N-terminal region of STI1 interacts with high affinity with amino acids 450-480 of PIAS1. Knockdown of PIAS1 in astrocytes impairs the accumulation of nuclear STI1 in response to irradiation. Moreover, a PIAS1 mutant lacking the STI1 binding site is unable to increase STI1 nuclear retention. Interestingly, in human glioblastoma multiforme PIAS1 expression is increased and we found a significant correlation between increased PIAS1 expression and STI1 nuclear localization. These experiments provide evidence that direct interaction between STI1 and PIAS1 is involved in the accumulation of nuclear STI1. This retention mechanism could facilitate nuclear chaperone activity. 23711903 Sorption of humic acid to functionalized multi-walled carbon nanotubes. The environmental behavior of carbon nanotubes (CNTs) and humic acid (HA) is a prominent concern, but effect of functionalities on their sorption is not clear yet. Functionalized multi-walled CNTs (MCNT15) and HA were used to study their sorption behavior. Sorption rate of HA to MCNTs was dominantly controlled by its diffusion from liquid-MCNT boundary to MCNT surfaces. The sorption is in the sequence of MCNT15 > MCNT15-NH2 > MCNT15-OH > MCNT15-COOH > MCNT15-Ni, which was dependent on their surface area and meso- and macro-pore volume. The functionalities of MCNTs regulated the sorption by affecting their interaction mechanisms (i.e., H-bonding, Ï€-Ï€, and hydrophobic interaction). Additionally, the amount of these functionalities on the MCNT surface reduced indirectly the sorption sites due to the steric hindrance. Electrostatic repulsion deceased the sorption of HA by MCNTs with increasing pH. This study demonstrated the importance of functionalities on the MCNTs for the sorption of HA. 23832110 Genomic imprinting is variably lost during reprogramming of mouse iPS cells. Derivation of induced pluripotent stem (iPS) cells is mainly an epigenetic reprogramming process. It is still quite controversial how genomic imprinting is reprogrammed in iPS cells. Thus, we derived multiple iPS clones from genetically identical mouse somatic cells. We found that parentally inherited imprint was variably lost among these iPS clones. Concurrent with the loss of DNA methylation imprint at the corresponding Snrpn and Peg3 imprinted regions, parental origin-specific expression of the Snrpn and Zim1 imprinted genes was also lost in these iPS clones. This loss of parental genomic imprinting in iPS cells was likely caused by the reprogramming process during iPS cell derivation because extended culture of iPS cells did not lead to significant increase in the loss of genomic imprinting. Intriguingly, one to several paternal chromosomes appeared to have acquired de novo methylation at the Snrpn and Zac1 imprinted regions in a high percentage of iPS clones. These results might have some implications for future therapeutic applications of iPS cells. Since DNA methylation imprint can be completely erased in some iPS clones at multiple imprinted regions, iPS cell reprogramming may also be employed to dissect the underlying mechanisms of erasure, reacquisition and maintenance of genomic imprinting in mammals. 23810758 Comparison of clinical targeted next-generation sequence data from formalin-fixed and fresh-frozen tissue specimens. Next-generation sequencing (NGS) has emerged as a powerful technique for the detection of genetic variants in the clinical laboratory. NGS can be performed using DNA from FFPE tissue, but it is unknown whether such specimens are truly equivalent to unfixed tissue for NGS applications. To address this question, we performed hybridization-capture enrichment and multiplexed Illumina NGS for 27 cancer-related genes using DNA from 16 paired fresh-frozen and routine FFPE lung adenocarcinoma specimens and conducted extensive comparisons between the sequence data from each sample type. This analysis revealed small but detectable differences between FFPE and frozen samples. Compared with frozen samples, NGS data from FFPE samples had smaller library insert sizes, greater coverage variability, and an increase in C to T transitions that was most pronounced at CpG dinucleotides, suggesting interplay between DNA methylation and formalin-induced changes; however, the error rate, library complexity, enrichment performance, and coverage statistics were not significantly different. Comparison of base calls between paired samples demonstrated concordances of >99.99%, with 96.8% agreement in the single-nucleotide variants detected and >98% accuracy of NGS data when compared with genotypes from an orthogonal single-nucleotide polymorphism array platform. This study demonstrates that routine processing of FFPE samples has a detectable but negligible effect on NGS data and that these samples can be a reliable substrate for clinical NGS testing. 23790127 "Holy cow, does that ever open up a can of worms": health care providers' experiences of inquiring about intimate partner violence. Primary care health care providers (HCPs) are likely to treat numerous women who are victims of intimate partner violence (IPV). In this study, we used interpretative phenomenological analysis to analyze semistructured interviews with nine HCPs (six family physicians and three nurse practitioners) in Ontario, Canada. Findings center on how HCPs interpret and make sense of their experiences inquiring about and receiving abuse disclosures. Overarching themes that we identified were asking and disclosure as a journey and disengaging in order to engage. Our findings underscore the importance of training HCPs to respond flexibly to sensitive situations. 23625019 Unmet needs in immigrant cancer survivors: a cross-sectional population-based study. Social suffering, language difficulties, and cultural factors may all make the cancer experience more difficult for immigrants. This study aimed to document unmet needs, and variables associated with these, in a population-based sample of first-generation immigrants and Anglo-Australians who had survived cancer. Participants were recruited via Australian cancer registries. Eligible cancer survivors had a new diagnosis 1-6 years earlier and were aged between 18 and 80 years at diagnosis. Eligible immigrant participants and parents were born in a country where Arabic, Chinese (Mandarin, Cantonese, and other dialects), or Greek is spoken, and they spoke one of these languages. A random sample of English-speaking Anglo-Australian-born controls was recruited. Five hundred ninety-six patients (277 immigrants) were recruited to the study (response rate, 26 %). Compared to Anglo-Australians, the adjusted odds ratio of Chinese immigrants for at least one unmet information/support need was 5.1 (95 % CI 3.1, 8.3) and for any unmet physical need was 3.1 (95 % CI 1.9, 5.1). For Greek, these were 2.0 (95 % CI 1.1, 4.0) and 2.7 (95 % CI 1.4, 5.2). Arabic patients had elevated, but not statistically significant, odds ratios compared to Anglo-Australians. Written information and having a specialist, support services, and other health professionals who spoke their language were in the top ten unmet needs amongst immigrants. Immigrant cancer survivors, several years after initial diagnosis, are more likely to have an unmet need for information or for help with a physical problem than Anglo-Australians. They strongly desire information and support in their own language. 23603774 Application of the ReNuMa model in the Sha He river watershed: tools for watershed environmental management. Models and related analytical methods are critical tools for use in modern watershed management. A modeling approach for quantifying the source apportionment of dissolved nitrogen (DN) and associated tools for examining the sensitivity and uncertainty of the model estimates were assessed for the Sha He River (SHR) watershed in China. The Regional Nutrient Management model (ReNuMa) was used to infer the primary sources of DN in the SHR watershed. This model is based on the Generalized Watershed Loading Functions (GWLF) and the Net Anthropogenic Nutrient Input (NANI) framework, modified to improve the characterization of subsurface hydrology and septic system loads. Hydrochemical processes of the SHR watershed, including streamflow, DN load fluxes, and corresponding DN concentration responses, were simulated following calibrations against observations of streamflow and DN fluxes. Uncertainty analyses were conducted with a Monte Carlo analysis to vary model parameters for assessing the associated variations in model outputs. The model performed accurately at the watershed scale and provided estimates of monthly streamflows and nutrient loads as well as DN source apportionments. The simulations identified the dominant contribution of agricultural land use and significant monthly variations. These results provide valuable support for science-based watershed management decisions and indicate the utility of ReNuMa for such applications. 23702311 The mitochondrial disease associated protein Ndufaf2 is dispensable for Complex-1 assembly but critical for the regulation of oxidative stress. Deficiency in human mitochondrial Complex-1 has been linked to a wide variety of neurological disorders. Homozygous deletion of the Complex-1 associated protein, Ndufaf2, leads to a severe juvenile onset encephalopathy involving degeneration of the substantia nigra and other sub-cortical regions resulting in adolescent lethality. To understand the precise role of Ndufaf2 in Complex-1 function and its links to neurologic disease, we studied the effects on Complex-1 assembly and function, as well as pathological consequences at the cellular level, in multiple in vitro models of Ndufaf2 deficiency. Using both Ndufaf2-deficient human neuroblastoma cells and primary fibroblasts cultured from Ndufaf2 knock-out mice we found that Ndufaf2-deficiency selectively reduces Complex-1 activity. While Ndufaf2 is traditionally referred to as an assembly factor of Complex-1, surprisingly, however, Ndufaf2-deficient cells were able to assemble a fully mature Complex-1 enzyme, albeit with reduced kinetics. Importantly, no evidence of intermediate or incomplete assembly was observed. Ndufaf2 deficiency resulted in significant increases in oxidative stress and mitochondrial DNA deletion, consistent with contemporary hypotheses regarding the pathophysiology of inherited mutations in Complex-1 disorders. These data suggest that Ndufaf2, unlike other Complex-1 assembly factors, may be more accurately described as a chaperone involved in proper folding during Complex-1 assembly, since it is dispensable for Complex-1 maturation but not its proper function. 23957179 Breastfeeding information in pharmacology textbooks: a content analysis. Women often need to take medicines while breastfeeding and pharmacists need to provide accurate information in order to avoid undue caution about the compatibility of medicines and breastfeeding. The objective of this study was to review information provided about breastfeeding in commonly used pharmacology textbooks. We asked 15 Australian universities teaching pharmacy courses to provide a list of recommended pharmacology textbooks in 2011. Ten universities responded, generating a list of 11 textbooks that we analysed for content relating to breastfeeding. Pharmacology textbooks outline the mechanisms of actions of medicines and their use: however, only a small emphasis is placed on the safety/compatibility of medicines for women during breastfeeding. Current pharmacology textbooks recommended by Australian universities have significant gaps in their coverage of medicine use in breastfeeding. Authors of textbooks should address this gap, so academic staff can recommend texts with the best lactation content. 23892571 Comparative pharmacology of the BRS-3 nonpeptide agonist, MK-5046; a universal peptide agonist and the peptide antagonist, Bantag-1, for human bombesin receptors. Bombesin-receptor-subtype-3(BRS-3) is an orphan G-protein-coupled receptor of the bombesin(Bn) family, whose natural ligand is unknown and which doesn't bind any natural Bn-peptide with high affinity. It is present in CNS, peripheral tissues and tumors,however its role in normal physiology/pathophysiology is largely unknown due to lack of selective ligands. Recently, a nonpeptide-agonist(MK-5046 ) and peptide-antagonist(Bantag-1) for BRS-3 were described, however there are limited studies on their pharmacology. To assess this we studied MK-5046 and Bantag-1 interactions with human Bn-receptors(BnRs)(hBRS-3,GRP-R,NMB-R) and compared them to the nonselective,peptide-agonist[D-Tyr6,βAla11,Phe13,Nle14]Bn-(6-14)(peptide#1). Receptor-activation was detected by activation of PLC,MAPK,FAK,paxillin and Akt. In hBRS-3 cells the relative affinities were:Bantag-1(1.3nM)>peptide#1(2nM)>MK-5046 (37-160nM)>GRP,NMB(>10μM), and the binding-dose-inhibition curves were broad(>4-logs),with Hill coefficients differing significantly from unity. Curve-fitting demonstrated high(MK-5046-Ki=0.08nM) and low-affinity(MK-5046-Ki=11-29nM)-binding sites. For PLC activation in hBRS-3 cells the relative potencies were:MK-5046 (0.02nM)>peptide#1(6nM)>GRP,NMB,Bantag-1(>10μM) and MK-5046 had a biphasic dose-response,whereas peptide#1's was monophasic. Bantag-1 was a specific hBRS-3-antagonist. In hBRS-3 cells,MK-5046 was a full-agonist for activation of MAPK,FAK,Akt and paxillin, however it was a partial-agonist for phospholipase-A2(PLA2) activation. The kinetics of activation/duration-of-action for PLC/MAPK activation of MK-5046 and peptide#1 differed with peptide#1 causing more rapid stimulation, however MK-5046 had more prolonged activity. This study shows that MK-5046 and Bantag-1 have high affinity/selectivity for hBRS-3. They also show the nonpeptide-MK-5046 and peptide#1 agonists differ markedly in their receptor coupling,ability to activate different signaling cascades and kinetics/duration of action. These results show their hBRS-3-receptor activation is not always concordant and could lead to markedly different cellular responses. 23860471 "It gives me a sense of belonging": Providing integrated health care and treatment to people with HCV engaged in a psycho-educational support group. Injection drug use (IDU) increases the risk of contracting hepatitis C virus (HCV) yet very few people living with HCV access effective, and potentially curative, treatments. The East Toronto Hepatitis C Program (ETHCP) was developed in 2006 and provides health care, treatment and support to people living with HCV who have complex mental health, physical health and psychosocial needs. The program is anchored in a 16-18 week psychosocial support group located within one of the 3 participating community-based health clinics. The objective of this study was to explore the experiences of individuals engaged in the ETHCP psycho-educational group. This phenomenological qualitative study consisted of semi-structured in-depth interviews with twenty randomly selected program participants. The three dominant themes that emerged from the analysis were program structure, group cohesion and group as agent for change. The ETHCP "one-stop shopping" model provided a stable foundation allowing for the development of group cohesion. Group cohesion was marked by the formation of intense relationships creating a safe and non-judgmental environment where participants could self-reflect, make social connections and feel cared for and accepted. Three types of relationships characterized group cohesion: relationship to self, relationships with individual group members and relationship to group as a whole. Within the nurturing group environment, participants could challenge themselves and others, ultimately enabling change. The results of our qualitative study suggest that it is the formation of strong group cohesion that facilitated participants' behavioural change, regardless of their level of substance use. The structure of the group provided stability and was characterized by consistent weekly meetings, knowledge exchange and the provision of multiple services in one location. The support from peers and staff allowed participants to develop personal goals. Participants began to see themselves in a new and changed way; expressing this change in a variety of positive behaviours. 23821322 Significance of serum immune markers in identification of global functional impairment in the oldest old: cross-sectional results from the BELFRAIL study. The large burden and coexistence of physical disability, cognitive impairment, and depression in the oldest old makes summary markers of global functioning of great value, allowing for risk stratification. Inflammation may be a common underlying cause or represents a final common pathway. The present study investigated the association between elevated serum inflammatory markers and global functioning and its underlying aspects. A representative sample of 415 community-dwelling elderly subjects participating in the BELFRAIL study, with a mean age of 85 years, was included in the present analysis. Data on physical performance, dependence, and mental aspects of functioning and serum levels of 15 inflammatory proteins, including cytokines, chemokines, and acute-phase proteins, were assessed. Interleukin (IL)-6 was negatively associated with global functioning (odds ratio (OR) 4.35). The odds ratios for C-reactive protein (CRP) (OR 2.37) and the combined score of IL-6 and CRP (OR 2.59) were lower or not significant. IL-6 was significantly associated with physical dependence and cognitive function, and only a highly elevated serum level was associated with physical performance. Physical dependence was associated with a highly elevated CRP serum level. The proportion of functionally impaired older persons with elevated IL-6 was 81.93 %, giving a low positive predictive value (0.38), but a high negative predictive value (0.87). So, IL-6 is strongly associated with global functioning and all of the individual aspects of functioning, except suspected depression, in community-dwelling persons 80 years and older. 23827209 Expression, purification and characterization of two truncated peste des petits ruminants virus matrix proteins in Escherichia coli, and production of polyclonal antibodies against this protein. Peste des petits ruminants virus (PPRV), the etiological agent of peste des petits ruminants, is classified into the genus Morbillivirus in the family Paramyxoviridae. The PPRV matrix (M) gene is composed of 1483 base pairs, encoding a 335 amino acids M protein with a molecular weight of approximately 38kD. We have demonstrated previously that the full-length M protein was expressed at an extremely low level or not even expressed in Escherichia coli BL21 (DE3). In this study, the M protein was split into two truncated forms to be successfully expressed in E. coli at a high level using the pET30a (+) vector, respectively, by analysis of SDS-PAGE, western blot and MALDI-TOF-MS. The optimization of culture conditions led us to perform the recombinant protein induction with 0.2mM IPTG at 28°C for 12h, whereby both proteins nevertheless were expressed in the insoluble form. Therefore, both His-tagged proteins were purified under the denaturing condition using a commercially available kit. Balb/c mice were immunized with the complex of purified proteins and then effectively produced polyclonal antibodies, which reached to a relatively high titer by the analysis of ELISA. The specificity of the prepared polyclonal antibodies was checked by western blot and immunofluorescence, revealing them with the desirable specificity against both non-denatured and denatured M proteins. 23839152 Adsorption of Methylene Blue Dye from Aqueous Solutions Using Eichhornia crassipes. Adsorption of methylene blue (MB) from aqueous solution using dried roots, stems, and leaves of Eichhornia crassipes biomass obtained from Lake Victoria was studied. Batch experimental results revealed that the adsorption process was highly dependent on adsorbent dosage, initial MB concentration, E. crassipes particle size and aqueous solution temperature. The isotherm data fitted Freundlich mathematical models with maximum dye adsorption of 35.37 mg g(-1). Roots adsorbed over 99 % of the MB in <5 min. Sorption kinetics followed a pseudo-second-order model. Results provide evidence that E. crassipes is an effective and inexpensive biomaterial for dye removal from aqueous dye solutions and industrial effluents. 23714334 Renal function and short-term outcome in stable outpatients with coronary, cerebrovascular or peripheral artery disease. The influence of renal function on outcome in stable outpatients with atherosclerotic disease has not been thoroughly studied. We used the FRENA Registry data to compare the incidence of subsequent ischemic events (myocardial infarction [MI], ischemic stroke or limb amputation) in patients with coronary (CAD), cerebrovascular (CVD) or peripheral artery disease (PAD), according to their estimated glomerular filtration rate (eGFR) at baseline. As of April 2012, 3860 patients were recruited in FRENA: 1439 with CAD, 1118 with CVD and 1303 with PAD. Over a mean follow-up of 14 ± 12 months, 97 patients suffered subsequent MI, 93 had ischemic stroke and 46 underwent limb amputation. In all, 2699 patients (70%) had eGFR > 60 mL/min/1.73 m(2), 1022 (26%) had 30-60 mL/min/1.73 m(2), and 139 (3.6%) had <30 mL/min/1.73 m(2). Among patients with CAD, the rate of subsequent MI was: 1.38 (95% CI: 0.85-2.11), 5.79 (95% CI: 3.90-8.31) and 18.8 (95% CI: 9.14-34.4) events per 100 patient-years, respectively. On multivariable analysis, the hazard ratio for MI (compared with patients with eGFR > 60 mL/min/1.73 m(2)) was of 1.77 (95% CI: 1.15-2.73) for patients with eGFR of 30-60 mL/min/1.73 m(2), and 3.15 (95% CI: 1.61-6.14) for those with eGFR < 30 mL/min/1.73 m(2). Among patients with CVD or PAD, there was no increasing rate of subsequent ischemic events with decreasing renal function. Among stable outpatients with CAD, there is an increasing rate of subsequent MI with decreasing renal function, independently of potentially confounding variables. These findings were not observed in patients with CVD or PAD. 23268606 Anti-inflammatory sesquiterpene derivatives from the leaves of Tripterygium wilfordii. Twelve new dihydroagarofuran sesquiterpene polyol esters, triptersinines A-L (1-12), and eight known sesquiterpene pyridine alkaloids were isolated from the leaves of Tripterygium wilfordii. Their structures were elucidated on the basis of spectroscopic analyses, including UV, IR, and NMR experiments ((1)H-(1)H COSY, NOESY, HSQC, and HMBC). Furthermore, in an in vitro bioassay, compounds 1, 9, 11, 13, 14, and 18 showed moderate inhibitory effects on nitric oxide production in LPS-induced macrophages at 5 μM; all compounds were inactive when tested against five human cancer cell lines (IC(50) values >1 μM). 23843270 Aging, the Central Nervous System, and Mobility. Mobility limitations are common and hazardous in community-dwelling older adults but are largely understudied, particularly regarding the role of the central nervous system (CNS). This has limited development of clearly defined pathophysiology, clinical terminology, and effective treatments. Understanding how changes in the CNS contribute to mobility limitations has the potential to inform future intervention studies. A conference series was launched at the 2012 conference of the Gerontological Society of America in collaboration with the National Institute on Aging and the University of Pittsburgh. The overarching goal of the conference series is to facilitate the translation of research results into interventions that improve mobility for older adults. Evidence from basic, clinical, and epidemiological studies supports the CNS as an important contributor to mobility limitations in older adults without overt neurologic disease. Three main goals for future work that emerged were as follows: (a) develop models of mobility limitations in older adults that differentiate aging from disease-related processes and that fully integrate CNS with musculoskeletal contributors; (b) quantify the contribution of the CNS to mobility loss in older adults in the absence of overt neurologic diseases; (c) promote cross-disciplinary collaboration to generate new ideas and address current methodological issues and barriers, including real-world mobility measures and life-course approaches. In addition to greater cross-disciplinary research, there is a need for new approaches to training clinicians and investigators, which integrate concepts and methodologies from individual disciplines, focus on emerging methodologies, and prepare investigators to assess complex, multisystem associations. 23764601 Fate of Triclocarban, Triclosan and Methyltriclosan during wastewater and biosolids treatment processes. Triclocarban (TCC) and Triclosan (TCS) are two antibacterial chemicals present in household and personal care products. Methyltriclosan is a biodegradation product of TCS formed under aerobic conditions. TCC and TCS are discharged to Waste Water Treatment Plants (WWTP) where they are removed from the liquid phase mainly by concentrating in the solids. This study presents a thorough investigation of TCC, TCS and MeTCS concentrations in the liquid phase (dissolved + particulate) as well as solid phases within a single, large WWTP in the U.S. Total TCC and TCS concentrations decreased by >97% with about 79% of TCC and 64% of TCS transferred to the solids. The highest TCC and TCS removal rates from the liquid phase were reached in the primary treatment mainly though sorption and settling of solids. The TCC mass balances showed that TCC levels remain unchanged through the secondary treatment (activated sludge process) and about an 18% decrease was observed through the nitrification-denitrification process. On the other hand, TCS levels decreased in both processes (secondary and nitrification-denitrification) by 10.4 and 22.6%, respectively. The decrease in TCS levels associated with observed increased levels of MeTCS in secondary and nitrification-denitrification processes providing evidence of TCS biotransformation. Dissolved-phase concentrations of TCC and TCS remained constant during filtration and disinfection. TCC and TCS highest sludge concentrations were analyzed in the primary sludge (13.1 ± 0.9 Î¼g g(-1) dry wt. for TCC and 20.3 ± 0.9 Î¼g g(-1) dry wt. for TCS) but for MeTCS the highest concentrations were analyzed in the secondary sludge (0.25 ± 0.04 Î¼g g(-1) dry wt.). Respective TCC, TCS and MeTCS concentrations of 4.15 ± 0.77; 5.37 ± 0.97 and 0.058 ± 0.003 kg d(-1) are leaving the WWTP with the sludge and 0.13 ± 0.01; 0.24 ± 0.07 and 0.021 ± 0.002 kg d(-1) with the effluent that is discharged. 23929752 Validation of the DRAGON Score in 12 Stroke Centers in Anterior and Posterior Circulation. The DRAGON score predicts functional outcome in the hyperacute phase of intravenous thrombolysis treatment of ischemic stroke patients. We aimed to validate the score in a large multicenter cohort in anterior and posterior circulation. Prospectively collected data of consecutive ischemic stroke patients who received intravenous thrombolysis in 12 stroke centers were merged (n=5471). We excluded patients lacking data necessary to calculate the score and patients with missing 3-month modified Rankin scale scores. The final cohort comprised 4519 eligible patients. We assessed the performance of the DRAGON score with area under the receiver operating characteristic curve in the whole cohort for both good (modified Rankin scale score, 0-2) and miserable (modified Rankin scale score, 5-6) outcomes. Area under the receiver operating characteristic curve was 0.84 (0.82-0.85) for miserable outcome and 0.82 (0.80-0.83) for good outcome. Proportions of patients with good outcome were 96%, 93%, 78%, and 0% for 0 to 1, 2, 3, and 8 to 10 score points, respectively. Proportions of patients with miserable outcome were 0%, 2%, 4%, 89%, and 97% for 0 to 1, 2, 3, 8, and 9 to 10 points, respectively. When tested separately for anterior and posterior circulation, there was no difference in performance (P=0.55); areas under the receiver operating characteristic curve were 0.84 (0.83-0.86) and 0.82 (0.78-0.87), respectively. No sex-related difference in performance was observed (P=0.25). The DRAGON score showed very good performance in the large merged cohort in both anterior and posterior circulation strokes. The DRAGON score provides rapid estimation of patient prognosis and supports clinical decision-making in the hyperacute phase of stroke care (eg, when invasive add-on strategies are considered). 23887812 Neural Correlates of Preparatory and Regulatory Control Over Positive and Negative Emotion. The present study used functional magnetic resonance imaging to investigate brain activation during preparatory and regulatory control while participants (N=24) were instructed either to simply view, or decrease their emotional response to, pleasant, neutral, or unpleasant pictures. A main effect of emotional valence on brain activity was found in the right precentral gyrus, with greater activation during positive than negative emotion regulation. A main effect of regulation phase was evident in the bilateral anterior prefrontal cortex (PFC), precuneus, posterior cingulate cortex, right putamen, and temporal and occipital lobes, with greater activity in these regions during preparatory than regulatory control. A Valence X Regulation interaction was evident in regions of ventromedial PFC and anterior cingulate cortex, reflecting greater activation while regulating negative than positive emotion, but only during active emotion regulation (not preparation). Conjunction analyses revealed common brain regions involved in differing types of emotion regulation including selected areas of left lateral PFC, inferior parietal lobe, temporal lobe, right cerebellum, and bilateral dorsomedial PFC. The right lateral PFC was additionally activated during the modulation of both positive and negative valence. Findings demonstrate significant modulation of brain activity during both preparation for, and active regulation of positive and negative emotional states. 23829298 Role of preoperative anemia for risk of transfusion and postoperative morbidity in fast-track hip and knee arthroplasty. Preoperative anemia has been associated with increased risk of allogeneic blood transfusion and postoperative morbidity and mortality. The prevalence of preoperative anemia and its association with postoperative outcomes has not previously been reported in relation to fast-track elective total hip arthroplasty (THA) and total knee arthroplasty (TKA). We aimed to evaluate the prevalence of preoperative anemia in elective fast-track THA and TKA and its association with risk of perioperative transfusion, prolonged length of hospital stay (LOS), and postoperative readmission. This was a prospective observational database study with data obtained from six high-volume Danish fast-track surgical centers. Preoperative hemoglobin and patient demographics were collected prospectively using questionnaires while outcome and transfusion data were collected using national databases and patient charts. Adjusted risk estimates for transfusion, prolonged LOS, and all-cause readmission according to preoperative anemia status were obtained by multivariate logistic regression. A total of 5.165 THA or TKA procedures were included with a mean patient age of 67 ± 11 years and a median LOS of 2 (interquartile range, 2-3) days. A total of 662 patients (12.8%) had preoperative anemia according to World Health Organization classification. Preoperative anemia was associated with increased risk of receiving transfusion during admission (odds ratio [OR], 4.7; 95% confidence interval [CI], 3.8-5.8), increased risk of readmission within 90 days from surgery (OR, 1.4; 95% CI, 1.1-1.9), and increased risk of LOS of more than 5 days (OR, 2.5; 95% CI, 1.9-3.4) after adjustment for preoperative patient-related risk factors. Preoperative anemia in elective fast-track THA and TKA is independently associated with transfusion and increased postoperative morbidity, supporting the need for preoperative evaluation and treatment. 23606128 Seasonal emaciation causes tissue redistribution and an increased potential for toxicity of lipophilic pollutants in farmed arctic fox (Vulpes lagopus). Many Arctic animals carry high body burdens of organochlorine contaminants (OCs) as a result of long-range transport of persistent pollutants. It has been shown that seasonal mobilization of body fat in these species results in increased blood concentration of OCs. The authors investigated OC assimilation, tissue distribution, and biotransformation in farmed Arctic fox (Vulpes lagopus) continuously fed a diet containing contaminated minke whale blubber or lard (control) from 8 wk of age in August 2003, until sampling when they were at their fattest (in November 2004) and leanest (in June 2005). Markedly higher tissue (liver, adrenals, brain, and blood) OC levels were found in June than in November despite low exposure to OCs during emaciation, suggesting that OCs had been redistributed from adipose tissues to vital organs. There were no differences in the activities of hepatic biotransforming enzymes between exposed fat and control fat foxes, except for 16α-hydroxylation, which was higher in exposed fat foxes. In emaciated foxes, ethoxyresorufin activity was higher in exposed than in control foxes, indicating an enhanced potential for toxicity of OCs with emaciation. Lower activities of 6β- and 2β-hydroxylation were found in lean than in fat foxes, irrespective of OC treatment. The results show that emaciation increase the toxic potential of accumulated OCs and emphasize that body adiposity must be considered when time-trend analyses, risk assessments, and effect studies are designed. Environ Toxicol Chem 2013;32:1784-1792. © 2013 SETAC. 23581848 Design and synthesis of a tetrahydroisoquinoline-based hydroxamate derivative (ZYJ-34v), an oral active histone deacetylase inhibitor with potent antitumor activity. In our previous study we developed a novel series of tetrahydroisoquinoline-based hydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors (Bioorg. Med. Chem., 2010, 18, 1761-1772., J. Med. Chem., 2011, 54, 2823-2838.), among which compound ZYJ-34c (1) was identified and validated as the most potent one with marked in vitro and in vivo antitumor potency (J. Med. Chem., 2011, 54, 5532-5539.). Herein further modification of 1 afforded another oral active analogue ZYJ-34v (2) with simplified structure and lower molecular weight. Biological evaluation of compound 2 showed efficacious inhibition against HDAC1, 2, 3 and 6, which was confirmed by western blot analysis results. Most importantly, compound 2 exhibited similar even more potent in vitro and in vivo antitumor activities relative to the approved HDAC inhibitor SAHA This article is protected by copyright. All rights reserved. 23598678 The role of apoptosis in blepharoptosis. PurposeThe purpose of this study is to evaluate the role of apoptosis in the pathogenesis of blepharoptosis.Patients and methodsForty-five eyelids of 43 consecutive patients (16 female, 27 males) that underwent levator resection surgery for ptosis correction were included in the study. Twenty-six of the eyelids had congenital myogenic ptosis and 19 had aponeurotic ptosis. Levator palpebrae superioris function and height of the vertical palpebral fissure were measured in all patients. After levator resection surgery, the distal part of the levator aponeurosis was fixed and sent for evaluation. Apoptotic cells were detected using Apop Tag Plus Peroxidase In Situ Apoptosis Detection Kit.ResultsThe mean levator palpebrae superioris function was 8.4 mm (range 5-10 mm) in congenital ptosis group and 12.1 mm (range 10-17 mm) in the aponeurotic ptosis group. The mean height of the vertical palpebral fissure in patients with congenital ptosis and aponeurotic ptosis were 6.5 mm (range 5-9 mm) and 6.1 mm (3-9 mm), respectively. The mean apoptotic index of congenital ptosis and aponeurotic ptosis were 27.3 (16-39) and 29.8 (18-41), respectively. There was no statistically significant difference between congenital and aponeurotic ptosis groups in a mean apoptotic index (P<0.05). Apoptotic index was not correlated with age, levator palpebrae superioris function, palpebral fissure height, and lid crease height in two groups.ConclusionWe found no statistically significant difference between two subtypes of blepharoptosis regarding apoptosis. According to this study, apoptosis seems to have no significant role in the development of aponeurotic blepharoptosis. 23842665 An Ecological Perspective on Medical Care: Environmental, Occupational, and Public Health Impacts of Medical Supply and Pharmaceutical Chains. Healthcare organizations are increasingly examining the impacts of their facilities and operations on the natural environment, their workers, and the broader community, but the ecological impacts of specific healthcare services provided within these institutions have not been assessed. This paper provides a qualitative assessment of healthcare practices that takes into account the life-cycle impacts of a variety of materials used in typical medical care. We conducted an ethnographic study of three medical inpatient units: a conventional cancer ward, palliative care unit, and a hospice center. Participant observations (73 participants) of healthcare and support staff including physicians, nurses, housekeepers, and administrators were made to inventory materials and document practices used in patient care. Semi-structured interviews provided insight into common practices. We identified three major domains that highlight the cumulative environmental, occupational health, and public health impacts of medical supplies and pharmaceuticals used at our research sites: (1) medical supply procurement; (2) generation, handling, and disposal of medical waste; and (3) pharmaceutical handling and disposal. Impacts discovered through ethnographic inquiry included occupational exposures to chemotherapy and infectious waste, and public health exposures to pharmaceutical waste. This study provides new insight into the environmental, occupational, and public health impacts resulting from medical practices. In many cases, the lack of clear guidance and regulations regarding environmental impacts contributed to elevated harms to the natural environment, workers, and the broader community. 23549262 Distinct signaling cascades elicited by different formyl Peptide receptor 2 (FPR2) agonists. The formyl peptide receptor 2 (FPR2) is a remarkably versatile transmembrane protein belonging to the G-protein coupled receptor (GPCR) family. FPR2 is activated by an array of ligands, which include structurally unrelated lipids and peptide/proteins agonists, resulting in different intracellular responses in a ligand-specific fashion. In addition to the anti-inflammatory lipid, lipoxin A4, several other endogenous agonists also bind FPR2, including serum amyloid A, glucocorticoid-induced annexin 1, urokinase and its receptor, suggesting that the activation of FPR2 may result in potent pro- or anti-inflammatory responses. Other endogenous ligands, also present in biological samples, include resolvins, amyloidogenic proteins, such as beta amyloid (Aβ)-42 and prion protein (Prp)106-126, the neuroprotective peptide, humanin, antibacterial peptides, annexin 1-derived peptides, chemokine variants, the neuropeptides, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP)-27, and mitochondrial peptides. Upon activation, intracellular domains of FPR2 mediate signaling to G-proteins, which trigger several agonist-dependent signal transduction pathways, including activation of phospholipase C (PLC), protein kinase C (PKC) isoforms, the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, the mitogen-activated protein kinase (MAPK) pathway, p38MAPK, as well as the phosphorylation of cytosolic tyrosine kinases, tyrosine kinase receptor transactivation, phosphorylation and nuclear translocation of regulatory transcriptional factors, release of calcium and production of oxidants. FPR2 is an attractive therapeutic target, because of its involvement in a range of normal physiological processes and pathological diseases. Here, we review and discuss the most significant findings on the intracellular pathways and on the cross-communication between FPR2 and tyrosine kinase receptors triggered by different FPR2 agonists. 23873309 Low heart rates predict incident atrial fibrillation in healthy middle-aged men. Background- Low resting heart rate (HR) has been associated with atrial fibrillation (AF) in athletes. We aimed to study whether low HR at rest or during exercise testing was a predictor of AF in initially healthy middle-aged men. Methods and Results- A total of 2014 healthy Norwegian men participated in a prospective cardiovascular survey, including a standardized bicycle exercise test in 1972 to 1975. During ≤35 years of follow-up (53 000 person-years of observation), 270 men developed incident AF, documented by scrutiny of health charts in all Norwegian hospitals. Risk estimation was analyzed with Cox proportional hazard models. Low exercise HR after 6 minutes exercise on the moderate workload of 100 W (HR100W) was a predictor of incident AF. Men with HR100W <100 beats per minute (n=260) were characterized by high physical fitness, low resting and low maximum HR, and they had 1.60-fold AF risk (95% confidence interval, 1.11-2.26) compared with men with HR100W ≥100 beats per minute when adjusted for age, systolic blood pressure, and physical fitness. Additional adjustment for relative heart volume slightly reduced the association. The subgroup of men (n=860) with hypertensive blood pressure measurements at baseline had the highest risk difference between low and high HR100W with hazard ratio 2.08 (1.19-3.45). Conclusions- Our data indicate that low exercise HR on a moderate workload is a long-term predictor of incident AF in healthy middle-aged men. Elevated baseline blood pressure substantially amplifies this risk. The present results suggest a relationship between increased vagal tone, high stroke volumes and incident AF, and particularly so in physically fit men. 23707237 Metastatic lesions with and without interleukin-18-dependent genes in advanced-stage melanoma patients. IL-18 is an immune-stimulating cytokine that promotes experimental melanoma metastasis via vascular endothelial growth factor (VEGF)-induced very late antigen (VLA)-4. We studied genes associated with the ability of melanoma cells to allow metastasis under IL-18 effects, and we verified their expression in metastatic lesions from patients with melanoma. Human melanoma cell lines with and without the IL-18 receptor (IL-18R)/VEGF/VLA-4-expressing phenotype were identified, and their metastatic potential was studied in nude mice. RNA from untreated and IL-18-treated melanoma phenotypes was hybridized to a cDNA microarray, and their signature genes were studied. RNA from primary and metastatic lesions from patients with melanoma was hybridized to a cDNA microarray to identify lesions with the transcript patterns of melanoma cells with and without the IL-18R/VEGF/VLA-4 phenotype. IL-18R/VEGF/VLA-4-expressing A375 and 1182 melanoma cells produced a higher metastasis number than 526 and 624.28 melanoma cells, not using this prometastatic pathway. Melanoma cells with and without the IL-18R/VEGF/VLA-4 phenotype had distinct transcript patterns. However, the type I transcriptional cluster, including cutaneous and lymph node metastases, but not the type II cluster, not including cutaneous metastases, had signature genes from IL-18-treated melanoma cells with, but not without, the IL-18R/VEGF/VLA-4 phenotype. Metastatic melanoma lesions with and without IL-18-dependent genes were identified, suggesting that melanoma metastasis developed via inflammation-dependent and inflammation-independent mechanisms. Signature genes from melanomas with and without the IL-18R/VEGF/VLA-4 phenotype may serve as diagnostic biomarkers of melanoma predisposition to prometastatic effects of IL-18. 23909993 Adalimumab for the treatment of psoriasis in real life: a retrospective cohort of 119 patients at a single spanish centre. Adalimumab approval by the European Medicines Agency on December 2007 as second-line therapy of moderate to severe chronic plaque psoriasis was based on scientific evidence from clinical trials, but patients in daily clinical practice are different and results may differ in different geographical settings. To analyse the efficacy, safety and retention of treatment with adalimumab in a cohort of patients with moderate to severe psoriasis at a referral centre in Barcelona, Spain. Retrospectively collected efficacy and safety data of a cohort of 119 consecutive patients treated with adalimumab for moderate to severe psoriasis in daily practice between January 2008 and March 2013. Efficacy was determined using as treated (AT) and intention-to-treat (ITT) analysis. Drug survival was analyzed by the Kaplan-Meier method with log-rank test and Cox regression. One hundred and nineteen patients received adalimumab therapy with mean treatment duration of 25 months (median 25, range, 2-60). In 49 (41%) of our cases, adalimumab was the first biologic ever used. PASI75 response rates at week 16, 6 months and 1 year of treatment were 64%, 67%, and 76% (AT) and 64%, 60%, and 54% (ITT), respectively. The corresponding PASI90 response rates were 49%, 60%, and 70% (AT), and 49%, 52%, and 50% (ITT), respectively. Biologic naïve patients had significantly higher PASI75 and PASI90 response rates at week 16, 6 months, and one year of treatment. Combination treatment (used in 22% of our patients) was associated with increased PASI75 and PASI90 response rates at 6 months. The variables which were associated with a significantly higher probability of drug survival were PASI75 response status at week 16, 6 months and 1 year, PASI90 response status at 6 months and 1 year, and biologic-naïve status of the patient. The ability to lengthen and need to shorten injection intervals to maintain response were respectively associated with higher and lower probability of drug survival. Multivariate analysis using Cox regression model showed PASI75 response status at 1 year (P=0.002) and lengthening of injection intervals (P=0.015) as the only significant variables. As regards safety, 48 adverse events (AE) occurred in 29 patients, and were serious in 8 patients (0.032 serious adverse events per patient-year). Paradoxical flares of psoriasis were seen in 3 patients and flares of arthritis in 2. Infections accounted for 53% of recorded AE and 88% of serious AE, and were the reason for discontinuation in 2 patients. The efficacy results are consistent with those of a previously published U.K. study. Even though biologic-naïve status and efficacy parameters denoting a good or excellent response at different time points appear to be associated with a higher probability of drug survival in this cohort of patients, PASI75 response status at 1 year and the ability to maintain response lengthening the injection intervals were the only independent variables predicting drug survival on multivariate analysis. Infections, including de novo infection by M. tuberculosis, accounted for most serious AE, and paradoxical flares of psoriasis and psoriatic arthritis are a relatively frequent occurrence in daily clinical practice. This article is protected by copyright. All rights reserved. 23918107 The airway microbiome and disease. Although traditionally thought to be sterile, accumulating evidence now supports the concept that our airways harbor a microbiome. Thus far, studies have focused upon characterizing the bacterial constituents of the airway microbiome in both healthy and diseased lungs, but what perhaps provides the greatest impetus for the exploration of the airway microbiome is that different bacterial phyla appear to dominate diseased as compared with healthy lungs. As yet, there is very limited evidence supporting a functional role for the airway microbiome, but continued research in this direction is likely to provide such evidence, particularly considering the progress that has been made in understanding host-microbe mutualism in the intestinal tract. In this review, we highlight the major advances that have been made discovering and describing the airway microbiome, discuss the experimental evidence that supports a functional role for the microbiome in health and disease, and propose how this emerging field is going to impact clinical practice. 23480170 Degradation and Rearrangement of a Lung Surfactant Lipid at the Air-Water Interface during Exposure to the Pollutant Gas Ozone. The presence of unsaturated lipids in lung surfactant is important for proper respiratory function. In this work, we have used neutron reflection and surface pressure measurements to study the reaction of the ubiquitous pollutant gas-phase ozone, O3, with pure and mixed phospholipid monolayers at the air-water interface. The results reveal that the reaction of the unsaturated lipid 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, POPC, with ozone leads to the rapid loss of the terminal C9 portion of the oleoyl strand of POPC from the air-water interface. The loss of the C9 portion from the interface is accompanied by an increase in the surface pressure (decrease in surface tension) of the film at the air-water interface. The results suggest that the portion of the oxidized oleoyl strand that is still attached to the lipid headgroup rapidly reverses its orientation and penetrates the air-water interface alongside the original headgroup, thus increasing the surface pressure. The reaction of POPC with ozone also leads to a loss of material from the palmitoyl strand, but the loss of palmitoyl material occurs after the loss of the terminal C9 portion from the oleoyl strand of the molecule, suggesting that the palmitoyl material is lost in a secondary reaction step. Further experiments studying the reaction of mixed monolayers composed of unsaturated lipid POPC and saturated lipid dipalmitoyl-sn-glycero-3-phosphocholine, DPPC, revealed that no loss of DPPC from the air-water interface occurs, eliminating the possibility that a reactive species such as an OH radical is formed and is able to attack nearby lipid chains. The reaction of ozone with the mixed films does cause a significant change in the surface pressure of the air-water interface. Thus, the reaction of unsaturated lipids in lung surfactant changes and impairs the physical properties of the film at the air-water interface. 23964255 The "Musical Emotional Bursts": a validated set of musical affect bursts to investigate auditory affective processing. The Musical Emotional Bursts (MEB) consist of 80 brief musical executions expressing basic emotional states (happiness, sadness and fear) and neutrality. These musical bursts were designed to be the musical analog of the Montreal Affective Voices (MAV)-a set of brief non-verbal affective vocalizations portraying different basic emotions. The MEB consist of short (mean duration: 1.6 s) improvisations on a given emotion or of imitations of a given MAV stimulus, played on a violin (10 stimuli × 4 [3 emotions + neutral]), or a clarinet (10 stimuli × 4 [3 emotions + neutral]). The MEB arguably represent a primitive form of music emotional expression, just like the MAV represent a primitive form of vocal, non-linguistic emotional expression. To create the MEB, stimuli were recorded from 10 violinists and 10 clarinetists, and then evaluated by 60 participants. Participants evaluated 240 stimuli [30 stimuli × 4 (3 emotions + neutral) × 2 instruments] by performing either a forced-choice emotion categorization task, a valence rating task or an arousal rating task (20 subjects per task); 40 MAVs were also used in the same session with similar task instructions. Recognition accuracy of emotional categories expressed by the MEB (n:80) was lower than for the MAVs but still very high with an average percent correct recognition score of 80.4%. Highest recognition accuracies were obtained for happy clarinet (92.0%) and fearful or sad violin (88.0% each) MEB stimuli. The MEB can be used to compare the cerebral processing of emotional expressions in music and vocal communication, or used for testing affective perception in patients with communication problems. 23935737 Posterior internal fixation plus vertebral bone implantation under navigational aid for thoracolumbar fracture treatment. The aim of this study was to investigate the method of posterior thoracolumbar vertebral pedicle screw reduction and fixation combined with vertebral bone implantation via the affected vertebral body under navigational aid for the treatment of thoracolumbar fractures. The efficacy of the procedure was also measured. Between June 2005 and March 2011, posterior thoracolumbar vertebral pedicle screw reduction and fixation plus artificial bone implantation via the affected vertebral pedicle under navigational aid was used to treat 30 patients with thoracolumbar fractures, including 18 males and 12 females, ranging in age from 21 to 57 years. Compared with the values prior to surgery, intraspinal occupation, vertebral height ratio and Cobb angle at the follow-up were significantly improved. At the long-term follow-up, the postoperative Cobb angle loss was <1° and the anterior vertebral body height loss was <2 mm. Posterior thoracolumbar vertebral pedicle screw reduction and fixation combined with vertebral bone implantation via the affected vertebral body under navigational aid may increase the accuracy and safety of surgery, and it is an ideal method of internal implantation. Bone implantation via the affected vertebral body may increase vertebral stability. 23484434 Progress and Developments in Tau Aggregation Inhibitors for Alzheimer Disease. Pharmacological approaches directed toward Alzheimer disease are diversifying in parallel with a growing number of promising targets. Investigations on the microtubule-associated protein tau yielded innovative targets backed by recent findings about the central role of tau in numerous neurodegenerative diseases. In this review, we summarize the recent evolution in the development of nonpeptidic small molecules tau aggregation inhibitors (TAGIs) and their advancement toward clinical trials. The compounds are classified according to their chemical structures, providing correlative insights into their pharmacology. Overall, shared structure-activity traits are emerging, as well as specific binding modes related to their ability to engage in hydrogen bonding. Medicinal chemistry efforts on TAGIs together with encouraging in vivo data argue for successful translation to the clinic. 23896308 Time to first treatment interruption in the Chinese methadone maintenance treatment programme. Methadone maintenance treatment (MMT) in China was established in 2004. The purpose of the present study was to estimate client retention and identify client factors associated with longer times in treatment. Data were abstracted from the MMT Data System from April 2008 to March 2010. Clients were considered to have interrupted treatment when they missed 30+ days of treatment. The median time in treatment was estimated using Kaplan-Meier methods and factors associated with the duration of treatment were evaluated using accelerated failure time models. Among 107,740 clients enrolled in MMT between 2008 and 2010, the median time spent in MMT among clients was 155 days but the majority (69%) did not attend every day. Estimated probabilities for treatment interruption were 53% at 6 months, 66% at 12 months and 77% at 24 months. Longer time in treatment was associated with doses ≥60mg (Time ratio (TR)=2.12, 95%CI=1.96-2.30) and having tested negative on their last urine opiate test (TR=2.15, 95%CI=2.03-2.27). The effect of continued drug use was significantly modified by attendance. Sensitivity analyses indicated a dose-response relationship. Irregular attendance suggests there are barriers to accessing services that need further attention. The Chinese MMT programme needs effective strategies to improve its treatment durations. 23665140 Synthesis of new 18F-radiolabeled silicon-based nitroimidazole compounds. The syntheses of new nitroimidazole compounds using silicon-[(18)F]fluorine chemistry for the potential detection of tumor hypoxia are described. [(18)F]silicon-based compounds were synthesized by coupling 2-nitroimidazole with silyldinaphtyl or silylphenyldi-tert-butyl groups and labeled by fluorolysis or isotopic exchange. Dinaphtyl compounds (6, 10) were labeled in 56-71% yield with a specific activity of 45 GBq/μmol, however these compounds ([(18)F]7 and [(18)F]11) were not stable in plasma. Phenyldi-tert-butyl compounds were labeled in 70% yield with a specific activity of 3 GBq/μmol by isotopic exchange, or in 81% yield by fluorolysis of siloxanes with a specific activity of 45 GBq/μmol. The labeled compound [(18)F]18 was stable in plasma and excreted by the liver and kidneys in vivo. In conclusion, the fluorosilylphenyldi-tert-butyl (SiFA) group is more stable in plasma than fluorosilyldiphenyl moiety. Thus, compound [(18)F]18 is suitable for further in vivo assessments. 23895031 Supravalvar aortic stenosis: current surgical approaches and outcomes. Supravalvar aortic stenosis (SVAS) is a congenital anomaly characterized by a discrete or diffuse narrowing of the ascending aorta. It may also be associated with right-ventricular outflow tract obstruction, aortic valve pathology and coronary ostial stenosis. While present in both familial and sporadic forms, it demonstrates a strong association with William-Beuren syndrome, both being anomalies associated with defects in the elastin gene. In this article, the authors have discussed the etiology, morphology, clinical presentation and genetic basis of SVAS. Various surgical approaches, both conventional and recent, have been discussed and demonstrated with the aid of diagrams. Single-, two- and three-sinus methods have been presented, along with a comparative analysis of early results, associated procedures, late mortality and reoperation. In conclusion, the authors have described their institutional experience of more than 40 years in the surgical management of SVAS. 23863484 Notch3 signaling gates cell cycle entry and limits neural stem cell amplification in the adult pallium. Maintaining the homeostasis of germinal zones in adult organs is a fundamental but mechanistically poorly understood process. In particular, what controls stem cell activation remains unclear. We have previously shown that Notch signaling limits neural stem cell (NSC) proliferation in the adult zebrafish pallium. Combining pharmacological and genetic manipulations, we demonstrate here that long-term Notch invalidation primarily induces NSC amplification through their activation from quiescence and increased occurrence of symmetric divisions. Expression analyses, morpholino-mediated invalidation and the generation of a notch3-null mutant directly implicate Notch3 in these effects. By contrast, abrogation of notch1b function results in the generation of neurons at the expense of the activated NSC state. Together, our results support a differential involvement of Notch receptors along the successive steps of NSC recruitment. They implicate Notch3 at the top of this hierarchy to gate NSC activation and amplification, protecting the homeostasis of adult NSC reservoirs under physiological conditions. 23912407 Editorial: interval cancers: learning from the past as we build for the future. While colonoscopy is the gold standard for the evaluation of the colon, research on post-colonoscopy colorectal cancers has increased our awareness of its limitations. In this issue of the Journal, Erichsen et al. provide evidence to suggest that post-colonoscopy colorectal cancers are most likely due to missed cancers at the time of the index colonoscopy, rather than due to aggressive tumor biology. Ultimately, studies demonstrating the shortcomings of colonoscopy are a call to action for the gastroenterology community to develop strategies and new technologies to improve the effectiveness of colonoscopy. 23604490 Balancing power density based quantum yield characterization of upconverting nanoparticles for arbitrary excitation intensities. Upconverting nanoparticles (UCNPs) have recently shown great potential as contrast agents in biological applications. In developing different UCNPs, the characterization of their quantum yield (QY) is a crucial issue, as the typically drastic decrease in QY for low excitation power densities can either impose a severe limitation or provide an opportunity in many applications. The power density dependence of the QY is governed by the competition between the energy transfer upconversion (ETU) rate and the linear decay rate in the depopulation of the intermediate state of the involved activator in the upconversion process. Here we show that the QYs of Yb(3+) sensitized two-photon upconversion emissions can be well characterized by the balancing power density, at which the ETU rate and the linear decay rate have equal contributions, and its corresponding QY. The results in this paper provide a method to fully describe the QY of upconverting nanoparticles for arbitrary excitation power densities, and is a fast and simple approach for assessing the applicability of UCNPs from the perspective of energy conversion. 22976914 Circadian rhythm of salivary cortisol in infants with congenital heart disease. Children with congenital heart disease (CHD) have associated extracardiac co-morbidities at the time of surgery and during ongoing growth and development. Perioperative events include disrupted glucose homeostasis, capillary leak, and fluid retention. The hypothalamic-pituitary-adrenal (HPA) axis has an important role in homeostasis in that the secretion of cortisol contributes to the response to stress, glucose regulation, blood volume control, and immune regulation. We investigated the diurnal rhythm of the HPA axis in infants with CHD by measuring salivary cortisol in the morning (0600-0900 h-circadian peak) and evening (2100-2400 h-circadian nadir). Twenty-nine infants aged 12 weeks to 1 year were included: 16 with acyanotic disease (SpO(2) ≥ 90 %) and 13 with cyanotic disease (SpO2 < 90 %). Morning salivary cortisol was similar between the two groups [acyanotic 7.0 nmol/L (1.8-23.1); cyanotic 9.7 nmol/L (0.9-15.6); p = 0.68]. Evening salivary cortisol was similar between the two groups [acyanotic 0.9 nmol/L (0.2-8.5); cyanotic 1.4 nmol/L (0.5-14.9); p = 0.32]. Both cyanotic and acyanotic groups demonstrated an intact diurnal rhythm. In conclusion, chronic hypoxia secondary to cyanotic CHD does not affect the circadian rhythm of the HPA axis. By 12 weeks of age, infants with hypoxia secondary to cyanotic CHD have a normal cortisol diurnal rhythm. 23851347 Despite Differences in Cytosolic Calcium Regulation, Lidocaine Toxicity Is Similar in Adult and Neonatal Rat Dorsal Root Ganglia In Vitro. Neuraxial local anesthetics may have neurological complications thought to be due to neurotoxicity. A primary site of action of local anesthetics is the dorsal root ganglia (DRG) neuron. Physiologic differences have been noted between young and adult DRG neurons; hence, the authors examined whether there were any differences in lidocaine-induced changes in calcium and lidocaine toxicity in neonatal and adult rat DRG neurons. DRG neurons were cultured from postnatal day 7 (P7) and adult rats. Lidocaine-induced changes in cytosolic calcium were examined with the calcium indicator Fluo-4. Cells were incubated with varying concentrations of lidocaine and examined for viability using calcein AM and ethidium homodimer-1 staining. Live imaging of caspase-3/7 activation was performed after incubation with lidocaine. The mean KCl-induced calcium transient was greater in P7 neurons (P < 0.05), and lidocaine significantly inhibited KCl-induced calcium responses in both ages (P<0.05). Frequency distribution histograms of KCl-evoked calcium increases were more heterogeneous in P7 than in adult neurons. With lidocaine, KCl-induced calcium transients in both ages became more homogeneous but remained different between the groups. Interestingly, cell viability was decreased by lidocaine in a dose-dependent manner similarly in both ages. Lidocaine treatment also activated caspase-3/7 in a dose- and time-dependent manner similarly in both ages. Despite physiological differences in P7 and adult DRG neurons, lidocaine cytotoxicity is similar in P7 and adult DRG neurons in vitro. Differences in lidocaine- and KCl-evoked calcium responses suggest the similarity in lidocaine cytotoxicity involves other actions in addition to lidocaine-evoked effects on cytosolic calcium responses. 23963088 Workplace empowerment and organizational commitment among nurses working at the Main University Hospital, Alexandria, Egypt. High-quality patient care depends on a nursing workforce that is empowered to provide care according to professional nursing standards. Numerous studies have established positive relationships between empowerment and important nursing outcomes such as work effectiveness, job satisfaction, and organizational commitment. A cross-sectional study design was used to assess the relationships between structural and psychological empowerment and their effects on hospital nurses' organizational commitment at the Main University Hospital in Alexandria governorate. The total number of nurses who participated in the study was 150 nurses, and four interview questionnaires were used to measure the study variables. The mean score percentage was higher for overall psychological empowerment (68.75%) than for overall structural empowerment (46.25%). There was a significant direct intermediate correlation between nurses' perceptions of overall structural and psychological work empowerment and their overall organizational commitment. There was no significant relationship between structural and psychological empowerment, organizational commitment and sociodemographic characteristics of nurses except for the overall organizational commitment with age (r=0.260), overall structural empowerment in the working department (P=0.031), and overall organizational commitment with nursing experience (significance=0.025). Overall psychological empowerment achieved a higher mean score percentage compared with overall structural empowerment. Changing workplace structures is within the mandate of nurses' managers in their roles as advocates for and facilitators of high-quality care. The most significant opportunity for improvement is in the area of formal power, including flexibility, adaptability, creativity associated with discretionary decision-making, visibility, and centrality to organizational purpose and goals. 22774979 An index for staging facial lipoatrophy and evaluation of the efficacy of the treatment with polymethylmethacrylate in HIV/AIDS patients: a pilot study. Background  Treatment of facial lipoatrophy of HIV/AIDS patients is mandatory by law in Brazil due to its negative impact on their quality of life. The index for facial lipoatrophy (ILA) is used as one of the inclusion criteria for patient treatment. Objectives  To define a correct diagnosis and staging of facial lipoatrophy, by employing the ILA. Patients and methods  This is an observational study of a series of case reports from patients submitted to facial lipoatrophy evaluation through ILA and treated with polymethylmethacrylate (PMMA) fillers. Facial lipoatrophy was classified in grades from I to IV, corresponding to mild, moderate, severe and very severe stage, according to ILA. Response to the treatment was defined as excellent (≥91%), good (71-90%), moderate (51-70%) and insufficient (≤50%). Results  A total of 20 patients were included in this study: 18 men and two women. Median age was 49 years (35-61) and average ILA was 9.9 (7.2-16.8). Ten patients presented facial lipoatrophy grade II (moderate), 5 grade III (severe) and 5 grade IV (very severe). The average volume of PMMA used was 13 mL (5.5-22 mL). All patients showed good or excellent response, with a median of 86% (74-100%). The most typical adverse effect was local oedema but there were no late adverse effects. Conclusion  The ILA is an excellent method for evaluation of facial lipoatrophy and also for the assessment of the response to therapy. Facial filling with PMMA showed efficacy and safety in the treatment of facial lipoatrophy in HIV/AIDS patients. 23722481 Effects of caffeinated versus decaffeinated energy shots on blood pressure and heart rate in healthy young volunteers. To evaluate the effects of a caffeinated 5-hour Energy shot compared with a decaffeinated 5-hour Energy shot as assessed by changes in blood pressure and heart rate in healthy, nonhypertensive volunteers. Randomized, double-blind, controlled, crossover study. University campus. Twenty healthy volunteers. Subjects were randomized to receive either the caffeinated 5-hour Energy shot or the decaffeinated 5-hour Energy shot; after a washout period of at least 6 days, subjects were given the alternate energy shot. Systolic (SBP) and diastolic (DBP) blood pressures were recorded for each subject at baseline and at 1, 3, and 5 hours after consumption of the energy shot. Heart rate, adverse effects, and energy levels were also assessed. Mean ± standard deviation (SD) baseline SBP for all study subjects was 114.06 ± 11.30 mm Hg and DBP was 69.53 ± 7.63 mm Hg. Mean changes in SBP between the caffeinated arm and the decaffeinated arm at the 1- and 3-hour time points were significantly increased compared with baseline (mean ± SD 6.08 ± 7.71 mm Hg at 1 hour [p=0.001] vs 3.33 ± 6.99 mm Hg at 3 hours [p=0.042]). Similarly, mean DBP changes between the caffeinated arm and the decaffeinated arm were significantly increased at the 1- and 3-hour time points compared with baseline (mean ± SD 5.18 ± 8.38 mm Hg at 1 hour [p=0.007] and 5.43 ± 7.21 mm Hg at 3 hours [p=0.005]). Heart rate, adverse effects, and energy levels were similar between the two groups. Caffeinated energy shots significantly increased SBP and DBP over a 3-hour period compared with decaffeinated energy shots in healthy, nonhypertensive individuals. 23863902 VP2 Dominated CD4+ T Cell Responses against Enterovirus 71 and Cross-Reactivity against Coxsackievirus A16 and Polioviruses in a Healthy Population. Enterovirus 71 (EV71)-associated hand-foot-mouth disease has become a major threat to public health in the Asia-Pacific region. Although T cell immunity is closely correlated with clinical outcomes of EV71 infection, little is known about T cell immunity baseline against EV71 and T cell immunogenecity of EV71 Ags in the population, which has restricted our understanding of immunoprotection mechanisms. In this study, we investigated the cellular immune responses against the four structural Ags of EV71 and determined the immunohierarchy of these Ags in healthy adults. A low frequency of EV71-responsive T cells was detected circulating in peripheral blood, and broad T cell immune responses could be identified in most of the subjects after in vitro expansion. We demonstrated that the VP2 Ag with broad distribution of immunogenic peptides dominates T cell responses against EV71 compared with VP1, VP3, and VP4. Furthermore, the responses were illuminated to be mainly single IFN-γ-secreting CD4(+) T cell dependent, indicating the previous natural acute viral infection of the adult population. Conservancy analysis of the immunogenic peptides revealed that moderately variant peptides were in the majority in coxsackievirus A16 (CV-A16) whereas most of the peptides were highly variant in polioviruses. Less efficient cross-reactivity against CV-A16 might broadly exist among individuals, whereas influences derived from poliovirus vaccination would be limited. Our findings suggest that the significance of VP2 Ag should be addressed in the future EV71-responsive immunological investigations. And the findings concerning the less efficient cross-reactivity against CV-A16 and limited influences from poliovirus vaccination in EV71-contacted population would contribute to a better understanding of immunoprotection mechanisms against enteroviruses. 23694949 Costs of second allogeneic hematopoietic cell transplantation. A second allogeneic transplantation after a prior allogeneic (allo-allo) or autologous (auto-allo) hematopoietic cell transplantation (HCT) is usually performed for graft failure, disease recurrence, secondary malignancy, and, as planned, auto-allo transplantation for some diseases. We sought to describe the costs of second allogeneic HCT and evaluate their relationship with patient characteristics and posttransplantation complications. Clinical information and medical costs for the first 100 days after transplantation of 245 patients (allo-allo, 55; auto-allo, 190) who underwent a second HCT between 2004 and 2010 were collected. Median costs of the second allogeneic HCT were U.S. $151,000 (range, U.S. $62,000-405,000) for the allo-allo group and U.S. $109,000 (range, U.S. $26,000-490,000) for the auto-allo group. Median length of hospital stay was 23 days (range, 0-76) for the allo-allo group and 9 days (range, 0-96) for the auto-allo group. Only the year of transplantation and posttransplantation complications were significantly associated with costs in both groups when both pre- and posttransplantation variables were considered. The overall costs of the second HCT were higher than the first in the allo-allo group. For the auto-allo group, there was no difference between the costs whether preformed as a planned tandem or as salvage for relapse. Our results suggest that second allogeneic HCT is costly, particularly if it follows a prior allogeneic transplantation, and is driven by the costs of complications. 23462506 Identification of functionally relevant lysine residues that modulate human farnesoid x receptor activation. Base amino acid lysine residues play an important role in regulation of nuclear receptors [e.g., farnesyl X receptor (FXR)], leading to enhanced or suppressed biologic activity. To understand the molecular mechanisms and the subsequent effects in modulating FXR functions in diverse biologic processes, we individually replaced eight highly conserved lysine residues of human FXR (hFXR) with arginine. The effects of each mutated FXR on target gene activation, subcellular localization, protein-protein association, and protein-DNA interaction were investigated. Results demonstrated that K122R, K210R, K339R, and K460R mutants of hFXR significantly impaired target gene [organic solute transporter α/β and bile salt export pump (BSEP)] promoter reporter activity in a ligand-dependent fashion. None of the four mutants affected the nuclear localization of FXR. Protein interaction studies show that K210R slightly but significantly decreased FXR/retinoid X receptor (RXR) binding affinity but enhanced the interaction of FXR with lysine methyltransferase Set7/9 by ∼21%. K460R decreased the FXR interaction with Set7/9 by ∼45% but had no significant effects on interaction with RXR. Electrophoretic mobility shift assays demonstrated that hFXR-K210R and -K339R reduced the protein-DNA (IR1 element at hBSEP promoter) binding affinity by ∼80 and ∼90%, respectively. Computational-based protein modeling studies were consistent with these results and provided further insights into the potential underlying mechanisms responsible for these results. In conclusion, four highly conserved lysine residues of hFXR, K122, K210, K339, and K460, have been identified that play a critical role in FXR target gene regulation and molecular interaction (protein-protein and protein-DNA). 23194545 Identification and thermal stability of purple-fleshed sweet potato anthocyanins in aqueous solutions with various pH values and fruit juices. Thirteen anthocyanins were identified in the purple-fleshed sweet potato cultivar Jihei No. 1. The main anthocyanins were 3-sophoroside-5-glucoside derivatives from cyanidin and peonidin, acylated with p-hydroxybenzoic acid, ferulic acid, or caffeic acid. A unique anthocyanin, delphinidin-3,5-diglucoside was also found. The thermal stability of purple-fleshed sweet potato anthocyanins (PSPAs) followed a first-order kinetics model. Aqueous solutions with various pH (2, 3, 4, 5, and 6) and fruit juices (apple, pear, grapefruit, orange, tangerine, kiwifruit, and lemon) were coloured with PSPAs. The enrichment and degradation kinetics of anthocyanins in these matrices were investigated at 80, 90, and 100°C. A higher stability of anthocyanins was obtained in aqueous solutions with pH 3 and 4 and in apple and pear juices. Moreover, the activation energies for PSPA degradation in aqueous solutions with various pH and fruit juices ranged from 66.56 kJ/mol to 111.57 kJ/mol and 46.76 kJ/mol to 75.68 kJ/mol, respectively. 23905910 Comparison of creatinine clearance estimates with routine measured clearance in adult jordanians with a kidney transplant. There are conflicting data on using the Cockroft-Gault formula and the Modification of Diet in Renal Disease formula to assess graft function in kidney transplants. This study uses a cohort of Jordanian kidney transplant patients to assess performance of the Cockroft-Gault formula and the Modification of Diet in Renal Disease equations by using the criterion standard of measured creatinine clearance. Creatinine clearance measured by 24-hour urine creatinine in patients with a kidney transplant was compared with the estimated clearance using the Cockroft-Gault formula and the Modification of Diet in Renal Disease equations. Correlation, limits of agreement, and concordance analyses were used. There was a positive correlation between both the Cockcroft-Gault (r=0.878; P < .001) and the Modification of Diet in Renal Disease (r=0.732; P < .001) equations with creatinine clearance. The former was statistically superior (P = .0416). Using Bland-Altman plots, the limits of agreement were wide for both methods. After log transformation, the limits of agreement were -0.06 to +0.27 for the Cockcroft-Gault formula, and -0.21 to + 0.26 for the Modification of Diet in Renal Disease. Concordance analyses showed a correlation coefficient of 0.7384 (95% CI: 0.6134 to 0.8273) when the Cockcroft-Gault formula was used, and 0.7257 (95% CI: 0.5622 to 0.8345) for the Modification of Diet in Renal Disease. Pearson P coefficient (precision) and bias correction factor Cb (accuracy) for the Cockcroft-Gault formula and for the Modification of Diet in Renal Disease were 0.8762, 0.8427, 0.7324, and 0.9908. In Jordanian patients with a renal transplant, although the Cockcroft-Gault formula performed slightly better than the Modification of Diet in Renal Disease equation in estimating creatinine clearance, neither of these equations can accurately predict renal graft function. 23828619 Biological and molecular variation of Iranian Cauliflower mosaic virus (CaMV) isolates. Seventeen provinces of Iran were surveyed during 2003-2012 to find Brassicaceae hosts of Cauliflower mosaic virus (CaMV). A total 397 samples were collected from plants with virus-like symptoms. Among those tested by ELISA, 255 samples (67.2 %) were found to be infected with CaMV. Mechanical transmission tests showed that the Iranian isolates have similar biological properties on a number of Brassica and Raphanus plant species and cultivars tested. However, the isolates varied in the severity of symptoms they induced and in the capacity to infect B. oleracea var. capitata, on the basis of which they were grouped into two distinct biotypes L/MMo (latent/mild mottle) and severe (S) infection. The molecular diversity of natural population of CaMV were investigated based on the complete sequences of OFR 6 of 36 Iranian isolates collected from different geographically distant regions in Iran alongside the sequences of 14 previously reported isolates. Phylogenetic analyses indicated that the Iranian CaMV isolates belong to two groups (GI and GII). Most of the Iranian isolates fell into GI with other exotic isolates; however, the isolates from North-East Iran with Xinjiang from China fell into GII. The phylogenetic group GII (the North-East Iranian isolates) closely corresponded to the S biological group however other Iranian isolates corresponded to the L/MMo biological group. The within-population diversity was lower than the between population diversity suggesting the contribution of a founder effect on diversification of CaMV isolates. The Iranian isolates were differentiated from other exotic CaMV isolates and clustered into two RFLP groups using Hpy99I which closely corresponded to the biological and phylogenetic groups. This study showed the evolutionary process in CaMV isolates is shaped by a combination of host range differentiation and nucleotide substitution using the approach of population genetics. 23948167 Controlled release of cisplatin from pH-thermal dual responsive nanogels. In this study, a pH-thermal dual responsive nanogel was applied for cisplatin (CDDP) delivery. CDDP was loaded into the nanogels via conjugation with the carboxyl groups in the nanogels. The conjugation was confirmed by FTIR and XPS. The bonding between CDDP and COOH can be broken by the H(+) or Cl(-). We found that the CDDP released much faster at more acidic environment. The Cl(-) concentration in the human body is about 95-105 mm. The conjugated bond could be easily attacked by Cl(-) while the nanosystem is injected into the body. In order to diminish the Cl(-) triggering release of CDDP from the nanogels, we introduced a thermal-responsive units-NIPAm into the nanogel structure. After NIPAm introduced, the CDDP released much slower from the nanogels at 37 °C in pH = 7.38 buffer in the present of Cl(-) (150 mm) than that without NIPAm. And the CDDP also released slower from the nanogels at 37 °C than at 25 °C. By in vitro release behavior studying, we found that CDDP release from the NIPAm containing nanogels can be accelerated by H(+) attacking and reduced by temperature arising. By cellular uptake observation, we found that the nanogels were mainly localized in the cytoplasm of the cancer cells. The CDDP-loaded nanogels exhibited longer circulation time in vivo while compared to free CDDP. And it has better anti-cancer performance than free CDDP in vivo therapy of breast cancer in mice model. Furthermore, some side effects of CDDP, such as renal toxicity, phlebitis, bone marrow suppression etc. have also been reduced by nanogels loading. The in vitro and in vivo results demonstrated that the dual responsible nanogel is a suitable CDDP delivery candidate. 23838305 Analysis of alkaloids in Lotus (Nelumbo nucifera Gaertn.) leaves by non-aqueous capillary electrophoresis using ultraviolet and mass spectrometric detection. Lotus leaves are a popular remedy in Asia to treat obesity, insomnia and mental impairment; alkaloids are considered most relevant for bioactivity. In this study the first CE method for the determination of all major alkaloids ((-)-nuciferine, (-)-nornuciferine, (-)-caaverine, (-)-armepavine, (+)-norarmepavine, (+)-isoliensinine and (+)-pronuciferine) in Nelumbo nucifera leaves was developed. The optimum buffer showed to be a solution of 100mM ammonium acetate in a mixture of methanol, acetonitrile and water, also containing 0.6% acid acetic. Applied voltage, temperature and detection wavelength were 25kV, 30°C and 225nm; the required analysis time was 15min. By CE-MS all standard compounds could be assigned in positive ESI mode, and two minor alkaloids were tentatively identified (n-nornuciferine and roemerine). A mixture of water, methanol and acetic acid served as sheath liquid in these experiments. The NACE assay was fully validated and utilized to analyze Lotus leaf samples collected in different parts of Vietnam. Respective results revealed significant qualitative and quantitative differences depending on growing area and season. Yet, in all samples (-)-nuciferine (0.34-0.63%), (-)-armepavine (0.13-0.20%), and (+)-isoliensinine (0.06-0.19%) were the most dominant alkaloids. The total alkaloid content varied from 0.72 to 1.41%. 23735638 FOXP3 demethylation as a means of identifying quantitative defects in regulatory T cells in acute coronary syndrome. The contribution of regulatory T cells (Tregs) to the pathogenesis of acute coronary syndrome (ACS) remains poorly understood. One core obstacle is the lack of Treg-specific markers. A highly conserved CpG enriched element in forkhead box P3 intron 1 (FOXP3 i l) is unmethylated only in Tregs, and measuring the unmethylation of FOXP3 i l can be used to identify the role of Tregs in clinical diseases. This study investigated whether analyzing the demethylation status of FOXP3 i 1 is a more reliable means than using Treg-specific surface markers in ACS. We evaluated circulating Tregs percentages on different levels including cell frequencies (CD4(+)CD25(hi)FOXP3(+)Tregs and CD4(+)CD25(hi)CD45(+)naïve Tregs) or FOXP3 mRNA, FOXP3 i 1 demethylation status and related cytokine secretion in 89 patients with ACS and 35 controls. FOXP3 i 1 demethylation assay showed that the amount of Tregs in ACS patients was significantly reduced than that in controls (p = 0.0005). However, flow cytometry analysis did not identify any reduction of CD4(+)CD25(hi)FOXP3(+)Tregs in ACS patients. Notably, younger patients had higher percentage of CD4(+)CD25(hi)FOXP3(+)Tregs but decreased percentage of CD4(+)CD25(hi)CD45(+)naïve Tregs than either controls or older patients. Furthermore, a DNA hypomethylation agent increased the amount of CD4(+)CD25(hi)FOXP3(+)Tregs and Tregs related cytokine IL-10 and suppressed the production of pro-inflammatory cytokine interferon-γ by inducing FOXP3 i 1 demethylation in vitro. A quantitative defect of Tregs, suggestive of decreased peripheral tolerance, could be a potential hallmark of ACS disease. Targeting FOXP3 i l demethylation might elevate the inhibitory activity of Tregs in ACS. 23324405 Evolution of novel tricyclic CRTh2 receptor antagonists from a (E)-2-cyano-3-(1H-indol-3-yl)acrylamide scaffold. (E)-2-(3-(3-((3-Bromophenyl)amino)-2-cyano-3-oxoprop-1-en-1-yl)-1H-indol-1-yl)acetic acid (1) was discovered in a HTS campaign for CRTh2 receptor antagonists. An SAR around this hit could be established and representatives with interesting activity profiles were obtained. Ring closing tactics to convert this hit series into a novel 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole based CRTh2 receptor antagonist series is presented. 22445908 Pancreatic cancer stem cells: Emerging target for designing novel therapy. In the past few years, there have been significant advances in the research on cancer stem cells (CSCs). The emerging evidences have demonstrated that CSCs and epithelial-mesenchymal transition (EMT)-type cells, which share molecular characteristics with CSCs, play critical roles in drug resistance, invasion, and metastasis. Pancreatic cancer (PC) has a high mortality due to both intrinsic (de novo) and extrinsic (acquired) drug resistance, leading to increased invasive and metastatic potential of PC cells. Therefore, targeting pancreatic CSCs and EMT-type cells could be a novel therapeutic strategy for the treatment of PC. In this article, we will review the current state of our knowledge on the role of pancreatic CSCs and EMT-type cells, and summarize the novel therapeutic strategies that could target pancreatic CSCs and EMT-type cells, leading to the reversal of EMT phenotype, the induction of drug sensitivity, and the inhibition of invasion and metastasis of PC, which is expected to yield better treatment outcome. 23614530 Effectiveness of FISK, an Invasiveness Screening Tool for Non-Native Freshwater Fishes, to Perform Risk Identification Assessments in the Iberian Peninsula. Risk assessments are crucial for identifying and mitigating impacts from biological invasions. The Fish Invasiveness Scoring Kit (FISK) is a risk identification (screening) tool for freshwater fishes consisting of two subject areas: biogeography/history and biology/ecology. According to the outcomes, species can be classified under particular risk categories. The aim of this study was to apply FISK to the Iberian Peninsula, a Mediterranean climate region highly important for freshwater fish conservation due to a high level of endemism. In total, 89 fish species were assessed by three independent assessors. Results from receiver operating characteristic analysis showed that FISK can discriminate reliably between noninvasive and invasive fishes for Iberia, with a threshold of 20.25, similar to those obtained in several regions around the world. Based on mean scores, no species was categorized as "low risk," 50 species as "medium risk," 17 as "moderately high risk," 11 as "high risk," and 11 as "very high risk." The highest scoring species was goldfish Carassius auratus. Mean certainty in response was above the category "mostly certain," ranging from tinfoil barb Barbonymus schwanenfeldii with the lowest certainty to eastern mosquitofish Gambusia holbrooki with the highest level. Pair-wise comparison showed significant differences between one assessor and the other two on mean certainty, with these two assessors showing a high coincidence rate for the species categorization. Overall, the results suggest that FISK is a useful and viable tool for assessing risks posed by non-native fish in the Iberian Peninsula and contributes to a "watch list" in this region. 23700291 Conversion of 2-deoxyglucose-induced growth inhibition to cell death in normoxic tumor cells. Inhibition of glucose metabolism has recently become an attractive target for cancer treatment. Accordingly, since 2-deoxyglucose (2-DG) competes effectively with glucose, it has come under increasing scrutiny as a therapeutic agent. The initial response of tumor cells to 2-DG is growth inhibition, which is thought to conserve energy and consequently protect cells from its ATP-lowering effects as a glycolytic inhibitor. However, since 2-DG also mimics mannose and thereby interferes with N-linked glycosylation, the question is raised of how this sugar analog inhibits tumor cell growth and whether the mechanism by which it protects cells can be manipulated to convert 2-DG-induced growth inhibition to cell death. Cell growth and death were measured via counting viable and dead cells based on trypan blue exclusion. Markers of ATP reduction and the unfolded protein response (UPR) were detected by Western blot. Protein functions were manipulated through chemical compounds, siRNA and the use of gene-specific wild-type and knock-out mouse embryonic fibroblasts (MEFs). At 2-DG concentrations that can be achieved in human plasma without causing significant side effects, we find (a) It induces growth inhibition predominantly by interference with glycosylation, which leads to accumulation of unfolded proteins in the endoplasmic reticulum activating the UPR; (b) Inhibition of PERK (but not ATF6 or IRE1), a major component of the UPR, leads to conversion of 2-DG-induced growth inhibition to cell death and (c) secondarily to PERK, inhibition of GCN2, a kinase that is activated in response to low intracellular glutamine, increases 2-DG's cytotoxic effects in PERK -/- MEFs. Overall, these findings present a novel anticancer strategy that can be translated into therapeutic gain as they uncover the metabolic target PERK, and to a lesser degree GCN2, that when inhibited convert 2-DG's static effect to a toxic one in tumor cells growing under normoxia. 23846185 Host Dependent Iridoid Glycoside Sequestration Patterns in Cionus hortulanus. Weevils of the genus Cionus (Curculionidae, Mecininae) sequester the iridoid glycosides (IGs) aucubin and catalpol from their host plants Scrophularia or Verbascum (Scrophulariaceae). Cionus hortulanus is the only member of the genus that feeds on both plant genera. We previously showed that sequestration patterns in C. hortulanus depend on the local host. To investigate whether IG patterns are driven by their availability in the hosts or genetic differences between populations, we collected C. hortulanus from S. nodosa in the field and reared them either on S. nodosa or on V. nigrum. The differences in IG concentrations were specific for the host plant upon which the weevils developed. Similar to monophagous species of the Cionini, individuals from S. nodosa had more aucubin than catalpol and mirrored the concentrations of their host plants. Specimens from V. nigrum, on the other hand, had higher concentrations of aucubin and of catalpol than their host. On V. nigrum, the ratio of catalpol to aucubin differed significantly between plant and beetle samples due to much higher catalpol concentrations in the weevils. Our data thus contradict genetically fixed differences between populations living on either plant but rather document the host plants' influence on the beetles' metabolism. 23852639 The effect of ovarian stimulation on the outcome of intrauterine insemination. Although intrauterine insemination is one of the oldest techniques in reproductive medicine, its significance is still controversially discussed. Many factors have been reported as influencing pregnancy rates after IUI. The aim of this retrospective analysis is to evaluate the success rate of repeated inseminations depending on the type of ovarian stimulation. Patients who underwent intrauterine insemination in Wiesbaden Kinderwunschzentrum between 1998 and 2010, not older than 45 years of age, with male subfertility were included in this study. On the whole, 5,346 inseminations on 2,180 patients were analyzed retrospectively. Females' mean age was 34.1, ranging from 19-45 years. In 433 cycles an insemination was performed during a natural cycle. 4,020 cycles were stimulated with recombinant FSH, 596 cycles with clomiphene, 194 with urinary FSH, 103 with HMG. The pregnancy rates range from 7.4 % in the clomiphene group to 14.4 % in the urinary FSH group. Clomiphene stimulation seems to offer the significantly lowest pregnancy rate (p = 0.03). The other types of stimulation do not differ significantly from each other concerning the pregnancy rate. Patients under 39 years of age do not profit from any ovarian stimulation. In 40 and more years of old patients, pregnancy rates are higher, if any stimulation was performed. To sum up, clomiphene stimulation showed to offer significantly lower pregnancy rates in comparison to the natural cycle, FSH stimulation and HMG stimulation in IUI treatment. While women younger than 40 seem not to profit from any ovarian stimulation, women over 40 do profit. 23749635 SARM is required for neuronal injury and cytokine production in response to central nervous system viral infection. Four of the five members of the Toll/IL-1R domain-containing adaptor family are required for signaling downstream of TLRs, promoting innate immune responses against different pathogens. However, the role of the fifth member of this family, sterile α and Toll/IL-1R domain-containing 1 (SARM), is unclear. SARM is expressed primarily in the CNS where it is required for axonal death. Studies in Caenorhabditis elegans have also shown a role for SARM in innate immunity. To clarify the role of mammalian SARM in innate immunity, we infected SARM(-/-) mice with a number of bacterial and viral pathogens. SARM(-/-) mice show normal responses to Listeria monocytogenes, Mycobacterium tuberculosis, and influenza virus, but show dramatic protection from death after CNS infection with vesicular stomatitis virus. Protection correlates with reduced CNS injury and cytokine production by nonhematopoietic cells, suggesting that SARM is a positive regulator of cytokine production. Neurons and microglia are the predominant source of cytokines in vivo, supporting a role for SARM as a link between neuronal injury and innate immunity. 23623548 The Demographic Transition Influences Variance in Fitness and Selection on Height and BMI in Rural Gambia. Recent human history is marked by demographic transitions characterized by declines in mortality and fertility [1]. By influencing the variance in those fitness components, demographic transitions can affect selection on other traits [2]. Parallel to changes in selection triggered by demography per se, relationships between fitness and anthropometric traits are also expected to change due to modification of the environment. Here we explore for the first time these two main evolutionary consequences of demographic transitions using a unique data set containing survival, fertility, and anthropometric data for thousands of women in rural Gambia from 1956-2010 [3]. We show how the demographic transition influenced directional selection on height and body mass index (BMI). We observed a change in selection for both traits mediated by variation in fertility: selection initially favored short females with high BMI values but shifted across the demographic transition to favor tall females with low BMI values. We demonstrate that these differences resulted both from changes in fitness variance that shape the strength of selection and from shifts in selective pressures triggered by environmental changes. These results suggest that demographic and environmental trends encountered by current human populations worldwide are likely to modify, but not stop, natural selection in humans. 23871127 A pilot randomized controlled trial of a depression and disease management program delivered by phone. Depression in medically ill patients occurs at twice the rate found in the general population. Though pharmacologic and psychotherapeutic interventions for depression are effective, response to treatment and access to care are barriers for this population. A multidimensional telehealth intervention was designed to focus on these barriers by delivering a phone based intervention that addressed managing one's illness and coping emotionally. Veterans with diabetes, hypertension, or chronic pain and depressive symptoms were randomized to one of three conditions: Usual Care (n=23), Illness Management Only (n=31), or Combined Psychotherapy and Illness Management (n=29). Those randomized to the Combined or Illness Management Only intervention group received 10 phone visits. Veterans in the Combined group received all aspects of the illness management program plus a manualized depression intervention. Subjects completed assessments at baseline, week 5, and 10 to test the main hypothesis that veterans in the Combined condition would have a greater decline in depressive symptoms. The Combined intervention yielded a significant decline in depressive symptoms when compared with Usual Care. However, the there was no significant difference between the Combined and Illness Management Only groups. This is a pilot study with a small sample size relative to a standard randomized controlled trial in psychotherapy. This telephone-based intervention succeeded in reducing depressive symptoms in veterans with chronic illness. It adds to the building evidence base for providing phone-delivered mental health services. 23831111 Thymic rejuvenation and aging. The thymus is a vital organ for homeostatic maintenance of the peripheral immune system. It is within this mediastinal tissue that T cells develop and are extensively educated and exported to the periphery for establishment of a functional and effective immune system. A striking paradoxical feature of this critical lymphoid tissue is that it undergoes profound age-associated involution. Thymic decline is of minimal consequence to healthy individuals, but the reduced efficacy of the immune system with age has direct etiological linkages with an increase in diseases including opportunistic infections, autoimmunity, and incidence/burden of cancer. Furthermore the inability of adults to restore immune function following insult induced by chemotherapy, ionizing radiation exposure or therapy, and infections (e.g. HIV-1) leads to increased morbidity and often mortality in the elderly. For these reasons, it is important that investigators strive to translate their understanding of mechanisms that drive thymic involution, and develop safe and effective strategies to rejuvenate the thymus in settings of clinical need. In this review, we present a discussion of the current status of thymic rejuvenation efforts associated with: sex steroid ablation, cytokines, growth factors, and hormones. 23590688 Validation study of uterine rupture registration in the Medical Birth Registry of Norway. To validate uterine rupture registration in the Medical Birth Registry of Norway (MBRN) between 1999 and 2008, and to identify rupture type and causes of incorrect or missed registration during 1967-2008. Population-based study. The validation sample was 392 958 maternities from 21 maternity units registered in MBRN and local Patient Administration Systems in 1999-2008. In addition we identified type of rupture and causes of incorrect registration among 2 422 934 maternities from 48 units, and 1 449 201 maternities from 21 units during 1967-2008. Information about uterine rupture in MBRN was compared with information in medical records. Sensitivity, specificity, positive and negative predictive value of uterine rupture registration in MBRN. In 1999-2008, there were 10 false positive cases among 151 uterine ruptures registered in MBRN. In addition, 82 ruptures not registered in MBRN, were identified through Patient Administration Systems. The sensitivity, specificity, positive and negative predictive value of the MBRN to detect uterine rupture was 63.2, 99.99, 93.4 and 99.98%, respectively. The incidence of uterine rupture changed after correction from 0.38 to 0.56/1000. During 1967-2008, false positive cases (125) were mainly due to wrong coding by MBRN. Around 60% of 141 false negative cases were due to lack of reporting by maternity units. Complete rupture accounted for 63.9% of ruptures registered in MBRN. The validity of MBRN data on uterine rupture is not optimal, diagnosis being under-reported by around 37%. Ticked boxes may improve the quality of registration. 23874748 miR-379 Regulates Cyclin B1 Expression and Is Decreased in Breast Cancer. MicroRNAs are small non-coding RNA molecules that control gene expression post-transcriptionally, and are known to be altered in many diseases including breast cancer. The aim of this study was to determine the relevance of miR-379 in breast cancer. miR-379 expression was quantified in clinical samples including tissues from breast cancer patients (n=103), healthy controls (n=30) and patients with benign breast disease (n=35). The level of miR-379 and its putative target Cyclin B1 were investigated on all breast tissue specimens by RQ-PCR. Potential relationships with gene expression and patient clinicopathological details were also determined. The effect of miR-379 on Cyclin B1 protein expression and function was investigated using western blot, immunohistochemistry and proliferation assays respectively. Finally, the levels of circulating miR-379 were determined in whole blood from patients with breast cancer (n=40) and healthy controls (n=34). The level of miR-379 expression was significantly decreased in breast cancer (Mean(SEM) 1.9 (0.09) Log10 Relative Quantity (RQ)) compared to normal breast tissues (2.6 (0.16) Log10 RQ, p<0.01). miR-379 was also found to decrease significantly with increasing tumour stage. A significant negative correlation was determined between miR-379 and Cyclin B1 (r=-0.31, p<0.001). Functional assays revealed reduced proliferation (p<0.05) and decreased Cyclin B1 protein levels following transfection of breast cancer cells with miR-379. Circulating miR-379 was not significantly dysregulated in patients with breast cancer compared to healthy controls (p=0.42). This data presents miR-379 as a novel regulator of Cyclin B1 expression, with significant loss of the miRNA observed in breast tumours. 23764805 Compact large area and high-quality Au film with a hierarchical structure and its application in SERS. We have described a novel and facile strategy for fabricating a compact large area and high-quality Au film with a hierarchical structure (HS) by using a polyaniline slice as a reductant. The unique morphology of the as-prepared Au HS film, which is controlled by the concentration of AuCl4(-), results in enhanced Raman signals toward probe molecules such as 4-aminothiophenol (4-ATP), 2-naphthalenethiol (2-NAT) and 4-mercaptobenzoic acid (4-MBA). The employed approach may shed some light on simultaneously fabricating and immobilizing unique Au micro/nanostructures. 23887385 Epileptic seizure-induced structural and functional changes in rat femur and tibia bone tissues: a Fourier transform infrared imaging study. ABSTRACT. The disease- and drug-related bone disorders are rapidly increasing in the population. It is previously reported that anti-epileptic drugs (AEDs) may cause osteopenia, osteoporosis, and fractures in epilepsy patients. However, it cannot be determined whether the bone disorders in epileptic patients are due to AED therapy and/or to epilepsy and epileptic seizures. There is no study in the literature which investigates the sole effects of epilepsy and epileptic seizures on bone tissues. The current study provides the first report on determination of the possible effects of epilepsy and epileptic seizures on long bone tissues. Wistar Albino Glaxo/Rijswijk rats, which are accepted as genetic rat models for human absence epilepsy, were compared with the healthy Wistar rats to get information about the sole effects of epilepsy and epileptic seizures on bones. Cortical regions of tibia and femur bones were studied by Fourier transform infrared microspectroscopy (FTIRM). According to FTIRM parameters, variation on bone mineral and matrix composition, including decreased mineral content, decreased collagen cross-links, increased carbonate substitution, and larger crystals in epileptic group compared to the healthy one, show severe effects of epilepsy and seizures on bone tissues for the first time. 23551115 Potential role for human P-glycoprotein in the transport of lacosamide. Antiepileptic drugs (AEDs) do not effectively treat 30-40% of patients with epilepsy. Export of AEDs by P-glycoprotein (Pgp, ABCB1, or MDR1), which is overexpressed in the blood-brain barrier in drug-resistant patients, may be a mechanism for resistance to AEDs. For most recently approved AEDs, whether they are transported by Pgp is unknown. We investigated whether a new AED, lacosamide (LCM), is a substrate of human Pgp. LLC-PK1 and MDCKII cells transfected with the human MDR1 gene were used to determine the substrate status of LCM in concentration equilibrium transport assays (CETAs). An equal concentration of drug was initially loaded in both the apical and basal chambers, and the concentration in both chambers was measured up to 4 h. The experiments were repeated in the presence of the Pgp inhibitors verapamil and tariquidar. Caco-2 assays were used to determine the intrinsic permeability and efflux ratio of LCM as well as its potential to inhibit digoxin, a Pgp substrate. Lacosamide was transported by MDR1-transfected cells from basolateral to apical sides. The efflux of LCM could be completely blocked by verapamil or tariquidar. In Caco-2 assays, LCM showed high permeability without a significant efflux ratio; it did not inhibit digoxin, a Pgp substrate. Although LCM is a substrate of Pgp in CETA, Caco-2 data demonstrated that passive diffusion should play a major role in the overall disposition of LCM. The critical role of Pgp should be addressed in vivo. 23298616 Polymeric "smart" coatings to prevent foreign body response to implantable biosensors. Application of implantable glucose biosensors for "real-time" monitoring is reliant on controlling the negative tissue reaction at the sensor tissue interphase. A novel polymer coating consisting of poly(lactic-co-glycolic) acid (PLGA) microsphere dispersed in poly(vinyl alcohol) (PVA) hydrogels was evaluated in combination with dummy sensors as a "smart" drug eluting biocompatible coating for implantable biosensors to prevent the foreign body response, and thus enhance sensor performance in vivo. The polymeric microspheres slowly release tissue-modifying drugs at the implantation sites to control the inflammation and fibrous encapsulation, while the hydrogel allows rapid analyte diffusion to the sensing elements. Dummy sensors with identical dimensions to that of the functional glucose sensors (0.5×0.5×5mm) were coated with the PLGA/PVA composites using a mold fabrication process. Both normal and diabetic rats were used in the current study to investigate the effect of the diabetic state on tissue sensor interactions. It was evident that the PLGA/PVA hydrogel composite was able to form a uniform coating around the dummy sensor and stayed intact throughout the course of the study (one month). Tissue samples containing dummy sensors that were coated with dexamethasone free composites exhibited acute and chronic inflammation as well as fibrous encapsulation in both normal and diabetic rats. However, the diabetic rats exhibited decreased intensity and delayed onset of the foreign body response following implantation of drug free dummy sensors in comparison to those of normal rats. On the other hand, tissues containing dummy sensors that were coated with dexamethasone containing composites remained normal (i.e. similar to untreated tissues), with no inflammatory reaction or fibrous encapsulation occurring over the one-month period in both the normal and diabetic rats. The feasibility of utilizing PLGA microsphere/PVA hydrogel composites as coatings for implantable biosensors was demonstrated. This polymeric composite is an innovative approach to control the foreign body reaction at the tissue-device interface to prolong biosensor lifetime. 23932730 Toxoplasma gondii in free-ranging wild small felids from Brazil: Molecular detection and genotypic characterization. Brazil harbors the largest number of wild Neotropical felid species, with ten of the twelve species recorded in the American continent. Although these animals are considered to be definitive hosts for Toxoplasma gondii, there are few descriptions of the parasite in these species. Here, we performed a molecular detection of T. gondii by amplification of the marker ITS-1 from tissue samples obtained from 90 free-ranging wild small Neotropical felids from Rio Grande do Sul - Brazil. Of the sampled animals, 34.4% (n=31) were positive including the species Puma yagouaroundi - jaguarondi (9/22), Leopardus geoffroyi - Geoffroy's cat (6/22), Leopardus tigrinus - oncilla (8/28), Leopardus wiedii - margay (6/10), Leopardus pardalis - ocelot (1/1) and Leopardus colocolo - Pampas cat (1/7). Toxoplasma DNA was detected with a frequency of 14.6% (63/433) in primary samples of tongue (16/56), brain (8/43), skeletal muscle (15/83), heart (7/63), diaphragm (3/56), vitreous humor (2/44), eye muscle (6/44) and eyeball (6/44). Multilocus PCR-RFLP genotyping of eleven small Neotropical felids using the molecular markers SAG1, 5'3'SAG2, alt. SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, Apico and CS3 allowed the partial characterization of eight genotypes. We fully characterized two new genotypes that have not been described previously in Brazil (Lw#31Tn from L. wiedii and Py#21Sm from P. yagouaroundi) and one genotype Py#56Br from P. yagouaroundi that has been described previously in isolates from cats, dogs and capybaras from São Paulo state. This study constitutes the first detection and genotypic characterization of T. gondii in free-ranging felids in Brazil, demonstrating the occurrence of the parasite in wild populations and suggesting its potential transmissibility to humans and other domestic and wild animals. 23930622 Molecular Dynamics Simulation of Chemokine Receptors in Lipid Bilayer: A Case Study on C-C Chemokine Receptor Type 2. Chemokine receptors belong to the membrane proteins that are included in many physiological phenomena. However, the mechanism of their action is unknown at the atomistic level in different aspects. In this study, a computational pipeline is exploited to investigate the molecular basis of how the structure of C-C chemokine receptor type 2, a prototypical chemokine receptor, is affected by lipid bilayer and an antagonist (INCB3344). This study includes homology modeling, molecular dynamics simulation in lipid bilayer, and docking. A detailed mechanism of INCB3344 has been described. Tyr 49, Trp 98, Tyr 120, His 121, and Glu 291 are proved to play important roles in binding. Integrating results obtained in this study and experimental data help us to suggest a two-step ligand-binding mechanism. The N-terminus of protein first sticks out from the extracellular domain suitable for the contact with the antagonist. Binding of ligand to this segment leads to the geometrical changes to facilitate the ligand interactions with extracellular loop 2 of C-C chemokine receptor type 2. Finally, the interactions occurring between extracellular loop 2 and ligand induce conformational changes in C-C chemokine receptor type 2 structure. These changes bring the ligand closer to the binding pocket, allowing the interaction between INCB3344 and the residues of active site. 23460473 Supramolecular cl⋅⋅⋅h and o⋅⋅⋅h interactions in self-assembled 1,5-dichloroanthraquinone layers on au(111). The role of halogen bonds in self-assembled networks for systems with Br and I ligands has recently been studied with scanning tunneling microscopy (STM), which provides physical insight at the atomic scale. Here, we study the supramolecular interactions of 1,5-dichloroanthraquinone molecules on Au(111), including Cl ligands, by using STM. Two different molecular structures of chevron and square networks are observed, and their molecular models are proposed. Both molecular structures are stabilized by intermolecular Cl⋅⋅⋅H and O⋅⋅⋅H hydrogen bonds with marginal contributions from Cl-related halogen bonds, as revealed by density functional theory calculations. Our study shows that, in contrast to Br- and I-related halogen bonds, Cl-related halogen bonds weakly contribute to the molecular structure due to a modest positive potential (σ hole) of the Cl ligands. 23801780 Differences in the metabolomic signatures of porcine follicular fluid collected from environments associated with good and poor oocyte quality. The microenvironment of the developing follicle is critical to the acquisition of oocyte developmental competence, which is influenced by several factors including follicle size and season. The aim of this study was to characterise the metabolomic signatures of porcine follicular fluid (FF) collected from good and poor follicular environments, using high-resolution proton nuclear magnetic resonance ((1)H-NMR) spectroscopy. Sow ovaries were collected at slaughter, 4 days after weaning, in summer and winter. The contents of small (3-4 mm) and large (5-8 mm) diameter follicles were aspirated and pooled separately for each ovary pair. Groups classified as summer-small (n=8), summer-large (n=15), winter-small (n=9) and winter-large (n=15) were analysed by (1)H-NMR spectroscopy. The concentrations of 11 metabolites differed due to follicle size alone (P<0.05), including glucose, lactate, hypoxanthine and five amino acids. The concentrations of all these metabolites, except for glucose, were lower in large FF compared with small FF. Significant interaction effects of follicle size and season were found for the concentrations of glutamate, glycine, N-acetyl groups and uridine. Succinate was the only metabolite that differed in concentration due to season alone (P<0.05). The FF levels of progesterone, androstenedione and oestradiol were correlated with the concentrations of most of the metabolites examined. The results indicate that there is a distinct shift in follicular glucose metabolism as follicles increase in diameter and suggest that follicular cells may be more vulnerable to oxidative stress during the summer months. Our findings demonstrate the power of (1)H-NMR spectroscopy to expand our understanding of the dynamic and complex microenvironment of the developing follicle. 23187066 Decolourization of direct blue 15 by Fenton/ultrasonic process using a zero-valent iron aggregate catalyst. Decolourization of direct azo dye, direct blue 15 (DB15), by an advanced Fenton process coupled with ultrasonic irradiation (Fenton/US) was investigated. Zero-valent iron (ZVI) aggregates were used as the catalyst. A positive synergistic effect occurred when Fenton's reagent was combined with ultrasonic irradiation. Experimental results showed that the optimum conditions for decolourization were pH 3.0, Fe(0) 1g/L, H(2)O(2) 5.15×10(-3)mol/L with ultrasound density of 120W/L at 60kHz. These conditions yielded 99% decolouration of 4.7×10(-5) M DB15 (4130 ADMI) solution within 10min. DB15 decolouration follows the first-order decolouration kinetics. Although the solutions containing H(2)CO(3), Cl(-), ClO(4)(-), NO(3)(-) and SO(4)(2-) ions did not have a significant effect on the decolouration, the H(2)PO(4)(-) ion did decrease the decolouration rate. High ultrasonic input power accelerated the reaction and increased decolourization efficiency. The cost effectiveness of this process at high ultrasound density could be controlled despite the high electricity costs incurred by the process. ZVI aggregates were reusable; however, an increase in the number of times ZVI was recycled decreased the decolourization rate. This study demonstrates that a Fenton/US process can effectively decolour the direct azo dye DB15 in wastewater. 23860587 Oxidative dehydrogenation of a new tetra-amine N4-donor macrocycle tunes the nickel(ii) spin state from high spin to low spin. The nickel(ii) spin state in a series of N4-donor macrocycles differing in the number of imine bonds is tuned from low spin (2 imines) to low or high spin (1 imine; non- or coordinating co-ligand) to high spin (no imines). 23924516 Identifying Symptoms of Depression and Anxiety in Students in the School Setting. Early detection of mental health problems in school-age children offers the opportunity for prompt referral to treatment which is critical to their success in school. School nurses are in a key position to screen for mental health issues in the school setting. This article discusses how school nurses began a new initiative to use two validated screening tools, the Patient Health Questionnaire-9 item for detecting depression and the 5-item Screen for Child Anxiety Related Emotional Disorders for detecting anxiety in middle school/high school-aged children in selected urban schools. Students having positive screens were referred to the multidisciplinary school-based Student Assistance Program team for further evaluation and referral. These screens improved the identification and referral for treatment of children suffering from anxiety and/or depression by expediting the connection to services. 23817405 Solvothermal synthesis of antimony sulfide dendrites for electrochemical detection of dopamine. Sb2S3 dendrites composed of 1-dimensional rods were prepared by a facile solvothermal reaction. The dosage of the poly(acrylic acid) (PAA) morphology-controlling reagent and the reaction temperature are key factors determining the final morphology of the product. Temporal experiments revealed that the formation of Sb2S3 dendrites experienced successive stages including precipitate reaction, crystallization and tip splitting. The as-prepared Sb2S3 dendrites were further employed as sensing material for electrochemical detection of dopamine (DA). A cyclic voltammogram (CV) showed that an Sb2S3 dendrite modified electrode enables the selective electro-oxidation of DA in the presence of ascorbic acid (AA). The constructed biosensor demonstrated a linear response range of 0.125-160 μM and a detection limit of 0.1 μM, which suggests that the Sb2S3 dendrites are promising sensing materials in the electrochemical analysis of DA. 23648457 A comparison of CMV detection in gastrointestinal mucosal biopsies using immunohistochemistry and PCR performed on formalin-fixed, paraffin-embedded tissue. Cytomegalovirus (CMV) can precipitate and exacerbate gastrointestinal (GI) mucosal injury. The gold standard for CMV detection in formalin-fixed, paraffin-embedded (FFPE) tissue is immunohistochemistry (IHC). Although CMV polymerase chain reaction (PCR) on fresh tissue may be a valuable adjunct to IHC, its utility is unknown for FFPE tissues. We therefore evaluated quantitative, real-time CMV PCR in a total of 102 FFPE GI biopsy specimens from 74 patients with a history of hematopoietic stem cell or solid organ transplant, inflammatory bowel disease, human immunodeficiency virus infection, or unspecified colitis. CMV DNA was detected by PCR in 90.9% (30/33) of IHC-positive, 14.5% (8/55) of IHC-negative, and 20.0% (1/5) of IHC-equivocal FFPE tissues. Quantitation of CMV DNA copies normalized to β-globin demonstrated a wide range of values (median 0.276; range, 0.0004 to 144.50). Importantly, 93.3% (14/15) of patients with IHC-positive, active colitis showed no evidence of CMV in matched concurrent, histologically normal biopsies tested by PCR. These results suggest that CMV PCR on FFPE GI biopsies complements IHC and has the potential to identify additional patients who may benefit from anti-CMV therapy. 23894603 Population-Based CD4 Counts in a Rural Area in South Africa with High HIV Prevalence and High Antiretroviral Treatment Coverage. Little is known about the variability of CD4 counts in the general population of sub-Saharan Africa countries affected by the HIV epidemic. We investigated factors associated with CD4 counts in a rural area in South Africa with high HIV prevalence and high antiretroviral treatment (ART) coverage. CD4 counts, health status, body mass index (BMI), demographic characteristics and HIV status were assessed in 4990 adult resident participants of a demographic surveillance in rural KwaZulu-Natal in South Africa; antiretroviral treatment duration was obtained from a linked clinical database. Multivariable regression analysis, overall and stratified by HIV status, was performed with CD4 count levels as outcome. Median CD4 counts were significantly higher in women than in men overall (714 vs. 630 cells/µl, p<0.0001), both in HIV-uninfected (833 vs. 683 cells/µl, p<0.0001) and HIV-infected adults (384.5 vs. 333 cells/µl, p<0.0001). In multivariable regression analysis, women had 19.4% (95% confidence interval (CI) 16.1-22.9) higher CD4 counts than men, controlling for age, HIV status, urban/rural residence, household wealth, education, BMI, self-reported tuberculosis, high blood pressure, other chronic illnesses and sample processing delay. At ART initiation, HIV-infected adults had 21.7% (95% CI 14.6-28.2) lower CD4 counts than treatment-naive individuals; CD4 counts were estimated to increase by 9.2% (95% CI 6.2-12.4) per year of treatment. CD4 counts are primarily determined by sex in HIV-uninfected adults, and by sex, age and duration of antiretroviral treatment in HIV-infected adults. Lower CD4 counts at ART initiation in men could be a consequence of lower CD4 cell counts before HIV acquisition. 23711353 Understanding the brown adipocyte as a contributor to energy homeostasis. Brown adipocytes are specialized cells capable of undergoing thermogenesis, a phenomenon regulated by the sympathetic nervous system, due to the presence of uncoupling protein 1 (UCP1). The recent demonstrations of their presence in adult humans, and the discovery that brown adipocytes can be derived from distinct precursors and express specific genes depending on their anatomic location, have sparked intense interest in enhancing the current understanding of their biology and relevance to human energy homeostasis. We provide an overview of the latest advances related to the developmental origins of brown adipocytes, discuss their regulation and function in both rodents and humans, and offer a critical perspective on the relevance of brown adipocyte-mediated thermogenesis in human physiology. 23833199 Oropharyngeal Dysphagia is a Risk Factor for Readmission for Pneumonia in the Very Elderly Persons: Observational Prospective Study. To determine whether oropharyngeal dysphagia is a risk factor for readmission for pneumonia in elderly persons discharged from an acute geriatric unit. Observational prospective cohort study with data collection based on clinical databases and electronic clinical notes. All elderly individuals discharged from an acute geriatric unit from June 2002 to December 2009 were recruited and followed until death or December 31, 2010. All individuals were initially classified according to the presence of oropharyngeal dysphagia assessed by bedside clinical examination. Main outcome measure was readmission for pneumonia. Clinical notes were reviewed by an expert clinician to verify diagnosis and classify pneumonia as aspiration or nonaspiration pneumonia. A total of 2,359 patients (61.9% women, mean age 84.9 y) were recruited and followed for a mean of 24 months. Dysphagia was diagnosed in 47.5% of cases. Overall, 7.9% of individuals were readmitted for pneumonia during follow-up, 24.2% of these had aspiration pneumonia. The incidence rate of hospital readmission for pneumonia was 3.67 readmissions per 100 person-years (95% CI 3.0-4.4) in individuals without dysphagia and 6.7 (5.5-7.8) in those with dysphagia, with an attributable risk of 3.02 readmissions per 100 person-years (1.66-4.38) and a rate ratio of 1.82 (1.41-2.36). Multivariate Cox regression showed an independent effect of oropharyngeal dysphagia, with a hazard ratio of 1.6 (1.15-2.2) for hospitalization for pneumonia, 4.48 (2.01-10.0) for aspiration pneumonia, and 1.44 (1.02-2.03) for nonaspiration pneumonia. Oropharyngeal dysphagia is a very prevalent and relevant risk factor associated with hospital readmission for both aspiration and nonaspiration pneumonia in the very elderly persons. 23881262 Spatio-temporal analysis of type 2 diabetes mellitus based on differential expression networks. T2DM is complex in its dynamical dependence on multiple tissues, disease states, and factors' interactions. However, most existing work devoted to characterizing its pathophysiology from one static tissue, individual factors, or single state. Here we perform a spatio-temporal analysis on T2DM by developing a new form of molecular network, i.e. 'differential expression network' (DEN), which can reflect phenotype differences at network level. Static DENs show that three tissues (white adipose, skeletal muscle, and liver) all suffer from severe inflammation and perturbed metabolism, among which metabolic functions are seriously affected in liver. Dynamical analysis on DENs reveals metabolic function changes in adipose and liver are consistent with insulin resistance (IR) deterioration. Close investigation on IR pathway identifies 'disease interactions', revealing that IR deterioration is earlier than that on SlC2A4 in adipose and muscle. Our analysis also provides evidence that rising of insulin secretion is the root cause of IR in diabetes. 23318222 Study of cerebello-thalamocortical pathway by transcranial magnetic stimulation in Parkinson's disease. Although functional changes in the activation of the cerebellum in Parkinson's disease (PD) patients have been consistently described, it is still debated whether such altered cerebellar activation is a natural consequence of PD pathophysiology or rather it involves compensatory mechanisms. We used different forms of cerebellar transcranial magnetic stimulation to evaluate the hypothesis that altered cerebello-cortical interactions can be observed in PD patients and to evaluate the role of dopaminergic treatment. We studied the effects of a single cerebellar magnetic pulse over the excitability of the contralateral primary motor cortex tested with motor-evoked potentials (MEPs) (cerebellar-brain inhibition-CBI) in a group of 16 PD patients with (ON) and without dopaminergic treatment (OFF), and in 16 age-matched healthy controls. Moreover, we also tested the effects of cerebellar continuous theta-burst stimulation (cTBS) on MEP amplitude, short intracortical inhibition (SICI) and short intracortical facilitation (SICF) tested in the contralateral M1 in 13 PD patients in ON and OFF and in 16 age-matched healthy controls. CBI was evident in controls but not in PD patients, even when tested in both ON and OFF conditions. Similarly, cerebellar cTBS reduced MEP amplitude and SICI in controls but not in PD patients under any condition. These results demonstrate that PD patients have deficient short-latency and long-lasting cerebellar-thalamocortical inhibitory interactions that cannot be promptly restored by standard dopaminergic medication. 23562990 Perinatal dyadic psychotherapy: design, implementation, and acceptability. Maternal postpartum depression (PPD) and mother-infant relationship dysfunction have reciprocal effects on each other and thus an integrated approach that addresses both problems simultaneously may lead to improved outcomes. This study aimed to determine the feasibility, acceptability, and preliminary efficacy of a new intervention, Perinatal Dyadic Psychotherapy (PDP), for the early treatment of maternal PPD. PDP is designed to promote maternal mental health and facilitate optimal mother-infant relationships via (a) a supportive, relationship-based, mother-infant psychotherapeutic component, and (b) a developmentally based infant-oriented component focused on promoting positive mother-infant interactions. This paper describes the pilot use of PDP with six acutely depressed postpartum women. Nurses delivered the intervention over eight home visits. Results indicate that PDP is a feasible, acceptable, and safe intervention with this population. All participants achieved remission of depression with significant reduction of depression and anxiety symptoms, suggesting that PDP is a promising treatment for PPD. 23523587 Type VIII collagen signals via β1 integrin and RhoA to regulate MMP-2 expression and smooth muscle cell migration. The extracellular matrix signals and regulates the behavior of vascular cells during the pathogenesis of atherosclerosis. Type VIII collagen, a short chain collagen, is scarcely present in normal arteries, but is dramatically upregulated in atherosclerosis and after other types of vascular injury. Cell culture studies have revealed that this protein supports smooth muscle cell (SMC) adhesion and stimulates migration, however little is known about the signaling or the mechanisms by which this occurs. SMCs isolated from wild-type C57BL/6 and type VIII collagen deficient mice were studied using assays to measure chemotactic and haptotactic migration, and remodeling and contraction of 3-dimensional type I collagen gels. Col8(-/-) SMCs exhibited impairments in migration, and a strongly adhesive phenotype with prominent stress fibers, stable microtubules and pronounced central basal focal adhesions. The addition of exogenous type VIII collagen to the Col8(-/-) SMCs rescued the impairments in migration, and restored cytoskeletal architecture so that it was similar to Col8(+/+) cells. We measured elevated levels of active GTP-RhoA in the Col8(-/-) cells, and this too was reversed by treatment with exogenous type VIII collagen. We showed that type VIII collagen normally suppresses RhoA activation through a beta-1 integrin dependent mechanism. MMP-2 levels were reduced in the Col8(-/-) SMCs, and knockdown of MMP-2 in Col8(+/+) SMCs partially recapitulated the decreases in migration and 3D gel contraction seen in Col8(-/-) cells, showing that type VIII collagen-stimulated migration was dependent on MMP-2. Inhibition of Rho restored MMP-2 activity in the Col8(-/-) cells, and partially rescued migration, demonstrating that the elevations in RhoA activity were responsible for the suppression of migration of these cells. In conclusion, we have shown that type VIII collagen signals through beta-1 integrin receptors to suppress RhoA, allowing optimal configuration of the cytoskeleton, and the stimulation of MMP-2-dependent cell migration. 23847649 Abundances of microRNAs in human cells can be estimated as a function of the abundances of YRHB and RHHK tetranucleotides in these microRNAs as an ill-posed inverse problem solution. Mature microRNAs (miRNAs) are small endogenous non-coding RNAs 18-25 nt in length. They program the RNA Induced Silencing Complex (RISC) to make it inhibit either messenger RNAs or promoter DNAs. We have found that the mean abundance of miRNAs in Arabidopsis is correlated with the abundance of DRYD tetranucleotides near the 3'-end and the abundance of WRHB tetranucleotides in the center of the miRNA sequence. Based on this correlation, we have estimated miRNA abundances in seven organs of this plant, namely: inflorescences, stems, siliques, seedlings, roots, cauline, and rosette leaves. We have also found that the mean affinity of miRNAs for two proteins in the Argonaute family (Ago2 and Ago3) in man is correlated with the abundance of YRHB tetranucleotides near the 3'-end and that the preference of miRNAs for Ago2 is correlated with the abundance of RHHK tetranucleotides in the center of the miRNA sequence. This allowed us to obtain statistically significant estimates of miRNA abundances in human embryonic kidney cells, HEK293T. These findings in relation to two taxonomically distant entities (man and Arabidopsis) fit one another like pieces of a jigsaw puzzle, which allowed us to heuristically generalize them and state that the miRNA abundance in the human brain may be determined by the abundance of YRHB and RHHK tetranucleotides in these miRNAs. 23054672 The epistemic integrity of scientific research. We live in a world in which scientific expertise and its epistemic authority become more important. On the other hand, the financial interests in research, which could potentially corrupt science, are increasing. Due to these two tendencies, a concern for the integrity of scientific research becomes increasingly vital. This concern is, however, hollow if we do not have a clear account of research integrity. Therefore, it is important that we explicate this concept. Following Rudolf Carnap's characterization of the task of explication, this means that we should develop a concept that is (1) similar to our common sense notion of research integrity, (2) exact, (3) fruitful, and (4) as simple as possible. Since existing concepts do not meet these four requirements, we develop a new concept in this article. We describe a concept of epistemic integrity that is based on the property of deceptiveness, and argue that this concept does meet Carnap's four requirements of explication. To illustrate and support our claims we use several examples from scientific practice, mainly from biomedical research. 23317937 Risperidone, a risk factor for valproate-induced encephalopathy? Valproate-induced encephalopathy (ViE) has been increasingly reported and several risk factors have been proposed. We report a case whereby a patient became encephalopathic while treated with valproate and upon initiation of risperidone. The underlying mechanism could be risperidone's interference with valproate's binding to albumin, raising free valproate levels, which would impair the urea cycle and reduce ammonia conversion, leading to a hyperammonemic encephalopathy. The present case suggests a causal link, although further studies will be necessary to establish this. Nevertheless, clinicians should be aware of this possible interaction and consider carefully before concomitant administration of valproate and risperidone, mainly in patients with other risk factors for ViE, so this complication can be avoid or promptly diagnosed and treated. 23802767 The challenges of licensing drugs for use in pregnancy. Most recommended obstetric therapeutic agents are not licensed for their purpose. There is a lack of funding for research and little development of new therapeutic agents for use in the treatment of pregnancy-related disorders. Current therapeutics used in maternal health and their licensing status are reviewed and suggestions for these shortfalls together with possible solutions considered. 23623857 Genetic stability of RSV-F expression and the restricted growth phenotype of a live attenuated PIV3 vectored RSV vaccine candidate (MEDI-534) following restrictive growth in human lung cells. MEDI-534 is the first live, attenuated and vectored respiratory syncytial virus (RSV) vaccine to be evaluated in seronegative children. It consists of a bovine/human parainfluenza virus type 3 (PIV3) backbone with the RSV fusion glycoprotein (RSV-F) expressed from the second position. The PIV3 fusion and hemaglutinin-neuraminidase proteins are human-derived. No small animal appropriately replicates the restrictive growth of bovine PIV3 (bPIV3) based viruses relative to human PIV3 (hPIV3) observed in the respiratory tract of rhesus monkeys and humans, making analysis of the genetic stability of the attenuation phenotype and maintenance of RSV-F expression difficult. Screening of multiple cell-lines identified MRC-5 cells as supporting permissive growth of hPIV3 while restricting bPIV3 and MEDI-534 growth. In MRC-5 cells, the peak titers of MEDI-534 were more than 20-fold lower compared to hPIV3 peak titers. After more than 10 multicycle passages in MRC-5 cells, genetic alterations were detected in MEDI-534 that contributed to a partial loss in restricted growth in MRC-5 cells and a decrease in RSV-F expression. These adaptive mutations did not occur in the RSV-F gene but were found in the polyA sequence upstream of the transgene. MRC-5 adapted MEDI-534 viruses (1) lost some attenuation but did not replicate to the level of hPIV3 in this cell line, (2) did not completely lose RSV-F expression and (3) were able to elicit a protective anti-RSV immune response in hamsters despite lower levels of RSV-F expression. Interestingly analysis of shed MEDI-534 from a recent clinical trial indicates that in some recipients similar mutations arise by day 7 or day 12 post immunization (in press) suggesting that these mutations can arise rapidly in the human host. The utility and limits of MRC-5 cells for characterizing the attenuation and RSV-F expression of MEDI-534 is discussed. 23845211 The use of fertility awareness methods (FAM) among young adult Latina and black women: what do they know and how well do they use it? Use of FAM among Latina and black women in the United States. Although a sizeable percentage of minority women use fertility awareness methods (FAM), little is known about their use in the United States. We sought to fill this gap by examining FAM use among Latina and black women - groups that have high rates of unintended childbearing and FAM use - focusing on knowledge, sources of information and accuracy of use. Unlike other methods, accurate use of FAM requires relatively high levels of knowledge. In-depth, semistructured interviews were conducted with 58 Latina and black women who were current or past users of FAM. Participants were recruited through local clinics and ads posted in neighborhoods and local Web sites. A purposive sample design was used to ensure that the sample included individuals with characteristics associated with FAM use. An inductive approach was used in the data analysis. Women learned about FAM from family, professionals and the Internet. In general, what they learned fell into one of two levels of information - basic or in-depth - and many women possessed moderate to low levels of knowledge. By decomposing accuracy of use into its components, we find that it is driven largely by knowledge. While the vast majority of women were abstaining from unprotected sex during what they believed to be their fertile window, only 34 of the 58 participants accurately identified their fertile period. Findings speak to a gap in reproductive literacy that has important implications for FAM users. The gap between behavior and knowledge could help account for high failure rates associated with FAM use. 23150983 Synthesis and antitubercular activity of 2-(substituted phenyl/benzyl-amino)-6-(4-chlorophenyl)-5-(methoxycarbonyl)-4-methyl-3,6-dihydropyrimidin-1-ium chlorides. A series of 2-(substituted phenyl/benzyl-amino)-6-(4-chlorophenyl)-5-(methoxycarbonyl)-4-methyl-3,6-dihydropyrimidin-1-ium chlorides 7-13 and 15 was synthesized in their hydrochloride salt form. The title compounds were characterized by FT-IR, NMR ((1)H and (13)C) and elemental analysis. They were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv, multidrug resistance tuberculosis and extensively drug resistance tuberculosis by agar diffusion method and tested for the cytotoxic action on peripheral blood mononuclear cells by MTT assay. Among all the tested compounds in the series, compounds 7 and 11 emerged as promising antitubercular agents at 16 μg/mL against multidrug resistance tuberculosis and over 64 μg/mL against extensively drug resistance tuberculosis. The conformational features and supramolecular assembly of the promising compounds 7 and 11 were determined by single crystal X-ray study. 23876123 Fasting glucose level is associated with nocturnal hypoglycemia in elderly male patients with type 2 diabetes. Abstract Background: Nocturnal hypoglycemia was a common and serious problem among patients with type 2 diabetes (T2DM), especially in the elderly. This study investigated whether fasting glucose was an indicator of nocturnal hypoglycemia in elderly male patients with T2DM. Methods: A total of 291 elderly male type 2 diabetic patients who received continuous glucose monitoring (CGM) between January 2007 and January 2011 were enrolled in the study. The association of fasting glucose and nocturnal hypoglycemia based on CGM data was analyzed, comparing with bedtime glucose. Results: Based on CGM data, patients with nocturnal hypoglycemia had significantly lower fasting glucose (5.88 ± 1.29 versus 6.92 ± 1.32 mmol/L) and bedtime glucose (7.33 ± 1.70 versus 8.01 ± 1.95 mmol/L) than patients without nocturnal hypoglycemia (both p < 0.01). Compared with the highest quartile, the lowest quartile of fasting glucose had a significantly increased risk of nocturnal hypoglycemia after the multiple adjustments (pfor trend < 0.001). However, this association did not appear in bedtime glucose. When the prediction of nocturnal hypoglycemia either by fasting glucose or bedtime glucose using the area under receiver operating characteristic (ROC) curve, fasting glucose but not bedtime glucose, was an indicator of nocturnal hypoglycemia, with an area under the ROC curve (AUC) of 0.714 (95% CI: 0.653 ∼ 0.774, p < 0.001). On the ROC curve, the Youden index was maximal when fasting glucose was 6.1 mmol/L. Conclusions: Fasting glucose may be a convenient and clinically useful indicator of nocturnal hypoglycemia in elderly male patients with T2DM. Risk of nocturnal hypoglycemia significantly increased when fasting glucose was less than 6.1 mmol/L. 23322407 Continuous exposure to low amplitude extremely low frequency electrical fields characterizing the vascular streaming potential alters elastin accumulation in vascular smooth muscle cells. In normal development and pathology, the vascular system depends on complex interactions between cellular elements, biochemical molecules, and physical forces. The electrokinetic vascular streaming potential (EVSP) is an endogenous extremely low frequency (ELF) electrical field resulting from blood flowing past the vessel wall. While generally unrecognized, it is a ubiquitous electrical biophysical force to which the vascular tree is exposed. Extracellular matrix elastin plays a central role in normal blood vessel function and in the development of atherosclerosis. It was hypothesized that ELF fields of low amplitude would alter elastin accumulation, supporting a link between the EVSP and the biology of vascular smooth muscle cells. Neonatal rat aortic smooth muscle cell cultures were exposed chronically to electrical fields characteristic of the EVSP. Extracellular protein accumulation, DNA content, and electron microscopic (EM) evaluation were performed after 2 weeks of exposure. Stimulated cultures showed no significant change in cellular proliferation as measured by the DNA concentration. The per-DNA normalized protein in the extracellular matrix was unchanged while extracellular elastin accumulation decreased 38% on average. EM analysis showed that the stimulated cells had a 2.85-fold increase in mitochondrial number. These results support the formulation that ELF fields are a potential factor in both normal vessel biology and in the pathogenesis of atherosclerotic diseases including heart disease, stroke, and peripheral vascular disease. 23404495 DNA transfection of bone marrow stromal cells using microbubble-mediated ultrasound and polyethylenimine: an in vitro study. Non-viral vector transfection efficiency is an issue affecting the clinical application of stem cell gene therapy. This study makes use of the synergistic effect of combining ultrasound (US) with microbubbles (MB) and polyethylenimine (PEI) to increase DNA transfection efficiency, which will enhance the efficiency of gene transfer to bone marrow stromal cells (BMSCs). The optimal parameters for primary-cultured rat-BMSC DNA transfection were examined. The study was arranged based on uniform design. Using a construct containing hepatocyte growth factor (HGF) tagged with enhanced green fluorescent protein (pEGFP-HGF) as example, the mixture of BMSCs, MB, and PEI:DNA complex were exposed to US with frequency of 1 MHz and 10 % duty cycle pulses. Other factors such as acoustic intensity (Q), MB dosage, and total treatment time (T) were also tested. The results were analyzed by regression analysis. Using the best match of parameters, Q = 0.6 W/cm(2), MB = 10(6)/ml, T = 30 s, different groups were compared. The cooperativity of MB-mediated US and PEI enhanced the gene transfection efficiency by nearly 38-times compared to the DNA without US group. Furthermore, the expression of HGF protein was confirmed by Western blot. The eGFP could be not only seen mainly at the cytoplasm, but also seen in the nucleus in a small proportion of the cells (<10 %) for up to 7 observed days. The transfected BMSCs maintained their capability of multi-directional differentiation and reproductive activity. Our results provide useful information in establishing a novel non-viral transfection method, which may be applied to clinical application in stem cell gene therapy. 23867123 Adverse impact of regional lymph node involvement in osteosarcoma. Metastatic dissemination in osteosarcoma occurs haematogenously, though regional lymph node involvement is rarely reported. We investigated incidence, patient characteristics and survival for patients with osteosarcoma and regional lymph node involvement at diagnosis. We identified 2748 cases of high-grade osteosarcoma with available information regarding regional lymph node involvement in the Surveillance Epidemiology and End Results database from 1973 to 2009. Demographics were compared using chi-squared tests or t-tests. Overall survival was estimated using Kaplan-Meier method and compared with log-rank tests. Multivariate analysis of overall survival was performed using Cox proportional hazards methods. There were 74 patients (2.7%) with regional lymph node involvement at diagnosis of whom 19 (0.7%) were pathologically confirmed. Patients with regional node involvement were more likely to have extraskeletal tumours, distant metastases, tumours arising outside the lower extremity (p<0.0001 for all comparisons) and larger tumours (p=0.033). Five-year overall survival in those with and without regional node involvement was 10.9% (95% confidence interval (CI) 4.6-20.4) and 54.3% (95% CI 52.2-56.4; p<0.0001). In multivariate analysis, regional node involvement remained predictive of inferior survival after controlling for differences in metastatic status, age, tumour site and extraskeletal origin (hazard ratio 2.05, 95% CI 1.57-2.67; p<0.0001). Similar survival results were found when the analysis was restricted to patients with pathologically confirmed positive or negative regional lymph nodes. This analysis confirms that regional node involvement is a significant adverse prognostic factor that is independent of metastatic status, extraskeletal origin, age and tumour site. 23959870 Low levels of copper disrupt brain amyloid-β homeostasis by altering its production and clearance. Whereas amyloid-β (Aβ) accumulates in the brain of normal animals dosed with low levels of copper (Cu), the mechanism is not completely known. Cu could contribute to Aβ accumulation by altering its clearance and/or its production. Because Cu homeostasis is altered in transgenic mice overexpressing Aβ precursor protein (APP), the objective of this study was to elucidate the mechanism of Cu-induced Aβ accumulation in brains of normal mice and then to explore Cu's effects in a mouse model of Alzheimer's disease. In aging mice, accumulation of Cu in brain capillaries was associated with its reduction in low-density lipoprotein receptor-related protein 1 (LRP1), an Aβ transporter, and higher brain Aβ levels. These effects were reproduced by chronic dosing with low levels of Cu via drinking water without changes in Aβ synthesis or degradation. In human brain endothelial cells, Cu, at its normal labile levels, caused LRP1-specific down-regulation by inducing its nitrotyrosination and subsequent proteosomal-dependent degradation due in part to Cu/cellular prion protein/LRP1 interaction. In APP(sw/0) mice, Cu not only down-regulated LRP1 in brain capillaries but also increased Aβ production and neuroinflammation because Cu accumulated in brain capillaries and, unlike in control mice, in the parenchyma. Thus, we have demonstrated that Cu's effect on brain Aβ homeostasis depends on whether it is accumulated in the capillaries or in the parenchyma. These findings should provide unique insights into preventative and/or therapeutic approaches to control neurotoxic Aβ levels in the aging brain. 23637348 Development and validation of a predicting model of all-cause mortality in patients with type 2 diabetes. OBJECTIVE To develop and validate a parsimonious model for predicting short-term all-cause mortality in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS Two cohorts of patients with T2DM were investigated. The Gargano Mortality Study (GMS, n = 679 patients) was the training set and the Foggia Mortality Study (FMS, n = 936 patients) represented the validation sample. GMS and FMS cohorts were prospectively followed up for 7.40 ± 2.15 and 4.51 ± 1.69 years, respectively, and all-cause mortality was registered. A new forward variable selection within a multivariate Cox regression was implemented. Starting from the empty model, each step selected the predictor that, once included into the multivariate Cox model, yielded the maximum continuous net reclassification improvement (cNRI). The selection procedure stopped when no further statistically significant cNRI increase was detected. RESULTS Nine variables (age, BMI, diastolic blood pressure, LDL cholesterol, triglycerides, HDL cholesterol, urine albumin-to-creatinine ratio, and antihypertensive and insulin therapy) were included in the final predictive model with a C statistic of 0.88 (95% CI 0.82-0.94) in the GMS and 0.82 (0.76-0.87) in the FMS. Finally, we used a recursive partition and amalgamation algorithm to identify patients at intermediate and high mortality risk (hazard ratio 7.0 and 24.4, respectively, as compared with those at low risk). A web-based risk calculator was also developed. CONCLUSIONS We developed and validated a parsimonious all-cause mortality equation in T2DM, providing also a user-friendly web-based risk calculator. Our model may help prioritize the use of available resources for targeting aggressive preventive and treatment strategies in a subset of very high-risk individuals. 23152116 Diatom frustules as light traps enhance DSSC efficiency. Diatoms are one of the most successful photosynthetic organisms and given the important role that their shells (frustules) play in light trapping we explored their use in multilayered materials for application as photoanodes in dye sensitised solar cells (DSSCs). We find a substantial improvement in energy conversion efficiency of 30%, increasing from 3.5% to 4.6% with diatom incorporation. 23506492 The hemodynamics of septic shock: a historical perspective. In the late 19th century, it was already known that severe infections could be associated with cardiovascular collapse, a fact essentially attributed to cardiac failure. A major experimental work in the rabbit, published by Romberg and Pässler in 1899, shifted attention to disturbed peripheral vascular tone as the mechanism of hypotension in these conditions. In the first half of the 20th century, great progresses were made in the pathophysiologic understanding of hemorrhagic and traumatic shocks, while researchers devoted relatively little attention to septic shock. Progress in the hemodynamic understanding of septic shock resumed with the advent of critical care units. The hyperdynamic state was recognized in the late fifties and early sixties. The present short review ends with landmark studies by Max Harry Weil, demonstrating the importance of venous pooling, and John H. Siegel, which introduced the concept of deficient peripheral utilization of oxygen, inspiring later work on the microvascular disturbances of septic shock. 23700297 The varying size of exit wounds from center-fire rifles as a consequence of the temporary cavity. To study the question whether and how the size and position of the temporary cavity influence the morphology and especially the size of a bullet exit wound, test shots were fired to composite models consisting of gelatine and pig soft tissue covered with skin (at the exit site). The dimensions of the composite model were determined such that the exit planes were located either at the level of the narrow channel or within the temporary cavity or behind it. The chronological sequence of wound formation and its relation to the current position of the bullet were documented by means of a high-speed camera. Test shots were fired from a distance of 10 m using 5.56 × 45 mm cartridges with full metal-jacketed pointed bullets (v 0 ∼ 912 m/s, E 0 ∼ 1,663 J). The study proved that the extension and position of the temporary wound cavity was decisive for the size of the exit wound: An exit plane within the cavity resulted in particularly large skin lesions, whereas the wound diameters were much smaller if the exit plane was located in front or behind the cavity. The exit hole reaches its maximum size only after the bullet has left the target synchronous to the staggered expansion of the temporary cavity. 22923492 Amino acid sequence of the ligand-binding domain of the aryl hydrocarbon receptor 1 predicts sensitivity of wild birds to effects of dioxin-like compounds. The sensitivity of avian species to the toxic effects of dioxin-like compounds (DLCs) varies up to 1000-fold among species, and this variability has been associated with interspecies differences in aryl hydrocarbon receptor 1 ligand-binding domain (AHR1 LBD) sequence. We previously showed that LD(50) values, based on in ovo exposures to DLCs, were significantly correlated with in vitro EC(50) values obtained with a luciferase reporter gene (LRG) assay that measures AHR1-mediated induction of cytochrome P4501A in COS-7 cells transfected with avian AHR1 constructs. Those findings suggest that the AHR1 LBD sequence and the LRG assay can be used to predict avian species sensitivity to DLCs. In the present study, the AHR1 LBD sequences of 86 avian species were studied, and differences at amino acid sites 256, 257, 297, 324, 337, and 380 were identified. Site-directed mutagenesis, the LRG assay, and homology modeling highlighted the importance of each amino acid site in AHR1 sensitivity to 2,3,7,8-tetrachlorodibenzo-p-dioxin and other DLCs. The results of the study revealed that (1) only amino acids at sites 324 and 380 affect the sensitivity of AHR1 expression constructs of the 86 avian species to DLCs and (2) in vitro luciferase activity of AHR1 constructs containing only the LBD of the species of interest is significantly correlated (r (2) = 0.93, p < 0.0001) with in ovo toxicity data for those species. These results indicate promise for the use of AHR1 LBD amino acid sequences independently, or combined with the LRG assay, to predict avian species sensitivity to DLCs. 23699973 Differential Exoproteome Analysis of Two Corynebacterium pseudotuberculosis Biovar Ovis Strains Isolated from Goat (1002) and Sheep (C231). Corynebacterium pseudotuberculosis is the etiologic agent of caseous lymphadenitis a chronic infectious disease affecting small ruminants. The 2D-DIGE technique was used to compare the exoproteomes of two C. pseudotuberculosis biovar ovis strains isolated from goat (strain 1002) and sheep (strain C231). Seventeen proteins differentially produced were identified here. Nine proteins appeared over-produced in the exoproteome of 1002 goat strain and 8 in that of C231 sheep strain. These proteins were related to various biological functions, such as the cell envelope, respiratory metabolism and proteolysis. This proteomic analysis revealed strain-specific exoproteins although each of the corresponding genes was found in both strain genomes. Such differential expression pattern may reflect inter-strain differences in adaptation to a specific host, in pathogenicity and or in antigenicity of this pathogenic bacterium. 23370472 DTI Values in Key White Matter Tracts from Infancy through Adolescence. DTI is an advanced neuroimaging technique that allows in vivo quantification of water diffusion properties as surrogate markers of the integrity of WM microstructure. In our study, we investigated normative data from a large number of pediatric and adolescent participants to examine the developmental trends in DTI during this conspicuous WM maturation period. DTI data in 202 healthy pediatric and adolescent participants were analyzed retrospectively. Fractional anisotropy and mean diffusivity values in the corpus callosum and internal capsule were fitted to an exponential regression model to delineate age-dependent maturational changes across the WM structures. The DTI metrics demonstrated characteristic exponential patterns of progression during development and conspicuous age-dependent changes in the first 36 months, with rostral WM tracts experiencing the highest slope of the exponential function. In contrast, the highest final FA and lowest MD values were detected in the splenium of the corpus callosum and the posterior limb of the internal capsule. Our analysis shows that the more caudal portions of the corpus callosum and internal capsule begin the maturation process earlier than the rostral regions, but the rostral regions develop at a more accelerated pace, which may suggest that rostral regions rely on development of more caudal brain regions to instigate their development. Our normative DTI can be used as a reference to study normal spatiotemporal developmental profiles in the WM and help identify abnormal WM structures in patient populations. 23554404 Effect of enzyme dehydration on alcalase-catalyzed dipeptide synthesis in near-anhydrous organic media. The effect of enzyme dehydration by molecular sieves on the coupling of phenylalanine amide and the carbamoylmethyl ester of N-protected phenylalanine in near-anhydrous tetrahydrofuran was investigated. This coupling was catalyzed by Alcalase covalently immobilized onto macroporous acrylic beads (Cov); these immobilized enzymes were hydrated prior to use. The dehydration kinetics of Cov by molecular sieve powder were determined by incubating Cov with different amounts of molecular sieve powder for different periods of time (0-80 h). Subsequently, the remaining coupling activity of Cov was measured. Dehydration-induced inactivation of Cov by molecular sieve powder was found to occur in three phases: (1) an initial, rapid, major dehydration-induced inactivation that takes place during the first activity measurement, (2) a phase of first-order inactivation, and (3) a plateau phase in activity. These dehydration kinetics were incorporated into a previously found reaction kinetics model. The resulting model was then used to fit progress curve data of the coupling in the presence of different amounts of molecular sieve powder. Upon establishment of parameter values, the model was used to predict independent data sets and found to work well. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 29:870-875, 2013. 23921618 Opportunities for sexual transmission of antiretroviral drug resistance among HIV-infected patients in care. To assess opportunities for transmitted drug resistance (TDR), we examined sexual risk behaviours, HIV viraemia and antiretroviral resistance among patients in care. A retrospective, cross-sectional analysis of clinical cohort data. For 244 UNC Center for AIDS Research HIV Clinical Cohort participants, demographic and behavioural data were obtained during in-person interviews between 2000 and 2011. Genotypic resistance tests were interpreted using WHO surveillance drug resistance mutations (SDRMs). Log-linear binomial regression was used to evaluate associations with TDR risk, defined as unprotected sex in the prior 6 months, HIV RNA at least 400 copies/ml and at least one SDRM. Participants included 91 (37%) women and 153 men, of whom 92 (60%) were MSM. Median age was 43 years; 70% were Black (n = 171). Most (97%) were antiretroviral-experienced; 44% had exposure to more than four regimens. Among 204 individuals on antiretrovirals, 42% reported suboptimal adherence and 29% were viraemic. Over half of participants had at least one SDRM (n = 131); 26 (11%) had triple-class resistance. Overall, 70% were sexually active, and 55% used condoms inconsistently. Thirty (12%) reported unprotected sex during periods of drug-resistant viraemia. Higher TDR risk was associated with prior homelessness [adjusted prevalence ratio (aPR) 2.20, 95% confidence interval (CI) 1.16-4.18], active substance use (aPR 3.12, 95% CI 1.47-6.62) and nonsignificantly with MSM (aPR 1.75, 95% CI 0.93-3.28). A small but significant proportion of clinic patients with drug-resistant HIV engage in sexual behaviours that place others at risk for TDR. Targeted efforts in secondary prevention could have an impact on TDR incidence, over time. 23869875 Adipose tissue PCB levels and CYP1B1 and COMT genotypes in relation to breast cancer risk in postmenopausal Danish women. Exposure to PCBs may be an etiologic factor for breast cancer. The cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) enzymes are involved in estrogen metabolism and PCB metabolism, both of which may relate to breast cancer susceptibility. Polymorphisms in genes regulating these enzymes control efficiency. Our objective was to assess whether CYP1B1 and COMT gene polymorphisms modulate the effect of PCBs in breast cancer risk, among postmenopausal Danish women. Neither CYP1B1 Leu432Val polymorphisms nor adipose tissue PCBs were independently associated with breast cancer risk. When assessing the independent effect of the COMT Val158Met polymorphism, we observed reduced risk for breast cancer amongst hormone replacement therapy using women who were homozygous carriers of the variant allele compared with those carrying the wild-type variant (RR = 0.41; 95% CI: 0.29-0.89). We found no statistically significant interactions between any of the PCB groups and CYP1B1 or COMT polymorphisms on the risk of breast cancer. 23918443 The predictive validity of a single leg bridge test for hamstring injuries in Australian Rules Football Players. Hamstring muscle strain injuries (HMSI) are the greatest injury problem in kicking sports such as Australian Rules Football. Reduced hamstring muscle strength is commonly perceived to be a risk factor for hamstring injury; however, evidence is inconclusive. Testing hamstring strength with the hip and knee at functional angles and assessing endurance parameters may be more relevant for examining the risk of hamstring injury. The primary aim of this prospective study was to examine if reduced hamstring muscle strength assessed with the single leg hamstring bridge (SLHB) was a risk factor for hamstring injury. Hamstring muscle strength of 482 amateur and semielite players from 16 football clubs, mean age 20.7 (range 16-34 years), was tested during the 2011 preseason. Players were then monitored throughout the 2011 playing season for HMSI. A total of 28 hamstring injuries, 16 right and 12 left, were recorded. Players who sustained a right HMSI during the season had a significantly lower mean right SLHB score (p=0.029), were older (p=0.002) and were more likely to have sustained a past right hamstring injury (p=0.02) or right knee injury (p=0.035). For left-sided hamstring injury, the injured group was more likely to be left leg dominant (p=0.001), older athletes (p=0.002) and there was a trend towards a history of left hamstring injury (p=0.07). This study demonstrated a significant deficit in preseason SLHB scores on the right leg of players that subsequently sustained a right-sided hamstring injury. Age, previous knee injury and a history of hamstring injury were other risk factors supported in this study. Low hamstring strength appears to be a risk factor for hamstring injury; however, due to the confounding variables and low injury rate in this study, further studies are required. 23836787 Phenological response of tundra plants to background climate variation tested using the International Tundra Experiment. The rapidly warming temperatures in high-latitude and alpine regions have the potential to alter the phenology of Arctic and alpine plants, affecting processes ranging from food webs to ecosystem trace gas fluxes. The International Tundra Experiment (ITEX) was initiated in 1990 to evaluate the effects of expected rapid changes in temperature on tundra plant phenology, growth and community changes using experimental warming. Here, we used the ITEX control data to test the phenological responses to background temperature variation across sites spanning latitudinal and moisture gradients. The dataset overall did not show an advance in phenology; instead, temperature variability during the years sampled and an absence of warming at some sites resulted in mixed responses. Phenological transitions of high Arctic plants clearly occurred at lower heat sum thresholds than those of low Arctic and alpine plants. However, sensitivity to temperature change was similar among plants from the different climate zones. Plants of different communities and growth forms differed for some phenological responses. Heat sums associated with flowering and greening appear to have increased over time. These results point to a complex suite of changes in plant communities and ecosystem function in high latitudes and elevations as the climate warms. 23619474 The relationship between FCN2 genotypes and serum ficolin-2 (L-ficolin) protein concentrations from a large cohort of neonates. The human FCN2 gene codes for ficolin-2 (L-ficolin), a major pattern recognition molecule and activator of the lectin pathway of complement. Seven single nucleotide polymorphisms of this gene were investigated in a large series of cord blood DNA samples. Mutations from the majority to the minority alleles at -602, -4 and +6359 were associated with an increase, while mutations at -986, -557, -64 and +6424 were associated with a decrease, in protein concentration. Full (7 loci) genotypes were obtained for 1229 unrelated neonates, 12 sets of twin siblings and one set of triplets. Forty-four separate genotypes were detected. Four genotypes accounted for more than half the unrelated neonates, and >90% had one of the 12 commonest genotypes. Genotypes were associated with significant differences in mean serum ficolin-2, but the intra-genotype concentration ranges were large and greater than the inter-genotype differences. Consequently, there were no associations between genotypes and low birthweight babies or perinatal infections, and only a weak relationship with preterm deliveries, despite all three adverse pregnancy features being significantly associated with serum ficolin-2 protein. FCN2 genotyping may be of value in clinical studies, but not as a substitute for total serum ficolin-2 protein measurement. 23872086 High molecular weight components of the injected venom of fish-hunting cone snails target the vascular system. The venom of marine cone snails is a rich source of pharmacotherapeutic compounds with striking target specificity and functional diversity. Small, disulfide-rich peptide toxins are the most well characterized active compounds in cone snail venom. However, reports on the presence of larger polypeptides have recently emerged. The majority of these studies have focused on the content of the dissected venom gland rather than the injected venom itself. Recent breakthroughs in the sensitivity of protein and nucleotide sequencing techniques allow for the exploration of the proteomic diversity of injected venom. Using mass spectrometric analysis of injected venoms of the two fish-hunting cone snails Conus purpurascens and Conus ermineus, we demonstrate the presence of angiotensin-converting enzyme-1 (ACE-1) and endothelin converting enzyme-1 (ECE-1), metalloproteases that activate potent vasoconstrictive peptides. ACE activity was confirmed in the venom of C. purpurascens and was significantly reduced in venom preincubated with the ACE inhibitor captopril. Reverse-transcription PCR demonstrated that these enzymes are expressed in the venom glands of other cone snail species with different prey preferences. These findings strongly suggest that cone snails employ compounds that cause disruption of cardiovascular function as part of their complex envenomation strategy, leading to the enhancement of neurotropic peptide toxin activity. To our knowledge, this is the first study to show the presence of ACE and ECE in the venom of cone snails. Identification of these vasoactive peptide-releasing proteases in the injected venoms of two fish-hunting cone snails highlights their role in envenomation and enhances our understanding of the complex hunting strategies utilized by these marine predators. Our findings on the expression of these enzymes in other cone snail species suggests an important biological role of ACE and ECE in these animals and points towards recruitment into venom from general physiological processes. 23657793 Clostridium Difficile Infection in Patients with HIV/AIDS. Clostridium difficile infection (CDI) affects significant numbers of hospitalized patients and is an increasing problem in the community. It is also among the most commonly isolated pathogens in HIV patients with diarrheal illness and is ≥2 fold more common in HIV-seropositive individuals. This association is stronger in those with low absolute CD4 T cell counts or meeting clinical criteria for an AIDS diagnosis, and was most pronounced before the wide availability of highly active antiretroviral therapy. The presentation and outcome of CDI in HIV appears similar to the general population. The increased risk can in part be attributed to increased hospitalization and antimicrobial use, but HIV related alterations in fecal microbiota, gut mucosal integrity, and humoral and cell mediated immunity are also likely to play a role. Here we review the evidence for these observations and the relevance of recent advances in the diagnosis and management of CDI for the HIV clinician. 23968307 Electrospray Ionization with Nanopipette Emitters with tip diameters of less than 100 nanometers. Work presented here demonstrates the ability of nanopipettes pulled to orifice diameters of less than 100 nanometers to function as electrospray ionization emitters for mass spectrometry. Mass spectrometric analysis of a series of peptides and proteins electrosprayed from pulled-quartz capillary nanopipette emitters with internal diameters ranging from 37-70 nm is detailed. Overall, the use of nanopipette emitters causes a shift towards the production of ions of higher charge states and leads to a reduction in width of charge-state distribution as compared to typical nanospray conditions. Further, nanopipettes show improved S/N and the same signal precision as typical nanospray, despite the much smaller dimensions. As characterized by SEM images acquired before and after spraying, nanopipettes are shown to be robust under conditions employed. Analytical calculations and numerical simulations are used to calculate the electric field at the emitter tip, which can be significant for the small diameter tips used. 23770211 Inhibition of protein kinase C βII isoform rescues glucose toxicity-induced cardiomyocyte contractile dysfunction: Role of mitochondria. Hyperglycemia leads to cytotoxicity in the heart. Although theories were postulated for glucose toxicity-induced cardiomyocyte dysfunction including oxidative stress, the mechanism involved still remains unclear. Recent evidence has depicted a role of protein kinase C (PKC) in diabetic complications while high concentrations of glucose stimulate PKC. This study examined the role of PKCβII in glucose toxicity-induced cardiomyocyte contractile and intracellular Ca(2+) aberrations. Adult rat cardiomyocytes were maintained in normal (NG, 5.5mM) or high glucose (HG, 25.5mM) medium for 12h. Contractile and intracellular Ca(2+) properties were measured using a video edge-detection system including peak shortening (PS), maximal velocity of shortening/relengthening (±dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR90), rise in intracellular Ca(2+) Fura-2 fluorescence intensity and intracellular Ca(2+) decay. Production of ROS/O2(-) and mitochondrial integrity were examined using fluorescence imaging, aconitase activity and Western blotting. High glucose triggered abnormal contractile and intracellular Ca(2+) properties including reduced PS, ±dL/dt, prolonged TR90, decreased electrically-stimulated rise in intracellular Ca(2+) and delayed intracellular Ca(2+) clearance, the effects of which were ablated by the PKCβII inhibitor LY333531. Inhibition of PKCβII rescued glucose toxicity-induced generation of ROS and O2(-), apoptosis, cell death and mitochondrial injury (reduced aconitase activity, UCP-2 and PGC-1α). In vitro studies revealed that PKCβII inhibition-induced beneficial effects were mimicked by the NADPH oxidase inhibitor apocynin and were canceled off by mitochondrial uncoupling using FCCP. These findings suggest the therapeutic potential of specific inhibition of PKCβII isoform in the management of hyperglycemia-induced cardiac complications. 23828311 A Tale of Two Rivers: Implications of Water Management Practices for Mussel Biodiversity Outcomes During Droughts. Droughts often pose situations where stream water levels are lowest while human demand for water is highest. Here we present results of an observational study documenting changes in freshwater mussel communities in two southern US rivers during a multi-year drought. During a 13-year period water releases into the Kiamichi River from an impoundment were halted during droughts, while minimum releases from an impoundment were maintained in the Little River. The Kiamichi observed nearly twice as many low-flow events known to cause mussel mortality than the Little, and regression tree analyses suggest that this difference was influenced by reduced releases. During this period mussel communities in the Kiamichi declined in species richness and abundance, changes that were not observed in the Little. These results suggest that reduced releases during droughts likely led to mussel declines in one river, while maintaining reservoir releases may have sustained mussel populations in another. 23378624 Pancreatic β-Cell Dysfunction and Risk of New-Onset Diabetes After Kidney Transplantation. OBJECTIVEChronic exposure to calcineurin inhibitors and corticosteroids poses renal transplant recipients (RTR) at high risk for development of new-onset diabetes after transplantation (NODAT). Pancreatic β-cell dysfunction may be crucial to the pathophysiology of NODAT and specific markers for β-cell dysfunction may have additive value for predicting NODAT in this population. Therefore, we prospectively investigated whether proinsulin, as a marker of pancreatic β-cell dysfunction, is associated with future development of NODAT and improves prediction of it.RESEARCH DESIGN AND METHODSAll RTR between 2001 and 2003 with a functioning graft for ≥1 year were considered eligible for inclusion, except for subjects with diabetes at baseline who were excluded. We recorded incidence of NODAT until April 2012.RESULTSA total of 487 RTR (age 50 ± 12 years, 55% men) participated at a median time of 6.0 (interquartile range [IQR], 2.6-11.5) years after transplantation. Median fasting proinsulin levels were 16.6 (IQR, 11.0-24.2) pmol/L. During median follow-up for 10.1 (IQR, 9.1-10.4) years, 42 (35%) RTR had development of NODAT in the highest quartile of the distribution of proinsulin versus 34 (9%) in the lowest three quartiles (P < 0.001). In Cox regression analyses, proinsulin (hazard ratio, 2.29; 95% confidence interval, 1.85-2.83; P < 0.001) was strongly associated with NODAT development. This was independent of age, sex, calcineurine inhibitors, prednisolone use, components of the metabolic syndrome, or homeostasis model assessment.CONCLUSIONSIn conclusion, fasting proinsulin is strongly associated with NODAT development in RTR. Our results highlight the role of β-cell dysfunction in the pathophysiology of NODAT and indicate the potential value of proinsulin for identification of RTR at increased risk for NODAT. 23902366 Effects of powder flow properties on capsule filling weight uniformity. Filling capsules with the right amount of powder ingredients is an important quality parameter. The purpose of this study was to develop effective laboratory methods for characterizing flow properties of pharmaceutical powder blends and correlating such properties to weight variability in filled capsules. The methods used for powder flow characterization were bulk and tapped density, gravitational displacement rheometer (GDR) flow index, Freeman Technology V.4 (FT4) powder rheometer compressibility, FT4 basic flow energy (BFE), and cohesion parameters [cohesion, (C) and flow factor (ffc)] measured in a shear cell also using the FT4. Capsules were filled using an MG2-G140 continuous nozzle dosator capsule-filling machine. Powder flow properties were the most predominant factors affecting the weight and weight variability in the filled capsules. Results showed that the weight variability decreased with increasing bulk and tapped density, ffc and BFE, while the weight variability increased with increasing compressibility, cohesion and GDR flow index. Powder flow properties of the final blends were significantly correlated to the final capsule weight and weight variability of the filled capsules. 23245854 Medical complication in adults with spina bifida. Cohort study. Spina bifida (SB) is a congenital malformation affecting the central nervous system (CNS) and is one of the most prevalent CNS disorders in children. Hydrocephalus (HC) is present in 80% of newborns with SB. The aim of the present study was to analyze the medical complications and to relate the complications to age at examination, the level of injury, AIS grade and presence of HC in adults with SB. SB patients were recruited from the Spinalis out-patient clinic at the Karolinska University Hospital at their annual follow-up. The patients underwent a thorough general and neurological examination and background data including medical complications were retrieved from the medical files. 127 of 157 (82%) SB patients (114 with MMC and 13 SB occulta) with a mean age of 34 years were included. Half of the patients had a complete SCI and a lumbar level was most common. Nearly 60% of the patients had HC. 88 patients (69%) suffered from at least one medical complication. Urinary tract infection (UTI), scoliosis and pain were the most common complications found in 46%, 30% and 28% of the patients, respectively. Less common complications were epilepsy, pressure ulcers (PU) and spasticity. SB gives a disability including motor, sensory dysfunctions and the patients suffer from a high frequency of medical complications like UTI, scoliosis, pain, and epilepsy. Data gives basis for adequate routines for medical examination at the follow-up. 23849208 Cholestasis induces reversible accumulation of periplakin in mouse liver. Periplakin (PPL) is a rod-shaped cytolinker protein thought to connect cellular adhesion junctional complexes to cytoskeletal filaments. PPL serves as a structural component of the cornified envelope in the skin and interacts with various types of proteins in cultured cells; its level decreases dramatically during tumorigenic progression in human epithelial tissues. Despite these intriguing observations, the physiological roles of PPL, especially in non-cutaneous tissues, are still largely unknown. Because we observed a marked fluctuation of PPL expression in mouse liver in association with the bile acid receptor farnesoid X receptor (FXR) and cholestasis, we sought to characterize the role of PPL in the liver and determine its contributions to the etiology and pathogenesis of cholestasis. Time- and context-dependent expression of PPL in various mouse models of hepatic and renal disorders were examined by immunohistochemistry, western blotting, and quantitative real-time polymerase chain reactions. The hepatic expression of PPL was significantly decreased in Fxr-/- mice. In contrast, the expression was dramatically increased during cholestasis, with massive PPL accumulation observed at the boundaries of hepatocytes in wild-type mice. Interestingly, the hepatic accumulation of PPL resulting from cholestasis was reversible. In addition, similar accumulation of PPL at cellular boundaries was found in epithelial cells around renal tubules upon ureteral obstruction. PPL may be involved in the temporal accommodation to fluid stasis in different tissues. Further examination of the roles for PPL may lead to the discovery of a novel mechanism for cellular protection by cytolinkers that is applicable to many tissues and in many contexts. 23531593 Active caspase-3 is removed from cells by release of caspase-3-enriched vesicles. Cleavage of Rho associated Coiled Coil kinase I (ROCK I) by caspase-3 contributes to membrane blebbing. Whether caspase-3 and ROCK I also play a role in the release of membrane vesicles is unknown. Therefore, we transfected a human breast cancer cell line (MCF-7) that is caspase-3 deficient, lacks membrane blebbing, and does not release membrane vesicles, with caspase-3. Cells expressing caspase-3 demonstrate both ROCK I-mediated membrane blebbing, and release of small (400-600nm) membrane vesicles in a ROCK I-independent manner. These membrane vesicles contain caspase-3, and are enriched in caspase-3 activity compared to the releasing cells. Caspase-3-containing vesicles are taken up by untransfected cells but the cells do not show any sign of apoptosis. In conclusion, we show that the release of caspase-3-enriched membrane vesicles and membrane blebbing are two differentially regulated processes. Furthermore, we hypothesize that packaging of caspase-3 into membrane vesicles contributes to cellular homeostasis by the removal of caspase-3, and concurrently, protects the cells' environment from direct exposure to caspase-3 activity. 23578615 Characterization of Muscat wines aroma evolution using comprehensive gas chromatography followed by a post-analytic approach to 2D contour plots comparison. This study presents the application of a headspace solid-phase microextraction (HS-SPME) method on the analysis of Muscat-based wines volatiles by comprehensive two-dimensional gas chromatography (GC×GC) and Time-Of-Flight mass spectrometry (TOF-MS). The aroma patterns were established for different samples of Asti Spumante and Moscato d'Asti wines, stored in bottles for 6months at different temperatures. Wines stored at 5°C for 6months did not show significant changes in flavor; otherwise, the samples stored at 15 and 25°C, showed a significant decrease in linalool, β-damascenone, ethyl hexanoate, and ethyl octanoate levels. In these last samples, α-terpineol, hotrienol, nerol oxide, furanic linalool oxides A/B and rose oxide concentrations significantly increased. A mathematical approach was developed and applied to raw data exported after the chromatographic course, in order (i) to normalise different 2D chromatograms, permitting their direct comparison and (ii) to automatically identify and calculate from pixel-to-pixel re-designed 2D chromatograms any differences among key volatile compounds. 23328331 Transcranial direct current stimulation (tDCS) relieved itching in a patient with chronic neuropathic pain. Itching is often called the second modality of nociception besides pain, and affects many chronic pain patients. This case report presents a first note on beneficial effects of transcranial direct current stimulation (tDCS) on itching associated with chronic neuropathic pain in a patient diagnosed with syringomyelia. tDCS is a novel noninvasive neuromodulatory method with promising therapeutic potential in pain and symptom management. The primary mechanism of tDCS is subthreshold modulation of the neuronal resting membrane potential that induces a polarity-dependent modification of N-Methyl-D-aspartate receptor function that plays a role in neuroplasticity. The patient, a 46-year-old white male diagnosed with syringomyelia 2 decades ago, continuously reported weakness in the arms and dyesthesias including pain and itch that fluctuated in severity. Pharmacological treatment with baclofen, duloxetine, and bupropion was partially helpful; however, did not prevent flares of pain and other dysesthesias, including itch. The patient underwent 3 tDCS treatment courses consisting of 20 minutes of tDCS on 5 consecutive days at each course over 13 months. Although there was no change in pain intensity or quality during or after tDCS, the treatment resulted in a reduction in itch to a mild, tolerable intensity that persisted for 3 to 4 months after each course, before returning to the pretreatment level. The patient has agreed to a plan of care that will incorporate neurostimulation every 4 to 6 months, as long as its effectiveness continues. This case provides a rationale for future studies of neuromodulatory treatments for itch, and indicates a potential clinical use of neuromodulation in patients with unrelieved itching. 23900404 Movement Scaling in Children With ADHD-Combined Type. Objective: The aim of the study was to investigate motor performance in children with ADHD using a size-scaling handwriting task. Method: In all, 14 male children with ADHD and 14 typically developing (TD) children (age 7-15) wrote 10-mm and 40-mm cursive letter "l." Results: Children with ADHD were unable to maintain their writing accurately at 40 mm, falling short by several millimeters; this was not evident in the TD children. Children with ADHD also had slightly faster and more fluent writing than TD children. Conclusion: It was concluded that children with ADHD have difficulties scaling handwriting movement in the larger 40-mm condition that may reflect poor planning and modulation of movement, despite having faster and more fluent movements.(J. of Att. Dis. 2013; XX(X) 1-XX). 23726539 Comparative genotoxicity of airborne particulate matter (PM2.5) using Salmonella, plants and mammalian cells. This study compared genotoxicity in bacteria, plants and cell cultures in areas at risk of exposure to airborne pollution. Genotoxicity of moderately polar organic extracts of PM2.5 from areas with urban airborne pollution (Site 1) and urban-industrial pollution (Site 2) was evaluated using microsuspension assays in Salmonella/microsome, micronucleus test with Tradescantia pallida (Trad-MN) with acute exposure, and in V79 (V79-MN) cells, Comet assay in V79 and human lymphocyte, besides Trad-MN in situ at Site 1. In the Salmonella/microsome assay all samples presented frameshift mutagenic activity (-/+S9), most intense at Site 2 (rev/m(3)). The presence of nitro-PAHs and hydroxylamines in PM2.5 was shown by positive mutagenic responses with YG1021 and YG1024. In tests with Trad-MN, no significant genotoxic responses were found (MN %). In V79-MN a genotoxic response was not found. The Comet assay damages were found in the DNA at Site 1 in both cell systems. Non-detection of genotoxicity with Trad-MN at sites or in environmental samples from polluted areas detected using other biomarkers suggests the need for careful evaluation when biomonitoring genotoxic compounds using plants. The microsuspension assay in Salmonella/microsome was sensitive to detect and identify different classes of airborne mutagenic compounds present in fine particulate matter in Porto Alegre city, showing that monitoring air quality with PM2.5 using this methodology is relevant. 23924714 Oxidative Stress during Development of Alcoholic Fatty Liver: Therapeutic Potential of Cacao Polyphenol. The lipid and antioxidative/oxidative profiles of livers from rats fed an ethanol liquid diet for 8 weeks provided evidence for an involvement of oxidative stress (e.g., phospholipid peroxidation) in the development of alcoholic fatty liver (AFL), possibly in an early stage. Cacao polyphenol supplementation produced an ameliorating effect, and may help in AFL prevention. 23899995 Hypomethylation of neuregulin in rats selectively bred for reduced sensorimotor gating. Low prepulse inhibition (PPI) of startle is associated with reduced sensorimotor gating found in schizophrenia. In rats with breeding-induced low PPI neuregulin (NRG1) methylation was significantly decreased in brain regions associated with this phenotype and with schizophrenia, i.e., the medial prefrontal cortex, the nucleus accumbens, and the ventral hippocampus, while methylation in the amygdala and dorsal hippocampus was less affected. The dopamine D2 receptor (DRD2) promoter region showed negligible changes between groups. Rats with low PPI may be used to understand the reduced epigenetic regulation found in schizophrenia, and eventually lead to the development of novel therapies. 23844777 Theoretical analysis of microtubules dynamics using a physical-chemical description of hydrolysis. Microtubules are cytoskeleton multifilament proteins that support many fundamental biological processes such as cell division, cellular transport, and motility. They can be viewed as dynamic polymers that function in nonequilibrium conditions stimulated by hydrolysis of GTP (guanosine triphosphate) molecules bound to their monomers. We present a theoretical description of microtubule dynamics based on discrete-state stochastic models that explicitly takes into account all relevant biochemical transitions. In contrast to previous theoretical analysis, a more realistic physical-chemical description of GTP hydrolysis is presented, in which the hydrolysis rate at a given monomer depends on the chemical composition of the neighboring monomers. This dependence naturally leads to a cooperativity in the hydrolysis. It is found that this cooperativity significantly influences all dynamic properties of microtubules. It is suggested that the dynamic instability in cytoskeleton proteins might be observed only for weak cooperativity, while the strong cooperativity in hydrolysis suppresses the dynamic instability. The presented microscopic analysis is compared with existing phenomenological descriptions of hydrolysis processes. Our analytical calculations, supported by computer Monte Carlo simulations, are also compared with available experimental observations. 23561129 Croton lechleri Müll. Arg. (Euphorbiaceae) stem bark essential oil as possible mutagen-protective food ingredient against heterocyclic amines from cooked food. The Amazonian Croton lechleri stem bark essential oil was tested for its anti-mutagenic potential by performing the Ames test against heterocyclic amines (HCAs), in continuing research on applicative functional profile of this phytocomplex as food ingredient (Rossi et al., 2011). Salmonella typhimurium strain TA98 was used with and without metabolic activation (S9 mix). The anti-mutagenic properties was assayed with the following HCAs: 2-amino-3-methylimidazo-[4,5-f]quinoline (IQ), 2-amino-3,4-dimethylimidazo-[4,5-f]quinoline (MeIQ), 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline (MeIQx), the imidazoles 2-amino-6-methyldipyrido-[1,2-a:3',2'-d]imidazole (Glu-P-1) and 2-aminodipirydo-[1,2-a:3',2'-d]imidazole (Glu-P-2). All HCAs with S9 induced mutagenicity at 10(-10)mol/plate. Without S9, IQ and MeIQ showed mutagenicity at 10(-8)mol/plate, MeIQx and Glu-P-1 at 10(-5)mol/plate, while Glu-P-2 was inactive. In presence of HACs (10(-9)mol/plate), C. lechleri essential oil was tested for mutagen-protective properties (concentration range: 0.01-0.10mg/plate) taking the Highest Uneffective Dose (HUD) as threshold reference. With S9 mix, C. lechleri essential oil displayed a significant reduction of revertants at 0.05mg/plate, from 21% to 34%. The essential oil showed mutagen-protective efficacy against IQ and MeIQ tested as direct mutagens (10(-7)mol/plate), with a revertants percentage reduction of 39% and 40%, respectively. No anti-mutagen capacity was noted for MeIQx and Glu-P-1 (10(-5)mol/plate). Since HACs are known as possible colon and liver cancer inducers, C. lechleri essential oil was tested for its cytotoxicity and anti-proliferative capacity against LoVo and HepG2 cancer cell lines showing IC50 of 74.95±0.05μg/ml (LoVo) and 82.28±0.03μg/ml (HepG2), displaying a promising role of this essential oil as a functional food ingredient with interesting mutagen preventing properties. 23846588 Overcoming Addictions, a Web-Based Application, and SMART Recovery, an Online and In-Person Mutual Help Group for Problem Drinkers, Part 1: Three-Month Outcomes of a Randomized Controlled Trial. Overcoming Addictions (OA) is an abstinence-oriented, cognitive behavioral, Web application based on the program of SMART Recovery. SMART Recovery is an organization that has adapted empirically supported treatment strategies for use in a mutual help framework with in-person meetings, online meetings, a forum, and other resources. To evaluate the effectiveness of OA and SMART Recovery (SR) with problem drinkers who were new to SMART Recovery. Our experimental hypotheses were: (1) all groups will reduce their drinking and alcohol/drug-related consequences at follow-up compared to their baseline levels, (2) the OA condition will reduce their drinking and alcohol/drug-related consequences more than the control group (SR), and (3) the OA+SR condition will reduce their drinking and alcohol/drug-related consequences more than the control group (SR only). We recruited 189 heavy problem drinkers primarily through SMART Recovery's website and in-person meetings throughout the United States. We randomly assigned participants to (1) OA alone, (2) OA+attend SMART Recovery (SR) meetings (OA+SR), or (3) attend SR only. Baseline and follow-ups were conducted via GoToMeeting sessions with a Research Assistant (RA) and the study participant. We interviewed significant others to corroborate the participant's self-report. Primary outcome measures included percent days abstinent (PDA), mean drinks per drinking day (DDD), and alcohol/drug-related consequences. The intent-to-treat analysis of the 3-month outcomes supported the first hypothesis but not the others. Participants in all groups significantly increased their percent days abstinent from 44% to 72% (P<.001), decreased their mean drinks per drinking day from 8.0 to 4.6 (P<.001), and decreased their alcohol/drug-related problems (P<.001). Actual use relationships were found for the OA groups, between SR online meetings and improvement in PDA (r=.261, P=.033). In addition in the OA groups, the number of total sessions of support (including SR & other meetings, counselor visits) was significantly related to PDA (r=.306, P=012) and amount of improvement in alcohol-related problems (r=.305, P=.012). In the SR only group, the number of face-to-face meetings was significantly related to all three dependent variables, and predicted increased PDA (r=.358, P=.003), fewer mean DDD (r=-.250, P=.039), and fewer alcohol-related problems (r=-.244, P=.045), as well as to the amount of improvement in all three of these variables. Six-month follow-ups have been completed, and the results are currently being analyzed. These results support our first experimental hypothesis but not the second or third. All groups significantly increased their PDA and decreased both their mean DDD and their alcohol-related problems, which indicates that both interventions being investigated were equally effective in helping people recover from their problem drinking. Clinicaltrials.gov NCT01389297; http://clinicaltrials.gov/ct2/show/NCT01389297 (Archived by WebCite at http://www.webcitation.org/6Hh5JC7Yw). 23386417 Androgen Receptor mRNA Measured by Quantitative Real Time PCR is Decreased in the Urethral Mucosa of Patients with Middle Idiopathic Hypospadias. Androgen action is exerted through the androgen receptor. The normal 46,XY genital virilization depends on androgen receptor gene expression, which is tissue specific, and requires normal androgen receptor mRNA levels in androgen sensitive tissues. Hypospadias is a frequent male genital abnormality, potentially related to reduced androgen sensitivity in genital tissues. The aim of this study was to compare, by quantitative real time PCR, the amount of androgen receptor mRNA in cells obtained from the urethral mucosa of patients with middle idiopathic hypospadias with the androgen receptor mRNA levels observed in control phimosis subjects with eutopic urethral opening. Prepubertal individuals were studied, including 41 controls and 17 hypospadias patients with mean (SD) ages of 4.7 (2.1) years and 4.0 (3.0) years, respectively. We observed significantly less androgen receptor mRNA in the urethral mucosa of patients with hypospadias than in the controls (p=0.002). The correlation between the level of androgen receptor mRNA expression and the penile size was almost statistically significant only in hypospadias patients (r=0.47; p=0.053). We also established the number of CAG repeats in exon 1 of the androgen receptor gene by GeneScan analysis. No significant difference was observed in the number of CAG repeats when patients and controls were compared. A negative correlation between the CAG repeats and penile size was detected in patients with hypospadias, but not in controls. Our data suggest that a critical lower level of androgen receptor mRNA expression could be a determining factor in the development of middle hypospadias. 23293885 BIBR 1532 Increases Arsenic Trioxide-mediated Apoptosis in Acute Promyelocytic Leukemia Cells: Therapeutic Potential for APL. The current treatment of acute promyelocytic leukemia with arsenic trioxide (ATO) has increased long-lasting complete remissions; however, a proportion of patients continues to die eventually as a result of disease recurrence. In an effort to enhance the effectiveness of the APL treatment, we designed experiments to evaluate the effects of ATO in combination with the lead compound of non-nucleoside inhibitor of telomerase, BIBR 1532. After combined treatments with BIBR 1532 and ATO, decreased cell viability index with a concomitant increase in apoptotic cell death was observed in NB4 leukemic cells. Apoptosis induced by the combined treatments was accompanied by elevated Bax/Bcl-2 molecular ratio and enhanced caspase 3 activation. Our study has also demonstrated that the combined treatment suppressed NB4 cell proliferative capacity and inhibited telomerase activity probably via transcriptional suppression of c-Myc and hTERT. In conclusion, this study may supply insight into the application of this new combination therapy to APL cells intrinsically less sensitive to routine therapies and suggested a novel combination therapy for patients with more aggressive disease; those who may not respond favorably to the arsenic mono-therapy. 23727809 Antibacterial effect of amentoflavone and its synergistic effect with antibiotics. Selaginella tamariscina is a traditional herb used in medicine. Phytochemical amentoflavone, a biflavonoid class of flavonoids, was isolated from the plant of Selaginella tamariscina. In this study, the antibacterial effects and combination effects of amentoflavone and conventional antibiotics such as ampicillin, cefotaxime, and chloramphenicol were investigated. These results showed that amentoflavone had a considerable antibacterial effect and synergistic interaction with antibiotics against various bacterial strains (fractional inhibitory concentration index ≤ 0.5), except for Streptococcus mutans. To study the mechanism(s) involved in the synergistic activities between amentoflavone and antibiotics, we detected hydroxyl radical formation using 3'-(p-hydroxyphenyl) fluorescein and measured the NAD(+)/NADH ratio by NAD(+) cycling assay. The results indicated that the formation of hydroxyl radical would be a cause of the synergistic effect and that this oxidative stress originated from a transient NADH depletion. This study suggests that amentoflavone synergizes with antibiotics and has potential as a therapeutic agent for antimicrobial chemotherapy. 23922446 The functional effects of color perception and color imagery. Functional imaging research and studies of brain-damaged patients suggest the mechanisms of color perception and color imagery have some degree of overlap. Previous research into color imagery has focused on compound images consisting of both color and form, e.g., whole objects. Little is known regarding the characteristics of pure color imagery-color without form structure. Binocular rivalry has proven to be a successful method for assessing mental imagery indirectly, quantitatively, and reliably. Here, we utilized this technique to access pure color imagery. Experiment 1 consisted of three conditions, in which participants were instructed to either imagine pure colors according to a letter cue, imagine pure colors in the presence of background luminance, or passively view weak perceptual color patches. Subsequently, a brief rivalry display was presented. Results indicated that perceptual dominance during rivalry was significantly biased by the participants' prior color imagery and perception. However, for imagery, the addition of background luminance attenuated this priming effect. In Experiment 2, we tested whether color imagery was location-specific in retinotopic space. Color imagery was only found to prime subsequent rivalry when the imagery and rivalry stimuli occurred at the same retinotopic location. These results demonstrate that imagery of pure colors without form structure can influence subsequent color perception and can be localized in retinotopic space. These results are consistent with previous studies examining mental imagery of compound visual stimuli and demonstrate the potential of investigations into mental imagery of individual visual features. 23368742 Successful closing of duodenal ulcer after endoscopic submucosal dissection with over-the-scope clip to prevent delayed perforation. Closure of post-endoscopic submucosal dissection (ESD) duodenal artificial ulcer is not common in the clinical setting. We consider that post-ESD ulcer closure by an over-the-scope-clip (OTSC) method is one of the most effective ways to prevent delayed perforation. We report here two cases of mucosal duodenal cancer in a 65-year-old woman and in a 78-year-old man. Pathological examinations of the resected specimens revealed well-differentiated adenocarcinomas. In these two clinical cases, we successfully carried out complete closures of post-ESD duodenal ulcer using OTSC without any complications. 23794643 Challenges in design and interpretation of chronic pain trials. The process of systematic review has shone a light on the methodology of randomized controlled trials. Notably, a range of potential biases hinders the interpretation of chronic pain trials. These include a consistent bias favouring active over placebo in trials that are small and of short duration. The use of the 'last observation carried forward' imputation method is known to inflate results, often generating statistically significance when adverse event withdrawals are high; in clinical practice terms, this is the wrong answer. Patients want outcomes of low pain scores, large reductions in pain and relief from associated symptoms, with improvements in ability to function and in quality of life. Some patients achieve this, but many do not. The distribution of benefit is skewed and the use of average pain scores, or change in pain, can be misleading compared with responder analysis in which withdrawal is regarded as non-response. Historically, chronic pain trials have had a simple classic or a crossover design. They have been small and short, and used inappropriate imputation and outcomes unconnected to the experiences of most patients. While these designs are useful for answering some questions, they may be insensitive for many interventions. Newer designs, like enriched enrolment randomized withdrawal (EERW) trials or clinical effectiveness trials, are potentially more interesting and informative. 23648522 Nutritional quality of major meals consumed away from home in Brazil and its association with the overall diet quality. The objective of the study is to evaluate the nutritional quality of meals consumed away from home and its association with overall diet quality. Data was obtained from 834 participants of a Health Survey in São Paulo, Brazil. Food intake was measured by a 24-hour dietary recall applied telephonically using the Automated Multiple-Pass Method. Overall dietary quality was assessed by the Brazilian Healthy Eating Index Revised (B-HEIR) and the Meal Quality Index (MQI) was used to evaluate dietary quality of the main meals. The association between the B-HEIR and the MQI was assessed by linear regression analysis. The consumption of at least one of the three main meals away from home was reported for 32% of respondents (70 adolescents, 156 adults and 40 elderly). The average MQI score of lunch consumed away from home was lower than lunch consumed at home, with higher amounts of total and saturated fats. The average score of B-HEIR was 58 points and was associated with the MQI score, energy, meal consumption location and gender. Lunch consumed away from home presented the worst quality, being higher in total and saturated fat. However, the meals consumed at home also need improvement. 23659489 Heart rate variability parameters do not correlate with pain intensity in healthy volunteers. When patients cannot indicate pain, physiological parameters may be useful. We tested whether heart rate variability (HRV) parameters, as reflection of sympathetic and vagal tone, can be used to quantify pain intensity. Prospective study. A standardized heat stimulus was applied to the forearm in 75 healthy volunteers during three study periods of 2 minutes. Before and after each application, pain intensity was measured by a visual analog scale (VAS) and inter beat interval (IBI) was recorded. Standard deviation of normal to normal beat intervals (SDNN) of the IBI, the power of the low (LF, 0.07-0.14 Hz) and high frequency (HF, 0.15-0.50 Hz) band, and LF/HF ratio were calculated. Log transformation resulted in normal distribution. Correlation between HRV parameters and pain intensity was assessed by Pearson's correlation coefficient. Data from 73 volunteers (44 women) could be analyzed. The mean age was 30 ± 11 years. Compared with baseline, during all heat periods, pain intensity measured by VAS increased from 2 ± 3 mm, 3 ± 5 mm, and 2 ± 4 mm, to 40 ± 20 mm, 42 ± 21 mm, and 44 ± 22 mm, respectively. Log transformed SDNN (lnSDNN) and LF (lnLF) decreased; lnSDNN from 4.0 ± 0.4 to 3.9 ± 0.5, P = 0.002; 4.0 ± 0.4 to 3.9 ± 0.5, P = 0.016; and 4.1 ± 0.4 to 3.9 ± 0.4, P = 0.004, respectively; lnLF from 6.3 ± 1.0 to 6.1 ± 1.2, P = 0.001; 6.4 ± 1.0 to 6.2 ± 1.1, P = 0.019; and 6.5 ± 1.0 to 6.2 ± 1.1, P = 0.020, respectively. No correlation of any HRV parameter with VAS score was found. HRV parameters may detect responses to heat pain, but are not suitable to assess pain intensity. 23871923 Biotransformation of benzimidazole anthelmintics in reed (Phragmites australis) as a potential tool for their detoxification in environment. Benzimidazole anthelmintics, the drugs against parasitic worms, are widely used in human as well as veterinary medicine. Following excretion, these substances may persist in the environment and impact non-target organisms. In order to test phytoremediation as a possible tool for detoxification of anthelmintics in environment, the biotransformation pathways of albendazole (ABZ) and flubendazole (FLU) were studied in reed (Phragmites australis) in vitro. Reed cells were able to uptake and biotransform both anthelmintics. Ten ABZ metabolites and five FLU metabolites were found. Some atypical biotransformation reactions (formation of glucosylglucosides, acetylglucosides and xylosylglucosides), which have not been described previously, were identified. Based on the obtained results, the schemes of metabolic pathways of ABZ and FLU in reed were proposed. Most of ABZ and FLU metabolites can be considered as anthelmintically less active; therefore uptake and biotransformation of these anthelmintics by reed could be useful for decrease of their toxicity in environment. 22736379 Pinosylvin Induces Cell Survival, Migration and Anti-Adhesiveness of Endothelial Cells via Nitric Oxide Production. Pinosylvin is a phenolic compound mainly found in the Pinus species. To determine the vascular functions of pinosylvin, we first examined both proliferation and apoptosis of bovine aortic endothelial cells (BAECs) in the presence of pinosylvin. When BAECs were treated with pinosylvin, etoposide- or starvation-induced apoptosis was shown to be significantly reduced. The anti-apoptotic effect of pinosylvin was mediated by inhibition of caspase-3. Moreover, pinosylvin was shown to activate endothelial nitric oxide synthetase (eNOS). At 1 pM, pinosylvin appeared to have a cell-proliferative effect in the endothelial cell. The pinosylvin-induced cell proliferation was declined by treatment with L-NAME, an eNOS inhibitor. Then, we found that pinosylvin had a stimulatory effect on cell migration and tube formation. These stimulatory effects suggest that pinosylvin is likely to act as a pro-angiogenic factor. Yet another effect of pinosylvin was inhibition of lipopolysaccharide-induced THP-1 cell adhesion to endothelial cells. Altogether, we propose that pinosylvin may be utilized as a phytotherapic agent for the prevention of cardiovascular inflammatory diseases. Copyright © 2012 John Wiley & Sons, Ltd. 23373510 Conventional xylene and xylene-free methods for routine histopathological preparation of tissue sections. Xylene customarily has been used as a clearing agent for routine tissue processing. Because xylene is a relatively hazardous solvent, laboratories are under pressure to seek less toxic alternatives for routine use. We prepared 30 paired soft tissue specimens for routine histopathological evaluation using conventional xylene and xylene-free methods to evaluate and compare their efficacy for fixation, processing, embedding, staining and turnaround time. All specimens were measured before and after processing. Three pathologists evaluated and scored the histological sections. Tissue shrinkage was greater when using the xylene method compared to the xylene-free method. The quality of tissue sections including tissue architecture; quality of staining; preservation of epithelial, fibrous, glandular, muscle and adipose tissue; inflammatory cells; and vascular tissue was better after using the xylene method, but differences were not statistically significant. Xylene-free method produced adequate results that nearly equaled the xylene method. Added advantages included cost effectiveness, better working atmosphere and decreased toxicity. 23760243 Characterization of a Critical Interaction between the Coronavirus Nucleocapsid Protein and Nonstructural Protein 3 of the Viral Replicase-Transcriptase Complex. The coronavirus nucleocapsid protein (N) plays an essential structural role in virions through a network of interactions with positive-strand viral genomic RNA, the envelope membrane protein (M), and other N molecules. Additionally, N protein participates in at least one stage of the complex mechanism of coronavirus RNA synthesis. We previously uncovered an unanticipated interaction between N and the largest subunit of the viral replicase-transcriptase complex, nonstructural protein 3 (nsp3). This was found through analysis of revertants of a severely defective mutant of murine hepatitis virus (MHV) in which the N gene was replaced with that of its close relative, bovine coronavirus (BCoV). In the work reported here, we constructed BCoV chimeras and other mutants of MHV nsp3 and obtained complementary genetic evidence for its association with N protein. We found that the N-nsp3 interaction maps to the amino-terminal ubiquitin-like domain of nsp3, which is essential for the virus. The interaction does not require the adjacent acidic domain of nsp3, which is dispensable. In addition, we demonstrated a complete correspondence between N-nsp3 genetic interactions and the ability of N protein to enhance the infectivity of transfected coronavirus genomic RNA. The latter function of N was shown to depend on both of the RNA-binding domains of N, as well as on the serine- and arginine-rich central region of N, which binds nsp3. Our results support a model in which the N-nsp3 interaction serves to tether the genome to the newly translated replicase-transcriptase complex at a very early stage of infection. 23651847 Exercise training improves cutaneous microvascular function in nonalcoholic fatty liver disease. The leading causes of mortality in nonalcoholic fatty liver disease (NAFLD) relate to cardiovascular disease (CVD). The contribution of nitric oxide (NO) to endothelial function, a surrogate of CVD risk, is currently unknown in NAFLD. We hypothesize that NO-mediated cutaneous microvessel function would be impaired in NAFLD compared with controls and that exercise would enhance microvessel function compared with conventional care. Thirteen NAFLD patients (aged 50 ± 3 yr, BMI 31 ± 1 kg/m²) and seven controls (48 ± 4 yr, 30 ± 2 kg/m²) were studied. NAFLD patients were randomized to either 16 wk of exercise or conventional care. Cutaneous microvessel function was examined using laser Doppler flowmetry combined with intradermal microdialysis of N(G)-monomethyl-l-arginine to assay the NO dilator response to local forearm heating. Magnetic resonance imaging and spectroscopy quantified abdominal and liver fat, respectively, and cardiorespiratory fitness was assessed. Differences in NO contribution to cutaneous blood flow between NAFLD and control individuals and between interventions were analyzed using general linear modeling. NO contribution to cutaneous blood flow was similar between NAFLD and controls (P = 0.47). Cardiorespiratory fitness was greater following exercise training compared with conventional care. NO contribution to cutaneous blood flow in response to heating at 42°C was 20.4% CVCmax (95% CI = 4.4, 36.4) greater following exercise training compared with conventional care (P = 0.02). Exercise training improves cutaneous microvascular NO function in NAFLD patients. The benefit of exercise training compared with conventional care strongly supports a role for exercise in the prevention of CVD in NAFLD. 22544889 Root repair after contact with mini-implants: systematic review of the literature. This systematic review identified and qualified the current evidence of dental root damage and repair after contact with mini-implants. The electronic databases Cochrane library, Ovid, Scirus, Scopus, and Virtual Health Library were used to search original articles from 1980 to December 2011. The inclusion criteria to select the articles were 1. randomized controlled trials and prospective clinical studies based on trials involving humans, 2. randomized controlled studies in animals, 3. use of mini-implants with a diameter less than 2.5 mm, and 4. root contact evaluation associated with the use of orthodontic mini-implants. Two authors independently reviewed and extracted data from the selected studies and a methodological quality assessment process was used to rank the studies classifying them as low moderate or high quality. The searches retrieved 579 citations. After initial selection, 17 studies were considered eligible and their full texts were assessed. Four of those were excluded because root damage was not evaluated and two were excluded because of overlapping samples. Eleven articles, nine in animals and two in humans, fulfilled the inclusion criteria. From these, two studies were ranked as presenting high methodological quality, eight were judged to be of moderate, and one of low quality. The evidence found suggested that the quality of root repair depends on the amount of damage caused by the mini-implant. When the damage is limited to the cementum or dentin, healing and almost complete and repair of the periodontal structure can occur. Mini-implants that injured the pulp were less likely to result in complete repair of the periodontal tissues. 23273751 Endophytic fungi from Miquelia dentata Bedd., produce the anti-cancer alkaloid, camptothecine. Camptothecine (Campothecin, CPT), a quinoline alkaloid, is a potent inhibitor of eukaryotic topoisomerase I. Several semi-synthetic derivatives of CPT are in clinical use against ovarian, small lung and refractory ovarian cancers. While CPT is produced by several plant species belonging to the Asterid clade, in recent years, efforts have been made to isolate endophytic fungi from some of these plants as possible alternative sources of CPT. In this study we report the isolation of three endophytic fungi from fruit and seed regions of Miquelia dentata (Icacinaceae), that produce CPT, 9-methoxy CPT (9-MeO-CPT) and 10-hydroxy CPT (10-OH-CPT). All the three fungi identified as, Fomitopsis sp. P. Karst (MTCC 10177), Alternaria alternata (Fr.) Keissl (MTCC 5477) and Phomposis sp. (Sacc.) produced CPT, 9-MeO-CPT and 10-OH-CPT in mycelial mats in shake flasks containing potato dextrose broth. Methanolic and ethyl acetate extracts of these fungal species were cytotoxic to colon and breast cancer cell lines. We discuss these results in the context of the recent interest in endophytic fungi as possible alternative sources of plant secondary metabolites. 23833088 The potential for antimicrobials to adversely affect mental state. This is a case report highlighting the influence that antimicrobials (clarithromycin in particular) can have on one's mental state. We discuss the case of a middle-aged woman who presented to an acute admissions unit under Irish Mental Health Act for involuntary admission because of concerns expressed by her family and general practitioner regarding a recent change in behaviour and onset of irritable mood. This lady was diagnosed with an episode of mania that was thought to be precipitated by a combination of psychosocial stressors, recent discontinuation of psychotropic medication and complicated by a recent course of clarithromycin. 23927856 The false thyroid capsule: new findings. Purpose: The false thyroid capsule is an important anatomical structure involved in thyroidectomy, yet it is rarely studied. This study aimed to define the anatomy of the false thyroid capsule, and its clinical significance. Methods: A prospective study was performed involving 151 patients with goitre who underwent thyroid lobectomy. The anatomy of the false thyroid capsule was carefully documented intra-operatively. Results: The false thyroid capsule enclosed the inferior and middle thyroid veins and the superior thyroid vessels, forming a mesentery-like structure by attaching to the gland. Once the unilateral lobe had been removed, the thyroid mesentery could be seen to have a C-shaped edge. The recurrent laryngeal nerve, inferior thyroid artery and parathyroid glands were located beneath the C-shaped edge of the thyroid mesentery. Conclusion: The thyroid mesentery is a distinctive structure that can be used as a guide for surgical dissection. 23850735 Evaluation of a commercially available carbohydrate deficient transferrin kit to detect beta-2-transferrin in cerebrospinal fluid using capillary electrophoresis. The aim of this study was to evaluate the CEofix™ CDT Capillary Electrophoresis (CE) kit for the detection of β-2-tranferrin (β-2-Tf) in cerebrospinal fluid (CSF). Evaluation was performed according to CLSI EP5-A and EP12-A guidelines. The method resolved β-2-Tf from other Tf isoforms. The C50 for β-Tf was determined to be 0.46mg/L. Neither hemoglobin nor bilirubin co-migrated with β-2-Tf. The CDT kit can be used for detecting β-2-Tf in CSF by CE. 23687232 The prevalence of burnout and depression and their association with adherence to safety and practice standards: a survey of United States anesthesiology trainees. The prevalence of burnout and depression in anesthesiology residents has not been determined. It is also unknown whether anesthesiology resident burnout/depression may affect patient care and safety. The primary objective of this study was to determine the prevalence of burnout and depression in anesthesiology residents in the United States. We hypothesized that residents at high risk of burnout and/or depression would report more medical errors as well as a lower rate of following principles identified as the best practice of anesthesiology. A cross-sectional survey was sent to 2773 anesthesiology residents in the United States. The questionnaire was divided into 5 parts examining trainees' demographic factors, burnout (Maslach Burnout Inventory), depression (Harvard depression scale), 10 questions designed to evaluate best practice of anesthesiology, and 7 questions evaluating self-reported errors. Best practices and self-reported error rates were compared among subjects with a high risk of burnout only, high risk of depression only, high risk of burnout and depression, and low risk of burnout and depression. Pairwise comparisons were considered significant at P < 0.004 and confidence intervals (CIs) reported at 99.6%. There were 1508 (54%) resident responds. High burnout risk was found in 41% (575 of 1417) of respondents. Working >70 hours per week, having >5 drinks per week, and female gender were associated with increased burnout risk. Twenty-two percent (298 of 1384) screened positive for depression. Working >70 hours of work per week, smoking, female gender, and having >5 drinks per week were associated with increased depression risk. Two hundred forty (17%) respondents scored at high risk of burnout and depression, 321 (23%) at high risk of burnout, 58 (4%) at high risk of depression only, and 764 (56%) at low risk of burnout or depression. Median best practice scores (maximum = 30) for residents at high risk of burnout (difference -2; 99.6% CI, -1 to -2; P < 0.001) or high risk of burnout and depression (difference -4; 99.6% CI, -3 to -6; P < 0.001) were lower than scores of residents at low risk for burnout or depression. Thirty-three percent of respondents with high burnout and depression risk reported multiple medication errors in the last year compared with 0.7% of the lower-risk responders (P < 0.001). Burnout, depression, and suicidal ideation are very prevalent in anesthesiology residents. In addition to effects on the health of anesthesiology trainees, burnout and depression may also affect patient care and safety. 23807288 Generation of iPS cells from normal and malignant hematopoietic cells. Induced pluripotent stem cells (iPSCs) can be generated from various types of cells with transduction of defined transcription factors. In addition to regenerative medicine, iPSCs have been used for the study of pathogenesis of inherited genetic diseases. Here, we presented the examples of the establishment of iPSCs from hematopoietic cells or fibroblasts from hematological disease patients. Hematopoietic cells would be a good donor source for establishing iPSCs owing to the high reprogramming efficiency. iPSCs can be generated not only from normal cells, but also from several types of tumor cells. However it is not so easy, because iPSCs from hematological malignancies have been established only from myeloproliferative neoplasms including chronic myelogenous leukemia (CML) and JAK2-V617F mutation-positive polycythemia vera (PV). iPSC technology has great potential to promote oncology research based on patient samples. 23402780 A quantitative comparison of data evaluation methods to derive diagnostic reference levels for CT from a dosimetric survey: Correlation analysis compared to simple evaluation strategies. To compare simple and sophisticated evaluation strategies for CT dosimetry surveys with focus on DRLs. Based on data from a nationwide Austrian CT dose survey, different evaluation strategies are compared. These were pooled data analysis, weight banding excluding data from patients with weights outside ±20 kg of the standard weights (70 and 75.6 kg representing the actual average weight), and a regression method estimating DLP probability distributions for the standard patient for each scanner before calculating quartiles. In the abdomen and chest region, weight restriction (-9% and -4% around 70 and 75.6 kg, respectively, compared to pooled data analysis) and statistically weighting each scanner equally (-9%) have the largest effect on DRLs derived. However, the difference in 3rd quartiles calculated using weight restriction alone compared to regression analysis is relatively small (<1% for 70 ± 20 and -6% for 75.6 ± 20 kg, respectively, trunk region). In the head/neck region the effect of weight restriction is less than in for scans of the trunk (-1.3% and -0.2%, respectively); the most prominent changes resulted from excluding scanners with less than 10 patient cases (-5%), and equally weighting scanners rather than cases (-3%). For adult CT examinations (different to a paediatric survey), quite simple evaluation strategies yield results very comparable to those from sophisticated strategies. 23739792 The effect of different feed delivery methods on time to consume feed and the resulting changes in postprandial metabolite concentrations in horses. Management techniques that reduce the insulin response to feeding in horses have application in preventing insulin resistance (IR) and potential associations (e.g., laminitis). Eight mature idle horses of BCS between 5 and 6.5 and with no previous indication of IR were fed a meal of concentrate under 4 feed delivery treatments in a repeated Latin Square design. Treatments were all based on a bucket of equal dimensions. The treatments included a control (CON) and 3 treatments hypothesized to increase time to consume feed (TCF): mobile obstacles above the feed (BALL), stationary obstacles below the feed (WAFF), and feed with water added (WTR). Jugular venous blood samples were taken at feed delivery, every 10 min for the first hour, and then every 30 min until 300 min after feed delivery. The TCF was different across treatment and was greater (P < 0.05) for BALL and WAFF when compared with CON and WTR. Glucose and insulin concentrations increased after feeding (P < 0.05) and tended to differ among treatments (P < 0.10). Peak insulin and glucose concentrations were affected by treatment as were the time to peak insulin and the area under the curve of insulin (P < 0.05). Therefore, feed delivery methods that include obstacles effectively increase TCF and attenuate postprandial glucose and insulin concentrations. A second experiment was designed to determine if the TCF changes associated with BALL and WAFF in Exp. 1 remain effective over a 4-d period. Four horses with no recent or regular history of consuming concentrates were fed concentrate meals for 4 consecutive d using the same treatments described in Exp. 1 and a Latin square design. Horses were subject to a 4-d adaptation period and were randomly assigned to 4-d treatment periods using the 4 previously described treatments. During adaptation, TCF decreased over time (P = 0.02). After adaptation, WAFF had greater TCF when compared with CON and WTR (P < 0.05) whereas WTR had the lowest TCF overall. Using obstacles to increase TCF on a daily basis may be an effective method to reduce postprandial glucose and insulin concentrations, thereby decreasing the risk of IR development in horses. 23237836 Synthesis and SAR of aminothiazole fused benzazepines as selective dopamine D2 partial agonists. Dopamine (D(2)) partial agonists (D2PAs) have been regarded as a potential treatment for schizophrenia patients with expected better side effect profiles than currently marketed antipsychotics. Herein we report the synthesis and SAR of a series of aminothiazole fused benzazepines as selective D(2) partial agonists. These compounds have good selectivity, CNS drug-like properties and tunable D(2) partial agonism. One of the key compounds, 8h, has good in vitro/in vivo ADME characteristics, and is active in a rat amphetamine-induced locomotor activity model. 23619428 Apolipoprotein E and its mimetic peptide suppress Th1 and Th17 responses in experimental autoimmune encephalomyelitis. Apolipoprotein E (apoE) has been detected to possess anti-inflammatory properties that can contribute to protection against experimental autoimmune encephalomyelitis (EAE). However, its impact on Th1 and Th17 responses in EAE is unclear. In this study, we induced EAE in apoE-/- mice and wild-type mice. We observed that the absence of apoE resulted in the increased proportion of Th1 and Th17 cells in the spleens and brains, as well as up-regulated expressions of proinflammatory cytokines (IL-17, IFN-γ, TNF-α, IL-12, IL-1β and IL-6) and transcription factors (RORγt and T-bet) in the CNS. ApoE-/- mice also showed the increased release of proinflammatory cytokines by macrophages in vitro. In addition, we used a mimetic peptide of apoE, which mimic the functions of apoE except for lipid transport. ApoE mimetic peptide could reverse the above negative effect in EAE. Thus, apoE can modulate Th1 and Th17 responses, likely through its inhibitory effect on the secretion of cytokines by macrophages. Our result also suggests that apoE mimetic peptide might be developed into a therapeutic agent for multiple sclerosis. 23318949 Re-print of "Intestinal luminal nitrogen metabolism: role of the gut microbiota and consequences for the host". Alimentary and endogenous proteins are mixed in the small intestinal lumen with the microbiota. Although experimental evidences suggest that the intestinal microbiota is able to incorporate and degrade some of the available amino acids, it appears that the microbiota is also able to synthesize amino acids raising the view that amino acid exchange between the microbiota and host can proceed in both directions. Although the net result of such exchanges remains to be determined, it is likely that a significant part of the amino acids recovered from the alimentary proteins are used by the microbiota. In the large intestine, where the density of bacteria is much higher than in the small intestine and the transit time much longer, the residual undigested luminal proteins and peptides can be degraded in amino acids by the microbiota. These amino acids cannot be absorbed to a significant extent by the colonic epithelium, but are precursors for the synthesis of numerous metabolic end products in reactions made by the microbiota. Among these products, some like short-chain fatty acids and organic acids are energy substrates for the colonic mucosa and several peripheral tissues while others like sulfide and ammonia can affect the energy metabolism of colonic epithelial cells. More work is needed to clarify the overall effects of the intestinal microbiota on nitrogenous compound metabolism and consequences on gut and more generally host health. 23873496 Using the concept of transient complex for affinity predictions in CAPRI rounds 20-27 and beyond. Predictions of protein-protein binders and binding affinities have traditionally focused on features pertaining to the native complexes. In developing a computational method for predicting protein-protein association rate constants, we introduced the concept of transient complex after mapping the interaction energy surface. The transient complex is located at the outer boundary of the bound-state energy well, having near-native separation and relative orientation between the subunits but not yet formed most of the short-range native interactions. We found that the width of the binding funnel and the electrostatic interaction energy of the transient complex are among the features predictive of binders and binding affinities. These ideas were very promising for the five affinity-related targets (T43-45, 55, and 56) of CAPRI rounds 20-27. For T43, we ranked the single crystallographic complex as number 1 and were one of only two groups that clearly identified that complex as a true binder; for T44, we ranked the only design with measurable binding affinity as number 4. For the nine docking targets, continuing on our success in previous CAPRI rounds, we produced 10 medium-quality models for T47 and acceptable models for T48 and T49. We conclude that the interaction energy landscape and the transient complex in particular will complement existing features in leading to better prediction of binding affinities. © Proteins 2013;. © 2013 Wiley Periodicals, Inc. 23525894 Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. We have investigated whether low-dose vitamin K2 supplements (menaquinone-7, MK-7) could beneficially affect bone health. Next to an improved vitamin K status, MK-7 supplementation significantly decreased the age-related decline in bone mineral density and bone strength. Low-dose MK-7 supplements may therefore help postmenopausal women prevent bone loss. Despite contradictory data on vitamin K supplementation and bone health, the European Food Safety Authorities (EFSA) accepted the health claim on vitamin K's role in maintenance of normal bone. In line with EFSA's opinion, we showed that 3-year high-dose vitamin K1 (phylloquinone) and K2 (short-chain menaquinone-4) supplementation improved bone health after menopause. Because of the longer half-life and greater potency of the long-chain MK-7, we have extended these investigations by measuring the effect of low-dose MK-7 supplementation on bone health. Healthy postmenopausal women (n = 244) received for 3 years placebo or MK-7 (180 Î¼g MK-7/day) capsules. Bone mineral density of lumbar spine, total hip, and femoral neck was measured by DXA; bone strength indices of the femoral neck were calculated. Vertebral fracture assessment was performed by DXA and used as measure for vertebral fractures. Circulating uncarboxylated osteocalcin (ucOC) and carboxylated OC (cOC) were measured; the ucOC/cOC ratio served as marker of vitamin K status. Measurements occurred at baseline and after 1, 2, and 3 years of treatment. MK-7 intake significantly improved vitamin K status and decreased the age-related decline in BMC and BMD at the lumbar spine and femoral neck, but not at the total hip. Bone strength was also favorably affected by MK-7. MK-7 significantly decreased the loss in vertebral height of the lower thoracic region at the mid-site of the vertebrae. MK-7 supplements may help postmenopausal women to prevent bone loss. Whether these results can be extrapolated to other populations, e.g., children and men, needs further investigation. 23901785 Predicting Enzyme-Substrate Specificity with QM/MM Methods: A Case Study of the Stereospecificity of d-Glucarate Dehydratase. The stereospecificity of d-glucarate dehydratase (GlucD) is explored by QM/MM calculations. Both the substrate binding and the chemical steps of GlucD contribute to substrate specificity. Although the identification of transition states remains computationally intensive, we suggest that QM/MM computations on ground states or intermediates can capture aspects of specificity that cannot be obtained using docking or molecular mechanics methods. 23064598 Feasibility of placement of an anterior cervical epidural blood patch for spontaneous intracranial hypotension. The dorsal epidural blood patch is a commonly used management technique for spontaneous intracranial hypotension from a dural CSF leak, but it may be less efficacious for cervical or ventral leaks. We report the technique of placing an anterior cervical blood patch for a large cervical ventral leak. To our best knowledge, this approach has not been reported. In the appropriately selected patient, an anterior cervical epidural blood patch may be safely used. 23612192 Molecular characterization of acquired enrofloxacin resistance in Mycoplasma synoviae field isolates. The in vitro activity of enrofloxacin against 73 Mycoplasma synoviae field strains isolated in Israel and Europe was determined by broth microdilution. Decreased susceptibility to enrofloxacin was identified in 59% of strains, with the MICs ranging from 1 to >16 μg/ml. The estimated MIC50 and MIC90 values for enrofloxacin were 2 and 8 μg/ml, respectively. Moreover, this study showed that 92% of recent Israeli field isolates (2009 to 2011) of M. synoviae have MICs of ≥ 2 μg/ml to enrofloxacin. Comparison of the quinolone resistance-determining regions (QRDRs) in M. synoviae isolates revealed a clear correlation between the presence of one of the amino acid substitutions Asp79-Asn, Thr80-Ala/Ile, Ser81-Pro, and Asp84-Asn/Tyr/His of the ParC QRDR and decreased susceptibility to enrofloxacin (MIC, ≥ 1 μg/ml). Amino acid substitutions at positions GyrA 87, GyrB 401/402, and ParE 420/454 were also identified, but there was no clear-cut correlation with susceptibility to enrofloxacin. Comparison of vlhA molecular profiles revealed the presence of 9 different genotypes in the Israeli M. synoviae field isolates and 10 genotypes in the European isolates; only one vlhA genotype (type 4) was identified in both cohorts. Based on results of vlhA molecular typing, several mechanisms for emergence and dissemination of Israeli enrofloxacin-resistant M. synoviae isolates are suggested. 23898410 Microbotryum silenes-saxifragae sp. nov. sporulating in the anthers of Silene saxifraga in southern European mountains. Currently, the monophyletic lineage of anther smuts on Caryophyllaceae includes 22 species classified in the genus Microbotryum. They are model organisms studied in many disciplines of fungal biology. A molecular phylogenetic approach was used to resolve species boundaries within the caryophyllaceous anther smuts, as species delimitation based solely on phenotypic characters was problematic. Several cryptic species were found amongst the anther smuts on Caryophyllaceae, although some morphologically distinct species were discernible, and most species were characterized by high host-specificity. In this study, anther smut specimens infecting Silene saxifraga were analysed using rDNA sequences (ITS and LSU) and morphology to resolve their specific status and to discuss their phylogenetic position within the lineage of caryophyllaceous anther smuts. The molecular phylogeny revealed that all specimens form a monophyletic lineage that is supported by the morphological trait of reticulate spores with tuberculate interspaces (observed in certain spores). This lineage cannot be attributed to any of the previously described species, and the anther smut on Silene saxifraga is described and illustrated here as a new species, Microbotryum silenes-saxifragae. This species clusters in a clade that includes Microbotryum species, which infect both closely and distantly related host plants growing in diverse ecological habitats. It appears possible that host shifts combined with changes to ecological host niches drove the evolution of Microbotryum species within this clade. 23552265 UVA photoirradiation of benzo[a]pyrene metabolites: induction of cytotoxicity, reactive oxygen species, and lipid peroxidation. Benzo[a]pyrene (BaP) is a prototype for studying carcinogenesis of polycyclic aromatic hydrocarbons (PAHs). We have long been interested in studying the phototoxicity of PAHs. In this study, we determined that metabolism of BaP by human skin HaCaT keratinocytes resulted in six identified phase I metabolites, for example, BaP trans-7,8-dihydrodiol (BaP t-7,8-diol), BaP t-4,5-diol, BaP t-9,10-diol, 3-hydroxybenzo[a]pyrene (3-OH-BaP), BaP (7,10/8,9)tetrol, and BaP (7/8,9,10)tetrol. The photocytotoxicity of BaP, 3-OH-BaP, BaP t-7,8-diol, BaP trans-7,8-diol-anti-9,10-epoxide (BPDE), and BaP (7,10/8,9)tetrol in the HaCaT keratinocytes was examined. When irradiated with 1.0 J/cm(2) UVA light, these compounds when tested at doses of 0.1, 0.2, and 0.5 μM, all induced photocytotoxicity in a dose-dependent manner. When photoirradiation was conducted in the presence of a lipid (methyl linoleate), BaP metabolites, BPDE, and three related PAHs, pyrene, 7,8,9,10-tetrahydro-BaP trans-7,8-diol, and 7,8,9,10-tetrahydro-BaP trans-9,10-diol, all induced lipid peroxidation. The formation of lipid peroxides by BaP t-7,8-diol was inhibited by NaN3 and enhanced by deuterated methanol, which suggests that singlet oxygen may be involved in the generation of lipid peroxides. The formation of lipid hydroperoxides was partially inhibited by superoxide dismutase (SOD). Electron spin resonance spin trapping experiments indicated that both singlet oxygen and superoxide radical anion were generated from UVA photoirradiation of BPDE in a light dose responding manner. 23409721 Computational models for predicting interactions with membrane transporters. Membrane transporters, including two members: ATP-binding cassette (ABC) transporters and solute carrier (SLC) transporters are proteins that play important roles to facilitate molecules into and out of cells. Consequently, these transporters can be major determinants of the therapeutic efficacy, toxicity and pharmacokinetics of a variety of drugs. Considering the time and expense of bio-experiments taking, research should be driven by evaluation of efficacy and safety. Computational methods arise to be a complementary choice. In this article, we provide an overview of the contribution that computational methods made in transporters field in the past decades. At the beginning, we present a brief introduction about the structure and function of major members of two families in transporters. In the second part, we focus on widely used computational methods in different aspects of transporters research. In the absence of a high-resolution structure of most of transporters, homology modeling is a useful tool to interpret experimental data and potentially guide experimental studies. We summarize reported homology modeling in this review. Researches in computational methods cover major members of transporters and a variety of topics including the classification of substrates and/or inhibitors, prediction of protein-ligand interactions, constitution of binding pocket, phenotype of non-synonymous single-nucleotide polymorphisms, and the conformation analysis that try to explain the mechanism of action. As an example, one of the most important transporters P-gp is elaborated to explain the differences and advantages of various computational models. In the third part, the challenges of developing computational methods to get reliable prediction, as well as the potential future directions in transporter related modeling are discussed. 23848936 Microbiological screening for earlier detection of central venous catheter-related bloodstream infections. Catheter-related bloodstream infections (CRBSIs) are currently detected with a reactive diagnostic policy, that is, application of tests to patients with clinically suspected CRBSI. The aim of our study was to evaluate whether CRBSIs could be anticipated in an earlier stage by microbiological screening using peptide nucleic acid fluorescence in situ hybridization (PNA FISH) with universal hybridization probes or acridine-orange leucocyte cytospin (AOLC) tests in haemodialysis and haematological patients with CVCs in situ compared with routine test. Peptide nucleic acid fluorescence in situ hybridization (PNA FISH) and AOLC tests using blood samples from both CVC lines in patients undergoing haemodialysis were performed three times a week and from one CVC line in haematological patients were performed daily. Results were compared with those obtained from routinely performed CRBSI diagnostic tests. One hundred fifteen patients with 139 catheter periods were investigated. The mean observation time per catheter period was 25 days (IQR 13·5-43·5), resulting in 5615 CVC days with a total of 4839 tested blood samples. Five CRBSI cases were detected by routine measures resulting in a CRBSI rate of 0·9/1000 catheter days. Four of five CRBSIs could be anticipated by positive PNA FISH and AOLC tests 2-8 days before the diagnosis was established with routine measures. The proactive anticipative strategy using microscopic examination of CVC blood samples to anticipate CRBSI in an earlier stage compared with routine measures is a new diagnostic approach in patients with CVCs and a high risk of developing CRBSI. 23221600 Human stearoyl-CoA desaturase 1 (SCD-1) gene expression is negatively regulated by thyroid hormone without direct binding of thyroid hormone receptor to the gene promoter. Stearoyl-CoA desaturase-1 (SCD-1) plays a pivotal role in an increase of triglyceride by an excess of dietary carbohydrate intake. Dietary carbohydrates increase SCD-1 gene expression in liver by sterol response element binding protein (SREBP)-1c-dependent and SREBP-1c -independent pathways. Previous report demonstrated that thyroid hormone (TH) negatively regulates mouse SCD-1 gene promoter before SREBP-1c was revealed. We reported that TH negatively regulates SREBP-1c recently. Therefore, in the current study, we examined whether and how TH regulates human SCD-1 gene expression and evaluated SREBP-1c effect on the negative regulation. Luciferase assays revealed that TH suppresses both mouse and human SCD-1 gene promoter activity. In SREBP-1 knockdown HepG2 cells, TH still suppresses SCD-1 gene promoter activity, and it also exerted the negative regulation under cotransfection of a small amount of SREBP-1c. These data indicated that SREBP-1c does not play the decisive role for the negative regulation by TH. The responsible region for the negative regulation in human SCD-1 gene promoter turned out to be between -124 and -92 bp, referred to as site A. Chromatin immunoprecipitation assays demonstrated that TH receptor-β is recruited to the region upon T(3) administration, although TR-β does not bind directly to site A. In conclusion, TH negatively regulates human SCD-1 gene expression in without direct binding of the TH receptor to the SCD-1 gene promoter. 23688619 Expression patterns of photoperiod and temperature regulated heading date genes in Oryza sativa. In plants, flowering is a major biological phenomenon, which is regulated by an array of interactions occurring between biotic and abiotic factors. In our study, we have compared the expression profiles of flowering genes involved in the flowering pathway, which are influenced by conditions like photoperiod and temperature from seedling to heading developmental stages in two Oryza sativa indica varieties, viz., Zhenshan 97 and Minghui 63 using a expression network approach. Using the network expression approach, we found 17 co-expressed genes having the same expression profile pattern as three key photoperiod flowering genes Hd1, Ehd1 and Hd3a. We also demonstrated that these three co-expressed genes have a similar simulation pattern as temperature flowering genes. Based on our observations, we hypothesize that photoperiod and temperature regulate flowering pathways independently. The present study provides a basis for understanding the network of co-expressed genes involved in flowering pathway and presents a way to demonstrate the behavior of specific gene sets in specific cultivars. 23517370 Time resolved photoelectron spectroscopy of thioflavin T photoisomerization: a simulation study. The excited state isomerization of thioflavin T (ThT) is responsible for the quenching of its fluorescence in a nonrestricted environment. The fluorescence quantum yield increases substantially upon binding to amyloid fibers. Simulations reveal that the variation of the twisting angle between benzothiazole and benzene groups (ϕ1) is responsible for the subpicosecond fluorescence quenching. The evolution of the twisting process can be directly probed by photoelectron emission with energies ε ≥ 1.0 eV before the molecule reaches the ϕ1-twisted configuration (∼300 fs). 23948923 Reduced Visual Event-Related Delta Oscillatory Responses in Amnestic Mild Cognitive Impairment. Mild cognitive impairment (MCI) is considered as a prodromal stage for Alzheimer's disease (AD) in the majority of cases. Event-related oscillations might be used for detection of cognitive deficits. Our group's earlier results showed diminished delta visual and auditory target oscillatory responses in AD, and we investigated whether this prevails for MCI. Eighteen MCI subjects and 18 age-matched healthy elderly controls were investigated. The maximum peak-to-peak amplitudes of oscillatory responses for each subject's averaged oscillatory target responses in delta, theta, and alpha frequency bands upon application of visual oddball paradigm were measured. Repeated measures of ANOVA was used to analyze four locations (frontal, central, parietal, occipital), at three coronal (left, midline, right) sites. Independent t tests were applied for post-hoc analyses. The oddball target delta response (0.5-3.0 Hz) was 26-32% lower in MCI than healthy controls over fronto-central-parietal regions [F(1.34) = 4.562, p = 0.04]. Without a group effect, theta oscillatory responses (4-7 Hz) showed significant differences in coronal electrodes indicating highest values over mid-electrode sites, and a anteriorposterior x coronal effect, being maximum at mid-central. Alpha frequency band analyses indicated no statistical differences. Peak-to-peak amplitudes of visual target delta oscillatory responses were lower in fronto-central-parietal regions in MCI than in healthy controls. This supports our earlier findings in AD, showing hypoactive delta fronto-central-parietal regions during cognitive tasks. These results indicate that event-related oscillations may detect early changes of brain dynamics in MCI, and deserves to be investigated as a candidate biomarker in further studies using multimodal techniques. 23111874 Nano-titanium dioxide induces genotoxicity and apoptosis in human lung cancer cell line, A549. The increased inhaled application of titanium dioxide nanoparticles (TiO(2) NPs) increases the potential pulmonary health risks. The present investigations were carried out to study the TiO(2) NPs-induced apoptosis, oxidative stress and genotoxicity in the human lung cancer cell line, A549, a widely used cell system for pulmonary toxicity studies. Tetrazolium bromide salt and lactate dehydrogenase release assays were used to study the cytotoxicity. The genotoxicity studies were carried out using cytokinesis block micronucleus assay. Apoptosis was confirmed by the formation of apoptotic bodies and altered expression (messenger RNA (mRNA) and protein) of markers such as P(53), P(21), Bax, Bcl(2) and cleaved caspase-3. Cells exposed to TiO(2) NPs (10 and 50 μg/ml) for 6-24 h shows significant induction in oxidative stress, that is, the production of reactive oxygen species and malondialdehyde and decrease in the activity of catalase and glutathione. TiO(2) NPs exposure also induces the formation of apoptotic bodies and micronucleus as marker of genotoxicity. A significant up-regulation in the expression of apoptosis markers such as P(53), P(21) and cleaved caspase-3 was observed, while the levels were down-regulated for Bcl(2) at both mRNA and protein levels. TiO(2) NPs exposure could not pose significant effects on Bax expression. Data indicate that nano-TiO(2) induces oxidative stress, genotoxicity and apoptosis in human lung cancer cell line, A549. Our result also identifies the mechanisms involved in TiO(2) NP-induced changes in A549 cells. Perhaps, reporting for the first time, the association of TiO(2) NPs-induced genotoxicity and apoptosis at transcriptional and translational level in the human lung cancer cell line, A549 cells. 23820243 Novel polymorphisms of the IGF1R gene and their association with average daily gain in Egyptian buffalo (Bubalus bubalis). The objective of this study was to detect insulin-like growth factor 1 receptor (IGF1R) polymorphisms, their allele, and genotype frequencies and to determine associations between these polymorphisms and growth traits in Egyptian water buffalo. Three loci of the IGF1R coding region were amplified by RT-PCR and, subsequently, subjected to sequence analysis, followed by single-strand conformation polymorphism to identify different allelic patterns. A total of 11 novel polymorphisms were detected; 6 SNPs among Egyptian water buffaloes and 5 polymorphisms compared with Indian buffalo (Y12700). Three of those polymorphisms; GAG Indel polymorphism, C261G, and G263C SNPs, were nonsynonymous mutations. The GAG Indel polymorphism led to deletion of E (glutamic) amino acid (aa) in the IGF1R of Egyptian water buffaloes compared with Indian buffalo. However, C261G SNP, which replaced A (alanine) by G (glycine) aa, and G263C SNP, which changed A (alanine) to P (proline) aa, were detected among Egyptian water buffaloes. Three different single-strand conformation polymorphism patterns were observed in exon 21: CC/CC, GG/GG, and CG/GC with frequencies of 0.291, 0.253, and 0.556, respectively. The heterozygous animals (CG/GC) had a higher ADG than homozygous animals (CC/CC and GG/GG) from birth to 6 mo of age. We conclude that the heterozygous haplotype, C261G/G263C, in exon 21 of the IGF1R gene is associated with the ADG during the early stages of life (from birth to 6 mo of age) and could be used as a genetic marker for selection of growth traits in Egyptian buffalo. 23903952 Prednisolone induces osteoporosis-like phenotype in regenerating zebrafish scales. We demonstrate that glucocorticoids induce an osteoporotic phenotype in regenerating scales of zebrafish. Exposure to prednisolone results in altered mineral content, enhanced matrix breakdown, and an osteoporotic gene-expression profile in osteoblasts and osteoclasts. This highlights that the zebrafish scale provides a powerful tool for preclinical osteoporosis research. This study aims to evaluate whether glucocorticoid (prednisolone) treatment of zebrafish induces an osteoporotic phenotype in regenerating scales. Scales, a readily accessible dermal bone tissue, may provide a tool to study direct osteogenesis and its disturbance by glucocorticoids. In adult zebrafish, treated with 25 Î¼M prednisolone phosphate via the water, scales were removed and allowed to regenerate. During regeneration scale morphology and the molar calcium/phosphorus ratio in scales were assessed and osteoblast and osteoclast activities were monitored by time profiling of cell-specific genes; mineralization was visualized by Von Kossa staining, osteoclast activity by tartrate-resistant acid phosphatase histochemistry. Prednisolone (compared to controls) enhances osteoclast activity and matrix resorption and slows down the build up of the calcium/phosphorus molar ratio indicative of altered crystal maturation. Prednisolone treatment further impedes regeneration through a shift in the time profiles of osteoblast and osteoclast genes that commensurates with an osteoporosis-like imbalance in bone formation. A glucocorticoid-induced osteoporosis phenotype as seen in mammals was induced in regenerating scalar bone of zebrafish treated with prednisolone. An unsurpassed convenience and low cost then make the zebrafish scale a superior model for preclinical studies in osteoporosis research. 23909245 Development of a bioactive implant for repair and potential healing of cranial defects. The repair of complex craniofacial bone defects is challenging and a successful result is dependent on the size of the defect, quality of the soft tissue covering the defect, and choice of reconstruction method. The objective of this study was to develop a bioactive cranial implant that could provide a permanent reconstructive solution to the patient by stimulating bone healing of the defect. In this paper the authors report on the feasibility and clinical results of using such a newly developed device for the repair of a large traumatic and therapy-resistant cranial bone defect. The patient had undergone numerous attempts at repair, in which established methods had been tried without success. A mosaic-designed device was manufactured and implanted, comprising interconnected ceramic tiles with a defined calcium phosphate composition. The clinical outcome 30 months after surgery revealed a restored cranial vault without postoperative complications. Computed tomography demonstrated signs of bone ingrowth. Examination with combined (18)F-fluoride PET and CT provided further evidence of bone healing of the cranial defect. 23702203 Northern Drosophila montana flies show variation both within and between cline populations in the critical day length evoking reproductive diapause. Reproductive diapause, and its correct timing, plays an important role in the life cycle of many insect species living in a seasonally varying environment at high latitudes. In the present paper we have documented variation in the critical day length (CDL) for adult reproductive diapause and the steepness of photoperiodic response curves (PPRCs) in seven clinal populations of Drosophila montana in Finland between the latitudes 61 and 67°N, paying special attention to variation in these traits within and between cline populations. The isofemale lines representing these populations showed a sharp transition from 0% to 100% in females' diapause incidence in the shortening day lengths, indicated by steep PPRCs. The mean CDL showed a clear latitudinal cline decreasing by 1.6h from North to South regardless of the age of the lines, variation within the populations (i.e. among lines) in this trait being up to 3h. The steepness of the PPRCs correlated with the age of the line and this trait showed no clear latitudinal cline. Further studies on a large number of lines from one D. montana population confirmed that while maintaining the flies in diapause preventing conditions in the laboratory has no effect on CDL, older lines had steeper PPRCs. High variation in CDL within and between D. montana cline populations is likely to be heritable and provide a good potential for the evolution of photoperiodic responses. Information on genetic variation in life-history traits, such as diapause, is of utmost importance for predicting the ability of insects to survive in seasonally changing environmental conditions and to respond to long term changes in the length of the growing period e.g. by postponing the timing of diapause towards shorter day length and later calendar date. 23955536 Luffa cylindrica and phytosterols bioconversion: from shake flask to jar bioreactor. Bioconversion of lipophilic compounds poorly soluble in water, such as sterols, required the use of chemicals and solubilizing agents. On the other hand, it was shown that immobilization of Mycobacterium species on the dried fruit of Luffa cylindrica (DFLC) allows a close interaction between immobilized cells and cholesterol particles and increases by then the product's yield. In this work, the use of DFLC in a 5-l jar bioreactor with phytosterols mixture (1 g/l) as substrate was assessed without addition of any chemicals or solubilizing agents. DFLC increased by a factor of four the volumetric productivity of androstenones (0.08 g/l day). Products were accumulated in the aqueous medium while substrates remained on the fibers of DFLC. This observation lets envisage a green semi-continuous process of androstenone production. DFLC has no influence on cell growth, and is moreover natural, inexpensive, non-toxic, and mechanically strong. 23788473 Comparison of methodological data measurement limits in CD4⁺ T lymphocyte flow cytometric enumeration and their clinical impact on HIV management. UK NEQAS for Leucocyte Immunophenotyping, an ILAC G13:2000 accredited External Quality Assessment (EQA) organization, with over 3000 international laboratories participating in 14 programmes, issues 2 proficiency testing samples of stabilized whole blood to 824 participants in the Immune Monitoring (lymphocyte subset) programme every two months. We have undertaken a study of 58,626 flow cytometric absolute CD4⁺ T lymphocyte count data sets from these laboratories over a 12-year-period (2001-2012) to determine counting method variation in data measurement limits and how this could influence the clinical management of HIV patients. Comparison of relative error and 99.9% confidence limits for absolute CD4⁺ T lymphocyte values was undertaken using dual platform (DP) and single platform (SP) data and showed that the SP consistently outperformed DP, giving lower relative errors and confidence limits at clinically significant absolute CD4⁺ T lymphocyte counts. Our data shows that absolute CD4⁺ T lymphocyte counts should be obtained using single platform technology to reduce the variability at clinically relevant levels. On data where results (irrespective of platform) were below the international treatment threshold of 350 cells/μl, there was no significant misclassification between either SP or DP techniques meaning most patients would receive the correct treatment at the correct time. However, results that were above the treatment level of 350 cells/μl had a significant difference (P = 0.04) between DP and SP platforms, suggesting patients monitored using DP technology were 20% more likely to start therapy prematurely than those monitored with SP technology. 23775176 Characterization of a cryogenic beam source for atoms and molecules. We present a combined experimental and theoretical study of beam formation from a cryogenic buffer gas cell. Atoms and molecules are loaded into the cell by laser ablation of a target, and are cooled and swept out of the cell by a flow of cold helium. We study the thermalization and flow dynamics inside the cell and measure how the speed, temperature, divergence and extraction efficiency of the beam are influenced by the helium flow. We use a finite element model to simulate the flow dynamics and use the predictions of this model to interpret our experimental results. 23953064 QTL mapping of egg albumen quality in egg layers. A fresh, good quality egg has a firm and gelatinous albumen that anchors the yolk and restricts growth of microbiological pathogens. As the egg ages, the gel-like structure collapses, resulting in thin and runny albumen. Occasionally thin albumen is found in a fresh egg, giving the impression of a low quality product. A mapping population consisting of 1599 F2 hens from a cross between White Rock and Rhode Island Red lines was set up, to identify loci controlling albumen quality. The phenotype for albumen quality was evaluated by albumen height and in Haugh units (HU) measured on three consecutive eggs from each F2 hen at the age of 40 weeks. For the fine-mapping analysis, albumen height and HU were used simultaneously to eliminate contribution of the egg size to the phenotype. Linkage analysis in a small population of seven half-sib families (668 F2) with 162 microsatellite markers spread across 27 chromosomes revealed two genome-wide significant regions with additive effects for HU on chromosomes 7 and Z. In addition, two putative genome-wide quantitative trait loci (QTL) regions were identified on chromosomes 4 and 26. The QTL effects ranged from 2 to 4% of the phenotypic variance. The genome-wide significant QTL regions on chromosomes 7 and Z were selected for fine-mapping in the full set composed of 16 half-sib families. In addition, their existence was confirmed by an association analysis in an independent commercial Hy-Line pure line. We identified four chicken genomic regions that affect albumen quality. Our results also suggest that genes that affect albumen quality act both directly and indirectly through several different mechanisms. For instance, the QTL regions on both fine-mapped chromosomes 7 and Z overlapped with a previously reported QTL for eggshell quality, indicating that eggshell membranes may play a role in albumen quality. 23527863 Low blood pressure and antihypertensive treatment are independently associated with physical and mental health status in patients with arterial disease: the SMART study. To investigate the independent effects of antihypertensive treatment and blood pressure (BP) levels on physical and mental health status in patients with arterial disease. Cross-sectional analyses were conducted within the single-centre Secondary Manifestations of ARTerial disease (SMART) study, in a hospital care setting. A total of 5877 patients (mean age 57 years) with symptomatic and asymptomatic arterial disease underwent standardized vascular screening. The primary outcome was self-rated physical and mental health assessed using the 36-item short-form health survey. In the total population, antihypertensive drug use and increased intensity of antihypertensive treatment were associated with poorer health status independent of important confounders including BP levels; adjusted mean differences [95% confidence interval (CI)] in physical and mental health between n = 0 and n â‰¥ 3 antihypertensives were -1.2 (-2.1; -0.3) and -3.5 (-4.4; -2.6), respectively. Furthermore, both lower systolic and lower diastolic BP levels were related to poorer physical and mental health status independent of antihypertensive treatment. Mean differences (95% CI) in physical and mental health status per SD decrease in systolic BP were -0.56 (-0.84; -0.27) and -0.32 (-0.61; -0.03) and per SD decrease in diastolic BP were -0.50 (-0.78; -0.23) and -0.08 (-0.36; 0.20), respectively. The association between low BP and poor health status was particularly present in patients with coronary artery disease. In a population of patients with asymptomatic and symptomatic arterial disease, antihypertensive treatment and lower BP levels are independently associated with poorer self-rated physical and mental health. These findings suggest that different underlying mechanisms may explain these independent associations. 23836501 Fully Automated Radiosynthesis of 2-[(18)F]Fludarabine for PET Imaging of Low-Grade Lymphoma. An efficient and fully automated radiosynthesis of 2-[(18)F]fluoro-9-β-D-arabinofuranosyl-adenine (2-[(18)F]fludarabine, [(18)F]-5) based on a GE TRACERlab™ FX-FN module has been developed. A 2-nitro purine derivative 3 was developed as precursor for labeling with fluorine-18. The radiosynthesis of [(18)F]-5 was performed in two steps in a single reactor with an intermediary purification on Sep-Pak® silica which involved the addition of a three-way valve on the original module. After hydrolysis, [(18)F]-5 was purified by semi-preparative high-pressure liquid chromatography (HPLC) and a quality control was established. The labeling precursor 3 was obtained in 45 % overall yield. Nucleophilic substitution with K(18)F/K2.2.2 afforded protected 2-[(18)F]fludarabine ([(18)F]-4) in 73 ±â€‰4 % , radiochemical yield (decay corrected to the end of bombardment (EOB)) and based on the initial [(18)F]F(-) activity. An aqueous ammonia/methanol solution was used for the deprotection reaction and gave the desired [(18)F]-5 in 67 ±â€‰3 % yield after 20 min at 70 °C based on HPLC profile. The process afforded pure 2-[(18)F]fludarabine in 48 ±â€‰3 % yield (decay corrected to the EOB) in 85 min, with a specific activity of 310 ±â€‰72 GBq/μmol at the end of synthesis (EOS) and a radiochemical purity up to 99 %. 23541680 Oxidation-specific epitopes and immunological responses: Translational biotheranostic implications for atherosclerosis. Oxidation-specific epitopes (OSE), present on oxidized LDL (OxLDL), apoptotic cells, cell debris and modified proteins in the vessel wall, accumulate in response to hypercholesterolemia, and generate potent pro-inflammatory, disease-specific antigens. They represent an important class of 'danger associated molecular patterns' (DAMPs), against which a concerted innate immune response is directed. OSE are recognized by innate 'pattern recognition receptors', such as scavenger receptors present on dendritic cells and monocyte/macrophages, as well as by innate proteins, such as IgM natural antibodies and soluble proteins, such as C-reactive protein and complement factor H. These innate immune responses provide a first line of defense against atherosclerosis-specific DAMPs, and engage adaptive immune responses, provided by T and B-2 cells, which provide a more specific and definitive response. Such immune responses are ordinarily directed to remove foreign pathogens, such as those found on microbial pathogens, but when persistent or maladaptive, lead to host damage. In this context, atherosclerosis can be considered as a systemic chronic inflammatory disease initiated by the accumulation of OSE type DAMPs and perpetuated by maladaptive response of the innate and adaptive immune system. Understanding this paradigm leads to new approaches to defining cardiovascular risk and suggests new modes of therapy. Therefore, OSE have become potential targets of diagnostic and therapeutic agents. Human and murine OSE-targeting antibodies have been developed and are now being used as biomarkers in human studies and experimentally in translational applications of non-invasive molecular imaging of oxidation-rich plaques and immunotherapeutics. 23261985 Site-specific modulation of brain glucocorticoid receptor and corticotropin-releasing hormone expression using lentiviral vectors. The glucocorticoid receptor (GR) and corticotropin-releasing hormone (CRH) are important molecular regulators of an individual's ability to respond to stressful stimuli in an adaptive manner. Impaired signaling of both GR and CRH often leads to dysfunction of the hypothalamic-pituitary-adrenal axis, which underlies the etiology of many affective disorders such as anxiety and depression. Studies focusing on how GR and CRH influence the stress response are limited as they generalize to broad brain regions, thus hindering identification of how specific CNS nuclei contribute to maladaptive stress responses. Our objective is to distinguish the site-specific involvement of GR and CRH in limbic regions involved in the stress response. With that intent, we use lentiviral (LV) vectors in combination with transgenic mouse lines, enabling us to modify expression of GR or CRH in a very localized manner. This paper describes the generation of several distinct LV vectors and transgenic mice models that will help further elucidate the site-specific actions of GR and CRH. 23894517 i3Drefine Software for Protein 3D Structure Refinement and Its Assessment in CASP10. Protein structure refinement refers to the process of improving the qualities of protein structures during structure modeling processes to bring them closer to their native states. Structure refinement has been drawing increasing attention in the community-wide Critical Assessment of techniques for Protein Structure prediction (CASP) experiments since its addition in 8(th) CASP experiment. During the 9(th) and recently concluded 10(th) CASP experiments, a consistent growth in number of refinement targets and participating groups has been witnessed. Yet, protein structure refinement still remains a largely unsolved problem with majority of participating groups in CASP refinement category failed to consistently improve the quality of structures issued for refinement. In order to alleviate this need, we developed a completely automated and computationally efficient protein 3D structure refinement method, i3Drefine, based on an iterative and highly convergent energy minimization algorithm with a powerful all-atom composite physics and knowledge-based force fields and hydrogen bonding (HB) network optimization technique. In the recent community-wide blind experiment, CASP10, i3Drefine (as 'MULTICOM-CONSTRUCT') was ranked as the best method in the server section as per the official assessment of CASP10 experiment. Here we provide the community with free access to i3Drefine software and systematically analyse the performance of i3Drefine in strict blind mode on the refinement targets issued in CASP10 refinement category and compare with other state-of-the-art refinement methods participating in CASP10. Our analysis demonstrates that i3Drefine is only fully-automated server participating in CASP10 exhibiting consistent improvement over the initial structures in both global and local structural quality metrics. Executable version of i3Drefine is freely available at http://protein.rnet.missouri.edu/i3drefine/. 23514669 Lacrimal gland pleomorphic adenoma masquerading as thyroid-associated ophthalmopathy. : Thyroid-associated ophthalmopathy is the most common cause of proptosis in adult female, especially those with positive thyroid antibody. Sometimes, other diagnoses should be considered. A 45-year-old female presented with progressive right proptosis and mild diplopia for 2 years. One year earlier, she had been diagnosed with thyroid-associated ophthalmopathy because of abnormal thyroid autoantibody. Computed tomography scan showed a 2.4- × 1.9- × 1.6-mm heterogeneous soft-tissue density lying above the left eye. Excisional biopsy of this mass revealed the histopathologic diagnosis of pleomorphic adenoma. This case highlights the need for including other diagnoses such as pleomorphic adenoma in the differential diagnosis of patients with proptosis, diplopia and abnormal thyroid antibody. 23444776 Development and validation of a simple LC method for the determination of phenacetin, coumarin, tolbutamide, chlorzoxazone, testosterone and their metabolites as markers of cytochromes 1A2, 2A6, 2C11, 2E1 and 3A2 in rat microsomal medium. Cytochrome P450 enzymes are responsible for the oxidative metabolism of most pharmaceutical compounds. A "cocktail" approach which employs simultaneous administration of a mixture of substrates of CYP enzymes was often used to assess the metabolic activity of multiple P450 forms in one experiment. Phenacetin, coumarin, tolbutamide, chlorzoxazone and testosterone are commonly used as probe substrates to evaluate cytochrome P450 function. An analytical strategy to simultaneously extract and analyze the five probe substrates and their major metabolites by HPLC-DAD was developed. The incubation was done with all the substrates in one step. The ten analytes were extracted simultaneously by solid-phase extraction (SPE) from rat liver microsomes. A C18 analytical column and mobile phase composed of acetonitrile and 0.02% aqueous phosphoric acid were used for the chromatographic separation with DAD detection. Limits of quantification varied between 0.02378 and 0.2361 microg/mL which contributed to quantify all these drugs and metabolites with UV detection. The method is applicable for the modeling and description of pharmacological interactions on rat cytochromes P450 or can be used for in vitro evaluation of cytochromes 1A2, 2A6, 2C11, 2E1 and 3A2. 22564044 Evolution by adapting surrogates. To deal with complex optimization problems plagued with computationally expensive fitness functions, the use of surrogates to replace the original functions within the evolutionary framework is becoming a common practice. However, the appropriate datacentric approximation methodology to use for the construction of surrogate model would depend largely on the nature of the problem of interest, which varies from fitness landscape and state of the evolutionary search, to the characteristics of search algorithm used. This has given rise to the plethora of surrogate-assisted evolutionary frameworks proposed in the literature with ad hoc approximation/surrogate modeling methodologies considered. Since prior knowledge on the suitability of the data centric approximation methodology to use in surrogate-assisted evolutionary optimization is typically unavailable beforehand, this paper presents a novel evolutionary framework with the evolvability learning of surrogates (EvoLS) operating on multiple diverse approximation methodologies in the search. Further, in contrast to the common use of fitness prediction error as a criterion for the selection of surrogates, the concept of evolvability to indicate the productivity or suitability of an approximation methodology that brings about fitness improvement in the evolutionary search is introduced as the basis for adaptation. The backbone of the proposed EvoLS is a statistical learning scheme to determine the evolvability of each approximation methodology while the search progresses online. For each individual solution, the most productive approximation methodology is inferred, that is, the method with highest evolvability measure. Fitness improving surrogates are subsequently constructed for use within a trust-region enabled local search strategy, leading to the self-configuration of a surrogate-assisted memetic algorithm for solving computationally expensive problems. A numerical study of EvoLS on commonly used benchmark problems and a real-world computationally expensive aerodynamic car rear design problem highlights the efficacy of the proposed EvoLS in attaining reliable, high quality, and efficient performance under a limited computational budget. 23817725 The Role of Cardiovascular Magnetic Resonance (CMR) and Computed Tomography (CCT) in Facilitating Heart Failure Management. Cardiovascular magnetic resonance (CMR) and cardiac computed tomography (CCT) offer advantages for detecting left or right ventricular dysfunction in patients with or suspected of heart failure. CMR does not expose patients to ionizing radiation, and thus is well-suited for functional assessments and serial studies. CCT provides high spatial resolution, making it useful for the identification of coronary arteriosclerosis associated with ischemic cardiomyopathy. In this review, the clinical applications of CMR and CCT are individually discussed, with comparisons made between them to examine the strengths of each modality. The major techniques for each modality are outlined, as well as their uses for the evaluation of cardiomyopathy in heart failure patients with reduced left ventricular ejection fraction, preserved left ventricular ejection fraction, and valvular heart disease. Finally, we review the utility of CMR and CCT in determining which patients will benefit from cardiac resynchronization therapy. 23648636 The syndrome of the "obsessive-compulsory scientist": a new mental disorder? Abstract Obsessive-compulsive disorder (OCD) is the fourth most common mental disorder. Such a high prevalence inherently means that several unsuspected individuals might be affected, plausibly including several scientists who might more or less unconsciously express obsessive-compulsory (OC) activities in their routine activity. 23924171 Combined Sulfur K-Edge XANES-EXAFS Study of the Effect of Protonation on the Sulfate Tetrahedron in Solids and Solutions. Sulfur K-edge X-ray absorption spectroscopy (XAS) has been used to distinguish between aqueous and solid sulfates and to investigate changes in their speciation. Data have been collected for tetrahedrally coordinated S in K2SO4 and KHSO4 solids and aqueous solutions. With a first qualitative analysis of the X-ray absorption near-edge structure (XANES) spectra, it has been observed that those for solids are much more structured and distinguishable from those of aqueous solutions. The protonation state has a strong effect on the white line of sulfates and has been assigned to the different charge delocalization in the samples, the effect of the solvating water molecules and multiple scattering effects. In the extended X-ray absorption fine structure (EXAFS) spectra, the backscattering from the first O shell dominated the EXAFS fine structure function, χ(k), but the nonlinear multiple scattering contributions occurring in the first coordination shell are significant and must be considered in the EXAFS analysis. The intensity of these contributions strongly depend on the symmetry of the system. For a distorted tetrahedron, the intensity of the multiple scattering contributions is less than that found in a regular tetrahedron. The FEFF code has been used to model the contributions of the multiple-scattering processes. The observed experimental evidence in the XAS data can be used to distinguish between sulfates in solids and liquids. This is applicable to many chemical, geochemical, and biological systems. 23425153 Directed organization of DNA filaments in a soft matter template. We have developed a noninvasive, all-optical, holographic technique for permanently aligning liquid crystalline DNA filaments in a microperiodic template realized in soft-composite (polymeric) materials. By combining optical intensity holography with a selective microfluidic etching process, a channelled microstructure has been realized which enables self-assembly of DNA. The striking chemicophysical properties of the structure immobilize the DNA filaments within the microchannels without the need of any kind of surface chemistry or functionalization. Polarized optical, confocal, and electronic microscopies have been used for characterizing the DNA geometry inside the microchannels in terms of birefringence, fluorescence, and nanoscale organization properties. In particular, observation of a far-field diffraction pattern confirms a periodic organization of the DNA filaments inside the polymeric template. 23578653 Flavonol glycosides with lipid accumulation inhibitory activity and simultaneous quantitative analysis of 15 polyphenols and caffeine in the flower buds of Camellia sinensis from different regions by LCMS. A simultaneous quantitative analytical method for 15 major polyphenols, e.g. five catechins (1-5) and 10 flavonols (6-15), as functional constituents in the extracts of "tea flowers", the flower buds of Camellia sinensis (Theaceae), has been developed. The content of caffeine (16), which showed similar chromatographic behaviour under the analytical conditions, was also determined. To approve the validity of the newly developed protocol, thirteen extracts of the plant's flower buds collected from different regions, i.e. China, Taiwan, Japan and India, were evaluated. The results indicated that the assay was reproducible and precise, and could be readily underutilised for the quality evaluation of tea flowers on the basis of polyphenols' contents. It was noteworthy that the contents of two major constituents, kaempferol 3-O-β-d-glucopyranosyl-(1→3)-α-l-rhamnopyranosyl-(1→6)-β-d-glucopyranoside (10) and kaempferol 3-O-β-d-glucopyranosyl-(1→3)-α-l-rhamnopyranosyl-(1→6)-β-d-galactopyranoside (11), varied by region where the flower buds were produced. A new flavonol glycoside, chakaflavonoside B (17), which was isolated in the course of this analytical study, was found to show oleic acid-albumin-induced lipid accumulation inhibitory activity. 23136033 CDK-EPI equation may be the most proper formula based on creatinine in determining glomerular filtration rate in Chinese patients with chronic kidney disease. To compare the performance of the Chronic Kidney Disease Epidemiology Collaboration (CDK-EPI) equation, the 24-h creatinine clearance rate (24hCCr), Cockroft-Gault (C-G) formula, the abbreviated Modification of Diet in Renal Disease (aMDRD) equation, the modified Modification of Diet in Renal Disease (mMDRD) equation in determining glomerular filtration rate (GFR) in Chinese patients with chronic kidney disease (CKD) and detect the most proper method to measure GFR in clinical practice. One hundred and fifty-four patients with CKD were enrolled in the present study. (99m)Tc-diethylene triamine pentaacetic acid ((99m)Tc-DTPA) plasma clearance method measured by dual plasma sampling method (rGFR) was considered as the reference standard. GFR was estimated simultaneously using five methods: (1) CDK-EPI equation (eGFR1); (2) 24hCCr (eGFR2); (3) C-G formula (eGFR3); (4) abbreviated MDRD equation (eGFR4); (5) mMDRD equation (eGFR5). The comparison of correlation, regression, bias, precision, accuracy, limit of agreement, and receiver-operating characteristics (ROC) for detecting CKD (with a GFR cutoff of 60 mL min(-1) 1.73 m(-2)) among the methods was analyzed to identify the most suitable method. All the equations correlated well with rGFR, and the correlation coefficient of CDK-EPI equation was the highest (reGFR1 = 0.922, P < 0.001). The Bland-Altman analysis showed that the limit of agreement for CDK-EPI equation was -25.5 to 30.3 mL min(-1) 1.73 m(-2), which was the least range among the tested equations. The CDK-EPI equation represented the best capability in precision (14.24 mL min(-1) 1.73 m(-2)). The ROC curve showed the best performance in detecting CKD. The accuracy within ±30 % of CDK-EPI equation, 24hCCr, and mMDRD equation was 72.08, 69.48, and 70.13 %, respectively, and no statistical significant difference was found (P > 0.05). However, CDK-EPI equation had the highest accuracy when compared with the other two equations (P < 0.05). And its performance on bias showed no statistically significant difference compared with other four equations. Although its bias and accuracy did not overmatch the other four equations in our patient group, the CDK-EPI equation outperformed the other equations based on creatinine in correlation, precision, limit of agreement, and detecting CKD, and it is very simple, time-saving, and cost-effective. So we recommend intensely that the CDK-EPI equation is the most suitable method in determining GFR in Chinese patients with CKD and can be applied generally in clinical practice. 23814018 PPARα and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia. High-dose glucocorticoids (GCs) can be a useful treatment for aggressive forms of chronic lymphocytic leukemia (CLL). However, their mechanism of action is not well understood, and resistance to GCs is inevitable. In a minimal, serum-free culture system, the synthetic GC dexamethasone (DEX) was found to decrease the metabolic activity of CLL cells, indicated by down-regulation of pyruvate kinase M2 (PKM2) expression and activity, decreased levels of pyruvate and its metabolites, and loss of mitochondrial membrane potential. This metabolic restriction was associated with decreased size and death of some of the tumor cells in the population. Concomitant plasma membrane damage increased killing of CLL cells by DEX. However, the nuclear receptor peroxisome proliferator activated receptor α (PPARα), which regulates fatty acid oxidation, was also increased by DEX, and adipocyte-derived lipids, lipoproteins, and propionic acid protected CLL cells from DEX. PPARα and fatty acid oxidation enzyme inhibitors increased DEX-mediated killing of CLL cells in vitro and clearance of CLL xenografts in vivo. These findings suggest that GCs prevent tumor cells from generating the energy needed to repair membrane damage, fatty acid oxidation is a mechanism of resistance to GC-mediated cytotoxicity, and PPARα inhibition is a strategy to improve the therapeutic efficacy of GCs. 23715176 Molecularly-imprinted nanoparticles that recognize Naja mossambica cytotoxins: binding studies and biological effects. We report the development of molecularly imprinted polyacrylamide nanoparticles that bind to and neutralize the activity of cytotoxins present in the venom of the Mozambique Spitting Cobra (Naja mossambica mossambica). The binding activity of these nanoparticles is avid and specific. These findings hold promise for the development of a synthetic antivenom. 23875777 Synaptodendritic recovery following HIV Tat exposure: Neurorestoration by phytoestrogens. HIV-1 infects the brain and, despite antiretroviral therapy, many infected individuals suffer from HIV-1-associated neurocognitive disorders (HAND). HAND is associated with dendritic simplification and synaptic loss. Prevention of synaptodendritic damage may ameliorate or forestall neurocognitive decline in latent HIV-1 infections. The HIV-1 transactivating protein (Tat) is produced during viral latency in the brain and may cause synaptodendritic damage. This study examined the integrity of the dendritic network after exposure to HIV-1 Tat by labeling filamentous actin (F-actin)-rich structures (puncta) in primary neuronal cultures. After 24 h of treatment, HIV-1 Tat was associated with the dendritic arbor and produced a significant reduction of F-actin-labeled dendritic puncta as well as loss of dendrites. Pre-treatment with either of two plant-derived phytoestrogen compounds (daidzein and liquiritigenin), significantly reduced synaptodendritic damage following HIV-1 Tat treatment. In addition, 6 days after HIV-1 Tat treatment, treatment with either daidzein, or liquiritigenin enhanced recovery, via the estrogen receptor, from HIV-1 Tat-induced synaptodendritic damage. These results suggest that either liquiritigenin or daidzein may not only attenuate acute synaptodendritic injury in HIV-1 but may also promote recovery from synaptodendritic damage. The HIV-1 transactivating protein (Tat) is produced during viral latency in the brain. Treatment with either daidzein or liquiritigenin restored the loss of synaptic connectivity produced by HIV-1 Tat. This neurorestoration was mediated by estrogen receptors (ER). These results suggest that plant-derived phytoestrogens may promote recovery from HIV-1-induced synaptodendritic damage. 23859657 The eradication of breast cancer cells and stem cells by 8-hydroxyquinoline-loaded hyaluronan modified mesoporous silica nanoparticle-supported lipid bilayers containing docetaxel. Breast cancer stem cells (BCSCs), which can fully recapitulate the tumor origin and are often resistant to chemotherapy and radiotherapy, are currently considered as a major obstacle for breast cancer treatment. To achieve the goal of both targeting BCSCs and bulk breast cancer cells, we developed 8-hydroxyquinoline-loaded hyaluronan modified mesoporous silica nanoparticles (MSN)-supported lipid bilayers (HA-MSS) and docetaxel-loaded MSS. The results showed that the size of all the nanoparticles was smaller than 200 nm. BCSCs were enriched from MCF-7 cells by a sphere formation method and identified with the CD44(+)/CD24(-) phenotype. Quantitative and qualitative analysis demonstrated that HA promotes the uptake of HA-MSS in CD44-overexpressing MCF-7 mammospheres, revealing the mechanism of receptor-mediated endocytosis. DTX or DTX-loaded MSS showed much enhanced cytotoxicity against MCF-7 cells compared with MCF-7 mammospheres, whereas 8-HQ or 8-HQ-loaded HA-MSS showed much enhanced cytotoxicity against MCF-7 mammospheres compared with MCF-7 cells. In the MCF-7 xenografts in mice, the combination therapy with DTX-loaded MSS plus 8-HQ-loaded HA-MSS produced the strongest antitumor efficacy, with little systemic toxicity (reflecting by loss of body weight) in mice. Thus, this combination therapy may provide a potential strategy to improve the therapy of breast cancer by eradication of breast cancer cells together with BCSCs. 23959527 Smad7 modulates TGF-beta signaling during cranial suture development to maintain suture patency. Craniosynostosis, the premature fusion of one or more sutures between the calvarial bones, is a common birth defect. Mutations in genes encoding receptors for the transforming growth factor-beta (TGFβ) family of signaling molecules have been associated with craniosynostosis, but how TGFβ signaling is regulated during suture development is not known. In the present study, we found that expression of Smad2 and Smad3, intracellular mediators of canonical TGFβ signaling, gradually increases during early postnatal suture development in rat in both the coronal suture (CS), which remains patent throughout life, and the posterior frontal suture (PFS), which undergoes programmed closure by postnatal day 22. The amounts of phosphorylated Smad2 and Smad3 proteins showed a similar gradual increase in the PFS and CS, but in the CS, Smad2/3 activation was suppressed after neonatal day 10. The suppression of Smad2/3 activation in the CS correlated with upregulation of Smad7 expression. We demonstrate that siRNA-mediated knockdown of Smad7 caused increased phosphorylation of Smad2 and Smad3 and induced osseous obliteration of the CS from postnatal day 10 to 22. The Smad7 siRNA-induced CS closure was associated with significantly increased levels of Fgf10 and phosphorylated ERK1/2 in the suture mesenchyme. Moreover, addition of the Erk1/2 inhibitor U0126 partially blocked Smad7-siRNA induced CS closure. These findings suggest that canonical TGFβ signaling induces suture closure at least in part through activation of FGF and ERK signaling, and that Smad7 plays an important role in maintaining suture patency by suppressing canonical TGFβ signaling during suture development. 23939098 Color constancy enhancement under poor illumination: errata. In an earlier Letter [Opt. Lett.36, 4821 (2011)] an error was made in an equation. That error is corrected here. 23879647 Real-time 2D/3D registration using kV-MV image pairs for tumor motion tracking in image guided radiotherapy. Intra-fractional respiratory motion during radiotherapy leads to a larger planning target volume (PTV). Real-time tumor motion tracking by two-dimensional (2D)/3D registration using on-board kilo-voltage (kV) imaging can allow for a reduction of the PTV though motion along the imaging beam axis cannot be resolved using only one projection image. We present a retrospective patient study investigating the impact of paired portal mega-voltage (MV) and kV images on registration accuracy. Material and methods. We used data from 10 patients suffering from non-small cell lung cancer (NSCLC) undergoing stereotactic body radiation therapy (SBRT) lung treatment. For each patient we acquired a planning computed tomography (CT) and sequences of kV and MV images during treatment. We compared the accuracy of motion tracking in six degrees-of-freedom (DOF) using the anterior-posterior (AP) kV sequence or the sequence of kV-MV image pairs. Results. Motion along cranial-caudal direction could accurately be extracted when using only the kV sequence but in AP direction we obtained large errors. When using kV-MV pairs, the average error was reduced from 2.9 mm to 1.5 mm and the motion along AP was successfully extracted. Mean registration time was 188 ms. Conclusion. Our evaluation shows that using kV-MV image pairs leads to improved motion extraction in six DOF and is suitable for real-time tumor motion tracking with a conventional LINAC. 23525882 Development and clinical usability of a new traction device "medical ring" for endoscopic submucosal dissection of early gastric cancer. Although various traction devices exist for endoscopic submucosal dissection (ESD), the effects of the material used in the devices on the human body has not been considered. Moreover, there has been no report on a device that facilitates dissection both on the oral and anal side of the lesion. We made a traction device that has no deleterious effects on the body and is noninvasive, easy to use, and enables a bilateral approach in ESD. We report the process of its creation and a prospective evaluation of its usage in actual ESD procedures. This study is prospective case control study. Thirty-seven patients for whom the device would be used were consecutively and prospectively enrolled (device used group). Control subjects in whom the device would not be used and who had lesions matched for size and location with those of the device used group were randomly selected (device not used group). Both groups were classified into three subgroups according to treatment difficulty: group A: easy; group B: intermediate; and group C: difficult. The dissection time per cm(2) in each group was examined. Dissection times in the device not used group/device used group were as follows: group A, 5.8/2.1 min/cm(2) (p < 0.01); group B, 6.1/3.8 min/cm(2) (p < 0.05); and group C, 7.9/3.6 min/cm(2) (p < 0.01), respectively. The newly developed medical ring was shown to be feasible and safe and allowed excellent visualization through suitable tension and facilitated rapid gastric ESD. 23161737 Detection of silver nanoparticles on a lab-on-chip platform. The prevalent use of silver nanoparticles (AgNPs) in commercial goods has brought forth an urgent need for environmental salvation. With the global river systems being contaminated by AgNPs, fast and efficient detection systems are needed to trace the presence of AgNPs in common water to prevent detrimental effects to the public health. In this work, the detection of AgNPs via electrochemical oxidation has been achieved on a "Lab-on-chip" platform. This platform provides a fast, convenient, and portable detection system for the detection of AgNPs in common water. 23644197 Synthesis and biological evaluation of novel phosphatidylinositol 3-kinase inhibitors: Solubilized 4-substituted benzimidazole analogs of 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474). A range of 4-substituted derivatives of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) were prepared in a search for more soluble analogs. 4-Aminoalkoxy substituents provided the most potent derivatives, with the 4-O(CH2)3NMe2 analog (compound 14) being identified as displaying the best overall activity in combination with good aqueous solubility (25 mg/mL for the hydrochloride salt). This compound was tested in a U87MG xenograft model, but displayed less potency than ZSTK474 as a result of an unfavorable pharmacokinetic profile. 23919736 Is an increase in skin temperature predictive of neuropathic foot ulceration in people with diabetes? A systematic review and meta-analysis. The aim of this systematic review was to evaluate the strength of the existing research to answer the question: Is an increase in skin temperature predictive of neuropathic foot ulceration in people with diabetes? This study is a systematic review and meta-analysis of temperature-monitoring in the prediction and prevention of diabetic foot ulceration. Two investigators conducted a literature search for all relevant articles from 1960 until July 2011. During this process the following data bases were searched: MEDLINE, Science Direct, AMED, Australian Medical Index, APAIS-Health, ATSIhealth, EMBASE, Web of Science and OneSearch. Keywords used in this search included diabetes, foot complications, ulceration, temperature-monitoring, prediction and prevention. Results of the meta-analysis support the theory that an increase in skin temperature is predictive of foot ulceration when compared with the same site on the contralateral limb. The theory that there is a mean norm foot temperature which can be used as a benchmark to monitor pathological change was unsupported by this meta-analysis. The conclusions derived from this review are based on the best available scientific evidence in this field. It is intended that the results of this study will improve clinical decision-making and encourage the appropriate measures used to predict and prevent ulceration in people with diabetes at high risk of foot complications. Based on quality studies in this area, the results of this review have indicated that the use of temperature-monitoring is an effective way to predict, and thus prevent, diabetic foot ulceration. 23950674 The genus Aphidura (Hemiptera, Aphididae) in the collection of the Muséum national d'Histoire naturelle of Paris, with six new species. Specimens were studied of 65 samples of the genus Aphidura (Aphididae, Aphidinae, Macrosiphini) from the collection of the Muséum national d'Histoire naturelle (Paris). The possible synonymies of three pairs of species are discussed. New aphid host plant relationships are reported for Aphidura bozhkoae, Aphidura delmasi, Aphidura ornata, Aphidura pannonica and Aphidura picta; this last species is recorded for first time from Afghanistan. The record of Aphidura pujoli from Pakistan is refuted. The fundatrices, oviparous females and males of Aphidura delmasi are described. Six new species are established: Aphidura gallica sp. n. and Aphidura amphorosiphon sp. n. from specimens caught on species of Silene (Caryophyllaceae) from France and Iran, respectively, Aphidura pakistanensis sp. n., Aphidura graeca sp. n. and Aphidura urmiensis sp. n. from specimens caught on species of Dianthus, Gypsophila and Spergula (Caryophyllaceae) from Pakistan, Greece and Iran, respectively, and Aphidura iranensis sp. n. from specimens caught on Prunus sp. from Iran. Modifications are made to the keys by Blackman and Eastop to aphids living on Dianthus, Gypsophyla, Silene, Spergula and Prinsepia and Prunus (Rosaceae). An identification key to apterous viviparous females of species of Aphidura is also provided. 23932643 Graft union formation in artichoke grafting onto wild and cultivated cardoon: An anatomical study. In order to develop a non-chemical method such as grafting effective against well-known artichoke soil borne diseases, an anatomical study of union formation in artichoke grafted onto selected wild and cultivated cardoon rootstocks, both resistant to Verticillium wilt, was performed. The cardoon accessions Belgio (cultivated cardoon) and Sardo (wild cardoon) were selected as rootstocks for grafting combinations with the artichoke cv. Romolo. Grafting experiments were carried out in the autumn and spring. The anatomical investigation of grafting union formation was conducted by scanning electron microscopy (SEM) on the grafting portions at the 3rd, 6th, 10th, 12th day after grafting. For the autumn experiment only, SEM analysis was also performed at 30d after grafting. A high affinity between artichoke scion and cardoon rootstocks was observed, with some genotype differences in healing time between the two bionts. SEM images of scion/rootstock longitudinal sections revealed the appearance of many interconnecting structures between the two grafting components just 3d after grafting, followed by a vascular rearrangement and a callus development during graft union formation. De novo formation of many plasmodesmata between scion and rootstock confirmed their high compatibility, particularly in the globe artichoke/wild cardoon combination. Moreover, the duration of the early-stage grafting process could be influenced not only by the scion/rootstock compatibility, but also by the seasonal conditions, being favored by lower temperatures and a reduced light/dark photoperiod. 23927731 Cyclic Tensile Strain Enhances Osteogenesis and Angiogenesis in Human Mesenchymal Stem Cells from Osteoporotic Donors. We have shown that uniaxial cyclic tensile strain of magnitude 10% promotes and enhances osteogenesis of human mesenchymal stem cells (hMSC) and human adipose derived stem cells (hASC) from normal, non-osteoporotic donors. In the present study, MSC from osteoporotic donors were analyzed for changes in mRNA expression in response to 10% uniaxial tensile strain to identify potential mechanisms underlying the use of this mechanical loading paradigm for prevention and treatment of osteoporosis. Human MSC isolated from three female, post-menopausal osteoporotic donors were analyzed for their responses to mechanical loading using microarray analysis of over 47,000 gene probes. Human MSC were seeded in three-dimensional collagen type I constructs to mimic the organic extracellular matrix (ECM) of bone and 10% uniaxial cyclic tensile strain was applied to promote osteogenesis. 79 genes were shown to be regulated within hMSC from osteoporotic donors in response to 10% cyclic tensile strain. Upregulation of six genes were further confirmed with real time RT-PCR: JUND and PLAUR, two genes identified as potential key molecules from network analysis; PIK3CD and WNT5B, two genes with known importance in bone biology; and, PDLIM4 and VEGFA, two genes that we have previously shown are significantly regulated in hASC in response to this mechanical stimulus. Function analysis indicated that 10% cyclic tensile strain induced expression of genes associated with cell movement, cell proliferation, and tissue development including development in musculoskeletal and cardiovascular systems. Our results demonstrate that hMSC from aged, osteoporotic donors are capable of enhanced osteogenic differentiation in response to 10% cyclic tensile strain with significant increases in expression of genes associated with enhanced cell proliferation, musculoskeletal development, and angiogenesis. Surprisingly, cyclic tensile strain of magnitude 10% not only enhanced osteogenesis in hMSC from osteoporotic donors but also enhanced expression of angiogenic factors. Better understanding and methodologies to promote osteogenesis in hMSC from elderly, osteoporotic donors may greatly facilitate achieving long-term success in bone regeneration and functional bone tissue engineering for this ever-growing patient population. 22323477 In vitro evaluation of the protective effects of 4-thujanol against mitomycin-C and cyclophosphamide-induced genotoxic damage in human peripheral lymphocytes. 4-Thujanol (sabinene hydrate), a bicyclic monoterpene alcohol, is found in the essential oils of many aromatic and medicinal plants and is widely used as a fragrance and flavouring agent in many different products. The aim of this study was to evaluate the protective effects of 4-thujanol against the genotoxic effects induced by mitomycin C (MMC) and cyclophosphamide (CP) in human lymphocytes, using the chromosome aberrations, sister chromatid exchanges, and micronucleus tests, in the absence and in the presence of S9 mix, respectively. The cells were treated with 0.25 µg/mL MMC and 28 µg/mL CP as alone and cotreated with 13 + 0.25, 26 + 0.25, and 52 + 0.25 µg/mL 4-thujanol + MMC and with 13 + 28, 26 + 28, and 52 + 28 µg/mL 4-thujanol + CP as a mixture. The present study showed that 4-thujanol was unable to reduce the genetic damage induced by MMC, in the absence of S9 mix. On the other hand, probably the metabolites of 4-thujanol act as an antagonist and markedly antagonize CP-induced genotoxicity, in the presence of S9 mix. In general, 4-thujanol + MMC and 4-thujanol + CP decreased the mitotic index, proliferation index and nuclear division index to the same extent or more than those of individual exposure of MMC or CP. In conclusion, 4-thujanol significantly reduced (p < 0.001) the genotoxic damage induced by CP but not MMC when compared with the respective positive control alone. We can suggest that 4-thujanol may improve the chemopreventive effects and may also reduce the harmful side effects of CP, which is widely used in chemotherapy against cancer, without reducing its antiproliferative activities. 23750737 Real-time observation of the formation of excited radical ions in bimolecular photoinduced charge separation: absence of the Marcus inverted region explained. Unambiguous evidence for the formation of excited ions upon ultrafast bimolecular photoinduced charge separation is found using a combination of femtosecond time-resolved fluorescence up-conversion, infrared and visible transient absorption spectroscopy. The reaction pathways are tracked by monitoring the vibrational energy redistribution in the product after charge separation and subsequent charge recombination. For moderately exergonic reactions, both donor and acceptor are found to be vibrationally hot, pointing to an even redistribution of the energy dissipated upon charge separation and recombination in both reaction partners. For highly exergonic reactions, the donor is very hot, whereas the acceptor is mostly cold. The asymmetric energy redistribution is due to the formation of the donor cation in an electronic excited state upon charge separation, confirming one of the hypotheses for the absence of the Marcus inverted region in photoinduced bimolecular charge separation processes. 23256867 Construction and Characterization of Molecular Nonwoven Fabrics Consisting of Cross-Linked Poly(γ-methyl-l-glutamate). Molecular nonwoven fabrics in the form of ultrathin layer-by-layer (LbL) helical polymer films with covalent cross-linking were assembled on substrates by an alternate ester-amide exchange reaction between poly(γ-methyl l-glutamate) (PMLG) and cross-linking agent ethylene diamine or 4,4'-diamino azobenzene. The regular growth of helical monolayers without excessive adsorption and the formation of amide bonds were confirmed by ultraviolet-visible (UV-vis) spectrophotometry, quartz crystal microbalance (QCM), ellipsometry, and infrared reflection-absorption spectroscopy (IR-RAS) measurements. Nanostructures with high uniformity and ultrathin films with few defects formed by helical rod segments of PMLG were characterized by atomic force microscopy (AFM) and Kelvin probe force microscopy (KFM). 23929928 Randomized Controlled Trial of Febuxostat Versus Allopurinol or Placebo in Individuals with Higher Urinary Uric Acid Excretion and Calcium Stones. Higher urinary uric acid excretion is a suspected risk factor for calcium oxalate stone formation. Febuxostat, a xanthine oxidoreductase inhibitor, is effective in lowering serum urate concentration and urinary uric acid excretion in healthy volunteers and people with gout. This work studied whether febuxostat, compared with allopurinol and placebo, would reduce 24-hour urinary uric acid excretion and prevent stone growth or new stone formation. In this 6-month, double-blind, multicenter, randomized controlled trial, hyperuricosuric participants with a recent history of calcium stones and one or more radio-opaque calcium stone ≥3 mm (as seen by multidetector computed tomography) received daily febuxostat at 80 mg, allopurinol at 300 mg, or placebo. The primary end point was percent change from baseline to month 6 in 24-hour urinary uric acid. Secondary end points included percent change from baseline to month 6 in size of index stone and change from baseline in the mean number of stones and 24-hour creatinine clearance. Of 99 enrolled participants, 86 participants completed the study. Febuxostat led to significantly greater reduction in 24-hour urinary uric acid (-58.6%) than either allopurinol (-36.4%; P=0.003) or placebo (-12.7%; P<0.001). Percent change from baseline in the size of the largest calcium stone was not different with febuxostat compared with allopurinol or placebo. There was no change in stone size, stone number, or renal function. No new safety concerns were noted for either drug. Febuxostat (80 mg) lowered 24-hour urinary uric acid significantly more than allopurinol (300 mg) in stone formers with higher urinary uric acid excretion after 6 months of treatment. There was no change in stone size or number over the 6-month period. 23954307 Advances in lipase-catalyzed esterification reactions. Lipase-catalyzed esterification reactions are among the most significant chemical and biochemical processes of industrial relevance. Lipases catalyze hydrolysis as well as esterification reactions. Enzyme-catalyzed esterification has acquired increasing attention in many applications, due to the significance of the derived products. More specifically, the lipase-catalyzed esterification reactions attracted research interest during the past decade, due to an increased use of organic esters in biotechnology and the chemical industry. Lipases, as hydrolyzing agents are active in environments, which contain a minimum of two distinct phases, where all reactants are partitioned between these phases, although their distribution is not fixed and changes as the reaction proceeds. The kinetics of the lipase-catalyzed reactions is governed by a number of factors. This article presents a thorough and descriptive evaluation of the applied trends and perspectives concerning the enzymatic esterification, mainly for biofuel production; an emphasis is given on essential factors, which affect the lipase-catalyzed esterification reaction. Moreover, the art of using bacterial and/or fungal strains for whole cell biocatalysis purposes, as well as carrying out catalysis by various forms of purified lipases from bacterial and fungal sources is also reviewed. 23355022 Depositional behaviour of C-org, N, P and K in the surface sediments of two shallow water bodies in a tropical coast, India. The present paper deals with the distribution of sediment and sediment-bound nutrients in two important coastal lagoons of southern Kerala such as the Ashtamudi Estuarine Lagoon in the Kollam district and the Kadinamkulam Lagoon in the Thiruvananthapuram district. Among the two lagoons, the former is coast perpendicular, and the latter is coast parallel. An analysis of the textural characteristics reveals that, in both lagoons, the estuarine mouth and areas close to it are dominated by sand and sand-rich sediment species, indicating a high-energy depositional regime prevailing the region. On the other hand, the silt and clay dominant arms are almost sheltered and enjoy a low-energy depositional environment. The nutrient and organic carbon contents in the sheltered areas are significantly higher than the most dynamic high-energy estuarine mouth regions. This peculiar behaviour of these coastal water bodies has to be given adequate importance while laying down strategies for the conservation and management of these fragile aquatic systems in the south-western coast of India in particular and tropical coasts of the world in general. 23879867 How Composition Methods Are Developed and Validated. Method validation is a critical prerequisite to performing analytical methods in the laboratory. A given analytical method is validated for a specific matrix or matrices. If the matrix to be tested is not included in the original scope of method validation, a validation must be performed to determine if the method is applicable to that particular matrix. A number of organizations, such as AOAC and ISO, publish peer-reviewed methods for cross-industry matrices, whereas others, such as AOCS and AACC, are focused on specific industry segments (fats/oils and cereal grains). When no validated method is available for the analyte of interest, method development and validation must first be performed to ensure that correct identification and quantification of the analyte are being observed and measured. Development of a new method requires an understanding of the chemistry and properties of the analyte to be tested, as well as the various types of instrumentation currently available. Method development and improvement is a continuous process, as technology advances and new instrumentation and techniques become available. This paper addresses some of the decisions related to method development but will primarily focus on validation as it applies to compositional testing of foods, crops, and commodities, the factors that determine method selection, and how extensive the validation need be. 23894398 The Bacterial Protein Azurin Impairs Invasion and FAK/Src Signaling in P-Cadherin-Overexpressing Breast Cancer Cell Models. P-cadherin overexpression occurs in about 30% of all breast carcinomas, being a poor prognostic factor for breast cancer patients. In a cellular background of wild-type E-cadherin, we have previously shown that its expression promotes invasion, motility and migration of breast cancer cells due to the induced secretion of metalloproteases (MMPs) to the extracellular medium and to the concomitant shedding of a pro-invasive soluble form of this protein (sP-cad). Azurin is secreted by Pseudomonas aeruginosa and induces in vitro and in vivo cytotoxicity after its preferential penetration in human cancer cells relative to normal cells. Three different breast cancer cell lines, MCF-7/AZ.Mock, MCF-7/AZ.Pcad and SUM149 were treated with sub-killing doses of azurin. Invasion of these cells was measured using Matrigel Invasion Assays and MTT assays were performed to determine cell viability upon treatment and the effects on cadherins expression was determined by Western blot and Immunofluorescence. Gelatin Zymography was used to determine activity of MMP2 in the conditioned media of azurin treated and untreated cells and the phosphorylation levels of intracellular signaling proteins were determined by Western blot. The invasive phenotype of these breast cancer cells was significantly reduced by azurin. Azurin (50-100 µM) also caused a specific decrease on P-cadherin protein levels from 30-50% in MCF-7/AZ.Pcad and SUM149 breast cancer cell lines, but the levels of E-cadherin remain unaltered. More, the levels of sP-cad and the activity of MMP2 were reduced in the extracellular media of azurin treated cells and we also observed a decrease in the phosphorylation levels of both FAK and Src proteins. Our data show that azurin specifically targets P-cadherin, not E-cadherin, abrogating P-cadherin-mediated invasive effects and signaling. Therefore, azurin could possibly be considered a therapeutic tool to treat poor-prognosis breast carcinomas overexpressing P-cadherin in a wild type E-cadherin context. 23953458 Determination of chlorophenols in water by headspace solid phase microextraction ion mobility spectrometry (HS-SPME-IMS). Chlorophenols (CPs) as persistent toxic compounds are of worldwide environmental concern. Usage of chlorinated phenols, especially pentachlorophenol (PCP), has been restricted or widely banned in many countries due to their possible adverse health effects even at low concentrations. Ion mobility spectrometry (IMS) has received increasing interest in environmental applications due to its unique characteristics, such as portability and speed of analysis. A range of sample introduction methods combined with IMS enable analysis from different environmental matrices. This study utilised headspace solid phase microextraction IMS (HS-SPME-IMS) in the determination of CPs from water samples. The extraction conditions were examined and the method was applied to real water samples. The developed method is suitable to detect CPs at milligram per liter level in water. Based on the results, SPME-IMS setup is feasible as an early warning system for water monitoring of pollutants present in drinking or surface water in case of environmental accidents or leakages. 23561088 Maqui berry (Aristotelia chilensis) and the constituent delphinidin glycoside inhibit photoreceptor cell death induced by visible light. The protective effects of maqui berry (Aristotelia chilensis) extract (MBE) and its major anthocyanins [delphinidin 3,5-O-diglucoside (D3G5G) and delphinidin 3-O-sambubioside-5-O-glucoside (D3S5G)] against light-induced murine photoreceptor cells (661W) death were evaluated. Viability of 661W after light treatment for 24h, assessed by the tetrazolium salt (WST-8) assay and Hoechst 33342 nuclear staining, was improved by addition of MBE, D3G5G, and D3S5G. Intracellular radical activation in 661W, evaluated using the reactive oxygen species (ROS)-sensitive probe 5-(and-6)-chloromethyl-2,7-dichlorodihydro fluorescein diacetate acetyl ester (CM-H2DCFDA), was reduced by MBE and its anthocyanins. The anti-apoptosis mechanism of MBE was evaluated by light-induced phosphorylation of p38. MBE significantly suppressed the light-induced phosphorylation of p38. These findings indicate that MBE and its anthocyanidins suppress the light-induced photoreceptor cell death by inhibiting ROS production, suggesting that the inhibition of phosphorylated-p38 may be involved in the underlying mechanism. 23700295 Critical role of TRPC6 channels in the development of human renal cell carcinoma. Renal cell carcinoma (RCC) is the most common tumor arising from the cells in the lining of tubules in the kidney. Some members of the Ca(2+)-permeable transient receptor potential canonical (TRPC) family of channel proteins have demonstrated a role in the proliferation of some types of cancer cells. In this study, we investigated the role of TRPC6 in the development of human RCC. RT-PCR and Western blotting were used to investigate TRPC6 expression in 1932 and ACHN cells. Immunohistochemical techniques were applied to study TRPC6 expression in 60 cases of RCC primary tissue samples and 10 cases of corresponding normal renal tissues. To inhibit TRPC6 activity or expression, RNA interference was used. The effects of TRPC6 channels on RCC cell viability and cell cycle progression were investigated by MTT and flow cytometry. TRPC6 was expressed in 1932 and ACHN cells. TRPC6 protein was detected in 73.3 % of RCC samples, and there was a significant difference compared with the normal renal samples (30 %) (p < 0.05). Moreover the level of TRPC6 expression was associated with RCC Fuhrman grade (p < 0.01). Blockade of TRPC6 channels in ACHN cells suppressed basal cell proliferation and partially inhibited HGF-induced cell proliferation. Furthermore, inhibition of TRPC6 channels expression prolonged the transition through G2/M phase in ACHN cells. In summary, expression of TRPC6 is markedly increased in RCC specimens and associated with RCC histological grade. TRPC6 plays an important role in ACHN cells proliferation. 23178380 Pulmonary delivery of an aerosolized recombinant human butyrylcholinesterase pretreatment protects against aerosolized paraoxon in macaques. Butyrylcholinesterase (BChE) is the leading pretreatment candidate against exposure to organophosphates (OPs), which pose an ever increasing public and military health. Since respiratory failure is the primary cause of death following acute OP poisoning, an inhaled BChE therapeutic could prove highly efficacious in preventing acute toxicity as well as the associated delayed neuropathy. To address this, studies have been performed in mice and macaques using Chinese Hamster Ovary cells (CHO)-derived recombinant (r) BChE delivered by the pulmonary route, to examine whether the deposition of both macaque (Ma) and human (Hu) rBChE administered as aerosols (aer) favored the creation and retention of an efficient protective "pulmonary bioshield" that could scavenge incoming (inhaled) OPs in situ thereby preventing entry into the circulation and inhibition of plasma BChE and AChE on red blood cells (RBC-AChE) and in cholinergic synapses. In contrast to parenteral delivery of rBChE, which currently requires posttranslational modification for good plasma stability, an unmodified aer-rBChE pretreatment given 1-40h prior to >1 LD50 of aer-paraoxon (Px) was able to prevent inhibition of circulating cholinesterase in a dose-dependent manner. These studies are the first to show protection by rBChE against a pesticide such as paraoxon when delivered directly into the lung and bode well for the use of a non-invasive and consumer friendly method of rHuBChE delivery as a human treatment to counteract OP toxicity. 23893554 Outcomes after primary chemoradiotherapy for N3 (> 6cm) head and neck squamous cell carcinoma following an FDG-PET guided neck management policy: Does size still matter? This study aimed to assess whether a positron emission tomography (PET)-directed policy remains appropriate for managing neck nodes larger than 6cm - N3 (>6cm) - in head and neck squamous cell carcinoma (HNSCC). All N3 (>6cm) patients treated with definitive chemoradiotherapy at our institution between 2005 and 2012 were included in the analysis. Patients underwent PET assessment prior to and 12 weeks after chemoradiotherapy. Neck dissections were performed for PET-avid residual nodal abnormalities after complete response at the primary site. Rate of isolated nodal failure (INF) was the primary outcome. Median follow-up from diagnosis for 33 patients was 30 months (range 6 -76). INF occurred in 2 (6%) patients; with neck dissections performed in 4 (12%) cases. First failure was predominantly distant metastatic - 10 (30%). The rate of INF remains low when following a PET-directed neck management policy after definitive chemoradiotherapy for N3 (>6cm) HNSCC. Head Neck, 2013. 23889924 Sequence polymorphisms of rfbT among the Vibrio cholerae O1 strains in the Ogawa and Inaba serotype shifts. Vibrio cholerae serogroup O1 has two major serotypes, Ogawa and Inaba, which may alternate among cholera epidemics. The rfbT gene is responsible for the conversion between the two serotypes. In this study, we surveyed the sequence variance of rfbT in the Ogawa and Inaba strains in China over a 48-year (1961-2008) period in which serotype shifts occurred among epidemic years. Various mutation events including single nucleotide, short fragment insertions/deletions and transposases insertions, were found in the rfbT gene of the Inaba strains. Ectopically introducing an intact rfbT could overcome the mutations by converting the Inaba serotype to the Ogawa serotype, suggesting the effects of these mutations on the function of RfbT. Characteristic rfbT mutations were recognized in the Inaba strains among Inaba serotype dominant epidemic years which were separate from the Ogawa dominant epidemics. Three distinguishable mutation sites in rfbT between the classical and the El Tor biotype strains were identified and could serve as biotype-specific biomarkers. Our results provide a comprehensive picture of the rfbT gene mutations among the V. cholerae O1 strains in different epidemic periods, which could be further used as the tracing markers in clonality analysis and dissemination surveillance of the epidemic strains. 23377578 Anterior Chamber Angle Imaging With Swept-Source Optical Coherence Tomography: Detecting the Scleral Spur, Schwalbe's Line, and Schlemm's Canal. To determine the visibility of the scleral spur (SS), Schwalbe's line (SL), and Schlemm's canal (SC) imaged by a swept-source optical coherence tomographer (OCT). One eye from each individual was randomly selected from 30 normal subjects and 30 patients with primary open-angle glaucoma for anterior segment imaging with a swept-source OCT. The angles were imaged with 2 protocols: (1) high-density (HD, a raster of 64 B-scans each with 512 A-scans over 8 mm) and (2) low-density scans (LD, 128 radial scans each with 512 A-scans over 16 mm). The visibility of the angle structures was determined by 2 masked observers and compared among the superior (90 degrees), nasal (0 degrees), inferior (270 degrees), and temporal (180 degrees) quadrants. The interobserver agreement for assessment of visibility of the angle structures was high with agreement coefficients ranging between 0.769 and 0.987. The SS, SL, and SC were visible by both observers in 95% to 100%, 68% to 98%, and 12% to 42% of a total of 240 (4×60) quadrants in 60 HD images, respectively. The visibility was reduced in LD images (50% to 95%, 0% to 10%, and 0%, respectively). The temporal and nasal quadrants generally had superior visibility of the angle structures than the superior and inferior quadrants. The SS, SL, and SC could be identified with the swept-source OCT although their visibility varied with the scan location and scan density. The SS was best visualized, followed by the SL and then the SC in the OCT images. 22547010 Sorafenib in advanced hepatocellular carcinoma: hypertension as a potential surrogate marker for efficacy. Advanced hepatocellular cancer (HCC) is an incurable disease with limited options for systemic treatment. Sorafenib was approved for advanced HCC based on trials in patients with Child-Pugh class A. We reviewed our experience retrospectively in patients with HCC who were treated with sorafenib with a focus on Child-Pugh B (CP-B) liver cirrhosis and effect of hypertension (HTN) on survival. We retrospectively reviewed medical charts of patients with documented advanced HCC who received sorafenib since 2007. Survival data were plotted according to Child-Pugh class and HTN. Results of 41 patients 39% had CP-B. Eighty-five percent were male and 67% had HCC due to viral hepatitis. Fifty-six percent received localized treatment before sorafenib. Five percent had a partial response and 39% had stable disease. Time to progression and overall survival (OS) for all patients were 3.2 and 6.2 months, respectively. Time to progression and OS were 4 and 8.4 months in Child-Pugh class A patients and 2 and 3.2 months in CP-B patients, which were statistically significant. Patients who had documented HTN while on treatment according to Common Terminology Criteria for Adverse Events version 3.0 had significantly better OS (18.2 vs. 4.5 mo; P=0.016). Development of HTN with sorafenib seems to be associated with a favorable effect on prognosis. Future trials should examine this observation. 23562770 Increased neural responses to unfairness in a loss context. Unfairness plays an important role in economic decision making. This fMRI study sought to investigate how the loss and the gain contexts could modulate behavioral and brain responses to unfairness by focusing on participants' rejection behaviors during an Ultimatum Game paradigm. Participants were scanned while they were playing the Ultimatum Game as responders in both loss and gain contexts, i.e. receiving ¥50 as gains and paying for ¥50 as losses. At the behavioral level, lower fairness ratings and higher rejection rates were revealed for unfair losses than unfair gains. At the neural level, left dorsolateral prefrontal cortex, bilateral anterior insula, anterior cingulate cortex/anterior middle cingulate cortex and bilateral dorsal striatum were associated with rejection (vs. acceptance) in the loss context, but not in the gain context. Together, our data indicated that participants may experience more unfairness in UG and stronger desire to sanction social norm violations in the loss context than in the gain context, inducing more fairness-related neutral activities when rejecting (vs. accepting) unfair losses than unfair gains. These findings shed light on the significance of context (i.e. loss or gain) in fairness-related social decision-making processes. 23619575 Cardiac performance correlates of relative heart ventricle mass in amphibians. This study used an in situ heart preparation to analyze the power output and stroke work of spontaneously beating hearts of four anurans (Rhinella marina, Lithobates catesbeianus, Xenopus laevis, Pyxicephalus edulis) and three urodeles (Necturus maculosus, Ambystoma tigrinum, Amphiuma tridactylum) that span a representative range of relative ventricle mass (RVM) found in amphibians. Previous research has documented that RVM correlates with dehydration tolerance and maximal aerobic capacity in amphibians. The power output (mW g(-1) ventricle mass) and stroke work (mJ g(-1) ventricle muscle mass) were independent of RVM and were indistinguishable from previously published results for fish and reptiles. RVM was significantly correlated with maximum power output (P max, mW kg(-1) body mass), stroke volume, cardiac output, afterload pressure (P O) at P max, and preload pressure (P I) at P max. P I at P max and P O at P max also correlated very closely with each other. The increases in both P I and P O at maximal power outputs in large hearts suggest that concomitant increases in blood volume and/or increased modulation of vascular compliance either anatomically or via sympathetic tone on the venous vasculature would be necessary to achieve P max in vivo. Hypotheses for variation in RVM and its concomitant increased P max in amphibians are developed. 23335133 Fluocinolone acetonide intravitreal implant (Iluvien®): in diabetic macular oedema. Fluocinolone acetonide intravitreal implant (Iluvien®) is an injectable, non-erodible, corticosteroid implant that is approved in several European countries for the treatment of chronic diabetic macular oedema (DMO). In analyses of two multinational trials in patients with DMO previously treated with macular laser photocoagulation, fluocinolone acetonide intravitreal implant 0.2 μg/day was significantly more efficacious than sham injection in improving visual acuity. At 24 months post injection, 29 % of fluocinolone acetonide intravitreal implant 0.2 μg/day recipients had an improvement in the best-corrected visual acuity (BCVA) letter score of ≥15 compared with 16 % in the sham injection group (p = 0.002) [primary endpoint]. Treatment benefit was most evident in the subgroup of patients whose duration of DMO was ≥3 years. In this subgroup at 36 months, 34 % of fluocinolone acetonide intravitreal implant 0.2 μg/day recipients had an increase in the BCVA score of ≥15, compared with 13 % of sham injection recipients (p < 0.001). Fluocinolone acetonide intravitreal implant recipients also had generally greater benefits than sham injection recipients on secondary endpoints. In patients who were phakic in the study eye at baseline, cataracts occurred in 82 % of fluocinolone acetonide intravitreal implant 0.2 μg/day recipients and 51 % of sham injection recipients. Overall, 37 % and 12 % of patients in the fluocinolone acetonide intravitreal implant and sham injection groups developed raised intraocular pressure (IOP), which was generally controlled with IOP-lowering drugs. 23469780 The finely regulating well-defined functional polymeric nanocarriers for anti-tumor immunotherapy. Cancer is the second leading cause of death around the world. Cancer may be induced by viral infection (EBV,HBV and HPV), bacterial infection (Helicobacter pylori), carcinogen, ultraviolet (UV) radiation exposure, and genetic mutation. Tumor can be suppressed by traditional surgery, radiotherapy, and/or chemotherapy with devastating side effects and very poor quality of postoperative life. The therapeutic index has been further promoted by the newly developed nanomedicine. However, the disseminated tumor cells can result in micrometastases. So the cancer can just be supresssed but not cured by these ways. Fortunately, the developments of immunology have successfully improved many disciplines with special effort on oncology. Various immune cells including B cells, T-lymphocytes (TL), natural killer(NK) cells, dendritic cells (DCs), macrophages, and polymorphonuclear leukocytes are recruited to the tumor. These immune cells can recognize, eliminate, and protect the body from viral, bacterial infections, and the transformed cells(pre-cancer cell) extension. The modification of host immune system, and/or the utilization of components of the immune system for cancer treatment are called immunotherapy. The immunotherapy is not only to target and kill tumor cells in aspecific manner, but also to alert the immune system to eradicate the disseminated tumor cells present in the blood circulation and micro-metastases in remote organs. Herein, the development of immunology, cancer immunotherapy,tumor immuno escape was introduced firstly. Then the correlations between host, the tumor and the nano particulates were proposed. And how to improve the cancer immunotherapy by finely nanocarrier's engineering (nanoimmunotherapy) was systematically illustrated with special focus on the unique pathology of tumor microenviroments and properties of immuno cells. 23939486 Factors Influencing the Increasing Disparity in LDL Cholesterol Control Between White and Black Patients With Diabetes in a Context of Active Quality Improvement. After implementing a multifaceted physician-directed quality improvement (QI) initiative, an increased disparity in low-density lipoprotein (LDL) cholesterol control between white and black diabetes patients was observed. To examine possible causes, a retrospective analysis of 962 black and white patients treated continuously between 2008 and 2010 was performed. At baseline, 55.0% of whites and 49.8% of blacks were controlled (5.2% disparity). The disparity increased, with 61.8% of whites and 44.6% of blacks having control in 2010 (17.2% disparity). Among patients uncontrolled at baseline, blacks were less likely to become controlled. Among patients controlled at baseline, blacks were less likely to remain controlled; accounting for patient characteristics and changes in lipid-lowering drug prescription regimens did not attenuate these relationships. Physician-facing, general QI interventions may be insufficient to produce equity in LDL cholesterol control. Helping patients maintain prior success controlling cholesterol appears as important in addressing this disparity as is helping uncontrolled patients achieve control. 23820271 Blood substitutes: evolution from noncarrying to oxygen- and gas-carrying fluids. The development of oxygen (O2)-carrying blood substitutes has evolved from the goal of replicating blood O2 transport properties to that of preserving microvascular and organ function, reducing the inherent or potential toxicity of the material used to carry O2, and treating pathologies initiated by anemia and hypoxia. Furthermore, the emphasis has shifted from blood replacement fluid to "O2 therapeutics" that restore tissue oxygenation to specific tissues regions. This review covers the different alternatives, potential and limitations of hemoglobin-based O2 carriers (HBOCs) and perfluorocarbon-based O2 carriers (PFCOCs), with emphasis on the physiologic conditions disturbed in the situation that they will be used. It describes how concepts learned from plasma expanders without O2-carrying capacity can be applied to maintain O2 delivery and summarizes the microvascular responses due to HBOCs and PFCOCs. This review also presents alternative applications of HBOCs and PFCOCs namely: 1) How HBOC O2 affinity can be engineered to target O2 delivery to hypoxic tissues; and 2) How the high gas solubility of PFCOCs provides new opportunities for carrying, dissolving, and delivering gases with biological activity. It is concluded that the development of current blood substitutes has amplified their applications horizon by devising therapeutic functions for O2 carriers requiring limited O2 delivery capacity restoration. Conversely, full, blood-like O2-carrying capacity reestablishment awaits the control of O2 carrier toxicity. 23514051 Laparoscopic surgery for inflammatory bowel disease-the experience in china. ABSTRACT Background: The incidence of inflammatory bowel disease (IBD) has risen rapidly in China over the last 15 years. Increasing numbers of people with IBD require surgery during their lifetime, but few reports of IBD in Eastern populations have been described to date. The aim of this study was to assess the short-term effects of the laparoscopic surgery for IBD in Chinese patients. Materials and methods: From February 2010 to March 2012, 35 patients with IBD underwent laparoscopic operations and the clinical data obtained for these patients were reviewed. Results: Patients with Crohn's disease (CD) (N = 21) and ulcerative colitis (UC) (N = 14) underwent laparoscopic surgery. In the CD group, the mean age was 37.4 years. Two patients (9.5%) required conversion to an open procedure. The median length of postoperative hospitalization was 9 (7-40) days. Overall morbidity was 26.3% and no patients required re-operation. In the UC group, the mean age was 55.2 years. The conversion rate was 14.3% (2/14). The median time to regular diet was 4 (3-10) days and the median length of postoperative hospitalization was 8 (7-25) days. Four patients developed postoperative complications and one patient developed ileostomy retraction requiring urgent operative intervention to rebuild the stoma. Conclusions: Laparoscopic surgery in patients with IBD can be accomplished safely and with reasonable operative times, conversion rates and morbidity rates. The main advantages of the laparoscopic approach are rapid recovery, improved cosmesis, less postoperative pain, and patient satisfaction. 23523012 Efficacy of decoquinate against Sarcocystis neurona in cell cultures. Decoquinate is a quinolone anticoccidial approved for use in the prevention of intestinal coccidiosis in farm animals. This compound has good activity against Toxoplasma gondii and Neospora caninum in cell cultures. The drug acts on the parasites' mitochondria. The activity of decoquinate against developing merozoites of 2 isolates of Sarcocystis neurona was examined in cell culture. Merozoite production at 10 days was completely inhibited when decoquinate was used at 20 or 240nM. The IC50 of decoquinate was 0.5±0.09nM for the Sn6 isolate of S. neurona from a horse and 1.1±0.6nM for the SnOP15 isolate of S. neurona from an opossum. Levamisole was toxic at 5μg/ml and no synergism was observed when decoquinate was combined with levamisole and tested against the Sn3YFP isolate of S. neurona. Decoquinate was cidal for developing schizonts of S. neurona at 240nM. 23402973 Clearance and bioavailability study through arterio-venous drug concentrations relationship. Venous plasma drug concentrations are routinely monitored in order to determine pharmacokinetic parameters or to establish relationships with drug pharmacodynamic and clinical effects. Arterial drug concentration is higher than the respective venous concentration during the period where drug input of the substance predominates, whereas venous drug concentration is higher during the long period where drug elimination becomes the main process. This arterial-venous difference responds to current bioavailability and clearance of the drug-individual systems. Following the vein/artery plasma drug concentration ratio at a non-eliminating organ it is possible to monitor both parameters time by time. This way of following up the pharmacokinetic systems allows us to detect any changes in drug absorption or disposition more efficiently, without the need of a long period of time and regardless the duration of such system modification. 23861129 Percutaneous edge-to-edge mitral valve repair : Current clinical evidence with the MitraClip System. In the past few years, a myriad of technologies have been developed for percutaneous repair of the mitral valve for patients with severe mitral regurgitation (MR) and at high risk for traditional open-heart mitral valve surgery. Among them, MitraClip has emerged as the only clinically safe and effective method for percutaneous mitral valve repair. This device mimics the surgical edge-to-edge mitral valve repair initially described by Dr. Alfieri. In this article, we review the current clinical evidence on the use of the MitraClip-from the randomized control trial EVEREST II to the information derived from expert high-volume centers. 23448723 Managing incidental genomic findings: legal obligations of clinicians. Purpose:Clinical whole-exome and whole-genome sequencing will result in a broad range of incidental findings, but clinicians' obligations to identify and disclose such findings are a matter of debate. We sought legal cases that could offer insights into clinicians' legal liability.Methods:We searched for cases in which incidental findings were related to the cause of action, using the search engines WestLaw, WestLaw Next, Lexis, and Lexis Advance.Results:We found no case law related to incidental findings from genetic testing but identified eight cases involving incidental findings in medical imaging. These cases suggest that clinicians may face liability for failing to disclose incidental findings that would have offered an opportunity for interventions to improve health outcome, if under the applicable standard of care, they fail to identify or appreciate the significance of the incidental finding or they negligently fail to notify other clinicians and/or the patient of the identified incidental finding. Other cases support liability for failure to refer appropriately to a clinician with greater expertise.Conclusions:Clinicians may face liability if they fail to disclose incidental information that could inform interventions to improve health outcome; information lacking clinical actionability is likely to have less import.Genet Med 2013:15(8):624-629. 23813797 The Role of Human Cytochrome P450 Enzymes in the Formation of 2-Hydroxymetronidazole: CYP2A6 is the High Affinity (Low Km) Catalyst. Despite metronidazole's widespread clinical use since the 1960s, the specific enzymes involved in its biotransformation have not been previously identified. Hence, in vitro studies were conducted to identify and characterize the cytochrome P450 enzymes involved in the formation of the major metabolite, 2-hydroxymetronidazole. Formation of 2-hydroxymetronidazole in human liver microsomes was consistent with biphasic, Michaelis-Menten kinetics. Although several cDNA-expressed P450 enzymes catalyzed 2-hydroxymetronidazole formation at a supratherapeutic concentration of metronidazole (2000 μM), at a "therapeutic concentration" of 100 μM only CYPs 2A6, 3A4, 3A5, and 3A7 catalyzed metronidazole 2-hydroxylation at rates substantially greater than control vector, and CYP2A6 catalyzed 2-hydroxymetronidazole formation at rates 6-fold higher than the next most active enzyme. Kinetic studies with these recombinant enzymes revealed that CYP2A6 has a Km = 289 μM which is comparable to the Km for the high-affinity (low-Km) enzyme in human liver microsomes, whereas the Km values for the CYP3A enzymes corresponded with the low-affinity (high-Km) component. The sample-to-sample variation in 2-hydroxymetronidazole formation correlated significantly with CYP2A6 activity (r ≥ 0.970, P < 0.001) at substrate concentrations of 100 and 300 μM. Selective chemical inhibitors of CYP2A6 inhibited metronidazole 2-hydroxylation in a concentration-dependent manner and inhibitory antibodies against CYP2A6 virtually eliminated metronidazole 2-hydroxylation (>99%). Chemical and antibody inhibitors of other P450 enzymes had little or no effect on metronidazole 2-hydroxylation. These results suggest that CYP2A6 is the primary catalyst responsible for the 2-hydroxylation of metronidazole, a reaction that may function as a marker of CYP2A6 activity both in vitro and in vivo. 23453401 Quantitative analysis of in vivo confocal microscopy images: A review. In vivo confocal microscopy (IVCM) is a non-invasive method of examining the living human cornea. The recent trend towards quantitative studies using IVCM has led to the development of a variety of methods for quantifying image parameters. When selecting IVCM images for quantitative analysis, it is important to be consistent regarding the location, depth, and quality of images. All images should be de-identified, randomized, and calibrated prior to analysis. Numerous image analysis software are available, each with their own advantages and disadvantages. Criteria for analyzing corneal epithelium, sub-basal nerves, keratocytes, endothelium, and immune/inflammatory cells have been developed, although there is inconsistency among research groups regarding parameter definition. The quantification of stromal nerve parameters, however, remains a challenge. Most studies report lower inter-observer repeatability compared with intra-observer repeatability, and observer experience is known to be an important factor. Standardization of IVCM image analysis through the use of a reading center would be crucial for any future large, multi-centre clinical trials using IVCM. 23096775 Development and Validation of the Survey of Organizational Research Climate (SORC). Development and targeting efforts by academic organizations to effectively promote research integrity can be enhanced if they are able to collect reliable data to benchmark baseline conditions, to assess areas needing improvement, and to subsequently assess the impact of specific initiatives. To date, no standardized and validated tool has existed to serve this need. A web- and mail-based survey was administered in the second half of 2009 to 2,837 randomly selected biomedical and social science faculty and postdoctoral fellows at 40 academic health centers in top-tier research universities in the United States. Measures included the Survey of Organizational Research Climate (SORC) as well as measures of perceptions of organizational justice. Exploratory and confirmatory factor analyses yielded seven subscales of organizational research climate, all of which demonstrated acceptable internal consistency (Cronbach's α ranging from 0.81 to 0.87) and adequate test-retest reliability (Pearson r ranging from 0.72 to 0.83). A broad range of correlations between the seven subscales and five measures of organizational justice (unadjusted regression coefficients ranging from 0.13 to 0.95) document both construct and discriminant validity of the instrument. The SORC demonstrates good internal (alpha) and external reliability (test-retest) as well as both construct and discriminant validity. 23684113 Effect of mood states and infertility stress on patients' attitudes toward embryo transfer and multiple pregnancy. To examine whether mood state or infertility stress influences perceptions of risk, preferences for embryo transfer, or views on multiple pregnancy. Observational cohort study. Hospital-based fertility clinic. One hundred seventy-six women participating in IVF treatment. None. Mood scores, ratings of risk, preference for multiple embryo transfer, and attitudes toward multiple pregnancy. Growing feelings of tension across the cycle corresponded with increases in the perceived riskiness of double-embryo transfer, but there was no change in strength of transfer preferences. Women experiencing negative moods, such as depression, viewed twin and triplet pregnancy as less likely, whereas increasing positive feelings across the cycle were associated with increasing desire for twin pregnancy. Overall, women perceived double- and triple-embryo transfer as less risky by cycle end than at cycle beginning and felt more certain about multiple-embryo transfer. The dyssynchrony observed among changes in mood, perceptions of risk, and transfer preferences challenges assumptions about the way medical risk information influences transfer preferences, and the findings suggest that mood states experienced during an IVF cycle might affect transfer preferences by influencing attitudes toward multiple pregnancy. Additional considerations beyond providing risk information are needed to facilitate effective patient decision making. 23704474 An Assessment of the Shared Allelic Architecture between Type II Diabetes and Prostate Cancer. To determine whether the alleles that influence type II diabetes risk and glycemic traits also influence prostate cancer risk. We used a multiple single-nucleotide polymorphisms (SNP) genotypic risk score to assess the average effect of alleles that increase type II diabetes risk or worsen glycemic traits on risk of prostate cancer in 19,662 prostate cancer cases and 19,715 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium and 5,504 prostate cancer cases and 5,834 controls from the Cancer Research UK (CRUK) prostate cancer study. Calculating the average additive effect of type II diabetes or glycemic trait risk alleles on prostate cancer risk using a logistic model revealed no evidence of a shared allelic architecture between type II diabetes, or worsened glycemic status, with prostate cancer risk [OR for type II diabetes alleles: 1.00 (P = 0.58), fasting glycemia alleles: 1.00 (P = 0.67), HbA1c alleles: 1.00 (P = 0.93), 2-hour OGTT alleles: 1.01 (P = 0.14), and HOMA-B alleles: 0.99 (P = 0.57)]. Using genetic data from large consortia, we found no evidence for a shared genetic etiology of type II diabetes or glycemic risk with prostate cancer. Our results showed that alleles influencing type II diabetes and related glycemic traits were not found to be associated with the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev; 22(8); 1473-5. ©2013 AACR. 23829458 Preliminary studies on pH-sensitive hydrogels and in vitro release profiles of two model drugs. The main aim of the present study was to develop a series of pH-sensitive hydrogels for targeted releasing drugs under simulated intestinal environment instead of stomach condition. These hydrogels were prepared via free radical polymerization with polyethylene glycol methacrylate 475 (PEGMA475), PEGMA950 and methacrylic acid as monomers, triethylene glycol dimethacrylate (TRGDMA), and ethylene glycol dimethacrylate as cross-link agents. The surface morphology and internal structures of hydrogels were detected by scanning electron microscope. The swelling experiments were also performed and the results revealed that the smart hydrogels were pH sensitive and their sensitiveness was reversible. Diclofenac sodium and bull serum albumin used as model drugs were loaded in the hydrogels to target releasing them in simulative intestinal tract. In vitro releasing studies showed that medicated hydrogels released model drugs slowly in acid conditions (pH 1.2), while the cumulated release amounts of drugs increased greatly when ambient pH value increased to 7.4. These phenomena indicated that these hydrogels tended to target release stimulating and destructible drugs in intestinal canal instead of gastric environment. 23750466 Fifteen-year follow-up of a randomized trial of a preventive intervention for divorced families: Effects on mental health and substance use outcomes in young adulthood. Objective: This 15-year follow-up assessed the effects of a preventive intervention for divorced families, the New Beginnings Program (NBP), versus a literature control condition (LC). Method: Mothers and their 9- to 12-year-olds (N = 240 families) participated in the trial. Young adults (YAs) reported on their mental health and substance-related disorders, mental health and substance use problems, and substance use. Mothers reported on YA's mental health and substance use problems. Disorders were assessed over the past 9 years (since previous follow-up) and 15 years (since program entry). Alcohol and marijuana use, other substance use and polydrug use, and mental health problems and substance use problems were assessed over the past month, past year, and past 6 months, respectively. Results: YAs in NBP had a lower incidence of internalizing disorders in the past 9 years (7.55% vs. 24.4%; odds ratio [OR] = .26) and 15 years (15.52% vs. 34.62%; OR = .34) and had a slower rate of onset of internalizing symptoms associated with disorder in the past 9 years (hazard ratio [HR] = .28) and 15 years (HR = .46). NBP males had a lower number of substance-related disorders in the past 9 years (d = 0.40), less polydrug (d = 0.55) and other drug use (d = 0.61) in the past year, and fewer substance use problems (d = 0.50) in the past 6 months than LC males. NBP females used more alcohol in the past month (d = 0.44) than LC females. Conclusions: NBP reduced the incidence of internalizing disorders for females and males and substance-related disorders and substance use for males. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 22974263 Negative information for building phylogenies. An absent word (also called a forbidden word or an unword in other contexts) in a sequence is a segment that does not appear in the given sequence. It is a minimal absent word if all its proper factors occur in the given sequence. In this article, we review the concept of minimal absent words, which includes the notion of shortest absent words but is much stronger. We present an efficient method for computing the minimal absent words of bounded length for DNA sequence using a Trie of bounded depth, representing bounded length factors. This method outputs the whole set of minimal absent words and furthermore our technique provides a linear-time algorithm with less memory usage than previous solutions. We also present an approach to distinguish sequences of different organisms using their minimal absent words. Our solution applies a length-weighted index to discriminate sequences and the results show that we can build phylogenetic tree based on the patent collected information. 23940514 NT Pro BNP Plasma Level and Atrial Volume Are Linked to the Severity of Liver Cirrhosis. Plasma levels of NT-pro-BNP, a natriuretic peptide precursor, are raised in the presence of fluid retention of cardiac origin and can be used as markers of cardiac dysfunction. Recent studies showed high levels of NT pro BNP in patients with cirrhosis. We assessed NT pro-BNP and other parameters of cardiac dysfunction in patients with cirrhosis, with or without ascites, in order to determine whether the behaviour of NT pro BNP is linked to the stage of liver disease or to secondary cardiac dysfunction. Fifty eight consecutive hospitalized patients mostly with viral or NAFLD-related cirrhosis were studied. All underwent abdominal ultrasound and upper GI endoscopy. Cardiac morpho-functional changes were evaluated by echocardiography and NT-pro-BNP plasma levels determined upon admission. Twenty-eight hypertensive patients, without evidence of liver disease served as controls. Fifty eight cirrhotic patients (72% men) with a median age of 62 years (11% with mild arterial hypertension and 31% with type 2 diabetes) had a normal renal function (mean creatinine 0.9 mg/dl, range 0.7-1.06). As compared to controls, cirrhotic patients had higher NT pro-BNP plasma levels (365.2±365.2 vs 70.8±70.6 pg/ml; p<0.001). Left atrial volume (LAV) (61.8±26.3 vs 43.5±14.1 ml; p = 0.001), and left ventricular ejection fraction (62.7±6.9 vs. 65.5±4%,; p = 0.05) were also altered in cirrhotic patients that in controls. Patients with F2-F3 oesophageal varices as compared to F0/F1, showed higher e' velocity (0.91±0.23 vs 0.66±0.19 m/s, p<0.001), and accordingly a higher E/A ratio (1.21±0.46 vs 0.89±0.33 m/s., p = 0.006). NT-pro-BNP plasma levels are increased proportionally to the stage of chronic liver disease. Advanced cirrhosis and high NT-pro-BNP levels are significantly associated to increased LAV and to signs of cardiac diastolic dysfunction. NT pro-BNP levels could hence be an useful prognostic indicators of early decompensation of cirrhosis. 23916736 Usefulness of Neutrophil-to-Lymphocyte Ratio to Predict In-hospital Outcomes in Infective Endocarditis. The neutrophil-to-lymphocyte ratio is an independent predictor of worse prognosis in both infectious and cardiovascular disease. We hypothesized that an increased neutrophil-to-lymphocyte ratio at admission would predict in-hospital unfavourable outcomes in patients with infective endocarditis (IE). We retrospectively analyzed clinical, laboratory, and echocardiographic data in a total of 121 consecutive adult patients (64 men; mean age, 54.7 ± 14.2 years) with definite IE. Among all patients, the prespecified clinical outcomes were experienced in 46 patients (38%). In-hospital mortality and central nervous system (CNS) events occurred in 29 (24%) and 21 patients (17%), respectively. The neutrophil-to-lymphocyte ratio at admission was found to be significantly higher for either composite end point. On using multiple Cox regression analysis, vegetation size ≥ 10 mm, end-stage renal disease, Staphylococcus aureus infection, low hemoglobin level, increased C-reactive protein (CRP) level, and high neutrophil-to-lymphocyte ratio at admission emerged as independent predictors of in-hospital unfavourable outcomes. In the receiver operating characteristics (ROC) curve analysis, a neutrophil-to-lymphocyte ratio > 7.1 had 80% sensitivity and 83% specificity in predicting adverse outcomes. High neutrophil-to-lymphocyte ratio at admission is an independent predictor of in-hospital mortality and CNS events in patients with IE. However, prospective validation of these findings is required. 23745619 Nonalcoholic Fatty liver disease and reduced serum vitamin d3 levels. Abstract Nonalcoholic fatty liver disease (NAFLD) and vitamin D3 deficiency are two highly prevalent pathologic conditions worldwide that share several cardiometabolic risk factors. In addition to its traditional calcium-related effects on the skeleton, vitamin D3 deficiency has now been recognized to exert nonskeletal adverse effects on several other organ systems. Accumulating epidemiological evidence suggests that low levels of serum 25-hydroxyvitamin D3 are associated with the presence and severity of NAFLD, independently of several potential confounders, including features of the metabolic syndrome. The molecular mechanisms of this association remain incompletely understood. A variety of biologically plausible mechanisms may mediate a hepato-protective role for the active metabolite of vitamin D3. 1α,25-dihydroxyvitamin D3 modulates the insulin signaling pathway/insulin resistance, suppresses fibroblast proliferation and collagen production, exerts anticoagulant and profibrinolytic effects, and modulates macrophage activity and inflammatory cytokine generation. Overall, the high prevalence of vitamin D3 deficiency and the plausible biological mechanisms linking this to NAFLD suggest that treatment of vitamin D3 deficiency to prevent and/or treat NAFLD is a promising field to explore. Large placebo-controlled randomized clinical trials are urgently needed to determine whether vitamin D3 supplementation could have any potential benefit in reducing the development and progression of NAFLD. 23707872 Highly sensitive electrochemical lead ion sensor harnessing peptide probe molecules on porous gold electrodes. Lead ion is one of the most hazardous and ubiquitous heavy metal pollutants and poses an increasing threat to the environment and human health. This necessitates rapid and selective detection and/or removal of lead ions from various soil and water resources. Recently, we identified several Pb²⁺ binding peptides via phage display technique coupled with chromatographic biopanning (Nian et al., 2010) where a heptapeptide (TNTLSNN) capable of recognizing Pb²⁺ with high affinity and specificity evolved. In the present study, an electrochemical sensor harnessing this Pb²⁺ affinity peptide as a probe on a porous gold electrode was developed. The three dimensional porous gold electrode was obtained from electrochemical deposition using the dynamic hydrogen bubble template method. A thin layer of poly(thiophene acetic acid) (PTAA) was coated on the porous gold surface. The Pb²⁺ recognizing peptide was immobilized via amide linkage on the PTAA. The developed biosensor was demonstrated to be fast, selective and reproducible in Pb²⁺ etection, exhibiting Pb²⁺-specific peak current values around -0.15 V in a broad concentration range (1-1×10⁷ nM) in 10 min despite the repeated use after regeneration. 23952266 The effects of stress on periodontal treatment: a longitudinal investigation using clinical and biological markers. To investigate the effects of psychosocial stress on the outcome of non-surgical periodontal treatment (NPT). Patients were categorized as stressed or unstressed, and the degree of stress was measured. One deep bleeding and one deep non-bleeding site ≥6 mm were selected in each patient for detailed investigation, and the clinical parameters were recorded before and at 6 months after NPT. Elastase and C-terminal teleopeptide of type I collagen (ICTP) were measured in gingival crevicular fluid (GCF) samples at both intervals. The baseline, clinical parameters and biological markers were similar in both stressed and unstressed groups, other than for GCF elastase levels, which were significantly higher in the stressed group of patients (p < 0.05). The effect of stress on the changes for clinical measurements and elastase levels in GCF was statistically significant for deep bleeding sites, with the response to treatment being poorer in the stressed group. The effects of smoking and the degree of stress were not statistically significant for any of the clinical or biological parameters (p > 0.05). Patients under psychosocial stress had a poorer outcome following NPT. The assessment of psychosocial stress may be valuable in the holistic management of periodontal disease. 23931420 Using Health Services Research to Meet ACGME Resident Research Requirements. Health services research is a field of research that crosses many disciplines. It represents a novel way to address the Accreditation Council for Graduate Medical Education requirements for scholarly activity of residents and faculty in academic radiology departments. In addition to meeting training requirements, it offers future radiologists the opportunity to develop skills that will be essential as we transition from a volume based health care delivery system to an outcome based delivery system. This report introduces examples of health services research projects and the types of data resources that are available to facilitate such projects. 23841894 Illegal yet developmentally normative: a descriptive analysis of young, urban adolescents' dating and sexual behaviour in Cape Town, South Africa. In South Africa, it is illegal for adolescents under age 16 years to engage in any sexual behaviour whether kissing, petting, or penetrative sex, regardless of consent. This cross-sectional study investigated the extent to which young adolescents engage in various sexual behaviours and the associations between dating status and sexual behaviours. Grade 8 adolescents (N = 474, ages 12--15 years, mean = 14.14 years) recruited from Cape Town schools completed surveys providing information about their sociodemographic backgrounds, dating experience, sexual behaviour, and substance use. Lower hierarchy sexual behaviours, such as kissing (71.4% of girls; 88.4% of boys), were more common than oral (3.9% of girls; 13.8% of boys), vaginal (9.3% of girls; 30.0% of boys), or anal (1.4% of girls; 10.5% of boys) sex. Currently dating girls and boys were more likely to engage in sexual behaviours including several risk behaviours in comparison to their currently non-dating counterparts. These risk behaviours included penetrative sex (21.1% of dating vs. 4.5% of non-dating girls; 49.4% of dating vs. 20.2% of non-dating boys), sex with co-occurring substance use (22.2% of dating vs. 0 non-dating girls; 32.1% of dating vs. 40% of non-dating boys), and no contraceptive use (26.1% of sexually experienced girls; 44.4% of sexually experienced boys). Among girls, there were significant associations between ever having penetrative sex and SES (OR = 2.592, p = 0.017) and never dating (OR = 0.330, p = 0.016). Among boys, there were significant associations between ever having penetrative sex and never dating (OR = 0.162, p = 0.008). Although the currently dating group of young adolescents appear to be a precocious group in terms of risk behaviour relative to the currently non-dating group, teenagers in both groups had experience in the full range of sexual behaviours. Many young adolescents are engaging in a variety of sexual behaviours ranging from kissing and touching to intercourse. Of particular concern are those engaging in risky sexual behaviour. These findings indicate that adolescents need to be prepared for sexual negotiation and decision-making from an early age through comprehensive and accessible education and health services; sections of current legislation may be a barrier to adopting such policies and practices. 23364358 Multifocal capillary hemangioma-like vascular proliferation of the kidney associated with clear cell renal cell carcinoma: a case report and review of the literature. We report the case of a 69-year-old man who underwent a radical left nephrectomy for a renal mass. Microscopically, the features were those of a clear cell-type renal cell carcinoma associated with 2 foci of capillary hemangioma-like vascular proliferation in the adjacent renal parenchyma. The main differential diagnosis and the possible pathogenesis of this vascular lesion are discussed. 23856752 Atomic level observation of octahedral distortions at the perovskite oxide heterointerface. For perovskite oxides, ABO3, slight octahedral distortions have close links to functional properties. While perovskite oxide heterostructures offer a good platform for controlling functionalities, atomistic understanding of octahedral distortion at the interface has been a challenge as it requires precise measurements of the oxygen atomic positions. Here we demonstrate an approach to clarify distortions at an atomic level using annular bright-field imaging in aberration-corrected scanning transmission electron microscopy, which provides precise mappings of cation and oxygen atomic positions from distortion-minimized images. This technique revealed significant distortions of RuO6 and ScO6 octahedra at the heterointerface between a SrRuO3 film and a GdScO3 substrate. We also found that structural mismatch was relieved within only four unit cells near the interface by shifting the oxygen atomic positions to accommodate octahedral tilt angle mismatch. The present results underscore the critical role of the oxygen atom in the octahedral connectivity at the perovskite oxide heterointerface. 23942708 Impact of a leptin SNP and zilpaterol hydrochloride (ZH) on growth and carcass characteristics in finishing steers. A total of 4,178 steers (mean initial BW = 403.9 ± 16.04 kg) were used to test the interactive effects, if any, of leptin R25C genotypes (CC, CT, or TT) and zilpaterol hydrochloride (ZH) feeding duration on growth performance and carcass traits. Steers were blocked by arrival at the feed yard, genotyped for the leptin SNP, allotted to genotype-specific pens (90 steers/pen), and assigned randomly within genotype and block to 0 or 21 d of dietary ZH. All pens within a block were slaughtered on the same day (132.1 ± 10.9 d on feed). Final BW of steers fed ZH was 6.0 kg heavier (P = 0.008), and ZH-fed steers had greater (P = 0.003) ADG than steers not fed ZH. Feeding ZH decreased DMI in steers with increased frequency of the T allele (9.67, 9.53, and 9.28 kg/d for CC, CT, and TT, respectively), but DMI increased with the frequency of the T allele (9.68, 9.90, and 10.1 kg for CC, CT, and TT, respectively) when ZH was not fed (leptin genotype × ZH, P = 0.011). At the conclusion of the study, ultrasonic fat was greatest for TT steers (11.4 + 0.28 mm) and least (P = 0.003) for CC steers (11.0 ± 0.25 mm). Regardless of ZH-feeding duration, TT steers produced a greater (P = 0.006) percentage of USDA yield grade (YG) 4, or higher, carcasses (5.4 vs. 2.7%) and a lesser (P = 0.006) percentage of YG 1 carcasses (17.7 vs. 26.8%) than CC steers. In addition, ZH-fed steers produced a greater (P < 0.001) percentage of USDA YG 1 carcasses (25.9 vs. 16.2%) and a lesser (P < 0.001) percentage of YG 4, or higher, carcasses (1.6 vs. 6.0%) than steers fed the control diet. Marbling scores and the percentage of carcasses grading USDA Choice and Prime were greater in TT- than CC-steers when fed diets devoid of ZH, but both marbling and quality grades did not differ among leptin genotypes when fed ZH for 21 d (leptin genotype × ZH, P ≤ 0.03). The amount of HCW gain tended to be less (P = 0.095) for steers of the TT genotype (12.7 kg) than either CC (16.3 kg) or CT (17.0 kg) genotypes. Results indicated that leptin R25C genotype impacted most traits associated with fatness, whereas feeding ZH for 21 d affected HCW and ADG positively, but impacted feed intake, marbling, and USDA quality grades negatively. 23588814 Classification and treatment of men with chronic prostatitis/chronic pelvic pain syndrome using the UPOINT system. Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common condition; however, many of the traditional therapies used in clinical practice fail to show efficacy when subjected to large randomized placebo-controlled trials. This may be because CP/CPPS is a heterogeneous syndrome rather than a specific disease which would explain the failure of "one size fits all" therapy. In order to direct appropriate therapy, we have developed a six-point clinical phenotyping system to evaluate patients with chronic urologic pelvic pain. The clinical domains are urinary symptoms, psychosocial dysfunction, organ-specific findings, infection, neurologic/systemic, and tenderness of muscles, which produces the acronym UPOINT. Each domain is diagnosed clinically and is associated with specific therapies. This approach is simple and has proven effective in our hands for patients even after many years of failed therapies. 23747759 Prasugrel 5 mg in the Very Elderly Attenuates Platelet Inhibition But Maintains Noninferiority to Prasugrel 10 mg in Nonelderly Patients: The GENERATIONS Trial, A Pharmacodynamic and Pharmacokinetic Study in Stable Coronary Artery Disease Patients. This study assessed pharmacodynamic (PD) response to the reduced prasugrel maintenance dose of 5 mg in very elderly (VE) patients (≥75 years of age). In the TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction 38) study prasugrel 10 mg reduced ischemic events versus clopidogrel 75 mg, but increased bleeding in VE patients. We examined PD and active metabolite pharmacokinetics (PKs) with prasugrel 5 and 10 mg and clopidogrel 75 mg in a 3-period (12 days each) blinded, crossover study in VE (n = 73; mean: 79 ± 3 years of age) or (n = 82) nonelderly (NE) (≥45 to <65 years of age; mean: 56 ± 5 years of age) stable coronary artery disease (CAD) patients receiving background aspirin. Assays included light transmission aggregometry (LTA), VerifyNow P2Y12 (VN-P2Y12), and vasodilator-associated stimulated phosphoprotein (VASP). The primary comparison was noninferiority of maximum platelet aggregation (MPA) comparing the median for prasugrel 5 mg in VE versus the 75th percentile for prasugrel 10 mg in NE, using a pre-specified 1-sided 97.5% confidence interval for the difference <15%. Prasugrel 5 mg in VE met the primary PD noninferiority criterion versus prasugrel 10 mg in NE. For prasugrel 5 mg, MPA was significantly lower (57 ± 14%) than clopidogrel (63 ± 14%; p < 0.001) in VE but higher than prasugrel 10 mg in NE (46 ± 12%; p < 0.001). PD response by LTA, VN-P2Y12, and VASP during all treatments appeared similar between age cohorts. Prasugrel 5 mg resulted in fewer VE poor responders than clopidogrel. Rates of mild bleeding were higher with prasugrel 10 mg but similar for prasugrel 5 mg versus clopidogrel 75 mg. In aspirin-treated stable CAD patients, prasugrel 5 mg in VE attenuated platelet inhibition while meeting pre-specified noninferiority criterion versus prasugrel 10 mg in NE, with significantly better PD response and fewer poor responders compared to clopidogrel 75 mg in VE. (Comparison of Prasugrel and Clopidogrel in Very Elderly and Non-Elderly Patients With Stable Coronary Artery Disease [GENERATIONS]; NCT01107912). 23923005 Molecular biomarkers of vascular dysfunction in obstructive sleep apnea. Untreated and long-lasting obstructive sleep apnea (OSA) may lead to important vascular abnormalities, including endothelial cell (EC) dysfunction, hypertension, and atherosclerosis. We observed a correlation between microcirculatory reactivity and endothelium-dependent release of nitric oxide in OSA patients. Therefore, we hypothesized that OSA affects (micro)vasculature and we aimed to identify vascular gene targets of OSA that could possibly serve as reliable biomarkers of severity of the disease and possibly of vascular risk. Using quantitative RT-PCR, we evaluated gene expression in skin biopsies of OSA patients, mouse aortas from animals exposed to 4-week intermittent hypoxia (IH; rapid oscillations in oxygen desaturation and reoxygenation), and human dermal microvascular (HMVEC) and coronary artery endothelial cells (HCAEC) cultured under IH. We demonstrate a significant upregulation of endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha-induced protein 3 (TNFAIP3; A20), hypoxia-inducible factor 1 alpha (HIF-1α?? and vascular endothelial growth factor (VEGF) expression in skin biopsies obtained from OSA patients with severe nocturnal hypoxemia (nadir saturated oxygen levels [SaO2]<75%) compared to mildly hypoxemic OSA patients (SaO2 75%-90%) and a significant upregulation of vascular cell adhesion molecule 1 (VCAM-1) expression compared to control subjects. Gene expression profile in aortas of mice exposed to IH demonstrated a significant upregulation of eNOS and VEGF. In an in vitro model of OSA, IH increased expression of A20 and decreased eNOS and HIF-1α expression in HMVEC, while increased A20, VCAM-1 and HIF-1αexpression in HCAEC, indicating that EC in culture originating from distinct vascular beds respond differently to IH stress. We conclude that gene expression profiles in skin of OSA patients may correlate with disease severity and, if validated by further studies, could possibly predict vascular risk in OSA patients. 23871598 The ability of three different models of frailty to predict all-cause mortality: Results from the European Male Aging Study (EMAS). Few studies have directly compared the ability of the most commonly used models of frailty to predict mortality among community-dwelling individuals. Here, we used a frailty index (FI), frailty phenotype (FP), and FRAIL scale (FS) to predict mortality in the EMAS. Participants were aged 40-79 years (n=2929) at baseline and 6.6% (n=193) died over a median 4.3 years of follow-up. The FI was generated from 39 deficits, including self-reported health, morbidities, functional performance and psychological assessments. The FP and FS consisted of five phenotypic criteria and both categorized individuals as robust when they had 0 criteria, prefrail as 1-2 criteria and frail as 3+ criteria. The mean FI increased linearly with age (r(2)=0.21) and in Cox regression models adjusted for age, center, smoking and partner status the hazard ratio (HR) for death for each unit increase of the FI was 1.49. Men who were prefrail or frail by either the FP or FS definitions, had a significantly increased risk of death compared to their robust counterparts. Compared to robust men, those who were FP frail at baseline had a HR for death of 3.84, while those who were FS frail had a HR of 3.87. All three frailty models significantly predicted future mortality among community-dwelling, middle-aged and older European men after adjusting for potential confounders. Our data suggest that the choice of frailty model may not be of paramount importance when predicting future risk of death, enabling flexibility in the approach used. 23877735 Neighborhood Repulsed Metric Learning for Kinship Verification. Kinship verification from facial images is an interesting and challenging problem in computer vision, and there is very limited attempts on tackle this problem in the iterature. In this paper, we propose a new neighborhood repulsed metric learning (NRML) method for kinship verification. Motivated by the fact that interclass samples (without kinship relations) with higher similarity usually lie in a neighborhood and are more easily misclassified than those with lower similarity, we aim to learn a distance metric under which the intraclass samples (with kinship relations) are pulled as close as possible and interclass samples lying in a neighborhood are repulsed and pushed away as far as possible, simultaneously, such that more discriminative information can be exploited for verification. To make better use of multiple feature descriptors to extract complementary information, we further propose a multiview NRML (MNRML) method to seek a common distance metric to perform multiple feature fusion to improve the kinship verification performance. Experimental results are presented to demonstrate the efficacy of our proposed methods. Lastly, we also test human ability in kinship verification from facial images and our experimental results show that our methods are comparable to that of human observers. 23919290 Stereoselective Synthesis of β-Alkylated α-Amino Acids via Palladium-Catalyzed Alkylation of Unactivated Methylene C(sp(3))-H Bonds with Primary Alkyl Halides. We report a new set of reactions based on the Pd-catalyzed alkylation of methylene C(sp(3))-H bonds of aliphatic quinolyl carboxamides with α-haloacetate and methyl iodide and applications in the stereoselective synthesis of various β-alkylated α-amino acids. These reactions represent the first generally applicable method for the catalytic alkylation of unconstrained and unactivated methylene C-H bonds with high synthetic relevance. When applied with simple isotope-enriched reagents, they also provide a convenient and powerful means to site-selectively incorporate isotopes into the carbon scaffolds of amino acid compounds. 23876428 Distinct enhancers of ptf1a mediate specification and expansion of ventral pancreas in zebrafish. Development of the pancreas and cerebellum require Pancreas-specific transcription factor-1a (Ptf1a), which encodes a subunit of the transcription factor complex PTF1. Ptf1a is required in succession for specification of the pancreas, proper allocation of pancreatic progenitors to endocrine and exocrine fates, and the production of digestive enzymes from the exocrine acini. In several neuronal structures, including the cerebellum, hindbrain, retina and spinal cord, Ptf1a is transiently expressed and promotes inhibitory neuron fates at the expense of excitatory fates. Transcription of Ptf1a in mouse is maintained in part by PTF1 acting on an upstream autoregulatory enhancer. However, the transcription factors and enhancers that initially activate Ptf1a expression in the pancreas and in certain structures of the nervous system have not yet been identified. Here we describe a zebrafish autoregulatory element, conserved among teleosts, with activity similar to that described in mouse. In addition, we performed a comprehensive survey of all non-coding sequences in a 67kb interval encompassing zebrafish ptf1a, and identified several neuronal enhancers, and an enhancer active in the ventral pancreas prior to activation of the autoregulatory enhancer. To test the requirement for autoregulatory control during pancreatic development, we restored ptf1a function through BAC transgenesis in ptf1a morphants, either with an intact BAC or one lacking the autoregulatory enhancer. We find that ptf1a autoregulation is required for development of the exocrine pancreas and full rescue of the ptf1a morphant phenotype. Similarly, we demonstrate that a ptf1a locus lacking the early enhancer region is also capable of rescue, but only supports formation of a hypoplastic exocrine pancreas. Through our dissection of the complex regulatory control of ptf1a, we identified separate cis-regulatory elements that underlie different aspects of its expression and function, and further demonstrated the requirement of maintained ptf1a expression for normal pancreatic morphogenesis. We also identified a novel enhancer that mediates initiation of ptf1a expression in the pancreas, through which the signals that specify the ventral pancreas are expected to exert their action. 23900549 Treatment seeking and barriers to treatment for alcohol use in persons with alcohol use disorders and comorbid mood or anxiety disorders. This study compared the prevalence and patterns of treatment seeking and barriers to alcohol treatment among individuals with alcohol use disorders (AUD) with and without comorbid mood or anxiety disorders. We used data from the national epidemiologic survey on alcohol and related conditions to examine alcohol treatment seeking, treatment settings and providers, perceived unmet need for treatment and barriers to such treatment. Our sample consisted of 5,003 individuals with AUD with a comorbid mood or anxiety disorder and 6,734 individuals with AUD but without mood or anxiety disorder comorbidity. The group with mood or anxiety disorder comorbidity was more likely to seek alcohol treatment than the group without such comorbidity (18 vs. 12 %, p < 0.001). The comorbid group was also more likely to perceive an unmet need for such treatment (8 vs. 3 %, p < 0.001) and to report a larger number of barriers (2.81 vs. 2.20, p = 0.031). Individuals with AUD with comorbid mood or anxiety disorders were more likely than those without to report financial barriers to alcohol treatment (19 vs. 10 %, p = 0.032). Individuals with AUD and comorbid mood or anxiety disorders would likely benefit from the expansion of financial access to alcohol treatments and integration of services envisioned under the Affordable Care Act. 23792320 Unveiling the mode of action of antibacterial labdane diterpenes from Alpinia nigra (Gaertn.) B. L. Burtt seeds. The labdane diterpene, (E)-labda-8(17), 12-diene-15, 16-dial (compound A) and its epoxide analogue, (E)-8β, 17-Epoxylabd-12-ene-15, 16-dial (compound B) were isolated from the seeds of Alpinia nigra for the first time. The antibacterial activities of both compounds were evaluated against three Gram-positive and four Gram-negative bacteria, and flow cytometric analysis revealed that these compounds caused significant damage to the bacterial cell membranes. Further, field emission scanning electron microscope imaging and cell leakage analysis confirmed that the labdane diterpenes were responsible for bacterial cell membrane damage and disintegration. Our findings provide new insight into the broad-spectrum effects of two natural labdane diterpenes that may be useful in the future development of herbal antibiotic products. 23962886 Long-term Clinical Outcomes of Statin Use for Chronic Heart Failure: A Meta-analysis of 15 Prospective Studies. The effect of statin treatment on the long-term prognosis in patients with chronic heart failure (CHF) remains uncertain. This study aimed to answer the question by a meta-analysis. The Cochrane databases, MEDLINE and EMBASE, were systematically searched. The eligibility of prospective studies that assigned CHF patients to receive statin treatment and a control (no statin treatment), had defined prognostic outcomes as primary endpoint, and had a minimal follow-up of 12 months was determined. Fifteen studies involving 45,110 patients were included in the analysis. Additional statin treatment was associated with reduced all-cause mortality (risk ratios [RR]=0.71, 95% confidence intervals [CI] 0.61-0.83) and reduced rehospitalisation rate for heart failure (RR=0.84, 95% CI 0.74-0.96). Statin treatment, however, had little impact on pump failure mortality, cardiovascular mortality, and sudden cardiac death. Atorvastatin treatment appeared to facilitate to reduce all-cause mortality (lnRR=0.61, p=0.05) and rehospitalisation for heart failure (lnRR=0.44, p=0.04) compared with non-atorvastatin therapy. Based on the available data, statins persistently decreased all-cause mortality and the incidence of rehospitalisation for heart failure in CHF patients, and the benefits might be partially associated with use of specific statin. 23895667 Macrolides for the long-term management of asthma - a meta-analysis of randomized clinical trials. Macrolide antibiotics, which have anti-inflammatory and immune modulatory effects, have been studied as adjuncts for the management of asthma. However, results have been contradictory and trials underpowered. We therefore sought to conduct a meta-analysis of randomized controlled trials (RCT). All RCT of prolonged macrolides (3+ weeks) for asthma treatment, published up to January 2013 in MEDLINE, Scopus, CINAHL, Highwire, and The Cochrane Collaboration Library, were included. Fixed- or random-effects models were used to calculate pooled weighted or standard mean differences (WMD or SMD, respectively). A total of 12 studies were included for analysis. The pooled effect of macrolides on FEV1 (eight trials, 381 subjects) was not significant (SMD 0.05, 95% CI -0.14-0.25), but there was a significant increase in peak expiratory flow (four trials, 419 subjects; WMD 6.7, 95% CI 1.35-12.06). Pooled analysis also showed significant improvements in symptom scores (eight studies, 478 subjects; WMD -0.46, 95% CI -0.60 to -0.32), quality of life (five trials, 346 subjects; WMD 0.18, 95% CI 0.001-0.37), and airway hyper-reactivity (two trials, 131 subjects; SMD 1.99, 95% CI 0.46-3.52). Post hoc evaluation showed limited statistical power to detect significant differences in FEV1. Macrolide administration for asthma for three or more weeks was not associated with improvement in FEV1, but produced significant improvements in peak expiratory flow, symptoms, quality of life, and airway hyper-reactivity. Macrolides may therefore be beneficial as adjunct asthma therapy. Future trials, focusing on long-term safety and effectiveness, should use standardized outcomes and procedures. 23824946 Diversity-oriented three-component reactions of diazo compounds with anilines and 4-oxo-enoates. Choosing a path: The title reaction can proceed through two different reaction pathways, and is controlled by the addition sequence of the substrates. Divergent polyfunctional products, pyrrolidines or linear α-amino ester derivatives, are obtained in good yields and high diastereoselectivities. 23404153 Transanal endoscopic microsurgery after neoadjuvant radiochemotherapy for locally advanced extraperitoneal rectal cancer: short-term morbidity and functional outcome. Transanal endoscopic microsurgery (TEM) after radiochemotherapy (RCT) has been reported in selected cases of locally advanced rectal cancer as an alternative to traditional radical resection with total mesorectal excision with a curative intent or as diagnostic tool to confirm a pathological complete response of the primary tumor. No study has evaluated functional outcome after TEM in preoperatively irradiated patients. This study was designed to evaluate short-term morbidity (according to Clavien's classifications) and establish (by a questionnaire) continence and evacuative function after RCT and TEM, at 1 year from surgery, analyzing the impact of RCT on postoperative outcomes. Patients with locally advanced rectal cancer treated by RCT and TEM (group 1) or with early T1 or adenomas treated only by TEM (group 2) entered this cohort comparative study. Twenty-two patients entered the study as group 1 and 25 as group 2. No postoperative mortality occurred. The morbidity rate was 36.4 % in group 1 vs. 16 % in group 2 (p = 0.114). The rate of suture dehiscence was 22.7 % in group 1 vs. 4 % in group 2 (p = 0.068). No grade III complications, reoperation, or hospital readmission within 30 days was recorded in either group. One year after surgery, continence and evacuative scores in group 1 were 1.05 ± 1.25 and 24.72 ± 2.79, respectively, which were similar to group 2 (p = 0.081 and 0.288, respectively). TEM after RCT in selected rectal cancer patients has an acceptable morbidity and functional results at 1 year from surgery. Preoperative irradiation could increase postoperative short-term morbidity, but it does not seem to influence evacuative or sphincter function after 1 year from surgery. 23916579 New cytotoxic triterpenoid saponins from the whole plant of Clematis lasiandra Maxim. Four new oleanane type triterpenoid saponins (1-4) and three known saponins (5-7) were isolated from the whole plant of Clematis lasiandra Maxim. The structures of the four new compounds were elucidated as 3-O-β-d-ribopyranosyl-(1→3)-α-l-rhamnopyranosyl-(1→2)-[β-d-glucopyranosyl-(1→4)]-β-d-xylopyranosyl hederagenin (1), 3-O-β-d-ribopyranosyl-(1→3)-α-l-rhamnopyranosyl-(1→2)-β-d-xylopyranosyl oleanolic acid 28-O-β-d-glucopyranosyl ester (2), 3-O-β-d-ribopyranosyl-(1→3)-α-l-rhamnopyranosyl-(1→2)-β-d-xylopyranosyl hederagenin (3) and 3-O-β-d-ribopyranosyl-(1→3)-α-l-rhamnopyranosyl-(1→2)-[β-d-glucopyranosyl-(1→4)]-α-l-arabinopyranosyl hederagenin (4) on the basis of extensive spectroscopic analysis and chemical evidence. Compounds 1-7 were evaluated for their cytotoxicity against human tumor cell lines HL-60, Hep-G2 and SGC-7901, and all of the evaluated saponins showed significant cytotoxicity to those three tumor cell lines with IC50 in the range from 1.40 to 19.50μmol/L except for compounds 2 and 6. 22967724 Cystic echinococcosis in slaughtered domestic ruminants from Tunisia. A total of 10,818 domestic ruminants (3913 cattle, 2722 sheep, 3779 goats, 404 dromedaries) slaughtered in various abattoirs in Tunisia between 2003 and 2010 were examined for the presence of Echinococcus granulosus hydatid cysts. The prevalence of cystic echinococcosis (CE) was 16.42% in sheep, 8.56% in cattle, 5.94% in dromedaries and 2.88% in goats. CE prevalence increased with age according to an asymptotic model and there was evidence of variation in infection pressure depending on the region of Tunisia where the animals were slaughtered. Cattle appeared to have the highest infection pressure of the species examined. The mean intensity of hepatic cysts was higher than that of pulmonary cysts in all species. The highest mean intensity of infection with E. granulosus larvae was observed in cattle (18.14) followed by sheep (9.58), goats (2.31) and dromedaries (2.12). The abundance of infection increased in a linear fashion with age in all animal species. Cyst abundance varied with species of animal and district of Tunisia. Cysts from dromedaries were more fertile (44.44%) than those from sheep (30.25%), goats (30.32%) and cattle (0.95%). The viability of the protoscoleces from fertile cysts from cattle (78.45%) was higher than those from sheep (70.71%) and camels (69.57%). The lowest protoscolex viability was recorded for hydatid cysts from goats (20.21%). This epidemiological study confirms the importance of CE in all domestic ruminant species, particularly in sheep, throughout Tunisia and emphasizes the need to interrupt parasite transmission by preventive integrated approaches in a CE control programme. 23881718 PAP/HIP protein is an obesogenic factor. In this paper we report the obesogenic role of the acute phase protein PAP/HIP. We found that the transgenic TgPAP/HIP mice develop spontaneous obesity under standard nutritional conditions, with high levels of glucose, leptin and LDL and low levels of triglicerides and HDL in blood. Accordingly, PAP/HIP-deficient mice are skinny under standard nutritional conditions. We also found that expression of PAP/HIP is induced in intestinal epithelial cells in response to gavage with olive oil and this induction is AG490 sensitive. We demonstrated that incubation of 3T3-L1 preadipocytes with a low concentration as 1 ng/ml of recombinant PAP/HIP results in accelerated BrdU incorporation in vitro. PAP/HIP-dependent adipocytes growth is sensitive to the MEK inhibitor U0126. Finally, patients with severe obesity present higher blood levels of PAP/HIP than non-obese control individuals. Altogether our data suggest that PAP/HIP could be a mediator of fat tissue development, released by the intestine and induced by the presence of food into the gut. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc. 23677011 Using high resolution electronic spectroscopy to probe the effects of ring twist on charge transfer in 2-phenylindole and N-phenylcarbazole. High resolution electronic spectra of 2-phenylindole (PI) and N-phenylcarbazole (PC) have been recorded in the collision-free environment of a molecular beam. Inertial defects determined from fits of the spectra were used to determine the twist angles between the two chromophores and their attached benzene rings in the ground (S0) and excited (S1) electronic states. PI was found to be significantly more planar than PC, especially in the S1 state. Stark-effect measurements of the permanent electric dipole moments of both molecules in both states show that significantly more charge is transferred from the phenyl group to the chromophore in PI (0.13e) than in PC (0.076e) when the photon is absorbed. Thereby demonstrated for the first time is a direct connection between photo-induced geometry change and charge transfer on excitation of an isolated molecule by light. 23499927 Arrhythmogenic effect of a crude extract from sea anemone Condylactis gigantea: Possible involvement of rErg1 channels. Sea anemones possess a number of peptide toxins that target ion channels which provide powerful tools to study the molecular basis of diverse signaling pathways. It is also acknowledged that currents through Erg1 K(+) channels in cardiac myocytes are important for electrical stability of the heart and alterations in its activity has been linked to the onset of a potentially life-threatening heart condition named long QT syndrome type 2. Here, we report that a crude extract from sea anemone Condylactis gigantea significantly increases the QT interval and has arrhythmogenic effects in the rat heart. Furthermore, a bioassay-guided purification procedure allowed the isolation of a chromatographic fraction containing a major component with a molecular mass of 4478 Da from the crude extract, which causes a significant inhibition of whole-cell patch-clamp currents through recombinant Erg1 channels, responsible of the rapid delayed rectifying current crucial for electrical activity in the heart. Further studies could provide relevant information on the molecular mechanism of C. gigantea peptide toxins which represent promising tools in studying the physiology of diverse ion channels. 23578390 Sodium fluoride induces apoptosis in odontoblasts via a JNK-dependent mechanism. Sodium fluoride (NaF) is widely used for the treatment of dental caries and dentin hypersensitivity. However, its pro-apoptotic effect on odontoblasts may lead to harmful side-effects. The purpose of this study was to evaluate the pro-apoptotic effects of NaF in odontoblasts and elucidate the possible underlying molecular mechanisms. NaF generated cytotoxic effects in odontoblast-lineage cell (OLC) in a dose- and time-dependent manner. Exposure of cells to 4mM NaF for 24h induced caspase-3 activation, ultrastructural alterations, and resulted in the translocation of Bax to the mitochondria and the release of cytochrome c from the mitochondrial inter-membrane space into the cytosol, indicating that fluoride-mediated apoptosis is mitochondria-dependent. Fluoride treatment also increased phosphorylation of JNK and ERK, but not p38, and apoptosis induced by fluoride was notably or partly suppressed by treatment with JNK or ERK inhibitors, respectively. Taken together, these findings suggest that NaF induces apoptosis in OLC odontoblasts through a JNK-dependent mitochondrial pathway. 23871970 Application of rapid cloud point extraction method for trace cobalt analysis coupled with spectrophotometric determination. In this work, the analytical performance of conventional spectrophotometer was improved through the coupling of effective preconcentration method with spectrophotometric determination. Rapidly synergistic cloud point extraction (RS-CPE) was used to pre-concentrate ultra trace cobalt and firstly coupled with spectrophotometric determination. The developed coupling was simple, rapid and efficient. The factors influencing RS-CPE and spectrophotometer were optimized. Under the optimal conditions, the limit of detection (LOD) was 0.6μgL(-1), with sensitivity enhancement factor of 23. The relative standard deviation (RSD) for seven replicate measurements of 50μgL(-1) of cobalt was 4.3%. The recoveries for the spiked samples were in the acceptable range of 93.8-105%. 23938389 Production of marker-free and RSV-resistant transgenic rice using a twin T-DNA system and RNAi. A twin T-DNA system is a convenient strategy for creating selectable marker-free transgenic plants. The standard transformation plasmid, pCAMBIA 1300, was modified into a binary vector consisting of two separate T-DNAs, one of which contained the hygromycin phosphotransferase (hpt) marker gene. Using this binary vector, we constructed two vectors that expressed inverted-repeat (IR) structures targeting the rice stripe virus (RSV) coat protein (CP) gene and the special-disease protein (SP) gene. Transgenic rice lines were obtained via Agrobacterium-mediated transformation. Seven independent clones harbouring both the hpt marker gene and the target genes (RSV CP or SP) were obtained in the primary transformants of pDTRSVCP and pDTRSVSP, respectively. The segregation frequencies of the target gene and the marker gene in the T1 plants were 8.72 percent for pDTRSVCP and 12.33 percent for pDTRSVSP. Two of the pDTRSVCP lines and three pDTRSVSP lines harbouring the homozygous target gene, but not the hpt gene, were strongly resistant to RSV. A molecular analysis of the resistant transgenic plants confirmed the stable integration and expression of the target genes. The resistant transgenic plants displayed lower levels of the transgene transcripts and specific small interfering RNAs, suggesting that RNAi induced the viral resistance. 23264447 Long-lasting inhibitory effect of apple and orange juices, but not grapefruit juice, on OATP2B1-mediated drug absorption. Enzyme-based grapefruit juice (GFJ)-drug interactions are mainly due to mechanism-based irreversible inhibition of metabolizing enzyme CYP3A4 by GFJ components, but the transporter organic anion transporting polypeptide (OATP)2B1 is also a putative site of interaction between drugs and fruit juices (FJ) in the absorption process. Here we aimed to investigate the effect of preincubation with FJ on OATP2B1-mediated transport of drugs in vitro. When OATP2B1-expressing Xenopus oocytes were preincubated with GFJ, orange juice (OJ), or apple juice (AJ), AJ induced a remarkable decrease in OATP2B1-mediated estrone-3-sulfate uptake in a concentration-dependent manner (IC(50) = 1.5%). A similar but less potent effect was observed with OJ (IC(50) = 21%), whereas GFJ had no effect. Similar results were obtained in preincubation studies using fexofenadine. Preincubation with OJ and AJ resulted in time-dependent inhibition of OATP2B1. Again, AJ had the more potent effect; its action lasted for at least 240 minutes, suggesting that AJ irreversibly inhibits OATP2B1-mediated drug uptake. Kinetic analysis revealed that coincubation and preincubation with AJ reduced OATP2B1-mediated estrone-3-sulfate uptake via competitive and noncompetitive mechanisms, respectively. Thus, OATP2B1 is functionally impaired through both competitive and long-lasting inhibition mechanisms by AJ and OJ, but not GFJ. Interestingly, although GFJ but not AJ is able to irreversibly inhibit CYP3A4, in the case of OATP2B1, AJ but not GFJ has a long-lasting inhibitory effect. Accordingly, complex FJ-drug interactions may occur in vivo, and their clinical significance should be examined. 23888131 Using Voxel-Based Morphometry to Examine the Relationship between Regional Brain Volumes and Memory Performance in Amnestic Mild Cognitive Impairment. Alzheimer's disease (AD) is a slowly progressive neurodegenerative disorder, in which morphological alterations of brain tissue develop many years before the first neuropsychological and clinical changes occur. Among the first and most prominent symptoms are deficiencies of declarative memory functions. This stage of precursory symptoms to AD has been described as amnestic mild cognitive impairment (aMCI) and is discussed as a potential AD prodrome. As therapy in the later stages of AD has been shown to be of limited impact, aMCI would be the key target for early intervention. For that purpose a comprehensive neuropsychological and anatomical characterization of this group is necessary. Previous neuropsychological investigations identified tests which are highly sensitive in diagnosing aMCI and very early AD. However, the sensitivity of those neuropsychological tests to the particular structural neuropathology in aMCI remains to be specified. To this end, we investigated 25 patients with single-domain aMCI. All participants underwent extensive neuropsychological testing and anatomical scanning with structural magnetic resonance imaging. Voxel-based morphometry (VBM) was performed to identify brain regions that show a significant correlation between regional brain volume and behavioral measures of memory and executive functioning. We found that performance in a variety of mnemonic tests was directly related to the integrity of the medial temporal lobe cortex (MTLC). Moreover, impairment of memory sub-functions in aMCI might be detected earlier than overt structural damage. By this, these findings contribute to the identification of cerebral structures associated with memory deficits in aMCI. 23852446 Watermelon-like iron nanoparticles: Cr doping effect on magnetism and magnetization interaction reversal. Cr-doped core-shell iron/iron-oxide nanoparticles (NPs) containing 0, 2, 5, and 8 at.% of Cr dopant were synthesized via a nanocluster deposition system and their structural and magnetic properties were investigated. We observed the formation of a σ-FeCr phase in 2 at.% of Cr doping in core-shell NPs. This is unique since it was reported in the past that the σ-phase forms above 20 at.% of Cr. The large coercive field and exchange bias are ascribed to the antiferromagnetic Cr2O3 layer formed with the Fe-oxide shell, which also acts as a passivation layer to decrease the Fe-oxide shell thickness. The additional σ-phase in the core and/or Cr2O3 in the shell cause the hysteresis loop to appear tight waisted near the zero-field axis. The exchange interaction competes with the dipolar interaction with the increase of σ-FeCr grains in the Fe-core. The interaction reversal has been observed in 8 at.% of Cr. The observed reversal mechanism is confirmed from the Henkel plot and delta M value, and is supported by a theoretical watermelon model based on the core-shell nanostructure system. 23946455 A strain-specific epitope of Enterovirus 71 identified by cryoEM of the complex with Fab from neutralizing antibody. Enterovirus 71 (EV71) is a picornavirus that causes outbreaks of hand foot and mouth disease (HFMD) primarily in the Asia-Pacific area. Unlike coxsackievirus A16, which also causes HFMD, EV71 induces severe neuropathology leading to high fatalities especially among children under the age of 6 years. Currently, no established vaccines or treatments are available against EV71 infection. The monoclonal antibody (MAb), MA28-7, neutralizes only specific strains of EV71 that have a conserved glycine at amino acid, VP1-145, a surface exposed residue that maps to the five-fold vertex, and has been implicated in receptor binding. The cryo-electron microscopy structure of a complex between EV71 and the Fab fragment of MA28-7 shows that only one Fab occupies each five-fold vertex. A positively-charged patch, which has also been implicated in receptor binding lies within the Fab footprint. We identify the strain-specific epitope of EV71 and discuss the possible neutralization mechanisms of the antibody. 23671227 Bridging the gap: does a specialist eating disorder service, aimed at developing a continuum of community care, make a difference? In 2010, the authors identified in a separate publication, Mind the evidence gap, the sparse evidence-base for the treatment of adult anorexia nervosa and barriers to accessing care. We report on the ensuing development, implementation and first 18-month results of a novel eating disorder service bridging the primary and specialist continuum of care in Victoria, Australia. Using literature review, stakeholder, and consumer and carer consultation, a model for a community eating disorder service was developed and then implemented. All patients entering the service were then assessed at intake and, if they gave consent, at 12 month follow-up. From December 2010 to July 2012, 208 patients accessed The Body Image Eating Disorders Treatment and Recovery Service (BETRS). Fifty-three per cent had a diagnosis of anorexia nervosa and the mean number of co-morbid psychiatric diagnoses was two. Twenty-three per cent attended a day patient programme and showed a significant improvement in their body mass index. Measures of depression, anxiety and eating disorder symptomatology showed a concomitant, significant decrease. The development of BETRS has led to markedly improved access and effectiveness of specialist services in the region. 23244580 Effects and mechanism of organ protection by cardiotrophin-1. Cardiotrophin-1 (CT-1), a member of the interleukin (IL)-6 family, is reported to exhibit a plethora of pleiotropic effects in the heart such as cytoprotective, pro-proliferative and pro-fibrotic ones. An extensive research has been devoted on proliferative and profibrotic effects of CT-1 on the heart. Thus the present review has been aimed to critically define the cytoprotective effects of CT-1 and the cellular and molecular mechanisms involved in them. Although many effects of CT-1 have been described on the heart, CT-1 has now also been reported to exhibit important protective effects in other organs such as liver, kidney or nervous system. CT-1 produces its effects through a unique receptor system comprising LIF receptor (LIFRβ) and a common signal transducer, the glycoprotein 130 (gp130). The signaling pathway downstream from gp130 is based on at least, three distinct pathways: 1) the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, 2) the p42/44 mitogen-activated protein kinase (p42/44 MAPK) pathway, also known as the extracellular receptor kinase-1/2 (ERK1/2) pathway, and 3) the phosphatidylinositol 3-OH kinase (PI3K)/Akt pathway. Since CT-1 easily achieves its cytoprotective effects via a combination of the above three signaling pathways, it becomes quite necessary to determine which pathway(s) is involved in each particular effect of CT-1. In each of its target organs, CT-1 may also display differential mechanisms of cytoprotection, and thus it is relevant to understand how these mechanisms are locally regulated. 23860612 Modified cisplatin, etoposide, and ifosfamide (PEI) salvage therapy for male germ cell tumors: long-term efficacy and safety outcomes. Since 1985, we introduced a modified combination of etoposide, ifosfamide, and cisplatin (PEI) as second-line therapy of adult male germ cell tumors with the aim to reduce toxic effect while maintaining efficacy over the original regimen. Patients received four cycles of ifosfamide at 2.5 g/m(2) on days 1-2, etoposide, and cisplatin at 100 and 33 mg/m(2), respectively, on days 3-5 every 21 days, followed by surgery. Results were stratified according to the International Germ Cell Consensus Classification Group-2 (IGCCCG-2). From February 1985 to January 2012, 189 patients were treated. 72.6% were IGCCCG-2 intermediate-to-very high risk. Thirty-five patients (18.5%) had a complete response, 67 (35.4%) a marker normalization (PRm-). Median follow-up was 122.1 months (inter-quartile range [IQR]: 71.4-232.0). Two-year progression-free and 5-year overall survival were 34.3% [95% confidence interval (CI) 28.1% to 41.9%] and 42.1% (95% CI 35.3% to 50.2%), respectively. Survival estimates compared favorably with those obtained by conventional dose chemotherapy (CDCT) regimens in each prognostic category. 70.4% of grade 3-4 neutropenia (25.5% febrile neutropenia), 48.1% thrombocytopenia, 21.2% anemia, 3.2% neurotoxic effect, and no severe renal toxic effect were recorded. Dose-modified Italian PEI should be considered as an appropriate benchmark for CDCT in the first salvage setting. 23905770 Comparison of the Effects of Ophthalmic Solutions on Human Corneal Epithelial Cells Using Fluorescent Dyes. Abstract Purpose: To investigate the effect of differently preserved ophthalmic solutions on the viability and barrier function of human corneal epithelial cells (HCEC) using fluorescent dyes. Methods: HCEC monolayers were exposed to the ophthalmic solutions containing benzalkonium chloride (BAK), edetate disodium, polyquad, stabilized oxychloro complex (Purite), sodium perborate, or sorbic acid for 5 min, 15 min, and 1 h. At 24 h after exposure, the cultures were assessed for metabolic activity using alamarBlue. The enzyme activity, membrane integrity, and apoptosis were evaluated using confocal microscopy. Barrier function was assessed using sodium fluorescein. Results: The metabolic assay showed that the BAK-preserved ophthalmic solutions significantly reduced cell viability after a 5-min exposure compared to the phosphate buffered saline treated control (P<0.05). Using confocal microscopy, the micrographs showed that BAK caused a reduction in the enzyme activity, increased membrane permeability, and decreased the number of viable cells. Ophthalmic solutions with new preservatives had varying time-dependent adverse effects on cell viability, and the preservative-free solution had the least effect on HCEC. Sodium fluorescein permeability showed that HCEC monolayers treated with BAK-preserved solutions were more permeable to sodium fluorescein than those treated by the other ophthalmic solutions (P<0.05). Conclusions: BAK-preserved solutions had greater adverse effects on metabolic activity, enzyme activity, membrane integrity, cell viability, and barrier function than the solutions that were not preserved with BAK. Our study suggests that BAK-free especially, preservative-free ophthalmic solutions are safer alternatives to BAK-preserved ones. 23676378 Relationship between EEG Beta power abnormality and early diagnosis of cognitive impairment post cerebral hemorrhage. Cerebral hemorrhage is a common disease of older adults, which could increase the risk of cognitive impairment. Electroencephalogram (EEG) characteristics can be analyzed to investigate the applied value in the assessment of cognitive impairment of the patients with cerebral hemorrhage. One hundred eighty-two patients (including patients with cognitive impairment [CHCI] and patients with cognitive normality [CHNC] with cerebral hemorrhage, and 120 normal healthy persons [control; CN]) were recruited between July 2008 to March 2012 at the department of neurology. All patients were analyzed by EEG, and analysis results were compared to the Montreal Cognitive Assessment (MoCA) scale, using the methods of correlation analysis, clustering analysis, and concordance analysis. The results indicated that patients with CHCI had significantly lower EEG beta power (0.814 ± 0.113 mcV(2)) relative to CHNC (1.601 ± 0.186 mcV(2), P < .01) or CN group (1.713 ± 0.201 mcV(2), P < .01). Significant negative correlation was found between the beta power and hemorrhage region, age, hemorrhage size, hemorrhage amount (r 1 = -.92223, r 2 = -.81084, r 3 = -.79258, r 4 = -.84961, respectively, all P < .001). There was good concordance between K-means clustering algorithm calculating the beta power and MoCA scoring (Kappa = 0.899, P < .001). In conclusion, the preliminary findings suggest that the recognition techniques of EEG hold considerable promise for the assessment of cognitive impairment post cerebral hemorrhage, which negatively related to the hemorrhage region, hemorrhage size, hemorrhage amount, and age. 23650169 Fetal safety of macrolides. Macrolide antibiotics are largely used in pregnancy for different bacterial infections. Their fetal safety has been studied by several groups, yielding opposing results. In particular, there have been studies claiming an association between macrolides and cardiovascular malformations. Exposure in early infancy has been associated with pyloric stenosis and intussusception. This has led to an avoidance in prescribing macrolides to pregnant women in several Scandinavian countries. The Objectives of the present study was to investigate the fetal safety of this class of drug by linking a large administrative database of drug dispensing and pregnancy outcome in Southern Israel. A computerized database of medications dispensed from 1999 to 2009 to all women registered in the Clalit health maintenance organization in southern Israel was linked with two computerized databases containing maternal and infant hospitalization records. Also, medical pregnancy termination data were analyzed. The following confounders were controlled for: maternal age, ethnicity, maternal pregestational diabetes, parity, and the year the mother gave birth or went through medical pregnancy termination. First- and third-trimester exposures to macrolide antibiotics as a group and to individual drugs were analyzed. During the study period there were 105,492 pregnancies among Clalit women that met the inclusion criteria. Of these, 104,380 ended in live births or dead fetuses and 1,112 in abortion due to medical reasons. In the first trimester of pregnancy, 1,033 women were exposed to macrolides. There was no association between macrolides and either major malformations [odds ratio (OR), 1.08; 95% confidence interval (CI), 0.84 to 1.38)] or specific malformations, after accounting for maternal age, parity, ethnicity, prepregnancy diabetes, and year of exposure. During the third trimester of pregnancy, 959 women were exposed to macrolides. There was no association between such exposure and perinatal mortality, low birth weight, low Apgar score, or preterm delivery. Similarly, no associations were demonstrated with pyloric stenosis or intussusception. Use of macrolides in the first trimester of pregnancy is not associated with an increased risk of major malformations. Exposure in the third trimester is not likely to increase neonatal risks for pyloric stenosis or intussusception in a clinically meaningful manner. 23859656 Microstructural constitutive model of active coronary media. Although vascular smooth muscle cells (VSMCs) are pivotal in physiology and pathology, there is a lack of detailed morphological data on these cells. The objective of this study was to determine dimensions (width and length) and orientation of swine coronary VSMCs and to develop a microstructural constitutive model of active media. The dimensions, spatial aspect ratio and orientation angle of VSMCs measured at zero-stress state were found to follow continuous normal (or bimodal normal) distributions. The VSMCs aligned off circumferential direction of blood vessels with symmetrical polar angles 18.7° ± 10.9°, and the local VSMC deformation was affine with tissue-level deformation. A microstructure-based active constitutive model was developed to predict the biaxial vasoactivity of coronary media, based on experimental measurements of geometrical and deformation features of VSMCs. The results revealed that the axial active response of blood vessels is associated with multi-axial contraction as well as oblique VSMC arrangement. The present morphological database is essential for developing accurate structural models and is seminal for understanding the biomechanics of muscular vessels. 23590644 Phase-selective sorbent xerogels as reclamation agents for oil spills. 12-Hydroxystearic acid (12-HSA) xerogels derived from 12-HSA-acetronitrile organogels are highly effective sorbent materials capable of adsorbing apolar, spilled materials in aqueous environments. 12-HSA xerogels made from 12-HSA-acetronitrile organogels are more effective than 12-HSA xerogels made from 12-HSA-pentane organogels because of the highly branched fibrillar networks established in acetonitrile molecular gels. This difference arises because of dissimilarities in the network structure between 12-HSA in various solvents. These xerogels, being thermoreversible, allow for both the spilled oil to be reclaimed but also the gelator may be reused to engineer new xerogels for oil spill containment and cleanup. 23908009 Maternal bisphenol a exposure during pregnancy and its association with adipokines in Mexican-American children. Bisphenol A (BPA) is a high volume production chemical that has been detected in 93% of the United States population. It is thought to have endocrine disrupting activity but human data are limited. In this study, we examined whether prenatal or concurrent urinary BPA concentrations are associated with key metabolism-related hormones, adiponectin and leptin (adipokines), in 9-year-old children. For this analysis, we used 188 mother-child pairs from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) prospective study. BPA was measured in urinary spot samples during early (12.6 ± 3.9 weeks gestation) and late (26.3 ± 2.5 weeks gestation) pregnancy and in 9-year-old children. We found that BPA concentrations during late pregnancy were associated with increased plasma leptin in boys (β = 0.06, P = 0.01), controlling for maternal prepregnancy body mass index (BMI), pregnancy soda consumption, and smoking, years in US prior to pregnancy, maternal education, household poverty status, child BMI and child soda, fast food and sweet snack consumption at 9 years. Additionally, we found that BPA concentrations during early pregnancy are directly associated with plasma adiponectin levels in girls (β = 3.71, P = 0.03). However, we did not find any significant relationships between concurrent BPA concentrations and 9-year child adiponectin or leptin. Overall, our data suggest that prenatal BPA concentrations may influence adipokine levels in 9-year-old children. Environ. Mol. Mutagen., 2013. © 2013 Wiley Periodicals, Inc. 23838804 Morphological transformation of hematite nanostructures during oxidation of iron. Oxidation of metals usually results in the formation of an oxide nanostructure with poorly controlled growth morphologies. By employing a simple mechanical approach that uses sandblasting to modify the surface roughness of iron substrates, we demonstrate that the morphologies of hematite (α-Fe2O3) nanostructures varying from the growth of one-dimensional nanowires to two-dimensional nanoblades can be achieved during the thermal oxidation of iron. Electron microscopy studies show that the effect of surface sandblasting is to effectively modify the oxide nucleation locations that define the growth shapes. The optical properties of hematite nanowires and nanoblades are examined for the demonstration of the morphology-property correlations. 23435847 Impact of childhood-onset type 1 diabetes on schooling: a population-based register study. AIMS/HYPOTHESIS: We investigated the impact of type 1 diabetes on educational achievements in compulsory and upper secondary school, as well as potential long-lasting effects. METHODS: Altogether 2,485 individuals with type 1 diabetes, diagnosed at the age of <15 years and born in 1972-1978, were selected from the Swedish Childhood Diabetes Register, which was linked to national population registers including the Swedish Education Register. For each individual, four controls from the general population, matched for year of birth and residence at the time of diagnosis, were selected by Statistics Sweden (n = 9,940). We analysed the impact of diabetes on final school grades at 16 years (compulsory school) and 19 years (upper secondary school) and on participation in the labour market at 29 years using linear, logistic, ordered logistic and quantile regression analyses, controlling for demographics and socioeconomic background. RESULTS: Diabetes had a negative effect on mean final grades (scale of 1-5) in compulsory school (-0.07, p < 0.001) and theoretical programmes in upper secondary school (-0.07, p = 0.001). Children with early-onset diabetes (0-4 years) suffered a greater disadvantage as a result of the disease (-0.15, p = 0.001 in compulsory school). The strongest effect was seen in the lowest deciles of the conditional distribution on mean final grades. At age 29, individuals with diabetes were less likely to be gainfully employed (OR 0.82, 95% CI 0.73, 0.91). CONCLUSIONS/INTERPRETATION: The small but significant negative effect of type 1 diabetes on schooling could affect opportunities for further education and career development. Attention must be paid in school to the special needs of children with diabetes. 23936036 The peripheral myeloid expansion driven by murine cancer progression is reversed by radiation therapy of the tumor. Expansion of myeloid-lineage leukocytes in tumor-bearing mice has been proposed as a cause of systemic immunosuppression. We demonstrate that radiation therapy of tumors leads to a decline in myeloid cell numbers in the blood and a decrease in spleen size. The frequency of myeloid cells does not decline to the level seen in tumor-free mice: we demonstrate that metastatic disease can prevent myeloid cell numbers from returning to baseline, and that tumor recurrence from residual disease correlates with re-expansion of myeloid lineage cells. Radiation therapy results in increased proliferation of T cells in the spleen and while T cell responses to foreign antigens are not altered by tumor burden or myeloid cell expansion, responses to tumor-associated antigens are increased after radiation therapy. These data demonstrate that myeloid cell numbers are directly linked to primary tumor burden, that this population contracts following radiation therapy, and that radiation therapy may open a therapeutic window for immunotherapy of residual disease. 23892977 A method of estimating inspiratory flow rate and volume from an inhaler using acoustic measurements. Inhalers are devices employed to deliver medication to the airways in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease. A dry powder inhaler (DPI) is a breath actuated inhaler that delivers medication in dry powder form. When used correctly, DPIs improve patients' clinical outcomes. However, some patients are unable to reach the peak inspiratory flow rate (PIFR) necessary to fully extract the medication. Presently clinicians have no reliable method of objectively measuring PIFR in inhalers. In this study, we propose a novel method of estimating PIFR and also the inspiratory capacity (IC) of patients' inhalations from a commonly used DPI, using acoustic measurements. With a recording device, the acoustic signal of 15 healthy subjects using a DPI over a range of varying PIFR and IC values was obtained. Temporal and spectral signal analysis revealed that the inhalation signal contains sufficient information that can be employed to estimate PIFR and IC. It was found that the average power (Pave) in the frequency band 300-600 Hz had the strongest correlation with PIFR (R(2) = 0.9079), while the power in the same frequency band was also highly correlated with IC (R(2) = 0.9245). This study has several clinical implications as it demonstrates the feasibility of using acoustics to objectively monitor inhaler use. 23832176 Agreement between radiological and computer navigation measurement of lower limb alignment. Accurate and reproducible measurements of limb alignment are necessary for planning, performing and evaluation of reconstructive knee surgery. Aim of this study was the comparison of the alignment measured on long-leg standing radiographs with the intraoperative data from a navigation system. The records of 135 consecutive patients who received computer-assisted TKA were examined. Technical quality of the long-leg radiographs (LLRs) was classified good, acceptable or poor according to the rotation of the leg. The difference between radiographic and navigation measurements of leg alignment was assessed. Preoperative LLRs were rated as good 56.3 % (71.1 % postoperatively), acceptable in 37.0 % (20.0 % postoperatively) and poor in 6.7 % (8.9 % postoperatively). The median difference between radiographic and navigation measurements increased with reduced quality of the LLR [good 1.5° (range 0.0°-9.9°), acceptable 2.5° (range 0.0°-15.0°), poor 4.5° (range 0.2°-9.5°)], but not with greater deformity. Median difference between both measurements in good radiographs was 1.7° (range 0.0°-9.9°) preoperatively and 1.2° (range 0.0°-7.0°) postoperatively. Difference between radiographic and navigation measurements of lower limb alignment is low if the LLR are obtained in neutral rotation. Larger differences between both measurements can occur even under these ideal conditions, and it is still unclear which measurement is closer to reality. Therefore, even if a navigation system is used during surgery, long-leg standing radiographs should currently not be abandoned. LEVEL OF EVIDENCE: III. 23736523 Cue-dependent memory-based smooth-pursuit in normal human subjects: importance of extra-retinal mechanisms for initial pursuit. Using a cue-dependent memory-based smooth-pursuit task previously applied to monkeys, we examined the effects of visual motion-memory on smooth-pursuit eye movements in normal human subjects and compared the results with those of the trained monkeys. These results were also compared with those during simple ramp-pursuit that did not require visual motion-memory. During memory-based pursuit, all subjects exhibited virtually no errors in either pursuit-direction or go/no-go selection. Tracking eye movements of humans and monkeys were similar in the two tasks, but tracking eye movements were different between the two tasks; latencies of the pursuit and corrective saccades were prolonged, initial pursuit eye velocity and acceleration were lower, peak velocities were lower, and time to reach peak velocities lengthened during memory-based pursuit. These characteristics were similar to anticipatory pursuit initiated by extra-retinal components during the initial extinction task of Barnes and Collins (J Neurophysiol 100:1135-1146, 2008b). We suggest that the differences between the two tasks reflect differences between the contribution of extra-retinal and retinal components. This interpretation is supported by two further studies: (1) during popping out of the correct spot to enhance retinal image-motion inputs during memory-based pursuit, pursuit eye velocities approached those during simple ramp-pursuit, and (2) during initial blanking of spot motion during memory-based pursuit, pursuit components appeared in the correct direction. Our results showed the importance of extra-retinal mechanisms for initial pursuit during memory-based pursuit, which include priming effects and extra-retinal drive components. Comparison with monkey studies on neuronal responses and model analysis suggested possible pathways for the extra-retinal mechanisms. 23830588 Recurrent transient monocular blindness from stenotic central retinal artery. Transient monocular blindness (TMB) is caused by a temporary reduction of blood flow to the retina or optic nerve. Even though embolism from the ipsilateral carotid artery has been considered the main mechanism of TMB, the vascular pathology remains unknown in many patients. A 42-year-old man presented with recurrent transient visual loss in the left eye for 2months. The attacks tended to develop more frequently when his head was bent down. Fluorescence angiography during an attack revealed hypoperfusion of the left central retinal artery (CRA) and cerebral angiography documented a focal isolated stenosis of the CRA at the origin. Aspirin and nimodipine reduced the attacks markedly. Stenosis of the CRA may be a cause of TMB. Intermittent vasospasm in addition to static hypoperfusion may have caused TMB in our patient with isolated CRA stenosis. 23891390 Cultural adaptation and validation of the Pelvic Floor Distress Inventory Short Form (PFDI-20) and Pelvic Floor Impact Questionnaire Short Form (PFIQ-7) Spanish versions. To develop a linguistically adapted and psychometrically validated Spanish version of the Pelvic Floor Distress Inventory and Pelvic Floor Impact Questionnaire Short Forms (PFDI-20 and PFIQ-7) to assess symptoms and quality of life in Spanish women with pelvic floor disorders. Cross-cultural linguistic adaptation was performed following the translation-backtranslation method in 30 native Spanish-speaking women with pelvic floor disorders to obtain PFDI-20 and PFIQ-7 Spanish versions. The psychometric properties were evaluated in 114 women with pelvic floor disorders. We calculated the reliability with the intraclass correlation coefficient and Cronbach's alpha coefficient, the validity with Spearman coefficient, the feasibility with the response rate and the filling time, and the ceiling and floor effects. Spanish versions of the PFDI-20 and PFIQ-7 achieved good semantic, conceptual, idiomatic and content equivalence. Concerning the psychometric validation, internal consistency was high with Cronbach's alpha coefficient of 0.837 (p<0.001) for PFDI-20 and 0.967 (p<0.001) for PFIQ-7. The test-retest reliability was 0.644 (p<0.001) for the PFDI-20 and 0.786 (p<0.001) for the PFIQ-7. Good construct validity was found with questionnaires: SF-12, EPIQ and ICIQ-SF. The average administration time was 10.1 (5.8)min for the PFDI-20, and 7.5 (4.7)min for the PFIQ-7. A ceiling effect was detected in the PFIQ-7 (25.4%). The PFDI-20 and PFIQ-7 Spanish versions showed semantic, conceptual, idiomatic and content equivalence with the original versions. Both instruments are reliable, valid and feasible to evaluate symptoms and quality of life in Spanish women with pelvic floor disorders. 23842082 Oligomers Modulate Interfibril Branching and Mass Transport Properties of Collagen Matrices. Mass transport within collagen-based matrices is critical to tissue development, repair, and pathogenesis, as well as the design of next-generation tissue engineering strategies. This work shows how collagen precursors, specified by intermolecular cross-link composition, provide independent control of collagen matrix mechanical and transport properties. Collagen matrices were prepared from tissue-extracted monomers or oligomers. Viscoelastic behavior was measured in oscillatory shear and unconfined compression. Matrix permeability and diffusivity were measured using gravity-driven permeametry and integrated optical imaging, respectively. Both collagen types showed an increase in stiffness and permeability hindrance with increasing collagen concentration (fibril density); however, different physical property-concentration relationships were noted. Diffusivity was not affected by concentration for either collagen type over the range tested. In general, oligomer matrices exhibited a substantial increase in stiffness and only a modest decrease in transport properties when compared with monomer matrices prepared at the same concentration. The observed differences in viscoelastic and transport properties were largely attributed to increased levels of interfibril branching within oligomer matrices. The ability to relate physical properties to relevant microstructure parameters, including fibril density and interfibril branching, is expected to advance the understanding of cell-matrix signaling, as well as facilitate model-based prediction and design of matrix-based therapeutic strategies. 23594312 Ethics of ARV Based Prevention: Treatment-as-Prevention and PrEP. Published data show that new HIV prevention strategies including treatment-as-prevention and pre-exposure prophylaxis (PrEP) using oral antiretroviral drugs (ARVs) are highly, but not completely, effective if regimens are taken as directed. Consequently, their implementation may challenge norms around HIV prevention. Specific concerns include the potential for ARV-based prevention to reframe responsibility, erode beneficial sexual norms and waste resources. This paper explores what rights claims uninfected people can make for access to ARVs for prevention, and whether moral claims justify the provision of ARV therapy to those who do not yet clinically require treatment as a way of reducing HIV transmission risk. An ethical analysis was conducted of the two strategies, PrEP and treatment-as-prevention, using a public health stewardship model developed by the Nuffield Bioethics Council to consider and compare the application of PrEP and treatment-as-prevention strategies. We found that treating the person with HIV rather than the uninfected person offers advantages in settings where there are limited opportunities to access care. A treatment-as-prevention strategy that places all the emphasis upon the positive person's adherence however carries a disproportionate burden of responsibility. PrEP remains an important option for receptive partners who face increased biological vulnerability. We conclude that the use of ARV for prevention is ethically justified, despite imperfect global to drugs for those in clinical need. The determination of which ARV-based HIV prevention strategy is ethically preferable is complex and must take into account both public health and interpersonal considerations. 23926266 Behavioral modulation of neural encoding of click-trains in the primary and nonprimary auditory cortex of cats. Neural representation of acoustic stimuli in the mammal auditory cortex (AC) has been extensively studied using anesthetized or awake nonbehaving animals. Recently, several studies have shown that active engagement in an auditory behavioral task can substantially change the neuron response properties compared with when animals were passively listening to the same sounds; however, these studies mainly investigated the effect of behavioral state on the primary auditory cortex and the reported effects were inconsistent. Here, we examined the single-unit spike activities in both the primary and nonprimary areas along the dorsal-to-ventral direction of the cat's AC, when the cat was actively discriminating click-trains at different repetition rates and when it was passively listening to the same stimuli. We found that the changes due to task engagement were heterogeneous in the primary AC; some neurons showed significant increases in driven firing rate, others showed decreases. But in the nonprimary AC, task engagement predominantly enhanced the neural responses, resulting in a substantial improvement of the neural discriminability of click-trains. Additionally, our results revealed that neural responses synchronizing to click-trains gradually decreased along the dorsal-to-ventral direction of cat AC, while nonsynchronizing responses remained less changed. The present study provides new insights into the hierarchical organization of AC along the dorsal-to-ventral direction and highlights the importance of using behavioral animals to investigate the later stages of cortical processing. 23780977 Profiles of ILY, VLY and Sm-hPAF interaction with human CD59. The molecular features of a new member of the bacterially -derived cytolysin family were examined. In particular, the interactive mechanisms of intermedilysin (ILY), vaginolysin (VLY), and Streptococcus mitis-derived human platelet aggregation factor (Sm-hPAF) with human CD59 (hCD59) were analyzed. Molecular models of VLY and Sm-hPAF were constructed based on X-ray data of ILY (protein data bank ID=1S3R), and their interactive profiles with hCD59 were examined using molecular simulation. Non-binding (NB) energy between ILY and hCD59 was three orders of magnitude higher than the energy between VLY and hCD59. NB energy between Sm-hPAF and hCD59 was similar to that between VLY and hCD59. A hydrogen bond (ILY Arg432-hCD59 Glu76) was observed between ILY and hCD59, and a stronger interaction was formed by flexible adjustment between them. 23936667 Selected Health Status Measures of Children from US Immigrant Families. Using the 2007 National Survey of Children's Health (N = 91,532), we studied the relationship between the joint effects of immigrant family type (foreign-born children, US-born children/one foreign-born parent, US-born children/both foreign-born parents, and US-born children/US-born parents) and race/ethnicity on various health measures (parent-reported physical and dental health, obesity/overweight, breast-feeding, school absence, injury, and chronic condition). We used weighted logistic regression to examine the independent effects of the 12-level joint variable on various health status measures while controlling for confounding factors. Overall, nearly one-third of families with both foreign-born parents were poor, and one-quarter of the parents in these households did not complete high school. Compared with non-Hispanic White US-born children, multivariable analyses indicate that all Hispanic children have higher odds of obesity, poor physical and dental health, with Hispanic foreign-born children 7 times as likely to report poor/fair physical health. Most children of immigrant parents were more likely to have been breast-fed and less likely to miss school more than 11 days. Child age and household poverty status were independently associated with most of the health status measures. Combined race/ethnicity and immigrant family type categories have heterogeneous associations with each health outcome measure examined. Culturally competent interventions and policies should be developed to serve these expanding communities. 23167621 Insight into tissue unbound concentration: utility in drug discovery and development. In a preclinical setting, plasma or whole tissue drug concentrations are often correlated with pharmacodynamics, although according to the free drug hypothesis, unbound drug concentration should be more pharmacologically relevant. Alternatively, blood concentrations may be a good surrogate for tissue concentration for passively permeable compounds. However, for a large number of compounds that are substrates for uptake and/or efflux transporters expressed at the tissue level, significant discrepancies are expected between unbound concentrations in blood and those in tissues. Consequently, attempts have been made to measure tissue unbound drug concentrations using tissue homogenates, slices and microdialysis. Mathematical expressions for calculating the rate and extent of drug distribution into tissues have also been established. For example, a ratio of unbound concentration in the tissue to that in plasma (K(p,uu)) is the best indicator of the extent of tissue distribution. Despite these technical advances, however, very few examples demonstrate a focus on tissue unbound drug concentrations in a preclinical setting. This review will illustrate various techniques to estimate tissue unbound drug concentrations, relevant parameters to calculate the rate and extent of tissue distribution and different factors affecting tissue unbound concentration. The review will also highlight various examples from the literature where tissue unbound drug concentrations have demonstrated a superior correlation with efficacy. The impact of tissue unbound drug concentrations on the projection of human efficacious dose is also discussed. 23921096 Show me how you walk and I tell you how you feel - A functional near-infrared spectroscopy study on emotion perception based on human gait. The ability to recognize and adequately interpret emotional states in others plays a fundamental role in regulating social interaction. Body language presents an essential element of nonverbal communication which is often perceived prior to mimic expression. However, the neural networks that underlie the processing of emotionally expressive body movement and body posture are poorly understood. 33 healthy subjects have been investigated using the optically based imaging method functional near-infrared spectroscopy (fNIRS) during the performance of a newly developed emotion discrimination paradigm consisting of faceless avatars expressing fearful, angry, sad, happy or neutral gait patterns. Participants were instructed to judge (a) the presented emotional state (emotion task) and (b) the observed walking speed of the respective avatar (speed task). We measured increases in cortical oxygenated haemoglobin (O2HB) in response to visual stimulation during emotion discrimination. These O2HB concentration changes were enhanced for negative emotions in contrast to neutral gait sequences in right occipito-temporal and left temporal and temporo-parietal brain regions. Moreover, fearful and angry bodies elicited higher activation increases during the emotion task compared to the speed task. Haemodynamic responses were correlated with a number of behavioural measures, whereby a positive relationship between emotion regulation strategy preference and O2HB concentration increases after sad walks was mediated by the ability to accurately categorize sad walks. Our results support the idea of a distributed brain network involved in the recognition of bodily emotion expression that comprises visual association areas as well as body/movement perception specific cortical regions that are also sensitive to emotion. This network is activated less when the emotion is not intentionally processed (i.e. during the speed task). Furthermore, activity of this perceptive network is, mediated by the ability to correctly recognize emotions, indirectly connected to active emotion regulation processes. We conclude that a full understanding of emotion perception and its neural substrate requires the investigation of dynamic representations and means of expression other than the face. 23846817 Metformin inhibits follicle-stimulating hormone (FSH) action in human granulosa cells: relevance to polycystic ovary syndrome. Background:Women with anovulatory polycystic ovary syndrome (PCOS) are generally insulin-resistant and as a consequence are often treated with the biguanide metformin. Results with metformin have however been variable with some studies demonstrating induction of regular cycles and an increase in ovulation, whereas others do not. Hence more understanding is needed regarding the mechanism of metformin's actions in ovarian granulosa cells especially in light of previous demonstrations of direct actions.Objective:The aim of this study was to investigate metformin's interaction with the FSH/cAMP/PKA pathway which is the primary signalling pathway controlling CYP19A1 (aromatase) expression in the ovary.Methods:The effect of metformin on FSH and forskolin-stimulated aromatase expression in human granulosa cells was measured by quantitative real-time PCR. Activity was assessed after transfection with promoter II-luciferase construct, and by a radioimmunoassay measuring conversion of androgen to estrogens. The effect on FSH receptor (FSHR) mRNA was assessed by qPCR. Levels of pCREB and CRTC2 were measured by Western blotting, and cAMP by a bioluminescent assay.Results:Metformin markedly reduced FSH but not forskolin-stimulated aromatase expression and activity. This effect was exerted by inhibition of basal- and ligand-induced up-regulation of FSHR expression. Metformin also reduced FSH-induced phosphorylation of CREB and hence CRE activity, which could potentially disrupt the CREB-CBP-CRTC2 co-activator complex that binds to CRE in promoter II of the aromatase gene. This is mediated in an AMPK-independent manner, and does not involve alteration of cAMP levels.Conclusion:These finding have implications for the use of metformin in the treatment of anovulation in women with PCOS. 23382379 Mammalian myosin-18A, a highly divergent myosin. The Mus musculus myosin-18A gene is expressed as two alternatively spliced isoforms, α and β, with reported roles in Golgi localization, in maintenance of cytoskeleton, and as receptors for immunological surfactant proteins. Both myosin-18A isoforms feature a myosin motor domain, a single predicted IQ motif, and a long coiled-coil reminiscent of myosin-2. The myosin-18Aα isoform, additionally, has an N-terminal PDZ domain. Recombinant heavy meromyosin- and subfragment-1 (S1)-like constructs for both myosin-18Aα and -18β species were purified from the baculovirus/Sf9 cell expression system. These constructs bound both essential and regulatory light chains, indicating an additional noncanonical light chain binding site in the neck. Myosin-18Aα-S1 and -18Aβ-S1 molecules bound actin weakly with Kd values of 4.9 and 54 μm, respectively. The actin binding data could be modeled by assuming an equilibrium between two myosin conformations, a competent and an incompetent form to bind actin. Actin binding was unchanged by presence of nucleotide. Both myosin-18A isoforms bound N-methylanthraniloyl-nucleotides, but the rate of ATP hydrolysis was very slow (<0.002 s(-1)) and not significantly enhanced by actin. Phosphorylation of the regulatory light chain had no effect on ATP hydrolysis, and neither did the addition of tropomyosin or of GOLPH3, a myosin-18A binding partner. Electron microscopy of myosin-18A-S1 showed that the lever is strongly angled with respect to the long axis of the motor domain, suggesting a pre-power stroke conformation regardless of the presence of ATP. These data lead us to conclude that myosin-18A does not operate as a traditional molecular motor in cells. 23932166 "I felt like a superhero": The experience of responding to drug overdose among individuals trained in overdose prevention. Overdose prevention programs (OPPs) train people who inject drugs and other community members to prevent, recognise and respond to opioid overdose. However, little is known about the experience of taking up the role of an "overdose responder" for the participants. We present findings from qualitative interviews with 30 participants from two OPPs in Los Angeles, CA, USA from 2010 to 2011 who had responded to at least one overdose since being trained in overdose prevention and response. Being trained by an OPP and responding to overdoses had both positive and negative effects for trained "responders". Positive effects include an increased sense of control and confidence, feelings of heroism and pride, and a recognition and appreciation of one's expertise. Negative effects include a sense of burden, regret, fear, and anger, which sometimes led to cutting social ties, but might also be mitigated by the increased empowerment associated with the positive effects. Findings suggest that becoming an overdose responder can involve taking up a new social role that has positive effects, but also confers some stress that may require additional support. OPPs should provide flexible opportunities for social support to individuals making the transition to this new and critical social role. Equipping individuals with the skills, technology, and support they need to respond to drug overdose has the potential to confer both individual and community-wide benefits. 23838183 Regulators of Calcium Homeostasis Identified by Inference of Kinetic Model Parameters from Live Single Cells Perturbed by siRNA. Assigning molecular functions and revealing dynamic connections between large numbers of partially characterized proteins in regulatory networks are challenges in systems biology. We showed that functions of signaling proteins can be discovered with a differential equations model of the underlying signaling process to extract specific molecular parameter values from single-cell, time-course measurements. By analyzing the effects of 250 small interfering RNAs on Ca(2+) signals in single cells over time, we identified parameters that were specifically altered in the Ca(2+) regulatory system. Analysis of the screen confirmed known functions of the Ca(2+) sensors STIM1 (stromal interaction molecule 1) and calmodulin and of Ca(2+) channels and pumps localized in the endoplasmic reticulum (ER) or plasma membrane. Furthermore, we showed that the Alzheimer's disease-linked protein presenilin-2 and the channel protein ORAI2 prevented overload of ER Ca(2+) and that feedback from Ca(2+) to phosphatidylinositol 4-kinase and PLCδ (phospholipase Cδ) may regulate the abundance of the plasma membrane lipid PI(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to control Ca(2+) extrusion. Thus, functions of signaling proteins and dynamic regulatory connections can be identified by extracting molecular parameter values from single-cell, time-course data. 23407584 Critical parameters in exfoliating graphite into graphene. Dispersing graphite into few-layers graphene sheets (GS) in water is very appealing as an environmental-friendly, low-cost, low-energy method of obtaining graphene. Very high GS concentrations in water (0.7 mg mL(-1)) were obtained by optimizing the nature of dispersant and the type of ultra-sonic generator. We find that a multi-step sonication procedure involving both tip and bath sources considerably enhances the yield of exfoliated GS. Raman and transmission electron microscopy indicate few-layers graphene patches with typical size of ∼0.65 μm in one dimension and ∼0.35 μm in the other. These were further employed in combination with water-dispersed CNTs to fabricate conductive transparent electrodes for a molecularly-controlled solar-cell with an open-circuit voltage of 0.53 V. 23969280 Real-time 3-dimensional contrast-enhanced ultrasound in detecting hemorrhage of blunt renal trauma: a rabbit experiment. The objective of this study is to evaluate the diagnostic value of real-time 3-dimensional contrast-enhanced ultrasound in the hemorrhage of blunt renal trauma. Eighteen healthy New Zealand white rabbits were randomly divided into 3 groups. Blunt renal trauma was performed on each group by using minitype striker. Ultrasonography, color Doppler flow imaging, and contrast-enhanced 2-dimensional and real-time 3-dimensional ultrasound were applied before and after the strike. The time to shock and blood pressure were subjected to statistical analysis. Then, a comparative study of ultrasound and pathology was carried out. All the struck kidneys were traumatic. In the ultrasonography, free fluid was found under the renal capsule. In the color Doppler flow imaging, active hemorrhage was not identified. In 2-dimensional contrast-enhanced ultrasound, active hemorrhage of the damaged kidney was characterized. Real-time 3-dimensional contrast-enhanced ultrasound showed a real-time and stereoscopic ongoing bleeding of the injured kidney. The wider the hemorrhage area in 4-dimensional contrast-enhanced ultrasound was, the faster the blood pressure decreased. Real-time 3-dimensional contrast-enhanced ultrasound is a promising noninvasive tool for stereoscopically and vividly detecting ongoing hemorrhage of blunt renal trauma in real time. 23702102 Characterization of Inertial Confinement Fusion (ICF) Targets Using PIXE, RBS, and STIM Analysis. Quality control of the inertial confinement fusion (ICF) target in the laser fusion program is vital to ensure that energy deposition from the lasers results in uniform compression and minimization of Rayleigh-Taylor instabilities. The technique of nuclear microscopy with ion beam analysis is a powerful method to provide characterization of ICF targets. Distribution of elements, depth profile, and density image of ICF targets can be identified by particle-induced X-ray emission, Rutherford backscattering spectrometry, and scanning transmission ion microscopy. We present examples of ICF target characterization by nuclear microscopy at Fudan University in order to demonstrate their potential impact in assessing target fabrication processes. 23452230 What Can We Learn about Dispersion from the Conformer Surface of n-Pentane? In earlier work [ Gruzman , D. ; Karton , A. ; Martin , J. M. L. J. Phys. Chem. A 2009 , 113 , 11974 ], we showed that conformer energies in alkanes (and other systems) are highly dispersion-driven and that uncorrected DFT functionals fail badly at reproducing them, while simple empirical dispersion corrections tend to overcorrect. To gain greater insight into the nature of the phenomenon, we have mapped the torsional surface of n-pentane to 10-degree resolution at the CCSD(T)-F12 level near the basis set limit. The data obtained have been decomposed by order of perturbation theory, excitation level, and same-spin vs opposite-spin character. A large number of approximate electronic structure methods have been considered, as well as several empirical dispersion corrections. Our chief conclusions are as follows: (a) the effect of dispersion is dominated by same-spin correlation (or triplet-pair correlation, from a different perspective); (b) singlet-pair correlation is important for the surface, but qualitatively very dissimilar to the dispersion component; (c) single and double excitations beyond third order are essentially unimportant for this surface; (d) connected triple excitations do play a role but are statistically very similar to the MP2 singlet-pair correlation; (e) the form of the damping function is crucial for good performance of empirical dispersion corrections; (f) at least in the lower-energy regions, SCS-MP2 and especially MP2.5 perform very well; (g) novel spin-component scaled double hybrid functionals such as DSD-PBEP86-D2 acquit themselves very well for this problem. 23429042 Low-dose bisphenol A and estrogen increase ventricular arrhythmias following ischemia-reperfusion in female rat hearts. Bisphenol A (BPA) is an environmental estrogenic endocrine disruptor that may have adverse health impacts on a range of tissue/systems. In previous studies, we reported that BPA rapidly promoted arrhythmias in female rodent hearts through alteration of myocyte calcium handling. In the present study we investigated the acute effects of BPA on ventricular arrhythmias and infarction following ischemia-reperfusion in rat hearts. Rat hearts were subjected to 20min of global ischemia followed by reperfusion. In female, but not male hearts, acute exposure to 1nM BPA, either alone or combined with 1nM 17β-estradiol (E2), during reperfusion resulted in a marked increase in the duration of sustained ventricular arrhythmias. BPA plus E2 increased the duration ventricular fibrillation, and the duration of VF as a fraction of total duration of sustained ventricular arrhythmia. The pro-arrhythmic effects of estrogens were abolished by MPP combined with PHTPP, suggesting the involvements of both ERα and ERβ signaling. In contrast to their pro-arrhythmic effects, BPA and E2 reduced infarction size, agreeing with previously described protective effect of estrogen against cardiac infarction. In conclusion, rapid exposure to low dose BPA, particularly when combined with E2, exacerbates ventricular arrhythmia following IR injury in female rat hearts. 23418013 Incorporating Graphene Oxide and Gold Nanoclusters: A Synergistic Catalyst with Surprisingly High Peroxidase-Like Activity Over a Broad pH Range and its Application for Cancer Cell Detection. A synergistic graphene oxide-gold nanocluster (GO-AuNC) hybrid has been constructed as an enzyme mimic that is able to show high catalytic activity over a broad pH range, especially at neutral pH. Importantly, the target-functionalized hybrid has been applied as a robust nanoprobe for selective, quantitative, and fast colorimetric detection of cancer cells. 23863486 The Pitx2:miR-200c/141:noggin pathway regulates Bmp signaling and ameloblast differentiation. The mouse incisor is a remarkable tooth that grows throughout the animal's lifetime. This continuous renewal is fueled by adult epithelial stem cells that give rise to ameloblasts, which generate enamel, and little is known about the function of microRNAs in this process. Here, we describe the role of a novel Pitx2:miR-200c/141:noggin regulatory pathway in dental epithelial cell differentiation. miR-200c repressed noggin, an antagonist of Bmp signaling. Pitx2 expression caused an upregulation of miR-200c and chromatin immunoprecipitation assays revealed endogenous Pitx2 binding to the miR-200c/141 promoter. A positive-feedback loop was discovered between miR-200c and Bmp signaling. miR-200c/141 induced expression of E-cadherin and the dental epithelial cell differentiation marker amelogenin. In addition, miR-203 expression was activated by endogenous Pitx2 and targeted the Bmp antagonist Bmper to further regulate Bmp signaling. miR-200c/141 knockout mice showed defects in enamel formation, with decreased E-cadherin and amelogenin expression and increased noggin expression. Our in vivo and in vitro studies reveal a multistep transcriptional program involving the Pitx2:miR-200c/141:noggin regulatory pathway that is important in epithelial cell differentiation and tooth development. 23965912 Early Onset Scoliosis: The Value of Serial Risser Casts. Treatment of early onset scoliosis (EOS) is challenging. In many cases, bracing will not be effective and growing rod surgery may be inappropriate. Serial, Risser casts may be an effective intermediate method of treatment. We studied 20 consecutive patients with EOS who received serial Risser casts under general anesthesia between 1999 and 2011. Analyses included diagnosis, sex, age at initial cast application, major curve severity, initial curve correction, curve magnitude at the time of treatment change or latest follow-up for those still in casts, number of casts per patient, the type of subsequent treatment, and any complications. There were 8 patients with idiopathic scoliosis, 6 patients with neuromuscular scoliosis, 5 patients with syndromic scoliosis, and 1 patient with skeletal dysplasia. Fifteen patients were female and 5 were male. The mean age at first cast was 3.8±2.3 years (range, 1 to 8 y), and the mean major curve magnitude was 74±18 degrees (range, 40 to 118 degrees). After initial cast application, the major curve measured 46±14 degrees (range, 25 to 79 degrees). At treatment change or latest follow-up for those still in casts, the major curve measured 53±24 degrees (range, 13 to 112 degrees). The mean time in casts was 16.9±9.1 months (range, 4 to 35 mo). The mean number of casts per patient was 4.7±2.2 casts (range, 1 to 9 casts). At the time of this study, 7 patients had undergone growing rod surgery, 6 patients were still undergoing casting, 5 returned to bracing, and 2 have been lost to follow-up. Four patients had minor complications: 2 patients each with superficial skin irritation and cast intolerance. Serial Risser casting is a safe and effective intermediate treatment for EOS. It can stabilize relatively large curves in young children and allows the child to reach a more suitable age for other forms of treatment, such as growing rods. Level IV; case series. 23822854 White Matter/Gray Matter Contrast Changes in Chronic and Diffuse Traumatic brain Injury. Signal intensity contrast of T1-weighted MRI scans has been associated with tissue integrity and reported as a sign of neurodegenerative changes in diseases such as AD. After severe traumatic brain injury (TBI), progressive structural changes occur in white and gray matter. In the current study, we assessed the signal intensity contrast of gray matter (GM) and white matter (WM) in patients with diffuse TBI in the chronic stage in order to (1) characterize the regional pattern of WM/GM changes in intensity contrast associated with traumatic axonal injury; (2) evaluate possible associations between this measure and DTI-fractional anisotropy (FA) for detecting white matter damage; and (3) investigate the correlates of both measures with cognitive outcomes. Structural T1 scans were processed with FreeSurfer software to identify the boundary and calculate the WM/GM contrast maps. Diffusion tensor images (DTI) were processed with FSL to obtain FA maps. The WM/GM contrast in TBI patients showed a pattern of reduction in almost all the brain except the visual and motor primary regions. The global FA values obtained from DTI correlated with the intensity contrast of all associative cerebral regions. WM/GM contrast correlated with memory functions, while FA global values correlated with tests measuring memory and mental processing speed. In conclusion, tissue contrast intensity is a very sensitive measure for detecting structural brain damage in chronic, severe and diffuse TBI but is less sensitive than FA for reflecting neuropsychological sequelae such as impaired mental processing speed. 23876130 Current strategies for the treatment of complicated intraabdominal infections. Introduction: Complicated intraabdominal infections (cIAIs) are a common cause of infection-related morbidity and mortality in hospitalized patients and present many challenges unique from other serious infections. cIAIs are generally polymicrobial in nature; however, controversy exists around the pathogenicity of some of the frequently identified microorganisms. Increasing antibiotic resistance among commonly isolated bacteria poses further challenges for clinicians managing patients with cIAIs. Areas covered: This article highlights the microbiology and recent trends in antibiotic resistance most relevant to cIAIs, provides recommendations for treatment using currently available antimicrobials and introduces antibiotics in development with potential roles in managing cIAIs. Expert opinion: Successful treatment of cIAI requires a combination of timely source control and thorough assessment of patient characteristics to guide selection of an appropriate empiric antimicrobial regimen. Specific considerations that should be made when choosing antibiotics include the origin of infection, presence of risk factors for potentially resistant pathogens and severity of disease. While it is encouraging that agents in development may prove helpful in the treatment of cIAIs with resistant pathogens, further identification of novel antibiotics is needed to address this growing concern. In addition, adherence to the principles of antimicrobial stewardship is needed if current antimicrobial resources are to be preserved for the treatment of cIAIs. 23868578 A General Approach To Fabricate Fe3 O4 Nanoparticles Decorated with Pd, Au, and Rh: Magnetically Recoverable and Reusable Catalysts for Suzuki CC Cross-Coupling Reactions, Hydrogenation, and Sequential Reactions. A facile strategy has been explored for loading noble metals onto the surface of ferrite nanoparticles with the assistance of phosphine-functionalized linkers. Palladium loading is shown to occur with participation of both the phosphine function and the surface hydroxyl groups. Hybrid nanoparticles containing simultaneously Pd and Au (or Rh) are obtained by successive loading of metals. Similarly, ferrite nanoparticles decorated with Pd, Au, and Rh have also been formed by using the same strategy. The catalytic properties of the new nanoparticles are evidenced in processes such as reduction of 4-nitrophenol or hydrogenation of styrene. Besides, the sequential process involving a cross-coupling reaction followed by reduction of 1-nitrobiphenyl has been successfully achieved by employing Pd/Au decorated nanoferrite particles. 23909687 Nickel allergy following EU regulation in Denmark, Germany, Italy and the United Kingdom. Nickel allergy is common worldwide. It is associated with hand dermatitis and sensitization is often induced by nickel-releasing jewellery. The European Union introduced legislation to control nickel content and release from jewellery and other consumer items through the EU Nickel Directive 1994, which came in to force in 2001 and is now part of the REACH regulation. To examine the effects of the EU Nickel regulations on the prevalence of nickel allergy in four European countries. Nickel patch test data from 180 390 patients were collected from national databases in Denmark, Germany, Italy and the UK from between 1985 and 2002 to 2010. Patients with suspected allergic contact dermatitis who had been patch tested with nickel sulphate 5% in petrolatum were included in the analysis. The main outcomes studied were the percentage of positive results to nickel patch test and change in trends with time in an age- and sex-stratified analysis. A statistically significant decrease of nickel allergy was observed in Danish, German and Italian women below the age of 30 years. In British female patients, this was observed between 2004 and 2010. In young men, a statistically significant decrease of nickel allergy was observed in Germany and the UK, whereas a non-significant increase was observed in Italy. There has been a reduction in the prevalence of nickel allergy in young women, contemporaneous with the introduction of the nickel regulation. A reduction is also suggested in German and British men. A causative effect of the regulatory intervention is the most likely explanation. This article is protected by copyright. All rights reserved. 23903068 Determination of ferric ions using surface-enhanced Raman scattering based on desferrioxamine-functionalized silver nanoparticles. A simple, robust and reproducible spectroscopic method based on surface-enhanced Raman scattering with nanomolar sensitivity has been developed for selective iron(iii) determination in aqueous solutions. 23883678 Integration of Thermal and Osmotic Regulation of Water Homeostasis: The Role of TRPV Channels. Maintenance of body water homeostasis is critical for preventing hyperthermia, because evaporative cooling is the most efficient means of dissipating excess body heat. Water homeostasis is achieved by regulation of water intake and water loss by the kidneys. The former is achieved by sensations of thirst that motivate water acquisition. While the latter is regulated by the antidiuretic action of vasopressin. Vasopressin secretion and thirst are stimulated by increases in the osmolality of the extracellular fluid as well as decreases in blood pressure and/or blood volume, signals that are precipitated by water depletion associated with the excess evaporative water loss required to prevent hyperthermia. In addition, they are stimulated by increases in body temperature. The sites and molecular mechanisms involved in integrating thermal and osmotic regulation of thirst and vasopressin secretion are reviewed here with a focus on the role of the thermal and mechanosensitive TRPV family of ion channels. 23957216 Facile Catch and Release of Fullerenes Using a Photoresponsive Molecular Tube. A novel M2L2 molecular tube capable of binding fullerene C60 was synthesized from bispyridine ligands with embedded anthracene panels and Ag(I) hinges. Unlike previous molecular cages and capsules, this open-ended tubular host can accommodate a single molecule of various C60 derivatives with large substituents. The fullerene guest can then be released by using the ideal, noninvasive external stimulus, light. 23718218 Visual detection of human infection with influenza A (H7N9) virus by subtype-specific reverse transcription loop-mediated isothermal amplification with hydroxynaphthol blue dye. A rapid and sensitive H7 and N9 subtype-specific reverse transcription loop-mediated isothermal amplification assay was developed respectively for visual detection of human-infected influenza A (H7N9) virus. The reaction was performed in one step in a single tube at 63°C for 60 min with the addition of hydroxynaphthol blue dye before amplification. The detection limits of both subtype-specific assays were comparable to those of validated H7 and N9 real-time PCR assays respectively and no cross-detection was observed with influenza A pandemic H1N1, H3N2, H5N1, H9N2 or influenza B virus. The assays were evaluated further with H7N9 virus-infected clinical specimens. 23623244 Epileptic prodromes: Are they nonconvulsive status epilepticus? The aim of this study was to assess how frequently prodromes occur in an adult patient group from a tertiary referral epilepsy centre and to investigate the EEG changes during the prodromes. 578 consecutive patients were interviewed on subjective phenomena, experiences heralding the seizures, for at least 30min before the start of the seizure. EEGs were recorded during the prodromes. Ten out of 490 included patients had prodromes (2%). We were able to record EEG during prodromes in 6 patients. Three patients had EEG changes corresponding to nonconvulsive status epilepticus. Three patients had unrevealing EEG recordings during prodromes. Our results suggest that at least in a part of the patients, the prodromes are actually ictal phenomena, and should be treated as nonconvulsive status epilepticus. 23957292 Lysine 1110 of TRPM2 is critical for channel activation. Transient receptor potential melastatin 2 (TRPM2) is a non-selective, Ca2+-permeable cation channel activated by ADP-ribose (ADPR) and H2O2. It is widely expressed in mammalian cells and plays an important role in the regulation of various cell functions. However, the mechanisms of TRPM2 channel activation are not fully understood. Previously, we reported that TRPM2 channel activation is induced by high intracellular chloride concentration. In this study, we investigated the functional role of lysine residue at position 1110 (K1110) in the membrane-proximal C-terminal region by site-directed mutagenesis. Substitution of the positive charged amino acid lysine (K1110) with neutral charged amino acid asparagine (K1110N) or negative charged amino acid glutamic acid (K1110E) generated mutants that failed to induce increase in free cytosolic calcium concentration ([Ca2+]i) not only by intracellular injection of chloride ion but also by H2O2 or ADPR. However, mutant generated by substitution of lysine with the same positive charged amino acid arginine (K1110R) displayed channel activity similar to wild-type TRPM2. Interestingly, in K1107N/K1110N double-point mutant, the impaired function of K1110N mutant in response to ADPR and H2O2, but not to chloride ion, was recovered. There were no changes in protein expression, membrane trafficking and oligomerization of the mutant channels. The extent of [Ca2+]i increase by H2O2 in TRPM2 mutants-expressing HEK cells was well correlated with the degree of susceptibility to H2O2-induced cell death. These results display a crucial role of a positive charged amino acid residue at position 1110 for TRPM2 channel activity. 23775355 Fracture risk and bone mineral density in metabolic syndrome: a meta-analysis. Background: The risk of bone fractures in subjects with the metabolic syndrome is unknown. We did a meta-analysis to assess the association between metabolic syndrome, risk of fractures, and bone mineral density (BMD). Materials and Methods: We did searches on electronic databases (Medline, Scopus, and ISI Web of Knowledge) until December 2012 and searched reports to identify studies in humans on bone fractures and BMD at different sites. Two independent reviewers collected the relevant reports. We did random-effects meta-analyses to determine the risk of fractures and BMD values associated with metabolic syndrome. Results: A total of 17 studies, with 35 datasets, were included. In 10 articles (14 datasets) including 1350 incident and 1628 prevalent fractures, metabolic syndrome was associated with a reduced fracture risk (risk ratio = 0.85, 95% confidence interval, 0.71-1.00; high heterogeneity: I(2) = 55%, P = .006). Omission of 2 outlier studies resulted in a significant negative association (risk ratio = 0.85, P = .012; I(2) = 34%, P = .130). Most of the reduced fracture risk was seen in cohort studies (18% reduced risk), suggesting a direction of causality; sex, site of fracture, and definition of the syndrome did not affect the estimates. In 16 articles, including 29 341 subjects, there was no difference in spine, femoral neck, or calcaneus BMD values between subjects with or without metabolic syndrome; mean differences ranged from 0.001 to 0.012 g/cm(2) (P > .10). Conclusions: This article shows a reduced risk of bone fractures associated with metabolic syndrome, without modification of BMD. The clinical significance of these findings remains uncertain and should be addressed in future prospective studies. 23731200 Does midline shift predict postoperative nausea in brain tumor patients undergoing awake craniotomy? A retrospective analysis. Abstract Background: The presence of midline shift on neuroradiologic studies in brain tumor patients represents mass effect from the tumor and surrounding edema. We hypothesized that baseline cerebral edema as measured by midline shift would increase postoperative nausea (PON). We studied the incidence of PON in brain tumor patients, with and without midline shift on preoperative magnetic resonance (MRI) or computed tomographic (CT) imaging, undergoing awake craniotomy. Methods: After IRB approval, we retrospectively extracted data from perioperative records between January 2005 and December 2010. Post-craniotomy nausea and pain scores were collected. Intraoperative anti-emetic, anesthetic, and analgesic regimens were assessed. Both the rescue anti-emetic and cumulative postoperative analgesic requirements were collected up to 12 hours postoperatively. The amount of midline shift on preoperative neuroimaging was gathered from radiology reports. Univariate comparisons between groups (no midline shift vs. midline shift) were made with t-tests for continuous variables, and chi-square tests for categorical variables. A multivariable analysis was performed to identify predictors of postoperative nausea. Limitations of this study include the retrospective design and the inability to gather accurate data regarding vomiting from the medical record. Results: Data from 386 patients were available for analysis. Patients were divided into two groups: no midline shift (n = 283) and midline shift (n = 103). The mean midline shift distance was 5.96 mm (95% CI [5.32, 6.59]). There was no difference in the incidence of nausea or pain scores between the two groups. More malignant brain tumor patients were in the midline shift group, as determined by the postoperative histopathological diagnosis (P < 0.05). Patients in the midline shift group also had longer anesthesia and surgical times (P < 0.05). Conclusion: In patients undergoing a standardized anesthetic for awake craniotomy for tumor resection, the presence of preoperative midline shift did not correlate with postoperative nausea. 23964717 Causes of death after surgery for colon cancer-impact of other diseases, urgent admittance, and gender. Abstract Objective. In patients with colon cancer, high age and comorbidity is common. In this population-based retrospective study we have investigated causes of death and the influence of urgent operation, and gender on survival. Material and methods. Medical records of 413 patients with verified colon cancer were reviewed. The diagnosis was made during 2000-2006 and operation was performed in 385 patients (93%). Results. The overall 5-year survival after surgery was 48.3%. At the end of the follow-up, 128 patients (54.9%) had verified colon cancer when they died but 105 patients (45.1%) had no signs of colon cancer. Their 5-year survival was 5.5% and 41.9%, respectively (p < 0.0001). Median survival time was significantly shorter after urgent compared with elective admittance, 20.7 months versus 77.9 months, and the 5-year survival 32.4% versus 57.9% (p = 0.0001). The tumor stage at operation was more favorable in patients dying with no signs of colon cancer than in those dying with cancer regarding stage I-II (66.7% versus 16.4%), and stage IV (1.0% versus 53.1%), but not regarding stage III (30.5% versus 29.7%). The overall survival in women who were operated was longer than in men (p = 0.045) as well as survival after elective admittance (p = 0.013). Conclusion. After a median follow-up of 56.1 months almost half of the patients who were dead had died from other causes than colon cancer. Ten percent of those patients had an incorrectly reported diagnosis of colon cancer as cause of death. Urgent admittance was associated with reduced survival time. The median survival time was longer in women than in men. 23578608 Role of plant stanol derivatives in the modulation of cholesterol metabolism and liver gene expression in mice. The present study was to evaluate the cholesterol-lowering effect of two novel plant stanol derivatives and its potential molecular mechanism in hyper-cholesterol mice induced by a high-cholesterol diet. Results showed that oral administration of plant stanyl hemisuccinate (2×, 5×) and plant stanyl sorbitol succinate (2×, 5×) effectively attenuated the serum total cholesterol and low density lipoprotein cholesterol levels, while had no effect on the serum triacylglycerol and high density lipoprotein cholesterol. And plant stanol derivatives decreased liver cholesterol concentration and increased faecal cholesterol output. Meanwhile, both plant stanyl hemisuccinate and plant stanyl sorbitol succinate could remarkably promote liver X receptor alpha (LXRα) expression, and increased cholesterol 7α-hydroxylase (CYP7A1) expression and faecal total bile acid output to varying degrees. These results suggested two novel plant stanol derivatives possessed hypocholesterolemic effect, and the cholesterol-lowering action of plant stanol derivatives may be through activating the potential LXRα-CYP7A1-bile acid excretion pathway. 23628218 Biodiesel production from Vietnam heterotrophic marine microalga Schizochytrium mangrovei PQ6. This work is to explore the potential of producing biodiesel and valuable co-products from the biomass of Schizochytrium mangrovei PQ6 which was isolated from Phu Quoc Island, Kien Giang province, Vietnam. This microalga contains high lipid content (up to 70% of dry cell weight) and high level of total fatty acids, which is ideal for making biodiesel. The production of fatty acid methyl esters (FAME) from this marine microalga resulted in a yield of 88% based on algal oil and 44% based on algal biomass. The process of separating the obtained FAME into a first fraction enriched with saturated FAME (SFAME) and a second fraction enriched with unsaturated FAME (UFAME) was then investigated to exploit the valuable co-products. The obtained results shown that the mass fraction of SFAME and UFAME were 70% and 30%, respectively. The UFAME fraction contains a high content of DHA (accounting for 69.000% of TFAs). The test results of the SFAME fraction indicated that specific gravity at 15°C, flash point, water and sediment, kinematic viscosity at 40°C, sulfated ash, sulfur, copper strip corrosion at 50°C, cetane number, carbon residue, iodine number, workmanship meet Vietnam Biodiesel B100 Standard. Moreover, the utilization of waste glycerol from biodiesel process as carbon source for the cultivation of the microalgae S. mangrovei PQ6 and Spirulina platensis was also investigated. 23834702 Persistence of Yellow Fever Vaccine-Induced Antibodies After Solid Organ Transplantation. Immunization using live attenuated vaccines represents a contra-indication after solid organ transplantation (SOT): consequently, transplant candidates planning to travel in countries where yellow fever is endemic should be vaccinated prior to transplantation. The persistence of yellow fever vaccine-induced antibodies after transplantation has not been studied yet. We measured yellow-fever neutralizing antibodies in 53 SOT recipients vaccinated prior to transplantation (including 29 kidney recipients and 18 liver recipients). All but one (98%) had protective titers of antibodies after a median duration of 3 years (min.: 0.8, max.: 21) after transplantation. The median antibody level was 40 U/L (interquartile range: 40-80). For the 46 patients with a known or estimated date of vaccination, yellow-fever antibodies were still detectable after a median time of 13 years (range: 2-32 years) post-immunization. Our data suggest there is long-term persistence of antibodies to yellow fever in SOT recipients who have been vaccinated prior to transplantation. 23776177 Inhaled birch pollen extract induces airway hyperresponsiveness via oxidative stress but independently of pollen-intrinsic NADPH oxidase activity, or the TLR4-TRIF pathway. Oxidative stress in allergic asthma may result from oxidase activity or proinflammatory molecules in pollens. Signaling via TLR4 and its adaptor Toll-IL-1R domain-containing adapter inducing IFN-β (TRIF) has been implicated in reactive oxygen species-mediated acute lung injury and in Th2 immune responses. We investigated the contributions of oxidative stress and TLR4/TRIF signaling to experimental asthma induced by birch pollen exposure exclusively via the airways. Mice were exposed to native or heat-inactivated white birch pollen extract (BPEx) intratracheally and injected with the antioxidants, N-acetyl-L-cysteine or dimethylthiourea, prior to sensitization, challenge, or all allergen exposures, to assess the role of oxidative stress and pollen-intrinsic NADPH oxidase activity in allergic sensitization, inflammation, and airway hyperresponsiveness (AHR). Additionally, TLR4 signaling was antagonized concomitantly with allergen exposure, or the development of allergic airway disease was evaluated in TLR4 or TRIF knockout mice. N-acetyl-L-cysteine inhibited BPEx-induced eosinophilic airway inflammation and AHR except when given exclusively during sensitization, whereas dimethylthiourea was inhibitory even when administered with the sensitization alone. Heat inactivation of BPEx had no effect on the development of allergic airway disease. Oxidative stress-mediated AHR was also TLR4 and TRIF independent; however, TLR4 deficiency decreased, whereas TRIF deficiency increased BPEx-induced airway inflammation. In conclusion, oxidative stress plays a significant role in allergic sensitization to pollen via the airway mucosa, but the pollen-intrinsic NADPH oxidase activity and TLR4 or TRIF signaling are unnecessary for the induction of allergic airway disease and AHR. Pollen extract does, however, activate TLR4, thereby enhancing airway inflammation, which is restrained by the TRIF-dependent pathway. 23361854 Intra-session test-retest reliability of pelvic floor muscle electromyography during running. The prevalence of female stress urinary incontinence is high, and young adults are also affected, including athletes, especially those involved in "high-impact" sports. To date there have been almost no studies testing pelvic floor muscle (PFM) activity during dynamic functional whole body movements. The aim of this study was the description and reliability test of PFM activity and time variables during running. A prospective cross-sectional study including ten healthy female subjects was designed with the focus on the intra-session test-retest reliability of PFM activity and time variables during running derived from electromyography (EMG) and accelerometry. Thirteen variables were identified based on ten steps of each subject: Six EMG variables showed good reliability (ICC 0.906-0.942) and seven time variables did not show good reliability (ICC 0.113-0.731). Time variables (e.g. time difference between heel strike and maximal acceleration of vaginal accelerator) showed low reliability. However, relevant PFM EMG variables during running (e.g., pre-activation, minimal and maximal activity) could be identified and showed good reliability. Further adaptations regarding measurement methods should be tested to gain better control of the kinetics and kinematics of the EMG probe and accelerometers. To our knowledge this is the first study to test the reliability of PFM activity and time variables during dynamic functional whole body movements. More knowledge of PFM activity and time variables may help to provide a deeper insight into physical strain with high force impacts and important functional reflexive contraction patterns of PFM to maintain or to restore continence. 23673078 Radioactive seed localisation (RSL) in the treatment of non-palpable breast cancers: systematic review and meta-analysis. This systematic review compares the outcomes of radioactive seed localisation (RSL) versus standard wire-guided localisation (WGL) in the management of non-palpable breast cancers. We performed a literature search of PubMed, EMBASE and the Cochrane database to identify clinical studies using RSL. Included studies examined invasive breast cancer and reported objective pathological outcome measurements. Quantitative data analyses were performed. 197 papers were identified with eight being clinically relevant to our study. From these eight studies there was only one identified as being a randomised controlled trial (RCT) and four as cohort studies having a control WGL group and included in the quantitative analysis. This provided an overall combined odds ratio (OR) 0.51 (95% CI, 0.36-0.72; z = 3.88; p = 0.0001) for involved surgical margin status; OR, 0.47 (95% CI, 0.33-0.69; z = 3.96; p < 0.0001) for re-operation rates and mean difference (MD) -1.32 (95% CI, -2.32, -0.32; z = 2.58; p = 0.01) for operative time favouring RSL over WGL. In the case of volume of specimens excised, MD 1.46; (95% CI, -22.35, 25.26; z = 0.12; p = 0.90) showing no statistical significance for volume of tissue excised in specimens between the two groups. The results of this systematic review demonstrate a statistically significant benefit of RSL over the gold standard of WGL in terms of involved margin status, re-operation rates and reduced operative time but no statistically significant difference with WGL in terms of volume of tissue excised in the treatment of non-palpable breast cancers. Adequately powered, multicentre RCTs are needed to validate these results. 23867909 Association of high-risk scores for obstructive sleep apnea with symptomatic bradyarrhythmias. Obstructive sleep apnea (OSA) may have an association with bradyarrhythmias but often remains undiagnosed. Our aim was to determine if patients with a high risk of OSA attending our cardiology clinics had an association with symptomatic bradyarrhythmias, as this information might lead to changes in management strategy. The Berlin questionnaire was used to assess risk of OSA in 190 patients, and they were divided into high-risk or low-risk groups. Demographic data and medical histories were recorded and patients groups were compared with t-tests and chi-square tests. A multivariate regression analysis was done to correct for confounding variables. The mean age of our sample population was 63.0 ± 14.7 years with a mean BMI of 29.5 ± 7.8 kg/m. Using the Berlin questionnaire, 41.3% of the patients were classified as high risk; 15.7% of the patients had a known diagnosis of OSA. Between high-risk and low-risk groups, there was no significant difference in the prevalence of bradyarrhythmias (22.5 vs. 15.2% P = 0.21), symptomatic sinus node dysfunction (14.4 vs. 11.4% P = 0.66) or atrioventricular block (10.8 vs. 6.3% P = 0.33). A multivariable logistic regression analysis demonstrated that dyslipidemia had the strongest association with a high risk for OSA, but not bradyarrhythmias. Based on the Berlin questionnaire, patients at a high risk for OSA did not have an increased prevalence of bradyarrhythmias. More studies are needed to assess the utility of evaluating patients with bradyarrhythmias for OSA prior to implanting permanent pacing devices. 23861308 Effect of drug treatment options on the mobility and expression of blaKPC. Both transposition and increases in gene expression have been implicated in the success of KPC-producing pathogens, but the stimulus required for these phenomena are unknown. It is possible that exposure to antimicrobials during patient treatment increases blaKPC expression or induces Tn4401 transposition. The purpose of this study was to determine if exposure to carbapenems or other antimicrobial drug classes could stimulate expression of blaKPC or the in vitro transposition of Tn4401. Five KPC-producing clinical isolates were evaluated in this study. Gene expression of RNA from each isolate exposed to subinhibitory, MIC or suprainhibitory levels of antibiotics was evaluated using real-time RT-PCR. Southern blots were performed on plasmids from isolates exposed to subinhibitory levels of antibiotics. There were subtle changes in blaKPC RNA expression following antibiotic exposure that were both strain and drug dependent. Multiple plasmids ranging from ∼8 to >200 kb were observed for the Enterobacteriaceae isolates, whereas the Pseudomonas aeruginosa isolate had one ∼55 kb plasmid. No changes in hybridization patterns or binding intensity for the blaKPC probe were observed after antibiotic exposure. While the changes in blaKPC RNA expression are subtle, the different responses observed suggest both strain- and genera-specific variations in response to different antibiotic treatments. 23398656 Reduction in sympathetic nerve activity as a possible mechanism for the hypothermic effect of oseltamivir, an anti-influenza virus drug, in normal mice. Oseltamivir, an anti-influenza virus drug, has strong antipyretic effects in mice (Biological and Pharmaceutical Bulletin, 31, 2008, 638) and patients with influenza. In addition, hypothermia has been reported as an adverse event. The prodrug oseltamivir is converted to oseltamivir carboxylate (OC), an active metabolite of influenza virus neuraminidase. In this study, core body temperature was measured in mice, and oseltamivir and OC were administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p). Low i.c.v. doses of oseltamivir and OC dose-dependently produced hypothermia. Zanamivir (i.c.v.), another neuraminidase inhibitor, did not produce hypothermia. These results suggested that the hypothermic effects of oseltamivir (i.p. and i.c.v.) and OC (i.c.v.) are not due to neuraminidase inhibition. OC (i.p.) did not lower body temperature. Although mecamylamine (i.c.v.) blocked the hypothermic effect of nicotine-administered i.c.v., the hypothermic effects of oseltamivir and OC (i.c.v.) were not blocked by mecamylamine (i.c.v.). The effect of oseltamivir (i.p.) was markedly increased by s.c.-pre-administered mecamylamine and also hexamethonium, a peripherally acting ganglionic blocker, suggesting their potentiating interaction at peripheral sites. The hypothermic effect of nicotine (i.c.v.) was decreased by lower doses of oseltamivir (i.c.v.), suggesting the anti-nicotinic action of oseltamivir. These results suggest that oseltamivir (i.p.) causes hypothermia through depression of sympathetic temperature regulatory mechanisms via inhibition of nicotinic receptor function and through unknown central mechanisms. 23859860 Sequential MR Angiography in Childhood Primary Angiitis of the CNS. Central nervous system (CNS) vasculitis is rare in childhood. Diagnosis is sometimes difficult, and imaging methods range from MRI to MRA to conventional angiography. In doubtful cases a brain biopsy is necessary for diagnostic purposes. We describe a 6-year old child affected with primary angiitis of the CNS who was treated successfully with corticosteroids and mycophenolate mofetil and who was followed with MRI and MRA, which guided treatment decisions throughout the disease course. Sequential images are shown. 23506120 Increased Levels of Inosine in a Mouse Model of Inflammation. One possible mechanism linking inflammation with cancer involves the generation of reactive oxygen, nitrogen, and halogen species by activated macrophages and neutrophils infiltrating sites of infection or tissue damage, with these chemical mediators causing damage that ultimately leads to cell death and mutation. To determine the most biologically deleterious chemistries of inflammation, we previously assessed products across the spectrum of DNA damage arising in inflamed tissues in the SJL mouse model nitric oxide overproduction ( Pang et al. ( 2007 ) Carcinogenesis 28 , 1807 - 1813 ). Among the anticipated DNA damage chemistries, we observed significant changes only in lipid peroxidation-derived etheno adducts. We have now developed an isotope-dilution, liquid chromatography-coupled, tandem quadrupole mass spectrometric method to quantify representative species across the spectrum of RNA damage products predicted to arise at sites of inflammation, including nucleobase deamination (xanthosine and inosine), oxidation (8-oxoguanosine), and alkylation (1,N(6)-ethenoadenosine). Application of the method to the liver, spleen, and kidney from the SJL mouse model revealed generally higher levels of oxidative background RNA damage than was observed in DNA in control mice. However, compared to control mice, RcsX treatment to induce nitric oxide overproduction resulted in significant increases only in inosine and only in the spleen. Further, the nitric oxide synthase inhibitor, N-methylarginine, did not significantly affect the levels of inosine in control and RcsX-treated mice. The differences between DNA and RNA damage in the same animal model of inflammation point to possible influences from DNA repair, RcsX-induced alterations in adenosine deaminase activity, and differential accessibility of DNA and RNA to reactive oxygen and nitrogen species as determinants of nucleic acid damage during inflammation. 23895059 Induced pluripotent stem cells for the treatment of stroke: the potential and the pitfalls. The extraordinary discovery of induced pluripotent stem cells (iPSCs) has led to the very real possibility that patient-specific cell therapy can be realized. The potential to develop cell replacement therapies outside the ethical and legal limitations, has initiated a new era of hope for regenerative strategies to treat human neurological disease including stroke. In this article, we will review and compare the current approaches to derive iPSCs from different somatic cells, and the induction into neuronal phenotypes, considering the advantages and disadvantages to the methodologies of derivation. We will highlight the work relating to the use of iPSC-based therapies in models of stroke and their potential use in clinical trials. Finally, we will consider future directions and areas of exploration which may promote the realization of iPSC-based cell replacement strategies for the treatment of stroke. 23733786 Expansion of the pseudo-autosomal region and ongoing recombination suppression in the Silene latifolia sex chromosomes. There are two very interesting aspects to the evolution of sex chromosomes: what happens after recombination between these chromosome pairs stops and why suppressed recombination evolves. The former question has been intensively studied in a diversity of organisms, but the latter has been studied largely theoretically. To obtain empirical data, we used codominant genic markers in genetic mapping of the dioecious plant Silene latifolia, together with comparative mapping of S. latifolia sex-linked genes in S. vulgaris (a related hermaphrodite species without sex chromosomes). We mapped 29 S. latifolia fully sex-linked genes (including 21 newly discovered from transcriptome sequencing), plus 6 genes in a recombining pseudo-autosomal region (PAR) whose genetic map length is ∼25 cM in both male and female meiosis, suggesting that the PAR may contain many genes. Our comparative mapping shows that most fully sex-linked genes in S. latifolia are located on a single S. vulgaris linkage group and were probably inherited from a single autosome of an ancestor. However, unexpectedly, our maps suggest that the S. latifolia PAR region expanded through translocation events. Some genes in these regions still recombine in S. latifolia, but some genes from both addition events are now fully sex-linked. Recombination suppression is therefore still ongoing in S. latifolia, and multiple recombination suppression events have occurred in a timescale of few million years, much shorter than the timescale of formation of the most recent evolutionary strata of mammal and bird sex chromosomes. 23677893 Do perceived social stress and resilience influence the effects of psychopathy-linked narcissism and CU traits on adolescent aggression? The current study explored the influences of social stress and resilience on the relation between psychopathy-linked personality characteristics (i.e., narcissism, dimensions of CU traits) and aggression with the expectation that social stress would exacerbate the relation, whereas resilience would mitigate it. In a sample of 154 at-risk adolescents (ages 16-18; 84% male), contrary to expectations, high social stress attenuated the relations of narcissism and callousness with aggression. Self-reported resilience attenuated the relation between callousness and aggression. The implications for understanding the role that these moderators might play in the association between adolescent psychopathic tendencies, particularly callousness, and aggression are discussed. Aggr. Behav. 39:381-390, 2013. © 2013 Wiley Periodicals, Inc. 23160941 Functional characterization of three mouse formyl peptide receptors. The evolutionary relationship and functional correlation between human formyl peptide receptors (FPRs) and their mouse counterparts remain incompletely understood. We examined three members of the mouse formyl peptide receptor subfamily (mFprs) and found that they differ in agonist preference and cellular distributions. When stably expressed in transfected rat basophilic leukemia (RBL-2H3) cells, mFpr1 was readily activated by N-formylated peptides derived from Listeria monocytogenes (fMIVTLF), Staphylococcus aureus (fMIFL), and mitochondria (fMMYALF). In contrast, the Escherichia coli-derived fMLF was 1000-fold less potent. The aforementioned peptides were much less efficacious at mFpr2, which responded better to the synthetic hexapeptide WKYMVm, the synthetic agonists Quin-C1 (a substituted quinazolinone), and compound 43 (a nitrosylated pyrazolone derivative). Saturation binding assays showed that mFpr1 and mFpr2 were expressed at similar levels on the cell surface, although their affinity for N-formyl-Met-Leu-Phe-Ile-Ile-Lys-fluorescein isothiocyanate varied by more than 1000-fold [dissociation constant (K(d)) values of 2.8 nM for mFpr1 and 4.8 μM for mFpr2]). Contrary to these receptors, mFpr-rs1 responded poorly to all the previously mentioned peptides that were tested. Fluorescent microscopy revealed an intracellular distribution pattern of mFpr-rs1. On the basis of these results, we conclude that mFpr1 is an ortholog of human FPR1 with certain pharmacologic properties of human FPR2/ALX, whereas mFpr2 has much lower affinity for formyl peptides. The intracellular distribution of mFpr-rs1 suggests an evolutionary correlation with human FPR3. 23620263 Asymmetric zinc-catalyzed hydrosilylation of ketones and the effect of carboxylate on the enantioselectivity. Several chiral ligands containing (R,R)-diaminocyclohexane moieties and pyrrole, furan, or benzene have been synthesized. These ligands were tested in enantioselective zinc-catalyzed hydrosilylation reactions; excellent enantioselectivities were obtained when the ligands containing (R,R)-diaminocyclohexane moieties and furan rings were used. For comparison, zinc chloride combined with different potassium carboxylate salts and ligands were also tested for catalytic hydrosilylation reactions. Chirality 25:275-280, 2013. © 2013 Wiley Periodicals, Inc. 23949186 The effect of oxygen vacancies on water wettability of a ZnO surface. In this study, the effect of oxygen vacancies on the water wettability of a hydrated ZnO(100) surface has been examined via molecular dynamics simulations with a reactive force field (ReaxFF). The results show that the oxygen vacancies on the ZnO surface change the structures of the ZnO surface and subsequently its water adsorption capability. While a 1 : 1 ratio of water to hydroxyl is observed for a water monolayer absorbed on ZnO(100) without oxygen vacancies, additional water adsorption as coordinate hydroxyl that resides on the vacancy site and bonds with three lattice zinc atoms is observed on the surfaces with oxygen vacancies. The results also show that the energy of the interaction per unit area between water and the hydrated ZnO surface is 55.1% higher in the presence of the oxygen vacancies than that without oxygen vacancies. This leads to a water contact angle of ∼115° for the hydrated ZnO(100) surface in the absence of vacancies and ∼21° with vacancies. The wetting kinetics of a water droplet on a ZnO(100) surface with and without oxygen vacancies are compared with the diffusion-limited reactive wetting and molecular kinetics models, respectively. In addition, the ordering of the vacancy sites is found not to significantly affect the wettability of the ZnO(100) surface. 23425525 High-resolution coherent three-dimensional spectroscopy of br2. In the past, high-resolution spectroscopy has been limited to small, simple molecules that yield relatively uncongested spectra. Larger and more complex molecules have a higher density of peaks and are susceptible to complications (e.g., effects from conical intersections) that can obscure the patterns needed to resolve and assign peaks. Recently, high-resolution coherent two-dimensional (2D) spectroscopy has been used to resolve and sort peaks into easily identifiable patterns for molecules where pattern-recognition has been difficult. For very highly congested spectra, however, the ability to resolve peaks using coherent 2D spectroscopy is limited by the bandwidth of instrumentation. In this article, we introduce and investigate high-resolution coherent three-dimensional spectroscopy (HRC3D) as a method for dealing with heavily congested systems. The resulting patterns are unlike those in high-resolution coherent 2D spectra. Analysis of HRC3D spectra could provide a means for exploring the spectroscopy of large and complex molecules that have previously been considered too difficult to study. 23253133 Antibody-drug conjugates for the treatment of cancer. With over 20 antibody-drug conjugates in clinical trials as well as a recently FDA-approved drug, it is clear that this is becoming an important and viable approach for selectively delivering highly cytotoxic agents to tumor cells while sparing normal tissue. This review discusses the critical aspects for this approach with an emphasis on the properties of the linker between the antibody and the cytotoxic payload that are required for an effective antibody-drug conjugate. Different linkers are illustrated with attention focused on (i) the specifics of attachment to the antibody, (ii) the polarity of the linker, (iii) the trigger on the linker that initiates cleavage from the drug, and (iv) the self-immolative spacer that liberates the active payload. Future directions in the field are proposed. 23870300 Influence of the Vitreomacular Interface on Outcomes of Ranibizumab Therapy in Neovascular Age-related Macular Degeneration. To investigate the influence of the vitreomacular interface (VMI) on the functional and anatomic efficacy of ranibizumab therapy in patients with neovascular age-related macular degeneration (AMD). Subanalysis of a prospective, 12-month, multicenter, phase IIIb trial. A total of 353 treatment-naïve patients with subfoveal choroidal neovascularization (CNV) receiving quarterly or monthly ranibizumab therapy. On monthly optical coherence tomography (OCT) scan sets, the VMI configuration was graded by a certified reading center into one of the following conditions: continuous posterior vitreoretinal attachment (PVA), vitreomacular adhesion (VMA), partial vitreous detachment without vitreomacular contact, or complete posterior vitreous detachment (PVD). Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) measurements were performed at monthly intervals. Analysis included patients with a minimum of 10 OCT examinations, including baseline and month 12 (n = 251). After integration of the VMI configuration over 12 months, patients were divided into one of the following categories: PVD (n = 162), release of vitreomacular contact (RELEASE; n = 48), VMA (n = 37), or PVA (n = 4). General estimation equation analyses were applied to test for noninferiority of quarterly versus monthly treatment. The BCVA and CRT changes at month 12. Mean BCVA changes in letters were +4.7 (PVD), +3.2 (RELEASE), and -0.2 (VMA) in the quarterly regimen and +4.9 (PVD), +12.7 (RELEASE), and +7.5 (VMA) in the monthly regimen. No difference in therapeutic efficiency between monthly and quarterly intervention was found in eyes with PVD, and quarterly treatment was noninferior to monthly treatment (P = 0.001). However, monthly treatment was superior to quarterly treatment in the RELEASE (P = 0.008) and VMA (P = 0.043) groups. Mean CRT changes were -98 and -96 μm (PVD), -117 and -136 μm (RELEASE), and -93 and -87 μm (VMA) in the monthly and quarterly regimens, respectively, without statistically significant differences. The configuration of the VMI seems to have an important effect on visual outcomes and need for retreatment. In patients with PVD, a lower treatment frequency may be feasible, whereas patients with RELEASE or VMA may benefit from intensive retreatment. These findings may serve as a basis for individualized treatment decisions in anti-angiogenic therapy of neovascular AMD and perhaps other indications. Proprietary or commercial disclosure may be found after the references. 23617225 Display of alcohol use on facebook: a content analysis. Abstract The present study has two main objectives. First, to examine how alcohol use is portrayed in the visual and textual references on Facebook, and second, to determine how friends react to these alcohol-related postings. A theoretically based content analysis of 160 Facebook profiles generated 2,575 pictures and 92 status updates referring to alcohol use, which represented about 6.50% of the pictures in the total sample and 2.90% of the status updates. These visual and textual references, as well as the peer reactions to these posts, mostly referred to alcohol use in a positive context (72.23% of the pictures and 72.83% of the messages). Furthermore, multiple regression analyses identified the number of Facebook friends and the number of status updates referring to alcohol use as significant predictors of the total number of uploaded pictures containing alcohol use. The results of this study are discussed within the framework of expectancy models of behavior and media effects theories, and show that alcohol-related references are quite common, while negative reactions to these posts are seldom. Further research into the effects of these visual and textual messages is warranted. 23557702 PKCδ Impaired Vessel Formation and Angiogenic Factor Expression in Diabetic Ischemic Limbs. Decreased collateral vessel formation in diabetic peripheral limbs is characterized by abnormalities of the angiogenic response to ischemia. Hyperglycemia is known to activate protein kinase C (PKC), affecting the expression and activity of growth factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). The current study investigates the role of PKCδ in diabetes-induced poor collateral vessel formation and inhibition of angiogenic factors expression and actions. Ischemic adductor muscles of diabetic Prkcd(+/+) mice exhibited reduced blood reperfusion, vascular density, and number of small vessels compared with nondiabetic Prkcd(+/+) mice. By contrast, diabetic Prkcd(-/-) mice showed significant increased blood flow, capillary density, and number of capillaries. Although expression of various PKC isoforms was unchanged, activation of PKCδ was increased in diabetic Prkcd(+/+) mice. VEGF and PDGF mRNA and protein expression were decreased in the muscles of diabetic Prkcd(+/+) mice and were normalized in diabetic Prkcd(-/-) mice. Furthermore, phosphorylation of VEGF receptor 2 (VEGFR2) and PDGF receptor-β (PDGFR-β) were blunted in diabetic Prkcd(+/+) mice but elevated in diabetic Prkcd(-/-) mice. The inhibition of VEGFR2 and PDGFR-β activity was associated with increased SHP-1 expression. In conclusion, our data have uncovered the mechanisms by which PKCδ activation induced poor collateral vessel formation, offering potential novel targets to regulate angiogenesis therapeutically in diabetic patients. 23919558 Solution-focused brief therapy from the perspective of clients with long-term physical health conditions. As long-term physical health conditions are becoming increasingly prevalent in our society, interventions are needed to help individuals live as well as possible. The research explores participants' experiences of solution-focused brief therapy (SFBT) with a view to determining helpful aspects of this. Eleven service users were interviewed, and interviews were analysed using inductive thematic analysis. Participants' responsibility for change and the strengths and resources they possessed were highlighted, along with the focus within therapy on goals. A number of specific SFBT techniques that were perceived as helpful during therapy were described such as reframing, competence talk and reflectiveness, as well as other factors that enabled engagement with the psychologist. 23944642 Anharmonic Calculation of the Structure, Vibrational Frequencies and Intensities of the NH3…Trans-HONO Complex. The equilibrium geometry of the NH3…trans-HONO complex and the harmonic vibrational frequencies and intensities are calculated in the MP2/aug-cc-pVTZ approximation with the basis set superposition error taken into account. Effects of anharmonic interactions on spectroscopic parameters are studied by solving vibrational Schrödinger equations in 1- 4 dimensions using the variational method. Anharmonic vibrational equations are formulated in the space of normal coordinates of the complex. Detailed analysis is performed for the H-bond stretching vibration and internal vibrations of trans-HONO isomer in the complex. The inter-mode anharmonicity and anharmonic coupling between two, three, and four vibrational modes are studied on the basis of correct ab initio potential energy surfaces calculated in the above approximation. The combinations of normal modes of the complex most strongly coupled to one another are examined. The calculated frequencies and intensities of vibrational bands are compared with the experimental data on the NH3…trans-HONO complex in an argon matrix and results of earlier calculations of monomeric HONO. In this calculation the strong resonance between the first excited state of the OH stretching vibration and the doubly excited state of the NOH bending vibration of trans-HONO isomer in the complex is thoroughly studied by solving vibrational equations in two and four dimensions. 23792761 Novel expanded porphyrin sensitized solar cells using boryl oxasmaragdyrin as the sensitizer. Oxasmaragdyrin boron complexes were prepared and applied in DSSCs. The HOMO-LUMO energy gap analyses and theoretical calculations revealed that these expanded porphyrins are ideal sensitizers for DSSCs. A device containing oxasmaragdyrin-BF2 as the sensitizer achieves an energy conversion efficiency of 5.7%. 23942291 Refractory hodgkin lymphoma. Despite the advances in the treatment of Hodgkin Lymphoma, patients with refractory disease still have a poor prognosis. Hodgkin Lymphoma can be refractory at first diagnosis or might become refractory later in the course of treatment. Both situations represent a therapeutic challenge. Intensified chemotherapy with BEACOPP escalated has been evaluated in early unfavourable and advanced Hodgkin Lymphoma and led to an improved tumour control and reduced rates of refractory disease. Furthermore, there is growing evidence for the role of tandem autologous transplant in breaking refractory disease. For patients relapsing after autologous transplant, more recent analyses have reported outcome and defined risk factors. The antibody drug conjugate brentuximab vedotin is a new, highly effective therapeutic option for these patients. Dose-reduced allogeneic transplant is a therapeutic alternative for patients relapsing after autologous transplant, but induction of a remission is the prerequisite for a successful allogeneic transplant. Brentuximab vedotin has been evaluated as a bridge to allogeneic transplant for patients refractory to conventional treatment. Recent therapeutic advances have improved the prognosis of Hodgkin Lymphoma by prevention or successful treatment of refractory disease. The use of new drugs such as brentuximab vedotin will hopefully further increase the cure rates. 23827481 Supercapacitive activities of potentiodynamically deposited nanoflakes of cobalt oxide (Co3O4) thin film electrode. In the present work, the Co3O4 thin films are successfully prepared via potentiodynamic electrodeposition method onto inexpensive stainless steel substrate. As-deposited films were heat treated at 623K for their conversion into Co3O4. These films were characterized by means of X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and scanning electron microscopy (SEM) techniques. The X-ray diffraction (XRD) study revealed the formation of cobalt oxide (Co3O4) with cubic crystal structure. The FT-IR study supports the formation of Co3O4 material. The SEM image of Co3O4 film showed nanoflake-like morphology with an average thickness of 100nm. Supercapacitive properties of Co3O4 thin film electrode were examined using cyclic voltammetry and charge-discharge techniques. The Co3O4 thin film electrode showed maximum specific capacitance of 365Fg(-1) in 1M KOH electrolyte at the scan rate of 5mVs(-1). The charge-discharge technique was employed to estimate the values of specific energy, power and coulombic efficiency as 64Whkg(-1), 21.53kWkg(-1) and 99%, respectively. 23287426 Novel treatment options for epilepsy: focus on perampanel. Perampanel is a new chemical entity recently approved in the United States (US) and European Union (EU) as adjunctive treatment of partial-onset seizures with and without secondary generalization in patients with epilepsy aged 12 years and older. Pharmacological studies suggest that perampanel acts with a new mechanism of action via non-competitive antagonism of the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor of glutamate, the main mediator of excitatory neurotransmission in the central nervous system. Perampanel is completely absorbed after oral administration. The drug is 95% bound to plasma proteins and is extensively metabolized by oxidation followed by glucuronidation. Perampanel has an elimination half-life of approximately 52-129h, allowing once daily dosing, with peak plasma levels observed 0.25-2h post-dose. Randomized placebo-controlled trials of adjunctive treatment have demonstrated that once-daily perampanel doses of 4-12mg/day significantly reduced partial-onset seizure frequency in patients with pharmacoresistant epilepsy along with a favorable tolerability profile. In perampanel pivotal trials, the most frequently reported treatment emergent adverse events (>10%) included dizziness, somnolence, fatigue and headache. Perampanel therapeutic response was maintained in patients included in the long term open-label extension studies for up to 4 years. Based on these data, perampanel offers a valuable option in the add-on treatment of partial-onset and secondarily generalized seizures. 22609856 In vitro biomonitoring of the genotoxic and oxidative potentials of two commonly eaten insects in southwestern Nigeria. In this study, the cytogenetic and oxidative effects of water soluble extracts of two commonly eaten insects, Zonocerus variegatus (Orthoptera: Pyrgomorphidae) and Oryctes boas (Solanales: Solanaceae), in southwestern Nigeria were evaluated on cultured human blood cells. The extracts were added to the cultures at various concentrations (0-2000 ppm). The chromosome aberration and micronucleus tests were used to find out the DNA and chromosomal damage potentials in vitro by aqueous insect extracts. To assess the oxidative effects of these insect extracts, total antioxidant capacity (TAC) and total oxidant status (TOS) levels were also measured. Our results indicated that these extracts did not show genotoxic effects at the tested concentrations. However, the extracts caused dose-dependent alterations in both TAC and TOS levels. Based on the findings, it was concluded that the studied insects can be consumed safely, but it is necessary to consider the cellular damages that are likely to appear depending on the oxidative stress. We also suggest that this in vitro approach for oxidative and genotoxicity assessments may be useful to compare the potential health risks of edible insects. 23113754 ADRB3 and PPARγ2 gene polymorphisms and their association with cardiovascular disease risk in postmenopausal women. Abstract Objectives The contribution of heritability to the development of cardiovascular disease (CVD) is of interest as the identification of genes enhancing the susceptibility of individuals to CVD may help the design of clinical interventions optimized for the individual's genome. Methods We studied the associations of polymorphism of ADRB3 and PPARγ2 genes with obesity indices, unfavorable lipid profile parameters and insulin resistance index HOMA in 343 postmenopausal women. Results No association was found between tested polymorphisms and CVD risk factors such as total cholesterol ≥ 5.0 mmol/l, high density lipoprotein cholesterol < 1.2 mmol/l, low density lipoprotein cholesterol > 3.0 mmol/l and triacylglycerols > 1.7 mmol/l. The presence of arterial hypertension and HOMA value ≥ 1.95 were also not related to these polymorphisms. A significant association between PPARγ2 gene polymorphism and total body fat mass (odds ratio = 1.90 at p = 0.037) as well as android fat deposit mass (odds ratio = 1.82 at p = 0.048) was found. Conclusions CVD risk factors in postmenopausal women are not directly associated with the polymorphisms of PPARγ2 and ADRB3 genes. We suggest that some indirect link between PPARγ2 gene polymorphism and susceptibility of postmenopausal women to CVD may exist. This suggestion is based on our finding that high total body fat mass and high android fat deposits are associated with the presence of the Pro12Ala allele of the PPARγ2 gene. 23677639 In vitro treatment of carcinoma cell lines with pancreatic (pro)enzymes suppresses the EMT programme and promotes cell differentiation. Previous research has suggested a putative utility of pancreatic (pro)enzymes in cancer treatment. The aim of the present study was to investigate the in vitro effects of a mixture of two pancreatic pro-enzymes, i.e., Chymotrypsinogen and Trypsinogen, and the enzyme Amylase on three human cancer cell lines, i.e., OE33 (derived from an oesophageal carcinoma), Panc1 (derived from a pancreatic carcinoma) and Caco-2 (derived from a colon carcinoma). After treatment of the three cancer cell lines with different doses of the (pro)enzymes for up to 7 days, we observed (i) growth inhibition in a dose-dependent manner, (ii) enhanced expression of β-catenin and E-cadherin and decreased expression of several epithelial-mesenchymal transition (EMT)-associated genes, such as Vimentin, Snail and Slug, (iii) differentiation of Caco-2 cells, including the appearance of cell-specific differentiated structures such as microvilli and tight junctions, the acquisition of a more regular polygonal morphology, and an increased expression of the intestinal differentiation markers alkaline phosphatase and cytokeratin 8, and (iv) differentiation of Panc1 cells, including the formation of cell aggregates, an increment on lamellar bodies and an increased expression of the pancreatic differentiation markers glucagon and insulin. Our results show that the treatment of three different human cancer cell lines with pancreatic (pro)enzymes results in an enhancement of cell adhesion, an attenuation of several EMT-associated markers, and an increase in the expression of several differentiation-associated markers, suggesting the acquisition of a less malignant phenotype and a decrease in proliferative capacity due to lineage-specific cellular differentiation. 23612522 ROS production and their influence on the cellular antioxidative system in human erythrocytes incubated with daunorubicin and glutaraldehyde. This study examined the effects of daunorubicin and glutaraldehyde on some parameters of erythrocytes. The aim of the article was to present the results of research aiming to identify the level of glutaraldehyde at which the hemoglobin oxidation, externalization of phosphatidylserine and the changes in the viability (hemolysis) of erythrocytes are not statistically significant and therefore this level of glutaraldehyde can be used for the drug carriers' preparation. Glutaraldehyde was used as a crosslinking agent to enhance the uptake of the drug within red blood cells and to prevent its leakage from the cells. Fluorescence microscopy, flow cytometry and fluorimetric measurements confirmed higher levels of the drug in glutaraldehyde-treated human erythrocytes. Unfortunately, substantial damage to the red blood cells was also noted. DNR increased oxidative processes in the cell, which in turn led to an increase in the reactive oxygen species (ROS) level. When the red blood cells were also treated with glutaraldehyde, ROS production was significantly higher. We also observed loss of both the reduced and the total glutathione. Moreover the decreased activity of glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (G6PD) was also observed. As hemoglobin, the erythrocytes' main component plays an essential role in the erythrocytes, the level of its oxidized form (metHb) in the erythrocytes and the phosphatidylserine exposure on the erythrocyte surface were also investigated. When higher concentrations of glutaraldehyde (0.0025-0.005%) were used for the uptake of DNR the elevated level of metHb was observed. Only at 0.0005% the level of oxidized form of Hb was within the physiological level and at that level the increase in the exposure of phosphatidylserine at the cell surface was not observed to be statistically significant. Moreover the percent of released hemoglobin was less than 1%. Based on these results it was concluded that glutaraldehyde can be used as a cross-linker between the drug (DNR) and the erythrocytes only at low concentration of about 0.0005%. 23714074 Disruption of circadian rhythms due to chronic constant light leads to depressive and anxiety-like behaviors in the rat. Depression is strongly associated with the circadian system, disruption of the circadian system leads to increased propensity to disease and to mood disorders including depression. The present study explored in rats the effects of circadian disruption by constant light on behavioral and hormonal indicators of a depressive-like condition and on the biological clock, the suprachiasmatic nucleus (SCN). Exposure to constant light for 8 weeks resulted in loss of circadian patterns of spontaneous general activity, melatonin and corticosterone. Moreover these rats exhibited anhedonia in a sucrose consumption test, and increased grooming in the open-field test, which reflects an anxiety-like condition. In the SCN decreased cellular activation was observed by c-Fos immunohistochemistry. In rats exposed to constant darkness, circadian behavioral and hormonal patterns remained conserved, however mild depresive-like indicators were observed in the anhedonia test and mild anxiety-like behaviors were observed in the open field test. Data indicate that chronic conditions of LL or DD are both disruptive for the activity of the SCN leading to depression- and anxiety-like behavior. Present results point out the main role played by the biological clock and the risk of altered photoperiods on affective behavior. 23916701 miR-18b inhibits TGF-β1-induced differentiation of hair follicle stem cells into smooth muscle cells by targeting SMAD2. Human hair follicle mesenchymal stem cells (hHF-MSCs) are capable of differentiating into smooth muscle cells (SMCs) in response to transforming growth factor-β (TGF-β), and thus can be used for cardiovascular tissue engineering and regenerative medicine. However, the precise molecular mechanisms underlying SMC conversion of hHF-MSCs are still undefined. MicroRNAs (miRNAs) are small noncoding RNAs that modulate gene expression post-transcriptionally by binding to the complementary sequences of targeted mRNAs. Accumulating evidence indicates that miRNAs are associated with SMC differentiation in vitro andin vivo. In this study, we revealed that miR-18b was significantly downregulated during TGF-β1-induced hHF-MSCs differentiation into SMC using miRNA array profiling and quantitative RT- PCR (qRT-PCR). Over-expression of miR-18b in hHF-MSCs led to remarkable downregulation of SMC-specific markers such as SMA and calponin proteins. On the contrary, inhibition of endogenous miR-18b by its antisense oligonucleotide antagomir-18b reversed the changes of SMA and calponin proteins. We also showed that SMAD2, a key transcription regulator in TGF-β signaling which was involved in SMC differentiation, is regulated by miR-18b. miR-18b could suppress the expression of SMAD2 protein by targeting the 3'UTR of SMAD2 gene without affecting its mRNA level in hHF-MSCs. Moreover, knockdown of SMAD2 by RNA interference could block the effect of inhibition of miR-18b on SMC differentiation, indicating that SMAD2 contributed to miR-18b mediated regulation of TGF-β-induced SMC differentiation. In conclusion, this study demonstrated that miR-18b regulated the TGF-β1-induced differentiation of hHF-MSCs into SMCs by targeting SMAD2 gene, and provided novel insights into the regulatory mechanisms of TGF-β-induced SMC differentiation. 23962564 C-peptide inhibitors of Ebola virus glycoprotein-mediated cell entry: Effects of conjugation to cholesterol and side chain-side chain crosslinking. We previously described potent inhibition of Ebola virus entry by a 'C-peptide' based on the GP2 C-heptad repeat region (CHR) targeted to endosomes ('Tat-Ebo'). Here, we report the synthesis and evaluation of C-peptides conjugated to cholesterol, and Tat-Ebo analogs containing covalent side chain-side chain crosslinks to promote α-helical conformation. We found that the cholesterol-conjugated C-peptides were potent inhibitors of Ebola virus glycoprotein (GP)-mediated cell entry (∼10(3)-fold reduction in infection at 40μM). However, this mechanism of inhibition is somewhat non-specific because the cholesterol-conjugated peptides also inhibited cell entry mediated by vesicular stomatitis virus glycoprotein G. One side chain-side chain crosslinked peptide had moderately higher activity than the parent compound Tat-Ebo. Circular dichroism revealed that the cholesterol-conjugated peptides unexpectedly formed a strong α-helical conformation that was independent of concentration. Side chain-side chain crosslinking enhanced α-helical stability of the Tat-Ebo variants, but only at neutral pH. These result provide insight into mechanisms of C-peptide inhibiton of Ebola virus GP-mediated cell entry. 23324934 Post-traumatic Stress Symptoms After Elective Lumbar Arthrodesis are Associated With Reduced Clinical Benefit. Prospective cohort study. To assess the impact of postoperative post-traumatic stress disorder (PTSD) symptoms on clinical outcomes after lumbar arthrodesis. Postoperative PTSD symptoms occur among many patients who underwent elective lumbar fusion. Although adverse impact of preoperative depression and psychiatric distress has been described, no reports have assessed the impact of postoperative PTSD symptoms on clinical outcomes after lumbar arthrodesis. Seventy-three patients undergoing elective lumbar spinal arthrodesis completed the PTSD Checklist-Civilian Version (PCL-C) at 3, 6, 9, and 12 months postoperatively. Short-Form 36 and the Oswestry Disability Index (ODI) were completed preoperatively and at 1 year postoperatively. Impact of postoperative PTSD symptoms, preoperative psychiatric diagnoses, and mental composite scores on clinical outcome scores and likelihood of reaching minimal clinically important difference for ODI and physical composite score (PCS) was evaluated. PTSD symptoms were reported in 22% of the cohort, with significantly reduced surgical benefit as measured by final (P < 0.0001 and P = 0.003) and total change (P = 0.013 and P = 0.032) in ODI and PCS scores, respectively. Likelihood of reaching minimal clinically important difference for both ODI and PCS was also reduced for patients reporting PTSD symptoms (P = 0.009 and P = 0.001, respectively). A preoperative psychiatric diagnosis correlated only with final ODI score (P = 0.008). Preoperative mental composite scores were significantly correlated with final ODI and PCS scores, as well as final change from preoperative and likelihood of reaching minimal clinically important difference for PCS, but not for ODI scores. Postoperative psychological distress was strongly correlated with reduced clinical benefit among patients who underwent elective lumbar arthrodesis, and seemed to be a stronger predictor of reduced clinical benefit than either major psychiatric diagnosis or preoperative mental composite scores. Efforts to reduce postoperative psychological distress may offer an opportunity to enhance patient reported clinical outcomes from elective spine surgery.Level of Evidence: 2. 23949361 Surgical management of tumors involving the orbit. IMPORTANCE Surgical treatment of orbital tumors is a complex task that requires thorough preparation and precise planning. Since a large variety of tumors of different origins, anatomical extents, and histologic subtypes affect the globe, no "1-size-fits-all" approach can be offered. OBJECTIVE To describe an integrative approach for the optimal surgical management of patients with orbital tumors based on a review of the literature and on our own experience at a high-volume cancer center. EVIDENCE REVIEW Peer-reviewed English-language literature and a single-center cohort of patients undergoing orbital exenteration with eye sparing, reconstruction, and preservation of orbital function. FINDINGS Surgical treatment of orbital tumors is a complex task that requires thorough preparation and precise planning that would be aided by an algorithm. CONCLUSIONS AND RELEVANCE We offer an algorithm that summarizes our approach toward the 2 main decision points of orbital surgery: extent of resection and method of reconstruction. 23846654 Temporal regulation of EGF signalling networks by the scaffold protein Shc1. Cell-surface receptors frequently use scaffold proteins to recruit cytoplasmic targets, but the rationale for this is uncertain. Activated receptor tyrosine kinases, for example, engage scaffolds such as Shc1 that contain phosphotyrosine (pTyr)-binding (PTB) domains. Using quantitative mass spectrometry, here we show that mammalian Shc1 responds to epidermal growth factor (EGF) stimulation through multiple waves of distinct phosphorylation events and protein interactions. After stimulation, Shc1 rapidly binds a group of proteins that activate pro-mitogenic or survival pathways dependent on recruitment of the Grb2 adaptor to Shc1 pTyr sites. Akt-mediated feedback phosphorylation of Shc1 Ser 29 then recruits the Ptpn12 tyrosine phosphatase. This is followed by a sub-network of proteins involved in cytoskeletal reorganization, trafficking and signal termination that binds Shc1 with delayed kinetics, largely through the SgK269 pseudokinase/adaptor protein. Ptpn12 acts as a switch to convert Shc1 from pTyr/Grb2-based signalling to SgK269-mediated pathways that regulate cell invasion and morphogenesis. The Shc1 scaffold therefore directs the temporal flow of signalling information after EGF stimulation. 23962381 Relationships between sensory evaluations of beef tenderness, shear force measurements and consumer characteristics. The supply of tender beef is an important challenge for the beef industry. Knowledge about the profile of consumers who are more optimistic or more accurate in their tenderness evaluations is important for product development and beef marketing purposes. Central location tests of beef steaks were performed in Norway and Belgium (n=218). Instrumental and sensorial tenderness of three muscles from Belgian Blue and Norwegian Red cattle was reported. Consumers who are optimistically evaluating tenderness were found to be more often male, less food neophobic, more positive towards beef healthiness, and showed fewer concerns about beef safety. No clear profile emerged for consumers who assessed tenderness similar to shear force measurements, which suggests that tenderness is mainly evaluated subjectively. The results imply a window of opportunities in tenderness improvements, and allow targeting a market segment which is less critical towards beef tenderness. 23420521 Sampling design for long-term regional trends in marine rocky intertidal communities. Probability-based designs reduce bias and allow inference of results to the pool of sites from which they were chosen. We developed and tested probability-based designs for monitoring marine rocky intertidal assemblages at Glacier Bay National Park and Preserve (GLBA), Alaska. A multilevel design was used that varied in scale and inference. The levels included aerial surveys, extensive sampling of 25 sites, and more intensive sampling of 6 sites. Aerial surveys of a subset of intertidal habitat indicated that the original target habitat of bedrock-dominated sites with slope ≤30° was rare. This unexpected finding illustrated one value of probability-based surveys and led to a shift in the target habitat type to include steeper, more mixed rocky habitat. Subsequently, we evaluated the statistical power of different sampling methods and sampling strategies to detect changes in the abundances of the predominant sessile intertidal taxa: barnacles Balanomorpha, the mussel Mytilus trossulus, and the rockweed Fucus distichus subsp. evanescens. There was greatest power to detect trends in Mytilus and lesser power for barnacles and Fucus. Because of its greater power, the extensive, coarse-grained sampling scheme was adopted in subsequent years over the intensive, fine-grained scheme. The sampling attributes that had the largest effects on power included sampling of "vertical" line transects (vs. horizontal line transects or quadrats) and increasing the number of sites. We also evaluated the power of several management-set parameters. Given equal sampling effort, sampling more sites fewer times had greater power. The information gained through intertidal monitoring is likely to be useful in assessing changes due to climate, including ocean acidification; invasive species; trampling effects; and oil spills. 23910681 Missed ulnar nerve injury and closed forearm fracture in a child. Ulnar nerve injury in closed fracture of forearm in children is uncommon.Commonly, neurapraxia is the reason for this palsy but other severe injuries or nerve entrapment has been reported in some cases. The importance of diagnosis concerning the types of the nerve injury lies in the fact that they have totally different management.We present a case of ulnar nerve deficit in a child following a closed fracture of the forearm bones. It is imperative to diagnose exact cause of palsy as it forms the basis for treatment. MRI scan can help diagnosis and accordingly guide the management. Simple nerve contusion should be treated conservatively, and exploration with fixation of the fracture should be done in lacerations and entrapments of the nerve. Surgery is not the treatment of choice in cases that could be managed conservatively. 23718801 Global health and justice: re-examining our values. Widening disparities in health within and between nations reflect a trajectory of 'progress' that has 'run its course' and needs to be significantly modified if progress is to be sustainable. Values and a value system that have enabled progress are now being distorted to the point where they undermine the future of global health by generating multiple crises that perpetuate injustice. Reliance on philanthropy for rectification, while necessary in the short and medium terms, is insufficient to address the challenge of economic and other systems spinning out of control. Innovative approaches are required and it is suggested that these could best emerge from in-depth multidisciplinary research supported by endeavours to promote a 'global mind-set.' 23588880 Ultrasonographic evaluation of the muscle architecture in patients with systemic lupus erythematosus. Systemic lupus erythematosus (SLE) is a multi-system chronic inflammatory disease with a broad spectrum of clinical and serological manifestations. Although clinical evidence of proximal skeletal muscle involvement is not rare in patients with SLE, there is no knowledge about the effects of SLE on the macroscopic structural parameters of the muscles. Therefore, in this study, we aimed to explore the muscle strength and structure of SLE patients using isokinetic testing and ultrasonographic imaging. Thirty-one SLE patients (5 men, 26 women) with a mean age of 38.61 ±â€‰10.68 years and mean disease duration of 3.71 ±â€‰3.23 years without any previous history of myositis and 31 age- and sex-matched healthy subjects were enrolled. Demographic and clinical characteristics of the patients were recorded. Ultrasonographic evaluations were performed with a 7- to 12-MHz linear probe from vastus lateralis and gastrocnemius muscles of the nondominant extremity. Measurements included muscle thickness, pennation angle, and fascicule length. Isokinetic nondominant knee muscle strength tests were performed at 60 and 180°/s. We found that muscle thickness, pennation angle, and fascicle length of vastus lateralis muscles were increased in patients with SLE in comparison to control subjects (p < 0.001, p = 0.007, and p = 0.217, respectively). On the other hand, the measurements pertaining to the gastrocnemius muscles were found to be similar between the two groups. We observed that all isokinetic knee muscle strength values were decreased in SLE patients, and knee strength values were found to be negatively correlated with age and positively correlated with height (all p < 0.01). We found that the structural and strength changes were seen in the proximal muscles of SLE patients. Pathophysiology and clinical relevance of these changes need to be further investigated. 23507146 HSF4 regulates DLAD expression and promotes lens de-nucleation. HSF4 mutations lead to both congenital and age-related cataract. The purpose of this study was to explore the mechanism of cataract formation caused by HSF4 mutations. The degradation of nuclear DNA is essential for the lens fiber differentiation. DNase 2β (DLAD) is highly expressed in lens cells, and mice with deficiencies in the DLAD gene develop nuclear cataracts. In this study, we found that HSF4 promoted the expression and DNase activity of DLAD by directly binding to the DLAD promoter. In contrast, HSF4 cataract causative mutations failed to bind to the DLAD promoter, abrogating the expression and DNase activity of DLAD. These results were confirmed by HSF4 knockdown in zebrafish, which led to incomplete de-nucleation of the lens and decreased expression and activity of DLAD. Together, our results suggest that HSF4 exerts its function on lens differentiation via positive regulation of DLAD expression and activity, thus facilitating de-nucleation of lens fiber cells. Our demonstration that HSF4 cataract causative mutations abrogate the induction of DLAD expression reveals a novel molecular mechanism regarding how HSF4 mutations cause cataractogenesis. 23927866 Low Incidence of Procedure-Related Major Adverse Cardiac Events After Alcohol Septal Ablation for Symptomatic Hypertrophic Obstructive Cardiomyopathy. Alcohol septal ablation (ASA) is a catheter-based intervention that has been used as an alternative to surgical myectomy in highly symptomatic patients with hypertrophic obstructive cardiomyopathy (HOCM). However, clinically relevant complications can result, including death and complete heart block (CHB) associated with syncope or resuscitation. This study was designed to evaluate the incidence of major ASA-related adverse cardiac events. This international multicentre retrospective study included 421 patients in 8 European centres who were treated using ASA from April 1998 to January 2011. Clinical and echocardiographic follow-up (3-6 months) was completed in 394 patients (94%). ASA led to a significant reduction in symptoms and outflow gradients, with 0.7% mortality. A total of 70 patients (17%) experienced mostly transient CHB during and after the procedure; in 30% of them, CHB occurred or recurred later than 24 hours after ASA. Ninety-seven percent of CHB occurred up to the fifth day after ASA. Permanent pacemakers for CHB were implanted in 35 patients (8%). Multivariate analysis identified intraprocedural bundle branch block and age as independent predictors of CHB. The results of the multicentre study demonstrate that ASA appears safe and efficacious, with low early mortality. The most frequent major complication after ASA was CHB (17%), which occurred late or was recurrent in almost one-third of these patients; 8% of patients required permanent pacemaker implantation. Independent predictors of CHB development were intraprocedural bundle branch block and age. Difficulty in predicting CHB should lead to close postprocedural monitoring and hospital stays lasting at least 5 days. 22740350 Effect of Morin on pharmacokinetics of Piracetam in rats, in vitro enzyme kinetics and metabolic stability assay using rapid UPLC method. The aim of this study was to investigate the effect of Morin on the pharmacokinetics of Piracetam in rats, in vitro enzyme kinetics and metabolic stability (high throughput) studies using human liver microsomes in UPLC. For pharmacokinetics studies, male Wistar rats were pretreated with Morin (10 mg/kg) for one week and on the last day, a single dose of Piracetam (50 mg/kg) was given orally. In another group, both Morin and Piracetam were co-administered to evaluate the acute effect of Morin on Piracetam. The control group received oral distilled water for one week and administered with Piracetam on the last day. As Morin is an inhibitor of P- Glycoprotein (P-gp) and CYP 3A, it was anticipated to improve the bioavailability of Piracetam. Amazingly, relative to control, the areas under the concentration time curve and peak plasma concentration of Piracetam were 1.50- and 1.45-fold, respectively, greater in the Morin-pretreated group. However, co-administration of Morin had no significant effect on these parameters. Apart from the aforementioned merits, the results of this study are further confirmed by clinical trials; Piracetam dosages should be adjusted to avoid potential drug interaction when Piracetam is used clinically in combination with Morin and Morin-containing dietary supplements. The in vitro enzyme kinetics were performed to determined km, Vmax & CLins . The in vitro metabolic stability executed for the estimation of metabolic rate constant and half-life of Piracetam. These studies also extrapolate to in vivo intrinsic hepatic clearance (Clint, in vivo ) from in vitro intrinsic hepatic clearance (CLint, in vitro ). Copyright © 2012 John Wiley & Sons, Ltd. 23844590 A qualitative study exploring factors associated with mothers' decisions to formula-feed their infants in Newfoundland and Labrador, Canada. Breastfeeding has numerous health benefits. In 2010, the province of Newfoundland and Labrador had the lowest breastfeeding initiation rate (64.0%) in Canada. Formula feeding is associated with well-known health risks. Exclusive formula feeding is the "cultural norm" in some regions of the province. Women appear resistant to changing their infant feeding behaviors and remain committed to their decision to formula-feed. The primary aim of this qualitative study was to examine individual factors that shaped mothers' decisions to formula-feed their infants. Nineteen mothers who were currently formula feeding their children participated in the study. Qualitative research in the form of focus groups was conducted in three communities in the province in 2010. A thematic content analysis identified the main themes that influenced mothers' decisions to formula-feed their infants. The main themes included issues concerning the support needed to breastfeed, the convenience associated with formula feeding, and the embarrassment surrounding breastfeeding in public. These findings help to better understand why mothers choose formula feeding over breastfeeding and may help to inform the development of public health interventions targeted at this population of mothers. 23841660 Surgical resection of developmental venous anomaly causing massive intracerebral haemorrhage: A case report. Cerebral developmental venous anomalies (DVAs) very rarely cause massive haematoma, but should be included in the differential diagnosis of atypical massive intracerebral haematoma (ICH). We describe a case of massive ICH caused only by a DVA and successfully treated by haematoma evacuation with surgical resection of the DVA. 23825034 Reversible Phase Transformation at the Solid-Liquid Interface: STM Reveals. Reversible supramolecular self-assemblies have attracted increasing attention in nanoscience and technology during the past few years due to their potential application in the extreme miniaturization of switches and other devices. The building blocks concerned can respond structurally, electronically, optically, and mechanically to external stimuli. Herein, we focus on the recent progress of the supramolecular self-assembly reversibly triggered by temperature, light, electric current, metal ions and protons at the solid-liquid interface. Following this general roadmap, supramolecular systems based on H-bonds, azobenzene derivatives, triple-decker complexes, and the guanine motif are successively discussed in this review. Notably, these reversible phase transformations can be probed by the scanning tunneling microscopy (STM) technique, which has been proven as an effective tool in surface science. 23733001 Impact of t(11;14)(q13;q32) on the Outcome of Autologous Hematopoietic Cell Transplantation in Multiple Myeloma. The t(11;14)(q13;q32) translocation is seen in 15%-20% patients with multiple myeloma (MM). It generally is not associated with worse outcomes. We studied the impact of t(11;14)(q13;q32) on outcome in patients with MM who received high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HCT). Eligible patients underwent high-dose chemotherapy followed by auto-HCT at the M.D. Anderson Cancer Center between February 2000 and August 2010, and had conventional cytogenetic (CC) or fluorescence in situ hybridization (FISH) results available before auto-HCT (n = 993). The cohort was divided into 3 groups of patients: (1) normal (diploid by CC and negative by FISH; n = 869); (2) t(11;14)(q13;q32) by CC or FISH (n = 27); and (3) high-risk (HR) abnormalities by CC or FISH (n = 97). Of the 27 patients with t(11;14)(q13;q32), 18 had isolated t(11;14)(q13;q32) and 9 had concurrent HR abnormalities. The primary objective was to compare outcomes in patients with t(11;14)(q13;q32) and patients with diploid or HR markers detected by CC or FISH studies. The median duration of follow-up in surviving patients was 37 months. The 3-year progression-free survival (PFS) was 47% for the normal group, 27% for the t(11;14)(q13;q32) group, and 13% for the HR group (P < .00001). The 3-year OS was 83% for the normal group, 63% for the t(11;14)(q13;q32) group, and 34% for the HR group (P < .00001). On multivariate analysis, t(11;14)(q13;q32) and HR abnormalities by CC or FISH and relapsed disease at auto-HCT were associated with shorter PFS, whereas t(11;14)(q13;q32) and HR abnormalities by CC or FISH, β2 microglobulin of >3.5, and relapsed disease at the time of auto-HCT were associated with shorter OS. In conclusion, patients with t(11;14)(q13;q32) had worse outcomes than patients with normal CC or FISH studies, but better outcomes than patients with HR markers detected by CC or FISH studies. 23777224 Risk of all-cause hospitalization in COPD patients initiating long-acting or short-acting beta agonist therapy. Abstract Objective: This retrospective claims study investigated the rates of all-cause hospitalization among chronic obstructive pulmonary disease (COPD) patients initiating treatment with short-acting beta agonists (SABA) or long-acting beta agonists (LABA). Methods: Data from the 5% national sample of Medicare enrollees for 2006-2008 were used. Patients initiating COPD therapy were identified as those with no COPD therapy for ≥ 6-months prior to initiating SABA or LABA (administered via dry-powder inhalers, metered-dose inhalers, or nebulizer) treatment. All patients were continuously eligible for Medicare Parts A, B, and D for 18 months. Those enrolled in Medicare Advantage, who had asthma, or were < 65 years old were excluded. Differences in the rates of all-cause hospitalizations and time to all-cause hospitalization during the 6-month follow-up period were examined, while adjusting for demographics, clinical indicators, and health service use. Results: Among 3017 COPD patients who met the inclusion criteria, 883 (30%) were LABA users and 2134 (70%) were SABA users. Overall, 21% of patients (16% [144/883] of LABA and 23% [492/2134] of SABA) had a hospitalization during the follow-up period. Mean time to hospitalization was 86 days for LABA vs 64 days for SABA patients (p < 0.05). The adjusted hazard ratio for hospitalization in a Cox proportional hazards model was 0.74 (95% CI = 0.62-0.90) for patients treated with LABA vs. SABA. Limitations: The analysis was adjusted for multiple background characteristics, but important measures of severity in COPD, such as measures of lung functioning, were not available and may have differed between patients treated with LABA or SABA. Conclusions: The results of this analysis indicate COPD patients initiating LABA treatment had a longer time to all-cause hospitalization and a 26% lower risk of hospitalization during the 6-months follow-up period compared to those initiating SABA therapy. 23735720 Occurrence and behavior of natural and anthropogenic (emerging and historical) halogenated compounds in marine biota from the Coast of Concepcion (Chile). Fifty-five biota samples from the Coast of Concepcion (Chile) were analyzed for PBDEs, emerging brominated FRs, halogenated norbornenes and naturally-occurring MeO-PBDEs. PBDEs, MeO-PBDEs and halogenated norbornenes were detected at concentration levels ranging from 11 to 170, nd to 118 and nd to 5.8ng/glw, respectively. However, emerging brominated FRs such as decabromodiphenylethane (DBDPE), hexabromobenzene (HBB) and pentabromoethylbenzene (PBEB) were not detected in any sample. Bioaccumulation and bioconcentration processes were evaluated for the different families of compounds. Biomagnification factors (BMFs) were calculated, and some PBDE congeners (BDE-28, BDE-183 and BDE-209) as well as MeO-PBDEs presented BMF>1, being values of the naturally occurring MeO-PBDEs higher than those obtained for PBDEs. As regards halogenated norbornenes, BMF<1 were found. 23937269 Synthesis, Structure, and Magnetic Properties of Bithiophene- and Terthiophene-Linked Manganese Metal-Organic Frameworks. A series of metal-organic frameworks (MOFs) containing manganese centers and oligothiophene dicarboxylate linkers have been synthesized: [Mn(3PhT2DC)(DMF)0.45(H2O)2.55·1.55DMF]n (1), [Mn6(3HT2DC)6(DMF)3(H2O)5·xDMF·yH2O]n (2), [Mn(T3DC)(H2O)2]n (3), [Mn(T3DC)(H2O)1.5]n (4), and [Mn(Ph2T3DC)(DMF)2]n (5) (H23PhT2DC = 3,3'-diphenyl-2,2-bithiophene-5,5'-dicarboxylic acid; H23HT2DC= 3,3'-dihexyl-2,2'-bithiophene-5,5'-dicarboxylic acid; H2T3DC = 2,2':5',2″-terthiophene-5,5″-dicarboxylic acid; H2Ph2T3DC = 3',4'-diphenyl-2,2':5',2″-terthiophene-5,5″-dicarboxylic acid, DMF = N,N-dimethylformamide). Compound 1 exists as a 2D sheet, 2-4 are 3D frameworks, and 5 is a 1D chain. Compounds 3 and 4 are isomers, and 3-5 are the first examples of crystallographically characterized terthiophene coordination polymers. In the case of 1, 2, and 5, the extended structure is sensitive to β substitution of the oligothiophene linkers. Compounds 1-3 and 5 show antiferromagnetic behavior with typical values of g and J, and 3 exhibits a spin canting transition at 40 K. 23578639 Proteolytic activities in fillets of selected underutilized Australian fish species. The hydrolytic activity of major endogenous proteases, responsible for proteolysis of myofibrillar proteins during post-mortem storage, may be an indicator of the textural quality of fish which influences consumer purchasing behaviour and thus market value of the final product. Furthermore, it may also influence the type and bioactive properties of the peptides released during post-mortem proteolysis of myofibrillar proteins. This study compared the activities of cathepsins B, B+L, D, H and calpain-like enzymes in crude muscle extracted from 16 Australian underutilized fish species. Fish species had a significant effect on the activity of these enzymes with barracouta showing the highest cathepsins B, B+L, D and H activities. Activities of cathepsins B and B+L were higher than cathepsin H for all studied species. The more commercially important rock ling and tiger flathead demonstrated higher cathepsin B+L activity, whereas gemfish and eastern school whiting showed higher activity towards cathepsin B. Underutilized fish species showing higher endogenous protease activities may be suitable for fish sauce production, whereas those with lower protease activities for surimi processing. 23895467 Zinc-Dependent Modulation of α2- and α3-Glycine Receptor Subunits by Ethanol. Strychnine-sensitive glycine receptors (GlyRs) are expressed throughout the brain and spinal cord and are among the strongly supported protein targets of alcohol. This is based largely on studies of the α1-subunit; however, α2- and α3-GlyR subunits are as or more abundantly expressed than α1-GlyRs in multiple forebrain brain areas considered to be important for alcohol-related behaviors, and uniquely some α3-GlyRs undergo RNA editing. Nanomolar and low micromolar concentrations of zinc ions potentiate GlyR function, and in addition to zinc's effects on glycine-activated currents, we have recently shown that physiological concentrations of zinc also enhance the magnitude of ethanol (EtOH)'s effects on α1-GlyRs. Using 2-electrode voltage-clamp electrophysiology in oocytes expressing either α2- or α3-GlyRs, we first tested the hypothesis that the effects of EtOH on α2- and α3-GlyRs would be zinc dependent, as we have previously reported for α1-GlyRs. Next, we constructed an α3P185L-mutant GlyR to test whether RNA-edited and unedited GlyRs contain differences in EtOH sensitivity. Last, we built a homology model of the α3-GlyR subunit. The effects of EtOH (20 to 200 mM) on both subunits were greater in the presence than in the absence of 500 nM added zinc. The α3P185L-mutation that corresponds to RNA editing increased sensitivity to glycine and decreased sensitivity to EtOH. Our findings provide further evidence that zinc is important for determining the magnitude of EtOH's effects at GlyRs and suggest that by better understanding zinc/EtOH interactions at GlyRs, we may better understand the sites and mechanisms of EtOH action. 23842078 The trespasses of property law. The purpose of this article is to identify a limit to the appropriate application of property law to the use and storage of bodily material. I argue here that property law ought to be limited to protecting 'contingent rights' and that recent cases where property rights have been recognised in semen represent the application of property law beyond this limit. I also suggest how the law ought to develop in order to avoid the overextensive use of property law. 23756782 Intermediate filaments are important for astrocyte response to oxidative stress induced by oxygen-glucose deprivation and reperfusion. As a response to central nervous system injury, astrocytes become reactive. Two cellular hallmarks of reactive gliosis are hypertrophy of astrocyte processes and upregulation of intermediate filament (nanofilament) proteins glial fibrillary acidic protein (GFAP), vimentin, nestin, and synemin. Astrocytes in mice devoid of GFAP and vimentin (GFAP (-/-) Vim (-/-)) do not form cytoplasmic intermediate filaments. GFAP (-/-) Vim (-/-) mice develop larger infarcts after ischemic stroke (Li et al. in J Cereb Blood Flow Metab 28(3):468-481, 2008). Here, we attempted to analyze the underlying mechanisms using oxygen-glucose deprivation (OGD), an in vitro ischemia model, examining a potential link between astrocyte intermediate filaments and reactive oxygen species (ROS). We observed a reorganization of the intermediate filament network in astrocytes exposed to OGD. ROS accumulation was higher in GFAP (-/-) Vim (-/-) than wild-type astrocytes when exposed to OGD followed by reperfusion or when exposed to hydrogen peroxide. These results indicate that the elimination of ROS is impaired in the absence of the intermediate filament system. Compared to wild-type astrocytes, GFAP (-/-) Vim (-/-) astrocytes exposed to OGD and reperfusion exhibited increased cell death and conferred lower degree of protection to cocultured neurons. We conclude that the astrocyte intermediate filament system is important for the cell response to oxidative stress induced by OGD followed by reperfusion. 23849660 Unraveling the covariation of low self-control and victimization: A behavior genetic approach. A growing body of literature examining the antecedents of victimization experiences has suggested that personality constructs play a role in the origins of victimization. Low self-control, in particular, represents a trait thought to directly increase the risk of victimization. At the same time, different lines of evidence suggest that genetic factors account for portions of the variance in both self-control and victimization. These findings leave open the possibility that the two traits might covary because of previously unmeasured genetic factors. The current analysis seeks to test this possibility. Additionally, we examine whether the covariation between self-control and victimization persists once genetic effects are held constant. Our findings suggest a nuanced explanation for the relationship between self-control and experiences of victimization. 23965340 Surface roughness induced electron mobility degradation in InAs nanowires. In this work, we present a study of the surface roughness dependent electron mobility in InAs nanowires grown by the nickel-catalyzed chemical vapor deposition method. These nanowires have good crystallinity, well-controlled surface morphology without any surface coating or tapering and an excellent peak field-effect mobility up to 15 000 cm(2) V(-1) s(-1) when configured into back-gated field-effect nanowire transistors. Detailed electrical characterizations reveal that the electron mobility degrades monotonically with increasing surface roughness and diameter scaling, while low-temperature measurements further decouple the effects of surface/interface traps and phonon scattering, highlighting the dominant impact of surface roughness scattering on the electron mobility for miniaturized and surface disordered nanowires. All these factors suggest that careful consideration of nanowire geometries and surface condition is required for designing devices with optimal performance. 23949072 Do motor impairments detected on onset of multiple sclerosis suggest an early second attack? A prospective one year single center study. Factors determining the clinically isolated syndrome (CIS) patient's likelihood of developing multiple sclerosis (MS) are important for the clinician who needs to identify patients warranting immunomodulatory treatments. To determine whether motor abnormalities found during the initial demyelinating event imply an increased risk of a second event within the first year. Fifty-two early onset CIS patients, volunteered to participate in the prospective study. Motor parameters collected at onset included gait, balance, lower limb peak isometric strength and fatigue index parameters. At the end of one year, patients were subdivided into two groups, those who had experienced a second demyelinating attack suggestive of MS and those who maintained their clinical status. Forty-nine patients were included in the final analysis. Within the first year, 24 patients experienced a second attack, while 25 maintained their neurological status. Patients who suffered a second demyelinating attack, demonstrated reduced overall lower limb peak strength compared with patients who maintained their clinical status (411.9 (S.E. = 32.1) vs. 514.8 (S.E. = 34.1). No differences were observed between groups in gait and balance parameters. An initial demyelinating event characterized by reduced lower limb strength can possibly suggest an increased risk of an early second attack. 23774663 Pharmacokinetic study of eight coumarins of Radix Angelicae Dahuricae in rats by gas chromatography-mass spectrometry. A sensitive, specific gas chromatography-mass spectrometry (GC-MS) method was established for the quantitative determination of eight coumarins of Radix Angelicae Dahuricae including coumarin, isopsoralen, psoralen, xanthotoxin, bergapten, osthole, imperatorin and oxypeucedanin in rat plasma. Nitrendipine was used as the internal standard (IS). The plasma samples were extracted by acetonitrile. GC separation was accomplished on a DB-5MS column with temperature programmed from 160°C (17min) to 190°C (10min) at the rate of 20°C/min, then to 240°C (5min) at 20°C/min, and finally to 280°C (14min) at 20°C/min. The detection was performed on a quadrupole mass spectrometer detector operated by full-scan mode (m/z 50-500). The lower limit of quantitation was 5-10ng/mL for eight coumarins, and the linear range was 5-1000ng/mL for the coumarins (R(2)>0.9990). All the validation data were within the required limits. After oral administration, the plasma concentration-time curves showed that the time for maximum concentration (Tmax) was 1.29 for coumarin, 1.83 for isopsoralen, 1.93 for psoralen, 1.30 for xanthotoxin, 2.04 for bergapten, 0.64 for osthole, 1.41 for imperatorin and 0.51h for oxypeucedanin. The plasma concentration of the eight coumarins was low, with a mean maximum plasma concentration (Cmax) <6.41μg/mL. Pharmacokinetic data analysis showed that the eight coumarins had different pharmacokinetic characteristics after oral administration. The method was successfully applied to pharmacokinetic studies of eight coumarins after oral administration in rats. 23958536 Progression of aortic regurgitation in asian patients with congenital sinus of valsalva aneurysm. Background: We reviewed the experience of An Zhen and Fu Wai Hospital for congenital sinus of Valsalva aneurysm (SVA) to determine risk factors for aortic valve replacement (AVR) and postoperative progression of aortic regurgitation (AR).Methods: Over a 7-year period, 255 patients underwent surgical repair of an SVA. Aneurysms originated from the right sinus and the noncoronary sinus in 212 patients (83.1%) and 38 patients (14.9%), respectively, and protruded into the right ventricle and right atrium in 171 patients (67.1%) and 80 patients (31.4%), respectively. AR presented in 142 patients (55.7%), 60 patients underwent AVR, and 13 patients underwent aortic valvuloplasty (3 patients eventually received AVR for valvuloplasty failure).Results: All patients survived the operation. Late death occurred in 2 patients (0.8%), and 2 patients (0.8%) experienced anticoagulation-related complications. Logistic regression analysis revealed that infective endocarditis, the cardiothoracic ratio, and a nonruptured SVA were risk factors for AVR. Late follow-up of 150 patients by echocardiographic assessment revealed that AR improved in 17 patients and worsened in 20 patients. Cox regression analysis revealed AR at discharge to be an independent risk factor for AR aggravation at late follow-up.Conclusions: SVA can be repaired with low mortality and excellent long-term results. AR at discharge is an important factor in determining AR aggravation at late follow-up after the operation. We recommend early diagnosis and aggressive treatment for SVA. 23711933 Repair of acute type a aortic dissections using open replacement with triple-branched stent grafts. Total arch replacement to treat type A aortic dissection is a complex procedure. To simplify the procedure, we used a triple-branched stent graft for total aortic arch replacement. Between February 2010 and June 2011, 27 patients (mean age, 52.7 ± 11.5 years), with acute type A aortic dissection underwent open surgical placement of a triple-branched stent graft for total arch reconstruction. All patients were discharged from the hospital. Mean cardiopulmonary bypass time was 160.5 ± 25.2 minutes, aortic cross-clamp time was 85.5 ± 18.4 minutes, and lower body arrest time was 30.2 ± 11.8 minutes. The mean drainage after the operation was 560 ± 120 mL, and the mean blood transfusion was 500 ± 150 mL. The mean length of stay after surgery was 13.5 ± 3.2 days. The mean follow-up time was 19.3 ± 7.6 months (range, 18 to 33 months). Follow-up was 100%. Endoleaks occurred in 3 patients after the operation, and 1 of them died 9 months after the operation. Follow-up computed tomography scans at 3 months showed the elimination of a false lumen in 24 patients. Using triple-branched stent grafts for total arch reconstruction in acute type A aortic dissections may be an effective technique to eliminate flow in the false lumen. 23541888 Acute brainstem compression by intratumoral hemorrhages in an intracranial hypoglossal schwannoma. A 77-year-old female in the hospital was found tachycardic and hypothermic by a nurse, and the patient's respiration subsequently ceased. Forensic autopsy revealed an intracranial cystic tumor that would have compressed the brainstem. On microscopic examination, the tumor was diagnosed as an Antoni A schwannoma growth, and recent multiple intratumoral hemorrhages in the intracranial schwannoma were observed, suggesting the sudden enlargement of the intracranial schwannoma due to intratumoral hemorrhaging. Accordingly, we diagnosed the cause of death as brainstem compression induced by the intratumoral hemorrhaging in the intracranial schwannoma. Meanwhile, a rhinopharyngeal tumor was also detected by the autopsy, which was compatible with an antemortem diagnosis of a dumbbell-shaped hypoglossal schwannoma. 23907545 Genetic and Environmental Influences on the Longitudinal Structure of Neuroticism: A Trait-State Approach. In this study, we sought to elucidate both stable and changing factors in the longitudinal structure of neuroticism using a behavioral genetic twin design. We tested whether this structure is best accounted for by a trait-state, a trait-only, or a state-only model. In line with classic views on personality, our results revealed substantial trait and state components. The contributions of genetic and environmental influences on the trait component were nearly equal, whereas environmental influences on the state component were much stronger than genetic influences. Although the overall findings were similar for older and younger twins, genetic influences on the trait component were stronger than environmental influences in younger twins, whereas the opposite was found for older twins. The current findings help to elucidate how the complex interplay between genetic and environmental factors contributes to both stability and change in neuroticism. 23860959 Phase I and pharmacokinetic/pharmacodynamic study of RO5126766, a first-in-class dual Raf/MEK inhibitor, in Japanese patients with advanced solid tumors. RO5126766, a highly selective dual Raf and MEK inhibitor, is a first-in-class tandem mitogen-activated protein kinase signaling pathway inhibitor. The objectives of this phase I study were to determine maximum-tolerated dose (MTD) and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of RO5126766 in Japanese patients with advanced solid tumors. Patients received a single oral dose of RO5126766 (0.8, 1.2, 1.8, or 2.25 mg) followed by continuous once-daily dosing at the same dosage in 28-day cycles. A 3 + 3 dose-escalation design was used. PD was evaluated by pMEK and pERK inhibition in peripheral blood mononuclear cells (PBMCs). A total of 12 patients were enrolled in cohorts of 0.8, 1.2, 1.8, and 2.25 mg/day. In the dose range tested, no dose-limiting toxicity was observed, and therefore, MTD was not defined. Main adverse events included acneiform dermatitis, creatine phosphokinase elevation, and ocular disorders. The plasma exposure of RO5126766 appeared to increase in a dose-proportional manner with a long plasma half-life (t 1/2) of 45.8-93.7 h. Following multiple dose administration, a steady-state condition was reached by Cycle 1 Day 8 (240 h). The inhibitory effects of RO5126766 on both pERK and pMEK in PBMCs increased in a dose-dependent manner. Five out of 12 patients achieved stable diseases, including a melanoma case with over 20 % shrinkage. RO5126766 has a manageable safety profile up to 2.25 mg/day once daily with a favorable PK/PD profile in Japanese patients with advanced solid tumors. 23835804 Building a live cell microscope: what you need and how to do it. In this post-genomic era, the predominant focus of biomedical research has moved towards elucidating the functionality of molecules at the cellular and subcellular level in integrated living systems. As such, biologic imaging has moved beyond the collection of static "snapshots" of the cellular state to the real-time visualization of cellular and molecular behavior in three-dimensional (3D) space. Live-cell imaging techniques can be used to assess protein abundance, as well as determine the functional role(s) and interactions of multiple unique molecules concurrently within the cellular environment, and determine the effects of these molecules on cell development, organization, and fate over extended periods of time. Such studies require advanced systems that allow multiparametric analysis of cells while maintaining their functional viability. This unit will focus on the design and implementation of modern live-cell imaging systems. We will examine the principle problems facing live-cell microscopists including: focus drift, cell viability, photo-toxicity, and data acquisition, and suggest appropriate solutions to these issues. Our goal in this unit is to provide individual scientists with the information required to implement live-cell imaging solutions within their own laboratories. Curr. Protoc. Cytom. 65:2.21.1-2.21.10. © 2013 by John Wiley & Sons, Inc. 23880316 Regulation of lipid synthesis genes and milk fat production in human mammary epithelial cell during secretory activation. Background: Expression of genes for lipid biosynthetic enzymes during initiation of lactation in humans is unknown. Objective: To study mRNA expression of lipid metabolic enzymes in human mammary epithelial cell (MEC) in conjunction with the measurement of milk fatty acid (FA) composition during secretory activation. Subjects: Gene expression from mRNA isolated from milk fat globule (MFG) and milk FA composition were measured from 6h to 42days postpartum in 7 normal women. Results: Over the first 96h postpartum, daily milk fat output increased several fold and mirrored expression of genes for all aspects of lipid metabolism and milk FA production including: lipolysis at the MEC membrane, FA uptake from blood, intracellular FA transport, de novo FA synthesis, FA and glycerol activation, FA elongation, FA desaturation, triglyceride synthesis, cholesterol synthesis, and lipid droplet formation. Expression of the gene for a key lipid synthesis regulator, sterol regulatory element-binding transcription factor1 (SREBF1), increased 2.0 fold by 36h and remained elevated over the study duration. Expression of genes for estrogen receptor1 (ESR1), thyroid hormone responsive protein (THRSP) and insulin-induced2 (INSIG2) increased progressively to plateau by 96h. In contrast, mRNA of peroxisome proliferator-activated receptor gamma (PPARG) decreased several fold. With the onset of lactation, increased de novo synthesis of FAs was the most prominent change in milk FA composition and mirrored the expression of FA synthesis genes. Conclusion: Milk lipid synthesis and secretion in humans is a complex process requiring the orchestration of a wide variety of pathways of which SREBF1 may play a primary role. 23863157 mTORC1 regulates the efficiency and cellular capacity for protein synthesis. mTORC1 (mammalian target of rapamycin complex 1) is activated by nutrients, growth factors and certain hormones. Signalling downstream of mTORC1 promotes protein synthesis by both activating the processes of translation initiation and elongation, in the short term, and the production of new ribosomes, in the longer term. mTORC1 signalling stimulates the translation of the mRNAs encoding the ribosomal proteins, activates RNA polymerases I and III, which make the rRNAs, and promotes the processing of the precursor for the main rRNAs. Taken together, these effects allow mTORC1 signalling to drive cell growth and proliferation. 23389092 Cloning, characterization and heterologous expression of the indolocarbazole biosynthetic gene cluster from marine-derived Streptomyces sanyensis FMA. The indolocarbazole (ICZ) alkaloids have attracted much attention due to their unique structures and potential therapeutic applications. A series of ICZs were recently isolated and identified from a marine-derived actinomycete strain, Streptomyces sanyensis FMA. To elucidate the biosynthetic machinery associated with ICZs production in S. sanyensis FMA, PCR using degenerate primers was carried out to clone the FAD-dependent monooxygenase gene fragment for ICZ ring formation, which was used as a probe to isolate the 34.6-kb DNA region containing the spc gene cluster. Sequence analysis revealed genes for ICZ ring formation (spcO, D, P, C), sugar unit formation (spcA, B, E, K, J, I), glycosylation (spcN, G), methylation (spcMA, MB), as well as regulation (spcR). Their involvement in ICZ biosynthesis was confirmed by gene inactivation and heterologous expression in Streptomyces coelicolor M1152. This work represents the first cloning and characterization of an ICZ gene cluster isolated from a marine-derived actinomycete strain and would be helpful for thoroughly understanding the biosynthetic mechanism of ICZ glycosides. 23967362 Serum metabolome and lipidome changes in adult patients with primary dengue infection. Dengue virus (DENV) is the most widespread arbovirus with an estimated 100 million infections occurring every year. Endemic in the tropical and subtropical areas of the world, dengue fever/dengue hemorrhagic fever (DF/DHF) is emerging as a major public health concern. The complex array of concurrent host physiologic changes has hampered a complete understanding of underlying molecular mechanisms of dengue pathogenesis. Systems level characterization of serum metabolome and lipidome of adult DF patients at early febrile, defervescence, and convalescent stages of DENV infection was performed using liquid chromatography- and gas chromatography-mass spectrometry. The tractability of following metabolite and lipid changes in a relatively large sample size (n = 44) across three prominent infection stages allowed the identification of critical physiologic changes that coincided with the different stages. Sixty differential metabolites were identified in our metabolomics analysis and the main metabolite classes were free fatty acids, acylcarnitines, phospholipids, and amino acids. Major perturbed metabolic pathways included fatty acid biosynthesis and β-oxidation, phospholipid catabolism, steroid hormone pathway, etc., suggesting the multifactorial nature of human host responses. Analysis of phospholipids and sphingolipids verified the temporal trends and revealed association with lymphocytes and platelets numbers. These metabolites were significantly perturbed during the early stages, and normalized to control levels at convalescent stage, suggesting their potential utility as prognostic markers. DENV infection causes temporally distinct serum metabolome and lipidome changes, and many of the differential metabolites are involved in acute inflammatory responses. Our global analyses revealed early anti-inflammatory responses working in concert to modulate early pro-inflammatory processes, thus preventing the host from development of pathologies by excessive or prolonged inflammation. This study is the first example of how an omic- approach can divulge the extensive, concurrent, and dynamic host responses elicited by DENV and offers plausible physiological insights to why DF is self limiting. 23912181 Prognostic factors in trabeculectomy with mitomycin C having history of previous glaucoma surgery. To evaluate the prognostic factors for surgical outcomes of subsequent trabeculectomy with mitomycin C (MMC) after prior incisional glaucoma surgery. We reviewed medical records of a total cohort of 781 trabeculectomies with MMC, and selected 125 patients (125 eyes). The primary endpoints included persistent intraocular pressure (IOP) of ≥21 or <5 mmHg, the need for additional glaucoma surgery and deterioration of visual acuity to no light perception. Univariate and Multivariate analyses were performed by using the Cox proportional hazards model. The mean follow-up period was 26.8 months. The probabilities of success at 1, 2, and 3 years were 80.6, 72.2, and 70.6 %, respectively. Multivariate analysis showed that a shorter time interval between prior glaucoma surgery and subsequent trabeculectomy [relative risk (RR), 0.8867/year; P = 0.0090] and the number of prior trabeculectomies (RR, 2.2645; P = 0.0029) were significant prognostic factors for subsequent failure of trabeculectomy with MMC. A short time period between prior glaucoma surgery and subsequent trabeculectomy and the number of prior trabeculectomies are associated with surgical failure of subsequent trabeculectomy with MMC. 23374163 Multidetector CT and radiographic findings of lung injuries secondary to cardiopulmonary resuscitation. Lung injury is one of the complications of cardiopulmonary resuscitation (CPR). This is the first study to describe the MDCT and radiographic findings of lung injuries secondary to CPR. A total of 44 patients who underwent CPR for a non-traumatic cause of cardiac arrest were retrospectively included in this study. We evaluated the presence of lung injuries in the initial chest radiograph and MDCT performed immediately after CPR and described the MDCT and radiographic findings of the CPR-associated lung injuries. Finally, we evaluated the temporal pattern of lung injury on the follow-up radiographies. Chest CT demonstrated lung injury in 54 lungs of 35 patients, while initial chest radiography detected lung abnormality in 37 lungs of 28 patients. The most common patterns of lung injuries on chest CT were bilateral (n=19), ground-glass opacity (n=30) and consolidation (n=26), distributed along the bronchovascular bundles (n=13). Most of the abnormalities were located in the posterior part of both upper lobes and both lower lobes (n=29). Among seven patients who did not have abnormalities in the initial chest radiograph, lung abnormalities were detected on the follow-up radiographies (mean follow-up duration=1.6 days, range=1-3 days) in five patients, and 28 patients who had lung abnormalities on initial radiograph were improved (n=19) or aggravated (n=8) on the follow-up radiographies. Lung injuries are frequent complications in patients who underwent CPR. Compared with radiography, MDCT has benefits for the detection and characterisation of CPR-associated lung injuries. The most common findings of lung injuries after CPR were bilateral ground glass opacity and consolidation, usually in the dependent area of both lungs. 23902204 Beyond the Checklist - What Else Health Care Can Learn from Aviation Teamwork and SafetyBeyond the Checklist - What Else Health Care Can Learn from Aviation Teamwork and Safety. This book has a foreword by Chesley 'Sully' Sullenberger, the pilot who ditched his plane in the Hudson River in 2009 without loss of life. 23895079 Nickel alloys in the oral environment. The use of nickel casting alloys for long-term restorations in dentistry has long been controversial. A 'tug-of-war' between economic, engineering and biological considerations is central to this controversy; nickel-casting alloys have low costs and favorable physical properties, but are corrosion-prone in the oral environment. Clinicians and researchers have questioned the safety of nickel-containing dental alloys because several nickel compounds are known to cause adverse biological effects in vivo and in vitro in contexts outside of dentistry. The debate revolves around the extent to which corrosion products from oral restorations cause intraoral or systemic biological problems. Current evidence suggests that nickel alloys may be used successfully and safely in dentistry if clinical risks are taken into account. However, these alloys may cause significant clinical problems, primarily allergenic and inflammatory, if the risks are ignored. 23813595 Quantitative determination of d- and l-threo enantiomers of methylphenidate in brain tissue by liquid chromatography-mass spectrometry. Methylphenidate, a psychostimulant used for the treatment of attention deficit hyperactivity disorder and narcolepsy, is administered as a 50:50 racemic mixture, despite the fact that d-methylphenidate has been shown to have greater pharmacologic activity. This paper presents a validated LC-MS/MS approach to separation and quantification of methylphenidate enantiomers using a vancomycin column and triethylammonium acetate to enhance the chiral separation. The method is applicable to the monitoring of these enantiomers in mouse brain, with a limit of detection of 0.5 ng/mL and a lower limit of quantification of 7.5 ng/mL. Copyright © 2013 John Wiley & Sons, Ltd. 23899766 Health Literacy in an Orthopaedic Trauma Patient Population: Improving Patient Comprehension with Informational Intervention. This study aims to evaluate the change in comprehension of diagnoses, treatment plans, and discharge instructions after orthopaedic trauma patients are given an informational document that includes pictorial representations at the time of discharge. It also seeks to determine if the intervention has a greater impact on patients with lower educational backgrounds. Prospective comparative cohort study. Academic Level 1 trauma center. From April to December 2011, 529 orthopaedic trauma patients with an operatively fixed isolated fracture were eligible for inclusion. 299 eligible questionnaires were collected (56.5% response rate). Patients were administered a questionnaire regarding their treatment and discharge instructions during their first postoperative clinic visit prior to being seen by a physician. The questionnaire included demographic information and questions regarding: (1) which bone was fractured; (2) type of implanted fixation; (3) weight-bearing status; (4) expected recovery time; and (5) need for DVT prophylaxis. All patients had received verbal instructions outlining this information at postoperative hospital discharge. During the second half of the study, patients were given an additional informational sheet with both text and pictorial representations at discharge. Multivariable log-binomial regression analyses were used to examine the impact of this intervention. 146 patients were given only the standard discharge instructions, while 153 patients were also administered the additional information document. The mean score for patients who received the intervention was 2.90 (out of 5) compared to the mean score of 2.54 for patients who did not receive the intervention (p=0.013). Patients who received the intervention were 1.3 times more likely to know which bone was fractured (p=0.007) and 1.1 times more likely to be able to correctly name the medication(s) they were prescribed for DVT prophylaxis (p=0.03). Overall performance on comprehension questionnaires in orthopaedic trauma patients was significantly improved via a text and pictorial intervention. The intervention did not preferentially aid patients with lower education backgrounds. Future studies should evaluate long-term postoperative results to determine if improved patient comprehension has an effect on surgical outcomes and patient satisfaction. 23086748 Effects of silver nanoparticles on the liver and hepatocytes in vitro. With the increasing use and incorporation of nanoparticles (NPs) into consumer products, screening for potential toxicity is necessary to ensure customer safety. NPs have been shown to translocate to the bloodstream following inhalation and ingestion, and such studies demonstrate that the liver is an important organ for accumulation. Silver (Ag) NPs are highly relevant for human exposure due to their use in food contact materials, dietary supplements, and antibacterial wound treatments. Due to the large number of different NPs already used in various products and being developed for new applications, it is essential that relevant, quick, and cheap methods of in vitro risk assessment suitable for these new materials are established. Therefore, this study used a simple hepatocytes model combined with an in vivo injection model to simulate the passage of a small amount of NPs into the bloodstream following exposure, e.g., via ingestion or inhalation, and examined the potential of Ag NPs of 20 nm diameter to cause toxicity, inflammation, and oxidative stress in the liver following in vivo exposures of female Wistar rats via iv injection to 50 μg of NPs and in vitro exposures using the human hepatocyte cell line C3A. We found that Ag NPs were highly cytotoxic to hepatocytes (LC(50) lactate dehydrogenase: 2.5 μg/cm(2)) and affected hepatocyte homeostasis by reducing albumin release. At sublethal concentrations with normal cell or tissue morphology, Ag NPs were detected in cytoplasm and nuclei of hepatocytes. We observed similar effects of Ag NPs on inflammatory mediator expression in vitro and in vivo with increase of interleukin-8 (IL-8)/macrophage inflammatory protein 2, IL-1RI, and tumor necrosis factor-α expression in both models and increased IL-8 protein release in vitro. This article presents evidence of the potential toxicity and inflammogenic potential of Ag NPs in the liver following ingestion. In addition, the similarities between in vitro and in vivo responses are striking and encouraging for future reduction, refinement, and replacement of animal studies by the use of hepatocyte cell lines in particle risk assessment. 23621326 GIANT EMBRYO encodes CYP78A13, required for proper size balance between embryo and endosperm in rice. Among angiosperms there is a high degree of variation in embryo/endosperm size in mature seeds. However, little is known about the molecular mechanism underlying size control between these neighboring tissues. Here we report the rice GIANT EMBRYO (GE) gene that is essential for controlling the size balance. The function of GE in each tissue is distinct, controlling cell size in the embryo and cell death in the endosperm. GE, which encodes CYP78A13, is predominantly expressed in the interfacing tissues of the both embryo and endosperm. GE expression is under negative feedback regulation; endogenous GE expression is upregulated in ge mutants. In contrast to the loss-of-function mutant with large embryo and small endosperm, GE overexpression causes a small embryo and enlarged endosperm. A complementation analysis coupled with heterofertilization showed that complementation of ge mutation in either embryo or endosperm failed to restore the wild-type embryo/endosperm ratio. Thus, embryo and endosperm interact in determining embryo/endosperm size balance. Among genes associated with embryo/endosperm size, REDUCED EMBRYO genes, whose loss-of-function causes a phenotype opposite to ge, are revealed to regulate endosperm size upstream of GE. To fully understand the embryo-endosperm size control, the genetic network of the related genes should be elucidated. 23586594 Interactive support interventions for caregivers of asthmatic children. Objectives. Asthmatic children and their parents constantly need to adjust their lifestyles due to asthma attacks. We evaluated the effectiveness of a self-management interactive support (SMIS) program for caregivers of asthmatic children. Methods. Children with persistent asthma were randomized into two groups, one receiving SMIS and the other receiving usual care (the control group). The SMIS program involved a three-month multifaceted behavioral intervention. Changes in the caregivers' knowledge and attitude regarding self-management, children's lung function, and number of emergency department visits and hospital admissions were examined at 12 months post-enrollment. Results. Sixty-five asthmatic children and caregivers (78% follow-up) completed the study. Primary caregivers in the SMIS group had significant improvements in knowledge and attitude regarding asthma compared to those in the control group (p < .05). Most importantly, knowledge about asthma medications and exacerbations significantly improved and attitudes toward medication adherence and dealing with asthma care became more positive in the SMIS group. The forced expiratory volume in one second was significantly improved in the SMIS group after 12 months (p < .05), and performance in the methacholine challenge test at the end of the study was significantly better in the SMIS group (p < .05). Participants in the SMIS group also had a lower rate of emergency room use (p < .05). Conclusion. The SMIS program for the self-management of asthma in children by their caregivers improved lung function and reduced the number of visits to the emergency departments. Interactive support interventions reinforce learning incentives and encourage self-care and maintenance of therapeutic regimens. 23439256 Subtypes of renal cell carcinoma: MRI and pathological features. Renal cell carcinoma (RCC) is the most common malignant tumor involving the kidney. Determining the subtypes of renal cell carcinoma is among the major goals of preoperative radiological work-up. Among all modalities, magnetic resonance imaging (MRI) has several advantages, such as inherent soft tissue contrast, detection of lipid and blood products, and excellent sensitivity to detect small amounts of intravenous contrast, which facilitate the discrimination of subtypes of RCC. In this article, we review MRI and pathological features used for determining the main histologic subtypes of RCC, including clear cell, papillary, collecting duct, chromophobe, multilocular cystic, and unclassified RCC. 23416648 Ameliorating effects of casein glycomacropeptide on obesity induced by high-fat diet in male Sprague-Dawley rats. The effect of casein glycomacropeptide (GMP) as a specific regulating mediator in obese rats induced by high-fat (HF) diet was investigated. Male obese Sprague-Dawley (SD) rats induced by high-fat diet for 8weeks period were fed high-fat, high-fat with GMP of 100mg/kg BW (HFLG), 200mg/kg BW (HFMG) and 400mg/kg BW (HFHG) for 6weeks. Compared with the high-fat control (HFC) group GMP supplementation significantly decreased adipose tissue weight, activity of fatty acid synthase (FAS) and glycerol-3-phosphate dehydrogenase (GPDH). Hepatic lipid droplet size, plasma and hepatic lipid levels markedly reduced. Moreover, GMP reduces plasma total cholesterol and low-density lipoprotein (LDL) cholesterol as well as hepatic-cholesterol and triglycerides. The liver steatosis observed in obese rats was also prevented by GMP supplement. In addition, GMP significantly diminished mitochondrial and liver malondialdehyde (MDA) production, and obviously elevated the activities of mitochondrial and hepatic superoxidase dismutase (SOD) and glutathione peroxidase (GSH-Px). Leptin production and proinflammatory cytokines such as TNF-α and IL-6 secretion decreased. Taken together, GMP can reduce lipid accumulation and enhance antioxidant capability of obese rats. It suggests that GMP can counteract high-fat diet-induced obesity, which might make it a potential ingredient with anti-obesity activity. 23652356 HIV Testing and Epidemiology in a Hospital-Based Surgical Cohort in Malawi. Despite the high prevalence of HIV in adults (11 %) in Malawi, testing among surgical patients is not routine. We examined the feasibility of universal opt-out HIV testing and counseling (HTC) on the surgical wards of Kamuzu Central Hospital in Lilongwe, Malawi, and sought to further delineate the role of HIV in surgical presentation and outcome. We reviewed HTC and surgical admission records from May to October 2011 and compared these data to data collected prospectively on patients admitted from November 2011 through April 2012, after universal HTC implementation. Prior to universal HTC, 270 of the 2,606 (10.4 %) surgical admissions were tested; 13 % were HIV-infected. After universal HTC implementation, HTC counselors reviewed 1,961 of the 2,488 admissions (79 %): 310 (16 %) had known status (157 seropositive, 153 seronegative) and 1,651 had unknown status (81 %). Among those with unknown status, 97 % (1,598, of 64 % of all admissions) accepted testing, of whom 9 % were found to be HIV-infected. Patients with longer lengths of stay (LOS) (mean = 11 vs. 5 days, p < 0.01) and those who underwent surgical intervention (odds ratio [OR] 2.5; confidence interval [CI] 2.0-3.1) were more likely to have a known status on discharge. HIV was more prevalence in patients with infection and genital/anal warts or ulcers and lower in trauma patients. HIV-positive patients received less surgical intervention (OR 0.69; CI 0.52-0.90), but there was no association between HIV status and length of stay or mortality. Universal opt-out HTC on the surgical wards was well accepted and increased the proportion of patients tested. High HIV prevalence in this setting merits implementation of universal HTC. 23752661 Rational design of carbon and TiO2 assembly materials: covered or strewn, which is better for photocatalysis? The rational design of carbonaceous hybrid nanostructures is very important for obtaining high photoactivity. TiO2 particles strewn with an optimal quantity of carbon nanodots have a much higher photoactivity than that of TiO2 covered with a carbon layer, showing the importance of carbon morphology in the photocatalysis of carbonaceous hybrid nanostructures. 23458667 Effect of homocysteinylation on structure, chaperone activity and fibrillation propensity of lens alpha-crystallin. Various chemical modifications can reduce chaperone activity of α-crystallin (α-Cry) and the loss of which has been implicated in the development of cataract diseases. The side chains of lysine residues are the target of both glycation and homocysteinylation, and lysine modification by the two reactions may similarly affect the structure and function of α- Cry. In this study, α-Cry was incubated with homocysteine thiolactone (HCTL), resulting in significant protein homocysteinylation, as determined with Ellman's assay. Homocysteinylation of α-Cry resulted in the reduction in surface hydrophobicity and alpha-helix to beta-sheet transition, as observed respectively with fluorescence and circular dichroism (CD) spectroscopy. The structural alteration of homocysteinylated α-Cry was accompanied by protein aggregation, including the formation of amyloid fibrils as detected by thioflavin T (ThT) fluorescence and Congo red (CR) absorption spectroscopy. The mobility shifts of homocysteinylated α-Cry on reducing and non-reducing SDS-PAGEs suggest that disulfide cross-linking in addition to lysine modification, also plays a role in aggregation of this protein. The chaperone activities of α-Cry, namely to prevent aggregation, to assist refolding and to restore activity of thermally stressed α-glucosidase (α-Gls) were reduced after homocysteinylation. Overall, this study suggests that similar to non-enzymatic glycation, homocysteinylation of α-Cry is a risk factor for the development of cataract disorders, for instance during hyperhomocysteinemia which is linked to the various ocular pathological disorders. 23494495 Fluid-attenuated inversion recovery vascular hyperintensities are not visible using 3D CUBE FLAIR sequence. Fluid-attenuated inversion recovery (FLAIR) vascular hyperintensities (FVH), initially described on 2D FLAIR images, are a useful imaging marker in patients with acute ischaemic stroke. We aimed to compare the sensitivity of the 3D CUBE FLAIR sequence with 2D FLAIR for the detection of FVH. Forty-seven consecutive patients admitted for a suspected stroke were explored by 2D and 3D CUBE FLAIR MR sequences at 1.5 and 3 T. Three blinded readers assessed FVH defined as hyperintensities within cerebral arteries. Location of FVH, acute brain infarct and arterial stenosis were also assessed. 2D images were compared with 3D images for the detection of FVH. Agreement between readers was assessed. Of the 47 patients, 21 FVHs were observed on 2D FLAIR images of 15 patients (11 with acute brain infarct and 11 with an arterial stenosis). No FVH was visualised on 3D CUBE FLAIR images for either proximal or distal locations. Agreement between readers was excellent. FVHs are not visible using 3D CUBE FLAIR images. This study suggests that, in suspected acute ischaemic stroke, the assessment of FVH should only be performed on conventional 2D FLAIR images. KEY POINTS : • Fluid-attenuated inversion recovery (FLAIR) vascular hyperintensities (FVH) are of neuroradiological importance. • FVHs are useful imaging markers in patients with an acute ischaemic stroke. • FVHs are not visible using 3D CUBE FLAIR images. • Assessment of FVH should be performed on conventional 2D FLAIR images. 23500544 Interrelationship between ATP-binding cassette transporters and oxysterols. ATP-binding cassette (ABC) transporters constitute a ubiquitous superfamily of membrane proteins responsible for the translocation of several substances across membranes using the chemical energy provided by ATP hydrolysis. ABC transporters participate in many physiological and pathophysiological processes, including cholesterol and lipid transportation and multidrug resistance. Oxysterols are the products of cholesterol oxidation, formed by both enzymatic and non-enzymatic mechanisms. The role of oxysterols in cholesterol metabolism and several diseases has been widely investigated, but many questions remain to be answered. Several lines of evidence link ABC transporter functions with cholesterol and oxysterol metabolism. This review discusses ABC transporters, oxysterols, and how they interact with each other. 23877117 Metagenome-wide analysis of antibiotic resistance genes in a large cohort of human gut microbiota. The human gut microbiota is a reservoir of antibiotic resistance genes, but little is known about their diversity and richness within the gut. Here we analyse the antibiotic resistance genes of gut microbiota from 162 individuals. We identify a total of 1,093 antibiotic resistance genes and find that Chinese individuals harbour the highest number and abundance of antibiotic resistance genes, followed by Danish and Spanish individuals. Single-nucleotide polymorphism-based analysis indicates that antibiotic resistance genes from the two European populations are more closely related while the Chinese ones are clustered separately. We also confirm high abundance of tetracycline resistance genes with this large cohort study. Our study provides a broad view of antibiotic resistance genes in the human gut microbiota. 23832054 Solution-processable n-type and ambipolar semiconductors based on a fused cyclopentadithiophenebis(dicyanovinylene) core. Two fused cyclopentadithiophenebis(dicyanovinylene) derivatives ( and ) with a low-lying LUMO energy level (-3.88 eV) and a rigid core structure were successfully synthesized. They have good thermal stability and form highly ordered packing structures both in the bulk solid state and in thin films. The field effect transistors fabricated from a solution of these two compounds showed ambipolar behaviour with major n-channel operation. exhibited electron mobility up to 0.16 cm(2) V(-1) s(-1). 23479325 Imaging quality of F-18-FDG PET/CT in the inpatient versus outpatient setting. The purpose of this study is to investigate potential differences in the image quality of inpatient versus outpatient F-18-FDG PET/CT to provide evidence for appropriate policies and procedures to be promulgated on inpatient referrals. 100 consecutive inpatient and 100 outpatient F-18-FDG PET/CT scans were compared from the same time period and PET/CT scanner. Each study was evaluated for a subjective overall rating (optimal vs. suboptimal), and also by objective measurements (SUVmean) in four background structures (brain, blood pool, liver, and muscle). 96 outpatient scans were rated optimal and 4 suboptimal whereas corresponding numbers for inpatient scans were 77 and 23 (p < 0.001). Of the objective indices, cerebellar SUV was significantly different in inpatient versus outpatient (5.3 vs. 6.9; p < 0.001) as well as suboptimal versus optimal rated groups (4.8 vs. 6.3; p < 0.001). While mean blood glucose was higher for inpatients (108.01 vs. 101.49 mg/dl; p = 0.017), it was not significantly different between optimal and suboptimal exams. Linear regression analysis between blood glucose levels and cerebellar uptake revealed an inverse relationship (R = -0.38, p < 0.001). There was a significantly higher number of inpatient PET/CT scans rated as suboptimal in comparison to outpatient scans. Decreased cerebellar uptake was present in suboptimal rated studies and in inpatient studies. Altered biodistribution is thus a potential etiology of reduced scan quality among inpatients. These findings, if duplicated among other readers and centers, may form the basis of quality control recommendations for inpatient PET/CT ordering patterns. 23896349 Towards a detailed atlas of protein-protein interactions. Protein interaction maps are the key to understand the complex world of biological processes inside the cell. Public protein databases have already catalogued hundreds of thousands of experimentally discovered interactions, and struggle to curate all the existing information dispersed through the literature. However, to be most efficient, standard protocols need to be implemented for direct submission of new interaction sets directly into databases. At the same time, great efforts are invested to expand the coverage of the interaction space and unveil the molecular details of such interactions up to the atomistic level. The net result will be the definition of a detailed atlas spanning the universe of protein interactions to guide the everyday work of the biologist. 23749081 Guidance of stem cells to a target destination in vivo by magnetic nanoparticles in a magnetic field. Stem cells contribute to physiological processes such as postischemic neovascularization and vascular re-endothelialization, which help regenerate myocardial defects or repair vascular injury. However, therapeutic efficacy of stem cell transplantation is often limited by inefficient homing of systemically administered cells, which results in a low number of cells accumulating at sites of pathology. In this study, anti-CD34 antibody-coated magnetic nanoparticles (Fe3O4@PEG-CD34) are shown to have high affinity to stem cells. The results of hemolysis rate and activated partial thromboplastin time (APTT) tests indicate that such nanoparticle may be used safely in the blood system. In vitro studies showed that a nanoparticle concentration of 100 μg/mL gives rise to a significant increase in cell retention using an applicable permanent magnet, exerting minimal negative effect on cell viability and migration. Subsequent in vivo studies indicate that nanopartical can specifically bind stem cells with good magnetic response. Anti-CD34 antibody coated magnetic nanoparticle may be used to help deliver stem cells to a lesion site in the body for better treatment. 22933327 Dual-responsive nanoparticles and their self-assembly. Dual-responsive nanoparticles are designed by functionalizing magnetic cores with light-responsive ligands. These materials respond to both light and magnetic fields and can be assembled into various higher-order structures, depending on the relative contributions of these two stimuli. 23798420 Evolutionary lag times and recent origin of the biota of an ancient desert (Atacama-Sechura). The assembly of regional biotas and organismal responses to anthropogenic climate change both depend on the capacity of organisms to adapt to novel ecological conditions. Here we demonstrate the concept of evolutionary lag time, the time between when a climatic regime or habitat develops in a region and when it is colonized by a given clade. We analyzed the time of colonization of four clades (three plant genera and one lizard genus) into the Atacama-Sechura Desert of South America, one of Earth's driest and oldest deserts. We reconstructed time-calibrated phylogenies for each clade and analyzed the timing of shifts in climatic distributions and biogeography and compared these estimates to independent geological estimates of the time of origin of these deserts. Chaetanthera and Malesherbia (plants) and Liolaemus (animal) invaded arid regions of the Atacama-Sechura Desert in the last 10 million years, some 20 million years after the initial onset of aridity in the region. There are also major lag times between when these clades colonized the region and when they invaded arid habitats within the region (typically 4-14 million years). Similarly, hyperarid climates developed ∼8 million years ago, but the most diverse plant clade in these habitats (Nolana) only colonized them ∼2 million years ago. Similar evolutionary lag times may occur in other organisms and habitats, but these results are important in suggesting that many lineages may require very long time scales to adapt to modern desertification and climatic change. 23902989 Effects of Chronic Akt/mTOR Inhibition by Rapamycin on Mechanical Overload-Induced Hypertrophy and Myosin Heavy Chain Transition in Masseter Muscle. To examine the effects of the Akt/mammalian target of rapamycin (mTOR) pathway on masseter muscle hypertrophy and myosin heavy chain (MHC) transition in response to mechanical overload, we analyzed the effects of bite-opening (BO) on the hypertrophy and MHC composition of masseter muscle of BO-rats treated or not treated with rapamycin (RAPA), a selective mTOR inhibitor. The masseter muscle weight in BO-rats was significantly greater than that in controls, and this increase was attenuated by RAPA treatment. Expression of slow-twitch MHC isoforms was significantly increased in BO-rats with/without RAPA treatment, compared with controls, but the magnitude of the increase was much smaller in RAPA-treated BO-rats. Phosphorylation of p44/42 MAPK (ERK1/2), which preserves fast-twitch MHC isoforms in skeletal muscle, was significantly decreased in BO-rats, but the decrease was abrogated by RAPA treatment. Calcineurin signaling is known to be important for masseter muscle hypertrophy and fast-to-slow MHC isoform transition, but expression of known calcineurin activity modulators was unaffected by RAPA treatment. Taken together, these results indicate that the Akt/mTOR pathway is involved in both development of masseter muscle hypertrophy and fast-to-slow MHC isoform transition in response to mechanical overload with inhibition of the ERK1/2 pathway and operates independently of the calcineurin pathway. 22515477 Quality of life domains affected in children with developmental coordination disorder: a systematic review. The quality of life (QOL) of children with developmental coordination disorder (DCD) is largely unknown, but evidence suggests that multiple QOL domains are affected by the disorder. While DCD is primarily considered a motor disorder, multiple studies have reported psychological and social concerns in children with this condition. Our primary aim was to present the current state of the evidence regarding the physical, psychological, and social QOL domains that can be affected in children with DCD. Systematic review of articles from seven databases through November 2010 (MEDLINE, EMBASE, CINAHL, PsycINFO, ERIC, CDSR, DARE) was conducted. Search terms included developmental coordination disorder, dyspraxia, quality of life, life satisfaction, well-being, activities of daily living, and participation. Two independent reviewers screened titles, abstracts, and full-text articles. Studies meeting the following criteria were selected: (1) sample comprised solely of individuals with coordination difficulties consistent with DCD; (2) outcome measures related to physical, psychological, or socials domains of QOL; and (3) articles published in English. Data were extracted by one author and verified by a second. Outcomes were categorized according to physical, psychological and social domains of QOL and study quality was rated by case definitions of DCD based on diagnostic criteria as per the Diagnostic and Statistical Manual - 4th edition. Forty-one articles were included. Most studies reported significantly poorer results in physical, psychological and social functioning in children with DCD compared with peers. Despite the impact of DCD on multiple domains, only one study used a QOL measure as an outcome. Although DCD impacts several QOL domains, the QOL of children with this disorder remains largely unknown. The next critical step is for clinicians and researchers to use QOL measures to gather information on how DCD may affect the QOL of children with this disorder. 23843409 A pedoprosthetic rehabilitation in patients with severe early childhood caries (S-ECC). Early childhood caries (ECC) is a rapid form of dental caries. ECC is the most common chronic childhood disease that can compromise a child's self-esteem, nutritional intake, oral development and quality of life, subsequently leading to malocclusion and psychological problems. The restoration of severely decayed primary teeth is often a difficult procedure that offers a great challenge to paediatric dentists. The present case series document the clinical management of patients suffering from severe early childhood caries using removable partial prosthesis restoring their masticatory function and aesthestics. The ultimate aim of the treatment was to improve psychological and physiological development leading to better functioning of the stomatognathic system. 23935807 Correction: Flavobacterium plurextorum sp. nov. Isolated from Farmed Rainbow Trout (Oncorhynchus mykiss). [This corrects the article on p. e67741 in vol. 8.]. 23838521 Transcriptional Mechanisms Underlying Hemoglobin Synthesis. The physiological switch in expression of the embryonic, fetal, and adult β-like globin genes has garnered enormous attention from investigators interested in transcriptional mechanisms and the molecular basis of hemoglobinopathies. These efforts have led to the discovery of cell type-specific transcription factors, unprecedented mechanisms of transcriptional coregulator function, genome biology principles, unique contributions of nuclear organization to transcription and cell function, and promising therapeutic targets. Given the vast literature accrued on this topic, this article will focus on the master regulator of erythroid cell development and function GATA-1, its associated proteins, and its frontline role in controlling hemoglobin synthesis. GATA-1 is a crucial regulator of genes encoding hemoglobin subunits and heme biosynthetic enzymes. GATA-1-dependent mechanisms constitute an essential regulatory core that nucleates additional mechanisms to achieve the physiological control of hemoglobin synthesis. 23260767 Conceptual design of integrated microfluidic system for magnetic cell separation, electroporation, and transfection. For the purposes of a successful ex vivo gene therapy we have proposed and analyzed a new concept of an integrated microfluidic system for combined magnetic cell separation, electroporation, and magnetofection. For the analysis of magnetic and electric field distribution (given by Maxwell equations) as well as dynamics of magnetically labeled cell and transfection complex, we have used finite element method directly interfaced to the Matlab routine solving Newton dynamical equations of motion. Microfluidic chamber has been modeled as a channel with height and length 1 mm and 1 cm, respectively. Bottom electrode consisted of 100 parallel ferromagnetic straps and the upper electrode was plate of diamagnetic copper. From the dynamics of magnetic particle motion we have found that the characteristic time-scales for the motion of cells (mean capture time âˆ¼ 4 s) and gene complexes (mean capture time âˆ¼ 3 min), when permanent magnets are used, are in the range suitable for efficient cell separation and gene delivery. The largest electric field intensity (∼10 kV/m) was observed at the edges of the microelectrodes, in the close proximity of magnetically separated cells, which is optimal for subsequent cell electroporation. 23689603 Enhanced field emission characteristics in metal-coated Si-nanocones. Metallic gold (Au) and platinum (Pt) thin films were deposited on silicon nanocones (Si-NCs) by sputtering to elucidate the effects of work function and conductivities on the field electron emission characteristics of surface-modified Si-NCs. The results showed that for Pt/Si-NCs and Au/Si-NCs, although the turn-on field defined at a corresponding current density of 10 μA cm(-2) only improved from 4.20 V μm(-1) for bare Si-NCs to 3.65 and 2.90 V μm(-1), respectively, the emission current density measured at 5.00 V μm(-1) was enhanced by orders of magnitude, reaching 1.82 mA cm(-2) for Au/Si-NCs. Compared to those obtained from various surface-modified Si-nanostructures, such as ZnO/Si-nanopillars and ferroelectrics/Si-nanotips, the current results represent an interesting alternative route for producing surface-modified Si-NCs that might be useful for optical and electronic applications. 23950965 Recovery from posttraumatic stress symptoms: a qualitative study of attributions in survivors of war. The study explored factors to which people traumatized by war attribute their recovery from posttraumatic symptoms and from war experiences. : In-depth interviews were conducted with two groups of participants with mental sequelae of the war in the former Yugoslavia: 26 people who had recovered from posttraumatic stress disorder (PTSD) and 17 people with ongoing symptoms of PTSD. Participants could attribute their recovery to any event, person or process in their life. The material was subjected to thematic analysis. Eight themes covered all factors to which participants attributed their recovery. Six themes described healing factors relevant for both groups of participants: social attachment and support, various strategies of coping with symptoms, personality hardiness, mental health treatment, received material support, and normalization of everyday life. In addition to the common factors, recovered participants reported community involvement as healing, and recovered refugees identified also feeling safe after resolving their civil status as helpful. Unique to the recovered group was that they maintained reciprocal relations in social attachment and support, employed future-oriented coping and emphasised their resilient personality style. The reported factors of recovery are largely consistent with models of mental health protection, models of resilience and recommended interventions in the aftermath of massive trauma. Yet, they add the importance of a strong orientation towards the future, a reciprocity in receiving and giving social support and involvement in meaningful activities that ensure social recognition as a productive and valued individual. The findings can inform psychosocial interventions to facilitate recovery from posttraumatic symptoms of people affected by war and upheaval. 23957877 Ultrasonic-assisted Synthesis of Surface-clean TiB2 Nanoparticles and their Improved Dispersion and Capture in Al-matrix Nanocomposites. Metal-matrix nanocomposites (MMNCs) have great potential for a wide range of applications. In order to provide high performance, effective nanoparticle (NP) dispersion in the liquid and NP capture within the metal grains during solidification is essential. In this work, we present the novel synthesis and structural characterization of surface-clean titanium diboride (TiB2) NPs with an average particle size of 20 nm, by ultrasonic-assisted reduction of fluorotitanate and fluoroboride salts in molten aluminum. The high-intensity ultrasonic field restricts NP growth. Using a master nanocomposite approach, the as-prepared TiB2 NPs are effectively incorporated into A206 alloys during solidification processing due to their clean surface, showing partial capture and significant grain refinement. 23831941 Efficient hybrid solar cells using PbSxSe1-x quantum dots and nanorods for broad-range photon absorption and well-assembled charge transfer networks. We present hybrid solar cells with high efficiency utilizing a novel donor-acceptor combination of poly[2,6-(4,4'-bis-(2-ethylhexyl)dithieno[3,2-b:2',3'-d]silole)-alt-4,7(2,1,3-benzothiadiazole)] (PSBTBT) and a PbSxSe1-x inorganic semiconductor. Several nanocomposite parameters are evaluated in order to improve the hybrid device efficiency, including donor-acceptor materials, surface modification of the inorganic semiconductor, and mixture of quantum dots (QDs) and nanorods (NRs) in the polymer matrix. A high power conversion efficiency (PCE) of ∼3.4% is attained from the optimal device with a PbS0.7Se0.3 QD : NR blending ratio of 0.3 : 0.7 (wt/wt) under air mass (AM) 1.5 solar illumination, which is attributed to the broad-range absorption of the solar energies and the efficient charge separation and transport dynamics. The optoelectronic and nanomorphological properties of these novel hybrid solar cells are described. 23758504 Computational and Experimental Investigations into the Conformations of Cyclic Tetra-α/β-peptides. We present a combined computational and experimental study of the energy landscapes of cyclic tetra-α/β-peptides. We have performed discrete path sampling calculations on a series of cyclic tetra-α/β-peptides to obtain the relative free energies and barriers to interconversion of their conformers. The most stable conformers of cyclo-[(β-Ala-Gly)2] contain all-trans peptide groups. The relative energies of the cis isomers and the cis-trans barriers are lower than in acyclic peptides but not as low as in the highly strained cyclic α-peptides. For cyclic tetra-α/β-peptides containing a single proline residue, of the type cyclo-[β-Ala-Xaa-β-Ala-Pro], the energy landscapes show that the most stable isomers containing cis and trans β-Ala-Pro have similar free energies and are separated by barriers of approximately 15 kcal mol(-1). We show that the underlying energy landscapes of cyclo-[β-Ala-Lys-β-Ala-Pro] and cyclo-[β-Ala-Ala-β-Ala-Pro] are similar, allowing the substitution of the flexible side chain of Lys with Ala to reduce the computational demand of our calculations. However, the steric bulk of the Val side chain in cyclo-[β-Ala-Val-β-Ala-Pro] affects the conformations of the ring, leading to significant differences between its energy landscape and that of cyclo-[β-Ala-Ala-β-Ala-Pro]. We have synthesized the cyclic peptide cyclo-[β-Ala-Lys-β-Ala-Pro], and NMR spectroscopy shows the presence of conformers that interconvert slowly on the NMR time scale at temperatures up to 80 °C. Calculated circular dichroism (CD) spectra for the proposed major isomer of cyclo-[β-Ala-Ala-β-Ala-Pro] are in good agreement with the experimental spectra of cyclo-[β-Ala-Lys-β-Ala-Pro], suggesting that the Ala cyclic tetrapeptide is a viable model for the Lys analogue. 23848601 Monitoring the prevalence of viable and dead cariogenic bacteria in oral specimens and in vitro biofilms by qPCR combined with propidium monoazide. Streptococcus mutans and Streptococcus sobrinus are associated with the development of dental caries in humans. However, previous diagnostic systems are unsuitable for monitoring viable cell numbers in oral specimens. Assessing the relationship between the numbers of viable and dead bacterial cells and oral status is important for understanding oral infectious diseases. Propidium monoazide (PMA) has been reported to penetrate dead cells following membrane damage and to cross-link DNA, thereby inhibiting DNA amplification. In the present study, we established an assay for selective analysis of two viable human cariogenic pathogens, S. mutans and S. sobrinus, using PMA combined with real-time PCR (PMA-qPCR). We designed species-specific primer sets for S. mutans and S. sobrinus, generated standard curves for measuring cell numbers, and evaluated the dynamic range of the assay. To determine the effectiveness of the assay, PMA was added to viable and autoclave-killed cell mixtures. PMA treatment effectively prevented DNA amplification from dead cells. No amplification of DNA from dead cells was observed in these organisms. In addition, we applied this assay to analyze viable cell numbers in oral specimens. A significant correlation was found between the number of viable S. mutans cells in saliva and that in plaque among caries-free patients, whereas no correlation was observed between saliva and carious dentin. The total and viable cell numbers in caries-positive saliva were significantly higher than those in caries-free saliva. Finally, we analyzed the usefulness of this assay for in vitro oral biofilm analysis. We applied PMA-qPCR for monitoring viable S. mutans cell numbers in vitro in planktonic cells and oral biofilm treated with hydrogen peroxide (H₂O₂). In planktonic cells, the number of viable cells decreased significantly with increasing H₂O₂ concentration, whereas only a small decrease was observed in biofilm cell numbers. PMA-qPCR is potentially useful for quantifying viable cariogenic pathogens in oral specimens and is applicable to oral biofilm experiments. This assay will help to elucidate the relationship between the number of viable cells in oral specimens and the oral status. 23949319 Short Leukocyte Telomere Length Predicts Risk of Diabetes in American Indians: The Strong Heart Family Study. Telomeres play a central role in cellular aging and shorter telomere length has been associated with age-related disorders including diabetes. However, a causal link between telomere shortening and diabetes risk has not been established. In a well-characterized longitudinal cohort of American Indians participating in the Strong Heart Family Study, we examined whether leukocyte telomere length (LTL) at baseline predicts incident diabetes independent of known diabetes risk factors. Among 2,328 participants free of diabetes at baseline, 292 subjects developed diabetes during an average 5.5 years of follow-up. Compared with subjects in the highest quartile (longest) of LTL, those in the lowest quartile (shortest) had an almost twofold increased risk of incident diabetes (HR 1.83, 95% CI, 1.26-2.66), whereas the risk for those in the second (HR 0.87, 95% CI, 0.59-1.29) and the third (HR 0.95, 95% CI, 0.65-1.38) quartiles was statistically nonsignificant. These findings suggest a nonlinear association between LTL and incident diabetes, and indicate that LTL could serve as a predictive marker for diabetes development in American Indians, who suffer from disproportionately high rates of diabetes. 23935054 The MerR-like regulator BrlR impairs Pseudomonas aeruginosa biofilm tolerance to colistin by repressing PhoPQ. While the MerR-like transcriptional regulator BrlR has been demonstrated to contribute to Pseudomonas aeruginosa biofilm drug tolerance to antimicrobial agents known as multidrug efflux pumps substrates, the role of BrlR to resistance to cationic antimicrobial peptides (CAP), which is based on reduced outer membrane susceptibility, is not known. Here we demonstrate that inactivation of brlR coincided with increased resistance of P. aeruginosa to colistin while overexpression of brlR resulted in increased susceptibility. brlR expression correlated with reduced transcript abundance of phoP, phoQ, pmrA, pmrB, and arnC. Inactivation of pmrA and pmrB had no effect on the susceptibility of P. aeruginosa biofilms to colistin while inactivation of phoP and phoQ rendered biofilms more susceptible compared to wild type. The susceptibility phenotype of ΔphoP biofilms to colistin was comparable to P. aeruginosa biofilms overexpressing brlR. BrlR was found to directly bind to oprH promoter DNA of the oprH-phoPQ operon. BrlR reciprocally contributed to colistin and tobramycin resistance in P. aeruginosa PAO1 and CF clinical isolates, with overexpression of brlR resulting in increased tobramycin-MICs and increased tobramycin resistance, but decreased colistin-MICs and increased colistin susceptibility. The opposite trend was observed upon brlR inactivation. The difference in susceptibility to colistin and tobramycin was eliminated by combination treatment of biofilms with both antibiotics. Our findings establish BrlR as an unusual member of the MerR family as it not only functions as a multidrug transport activators but also acts as a repressor of phoPQ expression, thus suppressing colistin resistance. 23102509 Efficacy of asiatic acid, a pentacyclic triterpene on attenuating the key enzymes activities of carbohydrate metabolism in streptozotocin-induced diabetic rats. Asiatic acid (AA), a triterpenoid derivative of Centella asiatica, has shown significant biological effects of antioxidant and anti-inflammatory activities. Aim of this investigation was to evaluate the antihyperglycemic effect of AA on the activities of hepatic enzymes of carbohydrate metabolism in streptozotocin (STZ)-induced diabetic rats. To induce diabetes mellitus, rats were injected with streptozotocin intraperitoneally at a single dose of 40 mg/kg b.w. Diabetic rats showed significant (p<0.05) increased in plasma glucose, glycosylated hemoglobin and significant (p<0.05) decreased in circulating insulin and hemoglobin. The altered activities of key enzymes such as glucose-6-phosphatase and fructose-1,6-bisphosphatase of carbohydrate metabolism significantly (p<0.05) increased whereas hexokinase, pyruvate kinase, glucose-6-phosphate dehydrogenase and glycogen content significantly (p<0.05) decreased in the liver of diabetic rats and also increased activities of aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP). Oral administration of AA (5, 10 and 20 mg/kg b.w.) and glibenclamide (600 μg/kg b.w.) to diabetic rats for 45 days prevented the above alteration and reverted to near normalcy. Protection of body weight loss of diabetic rats by AA was also observed. No significant effect was observed in normal rats treated with AA (20 mg/kg b.w.). In this search, AA found to be potential bioactive compound to regulate the carbohydrate metabolism by modulating the key regulatory enzymes in diabetic rats. These findings merit further research in this field. 23892371 Physiological Responses to Shifts in Multiple Environmental Stressors: Relevance in a Changing World. Population response to global change will depend on responses to a multivariate set of changes in abiotic habitat characteristics and biotic interactions. Organismal biologists seeking to make ecological inferences about the impacts of global change by studying physiological performance have traditionally performed carefully controlled experimental studies that examine one variable at a time. Those studies, while of high value, may not lead to accurate predictions of organismal responses in the natural habitat, where organisms experience concomitant changes in multiple environmental factors. The symposium "Physiological Responses to Simultaneous Shifts in Multiple Environmental Stressors: Relevance in a Changing World" focused on physiological studies in which multiple environmental variables were simultaneously examined and brought together an international group of early-career and established speakers with unique perspectives on studies of multistressors. In doing so, the objective of the symposium was to frame the necessary next steps for increasing predictive capacity of organismal responses to environmental shifts in the natural habitat, establish novel collaborations among researchers actively investigating physiological responses to a multivariate environment, and broaden the number of researchers conducting such studies. 23901856 Higher survival rates after trauma linked to national networks. TWENTY PER cent more patients are surviving severe trauma since the introduction of major trauma networks in 2010, audit data show. 23272906 Targeting mTOR: Evaluating the Therapeutic Potential of Resveratrol for Cancer Treatment. Resveratrol (3,4',5-trihydroxystilbene; RSV), a natural polyphenol found in a variety of daily food including grapes and red wine, has long been suspected to have multifaceted health beneficial properties, including anti-inflammation, anti-oxidant, and anticancer activities. Over the past few years, numerous studies have suggested that suppressing the activity of mammalian target of rapamycin (mTOR), a critical regulator of cell metabolism, growth, and proliferation, may provide a key mechanism underlying the anticarcinogenic properties of resveratrol. It has been found that resveratrol targets multiple components of the phosphatidylinositol 3- kinase(PI3K)/Akt and mTOR signaling pathways, including PI3K, Akt, PTEN, and DEPTOR, suggesting that this natural compound and its derivatives may offer a promising new cancer treatment. In the current review, we discuss recent findings on the molecular mechanisms regulating mTOR signaling and the therapeutic potential of resveratrol for cancer treatment by targeting mTOR. 23509003 Free radical reactions in two dimensions: a case study on photochlorination of graphene. Graphene, a two-dimensional giant-molecule of sp(2) -bonded carbon atoms, provides a perfect platform for studying free radical reaction chemistry in two-dimensions, which holds promise to control the chemical functionality of graphene. Free-radical photochlorination of graphene is used as an example to investigate the thickness, stacking order, and single- and double-side dependent reactivity in graphene. Anomalously low reactivity is observed in the photochlorination of AB-stacked bilayer graphene in comparison with that of few-layer graphene. Double-sided chlorination of graphene shows higher reactivity and chlorine coverage than single-sided reaction. It is also experimentally and theoretically demonstrated that chlorine free radicals at low coverage prefer to form a stable charge-transfer complex with graphene, which highly enhances graphene's conductivity and simultaneously generates a pseudo-bandgap through noninvasive doping. Moreover, the initial accumulation of chlorine radicals is considered as the rate-determining step of photochlorination of graphene. 23838727 The Impact of Parent-Delivered Intervention on Parents of Very Young Children with Autism. This study investigated the impact of a parent-coaching intervention based on the Early Start Denver Model (P-ESDM) on parenting-related stress and sense of competence. This was part of a multisite, randomized trial comparing P-ESDM (n = 49) with community intervention (n = 49) for children aged 12 and 24 months. The P-ESDM group reported no increase in parenting stress, whereas the Community group experienced an increase over the same 3-month period. Parental sense of competence did not differ. Number of negative life events was a significant predictor of parenting stress and sense of competence across both groups. This suggests that a parent-coaching intervention may help maintain parental adjustment directly after a child is diagnosed with ASD. 23656382 Sub-acute and chronic MRI findings in bilateral canine fibrotic contracture of the infraspinatus muscle. A six-year-old, 30-kg female German pointer dog was presented for examination with a history of pre-existing right-forelimb lameness and more recent (3 months) persistent lameness in the left-forelimb. Physical examination revealed mild left-forelimb lameness and a mild circumduction movement. There were no signs of pain or crepitation detected during manipulation of the shoulders, but the animal was unable to fully flex both glenohumeral joints. Magnetic resonance imaging, using fast recovery fast spin echo T2-weighted and fat saturated proton density sequences, revealed abnormal heterogeneous hypointensity in the right infraspinatus muscle and a heterogeneous hyperintense area in the left infraspinatus muscle. Surgical treatment consisting of a bilateral infraspinatus tenectomy resulted in improved limb function. Histopathological examination demonstrated tissue changes in the right infraspinatus, characterised by myofibre degeneration and fibrosis, compatible with a chronic degenerative process, while changes in the left infraspinatus muscle were characterised by variable degrees of fibre degeneration, haemorrhage and interstitial oedema. 23177789 Protein tyrosine phosphatase 1B inhibitory effect by dammarane-type triterpenes from hydrolyzate of total Gynostemma pentaphyllum saponins. Protein tyrosine phosphatase 1B (PTP1B) is an important factor in non-insulin-dependent diabetes mellitus (type-2 diabetes), and a promising target for treatment of diabetes and obesity. Therefore, the aim of this study is to investigate the inhibitory activities of constituents (three new together with twelve known triterpenes compounds) isolated from the hydrolyzate of total saponins from Gynostemma pentaphyllum. Their structures were accomplished mainly base on the spectroscopic methods, and then were further confirmed by X-ray crystal diffraction. All the compounds were evaluated for inhibitory activity against PTP1B. Current data suggested that the compounds 1, 3, 12, 13 and 14 were considered to be potential as antidiabetic agents, in which they could significantly inhibit the PTP1B enzyme activity in a dose-dependent manner. 23834351 Piezoelectric osteotomy for the placement of titanium implants in rabbits: histomorphometry study. To evaluate bone remodeling around dental implants inserted into recipient sites prepared using either the piezoelectric or the conventional drilling technique. Twenty-four male New Zealand white rabbits (4 months, 2.70 kg) received dental implants (3.3 mm diameter and 6 mm length) on the medial surface of the tibia and were divided into 3 groups (n = 8). Group I was euthanized at 7 days; group II, at 14; and group III, at 28 days. Each animal received four implants, two in the right and two in the left tibia (96 implants were installed). Each tibia was operated by the same technique, and there are therefore neighbor's implants installed by different techniques. Histomorphometric parameters were used: the volume occupied by trabecular bone around the implants (BV/TV), media thickness, separation and number of trabeculae around the loops, and the contact area (interface) directly between the bone and implant (BIC). BV/TV was similar for both techniques (P = 0.291). Reduction in trabecular thickness was observed for both techniques (P < 0.05), but then returned to prior levels, with no significant difference between techniques (P = 0.217). Trabecular number increased from day 7 to day 14 (P < 0.001) and remained constant afterward for both techniques. No difference in BIC was observed between techniques on day 28 (P = 0.961). Piezoelectric osteotomy allowed bone formation for osseointegration of titanium implants, was not associated with bone necrosis, and provided results similar to those of the conventional technique. The piezoelectric technique can be considered a viable alternative in dental implantology. 23472051 Biosafety data as confidential business information. Removal of confidentiality claims on biosafety data is necessary to adhere to standard scientific procedures of quality assurance, to increase transparency, to minimize impacts of conflicts of interests, and ultimately to improve public confidence in GMOs. 23926339 6-O sulfated and N-sulfated Syndecan-1 promotes baculovirus binding and entry into mammalian cells. Baculoviruses are insect specific viruses commonly found in nature. They are not able to replicate in mammalian cells but can transduce them when equipped with an appropriate mammalian cell active expression cassette. Though the viruses have been studied in several types of mammalian cells from different origin, the receptor that baculovirus uses to enter or interact with mammalian cells is not yet identified. Due to the wide tropism of the virus, the receptor has been suggested to be a generally found cell surface molecule. In this article, we investigated the interaction of baculovirus and mammalian cell surface heparan sulfate proteoglycans (HSPG) in more detail. Our data shows that baculovirus requires HSPG sulfation, particularly N- and 6-O-sulfation, to bind to and transduce mammalian cells. According to our results, baculovirus binds specifically to SDC-1 but does not interact with other syndecan types 2-4 or with glypicans. Competition experiments performed with SDC-1 antibody or recombinant SDC-1 protein inhibited baculovirus binding and SDC-1 overexpression enhanced baculovirus-mediated transduction. In conclusion, we show that SDC-1, a commonly found cell surface HSPG molecule, has a role in the binding and entry of baculovirus in vertebrate cells. The results presented here reveal important aspects of baculovirus entry and can serve as a basis for next generation baculovirus vector development for gene delivery. 23764758 Feasibility of atlantoaxial pedicle screws' placement in children 6-8 years of age: a cadaveric and tomographic study. The aims of this study were to evaluate the linear and angular dimensions of children's atlantoaxial pedicle using cadavers combined with axial computed tomography (CT) and to examine the feasibility of placing atlantoaxial pedicle screws (3.5 mm diameter) on the vertebrae of children 6-8 years of age. Fourteen cadaveric specimens, ranging in age from 6 to 8 years, were dissected to obtain their atlantoaxial vertebrae. We manually measured 12 linear anatomic parameters related to the atlantoaxial pedicle, its lateral mass, and the posterior arch under the vertebral artery groove. CT axial scanning of the atlantoaxial region was performed on 32 healthy children ranging in age from 6 to 8 years. The length of the atlantoaxial pedicles and the angle between the pedicle axis and the midline of the vertebral body were measured on the atlantoaxial transverse CT imaging. It is feasible to place a 3.5 mm screw in the atlantoaxial pedicle of children ranging in age from 6 to 8 years when the appropriate entry point and trajectory of the screw are chosen. 23897710 Electron beam induced radiation damage in the catalyst layer of a proton exchange membrane fuel cell. Electron microscopy is an essential tool for the evaluation of microstructure and properties of the catalyst layer (CL) of proton exchange membrane fuel cells (PEMFCs). However, electron microscopy has one unavoidable drawback, which is radiation damage. Samples suffer temporary or permanent change of the surface or bulk structure under radiation damage, which can cause ambiguity in the characterization of the sample. To better understand the mechanism of radiation damage of CL samples and to be able to separate the morphological features intrinsic to the material from the consequences of electron radiation damage, a series of experiments based on high-angle annular dark-field-scanning transmission scanning microscope (HAADF-STEM), energy filtering transmission scanning microscope (EFTEM), and electron energy loss spectrum (EELS) are conducted. It is observed that for thin samples (0.3-1 times λ), increasing the incident beam energy can mitigate the radiation damage. Platinum nanoparticles in the CL sample facilitate the radiation damage. The radiation damage of the catalyst sample starts from the interface of Pt/C or defective thin edge and primarily occurs in the form of mass loss accompanied by atomic displacement and edge curl. These results provide important insights on the mechanism of CL radiation damage. Possible strategies of mitigating the radiation damage are provided. SCANNING 9999:XX-XX, 2013. © 2013 Wiley Periodicals, Inc. 23537601 Lead, mercury, and cadmium in blood and their relation to diet among Swedish adults. The aim of the present study was to examine the body burden of lead (Pb), mercury (Hg), and cadmium (Cd) in blood among Swedish adults and the association between blood levels, diet and other lifestyle factors. The study was based on a subgroup (n=273) of the national survey Riksmaten 2010-2011 (4-day food records and questionnaire). Lead, Hg, and Cd were measured in whole blood, and Cd additionally in urine, by mass or fluorescence spectrometry methods. The median values (5-95th percentiles) of the metals in blood were as follows; Pb: 13.4 (5.8-28.6) μg/L, Hg: 1.13 (0.31-3.45) μg/L, and Cd: 0.19 (0.09-1.08) μg/L. All three metals increased with increasing age. Lead levels in blood were positively associated with intakes of game and alcohol, Hg was related to fish intake, and blood Cd related to smoking and low iron stores and to a low meat intake. Body burdens of the studied metals were generally below health based reference values, but several individuals had blood Pb levels above the reference point for possible nephrotoxic and developmental neurotoxic effects. As health effects cannot be excluded, individuals with high Pb exposure should aim at decreasing their body burden, both from food and from other exposure routes. 23456175 Current self-complianced and self-rectifying resistive switching in Ag-electroded single Na-doped ZnO nanowires. We demonstrate current self-complianced and self-rectifying bipolar resistive switching in an Ag-electroded Na-doped ZnO nanowire device. The resistive switching is controlled by the formation and rupture of an Ag nanoisland chain on the surface along the Na-doped ZnO nanowire. Na-doping plays important roles in both the self-compliance and self-rectifying properties. 23836383 Mitochondrial Encephalomyopathy Due to a Novel Mutation in ACAD9. IMPORTANCE Mendelian forms of complex I deficiency are usually associated with fatal infantile encephalomyopathy. Application of "MitoExome" sequencing (deep sequencing of the entire mitochondrial genome and the coding exons of >1000 nuclear genes encoding the mitochondrial proteome) allowed us to reveal an unusual clinical variant of complex I deficiency due to a novel homozygous mutation in ACAD9. The patient had an infantile-onset but slowly progressive encephalomyopathy and responded favorably to riboflavin therapy. OBSERVATION A 13-year-old boy had exercise intolerance, weakness, and mild psychomotor delay. Muscle histochemistry showed mitochondrial proliferation, and biochemical analysis revealed severe complex I deficiency (15% of normal). The level of complex I holoprotein was reduced as determined by use of Western blot both in muscle (54%) and in fibroblasts (57%). CONCLUSIONS AND RELEVANCE The clinical presentation of complex I deficiency due ACAD9 mutations spans from fatal infantile encephalocardiomyopathy to mild encephalomyopathy. Our data support the notion that ACAD9 functions as a complex I assembly protein. ACAD9 is a flavin adenine dinucleotide-containing flavoprotein, and treatment with riboflavin is advisable. 23947329 Zhang et al. Respond. We are delighted that our article has stimulated initiatives in pediatricians and specialists to form guidelines for clinical management of childhood lead exposure and poisoning. We applaud the Pediatric Environmental Health Specialty Unit (PEHSU) network for creating the "Recommendations on Medical Management of Childhood Lead Exposure and Poisoning" (The Recommendations, hereafter).(1) The publication of The Recommendations is very timely, with the Centers for Disease Control and Prevention (CDC) officially adopted a new standard for "acceptable" blood lead levels in American children at 5 micrograms per deciliter in May 2012. (Am J Public Health. Published online ahead of print August 15, 2013: e1. doi:10.2105/AJPH.2013.301524). 23868719 Adjective-noun order as representational structure: Native-language grammar influences perception of similarity and recognition memory. This article describes two experiments linking native-language grammar rules with implications for perception of similarity and recognition memory. In prenominal languages (e.g., English), adjectives usually precede nouns, whereas in postnominal languages (e.g., Portuguese), nouns usually precede adjectives. We explored the influence of such rules upon similarity judgments about, and recognition of, objects with multiple category attributes (one nominal attribute and one adjectival attribute). The results supported the hypothesized primacy effect of native-language word order such that nouns generally carried more weight for Portuguese speakers than for English speakers. This pattern was observed for judgments of similarity (i.e., Portuguese speakers tended to judge objects that shared a noun-designated attribute as more similar than did English speakers), as well as for false alarms in recognition memory (i.e., Portuguese speakers tended to falsely recognize more objects if they possessed a familiar noun attribute, relative to English speakers). The implications of such linguistic effects for the cognition of similarity and memory are discussed. 23931688 Coenzyme A-acylating propionaldehyde dehydrogenase (PduP) from Lactobacillus reuteri: Kinetic characterization and molecular modeling. 3-Hydroxypropionic acid (3-HP), an important C3 chemical for a bio-based industry, is natively produced by Lactobacillus reuteri from glycerol. Conversion of glycerol occurs via the intermediate 3-hydroxypropionaldehyde (3-HPA), followed by an ATP-producing pathway initiated by the CoA-acylating propionaldehyde dehydrogenase (PduP). The pduP gene of L. reuteri was cloned and expressed in Escherichia coli and the recombinant enzyme was purified to homogeneity for characterization of its activity and properties. Kinetic studies with propionaldehyde as substrate showed a maximum specific activity of 28.9U/mg, which is 80-fold higher than that reported previously. Maximum activity of 18U/mg was obtained at 3-HPA concentration of 7mM, above which substrate inhibition was observed. Substrate inhibition was also seen with coenzyme A at a concentration above 0.5mM and with NADP(+) above 9mM. A structure of PduP is proposed based on homology modeling. In silico docking of the co-factors coenzyme A and NAD(+), respectively, showed a common binding site consisting of amino acids Thr145, Ile275, Cys277 and Ser417, which through site-directed mutagenesis to alanine and kinetic studies, were confirmed as essential for the catalytic activity of PduP. 23844985 Decreased plasma concentrations of brain-derived neurotrophic factor (BDNF) in patients with functional hypothalamic amenorrhea. Abstract Introduction: Functional hypothalamic amenorrhea (FHA) is a non organic, secondary amenorrhea related to gonadotropin-releasing hormone pulsatile secretion impairment. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of survival-promoting molecules, plays an important role in the growth, development, maintenance and function of several neuronal systems. Aim of the study: The aim of the study was the evaluation of plasma BDNF concentrations in patients with the diagnosis of FHA. Material and methods. We studied 85 subjects diagnosed with FHA who were compared with 10 healthy, eumenorrheic controls with normal body mass index. Plasma BDNF and serum luteinizing hormone, follicle-stimulating hormone and estradiol (E2) concentrations were measured by immunoenzymatic method (enzyme-linked immunosorbent assay). Results: Significantly lower concentration of plasma BDNF was found in FHA patients (196.31 ± 35.26 pg/ml) in comparison to healthy controls (407.20 ± 25.71 pg/ml; p < 0.0001). In the control group, there was a strong positive correlation between plasma BDNF and serum E2 concentrations (r = 0.92, p = 0.0001) but in FHA group it was not found. Conclusions: Role of BDNF in FHA is not yet fully understood. There could be found studies concerning plasma BDNF concentrations in humans and animals in the literature. However, our study is one of the first projects which describes decreased plasma BDNF concentration in patients with diagnosed FHA. Therefore, further studies on BDNF in FHA should clarify the role of this peptide. 23706765 An increased diversity of HCV isolates were characterized among 393 patients with liver disease in China representing six genotypes, 12 subtypes, and two novel genotype 6 variants. We have recently determined HCV isolates among volunteer blood donors and IDUs in southern China and revealed the genotype distribution patterns not only different between the two studied cohorts but also from what we have sampled in 2002. A changed pattern could have also occurred among patients with liver disease. Both E1 and NS5B sequences of HCV were characterized among 393 patients with liver disease followed by phylogenetic analysis. Six HCV genotypes, 12 subtypes (1b: 65.9%, 6a: 17.1%, 2a: 7.4%, 3a: 3.6%, 3b: in 3.3%, 6e: 0.76%, and 1a, 1c, 2b, 2f, 4d, and 5a each 0.25%), and two novel genotype 6 variants were classified, showing the greatest complexity of HCV hitherto found in China. Although the predominance of 1b followed by 6a is largely consistent with what we have sampled in 2002, the identification of single isolates of 1c, 2f, 4d, 5a, and two novel HCV-6 variants were first reported. Excluding 4d from a European visitor, all the others were from Chinese patients. Since the 6a proportion (17.1%, 67/393) was unexpectedly lower than what we have recently detected among blood donors (34.8%, 82/236) and IDUs (51.5%, 70/136), further statistical analyses were conducted. Comparison of the mean ages showed that among the 393 patients, those infected with 1b were significantly (6.7 years) older than those with 6a, while the 393 patients as a whole were significantly older than the 236 blood donors (8.4 years) and 136 IDUs (12.6 years) we have recently reported. Explanations are that younger individuals had higher proportions of 6a infections while patients with liver disease could have acquired their infections earlier than volunteer blood donors and IDUs. Among 393 patients with liver disease, a great diversity in HCV was detected, which reflects a constantly changing pattern of HCV genotypes in China over time. 23647016 Significant spatial aggregation and fine-scale genetic structure in the homosporous fern Cyrtomium falcatum (Dryopteridaceae). Spores of homosporous ferns are small, wind-borne and thus have the potential for long-distance dispersal. This common perception has led to a prediction of near-random spatial genetic structure within fern populations. Spore dispersal and spore bank studies, however, indicate that most spores fall close to the maternal plant (< 5 m), supporting a prediction of significant fine-scale genetic structure (FSGS) within populations. To determine which of these two hypotheses is more likely to occur in nature, we measured inbreeding and quantified the spatial distribution of individuals and allozyme-based genotypes using spatial autocorrelation methods within four populations of the fern Cyrtomium falcatum in southern South Korea. Inbreeding levels were low, and all populations exhibited significant aggregation of individuals and strong FSGS. The present results support the second hypothesis, and the substantial FSGS in C. falcatum could reflect the unique features of most homosporous ferns (outcrossing mating systems that lead a majority of spores to occur at short distances and a very limited dispersal distance of male gametes). Although fern spores are physically analogous to orchid seeds, the intensity of FSGS exhibited in C. falcatum is four times stronger than that in 16 terrestrial orchid species. 23946517 Application of a newly-developed high sensitivity HBsAg chemiluminescent enzyme immunoassay for hepatitis B patients with HBs Ag seroclearance. Background: We modified and automated a highly sensitive chemiluminescent enzyme immunoassay (CLEIA) for surface antigen (HBsAg) detection using a combination of monoclonal antibodies, each for a specific epitope of HBsAg, and by improving the earlier conjugation technique. Methods: Of 471 HBV carriers seen 2009-2012 in our hospital, 26 were HBsAg-seronegative by Abbott ARCHITECT. Lumipulse HBsAg-HQ was used to re-check those 26 patients that demonstrated seroclearance by Abbott ARCHITECT. Results: Lumipulse HBsAg-HQ performance was compared with a quantitative HBsAg detection system (Abbott ARCHITECT) and the Roche COBAS TaqMan HBV-DNA assay (CTM, lower limit of detection 2.1 log copies/ml) using serum samples from patients determined to be HBsAg-seronegative by Abbott ARCHITECT. Results: Ten patients had spontaneous HBsAg loss. Of 8 patients treated with nucleotide analogues (NA), two were HBsAg-seronegative after stopping lamivudine therapy, and 6 during entecavir therapy. Eight acute hepatitis B (AH) patients became HBsAg-seronegative. Of all 26 patients, 16 were HBsAg-positive by Lumipulse HBsAg-HQ but negative by Abbott ARCHITECT. Differences between the two assays in detectable HBsAg persisted long-term in the spontaneous loss group (median 10 months), followed by the NA-treated group (2.5 months) and the AH group (0.5 months). In 9 patients, Lumipulse HBsAg-HQ detected HBsAg when HBV DNA was negative by CTM. HBsAg was also detected by Lumipulse HBsAg-HQ in 4 patients with anti-HBs above 10 mIU/ml, 3 of whom had no HBsAg escape mutations. Conclusions: The automatic highly sensitive HBsAg CLEIA Lumipulse HBsAg-HQ is a convenient and precise assay for HBV monitoring. 23702285 Placing the power of real options analysis into the hands of natural resource managers - taking the next step. This paper explores heuristic methods with potential to place the analytical power of real options analysis into the hands of natural resource managers. The complexity of real options analysis has led to patchy or ephemeral adoption even by corporate managers familiar with the financial-market origins of valuation methods. Intuitively accessible methods for estimating the value of real options have begun to evolve, but their evaluation has mostly been limited to researcher-driven applications. In this paper we work closely with Bush Heritage Australia to evaluate the potential of real options analysis to support the intuitive judgement of conservation estate managers in covenanting land with uncertain future conservation value due to climate change. The results show that modified decision trees have potential to estimate the option value of covenanting individual properties while time and ongoing research resolves their future conservation value. Complementing this, Luehrman's option space has potential to assist managers with limited budgets to increase the portfolio value of multiple properties with different conservation attributes. 23665565 Cosmogenic (7)Be and (22)Na in ground level air in Switzerland (1994-2011). We report monthly averages of weekly (7)Be and (22)Na concentrations in aerosol samples collected with high volume aerosol filters at 5 sampling sites in Switzerland from 1994 to 2011 ((7)Be) and from 2000 to 2011 ((22)Na). Monthly average concentrations of the two cosmogenic isotopes varied between 2600 and 4600 Î¼Bq/m(3) for (7)Be and between 0.2 Î¼Bq/m(3) and 0.5 Î¼Bq/m(3) for (22)Na. The (22)Na concentration in ground level air strongly increased from March to May, while a corresponding (7)Be increase was seen from March until July. The observed variations of the (7)Be and (22)Na activities together with the changes in the (7)Be/(22)Na ratio indicate input of stratospheric air between March and May, increased mixing of upper tropospheric air from June to August, and less exchange between the upper and lower troposphere in autumn and winter. Additionally, the 11-year solar cycle is clearly seen in the annual averages of the (7)Be concentrations. 23550693 Decreased Peripheral Blood CD4(+) /CD25(+) Regulatory T Cells in Patients with Alcoholic Hepatitis. Development of alcoholic hepatitis (AH) may be favored by the activation of the innate immune response. Recently, decreased numbers of circulating regulatory T cells (Tregs) have been reported in diseases associated with an immune activation status, but no studies have focused so far, in investigating the distribution of Tregs in chronic alcoholism and its potential association with liver disease. Here, we analyzed for the first time the frequency of peripheral blood (PB) Tregs and Treg subsets in AH and its relationship with the production of inflammatory cytokines by PB monocytes and dendritic cells (DCs). PB samples from 25 male patients with AH were studied; in parallel, 15 male chronic alcoholic patients without liver disease (AWLD) and 17 male healthy donors were also studied, as controls. The distribution of CD4(+) CD25(hi) CD127(-/lo) Tregs and their maturation subsets (naïve, central memory, and peripheral memory Tregs) was analyzed by flow cytometry. Spontaneous and in vitro-stimulated production of inflammatory cytokines by PB monocytes and DCs was analyzed by flow cytometry at the cytoplasmic level. Patients with AH showed decreased (p < 0.05) numbers of PB CD4(+) CD25(hi) CD127(-/lo) Tregs at the expense of all maturation-associated subsets, while AWLD and healthy subjects showed a similar (p > 0.05) distribution of PB CD4(+) CD25(hi) CD127(-/lo) Tregs. Interestingly, significantly increased amounts of spontaneously produced inflammatory cytokines were found among circulating monocyte-derived DCs and monocytes from AH (and AWLD) patients in comparison with healthy donors. Conversely, the ability of these cell subsets to produce cytokines after in vitro stimulation was lower (p < 0.05) in AH versus the 2 control groups. PB CD4(+) CD25(hi) CD127(-/lo) Tregs are significantly decreased in patients with AH when compared to both healthy and AWLD; this may contribute to explain the more pronounced activation of the innate immune response observed in AH, as reflected by an increased secretion of inflammatory cytokines by PB DCs and monocytes, and could facilitate the development of liver disease. 23839318 The effects of intrathecal and systemic adjuvants on subarachnoid block. Various intrathecal and systemic adjuvants to local anaesthetics have been found to improve the quality and extend the duration of spinal block. Intrathecal opioids are the most frequently used; the lipophilic fentanyl and sufentanil enhance and moderately prolong the sensory block, whereas the hydrophilic morphine significantly prolongs spinal analgesia. Nausea/vomiting, pruritus, urinary retention and respiratory depression are possible side effects. Adrenergic agonists, such as adrenaline and phenylephrine may prolong the block due to vasoconstriction, while clonidine and dexmedetomidine accelerate the onset and prolong the duration of block and analgesia. Hypotension, sedation and respiratory depression have been reported with clonidine. Other intrathecal adjuvants, such as midazolam, ketamine and neostigmine may also improve the quality of block and prolong analgesia, but are not popular because of their adverse effects. Intrathecal magnesium sulphate mainly potentiates the analgesic action of intrathecal opioids, without significant side effects. A positive impact on spinal analgesia has also been suggested -from animal studies- for intrathecal calcium channel blockers, while the analgesic efficacy of intrathecal nonsteroidal anti-inflammatory drugs remains questionable. Several drugs may also affect the spinal block characteristics after systemic administration. Opioids enhance, alpha-2 agonists and ketamine prolong the block, magnesium sulphate reduces postoperative analgesic consumption and nimodipine may delay the regression of sensory block. Nitrous oxide inhalation has also been found to enhance the level of sensory spinal block. Even though opioids are the most popular adjuvants to spinal local anaesthetics, a variety of drugs given intrathecally or systemically, can accelerate, improve and extend the spinal block. Key words: Adjuvants, Anaesthesia; Anaesthesia, Spinal; Intrathecal Injections; Intravenous Injections. 22859796 A Phase 2, randomized, partially blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes: results of the RADAR trial. We sought to determine the degree of anticoagulation reversal required to mitigate bleeding, and assess the feasibility of using pegnivacogin to prevent ischaemic events in acute coronary syndrome (ACS) patients managed with an early invasive approach. REG1 consists of pegnivacogin, an RNA aptamer selective factor IXa inhibitor, and its complementary controlling agent, anivamersen. REG1 has not been studied in invasively managed patients with ACS nor has an optimal level of reversal allowing safe sheath removal been defined. Non-ST-elevation ACS patients (n = 640) with planned early cardiac catheterization via femoral access were randomized 2:1:1:2:2 to pegnivacogin with 25, 50, 75, or 100% anivamersen reversal or heparin. The primary endpoint was total ACUITY bleeding through 30 days. Secondary endpoints included major bleeding and the composite of death, myocardial infarction, urgent target vessel revascularization, or recurrent ischaemia. Enrolment in the 25% reversal arm was suspended after 41 patients. Enrolment was stopped after three patients experienced allergic-like reactions. Bleeding occurred in 65, 34, 35, 30, and 31% of REG1 patients with 25, 50, 75, and 100% reversal and heparin. Major bleeding occurred in 20, 11, 8, 7, and 10% of patients. Ischaemic events occurred in 3.0 and 5.7% of REG1 and heparin patients, respectively. At least 50% reversal is required to allow safe sheath removal after cardiac catheterization. REG1 appears a safe strategy to anticoagulate ACS patients managed invasively and warrants further investigation in adequately powered clinical trials of patients who require short-term high-intensity anticoagulation. Clinical Trials Registration: ClinicalTrials.gov NCT00932100. 23845894 Non confirmatory electroencephalography in patients meeting clinical criteria for brain death: Scenario and impact on organ donation. To describe the causes and outcome of adult patients with preserved electroencephalographic activity despite clinical findings suggesting brain death (BD), and its impact on organ donation. Retrospective study of the clinical and electroencephalography (EEG) data of all adult patients admitted to our hospital between January 2001 and December 2011 in whom a comprehensive clinical diagnosis of BD was reached following absence of brainstem reflexes and confirmatory apnea tests, were obtained. All patients with clinical findings suggesting BD and an EEG showing brain activity were selected for the analysis. We calculated the brain death interval (BDI) as the time between the first complete clinical examination and confirmatory ancillary test, or the time between the first and second complete clinical examination for BD, in order to analyze the impact on family consent for organ donation. A complete clinical examination and EEG were diagnostic in 289 patients. In 279 (96.5%), the first EEG showed electrocerebral inactivity corroborating the clinical findings of BD. The mean BDI in this group was 4.2±5.8h (median; 1.8[1.0-3.5]). This value was significantly lower than in the group in which only two full clinical evaluations were performed (p<0.0001). In 10 out 289 (3.5%), the first EEG showed at least some brain activity. The mean BDI in this group was 27.2±13.8h (median; 22.9 [19.1-31.2]). In two cases, a third EEG was necessary before obtaining electrocerebral inactivity. A BDI>6h, was positively associated with a family refusal for organ donation (p=0.02). The rate of EEGs with electrocerebral activity despite clinical findings suggesting BD was only 3.5%. It occurred most frequently with severe brainstem damage. Although in this small percentage of patients, BD diagnosis was notably delayed, in the great majority of cases the use of EEG shortened the BDI. In our series, a BD diagnosis delay >6h negatively affected consent for organ donation. The use of EEG can decrease the time interval for brain death diagnosis. 23612320 Nonhuman primate retroviruses from Cambodia: High simian foamy virus prevalence, identification of divergent STLV-1 strains and no evidence of SIV infection. Nonhuman primates (NHPs) carry retroviruses such as simian immunodeficiency viruses (SIV), simian T-cell lymphotropic viruses (STLV) and simian foamy viruses (SFV). Here, we revisited NHPs from Cambodia to assess the prevalence and diversity of these retroviruses using updated viral detection tools. We screened blood from 118 NHPs consisting of six species (Macaca fascicularis (n=91), Macaca leonine (n=8), Presbytis cristata (n=3), Nycticebus coucang (n=1), Hylobates pileatus (n=14), and Pongo pygmaeus) (n=1) by using a Luminex-based multiplex serology assay that allows the detection of all known SIV/HIV and SFV lineages. We also used highly sensitive PCR assays to detect each simian retrovirus group. Positive PCR products were sequenced and phylogenetically analyzed to infer evolutionary histories. Fifty-three of 118 (44.9%) NHPs tested positive for SFV by serology and 8/52 (15.4%), all from M. fascicularis, were PCR-confirmed. The 8 novel SFV sequences formed a highly supported distinct lineage within a clade composed of other macaque SFV. We observed no serological or molecular evidence of SIV infection among the 118 NHP samples tested. Four of 118 (3.3%) NHPs were PCR-positive for STLV, including one M. fascicularis, one P. cristata, and two H. pileatus. Phylogenetic analyses revealed that the four novel STLV belonged to the PTLV-1 lineage, outside the African radiation of PTLV-1, like all Asian PTLV identified so far. Sequence analysis of the whole STLV-1 genome from a H. pileatus (C578_Hp) revealed a genetic structure characteristic of PTLV. Similarity analysis comparing the STLV-1 (C578_Hp) sequence with prototype PTLVs showed that C578_Hp is closer to PTLV-1s than to all other types across the entire genome. In conclusion, we showed a high frequency of SFV infection but found no evidence of SIV infection in NHPs from Cambodia. We identified for the first time STLV-1 in a P. cristata and in two H. pileatus. 23861852 Epo receptors are not detectable in primary human tumor tissue samples. Erythropoietin (Epo) is a cytokine that binds and activates an Epo receptor (EpoR) expressed on the surface of erythroid progenitor cells to promote erythropoiesis. While early studies suggested EpoR transcripts were expressed exclusively in the erythroid compartment, low-level EpoR transcripts were detected in nonhematopoietic tissues and tumor cell lines using sensitive RT-PCR methods. However due to the widespread use of nonspecific anti-EpoR antibodies there are conflicting data on EpoR protein expression. In tumor cell lines and normal human tissues examined with a specific and sensitive monoclonal antibody to human EpoR (A82), little/no EpoR protein was detected and it was not functional. In contrast, EpoR protein was reportedly detectable in a breast tumor cell line (MCF-7) and breast cancer tissues with an anti-EpoR polyclonal antibody (M-20), and functional responses to rHuEpo were reported with MCF-7 cells. In another study, a functional response was reported with the lung tumor cell line (NCI-H838) at physiological levels of rHuEpo. However, the specificity of M-20 is in question and the absence of appropriate negative controls raise questions about possible false-positive effects. Here we show that with A82, no EpoR protein was detectable in normal human and matching cancer tissues from breast, lung, colon, ovary and skin with little/no EpoR in MCF-7 and most other breast and lung tumor cell lines. We show further that M-20 provides false positive staining with tissues and it binds to a non-EpoR protein that migrates at the same size as EpoR with MCF-7 lysates. EpoR protein was detectable with NCI-H838 cells, but no rHuEpo-induced phosphorylation of AKT, STAT3, pS6RP or STAT5 was observed suggesting the EpoR was not functional. Taken together these results raise questions about the hypothesis that most tumors express high levels of functional EpoR protein. 23554292 Amorphous Ni(OH)2 Nanoboxes: Fast Fabrication and Enhanced Sensing for Glucose. Inspired by Pearson's hard and soft acid-base (HSAB) principle, uniform amorphous Ni(OH)2 nanoboxes with intact shell structures and various sizes are quickly fabricated by deliberately selecting S2 O3 (2-) as the coordinating etchant toward Cu2 O templates and optimizing the reaction conditions. It is found that not only the solvent system but also the employing of a surfactant is vital for the fabrication of the nanoboxes. Ni(OH)2 nanoboxes, as an example, demonstrate an improved electrochemical sensing ability for glucose, which might be due to their amorphous and hollow structural features. 23934347 ASSESSMENT OF NATURAL AND ANTHROPOGENIC RADIOACTIVITY LEVELS IN SOILS, ROCKS AND WATER IN THE VICINITY OF CHIRANO GOLD MINE IN GHANA. Studies have been carried out within and around the operational area of the Chirano Gold Mine Ltd of Ghana to ascertain the baseline radioactivity levels of naturally occurring radioactive materials as well as artificial radionuclides in the surface and underground mines. The analysis was carried out by using gamma spectrometry to quantify the radionuclides of interest, namely (238)U, (232)Th, (137)Cs and (40)K in soil, ore, waste rock and water samples. The average activity concentrations of (238)U, (232)Th, (40)K and (137)Cs in the soil/rock samples were 9.79±5.39, 9.18±7.06, 237.40±144.34 and 0.64±0.57 Bq kg(-1), respectively. For the water samples, the average activity concentrations were 0.86±0.67, 0.97±1.33 and 9.05±10.45 Bq l(-1) for (226)Ra, (232)Th and (40)K, respectively. The total annual effective dose to the public was estimated to be 0.13 mSv, which is below the International Commission on Radiological Protection recommended level of 1 mSv for public exposure control. The study also assessed the elemental concentrations of U, Th and K in the soil/rock samples from the gold mine and surrounding communities. The average concentrations of the U, Th and K were 0.82±0.48, 2.18±1.77 µg g(-1) and 0.77±0.47 %, respectively. The concentrations of U, Th and K were variable in soil and rock samples taken from different locations in the study area with values varying in the range 0.28-2.21, 0.24-6.50 µg g(-1) and 0.28-1.87 %, respectively. The concentrations of U, Th and K are far lower than the world average values but comparable with the range of similar studies for different countries. The concentration values of gross-alpha and gross-beta for all the water samples were below the Ghana Standards Authority and World Health Organisation recommended guideline values for drinking water quality. The results obtained in this study also show that radiation levels are within the natural background radiation levels found in the literature and compare well with those of similar studies for other countries including Ghana. 23420664 Microengineered PEG Hydrogels: 3D Scaffolds for Guided Cell Growth. Designing three-dimensional (3D) scaffolds for selective manipulation of cell growth is of high relevance for applications in regenerative medicine. Especially, scaffolds with oriented morphologies bear high potential to guide the restoration of specific tissues. The fabrication of hydrogel scaffolds that support long-term survival, proliferation, and unidirectional growth of embedded cells is presented here. Parallel channel structures are introduced into the bulk hydrogels by uniaxial freezing, providing stable, and uniform porosity suitable for cell invasion (pore diameters of 5-15 µm). In vitro assessment of the scaffolds with murine fibroblasts (NIH L929) shows a remarkable unidirectional movement along the channels, with the cells traveling several millimeters through the hydrogel. 23354545 A prospective study of selenium concentration and risk of preeclampsia in pregnant Iranian women: a nested case-control study. Preeclampsia remains a leading cause of maternal and perinatal mortality and morbidity worldwide; however, its specific etiology still remains obscure. Some studies implicate poor maternal selenium status predisposing the mother to preeclampsia. This study was designed to determine changes in plasma selenium levels in women having preeclampsia as compared with those with normal pregnancy. In a nested case-control study, 650 normal primigravida in their first 24-28 weeks participated in the study. After 3 months of follow-up of all subjects, blood selenium levels were measured in 38 women presenting consecutively with preeclampsia and in 38 women having a normal pregnancy by atomic absorption spectrophotometry. Birth outcomes were recorded, such as gestational age at delivery, height, weight, birth head circumflex and 1-min Apgar score. Preeclampsia affects about 5.84 % of pregnancies, and in our study, there were no significant differences in age, anthropometric indices, and family history of preeclampsia between the preeclamptic and control groups. The selenium concentrations in plasma in women with preeclampsia were significantly lower as compared with those in women with normal pregnancy (70.63 ± 21.41 versus 82.03 ± 15.54 μg/L, p < 0.05). Being in the bottom tertile of selenium concentration (less than 62.2 μg/L) was associated with greater risk of preeclampsia in pregnant women. The reduced selenium in the maternal circulations observed in the preeclamptic mothers support the hypothesis that insufficient selenium concentration may be a contributing factor to the pathophysiological mechanisms associated with preeclampsia, and optimizing the dietary selenium intake through supplementation could produce demonstrable clinical benefits. 23940492 Erythrodermic mycosis fungoides with hypereosinophilic syndrome: a rare presentation. Mycosis fungoides (MF) is the most common variant of primary cutaneous T-cell lymphoma (CTCL). It is generally associated with an indolent clinical course and characterised by well-defined clinicopathological features. Although rare, CTCLs constitute 65% of all cutaneous lymphoid malignancies, of which 50% are patients with MF. The erythrodermic variants of MF, a malignancy of mature, skin homing and clonal T lymphocytes, usually present in mid to late adulthood. Association with hypereosinophilia is important in prognosis. We report a case of erythrodermic MF with hypereosinophilic syndrome in a 22-year-old female presenting with gradually progressive intractable erythroderma with intensely pruritic multiple papules, plaques, and nodules involving more than 90% of body surface area. Diagnosis was confirmed by histopathological examination and immunophenotyping from multiple skin biopsies. 23856655 Biomechanical constraints remain major risk factors for low back pain. Results from a prospective cohort study in French male employees. Low back pain (LBP) is a major public health problem, with a considerable impact on workers. To model the risk of LBP in the male general working population. Repeated cross-sectional surveys in a wide occupational setting. A random sample of 2,161 men working in various occupations in a French region participated in a first survey in 2002, and 1,313 of these (60.8%) participated in a second survey in 2007. The self-reported prevalence of LBP during the previous week in the second survey. Twenty-one biomechanical, organizational, psychosocial, and individual factors were assessed in the first survey. The association between these potential risk factors and the prevalence of later LBP (in the second survey) was studied, using multistep logistic regression models. Three hundred ninety-four men reported LBP in the second survey (prevalence 30.0%). The final multivariate model highlighted four risk factors: frequent bending (odds ratio [OR], 1.45, 95% confidence interval [CI], 1.07-1.97 for bending forward only; and OR, 2.13, 95% CI, 1.52-3.00 for bending both forward and sideways), driving industrial vehicles (OR, 1.35; 95% CI, 1.00-1.81), working more hours than officially planned (OR, 1.38; 95% CI, 1.05-1.81), and reported low support from supervisors (OR, 1.35; 95% CI, 1.02-1.79). These results emphasize that biomechanical factors remain worth considering, even when psychosocial factors are taken into account, and provide a significant contribution to preventive strategies. 23844120 Structure-Guided Modification of Rhizomucor miehei Lipase for Production of Structured Lipids. To improve the performance of yeast surface-displayed Rhizomucor miehei lipase (RML) in the production of human milk fat substitute (HMFS), we mutated amino acids in the lipase substrate-binding pocket based on protein hydrophobicity, to improve esterification activity. Five mutants: Asn87Ile, Asn87Ile/Asp91Val, His108Leu/Lys109Ile, Asp256Ile/His257Leu, and His108Leu/Lys109Ile/Asp256Ile/His257Leu were obtained and their hydrolytic and esterification activities were assayed. Using Discovery Studio 3.1 to build models and calculate the binding energy between lipase and substrates, compared to wild-type, the mutant Asp256Ile/His257Leu was found to have significantly lower energy when oleic acid (3.97 KJ/mol decrease) and tripalmitin (7.55 KJ/mol decrease) were substrates. This result was in accordance with the esterification activity of Asp256Ile/His257Leu (2.37-fold of wild-type). The four mutants were also evaluated for the production of HMFS in organic solvent and in a solvent-free system. Asp256Ile/His257Leu had an oleic acid incorporation of 28.27% for catalyzing tripalmitin and oleic acid, and 53.18% for the reaction of palm oil with oleic acid. The efficiency of Asp256Ile/His257Leu was 1.82-fold and 1.65-fold that of the wild-type enzyme for the two reactions. The oleic acid incorporation of Asp256Ile/His257Leu was similar to commercial Lipozyme RM IM for palm oil acidolysis with oleic acid. Yeast surface-displayed RML mutant Asp256Ile/His257Leu is a potential, economically feasible catalyst for the production of structured lipids. 23824373 Matrix-assisted laser desorption ionization-time of flight mass spectrometry: a fundamental shift in the routine practice of clinical microbiology. Within the past decade, clinical microbiology laboratories experienced revolutionary changes in the way in which microorganisms are identified, moving away from slow, traditional microbial identification algorithms toward rapid molecular methods and mass spectrometry (MS). Historically, MS was clinically utilized as a high-complexity method adapted for protein-centered analysis of samples in chemistry and hematology laboratories. Today, matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) MS is adapted for use in microbiology laboratories, where it serves as a paradigm-shifting, rapid, and robust method for accurate microbial identification. Multiple instrument platforms, marketed by well-established manufacturers, are beginning to displace automated phenotypic identification instruments and in some cases genetic sequence-based identification practices. This review summarizes the current position of MALDI-TOF MS in clinical research and in diagnostic clinical microbiology laboratories and serves as a primer to examine the "nuts and bolts" of MALDI-TOF MS, highlighting research associated with sample preparation, spectral analysis, and accuracy. Currently available MALDI-TOF MS hardware and software platforms that support the use of MALDI-TOF with direct and precultured specimens and integration of the technology into the laboratory workflow are also discussed. Finally, this review closes with a prospective view of the future of MALDI-TOF MS in the clinical microbiology laboratory to accelerate diagnosis and microbial identification to improve patient care. 23508278 Endometrial cancer: preoperative staging using three-dimensional T2-weighted turbo spin-echo and diffusion-weighted MR imaging at 3.0 T: a prospective comparative study. To prospectively assess the efficacy of 3-T magnetic resonance (MR) imaging using the three-dimensional turbo spin-echo T2-weighted and diffusion-weighted technique (3D-TSE/DW) compared with that of conventional imaging using the two-dimensional turbo spin-echo T2-weighted and dynamic contrast-enhanced technique (2D-TSE/DCE) for the preoperative staging of endometrial cancer, with pathological analysis as the reference standard. Seventy-one women with endometrial cancer underwent MR imaging using 3D-TSE/DW (b = 1,000 s/mm(2)) and 2D-TSE/DCE. Two radiologists independently assessed the two imaging sets. Accuracy, sensitivity, and specificity for staging were analysed with the McNemar test; the areas under the receiver operating characteristic curve (Az) were compared with a univariate z-score test. The results for assessing deep myometrial invasion, accuracy, sensitivity, specificity and Az, respectively, were as follows: 3D-TSE/DW-observer 1, 87 %, 95 %, 85 % and 0.96; observer 2, 92 %, 84 %, 94 % and 0.95; 2D-TSE/DCE-observer 1, 80 %, 79 %, 81 % and 0.89; observer 2, 86 %, 84 %, 87 % and 0.86. Most of the values were higher with 3D-TSE/DW without significant differences (P > 0.12). For assessing cervical stromal invasion, there were no significant differences in those values for both observers (P > 0.6). Accuracy of 3D-TSE/DW was at least equivalent to that of the conventional technique for the preoperative assessment of endometrial cancer. • New techniques in MR imaging help assess patients with endometrial cancer. • A 3D T2-weighted TSE sequence seems equally as accurate as conventional techniques. • Three-dimensional TSE/DW imaging does not require intravenous contrast material and is relatively quick. • Tumour extent of endometrial cancer can be clearly shown on diffusion-weighted images. • Junctional zone can be visualised well on 3D-TSE T2-weighted images. 23806327 Analyses of direct and indirect impacts of a positive list system on pharmaceutical r&d investments. The South Korean government recently enacted a Positive List System (PLS) as a major change of the national formulary listing system and reimbursed prices for pharmaceutical products. Regardless of the primary goal of the PLS, its implementation might have spillover effects by influencing the pharmaceutical industry's research and development (R&D), potentially leading to a variety of responses by firms in relation to their R&D activities. We investigated the spillover effect of the PLS on R&D investments of the pharmaceutical industry in Korea through both direct and indirect channels, examining the influence of the PLS on sales profit and cash flow. Data from 9 years (5 before and 4 after PLS implementation) were drawn from the financial statements of firms whose stocks were exchanged in 2 official stock markets in Korea (526 firms) and additional pharmaceutical firms whose financial performance was officially audited by external reviewers (263 firms). Longitudinal analyses were conducted, using the panel nature of the data to control for permanent unobserved firm heterogeneity. Our results showed that the PLS was directly associated with R&D investments. In contrast, its indirect impacts stemming from the influence on sales profit and cash flow were minimal and statistically nonsignificant. The gross impact of the PLS on R&D investments increased moving further from the enactment year; R&D investments were reduced by 18.3% to 25.8% in 2009-2010 (compared with before PLS implementation) in the firm fixed-effects model. We also found that such negative direct and gross impacts of the PLS on R&D investments were significant only in firms without newly developed chemical entities. Considering the gross negative impact of the PLS on R&D investments of pharmaceutical firms and the heterogeneous response of these firms by the R&D activities, governmental efforts of cost-containment may need to consider the spillover impact of the PLS on pharmaceutical innovation. 23929255 Psycho-behavioral changes in children with type 1 diabetes mellitus. Type 1 diabetes mellitus (T1DM) is the most common type of diabetes in children. This study aimed to investigate psycho-behavioral changes in Chinese children with T1DM and to provide some advices for nurses, parents and other persons. Forty-five patients with T1DM (26 boys and 19 girls with a mean age of 10.40±3.01 years) were enrolled. According to the glycosylated hemoglobin levels recommended by the American Diabetes Association, the patients were subdivided into a well-controlled group and a poorly-controlled group. Fifty-three healthy children served as a control group. Psycho-behavioral changes were investigated by using Achenbach's Child Behavior Check List. Compared with the control group, the patients with T1DM had significantly higher mean scores for withdrawal, anxiety/depression, attention problems, delinquent behavior, aggressive behavior, externalizing problems, and internalizing problems (P<0.017). Moreover, the mean scores for somatic complaints in the poorly-controlled subgroup were significantly higher than those in the well-controlled subgroup (t=3.582, P=0.001). Compared with the control group, the well-controlled subgroup had higher scores for withdrawal, anxiety/depression, and internalizing problems (P<0.017). But the poorly-controlled subgroup had higher scores for withdrawal, somatic complaint, anxiety/depression, delinquent behavior, aggressive behavior, externalizing and internalizing problems (P<0.017). Children with T1DM may have some psycho-behavioral problems. Timely nursing interventions must be conducted to solve these problems. 23894049 Expansion of mesenchymal stem cells under atmospheric carbon dioxide. Stem cells are needed for an increasing number of scientific applications, including both fundamental research and clinical disease treatment. To meet this rising demand, improved expansion methods to generate high quantities of high quality stem cells must be developed. Unfortunately, the bicarbonate buffering system - which relies upon an elevated CO2 environment - typically used to maintain pH in stem cell cultures introduces several unnecessary limitations in bioreactor systems. Not only do artificially high dissolved CO2 levels negatively affect cell growth, but more importantly, the need to sparge CO2 into the system complicates the ability to control culture parameters. This control is especially important for stem cells, whose behavior and phenotype is highly sensitive to changes in culture conditions such as dissolved oxygen and pH. As a first step, this study developed a buffer to support expansion of mesenchymal stem cells (MSC) under an atmospheric CO2 environment in static cultures. MSC expanded under atmospheric CO2 with this buffer achieved equivalent growth rates without adaptation compared to those grown in standard conditions and also maintained a stem cell phenotype, self-renewal properties, and the ability to differentiate into multiple lineages after expansion. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 2013. 23760233 Structure and Receptor Binding Specificity of Hemagglutinin H13 from Avian Influenza A Virus H13N6. Interspecies transmission (host switching/jumping) of influenza viruses is a key scientific question that must be addressed. In addition to the vigorous research on highly pathogenic avian influenza viruses (HPAIVs), studies of the mechanism of interspecies transmission of low-pathogenic avian influenza viruses (LPAIVs) could also provide insights into host tropism and virulence evolution. Influenza A viruses harboring hemagglutinin (HA) H13 (e.g., H13N6) are LPAIVs. In this study, soluble H13 HA glycoprotein was purified, and its receptor binding activity was characterized. The results revealed that H13 exclusively binds the avian α2-3-linked sialic acid receptor; no binding to the mammalian α2-6-linked sialic acid receptor was detected. Furthermore, the molecular basis of the H13 receptor binding specificity was revealed by comparative analysis of the crystal structures of both receptor-bound H13 and H5 HAs, which might be contributed by the hydrophobic residue V186. Work with an H13N186 mutant confirmed the importance of V186 in the receptor binding specificity of H13 HA, which shows that the mutant protein reduced the binding of an avian receptor analog but increased the binding of a human receptor analog. Detailed structural analysis also demonstrated that the conserved binding sites of the recently well-studied broadly neutralizing human monoclonal antibodies targeting the HA2 domain are found in H13. Our results expand our understanding of virulence evolution, receptor binding preference, and species tropism of the LPAIVs and HPAIVs. 23504502 Genetic variants in DNA repair pathway genes and risk of esophageal squamous cell carcinoma and gastric adenocarcinoma in a Chinese population. The DNA repair pathways help to maintain genomic integrity and therefore genetic variation in the pathways could affect the propensity to develop cancer. Selected germline single nucleotide polymorphisms (SNPs) in the pathways have been associated with esophageal cancer and gastric cancer (GC) but few studies have comprehensively examined the pathway genes. We aimed to investigate associations between DNA repair pathway genes and risk of esophageal squamous cell carcinoma (ESCC) and GC, using data from a genome-wide association study in a Han Chinese population where ESCC and GC are the predominant cancers. In sum, 1942 ESCC cases, 1758 GC cases and 2111 controls from the Shanxi Upper Gastrointestinal Cancer Genetics Project (discovery set) and the Linxian Nutrition Intervention Trials (replication set) were genotyped for 1675 SNPs in 170 DNA repair-related genes. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-level associations were determined using the resampling-based adaptive rank-truncated product approach. The DNA repair pathways overall were significantly associated with risk of ESCC (P = 6.37 × 10(-4)), but not with GC (P = 0.20). The most significant gene in ESCC was CHEK2 (P = 2.00 × 10(-6)) and in GC was CLK2 (P = 3.02 × 10(-4)). We observed several other genes significantly associated with either ESCC (SMUG1, TDG, TP53, GTF2H3, FEN1, POLQ, HEL308, RAD54B, MPG, FANCE and BRCA1) or GC risk (MRE11A, RAD54L and POLE) (P < 0.05). We provide evidence for an association between specific genes in the DNA repair pathways and the risk of ESCC and GC. Further studies are warranted to validate these associations and to investigate underlying mechanisms. 23352510 Development of amino-pyrimidine inhibitors of c-Jun N-terminal kinase (JNK): kinase profiling guided optimization of a 1,2,3-benzotriazole lead. A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC(50)=16 and 66 nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation. 23377708 Genetics of type 2 diabetes and potential clinical implications. Type 2 diabetes (T2DM) is a common complex metabolic disorder that has a strong genetic component. Recent advances in genome-wide association studies have revolutionized our knowledge regarding the genetics of T2DM. There are at least 64 common genetic variants that are strongly associated with T2DM. However, the pathophysiologic roles of these variants are mostly unknown and require further functional characterization. The variants identified so far have a small effect size and their added effect explains less than 10 % of the T2DM heritability. The current ongoing whole exome and whole genome studies of T2DM are focused on identifying functionally important rare variants that have a stronger effect. Through these efforts, we will have a better understanding of the genetic architecture of T2DM and its pathophysiology. The potential clinical applications of genetic studies of T2DM include risk prediction, identification of novel therapeutic targets, genetic prediction of efficacy and toxicity of anti-diabetic medications, and eventually optimization of patient care through personalized genomic medicine. We hope further research in genetics of T2DM could aid patient care and improve outcomes of T2DM patients. 23799535 Biodegradable Lipids Enabling Rapidly Eliminated Lipid Nanoparticles for Systemic Delivery of RNAi Therapeutics. In recent years, RNA interference (RNAi) therapeutics, most notably with lipid nanoparticle-based delivery systems, have advanced into human clinical trials. The results from these early clinical trials suggest that lipid nanoparticles (LNPs), and the novel ionizable lipids that comprise them, will be important materials in this emerging field of medicine. A persistent theme in the use of materials for biomedical applications has been the incorporation of biodegradability as a means to improve biocompatibility and/or to facilitate elimination. Therefore, the aim of this work was to further advance the LNP platform through the development of novel, next-generation lipids that combine the excellent potency of the most advanced lipids currently available with biodegradable functionality. As a representative example of this novel class of biodegradable lipids, the lipid evaluated in this work displays rapid elimination from plasma and tissues, substantially improved tolerability in preclinical studies, while maintaining in vivo potency on par with that of the most advanced lipids currently available. 23940041 The Allosteric Role of the AAA+ Domain of ChlD from the Magnesium Chelatase of Synechocystis sp. PCC 6803. Magnesium chelatase is an AAA(+) ATPase that catalyzes the first step in chlorophyll biosynthesis, the energetically unfavorable insertion of a magnesium ion into a porphyrin ring. This enzyme contains two AAA(+) domains, one active in the ChlI protein and one inactive in the ChlD protein. Using a series of mutants in the AAA(+) domain of ChlD, we show that this site is essential for magnesium chelation and allosterically regulates Mg(2+) and MgATP(2-) binding. 23727045 Macrocyclic inhibitors of 3C and 3C-like proteases of picornavirus, norovirus, and coronavirus. The design, synthesis, and in vitro evaluation of the first macrocyclic inhibitor of 3C and 3C-like proteases of picornavirus, norovirus, and coronavirus are reported. The in vitro inhibitory activity (50% effective concentration) of the macrocyclic inhibitor toward enterovirus 3C protease (CVB3 Nancy strain), and coronavirus (SARS-CoV) and norovirus 3C-like proteases, was determined to be 1.8, 15.5 and 5.1 μM, respectively. 23900772 Unilateral mydriasis as the primary sign of neurosyphilis. Syphilis can mimic most ocular disorders, and there is no characteristic to distinguish ocular syphilis from other eye diseases. We report a rare case of a 41-year-old man who presented with an Adie's-like pupil as the only feature of neurosyphilis. The patient met the criteria for the diagnosis of neurosyphilis by the finding of positive cerebrospinal fluid-Venereal Disease Research Laboratory (CSF-VDRL) and CSF-Treponema pallidum particle agglutination tests. The patient was then treated with 2 g intravenous ceftriaxone per day for 15 days because of penicillin allergy. Nine months after anti-syphilitic treatment alone, the diameter of the patient's left pupil reduced from 10 to 5 mm. The CSF-VDRL test was negative. It is highly recommended that any patients with ocular disease that does not respond to the routine treatment should undergo syphilis evaluation to avoid misdiagnosis. 23873632 RANKL inhibition with denosumab does not influence 3-year progression of aortic calcification or incidence of adverse cardiovascular events in postmenopausal women with osteoporosis and high cardiovascular risk. Atherosclerosis and osteoporosis are chronic diseases that progress with age, and studies suggest aortic calcification, an indicator of atherosclerosis, is inversely associated with BMD. The OPG/RANK/RANKL system has been proposed as a shared regulatory system for bone and vasculature. Denosumab (DMAb), a monoclonal antibody against RANKL, improved BMD and reduced fracture risk in the FREEDOM trial. We evaluated whether or not treatment with DMAb influenced progression of aortic calcification (AC) and incidence of cardiovascular (CV) adverse events. We included 2,363 postmenopausal women with osteoporosis (1,142 placebo, 1,221 DMAb), selected from 7,808 participants in the FREEDOM trial (3,906 placebo, 3,902 DMAb), at high risk of CV events according to modified Raloxifene Use for the Heart (RUTH) criteria. CV adverse events were reported by participants. AC scores were assessed using a semi-quantitative method from lateral spine x-rays. Change in AC score from baseline to 12 (N = 1,377), 24 (N = 1,231) and 36 months (N = 1,045) was calculated as AC score at follow-up minus AC score at baseline. AC progression was defined as change in AC score > 0. Baseline characteristics, CV risk factors, and AC scores were similar between treatment groups. Mean age of participants was 74 years (range, 60-90), 88% were white, and 77% had AC score > 0 at baseline. Frequency of AC progression over 3 years did not differ between women in placebo (22%) and DMAb (22%) groups (p = 0.98). AC progression did not differ between treatment groups when analyzed by baseline estimated glomerular filtration rate or by baseline AC scores. Frequency of CV adverse events did not differ between placebo (40%) and DMAb (38%) groups (p = 0.26). In conclusion, DMAb treatment had no effect on progression of AC or incidence of CV adverse events compared to placebo. 23335183 Relationships between age of puberty onset and height at age 18 years in girls and boys. Changes during puberty may influence final adult height. Height is related to multiple health conditions, including lung function. We investigated the association between the age of onset of five puberty events and height at age 18 years, analyzing boys and girls separately. Of 1456 children recruited into the Isle of Wight birth cohort (1989-1990), 1313 were followed up at age 18 years. Height was measured, and age of pubertal onset was collected at age 18 years. Cluster analysis was performed on the five puberty events in boys and girls and linear regression was applied with the clusters predicting height at age 18 years. Individual linear regression analyses assessed the age of onset of each pubertal event as a potential predictor for height at age 18 years. Of the 1313 children followed up at age 18 years, 653 were males and 660 were females. All puberty variables had high internal consistency. In girls, earlier age of menarche, breast development, and growth spurt were related to shorter height. In boys, earlier age of growth spurt and slower progression through puberty were related to taller height at age 18 years. Given that boys and girls may have opposing associations between pubertal timing and adult height and that height is an important predictor of lung function, the effect of pubertal timing on respiratory health should be explored. 23870843 Economic Impact of Advanced Pediatric Cancer on Families. Despite emerging evidence of substantial financial distress in families of children with complex illness, little is known about economic hardship in families of children with advanced cancer. To describe perceived financial hardship, work disruptions, income losses, and associated economic impact in families of children with advanced cancer stratified by federal poverty level (FPL). Cross-sectional survey of 86 parents of children with progressive, recurrent, or nonresponsive cancer at three children's hospitals. Seventy-one families with complete income data (82%) are included in this analysis. Parental work disruptions were prevalent across all income levels, with 67 (94%) families reporting some disruption. At least one parent quit a job because of the child's illness in 29 (42%) families. Nineteen (27%) families described their child's illness as a great economic hardship. Income losses because of work disruptions were substantial for all families; families at or below 200% FPL, however, were disproportionately affected. Six (50%) of the poorest families lost more than 40% of their annual income as compared with two (5%) of the wealthiest families (P = 0.006). As a result of income losses, nine (15%) previously nonpoor families fell from above to below 200% FPL. The economic impact of pediatric advanced cancer on families is significant at all income levels, although poorer families suffer disproportionate losses. Development of ameliorative intervention strategies is warranted. 23669867 Multiple sclerosis and mitochondrial gene variations: a review. Multiple sclerosis (MS) is a debilitating disease of the central nervous system. Its etiology is still an unanswered enigma; its symptoms are varied and unpredictable; and there is no cure for it. Genetics has been introduced as a contributing factor to MS. Not only may MS stem from nuclear gene variations/mutations, but also it may arise from mitochondrial gene variations/mutations. The association of mitochondrial DNA variations/mutations with the pathogenesis of MS has, so far, been analyzed by several studies. This paper reviews the literature with regard to MS and corresponding mitochondrial DNA variations. 23922501 Kynurenine Pathway Pathologies: do Nicotinamide and Other Pathway Co-Factors have a Therapeutic Role in Reduction of Symptom Severity, Including Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM). The definition of dual tryptophan pathways has increased the understanding of the mind-body, body-mind dichotomy. The serotonergic pathway highlights the primary (endogenous) psychiatric disorders. The up-regulation of the kynurenine pathway by physical illnesses can cause neuropathic and immunological disorders1 associated with secondary neuropsychiatric symptoms. Tryptophan and nicotinamide deficiencies fall within the protein energy malnutrition (PEM) spectrum. They can arise if the kynurenine pathway is stressed by primary or secondary inflammatory conditions and the consequent imbalance of available catabolic/anabolic substrates may adversely influence convalescent phase efficiency. The replacement of depleted or reduced NAD+ levels and other cofactors can perhaps improve the clinical management of these disorders. Chronic fatigue syndrome (CFS) and fibromyalgia (FM) appear to meet the criteria of a tryptophan-kynurenine pathway disorder with potential neuroimmunological sequelae. Aspects of some of the putative precipitating factors have been previously outlined.2,3 An analysis of the areas of metabolic dysfunction will focus on future directions for research and management. 23806005 People are more likely to be insincere when they are more likely to accidentally tell the truth. Although people lie often, and mostly for self-serving reasons, they do not lie as much as they could. The "fudge factor" hypothesis suggests that one reason for people not to lie is that they do not wish to self-identify as liars. Accordingly, self-serving lies should be more likely when they are less obvious to the liars themselves. Here we show that the likelihood of self-serving lies increases with the probability of accidentally telling the truth. Players in our game could transmit sincere or insincere recommendations to their competitors. In line with the fudge factor hypothesis, players lied when their beliefs were based on flimsy evidence and did not lie when their beliefs were based on solid evidence. This is the first demonstration of a new moral hypocrisy paradox: People are more likely to be insincere when they are more likely to accidentally tell the truth. 23313243 Enhancing nicotine vaccine immunogenicity with liposomes. A major liability of existing nicotine vaccine candidates is the wide variation in anti-nicotine immune responses among clinical trial participants. In order to address this liability, significant emphasis has been directed at evaluating adjuvants and delivery systems that confer more robust potentiation of the anti-nicotine immune response. Toward that end, we have initiated work that seeks to exploit the adjuvant effect of liposomes, with or without Toll-like receptor agonist(s). The results of the murine immunization study described herein support the hypothesis that a liposomal nicotine vaccine formulation may provide a means for addressing the immunogenicity challenge. 23566339 A neuromorphic VLSI design for spike timing and rate based synaptic plasticity. Triplet-based Spike Timing Dependent Plasticity (TSTDP) is a powerful synaptic plasticity rule that acts beyond conventional pair-based STDP (PSTDP). Here, the TSTDP is capable of reproducing the outcomes from a variety of biological experiments, while the PSTDP rule fails to reproduce them. Additionally, it has been shown that the behaviour inherent to the spike rate-based Bienenstock-Cooper-Munro (BCM) synaptic plasticity rule can also emerge from the TSTDP rule. This paper proposes an analogue implementation of the TSTDP rule. The proposed VLSI circuit has been designed using the AMS 0.35 Î¼m CMOS process and has been simulated using design kits for Synopsys and Cadence tools. Simulation results demonstrate how well the proposed circuit can alter synaptic weights according to the timing difference amongst a set of different patterns of spikes. Furthermore, the circuit is shown to give rise to a BCM-like learning rule, which is a rate-based rule. To mimic an implementation environment, a 1000 run Monte Carlo (MC) analysis was conducted on the proposed circuit. The presented MC simulation analysis and the simulation result from fine-tuned circuits show that it is possible to mitigate the effect of process variations in the proof of concept circuit; however, a practical variation aware design technique is required to promise a high circuit performance in a large scale neural network. We believe that the proposed design can play a significant role in future VLSI implementations of both spike timing and rate based neuromorphic learning systems. 23878196 Immobilized HC-HA Polarizes LPS-Activated Macrophages toward M2 Phenotype. Despite the known anti-inflammatory effect of amniotic membrane (AM), its action mechanism remains largely unknown. HC-HA complex (HC-HA), purified from human amniotic membrane, consists of high molecular weight hyaluronic acid (HA) covalently linked to the heavy chain (HC) 1 of inter-α-trypsin inhibitor (IαI). In this study, we show that soluble HC-HA also contained PTX3 and induced the apoptosis of both fMLP or LPS-activated neutrophils and LPS-activated macrophages, while not affecting the resting cells. This enhanced apoptosis was caused by the inhibition of cell adhesion, spreading, and proliferation due to HC-HA binding of LPS-activated macrophages and preventing adhesion to the plastic surface. Preferentially, soluble HC-HA promoted phagocytosis of apoptotic neutrophils in resting macrophages, while immobilized HC-HA promoted phagocytosis in LPS-activated macrophages. Upon concomitant LPS stimulation, immobilized HC-HA but not HA polarized macrophages toward the M2 phenotype by downregulating IRF5 protein and preventing its nuclear localization, and downregulating IL-12, TNF-α, and NOS2. Additionally, IL-10, TGF-β1, PPAR-γ, LIGHT, and SPHK1 were upregulated and such M2 polarization was dependent on TLR ligation. Collectively, these data suggest HC-HA is a unique matrix component different from HA and uses multiple mechanisms to suppress M1 while promoting M2 phenotype. This anti-inflammatory action of HC-HA is highly desirable to promote wound healing in diseases heightened by unsuccessful transition from M1 to M2 phenotypes. 23265905 Design and synthesis of novel 2-methyl-4,5-substitutedbenzo[f]-3,3a,4,5-tetrahydro-pyrazolo[1,5-d][1,4]oxazepin-8(7H)-one derivatives as telomerase inhibitors. Eight novel 4,5-tetrahydropyrazolo[1,5-d][1,4]oxazepine derivatives have been synthesized and purified to be screened for anticancer activity. By a modified TRAP assay, some titled compounds were tested against telomerase, and compound 4a showed the most potent inhibitory activity with IC(50) value at 0.78 ± 0.22 μM. Western blot assays showed that compounds 4a and 4b could inhibit expression of Cyclin D1, TERT, phospho-AKT and PI3K/AKT pathway. 23813631 Epidemiology and management of chronic hepatitis E infection in solid organ transplantation: a comprehensive literature review. Hepatitis E virus (HEV) infection has emerged as a global public health issue. Although it often causes an acute and self-limiting infection with low mortality rates in the western world, it bears a high risk of developing chronic hepatitis in immunocompromised patients with substantial mortality rates. Organ transplant recipients who receive immunosuppressive medication to prevent rejection are thought to be the main population at risk for chronic hepatitis E. Therefore, there is an urgent need to properly evaluate the clinical impact of HEV in these patients. This article aims to review the prevalence, infection course, and management of HEV infection after solid organ transplantation by performing a comprehensive literature review. In addition, an in-depth emphasis of this clinical issue and a discussion of future development are also presented. Copyright © 2013 John Wiley & Sons, Ltd. 23872938 Intravenous Iron Supplementation in Distance Runners with Low or Suboptimal Ferritin. Iron deficiency is prevalent in distance runners and may impair endurance performance. Current practice of oral supplementation is slow and often not well tolerated. The aim of this study was to assess the efficacy of intravenous iron supplementation (ferric carboxymaltose) compared to oral supplementation (ferrous sulphate) on iron status, haemoglobin mass (Hbmass) and physiological indices of running performance in distance runners. 27 highly-trained distance runners with low (LOW) (ferritin <35μg.L and transferrin saturation <20%, or ferritin <15μg.L) or sub optimal (SUB) iron status (ferritin <65μg.L) were supplemented with either intravenous (IV) iron (Ferinject®) or oral (ORAL) supplements (Ferrogradumet) for 6 weeks. Iron status and Hbmass were assessed before supplementation and at 1, 2, 4, 6 and 8 weeks in the four groups (IV LOW, IV SUB, ORAL LOW, ORAL SUB). In addition, athletes completed a treadmill running test for running economy, lactate threshold and VO2max before and after supplementation. Both forms of supplementation substantially increased ferritin levels in all four groups. IV supplementation resulted in higher ferritin in both IV groups compared with both ORAL groups from week 1 onwards. Haemoglobin concentration did not change substantially in any group. Hbmass increased in IV LOW (mean; 90% Confidence limits) +4.9%; 1.1-8.9% and was accompanied by an increase in VO2max: +3.3%; 0.4-6.3% and run time to exhaustion: +9.3%; 0.9-18.3%. IV supplementation can effectively increase iron stores in iron deficient runners within 6 weeks and, if Hbmass is compromised, may enhance endurance capacity by facilitating erythropoiesis. Hbmass appears a more sensitive tool for measuring changes in whole body haemoglobin than haemoglobin concentration and may be useful in the diagnosis and follow-up for iron deficiency. 23891049 Targeting and Recanalization after Embolization with Calibrated Resorbable Microspheres versus Hand-cut Gelatin Sponge Particles in a Porcine Kidney Model. To report on polyethylene glycol hydrogel-based resorbable embolization microspheres (REM) that were synthesized to resorb in < 24 hours, before inflammation and vascular remodeling, to achieve a complete arterial recanalization and to compare targeting and recanalization of REM of 300-500 µm, 500-700 µm, and 700-900 µm with hand-cut gelatin sponge particles (GSP). Eight pigs underwent polar renal artery embolization with REM or GSP. Angiograms were obtained before embolization and 10 minutes and 7 days after embolization before pigs were sacrificed to determine the occlusion level, the percentage of occlusion, and the recanalization rate for each product. The distribution of embolic material was assessed in pathology, and infarction rate of the kidneys was measured. REM of 300-500 µm occluded more distal vessels than REM of 500-700 µm and 700-900 µm. At day 7, the recanalization rate was complete for the larger REM, whereas it was about 60% for the two smaller sizes. REM were completely degraded, with no residual material or inflammation. GSP occluded more proximal arteries than REM of 700-900 µm, were partly degraded at day 7, and were accompanied by a foreign body reaction in proximal and distal arteries. GSP recanalized at 79%. The infarction rate was higher with the two smaller sizes of REM and with GSP than with the largest REM. REM of different sizes targeted different occlusion levels in kidney arteries. GSP provided an extended occlusion level without actual targeting. Regardless of embolic material used, angiographic recanalization of renal arteries depended on the extent of necrosis. REM of 700-900 µm demonstrated the lowest infarction rate and the best recanalization rate. 23935903 Assumptions and properties of limiting pathway models for analysis of epistasis in complex traits. For most complex traits, results from genome-wide association studies show that the proportion of the phenotypic variance attributable to the additive effects of individual SNPs, that is, the heritability explained by the SNPs, is substantially less than the estimate of heritability obtained by standard methods using correlations between relatives. This difference has been called the "missing heritability". One explanation is that heritability estimates from family (including twin) studies are biased upwards. Zuk et al. revisited overestimation of narrow sense heritability from twin studies as a result of confounding with non-additive genetic variance. They propose a limiting pathway (LP) model that generates significant epistatic variation and its simple parametrization provides a convenient way to explore implications of epistasis. They conclude that over-estimation of narrow sense heritability from family data ('phantom heritability') may explain an important proportion of missing heritability. We show that for highly heritable quantitative traits large phantom heritability estimates from twin studies are possible only if a large contribution of common environment is assumed. The LP model is underpinned by strong assumptions that are unlikely to hold, including that all contributing pathways have the same mean and variance and are uncorrelated. Here, we relax the assumptions that underlie the LP model to be more biologically plausible. Together with theoretical, empirical, and pragmatic arguments we conclude that in outbred populations the contribution of additive genetic variance is likely to be much more important than the contribution of non-additive variance. 23539063 Diversity of the major capsid genes (g23) of T4-like bacteriophages in the eutrophic Lake Kotokel in East Siberia, Russia. Numerous studies revealed high diversity of T4-like bacteriophages in various environments, but so far, little is known about T4-like virus diversity in freshwater bodies, particularly in eutrophic lakes. The present study was aimed at elucidating molecular diversity of T4-like bacteriophages in eutrophic Lake Kotokel located near Lake Baikal by partial sequencing of the major capsid genes (g23) of T4-like bacteriophages. The majority of g23 fragments from Lake Kotokel were most similar to those from freshwater lakes and paddy fields. Despite the proximity and direct water connection between Lake Kotokel and Lake Baikal, g23 sequence assemblages from two lakes were different. UniFrac analysis showed that uncultured T4-like viruses from Lake Kotokel tended to cluster with those from the distant lake of the same trophic status. This fact suggested that the trophic conditions affected the formation of viral populations, particularly of T4-like viruses, in freshwater environments. 23815225 Isomorphous Substitution in a Flexible Metal-Organic Framework: Mixed-Metal, Mixed-Valent MIL-53 Type Materials. Mixed-metal iron-vanadium analogues of the 1,4-benzenedicarboxylate (BDC) metal-organic framework MIL-53 have been synthesized solvothermally in N,N'-dimethylformamide (DMF) from metal chlorides using initial Fe:V ratios of 2:1 and 1:1. At 200 °C and short reaction time (1 h), materials (Fe,V)(II/III)BDC(DMF1-xFx) crystallize directly, whereas the use of longer reaction times (3 days) at 170 °C yields phases of composition [(Fe,V)(III)0.5(Fe,V)0.5(II)(BDC)(OH,F)](0.5-)·0.5DMA(+) (DMA = dimethylammonium). The identity of the materials is confirmed using high-resolution powder X-ray diffraction, with refined unit cell parameters compared to known pure iron analogues of the same phases. The oxidation states of iron and vanadium in all samples are verified using X-ray absorption near edge structure (XANES) spectroscopy at the metal K-edges. This shows that in the two sets of materials each of the vanadium and the iron centers are present in both +2 and +3 oxidation states. The local environment and oxidation state of iron is confirmed by (57)Fe Mössbauer spectrometry. Infrared and Raman spectroscopies as a function of temperature allowed the conditions for removal of extra-framework species to be identified, and the evolution of μ2-hydroxyls to be monitored. Thus calcination of the mixed-valent, mixed-metal phases [(Fe,V)(III)0.5(Fe,V)0.5(II)(BDC)(OH,F)](0.5-)·0.5DMA(+) yields single-phase MIL-53-type materials, (Fe,V)(III)(BDC)(OH,F). The iron-rich, mixed-metal MIL-53 shows structural flexibility that is distinct from either the pure Fe material or the pure V material, with a thermally induced pore opening upon heating that is reversible upon cooling. In contrast, the material with a Fe:V content of 1:1 shows an irreversible expansion upon heating, akin to the pure vanadium analogue, suggesting the presence of some domains of vanadium-rich regions that can be permanently oxidized to V(IV). 23373654 The evolution of drugs on schistosoma treatment: looking to the past to improve the future. Schistosomiasis is a devastating worldwide widespread tropical disease that currently affects more than 230 million people, making it an issue of great socioeconomic and public health importance. Unfortunatelly there is a single drug for the treatment of all forms of schistosomiasis, praziquantel, which was introduced in therapy in 1980. The article goes by antimony compounds, emetine, hydantoin, nitrofurans, lucanthone, hycanthone, oxamniquine derivatives and organophosphates until it finally gets to praziquantel derivatives. The intent of this review is to provide a panorama of drugs that were and are being used in human chemotherapy looking to the past to improve rational design drugs in the future. Not only clinical used compounds will be shown but also synthesized and tested compounds in vitro and in vivo in animal models which haven't yet to be used in humans. Prospects for drug discovery and vaccines to be used in the treatment and prevention of schistosomiasis, clinical trials, concerns about the resistance/decreased effectiveness of the treatment, and patent database will also be discussed. At the end of the review the reader will notice that much has been done but much still needs to be done yet. 23861012 Erroneous Gambling-Related Beliefs as Illusions of Primary and Secondary Control: A Confirmatory Factor Analysis. Different classification systems for erroneous beliefs about gambling have been proposed, consistently alluding to 'illusion of control' and 'gambler's fallacy' categories. None of these classification systems have, however, considered the how the illusion of control and the gambler's fallacy might be interrelated. In this paper, we report the findings of a confirmatory factor analysis that examines the proposal that most erroneous gambling-related beliefs can be defined in terms of Rothbaum et al.'s (J Pers Soc Psychol, doi: 10.1037/0022-3514.42.1.5 , 1982) distinction between 'primary' and 'secondary' illusory control, with the former being driven to a large extent by the well-known gambler's fallacy and the latter being driven by a complex of beliefs about supernatural forces such as God and luck. A survey consisting of 100 items derived from existing instruments was administered to 329 participants. The analysis confirmed the existence of two latent structures (beliefs in primary and secondary control), while also offering support to the idea that gambler's fallacy-style reasoning may underlie both perceived primary control and beliefs about the cyclical nature of luck, a form of perceived secondary control. The results suggest the need for a greater focus on the role of underlying processes or belief structures as factors that foster susceptibility to specific beliefs in gambling situations. Addressing and recognising the importance of these underlying factors may also have implications for cognitive therapy treatments for problem gambling. 23907973 Tuberculosis of bilateral first costotransverse joints. Involvement of posterior spine constitutes to 1-6% of the cases of spinal tuberculosis (TB). To the best of our knowledge, TB of costotransverse joints has only been reported once in the literature. The purpose of this study is to describe a case of TB arthritis of costotransverse joints. A 22-year-old immunocompetent patient presented with a 3-month history of pain in the neck and upper back along with a swelling on the left side of the base of the neck. On performing an MRI of the cervicodorsal spine, there was evidence of destructive collections at the bilateral first and right-sided second costotransverse joints. The patient was diagnosed as a case of tubercular pathology and was managed successfully with antitubercular chemotherapy. 23268488 A sequence labeling approach to link medications and their attributes in clinical notes and clinical trial announcements for information extraction. The goal of this work was to evaluate machine learning methods, binary classification and sequence labeling, for medication-attribute linkage detection in two clinical corpora. We double annotated 3000 clinical trial announcements (CTA) and 1655 clinical notes (CN) for medication named entities and their attributes. A binary support vector machine (SVM) classification method with parsimonious feature sets, and a conditional random fields (CRF)-based multi-layered sequence labeling (MLSL) model were proposed to identify the linkages between the entities and their corresponding attributes. We evaluated the system's performance against the human-generated gold standard. The experiments showed that the two machine learning approaches performed statistically significantly better than the baseline rule-based approach. The binary SVM classification achieved 0.94 F-measure with individual tokens as features. The SVM model trained on a parsimonious feature set achieved 0.81 F-measure for CN and 0.87 for CTA. The CRF MLSL method achieved 0.80 F-measure on both corpora. We compared the novel MLSL method with a binary classification and a rule-based method. The MLSL method performed statistically significantly better than the rule-based method. However, the SVM-based binary classification method was statistically significantly better than the MLSL method for both the CTA and CN corpora. Using parsimonious feature sets both the SVM-based binary classification and CRF-based MLSL methods achieved high performance in detecting medication name and attribute linkages in CTA and CN. 23874944 Quantifying spatial variability of selected soil trace elements and their scaling relationships using multifractal techniques. Multifractal techniques were utilized to quantify the spatial variability of selected soil trace elements and their scaling relationships in a 10.24-ha agricultural field in northeast China. 1024 soil samples were collected from the field and available Fe, Mn, Cu and Zn were measured in each sample. Descriptive results showed that Mn deficiencies were widespread throughout the field while Fe and Zn deficiencies tended to occur in patches. By estimating single multifractal spectra, we found that available Fe, Cu and Zn in the study soils exhibited high spatial variability and the existence of anomalies ([α(q)max-α(q)min]≥0.54), whereas available Mn had a relatively uniform distribution ([α(q)max-α(q)min]≈0.10). The joint multifractal spectra revealed that the strong positive relationships (r≥0.86, P<0.001) among available Fe, Cu and Zn were all valid across a wider range of scales and over the full range of data values, whereas available Mn was weakly related to available Fe and Zn (r≥0.18, P<0.01) but not related to available Cu (r = -0.03, P = 0.40). These results show that the variability and singularities of selected soil trace elements as well as their scaling relationships can be characterized by single and joint multifractal parameters. The findings presented in this study could be extended to predict selected soil trace elements at larger regional scales with the aid of geographic information systems. 23914751 Adverse drug reaction labelling for atomoxetine, methylphenidate and modafinil: comparison of product information for oral formulations in australia, denmark and the United States. Medical product information contains information about efficacy and safety for marketed pharmaceuticals. Three studies have compared safety labelling for different therapeutic categories in different countries and detected large variations in a number of reported adverse drug reactions (ADRs). The rapid increase in use of medications for treatment of ADHD symptoms has created concern due to lack of information about effects from long-term use. The aim of this study was to compare ADR information in product information (PI)/summary of product characteristics (SPC) for oral formulations of atomoxetine, methylphenidate and modafinil marketed by the same pharmaceutical companies in Australia, Denmark and the United States. Discrepancies in listed ADRs were defined as types of ADRs (system organ class) not listed in all countries. For ADRs where discrepancies were detected, we extracted information about study design (clinical trials, spontaneous report). Discrepancies in ADR labelling for the medications were found across the three countries. A total of 75 ADR categories were listed for atomoxetine and 80% of these were listed in all three countries. For methylphenidate, totally 101 ADR categories and for modafinil 115 ADR categories were listed. For both substances approximately 60% of listed ADRs were found in all three countries. Discrepancies were primarily detected for ADRs information based on clinical trials. For methylphenidate, many ADRs labelled in Australia and Denmark were not mentioned in PIs issued in the United States. In conclusion, information about possible ADRs associated with the use of a specific product should be made available worldwide, as the prescriber information about medicines' safety profile should not depend on the country in which the medication is licensed. 23826730 "I have the right to a private life": Medical students' views about professionalism in a digital world. Background: Social media site use is ubiquitous, particularly Facebook. Postings on social media can have an impact on the perceived professionalism of students and practitioners. Aims: In this study, we explored the attitudes and understanding of undergraduate medical students towards professionalism, with a specific focus on online behaviour. Methods: A volunteer sample of students (n = 236) responded to an online survey about understanding of professionalism and perceptions of professionalism in online environments. Respondents were encouraged to provide free text examples and to elaborate on their responses through free text comments. Descriptive analyzes and emergent themes analysis were carried out. Results: Respondents were nearly unanimous on most questions of professionalism in the workplace, while 43% felt that students should act professionally at all times (including free time). Sixty-four free text comments revealed three themes: "free time is private time";" professionalism is unrealistic as a way of life"; and "professionalism should be a way of life". Conclusions: Our findings indicate a disconnect between what students report of what they understand of professionalism, and what students feel is appropriate and inappropriate in both online and real life behaviour. Curriculum needs to target understanding of professionalism in online and real environments and communicate realistic expectations for students. 23918513 Mad honey poisoning mimicking acute myocardial infarction. We report a case of acute poisoning in a 48-year-old man who presented with chest pain, abdominal pain, dizziness, sweatiness, blurred vision, and severe hypotension after ingestion of honey. His electrocardiogram showed sinus bradycardia and transient ST elevation. He made a good recovery after treatment with atropine and close monitoring. Grayanotoxin was detected in his urine and the honey he ingested, which confirmed a diagnosis of mad honey poisoning. This is a condition prevalent in the Black Sea region around Turkey but rarely seen locally. Although mad honey poisoning is life-threatening, early use of atropine is life-saving. Such poisoning may present with ST elevation in the electrocardiogram and symptoms mimicking acute myocardial infarction. It is therefore essential for clinicians to recognise this unusual form of poisoning and avoid the disastrous use of thrombolytic therapy. 23721501 Excellent outcome of living donor liver transplantation in patients with hepatopulmonary syndrome: a single centre experience. Hepatopulmonary syndrome (HPS) worsens the prognosis of cirrhosis and liver transplantation is only definitive treatment. There is paucity of data about role of living donor liver transplantation (LDLT) in HPS. Fourteen patients with HPS and cirrhosis who underwent LDLT were prospectively included. HPS was defined as PaO2 < 80 mmHg in presence of demonstrable macro-aggregated albumin (MAA) scan shunt fraction >6%. The study group composed of 11 male and three female patients, mean age 50.3 ± 8.6 yr. Most common presentations were dyspnea (92.8%), cyanosis (78.5%) and clubbing (64.2%). Mean model for end-stage liver disease (MELD) score was 18.2 ± 4.7, mean MAA shunt fraction was 23.0 ± 13.2%, mean PaO2 was 58.7 ± 8.4 mmHg. Two patients had very severe HPS (PaO2 <50 mmHg), five had severe HPS (PaO2 >50 <60 mmHg) and seven had moderate HPS (PaO2 >60 <80 mmHg). All patients underwent right lobe LDLT. The overall time to extubation was 2 (1-32 days) and for hospital stay was 20 (17-46 days). The main complications in post-LT course were infection in 57% (cytomegalovirus or bacterial). All the patients are alive and off oxygen at a mean follow up of 29 ± 25 months. We report one of the largest series of LDLT in HPS which has shown excellent results. 23823797 Does phloem-based resistance to aphid feeding affect host-plant acceptance for reproduction? Parturition of the pea aphid, Acyrthosiphon pisum, on two near-isogenic lines of Medicago truncatula. Probing behaviour (prior to parturition) and parturition of two clones (PS01 and N116) of the pea aphid, Acyrthosiphon pisum on two genotypes (near-isogenic lines (NILs)) (Q174_5.13 and Q174_9.10) of Medicago truncatula were investigated using electrical penetration graph (EPG) coupled with simultaneous visual monitoring for parturition. Line Q174_5.13 has been reported to show a phloem-based resistance to feeding in the clone PS01 but to be susceptible to the clone N116, whereas Q174_9.10 has shown to be susceptible to both aphid clones. The time taken to first parturition by clone PS01 was similar on Q174_5.13 and Q174_9.10. Prior to parturition, no aphids on Q174_5.13 contacted phloem, but 5% of the aphids on Q174_9.10 showed phloem salivation (recognized by EPG pattern E1). No phloem contact was observed with aphid clone N116 on either NILs of Medicago before first parturition occurred, and the time taken to first larviposition was similar on Q174_5.13 and Q174_9.10. The results indicate that the initiation of parturition of the clone PS01 and N116 on both NILs does not require the phloem contact and seems unchanged by a phloem-based resistance mechanism to feeding on Medicago. This finding suggests that host recognition and decisions about parturition occur before phloem contact or ingestion, and act independently on R-gene-mediated resistance. 23900279 Efficacy of methylprednisolone versus other pharmacologic interventions for the treatment of central post-stroke pain: a retrospective analysis. To determine if an oral, tapered methylprednisolone regimen is superior to other commonly used pharmacologic interventions for the treatment of central post-stroke pain (CPSP). In this study, the charts of 146 stroke patients admitted to acute inpatient rehabilitation were retrospectively reviewed. Patients diagnosed with CPSP underwent further chart review to assess numerical rating scale for pain scores and as-needed pain medication usage at different time points comparing CPSP patients treated with methylprednisolone to those treated with other pharmacologic interventions. In the sample, 8.2% were diagnosed with CPSP during acute care or inpatient rehabilitation. Mean numerical rating scale for pain scores day of symptom onset did not differ between those patients treated with methylprednisolone versus those treated with other pharmacologic interventions (mean ± standard deviation; 6.1 ± 2.3 versus 5.7 ± 1.6, P = 0.77). However, mean numerical rating scale for pain scores differed significantly 1-day after treatment initiation (1.7 ± 2.1 versus 5.0 ± 1.9, P = 0.03) and 1-day prior to rehabilitation discharge (0.3 ± 0.9 versus 4.1 ± 3.2, P = 0.01) between the two groups. Compared to day of symptom onset, as-needed pain medication usage within the methylprednisolone group was marginally less 1-day after treatment initiation (Z = -1.73, P = 0.08) and 1-day prior to rehabilitation discharge (Z = -1.89, P = 0.06). No difference in as-needed pain medication usage existed within the non-steroid group at the same time points. Methylprednisolone is a potential therapeutic option for CPSP. The findings herein warrant study in prospective trials. 23345166 Isolation and synthesis of melodamide A, a new anti-inflammatory phenolic amide from the leaves of Melodorum fruticosum. Together with twelve known compounds (2-13), melodamide A (1), a new phenolic amide possessing p-quinol moiety, was purified and characterized from the methanolic extracts of the leaves of Melodorum fruticosum. The structure of melodamide A (1) was established with a combination of 2D NMR experiments, HR-ESI-MS and X-ray analyses. The other known compounds were identified by comparison of their spectroscopic and physical data with those reported in the literature. Moreover, some isolated compounds were examined for their inhibitory activity towards superoxide anion generation and elastase release in human neutrophils. Among the tested compounds, 1, 3, and 5 exhibited strong inhibition of superoxide anion generation with IC50 values ranging from 5.25 to 8.65 µM. Furthermore, synthesis and biological evaluation of melodamide A (1) and its analogs (14a-p) were described. 23772908 Musculoskeletal regeneration and its implications for the treatment of tendinopathy. Tendinopathies are common muskoloskeletal injuries that lead to pain and disability. Development and pathogenesis of tendinopathy is attributed to progressive pathological changes to the structure, function, and biology of tendon. The nature of this disease state, whether acquired by acute or chronic injury, is being actively investigated. Scarring, disorganized tissue, and loss of function characterize adult tendon healing. Recent work from animal models has begun to reveal the potential for adult mammalian tendon regeneration, the replacement of diseased with innate tissue. This review discusses what is known about musculoskeletal regeneration from a molecular perspective and how these findings can be applied to tendinopathy. Non-mammalian and mammalian models are discussed with emphasis on the potential of Murphy Roths Large mice to serve as a model of adult tendon regeneration. Comparison of regeneration in non-mammals, foetal mammals and adult mammals emphasizes distinctly different contributing factors to effective regeneration. 23685978 Rough eyes of the northeast-Asian wood white, Leptidea amurensis. The northeast-Asian wood white, Leptidea amurensis (Lepidoptera, Pieridae), belongs to the Dismorphiinae, a subfamily of the family Pieridae. We studied the structure of the compound eye in this species through a combination of anatomy, molecular biology and intracellular electrophysiology, with a particular focus on the evolution of butterfly eyes. We found that their eyes consist of three types of ommatidia, with a basic set of one short-, one middle- and one long-wavelength-absorbing visual pigment. The spectral sensitivities of the photoreceptors are rather simple, and peak in the ultraviolet, blue and green wavelength regions. The ommatidia have neither perirhabdomal nor fluorescent pigments, which modulate photoreceptor spectral sensitivities in a number of other butterfly species. These features are primitive, but the eyes of Leptidea exhibit another unique feature: the rough appearance of the ventral two-thirds of the eye. The roughness is due to the irregular distribution of facets of two distinct sizes. As this phenomenon exists only in males, it may represent a newly evolved sex-related feature. 23848368 The uses of overlap: Carer-child interaction involving a nine-year-old boy with auditory neuropathy. Abstract The subject of this single case study, Ricky, is a nine-year-old boy with a profound hearing loss arising from auditory neuropathy. Despite cochlear implantation at the age of two, his receptive language skills remain very restricted and his speech is unintelligible. Techniques of interactional linguistics are used to analyse recordings of Ricky and his mother during shared book reading. Both participants display competences in managing turn-taking and overlapping talk that enable them to progress the book-reading activity, to talk spontaneously on topically related matters and also to handle issues of phonetic and linguistic repair. Instances of both competitive and non-competitive overlap reveal that Ricky has access to interactionally important prosodic skills. The study thus reinforces the need, when assessing a child's potential to understand and use spoken language, to examine the child's talk from an interactional perspective. It further indicates that overlapping talk is not necessarily a problem; indeed it can be part of a solution to issues of interpersonal understanding that routinely arise in the course of talk-in-interaction. 23311673 Conceptualizing participation in context for children and youth with disabilities: an activity setting perspective. Abstract This article considers the conceptualization, operationalization and implications of "activity settings" for research on the recreation and leisure participation of children and youth with disabilities. Activity settings are contextualized settings that situate child and youth activities and their participation experiences. We discuss activity settings as an important construct for considering environmental qualities that provide opportunities for beneficial participation experiences for children and youth with disabilities. The article considers existing research using the concept of activity settings, the conceptualization of environment and contemporary issues in the measurement of participation and environment, indicating how these are addressed by an activity settings approach. We then describe the development of two quantitative measures of recreation and leisure activity settings - one assessing environmental qualities and the other assessing youth experiences - that have the potential to inform researchers, managers and clinicians about relationships between environmental qualities and participation experiences. Finally, we consider the implications of an activity settings approach for research, theory building and clinical practice. Implications for Rehabilitation An activity setting perspective can enhance understanding of the recreation and leisure participation of children and youth with disabilities. The Measure of Environmental Qualities of Activity Settings (MEQAS) and Self-reported Experiences of Activity Settings (SEAS) provide unique assessments of environmental qualities and experiences from an activity setting perspective. Clinicians might use the SEAS alone to understand particular youth experiences in certain types of settings, which may be limiting or facilitating development. The combined use of the SEAS and MEQAS can provide experiential profiles linked to activity setting qualities such as structure, type of activity and social partners, providing a valuable source of information about youth programs. 23830310 Femoral artery calcification as a determinant of success for percutaneous access for endovascular abdominal aortic aneurysm repair. This study was conducted to determine the outcomes and predictive factors for success during percutaneous endovascular aneurysm repair (PEVAR) using vascular closure devices (VCDs). The clinical data of patients who underwent PEVAR between 2005 and 2012 were retrospectively reviewed. Patient demographics, body mass index, sheath size, device types, diameter of femoral arteries, and extent and location of femoral artery calcification were recorded. Included were all consecutive patients treated by PEVAR with sheath sizes ranging from 12F to 24F. End points were technical success, conversion to open femoral artery repair, and complications. During this period, 752 patients were treated by EVAR. Of these, 391 femoral arteries in 222 patients (29.5%; 197 men, 25 women), with a mean age of 74.8 years (range, 51-93.7 years), underwent PEVAR (169 bilateral and 53 unilateral percutaneous access). Patients with >50% anterior femoral artery calcifications or those with previous femoral artery reconstructions were not offered PEVAR. Technical success of PEVAR was 96.4% (377 of 391), with an average of two VCDs used per groin. Fourteen intraoperative failures were managed with open femoral conversion using primary repair (five) or patch angioplasty (nine). In nine patients, the procedure was converted from local to general anesthesia. Four patients required a perioperative blood transfusion. There were no significant differences in body mass index (P = .26), femoral artery size preprocedure (P = .33) or postprocedure (P = .37), sheath size (≥20F vs ≤18F), or type of VCD used between the success and failure groups. Pairwise comparisons revealed increased failure rate (P < .001) between patients with <50% anterior wall calcification vs none, <50% anterior wall calcification vs <50% posterior wall calcification, and none vs >50% posterior calcification. There was no significant difference (P = .53) between patients with <50% posterior wall calcification and those with no calcification. The 30-day mortality of the entire group was 0.9% (2 of 222 patients). No deaths occurred after conversion to open femoral closure. At a mean follow-up of 30 months (range, 1-85.2 months), there were no long-term groin complications or iliac limb occlusions. PEVAR using VCDs can be performed with high technical success in patients with <50% anterior wall calcification, regardless of the size of the access sheath or the patient's body mass index. Femoral artery calcification, however, is a major determinant of failure. 23845721 Target lobe volume reduction and COPD outcome measures after endobronchial valve therapy. Endobronchial valve (EBV) therapy may be associated with improvements in COPD related outcomes and may therefore be linked to improvements in the BODE index.Data from 416 patients with advanced emphysema and hyperinflation across Europe and the United States, who were randomised to EBV (n=284) or conservative therapy (n=132) were analysed. Quantitative image analysis was used to compare the volume of the targeted lobe at baseline and at 6 months to determine target lobe volume reduction (TLVR).44% of patients receiving EBVs (vs. 24.7% of controls) had clinically significant improvements in the BODE index (p<0.001). BODE index was significantly reduced by 1.4±1.8, 0.2±1.3, and 0.1±1.3 points in patients with TLVR >50%, <50% TLVR >20%, and TLVR <20%, respectively (intergroup differences, p<0.001), but increased by 0.3±1.2 points in controls. Changes in BODE were predicted by baseline BODE, and correlated significantly with lobar exclusion and lung volumes at 6 months.A greater proportion of patients in the treatment than control group achieved a clinically meaningful improvement in BODE index, however, the likelihood of benefit was less than half in both groups. Patients in whom TLVR was obtained had greater improvements in clinical outcomes. 23688676 Naming outcome after left or right temporal lobectomy in patients with bilateral language representation by Wada testing. This study aimed to examine language outcome after left or right anterior temporal lobectomy (ATL) in patients with epilepsy with bilateral language representation on intracarotid sodium amobarbital (Wada) testing. Twenty-two patients with epilepsy with bilateral language (Wada laterality index between -50 and 50) underwent right ATL (RATL, n=10) or left ATL (LATL, n=12). All the patients were administered the Boston Naming Test preoperatively and six months postoperatively. Left anterior temporal lobectomy patients showed greater postoperative naming decline than RATL patients. Group differences were also observed on subtests of the Wada test. Performance on the Wada naming and comprehension subtests was better in the nonsurgical hemisphere than in the surgical hemisphere in the RATL group, but there was no difference between the nonsurgical and the surgical hemisphere naming and comprehension performance in the LATL group. Left anterior temporal lobectomy patients with bilateral language are at greater risk for naming decline than RATL patients with bilateral language. This difference may be due to relatively better naming and comprehension abilities in the nonsurgical hemisphere in the RATL group. 23963100 Ultrasensitive and recyclable SERS substrate based on Au-decorated Si nanowire arrays. Metallic nanoparticle (NP) decorated silicon nanowire (SiNW) heterostructures show significant promise in enhanced optical and opto-electrical properties due to the coupling of surface plasmon to nanowires. Here, recyclable Au-decorated silicon nanowire arrays (Au-SiNWAs) as surface-enhanced Raman scattering (SERS) substrates were successfully fabricated by a simple galvanic displacement reaction. The influence of different average size and aggregation level of Au NPs on SERS activity was explored. The SERS activity of the substrates strongly depends on the average size and aggregation level of Au NPs on the surface of the SiNWs, and the most optimal size and separation of AuNPs on the SiNWs can be achieved by controlling the reaction time. The optimized Au-SiNWA substrate exhibits ultrahigh sensitivity with an enhancement factor of 10(9), and is able to detect the analyte molecule at a concentration as low as 10(-11) M. More importantly, the SERS substrate is recyclable, as enabled by a self-cleaning function due to UV light photocatalytic degradation of the analyte molecules. The high sensitivity and recyclability of the Au-SiNWA SERS substrate is demonstrated by the detection of a model molecule rhodamine B (RhB). Our studies show that the unique Au-SiNWA SERS substrates have significant potential to put SERS into wider application. 23770100 B cell translocation gene, a direct target of miR-142-5p, inhibits vascular smooth muscle cell proliferation by down-regulating cell cycle progression. Vascular smooth muscle cell (VSMC) proliferation plays a key role in neointimal hyperplasia and restenosis. Here we report the role of the microRNA miR-142-5p and its downstream target genes on the proliferation of cultured VSMCs. miR-142-5p promoted VSMC proliferation by down-regulating B cell translocation gene 3 (BTG3). We found that BTG3 inhibited the expression of cell cycle regulatory genes and cell growth. As shown by luciferase reporter assay, miR-142-5p bound directly to the 3'-untranslated region of BTG3. Overexpression of miR-142-5p induced expression of cell cycle regulatory genes. Thus, BTG3, a novel, direct target of miR-142-5p, negatively regulates VSMC proliferation. 22446299 Common representation of pain and negative emotion in the midbrain periaqueductal gray. Human neuroimaging offers a powerful way to connect animal and human research on emotion, with profound implications for psychological science. However, the gulf between animal and human studies remains a formidable obstacle: human studies typically focus on the cortex and a few subcortical regions such as the amygdala, whereas deeper structures such as the brainstem periaqueductal gray (PAG) play a key role in animal models. Here, we directly assessed the role of PAG in human affect by interleaving in a single fMRI session two conditions known to elicit strong emotional responses-physical pain and negative image viewing. Negative affect and PAG activity increased in both conditions. We next examined eight independent data sets, half featuring pain stimulation and half negative image viewing. In sum, these data sets comprised 198 additional participants. We found increased activity in PAG in all eight studies. Taken together, these findings suggest PAG is a key component of human affective responses. 23552907 Atypical antipsychotics in the treatment of children and adolescents with pervasive developmental disorders. RATIONALE: Autism and related pervasive developmental disorders (PDD) are characterized by impairments in social interaction and communication, restricted interests, and repetitive and stereotyped patterns of behavior. Individuals with PDD frequently display irritability and disruptive behaviors including tantrums, self-injurious behavior, and aggression. Atypical antipsychotics are currently the most efficacious pharmacological interventions available for treatment of irritability associated with PDD. OBJECTIVES: This article aims to review the body of literature pertaining to the use of atypical antipsychotics in the treatment of patients with PDD. METHODS: A PubMed literature search was conducted using the following key words: autism, pervasive developmental disorders, atypical antipsychotics, risperidone, aripiprazole, quetiapine, ziprasidone, olanzapine, clozapine, paliperidone, iloperidone, asenapine, and lurasidone. Search terms were limited to English language, human subjects, and publication from 1999 to present. Relevant references from identified articles were also reviewed. RESULTS: The efficacy and tolerability of risperidone and aripiprazole for the treatment of irritability in autism have been established with multi-site, randomized, controlled trials. Studies supporting the use of other atypical antipsychotics are either limited in scope or less robust in their findings, though newer agents such as ziprasidone and paliperidone show promise. CONCLUSIONS: Atypical antipsychotics are currently first-line pharmacological agents for the treatment of irritability and associated behaviors in children with PDD. Further placebo-controlled studies are warranted to characterize the efficacy and tolerability of the majority of these medications. There is also a need for the development of novel, targeted drugs with more favorable long-term side effect profiles. 23877199 Myeloid leukemia with t(7;21)(p22;q22) and 5q deletion. The rare but recurrent RUNX1-USP42 fusion gene is the result of a t(7;21)(p22;q22) chromosomal translocation and has been described in 6 cases of acute myeloid leukemia (AML) and one case of refractory anemia with excess of blast. In the present study, we present the molecular genetic analysis and the clinical features of a t(7;21)(p22;q22)-positive AML case. PCR amplified two RUNX1-USP42 cDNA fragments but no reciprocal USP42-RUNX1 fragment indicating that the RUNX1-USP42 is the leukemogenic fusion gene. Sequencing of the two amplified fragments showed that exon 6 or exon 7 of RUNX1 (accession number NM_001754 version 3) was fused to exon 3 of USP42 (accession number NM_032172 version 2). The predicted RUNX1-USP42 fusion protein would contain the Runt homology domain (RHD), which is responsible for heterodimerization with CBFB and for DNA binding, and the catalytic UCH (ubiquitin carboxyl terminal hydroxylase) domain of the USP42 protein. The bone marrow cells in the present case also had a 5q deletion, and it was revealed that 5 out of the 8 reported cases (including the present case) with t(7;21)(p22;q22)/RUNX1-USP42 also had cytogenetic abnormalities of 5q. The fact that t(7;21) and 5q- occur together much more often than chance would allow seems to be unquestionable, although the pathogenetic connection between the two aberrations remains unknown. 23921994 Development of patient-centred standards of care for rheumatoid arthritis in Europe: the eumusc.net project. The eumusc.net project is a European Union (EU) commission and European League Against Rheumatism (EULAR)funded project that aims to facilitate equal standards for musculoskeletal health in all EU countries. One work-package was to develop evidence-based and patient-centred standards of care (SOC), for rheumatoid arthritis (RA) understandable for patients and professionals across Europe. A review of documents covering clinical practice 'guidelines' and SOC for RA was conducted. The obtained documents were evaluated using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) criteria, and all recommended methods to treat RA were extracted. Based on this information, a three-round Delphi exercise was performed including a consensus group meeting of 21 researchers and patient representatives. 16 patient-centred SOC were formulated including a lay version in the format of a checklist. An example is SOC 3: 'People with RA should receive a treatment plan developed individually between them and their clinician at each visit.' The corresponding checklist question reads: 'Have I received a treatment plan which includes an explanation of my management, expected goals and outcomes and important contact details?' CONCLUSIONS: The SOC for RA will be available in all 23 official European languages and contribute to more unified treatment approaches in Europe. 23313269 Triglyceride accumulation inhibitory effects of phenylpropanoid glycosides from Boschniakia rossica Fedtsch et Flerov. Bioassay-guided fractionation led to isolation of five new phenylpropanol glycosides, rossicasides G (1), H (2), I (3), J (4), and K (5), together with seven known compounds (6-12) from Boschniakia rossica. Their structures were elucidated by chemical and spectroscopic methods (UV, IR, HRESI-TOF-MS, 1D and 2D NMR). Activity screening results showed that some isolates had TG accumulation inhibitory effects in HepG2 cells. Furthermore, the structure-activity relationship was partly clarified. 23906780 Aqueous root extracts from Mimosa albida Humb. & Bonpl. ex Willd display antinociceptive activity in mice. In this work, we study whether aqueous extracts from the roots of Mimosa albida Humb. & Bonpl. ex Willd, a plant known in the Highlands of Chiapas, Mexico as "Lotóm chíx" are endowed with both antinociceptive and anxiolytic effects. ICR mice were systemically treated with aqueous extracts from Mimosa albida and the reference compounds (diazepam, dipyrone and/or fentanyl) and their behavior was evaluated in several behavioral tests. Administration of aqueous extracts from the roots of Mimosa albida resulted in a reduction of the nociception elicited in mice by both the hot plate (12.5, 25 and 50mg/kg; i.p.) and the acetic acid-induced writhing (25 and 50mg/kg; i.p.) tests. No effects were however observed both in the elevated plus-maze and hole board test (3.2, 12.5 and 25mg/kg; i.p.). In contrast, both locomotion (open field test) and motor coordination (rotarod test) were affected at doses (50, 100 y 200mg/kg; i.p.) higher than those having antinociceptive effects. These data suggest that in mice the systemic administration of low doses of aqueous extracts from the roots of Mimosa albida results in antinociceptive effects in several models of pain through mechanisms that do not involve the opioid system pathway. These results support the ethnopharmacological use of Mimosa albida in popular medicine. 23887770 Anorectal atresia with gross terminal colonic distension in Africa. Anorectal malformation (ARM) is a group of significant birth defects with geographic variation in incidence, individual phenotypes and regional geographic subtypes occurring in approximately 1:5,000 live births. Anorectal atresia with gross terminal colonic distension in the presence of an absent anal canal has also been known as 'pouch colon' which is mainly associated with the Indian subcontinent. Its prevalence is unknown but it is rare, possibly representing a fraction of 1 % of ARM. The problem seems to revolve around the gross terminal distension of the distal pouch which remains a significant surgical challenge to surgeons resulting in poorer postoperative continence in many instances. This study set out to collate data on ARM patients with gross terminal distension of the distal pouch from Africa to evaluate its epidemiology and outcome in African patients. Fifteen African paediatric surgical centres (7 South African and 8 African centres) were polled on the occurrence of anorectal atresia with gross terminal distension of the terminal bowel, an ARM variant. Data included ethnic group, age, gender as well as the anatomical pathology, classification and presence or absence of associated anomalies. Of 12 respondents, 8 (67 %) responded and sufficient data to classify and analyse were obtained from six of the eight positive replies (7 new cases). Abdominal X-ray showed a grossly dilated terminal portion of the colon in the presence of an imperforate anus. A colovesical fistula was observed in four (three males and one female cloaca). Three were associated with a colonic atresia, of which two were in the transverse colon and one in the sigmoid colon. Surgical corrective procedures were carried out in six, but one patient, with a cloaca, died prior to surgical correction. In this survey of 15 African centres, we have attempted to document the occurrence and presentation of anorectal atresia with gross terminal distension in Africa and report seven additional new cases. A possible association with associated conditions like colonic atresia requires further investigation. 23621567 Mechanism-based design of a photo-activatable firefly Luciferase. We developed a photo-activatable firefly luciferase (fLuc) whose activation can be controlled by light. A photocaged lysine analogue was site-specifically incorporated into fLuc to replace its key catalytic lysine residue-Lys529, rendering fLuc inactive until light-triggered removal of the caging group. This photo-induced gain-of-luminescence provides a facile approach for assessing the photolysis efficiency of this valuable photosensitive lysine analogue within the context of its carrier protein in vitro and in living cells. We further took advantage of the spatial and temporal activation feature of pfLuc for intracellular measurement of labile ATP levels without impairment of a cell's physiology. 23902312 Distribution, relative abundance and size composition of the threatened serranid Epinephelus daemelii in New South Wales, Australia. The aim of this study was to undertake baseline surveys on the distribution, relative abundance and total lengths (LT ) of a threatened epinephelid species, black cod Epinephelus daemelii, in New South Wales (NSW), Australia, their westernmost distribution. Diving surveys at 83 sites where E. daemelii were expected to occur were undertaken from 2009 to 2011 using 45 min roving diver counts. Sites were spread through northern NSW, including Lord Howe Island (LHI). Individual fish were measured using stereo-video, enabling accurate length measurement. Surveys were repeated at a sub-set of sites to assess temporal variation across days, seasons and years. A total of 117 E. daemelii were recorded during baseline surveys, occurring at 42% of the surveyed sites. Across all surveys, the highest numbers recorded (14-18 individuals at a site) were at the outer Solitary Islands and Fish Rock (Smoky Cape). Fewer E. daemelii were found southwards, but two sites in the Port Stephens-Great Lakes Marine Park had consistent numbers (three to six) over four annual surveys. Only 12 E. daemelii were recorded from eight of the 18 sites at LHI. The numbers observed at re-surveyed sites were generally stable over years. There were latitudinal and cross-shelf differences in LT . Individuals in the north were found to be significantly larger than those further south, and fish offshore were significantly larger than those inshore. The largest measured fish was 135 cm, smaller than the maximum LT (c. 170 cm) recorded for this species. The smallest fish was 26 cm. Overall, it is considered that the abundance of E. daemelii is low compared to anecdotal data even though they have been protected for c. 30 years in NSW. These findings provide an essential benchmark to assess ongoing status and response to protective management. 23665037 Diversification of the monoterpene synthase gene family (TPSb) in Protium, a highly diverse genus of tropical trees. Plant monoterpenes are a diverse class of secondary metabolites mediating biotic and abiotic interactions with direct effects on plant fitness. To evaluate the hypothesis that monoterpene diversity is related to functional diversification after gene duplication, we reconstructed the evolutionary history of monoterpene synthases (TPSb)--the genes underlying monoterpene synthesis--in Protium, a taxonomically and chemically diverse genus of tropical trees. We isolated multiple copies of TPSb genes from chemically divergent Protium species, reconstructed the phylogeny of this gene family, used maximum-likelihood estimation of selection coefficients, and inferred residues evolving under positive selection. We found evidence for one ancient and multiple more recent duplication events giving rise to three, and potentially five, copies of TPSb genes currently present in Protium. There was evidence for adaptive evolution in one copy with a positively selected residue likely involved in protein folding and product specificity. All other copies were inferred to be evolving under a combination of stabilizing and/or relaxed selection. Although gene copy number is consistent with the extensive phenotypic diversity in monoterpenes shown in Protium, selection analyses suggest that not all copies are undergoing divergent selection consistent with a coevolutionary arms race with enemies, but instead may be under stabilizing and relaxed selection consistent with signaling or physiological stress functionality. 23410246 Muscle regeneration and inflammation in patients with facioscapulohumeral muscular dystrophy. The aim of this study was to investigate whether inflammation and regeneration are prominent in mildly affected muscles of patients with facioscapulohumeral muscular dystrophy type 1A (FSHD1A). Inflammation in muscle has been suggested by MRI studies in patients with FSHD1A. We analysed immunohistological and histological stains of muscle biopsies from 24 patients with FSHD1A, using 10 patients with Becker muscular dystrophy (BMD) for comparison. Internalized nuclei were more prevalent in BMD (23.7 ± 10.8%) vs FSHD1A (6.3 ± 6.8%; P < 0.001), indicating more past regenerating fibres in BMD. Recently regenerating fibres, expressing neonatal myosin heavy chain and vimentin, did not differ significantly between patients with FSHD1A (1.1 ± 2.9%) and patients with BMD (1.8 ± 1.9%). Regeneration was not correlated with the number of KpnI restriction fragment repeats, an FSHD1A-defining genotype property within the D4Z4 locus, or overall disease severity in patients with FSHD1A. Macrophages were more prevalent in FSHD1A (0.50 ± 0.63 per mm(2) ) vs BMD (0.07 ± 0.07 per mm(2) ), whereas inflammatory T cells were equally infrequent. Macrophages were more prevalent in patients with FSHD1A and could be an important pathogenic mechanism for the initiation of the dystrophic process. Furthermore, regeneration was unrelated to genotype and disease severity in FSHD1A. 23540718 Tumor response and health-related quality of life in clinically selected patients from Asia with advanced non-small-cell lung cancer treated with first-line gefitinib: post hoc analyses from the IPASS study. In IPASS (NCT00322452), progression-free survival (PFS, primary endpoint) was significantly longer with first-line gefitinib versus carboplatin/paclitaxel in never/light ex-smokers with advanced pulmonary adenocarcinoma in Asia, both in the overall intent-to-treat (ITT) population and in the EGFR mutation-positive subgroup. To further characterize the clinical relevance of these data, we investigated objective response rate (ORR) and health-related quality of life (HRQoL) in patients treated with gefitinib. Objective response was assessed (RECIST) 6-weekly (previously reported). Post hoc assessments included median time to response, median duration of response and change in tumor size. The analysis of response population included those patients treated with gefitinib who responded (n = 262 from ITT; n = 94 from EGFR mutation-positive subgroup). The percentage of patients with deterioration in HRQoL (Functional Assessment of Cancer Therapy-Lung [FACT-L], Trial Outcome Index [TOI]) and symptoms (Lung Cancer Subscale [LCS]) at 4 months post-randomization was analyzed according to progression status (EFQ population grouped by progressors/non-progressors in both treatment arms). The ORR (ITT) and incidence of skin rash/acne (evaluable-for-safety) were summarized. In patients whose tumors responded to gefitinib, median time to response was 6.1 weeks in the ITT population (n = 262) and 6.0 weeks in the EGFR mutation-positive subgroup (n = 94); median duration of response was 9.7 and 8.7 months in these groups, respectively. There was significant tumor shrinkage with gefitinib. A greater percentage of patients in the EFQ population whose tumors progressed experienced deterioration in HRQoL and symptoms at 4 months versus patients whose tumors did not progress (FACT-L 33.7% vs 16.3%; TOI 33.7% vs 13.2%; LCS 31.7% vs 15.5%). In the gefitinib arm of the EFS population, incidence of rash was 75.8% and 68.1% in EGFR mutation-positive and -negative subgroups, respectively (with ORR for the gefitinib arm of the ITT 71.2% vs 1.1%, respectively). Patients whose tumors responded to first-line gefitinib experienced significant tumor shrinkage and a rapid, durable response. Deterioration in HRQoL and lung cancer symptoms at 4 months post-randomization was found to be associated with tumor progression, highlighting the role of patient-reported outcomes in the evaluation of advanced NSCLC disease. Rash was not supported as a predictive marker of response to gefitinib. 23846938 A proteomic comparison of formalin-fixed paraffin-embedded pancreatic tissue from autoimmune pancreatitis, chronic pancreatitis, and pancreatic cancer. Formalin-fixed paraffin-embedded (FFPE) tissue is a standard for specimen preservation, and as such FFPE tissue banks are an untapped resource of histologically-characterized specimens for retrospective biomarker investigation for pancreatic disease. We use liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) to compare FFPE specimens from three different diseases of the exocrine pancreas. We investigated the proteomic profile of FFPE pancreatic tissue from 9 archived specimens that were histologically classified as: autoimmune pancreatitis (n=3), chronic pancreatitis (n=3), and pancreatic cancer (n=3), using LC-MS/MS. This is a proteomic analysis experiment of FFPE pancreatic tissue in an academic center. FFPE tissue specimens were provided by Dana-Farber/Harvard Cancer Center (Boston, MA, USA). FFPE tissue specimens were collected via routine surgical resection procedures. We compared proteins identified from chronic pancreatitis, autoimmune pancreatitis, and pancreatic cancer FFPE pancreatic tissue. We identified 386 non-redundant proteins from 9 specimens. Following our filtering criteria, 73, 29, and 53 proteins were identified exclusively in autoimmune pancreatitis, chronic pancreatitis, and pancreatic cancer specimens, respectively. We report that differentially-expressed proteins can be identified among FFPE tissues specimens originating from individuals with different histological diagnoses. These proteins merit further confirmation with a greater number of specimens and orthogonal validation, such as immunohistochemistry. The mass spectrometry-based methodology used herein has the potential to enhance diagnostic biomarker and therapeutic target discovery, further advancing pancreatic research. 23401318 Joining Copper Oxide Nanotube Arrays Driven by the Nanoscale Kirkendall effect. Various annealing conditions (environment, temperature, and duration) are applied to study the nanoscale Kirkendall effect of copper (Cu) nanowire (NW) arrays on a Si substrate. The results show that an appropriate amount of oxygen supply is crucial for uniform transformation from Cu NWs (average diameter ∼50 nm) into Cu oxide nanotube arrays. An annealing duration of 30 min at 200 °C in a low vacuum environment reveals that the voids are not uniformly distributed at the Cu/Cu oxide interface. This suggests that void growth is due to surface diffusion of Cu along void surfaces. Annealing above 200 °C for 60 min resulted in complete transformation from Cu NWs into Cu oxide nanotubes. X-ray photoelectron spectroscopy characterization indicates that the Cu oxides formed at 200 °C and 300 °C are Cu(2) O and CuO, respectively. It is demonstrated that the transformation from Cu NW arrays into Cu oxide nanotube arrays can be combined with the joining of stacked Si chips in a single-process step with reasonable joint shear strength. Transmission electron microscopy-electron energy loss spectroscopy elemental mapping analysis reveals that the joint interface is Cu oxide. The outward diffusion of Cu driven by the nanoscale Kirkendall effect is believed to enhance the joining process. By controlling the environment, temperature, and duration, joined Cu(2) O or CuO nanotube stacked chips can be achieved, which serve as a platform for the further development of nanostructured, stacked devices. 23937279 Adsorbed fibrinogen enhances production of bone- and angiogenic-related factors by monocytes/macrophages. Macrophages are phagocytic cells with great importance in guiding multiple stages of inflammation and tissue repair. By producing a large number of biologically active molecules they can affect the behavior of other cells and events, such as the foreign body response and angiogenesis. Since protein adsorption to biomaterials is crucial for the inflammatory process, we addressed the ability of the pro-inflammatory molecule fibrinogen (Fg) to modulate macrophage behavior towards tissue repair/regeneration. For that we have used chitosan (Ch) as a substrate for Fg adsorption. Freshly isolated human monocytes were seeded on Ch substrates alone or previously adsorbed with Fg, and allowed to differentiate into macrophages for 10 days. Cell adhesion and morphology, formation of foreign body giant cells (FBGC) and secretion of a total of 80 cytokines and growth factors were evaluated. Both substrates showed similar numbers of adherent macrophages along differentiation as compared to RGD-coated surfaces, used as positive controls. Fg did not potentiate FBGC formation. Additionally, actin cytoskeleton staining revealed the presence of punctuate F-actin with more elongated and interconnecting cells on Ch substrates. Antibody array screening and quantification of inflammation- and wound-healing-related factors indicated an overall reduction on Ch-based substrates versus RGD-coated surfaces. At late times most inflammatory agents were down-regulated in the presence of Fg, in contrast to growth factor production which was stimulated by Fg. Importantly, on Ch+Fg substrates fully differentiated macrophages produced significant amounts of MIP-1, PDGF-BB, BMP-5 and BMP-7 compared to Ch alone. Also, other important factors involved in bone homeostasis and wound healing, such as GH, TGF-β3 and IGFBPs, as well as several angiogenic mediators, including EG-VEFG, FGF-7 and PIGF, were significantly promoted by Fg. This work provides new perspective on the inflammatory response in the context of bone repair/regeneration mediated by a pro-inflammatory protein (Fg) adsorbed onto a biomaterial (Ch) that does not otherwise exhibit osteogenic properties. 23823654 Role of Pulsatility in Hypothermic Reconditioning of Porcine Kidney Grafts by Machine Perfusion After Cold Storage. Brief in-house machine perfusion after cold storage (CS) (hypothermic reconditioning) has been proposed as a convenient tool to improve kidney graft function. The present study aimed to investigate the mechanistic role of vascular pulsatility in this context. Kidney function after cold preservation (4°C, 18 hr) and subsequent reconditioning by 90 min of pulsatile machine perfusion (PP) (30/20 mm Hg) or nonpulsatile machine perfusion (NPP) (30 mm Hg) was studied in an isolated kidney perfusion model in pigs (n=6 for both) and compared with simply CS grafts. Compared with CS, PP but not NPP significantly improved renal perfusate flow and urine production and significantly increased the reduction of perfusate levels of creatinine and urea during reperfusion. Perfusate levels of fatty acid binding protein, a marker of tubular cell injury, were dramatically reduced by PP but not NPP. PP and NPP lowered fractional excretion of sodium, but significance was only reached for PP. Molecular effects of PP comprised a significant (vs. CS) mRNA elevation of the endothelial anti-inflammatory transcription factor Krüppel-like factor 2 as well as endothelial nitric oxide synthase, along with significantly higher perfusate levels of the endogenous vasodilator nitric oxide. Functional efficiency of PP over CS was confirmed in additional porcine transplant experiments (n=5 for both) by, for example, up to threefold improved clearance of creatinine during the first days after transplantation. PP of 90 min shortly before transplantation seems to be an efficient mechanism to reduce proinflammatory endothelial phenotype and improve functional outcome of kidney grafts even after preceding static storage. 23458581 Electronic transitions of protonated and deprotonated amino acids in aqueous solution in the region 145-300 nm studied by attenuated total reflection far-ultraviolet spectroscopy. The electronic transitions of 20 naturally occurring amino acids in aqueous solution were studied with attenuated total reflection far-ultraviolet (ATR-FUV) spectroscopy in the region from 145 to 300 nm. From the measured ATR spectra of sample solutions, the FUV absorption spectra attributed to the amino acids were separated from the intense solvent absorption by using a modified Kramers-Kronig transformation method. The FUV absorption spectra of the amino acids reflect the protonation states of the backbone and side-chain structures. The contributions of the side chains to the spectra were also examined from the difference spectra subtracting the corresponding Gly spectrum from each spectrum. The observed spectra were compared mostly with the electronic transition studies of the molecular fragments of the amino acids in gas phase. The FUV spectra of the amino acids exhibited the intra- and intermolecular electronic interactions of the solute-solute as well as the solute-solvent, and those are essential factors to elucidate UV photochemical processes of the amino acids in aqueous solution. 23778963 Biosensing MAPs as "roadblocks": kinesin-based functional analysis of tau protein isoforms and mutants using suspended microtubules (sMTs). The concept of a reconstructed microtubule kinesin-based transport system was originally introduced for studies of underlying biophysical mechanisms of intracellular transport and its potential applications in bioengineering at micro- and nanoscale levels. However, several technically challenging shortcomings prohibit its use in practical applications. One of them is the propensity of microtubules to bind various protein molecules creating "roadblocks" for kinesin molecule movement and subsequently preventing efficient delivery of the molecular cargo. The interruption in kinesin movement strictly depends on the specific type of "roadblock", i.e. the microtubule associated protein (MAP). Therefore, we propose to use the "roadblock" effect as a molecular sensor that may be used for functional characterization of particular MAPs with respect to their role in MT-based transport and associated pathologies, such as neurodegeneration. Here, we applied a kinesin-based assay using a suspended MT design (sMT assay) to functionally characterize known MAP tau protein isoforms and common mutations found in familial frontotemporal dementia (FTD). The proposed sMT assay is compatible with an on-chip format and may be used for the routine characterization of MT associated molecules applicable to diagnostics and translational research. 23606366 Proteomic and cytokine plasma biomarkers for predicting progression from colorectal adenoma to carcinoma in human patients. In the present study, we screened proteomic and cytokine biomarkers between patients with adenomatous polyps and colorectal cancer (CRC) in order to improve our understanding of the molecular mechanisms behind turmorigenesis and tumor progression in CRC. To this end, we performed comparative proteomic analysis of plasma proteins using a combination of 2DE and MS as well as profiled differentially regulated cytokines and chemokines by multiplex bead analysis. Proteomic analysis identified 11 upregulated and 13 downregulated plasma proteins showing significantly different regulation patterns with diagnostic potential for predicting progression from adenoma to carcinoma. Some of these proteins have not previously been implicated in CRC, including upregulated leucine-rich α-2-glycoprotein, hemoglobin subunit β, Ig α-2 chain C region, and complement factor B as well as downregulated afamin, zinc-α-2-glycoprotein, vitronectin, and α-1-antichymotrypsin. In addition, plasma levels of three cytokines/chemokines, including interleukin-8, interferon gamma-induced protein 10, and tumor necrosis factor α, were remarkably elevated in patients with CRC compared to those with adenomatous polyps. Although further clinical validation is required, these proteins and cytokines can be established as novel biomarkers for CRC and/or its progression from colon adenoma. 23953211 Optical metal-organic framework sensor for selective discrimination of some toxic metal ions in water. This paper reports the development of a facile and effective approach, based on the use of Zr-based metal-organic frameworks (UiO-66) sensor with micropores geometry, shape and particle morphology for the visual detection and removal of ultra-traces of some toxic metal ions such as Bi(III), Zn(II), Pb(II), Hg(II) and Cd(II). UiO-66 was used as selective carriers for accommodating hydrophobic chromophore probes such as dithizone (DZ) without coupling agent for sensitive and selective discrimination of trace level of toxic analytes. The developed UiO-66 sensor was utilized for the detection of ultra-traces of some toxic metal ions with the naked eye. The new sensor displays high sensitivity and selectivity of a wide range of detectable metals analytes up to 10(-10)moldm(-3) in solution, in a rapid analyte uptake response (seconds). The developed sensor is stable, cost effective, easy to prepare, and would be useful for rapid detection and removal of ultra-traces of toxic metal ions in water samples. 23928893 Landes Highlights. CRM1 and NMD3 localize to the nucleolus and affect rRNA synthesis: mRNA secondary structure correlates with protein function and domains: Transcriptional changes induced by tumor dormancy-associated microRNA-190: Ribonuclease binase: A potential anticancer therapeutic: 23711721 Measurement of translesion synthesis by fluorescent capillary electrophoresis: 7,8-Dihydro-8-oxodeoxyguanosine bypass modulation by natural products. Translesion synthesis (TLS) relies on a series of specialized DNA polymerases able to insert a base either correctly or incorrectly opposite a lesion on a DNA template strand during replication or post-repair synthesis. To measure the correct or mutagenic outcome of 7,8-dihydro-8-oxodeoxyguanosine (8-oxodG) bypass by TLS DNA polymerases, a capillary electrophoresis (CE) method with fluorescent label has been developed. Two oligonucleotides were designed and hybridized: (i) a 72-mer oligonucleotide framing one 8-oxodG at position 40 and (ii) the 39-mer oligonucleotide complementary to the first strand from the 3' end to the lesion and labeled at the 5' end with a fluorochrome. After incubation with FHs 74 Int human intestinal epithelial cell nuclear proteins, in the presence of either deoxyadenosine triphosphate (dATP) or deoxycytidine triphosphate (dCTP), and denaturation, the resulting elongated oligomers were analyzed by fluorescent capillary electrophoresis. This primer extension assay was then validated in terms of linearity (linear range=0.5-2.5nM), detectability (limits of detection and quantification=0.023 and 0.091nM, respectively), and precision (total precisions=8.1% and 3.7% for dATP and dCTP, respectively, n=9). The addition of some natural phytochemicals to the reaction mix significantly influences the outcome of TLS either in an error-free way or in a mutagenic way. 23911564 Incidence of unanticipated uterine pathology at the time of minimally invasive abdominal sacrocolpopexy. To determine the incidence of unanticipated uterine pathology in women undergoing hysterectomy at the time of minimally invasive sacrocolpopexy (MISC). Retrospective case series. Classification: Canadian Task Force III SETTING: Four institutions in the United States. Women undergoing laparoscopic or robotically-assisted sacrocolpopexy with hysterectomy. None MEASUREMENTS AND MAIN RESULTS: We measured the incidence of clinically significant uterine pathology at the time of MISC. A total of 324 women had concurrent hysterectomy performed at the time of their MISC. The mean age and BMI were 56.1years and 26.9kg/m(2), respectively. Sixty-four percent were postmenopausal. Only 3/324(0.92%) had abnormal uterine pathology. There were no significant differences in age, BMI, or parity between the women with normal and abnormal uterine pathology. None of the three women reported abnormal uterine bleeding prior to surgery. All cases were premalignant and focal in nature. No cases of invasive carcinoma were identified. None of the patients needed further followup or treatment for their abnormal pathology. The risk of unanticipated uterine pathology at the time of minimally invasive sacrocolpopexy for pelvic organ prolapse is low. 23895127 Monocytes and macrophages as nanomedicinal targets for improved diagnosis and treatment of disease. The important role of monocytes and macrophages in diseases like cancer and atherosclerosis has started to get uncovered in the last decade. In addition, subsets of these cell types are believed to participate in the initiation and aggravation of several diseases including cancer and cardiovascular disease. For this reason, monocytes and macrophages have recently been identified as interesting targets for both diagnosis and treatment of the aforementioned pathologies. Compared with free therapeutic or imaging agents, nanoparticle formulations provide several advantages that improve the pharmacokinetics and bioavailability of these agents. In addition, the possibility of surface functionalization creates numerous ways to optimize nanoparticle delivery. Recent advances in nanomedicine have led to the development of multifunctional nanoparticles that allow simultaneous diagnosis and treatment of monocytes and macrophages with high specificity. Relying on the inherent ability of monocytes and macrophages to easily take up foreign particles, the use of nanoparticles provides a precious opportunity for the management of several inflammatory diseases. 23912652 Lymphocytic interstitial pneumonia as a manifestation of SLE and secondary Sjogren's syndrome. A 47-year-old woman with systemic lupus erythematosus (SLE) diagnosed at age of 35years was admitted for dyspnoea, substernal chest pain, dry mucosas and difficulty in swallowing. Physical examination revealed vesicular breath sounds bilaterally. Laboratory work showed antinuclear antibody (ANA) (speckled pattern, 1:40), positive anti-Sjogren's syndrome antigen (SSA) and antisingle side band (SSB) and negative double-strand DNA (dsDNA), with normal C3,C4,C50. A high-resolution chest CT scan demonstrated multiple bronchial cysts and diffuse interstitial infiltrates. Surgical lung biopsy revealed emphysematous changes and mild lymphocytic infiltrate around the bronchioles compatible with lymphocytic interstitial pneumonia diagnosis. This case illustrates a patient with primary SLE overlapped by initial manifestations of secondary Sjogren's syndrome (SS) presenting with associated autoimmune interstitial lung disease. Antibody markers, high-resolution chest CT scan and surgical lung biopsy were essential in evaluating this patient, confirming the interstitial lymphocytic infiltration of the lung. Primary SS (pSS) is the most commonly associated disease to lung interstitial pneumonia (LIP) (25%). High-resolution chest CT scan demonstrates areas of ground-glass attenuation, suggestive of interstitial disease. Surgical lung biopsy shows pathologic increase of mature lymphocyte cells and histiocytes. Most of the cases have a benign presentation and shortly relapse. Superimposed infection, pulmonary fibrosis and lymphoma develop in less than 20% of cases. Corticosteroids are the primary therapy. While pSS is commonly associated with interstitial lung involvement, secondary Sjogren's syndrome (sSS) is only rare. It has been described the initial sSS presentation by Sica symptoms development only, and our case is the first report of LIP presentation as initial manifestation of sSS. Our patient remained stable after corticosteroids and hydoxychloroquine therapy and no progression of disease after 6 months follow-up. 23417424 Hepatic growth hormone resistance after acute injury. Severe injury and infection are often followed by accelerated protein catabolism and acute insulin resistance. This results in several effects that complicate and prolong recovery, including weakness, immobility, impaired wound healing, and organ dysfunction. Recent studies have demonstrated the development of GH resistance during severe inflammation, providing a potential mechanism for the protein loss that follows injury and infection. To understand this GH resistance, we recently developed a murine model of acute injury. Mice were subjected to soft-tissue injury, alone or combined with hemorrhage, and injected iv with GH 30, 60, or 90 minutes later. Hepatic GH signaling was measured via Western analysis. GH-induced signal transducer and activator of transcription 5 phosphorylation was decreased immediately after completion of the trauma procedure, and at 30 and 60 minutes, but further decreased by 90 minutes after trauma. Combined trauma and hemorrhage resulted in severely decreased GH-induced signal transducer and activator of transcription 5 phosphorylation compared with trauma alone, and this was true at all time points studied. Western analysis revealed an apparent decrease in the molecular weight of the hepatic GH receptor (GHR) after trauma and hemorrhage, but not trauma alone. Additional studies determined that the hemorrhage-induced decrease in receptor size was not due to changes in GHR N-linked glycosylation. These results suggest that GH sensitivity is rapidly impaired after acute injury and that trauma combined with hemorrhage results in a more severe form of GH resistance resulting from alteration or inactivation of hepatic GHR. 23676303 Parvovirus evades interferon-dependent viral control in primary mouse embryonic fibroblasts. Engagement of innate viral sensors elicits a robust antiviral program via the induction of type I interferons (IFNs). Innate defense mechanisms against ssDNA viruses are not well defined. Here, we examine type I IFN induction and effectiveness in controlling a ssDNA virus. Using mouse embryonic fibroblasts (MEFs), we found that a murine parvovirus, minute virus of mice (MVMp), induced a delayed but significant IFN response. MEFs deficient in mitochondrial antiviral signaling protein (MAVS) mounted a wild-type IFN response to MVMp infection, indicating that RIG-I-dependent RNA intermediate recognition is not required for innate sensing of this virus. However, MVMp-induced IFNs, as well recombinant type I IFNs, were unable to inhibit viral replication. Finally, MVMp infected cells became unresponsive to Poly (I:C) stimulation. Together, these data suggest that the MVMp efficiently evades antiviral immune mechanisms imposed by type I IFNs, which may in part explain their efficient transmission between mice. 23898022 Do we really need high-sensitivity troponin immunoassays in the emergency department? Maybe not. Abstract The diagnosis of acute coronary syndrome (ACS) has challenged the minds of cardiologists, emergency physicians and laboratorists for decades. A major breakthrough has, however, occurred at the dawn of the third millennium, with development, commercialization and introduction into clinical practice of troponin immunoassays. A novel generation of these methods, conventionally defined as "high-sensitivity" (HS), has more recently emerged. These latest generation assays are characterized by improved analytical sensitivity, which would theoretically allow earlier and more efficient diagnosis of ACS. Despite the considerable amount of information gathered over the past few years about the clinical use of conventional and HS immunoassays, several doubts persist and - according to our personal perspective - the evidence that the latest generation methods would represent a real breakthrough in management of patients in short-stay units such as the emergency department is still an unresolved issue. Beside the mystifying nomenclature that characterizes several commercial tests, recent evidence suggests that the diagnostic performance of some contemporary sensitive methods would equal those of HS immunoassays for early diagnosis, serial assessment and even prognostication of patients. Conversely, the better diagnostic specificity of conventional methods may represent an advantage for triaging patients in overcrowded emergency departments. There is hence a tangible threat that the measurement of troponin with HS methods would become more or less an "expensive cholesterol of the third millennium", and this risk must be carefully considered in a world of limited resources. So, our answer to the question if we do really need HS troponin immunoassays in the emergency department is "maybe not". 23838326 Expression of klotho mRNA and protein in rat brain parenchyma from early postnatal development into adulthood. Without the age-regulating protein klotho, mouse lifespan is shortened and the rapid onset of age-related disorders occurs. Conversely, overexpression of klotho extends mouse lifespan. Klotho is most abundant in kidney and expressed in a limited number of other organs, including the brain, where klotho levels are highest in choroid plexus. Reports vary on where klotho is expressed within the brain parenchyma, and no data is available as to whether klotho levels change across postnatal development. We used in situ hybridization to map klotho mRNA expression in the developing and adult rat brain and report moderate, widespread expression across grey matter regions. mRNA expression levels in cortex, hippocampus, caudate putamen, and amygdala decreased during the second week of life and then gradually rose to adult levels by postnatal day 21. Immunohistochemistry revealed a protein expression pattern similar to the mRNA results, with klotho protein expressed widely throughout the brain. Klotho protein co-localized with both the neuronal marker NeuN, as well as, oligodendrocyte marker olig2. These results provide the first anatomical localization of klotho mRNA and protein in rat brain parenchyma and demonstrate that klotho levels vary during early postnatal development. 23750038 Clinico-pathological characteristics and clinical outcome of different histological types of pancreatic cancer in a large Middle European series. Pancreatic cancer (PC) is a heterogeneous disease in terms of histological and molecular subtypes. The aim of this study was to evaluate the prognostic impact of different histological subtypes on cancer-specific survival (CSS) in a large single-centre Middle European cohort. We retrospectively studied the records of 400 consecutive PC patients who were treated from 2004 to 2010 at a single tertiary academic centre. The association of histological subtypes and parameters such as tumour stage, tumour grade, levels of tumour markers carcinoembryonic antigen and CA19-9 at diagnosis, was studied. CSS was calculated using the Kaplan-Meier method, and the influence of each parameter on CSS was assessed with univariate and multivariable Cox proportional models. The survival time was significantly shorter in the ductal adenocarcinoma and acinar histological subtypes compared to neuroendocrine differentiation (p<0.001). No survival difference was observed between ductal adenocarcinomas and patients with a histological variant of ductal adenocarcinoma, namely, mucinous non-cystic adenocarcinoma (p=0.7). In multivariable analysis, ductal adenocarcinoma (HR=3.1, CI 1.6 to 6.1, p=0.001) and acinar carcinoma (HR=3.2, CI 1.3 to 8.5, p=0.016) were identified as independent predictors for CSS. Our findings suggest that the main histological subtype is an independent predictor of CSS in patients with PC. Thus, our data underline the importance of routine assessment of histological type in PC for individual risk assessment. However, no clinical rationale for the subdivision of ductal adenocarcinoma and mucinous non-cystic adenocarcinoma can be supported by our study. 23866721 Surface modification of PLGA nanoparticles via human serum albumin conjugation for controlled delivery of docetaxel. Poly lactic-co-glycolic acid (PLGA) based nanoparticles are considered to be a promising drug carrier in tumor targeting but suffer from the high level of opsonization by reticuloendothelial system due to their hydrophobic structure. As a result surface modification of these nanoparticles has been widely studied as an essential step in their development. Among various surface modifications, human serum albumin (HSA) possesses advantages including small size, hydrophilic surface and accumulation in leaky vasculature of tumors through passive targeting and a probable active transport into tumor tissues. PLGA nanoparticles of docetaxel were prepared by emulsification evaporation method and were surface conjugated with human serum albumin. Fourier transform infrared spectrum was used to confirm the conjugation reaction where nuclear magnetic resonance was utilized for conjugation ratio determination. In addition, transmission electron microscopy showed two different contrast media in conjugated nanoparticles. Furthermore, cytotoxicity of free docetaxel, unconjugated and conjugated PLGA nanoparticles was studied in HepG2 cells. Size, zeta potential and drug loading of PLGA nanoparticles were about 199 nm, -11.07 mV, and 4%, respectively where size, zeta potential and drug loading of conjugated nanoparticles were found to be 204 nm, -5.6 mV and 3.6% respectively. Conjugated nanoparticles represented a three-phasic release pattern with a 20% burst effect for docetaxel on the first day. Cytotoxicity experiment showed that the IC50 of HSA conjugated PLGA nanoparticles (5.4 mug) was significantly lower than both free docetaxel (20.2 mug) and unconjugated PLGA nanoparticles (6.2 mug). In conclusion surface modification of PLGA nanoparticles through HSA conjugation results in more cytotoxicity against tumor cell lines compared with free docetaxel and unconjugated PLGA nanoparticles. Albumin conjugated PLGA nanoparticles may represent a promising drug delivery system in cancer therapy. 23879907 Bilateral focal ablation of prostate tissue using low-energy direct current (LEDC): a preclinical canine study. To evaluate side-effects, erectile function and capability to preserve adjacent tissues of bilateral focal prostate ablation using low-energy direct current (LEDC) in a canine model. In all, 12 male Beagle dogs underwent bilateral focal prostate ablation using the NanoKnife™ LEDC system. Three 19 G monopolar electrodes were transperineally placed on each side of the prostate under transrectal ultrasonographic (TRUS) guidance using a triangular probe array. Intra- and postoperative side-effects were recorded. Erectile function was evaluated at baseline and 4-5 and 26-27 days after ablation. The dogs were killed humanely at 7 (six) and 30 days (six) for gross and microscopic evaluation of the prostate and adjacent organs. The median (range) prostate volume on TRUS was 12.1 (8.9-17.2) mL. The electrodes were placed at a median distance of 0.55-0.66 cm from the capsule, urethra and rectum. All procedures were completed successfully and recovery was uneventful. There were no episodes of urinary retention. All the dogs were able to achieve erections after ablation. Pathological analyses revealed inflammatory changes in the ablation zone at 7 days and replacement by fibrosis at 30 days. On microscopic examination no histological injury to the capsule, urethra, rectal wall or nervous structures was identified. In this study, bilateral focal prostate ablation using LEDC was safe and had a favourable side-effects profile limited to transient minor events. LEDC ablation effectively spared adjacent structures as well as physiological functions in all the dogs. 22551088 Physicochemical and morphological characterisation of nanoparticles from photocopiers: implications for environmental health. Abstract Several reports link printing and photocopying with genotoxicity, immunologic and respiratory diseases. Photocopiers and printers emit nanoparticles, which may be involved in these diseases. The physicochemical and morphological composition of these emitted nanoparticles, which is poorly understood and is critical for toxicological evaluations, was assessed in this study using both real-time instrumentation and analytical methods. Tests included elemental composition (40 metals), semi-volatile organics (100 compounds) and single particle analysis, using multiple high-sensitivity/resolution techniques. Identical analyses were performed on the toners and dust collected from copier's exhaust filter. Engineered nanoparticles, including titanium dioxide, iron oxide and fumed silica, and several metals were found in toners and airborne nanoscale fraction. Chemical composition of airborne nanoscale fraction was complex and reflected toner chemistry. These findings are important in understanding the origin and toxicology of such nanoparticles. Further investigation of their chemistry, larger scale exposure studies and thorough toxicological characterisation of emitted nanoparticles is needed. 23673573 Digital breast tomosynthesis versus mammography and breast ultrasound: a multireader performance study. To compare the diagnostic performance of single-view breast tomosynthesis (BT) with that of dual-view mammography (MX); to assess the benefit of adding the craniocaudal (CC) mammographic view to BT, and of adding BT to MX plus breast ultrasound, considered to be the reference work-up. One hundred and fifty-five consenting patients with unresolved mammographic and/or ultrasound findings or breast symptoms underwent conventional work-up plus mediolateral oblique-view BT of the affected breast. The final study set in 130 patients resulted in 55 malignant and 76 benign and normal cases. Seven breast radiologists rated the cases through five sequential techniques using a BIRADS-based scale: MX, MX + ultrasound, MX + ultrasound + BT, BT, BT + MX(CC). Multireader, multicase receiver operating characteristic (ROC) analysis was performed and performance of the techniques was assessed from the areas under ROC curves. The performance of BT and of BT + MX(CC) was tested versus MX; the performance of MX + ultrasound + BT tested versus MX + ultrasound. Tomosynthesis was found to be non-inferior to mammography. BT + MX(CC) did not appear to be superior to MX, and MX + ultrasound + BT not superior to MX + ultrasound. Overall, none of the five techniques tested outperformed the others. Further clinical studies are needed to clarify the role of BT as a substitute for traditional work-up in the diagnostic environment. • Digital breast tomosynthesis is a new adjunct to mammography and breast ultrasound. • We compared the diagnostic performance of these investigations in an experimental observer study. • Single-view breast tomosynthesis was confirmed as non-inferior to dual-view mammography. • None of the investigations (or combinations) tested outperformed the others. • Further prospective studies are needed to clarify precise role of tomosynthesis for diagnostic application. 23852949 Mitochondria and tumor progression in ulcerative colitis. The role of mitochondria in cancer is poorly understood. Ulcerative colitis (UC) is an inflammatory bowel disease that predisposes to colorectal cancer and is an excellent model to study tumor progression. Our goal was to characterize mitochondrial alterations in UC tumorigenesis. Nondysplastic colon biopsies from UC patients with high-grade dysplasia or cancer (progressors; n = 9) and UC patients dysplasia free (nonprogressors; n = 9) were immunostained for cytochrome C oxidase (COX), a component of the electron transport chain, and were quantified by multispectral imaging. For six additional progressors, nondysplastic and dysplastic biopsies were stained for COX and additional mitochondrial proteins including PGC1α, the master regulator of mitochondrial biogenesis. Mitochondrial DNA (mtDNA) copy number was determined by quantitative polymerase chain reaction. Generalized estimating equations with two-sided tests were used to account for correlation of measurements within individuals. Nondysplastic biopsies of UC progressors showed statistically significant COX loss compared with UC nonprogressors by generalized estimating equation (-18.5 units, 95% confidence interval = -12.1 to -24.9; P < .001). COX intensity progressively decreased with proximity to dysplasia and was the lowest in adjacent to dysplasia and dysplastic epithelium. Surprisingly, COX intensity was statistically significantly increased in cancers. This bimodal pattern was observed for other mitochondrial proteins, including PGC1α, and was confirmed by mtDNA copy number. Mitochondrial loss precedes the development of dysplasia, and it could be used to detect and potentially predict cancer. Cancer cells restore mitochondria, suggesting that mitochondria are needed for further proliferation. This bimodal pattern might be driven by transcriptional regulation of mitochondrial biogenesis by PGC1α. 23063746 Structure-based design and synthesis of novel pseudosaccharine derivatives as antiproliferative agents and kinase inhibitors. This study is concerned with the implementation of structure-based techniques for the design of new heterocyclic compounds based on pseudosaccharine scaffold with protein kinase inhibition activity. This nucleus was exploited based on the well-known quinazoline core and its interactions with several protein kinases. Two series of compounds employing this new scaffold were synthesized and evaluated at enzymatic and cellular levels. Compound 9b displayed broad spectrum antiproliferative activity on NCI 60-cell lines panel with mean GI50 of 5.4 μM. Investigation of the molecular mechanism showed probable inhibitory activity against Src kinase. 23874603 HIV-1 Vpr Modulates Macrophage Metabolic Pathways: A SILAC-Based Quantitative Analysis. Human immunodeficiency virus type 1 encoded viral protein Vpr is essential for infection of macrophages by HIV-1. Furthermore, these macrophages are resistant to cell death and are viral reservoir. However, the impact of Vpr on the macrophage proteome is yet to be comprehended. The goal of the present study was to use a stable-isotope labeling by amino acids in cell culture (SILAC) coupled with mass spectrometry-based proteomics approach to characterize the Vpr response in macrophages. Cultured human monocytic cells, U937, were differentiated into macrophages and transduced with adenovirus construct harboring the Vpr gene. More than 600 proteins were quantified in SILAC coupled with LC-MS/MS approach, among which 136 were significantly altered upon Vpr overexpression in macrophages. Quantified proteins were selected and clustered by biological functions, pathway and network analysis using Ingenuity computational pathway analysis. The proteomic data illustrating increase in abundance of enzymes in the glycolytic pathway (pentose phosphate and pyruvate metabolism) was further validated by western blot analysis. In addition, the proteomic data demonstrate down regulation of some key mitochondrial enzymes such as glutamate dehydrogenase 2 (GLUD2), adenylate kinase 2 (AK2) and transketolase (TKT). Based on these observations we postulate that HIV-1 hijacks the macrophage glucose metabolism pathway via the Vpr-hypoxia inducible factor 1 alpha (HIF-1 alpha) axis to induce expression of hexokinase (HK), glucose-6-phosphate dehyrogenase (G6PD) and pyruvate kinase muscle type 2 (PKM2) that facilitates viral replication and biogenesis, and long-term survival of macrophages. Furthermore, dysregulation of mitochondrial glutamate metabolism in macrophages can contribute to neurodegeneration via neuroexcitotoxic mechanisms in the context of NeuroAIDS. 23165312 Computer simulation study of nanoparticle interaction with a lipid membrane under mechanical stress. Pore formation of lipid bilayers under mechanical stress is critical to biological processes. A series of coarse grained molecular dynamics simulations of lipid bilayers with carbon nanoparticles different in size have been performed. Surface tension was applied to study the disruption of lipid bilayers by nanoparticles and the formation of pores inside the bilayers. The presence of small nanoparticles enhances the probability of water penetration thus decreasing the membrane rupture tension, while big nanoparticles have the opposite effect. Nanoparticle volume affects bilayer strength indirectly, and particle surface density can complicate the interaction. The structural, dynamic, elastic properties and lateral densities of lipid bilayers with nanoparticles under mechanical stress were analyzed. The results demonstrate the ability of nanoparticles to adjust the structural and dynamic properties of a lipid membrane, and to efficiently regulate the pore formation behavior and hydrophobicity of membranes. 23927257 An efficient method to study highly excited states at the ab initio level and application to ultralong Rydberg CsNe molecules. An efficient method to study highly excited states at the ab initio level has been introduced and applied to ultralong Rydberg CsNe molecules. Vibrational properties of Rydberg CsNe molecules are investigated on corresponding potential energy curves obtained by perturbation theory. The Rydberg CsNe molecules are associated with a Rydberg Cs(ns∕np) atom (n = 20-60) and a ground state Ne((1)S0) atom. The starting point for the perturbation treatment of corresponding Rydberg molecular potential energy curves is to generate accurate atomic Rydberg states from realistic ab initio effective core potential. According to the authors' knowledge this is a good reference for ultralong range molecules (order of 1000 Bohr radii) to be studied at the ab initio level. 23851709 An Observational Study of the Accuracy and Completeness of an Anesthesia Information Management System: Recommendations for Documentation System Changes. Anesthesia information management systems must often be tailored to fit the environment in which they are implemented. Extensive customization necessitates that systems be analyzed for both accuracy and completeness of documentation design to ensure that the final record is a true representation of practice. The purpose of this study was to determine the accuracy of a recently installed system in the capture of key perianesthesiadata. This study used an observational design and was conducted using a convenience sample of nurse anesthetists. Observational data of the nurse anesthetists'delivery of anesthesia care were collected using a touch-screen tablet computer utilizing an Access database customized observational data collection tool. A questionnaire was also administered to these nurse anesthetists to assess perceived accuracy, completeness, and satisfaction with the electronic documentation system. The major sources of data not documented in the system were anesthesiologist presence (20%) and placement of intravenous lines (20%). The major sources of inaccuracies in documentation were gas flow rates (45%), medication administration times (30%), and documentation of neuromuscular functiontesting (20%)-all of the sources of inaccuracies were related to the use of charting templates that were not altered to reflect the actual interventions performed. 23866105 VARIATIONS IN UNMET NEED FOR CONTRACEPTION IN ZAMBIA: DOES ETHNICITY PLAY A ROLE? Summary Ethnicity has been found to be a significant indicator of social position, and many studies have also established that ethnicity is a significant determinant of contraceptive use. This study aims to examine whether ethnicity is an important predictor of unmet need for contraception. Analysis was based on data for 4343 ever-married women drawn from the 2007 Zambia Demographic and Health Survey. Descriptive analysis indicates that in all ethnic groups except the Barotse and Tonga, women aged 15-49 years were married at an average age below 18. The highest mean number of children among the ethnic groups was 6.7, among the Bemba; the lowest was 5.9, among the Barotse. The highest proportion of women with an unmet need for contraception resided in the Eastern region. Multivariate logistic analyses reveal that children ever-born and region of residence were the most important predictors of unmet need for spacing, whereas for unmet need for limiting predictors were age at first marriage and partner's desire for children. Moreover, unmet need for spacing and limiting among women with secondary or higher education was significantly lower (47% and 50%, respectively) compared with those with no education. Ethnicity was not a significant predictor of unmet need for contraception. The findings stress the need for programmes aimed at enhancing the socioeconomic status of women. 23900722 Antiproliferative Effects of PACAP and VIP in Serum-Starved Glioma Cells. Emerging evidence have suggested that calorie restriction (CR) is a reliable method to decrease cancer development since it produces changes in tumor microenvironment that interfere with cell proliferation, tissue invasion, and formation of metastases. Studies on the role of pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) in cancer cells indicate that their influence on cell growth is either cell type specific or dependent on culture conditions. Evidence showing the effect of PACAP and VIP in glioma cells grown under conditions mimicking CR are currently unavailable. Therefore, we explored the effects of both PACAP and VIP in C6 glioma cells either grown in a normal growth medium or exposed to serum starvation, to resemble an acute condition of CR. Cell viability, expression of proteins related to cell proliferation (cyclin D1), apoptosis (Bcl2, p53, and cleaved caspase-3), and cell malignancy (GFAP and nestin) were assessed by MTT assay, immunoblot, and immunolocalization, respectively. Results demonstrated that CR significantly decreased cell proliferation, reduced levels of cyclin D1 and Bcl2, and increased the expression of p53 and cleaved caspase-3. Surprisingly, all of these CR-driven effects were further exacerbated by PACAP or VIP treatment. We also found that PACAP or VIP prevented GFAP decrease caused by CR and further reduced the expression of nestin, a prognostic marker of malignancy. In conclusion, these data demonstrate that PACAP and VIP possess antiproliferative properties against glioma cells that depend on the specific culture settings, further supporting the idea that CR might offer new avenues to improve peptide-oriented glioma cancer treatment. 23894427 Against all odds: genocidal trauma is associated with longer life-expectancy of the survivors. Does surviving genocidal experiences, like the Holocaust, lead to shorter life-expectancy? Such an effect is conceivable given that most survivors not only suffered psychosocial trauma but also malnutrition, restriction in hygienic and sanitary facilities, and lack of preventive medical and health services, with potentially damaging effects for later health and life-expectancy. We explored whether genocidal survivors have a higher risk to die younger than comparisons without such background. This is the first population-based retrospective cohort study of the Holocaust, based on the entire population of immigrants from Poland to Israel (N = 55,220), 4-20 years old when the World War II started (1939), immigrating to Israel either between 1945 and 1950 (Holocaust group) or before 1939 (comparison group; not exposed to the Holocaust). Hazard of death - a long-term outcome of surviving genocidal trauma - was derived from the population-wide official data base of the National Insurance Institute of Israel. Cox regression yielded a significant hazard ratio (HR = 0.935, CI (95%) = 0.910-0.960), suggesting that the risk of death was reduced by 6.5 months for Holocaust survivors compared to non-Holocaust comparisons. The lower hazard was most substantial in males who were aged 10-15 (HR = 0.900, CI (95%) = 0.842-0.962, i.e., reduced by 10 months) or 16-20 years at the onset of the Holocaust (HR = 0.820, CI (95%) = 0.782-0.859, i.e., reduced by18 months). We found that against all odds genocidal survivors were likely to live longer. We suggest two explanations: Differential mortality during the Holocaust and "Posttraumatic Growth" associated with protective factors in Holocaust survivors or in their environment after World War II. 23880749 Long-term Issues After the Fontan Procedure. The Fontan procedure is used to treat various serious congenital heart defects. Although many people who have had the procedure live productively into adulthood, as they age, they face several health issues due to the physiology of the Fontan circulation. This article reviews the 4 types of Fontan procedures and the changes caused by the surgery, including single-ventricle physiology, nonpulsatile pulmonary perfusion, systemic venous hypertension, and intracardiac scarring, as well as their sequelae. Key nursing assessment items and possible treatment strategies are reviewed. Additional topics, including pregnancy in patients who have undergone the procedure, infective endocarditis prophylaxis, and health-related quality of life, are briefly discussed. Options for Fontan failure, including Fontan conversion or transplantation, are presented. Potential future solutions are outlined. 23456256 Mesenchymal stem cells secretome: a new paradigm for central nervous system regeneration? The low regeneration potential of the central nervous system (CNS) represents a challenge for the development of new therapeutic strategies. Mesenchymal stem cells (MSCs) have been proposed as a possible therapeutic tool for CNS disorders. In addition to their differentiation potential, it is well accepted nowadays that their beneficial actions can also be mediated by their secretome. Indeed, it was already demonstrated, both in vitro and in vivo, that MSCs are able to secrete a broad range of neuroregulatory factors that promote an increase in neurogenesis, inhibition of apoptosis and glial scar formation, immunomodulation, angiogenesis, neuronal and glial cell survival, as well as relevant neuroprotective actions on different pathophysiological contexts. Considering their protective action in lesioned sites, MSCs' secretome might also improve the integration of local progenitor cells in neuroregeneration processes, opening a door for their future use as therapeutical strategies in human clinical trials. Thus, in this review we analyze the current understanding of MSCs secretome as a new paradigm for the treatment of CNS neurodegenerative diseases. 23512910 Mastoid Obliteration Using Three-Dimensional Composite Scaffolds Consisting of Polycaprolactone/β-Tricalcium Phosphate/Collagen Nanofibers: An In Vitro and In Vivo Study. Two different composite scaffolds, solid-freeform-fabricated PCL/β-TCP supplemented with and without collagen nanofibers are fabricated. These scaffolds are evaluated whether a combination of collagen nanofibers with PCL/β-TCP can promote osteogenesis in a mastoid obliteration. To assess the effects of the cellular activities of osteoblast-like-cells (MG63), SEM images and MTT assays are conducted. Experimental mastoid obliteration is performed using guinea pigs that are divided group A (PCL/β-TCP/collagen-nanofiber scaffold) and group B (PCL/β-TCP scaffold). The results reveal that PCL/β-TCP/collagen scaffold provide much broader cell attachment sites than PCL/β-TCP scaffold. The µ-CT and fluorescent microscopy results reveal that the acceleration of early new bone formation within the pores and scaffold itself at week 4 post-operation is more effective in group A. In addition, based on the results of the histological and µ-CT at 12 weeks post-surgery, the effective regeneration of bone in the PCL/β-TCP/collagen scaffold is appeared. 23839425 158 Dexamethasone's Effect in Multiple-Level Anterior Cervical Discectomy and Fusion. Patients with cervical myelopathy require decompressive procedures with fusion to relieve pressure on the cervical cord to prevent further functional loss. In long-segment constructs performed anteriorly, airway edema and impaired swallowing are commonly treated with steroid medication; this is believed to affect fusion rates. This study prospectively analyzes dexamethasone's effects on swallowing and fusion. A prospective, placebo-controlled, double-blinded, randomized study examining dexamethasone's effect in anterior cervical procedures was performed from 2008 to 2013. Patients included had anterior decompression and fusion ≥ 3 levels for myelopathy. Data collected included fusion rates, pertinent complications, swallowing function, mJOA, visual analogue score, SF-12, and Oswestry Disability Index (ODI). Fusion was assessed by CT at 6 months and 1 year. Sixty-one patients followed for 1 year were identified. 33 were randomized to dexamethasone, and 28 to saline. Two patients required postoperative intubation for airway edema, both of whom received placebo. Two patients required readmission within a week for severe dysphagia, and 1 for development of a DVT. For both groups, mJOA remained stable, whereas axial pain and ODI improved; administration of dexamethasone proved insignificant. In the placebo group, fusion rates were 61.5% at 6 months and 76.9% at 1 year. In the dexamethasone group, fusion rates were 33.3% at 6 months and 73.3% at 1 year, which proved significant at 6 months but not 1 year. Swallowing function (FOSS) was significantly better in the dexamethasone group at 2 weeks and 1 month. Length of stay was significantly shorter in the dexamethasone group when compared to placebo (2.5 vs 4.7 days). Multilevel anterior cervical discectomy and fusion is a reasonable operation for cervical myelopathy with minimal airway risks. Dexamethasone administration is safe to improve swallowing and control neck edema postoperatively to 1 month. It significantly decreases length of stay. It reduces fusion rates at 6 months, though not at 1 year. 23834553 Effects of cabergoline on hyperprolactinemia, psychopathology, and sexual functioning in schizophrenic patients. Antipsychotic medications are associated to different degrees with sexual dysfunction mainly through their potential to induce hyperprolactinemia. Prolactin (PRL) secretion is mainly regulated by the hypothalamic dopaminergic systems. We conducted this 6-month, parallel-group study to prospectively investigate the effects of the dopamine agonist cabergoline on sexual dysfunction in clinically stable patients with schizophrenia (DSM-IV, AP 194) and hyperprolactinemia (PRL > 20 ng/ml for men and PRL > 25 ng/ml for women). In total 80 patients were enrolled; 33 were receiving risperidone, 17 haloperidol, 11 amisulpride, and 8 risperidone microspheres long acting. Based on PRL levels (< 50, 50-99, or > 100 ng/ml), patients were assigned in 3 cabergoline doses (0.25, 0.5, and 1 mg/day in 38, 23, and 19 patients, respectively). The psychopathology was evaluated using the Positive and Negative Syndrom Scale (PANSS), and sexual dysfunction was evaluated using the Arizona Sexual Experiences Scale (ASEX). PRL levels were reduced in all patients, from 73.3 (± 46.8) to 42.0 (± 27.8) at Month 3 and 27.1 (± 20.4) at Month 6 (p < .001). ASEX scores declined from 19.1 (± 5.1) to 17.6 (± 5.5) at Month 3 and 15.0 (± 6.5) at Month 6 (p < .001). PANSS scores were reduced in the third and in the sixth month (p = .001 at 6 month vs. baseline). The decrease in PRL was not statistically different between groups. Our data suggest that cabergoline administration to clinically stable patients with schizophrenia may improve sexual functioning without adversely affecting their psychopathologic status, provided that the dose has been suited to the severity of the hyperprolactinemia. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23903041 Switchable mechanical DNA "arms" operating on nucleic acid scaffolds associated with electrodes or semiconductor quantum dots. Functional footholds linked to DNA scaffolds associated with surfaces provide nano-engineered assemblies acting as switching devices. By the assembly of a β-cyclodextrin receptor on one foothold, and a ferrocene-modified nucleic acid on a second foothold, the switchable and reversible, fuel-driven activation of "molecular arms" proceeds, transduced by electrochemical or optical signals. 23897727 Gender dysphoria in Asperger's syndrome: a caution. The incidence of Asperger's syndrome is reported as above average in young people presenting with gender dysphoria. Patients with Asperger's syndrome, however, are prone to obsessive preoccupations. This paper points out that the apparent dysphoria may in some cases prove to be a transient obsession. Cases from the author's clinical practice were reviewed. Two young men with histories suggesting Asperger's syndrome presented with strong convictions of gender dysphoria, asking for hormonal and surgical treatment. Treatment was withheld and after several years both came to repudiate their 'transgender phase'. Patients asking for sex reassignment should be assessed for indications of Asperger's syndrome. Irreversible treatments should be withheld until it is clear there is a genuine issue of transsexualism. 23863923 Captodiamine, a putative antidepressant, enhances hypothalamic BDNF expression in vivo by synergistic 5-HT2c receptor antagonism and sigma-1 receptor agonism. The putative antidepressant captodiamine is a 5-HT2c receptor antagonist and agonist at sigma-1 and D3 dopamine receptors, exerts an anti-immobility action in the forced swim paradigm, and enhances dopamine turnover in the frontal cortex. Captodiamine has also been found to ameliorate stress-induced anhedonia, reduce the associated elevations of hypothalamic corticotrophin-releasing factor (CRF) and restore the reductions in hypothalamic BDNF expression. Here we demonstrate chronic administration of captodiamine to have no significant effect on hypothalamic CRF expression through sigma-1 receptor agonism; however, both sigma-1 receptor agonism or 5-HT2c receptor antagonism were necessary to enhance BDNF expression. Regulation of BDNF expression by captodiamine was associated with increased phosphorylation of transcription factor CREB and mediated through sigma-1 receptor agonism but blocked by 5-HT2c receptor antagonism. The existence of two separate signalling pathways was confirmed by immunolocalisation of each receptor to distinct cell populations in the paraventricular nucleus of the hypothalamus. Increased BDNF induced by captodiamine was also associated with enhanced expression of synapsin, but not PSD-95, suggesting induction of long-term structural plasticity between hypothalamic synapses. These unique features of captodiamine may contribute to its ability to ameliorate stress-induced anhedonia as the hypothalamus plays a prominent role in regulating HPA axis activity. 23522726 The Ras GTPase-activating protein neurofibromin 1 promotes the positive selection of thymocytes. TCR-mediated activation of the Ras signaling pathway is critical for T cell development in the thymus and function in the periphery. However, which members of a family of Ras GTPase-activating proteins (RasGAPs) negatively regulate Ras activation in T cells is unknown. In this study we examined a potential function for the neurofibromin 1 (NF1) RasGAP in the T cell lineage with the use of T cell-specific NF1-deficient mice. Surprisingly, on an MHC class I-restricted TCR transgenic background, NF1 was found to promote thymocyte positive selection. By contrast, NF1 neither promoted nor inhibited the negative selection of thymocytes. In the periphery, NF1 was found to be necessary for the maintenance of normal numbers of naïve CD4⁺ and CD8⁺ T cells but was dispensable as a regulator of TCR-induced Ras activation, cytokine synthesis, proliferation and differentiation and death. These findings point to a novel unexpected role for NF1 in T cell development as well as a regulator of T cell homeostasis. 23839024 Femoral Neurogram Prior to Transpsoas Spinal Access at L4-5 Intervertebral Disc Space: A Proposed Screening Tool. Observational study. To illustrate the variability of the course of the femoral nerve across the L4-5 disc space, and to present a novel application of transforaminal epidural steroid injections (TFESI) in the visualization of femoral nerve roots. One concern regarding the lateral retroperitoneal transpsoas approach is the proximity of the lumbar plexus. Current techniques of assessing the proximity of neural tissue to the L4-5 disc space have limited capabilities. One hundred patients were selected for L4-5 TFESI (L4 selective nerve root blocks) due to lumbar radiculopathy. L4 neurograms were obtained while performing L4-5 TFESI under flouroscopic guidance, using a retroneural technique. The course of the L4 root/femoral nerve was then evaluated under fluoroscopy in the AP and lateral planes. Images were then reviewed by a radiologist, physiatrist, and two orthopaedic spine surgeons. Fluoroscopic evaluation revealed that the pattern of location of the femoral nerve was highly variable. In males, it was located 4.7% in Zone 2, 32.5% in Zone 3, 53.5% in Zone 4, and 9.3% in Zone P. In female patients, it was located 7.0% in Zone 2, 14% in Zone 3, 54.4% in Zone 4, 24.6% in ZoneP. An L4 neurogram will provide an accurate trajectory of L4 root/femoral nerve as it crosses the L4-5 intervertebral disc space. An accurate assessment is essential to help minimize the increasing frequency of thigh pain, parasthesias and weakness associated with the lateral access to the L4-5 intervertebral disc space. Femoral nerves that fall within Zones 2 and 3 will require more manipulation during retraction and may be better suited with a different surgical approach. 23833258 IL-2/Anti-IL-2 Complex Attenuates Renal Ischemia-Reperfusion Injury through Expansion of Regulatory T Cells. Regulatory T cells (Tregs) can suppress immunologic damage in renal ischemia-reperfusion injury (IRI), but the isolation and ex vivo expansion of these cells for clinical application remains challenging. Here, we investigated whether the IL-2/anti-IL-2 complex (IL-2C), a mediator of Treg expansion, can attenuate renal IRI in mice. IL-2C administered before bilateral renal IRI induced Treg expansion in both spleen and kidney, improved renal function, and attenuated histologic renal injury and apoptosis after IRI. Furthermore, IL-2C administration reduced the expression of inflammatory cytokines and attenuated the infiltration of neutrophils and macrophages in renal tissue. Depletion of Tregs with anti-CD25 antibodies abrogated the beneficial effects of IL-2C. However, IL-2C-mediated renal protection was not dependent on either IL-10 or TGF-β. Notably, IL-2C administered after IRI also enhanced Treg expansion in spleen and kidney, increased tubular cell proliferation, improved renal function, and reduced renal fibrosis. In conclusion, these results indicate that IL-2C-induced Treg expansion attenuates acute renal damage and improves renal recovery in vivo, suggesting that IL-2C may be a therapeutic strategy for renal IRI. 23943200 Cover: journal of basic microbiology. 8/2013. Cover illustration: The antibiotics produced by a biocontrol agent Bacillus pumilus SQR-N43 induced hyphal deformation and enlargement of cytoplasmic vacuoles in Rhizoctonia solani Q1 mycelium. (Photo: Xinqi Huang, Nanjing, China). 23843167 High throughput FRET analysis of protein-protein interactions by slide-based imaging laser scanning cytometry. Laser scanning cytometry (LSC) is a slide-based technique combining advantages of flow and image cytometry: automated, high-throughput detection of optical signals with subcellular resolution. Fluorescence resonance energy transfer (FRET) is a spectroscopic method often used for studying molecular interactions and molecular distances. FRET has been measured by various microscopic and flow cytometric techniques. We have developed a protocol for a commercial LSC instrument to measure FRET on a cell-by-cell or pixel-by-pixel basis on large cell populations, which adds a new modality to the use of LSC. As a reference sample for FRET, we used a fusion protein of a single donor and acceptor (ECFP-EYFP connected by a seven-amino acid linker) expressed in HeLa cells. The FRET efficiency of this sample was determined via acceptor photobleaching and used as a reference value for ratiometric FRET measurements. Using this standard allowed the precise determination of an important parameter (the alpha factor, characterizing the relative signal strengths from a single donor and acceptor molecule), which is indispensable for quantitative FRET calculations in real samples expressing donor and acceptor molecules at variable ratios. We worked out a protocol for the identification of adherent, healthy, double-positive cells based on light-loss and fluorescence parameters, and applied ratiometric FRET equations to calculate FRET efficiencies in a semi-automated fashion. To test our protocol, we measured the FRET efficiency between Fos-ECFP and Jun-EYFP transcription factors by LSC, as well as by confocal microscopy and flow cytometry, all yielding nearly identical results. Our procedure allows for accurate FRET measurements and can be applied to the fast screening of protein interactions. A pipeline exemplifying the gating and FRET analysis procedure using the CellProfiler software has been made accessible at our web site. © 2013 International Society for Advancement of Cytometry. 23042762 Glycopolymers and glyco-nanoparticles in biomolecular recognition processes and vaccine development. With advances in polymerization techniques as well as selective chemical modification of carbohydrates, glycopolymers and glyco-nanoparticles are emerging as an important class of materials with tailored properties or novel nanotechnology-based platforms for a number of applications. The field of the so-called glyco-nanotechnology is starting to show some promises for future clinical applications. Glyco-nanoparticles, due to their versatile nature, could offer a platform for the design of carbohydrate-based vaccines and possibly allow the development of new single-dose vaccines in disease areas of unmet need. This paper surveys the emerging roles of carbohydrate-based polymeric and nanomaterials for biomolecular recognition processes and vaccine development. 23601659 Scalable cell alignment on optical media substrates. Cell alignment by underlying topographical cues has been shown to affect important biological processes such as differentiation and functional maturation in vitro. However, the routine use of cell culture substrates with micro- or nano-topographies, such as grooves, is currently hampered by the high cost and specialized facilities required to produce these substrates. Here we present cost-effective commercially available optical media as substrates for aligning cells in culture. These optical media, including CD-R, DVD-R and optical grating, allow different cell types to attach and grow well on them. The physical dimension of the grooves in these optical media allowed cells to be aligned in confluent cell culture with maximal cell-cell interaction and these cell alignment affect the morphology and differentiation of cardiac (H9C2), skeletal muscle (C2C12) and neuronal (PC12) cell lines. The optical media is amenable to various chemical modifications with fibronectin, laminin and gelatin for culturing different cell types. These low-cost commercially available optical media can serve as scalable substrates for research or drug safety screening applications in industry scales. 23860295 Effects of Bronchodilators on Regional Lung Sound Distribution in Patients with Chronic Obstructive Pulmonary Disease. Background: Bronchodilators have been reported to influence regional lung ventilation in patients with chronic obstructive pulmonary disease (COPD), which may change regional lung sound distribution. Vibration response imaging (VRI) is a lung imaging system for the assessment of breath sounds. Objective: To evaluate the effects of a short-acting β2-agonist (SABA) on the regional distribution of lung sounds in COPD patients. Methods: A double-blind crossover trial was performed to compare the treatment of COPD patients with an SABA (20 µg of inhaled procaterol) versus a placebo. The percentage of regional lung sound energy [quantitative lung data (QLD)] was evaluated with VRI. VRI, spirometry, and impulse oscillometry (IOS) were performed immediately before and 30 min after SABA administration. Results: Ten male patients (69.6 ± 14.2 years of age, percentage predicted forced expiratory volume in 1 s: 43.8 ± 16.9%) were evaluated. The use of an SABA produced significant functional improvements in the spirometric and IOS measurements. Among the homogeneous emphysema patients (n = 7), the upper-lung QLD decreased (from 24.2 ± 5.8 to 18.8 ± 6.1%, p < 0.05) and the lower-lung QLD increased (from 37.9 ± 12.7 to 46.1 ± 14.3%, p < 0.05) following SABA inhalation. However, the significant redistribution of the regional lung QLD to the lower-lung field was not observed in 2 of the 3 inhomogeneous emphysema patients. Conclusion: The additional use of an SABA by COPD patients improved their pulmonary function, which was accompanied by changes in regional lung air flow. The distribution of emphysematous lesions and the bronchial reactivity to SABA appeared to affect the redistribution of the lung sounds following bronchodilator administration. 23892659 A hybrid of bees algorithm and flux balance analysis with OptKnock as a platform for in silico optimization of microbial strains. Microbial strain optimization focuses on improving technological properties of the strain of microorganisms. However, the complexities of the metabolic networks, which lead to data ambiguity, often cause genetic modification on the desirable phenotypes difficult to predict. Furthermore, vast number of reactions in cellular metabolism lead to the combinatorial problem in obtaining optimal gene deletion strategy. Consequently, the computation time increases exponentially with the increase in the size of the problem. Hence, we propose an extension of a hybrid of Bees Algorithm and Flux Balance Analysis (BAFBA) by integrating OptKnock into BAFBA to validate the result. This paper presents a number of computational experiments to test on the performance and capability of BAFBA. Escherichia coli, Bacillus subtilis and Clostridium thermocellum are the model organisms in this paper. Also included is the identification of potential reactions to improve the production of succinic acid, lactic acid and ethanol, plus the discussion on the changes in the flux distribution of the predicted mutants. BAFBA shows potential in suggesting the non-intuitive gene knockout strategies and a low variability among the several runs. The results show that BAFBA is suitable, reliable and applicable in predicting optimal gene knockout strategy. 23159918 Comparison of forward (ear-canal) and reverse (round-window) sound stimulation of the cochlea. The cochlea is normally driven with "forward" stimulation, in which sound is introduced to the ear canal. Alternatively, the cochlea can be stimulated at the round window (RW) using an actuator. During RW "reverse" stimulation, the acoustic flow starting at the RW does not necessarily take the same path as during forward stimulation. To understand the differences between forward and reverse stimulation, we measured ear-canal pressure, stapes velocity, RW velocity, and intracochlear pressures in scala vestibuli (SV) and scala tympani (ST) of fresh human temporal bones. During forward stimulation, the cochlear drive (differential pressure across the partition) results from the large difference in magnitude between the pressures of SV and ST, which occurs due to the high compliance of the RW. During reverse stimulation, the relatively high impedance of the middle ear causes the pressures of SV and ST to have similar magnitudes, and the differential pressure results primarily from the difference in phase of the pressures. Furthermore, the sound path differs between forward and reverse stimulation, such that motion through a third window is more significant during reverse stimulation. Additionally, we determined that although stapes velocity is a good estimate of cochlear drive during forward stimulation, it is not a good measure during reverse stimulation. This article is part of a special issue entitled "MEMRO 2012". 23837608 Insulin enhances metabolic capacities of cancer cells by dual regulation of glycolytic enzyme pyruvate kinase M2. Insulin is tightly associated with cancer progression; however, mechanistic insights into such observations are poorly understood. Recent studies show that metabolic transformation is critical to cancer cell proliferation. Here, we attempt to understand the role of insulin in promotion of cancer metabolism. To this end, the role of insulin in regulating glycolytic enzyme pyruvate kinase M2 (PKM2) was examined. We observed that insulin up-regulated PKM2 expression, through PI3K/mTOR mediated HIF1α induction, but significantly reduced PKM2 activity independent of this pathway. Drop in PKM2 activity was attributed to subunit dissociation leading to formation of low activity PKM2 oligomers, as assessed by density gradient centrifugation. However, tyrosine 105 phosphorylation of PKM2, known for inhibiting PKM2 activity, remained unaffected on insulin treatment. Interestingly, insulin-induced ROS was found responsible for PKM2 activity reduction. The observed changes in PKM2 status led to augmented cancer metabolism. Insulin-induced PKM2 up-regulation resulted in enhanced aerobic glycolysis as confirmed by PKM2 knockdown studies. Further, PKM2 activity reduction led to characteristic pooling of glycolytic intermediates and increased accumulation of NADPH; suggesting diversion of glucose flux towards macromolecular synthesis, necessary for cancer cell growth. The study identifies new PKM2-mediated effects of insulin on cancer metabolism, thus, advancing the understanding of insulin's role in cancer. 23722690 High-temperature mass spectrometric study of the vaporization processes and thermodynamic properties of melts in the PbO-B2O3-SiO2 system. The unique properties of the PbO-B2O3-SiO2 system, especially its extensive range of glass-forming compositions, make it valuable for various practical applications. The thermodynamic properties and vaporization of PbO-B2O3-SiO2 melts are not well established so far and the data obtained on these will be useful for optimization of technology and thermodynamic modeling of glasses. High-temperature Knudsen effusion mass spectrometry was used to study vaporization processes and to determine the partial pressures of components of the PbO-B2O3-SiO2 melts. Measurements were performed with a MS-1301 mass spectrometer. Vaporization was carried out using two quartz effusion cells containing the sample under study and pure PbO (reference substance). Ions were produced by electron ionization at an energy of 25 eV. To facilitate interpretation of the mass spectra, the appearance energies of ions were also measured. Pb, PbO and O2 were found to be the main vapor species over the samples studied at 1100 K. The PbO activities as a function of the composition of the system were derived from the measured PbO partial pressures. The B2O3 and SiO2 activities, the Gibbs energy of formation, the excess Gibbs energy of formation and mass losses in the samples studied were calculated. Partial pressures of the vapor species over PbO-B2O3-SiO2 melts were measured at 1100 K in the wide range of compositions using the Knudsen mass spectrometric method. The data enabled the PbO, B2O3, and SiO2 activities in these melts to be derived and provided evidence of their negative deviations from ideal behavior. 23864286 Effects of training experienced teachers in the use of the one-minute preceptor technique in the gross anatomy laboratory. The one-minute preceptor (OMP) is a time-efficient, learner-centered teaching method used in a busy ambulatory care setting. This project evaluated the effects of training experienced anatomy teachers in the use of the OMP in the gross anatomy laboratory on students' perceived learning. Second-year medical students from a five-year, undergraduate-entry, system- and problem-based medical program were divided randomly into two groups of 76 students each. The groups took part in the same gross anatomy laboratory session on different dates, supervised by the same two teachers (both with over 25 years of teaching experience). The teachers attended a workshop on the use of the OMP between the two sessions. Students were given a questionnaire at the end of the two sessions to indicate their agreements to statements regarding their learning experiences. Semistructured interviews were conducted with the two teachers after the second session. Results showed that training experienced anatomy teachers in the use of the OMP did not result in improvement of student learning perception in the gross anatomy laboratory. The experienced teachers have developed their own approaches with elements similar to those in the OMP: being learner centered and adaptable to individual student's needs, providing feedback, and enhancing teacher immediacy. They do not have an explicit structure such as the OMP, and are thus flexible and adaptive. Confining the teachers' teaching behaviors to the OMP structure could limit their performance. Although there are theoretical advantages for novice teachers in adopting the OMP technique, these advantages still need to be supported by further studies. Anat Sci Educ. © 2013 American Association of Anatomists. 23930915 Development of long-acting recombinant FVIII and FIX Fc fusion proteins for the management of hemophilia. Introduction: Prophylactic treatment with replacement clotting factor is the recommended regimen for patients with severe hemophilia to prevent bleeding episodes. However, currently available replacement clotting factors are limited by their relatively short half-lives and require intravenous injections up to three times weekly to maintain protective levels, which can impact compliance and, thus, patient outcomes. Areas covered: The potential advantages of long-acting coagulation factors, including reduced injection frequency, increased treatment adherence, and improved clinical outcomes, are discussed. Fragment crystallizable (Fc) fusion technology is introduced and the development of long-acting recombinant factor VIII Fc (rFVIIIFc) and recombinant factor IX Fc (rFIXFc) fusion proteins for the treatment of hemophilia A and B, respectively, are described. Preclinical and clinical studies of rFVIIIFc and rFIXFc showing improved pharmacokinetics over currently available products are reviewed. Expert opinion: Long-acting coagulation factors, including rFVIIIFc and rFIXFc, have the potential to change current paradigms of care for hemophilia A and B, respectively. Less frequent infusions may provide prolonged protection from bleeding and bleed resolution with fewer injections. In addition, long-acting coagulation factors provide an opportunity for improved individualized treatment for hemophilia. 23800578 PEGylation of lysine residues reduces the pro-migratory activity of IGF-I. The insulin-like growth factor (IGF) system is composed of ligands and receptors which regulate cell proliferation, survival, differentiation and migration. Some of these functions involve regulation by the extracellular milieu, including binding proteins and other extracellular matrix proteins. However, the functions and exact nature of these interactions remain incomplete. IGF-I variants PEGylated at lysines K27, K65 and K68, were assessed for binding to IGFBPs using BIAcore, and for phosphorylation of the IGF-IR. Furthermore, functional consequences of PEGylation were investigated using cell viability and migration assays. In addition, downstream signaling pathways were analyzed using phospho-AKT and phospho-ERK1/2 assays. IGF-I PEGylated at lysines 27 (PEG-K27), 65 (PEG-K65) or 68 (PEG-K68) was employed. Receptor phosphorylation was similarly reduced 2-fold with PEG-K65 and PEG-K68 in 3T3 fibroblasts and MCF-7 breast cancer cells, whereas PEG-K27 showed a more than 10- and 3-fold lower activation for 3T3 and MCF-7 cells, respectively. In addition, all PEG-IGF-I variants had a 10-fold reduced association rate to IGF binding proteins (IGFBPs). Functionally, all PEG variants lost their ability to induce cell migration in the presence of IGFBP-3/vitronectin (VN) complexes, whereas cell viability was fully preserved. Analysis of downstream signaling revealed that AKT was preferentially affected upon treatment with PEG-IGF-I variants whereas MAPK signaling was unaffected by PEGylation. PEGylation of IGF-I has an impact on cell migration but not on cell viability. PEG-IGF-I may differentially modulate IGF-I mediated functions that are dependent on receptor interaction as well as key extracellular proteins such as VN and IGFBPs. 23890994 Cadmium, smoking, and reduced levels of exhaled nitric oxide among US adults. Exposure to cadmium is known to be associated with reducing nitric oxide (NO) production in experimental conditions, but few studies have examined the association between environmental cadmium exposures and exhaled NO in human. We examined the association between blood cadmium levels and exhaled NO levels in a representative sample of US adults. This investigation was a cross-sectional study of 7813 adults (≥20 years) who participated in the 2007-2008 and 2009-2010 National Health and Nutrition Examination Survey and had their exhaled NO and blood cadmium measurements recorded. The geometric means of the exhaled NO and blood cadmium levels were 13.3ppb (95% CI: 12.7, 13.9) and 0.51μg/dL (95% CI: 0.48, 0.54), respectively. Higher blood cadmium levels were associated with decreased exhaled NO levels after adjusting for potential confounding variables. Additionally, a two-fold increase in the blood cadmium levels was associated with a 5% decrease in the exhaled NO levels. The results were significant regardless of the subjects' smoking status or serum cotinine levels, although the percent changes in the exhaled NO levels differed depending on the extent of smoking. Our findings suggest that blood cadmium levels may be associated with reduced levels of exhaled NO in a general sample of US adults. Moreover, cadmium may partially mediate the effect of smoking on exhaled NO production. 23885155 Coincidence of active Crohn's disease and florid endometriosis in the terminal ileum: A case report. Crohn's disease (CD), a variant of chronic inflammatory bowel disease, frequently affects the terminal ileum and coecal region. The clinical symptoms are often subtle and depend on the inflammatory activity of disease. In women of child-bearing age, florid intestinal endometriosis can simulate CD. Moreover, current pathophysiological concepts include intestinal endometriosis as a putative founder lesion for consecutive CD establishment. The report summarizes clinical and histomorphological data of a 35-year-old woman with the rare coincidence of florid intestinal endometriosis and CD both affecting the terminal ileum. The patient was suffering over 10 years from strong abdominal disorders including constipation, diarrhea, weight loss, and diffuse abdominal pain. In magnetic resonance imaging-Sellink, strong inflammation and intestinal obstruction of the terminal ileum were found. The laparoscopy revealed further evidence for existence of an inflammatory disease like CD, but brownish spots on the peritoneum were found indicative for endometriosis. Surgical resection of the terminal ileum and the coecal segment was performed followed by histopathological investigations. In transmural sections of the terminal ileum, histomorphological features of florid endometriosis intermingled with florid CD was found. The diagnostic findings were substantiated with a panel of immunohistological stainings. In conclusion, the findings demonstrate that florid endometriosis persists in florid CD lesions and the putative link between intestinal endometriosis and CD is more complex than previously assumed. 22944069 Lithium treatment induces proteasomal degradation of over-expressed acetylcholinesterase (AChE-S) and inhibit GSK3β. Lithium is one of the most widely used mood-stabilizing agents for the treatment of bipolar disorder. Lithium is also a potent inhibitor of glycogen synthase kinase-3β (GSK3β) activity, which is linked to Alzheimer's disease (AD). In experiments with cultured HEK293T cells, we show here that GSK3β stabilizes synaptic acetylcholinesterase (AChE-S), a critical component of AD development. Cells treated with lithium exhibited rapid proteasomal degradation of AChE-S. Furthermore treatment of the cells with MG132, an inhibitor of the 26S proteasome, prevented the destabilizing effect of lithium on AChE-S. Taken together, these findings suggest that regulation of AChE-S protein stability may be an important biological target of lithium therapy. 23869685 Core temperature and heart rate response to repeated bouts of firefighting activities. During live-fire firefighting operations and training evolutions, firefighters often consume multiple cylinders of air and continue to wear their personal protective equipment even after fire suppression activities have ceased. However, most studies have only reported core temperature changes during short-term firefighting activities and have shown a very modest increase in core temperature. Therefore, the purpose of this study is to evaluate core temperature and heart rate (HR) during repeated bouts of firefighting activity over ∼3 h. The results of this study show that core temperatures increase by an average of 1.9°C - to a larger magnitude than previously reported - and continue to increase during subsequent work cycles (38.4 vs. 38.7) even after long breaks of more than 30 min. The rate of core temperature increase during work continues to increase later in the training exercise (from 0.036 to 0.048°C/min), increasing the risk for exertional heat stress particularly if long-duration firefighting activity is required at these later times. Practitioner Summary: To date, core temperature and HR changes during firefighting have been reported for short-term studies, which may significantly underestimate the physiological burden of typical firefighting activities. Firefighter core temperatures are shown to increase to a larger magnitude than previously observed and the rate of rise in core temperature increases during subsequent firefighting activities. 23494447 The clinical characteristics at diagnosis of type 2 diabetes in a multi-ethnic population: the South London Diabetes cohort (SOUL-D). AIMS/HYPOTHESIS: This study aimed to investigate the clinical features of newly diagnosed type 2 diabetes in an urban multi-ethnic cohort. METHODS: A population-based cross-sectional design was used. People diagnosed with type 2 diabetes in the preceding 6 months were recruited from primary care practices in three adjacent inner-city boroughs of South London, serving a population in which 20% of residents are of black African or Caribbean ethnicity. Sociodemographic and biomedical data were collected by standardised clinical assessment and from medical records. Multiple logistic regression methods were used to report associations between ethnicity and diabetes-complication status. RESULTS: From 96 general practices, 1,506 patients were recruited. Their mean age was 55.6 (±11.07) years, 55% were men, 60% were asymptomatic at diagnosis and 51%, 38% and 11% were of white, black and South Asian/other ethnicity, respectively. Compared with white participants, black and South Asian/other participants were: younger (mean age 58.9 [±10.09], 52.4 [±11.19] and 51.5 [±10.42] years, respectively; p < 0.0001); less likely to have neuropathy (10.1%, 3.6% and 4.4%; p < 0.0001) or report coronary artery disease (12.7%, 4.8% and 7.3%; p < 0.0001). In logistic regression, compared with white participants, black participants had lower levels of macrovascular complications (OR 0.52, 95% CI 0.32, 0.84; p = 0.01). Male sex was independently associated with microvascular disease (OR 1.69, 95% CI 1.26, 2.28; p < 0.0001). CONCLUSIONS/INTERPRETATION: The prevalence of complications at time of diagnosis was lower than expected, especially in black and South Asian/other ethnic groups. However, in multi-ethnic inner-city populations, onset of type 2 diabetes occurred almost 10 years earlier in non-white populations than in white participants, predicating a prolonged morbidity. 23749850 Characterization of AtSTOP1 Orthologous Genes in Tobacco and Other Plant Species. Aluminum (Al) and proton (H(+)) tolerances are essential traits for plants to adapt to acid soil environments. In Arabidopsis (Arabidopsis thaliana), these tolerances are mediated by a zinc-finger transcription factor, SENSITIVE TO PROTON RHIZOTOXICITY1 (AtSTOP1), which regulates the transcription of multiple genes critical for tolerance to both stressors. Here, the functions of orthologous proteins (STOP1-like proteins) in other plant species were characterized by reverse genetics analyses and in planta complementation assays. RNA interference of a gene for NtSTOP1 repressed Al and H(+) tolerances of tobacco (Nicotiana tabacum) roots. Tobacco roots released citrate in response to Al, concomitant with the up-regulated transcription of an ortholog of an Al tolerance gene encoding a citrate-transporting multidrug and toxic compound extrusion protein. The RNA interference repression of NtSTOP1 blocked this process and also repressed the transcription of another orthologous gene for Al tolerance, ALUMINUM SENSITIVE3, which encodes a prokaryote-type transporter. These results demonstrated that NtSTOP1 regulates Al tolerance in tobacco through the transcriptional regulation of these genes. The in planta complementation assays revealed that other plant species, including woody plants, a legume, and a moss (Physcomitrella patens), possess functional STOP1-like proteins that can activate several H(+) and Al-tolerance genes in Arabidopsis. Knocking out the gene encoding the STOP1-like protein decreased the Al tolerance of P. patens. Together, our results strongly suggest that transcriptional regulation by STOP1-like proteins is evolutionarily conserved among land plants and that it confers the ability to survive in acid soils through the transcriptional regulation of Al- and H(+)-tolerance genes. 23895864 Photodegradation of textile dye Rhodamine B over a novel biopolymer-metal complex wool-Pd/CdS photocatalysts under visible light irradiation. A novel biopolymer-metal complex wool-Pd/CdS photocatalysts were prepared and exhibited high activity for photodegradation of Rh B under visible light irradiation. The wool-Pd could not only enhance the utilization rate of noble metal Pd but also significantly improve the activity of dye degradation. Wool-Pd was able to introduce Pd and PdS to effectively prohibit the recombination of photogenerated electrons and holes. The optimal weight percentage of wool-Pd in the photocatalyst was found to be 0.5wt%, which resulted in a good result of degradation of Rh B under visible light. It is obviously better in the catalyst efficiency than pure CdS. The photocatalysts were characterized by X-ray diffraction, diffuse reflectance UV-vis spectroscopy, energy-dispersive X-ray spectroscopy (EDX), X-ray photoelectron spectroscopic (XPS) studies, transmission electron microscopy (TEM). In a word, the prepared novel biopolymer-metal complex wool-Pd/CdS photocatalysts not only improve the degradation efficiency of Rh B, but also has a good advantage of recycling and cost-effective. It will have a good application prospect. In addition, the possible degradation pathway of Rh B was proposed in this paper. 23951692 Comparison between dexmedetomidine and remifentanil for controlled hypotension and recovery in endoscopic sinus surgery. We compared the efficacy of dexmedetomidine and remifentanil hydrochloride in intraoperative field conditions and recovery during endoscopic sinus surgery. Sixty-six patients (American Society of Anesthesiologists physical status I and II) scheduled for elective endoscopic sinus surgery were enrolled in this prospective, double-blinded, randomized study. The patients were randomly assigned to two groups. Propofol, 2 to 2.5 mg/kg, was administered to both groups to induce anesthesia, which was maintained with desflurane. One group received dexmedetomidine 1 microg/kg over 10 minutes at anesthesia induction, followed by 0.4 to 0.8 microg/kg per hour infusion during maintenance, whereas the other group received remifentanil 1 microg/kg over 1 minute at anesthesia induction, followed by 0.2 to 0.4 microg/kg per minute infusion during maintenance. Surgical conditions, hemodynamic parameters, intraoperative blood loss, time to extubation, sedation, and pain in the postanesthesia care unit (PACU) were recorded. There were no significant differences between the two groups with respect to surgical field conditions, blood loss, or extubation time. The sedation score (Modified Observer's Assessment of Alertness/Sedation) in the PACU was significantly lower in the dexmedetomidine group than in the remifentanil group (p < 0.001). No differences were found in total blood loss, surgical field conditions, hemodynamic parameters, time to extubation, or pain in the PACU when the two groups were compared (p > 0.05). Although remifentanil and dexmedetomidine both enabled hypotensive anesthesia and good intraoperative fields for endoscopic sinus surgery, recovery was faster with remifentanil than with dexmedetomidine in the immediate postoperative period. 23139010 High yield, reproducible and quasi-automated bilayer formation in a microfluidic format. A microfluidic platform is reported for various experimentation schemes on cell membrane models and membrane proteins using a combination of electrical and optical measurements, including confocal microscopy. Bilayer lipid membranes (BLMs) are prepared in the device upon spontaneous and instantaneous thinning of the lipid solution in a 100-μm dry-etched aperture in a 12.5-μm thick Teflon foil. Using this quasi-automated approach, a remarkable 100% membrane formation yield is reached (including reflushing in 4% of the cases), and BLMs are stable for up to 36 h. Furthermore, the potential of this platform is demonstrated for (i) the in-depth characterization of BLMs comprising both synthetic and natural lipids (1,2-diphytanoyl-sn-glycero-3-phosphocholine (DPhPC) and L-α-phosphatidylcholine (L-α-PC)/cholesterol, respectively) in terms of seal resistance, capacitance, surface area, specific capacitance, and membrane hydrophobic thickness; (ii) confocal microscopy imaging of phase separation in sphingomyelin/L-α-PC/cholesterol ternary membranes; (iii) electrical measurements of individual nanopores (α-hemolysin, gramicidin); and (iv) indirect assessment of the alteration of membrane properties upon exposure to chemical stimuli using the natural nanopore gramicidin as a sensor. 23892118 Combined spectral experiment and theoretical calculation to study the interaction of 1,4-dihydroxyanthraquinone for metal ions in solution. The interaction between 1,4-dihydroxyanthraquinone (1,4-DHA) and metal ions was studied by UV-Visible and fluorescence spectroscopies in solution. Time-dependent density functional theory calculations confirmed complex structures. The investigation results showed 1,4-DHA can selectively respond some metal ions and can be monitored by UV-Vis, fluorescence spectra and naked-eye. So 1,4-DHA has a potential application in the design of metal ions probe. More, as typical metal ions, Hg(2+) and Er(3+), their reaction abilities for 1,4-DHA were studied in detailed. Experimental results showed they have better response for 1,4-DHA. And theoretical calculation concluded that Er(3+) easily reacts with 1,4-DHA over Hg(2+) attributed to the low reaction energy of Er(3+)-1,4-DHA than Hg(2+)-1,4-DHA. 23933304 Separate parts of occipito-temporal white matter fibers are associated with recognition of faces and places. A central finding of functional MRI studies is the highly selective response of distinct brain areas in the occipital temporal cortex to faces and places. However, little is known about the association of white matter fibers with the processing of these object categories. In the current study we used DTI-based tractography to reconstruct two main fibers that connect the occipital lobe with the anterior temporal lobe (inferior longitudinal fasciculus-ILF) and with the frontal lobe (inferior fronto-occipital fasciculus-IFOF) in normal individuals. In addition to MRI scans subjects performed face, scene and body recognition tasks outside the scanner. Results show that recognition of faces and scenes were selectively associated with separate parts of the ILF. In particular, face recognition was highly associated with the fractional anisotropy (FA) of the anterior part of the ILF in the right hemisphere. In contrast, scene recognition was strongly correlated with the FA of the posterior and middle but not the anterior part of the ILF bilaterally. Our findings provide the first demonstration that faces and places are not only associated with distinct brain areas but also with separate parts of white matter fibers. 23815318 Complete mitochondrial genome of the tiger shark Galeocerdo cuvier (Carcharhiniformes: Carcharhinidae). Abstract The tiger shark Galeocerdo cuvier is the only member of the genus Galeocerdo. The complete mitochondrial genome of G. cuvier is presented for the first time in this study. The gene composition and arrangement in the mitogenome of G. cuvier is identical to most animal mitogenome. There are 22 bp short noncoding sequences and 44 bp overlaps in the mitogenome. The overall base composition is 31.8% A, 23.9% C, 13.0% G and 31.3% T. The dihydrouridine arm of tRNA-Ser2 was replaced by a simple loop and the other tRNAs could be folded into the typical cloverleaf structure. 23898091 Platinum-based Doublet Chemotherapy plus Bevacizumab Without Bevacizumab Maintenance in Advanced Non-small Cell Lung Cancer (NSCLC). We report on a retrospective, consecutive non-randomized group of patients who received bevacizumab plus chemotherapy without bevazicumab maintenance. Patients with adenocarcinoma subtype of NSCLC and advanced disease received carboplatin and vinorelbine together with bevazicumab for four cycles without bevazicumab maintenance. Overall survival (OS), progression-free survival (PFS), response rate (RR) and toxicity were reviewed. A total of 30 consecutive patients were included in a period of two years. RR, bleeding, thromboembolic and haematological complications were comparable to those of the literature. Median OS and PFS were 8.8 and 4.5 months for patients with performance status (PS) 0-1, while they were 2.6 and 1.2 months for those with PS 2, p-values being 0.006 and 0.039, respectively. The effect of maintenance bevazicumab on OS has not yet been established but it has been proven as being favourable on PFS. Our data suggest that patients with PS 2 should not receive this treatment. 23943609 A Computational Model Predicts That Gβγ Acts at a Cleft Between Channel Subunits to Activate GIRK1 Channels. The atrial G protein (heterotrimeric guanine nucleotide-binding protein)-regulated inwardly rectifying K(+) (GIRK1 and GIRK4) heterotetrameric channels underlie the acetylcholine-induced K(+) current responsible for vagal inhibition of heart rate and are activated by the G protein βγ subunits (Gβγ). We used a multistage protein-protein docking approach with data from published structures of GIRK1 and Gβγ to generate an experimentally testable interaction model of Gβγ docked onto the cytosolic domains of the GIRK1 homotetramer. The model suggested a mechanism by which Gβγ promotes the open state of a specific cytosolic gate in the channel, the G loop gate. The predicted structure showed that the Gβ subunit interacts with the channel near the site of action for ethanol and stabilizes an intersubunit cleft formed by two loops (LM and DE) of adjacent channel subunits. Using a heterologous expression system, we disrupted the predicted GIRK1- and Gβγ-interacting residues by mutation of one protein and then rescued the regulatory activity by mutating reciprocal residues in the other protein. Disulfide cross-linking of channels and Gβγ with cysteine mutations at the predicted interacting residues yielded activated channels. The mechanism of Gβγ-induced activation of GIRK4 was distinct from GIRK1 homotetramers. However, GIRK1-GIRK4 heterotetrameric channels activated by Gβγ displayed responses indicating that the GIRK1 subunit dominated the response pattern. This work demonstrated that combining computational with experimental approaches is an effective method for elucidating interactions within protein complexes that otherwise might be challenging to decipher. 23582973 Immunohistochemical characterization of neuroendocrine differentiation of canine anal sac glandular tumours. Histological features and expression of neuroendocrine markers were examined in 69 samples of canine anal sac glandular carcinomas (ASGCs). The tumours were classified into solid, rosette and tubular types and mixtures of these types. Tumour-associated death in dogs with solid tumours and mixed tumours with solid components was higher than in dogs with rosette and tubular type tumours. Chromogranin A immunoreactivity was observed in 28 of 69 samples (40.6%) irrespective of histological type and was localized to the marginal areas of the tumour nest and the basal areas of the tubular and rosette structures. Neuron-specific enolase immunoreactivity in neoplastic epithelial cells was observed in 32 cases (46.4%) and was less frequently observed in the tubular type (14.3%). Synaptophysin expression was present in 15.9% of cases and was least frequent in the tubular type. Twenty-one of the 69 samples expressed more than two neuroendocrine markers and were classified as carcinomas with neuroendocrine differentiation. There was no relationship between neuroendocrine differentiation and clinical outcome. These results suggest that some ASGCs have neuroendocrine differentiation regardless of histological pattern, but clinical outcome is more related to the histological pattern than to neuroendocrine differentiation. 23543240 Influence of reactive oxygen species on human sperm functions and fertilizing capacity including therapeutical approaches. Reactive oxygen species (ROS) are an array of molecules including oxygen-centered radicals, which are endowed with one or more unpaired electrons and non-radical oxygen derivatives such as hydrogen peroxide, which behave, to a large extent, like a double-edged sword in human sperm biology. This study aimed to overview the current knowledge of ROS in sperm physiology and pathology, as well as related therapies in spermatozoal dysfunction. We performed this study by searching for keywords from PUBMED, including reactive oxygen species, oxidative stress, sperm function, and antioxidant therapy. Low levels of ROS exert critical function in normal sperm physiology, such as fertilizing ability (acrosome reaction, hyperactivation, capacitation, and chemotaxis) and sperm motility; while increased ROS generation and/or decreased antioxidant capacity leads to the imbalance between oxidation and reduction in living systems, which is called sperm oxidative stress. This condition was widely considered to be a significant contributory factor to sperm DNA damage/apoptosis, lipid peroxidation, and reduced motility, which in turn, increased risk of male factor infertility/subfertility and birth defects. Under the current status quo, numerous subsequent studies have concentrated on antioxidant therapy. Although utility of such a therapeutic strategy significantly improved sperm function and motility in a myriad of experimental and clinical reports, the overall effectiveness still remains controversial mainly due to non-standardized assay to measure the level of ROS and sperm DNA damage, various antioxidant supplementation strategies, and inadequate fertilization and pregnancy data after clinical treatment. Therefore, standardized assessment and evaluation of ROS and total antioxidant capacity in semen should be established to keep ROS in a physiological level and prevent over-treatment of antioxidants toward reductive stress, which should be kept in mind, especially in assisted reproductive procedure. Moreover, the significance of large sample size populations, double-blind randomized, placebo-controlled clinical trials of antioxidant therapies is emphasized in this review to achieve optimal ingredients and dosage of antioxidants for patients with reactive oxygen-induced male fertility/subfertility. 23099914 Seasonal dynamics of ammonia/ammonium-oxidizing prokaryotes in oxic and anoxic wetland sediments of subtropical coastal mangrove. Mangrove wetlands are an important ecosystem in tropical and subtropical regions, and the sediments may contain both oxic and anoxic zones. In this study, ammonia/ammonium-oxidizing prokaryotes (AOPs) in yellow and black sediments with vegetation and non-vegetated sediments in a mangrove wetland of subtropical Hong Kong were investigated in winter and summer. The phylogenetic diversity of anammox bacterial 16S rRNA genes and archaeal and bacterial amoA genes (encoding ammonia monooxygenase alpha-subunit) were analyzed using PCR amplification and denaturing gradient gel electrophoresis to reveal their community structures. Quantitative PCR was also used to detect their gene abundances. The results showed that seasonality had little effect, but sediment type had a noticeable influence on the community structures and abundances of anammox bacteria. For ammonia-oxidizing archaea (AOA), seasonality had a small effect on their community structures, but a significant effect on their abundances: AOA amoA genes were significantly higher in winter than in summer. In winter, the vegetated yellow sediments had lower AOA amoA genes than the other types of sediments, but in summer, the vegetated yellow sediments had higher AOA amoA genes than the other types of sediments. Sediment type had no apparent effect on AOA community structures in winter. In summer, however, the vegetated yellow sediments showed obviously different AOA community structures from the other types of sediments. For ammonia-oxidizing bacteria (AOB), seasonality had a significant effect on their community structures and abundances: AOB amoA genes in winter were apparently higher than in summer, and AOB community structures were different between winter and summer. Sediment type had little effect on AOB community structures, but had a noticeable effect on the abundances: AOB amoA genes of the vegetated yellow sediments were obviously lower than the black ones in both seasons. This study has demonstrated that seasonality and sediment type affected community structures and abundances of AOPs differently in oxic and anoxic sediments of the mangrove wetland. 23661772 Heart rate and estimated energy expenditure of flapping and gliding in black-browed albatrosses. Albatrosses are known to expend only a small amount of energy during flight. The low energy cost of albatross flight has been attributed to energy-efficient gliding (soaring) with sporadic flapping, although little is known about how much time and energy albatrosses expend in flapping versus gliding during cruising flight. Here, we examined the heart rates (used as an instantaneous index of energy expenditure) and flapping activities of free-ranging black-browed albatrosses (Thalassarche melanophrys) to estimate the energy cost of flapping as well as time spent in flapping activities. The heart rate of albatrosses during flight (144 beats min(-1)) was similar to that while sitting on the water (150 beats min(-1)). In contrast, heart rate was much higher during takeoff and landing (ca. 200 beats min(-1)). Heart rate during cruising flight was linearly correlated with the number of wing flaps per minute, suggesting an extra energy burden of flapping. Albatrosses spend only 4.6±1.4% of their time flapping during cruising flight, which was significantly lower than during and shortly after takeoff (9.8±3.5%). Flapping activity, which amounted to just 4.6% of the time in flight, accounted for 13.3% of the total energy expenditure during cruising flight. These results support the idea that albatrosses achieve energy-efficient flight by reducing the time spent in flapping activity, which is associated with high energy expenditure. 23749968 Impaired CD4+ T-Cell Restoration in the Small Versus Large Intestine of HIV-1-Positive South Africans Receiving Combination Antiretroviral Therapy. Background. Human immunodeficiency virus type 1 (HIV-1) infection is associated with a massive depletion of intestinal CD4(+) T cells that is only partially reversed by combination antiretroviral therapy (cART). Here, we assessed the ability of nucleoside reverse-transcriptase inhibitor/nonnucleoside reverse-transcriptase inhibitor treatment to restore the CD4(+) T-cell populations in the intestine of South African patients with AIDS.Methods. Thirty-eight patients with advanced HIV-1 infection who had chronic diarrhea (duration, >4 weeks) and/or unintentional weight loss (>10% decrease from baseline) of uncertain etiology were enrolled. Blood specimens were collected monthly, and gastrointestinal tract biopsy specimens were collected before cART initiation (from the duodenum, jejunum, ileum, and colon), 3 months after cART initiation (from the duodenum), and 6 months after cART initiation (from the duodenum and colon). CD4(+), CD8(+), and CD38(+)CD8(+) T cells were quantified by flow cytometry and immunohistochemistry analyses, and the HIV-1 RNA load was determined by the Nuclisens assay.Results. CD4(+) T-cell and HIV-1 RNA levels were significantly lower, whereas CD8(+) T-cell levels, including activated CD38(+)CD8(+) T cell levels, were higher in the duodenum and jejunum, compared with the colon. After 6 months of cART, a significant but incomplete recovery of CD4(+) T cells was detected in the colon and peripheral blood but not in the duodenum. Failed restoration of the CD4(+) T-cell count in the duodenum was associated with nonspecific enteritis and CD8(+) T-cell activation.Conclusions. Strategies that target inflammation and immune activation in the small intestine may be required to expedite CD4(+) T-cell recovery and improve therapeutic outcomes. 23824527 Terms for the Quantitation of a Mixture of Stereoisomers. Various terms for the quantitation of a mixture of enantiomers and diastereomers are discussed. 23215021 Amplified fluorescent sensing of DNA using graphene oxide and a conjugated cationic polymer. We explore the interactions between a fluorescein (FAM)-labeled single-stranded DNA (P), graphene oxide (GO), and a cationic conjugated polymer, poly [(9,9-bis(6'-N,N,N-trimethylammonium)hexyl)-fluorenylene phenylene dibromide] (PFP). It is found that the fluorescence change of P-GO-PFP system is dependent on the addition order of P and PFP. When adding PFP into P/GO complex, the fluorescence resonance energy transfer (FRET) from PFP to P is inefficient. If P is added to PFP/GO complex, efficient FRET is obtained. This may be attributed to the equal binding ability for P and PFP to GO. The results of time-resolved fluorescence and fluorescence anisotropy support the different fluorescent response under different addition order of P and PFP to GO. Based on the above phenomenon, we demonstrate a method to reduce the high background signal of a traditional PFP-based DNA sensor by introducing GO. In comparison to the use of single PFP, the combination of PFP with GO-based method shows enhanced sensitivity with a detection limit as low as 40 pM for target DNA detection. 23867152 A randomized trial to consider the effect of Romanian deadlift exercise on the development of lumbar extension strength. To consider the efficacy of 10 weeks of Romanian deadlift (DL) training in increasing lumbar extension strength compared to isolated lumbar extension (LUMX) training. Comparison of pre- and post-test data for Romanian deadlift 1RM, and lumbar extension torque between and within groups. Male trained subjects (n = 36; (x¯±SD) 24.9 ± 6.5 years; 178.5 ± 5.2 cm; 81.6 ± 10.0 kg). Pre- and post-testing included a Romanian deadlift 1RM and isometric strength tests every 12° through full range of motion on the MedX lumbar extension machine (MedX, Ocala, FL). Repeated measures analysis of variance (ANOVA) with Bonferroni adjustments revealed that 1RM Romanian deadlift significantly increased from pre- to post-test in the DL group (p < 0.008; 143.3 ± 23.4 kg to 166.3 ± 21.9 kg) and the LUMX group (p < 0.008; 135.8 ± 23.1 kg to 146.0 ± 25.5 kg). In contrast, tested functional torque (TFT) significantly increased at 6 out of 7 joint angles (p < 0.008) for the LUMX group only. The control group showed no significant differences pre- to post-test. These data suggest that the Romanian deadlift does not enhance lumbar extension torque. However, performing specific isolated lumbar extension training appears to improve both lumbar extension torque and Romanian deadlift 1RM. 23908978 Effect of the telephone-delivered nutrition education on dietary intake and biochemical parameters in subjects with metabolic syndrome. As prevalence of metabolic syndrome has rapidly increased over the past decade, lifestyle changes including dietary habits are considered as a therapeutic cornerstone for metabolic syndrome, cardiovascular complications and type 2 diabetes. We evaluated the effectiveness of a telephone-delivered nutrition education to improve metabolic parameters compared with a single-visit with a dietitian in subjects with metabolic syndrome. A total of seventy-one adults who met diagnostic criteria for the metabolic syndrome were randomly assigned to either the single-visit group or the in-depth nutrition education group during a 3-month intervention study period. The in-depth telephone-delivered nutrition education group had an initial visit with a dietitian and additional two telephone counseling during the first 4 weeks of the study periods. Sixty-six subjects completed a 3-month intervention study. The trial examined participant's anthropometric changes and dietary intakes as well as changes in the metabolic syndrome factors. At the end of the trial, the in-depth nutrition education group showed significantly higher reduction in weight, body fat and abdominal circumference compared with the other group (p < 0.05). In the in-depth nutrition groups, the prevalence of metabolic syndrome was decreased to 45.5%, while 69.7% of the subjects were metabolic syndrome patients in the single-visit group (p < 0.05). These results demonstrate that the telephone-intervention counseling is a feasible mean to deliver dietary intervention in patients with metabolic syndrome. 23739176 α-catenin, vinculin, and F-actin in strengthening E-cadherin cell-cell adhesions and mechanosensing. Classical cadherins play a crucial role in establishing intercellular adhesion, regulating cortical tension, and maintaining mechanical coupling between cells. The mechanosensitive regulation of intercellular adhesion strengthening depends on the recruitment of adhesion complexes at adhesion sites and their anchoring to the actin cytoskeleton. Thus, the molecular mechanisms coupling cadherin-associated complexes to the actin cytoskeleton are actively being studied, with a particular focus on α-catenin and vinculin. We have recently addressed the role of these proteins by analyzing the consequences of their depletion and the expression of α-catenin mutants in the formation and strengthening of cadherin-mediated adhesions. We have used the dual pipette assay to measure the forces required to separate cell doublets formed in suspension. In this commentary, we briefly summarize the current knowledge on the role of α-catenin and vinculin in cadherin-actin cytoskeletal interactions. These data shed light on the tension-dependent contribution of α-catenin and vinculin in a mechanoresponsive complex that promotes the connection between cadherin and the actin cytoskeleton and their requirement in the development of adhesion strengthening. 23964684 Lysophosphatidylcholine-induced cytotoxicity in osteoblast-like MG-63 cells: Involvement of transient receptor potential vanilloid 2 (TRPV2) channels. Abstract Epidemiological studies indicate that patients suffering from atherosclerosis are predisposed to develop osteoporosis. Accordingly, atherogenic determinants such as oxidized low density lipoprotein (OxLDL) particles have been shown to alter bone cell functions. In this work, we investigated the cytotoxicity of lysophosphatidylcholine (lysoPC), a major phospholipid component generated upon LDL oxidation, on bone-forming MG-63 osteoblast-like cells. Cell viability was reduced by lysoPC in a concentration-dependent manner with a LC50 of 18.7 ± 0.7 μM. LysoPC-induced cell death was attributed to induction of both apoptosis and necrosis. Since impairment of intracellular calcium homeostasis is often involved in mechanism of cell death, we determined the involvement of calcium in lysoPC-induced cytotoxicity. LysoPC promoted a rapid and transient increase in intracellular calcium attributed to mobilization from calcium stores, followed by a sustained influx. Intracellular calcium mobilization was associated to phospholipase C (PLC)-dependent mobilization of calcium from the endoplasmic reticulum since inhibition of PLC or calcium depletion of reticulum endoplasmic with thapsigargin prevented the calcium mobilization. The calcium influx induced by lysoPC was abolished by inhibition of transient receptor potential vanilloid (TRPV) channels with ruthenium red whereas gadolinium, which inhibits canonical TRP (TRPC) channels, was without effect. Accordingly, expression of TRPV2 and TRPV4 were shown in MG-63 cells. The addition of TRPV2 inhibitor Tranilast in the incubation medium prevent the calcium influx triggered by lysoPC and reduced lysoPC-induced cytotoxicity whereas TRPV4 inhibitor RN 1734 was without effect, which confirms the involvement of TRPV2 activation in lysoPC-induced cell death. 23471852 Impact of primary biliary cirrhosis on perceived quality of life: the UK-PBC national study. Primary biliary cirrhosis (PBC) has a complex clinical phenotype, with debate about the extent and specificity of frequently described systemic symptoms such as fatigue. The aim of this study was to use a national patient cohort of 2,353 patients recruited from all clinical centers in the UK to explore the impact of disease on perceived life quality. Clinical data regarding diagnosis, therapy, and biochemical status were collected and have been reported previously. Detailed symptom phenotyping using recognized and validated symptom assessment tools including the PBC-40 was also undertaken and is reported here. Perception of poor quality of life and impaired health status was common in PBC patients (35% and 46%, respectively) and more common than in an age-matched and sex-matched community control group (6% and 15%, P < 0.0001 for both). Fatigue and symptoms of social dysfunction were associated with impaired perceived quality of life using multivariate analysis. Fatigue was the symptom with the greatest impact. Depression was a significant factor, but appeared to be a manifestation of complex symptom burden rather than a primary event. Fatigue had its greatest impact on perceived quality of life when accompanied by symptoms of social dysfunction, suggesting that maintenance of social networks is critical for minimizing the impact of fatigue. Conclusion: The symptom burden in PBC, which is unrelated to disease severity or ursodeoxycholic acid response, is significant and complex and results in significant quality of life deficit. The complexity of symptom burden, and its lack of relation to disease severity and treatment response, suggest that specific approaches to symptom management are warranted that address both symptom biology and social impact. 23963366 PKC-β exacerbates in vitro brain barrier damage in hyperglycemic settings via regulation of RhoA/Rho-kinase/MLC2 pathway. Stroke patients with hyperglycemia (HG) develop higher volumes of brain edema emerging from disruption of blood-brain barrier (BBB). This study explored whether inductions of protein kinase C-β (PKC-β) and RhoA/Rho-kinase/myosin-regulatory light chain-2 (MLC2) pathway may account for HG-induced barrier damage using an in vitro model of human BBB comprising human brain microvascular endothelial cells (HBMEC) and astrocytes. Hyperglycemia (25 mmol/L D-glucose) markedly increased RhoA/Rho-kinase protein expressions (in-cell westerns), MLC2 phosphorylation (immunoblotting), and PKC-β (PepTag assay) and RhoA (Rhotekin-binding assay) activities in HBMEC while concurrently reducing the expression of tight junction protein occludin. Hyperglycemia-evoked in vitro barrier dysfunction, confirmed by decreases in transendothelial electrical resistance and concomitant increases in paracellular flux of Evan's blue-labeled albumin, was accompanied by malformations of actin cytoskeleton and tight junctions. Suppression of RhoA and Rho-kinase activities by anti-RhoA immunoglobulin G (IgG) electroporation and Y-27632, respectively prevented morphologic changes and restored plasma membrane localization of occludin. Normalization of glucose levels and silencing PKC-β activity neutralized the effects of HG on occludin and RhoA/Rho-kinase/MLC2 expression, localization, and activity and consequently improved in vitro barrier integrity and function. These results suggest that HG-induced exacerbation of the BBB breakdown after an ischemic stroke is mediated in large part by activation of PKC-β.Journal of Cerebral Blood Flow & Metabolism advance online publication, 21 August 2013; doi:10.1038/jcbfm.2013.151. 23944947 Expression and localization of taste receptor genes in the vallate papillae of rats: effect of zinc deficiency. Abstract Conclusion: We found a difference in expression sites between TAS2Rs and ENaC (epithelial sodium channels). The number of TAS2R-positive cells and ENaC-positive cells were decreased in zinc-deficient diet rats. These findings suggest that decreased expression of taste receptor genes may play an important role in the onset of zinc deficiency-associated taste disorder. Objective: The present study was aimed at histologically investigating the expression and localization of TAS2Rs and ENaC in the vallate taste buds of rats. Changes in expression of the taste receptor genes in zinc-deficient rats were also investigated. Methods: The vallate papillae of five rats fed a normal diet and five rats fed a zinc-deficient diet were used. In situ hybridization was performed to investigate the expression and localization of TAS2Rs and ENaC. TAS2R-positive cells per taste bud were counted, and differences in number between the normal and zinc-deficient diet rats were investigated. Results: In the normal rats, expression of TAS2Rs was observed specifically in the taste bud cells. In contrast, ENaC-positive cells were observed in a part of the taste bud cells and a large number of epithelial cells. Fewer cells were positive for TAS2Rs and ENaC in the zinc-deficient diet rats. 23636797 CYP2E1 T7632A and 9-bp insertion polymorphisms and colorectal cancer risk: a meta-analysis based on 4,592 cases and 5,918 controls. Previous studies suggest that genetic factors play important roles in the development of colorectal cancer. CYP2E1 T7632A and 9-bp insertion polymorphisms may influence the risk of colorectal cancer, but published results are conflicting. We therefore conducted a meta-analysis comprising 9 case-control studies with 4,592 cases and 5,918 controls. Odds ratios (ORs) with 95 % confidence interval (95 % CI) were used to assess the strength of the associations of CYP2E1 T7632A and 9-bp insertion polymorphisms with colorectal cancer. For CYP2E1 T7632A polymorphism, meta-analysis showed that there was no significant association between the CYP2E1 T7632A polymorphism and colorectal cancer risk under all contrast models (A vs. T: OR = 1.06, 95 % CI 0.88-1.29, P = 0.528; AA vs. TT: OR = 0.85, 95 % CI 0.61-1.19, P = 0.351; AA/TA vs. TT: OR = 1.08, 95 % CI 0.87-1.34, P = 0.484; and AA vs. OR = 0.87, 95 % CI 0.62-1.21, P = 0.395). For CYP2E1 96-bp insertion polymorphism, meta-analysis showed that there was a significant association between the CYP2E1 96-bp insertion polymorphism and colorectal cancer risk under the allele contrast model and the dominant contrast model (for the allele contrast model: OR = 1.20, 95 % CI 1.06-1.36, P = 0.005; for the dominant contrast model: OR = 1.25, 95 % CI 1.07-1.45, P = 0.005). Subgroup analysis by race suggested that there was an obvious association between the CYP2E1 96-bp insertion polymorphism and colorectal cancer risk in Asians under the codominant contrast model. In conclusion, our meta-analysis demonstrates that there is a significant association between the CYP2E1 96-bp insertion polymorphism and colorectal cancer risk, and CYP2E1 9-bp insertion polymorphism is a risk factor for developing colorectal cancer. 23660308 Physicochemical and biological evaluation of poly(ethylene glycol) methacrylate grafted onto poly(dimethyl siloxane) surfaces for prosthetic devices. Poly(dimethyl siloxane) (PDMS) was surface-polymerized with poly(ethylene glycol)methacrylate (PEGMA) by surface-initiated atom transfer radical polymerization (SI-ATRP) in aqueous media at room temperature. Modification of the PDMS surface followed a three-step procedure: (i) PDMS surface hydroxylation by UV/ozone exposure, immediately followed by (ii) covalent attachment of the initiator, 1-trichlorosilyl-2-(chloromethylphenyl)ethane, onto the hydroxylated PDMS, via chemical vapor deposition; finally (iii) PDMS surface-polymerization of PEGMA by ATRP. Modified PDMS was characterized by water contact angle measurement, SEM, FTIR-ATR, and XPS. Results showed that modified surfaces had a hydrophilic character, given the water contact angles around 60°; FTIR-ATR and XPS analysis confirmed the presence of polymerized PEGMA on the surface of PDMS and the adhesion of Staphylococcus aureus GB 2/1 and Streptococcus salivarius GB 24/9 onto the modified surfaces was inhibited 94% and 81%, respectively. Finally, the modified PDMS showed no evidence of cytotoxic effects in in vitro assays using human skin fibroblasts. 23590534 A systematic review of overweight, obesity, and type 2 diabetes among Asian American subgroups. This systematic review synthesizes data published between 1988 and 2009 on mean BMI and prevalence of overweight, obesity, and type 2 diabetes among Asian subgroups in the U.S. We conducted systematic searches in Pub- Med for peer-reviewed, English-language citations that reported mean BMI and percent overweight, obesity, and diabetes among South Asians/Asian Indians, Chinese, Filipinos, Koreans, and Vietnamese. We identified 647 database citations and 23 additional citations from hand-searching. After screening titles, abstracts, and full-text publications, 97 citations remained. None were published between 1988 and 1992, 28 between 1993 and 2003, and 69 between 2004 and 2009. Publications were identified for the following Asian subgroups: South Asian (n=8), Asian Indian (n=20), Chinese (n=44), Filipino (n=22), Korean (n= 8), and Vietnamese (n=3). The observed sample sizes ranged from 32 to 4245 subjects with mean ages from 24 to 78 years. Among samples of men and women, the lowest reported mean BMI was in South Asians (22.1 kg/m(2)), and the highest was in Filipinos (26.8 kg/m(2)). Estimates for overweight (12.8-46.7%) and obesity (2.1-59.0%) were variable. Among men and women, the highest rate of diabetes was reported in Asian Indians with BMI ≥ 30 kg/m(2) (32.9%, age and sex standardized). This review suggests heterogeneity among U.S. Asian populations in cardiometabolic risk factors, yet comparisons are limited due to variability in study populations, methods, and definitions used in published reports. Future efforts should adopt standardized methods to understand overweight, obesity and diabetes in this growing U.S. ethnic population. 23942031 Why does serotonergic activity drastically decrease during REM sleep? Here, I postulate two hypotheses that can explain the missing link between sleep and the serotonergic system in terms of spine homeostasis and memory consolidation. As dendritic spines contain many kinds of serotonin receptors, and the activation of serotonin receptors generally increases the number of spines in the cortex and hippocampus, I postulate that serotonin neurons are down-regulated during sleep to decrease spine number, which consequently maintains the total spine number at a constant level. Furthermore, since synaptic consolidation during REM sleep needs long-term potentiation (LTP), and serotonin is reported to inhibit LTP in the cortex, I postulate that serotonergic activity must drastically decrease during REM sleep to induce LTP and do memory consolidation. Until now, why serotonergic neurons show these dramatic changes in the sleep-wake cycle remains unexplained; however, making these hypotheses, I can confer physiological meanings on these dramatic changes of serotonergic neurons in terms of spine homeostasis and memory consolidation. 23948595 Suppression of cyclin D1 by plasmid-based short hairpin RNA ameliorated experimental pulmonary vascular remodeling. Our previous study has demonstrated that a plasmid-based short hairpin RNA (shRNA) against cyclin D1 could attenuate the pulmonary artery smooth muscle cell (PASMC) proliferation and pulmonary vascular remodeling in smoking rats. In this report, we examined the efficiency of this shRNA plasmid in monocrotaline-induced pulmonary vascular remodeling. A single injection of monocrotaline induced pulmonary vascular remodeling and cyclin D1 over-expression in pulmonary vascular smooth muscle. The shRNA successfully suppressed the up-regulation of cyclin D1 in pulmonary vessels of monocrotaline-treated rats. Moreover, this shRNA decreased the percentage of muscularized vessels and the wall thickness of pulmonary vessels. So, we concluded that plasmid-based shRNA against cyclin D1 ameliorated pulmonary vascular remodeling in monocrotaline-treated rats. Cyclin D1 might be a potential target for the therapy of pulmonary vascular remodeling and pulmonary hypertension. 22609536 Impact of early-life stress, on group III mGlu receptor levels in the rat hippocampus: effects of ketamine, electroconvulsive shock therapy and fluoxetine treatment. The glutamatergic system is increasingly being viewed as a promising target for the development of novel treatments for depression. The group III metabotropic glutamate (mGlu) receptors (mGlu(4, 7) and (8) receptors) in particular are beginning to show promise in this respect. It remains unclear how antidepressant medications modulate mGlu receptors. In this study we investigated the effects of three antidepressant treatments (fluoxetine, ketamine and electroconvulsive shock therapy (ECT)). Ketamine is an NMDA receptor antagonist which possess a rapid antidepressant therapeutic profile and moreover is effective in cases of treatment-resistant depression. Furthermore, ECT is also a therapeutic strategy possessing increased efficacy compared to conventional monoamine based therapies. The effect these two highly efficacious treatments have on hippocampal group III mGlu receptors remains completely unexplored. To redress this deficit we investigated the effects these treatments and the prototypical selective serotonin reuptake inhibitor (SSRI) fluoxetine would have on hippocampal group III mGlu receptor mRNA levels in naïve Sprague-Dawley rats and rats which had undergone early-life stress in the form of the maternal separation (MS) procedure. We found MS significantly reduced mGlu(4) receptor expression and fluoxetine reversed this MS induced change. ECT and ketamine treatment significantly reduced mGlu(4) receptor expression in non-separated (NS) animals while having no effect in MS animals. Fluoxetine and ECT significantly increased mGlu(7) receptor expression in NS animals. This work demonstrates changes to mGlu(4) receptor expression may be a lasting molecular change which occurs due to early-life stress. Taken together our data shows there are selective changes to group III mGlu receptors under basal and early-life stress conditions. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23434029 Discovery of biological evaluation of pyrazole/imidazole amides as mGlu5 receptor negative allosteric modulators. Development of SAR in a 5-aryl-3-acylpyridinyl-pyrazoles and 1-aryl-4-acylpyridinyl imidazoles series of mGlu5 receptor negative allosteric modulators (mGluR5 NAMs) using a functional cell-based assay is described in this Letter. Analysis of the Ligand-lipophilic efficiency (LipE) of compounds provided new insight for the design of potent mGluR5 negative allosteric modulators with anti-depressant activities. 23774650 Unbiased screen reveals ubiquilin-1 and -2 highly associated with huntingtin inclusions. Recently mutations in ubiquilin-2 were identified in patients with amyotrophic lateral sclerosis (ALS) and ALS/dementia providing direct evidence for the importance of this protein in neurodegenerative diseases. Histological studies have suggested that ubiquilin-1/-2 are associated with various pathological inclusions including Lewy bodies in Parkinson's disease, neurofibrillary tangles in Alzheimer's disease, polyQ inclusions in expansion repeat diseases and various proteinopathies associated with ALS and frontotemporal dementia. Using specific ubiquilin-2 antibodies and a series of transgenic mouse models of proteinopathies associated with neurodegenerative disease, we show that ubiquilin-2 preferentially associates with huntingtin polyQ expansion aggregates compared to α-synuclein, tau and several other types of protein inclusions. These results were confirmed by similar findings for ubiquilin-1 and -2 in human brain tissue sections, where accumulation was observed in huntingtin inclusions, but only infrequently in other types of protein inclusions. In cultured cells, ubiquilin-2 associates with huntingtin/polyQ aggregates, but this is not compromised by disease-causing mutations. Although ubiquilin proteins can function as chaperones to shuttle proteins for degradation, there is persistent co-localization between ubiquilin-2 and polyQ aggregated proteins during disease progression in the N586-82Q-C63 Huntington's disease mouse model. Thus, the co-localization of ubiquilin-2 with the huntingtin aggregates does not appear to facilitate aggregate removal. 22820907 Current understanding of TRPM7 pharmacology and drug development for stroke. The initial excitement and countless efforts to find a pharmacological agent that disrupts the excitotoxic pathway of ischemic neuronal death have only led to disappointing clinical trials. Currently, a thrombolytic agent called recombinant tissue plasminogen activator (rt-PA) is the only pharmacological treatment available for patients with acute ischemic stroke in most countries. Even though its efficacy has been confirmed repeatedly, rt-PA is considerably underused due to reasons including a short therapeutic window and repeated complications associated with its use. A search for alternative mechanisms that may operate dependently or independently with the well-established excitotoxic mechanism has led researchers to the discovery of newly described non-glutamate mechanisms. Among the latter, transient receptor potential melastatin 7 (TRPM7) is one of the important nonglutamate mechanisms in stroke, which has been evaluated in both in-vitro and in-vivo. In this review, we will discuss the current state of pharmacological treatments of ischemic stroke and provide evidence that TRPM7 is a promising therapeutic target of stroke. 23061657 In vitro synergistic interaction between amide piplartine and antimicrobial peptide dermaseptin against Schistosoma mansoni schistosomula and adult worms. Schistosomiasis is one of the world's major public health problems, and praziquantel is the only available drug to treat this notable neglected disease. Drug combinations have been considered an important strategy for treatment of infectious diseases, which might enhance therapeutic efficacy and delaying resistance. In this study, we have examined the in vitro activities of the amide piplartine and the antimicrobial peptide dermaseptin 01 administered singly or in combination against Schistosoma mansoni of different ages including 3-hour-old and 7-day-old schistosomula and 49-day-old adult schistosomes as well as on egg output by adult worms. We calculated the median lethal concentrations (LC(50)) of 7.87 and 17.99 μM on 49-day-old adults, 11.02 and 71.58 μM on 7-day-old schistosomula, and 70.87 and 98.42 μM on 3-hour-old schistosomula for piplartine and dermaseptin, respectively. Most Piplartine/dermaseptin combinations showed synergistic effect, with combination index (CI) values less than 0.9 when S. mansoni adults or schistosomula were simultaneously incubated with both drugs in vitro; synergy between these two compounds was also indicated using isobolograms. Additionally, we observed alterations on the tegumental surface of schistosomula and adult schistosomes by means of laser scanning confocal microscopy. Furthermore, egg laying of surviving worms was considerably more reduced when exposed to the piplartine/dermaseptin combinations than each drug alone, and this inhibition was irreversible. This is the first report on the synergistic effect between piplartine and dermaseptin against S. mansoni and opens the route to further studies (e.g. in vivo) to characterize this combination in greater detail. 23790076 Preparation of magnetic recoverable nanosize Cu-Fe2O3/Fe photocatalysts. Iron based catalysts generally have the advantage of the easily operated magnetically recovery from application sites. In the present work, paramagnetic iron and copper core-shell nanoparticles having the iron fractions (X(Fe) = Fe/(Cu+Fe)) of 0.33-1.0 were prepared and characterized by in situ synchrotron X-ray absorption and scattering spectroscopy. During the temperature-programmed carbonization (TPC) of Cu(2+)- and Fe(3+)-β-cyclodextrin (CD) complexes, a rapid reduction of Cu(II) occurs at about 453 K together with a growth of the metallic copper (Cu). Iron proceeds in the distinct growth path. At 453-513 K, the Fe(III) → Fe(II) → Fe consecutive reduction is observed. The unreduced Fe(III) (7-13%) is coated on the surfaces of the Fe nanoparticles (as Fe2O3/Fe). Growth of the Fe nanoparticle is inhibited by the surface Fe2O3, while the steady growth in Cu is observed. The Cu has a size range of 14-18 nm in diameter, compared to the small Fe2O3/Fe ones (3-6 nm). Under the UV-visible light irradiation for four hours, methylene blue can be photocatalytically degraded (>90%) by the (Cu-Fe2O3/Fe)@C. The (Cu-Fe2O3/Fe)@C photocatalysts can effectively oxidize dye molecules, providing a promising alternative for dye degradation using solar energy. Recovery of the (Cu-Fe2O3/Fe)@C photocatalysts can be attained by applying external magnetic field to trap the ferromagnetic Cu-Fe2O3/Fe nanoparticles, which suggests an economically attractive process, especially applied in photocatalytic degradation of dye-contaminated wastewater. 23770646 Treatment or "high": Benzodiazepine use in patients on injectable heroin or oral opioids. Benzodiazepine (BZD) use is widespread among opioid-maintained patients worldwide. We conducted a cross-sectional survey to investigate motives and patterns of BZD use and psychiatric comorbidity in a convenience sample of patients (n=193) maintained on oral opioid agonists or diacetylmorphine (DAM). Prolonged BZD use and high-risk behaviors like parenteral use were common. After principal component analysis, motives were divided into those related to negative affect regulation, positive affect regulation (i.e. reward-seeking) and somato-medical problems. Negative affect regulation and somato-medical motives were associated with prolonged use. Psychiatric comorbidity was associated with several self-therapeutic motives, most importantly to lose anxiety. Patients maintained on DAM were more likely to be ex-users of BZD and report high positive affect regulation. Therefore, patients maintained on different agonists may have deviating motives for BZD use, which could be of importance when addressing this issue. Treatment of psychiatric comorbidity, in particular anxiety, depressive and sleeping disorders, may be helpful in reducing BZD use, particularly in patients maintained on oral opioids. 22926269 Protective factors in american Indian communities and adolescent violence. With their distinct cultural heritage and rural boundaries, American Indian reservation communities offer a unique opportunity to explore protective factors that help buffer adolescents from potential risk behaviors such as violence. Prior published research on Indian communities has not explored three potential protective factors for violence-parental monitoring of adolescents and friends, adolescents' self-efficacy to avoid fighting, and adolescents' interest in learning more about their traditional culture. This paper explores the relationship between these factors and reduced risk of reported violence. In 1998, 630 American Indian students in grades 6-12 were surveyed in five Midwestern, rural Indian reservation schools. Path analysis was used to identify the direct and indirect association of the three potential protective factors with reduced violence behavior. There were significant gender differences both in perceived parental monitoring and in adolescents' self-efficacy. For female adolescents, parental monitoring had the strongest inverse relationship with female adolescents' involvement in violence. Female adolescents' self-efficacy and their interest in learning more about their culture were also inversely associated with violence and therefore potentially important protectors. Male adolescents who reported more interest in learning the tribe's culture had better self-efficacy to avoid violence. However, self-efficacy did not successfully predict their reported involvement in peer violence. These findings support exploring gender differences, parental monitoring, self-efficacy training as well as cultural elements in future violence intervention studies. Further investigation is needed to identify protective factors for risk behaviors among male adolescents and test the generalizability to non-reservation based adolescents. 23879976 Sustainable rare diseases business and drug access: no time for misconceptions. Legislative incentives enacted in Europe through the Regulation (EC) No. 141/2000 to incentivize orphan drug development have over the last 12 years constituted a powerful impetus toward R&D directed at the rare diseases population.However, despite therapeutic promises contained in these projects and significant economic impact linked to burgeoning R&D expenditures, the affordability and value of OMPs has become a topic of health policy debate in Europe fueled by the perception that OMPs have high acquisition costs, and by misconceptions around pricing dynamics and rare-diseases business models. In order to maintain sustainable patient access to new and innovative therapies, it is essential to address these misconceptions, and to ensure the successful continuation of a dynamic OMPs R&D within rare-diseases public health policy.Misconceptions abound regarding the pricing of rare diseases drugs and reflect a poor appreciation of the R&D model and the affordability and value of OMPs.Simulation of potential financial returns of small medium sized rare diseases companies focusing on high priced drugs show that their economic returns are likely to be close to their cost of capital. Research in rare diseases is a challenging endeavour characterised by high fixed costs in which companies accrue substantial costs for several years before potentially generating returns from the fruits of their investments. Although heavily dependent upon R&D capabilities of each individual company or R&D organization, continuous flow of R&D financial investment should allow industry to increasingly include efficiencies in research and development in cost considerations to its customers. Industry should also pro-actively work on facilitating development of a specific value based pricing approach to help understanding what constitute value in rare diseases. Policy makers must reward innovation based upon unmet need and patient outcome. Broader understanding by clinicians, the public, and policy makers of the complexity of clinical programs to deliver OMPs to market is required to better comprehend the decisions needed and made by industry. In parallel, an overt effort to consider the impact of public policies on R&D investments is key to enable policy makers to better reconcile the incentives provided by public policy decisions and companies investments decisions in a more positive manner. 23947852 A generic π∗ shape resonance observed in energy-dependent photoelectron angular distributions from two-colour, resonant multiphoton ionization of difluorobenzene isomers. We present new evidence for the existence of a near threshold π∗ shape resonance as a common feature in the photoionization of each isomer of difluorobenzene. Experimentally, this is revealed by significant changes in the anisotropy of the photoelectron angular distributions (PADs) following the ionization of the optically aligned S1 state of these molecules at varying photon energies. Continuum multiple scattering Xα calculations reproduce this behaviour well, and allow the visualisation of the continuum shape resonances. The resonances are unusually narrow in energy (<1 eV), but nevertheless appear to extend right down to the ionization thresholds-exactly the low energy range typically accessed in laser-based resonance enhanced multiphoton ionization (REMPI) schemes. The anticipation of such pronounced energy dependence in the PADs and cross-sections sought for other molecules, and an ability to accurately predict such features, should be important for the reliable application and interpretation of experiments involving REMPI probing of those molecules. 23794108 The art of dying as an art of living: historical contemplations on the paradoxes of suicide and the possibilities of reflexive suicide prevention. The main aim of this paper is to reconstruct different aspects of the history of ideas of suicide, from antiquity to late modernity, and contemplate their dialectical tension. Reflexive suicide prevention, drawing on the ancient wisdom that the art of living is inseparable from the art of dying, takes advantage, it is argued, of the contradictory nature of suicide, and hence embraces, rather than trying to overcome, death, pain, grief, fear, hopelessness and milder depressions. This approach might facilitate the transformation of inner shame to inter-personal guilt, which is the precondition for coping with losses through grieving that is shared with others. The traditional projection of suicide on the 'Other', reinforced by modernity's bio-political suppression of death, has inhibited development of good suicide prevention. Awareness of the ambiguity and ambivalence found in suicide may work as a resource when measures are taken to address as many causal mechanisms as possible, and bringing special emphasis to external factors. 23812671 Vemurafenib synergizes with nutlin-3 to deplete survivin and suppresses melanoma viability and tumor growth. For patients with advanced melanoma, primary and secondary resistance to selective BRAF inhibition remains one of the most critically compelling challenges. One rationale argues that novel biologically informed strategies are needed to maximally cripple melanoma cells up front before compensatory mechanisms emerge. As p53 is uncommonly mutated in melanoma, restoration of its function represents an attractive adjunct to selective BRAF inhibition. Thirty-seven BRAF(V600E)-mutated melanoma lines were subjected to synergy studies in vitro using a combination of vemurafenib and nutlin-3 (Nt-3). In addition, cellular responses and in vivo efficacy were also determined. We also analyzed changes in the levels of canonical apoptotic/survival factors in response to vemurafenib. Dual targeting of BRAF(V600E) and Hdm2 with vemurafenib and Nt-3, respectively, synergistically induced apoptosis and suppressed melanoma viability in vitro and tumor growth in vivo. Suppression of p53 in melanoma cells abrogated Nt-3's effects fully and vemurafenib's effects partially. A survey of canonical survival factors revealed that both vemurafenib and Nt-3 independently attenuated levels of the antiapoptotic protein, survivin. Genetic depletion of survivin reproduces the cytotoxic effects of the combination strategy. These results show preclinical feasibility for overcoming primary vemurafenib resistance by restoring p53 function. Moreover, it identifies survivin as one downstream mediator of the observed synergism and a potential secondary target. Clin Cancer Res; 19(16); 4383-91. ©2013 AACR. 23970040 Lipopolysaccharide-Induced Inflammation Aggravates Irradiation-Induced Injury to the Young Mouse Brain. Radiotherapy is an effective treatment strategy in the treatment of brain tumors, but it is also a major cause of long-term complications, especially in survivors of pediatric brain tumors. Cognitive decline caused by cranial radiotherapy is thought, at least partly, to depend on injury to stem and progenitor cells in the dentate gyrus of the hippocampus. This study investigated the effects of lipopolysaccharide (LPS)-induced inflammation at the time of irradiation (IR) in the growing mouse brain. A single injection of LPS (0.3 mg/kg) was administered 24 h prior to cranial IR of 14-day-old male mice. LPS pretreatment increased the levels of the chemokine CCL2 and the cytokine IL-1β in the brain by 440 and 560%, respectively, compared to IR alone. IR disrupted hippocampal neurogenesis and the growth of the dentate gyrus, and the mice pretreated with LPS displayed an even more pronounced lack of growth than the vehicle-treated group 2 months after IR. The density of microglia was not affected, but LPS-pretreated mice displayed 48% fewer bromodeoxyuridine-positive cells and 43% fewer doublecortin-positive cells in the granule cell layer 2 months after IR compared with the vehicle-treated group. In conclusion, an ongoing inflammation in the brain at the time of IR further enhanced the IR-induced loss of neurogenesis, and may aggravate future cognitive deficits in patients treated with cranial radiotherapy. 23858094 Menaquinones, bacteria, and the food supply: the relevance of dairy and fermented food products to vitamin k requirements. Vitamin K exists in the food supply as phylloquinone, a plant-based form and as menaquinones (MKs), a collection of isoprenologues mostly originating from bacterial synthesis. Although multiple bacterial species used as starter cultures for food fermentations synthesize MK, relatively little is known about the presence and distribution of MK in the food supply and the relative contribution of MK to total dietary vitamin K intake. Dairy products may be a predominant source of dietary MK in many regions of the world, and there is recent interest in enhancing the MK content of dairy products through identification and selection of MK-producing bacteria in dairy fermentations. This interest is increased by emerging evidence that current dietary recommendations based on the classic role of vitamin K as an enzyme cofactor for coagulation proteins may not be optimal for supporting vitamin K requirements in extrahepatic tissues and that MK may have unique bioactivity beyond that as an enzyme cofactor. Observational studies have reported favorable associations between MK intake and bone and cardiovascular health. Although randomized trials have provided some evidence to support the beneficial effects of MK on bone, the evidence to date is not definitive, and randomized trials have not yet examined MK intake in relation to cardiovascular outcomes. Food production practices provide a means to enhance dietary MK availability and intake. However, parallel research is needed to optimize these production practices, develop comprehensive food MK content databases, and test hypotheses of unique beneficial physiological roles of MK beyond that achieved by phylloquinone. 23294368 Melt granulation in fluidized bed: a comparative study of spray-on versus in situ procedure. Abstract Objective: The aim of this study was to investigate the influence of process parameters, binder content and binder addition method on characteristics of the granules obtained by melt granulation (MG) in fluidized bed. Methods: Spray-on experiments were performed according to 2(3) full factorial design. The effect of binder content, molten binder feed rate, and spray air pressure on granule size and size distribution, granule shape, flowability and drug release rate was investigated. In the in situ experiments, the influence of binder particle size and binder content was evaluated. Solid-state characterization was performed by means of differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy. Results: Size of the granules obtained by spray-on procedure was significantly influenced by binder content and spray air pressure, while the width of particle size distribution was mainly affected by binder feed rate. Spray air pressure showed the most significant influence on granule shape. It was shown that smooth and spherical particles with good flow properties may be obtained by both procedures, spray-on and in situ MG. The results obtained indicated the influence of agglomeration mechanism on granule sphericity, with higher degree of granule sphericity observed when immersion and layering was the dominant mechanism. Paracetamol release from granulates was very rapid, but after compression of the granules into tablets, drug release was considerably slower. Solid-state analysis confirmed that the physical form of the granulate components remained unaffected after the MG process. Conclusion: The results presented indicate that MG in fluidized bed could be a good alternative to conventional granulation techniques. 23636454 RACK1 interacts with filamin-A to regulate plasma membrane levels of the cystic fibrosis transmembrane conductance regulator. Mutations in cystic fibrosis transmembrane regulator (CFTR), a chloride channel in the apical membranes of secretory epithelial cells, underlie the fatal genetic disorder cystic fibrosis. Certain CFTR mutations, including the common mutation ΔF508-CFTR, result in greatly decreased levels of active CFTR at the apical membrane. Direct interactions between CFTR and the cytoskeletal adaptors filamin-A (FlnA) and Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) stabilize the expression and localization of CFTR at the plasma membrane. The scaffold protein receptor for activated C kinase 1 (RACK1) also stabilizes CFTR surface expression; however, RACK1 does not interact directly with CFTR and its mechanism of action is unknown. In the present study, we report that RACK1 interacts directly with FlnA in vitro and in a Calu-3 airway epithelial cell line. We mapped the interaction between RACK1 and FlnA to the WD4 and WD6 repeats of RACK1 and to a segment of the large rod domain of FlnA, consisting of immunoglobulin-like repeats 8-15. Disruption of the RACK1-FlnA interaction causes a reduction in CFTR surface levels. Our results suggest that a novel RACK1-FlnA interaction is an important regulator of CFTR surface localization. 23744268 The Helmholtz-Hodge decomposition--a survey. The Helmholtz-Hodge Decomposition (HHD) describes the decomposition of a flow field into its divergence-free and curl-free components. Many researchers in various communities like weather modeling, oceanology, geophysics, and computer graphics are interested in understanding the properties of flow representing physical phenomena such as incompressibility and vorticity. The HHD has proven to be an important tool in the analysis of fluids, making it one of the fundamental theorems in fluid dynamics. The recent advances in the area of flow analysis have led to the application of the HHD in a number of research communities such as flow visualization, topological analysis, imaging, and robotics. However, because the initial body of work, primarily in the physics communities, research on the topic has become fragmented with different communities working largely in isolation often repeating and sometimes contradicting each others results. Additionally, different nomenclature has evolved which further obscures the fundamental connections between fields making the transfer of knowledge difficult. This survey attempts to address these problems by collecting a comprehensive list of relevant references and examining them using a common terminology. A particular focus is the discussion of boundary conditions when computing the HHD. The goal is to promote further research in the field by creating a common repository of techniques to compute the HHD as well as a large collection of example applications in a broad range of areas. 23379481 Activation of the anti-cancer agent upamostat by the mARC enzyme system. Abstract 1. Upamostat (Mesupron®) is a new small molecule serine protease inhibitor. The drug candidate was developed to inhibit the urokinase-type plasminogen activator (uPA) system, which plays a major role in tumor invasion and metastasis. Upamostat is currently in clinical development as an anti-metastatic and non-cytotoxic agent against pancreatic and breast cancer. 2. Upamostat is the orally available amidoxime- (i.e. hydroxyamidine-) prodrug of the pharmacologically active form, WX-UK1. In this study, the reductive enzymatic activation of upamostat to its corresponding amidine WX-UK1 was analyzed. 3. The recently discovered molybdenum enzyme "mitochondrial Amidoxime Reducing Component" (mARC) catalyses together with its electron transport proteins cytochrome b(5) and NADH cytochrome b(5) reductase the reduction of N-hydroxylated prodrugs. In vitro biotransformation assays with porcine subcellular fractions and the reconstituted human enzymes demonstrate an mARC-dependent N-reduction of upamostat. 22723252 A systematic review of the prevalence of herb usage among racial/ethnic minorities in the United States. Clinical studies display a wide range of herb use prevalence among racial/ethnic minorities in the United States. We searched databases indexing the literature including CINAHL, EMBASE, Global Health, CAB Abstracts, and Medline. We included studies that reported herbal medicine prevalence among ethnic minorities, African American, Hispanic, or Asian adults living in the United States. Data from 108 included studies found the prevalence of herb use by African Americans was 17 % (range 1-46 %); for Hispanics, 30 % (4-100 %); and for Asians, 30 % (2-73 %). Smaller studies were associated with higher reported herb use (p = 0.03). There was a significant difference (p = 0.01) between regional and national studies with regional studies reporting higher use. While herb usage surveys in racial/ethnic minorities show great variability, indications suggest high prevalence. More research is needed to understand herb use among ethnic/racial minorities, reasons for use, and barriers to disclosure of use to clinicians. 22872139 The association of strategic group and organizational culture with hospital performance in China. The policy environment in China is rapidly changing. Strategic planning may enable hospitals to respond more effectively to changes in their external environment, little evidence exists on the extent to which public hospitals in China adopt different strategies and the relationship between strategic decision-making and hospital performance. The purposes of our study were to determine the extent to which different hospitals adopt different strategies, whether strategies are associated with organizational culture and whether hospital strategies are associated with hospital performance. Presidents (or vice presidents), employees, and patients from 87 public hospitals were surveyed during 2009. Measures of strategic group were developed using cluster analysis based on the three dimensions of product position, competitive posture, and market position. Culture was measured using a tool developed by the investigators. Performance was measured based on profitability, patient satisfaction, and employee satisfaction with overall hospital development in the recent 5 years. The association of strategic group and organizational culture with hospital performance was analyzed using multivariate models. Chinese public general hospitals were classified into five strategic groups that had significant differences in product positioning, competitive posture, and market position. Hospitals of similar types based on regulation adopted different strategies. Organizational culture was not strongly associated with hospital strategic group. Although strategic group was associated with hospital profitability and patient satisfaction in the models with or without control for hospital location, these effects did not persist after controlling for organizational culture, hospital level, and hospital location. It is important for public hospitals in China to make effective strategic planning and align their organizational culture with the strategies for better execution and therefore better performance. Moreover, the method of hospital strategic grouping in the study provides a new way to analyze management issues within a strategic group and between strategic groups. 23817768 Aortic Outflow Cannula Tip Design and Orientation Impacts Cerebral Perfusion During Pediatric Cardiopulmonary Bypass Procedures. Poor perfusion of the aortic arch is a suspected cause for peri- and post-operative neurological complications associated with cardiopulmonary bypass (CPB). High-speed jets from 8 to 10FR pediatric/neonatal cannulae delivering ~1 L/min of blood can accrue sub-lethal hemolytic damage while also subjecting the aorta to non-physiologic flow conditions that compromise cerebral perfusion. Therefore, we emphasize the importance of cannulation strategy and hypothesize engineering better CPB perfusion through a redesigned aortic cannula tip. This study employs computational fluid dynamics to investigate novel diffuser-tipped aortic cannulae for shape sensitivity to cerebral perfusion, in an in silico cross-clamped aortic arch model modeled with fixed outflow resistances. 17 parametrically altered configurations of an 8FR end-hole and several diffuser cone angled tips in combination with jet incidence angles toward or away from the head-neck vessels were studied. Experimental pressure-flow characterizations were also conducted on these cannula tip designs. An 8FR end-hole aortic cannula delivering 1 L/min along the transverse aortic arch was found to give rise to backflow from the brachicephalic artery (BCA), irrespective of angular orientation, for the chosen ascending aortic insertion location. Parametric alteration of the cannula tip to include a diffuser cone angle (tested up to 7°) eliminated BCA backflow for any tested angle of jet incidence. Experiments revealed that a 1 cm long 10° diffuser cone tip demonstrated the best pressure-flow performance improvement in contrast with either an end-hole tip or diffuser cone angles greater than 10°. Performance further improved when the diffuser was preceded by an expanded four-lobe swirl inducer attachment-a novel component. In conclusion, aortic cannula orientation is crucial in determining net head-neck perfusion but precise angulations and insertion-depths are difficult to achieve practically. Altering the cannula tip to include a diffuser cone angle has been shown for the first time to have potential in ensuring a net positive outflow at the BCA. Cannula insertion distanced from the BCA inlet may also avoid backflow owing to the Venturi effect, but the diffuser tipped cannula design presents a promising solution to mitigate this issue irrespective of in vivo cannula tip orientation. 23474487 Topical administration of somatostatin prevents retinal neurodegeneration in experimental diabetes. Retinal neurodegeneration is an early event in the pathogenesis of diabetic retinopathy (DR). Somatostatin (SST) is an endogenous neuroprotective peptide that is downregulated in the diabetic eye. The aim of the study was to test the usefulness of topical administration of SST in preventing retinal neurodegeneration. For this purpose, rats with streptozotocin-induced diabetes mellitus (STZ-DM) were treated with either SST eye drops or vehicle for 15 days. Nondiabetic rats treated with vehicle served as a control group. Functional abnormalities were assessed by electroretinography (ERG), and neurodegeneration was assessed by measuring glial activation and the apoptotic rate. In addition, proapoptotic (FasL, Bid, and activation of caspase-8 and caspase-3) and survival signaling pathways (BclxL) were examined. Intraretinal concentrations of glutamate and its main transporter glutamate/aspartate transporter (GLAST) were also determined. Treatment with SST eye drops prevented ERG abnormalities, glial activation, apoptosis, and the misbalance between proapoptotic and survival signaling detected in STZ-DM rats. In addition, SST eye drops inhibited glutamate accumulation in the retina and GLAST downregulation induced by diabetes mellitus. We conclude that topical administration of SST has a potent effect in preventing retinal neurodegeneration induced by diabetes mellitus. In addition, our findings open up a new preventive pharmacological strategy targeted to early stages of DR. 23766128 A Human FSHB Promoter SNP Associated With Low FSH Levels in Men Impairs LHX3 Binding and Basal FSHB Transcription. FSH production is important for human gametogenesis. In addition to inactivating mutations in the FSHB gene, which result in infertility in both sexes, a G/T single-nucleotide polymorphism (SNP) at -211 relative to the transcription start site of the 5' untranslated region of FSHB has been reported to be associated with reduced serum FSH levels in men. In this study, we sought to identify the potential mechanism by which the -211 SNP reduces FSH levels. Although the SNP resides in a putative hormone response element, we showed that, unlike the murine gene, human FSHB was not induced by androgens or progestins in gonadotropes. On the other hand, we found that the LHX3 homeodomain transcription factor bound to an 11-bp element in the human FSHB promoter that includes the -211 nucleotide. Furthermore, we also demonstrated that LHX3 bound with greater affinity to the wild-type human FSHB promoter compared with the -211 G/T mutation and that LHX3 binding was more effectively competed with excess wild-type oligonucleotide than with the SNP. Finally, we showed that FSHB transcription was decreased in gonadotrope cells with the -211 G/T mutation compared with the wild-type FSHB promoter. Altogether, our results suggest that decreased serum FSH levels in men with the SNP likely result from reduced LHX3 binding and induction of FSHB transcription. 23795877 Self-efficacy and motivation to quit marijuana use among young women. Assessing motivation to quit substance use is recommended as part of brief interventions. The purpose of this study was to determine correlates of desire to quit marijuana use among young adult women enrolled in a brief motivational intervention trial. Participants were 332 female marijuana users, aged 18-24, who rated their current desire to quit using a single item change ladder. We hypothesized self-efficacy and prior quit attempts will interact in this population to increase motivation to quit. Participants had a mean age of 20.5 years, 67.7% were non-Hispanic Caucasian, and 60% had some desire to quit marijuana use. Using multivariate linear regression, quit desire was significantly lower among Caucasians (b = -.256; 95% CI -.489; -.037) and more frequent marijuana users (b = -.268; 95% CI -.372; -.166), and higher among those with previous quit attempts (b = .454; 95% CI .235; .671), and greater marijuana problem severity (b = .408; 95% CI .302; .514). Greater refusal self-efficacy was associated with greater quit desire among participants with previous quit attempts, but not among those without prior quit attempts (b = .241; 95% CI .050; .440). Understanding the factors relating to quit desire among marijuana users may allow clinicians to tailor counseling so as to increase readiness to quit and decrease use and its associated consequences. 23955294 Application of Lipopeptide Biosurfactant Isolated from a Halophile: Bacillus tequilensis CH for Inhibition of Biofilm. Biosurfactants are amphiphilic molecules having hydrophobic and hydrophilic moieties produced by various microorganisms. These molecules trigger the reduction of surface tension or interfacial tension in liquids. A biosurfactant-producing halophile was isolated from Lake Chilika, a brackish water lake of Odisha, India (19°41'39″N, 85°18'24″E). The halophile was identified as Bacillus tequilensis CH by biochemical tests and 16S rRNA gene sequencing and assigned accession no. KC851857 by GenBank. The biosurfactant produced by B. tequilensis CH was partially characterized as a lipopeptide using thin-layer chromatography, Fourier transform infrared spectroscopy, and nuclear magnetic resonance techniques. The minimum effective concentration of a biosurfactant for inhibition of pathogenic biofilm (Escherichia coli and Streptococcus mutans) on hydrophilic and hydrophobic surfaces was found to be 50 Î¼g ml(-1). This finding has potential for a variety of applications. 23844033 Identification and characterization of highly divergent simian foamy viruses in a wide range of new world primates from Brazil. Foamy viruses naturally infect a wide range of mammals, including Old World (OWP) and New World primates (NWP), which are collectively called simian foamy viruses (SFV). While NWP species in Central and South America are highly diverse, only SFV from captive marmoset, spider monkey, and squirrel monkey have been genetically characterized and the molecular epidemiology of SFV infection in NWPs remains unknown. We tested a large collection of genomic DNA (n  = 332) comprising 14 genera of NWP species for the presence of SFV polymerase (pol) sequences using generic PCR primers. Further molecular characterization of positive samples was carried out by LTR-gag and larger pol sequence analysis. We identified novel SFVs infecting nine NWP genera. Prevalence rates varied between 14-30% in different species for which at least 10 specimens were tested. High SFV genetic diversity among NWP up to 50% in LTR-gag and 40% in pol was revealed by intragenus and intrafamilial comparisons. Two different SFV strains infecting two captive yellow-breasted capuchins did not group in species-specific lineages but rather clustered with SFVs from marmoset and spider monkeys, indicating independent cross-species transmission events. We describe the first SFV epidemiology study of NWP, and the first evidence of SFV infection in wild NWPs. We also document a wide distribution of distinct SFVs in 14 NWP genera, including two novel co-speciating SFVs in capuchins and howler monkeys, suggestive of an ancient evolutionary history in NWPs for at least 28 million years. A high SFV genetic diversity was seen among NWP, yet these viruses seem able to jump between NWP species and even genera. Our results raise concerns for the risk of zoonotic transmission of NWP SFV to humans as these primates are regularly hunted for food or kept as pets in forest regions of South America. 23925174 Electronic and optical properties of Cr and Cr-N doped anatase TiO2 from screened Coulomb hybrid calculations. We studied the electronic and atomic structures of anatase TiO2 codoped with Cr and N using hybrid density functional theory calculations. The nonlocal screened Hartree-Fock exchange energy is partially mixed with the traditional semilocal exchange energy. This not only patches the bandgap underestimation but also improves the description of the anion/cation-driven impurity states and the magnetization of the dopants. Cr and/or N doping modifies the valence and conduction band edges of TiO2, leading to significant bandgap reduction. Hence, Cr, N and Cr-N doped TiO2 are promising for enhanced visible light absorbance. 23283976 Control of transcriptional fidelity by active center tuning as derived from RNA polymerase endonuclease reaction. Precise transcription by cellular RNA polymerase requires the efficient removal of noncognate nucleotide residues that are occasionally incorporated. Mis-incorporation causes the transcription elongation complex to backtrack, releasing a single strand 3'-RNA segment bearing a noncognate residue, which is hydrolyzed by the active center that carries two Mg(2+) ions. However, in most x-ray structures only one Mg(2+) is present. This Mg(2+) is tightly bound to the active center aspartates, creating an inactive stable state. The first residue of the single strand RNA segment in the backtracked transcription elongation complex strongly promotes transcript hydrolytic cleavage by establishing a network of interactions that force a shift of stably bound Mg(2+) to release some of its aspartate coordination valences for binding to the second Mg(2+) thus enabling catalysis. Such a rearrangement that we call active center tuning (ACT) occurs when all recognition contacts of the active center-bound RNA segment are established and verified by tolerance to stress. Transcription factor Gre builds on the ACT mechanism in the same reaction by increasing the retention of the second Mg(2+) and by activating the attacking water, causing 3000-4000-fold reaction acceleration and strongly reinforcing proofreading. The unified mechanism for RNA synthesis and degradation by RNA polymerase predicts that ACT also executes NTP selection thereby contributing to high transcription fidelity. 23700277 Tobacco karyotyping by accurate centromere identification and novel repetitive DNA localization. Tobacco (Nicotiana tabacum) is an amphidiploid species (2n = 4x = 48, genome constitution SSTT) derived from a natural hybrid between Nicotiana sylvestris (2n = 2x = 24, SS) and Nicotiana tomentosiformis (2n = 2x = 24, TT). Genomic in situ hybridization (GISH), using the genomic DNA from these ancestral species as probes, revealed the chromosomal origins (S or T) and the occurrence of intergenomic translocations in N. tabacum. Fluorescence in situ hybridization (FISH) was also used to distinguish between chromosomes. However, the use of repetitive DNA sequences as probes for FISH analysis is limited by an inability to identify all chromosomes. In addition to this limitation, the occurrence of chromosomal tertiary constrictions can easily lead to the misclassification of chromosomes. To overcome these issues, immunostaining with anti-N. tabacum centromere-specific histone H3 antibody was carried out to determine the centromere position of each chromosome, followed by FISH analysis with ten distinct repetitive DNA probes. This approach allowed us to identify 22 of the 24 chromosome pairs in N. tabacum and revealed novel intergenomic chromosome rearrangements and B-chromosome-like minichromosomes. Hence, the combination of immunostaining with FISH and GISH is critical to accurately karyotype tobacco. 23760347 Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study. IMPORTANCE Mood disorders frequently co-occur with medical diseases that involve inflammatory pathophysiologic mechanisms. Immune responses can affect the brain and might increase the risk of mood disorders, but longitudinal studies of comorbidity are lacking. OBJECTIVE To estimate the effect of autoimmune diseases and infections on the risk of developing mood disorders. DESIGN Nationwide, population-based, prospective cohort study with 78 million person-years of follow-up. Data were analyzed with survival analysis techniques and adjusted for calendar year, age, and sex. SETTING Individual data drawn from Danish longitudinal registers. PARTICIPANTS A total of 3.56 million people born between 1945 and 1996 were followed up from January 1, 1977, through December 31, 2010, with 91 637 people having hospital contacts for mood disorders. MAIN OUTCOMES AND MEASURES The risk of a first lifetime diagnosis of mood disorder assigned by a psychiatrist in a hospital, outpatient clinic, or emergency department setting. Incidence rate ratios (IRRs) and accompanying 95% CIs are used as measures of relative risk. RESULTS A prior hospital contact because of autoimmune disease increased the risk of a subsequent mood disorder diagnosis by 45% (IRR, 1.45; 95% CI, 1.39-1.52). Any history of hospitalization for infection increased the risk of later mood disorders by 62% (IRR, 1.62; 95% CI, 1.60-1.64). The 2 risk factors interacted in synergy and increased the risk of subsequent mood disorders even further (IRR, 2.35; 95% CI, 2.25-2.46). The number of infections and autoimmune diseases increased the risk of mood disorders in a dose-response relationship. Approximately one-third (32%) of the participants diagnosed as having a mood disorder had a previous hospital contact because of an infection, whereas 5% had a previous hospital contact because of an autoimmune disease. CONCLUSIONS AND RELEVANCE Autoimmune diseases and infections are risk factors for subsequent mood disorder diagnosis. These associations seem compatible with an immunologic hypothesis for the development of mood disorders in subgroups of patients. 23855953 Hydrolysis reactions of the taccalonolides reveal structure-activity relationships. The taccalonolides are microtubule stabilizers isolated from plants of the genus Tacca that show potent in vivo antitumor activity and the ability to overcome multiple mechanisms of drug resistance. The most potent taccalonolide identified to date, AJ, is a semisynthetic product generated from the major plant metabolite taccalonolide A in a two-step reaction. The first step involves hydrolysis of taccalonolide A to generate taccalonolide B, and then this product is oxidized to generate an epoxide group at C-22-C-23. To generate sufficient taccalonolide AJ for in vivo antitumor efficacy studies, the hydrolysis conditions for the conversion of taccalonolide A to B were optimized. During purification of the hydrolysis products, we identified the new taccalonolide AO (1) along with taccalonolide I. When the same hydrolysis reaction was performed on a taccalonolide E-enriched fraction, four new taccalonolides, assigned as AK, AL, AM, and AN (2-5), were obtained in addition to the expected product taccalonolide N. Biological assays were performed on each of the purified taccalonolides, which allowed for increased refinement of the structure-activity relationship of this class of compounds. 23866106 Lessons learned from child sexual abuse research: prevalence, outcomes, and preventive strategies. Although child sexual abuse (CSA) is recognized as a serious violation of human well-being and of the law, no community has yet developed mechanisms that ensure that none of their youth will be sexually abused. CSA is, sadly, an international problem of great magnitude that can affect children of all ages, sexes, races, ethnicities, and socioeconomic classes. Upon invitation, this current publication aims at providing a brief overview of a few lessons we have learned from CSA scholarly research as to heighten awareness of mental health professionals on this utmost important and widespread social problem. This overview will focus on the prevalence of CSA, the associated mental health outcomes, and the preventive strategies to prevent CSA from happening in the first place. 23884704 Sero-prevalence and risk factors study of brucellosis in small ruminants in Southern Zone of Tigray Region, Northern Ethiopia. This study reports a prevalence and risk factor survey of brucellosis in small ruminants in Southern Zone of Tigray Region, Northern Ethiopia between October 2011 and April 2012 to determine the sero-prevalence of small-ruminant brucellosis and to identify associated risk factors for the occurrence of disease in small ruminants under extensive production system. Multistage random sampling was followed to select locations, flocks, and individual animals. Laboratory analysis of serum samples provided sero-prevalence estimates for flocks and geographic location. Information on risk factors at the individual and flock level was obtained by examination of individual animal and a questionnaire interview to flock owners. The overall individual animal-level sero-prevalence of brucellosis in small ruminants was 3.5 % and flock level sero-prevalence was 28.3 %, and the within-flock sero-prevalence was ranged from 0 % to 22.2 % based on the Complement Fixation Test. Multivariable logistic regression showed that the major risk factors for flock level sero-positivity were flock size and abortion history. This study showed that small-ruminant brucellosis is prevalent in the study area. Larger flock size and history of previous abortion in the flock were major risk factors identified for sero-positivity of small-ruminant brucellosis. 23852962 Cytokine correlation between sinus tissue and nasal secretions among chronic rhinosinusitis and controls. Compare cytokine levels in sinus tissue to sinus secretions from controls and chronic rhinosinusitis patients. In vitro. Polyurethane foam sponges were placed into middle meati of patients with chronic rhinosinusitis without nasal polyps (CRSsNP), with polyps (CRSwNP), and controls. Sinus biopsies were then taken from the same location. Protein levels of tumor necrosis factor-alpha (TNF-α), interferon-γ (IFN-γ), and interleukins (IL) 2, 4, 6, 8, 10, and 17A were measured via cytometric bead assay for each sample. Protein values from sinus tissue and secretions were compared with Pearson's correlation between samples as well as one-way ANOVA with posthoc t test between groups. Samples from 43 patients in total were examined. Mucus was measured from 10 controls, 11 CRSsNP and 10 CRSwNP, and sinus tissue was measured from 10 controls, 15 CRSsNP and 10 CRSwNP. IL-8 and IFN-γ levels were outside of the detectable range of the assay. Levels of secreted IL-2, 4, 6, 10, and 17A correlated with tissue levels (P < 0.05 for all, r > 0.49) while TNF-α did not (P = 0.71). CRSsNP had elevated mucus levels of IL-2, 4, 6, 10, and 17A compared to controls. CRSwNP had elevated mucus levels of IL-4, 6, 10, 17A, and TNF-α compared to controls. Cytokine levels in sinus secretions correlate with levels in sinus tissue and are elevated in CRS versus control based on Th1/Th2 skewing. N/A (in vitro). Laryngoscope, 2013. 23489119 Family and community rejection and a congolese led mediation intervention to reintegrate rejected survivors of sexual violence in eastern democratic republic of congo. Our purpose in this study is to describe the multiple and inter-related health, economic, and social reasons for rejection and to provide an example of a Congolese-led family mediation program to reintegrate survivors into their families. We conducted this study in Eastern Democratic Republic of Congo (DRC) and included two focus group discussions and twenty-seven interviews. Rejection extends beyond physical dislocation to include economic and social aspects. Family mediation is a process requiring knowledge of traditions and norms. Understanding the context of rejection and supporting promising local reintegration efforts will likely improve health, economic, and social outcomes for the survivor, her family, and her community. 23949449 Jaspers' Critique of Essentialist Theories of Schizophrenia and the Phenomenological Response. This contribution reviews the fin de siècle and immediately following efforts (Berze, Gross, Jung, Stransky, Weygandt, and others) to find a fundamental psychological disturbance (psychologische Grundstörung) underlying the symptoms of dementia praecox, later renamed schizophrenia by Bleuler (1908, 1911). In his General Psychopathology (1913), Jaspers brings order into the field by bringing to psychopathology a scientific basis coupled with phenomenological rigor. He was critical of theories that proposed an essence of schizophrenia, which is merely asserted verbally. This imperative is reiterated by other members of the Heidelberg School (Gruhle, Mayer-Gross, and K. Schneider). Gruhle (1929) contended that the primary symptoms of schizophrenia, indicating an underlying but still unknown neurobiological disease process, are independent from one another. They cannot be brought under a single, current theoretical model. That is, schizophrenia cannot be explained in terms of a 'catchword', which is only thought but not empirically studied. Sobered but also inspired by Jaspers' rigor, phenomenological psychiatrists (Binswanger, Blankenburg, Conrad, Ey, and others) proposed more tempered models, which could be studied empirically or tested scientifically. This historical progression may be viewed as a dialectical process: First, bold, merely verbal assertions without method were made, then Jaspers followed with a sobering critique, and finally, the existential-phenomenological clinicians/researchers responded by producing fine-grained, rigorous phenomenological models, tempered by humility and self-critique, which led to hypotheses that could be tested in current clinical neuroscience. © 2013 S. Karger AG, Basel. 23940816 Genetic Diversity and Geographic Population Structure of Bovine Neospora caninum Determined by Microsatellite Genotyping Analysis. The cyst-forming protozoan parasite Neosporacaninum is one of the main causes of bovine abortion worldwide and is of great economic importance in the cattle industry. Recent studies have revealed extensive genetic variation among N. caninum isolates based on microsatellite sequences (MSs). MSs may be suitable molecular markers for inferring the diversity of parasite populations, molecular epidemiology and the basis for phenotypic variations in N. caninum, which have been poorly defined. In this study, we evaluated nine MS markers using a panel of 11 N. caninum-derived reference isolates from around the world and 96 N. caninum bovine clinical samples and one ovine clinical sample collected from four countries on two continents, including Spain, Argentina, Germany and Scotland, over a 10-year period. These markers were used as molecular tools to investigate the genetic diversity, geographic distribution and population structure of N. caninum. Multilocus microsatellite genotyping based on 7 loci demonstrated high levels of genetic diversity in the samples from all of the different countries, with 96 microsatellite multilocus genotypes (MLGs) identified from 108 N. caninum samples. Geographic sub-structuring was present in the country populations according to pairwise F ST . Principal component analysis (PCA) and Neighbor Joining tree topologies also suggested MLG segregation partially associated with geographical origin. An analysis of the MLG relationships, using eBURST, confirmed that the close genetic relationship observed between the Spanish and Argentinean populations may be the result of parasite migration (i.e., the introduction of novel MLGs from Spain to South America) due to cattle movement. The eBURST relationships also revealed genetically different clusters associated with the abortion. The presence of linkage disequilibrium, the co-existence of specific MLGs to individual farms and eBURST MLG relationships suggest a predominant clonal propagation for Spanish N. caninum MLGs in cattle. 23928717 Suprachoroidal electrical stimulation: effects of stimulus pulse parameters on visual cortical responses. Objective. Neural responses to biphasic constant current pulses depend on stimulus pulse parameters such as polarity, duration, amplitude and interphase gap. The objective of this study was to systematically evaluate and optimize stimulus pulse parameters for a suprachoroidal retinal prosthesis. Approach. Normally sighted cats were acutely implanted with platinum electrode arrays in the suprachoroidal space. Monopolar stimulation comprised of monophasic and biphasic constant current pulses with varying polarity, pulse duration and interphase gap. Multiunit responses to electrical stimulation were recorded in the visual cortex. Main results. Anodal stimulation elicited cortical responses with shorter latencies and required lower charge per phase than cathodal stimulation. Clinically relevant retinal stimulation required relatively larger charge per phase compared with other neural prostheses. Increasing the interphase gap of biphasic pulses reduced the threshold of activation; however, the benefits of using an interphase gap need to be considered in light of the pulse duration and polarity used and other stimulation constraints. Based on our results, anodal first biphasic pulses between 300-1200 µs are recommended for suprachoroidal retinal stimulation. Significance. These results provide insights into the efficacy of different pulse parameters for suprachoroidal retinal stimulation and have implications for the design of safe and clinically relevant stimulators for retinal prostheses. 23856971 2',4'-BNA bearing a chiral guanidinopyrrolidine-containing nucleobase with potent ability to recognize the CG base pair in a parallel-motif DNA triplex. In order to expand the target sequence used in triplex DNA formation, seven novel nucleotide analogues were synthesized and incorporated into triplex-forming oligonucleotides by post-elongation modification approaches. Among them, , equipped with a suitable restricted conformation of sugar and nucleobase moieties, was found to have the highest sequence-selectivity and affinity towards CG base pairs within double-stranded DNA. 23806620 Community event-based outreach screening for syphilis and other sexually transmissible infections among gay men in Sydney, Australia. Objectives Increased testing frequency is a key strategy in syphilis control, but achieving regular testing is difficult. The objective of this study is to describe a sexually transmissible infection (STI) testing outreach program (the Testing Tent) at a gay community event. Methods: Gay men attending the testing tent in 2010-11 completed a computer-assisted self-interview and were screened for STIs. Clinical, demographic, behavioural and diagnostic data were compared with gay men attending a clinic-based service during 2009. The Testing Tent was marketed on social media sites and data were extracted on the number of times the advertisements were viewed. Staffing, laboratory, marketing and venue hire expenses were calculated to estimate the cost of delivering the service. Results: Ninety-eight men attended the Testing Tent. They were older (median age: 42 years v. 30 years; P<0.001), had more sex partners (median: five in 3 months v. two; P<0.001) and more likely to inject drugs (9% v. 4%; P=0.034) than the 1006 clinic attendees, but were more likely to have previously tested for STIs (81% v. 69%; P=0.028) and to always use condoms for anal sex (59% v. 43%; P=0.005). Five cases of STIs were detected; the diagnostic yield was not significantly different from that of the clinic. The cost of the Testing Tent was A$28?440. Conclusion: Nonclinical testing facilities are an acceptable option and are accessed by gay men requiring regular testing, and may be an important addition to traditional testing environments. 23537834 Synthesis of oleic acid functionalized Fe3O4 magnetic nanoparticles and studying their interaction with tumor cells for potential hyperthermia applications. In the present study, oleic acid (OA) functionalized Fe3O4 magnetic nanoparticles (MN) were synthesized following modified wet method of MN synthesis. The optimum amount of OA required for capping of MN and the amount of bound and unbound/free OA was determined by thermogravimetric analysis (TGA). Further, we have studied the effect of water molecules, associated with MN, on the variation in their induction heating ability under alternating current (AC) magnetic field conditions. We have employed a new approach to achieve dispersion of OA functionalized MN (MN-OA) in aqueous medium using sodium carbonate, which improves their biological applicability. Interactions amongst MN, OA and sodium carbonate were studied by Fourier transform infrared spectroscopy (FT-IR). Intracellular localization of MN-OA was studied in mouse fibrosarcoma cells (WEHI-164) by prussian blue staining and confocal laser scanning microscopy (CLSM) using nile blue A as a fluorescent probe. Results showed MN-OA to be interacting mainly with the cell membrane. Their hyperthermic killing ability was evaluated in WEHI-164 cells by trypan blue method. Cells treated with MN-OA in combination with induction heating showed decreased viability as compared to respective induction heating controls. These results were supported by altered cellular morphology after treatment of MN-OA in combination with induction heating. Further, the magnitude of apoptosis was found to be ~5 folds higher in cells treated with MN-OA in combination with induction heating as compared to untreated control. These results suggest the efficacy of MN-OA in killing of tumor cells by cellular hyperthermia. 23892849 Importance of positron emission tomography-computed tomography (PET-CT) examination in rectal cancer staging - initial clinical experience. Aim Accurate preoperative staging is essential in determining optimal therapeutic procedures and planning for individual patients. Advances in imaging technology have raised interest in the potential role of positron emission tomography-computed tomography (PET-CT) examination for staging of rectal cancer. The primary end point of the study was the correct classification of the tumornode- metastases (TNM) tumor stage using whole-body PET-CT examination. Methods This prospective study was performed from October 2011 to October 2012. Patients with histopathological diagnosis of rectal cancer after biopsy underwent PET-CT before surgical treatment and TNM staging. Twenty patients who fulfilled inclusion criteria were included in the study. All of the patients were operated and histopathology served as the standard of reference. Results There was no statistical significance in T staging comparing PET-CT and histopathological staging, according to the Monte Carlo simulation (p=.066). Also, there was no statistical significance between two methods in mesorectal fascia involvement analysis (p=1). There was statistical difference between PET-CT and histopathological staging. Sensitivity of the PET-CT for N staging was 86.7% and it was higher than for the histopathology. Two patients showed liver metastases. Conclusion Positron emission tomography-computed tomography examination could play an important role in the initial staging for the rectal cancer. Good patient selection for preoperative chemoradiotherapy ensures survival benefit. Avoidance of unnecessary therapeutic procedures allows an acceptable quality of patient's life. Key words: imaging, stage, histopathology Med Glas. 23644274 Metabolic and molecular methods to evaluate the organoclay effects on a bacterial community. The aim of this work was to evaluate the influence exerted by two different commercial organoclays (DELLITE 43B and DELLITE 67G) on a model microbial consortium using microbial metabolic characterization with BIOLOG system and denaturing gradient gel electrophoresis (DGGE) molecular approach. The information obtained from the molecular analyses, in their complex, account for the differences in species composition induced on the reference consortium by the contact with the organoclays under study. DELLITE 43B resulted to produce a marked selective effect, stimulating the quantitative increase especially of Pseudomonas pseudoalcaligenes. A weaker effect was found for DELLITE 67G. On the other hand, Biolog analyses indicated a depressing action exerted by DELLITE 43B on the metabolic activity of the model microbial consortium as a whole. The presence of P. pseudoalcaligenes and B. borstelensis in the bacterial community after the treatments confirmed that a positive change in the microbial structure consortium occurred. 23370859 Dietary nitrate supplementation improves team sport-specific intense intermittent exercise performance. Recent studies have suggested that dietary inorganic nitrate (NO₃(-)) supplementation may improve muscle efficiency and endurance exercise tolerance but possible effects during team sport-specific intense intermittent exercise have not been examined. We hypothesized that NO₃(-) supplementation would enhance high-intensity intermittent exercise performance. Fourteen male recreational team-sport players were assigned in a double-blind, randomized, crossover design to consume 490 mL of concentrated, nitrate-rich beetroot juice (BR) and nitrate-depleted placebo juice (PL) over ~30 h preceding the completion of a Yo-Yo intermittent recovery level 1 test (Yo-Yo IR1). Resting plasma nitrite concentration ([NO₂(-)]) was ~400% greater in BR compared to PL. Plasma [NO₂(-)] declined by 20% in PL (P < 0.05) and by 54 % in BR (P < 0.05) from pre-exercise to end-exercise. Performance in the Yo-Yo IR1 was 4.2% greater (P < 0.05) with BR (1,704 ± 304 m) compared to PL (1,636 ± 288 m). Blood [lactate] was not different between BR and PL, but the mean blood [glucose] was lower (3.8 ± 0.8 vs. 4.2 ± 1.1 mM, P < 0.05) and the rise in plasma [K(+)] tended to be reduced in BR compared to PL (P = 0.08). These findings suggest that NO₃(-) supplementation may promote NO production via the nitrate-nitrite-NO pathway and enhance Yo-Yo IR1 test performance, perhaps by facilitating greater muscle glucose uptake or by better maintaining muscle excitability. Dietary NO₃(-) supplementation improves performance during intense intermittent exercise and may be a useful ergogenic aid for team sports players. 23732506 Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Microglia, the resident immune cells of the central nervous system (CNS), play an important role in CNS homeostasis during development, adulthood and ageing. Their phenotype and function have been widely studied, but most studies have focused on their local interactions in the CNS. Microglia are derived from a particular developmental niche, are long-lived, locally replaced and form a significant part of the communication route between the peripheral immune system and the CNS; all these components of microglia biology contribute to maintaining homeostasis. Microglia function is tightly regulated by the CNS microenvironment, and increasing evidence suggests that disturbances, such as neurodegeneration and ageing, can have profound consequences for microglial phenotype and function. We describe the possible biological mechanisms underlying the altered threshold for microglial activation, also known as 'microglial priming', seen in CNS disease and ageing and consider how priming may contribute to turning immune-to-brain communication from a homeostatic pathway into a maladaptive response that contributes to symptoms and progression of diseases of the CNS. 23707484 Fumaric acid attenuates the eotaxin-1 expression in TNF-α-stimulated fibroblasts by suppressing p38 MAPK-dependent NF-κB signaling. Eotaxin-1 is a potent chemoattractant for eosinophils and a critical mediator during the development of eosinophilic inflammation. Fumaric acid is an intermediate product of the citric acid cycle, which is source of intracellular energy. Although fumaric acid ameliorates psoriasis and multiple sclerosis, its involvement in eotaxin-1-mediated effects has not been assessed. In this study, we investigated the effects of fumaric acid on eotaxin-1 expression in a mouse fibroblast cell line. We found that fumaric acid significantly inhibited tumor necrosis factor-α (TNF-α-induced eotaxin-1 expression. This fumaric acid effect was mediated through the inhibition of p38 mitogen-activated protein kinase (MAPK)-dependent nuclear factor (NF)-κB signaling. We also found that fumaric acid operates downstream of MEKK3 during TNF-α-induced NF-κB signaling, which upregulated eotaxin-1 expression. In addition, fumaric acid attenuated expression of CC-chemokine receptor 3 (CCR3), an eotaxin-1 receptor, and adhesion molecules that play important roles in eosinophil binding to induce allergic inflammation. Taken together, these findings indicate that inhibiting TNF-α-induced eotaxin-1 expression by fumaric acid occurs primarily through suppression of NF-κB signaling, which is mediated by inhibiting p38 MAPK and suggest that fumaric acid may be used as a complementary treatment option for eotaxin-1-mediated diseases. 23394844 A potential role for lamellar insulin-like growth factor-1 receptor in the pathogenesis of hyperinsulinaemic laminitis. The reason why a sustained high concentration of insulin induces laminitis in horses remains unclear. Cell proliferation occurs in the lamellae during insulin-induced laminitis and in other species high concentrations of insulin can activate receptors for the powerful cell mitogen, insulin-like growth factor (IGF)-1. The first aim of this study was to determine if IGF-1 receptors (IGF-1R) are activated in the hoof during insulin-induced laminitis. Gene expression for IGF-1R and the insulin receptor (InsR) was measured using qRT-PCR, in lamellar tissue from control horses and from horses undergoing a prolonged euglycaemic, hyperinsulinaemic clamp (p-EHC), during the mid-developmental (24h) and acute (46h) phases of insulin-induced laminitis. Gene expression for both receptors was decreased 13-32-fold (P<0.05) at both time-points in the insulin-treated horses. A second aim was to determine if the down-regulation of the receptor genes could be accounted for by an increase in circulating IGF-1. Serum IGF-1 was measured at 0, 10, 25 and 46h post-treatment in horses given a p-EHC for approximately 46h, and in matched controls administered a balanced, electrolyte solution. There was no increase in serum IGF-1 concentrations during the p-EHC, consistent with down-regulation of both receptors by insulin. Stimulation of the IGF-1R by insulin may lead to inappropriate lamellar epidermal cell proliferation and lamellar weakening, a potential mechanism for hyperinsulinaemic laminitis. Targeting this receptor may provide insights into the pathogenesis or identify a novel therapy for hyperinsulinaemic laminitis. 23913259 Visualizing SNVs to quantify allele-specific expression in single cells. We present a FISH-based method for detecting single-nucleotide variants (SNVs) in exons and introns on individual RNA transcripts with high efficiency. We used this method to quantify allelic expression in cell populations and in single cells, and also to distinguish maternal from paternal chromosomes in single cells. 23427042 Acute waterborne copper toxicity to the euryhaline copepod Acartia tonsa at different salinities: Influence of natural freshwater and marine dissolved organic matter. The influence of natural dissolved organic matter (DOM) on acute waterborne Cu toxicity was evaluated in the euryhaline copepod Acartia tonsa at 3 different water salinities. Three sources of freshwater DOM (extracted by reverse osmosis) and 2 sources of marine DOM (extracted using a solid-phase technique) were used. Artificial salt water was used to prepare the experimental media. Different combinations of Cu concentrations and DOM sources and concentrations were tested at salinities of 5, 15, and 30 ppt. Toxicity data (48-h median lethal concentration [LC50] values) were calculated based on dissolved Cu concentrations. In a broad view, data showed that increasing salinity was protective against the acute waterborne Cu toxicity. In general, Cu toxicity was also lower in the presence than in the absence of DOM. Toxicity (48-h LC50) values from all treatments at the same salinity showed a positive linear relationship with the dissolved organic carbon (DOC). Thus, the protective effect of DOM against the acute Cu toxicity seems to be dependent mainly on the DOM concentration. However, it seems also to be dependent to some extent on the source of DOM used. In summary, findings reported in the present study clearly indicate that both salinity and DOM (source and concentration) should be taken into account in the development of an estuarine version of the biotic ligand model. Environ Toxicol Chem 2013;32:1412-1419. © 2013 SETAC. 23480484 Laparoendoscopic single-site surgery for acute adnexal pathology during pregnancy: preliminary experience. Abstract Objective: To report the feasibility of laparoendoscopic single port surgical approach for the management of huge adnexal cysts and adnexal torsion during pregnancy. To discuss the optimal method of entry into the peritoneal cavity for pregnant patients. Design: Two case report. Method and patient(s): Two pregnant patients with adnexal mass. First patient, suffering from persistent and progressive abdominal distention and pain on her 12th week of pregnancy, was diagnosed with an ovarian cyst in 18 cm diameter on left ovary. The other patient had IVF twin pregnancy and presented with left adnexal torsion on the 25th week of pregnancy Intervention(s): Single-port laparoscopic ovarian cystectomy on the 12th week of pregnancy in patient one and single-port left adnexectomy in a twin pregnancy on the 25th week of pregnancy in patient two. Main outcome measure(s): Feasibility of single port laparoscopic intervention during pregnancy for adnexal mass. Result(s): Complete resolution of the symptoms for both pregnant women after the surgeries. No fetal and maternal complication was diagnosed during both pregnancies. Conclusion(s): Single port laparoscopy with open-entry technique is feasible and might be a better surgical option for the pregnant patients with adnexal pathology. However, further studies with larger sample size are needed to reach clear conclusion. 23314071 Cellular and molecular mechanisms of accelerated fracture healing by COX2 gene therapy: studies in a mouse model of multiple fractures. This study sought to determine the cellular and molecular mechanisms of cyclooxygenase-2 (COX2) gene therapy to accelerate fracture repair in a mouse multiple tibial fractures model. The lenti-COX2 (or lenti-gfp control vector) was injected into fractures on day 1 post-fracture. At days 3-7, the COX2 treatment increased Sdf1-, Cxcr4-, Nes-, and Podxl-expressing mesenchymal stem cells (MSCs) within fracture calluses, suggesting an enhanced MSC recruitment or expansion. The COX2-treated mice formed smaller cartilaginous calluses that had less cartilage tissues than control mice. The expression of Sox9 mRNA was 7-fold less in COX2-treated than in control calluses at day 14, implying that COX2 reduces chondrocytic differentiation of MSCs. The therapy also enhanced angiogenesis as reflected by increased immunostaining of CD31, vWF, and α-SMA over controls in the cartilaginous callus at day 14-21. At which time, the COX2 gene therapy promoted bony remodeling of the cartilaginous callus to bridge the fracture gap that was accompanied by 2-fold increase in osteoclasts along the surface of the woven bone and an onset of osteogenesis. Blocking angiogenesis with daily injection of endostatin from day 4 to day 10 into fracture sites blocked the COX2-mediated reduction of callus size that was associated with an increase in hypertrophic chondrocytes and concomitant reduction in osteoclasts. In conclusion, COX2 accelerates fracture healing in part through three biological actions: 1) increased recruitment/expansion of MSCs; 2) decreased cartilaginous callus formation; and 3) increased angiogenesis-dependent cartilage remodeling. These effects were associated with an earlier onset of bony bridging of the fracture gap. 23831081 Urinary metabonomics study on toxicity biomarker discovery in rats treated with Xanthii Fructus. Xanthii Fructus (XF) is commonly called "Cang-Erzi" in traditional Chinese medicine (TCM) and widely used for the treatment of sinusitis, headache, rheumatism, and skin itching. However, the clinical utilization of XF is relatively restricted owing to its toxicity. To discover the characteristic potential biomarkers in rats treated with XF by urinary metabonomics. Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was applied in the study. The total ion chromatograms obtained from control and different dosage groups were distinguishable by a multivariate statistical analysis method. The greatest difference in metabolic profile was observed between high dosage group and control group, and the metabolic characters in rats treated with XF were perturbed in a dose-dependent manner. The metabolic changes in response for XF treatment were observed in urinary samples, which were revealed by orthogonal projection to latent structures discriminate analysis (OPLS-DA), and 10 metabolites could be served as the potential toxicity biomarkers. In addition, the mechanism associated with the damages of lipid per-oxidation and the metabolic disturbances of fatty acid oxidation were investigated. These results indicate that metabonomics analysis in urinary samples may be useful for predicting the toxicity induced by XF. 23733781 Minimal Residual Disease Assessed by Multiparameter Flow Cytometry in Multiple Myeloma: Impact on Outcome in the Medical Research Council Myeloma IX Study. PURPOSE To investigate the prognostic value of minimal residual disease (MRD) assessment in patients with multiple myeloma treated in the MRC (Medical Research Council) Myeloma IX trial. PATIENTS AND METHODS Multiparameter flow cytometry (MFC) was used to assess MRD after induction therapy (n = 378) and at day 100 after autologous stem-cell transplantation (ASCT; n = 397) in intensive-pathway patients and at the end of induction therapy in non-intensive-pathway patients (n = 245). Results In intensive-pathway patients, absence of MRD at day 100 after ASCT was highly predictive of a favorable outcome (PFS, P < .001; OS, P = .0183). This outcome advantage was demonstrable in patients with favorable and adverse cytogenetics (PFS, P = .014 and P < .001, respectively) and in patients achieving immunofixation-negative complete response (CR; PFS, P = .0068). The effect of maintenance thalidomide was assessed, with the shortest PFS demonstrable in those MRD-positive patients who did not receive maintenance and longest in those who were MRD negative and did receive thalidomide (P < .001). Further analysis demonstrated that 28% of MRD-positive patients who received maintenance thalidomide became MRD negative. MRD assessment after induction therapy in the non-intensive-pathway patients did not seem to be predictive of outcome (PFS, P = .1). CONCLUSION MRD assessment by MFC was predictive of overall outcome in patients with myeloma undergoing ASCT. This predictive value was seen in patients achieving conventional CR as well as patients with favorable and adverse cytogenetics. The effects of maintenance strategies can also be evaluated, and our data suggest that maintenance thalidomide can eradicate MRD in some patients. 23747712 Factors affecting the bioaccessibility of fluoride from seafood products. Fluoride is considered important for health because of its beneficial effect on the prevention of dental caries and on bone development in the child population. However, excessive intake has negative effects. The main pathway for exposure is oral, through consumption of drinking water, and some food products. Therefore its bioaccessibility (quantity of the element solubilized during the digestive process) is a parameter to be considered when estimating the risk/benefit associated with this element. The aim of the present study was to evaluate the influence of the digestion phase, gastrointestinal digestion factors (pH, pepsin and bile salt concentrations) and the presence of cations on the bioaccessibility of fluoride from seafood products. The results show that the solubilization of fluoride takes place entirely during the gastric phase. Its bioaccessibility is strongly influenced by conditions that favor the formation of insoluble complexes of fluoride with other elements present in the matrix. The factors that are most influential in reducing its bioaccessibility are the increase in pH in the gastric phase, the presence of cations, especially in the intestinal phase, and a low concentration of bile salts. 23424214 Effects of the combined artesunate and mefloquine antimalarial drugs on rat embryos. Artemisinins combination therapy (ACT) is the first choice therapy for falciparum malaria. Data on the safety of ACTs in pregnancy are limited and controversial and the use is not recommended on the first trimester. To evaluate the effects of isolated and combined artesunate (AS)/mefloquine (MQ) on embryo rats, pregnant rats were treated orally with AS (15 and 40 mg/kg body weight (bwt)/day), MQ (30 and 80 mg/kg bwt/day) and AS/MQ (15/30 and 40/80 mg/kg bwt/day) on days 9-11 post coitum (pc). The dams were euthanized on day 12 pc and gestational and embryos histological parameters were evaluated. Embryolethality and histopathological anomalies were significant when AS was given alone or combined with MQ. Combination of AS and MQ did not enhance their toxicity compared to their separate administrations; on the other side, there was a reduction in the toxic effects of the AS when combined with MQ. Isolated MQ did not induce developmental toxicity. 23747224 Inhibition of Candida albicans isocitrate lyase activity by cadiolides and synoilides from the ascidian Synoicum sp. Tris-aromatic furanones (1-4) and related bis-aromatic diesters (5 and 6) isolated from the dark red ascidian Synoicum sp., were evaluated for their inhibitory activities toward Candida albicans isocitrate lyase (ICL). These studies led to the identification of compounds 1, 3, and 4 as potent ICL inhibitors, with IC50 values of 7.62, 17.16, and 10.36 μM, respectively. Growth phenotype of ICL deletion mutants and Northern blot analysis data indicated that compound 1 inhibits the ICL expression in C. albicans under C2 carbon utilizing condition. 23770331 Altered behavioral aspects of aged mice lacking the cellular prion protein. The biological function of the prion protein, which is intimately involved in the onset of prion diseases, remains unclear. To understand whether the prion protein could play a role in animal behavior, a battery of tests was applied to young and aged mice that express, or not, the prion protein. In contrast to the similar results obtained in all young animals, we found that aged mice lacking the prion protein reacted to new and stressful environments differently than their wild-type counterparts. This may suggest that, upon aging, the absence of the prion protein results in altered neural processing at the basis of adaptation to new situations. 23455722 Neurons in the cingulate motor area signal context-based and outcome-based volitional selection of action. Volitional selection of action is subject to continuous adjustment under the influence of information obtained by monitoring behavioral consequences and by exploiting behavioral context based on prior knowledge about the environment. The rostral cingulate motor area (CMAr) is thought to be responsible for adjusting behavior by monitoring its consequences. To investigate whether the CMAr also plays a role in exploitation of behavioral context in action selection, we recorded neuronal activities from the CMAr while monkeys performed a reward-based motor selection task that required them to switch from one action to the other based on the amount of reward. We examined both the behavior of monkeys and the activity of CMA neurons quantitatively by constructing a hybrid reinforcement learning model incorporating context-based and outcome-based action values into a new action value. We found that CMAr neurons encoded the context-based action value by increasing or decreasing their firing rates gradually with the number of repetitions of the same movement (i.e., behavioral context). We also found that CMAr neurons encoded the context-based and outcome-based action values in two distinct time windows at single neuron and population levels. Our findings indicate that the CMAr is involved in behavioral adjustment of action selection by exploiting the behavioral context and not merely by monitoring reward outcome. 23810592 Short communication: Comparison of the newly developed DVE/OEB (2010) system and the National Research Council (2001) model in modeling metabolic characteristics of proteins in dairy cattle. The truly absorbed protein in the small intestine/degraded protein balance (DVE/OEB)2010 system is a recently developed protein evaluation system for ruminants. The objective of this study was to compare the DVE/OEB2010 system with the National Research Council (2001) model in determining the metabolic characteristics of proteins in dairy cattle. The metabolic characteristics of proteins in bioethanol feedstock and their co-products were compared in terms of (1) truly absorbed rumen synthesized microbial protein in the small intestine; (2) truly absorbed rumen undegraded feed protein in the small intestine; (3) endogenous protein in the digestive tract; (4) total truly absorbed protein in the small intestine; and (5) protein degraded balance. The DVE/OEB2010 system predicted 30% more truly absorbed rumen synthesized microbial protein in the small intestine, 4% more truly absorbed rumen undegraded feed protein in the small intestine, 64% more endogenous protein, 9% more total truly absorbed protein in the small intestine, but 27% less degraded protein balance. 23603147 Immunotoxicological effects of inorganic arsenic on gilthead seabream (Sparus aurata L.). Arsenic (As) has been associated with multitude of animal and human health problems; however, its impact on host immune system has not been extensively investigated. In fish, there are very few works on the potential risks or problems associated to the presence of arsenic. In the present study we have evaluated the effects of exposure (30 days) to sub-lethal concentrations of arsenic (5μM As2O3) in the teleost fish gilthead seabream (Sparus aurata), with special emphasis in the innate immune response. The arsenic concentration was determined using atomic fluorescence spectrometry (AFS) in liver and muscle of exposed fish showing As accumulation in the liver after 30 days of exposure. The hepatosomatic index was increased at significant extent after 10 days but returned to control values after 30 days of exposure. Histological alterations in the liver were observed including hypertrophy, vacuolization and cell-death processes. Focusing on the immunological response, the humoral immune parameters (seric IgM, complement and peroxidase activities) were no affected to a statistically significant extent. Regarding the cellular innate parameters, head-kidney leucocyte peroxidase, respiratory burst and phagocytic activities were significantly increased after 10 days of exposition compared to the control fish. Overall, As-exposure in the seabream affects the immune system. How this might interfere with fish biology, aquaculture management or human consumers warrants further investigations. This paper describes, for the first time, the immunotoxicological effects of arsenic exposure in the gilthead seabream, which is a species with the largest production in Mediterranean aquaculture. 23929385 Assessment of Nonlethal Methods for Predicting Muscle Tissue Mercury Concentrations in Coastal Marine Fishes. Caudal fin clips and dorsolateral scales were analyzed as a potential nonlethal approach for predicting muscle tissue mercury (Hg) concentrations in marine fish. Target fish were collected from the Narragansett Bay (Rhode Island, USA) and included black sea bass Centropristis striata [n = 54, 14-55 cm total length (TL)], bluefish Pomatomus saltatrix (n = 113, 31-73 cm TL), striped bass Morone saxatilis (n = 40, 34-102 cm TL), summer flounder Paralichthys dentatus (n = 64, 18-55 cm TL), and tautog Tautoga onitis (n = 102, 27-61 cm TL). For all fish species, Hg concentrations were greatest in muscle tissue [mean muscle Hg = 0.47-1.18 mg/kg dry weight (dw)] followed by fin clips (0.03-0.09 mg/kg dw) and scales (0.01-0.07 mg/kg dw). The coefficient of determination (R (2)) derived from power regressions of intraspecies muscle Hg against fin and scale Hg ranged between 0.35 and 0.78 (mean R (2) = 0.57) and 0.14-0.37 (mean R (2) = 0.30), respectively. The inclusion of fish body size interaction effects in the regression models improved the predictive ability of fins (R (2) = 0.63-0.80; mean = 0.71) and scales (R (2) = 0.33-0.71; mean = 0.53). According to the high level of uncertainty within the regression models (R (2) values) and confidence interval widths, scale analysis was deemed an ineffective tool for estimating muscle tissue Hg concentrations in the target species. In contrast, the examination of fin clips as predictors of muscle Hg had value as a cursory screening tool; however, this method should not be the foundation for developing human consumption advisories. It is also noteworthy that the efficacy of these nonlethal techniques was highly variable across fishes and likely depends on species-specific life-history characteristics. 23267238 Relation between aortic valve sclerosis and ankle-brachial index in participants clinically free of atherosclerotic vascular disease. Most patients with peripheral arterial disease (PAD) are asymptomatic and have similar vascular morbidity and mortality with patients with symptomatic PAD. Despite being a very highly prevalent disease, physicians underdiagnose and undertreat PAD. A total of 100 participants with aortic valve sclerosis (AVS) and 100 participants without AVS and age-, gender-, and cardiovascular risk factor-matched participants were enrolled. Ankle-brachial index (ABI) and AVS were evaluated by handheld Doppler device and echocardiography, respectively. There was significantly lower ABI in participants with AVS compared with those without AVS (1.04 ± 0.14 v 1.11 ± 0.07, P = .001). There was a negative correlation between ABI and AVS (r = -.29, P < .001). Linear regression analysis demonstrated an independent association between ABI and AVS (95% confidence interval [CI]: -0.91 to -0.27, P < .001) and β-blocker use (95% CI: -0.96 to -0.02, P: .04). Our findings confirm an association between AVS and PAD that may be attributed to shared vascular risk factors. 23528361 Atropa acuminata Royle Ex Lindl. blunts production of pro-inflammatory mediators eicosanoids., leukotrienes, cytokines in vitro and in vivo models of acute inflammatory responses. ETHNOPHARMACOLOGICAL RELEVANCE: Atropa acuminata Royle Ex Lindl. has been widely used in folk medicine for several inflammatory disorders such as arthritis, asthma, conjunctivitis, encephalitis, pancreatitis, peritonitis, acute infections and neuroinflammatory disorders. AIM OF THE STUDY: Our aim was to evaluate Atropa acuminata for its anti-inflammatory properties and to delineate its possible mechanism of action on the modulation of the inflammatory mediators. MATERIALS AND METHODS: We investigated the inhibitory action of ethanolic extract of Atropa acuminata (AAEE) on production of NO, TNF-α and IL-1β in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and also assayed it for COX 1/2 and 5-LOX inhibitory activities. Next AAEE was tested in acute inflammatory animal models., carragenean induced rat paw edema, carragenean induce pleurisy in rats and vascular permeability in mice and the effects on NO, PGE2 and LTB4 production in the pleural fluid and paw exudates were evaluated. In addition the effects on leukocyte migration and exudation and vascular permeability were also observed. RESULTS: Our findings summarized novel anti-inflammatory mechanisms for Atropa acuminata based on dual in vitro cyclooxygenase 1/2/ and 5-Lipoxygenase inhibitory activities and also significant downregulation of nitric oxide (NO) and pro-inflammatory cytokin (TNF-α and Il-1 β) release in LPS-stimulated RAW 246.7 macrophage cell line. In acute inflammatory models in vivo (carragenean induced edema, carragenean induced pleurisy in rats and vascular permeability in mice), AAEE exhibited an extensive diverse mechanism for anti-inflammatory properties. This was indicated on the basis of dose dependent suppression of multi targeted inflammatory mediators., NO, TNF-α and IL-1β, eicosanoids., PGE2 and leukotrienes., LTB4 along with significantly decreased leucocyte migration, exudation and decreased vascular permeability. These effects were more potent and prolonged than traditional NSAIDS, thereby indicating fewer side effects. AAEE was found to be safe for long term administration, as confirmed by the results of acute toxicity studies and MTT assay. The complex mode of action of the herbs was attributed possibly due to the high polyphenolic, flavanol and flavonoid content present in the extracts as observed by means of quantitative screening for phytochemicals. CONCLUSION: Our study provides scientific evidence to support the traditional anti-inflammatory uses of Atropa acuminata and is probably due to inhibitory effects on multiple inflammatory mediators which indicates a promising potential for the development of a strong anti-inflammatory agent from this plant. 23941655 Experience with the atrium advanta covered stent for aortic obstruction. We sought to assess the efficacy, safety and clinical outcomes of the Advanta V12™ covered stent in management of coarctation of the aorta (CoA). Stent functionality was assessed by review of angiographic imaging, clinical data at admission, discharge and at the last clinic visit, stent configuration on chest roentgenogram, radiation exposure, and complications. Between October 2009 and February 2012, 17 patients underwent stent implantation. There were 9-12, 2-14, and 6-16 mm diameter stents deployed. Balloon angioplasty after implantation was required in 2 patients. Mean percent recoil in the middle of the stent for the 12, 14, and 16 mm implants was 14%, 24%, and 24%, respectively. There was improvement in CoA diameter from 6.6 ± 3.2 to 11.5 ± 1.7 mm (P < 0.0001) and a reduction in the peak pressure gradient from 23.1 ± 10.1 to 0.8 ± 3.3 mmHg (P < 0.0001). No patient had a symptomatic complication. Left arm cuff blood pressure fell 24 hours after implantation and left arm to leg blood pressure gradient fell to <20 mmHg in all (P < 0.0001). Follow-up was a median 242 days and at the last clinic visit there were no statistically different findings from discharge. Five children (33%) required antihypertensive medications but 3 were off medication at latest follow-up. Three patients (18%) required reintervention. The implantation of the Advanta™ V12 stent for the treatment of CoA is safe and effective in the early term. However, further study is required to determine longer-term stent efficacy. 23884019 Two homochiral organocatalytic metal organic materials with nanoscopic channels. Two homochiral organocatalytic MOMs were prepared using tetra- and octa-carboxylate ligands, respectively. The nanoscopic channels in these MOMs are lined by organonocatalytic chiral phosphoric acid derivatives of binol and ocMOM-1 exhibited improved enantioselectivity over the parent ligand in the context of transfer hydrogenation of a series of benzoxazines. 23751155 Quantitative local photosynthetic flux measurements at isolated chloroplasts and thylakoid membranes using scanning electrochemical microscopy (SECM). Scanning electrochemical microscopy (SECM) offers a fast and quantitative method to measure local fluxes within photosynthesis. In particular, we have measured the flux of oxygen and ferrocyanide (Fe(CN)6(4-)), from the artificial electron acceptor ferricyanide (Fe(CN)6(3-)), using a stationary ultramicroelectrode at chloroplasts and thylakoid membranes (sourced from chloroplasts). Oxygen generation at films of chloroplasts and thylakoid membranes was detected directly during photosynthesis, but in the case of thylakoid membranes, this switched to sustained oxygen consumption at longer illumination times. An initial oxygen concentration spike was detected over both chloroplast and thylakoid membrane films, and the kinetics of the oxygen generation were extracted by fitting the experimental data to a finite element method (FEM) simulation. In contrast to previous work, the oxygen generation spike was attributed to the limited size of the plastoquinone pool, a key component in the linear electron transport pathway and a contributing factor in photoinhibition. Finally, the mobile nature of the SECM probe, and its high spatial resolution, also allowed us to detect ferrocyanide produced from a single thylakoid membrane. These results further demonstrate the power of SECM for localized flux measurements in biological processes, in this case photosynthesis, and that the high time resolution, combined with FEM simulations, allows the elucidation of quantitative kinetic information. 23931241 The Validity and Reliability of the Arabic Infant/Toddler Sensory Profile. ABSTRACT In this study, we report the translation process, validity, and reliability of the Arabic Infant/Toddler Sensory Profile (IT_SP). A multistep approach was implemented to ensure the accuracy and equivalency of the Arabic and original English IT_SP. Factor analysis indicated that item loadings for over 50% of the items on the Arabic version were identical to the English version; all but three items had logical loadings. Intraclass correlation coefficients (ICC) between scores on the Arabic and English versions reported by parents who were bilingual were >.90 supporting bilingual validity. Alpha coefficients for each section varied from .40 to .74, which was within the range of the English version (.17 to .86), and were thus similar. ICCs between scores for repeated assessments varied from .81 to .99 supporting test-retest reliability. The results support the validity and reliability of the Arabic IT_SP. 23868681 Recovery of Damaged Skeletal Muscle in mdx Mice through Low-intensity Endurance Exercise. The lack of dystrophin in mdx mice leads to cycles of muscle degeneration and regeneration processes. Various strategies have been proposed in order to reduce the muscle-wasting component of muscular dystrophy, including implementation of an exercise programme. The aim of this study was to examine how low-intensity endurance exercise affects the degeneration-regeneration process in dystrophic muscle of male mdx mice. Mice were subjected to low-intensity endurance exercise by running on a motorized Rota-Rod for 5 days/week for 6 weeks. Histomorphological analysis showed a significant reduction of measured inflammatory-necrotic areas in both gastrocnemius and quadriceps muscle of exercised mdx mice as compared to matched sedentary mdx mice. The degenerative-regenerative process was also evaluated by examining the protein levels of connexin 39 (Cx39), a specific gene expressed in injured muscles. Cx39 was not detected in sedentary wild type mice, whereas it was found markedly increased in sedentary mdx mice, revealing active muscle degeneration-regeneration process. These Cx39 protein levels were significantly reduced in muscles of mdx mice exercised for 30 and 40 days, revealing together with histomorphological analysis a strong reduction of degeneration process in mice subjected to low-intensity endurance exercise. Muscles of exercised mdx mice did not show significant changes in force and fatigue resistance as compared to sedentary mdx mice. Overall in this study we found that specific low-intensity endurance exercise induces a beneficial effect probably by reducing the degeneration of dystrophic muscle. 23942274 Cancer distress screening data: Translating knowledge into clinical action for a quality response. Objectives: The purpose of this paper is to summarize the use of the knowledge to action framework for adapting guidelines for practice and the evidence for effective implementation interventions to promote a quality response to cancer distress screening data. Methods: We summarize progress in screening implementation in Ontario, Canada and the application of a systematic approach for adapting knowledge to practice and use of evidence-based knowledge translation interventions to ensure the uptake of best practices to manage distress. Results: While significant progress has been made in the uptake of distress screening it is less clear if this has resulted in improvements in patient outcomes, i.e., reduced distress. The use of evidence-based knowledge translation strategies tailored to barriers at many levels of care delivery is critical to facilitate the uptake of distress screening data by the primary oncology team. Significance of results: There is a wealth of knowledge about the approaches that can be applied to translate knowledge into practice to improve psychosocial care and promote evidence-based distress management by the primary care oncology team. However, further implementation research is needed to advance knowledge about the most effective strategies in the context of cancer care. 23179742 Exploring the distribution and determinants of a change in recovery expectations following traumatic injury to victorian workers. Purpose To examine the frequency, distribution and determinants of a change in recovery expectations following non-life threatening acute orthopaedic trauma to Victorian workers. It is proposed that interventions to modify recovery expectations may reduce the burden associated with injury. However, it is not known whether recovery expectations change over time or the factors that are associated with change. Methods A prospective inception cohort study was carried out in which participants were recruited following presentation to hospital for treatment of their injury and followed for 6 months post-injury. Baseline data was obtained by survey and medical record review. Binary logistic regression was used to examine factors associated with a change in recovery expectations between week 2 and week 12 post-injury. Results The cohort comprised injured workers (n = 145) who had sustained nonlife threatening acute orthopaedic trauma. Factors associated with an improvement in recovery expectations or recovery timeframe included more years of education and higher social functioning. Participants whose injury involved a perception of responsibility by a third party were 7.18 (95 % CI 1.86-27.68) times more likely to change their recovery expectations to more negative expectations and less likely to change to an earlier recovery timeframe. Participants with more severe injuries were more likely to change their recovery timeframe to a longer timeframe. Conclusion Change in recovery expectations provide some information on injured workers who may benefit from targeted interventions to improve or maintain recovery expectations. The post-injury time-point at which recovery expectations are measured is important if recovery expectations are to inform long-term outcomes. 23934045 Application of parecoxib in post-uvulopalatopharyngoplasty analgesia. To investigate the postoperative analgesic effects of parecoxib for uvulopalatopharyngoplasty (UPPP). Patients with obstructive sleep apnoea syndrome who underwent UPPP were randomly divided into two groups. In group A, the incision-local block was performed with 5 ml of 0.5% ropivacaine injected subcutaneously before the end of surgery, then 20 ml of physiological saline was injected intravenously every 12 h for 2 days. In group B, in addition to the incision-local block, 40 mg parecoxib was injected intravenously 30 min before the end of UPPP and 40 mg parecoxib was injected intravenously every 12 h for 2 days. Postoperative pain was measured using a visual analogue scale (VAS). Adverse reactions were recorded. A total of 40 patients were randomized (n = 20 per group). Under resting conditions, the mean ± SD VAS pain scores were significantly higher in group A compared with group B at 24 h and 48 h after UPPP (24 h 4.0 ± 0.8 versus 2.6 ± 0.6; 48 h 3.8 ± 0.7 versus 2.4 ± 0.5; respectively). Under swallowing conditions, the mean ± SD VAS pain scores were significantly higher in group A compared with group B at 8 h, 24 h and 48 h after UPPP. Postoperative adverse reactions were similar in the two groups. Intravenous parecoxib combined with incision-local ropivacaine provided effective postoperative analgesia for patients with obstructive sleep apnoea syndrome, undergoing UPPP. 23943438 Significant role of μ-calpain (CANP1) in proliferation/survival of bovine skeletal muscle satellite cells. Calpains are a family of Ca(2+)-dependent intracellular cysteine proteases, including the ubiquitously expressed μ-calpain (CANP1) and m-calpain (CANP2). The CANP1 has been found to play a central role in postmortem proteolysis and meat tenderization. However, the physiological roles of CANP1 in cattle skeletal satellite cells remain unclear. In this study, three small interference RNA sequences (siRNAs) targeting CANP1 gene were designed and ligated into pSilencer plasmid vector to construct shRNA expression constructs. Suppression of CANP1 in satellite cells was evaluated using these shRNA expressing constructs. Our results revealed that all three siRNAs could downregulate the expression of CANP1. Suppression of CANP1 significantly reduced cell viability in cell proliferation when compared with control cells. We found a crosstalk between CANP1 and caspase systems, particularly suppression of CANP1 resulted in an increase in the expressions of apoptotic caspases such as caspase-3, caspase-6, caspase-7, caspase-8, and caspase-9, as well as heat-shock protein (HSP) systems. Additionally, suppression of CANP1 led to the upregulation of other apoptosis and DNA damage-regulating genes whilst at the same time downregulating proliferation, migration, and differentiation-regulating genes. The results of our findings report for the first time that suppression of CANP1 resulted in the activation of caspase and HSP systems which might in turn regulate apoptosis through the caspase-dependent cell death pathway. This clearly demonstrates the key roles of CANP1 in regulation of cell proliferation and survival. 23822315 Structure formation of surfactant membranes under shear flow. Shear-flow-induced structure formation in surfactant-water mixtures is investigated numerically using a meshless-membrane model in combination with a particle-based hydrodynamics simulation approach for the solvent. At low shear rates, uni-lamellar vesicles and planar lamellae structures are formed at small and large membrane volume fractions, respectively. At high shear rates, lamellar states exhibit an undulation instability, leading to rolled or cylindrical membrane shapes oriented in the flow direction. The spatial symmetry and structure factor of this rolled state agree with those of intermediate states during lamellar-to-onion transition measured by time-resolved scatting experiments. Structural evolution in time exhibits a moderate dependence on the initial condition. 23542596 MicroRNA-29 family, a crucial therapeutic target for fibrosis diseases. MicroRNAs (miRNAs) are a class of approximately 20-nucleotides single-stranded endogenous RNAs that regulate gene expression at the post-transcriptional level. miRNAs have recently been known to regulate cell proliferation, differentiation, and apoptosis. Fibrosis is the leading cause of organ dysfunction in diseases and results from an imbalance in the turnover of extracellular matrix components. Accumulating studies have demonstrated that miR-29 family participates in the development of liver fibrosis, renal fibrosis, pulmonary fibrosis, cardiac fibrosis. In this review, we are discussing the comprehensive role of miR-29 family in moderating profibrotic effect and its potential as therapeutic approach to fibrosis diseases. 23870264 Statistical Analysis of Peptide-Induced Graded and All-or-None Fluxes in Giant Vesicles. Antimicrobial, cytolytic, and cell-penetrating peptides induce pores or perturbations in phospholipid membranes that result in fluxes of dyes into or out of lipid vesicles. Here we examine the fluxes induced by four of these membrane-active peptides in giant unilamellar vesicles. The type of flux is determined from the modality of the distributions of vesicles as a function of their dye content using the statistical Hartigan dip test. Graded and all-or-none fluxes correspond to unimodal and bimodal distributions, respectively. To understand how these distributions arise, we perform Monte Carlo simulations of peptide-induced dye flux into vesicles using a very simple model. The modality of the distributions depends on the rate constants of pore opening and closing, and dye flux. If the rate constants of pore opening and closing are both much smaller than that of dye flux through the pore, all-or-none influx occurs. However, if one of them, especially the rate constant for pore opening, increases significantly relative to the flux rate constant, the process becomes graded. In the experiments, we find that the flux type is the same in giant and large vesicles, for all peptides except one. But this one exception indicates that the flux type cannot be used to unambiguously predict the mechanism of membrane permeabilization by the peptides. 23540571 Designing trials for pressure ulcer risk assessment research: methodological challenges. For decades various pressure ulcer risk assessment scales (PURAS) have been developed and implemented into nursing practice despite uncertainty whether use of these tools helps to prevent pressure ulcers. According to current methodological standards, randomised controlled trials (RCTs) are required to conclusively determine the clinical efficacy and safety of this risk assessment strategy. In these trials, PURAS-aided risk assessment has to be compared to nurses' clinical judgment alone in terms of its impact on pressure ulcer incidence and adverse outcomes. However, RCTs evaluating diagnostic procedures are prone to specific risks of bias and threats to the statistical power which may challenge their validity and feasibility. This discussion paper critically reflects on the rigour and feasibility of experimental research needed to substantiate the clinical efficacy of PURAS-aided risk assessment. Based on reflections of the methodological literature, a critical appraisal of available trials on this subject and an analysis of a protocol developed for a methodologically robust cluster-RCT, this paper arrives at the following conclusions: First, available trials do not provide reliable estimates of the impact of PURAS-aided risk assessment on pressure ulcer incidence compared to nurses' clinical judgement alone due to serious risks of bias and insufficient sample size. Second, it seems infeasible to assess this impact by means of rigorous experimental studies since sample size would become extremely high if likely threats to validity and power are properly taken into account. Third, means of evidence linkages seem to currently be the most promising approaches for evaluating the clinical efficacy and safety of PURAS-aided risk assessment. With this kind of secondary research, the downstream effect of use of PURAS on pressure ulcer incidence could be modelled by combining best available evidence for single parts of this pathway. However, to yield reliable modelling results, more robust experimental research evaluating specific parts of the pressure ulcer risk assessment-prevention pathway is needed. 23864657 Tumor Cell Migration and Invasion Are Enhanced by Depletion of Rap1 GTPase-activating Protein (Rap1GAP). The functional significance of the widespread down-regulation of Rap1 GTPase-activating protein (Rap1GAP), a negative regulator of Rap activity, in human tumors is unknown. Here we show that human colon cancer cells depleted of Rap1GAP are endowed with more aggressive migratory and invasive properties. Silencing Rap1GAP enhanced the migration of confluent and single cells. In the latter, migration distance, velocity, and directionality were increased. Enhanced migration was a consequence of increased endogenous Rap activity as silencing Rap expression selectively abolished the migration of Rap1GAP-depleted cells. ROCK-mediated cell contractility was suppressed in Rap1GAP-depleted cells, which exhibited a spindle-shaped morphology and abundant membrane protrusions. Tumor cells can switch between Rho/ROCK-mediated contractility-based migration and Rac1-mediated mesenchymal motility. Strikingly, the migration of Rap1GAP-depleted, but not control cells required Rac1 activity, suggesting that loss of Rap1GAP alters migratory mechanisms. Inhibition of Rac1 activity restored membrane blebbing and increased ROCK activity in Rap1GAP-depleted cells, suggesting that Rac1 contributes to the suppression of contractility. Collectively, these findings identify Rap1GAP as a critical regulator of aggressive tumor cell behavior and suggest that the level of Rap1GAP expression influences the migratory mechanisms that are operative in tumor cells. 23488816 Influence of extracellular matrix proteins and substratum topography on corneal epithelial cell alignment and migration. The basement membrane (BM) of the corneal epithelium presents biophysical cues in the form of topography and compliance that can impact the phenotype and behaviors of cells and their nuclei through modulation of cytoskeletal dynamics. In addition, it is also well known that the intrinsic biochemical attributes of BMs can modulate cell behaviors. In this study, the influence of the combination of exogenous coating of extracellular matrix proteins (ECM) (fibronectin-collagen [FNC]) with substratum topography was investigated on cytoskeletal architecture as well as alignment and migration of immortalized corneal epithelial cells. In the absence of FNC coating, a significantly greater percentage of cells aligned parallel with the long axis of the underlying anisotropically ordered topographic features; however, their ability to migrate was impaired. Additionally, changes in the surface area, elongation, and orientation of cytoskeletal elements were differentially influenced by the presence or absence of FNC. These results suggest that the effects of topographic cues on cells are modulated by the presence of surface-associated ECM proteins. These findings have relevance to experiments using cell cultureware with biomimetic biophysical attributes as well as the integration of biophysical cues in tissue-engineering strategies and the development of improved prosthetics. 22543978 Using social network analysis for assessing mental health and social services inter-organisational collaboration: findings in deprived areas in Brussels and London. Fragmentation in mental health and social care delivery should be addressed at the system level. A Social Network Analysis was carried out on relations between services in order to assess Leutz's levels of care integration: linkage, coordination, and full integration. Findings for deprived areas in Brussels and London show that linkage across clusters of services is weak in both networks. However, the integration of care relies on the level of linkage in London, while in Brussels it is more dependent on central services playing brokerage roles. The method offers a useful and complementary basis for evaluating the integration of care. 23739222 Altered expression of interleukin-6, interleukin-8 and their receptors in decidua of women with sporadic miscarriage. Are alterations in decidual expression of interleukin (IL)-6 and IL-8 associated with sporadic miscarriage? IL-6 and IL-8 secretion from decidual uterine natural killer (uNK) cells and macrophages isolated from women with spontaneous miscarriage was reduced compared with normal controls. Miscarriage is a common gynaecological problem with huge financial and personal implications. Eleven to twenty per cent of all clinically recognized pregnancies are lost before the 20th week of gestation, with miscarriages often being divided into early (≤12 completed weeks from last menstrual period) and late (≥13 weeks). Spiral artery remodelling is a key feature of early pregnancy; failure of this process has been implicated in sporadic miscarriage. The molecular triggers that initiate spiral artery remodelling are not clear, although cytokines such as IL-6 and IL-8 may play a role. This was a laboratory-based study using decidual and placental bed biopsy samples from women with sporadic miscarriage (n = 30) and termination of pregnancy controls (n = 30). Total adherent decidual cells, CD10(+) stromal cells, CD14(+) macrophages and CD56(+) uNK cells were isolated from decidua from apparently normal pregnancies that were terminated at either 8-10 or 12-14 weeks' gestation. In addition, CD14(+) macrophages and CD56(+) uNK cells were isolated from decidua from sporadic miscarriage at 8-10 weeks' gestation. Secreted IL-8 was measured in all isolated cell populations, while IL-6 was measured in CD14(+) macrophages and CD56(+) uNK cells from both sporadic miscarriage and normal controls. Placental bed biopsies were taken from women after sporadic miscarriage or termination of pregnancy at ≤12 completed weeks' or >13 weeks' gestational age, formalin-fixed, paraffin-embedded and immunostained for IL-6, IL-6Rα, GP130, IL-8, CXCR1, CXCR2 and CD13 (aminopeptidase N). Staining intensity for each factor was assessed in extravillous trophoblast cell populations, myometrial and decidual stroma, myometrial and decidual spiral arteries and decidual glandular epithelium. A CPA model was used to assess the potential role of IL-6 and IL-8 in spiral artery remodelling. IL-8 was secreted by total adherent decidual cells, CD10(+) stromal cells and CD14(+) macrophages at both 8-10 and 12-14 weeks' gestation, with CD14(+) cells secreting the highest levels. Both CD14(+) and CD56(+) cells isolated from decidua of early sporadic miscarriage produced lower IL-6 (P = 0.04, P = 0.01, respectively) and IL-8 levels (P = 0.0007, P = 0.002, respectively) compared with normal cases. In addition, altered expression of IL-6, IL-8 and their receptors was observed in various cell types in placental bed (myometrial stroma, glandular epithelium, interstitial extravillous trophoblast cells, vascular smooth muscle cells and endothelial cells) in sporadic miscarriage, particularly from later gestational ages. IL-6 and IL-8 disrupted vascular smooth muscle morphology and organization in an in vitro model of spiral artery remodelling. By the nature of sampling at the time of miscarriage, it was not possible to ascertain the cause or effect in the observed alterations of levels of IL-6 and IL-8 in sporadic miscarriage. Alterations in the expression of IL-6, IL-8 and their receptors may be associated with the aetiology of sporadic miscarriage, especially given the potential role of these cytokines in the regulation of trophoblast invasion and spiral artery remodelling. This project was supported by funding from Wellbeing of Women (RG1000). The authors have no competing interests to declare. Not applicable. 23836470 SugarBind database (SugarBindDB): a resource of pathogen lectins and corresponding glycan targets. SugarBindDB lists pathogen and biotoxin lectins and their carbohydrate ligands in a searchable format. Information is collected from articles published in peer-reviewed scientific journals. Help files guide the user through the search process and provide a review of structures and names of sugars that appear in human oligosaccharides. Glycans are written in the condensed form of the carbohydrate nomenclature system developed by the International Union of Pure and Applied Chemistry (IUPAC). Since its online publication by The MITRE Corporation in 2005, the database has served as a resource for research on the glycobiology of infectious disease. SugarBindDB is currently hosted by the Swiss Institute of Bioinformatics on the ExPASy server and will be enhanced and linked to related resources as part of the wider UniCarbKB initiative. Enhancements will include the option to display glycans in a variety of formats, including modified 2D condensed IUPAC and symbolic nomenclature. Copyright © 2013 John Wiley & Sons, Ltd. 23822176 Iron oxide @ polypyrrole nanoparticles as a multifunctional drug carrier for remotely controlled cancer therapy with synergistic antitumor effect. Multifunctional nanoplatforms that are safe and have multiple therapeutic functions together with imaging capabilities are highly demanded in the development of new cancer theranostic approaches. A number of near-infrared (NIR)-absorbing inorganic nanomaterials, although having shown great promise not only to photothermally ablate tumors but also to enhance the efficacy of other types of therapies, are not biodegradable and would be retained in the body for a long time. Herein, we develop a multifunctional nanocomposite by coating magnetic iron oxide nanoclusters with a near-infrared light-absorbing polymer polypyrrole (PPy), obtaining Fe3O4@PPy core-shell nanoparticles, which after functionalization with polyethylene glycol could be used for imaging-guided, remotely controlled cancer combination therapy. In this system, the Fe3O4 core, which could be gradually decomposed in physiological environments, is useful for magnetically controlled drug delivery as well as a magnetic resonance imaging contrast. The PPy shell, as an organic polymer, is able to load therapeutic molecules with aromatic structures and also exhibits a strong photothermal effect, which can be used to enhance the chemotherapeutic efficacy, showing an outstanding in vivo synergistic antitumor effect. Our work encourages further exploration of light-absorbing polymer-based nanocomposites for cancer combination therapy under remote physical controls. 23540648 Strategic use of conformational bias and structure based design to identify potent JAK3 inhibitors with improved selectivity against the JAK family and the kinome. Using a structure based design approach we have identified a series of indazole substituted pyrrolopyrazines, which are potent inhibitors of JAK3. Intramolecular electronic repulsion was used as a strategy to induce a strong conformational bias within the ligand. Compounds bearing this conformation participated in a favorable hydrophobic interaction with a cysteine residue in the JAK3 binding pocket, which imparted high selectivity versus the kinome and improved selectivity within the JAK family. 23792042 Microemulsion and poloxamer microemulsion-based gel for sustained transdermal delivery of diclofenac epolamine using in-skin drug depot: In vitro/in vivo evaluation. Microemulsion (ME) and poloxamer microemulsion-based gel (PMBG) were developed and optimized to enhance transport of diclofenac epolamine (DE) into the skin forming in-skin drug depot for sustained transdermal delivery of drug. D-optimal mixture experimental design was applied to optimize ME that contains maximum amount of oil, minimum globule size and optimum drug solubility. Three formulation variables; the oil phase X1 (Capryol(®)), Smix X2 (a mixture of Labrasol(®)/Transcutol(®), 1:2 w/w) and water X3 were included in the design. The systems were assessed for drug solubility, globule size and light absorbance. Following optimization, the values of formulation components (X1, X2, and X3) were 30%, 50% and 20%, respectively. The optimized ME and PMBG were assessed for pH, drug content, skin irritation, stability studies and ex vivo transport in rat skin. Contrary to PMBG and Flector(®) gel, the optimized ME showed the highest cumulative amount of DE permeated after 8h and the in vivo anti-inflammatory efficacy in rat paw edema was sustained to 12h after removal of ME applied to the skin confirming the formation of in-skin drug depot. Our results proposed that topical ME formulation, containing higher fraction of oil solubilized drug, could be promising for sustained transdermal delivery of drug. 23945662 Electrochemical synthesis on single cells as templates. The cell surface is made electrochemically active by interfacing with graphene sheets. The electrical and thermal properties of graphene allow the control of cell surface potential for electrochemical synthesis. Using this approach radially projecting ZnO nanorods are templated on the surface of single cells. This reported single cell photosensor has superior performance than similar devices made on planar surfaces. 23701412 Nanotopographic surfaces with defined surface chemistries from amyloid fibril networks can control cell attachment. We show for the first time the possibility of using networks of amyloid fibrils, adsorbed to solid supports and with plasma polymer coatings, for the fabrication of chemically homogeneous surfaces with well-defined nanoscale surface features reminiscent of the topography of the extracellular matrix. The robust nature of the fibrils allows them to withstand the plasma polymer deposition conditions used with no obvious deleterious effect, thus enabling the underlying fibril topography to be replicated at the polymer surface. This effect was seen despite the polymer coating thickness being an order of magnitude greater than the fibril network. The in vitro culture of fibroblast cells on these surfaces resulted in increased attachment and spreading compared to flat plasma polymer films with the same chemical composition. The demonstrated technique allows for the rapid and reproducible fabrication of substrates with nanoscale fibrous topography that we believe will have applications in the development of new biomaterials allowing, for example, the investigation of the effect of extracellular matrix mimicking nanoscale morphology on cellular phenotype. 23427008 PtCl2 -Catalyzed Tandem Enyne Cyclization/1,2 Ester Migration Reaction Controlled by Substituent Effects of All-Carbon 1,6-Enynyl Esters. On the move: A novel PtCl2 -catalyzed tandem 1,6-enyne cyclization/1,2-acyloxy migration reaction was developed, which was shown to be controlled by substitution effects. Using this method, a series of substituted enol esters containing the cyclopentenyl motif were prepared in moderate to high yields. 23421981 Plasmodium yoelii inhibitor of cysteine proteases is exported to exomembrane structures and interacts with yoelipain-2 during asexual blood-stage development. Plasmodium falciparum (Pf) blood stages express falstatin, an inhibitor of cysteine proteases (ICP), which is implicated in regulating proteolysis during red blood cell infection. Recent data using the Plasmodium berghei rodent malaria model suggested an additional role for ICP in the infection of hepatocytes by sporozoites and during liver-stage development. Here we further characterize the role of ICP in vivo during infection with Plasmodium yoelii (Py) and Pf. We found that Py-ICP was refractory to targeted gene deletion indicating an essential function during asexual blood-stage replication, but significant downregulation of ICP using a regulated system did not impact blood-stage growth. Py-ICP localized to vesicles within the asexual blood-stage parasite cytoplasm, as well as the parasitophorous vacuole, and was exported to dynamic exomembrane structures in the infected RBC. In sporozoites, expression was observed in rhoptries, in addition to intracellular vesicles distinct from TRAP containing micronemes. During liver-stage development, Py-ICP was confined to the parasite compartment until the final phase of liver-stage development when, after parasitophorous vacuolemembrane breakdown, it was released into the infected hepatocyte. Finally, we identified the cysteine protease yoelipain-2 as a binding partner of Py-ICP during blood-stage infection. These data show that ICP may be important in regulating proteolytic processes during blood-stage development, and is likely playing a role in liver stage-hepatocyte interactions at the time of exoerythrocytic merozoite release. 23797281 Metabolic abnormalities in lobar and subcortical brain regions of abstinent polysubstance users: magnetic resonance spectroscopic imaging. The aim of the study was to explore neurometabolic and associated cognitive characteristics of patients with polysubstance use (PSU) in comparison with patients with predominant alcohol use using proton magnetic resonance spectroscopy. Brain metabolite concentrations were examined in lobar and subcortical brain regions of three age-matched groups: 1-month-abstinent alcohol-dependent PSU, 1-month-abstinent individuals dependent on alcohol alone (ALC) and light drinking controls (CON). Neuropsychological testing assessed cognitive function. While CON and ALC had similar metabolite levels, persistent metabolic abnormalities (primarily higher myo-inositol) were present in temporal gray matter, cerebellar vermis and lenticular nuclei of PSU. Moreover, lower cortical gray matter concentration of the neuronal marker N-acetylaspartate within PSU correlated with higher cocaine (but not alcohol) use quantities and with a reduced cognitive processing speed. These metabolite group differences reflect cellular/astroglial injury and/or dysfunction in alcohol-dependent PSU. Associations of other metabolite concentrations with neurocognitive performance suggest their functional relevance. The metabolic alterations in PSU may represent polydrug abuse biomarkers and/or potential targets for pharmacological and behavioral PSU-specific treatment. 23712488 Assembling viral channel forming proteins: Vpu from HIV-1. Different routes of assembly are probed for the transmembrane domain (TMD) of the bitopic membrane protein Vpu from HIV-1. Vpu is responsible for the amplification of viral release from the host cell. The mode of action includes (i) heteroassembly with host factors and (ii) the formation of homo-oligomers, which are able to conduct ions across the lipid membrane. Two different routes of assembling short sequences of the N terminus, including the TMD of Vpu, Vpu1-32 , and Vpu8-26 , are presented by using a combination of classical molecular dynamics (MD) simulations combined with a docking approach. The rim of alanines (Ala-8, -11, -15, and -19) resembles an interlocking motif for the sequential assembly into a dimer and trimer. Simultaneous assembly results in oligomeric bundles (trimers to pentamers) with either tryptophans (Trp-23) or purely hydrophobic residues facing the center. Bundles, with serines facing the pore (Ser-24), are energetically not the lowest structures. For pentameric bundles with Ser-24 facing the pore, no water column develops during a short 25 ns MD simulation. © 2013 Wiley Periodicals, Inc. Biopolymers 99: 517-529, 2013. 23774601 The intracellular environment of human macrophages that produce nitric oxide promotes growth of mycobacteria. Nitric oxide (NO) is a diffusible radical gas produced from the activity of nitric oxide synthase (NOS). NOS activity in murine macrophages has a protective role against mycobacteria through generation of reactive nitrogen intermediates (RNIs). However, the production of NO by human macrophages has remained unclear due to the lack of sensitive reagents to detect NO directly. The purpose of this study was to investigate NO production and the consequence to mycobacteria in primary human macrophages. We found that Mycobacterium bovis BCG or Mycobacterium tuberculosis infection of human macrophages induced expression of NOS2 and NOS3 that resulted in detectable production of NO. Treatment with gamma interferon (IFN-γ), l-arginine, and tetrahydrobiopterin enhanced expression of NOS2 and NOS3 isoforms, as well as NO production. Both of these enzymes were shown to contribute to NO production. The maximal level of NO produced by human macrophages was not bactericidal or bacteriostatic to M. tuberculosis or BCG. The number of viable mycobacteria was increased in macrophages that produced NO, and this requires expression of nitrate reductase. An narG mutant of M. tuberculosis persisted but was unable to grow in human macrophages. Taken together, these data (i) enhance our understanding of primary human macrophage potential to produce NO, (ii) demonstrate that the level of RNIs produced in response to IFN-γ in vitro is not sufficient to limit intracellular mycobacterial growth, and (iii) suggest that mycobacteria may use RNIs to enhance their survival in human macrophages. 23732791 Microfluidic interrogation and mathematical modeling of multi-regime calcium signaling dynamics. Through microfluidic interrogation we analyzed real-time calcium responses of HEK293 cells stimulated with short pulses of the M3 muscarinic receptor ligand carbachol in two different concentration regimes. Lower ligand concentrations elicit oscillatory calcium signals while higher concentrations trigger a rapid rise that eventually settles down at a steady-state slightly above pre-stimulus levels, referred to as an acute signal. Cells were periodically pulsed with carbachol at these two concentration regimes using a custom-made microfluidic platform, and the resulting calcium signals were measured with a single fluorescent readout. Pulsed stimulations at these two concentration regimes resulted in multiple types of response patterns that each delivered complementary information about the M3 muscarinic receptor signaling pathway. These multiple types of calcium response patterns enabled development of a comprehensive mathematical model of multi-regime calcium signaling. The resulting model suggests that dephosphorylation of deactivated receptors is rate limiting for recovery of calcium signals in the acute regime (high ligand concentration), while calcium replenishment and IP3 production determine signal recovery in the oscillatory regime (low ligand concentration). This study not only provides mechanistic insight into multi-regime signaling of the M3 muscarinic receptor pathway, but also provides a general strategy for analyzing multi-regime pathways using only one fluorescent readout. 23648381 Focusing on the structure and the function of Pin1: new insights into the opposite effects of fever on cancers and Alzheimer's disease. A new molecular mechanism is proposed to explain the opposite effects of fever on cancers and Alzheimer's disease (AD). The proposal is based on the experimental discovery that the fever stress interferes the structure and the activity of Pin1, which plays uniquely opposite roles in the pathogenesis of cancers and AD. Pin1 is the only known cis-trans isomerase that specifically isomerizes the pSer/pThr-Pro motifs in proteins, facilitating kinds of signaling pathways. The up-regulation of Pin1 can amplify multiple oncogenic signaling pathways, resulting in cancers, while the down-regulation of Pin1 can cause many pathological characteristics of AD. Recently, we found that Pin1 is sensitive to heat treatment, and heating can gradually damage both of the structure and the function of Pin1. So, we hypothesize that the fever stress, which is usually induced by febrile diseases or hyperthermia treatment, may lead to the damaged structure of Pin1 and the decreased activity of it in vivo, resulting in the decreased risk of cancers and the increased risk of AD. Numerous epidemiological and experimental researches on cancers and AD support the hypothesis. The hypothesis not only provides new insights into the opposite effects of fever on cancers and AD, but also gives new clues for understanding the interacting effects of the environmental and the genetic factors in the complicated pathogenesis of cancers and AD. 23487391 Decreasing incidence of herpes zoster in the highly active antiretroviral therapy era. We evaluated the effect of highly active antiretroviral therapy (HAART) on the incidence of herpes zoster (HZ) in human immunodeficiency virus (HIV)-infected subjects. The annual incidence of HZ per 100 person-years decreased significantly from 6.3 episodes in 1987 to 1.0 episode in 2011, probably reflecting improved immune function. 23747439 Analysing biomass torrefaction supply chain costs. The objective of the present work was to develop a techno-economic system model to evaluate how logistics and production parameters affect the torrefaction supply chain costs under Swedish conditions. The model consists of four sub-models: (1) supply system, (2) a complete energy and mass balance of drying, torrefaction and densification, (3) investment and operating costs of a green field, stand-alone torrefaction pellet plant, and (4) distribution system to the gate of an end user. The results show that the torrefaction supply chain reaps significant economies of scale up to a plant size of about 150-200kiloton dry substance per year (ktonDS/year), for which the total supply chain costs accounts to 31.8euro per megawatt hour based on lower heating value (€/MWhLHV). Important parameters affecting total cost are amount of available biomass, biomass premium, logistics equipment, biomass moisture content, drying technology, torrefaction mass yield and torrefaction plant capital expenditures (CAPEX). 23880304 Trichostatin-A Modulates Claudin-1 mRNA Stability through the Modulation of Hu antigen R and Tristetraprolin in Colon Cancer Cells. Expression of claudin-1, a tight junction protein, is highly upregulated in colon cancer. We have reported that claudin-1 expression in colon cancer cells is epigenetically regulated as HDAC-inhibitors decrease claudin-1 mRNA stability and thus expression. In this regard, our data suggested a role of 3'-UTR in the regulation of HDAC-dependent regulation of claudin-1 mRNA stability. In current study, we demonstrate based upon our continued investigation that the ELAV like RNA-binding proteins (RBPs), Hu antigen R (HuR) and tristetraprolin (TTP) associate with the 3'UTR of claudin-1 mRNA to modulate its mRNA stability. Ribonomic and site-directed mutagenesis approach were used to confirm the binding of the HuR and TTP to claudin-1 3'UTR. We further confirmed their role in the stabilization of claudin-1 mRNA, under conditions of HDAC-inhibition. In summary, we report that HuR and TTP are the critical regulators of the post-transcriptional regulation of claudin-1 expression in colon cancer cells. We also demonstrate that inhibition of the HDACs by Trichostatin (TSA)-treatment decreased the binding of HuR while increasing the binding of TTP to claudin-1 3'UTR. Additionally, we provide data showing transcriptional regulation of claudin-1 expression, through the regulation of transcription factor Sp1. Taken together, we demonstrate epigenetic regulation of claudin-1 expression in colon cancer cells at transcriptional and post-transcriptional levels. 23933598 Quantifying nanoscale order in amorphous materials via scattering covariance in fluctuation electron microscopy. Fluctuation Transmission Electron Microscopy (FTEM) has a unique ability to probe topological order on the 1-3nm length scale in diffraction amorphous materials. However, extracting a quantitative description of the order has been challenging. We report that the FTEM covariance, computed at two non-degenerate Bragg reflections, is able to distinguish different regimes of size vs. volume fraction of order. The covariance analysis is general and does not require a material-specific atomistic model. We use a Monte-Carlo approach to compute different regimes of covariance, based on the probability of exciting multiple Bragg reflections when a STEM nanobeam interacts with a volume containing ordered regions in an amorphous matrix. We perform experimental analysis on several sputtered amorphous thin films including a-Si, nitrogen-alloyed GeTe and Ge2Sb2Te5. The samples contain a wide variety of ordered states. Comparison of experimental data with the covariance simulation reveals different regimes of nanoscale topological order. 23564364 Consensus statement from the consensus conference on bilateral total knee arthroplasty group. Controversy exists regarding many aspects of decision making pertaining to same-day versus staged bilateral TKA (BTKAs), including patient selection, perioperative management decisions, and other important choices. In the absence of suitable randomized trials, we sought to determine areas of consensus among national experts on the following questions: (1) What are the comparative risks of same-day BTKAs compared with unilateral TKA (UTKA) and staged BTKAs? (2) Who should be considered an appropriate candidate for same-day BTKAs? (3) What constitutes appropriate workup and perioperative management for BTKAs? (4) What is the optimal time between procedures if same-day BTKAs are not deemed appropriate? (5) Are there orthopaedic or rehabilitation considerations for BTKAs that might outweigh medical contraindications? In the setting of a consensus conference of national experts in orthopaedic surgery, anesthesiology, perioperative medicine, and epidemiology, the major questions surrounding same-day BTKAs were addressed by using an extensive literature review and the modified Delphi process. The process concluded with a meeting of participants and formulation of consensus statements. Eighty-one percent of participants agreed that BTKAs are more invasive and complex procedures associated with increased risk for perioperative adverse events compared with UTKA in an unselected group of patients. The consensus group agreed that physicians and hospitals should consider using more restrictive patient selection criteria and exclude those with a modified cardiac risk index greater than 3 to mitigate the potentially increased risk. The majority of the group agreed that perioperative assessment and management should reflect the higher level of acuity of same-day BTKAs. Eighty-one percent of participants agreed that if a patient is not deemed a candidate for same-day BTKAs, a second TKA should be scheduled no sooner than 3 months after the first. The entire group agreed that when there is a conflict between the orthopaedic need and the medical adequacy of same-day BTKAs, the medical concern for the patient's safety should prevail over the orthopaedic need. Experts perceived that same-day BTKAs increase medical risk, and thus a systematic approach to the management of patients should be taken to minimize complications. 23884602 Late-onset bleb-related endophthalmitis caused by Streptococcus pseudopneumoniae. We report our findings in a 63-year-old male who developed late-onset bleb-related endophthalmitis. The patient had undergone glaucoma surgery 46 years earlier, and had a thin-walled cystic bleb prior to the endophthalmitis in his right eye. He underwent immediate vitrectomy with intravitreal injections of ceftazidime and vancomycin. After surgery, he was given topical 0.5 % moxifloxacin and 1 % vancomycin, intravenous doripenem, and oral minocycline. Culture of the vitreous specimen identified Streptococcus pseudopneumoniae by 16S rRNA sequence analysis, by optochin susceptibility test, and by bile solubility test. Our findings indicate that S. pseudopneumoniae can be isolated from a late-onset bleb-related endophthalmitis and that molecular analysis and phenotypic testing can be accurate methods to identify S. pseudopneumoniae. 23843280 Regiodivergent nc and nn aryl coupling reactions of indoloterpenes and cycloether formation mediated by a single bacterial flavoenzyme. Radical diversification: Through the discovery of diverse indolosesquiterpene dimers in a strain heterologously expressing the xiamycin biosynthesis genes, the analysis of mutants, and biotransformation studies, it has been inferred that a single flavoprotein mediates NC and NN aryl coupling reactions, as well as the formation of a cyclic ether (oxiamycin). Synthetic emulation of this unusual transformation provides evidence for a radical-based mechanism. 23881246 Tissue-type plasminogen activator mediates neuronal detection and adaptation to metabolic stress. Adenosine monophosphate-activated protein kinase (AMPK) is an energy sensor that regulates cellular adaptation to metabolic stress. Tissue-type plasminogen activator (tPA) is a serine proteinase found in the intravascular space, where its main role is as thrombolytic enzyme, and in neurons, where its function is less well understood. Here, we report that glucose deprivation induces the mobilization and package of neuronal tPA into presynaptic vesicles. Mass spectrometry and immunohistochemical studies show that the release of this tPA in the synaptic space induces AMPK activation in the postsynaptic terminal, and an AMPK-mediated increase in neuronal uptake of glucose and neuronal adenosine 5'(tetrahydrogen triphosphate; ATP) synthesis. This effect is independent of tPA's proteolytic properties, and instead requires the presence of functional N-methyl-D-aspartate receptors (NMDARs). In agreement with these observations, positron emission tomography (PET) studies and biochemical analysis with synaptoneurosomes indicate that the intravenous administration of recombinant tPA (rtPA) after transient middle cerebral artery occlusion (tMCAO) induces AMPK activation in the synaptic space and NMDAR-mediated glucose uptake in the ischemic brain. These data indicate that the release of neuronal tPA or treatment with rtPA activate a cell signaling pathway in the synaptic space that promotes the detection and adaptation to metabolic stress.Journal of Cerebral Blood Flow & Metabolism advance online publication, 24 July 2013; doi:10.1038/jcbfm.2013.124. 23161368 Effects of a bioassay-derived ivermectin lowest observed effect concentration on life-cycle traits of the nematode Caenorhabditis elegans. The pharmaceutical ivermectin is used to treat parasitic infections, such as those caused by nematodes. While several studies have demonstrated the severe effects of ivermectin on non-target organisms, little is known about the drug's impact on free-living nematodes. In the present work, a full life-cycle experiment was conducted to estimate how an ivermectin lowest observed effect concentration derived from a Caenorhabditis elegans bioassay (endpoint reproduction) might translate into effects at the population level of this free-living nematode. The results showed that fecundity decreased to levels similar to those determined in the bioassay after a time of corresponding duration (18.6 % inhibition compared to the control), but the impact then rather weakened until the end of the experiment, at which point the net reproductive rate (R(0)) was still, but not significantly, reduced by 12.4 %. Moreover, the average lifespan, length of the reproductive period, maximum daily reproduction rate, and intrinsic rate of increase (r(m)) were significantly reduced by 30.0, 25.9, 11.2, and 3.5 %, respectively. The experiment revealed that a 4-day bioassay is protective enough for C. elegans with respect to ivermectin's effects on fecundity. However, the pronounced effects of a low drug concentration on survival, a highly elastic trait, may better account for the observed population-level response, i.e., a decrease of r(m), than the effects on fecundity. These results emphasize that full life-cycle experiments are valuable for assessment of pollutants, because the effects on several life-cycle traits can be simultaneously measured and integrated into an ecologically relevant parameter, the population growth rate, that reflects a population's response to a specific pollutant. 23219523 β-phenylethyl isothiocyanate reverses platinum resistance by a GSH-dependent mechanism in cancer cells with epithelial-mesenchymal transition phenotype. Platinum (Pt)-based chemotherapy is an important regimen in the clinical treatment of cancer, but development of drug resistance presents a major challenge. One key mechanism involved in resistance to Pt drugs is the decrease of intracellular Pt due to the drug efflux through the glutathione (GSH)-mediated export, and this is particularly significant in cancer cells with stem-cell like properties. In the present study, we showed that two Pt-resistant human cancer cell lines exhibited stem-cell like EMT properties, had high cellular GSH and accumulated significantly less cellular Pt compared to their parental cells, and failed to undergo apoptosis when exposed to Pt at the drug concentrations toxic to the parental cells. Importantly, we found that the natural compound β-phenylethyl isothiocyanate (PEITC) was able to effectively abolish this drug resistant mechanism by effective depletion of cellular GSH, leading to a significant increase in cellular Pt as well as DNA-bound Pt. A combination of PEITC and Pt showed a striking synergistic anticancer activity both in vitro and in vivo, as evidenced by an increase in drug-induced apoptosis, a loss of colony formation capacity, and significant suppression of tumor growth in mice. Taken together, our study shows a promising therapeutic strategy to overcome drug resistance to platinum-based chemotherapy and may potentially have broad implications in clinical treatment of cancer. 23950100 Floating-pulsatile Release Multiparticulate System for Choronopharmacotherapy: Effect of Some Hydrophobic Additives on the Buoyancy and Release Behavior of Particles. A blend of floating and pulsatile principles of a drug delivery system would have the advantage that a drug can be released in the upper gastrointestinal (GI) tract after a lag period, which is anticipated for chronotherapy. In this study, microballoons were prepared by an emulsion solvent diffusion technique using Eudragit S100, and hydrophobic additive (magnesium stearate, stearic acid or talc) for time- and site-specific drug release of piroxicam. The effect of hydrophobic additives on the production yield of floating microparticles, buoyant ability for 8 h, release of drug in simulated GI fluids (simulated gastric fluid [SGF] and simulated intestinal fluid [SIF]), mean particle size, apparent particle density, encapsulation efficiency of drug and physical state of incorporated drug were studied. Both production yield and buoyancy of the microballoons were affected by additives in the following order: magnesium stearate, stearic acid>free-additive>talc. The observed difference in yield and the buoyancy of the microballoons could be attributed to the hydrophobic character of the additives and the shell rigidity of the obtained microballoons. Incorporation of hydrophobic additives in the microballoons was found to impart the desired release properties to the microballoons by providing a 2-phase release pattern with initial slow release (5-6%) through 8 h in SGF followed by rapid pulse release (>92%) in SIF through 15 min. The microballoons co-formulated with magnesium stearate or stearic acid, combining excellent buoyancy and suitable drug release pattern of piroxicam, could be useful in chronopharmacotherapy in arthritis. 23455046 Poly(dopamine) coated gold nanocluster functionalized electrochemical immunosensor for brominated flame retardants using multienzyme-labeling carbon hollow nanochains as signal amplifiers. An electrochemical, signal amplified immunosensor was developed to detect 3-bromobiphenyl (BBP) by using a bio-inspired polydopamine (PDOP)/gold nanocluster (AuNc) as the sensor platform and multienzyme-labeled carbon hollow nanochains as the signal amplifier. The self-polymerized dopamine membrane on the AuNc-modified indium tin oxide (ITO) electrode were characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM), contact angle and electrochemical measurements. Such PDOP/AuNc platform featured the mild cross-linking reaction with the dense immobilization of BBP-antigens (BBP-Ag). Moreover, by using multiple horseradish peroxidase (HRP) and secondary antibodies (Ab2) modified one-dimensional carbon hollow nanochains (CHNc) as the signal enhancer, it held promise for improving the sensitivity and detection limit of the immunoassay. Based on the competitive immunoassay protocol, this immunosensor showed a linear range from 1 pM to 2 nM for BBP with a detection limit of 0.5 pM. Also, it exhibited high sensitivity, wide linear range, acceptable stability and reproducibility on a promising immobilization platform using a novel signal amplifier, which may extend its application in other environmental monitoring. 23935593 Review of Levetiracetam as a First Line Treatment in Status Epilepticus in the Adult Patients - What Do We Know so Far? With the advent of new antiepileptic drugs comes the potential for significant advances in the emergent management of status epilepticus. Traditional antiepileptic drugs possess side effect profiles that may limit their clinical utility or lead to increased patient morbidity or mortality. The relatively recent development of levetiracetam shows promise for effective control of acute status epilepticus in adults, but current objective data of its use as a first-line agent for control of status is quite limited. This paper serves to examine existing literature while considering levetiracetam as a first-line therapy in status in the adult patient population. Although existing studies are narrow in their scope, the present data lay a substantial foundation for further investigation of levetiracetam as a primary therapy in acute status epilepticus. 23890154 Melanomas of unknown primary have a mutation profile consistent with cutaneous sun-exposed melanoma. Melanoma of unknown primary (MUP) is an uncommon phenomenon whereby patients present with metastatic disease without an evident primary site. To determine their likely site of origin, we combined exome sequencing from 33 MUPs to assess the total rate of somatic mutations and degree of UV mutagenesis. An independent cohort of 91 archival MUPs was also screened for 46 hot spot mutations highly prevalent in melanoma including BRAF, NRAS, KIT, GNAQ, and GNA11. Results showed that the majority of MUPs exhibited high somatic mutation rates, high ratios of C>T/G>A transitions, and a high rate of BRAF (45 of 101, 45%) and NRAS (32 of 101, 32%) mutations, collectively indicating a mutation profile consistent with cutaneous sun-exposed melanomas. These data suggest that a significant proportion of MUPs arise from regressed or unrecognized primary cutaneous melanomas or arise de novo in lymph nodes from nevus cells that have migrated from the skin. 23165153 Pathophysiological roles of aldo-keto reductases (AKR1C1 and AKR1C3) in development of cisplatin resistance in human colon cancers. Cisplatin (cis-diamminedichloroplatinum, CDDP) is widely used for treatment of patients with solid tumors formed in various organs including the lung, prostate and cervix, but is much less sensitive in colon and breast cancers. One major factor implicated in the ineffectiveness has been suggested to be acquisition of the CDDP resistance. Here, we established the CDDP-resistant phenotypes of human colon HCT15 cells by continuously exposing them to incremental concentrations of the drug, and monitored expressions of aldo-keto reductases (AKRs) 1A1, 1B1, 1B10, 1C1, 1C2 and 1C3. Among the six AKRs, AKR1C1 and AKR1C3 are highly induced with the CDDP resistance. The resistance lowered the sensitivity toward cellular damages evoked by oxidative stress-derived aldehydes, 4-hydroxy-2-nonenal and 4-oxo-2-nonenal that are detoxified by AKR1C1 and AKR1C3. Overexpression of AKR1C1 or AKR1C3 in the parental HCT15 cells mitigated the cytotoxicity of the aldehydes and CDDP. Knockdown of both AKR1C1 and AKR1C3 in the resistant cells or treatment of the cells with specific inhibitors of the AKRs increased the sensitivity to CDDP toxicity. Thus, the two AKRs participate in the mechanism underlying the CDDP resistance probably via detoxification of the aldehydes resulting from enhanced oxidative stress. The resistant cells also showed an enhancement in proteolytic activity of proteasome accompanied by overexpression of its catalytic subunits (PSMβ9 and PSMβ10). Pretreatment of the resistant cells with a potent proteasome inhibitor Z-Leu-Leu-Leu-al augmented the CDDP sensitization elicited by the AKR inhibitors. Additionally, the treatment of the cells with Z-Leu-Leu-Leu-al and the AKR inhibitors induced the expressions of the two AKRs and proteasome subunits. Collectively, these results suggest the involvement of up-regulated AKR1C1, AKR1C3 and proteasome in CDDP resistance of colon cancers and support a chemotherapeutic role for their inhibitors. 23884352 Interpretation of the Coronary Artery Calcium Score in Combination with Conventional Cardiovascular Risk Factors: The Multi-Ethnic Study of Atherosclerosis (MESA). The coronary artery calcium (CAC) score predicts coronary heart disease (CHD) events, but methods for interpreting the score in combination with conventional CHD risk factors have not been established. We analyzed CAC scores and CHD risk factor measurements from 6757 Black, Chinese, Hispanic and white men and women aged 45-84 years in the Multi-Ethnic Study of Atherosclerosis (MESA). CAC was associated with age, sex, race-ethnicity, and all conventional CHD risk factors. Multivariable models using these factors predicted the presence of CAC (C-statistic = 0.789) and degree of elevation (16% of variation explained), and can be used to update a "pre-test" CHD risk estimate, such as the 10-year Framingham Risk Score, that is based on an individual's conventional risk factors. In scenarios where a high CAC score is expected, a moderately elevated CAC score of 50 is reassuring (e.g., reducing risk from 10% to 6% in a healthy older white man); but when a low/zero CAC score is expected, even with identical pre-test CHD risk, the same CAC score of 50 may be alarmingly high (e.g., increasing risk from 10% to 20% in a middle-aged black woman with multiple risk factors). Both the magnitude and direction of the shift in risk varied markedly with pre-test CHD risk and with the pattern of risk factors. Knowing what CAC score to expect for an individual patient, based on their conventional risk factors, may help clinicians decide when to order a CAC test and how to interpret the results. 23924606 Role of hypoxia inducible factor-1α in the regulation of the cancer-specific variant of organic anion transporting polypeptide 1B3 (OATP1B3), in colon and pancreatic cancer. Organic anion transporting polypeptide 1B3 (OATP1B3) was initially considered to be a liver-specific transporter, mediating the uptake of a variety of endogenous and xenobiotic substances. Over the past decade, several investigations reported that OATP1B3 is also expressed across multiple types of cancers. Only recently, our laboratory and others demonstrated the identity of cancer-specific OATP1B3 variants (csOATP1B3) arising from the use of an alternative transcription initiation site, different from the wildtype (WT) OATP1B3 expressed in the normal liver. However, the mechanisms regulating the expression of csOATP1B3 remained unknown. In our current study, we investigated the role of hypoxia and the involvement of hypoxia inducible factor-1α (HIF-1α) in regulating the transcription of csOATP1B3. Our RT-PCR and immunoblotting results indicated that csOATP1B3, but not WT OATP1B3, can be induced in response to ambient or chemical hypoxia (upon exposure to 1% O2 or cobalt chloride). Reporter assays with deletion and mutated constructs of the csOATP1B3 promoter revealed a functional hypoxia response element (HRE) located in the proximal upstream region. Constructs harboring the HRE displayed the upregulated reporter gene expression in response to hypoxia, but not when mutated. Electrophoretic mobility shift assays using a biotin-labeled csOATP1B3 promoter HRE probe indicated the binding of HIF-1α, which was blocked by an excess of unlabeled csOATP1B3 probe. Furthermore, siRNA-based knockdown of HIF-1α caused a substantial decrease in the expression level of csOATP1B3. Taken together, these findings demonstrate that the transcription of csOATP1B3 is actively engaged during hypoxia, through a commonly utilized pathway involving HIF-1α. 23969546 Bilateral Masseter and Internal Pterygoid Muscle Hypertrophy: A Diagnostic Challenge. Objective: To describe an unusual case of bilateral masseter and pterygoid muscle hypertrophy. Clinical Presentation and Intervention: A 53-year-old female patient presented with a bilateral, painless swelling at the parotid areas without improvement after using antibiotics/systemic corticosteroids/nonsteroidal anti-inflammatory agents. Her medical history included thyroid nodules, but no dental/occlusal disorders were observed. The initial differential diagnosis included salivary gland/jaw bone/masseter pathology, but the CT/MRI revealed only an increase in the size of the masseter and pterygoid muscles. The patient was informed of the benign nature of the swelling and was advised to discontinue the use of nonsteroidal anti-inflammatory agents. Conclusion: The bilateral hypertrophy of masseter muscles should be considered in differential diagnosis in cases of unilateral or bilateral swelling of the parotid or lateral mandible area. © 2013 S. Karger AG, Basel. 23835409 Metabolic interaction between anthocyanin and lignin biosynthesis is associated with peroxidase FaPRX27 in strawberry fruit. Plant phenolics have drawn increasing attention due to their potential nutritional benefits. Although the basic reactions of the phenolics biosynthetic pathways in plants have been intensively analyzed the regulation of their accumulation and flux through the pathway is not that well established. The aim of this study was to use a strawberry (Fragaria x ananassa) microarray to investigate gene expression patterns associated with the accumulation of phenylpropanoids, flavonoids and anthocyanins in strawberry fruit. An examination of the transcriptome, coupled with metabolite profiling data from different commercial varieties was undertaken to identify genes whose expression correlated with altered phenolics composition. Seventeen comparative microarray analyses revealed 15 genes that were differentially (> 200 fold) expressed in phenolics-rich versus poor varieties. The results were validated by heterologous expression of a peroxidase FaPRX27 gene which showed the highest altered expression level (> 900 fold). The encoded protein was functionally characterized and is assumed to be involved in lignin formation during strawberry fruit ripening. QTL analysis indicated that the genomic region of FaPRX27 is associated with the fruit color trait. Downregulation of the chalcone synthase gene and concomitant induction of FaPRX27 expression diverted the flux from anthocyanins to lignin. The results highlight the competition of the different phenolics pathways for their common precursors. The list of the 15 candidates provides new genes that are likely to impact polyphenol accumulation in strawberry fruit and could be used to develop molecular markers to select phenolics-rich germplasm. 23504202 Giant cell myocarditis associated with amoxicillin hypersensitivity reaction. We report a case of sudden unexpected death in an adult woman from florid myocarditis with necrosis, replacement fibrosis, and diffuse infiltration of the myocardium by eosinophils and conspicuous giant cells. Clinical history revealed that 3 weeks prior to death, shortly after commencing antibiotic therapy for the treatment of traumatic wound of a finger, she presented to the emergency room with a hypersensitivity reaction characterized by facial rash with edema and generalized pruritus. She was treated with antihistamines and discharged. The clinico-pathological correlation suggests a link between drug hypersensitivity and the giant cell myocarditis. 23660949 Umbilical cord blood transplant for malignancies: a hope or hype. Cord blood is a rich and unlimited source of hematopoietic stem cells for allogeneic stem cell transplant to treat a variety of oncologic, genetic, hematologic, and immunodeficiency disorders. Since the first successful cord blood transplant in 1988, a large number of cord blood banks have been established world over for collection and storage of cord blood for future use. Majority of such transplants are performed in children, however, the number in adults have been growing steadily in recent years. Results from various transplant registries reveals that a single cord blood provides enough stem cells to provide short and long term engraftment, and has low incidence and less severity of graft versus host disease. With a high booming birth rate and a large genetic diversity, India has potential to become the largest supplier of cord blood stem cells in world. To meet the future transplant need of the country sincere efforts from various institutes and government agencies are needed to increase the number of public cord blood banks in the country. In this article the author will focus on the issue of public and private cord blood banking; the role of physicians in educating and counseling families with regard to the utility of cord blood for donor itself as well as the future of umbilical cord blood transplant in India. 23489981 Cost effectiveness of high resolution computed tomography with interferon-gamma release assay for tuberculosis contact investigation. Tuberculosis contact investigation is one of the important public health strategies to control tuberculosis worldwide. Recently, high resolution computed tomography (HRCT) has been reported as a more accurate radiological method with higher sensitivity and specificity than chest X-ray (CXR) to detect active tuberculosis. In this study, we assessed the cost effectiveness of HRCT compared to CXR in combination with QuantiFERON(®)-TB Gold In-Tube (QFT) or the tuberculin skin test (TST) for tuberculosis contact investigation. We constructed Markov models using a societal perspective on the lifetime horizon. The target population was a hypothetical cohort of immunocompetent 20-year-old contacts with smear-positive tuberculosis patients in developed countries. Six strategies; QFT followed by CXR, QFT followed by HRCT, TST followed by CXR, TST followed by HRCT, CXR alone and HRCT alone were modeled. All costs and clinical benefits were discounted at a fixed annual rate of 3%. In the base-case analysis, QFT followed by HRCT strategy yielded the greatest benefit at the lowest cost ($US 6308.65; 27.56045 quality-adjusted life-years [QALYs])[year 2012 values]. Cost-effectiveness was sensitive to BCG vaccination rate. The QFT followed by HRCT strategy yielded the greatest benefits at the lowest cost. HRCT chest imaging, instead of CXR, is recommended as a cost effective addition to the evaluation and management of tuberculosis contacts in public health policy. 23945931 Discovery of cell-type specific regulatory elements in the human genome using differential chromatin modification analysis. Chromatin modifications have been comprehensively illustrated to play important roles in gene regulation and cell diversity in recent years. Given the rapid accumulation of genome-wide chromatin modification maps across multiple cell types, there is an urgent need for computational methods to analyze multiple maps to reveal combinatorial modification patterns and define functional DNA elements, especially those are specific to cell types or tissues. In this current study, we developed a computational method using differential chromatin modification analysis (dCMA) to identify cell-type-specific genomic regions with distinctive chromatin modifications. We then apply this method to a public data set with modification profiles of nine marks for nine cell types to evaluate its effectiveness. We found cell-type-specific elements unique to each cell type investigated. These unique features show significant cell-type-specific biological relevance and tend to be located within functional regulatory elements. These results demonstrate the power of a differential comparative epigenomic strategy in deciphering the human genome and characterizing cell specificity. 23300339 BSTA promotes mTORC2-mediated phosphorylation of Akt1 to suppress expression of FoxC2 and stimulate adipocyte differentiation. Phosphorylation and activation of Akt1 is a crucial signaling event that promotes adipogenesis. However, neither the complex multistep process that leads to activation of Akt1 through phosphorylation at Thr³⁰⁸ and Ser⁴⁷³ nor the mechanism by which Akt1 stimulates adipogenesis is fully understood. We found that the BSD domain-containing signal transducer and Akt interactor (BSTA) promoted phosphorylation of Akt1 at Ser⁴⁷³ in various human and murine cells, and we uncovered a function for the BSD domain in BSTA-Akt1 complex formation. The mammalian target of rapamycin complex 2 (mTORC2) facilitated the phosphorylation of BSTA and its association with Akt1, and the BSTA-Akt1 interaction promoted the association of mTORC2 with Akt1 and phosphorylation of Akt1 at Ser⁴⁷³ in response to growth factor stimulation. Furthermore, analyses of bsta gene-trap murine embryonic stem cells revealed an essential function for BSTA and phosphorylation of Akt1 at Ser⁴⁷³ in promoting adipocyte differentiation, which required suppression of the expression of the gene encoding the transcription factor FoxC2. These findings indicate that BSTA is a molecular switch that promotes phosphorylation of Akt1 at Ser⁴⁷³ and reveal an mTORC2-BSTA-Akt1-FoxC2-mediated signaling mechanism that is critical for adipocyte differentiation. 23042693 Inclusion compound based approach to forming arrays of artificial dipolar molecular rotors: a search for optimal rotor structures. Hexagonal tris(o-phenylenedioxy)cyclotriphosphazene (TPP) is used as ahost for organizing dipolar molecular rotor guests into regular trigonal arrays. Inclusion of molecular rotors with transversely dipolar rotators into TPP channels is followed by solid-state nuclear magnetic resonance, diifferential scanning calorimetry, X-ray diffraction, and dielectric spectroscopy. The more polar of the two rotors does not form an inclusion. The second rotor forms two different inclusions differing in crystallite size and the rotational barriers. 23913865 Acute and transient psychotic disorder in a developing country. Acute and transient psychotic disorders (ATPDs) are relatively under-researched. There is therefore a dearth of information on the disorders especially in developing countries, where they have been shown to be relatively common. To describe the socio-demographic and clinical characteristics of patients with ATPD, as well as to examine the factors that are associated with early recovery in patients with ATPD in a developing country. A review of 124 cases of untreated first episode of ATPD that presented at the University College Hospital, Ibadan, Nigeria over a five-year period. Of the new cases that presented at the psychiatry department of the hospital, 10.1% were ATPDs. There was no significant difference between the proportions of males and females presenting at the hospital (50.8% vs 49.2%). Mean age at presentation was 29.5 (SD = 9.6) years, while the mean duration of illness before presentation was 7.3 (SD = 6.1) days. Female gender was significantly associated with earlier recovery (p = .047). ATPDs are common in developing countries. The epidemiology in developing countries is probably different from that of the developed countries. 23600526 Demonstration of Efficient On-Chip Photon Transfer in Self-Assembled Optoplasmonic Networks. Plasmonic nanoantennas facilitate the manipulation of light fields on deeply sub-diffraction-limited length scales, but high dissipative losses in metals make new approaches for an efficient energy transfer in extended on-chip integrated plasmonic circuits mandatory. We demonstrate in this article efficient photon transfer in discrete optoplasmonic molecules comprising gold nanoparticle (NP) dimer antennas located in the evanescent field of a 2 μm diameter polystyrene bead, which served as an optical microcavity (OM). The optoplasmonic molecules were generated through a guided self-assembly strategy in which the OMs were immobilized in binding sites generated by quartz (SiO2) or silicon posts that contained plasmonic nanoantennas on their tips. Control of the post height facilitated an accurate positioning of the plasmonic antennas into the evanescent field of the whispering gallery modes located in the equatorial plane of the OM. Cy3 and Cy5.5 dyes were tethered to the plasmonic antennas through oligonucleotide spacers to act as on-chip light sources. The intensity of Cy3 was found to be increased relative to that of Cy5.5 in the vicinity of the plasmonic antennas where strongly enhanced electric field intensity and optical density of states selectively increase the excitation and emission rates of Cy3 due to spectral overlap with the plasmon. The fluorescent dyes preferentially emitted into the OM, which efficiently trapped and recirculated the photons. We experimentally determined a relative photon transfer efficiency of 44% in non-optimized self-assembled optoplasmonic molecules in this proof-of-principle study. 23611697 The influence of the functional capacity on subjective well-being and quality of life of patients with silicosis. Objectives: Silicosis is a fibrosing and irreversible lung disease. In China, 9870 new silicosis cases were reported in 2010. The physical and mental status of patients with silicosis should be paid attention to. The aims of this study were to evaluate the influence of the patients' functional capacity on subjective well-being (SWB) and quality of life (QOL), provide the scientific basis for further intervention measures, and improve their health status. Methods: We investigated 324 inpatients with silicosis during April 2011 to September 2011. The 6-minute walk test (6MWT) was the major methodology used to evaluate the functional capacity, the SF-12 (Short Form-12) to evaluate the QOL, and the MUNSH (Memorial University of Newfoundland Scale of Happiness) scale to evaluate the SWB. Results: The distance of 6MWT suggested a significant and positive correlation with SWB and QOL of patients with silicosis (P < 0.01). In China, patients with silicosis had low SWB and QOL. Conclusions: The SWB and QOL of patients with silicosis are still relatively low and their health status needs improvement. At the same time, longer distances walked by patients suggest more positive influences on their SWB and QOL. It indicates that when the 6MWT cooperates with SWB and QOL, it may be able to get more accurate evaluation results of patients' survival status. 23443266 Evaluation of a mobile clinical pathology laboratory developed for the home care of pediatric patients following transplantation of peripheral blood precursor cells. Abstract Background: A mobile clinical pathology laboratory (MoLab) was designed, outfitted and evaluated to improve the turnaround time (TAT) of laboratory tests performed in patients who receive follow-up care at home. Methods: Full blood counts (FBCs), basic clinical biochemistry tests on blood and urine, and basic coagulation and blood gases were measured using bench-top laboratory analyzers to perform point-of-care tests in a mobile setting. The quality of the results was evaluated on the instruments both while the vehicle was at rest and following movement during the course of routine activity. Results: The equivalence of the values produced by the point-of-care testing (POCT) and central laboratory (CL) measurement procedures was demonstrated and remained stable after movement in city traffic. The TATs ranged from a few minutes for FBCs to <20 min for extended clinical biochemistry tests. Conclusions: During the first 6 months of activity, the MoLab assured the provision of laboratory results for home care patients in a matter of minutes. This approach not only allowed for real-time modifications in therapy but also reduced the number of second visits by the home care medical team. Point-of-care tests performed on the MoLab were significantly more expensive than the same tests performed in the CL. However, the savings in patient hospitalization expenses and the reduced costs resulting from fewer second daily visits completely offset the costs of using the MoLab during the first 6-month pilot phase. 23875666 The role of necroptosis, an alternative form of cell death, in cancer therapy. Programmed cell death plays an important role in animal development, tissue homeostasis and eliminating harmful or virally infected cells. Necroptosis, a novel form of programmed cell death, is caspase independent but RIPK and RIPK3 dependent. Moreover, it is suggested that necroptosis can be specifically inhibited by small molecular inhibitors such as necrostatin-1. Its signaling pathways have something in common with apoptosis, although the molecular mechanisms of necroptosis need to be further elucidated. Previous evidences suggest that necroptosis has significant effects in regulating various physiological processes and disease, such as ischemic brain injury, immune system disorders and cancer. In this review, the molecular mechanism of necroptosis is described and how it could be manipulated in the treatment of cancer is summarized. 23872429 Stochastic stability of discrete-time Markovian jump delay neural networks with impulses and incomplete information on transition probability. The purpose of this letter is to investigate the stochastic stability for a class of discrete-time Markovian jump delay neural networks with impulses and incomplete information on transition probability. By using Lyapunov functionals, some new results are provided. The obtained results show that impulses can stochastically stabilize an unstable discrete-time Markovian jump delay neural network. The obtained results also show that the stability property of the impulse-free neural network can be retained even under certain destabilizing impulses. Two examples together with their simulations are also presented to show the effectiveness and the advantage of the obtained results. 23726939 Linking sex differences in corticosterone with individual reproductive behaviour and hatch success in two species of uniparental shorebirds. In birds, corticosterone (CORT) appears to facilitate reproductive activity because baseline and stress-induced CORT levels are elevated in breeding individuals compared with other times of the year. In particular, CORT is lower in the sex providing most of the parental care (i.e., incubation), which could be an important adaptation to tolerate stressors that result in abandoning reproduction. Therefore, one explanation for sex differences in CORT is that lower levels are favoured during the incubation/parental phase of reproduction. Using two species of uniparental shorebird - polyandrous red phalaropes (Phalaropus fulicarius) and polygynous white-rumped sandpipers (Calidris fuscicollis) - we predicted that the incubating sex would have lower baseline and stress-induced CORT, and incubating individuals with lower CORT would more effectively defend nests against a simulated intrusion, would return more quickly afterwards, and would ultimately have higher hatch success. We found that phalaropes followed the predicted pattern: incubating individuals (males) had lower baseline and stress-induced CORT than females but for baseline CORT these differences existed prior to males commencing incubation. Incubating male phalaropes with lower baseline and stress-induced CORT returned to incubate more quickly after a disturbance and there was non-significant tendency for baseline CORT to be lower in successful nests. In sandpipers, we observed no sex differences and no significant relationships between individual CORT levels and nest defence behaviours or hatch success. Our results demonstrate that in phalaropes at least, selection favours lower baseline and stress-induced CORT during the nesting period. These results can explain sex differences in stress-induced levels of CORT, however sex differences in baseline CORT were present prior to incubation. 23623752 First demonstration that brain CYP2D-mediated opiate metabolic activation alters analgesia in vivo. The response to centrally-acting drugs is highly variable between individuals and does not always correlate with plasma drug levels. Drug-metabolizing CYP enzymes in the brain may contribute to this variability by affecting local drug and metabolite concentrations. CYP2D metabolizes codeine to the active morphine metabolite. We investigate the effect of inhibiting brain, and not liver, CYP2D activity on codeine-induced analgesia. Rats received intracerebroventricular injections of CYP2D inhibitors (20μg propranolol or 40μg propafenone) or vehicle controls. Compared to vehicle-pretreated rats, inhibitor-pretreated rats had: a) lower analgesia in the tail-flick test (p<0.05) and lower areas under the analgesia-time curve (p<0.02) within the first hour after 30mg/kg subcutaneous codeine, b) lower morphine concentrations and morphine to codeine ratios in the brain (p<0.02 and p<0.05, respectively), but not in plasma (p>0.6 and p>0.7, respectively), tested at 30min after 30mg/kg subcutaneous codeine, and c) lower morphine formation from codeine ex vivo by brain membranes (p<0.04), but not by liver microsomes (p>0.9). Analgesia trended toward a correlation with brain morphine concentrations (p=0.07) and correlated with brain morphine to codeine ratios (p<0.005), but not with plasma morphine concentrations (p>0.8) or plasma morphine to codeine ratios (p>0.8). Our findings suggest that brain CYP2D affects brain morphine levels after peripheral codeine administration, and may thereby alter codeine's therapeutic efficacy, side-effect profile and abuse liability. Brain CYPs are highly variable due to genetics, environmental factors and age, and may therefore contribute to interindividual variation in the response to centrally-acting drugs. 23627914 Glycogen phosphorylase inhibitors: a patent review (2008 - 2012). Introduction: Glycogen phosphorylase (GP) is the enzyme responsible for the synthesis of glucose-1-phosphate, the source of energy for muscles and the rest of the body. The binding of different ligands in catalytic or allosteric sites assures activation and deactivation of the enzyme. A description of the regulation mechanism and the implications in glycogen metabolism are given. Areas covered: Deregulation of GP has been observed in diseases such as diabetes mellitus or cancers. Therefore, it appears as an attractive therapeutic target for the treatment of such pathologies. Numbers of inhibitors have been published in academic literature or patented in the last two decades. This review presents the main patent claims published between 2008 and 2012. Expert opinion: Good inhibitors with interesting IC50 and in vivo results are presented. However, such therapeutic strategy raises questions and some answers are proposed to bring new insights in the field. 23780888 Predicting Drug Responsiveness in Human Cancers Using Genetically Engineered Mice. To use genetically engineered mouse models (GEMM) and orthotopic syngeneic murine transplants (OST) to develop gene expression-based predictors of response to anticancer drugs in human tumors. These mouse models offer advantages including precise genetics and an intact microenvironment/immune system.EXPERIMENTAL DESIGN: We examined the efficacy of 4 chemotherapeutic or targeted anticancer drugs, alone and in combination, using mouse models representing 3 distinct breast cancer subtypes: Basal-like (C3(1)-T-antigen GEMM), Luminal B (MMTV-Neu GEMM), and Claudin-low (T11/TP53(-/-) OST). We expression-profiled tumors to develop signatures that corresponded to treatment and response, and then tested their predictive potential using human patient data.RESULTS: Although a single agent exhibited exceptional efficacy (i.e., lapatinib in the Neu-driven model), generally single-agent activity was modest, whereas some combination therapies were more active and life prolonging. Through analysis of RNA expression in this large set of chemotherapy-treated murine tumors, we identified a pair of gene expression signatures that predicted pathologic complete response to neoadjuvant anthracycline/taxane therapy in human patients with breast cancer.CONCLUSIONS: These results show that murine-derived gene signatures can predict response even after accounting for common clinical variables and other predictive genomic signatures, suggesting that mice can be used to identify new biomarkers for human patients with cancer. Clin Cancer Res; 1-11. ©2013 AACR. 23711836 Ingestion of marine debris plastic by the wedge-tailed shearwater Ardenna pacifica in the Great Barrier Reef, Australia. We present the first evidence of ingestion of plastic by seabirds from the southern Great Barrier Reef (GBR), Australia. The occurrence of marine debris ingestion in the wedge-tailed shearwater, Ardenna pacifica, on Heron Island was the focus of this preliminary research. Our findings indicate that 21% of surveyed chicks are fed plastic fragments by their parents, having ingested 3.2 fragments on average. The most common colours of ingested plastic fragments were off/white (37.5%) and green (31.3%). Ingested fragments had a mean size of 10.17±4.55 mm and a mean weight of 0.056±0.051 g. Our results indicate that further research is critical to understanding the extent of ingestion, colour preferences, and what impacts ingestion may have on these and other seabird populations in the GBR. 23228497 Color stability, conversion, water sorption and solubility of dental composites formulated with different photoinitiator systems. The aim of this study was to formulate materials with high color stability and reduced degradation by using photoinitiator systems derived from phosphine oxides alternative to the traditional camphorquinone (CQ)/amine system. Materials were formulated with the monomers BisGMA and TEGDMA as organic matrix. The photoinitiators tested were CQ+amine (EDMAB), phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide (BAPO), BAPO+EDMAB, diphenyl(2,4,6-trimethylbenzoyl)-phosphine oxide (TPO) and TPO+EDMAB. A 60% mass of silanated glass filler particles was added. Degree of CC conversion was evaluated by Fourier-transformed infrared spectroscopy 10min after photopolymerization. The color properties were evaluated by a digital spectrophotometer, applying the CIELab parameters, either before photoactivation, immediately after photoactivation, 24h after dry storage, and one month after water immersion. Water sorption and solubility were assessed by mass gain or loss after storage in water for 30 days. Data were analyzed using ANOVA and Tukey's test (5%). Degree of conversion did not differ statistically among all the tested formulations. Regarding color, only groups with TPO presented satisfactory color stability after one month of water storage (ΔE<3.3). Water sorption and water stability did not differ among the groups. Degree of conversion, water sorption and water solubility did not differ among all the tested groups. The TPO-based groups were the only materials with satisfactory color stability after one month of water storage. The use of a photoinitiator system containing TPO might improve the color stability of resin composites compared with the traditional CQ/amine system while attaining similar physico-chemical properties for the composite. 23921149 3,5,4'-Trimethoxystilbene, a natural methoxylated analog of resveratrol, inhibits breast cancer cell invasiveness by downregulation of PI3K/Akt and Wnt/β-catenin signaling cascades and reversal of epithelial-mesenchymal transition. The molecular basis of epithelial-mesenchymal transition (EMT) functions as a potential therapeutic target for breast cancer because EMT may endow breast tumor-initiating cells with stem-like characteristics and enable the dissemination of breast cancer cells. We have recently verified the antitumor activity of 3,5,4'-trimethoxystilbene (MR-3), a naturally methoxylated derivative of resveratrol, in colorectal cancer xenografts via an induction of apoptosis. The effect of MR-3 on EMT and the invasiveness of human MCF-7 breast adenocarcinoma cell line were also explored. We found that MR-3 significantly increased epithelial marker E-cadherin expression and triggered a cobblestone-like morphology of MCF-7 cells, while reciprocally decreasing the expression of mesenchymal markers, such as snail, slug, and vimentin. In parallel with EMT reversal, MR-3 downregulated the invasion and migration of MCF-7 cells. Exploring the action mechanism of MR-3 on the suppression of EMT and invasion indicates that MR-3 markedly reduced the expression and nuclear translocation of β-catenin, accompanied with the downregulation of β-catenin target genes and the increment of membrane-bound β-catenin. These results suggest the involvement of Wnt/β-catenin signaling in the MR-3-induced EMT reversion of MCF-7 cells. Notably, MR-3 restored glycogen synthase kinase-3β activity by inhibiting the phosphorylation of Akt, the event required for β-catenin destruction via a proteasome-mediated system. Overall, these findings indicate that the anti-invasive activity of MR-3 on MCF-7 cells may result from the suppression of EMT via down-regulating phosphatidylinositol 3-kinase (PI3K)/AKT signaling, and consequently, β-catenin nuclear translocation. These occurrences ultimately lead to the blockage of EMT and the invasion of breast cancer cells. 23687647 Compositional sorting dynamics in coexisting lipid bilayer phases with variations in underlying e-beam formed curvature pattern. Nanometer-scale curvature patterns of an underlying substrate are imposed on lipid multibilayers with each pattern imparting distinctly different sorting dynamics to a metastable pixelation pattern of coexisting liquid ordered (Lo)-liquid disordered (Ld) lipid phases. Therefore, this work provides pathways toward mechanical energy-based separations for analysis of biomembrane-associate species. The central design concept of the patterned sections of the silica substrate is a square lattice pattern of 100 nm projected radius poly(methyl methacrylate) (PMMA) hemispherical features formed by electron beam lithography which pixelates the coexisting phases in order to balance membrane bending and line energy. In one variation, we surround this pattern with three PMMA walls/fences 100 nm in height which substantially slows the loss of the high line energy pixelated Lo phase by altering the balance of two competing mechanism (Ostwald ripening vs. vesiculation). In another walled variation, we form a gradient of the spacing of the 100 nm features which forces partitioning of the Lo phase toward the end of the gradient with the most open (400 nm spacing) lattice pattern where a single vesicle could grow from the Lo phase. We show that two other variations distinctly impact the dynamics, demonstrating locally slowed loss of the high line energy pixelated Lo phase and spontaneous switching of the pixel location on the unit cell, respectively. Moreover, we show that the pixelation patterns can be regenerated and sharpened by a heating and cooling cycle. We argue that localized variations in the underlying curvature pattern have rather complex consequences because of the coupling and/or competition of dynamic processes to optimize mechanical energy such as lipid diffusion, vesiculation and growth, and phase/compositional partitioning. 23314913 The sequence of the enterococcal cytolysin imparts unusual lanthionine stereochemistry. The enterococcal cytolysin is a two-component lantibiotic of unknown structure with hemolytic activity that is important for virulence. We prepared cytolysin by coexpression of each precursor peptide with the synthetase CylM in Escherichia coli and characterized its structure. Unexpectedly, cytolysin is to our knowledge the first example of a lantibiotic containing lanthionine and methyllanthionine structures with different stereochemistries in the same peptide. The stereochemistry is determined by the sequence of the substrate peptide. 23835186 Item generation in the development of an inpatient experience questionnaire: a qualitative study. Patient experience is a key feature of quality improvement in modern health-care delivery. Measuring patient experience is one of several tools used to assess and monitor the quality of health services. This study aims to develop a tool for assessing patient experience with inpatient care in public hospitals in Hong Kong. Based on the General Inpatient Questionnaire (GIQ) framework of the Care Quality Commission as a discussion guide, a qualitative study involving focus group discussions and in-depth individual interviews with patients was employed to develop a tool for measuring inpatient experience in Hong Kong. All participants agreed that a patient satisfaction survey is an important platform for collecting patients' views on improving the quality of health-care services. Findings of the focus group discussions and in-depth individual interviews identified nine key themes as important hospital quality indicators: prompt access, information provision, care and involvement in decision making, physical and emotional needs, coordination of care, respect and privacy, environment and facilities, handling of patient feedback, and overall care from health-care professionals and quality of care. Privacy, complaint mechanisms, patient involvement, and information provision were further highlighted as particularly important areas for item revision by the in-depth individual interviews. Thus, the initial version of the Hong Kong Inpatient Experience Questionnaire (HKIEQ), comprising 58 core items under nine themes, was developed. A set of dimensions and core items of the HKIEQ was developed and the instrument will undergo validity and reliability tests through a validation survey. A valid and reliable tool is important in accurately assessing patient experience with care delivery in hospitals to improve the quality of health-care services. 23583021 Prognostic significance of acute postoperative seizures in extra-temporal lobe epilepsy surgery. This study aims to assess the prognostic value of acute postoperative seizures (APOS) in patients surgically treated for drug-resistant extra-temporal lobe (ET) epilepsy. We studied 77 consecutive patients with ET epilepsy who underwent epilepsy surgery and were followed up for at least 2years (mean duration of follow-up 6.2years, range 2-14). Medical charts were reviewed to identify APOS, defined as ictal events with the exception of auras occurring within the first 7days after surgery. Seizure outcome was determined at annual intervals. Patients who were in Engel Class I at the last contact were classified as having a favourable outcome. Seizure outcome was favourable in 47 patients (61%). The occurrence of APOS and incompleteness of resection were found to be independently associated with unfavourable outcome in a multiple regression model including all preoperative factors identified as outcome predictors in univariate analysis. Duration of illness was the only independent preoperative predictor of APOS. Our study suggests that APOS may predict long-term outcome in patients undergoing resective surgery for ET epilepsy. Given some study limitations, our findings should be regarded as preliminary and need confirmation from future larger, prospective, multicentre studies. Caution may be required in the clinical management of patients experiencing APOS. 23368814 Blastocystis spp.: Frequency and Subtype Distribution in Iron Deficiency Anemic Versus Non-Anemic Subjects from Egypt. Abstract :  Many helminthic and protozoal infections have been implicated in iron deficiency anemia (IDA) but few reports have suggested a link between Blastocystis sp. infection and IDA. Herein, we investigated the frequency and the association of the Blastocystis sp. genotype with IDA. Two-hundred and six stool samples were examined for Blastocystis sp. Samples were obtained from 96 cases with a confirmed diagnosis of IDA and 110 matched non-anemic controls. The prevalence of the parasite was significantly higher in the IDA group (54.2%) when compared to controls (17.3%) and was 34.5% in all study subjects. Thus, a relationship between Blastocystis sp. infection and IDA was confirmed. PCR amplification of isolates from cases with IDA and controls using subtype-specific sequenced-tagged site primers found that subtype 3 was the most common (83.3%), followed by subtype 1 (16.7%), and both had similar prevalence in both groups. Therefore, there was no correlation found between the Blastocystis sp. genotype and the occurrence of IDA. 23830570 Influence of long-term wearing of unstable shoes on compensatory control of posture: An electromyography-based analysis. This study investigated the influence of long-term wearing of unstable shoes (WUS) on compensatory postural adjustments (CPA) to an external perturbation. Participants were divided into two groups: one wore unstable shoes while the other wore conventional shoes for 8 weeks. The ground reaction force signal was used to calculate the anterior-posterior (AP) displacement of the centre of pressure (CoP) and the electromyographic signal of gastrocnemius medialis (GM), tibialis anterior (TA), rectus femoris (RF) and biceps femoris (BF) muscles was used to assess individual muscle activity, antagonist co-activation and reciprocal activation at the joint (TA/GM and RF/(BF+GM) pairs) and muscle group levels (ventral (TA+RF)/dorsal (GM+BF) pair) within time intervals typical for CPA. The electromyographic signal was also used to assess muscle latency. The variables described were evaluated before and after the 8-week period while wearing the unstable shoes and barefoot. Long-term WUS led to: an increase of BF activity in both conditions (barefoot and wearing the unstable shoes); a decrease of GM activity; an increase of antagonist co-activation and a decrease of reciprocal activation level at the TA/GM and ventral/dorsal pairs in the unstable shoe condition. Additionally, WUS led to a decrease in CoP displacement. However, no differences were observed in muscle onset and offset. Results suggest that the prolonged use of unstable shoes leads to increased ankle and muscle groups' antagonist co-activation levels and higher performance by the postural control system. 23211524 GATA2-induced silencing and LIM-homeodomain protein-induced activation are mediated by a bi-functional response element in the rat GnRH receptor gene. GATA2 transcription factor and LIM homeodomain proteins Islet1 (ISL1) and LIM homeobox 3 (LHX3) are suspected to be involved in gonadotrope cell fate and maintenance. The GnRH receptor gene (Gnrhr), crucial for gonadotrope function, is expressed in the pituitary gland from embryonic day 13.5 onward, well before LH and FSH β-subunits. This expression pattern together with the presence of WGATAR and TAAT motifs in Gnrhr promoter sequences suggests the involvement of early transcription factors in promoter activation. In this study, using a well-characterized transgenic mouse model, GATA2 was found colocalized with Gnrhr promoter activity in the pituitary. Transient transfection of Gnrhr promoter luciferase fusion constructs together with either GATA2 expression vectors or small interfering RNA in gonadotrope cell lines indicated that GATA2, which typically acts as a trans-activator, unexpectedly repressed Gnrhr promoter activity. Using DNA chromatography affinity and EMSA, we demonstrated that GATA2 operates via a response element containing a peculiar palindromic GATA motif that overlaps a critical TAAT motif involved in LHX3/ISL1 trans-activation. Indeed, despite the inhibitory action of GATA2, this element displayed a clear-cut enhancer activity in gonadotrope cells. Chromatin immunoprecipitation assays indicated that GATA2, LHX3, and ISL1 interact with a Gnrhr promoter fragment encompassing this element. The trans-repressive action of GATA2 on Gnrhr promoter activity is likely balanced or even hindered by trans-activating effects of LIM homeodomain proteins via this novel bifunctional LIM/GATA response element. Such a hierarchical interplay may contribute to finely adjust Gnrhr gene expression in gonadotrope cell lineage during pituitary development as well as in the adult animal. 23895017 Robust Iron Coordination Complexes with N-Based Neutral Ligands As Efficient Fenton-Like Catalysts at Neutral pH. The homogeneous Fenton-like oxidation of organic substrates in water with hydrogen peroxide, catalyzed by six different metal coordination complexes with N-based neutral ligands, was studied at ambient conditions and initial pH 7, employing hydrogen peroxide as the terminal oxidant. At low catalyst concentration, the catalytic oxidative depletion of toluene achieved by selected catalysts was much more efficient than that obtained by the Fenton reagent at pH 3. The influence of pH, the water matrix and the catalyst/hydrogen peroxide concentration were investigated for the oxidation of toluene employing [FeCl2(bpmcn)] (1, bpmcn = N,N'-bis(2-pyridylmethyl)-N,N'-dimethyl-trans-1,2-diaminocyclohexane), the most efficient catalyst of the series. Moreover, the evolution of catalysts [FeCl2(bpmcn)] (1) and [Fe(OTf)2(Pytacn)] (3, Pytacn = 1-(2-pyridylmethyl)-4,7-dimethyl-1,4,7-triazacyclononane, OTf = trifluoromethanesulfonate anion) during the course of the reaction was also studied by electrospray ionization mass spectrometry (ESI-MS). The oxidation products derived from toluene oxidation were also analyzed. A plausible mechanism of toluene degradation using [FeCl2(bpmcn)] (1) and [Fe(OTf)2(Pytacn)] (3) as catalysts was proposed, which involves the coexistence of a metal-based path, analogous to that operating in organic media where substrate oxidation is executed by an iron(V)-oxo-hydroxo species, in parallel to a Fenton-type process where hydroxyl radicals are formed. 23933595 Megalocytivirus-induced proteins of turbot (Scophthalmus maximus): Identification and antiviral potential. Megalocytivirus is an important fish pathogen with a broad host range that includes turbot. In this study, proteomic analysis was conducted to examine turbot proteins modulated in expression by megalocytivirus infection. Thirty five proteins from spleen were identified to be differentially expressed at 2days post-viral infection (dpi) and 7dpi. Three upregulated proteins, i.e. heat shock protein 70 (Hsp70), Mx protein, and natural killer enhancing factor (NKEF), were further analyzed for potential antiviral effect. For this purpose, turbot were administered separately with the plasmids pHsp70, pMx, and pNKEF, which express Hsp70, Mx, and NKEF respectively, before megalocytivirus infection. Viral dissemination and propagation in spleen were subsequently determined. The results showed that the viral loads in fish administered with pNKEF were significantly reduced. To examine the potential of Hsp70, Mx, and NKEF as immunological adjuvant, turbot were immunized with a DNA vaccine in the presence of pHsp70, pMx, or pNKEF. Subsequent analysis showed that the presence of pNKEF and pHsp70, but not pMx, significantly reduced viral infection and enhanced fish survival. Taken together, these results indicate that NKEF exhibits antiviral property against megalocytivirus, and that both NKEF and Hsp70 may be used in DNA vaccine-based control of megalocytivirus infection. This study provides the first proteomic picture of turbot in response to megalocytivirus infection. We demonstrated that megalocytivirus infection modulates the expression of turbot proteins associated with various cellular functions, and that one of the upregulated proteins, NKEF, exhibits antiviral effect when overexpressed in vivo, while another upregulated protein, Hsp70, exhibits adjuvant effect when co-immunized with a DNA vaccine. These results add molecular insights into turbot immune response induced by megalocytivirus and provide candidate proteins with application potentials in the control of megalocytivirus-associated disease. 23265490 Retention of aroma compounds from Mentha piperita essential oil by cyclodextrins and crosslinked cyclodextrin polymers. In this paper, the controlled release of aroma compounds from cyclodextrins (CDs) and CD polymers was studied by multiple headspace extraction (MHE) experiments. Mentha piperita essential oil was obtained by Soxhlet extraction and identification of the major compounds was performed by GC-MS analysis. Menthol, menthone, pulegone and eucalyptol were identified as the major components. Retention of standard compounds in the presence of different CDs and CD polymers has been realised by static headspace gas chromatography (SH-GC) at 25 °C in the aqueous or gaseous phase. Stability constants for standard compounds and for compounds in essential oil have been also determined with monomeric CD derivatives. The obtained results indicated the formation of a 1:1 inclusion complex for all the studied compounds. Molecular modelling was used to investigate the complementarities between host and guest. This study showed that β-CDs were the most versatile CDs and that β-CD polymers could perform the controlled release of aroma compounds. 23684765 MDA5 and ISG56 mediate CXCL10 expression induced by Toll-like receptor 4 activation in U373MG human astrocytoma cells. Toll-like receptor (TLR) 4 is a pattern recognition receptor, and recognizes not only bacterial lipopolysaccharide (LPS) but also endogenous danger-associated molecular patterns released from dying or injured cells. It has been reported that TLR4 signaling in astrocytes plays an important role in various neurological diseases. However, details of TLR4 signaling in astrocytes are not fully elucidated. In the present study, we demonstrated that TLR4 signaling, induced by LPS, increases the expression of melanoma differentiation-associated gene 5 (MDA5) and interferon (IFN)-stimulated gene 56 (ISG56) in U373MG human astrocytoma cells. We also found that nuclear factor-κB, p38 mitogen-activated protein kinase and IFN-β are involved in the expression of MDA5 and ISG56 induced by LPS. RNA interference experiments revealed that MDA5 and ISG56 positively regulate the LPS-induced expression of a chemokine CXCL10, but not CCL2. In addition, it was suggested that MDA5 and ISG56 constitute a positive feedback loop. These results suggest that MDA5 and ISG56 may contribute not only to physiological inflammatory reactions but also to the pathogenesis of various neurological diseases elicited by TLR4 in astrocytes, at least in part, by regulating the expression of CXCL10. 23956388 Methanosarcinaceae and acetate oxidising pathways dominate in high-rate thermophilic anaerobic digestion of waste activated sludge. This study investigates the process of high rate, high temperature methanogenesis to enable very high volumetric loading during anaerobic digestion of waste activated sludge. Reducing the HRT from 15-20 days in mesophilic digestion down to 3 days was achievable at a thermophilic temperature (55 °C) with stable digester performance and methanogenic activity. A volatile solids (VS) destruction of 33-35% was achieved on waste activated sludge, comparable to mesophilic processes with low organic acid levels (<200 mg/L COD). Methane yield (VS basis) was 150-180 LCH4/kgVSadded. According to 16S rRNA pyrotag sequencing and FISH the methanogenic community was dominated by Methanosarcinaceae, which have a high level of metabolic capability, including acetoclastic and hydrogenotrophic methanogenesis. Loss of function at two days HRT was accompanied by a loss of the methanogens according to pyrotag sequencing. The two acetate conversion pathways namely acetoclastic methanogenesis and syntrophic acetate oxidation were quantified by stable carbon isotope ratio mass spectrometry. The results showed that the majority of methane was generated by non-acetoclastic pathways, both in the reactors, and in off-line batch tests confirming that syntrophic acetate-oxidation is a key pathway at elevated temperatures. The proportion of methane due to acetate cleavage increased later in the batch, and it is likely that stable oxidation in the continuous reactor was maintained by application of the consistently low retention time. 23934249 Fretibacter rubidus gen. nov., sp. nov., isolated from seawater. A brick-red colored, curved-rod shaped, prostheca-bearing and non-motile bacterial strain, designated JC2236T, was isolated from a seawater sample of Jeju Island, Korea. Result of 16S rRNA gene sequence analysis indicated that the test strain belongs to the family Hyphomonadaceae and represents a distinct phyletic line that reflects a novel genus status within a clade containing genera Litorimonas, Hellea, Robiginitomaculum and Algimonas. The predominant isoprenoid quinone (Q10) and polar lipid profile (PG, GUDG and MGDG) were in line with those of most members of the family. However, the DNA G+C content (49.3 mol%), the abundance of C16:0, the requirement of sea salts for growth, and absence of cell motility differentiated strain JC2236T from other closely related genera. Overall enzymatic traits also demonstrated that the test strain does not closely affiliate with any of the previously described genera. Thus, based on polyphasic taxonomic data, it is proposed that strain JC2236T constitute a novel genus and a novel species belonging to the family Hyphomonadaceae. The name Fretibacter rubidus gen. nov., sp. nov. is therefore proposed for the isolate; type strain is JC2236T (= KACC 16935T = JCM 15585T). 23638877 Calcium channel blockers and dementia. Degenerative dementia is mainly caused by Alzheimer's disease and/or cerebrovascular abnormalities. Disturbance of the intracellular calcium homeostasis is central to the pathophysiology of neurodegeneration. In Alzheimer's disease, enhanced calcium load may be brought about by extracellular accumulation of amyloid-β. Recent studies suggest that soluble forms facilitate influx through calcium-conducting ion channels in the plasma membrane, leading to excitotoxic neurodegeneration. Calcium channel blockade attenuates amyloid-β-induced neuronal decline in vitro and is neuroprotective in animal models. Vascular dementia, on the other hand, is caused by cerebral hypoperfusion and may benefit from calcium channel blockade due to relaxation of the cerebral vasculature. Several calcium channel blockers have been tested in clinical trials of dementia and the outcome is heterogeneous. Nimodipine as well as nilvadipine prevent cognitive decline in some trials, whereas other calcium channel blockers failed. In trials with a positive outcome, BP reduction did not seem to play a role in preventing dementia, indicating a direct protecting effect on neurons. An optimization of calcium channel blockers for the treatment of dementia may involve an increase of selectivity for presynaptic calcium channels and an improvement of the affinity to the inactivated state. Novel low molecular weight compounds suitable for proof-of-concept studies are now available. 23799442 The synergy of medicine and art in the curriculum. This is a commentary in which a fourth-year medical student argues for the relevance of the arts and humanities and the need to sustain medical students' exposure to these through the medical curriculum. She writes that the point of incorporating the visual arts, literature, music, and other arts into the curriculum is not necessarily to "teach" professionalism but, rather, to offer students a viable, lifelong tool to reorient themselves as they move along in their training. The advantages that the humanities offer are multifactorial: They offer a space for discussion about topics such as death and dying-and coping with dying patients-such that students can feel safe and objective in sharing thoughts; they remind students of the patient experience; they eloquently distill muddy feelings into nuanced words; and they serve as an anchoring point for a state of mind that nurtures reflection over the disdain encouraged by the "hidden curriculum" of the wards. The author closes the commentary with excerpts from literature. 23344822 Interleukin-10 involvement in exposure to low dose of benzene. OBJECTIVE: To establish if serum levels of interleukin-10 (IL-10) in subjects exposed to benzene are connected with age, working years, and employment age. METHODS: We evaluated serum levels of IL-10 in 51 employees working in oil refinery (group A) and in 16 office workers who resided in the same area (group B). RESULTS: There was no statistically significant difference between serum concentrations of IL-10 in groups A and B. There was a statistically significant dependent relationship in group A between age, working years, and serum concentration of IL-10. There was a statistically significant and positive dependent relationship in group A between serum concentration of IL-10 and employment age. CONCLUSIONS: The role played by IL-10 in benzene immune suppression may be relevant and attention should be directed toward assessment of age, working years, and employment age in benzene-exposed populations. 23664838 Substrate elasticity as biomechanical modulator of tissue homeostatic parameters in corneal keratinocytes. This study aimed at identifying putative modulations of tissue homeostatic parameters in corneal keratinocytes in response to biomechanical cues as basis for innovative cornea biomechanical-tailored biomaterials. Since cornea epithelial biomechanics is already described for contacts on nanostructures, we herein analyzed cell response to mechanical substrate elasticity. Therefore, corneal keratinocytes were established on physiologically-relevant elastic substrates of 40kPa, 130kPa but also on non-physiological stiff substrates of 1.74MPa for 3 days. qPCR revealed that changes in gene expression were only marginal between 40kPa and 130kPa, while significant modulations were seen on 1.74MPa substrates for most tissue-innate biomarkers under study. Gene expression fairly coincided with the protein, with differentiation progression biomarkers involucrin and fillagrin being already significantly increased between elasticities of 40kPa and 130kPa. Regarding focal adhesions, reinforcement was seen for ß1 integrin and phospho- p(125FAK) between 40kPa and 130kPa, while from 130kPa to 1.74MPa actin redistributed and phospho-p(125FAK) was strikingly up-regulated. These findings suggest elasticity dependence for differentiation progression and focal adhesion dynamics of corneal keratinocytes, supporting the concept of biomechanics governed regulation of tissue homeostasis. Moreover, this concept in turn can be translated into prospective cornea-tailored biomaterials for therapeutic approaches in ophthalmology. 23743808 Persistent organic pollutants and abnormal geometry of the left ventricle in the elderly. Established risk factors for left ventricular hypertrophy (LVH) are hypertension, diabetes, and obesity. However, as these risk factors explain only part of the variation in left ventricular mass, we investigated whether persistent organic pollutants (POPs) might also play a role in LVH, because exposure to polychlorinated biphenyl 126 induced cardiac growth in rats. In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), left ventricular mass index (LVMI), relative wall thickness (RWT), and geometric groups of LVH, were determined by echocardiography and 21 POPs were measured by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS) in 1016 individuals aged 70 years. All individuals with a history of myocardial infarction were excluded from analysis (n = 72). Several of the POPs were related to abnormal left ventricular geometry before adjustment for established risk factors, but lost in significance following adjustment. However, the pesticide hexachlorobenzene (HCB) levels were significantly related to RWT, and concentric left ventricular remodeling, also following adjustment for sex, blood pressure, antihypertensive treatment, diabetes, and BMI (P <0.0001). In this cross-sectional study, circulating levels of HCB were related to increased wall thickness of the left ventricle and concentric left ventricular remodeling, independently of LVH risk factors, suggesting a role of this environmental contaminant in abnormal growth of the left ventricle. 23150485 Induction of multidrug resistance transporter ABCG2 by prolactin in human breast cancer cells. The multidrug transporter, breast cancer resistance protein, ABCG2, is up-regulated in certain chemoresistant cancer cells and in the mammary gland during lactation. We investigated the role of the lactogenic hormone prolactin (PRL) in the regulation of ABCG2. PRL dose-dependently induced ABCG2 expression in T-47D human breast cancer cells. This induction was significantly reduced by short-interfering RNA-mediated knockdown of Janus kinase 2 (JAK2). Knockdown or pharmacologic inhibition of the down-stream signal transducer and activator of transcription-5 (STAT5) also blunted the induction of ABCG2 by PRL, suggesting a role for the JAK2/STAT5 pathway in PRL-induced ABCG2 expression. Corroborating these findings, we observed PRL-stimulated STAT5 recruitment to a region containing a putative γ-interferon activation sequence (GAS) element at -434 base pairs upstream of the ABCG2 transcription start site. Introduction of a single mutation to the -434 GAS element significantly attenuated PRL-stimulated activity of a luciferase reporter driven by the ABCG2 gene promoter and 5'-flanking region containing the -434 GAS motif. In addition, this GAS element showed strong copy number dependency in its response to PRL treatment. Interestingly, inhibitors against the mitogen-activated protein kinase and phosphoinositide-3-kinase signaling pathways significantly decreased the induction of ABCG2 by PRL without altering STAT5 recruitment to the GAS element. We conclude that the JAK2/STAT5 pathway is required but not sufficient for the induction of ABCG2 by PRL. 23548164 Neoclerodanes as Atypical Opioid Receptor Ligands. The neoclerodane diterpene salvinorin A is the major active component of the hallucinogenic mint plant Salvia divinorum Epling and Játiva (Lamiaceae). Since the finding that salvinorin A exerts its potent psychotropic actions through the activation of opioid receptors, the site of action of morphine and related analogues, there has been much interest in elucidating the underlying mechanisms behind its effects. These effects are particularly remarkable because (1) salvinorin A is the first reported non-nitrogenous opioid receptor agonist and (2) its effects are not mediated through the previously investigated targets of psychotomimetics. This Perspective outlines our research program, illustrating a new direction to the development of tools to further elucidate the biological mechanisms of drug tolerance and dependence. The information gained from these efforts is expected to facilitate the design of novel agents to treat pain, drug abuse, and other central nervous system disorders. 23929457 Correlating the amount of urea, creatinine, and glucose in urine from patients with diabetes mellitus and hypertension with the risk of developing renal lesions by means of Raman spectroscopy and principal component analysis. ABSTRACT. Patients with diabetes mellitus and hypertension (HT) diseases are predisposed to kidney diseases. The objective of this study was to identify potential biomarkers in the urine of diabetic and hypertensive patients through Raman spectroscopy in order to predict the evolution to complications and kidney failure. Urine samples were collected from control subjects (CTR) and patients with diabetes and HT with no complications (lower risk, LR), high degree of complications (higher risk, HR), and doing blood dialysis (DI). Urine samples were stored frozen (-20°C) before spectral analysis. Raman spectra were obtained using a dispersive spectrometer (830-nm, 300-mW power, and 20-s accumulation). Spectra were then submitted to principal component analysis (PCA) followed by discriminant analysis. The first PCA loading vectors revealed spectral features of urea, creatinine, and glucose. It has been found that the amounts of urea and creatinine decreased as disease evoluted from CTR to LR/HR and DI (PC1, p<0.05), and the amount of glucose increased in the urine of LR/HR compared to CTR (PC3, p<0.05). The discriminating model showed better overall classification rate of 70%. These results could lead to diagnostic information of possible complications and a better disease prognosis. 23932773 Three-dimensional reconstruction of the pharyngeal tonsil innervation pattern in sheep. The pharyngeal tonsil has recently been identified as a new participant in airborne contamination by the ovine scrapie agent. In the context of scrapie pathogenesis, we conducted a three-dimensional reconstruction of the innervation pattern in the lymphoid compartments of this tonsil. This model confirmed that very few nerve fibres penetrated the lymphoid follicles and suggested that the nerve fibre distribution in the interfollicular and subepithelial areas is more suitable with neuro-invasion through direct contact between these nerve fibres and prion-transporting cells prior to or after prion amplification in the germinal centre of the pharyngeal tonsil lymphoid follicles. 22807022 Mapping of cerebral perfusion territories using territorial arterial spin labeling: techniques and clinical application. A knowledge of the exact cerebral perfusion territory which is supplied by any artery is of great importance in the understanding and diagnosis of cerebrovascular disease. The development and optimization of territorial arterial spin labeling (T-ASL) MRI techniques in the past two decades have made it possible to visualize and determine the cerebral perfusion territories in individual patients and, more importantly, to do so without contrast agents or otherwise invasive procedures. This review provides an overview of the development of ASL techniques that aim to visualize the general cerebral perfusion territories or the territory of a specific artery of interest. The first efforts of T-ASL with pulsed, continuous and pseudo-continuous techniques are summarized and subsequent clinical studies using T-ASL are highlighted. In the healthy population, the perfusion territories of the brain-feeding arteries are highly variable. This high variability requires special consideration in specific patient groups, such as patients with cerebrovascular disease, stroke, steno-occlusive disease of the large arteries and arteriovenous malformations. In the past, catheter angiography with selective contrast injection was the only available method to visualize the cerebral perfusion territories in vivo. Several T-ASL methods, sometimes referred to as regional perfusion imaging, are now available that can easily be combined with conventional brain MRI examinations to show the relationship between the cerebral perfusion territories, vascular anatomy and brain infarcts or other pathology. Increased availability of T-ASL techniques on clinical MRI scanners will allow radiologists and other clinicians to gain further knowledge of the relationship between vasculature and patient diagnosis and prognosis. Treatment decisions, such as surgical revascularization, may, in the near future, be guided by information provided by T-ASL MRI in close correlation with structural MRI and quantitative perfusion information. Copyright © 2012 John Wiley & Sons, Ltd. 23965640 A review of economic evaluations of behavior change interventions: setting an agenda for research methods and practice. The objective of this study was to review methodological quality of economic evaluations of lifestyle behavior change interventions (LBCIs) and to examine how they address methodological challenges for public health economic evaluation identified in the literature. Pubmed and the NHS economic evaluation database were searched for published studies in six key areas for behavior change: smoking, physical activity, dietary behavior, (illegal) drug use, alcohol use and sexual behavior. From included studies (n = 142), we extracted data on general study characteristics, characteristics of the LBCIs, methodological quality and handling of methodological challenges. Economic evaluation evidence for LBCIs showed a number of weaknesses: methods, study design and characteristics of evaluated interventions were not well reported; methodological quality showed several shortcomings and progress with addressing methodological challenges remained limited. Based on the findings of this review we propose an agenda for improving future evidence to support decision-making. Recommendations for practice include improving reporting of essential study details and increasing adherence with good practice standards. Recommendations for research methods focus on mapping out complex causal pathways for modeling, developing measures to capture broader domains of wellbeing and community outcomes, testing methods for considering equity, identifying relevant non-health sector costs and advancing methods for evidence synthesis. 23775140 Anion-directed assembly of a non-interpenetrated square-grid metal-organic framework with nanoscale porosity. A non-interpenetrated square grid metal-organic framework (MOF) comprised of octahedral Zn(II) ions and linear N,N'-di(4-pyridyl)-1,4,5,8-naphthalenediimide (DPNDI) ligands was formed in the presence of noncoordinating perchlorate counterions that occupied the cavities of the porous network by forming CH···anion hydrogen bonds with DPNDI ligands, whereas a linear coordination polymer was obtained when Zn(II)-coordinated nitrate ions were present as counterions. 23959784 Incorporation of Nucleoside Probes Opposite O(6) -Methylguanine by Sulfolobus solfataricus DNA Polymerase Dpo4: Importance of Hydrogen Bonding. O(6) -Methylguanine (O(6) -MeG) is a mutagenic DNA lesion, arising from the action of methylating agents on guanine (G) in DNA. Dpo4, an archaeal low-fidelity Y-family DNA polymerase involved in translesion DNA synthesis (TLS), is a model for studying how human Y-family polymerases bypass DNA adducts. Previous work showed that Dpo4-mediated dTTP incorporation is favored opposite O(6) -MeG rather than opposite G. However, factors influencing the preference of Dpo4 to incorporate dTTP opposite O(6) -MeG are not fully defined. In this study, we investigated the influence of structural features of incoming dNTPs on their enzymatic incorporation opposite O(6) -MeG in a DNA template. To this end, we utilized a new fluorescence-based primer extension assay to evaluate the incorporation efficiency of a panel of synthetic dNTPs opposite G or O(6) -MeG by Dpo4. In single-dNTP primer extension studies, the synthetic dNTPs were preferentially incorporated opposite G, relative to O(6) -MeG. Moreover, pyrimidine-based dNTPs were generally better incorporated than purine-based syn-conformation dNTPs. The results suggest that hydrophobicity of the incoming dNTP appears to have little influence on the process of nucleotide selection by Dpo4, with hydrogen bonding capacity being a major influence. Additionally, modifications at the C2-position of dCTP increase the selectivity for incorporation opposite O(6) -MeG without a significant loss of efficiency. 23483446 Validity of parentally reported febrile seizures: the generation R study. The objective of this study was to examine the validity of the diagnosis of "febrile seizure" as reported by parents. The study was embedded in a population-based prospective cohort study. Information on paroxysmal events was obtained by screening questions at ages 1, 2, and 3 years. One of these questions was the following: "Did your child have a febrile seizure?" If a screen-positive result was found, an additional questionnaire was sent and the medical record was consulted. Based on this information, paroxysmal events were classified by a pediatric neurologist as febrile seizure or other event. The validity of a positive reply to the screening question on febrile seizures was assessed, taking this classification as reference standard. Analyses were based on participants who reported at least one paroxysmal event (n = 610). The sensitivity of the positive reply to the question, "Did your child have a febrile seizure?", for the diagnosis of febrile seizures was 92%, the specificity 72%, the positive predictive value 41%, and the negative predictive value 98%. In conclusion, the sensitivity of the question, "Did your child have a febrile seizure?", is high. The positive predictive value is only 41%. Although this question may be appropriate as a screening instrument for febrile seizures, a second stage of evaluation is necessary to identify true cases. 23870279 Total glucosides of paeony prevents juxta-articular bone loss in experimental arthritis. Total glucosides of paeony (TGP) is a biologically active compound extracted from Paeony root. TGP has been used in rheumatoid arthritis therapy for many years. However, the mechanism by which TGP prevents bone loss has been less explored. TGP was orally administered for 3 months to New Zealand rabbits with antigen-induced arthritis (AIA). Digital x-ray knee images and bone mineral density (BMD) measurements of the subchondral knee bone were performed before sacrifice. Chondrocytes were observed using transmission electron microscopy (TEM). Histological analysis and mRNA expression of receptor activator of nuclear factor-B ligand (RANKL) and osteoprotegerin (OPG) were evaluated in joint tissues. The BMD value in TGP rabbits was significantly higher compared with that seen in the AIA model rabbits. In addition, the subchondral bone plate was almost completely preserved by TGP treatment, while there was a decrease in bone plate integrity in AIA rabbits. There was less damage to the chondrocytes of the TGP treated group. Immunohistochemical examination of the TGP group showed that a higher percentage of TGP treated chondrocytes expressed OPG as compared to the chondrocytes isolated from AIA treated animals. In contrast, RANKL expression was significantly decreased in the TGP treated group compared to the AIA group. In support of the immunohistochemistry data, the expression of RANKL mRNA was decreased and OPG mRNA expression was enhanced in the TGP group when compared to that of the AIA model group. These results reveal that TGP suppresses juxta-articular osteoporosis and prevents subchondral bone loss. The decreased RANKL and increased OPG expression seen in TGP treated animals could explain how administration of TGP maintains higher BMD. 23874002 Shielding effects in polymer-polymer reactions. V. Concentration dependence of contact formation between star-branched and linear chains. By use of the Dissipative Particle Dynamics (DPD) simulation technique mixtures of star-branched (arm number F = 4) and linear chains in athermal (good) solvent are analyzed regarding probabilities for intermolecular contacts of various reactive sites within different polymer coils. The accompanying sterical hindrances are described in the framework of shielding factors in order to investigate reactions and side reactions in radical polymerization and other techniques that involve polymer-polymer coupling. The shielding factors are studied as a function of total concentration from high dilution up to the bulk for different chain lengths of star-shaped and linear chains. Results indicate that their concentration dependence can be described by a power law for systems above the overlap concentration, whereas the chain length dependence vanishes when extrapolating to infinite chain lengths in that concentration range. Also the influence of the ratio of star chains and linear chains is studied for various concentrations. 23838203 Efficient production of polymer-grade l-lactate by an alkaliphilic Exiguobacterium sp. strain under nonsterile open fermentation conditions. In this study, a newly isolated alkaliphile Exiguobacterium sp. strain 8-11-1 was used to produce optically pure l-lactate. With an initial glucose concentration of 80g/L, a high overall l-lactic acid productivity of 8.15g/L/h was achieved using NaOH as a neutralizing agent. The fed-batch fermentations were carried out under both sterile and nonsterile conditions. Under the nonsterile condition, 125g/L l-lactic acid was obtained with a high percent yield and average productivity of 98.33% and 3.79g/L/h, respectively. These values were consistent with the results from sterile condition. No d-isomers of lactic acid were detected, resulting in an optical purity of 100% in both conditions. The high levels of optically pure l-lactic acid produced by Exiguobacterium sp. 8-11-1, combined with the ease of handling and low costs associated with the open fermentation strategy, provide a novel and potentially important approach for l-lactic acid production in the future. 23883927 Oil palm genome sequence reveals divergence of interfertile species in Old and New worlds. Oil palm is the most productive oil-bearing crop. Although it is planted on only 5% of the total world vegetable oil acreage, palm oil accounts for 33% of vegetable oil and 45% of edible oil worldwide, but increased cultivation competes with dwindling rainforest reserves. We report the 1.8-gigabase (Gb) genome sequence of the African oil palm Elaeis guineensis, the predominant source of worldwide oil production. A total of 1.535 Gb of assembled sequence and transcriptome data from 30 tissue types were used to predict at least 34,802 genes, including oil biosynthesis genes and homologues of WRINKLED1 (WRI1), and other transcriptional regulators, which are highly expressed in the kernel. We also report the draft sequence of the South American oil palm Elaeis oleifera, which has the same number of chromosomes (2n = 32) and produces fertile interspecific hybrids with E. guineensis but seems to have diverged in the New World. Segmental duplications of chromosome arms define the palaeotetraploid origin of palm trees. The oil palm sequence enables the discovery of genes for important traits as well as somaclonal epigenetic alterations that restrict the use of clones in commercial plantings, and should therefore help to achieve sustainability for biofuels and edible oils, reducing the rainforest footprint of this tropical plantation crop. 23276209 Alkyl substituted 2'-benzoylpyridine thiosemicarbazone chelators with potent and selective anti-neoplastic activity: novel ligands that limit methemoglobin formation. Thiosemicarbazone chelators, including the 2'-benzoylpyridine thiosemicarbazones (BpT) class, show marked potential as anticancer agents. Importantly, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) has been investigated in >20 phase I and II clinical trials. However, side effects associated with 3-AP administration include methemoglobinemia. Considering this problem, novel BpT analogues were designed bearing hydrophobic, electron-donating substituents at the para position of the phenyl group (RBpT). Their Fe(III/II) redox potentials were all within the range accessible to cellular oxidants and reductants, suggesting they can redox cycle. These RBpT ligands exhibited potent and selective antiproliferative activity, which was comparable or exceeded their BpT counterparts. Major findings include that methemoglobin formation mediated by the lipophilic t-BuBpT series was significantly (p < 0.05-0.001) decreased in comparison to 3-AP in intact red blood cells and were generally comparable to the control. These data indicate the t-BuBpT ligands may minimize methemoglobinemia, which is a marked advantage over 3-AP and other potent thiosemicarbazones. 23869753 White Wine Proteins: How Does the pH Affect Their Conformation at Room Temperature? Our studies focused on the determination of aggregation mechanisms of proteins occurring in wine at room temperature. Even if the wine pH range is narrow (2.8 to 3.7), some proteins are affected by this parameter. At low pH, the formation of aggregates and the development of a haze due to proteins sometimes occur. The objective of this work was to determine if the pH impacted the conformational stability of wine proteins. Different techniques were used: circular dichroism and fluorescence spectroscopy to investigate the modification of their secondary and tertiary structure and also SAXS to determine their global shape. Four pure proteins were used, two considered to be stable (invertase and thaumatin-like proteins) and two considered to be unstable (two chitinase isoforms). Two pH values were tested to emphasize their behavior (pH 2.5 and 4.0). The present work highlighted the fact that the conformational stability of some wine proteins (chitinases) was impacted by partial modifications, related to the exposure of some hydrophobic sites. These modifications were enough to destabilize the native state of the protein. These modifications were not observed on wine proteins determined to be stable (invertase and thaumatin-like proteins). 23836747 When seeing the same physician, highly activated patients have better care experiences than less activated patients. Measures of the patient care experience are now routinely used in public reports and increasingly influence health provider payment. We examined data from 5,002 patients of forty-nine primary care providers to explore the relationship between patient activation-a term referring to the knowledge, skills, and confidence a patient has for managing his or her health care-and the patient care experience. We found that patients at higher levels of activation had more positive experiences than patients at lower levels seeing the same clinician. The observed differential was maintained when we controlled for demographic characteristics and health status. We did not find evidence that patients at higher levels of activation selected providers who were more patient-centric. The findings suggest that the care experience is transactional, shaped by both providers and patients. Strategies to improve the patient experience, therefore, should focus not only on providers but also on improving patients' ability to elicit what they need from their providers. 23884785 Total Trihalomethanes in Public Drinking Water Supply and Birth Outcomes: A Cross-Sectional Study. Reproductive effects of long-term, low-dose exposure to disinfectant by-products have not been consistently documented in large populations despite the known toxicity of high exposures and the wide-spread occurrence of low concentrations in public drinking water. We investigated the effect of low-dose exposure to total trihalomethanes (TTHM) on birth weight and gestational term in New York State. All singleton live births from 1998 through 2003 in 62 counties in New York State were linked with public water supply (PWS) system boundaries based on mother's residential address on birth certificate. Using the data from public water supply system, TTHM measurements were assigned geographically and temporally to each birth record linked with PWS boundary. Individual level maternal information including mother's race, ethnicity, education, employment status, smoking, age, along with adequacy of prenatal care utilization and infant's gender was used in a logistic model to adjust for potential confounding. A small non-linear association was detected between TTHM exposure and low birth weight (<2,500 g) births (OR 1.14; 95 % confidence interval (CI) 1.08-1.21), preterm births (OR 1.14; 95 % CI 1.08-1.20) and for small for gestational age births (OR 1.10; 95 % CI 1.04-1.16) suggesting a small increase in risk for these birth outcomes with chronic low maternal exposure to drinking water containing trihalomethanes. Maternal exposure to TTHMs during pregnancy may be associated with low birth weight, preterm births and small for gestational age births. 23770115 Genetic signature of a recent southern range shift in Glossina tachinoides in East Burkina Faso. In the eastern part of Burkina-Faso, the riverine tsetse fly, Glossina tachinoides Westwood, transmits African animal trypanosomosis that constitute a major constraint to sub-Saharan agriculture. To organize an efficient vector control campaign against this vector, it is crucial to identify and target isolated populations in order to prevent any risk of reinvasion. Previous entomological data using traps in this part of the country have suggested that G. tachinoides has now become discontinuously distributed with a western and an eastern tsetse belt. In this paper, we studied population genetics on G. tachinoides trapped in two sites, separated by 150kms, on the western and eastern sides of this "gap". We found that a significant differentiation does exist between the two sites and that it is fairly above than what was expected given the geographic distance. A comparison between observed and expected differentiation allowed estimating that the total separation between these two sites could have occurred around 10years ago (i.e. between 1 and 21years), which is in line with the dates of environmental changes that occurred in this area. This result will help the national PATTEC project to organize the tsetse eradication in this area. 23943433 Work-Function-Tuned Reduced Graphene Oxide via Direct Surface Functionalization as Source/Drain Electrodes in Bottom-Contact Organic Transistors. RGO electrodes with work functions that can be widely tuned using direct surface functionalization are demonstrated by self-assembled monolayers anchored onto the surfaces of the RGO electrodes, which can remarkably enhance the device performance of organic field-effect transistors. 23847512 Keep away from danger: dangerous objects in dynamic and static situations. Behavioral and neuroscience studies have shown that objects observation evokes specific affordances (i.e., action possibilities) and motor responses. Recent findings provide evidence that even dangerous objects can modulate the motor system evoking aversive affordances. This sounds intriguing since so far the majority of behavioral, brain imaging, and transcranial magnetic stimulation studies with painful and dangerous stimuli strictly concerned the domain of pain, with the exception of evidence suggesting sensitivity to objects' affordances when neutral objects are located in participants' peripersonal space. This study investigates whether the observation of a neutral or dangerous object in a static or dynamic situation differently influences motor responses, and the time-course of the dangerous objects' processing. In three experiments we manipulated: object dangerousness (neutral vs. dangerous); object category (artifact vs. natural); manual response typology (press vs. release a key); object presentation (Experiment 1: dynamic, Experiments 2 and 3: static); object movement direction (Experiment 1: away vs. toward the participant) or size (Experiments 2 and 3: big vs. normal vs. small). The task required participants to decide whether the object was an artifact or a natural object, by pressing or releasing one key. Results showed a facilitation for neutral over dangerous objects in the static situation, probably due to an affordance effect. Instead, in the dynamic condition responses were modulated by the object movement direction, with a dynamic affordance effect elicited by neutral objects and an escape-avoidance effect provoked by dangerous objects (neutral objects were processed faster when they moved toward-approached the participant, whereas dangerous objects were processed faster when they moved away from the participant). Moreover, static stimuli influenced the manual response typology. These data indicate the emergence of dynamic affordance and escaping-avoidance effects. 23888428 Acupuncture and assisted reproductive technology. Acupuncture is commonly undertaken during an assisted reproductive technology (ART) cycle although its role in improving live birth and pregnancy rates is unclear. To determine the effectiveness and safety of acupuncture as an adjunct to ART cycles for male and female subfertility. All reports which described randomised controlled trials of acupuncture in assisted conception were obtained through searches of the Menstrual Disorders and Subfertility Group Specialised Register, CENTRAL, Ovid MEDLINE, EMBASE, CINAHL (Cumulative Index to Nursing & Allied Health Literature), AMED , www.clinicaltrials.gov (all from inception to July 2013), National Research Register, and the Chinese clinical trial database (all to November 2012). Randomised controlled trials of acupuncture for couples who were undergoing ART, comparing acupuncture treatment alone or acupuncture with concurrent ART versus no treatment, placebo or sham acupuncture plus ART for the treatment of primary and secondary infertility. Women with medical illness that was deemed to contraindicate ART or acupuncture were excluded. Twenty randomised controlled trials were included in the review and nine were excluded. Study selection, quality assessment and data extraction were performed independently by two review authors. Meta-analysis was performed using odds ratio (OR) and 95% confidence intervals (CI). The outcome measures were live birth rate, clinical ongoing pregnancy rate, miscarriage rate, and any reported side effects of treatment. The quality of the evidence for the primary outcome (live birth) was rated using GRADE methods. This updated meta-analysis showed no evidence of overall benefit of acupuncture for improving live birth rate (LBR) regardless of whether acupuncture was performed around the time of oocyte retrieval (OR 0.87, 95% CI 0.59 to 1.29, 2 studies, n = 464, I(2) = 0%, low quality evidence) or around the day of embryo transfer (ET) (OR 1.22, 95% CI 0.87 to 1.70, 8 studies, n = 2505, I(2) = 69%, low quality evidence). There was no evidence that acupuncture had any effect on pregnancy or miscarriage rates, or had significant side effects. There is no evidence that acupuncture improves live birth or pregnancy rates in assisted conception. 23829667 Porous TiO2/C Nanocomposite Shells As a High-Performance Anode Material for Lithium-Ion Batteries. Porous TiO2/C nanocomposite shells with high capacity, excellent cycle stability, and rate performance have been prepared. The synthesis involves coating colloidal TiO2 nanoshells with a resorcinol-formaldehyde (RF) layer with controllable thickness through a sol-gel-like process, and calcining the composites at 700 °C in an inert atmosphere to induce crystallization from amorphous TiO2 to anatase and simultaneous carbonization from RF to carbon. The cross-linked RF polymer contributes to the high stability of the shell morphology and the porous nature of the shells. A strong dependence of the capacity on the amount of incorporated carbon has been revealed, allowing the optimization of the electrode structure for high-rate cell performance. 23842131 Modelling HIV incidence and survival from age-specific seroprevalence after antiretroviral treatment scale-up in rural South Africa. Our study uses sex- and age-specific HIV prevalence data from an ongoing population-based demographic and HIV survey to infer HIV incidence and survival in rural KwaZulu-Natal between 2003 and 2011, a period when antiretroviral treatment (ART) was rolled out on a large scale. Catalytic mathematical model for estimating HIV incidence and differential survival in HIV-infected persons on multiple rounds of HIV sero-prevalence. We evaluate trends of HIV incidence and survival by estimating parameters separately for women and men aged 15-49 years during three calendar periods (2003-05, 2006-08, 2009-2011) reflecting increasing ART coverage. We compare model-based estimates of HIV incidence with observed cohort-based estimates from the longitudinal HIV surveillance. Median survival after HIV infection increased significantly between 2003-2005 and 2009-2011 from 10.0 (95% confidence interval (CI) 8.8-11.2) to 14.2 (95% CI 12.6-15.8) years in women (p < 0.001) and from 10.0 (95% CI 9.2-10.8) to 14.0 (95% CI 10.6-17.4) years in men (p = 0.02). Our model suggests no statistically significant reduction of HIV incidence in the age-group 15-49 in 2009-2011 compared to 2003-2005. Age- and sex-specific model-based HIV incidence estimates were in good agreement with observed cohort-based estimates from the ongoing HIV surveillance. Our catalytic modelling approach using cross-sectional age-specific HIV prevalence data could be useful to monitor trends of HIV incidence and survival in other African settings with a high ART coverage. 23844030 Exocyst sec5 regulates exocytosis of newcomer insulin granules underlying biphasic insulin secretion. The exocyst complex subunit Sec5 is a downstream effector of RalA-GTPase which promotes RalA-exocyst interactions and exocyst assembly, serving to tether secretory granules to docking sites on the plasma membrane. We recently reported that RalA regulates biphasic insulin secretion in pancreatic islet β cells in part by tethering insulin secretory granules to Ca(2+) channels to assist excitosome assembly. Here, we assessed β cell exocytosis by patch clamp membrane capacitance measurement and total internal reflection fluorescence microscopy to investigate the role of Sec5 in regulating insulin secretion. Sec5 is present in human and rodent islet β cells, localized to insulin granules. Sec5 protein depletion in rat INS-1 cells inhibited depolarization-induced release of primed insulin granules from both readily-releasable pool and mobilization from the reserve pool. This reduction in insulin exocytosis was attributed mainly to reduction in recruitment and exocytosis of newcomer insulin granules that undergo minimal docking time at the plasma membrane, but which encompassed a larger portion of biphasic glucose stimulated insulin secretion. Sec5 protein knockdown had little effect on predocked granules, unless vigorously stimulated by KCl depolarization. Taken together, newcomer insulin granules in β cells are more sensitive than predocked granules to Sec5 regulation. 23880760 Regulation of hypoxia-iinducible factor 1α (HIF-1α) by lysophosphatidic acid is dependent on interplay between p53 and Kruppel-like factor 5. Hypoxia-inducible factor 1α (HIF-1α) and p53 are pivotal regulators of tumor growth. Lysophosphatidic acid (LPA) is a lipid mediator that functions as a mitogen by acting through LPA receptors. We have previously shown that LPA stimulates HIF-1α expression in colon cancer cells. To determine the mechanism of HIF-1α induction by LPA, we compared the effect of LPA on HIF-1α in several colon cancer cell lines. LPA transcriptionally induced HIF-1α in colon cancer cells. HIF-1α induction was observed in cells expressing WT p53, where LPA decreased p53 expression. However, LPA failed to induce HIF-1α when the p53 gene is mutated. A decrease in p53 expression was dependent on induction of p53-specific E3 ubiquitin ligase Mdm2 by LPA. Kruppel-like factor 5 (KLF5) is an effector of LPA-induced proliferation of colon cancer cells. Because HIF-1α was necessary for LPA-induced growth of colon cancer cells, we determined the relationship between KLF5 and HIF-1α by a loss of function approach. Silencing of KLF5 inhibited LPA-induced HIF-1α induction, suggesting that KLF5 is an upstream regulator of HIF-1α. KLF5 and p53 binding to the Hif1α promoter was assessed by ChIP assay. LPA increased the occupancy of the Hif1α promoter by KLF5, while decreasing p53 binding. Transfection of HCT116 cells with KLF5 or p53 attenuated binding of the other transcription factor. These results identify KLF5 as a transactivator HIF-1α, and show that LPA regulates HIF-1α by dynamically modulating interaction with KLF5 and p53. 23956319 Gerontology and Geriatrics in Dutch medical education. Background: The world population is ageing and healthcare services require trained staff who can address the needs of older patients. In this study we determined how current medical education prepares Dutch students of medicine in the field of Gerontology and Geriatrics (G&G). Methods: Using a checklist of the essentials of G&G, we assessed Dutch medical education on three levels. On the national level we analysed the latest National Blueprint for higher medical education (Raamplan artsopleiding 2009). On the faculty level we reviewed medical curricula on the basis of interviews with program directors and inspection of course materials. On the student level we assessed the topics addressed in the questions of the cross-institutional progress test (CIPT). Results: The Nat ional Bluepr int contains few specific G&G objectives. Obligatory G&G courses in medical schools on average amount to 2.2% of the total curriculum measured as European Credit Transfer System units (ECTS). Only two out of eight medical schools have practical training during the Master phase in the form of a clerkship in G&G. In the CIPT, on average 1.5% of questions cover G&G. Conclusion: Geriatric education in the Netherlands does not seem to be in line with current demographic trends. The National Blueprint falls short of providing sufficiently detailed objectives for education on the care of older people. The geriatric content offered by medical schools is varied and incomplete, and students are only marginally tested on their knowledge of G&G in the CIPT. 23963334 Intensity of Anticoagulation and Clinical Outcomes in Acute Cardioembolic Stroke: The Fukuoka Stroke Registry. The relationship between the intensity of anticoagulation at the onset of acute cardioembolic stroke and clinical outcome after stroke is unclear. Here, we elucidated the relationship between prothrombin time-international normalized ratio (PT-INR) values on admission and clinical outcomes in patients with acute cardioembolic stroke. A total of 602 patients from the Fukuoka Stroke Registry in Japan who had been treated with warfarin but developed cardioembolic stroke were enrolled. The patients were classified into 3 groups according to their PT-INR values on admission: PT-INR <1.50, 411 patients; PT-INR 1.50 to 1.99, 146 patients; and PT-INR ≥2.00, 45 patients. The associations between PT-INR categories and severe neurological deficits (National Institutes of Health Stroke Scale ≥10) on admission and poor functional outcome (modified Rankin scale 4-6) at discharge were investigated using a logistic regression analysis. Neurological deficits on admission were less severe, and functional outcome at discharge was more favorable as the PT-INR level on admission increased. The multivariate analysis revealed that severe neurological deficits were inversely associated with PT-INR on admission (PT-INR 1.50-1.99: odds ratio, 0.66; 95% confidence interval, 0.43-1.00; PT-INR ≥2.00: odds ratio, 0.41; 95% confidence interval, 0.20-0.83; compared with a reference group of PT-INR <1.50). Poor functional outcome was less likely in patients with PT-INR ≥2.00 (odds ratio, 0.20; 95% confidence interval, 0.06-0.55) after adjustment for confounders. Prestroke PT-INR ≥2.0 is associated with favorable clinical outcomes after acute cardioembolic stroke. 23834510 Somatotype, training and performance in Ironman athletes. Abstract The aim of this study was to describe the physiques of Ironman athletes and the relationship between Ironman's performance, training and somatotype. A total of 165 male and 22 female competitors of the Ironman Switzerland volunteered in this study. Ten anthropometric dimensions were measured, and 12 training and history variables were recorded with a questionnaire. The variables were compared with the race performance. The somatotype was a strong predictor of Ironman performance (R=0.535; R (2) =0.286; sign. p<0.001) in male athletes. The endomorphy component was the most substantial predictor. Reductions in endomorphy by one standard deviation as well as an increased ectomorphy value by one standard deviation lead to significant and substantial improvement in Ironman performance (28.1 and 29.8 minutes, respectively). An ideal somatotype of 1.7-4.9-2.8 could be established. Age and quantitative training effort were not significant predictors on Ironman performance. In female athletes, no relationship between somatotype, training and performance was found. The somatotype of a male athlete defines for 28.6% variance in Ironman performance. Athletes not having an ideal somatotype of 1.7-4.9-2.8 could improve their performance by altering their somatotype. Lower rates in endomorphy, as well as higher rates in ectomorphy, resulted in a significant better race performance. The impact of somatotype was the most distinguished on the run discipline and had a much greater impact on the total race time than the quantitative training effort. These findings could not be found in female athletes. 23751334 Modelling nitrogen leaching from sewage sludge application to arable land in the Lombardy region (northern Italy). Sewage sludge can be used as fertiliser, offering the possibility of safely recycling this waste product as a resource in agricultural applications. As the environmental concerns related to waste recycling in agricultural applications are well-known, restrictions on the use of sewage sludge have been implemented by the EU and local authorities. This work aimed to evaluate the nitrogen leaching associated with the application of sludge and the effectiveness of the temporal restrictions on its application implemented to safeguard the environment in the Lombardy region of northern Italy (120days in Nitrate Vulnerable Zones and 90days elsewhere) using the CropSyst model which was first validated. The effects of fertilisation using four different sludge types on N leaching were simulated at five sites under cultivation with maize and rice crops; six different timing schemes for sludge application were tested, three of which involved dates that were in agreement (AT) with the regulation, while the other three were not in agreement (NAT). We detected a significant effect of the sludge type and application timing, whereas the effect of their interaction was never significant. The mean annual leaching was 22 to 154kgNha(-1). The higher the ammonium N content in the sludge was, the greater the potential for N leaching was found to be. For the maize crop, the distribution of sludge in the late fall period resulted in significantly greater N leaching (61kgNha(-1)) and led to lower yields (9t DMha(-1)) compared to late winter fertilisation (49kgNha(-1); 10t DMha(-1)), whereas no differences in N leaching or yield were detected between AT and NAT, which was also observed for the rice crop. Therefore, the applied temporal constraints did not always appear to be advantageous for protecting the environment from leaching. 23861030 ZincExplorer: an accurate hybrid method to improve the prediction of zinc-binding sites from protein sequences. As one of the most important trace elements within an organism, zinc has been shown to be involved in numerous biological processes and closely implicated in various diseases. The zinc ion is important for proteins to perform their functional roles. To provide in-depth functional annotation of zinc-binding proteins, an initial but crucial step is the accurate recognition of zinc-binding sites. Motivated by the biological importance of zinc, we propose a new method called ZincExplorer to predict zinc-binding sites from protein sequences. ZincExplorer is a hybrid method that can accurately predict zinc-binding sites from protein sequences. It integrates the outputs of three different types of predictors, namely, SVM-, cluster- and template-based predictors. Four types of zinc-binding amino acids CHEDs (i.e. CYS, HIS, ASP and GLU) could be predicted using ZincExplorer. It achieved a high AURPC (Area Under Recall-Precision Curve) of 0.851, and a precision of 85.6% (specificity = 98.4%, MCC = 0.747) at the 70.0% recall for the CHEDs on the 5-fold cross-validation test. When tested on an independent dataset containing 2023 zinc-binding CHEDs and 14 493 non-zinc-binding CHEDs, it achieved about 3-8% higher AURPC in comparison to two other sequence-based predictors. Moreover, ZincExplorer could also identify the interdependent relationships (IRs) of the predicted zinc-binding sites bound to the same zinc ion, which makes it a useful tool for providing in-depth zinc-binding site annotation. 23519952 Multisite quantitative ultrasound for the prediction of fractures over five years of follow-up: The Canadian Multicentre Osteoporosis Study. This study assessed the ability of multisite quantitative ultrasound (mQUS) to predict fracture over a five-year follow-up. Participants were a subset of the Canadian Multicentre Osteoporosis Study. mQUS-assessed speed of sound (SOS in m/s) at three sites (distal radius, tibia and phalanx) and extensive questionnaires were completed, after which participants were followed for five years and incident fractures recorded. Two survival analyses were completed for each site - a univariate analysis and an adjusted multivariate analysis controlling for age, anti-resorptive use, femoral neck bone mineral density, number of diseases, previous fractures, BMI, parental history of hip fracture, current smoking, current alcoholic drinks >3 per day, current using glucocorticoids, and rheumatoid arthritis diagnosis (variables from the FRAX 10-year fracture risk assessment tool). The unit of change for regression analyses was one standard deviation for all measurement sites, specific to site and sex. Separate analyses were completed for all clinical fractures, non-vertebral fractures and hip fractures by sex. There were 2633 women and 1108 men included and they experienced 204 incident fractures over five years (5.5% fractured). Univariate models revealed statistically significant (p < 0.05) predictive ability of mQUS for all three measurement sites for women alone for all three fracture types (one standard deviation decrease in SOS was associated with a 52-130% increase in the risk of fracture), but not for the men's group. The adjusted model found that measures at the distal radius and tibia in the women's group could significantly (p < 0.05) predict all clinical fractures and non-vertebral fractures within the next five years (one standard deviation decrease in SOS was associated with a 25-31% increase in the risk of fracture). mQUS provided significant five-year clinical fracture prediction in women, independent of bone mineral density and other significant risk factors for fracture, when measured at the distal radius and tibia sites. © 2013 American Society for Bone and Mineral Research. 23763301 Matrix metalloproteinase, hyaluronidase and elastase inhibitory potential of standardized extract of Centella asiatica. Abstract Context: Centella asiatica (L.) Urban (Apiaceae), a valuable herb described in Ayurveda, is used in the indigenous system of medicine as a tonic to treat skin diseases. Objective: Centella asiatica methanol extract and its ethyl acetate, n-butanol and aqueous fraction, were subjected for the evaluation of skin care potential through the in vitro hyaluronidase, elastase and matrix metalloproteinase-1 (MMP-1) inhibitory assay. Materials and methods: The C. asiatica plant was extracted with methanol and fractionated with ethyl acetate, n-butanol and water. The enzymatic activities were evaluated using ursolic acid and oleanolic acid as standards. Isolate molecule asiaticoside was quantified in the crude extract and fractions through high-performance liquid chromatography (HPLC) and structural was characterized by liquid chromatography-mass spectroscopy (LC-MS) and (1)H nuclear magnetic resonance (NMR). Isolated compound was also evaluated for in vitro enzyme assays. Results: Extract exhibited anti-hyaluronidase and anti-elastase activity with IC50 of 19.27 ± 0.37 and 14.54 ± 0.39 µg/mL, respectively, as compared to ursolic acid. Centella asiatica n-butanol fraction (CAnB) and isolated compound showed significant hyaluronidase (IC50 = 27.00 ± 0.43 and 18.63 ± 0.33 µg/mL) and elastase (IC50 = 29.15 ± 0.31 and 19.45 ± 0.25 µg/mL) inhibitory activities, respectively, and also showed significant MMP-1 inhibition (p < 0.05 and p < 0.01). Discussion and conclusion: n-Butanol fraction was found to be most effective among the all fractions from which asiaticoside was isolated and further quantified by HPLC. This work concludes that the asiaticoside from C. asiatica may be a prospective agent for skin care. 23922795 Hinged plakin domains provide specialized degrees of articulation in envoplakin, periplakin and desmoplakin. Envoplakin, periplakin and desmoplakin are cytoskeletal proteins that provide structural integrity within the skin and heart by resisting shear forces. Here we reveal the nature of unique hinges within their plakin domains that provides divergent degrees of flexibility between rigid long and short arms composed of spectrin repeats. The range of mobility of the two arms about the hinge is revealed by applying the ensemble optimization method to small-angle X-ray scattering data. Envoplakin and periplakin adopt 'L' shaped conformations exhibiting a 'helicopter propeller'-like mobility about the hinge. By contrast desmoplakin exhibits essentially unrestricted mobility by 'jack-knifing' about the hinge. Thus the diversity of molecular jointing that can occur about plakin hinges includes 'L' shaped bends, 'U' turns and fully extended 'I' orientations between rigid blocks of spectrin repeats. This establishes specialised hinges in plakin domains as a key source of flexibility that may allow sweeping of cellular spaces during assembly of cellular structures and could impart adaptability, so preventing irreversible damage to desmosomes and the cell cytoskeleton upon exposure to mechanical stress. 23877302 DNA unmethylome profiling by covalent capture of CpG sites. Dynamic patterns of cytosine-5 methylation and successive hydroxylation are part of epigenetic regulation in eukaryotes, including humans, which contributes to normal phenotypic variation and disease risk. Here we present an approach for the mapping of unmodified regions of the genome, which we call the unmethylome. Our technique is based on DNA methyltransferase-directed transfer of activated groups and covalent biotin tagging of unmodified CpG sites followed by affinity enrichment and interrogation on tiling microarrays or next generation sequencing. Control experiments and pilot studies of human genomic DNA from cultured cells and tissues demonstrate that, along with providing a unique cross-section through the chemical landscape of the epigenome, the methyltransferase-directed transfer of activated groups-based approach offers high precision and robustness as compared with existing affinity-based techniques. 23624628 Aortic pulse wave velocity and reflecting distance estimation from peripheral waveforms in humans: detection of age- and exercise training-related differences. We hypothesized that demographic/anthropometric parameters can be used to estimate effective reflecting distance (EfRD), required to derive aortic pulse wave velocity (APWV), a prognostic marker of cardiovascular risk, from peripheral waveforms and that such estimates can discriminate differences in APWV and EfRD with aging and habitual endurance exercise in healthy adults. Ascending aortic pressure waveforms were derived from peripheral waveforms (brachial artery pressure, n = 25; and finger volume pulse, n = 15) via a transfer function and then used to determine the time delay between forward- and backward-traveling waves (Δtf-b). True EfRDs were computed as directly measured carotid-femoral pulse wave velocity (CFPWV) × 1/2Δtf-b and then used in regression analysis to establish an equation for EfRD based on demographic/anthropometric data (EfRD = 0.173·age + 0.661·BMI + 34.548 cm, where BMI is body mass index). We found good agreement between true and estimated APWV (Pearson's R² = 0.43; intraclass correlation = 0.64; both P < 0.05) and EfRD (R² = 0.24; intraclass correlation = 0.40; both P < 0.05). In young sedentary (22 ± 2 years, n = 6), older sedentary (62 ± 1 years, n = 24), and older endurance-trained (61 ± 2 years, n = 14) subjects, EfRD (from demographic/anthropometric parameters), APWV, and 1/2Δtf-b (from brachial artery pressure waveforms) were 52.0 ± 0.5, 61.8 ± 0.4, and 60.6 ± 0.5 cm; 6.4 ± 0.3, 9.6 ± 0.2, and 8.1 ± 0.2 m/s; and 82 ± 3, 65 ± 1 and 76 ± 2 ms (all P < 0.05), respectively. Our results demonstrate that APWV derived from peripheral waveforms using age and BMI to estimate EfRD correlates with CFPWV in healthy adults. This method can reliably detect the distal shift of the reflecting site with age and the increase in APWV with sedentary aging that is attenuated with habitual endurance exercise. 23756461 Direct interaction of FtsZ and MreB is required for septum synthesis and cell division in Escherichia coli. How bacteria coordinate cell growth with division is not well understood. Bacterial cell elongation is controlled by actin-MreB while cell division is governed by tubulin-FtsZ. A ring-like structure containing FtsZ (the Z ring) at mid-cell attracts other cell division proteins to form the divisome, an essential protein assembly required for septum synthesis and cell separation. The Z ring exists at mid-cell during a major part of the cell cycle without contracting. Here, we show that MreB and FtsZ of Escherichia coli interact directly and that this interaction is required for Z ring contraction. We further show that the MreB-FtsZ interaction is required for transfer of cell-wall biosynthetic enzymes from the lateral to the mature divisome, allowing cells to synthesise the septum. Our observations show that bacterial cell division is coupled to cell elongation via a direct and essential interaction between FtsZ and MreB. 23873662 A Methyl Methacrylate-HEMA-CLn Copolymerization Investigation: From Kinetics to Bioapplications. The radical copolymerization kinetics of methyl methacrylate (MMA) and poly-ϵ-caprolactone macromonomer functionalized with a vinyl end group (HEMA-CLn ) is studied using a pulsed-laser technique. The reactivity ratios for this system are near unity, while a linear relationship between kp ,cop , the copolymer-averaged propagation rate coefficient, and the composition of macromonomer in the feed (0-80 wt% range) is determined. At 50 wt% macromonomer in the feed, a 1.67 ± 0.02 and 1.64 ± 0.06 increase in kp,cop /kp,MMA is determined for HEMA-CL3 and HEMA-CL2 , respectively. These macromonomers are adopted to synthesize nanoparticles (NPs) in the range of 100-150 nm through batch emulsion free radical polymerization (BEP) to produce partially degradable drug delivery carriers. The produced NPs are tested in 4T1 cell line and show excellent characteristics as carriers: they do not affect cell proliferation, and a relevant number of NPs, thousands per cell, are internalized. 23416261 Modulation of melanogenesis and antioxidant defense system in melanocytes by amikacin. Amikacin is principally used to treat infections caused by microorganisms resistant to other aminoglycosides. Ototoxicity is one of the side effects of amikacin, but the causative mechanism of damage to the ear has not been fully established. Thus, the aim of this work was to examine the impact of amikacin on the melanogenesis and antioxidant defense system in cultured human normal melanocytes (HEMa-LP). Amikacin induced the concentration - dependent loss in melanocytes viability. The value of EC50 was determined to be ~7.5 mM. The analyzed antibiotic inhibited melanin biosynthesis in concentration-dependent manner. Increasing the amikacin concentration also resulted in a decrease in cellular tyrosinase activity. To study the antioxidant defense system in melanocytes, the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) in cells exposed to amikacin were determined. Significant changes in cellular antioxidant enzymes activities were observed. Modulation of melanogenesis and the antioxidant status of melanocytes resulting from the use of amikacin in vitro may explain a potential role of melanin and melanocytes in the mechanisms of aminoglycosides ototoxic effects in vivo. 23968866 Prognostic value of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 blood levels in breast cancer. High circulating insulin-like growth factor 1 (IGF-1) levels are firmly established as a risk factor for developing breast cancer, especially estrogen positive tumors. The effect of circulating IGF-1 on prognosis once a tumor is established is unknown. The authors explored the effect of IGF-1 blood levels and of it's main binding protein, IGFBP-3, on overall survival and occurrence of second primary breast tumors in breast cancer patients, as well as reproductive and lifestyle factors that could modify this risk. Patients were accrued from six hospitals in the Netherlands between 1998 and 2003. Total IGF-1 and IGFBP-3 were measured in 582 plasma samples. No significant association between IGF-1 and IGFBP-3 plasma levels and overall survival was found. However, in a multivariate Cox regression model including standard prognostic variables high IGF-1 levels were related to worse overall survival in patients receiving endocrine therapy (HR = 1.37, 95% CI: 1.11, 1.69, P 0.004). These data at least indicate that higher IGF-1 levels, and as a consequence most likely IGF-1-induced signaling, are related to a less favorable overall survival in breast cancer patients treated with endocrine therapy. Interventions aimed at reducing circulating levels of IGF-1 in hormone receptor positive breast cancer may improve survival. 23883137 The effectiveness of individual placement and support for people with mental illness new on social benefits: a study protocol. In Switzerland, people with a severe mental illness and unable to work receive disability benefits ('IV-pension'). Once they are granted these benefits, the chances to regain competitive employment are usually small. However, previous studies have shown that individual placement and support (IPS) supports a successful reintegration into competitive employment. This study focuses on the integration of newly appointed IV-pensioners, who have received an IV-pension for less than a year. The present pilot project ZHEPP (Zürcher Eingliederungs-Pilot Projekt; engl.: Zurich integration pilot project) is a randomized controlled trial (RCT). The 250 participants will be randomized to either the intervention or the control group. The intervention group receives support of a job coach according to the approach of IPS. Participants in the control group do not receive IPS support. Participation takes a total of two years for each participant. Each group is interviewed every six months (T0-T4). A two-factor analysis of variance will be conducted with the two factors group (intervention versus control group) and outcome (employment yes/no). The main criterion of the two-factor analysis will be the number of competitive employment contracts in each group. This study will focus on the impact of IPS on new IV-pensioners and aims to identify predictors for a successful integration. Furthermore, we will examine the effect of IPS on stigma variables and recovery orientation. ISRCTN54951166. 22431306 Differential roles of right temporal cortex and broca's area in pitch processing: Evidence from music and mandarin. Superior temporal and inferior frontal cortices are involved in the processing of pitch information in the domain of language and music. Here, we used fMRI to test the particular roles of these brain regions in the neural implementation of pitch in music and in tone language (Mandarin) with a group of Mandarin speaking musicians whose pertaining experiences in pitch are similar across domains. Our findings demonstrate that the neural network for pitch processing includes the pars triangularis of Broca's area and the right superior temporal gyrus (STG) across domains. Within this network, pitch sensitive activation in Broca's area is tightly linked to the behavioral performance of pitch congruity judgment, thereby reflecting controlled processes. Activation in the right STG is independent of performance and more sensitive to pitch congruity in music than in tone language, suggesting a domain-specific modulation of the perceptual processes. These observations provide a first glimpse at the cortical pitch processing network shared across domains. Hum Brain Mapp 34:2045-2054, 2013. © 2012 Wiley Periodicals, Inc. 23463624 A randomized phase II study comparing capecitabine alone with capecitabine and oral cyclophosphamide in patients with advanced breast cancer-cyclox II. Capecitabine and cyclophosphamide are active in patients with advanced breast cancer, have non-overlapping toxic effects and synergy pre-clinically. We explored the efficacy and toxic effect of an all-oral combination of capecitabine with cyclophosphamide versus capecitabine alone in a multicentre, randomized, phase II study. Patients with locally advanced or metastatic breast cancer were randomized to treatment with capecitabine given continuously (666 mg/m(2) b.i.d. days 1-28) alone (C) or with oral cyclophosphamide (100 mg/m(2) days 1-14 of a 28-day cycle) (CCy) for up to six cycles. Eighty-two patients were randomized. There was no complete response. The proportions with partial response were 36% on C and 44% on CCy, a difference of 7.9% [95% confidence interval (CI) -13.4 to 29.1]. Significant toxic effect was uncommon: grade ≥3 diarrhoea in 4 (10%) versus 1 (3%) patients; grade ≥3 fatigue in 2 (5%) versus 5 patients (13%) and grade ≥2 hand-foot syndrome in 7 (17%) versus 11 (28%) patients receiving C versus CCy, respectively. Median progression-free survival was 3.1 months on C and 6.9 months on CCy, not significantly different statistically. There was no difference in overall survival. The difference in tumour response suggests a reasonable chance that CCy is superior to C alone. 23905832 Chronic rhinosinusitis in children. Chronic rhinosinusitis (CRS) affects nearly 37 million people in the United States each year and accounts for approximately $6 billion in direct and indirect health care costs. Despite its prevalence and significant impact, little is known about its exact cause and pathophysiology, and significant controversy remains regarding appropriate treatment options. Basic science research, however, has shown recent promise toward improving understanding of the innate and environmental factors underlying the pathophysiology of CRS. The hope is that this will also lead to advances in treatment for children adversely affected by this common yet complicated disease. 23552393 Understanding sample size determination in nursing research. Sample size determination is a natural consideration in the planning stages of most research studies. The purpose of this work is to provide an overview of modern methods of sample size determination and describe some of the challenges to be aware of and pitfalls to avoid in applying these various methods. Although sample size can be determined in many ways, the most commonly used approach has relied on classical hypothesis-based methods of power analysis. Several challenges often arise with traditional power analysis. For example, the statistical methods used in a power analysis may not adequately address the complexities of the data collected in a research study. The American Psychological Association currently accepts and endorses the use of two methods, power analysis and precision estimation, for sample size determination. Precision estimation is a viable alternative to the traditional power analysis approach. Recommendations for deciding on an approach are provided. 23732482 Benzo(a)pyrene modulates fluoranthene-induced cellular responses in HT-29 colon cells in a dual exposure system. Our environment is contaminated with a diverse array of chemicals; one of which is polycyclic aromatic hydrocarbons (PAHs). While some PAHs are potent by nature, others undergo interactions such as additivity, synergism, antagonism or potentiation to manifest their toxicity. Therefore, the objective of this study was to investigate whether exposure to benzo(a)pyrene (BaP), a PAH compound influences the cytotoxicity and metabolism of fluoranthene (FLA; another PAH compound) using HT-29 cells. Cells cultured in Dulbecco's Modified Eagle Medium were treated with 1, 5, 10, 25μM BaP and FLA (0.01% dimethylsulfoxide as vehicle) individually and in combination over the course of 0-96h. At the end of exposure, cells were stained with propidium iodide and the changes in cell cycle were analyzed using FACS analysis. Apoptosis was determined by caspase-3 assay. Post-incubation, samples were extracted and analyzed for FLA metabolites by reverse-phase HPLC with fluorescence detection. Cells exposed to BaP+FLA showed a marginal decrease in growth as compared to FLA alone and vehicle controls. Also, a decline in the percentage of cells in the S and G2 phases compared to G1 phase of cell cycle was noted when cells were treated with BaP and FLA together, compared to individual FLA treatment. The rate of FLA metabolism was more when cells were exposed to FLA in combination with BaP, compared to FLA alone. The enhanced biotransformation of FLA as a result of concomitant exposure to BaP may have implications for colon cancer risks arising from human dietary exposure to PAH mixtures through consumption of barbecued meat. 23950896 Chemoprevention of Skin Cancer with 1,1-Bis (3'-Indolyl)-1-(Aromatic) Methane Analog through Induction of the Orphan Nuclear Receptor, NR4A2 (Nurr1). The objective of this study was to demonstrate the anti-skin cancer and chemopreventive potential of 1,1-bis(3'-indolyl)-1-(p-chlorophenyl methane) (DIM-D) using an in vitro model. In vitro cell cytotoxicity and viability assays were carried out in A431 human epidermoid carcinoma cell line and normal human epidermal keratinocytes (NHEK) respectively by crystal violet staining. Apoptosis induction in A431 cells (DIM-D treated) and NHEK cells pretreated with DIM-D (2 hr) prior to UVB irradiation, were assessed. The accumulation of reactive oxygen species (ROS) in DIM-D pretreated NHEK cells (2 hr) prior to UVB exposure was also determined. Immunocytochemistry and western blot analysis was performed to determine cleaved caspase 3 and DNA damage markers in DIM-D treated A431 cells and in DIM-D pretreated NHEK cells prior to UVB irradiation. The IC50 values of DIM-D were 68.7±7.3, 48.3±10.1 and 11.5±3.1 μM whilst for Epigallocatechin gallate (EGCG) were 419.1±8.3, 186.1±5.2 and 56.7±3.1 μM for 24, 48 and 72 hr treatments respectively. DIM-D exhibited a significantly (p<0.05) greater induction of DNA fragmentation in A431 cells compared to EGCG with percent cell death of 38.9. In addition, DIM-D induced higher expression in A431 cells compared to EGCG of cleaved caspase 3 (3.0-fold vs. 2.4-fold changes), Nurr1 (2.7-fold vs. 1.7-fold changes) and NFκB (1.3-fold vs. 1.1-fold changes). DIM-D also exhibited chemopreventive activity in UVB-irradiated NHEK cells by significantly (p<0.05) reducing UVB-induced ROS formation and apoptosis compared to EGCG. Additionally, DIM-D induced expression of Nurr1 but reduced expression of 8-OHdG significantly in UVB-irradiated NHEK cells compared to EGCG and UV only. Our results suggest that DIM-D exhibits Nurr1-dependent transactivation in the induction of apoptosis in A431 cells and it protects NHEK cells against UVB-induced ROS formation and DNA damage. 23681491 Neurovascular function and sudorimetry in health and disease. In this review of thermoregulatory function in health and disease, we review the basic mechanisms controlling skin blood flow of the hairy and glabrous skin and illustrate the major differences in blood flow to glabrous skin, which is, in essence, sympathetically mediated, while hairy skin is dependent upon neuropeptidergic signals, nitric oxide, and prostaglandin, among others. Laser Doppler methods of quantification of blood flow--in response to iontophoresis of acetylcholine or heat--and nociceptor-mediated blood flow have relatively uniformly demonstrated an impaired capacity to increase blood flow to the skin in diabetes and in its forerunners, prediabetes and the metabolic syndrome. This reduced capacity is likely to be a significant contributor to the development of foot ulcerations and amputations in diabetes, and means of increasing blood flow are clearly needed. Understanding the pathogenic mechanisms is likely to provide a means of identifying a valuable therapeutic target. Thermoregulatory control of sweating is intimately linked to the autonomic nervous system via sympathetic C fibers, and sweat glands are richly endowed with a neuropeptidergic innervation. Sweating disturbances are prevalent in diabetes and its precursors, and quantification of sweating may be useful as an index of diagnosis of somatic and, probably, autonomic dysfunction. Moreover, quantifying this disturbance in sweating by various methods may be useful in identifying the risk of progression from prediabetes to diabetes, as well as responses to therapeutic intervention. We now have the technological power to take advantage of this physiological arrangement to better understand, monitor, and treat disorders of small nerve fibers and the somatic and autonomic nervous system (ANS). Newer methods of sudomotor function testing are rapid, noninvasive, not technically demanding, and accessible to the outpatient clinic. Whether the potential applications are screening for diabetes, following poorly controlled diabetes subjects during alteration of their treatment regimen, or simply monitoring somatic and autonomic function throughout the course of treatment, sudorimetry can be an invaluable tool for today's clinicians. 23673158 Effects of intraportal exenatide on hepatic glucose metabolism in the conscious dog. Incretins improve glucose metabolism through multiple mechanisms. It remains unclear whether direct hepatic effects are an important part of exenatide's (Ex-4) acute action. Therefore, the objective of this study was to determine the effect of intraportal delivery of Ex-4 on hepatic glucose production and uptake. Fasted conscious dogs were studied during a hyperglycemic clamp in which glucose was infused into the hepatic portal vein. At the same time, portal saline (control; n = 8) or exenatide was infused at low (0.3 pmol·kg⁻¹·min⁻¹, Ex-4-low; n = 5) or high (0.9 pmol·kg⁻¹·min⁻¹, Ex-4-high; n = 8) rates. Arterial plasma glucose levels were maintained at 160 mg/dl during the experimental period. This required a greater rate of glucose infusion in the Ex-4-high group (1.5 ± 0.4, 2.0 ± 0.7, and 3.7 ± 0.7 mg·kg⁻¹·min⁻¹ between 30 and 240 min in the control, Ex-4-low, and Ex-4-high groups, respectively). Plasma insulin levels were elevated by Ex-4 (arterial: 4,745 ± 428, 5,710 ± 355, and 7,262 ± 1,053 μU/ml; hepatic sinusoidal: 14,679 ± 1,700, 15,341 ± 2,208, and 20,445 ± 4,020 μU/ml, 240 min, area under the curve), whereas the suppression of glucagon was nearly maximal in all groups. Although glucose utilization was greater during Ex-4 infusion (5.92 ± 0.53, 6.41 ± 0.57, and 8.12 ± 0.54 mg·kg⁻¹·min⁻¹), when indices of hepatic, muscle, and whole body glucose uptake were expressed relative to circulating insulin concentrations, there was no indication of insulin-independent effects of Ex-4. Thus, this study does not support the notion that Ex-4 generates acute changes in hepatic glucose metabolism through direct effects on the liver. 23561159 Distribution of carotenoids in endosperm, germ, and aleurone fractions of cereal grain kernels. To compare the distribution of carotenoids across the grain, non-corn and corn cereals were hand dissected into endosperm, germ and aleurone fractions. Total carotenoid content (TCC) and carotenoid composition were analysed using spectrophotometry and HPLC. Cereal carotenoid composition was similar; however, concentrations varied significantly (p<0.05). Endosperm fractions had TCC ranging from 0.88 to 2.27 and 14.17 to 31.35mg/kg in non-corn cereals and corn, respectively. TCC, lutein and zeaxanthin in germ fractions were higher in non-corn cereals than in corn. Lutein and zeaxanthin contents were lower in non-corn cereal endosperms. The aleurone layer had zeaxanthin levels 2- to 5-fold higher than lutein among the cereals. Positive significant correlations (p<0.05) were found between TCC, carotenoids analysed by HPLC and DPPH results. This study is the first to report on carotenoid composition of the aleurone layer. Our findings suggest that the aleurone of wheat, oat, corn and germ of barley have significantly enhanced carotenoid levels. 23439872 Strain-dependent dysregulation of one-carbon metabolism in male mice is associated with choline- and folate-deficient diet-induced liver injury. Dysregulation of one-carbon metabolism-related metabolic processes is a major contributor to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). It is well established that genetic and gender-specific variations in one-carbon metabolism contribute to the vulnerability to NAFLD in humans. To examine the role of one-carbon metabolism dysregulation in the pathogenesis and individual susceptibility to NAFLD, we used a "population-based" mouse model where male mice from 7 inbred were fed a choline- and folate-deficient (CFD) diet for 12 wk. Strain-dependent down-regulation of several key one-carbon metabolism genes, including methionine adenosyltransferase 1α (Mat1a), cystathionine-β-synthase (Cbs), methylenetetrahydrofolate reductase (Mthfr), adenosyl-homocysteinase (Ahcy), and methylenetetrahydrofolate dehydrogenase 1 (Mthfd1), was observed. These changes were strongly associated with interstrain variability in liver injury (steatosis, necrosis, inflammation, and activation of fibrogenesis) and hyperhomocysteinemia. Mechanistically, the decreased expression of Mat1a, Ahcy, and Mthfd1 was linked to a reduced level and promoter binding of transcription factor CCAAT/enhancer binding protein β (CEBPβ), which directly regulates their transcription. The strain specificity of diet-induced dysregulation of one-carbon metabolism suggests that interstrain variation in the regulation of one-carbon metabolism may contribute to the differential vulnerability to NFLD and that correcting the imbalance may be considered as preventive and treatment strategies for NAFLD.-Pogribny, I. P., Kutanzi, K., Melnyk, S., de Conti, A., Tryndyak, V., Montgomery, B., Pogribna, M., Muskhelishvili, L., Latendresse, J. R., James, S. J., Beland, F. A., Rusyn, I. Strain-dependent dysregulation of one-carbon metabolism in male mice is associated with choline- and folate-deficient diet-induced liver injury. 23927281 Effective protein-protein interaction from structure factor data of a lysozyme solution. We report the determination of an effective protein-protein central potential for a lysozyme solution, obtained from the direct inversion of the total structure factor of the system, as extracted from small angle neutron scattering. The inversion scheme rests on a hypernetted-chain relationship between the effective potential and the structural functions, and is preliminarily tested for the case of a Lennard-Jones interaction. The characteristics of our potential are discussed in comparison with current models of effective interactions in complex fluids. The phase behavior predictions are also investigated. 23835518 Concurrent assessments of lower limb loading patterns, mechanical muscle strength and functional performance in ACL-patients - A cross-sectional study. Full recovery in muscle strength and functional performance may not be achieved after ACL-injury. Aim: The aim of this study is to investigate loading patterns during jumping, muscle function and functional performance in ACL-reconstructed patients and to investigate the origin of between-limb asymmetry by means of a 3-dimensional movement analysis. Design is cross-sectional. 23 ACL-reconstructed men (27.2±7.5years, BMI: 25.4±3.2) 27±7month post-surgery and 25 matched controls (27.2±5.4years, BMI: 24.1±1.8) were included. Participants performed (i) bilateral and (ii) unilateral counter movement jumps (CMJ). A 3-D movement analysis was performed by a six-camera Vicon MX-system. Subsequently, jump height (JH), knee joint range of motion (ROM), peak and mean sagittal knee moments were analyzed (iii) one-leg maximal jump for distance was performed, and (iv) maximal unilateral isometric knee extensor and flexor strength (MVC) were measured using stabilized dynamometry. No in-between group differences in age or BMI were observed. CMJ: Between-limb asymmetry ratios for ROM differed (p<0.01) between patients and controls in both types of CMJ (96.1% vs. 102.6% and 87.0% vs. 99.9% in bilateral and single-leg CMJs, respectively). Jump for distance: Patients demonstrated greater (p<0.01) asymmetry for jump length (92.9% vs. 98.6%). MVC: Asymmetry in hamstring MVC was greater (p<0.001) for patients than controls (77.4% vs. 101.3%). ACL-patients showed reduced function of the operated leg ~2years post ACL-reconstruction, especially for hamstring MVC. Hamstrings are important protagonists to the ACL, thus representing a potential risk factor for secondary ACL-rupture and/or osteoarthritis. 23305664 Neuroecology: a fly's bug detector. Drosophila avoid food contaminated by pathogenic bacteria and fungi using an olfactory pathway that is exquisitely tuned to a single microbial odour. 23963458 Loss of Tumor Suppressor PTEN Induces Leptin Mediated Leptin Gene Expression: A Feed-Forward Loop Operating in the Lung. Elevated levels of systemic and pulmonary leptin are associated with lung diseases and cancer. However, the roles and mechanisms of leptin gene expression in lung pathologies, including cancer remain elusive. Herein, using conditional deletion of tumor suppressor gene Pten (Phosphatase and tensin homologue) in the lung epithelium in vivo in transgenic mice and human PTEN-null lung epithelial cells, we identify leptin driven feed-forward signaling loop. Loss of Pten in the lung epithelial cells in vivo, activated adipokine signaling, and induced leptin synthesis as ascertained by mRNA profiling and pathway analysis. Transcription factors NRF-1, C/EBP-δ, and STAT3, mediated leptin gene transcription as revealed by leptin promoter deletions and mutations, chromatin immunoprecipitation (ChIP) and gain and loss of function studies in lung epithelial cells. Leptin treatment increased lung epithelial cell proliferation, and induced expression of leptin and leptin-receptor via PI3K/AKT/mTOR MEK/ERK and JAK2/STAT3 pathways. Expression of constitutively active MEK-1, AKT and STAT3 proteins increased, while treatment with MEK, PI3K, AKT and mTOR inhibitors decreased leptin gene expression, indicating that leptin in turn, further induced its own gene expression. Leptin mediated leptin/leptin-receptor gene expression, likely amplifies leptin signaling that may contribute to the pathogenesis and severity of lung diseases and cancer, resulting in poor clinical outcomes. Thus, targeted inhibition of the leptin mediated feed-forward loop provides a novel rationale for pharmacotherapy of disease associated with lung injury and remodeling, including lung cancer. 23913579 Challenges in pharmacologic management of the hospitalized patient with psychiatric comorbidity. Psychiatric comorbidity is common in the inpatient medical population. Hospitalists are frequently faced with decisions regarding the psychopharmacologic management of medically ill patients, yet receive limited psychiatric training. This review aims to assist the hospitalist in making an informed decision about the continuation of home psychotropic medications in the medically ill patient. A PubMed literature review was performed to obtain information on the effects of psychotropic medication discontinuation. In addition, the literature was reviewed regarding the potential challenges of psychotropic medication continuation. A growing number of studies demonstrate high rates of relapse when medications are discontinued in patients suffering from mood disorders, schizophrenia, and anxiety disorders. Abrupt cessation of psychotropics is especially dangerous, leading to a greater chance of destabilization. Discontinuation syndromes, with prominent physical symptoms, may also result from sudden psychotropic cessation. Conversely, continuing home psychotropic medication may cause adverse effects due to drug-drug interactions or changing pharmacokinetics. This review examines the risks of psychotropic discontinuation as well as the challenges of psychotropic continuation in the medically ill patient. When making complex psychopharmacologic decisions, hospitalists should employ all available resources, including pharmacists and consult-liaison psychiatrists. Ultimately, physicians and patients must make collaborative decisions, weighing the risks and benefits of psychiatric medications. Journal of Hospital Medicine 2013. © 2013 Society of Hospital Medicine. 23480340 Comparative analysis of adiponectin isoform distribution in pregnant women with gestational diabetes mellitus and after delivery. To evaluate the distribution of circulating adiponectin isoforms in pregnant women with gestational diabetes mellitus (GDM) and compare isoform distribution changes 12 months after delivery. University Hospital. Sixty-four consecutive pregnant women who underwent routine prenatal tests for GDM between 24 and 28 weeks of gestation. The study group included 36 women diagnosed with GDM, 30 of whom underwent re-testing for diabetes 12 months after delivery. The control group included 28 healthy pregnant women. Quantitative determination of total adiponectin and its isoforms in serum was performed with the multimeric adiponectin enzyme-linked immunosorbent assay. Total adiponectin concentration in women with GDM was significantly lower than in women without GDM. Among adiponectin isoforms, significantly lower concentrations of multimers and trimers in women with GDM were found in comparison to controls, while the concentration of hexamers did not differ between the groups. After delivery, a significant increase in total adiponectin and in the concentration of multimers and trimers was found in women with history of GDM. Additionally, we found that multimers and hexamers were negatively correlated with body mass index before and during gestation, as well as after delivery, and middle molecular weight isoforms in gestation were negatively correlated with birthweight. Hypoadiponectinemia during GDM was characterized by a significant, reversible decrease in multimeric levels; thus this isoform seems to function in a cohesive way with total adiponectin. Negative correlations of adiponectin isomers with body mass index indicate that there is a possibility to normalize total adiponectin and prevent GDM. 23578560 Differential internalization of amphotericin B--conjugated nanoparticles in human cells and the expression of heat shock protein 70. Although a variety of nanoparticles (NPs) functionalized with amphotericin B, an antifungal agent widely used in the clinic, have been studied in the last years their cytotoxicity profile remains elusive. Here we show that human endothelial cells take up high amounts of silica nanoparticles (SNPs) conjugated with amphotericin B (AmB) (SNP-AmB) (65.4 ± 12.4 pg of Si per cell) through macropinocytosis while human fibroblasts internalize relatively low amounts (2.3 ± 0.4 pg of Si per cell) because of their low capacity for macropinocytosis. We further show that concentrations of SNP-AmB and SNP up to 400 μg/mL do not substantially affect fibroblasts. In contrast, endothelial cells are sensitive to low concentrations of NPs (above 10 μg/mL), in particular to SNP-AmB. This is because of their capacity to internalize high concentration of NPs and high sensitivity of their membrane to the effects of AmB. Low-moderate concentrations of SNP-AmB (up to 100 μg/mL) induce the production of reactive oxygen species (ROS), LDH release, high expression of pro-inflammatory cytokines and chemokines (IL-8, IL-6, G-CSF, CCL4, IL-1β and CSF2) and high expression of heat shock proteins (HSPs) at gene and protein levels. High concentrations of SNP-AmB (above 100 μg/mL) disturb membrane integrity and kill rapidly human cells (60% after 5 h). This effect is higher in SNP-AmB than in SNP. 23625723 Antitumor T cell responses in bladder cancer are directed against a limited set of antigens and are modulated by regulatory T cells and routine treatment approaches. Regulatory T cells (Tregs) play a key role in cancer immune escape. We identified target antigens of spontaneous tumor-specific T cell responses in urothelial carcinoma (UC) and evaluated their modulation by treatment and Treg. We determined Treg target antigens in UC. Fifty-six UC and 13 control patients were prospectively enrolled. Blood was drawn before and after routine treatment. Changes in Treg frequency were measured by fluorescence cytometry and the T effector cell (Teff) response against a set of nine tumor-associated antigens (TAAs) was monitored with an interferon-gamma ELISpot. Antigen specificity of Treg was determined by their increased capacity to inhibit after TAA-specific activation the proliferation of an autologous T cell population. The highest difference in the overall response rate for the total T cell population was observed for epidermal growth factor receptor (EGFR) (UC: 23% and controls: 0%). After depleting Treg, also new york esophageal (NYES)O1 (19 and 0%) and MUC20 (27 and 0%) were more frequently recognized in UC patients. In metastasized patients, the TAA-directed T cell response was augmented by Treg depletion. Tumor resection seemed to diminish Treg suppression of TAA-specific immunity, whereas chemotherapy had no effect. We demonstrated the existence of TAA-specific Treg in UC, which share antigen specificities with Teff. The coexistence of TAA-specific Treg and Teff was very rare. Treg frequencies in the peripheral blood were not changed by therapy. In summary, we identified potentially immunologically relevant TAA in UC. TAA-specific T cell responses against these antigens are suppressed by Treg. We identified TAA-specific Treg in UC patients, which do not cooccur with TAA-specific Teff. 23645321 Syndromic versus nonsyndromic atlantoaxial dislocation: do clinico-radiological differences have a bearing on management? This prospective study attempts to study the clinico-radiological differences between patients with syndromic AAD (SAAD), non-syndromic AAD (NSAAD), and AAD with Klippel-Feil anomaly (AADKFA) that may impact management. In 46 patients with AAD [SAAD (including Morquio, Down, Larson and Marshall syndrome and achondroplasia; n = 6); NSAAD(n = 20); and, AADKFS (n = 20)], myelopathy was graded as mild (n = 17, 37 %), moderate (15, 32.5 %) or severe (14, 30.5 %) based on Japanese Orthopaedic Association Score modified for Indian patients (mJOAS). Basilar invagination (BI), basal angle, odontoid hypoplasia, facet-joint angle, effective canal diameter, Ishihara curvature index, and angle of retroversion of odontoid and vertebral artery (VA) variations were also studied. Clinico-radiological differences were assessed by Fisher's exact test, and mean craniometric values by Kruskal-Wallis test (p value ≤ 0.05 significant) Incidence of irreducible AAD in SAAD (n = 0), NSA AD (11.55 %) and AADKFS (n = 18.90 %) showed significant difference (p = 0.01). High incidence of kyphoscoliosis (83 %) and odontoid hypoplasia (83 %) in SAAD, and assimilated atlas and BI in NSAAD and AADKFA groups were found. In AADKFA, effective canal diameter was significantly reduced(p = 0.017) with increased Ishihara index and increased angle of odontoid retroversion; 61 % patients had VA variations. Thirty-five patients underwent single-stage transoral decompression with posterior fusion (for irreducible AAD) or direct posterior stabilization (for reducible AAD). Postoperative mJOAS evaluation often revealed persistent residual myelopathy despite clinical improvement. Myelopathy is induced by recurrent cord trauma due to reducible AAD in SAAD, and compromised cervicomedullary canal diameter in NSAAD and AADKFA. SAAD in children may be missed due to incomplete odontoid ossification or coexisting angular deformities. In AADKFA, decisions regarding vertebral levels to be included in posterior stabilization should take into consideration intact intervening motion segments and compensatory cervical hyperlordosis. Following VA injury, endovascular primary vessel occlusion/stenting across pseudoaneurysm preempts delayed rehemorrhage. 23685045 Glycosylsphingolipids from Euonymus japonicus Thunb. The stem bark of Euonymus japonicus Thunb. led to the isolation of three new glycosylsphingolipids (1-3), 1-O-[-L-rhamnopyranosyl-(1→2)-β-D-glucopyranosyl]-(2S,3R,9E)-2-N-[(2R)-hydroxystearoyl]-octadecasphinga-9-ene (euojaposphingoside A, 1), 1-O-[β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl]-(2S,3R,4R,11E)-2-N-[(2R)-hydroxydocasanoyl]-octadecasphinga-11-ene (euojaposphingoside B, 2), 1-O-[β-D-glucopyranosyl]-2'-O-[β-D-glucopyranosyl]-(2S,3R,4R,11E)-2-N-[(2R)-hydroxytetracosanoyl]-octadecasphinga-11-ene (euojaposphingoside C, 3) along with three known glycosylsphingolipids (4-6), 1-O-[β-D-glucopyranosyl]-(2S,3R,9E)-3-hydroxymethyl-2-N-[(2R)-hydroxynonacosanoyl)-tridecasphinga-9-ene (4), 1-O-[β-D-glucopyranosyl]-(2S,3R,9E,12E)-2-N-[(2R)-hydroxytetracosanoyl] octadecasphinga-9,12-diene (5), 1-O-[β-D-glucopyranosyl]-(2S,3R,5R,9E)-2-N-[tridecanoyl] nonacosasphinga-9-ene (6), lupeol (7), stigmasterol (8), sitosterol (β and α) (9,10) and β-carotene (11). The structure of all the compounds was achieved by spectroscopic and chemical data analysis. The antiplasmodial, antileismanial and cytotoxic activity of all compounds was tested. 22951946 Design of a testing strategy using non-animal based test methods: Lessons learnt from the ACuteTox project. In the framework of toxicology, a testing strategy can be viewed as a series of steps which are taken to come to a final prediction about a characteristic of a compound under study. The testing strategy is performed as a single-step procedure, usually called a test battery, using simultaneously all information collected on different endpoints, or as tiered approach in which a decision tree is followed. Design of a testing strategy involves statistical considerations, such as the development of a statistical prediction model. During the EU FP6 ACuteTox project, several prediction models were proposed on the basis of statistical classification algorithms which we illustrate here. The final choice of testing strategies was not based on statistical considerations alone. However, without thorough statistical evaluations a testing strategy cannot be identified. We present here a number of observations made from the statistical viewpoint which relate to the development of testing strategies. The points we make were derived from problems we had to deal with during the evaluation of this large research project. A central issue during the development of a prediction model is the danger of overfitting. Procedures are presented to deal with this challenge. 23553721 Secreted proteases of Trypanosoma brucei gambiense: Possible targets for sleeping sickness control? Human African trypanosomiasis (HAT) is caused by trypanosomes of the species Trypanosoma brucei and belongs to the neglected tropical diseases. Presently, WHO has listed 36 countries as being endemic for sleeping sickness. No vaccine is available, and disease treatment is difficult and has life-threatening side effects. Therefore, there is a crucial need to search for new therapeutic targets against the parasite. Trypanosome excreted-secreted proteins could be promising targets, as the total secretome was shown to inhibit, in vitro, host dendritic cell maturation and their ability to induce lymphocytic allogenic responses. The secretome was found surprisingly rich in various proteins and unexpectedly rich in diverse peptidases, covering more than ten peptidase families or subfamilies. Given their abundance, one may speculate that they would play a genuine role not only in classical "housekeeping" tasks but also in pathogenesis. The paper reviews the deleterious role of proteases from trypanosomes, owing to their capacity to degrade host circulating or structural proteins, as well as proteic hormones, causing severe damage and preventing host immune response. In addition, proteases account for a number of drug targets, such drugs being used to treat severe diseases such AIDS. This review underlines the importance of secreted proteins and especially of secreted proteases as potential targets in HAT-fighting strategies. It points out the need to conduct further investigations on the specific role of each of these various proteases in order to identify those playing a central role in sleeping sickness and would be suitable for drug targeting. © 2013 BioFactors, 39(4):407-414, 2013. 23376140 Hepatocytes display a compensatory survival response against cadmium toxicity by a mechanism mediated by EGFR and Src. Although the liver is a cadmium-target organ, hepatocyte response involved in its toxicity is not yet elucidated. A link between this heavy metal treatment and Stat3 signaling pathways was examined in primary mouse hepatocytes. We provided evidence of a novel link among NADPH oxidase and Stat3 signaling, mediated by Src, EGFR, and Erk1/2. Cadmium activates NADPH oxidase. ROS produced by this oxidase activates Src, enable that in turn, transactivates EGFR that activates Stat3 in tyrosine, allowing its dimerization. Also, ROS from NADPH oxidase favors ERK1/2 activation that phosphorylates Stat3 in serine, resulting in a compensatory or adaptive survival response such as production of metallothionein-II in short Cd exposure times. However, after 12h CdCl2 treatment, cell viability diminished in 50%, accompanied by a drastic decrease of metallothionein-II production, and an increase in p53 activation and the pro-apoptotic protein Bax. 23598799 Mesoporous anatase TiO2 nanocups with plasmonic metal decoration for highly active visible-light photocatalysis. This communication describes a method for facile synthesis of mesoporous anatase TiO2 nanocup crystals. The novel cuplike morphology of TiO2 decorated with gold (Au-TiO2) yields remarkably high photocatalytic activity for degradation of methylene blue under visible light irradiation. 23624036 Encapsulation of chimeric protein rSAG1/2 into poly(lactide-co-glycolide) microparticles induces long-term protective immunity against Toxoplasma gondii in mice. In the present study, the poly(lactide-co-glycolide) (PLG) polymer was used as an adjuvant to encapsulate the chimeric protein rSAG1/2 for preparing a microparticle vaccine against Toxoplasma gondii. The resulting PLG-encapsulated rSAG1/2 (PLG-rSAG1/2) microparticles, 1.27-1.65μm in diameter, showed 72-83% entrapment efficiency. The amount of released rSAG1/2 protein from microparticles gradually increased over a long 56-day period and the protein still retained its antigenicity. Intraperitoneal immunization with the microparticles in BALB/c mice elicited significant long-term (10weeks) humoral and cell-mediated immune responses, accompanied by secretion of a large amount of IFN-γ, to achieve strong protection (83%) against a lethal subcutaneous tachyzoite challenge. In conclusion, we have successfully encapsulated rSAG1/2 with the PLG polymer to produce stable microparticles that can effectively induce not only long-term immunity but also high protection against T. gondii. These crucial data would be advantageous for developing long-term Toxoplasma vaccines for future use in humans and animals. 23885677 The IRAD Classification System for Characterizing Survival after Aortic Dissection. The classification of aortic dissection into acute (<14 days from symptom onset) versus chronic (≥14 days) is based on survival estimates of patients treated decades before modern diagnostic and treatment modalities were available. A new classification of aortic dissection in the current era may provide clinicians with a more precise method of characterizing the interaction of time, dissection location, and treatment type with survival. We developed separate Kaplan-Meier survival curves for Type A and Type B aortic dissection using data from the International Registry of Aortic Dissection (IRAD). Daily survival was stratified based on type of therapy provided: medical therapy alone (medical), nonsurgical intervention plus medical therapy (endovascular), and open surgery plus medical therapy (surgical). The log-rank statistic was used to compare the survival curves of each management type within Type A and Type B aortic dissection. There were 1815 patients included, 67.3% male with mean age 62.0 ± 14.2 years. When survival curves were constructed, 4 distinct time periods were noted: hyperacute (symptom onset to 24 hours), acute (2-7 days), subacute (8-30 days), and chronic (>30 days). Overall survival was progressively lower through the 4 time periods. This IRAD classification system can provide clinicians with a more robust method of characterizing survival after aortic dissection over time than previous methods. This system will be useful for treating patients, counseling patients and families, and studying new diagnostic and treatment methods. 23743521 Decreased respiratory rate variability during mechanical ventilation is associated with increased mortality. Patients on ventilatory support often experience significant changes in respiratory rate. Our aim was to determine the possible association between respiratory rate variability (RRV) and outcomes in these patients. A longitudinal, prospective, observational study of patients mechanically ventilated for at least 12 h performed in a medical-surgical intensive care unit. Patients were enrolled within 24 h of the initiation of ventilatory support. We measured airway signals continuously for the duration of ventilatory support and calculated expiratory flow frequency spectra at 2.5-min intervals. We assessed RRV using the amplitude ratio of the flow spectrum's first harmonic to the zero frequency component. Measures of the amplitude ratio were averaged over the total monitored time. Patients with time-averaged amplitude ratios <40 % were classified as high RRV and those ≥40 % as low RRV. All-cause mortality rates were assessed at 28 and 180 days from enrollment with a Cox proportional hazards model adjusted for disease acuity by the simplified acute physiology score II. We enrolled 178 patients, of whom 47 had high RRV and 131 low RRV. Both groups had similar disease acuity upon enrollment. The 28- and 180-day mortality rates were greater for low RRV patients with hazard ratios of 4.81 (95 % CI 1.85-12.65, p = 0.001) and 2.26 (95 % CI 1.21-4.20, p = 0.01), respectively. Independent predictors of 28-day mortality were low RRV, i.v. vasopressin, and SAPS II. Decreased RRV during ventilatory support is associated with increased mortality. The mechanisms responsible for this finding remain to be determined. 23695213 Focal adhesion kinase is required for IGF-I-mediated growth of skeletal muscle cells via a TSC2/mTOR/S6K1-associated pathway. Focal adhesion kinase (FAK) is an attachment complex protein associated with the regulation of muscle mass through as-of-yet unclear mechanisms. We tested whether FAK is functionally important for muscle hypertrophy, with the hypothesis that FAK knockdown (FAK-KD) would impede cell growth associated with a trophic stimulus. C2C12 skeletal muscle cells harboring FAK-targeted (FAK-KD) or scrambled (SCR) shRNA were created using lentiviral transfection techniques. Both FAK-KD and SCR myotubes were incubated for 24 h with IGF-I (10 ng/ml), and additional SCR cells (±IGF-1) were incubated with a FAK kinase inhibitor before assay of cell growth. Muscle protein synthesis (MPS) and putative FAK signaling mechanisms (immunoblotting and coimmunoprecipitation) were assessed. IGF-I-induced increases in myotube width (+41 ± 7% vs. non-IGF-I-treated) and total protein (+44 ± 6%) were, after 24 h, attenuated in FAK-KD cells, whereas MPS was suppressed in FAK-KD vs. SCR after 4 h. These blunted responses were associated with attenuated IGF-I-induced FAK Tyr(397) phosphorylation and markedly suppressed phosphorylation of tuberous sclerosis complex 2 (TSC2) and critical downstream mTOR signaling (ribosomal S6 kinase, eIF4F assembly) in FAK shRNA cells (all P < 0.05 vs. IGF-I-treated SCR cells). However, binding of FAK to TSC2 or its phosphatase Shp-2 was not affected by IGF-I or cell phenotype. Finally, FAK-KD-mediated suppression of cell growth was recapitulated by direct inhibition of FAK kinase activity in SCR cells. We conclude that FAK is required for IGF-I-induced muscle hypertrophy, signaling through a TSC2/mTOR/S6K1-dependent pathway via means requiring the kinase activity of FAK but not altered FAK-TSC2 or FAK-Shp-2 binding. 23834990 How do United Kingdom (UK) medical schools identify and support undergraduate medical students who 'fail' communication assessments? A national survey. The doctor's ability to communicate effectively (with patients, relatives, advocates and healthcare colleagues) relates directly to health outcomes, and so is core to clinical practice. The remediation of medical students' clinical communication ability is rarely addressed in medical education literature. There is nothing in the current literature reporting a contemporary national picture of how communication difficulties are managed, and the level of consequence (progression implications) for students of performing poorly. This survey aimed to consolidate practices for identifying and processes for managing students who 'fail' communication assessments across all UK medical schools. Data were collected via an email survey to all leads for clinical communication in all UK Medical Schools for the UK Council for Clinical Communication in Undergraduate Medical Education. All but two participating Schools reported some means of support and/or remediation in communication. There was diversity of approach, and variance in the level of systemisation adopted. Variables such as individuality of curricula, resourcing issues, student cohort size and methodological preferences were implicated as explaining diversity. Support is relatively ad hoc, and often in the hands of a particular dedicated individual or team with an interest in communication delivery with few Schools reporting robust, centralised, school level processes. This survey has demonstrated that few Medical Schools have no identifiable system of managing their students' clinical communication difficulties. However, some Schools reported ad hoc approaches and only a small number had a centralised programme. There is scope for discussion and benchmarking of best practice across all Schools with allocation of appropriate resources to support this. 23871964 A new fast algorithm for solving the minimum spanning tree problem based on DNA molecules computation. The minimum spanning tree (MST) problem is to find minimum edge connected subsets containing all the vertex of a given undirected graph. It is a vitally important NP-complete problem in graph theory and applied mathematics, having numerous real life applications. Moreover in previous studies, DNA molecular operations usually were used to solve NP-complete head-to-tail path search problems, rarely for NP-hard problems with multi-lateral path solutions result, such as the minimum spanning tree problem. In this paper, we present a new fast DNA algorithm for solving the MST problem using DNA molecular operations. For an undirected graph with n vertex and m edges, we reasonably design flexible length DNA strands representing the vertex and edges, take appropriate steps and get the solutions of the MST problem in proper length range and O(3m+n) time complexity. We extend the application of DNA molecular operations and simultaneity simplify the complexity of the computation. Results of computer simulative experiments show that the proposed method updates some of the best known values with very short time and that the proposed method provides a better performance with solution accuracy over existing algorithms. 23123298 Helenalin-induced apoptosis is dependent on production of reactive oxygen species and independent of induction of endoplasmic reticulum stress in renal cell carcinoma. Helenalin, a sesquiterpene lactone, exhibits anti-inflammatory and anti-tumor activities. Here, we investigated whether helenalin could induce apoptosis in human renal carcinoma Caki cells. Helenalin increased apoptosis in dose dependent manner in Caki cells, and also induced apoptosis in other carcinoma cells, such as human renal carcinoma ACHN cells, human colon carcinoma HT29 and HCT116 cells. We found that helenalin markedly induced endoplasmic reticulum (ER) stress-related genes, such as regulated in development and DNA damage responses (REDD) 1, activating transcription factor-4 (ATF4) and/or the CCAAT enhancer-binding protein-homologous protein (CHOP). However, down-regulation of ATF4 and/or CHOP expression by siRNA had no effect on helenalin-induced apoptosis in Caki and HCT116 cells. Helenalin increased production of intracellular reactive oxygen species (ROS). Furthermore, ROS scavengers, N-acetylcystine (NAC), and glutathione ethyl ester (GEE), reduced helenalin-induced apoptosis. Taken together, helenalin induced apoptosis via ROS generation in human renal carcinoma Caki cells. 23674206 MicroPET/CT imaging of αvβ₃ integrin via a novel ⁶⁸Ga-NOTA-RGD peptidomimetic conjugate in rat myocardial infarction. The αvβ3 integrin is expressed in angiogenic vessels and is a potential target for molecular imaging of evolving pathological processes. Its expression is upregulated in cancer lesions and metastases as well as in acute myocardial infarction (MI) as part of the infarct healing process. The purpose of our study was to determine the feasibility of a new imaging approach with a novel (68)Ga-2,2',2″-(1,4,7-triazonane-1,4,7-triyl)triacetic acid (NOTA)-arginine-glycine-aspartic acid (RGD) construct to assess integrin expression in the evolving MI. A straightforward labelling chemistry to attach the radionuclide (68)Ga to a NOTA-based chelating agent conjugated with a cyclic RGD peptidomimetic is described. Affinity for αvβ₃ integrin was assessed by in vitro receptor binding assay. The proof-of-concept in vivo studies combined the (68)Ga-NOTA-RGD with the flow tracer (13)N-NH₃ imaging in order to obtain positron emission tomography (PET)/CT imaging of both integrin expression and perfusion defect at 4 weeks after infarction. Hearts were then processed for immunostaining of integrin β₃. NOTA-RGD conjugate displayed a binding affinity for αvβ₃ integrin of 27.9 ± 6.8 nM. (68)Ga-NOTA-RGD showed stability without detectable degradation or formation of by-products in urine up to 2 h following injection in the rat. MI hearts exhibited (68)Ga-NOTA-RGD uptake in correspondence to infarcted and border zone regions. The tracer signal drew a parallel with vascular remodelling due to ischaemia-induced angiogenesis as assessed by immunohistochemistry. As compared to similar imaging approaches using the (18)F-galacto-derivative, we documented for the first time with microPET/CT imaging the (68)Ga-NOTA-RGD derivative that appears eligible for PET imaging in animal models of vascular remodelling during evolving MI. The simple chemistry employed to synthesize the (68)Ga-based radiotracer may greatly facilitate its translation to a clinical setting. 23827204 A systematic review and economic evaluation of subcutaneous and sublingual allergen immunotherapy in adults and children with seasonal allergic rhinitis. Severe allergic rhinitis uncontrolled by conventional medication can substantially affect quality of life. Immunotherapy involves administering increasing doses of a specific allergen, with the aim of reducing sensitivity and symptomatic reactions. Recent meta-analyses have concluded that both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are more effective than placebo in reducing symptoms. It is uncertain which route of administration is more effective and whether or not treatment is cost-effective. To determine the comparative clinical effectiveness and cost-effectiveness of SCIT and SLIT for seasonal allergic rhinitis in adults and children. Electronic databases {MEDLINE, EMBASE, The Cochrane Library [Cochrane Central Register of Controlled Trials (CENTRAL)], NHS Economic Evaluation Database (NHS EED)} and trial registries (from inception up to April 2011). Standard systematic review methods were used for study selection, data extraction and quality assessment. Double-blind randomised, placebo-controlled trials of SCIT or SLIT, or of SCIT compared with SLIT, and economic evaluations were included. Meta-analysis and indirect comparison meta-analysis and meta-regression were carried out. A new economic model was constructed to estimate cost-utility. Meta-analyses found statistically significant effects for SCIT and SLIT compared with placebo across a number of outcome measures and for the vast majority of subgroup analyses (type and amount of allergen, duration of treatment). There was less evidence for children, but some results in favour of SLIT were statistically significant. Indirect comparisons did not provide conclusive results in favour of either SCIT or SLIT. Economic modelling suggested that, when compared with symptomatic treatment (ST), both SCIT and SLIT may become cost-effective at a threshold of £20,000-30,000 per quality-adjusted life-year (QALY) from around 6 years, or 5 years for SCIT compared with SLIT (NHS and patient perspective). It is uncertain to what extent changes in the outcome measures used in the trials translate into clinically meaningful benefits. Cost-effectiveness estimates are based on a simple model, limited data and a number of assumptions, and should be seen as indicative only. A benefit from both SCIT and SLIT compared with placebo has been consistently demonstrated, but the extent of this effectiveness in terms of clinical benefit is unclear. Both SCIT and SLIT may be cost-effective compared with ST from around 6 years (threshold of £20,000-30,000 per QALY). Further research is needed to establish the comparative effectiveness of SCIT compared with SLIT and to provide more robust cost-effectiveness estimates. The National Institute for Health Research Health Technology Assessment programme. 23160090 Hydroxysafflor yellow a inhibits lipopolysaccharide-induced inflammatory signal transduction in human alveolar epithelial A549 cells. Hydroxysafflor yellow A (HSYA) is an active ingredient obtained from the flower of Carthamus tinctorius L. The present study investigated the effects of HSYA on lipopolysaccharide (LPS)-induced inflammatory signal transduction in human alveolar epithelial A549 cells. A549 cells stimulated with LPS were incubated with three doses of HSYA (1, 4 and 16μmol/L). HSYA suppressed the expression of TLR-4, Myd88, ICAM-1, TNFα, IL-1β and IL-6 at the mRNA and protein level, and inhibited the adhesion of leukocytes to A549 cells. HSYA treatment also decreased NF-κB p65 nuclear translocation and inhibited the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK). These findings suggest that HSYA effectively inhibits LPS-induced inflammatory signal transduction in A549 cells. 23962083 Comparison of historical bottleneck effects and genetic consequences of re-introduction in a critically endangered island passerine. Re-introduction is an important tool for recovering endangered species; however, the magnitude of genetic consequences for re-introduced populations remains largely unknown, in particular the relative impacts of historical population bottlenecks compared to those induced by conservation management. We characterize 14 microsatellite loci developed for the Seychelles paradise flycatcher and use them to quantify temporal and spatial measures of genetic variation across a 134-year time frame encompassing a historical bottleneck that reduced the species to ~28 individuals in the 1960s, through the initial stages of recovery and across a second contemporary conservation-introduction-induced bottleneck. We then evaluate the relative impacts of the two bottlenecks, and finally apply our findings to inform broader re-introduction strategy. We find a temporal trend of significant decrease in standard measures of genetic diversity across the historical bottleneck, but only a nonsignificant downward trend in number of alleles across the contemporary bottleneck. However, accounting for the different timescales of the two bottlenecks (~40 historical generations versus <1 contemporary generation), the loss of genetic diversity per generation is greater across the contemporary bottleneck. Historically, the flycatcher population was genetically structured; however, extinction on four of five islands has resulted in a homogeneous contemporary population. We conclude that severe historical bottlenecks can leave a large footprint in terms of sheer quantity of genetic diversity lost. However, severely depleted genetic diversity does not render a species immune to further genetic erosion upon re-introduction. In some cases, the loss of genetic diversity per generation can, initially at least, be greater across re-introduction-induced bottlenecks. 23791221 Systemic Absorption and Pharmacokinetics of Single-dose Early Intravesical Mitomycin C After Transurethral Resection of Non-muscle-invasive Bladder Cancer. To study the systemic absorption and pharmacokinetics of a single dose of intravesical mitomycin C (MMC) given immediately after transurethral resection of bladder tumor (TURBT). Fourteen patients with primary or recurrent non-muscle-invasive bladder cancer were eligible for a single early intravesical instillation of MMC (40 mg in 50 mL distilled water) administered immediately after TURBT. Blood samples were obtained at baseline and at 20, 40, 60 (time of voiding), 90, 120, and 150 minutes after instillation. Concentrations of the drug were determined by validated high-performance liquid chromatography assay. During TURBT, we counted the number of excursions of the resecting loop required to completely eradicate the tumor, including a portion of the underlying muscular wall. TURBTs were categorized as small and large, defined as requiring â‰¤6 or >6 full excursions of the resecting loop, respectively. Maximal MMC plasma concentrations were reached 40 minutes after instillation. At 150 minutes, only minimal drug plasma levels were detectable in 4 patients. The highest plasma peak was 49.25 ng/mL. In the first samples, at 20 minutes after instillation, the plasma concentration of MMC was significantly correlated with the extent of TURBT (P = .026). Four patients (28.6%) complained of G1 side effects, 3 after a large TURBT and 1 after a small TURBT, and 1 patient had G2 dysuria after a large TURBT. Low peak blood levels of MMC are observed after a single-dose intravesical instillation immediately after TURBT, with low systemic and local toxicity. The early absorption rate depends on TURBT extension. 23910992 Effect of decapitation and nutrient applications on shoot branching, yield, and accumulation of secondary metabolites in leaves of Stevia rebaudiana Bertoni. The axillary buds of stevia (Stevia rebaudiana Bertoni) often remain dormant for a long time and sometimes remain dormant permanently until the plants enter into the reproductive stage. The present study was conducted to ascertain whether decapitation and foliar fertilization enhance the productivity and quality of stevia through breaking the apical dominance and increasing physiological activities. Ten treatment combinations comprising two cultural operations (non-decapitation and decapitation) and five foliar spray treatments (water spray control, KNO3 @ 5.0gL(-1), Ca(NO3)2 @ 4.06gL(-1), CuSO4·5H2O 2.0gL(-1) and (NH4)6Mo7O24 @ 1.0gL(-1)) were applied. The decapitation of apical buds of stevia increased the branches and increased dry leaf yield by 13 and 17% compared with non-decapitation during 2010 and 2011, respectively, without affecting quality. Foliar application of nutrient solutions also exerted a considerable effect on growth parameters, yield attributes and chlorophyll content, and significantly (P=0.05) higher dry leaf yield ranging from 8 to 26% over the control. Among the foliar spray treatments, KNO3 @ 5.0gL(-1) and Ca (NO3)2 4.06gL(-1) were found most effective in dry leaf yield. Thus, the decapitation of apical buds and foliar application of KNO3 and Ca (NO3)2 could enhance the productivity of stevia through improving the growth of axillary buds and physiological activities. 23939832 MiR-26b is down-regulated in carcinoma-associated fibroblasts from ER positive breast cancers leading to enhanced cell migration and invasion. Carcinoma-associated fibroblasts (CAFs) influence behaviour of cancer cells but roles of microRNAs in this interaction are unknown. We report microRNAs that are differentially expressed between breast normal fibroblasts and CAFs of estrogen receptor positive cancers, and explore influences of one of these, miR-26b, on breast cancer biology. We identified differentially expressed microRNAs by expression profiling of clinical samples and a tissue culture model: miR-26b was the most highly deregulated microRNA. Using qPCR, miR-26b was confirmed as down-regulated in fibroblasts from 15 of 18 further breast cancers. Next, we examined whether manipulation of miR-26b expression changed breast fibroblast behaviour. Reduced miR-26b expression caused fibroblast migration and invasion to increase by up to 3-fold in scratch-closure and trans-well assays. Furthermore, in co-culture with MCF7 breast cancer epithelial cells, fibroblasts with reduced miR-26b expression enhanced both MCF7 migration in trans-well assays, and MCF7 invasion from 3-dimensional spheroids by up to 5-fold. Mass spectrometry was used to identify expression changes associated with reduction of miR-26b expression in fibroblasts. Pathway analyses of differentially expressed proteins revealed that glycolysis/TCA cycle, and cytoskeletal regulation by Rho GTPases are down-stream of miR-26b. In addition, 3 novel miR-26b targets were identified (TNKS1BP1, CPSF7, COL12A1) and expression of each in cancer stroma was shown to be significantly associated with breast cancer recurrence. miR-26b in breast CAFs is a potent regulator of cancer behaviour in estrogen receptor positive cancers, and have identified key genes and molecular pathways that act down-stream of miR-26b in CAFs. 23712911 Ionic size dependent electroosmosis in ion-selective microchannels and nanochannels. Electrokinetics in salt-free media (in which counterions are only present) is central to the performance of many systems of modern technological relevance, ranging from ion-selective nanopores to electronic papers. Here, we introduce an analytical theory to describe the size dependence of electroosmosis in such typical scenarios, exhibiting an interesting confluence of the implications of interdependence of the electroosmotic transport mechanisms, ionic sizes, and confinement dimensions along with the counterion concentration. Our results do reveal that the concerned mobility parameter, describing the strength of electroosmotic transport, increases simultaneously with increments in the surface charge density as well as an ionic size factor (also known as the steric factor), bearing far-ranging consequences in microfluidic and nanofluidic technology. 23959641 Supramolecular Polymerization in Microfluidic Channels: Spatial Control Over Multiple Intermolecular Interactions. A novel supramolecular assembly has been developed in conjugation with microfluidics. Self-assembly of the programmed molecules was controlled precisely, in space and time, in a microflow channel as a result of a homogeneous solvent mixing process. Furthermore, through continuous organization of component molecules followed by orientation along microflow, the self-assembling event containing different molecules was spatially controlled from nano to micrometer scale in a single stream (GMP=guanosine 5'-monophosphate). 23928241 Breast magnetic resonance imaging for screening high-risk women. Mammography is the only imaging modality that has been validated by multiple randomized clinical trials and meta-analyses to reduce mortality from breast cancer. Although it is demonstrated to be effective in reducing mortality from breast cancer, mammography has its limitations, especially in young high-risk women with dense breasts. Other imaging modalities have been pursued as an adjunct screening modality in this population. Of these, the most widely accepted is contrast-enhanced breast magnetic resonance (MR) imaging. This article reviews current recommendations and limitations of using MR imaging of the breast to screen asymptomatic women at high risk for breast cancer. 23909409 The single-dose pharmacokinetics of Alitretinoin and its metabolites are not significantly altered in patients with cirrhosis. Oral therapy with Alitretinoin (9-cis-retinoic acid, Toctino(®) ) was recently marketed for the treatment of chronic hyperkeratotic hand eczema. Since Alitretinoin is highly lipophilic and mainly metabolized in the liver, it is currently considered to be contraindicated in patients with liver disease. However, the pharmacokinetics and metabolism of Alitretinoin have not yet been studied in these patients. To study the single-dose pharmacokinetics and metabolism of Alitretinoin and its metabolites in patients with cirrhosis following oral administration of 30 mg of Alitretinoin. Eight patients with cirrhosis and eight matched volunteer healthy controls were given a single oral dose of 30 mg of Alitretinoin. Blood and urine samples were collected during the following 24-hour study period. Samples were analyzed for Alitretinoin and for known metabolites using reversed-phase high performance liquid chromatography. The pharmacokinetics were then evaluated using standard non-compartmental models. No significant differences were found between the healthy controls and the patients with cirrhosis when analyzing the pharmacokinetic parameters of Alitretinoin and its metabolites. Hence, mean half-lives of Alitretinoin were 5.3 and 5.6 h (p=0.34) and oral clearances were 1.9 and 1.34 L kg(-1) h(-1) (p=0.14) in the patient group and the healthy control group, respectively. The metabolism and pharmacokinetics of Alitretinoin following oral administration of the recommended dose of 30 mg for the treatment of severe hand eczema were similar in patients with cirrhosis and in healthy controls. If indicated, Alitretinoin can be used in these patients with careful and close monitoring. This article is protected by copyright. All rights reserved. 22824191 Propranolol restores cognitive deficits and improves amyloid and Tau pathologies in a senescence-accelerated mouse model. Ageing is associated with a deterioration of cognitive performance and with increased risk of neurodegenerative disorders. Hypertension is the most-prevalent modifiable risk factor for cardiovascular morbidity and mortality worldwide, and clinical data suggest that hypertension is a risk factor for Alzheimer's disease (AD). In the present study we tested whether propranolol, a β-receptor antagonist commonly used as antihypertensive drug, could ameliorate the cognitive impairments and increases in AD-related markers shown by the senescence-accelerated mouse prone-8 (SAMP8). Propranolol administration (5 mg/kg for 3 weeks) to 6-month-old SAMP8 mice attenuated cognitive memory impairments shown by these mice in the novel object recognition test. In the hippocampus of SAMP8 mice it has been found increases in Aβ(42) levels, the principal constituent of amyloid plaques observed in AD, accompanied by both an increased expression of the cleaving enzyme BACE1 and a decreased expression of the degrading enzyme IDE. All these effects were reversed by propranolol treatment. Tau hyperphosphorylation (PHF-1 epitope) shown by SAMP8 mice at this age was also decreased in the hippocampus of propranolol-treated mice, an effect probably related to a decrease in JNK1 expression. Interestingly, propranolol also phosphorylated Akt in SAMP8 mice, which was associated with an increase of glycogen synthase kinase-3β phosphorylation, contributing therefore to the reductions in Tau hyperphosphorylation. Synaptic pathology in SAMP8 mice, as shown by decreases in synaptophysin and BDNF, was also counteracted by propranolol treatment. Overall, propranolol might be beneficial in age-related brain dysfunction and could be an emerging candidate for the treatment of other neurodegenerative diseases. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23926077 Multiscale metabolic modeling: dynamic flux balance analysis on a whole plant scale. Plant metabolism is characterized by a unique complexity on the cellular, tissue and organ level. On a whole plant scale changing source- and sink-relations accompanying plant development add another level of complexity to metabolism. With the aim of getting a spatio-temporal resolution of source-sink interactions in crop plant metabolism, a multiscale metabolic modeling (MMM) approach was applied which integrates static organ-specific models with a whole plant dynamic model. Allowing for a dynamic flux balance analysis (dFBA) on a whole plant scale, the MMM approach was used to decipher the metabolic behavior of source and sink organs during the generative phase of the barley plant. It reveals a sink-to-source shift of the barley stem caused by the senescence-related decrease in leaf source-capacity which is not sufficient to meet the nutrient requirements of sink organs such as the growing seed. The MMM platform represents a novel approach for the in silico analysis of metabolism on a whole plant level, allowing for a systemic, spatio-temporally resolved understanding of metabolic processes involved in carbon partitioning, thus providing a novel tool for studying yield stability and crop improvement. 23861313 Characterization of collagen and cholesterol deposition in atherosclerotic arterial tissue using non-linear microscopy. Atherosclerosis is characterized by the accumulation of lipids within the arterial wall and is commonly diagnosed using standard histology. Non-linear microscopy represents a possible label-free alternative to standard diagnostic methods for imaging various tissue components. Here we employ SHG and CARS microscopy for imaging thin cross-sections of atherosclerotic arterial tissue, demonstrating that both cholesterol deposition in the lumen and collagen in the normal arterial wall can be imaged and discriminated using SHG and CARS microscopy. A simultaneous detection of both forward and backward scattered SHG signals allows distinguishing collagen fibres from cholesterol. Further analysis, based on image pattern evaluation algorithms, is used to characterize collagen organization in the healthy arterial wall against collagen found within plaques. Different values of fibre mean size, distribution and anisotropy are calculated for lumen and media prospectively allowing for automated classification of atherosclerotic lesions. The presented method represents a promising diagnostic tool for evaluating atherosclerotic tissue. (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim). 23496258 Why carers of people with dementia do not utilise out-of-home respite services. While many people with dementia require institutional care, having a co-resident carer improves the likelihood that people can live at home. Although caregiving can have positive aspects, carers still report a high need for respite. Despite this need, the use of respite services for carers of people with dementia is often low. This article investigates carer beliefs regarding out-of-home respite services and why some carers do not utilise them. A total of 152/294 (51.7%) carers of community-dwelling people with dementia (NSW, Australia) who were sent a survey completed it (November 2009-January 2010). Despite reporting unmet need for both services, 44.2% of those surveyed were not utilising day respite and 60.2% were not utilising residential respite programmes. Binary logistic regression models were used to examine factors associated with non-use using the Theory of Planned Behaviour within an expanded Andersen Behavioural Model on a final sample of 113 (due to missing data). The model explained 66.9% of the variation for day centres, and 42% for residential respite services. Beliefs that service use would result in negative outcomes for the care recipient were strongly associated with non-use of both day care [OR 13.11; 95% CI (3.75, 45.89)] and residential respite care [OR 6.13; 95% CI (2.02, 18.70)] and were more strongly associated with service non-use than other predisposing, impeding and need variables. For some carers who used services despite negative outcome beliefs, the benefits of respite service use may also be diminished. To improve use of out-of-home respite services in this vulnerable group, service beliefs should be addressed through service development and promotion that emphasises benefits for both carer and care recipients. Future research utilising behavioural service models may also be improved via the inclusion of service beliefs in the study of health and social service use. 23545287 The performance of silk scaffolds in a rat model of augmentation cystoplasty. The diverse processing plasticity of silk-based biomaterials offers a versatile platform for understanding the impact of structural and mechanical matrix properties on bladder regenerative processes. Three distinct groups of 3-D matrices were fabricated from aqueous solutions of Bombyx mori silk fibroin either by a gel spinning technique (GS1 and GS2 groups) or a solvent-casting/salt-leaching method in combination with silk film casting (FF group). SEM analyses revealed that GS1 matrices consisted of smooth, compact multi-laminates of parallel-oriented silk fibers while GS2 scaffolds were composed of porous (pore size range, 5-50 μm) lamellar-like sheets buttressed by a dense outer layer. Bi-layer FF scaffolds were comprised of porous foams (pore size, ~400 μm) fused on their external face with a homogenous, nonporous silk film. Silk groups and small intestinal submucosa (SIS) matrices were evaluated in a rat model of augmentation cystoplasty for 10 weeks of implantation and compared to cystotomy controls. Gross tissue evaluations revealed the presence of intra-luminal stones in all experimental groups. The incidence and size of urinary calculi was the highest in animals implanted with gel spun silk matrices and SIS with frequencies ≥57% and stone diameters of 3-4 mm. In contrast, rats augmented with FF scaffolds displayed substantially lower rates (20%) and stone size (2 mm), similar to the levels observed in controls (13%, 2 mm). Histological (hematoxylin and eosin, Masson's trichrome) and immunohistochemical (IHC) analyses showed comparable extents of smooth muscle regeneration and contractile protein (α-smooth muscle actin and SM22α) expression within defect sites supported by all matrix groups similar to controls. Parallel evaluations demonstrated the formation of a transitional, multi-layered urothelium with prominent uroplakin and p63 protein expression in all experimental groups. De novo innervation and vascularization processes were evident in all regenerated tissues indicated by Fox3-positive neuronal cells and vessels lined with CD31 expressing endothelial cells. In comparison to other biomaterial groups, cystometric analyses at 10 weeks post-op revealed that animals implanted with the FF matrix configuration displayed superior urodynamic characteristics including compliance, functional capacity, as well as spontaneous non voiding contractions consistent with control levels. Our data demonstrate that variations in scaffold processing techniques can influence the in vivo functional performance of silk matrices in bladder reconstructive procedures. 23123253 New tools in diagnosis and biomonitoring of intoxications with organophosphorothioates: Case studies with chlorpyrifos and diazinon. Organophosphate (OP) pesticides are neurotoxic compounds that are widely used in agriculture. Classical methods for monitoring OP exposure comprise the measurement of intact OP, its metabolites or cholinesterase activity. Newly developed methods focus on the analysis of the OP adduct bound to proteins such as butyrylcholinesterase (BuChE) and albumin. These adducts can be analyzed by means of fluoride reactivation or by analysis with LC-MS/MS of the pepsin or pronase digest of butyrylcholinesterase and albumin, respectively. The utility of these methods is illustrated through the analysis of plasma samples obtained from patients taken 1-49days after ingestion of the organophosphate pesticides chlorpyrifos and/or diazinon. Thus, in this particular case several independent methodologies were applied to the biomedical samples, all pointing to the same exposure. 23740864 Base-Catalyzed Synthesis of Substituted Indazoles under Mild, Transition-Metal-Free Conditions. Back to basics: A transition-metal-free method developed for the synthesis of indazoles involves an inexpensive catalytic system composed of a diamine and K2 CO3 . Various (Z)-2-bromoacetophenone tosylhydrazones were converted into indazoles at room temperature in excellent yields (see example; Ts=p-toluenesulfonyl). The yield was improved by photoisomerization with UV light when E/Z isomeric mixtures of the starting material were used. 23856525 Interactions with selected drug renal transporters and transporter-mediated cytotoxicity in antiviral agents from the group of acyclic nucleoside phosphonates. Members of acyclic nucleoside phosphonates (ANPs) possess antiviral and antiproliferative activities. However, several clinically important ANPs may cause renal injury, most likely due to their active accumulation in the renal tubular cells. The goal of this study was to investigate in vitro relationships between the affinity of several structurally related potent ANPs to selected human transporters and their cytotoxicity. SLC (solute carrier family) transporters (hOAT1, hOCT2, hCNT2, hCNT3) and ABC (ATP-binding cassette) transporters (MDR1, BCRP), which are typically expressed in the kidney, were included in the study. The transport and toxic parameters of the tested compounds were compared to those of two clinically approved ANPs, adefovir and tenofovir. Transport studies with transiently transfected cells were used as the main method in the experiments. Most of the ANPs studied showed the potency to interact with hOAT1. GS-9191, a double prodrug of PMEG, displayed an affinity for hOAT1 comparable with that of adefovir and tenofovir. No significant interaction of the tested ANPs with hOCT2, hCNT2 and hCNT3 was observed. Only GS-9191 was found to be a strong inhibitor for both MDR1 and BCRP. PMEO-DAPy showed the potency to interact with MDR1. Most of the tested substances caused a significant decrease in cellular viability in the cells transfected with hOAT1. Only with the exclusion of GS-9191, a relatively lipophilic compound, did the in vitro cytotoxicity of the ANPs closely correspond to their potential to interact with hOAT1. The increased cytotoxicity of the studied ANPs found in OAT1 transfected cells was effectively reduced by OAT inhibitors probenecid and quercetin. The higher cytotoxicity of the compounds with affinity to hOAT1 proved in the inhibitory experiments evidences that ANPs are not only inhibitors but also substrates of hOAT1. Any clear relationship between the potency of ANPs to inhibit the studied efflux transporters and their cytotoxicity was not demonstrated. In conclusion, the study documented that among the studied transporters hOAT1 seems to be the decisive determinant for renal handling in most of the tested ANPs. This transporter may also play an important role in the mechanism of their potential cytotoxic effects. These facts are in good accordance with previous findings in the clinically used ANPs. 23833191 Formation of Arabidopsis Cryptochrome 2 Photobodies in Mammalian Nuclei: APPLICATION AS AN OPTOGENETIC DNA DAMAGE CHECKPOINT SWITCH. Nuclear bodies are discrete suborganelle structures that perform specialized functions in eukaryotic cells. In plant cells, light can induce de novo formation of nuclear bodies called photobodies (PBs) composed of the photosensory pigments, phytochrome (PHY) or cryptochrome (CRY). The mechanisms of formation, the exact compositions, and the functions of plant PBs are not known. Here, we have expressed Arabidopsis CRY2 (AtCRY2) in mammalian cells and analyzed its fate after blue light exposure to understand the requirements for PB formation, the functions of PBs, and their potential use in cell biology. We found that light efficiently induces AtCRY2-PB formation in mammalian cells, indicating that, other than AtCRY2, no plant-specific proteins or nucleic acids are required for AtCRY2-PB formation. Irradiation of AtCRY2 led to its degradation; however, degradation was not dependent upon photobody formation. Furthermore, we found that AtCRY2 photobody formation is associated with light-stimulated interaction with mammalian COP1 E3 ligase. Finally, we demonstrate that by fusing AtCRY2 to the TopBP1 DNA damage checkpoint protein, light-induced AtCRY2 PBs can be used to activate DNA damage signaling pathway in the absence of DNA damage. 23782431 Klebsiella necrotizing soft tissue infections in liver transplant recipients: a case series. Necrotizing soft tissue infections (NSTI) are rare but carry high mortality rates. NSTI with Klebsiella species have been previously described as associated with Klebsiella liver abscesses and endophthalmitis. Here, we describe 6 cases of NSTI in liver transplant recipients associated with Klebsiella pneumoniae, 4 of which were K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae (CRKP). Increased awareness of this emerging pathogen and its association with necrotizing skin and soft tissue infection is critical, as early recognition and debridement may improve survival. Antimicrobial treatment of CRKP infections remains an ongoing challenge and implementation of enhanced infection control measures is essential. 23256532 Structural-Functional Studies of Burkholderia cenocepaciad-Glycero-β-d-manno-heptose 7-Phosphate Kinase (HldA) and Characterization of Inhibitors with Antibiotic Adjuvant and Antivirulence Properties. As an essential constituent of the outer membrane of Gram-negative bacteria, lipopolysaccharide contributes significantly to virulence and antibiotic resistance. The lipopolysaccharide biosynthetic pathway therefore serves as a promising therapeutic target for antivirulence drugs and antibiotic adjuvants. Here we report the structural-functional studies of d-glycero-β-d-manno-heptose 7-phosphate kinase (HldA), an absolutely conserved enzyme in this pathway, from Burkholderia cenocepacia. HldA is structurally similar to members of the PfkB carbohydrate kinase family and appears to catalyze heptose phosphorylation via an in-line mechanism mediated mainly by a conserved aspartate, Asp270. Moreover, we report the structures of HldA in complex with two potent inhibitors in which both inhibitors adopt a folded conformation and occupy the nucleotide-binding sites. Together, these results provide important insight into the mechanism of HldA-catalyzed heptose phosphorylation and necessary information for further development of HldA inhibitors. 23602938 The intergenerational transmission of smoking in adulthood: a 25-year study of maternal and offspring maladaptive attributes. While smoking is a major cause of mortality and morbidity, and maternal smoking is a risk factor for smoking among their offspring, the mechanisms involved in the intergenerational transmission of smoking are not well understood. This study examines the pathways from maternal and adolescent child factors, and the parent-child relationship, to smoking among the adult offspring, approximately 25 years later. Data for the present analysis were based on time waves 2 (T2; 1983) and 7 (T7; 2007-2009) of an on-going study of a community sample of mothers and their children. Offspring and mother X¯ ages were 14.1 and 40.0 years, respectively, at T2, and 36.6 and 65.0 years, respectively, at T7. At T2, trained interviewers administered individual structured interviews. Psychosocial questionnaires were self-administered at T7. Structural equation modeling (SEM) was used to analyze the interrelationships among maternal and offspring attributes (T2 and T7). SEM results indicated a satisfactory model fit (RMSEA=0.052; CFI=0.91; SRMR=0.057), and confirmed hypothesized pathways. One pathway linked maternal maladaptive attributes (T2) to the mother-adolescent child attachment relationship (T2), which was associated with the offspring's maladaptive attributes over time (T2 to T7), which then predicted the adult offspring's smoking (T7). Other pathways highlighted the stability of maternal smoking, the continuity of maladaptive attributes, and less offspring educational attainment as predictors of offspring smoking at T7. Findings suggest the importance of early interventions to treat maternal smoking, maternal and offspring maladaptive attributes, and the mother-child relationship in order to reduce risk factors for the intergenerational transmission of smoking behavior. Interventions which enhance educational success should also prove effective in reducing smoking. 23834451 The cost of wound debridement: a Canadian perspective. Debridement is integral to wound bed preparation by removing devitalised tissue, foreign material, senescent cells, phenotypically abnormal/dysfunctional cells (cellular burden) and bacteria sequestrum (biofilm). While the body of evidence to substantiate the benefits of debridement is growing, little is known about the cost-effectiveness of each debridement method. The purpose of this analysis was to compare cost-effectiveness of various debridement methods and clinical outcomes to help inform clinicians and policy makers of the cost-effectiveness associated with the various types of therapies and the impact they can have on the Canadian health care system. Results indicated that sharp debridement was the most cost-effective followed by enzymatic debridement method. 23715674 Analysis of monosaccharides and oligosaccharides in the pulp and paper industry by use of capillary zone electrophoresis: a review. Carbohydrate analysis is an important source of the information required for understanding and control of pulp and paper processes. The behavior of cellulose and hemicelluloses in the process, carbohydrate-lignin interactions, and the enzymatic treatment of fibers are examples of situations for which reliable, fast, qualitative, and quantitative methods are required. New uses of lignocellulosic material have further increased the need for carbohydrate analysis. This review collates and summarizes the most important findings and approaches in the analysis of wood-based carbohydrates by use of capillary zone electrophoresis and provides an analysis of the effect of different conditions on the separation, showing the advantages and limitations of the methods used. It provides guidelines for achieving higher quality and improved separation efficiency in carbohydrate analysis. 23281423 Is this the dose for you?: the role of modeling. To make an informed benefit-risk evaluation of a drug, a range of doses needs to be evaluated and its dose-response and exposure-response relationships for safety and effectiveness assessed during drug development (International Conference on Harmonisation E4). Once a safe and effective population dose (or doses) has been determined for indicated use(s), the individual patient dose can then be adjusted based on patient-specific factors (e.g., age, race, genetics, organ functions, concomitant medications). 23861869 Cytomegalovirus pp71 Protein Is Expressed in Human Glioblastoma and Promotes Pro-Angiogenic Signaling by Activation of Stem Cell Factor. Glioblastoma multiforme (GBM) is a highly malignant primary central nervous system neoplasm characterized by tumor cell invasion, robust angiogenesis, and a mean survival of 15 months. Human cytomegalovirus (HCMV) infection is present in >90% of GBMs, although the role the virus plays in GBM pathogenesis is unclear. We report here that HCMV pp71, a viral protein previously shown to promote cell cycle progression, is present in a majority of human GBMs and is preferentially expressed in the CD133+, cancer stem-like cell population. Overexpression of pp71 in adult neural precursor cells resulted in potent induction of stem cell factor (SCF), an important pro-angiogenic factor in GBM. Using double immunofluorescence, we demonstrate in situ co-localization of pp71 and SCF in clinical GBM specimens. pp71 overexpression in both normal and transformed glial cells increased SCF secretion and this effect was specific, since siRNA mediated knockdown of pp71 or treatment with the antiviral drug cidofovir resulted in decreased expression and secretion of SCF by HCMV-infected cells. pp71- induced upregulation of SCF resulted in downstream activation of its putative endothelial cell receptor, c-kit, and angiogenesis as measured by increased capillary tube formation in vitro. We demonstrate that pp71 induces a pro-inflammatory response via activation of NFΚB signaling which drives SCF expression. Furthermore, we show that pp71 levels and NFKB activation are selectively augmented in the mesenchymal subtype of human GBMs, characterized by worst patient outcome, suggesting that HCMV pp71-induced paracrine signaling may contribute to the aggressive phenotype of this human malignancy. 23970176 The advantage of using 3-week data to predict response to aripiprazole at week 6 in first-episode psychosis. We investigated the efficacy and safety of aripiprazole in first-episode psychosis and explored the association between early response and later response to this medication. This was a 6-week, open-label, multicenter trial. The study population consisted of 59 patients with a DSM-IV diagnosis of a schizophreniform disorder, schizoaffective disorder, schizophrenia, or psychotic disorder not otherwise specified. The primary outcome measures were the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression-Severity scale. To assess the safety, we measured the drug-related adverse events, weight, and lipid-related variables. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated for the response status at weeks 2 and 3 to predict the subsequent response at week 6. Among the 59 participants, 38 were able to complete the 6-week trial. Treatment with aripiprazole resulted in significant improvement in the PANSS and Clinical Global Impression scores over time. The response rate (defined as a ≥30% decrease in the PANSS total score from baseline to the last observation) was 69.1%. The most accurate prediction of later response in terms of negative predictive value and specificity was a reduction in the PANSS total score from baseline to week 3 of at least 20%. Aripiprazole had a modest side effect burden and was characterized by a safe profile with respect to weight and metabolic side effects. These results indicate that aripiprazole is effective and safe in the treatment of first-episode psychosis. The response at week 3, rather than week 2, predicted the later response more accurately. 23941857 Triple antithrombotic therapy is the independent predictor for the occurrence of major bleeding complications: analysis of percent time in therapeutic range. Triple antithrombotic therapy increases the risk of bleeding events in patients undergoing percutaneous coronary intervention. However, it remains unclear whether good control of percent time in therapeutic range is associated with reduced occurrence of bleeding complications in patients undergoing triple antithrombotic therapy. This study included 2648 patients (70±11 years; 2037 men) who underwent percutaneous coronary intervention with stent in the Ibaraki Cardiovascular Assessment Study registry and received dual antiplatelet therapy with or without warfarin. Clinical end points were defined as the occurrence of major bleeding complications (MBC), major adverse cardiac and cerebrovascular event, and all-cause death. Among these 2648 patients, 182 (7%) patients received warfarin. After a median follow-up period of 25 months (interquartile range, 15-35 months), MBC had occurred in 48 (2%) patients, major adverse cardiac and cerebrovascular event in 484 (18%) patients, and all-cause death in 206 (8%) patients. Multivariable Cox regression analysis revealed that triple antithrombotic therapy was the independent predictor for the occurrence of MBC (hazard ratio, 7.25; 95% confidence interval, 3.05-17.21; P<0.001). The time in therapeutic range value did not differ between the patients with and without MBC occurrence (83% [interquartile range, 50%-90%] versus 75% [interquartile range, 58%-87%]; P=0.7). However, the mean international normalized ratio of prothrombin time at the time of MBC occurrence was 3.3±2.1. Triple antithrombotic therapy did not have a predictive value for the occurrence of all-cause death (P=0.1) and stroke (P=0.2). Triple antithrombotic therapy predisposes patients to an increased risk of MBC regardless of the time in therapeutic range. 23921422 Targeted Motor Rehabilitation Dissociates Corticobulbar Versus Corticospinal Dysfunction in an Animal Model of Parkinson's Disease. Recent evidence suggests that motor training may be beneficial for slowing the onset of motor impairments in Parkinson's disease (PD). To examine the impact of targeted rehabilitation on limb motor and cranial motor function and the corresponding corticospinal and corticobulbar circuits in a rodent model of PD. Baseline performance of limb (reaching) and cranial (licking) motor function were established prior to and 6 weeks following unilateral intrastriatal 6-hydroxydopamine (6-OHDA) infusions. Animals then received 6 weeks of limb motor rehabilitation (LMR) or cranial motor rehabilitation (CMR), after which motor performance was reassessed. Intracortical microstimulation (ICMS) was used to generate motor maps of corresponding corticospinal (forelimb) and corticobulbar (tongue) movement representations within the motor cortex ipsilateral to the 6-OHDA infusion. Quantitative tyrosine hydroxylase (TH) immunohistochemistry was performed to determine levels of striatal TH depletion in 6-OHDA animals using near infrared densitometry. (1) unilateral intrastriatal dopamine depletion impaired both reaching accuracy and lick force; (2) targeted LMR ameliorated impairments in reaching performance; however, CMR did not improve lick force impairments; (3) unilateral dopamine depletion significantly reduced forelimb but not tongue motor map topography; (4) LMR partially restored forelimb motor maps, whereas CMR did not alter tongue motor maps; and (5) significant correlations were observed between skilled reaching accuracy, forelimb motor map area, and TH depletion, but no relationships were revealed for cranial motor function, motor maps, or TH depletion. These data demonstrate dissociation between striatal dopamine depletion, limb versus cranial motor function, and targeted motor rehabilitation in a rodent model of PD. 23632085 Anti-allergic actions of rottlerin from Mallotus philippinensis in experimental mast cell-mediated anaphylactic models. Allergy is an acquired hypersensitivity reaction of the immune system mediated by cross-linking of the allergen-specific IgE-bound high-affinity IgE receptors, leading to immediate mast cell degranulation. Rottlerin is an active molecule isolated from Mallotus philippinensis, a medicinal plant used in Ayurvedic Medicine System for anti-allergic and anti-helminthic treatments. The present study investigated potential anti-allergic effects of rottlerin in animal models of IgE-dependent anaphylaxis and the anti-allergic mechanisms of action of rottlerin in mast cells. Anti-allergic actions of rottlerin were evaluated in passive cutaneous anaphylaxis and passive systemic anaphylaxis mouse models, and in anaphylactic contraction of bronchial rings isolated from sensitized guinea pigs. Direct mast cell-stabilizing effect of rottlerin was examined in RBL-2H3 mast cell line. Anti-allergic signaling mechanisms of action of rottlerin in mast cells were also examined. Rottlerin prevented IgE-mediated cutaneous vascular extravasation, hypothermia, elevation in plasma histamine level and tracheal tissue mast cell degranulation in mice in a dose-dependent manner. In addition, rottlerin suppressed ovalbumin-induced guinea pig bronchial smooth muscle contraction. Furthermore, rottlerin concentration-dependently blocked IgE-mediated immediate release of β-hexosaminidase from RBL-2H3 mast cells. Rottlerin was found to inhibit IgE-induced PLCγ1 and Akt phosphorylation, production of IP3 and rise in cytosolic Ca(2+) level in mast cells. We report here for the first time that rottlerin possesses anti-allergic activity by blocking IgE-induced mast cell degranulation, providing a foundation for developing rottlerin for the treatment of allergic asthma and other mast cell-mediated allergic disorders. 23817355 Reynolds numbers influence the directionality of self-propelled microjet engines in the 10(-4) regime. The motion directionality of self-propelled bubble-jet microengines is influenced by their velocities and/or viscosity of the media in which they move. The influence of the fuel concentration from 1 to 3 wt% of H2O2 in 0.5% steps and of the glycerol fraction from 0 to 64% in aqueous solution on the directionality of the microjets motions is examined systematically. We show that with decreasing Reynolds numbers of the system (that is, with increasing viscosity or decreasing velocity of the microjets), the directionality of the motion shifts from circular to linear motion. This translates to a shorter travel time towards a designated target for the microjets despite moving at a slower speed, since the movements are linear instead of circular. We show that such dependence of trajectories of microjets on Re is a general issue. This observation has a strong implication for the real-world applications of microjets. 23872001 Pyroglutamyl apelin-13 identified as the major apelin isoform in human plasma. Apelin is emerging as an important hormone regulator of cardiovascular homoeostasis and an important biomarker for heart failure. Apelin concentrations have historically been measured by immunoassays; however, reported apelin concentrations measured in healthy volunteers show a large disparity from a few picograms per milliliter (pg/ml) to several nanograms per milliliter (ng/ml). Apelin exists in several isoforms ranging in size from 12 to 36 residues, and immunoassays generally cannot distinguish the specific forms present. In this study, an optimized method for enriching apelin peptides with cation-exchange beads followed with mass spectrometry analysis is presented. Apelin peptides are labile in plasma at physiological conditions; however, by lowering the plasma pH to 4.5, the recovery of apelin peptides can be increased significantly. Through optimizing the cation-exchange extraction process, we improved the lower limit of detection for most of the apelin peptides monitored to a few pg/ml. Using the improved method, we detected pyroglutamyl apelin-13 [(pyr)apelin-13] as the major apelin isoform present in plasma from several healthy volunteers at concentrations ranging from 7.7 to 23.3pg/ml. 22082826 Heat stress decreases testicular germ cell proliferation and increases apoptosis in short term: an immunohistochemical and ultrastructural study. Scrotal hyperthermia has been known as a cause of male infertility but the exact mechanism leading to impaired spermatogenesis is unknown. This work was aimed to investigate the role of scrotal hyperthermia on cell proliferation and apoptosis in testes. The rats were randomly allotted into one of the four experimental groups: A (control), B (1 day after scrotal hyperthermia), C (14 days after scrotal hyperthermia), and D (35 days after scrotal hyperthermia); each group comprised 7 animals. Scrotal hyperthermia was carried out in a thermostatically controlled water bath at 43°C for 30 min once daily for 6 consecutive days. Control rats were treated in the same way, except the testes were immersed in a water bath maintained at 22°C. Hyperthermia-exposed rats were killed under 50 mg/kg ketamine anaesthesia and tissue samples were obtained for biochemical and histopathological investigations. Hyperthermia treatment significantly decreased the testicular antioxidant system, including decreases in the glutathione level, superoxide dismutase, and glutathione peroxidase activities. Moreover, exposure to hyperthermia resulted in lipid peroxidation increase in testes. Our data indicate a significant reduction in the expression of proliferating cell nuclear antigen and an enhancement in the activity of terminal deoxynucleotidyl transferase dUTP nick end labelling after scrotal hyperthermia. In scrotal hyperthermia, the mitochondrial degeneration, dilatation of smooth endoplasmic reticulum, and enlarged intercellular spaces were observed in both Sertoli and spermatid cells. Scrotal hyperthermia is one of the major factors that impair spermatogenesis in testis. This heat stress is shown to be closely associated with oxidative stress, followed by apoptosis of germ cells. 23607495 Improving quality and safety in the hospital: the link between organizational culture, burnout, and quality of care. The need to improve quality of care represents a major goal of all health care systems. The objective of this series is to illuminate how the contextual factors of hospitals from eight European countries, and the well-being of their healthcare professionals, contribute to either construct or degrade quality of care. The studies reported here provide an important bottom-up perspective on quality of care, and the way that burnout and organizational culture are intertwined within it. Overall, the collected studies represent an in-depth examination through focus groups of the experiences of 153 physicians, 133 nurses, and 46 patients from Greece, Portugal, Bulgaria, Romania, Ireland, Turkey, Croatia, and the Republic of Macedonia. Each paper makes a unique contribution to the understanding of how institutional contexts, organizational management, and job characteristics impose constrains, both on the capacity of health workers for better treatment decisions and choices, but also on their day-to-day professional satisfaction and quality of life. Taken as a whole, the papers make an even greater contribution, by pointing out the underlying similarities and differences across these eight European countries. 23831975 Spectroscopic analysis and efficient diode-pumped 2.0μm emission in Ho(3+)/Tm(3+) codoped fluoride glass. Intense 2.0μm emission has been obtained in Ho(3+)/Tm(3+) codoped ZBLAY glass pumped by common laser diode. Three intensity parameters and radiative properties have been determined from the absorption spectrum based on the Judd-Ofelt theory. The 2μm emission characteristics and the energy transfer mechanism upon excitation of a conventional 800nm laser diode are investigated. Efficient Tm(3+) to Ho(3+) energy transfer processes have been observed in present glass and investigated using steady-state and time-resolved optical spectroscopy measurement. The energy transfer microscopic parameter has been calculated with the Inokuti-Hirayama and Förster-Dexter models. High quantum efficiency of 2μm emission (80.35%) and large energy transfer coefficient from Tm(3+) to Ho(3+) indicates this Ho(3+)/Tm(3+) codoped ZBLAY glass is a promising material for 2.0μm laser. 23426956 Chromatin Remodeling by Rosuvastatin Normalizes TSC2-/meth Cell Phenotype through the Expression of Tuberin. Tuberous sclerosis complex (TSC) is a multi-systemic syndrome caused by mutations in TSC1 or TSC2 gene. In TSC2-null cells, Rheb, a member of the Ras family of GTPases, is constitutively activated. Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase and block the synthesis of isoprenoid lipids with inhibition of Rheb farnesylation and RhoA geranylgeranylation. The effects of rosuvastatin on the function of human TSC2(-/-) and TSC2(-/meth) α-actin smooth muscle (ASM) cells have been investigated. The TSC2(-/-) and TSC2(-/meth) ASM cells, previously isolated in our laboratory from the renal angiomyolipoma of two TSC patients, do not express tuberin and bear loss of heterozigosity caused by a double hit on TSC2 and methylation of TSC2 promoter, respectively. Exposure to rosuvastatin affected TSC2(-/meth) ASM cell growth and promoted tuberin expression by acting as a demethylating agent. This occurred without changes in interleukin release. Rosuvastatin also reduced RhoA activation in TSC2(-/meth) ASM cells, and it required coadministration with the specific mTOR (mammalian target of rapamycin) inhibitor rapamycin to be effective in TSC2(-/-) ASM cells. Rapamycin enhanced rosuvastatin effect in inhibiting cell proliferation in TSC2(-/-) and TSC2(-/meth) ASM cells. Rosuvastatin alone did not alter phosphorylation of S6 and extracellular signal-regulated kinase (ERK), and at the higher concentration, rosuvastatin and rapamycin slightly decreased ERK phosphorylation. These results suggest that rosuvastatin may potentially represent a treatment adjunct to the therapy with mTOR inhibitors now in clinical development for TSC. In particular, rosuvastatin appears useful when the disease is originated by epigenetic defects. 23789908 What does it mean to predict one's own utterances? Many authors have recently highlighted the importance of prediction for language comprehension. Pickering & Garrod (P&G) are the first to propose a central role for prediction in language production. This is an intriguing idea, but it is not clear what it means for speakers to predict their own utterances, and how prediction during production can be empirically distinguished from production proper. 23702063 Upper cervical spine movement during intubation with different airway devices. Prevention of secondary neurologic injury is critical during the airway management of a trauma patient. Trauma patients are assumed to have an unstable cervical spine (C-spine) until proven otherwise: orotracheal intubation during airway management may result in a certain amount of C-spine movement. This study, therefore, aimed to compare C-spine movement within different advanced airway devices (Macintosh blade, McCoy Blade, LMA, I-LMA, and Combitube) during airway management. A total of 3 fresh frozen cadavers were used. The cadavers were consecutively intubated by 4 different postgraduate year residents with LMA4, I-LMA5, Combitube (37F), Macintosh 3, and McCoy blades. The cinefluoroscopic view of the entire intubation process was recorded, and vertebral body angles were calculated. At the C0C1 level, compared with the McCoy laryngoscope (median, 7°), the LMA (median, 2.5°) and the Combitube (median, 1.5°) caused less extension of the cervical vertebra. In addition, the Combitube (median, -1°) and the I-LMA (median, -2°) caused less extension of the C2C3 region when compared with the Macintosh laryngoscope (median, 3°). There was no significant difference between groups at the C1C2, C3C4, and C4C5 segments. Supraglottic devices used during airway management cause C-spine movement less or equal to conventional laryngoscopes. Furthermore, because of ease of training and blind insertion, supraglottic devices can be safely used with trauma patients when C-spine integrity is a concern. 23759357 Synbiotic formulation of probiotic and lactulose combination for hepatic encephalopathy treatment: a realistic hope? Gut-produced ammonia plays a vital role in the pathogenesis of hepatic encephalopathy because cirrhotic liver fails to clear toxic metabolites. Small intestinal bacterial overgrowth and delayed gastrointestinal transit time in cirrhosis add to the pathogenesis. Lactulose is a mainstay in the treatment of hepatic encephalopathy. Another benefit of lactulose is its prebiotic effect on probiotics that reduce the activity of bacterial urease, resulting in decreased hyperammoneamia and increased elimination of ammonia and other nitrogenous waste through enteric toxin reduction technology. Synbiotic formulation of probiotic and lactulose can synergistically/additively reduce ammonia production, increase utilization and excretion of ammonia and other nitrogenous wastes, thereby improving the well-being of patients with hepatic encephalopathy. We hypothesize that oral administration of a synbiotic formulation prepared from a combination of selected microbial strains of probiotics and lactulose will offer additional protection against hepatic encephalopathy via intra-intestinal extraction of toxic solutes in patients with cirrhosis. 23936212 Human left ventral premotor cortex mediates matching of hand posture to object use. Visuomotor transformations for grasping have been associated with a fronto-parietal network in the monkey brain. The human homologue of the parietal monkey region (AIP) has been identified as the anterior part of the intraparietal sulcus (aIPS), whereas the putative human equivalent of the monkey frontal region (F5) is located in the ventral part of the premotor cortex (vPMC). Results from animal studies suggest that monkey F5 is involved in the selection of appropriate hand postures relative to the constraints of the task. In humans, the functional roles of aIPS and vPMC appear to be more complex and the relative contribution of each region to grasp selection remains uncertain. The present study aimed to identify modulation in brain areas sensitive to the difficulty level of tool object - hand posture matching. Seventeen healthy right handed participants underwent fMRI while observing pictures of familiar tool objects followed by pictures of hand postures. The task was to decide whether the hand posture matched the functional use of the previously shown object. Conditions were manipulated for level of difficulty. Compared to a picture matching control task, the tool object - hand posture matching conditions conjointly showed increased modulation in several left hemispheric regions of the superior and inferior parietal lobules (including aIPS), the middle occipital gyrus, and the inferior temporal gyrus. Comparison of hard versus easy conditions selectively modulated the left inferior frontal gyrus with peak activity located in its opercular part (Brodmann area (BA) 44). We suggest that in the human brain, vPMC/BA44 is involved in the matching of hand posture configurations in accordance with visual and functional demands. 23831333 TEMPORARY REMOVAL: A regulatory role of K(+)-Cl(-) cotransporter in the cell cycle progression of breast cancer MDA-MB-231 cells. The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. 23502972 Red Cell Volume Expansion at Altitude: A Meta-analysis and Monte Carlo Simulation. Altitude acclimatization is associated with a rapid increase in hematocrit. The time course and the contribution of the red cell volume expansion are not clear. The purpose of the present meta-analysis was to explore how much altitude exposure is required to induce polycythemia in healthy lowlanders. A systematic review was performed of 66 published articles (including 447 volunteers) identified through literature search. We performed a mixed-model random-effects meta-analysis and a Monte Carlo simulation on the extracted data. The following results were obtained in this study: 1) the red cell volume expansion for a given duration of exposure is dependent on altitude (P < 0.0001), that is, that the increase in red cell volume was accelerated at higher altitudes; and 2) the extent of the erythropoietic response depends on the initial red cell volume (P < 0.0001). It seems that exposure time must exceed 2 wk at an altitude of more than 4000 m to exert a statistically significant effect. At lower altitudes, longer exposure times are needed with altitudes lower than 3000 m not yielding an increase within 4 wk. Red cell volume response to hypoxia is generally slow, although it accelerates with increasing altitude. This, in combination with a dependency on initial red cell volume, suggests that, for example, athletes may need to spend more time at altitude to see an effect on red cell volume than commonly recommended. 23828068 Synthesis, Chiroptical Properties and Density Functional Theory Calculations of 3,3'-Biphenyl-2,2'-BiTropone. The synthesis of new bitropone derivatives, namely, 3,3'-biphenyl-2,2'-bitropone and 7,7'-biphenyl-2,2'-bitropone, are reported. Isolation of enantiomers arising from restricted rotation around the C-C bond connecting the tropone moieties was attempted by means of chiral high performance liquid chromatography (HPLC). No separation was obtained for 7,7'-biphenyl-2,2'-bitropone. For 3,3'-biphenyl-2,2'-bitropone, difficulties were encountered because of the low separation factor of the peaks and the presence of a rapid racemization process. However, quantitative chiroptical data on the antipodes were obtained by linking a circular dichroism (CD) spectrometer and a UV-vis spectrophotometric detector in series to the HPLC instrument. The analysis of the CD and UV-vis spectra in terms of absolute conformations was done with the help of theoretical calculations performed at the Density Functional Theory (DFT) level. The most stable conformations of the 3,3'-biphenyl-2,2'-bitropone in its ground state were obtained. Starting from these minimum energy conformations, it was possible to compute theoretical CD and UV absorption spectra that fit well with the experimental ones. From this comparison the absolute configuration to the antipodes was assigned. Finally, the effect of the presence of the two lateral phenyl substituents on the structure of the bitropone and hence on the CD spectrum is discussed. Chirality 00:000-000, 2013. © 2013 Wiley Periodicals, Inc. 23749407 Review on intermediate filaments of the nervous system and their pathological alterations. Intermediate filaments (IFs) of the nervous system, including neurofilaments, α-internexin, glial fibrillary acidic protein, synemin, nestin, peripherin and vimentin, are finely expressed following elaborated cell, tissue and developmental specific patterns. A common characteristic of several neurodegenerative diseases is the abnormal accumulation of neuronal IFs in cell bodies or along the axon, often associated with impairment of the axonal transport and degeneration of neurons. In this review, we also present several perturbations of IF metabolism and organization associated with neurodegenerative disorders. Such modifications could represent strong markers of neuronal damages. Moreover, recent data suggest that IFs represent potential biomarkers to determine the disease progression or the differential stages of a neuronal disorder. Finally, recent investigations on IF expression and function in cancer provide evidence that they may be useful as markers, or targets of brain tumours, especially high-grade glioma. A better knowledge of the molecular mechanisms of IF alterations, combined to neuroimaging, is essential to improve diagnosis and therapeutic strategies of such neurodegenerative diseases and glioma. 23777237 Creation of a new femtosecond laser-assisted mini-flap to enhance late regression after LASIK. To describe a method of LASIK enhancement in which a new femtosecond laser-assisted mini-flap is created over the original LASIK flap. The 60-kHz IntraLase femtosecond laser (IntraLase Corp., Irvine, CA) was used to create a new mini-flap over an original LASIK flap for the re-treatment of late regression after LASIK. The diameter of the mini-flap was 7 mm and the attempted flap depth was 100 μm. The procedure was performed on 10 eyes of 7 patients. No intraoperative or postoperative complications developed in any case during the follow-up. At the 6-month follow-up visit, all eyes were within ±0.5 diopters of the targeted refraction. The preliminary results suggest that creation of a femtosecond laser-assisted mini-flap over a previous LASIK flap seems to be a safe and effective procedure for the enhancement of late regression after LASIK. By creating a femtosecond laser-assisted mini-flap that is smaller in diameter than the original flap, the adhesion of the primary flap edges and peripheral interface remain intact, thus decreasing the risk of dislocation of the original LASIK flap and of losing a sliver of tissue. 23944160 The tail-associated depolymerase of Erwinia amylovora phage L1 mediates host cell adsorption and enzymatic capsule removal, which can enhance infection by other phage. The depolymerase enzyme (DpoL1) encoded by the T7-like phage L1 efficiently degrades amylovoran, an important virulence factor and major component of the extracellular polysaccharide (EPS) of its host, the plant pathogen Erwinia amylovora. Mass spectrometry analysis of hydrolysed EPS revealed that DpoL1 cleaves the galactose-containing backbone of amylovoran. The enzyme is most active at pH 6 and 50°C, and features a modular architecture. Removal of 180 N-terminal amino acids was shown not to affect enzyme activity. The C-terminus harbours the hydrolase activity, while the N-terminal domain links the enzyme to the phage particle. Electron microscopy demonstrated that DpoL1-specific antibodies cross-link phage particles at their tails, either lateral or frontal, and immunogold staining confirmed that DpoL1 is located at the tail spikes. Exposure of high-level EPS-producing Er. amylovora strain CFBP1430 to recombinant DpoL1 dramatically increased sensitivity to the Dpo-negative phage Y2, which was not the case for EPS-negative mutants or low-level EPS-producing Er. amylovora. Our findings indicate that enhanced phage susceptibility is based on enzymatic removal of the EPS capsule, normally a physical barrier to Y2 infection, and that use of DpoL1 together with the broad host range, virulent phage Y2 represents an attractive combination for biocontrol of fire blight. 23844122 A Luminex Assay Detects Amyloid β Oligomers in Alzheimer's Disease Cerebrospinal Fluid. Amyloid beta (aβ) protein assembles into larger protein aggregates during the pathogenesis of Alzheimer's disease (AD) and there is increasing evidence that soluble aβ oligomers are a critical pathologic species. Diagnostic evaluations rely on the measurement of increased tau and decreased aβ42 in the cerebrospinal fluid (CSF) from AD patients and evidence for oligomeric aβ in patient CSF is conflicting. In this study, we have adapted a monoclonal single antibody sandwich ELISA assay to a Luminex platform and found that this assay can detect oligomerized aβ42 and sAPPα fragments. We evaluated oligomeric aβ reactivity in 20 patients with AD relative to 19 age matched controls and compared these values with a commercially available Alzbio3 kit that detects tau, phosphorylated tau and aβ42 on the same diagnostic platform. We found that CSF samples of patients with AD had elevated aβ oligomers compared to control subjects (p < 0.05) and the ratio of aβ oligomers to aβ42 was also significantly elevated (p < 0.0001). Further research to develop high sensitivity analytical platforms and rigorous methods of developing stable assay standards will be needed before the analysis of oligomeric aβ becomes a routine diagnostic assay for the evaluation of late onset AD patients. 23959757 Do men consult less than women? An analysis of routinely collected UK general practice data. To examine whether gender differences in primary care consultation rates (1) vary by age and deprivation status and (2) diminish when consultation for reproductive reasons or common underlying morbidities are accounted for. Cross-sectional study of a cohort of patients registered with general practice. UK primary care. Patients (1 869 149 men and 1 916 898 women) registered with 446 eligible practices in 2010. Primary care consultation rate. This study analyses routinely collected primary care consultation data. The crude consultation rate was 32% lower in men than women. The magnitude of gender difference varied across the life course, and there was no 'excess' female consulting in early and later life. The greatest gender gap in primary care consultations was seen among those aged between 16 and 60 years. Gender differences in consulting were higher in people from more deprived areas than among those from more affluent areas. Accounting for reproductive-related consultations diminished but did not eradicate the gender gap. However, consultation rates in men and women who had comparable underlying morbidities (as assessed by receipt of medication) were similar; men in receipt of antidepressant medication were only 8% less likely to consult than women in receipt of antidepressant medication (relative risk (RR) 0.916, 95% CI 0.913 to 0.918), and men in receipt of medication to treat cardiovascular disease were just 5% less likely to consult (RR=0.950, 95% CI 0.948 to 0.952) than women receiving similar medication. These small gender differences diminished further, particularly for depression (RR=0.950, 95% CI 0.947 to 0.953), after also taking account of reproductive consultations. Overall gender differences in consulting are most marked between the ages of 16 and 60 years; these differences are only partially accounted for by consultations for reproductive reasons. Differences in consultation rates between men and women were largely eradicated when comparing men and women in receipt of medication for similar underlying morbidities. 23776166 Modification of triclosan scaffold in search of improved inhibitors for enoyl-acyl carrier protein (ACP) reductase in Toxoplasma gondii. Through our focused effort to discover new and effective agents against toxoplasmosis, a structure-based drug design approach was used to develop a series of potent inhibitors of the enoyl-acyl carrier protein (ACP) reductase (ENR) enzyme in Toxoplasma gondii (TgENR). Modifications to positions 5 and 4' of the well-known ENR inhibitor triclosan afforded a series of 29 new analogues. Among the resulting compounds, many showed high potency and improved physicochemical properties in comparison with the lead. The most potent compounds 16 a and 16 c have IC50 values of 250 nM against Toxoplasma gondii tachyzoites without apparent toxicity to the host cells. Their IC50 values against recombinant TgENR were found to be 43 and 26 nM, respectively. Additionally, 11 other analogues in this series had IC50 values ranging from 17 to 130 nM in the enzyme-based assay. With respect to their excellent in vitro activity as well as improved drug-like properties, the lead compounds 16 a and 16 c are deemed to be excellent starting points for the development of new medicines to effectively treat Toxoplasma gondii infections. 23821548 RLIP76 Protein Knockdown Attenuates Obesity Due to a High-fat Diet. Feeding a Western high-fat diet (HFD) to C57BL/6 mice induces obesity, associated with a chronic inflammatory state, lipid transport, and metabolic derangements, and organ system effects that particularly prominent in the kidneys. Here, we report that RLIP76 homozygous knock-out (RLIP76(-/-)) mice are highly resistant to obesity as well as these other features of metabolic syndrome caused by HFD. The normal increase in pro-inflammatory and fibrotic markers associated with HFD induced obesity in wild-type C57B mice was broadly and nearly completely abrogated in RLIP76(-/-) mice. This is a particularly striking finding because chemical markers of oxidative stress including lipid hydroperoxides and alkenals were significantly higher in RLIP76(-/-) mice. Whereas HFD caused marked suppression of AMPK in wild-type C57B mice, RLIP76(-/-) mice had baseline activation of AMP-activated protein kinase, which was not further affected by HFD. The baseline renal function was reduced in RLIP76(-/-) mice as compared with wild-type, but was unaffected by HFD, in marked contrast to severe renal impairment and glomerulopathy in the wild-type mice given HFD. Our findings confirm a fundamental role of RLIP76 in regulating the function of obesity-promoting pro-inflammatory cytokines, and provide a novel mechanism for targeted therapy of obesity and metabolic syndrome. 23268337 Naturally occurring HCA1 missense mutations result in loss of function: potential impact on lipid deposition. The hydroxy-carboxylic acid receptor (HCA1) is a G protein-coupled receptor that is highly expressed on adipocytes and considered a potential target for the treatment of dyslipidemia. In the current study, we investigated the pharmacological properties of naturally occurring variants in this receptor (H43Q, A110V, S172L, and D253H). After transient expression of these receptors into human embryonic kidney 293 cells, basal and ligand-induced signaling were assessed using luciferase reporter gene assays. The A110V, S172L, and D253 variants showed reduced basal activity; the S172L mutant displayed a decrease in potency to the endogenous ligand L-lactate. Both the S172L and D253H variants also showed impaired cell surface expression, which may in part explain the reduced activity of these receptors. The impact of a loss in HCA1 function on lipid accumulation was investigated in the adipocyte cell line, OP9. In these cells, endogenous HCA1 transcript levels rapidly increased and reached maximal levels 3 days after the addition of differentiation media. Knockdown of HCA1 using siRNA resulted in an increase in lipid accumulation as assessed by quantification of Nile Red staining and TLC analysis. Our data suggest that lipid homeostasis may be altered in carriers of selected HCA1 missense variants. 22659408 Glycine release is regulated by metabotropic glutamate receptors sensitive to mGluR2/3 ligands and activated by N-acetylaspartylglutamate (NAAG). The presence of metabotropic glutamate receptors (mGluRs) of group II modulating glycine exocytosis from glycinergic nerve endings of mouse spinal cord was investigated. Purified synaptosomes were selectively prelabeled with [(3)H]glycine through the neuronal transporter GlyT2 and subsequently depolarized by superfusion with 12 mM KCl. The selective mGluR2/3 agonist LY379268 inhibited the K(+)-evoked overflow of [(3)H]glycine in a concentration-dependent manner (EC(50) about 0.2 nM). The effect of LY379268 was prevented by the selective mGluR2/3 antagonist LY341495 (IC(50) about 1 nM). N-acetylaspartylglutamate (NAAG) inhibited [(3)H]glycine overflow with extraordinary potency (EC(50) about 50 fmol). In contrast, glutamate was ineffective up to 0.1 nM, excluding that glutamate contamination of commercial NAAG samples is responsible for the reported activity of NAAG at mGluR3. LY341495 antagonized the NAAG inhibition of [(3)H]glycine release. The effect of a combination of maximally effective concentrations of LY379268 and NAAG exhibited no additivity. The non-hydrolysable NAAG analogue N-acetylaspartyl-β-linked glutamate (β-NAAG) antagonized NAAG and LY379268. In conclusion, our results show that glycinergic nerve endings in spinal cord are endowed with group II mGluRs mediating inhibition of glycine exocytosis. NAAG can activate these presynaptic receptors with extremely high affinity and with characteristics compatible with the reported mGluR3 pharmacology. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23659597 Significant morbidity and mortality attributable to rothia mucilaginosa infections in children with hematological malignancies or following hematopoietic stem cell transplantation. Rothia mucilaginosa is a gram-positive coccus that poses a diagnostic challenge and often requires DNA pyrosequencing for diagnosis as it can be easily mistaken for coagulase-negative staphylococci on initial culture results. While it is often times normal human oral and upper respiratory tract microbiota, it can be a virulent pathogen in immunocompromised patients. Most commonly, it causes bacteremia (catheter and non-catheter related) and meningitis in these patients. Our objective was to report the incidence of R. mucilaginosa infections in neutropenic children with hematological malignancies or following hematopoietic stem cell transplantation at a major children's hospital. We report 11 patients in this cohort who developed clinically significant R. mucilaginosa infections, including three deaths directly attributable to this microorganism. Three patients developed significant neurological involvement, accounting for two of the deaths, and one patient died of disseminated infection. Except for one, all patients had severe neutropenia, central line catheters, and mucosal breakdown at the time of infection. Patients who succumbed never achieved neutrophil recovery. In conclusion, R. mucilaginosa can lead to life-threatening infections in immunocompromised hosts, especially in profoundly neutropenic patients. 23416946 Transcription forms and remodels supercoiling domains unfolding large-scale chromatin structures. DNA supercoiling is an inherent consequence of twisting DNA and is critical for regulating gene expression and DNA replication. However, DNA supercoiling at a genomic scale in human cells is uncharacterized. To map supercoiling, we used biotinylated trimethylpsoralen as a DNA structure probe to show that the human genome is organized into supercoiling domains. Domains are formed and remodeled by RNA polymerase and topoisomerase activities and are flanked by GC-AT boundaries and CTCF insulator protein-binding sites. Underwound domains are transcriptionally active and enriched in topoisomerase I, 'open' chromatin fibers and DNase I sites, but they are depleted of topoisomerase II. Furthermore, DNA supercoiling affects additional levels of chromatin compaction as underwound domains are cytologically decondensed, topologically constrained and decompacted by transcription of short RNAs. We suggest that supercoiling domains create a topological environment that facilitates gene activation, providing an evolutionary purpose for clustering genes along chromosomes. 23681398 Glycosylation status of serum in inflammatory arthritis in response to anti-TNF treatment. Objective. Glycosylation is the most common post-translational modification and is altered in disease. The typical glycosylation change in patients with inflammatory arthritis (IA) is a decrease in galactosylation levels on IgG. The aim of this study is to evaluate the effect of anti-TNF therapy on whole serum glycosylation from IA patients and determine whether these alterations in the glycome change upon treatment of the disease. Methods. Serum samples were collected from 54 IA patients before treatment and at 1 and 12 months after commencing anti-TNF therapy. N-linked glycans from whole serum samples were analysed using a high-throughput hydrophilic interaction liquid chromatography-based method. Results. Glycosylation on the serum proteins of IA patients changed significantly with anti-TNF treatment. We observed an increase in galactosylated glycans from IgG, also an increase in core-fucosylated biantennary galactosylated glycans and a decrease in sialylated triantennary glycans with and without outer arm fucose. This increase in galactosylated IgG glycans suggests a reversing of the N-glycome towards normal healthy profiles. These changes are strongly correlated with decreasing CRP, suggesting a link between glycosylation changes and decreases in inflammatory processes. Conclusion. Glycosylation changes in the serum of IA patients on anti-TNF therapy are strongly associated with a decrease in inflammatory processes and reflect the effect of anti-TNF on the immune system. 23323717 Diterpenoid alkaloids from Aconitum kirinense. A new C(18)-diterpenoid alkaloid, kirinenine A (1), was isolated from the root of Aconitum kirinense, along with eight known diterpenoid alkaloids. The structures of all compounds were characterized on the basis of extensive NMR and MS analyses and by comparison with literature values, and the new one was further confirmed by X-ray crystallographic diffraction. All the compounds were isolated from the title plant for the first time. 23682685 Immune thrombocytopenia - what are the new treatment options? Introduction: Primary immune thrombocytopenia (ITP) is a minor disease for many patients; however, the natural history is variable and unpredictable. Many patients who are in otherwise good health can be left untreated, especially if their platelet counts are close to 20 × 10(9)/l. The overall mortality rate for ITP is < 1%, and the morbidity and mortality associated with treatment can be worse than the disease. Areas covered: ITP is not purely due to platelet destruction and in a significant proportion platelet production is sub-optimal; the review will cover the newer developments with the thrombopoietin receptor agonists (TPOrAs) of which two agents, romiplostim and eltrombopag, are now licensed and these will be placed in context to conventional treatment. Expert opinion: There is an increasing understanding of the natural history of ITP and an increasing evidence-based approach to the disease and its management. Treatment should be aimed at the patient with a bleeding risk and should minimise the risk of adverse effects while maximising the chances of response. Few, if any, treatments are curative and treatment strategies need to be designed in ITP that manage patients with what can be a life-long condition with periodic relapses. 23884064 Combination interventions to prevent HCV transmission among people who inject drugs: modeling the impact of antiviral treatment, needle and syringe programs, and opiate substitution therapy. Background. Interventions such as opiate substitution therapy (OST) and high-coverage needle and syringe programs (HCNSP) cannot substantially reduce hepatitis C virus (HCV) prevalence among people who inject drugs (PWID). HCV antiviral treatment may prevent onward transmission. We project the impact of combining OST, HCNSP, and antiviral treatment on HCV prevalence/incidence among PWID. Methods. An HCV transmission model among PWID was used to project the combinations of OST, HCNSP, and antiviral treatment required to achieve different prevalence and incidence reductions within 10 years for 3 chronic prevalence scenarios and the impact of HCV treatment if only delivered through OST programs. Multivariate and univariate sensitivity analyses were performed. Results. Large reductions (>45%) in HCV chronic prevalence over 10 years require HCV antiviral treatment. Scaling up OST and HCNSP substantially reduces the treatment rate required to achieve specific HCV prevalence reductions. If OST and HCNSP coverage were increased to 40% each (no coverage at baseline), then annually treating 10, 23, or 42 per 1000 PWID over 10 years would halve prevalence for 20%, 40%, or 60% baseline chronic HCV prevalences, respectively. Approximately 30% fewer treatments are necessary with new direct-acting antivirals. If coverage of OST and HCNSP is 50% at baseline, similar prevalence reductions require higher treatment rates for the same OST and HCNSP coverage. Conclusions. Combining antiviral treatment with OST with HCNSP is critical for achieving substantial reductions (>50%) in HCV chronic prevalence over 10 years. Empirical studies are required on how best to scale up antiviral treatment and combine treatment with other interventions. 23895382 Phosphine-Catalyzed [3 + 2] Cycloaddition of Sulfamate-Derived Cyclic Imines with Allenoate: Synthesis of Sulfamate-Fused Dihydropyrroles. Ph3P-catalyzed [3 + 2] cycloaddition reaction of sulfamate-derived cyclic imines with allenoate has been developed, affording sulfamate-fused dihydropyrroles under very mild conditions in high yields. Using amino acid-based bifunctional phosphine as chiral catalyst, its asymmetric variant provided the corresponding products in good yields with moderate to excellent enantiomeric excesses (up to 91% yield and up to 98% ee). Subsequent transformations of the heterocyclic products gave various pharmaceutically attractive compounds. 23564629 Evaluating temporal relations in clinical text: 2012 i2b2 Challenge. The Sixth Informatics for Integrating Biology and the Bedside (i2b2) Natural Language Processing Challenge for Clinical Records focused on the temporal relations in clinical narratives. The organizers provided the research community with a corpus of discharge summaries annotated with temporal information, to be used for the development and evaluation of temporal reasoning systems. 18 teams from around the world participated in the challenge. During the workshop, participating teams presented comprehensive reviews and analysis of their systems, and outlined future research directions suggested by the challenge contributions. The challenge evaluated systems on the information extraction tasks that targeted: (1) clinically significant events, including both clinical concepts such as problems, tests, treatments, and clinical departments, and events relevant to the patient's clinical timeline, such as admissions, transfers between departments, etc; (2) temporal expressions, referring to the dates, times, durations, or frequencies phrases in the clinical text. The values of the extracted temporal expressions had to be normalized to an ISO specification standard; and (3) temporal relations, between the clinical events and temporal expressions. Participants determined pairs of events and temporal expressions that exhibited a temporal relation, and identified the temporal relation between them. For event detection, statistical machine learning (ML) methods consistently showed superior performance. While ML and rule based methods seemed to detect temporal expressions equally well, the best systems overwhelmingly adopted a rule based approach for value normalization. For temporal relation classification, the systems using hybrid approaches that combined ML and heuristics based methods produced the best results. 23952100 Serial Echocardiography in Very Preterm Infants: A Pilot Randomized Trial. To determine whether routine echocardiography increases diagnosis and treatment of patent ductus arteriosus (PDA) and whether randomized non-disclosure is a feasible strategy for studying PDA management. 2 center pilot randomized, controlled trial. 88 infants with birth weights <1250 grams and gestational ages <30 weeks were randomized to disclosure or non-disclosure of serial echocardiogram findings. Echocardiograms were performed at 3-5 and 7-10 days of life. The primary outcome was time to regain birth weight. 100% of echocardiograms in the disclosure group were disclosed; 16% (echocardiogram #1) and 29% (echocardiogram #2) were disclosed in the non-disclosure group. There was a statistically non-significant decrease in drug therapy for PDA in the non-disclosure group (adjusted odds ratio [AOR] 0.56, 95% confidence interval [CI] 0.24-1.34). There was no difference in time to regain birth weight or in other important neonatal outcomes. However, infants in the non-disclosure group were more likely to demonstrate appropriate weight loss and then regain birth weight within 7-14 days (AOR 2.64, 95% CI 1.08-6.44). Randomized non-disclosure of echocardiograms is a feasible strategy for evaluation of approaches to PDA management in very preterm infants. Avoidance of routine echocardiography may reduce drug therapy for PDA without adverse clinical effects. This article is protected by copyright. All rights reserved. 22751184 Recent advances toward defining the benefits and risks of erythrocyte transfusions in neonates. Like many treatments available to small or ill neonates, erythrocyte transfusions carry both benefits and risks. This review examines recent publications aimed at better defining those benefits and those risks, as means of advancing evidence-based neonatal intensive care unit transfusion practices. Since decisions regarding whether to not to order an erythrocyte transfusion are based, in part, on the neonate's blood haemoglobin concentration, the authors also review recent studies aimed at preventing the haemoglobin from falling to a point where a transfusion is considered. 23602842 Vulvar embryonal rhabdomyosarcoma: a case report. Embryonal rhabdomyosarcoma (ERMS) is a rare malignant neoplasm found in both male and female children. It typically presents as a protruding vaginal mass with vaginal bleeding in girls less than 8 years of age. It is often seen as the sarcoma botryoides histologic sub type. This report represents the first case study of ERMS presenting as a vulvar mass. The article further explores the etiologies of pediatric vulvar masses, including ERMS, and the suggested diagnostic and treatment modalities. 23877146 Use of Cyanide Antidotes in Burn Patients With Suspected Inhalation Injuries in North America: A Cross-Sectional Survey. This study aimed to assessthe use of cyanide antidotes and the determine the opinion on empiric administration of hydroxocobalamin in North American burn patients with suspected smoke inhalation injuries.sAn online cross-sectional survey was sent to directors of 90 major burn centers in North America, which were listed on the American Burn Association Web site. A multiple-choice format was used to determine the percentage of patients tested for cyanide poisoning on admission, the current administration of a cyanide antidote based solely on clinical suspicion of poisoning, and the antidote used. To ascertain views on immediate administration of hydroxocobalamin before confirmation of cyanide poisoning an option was included to expand the response in written format. Twenty-nine of 90 burn directors (32%) completed the survey. For the population of interest, the majority of burn centers (59%) do not test for cyanide poisoning on admission and do not administer an antidote based solely on clinical suspicion of cyanide poisoning (58%). The most commonly available antidote is hydroxocobalamin (50%), followed by the cyanide antidote kit (29%). The opinion regarding instant administration of hydroxocobalamin when inhalation injury is suspected is mixed: 31% support its empiric use, 17% do not, and the remaining 52% have varying degrees of confidence in its utility. In North America, most patients burnt in closed-space fires with inhalation injuries are neither tested for cyanide poisoning in a timely manner nor empirically treated with a cyanide antidote. Although studies have shown the safety and efficacy of empiric and immediate administration of hydroxocobalamin, most centers are not willing to do so. 23418096 Spatial reconstruction by patients with hippocampal damage is dominated by relational memory errors. Hippocampal damage causes profound yet circumscribed memory impairment across diverse stimulus types and testing formats. Here, within a single test format involving a single class of stimuli, we identified different performance errors to better characterize the specifics of the underlying deficit. The task involved study and reconstruction of object arrays across brief retention intervals. The most striking feature of patients' with hippocampal damage performance was that they tended to reverse the relative positions of item pairs within arrays of any size, effectively "swapping" pairs of objects. These "swap errors" were the primary error type in amnesia, almost never occurred in healthy comparison participants, and actually contributed to poor performance on more traditional metrics (such as distance between studied and reconstructed location). Patients made swap errors even in trials involving only a single pair of objects. The selectivity and severity of this particular deficit creates serious challenges for theories of memory and hippocampus. 23222539 Chromatin-dependent and -independent regulation of DNA replication origin activation in budding yeast. To elucidate the role of the chromatin environment in the regulation of replication origin activation, autonomously replicating sequences were inserted into identical locations in the budding yeast genome and their activation times in S phase determined. Chromatin-dependent origins adopt to the firing time of the surrounding locus. In contrast, the origins containing two binding sites for Forkhead transcription factors are activated early in the S phase regardless of their location in the genome. Our results also show that genuinely late-replicating parts of the genome can be converted into early-replicating loci by insertion of a chromatin-independent early replication origin, ARS607, whereas insertion of two Forkhead-binding sites is not sufficient for conversion. 23845777 Molecular characterization of WFS1 in an Iranian family with Wolfram syndrome reveals a novel frameshift mutation associated with early symptoms. Wolfram syndrome (WS) is a rare autosomal recessive neurodegenerative disorder that represents a likely source of childhood diabetes especially among countries in the consanguinity belt. The main responsible gene is WFS1 for which over one hundred mutations have been reported from different ethnic groups. The aim of this study was to identify the molecular etiology of WS and to perform a possible genotype-phenotype correlation in Iranian kindred. An Iranian family with two patients was clinically studied and WS was suspected. Genetic linkage analysis via 5 STR markers was carried out. For identification of mutations, DNA sequencing of WFS1 including all the exons, exon-intron boundaries and the promoter was performed. Linkage analysis indicated linkage to the WFS1 region. After DNA sequencing of WFS1, one novel pathogenic mutation, which causes frameshift alteration c.2177_2178insTCTTC (or c.2173_2177dupTCTTC) in exon eight, was found. The genotype-phenotype correlation analysis suggests that the presence of the homozygous mutation may be associated with early onset of disease symptoms. This study stresses the necessity of considering the molecular analysis of WFS1 in childhood diabetes with some symptoms of WS. 23878281 Liver Fibrosis: Histopathologic and Biochemical Influences on Diagnostic Efficacy of Hepatobiliary Contrast-enhanced MR Imaging in Staging. Purpose:To evaluate the diagnostic performance of gadoxetic acid-enhanced magnetic resonance (MR) imaging in the staging of liver fibrosis in patients with diffuse chronic liver diseases (CLDs) and to investigate the factors that may influence the results.Materials and Methods:With the approval of the Hospital Ethics Committee and waiver of the informed consent requirement, data in 102 patients with histologically proven liver fibrosis (classified according to the METAVIR system) of various underlying causes were retrospectively analyzed. Patients underwent 3.0-T MR imaging with gadoxetic acid. The signal intensity of the liver was defined by using region of interest measurements before contrast material injection and in the hepatobiliary phase (20 minutes after contrast material administration), and relative enhancement was calculated. Univariate and multivariate regression analyses were applied to identify variables associated with relative enhancement measurements, and the performance of relative enhancement measurements in the staging of liver fibrosis was assessed by using area under the receiver operating characteristic curve (AUC) analysis.Results:At analysis of the relationship between enhancement measurements and histologic parameters, the relative enhancement values correlated strongly with liver fibrosis stage (r = -0.65, P < .0001) and moderately with necroinflammatory activity grades (r = -0.41, P = .002) and the presence of iron load (r = -0.21, P = .05). In multivariate analysis, only liver fibrosis stage independently influenced relative enhancement values (P < .001). The measurements performed well in the staging of liver fibrosis, with an AUC of 0.81 for stages of F1 or greater, 0.82 for stages of F2 or greater, 0.85 for stages of F3 or greater, and 0.83 for stage F4. Increased aspartate aminotransferase, gammaglutamyl transpeptidase, and alkaline phosphatase levels were independent predictors of false-negative results.Conclusion:The presence of hepatic fibrosis can be assessed with good discrimination by using gadoxetic acid-enhanced MR imaging, but assessment can be confounded in the setting of abnormal aspartate aminotransferase, gammaglutamyl transpeptidase, and alkaline phosphatase levels.© RSNA, 2013. 23816215 Perceived patient safety culture in a critical care transport program. The purpose of this study was to examine the association among selected safety culture dimensions and safety outcomes in the context of a critical care transport (CCT) program. A descriptive cross-sectional correlational design used the Agency for Healthcare Research and Quality Hospital Survey on Patient Safety Culture to validate perceived safety culture among personnel (n = 76) in a large Midwestern CCT program. Findings revealed significant associations between 1) teamwork and frequency of error reporting (r = .428, P < .001), overall perception of safety (r = .745, P < .001), and perceived patient safety grade (r = -.681, P < .001); 2) between perception of manager actions promoting safety and frequency of error reporting (r = .521, P < .001), overall perception of safety (r = .779, P < .001), and perceived patient safety grade (r = -.756, P < .001); and 3) between communication openness and frequency of error reporting (r = .575, P < .001), overall perception of safety (r = .588, P < .001), and perceived patient safety grade (r = -.627, P < .001). The study supports other literature showing significant associations among safety culture dimensions and safety outcomes and provides a framework for future research on safety culture in CCT programs. 23347198 Comparison of alternating pressure mattresses and overlays for prevention of pressure ulcers in ventilated intensive care patients: a quasi-experimental study. To compare the effectiveness of alternating pressure air mattresses vs. overlays to prevent pressure ulcers in mechanically ventilated patients in intensive care units. Pressure ulcers prevention is an important issue in the nursing of critically ill patients. It is not clear whether alternating pressure air mattresses are more effective than overlays to prevent pressure ulcers. Prospective quasi-experimental study. A prospective quasi-experimental study was conducted among patients in the medical-surgery intensive care unit of a university hospital on mechanical ventilation ≥24 hours during two time periods (2001 and 2006). Overlays were used in 2001 and mattresses in 2006. Primary outcome was the incidence of pressure ulcers grade ≥II (according to the European Pressure Ulcer Advisory Panel) during intensive care unit stay. The study included 221 patients (116 in 2001 and 105 in 2006). Baseline characteristics were similar between groups except for a higher Acute Physiology and Chronic Health Evaluation III score, total and first-day respiratory Sequential Organ Failure Assessment Score on day 1 in overlay group. There was significantly lower incidence density in the mattress vs. overlay group (12·41 cases/1000 days vs. 18·67 cases/1000 days of stay). The multivariate analyses showed the use of the mattress to be a protective factor against pressure ulcer onset. This quasi-experiment study that alternative pressure air mattresses were more effective than alternating pressure air overlays in preventing pressure ulcers in mechanically ventilated critical care patients. 23968620 Comparison of the American-European Consensus Group Sjogren's syndrome classification criteria to newly proposed American College of Rheumatology criteria in a large, carefully characterised SICCA cohort. To compare the performance of the American-European Consensus Group (AECG) and the newly proposed American College of Rheumatology (ACR) classification criteria for Sjögren's Syndrome (SS) in a well-characterised sicca cohort, given ongoing efforts to resolve discrepancies and weaknesses in the systems. In a multidisciplinary clinic for the evaluation of sicca, we assessed features of salivary and lacrimal gland dysfunction and autoimmunity as defined by tests of both AECG and ACR criteria in 646 participants. Global gene expression profiles were compared in a subset of 180 participants. Application of the AECG and ACR criteria resulted in classification of 279 and 268 participants with SS, respectively. Both criteria were met by 244 participants (81%). In 26 of the 35 AECG+/ACR participants, the minor salivary gland biopsy focal score was ≥1 (74%), while nine had positive anti-Ro/La (26%). There were 24 AECG-/ACR+ who met ACR criteria mainly due to differences in the scoring of corneal staining. All patients with SS, regardless of classification, had similar gene expression profiles, which were distinct from the healthy controls. The two sets of classification criteria yield concordant results in the majority of cases and gene expression profiling suggests that patients meeting either set of criteria are more similar to other SS participants than to healthy controls. Thus, there is no clear evidence for increased value of the new ACR criteria over the old AECG criteria from the clinical or biological perspective. It is our contention, supported by this report, that improvements in diagnostic acumen will require a more fundamental understanding of the pathogenic mechanisms than is at present available. 23693027 Congenital hypothyroidism alters the oxidative status, enzyme activities and morphological parameters in the hippocampus of developing rats. Congenital hypothyroidism is associated with delay in cell migration and proliferation in brain tissue, impairment of synapse formation, misregulation of neurotransmitters, hypomyelination and mental retardation. However, the mechanisms underlying the neuropsychological deficits observed in congenital hypothyroidism are not completely understood. In the present study we proposed a mechanism by which hypothyroidism leads to hippocampal neurotoxicity. Congenital hypothyroidism induces c-Jun-N-terminal kinase (JNK) pathway activation leading to hyperphosphorylation of the glial fibrillary acidic protein (GFAP), vimentin and neurofilament subunits from hippocampal astrocytes and neurons, respectively. Moreover, hyperphosphorylation of the cytoskeletal proteins was not reversed by T3 and poorly reversed by T4. In addition, congenital hypothyroidism is associated with downregulation of astrocyte glutamate transporters (GLAST and GLT-1) leading to decreased glutamate uptake and subsequent influx of Ca(2+) through N-methyl-D-aspartate (NMDA) receptors. The Na(+)-coupled (14)C-α-methyl-amino-isobutyric acid ((14)C-MeAIB) accumulation into hippocampal cells also might cause an increase in the intracellular Ca(2+) concentration by opening voltage-dependent calcium channels (VDCC). The excessive influx of Ca(2+) through NMDA receptors and VDCCs might lead to an overload of Ca(2+) within the cells, which set off glutamate excitotoxicity and oxidative stress. The inhibited acetylcholinesterase (AChE) activity might also induce Ca(2+) influx. The inhibited glucose-6-phosphate dehydrogenase (G6PD) and gamma-glutamyl transferase (GGT) activities, associated with altered glutamate and neutral amino acids uptake could somehow affect the GSH turnover, the antioxidant defense system, as well as the glutamate-glutamine cycle. Reduced levels of S100B and glial fibrillary acidic protein (GFAP) take part of the hypothyroid condition, suggesting a compromised astroglial/neuronal neurometabolic coupling which is probably related to the neurotoxic damage in hypothyroid brain. 23939643 Cluster headache. Cluster headache causes severe unilateral temporal or periorbital pain, lasting 15 to 180 minutes and accompanied by autonomic symptoms in the nose, eyes, and face. Headaches often recur at the same time each day during the cluster period, which can last for weeks to months. Some patients have chronic cluster headache without remission periods. The pathophysiology of cluster headache is not fully understood, but may include a genetic component. Cluster headache is more prevalent in men and typically begins between 20 and 40 years of age. Treatment focuses on avoiding triggers and includes abortive therapies, prophylaxis during the cluster period, and long-term treatment in patients with chronic cluster headache. Evidence supports the use of supplemental oxygen, sumatriptan, and zolmitriptan for acute treatment of episodic cluster headache. Verapamil is first-line prophylactic therapy and can also be used to treat chronic cluster headache. More invasive treatments, including nerve stimulation and surgery, may be helpful in refractory cases. 23742051 Attention deficit hyperactivity disorder in the European adult population: prevalence, disease awareness, and treatment guidelines. Abstract Background: Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurobiological disorder with childhood onset and persistence into adolescence and adulthood. Methods: Our literature review reports scientific publications and guidelines on the treatment of adult ADHD, with a particular focus on European countries, identified by literature searches in Medline and Embase. The final literature search was performed in July 2012, incorporating literature from 1974 to 2012. The primary research parameters were 'Europe' (including single European countries), 'ADHD', 'attention deficit disorder', 'attention deficit', 'attention disorder', and 'hyperactivity'. Secondary search parameters were 'comorbid', 'epidemiology' or 'prevalence', 'disease management', 'drug therapy', or 'therapy'. The main searches were also limited to adults and English language publications. The papers identified by this literature review were selected for inclusion by consensus of the authors based on clinical relevance. Results: Appropriate resources for the diagnosis and treatment of adult ADHD in Europe are scarce, and many cases go untreated, particularly because of the frequent presence of psychiatric comorbidities. Apart from atomoxetine, and an extended-release form of methylphenidate in Germany, no other medications have been approved for starting treatment in adult ADHD patients in the European Union. However, a variety of stimulant and non-stimulant medications are used off-label, and a number of studies have confirmed that these medications are well tolerated and effective in adult patients with ADHD. Conclusions: Our results emphasize the need for broader access to effective treatments for adult ADHD patients in Europe. 23969549 Compressed sampling for boundary measurements in three-dimensional electrical impedance tomography. Electrical impedance tomography (EIT) utilizes electrodes on a medium's surface to produce measured data from which the conductivity distribution inside the medium is estimated. For the cases that relocation of electrodes is impractical or no a priori assumptions can be made to optimize the electrodes placement, a large number of electrodes may be needed to cover all possible imaging volume. This may occur in dynamically varying conductivity distribution in 3D EIT. Three-dimensional EIT then requires inverting very large linear systems to calculate the conductivity field, which causes significant problems regarding storage space and reconstruction time in addition to that data acquisition for a large number of electrodes will reduce the achievable frame rate, which is considered as major advantage of EIT imaging. This study proposes an idea to reduce the reconstruction complexity based on the well-known compressed sampling theory. By applying the so-called model-based CoSaMP algorithm to large size data collected by a 256 channel system, the size of forward operator and data acquisition time is reduced to those of a 32 channel system, while accuracy of reconstruction is significantly improved. The results demonstrate great capability of compressed sampling for overriding the challenges arising in 3D EIT. 23690431 Impact of intraoperative hyperglycaemia on renal dysfunction after off-pump coronary artery bypass. Acute kidney injury (AKI) is one of the most frequently occurring complications after off-pump coronary artery bypass graft (OPCAB). Hyperglycaemia is a major, potentially modifiable risk factor of adverse outcome after cardiac surgery known to aggravate organ damage. The aim of this study was to address the association between intraoperative glucose concentration and postoperative AKI in patients who underwent OPCAB. The medical records of 880 consecutive patients were retrospectively reviewed. Patients were divided into three groups according to the time-weighted average of intraoperative glucose concentrations (<110, 110-150 and >150 mg/dl), and the incidence of AKI (increase of serum creatinine to >2.0 mg/dl and 2 × most recent preoperative value or a new requirement for dialysis) was compared. Multivariate logistic regression analysis was performed to identify independent risk factors for postoperative AKI. The incidence of AKI was higher in patients with a glucose level >150 mg/dl than in patients with a glucose level = 110-150 mg/dl [8% (20 of 251) vs 3% (14 of 453), P = 0.004]. On multivariate analysis, glucose >150 mg/dl (odds ratio [OR], 2.78; 95% confidence interval [CI], 1.12-6.86, P = 0.027), coefficient of variation of glucose (OR, 1.04; 95% CI, 1.01-1.07, P = 0.027) and preoperative serum creatinine >1.4 mg/dl (OR, 8.81; 95% CI, 3.90-19.9, P < 0.001) were identified as independent risk factors for postoperative AKI. Intraoperative glucose concentration >150 mg/dl and increased variability of glucose were independently associated with AKI after OPCAB. Tight intraoperative glycaemic control (<110 mg/dl) does not seem to provide additional benefit in terms of AKI. 23733371 Neurodegenerative and inflammatory biomarkers in cerebrospinal fluid in patients with Cushing's syndrome in remission. Patients with Cushing's syndrome (CS) in long-term remission have impaired cognitive function. Cerebrospinal fluid (CSF) biomarkers are important diagnostic tools in the work-up of patients with cognitive impairment. The aim of this study was to analyze neurodegenerative and inflammatory biomarkers in the CSF of patients with CS in remission. A cross-sectional, single-center study. Twelve women previously treated for CS and six healthy subjects. Neurodegenerative CSF markers: total tau, hyperphosphorylated tau, amyloid beta peptides, soluble amyloid precursor protein alpha and beta, neurofilament light proteins, glial fibrillary acidic protein, and monocyte chemoattractant protein 1; and inflammatory CSF markers: interferon gamma, interleukin (IL) 1B, IL2, IL4, IL5, IL8, IL10, IL12p70, IL13, and tumor necrosis factor alpha. The mean age (mean±S.D.) was similar in patients with CS in remission (44.9±14 years) and healthy subjects (42.3±15.7 years; P=0.726). No differences were observed in the concentrations of any neurodegenerative biomarkers between the patients and healthy subjects. Nor were the concentrations of inflammatory biomarkers different between the groups. The pattern of neurodegenerative and inflammatory biomarkers in the CSF of patients with CS in remission does not differ from that of the healthy subjects. The underlying mechanisms of the cognitive deficits in patients with CS in remission are different from those observed in patients with neurodegenerative disorders and remain to be explained. 23842144 Intraguild relationships between sympatric predators exposed to lethal control: predator manipulation experiments. Terrestrial top-predators are expected to regulate and stabilise food webs through their consumptive and non-consumptive effects on sympatric mesopredators and prey. The lethal control of top-predators has therefore been predicted to inhibit top-predator function, generate the release of mesopredators and indirectly harm native fauna through trophic cascade effects. Understanding the outcomes of lethal control on interactions within terrestrial predator guilds is important for zoologists, conservation biologists and wildlife managers. However, few studies have the capacity to test these predictions experimentally, and no such studies have previously been conducted on the eclectic suite of native and exotic, mammalian and reptilian taxa we simultaneously assess. We conducted a series of landscape-scale, multi-year, manipulative experiments at nine sites spanning five ecosystem types across the Australian continental rangelands to investigate the responses of mesopredators (red foxes, feral cats and goannas) to contemporary poison-baiting programs intended to control top-predators (dingoes) for livestock protection. Short-term behavioural releases of mesopredators were not apparent, and in almost all cases, the three mesopredators we assessed were in similar or greater abundance in unbaited areas relative to baited areas, with mesopredator abundance trends typically either uncorrelated or positively correlated with top-predator abundance trends over time. The exotic mammals and native reptile we assessed responded similarly (poorly) to top-predator population manipulation. This is because poison baits were taken by multiple target and non-target predators and top-predator populations quickly recovered to pre-control levels, thus reducing the overall impact of baiting on top-predators and averting a trophic cascade. These results are in accord with other predator manipulation experiments conducted worldwide, and suggest that Australian populations of native prey fauna at lower trophic levels are unlikely to be negatively affected by contemporary dingo control practices through the release of mesopredators. We conclude that contemporary lethal control practices used on some top-predator populations do not produce the conditions required to generate positive responses from mesopredators. Functional relationships between sympatric terrestrial predators may not be altered by exposure to spatially and temporally sporadic application of non-selective lethal control. 23891900 Unexpected association of the "inhibitory" neuroligin 2 with excitatory PSD95 in neuropathic pain. In the spinal nerve ligation (SNL) model of neuropathic pain, synaptic plasticity shifts the excitation/inhibition balance toward excitation in the spinal dorsal horn. We investigated the deregulation of the synaptogenic neuroligin (NL) molecules, whose NL1 and NL2 isoforms are primarily encountered at excitatory and inhibitory synapses, respectively. In the dorsal horn of SNL rats, NL2 was overexpressed whereas NL1 remained unchanged. In control animals, intrathecal injections of small interfering RNA (siRNA) targeting NL2 increased mechanical sensitivity, which confirmed the association of NL2 with inhibition. By contrast, siRNA application produced antinociceptive effects in SNL rats. Regarding NL partners, expression of the excitatory postsynaptic scaffolding protein PSD95 unexpectedly covaried with NL2 overexpression, and NL2/PSD95 protein interaction and colocalization increased. Expression of the inhibitory scaffolding protein gephyrin remained unchanged, indicating a partial change in NL2 postsynaptic partners in SNL rats. This phenomenon appears to be specific to the NL2(-) isoform. Our data showed unexpected upregulation and pronociceptive effects of the "inhibitory" NL2 in neuropathic pain, suggesting a functional shift of NL2 from inhibition to excitation that changed the synaptic ratio toward higher excitation. 23548939 Resistin decreases insulin-like growth factor I-induced steroid production and insulin-like growth factor I receptor signaling in human granulosa cells. To identify resistin in human ovarian follicles and investigate the effect and the molecular mechanisms associated with resistin on steroidogenesis in human granulosa cells (GCs). The effects of recombinant human resistin on the secretion of progesterone (P) and estradiol (E2) by cultured human GCs were investigated. Academic institutions. Twenty infertile and healthy women undergoing IVF. Primary human GC cultures stimulated with recombinant human resistin (10 ng/mL). Determination of messenger RNA (mRNA) and protein expression of resistin in fresh human GCs by reverse transcriptase-polymerase chain reaction (RT-PCR), immunoblot and immunohistochemistry, respectively; measurement of P and E2 levels in the conditioned media by radioimmunoassay; determination of cell proliferation by tritiated thymidine incorporation; and analysis of signaling pathways activation by immunoblot analysis. Human GCs and theca cells express resistin. In primary human GCs, resistin decreases P and E2 secretion in response to insulin-like growth factor I (IGF-I). This was associated with a reduction in the P450 aromatase and P450scc (cholesterol side-chain cleavage cytochromes P450) (P450scc) protein levels but not those of 3β-hydroxysteroid dehydrogenase (3β-HSD) or steroidogenic acute regulatory protein (StAR) and with a decrease in IGF-I-induced IGF-I receptor and mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Resistin treatment does not affect IGF-I-induced cell proliferation and basal steroidogenesis (there is no IGF-I or follicle-stimulating hormone stimulation). In the basal state, resistin rapidly stimulates Akt and MAPK ERK1/2 and p38 phosphorylation in primary human GCs. Resistin is present in human GCs and theca cells. It decreases P and E2 secretion, P450scc and P450 aromatase protein levels, and IGF-IR signaling in response to IGF-I in primary human GCs. 23395163 How sugar tunes your clock. While cellular circadian clocks are set by the light/dark cycle, these clocks can be reset by what we eat. Two papers in this issue of Cell Metabolism reveal that O-GlcNAcylation of clock proteins, which is dependent on nutrients, adjusts our circadian clock (Kaasik et al., 2013; Li et al., 2013). 23943050 The "PIP Problem": Clinical and Histologic Characteristics. Implants from Poly Implant Prothése (PIP), the French manufacturer, showed increased risk of implant rupture and silicone leakage through the shell. Concerns also exist about the potential irritant behavior of silicone gel filler in these implants. This report presents the clinical, histologic, and microbiologic characteristics of a capsule and a siliconoma from a patient with a ruptured PIP implant. A 41-year-old woman submitted to breast augmentation in 2005 with PIP silicone gel implants presented with a recent history of progressive asymmetric breast enlargement and an enlarged lymph node on her right axilla. No capsular contracture was observed. A breast ultrasonography showed intra- and extracapsular ruptures of the right implant. The woman underwent explantation. Histologic analysis of the breast capsules showed a thin capsule with a chronic, mild inflammatory response. Microbiologic analysis showed no bacterial agent. The irritant behavior of the PIP silicone gel previously described was not able to produce capsular contracture or an exuberant inflammatory reaction. Studies to evaluate the potential risks of the silicone gel and to define the hazards for women implanted with those prostheses are urgently needed. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . 23906280 Structuring β-Ga2O3 Photonic Crystal Photocatalyst for Efficient Degradation of Organic Pollutants. Coupling photocatalysts with photonic crystals structure is based on the unique property of photonic crystals in confining, controlling, and manipulating the incident photons. This combination enhances the light absorption in photocatalysts and thus greatly improves their photocatalytic performance. In this study, Ga2O3 photonic crystals with well-arranged skeleton structures were prepared via a dip-coating infiltration method. The positions of the electronic band absorption for Ga2O3 photonic crystals could be made to locate on the red edge, on the blue edge, and away from the edge of their photonic band gaps by changing the pore sizes of the samples, respectively. Particularly, the electronic band absorption of the Ga2O3 photonic crystal with a pore size of 135 nm was enhanced more than other samples by making it locate on the red edge of its photonic band gap, which was confirmed by the higher instantaneous photocurrent and photocatalytic activity for the degradation of various organic pollutants under ultraviolet light irradiation. Furthermore, the degradation mechanism over Ga2O3 photonic crystals was discussed. The design of Ga2O3 photonic crystals presents a prospective application of photonic crystals in photocatalysis to address light harvesting and quantum efficiency problems through manipulating photons or constructing photonic crystal structure as groundwork. 23871172 A Useful Surgical Technique for Retrieval of a Broken Guide Pin in the Midfoot. Perioperative instrument breakage is not an infrequent occurrence, even for experienced surgeons. The most commonly reported instrument breaks in orthopedic procedures are drill bits, followed by Kirschner wires and cannulated guide pins. The reasons for failure include improper technique and repetitive use. The retrieval of broken hardware can be technically challenging, particularly if the fragment has become embedded in bone. Retrieval methods have been described for cannulated guide pin fragments in the hip; however, no specific techniques have been described for the retrieval of guide pin fragments embedded in the bones of the foot. In the present report, we describe a technique we have found useful for retrieval of a guide pin fragment that had broken off during a Lisfranc fracture repair 6 weeks earlier. The technique was used in a delayed situation; however, we believe it would be even easier to use during an intraoperative breakage. 23743723 Immune response to HIV. Major advances have been made in the delineation of HIV-specific immune response and in the mechanisms of virus escape. The kinetics of the immunological and virological events occurring during primary HIV infection indicate that the establishment of the latent HIV reservoir, the major obstacle to HIV eradication likely occurs during the very early stages of primary infection, that is, the 'eclipse phase', prior to the development of the HIV-specific immune response which has limited efficacy in the control of the early events of infection. Therefore, the window of opportunity to develop effective interventions either to clear HIV during primary infection or to prevent rebound of HIV in patients successfully treated who stop antiretroviral therapy is very narrow. Genetic factors most strongly associated with nonprogressive infection are human leukocyte antigen (HLA) class I alleles and particularly HLA-B5701. CD4 and CD8 T-cell responses with polyfunctional profile are associated with nonprogressive infection. Broader neutralizing antibodies are detected 3-4 years after infection, generated only in 20% of individuals but show no efficacy in the control of HIV replication. In the present review, we shall discuss the different components of the HIV-specific immune response elicited by the infection, the kinetics of these responses during primary infection and the changes following transition to the chronic phase of infection, and the functional profile of 'effective' versus 'noneffective' HIV-specific immune responses. 23879938 DCJ-indel and DCJ-substitution distances with distinct operation costs. Classical approaches to compute the genomic distance are usually limited to genomes with the same content and take into consideration only rearrangements that change the organization of the genome (i.e. positions and orientation of pieces of DNA, number and type of chromosomes, etc.), such as inversions, translocations, fusions and fissions. These operations are generically represented by the double-cut and join (DCJ) operation. The distance between two genomes, in terms of number of DCJ operations, can be computed in linear time. In order to handle genomes with distinct contents, also insertions and deletions of fragments of DNA - named indels - must be allowed. More powerful than an indel is a substitution of a fragment of DNA by another fragment of DNA. Indels and substitutions are called content-modifying operations. It has been shown that both the DCJ-indel and the DCJ-substitution distances can also be computed in linear time, assuming that the same cost is assigned to any DCJ or content-modifying operation. In the present study we extend the DCJ-indel and the DCJ-substitution models, considering that the content-modifying cost is distinct from and upper bounded by the DCJ cost, and show that the distance in both models can still be computed in linear time. Although the triangular inequality can be disrupted in both models, we also show how to efficiently fix this problem a posteriori. 23669605 Consumer perceptions about a community pharmacy-based medication take back program. The stockpiling and improper disposal of unused or expired medications has the potential to harm the environment and humans. Community-based medication take-back programs have been established to ensure proper disposal of unused drugs; however, few of these programs present consumers' perceptions about the program. Therefore, the main aims of this pilot study are 1) to assess the users' and non-users' perceptions about a medication take-back program and 2) to determine if perceptions differ between users and non-users. The results are based on a survey administered to 35 users and 20 non-users of a medication take-back program located at a community pharmacy in Texas. The majority of users were participating in a take-back service for the first time. Though most non-users had never participated in a take-back program, they would consider participating in the future. All users viewed the medication take-back program as a valuable service, while nearly all (90%) non-users viewed the program as a potentially valuable service. The primary reason for participating in the service was to protect the environment. Most respondents (users and non-users) were likely to choose a pharmacy that provides the take-back service more than a pharmacy that does not. More than half of respondents positively viewed paying for the service on a per weight basis. In comparison to non-users, users were significantly older, had more favorable perceptions about paying for the service, and were more likely to choose a pharmacy that provides the service. This pilot study presents overall favorable user perceptions toward medication-take back services and supports the need to establish more community-based take back programs to meet the needs of consumers. 23473268 Mechanistic investigation of seeded growth in triblock copolymer stabilized gold nanoparticles. We report the seeded synthesis of gold nanoparticles (GNPs) via the reduction of HAuCl4 by (L31 and F68) triblock copolymer (TBP) mixtures. In the present study, we focused on [TBP]/[Au(III)] ratios of 1-5 (≈1 mM HAuCl4) and seed sizes ~20 nm. Under these conditions, the GNP growth rate is dominated by both the TBP and seed concentrations. With seeding, the final GNP size distributions are bimodal. Increasing the seed concentration (up to ~0.1 nM) decreases the mean particle sizes 10-fold, from ~1000 to 100 nm. The particles in the bimodal distribution are formed by the competitive direct growth in solution and the aggregative growth on the seeds. By monitoring kinetics of GNP growth, we propose that (1) the surface of the GNP seeds embedded in the TBP cavities form catalytic centers for GNP growth and (2) large GNPs are formed by the aggregation of GNP seeds in an autocatalytic growth process. 23904254 Water-fat separation imaging of the heart with standard magnetic resonance bSSFP CINE imaging. To study balanced steady-state free precession CINE phase-sensitive water-fat separation imaging in four cardiac imaging planes to determine the necessary phase correction and image artifacts particular to this technique. Ten healthy volunteers and two subjects with known heart pathologies were studied with standard balanced steady-state free precession CINE imaging. Water-only and fat-only images were calculated using sign detection of the real part of the complex image after phase correction with constant and linear terms. Phase correction values were determined using both manual and automated methods. Differences in phase correction values between imaging planes, cardiac phases, coil elements, automated image reconstruction parameters as well as artifact scores between the automated and manual methods were studied with statistical tests. Water-fat separation performed well in the heart after constant and linear phase correction. Both constant (p = 0.8) and linear x (p = 1) and y (p = 1) phase correction values did not vary significantly across cardiac phases, but varied significantly among the coils (p < 0.001) and imaging planes (p < 0.001). False water-fat separation artifacts were most frequent in the chest/back and also were present at the mitral and aortic valves. Constant and linear phase correction is necessary to provide consistent results in standard imaging planes using a balanced steady-state free precession water-fat separation postprocessing algorithm applied to standard cardiac CINE imaging. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc. 23612449 Assuring Safety Without Animal Testing: The Case for the Human Testis In Vitro. From 15-17 June 2011, a dedicated workhop was held on the subject of in vitro models for mammalian spermatogenesis and their applications in toxicological hazard and risk assessment. The workshop was sponsored by the Dutch ASAT initiative (Assuring Safety without Animal Testing), which aims at promoting innovative approaches towards toxicological hazard and risk assessment on the basis of human and in vitro data, and replacement of animal studies. Participants addressed the state of the art regarding human and animal evidence for compound mediated testicular toxicity, reviewed existing alternative assay models, and brainstormed about future approaches, specifically considering tissue engineering. The workshop recognized the specific complexity of testicular function exemplified by dedicated cell types with distinct functionalities, as well as different cell compartments in terms of microenvironment and extracellular matrix components. This complexity hampers quick results in the realm of alternative models. Nevertheless, progress has been achieved in recent years, and innovative approaches in tissue engineering may open new avenues for mimicking testicular function in vitro. Although feasible, significant investment is deemed essential to be able to bring new ideas into practice in the laboratory. For the advancement of in vitro testicular toxicity testing, one of the most sensitive end points in regulatory reproductive toxicity testing, such an investment is highly desirable. 23775325 A systematic review of studies on anatomical position of electrode contacts used for chronic subthalamic stimulation in Parkinson's disease. The dorso-lateral part of the subthalamic nucleus (STN) is considered as the usual target of deep brain stimulation for Parkinson's disease. Nevertheless, the exact anatomical location of the electrode contacts used for chronic stimulation is still a matter of debate. The aim of this study was to perform a systematic review of the existing literature on this issue. We searched for studies on the anatomical location of active contacts published until December 2012. We identified 13 studies, published between 2002 and 2010, including 260 patients and 466 electrodes. One hundred and sixty-four active contacts (35 %) were identified within the STN, 117 (25 %) at the interface between STN and the surrounding structures, 184 (40 %) above the STN and one within the substantia nigra. We observed great discrepancies between the different series. The contra-lateral improvement was between 37 and 78.5 % for contacts located within the STN, between 48.6 and 73 % outside the STN, between 65.3 and 66 % at the interface. The authors report no clear correlation between anatomical location and stimulation parameters. Post-operative analysis of the anatomical location of active contacts is difficult, and all the methods used are debatable. The relationship between the anatomical location of active contacts and the clinical effectiveness of stimulation is unclear. It would be necessary to take into account the volume of the electrode contacts and the diffusion of the stimulation. We can nevertheless assume that the interface between dorso-lateral STN, zona incerta and Forel's fields could be directly involved in the effects of stimulation. 23953858 Intraoperative stress and anxiety reduction with music therapy: A controlled randomized clinical trial of efficacy and safety. The purpose of this study was to investigate the music therapy (MT) effect in levels of intraoperative anxiety in patients undergoing crossectomy with stripping of the great saphenous vein and to assess the efficacy, safety, and feasibility of this alternative therapy as a complement of standard intraoperative care. The study is a simple blind, controlled, parallel groups, prospective randomized clinical trial. Patients were allocated by means of randomized controlled sampling. The study was performed in the surgery room of Getafe University Hospital in Madrid. The study was carried out in 40 patients, 20 randomized to the experimental group and 20 randomized to the control group, with an age range from 27 to 70 years. The control group was given intraoperative routine attention, and the experimental group was given an MT passive intervention that consisted of audition of musical fragments during varicose veins surgery. These pieces previously showed relaxing actions on the cardiovascular system. The anxiety levels were measured by means of pre- and postsurgical questionnaires by a blinded investigator for the study arm to which the patients had been randomized. Heart rate and systolic and diastolic blood pressures were determined during the intervention, and adrenaline and noradrenaline plasma levels were determined before and after the surgical procedure. The majority of the patients in the MT group (95%) and standard care group (90%) completed the study. There were no statistical differences between the control and experimental groups in heart rate gradient or systolic and diastolic blood pressures measured after the intervention. The anxiety state and the stress feeling scale score after surgery were significantly inferior in the MT group (94.7% vs 57.9% decrease in anxiety levels, P < .05, and stress score of 1.31 vs 2.36, P < .05, respectively). The adverse events ratio was low and occurred with similar frequency in both groups. The MT intervention was easily implemented in the context of nursing care received during varicose vein surgery and was positively accepted and valued by the majority of the patients. MT is a safe procedure that is proved to reduce anxiety and stress in the study patients. 23890413 Nightly biting cycles of malaria vectors in a heterogeneous transmission area of eastern Amazonian Brazil. The biting cycle of anopheline mosquitoes is an important component in the transmission of malaria. Inter- and intraspecific biting patterns of anophelines have been investigated using the number of mosquitoes caught over time to compare general tendencies in host-seeking activity and cumulative catch. In this study, all-night biting catch data from 32 consecutive months of collections in three riverine villages were used to compare biting cycles of the five most abundant vector species using common statistics to quantify variability and deviations of nightly catches from a normal distribution. Three communities were selected for study. All-night human landing catches of mosquitoes were made each month in the peridomestic environment of four houses (sites) for nine consecutive days from April 2003 to November 2005. Host-seeking activities of the five most abundant species that were previously captured infected with Plasmodium falciparum, Plasmodium malariae or Plasmodium vivax, were analysed and compared by measuring the amount of variation in numbers biting per unit time (co-efficient of variation, V), the degree to which the numbers of individuals per unit time were asymmetrical (skewness = g1) and the relative peakedness or flatness of the distribution (kurtosis = g2). To analyse variation in V, g1, and g2 within species and villages, we used mixed model nested ANOVAs (PROC GLM in SAS) with independent variables (sources of variation): year, month (year), night (year X month) and collection site (year X month). The biting cycles of the most abundant species, Anopheles darlingi, had the least pronounced biting peaks, the lowest mean V values, and typically non-significant departures from normality in g1 and g2. By contrast, the species with the most sharply defined crepuscular biting peaks, Anopheles marajoara, Anopheles nuneztovari and Anopheles triannulatus, showed high to moderate mean V values and, most commonly, significantly positive skewness (g1) and kurtosis (g2) moments. Anopheles intermedius was usually, but not always, crepuscular in host seeking, and showed moderate mean V values and typically positive skewness and kurtosis. Among sites within villages, significant differences in frequencies of departures from normality (g1 and g2) were detected for An. marajoara and An. darlingi, suggesting that local environments, such as host availability, may affect the shape of biting pattern curves of these two species. Analyses of co-efficients of variation, skewness and kurtosis facilitated quantitative comparisons of host-seeking activity patterns that differ among species, sites, villages, and dates. The variable and heterogeneous nightly host-seeking behaviours of the five exophilic vector species contribute to the maintenance of stable malaria transmission in these Amazonian villages. The abundances of An. darlingi and An. marajoara, their propensities to seek hosts throughout the night, and their ability to adapt host-seeking behaviour to local environments, contribute to their impact as the most important of these vector species. 23890153 Purple Acid Phosphatase5 is required for maintaining basal resistance against Pseudomonas syringae in Arabidopsis. Plants have evolved an array of constitutive and inducible defense strategies to restrict pathogen ingress. However, some pathogens still manage to invade plant and impair growth and productivity. Previous studies have revealed several key regulators of defense responses, and efforts have been made to use this information to develop disease resistant crop plants. These efforts are often hampered by the complexity of defense signaling pathways. To further elucidate the complexity of defense responses, we screened a population of T-DNA mutants in Colombia-0 background that displayed altered defense responses to virulent Pseudomonas syringae pv. tomato DC3000 (Pst DC3000). In this study, we demonstrated that the Arabidopsis Purple Acid Phosphatse5 (PAP5) gene, induced under prolonged phosphate (Pi) starvation, is required for maintaining basal resistance to certain pathogens. The expression of PAP5 was distinctly induced only under prolonged Pi starvation and during the early stage of Pst DC3000 infection (6 h.p.i). T-DNA tagged mutant pap5 displayed enhanced susceptibility to the virulent bacterial pathogen Pst DC3000. The pap5 mutation greatly reduced the expression of pathogen inducible gene PR1 compared to wild-type plants. Similarly, other defense related genes including ICS1 and PDF1.2 were impaired in pap5 plants. Moreover, application of BTH (an analog of SA) restored PR1 expression in pap5 plants. Taken together, our results demonstrate the requirement of PAP5 for maintaining basal resistance against Pst DC3000. Furthermore, our results provide evidence that PAP5 acts upstream of SA accumulation to regulate the expression of other defense responsive genes. We also provide the first experimental evidence indicating the role PAP5 in plant defense responses. 23907685 Preparation, characterization, and application of a new stationary phase containing different kinds of amine groups. A new stationary phase containing primary amine and tertiary amine groups was synthesized and its structure was confirmed by infrared spectra, elemental analysis, and zeta potential. This new material was packed into a stainless steel column and the effect of acetonitrile (ACN) content in mobile phase on retention was evaluated using probes of nucleosides, sulfanilamides, and quinolone compounds. This showed hydrophilic interaction, ion interaction, or a mixed-mode retention mechanism for different kinds of solutes, respectively. The effects of the pH and ion strength of the mobile phase were investigated to further understand the retention mechanism of the new stationary phase. The interaction forces caused by the new phase included adsorption, electrostatic function, and ion exchange. The new material could be used as a stationary phase in different high-performance liquid chromatography modes. 23951069 Aberrant functional connectivity of resting state networks in transient ischemic attack. Transient ischemic attack (TIA) is usually defined as a neurologic ischemic disorder without permanent cerebral infarction. Studies have showed that patients with TIA can have lasting cognitive functional impairment. Inherent brain activity in the resting state is spatially organized in a set of specific coherent patterns named resting state networks (RSNs), which epitomize the functional architecture of memory, language, attention, visual, auditory and somato-motor networks. Here, we aimed to detect differences in RSNs between TIA patients and healthy controls (HCs). Twenty one TIA patients suffered an ischemic event and 21 matched HCs were enrolled in the study. All subjects were investigated using cognitive tests, psychiatric tests and functional magnetic resonance imaging (fMRI). Independent component analysis (ICA) was adopted to acquire the eight brain RSNs. Then one-sample t-tests were calculated in each group to gather the spatial maps of each RSNs, followed by second level analysis to investigate statistical differences on RSNs between twenty one TIA patients and 21 controls. Furthermore, a correlation analysis was performed to explore the relationship between functional connectivity (FC) and cognitive and psychiatric scales in TIA group. Compared with the controls, TIA patients exhibited both decreased and increased functional connectivity in default mode network (DMN) and self-referential network (SRN), and decreased functional connectivity in dorsal attention network (DAN), central-executive network (CEN), core network (CN), somato-motor network (SMN), visual network (VN) and auditory network (AN). There was no correlation between neuropsychological scores and functional connectivity in regions of RSNs. We observed selective impairments of RSN intrinsic FC in TIA patients, whose all eight RSNs had aberrant functional connectivity. These changes indicate that TIA is a disease with widely abnormal brain networks. Our results might put forward a novel way to look into neuro-pathophysiological mechanisms in TIA patients. 23392476 Hepatic steatosis is associated with lower incidence of liver metastasis from colorectal cancer. Both hepatic steatosis (HS) and colorectal cancer (CRC) are conditions associated with metabolic syndrome. The liver is the most frequent site of distant metastasis of CRC; however, the impact of HS on the incidence of liver metastasis of CRC is not clearly defined. Then, the correlation with the presence or absence of HS was analyzed. A total of 604 CRC patients receiving curative surgical resection who had a preoperative non-enhanced computed tomography (CT) were enrolled. The mean attenuation values (in Hounsfield units) of the liver and spleen were obtained on a plain CT slice, and the patients with liver-spleen attenuation ratio lower than 1.1 were objectively defined as HS. The clinicopathological features of these patients were analyzed, and the association between HS and the clinical features of CRC was examined. Sixty-three (10.4 %) among the 604 patients were diagnosed as HS. Recurrence-free survival (RFS) and hepatic RFS, but not extrahepatic RFS, were significantly higher in the group with HS (p = 0.04 and p = 0.006). However, this effect was not evident in the group of patients with obesity, defined as body mass index > 25.0. Among the stage I~III cases, HS was significantly associated with lower hepatic, but not extrahepatic, RFS. Moreover, absence of HS was an independent risk factor for hepatic RFS (p = 0.003). Metastases of CRC are less frequent in fatty liver. Steatosis may be an unfavorable microenvironment for metastatic formation in the liver. 23172565 Operative Intercostal Chest Drain Is Not Required following Extrapleural or Transpleural Esophageal Atresia Repair. Background Approximately half of the United Kingdom patients undergoing esophageal atresia (OA) repair have an operative intercostal chest drain (ICD) placed (2008 British Association of Pediatric Surgeons Congenital Anomalies Surveillance Study data). We reviewed our experience of OA repairs to evaluate if an ICD placement is necessary.Methods Patients with OA/distal tracheoesophageal fistula (TOF), treated between January 1990 and January 2010, were identified by retrospective review of a prospectively maintained electronic database and patient case notes.Main Results A total of 112 consecutive patients were identified, of whom 107 were included (73 male). Five were excluded as no case notes were available. Median birth weight was 2,597 g (range 924 to 4,245 g) and median gestational age was 38 weeks (27 to 41 weeks). Median age at discharge was 22 days (3 to 440 days) and median follow-up was 3.5 years (0 to 18 years). Patients were analyzed in two groups-group 1 (n = 73) had an extrapleural (EP) repair, of which 23 had a pleural breach and group 2 (n = 34) had a purposeful transpleural (TP) approach (surgeon preference). Eleven patients (10%) had an operative ICD, of which six patients were in group 1 and five in group 2. These 11 patients had an uncomplicated postoperative course and all operative ICD were removed within 48 hours of surgery. Of the 96 patients that did not have an operative ICD, only 2 (2%) required postoperative intervention. One patient, in group 2, had a postoperative ICD inserted for a simple pneumothorax at 12 hours and removed at 48 hours. The other patient, in group 1, had a clinically detected anastomotic leak after 48 hours and required operative repair.Conclusion An operative ICD is not required following OA/distal TOF repair, whether the approach is EP or TP. ICD that were electively placed (in 10%) served no clinical purpose. 23625967 Microfluidic affinity and ChIP-seq analyses converge on a conserved FOXP2-binding motif in chimp and human, which enables the detection of evolutionarily novel targets. The transcription factor forkhead box P2 (FOXP2) is believed to be important in the evolution of human speech. A mutation in its DNA-binding domain causes severe speech impairment. Humans have acquired two coding changes relative to the conserved mammalian sequence. Despite intense interest in FOXP2, it has remained an open question whether the human protein's DNA-binding specificity and chromatin localization are conserved. Previous in vitro and ChIP-chip studies have provided conflicting consensus sequences for the FOXP2-binding site. Using MITOMI 2.0 microfluidic affinity assays, we describe the binding site of FOXP2 and its affinity profile in base-specific detail for all substitutions of the strongest binding site. We find that human and chimp FOXP2 have similar binding sites that are distinct from previously suggested consensus binding sites. Additionally, through analysis of FOXP2 ChIP-seq data from cultured neurons, we find strong overrepresentation of a motif that matches our in vitro results and identifies a set of genes with FOXP2 binding sites. The FOXP2-binding sites tend to be conserved, yet we identified 38 instances of evolutionarily novel sites in humans. Combined, these data present a comprehensive portrait of FOXP2's-binding properties and imply that although its sequence specificity has been conserved, some of its genomic binding sites are newly evolved. 23888435 Presumably hospital-transmitted Clostridium difficile infections based on epidemiological linkage. Given the traditionally low CDAD (Clostridium difficile associated diarrhoea) prevalence in Switzerland, CDAD patients are not routinely contact-isolated in our institution. In light of the globally changing C. difficile epidemiology, we sought to determine our institutional CDAD rate and to detect possible hospital transmission by means of epidemiological linkage. We included every CDAD patient hospitalised in our institution, a tertiary-care hospital in eastern Switzerland, in 2009/2010. Patients with healthcare facility associated (HCFA) CDAD were grouped into cases with and without exposure to an infectious CDAD patient. Exposure was defined as sharing the room/ward with an infectious patient before symptom onset, either at the same time or within 30 days after discharge of the infectious patient. Molecular strain typing was not performed. We registered 141 CDAD episodes. Among them 108 were HCFA (associated with our institution), corresponding to an incidence of 2.3/10,000 patient days. Fifty-six percent (60/108) were exposed to an infectious CDAD patient, suggesting hospital transmission. The number of patients without exposure remained relatively stable, whereas presumably transmitted cases - often occurring within spatiotemporal clusters - showed high variability over time. Presumably transmitted cases were significantly older (p = 0.032) and more likely to have a Charlson score >1 (p = 0.001). In our setting, 56% of healthcare associated CDAD cases have been exposed to an infectious CDAD patient. In view of the clustering of these presumed hospital transmissions, we consider an intensification of our current infection control measures, mainly on wards with elderly and comorbid patients which are particularly prone to C. difficile transmission. 23940934 Lessons in delivering good care. Education is at the heart of St Christopher's Hospice's mission to make palliative care widely available--it is now one of the largest providers of end of life care education. Its approach influenced Mid Staffs public inquiry chair Robert Francis's recommendations on nurse training. 22538087 Tonic GABA(A) receptor-mediated signalling in temporal lobe epilepsy. The tonic activation of extrasynaptic GABAA receptors by extracellular GABA provides a powerful means of regulating neuronal excitability. A consistent finding from studies that have used various models of temporal lobe epilepsy is that tonic GABAA receptor-mediated conductances are largely preserved in epileptic brain (in contrast to synaptic inhibition which is often reduced). Tonic inhibition is therefore an attractive target for antiepileptic drugs. However, the network consequences of a commonly used approach to augment tonic GABAA receptor-mediated conductances by global manipulation of extracellular GABA are difficult to predict without understanding how epileptogenesis alters the pharmacology and GABA sensitivity of tonic inhibition, and how manipulation of tonic conductances modulates the output of individual neurons. Here we review the current literature on epilepsy-associated changes in tonic GABAA receptor-mediated signalling, and speculate about possible effects they have at the network level. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'. 23639366 The effects of cryoablation on renal cell carcinoma perfusion and glomerular filtration rate measured using dynamic contrast-enhanced MRI: A feasibility study. To assess the effect of cryoablation on renal cell carcinoma (RCC) perfusion and single kidney (SK) glomerular filtration rate (GFR) using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). Eighteen patients undergoing percutaneous cryoablation of a solitary RCC between August 2010 and November 2011 were evaluated with DCE-MRI immediately before and 1 month post-cryoablation. DCE-MRI data were acquired with 2 s temporal resolution in a coronal plane during the first pass of a 0.1 mmol/kg bolus dose of Gd-DOTA. Perfusion of the RCC (in ml/min/100 ml tissue) was estimated using a maximum slope technique. An index of SK GFR (SK-GFRi) was assessed using data acquired every 30 s for the following 3 min in the axial plane and analysed using Rutland-Patlak plots. This was compared to the GFR estimated by creatinine clearance (eGFR). Perfusion in the zone of ablation decreased significantly (p<0.001) from a mean of 98.0 ± 37.5 ml/min/100 ml pre-cryoablation to 11.6 ± 4.1 ml/min/100 ml post-cryoablation; a mean decrease of 88.2%. Functional analysis was performed in seventeen patients. eGFR was underestimated by SK-GFRi which decreased significantly in tumour-bearing (-31.7%, p = 0.011), but not in contralateral kidneys (-4.4%, p = 0.14). It is feasible to measure RCC perfusion pre- and post-cryoablation using DCE-MRI. The significant decrease within the zone of ablation suggests that this technique may be useful for assessment of treatment response. Further work is required to address the underestimation of eGFR by SK-GFRi and to validate the perfusion findings. 23674371 Electron-induced reductive debromination of 2,3,4-tribromodiphenyl ether: a computational study. To better understand the mechanism of the electron induced elimination of the bromide anion, we examined at the B3LYP/6-31+G(d) level electron capture by 2,3,4-tribromodiphenyl ether (BDE-21) followed by the release of the bromide anion and a radical. Both the geometry and energy of the BDE-21 neutral and its possible anionic states were studied. A significant relationship was found between the total energy and the length of the C-Br bonds by the analysis of the potential energy surface for the anionic states. Debromination preference for the bromine substituted positions was theoretically evaluated as meta-Br > ortho-Br > para-Br. The reaction profiles of the electron-induced debromination of BDE-21 demonstrated that, in general, the presence of a solvent makes the electron induced reductive debromination of BDE-21 significantly more advantageous, and the stabilization effect of the solvent on the reaction intermediates would make the electron attachment and dissociation relatively effective in comparison with the results from the gas-phase calculations. 23711100 Abatacept or infliximab for patients with rheumatoid arthritis and inadequate response to methotrexate: an Italian trial-based and real-life cost-consequence analysis. In the 1-year, double-blind, placebo-controlled ATTEST trial, efficacy of abatacept or infliximab versus placebo was reported in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). The current study estimated trial-based and real-life costs of abatacept and infliximab for achieving pre-defined remission or low disease activity state (LDAS). Quantity of drug, serious adverse event (SAE) rates and time (months) in remission or LDAS were taken from ATTEST for the trial-based calculation to derive a cost per remitting/LDAS patient and a cost per patient-month in remission/LDAS. Trial-based and real-life scenarios were performed. The annual trial-based costs per remitting/LDAS patient were €70.238/€37.208 for abatacept and €85.565/€46.602 for infliximab. In the first 6 months of the ATTEST trial, costs per patient-month in remission/LDAS were higher for abatacept (€11.024 and €6.018, respectively), relative to infliximab (€8.347 and €4.174, respectively). Over the full 12-month trial period cost per month in remission/LDAS estimates were only slightly in favour of infliximab (€6.959/€3.625) relative to abatacept (€7.297/€3.909). Assuming extension of treatment under real life conditions the cost per month in remission/LDAS turned substantially in favour of abatacept (€5.321/€2.819), as compared to infliximab (€7.189/€3.916). The higher initiation cost for abatacept to achieve remission/LDAS would be offset after a total 14.6 and 16.1 months of treatment, respectively, if treatment extended beyond 6 months under real-life conditions. These results proved to be robust when it was assumed that the (i) sharing of vials across patients completely averted infliximab wastage, (ii) AE risks were similar and (iii) onset of response was slower for abatacept. Our findings suggest a lower cost-consequence for abatacept during real-life treatment. 23538122 Poor short term outcome with a metal-on-metal total hip arthroplasty. Metal-on-metal (MoM) bearings for total hip arthroplasty (THA) have come under scrutiny with reports of high failure rates. Clinical outcome studies with several commercially available MoM THA bearings remain unreported. We evaluated 78 consecutive MoM THAs from a single manufacturer in 68 patients. Sixty-six received cobalt-chrome (CoCr) monoblock and 12 received modular titanium acetabular cups with internal CoCr liners. Femoral components were titanium with modular necks. At average 2.1years postoperatively, 12 THAs (15.4%) demonstrated aseptic failure (10 revisions, 2 revision recommended). All revised hips demonstrated capsular necrosis with positive histology reaction for aseptic lymphocytic vasculitis-associated lesions/adverse local tissue reactions. Prosthetic instability following revision surgery was relatively common. Female gender was a strong risk factor for failure, though smaller cups were not. Both monoblock and modular components fared poorly. Corrosion was frequently observed around the proximal and distal end of the modular femoral necks. 23712341 Effects of dental bleaching on the color, translucency and fluorescence properties of enamel and dentin. The objective of this study was to evaluate the color, translucency and fluorescence of bovine enamel and dentin submitted to different bleaching modalities. Pairs of enamel and dentin discs (3 mm in diameter) were obtained from 150 bovine teeth. In 75 of the pairs, one specimen had the enamel removed (Dentin Group). The dentin was removed from one specimen of the remaining 75 pairs (Enamel Group) and the other specimen was left unaltered (Enamel + Dentin). The evaluation of color, translucency and fluorescence was performed with a spectrophotometer using the CIE L* a* b*. Each group was subdivided into three subgroups: Control, composed of specimens that were not bleached, and two experimental subgroups, bleached with either 10% carbamide peroxide (CP10%) or 35% hydrogen peroxide (HP35%). The CP10% bleaching gel was applied 2 h/day for 14 days. The HP35% bleaching agent was applied using two applications of 30 min each, with a one week interval between each application. When not being bleached, the specimens were immersed in artificial saliva. The color, translucency and fluorescence ratings were assessed using spectrophotometry 7 days after the treatment. Regarding color, significant differences were found between bleaching techniques in the groups Enamel and Enamel + Dentin, with a higher color difference for HP35%. Bleaching did not change the translucency of the dental tissues. There were significant differences for fluorescence for the HP35% subgroups of Dentin and Enamel + Dentin, and for the CP10% subgroup of Enamel. Dental bleaching changed the color and fluorescence of the dental tissues, however translucency was not affected. 23624670 Controlled electrochemical deposition and transformation of hetero-nanoarchitectured electrodes for energy storage. A review of electrochemically synthesized nanomaterials with different controllable architectures for electrochemical energy storage devices is shown. It is demonstrated that these nano-architectures can be created either by electrodeposition or by the electrochemical transformation of materials. Electrochemical synthesis is presented here as it provides intimate contact between the electrode and current collector and also promotes an electronic pathway for all materials to be connected to the circuit. Although still in their infancy, electrosynthesized nano-architectures show promise to be used in future electrochemical energy storage devices as utilization of this method bypasses the need for bulky conductive additives and electrochemically inactive binders. Furthermore, electrochemical transformations can be used to create additional architectural features or change the chemical make-up of the electrode. This review is meant to show the creativity of current science when it comes to these nano-architectured electrodes. It is organized by technique used for synthesis including hard template, soft template, and template-free synthesis along with electrochemical transformation techniques. 23139354 Identification of cross-species shared transcriptional networks of diabetic nephropathy in human and mouse glomeruli. Murine models are valuable instruments in defining the pathogenesis of diabetic nephropathy (DN), but they only partially recapitulate disease manifestations of human DN, limiting their utility. To define the molecular similarities and differences between human and murine DN, we performed a cross-species comparison of glomerular transcriptional networks. Glomerular gene expression was profiled in patients with early type 2 DN and in three mouse models (streptozotocin DBA/2, C57BLKS db/db, and eNOS-deficient C57BLKS db/db mice). Species-specific transcriptional networks were generated and compared with a novel network-matching algorithm. Three shared human-mouse cross-species glomerular transcriptional networks containing 143 (Human-DBA STZ), 97 (Human-BKS db/db), and 162 (Human-BKS eNOS(-/-) db/db) gene nodes were generated. Shared nodes across all networks reflected established pathogenic mechanisms of diabetes complications, such as elements of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and vascular endothelial growth factor receptor (VEGFR) signaling pathways. In addition, novel pathways not previously associated with DN and cross-species gene nodes and pathways unique to each of the human-mouse networks were discovered. The human-mouse shared glomerular transcriptional networks will assist DN researchers in selecting mouse models most relevant to the human disease process of interest. Moreover, they will allow identification of new pathways shared between mice and humans. 23925683 Full-term broad ligament pregnancy. A broad ligament pregnancy is an extremely rare condition. The eventuality of such pregnancies reaching full term is even rarer. A full-term broad ligament pregnancy occurring through a rent in a previous lower segment caesarean scar has only been mentioned in literature but not reported. Our patient is an unbooked case, reported to us at 39 weeks of pregnancy. On clinical examination, an ultrasound and an MRI, a diagnosis of abdominal pregnancy was made. Ultimately the final diagnosis was made only on laparotomy. A broad ligament pregnancy was found with a rent in the previous caesarean scar communicating the fetal sac. 23912842 Controlling frustrated liquids and solids with an applied field in a kagome Heisenberg antiferromagnet. Quantum spin-1/2 kagome Heisenberg antiferromagnet is the representative frustrated system possibly hosting a spin liquid. Clarifying the nature of this elusive topological phase is a key challenge in condensed matter; however, even identifying it still remains unsettled. Here we apply a magnetic field and discover a series of spin-gapped phases appearing at five different fractions of magnetization by means of a grand canonical density matrix renormalization group, an unbiased state-of-the-art numerical technique. The magnetic field dopes magnons and first gives rise to a possible Z3 spin liquid plateau at 1/9 magnetization. Higher field induces a self-organized super-lattice unit, a six-membered ring of quantum spins, resembling an atomic orbital structure. Putting magnons into this unit one by one yields three quantum solid plateaus. We thus find that the magnetic field could control the transition between various emergent phases by continuously releasing the frustration. 23454626 Antivenom for snakebite envenoming in Sri Lanka: The need for geographically specific antivenom and improved efficacy. Sri Lanka is a tropical developing island nation that endures significant economic and medical burden as a result of snakebite envenomation, having not only a high prevalence of envenomations, but also one of the highest incidence rates (200 snakebites/100,000 people/year) of venomous snakebite in the world (Kasturiratne et al., 2005). Ironically, the very snakes responsible for this human morbidity and mortality are a valuable a biomedical and ecological national resource, despite the medical and economic consequences of envenomation. Currently, no snake antivenom is produced using venoms from native Sri Lankan snakes as immunogens, and there is a true need for an efficacious Sri Lanka, poly-specific snake antivenom. An approach to fulfilling this need via combining the scientific, technological and economical resources from Costa Rica and the United States with the knowledge and talent of Sri Lankan official governmental agencies, legal counsels, environmental, medical and veterinary academic institutions, and religious and cultural leaders has been initiated, coordinated and funded by Animal Venom Research International (AVRI), a nonprofit charity. This bridging of nations and the cooperative pooling of their resources represents a potential avenue for antivenom development in a developing country that suffers the consequences of few specific resources for the medical management of venomous snakebite. The desired final outcome of such an endeavor for Sri Lanka is, most importantly, improved medical outcomes for snakebite patients, with enhanced and expanded science and technology relating to snake venoms and antivenoms, and the collateral benefits of reduced economic cost for the country. 23894317 Interaction between Trehalose and MTHase from Sulfolobus solfataricus Studied by Theoretical Computation and Site-Directed Mutagenesis. Maltooligosyltrehalose trehalohydrolase (MTHase) catalyzes the release of trehalose by cleaving the α-1,4-glucosidic linkage next to the α-1,1-linked terminal disaccharide of maltooligosyltrehalose. Computer simulation using the hydrogen bond analysis, free energy decomposition, and computational alanine scanning were employed to investigate the interaction between maltooligosyltrehalose and the enzyme. The same residues that were chosen for theoretical investigation were also studied by site-directed mutagenesis and enzyme kinetic analysis. The importance of residues determined either experimentally or computed theoretically were in good accord with each other. It was found that residues Y155, D156, and W218 of subsites -2 and -3 of the enzyme might play an important role in interacting with the ligand. The theoretically constructed structure of the enzyme-ligand complex was further validated through an ab initio quantum chemical calculation using the Gaussian09 package. The activation energy computed from this latter study was very similar to those reported in literatures for the same type of hydrolysis reactions. 23933674 Juvenile polyp. The most frequent clinical presentation of intestinal polyps is painless rectal bleeding. Although colonoscopy is the modality of choice for the diagnosis of intestinal polyps, sonography may be the first diagnostic tool in the evaluation of children with bloody stools. Ultrasonography has the advantage of being safe and noninvasive. 23952077 Relation of Periodontitis and Metabolic Syndrome with Gestational Glucose Metabolism Disorder. Background: Gestational diabetes mellitus and Metabolic Syndrome has been related to periodontitis. Our objective was to establish the relationship between them in pregnant women affected by Gestational Glucose Metabolism Disorder. Materials and Methods: In 188 positive O´Sullivan test pregnant women, an oral glucose tolerance test was performed to diagnose Gestational-Diabetes-Mellitus. Periodontal parameters, mother´s age, Pre-pregnancy Weight/Height, Pre-pregnancy-BMI, blood pressure, gestational age, birthweight, glucose, C-reactive-protein, triglycerides, total cholesterol, LDL-c, HDL-c and VLDL-c cholesterol, glycosylated haemoglobin were recorded at 24-28 weeks of pregnancy. Results: Pre-pregnancy weight, Pre-pregnancy BMI, systolic and diastolic blood pressure, VLDL cholesterol and glucose parameters were higher in GDM compare with POT patients (p<0.05). VLDL Cholesterol, Triglycerides and Oral-Glucose-Tolerance-Test (OGTT) 2h were higher in Periodontitis patients compare with Non-Periodontitis patients (p<0.05). HbA1c, Triglycerides, OGTT 1h and 2h were positively related with Probing Pocket Depth and Clinical Attachment Level; Blood glucose was related only with BOP (p<0.05). HbA1c, OGTT basal, OGTT 1h and 2h were positively related with Pre-pregnancy BMI and blood pressure; HDL cholesterol was negatively related with Pre-pregnancy BMI; CRP was positively related with Pre-pregnancy BMI and diastolic blood pressure (p<0.05). Conclusions: Our data support the relationship between periodontal disease and some biochemical parameters such as lipid and glucose data in pregnancy, and also between MeS and biochemical parameters. 23411279 Phenolics content and antioxidant and anti-inflammatory activities of legume fractions. Two faba bean (Vicia faba L.) subspecies major and minor and lentil seeds grown in Algeria were separated into cotyledons and hulls. These fractions, together with their corresponding whole seeds, were extracted with two solvents, aqueous (70%) acetone and (80%) ethanol, and evaluated for antioxidant activity in relation to their phenolic contents. Acetone selectively extracted tannins from faba beans. The hulls always exhibited high antioxidant activity, measured using the reducing power (RP), antiradical activity (DPPH) or oxygen radical absorbance capacity (ORAC) assays. Aqueous ethanol (80%) extract of lentil hulls exhibited high antioxidant and anti-inflammatory activities preferentially inhibiting 15-LOX (IC(50), 55 μg/ml), with moderate COX-1 (IC(50), 66 μg/ml) and COX-2 (IC(50), 119 μg/ml) inhibitory effects on the COX pathway, whereas faba bean hull extracts exerted relatively mild LOX inhibitory activity. 23889861 Predicting persistency of DSM-5 alcohol use disorder and examining drinking patterns of recently remitted persons: a prospective general population study. To establish the 3-year persistency rate of alcohol use disorder (AUD) and its predictors, and to examine drinking patterns of recently remitted persons. The Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2) surveyed a nationally representative sample of adults (aged 18-64) at baseline (response=65.1%) and 3-year follow-up (response=80.4%). People with AUD at baseline, as defined by DSM-5 (n=198). AUD, drinking patterns and mental disorders were assessed using the Composite International Diagnostic Interview 3.0. Other predictors were assessed with an additional questionnaire. Predictors of persistency were examined with univariable and multivariable logistic regression analyses. The AUD persistency rate was 29.5% (95% CI=20.0-39.0). In the multivariable model, the older (25-34 and 35-44) age groups had lower AUD persistency (odds ratio (OR)=0.05; p=.014 and OR=0.14; p=.028, respectively) than the youngest age group (18-24). A higher number of weekly drinks and a comorbid anxiety disorder predicted AUD persistency (OR=1.03; p=.043 and OR=4.56; p=.046, respectively). Furthermore, remission was associated with a reduction of 6 drinks per week between T0 and T1 . It should be noted however that 35.8% (95% CI=22.4-49.2) of persons in diagnostic remission still drank more than the recommended maximum (>7/14 drinks weekly for women/men). Only a minority of people in the Netherlands with alcohol use disorder (AUD) as defined by DSM-5 still have the disorder 3 years later. Factors that help identify people at risk of AUD persistence are: younger age, a higher number of weekly drinks and a comorbid anxiety disorder. A substantial number of people recently in diagnostic remission still drink above the maximum recommended level. 23889004 Transmission Electron Microscopy and Time Resolved Optical Spectroscopy Study of the Electronic and Structural Interactions of ZnO Nanorods with Bovine Serum Albumin. The adsorption behavior and electronic interactions of bovine serum albumin (BSA) with ZnO nanorod surfaces were investigated using high-resolution transmission electron microscopy as well as stationary and time-resolved optical spectroscopy techniques. Transmission electron microscopy shows that ZnO nanorod surfaces are surrounded by a homogeneous amorphous BSA film with thicknesses between ∼2.5 and 5.0 nm. The electronic structure and adsorption geometry of BSA were examined using high-angle annular dark field scanning transmission electron microscopy combined with electron energy loss spectroscopy. The adsorption process was observed to result into an unfolded conformation of BSA becoming predominantly bound in the side-on orientation at the ZnO surface. This adsorption mode of the BSA molecules allows for a strong interaction with surface states of the ZnO nanorods. This is obvious from its efficient quenching of the defect-center photoluminescence of ZnO. Complementary information of electronic interactions across the ZnO nanorod interface was obtained from femtosecond transient absorption spectroscopy experiments. The rise dynamics of the measured transients revealed altered hole trapping dynamics and, thus, indicated to heterogeneous charge transfer as emerging from adsorbed BSA molecules to defect centers of the ZnO interface. 23933580 Slc26a6 functions as an electrogenic Cl-/HCO3- exchanger in cardiac myocytes. Alterations in cardiac acid-base balance can produce profound impact on excitation-contraction coupling, and precipitate cardiac dysfunction and arrhythmias. A member of the solute carrier (SLC) family, Slc26a6, has been shown to be a chloride-hydroxyl exchanger and the predominant chloride-bicarbonate exchanger in the mouse heart. However, the exact isoforms and functional characteristics of cardiac Slc26a6 remain unknown. The objective of the present study is to determine the molecular identity of cardiac Slc26a6 isoforms, examine their cellular expressions in the heart, and test the function of Slc26a6 in cardiomyocytes.Methods and ResultsWe examined the expression and function of slc26a6 in mouse cardiomyocytes using RT-PCR, immunofluorescence confocal microscopy and patch-clamp technique coupled with the fast solution exchange system. We identified four cardiac Slc26a6 isoforms, denoted C-a, C-b, C-c, and C-d, and detected significant expression of Slc26a6 in the plasma membrane of both atrial and ventricular myocytes. Isoforms C-a and C-b share the same sequence with the previously reported murine Slc26a6a and Slc26a6b, respectively. Isoform C-c lacks an alternate in-frame exon 12, while C-d is a C-terminal truncated form resulting from 102 bp exon insertion between exon 15 and 16 compared to C-b. Patch-clamp recordings demonstrated electrogenic Cl(-)/oxalate and electrogenic Cl(-)/HCO3(-) exchange activities in cardiomyocytes. We demonstrate that cardiac myocytes express different isoforms of Slc26a6 which encode electrogenic Cl(-)/HCO3(-) and Cl(-)/oxalate exchangers. The electrogenic nature of the Cl(-)/HCO3(-) exchange of cardiac Slc26a6 suggests important roles in regulating acid-base balance in the heart. 23958332 Pilot study of a social network intervention for heroin users in opiate substitution treatment: study protocol for a randomized controlled trial. Research indicates that 3% of people receiving opiate substitution treatment (OST) in the UK manage to achieve abstinence from all prescribed and illicit drugs within 3 years of commencing treatment, and there is concern that treatment services have become skilled at engaging people but not at helping them to enter a stage of recovery and drug abstinence. The National Treatment Agency for Substance Misuse recommends the involvement of families and wider social networks in supporting drug users' psychological treatment, and this pilot randomized controlled trial aims to evaluate the impact of a social network-focused intervention for patients receiving OST. In this two-site, early phase, randomized controlled trial, a total of 120 patients receiving OST will be recruited and randomized to receive one of three treatments: 1) Brief Social Behavior and Network Therapy (B-SBNT), 2) Personal Goal Setting (PGS) or 3) treatment as usual. Randomization will take place following baseline assessment. Participants allocated to receive B-SBNT or PGS will continue to receive the same treatment that is routinely provided by drug treatment services, plus four additional sessions of either intervention. Outcomes will be assessed at baseline, 3 and 12 months. The primary outcome will be assessment of illicit heroin use, measured by both urinary analysis and self-report. Secondary outcomes involve assessment of dependence, psychological symptoms, social satisfaction, motivation to change, quality of life and therapeutic engagement. Family members (n = 120) of patients involved in the trial will also be assessed to measure the level of symptoms, coping and the impact of the addiction problem on the family member at baseline, 3 and 12 months. This study will provide experimental data regarding the feasibility and efficacy of implementing a social network intervention within routine drug treatment services in the UK National Health Service. The study will explore the impact of the intervention on both patients receiving drug treatment and their family members. Trial Registration Number: ISRCTN22608399ISRCTN22608399 registration: 27/04/2012Date of first randomisation: 14/08/2012. 23821680 Micropatterning of Silica Nanoparticles by Electrospray Deposition through a Stencil Mask. This article describes the local deposition, or micropatterning, of silica nanoparticles (NPs) using an electrospray method with a stencil mask. The proposed technique can be carried out in a single step at room temperature and atmospheric pressure under dry conditions, allowing it to be used with water- or vacuum-sensitive materials, and leading to cost reductions and high throughput. An evaluation of the patterning accuracy using a 20 µm thick mask showed that for patterns with line widths greater than 50 µm, the pattern was reproduced with an accuracy greater than 95%. When silver NPs were preferably deposited on the silica NPs using a modified silver mirror reaction, they were found to exhibit strong surface-enhanced Raman scattering effects. The proposed process is readily applicable to the development of high-performance micro total analysis systems. 23895077 Colorectal tissue engineering: prerequisites, current status and perspectives. Gastrointestinal tissue engineering has emerged over the past 20 years and was often focused on esophagus, stomach or small intestine, whereas bioengineering researches of colorectal tissue are scarce. However, some promising results have been obtained in animal models. Refinements should be performed in scaffold and cell source selection to allow smooth muscle layer regeneration. Indeed, synthetic and natural polymers such as small intestinal submucosa and collagen sponge seeded with organoid units or smooth muscle cells did not allow smooth muscle regeneration. Mesenchymal stem cells derived from adipose tissue seeded on composite scaffold could represent an interesting way to achieve this goal. This article reviews potential indications, current status and perspectives of tissue engineering in the area of colorectal surgery. 23935839 Association of preexisting drug-resistance mutations and treatment failure in hepatitis B patients. The role of preexisting minority drug-resistance mutations in treatment failure has not been fully understood in chronic hepatitis B patients. To understand mechanisms of drug resistance, we analyzed drug-resistance mutations in 46 treatment-failure patients and in 29 treatment-naïve patients and determined linkage patterns of the drug-resistance mutations in individual viral genomes using a highly sensitive parallel allele-specific sequencing (PASS) method. Lamivudine resistance (LAMr) mutations were predominant in treatment-failure patients, irrespective of the inclusion of LAM in the regimen. The primary LAMr mutations M204V and M204I were detected in 100% and 30% of the treatment-failure patients, respectively. Two secondary LAMr mutations (L180M and V173L) were also found in most treatment-failure patients (87% and 78%, respectively). The linkages containing these three mutations dominated the resistant viruses. Importantly, minority LAMr mutations present in <2% of the viral population were detected in 83% of the treatment-naïve patients. Moreover, the low-frequency same linked LAMr mutations (<0.15%) were detected in 24% of the treatment-naïve patients. Our results demonstrate that the selection of preexisting minority linked LAMr mutations may be an important mechanism for the rapid development of LAM resistance, caution the continuous use of LAM to treat drug-experienced and -naïve hepatitis B patients, and underline the importance of the detection of minority single and linked drug-resistance mutations before initiating antiviral therapy. 23942756 Ultraviolet light exposure stimulates HMGB1 release by keratinocytes. The primary cause of non-melanoma skin cancer is ultraviolet (UV) light from the sun. Many studies have demonstrated that cutaneous inflammation resulting from UV exposure is important for the development of skin cancer. In fact, anti-inflammatory drugs have been shown to be effective in preventing skin cancer in animal models and in clinical trials. One new class of inflammatory mediators that could regulate UV-induced inflammation and skin carcinogenesis is alarmins. Alarmins are endogenous molecules that act as potent pro-inflammatory mediators when they are released by cells or accumulate extracellularly. The purpose of the current studies was to examine the expression and release of the alarmin high mobility group box 1 (HMGB1) after acute and chronic UV irradiation. Acute UV exposure stimulated the release of HMGB1 in cultured human keratinocytes and epidermal keratinocytes in murine skin. HMGB1 release correlated with pro-inflammatory cytokine production in vitro and inflammatory cell infiltration in vivo. HMGB1 was also examined in tumors arising in chronically irradiated murine skin. HMGB1 protein expression in low grade, benign papillomas was similar to adjacent skin. However, HMGB1 staining was more widespread with a higher number of HMGB1-positive cells observed in high grade papillomas and malignant tumors. Overall, the data suggest that HMGB1 may be an important regulator of UV-induced cutaneous inflammation and tumor formation. Additional studies are needed to assess whether targeting HMGB1 would be a useful strategy to prevent tumors from developing in response to chronic UV exposure. 23254340 Focal adhesion size uniquely predicts cell migration. Focal adhesions are large protein complexes organized at the basal surface of cells, which physically connect the extracellular matrix to the cytoskeleton and have long been speculated to mediate cell migration. However, whether clustering of these molecular components into focal adhesions is actually required for these proteins to regulate cell motility is unclear. Here we use quantitative microscopy to characterize descriptors of focal adhesion and cell motility for mouse embryonic fibroblasts and human fibrosarcoma cells, across a wide range of matrix compliance and following genetic manipulations of focal adhesion proteins (vinculin, talin, zyxin, FAK, and paxilin). This analysis reveals a tight, biphasic gaussian relationship between mean size of focal adhesions (not their number, surface density, or shape) and cell speed. The predictive power of this relationship is comprehensively validated by disrupting nonfocal adhesion proteins (α-actinin, F-actin, and myosin II) and subcellular organelles (mitochondria, nuclear DNA, etc.) not known to affect either focal adhesions or cell migration. This study suggests that the mean size of focal adhesions robustly and precisely predicts cell speed independently of focal adhesion surface density and molecular composition.-Kim, D.-H., Wirtz, D. Focal adhesion size uniquely predicts cell migration. 23812551 Randomized clinical trial of arginine-supplemented enteral nutrition versus standard enteral nutrition in patients undergoing gastric cancer surgery. Significant malnutrition exists in a high percentage of patients with gastric cancer. It is, therefore, crucial to establish an effective means to provide nutrition for these patients. This prospective, randomized, double-blinded clinical trial aims to assess the long-term survival of arginine-supplementation enteral nutrition versus standard enteral nutrition in malnourished patients with gastric cancer. The control group (36 cases) received postoperative standard enteral nutrition. Meanwhile, the arginine-supplementation group (37 cases) adopted the same nutrition product but enriched with arginine (9.0 g/L). The primary study objective was overall survival (OS). Secondary endpoints were progression-free survival (PFS); serum parameters including total protein, albumin, proalbumin, and transferrin obtained on preoperative day 1, postoperative day 2, and day 12; CD4(+) and CD8(+) T cells, natural killer (NK) cells, immunoglobulin M (IgM), and immunoglobulin G (IgG) obtained on preoperative day 1 and postoperative day 7. No significant differences in baseline characteristics were observed between groups. The group receiving arginine-enriched nutrition had a significantly better OS (P = 0.03, 41 vs. 30.5 months) and better PFS (P = 0.02, 18 vs. 11.5 months). On postoperative day 7, CD4(+) T cells, NK cells, IgM and IgG levels of the arginine-supplemented group increased prominently and were significantly higher than those of the control group and those on preoperative day 1. There is no significant difference in the serum total protein, albumin, proalbumin, and transferrin levels between the two arms. Arginine-supplemented enteral nutrition significantly improves long-term survival and restores immunity in malnourished gastric cancer. 23929269 Direct comparison of eight national FRAX® tools for fracture prediction and treatment qualification in Canadian women. We compared the calibration of FRAX tools from Canada, the US (white), UK, Sweden, France, Australia, New Zealand, and China when used to assess fracture risk in 36,730 Canadian women. Our data underscores the importance of applying country-specific FRAX tools that are based upon high-quality national fracture epidemiology. A FRAX® model for Canada was constructed for prediction of hip fracture and major osteoporotic fracture (MOF) using national hip fracture and mortality data. We examined the calibration of this model in Canadian women and compared it with seven other FRAX tools. In women aged ≥50 years with baseline bone mineral density (BMD) measures identified from the Manitoba Bone Density Program, Canada (n = 36,730), 10-year fracture probabilities were calculated with and without BMD using selected country-specific FRAX tools. FRAX risk estimates were compared with observed fractures ≤10 years (506 hip, 2,380 MOF). Ten-year fracture risk was compared with predicted probabilities, and proportions exceeding specific treatment thresholds contrasted. For hip fracture prediction, good calibration was observed for FRAX Canada and most other country-specific FRAX tools, excepting Sweden (risk overestimated) and China (risk underestimated). For MOF prediction, greater between-country differences were seen; FRAX Sweden and FRAX China showed the largest over- and underestimation in this Canadian population. Relative to treatment qualification based upon FRAX Canada, treatment of high-hip fracture probability (≥3 %) was greater by FRAX Sweden (ratio 1.41 without and 1.55 with BMD), and markedly less by FRAX China (ratio 0.09 without and 0.11 with BMD). Greater between-country differences were observed for treat4ment of high MOF (≥20 %); FRAX Sweden again greatly increased (ratio 1.76 without and 1.83 with BMD), and FRAX China severely reduced treatment qualification (ratio 0.00 without and 0.01 with BMD). The use of country-specific FRAX tools, accurately calibrated to the target population, is essential. Relatively small calibration differences can have large effects on high-risk categorization and treatment qualification. 23727023 Reoxygenation using a novel CO2 therapy decreases the metastatic potential of osteosarcoma cells. Osteosarcoma is the most common primary solid malignant bone tumor. Despite substantial improvements in surgery and chemotherapy, metastasis remains a major cause of fatal outcomes, and the molecular mechanisms of metastasis are still poorly understood. Hypoxia, which is common in malignant tumors including osteosarcoma, increases expressions of hypoxia inducible factor (HIF)-1α, matrix metalloproteinase (MMP)-2 and MMP-9, and can induce invasiveness. As we previously showed a novel transcutaneous CO2 application to decrease HIF-1α expression and induce apoptosis in malignant fibrous histiocytoma, we hypothesize that transcutaneous CO2 application could suppress metastatic potential of osteosarcoma by improving hypoxic conditions. Here, we examined the effects of transcutaneous CO2 application on apoptosis, and development of pulmonary metastasis using a highly metastatic osteosarcoma cell line, LM8. Transcutaneous CO2 application significantly decreased tumor growth and pulmonary metastasis in LM8 cells. Apoptotic activity increased, and intratumoral hypoxia was improved with decreased expressions of HIF-1α, MMP-2 and MMP-9, significantly, in the CO2-treated tumors. In conclusion, we found that transcutaneous CO2 application can induce tumor cell apoptosis and might suppress pulmonary metastasis by improvement of hypoxic conditions with decreased expressions of HIF-1α and MMPs in highly metastatic osteosarcoma cell. These findings strongly indicate that this novel transcutaneous CO2 therapy could be a therapeutic breakthrough for osteosarcoma patients. 23851189 Lymphogranuloma venereum diagnoses among men who have sex with men in the UK: interpreting a cross-sectional study using an epidemic phase-specific framework. To investigate the drivers behind the epidemic expansion of lymphogranuloma venereum (LGV) cases in late 2009 to help inform infection control. An epidemic curve of all LGV diagnoses between 2003 and mid-2012 was plotted and divided into the initial detection period, and endemic, growth and hyperendemic phases. Detailed clinical and behavioural data were collected and logistic regression was used to compare the characteristics of diagnoses made during the growth and endemic phases. Between April 2003 and June 2012, 2138 cases of LGV were diagnosed. Enhanced surveillance data were available for 1370 of whom 1353 were men who have sex with men (MSM). 98% of MSM presented with proctitis, 82% were HIV positive, 20% were hepatitis C virus (HCV) antibody positive, and 67% lived in London. Growth phase cases (n=488) were more likely to report meeting sexual contacts at sex parties (11% vs 6%, p=0.014), unprotected receptive or insertive oral intercourse (93% vs 86%, p=0.001; 92% vs 85%, p=0.001) and sharing sex toys (8% vs 4%; p=0.011), and to be diagnosed HIV positive (86% vs 80%; p=0.014), than endemic phase cases (n=423). Unprotected receptive anal intercourse was equally likely to be reported in both phases (71% vs 73%). After adjustment, cases in the growth phase were more likely to meet new contacts at sex parties (p=0.031) and be HIV positive (p=0.045). Rapid epidemic growth coincided with an intensification of unprotected sexual activity among a core population of HIV-positive MSM. Efforts to develop innovative interventions for this hard-to-reach population are needed. 23879367 Noncoding RNAs in DNA Repair and Genome Integrity. Significance: The well-studied sequences in the human genome are those of protein-coding genes, which account for only 1-2% of the total genome. However, with the advent of high-throughput transcriptome sequencing technology, we now know that about 90% of our genome is extensively transcribed and that the vast majority of them are transcribed into noncoding RNAs (ncRNAs). It is of great interest and importance to decipher the functions of these ncRNAs in humans. Recent Advances: In the last decade, it has become apparent that ncRNAs play a crucial role in regulating gene expression in normal development, stress responses to internal and environmental stimuli, and in human diseases. Critical Issues: In addition to those constitutively expressed structural RNA, such as ribosomal and transfer RNAs, regulatory ncRNAs can be classified as microRNAs (miRNAs), Piwi-interacting RNAs (piRNAs), small interfering RNAs (siRNAs), small nucleolar RNAs (snoRNAs) and long noncoding RNAs (lncRNAs). However, little is known about the biological features and functional roles of these ncRNAs in DNA repair and genome instability although a number of miRNAs and lncRNAs are regulated in the DNA damage response. Future Directions: A major goal of modern biology is to identify and characterize the full profile of ncRNAs with respect to normal physiological functions and roles in human disorders. Clinically relevant ncRNAs will also be evaluated and targeted in therapeutic applications. 23466257 Gonadotropin releasing hormone and brooding behavior in the native Thai hen. Changes in the number of hypothalamic gonadotropin releasing hormone-I (GnRH-I) neurons within the Nucleus commissurae pallii (nCPa) were associated with the reproductive cycle of native Thai chickens. In order to further understand the association of GnRH-I in the regulation of brooding behavior in this bird, the native Thai chickens were divided into two groups; chick-rearing (R) and non-chick-rearing (NR) hens. Numbers of visible of GnRH-I-immunoreactive (GnRH-I-ir) neurons in the hypothalamus of R and NR hens were compared utilizing immunohistochemistry. Numbers of visible GnRH-I-ir neurons within the Nucleus anterior medialis hypothalami, Nucleus suprachaiasmaticus, pars medialis, Nucleus septalis lateralis, Nucleus paraventricularis magnocellularis, and Regio lateralis hypothalami areas were observed in both groups, but no differences were seen between R and NR hens. The number of visible GnRH-I neurons in the nCPa was higher (P<0.05) in the NR than in R hens, and increased in NR hens by day 14 after chick removal. These findings suggest, for the first time, an association of the GnRH system with brooding behavior in continuously breeding birds. Furthermore, the expression of brooding behavior of native Thai chickens might be regulated, in part, by GnRH-I neurons in the nCPa. 23897180 Increased serum phosphate concentrations in patients with advanced chronic kidney disease treated with diuretics. Background: Serum phosphate concentrations usually show great variability in patients with advanced chronic kidney disease (ACKD) not on dialysis. Diuretics treatment can have an influence over the severity of mineral-bone metabolism alterations related to ACKD, but their effect on serum phosphate levels is less known. Objectives: This study aims to determine whether diuretics are independently associated with serum phosphate levels, and to investigate the mechanisms by which diuretics may affect phosphate metabolism. Material and Method: 429 Caucasian patients with CKD not on dialysis were included in this cross-sectional study. In addition to conventional serum biochemical measures, the following parameters of renal phosphate excretion were assessed: 24-hours urinary phosphate excretion, tubular maximum phosphate reabsorption (TmP), and fractional excretion of phosphate (FEP). Results: 58% of patients were on treatment with diuretics. Patients on diuretics showed significantly higher mean serum phosphate concentration (4.78±1.23 vs. 4.24±1.04mg/dl; P<.0001), and higher TmP per GFR (2.77±0.72 vs. 2.43±0.78mg/dl; P<.0001) than those not treated with diuretics. By multivariate linear and logistic regression, significant associations between diuretics and serum phosphate concentrations or hyperphosphataemia remained after adjustment for potential confounding variables. In patients with the highest phosphate load adjusted to kidney function, those treated with diuretics showed significantly lower FEP than those untreated with diuretics. Conclusions: Treatment with diuretics is associated with increased serum phosphate concentrations in patients with ACKD. Diuretics may indirectly interfere with the maximum renal compensatory capacity to excrete phosphate. Diuretics should be considered in the studies linking the relationship between serum phosphate concentrations and cardiovascular alterations in patients with CKD. 23305426 Quantifying intrinsic ion-driven conformational changes in diphenylacetylene supramolecular switches with cryogenic ion vibrational spectroscopy. We report how two flexible diphenylacetylene (DPA) derivatives distort to accommodate both cationic and anionic partners in the binary X(±)·DPA series with X = TMA(+) (tetramethylammonium), Na(+), Cl(-), Br(-), and I(-). This is accomplished through theoretical analysis of X(±)·DPA·2D2 vibrational spectra, acquired by predissociation of the weakly bound D2 adducts formed in a 10 K ion trap. DPA binds the weakly coordinating TMA(+) ion with an arrangement similar to that of the neutral compound, whereas the smaller Na(+) ion breaks all intramolecular H-bonds yielding a structure akin to the transition state for interconversion of the two conformations in neutral DPA. Halides coordinate to the urea NH donors in a bidentate H-bonded configuration analogous to the single intramolecular H-bonded motif identified at high chloride concentrations in solution. Three positions of the "switch" are thus identified in the intrinsic ion accommodation profile that differ by the number of intramolecular H-bonds (0, 1, or 2) at play. 23848266 Mineral Biofortification Strategies for Food Staples: The Example of Common Bean. Common bean is the most important directly consumed legume, especially in the least developed countries of Africa (e.g., Burundi, Democratic Republic of Congo, Rwanda, and Uganda) and Latin America (e.g., Guatemala, Nicaragua, and El Salvador). Biofortification is the process of improving staple crops for mineral or vitamin content as a way to address malnutrition in developing countries. The main goals of mineral biofortification have been to increase the concentration of iron or zinc in certain major cereals and legumes. In humans, iron is essential for preventing anemia and for the proper functioning of many metabolic processes, whereas zinc is essential for adequate growth and for resistance to gastroenteric and respiratory infections, especially in children. This paper outlines the advantages and needs of mineral biofortification in common bean, starting with the steps of breeding for the trait such as germplasm screening, inheritance, physiological, or bioavailability studies and finishing with product development in the form of new biofortified varieties. 23727877 CA II, a potential biomarker by proteomic analysis, exerts significant inhibitory effect on the growth of colorectal cancer cells. In the Western world, colorectal cancer (CRC) is the third most common cancer with poor prognosis. To identify the proteins and to elucidate the possible mechanisms involved in colorectal carcinogenesis, 2-DE coupled with MS/MS analysis were employed to compare the global protein profile between CRC and individual matched normal tissues from 8 CRC patients. Of 36 proteins identified, carbonic anhydrase II (CA II) was one of most significantly altered and its downregulation in CRC tissues was verified by RT-PCR, western blotting and immunohistochemistry methods, suggesting that CA II may serve as a potential biomarker for CRC diagnosis. To investigate the function and mechanisms of CA II in CRC, a stable SW480 colorectal cancer cell line overexpressing CA II was established. It was shown that overexpression of CA II remarkably suppressed tumor cell growth both in vitro and in vivo, which was in part interpreted by cell cycle arrest at G0/G1 and G2 phase. Further mechanism analysis revealed that the sensitivity of colorectal cancer cells to chemotherapy drugs could be increased by CA II overexpression. Taken together, these data suggest that CA II may be a potential biomarker for early diagnosis of CRC and the results may contribute to a better understanding of the molecular mechanism of CRC and colorectal cancer treatment. 23822140 Sudden Death Due to Hydatid Disease: A Six-Year Study in the Northern Part of Tunisia. Human ecchinococcosis also known as hydatid disease is a zoonotic infection caused by the tapeworm Ecchinococcus with 2-3 Million cases worldwide. We hereby report a 6 years period study of Sudden death due to hydatidosis aiming to analyze the epidemiological criteria, death circumstances, and autopsy observations attributed to hydatid disease. During the past 6 years, 26 death cases were due to hydatid disease. Our analysis shows that the sex ratio (M/F) was 1.6, the mean age was 31-year old, and 65% of the subjects lived in rural places. In 17 cases, death occurred in the victim's place, five victims died after a heavy exercise, and in two cases, death occurred immediately after trauma. At autopsy, 91% of the cysts were found in the liver. In three cases, death followed a septic state, and in two cases, it followed an acute respiratory failure. Death was attributed to anaphylaxis in 17 cases. 23242209 Cumulative viral evolutionary changes in chronic hepatitis B virus infection precedes hepatitis B e antigen seroconversion. To examine viral evolutionary changes and their relationship to hepatitis B e antigen (HBeAg) seroconversion. A matched case-control study of HBeAg seroconverters (n=8) and non-seroconverters (n=7) with adequate stored sera before seroconversion was performed. Nested PCR, cloning and sequencing of hepatitis B virus (HBV) precore/core gene was performed. Sequences were aligned using Clustal X2.0, followed by construction of phylogenetic trees using Pebble 1.0. Viral diversity, evolutionary rates and positive selection were then analysed. Baseline HBV quasispecies viral diversity was identical in seroconverters and non-seroconverters 10 years before seroconversion but started to increase approximately 3 years later. Concurrently, precore stop codon (PSC) mutations appeared. Some 2 years later, HBV-DNA declined, together with a dramatic reduction in HBeAg titres. Just before HBeAg seroconversion, seroconverters had HBV-DNA levels 2 log lower (p=0.008), HBeAg titres 310-fold smaller (p=0.02), PSC mutations > 25% (p<0.001), viral evolution 8.1-fold higher (p=0.01) and viral diversity 2.9-fold higher (p<0.001), compared to non-seroconverters, with a 9.3-fold higher viral diversity than baseline (p=0.011). Phylogenetic trees in seroconverters showed clustering of separate time points and longer branch lengths than non-seroconverters (p=0.01). Positive selection was detected in five of eight seroconverters but none in non-seroconverters (p=0.026). There was significant negative correlation between viral diversity (rs=-0.60, p<0.001) and HBV-DNA or HBeAg (rs=-0.58, p=0.006) levels; and positive correlation with PSC mutations (rs=0.38, p=0.009). Over time, the significant positive correlation was viral diversity (rs=0.65, p<0.001), while negative correlation was HBV-DNA (rs=-0.627, p<0.001) and HBeAg levels (rs=-0.512, p=0.015). Cumulative viral evolutionary changes that precede HBeAg seroconversion provide insights into this event that may have implications for therapy. 23878251 Oscillatory activity in the monkey hippocampus during visual exploration and memory formation. Primates explore the visual world through the use of saccadic eye movements. Neuronal activity in the hippocampus, a structure known to be essential for memory, is modulated by this saccadic activity, but the relationship between visual exploration through saccades and memory formation is not well understood. Here, we identify a link between theta-band (3-12 Hz) oscillatory activity in the hippocampus and saccadic activity in monkeys performing a recognition memory task. As monkeys freely explored novel images, saccades produced a theta-band phase reset, and the reliability of this phase reset was predictive of subsequent recognition. In addition, enhanced theta-band power before stimulus onset predicted stronger stimulus encoding. Together, these data suggest that hippocampal theta-band oscillations act in concert with active exploration in the primate and possibly serve to establish the optimal conditions for stimulus encoding. 23692351 Room-temperature sol-gel derived molybdenum oxide thin films for efficient and stable solution-processed organic light-emitting diodes. Molybdenum oxide (MoO3) thin films were prepared by sol-gel methods at room temperature from the precursors of MoO3 powder mixing into NH3 or H2O2 solution and then directly treated by UV-ozone instead of widely used high-temperature annealing. Atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), and ultraviolet photoelectron spectroscopy (UPS) characteristics demonstrated that the room-temperature sol-gel derived MoO3 thin films exhibited excellent uniformity, unchanged chemical structure, and high work function. For the first time, the novel solution-processed MoO3 thin films were successfully applied as the hole injection layers (HILs) for solution-processed organic light-emitting diodes (OLEDs). The efficiencies of the resulting OLEDs were comparable or even higher than that of the device using PEDOT:PSS as the HIL. More importantly, the lifetimes of the solution-processed OLEDs are improved by nearly 2 orders of magnitude. This study should provide a potential approach to develop low-cost, high-performance, and long-lifetime OLEDs for practical applications. 23881962 Primary care and population factors associated with NHS Health Check coverage: a national cross-sectional study. Introduction High and equitable coverage of systematic cardiovascular disease (CVD) prevention programmes, such as the NHS Health Check programme in England, is essential if they are to effectively reduce the population CVD burden. We conducted a cross-sectional study using data from 151 English primary care trusts (PCTs) on NHS Health Check coverage during 2011-12. We examined the associations between programme coverage and primary care and population factors, including patient demographics, primary care workforce and cardiovascular health need. Median coverage of NHS Health Checks was 8.2%, with wide PCT-level variation (range = 0-29.8%). Coverage was significantly higher in PCTs in the most deprived areas compared with the least deprived (P = 0.035), adjusting for covariates. Significant negative associations between coverage and a higher proportion of PCT population aged 40-74 years-the eligible Health Check age group, a larger total population size and higher practice staffing levels were found in the unadjusted analyses. NHS Health Check coverage during 2011-12 was lower than the government projection of 18% coverage. Coverage must be increased through concerted multi-disciplinary strategies, for the programme to improve cardiovascular health in England. Considerable variation in participation between PCTs warrants attention, with enhanced support for poor performers. 23663006 The potential role of valsartan + AHU377 ( LCZ696 ) in the treatment of heart failure. Introduction: Heart failure remains a syndrome with a very high mortality rate and a poor quality of life. For patients with heart failure and a preserved ejection fraction (HFpEF), no drugs have shown to improve mortality and morbidity, and therefore novel drugs are highly needed. LCZ696 , a first in class angiotensin receptor neprilysin inhibitor (ARNi), might be an interesting novel drug for the treatment of heart failure. Areas covered: Previous studies have shown promising effects of a combination drug with a neutral endopeptidase and an angiotensin-converting enzyme inhibitor (omapatrilat) for the treatment of patients with heart failure. However, the occurrence of angioedema prevented the drug from further development. The majority of this paper will discuss the metabolism, pharmacokinetics, pharmacodynamics, clinical effects, and safety of LCZ696, with a particular focus on heart failure. Expert opinion: LCZ696 is superior to valsartan alone in reducing blood pressure. Preliminary results from a Phase II trial showed that LCZ696 reduced NT-proBNP to a greater extent than valsartan alone, and in addition LCZ696 had beneficial effects on symptoms. With these promising first results, the results of ongoing further studies in heart failure are eagerly awaited. 23402887 A comparison of the infant car seat challenge and the polysomnogram at the time of hospital discharge. The American Academy of Pediatrics recommends all infants born at <37 weeks gestation spend a period of observation in a car seat prior to hospital discharge to assess for apnoea, bradycardia or oxygen desaturation. The most recent Cochrane review suggested further studies to determine if the infant car seat challenge (ICSC) accurately predicts the risk of clinically adverse events. We reviewed our experience with the ICSC and the polysomnogram (PSG) to determine if the ICSC accurately predicts the risk of adverse events when compared with the PSG. Retrospective chart review of all infants in our institution who had an ICSC and a PSG between January 2005 and December 2008. 785 infants had ICSCs. In addition, 313 infants (56.6%) had an abnormal PSG, even though the vast majority, 158 (88.3%), passed their ICSC. There were no significant differences in gestational age at birth, birth weight, chronological age at study or postmenstrual age at study between infants who either passed or failed the ICSC with those who passed or failed the PSG. The sensitivity of the ICSC was 0.11 and specificity was 0.96. The positive predictive value of the ICSC was 0.77 and the negative predictive value was 0.45. The ICSC has a low negative predictive value (0.45) when compared with the PSG as a reference standard for identifying adverse cardiorespiratory events. Although less time consuming and cumbersome than extended polysomnography, the ICSC is not a reliable substitute. 23475395 Histamine, carbachol, and serotonin induce hyperresponsiveness to ATP in guinea pig tracheas: involvement of COX-2 pathway. Extracellular ATP promotes an indirect contraction of airway smooth muscle via the secondary release of thromboxane A2 (TXA2) from airway epithelium. Our aim was to evaluate if common contractile agonists modify this response to ATP. Tracheas from sensitized guinea pigs were used to evaluate ATP-induced contractions before and after a transient contraction produced by histamine, carbachol, or serotonin. Epithelial mRNA for COX-1 and COX-2 was measured by RT-PCR and their expression assessed by immunohistochemistry. Compared with the initial response, ATP-induced contraction was potentiated by pretreatment with histamine, carbachol, or serotonin. Either suramin (antagonist of P2X and P2Y receptors) plus RB2 (antagonist of P2Y receptors) or indomethacin (inhibitor of COX-1 and COX-2) annulled the ATP-induced contraction, suggesting that it was mediated by P2Y receptor stimulation and TXA2 production. When COX-2 was inhibited by SC-58125 or thromboxane receptors were antagonized by SQ-29548, just the potentiation was abolished, leaving the basal response intact. Airway epithelial cells showed increased COX-2 mRNA after stimulation with histamine or carbachol, but not serotonin, while COX-1 mRNA was unaffected. Immunochemistry corroborated this upregulation of COX-2. In conclusion, we showed for the first time that histamine and carbachol cause hyperresponsiveness to ATP by upregulating COX-2 in airway epithelium, which likely increases TXA2 production. Serotonin-mediated hyperresponsiveness seems to be independent of COX-2 upregulation, but nonetheless is TXA2 dependent. Because acetylcholine, histamine, and serotonin can be present during asthmatic exacerbations, their potential interactions with ATP might be relevant in its pathophysiology. 23408008 Heredity, development and evolution: the unmodern synthesis of E.S. Russell. In 1930, while R.A. Fisher, J.B.S. Haldane, E.B. Ford and S.G. Wright were laying the foundations of what a decade later J.S. Huxley dubbed "Modern Synthesis", E.S. Russell published a groundbreaking work, The Interpretation of Development and Heredity. In this book Russell not only condemned Mendelian genetics and neo-Darwinism, but also proposed an alternative synthesis unifying heredity, development, and evolution. The book did not represent the work of a mind operating in isolation. Rather, it was a synthetic work connecting ideas and doctrines of many influential scientists working in Europe and the USA. Through the analysis of archival documents and rarely or never mentioned sources, this article provides an unconventional picture of Russell's theoretical biology. It will be shown that Russell was an international celebrity; he was at the centre of a large network of scholars who shared his ideas and insights. He was one of several biologists arguing for a different synthesis; a synthesis perhaps less visible, less institutionalised, and less 'modern', nevertheless with its influential advocates and international support. Finally, this study shows that Russell's synthesis was not rooted in the classic pantheon of towering figures in the history of biology, i.e. Darwin, Wallace, and Mendel, but was based on the teachings of Kant, Goethe, Cuvier, von Baer, and Müller. 23461677 Static cardiomyoplasty with synthetic elastic net suppresses ventricular dilatation and dysfunction after myocardial infarction in the rat: a chronic study. Although static cardiomyoplasty prevents the left ventricle (LV) from dilatation, it may interfere with diastolic relaxation, or cause restriction. We developed a synthetic net with dual elasticity and tested its effect late after myocardial infarction in the rat. LV pressure-volume relationships (PVR) were successively analyzed before, after intravenous volume load, and 10 minutes after occlusion of the left anterior descending artery. Rats were then randomized into groups receiving synthetic net wrapping around the heart (NET+, n = 8) and only partially behind LV (NET-, n = 9), and they underwent the same PVR studies 6 weeks later. End-diastolic and end-systolic PVR were defined, and LV size and function were compared under standardized loading conditions. Although there was no difference in Day 0, increase in LV end-diastolic and end-systolic volumes were significantly attenuated in NET+ rats 6 weeks later when there was a significant correlation between LV volumes by PVR estimation and actual measurements, with significant differences in both measures between the groups: NET+ < NET-. The presence or absence of net did not show restrictive hemodynamics under acute volume load. Static cardiomyoplasty using a synthetic elastic net significantly attenuated LV dilatation and dysfunction without restriction late after myocardial infarction in the rat. 23877958 Conservation caring: Measuring the influence of zoo visitors' connection to wildlife on pro-conservation behaviors. Zoos in the 21st century are striving to make effective contributions to conservation. Although zoos are extremely popular and host over 600 million visitors worldwide, one challenge zoos face is how to effectively engage visitors and raise awareness and action for conservation. To this end, zoos commonly rely on charismatic megafauna, which have been shown to elicit a connection with zoo visitors. However, little is known about how to measure a connection to a species or how this connection may influence conservation behaviors. This study had two sequential objectives. The first was to develop a scale to measure visitors' connection to a species (Conservation Caring). The second was to investigate the relationship of Conservation Caring to pro-conservation behaviors, following a zoo experience. Pre- (n = 411) and post-visit (n = 452) responses were collected from three sites in order to assess the reliability and validity of a scale to measure Conservation Caring. Structural equation modeling was used to explore the relationship between Conservation Caring and pro-conservation behaviors. Conservation Caring was deemed a valid and reliable scale and was a strong predictor of species oriented behaviors (β = 0.62), for example, "adopting" an animal, but a weak predictor for biodiversity oriented behaviors (β = 0.07), for example, supporting sustainability policies. Results support the role zoos can play in fostering a connection to wildlife and stimulating pro-conservation behaviors. Additionally, visitors connected to a wide array of animals. On the basis of these results, zoos may recruit a wider assemblage of species as potential flagships. Zoo Biol. XX:XX-XX, 2013. © 2013 Wiley Periodicals Inc. 23836576 Serum Levels of Neopterin during Antimicrobial Treatment for Mycobacterium ulcerans Infection. Neopterin is closely associated with activation of the cellular immune system. Neopterin levels differed between controls and patients with Buruli ulcer disease. No differences between patients with or without paradoxical responses were observed. Therefore, neopterin has no value in detecting paradoxical responses among patients with limited Buruli ulcer disease. Neopterin levels were lower in patients receiving clarithromycin. This finding might indicate a slower cellular immune recovery, with possible consequences in future therapy with clarithromycin. 23194565 Detection of pyrrolizidine alkaloids in commercial honey using liquid chromatography-ion trap mass spectrometry. Pyrrolizidine alkaloids (PAs) are known secondary plant metabolites which can cause hepatotoxicity in both humans and livestock. PAs can be consumed through the use of plants for food, medicinal purposes and as contaminants of agricultural crops and food. PA contaminated grain has posed the largest health risk, although any PA contamination in our food chain should be recognised as a potential health threat. For this purpose, retail honeys were tested by LC-MS/MS. The method allows for specific identification of toxic retronecine and otonecine-type PAs by comparison to reference compounds via a spectral library. In total, 50 honey samples were matched to the reference spectra within a set of tolerance parameters. Accurate data analysis and quick detection of positive samples was possible. Positive samples contained an average PA concentration of 1260 μg kg(-1) of honey. Good linear calibrations were obtained (R(2)>0.991). LOD and LOQ ranged from 0.0134 to 0.0305 and 0.0446 to 0.1018 μg mL(-1), respectively. 23859927 Receipt of human papillomavirus vaccine among privately insured adult women in a U.S. Midwestern Health Maintenance Organization. To describe human papillomavirus (HPV) vaccine coverage among adult privately insured women including variation in coverage by race/ethnicity. This cross-sectional, observational study included women 18-26years of age with continuous enrollment in a U.S. Midwestern health insurance plan and at least one visit to a plan affiliated practice. Vaccination data came from insurance claims and the electronic medical record. Primary outcomes were: receipt of at least 1 HPV vaccine (HPV1) and completion of the 3-dose HPV vaccine series (HPV3). Coverage was described for the entire cohort and stratified by race/ethnicity. For a subset of women, automated data was compared to personal recall. As of June 2010, among 2546 privately insured women 18-26years, 72.7% had received their first HPV vaccine and 57.9% completed the 3-dose series. Compared to white women, African American and Asian women had significantly lower coverage for HPV1 and HPV3. There was 94.5% (95% CI: 88.5-100%) agreement between personal recall and claims/EMR for receiving HPV1. In this cohort of privately insured women, a majority received HPV1 and more than half completed the 3-dose vaccine series. Marked disparities in receipt of HPV vaccine by race/ethnicity were observed. 23545560 Electroactive nanoparticle directed assembly of functionalized graphene nanosheets into hierarchical structures with hybrid compositions for flexible supercapacitors. Hierarchical structures of hybrid materials with the controlled compositions have been shown to offer a breakthrough for energy storage and conversion. Here, we report the integrative assembly of chemically modified graphene (CMG) building blocks into hierarchical complex structures with the hybrid composition for high performance flexible pseudocapacitors. The formation mechanism of hierarchical CMG/Nafion/RuO2 (CMGNR) microspheres, which is triggered by the cooperative interplay during the in situ synthesis of RuO2 nanoparticles (NPs), was extensively investigated. In particular, the hierarchical CMGNR microspheres consisting of the aggregates of CMG/Nafion (CMGN) nanosheets and RuO2 NPs provided large surface area and facile ion accessibility to storage sites, while the interconnected nanosheets offered continuous electron pathways and mechanical integrity. The synergistic effect of CMGNR hybrids on the supercapacitor (SC) performance was derived from the hybrid composition of pseudocapacitive RuO2 NPs with the conductive CMGNs as well as from structural features. Consequently, the CMGNR-SCs showed a specific capacitance as high as 160 F g(-1), three-fold higher than that of conventional graphene SCs, and a capacitance retention of >95% of the maximum value even after severe bending and 1000 charge-discharge tests due to the structural and compositional features. 23369536 Synthesis and biological evaluation of nucleoside analogues than contain silatrane on the basis of the structure of acyclovir (ACV) as novel inhibitors of hepatitis B virus (HBV). Hepatitis B virus (HBV) infection causes major public health problems worldwide. Acyclovir (ACV) is mainly used to inhibit herpes simplex virus (HSV) rather than HBV. In this study, we used the combination principle to design and synthesize nucleoside analogues that contain silatrane on the basis of the structure of ACV. We found that the compounds were effective inhibitors of HBV, both in vitro and in vivo. All of the compounds showed suppressive activity on the expression of HBV surface antigen (HBsAg) and HBV e antigen (HBeAg) in the HepG2.2.15 cell line with low cytotoxicity. One of compounds was studied in HBV transgenic mice model, and the test results showed its ability to reduce the levels of HBsAg, HBeAg and HBV DNA by ELASE and qPCR. Furthermore, significant improvement of T lymphocyte was observed after treatment, as evaluated by flow cytometry (FCM). 23739841 Anticoagulation beyond direct thrombin and factor Xa inhibitors: indications for targeting the intrinsic pathway? Antithrombotic drugs like vitamin K antagonists and heparin have been the gold standard for the treatment and prevention of thromboembolic disease for many years. Unfortunately, there are several disadvantages of these antithrombotic drugs: they are accompanied by serious bleeding problems, it is necessary to monitor the therapeutic window, and there are various interactions with food and other drugs. This has led to the development of new oral anticoagulants, specifically inhibiting either thrombin or factor Xa. In terms of effectiveness, these drugs are comparable to the currently available anticoagulants; however, they are still associated with issues such as bleeding, reversal of the drug and complicated laboratory monitoring. Vitamin K antagonists, heparin, direct thrombin and factor Xa inhibitors have in common that they target key proteins of the haemostatic system. In an attempt to overcome these difficulties we investigated whether the intrinsic coagulation factors (VIII, IX, XI, XII, prekallikrein and high-molecular-weight kininogen) are superior targets for anticoagulation. We analysed epidemiological data concerning thrombosis and bleeding in patients deficient in one of the intrinsic pathway proteins. Furthermore, we discuss several thrombotic models in intrinsic coagulation factor-deficient animals. The combined results suggest that intrinsic coagulation factors could be suitable targets for anticoagulant drugs. 23913007 Diffusion in the extracellular space in brain and tumors. Diffusion of solutes and macromolecules in the extracellular space (ECS) in brain is important for non-synaptic intercellular communication, extracellular ionic buffering, and delivery of drugs and metabolites. Diffusion in tumor ECS is important for delivery of anti-tumor drugs. The ECS in brain comprises ∼20% of brain parenchymal volume and contains cell-cell gaps down to ∼50 nm. We have developed fluorescence methods to quantify solute diffusion in the ECS, allowing measurements deep in solid tissues using microfiberoptics with micron tip size. Diffusion through the tortuous ECS in brain is generally slowed by ∼3-5-fold compared with that in water, with approximately half of the slowing due to tortuous ECS geometry and half due to the mildly viscous extracellular matrix (ECM). Mathematical modeling of slowed diffusion in an ECS with reasonable anatomical accuracy is in good agreement with experiment. In tumor tissue, diffusion of small macromolecules is only mildly slowed (<3-fold slower than in water) in superficial tumor, but is greatly slowed (>10-fold) at a depth of few millimeters as the tumor tissue becomes more compact. Slowing by ECM components such as collagen contribute to the slowed diffusion. Therefore, as found within cells, cellular crowding and highly tortuous transport can produce only minor slowing of diffusion in the ECS. 23231413 An optimized RAD51 inhibitor that disrupts homologous recombination without requiring Michael acceptor reactivity. Homologous recombination (HR) is an essential process in cells that provides repair of DNA double-strand breaks and lesions that block DNA replication. RAD51 is an evolutionarily conserved protein that is central to HR. Overexpression of RAD51 protein is common in cancer cells and represents a potential therapeutic target in oncology. We previously described a chemical inhibitor of RAD51, called RI-1 (referred to as compound 1 in this report). The chloromaleimide group of this compound is thought to act as a Michael acceptor and react with the thiol group on C319 of RAD51, using a conjugate addition-elimination mechanism. In order to reduce the likelihood of off-target effects and to improve compound stability in biological systems, we developed an analogue of compound 1 that lacks maleimide-based reactivity but retains RAD51 inhibitory activity. This compound, 1-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)-4-morpholino-1H-pyrrole-2,5-dione, named RI-2 (referred to as compound 7a in this report), appears to bind reversibly to the same site on the RAD51 protein as does compound 1. Like compound 1, compound 7a specifically inhibits HR repair in human cells. 23827820 The effectiveness comparison of Jitai tablets versus methadone in community-based drug treatment: A 1-year follow-up study. The aim of the study was to compare the effectiveness of Jitai tablets (JTT) versus methadone in a community drug treatment program. A cohort study was conducted with 386 eligible subjects from 7 districts to 65 communities in Shanghai. The subjects were placed into the JTT group (n=206) or the methadone group (n=180). The data were collected at 8-, 26- and 52-week follow-ups. The retention rates of the methadone group at the 8-, 26-, and 52-week follow-ups were 97.78%, 91.67%, and 85.00%, respectively. The retention rates of the JTT group at these follow-ups were 90.78%, 83.50%, and 74.27%, respectively. A Chi-square test indicated a significant difference, and the P values were 0.0037, 0.0161, and 0.0095 for each follow-up. The relapse rates for the JTT group were 3.88%, 6.31% and 11.17% for each follow-up, and those for the methadone group were 1.11%, 2.78%, and 7.78% for each follow-up. The Chi-square test indicated no significance, and the P values were 0.1128, 0.1005 and 0.2594. A survival analysis indicated that the relapse survival curve had no significant difference between the two groups (log-rank test, P=0.188). Methadone and JTT combined with psychological intervention and social support provided effective maintenance treatment and relapse prevention in a community drug treatment program. The retention rate in the methadone group was higher, but the JTT group had the same relapse prevention as the methadone group. JTT can be recommended to clinical doctors and drug addicts. 23761063 Old and new tools to assess dyspnea in the hospitalized patient. In the assessment of dyspnea one has to take into account both the patient's own experience of the symptom and the clinicians observations of breathing rates, sounds and effort to get a complete picture. In addition, to choose appropriate treatment, the underlying cause of dyspnea needs to be assessed. While tools for clinical evaluation of heart failure have gained great interest in research and found a place in guidelines and clinical practice, the same cannot be said for instruments to assess patient self-reported dyspnea. To date, no specific dyspnea rating tool has been recommend over another. Reports from clinical practice are lacking and large; international studies in this field are warranted. 23863079 Interactions between Grafted Cationic Dendrimers and Anionic Bilayer Membranes. We use polymer self-consistent field theory to study the physics involved in the permeation of charged dendrimer molecules across anionic lipid bilayer membranes. We specifically examine the influence of dendrimer shape deformations, neutral grafts, and pH conditions on the interactions between dendrimers and membranes. Our results indicate that the ability of the dendrimer to undergo conformational rearrangements plays a crucial role in influencing the interactions between the dendrimer and the membrane. At neutral pH, we observe that dendrimers with grafted chains are repelled by the anionic bilayers. However, decreasing the solution pH to endosomal conditions results in attractive dendrimer-membrane interactions under some parametric conditions. We observe that dendrimer insertion into the membrane results in a decreased value in membrane tension at which rupture occurs and, furthermore, that the rupture tension decreases with the addition of grafts to the dendrimer. Our results suggest that dendrimers grafted with neutral polymers can serve as effective pH sensitive delivery vectors. 23904347 A model to assess the feasibility of shifting reaction equilibrium by acetone removal in the transamination of ketones using 2-propylamine. Acetone removal by evaporation has been proposed as a simple and cheap way to shift the equilibrium in the biocatalytic asymmetric synthesis of optically pure chiral amines, when 2-propylamine is used as the amine donor (see Scheme 1). However, dependent on the system properties, this may or may not be a suitable strategy. To avoid excessive laboratory work a model was used to assess the process feasibility. The results from the current study show that a simple model of the acetone removal dependence on temperature and sparging gas flowrate can be developed and fits the experimental data well. The model for acetone removal was then coupled to a simple model for biocatalyst kinetics and also for loss of substrate ketone by evaporation. The three models were used to simulate the effects of varying the critical process parameters and reaction equilibrium constants (K eq) as well as different substrate ketone volatilities (Henry's constant). The simulations were used to estimate the substrate losses and also the maximum yield that could be expected. The approach was seen to give a clear indication for which target amines the acetone evaporation strategy would be feasible and for which amines it would not. The study also shows the value of a modelling approach in conceptual process design prior to entering a biocatalyst screening or engineering program to assess the feasibility of a particular process strategy for a given target product. Biotechnol. Bioeng. © 2013 Wiley Periodicals, Inc. 23489296 Tumour necrosis factor receptors and apoptosis of alveolar macrophages during early infection with attenuated and virulent Mycobacterium bovis. Apoptosis of macrophages has been reported as an effective host strategy to control the growth of intracellular pathogens, including pathogenic mycobacteria. Tumour necrosis factor-α (TNF-α) plays an important role in the modulation of apoptosis of infected macrophages. It exerts its biological activities via two distinct cell surface receptors, TNFR1 and TNFR2, whose extracellular domain can be released by proteolysis forming soluble TNF receptors (sTNFR1 and sTNFR2). The signalling through TNFR1 initiates the majority of the biological functions of TNF-α, leading to either cell death or survival whereas TNFR2 mediates primarily survival signals. Here, the expression of TNF-α receptors and the apoptosis of alveolar macrophages were investigated during the early phase of infection with attenuated and virulent mycobacteria in mice. A significant increase of apoptosis and high expression of TNFR1 were observed in alveolar macrophages at 3 and 7 days after infection with attenuated Mycobacterium bovis but only on day 7 in infection with the virulent M. bovis. Low surface expression of TNFR1 and increased levels of sTNFR1 on day 3 after infection by the virulent strain were associated with reduced rates of apoptotic macrophages. In addition, a significant reduction in apoptosis of alveolar macrophages was observed in TNFR1(-/-) mice at day 3 after bacillus Calmette-Guérin infection. These results suggest a potential role for TNFR1 in mycobacteria-induced alveolar macrophage apoptosis in vivo. In this scenario, shedding of TNFR1 seems to contribute to the modulation of macrophage apoptosis in a strain-dependent manner. 22863241 Peripheral multifocal chorioretinitis: Complications, prognosis and relation with sarcoidosis. Purpose:  To investigate the prognosis and complications in patients with peripheral multifocal chorioretinitis (PMC). PMC is a posterior or panuveitis characterized by chronic bilateral vitritis and punched-out lesions in the peripheral retina which occurs commonly in elderly white women and is associated with sarcoidosis. Prognosis and complications are largely unknown. Methods:  A structured literature search in PubMed, Embase and Cochrane was performed to identify relevant articles. Articles were screened, and the remaining articles were critically appraised based on relevance and validity. Results:  The search yielded 267 articles. Eight relevant articles were retrieved. All studies reported on moderate visual impairment. Macular oedema occurred in 60% of the patients with PMC (range, 0-71%), glaucoma in 27% (range, 25-43%) and an epiretinal membrane in 21% (range, 0-28%). In total, 47% had proven or presumed sarcoidosis. Treatment usually comprised topical corticosteroids, periocular steroid injections and systemic corticosteroids regularly in combination with methotrexate. Conclusion:  The prognosis of patients with PMC is characterized by a rather poor visual outcome and the relatively high prevalence of complications. PMC is strongly associated with sarcoidosis. Solid proof for the treatment efficacy of PMC is lacking. 23866875 JAAD Grand Rounds quiz: Multiple papules on the nose. Instructions: In answering each question, refer to the specific directions provided. Because it is often necessary to provide information occurring later in a series that give away answers to earlier questions, please answer the questions in each series in sequence. 23929564 Effect of Er:YAG laser pretreatment on bond strength of a composite core build-up material to fiber posts. The study evaluated the micro push-out bond strength of resin material (Multicore Flow) to two types of fiber posts (FP), namely fiber-reinforced composite (FRC) Postec and Radix Fiber posts using Er:YAG laser pretreatment. FP were divided into four groups, two being control groups. Before the core build-up procedure, representative specimens from each group were chosen to determine the surface roughness (Ra) at three different areas using a contact profilometer, while after the procedure, 1.5-mm-thick discs were sectioned and the micro push-out method was used to assess the bond strength of the core build-up material to the fiber post in each group. Two-way analysis of variance was used for statistical analysis with the level of significance set at p < 0.05. Scanning electron microscopy was used to analyze the post surfaces after Er:YAG laser pretreatment and to classify the failure mode after loading. The type of pretreatment (p < 0.001) and an interaction between the pretreatment and type of post (p < 0.001) had a significant effect on the bond strength, while the type of post did not (p = 0.965). The mean bond strength in the Er:YAG laser pretreatment group was significantly lower compared to the FRC Postec posts control group (p < 0.001), while there was no significant difference between the Radix Fiber posts groups (p = 0.680). Mean Ra values from the Er:YAG laser pretreatment groups were significantly higher compared to control groups (p < 0.001). Er:YAG laser pretreatment at tested parameters negatively affected the bond strength of Multicore to FP and cannot be recommended as a standard procedure. 23835847 Gender Identity Disorder and Autism Spectrum Disorder in a 23-Year-Old Female. We describe the case of a 23-year-old woman with Gender Identity Disorder (GID) asking for a cross-sex hormonal treatment with sex reassignment surgery and who was recently diagnosed with Autism Spectrum Disorder (ASD). Gender identity clinics are now reporting an overrepresentation of individuals with ASD among GID patients. The prevalence of ASD is 10-fold higher among GID patients than in general population. However, few case reports or studies have explored the co-occurrence of ASD and GID. This co-occurrence is relevant for diagnostic and clinical management and also raises important theoretical issues. 23563129 Post-mortem cardiac 3-T magnetic resonance imaging: visualization of sudden cardiac death? This study aimed to investigate post-mortem magnetic resonance imaging (pmMRI) for the assessment of myocardial infarction and hypointensities on post-mortem T2-weighted images as a possible method for visualizing the myocardial origin of arrhythmic sudden cardiac death. Sudden cardiac death has challenged clinical and forensic pathologists for decades because verification on post-mortem autopsy is not possible. pmMRI as an autopsy-supporting examination technique has been shown to visualize different stages of myocardial infarction. In 136 human forensic corpses, a post-mortem cardiac MR examination was carried out prior to forensic autopsy. Short-axis and horizontal long-axis images were acquired in situ on a 3-T system. In 76 cases, myocardial findings could be documented and correlated to the autopsy findings. Within these 76 study cases, a total of 124 myocardial lesions were detected on pmMRI (chronic: 25; subacute: 16; acute: 30; and peracute: 53). Chronic, subacute, and acute infarction cases correlated excellently to the myocardial findings on autopsy. Peracute infarctions (age range: minutes to approximately 1 h) were not visible on macroscopic autopsy or histological examination. Peracute infarction areas detected on pmMRI could be verified in targeted histological investigations in 62.3% of cases and could be related to a matching coronary finding in 84.9%. A total of 15.1% of peracute lesions on pmMRI lacked a matching coronary finding but presented with severe myocardial hypertrophy or cocaine intoxication facilitating a cardiac death without verifiable coronary stenosis. 3-T pmMRI visualizes chronic, subacute, and acute myocardial infarction in situ. In peracute infarction as a possible cause of sudden cardiac death, it demonstrates affected myocardial areas not visible on autopsy. pmMRI should be considered as a feasible post-mortem investigation technique for the deceased patient if no consent for a clinical autopsy is obtained. 23720488 COPRED: prediction of fold, GO molecular function and functional residues at the domain level. Only recently the first resources devoted to the functional annotation of proteins at the domain level started to appear. The next step is to develop specific methodologies for predicting function at the domain level based on these resources, and to implement them in web servers to be used by the community. In this work, we present COPRED, a web server for the concomitant prediction of fold, molecular function and functional sites at the domain level, based on a methodology for domain molecular function prediction and a resource of domain functional annotations previously developed and benchmarked. Availability and implementation: COPRED can be freely accessed at http://csbg.cnb.csic.es/copred. The interface works in all standard web browsers. WebGL (natively supported by most browsers) is required for the in-line preview and manipulation of protein 3D structures. The website includes a detailed help section and usage examples. pazos@cnb.csic.es. 23693136 The application of support vector regression for prediction of the antiallodynic effect of drug combinations in the mouse model of streptozocin-induced diabetic neuropathy. Drug interactions are an important issue of efficacious and safe pharmacotherapy. Although the use of drug combinations carries the potential risk of enhanced toxicity, when carefully introduced it enables to optimize the therapy and achieve pharmacological effects at doses lower than those of single agents. In view of the development of novel analgesic compounds for the neuropathic pain treatment little is known about their influence on the efficacy of currently used analgesic drugs. Below we describe the preliminary evaluation of support vector machine in the regression mode (SVR) application for the prediction of maximal antiallodynic effect of a new derivative of dihydrofuran-2-one (LPP1) used in combination with pregabalin (PGB) in the streptozocin-induced neuropathic pain model in mice. Based on SVR the most effective doses of co-administered LPP1 (4mg/kg) and PGB (1mg/kg) were predicted to cause the paw withdrawal threshold at 6.7g in the von Frey test. In vivo for the same combination of doses the paw withdrawal was observed at 6.5g, which confirms good predictive properties of SVR. 23946177 Adult cancer pain. Pain is a common symptom associated with cancer and its treatment. Pain management is an important aspect of oncologic care, and unrelieved pain significantly comprises overall quality of life. These NCCN Guidelines list the principles of management and acknowledge the range of complex decisions faced in the management oncologic pain. In addition to pain assessment techniques, these guidelines provide principles of use, dosing, management of adverse effects, and safe handling procedures of pharmacologic therapies and discuss a multidisciplinary approach for the management of cancer pain. 23530530 Laser welding of ruptured intestinal tissue using plasmonic polypeptide nanocomposite solders. Approximately 1.5 million people suffer from colorectal cancer and inflammatory bowel disease in the United States. Occurrence of leakage following standard surgical anastomosis in intestinal and colorectal surgery is common and can cause infection leading to life-threatening consequences. In this report, we demonstrate that plasmonic nanocomposites, generated from elastin-like polypeptides (ELPs) cross-linked with gold nanorods, can be used to weld ruptured intestinal tissue upon exposure to near-infrared (NIR) laser irradiation. Mechanical properties of these nanocomposites can be modulated based on the concentration of gold nanorods embedded within the ELP matrix. We employed photostable, NIR-absorbing cellularized and noncellularized GNR-ELP nanocomposites for ex vivo laser welding of ruptured porcine small intestines. Laser welding using the nanocomposites significantly enhanced the tensile strength, leakage pressure, and bursting pressure of ruptured intestinal tissue. This, in turn, provided a liquid-tight seal against leakage of luminal liquid from the intestine and resulting bacterial infection. This study demonstrates the utility of laser tissue welding using plasmonic polypeptide nanocomposites and indicates the translational potential of these materials in intestinal and colorectal repair. 22430919 The nonhematopoietic effects of erythropoietin in skin regeneration and repair: from basic research to clinical use. Erythropoietin (EPO) is the main regulator of red blood cell production but there exists also a variety of nonhematopoietic properties. More recent data show that EPO is also associated with the protection of tissues suffering from ischemia and reperfusion injury as well as with improved regeneration in various organ systems, in particular the skin. This review highlights the mechanisms of EPO in the different stages of wound healing and the reparative processes in the skin emphasizing pathophysiological mechanisms and potential clinical applications. There is clear evidence that EPO effectively influences all wound-healing phases in a dose-dependent manner. This includes inflammation, tissue, and blood vessel formation as well as the remodeling of the wound. The molecular mechanism is predominantly based on an increased expression of the endothelial and inducible nitric oxide (NO) synthase with a consecutive rapid supply of NO as well as an increased content of vascular endothelial growth factor (VEGF) in the wound. The improved understanding of the functions and regulatory mechanisms of EPO in the context of wound-healing problems and ischemia/reperfusion injury, especially during flap surgery, may lead to new considerations of this growth hormone for its regular clinical application in patients. 23600698 Sulfonated Polyaniline-Based Organic Electrodes for Controlled Electrical Stimulation of Human Osteosarcoma Cells. Electrically conducting polymers (CPs) were found to stimulate various cell types such as neurons, osteoblasts, and fibroblasts in both in vitro and in vivo studies. However, to our knowledge, no studies have been reported on the utility of CPs in stimulation of cancer or tumor cells in the literature. Here we report a facile fabrication method of self-doped sulfonated polyaniline (SPAN)-based interdigitated electrodes (IDEs) for controlled electrical stimulation of human osteosarcoma (HOS) cells. Increased degree of sulfonation was found to increase the SPAN conductivity, which in turn improved the cell attachment and cell growth without electrical stimulation. However, an enhanced cell growth was observed under controlled electrical (AC) stimulation at low applied voltage and frequency (≤800 mV and ≤1 kHz). The cell growth reached a maximum threshold at an applied voltage or frequency and beyond which pronounced cell death was observed. We believe that these organic electrodes may find utility in electrical stimulation of cancer or tumor cells for therapy and research and may also provide an alternative to the conventional metal-based electrodes. 23775073 A Reaction Center-dependent Photoprotection Mechanism in a Highly Robust Photosystem II from an Extremophilic Red Alga, Cyanidioschyzon merolae. Members of the rhodophytan order Cyanidiales are unique among phototrophs in their ability to live in extremely low pH levels and moderately high temperatures. The photosynthetic apparatus of the red alga Cyanidioschyzon merolae represents an intermediate type between cyanobacteria and higher plants, suggesting that this alga may provide the evolutionary link between prokaryotic and eukaryotic phototrophs. Although we now have a detailed structural model of photosystem II (PSII) from cyanobacteria at an atomic resolution, no corresponding structure of the eukaryotic PSII complex has been published to date. Here we report the isolation and characterization of a highly active and robust dimeric PSII complex from C. merolae. We show that this complex is highly stable across a range of extreme light, temperature, and pH conditions. By measuring fluorescence quenching properties of the isolated C. merolae PSII complex, we provide the first direct evidence of pH-dependent non-photochemical quenching in the red algal PSII reaction center. This type of quenching, together with high zeaxanthin content, appears to underlie photoprotection mechanisms that are efficiently employed by this robust natural water-splitting complex under excess irradiance. In order to provide structural details of this eukaryotic form of PSII, we have employed electron microscopy and single particle analyses to obtain a 17 Å map of the C. merolae PSII dimer in which we locate the position of the protein mass corresponding to the additional extrinsic protein stabilizing the oxygen-evolving complex, PsbQ'. We conclude that this lumenal subunit is present in the vicinity of the CP43 protein, close to the membrane plane. 23681973 A collaborative approach to perinatal and infant mental health service delivery in Australia. The objective of this paper is to report on the development and implementation of a community-based perinatal and infant mental health day program for mothers with psychiatric illness. The program was initiated through interagency collaboration between adult mental health, infant mental health and community child health services in Queensland, Australia in response to calls for an integrated approach that could be delivered state-wide if successful. Preliminary results of the program's evaluation are provided. A pre-post survey design was used to assess the influence the program had on maternal mental and emotional well-being and the maternal-infant relationship. Twenty-one women receiving treatment for perinatal mental illness gave consent to attend the 6-week day program integrating three currently separate and discrete services: adult mental health, infant mental health and community child health. Clinically and statistically significant improvements were observed for maternal mental health, and parent-infant relationships following the program. These findings support interagency collaboration between adult mental health, infant mental health and community child health services to deliver services to women with mental illness with newborns and their families. The utility of using a collaborative approach in a community setting endorses more comprehensive and longer-term evaluation of effectiveness and cost benefit. 23937165 Case of maternal and fetal deaths due to severe congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome) during pregnancy. Upshaw-Schulman syndrome (USS) involves a congenital deficiency of von Willebrand factor-cleaving metalloprotease (ADAMTS13) activity due to gene mutations. Female patients develop overt thrombotic thrombocytopenic purpura (TTP) caused by a decline of ADAMTS13 activity in pregnancy. A 23-year-old nulliparous Japanese woman died due to severe, rapid progression of TTP with intrauterine fetal death at 20 weeks of gestation after its onset, even though she underwent intensive treatment which included plasma exchange. She had a history of idiopathic thrombocytopenic purpura at the age of 3 years. The patient's ADAMTS13 activity was of very low level. It should be borne in mind that there is the possibility of rapidly progressive fulminant USS during pregnancy. 23893211 A low-frequency versatile wireless power transfer technology for biomedical implants. Implantable biomedical sensors and actuators are highly desired in modern medicine. In many cases, the implant's electrical power source profoundly determines its overall size and performance . The inductively coupled coil pair operating at the radio-frequency (RF) has been the primary method for wirelessly delivering electrical power to implants for the last three decades . Recent designs significantly improve the power delivery efficiency by optimizing the operating frequency, coil size and coil distance . However, RF radiation hazard and tissue absorption are the concerns in the RF wireless power transfer technology (RF-WPTT) , . Also, it requires an accurate impedance matching network that is sensitive to operating environments between the receiving coil and the load for efficient power delivery . In this paper, a novel low-frequency wireless power transfer technology (LF-WPTT) using rotating rare-earth permanent magnets is demonstrated. The LF-WPTT is able to deliver 2.967 W power at  âˆ¼ 180 Hz to an 117.1 Ω resistor over 1 cm distance with 50% overall efficiency. Because of the low operating frequency, RF radiation hazard and tissue absorption are largely avoided, and the power delivery efficiency from the receiving coil to the load is independent of the operating environment. Also, there is little power loss observed in the LF-WPTT when the receiving coil is enclosed by non-magnetic implant-grade stainless steel. 23902596 Social participation and mental health: moderating effects of gender, social role and rurality. Previous studies have reported that older people's social participation has positive effects on their health. However, some studies showed that the impacts of social participation on health differ by gender. We sought to examine whether the effects of social participation on mental health differ for men and women in a Japanese population. We also examined the moderating influence of social position within the organization as well as urban/rural locality. We used two waves of the Aichi Gerontological Evaluation Study's longitudinal survey, which targeted residents with aged 65 years or over (n = 2,728) in a central part of Japan. The first wave survey was conducted in 2003, and the second wave in 2006. Depressive symptoms of the study participants were assessed using the short version of the Geriatric Depression Scale (GDS-15). A multilevel logistic regression model was used with individual-level as level 1 and the school district-level as level 2. We found that higher social participation and performing key roles in the organization had protective effects on depressive symptoms for women. However, there were no main effects of these variables for the mental health of men. We found an interaction between social participation, organizational position, and rural residence among men only. That is, men who occupied leadership positions in organizations reported better mental health, but only in rural areas. Our findings support the notion that increasing the opportunities for social participation improves older people's heath, especially for women. However, in the rural Japanese context, offering men meaningful roles within organizations may be important. 22812659 Androgen insensitivity syndrome. Androgen insensitivity syndrome (AIS) is a disorder caused by a mutation of the gene encoding the androgen receptor (AR; Xq11-q12). The prevalence of AIS has been estimated to be one case in every 20,000 to 64,000 newborn males for the complete syndrome (CAIS), and the prevalence is unknown for the partial syndrome (PAIS). The symptoms range from phenotypically normal males with impaired spermatogenesis to phenotypically normal women with primary amenorrhea. Various forms of ambiguous genitalia have been observed at birth. The diagnosis is confirmed by determining the exact mutation in the AR gene. PAIS individuals require precise diagnosis as early as possible so that the sex can be assigned, treatment can be recommended, and they can receive proper genetic counseling. After birth, differential diagnosis should be performed using other forms of abnormal sexual differentiation of primary amenorrhea. The treatment of AIS is based on reinforcement sexual identity, gonadectomy planning, and hormone replacement therapy. The prognosis for CAIS is good if the testicular tissue is removed at the appropriate time. For PAIS, the prognosis depends on the ambiguity of the genitalia and physical and psychosocial adjustment to the assigned sex. 23824791 Peptide aptamers that bind to geminivirus replication proteins confer a resistance phenotype to tomato yellow leaf curl virus and tomato mottle virus infection in tomato. Geminiviruses constitute a large family of single-stranded DNA viruses that cause serious losses in important crops worldwide. They often exist in disease complexes and have high recombination and mutation rates, allowing them to adapt rapidly to new hosts and environments. Thus, an effective resistance strategy must be general in character and able to target multiple viruses. The geminivirus replication protein (Rep) is a good target for broad-based disease control because it is highly conserved and required for viral replication. In an earlier study, we identified a set of peptide aptamers that bind to Rep and reduce viral replication in cultured plant cells. In this study, we selected 16 of the peptide aptamers for further analysis in yeast two-hybrid assays. The results of these experiments showed that all 16 peptide aptamers interact with all or most of the Rep proteins from nine viruses representing the three major Geminiviridae genera and identified two peptide aptamers (A22 and A64) that interact strongly with different regions in the Rep N terminus. Transgenic tomato lines expressing A22 or A64 and inoculated with Tomato yellow leaf curl virus or Tomato mottle virus exhibited delayed viral DNA accumulation and often contained lower levels of viral DNA. Strikingly, the effect on symptoms was stronger, with many of the plants showing no symptoms or strongly attenuated symptoms. Together, these results established the efficacy of using Rep-binding peptide aptamers to develop crops that are resistant to diverse geminiviruses. 23924131 Searching for my friend Mary who I trained with in the 1960s. Can Nursing Standard readers please help me to find a friend I trained with at the Withington Community Hospital in Manchester from 1967-70? 23242940 Probabilistic health risk assessment for ingestion of seafood farmed in arsenic contaminated groundwater in Taiwan. Seafood farmed in arsenic (As)-contaminated areas is a major exposure pathway for the ingestion of inorganic As by individuals in the southwestern part of Taiwan. This study presents a probabilistic risk assessment using limited data for inorganic As intake through the consumption of the seafood by local residents in these areas. The As content and the consumption rate are both treated as probability distributions, taking into account the variability of the amount in the seafood and individual consumption habits. The Monte Carlo simulation technique is utilized to conduct an assessment of exposure due to the daily intake of inorganic As from As-contaminated seafood. Exposure is evaluated according to the provisional tolerable weekly intake (PTWI) established by the FAO/WHO and the target risk based on the US Environmental Protection Agency guidelines. The assessment results show that inorganic As intake from five types of fish (excluding mullet) and shellfish fall below the PTWI threshold values for the 95th percentiles, but exceed the target cancer risk of 10(-6). The predicted 95th percentile for inorganic As intake and lifetime cancer risks obtained in the study are both markedly higher than those obtained in previous studies in which the consumption rate of seafood considered is a deterministic value. This study demonstrates the importance of the individual variability of seafood consumption when evaluating a high exposure sub-group of the population who eat higher amounts of fish and shellfish than the average Taiwanese. 23910744 Does adding pharmaceutical medication contribute to empirically supported psychological treatment for anxiety disorders? Background: The goal of this work is to determine whether the combined use of empirically supported psychological treatments (ESTs) and pharmacological therapy (PT) achieves better results than the isolated use of ESTs in the treatment of Anxiety Disorders (AD) in a welfare clinical setting. Method: A quasi-experimental study was designed, with a sample of 287 patients with primary diagnosis of AD. Of the patients, 25.1% (n = 72) received ESTs+PT and 74.9% (n = 216), only ESTs. At pretreatment, no intergroup differences were observed in anxiety and depressive symptoms, duration of the problem and comorbidity, but there were differences for previous treatments (they were fewer in the EST group). Results: After the intervention, both groups showed similar degree of completion, compliance with treatment, task performance and similar effectiveness at post treatment but EST+PT was significantly longer (16.58 sessions vs. 13.04 sessions). Conclusions: It is concluded that adding PT to EST does not improve the results but it does increase the cost and duration of treatment, thereby reducing the efficiency of the intervention. 22661413 Demonstration of tuning to stimulus orientation in the human visual cortex: a high-resolution FMRI study with a novel continuous and periodic stimulation paradigm. Cells in the animal early visual cortex are sensitive to contour orientations and form repeated structures known as orientation columns. At the behavioral level, there exist 2 well-known global biases in orientation perception (oblique effect and radial bias) in both animals and humans. However, their neural bases are still under debate. To unveil how these behavioral biases are achieved in the early visual cortex, we conducted high-resolution functional magnetic resonance imaging experiments with a novel continuous and periodic stimulation paradigm. By inserting resting recovery periods between successive stimulation periods and introducing a pair of orthogonal stimulation conditions that differed by 90° continuously, we focused on analyzing a blood oxygenation level-dependent response modulated by the change in stimulus orientation and reliably extracted orientation preferences of single voxels. We found that there are more voxels preferring horizontal and vertical orientations, a physiological substrate underlying the oblique effect, and that these over-representations of horizontal and vertical orientations are prevalent in the cortical regions near the horizontal- and vertical-meridian representations, a phenomenon related to the radial bias. Behaviorally, we also confirmed that there exists perceptual superiority for horizontal and vertical orientations around horizontal and vertical meridians, respectively. Our results, thus, refined the neural mechanisms of these 2 global biases in orientation perception. 23952813 "Amide Resonance" in the Catalysis of 1,2-α-l-Fucosidase from Bifidobacterium bifidum. Bifidobacterium is a genus of Gram-positive bacteria, which is important in the absorption of nourishment from the human milk oligosaccharides (HMO). We present here the detailed simulation of the enzymatic hydrolysis of 2'-fucosyllactose catalyzed by 1,2-α-l-fucosidase from Bifidobacterium bifidum using the combined quantum mechanical and molecular mechanical approach. Molecular dynamics simulations and free energy profiles support that the overall reaction is a stepwise mechanism. The first step is the proton transfer from N423 to D766, and the second step involves the hydrolysis reaction via the inversion mechanism catalyzed by the amide group of N423. Assisted by D766, N423 serves as the general base to activate the water molecule to attack the anomeric carbon center. E566 is the general acid to facilitate the cleavage of glycosidic bond between l-fucose and galactose units. The intrinsic resonance structure for the side chain amide group of the asparagine residue is shown to be the origin to the catalytic activity, which is also confirmed by the mutagenesis simulation of N423G. 23409919 Index of refraction, density, and solubility of ammonium iodide solutions at high pressure. An asymmetric moissanite anvil cell is used to study aqueous solutions of ammonium iodide at pressures up to 10 kbar. The index of refraction is measured using the rotating Fabry-Perot technique, with an accuracy of approximately 1%. The mass density and molar volume of the solutions are estimated using the measured index values, and the molar volume is used to predict the pressure dependence of the solubility. The solubility derived from the index of refraction measurements is shown to agree with that which is determined by direct observation of the onset of crystallization. 23835645 Self-assembly of hierarchical MoSx/CNT nanocomposites (2 1000 mAh/g) was achieved at the current density of 50 mA g(-1), which is much higher than theoretical numbers for either MWNTs or MoS2 along (~372 and ~670 mAh/g, respectively). We anticipate 2D nanosheets/1D MWNTs nanocomposites will be promising materials in new generation practical LIBs. 23938276 Two Items Remembered as Precisely as One: How Integral Features Can Improve Visual Working Memory. In the ongoing debate about the efficacy of visual working memory for more than three items, a consensus has emerged that memory precision declines as memory load increases from one to three. Many studies have reported that memory precision seems to be worse for two items than for one. We argue that memory for two items appears less precise than that for one only because two items present observers with a correspondence challenge that does not arise when only one item is stored-the need to relate observations to their corresponding memory representations. In three experiments, we prevented correspondence errors in two-item trials by varying sample items along task-irrelevant but integral (as opposed to separable) dimensions. (Initial experiments with a classic sorting paradigm identified integral feature relationships.) In three memory experiments, our manipulation produced equally precise representations of two items and of one item. 23820421 Positive experiences of patient-centred care are associated with intentions to comply with fertility treatment: findings from the validation of the Portuguese version of the PCQ-Infertility tool. Are positive experiences of different aspects of patient-centred care (PCC) associated with higher intentions to comply with fertility treatment? Positive experiences regarding information received, respect from staff about values and preferences, continuity in treatment and competence of staff are directly associated with higher compliance intentions, while positive experiences regarding accessibility to and involvement in the treatment and communication with staff are indirectly associated, via associations with less concerns about treatment. The quality of infertility services can influence patients' intentions to comply with treatment. Patients cite negative care experiences as one of the main reasons why they discontinue treatment prematurely. Delivering PCC in routine infertility care is associated with higher quality of life and lower distress during treatment. In this cross-sectional study of 265 women and 83 men, we investigated first, the psychometric properties of the Portuguese version of the Patient-Centredness Questionnaire (PCQ)-Infertility tool, which assesses infertility PCC, and secondly, the associations between PCC and intentions to comply with treatment. Men and women undergoing fertility diagnostic investigation or treatment at Portuguese fertility clinics were recruited online and in clinical setting. Participants filled out a socio-demographic and fertility data file and other questionnaires to assess PCC (PCQ-Infertility), intentions to comply with treatment (FertiQoL Persistence Scale), wellbeing (Anxiety and Depression subscales of the BSI and FertiQoL), concerns about treatment (CART Scale) and treatment tolerability (FertiQoL Tolerability Domain). There were 265 women and 83 men who completed the questionnaires. The confirmatory factor analysis for the PCQ-Infertility indicated a good fit [X(2) = 479.097; P < 0.001; comparative fit index = 0.929; root mean square error of approximation = 0.058 (0.051-0.065)]. All PCQ-Infertility dimensions showed good internal consistency (α ≥ 0.70, excepting for organization: α = 0.57). Information provision, respect for patients' values, continuity of care and competence of the team were directly associated with higher intentions to comply with treatment (r from 0.13 to 0.23). Greater accessibility, patient involvement and good communication were negatively associated with concerns about treatment (r from -0.14 to -0.16) and less concerns were associated with higher intentions to comply with treatment (r from -0.14 to -0.15). Of the sample, 49% were recruited online. Patients recruited online had higher education and were more likely to be undergoing assisted reproduction treatment and this could have influenced the ratings of PCC reported. We did not account for treatment prognosis factors and/or doctor censuring and this may have resulted in underestimation of the strength of associations reported involving compliance intentions. The cross-sectional design of the study does not allow for cause and effect analysis between the study variables. To promote treatment compliance, clinics should allow patients to establish stable relationships with a reference doctor who is competent and respectful of their interests and values and who provides them with the information they need. Clinics can also alleviate their patients' concerns regarding medical procedures by ensuring that these professionals are easily accessible, have good communication skills, and involve patients in the treatment process and associated decision-making. The Portuguese version of the PCQ-Infertility tool is valid and reliable. No external funding was either sought or obtained for this study and no competing interests are declared. NA. 23090054 Activity, distribution, and abundance of methane-oxidizing bacteria in the near surface soils of onshore oil and gas fields. Methane-oxidizing bacteria (MOB) have long been used as an important biological indicator for oil and gas prospecting, but the ecological characteristics of MOB in hydrocarbon microseep systems are still poorly understood. In this study, the activity, distribution, and abundance of aerobic methanotrophic communities in the surface soils underlying an oil and gas field were investigated using biogeochemical and molecular ecological techniques. Measurements of potential methane oxidation rates and pmoA gene copy numbers showed that soils inside an oil and gas field are hot spots of methane oxidation and MOB abundance. Correspondingly, terminal restriction fragment length polymorphism analyses in combination with cloning and sequencing of pmoA genes also revealed considerable differences in the methanotrophic community composition between oil and gas fields and the surrounding soils. Principal component analysis ordination furthermore indicated a coincidence between elevated CH4 oxidation activity and the methanotrophic community structure with type I methanotrophic Methylococcus and Methylobacter, in particular, as indicator species of oil and gas fields. Collectively, our results show that trace methane migrated from oil and gas reservoirs can considerably influence not only the quantity but also the structure of the methanotrophic community. 23834297 Smoking induced heavy metals and periodontitis: findings from the Korea National Health and Nutrition Examination Surveys 2008-2010. Exposure to hazardous heavy metals such as cadmium and lead may contribute to increased oxidative stress and inflammation in the periodontal tissue. We aimed to evaluate the association between serum cadmium and lead levels and periodontitis. Pooled cross-sectional data from the Korea National Health and Nutrition Examination Surveys 2008-2010 were used. Periodontitis was defined as WHO community periodontal index. Active smokers were defined as self-reported current smokers or those with measured urine cotinine ≥164 ng/ml measurements. Serum cadmium and lead levels were measured using graphite furnace atomic absorption spectrometry. Multiple logistic regression analysis was used to estimate the odds ratios (OR) for periodontitis. The mean cadmium and lead levels were significantly higher in the periodontitis group compared with control population. A progressive increase in serum heavy metals were found as the number of sextants with periodontitis. The ORs for periodontitis were significantly associated with serum cadmium (OR = 1.37; 95% CI 1.00-1.87) and lead levels (OR = 1.60; 95% CI 1.15-2.21). The association between periodontitis and smoking was attenuated after adjusting for serum cadmium concentration. We demonstrated a significant association between periodontitis and serum cadmium and lead concentrations. Cadmium appeared to partially mediate the association between smoking and periodontitis. 23764616 Networking and rheology of concentrated clay suspensions "matured" in mineral medicinal water. This work studied the influence of "maturation" conditions (time and agitation) on aggregation states, gel structure and rheological behaviour of a special kind of pharmaceutical semisolid products made of concentrated clay suspensions in mineral medicinal water. Maturation of the samples was carried out in distilled and sulphated mineral medicinal water, both in static conditions (without agitation) and with manual stirring once a week, during a maximum period of three months. At the measured pH interval (7.5-8.0), three-dimensional band-type networks resulting from face/face contacts were predominant in the laminar (disc-like) clay suspensions, whereas the fibrous (rod-like) particles formed micro-aggregates by van der Waals attractions. The high concentration of solids in the studied systems greatly determined their behaviour. Rod-like sepiolite particles tend to align the major axis in aggregates promoted by low shearing maturation, whereas aggregates of disc-like smectite particles did not have a preferential orientation and their complete swelling required long maturation time, being independent of stirring. Maturation of both kinds of suspensions resulted in improved rheological properties. Laminar clay suspensions became more structured with time, independently from static or dynamic maturation conditions, whereas for fibrous clay periodic agitation was also required. Rheological properties of the studied systems have been related to aggregation states and networking mechanisms, depending on the type of clay minerals constituents. Physical stability of the suspensions was not impaired by the specific composition of the Graena medicinal water. 23380918 Formation of polymersomes with double bilayers templated by quadruple emulsions. Polymersomes, vesicles composed of bilayer membranes of amphiphilic block-copolymers, are promising delivery vehicles for long-term storage and controlled release of bioactives; enhanced stability of the membrane makes polymersomes potentially useful in a wide range of biological delivery applications by comparison with liposomes. However, unilamellar structure is intrinsically fragile when subjected to external stress. Here, we report a microfluidic approach to produce polymersomes with double bilayers, providing higher stability and lower permeability than unilamellar polymersomes. To achieve this, we developed a new design of a capillary microfluidic device to produce quadruple-emulsion drops which serve as a template for the polymersomes-in-polymersomes. When two bilayers are attracted by depletion in polymersomes-in-polymersomes, the inner polymersomes protrude and bud, forming double bilayers. We confirm these structures are indeed double bilayers using microaspiration and selective doping of the leaflets with nanoparticles. The resultant polymersomes have great potential as highly stable and biocompatible microcarriers for robust encapsulation and storage of bioactives such as drugs, cosmetics and nutrients. 23411292 Effect of TiO2 photocatalytic activity in a HDPE-based food packaging on the structural and microbiological stability of a short-ripened cheese. A high density polyethylene (HDPE)/calcium carbonate (CaCO(3)) film containing TiO(2) was prepared via blown film extrusion process. The photocatalytic properties of this film were evaluated by voltammetric, UV-Vis spectrophotometric and gas chromatographic measurements following the decomposition rate of suitably selected molecular probes, such as 4-hydroxybenzoic acid and methylene blue. The film containing 1% w/w of TiO(2) displayed a profitable and reproducible photoinduced degradation activity towards target organic compounds. The effect of packaging photocatalytic activity on the structural and microbiological stability of a short-ripened cheese was studied. Cheese structure was assessed by dynamic, small deformation rheological tests. A container consisting of a multilayer material, where the layer brought in contact with the food, made from the HDPE+CaCO(3)+TiO(2) composite matrix, was able to provide a greater maintenance of the original cheese structure than a rigid container currently used, mainly due to the inhibition of lactic acid bacteria and coliforms. 23898417 Luteocirrhus shearii gen. sp. nov. (Diaporthales, Cryphonectriaceae) pathogenic to Proteaceae in the South Western Australian Floristic Region. Morphological and DNA sequence characteristics of a pathogenic fungus isolated from branch cankers in Proteaceae of the South West Australian Floristic Region elucidated a new genus and species within Cryphonectriaceae (Diaporthales). The pathogen has been isolated from canker lesions in several Banksia species and Lambertia echinata subsp. citrina, and is associated with a serious decline of the rare B. verticillata. Lack of orange pigment in all observed structures except cirrhi, combined with pulvinate to globose black semi-immersed conidiomata with paraphyses, distinguishes the canker fungus from other genera of Cryphonectriaceae. This was confirmed by DNA sequence analysis of the ITS regions, β-tubulin, and LSU genes. The fungus (sexual morph unknown) is described as Luteocirrhus shearii gen. sp. nov. Lesions in seedlings of Banksia spp. following wound inoculation and subsequent recovery confirm Koch's postulates for pathogenicity. This pathogen of native Proteaceae is currently an emerging threat, particularly toward B. baxteri and B. verticillata. 23294321 Discovery of a potent and selective free fatty acid receptor 1 agonist with low lipophilicity and high oral bioavailability. The free fatty acid receptor 1 (FFA1, also known as GPR40) mediates enhancement of glucose-stimulated insulin secretion and is emerging as a new target for the treatment of type 2 diabetes. Several FFA1 agonists are known, but the majority of these suffer from high lipophilicity. We have previously reported the FFA1 agonist 3 (TUG-424). We here describe the continued structure-activity exploration and optimization of this compound series, leading to the discovery of the more potent agonist 40, a compound with low lipophilicity, excellent in vitro metabolic stability and permeability, complete oral bioavailability, and appreciable efficacy on glucose tolerance in mice. 23943236 Optimization of the C11-BODIPY(581/591) dye for the determination of lipid oxidation in Chlamydomonas reinhardtii by flow cytometry. Lipid oxidation is a recognized end point for the study of oxidative stress and is an important parameter to describe the mode of micropollutant action on aquatic microorganisms. Therefore, the development of quick and reliable methodologies probing the oxidative stress and damage in living cells is highly sought. In the present proof-of-concept work, we examined the potential of the fluorescent dye C11-BODIPY(591/581) to probe lipid oxidation in the green microalga Chlamydomonas reinhardtii. C11-BODIPY(591/581) staining was combined with flow cytometry measurements to obtain multiparameter information on cellular features and oxidative stress damage within single cells. First, staining conditions were optimized by exploring the capability of the dye to stain algal cells under increasing cell and dye concentrations and different staining procedures. Then lipid oxidation in algae induced by short- and long-term exposures to the three metallic micropollutants, copper, mercury, and nanoparticulate copper oxide, and the two organic contaminants, diethyldithiocarbamate (DDC) and diuron was determined. In this work we pointed out C11-BODIPY(591/581) applicability in a wide range of exposure conditions, including studies of oxidation as a function of time and that it is suitable for in vivo measurements of lipid oxidation due to its high permeation and stability in cells and its low interference with algal autofluorescence. © 2013 International Society for Advancement of Cytometry. 23841533 Isotope-Coded ATP Probe for Quantitative Affinity Profiling of ATP-Binding Proteins. ATP-binding proteins play significant roles in numerous cellular processes. Here, we introduced a novel isotope-coded ATP-affinity probe (ICAP) as an acylating agent to simultaneously enrich and incorporate isotope label to ATP-binding proteins. By taking advantage of the quantitative capability of this isotope-coded probe, we devised an affinity profiling strategy to comprehensively characterize ATP-protein interactions at the entire proteome scale. False-positive identification of ATP-binding sites derived from nonspecific labeling was effectively minimized through the comparison of the labeling behaviors of lysine residues with the use of low and high concentrations of the ICAP reagents. A total of 258 previously known ATP-binding proteins from lysates of HeLa-S3 and Jurkat-T cells were validated with this affinity profiling assay. Additionally, we demonstrated that this novel quantitative ATP-affinity profiling strategy is particularly useful for unveiling previously unrecognized nucleotide-binding sites in ATP-binding proteins. For example, our profiling results revealed K356 as a new ATP-binding site in HSP90. Furthermore, 293 proteins without documented ATP-binding GO were predicted to be ATP-binding proteins on the basis of our quantitative affinity profiling results. We also uncovered, for the first time, the ATP-binding capability of human proliferating cell nuclear antigen (PCNA), identified the lysine residue involved in ATP binding, and validated the protein's capacity in ATP binding with an independent assay. The ICAP approach described in the present paper should be generally applicable for the quantitative assessment of ATP-binding proteins in proteomic samples from cells and tissues. 23847476 Cortical sources of ERP in prosaccade and antisaccade eye movements using realistic source models. The cortical sources of event-related-potentials (ERP) using realistic source models were examined in a prosaccade and antisaccade procedure. College-age participants were presented with a preparatory interval and a target that indicated the direction of the eye movement that was to be made. In some blocks a cue was given in the peripheral location where the target was to be presented and in other blocks no cue was given. In Experiment 1 the prosaccade and antisaccade trials were presented randomly within a block; in Experiment 2 procedures were compared in which either prosaccade and antisaccade trials were mixed in the same block, or trials were presented in separate blocks with only one type of eye movement. There was a central negative slow wave occurring prior to the target, a slow positive wave over the parietal scalp prior to the saccade, and a parietal spike potential immediately prior to saccade onset. Cortical source analysis of these ERP components showed a common set of sources in the ventral anterior cingulate and orbital frontal gyrus for the presaccadic positive slow wave and the spike potential. In Experiment 2 the same cued- and non-cued blocks were used, but prosaccade and antisaccade trials were presented in separate blocks. This resulted in a smaller difference in reaction time between prosaccade and antisaccade trials. Unlike the first experiment, the central negative slow wave was larger on antisaccade than on prosaccade trials, and this effect on the ERP component had its cortical source primarily in the parietal and mid-central cortical areas contralateral to the direction of the eye movement. These results suggest that blocked prosaccade and antisaccade trials results in preparatory or set effects that decreases reaction time, eliminates some cueing effects, and is based on contralateral parietal-central brain areas. 23967088 An in silico analysis of troponin I mutations in hypertrophic cardiomyopathy of Indian origin. Hypertrophic Cardiomyopathy (HCM) is an autosomal dominant disorder of the myocardium which is hypertrophied resulting in arrhythmias and heart failure leading to sudden cardiac death (SCD). Several sarcomeric proteins and modifier genes have been implicated in this disease. Troponin I, being a part of the Troponin complex (troponin I, troponin C, troponin T), is an important gene for sarcomeric function. Four mutations (1 novel) were identified in Indian HCM cases, namely, Pro82Ser, Arg98Gln, Arg141Gln and Arg162Gln in Troponin I protein, which are in functionally significant domains. In order to analyse the effect of the mutations on protein stability and protein-protein interactions within the Troponin complex, an in silico study was carried out. The freely available X-ray crystal structure (PDB ID: 1JIE) was used as the template to model the protein followed by loop generation and development of troponin complex for both the troponin I wild type and four mutants (NCBI ID: PRJNA194382). The structural study was carried out to determine the effect of mutation on the structural stability and protein-protein interactions between three subunits in the complex. These mutations, especially the arginine to glutamine substitutions were found to result in local perturbations within the troponin complex by creating/removing inter/intra molecular hydrogen bonds with troponin T and troponin C. This has led to a decrease in the protein stability and loss of important interactions between the three subunits. It could have a significant impact on the disease progression when coupled with allelic heterogeneity which was observed in the cases carrying these mutations. However, this can be further confirmed by functional studies on protein levels in the identified cases. 23922821 Gene Expression Profiles Deciphering Leaf Senescence Variation between Early- and Late-Senescence Cotton Lines. Leaf senescence varies greatly among genotypes of cotton (Gossypium hirsutium L), possibly due to the different expression of senescence-related genes. To determine genes involved in leaf senescence, we performed genome-wide transcriptional profiling of the main-stem leaves of an early- (K1) and a late-senescence (K2) cotton line at 110 day after planting (DAP) using the Solexa technology. The profiling analysis indicated that 1132 genes were up-regulated and 455 genes down-regulated in K1 compared with K2 at 110 DAP. The Solexa data were highly consistent with, and thus were validated by those from real-time quantitative PCR (RT-PCR). Most of the genes related to photosynthesis, anabolism of carbohydrates and other biomolecules were down-regulated, but those for catabolism of proteins, nucleic acids, lipids and nutrient recycling were mostly up-regulated in K1 compared with K2. Fifty-one differently expressed hormone-related genes were identified, of which 5 ethylene, 3 brassinosteroid (BR), 5 JA, 18 auxin, 8 GA and 1 ABA related genes were up-regulated in K1 compared with K2, indicating that these hormone-related genes might play crucial roles in early senescence of K1 leaves. Many differently expressed transcription factor (TF) genes were identified and 11 NAC and 8 WRKY TF genes were up-regulated in K1 compared with K2, suggesting that TF genes, especially NAC and WRKY genes were involved in early senescence of K1 leaves. Genotypic variation in leaf senescence was attributed to differently expressed genes, particularly hormone-related and TF genes. 23733656 Evolution of sex differences in lifespan and aging: Causes and constraints. Why do the two sexes have different lifespans and rates of aging? Two hypotheses based on asymmetric inheritance of sex chromosomes ("unguarded X") or mitochondrial genomes ("mother's curse") explain sex differences in lifespan as sex-specific maladaptation leading to increased mortality in the shorter-lived sex. While asymmetric inheritance hypotheses equate long life with high fitness, considerable empirical evidence suggests that sexes resolve the fundamental tradeoff between reproduction and survival differently resulting in sex-specific optima for lifespan. However, selection for sex-specific values in life-history traits is constrained by intersexual genetic correlations resulting in intra-locus sexual conflict over optimal lifespan. The available data suggest that the evolution of sexual dimorphism only partially resolves these conflicts. Sexual conflict over optimal trait values, which has been demonstrated in model organisms and in humans, is likely to play a key role in shaping the evolution of lifespan, as well as in maintaining genetic variation for sex-specific diseases. 23824432 Utility of Genetic Testing for the Detection of Late-Onset Hearing Loss in Neonates. To demonstrate the utility of molecular testing in the detection of potentially important causes of delayed hearing loss missed by current audiometric screening at birth. We enrolled infants who received a newborn audiometric hearing screen and a filter paper blood collection for state newborn screening. A central laboratory ran the SoundGene® panel. Of 3681 infants studied, 35 (0.95%) had a positive SoundGene® panel; 16 had mitochondrial mutations; 9 Pendred mutations; 5 were CMV DNA positive; 2 had connexin mutations; and 3 had a combination of different mutations. Infants with an abnormal SoundGene® panel were at increased risk for hearing loss compared to neonates without mutations. Three (8.5%) of the 35 subjects had persistent hearing loss compared to 5 (0.21%) of 2398 subjects with no report of mutation (p < 0.01). Of 3681 infants studied, 8 (0.24%) subjects had persistent hearing loss; 5 (62.5%) had abnormal newborn audiometric screens; 2 (25%) had an abnormal SoundGene® panel (1 CMV positive, 1 had a mitochondrial mutation); and 1 (12.5%) had no identifiable risk factors. A positive SoundGene® panel identifies infants who are not identified by audiometric testing and may be at risk for hearing loss. 23736843 Osmoregulation, vasopressin, and cAMP signaling in autosomal dominant polycystic kidney disease. Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent inherited nephropathy. This review will focus on the vasopressin and 3'-5'-cyclic adenosine monophosphate (cAMP) signaling pathways in ADPKD and will discuss how these insights offer new possibilities for the follow-up and treatment of the disease. Defective osmoregulation is an early manifestation of ADPKD and originates from both peripheral (renal effect of vasopressin) and central (release of vasopressin) components. Copeptin, which is released from the vasopressin precursor, may identify ADPKD patients at risk for rapid disease progression. Increased levels of cAMP in tubular cells, reflecting modifications in intracellular calcium homeostasis and abnormal stimulation of the vasopressin V2 receptor (V2R), play a central role in cystogenesis. Blocking the V2R lowers cAMP in cystic tissues, slows renal cystic progression and improves renal function in preclinical models. A phase III clinical trial investigating the effect of the V2R antagonist tolvaptan in ADPKD patients has shown that this treatment blunts kidney growth, reduces associated symptoms and slows kidney function decline when given over 3 years. These advances open perspectives for the understanding of cystogenesis in ADPKD, the mechanisms of osmoregulation, the role of polycystins in the brain, and the pleiotropic action of vasopressin. 23580458 Magnetic Cooling at a Single Molecule Level: a Spectroscopic Investigation of Isolated Molecules on a Surface. A sub-monolayer distribution of isolated molecular Fe14 (bta)6 nanomagnets is deposited intact on a Au(111) surface and investigated by X-ray magnetic circular dichroism spectroscopy. The entropy variation with respect to the applied magnetic field is extracted from the magnetization curves and evidences high magnetocaloric values at the single molecule level. 23861972 When are statins cost-effective in cardiovascular prevention? A systematic review of sponsorship bias and conclusions in economic evaluations of statins. We examined sponsorship of published cost-effectiveness analyses of statin use for cardiovascular (CV) prevention, and determined whether the funding source is associated with study conclusions. We searched PubMed/MEDLINE (up to June 2011) to identify cost-effectiveness analyses of statin use for CV prevention reporting outcomes as incremental costs per quality-adjusted life years (QALY) and/or life years gained (LYG). We examined relationships between the funding source and the study conclusions by means of tests of differences between proportions. Seventy-five studies were included. Forty-eight studies (64.0%) were industry-sponsored. Fifty-two (69.3%) articles compared statins versus non-active alternatives. Secondary CV prevention represented 42.7% of articles, followed by primary CV prevention (38.7%) and both (18.7%). Overall, industry-sponsored studies were much less likely to report unfavourable or neutral conclusions (0% versus 37.1%; p<0.001). For primary CV prevention, the proportion with unfavourable or neutral conclusions was 0% for industry-sponsored studies versus 57.9% for non-sponsored studies (p<0.001). Conversely, no statistically significant differences were identified for studies evaluating secondary CV prevention (0% versus 12.5%; p=0.222). Incremental costs per QALY/LYG estimates reported in industry-sponsored studies were generally more likely to fall below a hypothetical willingness-to-pay threshold of US $50,000. Our systematic analysis suggests that pharmaceutical industry sponsored economic evaluations of statins have generally favored the cost-effectiveness profile of their products particularly in primary CV prevention. 23815619 Evaluation of the adjuvant effect of Salmonella-based Escherichia coli heat-labile toxin B subunits on the efficacy of a live Salmonella-delivered avian pathogenic Escherichia coli vaccine. The present study evaluated the adjuvant effect of live attenuated salmonella organisms expressing the heat-labile toxin of Escherichia coli B subunit (LTB) on the efficacy of an avian pathogenic Escherichia coli (APEC) vaccine. The Asd(+) (aspartate semialdehyde dehydrogenase) plasmid pMMP906 containing the LTB gene was introduced into a Salmonella enterica Typhimurium strain lacking the lon, cpxR and asd genes to generate the adjuvant strain. Live recombinant Salmonella-delivered APEC vaccine candidates were used for this study. The birds were divided into three groups: group A, non-vaccinated controls; group B, immunized with vaccine candidates only; and group C, immunized with vaccine candidates and the LTB strain. The immune responses were measured and the birds were challenged at 21 days of age with a virulent APEC strain. Group C showed a significant increase in plasma IgG and intestinal IgA levels and a significantly higher lymphocyte proliferation response compared with the other groups. Upon challenge with the virulent APEC strain, group C showed effective protection whereas group B did not. We also attempted to optimize the effective dose of the adjuvant. The birds were immunized with the vaccine candidates together with 1×10(7) or 1×10(8) colony-forming units of the LTB strain and were subsequently challenged at 3 weeks of age. The 1×10(7) colony-forming units of the LTB strain showed a greater adjuvant effect with increased levels of serum IgG, intestinal IgA and a potent lymphocyte proliferation response, and yielded higher protection against challenge. Overall, the LTB strain increased the efficacy of the Salmonella -delivered APEC vaccine, indicating that vaccination for APEC along with the LTB strain appears to increase the efficacy for protection against colibacillosis in broiler chickens. 23730683 A novel tantalum-based sol-gel packed microextraction syringe for highly specific enrichment of phosphopeptides in MALDI-MS applications. A new tantalum-based sol-gel material was synthesized using a unique sol-gel synthesis pathway by PEG incorporation into the sol-gel structure without performing a calcination step. This improved its chemical and physical properties for the high capacity and selective enrichment of phosphopeptides from protein digests in complex biological media. The specificity of the tantalum-based sol-gel material for phosphopeptides was evaluated and compared with tantalum(V) oxide (Ta2O5) in different phosphopeptide enrichment applications. The tantalum-based sol-gel and tantalum(V) oxide were characterized in detail using FT-IR spectroscopy, X-ray diffraction (XRD) and scanning electron microscopy (SEM), and also using a surface area and pore size analyzer. In the characterization studies, the surface morphology, pore volume, crystallinity of the materials and PEG incorporation into the sol-gel structure to produce a more hydrophilic material were successfully demonstrated. The X-ray diffractograms of the two different materials were compared and it was noted that the broad signals of the tantalum-based sol-gel clearly represented the amorphous structure of the sol-gel material, which was more likely to create enough surface area and to provide more accessible tantalum atoms for phosphopeptides to be easily adsorbed when compared with the neat and more crystalline structure of Ta2O5. Therefore, the phosphopeptide enrichment performance of the tantalum-based sol-gels was found to be remarkably higher than the more crystalline Ta2O5 in our studies. Phosphopeptides at femtomole levels could be selectively enriched using the tantalum-based sol-gel and detected with a higher signal-to-noise ratio by matrix-assisted laser desorption/ionization-mass spectrometer (MALDI-MS). Moreover, phosphopeptides in a tryptic digest of non-fat bovine milk as a complex real-world biological sample were retained with higher yield using a tantalum-based sol-gel. Additionally, the sol-gel material was packed into a standard syringe (0.5 mL) to enhance the ease of use of the sol-gel material and for the elimination of additional mixing and separation procedures during the adsorption, washing and elution steps of the enrichment procedure. It was found that up to 28 phosphopeptides in milk digest were easily detectable by MALDI-MS at femtomole levels (around 20 fmol) using the microextraction syringe within less than one minute. 23798402 Molecular basis for chromatin binding and regulation of MLL5. The human mixed-lineage leukemia 5 (MLL5) protein mediates hematopoietic cell homeostasis, cell cycle, and survival; however, the molecular basis underlying MLL5 activities remains unknown. Here, we show that MLL5 is recruited to gene-rich euchromatic regions via the interaction of its plant homeodomain finger with the histone mark H3K4me3. The 1.48-Å resolution crystal structure of MLL5 plant homeodomain in complex with the H3K4me3 peptide reveals a noncanonical binding mechanism, whereby K4me3 is recognized through a single aromatic residue and an aspartate. The binding induces a unique His-Asp swapping rearrangement mediated by a C-terminal α-helix. Phosphorylation of H3T3 and H3T6 abrogates the association with H3K4me3 in vitro and in vivo, releasing MLL5 from chromatin in mitosis. This regulatory switch is conserved in the Drosophila ortholog of MLL5, UpSET, and suggests the developmental control for targeting of H3K4me3. Together, our findings provide first insights into the molecular basis for the recruitment, exclusion, and regulation of MLL5 at chromatin. 23861480 An exploratory investigation amongst Australian mothers regarding pharmacies and opportunities for nutrition promotion. The early years life-stage (1 year either side of childbirth) is an important period for preventive action focusing on optimizing nutritional health for mothers and babies. Community pharmacy is a much utilized, easily accessed setting for health promotion and exposure to the primary health care system. The literature suggests that there has been limited exploration of pharmacy utilization by mothers, particularly in the context of nutrition focused health promotion. This study aimed to explore mothers' expectations and experiences of pharmacy based health care and to explore mothers' attitudes and opinions regarding opportunities and scope for nutrition-related health promotion in pharmacy. Qualitative semi-structured telephone interviews were conducted amongst a purposive sample of 28 mothers from across Queensland, Australia. Interviews were transcribed and analysed thematically using an iterative approach. Participants as relatively frequent users of pharmacy services accessed pharmacy for medicines or product related concerns but expected information and health advice to be available. Opportunities for nutrition promotion in pharmacy, identified by participants, related primarily to addressing their personal needs for information, advice and support during this life-stage. Improving and reorienting pharmacy staff practices may contribute to more supportive guidance being provided to mothers in this setting. 23951261 Diabetes-Induced Superoxide Anion and Breakdown of the Blood-Retinal Barrier: Role of the VEGF/uPAR Pathway. Diabetes-induced breakdown of the blood-retinal barrier (BRB) has been linked to hyperglycemia-induced expression of vascular endothelial growth factor (VEGF) and is likely mediated by an increase in oxidative stress. We have shown that VEGF increases permeability of retinal endothelial cells (REC) by inducing expression of urokinase plasminogen activator receptor (uPAR). The purpose of this study was to define the role of superoxide anion in VEGF/uPAR expression and BRB breakdown in diabetes. Studies were performed in streptozotocin diabetic rats and mice and high glucose (HG) treated REC. The superoxide dismutase (SOD) mimetic tempol blocked diabetes-induced permeability and uPAR expression in rats and the cell permeable SOD inhibited HG-induced expression of uPAR and VEGF in REC. Inhibiting VEGFR blocked HG-induced expression of VEGF and uPAR and GSK-3β phosphorylation in REC. HG caused β-catenin translocation from the plasma membrane into the cytosol and nucleus. Treatment with HG-conditioned media increased REC paracellular permeability that was blocked by anti-uPA or anti-uPAR antibodies. Moreover, deletion of uPAR blocked diabetes-induced BRB breakdown and activation of MMP-9 in mice. Together, these data indicate that diabetes-induced oxidative stress triggers BRB breakdown by a mechanism involving uPAR expression through VEGF-induced activation of the GSK3β/β-catenin signaling pathway. 23907057 Ag-silica composite nanotube with controlled wall structures for biomedical applications. A range of Ag-silica composite nanotubes with tailored wall structures were successfully synthesized in situ by single-nozzle electrospinning. By increasing AgNO3 concentration, the wall structure of Ag-silica tubes changes from dense to porous, and eventually turns into a 'lace-like' structure. This is attributed to Ag ions doping into the SiOSi network of precursors, as illustrated in FTIR study. More importantly, Ag-silica composite nanotubes show robust antibacterial activity against both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli microorganisms. Therefore, it is a breakthrough of the nanostructure biomaterial research for future medical applications that require strong antibacterial properties. 23964849 Odorant receptors of a primitive hymenopteran pest, the wheat stem sawfly. The wheat stem sawfly, Cephus cinctus, is an herbivorous hymenopteran that feeds exclusively on members of the Graminae family. Synanthropically, it has become one of the most important insect pests of wheat grown in the northern Great Plains region of the USA and Canada. Insecticides are generally ineffective because of the wheat stem sawfly's extended adult flight period and its inaccessible larval stage, during which it feeds within the wheat stems, making it virtually intractable to most pest management strategies. While research towards integrated pest management strategies based on insect olfaction has proved promising, nothing is known about the molecular basis of olfaction in this important pest species. In this study we identified 28 unique odorant receptor (Or) transcripts from an antennal transcriptome. A phylogenetic analysis with the predicted Ors from the honey bee and jewel wasp genomes revealed at least four clades conserved amongst all three Hymenoptera species. Antennal expression levels were analysed using quantitative real-time PCR, and one male-biased and five female-biased Ors were identified. This study provides the basis for future functional analyses to identify behaviourally active odours that can be used to help develop olfactory-mediated pest management tools. 23845563 Effects of citalopram and escitalopram on fMRI response to affective stimuli in healthy volunteers selected by serotonin transporter genotype. This study was designed to assess whether functional magnetic resonance imaging (fMRI) following antidepressant administration (pharmaco-fMRI) is sufficiently sensitive to detect differences in patterns of activation between enantiomers of the same compound. Healthy adult males (n=11) participated in a randomized, double-blind, cross-over trial with three medication periods during which they received citalopram (racemic mixture), escitalopram (S-citalopram alone), or placebo for 2 weeks. All participants had high expression serotonin transporter genotypes. An fMRI scan that included passive viewing of overt and covert affective faces and affective words was performed after each medication period. Activation in response to overt faces was greater following escitalopram than following citalopram in the right insula, thalamus, and putamen when the faces were compared with a fixation stimulus. For the rapid covert presentation, a greater response was observed in the left middle temporal gyrus in the happy versus fearful contrast following escitalopram than following citalopram. Thus, the combination of genomics and fMRI was successful in discriminating between two very similar drugs. However, the pattern of activation observed suggests that further studies are indicated to understand how to optimally combine the two techniques. 23880055 Tolerance to the antiallodynic effects of the peripherally acting opioid loperamide hydrochloride develops in nerve-injured rats. Peripherally acting opioids are potentially attractive drugs for the clinical management of certain chronic pain states due to the lack of centrally mediated adverse effects. However, it remains unclear whether tolerance develops to peripheral opioid analgesic effects under neuropathic pain conditions. We subjected rats to L5 spinal nerve ligation (SNL) and examined the analgesic effects of repetitive systemic and local administration of loperamide hydrochloride, a peripherally acting opioid agonist. We found that the inhibition of mechanical hypersensitivity, an important manifestation of neuropathic pain, by systemic loperamide (1.5mg/kg subcutaneously) decreased after repetitive drug treatment (tolerance-inducing dose: 0.75to 6.0mg/kg subcutaneously). Similarly, repeated intraplantar injection of loperamide (150μg/50μL intraplantarly) and DAMGO (300μg/50μL), a highly selective mu-opioid receptor (MOR) agonist, also resulted in decreased inhibition of mechanical hypersensitivity. Pretreatment with naltrexone hydrochloride (5mg/kg intraperitoneally) and MK-801 (0.2mg/kg intraperitoneally) attenuated systemic loperamide tolerance. Western blot analysis showed that repetitive systemic administration of morphine (3mg/kg subcutaneously), but not loperamide (3mg/kg subcutaneously) or saline, significantly increased MOR phosphorylation in the spinal cord of SNL rats. In cultured rat dorsal root ganglion neurons, loperamide dose-dependently inhibited KCl-induced increases in [Ca(2+)]i. However, this drug effect significantly decreased in cells pretreated with loperamide (3μM, 72hours). Intriguingly, in loperamide-tolerant cells, the delta-opioid receptor antagonist naltrindole restored loperamide's inhibition of KCl-elicited [Ca(2+)]i increase. Our findings indicate that animals with neuropathic pain may develop acute tolerance to the antiallodynic effects of peripherally acting opioids after repetitive systemic and local drug administration. 23327465 Use of a Routh-Russel deformation map to achieve film formation of a latex with a high glass transition temperature. In the film formation of latex, particle deformation can occur by processes of wet sintering, dry sintering, or capillary action. When latex films dry nonuniformly and when particles deform and coalesce while the film is still wet, a detrimental skin layer will develop at the film surface. In their process model, Routh and Russel proposed that the operative particle deformation mechanism can be determined by the values of control parameters on a deformation map. Here, the film formation processes of three methyl methacrylate/butyl acrylate copolymer latexes with high glass transition temperatures (T(g)), ranging from 45 to 64 °C, have been studied when heated by infrared radiation. Adjusting the infrared (IR) power density enables the film temperature, polymer viscosity, and evaporation rate during latex film formation to be controlled precisely. Different polymer particle deformation mechanisms have been demonstrated for the same latex under a variety of film formation process conditions. When the temperature is too high, a skin layer develops. On the other hand, when the temperature is too low, particles deform by dry sintering, and the process requires extended time periods. The deduced mechanisms can be interpreted and explained by the Routh-Russel deformation maps. Film formation of hard (high T(g)) coatings is achieved without using coalescing aids that emit volatile organic compounds (VOCs), which is a significant technical achievement. 23067063 Object-based benefits without object-based representations. Influential theories of visual working memory have proposed that the basic units of memory are integrated object representations. Key support for this proposal is provided by the same object benefit: It is easier to remember multiple features of a single object than the same set of features distributed across multiple objects. Here, we replicate the object benefit but demonstrate that features are not stored as single, integrated representations. Specifically, participants could remember 10 features better when arranged in 5 objects compared to 10 objects, yet memory for one object feature was largely independent of memory for the other object feature. These results rule out the possibility that integrated representations drive the object benefit and require a revision of the concept of object-based memory representations. We propose that working memory is object-based in regard to the factors that enhance performance but feature based in regard to the level of representational failure. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23295228 Potential monovalent cation-binding sites in aldehyde dehydrogenases. Potassium ions are non-essential activators of several aldehyde dehydrogenases (ALDHs), whereas a few others require the cation for activity. Two kinds of cation-binding sites, which we named intra-subunit and inter-subunit, have been observed in crystal structures of ALDHs, and based on reported crystallographic data, we here propose the existence of a third kind located in the central cavity of some tetrameric ALDHs. Given the high structural similarity between these enzymes, cation-binding sites may be present in many other members of this superfamily. To explore the prevalence of these sites, we compared 37 known crystal structures from 13 different ALDH families and evaluated the possible existence of a cation on the basis of the number, distance and geometry of its potential interactions, as well as of B-factor values of modeled cations obtained in new refinements of some reported crystal structures. Also, by performing multiple alignments of 855 non-redundant amino acid sequences, we assessed the degree of conservation in their respective families of the amino acid residues putatively relevant for cation binding. Among the ALDH enzymes studied, and according to our analyses, potential intra-subunit cation-binding sites seem to be present in most members of ALDH2, ALDH1L, ALDH4, ALDH5, ALDH7, ALDH10, and ALDH25 families, as well as in the bacterial and fungal members of the ALDH9 family and in a few ALDH1, ALDH6, ALDH11 and ALDH26 enzymes; potential inter-subunit sites in members of ALDH1L, ALDH3, ALDH4 from bacillales, ALDH5, ALDH7, ALDH9, ALDH10, ALDH11 and ALDH25 families; and potential central-cavity sites only in some bacterial and animal ALDH9s and in most members of the ALDH1L family. Because potassium is the most abundant intracellular cation, we propose that these are potassium-binding sites, but the specific structural and/or functional roles of the cation bound to these different sites remain to be investigated. 23845402 Delayed early passive motion is harmless to shoulder rotator cuff healing in a rabbit model. Postoperative passive motion is the most widely accepted rehabilitation protocol after rotator cuff repair; however, a rotator cuff retear remains a frequent surgical complication. Clinical outcomes indicate that early passive motion is harmless to rotator cuff healing, but no laboratory evidence supports this proposition. (1) Immediate postoperative immobilization improves rotator cuff healing in rabbits. (2) Early passive motion after short-term immobilization does not harm rotator cuff healing in rabbits. Controlled laboratory study. An injury to the supraspinatus tendon was created and repaired in 90 New Zealand White rabbits, after which they were randomly separated into 3 groups: (1) nonimmobilization (NI; n = 30), (2) continuous immobilization (IM; n = 30), and (3) immobilization with early passive motion (IP; n = 30). At 3, 6, and 12 weeks postoperatively, 5 rabbits from each group were sacrificed for histological evaluation, biomechanical testing, and magnetic resonance imaging. The histological study demonstrated better postoperative healing in the IM and IP groups, with clusters of chondrocytes accumulated at the tendon-bone junction. Magnetic resonance imaging illustrated that the tendon-bone junction was intact in the IM and IP groups. The magnetic resonance quantification analysis showed that the signal-to-noise quotient (SNQ) of the NI group was not significantly higher than that of the immobilization groups at 3 weeks (P = .232) or 6 weeks (P = .117), but it was significantly different at 12 weeks (NI vs IM, P = .006; NI vs IP, P = .009). At 12 weeks, the failure load was significantly higher in the IM and IP groups than in the NI group (NI vs IM, P = .002; NI vs IP, P = .002), but no difference was found between the IM and IP groups (P = .599). Immediate postoperative immobilization led to better tendon-bone healing than immediate postoperative mobilization, and under immobilization, early passive motion was harmless to tendon-bone healing in this study. The results have an implication in supporting the rehabilitation protocol of early passive motion after rotator cuff repair. 23211060 Leptin and leucine synergistically regulate protein metabolism in C2C12 myotubes and mouse skeletal muscles. Leucine and leptin play important roles in regulating protein synthesis and degradation in skeletal muscles in vitro and in vivo. However, the objective of the present study was to determine whether leptin and leucine function synergistically in regulating protein metabolism of skeletal muscles. In the in vitro experiment, C2C12 myotubes were cultured for 2 h in the presence of 5 mm-leucine and/or 50 ng/ml of leptin. In the in vivo experiment, C57BL/6 and ob/ob mice were randomly assigned to be fed a non-purified diet supplemented with 3 % L-leucine or 2·04 % L-alanine (isonitrogenous control) for 14 d. Ob/ob mice were injected intraperitoneally with sterile PBS or recombinant mouse leptin (0·1 μg/g body weight) for 14 d. In C57BL/6 mice, dietary leucine supplementation increased (P< 0·05) plasma leptin, leptin receptor expression and protein synthesis in skeletal muscles, but reduced (P< 0·05) plasma urea and protein degradation in skeletal muscles. Dietary leucine supplementation and leptin injection increased the relative weight of the gastrocnemius and soleus muscles in ob/ob mice. Moreover, leucine and leptin treatments stimulated (P< 0·05) protein synthesis and inhibited (P< 0·05) protein degradation in C2C12 myotubes and skeletal muscles of ob/ob mice. There were interactions (P< 0·05) between the leucine and leptin treatments with regard to protein metabolism in C2C12 myotubes and soleus muscles of ob/ob mice but not in the gastrocnemius muscles of ob/ob mice. Collectively, these results suggest that leptin and leucine synergistically regulate protein metabolism in skeletal muscles both in vitro and in vivo. 23333576 Areca nut procyanidins ameliorate streptozocin-induced hyperglycemia by regulating gluconeogenesis. Hepatic gluconeogenesis is a major contributor to blood glucose in diabetes mellitus. Our previous study indicated that areca nut extract enriched with catechin-based procyanidins from oligomers to polymers gave rise to anti-inflammatory effects in vitro and in vivo. Here we have surveyed the molecular features of areca nut procyanidins (ANPs) using quadrupole time-of-flight liquid chromatography/mass spectrometry (Q-TOF LC/MS) and the resulting mass spectrum accurately described ANP from monomer to hexadecamer. Furthermore, the potential of ANP in terms of blood glucose homeostasis was explored using cyclic adenosine monophosphate (cAMP)/dexamethasone stimulated primary mouse hepatocytes and multiple low dose streptozocin (MLD-STZ) treated mice. With the primary hepatocytes, ANP dose-dependently inhibited gluconeogenesis and reduced the mRNA expression of two gluconeogenic key enzymes, phosphoenol-pyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Intragastrically feeding of 10mg/kg ANP for 4weeks reduced the levels of fasting blood glucose, PEPCK and G6Pase in MLD-STZ mice. In additional, the level of 5'-AMP-activated protein kinase (AMPK) expression showed a trend towards being restored in the ANP treated MLD-STZ-mice. This study indicated that ANP has the potential to improve hyperglycemia by regulating gluconeogenic related kinases in MLD-STZ-mice. 23728492 A closer look at osteoarthritis. Osteoarthritis (OA) is the most common form of arthritis affecting 26.9 million Americans. OA is a degenerative disorder of the synovial joint that leads to pain, stiffness, and decreased function of the affected joint. An understanding of both the nonpharmacologic and pharmacologic management of OA is essential for nurse practitioners. 23887864 Association of laboratory test result availability and rehospitalizations in an outpatient parenteral antimicrobial therapy programme. Laboratory tests are usually requested for monitoring during outpatient parenteral antimicrobial therapy (OPAT), but these recommendations are not always followed. The purpose of this study was to determine whether rehospitalization during the OPAT course is associated with the availability of these test results to the treating physician. Electronic health records (EHRs) from all patients in the Cleveland Clinic OPAT registry with start dates from 1 January to 28 February 2011 were reviewed in a retrospective cohort study. Comprehensive data on patient and OPAT characteristics were obtained for the first OPAT course per patient. Availability of laboratory test results was defined as documentation of results of at least one recommended test in the health system's EHR. Proportions of patients rehospitalized were compared for OPAT courses with test results available and non-available. Adjustments were made for patient age, hospital length of stay, anticipated OPAT duration, OPAT site and Charlson comorbidity index score. Four hundred patients received OPAT during the study period; 60% at home, 36% in skilled nursing facilities or long-term acute care facilities and 4% in other settings. Recommended monitoring laboratory test results were available to infectious disease physicians in 291 (73%) OPAT episodes. There were 82 patient readmissions (21%) while on OPAT. In a multivariable logistic regression model, non-availability of recommended test results was independently associated with readmissions while on OPAT (adjusted OR 2.53; 95% CI 1.36-4.73). Non-availability of recommended test results to treating physicians for patients on OPAT is associated with increased readmissions during OPAT. 23870302 Ten-Year Results of a Randomized Controlled Trial Comparing 0.02% Mitomycin C and Limbal Conjunctival Autograft in Pterygium Surgery. To compare the long-term outcome of pterygium surgery and the long-term effect on endothelial counts after mitomycin C (MMC) or limbal conjunctival autograft (LCAU) in pterygium surgery. We performed a 10-year follow-up study of a randomized controlled trial. A total of 115 eyes of 114 patients with primary pterygium were treated with intraoperative MMC (n = 63) or LCAU transplants (n = 52). A total of 76 patients completed the current 10-year long-term follow-up (47 in the MMC group, 29 in the LCAU group). This is a follow-up study of a randomized controlled trial of a cohort of 114 patients in 2 groups that was performed at the Prince of Wales Hospital 10 years ago: group 1, intraoperative 0.02% MMC for 5 minutes; group 2, LCAU. Consecutive patients enrolled in the original study (recruitment began in February 2001) were invited back for a detailed clinical examination to document the long-term outcome of both surgical groups. The main outcome measures included the recurrence rate, residual conjunctival bed status, complications, and corneal endothelial cell density (ECD) differences. A total of 115 eyes of 114 patients were enrolled and randomized in our previous study. For the current study, 76 of the 114 patients (47 in the MMC group, 29 in the LCAU group) were contacted, whereas 18 patients were lost to follow-up and 20 patients had died. The mean follow-up period was 138±2 months in the MMC group and 137±2 months in the LCAU group. Twelve of 47 patients (25.5%) in the original MMC group and 2 of 29 patients (6.9%) in the LCAU group had recurrent pterygium (P = 0.021). The mean ECD was 2392±342 cells/mm(2) in the MMC group and 2390±388 cells/mm(2) in the LCAU group (P = 0.978). There was no significant difference in the ECD between the operated eyes and the fellow eyes in both groups (P = 0.926 MMC, P = 0.468 LCAU). No other significant ocular complications were observed in either group at the 10-year postoperative follow-up. Limbal conjunctival autograft was more effective than intraoperative MMC in minimizing pterygium recurrence at the 10-year follow-up. Treatment with intraoperative MMC was not associated with long-term corneal endothelial cell loss. The author(s) have no proprietary or commercial interest in any materials discussed in this article. 23915277 Native Portal Vein Embolization for Persistent Hyperoxaluria Following Kidney and Auxiliary Partial Liver Transplantation. Type 1 primary hyperoxaluria (PH1) causes renal failure, for which isolated kidney transplantation (KT) is usually unsuccessful treatment due to early oxalate stone recurrence. Although hepatectomy and liver transplantation (LT) corrects PH1 enzymatic defect, simultaneous auxiliary partial liver transplantation (APLT) and KT have been suggested as an alternative approach. APLT advantages include preservation of the donor pool and retention of native liver function in the event of liver graft loss. However, APLT relative mass may be inadequate to correct the defect. We here report the first case of native portal vein embolization (PVE) to increase APLT to native liver mass ratio (APLT/NLM-R). Following initial combined APLT-KT, both allografts functioned well, but oxalate plasma levels did not normalize. We postulated the inadequate APLT/NLM-R could be corrected by trans-hepatic native PVE. The resulting increased APLT/NLM-R decreased serum oxalate to normal levels within 1 month following PVE. We conclude that persistently elevated oxalate levels after combined APLT-KT for PH1 treatment, results from inadequate relative functional capacity. This can be reversed by partial native PVE to decrease portal flow to the native liver. This approach might be applicable to other scenarios where partial grafts have been transplanted to replace native liver function. 23892196 Pigment epithelium-derived factor promotes Fas-induced cardiomyocyte apoptosis via its receptor phospholipase A2. Cardiovascular diseases cause significant morbidity and mortality worldwide. Recently, our research team demonstrated that a multifunctional cytokine, pigment epithelium-derived factor (PEDF), plays a critical role in regulating myocardial infarction. However, few researchers have studied the molecular mechanisms by which PEDF and its receptors influence the pathophysiology of cardiovascular disease. We tested the hypothesis that PEDF affects cardiomyocyte apoptosis under hypoxic conditions and determined the role that its receptors phospholipase A2 (PLA2) and laminin receptor play in this process. Cardiomyocytes were isolated from neonatal mice and treated with PEDF under normoxic and hypoxic conditions; then, apoptosis was assessed using Annexin V/PI staining and flow cytometry. Western blotting and immunofluorescence staining were used to detect PEDF receptor expression, and siRNA knockdown of PEDF receptors was performed to determine which receptor was involved in mediating cardiomyocyte apoptosis. Our results demonstrated that PEDF increased cardiomyocyte apoptosis during hypoxia via Fas and that PEDF receptors were expressed on cardiomyocyte cell membranes. Furthermore, siRNA experiments indicated that the PEDF receptor PLA2 was responsible for inducing cardiomyocyte apoptosis via the Fas pathway. PEDF promoted Fas-induced cardiomyocyte apoptosis via its receptor PLA2. 23172617 Adiposity and glucose intolerance exacerbate components of metabolic syndrome in children consuming sugar-sweetened beverages: QUALITY cohort study. What is already known about this subject The increase in sugar-sweetened beverage (SSB) consumption over the last generation is temporally associated with epidemic levels of childhood obesity. There is increasing evidence linking added sugar consumption to the development of metabolic syndrome and type 2 diabetes. What this study adds Higher SSB consumption is associated with elevated systolic blood pressure and greater insulin resistance among overweight/obese children whereas these associations are not evident among normal-weight children. In youth with impaired glucose tolerance, higher SSB consumption is strongly associated with greater adiposity. Sugar-sweetened beverage (SSB) consumption is linked to weight gain and metabolic syndrome (MetS) components in children, but whether these associations are modified by excess weight and glucose tolerance status in children is not known. The objective of this study was to examine the cross-sectional associations between SSB intake and MetS components among children above and below the 85th body mass index (BMI) percentile and those with and without impaired glucose tolerance (IGT). Data were from the QUébec Adiposity and Lifestyle InvesTigation in Youth study (2005-2008). Caucasian children aged 8-10 years (n = 632) were recruited from 1040 primary schools in Québec, Canada. SSB consumption was assessed by three 24-h dietary recalls, body fat mass by dual-energy absorptiometry, physical activity by 7-d accelerometer. Multivariate linear regressions were used, with age, sex, fat mass index and physical activity as covariates, including waist circumference (WC), systolic blood pressure (SBP), concentrations of triglyceride and high-density lipoprotein cholesterol and homeostasis model assessment of insulin resistance (HOMA-IR) as outcome variables. Among overweight children, a 100-mL higher SSB consumption was associated with a 0.1-unit higher HOMA-IR (P = 0.009) and a 1.1-mm Hg higher SBP (P = 0.001). In children with IGT, a 100-mL higher SSB consumption was associated with a 1.4-mm Hg higher SBP and a 4.0-cm higher WC (P < 0.001). These associations were not observed among children <85th BMI percentile. Our results suggest that the association between higher SSB consumption and MetS components is more evident in overweight/obese and glucose-intolerant children. 23458473 Isolation of thermally stable cellulose nanocrystals by phosphoric Acid hydrolysis. On account of their intriguing mechanical properties, low cost, and renewable nature, high-aspect-ratio cellulose nanocrystals (CNCs) are an attractive component for many nanomaterials. Due to hydrogen bonding between their surface hydroxyl groups, unmodified CNCs (H-CNCs) aggregate easily and are often difficult to disperse. It is shown here that on account of ionic repulsion between charged surface groups, slightly phosphorylated CNCs (P-CNCs, average dimensions 31 ± 14 × 316 ± 127 nm, surface charge density = 10.8 ± 2.7 mmol/kg cellulose), prepared by controlled hydrolysis of cotton with phosphoric acid, are readily dispersible and form stable dispersions in polar solvents such as water, dimethyl sulfoxide, and dimethylformamide. Thermogravimetric analyses reveal that these P-CNCs exhibit a much higher thermal stability than partially sulfated CNCs (S-CNCs), which are frequently employed, but suffer from limited thermal stability. Nanocomposites of an ethylene oxide-epichlorohydrin copolymer and H-CNCs, S-CNCs, and P-CNCs were prepared, and their mechanical properties were studied by dynamic mechanical thermal analysis. The results show that P-CNCs offer a reinforcing capability that is comparable to that of H-CNCs or S-CNCs. 23910454 24-Branched Δ5 sterols from Laurencia papillosa red seaweed with antibacterial activity against human pathogenic bacteria. Methanol extract of thirty-eight seaweeds samples were first screened against Gram-positive (Staphylococcus aureus ATCC 25923 and Bacillus subtilis ATCC 6051) and -negative (Escherichia coli ATCC 8739 and Pseudomonas aerugenosa ATCC 9027) bacteria. Laurencia papillosa (Ceramiales, Rhodomelaceae, Rhodophyta) gave maximum antimicrobial activity against these bacteria. It was finally tested against four clinical Gram-negative isolates (E. coli, P. aerugenosa, Klebsiella pneumoniae and Shigella flexineri) and exhibited antibacterial activity. The extract was fractionated by column chromatography and the active fraction was identified as a cholesterol derivative, 24-propylidene cholest-5-en-3β-ol using gas chromatography mass spectrometry (GC-MS). The electrospray ionization mass spectrometry (ESI-MS) and FT-IR spectroscopic analysis also supported the structure of the compound. The minimum inhibitory concentration ranged from 1.2 to 1.7μg/mL (IC50) against clinical isolates. This is the first report of antibacterial activity of this cholesterol derivative. This compound could be exploited as potential lead molecule against broad spectrum drug development. The results also affirm the potential of seaweeds as an important natural source of antimicrobial compounds for pharmaceutical industries. 23921154 The nitrite-oxidizing community in activated sludge from a municipal wastewater treatment plant determined by fatty acid methyl ester-stable isotope probing. Metabolically-active autotrophic nitrite oxidizers from activated sludge were labeled with (13)C-bicarbonate under exposure to different temperatures and nitrite concentrations. The labeled samples were characterized by FAME-SIP (fatty acid methyl ester-stable isotope probing). The compound cis-11-palmitoleic acid, which is the major lipid of the most abundant nitrite oxidizer in activated sludge, Candidatus Nitrospira defluvii, showed (13)C-incorporation in all samples exposed to 3mM nitrite. Subsequently, the lipid cis-7-palmitoleic acid was labeled, and it indicated the activity of a nitrite oxidizer that was different from the known Nitrospira taxa in activated sludge. The highest incorporation of cis-7-palmitoleic acid label was found after incubation with a nitrite concentration of 0.3mM at 17 and 22°C. While activity of Nitrobacter populations could not be detected by the FAME-SIP approach, an unknown nitrite oxidizer with the major lipid cis-9 isomer of palmitoleic acid exhibited (13)C-incorporation at 28°C with 30mM nitrite. These results indicated flexibility of nitrite-oxidizing guilds in a complex community responding to different conditions. Labeled lipids so far not described for activated sludge-associated nitrifiers indicated the presence of unknown nitrite oxidizers in this habitat. The FAME-SIP-based information can be used to define appropriate conditions for the enrichment of nitrite-oxidizing guilds from complex samples. 23041017 Coronary artery disease and HIV; getting to the HAART of the matter. Premature coronary disease is an important emerging paradigm affecting contemporary HIV patients. Through immune reconstruction HIV causes multisystem pathology. Recent advances in the treatment of AIDS, mainly highly active retroviral therapy (HAART), have transformed this previously terminal illness to a chronic disease. However, an interplay between traditional risk factors in a high risk predominantly male population together with the effect of the long term use of HAART in inducing a metabolic syndrome is leading to a premature and aggressive coronary artery disease phenotype not previously recognised. An association between HAART and increased cardiovascular events appears to exist. However, currently this risk appears to be low, and HAART is vital to maintain adequate viral suppression and disease control. HAART- and viral-associated dyslipidaemia can pose a significant challenge to the clinician as drug interactions may precipitate drug toxicity. In our institution a varied phenotypic pattern of coronary disease is seen angiographically from severe atherosclerotic calcific disease through to aneurysm formation and thrombotic occlusion. This is illustrated by case studies. There is a need for aggressive primary and secondary prevention strategies in this important sub-group of patients with a multi-disciplinary approach required in the management including cardiologists, metabolic physicians and lipidologists. 23630189 Case report of flipper anatomic anomaly of Sotalia guianensis from Sepetiba Bay, Rio de Janeiro. The cetacean flipper consists of a soft tissue that encases most of the forelimb containing humerus, radius, ulna, carpals, metacarpals, and phalanges. Several studies have documented the typical cetacean's flipper anatomy, but only a few described digital anomalies and the most common are fusions and supernumerary such as polydactily and polyphalangy. The flippers of the Guiana dolphin, Sotalia guianensis have a falciform general aspect showing individual differences and marks produced by individual contact in social interactions that mainly occur on the posterior border. Here, we report for the first time a case of flippers with anatomical anomalies of loss of digits and deviation of radius of an adult S. guianensis from Baía de Sepetiba (22°54'-23°04', 43°36'-44°02'W), Rio de Janeiro, Southeastern Brazil. 23886993 A simple sheath removal after open trans-femoral catheterization procedure: the ZIP technique. The ZIP technique, a surgical equivalent of the 'Preclose' technique, useful for transcatheter aortic valve implantation or endovascular aortic aneurysm repair is described. While percutaneous closure devices are expensive, need a long learning curve and are associated with primary failure, the ZIP technique is easy and allows a quick, safe and anatomical closure of the artery. This procedure avoids arterial cross-clamping and no purse-string effect was demonstrated using Doppler ultrasound examination. 23926042 Encoding of near-range spatial information by descending interneurons in the stick insect antennal mechanosensory pathway. Much like mammals use their whiskers, insects use their antennae for tactile near-range orientation during locomotion. Stick insects rapidly transfer spatial information about antennal touch location to the front legs, allowing for aimed reach-to-grasp movements. This adaptive behavior requires a spatial coordinate transformation from "antennal contact space" to "leg posture space". Therefore, a neural pathway must convey proprioceptive and tactile information about antennal posture and contact site to thoracic motor networks. Here, we analyze proprioceptive encoding properties of descending interneurons (DINs) that convey information about antennal posture and movement to the thoracic ganglia. Based on the response properties of 110 DINs to imposed movement of the distal antennal joint, we distinguish five functional DIN groups according to their sensitivity to three parameters: movement direction, movement velocity, and antennal joint angle. These groups are: Simple position-sensitive DINs which signal the antennal joint angle; Dynamic position-sensitive DINs which signal the joint angle with strong dependency on movement; Unspecific movement-sensitive DINs which signal movement but not the velocity, position or direction of movement; and ON- and OFF-type velocity-sensitive DINs. The activity of the latter two is increased/attenuated during antennal movement with the spike rate increasing/decreasing linearly with antennal joint angle velocity. Some movement-sensitive DINs convey spikes to the thorax within 11 ms, suggesting a rapid, direct pathway from antennal mechanosensory to thoracic motor networks. We discuss how the population of DINs could provide the neural basis for the intersegmental spatial coordinate transfer between a touch sensor of the head and thoracic motor networks. 23969364 Assessing Residents' Written Learning Goals and Goal Writing Skill: Validity Evidence for the Learning Goal Scoring Rubric. To provide validity evidence for use of the Learning Goal Scoring Rubric to assess the quality of written learning goals and residents' goal writing skills. This two-part study used the rubric to assess University of Colorado third-year pediatric residents' written learning goals to obtain validity evidence. In study 1, five raters independently scored 48 goals written in 2010-2011 and 2011-2012 by 48 residents, who also responded to the Jefferson Scale of Physician Lifelong Learning (JeffSPLL). In study 2, two raters independently scored 48 goals written in 2011-2012 by 12 residents. Intraclass correlation coefficients (ICCs) assessed rater agreement to provide evidence for response process. Generalizability theory assessed internal structure. Independent-samples Mann-Whitney U tests and correlations assessed relationship to other variables. Content was matched to published literature and instructional methods. The ICC was 0.71 for the overall rubric. In study 1, where the generalizability study's (G study's) object of measurement was learning goals, the phi coefficient was 0.867. In study 2, where the G study's object of measurement was the resident (goal writing skill), the phi coefficient was 0.751. The total mean score of residents with goal writing training was significantly higher than that of those without (7.54 versus 4.98, P < .001). Correlation between goal quality and JeffSPLL score was not significant. Investigators agreed that the content matched the published literature and instructional methods. Preliminary validity evidence indicates that this scoring rubric can assess learning goal quality and goal writing skill. 23684381 miR-155* mediates suppressive effect of PTEN 3'-untranslated region on AP-1/NF-κB pathway in HTR-8/SVneo cells. Among miRNAs, miR-155 is a known regulator of immune system. Accumulating studies have revealed the connections between miR-155 and activator protein 1 (AP-1)/nuclear factor (NF)-κB. However, miR-155*, a miR-155 paralog, has so far been less studied. Here we demonstrated that miR-155*, induced by lipopolysaccharide (LPS) in an AP-1/NF-κB dependent manner, played a positive feedback role in AP-1/NF-κB pathway via targeting interleukin-1 receptor-associated kinase M (IRAKM) and NF-κB inhibitor interacting Ras-like 1 (NKIRAS1) in trophoblasts. Our study further proved that miR-155*-targeted PTEN 3'-untranslated region (3'UTR) increased IRAKM and NKIRAS1 expression by competing for miR-155* binding, thereby suppressing AP-1/NF-κB activation induced by LPS. 23233429 Etiological and molecular profile of hepatocellular cancer from India. Hepatocellular carcinoma (HCC) cases are underreported in India. Our study was designed to investigate the etiological profile of HCC cases in India and compare with global incidence. The study included 348 HCC and 375 chronic liver disease cases without HCC as controls. Samples were screened for hepatitis B virus (HBV)/hepatitis C virus (HCV) infections using enzyme-linked immunosorbent assay and polymerase chain reaction (PCR). HBV-DNA and HCV-RNA genotyping was performed by PCR-restriction fragment length polymorphism. All cases were also assessed for other possible risk factors of HCC. Among HCC cases, 62.6% were positive for HBV, 26.7% for HCV and 3.2% had coinfection. Around 17% of HCC cases had aflatoxin-B1 exposure. HBV genotype D (odds ratio, OR = 1.76) and mixed genotypes (OR = 6.86) had higher risk of HCC development. The risk of HCC was twofold (OR = 2.26) in patients with high HBV-DNA levels. Moreover, our findings were unable to establish a clear differential effect of HCV genotype (OR = 1.48) and high viral load (OR = 1.21) on HCC development. In India, HBV is the major risk factors, whereas alcohol, smoking and diabetes are nonsignificantly associated. Asian countries such as Hong Kong and Taiwan also had high incidence of HBV-related HCC. Contrarily, countries from Europe and USA reported HCV as predominant cause of HCC. Further, aflatoxin could be a possible risk of HCC in the population. However, in comparison to the countries such as China and Taiwan (high Aflatoxin exposure), the aflatoxin level is relatively low in our patients. High HBV-DNA levels and HBV/D increased the risk of HCC. However, neither genotype nor virus loads of HCV affected prognosis of HCC patients in our study. 23860696 A rare cause of acute coronary syndrome: electrical shock. Electrical shock can cause death, disability, and any degree of damage to various organs and systems. Coronary angiography (CA) could help us for underlying condition, and for treatment choice. Herein, we reported electrical shock insulted patient whose electrocardiography showed anterior ST elevation, such as myocardial infarction electrocardiographic findings with angiographically normal coronary arteries. 23870215 Quantification of risk for early unplanned readmission after rectal resection: a single-center study. Several factors predictive of readmission after colorectal surgery have been identified. Although often grouped together in readmission studies, colon and rectal resections differ in many ways. The aim of this study was to identify factors associated with readmission after rectal resection. We performed a retrospective, single-center cohort study of 565 patients who underwent rectal resections at a tertiary referral center in 2010 and 2011. The main outcomes measure was readmission within 30 days. Univariate comparison between readmitted and nonreadmitted patients was followed by a stepwise logistic regression to identify independent risk factors for readmission. There were 105 patients (18.6%) readmitted. Indication (inflammatory bowel disease [IBD], p = 0.008), type of operation (pelvic pouch surgery, p = 0.02), use of laparoscopy (readmission 27.8% vs 14%, p < 0.001), and length of operation (p < 0.001) were associated with a higher readmission rate on univariate analysis. Neither preoperative chemoradiation (p = 0.89) nor American Society of Anesthesiologists class (p = 0.09) was associated with readmission. Logistic regression showed use of laparoscopy (odds ratio [OR] 1.94, 95% CI 1.23 to 3.07), initial diagnosis of IBD (OR 1.84, 95% CI 1.17 to 2.93), and length of operation (OR 1.09, 95% CI 1.03 to 1.16 per 30 minutes) to be independent risk factors. Risks of readmission were 6.7%, 13.4%, 27.4%, and 27.4% with 0, 1, 2, or 3 positive risk factors, respectively. Readmission after rectal resection is associated with the indication for surgery and the operative technique used. Optimization of factors related to the underlying pathology and careful appraisal of the operative technique may result in decreased readmission after proctectomy. 23694843 Influence of crystal structure on debonding failure of zirconia veneered restorations. Delamination of porcelain from intact zirconia framework was recently reported as the most common failure mode of these restorations. The aim of this study was to investigate the influence of different laboratory surface treatments on crystals structure and fracture strength of zirconia veneered restorations. Zirconia discs received airborne particle abrasion with either 50 or 120μm alumina particles then half of the specimens were annealed to remove surface pre-stresses, while assintered discs served as a control. Crystal structure of each group was evaluated using X-ray diffraction analysis (XRD). The discs were then veneered with porcelain and biaxially loaded to fracture with the veneer surface in tension (α=0.05). Regarding debonding failure, 50μm particle abrasion significantly increased biaxial flexure strength compared to as-sintered specimens. On the contrary 120μm particle abrasion resulted in significant reduction in flexure strength and was associated with higher percent of monoclinic phase (7%). However for both types of particle sizes, annealing reduced initial failure load as it led to complete reverse transformation of the monoclinic phase which was associated with zirconia grain pull-out at the critical crack location. Paying attention to the surface treatment of zirconia before veneering could reduce chances of delamination and significantly improve the strength of the bilayered restorations. 23938604 Enhanced autophagy is required for survival in EGFR-independent EGFR-mutant lung adenocarcinoma cells. Lung cancers harboring epidermal growth factor receptor (EGFR) mutations depend on constitutive activation of the kinase for survival. Although most EGFR-mutant lung cancers are sensitive to EGFR tyrosine kinase inhibitors (TKIs) and shrink in response to treatment, acquired resistance to TKI therapy is common. We demonstrate here that two EGFR-mutated lung adenocarcinoma cell lines, HCC827 and HCC4006, contain a subpopulation of cells that have undergone epithelial-to-mesenchymal transition and survive independent of activated EGFR. These EGFR-independent cancer cells, herein termed gefitinib-resistant (GR) cells, demonstrate higher levels of basal autophagy than their parental cells and thrive under hypoxic, reduced-serum conditions in vitro; this somewhat simulates the hypoxic environment common to cancerous tissues. We show that depletion of the essential autophagy gene, ATG5, by small interfering RNA (siRNA) or chloroquine, an autophagy inhibitor, markedly reduces GR cell viability under hypoxic conditions. Moreover, we show a significant elevation in caspase activity in GR cells following knockdown of ATG5. These results suggest that GR cells can evade apoptosis and survive in hostile, hypoxic environments with constant autophagic flux. We also show the presence of autophagosomes in some cancer cells from patient samples, even in untreated EGFR-mutant lung cancer tissue samples. Together, our results indicate that autophagy inhibitors alone or in combination with EGFR TKIs may be an effective approach for the treatment of EGFR-mutant lung cancers, where basal autophagy of some cancer cells is upregulated.Laboratory Investigation advance online publication, 12 August 2013; doi:10.1038/labinvest.2013.102. 23907215 Expression of Aryl Hydrocarbon Receptor Nuclear Translocator Enhances Cisplatin Resistance by Upregulating MDR1 Expression in Cancer Cells. The identification of molecular pathways in cancer cells is important for understanding the cells' underlying biology and for designing effective cancer therapies. We demonstrate that the expression of aryl hydrocarbon receptor (AhR) nuclear translocator (ARNT) is critical during the development of cisplatin resistance. The reduced expression of ARNT was correlated with cisplatin-induced cell death in drug-sensitive cells. In addition, suppression of ARNT reversed the characteristics of cisplatin-resistant cells, making these cells cisplatin sensitive, and significantly enhanced caspase-3 activation, DNA fragmentation, and apoptosis. The inhibition of colony formation, regulated by cisplatin, was more significant in ARNT-knockdown cells than in parental cells. In a xenograft analysis of severe combined immunodeficiency (SCID) mice, cisplatin also efficiently inhibited ARNT-deficient c4 tumors but not ARNT-containing vT2 tumor formation. Furthermore, the downregulation of multidrug resistance 1 (MDR1) expression and retention of drugs in cells caused by suppression of ARNT, resulting in the resensitization of drug-resistant cells to cisplatin, was observed. The overexpression of ARNT interacted with Sp1 to enhance the expression of MDR1 through Sp1-binding sites on the MDR1 promoter, resulting in a reversal of the effect of cisplatin on cell death. In addition, ARNT-induced MDR1 expression was inhibited in Sp1-knockdown cells. These results reveal previously unrecognized, multifaceted functions of ARNT in establishing the drug-resistant properties of cancer cells by the upregulation of MDR1, highlighting ARNT's potential as a therapeutic target in an important subset of cancers. 23523270 Functional and structural aging of the speech sensorimotor neural system: functional magnetic resonance imaging evidence. The ability to perceive and produce speech undergoes important changes in late adulthood. The goal of the present study was to characterize functional and structural age-related differences in the cortical network that support speech perception and production, using magnetic resonance imaging, as well as the relationship between functional and structural age-related changes occurring in this network. We asked young and older adults to observe videos of a speaker producing single words (perception), and to observe and repeat the words produced (production). Results show a widespread bilateral network of brain activation for Perception and Production that was not correlated with age. In addition, several regions did show age-related change (auditory cortex, planum temporale, superior temporal sulcus, premotor cortices, SMA-proper). Examination of the relationship between brain signal and regional and global gray matter volume and cortical thickness revealed a complex set of relationships between structure and function, with some regions showing a relationship between structure and function and some not. The present results provide novel findings about the neurobiology of aging and verbal communication. 23624173 Regulation of zebrafish CYP3A65 transcription by AHR2. CYP3A proteins are the most abundant CYPs in the liver and intestines, and they play a pivotal role in drug metabolism. In mammals, CYP3A genes are induced by various xenobiotics through processes mediated by PXR. We previously identified zebrafish CYP3A65 as a CYP3A ortholog that is constitutively expressed in gastrointestinal tissues, and is upregulated by treatment with dexamethasone, rifampicin or tetrachlorodibenzo-p-dioxin (TCDD). However, the underlying mechanism of TCDD-mediated CYP3A65 transcription is unclear. Here we generated two transgenic zebrafish, Tg(CYP3A65S:EGFP) and Tg(CYP3A65L:EGFP), which contain 2.1 and 5.4 kb 5' flanking sequences, respectively, of the CYP3A65 gene upstream of EGFP. Both transgenic lines express EGFP in larval gastrointestinal tissues in a pattern similar to that of the endogenous CYP3A65 gene. Moreover, EGFP expression can be significantly induced by TCDD exposure during the larval stage. In addition, EGFP expression can be stimulated by kynurenine, a putative AHR ligand produced during tryptophan metabolism. AHRE elements in the upstream regulatory region of the CYP3A65 gene are indispensible for basal and TCDD-induced transcription. Furthermore, the AHR2 DNA and ligand-binding domains are required to mediate effective CYP3A65 transcription. AHRE sequences are present in the promoters of many teleost CYP3 genes, but not of mammalian CYP3 genes, suggesting that AHR/AHR2-mediated transcription is likely a common regulatory mechanism for teleost CYP3 genes. It may also reflect the different environments that terrestrial and aquatic organisms encounter. 23942299 Management of sarcomas of the uterus. Uterine sarcomas are rare malignancies accounting for 8-10% of all uterine malignancies, but are significantly more aggressive and have worse prognosis. Management of uterine sarcomas including leiomyosarcoma (LMS), endometrial stromal sarcoma, high-grade undifferentiated sarcoma and adenosarcoma is reviewed. Uterine carcinosarcomas are staged and treated similarly to high-grade epithelial endometrial carcinomas and are no longer considered uterine sarcomas. Gemcitabine/docetaxel with doxorubicin holds promise for the treatment of LMS. A recently developed nomogram was demonstrated to predict disease recurrence in patients with LMS which may allow us to identify a subset of patients who are likely to recur and target this population for adjuvant systemic therapy. Cytogenetic abnormalities have been identified that allow differentiation of endometrial stromal sarcomas from high-grade undifferentiated uterine sarcomas which may be useful in pathologically difficult cases. Uterine sarcomas are a heterogeneous group of tumors. To date, limited advancements have been made in discovering targeted therapies to these tumors. Chemotherapy with gemcitabine/docetaxel followed by doxorubicin holds promise in the treatment of LMS. Given the rarity of these tumors and the lack of clinical trials to guide management, patients with uterine sarcomas should be encouraged to enroll on clinical trials. 23747561 Gold nanoparticle exposure induces growth and yield enhancement in Arabidopsis thaliana. Nanotechnology has the potential to revolutionize agriculture field. Towards this effort, carbon nanotubes have recently been reported to induce growth enhancement of tobacco cells. In this study, exposure to 24nm size gold nanoparticles (GNPs) at 10μg/ml concentration was found to enhance the total seed yield of Arabidopsis thaliana by 3 times over the control. In addition, 24nm size GNP exposure at both 10 and 80μg/ml concentrations has significantly improved seed germination rate, vegetative growth and free radical scavenging activity. A considerable correlation was found between expression of key plant regulatory molecules, microRNAs (miRs) and seed germination, growth and antioxidant potential of A. thaliana on GNP exposure. This is the first report showing GNPs as a promising tool to enhance seed yield of plants. 23628848 Prostate cancer susceptibility genes on 8p21-23 in a Dutch population. Background:Prostate cancer is the most commonly diagnosed cancer in men in Europe and the United States. Numerous studies have indicated genetics to have a major role in the aetiology of this disease; as much as 42% of the risk may be explained by heritable factors. Genome-wide association studies have detected an association between prostate cancer and chromosome 8p21-23. In this study, we analysed eight microsatellite (MS) markers in that region in order to confirm previous results and narrow down the location of candidate prostate cancer genes.Methods:292 cases and 278 controls were selected from the Netherlands Cohort Study (NLCS). The following MSs were used in the analyses: D8S136, D8S1734, D8S1742, D8S261, D8S262, D8S351, D8S511 and D8S520. Associations were evaluated using a χ(2) test and logistic regression. We checked for any effects on the association by tumour stage.Results:Associations that were found confirmed previous research that pointed to the 8p21-23 region. Two MSs: D8S136 (odds ratio (OR), 0.69; P=4.00 × 10(-28)), and D8S520 (OR, 0.80; P=3.37 × 10(-11)), were consistently and strongly related with prostate cancer. Genotype analysis showed an additive effect for D8S136 (P-trend=6.22 × 10(-03)) and D8S520 (P-trend=2.62 × 10(-22)), suggesting an increased risk for people with a short number of repeats on both alleles at those markers.Conclusions:This study provides strong evidence that the 8p21-23 region is likely to harbour prostate cancer genes. 23103562 TNF-α-mediated NF-κB survival signaling impairment by cisplatin enhances JNK activation allowing synergistic apoptosis of renal proximal tubular cells. Cisplatin-induced nephrotoxicity is an important limiting factor for cisplatin use. Tumor necrosis factor-α (TNF-α) is known to contribute to cisplatin-induced nephrotoxicity by inducing an inflammatory process aggravating the primary injury, thereby resulting in acute kidney injury (AKI). The present study investigates the pathways synergistically activated by cisplatin and TNF-α responsible for TNF-α-enhanced cisplatin-induced renal cell injury. To do so, immortalized renal proximal tubular epithelial cells (IM-PTECs) were co-treated with TNF-α and cisplatin. Under these conditions, cisplatin induced dose-dependent apoptosis in IM-PTECs, which was significantly enhanced by TNF-α. Transcriptomic analysis revealed that cisplatin inhibited the typical TNF-α response and cisplatin/TNF-α treatment up-regulated cell death pathways while it down-regulated survival pathways compared to cisplatin alone. In concordance, the gene expression levels of kidney injury markers combined with activation of specific inflammatory mediators were enhanced by cisplatin/TNF-α treatment, resembling the in vivo cisplatin-induced nephrotoxicity response. Furthermore, combined cisplatin/TNF-α treatment inhibited NF-κB nuclear translocation and NF-κB-mediated gene transcription leading to enhanced and prolonged JNK and c-Jun phosphorylation. JNK sustained activation further inhibited NF-κB signaling via a feedback loop mechanism. This led to an alteration in the transcription of the NF-κB-induced anti-apoptotic genes c-IAP2, Bcl-XL, Bruce and Bcl2 and pro-apoptotic genes Bfk and Xaf1 and consequently to sensitization of the IM-PTECs toward cisplatin/TNF-α-induced toxicity. In conclusion, our findings support a model whereby renal cells exposed to both cisplatin and TNF-α switch into a more pro-apoptotic and inflammatory program by altering their NF-κB/JNK/c-Jun balance. 23564370 Gene expression profiling of three different stressors in the water flea Daphnia magna. Microarrays are an ideal tool to screen for differences in gene expression of thousands of genes simultaneously. However, often commercial arrays are not available. In this study, we performed microarray analyses to evaluate patterns of gene transcription following exposure to two natural and one anthropogenic stressor. cDNA microarrays compiled of three life stage specific and three stressor-specific EST libraries, yielding 1734 different EST sequences, were used. We exposed juveniles of the water flea Daphnia magna for 48, 96 and 144 h to three stressors known to exert strong selection in natural populations of this species i.e. a sublethal concentration of the pesticide carbaryl, infective spores of the endoparasite Pasteuria ramosa, and fish predation risk mimicked by exposure to fish kairomones. A total of 148 gene fragments were differentially expressed compared to the control. Based on a PCA, the exposure treatments were separated into two main groups based on the extent of the transcriptional response: a low and a high (144 h of fish or carbaryl exposure and 96 h of parasite exposure) stress group. Firstly, we observed a general stress-related transcriptional expression profile independent of the treatment characterized by repression of transcripts involved in transcription, translation, signal transduction and energy metabolism. Secondly, we observed treatment-specific responses including signs of migration to deeper water layers in response to fish predation, structural challenge of the cuticle in response to carbaryl exposure, and disturbance of the ATP production in parasite exposure. A third important conclusion is that transcription expression patterns exhibit stress-specific changes over time. Parasite exposure shows the most differentially expressed gene fragments after 96 h. The peak of differentially expressed transcripts came only after 144 h of fish exposure, while carbaryl exposure induced a more stable number of differently expressed gene fragments over time. 23860674 Early conversion to below-elbow cast for non-reduced diaphyseal both-bone forearm fractures in children is safe: preliminary results of a multicentre randomised controlled trial. This multicentre randomised controlled trial was designed to explore whether 6 weeks above-elbow cast (AEC) or 3 weeks AEC followed by 3 weeks below-elbow cast (BEC) cause similar limitation of pronation and supination in non-reduced diaphyseal both-bone forearm fractures in children. Children were randomly allocated to 6 weeks AEC or to 3 weeks AEC followed by 3 weeks BEC. The primary outcome was limitation of pronation and supination after 6 months. The secondary outcomes were re-displacement of the fracture, complication rate, limitation of flexion and extension of wrist and elbow, cast comfort, cosmetics, complaints in daily life and assessment of radiographs. A group of 23 children was treated with 6 weeks AEC and 24 children with 3 weeks AEC and 3 weeks BEC. The follow-up rate was 98 % with a mean follow-up of 7.0 months. The mean limitation of pronation and supination was 23.3 ± 22.0 for children treated with AEC and 18.0 ± 16.9 for children treated with AEC and BEC. The other study outcomes were similar in both groups. Early conversion to BEC is safe in the treatment of non-reduced diaphyseal both-bone forearm fractures in children. Multicentre randomised controlled trial, Level II. 23824873 Demographic, socioeconomic, disease history, dietary and lifestyle cancer risk factors associated with alcohol consumption. Data are lacking regarding the association of alcohol consumption with a broad range of other cancer risk factors. Objectives: (i) to assess which sociodemographic, lifestyle and dietary factors were associated with alcohol consumption; (ii) to identify profiles of alcohol consumers by beverage type; (iii) to estimate the number of cancer risk factors accumulated on the individual level according to alcohol consumption. Alcohol and dietary intakes were assessed by six 24 hr records among 29,566 adults of the NutriNet-Santé cohort. Factors associated with alcohol consumption (nondrinkers (reference)/< 10 g/day/≥ 10 g/day) were assessed by polytomic multivariate logistic regression stratified by gender. Among alcohol consumers, percentages of alcohol brought by each beverage type were compared across sociodemographic and lifestyle characteristics using Kruskal-Wallis rank tests. Several factors were associated with alcohol consumption ≥ 10 g/day in both genders: older age (pmen  = 0.02, pwomen  < 0.0001), smoking (pmen&women  < 0.0001), higher socioprofessional category (pmen&women  < 0.0001), higher income (pmen  = 0.003, pwomen  < 0.0001) and less healthy dietary intakes. Profiles of subjects varied across alcoholic beverage types. Men with history of cardiovascular disease (p = 0.0002) or depression (p = 0.03) and women with history of cirrhosis (p < 0.0001) consumed less alcohol. In women, personal history of cancer was associated with a lower proportion of moderate alcohol users only (< 10 g/day, p = 0.04). In both genders, higher alcohol drinkers clustered more cancer risk factors (median = 5, apart from alcohol) than nondrinkers (median = 4), p < 0.0001. The multiplicity of deleterious lifestyle behaviors combined with alcohol drinking must be taken into account in cancer prevention efforts. Gender-specific medical advice for people with personal or family history of alcohol-related diseases, including cancer, should be strengthened. 23942210 Effect of engineered anisotropy on the susceptibility of human pluripotent stem cell-derived ventricular cardiomyocytes to arrhythmias. Human (h) pluripotent stem cells (PSC) such as embryonic stem cells (ESC) can be directed into cardiomyocytes (CMs), representing a potential unlimited cell source for disease modeling, cardiotoxicity screening and myocardial repair. Although the electrophysiology of single hESC-CMs is now better defined, their multi-cellular arrhythmogenicity has not been thoroughly assessed due to the lack of a suitable experimental platform. Indeed, the generation of ventricular (V) fibrillation requires single-cell triggers as well as sustained multi-cellular reentrant events. Although native VCMs are aligned in a highly organized fashion such that electrical conduction is anisotropic for coordinated contractions, hESC-derived CM (hESC-CM) clusters are heterogenous and randomly organized, and therefore not representative of native conditions. Here, we reported that engineered alignment of hESC-VCMs on biomimetic grooves uniquely led to physiologically relevant responses. Aligned but not isotropic control preparations showed distinct longitudinal (L) and transverse (T) conduction velocities (CV), resembling the native human V anisotropic ratio (AR = LCV/TCV = 1.8-2.0). Importantly, the total incidence of spontaneous and inducible arrhythmias significantly reduced from 57% in controls to 17-23% of aligned preparations, thereby providing a physiological baseline for assessing arrhythmogenicity. As such, promotion of pro-arrhythmic effect (e.g., spatial dispersion by β adrenergic stimulation) could be better predicted. Mechanistically, such anisotropy-induced electrical stability was not due to maturation of the cellular properties of hESC-VCMs but their physical arrangement. In conclusion, not only do functional anisotropic hESC-VCMs engineered by multi-scale topography represent a more accurate model for efficacious drug discovery and development as well as arrhythmogenicity screening (of pharmacological and genetic factors), but our approach may also lead to future transplantable prototypes with improved efficacy and safety against arrhythmias. 23643588 Anti-hypertrophic and anti-oxidant effect of beta3-adrenergic stimulation in myocytes requires differential neuronal NOS phosphorylation. Stimulation of β3-adrenoreceptors (β3-AR) blunts contractility and improves chronic left ventricular function in hypertrophied and failing hearts in a neuronal nitric oxide synthase (nNOS) dependent manner. nNOS can be regulated by post-translational modification of stimulatory phosphorylation residue Ser1412 and inhibitory residue Ser847. However, the role of phosphorylation of these residues in cardiomyocytes and β3-AR protective signaling has yet to be explored. We tested the hypothesis that β3-AR regulation of myocyte stress requires changes in nNOS activation mediated by differential nNOS phosphorylation. Endothelin (ET-1) or norepinephrine induced hypertrophy in rat neonatal ventricular cardiomyocytes (NRVMs) was accompanied by increased β3-AR gene expression. Co-administration of the β3-AR agonist BRL-37433 (BRL) reduced cell size and reactive oxygen species (ROS) generation, while augmenting NOS activity. BRL-dependent augmentation of NOS activity and ROS suppression due to NE were blocked by inhibiting nNOS (L-VNIO). BRL augmented nNOS phosphorylation at Ser1412 and dephosphorylation at Ser847. Cells expressing constitutively dephosphorylated Ser1412A or phosphorylated Ser847D nNOS mutants displayed reduced nNOS activity and a lack of BRL modulation. BRL also failed to depress ROS from NE in cells with nNOS-Ser847D. Inhibiting Akt decreased BRL-induced nNOS-Ser1412 phosphorylation and NOS activation, whereas Gi/o blockade blocked BRL-regulation of both post-translational modifications, preventing enhancement of NOS activity and ROS reduction. BRL resulted in near complete dephosphorylation of Ser847 and a moderate rise in Ser1412 phosphorylation in mouse myocardium exposed to chronic pressure-overload. β3-AR regulates myocardial NOS activity and ROS via activation of nNOS involving reciprocal changes in phosphorylation at two regulatory sites. These data identify a novel and potent anti-oxidant and anti-hypertrophic pathway due to nNOS post-translational modification that is coupled to β3-AR receptor stimulation. 23867861 Symptomatic abdominal aortic aneurysm repair: to wait or not to wait. Aim: In patients with a symptomatic abdominal aortic aneurysm (sAAA), acute intervention theoretically reduces rupture risk prior to surgery whereas delayed intervention provides surgery under optimised conditions. In the present study we evaluated differences in 30-day mortality in patients with a sAAA operated within 12 hours compared to patients who received treatment after 12 hours and who were optimised for surgery. Methods: All patients with a sAAA who were treated within one week after presentation were included in the analyses. The 30-day mortality rates of patients operated within 12 hours were compared to those operated after 12 hours, adjusted for type of operation and for all potential confounders. Results: Of the 89 included patients, 37 patients received surgery within 12 hours. In patients treated within 12 hours, 30-day mortality rate was 6 (16.2%) compared to 3 (5.8%) in patients treated after 12 hours (odds ratio 0.316; CI 0.074-1.358). When adjusted for type of operation and other confounders, odds ratios were 0.305 (CI 0.066-1.405) and 0.270 (CI 0.015-4.836), respectively. Conclusion: In a substantial amount of patients with an alleged symptomatic AAA, delayed surgery with patient optimisation might be justified. However, specific criteria in order to select patients that might benefit from delayed surgery need further investigation. 23266450 Combined delivery of BMP-2 and bFGF from nanostructured colloidal gelatin gels and its effect on bone regeneration in vivo. During the process of bone regeneration, a multitude of morphogenetic signaling factors regulate cellular behavior and ultimately tissue response. These factors are presented to cells under strong spatial and temporal control, which stresses the relevance of controlled delivery of multiple growth factors for bone tissue regeneration. This demand for biomimetic delivery has prompted the development of a novel generation of biomaterials that is capable of delivering multiple growth factors in a controlled manner. Therefore, the current study has exploited the strong capacity of colloidal gels solely made of oppositely charged gelatin nanospheres to obtain controlled release of angiogenic and osteogenic growth factors. The release kinetics of dual delivery of osteogenic bone morphogenetic protein-2 (BMP-2) and angiogenic basic fibroblast growth factor (bFGF) were investigated in vitro by radiolabeling the respective growth factors and monitoring their release in vitro. Furthermore, the effect of single or dual delivery of BMP-2 and bFGF on bone regeneration was evaluated in vivo using a rat femoral condyle defect model. The in vitro results confirmed that the delivery kinetics of BMP-2 and/or bFGF are more dependent on the degree of crosslinking than on the type of gelatin. Sequential release characterized by rapid release of angiogenic bFGF and more sustained release of BMP-2 was obtained by loading bFGF onto cationic nanospheres of low crosslinking density and BMP-2 onto anionic nanospheres of high crosslinking density. The in vivo study demonstrated the biocompatibility and biodegradability of bare colloidal gelatin gels, and did not show any adverse effects on the process of bone healing after 4 week of implantation since the volumes of new bone formation were comparable to empty control defects. An obvious stimulatory effect on bone regeneration was observed for the colloidal gels loaded with BMP-2, whereas bFGF-loaded colloidal gelatin gels did not influence the rate of bone regeneration. In contrast, the combined delivery of BMP-2 and bFGF resulted into an inhibitory effect on osteogenesis under the current experimental conditions. Summarizing, the current study proved that nanostructured colloidal gelatin gels are suitable carriers for programmed and sustained release of multiple therapeutic proteins for tissue regeneration. 23742695 Differential expression of mitogen activating protein kinases in periodontitis. Following toll-like receptor (TLR) engagement, lipopolysaccharide (LPS) can stimulate the expression of pro-inflammatory cytokines thus activating the innate immune response. The production of inflammatory cytokines results, in part, from the activation of kinase-induced signalling cascades and transcriptional factors. Of the four distinct classes of mitogen-activated protein kinases (MAPK) described in mammals, p38, c-Jun N-terminal activated kinases (JNK1-3) and extracellular activated kinases (ERK1,2) are the best studied. Previous data have established that p38 MAPK signalling is required for inflammation and bone loss in periodontal disease pre-clinical animal models. In this study, we obtained healthy and diseased periodontal tissues along with clinical parameters and microbiological parameters. Excised fixed tissues were immunostained with total and phospho-specific antibodies against p38, JNK and ERK kinases. Intensity scoring from immunostained tissues was correlated with clinical periodontal parameters. Rank correlations with clinical indices were statistically significantly positive (p-value < 0.05) for total p38 (correlations ranging 0.49-0.68), phospho-p38 (range 0.44-0.56), and total ERK (range 0.52-0.59) levels, and correlations with JNK levels also supported association (range 0.42-0.59). Phospho-JNK and phospho-ERK showed no significant positive correlation with clinical parameters of disease. These data strongly implicate p38 MAPK as a major MAPK involved in human periodontal inflammation and severity. 23905572 Depression following myocardial infarction. Myocardial infarction (MI) is a severe life event that is accompanied by an increased risk of depression. Mounting evidence suggests that post-MI depression is associated with adverse outcomes, but the underlying mechanisms of this association remain unclear, and no previous studies have examined whether the mental burden of MI is so heavy that it increases the risk of suicide. Although post-MI depression is common and burdensome, the condition remains under-recognised and under-treated. The development of new strategies to improve the quality of care for people with post-MI depression requires thorough understanding of the mechanisms that influence the prognosis as well as knowledge of the present care provided. The purpose of this PhD thesis is accordingly subdivided into four specific aims: 1. To estimate the prevalence of depression in people with MI after three months, and to estimate the provided hospital-based psychosocial rehabilitation (Paper I); 2. To examine GPs' practice of screening for depression in people with MI, and to analyse whether the screening rate varied among subgroups of people with a particularly high risk of post-MI depression (Paper II); 3. To examine the association between post-MI depression and new cardiovascular events or death, taking potential mediators into account (Paper III); 4. To examine the association between MI and suicide (Paper IV). Two different study designs were employed: a population-based cohort study using data obtained from registers and questionnaires sent to MI patients and their GPs (Paper I-III); a nationwide population-based matched case-control study using data obtained from registers (Paper IV). Three months after having suffered MI, about one fifth of the patients in our study had depression according to the Hospital Anxiety and Depression Scale (HADS). Upwards of half of the patients had participated in some rehabilitation, thirty per cent had participated in psychosocial support and three per cent reported that they had been examined for depression by questionnaire during the hospital-based rehabilitation. The rate of participation in psychosocial support and examination for depression was the same for patients with or without depression at three months following MI. A good fourth of the patients' GPs stated that they had screened the patient for depression within the first year after the patient suffered an MI. Three months after the MI, the screening rate was higher among patients with a history of mental illness and among patients with anxiety or depression than among patients without these conditions. Most of the GPs who performed screening followed guidelines by asking about specific depressive symptoms. According to the HADS, depression three months after MI was associated with an increased risk of a new cardiovascular event or death. This association was partly explained by the underlying cardiac disease severity and physical inactivity, but depression remained an independent prognostic risk factor after adjusting for these potential confounders. We found a tendency towards a weaker association with increasing physical activity and among users of antidepressants. MI was strongly associated with an increased risk of suicide. This risk was particularly high immediately after the MI, but remained high for more than five years after the MI. The association between MI and suicide remained stable throughout the study period (1981-2006), although many other factors changed (e.g. suicide rate, treatment of MI). 23935581 HDDM: Hierarchical Bayesian estimation of the Drift-Diffusion Model in Python. The diffusion model is a commonly used tool to infer latent psychological processes underlying decision-making, and to link them to neural mechanisms based on response times. Although efficient open source software has been made available to quantitatively fit the model to data, current estimation methods require an abundance of response time measurements to recover meaningful parameters, and only provide point estimates of each parameter. In contrast, hierarchical Bayesian parameter estimation methods are useful for enhancing statistical power, allowing for simultaneous estimation of individual subject parameters and the group distribution that they are drawn from, while also providing measures of uncertainty in these parameters in the posterior distribution. Here, we present a novel Python-based toolbox called HDDM (hierarchical drift diffusion model), which allows fast and flexible estimation of the the drift-diffusion model and the related linear ballistic accumulator model. HDDM requires fewer data per subject/condition than non-hierarchical methods, allows for full Bayesian data analysis, and can handle outliers in the data. Finally, HDDM supports the estimation of how trial-by-trial measurements (e.g., fMRI) influence decision-making parameters. This paper will first describe the theoretical background of the drift diffusion model and Bayesian inference. We then illustrate usage of the toolbox on a real-world data set from our lab. Finally, parameter recovery studies show that HDDM beats alternative fitting methods like the χ(2)-quantile method as well as maximum likelihood estimation. The software and documentation can be downloaded at: http://ski.clps.brown.edu/hddm_docs/ 23929358 Unprecedented infinite lanthanide hydroxide ribbons [Ln3(μ3-OH)3]n(6n+) in a 3-D metal-organic framework. Unprecedented infinite lanthanide hydroxide ribbons interconnected by Pra2biim(2-) (H2Pra2biim = 1'-di(propionic acid)-2,2'-biimidazole) into 3-D [Ln3(μ3-OH)3(Pra2biim)3 (H2O)2]n·4nH2O (Ln = Nd, Pr and La) have been achieved by utilizing the unique H2Pra2biim-Ln(3+) hydrolysis system. The LnLn antiferromagnetic coupling with magnetic anisotropy has been observed. 23493958 Fabrication and multifunction integration of microfluidic chips by femtosecond laser direct writing. In the pursuit of modern microfluidic chips with multifunction integration, micronanofabrication techniques play an increasingly important role. Despite the fact that conventional fabrication approaches such as lithography, imprinting and soft lithography have been widely used for the preparation of microfluidic chips, it is still challenging to achieve complex microfluidic chips with multifunction integration. Therefore, novel micronanofabrication approaches that could be used to achieve this end are highly desired. As a powerful 3D processing tool, femtosecond laser fabrication shows great potential to endow general microfluidic chips with multifunctional units. In this review, we briefly introduce the fundamental principles of femtosecond laser micronanofabrication. With the help of laser techniques, both the preparation and functionalization of advanced microfluidic chips are summarized. Finally, the current challenges and future perspective of this dynamic field are discussed based on our own opinion. 23852041 Deformation field validation and inversion applied to adaptive radiation therapy. Development and implementation of chronological and anti-chronological adaptive dose accumulation strategies in adaptive intensity-modulated radiation therapy (IMRT) for head-and-neck cancer. An algorithm based on Newton iterations was implemented to efficiently compute inverse deformation fields (DFs). Four verification steps were performed to ensure a valid dose propagation: intra-cell folding detection finds zero or negative Jacobian determinants in the input DF; inter-cell folding detection is implemented on the resolution of the output DF; a region growing algorithm detects undefined values in the output DF; DF domains can be composed and displayed on the CT data. In 2011, one patient with nonmetastatic head and neck cancer selected from a three phase adaptive DPBN study was used to illustrate the algorithms implemented for adaptive chronological and anti-chronological dose accumulation. The patient received three (18)F-FDG-PET/CTs prior to each treatment phase and one CT after finalizing treatment. Contour propagation and DF generation between two consecutive CTs was performed in Atlas-based autosegmentation (ABAS). Deformable image registration based dose accumulations were performed on CT1 and CT4. Dose propagation was done using combinations of DFs or their inversions. We have implemented a chronological and anti-chronological dose accumulation algorithm based on DF inversion. Algorithms were designed and implemented to detect cell folding. 23428655 Emerging roles of actin cytoskeleton regulating enzymes in drug addiction: actin or reactin'? Neurons rely on their cytoskeleton to give them shape and stability, and on cytoskeletal dynamics for growth and synaptic plasticity. Because drug addiction is increasingly seen as the inappropriate learning of strongly reinforcing stimuli, the role of the cytoskeleton in shaping drug memories has been of increasing interest in recent years. Does the cytoskeleton have an active role in shaping these memories, and to what extent do alterations in the cytoskeleton reflect the acute actions of drug exposure, or homeostatic reactions to the chronic exposure to drugs of abuse? Here we will review recent advances in understanding the role of the cytoskeleton in the development of drug addiction, with a focus on actin filaments, as they have been studied in greater detail. 23183423 Dynamics of silver nanoparticle formation and agglomeration inside the cavitation bubble after pulsed laser ablation in liquid. The formation of nanoparticles within the laser-induced cavitation bubble is studied in situ using small angle X-ray scattering with high spatiotemporal resolution. Directly after laser ablation, two different particle fractions consisting of compact primary particles of 8-10 nm size and agglomerates of 40-60 nm size are formed. The abundance of these species is strongly influenced by the dynamics of the oscillating cavitation bubble. Primary particle mass is most abundant during maximal expansion of the first bubble and reappears a little weaker in the rebound. In contrast to this, the mass abundance of agglomerates is relatively low in the first bubble but strongly increases during first bubble collapse and following rebound. Although most of the ablated material is trapped inside the bubble and follows its oscillation, a minor fraction of both species could be detected outside the cavitation bubble even before its final collapse. 23928723 Characterization of two naturally truncated, Ssb-like proteins from the nitrogen-fixing cyanobacterium, Anabaena sp. PCC7120. Single-stranded (ss) DNA-binding (Ssb) proteins are vital for all DNA metabolic processes and are characterized by an N-terminal OB-fold followed by P/G-rich spacer region and a C-terminal tail. In the genome of the heterocystous, nitrogen-fixing cyanobacterium, Anabaena sp. strain PCC 7120, two genes alr0088 and alr7579 are annotated as ssb, but the corresponding proteins have only the N-terminal OB-fold and no P/G-rich region or acidic tail, thereby rendering them unable to interact with genome maintenance proteins. Both the proteins were expressed under normal growth conditions in Anabaena PCC7120 and regulated differentially under abiotic stresses which induce DNA damage, indicating that these are functional genes. Constitutive overexpression of Alr0088 in Anabaena enhanced the tolerance to DNA-damaging stresses which caused formation of DNA adducts such as UV and MitomycinC, but significantly decreased the tolerance to γ-irradiation, which causes single- and double-stranded DNA breaks. On the other hand, overexpression of Alr7579 had no significant effect on normal growth or stress tolerance of Anabaena. Thus, of the two truncated Ssb-like proteins, Alr0088 may be involved in protection of ssDNA from damage, but due to the absence of acidic tail, it may not aid in repair of damaged DNA. These two proteins are present across cyanobacterial genera and unique to them. These initial studies pave the way to the understanding of DNA repair in cyanobacteria, which is not very well documented. 23891821 Characterization of 10 MADS-box genes from Pyrus pyrifolia and their differential expression during fruit development and ripening. We cloned 10 Japanese pear (Pyrus pyrifolia) MIKC-type II MADS-box genes, and analyzed their expression during fruit development and ripening. PpMADS2-1 was APETALA (AP)1-like; PpMADS3-1 was FRUITFULL (FUL)/SQUAMOSA (SQUA)-like; PpMADS4-1 was AGAMOUS-like (AGL)6; PpMADS5-1 and PpMADS8-1 were SUPPRESSOR OF OVEREXPRESSION OF CONSTANS (SOC)-like; PpMADS9-1, PpMADS12-1, PpMADS14-1 and PpMADS16-1 were SEPALLATA (SEP)-like; while PpMADS15-1 was AGL/SHATTERPROOF (SHP)-like. Phylogenetic analysis showed their grouping into five major clades (and 10 sub-clades) that was consistent with their diverse functional types. Expression analysis in flower tissue revealed their distinct putative homeotic functional classes: A-class (PpMADS2-1, PpMADS3-1, PpMADS4-1, and PpMADS14-1), C-class (PpMADS15-1), E-class (PpMADS9-1, PpMADS12-1, and PpMADS16-1) and E (F)-class (PpMADS5-1 and PpMADS8-1). Differential gene expression was observed in different fruit tissues (skin, cortex and core) as well as in the cortex during the course of fruit development and ripening. Collectively, our results suggest their involvement in the diverse aspects of plant development including flower development and the course of fruit development and ripening. 23917877 Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century. Cancer is a heterogeneous disease manifest in many forms. Tumor histopathology can differ significantly among patients and cellular heterogeneity within tumors is common. A primary goal of cancer biologists is to better understand tumorigenesis and cancer progression; however, the complex nature of tumors has posed a substantial challenge to unlocking cancer's secrets. The cancer stem cell (CSC) paradigm for the pathobiology of solid tumors appropriately acknowledges phenotypic and functional tumor cell heterogeneity observed in solid tumors and accounts for the disconnect between drug approval based on response and the general inability of approved therapies to meaningfully impact survival due to their failure to eradicate these most important of cellular targets. First proposed to exist decades ago, CSC have only recently begun to be precisely identified due to technical advancements that facilitate identification, isolation, and interrogation of distinct tumor cell subpopulations with differing ability to form and perpetuate tumors. Precise identification of CSC populations and the complete hierarchy of cells within solid tumors will facilitate more accurate characterization of patient subtypes and ultimately contribute to more personalized and effective therapies. Rapid advancement in the understanding of tumor biology as it exists in patients requires cooperation among institutions, surgeons, pathologists, cancer biologists and patients alike, primarily because this translational research is best done with patient-derived tissue grown in the xenograft setting as patient-derived xenografts. This review calls for a broader change in the approaches taken to study cancer pathobiology, highlights what implications the CSC paradigm has for pathologists and cancer biologists alike, and calls for greater collaboration between institutions, physicians and scientists in order to more rapidly advance our collective understanding of cancer.Laboratory Investigation advance online publication, 5 August 2013; doi:10.1038/labinvest.2013.92. 23456506 Expression of fibroblast growth factor 19 is associated with recurrence and poor prognosis of hepatocellular carcinoma. Fibroblast growth factor 19 (FGF19)-mediated activation of mitogen-activated protein kinase and the β-catenin pathway may be involved in the development and progression of hepatocellular carcinoma. This study aimed to elucidate the prognostic significance of FGF19 protein expression in hepatocellular carcinoma patients. By immunohistochemistry, we investigated the expression of FGF19 protein in tumor tissue from 281 hepatocellular carcinoma patients who underwent curative hepatectomy. Univariate and multivariate analyses were performed to evaluate its predictive value for tumor recurrence and survival of patients. The median follow-up period was 75.6 months. FGF19 protein expression was observed in 135 (48.0 %) of the 281 hepatocellular carcinomas. FGF19 expression was significantly associated with larger tumor size (P < 0.001), and higher BCLC stage (P = 0.001). FGF19 expression was correlated with the early recurrence (P < 0.001), but not with the late recurrence (P = 0.582). FGF19 expression (P = 0.002), viral etiology (P = 0.028), and intrahepatic metastasis (P < 0.001) were independent predictors of early recurrence. Multivariate analyses of survival revealed that FGF19 expression (P < 0.001), intrahepatic metastasis (P < 0.001), and liver cirrhosis (P = 0.019) were independent predictors of shorter disease-free survival. FGF19 expression (P = 0.005), larger tumor size (P = 0.038), major portal vein invasion (P = 0.048), intrahepatic metastasis (P < 0.001), lower albumin level (P = 0.024), and liver cirrhosis (P = 0.031) were independent predictors of shorter disease-specific survival. FGF19 protein expression might be an effective predictor of early recurrence and a marker for poor prognosis of hepatocellular carcinoma after curative hepatectomy, indicating that FGF19 might be a potential preventive target in hepatocellular carcinoma patients. 23891657 Corticosterone mediated costs of reproduction link current to future breeding. Life-history theory predicts that costs are associated with reproduction. One possible mediator of costs involves the secretion of glucocorticoid hormones, which in birds can be measured in feathers grown during the breeding period. Glucocorticoids mediate physiological responses to unpredictable environmental or other stressors, but they can also function as metabolic regulators during more predictable events such as reproduction. Here we show that corticosterone ("Cort") in feathers grown during the breeding season reflects reproductive effort in two Antarctic seabird species (giant petrels, Macronectes spp.). In females of both species, but not males, feather Cort ("fCort") was nearly 1.5-fold higher in successful than failed breeders (those that lost their eggs/chicks), suggesting a cost of successful reproduction, i.e., high fCort levels in females reflect the elevated plasma Cort levels required to support high metabolic demands of chick-rearing. Successful breeding also led to delayed moult prior to winter migration. The fCort levels and pre-migration moult score that we measured at the end of current breeding were predictive of subsequent reproductive effort in the following year. Birds with high fCort and a delayed initiation of moult were much more likely to defer breeding in the following year. Cort levels and the timing of moult thus provide a potential mechanism for the tradeoff between current and future reproduction. 23845029 Transportation Conditions for Prompt Use of Ex Vivo Expanded and Freshly Harvested Clinical-Grade Bone Marrow Mesenchymal Stromal/Stem Cells for Bone Regeneration. Successful preliminary studies have encouraged a more translational phase for stem cell research. Nevertheless, advances in the culture of human bone marrow-derived mesenchymal stromal/stem cells (hBM-MSC) and osteoconductive qualities of combined biomaterials can be undermined if necessary cell transportation procedures prove unviable. We aimed at evaluating the effect of transportation conditions on cell function, including the ability to form bone in vivo, using procedures suited to clinical application. hBM-MSC expanded in current Good Manufacturing Practice (cGMP) facilities (cGMP-hBM-MSC) to numbers suitable for therapy were transported overnight within syringes and subsequently tested for viability. Scaled-down experiments mimicking shipment for 18 h at 4°C tested the influence of three different clinical-grade transportation buffers (0.9% saline alone or with 4% human serum albumin [HSA] from two independent sources) compared with cell maintenance medium. Cell viability after shipment was >80% in all cases, enabling evaluation of (1) adhesion to plastic flasks and hydroxyapatite tricalcium phosphate osteoconductive biomaterial (HA/β-TCP 3D scaffold); (2) proliferation rate; (3) ex vivo osteogenic differentiation in contexts of 2D monolayers on plastic and 3D HA/β-TCP scaffolds; and (4) in vivo ectopic bone formation after subcutaneous implantation of cells with HA/β-TCP scaffold into NOD/SCID mice. Von Kossa staining was used to assess ex vivo osteogenic differentiation in 3D cultures, providing a quantifiable test of 3D biomineralization ex vivo as a rapid, cost-effective potency assay. Near-equivalent capacities for cell survival, proliferation, and osteogenic differentiation were found for all transportation buffers. Moreover, cGMP-hBM-MSC transported from a production facility under clinical-grade conditions of 4% HSA in 0.9% saline to a destination 18 h away showed prompt adhesion to HA/β-TCP 3D scaffold and subsequent in vivo bone formation. A successfully validated transportation protocol extends the applicability of fresh stem cells involving multicentric trials for regenerative medicine. 23588057 An extracorporeal membrane oxygenation cannulation curriculum featuring a novel integrated skills trainer leads to improved performance among pediatric cardiac surgery trainees. American Heart Association guidelines recommend timely extracorporeal membrane oxygenation (ECMO) cannulation during cardiopulmonary resuscitation for pediatric cardiac arrest refractory to conventional resuscitation. Traditional cannulation training relies on the apprenticeship model. We hypothesized that a simulation-based ECMO cannulation curriculum featuring a novel integrated skills trainer would improve ECMO cannulation during cardiopulmonary resuscitation performance by cardiothoracic surgery trainees. An embedded surgical neck cannulation trainer, designed in collaboration with expert surgeons, formed the focus for a simulation-based cannulation curriculum. The course included a didactic presentation and 2 neck cannulations during cardiopulmonary resuscitation with video-assisted expert feedback with a further cannulation at 3 months. Primary outcome was time to cannulation on the trainer. Secondary outcomes were performance on a validated Global Rating Scale (GRS) of surgical technique and a novel Composite ECMO Cannulation Score (CECS). Ten cardiothoracic surgery trainees participated. The trainer was rated as authentic, and sessions was rated as highly useful. Median time to cannulation decreased between cannulation 1 and 2 (15 minutes 24 seconds vs. 12 minutes 15 seconds, P = 0.002). Improvement was sustained at 3 months (13 minutes 36 seconds, P = 0.157 vs. attempt 2). Likewise, GRS increased significantly at attempt 2 versus 1 (77% vs. 62%, P = 0.003) as did CECS (88% vs. 52%, P = 0.002). No deterioration in GRS or CECS was measured at 3 months. Cardiothoracic surgery trainees found a contextualized ECMO cannulation during cardiopulmonary resuscitation cannulation curriculum to be highly useful and demonstrated sustained improvement in time to cannulation, CECS, and GRS. Further work will focus on determining the clinical impact of this training and defining the optimal interval and number of training sessions. 23888874 The anticancer drug tirapazamine has antimicrobial activity against Escherichia coli, Staphylococcus aureus and Clostridium difficile. Rapidly increasing bacterial resistance to existing therapies creates an urgent need for the development of new antibacterials. Tirapazamine (TPZ, 3-amino-1,2,4-benzotriazine 1,4 dioxide) is a prodrug undergoing clinical trials for various types of cancers. In this study, we showed that TPZ has antibacterial activity, particularly at low oxygen levels. With Escherichia coli, TPZ was bactericidal under both aerobic and anaerobic conditions. Escherichia coli mutants deficient in homologous recombination were hypersusceptible to TPZ, suggesting that drug toxicity may be due to DNA damage. Moreover, E. coli strains deleted for genes encoding putative reductases were resistant to TPZ, implying that these enzymes are responsible for conversion of the prodrug to a toxic compound. Fluoroquinolone-resistant E. coli strains were as susceptible to TPZ as a wild-type strain. Methicillin-resistant Staphylococcus aureus strains were also susceptible to TPZ (MIC = 0.5 Î¼g mL(-1) ), as were pathogenic strains of Clostridium difficile (MIC = 7.5 ng mL(-1) ). TPZ may merit additional study as a broad-spectrum antibacterial, particularly for anaerobes. 23865788 A Critical Evaluation of the Evidence for Ovarian Conservation Versus Removal at the Time of Hysterectomy for Benign Disease. Abstract Background: Women undergoing hysterectomy for benign disease are presented with the choice of ovarian conservation or removal. The beneficial effect on ovarian cancer must be weighed against the risks of ovarian hormone withdrawal. Wide variations in practice patterns exist. Methods: The purpose of this review article is to summarize and critically evaluate the existing primary evidence regarding the impact of adnexal conservation versus removal on the specific health issues of ovarian cancer, coronary heart disease (CHD), sexual and cognitive function, and osteoporotic hip fractures. Results: Elective bilateral salpingo-oophorectomy (BSO) in women under 50 years is associated with an increased risk of CHD and sexual dysfunction. In women older than 50 years, there is no observed association between BSO and CHD, sexual dysfunction, osteoporotic hip fractures, or cognitive function. Oophorectomy is associated with a lower risk of death from ovarian cancer. Conclusion: Elective BSO should be discouraged in women under 50 years old. In postmenopausal women, however, BSO can reduce ovarian cancer rates without an adverse impact on CHD, sexual dysfunction, hip fractures, or cognitive function. 23860300 Overlap of Diseases Underlying Ischemic Stroke: The ASCOD Phenotyping. ASCOD phenotyping (A, atherosclerosis; S, small vessel disease; C, cardiac pathology; O, other causes; and D, dissection) assigns a degree of likelihood to every potential cause (1 for potentially causal, 2 for causality is uncertain, 3 for unlikely causal but disease is present, 0 for absence of disease, and 9 for insufficient workup to rule out the disease) commonly encountered in ischemic stroke. We used ASCOD to investigate the overlap of underlying vascular diseases and their prognostic implication. A single rater applied ASCOD in 405 patients enrolled in the Asymptomatic Myocardial Ischemia in Stroke and Atherosclerotic Disease study. A was present in 90% of patients (A1=43% and A2=15%), C in 52% (C1=23% and C2=14%), and S in 66% (S1=11% and S2=2%). On the basis of grades 1 and 2, 25% of patients had multiple underlying diseases, and 80% when all 3 grades were considered. The main overlap was found between A and C; among C1 patients, A was present in 92% of cases (A1=28%, A2=20%, and A3=44%). Conversely, among A1 patients, C was present in 47% of cases (C1=15%, C2=15%, and C3=17%). Grades for C were associated with gradual increase in the 3-year risk of vascular events, whereas risks were similar across A grades, meaning that the mere presence of atherosclerotic disease qualifies for high risk, regardless the degree of likelihood for A. ASCOD phenotyping shows that the large overlap among the 3 main diseases, and the high prevalence of any form of atherosclerotic disease, reinforces the need to systematically control atherosclerotic risk factors in all ischemic strokes. 23582108 Computed Tomography Angiography in the Diagnosis of ANCA-Associated Small- and Medium-Vessel Vasculitis. Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that typically occurs without detectable antineutrophil cytoplasmic antibody. It leads to aneurysm formation by affecting muscular arteries, usually those of medium size but also occasionally those of small size. Kidney involvement is common, leading to reduced glomerular filtration rate, hypertension, rupture of renal arterial aneurysms causing perinephric hematomas, and renal infarctions in those with severe vasculitis. Similar to PAN, microscopic polyangiitis (MPA) leads to aneurysm formation; however, MPA usually is associated with antineutrophil cytoplasmic antibody, and glomerulonephritis is a more common feature of MPA. Although kidney biopsy may show classic vascular changes in both PAN and MPA, this procedure is not without risk of significant bleeding due to aneurysm rupture. We present 2 cases of renal aneurysms that were diagnosed as MPA using computed tomography angiography (CTA), allowing implementation of appropriate immunosuppressive therapy. Follow-up CTA after treatment showed resolution of all previously observed abnormalities. CTA is a useful alternative to kidney biopsy in establishing both the extent of disease in renal aneurysms and allowing for tracking of disease progression and response to therapy. 23954271 Domestic cat microsphere immunoassays: Detection of antibodies during feline immunodeficiency virus infection. Microsphere immunoassays (MIAs) allow rapid and accurate evaluation of multiple analytes simultaneously within a biological sample. Here we describe the development and validation of domestic cat-specific MIAs for a) the quantification of total IgG and IgA levels in plasma, and b) the detection of IgG and IgA antibodies to feline immunodeficiency virus (FIV) capsid (CA) and surface (SU) proteins, and feline CD134 in plasma. These assays were used to examine the temporal antibody response of domestic cats infected with apathogenic and pathogenic FIVs, and domestic cats infected with parental and chimeric FIVs of varying pathogenicity. The results from these studies demonstrated that a) total IgG antibodies increase over time after infection; b) α-CA and α-SU IgG antibodies are detectable between 9 and 28days post-infection and increase over time, and these antibodies combined represent a fraction (1.8 to 21.8%) of the total IgG increase due to infection; c) measurable α-CD134 IgG antibody levels vary among individuals and over time, and are not strongly correlated with viral load; d) circulating IgA antibodies, in general, do not increase during the early stage of infection; and e) total IgG, and α-CA and α-SU IgG antibody kinetics and levels vary with FIV viral strain/pathogenicity. The MIAs described here could be used to screen domestic cats for FIV infection, and to evaluate the FIV-specific or total antibody response elicited by various FIV strains/other diseases. 23970169 Both Chronic Kidney Disease and Nocturnal Blood Pressure Associate with Strokes in the Elderly. Background: Among elderly hypertensive patients, we aimed to assess the association of nocturnal blood pressure (BP) pattern on stroke; interaction of dipping pattern with kidney disease was explored. Methods: We retrospectively analyzed the records of 1,276 elderly (≥60 years) hypertensive Japanese patients (mean 74 years; 40% were men) who had measurements of estimated glomerular filtration rate and ambulatory BP. Results: Stroke events occurred in 73 people over an average of 3.2 years (4,026 person-years). Chronic kidney disease (CKD) at baseline (n = 634, 50%) was more prevalent in people with strokes (71%) than those without strokes (48%; p < 0.01). Both CKD and nocturnal systolic BP (SBP) increase (10 mm Hg) were independently associated with increased risk for stroke [hazard ratio (HR), 1.9; 95% confidence interval (CI), 1.1-3.1 for CKD and HR 1.2; 1.1-1.4 for SBP]. After adjustment for office SBP, a 10-mm Hg increase in nocturnal SBP was similarly associated with strokes in patients with CKD (HR 1.2; 95% CI 1.0-1.3) and those without CKD (HR 1.2; 95% CI 0.97-1.5). Although reverse dipping (nocturnal SBP ≥ daytime SBP) was associated with stroke only in patients with CKD (HR 2.1; 95% CI 1.1-4.1) and not those without CKD (HR 1.1; 95% CI 0.3-3.8), the interaction effect was not significant (p = 0.30). Conclusion: In elderly hypertensive patients, both high nocturnal SBP and CKD are independent risk factors for stroke. © 2013 S. Karger AG, Basel. 23893199 Exploiting jump-resonance hysteresis in silicon auditory front-ends for extracting speaker discriminative formant trajectories. Jump-resonance is a phenomenon observed in non-linear circuits where the amplitude of the output signal exhibits an abrupt jump when the frequency of the input signal is varied. For [Formula: see text] filters used in the design of analog auditory front-ends (AFEs), jump-resonance is generally considered to be undesirable and several techniques have been proposed in literature to avoid or alleviate this artifact. In this paper we explore the use of jump-resonance based hysteresis in [Formula: see text] band-pass filters for encoding speech formant trajectories. Using prototypes of silicon AFEs fabricated in a 0.5 μm CMOS process, we demonstrate the benefits of the proposed approach for extracting speaker discriminative features. These benefits are validated using speaker recognition experiments where consistent improvements in equal-error-rates (EERs) are achieved using the jump-resonance based features as compared to conventional features. 23964670 The Influence of Complementary and Alternative Medicine Use in Pregnancy on Labor Pain Management Choices: Results from a Nationally Representative Sample of 1,835 Women. Abstract Objectives: This study examines involvement with a range of complementary and alternative medicine (CAM) during pregnancy on the use of pharmacologic (PPMT) and nonpharmacologic (NPMT) pain management techniques for labor and birth. Design: Longitudinal analysis of survey data. Participants: A substudy (n=2445) of the "young" cohort of the nationally representative Australian Longitudinal Study on Women's Health was conducted. Outcome measures: Use of PPMT and NPMT during labor and birth. Results: The survey was completed by 1835 women (response rate, 79.2%). Most respondents used either intrapartum PPMT (81.9%) or NPMT (74.4%). Many (60.7%) used some form of CAM during pregnancy and also used PPMT during birth. More than two thirds of women (66.7%) who used NPMT used CAM during pregnancy. There was a general trend of increased likelihood of NPMT use by women who applied CAM during pregnancy. There was an inverse effect on use of epidural analgesia for women who consumed herbal teas during pregnancy (odds ratio, 0.60). Conclusions: Because of the study design, this paper does not confirm a causative relationship between the use of CAM during pregnancy and intrapartum pain management choices. It does, however, indicate that the use of CAM during pregnancy may not significantly affect the uptake of intrapartum PPMT, despite possible attempts to reduce PPMT by using NPMT. It also highlights the possibility of potential interactions between CAM and PPMT, given the high prevalence of concomitant use. 23023819 A path analysis of the variables related to the quality of life of mothers with disabled children in Korea. This study examines how different variables affect the quality of life of mothers of children with disabilities. We attempted to identify the relationship between child variables (age and whether the child has single or multiple disabilities), economic variables (monthly income and average monthly treatment cost), mother-related variables (parenting stress) and social variables (social support) as predictors of the quality of life of mothers of children with disabilities, and the path along which these variables affect their quality of life. The dataset comprised 160 mothers of children with disabilities, who resided in Seoul city and Gyeonggi province. The participants answered questions related to their general information, quality of life, social support and parenting stress. The data were analysed using SPSS 17.0 and AMOS 16.0. We found that social support not only influences the quality of life through parenting stress but also is a direct factor. We also found that both whether a child had single or multiple disabilities and the average monthly treatment cost were significant factors that influenced the parent's quality of life indirectly through parenting stress. Moreover, we concluded that whereas the age of children with disabilities is only a direct impact on the mother's quality of life, monthly income has a direct influence on both parenting stress and quality of life separately, but it does not directly influence quality of life through parenting stress. In our opinion, this is the first study that has conducted a holistic analysis of the quality of life of Korean mothers of children with disabilities by considering a range of variables. Copyright © 2012 John Wiley & Sons, Ltd. 23949642 Effects of Cd, Zn and Cd + Zn Combination on ATPase Activitiy in the Gill and Muscle of Tilapia (Oreochromis niloticus). This study investigated the responses of Na(+)/K(+)-ATPase, Mg(2+)-ATPase and Ca(2+)-ATPase in the gill and muscle of a freshwater fish Oreochromis niloticus exposed to 1 Î¼g/mL of Cd and Zn and their mixture for different periods (0, 7, 14, 21 and 28 days). At the end of experimental periods, the activities Na(+)/K(+)-ATPase, Mg(2+)-ATPase and Ca(2+)-ATPase in gill tissues and only Ca(2+)-ATPase activity in muscle tissues were measured. Gill Na(+)/K(+)-ATPase activity generally decreased following single metal exposures, whereas their combinations increased its activity. Gill Ca(2+)-ATPase activity decreased relative to the control at most exposure times for single exposures of Zn and Cd, as well as for the combined exposure. There was no gill Ca(2+)-ATPase activity after 28 days of exposure to Zn and Cd combined. Mg(2+)-ATPase activity was not affected significantly in gill tissue by exposure to Zn and Cd individually or in combination. Muscle Ca(2+)-ATPase activity also decreased significantly following metal exposure, but not as greatly as in the gill tissue. Tissue protein levels were mostly unaffected by metal exposures. This study showed that certain ATPases are highly sensitive to metal exposure whether the metals are essential or non essential, and suggests using gill tissue Na(+)/K(+)-ATPase and Ca(2+)-ATPase as sensitive biomarkers in metal contaminated waters. 23927243 A variational method for density functional theory calculations on metallic systems with thousands of atoms. A new method for finite-temperature density functional theory calculations which significantly increases the number of atoms that can be simulated in metallic systems is presented. A self-consistent, direct minimization technique is used to obtain the Helmholtz free energy of the electronic system, described in terms of a set of non-orthogonal, localized functions which are optimized in situ using a periodic-sinc basis set, equivalent to plane waves. Most parts of the calculation, including the demanding operation of building the Hamiltonian matrix, have a computational cost that scales linearly with the number of atoms in the system. Also, this approach ensures that the Hamiltonian matrix has a minimal size, which reduces the computational overhead due to diagonalization, a cubic-scaling operation that is still required. Large basis set accuracy is retained via the optimization of the localized functions. This method allows accurate simulations of entire metallic nanostructures, demonstrated with calculations on a supercell of bulk copper with 500 atoms and on gold nanoparticles with up to 2057 atoms. 23902184 Former Mid Staffs nursing director denies 29 breaches of NMC code. The nursing director of Mid Staffordshire NHS Foundation Trust at the height of its troubles sought to defend her conduct last week. 23818530 ICD-11 should not repeat the mistakes made by DSM-5. Having two systems of psychiatric diagnosis creates unnecessary confusion therefore it would be desirable to achieve increased consistency between ICD-11 and DSM-5. Unfortunately, however, DSM-5 has included many controversial suggestions that have weak scientific support and insufficient risk-benefit analysis. As a result ICD-11 should learn from the DSM-5 mistakes rather than repeating them. 23582739 Missing marine protected area (MPA) targets: How the push for quantity over quality undermines sustainability and social justice. International targets for marine protected areas (MPAs) and networks of MPAs set by the World Summit on Sustainable Development and United Nations Convention on Biological Diversity failed to meet their 2012 deadline and have been extended to 2020. Whilst targets play an important role in building momentum for conservation, they are also responsible for the recent designation of several extremely large no-take MPAs, which pose significant long-term monitoring and enforcement challenges. This paper critically examines the effectiveness of MPA targets, focusing on the underlying risks to achieving Millennium Development Goals posed by the global push for quantity versus quality of MPAs. The observations outlined in this paper have repercussions for international protected area politics with respect to (1) the science-policy interface in environmental decision-making, and (2) social justice concerns in global biodiversity conservation. 23628351 The short- and long-term effects on the visual system of children following exposure to maternal substance misuse in pregnancy. To document the prevalence of ophthalmic morbidities in babies born to mothers who misused substances in pregnancy and to assess whether it changes over 5 years. Retrospective comparative case series. The series included: (1) a retrospective review of 301 children born between 2000 and 2004 to mothers misusing substances during pregnancy; (2) assessment at 5-year follow-up of this cohort; and (3) comparison with 7887 age-matched controls drawn from the preschool screening cohort in the north of Scotland in the same time period. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. Following data collection in both patient and control groups, the following were calculated: (1) rate of referral to the ophthalmology department; (2) prevalence of nystagmus and strabismus at presentation in the study group and at 5 years of age in both patient and control group; (3) prevalence of reduced visual acuity and lack of stereopsis. Ophthalmology referrals, strabismus, and nystagmus were found to be statistically significantly higher in the study group compared with the control group. In the study group, at baseline referral, 46 of 301 (15.3%) had strabismus (2.8% in control group) and 11 of 301 (3.7%) nystagmus (0.004% in control group). At 5-year follow-up, the prevalence of strabismus was 14.0% (OR 5.70, 95% CI: 4.01-8.12) and that of nystagmus was 3.3% (OR 90.34, 95% CI 24.73-330.02). A total of 42.4% of these children at age 5 had no demonstrable binocular vision and 28.2% had visual acuity of 0.3 (logMAR) or worse in 1 or both eyes. Clinic attendance at last follow-up was poor (61.9%). Exposure to maternal drug misuse in utero is associated with a statistically significantly higher prevalence of strabismus and nystagmus. These abnormalities tend to persist at 5 years of age and are associated with long-term visual morbidity, such as lack of binocularity and poor visual acuity. Our study highlights the need for ophthalmologic surveillance of this population and supports attendance, as nonattendance may be linked to more problems with substance misuse in parents and greater pathology in the child. 23411310 Concentrations of PCDD/Fs, dioxin-like PCBs, PBDEs, and hexachlorobenzene in fat samples from cattle of different ages and gender in Korea. Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), dioxin-like polychlorinated biphenyls (DL-PCBs), polybrominated diphenyl ethers (PBDEs), and hexachlorobenzene (HCB) concentrations were determined in abdominal fat samples from 30 cattle. The relationships between chemicals, age, and gender were investigated. The concentration of PCDD/Fs ranged from 0.01 to 1.36 pg TEQ g(-1) fat, DL-PCBs ranged from 0.17 to 1.64 pg TEQ g(-1) fat, PBDEs ranged from 135 to 725 pgg(-1) fat, and HCB ranged from 25.5 to 2061 pgg(-1) fat. A comparison between cattle's age and gender vs. the concentration of contaminants revealed higher concentrations of PCDD/Fs and DL-PCBs in cattle aged more than 3 years; no difference between genders was apparent. Moreover, the concentrations of PBDEs in cattle fat did not correspond with the age of cattle. Relative to cattle 1.5-2.5 years of age, cattle aged 3 and 4 years had higher concentration of HCB but the concentration difference was not clear at age 5. Human exposures to these compounds from beef sources were calculated based on beef consumption. 23935073 A specific N-terminal extension of the 8 kDa domain is required for DNA end-bridging by human Polμ and Polλ Human DNA polymerases mu (Polµ) and lambda (Polλ) are X family members involved in the repair of double-strand breaks in DNA during non-homologous end joining. Crucial abilities of these enzymes include bridging of the two 3' single-stranded overhangs and trans-polymerization using one 3' end as primer and the other as template, to minimize sequence loss. In this context, we have studied the importance of a previously uncharacterised sequence ('brooch'), located at the N-terminal boundary of the Polß-like polymerase core, and formed by Tyr(141), Ala(142), Cys(143), Gln(144) and Arg(145) in Polµ, and by Trp(239), Val(240), Cys(241), Ala(242) and Gln(243) in Polλ. The brooch is potentially implicated in the maintenance of a closed conformation throughout the catalytic cycle, and our studies indicate that it could be a target of Cdk phosphorylation in Polµ. The brooch is irrelevant for 1 nt gap filling, but of specific importance during end joining: single mutations in the conserved residues reduced the formation of two ended synapses and strongly diminished the ability of Polµ and polymerase lambda to perform non-homologous end joining reactions in vitro. 23395978 Interspecies extrapolation based on the RepDose database--a probabilistic approach. Repeated dose toxicity studies from the RepDose database (DB) were used to determine interspecies differences for rats and mice. NOEL (no observed effect level) ratios based on systemic effects were investigated for three different types of exposure: inhalation, oral food/drinking water and oral gavage. Furthermore, NOEL ratios for local effects in inhalation studies were evaluated. On the basis of the NOEL ratio distributions, interspecies assessment factors (AF) are evaluated. All data sets were best described by a lognormal distribution. No difference was seen between inhalation and oral exposure for systemic effects. Rats and mice were on average equally sensitive at equipotent doses with geometric mean (GM) values of 1 and geometric standard deviation (GSD) values ranging from 2.30 to 3.08. The local AF based on inhalation exposure resulted in a similar distribution with GM values of 1 and GSD values between 2.53 and 2.70. Our analysis confirms former analyses on interspecies differences, including also dog and human data. Furthermore it supports the principle of allometric scaling according to caloric demand in the case that body doses are applied. In conclusion, an interspecies distribution animal/human with a GM equal to allometric scaling and a GSD of 2.5 was derived. 23839604 Severe neonatal complication of transverse lie after preterm premature rupture of membranes. Both transverse lie and preterm premature rupture of membranes (PPROM) are associated with neonatal morbidity and mortality. We present a neonate born at 29 weeks gestation with severe birth trauma after PPROM and transverse lie. The patient had extensive swelling and areas of desquamated and necrotic skin of the right lower limb. Neonatal compartment syndrome (NCS) was suspected. Perfusion of the limb improved after decompressing subcutaneous incisions. A fetus in transverse lie may be mechanically damaged in the case of PPROM, especially at an early gestational age. Early recognition is of great interest in the management and prognosis of NCS. 23921360 Chemoprevention of Prostate Cancer by D,L-Sulforaphane Is Augmented by Pharmacological Inhibition of Autophagy. There is preclinical evidence that oral administration of D,L-sulforaphane (SFN) can decrease the incidence or burden of early-stage prostate cancer (PIN) and well-differentiated cancer (WDC), but not late-stage poorly differentiated cancer (PDC). Because SFN treatment induces cytoprotective autophagy in cultured human prostate cancer cells, the present study tested the hypothesis that chemopreventive efficacy of SFN could be augmented by pharmacological inhibition of autophagy using chloroquine (CQ). Incidence of PDC characterized by prostate weight of >1g was significantly lower in the SFN+CQ group compared with control (P=0.004), CQ (P=0.026) or SFN group (P=0.002 by Fisher's exact test). Average size of the metastatic lymph-node was lower by about 42% in the SFN+CQ group compared with control (P=0.043 by Wilcoxon test). On the other hand, the SFN+CQ combination was not superior to SFN alone with respect to inhibition of incidence or burden of microscopic PIN or WDC. SFN treatment caused in vivo autophagy as evidenced by transmission electron microscopy. Mechanistic studies showed that prevention of prostate cancer and metastasis by the SFN+CQ was associated with decreased cell proliferation, increased apoptosis, alterations in protein levels of autophagy regulators Atg5 and phospho-mTOR, and suppression of biochemical features of epithelial-mesenchymal transition. Plasma proteomics identified protein expression signature that may serve as biomarker of SFN+CQ exposure/response. This study offers a novel combination regimen for future clinical investigations for prevention of prostate cancer in humans. 23918231 Study on the In Vitro Effects of the Mixtures of Polycyclic Aromatic Hydrocarbons (PAHs) and Heavy Metals on Ethoxyresorufin-O-Deethylase (EROD) Activity in Mossambica tilapia Liver. This paper reports in vitro effects of individual heavy metals (Cd(2+), Cu(2+) and Hg(2+)), and PAHs, including benzo[a]pyrene(BaP), indeno[1,2,3-cd]pyrene (IP) and fluoranthene (FL), and their mixtures on ethoxyresorufin-O-deethylase (EROD) activities using a plate-reader method. The results showed that all three metals inhibited EROD activity, while BaP/IP significantly induced the enzyme. However, FL alone decreased EROD activity. Moreover, co-treatment with BaP/IP and heavy metals inhibited PAH-induced EROD activities, while combined exposure to FL and heavy metals induced FL-inhibited EROD activities. 23322650 Pain catastrophizing moderates the effects of pain-contingent task interruptions. A prominent behavioural consequence of pain is the temporary suspension of current activities with intent to resume them later. Little is known about the effects of such pain-contingent task interruptions. This experiment examines the influence of pain-contingent interruptions on the amount of time spent performing a cognitive achievement task: We expected that people would spend more time on task when task performance was interrupted in response to pain (vs. no interruption), and that negative mood and pain catastrophizing would enhance this negative impact. Healthy volunteers read behaviour descriptions until they felt they could form a good impression. Before task performance, participants underwent a negative or positive mood induction. During the task, all participants expected painful stimulation. Half of the participants in each mood induction group received an acute (electrocutaneous) pain stimulus, resulting in a 2-min break from the task. The other participants received no sensory stimulation during task performance and their performance was not interrupted. Results revealed no effect of mood on task performance (i.e., total number of descriptions read). There was, however, a significant interaction between task interruption and pain catastrophizing, indicating that participants with low levels of catastrophizing tended to read more descriptions when performance was interrupted than when not, whereas participants reporting relatively high levels of catastrophizing showed the reverse behavioural pattern. The impact of pain-contingent task interruptions was reversed in participants reporting relatively high levels of pain catastrophizing. Results are discussed with regard to interruption management in the context of chronic pain. 23902762 Knockdown of cyclin-dependent kinase 10 (cdk10) Impairs Neural Progenitor Survival via Modulation of raf1a Expression. In this study, we used zebrafish as an animal model to elucidate the developmental function of cdk10 in vertebrates. In situ hybridization analyses demonstrated that cdk10 is expressed throughout the development, with a relative enrichment in the brain in the late stages. Similar to its mammalian ortholog, cdk10 can interact with the transcription factor Ets2 and exhibit kinase activity by phosphorylating histone H1. Morpholino-based loss of cdk10 expression caused apoptosis in sox2-positive cells and decreased the expression of subsequent neuronal markers. Acetylated tubulin staining revealed a significant reduction in the number of Rohon-Beard sensory neurons in cdk10 morphants. This result is similar to that demonstrated by decreased islet-2 expression in the dorsal regions. Moreover, cdk10 morphants exhibited a marked loss of huC-positive neurons in the telencephalon and throughout the spinal cord axis. The population of retinal ganglion cells was also diminished in cdk10 morphants. These phenotypes were rescued by co-injection of cdk10 mRNA. Interestingly, the knockdown of cdk10 significantly elevated raf1a mRNA expression. Meanwhile, the MEK inhibitor (U0126) recovered sox2 and ngn1 transcript levels in cdk10 morphants. Our findings provide the first functional characterization of cdk10 in vertebrate development and reveal its critical function in neurogenesis by modulation of raf1a expression. 23852946 Kinetic resolution and stereoselective synthesis of 3-substituted aspartic acids by using engineered methylaspartate ammonia lyases. Enzymatic amino acid synthesis: Kinetic resolution and asymmetric synthesis of various valuable 3-substituted aspartic acids, which were obtained in fair to good yields with diastereomeric ratio values of up to >98:2 and enantiomeric excess values of up to >99 %, by using engineered methylaspartate ammonia lyases are described. These biocatalytic methodologies for the selective preparation of aspartic acid derivatives appear to be attractive alternatives for existing chemical methods. 23825873 Testing transparency. Interview by Fiona Fleck. An international movement to boost transparency in clinical trials is gathering momentum. Iain Chalmers, who has championed these issues for many years, talks to Fiona Fleck. 23956224 The prognostic effect of high diagnostic WT1 gene expression in pediatric AML depends on WT1 SNP rs16754 status: Report from the Children's Oncology Group. WT1 is aberrantly over-expressed in most cases of AML. We recently demonstrated that WT1 SNP rs16754 correlates with favorable outcome and high diagnostic WT1 expression in childhood AML. We examined the clinical correlates of diagnostic WT1 expression within a contemporary COG trial and determined whether its prognostic impact differs between SNP+ and SNP- patients. WT1 mRNA expression was measured via qRT-PCR in diagnostic specimens obtained from 225 patients enrolled on COG-AAML03P1. Direct sequencing of WT1 exon 7 was performed to determine SNP rs16754 genotype. WT1 expression was correlated with disease characteristics, SNP status, and outcome. Patients were categorized into four groups (quartiles: Q1 through Q4) based on diagnostic WT1 expression for analysis. FLT3/ITD (P = 0.017) and WT1 mutations (P < 0.001) both occurred more frequently in patients with the highest WT1 expression. SNP rs16754 frequency did not vary significantly among the quartiles. When all patients were considered, survival outcomes were similar between quartiles. However, when only SNP- patients (n = 150) were analyzed, those with highest WT1 expression (Q4) had the poorest OS (51% vs. 72% for Q1-Q3, P = 0.006) and EFS (35% vs. 54% for Q1-Q3, P = 0.031). Among SNP+ patients (n = 75), survival did not vary significantly between WT1 expression quartiles. Although WT1 expression was not prognostic when all patients were considered together, stratifying patients by SNP rs16754 genotype revealed significant differences in outcome. In SNP- patients, high WT1 expression predicted decreased survival in univariate, but not multivariate, analysis, due to a preponderance of high-risk cyto/molecular abnormalities in the highest expression quartile. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc. 23122112 Electronic nose and GC-MS analysis of volatile compounds in Tuber magnatum Pico: evaluation of different storage conditions. The characteristic aromatic composition of white truffles (Tuber magnatum Pico) determines its culinary and commercial value. However modifications of truffle organoleptic proprieties occur during preservation. A study of headspace of white truffles by using Electronic nose (E-nose), gas chromatography-mass spectrometry (GC-MS) and sensory analyses was performed. Truffles were stored at different conditions for 7 days: +4 and +8°C wrapped in blotting paper or covered by rice or none of the above. Headspace E-nose measurements and sensory analyses were performed each day. Statistical multivariate analysis of the data showed the capability of E-nose to predict sensorial analysis scores and to monitor aroma profile changes during storage. Truffle's volatile molecules were also extracted by headspace solid phase microextraction technique and separated and identified by GC-MS. Partial Components Analysis of data was performed. E-nose and GC-MS results were in agreement and showed that truffle storage in paper at +8°C seemed to be the best storage condition. 23836543 Velocity encoding with the slice select refocusing gradient for faster imaging and reduced chemical shift-induced phase errors. To investigate a novel phase-contrast MRI velocity-encoding technique for faster imaging and reduced chemical shift-induced phase errors. Velocity encoding with the slice select refocusing gradient achieves the target gradient moment by time shifting the refocusing gradient, which enables the use of the minimum in-phase echo time (TE) for faster imaging and reduced chemical shift-induced phase errors. Net forward flow was compared in 10 healthy subjects (N = 10) within the ascending aorta (aAo), main pulmonary artery (PA), and right/left pulmonary arteries (RPA/LPA) using conventional flow compensated and flow encoded (401 Hz/px and TE = 3.08 ms) and slice select refocused gradient velocity encoding (814 Hz/px and TE = 2.46 ms) at 3 T. Improved net forward flow agreement was measured across all vessels for slice select refocused gradient compared to flow compensated and flow encoded: aAo vs. PA (1.7% ± 1.9% vs. 5.8% ± 2.8%, P = 0.002), aAo vs. RPA + LPA (2.1% ± 1.7% vs. 6.0% ± 4.3%, P = 0.03), and PA vs. RPA + LPA (2.9% ± 2.1% vs. 6.1% ± 6.3%, P = 0.04), while increasing temporal resolution (35%) and signal-to-noise ratio (33%). Slice select refocused gradient phase-contrast MRI with a high receiver bandwidth and minimum in-phase TE provides more accurate and less variable flow measurements through the reduction of chemical shift-induced phase errors and a reduced TE/repetition time, which can be used to increase the temporal/spatial resolution and/or reduce breath hold durations. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc. 23948306 In brown adipocytes, adrenergically induced β1-/β3-(Gs)-, α2-(Gi)- and α1-(Gq)-signalling to Erk1/2 activation is not mediated via EGF receptor transactivation. Brown adipose tissue is unusual in that the neurotransmitter norepinephrine influences cell destiny in ways generally associated with effects of classical growth factors: regulation of cell proliferation, of apoptosis, and progression of differentiation. The norepinephrine effects are mediated through G-protein-coupled receptors; further mediation of such stimulation to e.g. Erk1/2 activation is in general cell biology accepted to occur through transactivation of the EGF receptor (by external or internal pathways). We have examined here the significance of such transactivation in brown adipocytes. Stimulation of mature brown adipocytes with cirazoline (α1-adrenoceptor coupled via Gq), clonidine (α2 via Gi) or CL316243 (β3 via Gs) or via β1-receptors significantly activated Erk1/2. Pretreatment with the EGF receptor kinase inhibitor AG1478 had, remarkably, no significant effect on Erk1/2 activation induced by any of these adrenergic agonists (although it fully abolished EGF-induced Erk1/2 activation), demonstrating absence of transactivation. Results with brown preadipocytes (cells in more proliferative states) were not qualitatively different. Joint stimulation of all adrenoceptors with norepinephrine did not result in synergism on Erk1/2 activation. AG1478 action on EGF-stimulated Erk1/2 phosphorylation showed a sharp concentration-response relationship (IC50 0.3µM); a minor apparent effect of AG1478 on norepinephrine-stimulated Erk1/2 phosphorylation showed nonspecific kinetics, implying caution in interpretation of partial effects of AG1478 as reported in other systems. Transactivation of the EGF receptor is clearly not a universal prerequisite for coupling of G-protein coupled receptors to Erk1/2 signalling cascades. 23774294 Effect of NaCl on the heavy metal tolerance and bioaccumulation of Zygosaccharomyces rouxii and Saccharomyces cerevisiae. Application of microorganisms as bioremediators for heavy metal removal in high salt environment is usually restricted by high salt concentrations. The effect of NaCl on the heavy metal tolerance and bioaccumulation of Zygosaccharomyces rouxii and Saccharomyces cerevisiae was investigated. For both yeasts, NaCl improved the cadmium and zinc tolerance, reduced the copper tolerance, and showed no obvious effect on the lead and iron tolerance. The bioaccumulation capacities of copper, zinc, and iron increased but the cadmium bioaccumulation capacities decreased after the addition of NaCl. NaCl obviously affected the amount of heavy metals removed intracellularly and on the cell surface. The heavy metal removal was not overwhelmingly inhibited by elevated NaCl concentrations, especially for Z. rouxii, and in some cases NaCl improved their removal ability. The salt-tolerant Z. rouxii that showed more powerful heavy metal tolerance and removal ability might be more suitable for heavy metal removal in high salt environment. 23872196 Differential actions of the prostacyclin analogues treprostinil and iloprost and the selexipag metabolite, MRE-269 (ACT-333679) in rat small pulmonary arteries and veins. The prostacyclin (IP) receptor agonists, treprostinil, iloprost and the selexipag metabolite, MRE-269 (ACT-333679) were evaluated in rat distal pulmonary blood vessels. Small pulmonary arteries and veins were pre-contracted with the thromboxane mimetic, U46619 (25 and 100nM, respectively), and relaxation determined with and without IP receptor antagonists, RO1138452 and RO3244794. In arteries, treprostinil was a more potent vasorelaxant than iloprost, while the efficacy of iloprost was greater. In pulmonary arteries, treprostinil-induced relaxation was essentially abolished by both IP antagonists (1μM), while responses to iloprost were partially inhibited. Both treprostinil and iloprost were equipotent, prominently relaxing pulmonary veins with responses being similarly and partially sensitive to IP antagonists. In contrast, RO1138452 failed to inhibit relaxations to MRE-269 in either pulmonary arteries or veins, suggesting no involvement of typical IP receptors. Thus, rat pulmonary tissues cannot be considered appropriate to assess classical IP receptors using the proposed highly selective non-prostanoid agonist MRE-269, contrasting with the IP receptor agonism profile of prostacyclin analogues, iloprost and treprostinil. 23897661 Computational approaches for understanding energy metabolism. There has been a surge of interest in understanding the regulation of metabolic networks involved in disease in recent years. Quantitative models are increasingly being used to interrogate the metabolic pathways that are contained within this complex disease biology. At the core of this effort is the mathematical modeling of central carbon metabolism involving glycolysis and the citric acid cycle (referred to as energy metabolism). Here, we discuss several approaches used to quantitatively model metabolic pathways relating to energy metabolism and discuss their formalisms, successes, and limitations. WIREs Syst Biol Med 2013. doi: 10.1002/wsbm.1238 Conflict of interest: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website. 23945737 Application of a force sensor to improve the reliability of measurement with articulated arm coordinate measuring machines. A study of the operator contact force influence on the performance of Articulated Arm Coordinate Measuring Machines (AACMMs) is presented in this paper. After developing a sensor capable of measuring the contact force applied by an operator, a ring gauge has been used to analyse the relationship between the contact force and diameter and form errors measured with the AACMM. As a result, contact force has been proved as one of the main factors influencing the AACMM performance. A probe deflection model based on the Finite Element Method (FEM) has been also proposed in order to obtain the AACMM probe deflection caused by contact force. This allows measurement correction by comparing them with reference values, specifically, a ring gauge. Experimental test results show a significant measurement improvement that minimizes diameter error. Finally, an uncertainty evaluation for the contact force sensor and AACMM measurements with and without probe deflection model has been carried out in order to validate the ability of the sensor and the methodology followed. 23894479 Association of early age at establishment of chronic hepatitis B infection with persistent viral replication, liver cirrhosis and hepatocellular carcinoma: a systematic review. Age at infection with hepatitis B virus (HBV) is a known risk factor for chronic HBV infection. However, in addition, there is some evidence that early age at infection further increases the risk of primary liver cancer beyond its association with increased risk of chronic infection. This systematic review of observational studies assesses the association between age at initiation of chronic HBV infection and liver cirrhosis, hepatocellular carcinoma, and their predictors including indicators of ongoing viral replication and hepatic damage. The review includes birth order and maternal HBV serology as proxies for age at infection. Electronic searches in two English-language (Medline and Embase, until Jan 2012) and two Chinese-language (CNKI and SinoMed, until Sep 2012) databases without language restriction and manual search through reference lists identified 7,077 papers, of which 19 studies of 21 outcomes (8 primary liver cancer, 1 liver cirrhosis, 10 viral replication and 2 liver inflammation) are included. One study directly examined the age at infection in a longitudinal cohort, 12 assessed maternal sero-status and 6 investigated birth order. The direction of associations in all studies was in accordance with our hypothesis that earlier age at infection is associated with worse outcomes in addition to its effect of increasing the probability of chronic HBV infection. This has implications for the control of hepatitis B. 23877119 A new sensor for detection of CH3CN and ClCH2CN vapors based on vapoluminescent platinum(ii) complex. The planar platinum(ii) complex [Pt(Me3SiC[triple bond, length as m-dash]CbpyC[triple bond, length as m-dash]CSiMe3)(C[triple bond, length as m-dash]CC6H4Et-4)2] (1) with 5,5-bis(trimethylsilylethynyl)-2,2'-bipyridine was prepared and characterized. Solid-state 1 exhibits unusual, selective and reversible luminescence vapochromism to CH3CN and ClCH2CN vapors, which is useful for the detection of these hazardous vapors. A vapochromic cycle was monitored by dynamic variations in emission spectra and X-ray diffraction (XRD) patterns. Both X-ray crystallographic and density functional theory studies suggest that the vapochromic and vapoluminescent behavior of 1 are induced by the variation in the intermolecular Pt-Pt interactions. 23571552 Dissemination of a pSCFS3-like cfr-carrying plasmid in Staphylococcus aureus and Staphylococcus epidermidis clinical isolates recovered from hospitals in Ohio. Nineteen linezolid-resistant Staphylococcus epidermidis and two Staphylococcus aureus isolates recovered from two medical institutions in northeast Ohio and an S. aureus cfr index strain previously collected in the same facilities during the 2007 SENTRY Antimicrobial Surveillance Program were investigated for the genetic basis of oxazolidinone resistance and the location of cfr. S. aureus isolates were typed by pulsed-field gel electrophoresis (PFGE), spa typing, and multilocus sequence typing (MLST). The location of cfr was determined by Southern blotting and hybridization. Plasmid sequencing was performed using the 454 Life Sciences (Roche) GS-FLX DNA platform. The two S. aureus isolates showed unique PFGE patterns but were multilocus sequence type 5 (ST5) and spa type t002, whereas the S. aureus index strain was ST239 and t037. Southern blot and hybridization experiments showed that cfr was plasmid located and that the S. epidermidis isolates, one of the S. aureus isolates, and the S. aureus index strain shared an identical cfr-carrying plasmid (39.3 kb). Sequencing results confirmed these findings. A 10-kb fragment containing cfr showed the highest identity (99.9%) to a 9.5-kb fragment of plasmid pSCFS3 from a bovine Staphylococcus lentus isolate from Germany. In addition, these 39.3-kb plasmids from human S. epidermidis and S. aureus exhibited BglII restriction profiles very similar to that observed for plasmid pSCFS3. The cfr-carrying plasmid detected in the remaining S. aureus isolate (7.9 kb) was distinct and showed the highest identity to the chromosomal cfr integrate found in the chromosomal DNA of a Proteus vulgaris isolate from a pig in China. 23851259 FG7142, yohimbine, and βCCE produce anxiogenic-like effects in the elevated plus-maze but do not affect brainstem activated hippocampal theta. The neurobiological underpinnings of anxiety are of paramount importance to selective and efficacious pharmaceutical intervention. Hippocampal theta frequency in urethane anaesthetized rats is suppressed by all known (and some previously unknown) anti-anxiety (anxiolytic) drugs. Although these findings support the predictive validity of this assay, its construct validity (i.e., whether theta frequency actually indexes anxiety per se) has not been a subject of systematic investigation. We reasoned that if anxiolytic drugs suppress hippocampal theta frequency, then drugs that increase anxiety (i.e., anxiogenic agents) should increase theta frequency, thus providing evidence of construct validity. We used three proven anxiogenic drugs - two benzodiazepine receptor inverse agonists, N-methyl-β-carboline-3-carboxamide (FG7142) and β-carboline-3-carboxylate ethyl ester (βCCE), and one α2 noradrenergic receptor antagonist, 17α-hydroxy-yohimban-16α-carboxylic acid methyl ester (yohimbine) as pharmacological probes to assess the construct validity of the theta model. Although all three anxiogenic drugs significantly increased behavioural measures of anxiety in the elevated plus-maze, none of the three increased the frequency of hippocampal theta oscillations in the neurophysiological model. As a positive control, we demonstrated that diazepam, a proven anxiolytic drug, decreased the frequency of hippocampal theta, as in all other studies using this model. Given this discrepancy between the significant effects of anxiogenic drugs in the behavioural model and the null effects of these drugs in the neurophysiological model, we conclude that the construct validity of the hippocampal theta model of anxiety is questionable. 23406444 Selective uptake of influenza vaccine and pregnancy outcomes. Abstract Objective: To describe the characteristics of pregnant women who accept the influenza vaccine and evaluate the relationship between vaccination and adverse pregnancy outcomes. Methods: Retrospective cohort study of women receiving prenatal care during the 2009-2011 influenza seasons. Vaccination status was ascertained through our perinatal record system and clinic vaccination logs. Pregnancy outcomes included a primary composite of miscarriage, fetal demise, preterm birth (PTB) <37 weeks and neonatal demise. Stratification and logistic regression were used to adjust for potential confounders. Results: Of 3104 eligible pregnant women, 1094 (35%) received the influenza vaccine. Women vaccinated were more likely to be older, obese, primiparae, and have medical complications or a prior PTB. In univariable analyses, flu vaccination was associated with increased adverse composite outcome and PTB. After multivariable adjustments, vaccination was no longer associated with adverse outcomes in women with medical complications but remained associated with adverse outcomes among those without known co-morbidity. Conclusions: Vaccination was associated with an increased adverse composite outcome in pregnant women without identified co-morbidity but not those with co-morbidities. This association is likely due to selection bias, which should be considered in planning of observational studies of the impact of vaccination on pregnancy outcomes. 23726764 IL-22 secreting CD4+ T cells in the patients with neuromyelitis optica and multiple sclerosis. Interleukin (IL)-22 secreting CD4(+) T (Th22) cells and IL-22 are involved in the pathogenesis of autoimmune disease, but their role in neuromyelitis optica (NMO) and multiple sclerosis (MS) is unclear. We measured the proportion of Th22, Th17, CD4(+)IL-22(+)IL-17A(+) T cells and serum IL-22 in NMO and MS patients. The proportion of Th22 cells, Th17 cells and serum IL-22 were increased in patients with NMO and MS. Our findings suggest that increased Th22 cells may play an important role in the pathogenesis of NMO and MS. 23946401 Number of spikes in climbing fibers determines the direction of cerebellar learning. Cerebellar learning requires context information from mossy fibers and a teaching signal through the climbing fibers from the inferior olive. Although the inferior olive fires in bursts, virtually all studies have used a teaching signal consisting of a single pulse. Following a number of failed attempts to induce cerebellar learning in decerebrate ferrets with a nonburst signal, we tested the effect of varying the number of pulses in the climbing fiber teaching signal. The results show that training with a single pulse in a conditioning paradigm in vivo does not result in learning, but rather causes extinction of a previously learned response. 23832114 Pro-crossover factors regulate damage-dependent apoptosis in the Caenorhabditis elegans germ line. During meiosis, DNA double-strand breaks (DSBs) are physiologically induced to start the recombination process and promote the formation of interhomologue crossovers (COs), which are required to ensure faithful chromosome segregation into the gametes. The timely repair of DSBs is an essential part of the meiotic programme, as accumulation of unprocessed DSBs during the pachytene stage of meiotic prophase triggers a DNA damage checkpoint response that induces apoptosis of damaged cells. We show that CO-promoting factors MSH-4, MSH-5, and ZHP-3, but not COSA-1, are required for the apoptotic response of the meiotic DNA damage checkpoint. Lack of MSH-4 or MSH-5 suppresses the apoptotic response observed in some DNA repair-defective mutants such as fcd-2 and brc-1 (orthologues of FANCD2 and BRCA1), irrespectively of the amount of DSBs present in pachytene nuclei. Although ionizing radiation fails to induce apoptosis in msh-4/5-mutant backgrounds, it induces transcriptional activation of the apoptosis-activator egl-1, which is controlled by the Caenorhabditis elegans p53 orthologue CEP-1. This finding suggests that MSH-4/5 involvement in the apoptotic response occurs downstream or independently of damage sensing and checkpoint activation. This study establishes a role for pro-CO factors MSH-4/5 and ZHP-3 in the execution of apoptosis at late meiotic prophase following the accumulation of exogenous or endogenous DNA damage. 23950810 Correction: Cytoplasmic Skp2 Expression Is Associated with p-Akt1 and Predicts Poor Prognosis in Human Breast Carcinomas. [This corrects the article on p. e52675 in vol. 7.]. 23952240 Self-Assembled Carbon Nanotube Honeycomb Networks Using a Butterfly Wing Template as a Multifunctional Nanobiohybrid. Insect wings have many unique and complex nano/microstructures that are presently beyond the capabilities of any current technology to reproduce them artificially. In particular, Morpho butterflies are an attractive type of insect because their multifunctional wings are composed of nano/microstructures. In this paper, we show that carbon nanotube-containing composite adopts honeycomb-shaped networks when simply self-assembled on Morpho butterfly wings used as a template. The unique nano/microstructure of the composites exhibits multifunctionalities such as laser-triggered remote-heating, high electrical conductivity, and repetitive DNA amplification. Our present study highlights the important progress that has been made toward the development of smart nanobiomaterials for various applications such as digital diagnosis, soft wearable electronic devices, photosensors, and photovoltaic cells. 23869434 Water Loss Control Using Pressure Management: Life-cycle Energy and Air Emission Effects. Pressure management is one cost-effective and efficient strategy for controlling water distribution losses. This paper evaluates the life-cycle energy use and emissions for pressure management zones in Philadelphia, Pennsylvania, and Halifax, Nova Scotia. It compares water savings using fixed-outlet and flow-modulated pressure control to performance without pressure control, considering the embedded electricity and chemical consumption in the lost water, manufacture of pipe and fittings to repair breaks caused by excess pressure, and pressure management. The resulting energy and emissions savings are significant. The Philadelphia and Halifax utilities both avoid approximately 130 million liters in water losses annually using flow-modulated pressure management. The conserved energy was 780 GJ and 1900 GJ while avoided greenhouse gas emissions were 50 Mg and 170 Mg a year by Philadelphia and Halifax, respectively. The life-cycle financial and environmental performance of pressure management systems compares favorably to the traditional demand management strategy of installing low-flow toilets. The energy savings may also translate to cost-effective greenhouse gas emission reductions depending on the energy mix used, an important advantage in areas where water and energy are constrained and/or expensive and greenhouse gas emissions are regulated as in California, for example. 23946666 Association between muscle atrophy/weakness and health care costs and utilization among patients receiving total knee replacement surgery: a retrospective cohort study. The aim of the study reported here was to examine health care resource utilization, costs, and risk of rehospitalization for total knee replacement (TKR) patients with and without muscle atrophy/weakness (MAW). Individuals aged 50-64 years with commercial insurance or 65+ years with Medicare Supplemental Insurance (Medicare) who had a hospitalization for TKR between January 1, 2006 and September 30, 2009 were identified from a large US claims database. First hospitalization for TKR was defined as the index stay. All patients were classified into three cohorts according to when MAW was diagnosed relative to TKR: pre-MAW, post-MAW, and no MAW. The association between MAW and health care costs over the 12-month post-index period and the probability of rehospitalization were assessed via multivariate regressions. The study sample included 53,696 Medicare and 46,058 commercial insurance TKR patients. Controlling for cross-cohort differences, both the pre- and post-MAW cohorts had significantly higher total health care costs (Medicare US$4,201 and US$9,404 higher, commercial insurance US$2,737 and US$6,640 higher, respectively) than the no MAW cohort (all P < 0.05). The post-MAW cohort in both populations was also more likely to have any all-cause or replacement-related rehospitalization compared with the no MAW cohort. Among US patients undergoing TKR, those with MAW had higher health care utilization and costs than patients without MAW. 23333176 Physical exercise and its effects on coronary artery disease. The beneficial effects of physical exercise on stable coronary artery disease (CAD) have been shown by an increasing number of studies. Exercise training leads to an improved bioavailability of the endothelial nitric oxide and partially attenuates endothelial dysfunction. Further effects are an economization of ventricular function and a reduction of cardiovascular risk factors. In clinical studies exercise training was associated with a decreased total and cardiovascular mortality and a reduced angina pectoris threshold. Thus exercise training has developed to an evidence-based therapeutic option of stable CAD with a Class Ia recommendation in the guidelines. 23301560 Amino acid grafted chitosan for high performance gene delivery: comparison of amino acid hydrophobicity on vector and polyplex characteristics. To develop a safe, effective, and biocompatible gene delivery vector, a series of hydrophobic amino acid grafted chitosan (AGC) derivatives were synthesized by carbodiimide mediated coupling reaction. Chemical characterization of AGC polymers was performed by NMR and elemental analysis. AGC polymers demonstrated excellent blood compatibility and cell viability, as evaluated by hemolysis and MTT assay, respectively. AGC polymers could effectively bind and condense plasmid DNA (pDNA) to form polyplexes in the size range of 161-263 nm and possessed net cationic charge. The resultant polyplex showed 3.4-5.4-fold greater cellular uptake and 13-30-fold higher transfection efficiency in HEK 293 cells as compared to unmodified chitosan. Moreover, both cellular uptake and transfection efficiency improved with the increasing amino acid hydrophobicity. Hydrophobic amino acid substitution contributed to the enhance pDNA release at cytosolic pH. These data demonstrate AGC polymers as a promising novel nonviral gene delivery vector. 23894418 Identification of Key Uric Acid Synthesis Pathway in a Unique Mutant Silkworm Bombyx mori Model of Parkinson's Disease. Plasma uric acid (UA) levels decrease following clinical progression and stage development of Parkinson's disease (PD). However, the molecular mechanisms underlying decreases in plasma UA levels remain unclear, and the potential to apply mutagenesis to a PD model has not previously been discovered. We identified a unique mutant of the silkworm Bombyx mori (B.mori) op. Initially, we investigated the causality of the phenotypic "op" by microarray analysis using our constructed KAIKO functional annotation pipeline. Consequently, we found a novel UA synthesis-modulating pathway, from DJ-1 to xanthine oxidase, and established methods for large-scale analysis of gene expression in B. mori. We found that the mRNA levels of genes in this pathway were significantly lower in B. mori op mutants, indicating that downstream events in the signal transduction cascade might be prevented. Additionally, levels of B.mori tyrosine hydroxylase (TH) and DJ-1 mRNA were significantly lower in the brain of B. mori op mutants. UA content was significantly lower in the B. mori op mutant tissues and hemolymph. The possibility that the B. mori op mutant might be due to loss of DJ-1 function was supported by the observed vulnerability to oxidative stress. These results suggest that UA synthesis, transport, elimination and accumulation are decreased by environmental oxidative stress in the B. mori op mutant. In the case of B. mori op mutants, the relatively low availability of UA appears to be due both to the oxidation of DJ-1 and to its expenditure to mitigate the effects of environmental oxidative stress. Our findings are expected to provide information needed to elucidate the molecular mechanism of decreased plasma UA levels in the clinical stage progression of PD. 23827813 Practical approaches to designing novel protein assemblies. Molecular self-assembly offers a means by which sophisticated materials can be constructed with unparalleled precision. Designing self-assembling protein structures is of particular interest as a result of the unique functional capabilities of proteins. Custom-designed protein materials could lead to new possibilities in therapeutics, bioenergy, and materials science. Although the field was long hampered by the challenges involved in designing such complex molecules, novel approaches and computational tools have recently led to remarkable progress. Here we review recent design studies in the context of three fundamental aspects of self-assembling materials: subunit organization, subunit interactions, and regulation of assembly. 23917845 Cross-linking and mass spectrometry methodologies to facilitate structural biology: finding a path through the maze. Multiprotein complexes, rather than individual proteins, make up a large part of the biological macromolecular machinery of a cell. Understanding the structure and organization of these complexes is critical to understanding cellular function. Chemical cross-linking coupled with mass spectrometry is emerging as a complementary technique to traditional structural biology methods and can provide low-resolution structural information for a multitude of purposes, such as distance constraints in computational modeling of protein complexes. In this review, we discuss the experimental considerations for successful application of chemical cross-linking-mass spectrometry in biological studies and highlight three examples of such studies from the recent literature. These examples (as well as many others) illustrate the utility of a chemical cross-linking-mass spectrometry approach in facilitating structural analysis of large and challenging complexes. 23875738 Vitamin D deficiency impacts on expression of toll-like receptor-2 and cytokine profile: a pilot study. Vitamin D is believed to play an important role outside the endocrine system in the regulation of the immune system, and in cellular proliferation and differentiation. The aim of the study was to investigate the impact of vitamin D levels on innate immunity. Participants for this prospective, longitudinal study were recruited amongst otherwise healthy staff of a large hospital in Victoria, Australia. Those fulfilling the inclusion criteria, including a vitamin D level of <50 nmol/L, were supplemented. Using flow cytometry, expression of the innate immune receptors TLR2, TLR4 and CD86 was measured on peripheral blood mononuclear cells (PBMCs) collected prior to vitamin D treatment and then at 1 and 3 months. Additonally, PBMCs at each timepoint were stimulated with specific TLR ligands and resultant supernatants were assayed for the cytokines TNFα, IL-6, IFN-α and IP-10. In participants whose vitamin D level was >100 nmol/L post supplementation (n=11), TLR2 expression on PBMCs increased significantly, with no change noted in TLR4 or CD86 expression. Stimulation of vitamin D deficient samples with TLR ligands produced a number of proinflammatory cytokines, which were significantly reduced upon vitamin D normalisation. In patients whose levels returned to a deficient level at 3 months despite ongoing low-level supplementation, an increase in the pro-inflamamtory state returned. This suggests that vitamin D may play an important role in ensuring an appropriate baseline pro-inflammatory state. This ex-vivo pilot study adds clinical evidence supporting a possibly important role for vitamin D in innate immunity. If confirmed, this unique clinical study has potentially significant implications for the treatment of a variety of inflammatory conditions, where achieving optimal vitamin D levels may help reduce inflammation. 23881360 Role of RNA Structure Motifs in IRES-Dependent Translation Initiation of the Coxsackievirus B3: New Insights for Developing Live-Attenuated Strains for Vaccines and Gene Therapy. Internal ribosome entry site (IRES) elements are highly structured RNA sequences that function to recruit ribosomes for the initiation of translation. In contrast to the canonical cap-binding, the mechanism of IRES-mediated translation initiation is still poorly understood. Translation initiation of the coxsackievirus B3 (CVB3), a causative agent of viral myocarditis, has been shown to be mediated by a highly ordered structure of the 5' untranslated region (5'UTR), which harbors an IRES. Taking into account that efficient initiation of mRNA translation depends on temporally and spatially orchestrated sequence of RNA-protein and RNA-RNA interactions, and that, at present, little is known about these interactions, we aimed to describe recent advances in our understanding of molecular structures and biochemical functions of the translation initiation process. Thus, this review will explore the IRES elements as important RNA structures and the significance of these structures in providing an alternative mechanism of translation initiation of the CVB3 RNA. Since translation initiation is the first intracellular step during the CVB3 infection cycle, the IRES region provides an ideal target for antiviral therapies. Interestingly, the 5' and 3'UTRs represent promising candidates for the study of CVB3 cardiovirulence and provide new insights for developing live-attenuated vaccines. 23606509 Testosterone replacement therapy does not promote priapism in hypogonadal men with sickle cell disease: 12-month safety report. Hypogonadism, which is highly prevalent in men with sickle cell disease (SCD), affects quality of life and causes great morbidity. The safety of testosterone replacement therapy (TRT) in SCD in relation to priapism episodes is relatively unknown. Our aim was to monitor the safety of TRT in a cohort of seven hypogonadal men with SCD. Testosterone undecanoate (Nebido) 1 g was administered intramuscularly to adult men with homozygous SCD (Hb SS) having hypogonadism [serum total testosterone ≤12.0 nmol/L (346 ng/dL), reference range 12.5-38.1 nmol/L (360-1098 ng/dL)] for 12 months. Serum total testosterone, haemoglobin, haematocrit, renal and liver function tests, glucose and PSA measurements were done at baseline and 12-month follow-up. Trough serum total testosterone, haemoglobin and haematocrit were measured three monthly. Priapism events and adverse drug events were assessed every 3 months. International Index of Erectile Function (IIEF), Androgen Deficiency in the Ageing Male (ADAM) and World Health Organization Quality of Life (WHOQOL) questionnaires were administered at baseline, 6 and 12 months. Seven men with a mean age of 34.4 years were treated. Median total testosterone increased from 10.6 to 11.2 nmol/L (p = 0.46). Median serum lactate dehydrogenase levels decreased from 1445 to 1143.5 IU/L (p < 0.05), while all other laboratory indices remained stable. Injection site pain was the most frequently reported adverse event, with no increases in painful crises, hypersensitivity or oedema. After TRT, there was no significant increase in priapism frequency. Median questionnaire scores were increased for the IIEF (46-68, p = 0.018), reduced for ADAM (5.0-2.0, p = 0.016) and unchanged for WHOQOL (98-103, p = 0.086). TRT using testosterone undecanoate with eugonadal intent for hypogonadism appears to be safe in men with SCD. This treatment does not appear to promote priapism occurrences and rather it possibly improves sexual function. Future prospective evaluations in larger groups of hypogonadal men with SCD are necessary to confirm these findings. 23951281 The comparison of the effects of three physiotherapy techniques on hamstring flexibility in children: a prospective, randomized, single-blind study. The aim of the study was to evaluate changes in hamstring flexibility in 120 asymptomatic children who participated in a 6-week program consisting of one physiotherapy session per week and daily home exercises. The recruitment criteria included age (10-13 years), no pain, injury or musculoskeletal disorder throughout the previous year, physical activity limited to school sport. Subjects were randomly assigned to one of the three groups: (1) post-isometric relaxation - PIR (n = 40), (2) static stretch combined with stabilizing exercises - SS (n = 40) and (3) stabilizing exercises - SE (n = 40). Hamstring flexibility was assessed with straight leg raise (SLR), popliteal angle (PA) and finger-to-floor (FTF) tests. The examinations were conducted by blinded observers twice, prior to the program and a week after the last session with the physiotherapist. Twenty-six children who did not participate in all six exercise sessions with physiotherapists were excluded from the analysis. The results obtained by 94 children were analyzed (PIR, n = 32; SS, n = 31; SE, n = 31). In the PIR and SS groups, a significant (P<0.01) increase in SLR, PA, FTF results was observed. In the SE group, a significant (P<0.001) increase was observed in the SLR but not in the PA and FTF (P>0.05). SLR result in the PIR and SS groups was significantly (P<0.001) higher than in the SE group. As far as PA results are concerned, a significant difference was observed only between the SS and SE groups (P = 0.014). There were no significant (P = 0.15) differences regarding FTF results between the three groups. Post-isometric muscle relaxation and static stretch with stabilizing exercises led to a similar increase in hamstring flexibility and trunk forward bend in healthy 10-13-year-old children. The exercises limited to straightening gluteus maximus improved the SLR result, but did not change the PA and FTF results. 23921641 Alteration in the cavity size adjacent to the active site of RB69 DNA polymerase changes its conformational dynamics. Internal cavities are a common feature of many proteins, often having profound effects on the dynamics of their interactions with substrate and binding partners. RB69 DNA polymerase (pol) has a hydrophobic cavity right below the nucleotide binding pocket at the tip of highly conserved L415 side chain. Replacement of this residue with Gly or Met in other B family pols resulted in higher mutation rates. When similar substitutions for L415 were introduced into RB69pol, only L415A and L415G had dramatic effects on pre-steady-state kinetic parameters, reducing base selectivity by several hundred fold. On the other hand, the L415M variant behaved like the wild-type. Using a novel tC(o)-tCnitro Förster Resonance Energy Transfer (FRET) assay, we were able to show that the partition of the primer terminus between pol and exonuclease (exo) domains was compromised with the L415A and L415G mutants, but not with the L415M variant. These results could be rationalized by changes in their structures as determined by high resolution X-ray crystallography. 23695772 Effects of direct Renin inhibition on atherosclerotic biomarkers in patients with stable coronary artery disease and type 2 diabetes mellitus. To evaluate whether the direct renin inhibitor, aliskiren, has a more favorable effect compared to amlodipine on atherosclerotic biomarkers in patients with stable coronary artery disease and diabetes currently receiving standard secondary prevention therapy. A total of 38 patients were randomly assigned initially to either aliskiren (150 mg daily) or amlodipine (5 mg daily) for 2 weeks after which the dose of either medication was increased to its maximum daily dose for 4 additional weeks. Baseline and 6-week blood samples were analyzed for changes from baseline and between treatment groups for vascular and intracellular cell adhesion molecule, C-reactive protein, nitric oxide, plasminogen activator inhibitor 1, 8-isoprostane, and thiobarbituric acid reactive substances. Thirty-one patients completed the study. More of the dropouts occurred in patients receiving aliskiren. Systolic blood pressure decreased in both treatment arms with no differences between the groups being noted. Plasminogen activator inhibitor 1, nitric oxide, and C-reactive protein concentrations increased in both groups from baseline but changes from baseline or between groups were not significant. Vascular and intracellular cell adhesion molecule, thiobarbituric acid reactive substances, and isoprostane concentrations decreased in each treatment arm from baseline, but these changes were not significant and no differences were noted between the groups. Treatment with either aliskiren or amlodipine did not significantly alter surrogate biomarkers of atherosclerosis in patients with both diabetes and established cardiovascular disease already receiving appropriate secondary cardiovascular prevention therapy. The study is limited in its size and duration to see an effect. 23595883 Dominant effects of the Huntington's disease HTT CAG repeat length are captured in gene-expression data sets by a continuous analysis mathematical modeling strategy. In Huntington's disease (HD), the size of the expanded HTT CAG repeat mutation is the primary driver of the processes that determine age at onset of motor symptoms. However, correlation of cellular biochemical parameters also extends across the normal repeat range, supporting the view that the CAG repeat represents a functional polymorphism with dominant effects determined by the longer allele. A central challenge to defining the functional consequences of this single polymorphism is the difficulty of distinguishing its subtle effects from the multitude of other sources of biological variation. We demonstrate that an analytical approach based upon continuous correlation with CAG size was able to capture the modest (∼21%) contribution of the repeat to the variation in genome-wide gene expression in 107 lymphoblastoid cell lines, with alleles ranging from 15 to 92 CAGs. Furthermore, a mathematical model from an iterative strategy yielded predicted CAG repeat lengths that were significantly positively correlated with true CAG allele size and negatively correlated with age at onset of motor symptoms. Genes negatively correlated with repeat size were also enriched in a set of genes whose expression were CAG-correlated in human HD cerebellum. These findings both reveal the relatively small, but detectable impact of variation in the CAG allele in global data in these peripheral cells and provide a strategy for building multi-dimensional data-driven models of the biological network that drives the HD disease process by continuous analysis across allelic panels of neuronal cells vulnerable to the dominant effects of the HTT CAG repeat. 23111597 Substrate oxidation by dye-decolorizing peroxidases (DyPs) from wood- and litter-degrading agaricomycetes compared to other fungal and plant heme-peroxidases. Catalytic and physicochemical properties of representative fungal dye-decolorizing peroxidases (DyPs) of wood- (WRF) and litter-decomposing white-rot fungi (LDF) are summarized and compared, including one recombinant Mycetinis scorodonius DyP (rMscDyP; LDF), the wild-type Auricularia auricula-judae DyP (AauDyP; WRF), and two new DyPs secreted by the jelly fungi Exidia glandulosa (EglDyP; WRF) and Mycena epipterygia (MepDyP; LDF). Homogeneous preparations of these DyPs were obtained after different steps of fast protein liquid chromatography, and they increase the total number of characterized fungal DyP proteins to eight. The peptide sequences of AauDyP, MepDyP, and EglDyP showed highest homologies (52-56%) to the DyPs of M. scorodonius. Five out of the eight characterized fungal DyPs were used to evaluate their catalytic properties compared to classic fungal and plant heme peroxidases, namely lignin peroxidase of Phanerochaete chrysosporium (PchLiP; WRF), versatile peroxidase of Bjerkandera adusta (BadVP; WRF), and generic peroxidases of Coprinopsis cinerea (CiP) and Glycine max (soybean peroxidase=SBP). All DyPs tested possess unique properties regarding the stability at low pH values: 50-90% enzymatic activity remained after 4-h exposition at pH 2.5, and the oxidation of nonphenolic aromatic substrates (lignin model compounds) was optimal below pH 3. Furthermore, all DyPs efficiently oxidized recalcitrant dyes (e.g., Azure B) as well as the phenolic substrate 2,6-dimethoxyphenol. Thus, DyPs combine features of different peroxidases on the functional level and may be part of the biocatalytic system secreted by fungi for the oxidation of lignin and/or toxic aromatic compounds. 23474089 Fish oil-supplementation increases appetite in healthy adults. A randomized controlled cross-over trial. Marine n-3 fatty acids are hypothesized to have beneficial effects on obesity and cancer cachexia possibly via an effect on appetite. The aim of this study was to investigate, if fish oil-supplementation affects appetite in healthy individuals. In a randomized cross-over study, 20 normal-weight subjects (50% females) were given ten 0.5-mL capsules/day of fish oil or soybean oil for 3 weeks separated by 1-week wash-out. In the end of each period, appetite was assessed by 10-cm visual analog scales immediately before and after a standardized breakfast. Results were analyzed in accordance with the paired design considering oil sequence and gender. All subjects completed both periods with a compliance of 96% and oil sequence did not affect the results. There was no difference between the two supplements in any pre-breakfast appetite scores, but the post-prandial sensation of being full was 1.21 cm (0.20; 2.22) lower after the fish oil-period. Furthermore, there was a supplement × gender-interaction on "desire to eat more" due to a score increase of 1.09 cm (0.28; 1.90) in women only. These results suggest that marine n-3 fatty acid may increase appetite. This finding would be potentially beneficial for patients with compromised nutritional status. 23790879 Cycloartenyl trans-ferulate, a component of the bran byproduct of sake-brewing rice, inhibits mammalian DNA polymerase and suppresses inflammation. During the screening of selective DNA polymerase (pol) inhibitors, we isolated cycloartenyl trans-ferulate (CAF), which is a major component of γ-oryzanol, which is a byproduct formed during the production of Japanese rice wine "sake". CAF selectively inhibited the activity of mammalian A, B, and X pol families, but Y family pols were not affected. CAF did not influence the activities of plant or prokaryotic pols, nor the activity of other DNA metabolic enzymes tested. Individual chemical components of CAF, including cycloartenol (CA) and ferulic acid (FA), did not inhibit pol enzyme activities. CAF suppressed TPA (12-O-tetradecanoylphorbol-13-acetate)-induced inflammation in the mouse ear, but CA and FA did not. The ability to inhibit mammalian pol enzymes in vitro was positively correlated with their propensity to suppress inflammation in vivo. These results suggest that this byproduct formed during the sake-brewing process is useful as an anti-inflammatory agent. 23801097 Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Very-low-carbohydrate diets or ketogenic diets have been in use since the 1920s as a therapy for epilepsy and can, in some cases, completely remove the need for medication. From the 1960s onwards they have become widely known as one of the most common methods for obesity treatment. Recent work over the last decade or so has provided evidence of the therapeutic potential of ketogenic diets in many pathological conditions, such as diabetes, polycystic ovary syndrome, acne, neurological diseases, cancer and the amelioration of respiratory and cardiovascular disease risk factors. The possibility that modifying food intake can be useful for reducing or eliminating pharmaceutical methods of treatment, which are often lifelong with significant side effects, calls for serious investigation. This review revisits the meaning of physiological ketosis in the light of this evidence and considers possible mechanisms for the therapeutic actions of the ketogenic diet on different diseases. The present review also questions whether there are still some preconceived ideas about ketogenic diets, which may be presenting unnecessary barriers to their use as therapeutic tools in the physician's hand. 23942760 Synthesis, spectroscopic and biological studies of a fluorescent Pt(ii) (terpy) based 1,8-naphthalimide conjugate as a DNA targeting agent. The bi-functional complex [Pt(II)(terpy)(py-naphth)](NO3)2(), incorporating both 2,2':6',2''-terpyridine and 4-N,N'-dimethylamino-1,8-naphthalimide moieties, displays a high binding affinity for DNA as well as displaying cytotoxicity towards and inducing apoptosis in malignant cell lines. 23602414 Distribution characteristics and potential ecological risk assessment of heavy metals (Cu, Pb, Zn, Cd) in water and sediments from Lake Dalinouer, China. The concentrations of Cu, Pb, Zn and Cd were measured in water and sediment to determine their distribution characteristics and potential ecological risks of the Lake Dalinouer. The results revealed that the dominate form of Cu, Pb, Cd and Zn in surface sediments respectively were organic sulfides, Fe-Mn oxides, carbonates and Fe-Mn oxides, with a mean content of 4.28mgkg(-1), 0.76mgkg(-1), 7.84μgkg(-1) and 1.77mgkg(-1), respectively; the concentrations of bio-available metals had an increase tendency from the northeast to the southwest part of this lake. Acid volatile sulfides (AVS) and simultaneously extracted metal (SEM) were used to predict the potential bioavailability of heavy metals. The horizontal distribution of AVS (0.15-2.4μmolg(-1), mean 0.53μmolg(-1)) in surface sediments shows an increasing trend from southwest to northeast of the lake, whereas SEM (0.02-0.99μmolg(-1), mean 0.37μmolg(-1)) had an opposite pattern. The relative high salt and pH which restrained the bioactivities of sulfate-reducing bacteria (SRB) were the main controlling factor in AVS concentrations. The vertical variation of AVS concentration in sediment core increased with depth and different from SEM. Potential ecological risk index (PERI) and geo-accumulation index (Igeo) were used to assess heavy metals accumulation. The results indicated that moderate contamination of most heavy metals was prevalent and presented a decreased trend from southern to northern of the lake, and element Cd emerged the greatest potential ecological risk. The pollution of heavy metal in the southern of the Lake Dalinouer should be taken into consideration seriously. 23910058 In vitro regulation of hepatocellular carcinoma cell viability, apoptosis, invasion, and AEG-1 expression by LY294002. Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, and is characterized by advanced clinical stages at diagnosis and very poor prognosis. This study investigated the effects of PI3K inhibitor, LY294002, on suppression of astrocyte elevated gene-1 (AEG-1) and regulation of HCC cell viability, apoptosis, and invasion in vitro. Cell lines derived from normal liver and HCC were treated with LY294002 and evaluated by RT-PCR, western blot, cell viability, migration, and invasion assays. The data showed that AEG-1 mRNA and protein were overexpressed in HCC cells, compared to the normal liver cells. LY294002 treatment of HCC cells significantly reduced tumor cell viability, but promoted apoptosis. Tumor cell migration and invasion assays showed that LY294002 treatment also decreased the capacity of HCC cell migration and invasion. Molecularly, LY294002 treatment down-regulated AEG-1 expression, AKT and GSK3β phosphorylation, and expression of cyclinD1, CDK4, VEGF and Bcl2, but up-regulated Bax and c-Myc expression. The data from this study demonstrated usefulness of LY294002 for effective control of HCC. Future studies should investigate the effects of LY294002 on HCC cells in vivo before initiating clinical trials in HCC patients. 23135154 Dietary Aloe vera components' effects on cholesterol lowering and estrogenic responses in juvenile goldfish, Carassius auratus. Aloes are now considered a very interesting source of bioactive compounds among which phytosterols should play a major role. The present study is an attempt to investigate the hypocholesterolemic activity of Aloe vera associated with its impact on the reproductive status of juvenile goldfish. Therefore, the short- and long-term effects of feeding supplementary diet containing aloe components (20 mg aloe/g diet; 2%) on plasma lipids, plasma vitellogenin, and hepatic estrogen receptor α/β1 mRNA levels in goldfish were examined. Results of GC-MS for phytosterols show high abundance of β-sitosterol in freeze-dried powder of Aloe vera whole leaves. Moreover, a 2% aloe powder dietary supplement was not found estrogenic in juvenile goldfish after either 7- or 30-day treatment, but was consistent in plasma hypocholesterolemic effects following long-term exposure. The present data further support that plasma cholesterol modulation induced by phytosterols may not be related to estrogen-like activity. 23239459 Toll-like receptor activity in patients with obstructive sleep apnea. Obstructive sleep apnea (OSA) has been linked to chronic inflammation and cardiovascular diseases. Considerable evidence suggests that innate immune defense mechanisms might interact with proinflammatory pathways and contribute to atherogenesis. We hypothesized that the classical pathogen recognition receptors of the innate immune response, Toll-like receptors, are involved in modulating the inflammatory response in OSA. Expression of TLR2 and TLR4 on circulating monocytes from 29 subjects with documented OSA and 18 controls were compared with the use of flow cytometry and reverse transcription-polymerase chain reaction at baseline and after 8 weeks of continuous positive airway pressure (CPAP). There was a significant increase in both TLR2 and TLR4 surface expression and mRNA levels on monocytes after adjustment for age, body mass index, and waist-to-hip ratio. This was paralleled by enhanced nuclear factor-κB nuclear binding and an increased release of IL-6, INF-γ, and TNF-α in OSA versus control subjects. Following 8 weeks of treatment, continuous positive airway pressure downregulated TLR2 and TLR4 expression and abrogated the release of inflammatory cytokines. OSA is associated with enhanced expression and signaling events downstream of TLR2 and TLR4 in circulating monocytes. These observations are mitigated by CPAP therapy, which suggest that TLR2 and TLR4 activation may be involved as a signaling mechanism in immune-mediated progression of atherosclerosis in OSA. 23660683 Metformin inhibits glioma cell U251 invasion by downregulation of fibulin-3. Fibulin-3 has been considered as a regulator of glioma cell invasion, but little is known about the molecules regulating fibulin-3 expression. Metformin, an oral antidiabetic drug in the biguanide class, is known to inhibit proliferation and metastasis in a variety of cancer cells. In the present study, we determined the effect of metformin on the expression of fibulin-3 in U251 Human glioma cells. Metformin potently suppressed U251 cell adhesion and invasion. Metformin inhibited the expression of fibulin-3 at the transcriptional level. Moreover, metformin abolished the protein expression of fibulin-3 in a concentration-dependent manner. Furthermore, this compound suppressed the expression of matrix metalloproteinase-2, a key effector of glioma cell invasion, regulated by fibulin-3. Taken together, our results suggest that metformin abolishes fibulin-3 expression and subsequently inhibits invasion of glioma cells. 23123250 A combination of [+] and [-]-Huperzine A improves protection against soman toxicity compared to [+]-Huperzine A in guinea pigs. The neuropathologic mechanisms after exposure to lethal doses of nerve agent are complex and involve multiple biochemical pathways. Effective treatment requires drugs that can simultaneously protect by reversible binding to the acetylcholinesterase (AChE) and blocking cascades of seizure related brain damage, inflammation, neuronal degeneration as well as promoting induction of neuroregeneration. [-]-Huperzine A ([-]-Hup A), is a naturally occurring potent reversible AChE inhibitor that penetrates the blood-brain barrier. It also has several neuroprotective effects including modification of beta-amyloid peptide, reduction of oxidative stress, anti-inflammatory, anti-apoptotic and induction and regulation of nerve growth factor. Toxicities at higher doses restrict the neuroporotective ability of [-]-Hup A for treatment. The synthetic stereoisomer, [+]-Hup A, is less toxic due to poor AChE inhibition and is suitable for both pre-/post-exposure treatments of nerve agent toxicity. [+]-Hup A block the N-methyl-d-aspartate (NMDA)-induced seizure in rats, reduce excitatory amino acid induced neurotoxicity and also prevent soman induced toxicity with minimum performance decrement. Unique combinations of two stereo-isomers of Hup A may provide an excellent pre/post-treatment drug for the nerve agent induced seizure/status epilepticus. We investigated a combination of [+]-Hup A with a small dose of [-]-Hup A ([+] and [-]-Hup A) against soman toxicity. Our data showed that pretreatment with a combination [+] and [-]-Hup A significantly increased the survival rate and reduced behavioral abnormalities after exposure to 1.2×LD50 soman compared to [+]-Hup A in guinea pigs. In addition, [+] and [-]-Hup A pretreatment inhibited the development of high power of EEG better than [+]-Hup A pretreatment alone. These data suggest that a combination of [+] and [-]-Hup A offers better protection than [+]-Hup A and serves as a potent medical countermeasure against lethal dose nerve agent toxicity in guinea pigs. 23868129 Draft Genome Sequence of the Moderately Halophilic Gammaproteobacterium Halomonas anticariensis FP35T. Halomonas anticariensis strain FP35(T) is a moderately halophilic bacterium isolated from a soil sample taken from Fuente de Piedra, a saline wetland in the province of Málaga (Spain), which produces an exopolysaccharide and quorum-sensing signaling molecules of the type N-acylhomoserine lactone. We report here the draft genome sequence of this gammaproteobacterium. 23389098 Subpulmonary stenosis assessed in midtrimester fetuses with tetralogy of fallot: a novel method for predicting postnatal clinical outcome. This study aimed to determine whether quantification of subpulmonary stenosis (SPS) in tetralogy of Fallot (TOF) in the second-trimester fetus can predict postnatal clinical outcome measured by pulmonary valve size and/or timing or type of intervention. The study retrospectively identified fetuses with TOF from 1998 to 2010 diagnosed at 26 weeks gestation or earlier. The data evaluated included pre- and postnatal pulmonary valve z-scores (PVZ). To quantify fetal SPS, the authors created a novel index, the SPS/DAO ratio, a ratio of the minimum infundibular diameter to the descending aorta diameter (DAO). Multiple linear regression was used to predict postnatal PVZ from prenatally determined parameters, including SPS/DAO. Fetal parameters were analyzed by logistic regression for association with postnatal outcomes, namely, timing of surgery (<1 month), used as a surrogate for severity, and type of surgery [transannular patch (TAP) vs valve sparing surgery]. A total of 23 fetuses met the inclusion criteria. The mean gestational age was 21.8 ± 1.9 weeks (range, 16.6-25.4 weeks). There was excellent correlation between predicted and measured PVZ (r = 0.82; p < 0.0001) using the following derived equation: -3.68 + (0.91 Ã— prenatal PVZ) - (4.44 Ã— SPS/DAO) - 3.19 (prenatal PVZ Ã— SPS/DAO). An SPS/DAO value lower than 0.5 had 100 % sensitivity and 56 % specificity for repair before the age of 1 month, and a value lower than 0.47 had 100 % sensitivity and 75 % specificity for TAP repair. Prenatal PVZ and the SPS/DAO ratio at 26 weeks gestation or earlier can reliably predict postnatal PVZ in fetuses with TOF. Quantification of SPS with the SPS/DAO ratio identifies patients who may require early intervention secondary to disease severity and may predict the type of repair, thereby influencing prenatal counseling. 23891696 Osteoarthritis year 2013 in review: imaging. To review recent original research publications related to imaging of osteoarthritis (OA) and identify emerging trends and significant advances. Relevant articles were identified through a search of the PubMed database using the query terms "OA" in combination with "imaging", "radiography", "MRI", "ultrasound", "computed tomography", and "nuclear medicine"; either published or in press between March 2012 and March 2013. Abstracts were reviewed to exclude review articles, case reports, and studies not focused on imaging using routine clinical imaging measures. Initial query yielded 932 references, which were reduced to 328 citations following the initial review. MRI (118 references) and radiography (129 refs) remain the primary imaging modalities in OA studies, with fewer reports using computed tomography (CT) (35 refs) and ultrasound (23 refs). MRI parametric mapping techniques remain an active research area (33 refs) with growth in T2*- and T1-rho mapping publications compared to prior years. Although the knee is the major joint studied (210 refs) there is interest in the hip (106 refs) and hand (29 refs). Imaging continues to focus on evaluation of cartilage (173 refs) and bone (119 refs). Imaging plays a major role in OA research with publications continuing along traditional lines of investigation. Translational and clinical research application of compositional MRI techniques is becoming more common driven in part by the availability of T2 mapping data from the Osteoarthritis Initiative (OAI). New imaging techniques continue to be developed with a goal of identifying methods with greater specificity and responsiveness to changes in the joint, and novel functional neuroimaging techniques to study central pain. Publications related to imaging of OA continue to be heavily focused on quantitative and semiquantitative MRI evaluation of the knee with increasing application of compositional MRI techniques in the hip. 23943866 Phosphorylation of the Smo tail is controlled by membrane localization and is dispensable for clustering. The Hedgehog (Hh) signalling cascade is highly conserved and involved in development and disease throughout evolution. Nevertheless, in comparison with other pathways our mechanistic understanding of Hh signal transduction is remarkably incomplete. In the absence of ligand, the Hh receptor Patched (Ptc) represses the key signal transducer Smoothened (Smo) through an unknown mechanism. Hh binding to Ptc alleviates this repression, causing Smo redistribution to the plasma membrane, phosphorylation and opening of the Smo cytoplasmic tail, and Smo oligomerization. However, the order and interdependence of these events is as yet poorly understood. We have mathematically modelled and simulated Smo activation for two alternative modes of pathway activation, with Ptc primarily affecting either Smo localization or phosphorylation. Visualizing Smo activation through a novel, fluorescence based reporter allowed us to test these competing models. Here we show that Smo localization to the plasma membrane is sufficient for phosphorylation of the cytoplasmic tail in the presence of Ptc. Using fluorescence cross-correlation spectroscopy (FCCS) we furthermore demonstrate that inactivation of Ptc by Hh induces Smo clustering irrespective of Smo phosphorylation. Our observations therefore support a model of Hh signal transduction whereby Smo subcellular localization and not phosphorylation is the primary target of Ptc function. 23836869 Pouring Salt on a Wound: Pseudomonas aeruginosa Virulence Factors Alter Na+ and Cl- Flux in the Lung. Pseudomonas aeruginosa is a ubiquitous opportunistic pathogen with multiple niches in the human body, including the lung. P. aeruginosa infections are particularly damaging or fatal for patients with ventilator-associated pneumonia, chronic obstructive pulmonary disease, and cystic fibrosis (CF). To establish an infection, P. aeruginosa relies on a suite of virulence factors, including lipopolysaccharide, phospholipases, exoproteases, phenazines, outer membrane vesicles, type III secreted effectors, flagella, and pili. These factors not only damage the epithelial cell lining but also induce changes in cell physiology and function such as cell shape, membrane permeability, and protein synthesis. While such virulence factors are important in initial infection, many become dysregulated or nonfunctional during the course of chronic infection. Recent work on the virulence factors alkaline protease (AprA) and CF transmembrane conductance regulator inhibitory factor (Cif) show that P. aeruginosa also perturbs epithelial ion transport and osmosis, which may be important for the long-term survival of this microbe in the lung. Here we discuss the literature regarding host physiology-altering virulence factors with a focus on Cif and AprA and their potential roles in chronic infection and immune evasion. 23331020 Planar to 3D transition in the B6H(y) anions. Potential energy surfaces of anionic B(6)H(y) clusters were sampled using the coalescence kick method. We found that the planar to three-dimensional transition occurs in this system when y = 4. This is an important discovery because this transition suggests a major structural change as a function of dehydrogenation for the stoichiometric B(n)H(n)(-) polyhedral boranes. We also found that the B(6)H(3)(-) global minimum structure has an optical isomer. The chemical bonding patterns revealed by the adaptive natural density partitioning (AdNDP) analysis explain the geometric structure of all clusters presented here. From our chemical bonding analysis, we concluded that the 2D-3D transition occurs at B(6)H(4)(-) because the addition of one extra hydrogen atom further destroys the network of the peripheral 2c-2e B-B σ-bonding, making planar structures less stable, and because the distorted octahedral structure provides some occupation of all s- and p-AOs of boron, avoiding the presence of any empty atomic orbitals. Theoretical vertical electron detachment energies (VDEs) were calculated for comparison with future experimental work. 23783245 Low-energy regeneration and high productivity in a lanthanide-hexacarboxylate framework for high-pressure CO2-CH4-H2 separation. A porous lanthanide-organic framework UTSA-62a of a topology has been synthesized from a hexacarboxylate and structurally characterized, exhibiting significant potential for use in CO2-CH4-H2 separation (H2 purification) processes with high productivities and low regeneration costs when operating at high pressure and room temperature. 23139356 Intrahypothalamic estradiol regulates glucose metabolism via the sympathetic nervous system in female rats. Long-term reduced hypothalamic estrogen signaling leads to increased food intake and decreased locomotor activity and energy expenditure, and ultimately results in obesity and insulin resistance. In the current study, we aimed to determine the acute obesity-independent effects of hypothalamic estrogen signaling on glucose metabolism. We studied endogenous glucose production (EGP) and insulin sensitivity during selective modulation of systemic or intrahypothalamic estradiol (E2) signaling in rats 1 week after ovariectomy (OVX). OVX caused a 17% decrease in plasma glucose, which was completely restored by systemic E2. Likewise, the administration of E2 by microdialysis, either in the hypothalamic paraventricular nucleus (PVN) or in the ventromedial nucleus (VMH), restored plasma glucose. The infusion of an E2 antagonist via reverse microdialysis into the PVN or VMH attenuated the effect of systemic E2 on plasma glucose. Furthermore, E2 administration in the VMH, but not in the PVN, increased EGP and induced hepatic insulin resistance. E2 administration in both the PVN and the VMH resulted in peripheral insulin resistance. Finally, sympathetic, but not parasympathetic, hepatic denervation blunted the effect of E2 in the VMH on both EGP and hepatic insulin sensitivity. In conclusion, intrahypothalamic estrogen regulates peripheral and hepatic insulin sensitivity via sympathetic signaling to the liver. 23870689 Factors affecting the job satisfaction levels and quit intentions of academic nurses. The descriptively designed study was conducted in order to determine academic nurses' job satisfaction levels, intention of leaving job and effective reasons. The study was implemented in 10 nursing schools offering postgraduate and doctoral education in Turkey, and data was collected from academics working in these schools who agreed to participate in the study. After obtaining the required approval from the ethics committees and institutional permissions, data was collected from 248 academic nurses using a personal information form and a "Job Satisfaction Scale" between June 2009 and January 2010. The data was analyzed by frequency and percentage distribution, using Cronbach's Alpha coefficient, ANOVA, Qui-Square and Tukey's HSD test for advanced analysis methods with SPSS 11.5 statistics packet software. This study concludes that academic nurses are moderately satisfied with their jobs. In addition, job satisfaction was found to be lower among research assistants, assistant professors, nurses with less than 10years of academic experience, nurses who have completed their doctorate dissertations, or who are working on appointment or contract basis. 23837675 Self-Adjuvanting Polymer-Peptide Conjugates As Therapeutic Vaccine Candidates against Cervical Cancer. Dendrimers are structurally well-defined, synthetic polymers with sizes and physicochemical properties often resembling those of biomacromolecules (e.g., proteins). As a result, they are promising candidates for peptide-based vaccine delivery platforms. Herein, we established a synthetic pathway to conjugate a human papillomavirus (HPV) E7 protein-derived peptide antigen to a star-polymer to create a macromolecular vaccine candidate to treat HPV-related cancers. These conjugates were able to reduce tumor growth and eradicate E7-expressing TC-1 tumors in mice after a single immunization, without the help of any external adjuvant. 23953405 21st century climate change in the European Alps-A review. Reliable estimates of future climate change in the Alps are relevant for large parts of the European society. At the same time, the complex Alpine region poses considerable challenges to climate models, which translate to uncertainties in the climate projections. Against this background, the present study reviews the state-of-knowledge about 21st century climate change in the Alps based on existing literature and additional analyses. In particular, it explicitly considers the reliability and uncertainty of climate projections. Results show that besides Alpine temperatures, also precipitation, global radiation, relative humidity, and closely related impacts like floods, droughts, snow cover, and natural hazards will be affected by global warming. Under the A1B emission scenario, about 0.25°C warming per decade until the mid of the 21st century and accelerated 0.36°C warming per decade in the second half of the century is expected. Warming will probably be associated with changes in the seasonality of precipitation, global radiation, and relative humidity, and more intense precipitation extremes and flooding potential in the colder part of the year. The conditions of currently record breaking warm or hot winter or summer seasons, respectively, may become normal at the end of the 21st century, and there is indication for droughts to become more severe in the future. Snow cover is expected to drastically decrease below 1500-2000m and natural hazards related to glacier and permafrost retreat are expected to become more frequent. Such changes in climatic parameters and related quantities will have considerable impact on ecosystems and society and will challenge their adaptive capabilities. 23648227 Association between major depressive disorder and the norepinephrine transporter polymorphisms T-182C and G1287A: A meta-analysis. Previous studies have implicated norepinephrine transporter (NET) gene polymorphisms in the etiology of major depressive disorder (MDD). Recently, two single nucleotide NET polymorphisms, T-182C (rs2242446) in the promoter region and G1287A (rs5569) in exon 9, were found to be associated with MDD in different populations. However, inconsistent and inconclusive results have also been obtained. In this study, we examined whether rs2242446 and rs5569 genetic variants are related to the etiology of MDD using a meta-analysis. Relevant case-control studies were retrieved by database searching and selected according to established inclusion criteria. Eight articles were identified that tested the relationship between the NET T-182C and/or G1287A polymorphism and MDD. Statistical analyses revealed no significant association between these polymorphisms and MDD (OR=1.23, 95% CI=0.77-1.97, P=0.38 for T-182C; OR=1.00, 95% CI=0.78-1.29, P=0.99 for G1287A). The results must be treated with caution because of the small sample sizes of several included studies. Our findings suggest that the NET T-182C and G1287A polymorphisms are not susceptibility factors for MDD. 23943650 Diminutive somatic deletions in the 5q region lead to a phenotype atypical of classical 5q- syndrome. Classical 5q- syndrome is an acquired macrocytic anemia of the elderly. Similar to Diamond Blackfan anemia (DBA), an inherited red cell aplasia, the bone marrow is characterized by a paucity of erythroid precursors. RPS14 deletions in combination with other deletions in the region have been implicated as causative of the 5q- syndrome phenotype. We asked if smaller, less easily detectable deletions could account for a syndrome with a modified phenotype. We employed SNP array genotyping to identify small deletions in patients diagnosed with DBA and other anemias lacking molecular diagnoses. Diminutive mosaic deletions, involving RPS14, were identified in a 5-year-old patient with non-classical DBA and in a 17-year-old patient with myelodysplastic syndrome. Patients with non-classical DBA and other hypoproliferative anemias may have somatically acquired 5q deletions with RPS14 haploinsufficiency not identified by FISH or cytogenetic testing thus refining the spectrum of disorders with 5q- deletions. This study is registered at ClinicalTrials.gov, Identifier: NCT00106015. 23956129 Isolation and characterization of a TERMINAL FLOWER 1 homolog from Prunus serotina Ehrh. Flowering control is one of the several strategies for gene containment of transgenic plants. TERMINAL FLOWER 1 (TFL1) is known to be involved in the transcriptional repression of genes for inflorescence development. Two TFL1 transcripts with different 3' UTR were cloned from black cherry (Prunus serotina Ehrh.) using reverse transcription-polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE). Corresponding to the two TFL1 transcripts, two PsTFL1 gene sequences, 1248 bp and 1579 bp, were obtained and both contained the same 519 bp coding region which encoded a putative protein of 172 amino acid residues. The phylogenetic analysis of the amino acid sequences showed high identity of PsTFL1 to TFL1 orthologs of other Prunus species, including Yoshino cherry (Prunus × yedoensis Matsum.), peach (Prunus persica (L.) Batsch), apricot (Prunus armeniaca L.) and Japanese apricot (Prunus mume Sieb. et Zucc.). The real-time quantitative PCR detected a single copy of PsTFL1 gene sequences in the black cherry genome with two alleles. The gene expression of PsTFL1 was examined in several tissues including the stems, leaves, shoot tips, and vegetative and floral buds. The highest mRNA level was detected in shoot tips, and the lowest level in the leaves. Transgenic Arabidopsis thaliana (L.) Heynh. plants overexpressing PsTFL1 showed significantly delayed flowering. These plants also showed largely increased vegetative growth, plant height, number of nodes, trichome density, and the conversion of flower to shoot was observed at each node and shoot apex. 23411179 Analysis of the blackening of green pepper (Piper nigrum Linnaeus) berries. This paper investigates polyphenol oxidase (PPO) activity, reduced weight percentage after sun drying, and the changes in colour and appearance of green pepper (Piper nigrum Linnaeus) berries after blanching and sun drying. The results show that the degree of reduced weight percentage and browning in green pepper berries after blanching for 10 min is greater at 100°C than at 90 and 80°C. Moreover, the samples blanched at 100°C for 10 min had the fastest water loss, but the lowest PPO activity. Thus, the PPO enzymatic oxidation of polyphenols might not be the only reason for the browning of green pepper berries. This result is significantly different from that of Variyar, Pendharkar, Banerjeea, and Bandyopadhyay (1988) and therefore deserves further study. 23928377 Late-Onset Exercise in Female Rat Offspring Ameliorates the Detrimental Metabolic Impact of Maternal Obesity. Rising rates of maternal obesity/overweight bring the need for effective interventions in offspring. We observed beneficial effects of postweaning exercise, but the question of whether late-onset exercise might benefit offspring exposed to maternal obesity is unanswered. Thus we examined effects of voluntary exercise implemented in adulthood on adiposity, hormone profiles, and genes involved in regulating appetite and metabolism in female offspring. Female Sprague Dawley rats were fed either normal chow or high-fat diet (HFD) ad libitum for 5 weeks before mating and throughout gestation/lactation. At weaning, female littermates received either chow or HFD and, after 7 weeks, half were exercised (running wheels) for 5 weeks. Tissues were collected at 15 weeks. Maternal obesity was associated with increased hypothalamic inflammatory markers, including suppressor of cytokine signaling 3, TNF-α, IL-1β, and IL-6 expression in the arcuate nucleus. In the paraventricular nucleus (PVN), Y1 receptor, melanocortin 4 receptor, and TNF-α mRNA were elevated. In the hippocampus, maternal obesity was associated with up-regulated fat mass and obesity-associated gene and TNF-α mRNA. We observed significant hypophagia across all exercise groups. In female offspring of lean dams, the reduction in food intake by exercise could be related to altered signaling at the PVN melanocortin 4 receptor whereas in offspring of obese dams, this may be related to up-regulated TNF-α. Late-onset exercise ameliorated the effects of maternal obesity and postweaning HFD in reducing body weight, adiposity, plasma leptin, insulin, triglycerides, and glucose intolerance, with greater beneficial effects in offspring of obese dams. Overall, hypothalamic inflammation was increased by maternal obesity or current HFD, and the effect of exercise was dependent on maternal diet. In conclusion, even after a significant sedentary period, many of the negative impacts of maternal obesity could be improved by voluntary exercise and healthy diet. 23760739 Current survival measures reliably reflect modern sequential treatment in CML: Correlation with prognostic stratifications. Using the data of 723 chronic myeloid leukemia (CML) patients in the chronic phase, we analyzed the prognostic value of the Sokal, Euro, and EUTOS scores as well as the level of BCR-ABL1 and the achievement of complete cytogenetic response (CCgR) at 3 months of imatinib therapy in relation to the so-called current survival measures: the current cumulative incidence (CCI) reflecting the probability of being alive and in CCgR after starting imatinib therapy; the current leukemia-free survival (CLFS) reflecting the probability of being alive and in CCgR after achieving the first CCgR; and the overall survival. The greatest difference between the CCI curves at 5 years after initiating imatinib therapy was observed for the BCR-ABL1 transcripts at 3 months. The 5-year CCI was 94.3% in patients with BCR-ABL1 transcripts ≤ 10% and 57.1% in patients with BCR-ABL1 transcripts > 10% (P = 0.005). Therefore, the examination of BCR-ABL1 transcripts at 3 months may help in early identification of patients who are likely to perform poorly with imatinib. On the other hand, CLFS was not significantly affected by the considered stratifications. In conclusion, our results indicate that once the CCgR is achieved, the prognosis is good irrespective of the starting prognostic risks. Am. J. Hematol. 88:790-797, 2013. © 2013 Wiley Periodicals, Inc. 23253172 Neurochemical control of rapid stress-induced changes in brain aromatase activity. In the male brain, the medial preoptic nucleus (POM) is known to be a critical relay for the activation of sexual behaviour, with the aromatisation of testosterone into 17β-oestradiol (E2 ) playing a key role. Acute stress has been shown to differentially modulate the aromatase enzyme in this and other brain nuclei in a sex-specific manner. In POM specifically, stress induces increases in aromatase activity (AA) that are both rapid and reversible. How the physiological processes initiated during an acute stress response mediate sex- and nuclei- specific changes in AA and which stress response hormones are involved remains to be determined. By examining the relative effects of corticosterone (CORT), arginine vasotocin (AVT, the avian homologue to arginine vasopressin) and corticotrophin-releasing factor (CRF), the present study aimed to define the hormone profile regulating stress-induced increases in AA in the POM. We found that CORT, AVT and CRF all appear to play some role in these changes in the male brain. In addition, these effects occur in a targeted manner, such that modulation of the enzyme by these hormones only occurs in the POM rather than in all aromatase-expressing nuclei. Similarly, in the female brain, the experimental effects were restricted to the POM but only CRF was capable of inducing the stress-like increases in AA. These data further demonstrate the high degree of specificity (nuclei-, sex- and hormone-specific effects) in this system, highlighting the complexity of the stress-aromatase link and suggesting modes through which the nongenomic modulation of this enzyme can result in targeted, rapid changes in local oestrogen concentrations. 23720497 The role of the peritoneum in the pathogenesis of endometriosis. BACKGROUND Endometriosis affects 6-10% of women of reproductive age and is associated with chronic pelvic pain, dysmenorrhoea, dyspareunia and infertility. Endometriosis is defined by the presence of endometrial tissue outside the uterus, most commonly attached to the pelvic peritoneum. The endometrium in women with endometriosis is reported to be altered and there is increasing evidence that the phenotype of the pelvic peritoneum may also play a role in the establishment and maintenance of the disease. The aim of this review is to discuss the putative role of the pelvic peritoneum in the pathophysiology of peritoneal endometriosis. METHODS A review was undertaken of the published literature on (i) the anatomy and physiology of the peritoneum and (ii) the potential roles played by peritoneal cells in the establishment and maintenance of peritoneal endometriosis. The current understanding of the biology of peritoneal endometriosis is summarized and the potential interaction of the peritoneum with ectopic endometrial cells in endometriosis is highlighted. RESULTS Several studies indicate that differential expression of peritoneal mesothelial adhesion factors occurs in women with endometriosis, providing potential ectopic endometrial cell attachment sites for the establishment of endometriosis lesions. Changes in the peritoneal mesothelial cell phenotype, including loss of tight junctions, may allow ectopic cells to bind to, or early lesions to invade into, the extracellular matrix. Epithelial-to-mesenchymal transition of peritoneal mesothelial cells may also lead to an increase in lesion invasion and formation of fibrotic tissue in and around the lesion. There is evidence that the peritoneal mesothelium may also play a role in the invasion potential of ectopic cells by production of MMPs increasing local tissue remodelling. Peritoneal immune scavenging function may be lowered in women with endometriosis; for example there is a notable increase in macrophage-derived secretion products in women with endometriosis associated with increases in cell proliferation, cell adhesion and neovascularization. CONCLUSIONS The pelvic peritoneum appears to play a key role in the development and maintenance of endometriosis. 23932754 A trial of indication based prescribing of antihypertensive medications during computerized order entry to improve problem list documentation. Maintenance of problem lists in electronic medical records is required for the meaningful use incentive and by the Joint Commission. Linking indication with prescribed medications using computerized physician order entry (CPOE) can improve problem list documentation. Prescribing of antihypertensive medications is an excellent target for interventions to improve indication-based prescribing because antihypertensive medications often have multiple indications and are frequently prescribed. To measure the accuracy and completeness of electronic problem list additions using indication-based prescribing of antihypertensives. Clinical decision support (CDS) was implemented so that orders of antihypertensives prompted ordering physicians to select from problem list additions indicated by that medication. An observational analysis of 1000 alerts was performed to determine the accuracy of physicians' selections. At least one accurate problem was placed 57.5% of the time. Inaccurate problems were placed 4.8% of the time. Accuracy was lower in medications with multiple indications and the likelihood of omitted problems was higher compared to medications whose only indication was hypertension. Attending physicians outperformed other clinicians. There was somewhat lower accuracy for inpatients compared to outpatients. CDS using indication-based prescribing of antihypertensives produced accurate problem placement roughly two-thirds of time with fewer than 5% inaccurate problems placed. Performance of alerts was sensitive to the number of potential indications of the medication and attendings vs. other clinicians prescribing. Indication-based prescribing during CPOE can be used for problem list maintenance, but requires optimization. 23410191 Photothermal tautomerization of a UV sunscreen (4-tert-butyl-4'-methoxydibenzoylmethane) in acetonitrile studied by steady-state and laser flash photolysis. The photothermal tautomerization processes between enol and keto forms of 4-tert-butyl-4'-methoxydibenzoylmethane (trade name, Avobenzone) in acetonitrile have been studied by steady-state and laser flash photolysis. The keto form is produced upon photolysis of the enol in only acetonitrile with a quantum yield of 0.014. The molar absorptivity of the keto form was determined. Phototautomerization from the keto to the enol form was not seen. Laser flash photolysis of the keto form recognized the formation of the triplet state. In the dark, the keto form underwent thermal tautomerization to the enol with a lifetime of 5.1 h at 295 K. The enolization rate in acetonitrile was not accelerated by the presence of alcohols and/or water but increased with increasing temperature and followed the Arrhenius expression. The activation energy and the frequency factor were determined for the enolization process from the keto to the enol form. On the basis of the energy states of the tautomers and isomers as estimated by DFT calculations, a schematic energy diagram was determined for the photothermal tautomerization processes in acetonitrile. 23428306 Components of the Interleukin-6 transsignalling system are associated with the metabolic syndrome, endothelial dysfunction and arterial stiffness. OBJECTIVE: The metabolic syndrome (MetS) is an increasing epidemiologic challenge and cardiovascular risk factor. Interleukin-6 (IL-6) is a cytokine that exerts its biological function via a complex orchestration of soluble and membrane bound receptors. We have investigated associations between IL-6 and its soluble receptors, soluble IL-6 receptor (sIL-6r) and soluble glycoprotein 130 (sGP130) and the metabolic syndrome. Furthermore, we have investigated possible associations with endothelial dysfunction and arterial stiffness. METHODS: A total of 563 subjects were included in this study. The Adult Treatment Panel III criteria of the National Cholesterol Education Program were used for the definition of MetS. We used commercially available ELISA to analyse circulating levels of the markers. Pulse wave propagation time (PWP) was determined to assess arterial stiffness. RESULTS: The criteria for having MetS were filled by 221 subjects. sGP130, sIL-6r and IL-6 levels were elevated in subjects with MetS (p<0.05 for all markers), and are associated with increasing components of MetS. Particularly hypertriglyceridaemia, hypertension and fasting plasma glucose (FPG) seem to carry this association. sGP130 (p<0.01), IL-6 (p<0.05) and partially sIL-6r (p<0.05) correlated with markers of endothelial function (E-selectin, I-CAM-1, V-CAM-1) and inversely with PWP after adjustment for relevant covariates. CONCLUSION: sGP130, sIL-6r and IL-6 were significantly elevated in subjects with MetS. In addition, sGP130, IL-6 and partially sIL-6r were associated with markers of endothelial function and arterial stiffness. This finding sheds new light on the role of these inflammatory cytokines in subjects with MetS and the development and progression of clinically silent atherosclerosis. 23839611 Imatinib in neurofibromatosis type 2. A 30-year-old man with a 10-year history of neurofibromatosis type 2 (NF-2) and minimal hearing in his left ear, presented with rapidly progressive disease and risk of total hearing loss. He was started on imatinib and achieved stable disease for 4 months, after which the drug was ceased due to toxicity. He was then treated with bevacizumab for 8 months with a best response of stable disease. 23624311 Foxg1 is required to limit the formation of ciliary margin tissue and Wnt/β-catenin signalling in the developing nasal retina of the mouse. The ciliary margin (CM) develops in the peripheral retina and gives rise to the iris and the ciliary body. The Wnt/β-catenin signalling pathway has been implicated in ciliary margin development. Here, we tested the hypothesis that in the developing mouse retina Foxg1 is responsible for suppressing the Wnt/β-catenin pathway and restricting CM development. We showed that there is excess CM tissue in Foxg1(-/-) null embryos and this expansion is more pronounced in the nasal retina where Foxg1 normally shows its highest expression levels. Results on expression of a reporter allele for Wnt/β-catenin signalling and of Lef1, a target of Wnt/β-catenin signalling, displayed significant upregulation of this pathway in Foxg1(-/-) nulls at embryonic days 12.5 and 14.5. Interestingly, this upregulation was observed specifically in the nasal retina, where normally very few Wnt-responsive cells are observed. These results indicate a suppressive role of Foxg1 on this signalling pathway. Our results reveal a new role of Foxg1 in limiting CM development in the nasal peripheral retina and add a new molecular player in the developmental network involved in CM specification. 23839729 The Effect of an Increased Training Volume on Oxidative Stress. This study examined the influence of training volume on resting and exercise-induced plasma markers of oxidative stress (MDA concentration) and antioxidant status (GPX, CAT & SOD erythrocyte activities). Moderately trained participants (TG) (n=6; 4 males and 2 females; 25±1.8 years) and sedentary control subjects (CG) participated in the 8-week investigation. The TG increased their training volume from ~4.9 to ~18 h.wk-1 by the end of the investigation. Before the increase in training volume and at 2-week intervals the TG completed a 30 km cycling time trial (TT30) where resting-and post-exercise blood was -sampled and analysed for oxidative stress and antioxidant status. The CG had their resting blood sampled and analysed fortnightly. The data showed that TT30 performance improved in the first 4 weeks but remained unchanged in the last 4. Resting plasma MDA and CAT increased in response to training, with no change in the resting activities of erythrocyte GPX and SOD. Post-TT30 MDA and CAT increased over the training period and training hours positively related to both resting-and post-TT30 MDA. The increase in resting MDA and the up-regulation in CAT in response to an increased training volume may have a role in the identification of a training and performance plateau. 23936676 Gastrostomy tube use after transoral robotic surgery for oropharyngeal cancer. Objective. To evaluate factors that influence gastrostomy tube (g-tube) use after transoral robotic surgery (TORS) for oropharyngeal (OP) cancer. Study Design/Methods. Retrospective review of TORS patients with OP cancer. G-tube presence was recorded before and after surgery at followup. Kaplan-Meier and Cox hazards model evaluated effects of early (T1 and T2) and advanced (T3, T4) disease, adjuvant therapy, and free flap reconstruction on g-tube use. Results. Sixteen patients had tonsillar cancer and 13 tongue base cancer. Of 22 patients who underwent TORS as primary therapy, 17 had T1 T2 stage and five T3 T4 stage. Seven underwent salvage therapy (four T1 T2 and three T3 T4). Nine underwent robotic-assisted inset free flap reconstruction. Seventeen received adjuvant therapy. Four groups were compared: primary early disease (PED) T1 and T2 tumors, primary early disease with adjunctive therapy (PEDAT), primary advanced disease (PAD) T3 and T4 tumors, and salvage therapy. Within the first year of treatment, 0% PED, 44% PEDAT, 40% PAD, and 57% salvage patients required a g-tube. Fourteen patients had a temporary nasoenteric tube (48.3%) postoperatively, and 10 required a g-tube (34.5%) within the first year. Four of 22 (18.2%) with TORS as primary treatment were g-tube dependent at one year and had received adjuvant therapy. Conclusion. PED can be managed without a g-tube after TORS. Similar feeding tube rates were found for PEDAT and PAD patients. Salvage patients have a high rate of g-tube need after TORS. 23959629 Reaction of small heat-shock proteins to different kinds of cellular stress in cultured rat hippocampal neurons. Upregulation of small heat-shock proteins (sHsps) in response to cellular stress is one mechanism to increase cell viability. We previously described that cultured rat hippocampal neurons express five of the 11 family members but only upregulate two of them (HspB1 and HspB5) at the protein level after heat stress. Since neurons have to cope with many other pathological conditions, we investigated in this study the expression of all five expressed sHsps on mRNA and protein level after sublethal sodium arsenite and oxidative and hyperosmotic stress. Under all three conditions, HspB1, HspB5, HspB6, and HspB8 but not HspB11 were consistently upregulated but showed differences in the time course of upregulation. The increase of sHsps always occurred earlier on mRNA level compared with protein levels. We conclude from our data that these four upregulated sHsps (HspB1, HspB5, HspB6, HspB8) act together in different proportions in the protection of neurons from various stress conditions. 23906036 The P2X7 receptor-inflammasome complex has a role in modulating the inflammatory response in primary Sjögren's syndrome. Innate and adaptive immunity may contribute to gland dysfunction in patients with primary Sjögren's syndrome (pSS). The P2X7 receptor (P2X7 R)-NLRP3 inflammasome complex modulates the release of the inflammatory cytokines IL-1β and IL-18. The presence of P2X7 R in salivary glands suggests an interesting scenario for the initiation and amplification of the innate immune response in pSS. Therefore, the aim of this study was to assess the role of the P2X7 R-NLRP3 inflammasome in pSS. Twenty-one consecutive patients with pSS according to the American-European Consensus Group criteria and 15 patients with sicca syndrome (i.e. without Sjögren's syndrome, non-SS) were enrolled in this study, together with six control (CTL) subjects. Expression of the P2X7R-NLRP3 platform and IL-18 was determined by real-time PCR and western blotting in gland specimens and peripheral lymphomonocytes; data were related to patients\x92 clinical, serological and histopathological characteristics. The presence of IL-18 was determined in gland and saliva samples. P2X7 R expression was significantly higher in salivary glands from individuals with pSS than in those from non-SS and CTL subjects. Accordingly, the gene expression levels of the inflammasome components NLRP3, ASC and caspase-1 were significantly higher in pSS gland specimens, and this was paralleled by an increased expression of mature IL-18 in pSS saliva samples. The expression of both the P2X7 R and the inflammasome components was a marker of disease-related glandular involvement, being increased in patients with anti-Ro/SSA positivity and correlated with focus score. The results of this study suggest an involvement of the P2X7 R-inflammasome-caspase-1-IL-18 axis in the development of pSS exocrinopathy. This finding provides the basis for studying the complex mechanisms underlying pSS, as well as for developing novel potential therapeutic strategies. 23741975 Rapamycin interacts synergistically with idarubicin to induce T-leukemia cell apoptosis in vitro and in a mesenchymal stem cell simulated drug-resistant microenvironment via Akt/mammalian target of rapamycin and extracellular signal-related kinase signaling pathways. T-cell acute lymphoblastic leukemias (T-ALLs) are clonal lymphoid malignancies with a poor prognosis, and still a lack of effective treatment. Here we examined the interactions between the mammalian target of rapamycin (mTOR) inhibitor rapamycin and idarubicin (IDA) in a series of human T-ALL cell lines Molt-4, Jurkat, CCRF-CEM and CEM/C1. Co-exposure of cells to rapamycin and IDA synergistically induced T-ALL cell growth inhibition and apoptosis mediated by caspase activation via the intrinsic mitochondrial pathway and extrinsic pathway. Combined treatment with rapamycin and IDA down-regulated Bcl-2 and Mcl-1, and inhibited the activation of phosphoinositide 3-kinase (PI3K)/mTOR and extracellular signal-related kinase (ERK). They also played synergistic pro-apoptotic roles in the drug-resistant microenvironment simulated by mesenchymal stem cells (MSCs) as a feeder layer. In addition, MSCs protected T-ALL cells from IDA cytotoxicity by up-regulating ERK phosphorylation, while rapamycin efficiently reversed this protective effect. Taken together, we confirm the synergistic antitumor effects of rapamycin and IDA, and provide an insight into the potential future clinical applications of combined rapamycin-IDA regimens for treating T-cell malignancies. 23581395 Impact of homocysteine on cortical perfusion and cognitive decline in mild Alzheimer's dementia. Elevated plasma total homocysteine level (tHcy) is associated with increased risk of dementia via increased white matter changes or reduction in cortical volume. Whether tHcy has an independent impact on regional perfusion and if it can predict a more rapid cognitive decline in mild Alzheimer dementia (AD) warrants investigation. Eighty AD patients with a clinical dementia rating of 1 were enrolled. Their Cognitive Ability Screening Instrument (CASI) scores on enrolment and after 1 year of follow-up as well as their perfusion index (PI) from single photon emission computed tomography upon enrolment were analyzed. In cross-sectional analysis, elevated tHcy was associated with lower frontal PI independent of cerebrovascular risk factors (β = -0.35, P = 0.009). The CASI scores correlated with temporo-parietal PI (Pearson r range 0.3-0.39, P < 0.01) but not with tHcy or frontal PI. By longitudinal analysis, only tHcy level was related to a more rapid cognitive decline (odds ratio for executive function score 1.82; odds ratio for total CASI score 1.74). Cognitive performance in mild AD can be reflected by hypo-perfusion of the temporo-parietal region while frontal hypo-perfusion may be mediated by tHcy. tHcy level is an independent risk factor for rapid cognitive decline, especially in the executive function. 23873866 Differential Regulation of White-Opaque Switching by Individual Subunits of C. albicans Mediator. The multi-subunit eukaryotic Mediator complex integrates diverse positive and negative gene regulatory signals and transmits them to the core transcription machinery. Mutations in individual subunits within the complex can lead to decreased or increased transcription of certain subsets of genes, which are highly specific to the mutated subunit. Recent studies suggest a role for Mediator in epigenetic silencing. Using white-opaque morphological switching in C. albicans as a model we have shown that Mediator is required for the stability of both the epigenetic silenced (white) and active (opaque) states of the bi-stable transcription circuit driven by the master regulator Wor1. Individual deletions of eight C. albicans Mediator subunits has shown that different Mediator subunits have dramatically diverse effects on the directionality, frequency and environmental induction of epigenetic switching. Among the Mediator deletion mutants analyzed, only Med12 has a steady state transcriptional effect on the components of the Wor1 circuit that clearly corresponds to its effect on switching. Med16 and Med9 have been found to be among a small subset of genes that are required for the stability of both the white and opaque states. Deletion of the Med3 subunit completely destabilizes the opaque state, even though the Wor1 transcription circuit is intact and can be driven by ectopic expression of Wor1. The highly impaired ability of the med3 deletion mutant to mate, even when Wor1 expression is ectopically induced, reveals that the activation of the Wor1 circuit can be decoupled from the opaque state and one of its primary biological consequences. 23879174 Photocontrol over Cucurbit[8]uril Complexes: Stoichiometry and Supramolecular Polymers. Herein we report the photocontrol of cucurbit[8]uril (CB[8])-mediated supramolecular polymerization of azobenzene-containing monomers. The CB[8] polymers were characterized both in solution and in the solid state. These host-guest complexes can be reversibly switched between highly thermostable photostationary states. Moreover, a remarkable stabilization of Z-azobenzene was achieved by CB[8] complexation, allowing for structural characterization in the solid state. 23538121 Degradation of 2,4-dinitrophenol using a combination of hydrodynamic cavitation, chemical and advanced oxidation processes. In the present work, degradation of 2,4-dinitrophenol (DNP), a persistent organic contaminant with high toxicity and very low biodegradability has been investigated using combination of hydrodynamic cavitation (HC) and chemical/advanced oxidation. The cavitating conditions have been generated using orifice plate as a cavitating device. Initially, the optimization of basic operating parameters have been done by performing experiments over varying inlet pressure (over the range of 3-6 bar), temperature (30 °C, 35 °C and 40 °C) and solution pH (over the range of 3-11). Subsequently, combined treatment strategies have been investigated for process intensification of the degradation process. The effect of HC combined with chemical oxidation processes such as hydrogen peroxide (HC/H2O2), ferrous activated persulfate (HC/Na2S2O8/FeSO4) and HC coupled with advanced oxidation processes such as conventional Fenton (HC/FeSO4/H2O2), advanced Fenton (HC/Fe/H2O2) and Fenton-like process (HC/CuO/H2O2) on the extent of degradation of DNP have also been investigated at optimized conditions of pH 4, temperature of 35 °C and inlet pressure of 4 bar. Kinetic study revealed that degradation of DNP fitted first order kinetics for all the approaches under investigation. Complete degradation with maximum rate of DNP degradation has been observed for the combined HC/Fenton process. The energy consumption analysis for hydrodynamic cavitation based process has been done on the basis of cavitational yield. Degradation intermediates have also been identified and quantified in the current work. The synergistic index calculated for all the combined processes indicates HC/Fenton process is more feasible than the combination of HC with other Fenton like processes. 23950039 Neonatal murine skin-derived cells transplanted using a mini-chamber model produce robust and normal hair. Hair follicle reconstitution models are useful tools for investigating signalling and cytokines during hair follicle morphogenesis and cycling. The chamber model is one of the most established methods available for the study of hair follicle reconstitution and appears to be the most reproducible. However, the chamber model has several deficiencies: infection of skin wounds and subsequent animal death commonly occur, a large number of cells are required and only one chamber can be transplanted onto each animal. We modified these deficiencies by using a mini-chamber method, which has the advantages of having a high graft take rate, requiring fewer cells and allowing several mini-chambers to be transplanted onto each animal. In our study, cultured dermal cells at different passages (0 to high) lost the ability to reconstruct hair follicles, but dermal cells cultured overnight (12 h) retained this ability. Using the assay, newborn mice dermal cells that were freshly isolated and cultured overnight (12 h), as well as cultured dermal papilla cells from mice vibrissa follicles, all reconstructed hair follicles. However, cultured dermal papilla cells from human scalp follicles could not reconstruct hair follicles. Copyright © 2013 John Wiley & Sons, Ltd. 23904355 GSK-3β function in bone regulates skeletal development, whole body metabolism and male life span. Glycogen synthase kinase 3 beta (GSK-3β) is an essential negative regulator or "brake" on many anabolic-signalling pathways including Wnt and insulin. Global deletion of GSK-3β results in perinatal lethality and various skeletal defects. The goal of our research was to determine GSK-3β cell-autonomous effects and postnatal roles in the skeleton. We used the 3.6Kb Col1a1 promoter to inactivate the Gsk3b gene (Col1a1-Gsk3b KO) in skeletal cells. Mutant mice exhibit decreased body fat and postnatal bone growth, as well as delayed development of several skeletal elements. Surprisingly, the mutant mice display decreased circulating glucose and insulin levels despite normal expression of GSK-3β in metabolic tissues. We showed that these effects are due to an increase in global insulin sensitivity. Most of the male mutant mice died post weaning. Prior to death, blood glucose changed from low to high, suggesting a possible switch from insulin sensitivity to resistance. These male mice die with extremely large bladders that are preceded by damage to the urogenital tract, defects that are also seen type II diabetes. Our data suggests that skeletal-specific deletion of GSK-3β affects global metabolism and sensitizes male mice to developing type II diabetes. 23873959 Single molecule quantitation and sequencing of rare translocations using microfluidic nested digital PCR. Cancers are heterogeneous and genetically unstable. New methods are needed that provide the sensitivity and specificity to query single cells at the genetic loci that drive cancer progression, thereby enabling researchers to study the progression of individual tumors. Here, we report the development and application of a bead-based hemi-nested microfluidic droplet digital PCR (dPCR) technology to achieve 'quantitative' measurement and single-molecule sequencing of somatically acquired carcinogenic translocations at extremely low levels (<10(-6)) in healthy subjects. We use this technique in our healthy study population to determine the overall concentration of the t(14;18) translocation, which is strongly associated with follicular lymphoma. The nested dPCR approach improves the detection limit to 1 × 10(-7) or lower while maintaining the analysis efficiency and specificity. Further, the bead-based dPCR enabled us to isolate and quantify the relative amounts of the various clonal forms of t(14;18) translocation in these subjects, and the single-molecule sensitivity and resolution of dPCR led to the discovery of new clonal forms of t(14;18) that were otherwise masked by the conventional quantitative PCR measurements. In this manner, we created a quantitative map for this carcinogenic mutation in this healthy population and identified the positions on chromosomes 14 and 18 where the vast majority of these t(14;18) events occur. 23291834 Pancreatic retention cyst: multi-modality imaging findings and review of the literature. To investigate the multi-modality imaging presentation of the pancreatic retention cyst (PRC) with pathologic correlation. Imaging data including CT, MRI, endoscopic ultrasonography (EUS) and EUS guided fine needle aspiration (EUS-FNA), and endoscopic retrograde cholangiopancreatography (ERCP) in fifteen patients (five males and ten females; mean age, 44.5 years) with pathologically proven PRC were analyzed retrospectively, and imaging features were correlated with pathological findings. Sixteen PRCs of 15 patients were included in this study. The mean size of PRCs was 4.4 Ã— 4.6 cm (range 0.5 Ã— 0.6-8.1 Ã— 10.1 cm). PRC were round (n = 11), oval (n = 2), or lobular (n = 3). Punctiform calcification of the wall on CT (n = 2), thin septa (n = 4), thin wall (n = 3), and dilation of upstream pancreatic duct (n = 6; mean diameter, 4.3 mm) were detected. Dilation of upstream pancreatic duct was smooth in five PRCs and irregular in one PRC with pancreatic duct with punctiform calcification. Communication of PRCs with pancreatic duct was seen in two patients (one on CT, one on ERCP). Pancreatic inflammation and neoplasm were detected in four and two patients, respectively. PRC typically presents as a well-defined, round cystic lesion, and different associated pathologic conditions including pancreatic inflammation and neoplasm may be detected in some patients on the multi-modality imaging examinations. Smooth dilation of upstream pancreatic duct with uncommon communication to the cyst may be helpful for the differentiation. Combination of a variety of imaging modalities could contribute to improve the diagnosis. 23747006 Recurrent fractures as a new skeletal problem in the course of Angelman syndrome. Angelman syndrome is a genetically inherited syndrome with severe retardation of psychomotor development and speech disturbances, usually accompanied by epilepsy, typical dysmorphic features, and some skeletal symptoms. The aim of the current report is to present new skeletal symptoms which may occur in the course of AS, based on a case report of an 8-year-old girl with confirmed 15q11;12 microdeletion and recurrent low-trauma bone fractures. According to our knowledge it is the first report of such skeletal symptoms in patient with a diagnosis of AS. 23944611 Terminally Grafted Chain Layers in Oligomer-Monomer Solutions: Predictions from a Density Functional Theory. The structure of grafted chain layers immersed in an explicit solvent consisting of chain molecules is studied using density functional theory. We consider bonded layers built of short grafted chains at a moderate grafting density. We investigate the grafted layers in contact with oligomeric solvents and oligomer-monomer solutions. The chain molecules are freely jointed spherical segments. The substrate is assumed to be inert with respect to the grafted chains. The mobile molecules interact with the surface via Lennard-Jones (9-3) potential. The interactions between mobile chains, monomers, as well as segments of the tethered chains are described by Lennard-Jones (12-6) potential. We discuss how the structure of the grafted chain layer depends on the length of mobile chains and strengths of grafted chain-oligomer, oligomer-substrate, oligomer-oligomer, and oligomer-monomer interactions. We study the impact of mixture composition on the height of the bonded layer for selected model systems. The results are consistent with previous experimental and simulation data. 23786742 Subthalamic nucleus deep brain stimulation: an invaluable role for MER. Subthalamic nucleus (STN) deep brain stimulation (DBS) is currently the main surgical procedure for medically refractory Parkinson's disease. The benefit of intra-operative microelectrode recording (MER) for the purpose of neurophysiological localization and mapping of the STN continues to be debated. A retrospective review of the charts and operative reports of all patients receiving STN DBS implantation for Parkinson's disease at our institution from January 2004 to March 2011 was done. Data from 43 of 44 patients with Parkinson's disease treated with STN DBS were reviewed. The average number of tracts on the left was 2.4, versus 2.3 on the right. The average dorsal and ventral anatomical boundaries of the STN based on Schaltenbrand's Stereotactic Atlas were estimated to be at -5.0 mm above and +1.4 mm below target respectively. The average dorsal and ventral boundaries of the STN using MER were -2.6 mm above and +2.0 mm below target respectively. The average dorsal-ventral distance of the STN as predicted by Stereotactic Atlas was 6.4 mm, compared to 4.6 mm as determined by MER. MER demonstrated the average dorsal and ventral boundaries on the left side were -2.6 mm and +2.2 mm from target respectively, while the average dorsal and ventral boundaries on the right side were -2.5 mm and +1.8 mm from target respectively with MER. MER in STN DBS surgery demonstrated measurable difference between stereotactic atlas/MRI STN target and neurophysiologic STN localization. 23703320 Co-processing CH4 and oxygenates on Mo/H-ZSM-5: 2. CH4-CO2 and CH4-HCOOH mixtures. Co-processing of formic acid or carbon dioxide with CH4 (FA/CH4 = 0.01-0.03 and CO2/CH4 = 0.01-0.03) on Mo/H-ZSM-5 catalysts at 950 K with the prospect of kinetically coupling dehydrogenation and deoxygenation cycles results instead in a two-zone, staged bed reactor configuration consisting of upstream oxygenate/CH4 reforming and downstream CH4 dehydroaromatization. The addition of an oxygenate co-feed (oxygenate/CH4 = 0.01-0.03) causes oxidation of the active molybdenum carbide catalyst while producing CO and H2 until completely converted. Forward rates of C6H6 synthesis are unaffected by the introduction of an oxygenate co-feed after rigorously accounting for the thermodynamic reversibility caused by the H2 produced in oxygenate reforming reactions and the fraction of the active catalyst deemed unavailable for CH4 DHA. All effects of co-processing oxygenates with CH4 can be construed in terms of an approach to equilibrium. 23624385 The extraction and analysis of cylindrospermopsin from human serum and urine. The naturally derived cyanotoxin, cylindrospermopsin (CYN), has been detected in freshwater systems worldwide and poses a threat to human health. The methods for the extraction and detection of this toxin in source water are well documented, but methods for CYN determination in exposed individuals have not been investigated. In this study, the extraction and detection of CYN from two different matrices, serum and urine, was explored. Both serum and urine matrices inherently produce interference with analytical analyses and require extensive clean-up. Methods for extraction of CYN from both matrices were developed and validated using fortified samples. Serum extraction included homogenization followed by protein precipitation and solid phase extraction (SPE). Urine samples were processed using filtration, pH manipulation, and SPE. Analyses using a commercially available enzyme-linked immunosorbent assay (ELISA) and liquid chromatography coupled with mass spectrometry (LC/MS/MS) were assessed. Matrix effects inhibited ELISA's use as a quantitative tool for both matrices. LC/MS/MS was determined to be the most effective and reproducible means to detect and quantify CYN. The method detection limits determined in this study using LC/MS/MS were 0.25 and 0.50 ng mL(-1) for serum and urine, respectively. This method can be used to test individuals exposed to blooms of cyanobacteria producing CYN. 23876153 Diseases Associated with General Amino Acid Transporters of the Solute Carrier 6 Family (SLC6). Amino acid transporters of the SLC6 family mediate the Na(+)-dependent uptake of neutral amino acids into neurons and epithelial cells of the intestine, kidney and other organs. They are integral parts of amino acid homeostasis in the whole body and the brain. In the intestine they are involved in protein absorption, while in the kidney they regulate plasma amino acid concentrations through reabsorption. The metabolic role of SLC6 amino acid transporters in the brain is less clear and most likely related to anaplerosis of the TCA cycle. Mutations in these transporters cause rare inherited disorders such as Hartnup disorder and iminoglycinuria. They may also play a role in complex traits such as depression, anxiety, obesity, diabetes and cancer. The review does not cover the transport of neurotransmitter amino acids. 23444960 Temperature dependence of transport properties of spiro-MeOTAD as a hole transport material in solid-state dye-sensitized solar cells. The internal transport and recombination parameters of solid-state dye-sensitized solar cells (ssDSCs) using the amorphous organic semiconductor 2,2',7,7'-tetrakis(N,N-di-p-methoxyphenylamine)-9,9'-spirobifluorene (spiro-MeOTAD) as a hole transport material (HTM) are investigated using electrical impedance spectroscopy. Devices were fabricated using flat and nanostructured TiO2 and compared to systems using nanostructured ZrO2 to differentiate between the transport processes within the different components of the ssDSC. The effect of chemically p-doping the HTM on its transport was investigated, and its temperature dependence was examined and analyzed using the Arrhenius equation. Using this approach the activation energy of the hole hopping transport within the undoped spiro-MeOTAD film was determined to be 0.34 ± 0.02 and 0.40 ± 0.02 eV for the mesoporous TiO2 and ZrO2 systems, respectively. 23945268 Comments on the "No-Prop" algorithm. This letter points out that the main ideas and conclusions of the "The No-Prop algorithm" paper which has recently appeared in this journal were proposed earlier by G.-B. Huang et al. 10 years ago and intensively discussed and applied by other authors in the past 10 years. 23596171 Extracellular nucleotides inhibit oxalate transport by human intestinal Caco-2-BBe cells through PKC-δ activation. Nephrolithiasis remains a major health problem in Western countries. Seventy to 80% of kidney stones are composed of calcium oxalate, and small changes in urinary oxalate affect risk of kidney stone formation. Intestinal oxalate secretion mediated by the anion exchanger SLC26A6 plays an essential role in preventing hyperoxaluria and calcium oxalate nephrolithiasis, indicating that understanding the mechanisms regulating intestinal oxalate transport is critical for management of hyperoxaluria. Purinergic signaling modulates several intestinal processes through pathways including PKC activation, which we previously found to inhibit Slc26a6 activity in mouse duodenal tissue. We therefore examined whether purinergic stimulation with ATP and UTP affects oxalate transport by human intestinal Caco-2-BBe (C2) cells. We measured [¹⁴C]oxalate uptake in the presence of an outward Cl⁻ gradient as an assay of Cl⁻/oxalate exchange activity, ≥50% of which is mediated by SLC26A6. We found that ATP and UTP significantly inhibited oxalate transport by C2 cells, an effect blocked by the PKC inhibitor Gö-6983. Utilizing pharmacological agonists and antagonists, as well as PKC-δ knockdown studies, we observed that ATP inhibits oxalate transport through the P2Y₂ receptor, PLC, and PKC-δ. Biotinylation studies showed that ATP inhibits oxalate transport by lowering SLC26A6 surface expression. These findings are of potential relevance to pathophysiology of inflammatory bowel disease-associated hyperoxaluria, where supraphysiological levels of ATP/UTP are expected and overexpression of the P2Y₂ receptor has been reported. We conclude that ATP and UTP inhibit oxalate transport by lowering SLC26A6 surface expression in C2 cells through signaling pathways including the P2Y₂ purinergic receptor, PLC, and PKC-δ. 23546648 Association of serum total bilirubin levels with the severity, extent and subtypes of coronary atherosclerotic plaques detected by coronary CT angiography. In this study, we aimed to evaluate whether serum total bilirubin was associated with the severity and morphology of coronary atherosclerotic plaques detected by computed tomography angiography (CTA). The study population consisted of 1,115 patients (55.2 % men) who underwent dual-source 64-slice CTA for the assessment of coronary artery disease (CAD). Coronary arteries were evaluated on 16 segment basis and critical coronary plaque was described as luminal narrowing >50 %, whereas plaque morphology was assessed on per segment basis. Serum bilirubin levels were determined using commercially available assay kits. The critical atherosclerotic lesions were detected in 431/1,115 (38.6 %) subjects by CTA. Serum total bilirubin levels were found to be lower in patients with any coronary plaque (0.62 ± 0.21 vs. 0.70 ± 0.25 mg/dL, p = 0.002). Also bilirubin level was lower in patients with critical stenosis compared to non-critical stenosis (0.57 ± 0.18 vs. 0.70 ± 0.24 mg/dL, p < 0.001). Subjects having primarily noncalcified plaque (NCP) and mixed plaque (MP) have lower bilirubin levels compared to calcified plaque (CP) and normal subjects (0.62 ± 0.20 for NCP and 0.60 ± 0.19 for MP, 0.65 ± 0.26 for CP and 0.71 ± 0.25 for normal subjects, p < 0.001). This independent association was remained for NCP after multinominal regression analysis (OR: 0.76; 95 % CI 0.58-0.88; p < 0.001). Our study demonstrated that serum bilirubin level was significantly associated with the presence, severity and the noncalcified morphology of atherosclerotic plaques detected by CTA. Further prospective clinical studies are needed to clarify the exact physiopathologic and prognostic role of bilirubin in CAD. 23789977 Dendritic gold nanowire growth observed in liquid with transmission electron microscopy. The growth of nanoscale gold dendrites was studied in situ in a thin liquid film with transmission electron microscopy (TEM) using a liquid cell with silicon nitride (SiN) windows. Gold nanoparticle seeds were covered by a thin liquid layer containing precursor solution. Dendrite nucleation was induced by the electron beam leading to an initial burst of growth. The growth then settled at tip velocities between 0.1 and 2.0 nm/s for different dendrites. Tip velocities fluctuated as different dendrite geometries grew from the tips. Those dendrites showing granularities in their structure experienced the largest growth speed. Comparison of the observed velocities with diffusion-limited growth rates suggests that dendrite growth in thin films at this scale is limited by diffusion. The described method may find application in research on the mechanisms behind dendrite growth and also to study other types of anisotropic growth of nanomaterials driven by crystal and twin geometries. 23334403 Almorexant effects on CYP3A4 activity studied by its simultaneous and time-separated administration with simvastatin and atorvastatin. PURPOSE: To characterise further the previously observed cytochrome P450 3A4 (CYP3A4) interaction of the dual orexin receptor antagonist almorexant. METHODS: Pharmacokinetic interactions were investigated (n = 14 healthy male subjects in two treatment groups) between almorexant at steady-state when administered either concomitantly or 2 h after administration of single doses of simvastatin (40 mg) or atorvastatin (40 mg). RESULTS: Almorexant dose-dependently increased simvastatin exposure (AUC(0-∞)) when administered concomitantly [geometric mean ratios (90 % CI): 2.5 (2.1, 2.9) (100 mg), 3.9 (3.3, 4.6) (200 mg)], but not C(max) [3.7 (3.0, 4.5) for both doses]. Time-separated administration resulted in relevant reductions of the interaction [AUC(0-∞): 1.4 (1.2, 1.7) (100 mg), 1.7 (1.5, 2.0) (200 mg); C(max): 1.5 (1.3, 1.9) (100 mg), 1.9 (1.6, 2.4) (200 mg)]. Similar results were obtained for hydroxyacid simvastatin. Independent of almorexant dose and relative time of administration, AUC(0-∞) and C(max) of atorvastatin increased (ratios ranged from 1.1 to 1.5). AUC(0-∞) and C(max) of o-hydroxy atorvastatin decreased dose-independently [AUC(0-∞): 0.8 (0.8, 0.9) (100 mg), 0.6 (0.5, 0.6) (200 mg); C(max): 0.3 (0.3, 0.4) (100 mg), 0.2 (0.2, 0.3) (200 mg)] when atorvastatin was concomitantly administered. C(max) of o-hydroxy atorvastatin slightly decreased (0.8 for both doses) following time-separated administration; AUC(0-∞) was unchanged. CONCLUSIONS: Whereas almorexant increased simvastatin exposure dose- and relative time of administration-dependently, atorvastatin exposure increased to a smaller extent and irrespective of dose and time. This suggests that the observed interaction of almorexant with simvastatin is mainly caused by intestinal CYP3A4 inhibition, whereas the interaction with atorvastatin is more due to hepatic CYP3A4 inhibition. 23790910 A novel glycoprotein from mushroom Hypsizygus marmoreus (Peck) Bigelow with growth inhibitory effect against human leukaemic U937 cells. This study was to isolate the anti-leukaemic component from edible mushroom Hypsizygus marmoreus (Peck) Bigelow. Crude protein was extracted from the basidioma, and then purified with DEAE-Sepharose CL-6B ion exchange chromatography followed by Sephacryl S-300 gel filtration. A protein which exerted high growth inhibitory effect on human leukaemic U937 cells and sufficient toxicological safety on normal human white blood cells was isolated and named HM-3A. Electrophoresis showed HM-3A approximately 52kDa in size. N-terminal analysis found the amino acid sequence ATTQWKTSAA and confirmed HM-3A a novel protein. High-performance anion-exchange column chromatography revealed HM-3A a glycoprotein with galactose as the major monosaccharide. Haemagglutination assay proved it non-lectin. We suggest that HM-3A is worth further investigation for antitumour use. 23792696 Picoliter droplets developed as microreactors for ultrafast synthesis of multi-color water-soluble CdTe quantum dots. Picoliter droplets were developed as microreactors for ultrafast and continuous synthesis of multi-color, water-soluble CdTe quantum dots (QDs). Through a slight change in the local controllable reaction temperature of 1-2 °C, we could obtain a series of different colored fluorescent QDs in about 1 min. 23850147 UDP-glucuronosyltransferase 2B17 genotype and the risk of lung cancer among Austrian Caucasians. Background: The enzyme uridine diphospho glucuronosyltansferase 2B17 (UGT2B17) glucuronidates several endogenous and exogenous compounds, including carcinogens from tobacco smoke like 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanl (NNAL). UGT2B17 shows a remarkable copy number variation (CNV) and an association between deletion genotype and increased risk of lung adenocarcinoma in women has been previously reported. Methods: We investigated the UGT2B17 CNV by PCR in 453 Austrian lung cancer patients and in 449 healthy donors and analyzed the impact on lung cancer susceptibility and outcome. Results: Copy numbers of UGT2B17 were 44.4% (+/+), 42.2% (+/-) and 13.5% (-/-) in lung cancer patients and 43.0% (+/+), 46.3% (+/-) and 10.7% (-/-) among healthy donors. The null genotype was not significantly more frequent among women with adenocarcinoma compared to healthy women (p=0.59). There was no association with overall survival (p=0.622) and no significant sex-associated (p=0.423) or histology-related impact on development of lung cancer. Conclusion: UGT2B17 deletion genotype was not associated with a significant risk for lung cancer development or outcome in our Central European patient cohort. Our study indicates that UGT2B17 is not a crucial factor in lung carcinogenesis among Caucasians and shows the importance of investigating such markers in large cohorts from different populations. 23787770 Sleep and movement disorders. The aim is to review sleep disturbances in different movement disorders, mainly Parkinson's disease, and highlight current concepts on merging the boundaries between movement disorders and dissociative states of being. Since the observation that rapid eye movement sleep behavior disorder (RBD) may be an early marker of neurodegeneration, many studies focused on this disorder for the opportunity to explore the pathogenetic mechanisms underlying movement disorder and future neuroprotective therapies. It is also increasingly evident that this disorder is a possible marker for incoming dementia and for a general worst prognosis. Mechanisms of excessive daytime sleepiness in Parkinson's disease are still to be clarified and, if the role of hypocretin neuron loss is still doubtful, attention is moving to the role of monoaminergic system disruption. The role of dopamine in circadian rhythm regulation is opening new scenarios, namely the disruption of clock genes expression. Finally, the close relationship between sleep and movement disorder is emerging also in primarly sleep disorders. Recent studies provided new insights into the links between sleep and movement disorder that may simplify the diagnostic process and shed light on the underlying pathophysiological mechanisms. 23918173 Host Signal Transduction and Protein Kinases Implicated in Legionella Infection. Modulation of the phosphorylation status of proteins by both kinases and phosphatases plays an important role in cellular signal transduction. Challenge of host cells by Legionella pneumophila manipulates the phosphorylation state of multiple host factors. These changes play roles in bacterial uptake, vacuole modification, cellular survival, and the immune response. In addition to modification by host cell kinases in response to the bacterium, L. pneumophila translocates bacterial kinases into the host cell that may contribute to further signaling modifications. Proper regulation of host cell signaling by L. pneumophila is necessary for its ability to replicate intracellulary, while avoiding host defenses. 23668188 STIM1 negatively regulates Ca²⁺ release from the sarcoplasmic reticulum in skeletal myotubes. STIM1 (stromal interaction molecule 1) mediates SOCE (store-operated Ca²⁺ entry) in skeletal muscle. However, the direct role(s) of STIM1 in skeletal muscle, such as Ca²⁺ release from the SR (sarcoplasmic reticulum) for muscle contraction, have not been identified. The times required for the maximal expression of endogenous STIM1 or Orai1, or for the appearance of puncta during the differentiation of mouse primary skeletal myoblasts to myotubes, were all different, and the formation of puncta was detected with no stimulus during differentiation, suggesting that, in skeletal muscle, the formation of puncta is a part of the differentiation. Wild-type STIM1 and two STIM1 mutants (Triple mutant, missing Ca²⁺-sensing residues but possessing the intact C-terminus; and E136X, missing the C-terminus) were overexpressed in the myotubes. The wild-type STIM1 increased SOCE, whereas neither mutant had an effect on SOCE. It was interesting that increases in the formation of puncta were observed in the Triple mutant as well as in wild-type STIM1, suggesting that SOCE-irrelevant puncta could exist in skeletal muscle. On the other hand, overexpression of wild-type or Triple mutant, but not E136X, attenuated Ca²⁺ releases from the SR in response to KCl [evoking ECC (excitation-contraction coupling) via activating DHPR (dihydropyridine receptor)] in a dominant-negative manner. The attenuation was removed by STIM1 knockdown, and STIM1 was co-immunoprecipitated with DHRP in a Ca²⁺-independent manner. These results suggest that STIM1 negatively regulates Ca²⁺ release from the SR through the direct interaction of the STIM1 C-terminus with DHPR, and that STIM1 is involved in both ECC and SOCE in skeletal muscle. 23964610 Using ibuprofen to treat croup in six children presenting to an emergency unit. Between January and April 2013, we performed a simple explorative study with oral ibuprofen 8 mg/kg in six consecutive children - four boys and two girls aged from one to seven-years-of-age (median four years) - who presented to our emergency unit with a rather mild attack of croup. This letter reports our initial experiences of this treatment. Croup is characterised by inspiratory stridor, barking cough, and hoarseness that typically occur in children between one and six-years-of-age. It results from inflammation in the larynx and subglottic airway, which is mostly caused by a parainfluenza virus (1). This article is protected by copyright. All rights reserved. 23330673 Infection trials in mice suggest that Macrorhabdus ornithogaster is not capable of growth in mammals. Abstract The objective of this study was to determine if Macrorhabdus ornithogaster, a yeast recovered from the junction of the proventriculus and ventriculus of the stomach of parrots and other birds, can infect mice. Fifteen healthy ARC (S) female mice (age 10 weeks) were incoculated with M. ornithogaster by gavage at (two different dosage rates [n = 5]) or intraperitoneal injection (n = 5) (one dosage rate). They were euthanized 5 days later and examined for gross and microscopic evidence of infection. Macrorhabdus ornithogaster was not found to colonize the stomach, peritoneum, or viscera of the challeneged mice. The results of this study show that M. ornithogaster is not able to infect mice by the oral and intraperitoneal routes of administration and suggest that infection in mammals is unlikely to occur. 23790918 Antioxidant activity of white rice, brown rice and germinated brown rice (in vivo and in vitro) and the effects on lipid peroxidation and liver enzymes in hyperlipidaemic rabbits. Antioxidant activity of different rice extract and the effect on the levels of antioxidant enzyme activity, superoxide dismutase (SOD) and glutathione peroxidase (GPx), vitamin E, lipid peroxidation and liver enzymes in hyperlipidaemia rabbits were investigated. Germinated brown rice (GBR) has the highest antioxidant activity compared to white rice (WR) and brown rice (BR). All rice grains increased the activity of SOD and GPx. However, vitamin E levels increased only in the groups that received the BR and GBR diets. The reduction of lipid peroxidation levels and activity of hepatic enzymes (alanine transferase, ALT and aspartate transaminase, AST) were only significantly observed in the GBR group. In conclusion, GBR supplementation has the greatest impact on increasing antioxidant enzyme activity and vitamin E level and on reducing lipid peroxidation in hypercholesterolaemia rabbit, thereby preventing the formation of atherosclerotic plaques. Furthermore, GBR diet can also reduce the level of hepatic enzymes. 23510953 Emerging concepts on the epigenetic and transcriptional regulation of the Kiss1 gene. Kisspeptin and its receptor have been implicated as critical regulators of reproductive physiology, with humans and mice without functioning kisspeptin systems displaying severe pubertal and reproductive defects. Alterations in the expression of Kiss1 (the gene encoding kisspeptin) over development, along with differences in Kiss1 expression between the sexes in adulthood, may be critical for the maturation and functioning of the neuroendocrine reproductive system and could possibly contribute to pubertal progression, sex differences in luteinizing hormone secretion, and other facets of reproductive physiology. It is therefore essential to understand how Kiss1 gene expression develops and what possible regulatory mechanisms govern the modulation of its expression. A number of recent studies, primarily in rodent or cell line models, have focused on the contributions of epigenetic mechanisms to the regulation of Kiss1 gene expression; thus far, mechanisms such as DNA methylation, histone acetylation, and histone methylation have been investigated. This review discusses the most recent findings on the epigenetic control of Kiss1 expression in adulthood, the evidence for epigenetic factors affecting Kiss1 expression during puberty and development, and findings regarding the contribution of epigenetics to the sexually dimorphic expression of Kiss1 in the hypothalamus. 23887286 Prevalence, extent and composition of coronary plaque in patients with rheumatoid arthritis without symptoms or prior diagnosis of coronary artery disease. Accelerated cardiovascular morbidity and mortality occur in patients with rheumatoid arthritis (RA). We evaluated the presence, burden and compositional differences of coronary plaque in patients with RA without symptoms or diagnosis of coronary artery disease (CAD) compared against controls. One hundred and fifty patients with RA and 150 matched controls underwent 64-slice CT angiography (CTA) for evaluation of coronary plaque. Numbers of segments with plaque per patient (Segment involvement score (SIS)), degree of segment stenosis (stenosis severity score (SSS)), plaque size (plaque burden score (PBS)), and composition were assessed using a standardised American Heart Association 15-segment model. Lesions were classified as non-calcified plaque (NCP), mixed (MP), and fully calcified plaque (CP). Higher proportion of patients with RA had plaque when compared with controls (71% vs 45%, p<0.0001); 13.5% of total RA segments harboured plaque compared with 6% in controls (p<0.0001), and all plaque types were higher (p<0.001). Multivessel disease, both non-obstructive and obstructive, was more prevalent, and quantitative measures of stenotic plaque severity (SSS) and extent (PBS) were higher in RA, even after adjustments for cardiac risk factors (p<0.01 for all). A steeper progression of plaque with age was seen in RA. Disease activity associated only with presence of NCP and MP, whereas patient age was the only predictor of fully CP. RA patients without CAD have higher prevalence, extent, and severity of all types of coronary plaque. Residual disease activity associates with presence of higher risk NCP and MP potentially contributing to future adverse cardiac events. 23939135 Multi-locus species tree for the Amazonian peacock basses (Cichlidae: Cichla): Emergent phylogenetic signal despite limited nuclear variation. The inference of phylogenies of closely related species is obstructed by phenomena such as porous species boundaries and deep coalescence, and is often exacerbated by low levels of nucleotide variation among most loci surveyed in phylogenetic studies. We investigated the utility of twenty-one nuclear loci that had a range of 5-40 (median of 14) variable sites per locus to estimate the phylogeny of the genus Cichla, a group of 15 Neotropical cichlid fishes that began to diverge in the early to mid Miocene. We found that under a concatenated approach, the least variable loci, while contributing less to the overall phylogenetic signal (posterior node support), nevertheless provided information that increased support for the final tree. Moreover, this was not a result of misdirection by mutational noise, as the inference from all data was far superior to those from reduced datasets (those with more variable loci) in terms of the relative precision of posterior tree space. Phylogenetic methods that allowed each locus to have a separate genealogy, including Bayesian concordance analysis and a multispecies coalescent model, provided phylogenies that were also compatible with the concatenated tree in terms of the eight recently delimited species of Cichla, albeit with somewhat diminished support for some branches. In contrast, described species that still regularly exchange genes showed unstable relationships among analyses: not a surprising result from analyses that assume that gene tree heterogeneity results from incomplete lineage sorting and not gene flow. Importantly, we also observed that the confidence intervals for node ages in the coalescent analyses were quite wide, and likely susceptible to influence of the prior on node density (e.g. birth-death). 23477569 Study on the reduction of atmospheric mercury emissions from mine waste enriched soils through native grass cover in the Mt. Amiata region of Italy. Atmospheric mercury emissions from mine-waste enriched soils were measured in order to compare the mercury fluxes of bare soils with those from other soils covered by native grasses. Our research was conducted near Mt. Amiata in central Italy, an area that was one of the largest and most productive mining centers in Europe up into the 1980s. To determine in situ mercury emissions, we used a Plexiglas flux chamber connected to a portable mercury analyzer (Lumex RA-915+). This allowed us to detect, in real time, the mercury vapor in the air, and to correlate this with the meteorological parameters that we examined (solar radiation, soil temperature, and humidity). The highest mercury flux values (8000ngm(-2)h(-1)) were observed on bare soils during the hours of maximum insulation, while lower values (250ngm(-2)h(-1)) were observed on soils covered by native grasses. Our results indicate that two main environmental variables affect mercury emission: solar radiation intensity and soil temperature. The presence of native vegetation, which can shield soil surfaces from incident light, reduced mercury emissions, a result that we attribute to a drop in the efficiency of mercury photoreduction processes rather than to decreases in soil temperature. This finding is consistent with decreases in mercury flux values down to 3500ngm(-2)h(-1), which occurred under cloudy conditions despite high soil temperatures. Moreover, when the soil temperature was 28°C and the vegetation was removed from the experimental site, mercury emissions increased almost four-fold. This increase occurred almost immediately after the grasses were cut, and was approximately eight-fold after 20h. Thus, this study demonstrates that enhancing wild vegetation cover could be an inexpensive and effective approach in fostering a natural, self-renewing reduction of mercury emissions from mercury-contaminated soils. 23870879 Effects of phytate and minerals on the bioavailability of oxalate from food. Phytate and mineral cations are both considered as important dietary factors for inhibiting the crystallisation of calcium oxalate kidney stones in susceptible individuals. In this paper, the phytate and mineral composition of whole bran cereals (wheat, barley and oat) and legumes were determined together with their soluble and insoluble oxalate concentrations in order to investigate the effects on oxalate solubility. The oat bran sample had the highest soluble oxalate concentration at 79±1.3mg/100g, while total and soluble oxalate concentrations in the food samples studied range from 33 to 199mg/100g and 14 to 79mg/100g, respectively. The phytate concentration was in the range from 227 to 4393mg/100g and the concentrations of cations were in the range 54-70mg/100g for calcium, 75-398mg/100g for magnesium, 244-1529mg/100g for potassium and 4-11mg/100g for iron. Soluble oxalate concentration did not increase in proportion to total oxalate, and the phytate concentration in all foods was sufficient to contribute to an increase in soluble oxalate concentration by binding calcium. 23788494 The Binding of Benzoarylsulfonamide Ligands to Human Carbonic Anhydrase is Insensitive to Formal Fluorination of the Ligand. It's the water that matters. Pairs of benzo- and perfluorobenzoarylsulfonamide ligands bind to human carbonic anhydrase with a conserved binding geometry, an enthalpy-driven binding, and indistinguishable binding affinities. These data support the pervasive theory that the lock-and-key model disregards an important component of binding: the water, which fills the binding pocket of the protein and surrounds the ligand. 23915543 Rapid genotyping by low-coverage resequencing to construct genetic linkage maps of fungi: a case study in Lentinula edodes. Genetic linkage maps are important tools in breeding programmes and quantitative trait analyses. Traditional molecular markers used for genotyping are limited in throughput and efficiency. The advent of next-generation sequencing technologies has facilitated progeny genotyping and genetic linkage map construction in the major grains. However, the applicability of the approach remains untested in the fungal system. Shiitake mushroom, Lentinula edodes, is a basidiomycetous fungus that represents one of the most popular cultivated edible mushrooms. Here, we developed a rapid genotyping method based on low-coverage (~0.5 to 1.5-fold) whole-genome resequencing. We used the approach to genotype 20 single-spore isolates derived from L. edodes strain L54 and constructed the first high-density sequence-based genetic linkage map of L. edodes. The accuracy of the proposed genotyping method was verified experimentally with results from mating compatibility tests and PCR-single-strand conformation polymorphism on a few known genes. The linkage map spanned a total genetic distance of 637.1 cM and contained 13 linkage groups. Two hundred sequence-based markers were placed on the map, with an average marker spacing of 3.4 cM. The accuracy of the map was confirmed by comparing with previous maps the locations of known genes such as matA and matB. We used the shiitake mushroom as an example to provide a proof-of-principle that low-coverage resequencing could allow rapid genotyping of basidiospore-derived progenies, which could in turn facilitate the construction of high-density genetic linkage maps of basidiomycetous fungi for quantitative trait analyses and improvement of genome assembly. 23644089 Severe aortic stenosis and coronary artery disease-implications for management in the transcatheter aortic valve replacement era: a comprehensive review. Management of coronary artery disease (CAD) in patients with severe aortic stenosis (AS) referred for transcatheter aortic valve replacement (TAVR) is posing challenges. Due to limited and heterogeneous data on the prevalence and clinical impact of CAD on the outcomes of TAVR and the management strategies for CAD in patients undergoing TAVR, we performed a comprehensive review of the literature. Significant CAD is present in 40% to 75% of patients undergoing TAVR. The impact of CAD on outcomes after TAVR remains understudied. Based on existing data, not all patients require revascularization before TAVR. Percutaneous coronary intervention (PCI) should be considered for severely stenotic lesions in proximal coronaries that subtend a large area of myocardium at risk. Ongoing studies randomizing patients to surgical or percutaneous management strategies for severe AS will help provide valuable data regarding the impact of CAD on TAVR outcomes, the role of PCI, and its timing in relation to TAVR. 23880521 Electrophoretic nanotechnology of graphene-carbon nanotube and graphene-polypyrrole nanofiber composites for electrochemical supercapacitors. Thin films of multiwalled carbon nanotubes (MWCNT), graphene and polypyrrole (PPy) nanofibers were prepared by cathodic electrophoretic deposition (EPD) from aqueous suspensions, containing safranin (SAF) as a new dispersant. The results of Fourier transform infrared spectroscopy, UV-Vis spectroscopy studies and sedimentation tests, coupled with deposition yield and electron microscopy data showed that SAF adsorbed on MWCNT, graphene and PPy, provided their dispersion and charging in the suspensions and allowed efficient EPD. The deposition yield can be controlled by the variation of SAF concentration in the suspensions and deposition time. The use of SAF as a co-dispersant for MWCNT, graphene and PPy, allowed controlled EPD of composite graphene-MWCNT and graphene-PPy films. The proposed approach for the deposition of PPy paves the way for EPD of neutral polymers using organic dyes as dispersing and charging agents. The composite films were investigated for application in electrochemical supercapacitors (ES). The graphene-MWCNT and graphene-PPy films showed significant increase in capacitance, decrease in resistance and increase in capacitance retention at high charge-discharge rates compared to the films of individual components. The analysis of electrochemical testing results and electron microscopy data provided an insight into the influence of composite microstructure on electrochemical performance. The composites, prepared by EPD are promising materials for electrodes of ES. 22369145 Modulated release of 5-fluorouracil from pH-sensitive and colon targeted pellets: an industrially feasible approach. Pellets, reliant on pH-sensitivity and time-dependency for drug delivery, provide one of the most versatile opportunities for targeting colon. 5-Fluorouracil (5-FU) loaded pellets were prepared by extrusion-spheronization using Avicel(®) PH101 as a spheronization aid and hydroxypropylmethylcellulose K4M (HPMC K4M) solution as a binder. A 3(2) full factorial design was employed to optimize spheronization speed and time. Obtained pellets were evaluated for flow properties, pellet size, roundness and aspect ratio. Optimized batch was coated in a bottom-spray fluidized bed processor (FBP) with an inner coat of sustained release polymer Eudragit NE30D and an outer coat of pH-sensitive polymer Eudragit FS30D. The coating levels were statistically optimized and in vitro drug release was monitored by changing pH media method. Optimized system with 15% inner and outer coating levels revealed t(50%) (time required for 50% drug release) to be about 9 h while almost complete drug was released in 24 h (98.71 ± 1.33%) with highest dissolution efficiency (DE(24h)) of 58.71%. The optimization model was validated; the predicted and experimental/actual values for validation batch (M1) were in close tolerance and the standard error (SE) was also small. Drug release was also studied at pH 7.4. Scanning electron microscopy (SEM) demonstrated average coating thickness to be 32.50 ± 3.0 µm. Hence, the present study provides constructive results for colon targeting of 5-FU pellets with industrially feasible processes. 23860952 Diabetes and prostate cancer screening in black and white men. Prior studies conducted primarily among white men find a reduced risk of prostate cancer associated with time since developing diabetes. While biologic explanations are plausible, the association may in part arise from more frequent prostate cancer screening among those with a diabetes diagnosis. The purpose of the present study was to investigate the association between diabetes and prostate cancer screening. We examined differences in prostate cancer screening (prostate-specific antigen and/or digital rectal examination) testing practices after a diabetes diagnosis among lower-income persons living in the southeastern United States and enrolled in the Southern Community Cohort Study between 2002 and 2009. Baseline in-person interviews collected information on history of diabetes and prostate cancer screening from 18,809 black and 6,404 white men aged 40-79 years. After adjustment for confounding, diabetic black [odds ratio (OR) 1.12, 95 % confidence interval (CI) 1.01-1.25] and white (OR 1.25, 95 % CI 1.03-1.51) men were more likely to undergo recent prostate cancer screening compared to non-diabetic men of the same race. The increased risk for prostate cancer screening, however, occurred primarily within the first 12 months after diabetes diagnosis. Our results suggest that a diabetes diagnosis modestly increases the likelihood of having a prostate cancer screening test for both black and white men. The prevalence of screening was higher nearer to the time of diabetes diagnosis, which may contribute to an early increase in prostate cancer detection followed by lower prostate cancer detection after an extended time. 23867502 ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling. Nephrotic syndrome (NS) is divided into steroid-sensitive (SSNS) and -resistant (SRNS) variants. SRNS causes end-stage kidney disease, which cannot be cured. While the disease mechanisms of NS are not well understood, genetic mapping studies suggest a multitude of unknown single-gene causes. We combined homozygosity mapping with whole-exome resequencing and identified an ARHGDIA mutation that causes SRNS. We demonstrated that ARHGDIA is in a complex with RHO GTPases and is prominently expressed in podocytes of rat glomeruli. ARHGDIA mutations (R120X and G173V) from individuals with SRNS abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA, indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS variant than RHOA. Moreover, the mutations enhanced migration of cultured human podocytes; however, enhanced migration was reversed by treatment with RAC1 inhibitors. The nephrotic phenotype was recapitulated in arhgdia-deficient zebrafish. RAC1 inhibitors were partially effective in ameliorating arhgdia-associated defects. These findings identify a single-gene cause of NS and reveal that RHO GTPase signaling is a pathogenic mediator of SRNS. 23329130 The function of digestive enzymes on Cu, Zn, and Pb release from soil in in vitro digestion tests. The bioaccessibility of soil heavy metals is the solubility of soil heavy metals in synthetic human digestive juice, which is usually determined using in vitro digestion test. To reveal the effects of digestive enzymes on soil heavy metals bioaccessibility, three representative in vitro digestion tests, Simple Bioaccessibility Extraction Test (SBET), Physiologically Based Extraction Test (PBET), and Simple Gastrointestinal Extraction Test (SGET), were chosen. The bioaccessibility of soil Cu, Zn, and Pb in each method were respectively evaluated with and without digestive enzymes, and the differences were compared. The results showed that the effects of digestive enzymes varied with different methods and elements. Because of digestive enzymes addition, the environmental change from acid gastric phase to neutral intestinal phase of PBET did not result in apparently decrease of the bioaccessibility of soil Cu. However, the solubility of soil Zn and Pb were pH-dependent. For SGET, when digestive enzymes were added, its results reflected more variations resulting from soil and element types. The impacts of digestive enzymes on heavy metal dissolution are mostly seen in the intestinal phase. Therefore, digestive enzyme addition is indispensable to the gastrointestinal digestion methods (PBET and SGET), while the pepsin addition is not important for the methods only comprised of gastric digestion (SBET). 23817570 A genome-wide association study identifies two new cervical cancer susceptibility loci at 4q12 and 17q12. To identify new genetic risk factors for cervical cancer, we conducted a genome-wide association study in the Han Chinese population. The initial discovery set included 1,364 individuals with cervical cancer (cases) and 3,028 female controls, and we selected a 'stringently matched samples' subset (829 cases and 990 controls) from the discovery set on the basis of principal component analysis; the follow-up stages included two independent sample sets (1,824 cases and 3,808 controls for follow-up 1 and 2,343 cases and 3,388 controls for follow-up 2). We identified strong evidence of associations between cervical cancer and two new loci: 4q12 (rs13117307, Pcombined, stringently matched = 9.69 × 10(-9), per-allele odds ratio (OR)stringently matched = 1.26) and 17q12 (rs8067378, Pcombined, stringently matched = 2.00 × 10(-8), per-allele ORstringently matched = 1.18). We additionally replicated an association between HLA-DPB1 and HLA-DPB2 (HLA-DPB1/2) at 6p21.32 and cervical cancer (rs4282438, Pcombined, stringently matched = 4.52 × 10(-27), per-allele ORstringently matched = 0.75). Our findings provide new insights into the genetic etiology of cervical cancer. 23821669 Characterization at nucleotide resolution of the homogeneously staining region sites of insertion in two cancer cell lines. The mechanisms of formation of intrachromosomal amplifications in tumours are still poorly understood. By using quantitative polymerase chain reaction, DNA sequencing, chromosome walking, in situ hybridization on metaphase chromosomes and whole-genome analysis, we studied two cancer cell lines containing an MYC oncogene amplification with acquired copies ectopically inserted in rearranged chromosomes 17. These intrachromosomal amplifications result from the integration of extrachromosomal DNA molecules. Replication stress could explain the formation of the double-strand breaks involved in their insertion and in the rearrangements of the targeted chromosomes. The sequences of the junctions indicate that homologous recombination was not involved in their formation and support a non-homologous end-joining process. The replication stress-inducible common fragile sites present in the amplicons may have driven the intrachromosomal amplifications. Mechanisms associating break-fusion-bridge cycles and/or chromosome fragmentation may have led to the formation of the uncovered complex structures. To our knowledge, this is the first characterization of an intrachromosomal amplification site at nucleotide resolution. 23851225 Characterization of the enzymatic activity of Clostridium perfringens TpeL. TpeL is a toxin produced by Clostridium perfringens which belongs to the large clostridial glucosylating toxin family. It was shown that TpeL modifies Ras using UDP-glucose or UDP-N-acetylglucosamine as cosubstrates (Guttenberg et al., 2012; Nagahama et al., 2011). We confirmed that TpeL preferentially glucosaminates the three isoforms of Ras (cH-Ras, N-Ras, and K-Ras) from UDP-N-acetylglucosamine and to a lower extent Rap1a and R-Ras3, and very weakly Rac1. In contrast to previous report, we observed that Ral was not a substrate of TpeL. In addition, we confirmed by in vitro glucosylation and mass spectrometry that TpeL modifies cH-Ras at Thr35. 23161216 The role of voltage-gated potassium channels Kv2.1 and Kv2.2 in the regulation of insulin and somatostatin release from pancreatic islets. The voltage-gated potassium channels Kv2.1 and Kv2.2 are highly expressed in pancreatic islets, yet their contribution to islet hormone secretion is not fully understood. Here we investigate the role of Kv2 channels in pancreatic islets using a combination of genetic and pharmacologic approaches. Pancreatic β-cells from Kv2.1(-/-) mice possess reduced Kv current and display greater glucose-stimulated insulin secretion (GSIS) relative to WT β-cells. Inhibition of Kv2.x channels with selective peptidyl [guangxitoxin-1E (GxTX-1E)] or small molecule (RY796) inhibitors enhances GSIS in isolated wild-type (WT) mouse and human islets, but not in islets from Kv2.1(-/-) mice. However, in WT mice neither inhibitor improved glucose tolerance in vivo. GxTX-1E and RY796 enhanced somatostatin release in isolated human and mouse islets and in situ perfused pancreata from WT and Kv2.1(-/-) mice. Kv2.2 silencing in mouse islets by adenovirus-small hairpin RNA (shRNA) specifically enhanced islet somatostatin, but not insulin, secretion. In mice lacking somatostatin receptor 5, GxTX-1E stimulated insulin secretion and improved glucose tolerance. Collectively, these data show that Kv2.1 regulates insulin secretion in β-cells and Kv2.2 modulates somatostatin release in δ-cells. Development of selective Kv2.1 inhibitors without cross inhibition of Kv2.2 may provide new avenues to promote GSIS for the treatment of type 2 diabetes. 23859749 Effect of Nd:YAG Laser Bleaching and Antioxidizing Agents on the Shear Bond Strength of Brackets. Abstract Objective: The aims of this study were to evaluate the effect of hydrogen peroxide bleaching agents, both nonactivated and activated by a neodymium:yttrium-aluminum-garnet (Nd:YAG) laser, and of antioxidant treatment on the shear bond strength (SBS) of orthodontic brackets. Background data: Nd:YAG laser activation is expected to accelerate the bleaching therapy without decrease shear bond strength. Materials and methods: Ninety extracted maxillary central incisors were divided into two experimental groups and a control group. Group I was the control group, Group II was bleached with 35% hydrogen peroxide and had no photoactivation, and Group III was bleached with 35% hydrogen peroxide with activation by a Nd:YAG laser (4.0 W, 60 Hz frequency, 1 mm distance, 20 sec). Each group was divided into two subgroups: Subgroup A was immersed in artificial saliva for 2 weeks, and then bonded using the total etch system, whereas subgroup B was treated with an antioxidant agent (10% sodium ascorbate) and then bonded using the same system. The samples were stored in water for 24 h at 37°C, and thermocycled. The SBS in megapascals (MPa) was determined by a shear test with 1 mm/min crosshead speed, and failure types were classified with modified adhesive remnant index scores. The data were analyzed with two way analyses of variance, Tukey, and χ(2) tests at the α=0.05 level. Results: In both Groups II and III, the SBSs of brackets bonded after bleaching (Group II 15.16, Group III 17.50 MPa) were significantly lower than those of brackets in the bonded unbleached group (Group I 22.13 MPa); however, sodium ascorbate treatment significantly increased the SBSs of brackets in the bleached groups (Group II 21.52, Group III 22.43 MPa), but had an insignificant effect on the SBS of the control group (Group I 23.66MPa). Conclusions: Hydrogen peroxide bleaching agents reduce the SBSs both with and without Nd:YAG laser activation; however, treatment of the bleached enamel surface with 10% sodium ascorbate prior to bonding negates the effect. 22659090 Pharmacological profiling of native group II metabotropic glutamate receptors in primary cortical neuronal cultures using a FLIPR. The group II metabotropic glutamate (mGlu) receptors comprised of the mGlu2 and mGlu3 receptor subtypes have gained recognition in recent years as potential targets for psychiatric disorders, including anxiety and schizophrenia. In addition to studies already indicating which subtype mediates the anxiolytic and anti-psychotic effects observed in disease models, studies to help further define the preferred properties of selective group II mGlu receptor ligands will be essential. Comparison of the in vitro properties of these ligands to their in vivo efficacy and tolerance profiles may help provide these additional insights. We have developed a relatively high-throughput native group II mGlu receptor functional assay to aid this characterisation. We have utilised dissociated primary cortical neuronal cultures, which after 7 days in vitro have formed functional synaptic connections and display periodic and spontaneous synchronised calcium (Ca(2+)) oscillations in response to intrinsic action potential bursts. We herein demonstrate that in addition to non-selective group II mGlu receptor agonists, (2R,4R)-APDC, LY379268 and DCG-IV, a selective mGlu2 agonist, LY541850, and mGlu2 positive allosteric modulators, BINA and CBiPES, inhibit the frequency of synchronised Ca(2+) oscillations in primary cultures of rat and mouse cortical neurons. Use of cultures from wild-type, mGlu2(-/-), mGlu3(-/-) and mGlu2/3(-/-) mice allowed us to further probe the contribution of mGlu2 and mGlu3, and revealed LY541850 to be a partial mGlu2 agonist and a full mGlu3 antagonist. Overnight pre-treatment of cultures with these ligands revealed a preferred desensitisation profile after treatment with a positive allosteric modulator. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23853763 Sense of coherence of reindeer herders and other Samis in comparison to other Swedish citizens. Samis are indigenous people in north Europe. In the territory called Sápmi (Lapland), reindeer herding is the traditional base for the Sami economy. The relation between living conditions and positive health of the Swedish Samis has been sparsely studied. As health is closely linked to sense of coherence (SOC), an understanding of the background factors to SOC may contribute knowledge that might be useful in promoting living conditions and health. The study examines relations between the level of SOC and background factors from surveys in a Sami population (n=613) in comparison to a non-Sami population (n=525) in Sweden, and in comparison between 2 subsamples of Samis, that is, herders and non-herders. There are more similarities than differences between the Sami and non-Sami populations. However, dividing the Sami population, reindeer herders had significantly lower SOC, and in specific the subcomponent manageability, that is, less ability to use available resources to meet different demands in life, compared to non-herders. In addition to age and health, predictors of SOC are related to the life form of reindeer husbandry and the belonging to the herding community. 23690405 Leptospiral Outer Membrane Protein LipL41 Is Not Essential for Acute Leptospirosis but Requires a Small Chaperone Protein, Lep, for Stable Expression. Leptospirosis is a worldwide zoonosis caused by pathogenic Leptospira spp., but knowledge of leptospiral pathogenesis remains limited. However, the development of mutagenesis systems has allowed the investigation of putative virulence factors and their involvement in leptospirosis. LipL41 is the third most abundant lipoprotein found in the outer membranes of pathogenic leptospires and has been considered a putative virulence factor. LipL41 is encoded on the large chromosome 28 bp upstream of a small open reading frame encoding a hypothetical protein of unknown function. This gene was named lep, for LipL41 expression partner. In this study, lipL41 was found to be cotranscribed with lep. Two transposon mutants were characterized: a lipL41 mutant and a lep mutant. In the lep mutant, LipL41 protein levels were reduced by approximately 90%. Lep was shown through cross-linking and coexpression experiments to bind to LipL41. Lep is proposed to be a molecular chaperone essential for the stable expression of LipL41. The roles of LipL41 and Lep in the pathogenesis of Leptospira interrogans were investigated; surprisingly, neither of these two unique proteins was essential for acute leptospirosis. 23877745 Assessment of the adherence of cardiologists to guidelines for the treatment of atrial fibrillation. No local studies evaluating the knowledge of cardiologists on the management of atrial fibrillation (AF) and their adherence to these guidelines are available. To evaluate the knowledge of cardiologists on the guidelines and clinical practices for the treatment of AF, correlating it to the time since medical graduation. Cross-sectional study randomly including cardiologists affiliated to the Society of Cardiology of the State of Rio Grande do Sul (Sociedade de Cardiologia do Estado do Rio Grande do Sul - SOCERGS). The physicians were divided into two groups, according to time since graduation: those graduated for more (G1) or less (G2) than 25 years. Of the 859 SOCERGS members, 150 were interviewed, and six refused to participate in the study. G1 comprised 71 physicians, and G2, 73. Differences were observed in regard to the following variables: use of betablockers as the first-choice drug for the control of AF response in 59.2% (G1) vs 91.8% (G2) (p<0.0001); use of digoxin as the preferred drug for the control of AF response in 19.7% (G1) vs 0% (G2) (p< 0.0001); warfarin as the preferred anticoagulant in 71.8% (G1) vs 93.2% (G2) (p=0.009); application of a risk score for anticoagulation in 73.2% (G1) vs 87.7% (G2) (p=0.02). In questions regarding the knowledge about the Brazilian Society of Cardiology's guideline for AF, the overall percentage of right answers was 82.3%. Most of the clinical measures regarding the management of AF comply with the guidelines, and the clinical practice differs according with the time since graduation. 23829690 Effects of Ethnic Targeting on the Perceived Effectiveness of Cancer Prevention Messages Among Latinas and Non-Latina White Women. In general, efforts to target Latinos are made through Spanish-language messages, yet 75% of U.S. Latinos are bilingual or English dominant. Acculturation (adapting mainstream traits) is associated with increased lifestyle-related risk behaviors. Latinos maintain cultural traits and ethnic identification even as they appear to acculturate (e.g., through language). This raises questions about how to communicate health information to more-acculturated Latinos who are not reached by traditional Spanish outreach yet may not identify with general-market messages. This study tested the relative efficacy of English-language messages targeted to Latinas, compared with general-market messages, among highly acculturated Latina women and non-Latina White women. In this pair of online experiments, Latinas (n = 715) and non-Latina White women (n = 704) rated the perceived effectiveness of general-market versus Latina-targeted Pap smear and mammogram public service announcements. In 1 of 2 experiments ethnically targeted messages were rated relatively more effective for the intended audience and equally effective for the general audience. The author discusses implications for how campaigns reach U.S. Latinos across the acculturation spectrum. 23001890 Towards a new procreation ethic: the exemplary instance of cleft lip and palate. The improvement of ultrasound scan techniques is enabling ever earlier prenatal diagnosis of developmental anomalies. In France, apart from cases where the mother's life is endangered, the detection of "particularly serious" conditions, and conditions that are "incurable at the time of diagnosis" are the only instances in which a therapeutic abortion can be performed, this applying up to the 9th month of pregnancy. Thus numerous conditions, despite the fact that they cause distress or pain or are socially disabling, do not qualify for therapeutic abortion, despite sometimes pressing demands from parents aware of the difficulties in store for their child and themselves, in a society that is not very favourable towards the integration and self-fulfilment of people with a disability. Cleft lip and palate (CLP), although it can be completely treated, is one of the conditions that considerably complicates the lives of child and parents. Nevertheless, the recent scope for making very early diagnosis of CLP, before the deadline for legal voluntary abortion, has not led to any wave of abortions. CLP in France has the benefit of a exceptional care plan, targeting both the health and the integration of the individuals affected. This article sets out, via the emblematic instance of CLP, to show how present fears of an emerging "domestic" or liberal eugenic trend could become redundant if disability is addressed politically and medically, so that individuals with a disability have the same social rights as any other citizen. 23960453 Interfractional variation of radiation target and adaptive radiotherapy for totally resected glioblastoma. This study aimed to evaluate the effects of volume adapted re-planning for radiotherapy (RT) after gross total resection (GTR) for glioblastoma. Nineteen patients with glioblastoma who underwent GTR and postoperative RT were analyzed. The volumes of the surgical cavity on computed tomography (CT) obtained one day after GTR (CT0), the first RT simulation CT (sim-CT1), and the second simulation CT for the boost RT plan (sim-CT2) were compared. The boost RT plan was based on the surgical cavity observed on the sim-CT2 (boost RTP2) and was compared with that based on the surgical cavity observed on the sim-CT1 (boost RTP1). The volume reduction ratios were 14.4%-51.3% (median, 29.0%) between CT0 and sim-CT1 and -7.9%-71.9% (median, 34.9%) between sim-CT1 and sim-CT2 (P < 0.001). The normal brain volumes in boost RTP1 were significantly reduced in boost RTP2, especially at high dose levels. Target volume in sim-CT2 which was not covered with the boost RTP1, developed in five cases (26.3%). The surgical cavity volume was reduced following surgery in patients with glioblastoma who underwent GTR. The application of volume-adapted re-planning during RT could decrease the irradiated volume of normal brain and prevent a target miss for boost RT. 23455039 Revised conformational assignments and conformational evolution of tyrosine by laser desorption supersonic jet laser spectroscopy. The number of conformers and their structures of tyrosine are reassigned on the basis of resonance enhanced multiphoton ionization (REMPI), ultraviolet-ultraviolet hole burning (UV-UV HB), infrared (IR) dip spectra, and quantum chemical calculations. From comparison between REMPI and UV-UV HB spectra, it was found that 12 conformers coexist in the supersonic jet. The structures of these conformers are determined by the IR spectra and theoretical calculations. The number of conformers is more than that reported in the previous reports (8 conformers), and is rationalized by the systematic formation of conformers from simpler molecules without substituents, just like evolution. The importance of dipole-dipole interaction between an amino-acid chain and hydroxyl group at the benzene ring was also discussed. 23850990 Propionyl-L-carnitine induces eNOS activation and nitric oxide synthesis in endothelial cells via PI3 and Akt kinases. Propionyl-l-carnitine (PLC) is a natural short-chain derivative of l-carnitine (LC), a natural amino acid that plays an important role in fatty acid metabolism. Recent studies suggest that PLC has vascular protective effects. Because of the importance of endothelial nitric oxide synthase (eNOS) and its product, antiatherogenic molecule nitric oxide (NO), in vascular endothelial function, we sought to elucidate that if PLC would stimulate eNOS and its upstream activators Akt and phosphatidylinositol 3-kinase (PI3 Kinase) in cultured human aortic endothelial cells (HAEC). PLC caused eNOS phosphorylation at Ser-1177, and dominant negative Akt and a novel Akt-selective inhibitor MK-2206 inhibited both PLC-mediated phosphorylation and activation of the enzyme. PI3 kinase inhibition also blocked the phosphorylation and activation of eNOS by PLC. Studies with specific drug inhibitors PD173955 and PP2 showed that the non-receptor tyrosine kinase, src, is an upstream stimulator of the PI3 kinase-Akt pathway in this pathway. In addition, PLC significantly decreased intracellular ATP/ADP ratio and activate AMPK, subsequently leading to Src activation. Finally, we demonstrated that the effects of PLC to augment eNOS activity were associated with a net increase in NO release from endothelial cells. NO production following incubation with PLC was abolished in endothelial cells coincubated with L-NAME, PD173955, LY294002, MK-2206 and compound C. In conclusion, PLC, via AMPK/Src-mediated signaling that leads to activation of PI3 kinase and Akt, stimulates eNOS, leading to increased production of NO. 23122123 'Emerging' mycotoxins in cereals processing chains: changes of enniatins during beer and bread making. Enniatins represent an emerging food safety issue because of their extensive incidence, documented in recent decades, in various small grain cereals. This study was concerned with the fate of these Fusarium mycotoxins within malting, brewing, milling and baking, when employed for the processing of contaminated barley and wheat. Besides enniatins A, A1, B and B1, also deoxynivalenol and its conjugated form (deoxynivalenol-3-glucoside) were determined in almost all tested cereal-based samples. Significant decline of enniatins occurred within all technologies, with the largest drop in their concentrations observed in the brewing process. While enniatins were not detectable in final beers, they were almost quantitatively transferred to spent grains, probably because of their limited water solubility. Regarding bread baking, levels of enniatins decreased down to 30% of their concentration in the initial flour used for baking. In this case, degradation at higher temperatures might be assumed. 23826786 Investigating tendon mineralisation in the avian hindlimb: a model for tendon ageing, injury and disease. Mineralisation of the tendon tissue has been described in various models of injury, ageing and disease. Often resulting in painful and debilitating conditions, the processes underlying this mechanism are poorly understood. To elucidate the progression from healthy tendon to mineralised tendon, an appropriate model is required. In this study, we describe the spontaneous and non-pathological ossification and calcification of tendons of the hindlimb of the domestic chicken (Gallus gallus domesticus). The appearance of the ossified avian tendon has been described previously, although there have been no studies investigating the developmental processes and underlying mechanisms leading to the ossified avian tendon. The tissue and cells from three tendons - the ossifying extensor and flexor digitorum longus tendons and the non-ossifying Achilles tendon - were analysed for markers of ageing and mineralisation using histology, immunohistochemistry, cytochemistry and molecular analysis. Histologically, the adult tissue showed a loss of healthy tendon crimp morphology as well as markers of calcium deposits and mineralisation. The tissue showed a lowered expression of collagens inherent to the tendon extracellular matrix and presented proteins expressed by bone. The cells from the ossified tendons showed a chondrogenic and osteogenic phenotype as well as tenogenic phenotype and expressed the same markers of ossification and calcification as the tissue. A molecular analysis of the gene expression of the cells confirmed these results. Tendon ossification within the ossified avian tendon seems to be the result of an endochondral process driven by its cells, although the roles of the different cell populations have yet to be elucidated. Understanding the role of the tenocyte within this tissue and the process behind tendon ossification may help us prevent or treat ossification that occurs in injured, ageing or diseased tendon. 23437852 Lagged relationships among sleep disturbance, fatigue, and depressed mood during chemotherapy. Recent research suggests that sleep disturbance, fatigue, and depressed mood form a symptom cluster in patients treated with chemotherapy. To date, however, no studies have examined lagged relationships among these symptoms during chemotherapy, a time when symptom variability is high. The aim of the current study was to examine lagged changes among daily symptoms during platinum-based chemotherapy. Participants were 78 women with gynecologic cancer (mean age 63 years, SD = 11; 91% Caucasian, 97% non-Hispanic). Sleep disturbance was assessed via wrist actigraphy, whereas fatigue and depressed mood were assessed via daily diary in the week after participants' first chemotherapy infusion. Latent change score models (LCS) were used to examine lagged relationships between symptom pairs. High levels of sleep disturbance (i.e., minutes awake at night) were associated with earlier subsequent peaks in fatigue, and high levels of fatigue were associated with higher subsequent levels of depressed mood. These findings suggest that sleep disturbance, fatigue, and depressed mood occur in a cascade pattern during chemotherapy, in which increases in sleep disturbance contribute to fatigue, which, in turn, contributes to depressed mood. Interventions targeting symptoms early in the cascade, such as sleep disturbance, may provide benefits across multiple downstream symptoms. 23954260 Fasciola hepatica - where is 28S ribosomal RNA? Advanced molecular biology techniques are currently used to develop new effective strategies against fasciolosis. Assesment of the quality of extracted total RNA is an important step prior to commencing many molecular biology methods such as transcriptomics. However, RNA quality assessment is complicated for some organisms, including Fasciola hepatica, by the abscence of a 28S rRNA peak/band, when assessed with modern protocols. In this study, electrophoretic profiles of F. hepatica ribosomal RNAs were evaluated using microfluidics capillary based and conventional non-denaturating gel electrophoresis methods. An important modification to recommended protocols, the exclusion of heat-denaturation step, in the microfluidics capillary based electrophoresis is critical to visualise the expected 28S rRNA and obtain an RNA integrity number (RIN). The intensity of the 28S rRNA band is reduced by the effect of non-denaturating gel electrophoresis. 23557100 Self-correction of chromosomal abnormalities in human preimplantation embryos and embryonic stem cells. Aneuploidy is commonly seen in human preimplantation embryos, most particularly at the cleavage stage because of genome activation by third cell division. Aneuploid embryos have been used for the derivation of normal embryonic stem cell (ESC) lines and developmental modeling. This review addresses aneuploidies in human preimplantation embryos and human ESCs and the potential of self-correction of these aberrations. Diploid-aneuploid mosaicism is the most frequent abnormality observed; hence, embryos selected by preimplantation genetic diagnosis at the cleavage or blastocyst stage could be partly abnormal. Differentiation is known as the barrier for eliminating mosaic embryos by death and/or decreased division of abnormal cells. However, some mosaicisms, such as copy number variations could be compatible with live birth. Several reasons have been proposed for self-correction of aneuploidies during later stages of development, including primary misdiagnosis, allocation of the aneuploidy in the trophectoderm, cell growth advantage of diploid cells in mosaic embryos, lagging of aneuploid cell division, extrusion or duplication of an aneuploid chromosome, and the abundance of DNA repair gene products. Although more studies are needed to understand the mechanisms of self-correction as a rare phenomenon, most likely, it is related to overcoming mosaicism. 23945678 The effect of the proximity of patients' nearest alternative hospital on their intention to search for information on hospital quality. In several countries, patients are encouraged to choose health care providers. Simultaneously, there is a tendency towards the concentration of health care, which might lessen the choice. Our aim was to assess the impact of patients' distances from their providers on their information-seeking, which is one element of choice. Two thousand members of the Dutch Health Care Consumer Panel were sent a questionnaire that included a question on whether they would search for information about hospitals to inform their choice. Distances from providers were obtained from a database that includes the distances between all postcodes in the Netherlands. To assess the influence of distance on information-seeking, logistic regression analyses were conducted. There was a good response (75%). Older, less educated respondents were less inclined to seek information when their nearest alternative was located further away (OR 0.85; 95% CI: 0.79-0.92), and younger, more educated respondents were more inclined to search in this situation (OR 1.11; 95% CI: 1.01-1.22). As fewer older, less educated patients would search for information to guide their choice, they might not opt for the best hospital. Additionally, the need for providers to compete for the patronage of these patients might be lessened. 23611835 Molecular Mechanisms of the antitumor activity of SB225002: A novel microtubule inhibitor. SB225002 (SB) is an IL-8 receptor B (IL-8RB) antagonist that has previously been shown to inhibit IL-8-based cancer cell invasion, and to possess in vivo anti-inflammatory and anti-nociceptive effects. The present study presented an evidence for the cell cycle-targeting activity of SB in a panel of p53-mutant human cancer cell lines of different origin, and investigated the underlying molecular mechanisms. A combination of cell cycle analysis, immunocytometry, immunoblotting, and RNA interference revealed that SB induced a BubR1-dependent mitotic arrest. Mechanistically, SB was shown to possess a microtubule destabilizing activity evidenced by hyperphosphorylation of Bcl2 and BclxL, suppression of microtubule polymerization and induction of a prometaphase arrest. Molecular docking studies suggested that SB has a good affinity towards vinblastine-binding site on β-tubulin subunit. Of note, SB265610 which is a close structural analogue of SB225002 with a potent IL-8RB antagonistic activity did not exhibit a similar antimitotic activity. Importantly, in P-glycoprotein overexpressing NCI/Adr-Res cells the antitumor activity of SB was unaffected by multidrug resistance. Interestingly, the mechanisms of SB-induced cell death were cell-line dependent, where in invasive hepatocellular carcinoma HLE cells the significant contribution of BAK-dependent mitochondrial apoptosis was demonstrated. Conversely, SB activated p38 MAPK signaling in colorectal adenocarcinoma cells SW480, and pharmacologic inhibition of p38 MAPK activity revealed its key role in mediating SB-induced caspase-independent cell death. In summary, the present study introduced SB as a promising antitumor agent which has the potential to exert its activity through dual mechanisms involving microtubules targeting and interference with IL-8-drivin cancer progression. 23822974 Comparisons of metabolic and physiological changes in rats following short term oral dosing with pesticides commonly found in food. (1)H Nuclear Magnetic Resonance spectroscopy has been used to profile urinary metabolites in male Fischer F344 rats in order to assess the metabolic changes induced by oral exposure to two benzimidazole fungicides (carbendazim and thiabendazole) and two bipyridyllium herbicides (chlormequat and mepiquat). Exposure levels were selected to be lower than those expected to cause overt signs of toxicity. We then compared the sensitivity of the metabolomics approach to more traditional methods of toxicity assessment such as the measurement of growth and organ weights. Separate, acute exposure experiments were conducted for each pesticide to identify potential metabolic markers of exposure across four doses (and a control). Growth, organ weights and feeding/drinking rates were not significantly affected by any compounds at any dose levels tested. In contrast, metabolic responses were detected within 8 and 24h for chlormequat and mepiquat, and after 24h for carbendazim and thiabendazole. These results demonstrate the potential for the use of metabolomics in food toxicity testing. 23969269 Pressure to produce=pressure to reduce accident reporting? Each year, more than 4 million U.S. workers are injured on the job - several thousand die (Bureau of Labor Statistics, 2008). Despite these staggering numbers, research suggests that they are gross underestimates of the true volume of workplace related illnesses and injuries due to accident under-reporting. Although accident under-reporting has been well-documented, less is known regarding why this occurs. The current study suggests that under-reporting may in part be due to high levels of perceived production pressure. Specifically, this study tested the hypotheses that production pressure would be related to more experienced accidents overall and more negative attitudes toward reporting accidents. Further, we expected that production pressure would exacerbate the under-reporting of accidents. Survey data were collected from a sample of 212 copper mining workers located in the southwestern United States. The survey measured employee perceptions regarding production pressure, attitudes toward reporting accidents, perceived consequences of reporting accidents, and actual reporting behaviors (e.g., types and numbers of accidents experienced vs. reported). As predicted, the average number of experienced accidents per employee was significantly higher (M=2.84) than the number of reported accidents (M=.49). In addition, production pressure was related to more negative reporting attitudes. Individuals who had positive reporting attitudes were injured less frequently; however, when an incident occurred, they were more likely to report it. Finally, higher levels of production pressure were related to greater accident under-reporting. Additionally, employees who perceived high levels of production pressure not only experienced more accidents overall, they also reported fewer of them to the organization. Implications for occupational safety initiatives - particularly in the current economic climate - are discussed, as are methodological challenges of conducting research in this area. 23122133 An extract procedure for studying the free and glycosilated aroma compounds in grapes. In this study seven published methods of extraction of skin free and bound volatile compounds have been compared. The free and bound volatiles were separated by solid phase extraction (SPE) and then analysed by gas chromatography coupled with mass spectrometry (GC-MS). The results showed that the extraction of volatile compounds from grapes is highly affected by extraction solution features. The solution at pH 3.2 and 0% ethanol resulted the most effective as it led to the extraction of a higher number and amount of free and glycosilated volatile compounds. The selected extraction method of grape skin and the process of pulp juice were validated for quantitative determination of a wide range of grape aroma compounds. A total of 37 free and bound grape aroma compounds were quantified by GC-MS in selective ion monitoring modality (SIM). Among them, 26 volatile compounds resulted validated in grape skin and pulp juice. 22611016 Usefulness of administration of non-organophosphate cholinesterase inhibitors before acute exposure to organophosphates: assessment using paraoxon. Reversible acetylcholinesterase (AChE) inhibitors can protect against the lethal effects of irreversible organophosphorus AChE inhibitors (OPCs), when administered before OPC exposure. We have assessed in vivo the mortality-reducing efficacy of a group of known AChE inhibitors, when given in equitoxic dosage before exposure to the OPC paraoxon. Protection was quantified in rats by determining the relative risk (RR) of death. Best in vivo protection from paraoxon-induced mortality was observed after prophylactic administration of physostigmine (RR = 0.30) or the oxime K-27 (RR = 0.34); both treatments were significantly superior to the pre-treatment with all other tested compounds, including the established substance pyridostigmine. Tacrine (RR = 0.67), ranitidine (RR = 0.72), pyridostigmine (RR = 0.76), tiapride (RR = 0.80) and 7-MEOTA (RR = 0.86) also significantly reduced the relative risk of paraoxon-induced death, but to a lesser degree. Methylene blue, amiloride and metoclopramide had an unfavorable effect (RR ≥ 1), significantly increasing mortality. When CNS penetration by prophylactic is undesirable K-27 is a promising alternative to pyridostigmine. Copyright © 2012 John Wiley & Sons, Ltd. 23410538 The in vitro and in vivo effects of nicotine on bone, bone cells and fracture repair. INTRODUCTION: Cigarette smoke has negative effects on bone metabolism and fracture repair. However, no study has reviewed effects of nicotine on bone and fracture repair independent of other constituents of cigarette smoke. The authors review the existing evidence of the effect of nicotine on 'bone' and 'bone cells' and fracture repair, drawing conclusions relevant to clinical practice and future research. AREAS COVERED: A literature review was conducted using PRISMA guidelines and PubMed, Cochrane, MEDLINE/OVID, EMBASE, NHS Evidence and Google scholar databases. Articles were included if they specifically investigated the effects of nicotine on 'bone' or fracture repair in animal or human models or in vitro effects on 'bone cells'. A total of 64 papers were included in this review, of which 15 were human in vitro studies and 49 animal studies wherein 9 were in vitro and 40 in vivo. In vivo studies of the effects of nicotine in animals demonstrated widespread effects on bone including osteoneogenesis, osseointegration, steady-state skeletal bone and genes and cytokines relevant to bone cell physiology and bone homeostasis. In these studies, nicotine's effects are predominately negative, inhibiting bone cell metabolism and fracture repair, whereas most in vitro studies reported biphasic responses in all bone cells except osteoclastic cells. EXPERT OPINION: The review suggests that nicotine has effects on osteoneogenesis, osseointegration and steady-state skeletal bone in animal in vivo models, as well as effects on all 'bone cells', via several mechanisms in both animal and human cell in vitro studies. The effect of nicotine is dose-dependent, with higher concentrations having predominantly negative effects, whereas at low concentrations a stimulatory effect is seen. Stimulatory effects on certain cells may indicate a possible, limited therapeutic role; advice regarding smoking cessation perioperatively should remain due to the other harmful components of cigarette smoke, but there may be scope for allowing the use of nicotine patches instead of complete abstention. Further research into clinical outcomes is required before the exact response of bone and fracture repair in humans to nicotine is known. 23506783 'Bacoside B' - the need remains for establishing identity. Bacopa monnieri is fast gaining popularity for its beneficial effects on cognition and memory. The active constituents of the plant were putatively identified as 'bacosides A and B' in older publications. Subsequently 'bacoside A' was identified as a mixture of four saponins [bacoside A3 (1), bacopaside II (2), bacopasaponin C (3) and the jujobogenin isomer of the latter (4)] and was considered as part of major constituents of the herb along with bacopaside I (5). These major saponins now form part of analytical monographs in many Pharmacopoeia. However identity of 'bacoside B' still appears controversial with seemingly contradictory information available in the scientific literature. At the same time quality of many extracts and herbal products derived from the plant is still being determined based on the content of 'bacosides A and B'. We have elaborated these issues in this article along with our recommendations to move forward towards achieving scientific clarity on the subject. 23733807 Effect of different post mortem temperatures on carcass quality of suckling lamb. The effect of post mortem treatment on microbiological lamb carcass quality was studied. Suckling lambs carcasses were assigned to three different post mortem treatments: conventional (2  for 24 h), ultra-rapid (-20  for 3.5 h then 2  until 24 h post mortem) and slow (12   for 7 h then 2  until 24 h post mortem). Carcass pH and temperature were measured at 0, 3.5, 7 and 24 h post slaughter. Lamb carcasses were sampled for total aerobic viable and Enterobacteriaceae counts just after dressing and 24 h post mortem. A significant effect (p < 0.05) of post mortem treatment on carcasses temperature and pH was found corresponding the faster pH fall to slowly chilled muscles. However, no differences were found at 24 h post mortem among treatments in both parameters. Regarding microbiological results, carcasses of ultra-rapid treatment had the lowest total aerobic viable and Enterobacteriaceae counts and those belonging to conventional treatment had the highest total aerobic viable counts. From 0 to 24 h post mortem, an increase of total aerobic viable was observed in conventional and slow treatments whilst Enterobacteriaceae counts remained constant in all cases. From a microbiological point of view, the ultra-rapid treatment was the only one allowed to maintain the hygienic carcasses quality. However, according to pH and temperature results the carcasses subjected to this treatment may be susceptible to cold shortening. 23880881 Mixed emotions: the contribution of alexithymia to the emotional symptoms of autism. It is widely accepted that autism is associated with disordered emotion processing and, in particular, with deficits of emotional reciprocity such as impaired emotion recognition and reduced empathy. However, a close examination of the literature reveals wide heterogeneity within the autistic population with respect to emotional competence. Here we argue that, where observed, emotional impairments are due to alexithymia-a condition that frequently co-occurs with autism-rather than a feature of autism per se. Alexithymia is a condition characterized by a reduced ability to identify and describe one's own emotion, but which results in reduced empathy and an impaired ability to recognize the emotions of others. We briefly review studies of emotion processing in alexithymia, and in autism, before describing a recent series of studies directly testing this 'alexithymia hypothesis'. If found to be correct, the alexithymia hypothesis has wide-reaching implications for the study of autism, and how we might best support subgroups of autistic individuals with, and without, accompanying alexithymia. Finally, we note the presence of elevated rates of alexithymia, and inconsistent reports of emotional impairments, in eating disorders, schizophrenia, substance abuse, Parkinson's Disease, multiple sclerosis and anxiety disorders. We speculate that examining the contribution of alexithymia to the emotional symptoms of these disorders may bear fruit in the same way that it is starting to do in autism. 23838618 Development and initial validation of a content taxonomy for patient records in general dentistry. Develop and validate an initial content taxonomy for patient records in general dentistry. Phase 1 - obtain 95 de-identified patient records from 11 general dentists in the United States. Phase 2 - extract individual data fields (information items), both explicit (labeled) and implicit (unlabeled), from records, and organize into categories mirroring original field context. Phase 3 - refine raw list of information items by eliminating duplicates/redundancies and focusing on general dentistry. Phase 4 - validate all items regarding inclusion and importance using a two-round Delphi study with a panel of 22 general dentists active in clinical practice, education, and research. Analysis of 76 patient records from 9 dentists, combined with previous work, yielded a raw list of 1509 information items. Refinement reduced this list to 1107 items, subsequently rated by the Delphi panel. The final model contained 870 items, with 761 (88%) rated as mandatory. In Round 1, 95% (825) of the final items were accepted, in Round 2 the remaining 5% (45). Only 45 items on the initial list were rejected and 192 (or 17%) remained equivocal. Grounded in the reality of clinical practice, our proposed content taxonomy represents a significant advance over existing guidelines and standards by providing a granular and comprehensive information representation for general dental patient records. It offers a significant foundational asset for implementing an interoperable health information technology infrastructure for general dentistry. 23527587 Coarse-grained model for predicting RNA folding thermodynamics. We present a thermodynamically robust coarse-grained model to simulate folding of RNA in monovalent salt solutions. The model includes stacking, hydrogen bond, and electrostatic interactions as fundamental components in describing the stability of RNA structures. The stacking interactions are parametrized using a set of nucleotide-specific parameters, which were calibrated against the thermodynamic measurements for single-base stacks and base-pair stacks. All hydrogen bonds are assumed to have the same strength, regardless of their context in the RNA structure. The ionic buffer is modeled implicitly, using the concept of counterion condensation and the Debye-Hückel theory. The three adjustable parameters in the model were determined by fitting the experimental data for two RNA hairpins and a pseudoknot. A single set of parameters provides good agreement with thermodynamic data for the three RNA molecules over a wide range of temperatures and salt concentrations. In the process of calibrating the model, we establish the extent of counterion condensation onto the single-stranded RNA backbone. The reduced backbone charge is independent of the ionic strength and is 60% of the RNA bare charge at 37 °C. Our model can be used to predict the folding thermodynamics for any RNA molecule in the presence of monovalent ions. 23628914 The actin cytoskeleton in presynaptic assembly. Dramatic morphogenetic processes underpin nearly every step of nervous system development, from initial neuronal migration and axon guidance to synaptogenesis. Underlying this morphogenesis are dynamic rearrangements of cytoskeletal architecture. Here we discuss the roles of the actin cytoskeleton in the development of presynaptic terminals, from the elaboration of terminal arbors to the recruitment of presynaptic vesicles and active zone components. The studies discussed here underscore the importance of actin regulation at every step in neuronal circuit assembly. 23949209 Unusual formation of thiaisoporphyrins from 21-thiaporphyrins. We report the unusual formation of thiaisoporphyrins containing bridging sp(3)meso carbon between two pyrroles when 21-thiaporphyrins were reacted with PhBCl2 in dry toluene at reflux temperature. 23743620 Intracellular Ion Channel CLIC1: Involvement in Microglia-Mediated β-Amyloid Peptide(1-42) Neurotoxicity. Microglia can exacerbate central nervous system disorders, including stroke and chronic progressive neurodegenerative diseases such as Alzheimer disease. Mounting evidence points to ion channels expressed by microglia as contributing to these neuropathologies. The Chloride Intracellular Channel (CLIC) family represents a class of chloride intracellular channel proteins, most of which are localized to intracellular membranes. CLICs are unusual in that they possess both soluble and integral membrane forms. Amyloid β-peptide (Aβ) accumulation in plaques is a hallmark of familial Alzheimer disease. The truncated Aβ25-35 species was shown previously to increase the expression of CLIC1 chloride conductance in cortical microglia and to provoke microglial neurotoxicity. However, the highly pathogenic and fibrillogenic full-length Aβ1-42 species was not examined, nor was the potential role of CLIC1 in mediating microglial activation and neurotoxicity by other stimuli (e.g. ligands for the Toll-like receptors). In the present study, we utilized a two chamber Transwellâ„¢ cell culture system to allow separate treatment of microglia and neurons while examining the effect of pharmacological blockade of CLIC1 in protecting cortical neurons from toxicity caused by Aβ1-42- and lipopolysaccaride-stimulated microglia. Presentation of Aβ1-42 to the upper, microglia-containing chamber resulted in a progressive loss of neurons over 3 days. Neuronal cell injury was prevented by the CLIC1 ion channel blockers IAA-94 [(R(+)-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5yl)-oxy] acetic acid)] and niflumic acid (2-{[3-(trifluoromethyl)phenyl]amino}nicotinic acid) when presented to the upper chamber only. Incubation of microglia with lipopolysaccharide plus interferon-γ led to neuronal cell injury which, however, was insensitive to inhibition by the CLIC1 channel blockers, suggesting a degree of selectivity in agents leading to CLIC1 activation. 23875672 3 Tesla multiparametric MRI for GTV-definition of Dominant Intraprostatic Lesions in patients with Prostate Cancer--an interobserver variability study. To evaluate the interobserver variability of gross tumor volume (GTV) - delineation of Dominant Intraprostatic Lesions (DIPL) in patients with prostate cancer using published MRI criteria for multiparametric MRI at 3 Tesla by 6 different observers. 90 GTV-datasets based on 15 multiparametric MRI sequences (T2w, diffusion weighted (DWI) and dynamic contrast enhanced (DCE)) of 5 patients with prostate cancer were generated for GTV-delineation of DIPL by 6 observers. The reference GTV-dataset was contoured by a radiologist with expertise in diagnostic imaging of prostate cancer using MRI. Subsequent GTV-delineation was performed by 5 radiation oncologists who received teaching of MRI-features of primary prostate cancer before starting contouring session. GTV-datasets were contoured using Oncentra Masterplan® and iplan® Net. For purposes of comparison GTV-datasets were imported to the Artiview® platform (Aquilab®), GTV-values and the similarity indices or Kappa indices (KI) were calculated with the postulation that a KI > 0.7 indicates excellent, a KI > 0.6 to < 0.7 substantial and KI > 0.5 to < 0.6 moderate agreement. Additionally all observers rated difficulties of contouring for each MRI-sequence using a 3 point rating scale (1 = easy to delineate, 2 = minor difficulties, 3 = major difficulties). GTV contouring using T2w (KI-T2w = 0.61) and DCE images (KI-DCE = 0.63) resulted in substantial agreement. GTV contouring using DWI images resulted in moderate agreement (KI-DWI = 0.51). KI-T2w and KI-DCE was significantly higher than KI-DWI (p = 0.01 and p = 0.003). Degree of difficulty in contouring GTV was significantly lower using T2w and DCE compared to DWI-sequences (both p < 0.0001). Analysis of delineation differences revealed inadequate comparison of functional (DWI, DCE) to anatomical sequences (T2w) and lack of awareness of non-specific imaging findings as a source of erroneous delineation. Using T2w and DCE sequences at 3 Tesla for GTV-definition of DIPL in prostate cancer patients by radiation oncologists with knowledge of MRI features results in substantial agreement compared to an experienced MRI-radiologist, but for radiotherapy purposes higher KI are desirable, strengthen the need for expert surveillance. DWI sequence for GTV delineation was considered as difficult in application. 23945373 Whole Genome Sequencing analysis of intrapatient microevolution in Mycobacterium tuberculosis: Potential impact on the inference of tuberculosis transmission. Background. It has been accepted that the infection by M. tuberculosis (MTB) can be more heterogeneous than considered. The emergence of clonal variants caused by microevolution events leading to population heterogeneity is a phenomenon largely unexplored. Until now, we could only superficially analyze this phenomenon by standard fingerprinting (RFLP and VNTR).Methods. In this study we applied whole genome sequencing for a more in-depth analysis of the scale of microevolution both at the intrapatient and interpatient scenarios.Results. We found that the amount of variation accumulated within a patient can be as high as that observed between patients along a chain of transmission. Intrapatient diversity was found both at the extrapulmonary and respiratory sites, meaning that this variability can be transmitted and impact on the inference of transmission events. One of the events studied allowed us to track for a single strain the complete process of i) interpatient microevolution, ii) intrapatient respiratory variation, and iii) isolation of different variants at different infected sites of this patient.Conclusions. Our study adds new data to the understanding of variability in MTB in a wide clinical scenario and alerts about the difficulties of establishing thresholds to differentiate relatedness in MTB with epidemiological purposes. 23805848 Synthesis of sulfonated oxindoles by potassium iodide catalyzed arylsulfonylation of activated alkenes with sulfonylhydrazides in water. A catalytic system consisting of KI, 18-crown-6, and TBHP for arylsulfonylation of activated alkenes with sulfonylhydrazides as sulfonyl precursor is described. This protocol provides a practical and environmentally benign method for the construction of sulfonated oxindoles in water. 23747820 Using a toxicokinetics approach to explain the effect of soil pH on cadmium bioavailability to Folsomia candida. The aim of this study was to improve our understanding of metal bioavailability in soil by linking the biotic ligand approach with toxicokinetics modelling. We determined cadmium bioaccumulation kinetics in Folsomia candida (Collembola) as a function of soil pH. Animals were exposed for 21 days to LUFA 2.2 soil at 5 or 20 Î¼g Cd g(-1) dry soil followed by 21 days elimination in clean soil. Internal cadmium concentrations were modelled using a first-order one-compartment model, relating uptake rate constants (k1) to total soil, water or 0.01 M CaCl2 extractable and porewater concentrations. Based on total soil concentrations, k1 was independent of soil pH while it strongly increased with increasing pH based on porewater concentrations explaining the reduced competition of H(+) ions making cadmium more bioavailable in pore water at high pH. This shows that the principles of biotic ligand modelling are applicable to predict cadmium accumulation kinetics in soil-living invertebrates. 23725023 X-ray photoemission spectroscopy investigation of the interaction between 4-mercaptopyridine and the anatase TiO2 surface. In polymer-metal oxide hybrid solar cells, an extremely careful engineering of the interface is required to ensure good device performances. Recently, very promising results have been obtained by functionalizing titanium dioxide (TiO2) by means of 4-mercaptopyridine (4-MPy) molecules, showing the beneficial effect of these molecules on the interface morphology. This study investigates the nature of the interaction of 4-MPy molecules with the TiO2 surface by means of X-ray photoemission spectroscopy. In order to mimic the device processing conditions, our analysis is carried out on molecules adsorbed from solution on a nanocrystalline surface. According to our analysis, 4-MPy molecules (C5H5NS) are likely bound with the oxide through the nitrogen atom. The bonding precedes either via a covalent interaction with Lewis surface sites, or via hydrogen mediation, possibly in the form of hydrogen bonds. Interestingly, in the latter case, we also observe strong changes in the spectroscopic features attributed to the thiol group. 23434788 Sexual and reproductive health in a UK cohort of young adults perinatally infected with HIV. To assess sexual health and behaviour outcomes of young adults with perinatally acquired HIV-1 (PaHIV), and audit sexual health interventions against published standards of care. Retrospective case note audit of 16-25-year-olds with PaHIV attending a dedicated transition clinic from January 2005 to 2011. Fifty-two young adults, 31 women, median age 20 years. 41 were sexually active; median age of coitarche 16 years. Median number of lifetime partners was 3.5, and five reported non-consensual sex. All had a sexually transmitted infection (STI) screen; 6 were diagnosed with an STI, genital warts (human papilloma virus) most frequently. The median interval from coitarche to first STI screen was 2 years. The pregnancy incidence was 103 per 1000 person years. 18/25 (72%) sexually active women had a cervical smear, four had colposcopy. All patients had hepatitis B virus (HBV) serology. 47 had not been vaccinated against HBV prior to transition. 23 completed HBV vaccination of which 11 had surface antibody >100 IU/ml at 1 year. The majority of our cohort was sexually active while still under the care of paediatric health services. Cervical screening and hepatitis B vaccination rates fell short of audit standards. Vaccination for hepatitis B should be considered prior to transfer of care to adult HIV services. 23939228 Evaluation of the dependence of CEST-EPI measurement on repetition time, RF irradiation duty cycle and imaging flip angle for enhanced pH sensitivity. Chemical exchange saturation transfer (CEST) is a magnetic resonance imaging (MRI) contrast mechanism that can detect dilute CEST agents and microenvironmental properties, with a host of promising applications. Experimental measurement of the CEST effect is complex, and depends on not only CEST agent concentration and exchange rate, but also experimental parameters such as RF irradiation amplitude and scheme. Although echo planar imaging (EPI) has been increasingly used for CEST MRI, the relationship between CEST effect and repetition time (TR), RF irradiation duty cycle (DC) and EPI flip angle (α) has not been fully evaluated and optimized to enhance CEST MRI sensitivity. In addition, our study evaluated gradient echo CEST-EPI by quantifying the CEST effect and its signal-to-noise ratio per unit time (SNRput) as functions of TR, DC and α. We found that CEST effect increased with TR and DC but decreased with α. Importantly, we found that SNRput peaked at intermediate TRs of about twice the T1 and α, at approximately 75°, and increased with RF DC. The simulation results were validated using a dual-pH creatine-gel CEST phantom. In summary, our study provides a useful framework for optimizing CEST MRI experiments. 23969953 Randomised in situ Study on the Efficacy of a Tin/Chitosan Toothpaste on Erosive-Abrasive Enamel Loss. Tin is a notable anti-erosive agent, and the biopolymer chitosan has also shown demineralisation-inhibiting properties. Therefore, the anti-erosive/anti-abrasive efficacy of the combination of both compounds was tested under in situ conditions. Twenty-seven volunteers were included in a randomised, double-blind, three-cell crossover in situ trial. Enamel specimens were recessed on the buccal aspects of mandibular appliances, extraorally demineralised (6 × 2 min/day) and intraorally treated with toothpaste slurries (2 × 2 min/day). Within the slurry treatment time, one-half of the specimens received additional intraoral brushing (5 s, 2.5 N). The tested toothpastes included a placebo toothpaste, an experimental NaF toothpaste (1,400 ppm F(-)) and an experimental F/Sn/chitosan toothpaste (1,400 ppm F(-), 3,500 ppm Sn(2+), 0.5% chitosan). The percentage reduction of tissue loss (slurry exposure/slurry exposure + brushing) compared to placebo was 19.0 ± 47.3/21.3 ± 22.4 after use of NaF and 52.5 ± 30.9/50.2 ± 34.3 after use of F/Sn/chitosan. F/Sn/chitosan was significantly more effective than NaF (p ≤ 0.001) and showed good efficacy against erosive and erosive-abrasive tissue loss. This study suggests that the F/Sn/chitosan toothpaste could provide good protection for patients who frequently consume acidic foodstuffs. 23803534 A systematic review and meta-analysis of dynamic tests and related force plate parameters used to evaluate neuromusculoskeletal function in foot and ankle pathology. Force plates are commonly used to register ground reaction forces in order to assess neuromusculoskeletal function of the ankle joint. There exists a great variety in dynamic tests on force plates and in parameters calculated from ground reaction forces in order to evaluate neuromusculoskeletal function of the ankle. The purpose of this study was to evaluate which dynamic tests and force plate parameters are most sensitive to differences between and within groups with regard to foot and ankle pathology. A systematic review and meta-analysis was performed evaluating studies that compared force plate parameters of dynamic tests between patients with foot and ankle pathology, and healthy controls. Data were pooled per parameter and test category. Given the clinical heterogeneity, we constructed comprehensive recommendation criteria to indicate a 'proven relevant parameter' or 'candidate relevant parameter'. A total of 34 studies were included, and 58 relevant comparisons were identified. Results were subdivided by test category: walking, running, landing (in anteroposterior direction), sideways (movement in mediolateral direction) and termination (movement in anteroposterior direction). The 'walking' test showed significant differences in a great variety of pathologies, with the magnitude and timing of the 'second peak vertical force' as proven relevant parameters. The 'landing' test detected differences due to ankle instability, with 'time to stabilization in anteroposterior direction' as proven relevant parameter. This study provides recommendations concerning the potential of various dynamic tests and force plate parameters as a tool to compare neuromusculoskeletal function between patients with foot and ankle pathology and healthy controls. 23567998 Transport of gabapentin by LAT1 (SLC7A5). Gabapentin is used in the treatment of epilepsy and neuropathic pain. Gabapentin has high and saturable permeability across the BBB, but no mechanistic studies underpinning this process have been reported. The aim of the current study was to investigate the transport of gabapentin in a model of the BBB, identify the important drug transporter(s) and to use mathematical modelling to quantify the processes involved. A human brain endothelial cell line (hCMEC/D3) was utilised as an in-vitro model of the BBB. Uptake of radiolabeled gabapentin into cells in the presence of chemical inhibitors, siRNA or overexpressed drug transporters of interest was investigated. Gabapentin was demonstrated to be a LAT1 substrate in brain endothelial cells (LAT1-process; Km=530μM and Vmax=7039pmoles/million cells/min versus other-processes; Km=923μM and Vmax=3656pmoles/million cells/min) and in transfected HEK 293 LAT1 cells (LAT1-process; Km=217μM and Vmax=5192pmoles/million cells/min versus otherprocesses; Km=1546μM and Vmax=3375pmoles/million cells/min). At physiological concentrations of gabapentin, LAT1 mediated transport was 3 or ~10-fold higher than the other transport processes in the two systems, respectively, demonstrating clear selectivity for gabapentin. In-silico structural homology modelling confirmed that LAT1 could have the LeuT conserved fold and functions by the alternative access mechanism. Mathematical modelling of this mechanism revealed revised significance of Vmax and Km so that a low Km may not necessarily imply a high affinity transport process. Gabapentin was negative for OCT like transport and LAT2 activity in the hCMEC/D3 and OCT1 transfected cells. Our data shows that gabapentin is a substrate for the influx transporter LAT1 at therapeutic concentrations. 23831536 Synthesis of lignocellulosic polymer with improved chemical resistance through free radical polymerization. Rising environmental awareness has resulted in a renewed interest in biological macromolecules obtained from renewable resources. So in view of technological significance of natural lignocellulosic polymers in numerous applications, the present study is an attempt to synthesize lignocellulosic polymers based graft copolymers using free radical polymerization. Different reaction conditions have been studied to synthesize the lignocellulosic graft copolymers. The graft copolymers have been characterized with scanning electron micrography (SEM), Fourier transform infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA). The grafted samples have also been screened against different physico-chemical conditions to assess their applicability in different applications. 23142325 The role of mitochondria and biotransformation in abamectin-induced cytotoxicity in isolated rat hepatocytes. Abamectin (ABA), which belongs to the family of avermectins, is used as a parasiticide; however, ABA poisoning can impair liver function. In a previous study using isolated rat liver mitochondria, we observed that ABA inhibited the activity of adenine nucleotide translocator and FoF1-ATPase. The aim of this study was to characterize the mechanism of ABA toxicity in isolated rat hepatocytes and to evaluate whether this effect is dependent on its metabolism. The toxicity of ABA was assessed by monitoring oxygen consumption and mitochondrial membrane potential, intracellular ATP concentration, cell viability, intracellular Ca(2+) homeostasis, release of cytochrome c, caspase 3 activity and necrotic cell death. ABA reduces cellular respiration in cells energized with glutamate and malate or succinate. The hepatocytes that were previously incubated with proadifen, a cytochrome P450 inhibitor, are more sensitive to the compound as observed by a rapid decrease in the mitochondrial membrane potential accompanied by reductions in ATP concentration and cell viability and a disruption of intracellular Ca(2+) homeostasis followed by necrosis. Our results indicate that ABA biotransformation reduces its toxicity, and its toxic action is related to the inhibition of mitochondrial activity, which leads to decreased synthesis of ATP followed by cell death. 23870004 Parents' experiences with neonatal home care following initial care in the neonatal intensive care unit: a phenomenological hermeneutical interview study. A descriptive study of parents' experiences with neonatal home care following initial care in the neonatal intensive care unit. As survival rates improve among premature and critically ill infants with an increased risk of morbidity, parents' responsibilities for neonatal care grow in scope and degree under the banner of family-centred care. Concurrent with medical advances, new questions arise about the role of parents and the experience of being provided neonatal care at home. An interview study with a phenomenological hermeneutic approach. Parents from a Swedish neonatal (n = 22) home care setting were extensively interviewed within one year of discharge. Data were collected during 2011-2012. The main theme of the findings is that parents experience neonatal home care as an inner emotional journey, from having a child to being a parent. This finding derives from three themes: the parents' experience of leaving the hospital milieu in favour of establishing independent parenthood, maturing as a parent and processing experiences during the period of neonatal intensive care. This study suggests that neonatal home care is experienced as a care structure adjusted to incorporate parents' needs following discharge from a neonatal intensive care unit. Neonatal home care appears to bridge the gap between hospital and home, supporting the family's adaptation to life in the home setting. Parents become empowered to be primary caregivers, having nurse consultants serving the needs of the whole family. Neonatal home care may therefore be understood as the implementation of family-centred care during the transition from NICU to home. 22997202 Pediatric chronic lower respiratory disorders: Microbiological and immunological phenotype. The role of infectious agents in children with recurrent/chronic lower respiratory disorders (R/CLRDs) is not clear, whereas it has been largely studied in acute respiratory diseases. The purpose of the study was to evaluate the frequency of infections, in particular viral infections, in children with R/CLRDs correlating their presence with clinical/biohumoral parameters. Eighty children affected by R/CLRDs underwent bronchoscopy and analysis of bronchoalveolar lavage (BAL) for cells, mediators (eosinophil cationic protein-ECP, interleukin-IL-8, tumor necrosis factor-TNFα) and pathogens (viruses and bacteria). Viral genomes were detected in 50/80 (62.5%) children. Rhinovirus, the principal detected virus (26/50, 52%), occurred more frequently in male children. Higher percentages of BAL neutrophils and IL-8 values were detected in virus positive than negative children. ECP values resulted significantly higher in the children with rhinovirus than in those with other viruses. No other statistically significant correlation between viral findings and clinical/biohumoral data were found. Respiratory viruses, especially rhinovirus, seem to play an important role in children with R/CLRDs. They are associated with changes in BAL cellularity and inflammatory cytokines. Further studies are needed to confirm the persistence of viruses in these patients and to identify eventual therapeutic strategies. Pediatr Pulmonol. 2013; 48:780-788. © 2012 Wiley Periodicals, Inc. 23967144 The Genome of the Moderate Halophile Amycolicicoccus subflavus DQS3-9A1(T) Reveals Four Alkane Hydroxylation Systems and Provides Some Clues on the Genetic Basis for Its Adaptation to a Petroleum Environment. The moderate halophile Amycolicicoccus subflavus DQS3-9A1(T) is the type strain of a novel species in the recently described novel genus Amycolicicoccus, which was isolated from oil mud precipitated from oil produced water. The complete genome of A. subflavus DQS3-9A1(T) has been sequenced and is characteristic of harboring the genes for adaption to the harsh petroleum environment with salinity, high osmotic pressure, and poor nutrient levels. Firstly, it characteristically contains four types of alkane hydroxylases, including the integral-membrane non-heme iron monooxygenase (AlkB) and cytochrome P450 CYP153, a long-chain alkane monooxygenase (LadA) and propane monooxygenase. It also accommodates complete pathways for the response to osmotic pressure. Physiological tests proved that the strain could grow on n-alkanes ranging from C10 to C36 and propane as the sole carbon sources, with the differential induction of four kinds of alkane hydroxylase coding genes. In addition, the strain could grow in 1-12% NaCl with the putative genes responsible for osmotic stresses induced as expected. These results reveal the effective adaptation of the strain DQS3-9A1(T) to harsh oil environment and provide a genome platform to investigate the global regulation of different alkane metabolisms in bacteria that are crucially important for petroleum degradation. To our knowledge, this is the first report to describe the co-existence of such four types of alkane hydroxylases in a bacterial strain. 23935709 Mucinous cystadenocarcinoma of the appendix in which contrast-enhanced ultrasonography was useful for assessing blood flow in a focal nodular lesion in the tumor cavity: A case report. A 63-year-old woman was admitted to hospital with pain in the right lower quadrant. Abdominal computed tomography (CT) revealed a 60-mm cystic mass at a site corresponding to the appendix. The mass wall on the appendicular ostium was thickened and enhanced by contrast, while calcification was observed in the mass wall on the appendicular tip. No projection was observed in the mass cavity. On abdominal ultrasonography (US), the mass wall on the appendicular ostium was thickened and projections were observed at two sites in the mass cavity. On contrast-enhanced US (CEUS), only one of these projections was enhanced. Based on the thickened and contrast-enhanced wall of the mass on the appendicular ostium on CT and US, as well as the contrast enhancement of a projection on US, the mass was diagnosed as mucinous cystadenocarcinoma of the appendix. Ileocecal resection was subsequently performed on day 10. A detailed examination of the surgical specimen revealed carcinoma cells in the mass wall on the appendicular ostium. The contrast-enhanced projection was identified as granulation tissue that had grown to come into contact with the tumor, while the non-contrast-enhanced projection was identified as solidified mucus. US enabled successful visualization of projections in the mass cavity that were not visible on abdominal CT. CEUS also proved useful for assessing blood flow in these projections. 23820751 CMRF35-like molecule 1 (CLM-1) regulates eosinophil homeostasis by suppressing cellular chemotaxis. Eosinophil accumulation in health and disease is a hallmark characteristic of mucosal immunity and type 2 helper T cell (Th2) inflammation. Eotaxin-induced CCR3 (chemokine (C-C motif) receptor 3) signaling has a critical role in eosinophil chemotactic responses. Nevertheless, the expressions of immunoreceptor tyrosine-based inhibitory motif-bearing receptors such as CMRF35-like molecule-1 (CLM-1) and their ability to govern eosinophil migration are largely unknown. We now report that CLM-1 (but not CLM-8) is highly and distinctly expressed by colonic and adipose tissue eosinophils. Furthermore, Clm1(-/-) mice display elevated baseline tissue eosinophilia. CLM-1 negatively regulated eotaxin-induced eosinophil responses including eosinophil chemotaxis, actin polymerization, calcium influx, and extracellular signal-regulated kinase (ERK)-1/2, but not p38 phosphorylation. Addition of CLM-1 ligand (e.g., phosphatidylserine) rendered wild-type eosinophils hypochemotactic in vitro and blockade of CLM-1/ligand interactions rendered wild-type eosinophils hyperchemotactic in vitro and in vivo in a model of allergic airway disease. Interestingly, suppression of cellular recruitment via CLM-1 was specific to eosinophils and eotaxin, as leukotriene B4 (LTB4)- and macrophage inflammatory protein-1α (MIP-1α)-induced eosinophil and neutrophil migration were not negatively regulated by CLM-1. Finally, peripheral blood eosinophils obtained from allergic rhinitis patients displayed elevated CLM-1/CD300f levels. These data highlight CLM-1 as a novel regulator of eosinophil homeostasis and demonstrate that eosinophil accumulation is constantly governed by CLM-1, which negatively regulates eotaxin-induced eosinophil responses.Mucosal Immunology advance online publication 3 July 2013; doi:10.1038/mi.2013.47. 23786852 Perceived Relapse Risk and Desire for Medication Assisted Treatment among Persons Seeking Inpatient Opiate Detoxification. Most patients with opioid addiction do not receive medication at the time of discharge from brief inpatient detoxification programs despite the high risk of relapse and the availability of three FDA-approved medications. We surveyed 164 inpatient opioid detoxification patients to assess desire for pharmacotherapy following detoxification program discharge. Participants were predominantly male (71.3%) and 80% had detoxed in the past. Reporting on their most recent previous inpatient detoxification, 27% had relapsed the day they were discharged, 65% within a month of discharge, and 90% within a year of discharge. 63% reported they wanted medication-assisted treatment (MAT) after discharge from the current admission. The odds of desiring a treatment medication increased by a factor of 1.02 for every 1% increase in perceived relapse risk (p<.01). These data suggest patient preference discussions including relapse risk could increase post-detox abstinence. Source of funding: K24 DA00512. 23932829 First step to reducing infection risk as a system: Evaluation of infection prevention processes for 71 hospitals. Hospitals can better focus their efforts to prevent health care-associated infections (HAIs) if they identify specific areas for improvement. We administered a 96-question survey to infection preventionists at 71 Ascension Health hospitals to evaluate opportunities for the prevention of catheter-associated urinary tract infection, central line-associated bloodstream infection, ventilator-associated pneumonia, and surgical site infection. Seventy-one (100%) infection preventionists completed the survey. The majority of hospitals had established policies for urinary catheter placement and maintenance (55/70, 78.6%), central venous catheter maintenance (68/71, 95.8%), and care for the mechanically ventilated patient (62/66, 93.9%). However, there was variation in health care worker practice and evaluation of competencies and outcomes. When addressing device need, 55 of 71 (77.5%) hospitals used a nurse-driven evaluation of urinary catheter need, 26 of 71 (36.6%) had a team evaluation for central venous catheters on transfer out of intensive care, and 53 of 57 (93%) assessed daily ventilator support for continued need. Only 19 of 71 (26.8%) hospitals had annual nursing competencies for urinary catheter placement and maintenance, 29 of 71 (40.8%) for nursing venous catheter maintenance, and 38 of 66 (57.6%) for appropriate health care worker surgical scrubbing. We suggest evaluating infection prevention policies and practices as a first step to improvement efforts. The next steps include implementing spread of evidence-based practices, with focus on competencies and feedback on performance. 23616415 Erectile dysfunction in the cardiovascular patient. Erectile dysfunction is common in the patient with cardiovascular disease. It is an important component of the quality of life and it also confers an independent risk for future cardiovascular events. The usual 3-year time period between the onset of erectile dysfunction symptoms and a cardiovascular event offers an opportunity for risk mitigation. Thus, sexual function should be incorporated into cardiovascular disease risk assessment for all men. A comprehensive approach to cardiovascular risk reduction (comprising of both lifestyle changes and pharmacological treatment) improves overall vascular health, including sexual function. Proper sexual counselling improves the quality of life and increases adherence to medication. This review explores the critical connection between erectile dysfunction and cardiovascular disease and evaluates how this relationship may influence clinical practice. Algorithms for the management of patient with erectile dysfunction according to the risk for sexual activity and future cardiovascular events are proposed. 23912974 Efficacy and safety of sitagliptin as add-on therapy on glycemic control and blood glucose fluctuation in Japanese type 2 diabetes subjects ongoing with multiple daily insulin injections therapy. To assess the efficacy and safety of adding sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in subjects with type 2 diabetes inadequately controlled with multiple daily insulin injections therapy (MDI). HbA1c, 1,5-anhydroglucitol (1,5-AG), body mass index (BMI), insulin doses, six-point self-measured plasma glucose (SMPG) profiles were assessed before, after 12 weeks, and after 24 weeks of MDI with 50 mg/day of sitagliptin in 40 subjects with type 2 diabetes. Safety endpoints included hypoglycemia and any adverse events. HbA1c significantly decreased during the first 12 weeks ( -0.64 ± 0.60 %), and was sustained over 24 weeks ( -0.69 ± 0.85 %). 1,5-AG increased significantly from 7.5 ± 4.5 μg/mL at baseline to 9.6 ± 5.5 μg/mL after 24 weeks. The bolus insulin dose at 12 weeks was decreased, and the mean plasma glucose, the SD of daily glucose, M-value, and the mean amplitude of glycemic excursions (MAGE) also decreased significantly as compared with baseline values. BMI and frequency of hypoglycemia were not changed significantly. Univariate linear regression analyses revealed that % change in HbA1c was significantly associated with BMI, and % changes in the indexes of glycemic instability (SD of daily glucose and MAGE) were significantly associated with age. In conclusion, adding sitagliptin to MDI significantly improved glycemic control and decreased the daily glucose fluctuation in subjects with type 2 diabetes inadequately, without weight gain or an increase in the incidence of hypoglycemia. This trial was registered with UMIN (no. UMIN000010157). 23891137 Linear and micronodular neuroendocrine cell hyperplasia in an ovarian mucinous cystadenoma. We report a rare case of an ovarian mucinous cystadenoma in which there were peculiar neuroendocrine micronests composed of gastrin-immunoreactive cells. There was no clinical evidence of hypergastrinemia. The mucinous component of the neoplasm was represented by columnar cells mostly expressing a gastric phenotype with MUC5AC and claudin 18 positivity, which was consistent with the presence of interspersed gastrin cells. The tumoral stroma displayed areas of luteinization with cells intensely positive for α-inhibin, MART-1 and calretinin. 23747303 Unphosphorylated calponin enhances the binding force of unphosphorylated myosin to actin. Smooth muscle has the distinctive ability to maintain force for long periods of time and at low energy costs. While it is generally agreed that this property, called the latch-state, is due to the dephosphorylation of myosin while attached to actin, dephosphorylated-detached myosin can also attach to actin and may contribute to force maintenance. Thus, we investigated the role of calponin in regulating and enhancing the binding force of unphosphorylated tonic muscle myosin to actin. To measure the effect of calponin on the binding of unphosphorylated myosin to actin, we used the laser trap assay to quantify the average force of unbinding (Funb) in the absence and presence of calponin or phosphorylated calponin. Funb from F-actin alone (0.12±0.01pN; mean±SE) was significantly increased in the presence of calponin (0.20±0.02pN). This enhancement was lost when calponin was phosphorylated (0.12±0.01pN). To further verify that this enhancement of Funb was due to the cross-linking of actin to myosin by calponin, we repeated the measurements at high ionic strength. Indeed, the Funb obtained at a [KCl] of 25mM (0.21±0.02pN; mean±SE) was significantly decreased at a [KCl] of 150mM, (0.13±0.01pN). This study provides direct molecular level-evidence that calponin enhances the binding force of unphosphorylated myosin to actin by cross-linking them and that this is reversed upon calponin phosphorylation. Thus, calponin might play an important role in the latch-state. This study suggests a new mechanism that likely contributes to the latch-state, a fundamental and important property of smooth muscle that remains unresolved. 23298337 Differences in standing and sitting postures of youth with idiopathic scoliosis from quantitative analysis of digital photographs. The objective of this study was to explore whether differences in standing and sitting postures of youth with idiopathic scoliosis could be detected from quantitative analysis of digital photographs. Standing and sitting postures of 50 participants aged 10-20-years-old with idiopathic scoliosis (Cobb angle: 15° to 60°) were assessed from digital photographs using a posture evaluation software program. Based on the XY coordinates of markers, 13 angular and linear posture indices were calculated in both positions. Paired t-tests were used to compare values of standing and sitting posture indices. Significant differences between standing and sitting positions (p < 0.05) were found for head protraction, shoulder elevation, scapula asymmetry, trunk list, scoliosis angle, waist angles, and frontal and sagittal plane pelvic tilt. Quantitative analysis of digital photographs is a clinically feasible method to measure standing and sitting postures among youth with scoliosis and to assist in decisions on therapeutic interventions. 23683899 Biochemical and physiological responses in Caenorhabditis elegans exposed to sublethal concentrations of the organophosphorus insecticide, monocrotophos. The objective of this study was to investigate the impact of sublethal concentrations of MCP on definitive markers of toxicity and oxidative balance in the nematode, Caenorhabditis elegans. Exposure of worms to 0.85, 1.7 and 3.4mM (1/40, 1/20 and 1/10 LC50; LC50=34 mM) for 4h at 20°C induced significant perturbations in physiological parameters such as decreased brood size (47-73%), increased paralysis (47-85%) and inhibition of the activities of acetylcholinesterase (75-86%) and carboxylesterase (76-81%). These changes were accompanied by distinct oxidative impairments as evidenced by increased reactive oxygen species, decline in glutathione content and decrease in superoxide dismutase activity. Our results clearly demonstrate that low concentrations of MCP may alter the physiological and biochemical status in the nematode, thereby affecting the organism's fitness. Our findings on C. elegans provide an easy diagnosis for OPI contamination and may become helpful in evaluating the ecotoxicological effects of OPI in the aquatic environment near agricultural fields. 23824495 A case of delayed methotrexate clearance following administration of a complementary medication containing chlorophyll. A 54-year-old male with relapsed primary cerebral lymphoma and normal renal function was treated with methotrexate (MTX) 3 g/m(2) monthly by intravenous infusion. Throughout treatment the patient self-administered a complementary medicine (Jason Winter's chlorophyll®), which he was advised to cease during methotrexate treatment due to the potential for unknown interactions. For the first four cycles, chlorophyll was ceased two days prior to commencement of methotrexate and withheld until clearance. These cycles were administered without complication, and the methotrexate level reduced to <0.05 µmol/L within three days of each dose. Prior to cycle 5, chlorophyll was not ceased and there were no changes to concomitant medications. A literature search found no documented interactions between methotrexate and chlorophyll and the chemotherapy was administered without a delay in treatment. The methotrexate level three days post-administration was 0.36 µmol/L and did not reduce to <0.05 µmol/L until day 10. Consequently, from cycles 6 to 12, the methotrexate dose was halved, and the patient ceased chlorophyll 48 h prior to methotrexate administration until clearance. There were no further episodes of delayed methotrexate clearance. No impurities were detected in a sample of Jason Winter's chlorophyll®. It is therefore likely that the patient's delayed methotrexate clearance was due to an interaction with chlorophyll. It is recommended that such chlorophyll containing preparations be avoided in patients treated with methotrexate. 23664728 Structure of the capsular polysaccharides and lipopolysaccharides from Haemophilus parasuis strains ER-6P (serovar 15) and Nagasaki (serovar 5). Haemophilus parasuis is a Gram-negative bacterium from the family Pasteurellaceae and a swine pathogen. H. parasuis is found in the upper respiratory tract of piglets and produces Glässer's disease, an invasive disease characterized by polyserositis. H. parasuis contains a short lipopolysaccharide (LPS) or lipooligosaccharide (LOS) reported to play a partial role in interaction with host cells. The presence of capsule has been phenotypically demonstrated in certain H. parasuis strains and its role in virulence has been suggested, but the chemical structure of the surface polysaccharides of this bacterium was unknown. The structure of capsular polysaccharide (CPS) and LOS from virulent strains ER-6P and Nagasaki was studied by NMR spectroscopy, mass spectrometry and chemical methods. CPS from both strains had the same main chain with disaccharide repeating unit, substituted with α-Neu5R-(2-3)-α-GalNAc-(1-P-(strain ER-6P) or α-Neu5R-(2-3)-α-Gal-(1-P-strain Nagasaki) side chains, where R is the N-acetyl or N-glycolyl group. Glycolyl-neuraminic acid is widely found in animal glycoproteins, but it apparently has not been found in bacteria before, and might be important for the biology of this microorganism. Ac and Gc were present in equal amounts in the strain ER-6P but Nagasaki contained only about 20% of Gc substituent. Both strains produced the same LPS of a rough type with a single phosphorylated Kdo linking core and lipid A parts. LOS structure was similar to some strains of H. influenzae and contained a globotetraose terminal sequence. 23567628 High-κ GdTixOy sensing membrane-based electrolyte-insulator-semiconductor with magnetic nanoparticles as enzyme carriers for protein contamination-free glucose biosensing. This paper reports an electrolyte-insulator-semiconductor (EIS) device featuring a novel high-κ GdTixOy sensing membrane for high-performance pH sensing and glucose biosensing. The effect of the annealing temperature (700, 800, or 900°C) on the sensing properties of the GdTixOy membranes was investigated. The GdTixOy EIS device annealed at 900°C exhibited the greatest pH sensing performance, including the highest sensitivity (62.12mV/pH), the smallest hysteresis voltage (5mV), and the lowest drift rate (0.4mV/h), presumably because of its well-crystallized GdTixOy structure. To overcome the problems typically encountered during the practical application of biosensors (e.g., protein adsorption; preservation of enzymatic activity), we employed Fe3O4-based magnetic nanoparticles (MNPs) as enzyme carriers. The adsorption of serum protein on the unmodified sensing membrane led to poor EIS-based pH sensing (r(2)=0.71); the performance was greatly improved, however, after attaching the MNPs to the sensing membrane, thereby blocking protein adsorption significantly (by 98%) and allowing excellent pH sensing (r(2)=0.99). Moreover, we prepared a hybrid configuration of the proposed GdTixOy membrane-EIS, with magnetically attached glucose oxidase-immobilized MNPs, for glucose biosensing. The use of MNPs as enzyme carriers effectively preserved the enzymatic activity of glucose oxidase, with 45.3% of the original enzymatic activity retained after 120h of storage at 4°C (compared with complete loss of the free enzyme's activity under the same storage conditions). In addition, the proposed biosensor exhibited superior detection sensitivity of 11.03mV/mM relative to that (8.17mV/mM) obtained using the conventional enzyme immobilization method. Finally, we established the accuracy of the proposed method for blood glucose measurement; gratifyingly, blood glucose detection was comparable with the high-sensitivity glucose quantification obtained using a commercial glucose assay kit. 23770309 Influence of parenchymal heterogeneity on airway-parenchymal interdependence. To estimate the influence of parenchymal heterogeneities on airway-parenchymal interdependence, we considered a circular airway embedded within elastic parenchyma modeled as (1) a hexagonal spring network, (2) a triangular spring network, or (3) a continuum. The deformation in the parenchyma due to active airway contraction was simulated using the finite element method. Random perturbations of elastic moduli in the parenchyma did not significantly affect the overall pattern of force transmission. By contrast, when elastic moduli were increased along a path projecting radially outward from the airway, the hexagonal spring network model predicted significantly increased force along this line as the airway contracted, but this was not observed in other two models. These results indicate that tissue heterogeneities generally have minimal effect on the global nature of airway-parenchymal interdependence. However, in the exceptional circumstance of scar tissue aligned radially from the airway wall, parenchymal distortion forces may propagate much farther from the airway wall than was previously thought. 23298751 A spatiotemporal comparison between olfactory and trigeminal event-related potentials. The present study compared the temporal and spatial aspects of human olfactory and trigeminal processing. A relatively selective trigeminal stimulus, CO2, and a relatively selective olfactory stimulus, H2S, were delivered with an olfactometer to young, healthy volunteers. The analysis was performed in a classical (5-electrode, main ERPs peaks) and modern approach (high topographical resolution, inverse solution, source localization). Results of microstate segmentation highlighted 5 maps that generally described the two processes at cerebral level. The trigeminal response differed from the olfactory response up to 300ms after stimulus onset. In this time range, source analysis pointed out that the olfactory stimulation involved olfactory related areas, while trigeminal stimulation involved noxious/somatosensory specific brain areas. Moreover, from 300ms on our data showed a similarity between the two processes. Statistical parametrical mapping of the differences between conditions suggested greater activation in a specific motor/sniffing network for the CO2 stimulation (probably related to a regulation of the potential noxious stimulus) and a greater activation of the ipsilateral primary olfactory cortex for H2S. 23954285 Genotoxic effects of bisphenol A on somatic cells of female mice, alone and in combination with X-rays. Bisphenol A (BPA), a monomer used in the manufacture of epoxy, polycarbonate, and polystyrene resins, is a xenoestrogen present in many consumer products. We investigated the effects of 2-week exposure to BPA, either alone or in combination with X-rays, on the induction of DNA damage in somatic cells of female mice in vivo. The micronucleus and alkaline comet assays were used to evaluate genotoxicity. BPA induced DNA strand breaks in lung cells but not in bone marrow lymphocytes, liver, kidney, or spleen cells. Induction of micronuclei was observed only in polychromatic reticulocytes of peripheral blood. Levels of damage following combination exposure to ionizing radiation plus BPA depended on tissue, assay, and time. 23828094 Effects of interpupillary distance on stereoacuity: the Frisby Davis distance stereotest versus a 3-dimensional distance stereotest. To evaluate the effect of interpupillary distance (IPD) on stereoacuity using 2 kinds of stereoacuity tests in a normal population. The distance stereoacuities of 33 healthy volunteers with no evidence of ocular diseases were measured with the Frisby Davis distance (FD2) stereotest and a 3-dimensional monitor-based distance stereotest (distance 3-D stereotest). These 2 kinds of stereotests were repeated using horizontal periscopes to increase the IPD 2- and 3-fold in order to investigate the effect of IPD increase on stereoacuity. The mean age of the participants was 28.5 years (range 20-41 years). The mean logarithms of the individual minimum angle of stereodiscrimination (logMAS) were 1.04 ± 0.23 (range 0.70-1.48 logMAS) with the FD2 stereotest and 1.52 ± 0.19 (range 1.00-1.85 logMAS) with the distance 3-D stereotest. As the IPD increased 2- and 3-fold, the logMAS measured with the FD2 stereotest improved from 1.04 to 0.98 and 0.91 (P = 0.061 and P = 0.003), respectively, and those measured with the distance 3-D stereotest worsened from 1.52 to 1.73 and 1.85 (P < 0.001 and P < 0.001), respectively. Changes in IPD measured with the FD2 stereotest exhibited opposite effects to those measured with the distance 3-D stereotest. This reflects what is known to happen in the real world, i.e., that stereoacuity improves as IPD increases. 23869882 Solubility of Lead and Copper in Biochar-Amended Small Arms Range Soils: Influence of Soil Organic Carbon and pH. Biochar is often considered a strong heavy metal stabilizing agent. However, biochar in some cases had no effects on, or increased the soluble concentrations of, heavy metals in soil. The objective of this study was to determine the factors causing some biochars to stabilize and others to dissolve heavy metals in soil. Seven small arms range soils with known total organic carbon (TOC), cation exchange capacity, pH, and total Pb and Cu contents were first screened for soluble Pb and Cu concentrations. Over 2 weeks successive equilibrations using weak acid (pH 4.5 sulfuric acid) and acetate buffer (0.1 M at pH 4.9), Alaska soil containing disproportionately high (31.6%) TOC had nearly 100% residual (insoluble) Pb and Cu. This soil was then compared with sandy soils from Maryland containing significantly lower (0.5-2.0%) TOC in the presence of 10 wt % (i) plant biochar activated to increase the surface-bound carboxyl and phosphate ligands (PS450A), (ii) manure biochar enriched with soluble P (BL700), and (iii) unactivated plant biochars produced at 350 °C (CH350) and 700 °C (CH500) and by flash carbonization (corn). In weak acid, the pH was set by soil and biochar, and the biochars increasingly stabilized Pb with repeated extractions. In pH 4.9 acetate buffer, PS450A and BL700 stabilized Pb, and only PS450A stabilized Cu. Surface ligands of PS450A likely complexed and stabilized Pb and Cu even under acidic pH in the presence of competing acetate ligand. Oppositely, unactivated plant biochars (CH350, CH500, and corn) mobilized Pb and Cu in sandy soils; the putative mechanism is the formation of soluble complexes with biochar-borne dissolved organic carbon. In summary, unactivated plant biochars can inadvertently increase dissolved Pb and Cu concentrations of sandy, low TOC soils when used to stabilize other contaminants. 23921558 "Re-growth Etching" to Large-sized Porous Gold Nanostructures. A new method, named "re-growth etching", which introduces a unique etchant "Au(I)", has been developed to fabricate large-sized porous gold nanostructures. The size of nanostructures and the number of pores can be regulated by the molar ratio of Ag and Au in the precursor. We have evaluated their performance by a model reaction of the reduction of 4-nitrophenol. The catalytic property of porous Au from Ag67.6Au32.4 (Sample 3) is higher than those of other obtained products, which are mainly attributed to its hollows-interior, porous-exterior, and the large amount of Au. The method for the large-sized porous metal nanostructures has been established for the first time and shows the potential of this route to expand the scope of fabricating porous metal nanostructures. 23685739 Muscle activation patterns in infants with myelomeningocele stepping on a treadmill. To characterize how infants with myelomeningocele (MMC) activate lower limb muscles over the first year of life, without practice, while stepping on a motorized treadmill. Twelve infants with MMC were tested longitudinally at 1, 6, and 12 months. Electromyography was used to collect data from the tibialis anterior, lateral gastrocnemius, rectus femoris, biceps femoris. Across the first year, infants showed no electromyographic activity for approximately 50% of the stride cycle with poor rhythmicity and timing of muscles, when activated. Single muscle activation predominated; agonist-antagonist coactivation was low. Probability of individual muscle activity across the stride decreased with age. Infants with MMC show high variability in timing and duration of muscle activity, few complex combinations, and very little change over time. 23503868 Mycorrhizal responsiveness of maize (Zea mays L.) genotypes as related to releasing date and available P content in soil. The aim of this study was to compare the mycorrhizal responsiveness among old and recent Chinese maize genotypes (released from 1950s to 2008) in low- and high-Olsen-P soils and to identify parameters that would indicate the relationships between the mycorrhizal responsiveness and the functional traits related to P uptake of maize. A greenhouse factorial experiment was conducted. The factors were maize genotype [Huangmaya (HMY), Zhongdan 2 (ZD2), Nongda 108 (ND108), and NE15], inoculation with or without arbuscular mycorrhizal fungi (AMF) (Rhizophagus irregularis), and Olsen-P levels (4, 9, 18, 36, or 60 mg P kg(-1)). Old and recently released genotypes differed in their response to AMF under low- and high-P supply. Three kinds of responses (in terms of shoot growth) were observed: the response was positive if the soil P content was low, but negative if the soil Olsen-P content was high (HMY and ND108); the response was neutral regardless of soil P content (ZD2); and the response was positive regardless of soil P content (NE15). Principle component (PC) analysis showed that the first PC comprised morphological and physiological traits of maize roots, and the second PC comprised mycorrhizal traits. The opposite was the case, however, in high-P soil. It is concluded that maize breeding selection from 1950s to 2000s is not always against the AM association and that AMF play positive roles in promoting the growth of some maize genotypes in high-P soil. The root length colonization by efficient AMF might be a useful parameter for breeding varieties with increased mycorrhizal responsiveness. 23769877 Expression patterns of CXCR4 in different colon tissue segments of patients with Hirschsprung's disease. C-X-C chemokine receptor type 4 (CXCR4) plays a crucial role in a wide range of physiological and pathological processes, including the migration of stem cells, such as neural crest-derived cells. Hirschsprung's disease (HSCR), a developmental disorder characterized by the absence of ganglion cells, is regarded as the consequence of the premature arrest of the craniocaudal migration of neural crest-derived cells (NCDCs) in the gastrointestinal tract during the development of the enteric nervous system (ENS). In this study, colon tissue samples from 61 HSCR patients were surgically collected and divided into aganglionic, oligoganglionic and normal ganglionic segments. Quantitative real-time polymerase chain reactions (PCR), Western blotting, and immunohistochemical and immunofluorescence staining were performed to analyze the expression levels and patterns of CXCR4 in different colon tissue segments. The expression levels of CXCR4 mRNA and protein in the aganglionic segments were decreased compared to the normal ganglionic and oligoganglionic colon segments (p<0.01). Immunohistochemical staining showed that intensive CXCR4 staining was detected in the ganglion cells and the supporting glial cells in the ganglion in control colon specimens and normal ganglionic and oligoganglionic colon segments from the HSCR patients; however, CXCR4 staining was significantly decreased in the aganglionic colon segments. Immunofluorescence staining showed that CXCR4 staining was mainly detected in the ganglia where RET-positive ganglion cells were observed. Elucidating CXCR4 expression patterns in colon segments could be the basis for further investigations of the potential role of CXCR4 in ENS development. 23621376 Predicting ocular residual astigmatism using corneal and refractive parameters: a myopic eye study. To investigate the nature of ocular residual astigmatism (ORA) in myopic patients and to identify indicators to predict a patient's ORA from corneal and ocular refractive data. In total, 356 myopic eyes from 178 patients (M:F = 41:137) were examined using a Scheimpflug keratometer (Pentacam) and a wavefront analyzer (WaveScan). Vertex distance-adjusted total ocular astigmatism and corneal astigmatism [anterior corneal power (ACP) and true net power (TNP)] were used to calculate ORA, respectively. A power vector system (J0 and J45) was adopted for the astigmatism analysis. The mean age of the study eyes was 27.6 ± 5.0 years, and mean refractive spherical equivalent, sphere and cylinder was -4.94 ± 1.90 diopter, -4.42 ± 1.87 diopter, and -1.05 ± 0.82, respectively. Corneal astigmatism measured by TNP was more representative of total ocular astigmatism than ACP (p < 0.001). Both the J0 and J45 components of ORA showed significant negative correlation with corneal astigmatism measured by ACP and TNP (p < 0.001). ORA (J0 and J45) was negatively correlated with total ocular spherical equivalent and positively correlated with total ocular astigmatism. We verified the general compensatory effect of corneal astigmatism by internal optics in myopic patients. TNP was closer to refractive astigmatism than ACP was. Total ocular spherical equivalent and total ocular astigmatism showed significant correlation with ORA. Therefore these can be possible indicators to predict ORA. 23490245 Durability of left ventricular assist devices: Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) 2006 to 2011. The present study compared the interval until device exchange or death from pump-related failure in patients with pulsatile versus continuous flow left ventricular assist devices. Data from Interagency Registry for Mechanically Assisted Circulatory Support (June 23, 2006, to March 31, 2011) compared the durability of implanted pulsatile and continuous flow left ventricular assist devices. The durability issues included pump replacement for infection, thrombosis-hemolysis, driveline failure, or pump drive unit failure, and death from driveline or pump drive unit failure. A total of 3302 left ventricular assist devices were implanted (486 pulsatile, 2816 continuous flow) and 98 pump exchanges or deaths from durability issues (46 pulsatile, 52 continuous flow; 3% of implants). The interval to device issue was greater for the continuous flow than for the pulsatile devices (P < .001). A comparisons of the causes for pump exchange or pump-related death showed (1) greater freedom from pump failure in the continuous flow compared with the pulsatile left ventricular assist devices (10 events/2816 continuous flow implants vs 39 events/486 pulsatile implants; P < .0001); (2) similar exchange or pump-related death for driveline failure (1/486 pulsatile vs 7/2816 continuous flow; P = .82); (3) similar exchange or pump-related death for thrombosis-hemolysis (2/486 pulsatile vs 28/2816 continuous flow; P = .25); and (4) fewer exchanges or pump-related deaths from infection in continuous flow left ventricular assist devices (4/486 pulsatile vs 7/2816 continuous flow; P = .034). Competing outcomes analysis corroborated this finding, with 54% of continuous flow versus 23% of pulsatile patients alive and receiving support at 12 months after implantation. The Analysis of Interagency Registry for Mechanically Assisted Circulatory Support data showed greater durability for continuous flow than for pulsatile left ventricular assist devices. Even longer durations of support can be expected if pump durability continues to improve. 23895249 Optimal Design of Permeable Fiber Network Structures for Fog Harvesting. Fog represents a large untapped source of potable water, especially in arid climates. Numerous plants and animals use textural and chemical features on their surfaces to harvest this precious resource. In this work, we investigate the influence of the surface wettability characteristics, length scale, and weave density on the fog-harvesting capability of woven meshes. We develop a combined hydrodynamic and surface wettability model to predict the overall fog-collection efficiency of the meshes and cast the findings in the form of a design chart. Two limiting surface wettability constraints govern the re-entrainment of collected droplets and clogging of mesh openings. Appropriate tuning of the wetting characteristics of the surfaces, reducing the wire radii, and optimizing the wire spacing all lead to more efficient fog collection. We use a family of coated meshes with a directed stream of fog droplets to simulate a natural foggy environment and demonstrate a five-fold enhancement in the fog-collecting efficiency of a conventional polyolefin mesh. The design rules developed in this work can be applied to select a mesh surface with optimal topography and wetting characteristics to harvest enhanced water fluxes over a wide range of natural convected fog environments. 23380177 The role of short-term oxygen administration in the prevention of intimal hyperplasia. Intimal hyperplasia (IH) is the cause of most failed arteriovenous fistulas (AVFs), resulting in repeat procedures and leading to increased utilization of scarce health care resources. Our laboratory has previously demonstrated the role of supplemental oxygen in preventing IH and smooth muscle cell proliferation (SMCp) at an artery-to-graft anastomosis and at the deployment site of an intra-arterial stent. This study examines the effect of supplemental oxygen in preventing IH and SMCp in an AVF in a rabbit model. Ninety-six rabbits were randomized into four groups: group 1, control; group 2, no surgery with supplemental oxygen; group 3, AVF without supplemental oxygen; and group 4, AVF with supplemental oxygen. Rabbits receiving supplemental oxygen received 30% oxygen for up to 42 days. Specimens were collected in all groups at days 1, 3, 7, 21, 42, and 90. IH and SMCp were measured at the AVF site as well as in the artery and vein proximal and distal to the AVF. IH was first noted at day 7 and significantly increased through day 90 at all locations in the nonoxygen-supplemented groups. No significant IH was noted in the oxygen-supplemented group at any location or any time point. SMCp was noted at day 3 through day 21 in the nonoxygen-supplemented group, whereas almost no SMCp was noted in the oxygen-supplemented group at any location or time point. Without oxygen supplementation, SMCp begins at day 3 and is no longer noted at day 21 after creation of an AVF, whereas IH begins by day 7 and increases at least through day 90 after creation of an AVF. Forty-two days of 30% supplemental oxygen inhibits IH and SCMp after creation of an AVF. These data suggest a role for the short-term administration of low-dose O2 to prevent both IH and SMCp after creation of an AVF that may prolong patency and function. 23947946 Systematic review of available evidence on 11 high-priced inpatient orphan drugs. Attention for Evidence Based Medicine (EBM) is growing, but evidence for orphan drugs is argued to be limited and inferior. This study systematically reviews the available evidence on clinical effectiveness, cost-effectiveness and budget impact for orphan drugs. A systematic review was performed in PubMed, Embase, NHS EED and HTA databases for 11 inpatient orphan drugs listed on the Dutch policy rule on orphan drugs. For included studies, we determined the type of study and various study characteristics. A total of 338 studies met all inclusion criteria. Almost all studies (96%) focused on clinical effectiveness of the drug. Of these studies, most studies were case studies (41%) or observational studies (39%). However, for all orphan diseases at least one experimental or quasi-experimental study was found, and a randomized clinical trial was available for 60% of the orphan drugs. Eight studies described the cost-effectiveness of an orphan drug; an equal number described an orphan drug's budget impact. Despite the often heard claim that RCTs are not feasible for orphan drugs, we found that an RCT was available in 60% of orphan drugs investigated. Cost-effectiveness and budget impact analyses for orphan drugs are seldom published. 23671263 Insulin and IGF-I inhibit GH synthesis and release in vitro and in vivo by separate mechanisms. IGF-I is considered a primary inhibitor of GH secretion. Insulin may also play an important role in regulating GH levels because insulin, like IGF-I, can suppress GH synthesis and release in primary pituitary cell cultures and insulin is negatively correlated with GH levels in vivo. However, understanding the relative contribution insulin and IGF-I exert on controlling GH secretion has been hampered by the fact that circulating insulin and IGF-I are regulated in parallel and insulin (INSR) and IGF-I (IGFIR) receptors are structurally/functionally related and ubiquitously expressed. To evaluate the separate roles of insulin and IGF-I in directly regulating GH secretion, we used the Cre/loxP system to knock down the INSR and IGFIR in primary mouse pituitary cell cultures and found insulin-mediated suppression of GH is independent of the IGFIR. In addition, pharmacological blockade of intracellular signals in both mouse and baboon cultures revealed insulin requires different pathways from IGF-I to exert a maximal inhibitory effect on GH expression/release. In vivo, somatotrope-specific knockout of INSR (SIRKO) or IGFIR (SIGFRKO) increased GH levels. However, comparison of the pattern of GH release, GH expression, somatotrope morphometry, and pituitary explant sensitivity to acute GHRH challenge in lean SIRKO and SIGFRKO mice strongly suggests the primary role of insulin in vivo is to suppress GH release, whereas IGF-I serves to regulate GH synthesis. Finally, SIRKO and/or SIGFRKO could not prevent high-fat, diet-induced suppression of pituitary GH expression, indicating other factors/tissues are involved in the decline of GH observed with weight gain. 23885934 Nonarteriosclerotic vascular disease. Thromboangiitis obliterans, or Buerger disease, is a chronic nonatherosclerotic endarteritis manifesting as inflammation and thrombosis of distal extremity small and medium-sized arteries resulting in relapsing episodes of distal extremity ischemia. Takayasu arteritis is a rare syndrome characterized by inflammation of the aortic arch, pulmonary, coronary, and cerebral vessels, presenting with cerebrovascular symptoms, myocardial ischemia, or upper extremity claudication in young, often female, patients. Kawasaki disease is a small- and medium-vessel acute systemic vasculitis of young children, with morbidity and mortality stemming from coronary artery aneurysms. Microscopic polyangiitis, Churg-Strauss syndrome, and Wegener granulomatosis are systemic small-vessel vasculitides, affecting arterioles, capillary beds and venules, and each presenting with variable effects on the pulmonary, renal and gastrointestinal systems. 23221948 Multimodal MR Imaging (Diffusion, Perfusion, and Spectroscopy): Is It Possible to Distinguish Oligodendroglial Tumor Grade and 1p/19q Codeletion in the Pretherapeutic Diagnosis? Pretherapeutic determination of tumor grade and genotype in grade II and III oligodendroglial tumors is clinically important but is still challenging. Tumor grade and 1p/19q status are currently the 2 most important factors in therapeutic decision making for patients with these tumors. Histopathology and cMRI studies are still limited in some cases. In the present study, we were interested in determining whether the combination of PWI, DWI, and MR spectroscopy could help distinguish oligodendroglial tumors according to their histopathologic grade and genotype. We retrospectively reviewed 50 adult patients with grade II and III oligodendrogliomas and oligoastrocytomas who had DWI, PWI, and MR spectroscopy at short and long TE data and known 1p/19q status. Univariate analyses and multivariate random forest models were performed to determine which criteria could differentiate between grades and genotypes. ADC, rCBV, rCBF, and rK2 were significantly different between grade II and III oligodendroglial tumors. DWI, PWI, and MR spectroscopy showed no significant difference between tumors with and without 1p/19q loss. Separation between tumor grades and genotypes with cMRI alone showed 31% and 48% misclassification rates, respectively. Multimodal MR imaging helps to determine tumor grade and 1p/19q genotype more accurately (misclassification rates of 17% and 40%, respectively). Although multimodal investigation of oligodendroglial tumors has a lower contribution to 1p/19q genotyping compared with cMRI alone, it greatly improves the accuracy of grading of these neoplasms. Use of multimodal MR imaging could thus provide valuable information that may assist clinicians in patient preoperative management and treatment decision making. 23368645 Direct atomic-level observation and chemical analysis of ZnSe synthesized by in situ high-throughput reactive fiber drawing. We demonstrate a high-throughput method for synthesizing zinc selenide (ZnSe) in situ during fiber drawing. Central to this method is a thermally activated chemical reaction occurring across multiple interfaces between alternately layered elemental zinc- (Zn-) and selenium- (Se-) rich films embedded in a preform and drawn into meters of fiber at a temperature well below the melting temperature of either Zn or ZnSe. By depositing 50 nm thick layers of Zn interleaved between 1 μm thick Se layers, a controlled breakup of the Zn sheet is achieved, thereby enabling a complete and controlled chemical reaction. The thermodynamics and kinetics of this synthesis process are studied using thermogravimetric analysis and differential scanning calorimetry, and the in-fiber compound is analyzed by a multiplicity of materials characterization tools, including transmission electron microscopy, Raman microscopy, energy-dispersive X-ray spectroscopy, and X-ray diffraction, all resulting in unambiguous identification of ZnSe as the compound produced from the reactive fiber draw. Furthermore, we characterize the in-fiber ZnSe/Se97S3 heterojunction to demonstrate the prospect of ZnSe-based fiber optoelectronic devices. The ability to synthesize new compounds during fiber drawing at nanometer scale precision and to characterize them at the atomic-level extends the architecture and materials selection compatible with multimaterial fiber drawing, thus paving the way toward more complex and sophisticated functionality. 23883002 Communication: Quantum dynamics in classical spin baths. A formalism for studying the dynamics of quantum systems embedded in classical spin baths is introduced. The theory is based on generalized antisymmetric brackets and predicts the presence of open-path off-diagonal geometric phases in the evolution of the density matrix. The weak coupling limit of the equation can be integrated by standard algorithms and provides a non-Markovian approach to the computer simulation of quantum systems in classical spin environments. It is expected that the theory and numerical schemes presented here have a wide applicability. 23900965 Diagnosis and Management of Paraneoplastic Neurologic Disorders. Paraneoplastic neurologic disorders (PND) are a heterogeneous group of immune-mediated neurological disorders associated with systemic cancers. When a PND is diagnosed, prompt identification and treatment of the associated tumor is important as PND stabilization and in some cases improvement have been reported after tumor treatment. The cancer, however, may be small and difficult to detect or the onset of the PND may precede the development of the cancer by months or years. In the latter cases, patients often initially present to neurologists or internists who will need assistance from their oncology colleagues to uncover the cancer. It is therefore important to be aware of the associations of common cancers with specific PND syndromes and the significance in some PND of the presence in serum and/or cerebrospinal fluid (CSF) of specific antineuronal antibodies. Together, this information can focus the search for the tumor or support continued vigilance. Previously thought to be poorly responsive to therapies, it is now recognized that there is a subgroup of PND, mostly associated with antibodies to antigens on the neuronal cell surface that are highly treatment responsive. Treatments aimed at the PND are mostly immunosuppressive and include corticosteroids, plasma exchange and intravenous immunoglobulins (IVIg). Immunosuppressive chemotherapeutics and B-cell targeting drugs such as rituximab also may be useful. Although cancer patients tolerate these therapies, there is the risk of increased toxicity when combined with tumor-directed treatments and treatment plans should be coordinated between specialists. 23389921 The reciprocal cerebellar circuitry in human hereditary ataxia. Clinicoanatomic correlation in the spinocerebellar ataxias (SCA) and Friedreich's ataxia (FRDA) is difficult as these diseases differentially affect multiple sites in the central and peripheral nervous systems. A new way to study cerebellar ataxia is the systematic analysis of the "reciprocal cerebellar circuitry" that consists of tightly organized reciprocal connections between Purkinje cells, dentate nuclei (DN), and inferior olivary nuclei (ION). This circuitry is similar to but not identical with the "cerebellar module" in experimental animals. Neurohumoral transmitters operating in the circuitry are both inhibitory (γ-aminobutyric acid in corticonuclear and dentato-olivary fibers) and excitatory (glutamate in olivocerebellar or climbing fibers). Glutamatergic climbing fibers also issue collaterals to the DN. The present study applied five immunohistochemical markers in six types of SCA (1, 2, 3, 6, 7, 17), genetically undefined SCA, FRDA, and FRDA carriers to identify interruptions within the circuitry: calbindin-D28k, neuron-specific enolase, glutamic acid decarboxylase, and vesicular glutamate transporters 1 and 2. Lesions of the cerebellar cortex, DN, and ION were scored according to a guide as 0 (normal), 1 (mild), 2 (moderate), and 3 (severe). Results of each of the five immunohistochemical stains were examined separately for each of the three regions. Combining scores of each anatomical region and each stain yielded a total score as an indicator of pathological severity. Total scores ranged from 16 to 38 in SCA-1 (nine cases); 22 to 39 in SCA-2 (six cases); 9 to 15 in SCA-3 (four cases); and 13 and 25 in SCA-6 (two cases). In single cases of SCA-7 and SCA-17, scores were 16 and 31, respectively. In two genetically undefined SCA, scores were 36 and 37, respectively. In nine cases of FRDA, total scores ranged from 11 to 19. The low scores in SCA-3 and FRDA reflect selective atrophy of the DN. The FRDA carriers did not differ from normal controls. These observations offer a semiquantitative assessment of the critical role of the DN in the ataxic phenotype of SCA and FRDA while other parts of the circuitry appear less important. 23713473 Correlation between Conformational Equilibria of Free Host and Guest Binding Affinity in Non-preorganized Receptors. Positive cooperativity between host conformational equilibria and guest binding has been widely reported in protein receptors. However, reported examples of this kind of cooperativity in synthetic hosts are scarce and largely serendipitous, among other things because it is hard to envision systems which display this kind of cooperativity. In order to shed some light on the correlation between conformational equilibria of free host and guest binding, selected structural modifications have been performed over a family of nonpreorganized hosts in order to induce conformational changes and to analyze their effect on the binding affinity. The conformational effect was evaluated by a theoretical conformational search and correlated with the ability of the receptors. All data suggest that those receptors that display the best association constants are able to sample folded conformations analogous to the conformational requirements for the binding of the guests. On the contrary, for those receptors where folded conformers are scarce, then the association constant and enantioselectivity clearly drop. 23831748 Plate column biosorption of Cu(II) on membrane-type biosorbent (MBS) of Penicillium biomass: Optimization using statistical design methods. Based on the coupling of biosorption and membrane separation, a low cost membrane-type biosorbent (MBS) of Penicillium biomass was prepared. The surface morphology, pore properties and functional groups were studied via the characterization of MBS. Batch biosorption experiments indicated the maximum biosorption capacity of Cu(II) on MBS was 126.58mg/g and about 90% of that on chitosan membrane. A plate column reactor filled with multi-layer of MBS was built for treatment of wastewater contaminated by Cu(II). The biosorption process factors were screened using Plackett-Burman design and three significant variables were selected for further optimization via response surface methodology (RSM) based on Box-Behnken model. A statistically second-order polynomial model was constructed with the error below 1.22%, on the basis of which the three-dimensional response surfaces were plotted. The prepared membrane-type biosorbent could be used successfully for 10 biosorption-desorption-regeneration cycles without decreasing its biosorption ability obviously. 23896195 Controlled penetration of ceramides into and across the stratum corneum using various types of microemulsions and formulation associated toxicity studies. Several skin diseases such as psoriasis and atopic dermatitis are associated with the depletion or disturbance of stratum corneum (SC) lipids such as ceramides (CERs), free fatty acids and cholesterol. Studies suggested that replenishment of these lipids might help to treat diseased, affected or aged skin. With this premises in mind, there are some formulations in the market that contain SC lipids and currently, to facilitate permeation of the lipids deep into the SC, various CERs, and other SC lipid microemulsions (MEs) were developed and characterised using lecithin or TEGO® CARE PL 4 (TCPL4) as base surfactants. However, to date, there are no reports that involve the permeability of SC lipids into and across the SC, and therefore, the penetration of CER [NP] as a model ceramide from various formulations was investigated ex vivo using Franz diffusion cell. Besides, the toxicity of the MEs was assessed using hen's egg test chorioallantoic membrane (HET-CAM). The results of the study showed that CER [NP] could not permeate into deeper layers of the SC from a conventional hydrophilic cream. Unlike the cream, CER [NP] permeated into the deeper layers of the SC from both type of MEs, where permeation of the CER was more and into deeper layers from droplet type and lecithin-based MEs than bicontinuous (BC) type and TCPL4 based MEs, respectively. The CER also permeated into deeper layers from ME gels which was, however, shallow and to a lesser extent when compared with the MEs. The results of HET-CAM showed that both MEs are safe to be used topically, with lecithin-based MEs exhibiting better safety profiles than TCPL4 based MEs. Concluding, the study showed that the MEs are safe to be used on the skin for the controlled penetration of CER [NP] deep into the SC. 23936366 Conditional knockout of tumor overexpressed gene in mouse neurons affects RNA granule assembly, granule translation, LTP and short term habituation. In neurons, specific RNAs are assembled into granules, which are translated in dendrites, however the functional consequences of granule assembly are not known. Tumor overexpressed gene (TOG) is a granule-associated protein containing multiple binding sites for heterogeneous nuclear ribonucleoprotein (hnRNP) A2, another granule component that recognizes cis-acting sequences called hnRNP A2 response elements (A2REs) present in several granule RNAs. Translation in granules is sporadic, which is believed to reflect monosomal translation, with occasional bursts, which are believed to reflect polysomal translation. In this study, TOG expression was conditionally knocked out (TOG cKO) in mouse hippocampal neurons using cre/lox technology. In TOG cKO cultured neurons granule assembly and bursty translation of activity-regulated cytoskeletal associated (ARC) mRNA, an A2RE RNA, are disrupted. In TOG cKO brain slices synaptic sensitivity and long term potentiation (LTP) are reduced. TOG cKO mice exhibit hyperactivity, perseveration and impaired short term habituation. These results suggest that in hippocampal neurons TOG is required for granule assembly, granule translation and synaptic plasticity, and affects behavior. 23715884 What micronutrient deficiencies should be considered in distinct neurological disorders? The expanding understanding of the biochemical and physiologic role of micronutrients, commonly referred to as vitamins and minerals, is driving the identification of their consequences in both deficiency and toxicity. Neural tissue is quite sensitive to physiologic changes, and as such, micronutrient deficiencies can have significant and profound effects on the functioning of both the central and peripheral nervous systems. Understanding which micronutrients can affect the nervous system can aid physician identification of these neurological symptoms and signs, leading to diagnostic testing and appropriate therapy. 23547621 Traumatic brain injury: oxidative stress and neuroprotection. Abstract Significance: A vast amount of circumstantial evidence implicates high energy oxidants and oxidative stress as mediators of secondary damage associated with traumatic brain injury. The excessive production of reactive oxygen species due to excitotoxicity and exhaustion of the endogenous antioxidant system induces peroxidation of cellular and vascular structures, protein oxidation, cleavage of DNA, and inhibition of the mitochondrial electron transport chain. Recent Advances: Different integrated responses exist in the brain to detect oxidative stress, which is controlled by several genes termed vitagens. Vitagens encode for cytoprotective heat shock proteins, and thioredoxin and sirtuins. Critical Issues and Future Directions: This article discusses selected aspects of secondary brain injury after trauma and outlines key mechanisms associated with toxicity, oxidative stress, inflammation, and necrosis. Finally, this review discusses the role of different oxidants and presents potential clinically relevant molecular targets that could be harnessed to treat secondary injury associated with brain trauma. Antioxid. Redox Signal. 19, 836-853. 23896215 Palmitoylethanolamide: From endogenous cannabimimetic substance to innovative medicine for the treatment of cannabis dependence. Palmitoylethanolamide (PEA) is a fatty acid amide showing some pharmacodynamic similarities with Δ(9)-tetrahydrocannabinol, the principal psychoactive compound present in the cannabis plant. Like Δ(9)-tetrahydrocannabinol, PEA can produce a direct or indirect activation of cannabinoid receptors. Furthermore, it acts as an agonist at TRPV1 receptor. The hypothesis is that PEA has anti-craving effects in cannabis dependent patients, is efficacious in the treatment of withdrawal symptoms, produces a reduction of cannabis consumption and is effective in the prevention of cannabis induced neurotoxicity and neuro-psychiatric disorders. 23479060 Genotoxic effects of the water-soluble fraction of heavy oil in the brackish/freshwater amphipod Quadrivisio aff. lutzi (Gammaridea) as assessed using the comet assay. Amphipod crustaceans have been widely used as invertebrate models in ecotoxicology due to their importance in the food chain. However, few studies have evaluated the genotoxic effects of pollutants in this model using the comet assay. The main obstacle to using amphipods in the comet assay is the difficulty in obtaining enough blood cells from a single individual. In this study, we evaluated the genotoxic effects of the water-soluble fraction (WSF) of heavy oil on the brackish/freshwater amphipod Quadrivisio aff. lutzi, which is common in the coastal lagoons of southeastern Brazil, using hemocytes obtained from single amphipods (without pooling) after optimizing hemolymph extraction. The comet assay revealed significantly higher DNA damage levels (2- to 6-fold higher) in treated amphipods compared to untreated ones with a sublethal concentration of 17.6 % of the WSF within 72 h of treatment. Two independent experiments confirmed an "up and down" pattern of DNA damage, measured as the % of DNA contained in the tail of the comets. Elevations in DNA damage levels were observed at the 6 and 48 h time points, while very low levels of DNA damage were observed at the 24 and 72 h time points. Furthermore, the comet assay revealed gender variability in the levels of DNA damage after short-term exposure. 23903011 Outbreak of Pneumocystis Pneumonia in Renal and Liver Transplant Patients Caused by Genotypically Distinct Strains of Pneumocystis jirovecii. An outbreak of 29 cases of Pneumocystis jirovecii pneumonia (PCP) occurred among renal and liver transplant recipients (RTR and LTR) in the largest Danish transplantation centre between 2007 and 2010, when routine PCP prophylaxis was not used. P. jirovecii isolates from 22 transplant cases, 2 colonized RTRs, and 19 Pneumocystis control samples were genotyped by restriction fragment length polymorphism and multilocus sequence typing analysis. Contact tracing was used to investigate transmission. Potential risk factors were compared between PCP cases and matched non-PCP transplant patients. Three unique Pneumocystis genotypes were shared among 19 of the RTRs, LTRs, and a colonized RTR in three distinct clusters, two of which overlapped temporally. In contrast, Pneumocystis control samples harbored a wide range of genotypes. Evidence of possible nosocomial transmission was observed. Among several potential risk factors, only cytomegalovirus viremia was consistently associated with PCP (P=0.03; P=0.009). Mycophenolate mofetil was associated with PCP risk only in the RTR population (P=0.04). We identified three large groups infected with unique strains of Pneumocystis and provide evidence of an outbreak profile and nosocomial transmission. LTRs may be infected in PCP outbreaks simultaneously with RTRs and by the same strains, most likely by interhuman transmission. Patients are at risk several years after transplantation, but the risk is highest during the first 6 months after transplantation. Because patients at risk cannot be identified clinically and outbreaks cannot be predicted, 6 months of PCP chemoprophylaxis should be considered for all RTRs and LTRs. 23421766 The Arabidopsis tandem CCCH zinc finger proteins AtTZF4, 5 and 6 are involved in light-, abscisic acid- and gibberellic acid-mediated regulation of seed germination. Tandem CCCH zinc finger proteins (TZFs) are post-transcriptional regulators of gene expression in animals and yeast. Genetic studies indicate that plant TZFs are involved in hormone-mediated developmental and environmental responses. We have demonstrated previously that Arabidopsis AtTZF1 can localize to processing bodies (PBs) and stress granules (SGs), and affects abscisic acid (ABA)- and gibberellic acid (GA)-mediated growth, stress and gene expression responses. Here we show that AtTZF4, 5 and 6 are specifically expressed in seeds. Consistent with the observation that their expression levels decline during seed imbibition, AtTZF4, 5 and 6 are up-regulated by ABA and down-regulated by GA. Mutant analyses indicate that AtTZF4, 5 and 6 act as positive regulators for ABA- and negative regulators for light- and GA-mediated seed germination responses. Results of gene expression analysis indicate that AtTZF4, 5 and 6 affect seed germination by controlling genes critical for ABA and GA response. Furthermore, AtTZF4, 5 and 6 can co-localize with both PB and SG markers in Arabidopsis cells. Specifically, AtTZF6 can be assembled into PBs and SGs in embryos with the induction of stress hormone methyl jasmonate under the control of native AtTZF6 promoter. 23832630 Temperature dependence of the polarization and the dielectric constant near the paraelectric-ferroelectric transitions in BaTiO3. Temperature dependences of the spontaneous polarization and the dielectric constant are calculated near the paraelectric-ferroelectric (cubic-tetragonal) transition in BaTiO3 using our mean field model. By expanding the free energy in terms of the spontaneous polarization (order parameter), expressions for the temperature dependence of the spontaneous polarization and the dielectric constant are derived. By considering the temperature dependence of the Raman frequencies for the lattice mode (∼310 cm(-1)) which is related to the spontaneous polarization, the experimental data from the literature is analyzed near the first order paraelectric-ferroelectric transition in BaTiO3. The dielectric constant is then calculated as a function of temperature for the cubic-tetragonal transition in BaTiO3. Our results show that the observed behavior of the spontaneous polarization in the ferroelectric phase (TTC) and ferroelectric phases, can be described adequately by the mean field model studied here for BaTiO3. 23808512 Prediction of fluid responsiveness using dynamic preload indices in patients undergoing robot-assisted surgery with pneumoperitoneum in the Trendelenburg position. We investigated the abilities of pulse pressure variation (PPV) and stroke volume variation (SVV) to predict fluid responsiveness during robot-assisted laparoscopic prostatectomy, requiring pneumoperitoneum and the Trendelenburg position. In 42 patients without cardiopulmonary disease, PPV and SVV were measured before and after administration of 500 ml colloid under pneumoperitoneum combined with the steep Trendelenburg position (35°). Fluid responsiveness was defined as a ≥15% increase in stroke volume after the fluid loading measured using transoesophageal echocardiography. Of the 42 included patients, 22 were responders and 20 were non-responders. A PPV of ≥9.5% identified responders with a sensitivity of 77.3% and a specificity of 90.0%, and a SVV of ≥9.5% also identified responders with a sensitivity of 77.3% and a specificity of 75.0%. The area under receiver operating characteristic curves for PPV and SVV were 0.87 (P <0.001) and 0.81 (P=0.001), respectively. The findings suggest that both PPV and SVV could be useful predictors of fluid responsiveness in patients without cardiopulmonary disease undergoing robotic laparoscopic surgery with pneumoperitoneum in the Trendelenberg position. 23426622 The effect of an AGE-rich dietary extract on the activation of NF-κB depends on the cell model used. Advanced glycation end products (AGEs) are the results of a chemical reaction of reactive aldehydes, such as sugars, with amino acid side chains. AGEs can be formed by the heating process of the food and taken up with the diet. They are thought to be at least in part responsible for major complications in age-related diseases. The activation of the transcription factor NF-κB plays a prominent role in AGE-induced cell signaling. This study aimed to elucidate the effect of exogenous AGEs on NF-κB activation in different cell models. Therefore a bread crust extract commonly found in a Western diet was chosen as an AGE-rich sample. Using RP-HPLC, 23 fractions from the bread crust extract were obtained. The immunodetection with specific antibodies for N-carboxymethyllysine arg-pyrimidine, pentosidine and 3-deoxyglucosone-imidazolone showed that the majority of the AGEs were located in the late fractions. Three different NF-κB reporter cell lines including NF-κB/293/GFP-Luc™, NF-κB/Jurkat/GFP™ and RAW/NF-κB/SEAPorter™ were stimulated with the 23 fractions. There was no direct correlation between the AGE content in the fractions and the cell activation. Whereas in Jurkat-T-cells, the stimulation seems to correlate at least in part with the AGE content, in HEK-293 epithelial cell nearly all fractions can stimulate NF-κB. In macrophages few fractions stimulate NF-κB whereas some fractions even inhibit the p38 MAP kinase. The highest expression of the AGE receptors like RAGE, AGER-1, AGER-2 and AGER-3 was detected in the macrophage RAW cell line. In conclusion the present study showed a new approach to study bioactive compounds in bread crust extract. The identification of the bioactive compounds is still ongoing. 23966903 Classification of schizophrenia patients based on resting-state functional network connectivity. There is a growing interest in automatic classification of mental disorders based on neuroimaging data. Small training data sets (subjects) and very large amount of high dimensional data make it a challenging task to design robust and accurate classifiers for heterogeneous disorders such as schizophrenia. Most previous studies considered structural MRI, diffusion tensor imaging and task-based fMRI for this purpose. However, resting-state data has been rarely used in discrimination of schizophrenia patients from healthy controls. Resting data are of great interest, since they are relatively easy to collect, and not confounded by behavioral performance on a task. Several linear and non-linear classification methods were trained using a training dataset and evaluate with a separate testing dataset. Results show that classification with high accuracy is achievable using simple non-linear discriminative methods such as k-nearest neighbors (KNNs) which is very promising. We compare and report detailed results of each classifier as well as statistical analysis and evaluation of each single feature. To our knowledge our effects represent the first use of resting-state functional network connectivity (FNC) features to classify schizophrenia. 23505636 Cobalt chloride speciation, mechanisms of cytotoxicity on human pulmonary cells, and synergistic toxicity with zinc. Cobalt is used in numerous industrial sectors, leading to occupational diseases, particularly by inhalation. Cobalt-associated mechanisms of toxicity are far from being understood and information that could improve knowledge in this area is required. We investigated the impact of a soluble cobalt compound, CoCl(2)·6H(2)O, on the BEAS-2B lung epithelial cell line, as well as its impact on metal homeostasis. Cobalt speciation in different culture media, in particular soluble and precipitated cobalt species, was investigated via theoretical and analytical approaches. The cytotoxic effects of cobalt on the cells were assessed. Upon exposure of BEAS-2B cells to cobalt, intracellular accumulation of cobalt and zinc was demonstrated using direct in situ microchemical analysis based on ion micro-beam techniques and analysis after cell lysis by inductively coupled plasma mass spectrometry (ICP-MS). Microchemical imaging revealed that cobalt was rather homogeneously distributed in the nucleus and in the cytoplasm whereas zinc was more abundant in the nucleus. The modulation of zinc homeostasis led to the evaluation of the effect of combined cobalt and zinc exposure. In this case, a clear synergistic increase in toxicity was observed as well as a substantial increase in zinc content within cells. Western blots performed under the same coexposure conditions revealed a decrease in ZnT1 expression, suggesting that cobalt could inhibit zinc release through the modulation of ZnT1. Overall, this study highlights the potential hazard to lung function, of combined exposure to cobalt and zinc. 23929473 Complete Genome Sequence of Tick-Borne Encephalitis Virus Strain A104 Isolated from a Yellow-Necked Mouse (Apodemus flavicollis) in Austria. Tick-borne encephalitis virus (TBEV) strain A104 was isolated from the brain of a yellow-necked mouse in Austria in 1990. The complete genome sequence was 11,097 nucleotides long. Comparison with TBEV prototype strain Neudoerfl showed 32 amino acid exchanges and the absence of an internal poly(A) stretch within the 3' noncoding region. 23246530 Mechanisms underlying induction of LTP-associated changes in short-term dynamics of transmission at immature synapses. While the activity-dependent mechanisms guiding functional maturation of synaptic transmission postsynaptically are well characterized, less is known about the corresponding presynaptic mechanisms. Here we show that during the first postnatal week, a subset of CA3-CA1 synapses express postsynaptically induced LTP that is tightly associated with a robust decrease in synaptic facilitation, consistent with an increase in release probability (P(r)). The loss of facilitation is readily induced by physiologically relevant pairing protocols at immature synapses and is dependent on activation of NMDA-receptors but not L-type calcium channels. The putative pre- and postsynaptic components of neonatal LTP were distinguished in their downstream signaling requirements, PKC activity being selectively needed for the decrease in facilitation but not for synaptic potentiation per se. These data suggest that maturation of glutamatergic synapses involves a critical period during which presynaptic function is highly susceptible to activity-dependent regulation via a PKC-dependent mechanism. 23489348 The use of U-500 regular insulin in the management of patients with obesity and insulin resistance. The rise in prevalence of obesity and diabetes has created a challenge in managing increasing numbers of patients who require high doses of insulin. This article reviews the published literature on the properties of U-500 insulin and its use in clinical practice. U-500 insulin is likely to have a longer time to peak effect and a longer duration of action than similar doses of U-100 insulin. Evidence for its use in clinical practice rests on retrospective case series, which suggests that the use of U-500 insulin either by multiple daily injections or a continuous subcutaneous insulin infusion is effective in improving glycaemic control. To prevent insulin dosing and administration errors, great care must be taken in providing staff and patient education, and in developing policies for the management of patients on U-500 insulin who are admitted to hospital. 23549521 Transfer of training between distinct motor tasks after stroke: implications for task-specific approaches to upper-extremity neurorehabilitation. . Although task-specific training is emerging as a viable approach for recovering motor function after stroke, there is little evidence for whether the effects of such training transfer to other functional motor tasks not directly practiced in therapy. . The purpose of the current study was to test whether training on one motor task in individuals with chronic hemiparesis poststroke would transfer to untrained tasks that were either spatiotemporally similar or different. . In all, 11 participants with chronic mild to moderate hemiparesis following stroke completed 5 days of supervised massed practice of a feeding task with their affected side. Performance on the feeding task, along with 2 other untrained functional upper-extremity motor tasks (sorting, dressing) was assessed before and after training. . Performance of all 3 tasks improved significantly after training exclusively on 1 motor task. The amount of improvement in the untrained tasks was comparable and was not dependent on the degree of similarity to the trained task. . Because the number and type of tasks that can be practiced are often limited within standard stroke rehabilitation, results from this study will be useful for designing task-specific training plans to maximize therapy benefits. 23697756 Synthesis of mesoporous ceria/titania thin films for self-cleaning applications. CeO2/TiO2 thin films with a three-dimensional (3D) cubic structure were synthesized. Firstly, mesostructured 3D TiO2 films with high surface area and thermally stable have been prepared. Secondly, CeO2 was deposited on 3D mesoporous TiO2 film by two pathways: (i) cerium nitrate sol in presence of poly(ethylene glycol) was deposited on the prepared mesoporous TiO2 films by spin-coating to obtain 1, 3, and 5 layers CeO2/TiO2 and (ii) the second pathway, for thick CeO2, the prepared mesoporous TiO2 films were suspended into the high concentration of cerium nitrate in presence of poly(ethylene glycol) for 24h with magnetic stirring. FE-SEM images of the mesoporous CeO2/TiO2 films were crack-free and indicated a random worm-like network of the mesopores. The XRD patterns show for all prepared samples only TiO2 anatase phase. At five layers CeO2/TiO2, a weak and diffuse diffraction peak arises, corresponding to (111) plane of cubic CeO2. Methylene blue degradation was conducted to characterize the photocatalytic activity of films and compared with that of commercially available Pilkington Activ™ glass by the determination of their photonic efficiencies. Photonic efficiency of mesoporous TiO2~3.39% is higher than Pilkington Activ™ glass~10 times, probably due to the much larger surface area of the mesoporous films and its high crystallinity. Five layers CeO2/TiO2 films showed two times higher photoactivity for MB oxidation than mesoporous TiO2 film, and its photonic efficiency was found to be ~20 times higher than Pilkington Activ™ glass. Five layers CeO2/TiO2 was fixed after being used repetitively for five times. 23789837 Polyvinyl alcohol-cellulose nanofibrils-graphene oxide hybrid organic aerogels. Hybrid organic aerogels consisting of polyvinyl alcohol (PVA), cellulose nanofibrils (CNFs), and graphene oxide nanosheets (GONSs) were prepared using an environmentally friendly freeze-drying process. The material properties of these fabricated aerogels were measured and analyzed using various characterization techniques including compression testing, scanning electron microscopy, thermogravimetric (TGA) analysis, Brunauer-Emmet-Teller (BET) surface area analysis, and contact angle measurements. These environmentally friendly, biobased hybrid organic aerogels exhibited a series of desirable properties including a high specific compressive strength and compressive failure strain, ultralow density and thermal conductivity, good thermal stability, and moisture resistance, making them potentially useful for a broad range of applications including thermal insulation. 23807232 Stepwise reagent introduction-based droplet platform for multiplexed DNA sensing. A stepwise reagent introduction (SRI)-based droplet platform is reported to apply in multiplexed DNA sensing via droplet imaging and manipulation techniques. The feature of SRI-based droplet platform is that the multiplexed DNA measurements are performed simultaneously without the need for expensive optical instruments. This is achieved by sequentially driving five different DNA probes labeled with carboxyfluorescein into the same chip channel to individually form droplet and fuse with target DNAs and graphene oxide droplets. Based on the variation of droplet color and fluorescence intensity, rapidly qualitative and quantitative DNA analysis are realized. The cooperation between SRI mode and droplet platform thus opens up the possibility of greatly simplified DNA sensing in high throughput format without complicated fluorescent labeling and chip design. 23042669 Distributed spirals: A new class of three-dimensional k-space trajectories. This work presents a new class of three-dimensional spiral based-trajectories for sampling magnetic resonance data. The distributed spirals trajectory efficiently traverses a cylinder or sphere or intermediate shape in k-space. The trajectory is shown to be nearly as efficient as a conventional stack of spirals trajectory in terms of scan time and signal-to-noise ratio, while reducing coherent aliasing in all three spatial directions and reducing Gibbs ringing due to the nature of collecting data from a sphere in k-space. The trajectory uses a single two-dimensional spiral waveform with the addition of a single orthogonal waveform which is scaled with each repetition, making it relatively easy to implement. Blurring from off-resonance only occurs in two dimensions due to the temporal nature of the sampling. Magn Reson Med 70:413-419, 2013. © 2012 Wiley Periodicals, Inc. 23785181 Children's Identification of Consonants in a Speech-Shaped Noise or a Two-Talker Masker. To evaluate child-adult differences for consonant identification in a noise or a 2-talker masker. Error patterns were compared across age and masker type to test the hypothesis that errors with the noise masker reflect limitations in the peripheral encoding of speech, whereas errors with the 2-talker masker reflect target-masker confusions within the central auditory system. A repeated-measures design compared the performance of children (5-13 years) and adults in continuous speech-shaped noise or a 2-talker masker. Consonants were identified from a closed set of 12 using a picture-pointing response. In speech-shaped noise, children under age 10 years performed more poorly than adults, but performance was adultlike for 11- to 13-year-olds. In the 2-talker masker, significant child-adult differences were observed in even the oldest group of children. Systematic clusters of consonant errors were observed for children in the noise masker and for adults in both maskers, but not for children in the 2-talker masker. These results suggest a more prolonged time course of development for consonant identification in a 2-talker masker than in a noise masker. Differences in error patterns between the maskers support the hypothesis that errors with the 2-talker masker reflect failures of sound segregation. 23889058 Dendrimers with large nonlinear optical performance by introducing isolation chromophore, utilizing the ar/ar(f) self-assembly effect, and modifying the topological structure. By the combination of divergent and convergent approach, a new series of NLO dendrimers (G1-PFPh-NS-GL to G3-PFPh-NS-GL) was conveniently prepared with satisfied yields through the powerful "click chemistry" reaction, in which perfluoroaromatic rings were introduced in the periphery, two types of chromophores were arranged with regular AB structure, and their topological structure was improved to a more spherical shape. All the dendrimers demonstrated good processability, and G1-PFPh-NS-GL exhibited the highest NLO effect of 221 pm/V among the three dendrimers. 23789839 Immune alterations and immunotherapy prospects in head and neck cancer. Introduction: Several literature sources have suggested that subjects with head and neck squamous cell carcinoma (HNSCC) display significant abnormalities of immunocompetent cells and cytokine secretion. Serious side effects and only a limited success with traditional therapies in HNSCC dictate the need for newer therapies. Areas covered: This article comprehensively reviews the immune system alterations in HNSCC and the rationale behind various experimental immunotherapies, aiming at keeping this disease under control. Relevant publications were identified through the PubMed database search. The ongoing clinical trials regarding experimental immunotherapy agents in HNSCC were accessed at www.clinicaltrials.gov . The obtained information was thoroughly analyzed and systematized. Expert opinion: Important and severe immune defects including T-cell dysfunction, cytokine alterations and antigen presentation defects are present in patients with HNSCC. In addition, tumor microenvironment was shown to play a critical role in the HNSCC progression. These discoveries have triggered a growing interest in immunotherapy as a potential treatment strategy for HNSCC. Effective immunotherapy could avoid the toxic side effects plaguing the current management of HNSCC. It is also hoped that immunotherapy will have long-lasting effects due to induction of immunologic memory. Promising directions include nonspecific immune stimulation, targeting specific HNSCC tumor antigens and therapeutic vaccines among others. These new agents may expand the existing therapy options for HNSCC in future. 23187064 Effects of ultrasound frequency and acoustic amplitude on the size of sonochemically active bubbles - Theoretical study. Numerical simulation of chemical reactions inside an isolated spherical bubble of oxygen has been performed for various ambient bubble radii at different frequencies and acoustic amplitudes to study the effects of these two parameters on the range of ambient radius for an active bubble in sonochemical reactions. The employed model combines the dynamic of bubble collapse with the chemical kinetics of single cavitation bubble. Results from this model were compared with some experimental results presented in the literature and good apparent trends between them were observed. The numerical calculations of this study showed that there always exists an optimal ambient bubble radius at which the production of oxidizing species at the end of the bubble collapse attained their upper limit. It was shown that the range of ambient radius for an active bubble increased with increasing acoustic amplitude and decreased with increasing ultrasound frequency. The optimal ambient radius decreased with increasing frequency. Analysis of curves showing optimal ambient radius versus acoustic amplitude for different ultrasonic frequencies indicated that for 200 and 300kHz, the optimal ambient radius increased linearly with increasing acoustic amplitude up to 3atm. However, slight minima of optimal radius were observed for the curves obtained at 500 and 1000kHz. 23546614 The consumption of n-3 polyunsaturated fatty acids differentially modulates gene expression of peroxisome proliferator-activated receptor alpha and gamma and hypoxia-inducible factor 1 alpha in subcutaneous adipose tissue of obese adolescents. The aim of this study was to evaluate the effect of long-chain omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation on metabolic state and gene expression in subcutaneous adipose tissues of obese adolescents. Obese adolescents (n = 26, 10 girls and 16 boys) aged 12.4 ± 2.1 years were assigned to a 12-week regimen of n-3 PUFA intake. Five times per day, subjects received a food supplement consisting of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (3 g per day, 944 mg EPA, and 2,088 mg DHA). Blood parameters were measured, and subcutaneous adipose tissue biopsies were analyzed to determine gene expression at baseline and after 12 weeks. Student's t test and the Wilcoxon signed-rank test were used to estimate differences in arithmetic means of pre- and post-dietary supplementation for various anthropometric, biochemical, clinical, and gene expression parameters. After 12 weeks, n-3 PUFA consumption was associated with decreased body mass index (29.7 ± 4.6 vs. 27.8 ± 4.4 kg/m(2); P < 0.001), waist circumference (93.2 ± 9.9 vs. 90.5 ± 10.0 cm; P < 0.003), hip circumference (102.9 ± 10.9 vs. 101.1 ± 10.9 cm; P < 0.014), and blood triglyceride levels (220.8 ± 27.4 vs. 99.7 ± 32.7 mg/dL; P < 0.001). Fatty acid supplementation/n3 PUFA supplementation was associated with a downregulated expression of the genes encoding PPARγ and PGC-1α (P < 0.001), and an upregulated expression of the genes encoding PPARα (P < 0.007) and SREBP1 (P < 0.021). The expressions of SOD2 (P < 0.04), CAT (P < 0.001), GPX3 (P < 0.032) and HIF-1α protein also decreased. Our study demonstrated that n-3 PUFA consumption and dietary restriction improved the anthropometric parameters and decreased the triglycerides levels of the adolescents, suggesting a reduction in hypoxia in subcutaneous adipose tissue. 23749971 Regulation of the ald Gene Encoding Alanine Dehydrogenase by AldR in Mycobacterium smegmatis. The regulatory gene aldR was identified 95 bp upstream of the ald gene encoding l-alanine dehydrogenase in Mycobacterium smegmatis. The AldR protein shows sequence similarity to the regulatory proteins of the Lrp/AsnC family. Using an aldR deletion mutant, we demonstrated that AldR serves as both activator and repressor for the regulation of ald gene expression, depending on the presence or absence of l-alanine. The purified AldR protein exists as a homodimer in the absence of l-alanine, while it adopts the quaternary structure of a homohexamer in the presence of l-alanine. The binding affinity of AldR for the ald control region was shown to be increased significantly by l-alanine. Two AldR binding sites (O1 and O2) with the consensus sequence GA-N2-ATC-N2-TC and one putative AldR binding site with the sequence GA-N2-GTT-N2-TC were identified upstream of the ald gene. Alanine and cysteine were demonstrated to be the effector molecules directly involved in the induction of ald expression. The cellular level of l-alanine was shown to be increased in M. smegmatis cells grown under hypoxic conditions, and the hypoxic induction of ald expression appears to be mediated by AldR, which senses the intracellular level of alanine. 23957930 Context matters: The structure of task goals affects accuracy in multiple-target visual search. Career visual searchers such as radiologists and airport security screeners strive to conduct accurate visual searches, but despite extensive training, errors still occur. A key difference between searches in radiology and airport security is the structure of the search task: Radiologists typically scan a certain number of medical images (fixed objective), and airport security screeners typically search X-rays for a specified time period (fixed duration). Might these structural differences affect accuracy? We compared performance on a search task administered either under constraints that approximated radiology or airport security. Some displays contained more than one target because the presence of multiple targets is an established source of errors for career searchers, and accuracy for additional targets tends to be especially sensitive to contextual conditions. Results indicate that participants searching within the fixed objective framework produced more multiple-target search errors; thus, adopting a fixed duration framework could improve accuracy for career searchers. 23786322 Renovascular hypertension leads to DNA damage and apoptosis in bone marrow cells. Angiotensin II (Ang II), which plays a pivotal role in the pathophysiology of the two-kidney, one-clip (2K1C) Goldblatt hypertension, has been associated with augmented generation of reactive oxygen species (ROS) in some cells and tissues. In the present study, we evaluated the influence of 2K1C hypertension on oxidative stress, DNA fragmentation, and apoptosis of bone marrow (BM) cells. Two weeks after the renal artery clipping or Sham operation, flow cytometry analysis showed a higher production of superoxide anions (approximately sixfold) and hydrogen peroxide (approximately twofold) in 2K1C hypertensive than in Sham normotensive mice. 2K1C mice also showed an augmented DNA fragmentation (54%) and apoptotic cells (21%). Our data show that the 2K1C renovascular hypertension is characterized by an increased production of ROS, DNA damage, and apoptosis of BM, which is a fundamental source of the cells involved in tissue repair. 23628896 Ubiquitous trisulfur radical anion: fundamentals and applications in materials science, electrochemistry, analytical chemistry and geochemistry. The trisulfur radical anion [S3]˙(-) is well-known from inorganic chemistry textbooks as the blue chromophore in ultramarine blues in which this highly reactive species is trapped in a zeolitic framework. Recent findings have revealed that [S3]˙(-) has a multi-faceted role in a variety of media, including alkali metal-sulfur batteries, aqueous solutions at high temperatures and pressures, and ionic liquids; it has also been used to detect trace amounts of water in organic solvents. This tutorial review illustrates how various physical techniques are used to identify a reactive species in solution and shows how elucidation of electronic structures can be used to explain spectroscopic and structural properties. Examples of the function of [S3]˙(-) in materials science, electrochemistry, analytical chemistry and geochemistry are used to illustrate the widespread influence of this fundamentally important triatomic sulfur species. 23831545 Characterization of freshwater natural dissolved organic matter (DOM): Mechanistic explanations for protective effects against metal toxicity and direct effects on organisms. Dissolved organic matter (DOM) exerts direct and indirect influences on aquatic organisms. In order to better understand how DOM causes these effects, potentiometric titration was carried out for a wide range of autochthonous and terrigenous freshwater DOM isolates. The isolates were previously characterized by absorbance and fluorescence spectroscopy. Proton binding constants (pKa) were grouped into three classes: acidic (pKa≤5), intermediate (58.5). Generally, the proton site densities (LT) showed maximum peaks at the acidic and basic ends around pKa values of 3.5 and 10, respectively. More variably positioned peaks occurred in the intermediate pKa range. The acid-base titrations revealed the dominance of carboxylic and phenolic ligands with a trend for more autochthonous sources to have higher total LT. A summary parameter, referred to as the Proton Binding Index (PBI), was introduced to summarize chemical reactivity of DOMs based on the data of pKa and LT. Then, the already published spectroscopic data were explored and the specific absorbance coefficient at 340nm (i.e. SAC340), an index of DOM aromaticity, was found to exhibit a strong correlation with PBI. Thus, the tendencies observed in the literature that darker organic matter is more protective against metal toxicity and more effective in altering physiological processes in aquatic organisms can now be rationalized on a basis of chemical reactivity to protons. 23910908 An evaluation of the possible interaction of gastric acid suppressing medication and the EGFR tyrosine kinase inhibitor erlotinib. As the bioavailability of erlotinib is dependent on gastric pH, an increase in gastric pH via the concurrent use of gastric acid suppressive medications (AS) may reduce its bioavailability and efficacy. We retrospectively analyzed the BR.21 trial database to pragmatically evaluate the impact of AS use on the median plasma drug levels of erlotinib, adverse events and outcome of participants. Monthly median plasma levels of erlotinib were compared between participants utilizing AS and those who did not using a Wilcoxon test. Interaction p-value for AS users and AS non-users was performed using a multivariate Cox model with a time-dependent covariate for AS use. Grade 2 adverse events were compared using Fisher's Exact Test. The median plasma erlotinib level was not significantly different between AS users and AS non-users, and AS use did not appear to incur a negative impact on PFS or OS (Interaction p-values: PFS p=0.16; OS p=0.81). AS users receiving erlotinib had a similar frequency of rash (50.5% vs. 42.0%, p=0.08) and a statistically higher rate of diarrhea (27.9% vs. 15.6%, p=0.001) compared to AS non-users. In addition, AS users had higher rates of infections (erlotinib arm: 33.7% vs. 20.0%, p<0.0001; placebo arm: 22.7% vs. 10.8%, p=0.02). This retrospective analysis found that the co-administration of AS and erlotinib did not appear to have a significant impact on the median plasma drug levels or outcome. 23963868 Outcomes of Esophagectomy for Esophageal Achalasia in the United States. While the outcomes after Heller myotomy have been extensively reported, little is known about patients with esophageal achalasia who are treated with esophagectomy. This was a retrospective analysis using the Nationwide Inpatient Sample over an 11-year period (2000-2010). Patients admitted with a primary diagnosis of achalasia who underwent esophagectomy (group 1) were compared to patients with esophageal cancer who underwent esophagectomy (group 2) during the same time period. Primary outcome was in-hospital mortality. Secondary outcomes included length of stay, postoperative complications, and total hospital charges. A propensity-matched analysis was conducted comparing the same outcomes between group 1 and well-matched controls in group 2. Nine hundred sixty-three patients with achalasia and 18,003 patients with esophageal cancer underwent esophagectomy. The propensity matched analysis showed a trend toward a higher mortality in group 2 (7.8 vs. 2.9 %, p = 0.08). Postoperative length of stay and complications were similar in both groups. Total hospital charges were higher for the achalasia group ($115,087 vs. $99, 654.2, p = 0.006). This is the largest study to date examining outcomes after esophagectomy in patients with achalasia. Based on our findings, esophagectomy can be considered a safe option, and surgeons should not be hindered by a perceived notion of prohibitive operative risk in this patient population. 23535454 In vivo human hippocampal cingulate connectivity: A corticocortical evoked potentials (CCEPs) study. To investigate the human limbic system using cortico-cortical evoked potential (CCEP), which reveals the brain networks. Five patients with nonlesional medically intractable focal epilepsy with ictal onset outside the limbic system were enrolled. All patients underwent stereoelectroencephalogram electrode implantation in order to delineate the epileptogenic zone. Alternating 1Hz electrical stimuli were delivered to the hippocampus and posterior cingulate gyrus. A total of sixty stimuli were averaged in each trial to obtain CCEP responses. Hippocampal stimulation elicited prominent CCEP responses in the posterior cingulate gyrus. The latencies of early (N1) and late (N2) negative peak ranged 20-60ms and 102-175ms respectively. In addition, CCEP responses were observed in the posterior parahippocampal gyrus, medial superior frontal gyrus (SFG) and orbitofrontal cortex. Stimulation of posterior cingulate contacts induced CCEPs in the hippocampus with N1 and N2 latencies of 25-43ms and 90-234ms respectively in all five patients. This finding supports the assertion that the hippocampus is connected with the posterior cingulate gyrus, posterior parahippocampal gyrus, medial SFG and orbitofrontal cortex. The hippocampus and posterior cingulate gyrus have a bidirectional network through the cingulum. The present study provides new insight into the human limbic network. 23869221 An Improved Method for TAL Effectors DNA-Binding Sites Prediction Reveals Functional Convergence in TAL Repertoires of Xanthomonas oryzae Strains. Transcription Activators-Like Effectors (TALEs) belong to a family of virulence proteins from the Xanthomonas genus of bacterial plant pathogens that are translocated into the plant cell. In the nucleus, TALEs act as transcription factors inducing the expression of susceptibility genes. A code for TALE-DNA binding specificity and high-resolution three-dimensional structures of TALE-DNA complexes were recently reported. Accurate prediction of TAL Effector Binding Elements (EBEs) is essential to elucidate the biological functions of the many sequenced TALEs as well as for robust design of artificial TALE DNA-binding domains in biotechnological applications. In this work a program with improved EBE prediction performances was developed using an updated specificity matrix and a position weight correction function to account for the matching pattern observed in a validation set of TALE-DNA interactions. To gain a systems perspective on the large TALE repertoires from X. oryzae strains, this program was used to predict rice gene targets for 99 sequenced family members. Integrating predictions and available expression data in a TALE-gene network revealed multiple candidate transcriptional targets for many TALEs as well as several possible instances of functional convergence among TALEs. 23776215 Molecular hyperdiversity defines populations of the nematode Caenorhabditis brenneri. The biology of Sydney Brenner's eponymous species of nematode, Caenorhabditis brenneri, is little known to science, despite its famous sibling Caenorhabditis elegans. Here we demonstrate that C. brenneri harbors the most molecular diversity of any eukaryote, with its 14.1% of polymorphic synonymous sites between individuals being 150-fold greater than humans and most comparable to hyperdiverse bacteria. This diversity is not an artifact of cryptic species divergence but reflects an enormous pan-tropical population, confirmed by fully viable genetic crosses between continents, extensive intralocus recombination, selection on codon use, and only weak geographic genetic structure. These findings in an animal galvanize tests of theory about the evolution of complexity in genomes and phenotypes and enable molecular population genetics methods to finely resolve uncharacterized functional noncoding elements. 23874793 Natural Killer Cell Cytokine Response to M. bovis BCG Is Associated with Inhibited Proliferation, Increased Apoptosis and Ultimate Depletion of NKp44(+)CD56(bright) Cells. Mycobacterium bovis BCG, a live attenuated strain of M. bovis initially developed as a vaccine against tuberculosis, is also used as an adjuvant for immunotherapy of cancers and for treatment of parasitic infections. The underlying mechanisms are thought to rely on its immunomodulatory properties including the recruitment of natural killer (NK) cells. In that context, we aimed to study the impact of M. bovis BCG on NK cell functions. We looked at cytotoxicity, cytokine production, proliferation and cell survival of purified human NK cells following exposure to single live particles of mycobacteria. We found that M. bovis BCG mediates apoptosis of NK cells only in the context of IL-2 stimulation during which CD56(bright) NK cells are releasing IFN-γ in response to mycobacteria. We found that the presence of mycobacteria prevented the IL-2 induced proliferation and surface expression of NKp44 receptor by the CD56(bright) population. In summary, we observed that M. bovis BCG is modulating the functions of CD56(bright) NK cells to drive this subset to produce IFN-γ before subsequent programmed cell death. Therefore, IFN-γ production by CD56(bright) cells constitutes the main effector mechanism of NK cells that would contribute to the benefits observed for M. bovis BCG as an immunotherapeutic agent. 23009594 Police referrals to a psychiatric hospital: experiences of nurses caring for police-referred admissions. Police are a major source of referral to psychiatric hospitals in industrialized countries with mental health legislation. However, little attention has been paid to nurses' experience of caring for police-referred patients to psychiatric hospitals. This study utilized a Heideggerian phenomenological framework to explore the experiences of nine nurses caring for patients referred by the police, through semistructured interviews. Two major themes emerged from the hermeneutic analyses of interviews conducted with nurse participants: (i) 'expecting "the worst" '; and (ii) 'balancing therapeutic care and forced treatment'. Expecting 'the worst' related to the perceptions nurse participants had about patients referred by the police. This included two sub-themes: (i) 'we are here to care for whoever they bring in'; and (ii) 'but who deserves care?' The second theme balancing therapeutic care and forced treatment included the sub-themes: (i) 'taking control, taking care'; and (ii) 'managing power'. The study raises ethical and skill challenges for nursing including struggling with the notion of who deserves care, and balancing the imperatives of legislation with the need to work within a therapeutic framework. 23830375 Amelioration of ethanol-induced liver injury in rats by nanogold flakes. The purpose of this study was to investigate the protective effects of nanogold flakes against alcoholic liver disease. Six-week-old male Wistar rats were divided into 6 groups: C (control liquid diet), CLF (control liquid diet with gold flakes at 1.03 mg/kg body weight [BW]/day), CHF (control liquid diet with gold flakes at 5.15 mg/kg BW/day), E (ethanol liquid diet), ELF (ethanol liquid diet with gold flakes at 1.03 mg/kg BW/day), and EHF (ethanol liquid diet with gold flakes at 5.15 mg/kg BW/day). The liquid diets were prepared daily. Gold flakes were added to the ethanol 1 h before preparing the ethanol liquid diets, as an aging process. After 10 weeks, rats in group E showed significantly higher plasma aspartate transaminase (AST) and alanine transaminase (ALT) activities than those in group C. A significantly increased concentration of hepatic triglyceride (TG) was found in group E. Furthermore, higher hepatic glutathione reductase (GRD), superoxide dismutase (SOD), and catalase (CAT) activities together with higher tumor necrosis factor (TNF)-α concentration and higher hepatic cytochrome (CYP2E1) protein expression were also observed in group E. In contrast, the hepatic TG concentration in group EHF was significantly lower than that of group E. In addition, hepatic glutathione peroxidase (GPX), SOD, and CAT activities together with TNF-α concentration and hepatic CYP2E1 protein expression in group EHF were significantly lower than those in group E. We concluded that nanogold flakes might ameliorate alcohol-induced liver injury by maintaining the hepatic antioxidative status. In addition, nanogold flakes may reduce fat accumulation caused by chronic ethanol feeding via decreasing hepatic TNF-α. 23471692 Comparative analysis of microbial profiles in cow rumen fed with different dietary fiber by tagged 16S rRNA gene pyrosequencing. The ruminal microbiome of cattle plays an important role not only in animal health and productivity but also in food safety and environment. Microbial profiles of rumen fluid obtained from dairy cows fed on three different fiber/starch diet compositions were characterized. Tagged 16S rRNA gene pyrosequencing and statistical analysis revealed that the dominant ruminal bacteria shared by all three sample groups belonged to phyla Bacteroidetes, Firmicutes, and Proteobacteria. However, the relative abundance of these bacterial groups was markedly affected by diet composition. In animals fed with a high fiber diet, the fibrolytic and cellulolytic bacteria Lachnospiraceae, Ruminococcaceae, and Fibrobacteraceae were found in highest abundance compared with animals fed other diets with lower fiber content. The polysaccharide-degrading Prevotellaceae and Flavobacteriaceae bacteria were most abundant in the rumen of cows fed on diet with the highest starch content. These data highlight the ruminal microbiome's ability to adapt to feed composition and also provide a basis for the development of feed formulation systems designed to improve livestock productivity. 23333790 Genotoxic and inflammatory effects of organic extracts from traffic-related particulate matter in human lung epithelial A549 cells: the role of quinones. Traffic-related particulate matter (PM) is associated with adverse health effects. Quinones present in the traffic-related PM are hypothesized to contribute to these harmful effects through reactive oxygen species (ROS) generation. However, the impacts of the traffic-related PM and quinones on inflammatory processes and genotoxic damages are less well known. In present study we aimed to examine the genotoxic and inflammatory impacts of organic extracts from traffic-related PM (oTRP) in human lung epithelial A549 cells, and reveal the contributions from quinones. Significant cytotoxicity and DNA damage were caused by oTRP. The pro-inflammatory genes, interleukin-6 (Il-6), interleukin-8 (Il-8) and tumor necrosis factor (Tnf), and two aromatic hydrocarbon receptor-regulated genes, Cyp1a1 and 1b1, were significantly up-regulated by oTRP. A concomitant increase in ROS was observed, suggesting that oTRP may mediate genotoxic and inflammatory effects through oxidative stress pathway. Second, the effects from two typical airborne quinones, 9,10-anthraquinone (AQ) and 1,4-naphthroquinone (NQ) were compared. NQ, but not AQ, induced significant DNA damage in A549 cells. NQ up-regulated Il-8, Tnf, and Mcp-1 genes, while AQ induced the expression of Rantes gene. These results suggest that the NQ and AQ may participate in the pro-inflammatory responses through releasing different types of cytokines/chemokines. 23408315 Same day discharge, surgical training and early complications after open and laparoscopic repair of primary paraumbilical hernia. The aims of this study were to compare same day discharges and early complications after open and laparoscopic primary paraumbilical hernia (PUH) repair, including the procedures performed by surgical trainees (STs). All patients who had open (suture or mesh) and laparoscopic repair of primary PUH in the Day Surgery Unit (DSU) between January 2007 and June 2009 were identified from the hospital database. The database was questioned regarding the grade of operating surgeon, type of surgical repair, day of admission and discharge from the DSU, and a patient's return to surgical services. Data were stored in Microsoft Excel(®) (TM 2007). Statistical significance was determined using Fisher's exact test. PUH was repaired in 337 patients: 252/337 (74.8 %) had open and 85/337 (25.2 %) had laparoscopic repair. Significantly, more patients were discharged home on the day of surgery after an open repair compared to the laparoscopic repair: open repair 187/252 (74.2 %), laparoscopic repair 35/85 (41.17 %), P = 0.0001. Overall early complications such as wound complications and hospital re-visits were similar in both groups: open repair 6.3 % (16/252), laparoscopic repair 11.7 % (10/85), P = 0.1554. STs performed 142/337 (42.1 %) of the PUH repairs with similar same day discharges from the DSU: STs 64.7 % (92/142), consultant surgeons 66.7 % (130/195), P = 0.7285. The difference in hernia recurrence between open repair 7/252 (2.78 %) and laparoscopic group 0/85 was not significant (P = 0.1985). Patients with PUH repair were more likely to go home on the day of surgery after open than after laparoscopic repair. This was not affected by the grade of the operating surgeon. Early complications were similar following open and laparoscopic repair of primary PUH. 23884641 Trichostatin a enhances differentiation of human induced pluripotent stem cells to cardiogenic cells for cardiac tissue engineering. Abstract Human induced pluripotent stem (iPS) cells are a promising source of autologous cardiomyocytes to repair and regenerate myocardium for treatment of heart disease. In this study, we have identified a novel strategy to enhance cardiac differentiation of human iPS cells by treating embryoid bodies (EBs) with a histone deacetylase inhibitor, trichostatin A (TSA), together with activin A and bone morphogenetic protein 4 (BMP4). Over a narrow window of concentrations, TSA (1 ng/ml) directed the differentiation of human iPS cells into a cardiomyocyte lineage. TSA also exerted an additive effect with activin A (100 ng/ml) and BMP4 (20 ng/ml). The resulting cardiomyocytes expressed several cardiac-specific transcription factors and contractile proteins at both gene and protein levels. Functionally, the contractile EBs displayed calcium cycling and were responsive to the chronotropic agents isoprenaline (0.1 μM) and carbachol (1 μM). Implanting microdissected beating areas of iPS cells into tissue engineering chambers in immunocompromised rats produced engineered constructs that supported their survival, and they maintained spontaneous contraction. Human cardiomyocytes were identified as compact patches of muscle tissue incorporated within a host fibrocellular stroma and were vascularized by host neovessels. In conclusion, human iPS cell-derived cardiomyocytes can be used to engineer functional cardiac muscle tissue for studying the pathophysiology of cardiac disease, for drug discovery test beds, and potentially for generation of cardiac grafts to surgically replace damaged myocardium. 23884141 CXCR4-overexpressing bone marrow-derived mesenchymal stem cells improve repair of acute kidney injury. Bone marrow-derived mesenchymal stem cells (BMSCs) transplantation can repair acute kidney injury (AKI), but with limited effect. We test the hypothesis that CXCR4 overexpression improves BMSCs repair ability and that this is related to increased release of cytokines. Hypoxia/re-oxygenation pretreated renal tubular epithelial cells (HR-RTECs) were used. BMSCs, null-BMSCs and CXCR4-BMSCs were co-cultured with HR-RTECs. The number of migrating BMSCs was counted. Proliferating cell nuclear antigen (PCNA) expression, cell death and expressions of cleaved Caspase-3 and Bcl-2 in the co-cultured HR-RTECs were measured. Cytokeratin 18 (CK18) expression and cytokine secretions for the BMSCs cultured with HR-RTEC supernatant were detected. BMSC homing, renal function, proliferation and cell death of tubular cells were assayed in the AKI mouse model. CXCR4-BMSCs showed a remarkable expression of CXCR4. Stromal cell-derived factor-1 (SDF-1) in the HR-RTEC supernatant was increased. Migration of BMSCs was CXCR4-dependent. Proportions of CK18(+) cells in BMSCs, null-BMSCs and CXCR4-BMSCs showed no difference. However, CXCR4 overexpression in BMSCs stimulated secretion of BMP-7, HGF, and IL-10. The neutralizing anti-CXCR4 antibody AMD3100 abolished this. In the co-cultured HR-RTECs, proportion of PCNA(+) cells and Bcl-2 expression were enhanced; however, proportion of Annexin V+ cells and expression of cleaved Caspase-3 were reduced. The in vivo study showed increased homing of CXCR4-BMSCs in kidneys, associated with improved renal function, reduced ATN scoring, accelerated mitogenic response of tubular cells, and reduced tubular cell death. The enhanced homing and paracrine actions of BMSCs with CXCR4 overexpression suggest beneficial effects of such cells in BMSC-based therapy of AKI. 23415610 Beneficial effect of the non-psychotropic plant cannabinoid cannabigerol on experimental inflammatory bowel disease. Inflammatory bowel disease (IBD) is an incurable disease which affects millions of people in industrialized countries. Anecdotal and scientific evidence suggests that Cannabis use may have a positive impact in IBD patients. Here, we investigated the effect of cannabigerol (CBG), a non-psychotropic Cannabis-derived cannabinoid, in a murine model of colitis. Colitis was induced in mice by intracolonic administration of dinitrobenzene sulphonic acid (DNBS). Inflammation was assessed by evaluating inflammatory markers/parameters (colon weight/colon length ratio and myeloperoxidase activity), by histological analysis and immunohistochemistry; interleukin-1β, interleukin-10 and interferon-γ levels by ELISA, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) by western blot and RT-PCR; CuZn-superoxide dismutase (SOD) activity by a colorimetric assay. Murine macrophages and intestinal epithelial cells were used to evaluate the effect of CBG on nitric oxide production and oxidative stress, respectively. CBG reduced colon weight/colon length ratio, myeloperoxidase activity, and iNOS expression, increased SOD activity and normalized interleukin-1β, interleukin-10 and interferon-γ changes associated to DNBS administration. In macrophages, CBG reduced nitric oxide production and iNOS protein (but not mRNA) expression. Rimonabant (a CB1 receptor antagonist) did not change the effect of CBG on nitric oxide production, while SR144528 (a CB2 receptor antagonist) further increased the inhibitory effect of CBG on nitric oxide production. In conclusion, CBG attenuated murine colitis, reduced nitric oxide production in macrophages (effect being modulated by the CB2 receptor) and reduced ROS formation in intestinal epithelial cells. CBG could be considered for clinical experimentation in IBD patients. 23891791 Spontaneous and electrically-evoked catecholamine secretion from long-term cultures of bovine adrenal chromaffin cells. Catecholamine release was measured from bovine adrenal medullary chromaffin cell (CC) cultures maintained over a period of three months. Cells were plated over simple biocompatible cell platforms with electrical stimulation capability and at specified times transferred to an acrylic superfusion chamber designed to allow controlled flow of superfusate over the culture. Catecholamine release was measured from the superfusates using fast cyclic voltammetry before, during and after electrical stimulation of the cells. Immunocytochemical staining of CC cultures revealed that they were composed of epinephrine (EP) and/or norepinephrine (NE) type cells. Both spontaneous and evoked-release of catecholamines from CCs were observed throughout the testing period. EP predominated during spontaneous release, whereas NE was more prevalent during electrically-evoked release. Electrical stimulation for 20s, increased total catecholamine release by 60-130% (measured over a period of 500s) compared to that observed for an equivalent 20s period of spontaneous release. Stimulus intensity was correlated with the amount of evoked release, up to a plateau which was observed near the highest intensities. Shorter intervals between stimulation trials did not significantly affect the initial amount of release, and the amount of evoked release was relatively stable over time and did not decrease significantly with age of the culture. The present study demonstrates long-term survival of CC cultures in vitro and describes a technique useful for rapid assessment of cell functionality and release properties of cultured monoaminergic cell types that later can be transplanted for neurotransmitter replacement following injury or disease. 23438077 Robust ordered cubic mesostructured polymer/silica composite films grown at the air/water interface. Polymer/silica composite films, stable to calcination, were produced using catanionic surfactant mixtures (hexadecyltrimethylammonium bromide (CTAB) and sodium dodecyl sulfate (SDS)) and polymers (polyethylenimine (PEI) or polyacrylamide (PAAm)) at the air/water interface. Film formation processes were probed by time-resolved neutron reflectivity measurements. Grazing incidence X-ray diffraction (GID) measurements indicate that the mesophase geometry of the interfacial films could be controlled to give lamellar, 2D hexagonal, and several cubic phases (Pn3¯m, Fm3¯m, and Im3¯m) by varying the polyelectrolyte molecular weight, polyelectrolyte chemical nature, or the cationic:anionic surfactant molar ratio. On the basis of GID results, a phase diagram for the catanionic surfactant/polyelectrolyte/TMOS film system was drawn. These films can be easily removed from the interface and mesoporous silica films which retain the film geometry can be obtained after calcination; moreover, this film preparation method provides a simple way to impart polymer functionality into the mesostructured silica wall, which means these films have potential applications in a variety of fields such as catalysis, molecular separation, and drug delivery. 23881350 Synthesis and characterization of Co(iii) amidoamine complexes: influence of substituents of the ligand on catalytic cyclic carbonate synthesis from epoxide and carbon dioxide. A series of amidoamine ligands (1) and their cobalt(iii) complexes (2) were synthesized and characterized by various spectroscopic techniques including (1)H-NMR and X-ray crystallographic techniques. X-ray crystallography shows that one of the complexes, 2a, forms a chiral coordination polymer due to bridge formation with Li(+) associated with the complex, although the ligand is achiral. Complex 2 was employed for catalytic synthesis of cyclic carbonates from epoxides and carbon dioxide (CO2) in a solvent free condition. A strong influence of the substituents on the ligand 1 was revealed by the varied activity of complex 2. The presence of electron withdrawing groups such as chloro (2b) and nitro (2c) increases the Lewis acidity of the catalyst, which, in turn, enhances the catalytic activity of 2. An electron withdrawing group containing complexes (2b and 2c) showed exceptionally high catalytic activity with a turnover frequency (TOF) of 662 and 602 h(-1) respectively at 130 °C and 300 psig CO2 pressure. On the other hand, our studies indicate that a catalyst with an electron releasing group (2d) showed relatively lower activity with a TOF of 488 h(-1) under similar reaction conditions. Our results show that cobalt(iii) complexes follow the reactivity order of 2d < 2a < 2c < 2b. 23836876 Gradient echo magnetic resonance imaging correlates with clinical measures and allows visualization of veins within multiple sclerosis lesions. Conventional magnetic resonance imaging (MRI) methods do not quantify the severity of multiple sclerosis (MS) white matter lesions or measure pathology within normal-appearing white matter (NAWM). Gradient Echo Plural Contrast Imaging (GEPCI), a fast MRI technique producing inherently co-registered images for qualitative and quantitative assessment of MS, was used to 1) correlate with disability; 2) distinguish clinical MS subtypes; 3) determine prevalence of veins co-localized within lesions in WM. Thirty subjects representing relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS) subtypes were scanned with clinical and GEPCI protocols. Standard measures of physical disability and cognition were correlated with magnetic resonance metrics. Lesions with central veins were counted for RRMS subjects. Tissue damage load (TDL-GEPCI) and lesion load (LL-GEPCI) derived with GEPCI correlated better with MS functional composite (MSFC) measures and most other neurologic measures than lesion load derived with FLAIR (LL-FLAIR). GEPCI correctly classified clinical subtypes in 70% subjects. A central vein could be identified in 76% of WM lesions in RRMS subjects on GEPCI T2*-SWI images. GEPCI lesion metrics correlated better with neurologic disability than lesion load derived using FLAIR imaging, and showed promise in classifying clinical subtypes of MS. These improvements are likely attributable to the ability of GEPCI to quantify tissue damage. 23503611 Cellular effects of manufactured nanoparticles: effect of adsorption ability of nanoparticles. Nanoparticles are important industrial materials. However, many nanoparticles show biological effects, including toxic activity. Metal ion release is the most important factor affecting the biological effects of nanoparticles. In addition, nanoparticles have large adsorption ability. The adsorption ability, in particular protein adsorption to nanoparticles, has an effect on cellular uptake and cellular metabolisms. Moreover, the adsorption ability of nanoparticles causes artificial effects in in vitro systems. Consequently, accurate determination of released or secreted proteins such as lactate dehydrogenase and cytokines adsorbed to nanoparticles is affected. In addition, artificial effects cause overestimation or underestimation of the cytotoxicity of nanoparticles. Therefore, measurement of the protein adsorption of nanoparticles is important. Some methods for the determination of the adsorption to nanoparticles have been suggested. The flow field-flow fractionation method is one of the efficient techniques for determining proteins on the surface of nanoparticles. The cellular effects caused by nanoparticles should be carefully considered. 23736663 Glia co-culture with neurons in microfluidic platforms promotes the formation and stabilization of synaptic contacts. Two novel microfluidic cell culture schemes, a vertically-layered set-up and a four chamber set-up, were developed for co-culturing central nervous system (CNS) neurons and glia. The cell chambers in these devices were separated by pressure-enabled valve barriers, which permitted us to control communication between the two cell types. The unique design of these devices facilitated the co-culture of glia with neurons in close proximity (∼50-100 μm), differential transfection of neuronal populations, and dynamic visualization of neuronal interactions, such as the development of synapses. With these co-culture devices, initial synaptic contact between neurons transfected with different fluorescent markers, such as green fluorescent protein (GFP) and mCherry-synaptophysin, was imaged using high-resolution fluorescence microscopy. The presence of glial cells had a profound influence on synapses by increasing the number and stability of synaptic contacts. Interestingly, as determined by liquid chromatography-ion mobility-mass spectrometry, neuron-glia co-cultures produced elevated levels of soluble factors compared to that secreted by individual neuron or glia cultures, suggesting a potential mechanism by which neuron-glia interactions could modulate synaptic function. Collectively, these results show that communication between neurons and glia is critical for the formation and stability of synapses and point to the importance of developing neuron-glia co-culture systems such as the microfluidic platforms described in this study. 23180664 Enantioseparation of four organophosphonate derivatives on N-(3,5-dinitrobenzoyl)-L-leucine-n-propylamide stationary phase by molecular modeling. Four groups of organophosphonate derivatives enantiomers were separated on N-(3,5-dinitrobenzoyl)-S-leucine chiral stationary phase. The three-dimensional structures of the complexes between the single enantiotopic chiral compounds and chiral stationary phase have been studied using molecular model and molecular dynamics simulation. Detailed results regarding the conformation, auto-docking, and thermodynamic estimation are presented. The elution order of the enantiomer could be determined from the energy. The predicted chiral discrimination was obtained by computational results. 23870134 Association of tumor necrosis factor-alpha promoter variants with risk of HPV-associated oral squamous cell carcinoma. Tumor necrosis factor alpha (TNF-α) plays an important role in inflammation, immunity, and defense against infection and clearance of human papillomavirus (HPV). Thus, genetic variants may modulate individual susceptibility to HPV-associated oral squamous cell carcinoma (OSCC). In this study we genotyped four common single nucleotide polymorphisms (SNPs) in the TNF-α promoter [ -308G > A(rs1800629), -857C > T (rs1799724), -863C > A (rs1800630), and -1031T > C (rs1799964)] and determined HPV16 serology in 325 OSCC cases and 335 matched controls and tumor HPV status in 176 squamous cell carcinomas of the oropharynx (SCCOP) patients. Univariate and multivariable logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). We found that HPV16 seropositivity alone was associated with an increased risk of OSCC (OR, 3.1; 95% CI, 2.1-4.6), and such risk of HPV16-associated OSCC was modified by each SNP. Patients with both HPV16 seropositivity and variant genotypes for each SNP had the highest risk when using patients with HPV16 seronegativity and a wild-type genotype as a comparison group. Moreover, similar results were observed for the combined risk genotypes of four variants and all such significant associations were more pronounced in several subgroups, particularly in SCCOP patients and never smokers. Notably, the combined risk genotypes of four variants were also significantly associated with tumor HPV-positive SCCOP. Taken together, these results suggest that TNF-α SNPs may individually or, more likely, jointly affect individual susceptibility to HPV16-associated OSCC, particularly SCCOP and never smokers. Validation of our findings is warranted. 23815393 Neurofibromas of the bladder in a child with neurofibromatosis type 1 causing chronic renal disease. Abstract Neurofibromatosis type 1 (NF1) is an autosomal-dominant inherited disorder and its prominent feature is the neurofibroma and renal involvement includes renal artery stenosis and renal artery aneurysms causing renovascular hypertension. The genitourinary tract may be rarely involved, leading to urinary symptoms of obstruction and hydronephrosis. Herein, we report a 12-year-old boy with chronic renal failure associated with neurofibromas of the bladder, which leads to urinary obstruction. 23919953 Multiscale modelling of coupled Ca2+ channels using coloured stochastic Petri nets. Stochastic modelling of coupled Ca2+ channels is a challenge, especially when the coupling of the channels, as determined by their spatial arrangement relative to each other, has to be considered at multiple spatial scales. In this study, the authors address this problem using coloured stochastic Petri nets (𝒮𝒫𝒩𝒸) as high-level description to generate continuous-time Markov chains. The authors develop several models with increasing complexity. They first apply 𝒮𝒫𝒩𝒸 to model single clusters of coupled Ca2+ channels arranged in a regular or irregular lattice, where they describe how to represent the geometrical arrangement of Ca2+ channels relative to each other using colours. They then apply this modelling idea to construct more complex models by modelling spatially arranged clusters of channels. The authors' models can be easily reproduced and adapted to different scenarios. 23648092 Allocation concealment: a methodological review. The accurate reporting of the trial methodology and results is essential for accurate judgement on the quality of the research. This review aims to assess the impact of the adequacy of allocation concealment on treatment effect estimates. A search was performed in MEDLINE (via the Ovid platform) to identify all randomized controlled trials (RCTs) indexed in January 2011 within its set of 'core clinical journals'. Meta-regression was undertaken on a subset of two arm trials to quantify the association between adequacy of allocation concealment and effect size. Adequate allocation concealment methods were used in 27% (n = 23) of included trials. There was insufficient information given in 68% (n = 58) of trials to make a judgement on allocation concealment. Meta-regression showed that there was a trend, not statistically significant, towards a smaller effect size between adequacy of allocation concealment and effect sizes. This review highlighted that research needs to be reported to a higher standard and there are many trials reporting poor methods of allocation concealment within the small sample of trials included in this review. 23865626 Bowel necrosis following endovascular revascularization for chronic mesenteric ischemia: a case report and review of the literature. Endovascular revascularization has recently been established as a less invasive treatment method for chronic mesenteric ischemia. However, intestinal necrosis caused by distal embolization following this procedure has not been emphasized. The present report describes a 59-year-old man who was treated with endovascular revascularization for chronic mesenteric ischemia. After the procedure, he was diagnosed with intestinal necrosis caused by distal embolization. Despite emergent bowel resection, he died on postoperative day 109. Although endovascular revascularization for chronic mesenteric ischemia is less invasive and may be suitable for high-risk patients, attention should be paid to avoid embolic complications that can cause intestinal infarction possibly leading to a fatal condition. 23890497 Pain and carpal tunnel syndrome. Pain is not a classical symptom of carpal tunnel syndrome (CTS), with the exception of numbness that is so intense that it is described by patients as painful. The primary aim of our study was to determine which factors correlated with pain for patients diagnosed with CTS. We prospectively assessed all patients diagnosed with CTS in our unit over a 1-year period. We recorded demographic details for all patients, including past medical history, body mass index, smoking, and occupation. The diagnosis and severity of carpal tunnel syndrome were established through a combination of history, clinical assessment, and nerve conduction studies. Of 275 patients diagnosed and treated for CTS, 183 were women (67%), the mean age was 55 years (range, 22-87 y), and 166 cases were bilateral (60%). The mean body mass index was 29.5 kg/m(2) (range, 17-48 kg/m(2)), and 81 patients smoked (30%). Patients completed a Short Form-McGill pain questionnaire (SF-MPQ) as a measure of pain at initial presentation. We assessed outcome 1 year after intervention using the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) score. We found no association between pain according to the SF-MPQ and the positive clinical signs of CTS or positive nerve conduction studies. Multivariate analysis demonstrated that smoking and bilateral disease independently correlated with the overall SF-MPQ, with similar findings on subanalysis. Independent factors associated with an increased improvement in the QuickDASH at 1 year were the presentation QuickDASH score, positive nerve conduction studies, and smoking. The only independent factors that correlated with pain at presentation of CTS were smoking and bilateral disease. Pain according to the SF-MPQ was not associated with classical clinical findings of the disease or with positive findings on nerve conduction testing. Prognostic I. 23693133 Factors affecting subjective memory complaints in the AIBL aging study: biomarkers, memory, affect, and age. The prognostic value of subjective memory complaints (SMCs) in the diagnosis of dementia of the Alzheimer's type is unclear. While some studies have found an association between SMCs and cognitive decline, many have found a stronger association with depression, which raises questions about their diagnostic utility. We examined the cross-sectional association between SMC severity (as measured using the MAC-Q, a brief SMC questionnaire) and affect, memory, and Alzheimer's disease (AD) biomarkers (β-amyloid deposition and the apolipoprotein E ε4 (APOEε4) allele) in healthy elderly controls (HC; M = 78.74 years, SD = 6.7) and individuals with mild cognitive impairment (MCI; M = 72.74 years, SD = 8.8). We analyzed a subset of individuals drawn from the Australian Imaging Biomarkers and Lifestyle (AIBL) Study of Aging. SMCs were more severe in MCI patients than in HCs. SMC severity was related to affective variables and the interaction between age and group membership (HC/MCI). Within the HC group, SMC severity was related to affective variables only, while severity correlated only with age in the MCI group. SMCs were not related to cognitive variables or AD biomarkers. SMCs were related to solely by poorer mood (greater depressive and anxious symptomatology) in the cognitively healthy elderly however mean levels were subclinical. This finding argues for the assessment of affective symptomatology in conjunction with cognitive assessment in elderly memory complainers. Future AIBL research will focus on assessing other AD biomarkers, such as brain atrophy and Aβ plasma markers, in relation to complaint severity. Once our 36-month follow-up data are collected, we propose to assess whether SMCs can predict future cognitive decline. 23892937 Interleukin-1β Promotes Long-Term Potentiation in Patients with Multiple Sclerosis. The immune system shapes synaptic transmission and plasticity in experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis (MS). These synaptic adaptations are believed to drive recovery of function after brain lesions, and also learning and memory deficits and excitotoxic neurodegeneration; whether inflammation influences synaptic plasticity in MS patients is less clear. In a cohort of 59 patients with MS, we found that continuous theta-burst transcranial magnetic stimulation did not induce the expected long-term depression (LTD)-like synaptic phenomenon, but caused persisting enhancement of brain cortical excitability. The amplitude of this long-term potentiation (LTP)-like synaptic phenomenon correlated with the concentration of the pro-inflammatory cytokine interleukin-1β (IL-1β) in the cerebrospinal fluid. In MS and EAE, the brain and spinal cord are typically enriched of CD3(+) T lymphocyte infiltrates, which are, along with activated microglia and astroglia, a major cause of inflammation. Here, we found a correlation between the presence of infiltrating T lymphocytes in the hippocampus of EAE mice and synaptic plasticity alterations. We observed that T lymphocytes from EAE, but not from control mice, release IL-1β and promote LTP appearance over LTD, thereby mimicking the facilitated LTP induction observed in the cortex of MS patients. EAE-specific T lymphocytes were able to suppress GABAergic transmission in an IL-1β-dependent manner, providing a possible synaptic mechanism able to lower the threshold of LTP induction in MS brains. Moreover, in vivo blockade of IL-1β signaling resulted in inflammation and synaptopathy recovery in EAE hippocampus. These data provide novel insights into the pathophysiology of MS. 23948864 Shockwave Therapy Differentially Stimulates Endothelial Cells: Implications on the Control of Inflammation via Toll-Like Receptor 3. Shock wave therapy (SWT) reportedly improves ventricular function in ischemic heart failure. Angiogenesis and inflammation modulatory effects were described. However, the mechanism remains largely unknown. We hypothesized that SWT modulates inflammation via toll-like receptor 3 (TLR3) through the release of cytosolic RNA. SWT was applied to human umbilical vein endothelial cells (HUVECs) with 250 impulses, 0.08 mJ/mm(2) and 3 Hz. Gene expression of TLR3, inflammatory genes and signalling molecules was analysed at different time points by real-time polymerase chain reaction. SWT showed activation of HUVECs: enhanced expression of TLR3 and of the transporter protein for nucleic acids cyclophilin B, of pro-inflammatory cytokines cyclophilin A and interleukin-6 and of anti-inflammatory interleukin-10. No changes were found in the expression of vascular endothelial cell adhesion molecule. SWT modulates inflammation via the TLR3 pathway. The interaction between interleukin (IL)-6 and IL-10 in TLR3 stimulation can be schematically seen as a three-phase regulation over time. 23891454 A Genetic Score Can Identify Men at High Risk for Prostate Cancer Among Men With Prostate-Specific Antigen of 1-3 ng/ml. The diagnostic performance of a genetic score based on single nucleotide polymorphisms (SNPs) is unknown in the prostate-specific antigen (PSA) range of 1-3 ng/ml. A substantial proportion of men in this PSA span have prostate cancer (PCa), but biomarkers to determine who should undergo a prostate biopsy are lacking. To evaluate whether a genetic risk score identifies men in the PSA range of 1-3 ng/ml who are at higher risk for PCa. Men aged 50-69 yr with PSA 1-3 ng/ml and without a previous prostate biopsy were selected from the STHLM2 cohort. Of 2696 men, 49 SNPs were genotyped, and a polygenic risk score was calculated. Of these men, 860 were invited according to risk score, and 172 underwent biopsy. The risk of PCa was assessed using univariate and multivariate logistic regression analysis. PCa was diagnosed in 47 of 172 participants (27%), with Gleason sum 6 in 36 of 47 men (77%) and Gleason sum ≥7 in 10 of 47 men (21%); one man had intraductal cancer. The genetic score was a significant predictor of a positive biopsy (p=0.028), even after adjusting for PSA, ratio of free to total PSA, prostate volume, age, and family history. There was an increase in the odds ratio of 1.60 (95% confidence interval, 1.05-2.45) with increasing genetic risk score. The absolute risk difference of positive biopsy was 19 percentage points, comparing the high and low genetic risk group (37% vs 18%). A risk score based on SNPs predicts biopsy outcome in previously unbiopsied men with PSA 1-3 ng/ml. Introducing a genetic-based risk stratification tool can increase the proportion of men being classified in line with their true risk of PCa. 23122875 Postoperative femoral component rotation and femoral anteversion after total knee arthroplasty in patients with distal femoral deformity. We asked whether total knee arthroplasty (TKA) in patients with distal femoral deformity (DFD) would change femoral component rotation (FCR) and investigated the correlation between DFD and femoral anteversion (FA). 75 patients were divided into two groups according to the preoperative posterior condylar angle (PCA); group A without DFD (PCA<7°), group B with DFD (PCA>7°). We evaluated the different angles on the CT scan: (1) PCA, (2) angle between the line which is perpendicular to the Whiteside's line and PCL (WLP), and (3) FA. The mean FCRs were external rotation of 0.21°+2.75° in group A and internal rotation of 4.48°+2.51° in group B (P=0.001). The mean preoperative and postoperative FAs were similar in group A but were significantly different in group B (P=0.035). DFD resulted in excessive internal rotation of the femoral component. There was a secondary decrease in FA in patients with DFD. 23863491 Assessment of team training in management of adverse acute events occurring during cardiopulmonary bypass procedure: a pilot study based on an animal simulation model (Fouilloux, Team training in cardiac surgery). Successful cardiac surgery is highly dependent upon effective and efficient teamwork. Practical training and development will further enhance the team ability to react to a series of low-frequency occurring adverse events during cardiopulmonary bypass (CPB). One of our specialized educational programs focuses on training the whole team. This training is based on an original animal simulation model. The objective of this pilot study was to assess our method of training and learning in an attempt to optimize and improve team management and functioning. Four members of the same cardiac surgery team joined our program. They performed a common procedure, with a cardiopulmonary bypass (CPB) circuit set up to produce several adverse incidents. Events management was analyzed and debriefed in technical and non-technical perspectives. Management of the adverse events was significantly improved. Discussion and debriefing time was fundamental in identifying the most appropriate management for each event. Rescue procedures were assimilated and team training was found to be effective, with the time reduced by up to 50% for 3 events and by up to 70% for air embolism. Our pilot program is an innovative, low-cost tool for the improvement of the management of adverse events occurring during CPB. It includes the different components of surgical education and training. Such an educational tool might be relevant for training. To confirm those encouraging results, it should be assessed in a larger surgical team panel. Further investigations are required for assessing efficiency in real conditions. 23845053 Aspects of Sexual Self-Schema in Premenopausal Women with Dyspareunia: Associations with Pain, Sexual Function, and Sexual Distress. Although it is known that women with dyspareunia suffer from impaired psychological and sexual functioning, the study of the various dimensions of sexual self-schema and their associations with these outcomes has been neglected. To examine whether self-image cognitions about vaginal penetration, body image, and feelings and beliefs about one's own genitals contribute to the variance in pain, sexual functioning, and sexual distress. Premenopausal women (n = 231; M age = 24.85, SD = 5.55) with self-reported dyspareunia completed an online survey focusing on self-image cognitions about vaginal penetration, body image, female genital self-image, pain during intercourse, sexual functioning, sexual distress, anxiety, and catastrophizing. (i) Pain intensity during intercourse, (ii) the Female Sexual Function Index without the Pain subscale, and (iii) the Female Sexual Distress Scale. Controlling for anxiety and catastrophizing, negative self-image cognitions about vaginal penetration, negative body image, and negative genital self-image together accounted for a portion of the variance in increased pain intensity, sexual dysfunction, and sexual distress. However, only self-image cognitions about vaginal penetration (β = 0.25, P = 0.005) contributed uniquely to the variance in pain intensity, whereas self-image cognitions about vaginal penetration (β = -0.18, P = 0.048) and genital self-image (β = 0.21, P = 0.008) contributed independently to the variance in sexual functioning. Finally, self-image cognitions about vaginal penetration (β = 0.28, P < 0.001), body image (β = 0.24, P < 0.001) and genital self-image (β = -0.14, P = 0.006) each contributed independently to the variance in sexual distress. Findings suggest that self-image cognitions about vaginal penetration and feelings and beliefs about one's own body and genitals are associated with pain and sexuality outcomes in women with dyspareunia. Pazmany E, Bergeron S, Van Oudenhove L, Verhaeghe J, and Enzlin P. Aspects of sexual self-schema in premenopausal women with dyspareunia: Associations with pain, sexual function, and sexual distress. J Sex Med **;**:**-**. 23927411 Phylogeography of Sophora davidii (Leguminosae) across the 'Tanaka-Kaiyong Line', an important phytogeographic boundary in Southwest China. The 'Tanaka-Kaiyong Line' (TKL) is a major phytogeographic boundary in Southwest China, separating East Asia's Sino-Himalayan and Sino-Japanese Floras. However, little is known about the importance of this boundary in promoting intraspecific phylogeographic subdivision and divergence. Using chloroplast (cpDNA) and nuclear-intron (nDNA) sequence data, we reconstructed the population history of Sophora davidii, a drought-tolerant riparian shrub widely distributed on either side of the TKL. Specifically, we aimed at testing two long-standing explanations for possible vicariant events across the TKL: (i) Late Pliocene (c. 3 Ma) geological uplift of the eastern Qinghai-Tibetan Plateau (QTP) or (ii) a sharp environmental gradient associated with the establishment of different monsoon regimes on either side of the TKL during the (Late) Pleistocene. Our genealogical analyses detected a major west-east split in cpDNA, geographically largely consistent with the TKL, and dated to c. 1.28 Ma (95% HPD: 0.21-2.96 Ma), hence postdating the latest phase of eastern QTP uplift. Furthermore, integrating cpDNA phylogeographic patterns with mismatch analyses, we found multiple refugial isolation and long-term demographic stability of populations in the west (Hengduan Mountain Range) compared with extensive range expansions in the east, possibly during the last glacial period(s) and followed by differentiation into regional sublineages (southeast: Yunnan-Guizhou Plateau vs. northeast: Qinling Mts./Loess Plateau). Although nuclear differentiation was less marked, the geographical pattern of nDNA haplotypes provided some further indication of the species' eastward expansion, possibly from source populations located just east of the TKL (lower Jinshajiang region). Overall, the present data reject the geological (tectonic) explanation for the TKL and, instead, provide supportive evidence for its role as a climatically driven barrier to present-day plant dispersal. In addition, our study highlights changing temperatures and vegetation types during the last glacial period(s), along with aspects of regional topography, to be important determinants of the glacial eastward expansion of S. davidii. In consequence, our study lends support to a 'glacial out-of-Hengduan Mts'. hypothesis for the xerophytic-riparian flora of Southwest China, which in turn is inconsistent with the traditional view of the TKL as a 'classical' vicariant-biogeographic boundary. 23893389 Triple-Shape Effect in Polymer-Based Composites by Cleverly Matching Geometry of Active Component with Heating Method. A triple-shape effect is created for a segmented device consisting of an active component encapsulated in a highly flexible polymer network. Segments with the same composition but different interface areas can be recovered independently either at specific field strengths (Hsw ) during inductive heating, at a specific time during environmentally heating, or at different airflow during inductive heating at constant H. Herein the type of heating method regulates the sequence order. 23707381 A Naturally Occurring Vif Mutant (I107T) Attenuates Anti-APOBEC3G Activity and HIV-1 Replication. The human immunodeficiency virus type 1 (HIV-1) Vif protein counteracts the antiviral activity of the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3) family of proteins by targeting the proteins for degradation through the ubiquitin-proteasome pathway. Previous mutagenic studies have shown that multiple domains of Vif are required for interacting with APOBEC3G proteins and the proteasome pathway. However, very few mutagenesis and functional analyses of patient-derived Vif proteins have been conducted. In this study, we amplified and cloned the HIV-1 vif genes from the peripheral blood mononuclear cells (PBMCs) of five HIV-1-infected individuals in Nairobi and further tested the impact of the genes on anti-A3G activity and HIV-1 replication. The gene sequence analysis revealed high genetic variation of vif genes from different HIV-1-infected individuals. Interestingly, the Vif proteins derived from two of the three long-term survivors (LTSs) displayed a significantly impaired ability to mediate the degradation of A3G. In particular, a single amino acid change (I107T) in one of the non-functional LTS Vif variants, which has not been previously identified in the Los Alamos databases of vif sequences, was found to be responsible for the lack of anti-A3G activity. Further study demonstrated that HIV-1 carrying an I107T Vif mutation displayed significantly reduced fitness in A3G(+) T cells and PBMCs. Moreover, co-infecting A3G(+) T cells with both the wild-type and I107T Vif viruses resulted in decreased viral replication. Overall, the results of this study indicate that the HIV-1 Vif residue I107 is important for its anti-APOBEC3G activity and viral replication, which may have implications for viral fitness in vivo. 23955950 Measurement of the time required for termites to pass each other in tunnels of different curvatures. Subterranean termites construct complex tunnel networks for foraging. During travel in the tunnels, termites often encounter one another when passing in opposite directions. Such encounters are likely to affect the "movement efficiency," which is the time required for a termite to travel a certain distance in a tunnel. In this study, we explored how individual-individual encounters affect movement efficiency in tunnels by measuring the time (τ) taken by two termites to pass one another in tunnels of different curvatures. Artificial tunnels of 5 cm in length and variable widths (W) of 2, 3, or 4 mm were made. Tunnel distance (D) was 2, 3, 4, or 5 cm. When D had a higher value, curvature was lower. When W = 2, τ was significantly shorter in the tunnel with D = 5 than in tunnels of D = 2, 3, or 4, whereas τ was statistically the same for D = 2, 3 and 4. When W = 3, τ was shorter in the tunnel with D = 5 than for D = 3 and 4, while τ was longer in the tunnel with D = 2 than for D = 3 and 4. When W = 4, τ was longer in the tunnels with D = 2 and 3 than for D = 4 and 5. Based on these observations, 3 types of termite behavior were identified: biased walking, backward walking, and zigzag walking. We considered these results in relation to foraging efficiency. 23924646 Adipose-derived stem cells inhibit the contractile myofibroblast in Dupuytren's disease. In an attempt to provide minimally invasive treatment for Dupuytren's disease, percutaneous disruption of the affected tissue followed by lipografting is being trialled. Contractile myofibroblasts drive this fibroproliferative disorder whereas stem cells have recently been implicated in preventing fibrosis. Therefore, we tested the role of stem cells in modulating myofibroblast activity in Dupuytren's disease. We compared the effect of co-culturing Dupuytren's myofibroblasts with either adipose or bone marrow-derived stem cells on isometric force contraction and associated levels of α-SMA mRNA and protein expression. We also tested the effect of these stem cells on Dupuytren's myofibroblast proliferation and assessed whether this was mediated by cell-cell contact or by a paracrine mechanism. Addition of adipose-derived stem cells to Dupuytren's myofibroblasts reduced the contraction of the latter with corresponding reduction of α-SMA protein expression, probably through a dilution effect. In contrast, bone marrow-derived stem cells increased the myofibroblast contractility. In addition, adipose-derived stem cells inhibit myofibroblast proliferation and mediate these effects by soluble factors, influenced by cell-cell contact dependent signalling. Adipose-derived stem cells inhibit the contractile myofibroblast in Dupuytren's disease and these findings lend support to the potential benefit of lipografting in conjunction with aponeurotomy as a novel strategy in the treatment of Dupuytren's disease. 23583797 1790 G/A polymorphism, but not 1772 C/T polymorphism, is significantly associated with cancers: an update study. This study aimed to investigate the association between PASD8 gene and cancers. For 1772 C/T polymorphism (rs11549465), it included 5552 cases and 8044 controls, and for 1790 G/A (rs11549467), 3381 cases and 5830 controls. The allele-analysis results showed that 1772 C/T (rs11549465) was significantly associated with cancers (OR: 1.177, 95% CI: 1.011-1.369, p=0.035). And results of genotype-analysis indicated that 1790 G/A (rs11549467) had a significant relationship with cancers. (OR: 0.736, 95% CI: 0.595-0.910, p=0.005). For 1790 G/A (rs11549467), the association was significant when subdivided by different kinds of cancers. And no association existed when subdivided into population-type subgroups. In conclusion, PASD8 gene played an important role in the development of cancers. 23858510 Broad Overview of a Clinical and Commercial Experience With CoolSculpting. Background: Cryolipolysis has been shown to be a safe and effective noninvasive procedure for the reduction of localized subcutaneous fat. Objectives: The authors examine the safety, efficacy, and procedural growth of cryolipolysis (via the CoolSculpting device; Zeltiq, Pleasanton, California) in a single plastic surgery practice. Methods: A retrospective chart review was conducted for 528 consecutive patients who underwent cryolipolysis treatment from January 2010 to December 2012. The number of patients, the number of treatment cycles, the average number of cycles per patient, all treatment areas, and all procedural complications were recorded and analyzed. Overall practice growth with the device was also analyzed. Results: Over the study period, 1785 anatomic sites were treated with 2729 cycles, primarily in the lower abdomen (28%, n = 490 cycles), upper abdomen (11%, n = 189), left flank (19%, n = 333), right flank (19%, n = 333), inner thigh (6%, n = 111), outer thigh (5%, n = 87), and back (6%, n = 99). The age distribution for men and women was similar (46.6 ± 12.8 years for women and 46.5 ± 12.3 years for men; overall range, 18-79 years). Only 3 cases of mild or moderate pain/neuralgia were reported and resolved in 4 or fewer days. No adverse events were reported. Procedure volume showed consistent growth, with treatment cycles increasing by 823% by 2012. Conclusions: Based on the results in this single plastic surgery practice, cryolipolysis is a safe and effective nonsurgical body contouring method associated with high patient satisfaction that can generate steady, significant business growth. Level of Evidence: 4. 23043462 Songaricalarins A-E, cytotoxic oplopane sesquiterpenes from Ligularia songarica. Five new highly oxygenated oplopane sesquiterpenes, songaricalarins A-E (1-5), and two known analogues (6 and 7) were isolated from the roots and rhizomes of Ligularia songarica. Their structures and configurations were elucidated by spectroscopic methods, including 2D-NMR techniques, and the structure of 1 was confirmed by single-crystal X-ray diffraction. All compounds were evaluated for in vitro cytotoxic activity against cultured A-549, MCF-7, KB, and KBVIN cells, and 4 exhibited cytotoxicity with EC50 values of 4.9, 0.8, 3.4, and 3.2 μg/mL, respectively. 23545334 Worksite wellness: increasing adoption of workplace health promotion programs. Worksite wellness programs are important interventions to protect and promote employee health. They help reduce direct and indirect health care costs, absenteeism, and presenteeism; avoid illness or injury; and improve the quality of work life and morale. This Tool introduces key concepts and strategic tips for planning workplace-based wellness programs rather than individual health promotion events, while highlighting organizational change and development theories central to introducing and implementing effective proactive worksite wellness programs. 23865707 Quadrivalent human papillomavirus vaccine uptake in adolescent boys and maternal utilization of preventive care and history of sexually transmitted infections. Objectives. We examined whether maternal utilization of preventive care and history of sexually transmitted infections (STIs) predicted quadrivalent human papillomavirus vaccine (HPV4) uptake among adolescent boys 1 year following the recommendation for permissive use of HPV4 for males. Methods. We linked maternal information with electronic health records of 254 489 boys aged 9 to 17 years who enrolled in Kaiser Permanente Southern California health plan from October 21, 2009, through December 21, 2010. We used multivariable Poisson regression with robust error variance to examine whether HPV4 initiation was associated with maternal uptake of influenza vaccine, Papanicolaou (Pap) screening, and history of STIs. Results. We identified a modest but statistically significant association between initiation of HPV4 series and maternal receipt of influenza vaccine (rate ratio [RR] = 1.16; 95% confidence interval [CI] = 1.07, 1.26) and Pap screening (RR = 1.13; 95% CI = 1.01, 1.26). Boys whose mothers had a history of genital warts were more likely to initiate HPV4 (RR = 1.47; 95% CI = 0.93, 2.34), although the association did not reach statistical significance (P = .1). Conclusions. Maternal utilization of preventive care and history of genital warts may influence HPV4 uptake among adolescent boys. The important role of maternal health characteristics and health behaviors needs be considered in intervention efforts to increase vaccine uptake among boys. 23970156 Multiple-Type Human Papillomavirus (HPV) Infections: A Cross-Sectional Analysis of the Prevalence of Specific Types in 309,000 Women Referred for HPV Testing at the Time of Cervical Cytology. To determine the frequency of multiple-type cervical human papillomavirus (HPV) infections, and whether any types are involved in multiple-type infections more or less frequently than might be expected if these infections occur randomly. In this retrospective analysis of type-specific HPV testing, results from women 18 to 65 years old with samples collected between July 2007 and May 2011 were considered.Multivariate logistic regression analysis was used to model the presence of each of the 24 most prevalent HPV types, adjusting for one other HPV type, age, laboratory region, and age-by-region interactions. Human papillomavirus infection was present in 74,543 (24.1%) of 309,471 women and 65,492 (21.1%) were positive for one of the top 24 most prevalent HPV types. The most common HPV type was type 16, occurring in 4.1% of the entire sample. A total of 14,181 women were positive for 2 or more HPV types (4.6% of entire sample and 19.0% of HPV-positive sample). Two-way HPV type comparisons were analyzed. Types 52, 53, 81, and 83 were more likely to occur in multiple infections with other types; and types 16, 58, and 66 were less likely to occur in multiple infections with other types. Human papillomavirus types 72 and 81 have the strongest positive relationship (odds ratio, 5.2; 95% confidence interval, 3.6-7.4). Human papillomavirus types 33 and 66 have the strongest negative relationship (odds ratio, 0.4; 95% confidence interval, 0.2-0.6). In this population, multiple-type HPV infections were present in 4.6% of all women. Our findings suggest that there may be both competitive and cooperative interactions between HPV types. 23669190 Cyclopropane-ring formation in the acyl groups of chlorosome glycolipids is crucial for acid resistance of green bacterial antenna systems. Green photosynthetic bacteria have unique light-harvesting antenna systems called chlorosomes. Chlorobaculum tepidum, a model organism of the bacteria, biosynthesized monogalactosyl- and rhamnosylgalactosyldiacylglycerides possessing a methylene-bridged palmitoleyl group characterized by a cis-substituted cyclopropane ring as the dominant glycolipids of its chlorosome surface. The formation of the cyclopropane ring was chemically inhibited by supplementation of sinefungin, an analog of S-adenosyl-L-methionine, into the bacterial cultivation. The presence of the cyclopropane ring reinforced acid resistance of the light-harvesting chlorosomes and suppressed acidic demetalation (pheophytinization) of bacteriochlorophyll-c pigments constructing the core part of chlorosomes. The ring-formation would represent direct and post-synthetic modifications of chlorosome membrane properties and was tolerant of acidic environments. 23842084 Impact of hypertension on vascular remodeling in patients with psoriatic arthritis. We studied the impact of hypertension along with traditional and new cardiovascular risk factors on the structural and functional properties of arteries in psoriatic arthritis (PsA) patients. We examined 42 PsA subjects (aged 51±9 years) stratified according to hypertensive status (19 normotensive, PsA-NT and 23 hypertensives, PsA-HT). Thirty-eight normotensive subjects (C-NT) and 23 hypertensives (C-HT) comparable by age and sex served as controls. Mean carotid intima-media thickness (mean-IMT) and mean of the maximum IMT (M-Max) were evaluated by ultrasound in carotid artery segment bilaterally. Post-occlusion flow-mediated dilation (FMD) of the brachial artery was evaluated by ultrasonography. These parameters were correlated with risk factors, markers of inflammation and disease activity. Values of mean-IMT were higher in both groups of PsA patients compared with C-NT (0.68 mm in PsA-NT and 0.75 mm in PsA-HT versus 0.61 mm in C-NT). PsA-HT displayed higher M-Max (0.95 mm) versus both C-HT (0.71 mm) and PsA-NT (0.79 mm). FMD was impaired in PsA subjects compared with C-NT (5.7% in PsA-NT and 6.0% PsA-HT versus 9.3% in C-NT), whereas there was no difference among PsA-HT, PsA-NT, and C-HT groups. Values of carotid IMT were directly related to tumor necrosis factor (TNF)-α, osteoprotegerin (OPG), blood pressure and lipid profile levels. FMD showed an inverse relationship with TNF-α and blood pressure, but no correlation with lipids. In conclusion, PsA per se implies a pro-atherogenic remodeling, which is enhanced by the hypertensive status. TNF-α and OPG may have an independent role in the development of such vascular damage.Journal of Human Hypertension advance online publication, 11 July 2013; doi:10.1038/jhh.2013.62. 23787967 Relationship between electrically evoked auditory brainstem response and auditory performance after cochlear implant in patients with auditory neuropathy spectrum disorder. To analyze the pattern of electrically evoked auditory brainstem response (EABR) in auditory neuropathy spectrum disorder (ANSD) patients and to compare their performances with controls. Retrospective analysis. Tertiary referral center. Eleven patients with ANSD and 9 control subjects with sensorineural hearing loss who did not have neural pathology. Diagnostic. Patients and control subjects each received a cochlear implant (CI) and underwent EABR. EABR threshold, wave V latency, and amplitude were measured as EABR parameters. The results of EABR were categorized as good response, variable response, or no response. Speech perception ability was assessed by the categories of auditory performance (CAP) score. All controls responded to EABR, whereas 6 of the 11 ANSD patients did not respond to EABR. The EABR threshold of the ANSD patients was measured almost within the value of disease controls. However, the Wave V latency displayed variable lengths, and the amplitude showed a wider distribution compared with the value of the disease control. The EABR response group among the ANSD patients showed relatively good performance after CI. In contrast, the nonresponse group demonstrated variable outcomes, although all of them still benefited from CI. The data suggested that all ANSD patients require CI and that EABR results can help establish realistic expectations about future performance. Even if electrical stimulation fails to generate sufficiently synchronized signal for eliciting EABR, CI provides at least partial, measurable auditory benefit in ANSD. 23553601 Role of Interleukin-1 Inhibitors in the Management of Gout. Interleukin-1 (IL-1) inhibitors potentially have a role as antiinflammatory agents in refractory gout or for patients who are unable to tolerate conventional therapy, such as nonsteroidal antiinflammatory drugs (NSAIDs), colchicine, or glucocorticoids, for acute attacks. Additionally, IL-1 inhibitors may also help patients with polyarticular and tophaceous gout by making them less vulnerable to breakthrough attacks during initiation of chronic urate-lowering treatment, the mainstay of gout therapy. Because evidence highlights the role of proinflammatory cytokine IL-1 in the inflammation process during an acute gouty attack, IL-1 inhibitors are used to modulate the pathogenesis of a variety of autoinflammatory diseases, providing support for its potential role in the inflammatory process of gout. After NSAIDs, colchicine, and steroids, IL-1 inhibitors are beneficial as fourth-line therapy for acute gout attacks due to their high cost and limited clinical experience. The IL-1 inhibitors used in gout are anakinra, canakinumab, and rilonacept. Based on published evidence, anakinra has limited support in the form of anecdotal case reports to justify its use for treating gout. Canakinumab's toxic profile in clinical trials precludes its use in treating patients for gout, and rilonacept shows promise with a few well-designed studies to support its use in gout patients initiating urate-lowering treatment. When combined with current traditional therapies, these newer agents present clinicians and patients with more potential treatment options in the difficult-to-treat gout population. 23663927 Cardiovascular toxicity evaluation of silica nanoparticles in endothelial cells and zebrafish model. Environmental exposure to nanomaterials is inevitable as nanomaterials become part of our daily life, and as a result, nanotoxicity research is gaining attention. However, most investigators focus on the evaluation of overall toxicity instead of a certain organism system. In this regard, the evaluation of cardiovascular effects of silica nanoparticles was preformed in vitro and in vivo. It's worth noting that silica nanoparticles induced cytotoxicity as well as oxidative stress and apoptosis. ROS and apoptosis were considered as major factor to endothelial cells dysfunction, involved in several molecular mechanisms of cardiovascular diseases. In vivo study, mortality, malformation, heart rate and whole-embryo cellular death were measured in zebrafish embryos. Results showed that silica nanoparticles induced pericardia toxicity and caused bradycardia. We also examined the expression of cardiovascular-related proteins in embryos by western blot analysis. Silica nanoparticles inhibited the expression of p-VEGFR2 and p-ERK1/2 as well as the downregulation of MEF2C and NKX2.5, revealed that silica nanoparticles could inhibit the angiogenesis and disturb the heart formation and development. In summary, our results suggest that exposure to silica nanoparticles is a possible risk factor to cardiovascular system. 23946695 A review on renal toxicity profile of common abusive drugs. Drug abuse has become a major social problem of the modern world and majority of these abusive drugs or their metabolites are excreted through the kidneys and, thus, the renal complications of these drugs are very common. Morphine, heroin, cocaine, nicotine and alcohol are the most commonly abused drugs, and their use is associated with various types of renal toxicity. The renal complications include a wide range of glomerular, interstitial and vascular diseases leading to acute or chronic renal failure. The present review discusses the renal toxicity profile and possible mechanisms of commonly abused drugs including morphine, heroin, cocaine, nicotine, caffeine and alcohol. 23951352 Livestock-Associated Methicillin-Resistant Staphylococcus aureus (LA-MRSA) Isolates of Swine Origin Form Robust Biofilms. Methicillin-resistant Staphylococcus aureus (MRSA) colonization of livestock animals is common and prevalence rates for pigs have been reported to be as high as 49%. Mechanisms contributing to the persistent carriage and high prevalence rates of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) strains in swine herds and production facilities have not been investigated. One explanation for the high prevalence of MRSA in swine herds is the ability of these organisms to exist as biofilms. In this report, the ability of swine LA-MRSA strains, including ST398, ST9, and ST5, to form biofilms was quantified and compared to several swine and human isolates. The contribution of known biofilm matrix components, polysaccharides, proteins and extracellular DNA (eDNA), was tested in all strains as well. All MRSA swine isolates formed robust biofilms similar to human clinical isolates. The addition of Dispersin B had no inhibitory effect on swine MRSA isolates when added at the initiation of biofilm growth or after pre-established mature biofilms formed. In contrast, the addition of proteinase K inhibited biofilm formation in all strains when added at the initiation of biofilm growth and was able to disperse pre-established mature biofilms. Of the LA-MRSA strains tested, we found ST398 strains to be the most sensitive to both inhibition of biofilm formation and dispersal of pre-formed biofilms by DNaseI. Collectively, these findings provide a critical first step in designing strategies to control or eliminate MRSA in swine herds. 23915256 Patient and primary care provider experience using a family health history collection, risk stratification, and clinical decision support tool: a type 2 hybrid controlled implementation-effectiveness trial. Family health history (FHH) is the single strongest predictor of disease risk and yet is significantly underutilized in primary care. We developed a patient facing FHH collection tool, MeTree(c), that uses risk stratification to generate clinical decision support for breast cancer, colorectal cancer, ovarian cancer, hereditary cancer syndromes, and thrombosis. Here we present data on the experience of patients and providers after integration of MeTree(c) into 2 primary care practices. This was a Type 2 hybrid controlled implementation-effectiveness study in 3 community-based primary care clinics in Greensboro, NC. All non-adopted adult English speaking patients with upcoming routine appointments were invited. Patients were recruited from December 2009 to the present and followed for one year. Ease of integration of MeTree(c) into clinical practice at the two intervention clinics was evaluated through patient surveys after their appointment and at 3 months post-visit, and physician surveys 3 months after tool integration. Total enrollment =1,184. Average time to complete MeTree(c) = 27 minutes. Patients found MeTree(c): easy to use (93%), easy to understand (97%), useful (98%), raised awareness of disease risk (85%), and changed how they think about their health (86%). Of the 26% (N = 311) asking for assistance to complete the tool, age (65 sd 9.4 vs. 57 sd 11.8, p-value < 0.00) and large pedigree size (24.4 sd 9.81 vs. 22.2 sd 8.30, p-value < 0.00) were the only significant factors; 77% of those requiring assistance were over the age of 60. Providers (N = 14) found MeTree(c): improved their practice (86%), improved their understanding of FHH (64%), made practice easier (79%), and worthy of recommending to their peers (93%). Our study shows that MeTree(c) has broad acceptance and support from both patients and providers and can be implemented without disruption to workflow. 23223450 Prolyl 4-hydroxlase activity is essential for development and cuticle formation in the human infective parasitic nematode Brugia malayi. Collagen prolyl 4-hydroxylases (C-P4H) are required for formation of extracellular matrices in higher eukaryotes. These enzymes convert proline residues within the repeat regions of collagen polypeptides to 4-hydroxyproline, a modification essential for the stability of the final triple helix. C-P4H are most often oligomeric complexes, with enzymatic activity contributed by the α subunits, and the β subunits formed by protein disulfide isomerase (PDI). Here, we characterize this enzyme class in the important human parasitic nematode Brugia malayi. All potential C-P4H subunits were identified by detailed bioinformatic analysis of sequence databases, function was investigated both by RNAi in the parasite and heterologous expression in Caenorhabditis elegans, whereas biochemical activity and complex formation were examined via co-expression in insect cells. Simultaneous RNAi of two B. malayi C-P4H α subunit-like genes resulted in a striking, highly penetrant body morphology phenotype in parasite larvae. This was replicated by single RNAi of a B. malayi C-P4H β subunit-like PDI. Surprisingly, however, the B. malayi proteins were not capable of rescuing a C. elegans α subunit mutant, whereas the human enzymes could. In contrast, the B. malayi PDI did functionally complement the lethal phenotype of a C. elegans β subunit mutant. Comparison of recombinant and parasite derived material indicates that enzymatic activity may be dependent on a non-reducible covalent link, present only in the parasite. We therefore demonstrate that C-P4H activity is essential for development of B. malayi and uncover a novel parasite-specific feature of these collagen biosynthetic enzymes that may be exploited in future parasite control. 23740512 Patellofemoral joint loading during stair ambulation in people with patellofemoral osteoarthritis. To determine whether people with patellofemoral (PF) joint osteoarthritis (OA) ascend and descend stairs with different PF joint loading, knee joint moments, lower limb kinematics, and muscle forces compared to healthy people. We recruited 17 participants with isolated PF joint OA, 13 participants with concurrent PF joint OA and tibiofemoral (TF) joint OA, and 21 age-matched controls. Joint kinematics and ground reaction forces were measured while participants ascended and descended stairs at a self-selected speed. Musculoskeletal computer modeling was used to determine lower limb muscle forces and the PF joint reaction force, and these parameters were compared between groups by analysis of variance. Compared to their healthy counterparts, participants with isolated PF joint OA and participants with concurrent PF and TF joint OA ascended and descended stairs with lower knee extension moments, lower quadriceps muscle forces, lower PF joint reaction forces, and increased anterior pelvic tilt. Participants with OA also ascended stairs with increased hip flexion angles and descended stairs with smaller knee flexion angles and smaller hip abductor muscle forces. No differences were evident between the two groups with OA. Compared to their healthy counterparts, people with PF joint OA (with or without concurrent TF joint OA) exhibit lower PF joint reaction forces during stair ascent and descent, in conjunction with lower knee extension moments and lower quadriceps muscle forces. 23850503 Windows of vulnerability: Maternal separation, age, and fluoxetine on adolescent depressive-like behavior in rats. Early exposure to stressful life events plays a significant role in adolescent depression. Clinical studies have identified a number of factors that increase the risk of depression, including sex of the subject, duration of the stressor, and genetic polymorphisms that elevate serotonin levels. In this study we used the maternal separation (MS) model to investigate to what extent these factors interacted during development to manifest in depressive-like behavior in male and female rats. The triadic model of learned helplessness parses depressive-like behavior into aspects of controllable, uncontrollable, and motivational behaviors. This model was used to investigate how the timing of MS between the ages of postnatal day (P) 2-9 and P9-16 interacted with either simultaneous vehicle (saline; 1ml/kg; i.p.) or fluoxetine (10mg/kg) exposure, which was used to enhance serotonin levels; these experiments also compared the effect of a vehicle injection during these developmental periods to a no injection control. Vehicle injections alone increased helplessness in the controllable condition in male rats when injected between P9-16 only, and did not interact further with MS. MS at both ages decreased controllability in male adolescents; females demonstrated an increase in controllability after MS. Elevated serotonin at P2-9 increased escape latencies in male and female control and MS subjects. Fluoxetine exposure at P9-16 increased helplessness in controls. Fluoxetine decreased helplessness in MS males independent of age, but increases helplessness in MS females. This study highlights the importance of age of MS (MS between P2-9 increases helplessness in males more than females), the duration of the stressor (previous results show females are effected by longer MS [P2-20], but not shorter [this study]), and that elevated serotonin increases escape latencies to a greater extent in females. 23673206 Sources, fluxes and risk of organic micropollutants to the Cantabrian Sea (Spain). The sources, distribution and risk of 51 organic micropollutants (OMPs) in the Cantabrian coastal environment (NW Spain) were evaluated. Gas chromatography coupled to tandem mass spectrometry was used to determine polycyclic aromatic hydrocarbons, polychlorinated biphenyls, organochlorinated pesticides, polybrominated diphenyl ethers, phthalates esters, bisphenol A and alkylphenols. 45 OMPs were detected in coastal/estuarine waters. Wastewater treatment plant effluents and emissary discharges were identified as the main sources of contamination. The accumulation of OMPs in sediments and the bioaccumulation in 21 days caged mussels were also assessed. Chemical results were combined with the "Combined Monitoring-based and Modeling-based Priority Setting Scheme" COMMPS procedure for risk assessment analysis. Finally, the chemical status of the different sampling locations was estimated using site risk indexes. Those indexes can be conveniently displayed in quality geographical maps and are considered a valuable tool for the environmental management and risk assessment of the region under study. 23832810 Can Physical Activity Improve Peak Bone Mass? The pediatric origin of osteoporosis has led many investigators to focus on determining factors that influence bone gain during growth and methods for optimizing this gain. Bone responds to bone loading activities by increasing mass or size. Overall, pediatric studies have found a positive effect of bone loading on bone size and accrual, but the types of loads necessary for a bone response have only recently been investigated in human studies. Findings indicate that responses vary by sex, maturational status, and are site-specific. Estrogen status, body composition, and nutritional status also may influence the bone response to loading. Despite the complex interrelationships among these various factors, it is prudent to conclude that increased physical activity throughout life is likely to optimize bone health. 23637134 The influence of acute resistance exercise on cyclooxygenase-1 and -2 activity and protein levels in human skeletal muscle. This study evaluated the activity and content of cyclooxygenase (COX)-1 and -2 in response to acute resistance exercise (RE) in human skeletal muscle. Previous work suggests that COX-1, but not COX-2, is the primary COX isoform elevated with resistance exercise in human skeletal muscle. COX activity, however, has not been assessed after resistance exercise in humans. It was hypothesized that RE would increase COX-1 but not COX-2 activity. Muscle biopsies were taken from the vastus lateralis of nine young men (25 ± 1 yr) at baseline (preexercise), 4, and 24 h after a single bout of knee extensor RE (three sets of 10 repetitions at 70% of maximum). Tissue lysate was assayed for COX-1 and COX-2 activity. COX-1 and COX-2 protein levels were measured via Western blot analysis. COX-1 activity increased at 4 h (P < 0.05) compared with preexercise, but returned to baseline at 24 h (PRE: 60 ± 10, 4 h: 106 ± 22, 24 h: 72 ± 8 nmol PGH2·g total protein(-1)·min(-1)). COX-2 activity was elevated at 4 and 24 h after RE (P < 0.05, PRE: 51 ± 7, 4 h: 100 ± 19, 24 h: 98 ± 14 nmol PGH2·g total protein(-1)·min(-1)). The protein level of COX-1 was not altered (P > 0.05) with acute RE. In contrast, COX-2 protein levels were nearly 3-fold greater (P > 0.05) at 4 h and 5-fold greater (P = 0.06) at 24 h, compared with preexercise. In conclusion, COX-1 activity increases transiently with exercise independent of COX-1 protein levels. In contrast, both COX-2 activity and protein levels were elevated with exercise, and this elevation persisted to at least 24 h after RE. 23443344 Assessment of female prevalence of overactive bladder (OAB) in Barcelona using a self-administered screening questionnaire: the Cuestionario de Autoevaluación del Control de la Vejiga (CACV). Overactive bladder (OAB) syndrome is common urological condition, usually underdiagnosed and difficult to identify. The screening of lower urinary tract symptoms (LUTS) through patient self-administered questionnaires can be useful not only for timely identification of these patients but to implement early interventions for symptoms and their implication in a patients' quality of life (QOL). Our objective was to assess the prevalence of OAB symptoms in patients attending general gynecology units in Barcelona, Spain, through a self-administered screening questionnaire. A cross-sectional, multicenter, observational, epidemiological study was carried out at general gynecology units of ten primary health centers in Barcelona, Spain. The study was conducted during a patient's single visit through self-administered forms. Patients recorded sociodemographic data, medical history and comorbidities, and scored the presence and bother related to specific urological symptoms using the Cuestionario de Autoevaluación del Control de la Vejiga (CACV), the validated Spanish version of the Bladder Control Self-Assessment Questionnaire (B-SAQ). A score ≥6 on the symptoms scale of the CACV was taken as an indicator of suspected OAB. One thousand and four women aged between 18 and 82 participated in the study. The overall prevalence of OAB was 11.8 %. A patient being >50 years was significantly associated with suspected OAB in comparison with the younger group [odds ratio (OR) 3.1 (2.1-4.7); p < 0,001]. Overactive bladder showed significant association with factors other than age, menopause, and previous urogynecological history, such as high body mass index (BMI) and parity. The estimated prevalence of suspected OAB in patients attending general gynecological services in Barcelona is 11.8 %. Overweight or obese patients and those with three or more children were found to be at elevated risk for developing OAB. 23830608 Automated patient identity recognition by analysis of chest radiograph features. The aim of this study was to develop a computerized scheme for automated identity recognition based on chest radiograph features. The proposed method was evaluated on a database consisting of 1000 pairs of posteroanterior chest radiographs. The method was based on six features: length of the lung field, size of the heart, area of the body, and widths of the upper, middle, and lower thoracic cage. The values for the six features were determined from a chest image, and absolute differences in feature values between the two images (feature errors) were used as indices of image similarity. The performance of the proposed method was evaluated by receiver operating characteristic (ROC) analysis. The discriminant performance was evaluated as the area Az under the ROC curve. The discriminant performance Az of the feature errors for lung field length, heart size, body area, upper cage width, middle cage width, and lower cage width were 0.794 ± 0.005, 0.737 ± 0.007, 0.820 ± 0.008, 0.860 ± 0.005, 0.894 ± 0.006, and 0.873 ± 0.006, respectively. The combination of the six feature errors obtained an Az value of 0.963 ± 0.002. The results indicate that combining the six features yields a high discriminant performance in recognizing patient identity. The method has potential usefulness for automated identity recognition to ensure that chest radiographs are associated with the correct patient. 23083917 Cortisol response and desire to binge following psychological stress: comparison between obese subjects with and without binge eating disorder. While stress and negative affect are known to precede "emotional eating", this relationship is not fully understood. The objective of this study was to explore the relationship between induced psychological stress, hypothalamic-pituitary-adrenal (HPA) axis activity, and eating behavior in binge eating disorder (BED). The Trier Social Stress Test (TSST) was applied in obese participants with (n=8) and without BED (n=8), and normal weight controls (n=8). Psychological characteristics, eating-related symptoms, and cortisol secretion were assessed. Baseline stress, anxiety and cortisol measures were similar in all groups. At baseline desire to binge was significantly higher among the BED group. While the TSST induced an increase in cortisol levels, a blunted cortisol response was observed in the BED group. In the BED group, a positive correlation was found between cortisol (area under the curve) levels during the TSST and the change in VAS scores for desire to binge. Post-TSST desire to binge and sweet craving were significantly higher in the BED group and correlated positively with stress, anxiety, and cortisol response in the BED group only. These results suggest chronic down-regulation of the HPA axis in participants with BED, and a relationship between psychological stress, the acute activation of the HPA axis, and food craving. 23432081 Symmetrical Windowing for Quantum States in Quasi-Classical Trajectory Simulations. A microscopically reversible approach toward computing reaction probabilities via classical trajectory simulation has been developed that bins trajectories symmetrically on the basis of their initial and final classical actions. The symmetrical quasi-classical (SQC) approach involves defining a classical action window function centered at integer quantum values of the action, choosing a width parameter that is less than unit quantum width, and applying the window function to both initial reactant and final product vibrational states. Calculations were performed using flat histogram windows and Gaussian windows over a range of width parameters. Use of the Wigner distribution function was also investigated as a possible choice. It was demonstrated for collinear H + H2 reactive scattering on the BKMP2 potential energy surface that reaction probabilities computed via the SQC methodology using a Gaussian window function of 1/2 unit width produces good agreement with quantum mechanical results over the 0.4-0.6 eV energy range relevant to the ground vibrational state to the ground vibrational state reactive transition. 23860852 Role of cationization and multimers formation for diastereomers differentiation by ion mobility-mass spectrometry. Stereochemistry plays an important role in biochemistry, particularly in therapeutic applications. Indeed, enantiomers have different biological activities, which can have important consequences. Many analytical techniques have been developed in order to allow the identification and the separation of stereoisomers. Here, we focused our work on the study of small diastereomers using the coupling of traveling wave ion mobility and mass spectrometry (TWIMS-MS) as a new alternative for stereochemistry study. In order to optimize the separation, the formation of adducts between diastereomers (M) and different alkali cations (X) was carried out. Thus, monomers [M + X](+) and multimers [2M + X](+) and [3M + X](+) ions have been studied from both experimental and theoretical viewpoints. Moreover, it has been shown that the study of the multimer [2Y + M + Li](+) ion, in which Y is an auxiliary diastereomeric ligand, allows the diastereomers separation. The combination of cationization, multimers ions formation, and IM-MS is a novel and powerful approach for the diastereomers identification. Thus, by this technique, diastereomers can be identified although they present very close conformations in gaseous phase. This work presents the first TWIMS-MS separation of diastereomers, which present very close collision cross section thanks to the formation of multimers and the use of an auxiliary diastereomeric ligand. 23562384 Comparison of C-reactive protein and fibrinogen levels in patients having anterior wall ST-Segment elevation myocardial infarction with versus without left ventricular thrombus (from a primary percutaneous coronary intervention cohort). We tested the hypothesis that admission serum inflammatory biomarkers may predict risk of early left ventricular (LV) thrombus formation in patients with first-ever anterior wall ST-segment elevation myocardial infarction (STEMI). Medical records of 207 patients admitted to our department between January 2006 and April 2012 for first-ever diagnosed anterior wall STEMI and treated with primary percutaneous coronary intervention (PPCI) were reviewed. Serum C-reactive protein (CRP) and fibrinogen levels were determined from blood samples taken before PPCI. Patients underwent an initial cardiac echocardiography on days 1 or 2 of admission and a second echocardiography on days 5 to 7 of hospitalization. An early LV thrombus was detected on the second echocardiogram in 11 patients (11 of 207, 5%), 6 of whom had also displayed an LV thrombus already during their first echocardiogram. Patients with an LV thrombus had significantly higher mean serum CRP levels than those without an LV thrombus (48 mg/L vs 8.4 mg/L, p = 0.001), and a trend for higher fibrinogen levels was also observed (398 ± 135 mg/dl vs 312 ± 82 mg/dl, p = 0.063). Following adjustment to other variables and the performance of multiple logistic regression, the CRP (relative risk 4.63, p = 0.004) and fibrinogen (relative risk 1.006, p = 0.033) levels were independent predictors of LV thrombus formation. We conclude that admission serum CRP and fibrinogen levels are independent predictors for early LV thrombus formation complicating a first-ever anterior wall STEMI. 23968649 Nintendo Wii rehabilitation ("Wii-hab") provides benefits in Parkinson's disease. Parkinson's disease (PD) impairs both activities of daily living (ADLs) and motor function and has adverse effects on mood in many patients. While dopaminergic medications are quite helpful for motor and ADLs impairments in PD, complementary therapies are also important in helping patients achieve maximum benefits and quality of life. We hypothesized that the Nintendo Wii (Wii) is a useful tool in improving motor and non-motor aspects in patients with PD, given its ability to drive functional movements and interactive nature. We enrolled twenty subjects with early to mid-stage PD in an open-label within-subjects study design where each subject was evaluated at baseline and then re-evaluated after playing the Wii three times per week for four weeks. Subjects were then re-evaluated one month later after not playing the Wii for a month to see if effects carried over. Subjects demonstrated significant improvements in the primary outcome measure (Nottingham Extended Activities of Daily Living Test (NEADL)), quality of life (PDQ-39) and motor function (UPDRS), and a trend toward improved mood (HAM-D) after four weeks of Wii therapy. Follow-up assessments one month later showed continued improvement for quality of life and UPDRS scores. The results demonstrate that Wii therapy provides short-term motor, non-motor, and quality of life benefits in PD. Further studies are needed to determine if there are long-term benefits of Wii therapy in PD. 23910076 On Your (Methyl) Mark, Get TET1, Go! Tet proteins and DNA demethylation are key regulators of embryonic stem cells, but their roles in development and tissue stem cells remain unclear. In this issue, Zhang et al. (2013) show that Tet1 regulates adult hippocampal neurogenesis by controlling progenitor proliferation, and Tet1 deficiency generates defects in learning and memory. 23857614 Latin American consensus on guidelines for chronic migraine treatment. Chronic migraine is a condition with significant prevalence all around the world and high socioeconomic impact, and its handling has been challenging neurologists. Developments for understanding its mechanisms and associated conditions, as well as that of new therapies, have been quick and important, a fact which has motivated the Latin American and Brazilian Headache Societies to prepare the present consensus. The treatment of chronic migraine should always be preceded by a careful diagnosis review; the detection of possible worsening factors and associated conditions; the stratification of seriousness/impossibility to treat; and monitoring establishment, with a pain diary. The present consensus deals with pharmacological and nonpharmacological forms of treatment to be used in chronic migraine. 23627674 EFNS review on the role of muscle biopsy in the investigation of myalgia. Myalgia, defined as any pain perceived in muscle, is very common in the general population and a frequent cause for referral to neurologists, rheumatologists and internists in general. It is however only rarely due to primary muscle disease and often referred from ligaments, joints, bones, the peripheral and central nervous system. A muscle biopsy should only be performed if this is likely to be diagnostically useful. At present no 'guidelines' exist. An EFNS panel of muscle specialists was set to review relevant studies from PubMed dating as far back as 1/1/1990. Only Class IV studies were available and therefore the recommendations arrived at are 'best practice recommendations' based on information harvested from the literature search and expert opinion. Muscle cramps should be recognized while drugs, infections, metabolic/ endocrinological and rheumatological causes of myalgia should be identified from the history and examination and pertinent laboratory tests. A muscle biopsy is more likely to be diagnostically useful if myalgia is exertional and if one or more of the following apply: i) there is myoglobinuria, (ii) there is a second wind phenomenon, (iii) there is muscle weakness, (iv) there is muscle hypertrophy /atrophy, (v) there is hyperCKemia (>2-3× normal), and (vi) there is a myopathic EMG. Patients presenting with myalgia can be recommended to have a biopsy based on careful history and examination and on simple laboratory screening. 23773150 Physical properties, ion-ion interactions, and conformational States of ionic liquids with alkyl-phosphonate anions. We investigate the ionic conductivities, phase behaviors, conformational states, and interactions of three ionic liquids based on imidazolium cations and phosphonate anions with varying alkyl chain lengths. All three ionic liquids show high conductivities, with 1,3-dimethylimidazolium methyl-phosphonate [DiMIm(MeO)(H)PO2] being the most conductive (7.3 × 10(-3) S cm(-1) at 298 K). The high ionic conductivities are a result of the low glass-transition temperatures, Tg, which do not change significantly upon changing the cation and/or anion size. However, there is a slight dependence of the temperature behavior of the conductivity on the size of the ions, as seen from the fragility parameter (D) obtained from fits to the Vogel-Fulcher-Tammann equation. The molecular-level structure and interactions of the phosphonate anions were examined by Raman spectroscopy and first-principles calculations. The calculations identify two stable conformations for the methyl- and ethyl-phosphonate anions by rotation of the methyl and ethyl groups, respectively. The broad Raman signatures of the anions suggest the coexistence of two anion conformers in the ionic liquids and non-negligible cation-anion interactions, with a dependence on the position and shape of the bands of the cation species and the alkyl group of the anion. 23760506 O-glycosylation as a novel control mechanism of peptidoglycan hydrolase activity. Acm2, the major autolysin of Lactobacillus plantarum, is a tripartite protein. Its catalytic domain is surrounded by an O-glycosylated N-terminal region rich in Ala, Ser, and Thr (AST domain), which is of low complexity and unknown function, and a C-terminal region composed of five SH3b peptidoglycan (PG) binding domains. Here, we investigate the contribution of these two accessory domains and of O-glycosylation to Acm2 functionality. We demonstrate that Acm2 is an N-acetylglucosaminidase and identify the pattern of O-glycosylation (21 mono-N-acetylglucosamines) of its AST domain. The O-glycosylation process is species-specific as Acm2 purified from Lactococcus lactis is not glycosylated. We therefore explored the functional role of O-glycosylation by purifying different truncated versions of Acm2 that were either glycosylated or non-glycosylated. We show that SH3b domains are able to bind PG and are responsible for Acm2 targeting to the septum of dividing cells, whereas the AST domain and its O-glycosylation are not involved in this process. Notably, our data reveal that the lack of O-glycosylation of the AST domain significantly increases Acm2 enzymatic activity, whereas removal of SH3b PG binding domains dramatically reduces this activity. Based on this antagonistic role, we propose a model in which access of the Acm2 catalytic domain to its substrate may be hindered by the AST domain where O-glycosylation changes its conformation and/or mediates interdomain interactions. To the best of our knowledge, this is the first time that O-glycosylation is shown to control the activity of a bacterial enzyme. 23843344 Sulfur-Bridged BODIPY DYEmers. Reactions of BODIPY monomers with sulfur nucleophiles and electrophiles result in the formation of new BODIPY dimers. Mono- and disulfur bridges are established, and the new dyestuff molecules were studied with respect to their structural, optical, and electrochemical properties. X-ray diffraction analyses reveal individual angulated orientations of the BODIPY subunits in all cases. DFT calculations provide solution conformers of the DYEmers which deviate in a specific manner from the crystallographic results. Clear exciton-like splittings are observed in the absorption spectra, with maxima at up to 628 nm, in combination with the expected weak fluorescence in polar solvents. A strong communication between the BODIPY subunits was detected by cyclic voltammetry, where two separated one-electron oxidation and reduction waves with peak-to-peak potential differences of 120-400 mV are observed. The qualitative applicability of the exciton model by Kasha for the interpretation of the absorption spectral shape with respect to the conformational state, subunit orientation and distance, and conjugation through the different sulfur bridges, is discussed in detail for the new BODIPY derivatives. This work is part of our concept of DYEmers, where the covalent oligomerisation of BODIPY-type dye molecules with close distances is leading to new functional dyes with predictable properties. 23392131 In vivo Raman spectroscopy of oral buccal mucosa: a study on malignancy associated changes (MAC)/cancer field effects (CFE). Occurrence of metachronous and synchronous secondary tumors in oral cavities has been associated with poor prognosis and decreased 5-year disease-free survival rates. The origin of secondary tumors in the oral cavity has been primarily attributed to cancer field effects (CFE) or malignancy-associated changes (MAC) in uninvolved areas. Classification of normal, cancerous and pre-cancerous oral lesions by in vivo Raman spectroscopy (RS) has already been demonstrated. In the present study, MAC/CFE in oral buccal mucosa were explored. In vivo Raman spectra from 84 subjects (722 spectra) under five categories - cancer and contralateral normal (opposite side of tumor), healthy controls (no tobacco habit, no cancer), habitués healthy controls (tobacco habit, no cancer) and non-habitués contralateral normal (no tobacco habit with cancer) were acquired. Mean and difference spectra suggest that loss of lipids and additional features representing proteins and DNA are characteristics of all pathological conditions, with respect to healthy controls. Spectral data were analyzed by PC-LDA followed by leave-one-out cross-validation. Results suggest that Raman characteristics of mucosa of healthy controls are exclusive, while those of habitués healthy controls are similar to those of contralateral normal mucosa. It was observed that the cluster of non-habitués contralateral normal mucosa is different from habitués healthy controls, suggesting that malignancy associated changes can be identified and also indicating that transformation of uninvolved oral mucosa due to tobacco habit or malignancy is different. The findings of the study demonstrate the potential of RS in identifying early transformation changes in oral mucosa and the efficacy of this approach in oral cancer applications. 23638623 Glucocorticoid therapy as a significant risk factor for osteoporosis and fractures in an Italian postmenopausal population. To analyze the potential effects of glucocorticoid treatment without an osteoporosis prevention strategy and to precociously identify patients at high risk of osteoporosis and fragility fractures in the postmenopausal period. A total of 382 postmenopausal patients, 177 exposed and 205 not exposed to glucocorticoid therapy, were studied using a standard questionnaire. Epidemiological as well as clinical data that included the most recent absorptiometry test results were examined. Osteoporosis and fractures were frequent in the postmenopausal glucocorticoid-treated patients. Fragility fractures occurred more frequently in glucocorticoid-treated patients (vertebral fractures represented 45% of all fractures) than in the non-glucocorticoid-treated patients. In particular, the highest fracture percentage was found in 50- to 65-year-old glucocorticoid-treated patients, a subset of patients showing a prevalence of osteoporosis similar to that of non-exposed menopausal subjects older than 65. Glucocorticoid therapy increases the risk of fragility fractures fivefold and doubles the risk of osteoporosis in menopausal patients. Glucocorticoid treatments put menopausal patients at a high risk of incurring fragility fractures even in the early postmenopausal period. The management of strategies for fracture prevention must take into consideration early intervention in patients undergoing or about to undergo glucocorticoid treatment. 23935374 Update on imatinib for gastrointestinal stromal tumors: duration of treatment. Gastrointestinal stromal tumors (GISTs) are the most common sarcoma of the gastrointestinal tract, with transformation typically driven by activating mutations of c-KIT and less commonly platelet-derived growth factor receptor alpha (PDGFRA). Successful targeting of c-KIT and PDGFRA with imatinib, a tyrosine kinase inhibitor (TKI), has had a major impact in advanced GIST and as an adjuvant and neoadjuvant treatment. If treatment with imatinib fails, further lines of TKI therapy have a role, but disease response is usually only measured in months, so strategies to maximize the benefit from imatinib are paramount. Here, we provide an overview of the structure and signaling of c-KIT coupled with a review of the clinical trials of imatinib in GIST. In doing so, we make recommendations about the duration of imatinib therapy and suggest how best to utilize imatinib in order to improve patient outcomes in the future. 23830411 Paraplegia in a chiropractic patient secondary to atraumatic dural arteriovenous fistula with perimedullary hypertension: case report. Intracranial dural arteriovenous fistulas are abnormal communications between higher-pressure arterial circulation and lower-pressure venous circulation. This abnormal communication can result in important and frequently misdiagnosed neurological abnormalities.A case of rapid onset paraplegia following cervical chiropractic manipulation is reviewed. The patient's generalized spinal cord edema, lower extremity paraplegia and upper extremity weakness, were initially believed to be a complication of the cervical spinal manipulation that had occurred earlier on the day of admission. Subsequent diagnostic testing determined the patient suffered from impaired circulation of the cervical spinal cord produced by a Type V intracranial arteriovenous fistula and resultant venous hypertension in the pontomesencephalic and anterior spinal veins.The clinical and imaging findings of an intracranial dural arteriovenous fistula with pontomesencephalic venous congestion and paraplegia are reviewed.This case report emphasizes the importance of thorough and serial diagnostic imaging in the presence of sudden onset paraplegia and the potential for error when concluding atypical neurological presentations are the result of therapeutic misadventure. 22902307 A human hemi-cornea model for eye irritation testing: quality control of production, reliability and predictive capacity. We have developed a 3-dimensional human hemi-cornea which comprises an immortalized epithelial cell line and keratocytes embedded in a collagen stroma. In the present study, we have used MTT reduction of the whole tissue to clarify whether the production of this complex 3-D-model is transferable into other laboratories and whether these tissues can be constructed reproducibly. Our results demonstrate the reproducible production of the hemi-cornea model according to standard operation procedures using 15 independent batches of reconstructed hemi-cornea models in two independent laboratories each. Furthermore, the hemi-cornea tissues have been treated with 20 chemicals of different eye-irritating potential under blind conditions to assess the performance and limitations of our test system comparing three different prediction models. The most suitable prediction model revealed an overall in vitro-in vivo concordance of 80% and 70% in the participating laboratories, respectively, and an inter-laboratory concordance of 80%. Sensitivity of the test was 77% and specificity was between 57% and 86% to discriminate classified from non-classified chemicals. We conclude that additional physiologically relevant endpoints in both epithelium and stroma have to be developed for the reliable prediction of all GHS classes of eye irritation in one stand alone test system. 23874118 An autopsy case of pulmonary fissure induced by zygomycosis. For immunodeficient patients, fungi are life-threatening pathogens. In this paper, we present an autopsy case of combined zygomycosis and aspergillosis. A female in her 70s on chronic hemodialysis was admitted to a hospital suffering bloody sputum, dyspnea, and fever, probably due to perinuclear anti-neutrophil cytoplasmic antibody-related vasculitis. Antibiotics were administered and immunosuppressive therapy was started, resulting in an improvement in her condition. Pneumonia later developed, followed by pulmonary bleeding and intractable pneumothorax from which she ultimately died. On autopsy, the upper lobe of the left lung was found to have hemorrhagic necrosis and showed a large longitudinal fissure. Microscopically, Zygomycota were observed in both the lungs and heart, while Aspergillus was found in the middle lobe of the right lung. Zygomycosis, which usually has a poor prognosis, is assumed to have induced hemorrhagic infarction of the lungs, inducing pulmonary bleeding and necrosis, despite the use of lipid formulations of amphotericin B, which are effective medicines against Zygomycota. 23736966 Voclosporin food effect and single oral ascending dose pharmacokinetic and pharmacodynamic studies in healthy human subjects. Voclosporin (VCS) is a novel calcineurin (CN) inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. These studies evaluated the single ascending dose pharmacokinetics (PK) and pharmacodynamics (PD, CN activity) of VCS and the effect of food. VCS was administered orally in single doses of 0.25 through 4.5 mg/kg in 62 subjects in the single ascending dose study and as a single oral 1.5 mg/kg dose to 18 subjects after fasting, consumption of a low-fat and high-fat meal. Non-compartmental PK, PD, and PKPD correlation were evaluated. Following single oral doses, systemic exposure increased in a linear manner and demonstrated 1:1 dose-proportional, first-order linear PK above 1.5 mg/kg. VCS inhibited CN activity in a dose-related fashion with maximal inhibition peaking at 3.0 mg/kg. PKPD correlation indicated an EC50 of 78.3 ± 6.8 ng/mL. Administration of VCS with a low-fat and high-fat meal decreased Cmax by 29% and 53%, respectively, and AUCinf by 15% and 25%, respectively. Following ascending single doses of VCS, exposure increased in a linear fashion. A food effect on exposure was demonstrated, with a more pronounced effect following a high-fat meal. VCS concentrations were also found to correlate with CN activity. 23265883 Discovery of nosokophic acid, a predicted intermediate of moenomycins, from nosokomycin-producing Streptomyces sp. K04-0144. A new actinomycete metabolite designated nosokophic acid was isolated from the culture broth of nosokomycin-producing Streptomyces sp. K04-0144, and the structure was elucidated by various NMR experiments. Nosokophic acid was found to be 3-phosphoglycosyl-2-sesquiterpenyl dihydroxypropionic acid, a predicted biosynthetic intermediate of nosokomycin-related moenomycins. The compound showed no activity against MRSA, but potentiated imipenem activity against MRSA by 512-fold. 23695781 Wheelchair exercise capacity in spinal cord injury up to five years after discharge from inpatient rehabilitation. Objective: To elucidate the course and determinants of wheelchair exercise capacity in spinal cord injury up to 5 years after discharge from inpatient rehabilitation, and to describe loss to follow-up. Design: Prospective cohort study, with measurements at the start and discharge from inpatient rehabilitation, 1 and 5 years after discharge. Subjects: A total of 225 wheelchair-dependent persons with spinal cord injury. Methods: Random coefficient analysis of the course and determinants of peak aerobic power output (POpeak) and peak oxygen uptake (VO2peak). Results: A total of 162 participants attended 1 or more peak exercise tests and were analysed. Significant changes were found for both VO2peak and POpeak between start and 5 years after discharge, and discharge and 5 years after discharge. No significant changes were found for VO2peak and POpeak between 1 year and 5 years after discharge. Age, gender, level and completeness of lesion were determinants for level of VO2peak and age, gender, and level of lesion for level of POpeak. No significant determinants were found for the course of wheelchair exercise capacity. The 63 participants who were not analysed were older, and showed more persons with a tetraplegia. Conclusion: Wheelchair exercise capacity of persons with spinal cord injury stabilizes at between 1 and 5 years after discharge. The participants appear to be a positive selection of the total study group. 23903804 Donor-acceptor meso-alkynylated ferrocenyl BODIPYs: synthesis, structure, and properties. meso-Alkynylated ferrocenyl BODIPYs () with varying conjugation length have been designed, and synthesized using the palladium catalyzed Sonogashira cross-coupling reaction of meso-chloro BODIPY with the corresponding ferrocenylethynes. These BODIPYs have been designed to improve the electronic communication between the donor ferrocene, and the acceptor BODIPY. The photonic and electrochemical properties indicate charge transfer (CT) from the ferrocene to the BODIPY. Single crystal X-ray structures of , , and show interesting supramolecular interactions. Computational studies were used to study the electronic structure of the BODIPYs. 23933808 Do wheelchairs spread pathogenic bacteria within hospital walls? Transmission of nosocomial pathogens has been linked to transient colonization of health care workers, medical devices and other constituents of patients' environment. In this paper we present our findings concerning the presence of pathogenic bacteria on wheelchairs, and the possibility that wheelchairs constitute a reservoir of these bacteria and a means of spreading them. In this work we examined four wheelchairs, each from a different location: the internal medicine ward, the emergency department, the general surgery ward and wheelchair stockpile of the transportation unit of the hospital. The samples were collected and cultured on different media. Bacterial identification and antimicrobial sensitivity testing were carried out using accepted practices in the microbiology laboratory. We found that wheelchairs are contaminated with several pathogenic bacteria, among them antibiotic-resistant strains such as MRSA, Pseudomonas aeruginosa, Acinetobacter baumanni etc. Since there is no specific guideline protocol that deals with disinfection and cleaning frequency of wheelchairs in hospitals, we suggest each hospital to write one. 23726222 Vibrio ordalii antimicrobial susceptibility testing--modified culture conditions required and laboratory-specific epidemiological cut-off values. The present study aimed to determine oxytetracycline (OTC), florfenicol (FLO) and oxolinic acid (OXO) MICs and zone diameters for 24 Chilean Vibrio ordalii isolates using the methods for broth dilution susceptibility testing of bacteria isolated from aquatic animals and the methods for antimicrobial disk susceptibility testing of bacteria isolated from aquatic animals guidelines published by the Clinical Laboratory Standards Institute (CLSI). The results were then used in a normalized resistance interpretation (NRI) analysis to establish tentative laboratory-specific epidemiological cut-off (ECOFF) values. MIC results were similar at the two tested temperatures (22 °C and 18 °C). At 18 °C, the NRI analysis of OTC, FLO and OXO MIC data calculated laboratory-specific ECOFF values and non-wild-type (NWT) rates to be ≤4 mg/l (24%), ≤16 mg/l (4%) and ≤8 mg/l (25%), respectively. Tests performed with all V. ordalii isolates following the officially recommended incubation temperature (22 °C) revealed difficulties in measuring inhibition zone diameters. When disk diffusion tests were performed using Mueller-Hinton agar with 1% NaCl (MHA-1) at 18 °C the inhibition zone diameter distributions showed the formation of WT populations which could be defined using NRI analysis. For OTC the laboratory-specific ECOFF value was ≥38 mm with NWT rate of 16.7%. For FLO and OXO, the laboratory-specific ECOFF values were ≥38 and ≥40, respectively, generating NWT rates of 25 and 46%, respectively. Although the CLSI suggests testing Vibrio spp. on MHA-1 at 22 °C, we found measurements of the 24 isolates were better defined and normally distributed at 18 °C. This is the first study determining the MIC and disk diffusion test of V. ordalii isolated from diseased salmonids, where laboratory-specific ECOFF values could be established. Also resistance to OTC, FLO and OXO among some Chilean isolates was demonstrated. 23742887 Genetic diversity of the golden potato cyst nematode Globodera rostochiensis and determination of the origin of populations in Quebec, Canada. The golden cyst nematode (Globodera rostochiensis), native to South America, has been introduced in many parts of the world, including Europe and North America. Recently, it was found for the first time in the province of Quebec, Canada in the locality of St. Amable near Montreal. To date, very few studies have examined the population genetics of this pest. Consequently, there is a lack of knowledge about the genetic structure and evolution of this nematode. In this study, twelve new microsatellite markers were developed in order to explore these questions. These markers were used to genotype fifteen populations originating from different regions of the world, including five from Canada. Within populations, the highest genetic diversity was consistently observed in the populations from Bolivia, the postulated region of origin of the golden nematode, and the lowest in populations from British Columbia (Canada) and New York (USA). The two Quebec populations were very similar to each other and to the population found in Newfoundland, but surprisingly, they were significantly different from three other North American populations including those from New York and British Columbia. Based on our results, we conclude that the golden cyst nematode has been introduced in North America at least twice from distinct regions of the world. 23932648 Margin comments in dermatopathology reports on dysplastic nevi influence re-excision rates. Dermatopathology reports influence clinical management, but it is not clear to what extent comments on margin involvement of histopathologically dysplastic nevi (HDN) influence decisions about re-excision or complete excision. We sought to determine if standardized margin comments (MCs) on HDN influence re-excision rates. By reviewing medical records, we compared re-excision rates of HDN reported with (May 2011 to December 2012) and without (January 2007 to December 2010) standardized MCs, and surveyed clinicians to assess perceptions of the impact of MCs on their management of HDN. Of 584 HDN, 302 had MCs and 282 did not. Re-excision was recommended or performed at a significantly higher rate for patients in the group without MCs (51.8%, 146 of 282) than in the MC group (39.4%, 119 of 302); P = .003 regardless of margin status. This difference was observed among HDN diagnosed as mildly and moderately dysplastic but not for severely dysplastic nevi. In all, 40% (16 of 40) of clinicians responded that they are more likely to biopsy pigmented lesions with a clinical margin of normal-appearing skin than they were before MCs were routinely included in dermatopathology reports. This was a retrospective study. Re-excision rates were significantly lower in patients who had HDN reported with standardized MCs. MCs may help reduce re-excision rates, with associated reduction in health care use, cost, and morbidity. 23931947 Divorce and changes in the prevalence of psychotropic medication use: A register-based longitudinal study among middle-aged Finns. The annual prevalence of psychotropic medication use exceeds 10 percent in Europe and the United States, the prevalence being higher among the divorced than the married. We analysed changes in the three-month prevalence of psychotropic medication use (psycholeptics and psychoanaleptics excluding medication for dementia) by proximity to divorce, sex, medication type and socio-demographic characteristics, using register-data on 304,111 Finns between 25 and 64 years of age, of whom 23,956 divorced between 1995 and 2003 and 142,093 were continuously married from 1995 to 2004. Five years before divorce, men and women already displayed about one percentage point higher prevalence of psychotropic medication use than those who continued their marriage. The excess prevalence increased with approaching divorce and peaked six to nine months before divorce, reaching 7.3 percent (95% CI 6.8-8.0) among divorcing men and 8.1 percent (95% CI 7.5-8.8) among divorcing women. The peak was followed by an 18-month decline, after which the excess compared to the continuously married settled at nearly three percentage points. The excess was not due to being socio-economically disadvantaged, and socio-demographic factors also seemed to have few modifying effects. The changes in prevalence were largest for antidepressants and almost non-existent for antipsychotics. Our results suggest that the high prevalence of psychotropic medication use among the divorced results both from selective factors already present five years before divorce and the acute and long-term causal effects of becoming and being divorced. Counselling is needed for individuals in the process of divorce, rather than economic support for divorced individuals. 23092918 mTOR inhibition modulates epileptogenesis, seizures and depressive behavior in a genetic rat model of absence epilepsy. Several signaling pathways are believed to be involved in the epileptogenic process that triggers the subsequent changes in the brain causing epilepsy. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that in the brain, regulates several important physiological functions such as neuronal development and synaptic plasticity, and also seems to be involved in many pathologies, including epilepsy and psychiatric disorders. Previous work in animal models of both genetic and acquired generalized convulsive epilepsies, has suggested that modulators of the mTOR signaling pathway may have beneficial neuroprotective and antiepileptogenic effects. Here, we investigated for the first time, the effect of some treatment schedules (i.e. early chronic, sub-chronic and acute) with the specific mTOR inhibitor rapamycin, on the development of absence seizures and seizure parameters as well as depressive-like behavior in WAG/Rij rats, a genetic model of absence epilepsy, epileptogenesis and mild-depression comorbidity. In addition, we studied the possible interaction between rapamycin treatment and the effects of bacterial lipopolysaccharide (LPS) endotoxin administration, which is known to aggravate absence seizures through generation of increased neuroinflammatory responses. We found that rapamycin (early chronic treatment for 17 weeks, starting at P45) exhibited clear antiepileptogenic properties also in this animal epilepsy model; however, this effect was accompanied by unexpected prodepressant effects. Both acute and sub-chronic (7 day) treatments also had anti-absence properties, but the sub-chronic treatment produced contrasting antidepressant properties in the WAG/Rij rats that were not seen in control Wistar rats. The rapamycin/LPS co-administration studies showed that rapamycin blocked or prevented the LPS-dependent increase in absence seizures, suggesting an anti-inflammatory-like protective action. In conclusion, we have demonstrated a novel antiepileptogenic effect of rapamycin in a well-established animal model of absence epilepsy, and we suggest that this effect may be mediated by the inhibition of inflammatory processes that are developed in the brain of these specific animals during epileptogenesis and during seizures. Our experiments here suggest new insights into this intriguing field, which deserves to be further explored. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'. 23356826 Two new glycosides from Vitex negundo. Two new glycosides, 2-methyl pyromeconic acid 3-O-β-d-glucopyranoside-6'-(O-4″-hydroxybenzoate) (1), 6'-O-p-hydroxybenzoyl-gardoside (2) and four known iridoid glycosides (3-6) were isolated from the whole plant of Vitex negundo. Their structures were elucidated on the basis of spectroscopic methods including HR-ESI-MS, 1D and 2D NMR. 23625190 Human pluripotent stem cell differentiation into authentic striatal projection neurons. Here we present the principles and steps of a protocol that we have recently developed for the differentiation of hES/iPS cells into the authentic human striatal projection medium spiny neurons (MSNs) that die in Huntington's Disease (HD). Authenticity is judged by the convergence of multiple features within individual cells. Our procedure lasts 80 days and couples neural induction via BMP/TGF-β inhibition with exposure to the developmental factors sonic hedgehog (SHH) and dickkopf1 (DKK-1) to drive ventral telencephalic specification, followed by terminal differentiation [1]. Authenticity of the resulting neuronal population is monitored by the appearance of FOXG1(+)/GSX2(+) progenitor cells of the lateral ganglionic eminence (LGE) at day 15-25 of differentiation, followed by appearance of CTIP2-, FOXP1- and FOXP2-positive cells at day 45. These precursor cells then mature into MAP2(+)/GABA(+) neurons with 20 % of them ultimately co-expressing the DARPP-32 and CTIP2 diagnostic markers and carrying electrophysiological properties expected for fully functional MSNs.The protocol is characterized by its replicability in at least three human pluripotent cell lines. Altogether this protocol defines a useful platform for in vitro developmental neurobiology studies, drug screening, and regenerative medicine approaches. 23949949 Clinical Management of Resistant Hypertension : Practical recommendations from the Italian Society of Hypertension (SIIA). According to recent hypertension guidelines, resistant hypertension is a clinical condition characterized by the presence of BP values above the recommended limits of the reference values (BP >140/90 mmHg). The prevalence of this clinical condition is about 10 % of the essential hypertensives. A proper diagnosis and management of resistant hypertension should go trough careful, mandatory clinical step, aimed at excluding the presence of pseudo-resistance hypertension. In this report, we summarized the practical recommendations are targeting both the general practitioner and the specialist who play an active role in the clinical management of patients with arterial hypertension. 23922393 Sea surface height evidence for long-term warming effects of tropical cyclones on the ocean. Tropical cyclones have been hypothesized to influence climate by pumping heat into the ocean, but a direct measure of this warming effect is still lacking. We quantified cyclone-induced ocean warming by directly monitoring the thermal expansion of water in the wake of cyclones, using satellite-based sea surface height data that provide a unique way of tracking the changes in ocean heat content on seasonal and longer timescales. We find that the long-term effect of cyclones is to warm the ocean at a rate of 0.32 ± 0.15 PW between 1993 and 2009, i.e., ∼23 times more efficiently per unit area than the background equatorial warming, making cyclones potentially important modulators of the climate by affecting heat transport in the ocean-atmosphere system. Furthermore, our analysis reveals that the rate of warming increases with cyclone intensity. This, together with a predicted shift in the distribution of cyclones toward higher intensities as climate warms, suggests the ocean will get even warmer, possibly leading to a positive feedback. 23917310 R-thanatin inhibits the growth and biofilm formation of methicillin-resistant Staphylococcus epidermidis in vivo and in vitro. Staphylococcus epidermidis (S. epidermidis) is one of the most frequent causes of device-associated infections, because it is known to cause biofilms that grow on catheters or other surgical implant. The persistent increasing resistance of S. epidermidis, and other coagulase-negative staphylococci (CoNS), has driven the need for newer antibacterial agents with innovative therapeutic strategies. Thanatin is reported to display potent antibiotic activities especially against extended-spectrum beta lactamase-producing Escherichia coli. The present study aimed to investigate whether a shorter derivative peptide (R-thanatin) could be used as novel antibacterial agents. We found that R-thanatin was highly potent against coagulase-negative staphylococci in vitro, such as S. epidermidis, S. haemolyticus and S. hominis, and inhibited biofilm formation at subinhibitory concentration. Properties of little toxcicity to hRBC and human umbilical vein endothelial cells, low incidence of resistance and relatively high stability in plasma were confirmed. Excellent in vivo protective effects were also observed on MRSE induced urinary tract infection model of rat. Electron microscopy and confocal laser-scanning microscopy analyses suggested that R-thanatin disturbed cell division of MRSE severely, which might be the reason for growth inhibition of MRSE. These findings indicate that R-thanatin is active against the growth and biofilm formation of MRSE in vitro and in vivo. R-thanatin might be considered as a specific drug candidate for treating CoNS infections. 23486181 High-throughput quantification of the mechanical competence of murine femora - A highly automated approach for large-scale genetic studies. Animal models are widely used to gain insight into the role of genetics on bone structure and function. One of the main strategies to map the genes regulating specific traits is called quantitative trait loci (QTL) analysis, which generally requires a very large number of animals (often more than 1000) to reach statistical significance. QTL analysis for mechanical traits has been mainly based on experimental mechanical testing, which, in view of the large number of animals, is time consuming. Hence, the goal of the present work was to introduce an automated method for large-scale high-throughput quantification of the mechanical properties of murine femora. Specifically, our aims were, first, to develop and validate an automated method to quantify murine femoral bone stiffness. Second, to test its high-throughput capabilities on murine femora from a large genetic study, more specifically, femora from two growth hormone (GH) deficient inbred strains of mice (B6-lit/lit and C3.B6-lit/lit) and their first (F1) and second (F2) filial offsprings. Automated routines were developed to convert micro-computed tomography (micro-CT) images of femora into micro-finite element (micro-FE) models. The method was experimentally validated on femora from C57BL/6J and C3H/HeJ mice: for both inbred strains the micro-FE models closely matched the experimentally measured bone stiffness when using a single tissue modulus of 13.06GPa. The mechanical analysis of the entire dataset (n=1990) took approximately 44 CPU hours on a supercomputer. In conclusion, our approach, in combination with QTL analysis could help to locate genes directly involved in controlling bone mechanical competence. 23951255 Long-Term Monitoring of Microsporidia, Cryptosporidium and Giardia Infections in Western Lowland Gorillas (Gorilla gorilla gorilla) at Different Stages of Habituation in Dzanga Sangha Protected Areas, Central African Republic. Infectious diseases pose one of the greatest threats to endangered species, and a risk of gastrointestinal parasite transmission from humans to wildlife has always been considered as a major concern of tourism. Increased anthropogenic impact on primate populations may result in general changes in communities of their parasites, and also in a direct exchange of parasites between humans and primates. To evaluate the impact of close contact with humans on the occurrence of potentially zoonotic protists in great apes, we conducted a long-term monitoring of microsporidia, Cryptosporidium and Giardia infections in western lowland gorillas at different stages of the habituation process, humans, and other wildlife in Dzanga-Sangha Protected Areas in the Central African Republic. We detected Encephalitozoon cuniculi genotypes I and II (7.5%), Enterocytozoon bieneusi genotype D and three novel genotypes (gorilla 1-3) (4.0%), Giardia intestinalis subgroup A II (2.0%) and Cryptosporidium bovis (0.5%) in gorillas, whereas in humans we found only G. intestinalis subgroup A II (2.1%). In other wild and domestic animals we recorded E. cuniculi genotypes I and II (2.1%), G. intestinalis assemblage E (0.5%) and C. muris TS03 (0.5%). Due to the non-specificity of E. cuniculi genotypes we conclude that detection of the exact source of E. cuniculi infection is problematic. As Giardia intestinalis was recorded primarily in gorilla groups with closer human contact, we suggest that human-gorilla transmission has occurred. We call attention to a potentially negative impact of habituation on selected pathogens which might occur as a result of the more frequent presence of humans in the vicinity of both gorillas under habituation and habituated gorillas, rather than as a consequence of the close contact with humans, which might be a more traditional assumption. We encourage to observe the sections concerning hygiene from the IUCN best practice guidelines for all sites where increased human-gorilla contact occurs. 23948077 Transcriptomic responses of European flounder (Platichthys flesus) liver to a brominated flame retardant mixture. Male European flounder (Platichthys flesus) were exposed to a technical mixture of brominated diphenyl ethers (PDBEs, DE-71, Pentamix) that had been purified to remove contaminating dioxins. Controls were exposed to carrier solvent alone. Fish were exposed to decadally increasing concentrations of Pentamix via both sediment and spiked food. The GENIPOL P. flesus cDNA microarray, differentially expressed gene profiling (DEG) and quantitative PCR were employed to detect hepatic transcriptional differences between exposed fish and controls. Gene transcriptional changes were more sensitive to Pentamix exposure than biomarkers measured previously. Pentamix exposure induced transcripts coding for enzymes of xenobiotic metabolism (CYP1A, aldo-keto reductases) and elicited endocrine disruption (vitellogenin and thyroid hormone receptor alpha), with effects on CYP1A and VTG occurring at the highest exposure. Ontology analysis clearly showed dose-responsive changes indicative of oxidative stress, induction of mitochondrial dysfunction, and apoptosis. We conclude that exposure to PBDEs in both sediment and food has a significant adverse effect on a broad range of crucial biochemical processes in the livers of this widely distributed estuarine fish species, the flounder. 23891267 Neoadjuvant hormonal therapy for endocrine sensitive breast cancer: A systematic review. In recent years, studies investigating neoadjuvant therapies have been emerging, because of the additional benefits it provides in terms of facilitating less extensive surgery and the possibility of investigating tumor biological features and response. Neoadjuvant hormonal therapy (NHT) is, in general, considered to be a suitable option for hormone receptor (HR)-positive patients who are unfit for chemotherapy or surgery, and is increasingly being utilized to achieve tumor downsizing before surgery in postmenopausal women. Studies investigating NHT were reviewed for tumor response data. NHT demonstrated similar efficacy to neoadjuvant chemotherapy (NCT) in HR-positive breast cancer patients. Clinical responses ranged from 13.5% to 100%, with treatment periods between 3 and 24months. In studies comparing tamoxifen with aromatase inhibitors, the latter were superior in terms of tumor response and rates of breast-conserving surgery (BCS). In most studies with treatment durations longer than 3months, tumor response rates increased. Therefore, longer durations of NHT are feasible and should be considered as an alternative to NCT in selected patients. 23616308 Believe, and you will achieve: changes over time in self-efficacy, engagement, and performance. In order to answer the question whether changes in students' self-efficacy levels co-vary with similar changes in engagement and performance, a field study and an experimental study were conducted among university students. In order to do this, we adopted a subgroup approach. We created "natural" (Study 1) and manipulated (Study 2) subgroups based upon their change in self-efficacy over time and examined whether these subgroups showed similar changes over time in engagement and performance. The results of both studies are partly in line with Social Cognitive Theory, in that they confirm that changes in self-efficacy may have a significant impact on students' changes in cognition and motivation (i.e. engagement), as well as behavior (i.e. performance). More specifically, our results show that students' increases/decreases in self-efficacy were related to corresponding increases/decreases in their study engagement and task performance over time. Examining the consequences of changes in students' self-efficacy levels seems promising, both for research and practice. 23789841 Photoassisted synthesis of enantiopure alkaloid mimics possessing unprecedented polyheterocyclic cores. Enantiopure alkaloid mimics are synthesized via high yielding intramolecular cycloadditions of photogenerated azaxylylenes tethered to pyrroles, with further growth of molecular complexity via post-photochemical transformations of primary photoproducts. This expeditious access to structurally unprecedented polyheterocyclic cores is being developed in the context of diversity-oriented synthesis, as the modular design allows for rapid "pre-assembly" of diverse photoprecursors from simple building blocks/diversity inputs. 23918379 Forebrain dopamine neurons project down to a brainstem region controlling locomotion. The contribution of dopamine (DA) to locomotor control is traditionally attributed to ascending dopaminergic projections from the substantia nigra pars compacta and the ventral tegmental area to the basal ganglia, which in turn project down to the mesencephalic locomotor region (MLR), a brainstem region controlling locomotion in vertebrates. However, a dopaminergic innervation of the pedunculopontine nucleus, considered part of the MLR, was recently identified in the monkey. The origin and role of this dopaminergic input are unknown. We addressed these questions in a basal vertebrate, the lamprey. Here we report a functional descending dopaminergic pathway from the posterior tuberculum (PT; homologous to the substantia nigra pars compacta and/or ventral tegmental area of mammals) to the MLR. By using triple labeling, we found that dopaminergic cells from the PT not only project an ascending pathway to the striatum, but send a descending projection to the MLR. In an isolated brain preparation, PT stimulation elicited excitatory synaptic inputs into patch-clamped MLR cells, accompanied by activity in reticulospinal cells. By using voltammetry coupled with electrophysiological recordings, we demonstrate that PT stimulation evoked DA release in the MLR, together with the activation of reticulospinal cells. In a semi-intact preparation, stimulation of the PT elicited reticulospinal activity together with locomotor movements. Microinjections of a D1 antagonist in the MLR decreased the locomotor output elicited by PT stimulation, whereas injection of DA had an opposite effect. It appears that this descending dopaminergic pathway has a modulatory role on MLR cells that are known to receive glutamatergic projections and promotes locomotor output. 23131800 In vitro and in vivo evaluation of an in situ gel forming system for the delivery of PEGylated octreotide. The objective of this study was to develop a controlled delivery system for PEGylated octreotide using a Poloxamer based in situ gel forming polymer. PEGylated octreotide kept its full biological activity and higher serum half-life compared to the original octreotide. The designed drug delivery system contained low concentration of Poloxamer 407 (P407) (<0.16%) with polyvinyl alcohol (PVA) as a polymeric additive. Rheological measurements of gel vehicle formulations indicated that the in situ gel forming system with optimum sol-gel transition temperature of 28.7°C could be formed using a combination of P407 and PVA at ratio of 15-10% (w/v). The effect of formulation additives such as buffering agents on rheological behavior demonstrated that sodium bicarbonate and lactic acid have opposite effect on sol-gel transition temperature of the system. Using buffering agents, it was possible to shift the sol-gel transition to lower or higher temperatures. The in vitro release profiles of octreotide and PEGylated octreotide from the selected P407/PVA formulations were measured using a membrane-less device. PEGylated octreotide showed slower release rate from the gel system with different release kinetic compared to octreotide. In animal studies, a sustained release rate was achieved with both PEGylated and non-PEGylated octreotide, but longer delivery was observed for PEGylated octreotide. Tissue histopathological studies confirmed the biocompatibility of the delivery system for PEGylated octreotide, supporting the suitability of P407/PVA mixture as an injectable drug delivery system. The total effects of increasing PEGylated peptide half-life and prolonged release from thermoresponsive gel system offer the potential for sustained delivery of PEGylated octreotide. 23908643 The role of fingers in number processing in young children. The aim of the present study was to investigate the relationship between finger counting and numerical processing in 4-7-year-old children. Children were assessed on a variety of numerical tasks and we examined the correlations between their rates of success and their frequency of finger use in a counting task. We showed that children's performance on finger pattern comparison and identification tasks did not correlate with the frequency of finger use. However, this last variable correlated with the percentages of correct responses in an enumeration task (i.e., Give-N task), even when the age of children was entered as a covariate in the analysis. Despite this correlation, we showed that some children who never used their fingers in the counting task were able to perform optimally in the enumeration task. Overall, our results support the conclusion that finger counting is useful but not necessary to develop accurate symbolic numerical skills. Moreover, our results suggest that the use of fingers in a counting task is related to the ability of children in a dynamic enumeration task but not to static tasks involving recognition or comparison of finger patterns. Therefore, it could be that the link between fingers and numbers remain circumscribed to counting tasks and do not extent to static finger montring situations. 23688711 Enhanced depth imaging optical coherence tomography of the choroid in central retinal vein occlusion. To evaluate subfoveal choroidal thickness in patients with central retinal vein occlusion (CRVO) using enhanced depth imaging optical coherence tomography. Retrospective observational study. We measured bilateral subfoveal choroidal thickness, averaged for 100 scans, in 36 patients (mean age, 66 ± 15 years; 26 women and 10 men) with unilateral CRVO by using the enhanced depth imaging methods of the Spectralis optical coherence tomography system. Twenty-two patients were treated with intravitreal bevacizumab (1.25 mg/0.05 mL), and subfoveal choroidal thickness was measured before and after treatment. Statistical analysis was performed to compare subfoveal choroidal thickness of CRVO and fellow eyes and to compare subfoveal choroidal thickness before and after intravitreal bevacizumab. Mean subfoveal choroidal thickness measured in 36 eligible eyes of 36 patients was 257.1 ± 83.2 Î¼m, which was significantly greater than that in fellow eyes (222.6 ± 67.8 Î¼m; P < .01, paired t test). There was strong correlation between CRVO eyes and fellow eyes (r = 0.79, P < .01). Mean subfoveal choroidal thickness after intravitreal bevacizumab was 227.7 ± 65.1 Î¼m, which was significantly thinner than that before intravitreal bevacizumab therapy (266.9 ± 79.0 Î¼m; P < .01, paired t test). Subfoveal choroidal thickness of CRVO eyes was significantly greater than that of fellow eyes and decreased significantly after intravitreal bevacizumab treatment. Enhanced depth imaging optical coherence tomography can be used to evaluate choroidal involvement in CRVO and may assist noninvasive diagnosis and management of this disease. 23898235 A paradoxical association of an oxytocin receptor gene polymorphism: early-life adversity and vulnerability to depression. Several prosocial behaviors may be influenced by the hormone oxytocin. In line with this perspective, the oxytocin receptor (OXTR) gene single nucleotide polymorphism (SNP), rs53576, has been associated with a broad range of social behaviors. In this regard, the G allele of the OXTR SNP has been accompanied by beneficial attributes such as increased empathy, optimism, and trust. In the current study among university students (N = 288), it was shown that early-life maltreatment was associated with depressive symptoms, and that the OXTR genotype moderated this relationship, such that under high levels of childhood maltreatment, only individuals with GG/GA genotype demonstrated increased depressive symptomatology compared to those with the AA genotype. In addition, the role of distrust in mediating the relation between childhood maltreatment and depression seemed to be more important among G allele carriers compared to individuals with the AA genotype. Thus, a breach in trust (i.e., in the case of early-life abuse or neglect) may have a more deleterious effect among G carriers, who have been characterized as more prosocial and attuned to social cues. The data suggested that G carriers of the OXTR might favor social sensitivity and thus might have been more vulnerable to the effects of early-life adversity. 23687336 Connective tissue growth factor activates pluripotency genes and mesenchymal-epithelial transition in head and neck cancer cells. The epithelial-mesenchymal transition (EMT) is a key mechanism in both embryonic development and cancer metastasis. The EMT introduces stem-like properties to cancer cells. However, during somatic cell reprogramming, mesenchymal-epithelial transition (MET), the reverse process of EMT, is a crucial step toward pluripotency. Connective tissue growth factor (CTGF) is a multifunctional secreted protein that acts as either an oncoprotein or a tumor suppressor among different cancers. Here, we show that in head and neck squamous cell carcinoma (HNSCC), CTGF promotes the MET and reduces invasiveness. Moreover, we found that CTGF enhances the stem-like properties of HNSCC cells and increases the expression of multiple pluripotency genes. Mechanistic studies showed that CTGF induces c-Jun expression through αvβ3 integrin and that c-Jun directly activates the transcription of the pluripotency genes NANOG, SOX2, and POU5F1. Knockdown of CTGF in TW2.6 cells was shown to reduce tumor formation and attenuate E-cadherin expression in xenotransplanted tumors. In HNSCC patient samples, CTGF expression was positively correlated with the levels of CDH1, NANOG, SOX2, and POU5F1. Coexpression of CTGF and the pluripotency genes was found to be associated with a worse prognosis. These findings are valuable in elucidating the interplay between epithelial plasticity and stem-like properties during cancer progression and provide useful information for developing a novel classification system and therapeutic strategies for HNSCC. 23925945 Carvacrol ameliorates thioacetamide-induced hepatotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in liver of Wistar rats. The present study was designed to investigate the protective effects of carvacrol against thioacetamide (TAA)-induced oxidative stress, inflammation and apoptosis in liver of Wistar rats. In this study, rats were subjected to concomitant prophylactic oral pretreatment of carvacrol (25 and 50 mg kg(-1) body weight (b.w.)) against the hepatotoxicity induced by intraperitoneal administration of TAA (300 mg kg(-1) b.w.). Efficacy of carvacrol against the hepatotoxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, histopathological changes, and expressions of inflammation and apoptosis. Carvacrol pretreatment prevented deteriorative effects induced by TAA through a protective mechanism in a dose-dependent manner that involved reduction of oxidative stress, inflammation and apoptosis. We found that the protective effect of carvacrol pretreatment is mediated by its inhibitory effect on nuclear factor kappa B activation, Bax and Bcl-2 expression, as well as by restoration of histopathological changes against TAA administration. We may suggest that carvacrol efficiently ameliorates liver injury caused by TAA. 23556340 Anticancer activity of the liposome-encapsulated cyclic dipeptides, cyclo(His-Gly) and cyclo(His-Ala). Cyclic dipeptides have been well characterized for their biological activity, including antimicrobial and anticancer activities. Cyclo(His-Gly) and cyclo(His-Ala) have also recently demonstrated significant anticancer activity against a range of cell lines, however, as a result of their physicochemistry, namely high solubility and low lipophilicity, it can be predicted that cellular permeability would be low, making them ideal candidates for liposome drug delivery. Liposomes were composed of phosphatidylcholine, hydrogenated soy phosphatidylcholine (HSPC), stearylamine, alpha-tocopherol and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (PEG-DSPE) or folate-polyethylene glycol-cholesteryl hemisuccinate (F-PEG-CHEMS) using the thin-film hydration method and characterized for size and encapsulation. The cytotoxic activity of the encapsulated cyclic dipeptides was tested against HeLa, low folate HeLa and MCF-7 cells and found to have limited improvement in activity. However, modification of the polyethylene glycol with folic acid to target folate receptors significantly decreased the IC50 values recorded in all cells lines tested, particularly HeLa cells cultured in media containing physiological concentrations of folic acid with the lowest IC50 being recorded as 0.0962 mM for folate-targeted cyclo(His-Ala). Therefore, hydrophilic cyclic dipeptides are ideal candidates for inclusion into targeted drug delivery systems such as liposomes. 23175451 Comparing clinicians' use of an anticoagulation management service and usual care in ambulatory oncology. Purpose: There is no consensus in the oncology community about the optimal model for anticoagulation management of ambulatory cancer patients. To understand oncologists' preferences regarding anticoagulation management, we compared the characteristics of patients referred to an oncology-oriented anticoagulation management service with "usual care" patients managed by the patient's primary oncologist. We performed a retrospective medical record review of ambulatory oncology patients' anticoagulation care at a comprehensive cancer center. We examined the characteristics of 33 patients anticoagulated before implementation of a dedicated oncology anticoagulation management service. We compared this group with 33 patients managed by the anticoagulation management service and with 39 usual care patients managed by the primary oncologist after the anticoagulation management service was created. We also examined differences in laboratory test utilization, time in the therapeutic range (for patients anticoagulated with warfarin), and anticoagulation-related adverse events during a 3-month assessment period. Anticoagulation management service patients were more likely to be treated for hematologic malignancies, use erythropoietin stimulating agents, and require warfarin management for previous venous thromboembolic disease compared to usual care patients. In contrast, oncologists were more likely to manage anticoagulation care of patients with advanced solid tumors undergoing active chemotherapy. Anticoagulation management service and usual care patients on warfarin therapy had comparable time in the therapeutic range and complication rates. Oncologists selectively referred patients to the anticoagulation management service. Anticoagulation management service patients' warfarin control and complication rates were comparable to care provided by the primary oncologist, suggesting that an oncology-specific anticoagulation management service may be a feasible and effective option for anticoagulation management of ambulatory oncology patients. 23623839 Production of Cyr61 protein is modulated by extracellular acidification and PI3K/Akt signaling in prostate carcinoma PC-3 cells. High expression of Cyr61, an extracellular cysteine-rich heparin-binding protein, has been associated with a malignant cell phenotype and poor outcome in prostate cancers. Although Cyr61 was found by us to be overproduced in androgen-independent PC-3 cells treated with N-acetylcysteine (NAC), its significance is still unclear. We therefore aimed to determine how and why Cyr61 protein is overexpressed in NAC-treated cells. Here, we found that Cyr61 protein level markedly increased in cells treated with NAC at high cell seeding density. Silencing of Cyr61 by siRNA induced enhanced activity of caspase-3/7, upregulation of the proapototic Bok, BimL and BimS, cleavage of apoptosis hallmarkers such as Bax, PARP and caspase-3, and downregulation of antiapoptotic Bcl2, Bcl-xL and Mcl-1 proteins. NAC treatment caused a reduction of extracellular medium pH to acidic and an increase in Akt phosphorylation, after which the replacement with NAC-free medium returned them to control levels within 24h. Acid stimulation increased the levels of Cyr61 and p-Akt proteins, whereas it suppressed the induction of proapoptotic and antiapoptotic proteins. Overall, our data indicate that PC-3 cells overproduce Cyr61 protein via activation of the PI3K/Akt signaling as a part of the survival mechanisms under the conditions causing extracellular acidity and further cytotoxicity. 23291325 Toxic effects of lead exposure in Wistar rats: involvement of oxidative stress and the beneficial role of edible jute (Corchorus olitorius) leaves. Lead (Pb) is considered to be a multi-target toxicant. The present study was undertaken to evaluate the protective effect of aqueous extract of Corchorus olitorius leaves against Pb-acetate induced toxic manifestation in blood, liver, kidney, brain and heart of Wistar rats. The Pb-acetate (5mg/kg body weight) treated rats exhibited a significant inhibition of co-enzymes Q, antioxidant enzymes and reduced glutathione levels in the tissues. In addition, the extent of lipid peroxidation, DNA fragmentation and haematological parameters were significantly altered in the Pb-acetate treated rats as compared to control. Simultaneous administration of test extract (25, 50 and 100mg/kg body weight), could significantly restore the biochemical and haematological parameters near to the normal status through antioxidant activity and/or by preventing bioaccumulation of Pb within the tissues of experimental rats. Presence of substantial quantity of phenolics and flavonoids in the extract may be responsible for the observed protective role against Pb-intoxication. 23027385 The organometallic chemistry of cycloheptatrienyl zirconium complexes. This tutorial review summarizes the organometallic chemistry derived from the half-sandwich complex [(η(7)-C(7)H(7))ZrCl(tmeda)], which was used as an efficient and versatile starting material for the incorporation of monoanionic ligands into the cycloheptatrienyl zirconium coordination sphere by conventional salt metathesis reactions. A broad variety of ligands was employed, affording novel and previously inaccessible cycloheptatrienyl (sandwich) complexes of the type [(η(7)-C(7)H(7))Zr(Y)]; Y comprises pentadienyl, cyclopentadienyl, allyl, phospholyl, boratabenzene, imidazolin-2-iminato and amido systems. The cycloheptatrienyl ring in these systems usually acts as an "innocent spectator ligand", but reactivity can arise from the second ligand Y or the Lewis acidity of the, formally, Zr(+iv) center, which was probed in selected examples and put in perspective to related studies. The corresponding results emphasize why the use of [(η(7)-C(7)H(7))ZrCl(tmeda)] is clearly an advancement in the chemistry of the still fairly unexplored area of cycloheptatrienyl transition metal complexes. 23388064 Comparison of independent and combined metabolic effects of chronic treatment with (pGlu-Gln)-CCK-8 and long-acting GLP-1 and GIP mimetics in high fat-fed mice. The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and cholecystokinin (CCK) are gastrointestinal peptides with important physiological effects. However, rapid enzymatic degradation results in short-lived biological actions. This study has examined metabolic actions of exendin-4, GIP[mPEG] and a novel CCK-8 analogue, (pGlu-Gln)-CCK-8 as enzymatically stable forms of GLP-1, GIP and CCK, respectively. All peptides significantly (p < 0.01-p < 0.001) stimulated insulin secretion from BRIN BD11 cells, and acute in vivo experiments confirmed prominent antihyperglycaemic and insulinotropic responses to GLP-1 or GIP receptor activation in normal mice. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with exendin-4 or GIP[mPEG] in high fat-fed mice significantly decreased accumulated food intake (p < 0.05-p < 0.01), body weight gain (p < 0.05-p < 0.01) and improved (p < 0.05) insulin sensitivity in high fat-fed mice. However, there was no evidence for superior effects compared to (pGlu-Gln)-CCK-8 alone. Combined treatment of (pGlu-Gln)-CCK-8 and exendin-4 resulted in significantly (p < 0.05) lowered circulating glucose levels and improved (p < 0.05) intraperitoneal glucose tolerance. These effects were superior to either treatment regime alone but not associated with altered insulin concentrations. A single injection of (pGlu-Gln)-CCK-8, or combined with exendin-4, significantly (p < 0.05) lowered blood glucose levels 24 h post injection in untreated high fat-fed mice. This study highlights the potential of (pGlu-Gln)-CCK-8 alone and in combination with incretin hormones for the treatment of type 2 diabetes. 23590666 Trends in the utilization of percutaneous and open nephrolithotomy in the treatment of renal calculi. Abstract Purpose: To evaluate trends in the use of percutaneous nephrolithotomy (PCNL) and nephrolithotomy (NL) in patients with renal pelvis calculi. Materials and Methods: An analysis of the 5% Medicare Public Use Files (years 2001, 2004, 2007, and 2010) was performed to assess changes in the use of PCNL and NL over a 10-year period. Patients were identified using the International Classification of Diseases-9 (cm) and Current Procedure Terminology codes. Statistical analyses, including the Fisher and chi-square tests and multivariate regression analyses, were performed using SAS 9.3 (SAS Institute Inc, Cary, NC) and SPSS v20 (IBM Corp., Armonk, NY). Results: A total of 26,100 patients underwent either PCNL or NL. Use of PCNL and NL decreased from 3.1% to 2.5% in patients with a diagnosis of stones (P<0.0001). Women (odds ration [OR]=1.19, P=0.003) were more likely to undergo surgery. Patients aged ≥65 years were less likely to be treated (OR=0.65-0.71, P<0.05). Patients treated after 2004 were less likely to undergo surgery (OR=0.77-0.84, P<0.05). The use of PCNL exceeded NL at a stable 10:1 ratio. Conclusions: The use of PCNL and NL for treatment of patients with stone disease slightly decreased from 2001 to 2010, although the number of patients with renal calculi increased. The use of PCNL vs NL was unchanged during this period. Multiple inequalities existed in overall surgical treatment rates and were influenced by sociodemographic factors such as age and sex. 23860308 Karl Jaspers' Multiperspectivalism. In later editions of his General Psychopathology, Karl Jaspers prescribes many different methods and theoretical points of view for psychopathologists to utilize. Each of these perspectives on the subject matter of psychopathology, however, gives the investigator access to only one dimension of the patient's being. Hence, Jaspers insists that several different perspectives must be employed in order to avoid a one-sided and partial comprehension of the patient and his or her problem. He advocates a multiperspectival approach in psychopathology. Nevertheless, Jaspers remains aware that the patient is a unified whole. This unified whole, however, is not knowable as such, but can rather be approached only under the guidance of an 'idea' of the whole. Jaspers takes the basic notion of 'idea' (Idee) from Kant, but he modifies and uses it for his own purposes. Jaspers' multiperspectivalism may seem to invite charges of relativism because it leaves the psychopathologist to 'pick and choose' any method or theory he or she prefers. This charge is addressed by admitting that there does exist a certain relativism in Jaspers' position in that any one perspective does provide only one approach to the reality of the patient and that other equally useful perspectives could have been chosen. However, each perspective itself can be subjected to test by evidence, and in such tests, claims made from that perspective can be found to be true or false. Helen Longino's theory of scientific knowledge helps support such a thesis. © 2013 S. Karger AG, Basel. 22833344 A multicenter, phase II study of epirubicin/cyclophosphamide followed by docetaxel and concurrent trastuzumab as primary systemic therapy for HER-2 positive advanced breast cancer (the HER2NAT study). The outcome in patients with human epidermal growth factor receptor-2 (HER-2)-positive locally advanced breast cancer may be improved by integrating trastuzumab with primary systemic therapy (PST). The efficacy and safety of PST comprising EC (epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2), four cycles every 3 weeks) followed by docetaxel (75 mg/m(2), four cycles every 3 weeks) and concurrent trastuzumab (loading dose 4 mg/kg followed by 2 mg/kg, 12 cycles every week) was investigated in a multicenter, prospective, phase II study in patients with HER-2-positive stage IIIB/IIIC/IV breast cancer. The primary endpoint was pathologic complete response (pCR) including the tumor intraductal component confirmed by central pathologic review. In total, 38 patients were enrolled (stage IIIB, 63.2 %; IIIC, 23.7 %; IV, 13.2 %; estrogen receptor- and/or progesterone receptor-positive, 47.4 %). The pCR rate was 16.2 % in the primary tumor (six of 37 patients in the Full Analysis Set) and 56.8 % (21/37) in the ipsilateral axillary lymph nodes. Treatment was given according to protocol in 28 of 37 patients; six of 28 in the Per-Protocol Set achieved pCR (21.4 %). The clinical response rate was 67.6 % (25/37 patients; complete response, 13.5 %; partial response, 54.1 %). No patients developed congestive heart failure; however, three patients had a non-symptomatic decrease of >10 % of left ventricular ejection fraction. PST including concurrent use of trastuzumab combined with docetaxel is effective and well-tolerated in HER-2-positive advanced breast cancer patients, including those patients requiring mastectomy for local control. 23517501 1,4,2-Benzo/pyridodithiazine 1,1-Dioxides Structurally Related to the ATP-Sensitive Potassium Channel Openers 1,2,4-Benzo/pyridothiadiazine 1,1-Dioxides Exert a Myorelaxant Activity Linked to a Distinct Mechanism of Action. The synthesis of diversely substituted 3-alkyl/aralkyl/arylamino-1,4,2-benzodithiazine 1,1-dioxides and 3-alkylaminopyrido[4,3-e]-1,4,2-dithiazine 1,1-dioxides is described. Their biological activities on pancreatic β-cells and on smooth muscle cells were compared to those of the reference ATP-sensitive potassium channel (KATP channel) openers diazoxide and 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide. The aim was to assess the impact on biological activities of the replacement of the 1,2,4-thiadiazine ring by an isosteric 1,4,2-dithiazine ring. Most of the dithiazine analogues were found to be inactive on the pancreatic tissue, although some compounds bearing a 1-phenylethylamino side chain at the 3-position exerted a marked myorelaxant activity. Such an effect did not appear to be related to the opening of KATP channels but rather reflected a mechanism of action similar to that of calcium channel blockers. Tightly related 3-(1-phenylethyl)sulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxides were also found to exert a pronounced myorelaxant activity, resulting from both a KATP channel activation and a calcium channel blocker mechanism. The present work highlights the critical importance of an intracyclic NH group at the 4-position, as well as an exocyclic NH group linked to the 3-position of the benzo- and pyridothiadiazine dioxides, for activity on KATP channels. 23869240 Triglyceride/HDL Ratio as a Screening Tool for Predicting Success at Reducing Anti-Diabetic Medications Following Weight Loss. Intentional weight loss, by reducing insulin resistance, results in both better glycemic control and decreased need for anti-diabetic medications. However, not everyone who is successful with weight loss is able to reduce anti-diabetic medication use. In this retrospective cohort study, we assessed the predictive accuracy of baseline triglyceride (TGL)/HDL ratio, a marker of insulin resistance, to screen patients for success in reducing anti-diabetic medication use with weight loss. Case records of 121 overweight and obese attendees at two outpatient weight management centers were analyzed. The weight loss intervention consisted of a calorie-restricted diet (~1000Kcal/day deficit), a behavior modification plan, and a plan for increasing physical activity. Mean period of follow-up was 12.5 ± 3.5 months. By study exit, mean weight loss and mean HbA1c% reduction were 15.4 ± 5.5 kgs and 0.5 ± 0.2% respectively. 81 (67%) in the study cohort achieved at least 1 dose reduction of any anti-diabetic medication. Tests for predictive accuracy of baseline TGL/HDL ratio ≤ 3 to determine success with dose reductions of anti-diabetic medications showed a sensitivity, specificity, positive predictive value, negative predictive value, area under the curve, likelihood ratio (LR) + and LR-of 81, 83, 90, 70, 78, 4.8 and 0.2, respectively. Reproducibility of TGL/HDL ratio was acceptable. TGL/HDL ratio shows promise as an effective screening tool to determine success with dose reductions of anti-diabetic medications. The results of our study may inform the conduct of a systematic review using data from prior weight loss trials. 23847093 Determination of hypoglycaemia induced by insulin or its synthetic analogues post mortem. The determination of human insulin or its synthetic analogues in post-mortem specimens represents a challenge for forensic toxicologists due to its proven instability in post-mortem blood. We present two cases of an insulin-induced hypoglycaemia. In the first case, ante-mortem material was available for the detection of an injection with human insulin. Human insulin was detected by immunopurification with magnetic beads and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses at a concentration of 5180 μU/ml. The molar ratio human insulin:C-peptide was 111. The second case describes a suicide by self-injection of Insulin lispro and determination of the drug after pre-extraction with methanol and immunopurification by LC-MS/MS at the injection site, in vitreous humour and organs. Apart from the well-known matrices - femoral blood and urine - the specimen vitreous humour and the injection site promise the best possibilities for a proof of insulin at autopsy. In addition to insulin analyses, the parameters C-peptide, proinsulin, glucose, lactate, and sulfonylureas should be measured in case of suspected fatal hypoglycaemia. Copyright © 2013 John Wiley & Sons, Ltd. 23649928 Functional Analysis of a De Novo ACTB Mutation in a Patient with Atypical Baraitser-Winter Syndrome. Exome sequence analysis can be instrumental in identifying the genetic etiology behind atypical disease. We report a patient presenting with microcephaly, dysmorphic features, and intellectual disability with a tentative diagnosis of Dubowitz syndrome. Exome analysis was performed on the patient and both parents. A de novo missense variant was identified in ACTB, c.349G>A, p.E117K. Recent work in Baraitser-Winter syndrome has identified ACTB and ACTG1 mutations in a cohort of individuals, and we rediagnosed the patient with atypical Baraitser-Winter syndrome. We performed functional characterization of the variant actin and show that it alters cell adhesion and polymer formation supporting its role in disease. We present the clinical findings in the patient, comparison of this patient to other patients with ACTB/ACTG1 mutations, and results from actin functional studies that demonstrate novel functional attributes of this mutant protein. 23793889 Autonomic dysfunction in ICU-acquired weakness: a prospective observational pilot study. Intensive care unit-acquired weakness (ICU-AW) is a frequent complication of critical illness. It is unknown if patients with ICU-AW also have autonomic dysfunction, another frequent neurological complication of critical illness. We hypothesized that patients who develop ICU-AW also develop autonomic dysfunction. Furthermore, we hypothesized that patients with ICU-AW are more prone to develop autonomic dysfunction compared to patients without ICU-AW. This was an observational cohort study of patients newly admitted to the ICU. Autonomic dysfunction was measured daily using heart rate variability (HRV) to a maximum of 15 days after admission. ICU-AW was diagnosed using the Medical Research Council score. Abnormal HRV was defined using age-matched reference values. The association between ICU-AW and HRV was analyzed using linear mixed effects models. We included 83 patients, 15 (18 %) of whom were diagnosed with ICU-AW. Of 279 HRV measurements, 204 could be analyzed. Abnormal HRV was found in all critically ill patients irrespective of the presence of ICU-AW (ICU-AW 100 % (IQR 71-100) vs. no ICU-AW 100 % (IQR 40-100); p = 0.40). Mechanical ventilation, sedation, norepinephrine, heart rate, and HRV artifacts were identified as confounders for HRV. ICU-AW was not associated with HRV. Abnormal HRV is frequent in critically ill patients, both with and without ICU-AW. It is unlikely that patients with ICU-AW are more prone to develop abnormal HRV. However, we found that abnormal HRV may not be an accurate indicator of autonomic dysfunction because of confounders. 23542451 Growth hormone-releasing hormone-producing pancreatic neuroendocrine tumor in a multiple endocrine neoplasia type 1 family with an uncommon phenotype. The objective of this study was to describe a multiple endocrine neoplasia type 1 (MEN1) family characterized by primary hyperparathyroidism, in association with acromegaly because of ectopic growth hormone-releasing hormone (GHRH) secretion by a pancreatic neuroendocrine tumor in a young man and with a bronchial carcinoid in his mother. We investigate the clinical, radiological imaging, histopathologic findings, and therapy. An 18-year-old man successfully underwent subtotal parathyroidectomy for primary hyperparathyroidism. A subsequent genetic analysis showed a MEN1 gene mutation. Three years later, acromegaly because of ectopic GHRH secretion was diagnosed (pituitary MRI negative and elevated GHRH levels). A search for an ectopic tumor was unsuccessful and somatostatin analog therapy was started. Successively, scintigraphy with somatostatin analogs (68-Ga-DOTATOC-PET) showed three focal areas in the pancreatic tail. Distal pancreatectomy showed multiple pancreatic neuroendocrine tumors and hormonal status was normalized. Afterwards, the evaluation of the patient's mother, carrying the same mutation, indicated a primary hyperparathyroidism and a 4 cm lung mass. The patient underwent subtotal pneumonectomy and the histological analysis was consistent with the diagnosis of a typical bronchial carcinoid. In conclusion, an atypical phenotype may be recorded in MEN1 families, thus emphasizing the importance of the new imaging and surgical techniques in the diagnosis and treatment of such a rare disease. 23341167 Novel type II fatty acid biosynthesis (FAS II) inhibitors as multistage antimalarial agents. Malaria is a potentially fatal disease caused by Plasmodium parasites and poses a major medical risk in large parts of the world. The development of new, affordable antimalarial drugs is of vital importance as there are increasing reports of resistance to the currently available therapeutics. In addition, most of the current drugs used for chemoprophylaxis merely act on parasites already replicating in the blood. At this point, a patient might already be suffering from the symptoms associated with the disease and could additionally be infectious to an Anopheles mosquito. These insects act as a vector, subsequently spreading the disease to other humans. In order to cure not only malaria but prevent transmission as well, a drug must target both the blood- and pre-erythrocytic liver stages of the parasite. P. falciparum (Pf) enoyl acyl carrier protein (ACP) reductase (ENR) is a key enzyme of plasmodial type II fatty acid biosynthesis (FAS II). It has been shown to be essential for liver-stage development of Plasmodium berghei and is therefore qualified as a target for true causal chemoprophylaxis. Using virtual screening based on two crystal structures of PfENR, we identified a structurally novel class of FAS inhibitors. Subsequent chemical optimization yielded two compounds that are effective against multiple stages of the malaria parasite. These two most promising derivatives were found to inhibit blood-stage parasite growth with IC(50) values of 1.7 and 3.0 μM and lead to a more prominent developmental attenuation of liver-stage parasites than the gold-standard drug, primaquine. 23633165 Training transfer: scientific background and insights for practical application. Training transfer as an enduring, multilateral, and practically important problem encompasses a large body of research findings and experience, which characterize the process by which improving performance in certain exercises/tasks can affect the performance in alternative exercises or motor tasks. This problem is of paramount importance for the theory of training and for all aspects of its application in practice. Ultimately, training transfer determines how useful or useless each given exercise is for the targeted athletic performance. The methodological background of training transfer encompasses basic concepts related to transfer modality, i.e., positive, neutral, and negative; the generalization of training responses and their persistence over time; factors affecting training transfer such as personality, motivation, social environment, etc. Training transfer in sport is clearly differentiated with regard to the enhancement of motor skills and the development of motor abilities. The studies of bilateral skill transfer have shown cross-transfer effects following one-limb training associated with neural adaptations at cortical, subcortical, spinal, and segmental levels. Implementation of advanced sport technologies such as motor imagery, biofeedback, and exercising in artificial environments can facilitate and reinforce training transfer from appropriate motor tasks to targeted athletic performance. Training transfer of motor abilities has been studied with regard to contralateral effects following one limb training, cross-transfer induced by arm or leg training, the impact of strength/power training on the preparedness of endurance athletes, and the impact of endurance workloads on strength/power performance. The extensive research findings characterizing the interactions of these workloads have shown positive transfer, or its absence, depending on whether the combinations conform to sport-specific demands and physiological adaptations. Finally, cross-training as a form of concurrent exercising in different athletic disciplines has been examined in reference to the enhancement of general fitness, the preparation of recreational athletes, and the preparation of athletes for multi-sport activities such as triathlon, duathlon, etc. 23893638 Identification and quantification of different species in animal fibres by LC/ESI-MS analysis of keratin-derived proteolytic peptides. In the present paper, a proteomic method for species determination in fibres has been developed. Keratin was extracted from yak, wool and cashmere fibres and digested by trypsin, providing peptide mixtures that were analyzed by liquid chromatography coupled with electrospray mass spectrometry (LC/ESI-MS) in order to identify peptidic species-specific markers able to differentiate the fibres. Several suitable peptide markers were identified and validated in different fibres of different origin and having undergone different technological treatments, showing 100% specificity and 100% selectivity. Most of the peptide markers were also identified by means of high-resolution mass spectrometry, confirming the origin from species-specific keratin sequences. Some peptides were also used for the quantification of the different species in mixed fibres by LC/ESI-MS. Validation experiments and blind tests confirmed their ability to act as very specific quantitative and qualitative markers. The method here developed is a valid complement to the standard benchmark methods for fibre identification and quantification and will be very useful for assessing the authenticity of textile products. Copyright © 2013 John Wiley & Sons, Ltd. 23564915 Adding Once-Daily Lixisenatide for Type 2 Diabetes Inadequately Controlled With Newly Initiated and Continuously Titrated Basal Insulin Glargine: A 24-week, randomized, placebo-controlled study (GetGoal-Duo 1). OBJECTIVE When oral therapy for type 2 diabetes is ineffective, adding basal insulin improves glycemic control. However, when glycated hemoglobin (HbA1c) remains elevated because of postprandial hyperglycemia, the next therapeutic step is controversial. We examined the efficacy and safety of lixisenatide in patients with HbA1c still elevated after initiation of insulin glargine. RESEARCH DESIGN AND METHODS This double-blind, parallel-group trial enrolled patients with HbA1c 7-10% despite oral therapy. Insulin glargine was added and systematically titrated during a 12-week run-in, after which candidates with fasting glucose ≤7.8 mmol/L and HbA1c 7-9% were randomized to lixisenatide 20 µg or placebo for 24 weeks while insulin titration continued. The primary end point was HbA1c change after randomization. RESULTS The randomized population (n = 446) had mean diabetes duration of 9.2 years, BMI 31.8 kg/m(2), and daily glargine dosage of 44 units. HbA1c had decreased during run-in from 8.6 to 7.6%; adding lixisenatide further reduced HbA1c by 0.71 vs. 0.40% with placebo (least squares mean difference, -0.32%; 95% CI, -0.46 to -0.17; P < 0.0001). More participants attained HbA1c <7% with lixisenatide (56 vs. 39%; P < 0.0001). Lixisenatide reduced plasma glucose 2 h after a standardized breakfast (difference vs. placebo -3.2 mmol/L; P < 0.0001) and had a favorable effect on body weight (difference vs. placebo -0.89 kg; P = 0.0012). Nausea, vomiting, and symptomatic hypoglycemia <3.3 mmol/L were more common with lixisenatide. CONCLUSIONS Adding lixisenatide to insulin glargine improved overall and postprandial hyperglycemia and deserves consideration as an alternative to prandial insulin for patients not reaching HbA1c goals with recently initiated basal insulin. 23275348 The naphthoquinone diospyrin is an inhibitor of DNA gyrase with a novel mechanism of action. Tuberculosis and other bacterial diseases represent a significant threat to human health. The DNA topoisomerases are excellent targets for chemotherapy, and DNA gyrase in particular is a well-validated target for antibacterial agents. Naphthoquinones (e.g. diospyrin and 7-methyljuglone) have been shown to have therapeutic potential, particularly against Mycobacterium tuberculosis. We have found that these compounds are inhibitors of the supercoiling reaction catalyzed by M. tuberculosis gyrase and other gyrases. Our evidence strongly suggests that the compounds bind to the N-terminal domain of GyrB, which contains the ATPase active site, but are not competitive inhibitors of the ATPase reaction. We propose that naphthoquinones bind to GyrB at a novel site close to the ATPase site. This novel mode of action could be exploited to develop new antibacterial agents. 23841672 Simultaneous Analysis of Trace Polymer Additives in Plastic Beverage Packaging by Solvent Sublation Followed by High-Performance Liquid Chromatography. Using solvent sublation (SS), a novel pretreatment method for separating and concentrating antioxidants and ultraviolet absorbers from plastic beverage packaging was developed, and these target compounds were quantitatively analyzed by high-performance liquid chromatography (HPLC). In the pretreatment section, the effects of the sublation solvent, solution pH, NaCl concentration, nitrogen flow rate, sublation time, and light condition on the sublation efficiency were investigated in detail and the optimal conditions of the solvent sublation process were selected. The analytical method of SS-HPLC showed good linearity in the range from 0.33 to 667 ng/mL with good presenting regression coefficients (0.9995 ≥ R(2) ≥ 0.9972). Low limits of detection (LODs) of 0.34-1.25 ng/mL and limits of quantification (LOQs) of 1.13-4.15 ng/mL were achieved. The mean recoveries were in the range from 88.73 to 107.65% at 20, 30, and 40 ng/mL spiked levels, and the relative standard deviations (RSDs) were in the range from 2.16 to 10.55%. 23149549 Characterization of cultured epithelial cells using a novel technique not requiring enzymatic digestion for subculturing. Our laboratory had developed a methodology to expand epithelial cells in culture by growing keratinocyte monolayers, under large volumes of medium that produces large numbers of keratinocytes that leave the monolayer and move into suspension. The cells have been defined as epithelial Pop Up Keratinocytes or ePUKs cells and appear to be highly suitable for clinical applications. In this publication we extend the characterization of the cells with a detailed analysis of the capabilities of the monolayer of a single culture flask to produce, over time, ePUK cells. The cells were characterized using standard epithelial markers for proliferation and differentiation. Analysis of morphology of the monolayer formed and total number of cells produced is presented for a variety of human epithelial cell strains. These keratinocytes provide an additional controlled human cell system for investigation of the mechanisms regulating epithelia cell growth and differentiation and since they are produced in large numbers, they are highly suitable for use in epithelial cell banking. 23514379 Serotonin - kynurenine hypothesis of depression: historical overview and recent developments. This mini-review focuses on the studies of late Prof. IP Lapin (1903 - 2012) and his research team on the role of methoxyindole and kynurenine (KYN) pathways of tryptophan (TRP) metabolism in the pathogenesis of depression and action mechanisms of antidepressant effect. In the late 60s of the last century Prof. IP Lapin suggested that "intensification of central serotoninergic processes is a determinant of the thymoleptic (mood elevating) component" while "activation of noradrenergic processes is responsible for psychoenergetic and motor-stimulating component of the clinical antidepressant effect". The cause of serotonin deficiency in depression was attributed to the shunt of TRP "metabolism away from serotonin production towards KYN production" due to cortisol-induced activation of liver enzyme, tryptophan 2,3- dioxygenase, the rate-limiting enzyme of TRP - KYN pathway. Prof. Lapin suggested and discovered that KYN and its metabolites affect brain functions, and proposed the role of neurokynurenines in pathogenesis of depression and action mechanisms of antidepressant effect (kynurenine hypothesis). Further research suggested the antidepressant and cognition- enhancing effects of post-serotonin metabolite, N-acetylserotonin (NAS), an agonist to tyrosine kinase B (TrkB) receptor; and link between depression and chronic inflammation-associated disorders (e.g., insulin resistance, hepatitis C virus) via inflammation-induced activation of indoleamine 2,3- dioxygenase, brain located rate-limiting enzyme of TRY - KYN metabolism. NAS and kynurenines might be the targets for prevention and treatment of depression and associated conditions. 23815588 Colloidal polarization of yolk/shell particles by reconfiguration of inner cores responsive to an external magnetic field. Yolk/shell particles, which were hollow silica particles containing a movable magnetic silica core (MSC), were prepared by removing a middle polystyrene layer from multilayered particles of MSC/polystyrene/silica shell with heat treatment followed by a slight etching with a basic solution. An ac electric field was applied to the suspension of the yolk/shell particles to form pearl chains (1D structure) of yolk/shell particles. Observation with an optical microscope showed that the MSCs in the silica compartment of the pearl chains had a zigzag structure under the electric field. An external magnetic field applied to the suspension could form a novel structure of doublet MSC in the shell compartment of the quasi-pearl chain structure. Application of a magnetic field was also performed for 2D hexagonally close-packed assemblies of the yolk/shell particles, which could two-dimensionally form a doublet structure of MSCs as if they were polarized in the compartment. Switching on/off the magnetic field successfully controlled the positional ordering of cores in the consolidated silica shell. 23912708 Combination of Ad-sTRAIL with the chemotherapeutic drug cisplatin synergistically enhances their pro-apoptotic ability in human breast cancer cells. Tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand (TRAIL or Apo2L) is a member of the tumor necrosis factor superfamily that induces apoptosis in various cancer cell types but not in most normal cells. However, it is clear that not all cancer cells are sensitive to the killing effects of TRAIL, including breast cancer. Previous studies have demonstrated that chemotherapeutic drugs sensitize tumor cells to apoptosis induced by TRAIL in several types of malignancies. In the present study, we studied the effects of TRAIL combined with cisplatin on two breast cancer cell lines MDA-MB-468 and HCC-1937 in vitro. MTT assay, crystal violet staining assay, DAPI staining assay and flow cytometric analysis were undertaken to evaluate the enhancement of breast cancer cell death using Ad-sTRAIL and/or cisplatin. The levels of apoptotic molecules in signal transduction pathways were analyzed by real-time RT-PCR and western blotting. We found that co-treatment with Ad-sTRAIL and cisplatin exhibited stronger cytotoxicity and induced more significant apoptosis in breast cancer cells compared with Ad-sTRAIL or cisplatin alone. Pretreatment with cisplatin significantly enhanced the expression of DR5. Moreover, the induction of apoptosis by TRAIL plus cisplatin was accompanied by the downregulation of cFLIP and BCL2L1, and simultaneously robust enzymatic activation of caspase-8, culminating in decreased cancer cell survival. The present study revealed that TRAIL conjugated with cisplatin exhibited a markedly increased cytotoxic and apoptosis-inducing effect on breast cancer cells. 23541515 The influence of the BCL11A polymorphism on the phenotype of patients with beta thalassemia could be affected by the beta globin locus control region and/or the Xmn1-HBG2 genotypic background. To study the influence of the β globin locus control region (LCR) genotypic background on the phenotype modifying role of BCL11A polymorphisms, 100 cases of thalassemia, 48 homozygous for the A allele and 52 homozygous for the G allele at the 5'HS4-LCR palindromic polymorphic site were genotyped for two BCL11A single nucleotide polymorphisms (rs11886868 and rs766432) in the intronic region of this gene. The effect of these polymorphisms on HbF variation was also examined in 122 normal individuals. The 5'HS4-LCR had the most significant role in determining the phenotype of these thalassemia patients. BCL11A polymorphisms showed a significant role in determining the phenotype of patients homozygous for the G allele at 5'HS4-LCR. However, the majority of patients homozygous for the A allele at 5'HS4-LCR, showed a severe phenotype, regardless of the BCL11A genotype. These results, without undermining the strength of BCL11A as a silencer of the γ globin gene, suggest that the LCR background, by governing the state of BCL11A binding to this region, plays a more significant role in determining the thalassemia phenotype than the level of BCL11A protein expression, that might be influenced by single nucleotide polymorphisms in intronic regions of the BCL11A gene. Functional studies to confirm the interactions between BCL11A and LCR could be useful in designing pharmacogenetic strategies for the treatment of beta thalassemia major. 23881623 Functional MRI and outcome in traumatic coma. Advances in task-based functional MRI (fMRI), resting-state fMRI (rs-fMRI), and arterial spin labeling (ASL) perfusion MRI have occurred at a rapid pace in recent years. These techniques for measuring brain function have great potential to improve the accuracy of prognostication for civilian and military patients with traumatic coma. In addition, fMRI, rs-fMRI, and ASL perfusion MRI have provided novel insights into the pathophysiology of traumatic disorders of consciousness, as well as the mechanisms of recovery from coma. However, functional neuroimaging techniques have yet to achieve widespread clinical use as prognostic tests for patients with traumatic coma. Rather, a broad spectrum of methodological hurdles currently limits the feasibility of clinical implementation. In this review, we discuss the basic principles of fMRI, rs-fMRI, and ASL perfusion MRI and their potential applications as prognostic tools for patients with traumatic coma. We also discuss future strategies for overcoming the current barriers to clinical implementation. 23803409 A novel activation-induced cytidine deaminase (AID) mutation in Brazilian patients with hyper-IgM type 2 syndrome. Activation-induced cytidine deaminase (AID) is a DNA editing protein that plays an essential role in three major events of immunoglobulin (Ig) diversification: somatic hypermutation, class switch recombination and Ig gene conversion. Mutations in the AID gene (AICDA) have been found in patients with autosomal recessive Hyper-IgM (HIGM) syndrome type 2. Here, two 9- and 14-year-old Brazilian sisters, from a consanguineous family, were diagnosed with HIGM2 syndrome. Sequencing analysis of the exons from AICDA revealed that both patients are homozygous for a single C to G transversion in the third position of codon 15, which replaces a conserved Phenylalanine with a Leucine. To our knowledge, this is a new AICDA mutation found in HIGM2 patients. Functional studies confirm that the homologous murine mutation leads to a dysfunctional protein with diminished intrinsic cytidine deaminase activity and is unable to rescue CSR when introduced in Aicda(-/-)stimulated murine B cells. We briefly discuss the relevance of AICDA mutations found in patients for the biology of this molecule. 23936081 Environmental and Parental Influences on Offspring Health and Growth in Great Tits (Parus major). Sexual selection requires both that there is heritable variation in traits related to fitness, and that either some of this variation is linked to traits of the parents, and/or that there are direct benefits of choosing particular individuals as mates. This suggests that if direct benefits are important offspring performance should be predicted by traits of the rearing adults. But if indirect benefits are more significant offspring performance should be predicted by traits of the adults at the nest-of-origin. We conducted cross-fostering experiments in great tits (Parus major) over four years, in two of which we manipulated environmental conditions by providing supplemental food. In a third year, some nestlings were directly supplemented with carotenoids. Nestlings in broods whose rearing adults received supplemental food were heavier and had improved immune responses even when controlling for body mass. Nestling immune function was related to measures of the yellow plumage color of both the rearing male and the putative father. Nestling body mass was influenced by the coloration of both the rearing female and the genetic mother. Our results suggest that features of both their social and putative genetic parents influence nestling health and growth. From this it would appear that females could be gaining both direct and indirect benefits through mate choice of male plumage traits and that it would be possible for males to similarly gain through mate choice of female traits. 23885048 Effects of vitamin C and vitamin D administration on mood and distress in acutely hospitalized patients. Hypovitaminosis C and D are highly prevalent in acute-care hospitals. Malnutrition with regard to these vitamins has been linked to mood disturbance and cognitive dysfunction. The objective was to determine whether vitamin C or D supplementation improves mood state or reduces psychological distress in acutely hospitalized patients with a high prevalence of hypovitaminosis C and D. A randomized, double-blind, active-control clinical trial compared the effects of vitamin C (500 mg twice daily) with those of high-dose vitamin D (5000 IU/d) on mood (Profile of Mood States) and psychological distress (Distress Thermometer). Vitamin C provided for a mean of 8.2 d increased plasma vitamin C concentrations to normal (P < 0.0001) and was associated with a 71% reduction in mood disturbance (P = 0.0002) and a 51% reduction in psychological distress (P = 0.0002). High-dose vitamin D provided for a mean of 8.1 d increased plasma 25-hydroxyvitamin D [25(OH)D] concentrations (P < 0.0001), but not into the normal range, and had insignificant effects on mood (P = 0.067) and distress (P = 0.45). The changes in mood and distress in the vitamin C group were greater than those in the vitamin D group (P = 0.045 for mood; P = 0.009 for distress). Short-term therapy with vitamin C improves mood and reduces psychological distress in acutely hospitalized patients with a high prevalence of hypovitaminosis C and D. No conclusion is possible regarding the effects of vitamin D because the dose and duration of therapy were insufficient to raise 25(OH)D concentrations into the normal range. This trial was registered at clinicaltrials.gov as NCT01630720. 23316003 Study of intracellular delivery of doxorubicin from poly(lactide-co-glycolide) nanoparticles by means of fluorescence lifetime imaging and confocal Raman microscopy. The intracellular delivery of Doxorubicin (Dox) from poly(lactide-co-glycolide) (PLGA) nanoparticles stabilised with bovine serum albumin, in HepG2 cells, is studied via flow cytometry, fluorescence lifetime imaging microscopy (FLIM), confocal Raman microscopy (CRM) and cell viability studies. Flow cytometry shows that the initial uptake of PLGA and Dox follow the same kinetics. However, following 8 h of incubation, the fluorescence intensity and cellular uptake of Dox decreases, while in the case of PLGA both parameters remain constant. FLIM shows the presence of a single-lifetime species, with a lifetime of 1.15 ns when measured inside the cells. Cell viability decreases by approximately 20% when incubated for 24 h with PLGA loaded with Dox, with a particle concentration of 100 µg · mL(-1). At the single-cell level, CRM shows changes in the bands from DNA and proteins in the cell nucleus when incubated with PLGA loaded with Dox. 23349478 Activation of islet autoreactive naive T cells in infants is influenced by homeostatic mechanisms and antigen presenting capacity. Islet autoimmunity precedes type 1 diabetes onset. We previously found that islet autoimmunity rarely starts before age six months but reaches its highest incidence already at around 1 year of age. We now examine whether homeostatic expansion and immune competence changes seen in a maturating immune system may account for this marked variation in islet autoimmunity risk in the first year of life. We found naïve proinsulin- and GAD65-responsive T cells in cord blood of healthy newborns, with highest responses observed in children with type 1 diabetes susceptible HLA-DRB1/DQB1 genotypes. Homeostatic expansion characteristics with increased IL-7 concentrations and enhanced T cell responsiveness to IL-7 were observed throughout the first year of life. However, the ability of antigen-presenting cells to activate naïve T cells was compromised at birth, and cord blood monocytes had low surface expression of CD40 and HLA class II. In contrast, antigen presentation and expression of these molecules had reached competent adult levels by the high incidence age of 8 months. We propose that temporal changes in islet autoimmunity seroconversion in infants are a consequence of the changing balance between homeostatic drive and antigen presentation competence. These findings are relevant for early prevention of type 1 diabetes. 23257237 Fragile X syndrome: from targets to treatments. Fragile X syndrome (FXS) is one of the most prevalent and well-studied monogenetic causes of intellectual disability and autism and, although rare, its high penetrance makes it a desirable model for the study of neurodevelopmental disorders more generally. Indeed recent studies suggest that there is functional convergence of a number of genes that are implicated in intellectual disability and autism indicating that an understanding of the cellular and biochemical dysfunction that occurs in monogenic forms of these disorders are likely to reveal common targets for therapeutic intervention. Fundamental research into FXS has provided a wealth of information about how the loss of function of the fragile X mental retardation protein results in biochemical, anatomical and physiological dysfunction leading to the discovery of interventions that correct many of the core pathological phenotypes associated with animal models of FXS. Most promisingly such strategies have led to development of drugs that are now in clinical trials. This review highlights how progress in understanding disorders such as FXS has led to a new era in which targeted molecular treatment towards neurodevelopmental disorders is becoming a reality. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. 23395899 RNA polymerase II acts as an RNA-dependent RNA polymerase to extend and destabilize a non-coding RNA. RNA polymerase II (Pol II) is a well-characterized DNA-dependent RNA polymerase, which has also been reported to have RNA-dependent RNA polymerase (RdRP) activity. Natural cellular RNA substrates of mammalian Pol II, however, have not been identified and the cellular function of the Pol II RdRP activity is unknown. We found that Pol II can use a non-coding RNA, B2 RNA, as both a substrate and a template for its RdRP activity. Pol II extends B2 RNA by 18 nt on its 3'-end in an internally templated reaction. The RNA product resulting from extension of B2 RNA by the Pol II RdRP can be removed from Pol II by a factor present in nuclear extracts. Treatment of cells with α-amanitin or actinomycin D revealed that extension of B2 RNA by Pol II destabilizes the RNA. Our studies provide compelling evidence that mammalian Pol II acts as an RdRP to control the stability of a cellular RNA by extending its 3'-end. 22396192 The oxygen reactivity index and its relation to sensor technology in patients with severe brain lesions. The oxygen reactivity index (ORx) has been introduced to assess the status of cerebral autoregulation after traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH). Currently, there is some controversy about whether the ORx depends on the type of PbrO2-sensor technology used for its calculation. To examine if the probe technology does matter, we compared the ORx and the resulting optimal cerebral perfusion pressures (CPPopt) of simultaneously implanted Licox (CC1.SB, Integra Neuroscience, France) and Neurovent-PTO (Raumedic, Germany) probes in patients after aneurysmal SAH or severe TBI. Licox and Raumedic probes were implanted side by side in 11 patients after TBI or SAH. ORx and CPPopt were recorded continuously. The equivalence of both probes was examined using Bland-Altman analyses. The mean difference in ORx was 0.1, with Licox producing higher values. The limits of agreement regarding ORx ranged from -0.6 to +0.7. When both probes' ORx values were compared in each patient, no specific pattern in their relationship was seen. The mean difference in CPPopt was 0 mmHg with limits of agreement between -16.5 and +16.4 mmHg. Owing to the rather limited number of patients, we view the results of this study as preliminary. The main result is that Licox and Raumedic showed consistent differences in ORx and CPPopt. Therefore, ORx values of both probes cannot be interchanged and should not be viewed as equivalent. This should be taken into consideration when discussing ORx data generated by different PbrO2 probe types. 23629928 Health care use patterns for diarrhea in children in low-income periurban communities of karachi, pakistan. Abstract. Diarrhea causes 16% of all child deaths in Pakistan. We assessed patterns of healthcare use among caretakers of a randomly selected sample of 959 children ages 0-59 months in low-income periurban settlements of Karachi through a cross-sectional survey. A diarrheal episode was reported to have occurred in the previous 2 weeks among 298 (31.1%) children. Overall, 280 (80.3%) children sought care. Oral rehydration solution and zinc were used by 40.8% and 2%, respectively; 11% were admitted or received intravenous rehydration, and 29% sought care at health centers identified as sentinel centers for recruiting cases of diarrhea for a planned multicenter diarrheal etiology case-control study. Odds ratios for independent predictors of care-seeking behavior were lethargy, 4.14 (95% confidence interval = 1.45-11.77); fever, 2.67 (1.27-5.59); and stool frequency more than six per day, 2.29 (1.03-5.09). Perception of high cost of care and use of home antibiotics were associated with reduced care seeking: odds ratio = 0.28 (0.1-0.78) and 0.29 (0.11-0.82), respectively. There is a need for standardized, affordable, and accessible treatment of diarrhea as well as community education regarding appropriate care in areas with high diarrheal burden. 23956797 Using balance training to improve the performance of youth basketball players. The aim of this study was to evaluate the effectiveness of 12 weeks of balance training to improve the balance and vertical jump abilities of young basketball players. Twenty-three players from two teams in the Under Fifteen Basketball Excellence category participated in the study. Participants were divided into two training groups: balance training (BAL, n = 11) and isotonic training (ISO, n = 12). Both groups were tested for balance and vertical jumps at the beginning of the competitive season and at the end of 12 weeks of specific training programme. All of the tests were performed in sustained bipodalic and monopodalic (both right and left) positions. The results showed that players who participated in balance training for 12 weeks, compared to players who trained with isotonic machines, exhibited a significantly increase in balance (bipodalic 28.3 %; right 41.4 %; left 45.8 %; p < 0.01) and muscular power (bipodalic 8.1 %; right 13.5 %; left 12.5 %; p < 0.01) as measured through a vertical jump. In conclusion, balance training using unstable boards was an effective training method for improving balance and the vertical jump, which is a basketball-specific action that frequently occurs in this sport. 22698003 Blood flow response in small intestinal loops at different depths during negative pressure wound therapy of the open abdomen. High closure rates of the open abdomen have been reported following negative pressure wound therapy (NPWT). However, the method has occasionally been associated with increased development of intestinal fistulae. We have previously shown that the application of NPWT to the open abdomen causes a decrease in microvascular blood flow in the small intestinal loop and the omentum adjacent to the visceral protective layer of the dressing. In this study we investigate whether the negative pressure affects only small intestinal loops lying directly below the dressing or if it also affects small intestinal loops that are not in direct contact with the dressing. Six pigs underwent midline incision and application of NPWT to the open abdomen. The microvascular blood flow was measured in four intestinal loops at different depths from the visceral protective layer, at two different locations: beneath the dressing and at the anterior abdominal wall, before and after the application of NPWT of -50, -70, -100, -120, -150 and -170 mmHg, using laser Doppler velocimetry. Negative pressures between -50 and -170 mmHg caused a significant decrease in the microvascular blood flow in the intestinal loops in direct contact with the visceral protective layer. A slight, but significant, decrease in blood flow was also seen in the intestinal loops lying beneath these loops. The decrease in microvascular blood flow increased with the amount of negative pressure applied. No difference in blood flow was seen in the intestinal loops lying deeper in the abdominal cavity. A decrease in blood flow was seen in the upper two intestinal loops located apically and anteriorly, but not in the lower two, indicating that this is a local effect and that pressure decreases with distance from the source. A long-term decrease in blood flow in the intestinal wall may induce ischaemia and secondary necrosis in the intestinal wall, which could promote the development of intestinal fistulae. We believe that NPWT of the open abdomen is a very effective treatment, but that it could be improved by gaining more knowledge on the mechanisms involved. 23905763 Cost-effectiveness of caesarean sections in a post-conflict environment: a case study of Bunia, Democratic Republic of the Congo. This paper demonstrates the feasibility of health services research in an unstable environment during the transition from crisis to development and its importance for future planning. Effectiveness and the cost of caesarean sections (CSs) were investigated in Bunia, a town affected by conflict and insecurity, in the Democratic Republic of the Congo (DRC) in 2008. The CS rate was 9.7 per cent of expected deliveries. All CSs in the study sample were emergency procedures. A humanitarian non-governmental organisation (NGO) hospital, offering free services, performed 75 per cent of all CSs. The estimated provider cost for CS in 2008 at this hospital was USD 103,514 (that is, USD 144 per CS). With a cost of between USD 3.8 and 9.2 per year of health adjusted life expectancy (HALE) gained, CSs at the NGO hospital were very cost-effective. The estimates give an indication of funding requirements to maintain adequate access to CS after the departure of the humanitarian organisation. 23726675 A phase 2, double-blind, randomized, placebo-controlled, dose-escalation study to evaluate the efficacy, safety, and tolerability of naloxegol in patients with opioid-induced constipation. Naloxegol (previously known as NKTR-118) is a peripherally acting μ-opioid receptor antagonist engineered using polymer conjugate technology in development as an oral, once-daily agent for the treatment of opioid-induced constipation (OIC). Eligible patients with OIC (n=207), defined as <3 spontaneous bowel movements (SBMs) per week with accompanying symptoms, on a stable opioid regimen of 30-1000mg/day morphine equivalents for ⩾2 weeks were randomized to receive 4 weeks of double-blind placebo or naloxegol (5, 25, or 50mg) once daily in sequential cohorts after a 1-week placebo run-in. The primary end point, median change from baseline in SBMs per week after week 1 of drug administration, was statistically significant for the 25- and 50-mg naloxegol cohorts vs placebo (2.9vs 1.0 [P=0.0020] and 3.3 vs 0.5 [P=0.0001], respectively). The increase in SBMs vs placebo was maintained over 4 weeks for naloxegol 25mg (3.0 vs 0.8 [P=0.0022]) and 50mg (3.5 vs 1.0 [P<0.0001]). Naloxegol was generally well tolerated across all dosages. The most frequent adverse events (AEs) were abdominal pain, diarrhea, and nausea. Most AEs at 5 and 25mg/day were mild and transient. Similar AEs occurred with increased frequency and severity in the 50-mg cohort. There was no evidence of a statistically significant increase from baseline in pain, opioid use for the 25- and 50-mg cohorts, or centrally mediated opioid withdrawal signs and/or symptoms with naloxegol. These data demonstrate that once-daily oral naloxegol improves the frequency of SBMs compared with placebo and is generally well tolerated in this population of patients with OIC. 23891389 European Federation of Colposcopy quality standards Delphi consultation. Optimization of colposcopy practice requires a program of quality assurance including the monitoring of performance indicators. The European Federation of Colposcopy (EFC) aimed to identify a list of quality indicators for colposcopic practice, which are relevant, reproducible and practical across all of the member countries. A five-round Delphi consultation was conducted in 30 full, 5 associate and 4 potential member countries in order to determine a core list of quality indicators including optimal target ranges. Six indicators were selected from a list of 37 proposed standards. Two further rounds of consultation were conducted to determine expert opinion on the target level for each of the standards. The six indicators identified and corresponding targets were: documentation of whether or not the squamocolumnar junction has been seen (100%); colposcopy prior to treatment for abnormal cervical cytology (100%); percentage of excisional treatments/conizations to contain cervical intra-epithelial neoplasia grade two or worse (≥85%); percentage of excised lesions/conizations with clear margins (≥80%); and two indicators concerned the number of cases to be colposcoped per year: ≥50 low-grade/minor and ≥50 high-grade/major cytological abnormalities. A Delphi consultation identified six EFC quality indicators. These are a first step in an international attempt to optimize colposcopy practice throughout Europe. The current targets are based on expert opinion and may need adaptation in the future. Data are needed from European colposcopy settings to determine whether the indicators are achievable practice-based benchmarks and will help in improving and fine tuning the list of performance indicators and targets. 23719677 Ionic liquids from copper(II) complexes with alkylimidazole-containing tripodal ligands. Five-coordinate copper(II) complexes [Cu(L)Cl]X bearing alkylimidazole-containing tripodal ligands were prepared, where L = bis(2-dimethylaminoethyl)-((1-alkylimidazol-2-yl)methyl)amine and X = bis(trifluoromethanesulfonyl)amide (Tf2N) and PF6. The salts with hexyl ([1]X), propyl ([2]X), and methyl ([3]X) substituents in the ligand were prepared, of which [1]Tf2N and [2]Tf2N were ionic liquids with high viscosity at room temperature. X-ray crystal structure determination at low temperature revealed that the coordination geometry around the metal ion in [3]Tf2N was distorted trigonal bipyramidal, whereas that in [2]PF6 was close to square pyramidal. UV-vis absorption spectra of these salts were consistent with the coordination structures. 23709139 Morphological and scanning electron microscopic studies of the tongue of the Egyptian fruit bat (Rousettus aegyptiacus) and their lingual adaptation for its feeding habits. This study was carried out on the tongues of 12 adult normal healthy Egyptian fruit bats of both sexes. The tongue is protrusible, elongated flat with a rounded apex and its wide and thickness increase gradually toward the lingual root. There are four types of lingual papillae; two mechanical and two gustatory. The tongue divided into three parts (anterior, middle and posterior), each part subdivides into three regions; two lateral regions and median region, in addition to the lingual apex to the anterior region. The lingual papillae close to the median region of the tongue were posteriorly directed toward the pharynx, while theses present on the lateral regions of the tongue are directed medioposteriorly. There are sex subtypes of the filiform papillae; three on the anterior part (small, conical and giant), two on the middle part (cornflower and leaf-like papillae) while the posterior part contain rosette shape filiform papillae, in addition to transitional papillae and conical papillae. Two gustatory papillae represented by; small number of fungiform papillae which scattered among the filiform papillae on lingual apex and two lateral regions of the anterior and middle part of tongue, while the three circumvallate papillae on the posterior part were arranged in a triangle form. 23650172 Randomized trial of the virologic response during up to two years of entecavir-adefovir combination therapy in multiple-drug-refractory chronic hepatitis B virus patients. A 1-year trial with entecavir plus adefovir resulted in a rate of virological response (VR) higher than that seen with lamivudine plus adefovir in multiple-drug-refractory chronic hepatitis B (CHB) patients. This extension study enrolled 89 of 90 patients who completed a 52-week randomized trial comparing treatment with entecavir plus adefovir (EA) to treatment with lamivudine plus adefovir (LA). At the baseline of the original study, all patients had lamivudine-resistant hepatitis B virus (HBV) and serum HBV DNA > 2,000 IU/ml despite prior lamivudine plus adefovir therapy. Of the 89 enrolled patients, 45 initially randomized to receive entecavir plus adefovir and the other 44 randomized to receive lamivudine plus adefovir received entecavir plus adefovir for an additional 52 weeks (EA-EA and LA-EA, respectively). The proportions of patients with a VR (serum HBV DNA < 60 IU/ml) gradually increased in both groups and were comparable at week 104 (42.2% in the EA-EA group and 34.1% in the LA-EA group; P = 0.51). The mean reductions in serum HBV DNA from baseline in the two groups were similar (-2.8 log10 IU/ml and -2.8 log10 IU/ml, respectively; P = 0.87). At week 104, the number of patients who retained the preexisting HBV mutants resistant to adefovir or entecavir had decreased from 8 to 2 in the EA-EA group and from 15 to 6 in the LA-EA group (P = 0.27). Both study groups had favorable safety profiles. In conclusion, up to 104 weeks of entecavir plus adefovir treatment was associated with a progressive VR, a decrease of levels of preexisting drug-resistant mutants, and no selection for additional resistance mutants of HBV in multiple-drug-refractory CHB patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01023217.). 23411190 Assessment of antimicrobial and antiprotozoal activity of the olive oil macerate samples of Hypericum perforatum and their LC-DAD-MS analyses. Twenty-one samples of traditionally-prepared (home-made) and ready-made (commercial) St. John's Wort olive oil macerates were profiled for their in vitro antimicrobial and antiprotozoal activity. Their cytotoxic potential was evaluated on MRC-5 fibroblasts. In the antiprotozoal assays, ten of the oils inhibited Trypanosoma brucei rhodesiense (IC(50) 15.9-64.5 μg/mL), while only one oil exerted antimicrobial activity towards Staphylococcus aureus (IC(50)=88.7 μg/mL). LC-DAD-MS data revealed the presence of pseudohypericin (0.135-3.280 μg/g) and hypericin (0.277-6.634 μg/g) in all the oils, whereas chlorogenic acid (1.063 μg/g) was detected only in one oil sample. Hyperforin was detected in four (0.977-2.399 μg/g) and adhyperforin in six samples (0.005-3.165 μg/g). Hypericin and pseudohypericin were common in the active oils, whereas hyperforin, adhyperforin, and chlorogenic acid were absent in these samples. Our results indicated that if the correct plant material is used, the infused oils from Hypericum perforatum may contain active components. 23923017 Histone deacetylase inhibitor upregulates peroxisomal Fatty Acid oxidation and inhibits apoptotic cell death in abcd1-deficient glial cells. In X-ALD, mutation/deletion of ALD gene (ABCD1) and the resultant very long chain fatty acid (VLCFA) derangement has dramatically opposing effects in astrocytes and oligodendrocytes. While loss of Abcd1 in astrocytes produces a robust inflammatory response, the oligodendrocytes undergo cell death leading to demyelination in X-linked adrenoleukodystrophy (X-ALD). The mechanisms of these distinct pathways in the two cell types are not well understood. Here, we investigated the effects of Abcd1-knockdown and the subsequent alteration in VLCFA metabolism in human U87 astrocytes and rat B12 oligodendrocytes. Loss of Abcd1 inhibited peroxisomal β-oxidation activity and increased expression of VLCFA synthesizing enzymes, elongase of very long chain fatty acids (ELOVLs) (1 and 3) in both cell types. However, higher induction of ELOVL's in Abcd1-deficient B12 oligodendrocytes than astrocytes suggests that ELOVL pathway may play a prominent role in oligodendrocytes in X-ALD. While astrocytes are able to maintain the cellular homeostasis of anti-apoptotic proteins, Abcd1-deletion in B12 oligodendrocytes downregulated the anti-apototic (Bcl-2 and Bcl-xL) and cell survival (phospho-Erk1/2) proteins, and upregulated the pro-apoptotic proteins (Bad, Bim, Bax and Bid) leading to cell loss. These observations provide insights into different cellular signaling mechanisms in response to Abcd1-deletion in two different cell types of CNS. The apoptotic responses were accompanied by activation of caspase-3 and caspase-9 suggesting the involvement of mitochondrial-caspase-9-dependent mechanism in Abcd1-deficient oligodendrocytes. Treatment with histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) corrected the VLCFA derangement both in vitro and in vivo, and inhibited the oligodendrocytes loss. These observations provide a proof-of principle that HDAC inhibitor SAHA may have a therapeutic potential for X-ALD. 23919511 National health insurance, social influence and antenatal care use in Ghana. The study explores the importance of social influence and the availability of health insurance on maternal care utilization in Ghana through the use of antenatal care services. A number of studies have found that access to health insurance plays a critical role in women's decision to utilize antenatal care services. However, little is known about the role that social forces play in this decision. This study uses village-level data from the 2008 Ghana Demographic and Health Survey to investigate the effects of health insurance and social influences on the intensity of antenatal care utilization by Ghanaian women. Using GIS information at the village level, we employ a spatial lag regression model in this study. Results indicate that, controlling for a host of socioeconomic and geographical factors, women who have health insurance appear to use more antenatal services than women who do not. In addition, the intensity of antenatal visits appears to be spatially correlated among the survey villages, implying that there may be some social influences that affect a woman's decision to utilize antenatal care. A reason for this may be that women who benefit from antenatal care through positive pregnancy outcomes may pass this information along to their peers who also increase their use of these services in response. Traditional/Cultural leaders as "gate-keepers" may be useful in the dissemination of maternal health care information. Public health officials may also explore the possibility of disseminating information relating to maternal care services via the mass media. 23698562 The natural history of HIV infection. To review recent published literature around three areas: long-term nonprogression/viral control; predictors of viral load set point/disease progression; and the potential impact of antiretroviral therapy (ART) in early HIV infection. The natural course of untreated HIV infection varies widely with some HIV-positive individuals able to maintain high CD4 cell counts and/or suppressed viral load in the absence of ART. Although similar, the underlying mechanistic processes leading to long-term nonprogression and viral control are likely to differ. Concerted ongoing research efforts will hopefully identify host factors that are causally related to these phenotypes, thus providing opportunities for the development of novel treatment or preventive strategies. Although there is increasing evidence that initiation of ART during primary infection may prevent the immunological deterioration which would otherwise be seen in untreated HIV infection, recent studies do not address the longer term clinical benefits of ART at this very early stage. A better understanding of the relative influences of viral, host, and environmental factors on the natural course of HIV infection has the potential to identify novel targets for intervention to prevent and treat HIV-infected persons. 23529858 T-cell-derived, but not B-cell-derived, IL-10 suppresses antigen-specific T-cell responses in Litomosoides sigmodontis-infected mice. IL-10, a cytokine with pleiotropic functions is produced by many different cells. Although IL-10 may be crucial for initiating protective Th2 responses to helminth infection, it may also function as a suppressive cytokine preventing immune pathology or even contributing to helminth-induced immune evasion. Here, we show that B cells and T cells produce IL-10 during murine Litomosoides sigmodontis infection. IL-10-deficient mice produced increased amounts of L. sigmodontis-specific IFN-γ and IL-13 suggesting a suppressive role for IL-10 in the initiation of the T-cell response to infection. Using cell type-specific IL-10-deficient mice, we dissected different functions of T-cell- and B-cell-derived IL-10. Litomosoides sigmodontis-specific IFN-γ, IL-5, and IL-13 production increased in the absence of T-cell-derived IL-10 at early and late time points of infection. In contrast, B-cell-specific IL-10 deficiency did not lead to significant changes in L. sigmodontis-specific cytokine production compared to WT mice. Our results suggest that the initiation of Ag-specific cellular responses during L. sigmodontis infection is suppressed by T-cell-derived IL-10 and not by B-cell-derived IL-10. 23880341 Melatonin elevates apoptosis in human platelets via ROS mediated mitochondrial damage. Melatonin is a pineal hormone that regulates circadian and seasonal rhythms. The chronobiotic role of melatonin corresponds with a repertoire of pharmacological properties. Besides, it has a wide range of therapeutic applications. However, recent studies have demonstrated its direct interaction with platelets: at physiological concentration it promotes platelet aggregation; on the other hand, at pharmacological doses it raises intracellular Ca(2+) leading to platelet activation, thrombus formation and cardiovascular disorders. In order to further probe its effects on platelets, the current study targeted platelet apoptosis and melatonin was found to stimulate apoptosis. The mitochondrial pathway of apoptosis was mainly investigated because of its susceptibility to oxidative stress-inducing factors including therapeutic and dietary elements. Melatonin significantly increased the generation of intracellular ROS and Ca(2+), facilitating mitochondrial membrane depolarization, cytochrome c release, caspase activation, protein phosphorylation and phosphatidylserine externalization. Further, the overall toxicity of melatonin on platelets was confirmed by MTT and lactate dehydrogenase assays. The elevated rate of platelet apoptosis has far reaching consequences including thrombocytopenia. Besides, platelets undergoing apoptosis release microparticles, which fuel thrombus formation and play a significant role in the pathophysiology of a number of diseases. In many parts of the world melatonin is an over-the-counter dietary supplement and alternative medicine. Since, melatonin displays platelet proapoptotic effect at a concentration attainable through therapeutic dosage, the present study sends a warning signal to the chronic use of melatonin as a therapeutic drug and questions its availability without a medical prescription. 23776213 Trophic cascade alters ecosystem carbon exchange. Trophic cascades--the indirect effects of carnivores on plants mediated by herbivores--are common across ecosystems, but their influence on biogeochemical cycles, particularly the terrestrial carbon cycle, are largely unexplored. Here, using a (13)C pulse-chase experiment, we demonstrate how trophic structure influences ecosystem carbon dynamics in a meadow system. By manipulating the presence of herbivores and predators, we show that even without an initial change in total plant or herbivore biomass, the cascading effects of predators in this system begin to affect carbon cycling through enhanced carbon fixation by plants. Prolonged cascading effects on plant biomass lead to slowing of carbon loss via ecosystem respiration and reallocation of carbon among plant aboveground and belowground tissues. Consequently, up to 1.4-fold more carbon is retained in plant biomass when carnivores are present compared with when they are absent, owing primarily to greater carbon storage in grass and belowground plant biomass driven largely by predator nonconsumptive (fear) effects on herbivores. Our data highlight the influence that the mere presence of predators, as opposed to direct consumption of herbivores, can have on carbon uptake, allocation, and retention in terrestrial ecosystems. 23839510 Gelatin-Immobilised Poly(hydroxyethyl methacrylate) Cryogel for Affinity Purification of Fibronectin. In this work, fibronectin purification from human plasma with the gelatin-immobilised poly(hydroxyethyl methacrylate) (PHEMA) cryogel has been evaluated. The PHEMA cryogel was prepared by cryo-polymerisation which proceeds in an aqueous solution of monomer frozen inside a plastic syringe. The PHEMA cryogel contained interconnected macrochannels of 10-200 Î¼m in diameter. Gelatin molecules were covalently immobilised onto the PHEMA cryogel via carbodiimide activation. The gelatin-immobilised PHEMA cryogel was used to purify fibronectin from human plasma. Fibronectin adsorption from human plasma on the PHEMA cryogel was 0.30 mg/ml, while much higher adsorption values, up to 38 mg/ml, was obtained with the gelatin-immobilised PHEMA cryogel. The fibronectin adsorption capacity of the gelatin-immobilised PHEMA cryogel did not change with an increase in the flow rate of plasma. Up to 92 % of the adsorbed fibronectin was eluted using 2 M urea containing 1 M NaCl as elution agent. The adsorption-elution cycle was repeated ten times using the same PHEMA cryogel. No remarkable decrease was detected in the adsorption capacity of the gelatin-immobilised PHEMA cryogel. 23822519 A Relational Frame Theory Account of the Emergence of Sexual Fantasy. Sexual fantasy is common among humans and often serves to facilitate sexual arousal. Although some fantasies may be directly related to a person's past experiences, others may be unrelated to direct history, and these are thus more difficult to explain. Relational frame theory is a comprehensive account of human language and cognition that may assist in understanding the processes involved in the emergence of sexual fantasy. This article presents a primer on relational frame theory, along with examples of how relations between stimuli may influence a person's private experience of sexual fantasy. 23462812 Octahedral Co3O4 particles threaded by carbon nanotube arrays as integrated structure anodes for lithium ion batteries. Octahedral Co3O4 particles threaded by ultra-long multi-walled carbon nanotube (MWCNT) arrays were prepared by a hydrothermal process and subsequent calcination. The Co3O4 octahedron with the (111) facets attaches to MWCNTs uniformly and closely. The composite can be used as an integrated anode for lithium ion batteries (LIBs) without any other additives (such as conductive additives and polymer binder), which exhibits a high reversible capacity of 725 mA h g(-1) at a current density of 100 mA g(-1), and excellent cyclic stability without capacity degradation over 100 cycles at a current density of 500 mA g(-1). The high performance can be attributed to the unique structure: (i) the ultra-long MWCNT array facilitates fast electron transfer; (ii) the tight adhesion between Co3O4 and MWCNTs prevents particle drifting and agglomeration; (iii) the free space between MWCNTs promotes fast ion transport and alleviates the large volume variation during discharge-charge process. This work demonstrates the great potential of MWCNT arrays as substrate and provides insights for the design and direct use of MWCNT array-based materials in LIBs, which will be helpful for future development of high-performance electrode materials. 23536522 The effects of gender difference on monocrotaline-induced pulmonary hypertension in rats. The present study aimed to compare the effect of gender difference on hemodynamic consequences in the development of monocrotaline (MCT)-induced pulmonary hypertension in rat. The effect of antioxidant enzyme systems on the development of pulmonary hypertension mediated by the phytotoxin MCT and the effect of gender on these antioxidant systems were also investigated. For this purpose, the right ventricular pressures (RVPs) and right ventricular/heart weight (HW) ratios were compared between groups and the glutathione (GSH) level and superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST) activities were determined in lung and liver tissue samples of rats. RVP and right ventricular/HW ratios significantly increased in the MCT group compared to the control group. In the MCT group, RVP was significantly higher in males than females. MCT-induced pulmonary hypertension resulted in decreased GSH level, decreased GST and SOD activities and increased CAT activity in lung and liver tissues of both male and female rats. In addition, the lung and liver GSH level and GST and SOD levels were higher in female control rats compared to male control rats. The results of the present study, that antioxidant enzyme activities were different between the groups, highlight the possible role of oxidative stress in the pathogenesis of MCT-induced pulmonary hypertension in rats. Moreover, the lower antioxidant defense capacity of male rats than female rats may be considered as a cause of more aggressive course of MCT-induced pulmonary hypertension in males compared to females. 23570615 Extracellular Signal-Regulated Kinases (ERK) Inhibitors from Aristolochia yunnanensis. Six new sesquiterpenoids, aristoyunnolins A-F (1-6), an artifact of isolation [7-O-ethyl madolin W (7)], and 12 known analogues were isolated from stems of Aristolochia yunnanensis. The structures were determined by combined chemical and spectral methods, and the absolute configurations of compounds 2, 3, 5-7, 9, 14, and 17 were determined by the modified Mosher's method and CD analysis. Compounds 1-19 were screened using a bioassay system designed to evaluate the effect on mitogen-activated protein kinases (MAPKs) signaling pathways. Among three MAPKs (ERK1/2, JNK, and p38), compounds 1, 4, 10-13, 16, 18, and 19 exhibited selective inhibition of the phosphorylation of ERK1/2. Compounds 16 and 19 were more active than the positive control PD98059, a known inhibitor of the ERK1/2 signaling pathway. 23889377 Quantum Frameness for CPT Symmetry. We develop a theory of charge-parity-time (CPT) frameness resources to circumvent CPT superselection. We construct and quantify such resources for spin-0, 1/2, 1, and Majorana particles and show that quantum information processing is possible even with CPT superselection. Our method employs a unitary representation of CPT inversion by considering the aggregate action of CPT rather than the composition of separate C, P, and T operations, as some of these operations involve problematic antiunitary representations. 23776156 The RNase II/RNB family of exoribonucleases: putting the 'Dis' in disease. Important findings over the last years have shed new light onto the mechanistic details of RNA degradation by members of the RNase II/RNB family of exoribonucleases. Members of this family have been shown to be involved in growth, normal chloroplast biogenesis, mitotic control and cancer. Recently, different publications have linked human orthologs (Dis3 and Dis3L2) to important human diseases. This article describes the structural and biochemical characteristics of members of this family of enzymes, and the physiological implications that relate them with disease. WIREs RNA 2013, 4:607-615. doi: 10.1002/wrna.1180 Conflict of interest: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website. 23651555 Individuals' half-lives for 2,3,4,7,8-penta-chlorodibenzofuran (PeCDF) in blood: correlation with clinical manifestations and laboratory results in subjects with Yusho. In 1968, many people developed dioxin poisoning (Yusho) in Japan. Ingestion of 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-PeCDF) was considered to be the cause of this poisoning. Although some patients had high concentrations of 2,3,4,7,8-PeCDF in their blood, individuals' half-lives of 2,3,4,7,8-PeCDF were long. To evaluate the relationship between clinical and laboratory parameters and the individual half-life of 2,3,4,7,8-PeCDF in blood. Clinical and laboratory data were collected during annual check-ups from 2001 to 2008. We enrolled 71 patients, who were measured more than 3 times, and who had 2,3,4,7,8-PeCDF concentrations in blood >50pgg(-1) lipid. The half-life of 2,3,4,7,8-PeCDF for each patient was estimated using linear regression. Moreover, relationships between clinical and laboratory parameters and individual half-life were investigated by linear regression. A shortened individual half-life for 2,3,4,7,8-PeCDF was significantly correlated with an increased red blood cell count, increased viscous secretions from the meibomian glands, existing black comedones, and severe cedar pollen allergy. Symptoms that accelerate excretion of lipids from the body, such as viscous secretions from the meibomian glands, may lead to a shorter half-life of 2,3,4,7,8-PeCDF. Red blood cells are related to the half-life of 2,3,4,7,8-PeCDF. However, further studies are required to investigate the excretory mechanism of 2,3,4,7,8-PeCDF. 23843337 Functional Endothelial Progenitor Cells Selectively Recruit Neurovascular Protective Monocyte-Derived F4/80(+) /Ly6c(+) Macrophages in a Mouse Model of Retinal Degeneration. Retinitis pigmentosa is a group of inherited eye disorders that result in profound vision loss with characteristic retinal neuronal degeneration and vasculature attenuation. In a mouse model of retinitis pigmentosa, endothelial progenitor cells (EPC) from bone marrow rescued the vasculature and photoreceptors. However, the mechanisms and cell types underlying these protective effects were uncertain. We divided EPC, which contribute to angiogenesis, into two subpopulations based on their aldehyde dehydrogenase (ALDH) activity and observed that EPC with low ALDH activity (Alde-Low) had greater neuroprotection and vasoprotection capabilities after injection into the eyes of an rd1 mouse model of retinitis pigmentosa compared with EPC with high ALDH activity (Alde-High). Of note, Alde-Low EPC selectively recruited F4/80(+) /Ly6c(+) monocyte-derived macrophages from bone marrow into retina through CCL2 secretion. In addition, the mRNA levels of CCR2, the neurotrophic factors TGF-β1 and IGF-1, and the anti-inflammatory mediator interleukin-10 were higher in migrated F4/80(+) /Ly6c(+) monocyte-derived macrophages as compared with F4/80(+) /Ly6c(-) resident retinal microglial cells. These results suggest a novel therapeutic approach using EPC to recruit neuroprotective macrophages that delay the progression of neural degenerative disease. (178 words). 23903089 Local Skin Warming Enhances Color Duplex Imaging of Cutaneous Perforators. The perforator flap is one of the most useful techniques in reconstructive surgery. The operative procedure for these flaps will be greatly simplified if accurate localization of the course of the perforator can be preoperatively confirmed. However, small vessels with diameters less than 0.5 mm cannot be readily traced with conventional imaging techniques. Local skin warming temporarily increases cutaneous blood flow and vasodilation. In this study, we established a local skin warming procedure, and performed this before color duplex imaging to improve preoperative perforator mapping and enable precise flap design. 23103983 Active self-healing encapsulation of vaccine antigens in PLGA microspheres. Herein, we describe the detailed development of a simple and effective method to microencapsulate vaccine antigens in poly(lactic-co-glycolic acid) (PLGA) by simple mixing of preformed active self-microencapsulating (SM) PLGA microspheres in a low concentration aqueous antigen solution at modest temperature (10-38 °C). Co-encapsulating protein-sorbing vaccine adjuvants and polymer plasticizers were used to "actively" load the protein in the polymer pores and facilitate polymer self-healing at a temperature>the hydrated polymer glass transition temperature, respectively. The microsphere formulation parameters and loading conditions to provide optimal active self-healing microencapsulation of vaccine antigens in PLGA was investigated. Active self-healing encapsulation of two antigens, ovalbumin and tetanus toxoid (TT), in PLGA microspheres was adjusted by preparing blank microspheres containing different vaccine adjuvants (aluminum hydroxide (Al(OH)₃) or calcium phosphate). Active loading of vaccine antigen in Al(OH)₃-PLGA microspheres was found to: a) increase with an increasing loading of Al(OH)₃ (0.88-3 wt.%) and addition of porosigen, b) decrease when the inner Al(OH)₃/trehalose phase to 1 mL outer oil phase and size of microspheres was respectively >0.2 mL and 63 μm, and c) change negligibly by PLGA concentration and initial incubation (loading) temperature. Encapsulation of protein sorbing Al(OH)₃ in PLGA microspheres resulted in suppression of self-healing of PLGA pores, which was then overcome by improving polymer chain mobility, which in turn was accomplished by coincorporating hydrophobic plasticizers in PLGA. Active self-healing microencapsulation of manufacturing process-labile TT in PLGA was found to: a) obviate micronization- and organic solvent-induced TT degradation, b) improve antigen loading (1.4-1.8 wt.% TT) and encapsulation efficiency (~97%), c) provide nearly homogeneous distribution and stabilization of antigen in polymer, and d) provide improved in vitro controlled release of antigenic TT. 23748160 Morphological, genotypic, and physiological characterization of Acanthamoeba isolates from keratitis patients and the domestic environment in Vitoria, Espírito Santo, Brazil. Amoebae of the genus Acanthamoeba are free-living protozoa that can cause granulomatous encephalitis and keratitis in humans. In this study, four clinical and three household dust isolates obtained in Vitória, Espírito Santo, Brazil were characterized by their morphological, genotypic, and physiological properties. All isolates belonged to group II according to Pussard and Pons' cyst morphology. Analysis of their 18S rDNA sequence identified one isolate from household dust as genotype T11 and the others six samples as genotype T4. Five T4 isolates presented a highly variable region (DF3) in 18S rDNA identical to those previously described. Physiological assays carried out with trophozoites in co-culture with bacteria or in axenic conditions showed all samples tolerated temperatures up to 37°C, regardless of culture method. One keratitis isolate grew at 42°C in co-culture with bacteria. Most isolates in co-culture survived at 1.0M, except a T11 isolate, which tolerated up to 0.5M. The isolates did not grow at 42°C and did not tolerate 0.5M and 1.0M under axenic condition. This is the first report of 18S rRNA gene genotyping applied to Acanthamoeba isolated from keratitis patients in Brazil. The results also indicated that osmo-tolerance is dependent on the culture system. 23856192 Intracranially recorded interictal spikes: Relation to seizure onset area and effect of medication and time of day. The relationship between seizures and interictal spikes remains undetermined. We analyzed intracranial EEG (icEEG) recordings to examine the relationship between the seizure onset area and interictal spikes. 80 unselected patients were placed into 5 temporal, 4 extratemporal, and one unlocalized groups based on the location of the seizure onset area. We studied 4-h icEEG epochs, removed from seizures, from day-time and night-time during both on- and off-medication periods. Spikes were detected automatically from electrode contacts sampling the hemisphere ipsilateral to the seizure onset area. There was a widespread occurrence of spikes over the hemisphere ipsilateral to the seizure onset area. The spatial distributions of spike rates for the different patient groups were different (p<0.0001, chi-square test). The area with the highest spike rate coincided with the seizure onset area only in half of the patients. The spatial distribution of spike rates is strongly associated with the location of the seizure onset area, suggesting the presence of a distributed spike generation network, which is related to the seizure onset area. The spatial distribution of spike rates, but not the area with the highest spike rate, may hold value for the localization of the seizure onset area. 23611062 Pathogenic yersinia DNA in intestinal specimens of pediatric patients with Crohn's disease. Studies indicate a close relationship between Yersinia and Crohn's disease in adults. Our study tested 77 colonic specimens from children with Crohn's disease for the presence of Yersinia DNA using a validated polymerase chain reaction (PCR) assay. Control cases included specimens from 45 ulcerative colitis patients and 10 appendicitis patients. The presence of Yersinia in Crohn's specimens was significant compared to the control specimens (9% vs. 0%; p = 0.0055). While our study supports the medical literature, future studies are needed to determine if the relationship between Crohn's disease and Yersinia is an initiating or mediating factor in the pathogenesis of pediatric Crohn's disease. 23773892 Ex vivo porcine vaginal mucosal model of infection for determining effectiveness and toxicity of antiseptics. To develop a semi-high-throughput ex vivo mucosal model for determining efficacy and toxicity of antiseptics. Explants (5 mm) from freshly excised, porcine vaginal mucosa were infected with methicillin-sensitive Staphylococcus aureus (1 Ã— 10(6)  CFU) at the epithelial surface for 2 h. Haematoxylin and eosin staining revealed healthy uninfected tissue and only minor disruptions in tissue infected with methicillin susceptible Staph. aureus (MSSA), which remained in outer epithelial cell layers. After 2 h infection, 10 Î¼l of chlorhexidine digluconate (CHG, 3%), povidone-iodine (PI, 7·5%), octenidine dihydrochloride (OCT, 0·1%) or polyhexamethylene biguanide (PHMB, 0·1%) was applied. Antiseptics significantly reduced MSSA (1-4 log10  CFU/explants) after 0·25 h to 4 h. CHG, PHMB and OCT exhibited persistence at 24 h. In broth culture, CHG 0·012% and PI 0·625% achieved >6 log10 reductions at 2 h. PI-based formulations were more efficacious than unformulated PI. PI-based formulations exhibited no significant cytotoxicity on explants using an MTT assay. All antiseptics tested in the mucosal MSSA infection model reduced MSSA. CHG and PI were more potent in broth culture. We developed a semi-high-throughput mucosal model that can identify compounds or formulations with promising antimicrobial and limited cytotoxic properties. 22830980 Metabolism and disposition of [14C]n-butyl-p-hydroxybenzoate in male and female Harlan Sprague Dawley rats following oral administration and dermal application. n-Butyl-p-hydroxybenzoate (n-butylparaben, BPB) is an antioxidant used in foods, pharmaceuticals and cosmetics. This study investigated the disposition of ring-labelled [(14)C]BPB in Harlan Sprague Dawley rats, and in rat and human hepatocytes. BPB was rapidly cleared in hepatocytes from rat (t(1/2) = 3-4 min) and human (t(1/2) = 20-30 min). The major metabolites detected in rat hepatocytes were hydroxybenzoic acid and in human hepatocytes were hydroxybenzoic acid and hydroxyhippuric acid. [(14)C]BPB was administered to male rats orally at 10, 100 or 1000 mg/kg, intravenously at 10 mg/kg and dermally at 10 and 100 mg/kg; female rats were administered oral doses at 10 mg/kg. Oral doses of BPB were well-absorbed (>83%) and eliminated chiefly in urine (83-84%); ≤ 1% of the radioactivity remained in tissues at 24 h or 72 h after dosing. About 4% and 8%, respectively, of 100 mg/kg dermal doses were absorbed in 24 h and 72 h, and about 50% of a 10 mg/kg dose was absorbed in 72 h. Metabolites detected in urine included those previously reported, BPB-glucuronide, BPB-sulfate, hydroxybenzoic acid and hydroxyhippuric acid, but also novel metabolites arising from ring hydroxylation followed by glucuronidation and sulfation. 22171568 Maxillary Sinus Floor Augmentation Surgery with Autogenous Bone Grafts as Ceiling: A Pilot Study and Test of Principle. Background: Studies have pointed out that the mere elevation of the maxillary sinus membrane might suffice to allow for bone formation indicating the additional use of augmentation materials to be redundant. Purpose: The purpose of this study was to assess whether elevation of the sinus mucosal lining combined with applying an autologous bone graft as a ceiling and placement of a short implant would allow for bone formation around the implant thus surpassing the need for applying augmentation materials around the installed implants. Materials and Methods: Fourteen consecutive patients were subjected to maxillary sinus floor elevation surgery and simultaneous placement of an implant. Using the lateral bone-wall window technique, the membrane was exposed and elevated. Next, a bone graft taken from the zygomatic rim was placed as a ceiling above the inserted implant to ensure that the sinus membrane would not collapsed around a significant part of the implant. Finally, the bone window was returned in place. After connecting the healing abutment, the wound was closed. Results: All implants were stable and no implants were lost. There were no complications after harvesting the bone graft. Radiographic evaluation showed a bone gain of 3.2 ± 0.9 mm after 3 months and 3.6 ± 0.9 mm after 1 year. Less than 6% of the implant was not covered by bone after 1 year. Conclusion: Maxillary sinus membrane elevation and simultaneous placement of short endosseous implants with a bone graft as a ceiling on top of the implant result in predictable bone formation around the implant and good osseointegration on radiographs. 23856246 The Exomes of the NCI-60 Panel: A Genomic Resource for Cancer Biology and Systems Pharmacology. The NCI-60 cell lines are the most frequently studied human tumor cell lines in cancer research. This panel has generated the most extensive cancer pharmacology database worldwide. In addition, these cell lines have been intensely investigated, providing a unique platform for hypothesis-driven research focused on enhancing our understanding of tumor biology. Here, we report a comprehensive analysis of coding variants in the NCI-60 panel of cell lines identified by whole exome sequencing, providing a list of possible cancer specific variants for the community. Furthermore, we identify pharmacogenomic correlations between specific variants in genes such as TP53, BRAF, ERBBs, and ATAD5 and anticancer agents such as nutlin, vemurafenib, erlotinib, and bleomycin showing one of many ways the data could be used to validate and generate novel hypotheses for further investigation. As new cancer genes are identified through large-scale sequencing studies, the data presented here for the NCI-60 will be an invaluable resource for identifying cell lines with mutations in such genes for hypothesis-driven research. To enhance the utility of the data for the greater research community, the genomic variants are freely available in different formats and from multiple sources including the CellMiner and Ingenuity websites. Cancer Res; 73(14); 4372-82. ©2013 AACR. 23517060 Evidence of a novel role for Pygopus in rRNA transcription. Increased protein synthesis during cell proliferation is accompanied by a compensatory increase in efficient ribosome production, but the mechanisms by which cells adapt to this requirement are not fully understood. In the present study, we demonstrate evidence that Pygo (Pygopus), a protein originally identified as a core component of the Wnt-β-catenin transcription complex is also involved in rRNA transcription during cancer cell growth. Pygo was detected in the nucleoli of several transformed cell lines and was associated with treacle and UBF (upstream binding factor), proteins that are essential for ribosome biogenesis in development and cancer. Pygo was also detected at the ribosomal gene promoter along with core components of the rDNA (ribosomal DNA) transcription complex. RNAi (RNA interference)-mediated depletion of hPygo2 (human Pygo 2) reduced histone H4 acetylation at the rDNA promoter, down-regulated rRNA production, and induced growth arrest in both p53-positive and -negative cells. In p53-positive cells, hPygo2 knockdown triggered the ribosomal stress pathway, culminating in p53-dependent growth arrest at G1-phase of the cell cycle. The results of the present study suggest a novel involvement of Pygo in the promotion of rRNA transcription in cancer cells. 23224403 Factors associated with needs of users with severe mental disorders. For persons suffering from severe mental disorders (SMD), better quantification of needs may facilitate services planning and evaluation, as well as patient recovery. This study aimed to assess associations of sociodemographic, socioeconomic, service utilization, life events, social support and clinical variables with the level of perceived needs of users with SMD globally and according to their factorial structure. A total of 351 adults with SMD from Montreal (Canada) were interviewed using the Montreal Assessment of Needs Questionnaire and seven other standardized instruments. Clinical records were also consulted. Eight variables were associated with levels of needs. Four factors were extracted from the factor analysis and labeled respectively: Helplessness, Social Integration, Functional Skills and Interpersonal Relationships. Models built from needs assessment factors are stronger than global needs and have a greater association with pertinent variables. Linear regression models based on factors show the importance of satisfaction with life domains and substance abuse in association with higher levels of perceived needs. The recognition of variables associated with each factor would optimize care planning and implementation. 23872415 Glutamatergic receptors at developing synapses: The role of GluN3A-containing NMDA receptors and GluA2-lacking AMPA receptors. During brain development excitatory synapses exhibit significant changes in their postsynaptic receptors and activated signaling pathways. Calcium represents the most crucial signaling factor in synaptic transmission and plasticity. Therefore developmental changes in calcium-permeable channels on the membrane contribute significantly to the modulation of neurotransmission at excitatory synapses. The present review focuses on two types of "non-canonical" glutamate receptors in terms of calcium permeability: GluN3A-containing NMDA receptors (calcium-impermeable) and GluA2-lacking AMPA receptors (calcium permeable). The involvement of these receptors during development and their potential function in synaptic plasticity are discussed. The synaptic incorporation of these receptors would alter calcium permeability, and therefore the threshold/direction of further plastic changes. We believe that characterizing the dynamics of non-canonical glutamate receptors during development could provide insight into how these receptors are recruited or removed in pathological conditions. 23819586 New dicoumarol sodium compound: crystal structure, theoretical study and tumoricidal activity against osteoblast cancer cells. Enormous interest had been paid to the coordination chemistry of alkali and alkaline metal ions because of their role inside body viz; their Li+/Na+ exchange inside the cell lead to different diseases like neuropathy, hypertension, microalbuminuria, cardiac and vascular hypertrophy, obesity, and insulin resistance. It has been presumed that alkali metal ions (whether Na+ or K+) coordinated to chelating ligands can cross the hydrophobic cell membrane easily and can function effectively for depolarizing the ion difference. This unique function was utilized for bacterial cell death in which K+ has been found coordinated valinomycin (antibiotic). Distinct sodium adduct (1) with dicoumarol ligand, 4-Hydroxy-3-[(4-hydroxy-2-oxo-4a,8a-dihydro-2H-chromen-3-yl)-phenyl-methyl]-chromen-2-one (L) is isolated from the saturated solution of sodium methoxide. Single crystal X-ray diffraction studies of the adduct reveals that sodium is in the form of cation attached to a methoxide, methanol and a dicoumarol ligand where carbonyl functional groups of the coumarin derivative are acting as bridges. The sodium compound (1) is also characterized by IR, 1H-NMR, and 13C{1H}-NMR spectroscopic techniques. The composition is confirmed by elemental analysis. DFT study for 1 has been carried out using B3LYP/6-13G calculations which shown the theoretical confirmation of the various bond lengths and bond angles. Both the compounds were studied subsequently for the U2OS tumoricidal activity and it was found that L has LD50 value of 200 muM whereas the sodium analog cytotoxicity did not drop down below 60%. A sodium analogue (1) with medicinally important dicoumarol ligand (L) has been reported. The crystal structure and DFT study confirm the formation of cationic sodium compound with dicoumarol. The ligand was found more active than the sodium analog attributed to the instability of 1 in solution state. Coumarin compound with sodium was observed to be less cytotoxic than the ligand, its LD50 value never dropped below 60%. 23861935 Innate Immune Receptors in Human Airway Smooth Muscle Cells: Activation by TLR1/2, TLR3, TLR4, TLR7 and NOD1 Agonists. Pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs), NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs), recognize microbial components and trigger a host defense response. Respiratory tract infections are common causes of asthma exacerbations, suggesting a role for PRRs in this process. The present study aimed to examine the expression and function of PRRs on human airway smooth muscle cells (HASMCs). Expression of TLR, NLR and RLR mRNA and proteins was determined using real-time RT-PCR, flow cytometry and immunocytochemistry. The functional responses to ligand stimulation were investigated in terms of cytokine and chemokine release, cell surface marker expression, proliferation and proteins regulating the contractile state. HASMCs expressed functional TLR2, TLR3, TLR4, TLR7 and NOD1. Stimulation with the corresponding agonists Pam3CSK4, poly(I:C), LPS, R-837 and iE-DAP, respectively, induced IL-6, IL-8 and GM-CSF release and up-regulation of ICAM-1 and HLA-DR, while poly(I:C) also affected the release of eotaxin and RANTES. The proliferative response was slightly increased by LPS. Stimulation, most prominently with poly(I:C), down-regulated myosin light chain kinase and cysteinyl leukotriene 1 receptor expression and up-regulated β2-adrenoceptor expression. No effects were seen for agonist to TLR2/6, TLR5, TLR8, TLR9, NOD2 or RIG-I/MDA-5. Activation of TLR2, TLR3, TLR4, TLR7 and NOD1 favors a synthetic phenotype, characterized by an increased ability to release inflammatory mediators, acquire immunomodulatory properties by recruiting and interacting with other cells, and reduce the contractile state. The PRRs might therefore be of therapeutic use in the management of asthma and infection-induced disease exacerbations. 23959021 Aerobic Ru-catalyzed direct C2-olefination of N-heteroarenes with alkenes directed by a removable N-dimethylcarbamoyl group. A highly efficient and selective Ru-catalyzed direct C2-olefination of indoles, pyrroles, and carbazoles assisted by a removable N-dimethylcarbamoyl group has been developed by using O2 as the terminal oxidant. Both electron-deficient and unactivated alkenes are applicable to the protocol. 23899567 RBE of kV CBCT radiation determined by Monte Carlo DNA damage simulations. Due to the higher LET of kilovoltage (kV) radiation, there is potential for an increase in relative biological effectiveness (RBE) of absorbed doses of radiation from kV cone beam computed tomography (CBCT) sources in reference to megavoltage or Co-60 doses. This work develops a method for accurately coupling a Monte Carlo (MC) radiation transport code (PENELOPE) with the damage simulation (MCDS) to predict relative numbers of DNA double strand breaks (DSBs). The MCDS accounts for slowing down of electrons and delta ray production within the cell nucleus; however, determining the spectrum of electrons incident on the cell nucleus from photons interacting in a larger region of tissue is not trivial. PENELOPE simulations were conducted with a novel tally algorithm invoked where electrons incident on a detection material were tracked and both the incident energy and the final deposited dose were recorded. The DSB yield predicted by a set of MCDS runs of monoenergetic electrons was then looked up in a table and weighted by the specific energy of the incident electron. Our results indicate that the RBE for DSB induction is 1.1 for diagnostic x-rays with energies from 80 to 125 kVp. We found no significant change in RBE with depth or filtration. The predicted absolute DSB yields are about three times lower for cells irradiated under anoxic conditions than the yield in cells irradiated under normoxic (5%) or fully aerobic (100%) conditions. However, oxygen concentration has a negligible (±0.02) effect on the RBE of kV CBCT x-rays. 23566019 The RAD52 ortholog of Yarrowia lipolytica is essential for nuclear integrity and DNA repair. Yarrowia lipolytica (Yl) is a dimorphic fungus that has become a well-established model for a number of biological processes, including secretion of heterologous and chimerical proteins. However, little is known on the recombination machinery responsible for the integration in the genome of the exogenous DNA encoding for those proteins. We have carried out a phenotypic analysis of rad52 deletants of Y. lipolytica. YlRad52 exhibited 20-30% identity with Rad52 homologues of other eukaryotes, including Saccharomyces cerevisiae and Candida albicans. Ylrad52-Δ strains formed colonies on YPD-agar plates which were spinier and smaller than those from wild type, whereas in YPD liquid cultures they exhibited a decreased grow rate and contained cells with aberrant morphology and fragmented chromatin, supporting a role for homologous recombination (HR) in genome stability under nondamaging conditions. In addition, Ylrad52 mutants showed moderate to high sensitivity to UV light, oxidizing agents and compounds that cause single- (SSB) and double-strand breaks (DSB), indicating an important role for Rad52 in DNA repair. These findings extend to Yl previous observations indicating that RAD52 is a crucial gene for DNA repair in other fungi, including S. cerevisiae, C. albicans and Schizosaccharomyces pombe. 23906858 High Thoracic Epidural Analgesia as an Adjunct to General Anesthesia is Associated with Better Outcome in Low-to-Moderate Risk Cardiac Surgery Patients. The purpose of this study was to evaluate the addition of high thoracic epidural analgesia (HTEA) to general anesthesia in cardiac surgery patients to enhance the fast-track and improvement in outcome. Retrospective cohort study of prospectively registered data using population-based healthcare databases. One thousand seven hundred thirteen consecutive patients scheduled for elective coronary artery bypass grafting, aortic valve replacement, mitral valve surgery, and combinations eligible for supplementation with epidural analgesia. One thousand sixteen patients were matched and analyzed. University hospital, single center. To minimize bias and confounding, epidural patients were matched using EuroSCORE criteria to nonepidural in a 1:1 ratio requiring exact match on sex, age, patient factors, cardiac factors, and procedure type together with normal/moderate/poor left ventricular function, insulin-dependent diabetes, and on-pump/off-pump surgery. All together, 1,016 patients (508 each group) were identified with matching criteria. Outcome parameters were 30-day and 6-month mortality, postoperative dialysis, stroke, and myocardial infarction. Univariate analysis showed that epidural analgesia was associated with lower 6-month mortality (p = 0.021), lower frequency of postoperative dialysis (p = 0.029), and lower frequency of myocardial infarction (p = 0.049). No difference was seen in stroke (p = 0.341). However, adjusted odds ratio of selected perioperative variables showed that HTEA only had a positive impact on the frequency of postoperative dialysis (0.22 [0.06-0.74]). This large, uniquely matched single-center cohort was generated, and, subject to the listed limitations the authors concluded that supplemental HTEA to general anesthesia had a better outcome in low-risk cardiac surgery patients, with a significantly lower 6-month mortality rate compared with the control group. However, regression analysis revealed that HTEA only had an independently positive effect on the frequency of postoperative dialysis. 23902458 Metabolic considerations of drugs in the treatment of allergic diseases. Introduction: The clinical management of allergic diseases involves a number of drugs, most of which are extensively metabolized. This review aims to analyze the metabolism and the clinical implications of altered metabolism for these drugs. Areas covered: The authors present an overview of current knowledge of the metabolism of: antihistamine drugs, glucocorticoids, inhaled β-2 bronchodilators, anticholinergics and other drugs used in allergic diseases, such as cromoglycate, omalizumab, montelukast and epinephrine. Polymorphic drug metabolism is relevant for chlorpheniramine, loratadine and montelukast. Inhibition of drug metabolism is relevant for loratadine, methylprednisolone, fluticasone, mometasone, triamcinolone or prednisolone. Polymorphic pre-systemic metabolism may be relevant to budesonide, fluticasone, beclomethasone, mometasone or salmeterol. The authors also discuss the current information on gene variations according to the 1,000 genomes catalog and other databases. Finally, the authors review the clinical implications of these variations with a particular regard to drugs used in the management of allergic diseases. Expert opinion: Most drugs used in allergic diseases are extensively metabolized. Drug interaction or adverse reactions related to altered metabolism are relevant issues that should be considered in the management of allergic diseases. However, much additional research is required before defining pharmacogenomic biomarkers for the management of drugs used in allergic diseases. 23858509 Biexponential analysis of diffusion-weighted imaging: comparison of three different calculation methods in transplanted kidneys. Biexponential analysis has been used increasingly to obtain contributions of both diffusion and microperfusion to the signal decay in diffusion-weighted imaging DWI of different parts of the body. To compare biexponential diffusion parameters of transplanted kidneys obtained with three different calculation methods. DWI was acquired in 15 renal allograft recipients (eight men, seven women; mean age, 52.4 ± 14.3 years) using a paracoronal EPI sequence with 16 b-values (b = 0-750 s/mm(2)) and six averages at 1.5T. No respiratory gating was used. Three different calculation methods were used for the calculation of biexponential diffusion parameters: Fp, ADCP, and ADCD were calculated without fixing any parameter a priori (calculation method 1); ADCP was fixed to 12.0 µm(2)/ms, whereas Fp and ADCD were calculated using the biexponential model (calculation method 2); multistep approach with monoexponential fitting of the high b-value portion (b ≥ 250 s/mm(2)) for determination of ADCD and assessment of the low b intercept for determination of Fp (calculation method 3). For quantitative analysis, ROI measurements were performed on the according parameter maps. Mean ADCD values of the renal cortex using calculation method 1 were significantly lower than using calculation methods 2 and 3 (P < 0.001). There was a significant correlation between calculation methods 1 and 2 (r = 0.69 (P < 0.005) and calculation methods 1 and 3 (r = 0.59; P < 0.05) as well as calculation methods 2 and 3 (r = 0.98; P < 0.001). Mean Fp values of the renal cortex were higher with calculation method 1 than with calculation methods 2 and 3 (P < 0.001). For Fp, only the correlation between calculation methods 2 and 3 was significant (r = 0.98; P < 0.001). Biexponential diffusion parameters differ significantly depending on the calculation methods used for their calculation. 23770095 AtDGAT2 is a functional acyl-CoA:diacylglycerol acyltransferase and displays different acyl-CoA substrate preferences than AtDGAT1. Demonstration of the function of the Arabidopsis thaliana acyl-CoA:diacylglycerol acyltransferase 2 (AtDGAT2) has remained elusive despite biochemical testing of genetic mutants and overexpression lines. We show that transiently expressed AtDGAT2 in the Nicotiana benthamiana leaf resulted in an increase in triacylglycerol twice as great as the increase observed following parallel expression of AtDGAT1. AtDGAT2 showed higher conversion from labeled diacylglycerol to triacylglycerol compared to AtDGAT1, and was acyl-CoA dependent. In addition, AtDGAT2 had different acyl-CoA substrate preference than AtDGAT1. These results allow us to conclude that AtDAGT2 is a functional acyl-CoA:diacylglycerol acyltransferase enzyme that can catalyse substantial increase in TAG synthesis. 23343421 Cluster phases of decorated micellar solutions with macrocyclic ligands. An aqueous self-assembled micellar system (sodium dodecyl sulfate, SDS, decorated with various adhesive sites, cryptand Kryptofix 222 and crown ether 18-Crown-6 molecules) has been investigated by dynamic light scattering (DLS) and small angle x-ray scattering (SAXS) to have insights into the micellar structure, the micellar interactions, and the aggregation properties of the system. DLS demonstrates the existence of populations of aggregates in the submicrometer/micrometer range, while the Guinier analysis of the SAXS curves helps in detailing objects smaller than 30 nm. The aggregates of micelles are here named cluster phases of micelles (CPMs). Considering that SDS micelles in water do not aggregate at low concentration, it is shown that macrocyclic ligands induce the SDS micelle aggregation as a function of the concentration (i.e., investigated ligand/SDS molar ratios are 5.0, 1.5, 1.0, and 0.5) and hydrophobicity of the adhesive sites. The sizes and the percentages of the micelles and the CPMs have been monitored to test the stability and reversibility of the system. DLS results clearly show that the aggregation processes of the decorated micelles are reproducible at time intervals of the order of 1 month, while the stability may not be entirely maintained after a year. As an issue of particular relevance, the higher the ligand/surfactant molar ratio, the larger are the CPMs induced. The K222 ligand results in being more effective in promoting the micellar aggregation than 18C6 as a consequence of the different hydrophobicity. 23881871 The frequency and cancer risk associated with the atypical cytologic diagnostic category in endoscopic ultrasound-guided fine-needle aspiration specimens of solid pancreatic lesions: A meta-analysis and argument for a Bethesda system for reporting cytopathology of the pancreas. The atypical cytologic diagnostic category is ambiguous and presents a management problem for pathologists and clinicians. This meta-analysis reviewed the frequency and cancer risk associated with atypical diagnoses in endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimens of solid pancreatic lesions. PubMed and Scopus were searched using the keywords "EUS-FNA" and "pancreas." Articles were screened focusing on studies of solid lesions. Studies with information regarding the frequency and outcomes of atypical diagnoses were included; the "suspicious" category was excluded from the analysis. The frequency of atypical diagnoses and the associated risk were calculated using the Comprehensive Meta-Analysis software. The authors assessed whether the following factors explained the heterogeneity of the studies: rapid on-site interpretation; type of reference standard; the study type, size, and site; and the frequency of inadequate, atypical, and positive categories. A total of 23 studies with complete data regarding atypical diagnoses were identified, 12 of which had complete data available regarding outcomes. The frequency of the atypical category ranged from 1% to 14% (mean, 5.3%; 95% confidence interval, 4.1%-6.9%). The risk of malignancy associated with an atypical diagnosis ranged from 25% to 100% (mean, 58%; 95% confidence interval, 47%-69%). There was significant heterogeneity noted among the studies (I-squared, 62%; P = .0004). The frequency of the atypical category and its associated risk were found to be correlated only with the frequency of the specimens being positive for malignancy. The rate of atypical diagnoses of the pancreas is similar to that of the thyroid but the risk of malignancy is higher. Significant heterogeneity exists among the studies reporting atypical diagnoses. There is a need for standardization of the reporting and management of atypical diagnoses in EUS-FNA specimens from the pancreas. Cancer (Cancer Cytopathol) 2013. © 2013 American Cancer Society. 23857385 Antibiogram and characterization of resistance markers among Escherichia coli Isolates from urinary tract infections. Urinary tract infection is the most frequently diagnosed kidney and urologic disease, and Escherichia coli is by far its most common etiological agent. Uropathogenic E. coli are responsible for approximately 90% of urinary tract infections seen in individuals with ordinary anatomy therefore, it is essential to review the antibiogram of uropathogenic E. coli periodically to help clinicians decide on the appropriate therapy. We evaluated E. coli isolated from urinary tract infections at the National Salmonella and Escherichia Centre for antibiogram, plasmid transferability and stability of resistance markers. In total, 90.9% of the isolates were found to be sensitive to nitrofurantoin while the highest proportion of the isolates was found to be resistant to nalidixic acid. Minimum inhibitory concentrations of all antimicrobials for different isolates were well within the limits specified by the Clinical and Laboratory Standards Institute.  Resistance against tetracycline was not transferred either by conjugation and transformation. Streptomycin resistance was found to be lost in the maximum number of tested isolates showing loss at the 10th, 15th and 20th passages. Changing trends in antibiotic resistance necessitates the periodic generation of antibiogram data to help health authorities revise treatment strategies for urinary tract infections caused by E. coli. 23892851 Tubularized incised plate repair in circumcised adults. Aim In this study, the experience of tubularized incised plate repair in circumcised adults in terms of functional, cosmetic, and satisfactory results is reported. Methods Tubularized incised plate repair urethroplasty (TIPU) was performed to 27 circumcised adult patients between 2008- 2010; 19 (70.4%) had distal penile hypospadias and eight (29.6%) had midshaft hypospadias. All patients were operated by a single surgeon and were asked to fill out a questionnaire to asses functional and cosmetic results of the surgery. Results The mean age of patients was 22.0 years. All patients were controlled in urology office seven days after the removal of urethral catheter. They were controlled in the 3rd, 6th, and 12th month after the operation and they filled out the questionnaire in the 6th month after the operation in the TIP. The mean follow up was 13 months. Three (11.1%) patients had meatus stenosis and two (7.4%) urethral fistula as a complication. Twenty-four (88.8%) patients reported that they were satisfied about penile length, 26 (96.2%) about the appearance of the meatus, 25 (92.5%) about the appearance of the glans penis, 22 (81.4%) about the appearance of the foreskin, 23 (85.1%) about the straightness of the penis with erection, and 24 (88.8%) about the overall appearance of the penis. All patients were satisfied about the urinary flow and seven (100%) patients who were sexually active reported that they were satisfied with vaginal penetration and sexual satisfaction. Conclusion Tubularized incised plate repair technique reveals good functional and cosmetic results even in adults who were circumcised. Keywords: hypospadias, cosmetic outcome, circumcision Med Glas. 23886787 Protein and polysaccharide-composite sol-gel silicate film for an interference-free amperometric glucose biosensor. A novel permselective, organic-inorganic-hybrid, sol-gel silicate-film was chemically modified on an anodized platinum (Pt) electrode surface to form a selective, sensitive and interference-free amperometric glucose biosensor. This permselective hybrid sol-gel film consists of three organo-silanes [i.e., 3-aminopropyltriethoxysilane (APTES); tetraethoxysilane (TEOS); triethoxy-1H,1H,2H,2H-tridecafluoro-n-octylsilane (FAS)] and two biomacromolecules [i.e., bovine serum albumin (BSA) and a chitosan (CHIT)]. After the addition of the film to the Pt electrode, glucose oxidase (GOx) was covalently immobilized within the film with glutaraldehyde. The incorporation of the BSA and CHIT not only enhanced the permselectivity of H2O2 but also improved the activity of the immobilized GOx. The CHIT effectively suppressed any swelling of the film. Moreover, the conjugation of the FAS was especially effective in reducing the interference currents of AA and UA to levels less than 1/400 and 1/300 of the current of H2O2. The resulting organic-inorganic-hybrid sol-gel-film-based amperometric glucose biosensor exhibited rapid and sensitive responses to glucose (100% response in <3s, sensitivity: 1.84μAmM(-1), detection limit: 0.032mM), and the highly selective determination of glucose was possible, even in the presence of 0.1mM AA and UA. 23906654 Intensive complete decongestive physiotherapy for cancer-related upper-limb lymphedema: 11days achieved greater volume reduction than 4. Upper-limb lymphedema (ULL) occurs in 15-20% of women after breast-cancer treatment. Its intensive therapy relies on complete (complex) decongestive physiotherapy (CDP), whose duration is not well-established. Determine optimal intensive-phase CDP duration for lymphedema-volume reduction and factors predicting its success, with the hope of halving it from 11 to 4days. All patients with ULL (08/2011-06/2012) after breast-cancer treatment referred to our Department of Lymphology in a rehabilitation facility for 11days of CDP were eligible. Lymphedema volume was calculated using the truncated-cone formula. Volume reduction considered clinically relevant after 4days was defined as ≥75% of the total reduction obtained after 11days. We included 129 women (median age: 64 (range: 42-88) years). Mean (sd) lymphedema volume was 907 (558) ml at CDP onset, decreased to 712 (428) ml after 4days (vs. onset, P<.0001) and 606 (341) ml after 11days (vs. 4, P<.0001), corresponding to 33% total lymphedema-volume reduction. For all patients, 4days of CDP achieved 63% (sd 40%) of that total reduction, with ≥75% for 50 (39%) patients. Surgery-to-lymphedema-onset interval >2years was the only factor significantly associated with 4days achieving ≥75% of the total lymphedema-volume reduction. Intensive phase CDP for 11days obtained significantly more volume reduction of breast cancer-related ULL than 4. 23648326 Distinguishing dissolved organic matter at its origin: Size and optical properties of leaf-litter leachates. Dissolved organic matter (DOM) was leached from eight distinct samples of leaves taken from six distinct trees (red maple, bur oak at three times of the year, two sugar maple and two white spruce trees from disparate soil types). Multiple samples were taken over 72-96h of leaching. The size and optical properties of leachates were assessed using asymmetrical flow field-flow fractionation (AF4) coupled to diode-array ultraviolet/visible absorbance and excitation-emission matrix fluorescence detectors (EEM). The fluorescence of unfractionated samples was also analyzed. EEMs were analyzed using parallel factor analysis (PARAFAC) and principal component analysis (PCA) of proportional component loadings. Both the unfractionated and AF4-fractionated leachates had distinct size and optical properties. The 95% confidence ranges for molecular weight distributions were determined as: 210-440Da for spruce, 540-920Da for sugar maple, 630-800Da for spring oak leaves, 930-950Da for senescent oak, 1490-1670 for senescent red maple, and 3430-4270Da for oak leaves that were collected from the ground after spring thaw. In most cases the fluorescence properties of leachates were different for individuals from different soil types and across seasons; however, PCA of PARAFAC loadings revealed that the observed distinctiveness was chiefly species-based. Strong correlations were found between the molecular weight distribution of both unfractionated and fractionated leachates and their principal component loadings (R(2)=0.85 and 0.95, respectively). It is concluded that results support a species-based origin for differences in optical properties. 23406951 Exposure to lambda-cyhalothrin, a synthetic pyrethroid, increases reactive oxygen species production and induces genotoxicity in rat peripheral blood. Lambda-cyhalothrin (LTC) is a synthetic pyrethroid with a broad spectrum of insecticidal and acaricidal activities used to control a wide range of insect pests in a variety of applications. However, there is little known about its adverse effects, in particular those related to its genotoxicity in humans. To elucidate the genotoxicity mechanisms of LTC, the micronuclei (MN) frequencies, the levels of reactive oxygen species (ROS), erythrocyte osmotic fragility, nitrite (NO) formation, protein carbonyl (PCO) levels and malondialdehyde (MDA) production were evaluated for a period of 7, 14 and 21 days. Our results show that exposure rat to LTC (1/10DL50 = 6.23 mg/kg) for a period of 7, 14 and 21 days induced a noticeable genotoxic effect in rat peripheral blood evidenced by a significant increase in the frequency of MN only at day 21 of treatment. Significant differences between the two groups were observed in erythrocyte osmotic fragility. Further, a significant (p < 0.01) increase in ROS contents, NO formation, PCO levels and lipid peroxidation in erythrocytes were observed at different times of treatments, suggesting the implication of oxidative stress in its toxicity. These results confirm the genotoxic and the pro-oxidant effects of LTC in rat peripheral blood. 23968845 Low frequency mu-like activity characterizes cortical rhythms in epilepsy due to ring chromosome 20. To evaluate the spectral and spatial features of the cortical rhythms in patients affected by ring chromosome 20 - [r(20)]-syndrome. Twelve patients with [r(20)] syndrome were studied. As controls we enrolled 12 patients with idiopathic generalized epilepsy (IGE) and 12 healthy volunteers (HV). Blind source separation, spectral analyses and source reconstruction were applied in all cases in order to identify reliable spatio-temporal patterns of cortical activity. A theta-delta EEG rhythm was identified in [r(20)] patients, with spectral peak ranging between 3 and 7Hz and whose generators mapped over the sensory-motor cortices. A second peak laying at a frequency about double with respect to the first one was present in 6 cases. Analogue methodological approach in HV and IGE groups failed to show similar findings. EEG of [r(20)] patients reveals the existence of a highly reproducible EEG pattern arising from the sensory-motor system. The recognition of this peculiar EEG pattern could help the diagnostic work-up. Additionally, our findings supports the existence of a parallelism between this EEG trait and the physiological "mu" rhythm which is generate by the sensory-motor system. Such link suggests a sensory-motor system dysfunction in [r(20)] patients. 23340851 Psychosomatic symptom profiles in patients with restless legs syndrome. It has been reported that restless legs syndrome (RLS) might be associated with multiple psychosomatic symptoms. We aimed to identify which psychosomatic symptom is the most related in RLS patients compared to healthy controls. We also attempted to determine the relation between psychosomatic comorbidity and RLS severity regardless of sleep-related symptoms. One hundred two newly diagnosed patients with RLS and 37 healthy control subjects participated in the present study. The RLS patients were categorized as mild and severe based on the International RLS Study Group rating scale. Data on demographics were collected. All participants completed the Pittsburgh Sleep Quality Index, Athens Insomnia Scale, and Epworth Sleepiness Scale as sleep-related questionnaires. All participants completed the Symptom Checklist-90-Revision (SCL-90-R). RLS patients were found to have pervasive comorbid psychosomatic symptoms. Somatization was found to be the most significant contributing factor (OR 1.145, 95 % CI 1.061-1.234, p < 0.001) for psychosomatic comorbidity in RLS. Severe RLS patients were found to have poorer sleep quality than mild RLS patients. Furthermore, severe RLS patients had higher scores for most psychosomatic symptom domains in SCL-90-R. Anxiety was found to be the most independent contributing factor for psychosomatic comorbidity according to RLS severity (OR 1.145, 95 % CI 1.043-1.257, p = 0.005). Our study demonstrates that comorbid psychosomatic distress is considerable in patients with RLS. Furthermore, most psychosomatic comorbidity is increased with the RLS severity in association with poorer sleep quality. 22942129 Cardiovascular risk assessment in diabetes mellitus: comparison of the general Framingham risk profile versus the World Health Organization/International Society of Hypertension risk prediction charts in Arabs--clinical implications. We estimated the prevalence of cardiovascular disease (CVD) risk and its clinical implications among 1 110 Omani patients with type 2 diabetes mellitus (DM) using 2 different CVD risk tools: the general Framingham risk profile (GFRP) and the joint World Health Organization/International Society of Hypertension (WHO/ISH) risk prediction charts. The GFRP tool identified higher proportion of patients compared with joint WHO/ISH tool at 10-year CVD risk 10% to <20% and at 20% to <30%. At CVD risk ≥30%, both assessment tools identified similar proportions of patients (22% vs 24%; P=.120). Compared with WHO/ISH charts, the GFRP identified almost double the number of men eligible for aspirin treatment at CVD risk thresholds of ≥10% (86% vs 43%). In women, the proportions were, 66% and 45%, respectively. For statins, the figures were, 60% and 37%, for men and 28% and 36%, for women. In conclusion, the GFRP overestimates the number of patients eligible for primary prevention of CVD compared with the joint WHO/ISH method. 23831453 A complete multilocus species phylogeny of the tits and chickadees (Aves: Paridae). The avian family Paridae (tits and chickadees) contains c. 55 species distributed in the Palearctic, Nearctic, Afrotropics and Indomalaya. The group includes some of the most well-known and extensively studied avian species, and the evolutionary history, in particular the post-glacial colonization of the northern latitudes, has been comparably well-studied for several species. Yet a comprehensive phylogeny of the whole clade is lacking. Here, we present the first complete species phylogeny for the group based on sequence data from two nuclear introns and one mitochondrial gene for 67 taxa of parids. Our results strongly support the inclusion of the Fire-capped Tit (Cephalopyrus flammiceps), currently placed in the Remizidae, as the most basal member of the Paridae. The Yellow-browed Tit (Sylviparus modestus) and the Sultan Tit (Melanochlora sultanea) constitute the next two sequential branches whereas the remaining tits fall into two large clades, one of which contains the seed hoarding and nest excavating species. The indicated clades within these two groups are largely congruent with recent classifications, but with several unforeseen relationships, such as non-monophyly of the Sombre Tit (Poecile lugubris) and the Marsh Tit (Poecile palustris), as well as non-monophyly of both the African gray and the African black tits. Further, our results support a close relationship between the White-fronted Tit (Parus semilarvatus) and the varied Tit (Poecile varius) as well as a close relationship between the White-naped Tit (Parus nuchalis) and the Yellow-cheeked and Black-lored tits (Parus spilonotus and P. xanthogenys). Finally, Hume's Ground-tit (Pseudopodoces humilis) is found to be closely related to the Green-backed Tit (Parus monticolus) and the Great Tit (Parus major). We propose a new classification that is in accordance with this phylogeny. 23598895 Home-made Feeding Bottles Have Inadequacies in Their Nutritional Composition Regardless of Socioeconomic Class. Fifty-four and fifty samples of home-prepared feeding bottles for infants from a public health unit (low socioeconomic group, LSG) and from a private pediatric clinic (high socioeconomic group, HSG), respectively, were chemically analyzed, and their energy, macronutrient and iron contents were compared with the standard composition recommended for follow-up formulas. Cow's milk and sucrose and cereals added to the bottles were largely used in the study. Energy, protein and carbohydrate contents were higher than the recommended level in 75.9, 27.7 and 81.5% of LSG samples and 62.0, 48.0 and 34.0% of HSG samples, respectively. Fat content was lower than the recommended level in 83.3% of LSG and 58.0% of HSG samples. Excessive values of energy, carbohydrates and protein, low fat content and macronutrient imbalance were found regardless of the socioeconomic class, thus indicating the need to improve the domestic feeding bottles' preparation practices and discourage the use of cow's milk and the addition of other ingredients. 23404680 Functional UDP-glucuronyltransferase 2B15 polymorphism and bisphenol A concentrations in blood: results from physiologically based kinetic modelling. Bisphenol A (BPA) is a chemical in widespread use that is under scientific discussion due to its endocrine activity. Controversies exist about how to interpret reportedly high blood concentrations measured in uncontrolled situations. Physiologically based pharmaco-/toxicokinetic modelling resulted in 10-100-fold lower blood concentrations than those reported. Moreover, in controlled situations, BPA did not exceed the level of detection (<0.3 ng/ml) in human blood or urine. Using a validated human PBK model, this study investigated the influence of functionally relevant polymorphic UGT2B15, the enzyme mediating BPA metabolism, on the BPA concentration-time profile in human blood. Maximum concentrations (C (max)) and areas under the curves (AUCs) in blood from high and low metabolisers differed by a factor of 4.7 and 4.6, respectively (doses: 1 and 0.05 μg/kg/day). Low metabolisers excreted a greater proportion of BPA via the sulphate pathway compared to high metabolisers. This finding explains why C (max) and AUC increased to a smaller extent, as predicted from in vitro data obtained with transfected cells possessing only the UGT2B15 variants. The highest C (max) value calculated in the subject with the lowest metabolic clearance was roughly 40 pg/ml, which is far lower than reported high blood concentrations, which in turn cannot be explained by genetically impaired UGT2B15 activity. From the risk assessment perspective, our results indicate that the traditional uncertainty factor is sufficient to account for the variability in the polymorphic glucuronidation of BPA. 23902859 US in the assessment of acute scrotum. The acute scrotum is a medical emergency . The acute scrotum is defined as scrotal pain, swelling, and redness of acute onset. Scrotal abnormalities can be divided into three groups , which are extra-testicular lesion, intra-testicular lesion and trauma. This is a retrospective analysis of 164 ultrasound examination performed in patient arriving in the emergency room for scrotal pain.The objective of this article is to familiarize the reader with the US features of the most common and some of the least common scrotal lesions. Between January 2008 and January 2010, 164 patients aged few month and older with scrotal symptoms, who underwent scrotal ultrasonography (US), were retrospectively reviewed. The clinical presentation, outcome, and US results were analyzed. The presentation symptoms including scrotal pain, painless scrotal mass or swelling, and trauma. Of 164 patients, 125 (76%) presented with scrotal pain, 31 (19%) had painless scrotal mass or swelling and 8 (5%) had trauma. Of the 125 patients with scrotal pain, 72 had infection,10 had testicular torsion, 8 had testicular trauma, 18 had varicocele, 20 had hydrocele, 5 had cryptorchidism, 5 had scrotal sac and groin metastases, and 2 had unremarkable results. In the 8 patients who had history of scrotal trauma, US detected testicular rupture in 1 patients, scrotal haematomas in 2 patients .Of the 19 patients who presented with painless scrotal mass or swelling, 1 6 had extra-testicular lesions and 3 had intra-testicular lesions. All the extra-testicular lesions were benign. Of the 3 intra-testicular lesions, one was due to tuberculosis epididymo-orchitis, one was non-Hodgkin's lymphoma, and one was metastasis from liposarcoma US provides excellent anatomic detail; when color Doppler and Power Doppler imaging are added, testicular perfusion can be assessed. 23842732 Highly stable and flexible silver nanowire-graphene hybrid transparent conducting electrodes for emerging optoelectronic devices. A new AgNW-graphene hybrid transparent conducting electrode (TCE) was prepared by dry-transferring a chemical vapor deposition (CVD)-grown monolayer graphene onto a pristine AgNW TCE. The AgNW-graphene hybrid TCE exhibited excellent optical and electrical properties as well as mechanical flexibility. The AgNW-graphene hybrid TCE showed highly enhanced thermal oxidation and chemical stabilities because of the superior gas-barrier property of the graphene protection layer. Furthermore, the organic solar cells with the AgNW-graphene hybrid TCE showed excellent photovoltaic performance as well as superior long-term stability under ambient conditions. 22901526 Treatment of fractures of the condylar head with resorbable pins or titanium screws: an experimental study. We aimed to compare in vivo the stability of fixation of condylar fractures in sheep using sonic bone welding and standard titanium screws. We assessed stability of the osteosynthesis and maintenance of the height of the mandibular ramus. Height decreased slightly in both groups compared with the opposite side. The volume of the condyle increased considerably in both groups mainly because callus had formed. The results showed no significant disadvantages for pin fixation compared with osteosynthesis using titanium screws. 23674081 Design and Validation of a Colorimetric Test for the Genetic Diagnosis of Hemochromatosis Using α-Phosphorothioate Nucleotides. Hereditary hemochromatosis is an autosomal recessive disease highly prevalent in Northern Europe. Here we describe the performance of a genetic test for two mutations of the HFE gene (C282Y and H63D). It is based on a solid-phase PCR coupled with an α-phosphorothioate-mediated primer extension, conferring resistance to hydrolysis by ExoIII. Next, Elisa-like detection allows a colorimetric reading of the genetic test. We performed 322 tests (212 on the C282Y mutation, 110 on the H63D mutation) and compared the results with the RFLP method. Using OD ranges giving the minimum of uncertainty, the tests lead to high specificity and sensitivity, and they address the detection of mutated or normal bases in the HFE gene or the deduced phenotype (safe or ill), with positive predictive values or negative ones greater than 0.96. This method is therefore proposed as a primary test or as a confirming test. 23890008 A chemical biology approach to interrogate quorum-sensing regulated behaviors at the molecular and cellular level. Small molecule probes have been used extensively to explore biologic systems and elucidate cellular signaling pathways. In this study, we use an inhibitor of bacterial communication to monitor changes in the proteome of Salmonella enterica serovar Typhimurium with the aim of discovering unrecognized processes regulated by AI-2-based quorum-sensing (QS), a mechanism of bacterial intercellular communication that allows for the coordination of gene expression in a cell density-dependent manner. In S. typhimurium, this system regulates the uptake and catabolism of intercellular signals and has been implicated in pathogenesis, including the invasion of host epithelial cells. We demonstrate that our QS antagonist is capable of selectively inhibiting the expression of known QS-regulated proteins in S. typhimurium, thus attesting that QS inhibitors may be used to confirm proposed and elucidate previously unidentified QS pathways without relying on genetic manipulation. 23436029 Suicide plasmid-dependent IS1-element untargeted integration into Aeromonas veronii bv. sobria generates brown pigment-producing and spontaneous pelleting mutant. Foodborne Gram-negative pathogens belonging to the genus Aeromonas are variable in harboring insertion sequence (IS) elements that play an important role in the generation of dysfunctional relatives of known genes. Using suicide plasmids carrying an IS1-element, untargeted integration is a common problem during experimental trials to generate specific mutations by homologous recombination. In this work, different strains of Aeromonas veronii bv. sobria (AeG1 and ATCC 9071T), A. hydrophila ATCC 19570, and A. sobria ATCC 43979T are examined for acquisition of IS1-element from pYAK1 suicide plasmid. It was found that untargeted integration of IS1-element is encountered only in ATCC 9071T strain. Such untargeted integration generates a novel brown pigment-producing and spontaneous pelleting (BP(+)SP(+)) mutant. Furthermore, BP(+)SP(+) mutant strain secretes significantly higher quantity of PilF homologous protein than the wild-type strain and displays an enhanced protein tyrosine phosphorylation activity. Thus, current work shows that Aeromonas spp. strains are variable in their susceptibility for suicide plasmid-dependent IS1-element untargeted integration as well as the susceptible strain is changed to mimic pigment-producing and spontaneous pelleting strains that are naturally occurring among heterogeneous group of foodborne aeromonads. 23739229 Atrial fibrillation and cognitive decline: A longitudinal cohort study. We sought to determine whether in the absence of clinical stroke, people with atrial fibrillation experience faster cognitive decline than people without atrial fibrillation. We conducted a longitudinal analysis in the Cardiovascular Health Study, a community-based study of 5,888 men and women aged 65 years and older, enrolled in 1989/1990 or 1992/1993. Participants did not have atrial fibrillation or a history of stroke at baseline. Participants were censored when they experienced incident clinical stroke. Incident atrial fibrillation was identified by hospital discharge diagnosis codes and annual study ECGs. The main outcome was rate of decline in mean scores on the 100-point Modified Mini-Mental State Examination (3MSE), administered annually up to 9 times. Analyses included 5,150 participants, of whom 552 (10.7%) developed incident atrial fibrillation during a mean of 7 years of follow-up. Mean 3MSE scores declined faster after incident atrial fibrillation compared with no prior atrial fibrillation. For example, the predicted 5-year decline in mean 3MSE score from age 80 to age 85 was -6.4 points (95% confidence interval [CI]: -7.0, -5.9) for participants without a history of atrial fibrillation, but was -10.3 points (95% CI: -11.8, -8.9) for participants experiencing incident atrial fibrillation at age 80, a 5-year difference of -3.9 points (95% CI: -5.3, -2.5). In the absence of clinical stroke, people with incident atrial fibrillation are likely to reach thresholds of cognitive impairment or dementia at earlier ages than people with no history of atrial fibrillation. 23627903 How Selective Are the New Guidelines for Treatment of Subclinical Hypothyroidism for Patients with Thyrotropin Levels At or Below 10 mIU/L? Background: By consensus, a thyrotropin (TSH) level persistently >10 mIU/L is an indication for the treatment of subclinical hypothyroidism (SCH). Controversy exists regarding patients whose TSH level is elevated but <10 mIU/L. Recently, the American Thyroid Association (ATA) and the American Association of Clinical Endocrinologists (AACE) published their position about factors that should be considered in the decision on treating SCH. This study evaluated the frequency of these factors among adult (non-pregnant) women with SCH whose TSH levels are ≤10 mIU/L. Methods: The presence of the conditions that should be considered for the treatment of SCH according to ATA and AACE was evaluated in 252 women who were diagnosed with SCH and had TSH levels ≤10 mIU/L. Pregnant women were excluded. Results: Antithyroperoxidase antibodies (TPOAbs) were detected in 137 (54.3%) women. A high cardiovascular risk was observed in 43 (17%) women. Eighty (31.7%) women who were not at high cardiovascular risk presented at least one classical risk factor (arterial hypertension, elevated level of low-density lipoprotein-cholesterol or low level of high-density lipoprotein-cholesterol, smoking, or first-degree family history of premature coronary artery disease). At least one symptom or sign of hypothyroidism that could not be explained by another condition was observed in 180 (71.4%) women. Two hundred thirty-two (92%) women had positive TPOAbs, or at least one classical cardiovascular risk factor, or at least one symptom or sign of hypothyroidism. Conclusions: According to the new ATA and AACE guidelines, L-T4 therapy would be considered for 92% of women with SCH and TSH ≤10 mIU/L. 23749450 Targeted Sequence Capture Provides Insight into Genome Structure and Genetics of Male Sterility in a Gynodioecious Diploid Strawberry, Fragaria vesca ssp. bracteata (Rosaceae). Gynodioecy is a sexual system wherein females coexist with hermaphrodites. It is of interest not only because male-sterile plants are advantageous in plant breeding but also because it can be a crucial step in the evolutionary transition to entirely separate sexes (dioecy) from a hermaphroditic ancestor. The gynodioecious diploid wild strawberry, Fragaria vesca ssp. bracteata (Rosaceae), is a member of a clade with both dioecious and cultivated species, making it an ideal model in which to study the genetics of male sterility. To create a genetic map of F. v. ssp. bracteata, we identified informative polymorphisms from genomic sequencing (3-5x coverage) of two outbred plants from the same population. Using targeted enrichment, we sequenced 200 bp surrounding each of 6575 polymorphisms in 48 F1 offspring, yielding genotypes at 98% of targeted sites with mean coverage >100x, plus more than 600-kb high-coverage nontargeted sequence. With the resulting linkage map of 7802 stringently filtered markers (5417 targeted), we assessed recombination rates and genomic incongruities. Consistent with past work in strawberries, male sterility is dominant, segregates 1:1, and maps to a single location in the female. Further mapping an additional 55 offspring places male sterility in a gene-dense, 338-kb region of chromosome 4. The region is not syntenic with the sex-determining regions in the closely related octoploids, F. chiloensis and F. virginiana, suggesting either independent origins or translocation. The 57 genes in this region do not include protein families known to control male sterility and thus suggest alternate mechanisms for the suppression of male function. 23711785 Controlled release and antibacterial activity of antibiotic-loaded electrospun halloysite/poly(lactic-co-glycolic acid) composite nanofibers. Fabrication of nanofiber-based drug delivery system with controlled release property is of general interest in biomedical sciences. In this study, we prepared an antibiotic drug tetracycline hydrochloride (TCH)-loaded halloysite nanotubes/poly(lactic-co-glycolic acid) composite nanofibers (TCH/HNTs/PLGA), and evaluated the drug release and antibacterial activity of this drug delivery system. The structure, morphology, and mechanical properties of the formed electrospun TCH/HNTs/PLGA composite nanofibrous mats were characterized using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy, and tensile testing. We show that the incorporation of TCH-loaded HNTs within the PLGA nanofibers is able to improve the tensile strength and maintain the three-dimensional structure of the nanofibrous mats. In vitro viability assay and SEM morphology observation of mouse fibroblast cells cultured onto the fibrous scaffolds demonstrate that the developed TCH/HNTs/PLGA composite nanofibers are cytocompatible. More importantly, the TCH/HNTs/PLGA composite nanofibers are able to release the antibacterial drug TCH in a sustained manner for 42 days and display antimicrobial activity solely associated with the encapsulated TCH drug. With the improved mechanical durability, sustained drug release profile, good cytocompatibility, and non-compromised therapeutic efficacy, the developed composite electrospun nanofibrous drug delivery system may be used as therapeutic scaffold materials for tissue engineering and drug delivery applications. 23317339 Thermal sintering: a novel technique used in the design, optimization and biopharmaceutical evaluation of propranolol HCl gastric floating tablets. Abstract The objective of the present investigation was to study the applicability of thermal sintering technique for the development of gastric floating tablets of propranolol HCl. Formulations were prepared using four independent variables, namely (i) polymer quantity, (ii) sodium bicarbonate concentration, (iii) sintering temperature and (iv) sintering time. Floating lag time and t(95) were taken as dependent variables. Tablets were prepared by the direct compression method and were evaluated for physicochemical properties, in vitro buoyancy and dissolution studies. From the drug release studies, it was observed that drug retarding property mainly depends upon the sintering temperature and time of exposure. The statistically optimized formulation (PTSso) was characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry studies, and no significant chemical interaction between drug and polymer was observed. Optimized formulation was stable at accelerated conditions for a period of six months. PTSso was evaluated for in vivo buoyancy studies in humans for both fed and fasted states and found that gastric residence time of the floating tablets were enhanced by fed stage but not in fasted state. Optimized formulation PTSso and commercial formulation Ciplar LA 80 were subjected to bioavailability studies in healthy human volunteers by estimating pharmacokinetic parameters such as C(max), T(max), area under curve (AUC)(,) elimination rate constant (K(el)), biological half-life (t(1/2)) and mean residence time (MRT). There was a significant increase in the bioavailability of the propranolol HCl from PTSso formulation, which was evident from increased AUC levels and larger MRT values than Ciplar LA 80. 23757390 Dispersed Ru nanoclusters transformed from a grafted trinuclear Ru complex on SiO2 for selective alcohol oxidation. Ru nanoclusters (average diameter = 1.3 ± 0.3 nm) were successfully prepared by using a Ru3 cluster Ru3O(CH3COO)6(H2O)3·(CH3COO) grafted on a pyridine-functionalized SiO2 surface. The pyridine moiety dispersed on the SiO2 surface spread the Ru3 cluster, controlling its surface density, and the nanoclusterization of the Ru cluster proceeded on the surface. The structures of the Ru nanoclusters were characterized by means of elemental analysis; thermogravimetric analysis; FT-IR, UV/vis, and solid-state NMR spectroscopy; BET analysis; X-ray photoelectron spectroscopy; X-ray diffraction; transmission electron microscopy; and Ru K-edge X-ray absorption fine structure analysis. It was found that the catalytic activity for the selective oxidation of alcohol to the corresponding aldehyde using O2 highly depended on the dispersion and structures of the Ru particles, and the Ru nanocluster was found to be efficient in the selective oxidation of a variety of alcohols. 23774048 Activation of invariant natural killer T cells by α-galactosylceramide ameliorates myocardial ischemia/reperfusion injury in mice. Invariant natural killer T (iNKT) cells orchestrate tissue inflammation via regulating various cytokine productions. However the role of iNKT cells has not been determined in myocardial ischemia/reperfusion (I/R) injury. The purpose of this study was to examine whether the activation of iNKT cells by α-galactosylceramide (α-GC), which specifically activates iNKT cells, could affect myocardial I/R injury. I/R or sham operation was performed in male C57BL/6J mice. I/R mice received the injection of either αGC (I/R+αGC, n=48) or vehicle (I/R+vehicle, n=49) 30min before reperfusion. After 24h, infarct size/area at risk was smaller in I/R+αGC than in I/R+vehicle (37.8±2.7% vs. 47.1±2.5%, P<0.05), with no significant changes in area at risk. The numbers of infiltrating myeloperoxidase- and CD3-positive cells were lower in I/R+αGC. Apoptosis evaluated by TUNEL staining and caspase-3 protein was also attenuated in I/R+αGC. Myocardial gene expression of tumor necrosis factor-α and interleukin (IL)-1β in I/R+αGC was lower to 46% and 80% of that in I/R+vehicle, respectively, whereas IL-10, IL-4, and interferon (IFN)-γ were higher in I/R+αGC than I/R+vehicle by 2.0, 4.1, and 9.6 folds, respectively. The administration of anti-IL-10 receptor antibody into I/R+αGC abolished the protective effects of αGC on I/R injury (infarct size/area at risk: 53.1±5.2% vs. 37.4±3.5%, P<0.05). In contrast, anti-IL-4 and anti-IFN-γ antibodies did not exert such effects. In conclusion, activated iNKT cells by αGC play a protective role against myocardial I/R injury through the enhanced expression of IL-10. Therapies designed to activate iNKT cells might be beneficial to protect the heart from I/R injury. 23494191 Evaluating the use of algal pigments to assess the biological condition of streams. Assessments of stream condition using benthic algal communities have traditionally relied on taxonomy-based approaches to compare community structure at sites exposed to a stressor versus reference sites. Taxonomy-based methods are often effective, but they require high levels of training and are relatively time consuming and expensive. We examined the utility of assessing stream biological condition using algal pigments. We used gradient and control-impact study designs in 2008 and 2009 to compare the extent that algal pigments versus taxonomic descriptors of algal community structure varied along a 10.5-km stretch of the Flat River (South Nahanni River watershed, NWT, Canada) encompassing a gradient of nutrients and metals at sites upstream, adjacent to and downstream of a northern metals mine. We also calculated costs to quantify algal pigments relative to taxonomy-based methods. Multivariate analyses (ANOSIM tests, redundancy analysis) identified that pigment concentrations from benthic algal samples differed significantly (p < 0.05) between non-exposed and exposed river sites and were related to variations in water physico-chemical conditions. By contrast, community composition determined from taxonomy-based enumeration to the Order and Family levels did not differ significantly between non-exposed and exposed sites, and relations with water physico-chemical conditions were weaker and inconsistent between the study years. In-house costs to quantify algal pigments were lower than commercial rates to describe community structure using taxonomy. Thus, our data suggests that analysis of benthic algal pigments represents a viable and cost-effective bio-monitoring method for assessing anthropogenic effects on stream condition that merits further evaluation. 23732441 Analysis of an alternative to the H-atom abstraction mechanism in methane C-H bond activation by nonheme iron(IV)-oxo oxidants. The triplet δ-mechanism different from the previously reported ones, i.e., the π-channel with the unoccupied π(xz/yz)* (FeO) orbital and the σ-channel involving the unoccupied α-spin Fe(z2)*-σ orbital, has been theoretically described for the methane hydroxylation by [Fe(IV) = O(TMC)(SR)](+) and its derivative [Fe(IV) = O(TMC)(OH)](+) complex for the first time, and we have undertaken a detailed DFT study on the nature of this state by probing its geometry, electronic property and reactivity in comparison to all other possibilities. DFT calculations indicate that the electron transfer for the (3)δ-channel from the σ(C-H) orbital of the substrate to the final acceptor σ(x2-y2)* orbital of the catalyst occurs through a complex mechanism, which is initiated by the original α-spin electron transfer from the π* orbital of the catalyst to the σ(x2-y2)* orbital, where the α-spin electron from the σ(C-H) orbital of the substrate shifts to the just empty α-spin π* orbital of the catalyst via the O-p(x/y) based π(xz/yz)*-orbital concomitantly. It is also found that the electron-donating ability of the axial ligand could influence the reaction channels, evident by the distinction that the electron-deficient F(-) and CF3CO2(-) ligands react via the (3)σ-channel, whereas the electron-rich SR(-) and OH(-) ligands proceed by the (3)δ-channel. With respect to reactivity, the (3)δ-pathway has a comparable barrier to the (3)π and (5)π-pathways, which may offer a new approach for the specific control of C-H bond activation by the iron(IV)-oxo species. 23962243 PET imaging of tumor hypoxia using (18)F-labeled pimonidazole. Background. Tumor hypoxia contributes to loco-regional failure, and for optimal treatment planning, knowledge about tumor hypoxia in individual patients is required. Nitroimidazole-based tracers, which are retained in hypoxic cells, allow PET-based assessment of tumor hypoxia, but current tracers are characterized by slow tracer retention and clearance, resulting in low inter-tissue contrast. Pimonidazole is an immune detectable hypoxia marker widely used for detection of hypoxia in tumor samples. Pimonidazole has excellent chemical properties for hypoxia imaging, but labeling for non- invasive assay has not been attempted. Here we labeled pimonidazole with (18)F ([(18)F]FPIMO). Material and methods. [(18)F]FPIMO was produced by fluorination of 1-[2-O-tosyl-3-(2-nitroimidazole-1-yl)-propyl]-piperidine, which resulted in two isomeric interchangeable forms (named "5" and "6") with a radiochemical purity of 91-100%. [(18)F]FPIMO was tested by incubation of two different tumor cell lines at high and low oxygen levels. [(18)F]FPIMO was also administered to tumor-bearing mice and tracer retention in tumors, non-hypoxic reference tissues and tissues involved in drug metabolism/clearance was evaluated by various techniques. Results and conclusions. Retention of [(18)F]FPIMO was strongly hypoxia-driven in vitro, but isomeric form "5" was particularly promising and reached impressive anoxic-to-oxic retention ratios of 36 and 102, in FaDuDD and SiHa cells, respectively, following three hours of tracer incubation. This was equal to or higher than ratios measured using the established hypoxia tracer [(18)F]FAZA. [(18)F]FPIMO also accumulated in tumors grown in mice, and reached tumor levels that were two to six-fold higher than in muscle three hours post-administration. Furthermore, the intra-tumoral distribution of [(18)F]FPIMO (autoradiography) and unlabeled pimonidazole (immunohistochemistry) was largely identical. Nonetheless, [(18)F]FPIMO proved inferior to [(18)F]FAZA, since absolute tumor signal and intra-tumoral contrast was low, thus compromising PET imaging. Low tumor signal was coupled to extensive tracer accumulation in liver and kidneys, and analysis of blood metabolites revealed that [(18)F]FPIMO was metabolized rapidly, with little parent compound remaining 15 minutes post-administration. Ongoing work focuses on the possibility of labeling pimonidazole in different positions with (18)F to improve tracer stability in vivo. 23218950 Mutational consequences of dNTP pool imbalances in E. coli. The accuracy of DNA synthesis depends on the accuracy of the polymerase as well as the quality and concentration(s) of the available 5'-deoxynucleoside-triphosphate DNA precursors (dNTPs). The relationships between dNTPs and error rates have been studied in vitro, but only limited insights exist into these correlations during in vivo replication. We have investigated this issue in the bacterium Escherichia coli by analyzing the mutational properties of dcd and ndk strains. These strains, defective in dCTP deaminase and nucleoside diphosphate kinase, respectively, are characterized by both disturbances of dNTP pools and a mutator phenotype. ndk strains have been studied before, but were included in this study, as controversies exist regarding the source of its mutator phenotype. We show that dcd strains suffer from increased intracellular levels of dCTP (4-fold) and reduced levels of dGTP (2-fold), while displaying, as measured using a set of lacZ reversion markers in a mismatch-repair defective (mutL) background, a strong mutator effect for G·C→T·A and A·T→T·A transversions (27- and 42-fold enhancement, respectively). In contrast, ndk strains possess a lowered dATP level (4-fold) and modestly enhanced dCTP level (2-fold), while its mutator effect is specific for just the A·T→T·A transversions. The two strains also display differential mutability for rifampicin-resistant mutants. Overall, our analysis reveals for both strains a satisfactory correlation between dNTP pool alterations and the replication error rates, and also suggests that a minimal explanation for the ndk mutator does not require assumptions beyond the predicted effect of the dNTP pools. 23958892 Mesenchymal stem cell derived microvesicles: Trophic shuttles for enhancement of sperm quality parameters. Diminishing sperm quality during cryopreservation process ends up in a complete or partial loss of sperm's fertilizing potential. Rehabilitation of such affected sperm is crucial to improve their fertilizing potential. A variety of evidence has indicated that secreted microvesicles (MVs) from mesenchymal stem cells (MSCs) are involved in regeneration of injured endogenous cells via shuttling MSC trophic molecules. Sperm obtained from cauda epididymides of adult male Wistar rats were equally assigned to four separate groups. Following suspension in cryoprotectant extender, sperm were untreated or treated with increasing concentrations of MSC-derived MVs (25, 50 and 100μg). After incubation in successive steps, sperm were cryopreserved. The frozen-thawed sperm were assessed for viability, motility and antioxidant capacity parameters. Consequently, expression levels of surface adhesion molecules (CD29, CD44, ICAM-I and VCAM-I) involved in sperm fusogenic and signaling properties, were assessed by flow cytometry. Results showed an enhanced quality parameters and adhesive properties of cryopreserved sperm following treatment with MSC-derived MVs. 23481303 Toxicity and sublethal effects of seven insecticides to eggs of the flower bug Orius insidiosus (Say) (Hemiptera: Anthocoridae). The predatory bug Orius insidiosus is an important biological control agent of several insect pests, and is one of the most commonly used species in biological control programs worldwide. This study assessed the lethal and sublethal effects of insecticides on this species through life table, and classified the insecticides according to the definitions of toxicity given by the International Organization for Biological and Integrated Control of Noxious Animals and Plants (IOBC). A bioassay was carried out using a completely randomized design with eight treatments and 40 replicates. Eggs of O. insidiosus laid naturally in plant stems were immersed in aqueous solutions of the chemical products. Egg viability, duration of the embryonic period, survival of nymphs, and duration of the nymphal period were assessed daily. Insects that reached adulthood were paired and their reproduction assessed. The number of eggs produced and the survival of adults were assessed daily. The insecticides abamectin, cartap hydrochloride, spirotetramat+imidacloprid, and flubendiamid were classified as harmful. Pyriproxyfen and rynaxypyr were categorized as harmless and pymetrozine was classified as slightly harmful. Pyriproxyfen affected the population parameters rm, GT, DT, and λ, whereas other insecticides did not. 23965257 CONDOM USE AT SEXUAL DEBUT AMONG CHINESE YOUTH. Summary Chinese youth represent a high-risk group for sexually transmitted infections and unintended pregnancies, but there is little understanding of their sexual behaviours. Using nationally representative data, this study examines the social and demographic correlates of condom use by Chinese youth at sexual debut. It also examines the relationship context of condom use at sexual debut. The results indicate that condom use at sexual debut is very low in China, confirming that youth are a high-risk group. The results demonstrate that age and educational attainment are the primary indicators of condom use. Early sexual debut associates with a greater risk of unsafe sex at sexual debut and higher educational attainment increases the likelihood of self-protecting behaviours. The likelihood of self-protection also increases when sexual partners plan their sexual debut or discuss contraception beforehand. The results suggest that interventions are needed to provide youth with better knowledge about self-protection. 23956371 Controlling for exposure changes the relationship between ethnicity, deprivation and injury: an observational study of child pedestrian injury rates in London. Research has suggested that inequalities in risk exposure may help explain identified ethnic inequalities in child pedestrian injury risk. However, addressing risk exposure in epidemiological research presents theoretical and methodological challenges. This article conceptualises the risk of child pedestrian injury as related to both exposure levels (the quantity of time children spend as pedestrians) and the probability of a hazard where that exposure takes place (the quality of the road environment). To investigate the sensitivity of results on ethnic inequalities in child pedestrian injury risk in London to control for exposure and hazard levels. Using police records of injury 2000-2009, we modelled the relationship between ethnicity, deprivation and child pedestrian injury rates in London using characteristics of the road environment to control for hazard levels and restricting the analysis to the time of the weekday morning commute (7.00-9.00 am), when most children must make a journey to school, to control for exposure levels. Controlling for risk exposure in this way fundamentally changed the nature of the relationship between ethnicity, deprivation and child pedestrian injury. During the time of the morning commute to school, 'Black' children were found to have higher pedestrian injury rates in the least-deprived areas. To inform effective strategies for reducing injury inequality, it is vital that exposure to risk is both acknowledged and considered. 22301817 Cadmium concentrations in shrimp (Penaeus semisulcatus and Penaeus monodon) caught from the coastal areas in Southern Iran. This study was undertaken to determine the concentration of cadmium in two shrimp species, namely, Penaeus semisulcatus and Penaeus monodon caught from the coastal areas in southern Iran. Cadmium concentration was determined by graphite furnace atomic absorption spectrophotometry in 91 shrimp samples after nitric acid/perchloric acid digestion. Accuracy of the analysis was checked by various methods including the use of reference material. The mean ± SD of cadmium concentrations in shrimp samples were 0.128 ± 0.144 (μg/g). The cadmium concentrations ranged from 0.010 to 0.96 μg/g of the muscle tissues of shrimp. Higher cadmium concentration in shrimp samples was found in summer (significant p < 0.05). The results show that the mean concentration of cadmium in shrimp is lower than the maximum allowed levels according to International standards, although the concentration of cadmium in only one sample was more than the amount recommended by Food and Agriculture Organization. Therefore, no risk to the consumer arises from the cadmium contents of the shrimp caught in these areas. 23896810 Meta-Regression Analysis of Placebo Response in Antipsychotic Trials, 1970-2010. OBJECTIVE Large placebo response presents a major challenge for psychopharmacologic drug development and contributes to the increasing failure of psychiatric trials. The objective of this meta-regression analysis was to identify potential contributors to placebo response in randomized controlled trials of antipsychotic treatment in schizophrenia. METHOD The authors extracted trial design and clinical variables from eligible randomized controlled trials (N=50) identified through searches of MEDLINE (1960-2010) and other sources. Standardized mean change (SMC) was used as the effect size measure for placebo response, based on change scores on the Brief Psychiatric Rating Scale or the Positive and Negative Syndrome Scale from baseline to endpoint (2 to 12 weeks). RESULTS The results suggest significant heterogeneities (Q=387.83, df=49) in the magnitude of placebo response (mean SMC, -0.33, range -1.4 to 0.9) and in study quality. Both placebo SMC and study quality increased over time. Younger age, shorter duration of illness, greater baseline symptom severity, and shorter trial duration were significantly associated with greater placebo response, while country (United States compared with other countries) was not. More study sites, fewer university or Veterans Affairs treatment settings, and a lower percentage of patients assigned to receive placebo were associated with a greater placebo response, but these were not independent of publication year. Study quality affected the variability but not mean levels of placebo response. CONCLUSIONS This study identified important patient characteristics and trial design factors affecting the level of placebo response and hence the likelihood of detecting efficacy signals in randomized controlled trials. Future studies should test whether controlling these factors improves the detection of an antipsychotic effect. 23891078 Energy efficacy used to score organic refuse pretreatment processes for hydrogen anaerobic production. The production of hydrogen through Anaerobic Digestion (AD) has been investigated to verify the efficacy of several pretreatment processes. Three types of waste with different carbon structures have been tested to obtain an extensive representation of the behavior of the materials present in Organic Waste (OW). The following types of waste were selected: Sweet Product Residue (SPR), i.e., confectionary residue removed from the market after the expiration date, Organic Waste Market (OWM) refuse from a local fruit and vegetable market, and Coffee Seed Skin (CSS) waste from a coffee production plant. Several pretreatment processes have been applied, including physical, chemical, thermal, and ultrasonic processes and a combination of these processes. Two methods have been used for the SPR to remove the packaging, manual (SPR) and mechanical (SPRex). A pilot plant that is able to extrude the refuse to 200atm was utilized. Two parameters have been used to score the different pretreatment processes: efficiency (ξ), which takes into account the amount of energy produced in the form of hydrogen compared with the available energy embedded in the refuse, and efficacy (η), which compares the efficiency obtained using the pretreated refuse with that obtained using the untreated refuse. The best result obtained for the SPR was the basic pretreatment, with η=6.4, whereas the thermal basic pretreatment gave the highest value, η=17.0 for SPRex. The best result for the OWM was obtained through a combination of basic/thermal pretreatments with η=9.9; lastly, the CSS residue with ultrasonic pretreatment produced the highest quantity of hydrogen, η=5.2. 23963545 Plasmonic photocatalysis properties of Au nanoparticles precipitated anatase/rutile mixed TiO2 nanotubes. Anatase/rutile mixed titania nanotubes (TiO2 NTs) precipitated with gold nanoparticles (Au NPs), i.e. Au/TiO2, have been synthesized and investigated on visible photocatalysis properties. A deposition-precipitation (DP) method was adopted to reduce the gold precursor to Au NPs within the preformed TiO2 NTs by the emulsion electrospinning technique. The optimal visible photocatalytic activity was found in the sample Au3(DP350)/TiO2 with a loading of 3 wt% Au NPs and calcining at 350 °C. Through transmission electron microscopy, Au NPs of 4.16 nm diameter were observed at the interface between the anatase and rutile phases in the optimal Au3(DP350)/TiO2 sample, and these joint active sites at the interface were beneficial for charge separation. The obtained optimal photocatalytic efficiency of Au3(DP350)/TiO2 was ascribed to the synergistic effect of the enhanced visible absorption and the anatase/rutile mixed-phase composition, and the possible mechanism for this was discussed in detail. 23410250 Neural stem/progenitor cells display a low requirement for oxidative metabolism independent of hypoxia inducible factor-1alpha expression. Neural stem/progenitor cells (NSPCs) are multipotent cells within the embryonic and adult brain that give rise to both neuronal and glial cell lineages. Maintenance of NSPC multipotency is promoted by low oxygen tension, although the metabolic underpinnings of this trait have not been described. In this study, we investigated the metabolic state of undifferentiated NSPCs in culture, and tested their relative reliance on oxidative versus glycolytic metabolism for survival, as well as their dependence on hypoxia inducible factor-1alpha (HIF-1α) expression for maintenance of metabolic phenotype. Unlike primary neurons, NSPCs from embryonic and adult mice survived prolonged hypoxia in culture. In addition, NSPCs displayed greater susceptibility to glycolytic inhibition compared with primary neurons, even in the presence of alternative mitochondrial TCA substrates. NSPCs were also more resistant than neurons to mitochondrial cyanide toxicity, less capable of utilizing galactose as an alternative substrate to glucose, and more susceptible to pharmacological inhibition of the pentose phosphate pathway by 6-aminonicotinamide. Inducible deletion of exon 1 of the Hif1a gene improved the ability of NSPCs to utilize pyruvate during glycolytic inhibition, but did not alter other parameters of metabolism, including their ability to withstand prolonged hypoxia. Taken together, these data indicate that NSPCs have a relatively low requirement for oxidative metabolism for their survival and that hypoxic resistance is not dependent upon HIF-1α signaling. 23898111 Whole-body versus Segmental Bioelectrical Impedance Analysis in Patients with Edema of the Upper Limb After Breast Cancer Treatment. Aim: The purpose of this study was to compare whole-body (50 kHz alternating current) and segmental (5 kHz alternating current) bioelectrical impedance analysis (BIA) in the assessment of manifested edema of the upper limbs. Whole-body and segmental BIA were performed in 30 patients with edema of the upper limb following breast cancer treatment. Pearson correlation coefficient comparing both measurements was 0.8891 (p-value <0.0001) with corresponding least squares (r(2)) of 0.7904. Whole-body BIA seems to be a suitable method in the assessment of manifested edema of the upper limbs. 23873291 Relationship between major depressive disorder and associated painful physical symptoms: analysis of data from two pooled placebo-controlled, randomized studies of duloxetine. The aim of this study was to evaluate the relationship between painful physical symptoms (PPS) and outcomes in major depressive disorder (MDD). Post-hoc analysis of two identically designed 8-week trials compared the efficacy of 60 mg/day duloxetine (N=523) with that of placebo (N=532) in treating PPS associated with MDD. The Montgomery-Åsberg Depression Rating Scale (MADRS) total score, the Brief Pain Inventory (BPI) average pain score, and the Sheehan Disability Scale global functional impairment score assessed depression symptoms, pain, and functioning, respectively. Remission was defined as a MADRS score of 10 or less, and the BPI response subgroup was defined as a 50% or greater reduction from baseline. Path analyses assessed relationships among variables. Duloxetine-treated patients who had a 50% or greater reduction in BPI score at endpoint had higher rates of remission. Path analysis indicated that 16% of likelihood of remission in depression symptoms was because of the direct effect of treatment, 41% because of pain reduction, and 43% because of functional improvement. Path analysis also indicated that 51% of improvement in functioning was attributed to pain improvement and 43% to mood improvement. Results demonstrate that improvement in pain and mood contributes to functional improvement, and pain reduction and functional improvement increase the likelihood of remission of depressive symptoms with duloxetine treatment in patients with both MDD and PPS at baseline. 23907083 An in vitro study of alginate oligomer therapies on oral biofilms. The in vitro effect of a novel, oligosaccharide nanomedicine OligoG against oral pathogen-related biofilms, both alone and in the presence of the conventional anti-bacterial agent triclosan, was evaluated. The effect of OligoG±triclosan was assessed against established Streptococcus mutans and Porphyromonas gingivalis biofilms by bacterial counts and image analysis using LIVE/DEAD(®) staining and atomic force microscopy (AFM). The effect of triclosan and OligoG surface pre-treatments on bacterial attachment to titanium and polymethylmethacrylate was also studied. OligoG potentiated the antimicrobial effect of triclosan, particularly when used in combination at 0.3% against S. mutans grown in artificial saliva. OligoG was less effective against established P. gingivalis biofilms. However, attachment of P. gingivalis, to titanium in particular, was significantly reduced after surface pre-treatment with OligoG and triclosan at 0.01% when compared to controls. Light microscopy and AFM showed that OligoG was biocidal to P. gingivalis, but not S. mutans. OligoG and triclosan when used in combination produced an enhanced antimicrobial effect against two important oral pathogens and reduced bacterial attachment to dental materials such as titanium, even at reduced triclosan concentrations. Whilst the use of triclosan against oral bacteria has been widely documented, its synergistic use with OligoG described here, has not previously been reported. The use of lower concentrations of triclosan, if used in combination therapy with OligoG, could have environmental benefits. The potentiation of antimicrobial agents by naturally occurring oligomers such as OligoG may represent a novel, safe adjunct to conventional oral hygiene and periodontal therapy. The ability of OligoG to inhibit the growth and impair bacterial adherence highlights its potential in the management of peri-implantitis. 23530660 Quercetin induces insulin secretion by direct activation of L-type calcium channels in pancreatic beta cells. Quercetin is a natural polyphenolic flavonoid that displays anti-diabetic properties in vivo. Its mechanism of action on insulin-secreting beta cells is poorly documented. In this work, we have analysed the effects of quercetin both on insulin secretion and on the intracellular calcium concentration ([Ca(2+)]i) in beta cells, in the absence of any co-stimulating factor. Experiments were performed on both INS-1 cell line and rat isolated pancreatic islets. Insulin release was quantified by the homogeneous time-resolved fluorescence method. Variations in [Ca(2+)]i were measured using the ratiometric fluorescent Ca(2+) indicator Fura-2. Ca(2+) channel currents were recorded with the whole-cell patch-clamp technique. Quercetin concentration-dependently increased insulin secretion and elevated [Ca(2+)]i. These effects were not modified by the SERCA inhibitor thapsigargin (1 μmol·L(-1)), but were nearly abolished by the L-type Ca(2+) channel antagonist nifedipine (1 μmol·L(-1)). Similar to the L-type Ca(2+) channel agonist Bay K 8644, quercetin enhanced the L-type Ca(2+) current by shifting its voltage-dependent activation towards negative potentials, leading to the increase in [Ca(2+)]i and insulin secretion. The effects of quercetin were not inhibited in the presence of a maximally active concentration of Bay K 8644 (1 μmol·L(-1)), with the two drugs having cumulative effects on [Ca(2+)]i. Taken together, our results show that quercetin stimulates insulin secretion by increasing Ca(2+) influx through an interaction with L-type Ca(2+) channels at a site different from that of Bay K 8644. These data contribute to a better understanding of quercetin's mechanism of action on insulin secretion. 23660506 Development of ELISA methodologies for the direct determination of 17β-estradiol and 17α-ethinylestradiol in complex aqueous matrices. This study comprises the development of enzyme-linked immunosorbent assays (ELISAs) for the quantification of 17β-estradiol (E2) and 17α-ethinylestradiol (EE2) in complex aqueous matrices without any sample clean-up procedures. Salinity and dissolved organic matter were selected as potential interfering agents in the analysis of E2 and EE2. The optimization was performed in order to (i) overcome matrix effects, and to (ii) increase sensitivity. The addition of a sample buffer containing bovine serum albumin (BSA) prior to the sample was found to decrease the influence of matrix effects. Moreover, adjustments of this buffer's pH together with the optimization of tracer (T) dilution and incubation time were undertaken in order to lower the quantification range. The optimized methods allowed the quantification of E2 and EE2 in the ranges 0.03-200 Î¼g L(-1) and 0.02-10 Î¼g L(-1), respectively. The assays were applied to real aqueous samples. It was possible to do a first approach to the levels of E2 in Portuguese surface and waste waters; however, it was not feasible to detect EE2 in the samples tested. 23343414 The complete mitochondrial genome of the subarctic red king crab, Paralithodes camtschaticus (Decapoda, Anomura). We determined the complete mitochondrial (mt) genome sequence of the red king crab, Paralithodes camtschaticus (Decapoda, Anomura). P. camtschaticus is one of the largest arthropods and the most expensive commercially available gourmet seafood. The genome sequence of P. camtschaticus is 16,720 bp in size and its gene content, gene order, and transcriptional polarity are almost identical to those of the hermit crab Pagurus longicarpus, which is thought to be derived from a common ancestor. However, P. camtschaticus mtDNA showed tRNA translocation in two blocks compared to that of P. longicarpus. Prior to this study, complete mt genomes of only two species of Anomura have been reported. Thus, our genomic data will provide additional information for constructing the decapod phylogeny. 23825176 Cognitively stimulating activities to keep dementia at bay. Dementia affects a staggering proportion of individuals, imposing a huge cost to our society. There are currently no disease-modifying treatments for dementia, making lifestyle factors that influence dementia risk of utmost importance. One such lifestyle factor that has shown promise in delaying dementia onset is engagement in cognitively stimulating activities, such as reading, writing, and playing games.(1,2) However, the mechanisms by which these activities exert protective effects remain unclear (figure). 23747993 CD4(+) CD31(+) recent thymic emigrants in CHD7 haploinsufficiency (CHARGE syndrome): A case. Lymphocyte counts <2000cells/μL are associated with early death in infants with CHARGE (Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital hypoplasia, Ear anomalies/deafness) syndrome and CHD7 haploinsufficiency. Absence of recent thymic emigrants is also accompanied by an Omenn-like syndrome and infant death in CHD7 haploinsufficiency. Studies positively identifying recent thymic emigrants, in relation to CHD7 haploinsufficiency, are non-existent. Thirty two months of flow-cytometric work-up of an athymic (evaluated by four chest X-rays) infant, with a novel CHD7 deletion, demonstrated sparse (<50cells/mm(3)) but continuous egress of recent thymic emigrants (CD3(+) CD4(+) CD45RA(+) CD45RO(-) CD31(+)) and homeostatic lymphocyte expansion. Infectious or autoimmune episodes (e.g., Omenn-like syndrome) were not detected (despite lymphocyte counts <2000cells/μL) and excellent vaccination (tetanus, Haemophilus influenzae type B and pneumococcal conjugate vaccines) and proliferation (anti-CD3 and anti-CD28 stimulated) responses were recorded. Her CD4(+) T cells displayed Gaussian distributed TCR (CDR3) spectratypes (22 functional Vβ families). Her CD4(+) T cell profile was also characterized by a slightly increased proportion CD4(+) CD25(+) FoxP3(+) T cells. Since CD3(+) CD4(+) CD45RA(+) CD45RO(-) CD31(+) RTE are reported to be TCR diverse and to contain regulatory T cells, we found it important to report that continuously reduced numbers of CD3(+) CD4(+) CD45RA(+) CD45RO(-) CD31(+) RTE, in the context of CHD7 haploinsufficiency and despite severe lymphopenia, is consistent with an uneventful clinical outcome. 23443473 Evaluation of different chromogenic media for the detection of methicillin-resistant Staphylococcus aureus CC398 in broilers. Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) has emerged in a wide variety of animal species, including poultry. The objective of this study was to evaluate three different chromogenic media for MRSA clonal complex (CC) 398 detection in broilers. On three Belgian poultry farms, 50 broiler chickens were sampled per farm from both nose shell and cloaca. All swab specimens were enriched and inoculated the following day on three chromogenic media: chromID MRSA (bioMérieux), Brilliance MRSA 2 Agar (Oxoid) and MRSASelect (Bio-Rad). ChromID had the highest isolation rates, yet, Brilliance MRSA 2 Agar demonstrated the highest relative sensitivity, while MRSASelect and Brilliance MRSA 2 Agar showed the highest relative specificity. A subset of MRSA isolates was confirmed to be CC398 by the polymerase chain reaction (PCR) targeting sau1-hsdS1. In conclusion, Brilliance MRSA 2 Agar outperformed MRSASelect and chromID MRSA for the detection of MRSA in broilers. 23835269 Psychological wellbeing and posttraumatic stress associated with implantable cardioverter defibrillator therapy in young adults with genetic heart disease. Sudden cardiac death is a tragic complication of a number of genetic heart diseases. Implantable cardioverter defibrillator (ICD) therapy plays an important role in prevention of sudden death. The psychological consequences of ICD therapy in young people with genetic heart disease are poorly understood. This study sought to better understand psychological wellbeing and identify symptoms of posttraumatic stress in young people who had experienced an ICD shock. Eligible patients (ICD implanted over 12months prior) with an inherited cardiomyopathy or primary arrhythmogenic disorder, enrolled in the Australian Genetic Heart Disease Registry were included. Ninety patients completed the Hospital Anxiety and Depression Scale (HADS). Those patients who had an ICD shock (n=31) also completed the Impact of Events Scale-Revised (IES-R). While the mean HADS-Anxiety and IES-R scores were within the normal range in the total group (n=90), a significant subgroup reported symptoms of anxiety (38%), depression (17%) and posttraumatic stress (31%) indicative of the potential need for referral to clinical care. Overall, greater psychological distress in ICD patients was associated with female gender, a history of syncope, other comorbid medical conditions, and reporting of other distressing events (i.e., ICD complications). In those with an ICD shock, higher posttraumatic stress scores were associated with female gender and longer time to first shock. Patients with genetic heart diseases can experience psychological difficulties, including anxiety, depression and posttraumatic stress, related to ICD implantation and subsequent shocks. This signals the importance of offering patients access to targeted interventions, including psychological care and support. 23940382 Short-term exercise training augments α2-adrenoreceptor receptor mediated sympathetic vasoconstriction in resting and contracting skeletal muscle. We hypothesized that exercise training (ET) would alter α2 adrenoreceptor mediated sympathetic vasoconstriction. Sprague-dawley rats (n=30) were randomized to sedentary (S), mild- (M) or heavy-intensity (H) treadmill ET groups (5 days·week(-1) for 4 weeks). Following the exercise training component of the study, rats were anesthetised, instrumented for lumbar sympathetic chain stimulation, triceps surae muscle contraction and measurement of femoral vascular conductance (FVC). The percentage change of FVC in response to sympathetic stimulation was determined at rest and during contraction in control, α2 blockade (yohimbine), and combined α2 + nitric oxide (NO) blockade (L-NAME) conditions. ET augmented (p<0.05) sympathetic vasoconstrictor responses at rest and during contraction. Yohimbine reduced (p<0.05) the vasoconstrictor response in ET rats at rest (M: 2Hz: 8±2%; 5Hz: 9±4%; H: 2Hz: 14±5%; 5Hz: 11±6%) and during contraction (M: 2Hz: 9±2%; 5Hz: 9±5%; H: 2Hz: 8±3%; 5Hz: 6±6%) but did not change the response in S rats. The addition of L-NAME caused a larger increase (p<0.05) in the vasoconstrictor response in ET compared to S rats at rest (2Hz: S: 8±2%, M: 15±3%, H: 23±7%; 5Hz: S: 8±5%, M: 15±3%, H: 17±5%) and during contraction (2Hz: S: 9±3%, M: 18±3%, H: 22±6%; 5Hz: S: 9±5%, M: 22±4%, H:26±9%). Sympatholysis was greater (p<0.05) in ET compared to S rats. Blockade of α2 receptors and NO reduced (p<0.05) sympatholysis in ET, but had no effect on sympatholysis in S rats. In conclusion, ET increased α2-mediated vasoconstriction at rest and during contraction. 23860013 The antimicrobial agent C31G is effective for therapy for HSV-1 ocular keratitis in the rabbit eye model. The amphoteric C31G solution contains equimolar alkyl dimethlyglycine and alkyl dimethyl amine oxide buffered with citric acid. C31G acts as a broad spectrum antiviral and an antibacterial. No previous in vivo studies have been done to test C31G in an animal model of HSV-1 ocular keratitis. We assessed the anti-herpetic activity of C31G in the rabbit eye model using three treatment groups: (1) 1% trifluorothymidine (TFT); (2) 0.25% C31G plus 0.5% hydroxypropyl methylcellulose (HPMC); and (3) vehicle, 0.5% HPMC. Scarified rabbit corneas were inoculated with the HSV-1 strain McKrae. On post inoculation (PI) day 3, rabbits were placed in three balanced groups based on slit-lamp examination (SLE) scores. Treatment began on PI day 3, five times a day for five consecutive days. In addition to the daily, masked SLE scoring, the eyes were assessed daily for stromal opacity, scleral inflammation, neovascularization, eyelid inflammation, inflammatory discharge, and epiphora. C31G and TFT were very effective in reducing the lesions and pathogenesis associated with HSV-1 ocular keratitis. The vehicle control scores were significantly higher and did not effectively treat HSV-1 keratitis. C31G has the potential to be used to treat herpetic keratitis as well as other herpetic topical lesions in humans. 23969008 Respiratory failure due to infliximab induced interstitial lung disease. Although poorly understood, interstitial lung disease has been reported as a possible complication of tumor necrosis factor alpha inhibitors. We report a case of interstitial lung disease in a 64-year-old man with psoriasis 3 weeks after the initiation of infliximab treatment. The patient had received two fortnightly infusions of infliximab following a short course of methotrexate. Thoracic computed tomography showed bilateral ground glass and interstitial infiltrates, while the results of microbiology and immunologic workup were negative. Likewise, bronchoalveolar lavage detected neither typical nor atypical pathogens. Infliximab-induced interstitial lung injury was suspected and corticosteroid therapy was administered which resulted in rapid clinical and radiological improvement. This is one of the few reported cases of interstitial lung disease due to infliximab in the psoriasis population. The patient had no pre-existing lung pathology, while his previous exposure to methotrexate was minimal and was not temporally associated with the induction of interstitial lung disease. 23872846 Structural insights into the proton pumping by unusual proteorhodopsin from nonmarine bacteria. Light-driven proton pumps are present in many organisms. Here, we present a high-resolution structure of a proteorhodopsin from a permafrost bacterium, Exiguobacterium sibiricum rhodopsin (ESR). Contrary to the proton pumps of known structure, ESR possesses three unique features. First, ESR's proton donor is a lysine side chain that is situated very close to the bulk solvent. Second, the α-helical structure in the middle of the helix F is replaced by 310- and π-helix-like elements that are stabilized by the Trp-154 and Asn-224 side chains. This feature is characteristic for the proteorhodopsin family of proteins. Third, the proton release region is connected to the bulk solvent by a chain of water molecules already in the ground state. Despite these peculiarities, the positions of water molecule and amino acid side chains in the immediate Schiff base vicinity are very well conserved. These features make ESR a very unusual proton pump. The presented structure sheds light on the large family of proteorhodopsins, for which structural information was not available previously. 23953195 Synthesis and antiproliferative activities of quebecol and its analogs. Simple and efficient synthesis of quebecol and a number of its analogs was accomplished in five steps. The synthesized compounds were evaluated for antiproliferative activities against human cervix adenocarcinoma (HeLa), human ovarian carcinoma (SK-OV-3), human colon carcinoma (HT-29), and human breast adenocarcinoma (MCF-7) cancer cell lines. Among all the compounds, 7c, 7d, 7f, and 8f exhibited antiproliferative activities against four tested cell lines with inhibition over 80% at 75μM after 72h, whereas, compound 7b and 7g were more selective towards MCF-7 cell line. The IC50 values for compounds 7c, 7d, and 7f were 85.1μM, 78.7μM, and 80.6μM against MCF-7 cell line, respectively, showing slightly higher antiproliferative activtiy than the synthesized and isolated quebecol with an IC50 value of 104.2μM against MCF-7. 23831298 Contribution of new techniques to study the gait in old populations. For several years, the concept of "physiological senile gait" has been strongly contested and seems to be associated with abnormal gait. Indeed, some changes characteristic of senile gait appear early on in subjects with neurodegenerative pathologies. The aim of this article was to determine how recent contributions can improve the study of gait in old populations. This paper is a thematic review of recent contributions from medical imaging techniques as well as instrumental gait analysis techniques in older adults. This article did not focus on Parkinson's disease or other specific diseases bearing certain gait disturbances, since they belong to literature focusing on these particular disorders. This work was not intended as a systematic review but only as a thematic one conducted by geriatricians in order review the recent literature in order to better apprehend how new technics could be implemented within their clinical practice. Articles were selected in online Medline and Cochrane Library databases, and some were previously identified by the authors. This paper highlights the most recent contributions in magnetic resonance imaging, functional magnetic resonance imagery, positron emission tomography and instrumental gait analyzing devices better understanding the underlying gait mechanisms in elderly populations. This thematic review suggests that gait could be considered as a marker of "successful aging". Its evaluation associated to longitudinal follow-up could be useful to predict cognitive and functional changes in frail older adults. 23967249 The Therapeutic Effect on Bone Mineral Formation from Biomimetic Zinc Containing Tricalcium Phosphate (ZnTCP) in Zinc-Deficient Osteoporotic Mice. The aim of this study was to evaluate the therapeutic efficacy of biomimetic zinc-containing tricalcium phosphate (ZnTCP) produced by hydrothermally converting calcium carbonate exoskeletons from foraminifera, in the treatment of osteoporotic mice. X-Ray powder diffraction showed crystallographic structures matching JCPDS profile for tricalcium phosphate. Mass spectroscopy used to calculate total composition amount showed similar amount of calcium (5×10(4) µg/g) and phosphate (4×10(4) ppm) after conversion and the presence of zinc (5.18×10(3) µg/g). In vitro zinc release showed no release in PBS buffer and <1% zinc release in 7 days. In vivo evaluation was done in ovariectomized mice by implanting the ZnTCP samples in the soft tissues near the right femur bone for four weeks. Thirty ddY mice (5 weeks old, average weight of 21 g) were divided into six experimental groups (normal, sham, OVX, β-TCP, ZnTCP and direct injection of zinc). CT images were taken every two weeks where the bone mineral density (BMD) and bone mineral content (BMC) were calculated by software based on CT images. The ZnTCP group exhibits cortical and cancellous bone growth of 45% and 20% respectively. While sham, OVX and β-TCP suffered from bone loss. A correlation was made between the significant body weight increase in ZnTCP with the significant increase in plasma zinc level compared with OVX. The presented results indicate that biomimetic ZnTCP were effective in preventing and treating bone loss in osteoporotic mice model. 23966626 Reduced T-Dependent Humoral Immunity in CD20-Deficient Mice. CD20 is a tetraspanning membrane protein expressed on B lymphocytes. CD20 deficiency in both mice and humans has recently been shown to have deleterious effects on Ab responses to T-independent Ags; however, no effect on T-dependent immunity has been reported. In this study, we used a Cd20(-/-) mouse line to evaluate Ab responses to adeno-associated virus and SRBCs. The neutralizing Ab response to adeno-associated virus was significantly reduced by CD20 deficiency; both primary (IgM) and secondary (IgG1 and IgG2b) responses to SRBC were also reduced in Cd20(-/-) mice, and this was associated with a reduction in the number of germinal center B cells. A successful humoral response requires the integration of intracellular signaling networks that critically rely on calcium mobilization. In this article, we confirm that BCR-mediated calcium mobilization is reduced in Cd20(-/-) murine B cells after BCR stimulation in vitro, and further show that the reduction is due to an effect on calcium influx rather than calcium release from intracellular stores. Calcium-dependent upregulation of CD69 was impaired in CD20-deficient B cells, as was upregulation of CD86. Altogether, this study demonstrates a role for CD20 in B cell activation and T-dependent humoral immunity. 23915335 Immunological and nutritional factors in elderly people in low-level care and their association with mortality. This study examines associations between markers of nutritional status and lymphocyte subsets and seeks to determine if lymphocyte profile is predictive of survival in elderly Australians residing in aged care facilities. Aged yet still ambulatory subjects (n = 88, 73% female) living in low-level care and requiring minimal assistance were studied for 143 weeks. At baseline when participants were aged (mean +/- SD) 86.0 +/- 5.9 years, dietary intake was determined by 3-day weighed food record, body composition was assessed by dual energy X-ray absorptiometry (DXA) and a venous blood sample was taken. At baseline assessment, study participants were consuming nutrient-poor diets and most had symptoms of chronic disease. Although overweight, 40% exhibited sarcopenia. Markers of nutritional status did not relate closely to immune cell numbers (absolute or relative), which on average were within the normal range. Men had lower numbers of CD3+CD4+ cells (CD4+ T cells), a higher proportion of CD3- CD16+/- CD56+/- (natural killer (NK) cells) and a higher ratio of NK: CD4+ T cells than women (all P < 0.05). The main age-related changes evident were decreased T cells, particularly low CD4+ T cell counts, and increased numbers of CD19+ (B-cell) and NK cells. During the 143 week duration of follow-up, about one quarter of the study participants died, with death more likely in men than women (P < 0.01). Poor survival was predicted by the presence of decreased numbers of CD4+ T cells (hazard ratio (HR) 0.919, P < 0.01) and expanded numbers of NK cells (HR 1.085, P < 0.05) in the blood, and therefore the presence of a high NK: CD4+ T cell ratio (HR 30.521, P < 0.01). The NK: CD4+ T cell ratio may potentially have clinical utility for predicting longevity in elderly populations. Further studies are needed in other elderly populations to confirm this finding. 23869388 A new cycloartane nortriterpenoid from stem and leaf of Quercus variabilis. A new compound 3-acetyloxy-epicycloeucalenol-24-one (1), with 11 known compounds 3α-acetyloxy-4α,14α-dimethyl-9β,19-cycloergost-24-oic acid (2), 3-epicycloeucalenol (3), 3-epicycloeucalenyl-24-one (4), 3-epicycloeucalenyl acetate (5), 4β,14α-dimethyl-5α-ergosta-9β,19-cyclo-24(31)-en-3β-hydroxy-4α-carboxylic acid (6), cycloeucalenone (7), friedelin (8), epifriedelanol (9), lup-20 (29)-en-3β,30-diol (10), betulin (11), lupeol (12), was isolated from the stems and leaves of Quercus variabilis Blume. Seven compounds (1-7) showed anti-inflammatory activity. 23968337 The iTClamp Controls Junctional Bleeding in a Lethal Swine Exsanguination Model. Abstract Objective. Severe hemorrhage is a leading cause of death and difficult to control even by trained medical personnel. Current interventions have significant limitations in the prehospital setting; therefore, a need exists for a new and effective treatment. iTraumaCare has designed a temporary wound closure device, the iTClamp, which controls external hemorrhage from open wounds within compressible zones. The device approximates the wound edges, sealing the skin within a pressure bar, enabling creation of a hematoma and subsequent clot formation. The objective of this study is to test the effectiveness of the iTClamp to control external bleeding due to a major vascular injury to the groin in an in vivo swine model. Methods. Twenty Yorkshire-cross male swine were enrolled in this study. A complex groin injury was created by complete excision of the femoral artery and vein along with some surrounding muscle. The animals were divided into four treatment groups: control (no treatment), early iTClamp treatment, late iTClamp treatment, and standard gauze treatment. Survival rate, survival time, and blood loss were the primary endpoints. Physiologic parameters (heart rate, blood pressure, oxygen saturation) were monitored throughout the experiment and blood samples were collected to analyze partial thromboplastin time and fibrinogen. Results: All (100%) of the animals treated with the iTClamp lived through the end of the experiment, compared to 60% in standard gauze treated and 0% of untreated control animals (early and late iTClamp vs. control and standard gauze, Fisher's exact, p = 0.003). Both the early iTClamp and late iTClamp treatment groups survived significantly longer than the untreated control pigs (Mann-Whitney U-test, p < 0.009). External blood loss was significantly lower in animals treated with the iTClamp (early) compared to no treatment (Mann-Whitney U-test, p < 0.008). There was no significant change in physiologic or hematologic parameters between treatment groups. Conclusions: The iTClamp showed statistically significant improvement in survival, survival time, and estimated blood loss when compared to no treatment. This proof-of-concept study demonstrates the potential of the iTClamp to control severe bleeding and prevent blood loss. 23866739 Are structural brain abnormalities associated with suicidal behavior in patients with psychotic disorders? Suicide represents a major health problem world-wide. Nevertheless, the understanding of the neurobiological underpinnings of suicidal behavior remains far from complete. We compared suicide attempters to non-attempters, and high vs. low lethality attempters, to identify brain regions associated with suicidal behavior in patients with psychotic disorders. 489 individuals with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder I and 262 healthy controls enrolled in the B-SNIP study were studied. Groups were compared by attempt history and the highest medical lethality of previous suicide attempts. 97 patients had a history of a high lethality attempt, 51 of a low lethality attempt and 341 had no attempt history. Gray matter volumes were obtained from 3T structural MRI scans using FreeSurfer. ANCOVAs were used to examine differences between groups, followed by Hochberg multiple comparison correction. Compared to non-attempters, attempters had significantly less gray matter volume in bilateral inferior temporal and superior temporal cortices, left superior parietal, thalamus and supramarginal regions, right insula, superior frontal and rostral middle frontal regions. Among attempters, a history of high lethality attempts was associated with significantly smaller volumes in the left lingual gyrus and right cuneus. Compared to non-attempters, low lethality attempters had significant decreases in the left supramarginal gyrus, thalamus and the right insula. Structural brain abnormalities may distinguish suicide attempters from non-attempters and high from low lethality attempters among individuals with psychotic disorders. Regions in which differences were observed are part of neural circuitries that mediate inhibition, impulsivity and emotion, visceral, visual and auditory perception. 23676318 Hybrid peripheral nerve sheath tumors, including a malignant variant in type 1 neurofibromatosis. : The authors report a small case series of hybrid nerve sheath tumors occurring in the setting of type 1 neurofibromatosis. Four lesions were benign and consisted of plexiform neurofibromas with considerable areas of perineuriomatous differentiation in patients with type 1 neurofibromatosis. In these lesions, biphasic (Schwannian and perineuriomatous) differentiation was apparent on immunohistochemistry, with the perineuriomatous areas staining for epithelial membrane antigen, glut-1, and claudin-1 and being negative for S-100 protein. Three patients were members of a single family, with a history of various malignant neoplasms. Included in the series is 1 hybrid lesion in which neurofibromatous and perineuriomatous areas were clearly visible on hematoxylin- and eosin-stained slides. The lesion was unique in that it manifested malignant change in the S-100 protein-positive component, which was classified as malignant peripheral nerve sheath tumor. The malignant component showed areas with an epithelioid cell morphology. 23841610 Genetic diversity of Odontobutis potamophila from different geographic populations inferred from mtDNA control region. Abstract Odontobutis potamophila is a Chinese endemic species and an economically important fishery resource in the Yangtze River. The genetic variability of O. potamophila was studied based on the sequence analysis of mitochondrial DNA control region from 150 individuals of five geographical populations including from Dangtu (n = 30), Sheyang (n = 30), Yuyao (n = 30), Tai Lake nearby Dongxishan (n = 30) and Minjiang (n = 30). Among five populations, the genetic distance between Minjiang population and other populations (0.1186-0.1223) was larger than that among four populations except for Minjiang (0.0015-0.0198). In addition, 23 haplotypes were obtained and each population had special haplotypes. The samples from five sites had high haplotype diversity (0.80510) and low nucleotide diversity (0.04028). Through Tajima's D and Fu's F neutral testing and mismatch distribution test among all geographical populations, O. potamophila did not undergo recent population expansion. During the population evolution, O. potamophila experienced a balanced selection function and maintained a stable state and population size. Moreover, the haplotype Neighbor-Joining (NJ) tree was separated two haplotype groups. The NJ tree, TCS network and median-joining network could clearly separate the haplotypes of the specimens from different areas. Analysis of molecular variance and pairwise FST revealed an obvious genetic differentiation among different geographical populations, suggesting that O. potamophila in different geographical populations should be managed and conserved separately. 23288946 Cell wounding activates phospholipase D in primary mouse keratinocytes. Plasma membrane disruptions occur in mechanically active tissues such as the epidermis and can lead to cell death if the damage remains unrepaired. Repair occurs through fusion of vesicle patches to the damaged membrane region. The enzyme phospholipase D (PLD) is involved in membrane traffickiing; therefore, the role of PLD in membrane repair was investigated. Generation of membrane disruptions by lifting epidermal keratinocytes from the substratum induced PLD activation, whereas removal of cells from the substratum via trypsinization had no effect. Pretreatment with 1,25-dihydroxyvitamin D₃, previously shown to increase PLD1 expression and activity, had no effect on, and a PLD2-selective (but not a PLD1-selective) inhibitor decreased, cell lifting-induced PLD activation, suggesting PLD2 as the isoform activated. PLD2 interacts functionally with the glycerol channel aquaporin-3 (AQP3) to produce phosphatidylglycerol (PG); however, wounding resulted in decreased PG production, suggesting a potential PG deficiency in wounded cells. Cell lifting-induced PLD activation was transient, consistent with a possible role in membrane repair, and PLD inhibitors inhibited membrane resealing upon laser injury. In an in vivo full-thickness mouse skin wound model, PG accelerated wound healing. These results suggest that PLD and the PLD2/AQP3 signaling module may be involved in membrane repair and wound healing. 23034150 Living with side effects from cancer treatment - a challenge to target information. Patients with cancer experience side effects related to their antineoplastic treatment. Demands for efficiency limit the time patients spend with health professionals. This requires that professionals are able to offer adequate support to patients in coping with side effects of treatment in everyday life. However, it appears that the level of information about and support in living with side effects may be insufficient. To explore patients' experiences of how side effects from chemotherapy and radiotherapy impact everyday life as well as the information needs in coping with these side effects. Nine patients' experiences were analysed and interpreted using a phenomenological-hermeneutical approach. Data were collected through semi-structured interviews. The patients are deeply impacted by side effects in their everyday life. They struggle to take power but experience loss of control. They feel inexperienced without knowledge in an 'ongoing system', and because of lack of continuity, they do not come up with their real needs. To avoid pitfalls in the information, the patients need individualized support from the professionals. If the patients have to be supported during everyday life with side effects from cancer treatment in an individualized way, the professional must be aware that the patients risk adapting to the busy healthcare system. To empower the patient, the professional must be able to sense the patients' appeal for help and enter into caring relationships. To ensure targeted information, the relationship between nurse and patient must build on nursing values including the patients' illness - perspective. However, the professionals must take a critical look at how they provide information and how they act to empower the patients. 23419536 Uptake, retention and internalization of quantum dots in Daphnia is influenced by particle surface functionalization. Nanomaterials are a diverse group of compounds whose inevitable release into the environment warrants study of the fundamental processes that govern the ingestion, uptake and accumulation in aquatic organisms. Nanomaterials have the ability to transfer to higher trophic levels in aquatic ecosystems, and recent evidence suggests that the surface chemistry of both the nanoparticle and biological membrane can influence uptake kinetics. Therefore, our study investigates the effect of surface functionalization on uptake, internalization and depuration in Daphnia spp. Uncharged (polyethylene glycol; PEG), positively charged (amino-terminated: NH2) and negatively charged (carboxyl-modified; COOH) cadmium selenide/zinc sulfide quantum dots were used to monitor ingestion, uptake and depuration of nanometals in Daphnia magna and Ceriodaphnia dubia over 24h of exposure. These studies demonstrated that particles with higher negative charge (COOH quantum dots) were taken up to a greater extent by Daphnia (259.17±17.70 RFU/20 Daphnia) than either the NH2 (150.01±18.91) or PEG quantum dots (95.17±9.78), however this is likely related to the functional groups attached to the nanoparticles as there were no real differences in zeta potential. Whole body fluorescence associates well with fluorescent microscopic images obtained at the 24h timepoint. Confocal and electron microscopic analysis clearly demonstrated that all three types of quantum dots could cross the intestinal epithelial barrier and be translocated to other cells. Upon cessation of exposure, elimination of all three materials was biphasic with rapid initial clearance that likely represents elimination of material remaining in the GI tract followed by a much slower elimination phase that likely represents elimination of internalized material. These studies demonstrate that daphnids can take up intact nanomaterial from the water column and that this uptake is strongly influenced by particle surface functionalization. In addition, the usefulness of using quantum dots as a proxy for other nanometals (no acute toxicity, clear visualization in electron microscopy), in conjunction with several different imaging techniques in assessing uptake and accumulation of nanoparticles in daphnids was demonstrated. 23349399 Needed action in health literacy. Insights for action in the relatively new field of health literacy have been constrained by the emphasis on the literacy skills of the individuals. Early studies into the relationship between literacy and health outcomes were not appropriately balanced with examinations of individuals' skills and health system demands. Most studies focused on the measures of patients' reading skills without due attention to the health tasks undertaken, the health materials used, or the skills of providers with whom patients were interacting. Furthermore, public health is founded on the epidemiologic notion of the reciprocal relationship between individuals and environments. Early studies in health literacy did not attend to context-the physical and social environment of health-care settings. New initiatives in health literacy must bring attention to the demands and expectations of health systems and to the proficiencies of the various health professionals who prepare documents and information for the public and who interact with communities and patients. 23934571 The active form of goat insulin-like peptide 3 (INSL3) is a single-chain structure comprising three domains B-C-A, constitutively expressed and secreted by testicular Leydig cells. Abstract Relaxin-like factor (RLF), also called insulin-like peptide 3 (INSL3), is a member of the insulin/relaxin gene family and is produced by testicular Leydig cells. While the understanding of its effects is growing, very little is known about the structural and functional properties of native INSL3. Here, we demonstrate that native INSL3 isolated from goat testes is a single-chain structure with full biological activity, and is constitutively expressed and secreted by Leydig cells. Using a series of chromatography steps, native INSL3 was highly purified as a single 12-kDa peak as revealed by SDS-PAGE. MS/MS analysis provided 81% sequence coverage and revealed a distinct single-chain structure consisting of the B-, C-, and A-domains deduced previously from the INSL3 cDNA sequence. Moreover, the N-terminal peptide was six amino acid residues longer than predicted. Native INSL3 exhibited full bioactivity in HEK-293 cells expressing the receptor for INSL3. Immunoelectron microscopy and Western blot analysis revealed that INSL3 was secreted by Leydig cells through the constitutive pathway into blood and body fluids. We conclude, therefore, that goat INSL3 is constitutively secreted from Leydig cells as a B-C-A single-chain structure with full biological activity. 23904314 Wrong egg in the usual nest: Thyroid papillary carcinoma within a branchial cleft cyst. Branchial cleft cysts are the most common lesions to arise laterally in the neck. Ectopic thyroid tissue within a branchial cleft cyst is rare, and a papillary carcinoma arising from this tissue is extremely rare. We present a case of a lateral neck cyst representing a primary papillary carcinoma that arose in ectopic thyroid tissue within a branchial cleft cyst in a 41-year-old woman. After the mass was surgically excised, thyroid ultrasonography, thyroid scintigraphy, and whole-body F18-fluorodeoxyglucose-positron emission tomography/computed tomography detected no abnormality. The negative findings notwithstanding, surgery on the thyroid gland was planned, but the patient refused it. Therefore, she was followed up with ultrasonography and scintigraphy for 5 years, during which time she exhibited no evidence of recurrence. Total thyroidectomy is still the primary option in such cases, but when it cannot be performed for any reason, vigilant follow-up is essential. 23964204 Mind the fish: zebrafish as a model in cognitive social neuroscience. Understanding how the brain implements social behavior on one hand, and how social processes feedback on the brain to promote fine-tuning of behavioral output according to changes in the social environment is a major challenge in contemporary neuroscience. A critical step to take this challenge successfully is finding the appropriate level of analysis when relating social to biological phenomena. Given the enormous complexity of both the neural networks of the brain and social systems, the use of a cognitive level of analysis (in an information processing perspective) is proposed here as an explanatory interface between brain and behavior. A conceptual framework for a cognitive approach to comparative social neuroscience is proposed, consisting of the following steps to be taken across different species with varying social systems: (1) identification of the functional building blocks of social skills; (2) identification of the cognitive mechanisms underlying the previously identified social skills; and (3) mapping these information processing mechanisms onto the brain. Teleost fish are presented here as a group of choice to develop this approach, given the diversity of social systems present in closely related species that allows for planned phylogenetic comparisons, and the availability of neurogenetic tools that allows the visualization and manipulation of selected neural circuits in model species such as the zebrafish. Finally, the state-of-the art of zebrafish social cognition and of the tools available to map social cognitive abilities to neural circuits in zebrafish are reviewed. 23421872 Molecular orientation and dynamics of different sized organic radicals included in organic 1D nanochannels. The molecular orientation and dynamics of di-t-butylnitroxide (DTBN) and 4-oxo-2,2,6,6-tetramethyl-1-piperidinyl-1-oxyl (TEMPONE) radicals in the organic 1D nanochannels of tris(o-phenylenedioxy)cyclotriphosphazene (TPP) were investigated by examining inclusion compounds (ICs) diluted by the co-inclusion of nonradicals using electron spin resonance (ESR). Spectral simulation showed that the axial rotation of DTBN or TEMPONE molecules is excited in TPP nanochannels with activation energies of 3 and 10 kJ mol(-1), respectively. The rotation axes for both DTBN and TEMPONE were determined to be almost parallel to the principal y-axis of the g tensor, which agrees with the result reported for 2,2,6,6-tetramethyl-1-piperidinyl-1-oxyl (TEMPO) in TPP nanochannels, which has the activation energy of 5 kJ mol(-1). These results indicate that the molecular orientations of guest nitroxide radicals are almost independent of the molecular sizes of the guest radicals in TPP nanochannels, although the molecular dynamics are dependent on the molecular sizes. 23908120 Collagenases and cracks in the plaque. The core of an atheromatous plaque contains lipids, macrophages, and cellular debris, typically covered by a fibrous cap that separates the thrombogenic core from the blood. Rupture of the fibrous cap causes most fatal myocardial infarctions. Interstitial collagen confers tensile strength on the cap, as it does in skin and tendons. In 1994, Peter Libby and colleagues demonstrated overexpression of collagenolytic enzymes in atheromatous plaques and implicated MMPs in the destabilization of these lesions. 23212742 Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D3 through CYP3A4 induction in vitro and in vivo: Implications for drug-induced osteomalacia. Long-term therapy with certain drugs, especially cytochrome P450 (P450; CYP)-inducing agents, confers an increased risk of osteomalacia that is attributed to vitamin D deficiency. Human CYP24A1, CYP3A4, and CYP27B1 catalyze the inactivation and activation of vitamin D and have been implicated in the adverse drug response. In this study, the inducibility of these enzymes and monohydroxylation of 25-hydroxyvitamin D3 (25OHD3 ) were evaluated after exposure to P450-inducing drugs. With human hepatocytes, treatment with phenobarbital, hyperforin, carbamazepine, and rifampin significantly increased the levels of CYP3A4, but not CYP24A1 or CYP27B1 mRNA. In addition, rifampin pretreatment resulted in an 8-fold increase in formation of the major metabolite of 25OHD3 , 4β,25(OH)2 D3 . This inductive effect was blocked by the addition of 6',7'-dihydroxybergamottin, a selective CYP3A4 inhibitor. With human renal proximal tubular HK-2 cells, treatment with the same inducers did not alter CYP3A4, CYP24A1, or CYP27B1 expression. 24R,25(OH)2 D3 was the predominant monohydroxy metabolite produced from 25OHD3 , but its formation was unaffected by the inducers. With healthy volunteers, the mean plasma concentration of 4β,25(OH)2 D3 was increased 60% (p < 0.01) after short-term rifampin administration. This was accompanied by a statistically significant reduction in plasma 1α,25(OH)2 D3 (-10%; p = 0.03), and a nonsignificant change in 24R,25(OH)2 D3 (-8%; p = 0.09) levels. Further analysis revealed a negative correlation between the increase in 4β,25(OH)2 D3 and decrease in 1α,25(OH)2 D3 levels. Examination of the plasma monohydroxy metabolite/25OHD3 ratios indicated selective induction of the CYP3A4-dependent 4β-hydroxylation pathway of 25OHD3 elimination. These results suggest that induction of hepatic CYP3A4 may be important in the etiology of drug-induced osteomalacia. © 2013 American Society for Bone and Mineral Research. 23722168 Transport of nucleosides in the vcCNT facilitated by sodium gradients from molecular dynamics simulations. Nucleosides are required for DNA and RNA synthesis, and the nucleoside adenosine has a function in a variety of signaling processes. Nucleosides require a specialized class of integral membrane proteins, known as nucleoside transporters (NTs), for specific transport across cell membranes. NTs are also important determinants for the transport of nucleoside-derived drugs across cell membranes. Recently, the crystal structure of the vcCNT (Vibrio cholerae Concentrative Nucleoside Transporter) was reported. Here we perform molecular dynamics (MD) simulations for the vcCNT structure in the presence of various sodium gradients, since CNTs are sodium-coupled transporters. The results highlight the important role of sodium bound to the vcCNT in the transport of uridine. Our MD simulations show that, without NaCl, uridine remains stable in the binding pocket of the vcCNT. In the presence of 20 mM NaCl, uridine moves from the binding pocket and approaches the entrance of the intracellular side. In the presence of 100 mM NaCl, uridine passes through most part of the entrance and approaches the intracellular side. The polar/charged amino acids in the binding pocket are important in the transport process. They first "fix" the ribose and allow the uracil base of uridine to approach the entrance of the intracellular side, and then "release" the ribose to allow uridine to move freely into the intracellular side coupled with the movement of sodium ions and HP1b. Finally, we propose a detailed mechanism of the nucleoside transport from the binding pocket to the intracellular side of the vcCNT. 23587021 The tail wagging the dog - regulation of lipid metabolism by protein kinase C. Upon their discovery almost 40 years ago, isoforms of the lipid-activated protein kinase C (PKC) family were initially regarded only as downstream effectors of the second messengers calcium and diacylglycerol, undergoing activation upon phospholipid hydrolysis in response to acute stimuli. Subsequently, several isoforms were found to be associated with the inhibitory effects of lipid over-supply on glucose homeostasis, especially the negative cross-talk with insulin signal transduction, observed upon accumulation of diacylglycerol in insulin target tissues. The PKC family has therefore attracted much attention in diabetes and obesity research, because intracellular lipid accumulation is strongly correlated with defective insulin action and the development of type 2 diabetes. Causal roles for various isoforms in the generation of insulin resistance have more recently been confirmed using PKC-deficient mice. However, during characterization of these animals, it became increasingly evident that the enzymes play key roles in the modulation of lipid metabolism itself, and may control the supply of lipids between tissues such as adipose and liver. Molecular studies have also demonstrated roles for PKC isoforms in several aspects of lipid metabolism, such as adipocyte differentiation and hepatic lipogenesis. While the precise mechanisms involved, especially the identities of protein substrates, are still unclear, the emerging picture suggests that the currently held view of the contribution of PKC isoforms to metabolism is an over-simplification. Although PKCs may inhibit insulin signal transduction, these enzymes are not merely downstream effectors of lipid accumulation, but in fact control the fate of fatty acids, thus the tail wags the dog. 23852018 Dependence of Interaction Free Energy between Solutes on an External Electrostatic Field. To explore the athermal effect of an external electrostatic field on the stabilities of protein conformations and the binding affinities of protein-protein/ligand interactions, the dependences of the polar and hydrophobic interactions on the external electrostatic field, -Eext, were studied using molecular dynamics (MD) simulations. By decomposing Eext into, along, and perpendicular to the direction formed by the two solutes, the effect of Eext on the interactions between these two solutes can be estimated based on the effects from these two components. Eext was applied along the direction of the electric dipole formed by two solutes with opposite charges. The attractive interaction free energy between these two solutes decreased for solutes treated as point charges. In contrast, the attractive interaction free energy between these two solutes increased, as observed by MD simulations, for Eext = 40 or 60 MV/cm. Eext was applied perpendicular to the direction of the electric dipole formed by these two solutes. The attractive interaction free energy was increased for Eext = 100 MV/cm as a result of dielectric saturation. The force on the solutes along the direction of Eext computed from MD simulations was greater than that estimated from a continuum solvent in which the solutes were treated as point charges. To explore the hydrophobic interactions, Eext was applied to a water cluster containing two neutral solutes. The repulsive force between these solutes was decreased/increased for Eext along/perpendicular to the direction of the electric dipole formed by these two solutes. 23945937 Structural and functional insights into the molecular mechanism of rRNA m6A methyltransferase RlmJ. RlmJ catalyzes the m(6)A2030 methylation of 23S rRNA during ribosome biogenesis in Escherichia coli. Here, we present crystal structures of RlmJ in apo form, in complex with the cofactor S-adenosyl-methionine and in complex with S-adenosyl-homocysteine plus the substrate analogue adenosine monophosphate (AMP). RlmJ displays a variant of the Rossmann-like methyltransferase (MTase) fold with an inserted helical subdomain. Binding of cofactor and substrate induces a large shift of the N-terminal motif X tail to make it cover the cofactor binding site and trigger active-site changes in motifs IV and VIII. Adenosine monophosphate binds in a partly accommodated state with the target N6 atom 7 Å away from the sulphur of AdoHcy. The active site of RlmJ with motif IV sequence 164DPPY167 is more similar to DNA m(6)A MTases than to RNA m(6)2A MTases, and structural comparison suggests that RlmJ binds its substrate base similarly to DNA MTases T4Dam and M.TaqI. RlmJ methylates in vitro transcribed 23S rRNA, as well as a minimal substrate corresponding to helix 72, demonstrating independence of previous modifications and tertiary interactions in the RNA substrate. RlmJ displays specificity for adenosine, and mutagenesis experiments demonstrate the critical roles of residues Y4, H6, K18 and D164 in methyl transfer. 23443155 Epidemiological changes in rotavirus gastroenteritis in children under 5 years of age after the introduction of rotavirus vaccines in Korea. Rotavirus gastroenteritis is the leading cause of severe acute gastroenteritis in children worldwide and is associated with high hospitalization and mortality rates in children younger than 5 years of age. Vaccination is necessary to prevent rotavirus infection. Two live attenuated and orally administered rotavirus vaccines became commercially available in Korea. The aim of this study is to describe epidemiological changes in rotavirus gastroenteritis after the introduction of rotavirus vaccines in Korea. The medical records of 11,199 children younger than 5 years of age and hospitalized for acute gastroenteritis from August 2007 to July 2010 in eight Korean hospitals were reviewed. Rotavirus was detected in stool samples obtained from 2,959 children (26.42 %). The authors evaluated the percentage of rotavirus gastroenteritis among all acute gastroenteritis hospitalizations in eight hospitals located in different geographical areas and analyzed epidemiological changes in rotavirus gastroenteritis according to age, geographical area, and season. According to the findings, the percentage of rotavirus gastroenteritis showed a decrease in children eligible for vaccination during the study period. After introduction of the vaccine, reduced rates of rotavirus detection were observed in all of the geographical areas, and the greatest reduction was observed in Seoul. In Seoul, there was a marked delay of the rotavirus season. Conclusion: Epidemiologic changes in Korea after the introduction of rotavirus vaccine are consistent with changes observed in other countries. 23550906 Ulipristal acetate - safety and pharmacokinetics following multiple doses of 10-50 mg per day. Ulipristal acetate (UPA) is a novel selective progesterone receptor modulator for benign gynaecological conditions such as uterine myoma. The safety and pharmacokinetics of multiple-dose UPA and its N-mono-demethylated metabolite, PGL4002, were investigated in women. The double-blind, placebo-controlled study randomized 32 healthy women of reproductive age to receive 10 consecutive daily doses of placebo, 10, 20 or 50 mg UPA. Safety assessments included vital signs, physical examination, ECG, clinical laboratory tests and reporting of adverse events. Blood samples for pharmacokinetic analysis were collected on Days 1 and 10 at intervals until 168 h after multiple dosing. UPA was well tolerated at all doses. Mild or moderate adverse events occurred with similar frequency in UPA and placebo groups. UPA median tmax was 0·75 and 0·89 h, and mean plasma half-life was between 38 and 49 h. Cmax values (Day 1) were 42·2, 130·9 and 354·8 ng/mL for the UPA 10, 20 and 50 mg treatment groups, respectively. Corresponding Cmax values for Day 10 were 63·7, 169·8 and 454·9 ng/mL. AUCSS values on Day 10 were 216·6, 602·8 and 1655·7 ng h/mL after 10, 20 and 50 mg UPA, respectively. For the principal metabolite PGL4002, tmax and plasma elimination half-life values were similar to those of UPA. PGL4002 AUCSS Day 10 values were 84·7, 203·6 and 452·1 ng h/mL for 10, 20 and 50 mg groups, respectively. Daily administration of UPA at therapeutic and supratherapeutic doses was well tolerated by women of reproductive age. UPA exposure increases with dose. Exposure to PGL4002 is approximately one-third that of UPA. 23891025 Activity classification in users of ankle foot orthoses. A framework for activity classification using inertial sensors mounted on ankle foot orthoses (AFOs) is presented. A decision tree-nearest neighbor algorithm classifies activities using subject-specific training. Eight volunteer subjects wore modified bilateral AFOs with shank and foot mounted triaxial accelerometers and gyroscopes. The AFOs were fitted with hardware to induce different gait perturbations: free rotation of the ankle, plantarflexion or "equinus" gait, and locked ankle joint. For each condition, the subject performed eight gait activities at varied slopes and standing, sitting, and lying postures. Using video for ground truth, the algorithm had an overall mean sensitivity of 95% using 50% of the data (∼140s) for training and demonstrated upwards of 90% sensitivity with 25% of the data (∼70s) for training. High sensitivities (≥87%) and PPV (≥90%) were achieved for all annotated gait patterns for all perturbations, excluding stair climbing (63%, 77%) and descending (80%, 78%). Postures were classified with less sensitivity and PPV than gait activities: lying (98%, 93%), standing (80%, 84%) and sitting (64%, 75%). Non-annotated walking (68%) and standing (73%) were classified with less sensitivity than were corresponding annotated events. Our results indicate that AFOs are a suitable sensor platform for future research in activity classification and gait monitoring in AFO users with perturbed gait using limited training data. 23839463 196 Human Neural Stem Cell Transplantation in Chronic SCI: Interim Results of a Phase I/II Trial. Demonstration of the safety of human neural stem cells is critical for the overall development of intramedullary transplantation following spinal cord injury (SCI). We present interim results of an on-going Phase I/II trial 12 months after transplantation of human CNS stem cells (HuCNS-SC®, StemCells, Inc., Newark, California) in patients with chronic thoracic (T2-11) SCI. Special emphasis will be put on aspects of surgical administration and methods of thoracic segmental assessment. We will also address preliminary clinical neurophysiological and radiological outcomes following stem cell transplantation. Three ASIA Impairment Scale (AIS) A paraplegic patients were transplanted with allogenic HuCNS-SC cells between 3-12 months post-injury. There were no surgical complications or adverse changes directly attributed to the cells at the 12 months follow-up. Signs of segmental improvement were observed in 2 out of 3 AIS A patients, and the third subject remained stable. Based on the safety results in the first AIS A patients, recruitment of patients with incomplete injury (AIS B and C patients) has now commenced. We present 12 months interim safety and preliminary efficacy data of the first 3 AIS A SCI patients who underwent thoracic intramedullary transplantation of HuCNS-SC as part of an on-going open-label Phase I/II trial. 23911883 PHII-7 inhibits cell growth and induces apoptosis in leukemia cell line K562 as well as its MDR- counterpart K562/A02 through producing reactive oxygen species. Multidrug resistance (MDR) is a major obstacle that hinders the efficacy of chemotherapy in many human malignancies. PHII-7 is a derivative of indirubin, which is designed and synthesized by our laboratory. Our preliminary work indicates its potent antitumor activities in vitro and in vivo. Furthermore, based on the model of MDR cell line, we found its powerful effect in inhibiting the expression of P-glycoprotein (P-gp) and killing multidrug-resistant (MDR) cells. However, the detailed mechanism of PHII-7 remains to be explored. Reactive oxygen species are known for high reactive activity as they possess unmatched electrons. In this study, we showed that PHII-7 generated equal reactive oxygen species in parental K562 and its counterpart MDR K562/A02 cells. Pre-incubation with thiol antioxidants glutathione or N-acetyl-cysteine(NAC) almost abolished the cytotoxicity of PHII-7. Moreover, NAC abrogated DNA damage, cell cycle arrests and apoptosis induced by PHII-7. Our results collectively indicated that reactive oxygen species production induced by PHII-7 contributed to both apoptosis and cell cycle arrets in MDR K562/A02 cells, thus extending our prior related findings. Notably, JNK phosphorylation was induced by PHII-7 and pre-incubated of K562/A02 cells with NAC or inhibitor of JNK(SP006125) eliminated P-gp downregulation. Taken together, our results provide a detailed biochemical basis for further clinical application of PHII-7. 23931723 Radiation-Induced Bystander Signaling from Somatic Cells to Germ Cells in Caenorhabditis elegans. Recently, radiation-induced bystander effects (RIBE) have been studied in mouse models in vivo, which clearly demonstrated bystander effects among somatic cells. However, there is currently no evidence for RIBE between somatic cells and germ cells in animal models in vivo. In the current study, the model animal Caenorhabditis elegans was used to investigate the bystander signaling from somatic cells to germ cells, as well as underlying mechanisms C. elegans body size allows for precise microbeam irradiation and the abundant mutant strains for genetic dissection relative to currently adopted mouse models make it ideal for such analysis. Our results showed that irradiation of posterior pharynx bulbs and tails of C. elegans enhanced the level of germ cell apoptosis in bystander gonads. The irradiation of posterior pharynx bulbs also increased the level of DNA damage in bystander germ cells and genomic instability in the F1 progeny of irradiated worms, suggesting a potential carcinogenic risk in progeny even only somatic cells of parents are exposed to ionizing radiation (IR). It was also shown that DNA damage-induced germ cell death machinery and MAPK signaling pathways were both involved in the induction of germ cell apoptosis by microbeam induced bystander signaling, indicating a complex cooperation among multiple signaling pathways for bystander effects from somatic cells to germ cells. 23819611 Report of the Post Kala-azar Dermal Leishmaniasis (PKDL) Consortium Meeting, New Delhi, India, 27-29 June 2012. Post kala-azar dermal leishmaniasis (PKDL) is a neglected complication of visceral leishmaniasis (VL)-a deadly, infectious disease that claims approximately 20,000 to 40,000 lives every year. PKDL is thought to be a reservoir for transmission of VL, thus, adequate control of PKDL plays a key role in the ongoing effort to eliminate VL. Over the past few years, several expert meetings have recommended that a greater focus on PKDL was needed, especially in South Asia. This report summarizes the Post Kala-Azar Dermal Leishmaniasis Consortium Meeting held in New Delhi, India, 27-29 June 2012. The PKDL Consortium is committed to promote and facilitate activities that lead to better understanding of all aspects of PKDL that are needed for improved clinical management and to achieve control of PKDL and VL. Fifty clinicians, scientists, policy makers, and advocates came together to discuss issues relating to PKDL epidemiology, diagnosis, pathogenesis, clinical presentation, treatment, and control. Colleagues who were unable to attend participated during drafting of the consortium meeting report. 23850495 Frequent TMPRSS2-ERG rearrangement in prostatic small cell carcinoma detected by fluorescence in situ hybridization: the superiority of fluorescence in situ hybridization over ERG immunohistochemistry. Small cell carcinoma of the prostate is both morphologically and immunohistochemically similar to small cell carcinoma of other organs such as the urinary bladder or lung. TMPRSS2-ERG gene fusion appears to be a highly specific alteration in prostatic carcinoma that is frequently shared by small cell carcinoma. In adenocarcinoma, immunohistochemistry for the ERG protein product has been reported to correlate well with the presence of the gene fusion, although in prostatic small cell carcinoma, this relationship is not completely understood. We evaluated 54 cases of small cell carcinoma of the prostate and compared TMPRSS2-ERG gene fusion status by fluorescence in situ hybridization (FISH) to immunohistochemical staining with antibody to ERG. Of 54 cases of prostatic small cell carcinoma, 26 (48%) were positive for TMPRSS2-ERG gene fusion by FISH and 12 (22%) showed overexpression of ERG protein by immunohistochemistry. Of the 26 cases positive by FISH, 11 were also positive for ERG protein by immunohistochemistry. One tumor was positive by immunohistochemistry but negative by FISH. Urinary bladder small cell carcinoma (n = 25) showed negative results by both methods; however, 2 of 14 small cell carcinomas of other organs (lung, head, and neck) showed positive immunohistochemistry but negative FISH. Positive staining for ERG by immunohistochemistry is present in a subset of prostatic small cell carcinomas and correlates with the presence of TMPRSS2-ERG gene fusion. Therefore, it may be useful in confirming prostatic origin when molecular testing is not accessible. However, sensitivity and specificity of ERG immunohistochemistry in small cell carcinoma are decreased compared to FISH. 23483380 Spontaneous hip labrum regrowth after initial surgical débridement. Anecdotal evidence from second-look hip arthroscopies and animal studies has suggested spontaneous labral regrowth may occur after débridement. However, these observations have not been systematically confirmed. We (1) determined whether labral regrowth occurs after débridement in human hips; (2) if so, described the characteristics of the reconstituted labrum; and (3) determined the association, if any, of age with the presence and quality of labral regrowth. We retrospectively reviewed all 24 patients who previously had open hip surgical dislocation with labral débridement for treatment of femoroacetabular impingement (FAI) and concomitant hip arthroscopy 2 years after index procedure in association with planned removal of trochanteric hardware between January and December 1999. Data recorded included amount of labral resection at the index procedure using the clockface method, presence and quality of any labral regrowth, presence of any labral scarring or inflammation, and WOMAC(®) scores. Minimum clinical followup was 11 years (average, 12 years; range, 11-12 years). All patients demonstrated labral regrowth at arthroscopy at 2 years. Homogeneous regrowth of labral height was seen in 21 of 24 patients, with labral scarring noted in four of 24. Average WOMAC(®) score was 98 points (range, 90-100 points) at the time of hardware removal. Increasing patient age was independently associated with decreased WOMAC(®) score and inhomogeneous regrowth of the labrum. Labral regrowth after resection was seen in all patients at 2 years from index operation. Increasing age, however, was associated with poorer quality of the reconstituted labrum. Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. 23847004 A New Diamond Biosensor with Integrated Graphitic Microchannels for Detecting Quantal Exocytic Events from Chromaffin Cells. An MeV ion-microbeam lithographic technique can be successfully employed for the fabrication of an all-carbon miniaturized cellular biosensor based on graphitic microchannels embedded in a single-crystal diamond matrix. The device is functionally characterized for the in vitro recording of quantal exocytic events from single chromaffin cells, with high sensitivity and signal-to-noise ratio, opening promising perspectives for the realization of monolithic all-carbon cellular biosensors. 23963028 Outcome of 132 consecutive reconstructive operations for intestinal fistula--staged operation without primary anastomosis improved outcome in retrospective analysis. To study factors that influenced healing and survival after attempted closure of enterocutaneous fistula. Retrospective analysis of prospective data concerning 101 patients operated on 132 instances for 110 enterocutaneous fistulae at two hospitals. In all, 96 (87%) of the 110 fistulae healed and 92 (91%) patients survived. A total of 9 patients with unhealed fistula died. Multivariate analysis revealed jaundice as an independent factor for both death and failed closure and operation without anastomosis as an independent positive factor for healing. Failure rate was lower after an operation with stoma without anastomosis (6 of 43, 14%) than after an operation with anastomosis (30 of 89, 34%) p = 0.0213. Of the 36 instances with unhealed fistula, 13 (36%) could be ascribed to inadvertent bowel lesions at the reconstructive operation. In addition, univariate analysis revealed that patients with previous multiple laparotomies or with multiple operations for enterocutaneous fistula healed less likely and had higher mortality. A low serum albumin, high white blood cell count, high C-reactive protein concentration, high fistula output, total parenteral nutrition, and operation for recurrent fistula were associated with death together with long operation time and operative bleeding, both indicators of surgical complexity. Over time, staged surgery avoiding anastomosis increased from 27% to 57%. Mortality decreased from 12% to 6%, and healing increased from 73% to 94%. Chronic inflammation, malnutrition, and liver failure causing an impaired healing capacity are important reasons for failure. Staged operation without primary anastomosis may allow the patient to reverse this condition and improve outcome. The high surgical complexity is a negative factor that requires careful planning of the operation. 23729623 Structure and function of MK5/PRAK: the loner among the mitogen-activated protein kinase-activated protein kinases. Abstract Mitogen-activated protein kinase (MAPK) pathways are important signal transduction pathways that control pivotal cellular processes including proliferation, differentiation, survival, apoptosis, gene regulation, and motility. MAPK pathways consist of a relay of consecutive phosphorylation events exerted by MAPK kinase kinases, MAPK kinases, and MAPKs. Conventional MAPKs are characterized by a conserved Thr-X-Tyr motif in the activation loop of the kinase domain, while atypical MAPKs lack this motif and do not seem to be organized into the classical three-tiered kinase cascade. One functional group of conventional and atypical MAPK substrates consists of protein kinases known as MAPK-activated protein kinases. Eleven mammalian MAPK-activated protein kinases have been identified, and they are divided into five subgroups: the ribosomal-S6-kinases RSK1-4, the MAPK-interacting kinases MNK1 and 2, the mitogen- and stress-activated kinases MSK1 and 2, the MAPK-activated protein kinases MK2 and 3, and the MAPK-activated protein kinase MK5 (also referred to as PRAK). MK5/PRAK is the only MAPK-activated protein kinase that is a substrate for both conventional and atypical MAPK, while all other MAPKAPKs are exclusively phosphorylated by conventional MAPKs. This review focuses on the structure, activation, substrates, functions, and possible implications of MK5/PRAK in malignant and nonmalignant diseases. 23894356 Glucose Metabolism during Resting State Reveals Abnormal Brain Networks Organization in the Alzheimer's Disease and Mild Cognitive Impairment. This paper aims to study the abnormal patterns of brain glucose metabolism co-variations in Alzheimer disease (AD) and Mild Cognitive Impairment (MCI) patients compared to Normal healthy controls (NC) using the Alzheimer Disease Neuroimaging Initiative (ADNI) database. The local cerebral metabolic rate for glucose (CMRgl) in a set of 90 structures belonging to the AAL atlas was obtained from Fluro-Deoxyglucose Positron Emission Tomography data in resting state. It is assumed that brain regions whose CMRgl values are significantly correlated are functionally associated; therefore, when metabolism is altered in a single region, the alteration will affect the metabolism of other brain areas with which it interrelates. The glucose metabolism network (represented by the matrix of the CMRgl co-variations among all pairs of structures) was studied using the graph theory framework. The highest concurrent fluctuations in CMRgl were basically identified between homologous cortical regions in all groups. Significant differences in CMRgl co-variations in AD and MCI groups as compared to NC were found. The AD and MCI patients showed aberrant patterns in comparison to NC subjects, as detected by global and local network properties (global and local efficiency, clustering index, and others). MCI network's attributes showed an intermediate position between NC and AD, corroborating it as a transitional stage from normal aging to Alzheimer disease. Our study is an attempt at exploring the complex association between glucose metabolism, CMRgl covariations and the attributes of the brain network organization in AD and MCI. 23761411 Household-based socioeconomic position and diabetes-related mortality among married and cohabiting persons: findings from a census-based cohort study (Flanders, 2001-2010). Diabetes prevalence is high worldwide, affecting entire populations. Yet some population groups are more susceptible than others. In contemporary western societies, socioeconomically disadvantaged groups are disproportionally affected. The pattern is less clear for diabetes mortality. Researchers argue increasingly in favour of looking beyond individual socioeconomic position (SEP). In light of the above, this paper looks at the relationship between individual-based and household-based SEP measures and diabetes mortality. Data consisted of the Belgian 2001 census for the Flanders region linked to register data on cause-specific mortality during the period 2001-2010. The study population included all 35-year-old to 74-year-old official inhabitants of Flanders married or cohabiting at the 2001 census. Age-standardised death rates (direct standardisation) and mortality rate ratios (MRRs; Poisson regression) were computed for the different SEP groups. Inverse gradients were observed by own education, partner's education and housing status (combination of housing tenure and quality). For example, among 55-year-olds to 74-year-olds, MRRs according to partner's education were 3.0 (95% CI 2.4 to 3.8) for women with a lower-educated partner and 1.6 (95% CI 1.2 to 2.0) for women with a higher secondary-educated partner, relative to women with a higher-educated partner. As for housing status, diabetes-related mortality was particularly high among tenants and low-quality owners. The association between each of the SEP measures and diabetes-related mortality remained after adjusting for the other measures. There were large differences in diabetes-related mortality according to both individual-based and household-based SEP measures, indicating the importance of the individual and household levels for understanding socioeconomic inequalities in diabetes mortality. 23312470 A comparative protease stability study of synthetic macrocyclic peptides that mimic two endocrine hormones. Peptide therapeutics have traditionally faced many challenges including low bioavailability, poor proteolytic stability and difficult cellular uptake. Conformationally constraining the backbone of a peptide into a macrocyclic ring often ameliorates these problems and allows for the development of a variety of new drugs. Such peptide-based pharmaceuticals can enhance the multi-faceted functionality of peptide side chains, permitting the peptides to bind cellular targets and receptors necessary to impart their role, while protecting them from degrading cellular influences. In the work described here, we developed three cyclic peptides, VP mimic1, VP mimic2 and OT mimic1, which mimic endocrine hormones vasopressin and oxytocin. Making notable changes to the overall structure and composition of the parent hormones, we synthesized the mimics and tested their durability against treatment with three proteases chosen for their specificity: pepsin, alpha-chymotrypsin, and pronase. Vasopressin and oxytocin contain a disulfide linkage leaving them particularly vulnerable to deactivation from the reducing environment inside the cell. Thus, we increased the complexity of our assays by adding reducing agent glutathione to each mixture. Subsequently, we discovered each of our mimics withstood protease treatment with less degradation and/or a slower rate of degradation as compared to both parent hormones and a linear control peptide. 22705396 The potential of nicotinic enhancement of cognitive remediation training in schizophrenia. Cognitive deficits in schizophrenia are critically important predictors of long-term psychosocial outcome and are not significantly ameliorated by currently available medications. Cognitive remediation training has shown promise for alleviating cognitive symptoms of schizophrenia, but the clinical significance has often been limited by small effect sizes. Approaches that achieve larger improvement involve time requirements that can be cost-prohibitive within the current clinical care system. This mini-review evaluates the theoretical potential of a pharmacological enhancement strategy of cognitive remediation training with nicotinic acetylcholine receptor (nAChR) agonists. nAChR agonists can facilitate sensory processing, alertness, attention, learning and memory. While these effects may be too subtle and short-lasting to be of clinical relevance as a primary treatment of cognitive deficits, they constitute an ideal effects profile for enhancing training benefits. Several mechanisms are described through which repeated coupling of cognitive training challenges with nAChR stimulation may enhance and accelerate cognitive remediation training effects, advancing such interventions into more effective and practicable treatments of some of the most debilitating symptoms of schizophrenia. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23942123 Cytosolic flagellin-induced lysosomal pathway regulates inflammasome-dependent and -independent macrophage responses. NAIP5/NLRC4 (neuronal apoptosis inhibitory protein 5/nucleotide oligomerization domain-like receptor family, caspase activation recruitment domain domain-containing 4) inflammasome activation by cytosolic flagellin results in caspase-1-mediated processing and secretion of IL-1β/IL-18 and pyroptosis, an inflammatory cell death pathway. Here, we found that although NLRC4, ASC, and caspase-1 are required for IL-1β secretion in response to cytosolic flagellin, cell death, nevertheless, occurs in the absence of these molecules. Cytosolic flagellin-induced inflammasome-independent cell death is accompanied by IL-1α secretion and is temporally correlated with the restriction of Salmonella Typhimurium infection. Despite displaying some apoptotic features, this peculiar form of cell death do not require caspase activation but is regulated by a lysosomal pathway, in which cathepsin B and cathepsin D play redundant roles. Moreover, cathepsin B contributes to NAIP5/NLRC4 inflammasome-induced pyroptosis and IL-1α and IL-1β production in response to cytosolic flagellin. Together, our data describe a pathway induced by cytosolic flagellin that induces a peculiar form of cell death and regulates inflammasome-mediated effector mechanisms of macrophages. 23780229 Separation of chitosan by degree of acetylation using simple free solution capillary electrophoresis. Chitosan is a biopolymer of increasing significance, as well as a renewable and sustainable material. Its main molecular characteristics are molar mass and degree of acetylation (composition). Precise average degrees of acetylation were measured by quantitative (1)H solution-state NMR spectroscopy. While number-average degrees of acetylation had already been determined by (1)H NMR spectroscopy, weight-average degrees of acetylation are also determined and may be more relevant for some properties, such as mechanical properties. We report the first separation of chitosan according to its degree of acetylation using free solution capillary electrophoresis. Capillary electrophoresis separates chitosan in the 'critical conditions': the molar mass plays little role and the separation is by the degree of acetylation. It characterises the heterogeneity of chitosan samples in terms of composition (dispersity of the distribution of degrees of acetylation). This heterogeneity (broad distribution of degrees of acetylation) cannot be neglected contrary to a common assumption found in the literature. This fast and easy separation will allow establishing a structure-property relationships. 23796655 Development of a time-to-detect growth model for heat-treated Bacillus cereus spores. The microbiological safety and quality of Refrigerated Processed Foods of Extended Durability (REPFEDs) relies on a combination of mild heat treatment and refrigeration, sometimes in combination with other inhibitory agents that are ineffective when used alone. In this context, a predictive model describing the time-to-detect growth (measured by turbidimetry) of psychrotrophic Bacillus cereus spores submitted to various combinations of pH, water activity (aw), heat treatment and storage temperature was developed. As the inoculum was high, the time-to-detect growth was the sum of two times: for a large part of the spore lag time (time before germination and outgrowth) and to a lesser extent of the time to have subsequent vegetative cells growing up to a detectable level. A dataset of 434 combinations (of pH, aw, heat treatment, storage temperature and B. cereus strain), originally collected at Ghent University to build a growth/no-growth model for two Bacillus cereus strains, was re-interpreted as time-to-detect growth values. In the growth area (223 combinations) the time-to-detect growth was set as the longest time where none, or only one, of the 8 replicated wells showed growth. In the no-growth area (211 combinations) the time-to-detect growth was set as longer than the time where the experiment was stopped (60days or more) and analysed as a censored response. The factors of variation were heat-treatment intensity (85°C, 87°C and 90°C in a time range of 1 to 38min), storage temperature (8-30°C), pH (5.2-6.4) and aw (0.973-0.995). Two different strains were analysed. The model had a Gamma multiplicative structure; it was solved by Bayesian inference with informative prior distributions. To be implemented in a decision tool, for instance to calculate the process and formulation conditions required to achieve a given detection time, each Gamma term had some constraints: they had to be monotonous, continuous and algebraically simple mathematical functions (i.e. having analytical solution). Overall, the cumulative effect of various stressful conditions (pasteurisation process, low temperature, and low pH) enables to extend the time-to-detect growth up to 60days or more, whereas the heat-treatment on its own did not have a similar effect. For example, with the most heat resistant strain (strain 1, FF140), for a product at aw0.99, stored at 10°C, heat-treated at 90°C for 10min, a time-to-detect growth of 2days was expected when the pH equalled 6.5. Under the same conditions, if the pH was reduced to 5.8, the time-to-detect growth was predicted to be 11days (and 33days at pH5.5). After a pasteurisation at 90°C for 10min, for a product kept at 10°C, combinations of pH and aw such as pH6.0-aw0.97, pH5.7-aw0.98 or pH5.5-aw0.99 were predicted to extend the time-to-detect growth up to 30days. The developed model is a useful tool for REPFED producers to guarantee the safety of their products towards psychrotrophic B. cereus. 23703032 Application of replica exchange umbrella sampling to protein structure refinement of nontemplate models. We provide an assessment of a computational strategy for protein structure refinement that combines self-guided Langevin dynamics with umbrella-potential biasing replica exchange using the radius of gyration as a coordinate (Rg -ReX). Eight structurally nonredundant proteins and their decoys were examined by sampling conformational space at room temperature using the CHARMM22/GBMV2 force field to generate the ensemble of structures. Two atomic statistical potentials (RWplus and DFIRE) were analyzed for structure identification and compared to the simulation force-field potential. The results show that, while the Rg -ReX simulations were able to sample conformational basins that were more structurally similar to the X-ray crystallographic structures than the starting first-order ranked decoys, the potentials failed to detect these basins from refinement. Of the three potential functions, RWplus yielded the highest accuracy for recognition of structures that refined to an average of nearly 20% increase in native contacts relative to the starting decoys. The overall performance of Rg -ReX is compared to an earlier study of applying temperature-based replica exchange to refine the same decoy sets and highlights the general challenge of achieving consistently the sampling and detection threshold of 70% fraction of native contacts. 23949564 Percutaneous injection of autologous, culture-expanded mesenchymal stem cells into carpometacarpal hand joints: a case series with an untreated comparison group. In the present study, we describe six patients who received autologous mesenchymal stem cell (MSC) therapy for symptomatic carpometacarpal (CMC) joint and hand osteoarthritis (OA). Six patients who received injections of adult autologous culture expanded MSCs in their thumb CMC joints were followed for 1 year posttreatment, and matched with four procedure candidates who remained untreated. We observed positive outcomes in the treatment group for both symptoms and function related to the OA, compared with a reported worsening among the untreated controls. While these results should be interpreted with caution because of the small number of treated subjects and lack of placebo control and randomization, we find sufficient evidence for further investigation of MSC therapy as an alternative to more invasive surgery in patients with OA of the hand. 23281103 Temporal MRI characterization of gelatin/hyaluronic acid/chondroitin sulfate sponge for cartilage tissue engineering. A tri-copolymer sponge consisting of gelatin, hyaluronic acid, and chondroitin sulfate (GHC) was designed to mimic the cartilage environment in vivo for cartilage regeneration. The present study aimed to temporally characterize the magnetic resonance relaxation time of GHC constructs in vivo in a rodent heterotopic model. GHC sponges with cells (GHCc) or without cells (GHC) implanted in rat leg muscle were monitored using MRI (4.7 T MR scanner) on day 0, 7, 14, and 21 after implantation. The results revealed that the transverse relaxation time (T2) of GHC constructs decreased significantly over time when compared to the T2 of GHCc constructs. However, the longitudinal relaxation time (T1) of GHCc and GHC constructs remained stable. Moreover, hematoxylin and eosin and immunohistochemical staining with antibodies to S100 protein, and types I and II collagen showed that normal morphology, phenotype, and function of chondrocytes were preserved in the GHCc construct. Thus, we concluded that GHC constructs adequately support chondrocyte growth and function. On top of that, T2 may be a useful tool for monitoring cartilage regeneration in GHC constructs. 23913281 Percutaneous Paravalvular Leak Closure. Paravalvular leak (PVL) is a known complication of surgical and transcatheter valve replacement procedures. Patients most commonly present with congestive heart failure and/or hemolysis, and repeat surgical procedures to correct the PVL carries increased risk with reduced likelihood of success. As a result, percutaneous approaches to PVL closure have been developed, with a considerable emphasis on multimodality imaging for both diagnosis and procedural guidance in the cardiac catheterization laboratory. Large series' of percutaneous PVL closure have been recently published, with encouraging results with respect to both procedural success and clinical outcomes. In this paper, we provide a comprehensive review of imaging and procedural techniques for percutaneous PVL closure and present the data supporting this novel treatment strategy. 23885179 Acute and chronic effects of resistance exercise on blood pressure in elderly women and the possible influence of ACE I/D polymorphism. This study investigated the chronic effect of blood pressure (BP) and post-exercise hypotension (PEH) during resistance training (RT) and its relation with the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism in hypertensive elderly women. Participants were divided into two groups: an experimental group (EG) with exercise and a control group (CG) without exercise. The EG performed one adaptation month and one repetition maximum load (1RM) test at the end of this period. After the first month, the EG conducted a three-month program of RT at 60%, 70%, and 80% of 1RM, respectively, for each month. The CG was evaluated at the end of each month. Systolic (SBP) and diastolic (DBP) blood pressure (Microlife BP 3AC1-1) were measured, with the subject in a seated position, during an acute session for both GE and CG as follows: every 5 minutes for 20 minutes at pre-exercise rest, immediately after the resistance exercise and control, and every 15 minutes during 1 hour of recovery after exercise and CG. Analysis of covariance showed reduction in SBP and DBP (P ≤ 0.05) rest values after the RT program. PEH was observed only for the EG in acute sessions, for SBP after the second and third months (P ≤ 0.05), and for DBP after the second and fourth months (P ≤ 0.05). No significant differences in main effects and interaction effects between blood pressure and ACE I/D were observed. The occurrence of chronic reduction of blood pressure and PEH through EG may have a protective effect on the cardiovascular system with no ACE I/D polymorphism influence for this population. 23492953 Do screen-detected breast cancers have positive margins less often than clinically detected breast cancers? Positive tumour margins after breast-conserving surgery (BCS) have been selected as one of the major quality criteria for the surgical treatment of localized primary breast cancer. The national guideline states that the rate of positive margins should not exceed 30% in ductal carcinoma in situ and 20% in invasive cancers. We aimed to determine whether BCS in women with screen-detected breast cancer (SDBC) will have positive margins less often compared with women with clinically detected breast cancer (CDBC). Furthermore, the choice of subsequent therapy is studied when margins were positive after initial BCS. Women 50-75 years of age who underwent BCS for invasive breast cancer between July 2008 and December 2009 were selected from the Netherlands Cancer Registry. Data were merged with the National Cancer Screening Program, regions North and East, to identify women with SDBC. The relation to screening history, clinical and pathological factors was evaluated for correlation with margin status using multilevel analysis. Of 1537 women with an invasive breast cancer, 873 (57%) were diagnosed through the screening programme. SDBCs were significantly smaller (87 vs. 69% T1 tumours, i.e. ≤2 cm), more often well differentiated (33 vs. 26%), preoperatively confirmed (98 vs. 96%), diagnosed in a nonteaching hospital (60 vs. 66%) and more often had negative lymph nodes (LNs) (80 vs. 68%). In 170 out of 1537 women, the resection margins were positive. Multivariable analysis showed that hospital, tumour size, multifocality, positive LNs and absent preoperative confirmation were predictors of positive margins. No difference was found between women with SDBC and CDBC. Of women with positive margins, 90% underwent additional surgery. Women diagnosed with SDBC do not have a lower risk of having positive margins after BCS than women with CDBC. Although positive margins may occur in 11% of women with invasive tumours, well below the percentage recommended by the national guideline, the presence of encouraging factors by SDBC such as a smaller tumour size, unifocality, negative LNs and the presence of preoperative confirmation should not lead to performing a more sparing excision than is considered usual for comparable CDBC. 23432484 Salmonella Typhi OmpS1 and OmpS2 porins are potent protective immunogens with adjuvant properties. Salmonella enterica serovar Typhi (S. Typhi) is the causal agent of typhoid fever, a disease that primarily affects developing countries. Various antigens from this bacterium have been reported to be targets of the immune response. Recently, the S. Typhi genome has been shown to encode two porins--OmpS1 and OmpS2--which are expressed at low levels under in vitro culture conditions. In this study, we demonstrate that immunizing mice with either OmpS1 or OmpS2 induced production of specific, long-term antibody titres and conferred protection against S. Typhi challenge; in particular, OmpS1 was more immunogenic and conferred greater protective effects than OmpS2. We also found that OmpS1 is a Toll-like receptor 4 (TLR4) agonist, whereas OmpS2 is a TLR2 and TLR4 agonist. Both porins induced the production of tumour necrosis factor and interleukin-6, and OmpS2 was also able to induce interleukin-10 production. Furthermore, OmpS1 induced the over-expression of MHC II molecules in dendritic cells and OmpS2 induced the over-expression of CD40 molecules in macrophages and dendritic cells. Co-immunization of OmpS1 or OmpS2 with ovalbumin (OVA) increased anti-OVA antibody titres, the duration and isotype diversity of the OVA-specific antibody response, and the proliferation of T lymphocytes. These porins also had adjuvant effects on the antibody response when co-immunized with either the Vi capsular antigen from S. Typhi or inactivated 2009 pandemic influenza A(H1N1) virus [A(H1N1)pdm09]. Taken together, the data indicate that OmpS1 and OmpS2, despite being expressed at low levels under in vitro culture conditions, are potent protective immunogens with intrinsic adjuvant properties. 23603114 Identification of novel phospholipase A2 group IX members in metazoans. Sequence homologues of the bacterium Streptomyces violaceoruber and sea anemone Nematostella vectensis PLA2 pfam09056 members were identified in several bacteria, fungi and metazoans illustrating the evolution of this PLA2 sub-family. Comparison of their molecular structures revealed that bacteria and fungi members are part of the GXIV of PLA2s while metazoan representatives are similar with GIX PLA2 of the marine snail Conus magus. Members of GXIV and GIX PLA2s show modest overall sequence similarity (21-35%) but considerable motif conservation within the putative Ca(2+)-binding, catalytic sites and cysteine residue positions which are essential for enzyme function. GXIV PLA2s of bacteria and fungi typically contain four cysteine residues composing two intramolecular disulphide bonds. GIX PLA2 homologues were identified in cnidarians and molluscs and in a single tunicate but appear to be absent from other metazoan genomes. The mature GIX PLA2 deduced peptides contain up to ten cysteine residues capable of forming five putative disulphide bonds. Three disulphide bonds were identified in GIX PLA2s, two of which correspond to those localized in GXIV PLA2s. Phylogenetic analysis demonstrates that metazoan GIX PLA2s cluster separate from the bacterial and fungal GXIV PLA2s and both pfam09056 members form a group separate from the prokaryote and eukaryote GXIIA PLA2 pfam06951. Duplicate PLA2 pfam09056 genes were identified in the genomes of sea anemone N. vectensis and oyster Crassostrea gigas suggest that members of this family evolved via species-specific duplication events. These observations indicate that the newly identified metazoan pfam09056 members may be classified as GIX PLA2s and support the idea of the common evolutionary origin of GXIV and GIX PLA2 pfam09056 members, which emerged early in bacteria and were maintained in the genomes of fungi and selected extant metazoan taxa. 23897177 Natural progression of renal function in the elderly: analysis of poor prognosis factors associated with chronic kidney disease. In the last few years a debate has emerged on the range of normal renal function and the rate at which renal disease progresses in the elderly. In this review we analysed, on the basis of the results of the study Ancianos con enfermedad renal crónica del Hospital General de Segovia (Elderly people with chronic kidney disease of the Hospital General de Segovia), the poor prognosis factors associated with this disease: proteinuria, episodes of acute renal failure and heart failure, and the role of uric acid. Elderly people with chronic kidney disease who present these poor prognosis factors may benefit from follow-up by Nephrology. 23672760 A Comparison of Self-Assembly and Hydrogel Encapsulation as a Means to Engineer Functional Cartilaginous Grafts Using Culture Expanded Chondrocytes. Despite an increased interest in the use of hydrogel encapsulation and cellular self-assembly (often termed "self-aggregating" or "scaffold-free" approaches) for tissue-engineering applications, to the best of our knowledge, no study to date has been undertaken to directly compare both approaches for generating functional cartilaginous grafts. The objective of this study was to directly compare self-assembly (SA) and agarose hydrogel encapsulation (AE) as a means to engineer such grafts using passaged chondrocytes. Agarose hydrogels (5 mm diameter × 1.5 mm thick) were seeded with chondrocytes at two cell seeding densities (900,000 cells or 4 million cells in total per hydrogel), while SA constructs were generated by adding the same number of cells to custom-made molds. Constructs were either supplemented with transforming growth factor (TGF)-β3 for 6 weeks, or only supplemented with TGF-β3 for the first 2 weeks of the 6 week culture period. The SA method was only capable of generating geometrically uniform cartilaginous tissues at high seeding densities (4 million cells). At these high seeding densities, we observed that total sulphated glycosaminoglycan (sGAG) and collagen synthesis was greater with AE than SA, with higher sGAG retention also observed in AE constructs. When normalized to wet weight, however, SA constructs exhibited significantly higher levels of collagen accumulation compared with agarose hydrogels. Furthermore, it was possible to engineer such functionality into these tissues in a shorter timeframe using the SA approach compared with AE. Therefore, while large numbers of chondrocytes are required to engineer cartilaginous grafts using the SA approach, it would appear to lead to the faster generation of a more hyaline-like tissue, with a tissue architecture and a ratio of collagen to sGAG content more closely resembling native articular cartilage. 23867281 Vitamin D deficiency intensifies deterioration of risk factors, such as male sex and absence of vision, leading to increased postural body sway. Due to inconsistent findings, the influence of vitamin D on postural body sway (PBS) is currently under debate. This study evaluated the impact of vitamin D on PBS with regards to different foot positions and eye opening states in community-dwelling older individuals. In a cross-sectional study, we assessed PBS in 342 older individuals (264 females [average age (±SD): 68.3±9.0 years], 78 males [65.7±9.6 years]). A detailed medical history and vitamin D level were obtained for each individual. Fall risk was evaluated using the New York-Presbyterian Fall Risk Assessment Tool (NY PFRA). PBS parameters (area, distance, velocity, frequency) were evaluated on a pressure plate with feet in closed stance (CS) or hip-width stance (HWS), open eyes and closed eyes. Statistical analysis included logarithmic mixed models for repeated measures with the MIXED model procedure to test the influence of vitamin D (categorized in <10μg/l, 10-20μg/l, 21-30μg/l, >30μg/l), foot position, eye opening state, age, sex and frequency of physical activity on PBS. Vitamin D was not an independent risk factor for falls experienced in the last 12 months. Nonetheless, PBS was higher in patients with vitamin D deficiency (<10μg/l) in HWS (A/P p=0.028 and area p=0.037). Additionally, vitamin D deficiency intensified the deleterious effects of male sex (distance p=0.002) and absence of vision (area p<0.001) on PBS. Independent risk factors for increased PBS like male sex and absence of vision are additionally compromised by vitamin D deficiency. 23928546 Histoplasma Infection of Aortofemoral Bypass Graft. : Histoplasma infection of vascular grafts is extremely rare. To our knowledge, there are only 4 cases reported with Histoplasma capsulatum infection of the aortic graft. All had previous disseminated histoplasmosis and atherosclerotic peripheral vascular disease. They were treated surgically with explantation of the infected graft and reimplantation of new graft in extra-anatomic uninfected site. The authors present a new case of H capsulatum infection of aortofemoral bypass graft, but unlike the other cases, this case was managed without surgical intervention. 23440602 Visualization of mitotic arrest of cell cycle with bioluminescence imaging in living animals. Visualization of the cell cycle in living subjects has long been a big challenge. The present study aimed to noninvasively visualize mitotic arrest of the cell cycle with an optical reporter in living subjects. An N-terminal cyclin B1-luciferase fusion construct (cyclin B-Luc) controlled by the cyclin B promoter, as a mitosis reporter, was generated. HeLa or HCT116 cells stably expressing cyclin B-Luc reporter were used to evaluate its cell cycle-dependent regulation and ubiquitination-mediated degradation. We also evaluated its feasibility to monitor the mitotic arrest caused by Taxotere both in vitro and in vivo. We showed that the cyclin B-Luc fusion protein was regulated in a cell cycle-dependent manner and accumulated in the mitotic phase (M phase) in cellular assays. The regulation of cyclin B-Luc reporter was mediated by proteasome ubiquitination. In the present study, in vitro imaging showed that antimitotic reagents like Taxotere upregulated the reporter through cell cycle arrest in the M phase. Noninvasive longitudinal bioluminescence imaging further demonstrated an upregulation of the reporter consistent with mitotic arrest induced in tumor xenograft models. Induction of this reporter was also observed with a kinesin spindle protein inhibitor, which causes cell cycle blockage in the M phase. Our results demonstrate that the cyclin B-Luc reporter can be used to image whether compounds are capable, in vivo, of causing an M phase arrest and/or altering cyclin B turnover. This reporter can also be potentially used in high-throughput screening efforts aimed at discovering novel molecules that will cause cell cycle arrest at the M phase in cultivated cell lines and animal models. 23861873 Detection of Escherichia coli and Associated β-Lactamases Genes from Diabetic Foot Ulcers by Multiplex PCR and Molecular Modeling and Docking of SHV-1, TEM-1, and OXA-1 β-Lactamases with Clindamycin and Piperacillin-Tazobactam. Diabetic foot ulcer (DFU) is a common and devastating complication in diabetes. Antimicrobial resistance mediated by extended-spectrum β-lactamases (ESBLs) production by bacteria is considered to be a major threat for foot amputation. The present study deals with the detection of Escherichia coli and the prevalence of bla TEM, bla SHV and bla OXA genes directly from biopsy and swab of foot ulcers of diabetic patients. In total, 116 DFU patients were screened, of which 42 suffering with severe DFUs were selected for this study. Altogether 16 E. coli strains were successfully isolated from biopsy and/or swab samples of 15 (35.71%) patients. ESBL production was noted in 12 (75%) strains. Amplification of β-lactamase genes by multiplex PCR showed the presence of bla CTX-M like genes in 10 strains, bla TEM and bla OXA in 9 strains each, and bla SHV in 8 of the total 16 strains of E. coli. Out of the ten antibiotics tested, E. coli strains were found to be resistant to ampicillin (75%), cefoxitin (56.25%), cefazolin (50%), meropenem (37.5%), cefoperazone (25%), cefepime (31.25%), ceftazidime (56.25%), and cefotaxime (68.75%) but all showed sensitivity (100%) to clindamycin and piperacillin-tazobactam. 3D models of the most prevalent variants of β-lactamases namely TEM-1, SHV-1, OXA-1, and ESBL namely CTX-M-15 were predicted and docking was performed with clindamycin and piperacillin-tazobactam to reveal the molecular basis of drug sensitivity. Docking showed the best docking score with significant interactions, forming hydrogen bond, Van der Waals and polar level interaction with active site residues. Findings of the present study may provide useful insights for the development of new antibiotic drugs and may also prevent ESBLs-mediated resistance problem in DFU. The novel multiplex PCR assay designed in this study may be routinely used in clinical diagnostics of E. coli and associated bla TEM, bla SHV, and bla OXA like genes. 22984858 Personality disorders in men with sexual and violent criminal offense histories. Little is known about personality disorders (PDs) in offenders with histories of both sexual and (nonsexual) violent offenses. This study aimed to identify possible differences of PD profiles across three different offender groups with both sexual and violent (S+V), only sexual (S), and only violent (V) offenses. Nonviolent (N) offenders were used as a comparison group. Typing of individuals according to their offensive histories was performed on the basis of 259 psychiatric court reports that included the Structured Clinical Interview (SCID)-II for PD diagnostics. Men from the S+V group committed significantly more acts of rape and sexual coercion than the mere sexual offenders. Furthermore, S+V offenders showed the highest rates of PDs overall (68.3%), with every second offender being diagnosed with an antisocial PD and every third offender with a borderline PD. In summary, the results suggest that S+V offenders form a group of individuals with remarkable differences regarding PD profiles, the relatively highest frequencies of conduct disorders, familial addictive problems, and PDs overall. 23962706 Iron oxide/gold core/shell nanomagnetic probes and CdS biolabels for amplified electrochemical immunosensing of Salmonella typhimurium. There is an imminent need for rapid methods to detect and determine pathogenic bacteria in food products as alternatives to the laborious and time-consuming culture procedures. In this work, an electrochemical immunoassay using iron/gold core/shell nanoparticles (Fe@Au) conjugated with anti-Salmonella antibodies was developed. The chemical synthesis and functionalization of magnetic and gold-coated magnetic nanoparticles is reported. Fe@Au nanoparticles were functionalized with different self-assembled monolayers and characterized using ultraviolet-visible spectrometry, transmission electron microscopy, and voltammetric techniques. The determination of Salmonella typhimurium, on screen-printed carbon electrodes, was performed by square-wave anodic stripping voltammetry through the use of CdS nanocrystals. The calibration curve was established between 1×10(1) and 1×10(6)cells/mL and the limit of detection was 13cells/mL. The developed method showed that it is possible to determine the bacteria in milk at low concentrations and is suitable for the rapid (less than 1h) and sensitive detection of S. typhimurium in real samples. Therefore, the developed methodology could contribute to the improvement of the quality control of food samples. 23624801 Antibody-dependent cell lysis by NK cells is preserved after sarcoma-induced inhibition of NK cell cytotoxicity. Osteosarcoma and Ewing's sarcoma tumor cells are susceptible to IL15-induced or antibody-mediated cytolytic activity of NK cells in short-term cytotoxicity assays. When encountering the tumor environment in vivo, NK cells may be in contact with tumor cells for a prolonged time period. We explored whether a prolonged interaction with sarcoma cells can modulate the activation and cytotoxic activity of NK cells. The 40 h coculture of NK cells with sarcoma cells reversibly interfered with the IL15-induced expression of NKG2D, DNAM-1 and NKp30 and inhibited the cytolytic activity of NK cells. The inhibitory effects on receptor expression required physical contact between NK cells and sarcoma cells and were independent of TGF-β. Five days pre-incubation of NK cells with IL15 prevented the down-regulation of NKG2D and cytolytic activity in subsequent cocultures with sarcoma cells. NK cell FcγRIIIa/CD16 receptor expression and antibody-mediated cytotoxicity were not affected after the coculture. Inhibition of NK cell cytotoxicity was directly linked to the down-regulation of the respective NK cell-activating receptors. Our data demonstrate that the inhibitory effects of sarcoma cells on the cytolytic activity of NK cells do not affect the antibody-dependent cytotoxicity and can be prevented by pre-activation of NK cells with IL15. Thus, the combination of cytokine-activated NK cells and monoclonal antibody therapy may be required to improve tumor targeting and NK cell functionality in the tumor environment. 23936439 Does Virulence Assessment of Vibrio anguillarum Using Sea Bass (Dicentrarchus labrax) Larvae Correspond with Genotypic and Phenotypic Characterization? Vibriosis is one of the most ubiquitous fish diseases caused by bacteria belonging to the genus Vibrio such as Vibrio (Listonella) anguillarum. Despite a lot of research efforts, the virulence factors and mechanism of V. anguillarum are still insufficiently known, in part because of the lack of standardized virulence assays. We investigated and compared the virulence of 15 V. anguillarum strains obtained from different hosts or non-host niches using a standardized gnotobiotic bioassay with European sea bass (Dicentrarchus labrax L.) larvae as model hosts. In addition, to assess potential relationships between virulence and genotypic and phenotypic characteristics, the strains were characterized by random amplified polymorphic DNA (RAPD) and repetitive extragenic palindromic PCR (rep-PCR) analyses, as well as by phenotypic analyses using Biolog's Phenotype MicroArray™ technology and some virulence factor assays. Virulence testing revealed ten virulent and five avirulent strains. While some relation could be established between serotype, genotype and phenotype, no relation was found between virulence and genotypic or phenotypic characteristics, illustrating the complexity of V. anguillarum virulence. Moreover, the standardized gnotobiotic system used in this study has proven its strength as a model to assess and compare the virulence of different V. anguillarum strains in vivo. In this way, the bioassay contributes to the study of mechanisms underlying virulence in V. anguillarum. 23966193 A Comparative Analysis between Active and Passive Techniques for Underwater 3D Reconstruction of Close-Range Objects. In some application fields, such as underwater archaeology or marine biology, there is the need to collect three-dimensional, close-range data from objects that cannot be removed from their site. In particular, 3D imaging techniques are widely employed for close-range acquisitions in underwater environment. In this work we have compared in water two 3D imaging techniques based on active and passive approaches, respectively, and whole-field acquisition. The comparison is performed under poor visibility conditions, produced in the laboratory by suspending different quantities of clay in a water tank. For a fair comparison, a stereo configuration has been adopted for both the techniques, using the same setup, working distance, calibration, and objects. At the moment, the proposed setup is not suitable for real world applications, but it allowed us to conduct a preliminary analysis on the performances of the two techniques and to understand their capability to acquire 3D points in presence of turbidity. The performances have been evaluated in terms of accuracy and density of the acquired 3D points. Our results can be used as a reference for further comparisons in the analysis of other 3D techniques and algorithms. 23763698 The essential oils chemical compositions and antimicrobial, antioxidant activities and toxicity of three Hyptis species. Abstract Context: Hyptis suaveolens (Linn.) Poit., Hyptis rhomboidea Mart. et Gal., and Hyptis brevipes Poit., are three species of Hyptis Jacq. (Lamiaceae). Hyptis suaveolens is used for the treatment of fever, headache, gastrointestinal bloating and rheumatism in the traditional folk medicine; Hyptis rhomboidea for hepatitis, ulcer and swollen poison; and Hyptis brevipes for asthma and malaria. Objective: To characterize chemical compositions of the oils from three Hyptis species and evaluate their potential antimicrobial, radical scavenging activities and toxicities against brine shrimp. Materials and methods: The oils were obtained by hydrodistillation, and their chemical compositions were investigated by gas chromatography-mass spectrometry (GC-MS). Minimum inhibitory concentrations (MICs) were determined using the tube double-dilution technique. The antioxidant activities were investigated using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay and toxicities by the brine shrimp bioassay. Results: Forty-seven, 33 and 28 constituents of oils isolated, respectively, from H. suaveolens, H. rhomboidea and H. brevipes were identified. Among the essential oils, the strongest antioxidant activity was exhibited by H. brevipes with an SC50 value of 2.019 ± 0.25 μg mL(-1). The H. brevipes oil exhibited the strongest antimicrobial activity (3.125-6.25 μg mL(-1)) on pathogens employed in the assay. They all showed significant toxicities with median lethal concentration (LC50) values of 62.2 ± 3.07 μg mL(-1), 65.9 ± 6.55 μg mL(-1) and 60.8 ± 9.04 μg mL(-1), respectively. Discussion and conclusions: The three Hyptis species oils possess strong antimicrobial activities and toxicities. Hyptis rhomboidea and H. brevipes showed considerable antioxidant activity compared to the positive control. 23909741 Follow-up analysis of the efficacy of photodynamic therapy in actinic keratosis. I read with interest the study published by Dirschka et al. (1) on the long-term efficacy of photodynamic therapy in actinic keratosis. The study was performed on elderly and predominantly male patients that had suffered from multiple lesions on the sun-exposed face and scalp before therapy. This article is protected by copyright. All rights reserved. 23561077 Active films based on cocoa extract with antioxidant, antimicrobial and biological applications. Novel films of ethylene-vinyl alcohol copolymer (EVOH) containing flavonoid-rich cocoa were developed. To understand their potential application as active packaging material, antioxidant and antimicrobial properties of the films were determined as well as the antioxidant activity of the release compounds in Caco-2 human epithelial colorectal adenocarcinoma cells. Exposure of the films to aqueous food simulant showed antioxidant capacity. The release of cocoa extract components was dependent on the antioxidant concentration incorporated in the film and on temperature. Cocoa extract and the fraction obtained after in vitro gastrointestinal digestion presented antioxidant activity against oxidative stress induced by hydrogen peroxide in Caco-2 cells. Films with 10%, 15%, and 20% cocoa extract produced bactericidal effect against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli and Salmonella enterica. The application of films to an infant milk formula, previously inoculated with L. monocytogenes, inhibited the growth of bacteria 1.5log units the first day and showed sustained release, inhibiting 0.52 and 0.76log units, respectively, by the sixth day, while cocoa powder added directly did not produce any effect. 23933016 Expression of the glucocorticoid receptor is decreased in experimental Staphylococcus aureus sepsis. Glucocorticoid treatment in septic shock remains controversial after recent trials. We hypothesized that failure to respond to steroid therapy may be caused by decreased expression and/or function of glucocorticoid receptors (GR) and studied this in a mouse model of Staphylococcus aureus sepsis. The impact of timing of dexamethasone treatment was also investigated. Male C57BL/6J mice were intravenously inoculated with S. aureus and GR expression and binding ability in blood, spleen and lymph nodes were analysed by means of flow cytometry. GR translocation was analysed using Image Stream. Septic mice were administered dexamethasone at 22, 26, 48, 72 and 96 h after inoculation and body weight, as a sign of dehydration, was observed. GR expression was decreased in septic animals, but not the ligand binding capacity. GR translocation was decreased in septic mice compared to control animals. Early dexamethasone treatment (22 and 26 h) improved clinical outcome as studied by weight gain compared to when treatment was started at later time points (48, 72 and 96 h). Our data provide evidence that GR expression is progressively decreased in experimental sepsis and that dexamethasone has a decreased ability to translocate into the cell nucleus. This may explain why steroid treatment is only beneficial when administered early in sepsis and septic shock. 23811044 Dietary probiotic supplementation modulated gut microbiota and improved growth of juvenile rainbow trout (Oncorhynchus mykiss). In aquaculture, infectious diseases are the major cause of economic losses. Probiotic supplementation may change the microbiota of the digestive tract and modulate the immune defences and nutritional performance. This study was conducted to evaluate the dietary supplementation of multi-species (A: Bacillus sp., Pediococcus sp., Enterococcus sp., Lactobacillus sp.) and single-species probiotics (B: Pediococcus acidilactici) on growth performance and gut microbiota of rainbow trout (Oncorhynchus mykiss). A basal diet was supplemented with probiotic A or B, at two concentrations each (A1, A2, B1 and B2) or not supplemented (control treatment). Diets were distributed to 30 groups of 20 fish, 3 times a day. The gut microbiota was analysed at the end of the feeding trial (96days) with 16S rDNA denaturing gradient gel electrophoresis (16S-DGGE). Changes in gut microbial community were assessed by Shannon index (H´) and number of operational taxonomic units (OTUs). After 56days of feeding, weight gain was significantly improved in fish fed diet A1 when compared to the control group. Dietary probiotic supplementation changed the gut microbial composition. Number of OTUs (R) was higher in fish fed A1 (multi-species at lower concentration) than in control group, while H´ was higher in fish fed A1, B1 and B2. 23917753 Presentation, diagnosis and treatment of bilateral Rasmussen's encephalitis in a 12-year-old female. To describe the clinical course and pathological diagnosis of a 12-year-old female who presented with an acute syndrome of right hemispheric epilepsy and cortical dysfunction and brain MRI demonstrating atrophy of the left cerebral and right cerebellar hemispheres. The patient presented with occasional partial seizures consisting of a left calf sensation followed by left leg clonic jerking. Initial brain MRI showed left cerebral and right cerebellar atrophy with T2 hyperintensity in the left parietal region. After six months, the seizure frequency increased and semiology evolved to include frequent clonic movements of the left side of the face, arm and leg and epilepsia partialis continua (EPC) of the left arm and leg. There was progressive weakness of the left leg and, to a lesser extent, her left arm. MRI at this time demonstrated an additional T2 hyperintensity in the right frontal lobe. An extensive evaluation for paraneoplastic, mitochondrial, and genetic epilepsy syndromes was unrevealing. On biopsy evaluation, chronic T-cell mediated encephalitis was demonstrated within bilateral frontal lobes. Treatment with immunomodulatory therapy resulted in some improvement in her seizure frequency and motor function. Rasmussen's encephalitis can be a challenging diagnosis. The patient's clinical history, including EPC, with bilateral frontal lobe biopsies confirming a T-cell mediated encephalitis supports a diagnosis of bilateral Rasmussen encephalitis. This case highlights the diagnostic challenges and treatment dilemmas that arise in an adolescent presenting with bilateral inflammatory lesions of Rasmussen's encephalitis. [Published with video sequences]. 23194511 Phenolic profiles and antioxidant activity of litchi pulp of different cultivars cultivated in Southern China. The phenolic profiles and antioxidant activity of litchi pulp of 13 varieties were investigated. The free, bound and total phenolic contents were 66.17-226.03, 11.18-40.54, and 101.51-259.18 mg of gallic acid equivalents/100 g, respectively. The free, bound and total flavonoid contents were 16.68-110.33, 10.48-22.75, and 39.43-129.86 mg of catechin equivalents/100 g, respectively. Free phenolics and flavonoids contributed averagely 80.1% and 75% to their total contents, respectively. Six individual phenolics (gallic acid, chlorogenic acid, (+)-catechin, caffeic acid, (-)-epicatechin, and rutin) were detected in litchi pulp by HPLC. The contents of each compound in free and bound fractions were determined. Significant varietal discrepancy in antioxidant activity was also found by FRAP and DPPH scavenging capacity methods. Antioxidant activity was significantly correlated with phenolic and flavonoid contents. Thus, phenolics and flavonoids exist mainly in the free form in litchi pulp. There were significant varietal differences in phytochemical contents and antioxidant activity of litchi pulp. 23063875 Application of the acquired knowledge and implementation of the Sens-it-iv toolbox for identification and classification of skin and respiratory sensitizers. The contribution of the Sens-it-iv project to the reduction and replacement of animal experimentation is 3-fold. The funding of basic research has expanded the existing scientific knowledge thereby strengthening the understanding of the cellular and molecular mechanisms driving skin and respiratory sensitization. Examples are given on how a better understanding was used to improve existing test concepts. This knowledge was also applied to develop novel test systems. While some of test systems did not reach sufficient maturity for being considered for pre-validation others did and entered into the Sens-it-iv toolbox. In the process, developments outside the Sens-it-iv orbit were carefully followed and assessed in order to avoid duplication and to assure synergy between the ongoing activities (e.g. Cosmetics Europe Task Force for Sensitization). Tests from the Sens-it-iv toolbox were submitted to the European Reference Laboratory for Alternative Methods (EuRL-ECVAM) to initiate the rigid procedures for regulatory acceptance by national and international authorities. In spite of not being validated yet, selected tests were already applied in a weight-of-evidence approach in the context of REACH. Furthermore, several chemical, pharmaceutical, cosmetic and consumer product companies are currently assessing selected tests and testing strategies for their value as tools for screening and hazard identification using in house compounds and mixtures. The main points of concern related to transfer to and implementation by industry were cost, through-put and applicability domain, rather than regulatory acceptance. These issues are currently addressed in applied research projects which are financially supported by individual companies, or consortia of companies, representing the various industry sectors. 23354662 Monkeys would rather see and do: preference for agentic control in rhesus macaques. Rhesus monkeys (Macaca mulatta) engaged in a series of computerized tasks modeled on billiards and arcade games in order to determine their degree of preference for scenarios in which food rewards were contingent on their actions, as opposed to those in which outcomes appeared externally caused. Throughout these tasks, subjects showed a consistent preference for "agentic control," a state in which goal-directed behavior is directly responsible for motivating outcomes. Other factors like the frequency and timing of reward deliveries were precisely controlled and did not explain observed preferences. 21834859 Long-Term Function of Single-Implant Restorations: A 17- to 19-Year Follow-Up Study on Implant Infraposition Related to the Shape of the Face and Patients' Satisfaction. Background: Various levels of infraposition of single-implant restorations have been observed in long-term follow-up studies, but little knowledge is available on the biological mechanism behind this pattern. Purpose: The primary aim of this study is to report the frequency and severeness of implant infraposition in the anterior single-implant application after 17 to 19 years in function and, secondly, to try to relate these observations to anatomical appearance of the shape of the face of the patient. Materials and Methods: The present study comprised of 57 patients who were provided with 65 CeraOne™ single-tooth restorations (Nobel Biocare AB, Gothenburg, Sweden) between 1989 and 1991. Altogether 46 of these patients were treated with single implants in the anterior region. Besides clinical and radiographic data, clinical photographs, study casts, and patient's assessment of the long-term aesthetic result (visual analog scale) was collected at the termination of the present study. The degree of implant crown infraposition was related to assessed facial shape and to patient and clinical assessment of the aesthetic result by means of Pearson's correlation test. To increase the numbers of patients, another group of 25 patients presented in another similar study were pooled with the present material for prevalence calculations. Results: Altogether 47 patients showed up for the final examination after an average of 18 years (82%). Two implants failed (18 years cumulative survival rates [CSR]- 96.8%) and eight original single-crown restorations were replaced (CSR 83.8%). Three of the replaced crowns were replaced because of infraposition of the crowns. About 40% of the patients showed signs of infraposition, similar in younger and older age groups, but more frequently observed in female patients at termination of the study (p < 0.05). There was a weak trend indicating an association between "long-face" appearance and infraposition of the crown restoration (p > 0.05), and patients were more satisfied with the aesthetic clinical result than the participating clinicians (p < 0.05). Conclusion: Single-implant restorations in the anterior upper jaw may present small degrees of infraposition in long-term perspectives. Female patients seem to be at a higher risk of infraposition (p < 0.05), but no clear relationship between age at implant placement or facial shape and degree of infraposition was possible to establish (p > 0.05). Patients were more satisfied with the aesthetic result, as compared with the clinicians (p < 0.05), and patients seemed to pay less attention to the degree of infraposition in their aesthetic assessments, as compared with most of the clinicians. 23880387 Maturity and change in personality: Developmental trends of temperament and character in adulthood. We studied the developmental trends of temperament and character in a longitudinal population-based sample of Finnish men and women aged 20-45 years using the Temperament and Character Inventory model of personality. Personality was assessed in 1997, 2001, and 2007 (n = 2,104, 2,095, and 2,056, respectively). Mean-level changes demonstrated qualitatively distinct developmental patterns for character (self-directedness, cooperativeness, and self-transcendence) and temperament (novelty seeking, harm avoidance, reward dependence, and persistence). Character developed toward greater maturity, although self-transcendence decreased with age. However, self-transcendence was the strongest predictor of overall personality change. Cohort effects indicated lower level of self-transcendence and higher level of self-directedness and cooperativeness in younger birth cohorts. Regarding temperament, novelty seeking decreased and persistence increased slightly with age. Both high novelty seeking and high persistence predicted overall personality change. These findings suggest that temperament and character traits follow different kinds of developmental trajectories. 23757414 Zebrabow: multispectral cell labeling for cell tracing and lineage analysis in zebrafish. Advances in imaging and cell-labeling techniques have greatly enhanced our understanding of developmental and neurobiological processes. Among vertebrates, zebrafish is uniquely suited for in vivo imaging owing to its small size and optical translucency. However, distinguishing and following cells over extended time periods remains difficult. Previous studies have demonstrated that Cre recombinase-mediated recombination can lead to combinatorial expression of spectrally distinct fluorescent proteins (RFP, YFP and CFP) in neighboring cells, creating a 'Brainbow' of colors. The random combination of fluorescent proteins provides a way to distinguish adjacent cells, visualize cellular interactions and perform lineage analyses. Here, we describe Zebrabow (Zebrafish Brainbow) tools for in vivo multicolor imaging in zebrafish. First, we show that the broadly expressed ubi:Zebrabow line provides diverse color profiles that can be optimized by modulating Cre activity. Second, we find that colors are inherited equally among daughter cells and remain stable throughout embryonic and larval stages. Third, we show that UAS:Zebrabow lines can be used in combination with Gal4 to generate broad or tissue-specific expression patterns and facilitate tracing of axonal processes. Fourth, we demonstrate that Zebrabow can be used for long-term lineage analysis. Using the cornea as a model system, we provide evidence that embryonic corneal epithelial clones are replaced by large, wedge-shaped clones formed by centripetal expansion of cells from the peripheral cornea. The Zebrabow tool set presented here provides a resource for next-generation color-based anatomical and lineage analyses in zebrafish. 23877346 Cu(ii)-catalyzed domino reaction of 2H-azirines with diazotetramic and diazotetronic acids. Synthesis of 2-substituted 2H-1,2,3-triazoles. The Cu(ii)-catalyzed addition of two molecules of a 3-aryl-2H-azirine to diazotetramic or diazotetronic acids proceeds as a domino reaction with the formation of 1,2,3-triazole derivatives with ortho-fused (pyrrolo[3,4-b]pyrrol or furo[3,4-b]pyrrol) and spiro-cyclic (1-oxa-4,7-diazaspiro[4.4]nonane or 1,7-dioxa-4-azaspiro[4.4]nonane) substituents at the N2 position. The disclosed reaction is a new type of formation of a 1,2,3-triazole ring from (N-N) and (C-C-N) building blocks. 23908570 The recovery of optical quality after laser vision correction. To evaluate the optical quality after laser in situ keratomileusis (LASIK) or serial photorefractive keratectomy (PRK) using a double-pass system and to follow the recovery of optical quality after laser vision correction. This study measured the visual acuity, manifest refraction and optical quality before and one day, one week, one month, and three months after laser vision correction. Optical quality parameters including the modulation transfer function, Strehl ratio and intraocular scattering were evaluated with a double-pass system. This study included 51 eyes that underwent LASIK and 57 that underwent PRK. The optical quality three months post-surgery did not differ significantly between these laser vision correction techniques. Furthermore, the preoperative and postoperative optical quality did not differ significantly in either group. Optical quality recovered within one week after LASIK but took between one and three months to recover after PRK. The optical quality of patients in the PRK group seemed to recover slightly more slowly than their uncorrected distance visual acuity. Optical quality recovers to the preoperative level after laser vision correction, so laser vision correction is efficacious for correcting myopia. The double-pass system is a useful tool for clinical assessment of optical quality. 23839433 166 The Role of NgR1 Function in vivo After Spinal Cord Injury. Neuronal Nogo-66 receptor 1 (NgR1) has attracted attention as a converging point for mediating the effects of myelin-associate inhibitory ligands in the CNS, establishing the growth restrictive environment, and limiting axon regeneration following traumatic injury. However, the importance of NgR1 has been undermined by several studies that have shown the lack of substantial axon regeneration following spinal cord injury (SCI) in NgR1 knockout or knockdown animal models. To investigate the factors that may be contributing to the discrepancy, we used mice carrying either a homozygous or heterozygous null mutation in the NgR1 gene and subjected them to either a moderate or severe SCI. Locomotor function assessments revealed that the level of functional recovery is affected by the degree of injury suffered. Tract tracing of the corticospinal (CST) tract fibers revealed that NgR1 ablation enhanced local collateral sprouting in the mutant mice. Reactive astrocytes and chondroitin sulfate proteoglycans (CSPGs) are upregulated surrounding the injury site. MMP-9, which has been shown to degrade CSPGs, was significantly upregulated in the homozygous mutant mice compared to the heterozygous or wild-type mice. However, CSPG levels remained higher in the homozygous compared to the heterozygous mice, suggesting that the CSPG-degrading activity of MMP-9 may require the presence of NgR1. Together, these results suggest that NgR1 has important physiological functions, which may have been masked by redundant pathways or confounding factors in previous studies. Therapeutic strategies based on NgR1 antagonism, in combination with other treatment approaches, can have functionally important outcomes for patients suffering from SCI. 23665462 Cryopreservation of collared peccary (Pecari tajacu) semen using different freezing curves, straw sizes, and thawing rates. The objective of this study was to verify the effect of different freezing curves, straw sizes, and thawing rates on the cryopreservation of collared peccary semen. Twelve ejaculates were obtained from captive adult males by electroejaculation, and evaluated for sperm motility, kinetic rating, viability, morphology, and functional membrane integrity. The ejaculates were diluted in a coconut water extender (ACP-116c) with egg yolk and glycerol, packaged into 0.25 mL or 0.50 mL plastic straws and cryopreserved in liquid nitrogen following a slow (-10 °C/min) or a fast (-40 °C/min) freezing curve. After one week, samples were thawed at 37 °C/1 min or 70 °C/8s and evaluated as reported for fresh semen, and also for kinematic parameters (computerized analysis). A significant decrease in sperm motility and kinetic rating was observed after glycerol addition at 5 °C and also after thawing for all the treatments (P<0.05). Regarding post-thaw semen variables, no differences were verified between freezing curves when the same straw size and thawing rate were taken as reference (P>0.05). In general, values for sperm characteristics found after thawing at 37 °C were better preserved than at 70 °C (P<0.05), both in the use of 0.25 mL or 0.50 mL straws, which were similar for semen packaging (P>0.05). The evaluation of the kinematic parameters of sperm motility confirmed these results at values varying from 20% to 30% motile sperm for the samples tha wed at 37 °C, and values fewer than 12% motile sperm for samples thawed at 70 °C (P<0.05). In conclusion, we recommend the use of a fast freezing curve that reduces the time spent on the cryopreservation of collared peccary semen, which could be packaged both in 0.25 mL or 0.50 mL straws, but the thawing should be conducted at 37 °C/1 min. 23924948 Advances in the understanding of specific metabolic rates of major organs and tissues in humans. To present recent evidence on organ and tissue metabolic rates in humans to explain the variance in resting energy expenditure (REE). In humans, present knowledge on specific metabolic activities (i.e. ki-values) refers to seven organs and tissues - brain, heart, liver, kidneys, skeletal muscle, adipose tissue and residual mass - with ki-values of 240, 440, 200, 440, 13, 4.5 and 12 kcal/kg/day, provided by Elia in 1992. Detailed body composition data, as derived from whole body MRI together with measurements of whole body REE, were used to validate ki-values in nonobese, healthy and middle-aged adults. There is no sex difference, but minor, that is 2 and 3% deviations are found for age above 55 years and obesity, respectively. By contrast, in adolescents, differences of about 100 kcal/day or 7.3% of measured REE were observed. There is first evidence for changes in ki-values with either weight loss or weight regain after weight loss. Altogether these data suggest that in adolescence and at age above 55 years, in the obese and with weight change, organ and tissue masses differ in cellularity and/or their specific metabolic rates. Presently, direct assessment of specific organ and tissue metabolic rates in humans by either NMR spectroscopy or PET, together with detailed body composition analysis, has not been performed systematically. We need to become more skilled in methods and models used for detailed body composition analysis together with detailed assessment of energy expenditure in humans. 23890466 Infantile-onset Alexander disease in a child with long-term follow-up by serial magnetic resonance imaging: a case report. Alexander disease is a rare disorder resulting from a glial fibrillary acidic protein gene mutation which causes progressive degeneration of white matter. With the usual poor prognosis, there are few case reports with long-term follow-up. We report the five-year clinical course of Alexander disease in one case using serial magnetic resonance imaging. A 12-month-old Japanese male was referred to the pediatrics department in our hospital because of developmental retardation. Alexander disease was diagnosed by gene examination of the mutation of a glial fibrillary acidic protein. Magnetic resonance imaging findings showed abnormalities in white matter, deep gray matter, and medulla oblongata. Serial magnetic resonance imaging examinations until the age of five were performed and changes in magnetic resonance imaging findings were compared to the progression in clinical symptoms. Alexander disease is a very rare disease with a variety of clinical phenotypes. Therefore serial magnetic resonance imaging studies for long-term survival infantile cases including our case may be important in the analysis of the pathophysiological mechanism. 23601965 Ultrasonic monitoring of erosion/corrosion thinning rates in industrial piping systems. Monitoring pipe wall erosion/corrosion thinning rates is an important issue in petrochemical and power generation industries. In this paper, two signal processing techniques are utilized for estimating the thinning rate based on ultrasonic pipe wall thickness data collected over a short period of time. The first is a combination of cross-correlation and polynomial curve fitting and the second is a model-based estimation (MBE) scheme. These techniques are applied to data collected from an accelerated thinning rate apparatus and both show that they are capable of estimating the thinning rates quickly in short time periods with good accuracy. In laboratory applications, thinning rates as low as 10 μm/year were measured within 15 days with an uncertainty of ±1.5 μm/year by both techniques. Although the MBE technique can yield marginally better accuracy, the greater stability and computational speed of the cross-correlation technique make it the preferred choice for industrial use. 22665061 The p44/wdr77-dependent cellular proliferation process during lung development is reactivated in lung cancer. During lung development, cells proliferate for a defined length of time before they begin to differentiate. Factors that control this proliferative process and how this growth process is related to lung cancer are currently unknown. Here, we found that the WD40-containing protein (p44/wdr77) was expressed in growing epithelial cells at the early stages of lung development. In contrast, p44/wdr77 expression was diminished in fully differentiated epithelial cells in the adult lung. Loss of p44/wdr77 gene expression led to cell growth arrest and differentiation. Re-expression of p44/wdr77 caused terminally differentiated cells to re-enter the cell cycle. Our findings suggest that p44/wdr77 is essential and sufficient for proliferation of lung epithelial cells. P44/Wdr77 was re-expressed in lung cancer, and silencing p44/wdr77 expression strongly inhibited growth of lung adenocarcinoma cells in tissue culture and abolished growth of lung adenocarcinoma tumor xenografts in mice. The growth arrest induced by loss of p44/wdr77 expression was partially through the p21-Rb signaling. Our results suggest that p44/wdr77 controls cellular proliferation during lung development, and this growth process is reactivated during lung tumorigenesis. 23810412 Complement therapy in atypical haemolytic uraemic syndrome (aHUS). Central to the pathogenesis of atypical haemolytic uraemic syndrome (aHUS) is over-activation of the alternative pathway of complement. Inherited defects in complement genes and autoantibodies against complement regulatory proteins have been described. The use of plasma exchange to replace non-functioning complement regulators and hyper-functional complement components in addition to the removal of CFH-autoantibodies made this the 'gold-standard' for management of aHUS. In the last 4 years the introduction of the complement inhibitor Eculizumab has revolutionised the management of aHUS. In this review we shall discuss the available literature on treatment strategies to date. 23839512 Transient effects of methyltestosterone injection on different reproductive parameters of the hermaphrodite fish Kryptolebias marmoratus. To elucidate the action mechanism of environmental androgenic chemicals on fish reproductive activity by transient stimulation in heavily polluted areas, individuals of the hermaphrodite fish Kryptolebias marmoratus were injected once with six concentrations of methyltestosterone (MT) (0.1, 1, 5, 10, 50, and 100 Î¼g/g BW) intraperitoneally. The fish were sampled at intervals of 7, 15, and 30 days after a single injection. At 7 days after injection, mature oocytes were not observed in the MT-exposed groups except for the group exposed to 0.1 Î¼g MT, while testicular development was not remarkably different between any of the groups. Also, at 7 days after injection, hepatic estrogen receptor α (ERα) and vitellogenin (VTG) mRNA abundance decreased significantly in the MT-exposed groups despite no significant difference in plasma 17β-estradiol (E2) levels between any of the groups. This significant difference in VTG mRNA between the control and the MT-exposed groups persisted until 30 days after injection, although ERα mRNA abundance was not statistically different between any groups at 30 days after injection. Our results clearly show that a single injection of MT inhibits ovarian development rather than testicular development in the hermaphroditic gonad of K. marmoratus. Furthermore, our results demonstrate that a single injection of MT interfered with hepatic VTG mRNA synthesis mediated by the suppression of hepatic ERα mRNA transcription. 23891117 Regulated Membrane Protein Entry into Flagella Is Facilitated by Cytoplasmic Microtubules and Does Not Require IFT. The membrane protein composition of the primary cilium, a key sensory organelle, is dynamically regulated during cilium-generated signaling [1, 2]. During ciliogenesis, ciliary membrane proteins, along with structural and signaling proteins, are carried through the multicomponent, intensely studied ciliary diffusion barrier at the base of the organelle [3-8] by intraflagellar transport (IFT) [9-18]. A favored model is that signaling-triggered accumulation of previously excluded membrane proteins in fully formed cilia [19-21] also requires IFT, but direct evidence is lacking. Here, in studies of regulated entry of a membrane protein into the flagellum of Chlamydomonas, we show that cells use an IFT-independent mechanism to breach the diffusion barrier at the flagellar base. In resting cells, a flagellar signaling component [22], the integral membrane polypeptide SAG1-C65, is uniformly distributed over the plasma membrane and excluded from the flagellar membrane. Flagellar adhesion-induced signaling triggers rapid, striking redistribution of the protein to the apical ends of the cells concomitantly with entry into the flagella. Protein polarization and flagellar enrichment are facilitated by cytoplasmic microtubules. Using a conditional anterograde IFT mutant, we demonstrate that the IFT machinery is not required for regulated SAG1-C65 entry into flagella. Thus, integral membrane proteins can negotiate passage through the ciliary diffusion barrier without the need for a motor. 23597770 Aldosterone and myocardial extracellular matrix expansion in type 2 diabetes mellitus. Myocardial extracellular matrix expansion and reduced coronary flow reserve (CFR) occur in patients with type 2 diabetes mellitus without heart failure or coronary artery disease. Because aldosterone is implicated in the pathophysiology of cardiac fibrosis and vascular injury, the aim of this study was to test the hypothesis that aldosterone is associated with extracellular matrix expansion and reduced CFR in type 2 diabetes mellitus. Patients with type 2 diabetes mellitus without evidence of coronary artery disease were recruited. Blood pressure, lipid management, and glycemic control were optimized over 3 months. Cardiac magnetic resonance imaging with T1 mapping was used to measure myocardial extracellular volume (ECV). Cardiac positron emission tomography was used to assess CFR. On a liberal, 250 mEq/day sodium diet, 24-hour urinary aldosterone and change in serum aldosterone with angiotensin II stimulation were measured. Fifty-three participants with type 2 diabetes (68% men, mean age 53 ± 7 years, mean body mass index 32.2 ± 4.3 kg/m², mean glycosylated hemoglobin 6.8 ± 0.7%, mean systolic blood pressure 126 ± 14 mm Hg) without infarction or ischemia by cardiac magnetic resonance and positron emission tomography were studied. Subjects had impaired CFR (2.51 ± 0.83) and elevated ECV (0.36 ± 0.05), despite normal echocardiographic diastolic function and normal left ventricular function. Myocardial ECV, but not CFR, was positively associated with 24-hour urinary aldosterone excretion (r = 0.37, p = 0.01) and angiotensin II-stimulated aldosterone increase (r = 0.35, p = 0.02). In a best-overall multivariate model (including age, gender, body mass index, glycosylated hemoglobin, and blood pressure), 24-hour urinary aldosterone was the strongest predictor of myocardial ECV (p = 0.004). In conclusion, in patients with type 2 diabetes mellitus without coronary artery disease, aldosterone is associated with myocardial extracellular matrix expansion. These results implicate aldosterone in early myocardial remodeling in type 2 diabetes mellitus. 23859303 The efficacy and safety of fixed-dose combination of amlodipine/benazepril in Chinese essential hypertensive patients not adequately controlled with benazepril monotherapy: a multicenter, randomized, double-blind, double-dummy, parallel-group clinical trial. Abstract This double-blind, double-dummy clinical trial evaluated the efficacy and safety of two strengths of fixed-dose combination of amlodipine/benazepril in Chinese hypertensive patients not adequately controlled with benazepril. Of 442 patients who received treatment with benazepril 10 mg for 4 weeks, 341 patients failed to achieve to diastolic blood pressure (DBP) <90 mmHg. These non-responders were randomized to receive amlodipine/benazepril 2.5/10 mg, or amlodipine/benazepril 5/10 mg, or benazepril 10 mg for 8 weeks. BP reductions with amodipinel/benazepril 2.5/10 mg (15.2/11.8 mmHg) or amlodipine/benazepril 5/10 mg (15.4/12.4 mmHg) were significantly greater than that with benazepril 10 mg (9.88/9.46 mmHg) at study end (p < 0.01, combination versus benazepril). BP control rate was 83.8% with amlodipine/benazepril 2.5/10 mg, 80.2% with amlodipine/benazepril 5/10 mg, 64.9% with benazepril 10 mg at study end (p < 0.01, combination versus benazepril). Three groups were generally well tolerated. Our study indicated that amlodipine/benazepril fixed-dose combination offered significant additional BP reductions and BP control rate compared with the continuation of benazepril monotherapy. No significant differences were observed in both BP reductions and BP control rate between amlodipine/benazepril 2.5/10 mg and amlodipine/benazepril 5/10 mg. 23929950 SGK196 is a glycosylation-specific O-mannose kinase required for dystroglycan function. Phosphorylated O-mannosyl trisaccharide [N-acetylgalactosamine-β3-N-acetylglucosamine-β4-(phosphate-6-)mannose] is required for dystroglycan to bind laminin-G domain-containing extracellular proteins with high affinity in muscle and brain. However, the enzymes that produce this structure have not been fully elucidated. We found that glycosyltransferase-like domain-containing 2 (GTDC2) is a protein O-linked mannose β 1,4-N-acetylglucosaminyltransferase whose product could be extended by β 1,3-N-acetylgalactosaminyltransferase2 (B3GALNT2) to form the O-mannosyl trisaccharide. Furthermore, we identified SGK196 as an atypical kinase that phosphorylated the 6-position of O-mannose, specifically after the mannose had been modified by both GTDC2 and B3GALNT2. These findings suggest how mutations in GTDC2, B3GALNT2, and SGK196 disrupt dystroglycan receptor function and lead to congenital muscular dystrophy. 23670858 A specific and sensitive assay for blood levels of glycated CD59: A novel biomarker for diabetes. Increasing evidence links the complement system with complications of human diabetes. The complement regulatory protein CD59, an inhibitor of formation of membrane attack complex (MAC), is inhibited by hyperglycemia-induced glycation fostering increased deposition of MAC, a major effector of complement-mediated tissue damage. CD59, an ubiquitous GPI-anchored membrane protein, is shed from cell membranes by phospholipases generating a soluble form present in blood and urine. We established an enzyme-linked immunosorbent assay (ELISA) to measure serum/plasma glycated human CD59 (hCD59) (GCD59) and evaluated its potential as a diabetes biomarker. We used a synthetic peptide strategy to generate (a) a mouse monoclonal antibody to capture hCD59, (b) a rabbit monoclonal antibody to detect GCD59, and (c) a GCD59 surrogate for assay standardization. ELISA conditions were optimized for precision, reproducibility, and clinical sensitivity. The clinical utility of the assay was initially evaluated in 24 subjects with or without diabetes and further validated in a study that included 100 subjects with and 90 subjects without a diagnosis of diabetes. GCD59 (a) was significantly higher in individuals with than in individual without diabetes, (b) was independently associated with HbA1c, and (c) identified individuals with diabetes with high specificity and sensitivity. We report the development and standardization of a novel, sensitive, and specific ELISA for measuring GCD59 in blood. The assay distinguished individuals with diabetes from those without, and showed strong correlation between GCD59 and HbA1c. Because GCD59 likely contributes to the pathogenesis of diabetes complications, measurement of blood levels of GCD59 may be useful in the diagnosis and management of diabetes. Am. J. Hematol. 88:670-676, 2013. © 2013 Wiley Periodicals, Inc. 23531117 One-year randomized study of the endometrial safety and bleeding pattern of 0.25 mg drospirenone/0.5 mg 17β-estradiol in postmenopausal women. Abstract Objectives To investigate the long-term endometrial safety and bleeding pattern of the 0.25 mg drospirenone/0.5 mg 17β-estradiol (DRSP/E2) dose combination compared with 0.5 mg norethisterone acetate (NETA)/1.0 mg E2, in postmenopausal women. Methods A total of 662 postmenopausal women aged between 40 and 65 years with an indication for hormone therapy verified by the investigator were randomized to participate in this 1-year, double-blind, active comparator-controlled study. The primary efficacy variable was the proportion of women with an endometrial biopsy assessment of 'hyperplasia or worse' at any time during or after 13 cycles of treatment. Results No evaluable women in the DRSP/E2 or NETA/E2 groups had an endometrial biopsy result of 'hyperplasia or worse'. The incidence of amenorrhea was higher in the DRSP/E2 group than the NETA/E2 group during months 1-3 (69.0% vs. 56.0%), with comparable amenorrhea rates of approximately 80% during months 10-12. Improvements in menopausal symptoms (exploratory efficacy variables) were similar in the two groups, while there were fewer women with treatment-related adverse events (18.4% vs. 25.6%) or adverse events leading to discontinuation of study drug (8.4% vs. 15.1%) in the DRSP/E2 group than the NETA/E2 group. There were no treatment-related thromboembolic or cardiovascular events in the DRSP/E2 group vs. two events in the NETA/E2 group. Conclusions The low-dose, 0.25 mg DRSP/0.5 mg E2 dose combination met the criteria for endometrial safety and demonstrated a favorable risk/benefit profile in this 1-year, double-blind, randomized study of postmenopausal women. 22845684 A systematic review of the evidence on service user involvement in interpersonal skills training of mental health students. Service user involvement has become a common feature of education programmes for mental health students. However, little is known about the effects of this type of education on the interpersonal skills of students taking part. This paper reports findings from a systematic review that formed part of a wider investigation into service user involvement in teaching interpersonal skills. The review aimed to locate and assess the quality of the published evidence relating to the effects of service user involvement on mental health students interpersonal skills and to synthesize results, using a definition of interpersonal skill that includes attitudes, empathy and skills as its key components. Results from this study indicate that the quality of evidence in this area is poor. However, sufficient synthesis of the evidence base was possible to allow conclusions and recommendations for both research and practice. Conclusions were that the involvement of service users in this area is both acceptable and valuable for students and had specific impacts on attitudes, empathy and skills. Some difficulties and reservations about the style of involvement are discussed. Recommendations for the conduct of future research are also made. 23618971 Simultaneous UPLC-MS/MS assay for the detection of the traditional antipsychotics haloperidol, fluphenazine, perphenazine, and thiothixene in serum and plasma. Most antipsychotic drugs that are commonly prescribed in the USA are monitored by liquid and gas chromatographic methods. Method performance has been improved using ultra high pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). A rapid and simple procedure for monitoring haloperidol, thiothixene, fluphenazine, and perphenazine is described here. Antipsychotic drug concentrations in serum and plasma were determined by LCMS/MS (Waters Acquity UPLC TQD). The instrument is operated with an ESI interface, in multiple reaction monitoring (MRM), and positive ion mode. The resolution of both quadrupoles was maintained at unit mass with a peak width at half height of 0.7amu. Data analysis was performed using the Waters Quanlynx software. Serum or plasma samples were thawed at room temperature and a 100μL aliquot was placed in a tube. Then 300μL of precipitating reagent (acetonitrile-methanol [50:50, volume: volume]) containing the internal standard (0.12ng/μL Imipramine-D3) was added to each tube. The samples were vortexed and centrifuged. The supernatant was transferred to an autosampler vial and 8μL was injected into the UPLC-MS/MS. Utilizing a Waters Acquity UPLC HSS T3 1.8μm, 2.1×50mm column at 25ºC, the analytes were separated using a timed, linear gradient of acetonitrile and water, each having 0.1% formic acid added. The column is eluted into the LC-MS/MS to detect imipramine D3 at transition 284.25>89.10, haloperidol at 376.18>165.06, thiothixene at 444.27>139.24, fluphenazine at 438.27>171.11, and perphenazine at 404.19>143.07. Secondary transitions for each analyte are also monitored for imipramine D3 at 284.25>193.10, haloperidol at 376.18>122.97, thiothixene at 444.27>97.93, fluphenazine at 438.27>143.08, and perphenazine at 404.19>171.11. The run-time is 1.8min per injection with baseline resolved chromatographic separation. Results: The analytical measurement range was 0.2 to 12.0ng/mL for fluphenazine and perphenazine, and was 1 to 60.0ng/mL for haloperidol and thiothixene. Intra-assay and inter-assay imprecisions (CV) were less than 15% at two concentrations for each analyte. By utilizing a LC-MS/MS method we combined two previously established analytical assays into one, yielding a 75% time-savings on set-up, and a significantly shortened analytical run-time. These changes reduced the turn-around time for analysis and eliminated interference issues resulting in fewer injections and increased column lifetime. 23927467 Finding chemo: the search for marine-based pharmaceutical drugs active against cancer. Cancer affects the health of many people globally. The most common treatment that is used for cancer is chemotherapy, which has shown promising results but not without side effects. Some of these side effects jeopardise further treatment, and this eventually leads to advanced stages of malignancy and mortality. As a result, there is a need for better and safer anticancer compounds such as those found naturally. One of the most abundant natural environments to find such compounds is the sea, and this vast resource has been biomined since the 1950s. There are currently three marine anticancer agents marketed (Yondelis, Cytosar-U and Halaven), with several others undergoing clinical trials. This review discusses marine-derived products in clinical use and in clinical trials, and discusses available literature on the growth suppression or pro-apoptotic properties of these compounds, and the molecular mechanisms underpinning these cell biological phenomena. The marine environment may hold promising anticancer compounds within its depths, warranting further research to be performed in this area, albeit with respect for the natural ecosystems that are being explored for drug discover and subsequently used for drug development. 23898427 The clinical usefulness of ultrasound-aided fixation using an absorbable plate system in patients with zygomatico-maxillary fracture. Ultrasound-aided fixation is a recently developed alternative method of treatment of zygomatico-maxillary (ZM) fracture, and it can resolve the problems of excessive torsion force and subsequent fractures of screws. We conducted this study to evaluate the clinical usefulness of ultrasound-aided fixation as compared with the conventional fixation method using a drill and an expander in patients with ZM fracture. We conducted a retrospective study in 35 patients with ZM fracture who had been treated at our hospital during a period ranging from March of 2008 to December of 2010. We divided them into two groups: an ultrasound-aided fixation group, comprising 13 patients who underwent ultrasound-aided fixation (SonicWeld Rx, KLS Martin), and a conventional group, comprising 22 patients who underwent conventional fixation (Biosorb FX, Linvatec Biomaterials Ltd.). We compared such variables as sex, direction, age at operation, follow-up period, operation duration, number of fixed holes, and time to discharge between the two groups. The ultrasound-aided fixation reduced the operation duration by about 30 minutes as compared with that of conventional fixation. There was no significant difference in follow-up period, number of fixed holes, or time to discharge between the two groups. Furthermore, there were no complications in either group. The ultrasound-aided fixation of fractured ZM bone using an absorbable implant system is safe and effective in promptly reducing the bone fracture and providing satisfactory cosmetic outcomes over time. 23820420 The history of Belgian assisted reproduction technology cycle registration and control: a case study in reducing the incidence of multiple pregnancy. What is the effect of a legal limitation of the number of embryos that can be transferred in an assisted reproductive technology (ART) cycle on the multiple delivery rate? The Belgian national register shows that the introduction of reimbursement of ART laboratory costs in July 2003, and the imposition of a legal limitation of the number of embryos transferred in the same year, were associated with a >50% reduction of the multiple pregnancy rate from 27 to 11% between 2003 and the last assessment in 2010, without any reduction of the pregnancy rate per cycle. Individual Belgian IVF centres have published their results since the implementation of the law, and these show a decrease in the multiple pregnancy rate on a centre by centre basis. However, the overall national picture remains unpublished. Cohort study from 1990 to 2010 of all ART cycles in Belgium (2685 cycles in 1990 evolving to 19 110 cycles in 2010), with a retrospective analysis from 1990 to 2000 and prospective online data collection since 2001. Registration evolved from paper written reports per centre to a compulsory online registration of all ART cycles. From 2001 up to mid-2009, data were collected from Excel spread sheets or MS Access files into an MS Access database. Since mid-2009, data collection is done via a remote and secured web-based system (www.belrap.be) where centres can upload their data and get immediate feedback about missing data, errors and inconsistencies. National Belgian registration data show that reimbursement of IVF laboratory costs in July 2003, coupled to a legal limitation in the number of embryos transferred in utero, were associated with a 50% reduction of the multiple pregnancy rate from 27 to 11% without reduction of the pregnancy rate per cycle, and with an increase in the number of fresh and frozen ART cycles due to improved access to treatment. There is potential underreporting of complications of ART treatment, pregnancy outcome and neonatal health. Over the 20 years of registration, the pregnancy rate has remained constant, despite the reduction in the number of embryos transferred, optimization of laboratory procedures and stimulation protocols, introduction of quality systems and implementation of the EU Tissue Directive over the period 2004-2010. No external funding was sought for this study. None of the authors has any conflict of interest to declare. 23380989 Kocurin, the true structure of PM181104, an anti-methicillin-resistant Staphylococcus aureus (MRSA) thiazolyl peptide from the marine-derived bacterium Kocuria palustris. A new thiazolyl peptide, kocurin (1), was isolated from culture broths of a marine-derived Kocuria palustris. Its structural elucidation was accomplished using a combination of spectroscopic and chemical methods, including HRMS, extensive 1D and 2D NMR analysis, MS/MS fragmentation, and chemical degradation and Marfey's analysis of the resulting amino acid residues. The structure herein reported corrects that previously assigned to PM181104 (3). Kocurin displayed activity against methicillin-resistant Staphylococcus aureus (MRSA), with MIC values in the submicromolar range. 23875601 Nitration of silyl allenes to form functionalized nitroalkenes. An efficient nitration of silyl allenes with nitrogen dioxide radical, generated from NaNO2 and AcOH, to form α-nitro-α,β-unsaturated silyl oximes has been developed. A similar nitration could be achieved by using Fe(NO3)3·9H2O and FeCl3·6H2O, but different from the regioselective oxime formation, two regioisomeric chloride-trapped products were isolated with varying ratios depending on the steric bulk of the silyl group. A novel ring-closure reaction of α-nitro-α,β-unsaturated silyl oximes upon treating with TBAF to form isooxazolidinone derivatives was also developed. 23142433 Application of Resource Utilization in Dementia (RUD) instrument in a global setting. The Resource Utilization in Dementia (RUD) questionnaire is the most widely used instrument for resource use data collection in dementia, enabling comparison of costs of care across countries with differing health care provisions. Recent feedback from payers questioned its face validity given that health care provisions have changed since the initial development of the RUD in 1998. The aim of this study was to update the RUD to improve its face validity in Alzheimer's disease (AD) clinical research and its utility for health care resource allocation. An extensive PubMed review was conducted of current relevant resource items in AD in 15 countries. The findings were complemented by interviews with local care providers and experts in dementia care and health economics. Their proposed revisions were discussed with five leading dementia experts in North and South America, northern and southern Europe, and Asia. A new version of the RUD was developed based on their recommendations. RUD users identified a need for more information relevant to coverage decisions. Proposed revisions included changes to existing questions (e.g., to capture more accurately the number and type of health care visits) and the addition of new questions (e.g., on informal caregiver hours and the primary caregiver's hours of sleep). Several minor changes were made to the RUD instrument to improve the accuracy and precision of the data while maintaining comparability with the original version and reflecting current medical practice. The RUD Complete Version 4.0 is now available for use in future AD clinical trials. 23139159 Investigating the motion of diblock copolymer assemblies in ionic liquids by in situ electron microscopy. The movement of individual block copolymer micelles in free-standing films of ionic liquids is investigated by transmission electron microscopy with the aim of providing an easily accessible high-resolution imaging tool for the in situ observation of particle movement in a liquid environment. A proof of concept and first studies on the behavior of individual particles in the fluid are demonstrated. 23841621 Abiotic stresses affect Trichoderma harzianum T39-induced resistance to downy mildew in grapevine. Enhancement of plant defense through application resistance inducers seems a promising alternative to chemical fungicides for controlling crop diseases, but the efficacy can be affected by abiotic factors in the field. Plants respond to abiotic stresses with hormonal signals that may interfere with the mechanisms of induced systemic resistance (ISR) to pathogens. In this study we exposed grapevines to heat and/or drought to investigate the effects of abiotic stresses on grapevine resistance induced by Trichoderma harzianum T39 (T39) to downy mildew. Whereas the efficacy of T39-induced resistance was not affected by exposure to heat or drought, it was significantly reduced by combined abiotic stresses. Decrease of leaf water potential and up-regulation of heat-stress markers confirmed that plants reacted to abiotic stresses. Basal expression of defense-related genes and their up-regulation during T39-induced resistance were attenuated by abiotic stresses, in agreement with the reduced efficacy of T39. The evidence reported here suggests that exposure of crops to abiotic stress should be carefully considered to optimize the use of resistance inducers, especially in view of future global climate changes. Expression analysis of ISR markers genes could be helpful to identify when plants are responding to abiotic stresses, in order to optimize treatments with resistance inducers in field. 23266720 Expression profiles of hippocampal regenerative sprouting-related genes and their regulation by E-64d in a developmental rat model of penicillin-induced recurrent epilepticus. E-64d (a calpain and autophagy inhibitor) has previously been shown safe for the treatment of Alzheimer's disease in humans. In the present study, the potential protective mechanism of E-64d on hippocampal aberrant mossy fiber sprouting was examined in a developmental rat model of penicillin-induced recurrent epilepticus. A seizure was induced by penicillin every other day in Sprague-Dawley rats from postnatal day 21 (P21). The rats were randomly assigned into the control group (CONT1), the control plus E-64d (CONT2), the seizure group (EXP1) and the seizure plus E-64d (EXP2). On P51, mossy fiber sprouting and related gene expression in hippocampus were assessed by Timm staining and real-time RT-PCR methods, respectively. To validate the RT-PCR results, western blot analysis was performed on selected genes. E-64d obviously suppressed the aberrant mossy fiber sprouting in the supragranular region of dentate gyrus and CA3 subfield of hippocampus. Among the total twelve genes, six genes were strongly up- (MT-3, ACAT1, clusterin and ApoE) or down- (ZnT-1 and PRG-3) regulated by developmental seizures (EXP1) compared with that in the CONT1. Up-regulation of ApoE and Clusterin was blocked by pretreatment with E-64d both in mRNA and protein levels. Further, E-64d-pretreated seizure rats (EXP2) showed a significant downregulation of mRNA expression of PRG-1, PRG-3 and PRG-5, cathepsin B and ApoE, as well as up-regulated nSMase and ANX7 in hippocampus when compared with EXP1 rats. The results of the present study suggest that E-64d, an elective inhibitor of calpain and autophagy, is potentially useful in the treatment of developmental seizure-induced brain damage both by regulating abnormal zinc signal transduction and through the modulation of altered lipid metabolism via ApoE/clusterin pathway in hippocampus. 23313610 Toxic effects of dietary exposure to T-2 toxin on intestinal and hepatic biotransformation enzymes and drug transporter systems in broiler chickens. The effects of the mycotoxin T-2 on hepatic and intestinal drug-metabolizing enzymes (cytochrome P450) and drug transporter systems (MDR1 and MRP2) in poultry were investigated during this study. Broiler chickens received either uncontaminated feed, feed contaminated with 68μg/kg or 752μg/kg T-2 toxin. After 3weeks, the animals were euthanized and MDR1, MRP2, CYP1A4, CYP1A5 and CYP3A37 mRNA expression were analyzed using qRT-PCR. Along the entire length of the small intestine no significant differences were observed. In the liver, genes coding for CYP1A4, CYP1A5 and CYP3A37 were significantly down-regulated in the group exposed to 752μg/kg T-2. For CYP1A4, even a contamination level of 68μg/kg T-2 caused a significant decrease in mRNA expression. Expression of MDR1 was not significantly decreased in the liver. In contrast, hepatic MRP2 expression was significantly down-regulated after exposure to 752μg/kg T-2. Hepatic and intestinal microsomes were prepared to test the enzymatic activity of CYP3A. In the ileum and liver CYP3A activity was significantly increased in the group receiving 752μg/kg T-2 compared to the control group. The results of this study show that drug metabolizing enzymes and drug transporter mechanisms can be influenced due to prolonged exposure to relevant doses of T-2. 23131042 Evaluation of the metabolism and hepatotoxicity of xenobiotics utilizing precision-cut slices. 1. Precision-cut liver slices are a valuable in vitro model system to study the metabolism and toxicity of xenobiotics. Liver slices retain tissue architecture so that all cell types are present and intercellular communication between the various cell types is retained. 2. Precision-cut liver slices from humans and other species have been used to study pathways of phase I (e.g. cytochrome P450-dependent biotransformations) and II (e.g. conjugation with D-glucuronic acid, sulphate and glutathione) metabolism of a wide range of xenobiotics. 3. Liver slices can also be employed to investigate the induction and inhibition of xenobiotic metabolizing enzymes and to obtain kinetic data on the rates of metabolism of xenobiotics. 4. Precision-cut liver slices from humans and other species have been used to study the toxicity of a wide variety of xenobiotics. Toxicity can be assessed by various techniques including gene expression, morphological examination and a wide range of biochemical endpoints. 5. Precision-cut liver slices can be utilized to examine species differences in hepatic xenobiotic metabolism and xenobiotic-induced toxicity, thus permitting comparisons between animal species and humans. 23928751 Enhanced performance of inverted organic photovoltaic cells using CNTs-TiOX nanocomposites as electron injection layer. In this study, we fabricated inverted organic photovoltaic cells with the structure ITO/carbon nanotubes (CNTs)-TiOX/P3HT:PCBM/MoO3/Al by spin casting CNTs-TiOX nanocomposite (CNTs-TiOX) as the electron injection layer onto ITO/glass substrates. The power conversion efficiency (PCE) of the 0.1 wt% single-walled nanotubes (SWNTs)-TiOX nanocomposite device was almost doubled compared with the TiOX device, but with increasing concentration of the incorporated SWNTs in the TiOX film, the performance of the devices appeared to decrease rapidly. Devices with multi-walled NTs in the TiOX film have a similar trend. This phenomenon mainly depends on the inherent physical and chemical characteristics of CNTs such as their high surface area, their electron-accepting properties and their excellent carrier mobility. However, with increasing concentration of CNTs, CNTs-TiOX current leakage pathways emerged and also a recombination of charges at the interfaces. In addition, there was a significant discovery. The incorporated CNTs were highly conducive to enhancing the degree of crystallinity and the ordered arrangement of the P3HT in the active layers, due to the intermolecular Ï€-Ï€ stacking interactions between CNTs and P3HT. 23858091 Effect of dairy proteins on appetite, energy expenditure, body weight, and composition: a review of the evidence from controlled clinical trials. Evidence supports that a high proportion of calories from protein increases weight loss and prevents weight (re)gain. Proteins are known to induce satiety, increase secretion of gastrointestinal hormones, and increase diet-induced thermogenesis, but less is known about whether various types of proteins exert different metabolic effects. In the Western world, dairy protein, which consists of 80% casein and 20% whey, is a large contributor to our daily protein intake. Casein and whey differ in absorption and digestion rates, with casein being a "slow" protein and whey being a "fast" protein. In addition, they differ in amino acid composition. This review examines whether casein, whey, and other protein sources exert different metabolic effects and targets to clarify the underlying mechanisms. Data indicate that whey is more satiating in the short term, whereas casein is more satiating in the long term. In addition, some studies indicate that whey stimulates the secretion of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide more than other proteins. However, for the satiety (cholecystokinin and peptide YY) and hunger-stimulating (ghrelin) hormones, no clear evidence exists that 1 protein source has a greater stimulating effect compared with others. Likewise, no clear evidence exists that 1 protein source results in higher diet-induced thermogenesis and promotes more beneficial changes in body weight and composition compared with other protein sources. However, data indicate that amino acid composition, rate of absorption, and protein/food texture may be important factors for protein-stimulated metabolic effects. 23537388 Structural Changes in Cytochrome c Oxidase Induced by Binding of Sodium and Calcium Ions: An ATR-FTIR Study. Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy was used to investigate the binding of Na(+) and Ca(2+)cations to bovine cytochrome c oxidase in its fully oxidized and partially reduced, cyanide-ligated (a(2+)a3(3+)-CN) (mixed valence) forms. These ions induced distinctly different IR binding spectra, indicating that the induced structural changes are different. Despite this, their binding spectra were mutually exclusive, confirming their known competitive binding behavior. Dissociation constants for Na(+) and Ca(2+) with the oxidized enzyme were 1.2 mM and 11 μM, respectively and Na(+) binding appeared to involve cooperative binding of two Na(+). Ca(2+) binding induced a large IR spectrum, with prominent amide I/II polypeptide changes, bandshifts assigned to carboxylate and an arginine, and a number of bandshifts of heme a. The Na(+)-induced binding spectrum showed much weaker amide I/II and heme a changes but had similar shifts assignable to carboxylate and arginine residues. Yeast CcO also displayed a calcium-induced IR and UV/visible binding spectra, though of lower intensities. This was attributed to the difficulty in fully depleting Ca(2+) from its binding site, as has been found with bacterial CcOs. The implications of Ca(2+)/Na(+) ion binding are discussed in terms of structure and possible modulation of core catalytic function. 23964341 A case of squamous metaplasia of the stomach. Intestinal metaplasia of the stomach is a common metaplastic lesion associated with chronic gastritis and mucosal atrophy. However, squamous metaplasia is a comparatively rare condition. On endoscopy, squamous metaplasia is usually observed as a whitish mucosal lesion in the lesser curvature of the cardiac region of the stomach. When Lugol's iodine solution is applied, the lesion stains brown in the same way as normal esophageal mucosa. We report a case of 79-year-old man with a whitish flat lesion in the lesser curvature of the cardiac region on surveillance endoscopy after endoscopic treatment of gastric adenoma. The endoscopic biopsy showed stratified squamous epithelial mucosa. 23932287 Development of a UBFC biocatalyst fuel cell to generate power and treat industrial wastewaters. Agro-industry wastewaters normally contain high levels of organic matter and require suitable treatment before discharge. The use of Microbial fuel cells, a novel wastewater treatment, can provide advantages over existing treatment methods. In this study, an up-flow bio-filter circuit (UBFC) for treating wastewaters without chemical treatment or nutrient supplement, was developed to solve a clogging problem. The optimal conditions included an organic loading rate of 30.0gCOD/L-d, hydraulic retention time of 1.04day, pH level of 5.6-6.5 and aeration at 2.0L/min. External resistance of the circuit was tested. COD removal levels of 8.08, 20.1 and 26.67gCOD/L-d were obtained, while fed with sea food, biodiesel and palm oil mill wastewater, respectively. These rates are higher than for conventional technologies. The carbon fiber brush immobilized base increased the performance of the new UBFC by 17.54% over that obtained in a previous study, while the cost was slightly decreased about 4.48%. 23828543 Reusable and highly active supported copper(i)-NHC catalysts for Click chemistry. Immobilised [Cu(NHC)] catalysts are reported for the preparation of 1,2,3-triazoles. In addition to showing outstanding catalytic activity, the catalyst systems are easy to prepare and can be recycled many times. 23919152 Evidence for no sexual isolation between Drosophila albomicans and D. nasuta. Sexual isolation, the reduced tendency to mate, is one of the reproductive barriers that prevent gene flow between different species. Various species-specific signals during courtship contribute to sexual isolation between species. Drosophila albomicans and D. nasuta are closely related species of the nasuta subgroup within the Drosophila immigrans group and are distributed in allopatry. We analyzed mating behavior and courtship as well as cuticular hydrocarbon profiles within and between species. Here, we report that these two species randomly mated with each other. We did not observe any sexual isolation between species or between strains within species by multiple-choice tests. Significant difference in the courtship index was detected between these two species, but males and females of both species showed no discrimination against heterospecific partners. Significant quantitative variations in cuticular hydrocarbons between these two species were also found, but the cuticular hydrocarbons appear to play a negligible role in both courtship and sexual isolation between these two species. In contrast to the evident postzygotic isolation, the lack of sexual isolation between these two species suggests that the evolution of premating isolation may lag behind that of the intergenomic incompatibility, which might be driven by intragenomic conflicts. 23808822 Fibroblast growth factor receptor 1 gene amplification in pancreatic ductal adenocarcinoma. Pancreatic ductal adenocarcinomas (PDACs) are chemoresistant, resulting in extremely poor survival of patients; therefore, novel molecular targets, even in small subsets of genetically characterized tumours, are urgently needed. Tyrosine kinase receptor inhibitors (TKIs) are already in clinical use. The aims of this study were to examine the gene copy number and expression of fibroblast growth factor receptor 1 (FGFR1) in 155 patients with PDAC, and investigate the effects of the FGFR-specific inhibitor BGJ398 on FGFR1-amplified pancreatic tumour cells in vitro. Fluorescence in-situ hybridization (FISH) and immunohistochemical analysis of 155 PDACs were performed using tissue microarrays. Amplification of FGFR1 was found in 2.6% (4/155) of cases. Four per cent of tumours (5/125) were shown to express FGFR1 by immunohistochemistry. Sequence analysis demonstrated an activating KRAS mutation (exon 2) in all FGFR1-amplified cases. The FGFR1-amplified pancreatic carcinoma cell line PT45P1 showed high levels of FGFR1 mRNA and protein expression. Proliferation of this cell line can be inhibited using the FGFR1 inhibitor BGJ398. FGFR1 represents a potential new therapeutic target in a subset of patients harbouring FGFR1-amplified tumours. Identification of pancreatic cancers harbouring FGFR1 amplification may be important in preselecting patients and/or interpreting clinical studies using TKIs. 23897814 Kinetic Characterization of the ATPase and Actin-activated ATPase Activities of Acanthamoeba castellanii Myosin-2. Phosphorylation of S639 in loop-2 of the catalytic motor domain of the heavy chain of Acanthamoeba castellanii myosin-2 and the phosphomimetic mutation S639D have been shown previously to down-regulate the actin-activated ATPase activity of both the full-length myosin and single-headed subfragment-1 (Liu et al. (2013) Proc. Natl. Acad. Sci. USA 110, E23-32). In the present study we determined the kinetic constants for each step in the myosin and actomyosin ATPase cycles of recombinant wild-type S1 and S1-S639D. The kinetic parameter predominantly affected by the S639D mutation is the actin-activated release of inorganic phosphate from the myosin•ADP•Pi complex, which is the rate-limiting step in the steady-state actomyosin ATPase cycle. As consequence of this change, the duty ratio of this conventional myosin decreases. We speculate on the effect of S639 phosphorylation on the processive behavior of myosin-2 filaments. 23747315 Neem leaf glycoprotein is superior than Cisplatin and Sunitinib malate in restricting melanoma growth by normalization of tumor microenvironment. We have observed earlier that therapeutic treatment with neem leaf glycoprotein (NLGP) inhibits murine B16-melanoma growth in vivo and improves survivability of treated mice. Anti-tumor effect of NLGP is directly associated with enhanced CD8(+) T cell activity and downregulation of suppressive cellular functions. Objective of this present study is to know the efficacy of NLGP in comparison to two popular drugs, Cisplatin and Sunitinib malate (Sutent) in relation to the modulation of tumor microenvironment (TME). Analysis of cytokine milieu within TME revealed IL-10, TGFβ, IL-6 rich type 2 characters was significantly switched to type 1 microenvironment with dominance of IFNγ and IL-2 within NLGP-TME, which was not found in other cases; however Cisplatin-TME appeared better in type 2 to type 1 conversion than Sutent-TME as evidenced by RT-PCR, ELISA and immunohistochemical analysis. NLGP-TME educated CD8(+) T cells exhibited greater cytotoxicity to B16 Melanoma cells in vitro and these cells showed comparatively higher expression of cytotoxicity related molecules, perforin and granzyme B than Cisplatin-TME and Sutent-TME educated T cells. Adoptive transfer of NLGP-TME exposed T cells, but not PBS-TME exposed cells in mice, is able to significantly inhibit the growth of melanoma in vivo. Such tumor growth inhibition was in significantly lower extent when therapeutic CD8(+) T cells were exposed to either Cisplatin-TME or Sutent-TME or control-TME. Accumulated evidences strongly suggest that non toxic NLGP normalized TME allows T cells to perform optimally than other TMEs under study to inhibit the melanoma growth. 23659958 Photoelectron spectroscopy of non-steroidal anti-inflammatory drugs. The electronic structures of eight non-steroidal anti-inflammatory drugs (NSAIDs) had been studied by UV photoelectron spectroscopy (UPS) and high-level Green's function (GF) calculations. Our UPS data show that the electronic structure influences the measured biological activity of NSAID, but that it is not the dominating factor. The role of electronic structure needs to be considered in conjunction with other factors like steric properties of the COX active site and orientation of relevant residues in the same site. 23619759 Environmental exposure to combustion-derived air pollution is associated with reduced functional capacity in apparently healthy individuals. Prior toxicological exposure reports demonstrated the decremental effect of several air pollutants on the metabolic equivalents achieved during exercise testing (METs). There are no prior large scale epidemiological reports about the effect of environmental air pollution exposure on those parameters. We analyzed a cohort of apparently healthy individuals attending a screening survey program held between 2003 and 2009. Participants were included if residing within an 11 km radius from the nearest air pollution monitoring station. Linear regression models were fitted for the metabolic equivalents and adjusted to short- and long-term air pollutant exposure (particulate matter under 10 micron, sulfur dioxide, nitrogen dioxide, carbon monoxide and ozone). The models were adjusted for possible confounders that affect air pollution and stress testing measurements. The study population comprised 6,612 individuals (4,201 males and 2,411 females). We found a statistically significant short- and long-term negative correlation between air pollutants, mainly CO and NO2 and between the metabolic equivalents achieved. A similar short-term effect was found for SO2. We conclude that exposure to combustion-derived air pollutants has a short- and long-term decremental effect on cardiorespiratory fitness as measured by exercise stress testing. Our epidemiological data support previous toxicological reports. 23603839 Leukotriene B4 receptor BLT2 negatively regulates allergic airway eosinophilia. Leukotriene B4 (LTB4) has been implicated in the pathogenesis of allergic diseases. BLT2, a low-affinity LTB4 receptor, is activated by LTB4 and 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT). Although the high-affinity LTB4 receptor BLT1 has been shown to exert proinflammatory roles, the role of BLT2 in allergic inflammation has not been clarified. To study the function of BLT2 in development of asthma, we used mice model of ovalbumin (OVA)-induced allergic airway disease. The 12-HHT levels were elevated in bronchoalveolar lavage (BAL) fluids of OVA-sensitized/challenged wild-type mice. BLT2-deficient mice exhibited enhanced eosinophilia in BAL fluids after OVA exposure. Interleukin (IL)-13 levels in BAL fluids and IL-13-producing CD4(+) T cells in the lungs were elevated in BLT2-deficient mice compared to wild-type mice, whereas the levels of IL-4, IL-5, and interferon (IFN)-γ in BAL fluids and serum OVA-specific IgE were comparable. Transfection of BLT2-specific small interfering RNA enhanced IL-13 production in CD4(+) T cells in vitro. Expression of BLT2 mRNA in CD4(+) T cells was significantly reduced in patients with asthma compared to healthy control subjects. These findings indicate that BLT2 has a protective role in allergic airway inflammation and that diminished BLT2 expression in CD4(+) T cells may contribute to the pathophysiology of asthma.-Matsunaga, Y., Fukuyama, S., Okuno, T., Sasaki, F., Matsunobu, T., Asai, Y., Matsumoto, K., Saeki, K., Oike, M., Sadamura, Y., Machida, K., Nakanishi, Y., Kubo, M., Yokomizo, T., Inoue, H. Leukotriene B4 receptor BLT2 negatively regulates allergic airway eosinophilia. 23937825 Imaging appearances for recurrent nasopharyngeal carcinoma and post-salvage nasopharyngectomy. Nasopharyngeal carcinoma (NPC) is a head and neck neoplasm that occurs in endemic numbers among people of southern Chinese descent. External beam radiation to the nasopharyngeal bed and primary draining lymph node echelons is the mainstay of treatment with concurrent cisplatin-based chemotherapy for more advanced disease. Detection of residual and/or recurrent NPC has important clinical implications, as salvage protocols are available. The review aims to increase awareness of the imaging features of NPC recurrences at local and distant sites using computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography (PET). Important changes in imaging seen in patients after nasopharyngectomy are also discussed. 23453715 Group B streptococcal bacteremia in a major teaching hospital in Malaysia: a case series of eighteen patients. Group B Streptococcus (GBS) is a leading cause of infections such as meningitis and septicemia in neonates and pregnant women; however the significance of invasive GBS disease has not been clearly defined in non-pregnant adults. We reviewed the hospital records of 18 cases with GBS bacteremia who attended the Universiti Kebangsaan Malaysia Medical Centre from June 2010 to October 2011. We analyzed the clinical findings of both bacteremic adults and neonates and compared them to previous studies of GBS bacteremia. Serotyping was done by latex agglutination test using 10 distinct antisera (Ia, Ib, and II-IX). During the period of 1 year and 4 months, there were 18 patients with GBS bacteremia. Five cases occurred in neonates, one in a parturient woman, and 12 in other adults. All neonates with bacteremia were males and two of them were premature. Septicemia was the most common clinical presentation in neonates. They were treated with intravenous (IV) penicillin G and gentamicin. The adults included nine men (69%) and four women (31%). Their mean age was 60 years and all patients had more than two underlying conditions. The most common clinical syndrome was pneumonia (n=6, 46.5%). The others were peritonitis (n=3, 23.1%), primary bacteremia (n=2, 15.5%), septic arthritis (n=2, 15.5%), skin and soft tissue infection (n=1, 7.7%), meningitis (n=1, 8%), urinary tract infection (n=1, 8%), and intravascular device infection (n=1, 7.7%). Cardiovascular diseases (n=7, 53.8%) were the most common underlying conditions, and diabetes mellitus (n=5, 38.5%) was second. The other co-morbid conditions were hyperlipidemia (n=3, 23.1%), renal disease (n=3, 23.1%), liver disease and/or alcohol abuse (n=3, 23.1%), autoimmune disease or immunosuppressive condition (n=2, 15.5%), malignancy (n=2, 15.5%), respiratory disease (n=1, 8%), and postpartum condition (n=1, 8%), as well as miscellaneous conditions including intravenous drug abuse, HIV infection, and trauma (n=2, 15.5%). Polymicrobial bacteremia was found in five (45.4%) cases and Staphylococcus aureus was the most common concurrent bacterial isolate. Of the 18 GBS isolates in both adults and neonates, serotype Ia was predominant (38.9%), followed by VI (27.8%), V (11.1%), and III (5.5%); the remaining 16.7% were non-typeable. GBS bacteremia is a significant problem and is associated with serious underlying disease, which may result in a high rate of mortality, not only in neonates and pregnant women, but also in non-pregnant adults. 23688799 Effects of low protein diets on pigs with a lean genotype 2. Compositional traits measured with computed tomography (CT). The effects on compositional changes across the growing-finishing period (40-115 kg) of feeding pig diets with different protein and amino acid levels were investigated using CT scanning (at 60, 85 and 115 kg live weight). Pigs of a lean commercial genotype were fed a commercial control regime (C), or a low protein regime with either high (LP1) or low (LP2) essential amino acid levels, all balanced for net energy. In vivo CT measurements agreed well with post-slaughter sample joint dissection results for carcass tissue weights/proportions, and CT-measured muscle density predicted intramuscular fat accurately. Pigs on C and LP1 regimes did not differ significantly in composition during growth. However, pigs on the LP2 regime had significantly more fat (in carcass, internal and intra-muscular depots) and less muscle, from 85 kg onwards. Although fat levels differed depending on diet regime (LP2>others), proportions of fat in different body depots were unaffected. 23867291 A comparison between rib fracture patterns in peri- and post-mortem compressive injury in a piglet model. Forensic biomechanics is increasingly being used to explain how observed injuries occur. We studied infant rib fractures from a biomechanical and morphological perspective using a porcine model. We used 24, 6th ribs of one day old domestic pigs Sus scrofa, divided into three groups, desiccated (representing post-mortem trauma), fresh ribs with intact periosteum (representing peri-mortem trauma) and those stored at -20°C. Two experiments were designed to study their biomechanical behaviour fracture morphology: ribs were axially compressed and subjected to four-point bending in an Instron 3339 fitted with custom jigs. Morphoscopic analysis of resultant fractures consisted of standard optical methods, micro-CT (μCT) and Scanning Electron Microscopy (SEM). During axial compression fresh ribs did not fracture because of energy absorption capabilities of their soft and fluidic components. In flexure tests, dry ribs showed typical elastic-brittle behaviour with long linear load-extension curves, followed by short non-linear elastic (hyperelastic) behaviour and brittle fracture. Fresh ribs showed initial linear-elastic behaviour, followed by strain softening and visco-plastic responses. During the course of loading, dry bone showed minimal observable damage prior to the onset of unstable fracture. Frozen then thawed bone showed similar patterns to fresh bone. Morphologically, fresh ribs showed extensive periosteal damage to the tensile surface with areas of collagen fibre pull-out along the tensile surface. While all dry ribs fractured precipitously, with associated fibre pull-out, the latter feature was absent in thawed ribs. Our study highlights the fact that under controlled loading, fresh piglet ribs (representing perimortem trauma) did not fracture through bone, but was associated with periosteal tearing. These results suggest firstly, that complete lateral rib fracture in infants may in fact not result from pure compression as has been previously assumed; and secondly, that freezing of bone during storage may affect its fracture behaviour. 23735748 Hemocompatibility and anti-biofouling property improvement of poly(ethylene terephthalate) via self-polymerization of dopamine and covalent graft of zwitterionic cysteine. Inspired by the composition of adhesive proteins in mussels, we used self-polymerized dopamine to form a thin and surface-adherent polydopamine layer onto poly(ethylene terephthalate) (PET) sheet, followed by covalent grafting cysteine (Cys) to improve hemocompatibility and anti-biofouling property. The obtained surfaces were characterized by water contact angle measurements (WCA), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), and X-ray photoelectron spectroscopy (XPS) analysis. The results of platelet adhesion and protein adsorption tests showed that cysteine immobilized PET was endowed with improved resistance to nonspecific protein adsorption and platelet adhesion. The results of hemolysis rate test showed cysteine grafted PET (PET-g-Cys) had low hemolytic ability. Cell assay results showed that PET-g-Cys surface could greatly inhibit HeLa cell adhesion. These works provide an ideal hemocompatible and antifouling surface for biomedical applications. 23578626 Modeling and prediction of extraction profile for microwave-assisted extraction based on absorbed microwave energy. A modeling technique based on absorbed microwave energy was proposed to model microwave-assisted extraction (MAE) of antioxidant compounds from cocoa (Theobroma cacao L.) leaves. By adapting suitable extraction model at the basis of microwave energy absorbed during extraction, the model can be developed to predict extraction profile of MAE at various microwave irradiation power (100-600W) and solvent loading (100-300ml). Verification with experimental data confirmed that the prediction was accurate in capturing the extraction profile of MAE (R-square value greater than 0.87). Besides, the predicted yields from the model showed good agreement with the experimental results with less than 10% deviation observed. Furthermore, suitable extraction times to ensure high extraction yield at various MAE conditions can be estimated based on absorbed microwave energy. The estimation is feasible as more than 85% of active compounds can be extracted when compared with the conventional extraction technique. 23811056 Dissecting partner recognition by an intrinsically disordered protein using descriptive random mutagenesis. In view of getting insights into the molecular determinants of the binding efficiency of intrinsically disordered proteins (IDPs), we used random mutagenesis. As a proof of concept, we chose the interaction between the intrinsically disordered C-terminal domain of the measles virus nucleoprotein (NTAIL) and the X domain (XD) of the viral phosphoprotein and assessed how amino acid substitutions introduced at random within NTAIL affect partner recognition. In contrast with directed evolution approaches, we did not apply any selection and used the gene library approach not for production purposes but for achieving a better understanding of the NTAIL/XD interaction. For that reason, and to differentiate our approach from similar approaches that make use of systematic (i.e., targeted) mutagenesis, we propose to call it "descriptive random mutagenesis" (DRM). NTAIL variants generated by error-prone PCR were picked at random in the absence of selection pressure and were characterized in terms of sequence and binding abilities toward XD. DRM not only identified determinants of NTAIL/XD interaction that were in good agreement with previous work but also provided new insights. In particular, we discovered that the primary interaction site is poorly evolvable in terms of binding abilities toward XD. We also identified a critical NTAIL residue whose role in stabilizing the NTAIL/XD complex had previously escaped detection, and we identified NTAIL regulatory sites that dampen the interaction while being located outside the primary interaction site. Results show that DRM is a valuable approach to study binding abilities of IDPs. 23692145 Expansion of the analytical window for oil spill characterization by ultrahigh resolution mass spectrometry: beyond gas chromatography. Traditional tools for routine environmental analysis and forensic chemistry of petroleum have relied almost exclusively on gas chromatography-mass spectrometry (GC-MS), although many compounds in crude oil (and its transformation products) are not chromatographically separated or amenable to GC-MS due to volatility. To enhance current and future studies on the fate, transport, and fingerprinting of the Macondo well oil released from the 2010 Deepwater Horizon disaster, we created an extensive molecular library of the unadulterated petroleum to compare to a tar ball collected on the beach of Louisiana. We apply ultrahigh resolution Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry to identify compositional changes at the molecular level between native and weathered crude oil samples and reveal enrichment in polar compounds inaccessible by GC-based characterization. The outlined approach provides unprecedented detail with the potential to enhance insight into the environmental fate of spilled oil, improved toxicology, molecular modeling of biotic/abiotic weathering, and comprehensive molecular characterization for petroleum-derived releases. Here, we characterize more than 30,000 acidic, basic, and nonpolar unique neutral elemental compositions for the Macondo well crude oil, to provide an archive for future chemical analyses of the environmental consequences of the oil spill. 23867819 Glutathione S-transferase omega suppresses the defective phenotypes caused by PINK1 loss-of-function in Drosophila. Loss-of-function mutation of the PTEN-induced kinase 1 (PINK1) gene is a common cause of early-onset Parkinson's disease (PD). Glutathione S-transferase omega (GSTO) is a phase II detoxification enzyme that conjugates targets to glutathione, and has recently been implicated in parkin-associated PD. In this study, we found Drosophila GstO2 to be a novel genetic suppressor of the PINK1 loss-of-function mutant. We show that GstO2A expression is reduced in PINK1 mutants. Moreover, the upregulation of GstO2A restores muscle degeneration and dopaminergic neuron loss in PINK1 mutants. Given the previous data of a reduced expression of GstO2A and decreased glutathionylation of ATP synthase β subunit in parkin or PINK1 mutants, these results suggest that the function of GstO2 is regulated by the PINK1/parkin pathway and that GstO2 also has a protective role in PINK1-associated PD. 23645360 Differential regulation of Arabidopsis plastid gene expression and RNA editing in non-photosynthetic tissues. RNA editing is one of the post-transcriptional processes that commonly occur in plant plastids and mitochondria. In Arabidopsis, 34 C-to-U RNA editing events, affecting transcripts of 18 plastid genes, have been identified. Here, we examined the editing and expression of these transcripts in different organs, and in green and non-green seedlings (etiolated, cia5-2, ispF and ispG albino mutants, lincomycin-, and norflurazon-treated). The editing efficiency of Arabidopsis plastid transcripts varies from site to site, and may be specifically regulated in different tissues. Steady state levels of plastid transcripts are low or undetectable in etiolated seedlings, but most editing sites are edited with efficiencies similar to those observed in green seedlings. By contrast, the editing of some sites is completely lost or significantly reduced in other non-green tissues; for instance, the editing of ndhB-149, ndhB-1255, and ndhD-2 is completely lost in roots and in lincomycin-treated seedlings. The editing of ndhD-2 is also completely lost in albino mutants and norflurazon-treated seedlings. However, matK-640 is completely edited, and accD-794, atpF-92, psbE-214, psbF-77, psbZ-50, and rps14-50 are completely or highly edited in both green and non-green tissues. In addition, the expression of nucleus-encoded RNA polymerase dependent transcripts is specifically induced by lincomycin, and the splicing of ndhB transcripts is significantly reduced in the albino mutants and inhibitor-treated seedlings. Our results indicate that plastid gene expression, and the splicing and editing of plastid transcripts are specifically and differentially regulated in various types of non-green tissues. 23712536 Synthesis of glycerol-derived diallyl spiroorthocarbonates and the study of their antishrinking properties in acrylic dental resins. In this work was evaluated the efficiency of an antishrinkage additive in a dental resin. This additive was a mixture 1:1 of five and six-membered ring spiroorthocarbonates functionalized with allylic groups (SOC DA). The aim of this study was to reduce the shrinkage of a typical dental resin composed of a blend of the dimethacrylates, Glycerolate bisphenol A dimethacrylate (Bis-GMA)/2-[(3,5,5-trimethyl-6-[2-(2-methyl prop-2-enoyloxy) ethoxycarbonylamino] hexyl) carbamoyloxy] ethyl, 2-methyl prop-2-enoate, (UDMA)/triethyleneglycol dimethacrylate (TEGDMA) in a 50:30.20 molar ratio, and silicon dioxide as filler. SOC DA was added at 5, 10 and 20 mol% to the already mentioned formulation. It was found that the addition of 20 mol% of SOC DA decreased 53 % the shrinkage of the cured composite material, in comparison with a formulation where it was not added the antishrinkage additive. Besides, the kinetics of photopolymerization determined by Real-Time infrared spectroscopy, demonstrated that the addition of increasing concentration of SOC DA improved the conversion of double bonds of dimethacrylates. Additionally, the presence of SOC DA at 10 % mol, helped to increase the flexural strength and the compressive strength of the composite, as a consequence of the augment of the crosslink density, induced by the ring opening polymerization of SOC DA. 23749638 Percutaneous approaches for efficient cardiac gene delivery. Gene therapy for heart failure treatment is currently being optimized and validated. The results to date are encouraging but challenges remain before it becomes a therapeutic approach in clinical cardiology. Much effort is dedicated to improve gene transduction efficiency by improving the vectors and the delivery methods. Successful translation from the benchtop to the bedside requires teams including biologists focusing on vector modification and cardiologists refining delivery methods. Two key components for translation to the clinic include safety and efficacy. Transduction efficiency is closely linked to invasiveness in most delivery methods. However, current candidates for cardiac gene therapy are patients without effective treatment option and are in advanced heart failure, thus a less invasive approach is preferred. This review focuses on injection methods of gene delivery with emphasis on percutaneous and endovascular approaches to summarize currently available percutaneous gene delivery methods and their features. 23716196 HitPick: a web server for hit identification and target prediction of chemical screenings. High-throughput phenotypic assays reveal information about the molecules that modulate biological processes, such as a disease phenotype and a signaling pathway. In these assays, the identification of hits along with their molecular targets is critical to understand the chemical activities modulating the biological system. Here, we present HitPick, a web server for identification of hits in high-throughput chemical screenings and prediction of their molecular targets. HitPick applies the B-score method for hit identification and a newly developed approach combining 1-nearest-neighbor (1NN) similarity searching and Laplacian-modified naïve Bayesian target models to predict targets of identified hits. The performance of the HitPick web server is presented and discussed. The server can be accessed at http://mips.helmholtz-muenchen.de/proj/hitpick. monica.campillos@helmholtz-muenchen.de. 23688598 PDE2 and PDE10, but not PDE5, inhibition affect basic auditory information processing in rats. Phosphodiesterase type 2 (PDE2), type 10 (PDE10), and type 5 (PDE5) have been considered as relevant targets for cognition enhancement. Although it is well established that PDE inhibitors (PDE-Is) improve memory functions in animals, the effects on auditory information processing are less clear. The aim of this study was to test the effects of PDE2 (BAY 60-7550), PDE5 (vardenafil) and PDE10 (PQ-10) inhibition on sensory gating in rats. Vehicle or 1mg/kg of a specific PDE-I was given orally 30min before testing. EEG was recorded from the hippocampus, striatum and vertex. Sensory gating was found for the N1 in the vertex and hippocampus, as revealed by diminished amplitudes to S2 compared to S1. Administration of PDE-Is did not affect sensory gating. However, PDE2 inhibition increased the P1 peak after presentation of S1 at the vertex and PQ-10 increased the N1 peak in general compared to vehicle treatment at the hippocampus. PDE2 and PDE10 inhibition affect auditory information processing in general, whereas PDE5 inhibition has no effect. These findings suggest that the positive effects of PDE5 inhibition on cognition previously found in animals are possibly the results of an effect on higher cognitive functioning specifically, whereas the cognition enhancing effects of PDE2 and PDE10 inhibition might also be influenced by effects on earlier stages of information processing. 23435687 Avoidance behaviour response and esterase inhibition in the earthworm, Lumbricus terrestris, after exposure to chlorpyrifos. The avoidance response of earthworms to polluted soils has been standardised using a simple and low-cost test, which facilitates soil toxicity screening. In this study, the avoidance response of Lumbricus terrestris was quantified in chlorpyrifos-spiked soils, depending on the pesticide concentration and exposure duration. The inhibition of acetylcholinesterase (AChE) and carboxylesterase (CbE) activities was also determined as indirect measures of pesticide bioavailability. The effects of different chlorpyrifos concentrations were examined in a standardised test (two-chamber system) with 0.6, 3 and 15 mg/kg chlorpyrifos. A modification of the test involved a pre-exposure step (24, 48 or 72 h) in soils spiked with 15 mg/kg. In both protocols, earthworms were unable to avoid the contaminated soils. However, the esterase activities showed that all earthworms were exposed to chlorpyrifos. Acetylcholinesterase activity did not change in earthworms in the standardised behavioural test (0.58 ± 0.20 U/mg protein, mean ± SD; n = 72), whereas the CbE activity was significantly inhibited (62-87 % inhibition) in earthworms exposed to 3 and 15 mg/kg. In the modified test, earthworms had greatly inhibited AChE activity (0.088 ± 0.034 U/mg protein, n = 72), which was supported by reactivation of the inhibited enzyme activity in the presence of pralidoxime (2-PAM). Similarly, the CbE activity was significantly inhibited in earthworms with all treatments. This study suggests that the avoidance behaviour test for organophosphorus-contaminated soils could be supported by specific biomarkers to facilitate a better understanding of pesticide exposure and toxicity during this test. 23504855 The Pharmacokinetics and Pharmacodynamics of Zaleplon Delivered as a Thermally Generated Aerosol in a Single Breath to Volunteers. Pharmacokinetics, pharmacodynamics, safety, and tolerability of inhaled zaleplon were assessed in healthy volunteers. Forty participants received 0.5, 1, 2, or 4 mg zaleplon or placebo as a thermally generated aerosol in a randomized, double-blind, parallel-group, dose escalation study. Blood was collected up to 24 hours after dosing, and sedation was assessed up to 8 hours. Following inhalation, the observed median time to maximum plasma concentrations (25%, 75%) was 1.89 (1.45, 3.08) minutes and the mean (SD) elimination half-life was 1.24 (0.24) hours. The equilibration half-life for sedation (t1/2 ke0 ) was 1.16 (0.62, 2.17) minutes. The zaleplon AUC was dose proportional across doses, with a slope (90% confidence interval) of log-AUC versus log-dose of 0.92 (0.82, 1.02). No clinically significant changes were noted in laboratory values, vital signs, or spirometry. The most common adverse events were dizziness, somnolence, euphoria, headache, and visual disturbance. Zaleplon inhalation represents a safe, well-tolerated means of rapidly achieving effective plasma concentrations. 23838697 Peripheral Monocytes Derived From Patients With Cystic Fibrosis and Healthy Donors Secrete NGAL in Response to Pseudomonas aeruginosa Infection. Patients with cystic fibrosis (CF) develop chronic bacterial infections in the respiratory tract, reflecting dysfunctional innate immunity. Neutrophil gelatinase-associated lipocalin (NGAL) has 2 functions: one as an antibacterial host defense protein and the other as a physiological iron carrier. Neutrophil gelatinase-associated lipocalin (NGAL) has been validated as a biomarker for early kidney disease. The aim of this study was to determine whether NGAL could serve as a marker of acute pulmonary exacerbations in CF by measuring NGAL levels in serum samples from subjects with CF during stable clinic visits and during hospitalization for pulmonary exacerbations and comparing these levels to healthy controls and to patients without CF with significant infection. In addition, we aimed to determine if innate immunity cells other than neutrophils act as a source of NGAL. Circulating NGAL levels were measured by enzyme-linked immunosorbent assay in serum samples from 30 subjects with CF when hospitalized for an acute pulmonary exacerbation, 33 subjects with CF during stable clinic visits, 33 patients with sepsis, and 21 healthy controls. Secreted NGAL from CF and healthy control peripheral monocytes infected with Pseudomonas aeruginosa was also measured by enzyme-linked immunosorbent assay. Serum NGAL levels were elevated in the patients with CF compared to the healthy controls (P < 0.001). However, no difference in serum NGAL levels was found between subjects with CF with stable disease compared to subjects with CF undergoing pulmonary exacerbation. Furthermore, peripheral monocytes from CF and subjects without CF secreted NGAL upon infection with Pseudomonas aeruginosa and thereby may be contributing to the circulating NGAL levels observed. Our data show that peripheral monocytes secrete NGAL, and serum NGAL levels are widely distributed among subjects with CF, being elevated both when clinically stable and during a pulmonary exacerbation and thus NGAL is not a sensitive biomarker for pulmonary exacerbations. 23604141 Antifungal Azoles: Structural Insights into Undesired Tight Binding to Cholesterol-Metabolizing CYP46A1. Although there are currently three generations of antifungal azoles on the market, even the third generation agents show undesired interactions with human cytochrome P450 enzymes. CYP46A1 is a cholesterol-metabolizing P450 in the brain tightly binding a number of structurally distinct azoles. Previously, we determined the crystal structures of CYP46A1 in complex with voriconazole and clotrimazole, and in the present work we co-crystallized the P450 with posaconazole at 2.5 Å resolution. This long antifungal drug coordinates the P450 heme iron with the nitrogen atom of its terminal azole ring and adopts a linear configuration occupying the whole length of the substrate access channel and extending beyond the protein surface. Numerous drug-protein interactions determine the submicromolar Kd of posaconazole for CYP46A1. We compared the crystal structure of posaconazole-bound CYP46A1 with those of the P450 in complex with other drugs including the antifungal voriconazole and clotrimazole. We also analyzed the accommodation of posaconazole in the active site of the target enzymes, CYPs 51, from several pathogenic species. These and the solution studies with different marketed azoles, collectively, allowed us to identify the determinants of tight azole binding to CYP46A1 and generate an overall picture of azole binding to this important P450. The data obtained suggest that development of CYP51-specific antifungal agents will continue to be a challenge. Therefore, structural understanding of the azole binding not only to CYPs 51 from the pathogenic species but also to different human P450s is required to deal efficiently with this challenge. 23603833 Mapping the functional domains of TCblR/CD320, the receptor for cellular uptake of transcobalamin-bound cobalamin. The membrane receptor TCblR/CD320 binds transcobalamin (TC) saturated with vitamin B12 [cobalamin (Cbl)] and mediates cellular uptake of the vitamin. The specificity of TC for Cbl and of the receptor for TC-Cbl ensures efficient uptake of Cbl into cells. The high-affinity interaction of TCblR with TC-Cbl (Ka=10 nM(-1)) was investigated using deletions and mutations of amino acid sequences in TCblR. Only the extracellular region (aa 32-229) is needed for TC-Cbl binding, but the N-glycosylation sites (N126, N195, and N213) are of no importance for this function. Deleting the cysteine-rich region (aa 95-141) that separates the two low-density lipoprotein receptor type A (LDLR-A) domains does not affect TC-Cbl binding (Ka = 19-24 nM(-1)). The two LDLR-A domains (aa 54-89 and 132-167) with the negatively charged acidic residues involved in Ca(2+) binding are critical determinants of ligand binding. The cytoplasmic tail is apparently crucial for internalization of the ligand. Within this region, the RPLGLL motif and the PDZ binding motifs (QERL/KESL) appear to be involved in initiating and completing the process of ligand internalization. Mutations and deletions of these regions involved in binding and internalization of TC-Cbl are likely to produce the biochemical and clinical phenotype of Cbl deficiency.-Jiang, W., Nakayama, Y., Sequeira, J. M., Quadros, E. V. Mapping the functional domains of TCblR/CD320, the receptor for cellular uptake of transcobalamin-bound cobalamin. 23824570 DNA repair gene XRCC3 Thr241Met polymorphism and hepatocellular carcinoma risk. The DNA repair genes have been indicated as candidates in the risk of hepatocellular carcinoma (HCC). Published data on the association between X-ray repair cross-complementing group 3 (XRCC3), a critical member of the DNA repair genes, and HCC risk were contradictory. The aim of this meta-analysis was to assess the effect of XRCC3 Thr241Met polymorphism on HCC risk by pooling available data from published case-control studies. We calculated the pooled odds ratio (OR) with the corresponding 95 % confidence interval (95 % CI) to estimate the effect. Based on the inclusion criteria, six individual studies with 2,288 cases and 3,170 controls were included into our study. Overall, significant association between the XRCC3 Thr241Met variant and HCC risk was observed under the following contrast models (ORMet vs. Thr = 1.68, 95 %CI 1.08-2.62; ORMetMet vs. ThrThr = 5.54, 95 %CI 3.09-9.94; ORMetMet vs. ThrThr + ThrMet = 5.70, 95 % CI 4.24-7.64). Besides, the pooled ORs indicated that the XRCC3 Thr241Met polymorphism exerted risk effect on the HCC pathogenesis among Asians. Additionally, when stratifying by the status of smoking and hepatitis B virus infection, the XRCC3 Thr241Met variant was significantly associated with HCC risk among the HBsAg (+) individuals but not the HBsAg (-) individuals, smokers, and non-smokers. The present meta-analysis suggests that the XRCC3 Thr241Met polymorphism is an independent risk factor for HCC, particularly among Asians and the HBsAg (+) individuals. 23904241 Sleepiness in elderly veterans. This observational study seeks to describe the distribution of sleepiness among elderly male veterans and to explain the relationship between sleepiness and age, function, mobility, and depression in this population. Veterans who were age 60 or older and had two or more functional limitations based on their activities of daily living or instrumental activities of daily living were recruited in outpatient clinics. They were recruited as part of a longitudinal study and completed questionnaires reported here at the 18-month data collection time point. Veterans report higher sleepiness than normal controls. Self-reported sleepiness scores are similar to those of patients who have been diagnosed with sleep disturbances. Interventions to identify and support aging veterans with perceived sleepiness should be developed and carefully evaluated. 23962214 Hypothalamic integration of nutrient status and reproduction in the sheep. Nutrient availability is a determinant of reproductive success. It is well known that inadequate nutrition results in reproductive failure due to a number of factors including delay of puberty or anoestrous in post-pubertal animals. The lack of nutrients is detected primarily by changes in circulating nutrient molecules and hormones and communicated directly or indirectly to the hypothalamus and brain stem for integration. The general effect is that low nutrition leads to increased appetite stimulation and reduced reproductive performance. When nutrition is adequate, the reverse is true. Both aspects will be the focus of this review. One result of the lack of nutrients is a reduction in luteinizing hormone (LH) concentrations and pulse frequency. Nutrient signals, such as glucose availability, hormonal signals, such as insulin and leptin, and neuroendocrine signals, such as neuropeptide Y and corticotropin-releasing hormone, have been clearly demonstrated to interact to produce changes in LH and reproductive success. Other signals, such as fatty acids, ghrelin, agouti-related peptide, melanin-concentrating hormone, orexin, melanocyte-stimulating hormone, kisspeptin, neurokinin, dynorphin and gonadotropin inhibitory hormone may also play a role in integrating nutrition and reproduction. This review will focus on the major features of the reciprocal control of appetite and reproduction in sheep. 23661421 Dysregulating IRES-Dependent Translation Contributes to Overexpression of Oncogenic Aurora A Kinase. Overexpression of the oncoprotein Aurora A kinase occurs in multiple types of cancer, often early during cell transformation. To identify the mechanism(s) contributing to enhanced Aurora A protein expression, a comparison between normal human lung fibroblast and breast epithelial cells to nontumorigenic breast (MCF10A and MCF12A) and tumorigenic breast (MCF-7) and cervical cell lines (HeLa S3) was performed. A subset of these immortalized lines (MCF10A, MCF12A, and HeLa S3) exhibited increased levels of Aurora A protein, independent of tumorigenicity. The increase in Aurora A protein in these immortalized cells was not due to increased transcription/RNA stability, protein half-life, or cap-dependent translation. Assays utilizing monocistronic and dicistronic RNA constructs revealed that the 5'-leader sequence of Aurora A contains an internal ribosomal entry site (IRES), which is regulated in a cell cycle-dependent manner, peaking in G2/M phase. Moreover, IRES activity was increased in the immortalized cell lines in which Aurora A protein expression was also enhanced. Additional studies indicated that the increased internal initiation is specific to the IRES of Aurora A and may be an early event during cancer progression. These results identify a novel mechanism contributing to Aurora A kinase overexpression. Implications: The current study indicates that Aurora A kinase contributes to immortalization and tumorigenesis. Mol Cancer Res; 11(8); 887-900. ©2013 AACR. 23941991 New engineered antibodies against prions. A number of recently developed and approved therapeutic agents based on highly specific and potent antibodies have shown the potential of antibody therapy. As the next step, antibody-based therapeutics will be bioengineered in a way that they not only bind pathogenic targets but also address other issues, including drug targeting and delivery. For antibodies that are expected to act within brain tissue, like those that are directed against the pathogenic prion protein isoform, one of the major obstacles is the blood-brain barrier which prevents efficient transfer of the antibody, even of the engineered single-chain variants. We recently demonstrated that a specific prion-specific antibody construct which was injected into the murine tail vein can be efficiently transported into brain tissue. The novelty of the work was in that the cell penetrating peptide was used as a linker connecting both specificity-determining domains of the antibody peptide, thus eliminating the need for the standard flexible linker, composed of an arrangement of three consecutive (Gly 4Ser) repeats. This paves the road toward improved bioengineered antibody variants that target brain antigens. 23912399 Inpatient bariatric surgery among eligible black and white men and women in the United States, 1999-2010. We examined national trends in bariatric surgery for adults, focusing on differences in utilization by race and access to health care. We analyzed subjects eligible for bariatric surgery in the National Hospital Discharge Survey and the National Health and Nutrition Examination Survey for 1999-2010. Primary outcome measures included population-based estimates and comparison of blacks and whites eligible for surgery with those who actually received it. A higher percentage of black than white women and of black than white men were eligible for bariatric surgery. But a higher proportion of eligible white women and men than black women and men received bariatric surgery. 69.8% of eligible white women and 72.9% of white women who received bariatric surgery had private health insurance, compared with 49.9% and 71.1% of black women. 71.4% of eligible white men and 75.9% of white men who received bariatric surgery had private health insurance, compared with 52.4% and 74.7% of black men. Among men eligibility and surgery rates were lower than for women of the same race, and significant differences were found by race in the same directions as for women. Eligible whites received bariatric surgery at higher levels than eligible blacks, apparently partly because of differences in insurance coverage. 23660449 The effect of experimentally induced chronic hyperglycaemia on serum and pancreatic insulin, pancreatic islet IGF-I and plasma and urinary ketones in the domestic cat (Felis felis). Like in humans, diabetes mellitus is on the rise in cats. Feline diabetes is a suitable model for human type-2 diabetes. We investigated magnitude and timing of insulin suppression with induced hyperglycaemia and its relationship to plasma and urinary ketones and to pancreatic islet insulin. IGF-I is under discussion as a protective mechanism but little is known about its role in diabetes in general and its distinct localisation in feline pancreatic islets in particular. Thirteen healthy, adult cats were allocated to 2 groups and infused with glucose to maintain their blood glucose at a high or moderate concentration for 42 days resulting in insulin secretion suppression. After initial increase, insulin levels declined to baseline but were still detectable in the blood at a very low level after 6 weeks of glucose infusion and then increased after a 3 week recovery period. While IGF-I in healthy cats was primarily located in glucagon cells, in hyperglycaemia-challenge IGF-I was pronounced in the β-cells 3 weeks after ceasation of infusion. Six/8 cats developing glucose toxicity became ketonuric after 3-4 weeks. Gross lipaemia occurred approx 1 week prior to ketonuria. Ketonuric cats required 1-2 weeks of insulin therapy after-infusion until β-cell recovery. In conclusion, ketosis and hyperlipidaemia are likely to occur in diabetic cats with glucose at 30 mmol/L, especially after ≥2 weeks. Three weeks after ceasation of infusions, clinical and morphological recovery occurred. We propose a local protective effect of IGF-I to support survival and insulin production in the hyperglycaemic state and recovery period. 23847137 Systematic review: Work-related stress and the HSE Management Standards. BackgroundThe Health and Safety Executive (HSE) has defined six management standards representing aspects of work that, if poorly managed, are associated with lower levels of employee health and productivity, and increased sickness absence. The HSE indicator tool aims to measure organizations' performance in managing the primary stressors identified by the HSE management standards.AimsThe aims of the study are to explore how the HSE indicator tool has been implemented within organizations and to identify contexts in which the tool has been used, its psychometric properties and relationships with alternative measures of well-being and stress.MethodsStudies that matched specific criteria were included in the review. Abstracts were considered by two researchers to ensure a reliable process. Full texts were obtained when abstracts met the inclusion criteria.ResultsThirteen papers were included in the review. Using factor analysis and measures of reliability, the studies suggest that the HSE indicator tool is a psychometrically sound measure. The tool has been used to measure work-related stress across different occupational groups, with a clear relationship between the HSE tool and alternative measures of well-being. Limitations of the tool and recommendations for future research are discussed.ConclusionsThe HSE indicator tool is a psychometrically sound measure of organizational performance against the HSE management standards. As such it can provide a broad overview of sources of work-related stress within organizations. More research is required to explore the use of the tool in the design of interventions to reduce stress, and its use in different contexts and with different cultural and gender groups. 23824433 Is Central Auditory Processing Disorder present in psychosis? The scope of this study was to trace of central auditory processing issues in patients with first episode psychosis using a psychoacoustic test battery approach. Patients were included in the study on the basis of normal hearing sensitivity. A central auditory processing battery was implemented consisting of monaural and binaural tests with verbal and non-verbal stimuli. Seventeen control subjects were volunteers with no personal or family history of schizophrenia. Seventeen (17) patients were tested to evaluate central auditory processing abilities. Perceptual deficits in both non-verbal and verbal auditory stimuli are reported in this study with temporal central auditory processing deficits and a mean left ear left ear advantage (LEA) being documented in the patient group. This study points to the possibility of existence of central auditory processing deficits in first episode psychosis leading to schizophrenia. Audiologists should be aware of the psychiatric research pointing to enhanced verbal memory as a result of auditory training; linking bottom-up remediation with top-down improvement. 23851277 Adaptive Response of Vascular Endothelial Cells to an Acute Increase in Shear Stress Frequency. Local shear stress sensed by arterial endothelial cells is occasionally altered by changes in global hemodynamic parameters, e.g. heart rate and blood flow rate, as a result of normal physiological events. In a recently study, we demonstrated that, during the adaptive response to increased shear magnitude, porcine endothelial cells exhibited an unique phenotype featuring a transient increase in permeability and the upregulation of a set of anti-inflammatory and anti-oxidative genes. In the present study, we characterize the adaptive response of these cells to an increase in shear frequency, another important hemodynamic parameter with implications in atherogenesis. Endothelial cells were preconditioned by a basal-level sinusoidal shear stress of 15 ± 15 dynes/cm2 at 1 Hz, and the frequency was then elevated to 2 Hz. Endothelial permeability increased slowly after the frequency step-up, but the increase was relatively small. Using microarrays, we identified 37 genes that are sensitive to the frequency step-up. The acute increase in shear frequency upregulates a set of cell-cycle regulation and angiogenesis related genes. The overall adaptive response to the increased frequency is distinctly different from that to a magnitude step-up. However, consistent with the previous study, our data support the notion that endothelial function during an adaptive response is different than that of fully adapted endothelial cells. Our studies may also provide insights into the beneficial effects of exercise on vascular health: transient increases in frequency may facilitate endothelial repair, while similar increases in shear magnitude may keep excessive inflammation and oxidative stress at bay. 23897676 More Than Meets the Eye in Bacterial Cellulose: Biosynthesis, Bioprocessing, and Applications in Advanced Fiber Composites. Bacterial cellulose (BC) nanofibers are one of the stiffest organic materials produced by nature. It consists of pure cellulose without the impurities that are commonly found in plant-based cellulose. This review discusses the metabolic pathways of cellulose-producing bacteria and the genetic pathways of Acetobacter xylinum. The fermentative production of BC and the bioprocess parameters for the cultivation of bacteria are also discussed. The influence of the composition of the culture medium, pH, temperature, and oxygen content on the morphology and yield of BC are reviewed. In addition, the progress made to date on the genetic modification of bacteria to increase the yield of BC and the large-scale production of BC using various bioreactors, namely static and agitated cultures, stirred tank, airlift, aerosol, rotary, and membrane reactors, is reviewed. The challenges in commercial scale production of BC are thoroughly discussed and the efficiency of various bioreactors is compared. In terms of the application of BC, particular emphasis is placed on the utilization of BC in advanced fiber composites to manufacture the next generation truly green, sustainable and renewable hierarchical composites. 22982303 Biomarkers of Parkinson's disease: current status and future perspectives. This review summarizes major advances in biomarker discovery for diagnosis, differential diagnosis and progression of Parkinson's disease (PD), with emphasis on neuroimaging and biochemical markers. Potential strategies to develop biomarkers capable of predicting PD in the prodromal stage before the appearance of motor symptoms or correlating with nonmotor symptoms, an active area of research, are also discussed. 23806128 Effect of farming strategies on environmental impact of intensive dairy farms in Italy. Agriculture and animal husbandry are important contributors to global emissions of greenhouse (GHG) and acidifying gases. Moreover, they contribute to water pollution and to consumption of non-renewable natural resources such as land and energy. The Life Cycle Assessment (LCA) methodology allows evaluation of the environmental impact of a process from the production of inputs to the final product and to assess simultaneously several environmental impact categories among which GHG emissions, acidification, eutrophication, land use and energy use. The main purpose of this study was to evaluate, using the LCA methodology, the environmental impact of milk production in a sample of 41 intensive Italian dairy farms and to identify, among different farming strategies, those associated with the best environmental performances. The functional unit was 1 kg Fat and Protein Corrected Milk (FPCM). Farms showed characteristics of high production intensity: FPCM, expressed as tonnes per hectare, was 30·8±15·1. Total GHG emission per kg FPCM at farm gate was 1·30±0·19 kg CO2 eq. The main contributors to climate change potential were emissions from barns and manure storage (50·1%) and emissions for production and transportation of purchased feeds (21·2%). Average emission of gases causing acidification to produce 1 kg FPCM was 19·7±3·6 g of SO2 eq. Eutrophication potential was 9·01±1·78 ${\rm PO}_{\rm 4}^{{\rm 3} -} {\rm eq}.$ per kg FPCM on average. Farms from this study needed on average 5·97±1·32 MJ per kg FPCM from non-renewable energy sources. Energy consumption was mainly due to off-farm activities (58%) associated with purchased factors. Land use was 1·51±0·25 m2 per kg FPCM. The farming strategy based on high conversion efficiency at animal level was identified as the most effective to mitigate the environmental impact per kg milk at farm gate, especially in terms of GHG production and non-renewable energy use per kg FPCM. 23874833 Anorectal transplantation in human cadavers: mock anorectal allotransplantation. Anorectal transplantation is a method for patients who have lost their anorectal function or suffer from congenital anorectal dysfunction to recover this function, and this has been investigated in experimental animal models using pigs, dogs, and rats. In this study, we performed an examination of anorectal transplantation in human cadavers to investigate whether this procedure could be performed in patients. A 77-year-old woman cadaver 1 was used as the donor and a 98-year-old woman cadaver 2 was used as the recipient. Initially, abdominoperineal excision of the anus and rectum (the Miles' operation) was performed on the recipient. Next, an anorectal graft containing the pudendal nerve (PN), pudendal artery (PA), pudendal vein (PV), inferior mesenteric artery (IMA), and inferior mesenteric vein (IMV) was harvested from the donor. The donor graft was transplanted into the recipient by intestinal anastomosis and microneurovascular anastomoses orthotopically. The diameters of the PN (right/left), IMA, and IMV were 2.5 mm/2.5 mm, 2.0 mm, and 1.5 mm, respectively, in cadaver 1, and 2.0 mm/2.0 mm, 2.0 mm, and 2.0 mm, respectively, in cadaver 2. The length of the PN, PA, PV, IMA, and IMV in the graft was sufficient to allow proper anastomosis. This preliminary study indicated that human anorectal transplantation was possible anatomically and technically. We anticipate our study will aid in the potential future application of this procedure to human patients. 23752253 Emotion recognition in mild cognitive impairment: relationship to psychosocial disability and caregiver burden. Background: Impaired emotion recognition in dementia is associated with increased patient agitation, behavior management difficulties, and caregiver burden. Emerging evidence supports the presence of very early emotion recognition difficulties in mild cognitive impairment (MCI); however, the relationship between these impairments and psychosocial measures is not yet explored. Methods: Emotion recognition abilities of 27 patients with nonamnestic MCI (naMCI), 29 patients with amnestic MCI (aMCI), and 22 control participants were assessed. Self-report measures assessed patient functional disability, while informants rated the degree of burden they experienced. Results: Difficulties in recognizing anger was evident in the amnestic subtype. Although both the patient groups reported greater social functioning disability, compared with the controls, a relationship between social dysfunction and anger recognition was evident only for patients with naMCI. A significant association was found between burden and anger recognition in patients with aMCI. Conclusions: Impaired emotion recognition abilities impact MCI subtypes differentially. Interventions targeted at patients with MCI, and caregivers are warranted. 23194519 Identification of hydroxychavicol and its dimers, the lipase inhibitors contained in the Indonesian spice, Eugenia polyantha. Inhibition of pancreatic lipase is effective for a prevention of obesity. Eugenia polyantha is a tropical tree whose leaves are known as a spice and also as an ingredient for Jamu, the traditional medicine of Indonesia. We found inhibitory activity against pancreatic lipase in the extract of E. polyantha leaves. Purification of the active principals resulted in isolation of hydroxychavicol, and two structurally new dimers. All of the isolated compounds showed inhibitory activity against the porcine pancreatic lipase and high content of hydroxychavicol (1.83 wt.%) indicated this compound to be responsible for the majority of inhibitory activity of E. polyantha extract. Furthermore, hydroxychavicol is reported to possess anti-carcinogenic, anti-oxidant, anti-microbial and anti-inflammatory activity which is related to traditional usage of this plant. These results offer this plant as an attractive material for treating various health problems including obesity. 22921426 Lead-induced ER calcium release and inhibitory effects of methionine choline in cultured rat hippocampal neurons. Lead, a ubiquitous neurotoxicant, can result in learning and memory dysfunction. Long term potentiation in the hippocampus, a potential neural substrate for learning and memory, is thought to be linked to calcium-triggered intracellular events. In this study, laser scanning confocal microscopy was used to examine the effects of Pb(2+) on intracellular and endoplasmic reticulum free calcium concentration ([Ca(2+)](i) and [Ca(2+)](ER)) in cultured neonatal rat hippocampal neurons and their possible antagonism by methionine choline; understanding these effects would help explain the lead-induced cognitive and learning dysfunction and explore efficient safety and relief strategies. The results showed that Pb(2+) increased [Ca(2+)](i) and decreased [Ca(2+)](ER) linearly in a time- and concentration-dependant manner, and Pb(2+) addition after the applying of a ryanodine receptor (RyR) antagonist and an inositol-1,4,5-triphosphate receptor (IP(3)R) antagonist did not increase [Ca(2+)](i). The addition of 10, 20, or 40 mmol/L methionine choline simultaneously with addition of 10 μmol/L Pb(2+) decreased [Ca(2+)](i) in Ca(2+)-free culture medium by 39.0%, 66.0%, and 61.6%, respectively, in a concentration-dependant manner in a certain dose range. Our results suggest that Pb(2+) induces ER calcium release to increase the resting [Ca(2+)](i); and methionine choline inhibit this increase in [Ca(2+)](i). 23910079 Transplantable liver organoids made from only three ingredients. Liver cell therapies using induced pluripotent stem cells (iPSCs) are in development. A recent paper in Nature by Takebe et al. expands the range of liver diseases that could be treated with iPSC-derived hepatocytes by combining them with endothelial and stromal cells to generate organoids that survive and function extrahepatically. 23498967 Conformational epitope mapping of Pru du 6, a major allergen from almond nut. Tree nuts are a widely consumed food. Although enjoyed safely by most individuals, allergic reactions to tree nuts, including almond, are not uncommon. Almond prunin (Pru du 6), an 11S globulin (legumin), is an abundant nut seed protein and a major allergen. Conformational epitope mapping studies of prunin have been performed with a murine monoclonal antibody (mAb) 4C10. This mAb reacts with non-reduced but not reduced prunin in immunoblotting assays, indicating the recognition of a conformational epitope. 4C10 competes with patient IgE, as assessed by ELISA, indicating clinical significance of the epitope. To characterize the 4C10 epitope, hydrogen/deuterium exchange (HDX) monitored by 14.5 T Fourier transform ion cyclotron resonance mass spectrometry (MS) was performed on the native prunin-4C10 complex and on uncomplexed native prunin. Several epitope candidate peptides that differ in deuterium uptake between the complexed and uncomplexed forms were identified. The epitope was further mapped by analyzing chimeric molecules incorporating segments of the homologous soybean allergen, Gly m 6, in immunoassays. These data indicate that the 4C10 epitope overlaps with a subset of patient IgE binding epitopes on almond prunin and further supports HDX-MS as a valid technique for mapping conformational epitopes. 23952621 Hypovitaminosis D in Dogs with Spirocercosis. Spirocercosis in dogs is characterized by esophageal nodules that can undergo neoplastic transformation. Hypovitaminosis D has been associated with neoplasia formation. We hypothesized hypovitaminosis D in neoplastic spirocercosis and that it could be a risk factor for neoplastic transformation. To measure and compare vitamin D status, assessed by serum 25-hydroxyvitamin D [25(OH)D] concentrations in non-neoplastic (n = 25) and neoplastic (n = 26) spirocercosis client-owned dogs and healthy dogs (n = 24). Twenty-five non-neoplastic dogs, 26 neoplastic dogs, and 24 healthy dogs. Fifty-one dogs were randomly selected from 119 dogs diagnosed with spirocercosis presenting to our hospital, and further divided into non-neoplastic or neoplastic groups. Exclusion criteria included dogs less than 1 year old, with concurrent diseases, received corticosteroids, or treated prophylactically for spirocercosis. Serum 25(OH)D concentration was measured by high-performance liquid chromatography. Spirocercosis dogs' appetites were graded and compared. Serum 25(OH)D concentrations were significantly different among all groups (P < .001). 25-Hydroxyvitamin D concentrations were significantly lower in neoplastic group (median 30.7 nmol/L [range 14.7-62.2]) compared to non-neoplastic (median 52.7 nmol/L [range 19.1-129.7, P < .05]) and healthy groups (median 74.6 nmol/L [range 37.4-130.5, P < .005]). 25-hydroxyvitamin D concentrations were significantly lower in non-neoplastic spirocercosis dogs compared to healthy ones (P < .05). Neoplastic and non-neoplastic spirocercosis dogs had similar appetite scores (P = 1.0). 25-Hydroxyvitamin D concentrations were not significantly different between dogs with normal (P = .087) and abnormal (P = .125) appetites within neoplastic and non-neoplastic spirocercosis groups. Further studies are warranted to determine potential use of vitamin D treatment in spirocercosis and explore role of hypovitaminosis D in pathogenesis of malignant transformation. 23963642 The POSH/JIP-1 scaffold network regulates TCR-mediated JNK1 signals and effector function in CD8(+) T cells. Signals from the T-cell recognition of antigen program effector functions necessary to clear infections and tumors. The JNK pathway is critically important in regulating this process. In T lymphocytes, JNK1 and 2 have distinct functions dependent on the maturation state and cell type. However, the mechanisms that regulate their isoform specific activity and function are unclear. Here, we identify Plenty of SH3 (POSH) and JNK-interacting protein 1 (JIP-1) as a multi-protein scaffold network for TCR-mediated JNK1 activation in CD8(+) T-cells. Disruption of the POSH/JIP-1 complex led to profound defects in the activation of JNK1, as well as deficient activation or induction of the transcription factors c-Jun, T-bet and Eomesodermin. Furthermore, disruption of the POSH/JIP complex in CD8(+) T-cells resulted in impaired proliferation, decreased cytokine expression and the inability to control tumors. Collectively, these data identify a mechanism for the specific regulation of TCR-dependent JNK1 activation and function that is key for CD8(+) T-cell responses. This article is protected by copyright. All rights reserved. 23916766 Echinococcus multilocularis: Single hepatic lesion experimentally established without metastasis in rats. We herein describe the establishment of single hepatic lesions of Echinococcus multilocularis in rats. A 3mm incision was made on the liver with a surgical knife, and one small round vesicle of E. multilocularis (between 1×1mm and <2×2mm in diameter) was transplanted into the incision and covered with absorbable hemostat gauze. The presence and growth of the transplanted vesicle was monitored for 12weeks using magnetic resonance imaging (MRI). Hepatic lesions, the metacestode of this parasite were confirmed in 12 of 17 infected rats (70.6%) by MRI and macroscopic examinations. The average size of the metacestodes with brood capsules at 12weeks after the experimental transplantation of a single vesicle was 6.1±2.5mm×4.4±1.5mm. The smallest size of the metacestodes detected by MRI was approximately 3×3mm. This new approach of establishing single hepatic metacestodes of E. multilocularis in experimental animals is expected to be useful for analyzing the immune-pathological mechanisms of hepatic AE. 23818120 Steroids for idiopathic sudden sensorineural hearing loss. This is an update of a Cochrane review first published in The Cochrane Library in Issue 1, 2006 and previously updated in 2009.Idiopathic sudden sensorineural hearing loss (ISSHL) is a clinical diagnosis characterised by a sudden deafness of cochlear or retrocochlear origin in the absence of a clear precipitating cause. Steroids are commonly prescribed to treat this condition. There is no consensus on their effectiveness. To determine whether steroids in the treatment of ISSHL a) improve hearing (primary) and b) reduce tinnitus (secondary).To determine the incidence of significant side effects from the medication. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 22 April 2013. We identified all randomised controlled trials (with or without blinding) in which steroids were evaluated in comparison with either no treatment or a placebo. We considered trials including the use of steroids in combination with another treatment if the comparison control group also received the same other treatment. The two authors reviewed the full-text articles of all the retrieved trials of possible relevance and applied the inclusion criteria independently. We graded trials for risk of bias using the Cochrane approach. The data extraction was performed in a standardised manner by one author and rechecked by the other author. Where necessary we contacted investigators to obtain the missing information. Meta-analysis was neither possible nor considered appropriate because of the heterogeneity of the populations studied and the differences in steroid formulations, dosages and duration of treatment. We analysed and reported the quality of the results of each study individually. A narrative overview of the results is presented. Only three trials, involving 267 participants, satisfied the inclusion criteria and all three studies were at high risk of bias. One trial showed a lack of effect of oral steroids in improving hearing compared with the placebo control group. The second trial showed a significant improvement of hearing in 61% of the patients receiving oral steroid and in only 32% of the patients from the control group (combination of placebo-treated group and untreated control group). The third trial also showed a lack of effect of oral steroids in improving hearing compared with the placebo control. However, this trial did not follow strict inclusion criteria for participant selection and analysis of data was limited by significant exclusion of participants from the final analysis and lack of participant compliance to the treatment protocol. No clear evidence was presented in two trials about any harmful side effects of the steroids. Only one study declared that no patients suffered from adverse effects of the steroid treatment. The value of steroids in the treatment of idiopathic sudden sensorineural hearing loss remains unclear since the evidence obtained from randomised controlled trials is contradictory in outcome, in part because the studies are based upon too small a number of patients. 23640788 Material and structural properties of fin whale (Balaenoptera physalus) Zwischensubstanz. The oral anatomy of the fin whale (Balaenoptera physalus) consists of several major structures crucial to its engulfment method of feeding, such as stiff keratinized baleen plates, a large flaccid tongue, and a prominent vomer. One under-documented part of this anatomy is the cream white Zwischensubstanz that holds the baleen plates to the rostrum at their dorsal base. The mechanical and structural properties of Zwischensubstanz play a key role in baleen plate dynamics and, on the grand scale, contribute to baleen whales' filtration efficiency and attainment of large body size. Compression and tensile tests on the Zwischensubstanz sampled from an 18 m fin whale showed that this material unexpectedly exhibits linear isotropic behaviour with Elastic Modulus of 2.56 ± 0.60 MPa and hysteresis of 0.44 ± 0.02 in compression despite apparent unidirectional growth. Acting similar to a soft rubber, the Zwischensubstanz absorbs and dissipates the enormous forces acting on baleen plates during engulfment feeding while maintaining spacing between the plates to maximize filtration efficiency. Microscopic analysis provided images of connective tissue papillae penetrating the base of the Zwischensubstanz and developing within it to emerge as fully formed, keratinized baleen plates. The plates develop from the papillae and a connective tissue sheet within the 5-7 cm deep Zwischensubstanz. The Zwischensubstanz provides a keratin matrix of concentrically oriented fibers around each papilla forming the hard baleen plates and frayed fringes used for filter feeding. During this formation, the Zwischensubstanz remains unchanged and appears to slough away to allow the baleen plate to grow unhindered. J. Morphol. 274:947-955, 2013. © 2013 Wiley Periodicals, Inc. 23881705 Immune-mediated Mechanisms in the Pathoprogression of Amyotrophic Lateral Sclerosis. Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with selective loss of upper and lower motor neurons. At sites of motor neuron injury, neuroinflammation is a prominent pathological finding and is characterized by microglial activation, astrogliosis, and infiltration of monocytes and T-cells. Both innate and adaptive immune responses actively influence disease progression in animal models and in ALS patients, and promote neuroprotection or neurotoxicity at different stages of disease. The early immune reaction to signals from injured motor neurons is to rescue and repair damaged tissue. As disease accelerates, a shift occurs from beneficial immune responses (involving M2 microglia and regulatory T-cells) to deleterious immune responses (involving M1 microglia and Th1 cells). In this review, we underscore the importance of immune-mediated mechanisms in the pathogenesis of ALS and discuss the alterations and distinct phenotypes of immune cells at the different stages of disease. The better we understand the dynamic changes that occur within the immune system over the course of disease, the better we will be able to develop effective therapeutic regimens in ALS. 23890225 Clinical presentation and outcome of dengue viral infection in live-related renal transplant recipients in Karachi, Pakistan. In Pakistan, dengue viral infection has become hyper-endemic. Renal transplantation is also expanding. We aimed to study dengue in renal transplant recipients (RTR). We conducted a study of RTR reported to be anti-dengue immunoglobulin-M antibody positive from January 2009 to December 2010 at our institution in Karachi and follow their clinical course and outcome. Median age was 28 years; 75 (73.7%) were males. Clinical presentation included fever in 82 (80.4%), gastrointestinal symptoms in 35 (34.3%), hemorrhagic complications in 9 (8.8%), and thrombocytopenia in 97 (95%), which was of >15 days duration in 24%. Fever was seen less frequently in patients on high-dose (>7.5 mg) steroids as compared with low-dose (≤7.5 mg) steroids. Forty-four patients (43%) had primary and 58 (56.8%) had secondary dengue infection. Dengue fever (DF) occurred in 90 (88%), and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) occurred in 12 (11.7%). DHF/DSS was seen in 3 (6.8%) of those with primary and in 9 (15.5%) of those with secondary infection (P < 0.22). In secondary infection, patients on cyclosporine-containing regimen had less severe disease, with DHF/DSS in 22% as opposed to DF in 59% (P < 0.04). Of 102 RTR, 68 (66.7%) had graft dysfunction, 5 of whom died. Of the remaining 63, in 54 patients (85.7%) creatinine returned to baseline by an average of 12.6 days. Of 102 patients, 95 (93%) recovered and 7 (6.9%) died, 6 of whom had bacteremia with sepsis and 1 had respiratory failure. None died due to dengue infection alone. In conclusion, in RTR without life-threatening co-morbidities, the clinical course of dengue infection is mild, with good recovery and preserved renal function. 23467007 H-bonding networks of the distal residues and water molecules in the active site of Thermobifida fusca hemoglobin. The ferric form of truncated hemoglobin II from Thermobifida fusca (Tf-trHb) and its triple mutant WG8F-YB10F-YCD1F at neutral and alkaline pH, and in the presence of CN(-) have been characterized by resonance Raman spectroscopy, electron paramagnetic resonance spectroscopy, and molecular dynamics simulations. Tf-trHb contains three polar residues in the distal site, namely TrpG8, TyrCD1 and TyrB10. Whereas TrpG8 can act as a potential hydrogen-bond donor, the tyrosines can act as donors or acceptors. Ligand binding in heme-containing proteins is determined by a number of factors, including the nature and conformation of the distal residues and their capability to stabilize the heme-bound ligand via hydrogen-bonding and electrostatic interactions. Since both the RR Fe-OH(-) and Fe-CN(-) frequencies are very sensitive to the distal environment, detailed information on structural variations has been obtained. The hydroxyl ligand binds only the WT protein giving rise to two different conformers. In form 1 the anion is stabilized by H-bonds with TrpG8, TyrCD1 and a water molecule, in turn H-bonded to TyrB10. In form 2, H-bonding with TyrCD1 is mediated by a water molecule. Unlike the OH(-) ligand, CN(-) binds both WT and the triple mutant giving rise to two forms with similar spectroscopic characteristics. The overall results clearly indicate that H-bonding interactions both with distal residues and water molecules are important structural determinants in the active site of Tf-trHb. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins. 23466420 Gimatecan and other camptothecin derivatives poison Leishmania DNA-topoisomerase IB leading to a strong leishmanicidal effect. The aim of this work is the in vitro and ex vivo assessment of the leishmanicidal activity of camptothecin and three analogues used in cancer therapy: topotecan (Hycantim(®)), gimatecan (ST1481) and the pro-drug irinotecan (Camptosar(®)) as well as its active metabolite SN-38 against Leishmania infantum. The activity of camptothecin and its derivatives was studied on extracellular L. infantum infrared-emitting promastigotes and on an ex vivo murine model of infected splenocytes with L. infantum fluorescent amastigotes. In situ formation of SDS/KCl precipitable DNA-protein complexes in Leishmania promastigotes indicated that these drugs are DNA topoisomerase IB poisons. The inhibitory potency of camptothecin derivatives on recombinant L. infantum topoisomerase IB was assessed in vitro showing that gimatecan is the most active compound preventing the relaxation of supercoiled DNA at submicromolar concentrations. Cleavage equilibrium assays in Leishmania topoisomerase IB show that gimatecan changes the equilibrium towards cleavage at much lower concentrations than the other camptothecin derivatives and that this effect persists over time. Gimatecan and camptothecin were the most powerful compounds preventing cell growth of free-living L. infantum promastigotes within the same concentration range. All these compounds killed L. infantum splenocyte-infecting amastigotes within the nanomolar range. The amastigote form showed higher sensitivity to topoisomerase IB poisons (with high therapeutic selectivity indexes) than free-living promastigotes. All the compounds assayed poisoned L. infantum DNA topoisomerase IB leading to a strong leishmanicidal effect. Camptothecin derivatives are suitable for reducing the parasitic burden of ex vivo infected splenocytes. The selectivity index of gimatecan makes it a promising drug against this neglected disease. 23708088 Comparative effectiveness of PEEK rods versus titanium alloy rods in lumbar fusion: a preliminary report. Posterior lumbar instruments made of titanium and its alloys could change the physiological distribution of load at the instrumented and adjacent segments, which is a main cause of implant failure, non-fusion and adjacent segment degeneration. Posterior lumbar rods made of polyetheretherketone (PEEK) which is a semirigid alternative to titanium and its alloys have been introduced in lumbar fusion. This prospective study compared the radiological and clinical outcomes of patients undergoing lumbar fusion with PEEK rods versus titanium alloy rods. Using transpedicular fixation and lumbar fusion, 21 patients were treated with titanium alloy rods (TI group), and 20 patients with PEEK rods (PEEK group). Radiological and clinical outcomes were evaluated, including the status of the implanted instruments, fusion rate, lumbar lordosis angle (LA), disc space height (DH), visual analog score (VAS) for lower back pain (VAS-BP) and leg pain (VAS-LP), Japanese Orthopedic Association scoring system (JOA score) and complications. Clinical VAS-BP, VAS-LP and JOA scores were significantly improved at 3 months, 6 months, and 1 year postoperatively as compared with preoperative scores in both groups (p < 0.05), with similar levels of improvement observed at the same time points postoperatively between the two groups. The overall fusion rate was 100 % at the 1-year follow-up for both groups. No significant differences in lumbar lordosis angle were found preoperatively, 1 week and 1 year postoperatively in both groups (p > 0.05). The postoperative increase of disc space height and loss of disc space height during the follow-up showed a similar extent of change between both groups (p > 0.05). PEEK rods offer a similar radiological and clinical efficacy as titanium alloy rods. PEEK rods, as a semirigid implant with unique characteristics, may be an effective alternative treatment for patients with degenerative lumbar disease in lumbar fusion. 23707669 Long term consumption of flaxseed enriched diet decreased ovarian cancer incidence and prostaglandin E2 in hens. Ovarian cancer is the most lethal gynecological malignancy. Prevention may be the best approach to reduce ovarian cancer. Flaxseed is the richest vegetable source of omega-3 fatty acids which may be effective in the prevention of ovarian cancer. Prostaglandin E2 (PGE2) is the most pro-inflammatory ecoisanoid and one of the downstream products of two isoforms of cyclooxygenase (COX) enzymes: COX-1 and COX-2. Our objective was to determine if long-term consumption of a flaxseed enriched diet decreased ovarian cancer severity and incidence in the laying hen and to investigate its potential correlation with the expression of COX enzymes and PGE2 concentration. White Leghorn hens were fed 10% flaxseed-enriched or standard diet for 4years. The severity and incidence of ovarian cancer were determined by gross pathology and histology. COX-1 and COX-2 protein and mRNA expression and PGE2 concentrations in ovaries were measured by Western blot, quantitative real-time PCR and ELISA, respectively. The results demonstrated that there was a reduction in ovarian cancer severity and incidence in hens fed flaxseed diet. In correlation with decreased ovarian cancer severity and incidence, concentration of PGE2 and expression of COX-2 were diminished in ovaries of hens fed flaxseed. Our findings suggest that the lower levels of COX-2 and PGE2 are the main contributing factors in the chemo-suppressive role of long-term flaxseed consumption in ovarian cancer in laying hens. These findings may provide the basis for clinical trials of dietary intervention targeting prostaglandin biosynthesis for the prevention and treatment of ovarian cancer. 23897559 Silencing of the Smad nuclear interacting protein 1 (SNIP1) by siRNA inhibits proliferation and induces apoptosis in pituitary adenoma cells. Smad nuclear interacting protein 1 (SNIP1) gene encodes a protein that contains a conservative C-terminal forkhead-associated domain and functions as a transcriptional coactivator to regulate cell proliferation and cancer progression. This study aimed to investigate the clinical and biological significance of SNIP1 expression in pituitary adenoma. We analyzed SNIP1 expressions in mouse fibroblast L929 cells and mouse pituitary adenoma AtT-20 cells by Western blotting. SNIP1 gene knockdown by small interfering RNA (siRNA) transfection was performed to evaluate SNIP1 function in pituitary adenoma cell lines. As expected, SNIP1 was found to be upregulated in pituitary adenoma cells. The mRNA and protein levels of SNIP1 were inhibited in AtT-20 cells transfected with siRNAs, which led to decreased proliferation, increased apoptosis, and cycle arrest of pituitary adenoma cells. Concomitantly, c-Myc and cyclin D1 protein levels were reduced. These findings may provide novel targets for the treatment of pituitary adenoma. 23931901 Endoscopic ophthalmic surgery of the anterior segment. We summarize the uses of anterior segment endoscopic techniques and the basic science and technology of endoscopic cyclophotocoagulation (ECP) as compared with transscleral cyclophotocoagulation. This is followed by an analysis of patient selection for ECP, a description of surgical techniques, and clinical results. In addition, the ophthalmic endoscope has other uses in anterior segment surgeries. We discuss the techniques for these endoscope-assisted surgeries. 23703540 Application and surgical technique of total knee arthroplasties: a systematic comparative analysis using worldwide registers. The aim of this study was to compare total knee arthroplasty (TKA) procedures between different countries with regard to epidemiological data and surgical technique by reference to the worldwide arthroplasty registers. A systematic search was carried out using the EFORT website to identify the relevant arthroplasty registers. We extracted data with respect to the number of implanted TKAs, patients' age distribution, procedure types, and revision rates. After identification of 28 national arthroplasty registers, 11 offered sufficient data regarding the above mentioned parameters and were therefore included in the final analysis. A large variation was found in the annual number of primary TKA implantations per inhabitant with a reported range from 30 to 199 per 100,000 (mean 106). The fixation method varied strongly between the different registers as well, e.g. 90 % of totally cemented TKAs in Sweden, England and Wales, Slovakia, and New Zealand versus 54 % cemented fixation in Australia. Another significant difference between included countries was observed with respect to the use of patellar resurfacing in TKA. Whilst the Danish knee arthroplasty register reports a percentage of 72 % using a patellar button in TKA the register from Norway reports only a minority of 2 %. The comparison of arthroplasty registers revealed large differences regarding the annual number of primary TKAs per inhabitant and primary TKA procedure types. These variations may be explained by several factors such as patient demographics (prevalence of osteoarthritis) and national conditions such as healthcare systems (insurance status), number or availability of performing surgeons, medical facilities and surgeon-dependent factors such as definition of indications, education, tradition and experience. 23827671 Lessons from lipids in the fight against influenza. Influenza is a leading cause of morbidity and mortality worldwide, with vaccines and antiviral drugs having limited efficacy thus far. Two recent studies in Cell apply lipidomics approaches to identify bioactive lipid mediators influencing host inflammation, viral replication, and disease progression. 23850388 Mesenchymal Stem Cell Therapy Improves Diabetic Cardiac Autonomic Neuropathy and Decreases the Inducibility of Ventricular Arrhythmias. Diabetic cardiac autonomic neuropathy (DCAN) may cause fatal ventricular arrhythmias and increase mortality in diabetics. Mesenchymal stem cells (MSCs) can secrete various cytokines and growth factors exerting neurosupportive effects. In this study, we investigated the effect of MSC on DCAN in diabetic rats. Forty rats were divided into normal control, diabetes mellitus (DM) control, MSC treatment (6×10(6) MSCs via direct myocardial injection) and MSC-conditioned medium group (100μl via direct myocardial injection). Immunohistochemistry was used to measure choline acetyltransferase (ChAT, a marker for parasympathetic nerves) and tyrosine hydroxylase (TH, a marker for sympathetic nerves) positive nerve fibres in the ventricular myocardium. Heart rate variability and programmed electrical stimulation was used to assess the inducibility of ventricular arrhythmias in the animals. Two weeks after MSC treatment, the density of ChAT- and TH-positive nerve fibres in MSCs and MSC-conditioned medium group was higher than in DM control group (P<0.05 or P<0.01). The ChAT/TH ratio in MSC group was higher than in DM control group (0.37±0.014 vs. 0.27±0.020, P<0.01). The standard deviation of normal-to-normal R-R intervals in MSCs (5.13±0.69) and MSC-conditioned medium group (4.30±0.56) was higher than in DM control group (3.45±0.60, P<0.05). The inducibility of VAs in the MSC group was lower than in the DM control group. MSC therapy may promote cardiac nerve sprouting and increase the ratio of parasympathetic to sympathetic nerve fibres. It may also suppress the inducibility of ventricular arrhythmias in the diabetic rats. 23714269 Do omega-3 polyunsaturated fatty acids reduce risk of sudden cardiac death and ventricular arrhythmias? A meta-analysis of randomized trials. Omega-3 polyunsaturated fatty acids (PUFA) have demonstrated to have antiarrhythmic properties. However, randomized studies have shown inconsistent results. We aimed to analyze the effect of omega-3 PUFA on preventing potentially fatal ventricular arrhythmias and sudden cardiac death. Randomized trials comparing omega-3 PUFA to placebo and reporting sudden cardiac death (SCD) or first implanted cardioverter-defibrillator (ICD) event for ventricular tachycardia or fibrillation were included in this study. A meta-analysis using a random effects model was performed and results were expressed in terms of Odds Ratio (OR) and 95% Confidence Interval (CI) after evaluating for interstudy heterogeneity using I(2). The reported data were extracted on the basis of the intention-to-treat principle. A total of 32,919 patients were included in nine trials; 16,465 patients received omega-3 PUFA and 16,454 received placebo. When comparing omega-3 PUFA to placebo, there was nonsignificant risk reduction of SCD or ventricular arrhythmias (OR = 0.82 [95% CI: 0.60-1.21], p = 0.21 I(2) = 49.7%). Dietary supplementation with omega-3 PUFA does not affect the risk of SCD or ventricular arrhythmias. 23615271 Long-term results of amniotic membrane transplantation for partial limbal deficiency. To evaluate the long-term efficacy of amniotic membrane transplantation as a treatment option in cases with partial limbal deficiency. Sixteen eyes of 14 patients with partial limbal deficiency underwent amniotic membrane patch (AMP) or amniotic membrane graft with patch (AMGP) following keratectomy for conjunctivalization of the cornea. The average follow-up period was 52 months. We evaluated the mean corneal epithelialization time, visual acuity improvement, complications, and recurrence rate after the surgery. Eleven eyes underwent AMP, and the remaining 5 eyes received AMGP. All eyes eventually attained corneal reepithelialization. The mean time to reepithelialization was not significantly different between the AMP group (9 days) and the AMGP group (27 days). At the final follow-up visit, improved Landolt visual acuity was observed in 6 of the 11 eyes in the AMP group and in 2 of the 5 eyes in the AMGP group. No intraoperative complications were observed. However, 6 eyes in the AMP group and 3 eyes in the AMGP group had a recurrence or developed a persistent epithelial defect after mean durations of 21.2 and 17.7 months, respectively. Both AMP and AMGP appear to be effective in attaining corneal reepithelialization, but neither could provide stable, clear corneal epithelialization in the long term. 23811500 Establishment of a Simple Lactobacillus plantarum Cell Consortium for Cellulase-Xylanase Synergistic Interactions. Lactobacillus plantarum is an attractive candidate for bioprocessing of lignocellulosic biomass due to its high metabolic variability, including its ability to ferment both pentoses and hexoses, as well as its high acid tolerance, a quality often utilized in industrial processes. This bacterium grows naturally on biomass; however, it lacks the inherent ability to deconstruct lignocellulosic substrates. As a first step toward engineering lignocellulose-converting lactobacilli, we have introduced genes coding for a GH6 cellulase and a GH11 xylanase from a highly active cellulolytic bacterium into L. plantarum. For this purpose, we employed the recently developed pSIP vectors for efficient secretion of heterologous proteins. Both enzymes were secreted by L. plantarum at levels estimated at 0.33 nM and 3.3 nM, for the cellulase and xylanase, respectively, in culture at an optical density at 600 nm (OD600) of 1. Transformed cells demonstrated the ability to degrade individually either cellulose or xylan and wheat straw. When mixed together to form a two-strain cell-based consortium secreting both cellulase and xylanase, they exhibited synergistic activity in the overall release of soluble sugar from wheat straw. This result paves the way toward metabolic harnessing of L. plantarum for novel biorefining applications, such as production of ethanol and polylactic acid directly from plant biomass. 23933955 Occurrence and fate of perfluorinated acids in two wastewater treatment plants in Shanghai, China. Perfluorinated acids (PFAs) have drawn much attention due to their environmental persistence, ubiquitous existence, and bioaccumulation potential. The discharge of wastewater effluent from municipal wastewater treatment plants (WWTPs) is a significant source of PFAs to the environment. In this study, wastewater and sludge samples were collected from two WWTPs in Shanghai, China, to investigate the contamination level and fate of PFAs in different stages of processing. The total concentrations of PFAs (∑PFAs) in influent from plants A and B were 2,452 and 292 ng L(-1), respectively. Perfluoropentanoic acid (1,520 ±â€‰80 ng L(-1) in plant A and 89.2 ±â€‰12.1 ng L(-1) in plant B) was the predominant PFA in influent waters, followed by perfluorooctanoic acid. The concentration of ∑PFAs ranged from 75.0 to 126.0 ng g(-1) dry weight in sludge samples from plant B, with perfluorooctanesulfonic acid as the predominant contaminant. The concentrations and fate of PFAs in different WWTPs vary. The ∑PFAs entering plant A decreased significantly in the final effluent of activated sludge process, while that in plant B increased significantly in the final effluent of sequencing batch reactor system. The concentration changes could be due to the sorption onto sludge, or the degradation of PFAs precursors. 23651530 Hybrid PET/MR Imaging of the Heart: Feasibility and Initial Results. Purpose: To assess the feasibility of hybrid imaging of the heart with fluorine 18 fluorodeoxyglucose (FDG) on an integrated 3-T positron emission tomography (PET)/magnetic resonance (MR) imaging system. Materials and Methods: The present study was approved by the local institutional review board. Written informed consent was obtained from all patients before imaging. Twenty consecutive patients with myocardial infarction (n = 20) underwent cardiac PET/MR imaging examination. Ten patients underwent additional cardiac PET/computed tomography (CT) before PET/MR. Two-dimensional half-Fourier acquisition single-shot turbo spin-echo sequences, balanced steady-state free precession cine sequences, two-dimensional turbo inversion-recovery magnitude T2-weighted sequences, and late gadolinium-enhanced (LGE) segmented two-dimensional inversion-recovery turbo fast low-angle shot sequences were performed. According to the 17-segment model, PET tracer uptake, wall motion, and late gadolinium enhancement were visually assessed for each segment on a binary scale, and categorical intermethod agreement was calculated by using the Cohen κ. The maximum standardized uptake value was measured in corresponding myocardial locations on PET/CT and PET/MR images. Results: Agreement was substantial over all patients and segments between PET and LGE images (κ = 0.76) and between PET and cine images (κ = 0.78). In 306 segments, 97 (32%) were rated as infarcted on PET images, compared with 93 (30%) rated as infarcted on LGE images and with 90 (29%) rated as infarcted on cine images. In a subgroup of patients (n = 10) with an additional PET/CT scan, no significant difference in myocardial tracer uptake between PET/CT and PET/MR images was found (paired t test, P = .95). Conclusion: Cardiac PET/MR imaging with FDG is feasible and may add complementary information in patients with ischemic heart disease. © RSNA, 2013 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13130231/-/DC1. 23922209 YOGA FOR DEPRESSION: A SYSTEMATIC REVIEW AND META-ANALYSIS. Mind-body medical interventions are commonly used to cope with depression and yoga is one of the most commonly used mind-body interventions. The aim of this review was to systematically assess and meta-analyze the effectiveness of yoga for depression. Medline/PubMed, Scopus, the Cochrane Library, PsycINFO, and IndMED were searched through January 2013. Randomized controlled trials (RCTs) of yoga for patients with depressive disorders and individuals with elevated levels of depression were included. Main outcomes were severity of depression and remission rates, secondary outcomes were anxiety, quality of life, and safety. Twelve RCTs with 619 participants were included. Three RCTs had low risk of bias. Regarding severity of depression, there was moderate evidence for short-term effects of yoga compared to usual care (standardized mean difference (SMD) = -0.69; 95% confidence interval (CI) -0.99, -0.39; P < .001), and limited evidence compared to relaxation (SMD = -0.62; 95%CI -1.03, -0.22; P = .003), and aerobic exercise (SMD = -0.59; 95% CI -0.99, -0.18; P = .004). Limited evidence was found for short-term effects of yoga on anxiety compared to relaxation (SMD = -0.79; 95% CI -1.3, -0.26; P = .004). Subgroup analyses revealed evidence for effects in patients with depressive disorders and in individuals with elevated levels of depression. Due to the paucity and heterogeneity of the RCTs, no meta-analyses on long-term effects were possible. No RCT reported safety data. Despite methodological drawbacks of the included studies, yoga could be considered an ancillary treatment option for patients with depressive disorders and individuals with elevated levels of depression. 23921627 Effectiveness of Fundoplication at the Time of Gastrostomy in Infants With Neurological Impairment. IMPORTANCE Gastrostomy tube (GT) placement is the most common gastrointestinal operation performed on neonates. Concomitant fundoplication is used variably to prevent complications of gastroesophageal reflux, but its effectiveness is unproven. OBJECTIVE To compare the effect of fundoplication at the time of GT placement vs GT placement alone on subsequent reflux-related hospitalizations in infants with neurological impairment. DESIGN, SETTING, AND PARTICIPANTS Retrospective, observational cohort study, defined by birth between January 1, 2005, and December 31, 2010, at 42 children's hospitals in the United States, with a 1-year follow-up period among 4163 infants with neurological impairment who underwent GT placement with or without fundoplication during their neonatal intensive care unit stay. INTERVENTION Fundoplication and GT placement vs GT placement alone. MAIN OUTCOMES AND MEASURES One-year postprocedural reflux-related hospitalization rates, defined as hospitalization for asthma, mechanical ventilation, gastroesophageal reflux disease, and aspiration or other types of pneumonia. Propensity to undergo concomitant fundoplication was modeled using demographics, prior procedures (tracheostomy and mechanical ventilation), and prior diagnoses (eg, pneumonia, gastroesophageal reflux disease, and other comorbidities). RESULTS Overall, 4163 of 42 796 infants (9.7%) with neurological impairment admitted to the neonatal intensive care unit underwent GT placement alone or with fundoplication. Infants who concomitantly underwent fundoplication had more reflux-related hospitalizations during the first year than those who underwent GT placement alone (mean, 1.02; 95% CI, 0.93-1.10 vs mean, 0.92; 95% CI, 0.91-1.00). Of 1404 infants who underwent fundoplication, 1027 (73.1%) were matched based on propensity scores. The mean difference of the matched cohort for any reflux-related hospitalizations was -0.05 (95% CI, -0.20 to 0.15) per year. CONCLUSIONS AND RELEVANCE Infants with neurological impairment who underwent fundoplication at the time of GT placement did not have a reduced rate of reflux-related hospitalizations during the first year compared with those who underwent GT placement alone, despite propensity score matching. This may be due to a lack of effectiveness of fundoplication in preventing these complications or due to differences in the patient groups that were inadequately accounted for in the matching. 23942707 Alteration of Digestive Tract Microbiome in Neo-natal Holstein Bull Calves by Bacitracin Methylene Diasalicylate Treatment and Scours. The effects of bacitracin methylene disalicylate (BMD) and scours on the fecal microbiome, animal performance and health were studied in Holstein bull calves. Holstein bull calves (n = 150) were obtained from a single source at 12 to 24 h of age. Bull calves were randomly assigned to 1 of 2 treatments including CON (no BMD, n = 75 calves) and BMD (n = 75 calves). Starting 3 d after arrival, BMD was added into milk replacer (0.5 g/feeding; twice daily) and fed BMD for 10 consecutive d. No differences (P > 0.10) were observed in ADG for d 0 to 28 and d 0 to 56, DMI for d 0 to 28, d 29 to 56, and d 0 to 56, G:F for d 0 to 28, d 29 to 56, and d 0 to 56; ADG for d 29 to 56 tended to increase (P < 0.10) for BMD-treated calves compared with controls. Fecal samples were collected from 15 scouring calves and 10 cohorts (non-scouring calves received on the same day and administered the same treatment as the scouring calves). Animal morbidity and fecal score did not vary between the 2 treatments. Mortality was not influenced by the treatments in the BMD administration period or throughout the experiment. Fecal samples were subjected to pyrotagged 454 FLX pyrosequencing of 16srRNA gene amplicon to examine compositional dynamics of fecal microbes. Escherichia, Enterococcus, and Shigella had greater (P < 0.05) populations in the BMD group while Dorea, Roseburia, Faecalibacterium, Papillibacter, Collinsella, Eubacterium, Peptostreptococcus, and Prevotella were decreased (P < 0.05) by BMD treatment. Genus populations were also compared between scouring and nonscouring calves. Streptococcus was the only genus which had notable increase (P < 0.05) in fecal samples from scouring calves, while populations of Bacteroides, Roseburia, and Eubacterium were markedly (P < 0.05) greater in non-scouring calves. These results show that BMD has the ability to alter the composition of the fecal microbiome but failed to improve performance in Holstein bull calves. Discrepancy of microorganism profiles between scouring and nonscouring calves might be associated with the occurrence of scours and bacterial genera identified might be potential target of treating diarrhea. 23852268 Changes in Specialists' Perspectives on Cancer Genetic Testing, Prophylactic Surgery and Insurance Discrimination: Then and Now. We surveyed cancer genetics specialists in 1998 to learn what they would do if at 50 % risk to carry a BRCA or Lynch syndrome mutation. We chose to repeat our study 14 years later, to examine how perspectives have changed with the extensive data now available. In July 2012 we surveyed the National Society of Genetic Counselors (NSGC) Cancer Special Interest Group via an internet based survey. We found statistically significant increases in the percentage of specialists who: would undergo BRCA testing (p = 0.0006), opt for prophylactic bilateral mastectomy (p =0.0001), opt for prophylactic removal of their uterus and ovaries for Lynch syndrome (p =0.0057 and P = 0.0090, respectively), and bill testing to insurance (p >0.0001). There were also statistically significant decreases in the percentage of participants who would have their colon removed for Lynch syndrome (p = 0.0002) and use an alias when pursuing testing (p > 0.0001). Over the past 14 years there has been a major change in perspective amongst cancer genetic specialists regarding genetic testing, prophylactic surgery and insurance discrimination. 23780889 Combined Alloreactive CTL Cellular Therapy with Prodrug Activator Gene Therapy in a Model of Breast Cancer Metastatic to the Brain. Individual or combined strategies of cellular therapy with alloreactive CTLs (alloCTL) and gene therapy using retroviral replicating vectors (RRV) encoding a suicide prodrug activating gene were explored for the treatment of breast tumors metastatic to the brain. AlloCTL, sensitized to the HLA of MDA-MB-231 breast cancer cells, were examined in vitro for antitumor functionality toward breast cancer targets. RRV encoding the yeast cytosine deaminase (CD) gene was tested in vivo for virus spread, ability to infect, and kill breast cancer targets when exposed to 5-fluorocytosine (5-FC). Individual and combination treatments were tested in subcutaneous and intracranial xenograft models with 231BR, a brain tropic variant. AlloCTL preparations were cytotoxic, proliferated, and produced IFN-γ when coincubated with target cells displaying relevant HLA. In vivo, intratumorally placed alloCTL trafficked through one established intracranial 231BR focus to another in contralateral brain and induced tumor cell apoptosis. RRV-CD efficiently spread in vivo, infected 231BR and induced their apoptosis upon 5-FC exposure. Subcutaneous tumor volumes were significantly reduced in alloCTL and/or gene therapy-treated groups compared to control groups. Mice with established intracranial 231BR tumors treated with combined alloCTL and RRV-CD had a median survival of 97.5 days compared with single modalities (50-83 days); all experimental treatment groups survived significantly longer than sham-treated groups (median survivals 31.5 or 40 days) and exhibited good safety/toxicity profiles. The results indicate combining cellular and suicide gene therapies is a viable strategy for the treatment of established breast tumors in the brain. Clin Cancer Res; 19(15); 4137-48. ©2013 AACR. 23915541 Effect of predictor traits on accuracy of genomic breeding values for feed intake based on a limited cow reference population. The genomic breeding value accuracy of scarcely recorded traits is low because of the limited number of phenotypic observations. One solution to increase the breeding value accuracy is to use predictor traits. This study investigated the impact of recording additional phenotypic observations for predictor traits on reference and evaluated animals on the genomic breeding value accuracy for a scarcely recorded trait. The scarcely recorded trait was dry matter intake (DMI, n = 869) and the predictor traits were fat-protein-corrected milk (FPCM, n = 1520) and live weight (LW, n = 1309). All phenotyped animals were genotyped and originated from research farms in Ireland, the United Kingdom and the Netherlands. Multi-trait REML was used to simultaneously estimate variance components and breeding values for DMI using available predictors. In addition, analyses using only pedigree relationships were performed. Breeding value accuracy was assessed through cross-validation (CV) and prediction error variance (PEV). CV groups (n = 7) were defined by splitting animals across genetic lines and management groups within country. With no additional traits recorded for the evaluated animals, both CV- and PEV-based accuracies for DMI were substantially higher for genomic than for pedigree analyses (CV: max. 0.26 for pedigree and 0.33 for genomic analyses; PEV: max. 0.45 and 0.52, respectively). With additional traits available, the differences between pedigree and genomic accuracies diminished. With additional recording for FPCM, pedigree accuracies increased from 0.26 to 0.47 for CV and from 0.45 to 0.48 for PEV. Genomic accuracies increased from 0.33 to 0.50 for CV and from 0.52 to 0.53 for PEV. With additional recording for LW instead of FPCM, pedigree accuracies increased to 0.54 for CV and to 0.61 for PEV. Genomic accuracies increased to 0.57 for CV and to 0.60 for PEV. With both FPCM and LW available for evaluated animals, accuracy was highest (0.62 for CV and 0.61 for PEV in pedigree, and 0.63 for CV and 0.61 for PEV in genomic analyses). Recording predictor traits for only the reference population did not increase DMI breeding value accuracy. Recording predictor traits for both reference and evaluated animals significantly increased DMI breeding value accuracy and removed the bias observed when only reference animals had records. The benefit of using genomic instead of pedigree relationships was reduced when more predictor traits were used. Using predictor traits may be an inexpensive way to significantly increase the accuracy and remove the bias of (genomic) breeding values of scarcely recorded traits such as feed intake. 23954313 Impaired Emotional Learning and Involvement of the Corticotropin-Releasing Factor Signaling System in Patients with Irritable Bowel Syndrome. & Aims: Alterations in central corticotropin-releasing factor (CRF) signaling pathways have been implicated in the pathophysiology of anxiety disorders and irritable bowel syndrome (IBS). We aimed to characterize the effects of the CRF receptor 1 (CRF-R1) antagonist, GW876008, on brain and skin conductance responses (SCR) during acquisition and extinction of conditioned fear to the threat of abdominal pain in subjects with IBS and healthy individuals (controls). We performed a single center, randomized, double-blind, 3-period crossover study of 11 women with IBS (35.50 ± 12.48 y old) and 15 healthy women (controls) given a single oral dose (20 or 200 mg) of the CRF-R1 antagonist or placebo. Blood-oxygen-level-dependent (BOLD) responses were analyzed using functional magnetic resonance imaging in a tertiary care setting. Controls had greater SCR during acquisition than extinction, validating the fear conditioning paradigm. In contrast, during extinction, the women with IBS had greater SCR than controls-an effect normalized by administration of a CRF-R1 antagonist. Although the antagonist significantly reduced activity in the thalamus in patients with IBS and controls during acquisition, the drug produced greater suppression of BOLD activity in a wide range of brain regions in IBS patients during extinction, including the medial prefrontal cortex, pons, hippocampus, and anterior insula. Although CRF signaling via CRF-R1 is involved in fear acquisition and extinction learning related to expected abdominal pain in patients with IBS and controls, this system appears to be upregulated in patients with IBS. This upregulation might contribute to the previously reported abnormal brain responses to expected abdominal pain. 23932397 Directed evolution of thermotolerant malic enzyme for improved malate production. The directed evolution of the thermotolerant NADP(H)-dependent malic enzyme from Thermococcus kodakarensis was conducted to alter the cofactor preference of the enzyme from NADP(H) to NAD(H). The construction and screening of two generations of mutant libraries led to the isolation of a triple mutant that exhibited 6-fold higher kcat/Km with NAD(+) than the wild type. We serendipitously found that, in addition to the change in the cofactor preference, the reaction specificity of the mutant enzyme was altered. The reductive carboxylation of pyruvate to malate catalyzed by the wild type enzyme is accompanied by [Formula: see text] -independent reduction of pyruvate and gives lactate as a byproduct. The reaction specificity of the triple mutant was significantly shifted to malate production and the mutant gave a less amount of the byproduct than the wild type. When the triple mutant enzyme was used as a catalyst for pyruvate carboxylation with NADH, the enzyme gave 1.2 times higher concentration of malate than the wild type with NADPH. Single-point mutation analysis revealed that the substitution of Arg221 with Gly is responsible for the shift in reaction specificity. This finding may shed light on the catalytic mechanisms of malic enzymes and other related CO2- and/or [Formula: see text] -fixing enzymes. 23953272 Early origin of viviparity and multiple reversions to oviparity in squamate reptiles. Viviparity has putatively evolved 115 times in squamates (lizards and snakes), out of only ~ 140 origins in vertebrates, and is apparently related to colder climates and other factors such as body size. Viviparity apparently evolves from oviparity via egg-retention, and such taxa may thus still have the machinery to produce thick-shelled eggs. Parity mode is also associated with variable diversification rates in some groups. We reconstruct ancestral parity modes accounting for state-dependent diversification in a large-scale phylogenetic analysis, and find strong support for an early origin of viviparity at the base of Squamata, and a complex pattern of subsequent transitions. Viviparous lineages have higher rates of speciation and extinction, and greater species turnover through time. Viviparity is associated with lower environmental and body temperatures in lizards and amphisbaenians, but not female mass. These results suggest that parity mode is a labile trait that shifts frequently in response to ecological conditions. 23685710 Real-time sonoelastography of Achilles tendon in patients with ankylosing spondylitis. Real-time sonoelastography (SE) is a new ultrasound-based imaging technique that provides information on tissue elasticity and stiffness. We determined the efficacy of SE for assessing Achilles tendon abnormalities in patients with ankylosing spondylitis (AS). Forty-one consecutive AS patients and 32 asymptomatic healthy subjects were enrolled. Achillodynia was scored on a 0- to 100-mm visual analog scale. A high-resolution ultrasound machine equipped with an elastography-compatible linear probe was used to perform bilateral B-mode ultrasound, Doppler ultrasound, and SE examinations of Achilles tendons. Tendons were divided into proximal, middle, and distal segments. B-mode examinations included tendon thicknesses, echotextures, and enthesopathic findings. SE using color-coded images was performed in the same areas. Normal consistent tendon structures were coded as blue or green, and moderately (yellow) or severely (red) softened areas were considered pathological. The distal third of the Achilles tendons was the most commonly affected part in the AS patients compared with healthy subjects (p = 0.001), whose middle third was more commonly affected. Achillodynia intensity tended to be higher in patients with pathological B-mode or SE examination findings (p = 0.09 and p = 0.07 respectively). Softening detected by SE in the distal third was associated with enthesopathy findings such as calcaneal bone erosions (Fisher's X (2), p = 0.07) and tendinous enlargement (Fisher's X (2), p = 0.001). B-mode and SE findings had moderate to good correlation in the assessment of Achilles tendon abnormalities. Sonoelastography may be useful for the evaluation of tendon abnormalities in patients with AS; in addition; it may be useful for the evaluation of other inflammatory rheumatic conditions. 23913681 Uric acid secretion from adipose tissue and its increase in obesity. Obesity is often accompanied by hyperuricemia. However, purine metabolism in various tissues, especially on uric acid production, has not been fully elucidated. Here we report using mouse models that adipose tissue could produce and secrete uric acid through xanthine oxidoreductase (XOR), and the production was enhanced in obesity. Plasma uric acid was elevated in obese mice and attenuated by administration of XOR inhibitor, febuxostat. Adipose tissue was one of major organs which had abundant expressions and activities of XOR, and adipose tissues in obese mice had higher XOR activities than those of control mice. 3T3-L1 and mouse primary mature adipocytes produced and secreted uric acid into culture media. The secretion was inhibited by febuxostat in a dose-dependent manner or gene knockdown of XOR. Surgical ischemia in adipose tissue increased local uric acid production and secretion via XOR, with subsequent increase in circulating uric acid levels. Uric acid secretion from whole adipose tissue was increased in obese mice, and uric acid secretion from 3T3-L1 adipocytes was increased under hypoxia. Our results suggest that purine catabolism in adipose tissue could be enhanced in obesity. 23239137 A re-evaluation of fifteen years of European risk assessment using effect models. Ecological risk assessments of chemicals can be informed by a suite of effect models, including population and food web models. In the risk assessments conducted under EU regulation 793/93/EC, however, applications of such effect models are extremely scarce and toxicity-extrapolation approaches are often used instead. The objective of the present study was to re-evaluate these risk assessments using two types of effect models: species sensitivity distributions (SSDs, non-mechanistic), and food web models (mechanistic). Species sensitivity distributions significantly fitted the available toxicity data for up to 35% of the chemicals, depending on the trophic levels included and the amount of data available. Median hazardous concentrations for 5% of the species (HC5-50) estimated by the SSDs were less accurate predictors of measured community-level no observed effect concentration than food web model-derived HC5-50s, albeit data were available for seven chemicals only. For datasets with more than 10 data points, the 90% confidence interval of the estimated HC5s was narrower for the food web modeling approach than for the SSD approach. The HC5-50s predicted by the two approaches were two to five times (metals) and 10 to 100 times (organic chemicals) higher than the predicted no effect concentrations (PNECs) for the aquatic environment listed in the risk assessment reports. This suggests that the derived PNECs are protective for aquatic ecosystems. 23920270 Vitamin D therapy and related metabolomics: Is the calciferol dose and form the only requirements for successful clinical therapeutics? A nutraceutical that has exploded onto the prescription pad in recent years is the fat soluble vitamin, vitamin D. This is due to an increasing medical interest in the utility of the vitamin in the treatment and prevention of an array of diseases and ailments. Despite the continued debate over the correct dose, form and serum levels, many clinicians fail to achieve intended therapeutic responses with their patients and deficiencies still exist. This may be due to medical professionals being less aware of the multitude of factors that can influence treatment when dosing a product. In this paper we explore the magnitude of interactions that exist between the host physiology and the vitamin and cite such points as a reason for confounding treatment end points. Aspects that are proposed to influence treatment success more critically than dose and molecular form prescribed are: organ pathology, intracellular states, the endocrine system, concomitant products, genetics, lifestyle, quality of product, and modern delivery systems. 23666092 Automatic detection, localization, and volume estimation of ischemic infarcts in noncontrast computed tomographic scans: method and preliminary results. Sensitivity of noncontrast computed tomography (NCCT) in detecting hyperacute (<8 hours) and acute (<24 hours) cerebral infarction is low. We propose an automatic method to detect and localize ischemic infarct and to assess its volume from a single NCCT scan. The method automatically determines attenuation value ranges of cerebrospinal fluid and white and gray matter, separates the brain scan into the left and right hemispheres, and by analyzing hemisphere attenuation value distributions using percentile difference ratios, it detects, localizes, and quantifies the infarct without its segmentation. The method performance was evaluated on 576 patients with clinically confirmed stroke through NCCT scans acquired at 4 centers to measure how it matched with that of experts in detection, localization, and assessment of infarct volume. The time from the onset of symptoms ranged from 1.5 to 72 hours for 450 scans and more than 72 hours for 82 scans, most with pathologic findings in addition to cerebral infarction; the time was unavailable for 44 scans. In addition, the method was compared with the novice's (with 52 scans) and experienced readers' infarct detection (with 21 × 2 scans) in early ischemia detection (with the time from the onset of symptoms ranging from 1.5 to 7 hours). The method matches 100% the expert's infarct detection when chronic infarcts, leukoaraiosis cases, and infarct volumes less than 2 cm (determined by detection accuracy simulation) are excluded from the analysis. For all cases excluding infarct volumes less than 2 cm, the method detection accuracy is 95.7%. Overall, the method detection accuracy is 83.2%. The early method detection accuracy (≤3 hours) is 78.4%. The novice detection accuracy is 27.8% (≤3 hours), 37.5% (3 < to ≤ 8 hours), and 77.8% (>8 hours), whereas the expert detection accuracy for these cases is 100%. Moreover, the method detected all 21 early infarcts, of which 15 were missed by the stroke experts and 14 of 15 were missed by a general radiologist. The method performs automatic analysis in approximately 7 seconds. The results demonstrate potential benefits of our method for enhancing expert's performance because it quickly localizes the infarct and detects cases missed by experts, and it is to be considered as an aid in the emergency department because it substantially outperforms novice readers (100% vs 27%) in infarct detection on NCCT. 23308013 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced hypertension: The beneficial effects of melatonin. Objective: The purpose of the present study was to evaluate the effects of melatonin on biochemical and cardiovascular changes resulting from exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a polychlorinated dibenzo-para-dioxin.Methods: A total of 24 Sprague-Dawley rats were divided equally into the following four groups: (1) control group was administered with 0.5 mL corn oil by gavage and 0.5 cc vehicle of melatonin (proportionally nine parts physiological serum + one part ethyl alcohol) intraperitoneally for 4 weeks, (2) the melatonin group was given 5 mg/kg/day melatonin intraperitoneally for 4 weeks, (3) the TCDD group was given 500 ng/kg/day TCDD by gavage for 4 weeks and (4) the TCDD + melatonin group was given TCDD (500 ng/kg/day) by gavage and melatonin (5 mg/kg/day) intraperitoneally simultaneously for 4 weeks. Systolic blood pressure was evaluated by the tail-cuff method. Vascular responses to phenylephrine and acetylcholine were evaluated in the isolated thoracic aortas.Results: TCDD not only augmented the systolic blood pressure but also increased the contractile responses to phenylephrine in aorta. Melatonin reversed the blood pressure augmented by TCDD and decreased the contractile responses to phenylephrine in aorta. TCDD induced an increase in the malondialdehyde levels in kidney tissue and melatonin did not change it. Therefore, TCDD caused a decrease in glutathione levels in kidney tissues and melatonin reversed it.Conclusion: Present data demonstrated that TCDD may lead to an increase in blood pressure via increased renal oxidative stress and vascular reactivity. However, melatonin might ameliorate the blood pressure disturbed by TCDD in part by decreasing the oxidant activity induced by TCDD. 23688155 Microporous "honeycomb" films support enhanced bone formation in vitro. Substrate topography influences cell adhesion, proliferation, and differentiation. In this study, poly (ɛ-caprolactone) (PCL) films with a well-defined honeycomb structure of porosity 3-4, 5-6, 10-11, or 15-16 μm were contrasted with flat surfaces for their ability to support primary rat osteoblast adhesion and mineralized extracellular matrix deposition in vitro. Immunofluorescent visualization of vinculin and rhodamine phalloidin binding of actin were used to investigate cell adhesion and morphology. Localization of the alkaline phosphatase activity and Alizarin Red staining were performed to assess the osteoblast activity and deposition of a mineralized matrix. Scanning electron microscopy together with energy-dispersive X-ray spectroscopy was used to provide morphological analysis of cell-film interactions, the deposited matrix, and elemental analysis of the mineralized structures. After 24 h of culture, there were no differences in cell numbers on porous or flat PCL surfaces, but there were changes in cell morphology. Osteoblasts on honeycomb films had a smaller surface area and were less circular than cells on flat PCL. Analysis of cells cultured for 35 days under osteogenic conditions revealed that osteoblasts on all substrates acquired alkaline phosphatase activity, but levels of mineralized matrix were increased on films with 3-4-μm pore sizes. The bone-like matrix with a Ca:P ratio of 1.69±0.08 could be identified in larger areas often aligning with substrate topography. In addition, smaller spherical deposits (0.5-1 μm in diameter) with a Ca:P ratio of 1.3±0.08 were observed at the surface and particularly within the pores of the PCL film. Localization of vinculin showed significant decreases in the number of focal adhesion structures per unit cell area on 5-6, 10-11, and 15-16-μm surfaces compared to flat PCL, while focal complexes with a smaller area (0-2 μm(2)) were more abundant on 3-4 and 5-6-μm surfaces. Observation of cell interaction with these surfaces identified cytoplasmic protrusions that extended into and sealed the pores of these PCL films creating an extracellular space in which, the conditions could influence the deposition and formation of the mineralized matrix. 23777199 Regiocontrolled synthesis of polysubstituted pyrroles starting from terminal alkynes, sulfonyl azides, and allenes. 1-Sulfonyl-1,2,3-triazoles, readily prepared from terminal alkynes and sulfonyl azides, react with allenes in the presence of a nickel(0) catalyst to produce the corresponding isopyrroles. The initially produced isopyrroles are further converted to a wide range of polysubstituted pyrroles through double bond transposition and Alder-ene reactions. 23899099 High Throughput Ultralong (20 cm) Nanowire Fabrication Using a Wafer-Scale Nanograting Template. Nanowires are being actively explored as promising nanostructured materials for high performance flexible electronics, biochemical sensors, photonic applications, solar cells, and secondary batteries. In particular, ultralong (centimeter-long) nanowires are highly attractive from the perspective of electronic performance, device throughput (or productivity), and the possibility of novel applications. However, most previous works on ultralong nanowires have issues related to limited length, productivity, difficult alignment, and deploying onto the planar substrate complying with well-matured device fabrication technologies. Here, we demonstrate a highly ordered ultralong (up to 20 cm) nanowire array, with a diameter of 50 nm (aspect ratio of up to 4 000 000:1), in an unprecedented large (8 in.) scale (2 000 000 strands on a wafer). We first devised a perfectly connected ultralong nanograting master template on the whole area of an 8 in. substrate using a top-down approach, with a density equivalent to that achieved with e-beam lithography (100 nm). Using this large-area, ultralong, high-density nanograting template, we developed a fast and effective method for fabricating up to 20 cm long nanowire arrays on a plastic substrate, composed of metal, dielectric, oxide, and ferroelectric materials. As a suggestion of practical application, a prototype of a large-area aluminum wire grid polarizer was demonstrated. 23627642 Heart rate variability as a measure of autonomic dysfunction in men with advanced cancer. Autonomic dysfunction is common in patients with cancer and may have considerable negative effects on quality of life and mortality. This study retrospectively compared heart rate variability measured by the standard deviation of normal-to-normal intervals (SDNN) to Ewing test score, a composite score from a battery of five defined autonomic tests, in detection of autonomic dysfunction in 47 men with advanced cancer. The Ewing test score has been validated for diagnosis of autonomic dysfunction but is time-consuming and requires considerable patient co-operation; we hypothesised that SDNN, a much simpler test, is a useful alternative. The patients were categorised into three groups according to Ewing score: ≤2 (mild or no autonomic dysfunction), 2.5-3 (moderate) and ≥3.5 (severe). The SDNN (mean ± SD) for the three groups were 57.1 ± 26.9 ms 62.3 ± 22.4 ms and 37.7 ± 20.3 ms respectively. A significant negative correlation was found between Ewing score and SDNN (r = -0.40, P = 0.005). A SDNN of ≤40 ms had 63% sensitivity and 75% specificity in the diagnosis of severe autonomic dysfunction (i.e. Ewing score ≥3.5). The positive predictive value of SDNN ≤40 ms in predicting moderate/severe autonomic dysfunction was 89%. 23734933 Dermatological side-effects of telaprevir-based triple therapy for chronic hepatitis C in phase III trials in Japan. Telaprevir-based triple therapy is highly effective for chronic hepatitis C. However, concern has been expressed over the high frequency and severity of its dermatological side-effects compared with those associated with peginterferon (PEG-IFN) and ribavirin (RBV) therapy. Thus, here, we evaluated the dermatological adverse reactions of telaprevir-based triple therapy in Japanese multicenter phase III clinical trials in an attempt to characterize the dermatological side-effects and establish appropriate management plans. In these trials, 126 treatment-naïve patients and 141 treatment-failure patients were administrated telaprevir, PEG-IFN-α-2b and RBV for 12 weeks followed by PEG-IFN-α-2b and RBV for another 12 weeks (T12/PR24 group), and 63 treatment-naïve patients were administrated PEG-IFN-α-2b and RBV for 48 weeks (PR48 group). Dermatological adverse reactions developed in over 80% patients in both groups, and most of them were grade 1 or 2. In the T12/PR24 group, there were more grade 2 or grade 3 events, and the time to onset was earlier than that in the PR48 group. Most reactions could be managed with topical corticosteroids and oral antihistamines, and the rates of discontinuation due to dermatological reactions were not high even in the T12/PR24 group. In the T12/PR24 group, however, two cases of Stevens-Johnson syndrome and one case of drug rash with eosinophilia and systemic symptoms, which corresponds to drug-induced hypersensitivity syndrome in Japan, were reported. For appropriate treatments of individual dermatological adverse reactions, the judgment of discontinuation of antiviral drugs and treatment based on the severity are extremely important in this triple therapy. 23540418 Watching object related movements modulates mirror-like activity in parietal brain regions. We studied the activation of cortical motor and parietal areas during the observation of object related grasping movements. By manipulating the type of an object (realistic versus abstract) and the type of grasping (correct versus incorrect), we addressed the question how observing such object related movements influences cortical rhythmicity, especially the mu-rhythm, in the context of an "extended" human mirror neuron system (MNS). Multichannel electroencephalogram (EEG) was recorded during the observation of different object-related grasping actions in twenty healthy subjects. Different movies were presented, showing sequences of correct or incorrect hand grasping actions related to an abstract or realistic (daily life) object. Event-related de/synchronization (ERD/ERS) analyses revealed a larger ERD in the upper alpha (10-12Hz), beta (16-20Hz) and gamma (36-40Hz) frequency bands over parietal brain regions depending on the type of grasping. The type of object only influenced ERD patterns in the gamma band range (36-40Hz) at parietal sites suggesting a strong relation of gamma band activity and cortical object representation. Abstract and realistic objects produced lower beta band synchronization at central sites only, whereas depending on the type of grasping an ERS in the upper alpha band (10-12Hz) was observed. Depending on the type of the grasped object and the type of grasping stronger parietal cortical activation occurred during movement observation. Discussing the results in terms of an "extended" human mirror neuron system (MNS), it could be concluded that beside sensorimotor areas a stronger involvement of parietal brain regions was found depending on the type of object and grasping movement observed. 22847800 Pancreatic carcinoma-specific immunotherapy using synthesised alpha-galactosyl epitope-activated immune responders: findings from a pilot study. Dendritic cell (DC)-based and cytokine-induced killer cell (CIK)-based therapy can induce specific antitumor T-cell responses. This clinical pilot study examined the safety, the feasibility, and the outcome of tumor-specific immunotherapy for patients with advanced pancreatic adenocarcinoma. Alpha-Gal epitopes were synthesised on pancreatic carcinoma cell membranes with α1,3-galactosyltransferase in vitro. Subsequently, the addition of natural human anti-Gal IgG to the processed membranes resulted in opsonization and effective phagocytosis by DCs, which were co-cultured with newly differentiated CIKs from bone marrow stem cells to generate tumor-specific immune responders ex vivo. Fourteen patients with inoperable stage III/IV pancreatic adenocarcinoma were enrolled in the study; the treatment procedure consisted of injections of DCs and CIKs. Clinical observation showed that the procedure was safe and lacked serious side effects. Tests showed that 12 patients had strong positive delayed-type IV hypersensitivity to the autologous cancer cell lysate; robust systemic cytotoxicity elicited by interferon (IFN)γ expression by peripheral blood mononuclear cells; and significant increases in CD3+CD8+, CD3+CD45RO+, and CD3+CD56+ cells in peripheral blood lymphocytes after 3 injections. During the follow up, the percentages of CD3+CD8+, CD3+CD45RO+, and CD3+CD56+ cells returned to the normal range at 6 to 9 months after the third injection and IFNγ expression in the cells stayed at the higher level from the third injection to 24 months after the treatment. This new tumor-specific immunotherapy is safe, feasible, and has great potential for pancreatic carcinoma treatment. 23770817 Bright orange/red-emitting rhodium(III) and iridium(III) complexes: tridentate N^C^N-cyclometallating ligands lead to high luminescence efficiencies. Rhodium(III) complexes rarely display strong phosphorescence, in contrast to well-known iridium(III) complexes with cyclometallating ligands. This study shows how 1,3-bis(1-isoquinolyl)benzene cyclometallates to Rh(III) through N^C^N-coordination to give complexes with unprecedented phosphorescence quantum yields at room temperature. Their highly emissive Ir(III) analogues are also described. 23901067 Numerical simulation of Dean number and curvature effects on magneto-biofluid flow through a curved conduit. A numerical study is performed to investigate the magnetohydrodynamic viscous steady biofluid flow through a curved pipe with circular cross section under various conditions. A spectral method is applied as the principal tool for the numerical simulation with Fourier series, Chebyshev polynomials, collocation methods and an iteration method as secondary tools. The combined effects of Dean number, Dn, magnetic parameter, Mg, and tube curvature, δ, are studied. The flow patterns have been shown graphically for large Dean numbers as well as magnetic parameter and a wide range of curvatures, 0.01 ≤ δ ≤ 0.2. Two-vortex solutions have been found. Axial velocity has been found to increase with an increase of Dean number, whereas it is suppressed with greater curvature and magnetic parameters. For high magnetic parameter and Dean number and low curvature, almost all the fluid vortex strengths are weak. The study is relevant to magnetohydrodynamic blood flow in the cardiovascular system. 23948157 Simultaneous detection of bee viruses by multiplex PCR. Honey bee mortality is a serious problem that beekeepers in Argentina have had to face during the last 3 years. It is known that the consequence of the complex interactions between environmental and beekeeping parameters added to the effect of different disease agents such as viruses, bacteria, fungi and parasitic mites may result in a sudden collapse of the colony. In addition, multiple viral infections are detected frequently concomitantly in bee colonies. The aim of this study was to establish a multiplex polymerase chain reaction method for rapid and simultaneous detection of the most prevalent bee viruses. This multiplex PCR assay will provide specific, rapid and reliable results and allow for the cost effective detection of a particular virus as well as multiple virus infections in a single reaction tube. This method could be a helpful tool in the surveillance of the most frequently found bee viruses and to study the dynamics and the interactions of the virus populations within colonies. 23008503 Cyclooxygenase (COX)-1 and COX-2 both play an important role in the protection of the duodenal mucosa in cats. Although nonsteroidal anti-inflammatory drugs often cause ulcers in the duodenum in humans, the role of cyclooxygenase (COX) isoforms in the pathogenesis of duodenal ulcers has not been fully elucidated. We examined in cats the 1) ulcerogenic effects of selective COX-1 (SC-560, ketorolac) and COX-2 (celecoxib, meloxicam) inhibitors on the gastrointestinal mucosa, 2) effect of feeding and cimetidine on the expression of COX isoforms and prostaglandin E(2) (PGE(2)) level in the duodenum, and 3) localization of COX isoforms in the duodenum. COX inhibitors were administered after the morning meal in cats once daily for 3 days. Gastrointestinal lesions were examined on day 4. Localization and expression of COX isoforms (by immunohistochemistry, Western blot) and PGE(2) level (by enzyme immunoassay) were examined. Results were as follows. First, selective COX-1 or COX-2 inhibitors alone produced marked ulcers in the duodenum but did not cause obvious lesions in the small intestine. Coadministration of SC-560 and celecoxib produced marked lesions in the small intestine. Second, feeding increased both the expression of COX isoforms and PGE(2) level in the duodenum, and the effects were markedly inhibited by pretreatment with cimetidine. Third, COX-1 was localized in goblet and Brunner's gland cells, Meissner's and Auerbach's plexus, smooth muscle cells, and arterioles; and COX-2 was observed in capillaries, venules, and basal granulated cells. The expression of COX isoforms in the duodenum is up-regulated by feeding, and inhibition of either COX-1 or COX-2 causes ulcers in the duodenum, suggesting that both isoforms play an important role in the protection of the duodenal mucosa. 23311608 Diels-Alder mediated controlled release from a poly(ethylene glycol) based hydrogel. A synthetic amino acid bearing a furan functionality was developed and incorporated into peptide sequences using solid phase synthesis. Peptides expressing the furan moiety were attached to poly(ethylene glycol) (PEG) hydrogels through a thermally reversible covalent bond formed by a Diels-Alder reaction. Reactions of thiol and maleimide PEG macromers in an off-stoichiometric Michael addition were performed, such that the maleimide moiety was in excess, to create hydrogel networks with pendant Diels-Alder compatible tethering sites, that is, the maleimide. By making use of the Diels-Alder reaction, it was possible to control the release rate of reversibly bound moieties from the hydrogel by changing the temperature; higher temperatures favor a faster retro-Diels-Alder reaction and, therefore, a faster release from the polymer network. This concept was demonstrated by incorporating a fluorescently labeled furan-RGDS sequence into a hydrogel possessing excess maleimide functionalities and monitoring the subsequent liberation of RGDS at various temperatures, illustrating a Diels-Alder mediated release mechanism. The release profile was quantified at temperatures ranging from physiological (37 °C) to 80 °C. By changing the temperature, varying extents of release were attained over the time course of several days, ranging from 40% release for lower temperatures to complete release for the highest temperature considered. Further confirmation of a reaction-diffusion controlled release mechanism was obtained through comparison of experimental release data to a reaction-diffusion model of the release. In addition to thermal modulation, tuning of the release rate was accomplished by altering the number of possible Diels-Alder tethering sites present in the hydrogel. Increasing the amount of free maleimide and, therefore, the number of potential Diels-Alder reaction sites, effectively slowed the release of peptide from the polymer. For instance, doubling the amount of maleimide sites present in the hydrogel system decreased the amount of peptide released from approximately 60% to about 40% in the same span of time. 23704327 The giant spectrin βV couples the molecular motors to phototransduction and Usher syndrome type I proteins along their trafficking route. Mutations in the myosin VIIa gene cause Usher syndrome type IB (USH1B), characterized by deaf-blindness. A delay of opsin trafficking has been observed in the retinal photoreceptor cells of myosin VIIa-deficient mice. We identified spectrin βV, the mammalian β-heavy spectrin, as a myosin VIIa- and rhodopsin-interacting partner in photoreceptor cells. Spectrin βV displays a polarized distribution from the Golgi apparatus to the base of the outer segment, which, unlike that of other β spectrins, matches the trafficking route of opsin and other phototransduction proteins. Formation of spectrin βV-rhodopsin complex could be detected in the differentiating photoreceptors as soon as their outer segment emerges. A failure of the spectrin βV-mediated coupling between myosin VIIa and opsin molecules thus probably accounts for the opsin transport delay in myosin VIIa-deficient mice. We showed that spectrin βV also associates with two USH1 proteins, sans (USH1G) and harmonin (USH1C). Spectrins are supposed to function as heteromers of α and β subunits, but fluorescence resonance energy transfer and in vitro binding experiments indicated that spectrin βV can also form homodimers, which likely supports its αII-independent βV functions. Finally, consistent with its distribution along the connecting cilia axonemes, spectrin βV binds to several subunits of the microtubule-based motor proteins, kinesin II and the dynein complex. We therefore suggest that spectrin βV homomers couple some USH1 proteins, opsin and other phototransduction proteins to both actin- and microtubule-based motors, thereby contributing to their transport towards the photoreceptor outer disks. 23855825 Identification of novel modulators for ionotropic glutamate receptor, iGluA2 by in-silico screening. Ionotropic glutamate receptors (iGluAs, IUPHAR nomenclature) are the major excitatory amino acid neurotransmitter receptors in the mammalian central nervous system (CNS). iGluAs are potential therapeutic drug targets for various neurological disorders including ischemia, epilepsy, Parkinson's and Alzheimer's diseases. The known iGluA modulators, cyclothiazide (CTZ), IDRA-21, and other benzothiadiazide derivatives (ALTZ, HCTZ, and CLTZ) bind to the ligand-binding domain of flip-form of iGluA2 at the dimer interface, thereby increasing steady-state activation by reducing desensitization. To discover new modulator compounds, we performed virtual screening for the ligand binding domain (LBD) of iGluA2 against NCI Diversity Set III library containing 1597 compounds, and subsequently performed binding-energy analysis for selected compounds. The crystal structure of rat iGluA2 S1S2J (PDB ID: 3IJO) was used for docking studies. From this study, we obtained four compounds: (1) 10-2(methoxyethyl)-3-phenylbenzo[g]pteridine-2,4-dione, (2) 2-benzo[e]benzotriazol-2-yl-aniline, (3) 9-nitro-6H-indolo-(2,3,-b)quinoxaline, and (4) 1-hydroxy-n-(3-nitrophenyl)-2-napthamide. The binding mode of these four compounds is very similar to that of abovementioned established modulators: two molecules of each compound independently bind to the protein symmetrically at the dimer interface; occupy the subsites B, C, B' and C'; potentially interact with Ser518 and Ser775. Binding energy analysis shows that all the four hits are comparable to the drug molecule, CTZ, and hence, we propose that the discovered hits may be potential molecules to develop new chemical libraries for modulating the flip form of iGluA2 function. 23917723 Transcriptional regulation of guidance at the midline and in motor circuits. Axon navigation through the developing body of an embryo is a challenging and exquisitely precise process. Axonal processes within the nervous system harbor extremely complicated internal regulatory mechanisms that enable each of them to respond to environmental cues in a unique way, so that every single neuron has an exact stereotypical localization and axonal projection pattern. Receptors and adhesion molecules expressed on axonal membranes will determine their guidance properties. Axon guidance is thought to be controlled to a large extent through transcription factor codes. These codes would be responsible for the deployment of specific guidance receptors and adhesion molecules on axonal membranes to allow them to reach their targets. Although families of transcriptional regulators as well as families of guidance molecules have been conserved across evolution, their relationships seem to have developed independently. This review focuses on the midline and the neuromuscular system in both vertebrates and Drosophila in which such relationships have been particularly well studied. 23966105 Oral deferiprone for iron chelation in people with thalassaemia. Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through red blood cell transfusions.Repeated transfusions result in an excessive accumulation of iron in the body (iron overload), removal of which is achieved through iron chelation therapy. A commonly used iron chelator, deferiprone, has been found to be pharmacologically efficacious. However, important questions exist about the efficacy and safety of deferiprone compared to another iron chelator, desferrioxamine. To summarise data from trials on the clinical efficacy and safety of deferiprone and to compare the clinical efficacy and safety of deferiprone with desferrioxamine for thalassaemia. We searched the Cochrane Cystic fibrosis and Genetic Disorders Group's Haemoglobinopathies trials Register and MEDLINE, EMBASE, CENTRAL (The Cochrane Library), LILACS and other international medical databases, plus registers of ongoing trials and the Transfusion Evidence Library (www.transfusionevidencelibrary.com). We also contacted the manufacturers of deferiprone and desferrioxamine.All searches were updated to 05 March 2013. Randomised controlled trials comparing deferiprone with another iron chelator; or comparing two schedules or doses of deferiprone, in people with transfusion-dependent thalassaemia. Two authors independently assessed trials for risk of bias and extracted data. Missing data were requested from the original investigators. A total of 17 trials involving 1061 participants (range 13 to 213 participants per trial) were included. Of these, 16 trials compared either deferiprone alone with desferrioxamine alone, or a combined therapy of deferiprone and desferrioxamine with either deferiprone alone or desferrioxamine alone; one compared different schedules of deferiprone. There was little consistency between outcomes and limited information to fully assess the risk of bias of most of the included trials.Four trials reported mortality; each reported the death of one individual receiving deferiprone with or without desferrioxamine. One trial reported five further deaths in patients who withdrew from randomised treatment (deferiprone with or without desferrioxamine) and switched to desferrioxamine alone. Seven trials reported cardiac function or liver fibrosis as measures of end organ damage.Earlier trials measuring the cardiac iron load indirectly by magnetic resonance imaging (MRI) T2* signal had suggested deferiprone may reduce cardiac iron more quickly than desferrioxamine. However, a meta-analysis of two trials suggested that left ventricular ejection fraction was significantly reduced in patients who received desferrioxamine alone compared with combination therapy.  One trial, which planned five years of follow up, was stopped early due to the beneficial effects of combined treatment compared with deferiprone alone in terms of serum ferritin levels reduction.The results of this and three other trials suggest an advantage of combined therapy over monotherapy to reduce iron stores as measured by serum ferritin. There is, however, no conclusive or consistent evidence for the improved efficacy of combined deferiprone and desferrioxamine therapy over monotherapy from direct or indirect measures of liver iron. Both deferiprone and desferrioxamine produce a significant reduction in iron stores in transfusion-dependent, iron-overloaded people. There is no evidence from randomised controlled trials to suggest that either has a greater reduction of clinically significant end organ damage.Evidence of adverse events were observed in all treatment groups. Occurrence of any adverse event was significantly more likely with deferiprone than desferrioxamine in one trial, RR 2.24 (95% CI 1.19 to 4.23). Meta-analysis of a further two trials showed a significant increased risk of adverse events associated with combined deferiprone and desferrioxamine compared with desferrioxamine alone, RR 3.04 (95% CI 1.18 to 7.83). The most commonly reported adverse event was joint pain, which occurred significantly more frequently in patients receiving deferiprone than desferrioxamine, RR 2.64 (95% CI 1.21 to 5.77). Other common adverse events included gastrointestinal disturbances as well as neutropenia or leucopenia, or both. In the absence of data from randomised controlled trials, there is no evidence to suggest the need for a change in current treatment recommendations; namely that deferiprone is indicated for treating iron overload in people with thalassaemia major when desferrioxamine is contraindicated or inadequate. Intensified desferrioxamine treatment (by either subcutaneous or intravenous route) or use of other oral iron chelators, or both, remains the established treatment to reverse cardiac dysfunction due to iron overload. Indeed, the US Food and Drug Administration (FDA) recently only gave support for deferiprone to be used as a last resort for treating iron overload in thalassaemia, myelodysplasia and sickle cell disease. However, there is evidence that adverse events are increased in patients treated with deferiprone compared with desferrioxamine and in patients treated with combined deferiprone and desferrioxamine compared with desferrioxamine alone. There is an urgent need for adequately-powered, high-quality trials comparing the overall clinical efficacy and long-term outcome of deferiprone with desferrioxamine. 23872803 Does Medial Patellofemoral Ligament Reconstruction Decrease Patellar Height? A Preliminary Report. The purpose of this study was to evaluate the hypothesis that medial patellofemoral ligament (MPFL) reconstruction for patellar instability decreases patellar height. Preoperative and postoperative lateral knee radiographs of 38 adolescents who underwent MPFL reconstruction between 2005 and 2011 were reviewed. The Insall-Salvati index, Blackburne-Peel index, Caton-Deschamps index, and plateau-patella angle were measured on all radiographs to identify differences in patellar height. These patellar height indices were also measured on lateral knee radiographs of 25 adolescents (control group) who were treated conservatively for osteochondritis dissecans of the knee. The 2 groups were compared to account for patellar height changes secondary to growth and ossification. Intrarater reliability was measured for all patellar height indices at 1-month interval. Preoperatively, patients who underwent MPFL reconstruction had significantly greater patellar height on all indices compared with the control group before and after controlling for age and sex. The patients who underwent MPFL reconstruction showed a significantly greater decrease in patellar height on the Blackburne-Peel or Caton-Deschamps indices over time compared with the control group such that postoperatively there was no difference between groups in these patellar height indices. Furthermore, the change in patellar height indices after MPFL reconstruction did not differ between patients with less than or more than 1-year follow-up. All indices demonstrated good to excellent intrarater reliability. The present study showed a decrease in patellar height in the postoperative period in patients after MPFL reconstruction for patellar instability. Further investigation is necessary to determine the long-term effects of MPFL reconstruction on patellar height. Level III-therapeutic, case series. 23542316 Th17 cells and IL-17 are involved in the disruption of vulnerable plaques triggered by short-term combination stimulation in apolipoprotein E-knockout mice. Considerable evidence indicates that type 1 T helper (Th1)- and Th17-mediated immune responses promote the formation of atherosclerotic plaques while that CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) have a protective effect. However, the functions of diverse CD4(+) lymphocyte subsets in plaque rupture remain poorly understood because of a shortage of satisfactory plaque rupture models. Here, we established a murine model of atherosclerotic plaque rupture using a high-fat diet and collar placement on the carotid artery, and triggered plaque rupture by short-term stimulation with a combination of lipopolysaccharide, phenylephrine injection and cold in apolipoprotein E-knockout (ApoE(-/-)) mice. We investigated the associations between Th1 cells, Th17 cells and Tregs and plaque rupture by PCR, flow cytometry, ELISA and immunohistochemistry. In total, 75% (18/24) of vulnerable plaques, but no stable plaques, showed rupture characteristics. The proportion of Th17 cells was increased among splenocytes after treatment, but the changes in the levels of Th1 cells and Tregs were not related to rupture. Furthermore, the treatment resulted in high levels of interleukin-17 (IL-17) in the serum and in the region of plaque rupture. In vitro, IL-17 increased the level of apoptosis, a major factor associated with plaque rupture, in cultured murine vascular smooth muscle cells. Th17 cells and IL-17 may be involved in the disruption of vulnerable plaques triggered by short-term stimulation with lipopolysaccharide, phenylephrine injection and cold in ApoE(-/-)mice. 23967542 Fecal transplant for recurrent Clostridium difficile infection. Clostridium difficile infection (CDI) results in clinical manifestations ranging from mild diarrhea to life-threatening pseudomembranous colitis. Infection is most often initiated by antimicrobial therapy which causes an imbalance in normal colonic microflora. The pathogenesis of C. difficile is predominantly controlled by the production of its two cytotoxins, A and B, which damage the intestinal mucosa. In recent years a nationwide increase in the rate of CDI has been noted as well as an increase in mortality, reduced initial response to antimicrobials, extended resolution time, and increased rates of recurrence. Traditional treatment includes administration of antimicrobials. Fecal microbiota transplant (FMT) is an alternative therapy for CDI that is effective and promising in multiple CDI relapse patients. This paper will provide an overview of CDI epidemiology, pathogenesis, diagnosis, and treatment, and explore the case of a 53-year-old woman suffering from her sixth episode of CDI. 23916560 Isolation of polyketides from Prymnesium parvum (Haptophyta) and their detection by liquid chromatography/mass spectrometry metabolic fingerprint analysis. Prymnesium parvum is a microalga that forms blooms coupled with the presence of potent exotoxins; however, no chemical standards are currently available for the toxins. Streamlined methods are presented for the separation and enrichment of polyketide toxins, prymnesin-1 (prym1) and prymnesin-2 (prym2). Prymnesins were separated by reversed-phase chromatography and detected by positive-mode electrospray ionization MS to generate a unique metabolic fingerprint. More than 10 ions were detected and mass assignments were in agreement with predicted isotopic distributions for the intact compounds and related fragments; ions occurred as multiply protonated species and with common salt adducts. The most prevalent ion was observed at 919.88 m/z, which represents the aglycone [prymagly+2H](2+) backbone structure common to both molecules. Expanded mass spectra for this and related ions were in excellent agreement (<0.5ppm) with empirically derived spectra based on elemental composition and naturally occurring isotopes. These investigations have confirmed the isolation of polyketide prymnesins from whole cells, which heretofore has not been reproduced since their original characterization. Moreover, this study represents the first time these compounds have been verified in aqueous materials. These tools should allow the direct identification and analysis of polyketide prymnesins, which will greatly improve our understanding of these toxins in P. parvum. 23954073 Pentasaccharide resin glycosides from Ipomoea cairica and their cytotoxic activities. Six partially acylated pentasaccharide resin glycosides, cairicosides A-F, were isolated from the aerial parts of Ipomoea cairica. These compounds were characterized as a group of macrolactones of simonic acid A, partially acylated with different organic acids. The lactonization site of 11S-hydroxyhexadecanoic acid (jalapinolic acid) was bound to the second saccharide moiety at C-3 in cairicosides A-E, while at C-2 in cairicoside F. Structures were established by spectroscopic and chemical methods. Compounds cairicosides A-E exhibited moderate cytotoxicity against a small panel of human tumor cell lines with IC50 values in the range of 4.28-14.31μM. 23688491 Calcium pectinate-fenugreek seed mucilage mucoadhesive beads for controlled delivery of metformin HCl. Calcium pectinate-fenugreek seed mucilage (FSM) mucoadhesive beads containing metformin HCl was developed through ionic-gelation. Effects of pectin and FSM amounts on drug encapsulation efficiency (DEE) and cumulative drug release at 10h (R10 h) were optimized using 3(2) factorial design. The DEE (%) was within the range of 63.16 ± 2.88 to 96.03 ± 4.67% (w/w). The in vitro drug release from these beads (56.64 ± 1.47 to 93.63 ± 4.52% over 10h) was followed controlled-release (zero-order) pattern (R(2)=0.993 to 0.997) with super case-II transport mechanism. The average size of beads was within 1.47 ± 0.14 to 2.08 ± 0.18 mm. The beads were also characterized by SEM and FTIR. The swelling and mucoadhesivity of these beads were influenced by pH of the medium. The optimized beads also exhibited good mucoadhesivity and significant hypoglycemic effect in alloxan-induced diabetic rats over prolonged period after oral administration. 23924997 Organizing the HIV vaccine development effort. To describe and compare the diverse organizational structures and funding mechanisms applied to advance HIV preventive vaccine research and development and to help explain and inform evolving infrastructures and collaborative funding models. On the basis of models that have been tried, improved or abandoned over three decades, the field seems to have settled into a relatively stable set of diverse initiatives, each with its own organizational signature. At the same time, this set of organizations is forging cross-organizational collaborations, which promise to acquire newly emergent beneficial properties. Strong motivation to expedite HIV vaccine R&D has driven a diversity of customized and inventive organizational approaches, largely government and foundation funded. Although no one approach has proven a panacea, the field has evolved into a constellation of often overlapping organizations that complement or reinforce one another. The Global HIV Vaccine Enterprise, a responsive, rapidly evolving loose infrastructure, is an innovative collaboration to catalyze that evolution. 23931928 Students' and teachers' views of written feedback at undergraduate level: A literature review. To explore undergraduate students' expectations and teachers' views of written feedback. Narrative literature review. Seven electronic databases were searched for primary research published in English with additional manual searches and reference tracking. Systematic approach to search strategy, selection and appraisal of papers, data extraction and synthesis following Hawker et al.'s (2002) guidelines. 21 studies met the inclusion criteria. Four student themes were identified concerning written feedback: quality, quantity and location of feedback, feed-forward and timeliness. Teachers reported that time pressures, institutional policies, and administrative issues affect feedback provision. Rigorous research is needed to gain a better understanding of students' expectations of written feedback. Strategies need to be adopted to meet students' expectations and educate students to take an active role and reflect on the feedback received. 23956042 Crowdsourcing black market prices for prescription opioids. Prescription opioid diversion and abuse are major public health issues in the United States and internationally. Street prices of diverted prescription opioids can provide an indicator of drug availability, demand, and abuse potential, but these data can be difficult to collect. Crowdsourcing is a rapid and cost-effective way to gather information about sales transactions. We sought to determine whether crowdsourcing can provide accurate measurements of the street price of diverted prescription opioid medications. To assess the possibility of crowdsourcing black market drug price data by cross-validation with law enforcement officer reports. Using a crowdsourcing research website (StreetRx), we solicited data about the price that site visitors paid for diverted prescription opioid analgesics during the first half of 2012. These results were compared with a survey of law enforcement officers in the Researched Abuse, Diversion, and Addiction-Related Surveillance (RADARS) System, and actual transaction prices on a "dark Internet" marketplace (Silk Road). Geometric means and 95% confidence intervals were calculated for comparing prices per milligram of drug in US dollars. In a secondary analysis, we compared prices per milligram of morphine equivalent using standard equianalgesic dosing conversions. A total of 954 price reports were obtained from crowdsourcing, 737 from law enforcement, and 147 from the online marketplace. Correlations between the 3 data sources were highly linear, with Spearman rho of 0.93 (P<.001) between crowdsourced and law enforcement, and 0.98 (P<.001) between crowdsourced and online marketplace. On StreetRx, the mean prices per milligram were US$3.29 hydromorphone, US$2.13 buprenorphine, US$1.57 oxymorphone, US$0.97 oxycodone, US$0.96 methadone, US$0.81 hydrocodone, US$0.52 morphine, and US$0.05 tramadol. The only significant difference between data sources was morphine, with a Drug Diversion price of US$0.67/mg (95% CI 0.59-0.75) and a Silk Road price of US$0.42/mg (95% CI 0.37-0.48). Street prices generally followed clinical equianalgesic potency. Crowdsourced data provide a valid estimate of the street price of diverted prescription opioids. The (ostensibly free) black market was able to accurately predict the relative pharmacologic potency of opioid molecules. 23889963 Integrin β1 is critical for gastrin-releasing peptide receptor-mediated neuroblastoma cell migration and invasion. Gastrin-releasing peptide (GRP) and its receptor, GRP-R, are critically involved in neuroblastoma tumorigenesis; however, the molecular mechanisms and signaling pathways that are responsible for GRP/GRP-R-induced cell migration and invasion remain unclear. In this study, we sought to determine the cell signals involved in GRP/GRP-R-mediated neuroblastoma cell migration and invasion. Human neuroblastoma cell lines SK-N-SH, LAN-1, and IMR-32 were used for our study. Transwell migration and invasion assays were performed after GRP (10(-7) M) stimulation. The cDNA GEArray Microarray kit was used to determine GRP-R-induced gene expression changes. Protein and membrane expression of integrin subunits were confirmed by Western blotting and flow cytometry analysis. siRNA transfection was performed using Lipofectamine 2000. For scratch assay, a confluent monolayer of cells in 6-well plates were wounded with micropipette tip and observed microscopically at 24 to 72 h. GRP increased neuroblastoma cell migration and expressions of MMP-2 whereas the TIMP-1 level decreased. GRP-R overexpression stimulated SK-N-SH cell migration and upregulated integrin α2, α3, and β1 protein as well as mRNA expression. Targeted silencing of integrin β1 inhibited cell migration. GRP/GRP-R signaling contributes to neuroblastoma cell migration and invasion. Moreover, the integrin ß1 subunit critically regulates GRP-R-mediated neuroblastoma cell migration and invasion. 23665542 Chirality-dependent balance between hydrogen bonding and London dispersion in isolated (±)-1-indanol clusters. The aggregation behavior of racemic and enantiopure 1-indanol has been studied by FTIR spectroscopy, resonant ion dip IR spectroscopy, and spontaneous Raman scattering in supersonic jets. This triple experimental approach, augmented by homology to related molecular fragments and dispersion-corrected DFT predictions, allows disentangling the complex spectroscopic signature in the OH stretch range. Evidence for chirality-sensitive aggregation via isolated OH···π bonds in competition with cooperative ···OH···OH···π patterns is collected. An accurate description of London dispersion forces provides the key to its explanation. 23833128 Visual Crowding in V1. In peripheral vision, objects in clutter are difficult to identify. The exact cause of this "crowding" effect is unclear. To perceive coherent shapes in clutter, the visual system must integrate certain local features across receptive fields while preventing others from being combined. It is believed that this selective feature integration-segmentation process is impaired in peripheral vision, leading to crowding. We used functional magnetic resonance imaging (fMRI) to investigate the neural origin of crowding. We found that crowding was associated with suppressed fMRI signal as early as V1, regardless of whether attention was directed toward or away from a target stimulus. This suppression in early visual cortex was greatest for stimuli that produced the strongest crowding. In contrast, the pattern of activity was mixed in higher level visual areas, such as the lateral occipital cortex. These results support the view that the deficiency in feature integration and segmentation in peripheral vision is present at the earliest stages of cortical processing. 23851931 Activated phosphonated trifunctional chelates for highly sensitive lanthanide-based FRET immunoassays applied to total prostate specific antigen detection. The first example of an activated phosphonated trifunctional chelate (TFC) is presented, which combines a non-macrocyclic coordination site for lanthanide coordination based on two aminobis-methylphosphonate coordinating arms, a central bispyrazolylpyridyl antenna and an N-hydroxysuccinimide ester in para position of the central pyridine as an activated function for the labeling of biomaterial. The synthesis of the TFC is presented together with photo-physical studies of the related Tb and Eu complexes. Excited state lifetime measurements in H2O and D2O confirmed an excellent shielding of the cation from water molecules with a hydration number of zero. The Tb complex provides a high photoluminescence (PL) quantum yield of 24% in aqueous solutions (0.01 M Tris-HCl, pH 7.4) and a very long luminescence lifetime of 2.6 ms. The activated ligand was conjugated to different biological compounds such as streptavidin, and a monoclonal antibody against total prostate specific antigen (TPSA). In combination with AlexaFluor647 (AF647) and crosslinked allophycocyanin (XL665) antibody (ABs) conjugates, homogeneous time-resolved Fluorescence Resonance Energy Transfer (FRET) immunoassays of TPSA were performed in serum samples. The Tb donor-dye acceptor FRET pairs provided large Förster distances of 5.3 nm (AF647) and 7.1 nm (XL665). A detailed time-resolved FRET analysis of Tb donor and dye acceptor PL decays revealed average donor-acceptor distances of 4.2 nm (AF647) and 6.3 nm (XL665) within the sandwich immunocomplex and FRET efficiencies of 0.79 and 0.68, respectively. Very low detection limits of 1.4 ng mL(-1) (43 pM) and 2.4 ng mL(-1) (74 pM) TPSA were determined using a KRYPTOR fluorescence immunoanalyzer. These results demonstrate the applicability of our novel Tb-bioconjugates for highly sensitive clinical diagnostics. 23832652 Variations of the tautomeric preferences and π-electron delocalization for the neutral and redox forms of purine when proceeding from the gas phase (DFT) to water (PCM). Quantum-chemical calculations were performed for all possible nine neutral tautomers of purine and their oxidized and reduced forms in water {PCM//DFT(B3LYP)/6-311+G(d,p)} and compared to those in the gas phase {DFT(B3LYP)/6-311+G(d,p)}. PCM hydration influences geometries, π-electron delocalization, and relative energies of purine tautomers in different ways. Generally, the harmonic oscillator model of electron delocalization (HOMED) indices increase when proceeding from the gas phase to aequeous solution for the neutral and redox forms of purine. Their changes for the neutral and oxidized tautomers are almost parallel to the relative energies showing that aromaticity plays an important role in the tautomeric preferences. Tautomeric stabilities and tautomeric preferences vary when proceeding from the gas phase to water indicating additionally that intra- and intermolecular interactions affect tautomeric equilibria. The tautomeric mixture of neutral purine in the gas phase consists mainly of the N9H tautomer, whereas two tautomers (N9H and N7H) dominate in water. For oxidized purine, N9H is favored in the gas phase, whereas N1H in water. A gain of one electron dramatically changes the relative stabilities of the CH and NH tautomers that C6H and C8H dominate in the tautomeric mixture in the gas phase, whereas N3H in water. These variations show exceptional sensitivity of the tautomeric purine system on environment in the electron-transfer reactions. 23942142 Intercellular adhesion molecule 1: Recent findings and new concepts involved in mammalian spermatogenesis. Spermatogenesis, the process of spermatozoa production, is regulated by several endocrine factors, including testosterone, follicle stimulating hormone, luteinizing hormone and estradiol 17β. For spermatogenesis to reach completion, developing germ cells must traverse the seminiferous epithelium while remaining transiently attached to Sertoli cells. If germ cell adhesion were to be compromised for a period of time longer than usual, germ cells would slough the seminiferous epithelium and infertility would result. Presently, Sertoli-germ cell adhesion is known to be mediated largely by classical and desmosomal cadherins. More recent studies, however, have begun to expand long-standing concepts and to examine the roles of other proteins such as intercellular adhesion molecules. In this review, we focus on the biology of intercellular adhesion molecules in the mammalian testis, hoping that this information is useful in the design of future studies. 23151402 The enigmatic root cell - Emerging roles contributing to fluid homeostasis within the cochlear outer sulcus. Despite their curious morphology prompting numerous hypotheses of their normal function, the root cells lining the cochlear outer sulcus have long evaded physiological characterization. A growing body of evidence now suggests that they regulate the solute content of the endolymph and/or the perilymph, and may be essential in safe-guarding the global homeostasis of the cochlea. Immuno-labeling experiments have demonstrated polarized expression of key ion transport proteins, and recent electrophysiological recordings have identified specific membrane conductances. These studies have painted a clearer picture of how this unusual cell type may contribute to the maintenance of sound transduction, and how they may be central to pathological processes associated with various forms of hearing loss. This article is part of a Special Issue entitled "Annual Reviews 2013". 23954790 Lysine Succinylation Is a Frequently Occurring Modification in Prokaryotes and Eukaryotes and Extensively Overlaps with Acetylation. Recent studies have shown that lysines can be posttranslationally modified by various types of acylations. However, except for acetylation, very little is known about their scope and cellular distribution. We mapped thousands of succinylation sites in bacteria (E. coli), yeast (S. cerevisiae), human (HeLa) cells, and mouse liver tissue, demonstrating widespread succinylation in diverse organisms. A majority of succinylation sites in bacteria, yeast, and mouse liver were acetylated at the same position. Quantitative analysis of succinylation in yeast showed that succinylation was globally altered by growth conditions and mutations that affected succinyl-coenzyme A (succinyl-CoA) metabolism in the tricarboxylic acid cycle, indicating that succinylation levels are globally affected by succinyl-CoA concentration. We preferentially detected succinylation on abundant proteins, suggesting that succinylation occurs at a low level and that many succinylation sites remain unidentified. These data provide a systems-wide view of succinylation and its dynamic regulation and show its extensive overlap with acetylation. 23672939 Mechanical cell disruption for lipid extraction from microalgal biomass. Cell disruption is an integral part of the downstream operation required to produce biodiesel from microalgae. This study investigated the use of ultrasonication and high-pressure homogenization (HPH) as cell disruption methods for two microalgal species, Tetraselmis suecica (TS) and Chlorococcum sp. (C sp.). The kinetics of cell disruption followed a first-order model (0.652σ;=5.33 %, all data with 1282/0/38 data/restraints/parameters. 23921874 Effect of Smoking Cessation on Gestational and Postpartum Weight Gain and Neonatal Birth Weight. To examine the association among smoking cessation, gestational and postpartum weight gain, and neonatal birth weight. We analyzed prospectively collected data from 1,774 women with term singleton pregnancies. Smoking status during pregnancy was categorized as nonsmokers, smokers, and quitters; and smoking status 1 year postpartum as nonsmokers, smokers, relapsed quitters, and sustained quitters. The association between smoking status and gestational weight gain, weight gain 1 year postpartum, and neonatal birth weight was tested by linear regression analysis, and the association between smoking status and neonatal birth weight less than the 10th percentile for gestational age and sex was tested by multivariable logistic regression analysis. Gestational weight gain at 16 weeks of gestation was comparable for nonsmokers, smokers, and quitters. The adjusted mean gestational weight gain at 37 weeks of gestation was 2.0 kg (95% confidence interval [CI] 1.5-2.6) higher in quitters compared with nonsmokers. The rate of neonatal birth weight less than the 10th percentile was 21.7% among smokers, 8.0% among quitters, and 7.4% among nonsmokers. The adjusted odds ratio (OR) for birth weight less than 10th percentile was 3.6 (95% CI 2.5-5.2) in neonates born to smokers; the risk was similar for quitters (OR 1.0, 95% CI 0.6-1.6). One year after delivery, sustained quitters had a 2.4-kg (95% CI 1.6-3.1) higher adjusted postpartum weight gain than nonsmokers. Smoking cessation is associated with gestational as well as postpartum weight gain. However, smoking cessation is associated with a substantially lower rate of neonatal birth weight less than the 10th percentile. LEVEL OF EVIDENCE:: II. 23803292 Pressure-induced frustration in charge ordered spinel AlV₂O₄. AlV2O4 is the only spinel compound so far known that exists in the charge ordered state at room temperature. It is known to transform to a charge frustrated cubic spinel structure above 427 ° C. The presence of multivalent V ions in the pyrochlore lattice of the cubic spinel phase brings about the charge frustration that is relieved in the room temperature rhombohedral phase by the clustering of vanadium into a heptamer molecular unit along with a lone V atom. The present work is the first demonstration of pressure-induced frustration in the charge ordered state of AlV2O4. Synchrotron powder x-ray diffraction studies carried out at room temperature on AlV2O4 subjected to high pressure in a diamond anvil cell show that the charge ordered rhombohedral phase becomes unstable under the application of pressure and transforms to the frustrated cubic spinel structure. The frustration is found to be present even after pressure recovery. The possible role of pressure on vanadium t2g orbitals in understanding these observations is discussed. 23625740 Interspecific variations of inner ear structure in the deep-sea fish family melamphaidae. Inner ear structures are compared among three major genera of the deep-sea fish family Melamphaidae (bigscales and ridgeheads). Substantial interspecific variation is found in the saccular otoliths, including the presence of a unique otolithic "spur" in the genera Melamphaes and Poromitra. The variation in the saccular otolith is correlated with an increase in the number of hair bundle orientation groups on the sensory epithelia from the genera Scopelogadus to Poromitra to Melamphaes. The diverse structural variations found in the saccule may reflect the evolutionary history of these species. The sensory hair cell bundles in this family have the most variable shapes yet encountered in fish ears. In the saccule, most of the hair bundles are 15-20 μm high, an exceptional height for fish otolithic end organs. These bundles have large numbers of stereovilli, including some that reach the length of the kinocilium. In the utricle, the striolar region separates into two unusually shaped areas that have not been described in any other vertebrates. The brains in all species have a relatively small olfactory bulb and optic tectum, as well as an enlarged posterior cerebellar region that is likely to be involved in inner ear and lateral line (octavolateral) functions. Data from melamphaids support the hypothesis that specialized anatomical structures are found in the ears of some (if not most) deep-sea fishes, presumably enhancing their hearing sensitivity. 22236510 Functional electrical stimulation for chronic heart failure: a meta-analysis. We conducted a meta-analysis of randomized, controlled trials of combined electrical stimulation versus conventional exercise training or placebo control in heart failure patients. A systematic search was conducted of Medline (Ovid) (1950-September 2011), Embase.com (1974-September 2011), Cochrane Central Register of Controlled Trials and CINAHL (1981-September 2011). The search strategy included a mix of MeSH and free text terms for the key concepts heart failure, exercise training and functional electrical stimulation (FES). FES produced inferior improvements in peak VO2 when compared to cycle training: mean difference (MD) -0.32 ml.kg(-1).min(-1) (95% C.I. -0.63 to -0.02 ml.kg(-1).min(-1), p=0.04), however FES elicited superior improvements in peak VO2: MD 2.30 ml.kg(-1).min(-1) (95% C.I. 1.98 to 2.62 ml.kg(-1).min(-1), p<0.00001); and six minute walk distance to sedentary care or sham FES; MD 46.9 m (95% C.I. 22.5 to 71.3m, p=0.0002). There was no difference in change in quality of life between cycling and FES, but FES elicited significantly larger improvements in Minnesota Living with Heart Failure score than placebo or sham treatment; MD 1.15 (95% C.I. 0.69 to 1.61, p<0.00001). Moreover, the total FES intervention hours were strongly correlated with change in peak VO2, (r=0.80, p=0.02). Passive or active exercise is beneficial for patients with moderate to severe heart failure, but active cycling, or other aerobic/resistance activity is preferred in patients with heart failure who are able to exercise, and FES is the preferred modality in those unable to actively exercise. The benefits of FES may however, be smaller than those observed in conventional exercise training. Aggregate hours of electrical stimulation therapy were associated with larger improvements in cardio-respiratory fitness. 23809193 Rates of progression of weight and forced vital capacity as relevant measurement to adapt amyotrophic lateral sclerosis management for patient Result of a French multicentre cohort survey. To compare survival, to describe the progression of anthropometry, pulmonary capacity and functioning in ALS (Amyotrophic Lateral Sclerosis) and to identify the most relevant variables to adapt ALS management for patients. A cohort study was performed in French ALS centres between January 2003 and July 2005. Eligible patients were treated by Riluzole and had a slow vital capacity (SVC) or a forced vital capacity (FVC) at least equal to 60%. Demographic, medical and ALS characteristics were registered. Manual Muscular Testing (MMT) and ALS Functional Rating Scale (ALSFRS) were performed. Kaplan Meier method was used to analyse survival. ALS progression was measured by the percentage weight, FVC, SVC, MMT and ALSFRS loss and was analysed as longitudinal data using mixed model. Three hundred and eighty three patients were included. The median survival since ALS diagnosis was 2.34 years (95%CI 2.10-2.65). Mixed model analyses revealed a more significant worsening progression of weight and FVC loss for bulbar onset. The drop of ALSFRS and SVC is similar whatever the ALS forms. Rates of progression of weight and FVC should be regularly watched over to support neurologists to adapt ALS management for patients. 23255165 EMT markers in lung adenocarcinoma pleural effusion spheroid cells. Epithelial-to-mesenchymal transition (EMT) is a process in which cells undergo a developmental switch from epithelial to mesenchymal phenotype. This process has been related to embryologic morphogenesis but also to cancer progression and metastasis. The aim of the current study was to investigate the expression of EMT-related markers in adherent and spheroid cell cultures derived from malignant pleural effusions (MPEs) of patients affected by lung adenocarcinoma. On the basis of efficient in vitro propagation, six cases of MPEs were selected and analyzed by immunocytochemistry staining for EMT markers and by RT-PCR for transcription factors known to orchestrate EMT. EMT markers immunostaining showed in spheroids a statistically significant correlation between the loss of E-cadherin immunoreactivity and overexpression of N-cadherin (P < 0.001). Likewise loss of EpCAM epithelial marker was coincident with Vimentin overexpression (P < 0.001). RT-PCR analysis of transcription factors Snail, Slug, and Twist showed a highly variable expression, although a general trend to increase was observed. Importantly, in some selected cases it was possible to establish a precise relationship between spheroid formation, EMT switch and increased upregulation of the marker related to cancer stemness such as ALDH positivity. Therefore, MPE-derived cell cultures, while recapitulating the heterogeneity of lung cancer, are a suitable system to study the mechanisms at the basis of EMT and to understand its relationship with the generation of cancer stem cells. 23169898 Gemcitabine-induced gouty arthritis attacks. In this case report, we review the experience of a patient who presented with early stage pancreatic cancer (Stage IIb) who underwent a Whipple procedure and adjuvant chemoradiation. The patient's past medical history included early stage colon cancer in remission, post-traumatic-stress-disorder, hypertension, hyperlipidemia, osteoarthritis, gout, and pre-diabetes. Chemotherapy initially consisted of weekly gemcitabine. The patient developed acute gouty attacks after his second dose of gemcitabine, which brought him to the emergency room for emergent treatment on several occasions. Gemcitabine was held and treatment began with fluorouracil and concurrent radiation. After completion of his chemoradiation with fluorouracil, he was again treated with weekly gemcitabine alone. As soon as the patient started gemcitabine chemotherapy the patient developed gouty arthritis again, requiring discontinuation of chemotherapy. The patient received no additional treatment until his recent recurrence 8 months later where gemcitabine chemotherapy was again introduced with prophylactic medications consisting of allopurinol 100 mg by mouth daily and colchicine 0.6 mg by mouth daily throughout gemcitabine chemotherapy, and no signs of gouty arthritis occurred. To our knowledge, this is the first case report describing gout attacks associated with gemcitabine therapy. There is limited data available describing the mechanism that gouty arthritis may be precipitated from gemcitabine chemotherapy. Further monitoring and management may be required in patients receiving gemcitabine chemotherapy with underlying gout. 23864199 Trends, risk factors and mortality among women with venous thromboembolism during labour and delivery: a population-based study of 8 million births. Venous thromboembolism (VTE) is amongst the main causes of maternal death in the developed world. The objective of this study is to elucidate risk factors of VTE and specifically, predictors of fatal thromboembolic disease during the delivery. We conducted a population-based cohort study on 8 million birth records using the Healthcare Cost and Utilisation Project-Nationwide Inpatient Sample from 1999 to 2008 to estimate the incidence and case fatality of VTE's during labour admission. Logistic regression was used to calculate the odds ratio (OR) and corresponding 95 % confidence intervals (CIs) of demographic and obstetrical determinants of VTEs and fatal VTEs. The overall incidence of VTE was 167.7/100,000 births, increasing over the 10-year period, with an average case fatality rate of 0.41 %. VTE was associated with maternal age above 25, elderly primigravida, multigravida, black race, smoking, thrombophilia, cardiovascular disease, hypertension, obesity, postpartum haemorrhage and blood transfusion. Predictors of VTE fatalities included black race, hypertension, caesarean section and transfusion. VTE is a rare but serious condition that is increasing in incidence and is associated with a significant degree of maternal morbidity and mortality. Further research targeting prevention among high-risk groups is warranted. 23921322 Growth-Sparing Spinal Instrumentation in Skeletal Dysplasia. Study Design. Retrospective case seriesObjective. To report the outcomes of distraction-based, growth-sparing spinal instrumentation (GSSI) in patients with skeletal dysplasia.Summary of Background Data. Skeletal dysplasia patients with spinal deformity often undergo early fusion, further compromising an already small chest. Non-fusion techniques may provide a safe alternative and allow for thoracic growth.Methods. Between 2004 and 2010, 12 children with a diagnosis of various types of skeletal dysplasia underwent GSSI for severe spinal deformities. The mean duration of treatment with growing rods was 57 months (42 to 84 months). Nine patients were treated with growing rods (8 dual, 1single), and 3 were treated with vertical expandable prosthetic titanium rib (VEPTR; Synthes, West Chester, PA) Preoperative, initial postoperative, and final follow-up anteroposterior and lateral spine radiographs were measured for magnitude of deformity, junctional kyphosis, and implant failure.Results. The major curve Cobb angle improved from a mean of 79° preoperatively to a mean of 41° at the last follow-up (52%). There was a decrease in mean thoracic kyphosis from 77° preoperatively to 64° at final follow-up and an increase in mean lumbar lordosis from 58° preoperatively to 63° at final follow-up. The mean space available for the lungs increased by 26 mm on the concave and 24 mm on the convex side. Six patients required revision surgery for proximal junctional kyphosis. There were four rod failures and six hook and eight screw dislodgements. One patient with VEPTR had failed rib fixation that required revision.Conclusion. GSSI in patients with skeletal dysplasia and severe spinal deformity has a high complication and revision rate and surgeons should closely monitor these patients. The complication rate is comparable with previous reports on patients with other diagnoses. However, deformities were well controlled, some trunk growth was achieved, and fusion surgery was delayed in all cases. 23877920 Targeted and Untargeted Phytochemistry of Ligusticum canbyi: Indoleamines, Phthalides, Antioxidant Potential, and Use of Metabolomics as a Hypothesis-Generating Technique for Compound Discovery. Ligusticum canbyi (J.M. Coult & Rose) is a medicinal understory forest species used in traditional rituals and ceremonies for spiritual enlightenment and improved mental health. Very little is known about the phytochemical complexity or diversity of L. canbyi tissues or extracts. The current study was undertaken to determine whether Ligusticum tissues and extracts contain specifically targeted biologically active phytochemicals such as: melatonin, serotonin, Z-ligustilide, E-3-butylidenephthalide, and ferulic acid and to investigate the untargeted phytochemical complexity of the entire L. canbyi metabolome. The results of these studies identified melatonin and serotonin in roots and shoots of L. canbyi and L. porteri. Z-ligustilide, E-butylidenephthalide, and ferulic acid were quantified in roots and shoots of L. canbyi. Metabolomic analysis detected approximately 34,000 compounds in each L. canbyi extract, and predictive analysis suggests the presence of more than 70 putative phthalide metabolites. The relative contribution of the known metabolites and the unknown markers to the antioxidant potential of root and shoot tissues were compared, and it was determined that the majority of the antioxidant capacity could be attributed to ferulic acid in the tissues. These data provide new understandings of the phytomedicinal composition and potential mechanisms of activity of L. canbyi extracts and tissues. 23843208 Adolescent brain maturation is necessary for adult-typical mesocorticolimbic responses to a rewarding social cue. The interpretation of social cues must change during adolescence in order to promote appropriate social interactions in adulthood. For example, adult, but not juvenile, male Syrian hamsters find female pheromones contained in vaginal sections (VS) rewarding, and only adult hamsters engage in sexual behavior with a receptive female. We previously demonstrated that the rewarding value of VS is both testosterone- and dopamine-dependent. Additionally, VS induces Fos expression throughout the mesocorticolimbic circuit in adult but not juvenile hamsters. In this study, we determined whether or not treatment of juvenile male hamsters with testosterone is sufficient to promote adult-like neural responses to VS. Juvenile and adult male hamsters were gonadectomized and given empty or testosterone-filled subcutaneous capsules for one week. Hamsters were then exposed to either clean or VS-containing mineral oil on their nares, and brains were collected one hour later for immunohistochemistry to visualize Fos and tyrosine hydroxylase immunoreactive cells. Testosterone-treatment failed to promote adult-typical patterns of Fos expression in juvenile hamsters; indeed, in some brain regions, juveniles exposed to VS expressed less Fos compared to age-matched controls while, as expected, adults exposed to VS expressed greater Fos compared to age-matched controls. Age-related changes in tyrosine-hydroxylase expression were also observed. These data indicate that testosterone cannot activate the adult-typical pattern of Fos expression in response to female social cues in prepubertal males, and that additional neural maturation during adolescence is required for adult-typical mesocorticolimbic responses to female pheromones. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013. 23218402 Synergistic activity and mechanism of action of ceftazidime and apigenin combination against ceftazidime-resistant Enterobacter cloacae. The purpose of this investigation was to examine the antibacterial and synergistic effect of naturally occurring flavonoids, apigenin, quercetin, naringenin and ceftazidime when use singly and in combination against ceftazidime-resistant Enterobacter cloacae strains by minimum inhibitory concentration (MIC), checkerboard and viable count methods. The mode of actions were also studied by electronmicoscopy, enzyme assay, outer and inner membrane permeabilisation. The results showed that these strains were positive in the ESBL-ampC genes combination by multiplex PCR. These findings were confirmed by MICs that these strains were resistant to ceftazidime, cefepime and flomoxef at >1024, 16-24, >256 μg/ml respectively, while susceptible to imipenem at 1-2 μg/ml. The synergistic activity was observed at ceftazidime plus either apigenin or naringenin combinations with FIC indixes between <0.01 and <0.27 against these strains, whereas ceftazidime plus clavulanic acid or quercetin did not exhibit synergy. The modulation of ceftazidime-resistance by apigenin or narigenin significantly enhanced the activities of ceftazidime. The 5,7-OH group of A ring and one 4'-OH group of the B ring in apigenin and naringenin are important for synergistic activity. Viable counts showed that the killing of ceftazidime-resistant E. cloacae DMST 21394 (CREC) cells by 3 μg/ml ceftazidime was potentiated by 3 μg/ml apigenin to low levels (10(3) cfu/ml) over 6h. Electronmicroscopy clearly showed that ceftazidime 3 μg/ml in combination with 3 μg/ml of apigenin also caused marked morphological damage of cell wall, cell shape and plasma membrane of this strain. Enzymes assays indicated that apigenin showed marked inhibitory activity against penicillinase type IV from E. cloacae. The results for outer membrane (OM) permeabilization in both nitrocefin (NCF) assay and crystal violet uptake showed that the combination of ceftazidime plus apigenin significantly altered OM permeabilisation of CREC compared to control or single treatment of these agents. Both o-nitrophenyl-β-D-galactoside (ONPG) uptake and release of UV-absorbing material concentrations results exhibited that ceftazidime and apigenin combination damaged CREC cytoplasmic membrane (CM) and caused subsequent leakage of intracellular constituents. From the results, it can be concluded that apigenin and naringenin have the synergistic effect with ceftazidime to reverse bacterial resistance to this cephalosporin against CREC. This activity may be involved three mechanisms of action by apigenin. The first is on the peptidoglycan synthesis inhibition. The second mechanism is inhibition the activity of certain β-lactamase enzymes. The third mode of action is alteration of OM and CM permeabilization. Apigenin and naringenin have a sufficient margin of safety for therapeutic use. For this reason, apigenin and naringenin offer for the development of a valuable adjunct to ceftazidime against CREC, which currently almost cephalosporins resistance. 23891489 Management of vascular trauma from dog bites. Vascular trauma from large-dog bites present with a combination of crush and lacerating injuries to the vessel, as well as significant adjacent soft tissue injury and a high potential for wound complications. This retrospective case series evaluates our 15 years of experience in managing this uncommonly seen injury into suggested treatment recommendations. From our database, 371 adult patients presented with dog bites between July 1997 and June 2012. Twenty (5.4%) of those patients had vascular injuries requiring surgical intervention. Patient demographics, anatomic location of injury, clinical presentation, imaging modality, method of repair, and complication rates were reviewed to assess efficacy in preserving limb function. Pediatric patients were managed at the regional children's hospital and, therefore, not included in this study. Among the 20 surgically treated vascular injuries, there were 13 arterial-only injuries, two venous-only injuries, and five combination arterial and venous injuries. Seventeen patients (85%) had upper extremity injuries; three patients had lower extremity injuries (15%). The axillobrachial artery was the most commonly injured single vessel (n = 9/20; 45%), followed by the radial artery (n = 4/20; 20%). Surgical repair of vascular injuries consisted of resection and primary anastomosis (four), interposition bypass of artery with autogenous vein (13), and ligation (two), with (one) being a combination of bypass and ligation. All patients had debridement of devitalized tissue combined with pulse lavage irrigation and perioperative antibiotics. Associated injuries requiring repair included muscle and skin (n = 10/20; 50%), bone (n = 1/20; 5%), nerve (n = 1/20; 5%), and combinations of the three (n = 5/20; 25%). Postoperative antibiotic therapy was administered for 14.7 ± 8.2 days in all 20 patients. Four patients (20%) developed postoperative wound infections, although this did not compromise their vascular repair. Of the patients compliant with postoperative surveillance, all limbs (100%) were viable at discharge and at 1-year follow-up. Dog bite vascular injuries are an uncommon occurrence, where extremity pulse abnormalities are the most common presentation. These injuries are also associated with significant adjacent soft tissue trauma, which warrants aggressive debridement and perioperative antibiotic therapy. Despite vigilant management, nearly one-fifth of our patients sustained wound infections. All infections were successfully managed with broad-spectrum antibiotics, and all limbs were preserved 1-year postoperatively. 23227815 Microbial transformation of asiatic acid. Asiatic acid (1), a major pentacyclic triterpene of Centella asiatica, was subjected to transformation by Penicillium lilacinum ACCC 31890, Fusarium equiseti CGMCC 3.3658, and Streptomyces griseus CGMCC 4.18 strains. Incubation of asiatic acid with P. lilacinum ACCC 31890 and F. equiseti CGMCC 3.3658 gave an identical product: 2α,3β,15α,23-tetrahydroxyurs-12-en-28-oic acid (2). Biotransformation of asiatic acid by S. griseus CGMCC 4.18 resulted in three derivatives: 2α,3β,21β,23-tetrahydroxyurs-12-en-28-oic acid (3), 2α,3β,23-trihydroxyurs-12-en-28, 30-dioic acid (4), and 2α,3β,23,30-tetrahydroxyurs-12-en-28-oic acid (5). The structures of those derivatives were deduced from their spectral data. Products (2), (3), and (4) were new compounds. In addition, the in vitro cytotoxicities of those derivatives along with 1 were evaluated with several human cancer cell lines. 23800267 Improved docking of polypeptides with glide. Predicting the binding mode of flexible polypeptides to proteins is an important task that falls outside the domain of applicability of most small molecule and protein-protein docking tools. Here, we test the small molecule flexible ligand docking program Glide on a set of 19 non-α-helical peptides and systematically improve pose prediction accuracy by enhancing Glide sampling for flexible polypeptides. In addition, scoring of the poses was improved by post-processing with physics-based implicit solvent MM-GBSA calculations. Using the best RMSD among the top 10 scoring poses as a metric, the success rate (RMSD ≤ 2.0 Å for the interface backbone atoms) increased from 21% with default Glide SP settings to 58% with the enhanced peptide sampling and scoring protocol in the case of redocking to the native protein structure. This approaches the accuracy of the recently developed Rosetta FlexPepDock method (63% success for these 19 peptides) while being over 100 times faster. Cross-docking was performed for a subset of cases where an unbound receptor structure was available, and in that case, 40% of peptides were docked successfully. We analyze the results and find that the optimized polypeptide protocol is most accurate for extended peptides of limited size and number of formal charges, defining a domain of applicability for this approach. 23265763 Patient awareness of extraintestinal manifestations of inflammatory bowel disease. Patient awareness of extraintestinal manifestations of inflammatory bowel diseases is important in improving patient understanding of their disease and health outcomes. We aim to characterize patient awareness of extraintestinal complications related to their disease. A cross-sectional survey was administered from July 2011 to May 2012. All adult (>18years) IBD patients attending gastroenterology clinics at a major tertiary teaching hospital (Mount Sinai Hospital, Toronto, ON, Canada) with a confirmed diagnosis of inflammatory bowel disease were invited to participate. A total of 299 patients participated: 177 Crohn's disease, 104 ulcerative colitis, and 18 IBD-unclassified. The vast majority of respondents obtained their information from their gastroenterologist (92%) and from the internet (78%). Most patients felt their inflammatory bowel disease knowledge was "very good" (34%) or "enough to get by" (54%). Most patients were aware of risk of colon cancer (75%), arthritis (77%), dermatological manifestations (49%), ocular inflammation (47%), and osteoporosis (53%). However, few patients were aware of venous thromboembolism (18%), nephrolithiasis (12%), or primary sclerosing cholangitis (20%). The majority of respondents were unsure of the signs and symptoms of venous thromboembolism, that the risk was increased during flares and hospitalizations, and that they require prophylaxis during an inflammatory bowel disease-related hosp italization. Although the majority of respondents demonstrated awareness of most extraintestinal manifestations, few realized that venous thromboembolism was a life-threatening systemic complication of inflammatory bowel disease. Greater knowledge of venous thromboembolism would enable patients to more promptly seek potentially life-saving intervention. 23913947 Experimental relationships between levels of corticosterone in plasma and feathers in a free-living bird. Integrated measures of corticosterone (CORT), such as from feathers (CORTf), have intuitive appeal because they incorporate both the duration and amplitude of glucocorticoid secretion. An association between CORTf and plasma CORT has never been shown in wild birds, and it is unclear as to when and if these measures should be correlated, given that they are fundamentally different yet related measures of physiology. We hypothesized that CORTf should correlate with instantaneous measurements of plasma CORT when the latter reflect sustained changes in the activity of the hypothalamic-pituitary-adrenal (HPA) axis. To test this, we experimentally manipulated levels of plasma CORT in wild nestling tree swallows (Tachycineta bicolor) using 5-day time-release CORT pellets, and measured plasma CORT and growth parameters before, during, and at the end of hormone manipulation (days 7, 9, and 11 post-hatch, respectively). CORTf and plasma CORT were significantly positively related only when the latter was at its highest and most variable among individuals (day 9). A similar relationship was expected at day 11, but plasma CORT had returned to near original levels. Nestlings with higher CORTf were smaller, lighter, and less likely to fledge, but we did not detect seasonal effects on CORTf. Our results clearly demonstrate that CORTf from free-living birds can reflect plasma CORT, but correlations may not always be expected, especially if elevations in plasma CORT are relatively modest and of short duration. Our work suggests that CORTf is best used to study activity of the HPA axis over relatively long time frames and can be used effectively to advance avian ecology. 23469759 Synthesis and relaxometric characterization of a MRI Gd-based probe responsive to glutamic acid decarboxylase enzymatic activity. Novel contrast agent based systems, which selectively visualize specific cells, e.g., neurons in the brain, would be of substantial importance for the fast developing field of molecular magnetic resonance imaging (MRI). We report here the synthesis and in vitro validation of a Gd(III)-based contrast agent designed to act as an MRI responsive probe for imaging the activity of the enzyme glutamic acid decarboxylase (GAD) present in neurons. Upon the action of the enzyme, the Gd(III) complex increases its hydration sphere and takes on a residual positive charge that promotes its binding to endogenous macromolecules. Both effects contribute in a synergic way to generate a marked relaxation enhancement, which directly reports enzyme activity and will allow activity detection of GAD positive cells in vitro and in vivo selectively. 23643364 Inference based on diagnostic measures from studies of new imaging devices. Before using a new diagnostic imaging device regularly in a clinic, it should be studied using patients and radiologists. Often such studies report diagnostic performance in terms of sensitivity, specificity, area under the receiver operating characteristic curve (AUC), or differences thereof. In this report we look at how these studies differ from actual future clinical practice and how those differences may affect reported performance measures. We review signal detection (receiver operating characteristic) theory and decision theory. We compare diagnostic measures from several published studies in medical imaging and examine how they relate to theory and each other. We see that clinical decisions can be modeled using signal detection and decision theories. Sensitivity and specificity are inextricably linked with clinical factors, such as prevalence and costs. Imaging devices are used in many different ways in clinical practice, so that sensitivities, specificities, and AUCs measured in studies of new diagnostic imaging devices will differ from those in actual future clinical use. Measured sensitivities, specificities, and the directions of changes thereof are not necessarily consistent or reproducible across studies of new diagnostic devices. A change in the AUC, which should be independent of clinical costs or prevalence, is a consistent measure across similar studies, and a positive change in AUC is indicative of additional diagnostic information that will be available to radiologists in a future clinical environment. 23122095 Effect of extrusion conditions on physicochemical and sensorial properties of corn-broad beans (Vicia faba) spaghetti type pasta. Corn-broad bean spaghetti type pasta was made with a corn/broad bean flour blend in a 70:30 ratio, through an extrusion-cooking process (Brabender 10 DN single-screw extruder with a 3:1 compression ratio). The effect of temperature (T=80, 90 and 100°C) and moisture (M=28%, 31% and 34%) on the extrusion responses (specific consumption of mechanical energy and pressure) and the quality of this pasta-like product (expansion, cooking-related losses, water absorption, firmness and stickiness) was assessed. The structural changes of starch were studied by means of DSC and XRD. The extrusion-cooking process, at M=28% and T=100°C, is appropriate to obtain corn-broad bean spaghetti-type pasta with high protein and dietary fibre content and adequate quality. The cooking characteristics and resistance to overcooking depended on the degree of gelatinisation and formation of amylose-lipid complexes. The critical gelatinisation point was 46.55%; beyond that point, the quality of the product declines. 23439409 Difficulties in functioning 1 year after injury: the role of preinjury sociodemographic and health characteristics, health care and injury-related factors. To identify the role of preinjury sociodemographic and health characteristics, injury and injury-related health care characteristics in determining functional outcomes 12 months after injury. Prospective cohort study involving 1-year follow-up. Community. Study participants (N=2282; age range, 18-64y inclusive) were those in the Prospective Outcomes of Injury Study who completed the 12-month interview. The original cohort of 2856 were injured and registered with New Zealand's national no-fault injury insurance agency. With the exception of injury and hospitalization, information on predictors and outcomes was obtained directly from the participants, primarily by telephone interviews, approximately 3 and 12 months after their injury. Not applicable. The functional outcomes of interest were the 5 dimensions of the EQ-5D plus a cognitive dimension. Our multivariate analyses included adjustment for preinjury EQ-5D status and time between injury and the 12-month interview. Substantial portions of participants continued to have adverse outcomes, especially pain/discomfort, 12 months after their injury. The significance of factors varied by outcome. Factors adversely associated with at least 3 of the 6 outcomes were preinjury EQ-5D status, being female, aged 45 to 64 years, inadequate household income, preinjury disability, 2 or more prior chronic illnesses, smoking regularly, dislocation or sprains to the spine or upper extremities, and having a relatively severe injury. A range of preinjury sociodemographic and health characteristics are associated with several adverse functional outcomes 1 year after injury, independent of the nature and severity of injury. The latter, however, also have independent effects on the outcomes. 23602441 Synthesis and antiproliferative evaluation of piperazine-1-carbothiohydrazide derivatives of indolin-2-one. By varying the substituents (R(1)) at the indolin-2-one scaffold, a series of indolin-2-one derivatives bearing 4-phenylpiperazine-1-carbothiohydrazide moiety at the C3-position were synthesized and evaluated for their antiproliferative activity against three human cancer cell lines. We further selected the 5-chloroindolin-2-one moiety for the extension to another series of compounds by varying the substituents (R(2)) at the phenyl group connected with the piperazine ring. Among all the compounds synthesized, 6d and 6l were most potent with IC50 values of 3.59 and 5.58μM, respectively against A549 lung cancer cells, while 5f and 6l possessed IC50 values of 3.49 and 4.57μM, respectively against HCT-116 colon cancer cells which were comparable to that of Sunitinib, an indolin-2-one derivative in cancer therapy. 23828220 A novel self-assembling peptide with UV-responsive properties. A novel heptapeptide comprising Ile-Gln-Ser-Pro-His-Phe-Phe (IQSPHFF) identified and found to undergo self-assembly into microparticles in solution. To understand the effects of ultraviolet irradiation on the self-assembly process, IQSPHFF solutions were exposed to the UV light of 365 nm at room temperature. This exposure was found to have a profound effect on the morphology of the self-assembled aggregates, converting the microparticles to nanorod shapes. Circular dichroism and FT-IR studies indicated distinct structural differences in the arrangements of the peptide moeities before and after ultraviolet irradiation. However, Mass spectrum analysis and high performance liquid chromatography of the peptide molecules before and after UV irradiation demonstrated that the chemical structure of IQSPHFF was not changed. UV-visible spectroscopy and fluorescence spectroscopy studies showed that the absorption peak both increased after ultraviolet irradiation. Overall, our data show that the heptapeptide with UV-responsive properties. 23910950 FimH adhesin from host unrestricted Salmonella Enteritidis binds to different glycoprotein ligands expressed by enterocytes from sheep, pig and cattle than FimH adhesins from host restricted Salmonella Abortus-ovis, Salmonella Choleraesuis and Salmonella Dublin. Adhesion to gut tissues and colonization of the alimentary tract, two important stages in the pathogenesis of Salmonella, are mediated by FimH adhesin of type 1 fimbriae. It was suggested that minor differences in the structure of FimH are most likely associated with differences in adhesion specificities, and may determine the tropism of various Salmonella serovars to different species and tissues. We investigated this hypothesis by comparing the binding properties of FimH proteins from three Salmonella enterica serovars with limited (Choleraesuis, Dublin) or restricted (Abortusovis) host ranges to FimH from broad host range S. Enteritidis and mannose inactive FimH from S. Gallinarum. Although all active variants of FimH protein were able to bind mannose-rich glycoproteins (RNase B, HRP and Man-BSA) with comparable affinity measured by surface plasmon resonance, there were significant differences in the binding profiles of the FimH proteins from host restricted serovars and host unrestricted serovar Enteritidis, to glycoproteins from enterocyte cell lines established in vitro and derived from sheep, pig and cattle. When low-binding FimH adhesin from S. Enteritidis was subjected to Western blot analysis, it bound to surface membrane protein of about 130kDa, and high-binding FimH adhesins from S. Abortusovis, S. Choleraesuis and S. Dublin bound to surface membrane protein of about 55kDa present in each cell line. Differential binding of FimH proteins from host-restricted and broad-host-range Salmonella to intestinal receptors was confirmed using mutant FimH adhesins obtained by site-directed mutagenesis. It was found that the low-binding variant of FimH from S. Choleraesuis with mutation Leu57Pro lost the ability to bind protein band of 55kDa, but instead interacted with glycoprotein of about 130kDa. On the other hand, the high-binding variant of FimH adhesin from S. Enteritids with mutation Asn101Ser did not bind to its receptor of 130kDa, but instead it interacted with glycoprotein ligand of 55kDa. These results suggest that FimH adhesins of type 1 fimbriae are one of the factors responsible for different host-specificities of these Salmonella serovars. 23808780 Natural course of thyroid disease profile in a population in nutrition transition: Tehran Thyroid Study. There is a lack of data regarding the incidence rate, etiology, risk factors, and natural course of thyroid disorders and their relationship with cardiovascular disease and mortality in populations undergoing nutrition transition. Therefore, we aimed to assess the natural course of thyroid disease in Tehranians, a population in nutrition transition. Between March 1997 and December 2004, 5769 individuals, aged ≥ 20 years, were selected from district No.13 of Tehran and followed up every three years. Data on risk factors for cardiovascular disease such as diabetes, hyperlipidemia, smoking, obesity, hypertension, low levels of physical activity, and dietary habits were obtained at baseline and again every three years. Cardiovascular and mortality outcomes were assessed in detail. The results of this study will provide a better recognition regarding the incidence and risk factors of thyroid disorders and their relationship with cardiovascular outcomes and mortality in a community in nutrition transition. 23881200 Evidence for Rapamycin Toxicity in Pancreatic β-Cells and a Review of the Underlying Molecular Mechanisms. Rapamycin is used frequently in both transplantation and oncology. Although historically thought to have little diabetogenic effect, there is growing evidence of β-cell toxicity. This Review draws evidence for rapamycin toxicity from clinical studies of islet and renal transplantation, and of rapamycin as an anticancer agent, as well as from experimental studies. Together, these studies provide evidence that rapamycin has significant detrimental effects on β-cell function and survival and peripheral insulin resistance. The mechanism of action of rapamycin is via inhibition of mammalian target of rapamycin (mTOR). This Review describes the complex mTOR signaling pathways, which control vital cellular functions including mRNA translation, cell proliferation, cell growth, differentiation, angiogenesis, and apoptosis, and examines molecular mechanisms for rapamycin toxicity in β-cells. These mechanisms include reductions in β-cell size, mass, proliferation and insulin secretion alongside increases in apoptosis, autophagy, and peripheral insulin resistance. These data bring into question the use of rapamycin as an immunosuppressant in islet transplantation and as a second-line agent in other transplant recipients developing new-onset diabetes after transplantation with calcineurin inhibitors. It also highlights the importance of close monitoring of blood glucose levels in patients taking rapamycin as an anticancer treatment, particularly those with preexisting glucose intolerance. 23778991 Tunable electronic interactions between anions and perylenediimide. Over the past decade anion-π interaction has emerged as a new paradigm of supramolecular chemistry of anions. Taking advantage of the electronic nature of anion-π interaction, we have expanded its boundaries to charge-transfer (CT) and formal electron transfer (ET) events by adjusting the electron-donating and accepting abilities of anions and π-acids, respectively. To establish that ET, CT, and anion-π interactions could take place between different anions and π-acids as long as their electronic and structural properties are conducive, herein, we introduce 3,4,9,10-perylenediimide (PDI-1) that selectively undergoes thermal ET from strong Lewis basic hydroxide and fluoride anions, but remains electronically and optically silent to poor Lewis basic anions, as ET and CT events are turned OFF. These interactions have been fully characterized by UV/Vis, NMR, and EPR spectroscopies. These results demonstrate the generality of anion-induced ET events in aprotic solvents and further refute a notion that strong Lewis basic hydroxide and fluoride ions can only trigger nucleophilic attack to form covalent bonds instead of acting as sacrificial electron donors to π-acids under appropriate conditions. 23223407 Parenteral nutrition-associated hyperglycemia in non-critically ill inpatients increases the risk of in-hospital mortality (multicenter study). OBJECTIVE Hyperglycemia may increase mortality in patients who receive total parenteral nutrition (TPN). However, this has not been well studied in noncritically ill patients (i.e., patients in the nonintensive care unit setting). The aim of this study was to determine whether mean blood glucose level during TPN infusion is associated with increased mortality in noncritically ill hospitalized patients. RESEARCH DESIGN AND METHODS This prospective multicenter study involved 19 Spanish hospitals. Noncritically ill patients who were prescribed TPN were included prospectively, and data were collected on demographic, clinical, and laboratory variables as well as on in-hospital mortality. RESULTS The study included 605 patients (mean age 63.2 ± 15.7 years). The daily mean TPN values were 1.630 ± 323 kcal, 3.2 ± 0.7 g carbohydrates/kg, 1.26 ± 0.3 g amino acids/kg, and 0.9 ± 0.2 g lipids/kg. Multiple logistic regression analysis showed that the patients who had mean blood glucose levels >180 mg/dL during the TPN infusion had a risk of mortality that was 5.6 times greater than those with mean blood glucose levels <140 mg/dL (95% CI 1.47-21.4 mg/dL) after adjusting for age, sex, nutritional state, presence of diabetes or hyperglycemia before starting TPN, diagnosis, prior comorbidity, carbohydrates infused, use of steroid therapy, SD of blood glucose level, insulin units supplied, infectious complications, albumin, C-reactive protein, and HbA1c levels. CONCLUSIONS Hyperglycemia (mean blood glucose level >180 mg/dL) in noncritically ill patients who receive TPN is associated with a higher risk of in-hospital mortality. 23940754 Whey protein reduces early life weight gain in mice fed a high-fat diet. An increasing number of studies indicate that dairy products, including whey protein, alleviate several disorders of the metabolic syndrome. Here, we investigated the effects of whey protein isolate (whey) in mice fed a high-fat diet hypothesising that the metabolic effects of whey would be associated with changes in the gut microbiota composition. Five-week-old male C57BL/6 mice were fed a high-fat diet ad libitum for 14 weeks with the protein source being either whey or casein. Faeces were collected at week 0, 7, and 13 and the fecal microbiota was analysed by denaturing gradient gel electrophoresis analyses of PCR-derived 16S rRNA gene (V3-region) amplicons. At the end of the study, plasma samples were collected and assayed for glucose, insulin and lipids. Whey significantly reduced body weight gain during the first four weeks of the study compared with casein (P<0.001-0.05). Hereafter weight gain was similar resulting in a 15% lower final body weight in the whey group relative to casein (34.0±1.0 g vs. 40.2±1.3 g, P<0.001). Food intake was unaffected by protein source throughout the study period. Fasting insulin was lower in the whey group (P<0.01) and glucose clearance was improved after an oral glucose challenge (P<0.05). Plasma cholesterol was lowered by whey compared to casein (P<0.001). The composition of the fecal microbiota differed between high- and low-fat groups at 13 weeks (P<0.05) whereas no difference was seen between whey and casein. In conclusion, whey initially reduced weight gain in young C57BL/6 mice fed a high-fat diet compared to casein. Although the effect on weight gain ceased, whey alleviated glucose intolerance, improved insulin sensitivity and reduced plasma cholesterol. These findings could not be explained by changes in food intake or gut microbiota composition. Further studies are needed to clarify the mechanisms behind the metabolic effects of whey. 23621491 Study of Charge-Dependent Transport and Toxicity of Peptide-Functionalized Silver Nanoparticles Using Zebrafish Embryos and Single Nanoparticle Plasmonic Spectroscopy. Nanomaterials possess unusually high surface area-to-volume ratios, and surface-determined physicochemical properties. It is essential to understand their surface-dependent toxicity in order to rationally design biocompatible nanomaterials for a wide variety of applications. In this study, we have functionalized the surfaces of silver nanoparticles (Ag NPs, 11.7 ± 2.7 nm in diameters) with three biocompatible peptides (CALNNK, CALNNS, CALNNE) to prepare positively (Ag-CALNNK NPs+ζ), negatively (Ag-CALNNS NPs-2ζ), and more negatively charged NPs (Ag-CALNNE NPs-4ζ), respectively. Each peptide differs in a single amino acid at its C-terminus, which minimizes the effects of peptide sequences and serves as a model molecule to create positive, neutral and negative charges on the surface of the NPs at pH 4-10. We have studied their charge-dependent transport into early-developing (cleavage-stage) zebrafish embryos and their effects on embryonic development using dark-field optical microscopy and spectroscopy (DFOMS). We found that all three Ag-peptide NPs passively diffused into the embryos via their chorionic pore canals, and stayed inside the embryos throughout their entire development (120 h), showing charge-independent diffusion modes and charge-dependent diffusion coefficients. Notably, the NPs create charge-dependent toxic effects on embryonic development, showing that the Ag-CALNNK NPs+ζ (positively charged) are the most biocompatible while the Ag-CALNNE NPs-4ζ (more negatively charged) are the most toxic. By comparing with our previous studies of the same sized citrated Ag and Au NPs, the Ag-peptide NPs are much more biocompatible than the citrated Ag NPs, and nearly as biocompatible as the Au NPs, showing the dependence of nanotoxicity upon the surface charges, surface functional groups and chemical compositions of the NPs. This study also demonstrates powerful applications of single NP plasmonic spectroscopy for quantitative analysis of single NPs in vivo and in tissues, and reveals the possibility of rational design of biocompatible NPs. 23669229 Drug-Resistant Tuberculosis Treatment Complicated by Antiretroviral Resistance in HIV Coinfected Patients: A Report of Six Cases in Lesotho. Abstract. Treating drug-resistant tuberculosis (DR-TB) is particularly challenging in high human immunodeficiency virus (HIV) prevalence settings. Neither antiretroviral resistance testing nor viral load monitoring is widely available in sub-Saharan Africa, and antiretroviral resistance can complicate the clinical management for DR-TB/HIV coinfected patients. We describe six cases of antiretroviral resistance in DR-TB patients with HIV coinfection in Lesotho. Two patients died before or immediately after antiretroviral resistance was detected by genotyping; the remaining four patients were switched to effective antiretroviral therapy (ART) regimens. Favorable DR-TB treatment outcomes in coinfected patients require successful management of their HIV infection, including treatment with an effective ART regimen. Coinfected patients undergoing DR-TB treatment may require closer monitoring of their response to ART, including routine viral load testing, to ensure that they receive an effective ART regimen concurrent with DR-TB treatment. 23578613 An optimised method for the accurate determination of zeranol and diethylstilbestrol in animal tissues using isotope dilution-liquid chromatography/mass spectrometry. Isotope dilution-liquid chromatography/mass spectrometry (ID-LC/MS) has been established as a candidate reference method for the accurate determination of growth promoters (zeranol, taleranol, and diethylstilbesterol) in raw meat samples. Sample preparation processes including an enzymatic hydrolysis, extraction, and SPE clean-up were optimised. The sensitivity difference of trans- and cis-diethylstilbestrol (isomerizing in sample preparation processes) by the LC/MS was measured by running a trans/cis mixture (ratio measured by a quantitative NMR) with and without sample matrices, and applied for the determination of total diethylstilbestrol. Validity, repeatability, and reproducibility of the analytical method were tested by measuring gravimetrically fortified samples (chicken breast, bovine muscles, and porcine muscle) in a number of different time periods. Measurement results agreed with the fortified values within their uncertainties. The method provided accurate results of the target analytes in the range of 0.05-15μg/kg with the relative expanded uncertainty of 2-15%. 23823462 Disconnecting cognition. The aim is to assess whether the recent surge in brain 'connectivity' studies has improved our understanding of neurological deficits and in particular so-called disconnection syndromes. Across a large variety of brain diseases, functional connectivity measures obtained from 'resting state' studies show alterations in distributed neural networks that may be of explanatory value for disease severity. In parallel, studies of structural connectivity reveal how damage to identified fiber tracts can yield specific clinical symptoms. These methods are not only permitting testing of the disconnection mechanism in the few syndromes where it has classically been suspected, but also starting to propose disconnection accounts for other syndromes that have not been conceptualized this way before. Finally, both structural and functional connectivity studies contribute to improve the mechanistic understanding of cognitive deficits in disseminated white matter disease. In many respects, studies of structural and functional connectivity using MRI are providing critical novel empirical evidence for--and also against--disconnection as the relevant pathomechanism in neurological syndromes. At the same time, the observation of altered long-range correlation of activity in a wide variety of brain diseases may also be overinterpreted as disconnection, which dilutes an originally rather specific understanding of this concept. 23764235 Dietary melatonin supplementation alters uteroplacental amino acid flux during intrauterine growth restriction in ewes. Dietary melatonin supplementation during mid- to late-gestation increased umbilical artery blood flow and caused disproportionate fetal growth. This melatonin-induced increase in umbilical artery blood flow may alter nutrient availability to the fetus, which may lead to alterations in fetal size. The objectives of the current experiment were to determine amino acid (AA) and glucose concentrations as well as AA and glucose flux across the uteroplacenta using a mid- to late-gestation model of intrauterine growth restriction supplemented with dietary melatonin as a 2 × 2 factorial design. At day 50 of gestation, 32 ewes were supplemented with 5 mg of melatonin (MEL) or no melatonin (CON) and were allocated to receive 100% (adequate; ADQ) or 60% (restricted; RES) of nutrient requirements. On day 130 of gestation, uterine and umbilical blood flows were determined via Doppler ultrasonography during a non-survival surgery. Blood samples were collected under general anesthesia from the maternal saphenous artery, gravid uterine vein, umbilical artery, and umbilical vein for AA analysis and glucose. Total α-AA concentrations in maternal artery and gravid uterine vein were decreased (P < 0.05) in RES v. ADQ fed ewes. Maternal arterial - venous difference in total α-AA was increased (P ⩽ 0.01) in RES v. ADQ fed ewes, while total uterine α-AA flux was not different (P > 0.40) across all treatment groups. Fetal venous - arterial difference in total α-AA as well as uteroplacental flux of total α-AA were decreased (P < 0.05) in CON-RES v. CON-ADQ, and similar (P > 0.20) in MEL-RES v. CON-ADQ. Maternal concentrations and uterine flux of branched-chain AA (BCAA) were not different across all treatment groups; however, fetal uptake of BCAA was decreased (P < 0.05) in CON-RES v. CON-ADQ, and similar (P > 0.20) in MEL-RES v. CON-ADQ. Uterine uptake of glucose was not different (P ⩾ 0.08) across all treatment groups, while uteroplacental uptake of glucose was increased (P ⩽ 0.05) in RES v. ADQ ewes. In conclusion, maternal nutrient restriction increased maternal arterial - venous difference in total α-AA, while total uterine α-AA flux was unaffected by maternal nutrient restriction. Melatonin supplementation did not impact maternal serum concentrations or uterine flux of glucose or AA; however, melatonin did improve fetal BCAA uptake during maternal nutrient restriction. 23477604 Ocular effects of pegylated interferon-α in patients with chronic hepatitis B. Abstract Purpose: To evaluate the early retinal changes and its reflection on the visual field examination in chronic hepatitis B (CHB) patients using pegylated interferon-α (PEGIFN-α) monotherapy. Patients and methods: Thirty eyes of fifteen patients with CHB were examined prospectively for changes in the fundus examination and visual field examination (both Humphrey Perimetry and Frequency Doubling Perimetry). The patients were examined before and in 3 months intervals after starting the PEGIFN-α treatment. The changes in the fundus examination were noted and the visual field examinations, retinal nerve fiber thickness, Schirmer scores and color vision before and at 3 months of the treatment were compared. The statistical evaluation was performed with paired-t test, using SPSS 16.0 Inc. (Chicago, IL). Results: The mean age of the 15 patients (seven male, eight female) was 52.5 ± 12.4 years. There was no significant retinal change in none of the patients. Neither the visual field examination with Humphrey Field Analyzer nor the Frequency Doubling Perimetry results has demonstrated any significant change during 3 months follow-up. There was a statistically significant increase in the retinal nerve fiber layer (RNFL) thickness; while Schirmer test scores for dry eye assessment was significantly decreased. Conclusion: PEGIFN-α monotherapy, which is used for treatment of CHB, may cause some changes in the thickness of RNFL that may necessitate the close follow-up for further morphological changes of the optic disc in these patients. 23938012 Retrievable stent thrombectomy in the treatment of acute ischemic stroke: Analysis of a revolutionizing treatment technique. Acute ischemic stroke resulting from intracranial vessel occlusion is associated with high morbidity and mortality. The mainstays of therapy are fibrinolytics and mechanical thrombectomy in properly selected patients. A new Food and Drug Administration-approved technology to perform thrombectomy, retrievable stenting, may provide superior revascularization rates and improved patient outcomes. We analyzed the cumulative human experience reported for the Trevo Pro Retrieval System (Stryker, Kalamazoo, MI, USA) and the Solitaire FR Revascularization Device (ev3, Irvine, CA, USA) as the definitive treatment for acute ischemic stroke. A literature search was undertaken to identify studies using the retrievable stents published up to September 2012. Nineteen studies identified a total of 576 patients treated with either the Trevo (n=221) or Solitaire (n=355) devices. Pooled data analysis identified median baseline National Institutes of Health Stroke Scale scores of 18.5±0.289 (standard error of the mean) and 17.9±0.610, and time to recanalization of 53.9±23.6minutes and 59.0±8.0minutes for the Trevo and Solitaire groups, respectively. Recanalization was variably defined by individual studies, most commonly achieving at least a thrombolysis in cerebral infarction score of 2a-3 or a thrombolysis in myocardial infarction score of 2-3. Revascularization (83%, 82%), mortality (31%, 14%), hemorrhage (8%, 6%), device complications (5%, 6%), and good patient outcomes (51%, 47%) were found with the Trevo and Solitaire devices, respectively. Preliminary analysis reveals excellent clinical outcomes for retrievable stent technology. This may be attributable to both high rates of revascularization with a relatively short time to perfusion restoration. 23507034 Sox10-MCS5 enhancer dynamically tracks human oligodendrocyte progenitor fate. In this study, we sought to establish a novel method to prospectively and dynamically identify live human oligodendrocyte precursor cells (OPCs) and oligodendrocyte lineage cells from brain dissociates and pluripotent stem cell culture. We selected a highly conserved enhancer element of the Sox10 gene, known as MCS5, which directs reporter expression to oligodendrocyte lineage cells in mouse and zebrafish. We demonstrate that lentiviral Sox10-MCS5 induced expression of GFP at high levels in a subpopulation of human CD140a/PDGFαR-sorted OPCs as well as their immature oligodendrocyte progeny. Furthermore, we show that almost all Sox10-MCS5:GFP(high) cells expressed OPC antigen CD140a and human OPCs expressing SOX10, OLIG2, and PDGFRA mRNAs could be prospectively identified using GFP based fluorescence activated cells sorting alone. Additionally, we established a human induced pluripotent cell (iPSC) line transduced with the Sox10-MCS5:GFP reporter using a Rex-Neo cassette. Similar to human primary cells, GFP expression was restricted to embryoid bodies containing both oligodendrocyte progenitor and oligodendrocyte cells and co-localized with NG2 and O4-positive cells respectively. As such, we have developed a novel reporter system that can track oligodendrocyte commitment in human cells, establishing a valuable tool to improve our understanding and efficiency of human oligodendrocyte derivation. 23838439 DNA Replication Origins. The onset of genomic DNA synthesis requires precise interactions of specialized initiator proteins with DNA at sites where the replication machinery can be loaded. These sites, defined as replication origins, are found at a few unique locations in all of the prokaryotic chromosomes examined so far. However, replication origins are dispersed among tens of thousands of loci in metazoan chromosomes, thereby raising questions regarding the role of specific nucleotide sequences and chromatin environment in origin selection and the mechanisms used by initiators to recognize replication origins. Close examination of bacterial and archaeal replication origins reveals an array of DNA sequence motifs that position individual initiator protein molecules and promote initiator oligomerization on origin DNA. Conversely, the need for specific recognition sequences in eukaryotic replication origins is relaxed. In fact, the primary rule for origin selection appears to be flexibility, a feature that is modulated either by structural elements or by epigenetic mechanisms at least partly linked to the organization of the genome for gene expression. 23677569 Oligonucleotide suppression of bcl-2 in LNCaP cells is compensated by increased androgen sensitivity, p53 and oncogene activity, and suppressed caspase-3. Antisense oligonucleotides (oligos) have been employed against prostate cancer models in both in vivo and in vitro systems. While most target growth factors or their receptors, other oligos are directed against inhibitors of apoptosis or mediators of androgen action. Those which suppress bcl-2 activity (in prostate cancer patients) have even reached clinical trials. We evaluated a set of oligos which targeted and comparably suppressed the expression of bcl-2, an apoptosis inhibitory protein. Our first study reported that LNCaP cells were adapted by suppression of caspase-3 (a promoter of apoptosis). In this study we evaluated additional proteins associated with tumor progression and found the expression of the androgen receptor, its p300 and IL-6 co-activators, as well as v-myc (oncogenic) and (unexpectedly) tumor suppressor p53 genes to be enhanced. We conclude that oligo treatment directed against bcl-2, intended to stimulate apoptosis, can be evaded through compensatory changes in gene activity associated with additional regulators of apoptosis, androgen sensitivity and oncogenesis. This suggests that therapeutic suppression of bcl-2 can promote tumor resistance and transformation to a more aggressive (androgen and oncogene driven) phenotype. 23872287 Proximity to terror and post-traumatic stress: a follow-up survey of governmental employees after the 2011 Oslo bombing attack. To assess the prevalence of post-traumatic stress disorder (PTSD) symptoms among governmental employees after the 2011 Oslo bombing attack targeted towards the Norwegian Ministries, and to explore the importance of proximity to the bomb explosion as a predictor of PTSD. A cross-sectional study. Data were collected from a survey 10 months after the Oslo bombing on 22 July 2011. A total of 3520 employees were invited to the study. Net samples comprised 1927 employees in 14 of the 17 Norwegian Ministries. The employees reported where they were at the time of the explosion. PTSD was assessed with the Norwegian version of the PTSD checklist (PCL). A total of 207 of the 1881 (11%) ministerial employees who completed the survey were present at work when the bomb exploded. Of these, a quarter (24%, 95% CI 18.4 to 30.0) had symptom levels equivalent to PTSD, while the prevalence was approximately 4% among those not present at work. In the latter group the prevalence was similar irrespective of whether their location was in Oslo, other places in Norway or abroad. Leadership responsibility was associated with lower risk for PTSD. The risk of PTSD is mainly associated with being present at work at the time of a terror attack. For those not present at work, the risk of PTSD is low and independent of proximity to the terror scene. The findings may have implications for planning and priority of healthcare services after a work place terror attack. 23856336 Walking more slowly than with normal velocity: The influence on trunk and pelvis kinematics in young and older healthy persons. Few studies have addressed trunk and pelvis movements during gait, although they play an important role in gait control. The aim of this study was to compare trunk and pelvis kinematics between slower walking (1, 2, 3, 4kmph) and normal walking (5kmph), and between healthy adults who were young (n=15, 20-30years) and older (n=17, 50-60years). After 4min of treadmill walking, the 3-dimensional trunk and pelvis kinematics was measured (Polhemus Liberty™, 250Hz). A repeated measures ANOVA with simple contrasts was used to look for differences between the velocity conditions of walking and independent t-testing for comparison between the age groups (significance level: 5%, SPSS20). Walking more slowly than with normal velocity induces (1) a decrease in vertical center of mass of the trunk displacement, trunk lateral flexion and axial rotation and pelvis lateral and antero-posterior tilting, and (2) an increase in lateral and antero-posterior center of mass of the trunk displacement. Compared to young persons, older persons show: (1) larger pelvis axial rotations and trunk lateral and antero-posterior movements, and (2) smaller pelvis lateral tilting and trunk vertical movements and rotations. The literature reports that patients often walk slowly and that older persons show different gait patterns compared to young persons. This study shows that there are changes in trunk and pelvis kinematics (1) when walking more slowly than with normal velocity and (2) in older persons compared to young persons. These data could be taken into account in gait rehabilitation. 23966394 Effects of Cellular Activation on Anti-HIV-1 Restriction Factor Expression Profile in Primary Cells. Expression of cell-intrinsic antiviral factors suppresses HIV-1 replication. We hypothesized that cellular activation modulates host restriction and susceptibility to HIV-1 infection. We measured the gene expression of 34 antiviral factors in healthy PBMC. Cellular activation induced expression of ISG15, TRIM5α, BST-2/tetherin and certain APOBEC3-family members. Expression of RTF1, PAF1, TRIM11, TRIM26 and BST-2/tetherin correlated with decreased HIV-1 infectivity. This study demonstrates synchronous effects of activation-induced antiviral genes on HIV-1 infectivity, providing candidates for pharmacological manipulation. 23172657 Atomically flat, large-sized, two-dimensional organic nanocrystals. Large-sized, 2D single crystals of perylene are grown by both solution-cast and physical vapor transport methods. The crystals have a atomically flat parallelogram morphology and the aspect ratios of the lateral extension compared to the thickness are up to 10(3) . The atomically flat feature leads to good interface contact, making a single-crystal field-effect transistor with higher mobility. The mobility of atomically flat crystals can be 10(3) -10(4) times higher than rough crystals. 23938387 Rhodnius prolixus and Rhodnius robustus-like (Hemiptera, Reduviidae) wing asymmetry under controlled conditions of population density and feeding frequency. Habitat change in Rhodnius spp may represent an environmental challenge for the development of the species, particularly when feeding frequency and population density vary in nature. To estimate the effect of these variables in stability on development, the degree of directional asymmetry (DA) and fluctuating asymmetry (FA) in the wing size and shape of R. prolixus and R. robustus-like were measured under laboratory controlled conditions. DA and FA in wing size and shape were significant in both species, but their variation patterns showed both inter-specific and sexual dimorphic differences in FA of wing size and shape induced by nutrition stress. These results suggest different abilities of the genotypes and sexes of two sylvatic and domestic genotypes of Rhodnius to buffer these stress conditions. However, both species showed non-significant differences in the levels of FA between treatments that simulated sylvan vs domestic conditions, indicating that the developmental noise did not explain the variation in wing size and shape found in previous studies. Thus, this result confirm that the variation in wing size and shape in response to treatments constitute a plastic response of these genotypes to population density and feeding frequency. 23886810 Synthesis and insecticidal activities of 2,3-dihydroquinazolin-4(1H)-one derivatives targeting calcium channel. A series of compounds containing dihydroquinazolinone moiety was designed and synthesized. Amine bridge part was changed in comparison with known anthranilic diamides insecticides. Their insecticidal activities against oriental armyworm (Mythimna separata) indicated that most of the compounds showed moderate to high activities at the tested concentrations. In particular, compounds 5a and 5k showed 80% larvicidal activities against oriental armyworm at the concentration of 5mg/L. The present study also explored the possible effects of target compounds on the high voltage-gated calcium channel and the calcium channels in the endoplasmic reticulum in the central neurons isolated from the third instar larvae of Spodoptera exigua using whole-cell patch clamp and calcium imaging technique. The results showed that compound 5a activated the high voltage-gated calcium channel in the central neurons of S. exigua weakly. The peak currents only increased by 6% of the initial value at the end of the 10-min recording after treated with 0.22μM 5a, while chlorantraniliprole has an opposite effect. The effects of 5a on the intracellular calcium ion concentration ([Ca(2+)]i) in neurons were well investigated. The experimental results indicated that these novel compounds have different mechanism compared with chlorantraniliprole. 23829223 Influence of Activin A Supplementation During Human Embryonic Stem Cell Derivation on Germ Cell Differentiation Potential. Human embryonic stem cells (hESCs) are more similar to "primed" mouse epiblast stem cells (mEpiSCs). mEpiSCs, which are derived in Activin A, show an increased propensity to form primordial germ cell (PGC)-like cells in response to bone morphogenic protein 4 (BMP4). Hence, we hypothesized that hESCs derived in the presence of Activin A may be more competent in differentiating towards PGC-like cells after supplementation with BMP4 compared to standard hESC lines. We were able to successfully derive two hESC lines in the presence of Activin A, which were pluripotent and showed higher base levels of STELLA and cKIT compared to standard hESC lines derived without Activin A addition. Furthermore, upon differentiation as embryoid bodies in the presence of BMP4, we observed upregulation of VASA at day 7, both at the transcript and protein level compared to standard hESC lines, which appeared to take longer time for PGC specification. Unlike other hESC lines, nuclear pSMAD2/3 presence confirmed that Activin signalling was switched on in Activin A-derived hESC lines. They were also responsive to BMP4 based on nuclear detection of pSMAD1/5/8 and showed endodermal differentiation as a result of GATA-6 expression. Hence, our results provide novel insights into the impact of hESC derivation in the presence of Activin A and its subsequent influence on germ cell differentiation potential in vitro. 23454288 In vivo assessment of specific cytotoxic T lymphocyte killing. The direct killing of target cells by cytotoxic T lymphocytes (CTLs) plays a fundamental role in protective immunity to viral, bacterial, protozoan and fungi infections, as well as to tumor cells. In vivo cytotoxic assays take into account the interaction of target and effector cells in the context of the proper microenvironment making the analysis biologically more relevant than in vitro cytotoxic assays. Thus, the development, improvement and validation of in vivo methods are necessary in view of the importance of the results they may provide. We describe and discuss in this manuscript a method to evaluate in vivo specific cytotoxic T lymphocyte killing. We used as model system mice immunized with human recombinant replication-deficient adenovirus 5 (HAd5) containing different transgenes as the trigger of a CTL-mediated immune response. To these mice, we adoptively transferred syngeneic cells labeled with different vital fluorescent dyes. Donor cells were pulsed (target) or not (control non-target) with distinct CD8 T-cell epitopes, mixed in a 1:1 ratio and injected i.v. into immunized or non-immunized recipient mice. After 18-24h, spleen cells are collected and analysed by flow cytometry. A deviation from the 1:1 ratio of control and target cell populations indicates antigen specific lysis of target cells. 23936590 Decellularized porcine pulmonary arteries cross-linked by carbodiimide. The physical properties of the tissues are weakened after decellularization, and the exposed collagen fibers are prone to thrombogenesis. Several studies have proven that the use of carbodiimide (EDC) as a cross-linking agent can improve the properties of decellularized xenogeneic scaffold materials. We adopted EDC for the treatment of porcine pulmonary arteries in an effort to improve the physical properties of these arteries following decellularization. Twenty porcine pulmonary arteries were randomly divided into 3 groups. The control group (group A) consisted of fresh porcine pulmonary arteries with no further processing; group B was treated with trypsin and the detergent Triton X-100 to remove cells; and group C was cross-linked with EDC after trypsin and Triton X-100 treatment, as in group B. The pulmonary arteries were assessed based on water content, thickness, tensile strength, and thermal shrinkage temperature, to evaluate the physical properties of all of the samples. The scaffolds were then subcutaneously embedded in rabbits. These constructs were removed after 4 weeks and checked. The cells and matrix components of the arterial walls were removed and the fibrous scaffolds were retained. In group B, the moisture content of the pulmonary arterial walls was increased; and the thickness of the walls and the tensile strength of the pulmonary arteries were decreased in comparison with group A. In subcutaneous embedding of the group B samples in rabbits, after 4 weeks, fibroblasts had grown into the scaffolds and regenerated the tissue. The water content was decreased in the pulmonary arterial walls, there was an increase in the tensile strength and the thermal shrinkage temperature in group C compared with group B. The EDC-based cross-linking procedure can enhance the tensile strength of decellularized pulmonary arteries and decrease scaffold rejection and degradation and promote tissue regeneration in vivo. 23500140 Ubiquitin C-terminal hydrolase-L5 is required for high glucose-induced transforming growth factor-β receptor I expression and hypertrophy in mesangial cells. Transforming growth factor-β (TGF-β) is pivotal in the pathogenesis of diabetic nephropathy. Type 1 TGF-β receptor (TGF-βR1) is degraded by Smad7-dependent ubiquitination-proteasomal pathway, which is deubiquitinated by ubiquitin C-terminal hydrolase-L5 (UCHL5). Therefore, we studied the role of UCHL5 in high glucose (27.8mM)-induced TGF-βR1 protein expression in mouse mesangial (MES13) cells. UCHL5 short hairpin RNA (shRNA) was used to knock down UCHL5 while LY294002 and the dominant-negative p85 were used to inhibit phosphatidylinositol-3-kinase (PI3K). We found that high glucose increased phospho-Akt, TGF-βR1 mRNA and protein expression. High glucose also increased UCHL5 protein expression, which was attenuated by LY294002, the dominant-negative p85 and the dominant-negative CREB. High glucose-induced TGF-βR1 protein expression and TGF-βR1 protein deubiquitination were attenuated by UCHL5 shRNA. Additionally, high glucose-induced p21(WAF1), fibronectin protein expression and cell hypertrophy were attenuated by UCHL5 shRNA. However, high glucose-induced TGF-βR1 mRNA, p27(kip1) protein expression and growth inhibition were not affected by UCHL5 shRNA. Finally, glomerular UCHL5 and TGF-βR1 protein expression were increased in streptozotocin-diabetic rats at 8weeks. We conclude that PI3K-dependent UCHL5 is required for high glucose-induced TGF-βR1 protein expression in mesangial cells. UCHL5 is also required for high glucose-induced TGF-βR1 protein deubiquitination, p21(WAF1) and fibronectin protein expression and cell hypertrophy. 23912751 Coenzyme Q10 and male infertility: a meta-analysis. To evaluate the effect of coenzyme Q10 treatments in male infertility, specifically in these parameters: live birth and pregnancy rates, CoQ10 seminal concentration, sperm concentration, and sperm motility. Systematic review and meta-analysis in male infertility patients with CoQ10 oral treatments. Three trials were included: 149 males in CoQ10 group and 147 males in placebo group. None of the included trials provided any data regarding live births. The results of this meta-analysis show that supplementing infertile men with CoQ10 does not increase pregnancy rates. The analysis showed, among patients receiving CoQ10 treatment, a statistically significant increase in: CoQ10 seminal concentration (RR 49.55, 95 % CI 46.44 to 52.66, I(2) = 17 %), sperm concentration (RR 5.33, 95 % CI 4.18 to 6.47, I(2) = 58 %), and sperm motility (RR 4.50, 95 % CI 3.92 to 5.08, I(2) = 0 %) CONCLUSION: There is no evidence in the literature that CoQ10 increases either live birth or pregnancy rates, but there is a global improvement in sperm parameters. Adequately powered, robust trials of individual and combination antioxidant therapies are required to guide clinical practice. 23831752 Three nucleus-encoded subunits of mitochondrial cytochrome c oxidase of the whiteleg shrimp Litopenaeus vannamei: cDNA characterization, phylogeny and mRNA expression during hypoxia and reoxygenation. The mitochondrial cytochrome c oxidase (COX) catalyzes the reduction of oxygen to water playing a key role in the respiratory chain and ATP synthesis. The nucleus-encoded COX subunits do not participate in catalysis, but some are known to play a role in the expression, assembly and activity of the enzyme. Since hypoxia continuously affects the shrimp environment, it is important to study COX to understand their ability to deal with low oxygen levels. The goal of this research was to characterize the complementary DNA (cDNA) sequences of three nucleus-encoded subunits -coxIV, coxVa, and coxVb- and to evaluate the shrimp COX response to hypoxia by measuring their gene expression. The cDNA sequence of coxIV consisted of 532bp, which encodes a 17.47kDa protein, while coxVa cDNA consisted of 460bp and coded a protein of 17.11kDa, and the coxVb coding sequence consisted of 364bp encoding a 13.74kDa protein. Shrimp subunits do not have isoforms, and they are not differentially expressed during hypoxia, as observed in mammals. Coordinated changes were detected in the mRNA amounts of nuclear and mitochondrial subnits; these changes, at the transcriptional level, are suggested to be controlled through transcriptional factors Sp1 and NRF2. 23917608 Single-incision Laparoscopic Surgery Using a Homemade Transumbilical Port for Synchronous Colon and Hepatic Lesions: A Case Report. Single-incision laparoscopic surgery (SILS) is an emerging technique and has been utilized in various abdominal surgeries. Herein, we reported a case of synchronous colon and hepatic lesions that underwent right hemicolectomy and wedge resection of the liver by SILS. To the best of our knowledge, this is the first case report of synchronous colon and liver resection with SILS using homemade transumbilical port. 23434682 Protein O-mannosylation: What we have learned from baker's yeast. Background: Protein O-mannosylation is a vital type of glycosylation that is conserved among fungi, animals, and humans. It is initiated in the endoplasmic reticulum (ER) where the synthesis of the mannosyl donor substrate and the mannosyltransfer to proteins take place. O-mannosylation defects interfere with cell wall integrity and ER homeostasis in yeast, and define a pathomechanism of severe neuromuscular diseases in humans. Scope of review: On the molecular level, the O-mannosylation pathway and the function of O-mannosyl glycans have been characterized best in the eukaryotic model yeast Saccharomyces cerevisiae. In this review we summarize general features of protein O-mannosylation, including biosynthesis of the mannosyl donor, characteristics of acceptor substrates, and the protein O-mannosyltransferase machinery in the yeast ER. Further, we discuss the role of O-mannosyl glycans and address the question why protein O-mannosylation is essential for viability of yeast cells. General significance: Understanding of the molecular mechanisms of protein O-mannosylation in yeast could lead to the development of novel antifungal drugs. In addition, transfer of the knowledge from yeast to mammals could help to develop diagnostic and therapeutic approaches in the frame of neuromuscular diseases. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum. 23388040 Minimal peptide motif for non-covalent peptide-heparin hydrogels. Reduction of complexity of the extracellular matrix (ECM) to a non-covalent structure with minimal chemically defined components represents an attractive avenue for understanding the biology of the ECM. The resulting system could lead to the design of tailor-made biomaterials that incorporate varying functionalities. Negatively charged glycosaminoglycans are the major components of the ECM. Their interaction with positively charged proteins is important for dynamic three-dimensional scaffold formation and function. We designed and screened minimal peptide motifs whose conjugates with polyethylene glycol interact with heparin to form non-covalent hydrogels. Here we show the structure/function relationship of the (RA)(n) and (KA)(n) motifs and determined that both basic residues and the heparin-induced α-helix formation are important for the assembly process. Simple rules allowed us to tune various aspects of the matrix system such as the gelation rates, biodegradability, rheological properties, and biofunctionality. The hydrogels can encapsulate cells and support cell survival. 23817963 A highly porous 4,4-paddlewheel-connected NbO-type metal-organic framework with a large gas-uptake capacity. A highly porous 4,4-paddlewheel-connected NbO-type metal-organic framework (HNUST-2, HNUST represents Hunan University of Science and Technology) has been designed and synthesized by self-assembling [Cu2(COO)4] SBUs with a nanosized tetracarboxylate ligand prolonged by alkyne groups, 5,5'-(naphthalene-1,4-diylbis(ethyne-2,1-diyl))diisophthalic acid (H4NDED). HNUST-2 exhibits high structural stability, a porous non-interpenetration framework with open metal sites and excellent gas-uptake capacity. This MOF material possesses a high BET surface area of 2366 m(2) g(-1), a large unsaturated excess and total H2 uptake of 4.57 wt% and 5. 20 wt% at 20 bar and 77 K, respectively. Meanwhile, HNUST-2 also exhibits an excellent adsorption capacity for CO2 (18.07 mmol g(-1) at 20 bar and 298 K) and CH4 (85.6 cm(3) cm(-3) at 20 bar and 298 K) with a high selectivity for CO2 over N2 (22.9) and CH4 (4.9) at 298 K. 23881742 Update on treatment of essential tremor. Essential tremor is one of the most common movement disorders in the world. Although millions of people worldwide are affected by ET, only one medication, propranolol, is approved by the United States Food and Drug Administration to treat it. None of the medications currently used as ET therapy were developed specifically for this purpose, and select antihypertensive and antiepileptic medications remain at the forefront of ET therapy. Propranolol and primidone are considered "effective" agents that treat ET; topiramate, atenolol, and alprazolam are "probably effective", and nimodipine, nadolol, and clonazepam are "possibly effective". Medications that probably do not adequately treat ET include levetiracetam and pregabalin. Gabapentin appears to improve ET when used as monotherapy, but not when used as adjunct therapy. Sotalol has been found to be "probably effective" in treating ET in previous reviews, but it may be associated with arrhythmias and should not be routinely recommended. Botulinum toxin A may reduce limb tremor, but may cause dose dependent weakness. Deep brain stimulation (DBS) of the VIM is used as an alternative to pharmacological therapy of ET in patients who fail to adequately respond to medical therapy. The magnitude of effect from DBS is greater than from medical management, but more severe side effects are possible with surgery. Future treatment options for ET will depend on valid animal models, and a better understanding of its pathophysiology. 23875864 Long-term working memory deficits after concussion: Electrophysiological evidence. Abstract Background: Persistent complaints of lingering memory and concentration difficulties are common following a concussion, although the brain basis of these is unknown. Some suggest abnormalities can be found on the P300 event-related potential component, recorded using electroencephalography (EEG), despite unobservable cognitive impairments. Objective: To examine the P300 and cognitive performance following a remote concussion during an n-back task that varies in working memory load. Research design: Seventeen participants with a remote concussion and 17 controls performed a visual n-back task in which working memory demands were systematically increased by manipulating cognitive load. Participants also completed neuropsychological and self-report measures. Results: The concussion group showed a decrease in P300 amplitude compared to controls that was independent of working memory load on the n-back task. While no performance differences were observed between groups, P300 amplitude was negatively correlated with response times at higher loads in both groups. Conclusion: High functioning young adults with a remote concussion may have inefficient recruitment of processing resources for target identification, evident by the attenuated P300. The negative correlations between response time and P300 amplitude suggest that the time necessary to accurately respond to targets increases as the efficiency of allocating processing resources decreases during highly demanding working memory tasks. 23880541 Investigation into the functional impact of the vancomycin C-ring aryl chloride. A vancomycin aglycon analogue that possesses a reduced C-ring and an intact E-ring chloride was prepared and its antimicrobial activity towards Staphylococcus aureus and binding affinity to model cell wall ligands were established. Comparison of the derivative with a series of vancomycin aglycon analogues that possess and lack the chloro substituents on the aryl C- and E-rings defines the impact and further refines the role the C-ring chloride plays in promoting both target binding affinity and binding selectivity for d-Ala-d-Ala and its impact on antimicrobial activity. 23904238 Divergence of NHS choice policy in the UK: what difference has patient choice policy in England made? To examine the types of choices available to patients in the English NHS when being referred for acute hospital care in the light of the divergence of patient choice policy in the four countries of the UK. Case studies of eight local health economies in England, Scotland, Northern Ireland and Wales (two in each country); 125 semi-structured interviews with staff in acute services providers, purchasers and general practitioners (GPs). GPs and providers in England both had a clear understanding of the choice of provider policy and the right of patients to choose a provider. Other referral choices potentially available to patients in all four countries were date and time of appointment, site and specialist. In practice, the availability of these choices differed between and within countries and was shaped by factors beyond choice policy, such as the number of providers in an area. There were similarities between the four countries in the way choices were offered to patients, namely lack of clarity about the options available, limited discussion of choices between referrers and patients, and tension between offering choice and managing waiting lists. There are challenges in implementing pro-choice policy in health care systems where it has not traditionally existed. Differences between England and the other countries of the UK were limited in the way choice was offered to patients. A cultural shift is needed to ensure that patients are fully informed by GPs of the choices available to them. 23876538 Parthenolide reduces cell proliferation and prostaglandin E2 synthesis in human endometriotic stromal cells and inhibits development of endometriosis in the murine model. To evaluate the effects of parthenolide on human endometriotic cells and murine endometriotic lesions. Experimental study. University hospital and laboratory of animal science. Twenty women with ovarian endometrioma and 30 mice. Ectopic endometrial tissue from the endometrioma was collected. Human endometriotic stromal cells (ESCs) were pretreated with parthenolide and exposed to tumor necrosis factor (TNF)-α. Interleukin 8 (IL-8) and COX-2 gene expressions were evaluated by real-time reverse transcription-polymerase chain reaction. Interleukin-8 protein, prostaglandin E2 (PGE2) level, and intranuclear p65 protein concentration were determined by ELISA. Cell proliferation was assessed by 5-bromo-2'-deoxyuridine-ELISA. Phosphorylation of signaling pathways in ESCs was evaluated by Western blotting. Gene expression and proliferative activity in murine endometriosis-like lesions were assessed by real-time reverse transcription-polymerase chain reaction and Ki67 staining, respectively. With parthenolide pretreatment, TNF-α-induced IL-8 gene and protein expression in ESCs were diminished. Tumor necrosis factor α-induced COX-2 expression and PGE2 synthesis were also inhibited. Adding parthenolide repressed TNF-α-induced 5-bromo-2'-deoxyuridine incorporation and IκB phosphorylation in ESCs. As in vivo experiments, administering parthenolide reduced the number, surface area, and weight, the level of Vegf, Il-6, Mcp-1, and Lif gene expression, and the percentage of Ki67-positive cells in murine endometriosis-like lesions. Parthenolide repressed the development of endometriosis by suppressing the inflammatory peritoneal environment through the nuclear factor κB pathway. 23908425 Effect of shockwave therapy on plantar fasciopathy: A biomechanical prospective. It has been suggested that extracorporeal shockwave therapy is a safe and effective treatment for pain relief from recalcitrant plantar fasciopathy (PF). However, the changes in gait and associated biomechanical parameters have not been well characterised. We recruited 12 female patients with recalcitrant PF who had a mean age of 59 years (50 to 70) and mean body mass index of 25 kg/m(2) (22 to 30). The patients reported a mean duration of symptoms of 9.3 months (6 to 15). Shockwave therapy consisting of 1500 impulses (energy flux density 0.26 mJ/mm(2)) was applied for three sessions, each three weeks apart. A pain visual analogue scale (VAS) rating, plantar pressure assessment and motion analysis were carried out before and nine weeks after first shock wave therapy. It was demonstrated that patients increased their walking velocity and cadence as well indicating a decrease in pain after shockwave therapy. In the symptomatic foot, the peak contact pressure over the forefoot increased and the contact area over the digits decreased. The total foot impulse also decreased as did stance duration. The duration the centre of pressure remained in the hindfoot increased in the symptomatic foot after shockwave therapy. The differences in centre of pressure trajectory at baseline decreased at final follow-up. In conclusion, shockwave therapy not only decreased the pain VAS rating but also improved the gait parameters of the symptomatic foot in PF patients. Cite this article: Bone Joint J 2013;95-B:1088-93. 23843388 Diversification rates have declined in the Malagasy herpetofauna. The evolutionary origins of Madagascar's biodiversity remain mysterious despite the fact that relative to land area, there is no other place with consistently high levels of species richness and endemism across a range of taxonomic levels. Most efforts to explain diversification on the island have focused on geographical models of speciation, but recent studies have begun to address the island's accumulation of species through time, although with conflicting results. Prevailing hypotheses for diversification on the island involve either constant diversification rates or scenarios where rates decline through time. Using relative-time-calibrated phylogenies for seven endemic vertebrate clades and a model-fitting framework, I find evidence that diversification rates have declined through time on Madagascar. I show that diversification rates have clearly declined throughout the history of each clade, and models invoking diversity-dependent reductions to diversification rates best explain the diversification histories for each clade. These results are consistent with the ecological theory of adaptive radiation, and, coupled with ancillary observations about ecomorphological and life-history evolution, strongly suggest that adaptive radiation was an important formative process for one of the most species-rich regions on the Earth. These results cast the Malagasy biota in a new light and provide macroevolutionary justification for conservation initiatives. 23381662 Bayesian methods for pharmacokinetic/pharmacodynamic modeling of pazopanib-induced increases in blood pressure and transaminases. Relationships between plasma pazopanib concentrations and the probability of elevations in blood pressure, a marker of vascular endothelial growth factor receptor inhibition, and alanine aminotransferase (ALT) were investigated with logistic regression models. Data from a Phase I dose-escalation study in cancer patients (n = 57) were examined to determine the relationship between steady-state trough plasma pazopanib concentrations (Cτ ) and a clinically significant blood pressure increase, using a Bayesian logistic regression model. Data from 5 monotherapy studies in cancer patients (n = 344) were pooled to investigate the relationship between Cτ and maximum ALT ≥ 3× the upper limit of normal (ULN), using a Bayesian logistic regression model incorporating an asymptote. Both models were fit using WinBUGS. The median (95% credible interval, CrI) Cτ at which the probability of a clinically significant increase in blood pressure was 50% (EC50 ) was 12.3 μg/mL (6.12, 18.4). The median (95% CrI) EC50 for the maximum probability of ALT ≥ 3 × ULN was 15.4 μg/mL (3.8, 41.2) and the median (95% CrI) maximum probability of ALT ≥ 3 × ULN was 21% (14.5, 43.1). Results suggest that dose adjustments could be useful in managing the potential for hepatotoxicity. 23871449 The interaction of affective with psychotic processes: A test of the effects of worrying on working memory, jumping to conclusions, and anomalies of experience in patients with persecutory delusions. Worry has traditionally been considered in the study of common emotional disorders such as anxiety and depression, but recent studies indicate that worry may be a causal factor in the occurrence and persistence of persecutory delusions. The effect of worry on processes traditionally associated with psychosis has not been tested. The aim of the study was to examine the short-term effects of a bout of worry on three cognitive processes typically considered markers of psychosis: working memory, jumping to conclusions, and anomalous internal experience. Sixty-seven patients with persecutory delusions in the context of a non-affective psychotic disorder were randomised to a worry induction, a worry reduction, or a neutral control condition. They completed tests of the cognitive processes before and after the randomisation condition. The worry induction procedure led to a significant increase in worry. The induction of worry did not affect working memory or jumping to conclusions, but it did increase a range of mild anomalous experiences including feelings of unreality, perceptual alterations, and temporal disintegration. Worry did not affect the occurrence of hallucinations. The study shows that a period of worry causes a range of subtle odd perceptual disturbances that are known to increase the likelihood of delusions. It demonstrates an interaction between affective and psychotic processes in patients with delusions. 23639521 Sustained induction of cytochrome P4501A1 in human hepatoma cells by co-exposure to benzo[a]pyrene and 7H-dibenzo[c,g]carbazole underlies the synergistic effects on DNA adduct formation. To gain a deeper insight into the potential interactions between individual aromatic hydrocarbons in a mixture, several benzo[a]pyrene (B[a]P) and 7H-dibenzo[c,g]carbazole (DBC) binary mixtures were studied. The biological activity of the binary mixtures was investigated in the HepG2 and WB-F344 liver cell lines and the Chinese hamster V79 cell line that stably expresses the human cytochrome P4501A1 (hCYP1A1). In the V79 cells, binary mixtures, in contrast to individual carcinogens, caused a significant decrease in the levels of micronuclei, DNA adducts and gene mutations, but not in cell survival. Similarly, a lower frequency of micronuclei and levels of DNA adducts were found in rat liver WB-F344 cells treated with a binary mixture, regardless of the exposure time. The observed antagonism between B[a]P and DBC may be due to an inhibition of Cyp1a1 expression because cells exposed to B[a]P:DBC showed a decrease in Cyp1a1 mRNA levels. In human liver HepG2 cells exposed to binary mixtures for 2h, a reduction in micronuclei frequency was also found. However, after a 24h treatment, synergism between B[a]P and DBC was determined based on DNA adduct formation. Accordingly, the up-regulation of CYP1A1 expression was detected in HepG2 cells exposed to B[a]P:DBC. Our results show significant differences in the response of human and rat cells to B[a]P:DBC mixtures and stress the need to use multiple experimental systems when evaluating the potential risk of environmental pollutants. Our data also indicate that an increased expression of CYP1A1 results in a synergistic effect of B[a]P and DBC in human cells. As humans are exposed to a plethora of noxious chemicals, our results have important implications for human carcinogenesis. 23944203 A protocol for a multicentre randomised controlled trial of continuous beta-lactam infusion compared with intermittent beta-lactam dosing in critically ill patients with severe sepsis: the BLING II study. Beta-lactam antibiotics are largely administered by bolus dosing, despite displaying time-dependent pharmacokinetics and pharmacodynamics and there being a strong rationale for continuous administration. The randomised controlled trials conducted to date comparing the mode of betalactam administration have been inconclusive and limited by non-equivalent dosing, unblinded administration and small sample sizes. A multicentre, randomised controlled trial (the Beta-lactam Infusion Group [BLING] II study) is currently under way, comparing continuous infusion to standard bolus administration of beta-lactam antibiotics in critically ill patients, independent of dose. BLING II is a Phase IIB, double-blinded, randomised controlled trial recruiting 420 intensive care unit patients with severe sepsis to receive one of three beta-lactam study antibiotics (ticarcillin-clavulanate, piperacillin- tazobactam or meropenem) by either continuous infusion or intermittent bolus administration. The primary outcome is ICUfree days at Day 28. Secondary outcomes include 90-day survival, clinical cure 14 days after study antibiotic cessation, organ failure-free days at Day 14 and duration of bacteraemia. The study started in July 2012 and will provide clinical evidence as to whether continuous infusion of beta-lactam antibiotics is superior to intermittent bolus administration in critically ill patients with severe sepsis. A Phase III study powered for a survival end point may be justified, based on the results of our study. 23423573 A novel mechanism by which SDF-1β protects cardiac cells from palmitate-induced ER stress and apoptosis via CXCR7 and AMPK/p38 MAPK-mediated IL-6 generation. We studied the protective effect of stromal cell-derived factor-1beta (SDF-1β) on cardiac cells from lipotoxicity in vitro and diabetes in vivo. Exposure of cardiac cells to palmitate increased apoptosis by activating NADPH oxidase-associated nitrosative stress and endoplasmic reticulum (ER) stress, which abolished by pretreatment with SDF-1β via up-regulation of AMPK-mediated p38 MAPK phosphorylation and IL-6 production. The SDF-1β cardiac protection could be abolished by inhibition of AMPK, p38 MAPK or IL-6. Activation of AMPK or addition of recombinant IL-6 recaptured a similar cardiac protection. SDF-1β receptor CXCR4 antagonist AMD3100 or CXCR4 siRNA could not, but CXCR7 siRNA completely abolish SDF-1β's protection from palmitate-induced apoptosis and activation of AMPK and p38 MAPK. Administration of SDF-1β to diabetic rats, induced by high-fat-diet feeding with a small dose of streptozotocin, could significantly reduce cardiac apoptosis and increase in AMPK phosphorylation along with a prevention of diabetes-induced cardiac oxidative damage, inflammation, hypertrophy and remodeling. These results showed that SDF-1β protects palmitate-induced cardiac apoptosis, which is mediated by NADPH oxidase-activated nitrosative damage and ER stress, via CXCR7 to activate AMPK/p38 MAPK-mediated IL-6 generation. The cardiac protection by SDF-1β from diabetes-induced oxidative damage, cell death and remodeling was also associated with AMPK activation. 23396165 microRNAs in liver disease: from diagnostics to therapeutics. There is a need to identify effective biomarkers for diagnosis, prognosis and prediction of treatment efficacy for many liver diseases such as hepatocellular cancer, and chronic viral hepatitis. The identification of disease-specific alterations in microRNA expression and the ability to detect microRNAs in the circulation provide the basis for identifying novel clinically effective treatments and biomarkers. Knowledge regarding miRNA in human liver disease may eventually lead to serum or tissue biomarkers with clinical utility. A selection of relevant studies is reviewed. There are major challenges that need to be addressed prior to clinical application such as the need for careful validation of diagnostic miRNA candidates in well described clinical cohorts, and technical issues such as quantitation and standardization of assays. The rapid progress in therapeutic interventions using miRNA based strategies for chronic hepatitis C and hepatocellular cancer provides optimism for novel approaches that will build on the existing and emerging knowledge regarding miRNA in liver diseases. 23178164 Constant light disrupts the circadian rhythm of steroidogenic proteins in the rat adrenal gland. The circadian rhythm of corticosterone (CORT) secretion from the adrenal cortex is regulated by the suprachiasmatic nucleus (SCN), which is entrained to the light-dark cycle. Since the circadian CORT rhythm is associated with circadian expression of the steroidogenic acute regulatory (StAR) protein, we investigated the 24h pattern of hormonal secretion (ACTH and CORT), steroidogenic gene expression (StAR, SF-1, DAX1 and Nurr77) and the expression of genes involved in ACTH signalling (MC2R and MRAP) in rats entrained to a normal light-dark cycle. We found that circadian changes in ACTH and CORT were associated with the circadian expression of all gene targets; with SF-1, Nurr77 and MRAP peaking in the evening, and DAX1 and MC2R peaking in the morning. Since disruption of normal SCN activity by exposure to constant light abolishes the circadian rhythm of CORT in the rat, we also investigated whether the AM-PM variation of our target genes was also disrupted in rats exposed to constant light conditions for 5weeks. We found that the disruption of the AM-PM variation of ACTH and CORT secretion in rats exposed to constant light was accompanied by a loss of AM-PM variation in StAR, SF-1 and DAX1, and a reversed AM-PM variation in Nurr77, MC2R and MRAP. Our data suggest that circadian expression of StAR is regulated by the circadian expression of nuclear receptors and proteins involved in both ACTH signalling and StAR transcription. We propose that ACTH regulates the secretion of CORT via the circadian control of steroidogenic gene pathways that become dysregulated under the influence of constant light. 23678866 Blending Through-Space and Through-Bond π-π-Coupling in [2,2']-Paracyclophane-oligophenylenevinylene Molecular Wires. A series of ZnP-pCp-oPPV-C60 conjugates covalently connected through [2,2']-paracyclophane-oligophenylenevinylene (pCp-oPPV) bridges containing one, two, and three [2,2']-paracyclophanes (pCps) has been prepared in multistep synthetic procedures involving Horner-Wadsworth-Emmons olefination reactions and/or Heck type Pd-catalyzed reactions. Molecular modeling suggests that charge transfer is effectively mediated by the pCp-oPPVs through a predominant hole-transfer mechanism. Photophysical investigation supports molecular modeling and reveals two major trends. On one hand, C60 excitation of 1, 2, and 3 leads exclusively to charge transfer between pCp and C60 to afford a ZnP-(pCp-oPPV)(•+)-C60(•-) radical ion pair state without giving rise to a subsequent charge shift to yield the ZnP(•+)-pCp-oPPV-C60(•-) radical ion pair state. On the other hand, ZnP excitation of 1, 2, and 3 results in a rather slow charge transfer between ZnP and C60, after which the ZnP(•+)-pCp-oPPV-C60(•-) radical ion pair state evolves. In temperature-dependent ZnP fluorescence experiments, which were performed in the temperature range from 273 to 338 K, two domains are discernible: low and high temperature behaviors. In the low temperature range (i.e., below 30 °C) the rate constants do not change, suggesting that a superexchange mechanism is the modus operandi. In the high temperature range (i.e., >30 °C) the rate constants increase. Moreover, we find rather strong distance dependence for 1 and 2 and weak distance dependence for 2 and 3. A damping factor of 0.145 Å(-1) is derived for the former pair and 0.012 Å(-1) for the latter. 23910144 Abnormal origin of right coronary artery from left ventricle with bicuspid aortic stenosis. Anomalous coronary arteries are rare but can lead to serious complications during cardiac operations if not recognized. We report a 55-year-old woman with anomalous origin of the right coronary artery from the left ventricle, and bicuspid aortic valve stenosis. Coronary angiography and computerized tomographic angiography indicated the diagnosis preoperatively. She underwent aortic valve replacement and coronary artery bypass grafting subsequently, with good recovery. One adult and two children with the same right coronary artery anomaly have been reported in the literature. Preoperative diagnosis is essential in these cases, and long-term follow-up is warranted. 23898282 Usefulness of 320-row area detector computed tomography for the diagnosis of cystic falx meningioma. We present a case of cystic falx meningioma. Cystic meningioma is rare and not easy to diagnose preoperatively; it is often misdiagnosed as other tumors, including glial or metastatic tumors with cystic or necrotic changes. This study showed the potential impact of 320-row computed tomography (CT) on image-based diagnostic evaluation of cystic meningioma with special attention to the novel techniques of 4-dimensional CT angiography (4D-CTA) and CT whole-brain perfusion (CTP). 4D-CTA showed the arterial supply feeding the tumor and late enhancement of the tumor nodule, similar to that seen in meningioma by conventional angiography. CTP showed that the tumor had a higher cerebral blood flow and cerebral blood volume and a longer mean transit time than adjacent brain tissue. These findings were consistent with meningioma and reinforced the other imaging findings, resulting in the correct preoperative diagnosis. The new techniques available for 320-row CT can potentially be used to improve differential diagnosis and preoperative assessment of cystic tumors with nodules. 22830674 Clinical assessment, design and performance testing of mobile shower commodes for adults with spinal cord injury: an exploratory review. The purpose of this article is to explore evidence concerning clinical assessment, design and performance testing of mobile shower commodes used by adults with spinal cord injury (SCI). Searches of electronic databases, conference proceedings and key journals were undertaken with no restriction on language or study design. Keywords included spinal cord injury, lesion, sanichair, sanitary chair, shower chair, bowel chair and commode. A total of 20 publications were included in this review. Common approaches to clinical assessments were questionnaires and observational analysis to assess bowel care routines, function and skin integrity. Design features addressed access for bowel care, postural support, transfers, stability, use in wet environments and skin integrity. Objective performance measures addressed requirements for static stability, backward-sloping seat angles, arm supports and seat materials. Evidence reviewed was of low methodological quality and lacking in validated instruments to guide clinical practice. Further high-quality research is needed to identify bathing, showering and personal hygiene tasks affecting mobile shower commodes use and to develop validated clinical assessment tools. Performance testing to published standards is also needed. 23925853 Nitrogen and phosphorus fertilization negatively affects strigolactone production and exudation in sorghum. Strigolactones (SLs) are essential host recognition signals for both root parasitic plants and arbuscular mycorrhizal fungi, and SLs or their metabolites function as a novel class of plant hormones regulating shoot and root architecture. Our previous study indicated that nitrogen (N) deficiency as well as phosphorus (P) deficiency in sorghum enhanced root content and exudation of 5-deoxystrigol, one of the major SLs produced by sorghum. In the present study, we examined how N and P fertilization affects SL production and exudation in sorghum plants subjected to short- (5 days) or long-term (10 days) N or P deficiency and demonstrated their common and distinct features. The root contents and exudation of SLs in the N- or P-deficient sorghum plants grown for 6, 12 or 24 h with or without N or P fertilization were quantified by LC-MS/MS. In general, without fertilization, root contents and exudation of SLs stayed at similar levels at 6 and 12 h and then significantly increased at 24 h. The production of SLs responded more quickly to P fertilization than the secretion of SLs, while regulation of SL secretion began earlier after N fertilization. It is suggested that sorghum plants regulate SL production and exudation when they are subjected to nutrient deficiencies depending on the type of nutrient and degree of deficiency. 23816025 Heart failure performance measures: eligibility and implementation in the community. The goal of heart failure (HF) performance measures is to improve quality of care by assessing the implementation of guidelines in eligible patients. Little is known about the proportion of eligible patients and how performance measures are implemented in the community. We determined the eligibility for and adherence to performance measures and β-blocker therapy in a community-based cohort of hospitalized HF patients from January 2005 to June 2011. All of the 465 HF inpatients (median age 76 years, 48% men) included in the study received an ejection fraction assessment. Only 164 had an ejection fraction <40% thus were candidates for β-blocker and angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blocker (ARB) therapy. Considering absolute contraindications, 99 patients were eligible to receive ACE inhibitors/ARB, and 162 to receive β-blockers. Among these, 85% received ACE inhibitors/ARBs and 91% received β-blockers. Among the 261 individuals with atrial fibrillation, 89 were eligible for warfarin and 54% received it. Of 52 current smokers, 69% received cessation counseling during hospitalization. In the community, among eligible hospitalized HF patients, the implementation of performance measures can be improved. However, as most patients are not candidates for current performance measures, other approaches are needed to improve care and outcomes. 23640846 Oxygen-functionalized few-layer graphene sheets as active catalysts for oxidative dehydrogenation reactions. Invited for this month's cover is the group from the Center for Nanophase Materials Sciences (CNMS) at the Oak Ridge National Laboratory. The illustration is of the catalytic activity of the reported oxygen-functionalized few-layer graphenes, whereas the micrograph background image is of the same graphenes recorded by the authors using a new helium-ion microscope at the CNMS. Read the full text of the article at 10.1002/cssc.201200756. 23233534 A maternal "junk-food" diet reduces sensitivity to the opioid antagonist naloxone in offspring postweaning. Perinatal exposure to a maternal "junk-food" diet has been demonstrated to increase the preference for palatable diets in adult offspring. We aimed to determine whether this increased preference could be attributed to changes in μ-opioid receptor expression within the mesolimbic reward pathway. We report here that mRNA expression of the μ-opioid receptor in the ventral tegmental area (VTA) at weaning was 1.4-fold (males) and 1.9-fold (females) lower in offspring of junk-food (JF)-fed rat dams than in offspring of dams fed a standard rodent diet (control) (P<0.05). Administration of the opioid antagonist naloxone to offspring given a palatable diet postweaning significantly reduced fat intake in control offspring (males: 7.7 ± 0.7 vs. 5.4 ± 0.6 g/kg/d; females: 6.9 ± 0.3 vs. 3.9 ± 0.5 g/kg/d; P<0.05), but not in male JF offspring (8.6 ± 0.6 vs. 7.1 ± 0.5 g/kg/d) and was less effective at reducing fat intake in JF females (42.2 ± 6.0 vs. 23.1 ± 4.1% reduction, P<0.05). Similar findings were observed for total energy intake. Naloxone treatment did not affect intake of standard rodent feed in control or JF offspring. These findings suggest that exposure to a maternal junk-food diet results in early desensitization of the opioid system which may explain the increased preference for junk food in these offspring. 23696195 Influence of a clinical lifestyle-based weight loss program on the metabolic risk profile of metabolically normal and abnormal obese adults. It is unclear whether all obese individuals should be prescribed weight loss (WL) treatment. The effect of a clinically significant WL of 5% on metabolic factors among metabolically normal and abnormal overweight and obese (MNO and MAO) individuals was examined. The sample included 392 overweight and obese adults from the Wharton Medical Clinic. MAO was defined as having one or more clinically relevant aberrations in glucose, triglycerides, blood pressure (BP), high-density lipoprotein-C, low-density lipoprotein-C, preexisting, or current medication use for metabolic conditions. Of the 392 patients, 21.2% of the sample was MNO at baseline and 41.3% of the sample attained a 5% WL. Regardless of initial metabolic health status, improvements in most risk factors were observed with a 5% WL in comparison with those who did not lose weight. Even MAO patients who did not achieve a 5% WL still significantly improved BP and cholesterol over the treatment period. A clinically significant WL is beneficial for the cardiometabolic risk profile of both MNO and MAO. However, a 5% WL is not necessarily required to improve the cardiometabolic risk profile of MAO. Thus, lifestyle-based WL provides beneficial metabolic effects for all overweight and obese individuals, particularly those with significant metabolic aberrations. 23611491 DNA Interactions in Crowded Nanopores. The motion of DNA in crowded environments is a common theme in physics and biology. Examples include gel electrophoresis and the self-interaction of DNA within cells and viral capsids. Here we study the interaction of multiple DNA molecules within a nanopore by tethering the DNA to a bead held in a laser optical trap to produce a "molecular tug-of-war". We measure this tether force as a function of the number of DNA molecules in the pore and show that the force per molecule decreases with the number of molecules. A simple scaling argument based on a mean field theory of the hydrodynamic interactions between multiple DNA strands explains our observations. At high salt concentrations, when the Debye length approaches the size of the counterions, the force per molecule becomes essentially independent of the number of molecules. We attribute this to a sharp decrease in electroosmotic flow which makes the hydrodynamic interactions ineffective. 23839111 Extracorporeal cardiac shock wave therapy ameliorates myocardial fibrosis by decreasing the amount of fibrocytes after acute myocardial infarction in pigs. Extracorporeal shock wave (SW) therapy ameliorates cardiac remodeling after acute myocardial infarction (AMI). However, it remains to be examined whether and how SW therapy ameliorates myocardial fibrosis after AMI. Fibrocytes are associated with myocardial fibrosis. Thus, we examined whether SW therapy ameliorates myocardial fibrosis and whether fibrocytes are associated after AMI in pigs. AMI was created by coronary embolism. Twenty-five pigs were divided into three groups: AMI+SW group (AMI with SW therapy, n=15), AMI group (without SW therapy, n=5), and sham+SW group (SW therapy without AMI, n=5). The collagen area fraction was examined by Masson's trichrome staining. The presence of fibrocytes was identified by immunofluorescence and confocal microscopy. The location of CXCL12 was examined by immunohistochemistry. Compared with the AMI group, the AMI+SW group showed significantly ameliorated myocardial fibrosis in terms of collagen area fraction (27.21±8.13 vs. 10.13±4.96, P<0.05) and reduced fibrocytes (CD34/α-smooth muscle actin: 35.40±11.72 vs. 12.27±7.71, P<0.05; CXCR4/α-smooth muscle actin: 40.80±8.96 vs. 16.54±6.38, P<0.05). There were positive correlations between the collagen area fraction and the number of fibrocytes (r=0.936; P<0.05) and between the number of CXCR4 fibrocytes and the SDF-1/CXCL12 cells (r=0.802; P<0.05) in the three groups. The results show that SW therapy ameliorates myocardial fibrosis after AMI in pigs, which is associated with the decreased amount of fibrocytes. 23270585 Correlation of Fc-γ RIIA polymorphisms with latent Epstein-Barr virus infection and latent membrane protein 1 expression in patients with low grade B-cell lymphomas. Abstract Fc-γ RIIA (CD32), a member of the family of Fc-γ receptors, participates in the phagocytosis of bound to antibody antigens. The effectiveness of this function varies for its several haplotypes, and it participates in the pathogenesis of viral infections, according to recent studies. The genetic locus of Fc-γ RIIA consists of two allelic genes: 131-Arg (R131) and 131-His (H131). Our aim was to correlate Fc-γ RIIA polymorphisms, by studying the prevalence of each allele using PCR-RFLPs (polymerase chain reaction-restriction fragment length polymorphisms), with latent Epstein-Barr virus (EBV) infection and the expression of latent membrane protein 1 (LMP1) in 40 patients with leukemic low grade B-cell lymphomas. R131 was found in 84.2% of EBV-positive patients, but only in 28.5% of EBV-negative patients (p = 0.001). A similar correlation was found for R131 and LMP1 expression (84.6% vs. 28.5%) (p = 0.002). Our results support the hypothesis that Fc-γ RIIA polymorphisms are a genetic risk factor for latent EBV infection and the expression of its oncogenic latency proteins. 23857972 Phase III Trial of Sunitinib in Combination With Capecitabine Versus Capecitabine Monotherapy for the Treatment of Patients With Pretreated Metastatic Breast Cancer. PURPOSE Metastatic breast cancer (MBC) remains an incurable illness in the majority of cases, despite major therapeutic advances. This may be related to the ability of breast tumors to induce neoangiogenesis, even in the face of cytotoxic chemotherapy. Sunitinib, an inhibitor of key molecules involved in neoangiogenesis, has an established role in the treatment of metastatic renal cell and other cancers and demonstrated activity in a phase II trial in MBC. We performed a randomized phase III trial comparing sunitinib plus capecitabine (2,000 mg/m(2)) with single-agent capecitabine (2,500 mg/m(2)) in patients with heavily pretreated MBC. PATIENTS AND METHODS Eligibility criteria included MBC, prior therapy with anthracyclines and taxanes, one or two prior chemotherapy regimens for metastatic disease or early relapse after a taxane plus anthracycline adjuvant regimen, and adequate organ function and performance status. The primary end point was progression-free survival, for which the study had 90% power to detect a 50% improvement (from 4 to 6 months). Results A total of 442 patients were randomly assigned. Progression-free survival was not significantly different between the treatment arms, with medians of 5.5 months (95% CI, 4.5 to 6.0) for the sunitinib plus capecitabine arm and 5.9 months (95% CI, 5.4 to 7.6) for the capecitabine monotherapy arm (hazard ratio, 1.22; 95% CI, 0.95 to 1.58; one-sided P = .941). There were no significant differences in response rate or overall survival. Toxicity, except for hand-foot syndrome, was more severe in the combination arm. CONCLUSION The addition of sunitinib to capecitabine does not improve the clinical outcome of patients with MBC pretreated with anthracyclines and taxanes. 23583485 Inhibitory effects of gypenosides on seven human cytochrome P450 enzymes in vitro. Among the various possible causes for drug interactions, pharmacokinetic factors such as inhibition of drug-metabolizing enzymes, especially cytochrome P450 (CYP) enzymes, are regarded as the most frequent and clinically important. Gypenosides is widely used as functional food and over-the-counter drug in East Asia. In this study, the in vitro inhibitory effects of gypenosides on the major human CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) activities in human liver microsomes were examined using liquid chromatography-tandem mass spectrometry. Gypenosides showed the strongest inhibition of CYP2D6, followed by CYP2C8, CYP3A4 and CYP2C9. The IC50 values were 1.61μg/mL, 20.06μg/mL, 34.76μg/mL (CYP3A4/midazolam), 46.73μg/mL (CYP3A4/testosterone), and 54.52μg/mL, respectively. Gypenosides exhibited competitive inhibition of CYP2D6 (Ki=1.18). In conclusion, Gypenosides might cause herb-drug interactions via inhibition of CYP2D6. An in vivo study is needed to examine this further. 23912248 Hepatogenous Diabetes in Cirrhosis Is Related to Portal Pressure and Variceal Hemorrhage. The clinical impact and complications of hepatogenous diabetes (HD) on cirrhosis have not been elucidated. This study aimed to evaluate the relationship of HD with portal hypertension (PHT) and variceal hemorrhage and to assess the prevalence of HD. From July 2007 to December 2009, 75-g oral glucose tolerance test and insulin resistance (IR) were evaluated for 195 consecutive cirrhotic liver patients (M:F = 164:1, 53.0 ± 10.2 years) who had no history of diabetes mellitus. IR was calculated using the homeostasis model of assessment-insulin resistance (HOMA-IR) formula. Endoscopy for varices, hepatic venous pressure gradient (HVPG), and serologic tests were also conducted. HD was observed in 55.4 % (108/194) of the patients. Among them, 62.0 % required OGTT for diagnosis because they did not show an abnormal fasting plasma glucose level. The presence of HD showed a significant correlation with high Child-Pugh's score, variceal hemorrhage, and HVPG (p = 0.004, 0.002, and 0.019, respectively). In multivariate analysis, Child-Pugh's score (OR 1.43, 95 % CI 1.005-2.038) and HVPG (OR 1.15, 95 % CI 1.003-2.547) had significant relationships with HD. Patients with recent variceal hemorrhages (within 6 months) exhibited significantly higher glucose levels at 120 min in OGTT compared to patients without hemorrhages (p = 0.042). However, there was no difference in fasting glucose levels. The 120-min glucose level and HOMA-IR score were significantly and linearly correlated with HVPG (r (2) = 0.189, p < 0.001 and r (2) = 0.033, p = 0.011, respectively). HD and IR have significant relationships with PHT and variceal hemorrhage. Postprandial hyperglycemia in particular had a significant relationship with variceal hemorrhage. 23314047 Monocyclic β-lactams as antibacterial agents: facing antioxidant activity of N-methylthio-azetidinones. A series of N-methylthio-β-lactams with antibacterial activity were thoroughly evaluated as antioxidants. We found that only the presence of a polyphenolic moiety anchored to the β-lactam ring ensured an adequate antioxidant potency. New compounds, efficiently combining in one structure antioxidant and antibacterial activity, may provide a promising basis for the development of new leads useful in adverse clinical conditions such as in cystic fibrosis patients, in whom colonization by MRSA and epithelial damage by chronic pulmonary oxidative stress take place. 23557993 A diarylheptanoid phytoestrogen from Curcuma comosa, 1,7-diphenyl-4,6-heptadien-3-ol, accelerates human osteoblast proliferation and differentiation. Curcuma comosa Roxb. is ginger-family plant used to relieve menopausal symptoms. Previous work showed that C. comosa extracts protect mice from ovariectomy-induced osteopenia with minimal effects on reproductive organs, and identified the diarylheptanoid (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol (DPHD) as the major active component of C. comosa rhizomes. At 1-10μM, DPHD increased differentiation in transformed mouse osteoblasts, but the effect of DPHD on normal bone cells was unknown. We examined the concentration dependency and mechanism of action of DPHD relative to 17β-estradiol in nontransformed human osteoblasts (h-OB). The h-OB were 10-100 fold more sensitive to DPHD than transformed osteoblasts: DPHD increased h-OB proliferation at 10nM and, at 100nM, activated MAP kinase signaling within 30min. In long-term differentiation assays, responses of h-OB to DPHD were significant at 10nM, and optimal response in most cases was at 100nM. At 7-21 days, DPHD accelerated osteoblast differentiation, indicated by alkaline phosphatase activity and osteoblast-specific mRNA production. Effects of DPHD were eliminated by the estrogen receptor antagonist ICI182780. During differentiation, DPHD promoted early expression of osteoblast transcription factors, RUNX2 and osterix. Subsequently, DPHD accelerated production of bone structural genes, including COL1A1 and osteocalcin comparably to 17β-estradiol. In h-OB, DPHD increased the osteoprotegerin to RANKL ratio and supported mineralization more efficiently than 10nM 17β-estradiol. We conclude that DPHD promotes human osteoblast function in vitro effectively at nanomolar concentrations, making it a promising compound to protect bone in menopausal women. 23685366 A life cycle assessment of non-renewable energy use and greenhouse gas emissions associated with blueberry and raspberry production in northern Italy. This study examined the emissions produced during the pre-farm, farm and post-farm phases of the production cycle of raspberries and giant American whortleberries (blueberries) cultivated in one of the best-adapted areas in northern Italy. The pre-farm phase included the greenhouse gas emissions from the production of plants in the nursery and the transportation of the plants to the production farms. The farm phase involved the emissions of greenhouse gases from chemical products, the water used for irrigation, the generation of waste, and the consumption of electricity and other energy. The post-farm phase comprised the transportation of the products to the distribution centre (DC) and their storage in the DC. The use phase is not included in the system, nor is transportation from the supermarket to the home of the final consumer, but the disposal of the packaging is nevertheless taken into account. Indeed, the use of traditional plastic materials during both the field phase (nursery and cultivation) and the post-harvesting phase (packaging) produced the greatest estimated impact. 23751960 Comparison of two multiplexed PCR assays for the detection of HSV-1, HSV-2, and VZV with extracted and unextracted cutaneous and mucosal specimens. Several analyte specific reagents (ASRs) are available for the detection and differentiation of HSV-1, HSV-2, and VZV in clinical specimens. However, there is limited data on the test performance of these reagents used in multiplexed PCR assays. This study compared the performance of two multiplexed ASR sets for detection of HSV-1, HSV-2, and VZV in dermal specimens. Two commercially available ASRs were combined to produce multiplexed PCR assays for simultaneous detection of HSV-1, HSV-2, and VZV. Seeded samples were used to determine the limit of detection (LOD) for each assay. Patient samples (n=156) were tested in duplicate and results for each method compared to the reference standard of culture. Both extracted and unextracted specimens were used in the study. Both multiplexed PCR assays showed similar test performance, with minimal LOD differences observed. The LOD was 10(3)copies/mL for HSV-1 and HSV-2 using the Focus assay compared to 5×10(3)copies/mL and 2×10(4)copies/mL, respectively for the EraGen assay. Both assays showed equal performance for VZV with a LOD of 5×10(3)copies/mL. Analytical specificity testing showed no cross reactivity with other selected DNA viruses. Both assays showed similar performance when clinical samples were tested using both extracted and unextracted specimens. Commercially available ASRs can be successfully multiplexed for the PCR detection of HSV-1, HSV-2, and VZV using dermal specimens. Either direct testing or nucleic acid extracted specimens can be used with similar performance in these assays. 23826647 Effect of Chronic Periodontitis on Serum and Gingival Crevicular Fluid Oxidant and AntioXidant Status in Patients With Familial Mediterranean Fever Before and After Periodontal Treatment. Background: The aim of this study was to investigate the impact of periodontal status on oxidant-antioxidant status in patients with chronic periodontitis who experienced Familial Mediterranean Fever (FMF) and their response to nonsurgical periodontal therapy. Methods: Data were obtained from 13 FMF patients with generalized chronic periodontitis (FMF-CP), from 15 systemically healthy patients with generalized chronic periodontitis (CP), from 15 systemically and periodontal healthy controls (HC), and from 14 periodontally healthy FMF patients (FMF-HC). We recorded each participant's total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) in their gingival crevicular fluid and serum. We also measured probing depth, clinical attachment level, gingival and plaque indices in each participant. We recorded the gingival crevicular fluid and clinical parameters at baseline and 6 weeks after periodontal treatment. Results: The study showed statistically significant improvement of clinical parameters in both FMF-CP and CP groups after periodontal treatment. The baseline GCF-TOS and OSI levels were significantly higher in the CP group compared with the FMF-CP group (p < 0.05). After periodontal treatment, the GCF-TOS levels were significantly reduced in members of the FMF-CP group (p < 0.05). The GCF-TAS levels in members of the FMF-CP group were significantly higher than those of members of the HC group at baseline (p < 0.05). Serum-TAS levels in the FMF-CP group were significantly higher than those in the CP and HC groups at baseline (p < 0.05). The GCF-TOS level in the FMF-CP group was significantly higher than in the FMF-HC group at baseline and at 6 weeks. However, there were no significant differences in the serum-TOS and serum-OSI levels of those in the FMF-CP and CP groups at baseline and 6 weeks (p > 0.05). Conclusions: The results of our study showed that patients with FMF-CP displayed reduced oxidative stress and increased antioxidant status compared to those in the CP group and the healthy control group. 23831288 Single-particle Cryo-EM of calcium release channels: structural validation. Few tools are available to determine the structure of large integral membrane proteins such as intracellular Ca(2+) release channels, RyRs and IP3Rs. Single particle cryo-EM can readily determine the structure of such channels to intermediate resolution, and can be used to quantitatively assess conformational variability. However, due to the, often low, image contrast of these cryospecimens, methods for validation are critical to insure the accuracy of such structures, and to put limits on their interpretability. The low-resolution structure of RyR has been well established for some time, but high-resolution has been slow to emerge. The structure of IP3R channel by cryo-EM had a number of false-starts, but improved validation methods have recently lead to a demonstrably accurate reconstruction. 23585195 Impact of visceral obesity on cardiac parasympathetic activity in type 2 diabetics after coronary artery bypass graft surgery. The association between adiposity and heart rate variability (HRV) in patients with type 2 diabetes (T2D) after coronary artery bypass graft surgery (CABG) is not well documented. We evaluated the associations between indices of adiposity and HRV in patients with T2D with CABG and quantified the relationships of the volume of visceral (VVAT) and subcutaneous adipose tissue (VSAT) to HRV. One hundred and thirty-five men with T2D who underwent CABG participated in this study. HRV, BMI, waist circumference (WC), VVAT, and VSAT were measured. Correlations between indices of HRV and adiposity were evaluated and predictors of HRV modulation were identified. Patients were then divided into quartiles of VVAT and VSAT to further evaluate the influence of adiposity on HRV. Subjects were 65 ± 7 years old (mean ± SD) with a BMI of 30 ± 4 kg/m(2) and a WC of 105 ± 10 cm. BMI (r = -0.19) and WC (r = -0.25) were inversely correlated with low frequencies. VVAT correlated negatively with SD normal-to normal (SDNN) (r = -0.22, P < 0.01), indices of cardiac parasympathetic activity [rMSSD (r = -0.27), NN50 (r = -0.22), pNN50 (r = -0.26; all P < 0.05], and with low (r = -0.37) and high frequencies (r = -0.20; all P < 0.01). Patients with the lowest VVAT had the highest cardiac parasympathetic activity (P < 0.05). VVAT remained the best predictor of cardiac parasympathetic activity after adjustments for confounding parameters (P < 0.01). An increase in visceral adiposity, not BMI, seems to be associated with lower HRV in patients with T2D who had a CABG procedure. 23897353 Synergistic lithium chloride and glial cell line-derived neurotrophic factor delivery for peripheral nerve repair in a rodent sciatic nerve injury model. Restoring peripheral nerve function after long gap peripheral nerve damage is challenging. Lithium chloride has demonstrated neuroprotective qualities and therefore shows great potential therapeutic benefit for some neurodegenerative diseases. This study examined the synergistic combination of glial cell line-derived neurotrophic factor and lithium chloride and its effect on peripheral nerve regeneration in a rat sciatic nerve injury model. Polycaprolactone conduits with glial cell line-derived neurotrophic factor-loaded double-walled microspheres and local injections of lithium chloride, 1.5 or 2.5 mEq/kg body weight, were examined in a 15-mm rat sciatic nerve defect model. Eighteen Lewis male rats were divided randomly into control, 1.5-, and 2.5-mEq/kg lithium chloride injection groups. As an indicator of recovery, nerve sections were stained with S100, protein gene product 9.5 antibody, and toluidine blue. Nerves stained with S100 and protein gene product 9.5 antibody demonstrated a significantly increased density of Schwann cells and axons in the 2.5-mEq/kg lithium chloride injection-treated groups compared with both the control and 1.5-mEq/kg lithium chloride injection-treated groups (p < 0.05). At 6 weeks, histomorphometry revealed a significantly higher fiber density in the middle of the conduit for the 2.5-mEq/kg groups compared with the 1.5-mEq/kg group or the control group. Polycaprolactone nerve guides with glial cell line-derived neurotrophic factor-loaded double-walled microspheres and local injections of lithium chloride, 2.5-mEq/kg, represent a potentially viable guiding material for Schwann cell and axon migration and proliferation for the treatment of peripheral nerve regeneration. 23955922 Atomistic understanding of the C·T mismatched DNA base pair tautomerization via the DPT: QM and QTAIM computational approaches. It was established that the cytosine·thymine (C·T) mismatched DNA base pair with cis-oriented N1H glycosidic bonds has propeller-like structure (|N3C4C4N3| = 38.4°), which is stabilized by three specific intermolecular interactions-two antiparallel N4H…O4 (5.19 kcal mol(-1) ) and N3H…N3 (6.33 kcal mol(-1) ) H-bonds and a van der Waals (vdW) contact O2…O2 (0.32 kcal mol(-1) ). The C·T base mispair is thermodynamically stable structure (ΔGint = -1.54 kcal mol(-1) ) and even slightly more stable than the A·T Watson-Crick DNA base pair (ΔGint = -1.43 kcal mol(-1) ) at the room temperature. It was shown that the C·T ↔ C*·T* tautomerization via the double proton transfer (DPT) is assisted by the O2…O2 vdW contact along the entire range of the intrinsic reaction coordinate (IRC). The positive value of the Grunenberg's compliance constants (31.186, 30.265, and 22.166 Å/mdyn for the C·T, C*·T*, and TSC·T ↔ C*·T* , respectively) proves that the O2…O2 vdW contact is a stabilizing interaction. Based on the sweeps of the H-bond energies, it was found that the N4H…O4/O4H…N4, and N3H…N3 H-bonds in the C·T and C*·T* base pairs are anticooperative and weaken each other, whereas the middle N3H…N3 H-bond and the O2…O2 vdW contact are cooperative and mutually reinforce each other. It was found that the tautomerization of the C·T base mispair through the DPT is concerted and asynchronous reaction that proceeds via the TSC·T ↔ C*·T* stabilized by the loosened N4HO4 covalent bridge, N3H…N3 H-bond (9.67 kcal mol(-1) ) and O2…O2 vdW contact (0.41 kcal mol(-1) ). The nine key points, describing the evolution of the C·T ↔ C*·T* tautomerization via the DPT, were detected and completely investigated along the IRC. The C*·T* mispair was revealed to be the dynamically unstable structure with a lifetime 2.13·× 10(-13) s. In this case, as for the A·T Watson-Crick DNA base pair, activates the mechanism of the quantum protection of the C·T DNA base mispair from its spontaneous mutagenic tautomerization through the DPT. © 2013 Wiley Periodicals, Inc. 23747395 Dropped gallstones: spectrum of imaging findings, complications and diagnostic pitfalls. Spillage of gallstones into the abdominal cavity, referred to as "dropped gallstones" (DGs), occurs commonly during laparoscopic cholecystectomy. The majority of these spilled stones remain clinically silent; however, if uncomplicated DGs are not correctly identified on subsequent imaging, they may mimic peritoneal implants and cause unduly concern. A small percentage of DGs cause complications, including abscess and fistula formation. Recognising the DG within the abscess is critical for definitive treatment. This pictorial review illustrates the imaging appearances and complications of DGs on CT, MRI and ultrasound and emphasises pitfalls in diagnosis. 23871981 Cage occupancy and structural changes during hydrate formation from initial stages to resulting hydrate phase. Hydrate formation processes and kinetics are still not sufficiently understood on a molecular level based on experimental data. In particular, the cavity formation and occupancy during the initial formation and growth processes of mixed gas hydrates are rarely investigated. In this study, we present the results of our time-depending Raman spectroscopic measurements during the formation of hydrates from ice and gases or gas mixtures such as CH4, CH4-CO2, CH4-H2S, CH4-C3H8, CH4-iso-C4H10, and CH4-neo-C5H12 at constant pressure and temperature conditions and constant composition of the feed gas phase. All investigated systems in this study show the incorporation of CH4 into the 5(12) cavities as first step in the initial stages of hydrate formation. Furthermore, the results imply that the initial hydrate phases differ from the resulting hydrate phase having reached a steady state regarding the occupancy and ratio of the small and large cavities of the hydrate. 23927768 Preeclampsia is associated with increased maternal body weight in a northeastern Brazilian population. Preeclampsia is a disease with great variability in incidence across the world. The mortality is higher in lower income countries, where it is the leading cause of maternal mortality. This study aimed to determine the frequency of and risk factors for preeclampsia in a low income population from an urban area of Brazil. A prospective case control study of 242 women of which 30 developed preeclampsia, 4 had gestational hypertension, 2 had superimposed hypertension, 11 had spontaneous abortion, 13 were lost to follow up and 192 had normal pregnancy. This latter group was considered the normotensive controls. The rate of preeclampsia and the risk of cardiovascular disease, after onset of preeclampsia, were determined. Of the 218 women who completed the study, the frequency of hypertensive disorder of pregnancy was 16.5% (36 of 218) and of preeclampsia was 13.8% (30 of 218). Women with preeclampsia had a higher body mass index (BMI), mean of 25.3 +/- 4.8 compared to 23.5 +/- 3.7 for the normotensive controls, p = 0.02. The risk of preeclampsia increased with BMI [Odds ratio (OR) 1.12, 95% Confidence Interval (CI = 1.02;1.24, p-value = 0.023)]. Women with preeclampsia developed chronic hypertension more often than normotensive controls (p = 0.043) and their systolic and ambulatory blood pressure monitoring was elevated (p = 0.034). Women with preeclampsia had higher BMI even 5 years post-pregnancy (p = 0.008). Women who are overweight or older have an increased risk of preeclampsia. Previous history of preeclampsia increases the risk of early onset of chronic hypertension. Therefore, effective preventive measures are needed, particularly women at lower social economic stratum who have less access to proper medical care and adequate nutrition. 23618870 Amyloid beta and the longest-lived rodent: the naked mole-rat as a model for natural protection from Alzheimer's disease. Amyloid beta (Aβ) is implicated in Alzheimer's disease (AD) as an integral component of both neural toxicity and plaque formation. Brains of the longest-lived rodents, naked mole-rats (NMRs) approximately 32 years of age, had levels of Aβ similar to those of the 3xTg-AD mouse model of AD. Interestingly, there was no evidence of extracellular plaques, nor was there an age-related increase in Aβ levels in the individuals examined (2-20+ years). The NMR Aβ peptide showed greater homology to the human sequence than to the mouse sequence, differing by only 1 amino acid from the former. This subtle difference led to interspecies differences in aggregation propensity but not neurotoxicity; NMR Aβ was less prone to aggregation than human Aβ. Nevertheless, both NMR and human Aβ were equally toxic to mouse hippocampal neurons, suggesting that Aβ neurotoxicity and aggregation properties were not coupled. Understanding how NMRs acquire and tolerate high levels of Aβ with no plaque formation could provide useful insights into AD, and may elucidate protective mechanisms that delay AD progression. 23962182 Pt-Catalyzed C-C Activation Induced by C-H Activation. The catalytic cleavage of two C-C single bonds is achieved by treatment of the hydrocarbon substrate spiro[bicyclo[2.2.1]hept-2-ene-7,1'-cyclopropane] with Pt(II) catalysts such as (Me2bpy)PtPh(NTf2) (Me2bpy = 4,4'-dimethyl-2,2'-bipyridine, NTf2(-) = N(SO2CF3)2(-)). The surprising rearrangement product 1,2,4,7,7a-pentahydroindene is generated in good yield. The mechanism of C-C bond activation is investigated using NMR spectroscopy, electrospray ionization mass spectrometry, and deuterium labeling, along with density functional theory calculations. These studies support an unusual catalytic mechanism in which an initial masked C-H bond activation initiates successive C-C bond cleavage events. 23828599 Characterization of a periplasmic quinoprotein from Sphingomonas wittichii that functions as aldehyde dehydrogenase. The α-proteobacterium Sphingomonas wittichii RW1 is known for its ability to degrade dioxins and related toxic substances. Bioinformatic analysis of the genome indicated that this organism may contain the largest number of pyrroloquinoline quinone-dependent dehydrogenases of any bacteria sequenced so far. Sequence analysis also showed that one of these genes (swit_4395) encodes an enzyme that belongs to the class of periplasmic glucose dehydrogenases. This gene was fused to a pelB signal sequence and a strep-tag coding region at the 5' and 3' ends, respectively. The fusion product was cloned into the broad-host range expression vector pBBR1p264-Streplong and the corresponding protein was heterologously produced in Escherichia coli, purified via Strep-Tactin affinity chromatography, and characterized. The protein Swit_4395 had a subunit mass of 39.3 kDa and formed active homooctamers and homododecamers. The enzyme showed the highest activities with short- and medium-chain aldehydes (chain length C1-C6) and ketoaldehydes, such as methylglyoxal and phenylglyoxal. Butyraldehyde was the best substrate, with V max and apparent K M values of 3,970 U/mg protein and 12.3 mM, respectively. Pyrroloquinoline quinone was detected using UV-Vis spectroscopy and was found to be a prosthetic group of the purified enzyme. Therefore, Swit_4395 was identified as a pyrroloquinoline quinone-dependent aldehyde dehydrogenase. The enzyme could be purified from the native host when the expression vector was introduced into S. wittichii RW1, indicating homologous protein production. Overproduction of Swit_4395 in S. wittichii RW1 dramatically increased the tolerance of the bacterium toward butyraldehyde and thus might contribute to the detoxification of toxic aldehydes. 23708750 A water-dispersible, ferrocene-tagged peptide nanowire for amplified electrochemical immunosensing. A ferrocence (Fc)-tagged peptide comprising the phenylalanine-phenylalanine (Phe-Phe) sequence was synthesized and allowed to self-assemble into uniform nanowires with a diameter of ca. 100 nm and lengths in the range of 5-10 µm. The Fc-tagged peptide nanowire (Fc-PNW) become well dispersed in aqueous solution when coated with poly(diallyldimethylammonium chloride) (PDDA). Gold nanoparticles (AuNPs) and antibody molecules can then be adsorbed onto the Fc-PNW surface. The resultant antibody modified Fc-PNW was explored as a detection probe for sensitive electrochemical immunosensing in a sandwich assay wherein the capture antibody was attached onto a graphene/gold nanoparticle (AuNPs-GN) composite film. The as prepared electrochemical immunosensor possesses a low detection limit (5 fg/mL) for human IgG and a wide linear range encompassing four orders of magnitude (from 10 fg/mL to 100 pg/mL). Such a low detection limit stems from the significant signal amplification by the large number of Fc moieties on the PNW (for a 5-µm-long Fc-PNW, the number of Fc moieties is 5×10⁵). The electrochemical immunosensor is also highly selective and the sensor was demonstrated to be amenable to real sample analysis. 23459219 Skeletal muscle ryanodine receptor mutations associated with malignant hyperthermia showed enhanced intensity and sensitivity to triggering drugs when expressed in human embryonic kidney cells. Mutations within the gene encoding the skeletal muscle calcium channel ryanodine receptor can result in malignant hyperthermia. Although it is important to characterize the functional effects of candidate mutations to establish a genetic test for diagnosis, ex vivo methods are limited because of the low incidence of the disorder and sample unavailability. More than 250 candidate mutations have been identified, but only a few mutations have been functionally characterized. The human skeletal muscle ryanodine receptor complementary DNA was cloned with or without a disease-related variant. Wild-type and mutant calcium channel proteins were transiently expressed in human embryonic kidney-293 cells expressing the large T-antigen of simian virus 40, and functional analysis was carried out using calcium imaging with fura-2 AM. Six human malignant hyperthermia-related mutants such as R44C, R163C, R401C, R533C, R533H, and H4833Y were analyzed. Cells were stimulated with a specific ryanodine receptor agonist 4-chloro-m-cresol, and intracellular calcium mobility was analyzed to determine the functional aspects of mutant channels. Mutant proteins that contained a variant linked to malignant hyperthermia showed higher sensitivity to the agonist. Compared with the wild type (EC50 = 453.2 µM, n = 18), all six mutants showed a lower EC50 (21.2-170.4 µM, n = 12-23), indicating susceptibility against triggering agents. These six mutations cause functional abnormality of the calcium channel, leading to higher sensitivity to a specific agonist, and therefore could be considered potentially causative of malignant hyperthermia reactions. 23910876 DNA analysis of skeletal tissue recovered from the English Channel. This case study reports on DNA analysis from different skeletal elements of an individual recovered 2 years after going missing in the English Channel. Selected bones were also re-submerged for an additional 2 years and re-analysed. By comparing results from both time points, this study concludes that high-load-bearing bones, particularly the bones of the feet, appear to be a preferable source of DNA for identification of skeletal tissue recovered from similar conditions. 23822740 Clinicopathological significance of claudin-4 in gastric carcinoma. Aberrant expression of claudin proteins has been reported in a variety of cancers. Previous studies have demonstrated that overexpression of claudin may promote tumorigenesis and metastasis through increased invasion and survival of tumor cells. However, the prognostic significance of claudin-4 in gastric cancer remains unclear. Immunohistochemistry was used to analyze the expression of claudin-4 in 329 clinical gastric cancer specimens and 44 normal stomach samples, 21 intestinal metaplasia samples, and 21 adjacent precursor lesions dysplasia samples. Statistical analysis methods were used to evaluate the relationship between claudin-4 expression and various clinicopathological parameters. Univariate and multivariate analyses were performed, respectively, to detect the independent predictors of survival. Claudin-4 expression was present in only 7(15.9%) normal gastric samples, but expression of claudin-4 in the intestinal metaplasia lesions and dysplasia lesions was 90.5% and 95.2%, respectively. The expression of claudin-4 was significantly associated with histological differentiation (P < 0.001) and tumor growth patterns (P < 0.001) but not associated with patient survival. However, intermediate type staining of claudin-4 exhibited a trend of correlation with patients' survival (P = 0.023). The five-year survival rate with low expression of claudin-4 in intermediate type (76.4%) was similar to expanding type (64.5%), while the high expression group (46.6%) was closer to infiltrative type (50.7%). The findings in this study demonstrate claudin-4 aberrant expression in gastric cancer and precursor lesions. The expression of claudin-4 could serve as a basis for identifying gastric cancer of the intermediate type. 23715384 [PtBi2I12]2-: the first polyiodobismuthate containing an octahedral heterometallic unit. The complex [Na4((CH3)2CO)15][PtBi2I12]·3(CH3)2CO (1) has been prepared by the reaction of BiI3, NaI and H2[PtCl6]·6H2O and structurally characterized using X-ray diffractometry. It represents the first example of a polyiodobismuthate with an octahedral heterometallic unit. Interatomic interactions in the [PtBi2I12](2-) anion were characterized using the topological methods QTAIM and ELF. 23845216 Mark-Recapture with Multiple, Non-Invasive Marks. Non-invasive marks, including pigmentation patterns, acquired scars, and genetic markers, are often used to identify individuals in mark-recapture experiments. If animals in a population can be identified from multiple, non-invasive marks then some individuals may be counted twice in the observed data. Analyzing the observed histories without accounting for these errors will provide incorrect inference about the population dynamics. Previous approaches to this problem include modeling data from only one mark and combining estimators obtained from each mark separately assuming that they are independent. Motivated by the analysis of data from the ECOCEAN online whale shark (Rhincodon typus) catalog, we describe a Bayesian method to analyze data from multiple, non-invasive marks that is based on the latent-multinomial model of Link et al. (2010, Biometrics 66, 178-185). Further to this, we describe a simplification of the Markov chain Monte Carlo algorithm of Link et al. (2010, Biometrics 66, 178-185) that leads to more efficient computation. We present results from the analysis of the ECOCEAN whale shark data and from simulation studies comparing our method with the previous approaches. 23708742 An Ultrasonographic Study of Ovarian Antral Follicular Dynamics in Prepubertal Gilts During the Expected Activation of the Hypothalamo-pituitary-ovarian Axis. Daily transrectal ultrasonography was carried out in eight 4-5-month-old Polish Large White × Polish Landrace gilts for 42 days to monitor the growth of individual ovarian antral follicles ≥2 mm in diameter. In total, 52.4 ± 16.2 and 123.0 ± 6.7 follicles per gilt (mean ± SD) that grew to ≥4 mm were identified during the first and second 21-day study periods, respectively (P<0.01). Four follicular waves (defined as the synchronous growth of a group of follicles from 2-3 mm to ≥4 mm) emerged during the first period, and five waves emerged during the second period. The maximum diameters attained by the largest follicles of waves were 5.7 ± 0.6 and 7.0 ± 0.5 mm (first and second periods, respectively; P<0.01). The present results provide direct evidence for the rhythmic, wave-like pattern of antral follicle recruitment in prepubertal gilts. The number of follicles and maximum diameter they attain increase significantly during the expected activation of the hypothalamo-pituitary-ovarian axis in prepubescent gilts. 23296103 The genotoxicity of PEI-based nanoparticles is reduced by acetylation of polyethylenimine amines in human primary cells. The ultrasmall size and unique properties of polymeric nanoparticles (NPs) have led to raising concerns about their potential cyto- and genotoxicity on biological systems. Polyethylenimine (PEI) is a highly positive charged polymer and is known to have varying degree of toxic effect to cells based on its chemical structure (i.e., amount of primary and secondary amine). Herein, drug delivery carriers such as PEI-PLGA nanoparticles (PEI-NPs) and acetylated PEI-PLGA nanoparticles (AcPEI-NPs) were utilized to examine the effect of acetylation on NPs biocompatibility and genotoxicity, using human primary cells as in vitro model. Cell uptake of NPs was characterized along with their effects on cellular viability. The results indicate that both NPs showed an equivalent behavior in terms of uptake and biocompatibility. In depth analysis of NP uptake on cell biology evidenced that these nanoparticles induced dose dependant genotoxic effects. This phenomenon was significantly reduced by PEI acetylation. Endocytosed PEI-NPs trigger an oxidative stress on cells by inducing the production of reactive oxygen species (ROS), which cause DNA damage without apparently affecting cell viability. Thus, the genotoxicity of nanoparticles, that could be used as non-viral drug carriers, should be evaluated based on the intracellular level of ROS generation and DNA damage even in absence of a significant cell death. 23969419 Isolation and mutational analysis of circulating tumor cells from lung cancer patients with magnetic sifters and biochips. Detection and characterization of circulating tumor cells (CTCs) may reveal insights into the diagnosis and treatment of malignant disease. Technologies for isolating CTCs developed thus far suffer from one or more limitations, such as low throughput, inability to release captured cells, and reliance on expensive instrumentation for enrichment or subsequent characterization. We report a continuing development of a magnetic separation device, the magnetic sifter, which is a miniature microfluidic chip with a dense array of magnetic pores. It offers high efficiency capture of tumor cells, labeled with magnetic nanoparticles, from whole blood with high throughput and efficient release of captured cells. For subsequent characterization of CTCs, an assay, using a protein chip with giant magnetoresistive nanosensors, has been implemented for mutational analysis of CTCs enriched with the magnetic sifter. The use of these magnetic technologies, which are separate devices, may lead the way to routine preparation and characterization of "liquid biopsies" from cancer patients. 23091170 Neutrophil and eosinophil granulocytes as key players in a mouse model of chemical-induced asthma. Diisocyanates are an important cause of chemical-induced occupational asthma. This type of immunologically mediated asthma is often characterized by a predominant granulocytic inflammation in the airways, rather than an infiltration by lymphocytes. We sought to determine the contribution of granulocytes in the outcome of chemical-induced asthma using general and specific leukocyte depletion strategies in an established mouse model of isocyanate asthma. On days 1 and 8, BALB/c mice received dermal applications with toluene-2,4-diisocyanate (TDI) or vehicle (acetone olive oil), followed by two ip injections of cyclophosphamide (CP, days 11 and 13), or one iv injection of antigranulocyte receptor 1 (aGR1, day 13) monoclonal antibody (mAb), or two ip injections of Ly6G-specific mAb (1A8, days 13 and 14). On day 15, the mice were challenged (oropharyngeal administration) with TDI or vehicle. The next day, we assessed methacholine airway hyperreactivity (AHR); bronchoalveolar lavage differential cell count; histopathology and total serum IgE; and auricular lymphocyte subpopulations and release of interleukin (IL)-2, IL-4, IL-10, IL-13, and gamma interferon by these lymphocytes. CP depleted all leukocyte types and completely prevented AHR and airway inflammation. aGR1 depleted granulocytes and CD8(+) lymphocytes, which resulted in a partial prevention in AHR but no decrease in airway inflammation. Depletion of Ly6G-positive granulocytes, i.e., both neutrophils and eosinophils, prevented AHR and lung epithelial damage and significantly reduced airway inflammation. Injection of aGR1 or 1A8 led to significantly changed cytokine release patterns in TDI-treated mice. Granulocytes, both neutrophils and eosinophils, are key cellular players in this model of chemical-induced asthma. 23939105 Power scaling of high-efficiency 1.5 Î¼m cascaded Raman fiber lasers. High-power fiber lasers operating at the 1.5 Î¼m wavelength region have attractive features, such as eye safety and atmospheric transparency, and cascaded Raman fiber lasers offer a convenient method to obtain high-power sources at these wavelengths. A limitation to power scaling, however, has been the lower conversion efficiency of these lasers. We recently introduced a high-efficiency architecture for high-power cascaded Raman fiber lasers applicable for 1.5 Î¼m fiber lasers. Here we demonstrate further power scaling using this new architecture. Using numerical simulations, we identify the ideal operating conditions for the new architecture. We demonstrate a high-efficiency 1480 nm cascaded Raman fiber laser with an output power of 301 W, comparable to record power levels achieved with rare-earth-doped fiber lasers in the 1.5 Î¼m wavelength region. 23456173 Characterisation of novel uveal melanoma cell lines under serum-free conditions. The establishment of long-term uveal melanoma (UM) cell lines is difficult. However, studying living cells and their behaviour in the presence of other cells and the extracellular matrix is important in terms of understanding tumour biology and malignant behaviour. We have established three UM cell lines and report a first characterisation of these cell lines. Three established UM cell lines (UMT2, UMT26 and UMT33) were analysed according to their morphologic characteristics, melanocytic differentiation, adhesion on different extracellular matrices and proliferative activity. Copy number changes of chromosomes 1, 3, 6 and 8 were studied by multiplex ligation-dependent probe amplification (MLPA). Oncogenic mutations in UM involving exons 4 and 5 of GNAQ and GNA11, respectively, were analysed by sequencing. All cell lines grew in suspension. UMT2 cells were homogeneous, UMT26 and UMT33 cells heterogeneous with regard to cell size and pigmentation. All UM cell lines revealed a melanocytic differentiation. UMT2 and 33 adhered on various extracellular matrices, while UMT26 only adhered to basal membrane extract (BME). This difference corresponded to the different expression of various integrins. Ki67 was expressed by 89 % of UMT2 and 95 % of UMT33 cells, which thus were in a proliferative stage, while only 2 % of UMT26 cells revealed immunostaining for this proliferation marker. The doubling time of UMT2 was 3 days, 12 days for UMT33, and circa 3-4 months for UMT26. MLPA revealed disomy 3 in UMT2 and monosomy 3 in UMT33. The same point mutation was found in UMT2, 26 and 33, in exon 5 of GNA11 at codon 209 (p.Q209L). The establishment of UM cell lines under serum-free conditions is possible. Characterisation of UMT2, 26, and 33 revealed obvious differences in cytomorphology, melanocytic differentiation, adhesion on extracellular matrices, and proliferative activity. UMT2, 26 and 33 showed the same oncogenic mutation in exon 5 of GNA11. 23804387 Multiplex 5' Nuclease Quantitative Real-Time PCR for Clinical Diagnosis of Malaria and Species-Level Identification and Epidemiologic Evaluation of Malaria-Causing Parasites, Including Plasmodium knowlesi. Molecular diagnosis of malaria offers many potential advantages over microscopy, including identification of malaria to the species level in an era with few experienced microscopists. We developed high-throughput multiplex 5' nuclease quantitative PCR (qPCR) assays, with the potential to support large studies, to specifically identify Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. We compared qPCR to microscopy and confirmed discordant results with an alternative target PCR assay. The assays specifically detected 1 to 6 parasites/μl of blood. The clinical sensitivities (95% confidence intervals [CIs]) of the 4-plex assay to detect microscopically confirmed malaria were 95.8% (88.3 to 99.1%) for P. falciparum, 89.5% (75.2 to 97.1%) for P. vivax, 94.1% (71.3 to 99.9%) for P. ovale, and 100% (66.4 to 100%) for P. malariae. The specificities (95% CIs) were 98.6% (92.4 to 100%) for P. falciparum, 99% (84.8 to 100%) for P. vivax, 98.4% (94.4 to 99.8%) for P. ovale, and 99.3% (95.9 to 100%) for P. malariae. The clinical specificity for samples without malaria was 100%. The clinical sensitivity of the 5-plex assay for confirmed P. knowlesi malaria was 100% (95% CI, 69.2 to 100%), and the clinical specificity was 100% (95% CI, 87.2 to 100%). Coded retesting and testing with an alternative target PCR assay showed improved sensitivity and specificity of multiplex qPCR versus microscopy. Additionally, 91.7% (11/12) of the samples with uncertain species by microscopy were identified to the species level identically by both our multiplex qPCR assay and the alternative target PCR assay, including 9 P. falciparum infections. Multiplex qPCR can rapidly and simultaneously identify all 5 Plasmodium species known to cause malaria in humans, and it offers an alternative or adjunct to microscopy for clinical diagnosis as well as a needed high-throughput tool for research. 23739186 Anal transitional zone neoplasia in patients with familial adenomatous polyposis after restorative proctocolectomy and IPAA: incidence, management, and oncologic and functional outcomes. Restorative proctocolectomy and IPAA in patients with familial adenomatous polyposis may leave residual anal transitional zone mucosa that is prone to neoplasia. The aim of this study was to evaluate the long-term control of neoplasia at the IPAA, the functional outcomes, and the influence of anastomotic technique on these results. : This research is a retrospective cohort study from a prospective database. The investigation took place in a high-volume specialized colorectal surgery department. Patients with familial adenomatous polyposis who underwent IPAA between 1983 and 2010 were included. The primary outcomes measured were functional outcomes, quality of life, and the incidence of neoplasia in the anal transitional zone. Eighty-six patients underwent mucosectomy and 174 underwent stapled anastomosis with mean 155 ± 99 and 95 ± 70 months follow-up. Eighteen patients (20.9%) in the mucosectomy group and 59 patients (33.9%) in the stapled group developed anal transitional zone adenomas (p = 0.03). One of 86 (1.2%) patients undergoing mucosectomy and 3 of 174 (1.7%) patients undergoing stapled anastomosis developed cancer in the anal transitional zone (p > 0.05). Three of these patients underwent an abdominoperineal resection, but one who refused abdominoperineal resection underwent transanal excision with neoileoanal anastomosis. Patients undergoing a mucosectomy had a significantly higher rate of anastomotic stricture, but other complications were similar. Incontinence, seepage, and pad usage were higher in the mucosectomy group. Cleveland global quality-of-life score was 0.8 ± 0.2 in patients with handsewn anastomoses and 0.8 ± 0.3 in patients with a stapled anastomoses (p > 0.05). This study was limited by its nonrandomized retrospective design. Risk for the development of adenomas in the anal transitional zone is higher after a stapled IPAA than after a mucosectomy with handsewn anastomosis. However, control of anal transitional zone neoplasia results in a similar risk of cancer development. Because the stapled procedure is associated with better long-term functional outcomes than a mucosectomy, stapled IPAA is the preferable procedure for most patients with familial adenomatous polyposis. 23899532 Combination of cisplatin/S-1 in the treatment of patients with advanced gastric or gastroesophageal adenocarcinoma: Results of noninferiority and safety analyses compared with cisplatin/5-fluorouracil in the First-Line Advanced Gastric Cancer Study. The aim of developing oral fluorouracil (5-FU) is to provide a more convenient administration route with similar efficacy and the best achievable tolerance. S-1, a novel oral fluoropyrimidine, was specifically designed to overcome the limitations of intravenous fluoropyrimidine therapies. A multicentre, randomised phase 3 trial was undertaken to compare S-1/cisplatin (CS) with infusional 5-FU/cisplatin (CF) in 1053 patients with untreated, advanced gastric/gastroesophageal adenocarcinoma. This report discusses a post-hoc noninferiority overall survival (OS) and safety analyses. Results (1029 treated; CS=521/CF=508) revealed OS in CS (8.6 months) was statistically noninferior to CF (7.9 months) [hazard ratio (HR)=0.92 (two-sided 95% confidence interval (CI), 0.80-1.05)] for any margin equal to or greater than 1.05. Statistically significant safety advantages for the CS arm were observed [G3/4 neutropenia (CS, 18.6%; CF, 40.0%), febrile neutropenia (CS, 1.7%; CF, 6.9%), G3/4 stomatitis (CS, 1.3%; CF, 13.6%), diarrhoea (all grades: CS, 29.2%; CF, 38.4%) and renal adverse events (all grades: CS, 18.8%; CF, 33.5%)]. Hand-foot syndrome, infrequently reported, was mainly grade 1/2 in both arms. Treatment-related deaths were significantly lower in the CS arm than the CF arm (2.5% and 4.9%, respectively; P<0.047). CS is noninferior to CF with a better safety profile and provides a new treatment option for patients with advanced gastric carcinoma. 23669619 pH-sensitive micelles self-assembled from multi-arm star triblock co-polymers poly(ε-caprolactone)-b-poly(2-(diethylamino)ethyl methacrylate)-b-poly(poly(ethylene glycol) methyl ether methacrylate) for controlled anticancer drug delivery. A series of amphiphilic 4- and 6-armed star triblock co-polymers poly(ε-caprolactone)-b-poly(2-(diethylamino)ethyl methacrylate)-b-poly(poly(ethylene glycol) methyl ether methacrylate) (4/6AS-PCL-b-PDEAEMA-b-PPEGMA) were developed by a combination of ring opening polymerization and continuous activators regenerated by electron transfer atom transfer radical polymerization. The critical micelle concentration values of the star co-polymers in aqueous solution were extremely low (2.2-4.0mgl(-1)), depending on the architecture of the co-polymers. The self-assembled blank and doxorubicin (DOX)-loaded three layer micelles were spherical in shape with an average size of 60-220nm determined by scanning electron microscopy and dynamic light scattering. The in vitro release behavior of DOX from the three layer micelles exhibited pH-dependent properties. The DOX release rate was significantly accelerated by decreasing the pH from 7.4 to 5.0, due to swelling of the micelles at lower pH values caused by the protonation of tertiary amine groups in DEAEMA in the middle layer of the micelles. The in vitro cytotoxicity of DOX-loaded micelles to HepG2 cells suggested that the 4/6AS-PCL-b-PDEAEMA-b-PPEGMA micelles could provide equivalent or even enhanced anticancer activity and bioavailability of DOX and thus a lower dosage is sufficient for the same therapeutic efficacy. The results demonstrate that the pH-sensitive multilayer micelles could have great potential application in delivering hydrophobic anticancer drugs for improved cancer therapy. 23769824 The activation and differential signalling of the growth hormone receptor induced by pGH or anti-idiotypic monoclonal antibodies in primary rat hepatocytes. In this report, we have developed a panel of monoclonal anti-idiotypic antibodies to pGH by immunising BALB/c mice with a purified monoclonal anti-pGH antibody (1A3), among which one mAb, termed CG-8F, was selected for further characterisation. We found that CG-8F behaved as a typical Ab2β, not only conformationally competing with pGH for 1A3 but also exhibiting recognition for GHR in a rat hepatocyte model. We next examined the resulting signal transduction pathways triggered by this antibody in rat hepatocytes and found that both pGH and CG-8F could trigger the JAK2-STAT1/3/5-mediated signal transduction pathway. Furthermore, the phosphorylation kinetics of pSTAT1/3/5 induced by either pGH or CG-8F were remarkably similar in the dose-response and time course rat hepatocyte experiments. In contrast, only pGH, but not CG-8F, was capable of inducing ERK phosphorylation. Further experimental studies indicated that the two functional binding sites on CG-8F are required for GHR activation. This study partially reveals the mechanism of action of GH anti-idiotypic antibodies and also indicates that monoclonal anti-idiotypic antibodies represent an effective way to produce GH mimics, suggesting that it is possible to produce signal-specific cytokine agonists using an anti-idiotypic antibody approach. 23640862 NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS INDUCE A MITOPHAGY-ASSOCIATED ENDOTHELIAL DYSFUNCTION THAT IS REVERSED BY COENZYME Q10 CO-TREATMENT. Cardiovascular complications have been documented in HIV-1 infected populations, and antiretroviral therapy may play a role. Nucleoside reverse transcriptase inhibitors (NRTI) are antiretrovirals known to induce mitochondrial damage in endothelial cells, culminating in endothelial dysfunction, an initiating event in atherogenesis. Though the mechanism for NRTI-induced endothelial toxicity is not yet clear, our prior work suggested that a mitochondrial oxidative stress may be involved. To further delineate the mechanism of toxicity, endothelial cells were treated with NRTI of varying subclasses, and the level of reactive oxygen species (ROS) and mitochondrial function were assessed. To test whether rescue of mitochondrial electron transport attenuated NRTI-induced endothelial dysfunction, in some cases, cells were co-treated with the electron transport cofactor coenzyme Q10 (Q10). At 4-6h, NRTI increased levels of ROS but decreased the activities of electron transport chain complexes I-IV, levels of ATP and the NAD/NADH ratio. Moreover, nitric oxide levels were decreased, while endothelin-1 release was increased. Q10 abolished NRTI-induced mitochondria injury and effects on endothelial agonist production. Interestingly, in cells treated with NRTI only, markers for mitochondrial toxicity returned to baseline levels by 18-24h, suggesting a compensatory mechanism for clearing damaged mitochondria. Using confocal microscopy, with confirmation utilizing the autophagy and mitophagy markers LC-3 and NIX, respectively, we observed autophagy of mitochondria at 8-10 h after treatment. Q10 prevented NRTI-mediated increase in LC-3. These findings suggest that NRTI-induced mitophagy may be involved in NRTI-induced endothelial dysfunction and that this damage likely results from oxidant injury. Further, Q10 supplementation could potentially prevent NRTI-induced endothelial dysfunction. 23652569 Lysosomal acid lipase A and the hypercholesterolaemic phenotype. Mutations in lysosomal acid lipase A (LIPA) result in two phenotypes depending on the extent of lysosomal acid lipase (LAL) deficiency: the severe, early-onset Wolman disease or the less severe cholesteryl ester storage disease (CESD). In CESD, the severity of the symptoms, hepatomegaly and hypercholesterolaemia, can be highly variable, presenting in childhood or adulthood. Therefore, it is likely that many patients are undiagnosed or misdiagnosed. Nevertheless, LAL deficiency has been recognized for more than 25 years, but adequate therapeutic strategies are limited. CESD has an estimated prevalence of one in 90 000 to 170 000 individuals in the general population, confirming the likelihood that this disease is currently underdiagnosed. A number of studies have shown that in LIPA deficient patients the hypercholesterolaemic phenotype can be attenuated using statin therapy, and favourable effects on reduction of lipid accumulation in lysosomes have been reported. Targeting lysosomal exocytosis with LAL replacement therapy was shown to be successful in animal models and recently a phase I/II study demonstrated its safety and its potential metabolic efficacy on transaminase levels. The hypercholesterolaemic phenotype in CESD can be difficult to distinguish from other known hypercholesterolaemic disorders. In the majority of CESD cases with hypercholesterolaemia favourable responses on statin treatment are observed, but the effect on reduction of lipid accumulation in lysosomes needs to be further evaluated. Combining statins with LAL replacement therapy may provide a promising approach for optimal treatment of LIPA deficiencies in the future. 23887207 The cell cycle distribution should be given more consideration in cell-based in vitro toxicological studies. In this study, to discuss the importance of the cell cycle distribution in cell-based in vitro toxicity mechanism studies, diethyl sulfate (DES) was selected as a model chemical that induced the alteration of the cell cycle distribution in human bronchial epithelial cell line 16HBE 14o- (HBE) cells. Cells were treated with various concentrations of DES, cell proliferation and apoptosis were then determined. The results showed that DES concentration-dependently inhibited HBE cells proliferation and induced apoptosis. When cells were treated with 2.0 mM of DES for 20 or 28 h, significant S and G2/M phase accumulation was observed. Then, the relative cellular levels of Cdk4, p-Cdk2 (Thr160), Cyclins A and B1 in DES-treated HBE cells at 20 and 28 h were determined by two ways. The differences of the cell cycle distribution between DES and control groups were ignored in one way and eliminated by using flow cytometric cell sorting in the other. The results obtained by the two ways were quite different, which indicated that the cell cycle distribution might result in confounding if it was significantly different between the treated and control groups. Therefore, we propose that the cell cycle distribution should be given more consideration in cell-based in vitro toxicological studies. 23688803 A sensitive and specific PCR assay for the detection of Baylisascaris schroederi eggs in giant panda feces. Baylisascaris schroederi is one of the most common intestinal nematodes in giant pandas. It can cause severe baylisascariasis which is highly infectious in its natural hosts. A rapid and reliable diagnosis of parasite infections is crucial to protect giant pandas, as well as for environmental monitoring and disease surveillance. Here, we established a specific PCR assay for B. schroederi detection which was targeting a 331-bp long fragment of the mitochondrial cytochrome c oxidase subunit II (COII) gene. Fifty fresh fecal samples collected from captive giant pandas were tested by the established PCR assay and the traditional flotation technique. DNA extracted from a single B. schroederi egg could be successfully amplified, while no cross-reactivity was found with DNA from Ancylostoma caninum eggs. The detection rate of the PCR assay was 68%, which was higher than that of the traditional egg flotation (46%). Our findings demonstrated that the PCR assay is sensitive and specific for the detection and identification of B. schroederi eggs. Therefore, it could become a useful tool for the investigation of B. schroederi infections in giant pandas. 23696472 Electrophysiologic changes with incremental exercise in obstructive sleep apnea. In patients with obstructive sleep apnea (OSA), intermittent apnea and hypopnea might cause different adaptations in inspiratory and peripheral muscles. In this study we aimed to determine the changes that occur in muscle activation characteristics during incremental exercise testing in patients with severe OSA. Surface electromyography of inspiratory muscles and knee extensors was performed. Eleven men with severe OSA and 11 matched controls were recruited. Changes in muscle activity were compared by determining root mean square (RMS) and median power frequency (MPF) values obtained at different exercise intensities. The ratios of RMS to oxygen consumption in inspiratory muscles and vastus lateralis increased significantly at peak workload in the control group (P < 0.05), but not in the OSA group. Patients with severe OSA demonstrated an inability to increase motor unit recruitment of inspiratory muscles and knee extensors during incremental exercise. Muscle Nerve, 48: 212-218, 2013. 23970489 Proteomic Identification of Listeria monocytogenes Surface-Associated Proteins. This study aimed to identify proteins exposed on the surface of Listeria monocytogenes cells for diagnostic reagent development. Brief trypsin treatment of L. monocytogenes cells followed by peptide separation and identification by nano-LC and online-MS/MS was performed. In parallel, as a negative control, proteins secreted into the digest buffer as well as proteins from cell lysis were identified. One hundred and seventy-four proteins were identified in at least two of three trials in either the negative control or during cell digest. Nineteen surface, 21 extracellularly secreted, 132 cytoplasmic and two phage proteins were identified. The data has been deposited to the ProteomeXchange Consortium with identifier PXD00035. Immunofluorescence microscopy of L. monocytogenes cells revealed the surface localization of two potential candidates for L. monocytogenes isolation and detection: lipoprotein LMOf2365_0546 and PBPD1 (LMOf2365_2742). In this report, we present the first data set of surface exposed L. monocytogenes proteins currently available. This article is protected by copyright. All rights reserved. 22871098 Development of molecularly imprinted polymer as sustain release drug carrier for propranolol HCL. Applications of molecularly imprinted polymer (MIPs), is rapidly increasing, especially in the drug delivery field. Molecularly imprinted polymers are the molecular traps, which can entrap the specific molecule and also control its release. Polymer complexes were prepared with and without propranolol HCl as templates, MAA (methacrylic acid) as monomer and EGDMA (ethyleneglycol dimethacrylate) as crosslinker by solvent polymerization technique. Drug release pattern from these polymer complexes were compared and maximum drug release in 12 h was consider to optimize the ratio of MAA and EGDMA. Since, the maximum propranolol HCl release from polymer complex was low (62.15%) in optimized batch, inclusion complex of drug with β-cyclodextrin were prepared for the higher drug release (80.32%). The selected polymer complexes were treated with methanol for complete removal of the drug to form MIPs. These MIPs were reloaded with the drug and subjected for drug release. The release patterns from reloaded MIP's were observed to be slightly quicker than their corresponding MIP's. 23824222 Heat flux measurements for use in physiological and clothing research. Scientists use passive heat flow meters to measure body heat exchanges with the environment. In recent years, several such sensors have been developed and concerns about their proper calibration have been addressed. However, calibration methods have differed in the geometry of the heated device as well as in the heat transfer mechanism. Therefore, a comparison of calibration methods is needed in order to understand the obtained differences in calibration lines. We chose three commercially available heat flux sensors and placed them on four different heated devices: a hot plate, double hot plate, nude cylinder and a cylinder covered with a spacer material. We found differences between the calibration line of the manufacturer and our own measurements, especially when forced convection was involved as the main heat transfer mechanism. The results showed clearly that the calibration method should be chosen according to the intended purpose of use. In addition, we recommend use a thin, light heat flux sensor with good thermal conduction in human subject studies. 23434129 Genetic variability of HEV isolates: inconsistencies of current classification. Many HEV and HEV-like sequences have been reported during the last years, including isolates which may represent a number of potential new genera, new genotypes or new subtypes within the family Hepeviridae. Using the most common classification system, difficulties in the establishment of subtypes have been reported. Moreover the relevance of subtype classification for epidemiology can be questioned. In this study we have performed phylogenetic analyses based on whole capsid gene and complete HEV genomic sequences in order to evaluate the current classification of HEV at genotype and subtype levels. The results of our analyses modify the current taxonomy of genotype 3 and refine the established system for typing of HEV. In addition we suggest a classification for hepeviruses recently isolated from bats, ferrets, rats and wild boar. 23929684 Assessing FRET using spectral techniques. Förster resonance energy transfer (FRET) techniques have proven invaluable for probing the complex nature of protein-protein interactions, protein folding, and intracellular signaling events. These techniques have traditionally been implemented with the use of one or more fluorescence band-pass filters, either as fluorescence microscopy filter cubes, or as dichroic mirrors and band-pass filters in flow cytometry. In addition, new approaches for measuring FRET, such as fluorescence lifetime and acceptor photobleaching, have been developed. Hyperspectral techniques for imaging and flow cytometry have also shown to be promising for performing FRET measurements. In this study, we have compared traditional (filter-based) FRET approaches to three spectral-based approaches: the ratio of acceptor-to-donor peak emission, linear spectral unmixing, and linear spectral unmixing with a correction for direct acceptor excitation. All methods are estimates of FRET efficiency, except for one-filter set and three-filter set FRET indices, which are included for consistency with prior literature. In the first part of this study, spectrofluorimetric data were collected from a CFP-Epac-YFP FRET probe that has been used for intracellular cAMP measurements. All comparisons were performed using the same spectrofluorimetric datasets as input data, to provide a relevant comparison. Linear spectral unmixing resulted in measurements with the lowest coefficient of variation (0.10) as well as accurate fits using the Hill equation. FRET efficiency methods produced coefficients of variation of less than 0.20, while FRET indices produced coefficients of variation greater than 8.00. These results demonstrate that spectral FRET measurements provide improved response over standard, filter-based measurements. Using spectral approaches, single-cell measurements were conducted through hyperspectral confocal microscopy, linear unmixing, and cell segmentation with quantitative image analysis. Results from these studies confirmed that spectral imaging is effective for measuring subcellular, time-dependent FRET dynamics and that additional fluorescent signals can be readily separated from FRET signals, enabling multilabel studies of molecular interactions. © 2013 International Society for Advancement of Cytometry. 23324099 A community education initiative to improve using online health information: participation and impact. The Internet has become a major source of health information for the general public and has the potential to influence health behaviours; however, most people lack the knowledge and skills to use it insightfully. This paper reports on the evaluation of a community education program, in which a team of clinicians and consumer representatives from a large metropolitan hospital partnered with a major public library to provide free interactive workshops for the general public. The aim of the workshops was to improve participants' ability to find and use evidence-based health information on the Internet. The aim of the evaluation reported here was to study participation in and impact of these workshops. Researchers administered pre- and post-workshop surveys to 89 members of the general public who participated in a workshop. This study found not only similarities in participants' pre-workshop use of online health information compared with population-level studies but also some interesting differences. The workshop was found to have an overall positive impact on changing the way participants intended to look for and use health information in the future, and on improving their knowledge about evidence-based health information, with 63.5% of respondents stating that they would use health information in the future to ask a doctor new questions. These findings offer important evidence of the need to plan nuanced health literacy education and information strategies for the general public. 23372041 Novel locus including FGF21 is associated with dietary macronutrient intake. Dietary intake of macronutrients (carbohydrate, protein, and fat) has been associated with risk of chronic conditions such as obesity and diabetes. Family studies have reported a moderate contribution of genetics to variation in macronutrient intake. In a genome-wide meta-analysis of a population-based discovery cohort (n = 33 533), rs838133 in FGF21 (19q13.33), rs197273 near TRAF family member-associated NF-kappa-B activator (TANK) (2p24.2), and rs10163409 in FTO (16q12.2) were among the top associations (P < 10(-5)) for percentage of total caloric intake from protein and carbohydrate. rs838133 was replicated in silico in an independent sample from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE) Nutrition Working Group (n = 38 360) and attained genome-wide significance in combined analysis (Pjoint = 7.9 × 10(-9)). A cytokine involved in cellular metabolism, FGF21 is a potential susceptibility gene for obesity and type 2 diabetes. Our results highlight the potential of genetic variation for determining dietary macronutrient intake. 23922673 LDL Cholesterolemia as a Novel Risk Factor for Radiographic Progression of Rheumatoid Arthritis: A Single-Center Prospective Study. Dyslipidemia has been implicated in various musculoskeletal diseases, including rheumatoid arthritis (RA). Evidence is emerging that there might be a pathogenic interaction among inflammation, dyslipidemia, and adipokines. We prospectively investigated the association of cumulative lipid levels with radiographic progression of RA. RA patients (n = 242) underwent plasma cholesterol assessment at four visits. Disease activity parameters and X-rays of the hands and feet were also serially monitored in these patients. The cumulative inflammatory burden and lipid levels were estimated by time-integrated values. Serum leptin and adiponectin concentrations were determined by ELISA. When patients were divided into three groups according to time-integrated lipid levels, as expected, patients with LDL cholesterol and/or triglyceride levels in the third tertile had persistently higher ESR and CRP levels. In parallel, a more rapid radiographic progression over two years was observed in patients with higher LDL cholesterol and/or triglyceride levels. In multivariate analysis, time-integrated LDL cholesterol was independently associated with radiographic progression. Particularly, the risk of radiographic progression was 5.6-fold in a subgroup with both LDL cholesterol and triglyceride levels in the third tertile. Moreover, LDL cholesterol synergistically increased the adjusted probability of radiographic progression in patients with high serum leptin levels but not in those without. These results demonstrate that LDL cholesterolemia is a novel serum marker that can be used to predict radiographic progression of RA, which seems to be related to circulatory leptin levels. We suggest that personalized and more aggressive anti-rheumatic therapy is required for dyslipidemic subgroups in RA patients. 23876367 Neuroprotective effects of madecassoside in early stage of Parkinson's disease induced by MPTP in rats. In this study, we investigated the neuroprotective effects of madecassoside, isolated from the Chinese medicinal herb Centella asiatica, in the rat model of early phase of parkinsonism. During intragastric administrations of madecassoside for 7days, the rats were injected with MPTP on the 7th day. And for the following 14days, madecassoside were also administered. On the 14th day, the behavioral tests were assessed after 1h of administration. And then, the rats were sacrificed, substantia nigra and striatum were dissected. The content of DA, MDA, GSH, and Bcl-2/Bax gene expression levels and BDNF protein level was determined. Treatment with madecassoside was found to improve locomotor dysfunction and to protect dopaminergic neuron by antagonizing MPTP induced neurotoxicity. Madecassoside significantly attenuated the MPTP-induced reduction of dopamine in the striatum. The MDA contents were significantly decreased while the GSH levels, Bcl-2/Bax ratio and protein expression of BDNF were significantly increased in madecassoside treated groups. These results indicated that madecassoside was effective in recovering MPTP-induced early signs of parkinsonism via its neuroprotective effects including reversing the depletion of DA, antioxidant activity, increasing ratio of Bcl-2/Bax, increasing protein expression of BDNF. 23377780 Hypertrophic cardiomyopathy in neonates with congenital hyperinsulinism. Hypertrophic cardiomyopathy (HCM) is a well-recognised complication in infants of diabetic mothers and is attributed to a compensatory increase in fetal insulin secretion. Infants with congenital hyperinsulinism have excessive prenatal and postnatal insulin secretion due to defects in pathways of insulin secretion (most commonly the KATP channel). HCM has been reported in a few neonates with hyperinsulinism, but its extent and risk factors for its development have not been evaluated. Retrospective chart review of infants, age <3 months, with congenital hyperinsulinism managed by Children's Hospital of Philadelphia over a 3.5-year period. Gestational age, birth weight, hyperinsulinism form and treatments, echocardiogram results, cardiac/respiratory complications. 68 infants were included, 58 requiring pancreatectomy for diffuse (n=28) or focal (n=30) disease, 10 were diazoxide-sensitive. Twenty-five had echocardiograms performed. Ten had HCM, all of whom required pancreatectomy and eight of whom had confirmed ATP-sensitive potassium-hyperinsulinism. Subjects with HCM had younger gestational age 36(32, 38) than their surgical counterparts without HCM 38 (31.6, 43), p=0.02. HCM appears common in infants with severe hyperinsulinism. Routine echocardiogram and EKG of at-risk newborns should be considered. Fetal hyperinsulinism is the likely mediating factor for HCM in HI infants. 23438501 Deficient fear recognition in regular cocaine users is not attributable to elevated impulsivity or conduct disorder prior to cocaine use. We previously reported that regular recreational intranasal cocaine users exhibit impaired recognition of facial expressions of fear compared to occasional cocaine users and cocaine-naïve controls. The aim of the present study was to re-investigate this phenomenon after controlling for impulsivity, conduct disorder (CD) and anti-social personality disorder (ASPD). We employed a cross-sectional design to compare 31 cocaine-naïve participants, 35 occasional cocaine users and 20 regular recreational cocaine users. An emotional facial expression (EFE) task which comprised a male and a female face expressing six basic emotions morphed to differing degrees of emotional intensity was administered together with questionnaires to assess: CD, ASPD and impulsiveness. ASPD was not a significant covariate for EFE performance but impulsiveness and CD were significant covariates. After treating impulsiveness and CD as covariates we again observed a group difference in fear recognition ability attributable to the particularly impaired performance of regular cocaine users. This suggests that, although elevated impulsiveness and CD before the age of 15 years, may predispose a relative inability to recognize facial expressions of fear in adulthood, subsequent regular recreational use of cocaine represents an additional factor that is specifically associated with a selective deficit in fear recognition. 23677279 Observation of the long-lived triplet excited state of perylenebisimide (PBI) in C^N cyclometalated Ir(III) complexes and application in photocatalytic oxidation. Perylenebisimide (PBI) was used to prepare C^N cyclometalated Ir(III) complexes that show strong absorption of visible light and it is the first time the long-lived triplet excited state of PBI chromophore was observed in a transition metal complex (τT = 22.3 μs). Previously, the lifetime of the triplet state of PBI in transition metal complexes was usually shorter than 1.0 μs. Long-lived triplet excited states are useful for applications in photocatalysis or other photophysical processes concerning triplet-triplet-energy-transfer. PBI and amino-PBI were used for preparation of cyclometalated Ir(III) complexes (Ir-2 and Ir-3), in which the PBI chromophore was connected to the coordination center via C≡C π-conjugation bond. The new complexes show strong absorption in visible region (ε = 34,200 M(-1) cm(-1) at 541 nm for Ir-2, and ε = 19,000 at 669 nm for Ir-3), compared to the model complex Ir(ppy)(bpy)[PF6] Ir-1 (ε < 5000 M(-1) cm(-1) in the region beyond 400 nm). The nanosecond time-resolved transient absorption and DFT calculations indicated that PBI-localized long-lived (3)IL states were populated for Ir-2 and Ir-3 upon photoexcitation. The complexes were used as triplet photosensitizers for (1)O2-mediated photooxidation of 1,5-dihydronaphthalene to produce juglone, an important intermediate for preparation of anti-cancer compounds. (1)O2 quantum yields (Φ(Δ)) up to 91% were observed for the new Ir(III) complexes and the overall photosensitizing ability is much higher than the conventional Ir(III) complex Ir-1, which shows the typical weak visible light absorption in visible region. Our results are useful for preparation of transition metal complexes that show strong absorption of visible light and long-lived triplet excited state and for the application of these complexes in photocatalysis. 23834852 Serendipitous Recanalization of Basilar Artery Occlusion. To describe a case of recanalization of a basilar artery occlusion with intravenous (IV) tenecteplase. A 74-year-old man with a history of cardiomyopathy presented to an outside hospital with acute vertigo, dysarthria, gaze deviation, and ataxia. Computerized tomography arteriography demonstrated occlusion of the proximal basilar artery. IV tissue plasminogen activator was ordered; however, the patient received a cardiac dose of IV tenecteplase. The patient was transferred to our facility, whereby symptoms resolved, and repeat computerized tomography arteriography displayed recanalization of the basilar artery. Tenecteplase has enhanced biochemical and pharmacokinetic properties that may be ideal for treatment of basilar artery occlusion and should be further investigated in a randomized clinical trial. 23965213 Anesthetic implications of emergent Cesarean section in a parturient with Noonan syndrome and bacterial endocarditis. Noonan syndrome is a relatively common genetically transmitted disorder characterized by facial, cardiac, and musculoskeletal abnormalities. The management of a 27 year old woman with Noonan syndrome at 23 weeks' gestation, presenting with premature labor, who required an emergent Cesarean section for placental abruption, is presented. In addition to Noonan syndrome, this patient had bacterial endocarditis involving the mitral and aortic valves. The anesthetic implications of Noonan syndrome and endocarditis during pregnancy are presented. 23674374 Population management of diabetes in a high-need urban community in the bronx: the experience of montefiore medical center. Purpose The purpose of this study is to examine the impact of a Care Management Organization (CMO) Diabetes Disease Management Program (DDMP) in improving diabetes outcomes among high-risk patients with type 2 diabetes (T2DM) in the Bronx, New York. Methods An interventional, nonrandomized study design was used to assess the effectiveness of the DDMP. Patients older than 18 years who had T2DM and an A1C persistently 8% or greater or with a cardiovascular comorbidity were characterized as high risk and received intensive disease management. Patients served as their own controls, with data collection and analysis occurring 12 months prior to and 12 months after enrollment in DDMP. Data collection included screening rates for A1C, low-density lipoprotein (LDL) cholesterol, depression, smoking status, and annual influenza vaccine administration. Changes in A1C and LDL cholesterol were also analyzed. Statistical analyses were conducted using Minitab. McNemar's chi-square and paired t tests were used to assess within-group changes from baseline to final outcomes. Results Significant improvements in screening rates for A1C, LDL, depression, smoking status, and annual influenza vaccine administration were found among high-risk/intensively managed patients in the DDMP. Improvements in clinical measures were also achieved in this group. Provider and patient satisfaction surveys were positive, with 92% of patients believing that the program helped them better understand their disease. Conclusions A DDMP among high-risk patients has shown promise in improving the quality of care for patients with diabetes. This program has relevance for other integrated delivery systems that are developing accountable care approaches. 23894004 Reduced Serotonin Receptor Subtypes in a Limbic and a Neocortical Region in Autism. Autism is a behaviorally defined, neurological disorder with symptom onset before the age of 3. Abnormalities in social-emotional behaviors are a core deficit in autism, and are characterized by impaired reciprocal-social interaction, lack of facial expressions, and the inability to recognize familiar faces. The posterior cingulate cortex (PCC) and fusiform gyrus (FG) are two regions within an extensive limbic-cortical network that contribute to social-emotional behaviors. Evidence indicates that changes in brains of individuals with autism begin prenatally. Serotonin (5-HT) is one of the earliest expressed neurotransmitters, and plays an important role in synaptogenesis, neurite outgrowth, and neuronal migration. Abnormalities in 5-HT systems have been implicated in several psychiatric disorders, including autism, as evidenced by immunology, imaging, genetics, pharmacotherapy, and neuropathology. Although information is known regarding peripheral 5-HT in autism, there is emerging evidence that 5-HT systems in the central nervous system, including various 5-HT receptor subtypes and transporters, are affected in autism. The present study demonstrated significant reductions in 5-HT1A receptor-binding density in superficial and deep layers of the PCC and FG, and in the density of 5-HT2A receptors in superficial layers of the PCC and FG. A significant reduction in the density of serotonin transporters (5-HTT) was also found in the deep layers of the FG, but normal levels were demonstrated in both layers of the PCC and superficial layers of the FG. This study provides potential substrates for decreased 5-HT modulation/innervation in the autism brain, and implicate two 5-HT receptor subtypes as potential neuromarkers for novel or existing pharmacotherapies. Autism Res 2013, ●●: ●●-●●. © 2013 International Society for Autism Research, Wiley Periodicals, Inc. 23935371 Influence of acute coffee consumption on postprandial oxidative stress. Coffee has been reported to be rich in antioxidants, with both acute and chronic consumption leading to enhanced blood antioxidant capacity. High-fat feeding is known to result in excess production of reactive oxygen and nitrogen species, promoting a condition of postprandial oxidative stress. We tested the hypothesis that coffee intake following a high-fat meal would attenuate the typical increase in blood oxidative stress during the acute postprandial period. On 3 different occasions, 16 men and women consumed a high-fat milk shake followed by either 16 ounces of caffeinated or decaffeinated coffee or bottled water. Blood samples were collected before and at 2 and 4 hours following intake of the milk shake and analyzed for triglycerides (TAG), malondialdehyde (MDA), hydrogen peroxide (H2O2), and Trolox equivalent antioxidant capacity (TEAC). Values for TAG and MDA (P < 0.001), as well as for H2O2 (P < 0.001), increased significantly following milk shake consumption, with values higher at 4 hours compared with 2 hours post consumption for TAG and H2O2 (P < 0.05). TEAC was unaffected by the milk shake consumption. Coffee had no impact on TAG, MDA, H2O2, or TEAC, with no condition or interaction effects noted for any variable (P > 0.05). Acute coffee consumption following a high-fat milk shake has no impact on postprandial oxidative stress. 23924450 Evaluation of efficacy and safety of sunitinib regimen in 22 patients with metastatic renal cell carcinoma: at least 12-month follow-up. Sunitinib has been proved an effective new option for treatment of metastatic renal cell carcinoma (mRCC). Analysis of clinical data of 22 patients, who were exposed to sunitinib for at least 1 year, was conducted to evaluate the long-term efficacy and safety of sunitinib for the treatment of mRCC. A total of 54 patients with mRCC were treated with sunitinib malate, 50 mg/d orally, on a 4-weeks-on and 2-weeks-off dosing schedule in Peking University First Hospital. Treatment continued until disease progression, unacceptable adverse events (AEs), or death. Among them, 22 patients continued treatment for at least 1 year. The clinical data of these 22 patients were prospectively collected for analysis. AEs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0. Tumor response was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors. Median progression-free survival was 19.5 months until last follow-up. The best efficacy results achieved were complete response, partial response, and stable disease for 2, 9, and 11 patients, respectively. Objective response rate was 50%. The most common AEs were hand-foot syndrome (95%) and hypertension (91%). Other common AEs were thyroid-stimulating hormone elevation (82%), platelet decrease (77%), and loss of appetite (77%). Only one patient withdrew from treatment for cardiac infarction. Another nine patients experienced dose modifications or short-term suspensions. Long-term exposure to sunitinib malate showed encouraging efficacy in the treatment of mRCC. At the same time, the tolerability was good. 23625934 Escaping the behavioural 'spin' of evidence-based psychiatry: Merleau-Ponty's ontology of truth. To explore the limitations of the concept of 'truth' in the ontology of evidence-based psychiatry and to provide expanded ontological foundations for psychiatric practice based instead on the ontology of the French existential-phenomenologist, Maurice Merleau-Ponty. Evidence-based medicine is founded on a 'scientific' ontology of 'causality', which equates 'truth' with effecting statistically-significant changes in objective measures of disease by a specified treatment. Because of the absence of biological markers of disease in psychiatry, evidence-based psychiatry equates 'truth' with effecting changes in observable psychometric measures of behaviour. This is the same ontology underlying marketing 'spin' and all attempts to effect pre-determined behavioural change. In contrast, Merleau-Ponty's ontology rejects causality and mind/body duality, and views 'truth' as the expression of our deepest embodied feeling and perception of the world, which establishes all our thinking, and on which all our thinking relies, including 'scientific' thinking. Merleau-Ponty's ontology is therefore a preferable foundation for psychiatric practice, because it allows psychiatrists to consider the 'truth' of clinically important, but non-measurable, aspects of psychiatry while not excluding 'scientific' thinking, but recognising its limitations and potential for misuse. 23951179 Trichostatin A Modulates Thiazolidinedione-Mediated Suppression of Tumor Necrosis Factor α-Induced Lipolysis in 3T3-L1 Adipocytes. In obesity, high levels of tumor necrosis factor α (TNFα) stimulate lipolysis in adipocytes, leading to hyperlipidemia and insulin resistance. Thiazolidinediones (TZDs), the insulin-sensitizing drugs, antagonize TNFα-induced lipolysis in adipocytes, thereby increasing insulin sensitivity in diabetes patients. The cellular target of TZDs is peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor that controls many adipocyte functions. As a transcription factor, PPARγ is closely modulated by coregulators, which include coactivators and corepressors. Previous studies have revealed that in macrophages, the insulin-sensitizing effect of PPARγ may involve suppression of proinflammatory gene expression by recruiting the corepressor complex that contains corepressors and histone deacetylases (HDACs). Therefore, we investigated whether the corepressor complex is involved in TZD-mediated suppression of TNFα-induced lipolysis in 3T3-L1 adipocytes. Trichostatin A (TSA), a pan HDAC inhibitor (HDACI) that inhibits class I and II HDACs, was used to examine the involvement of HDACs in the actions of TZDs. TSA alone increased basal lipolysis and attenuated TZD-mediated suppression of TNFα-induced lipolysis. Increased basal lipolysis may in part result from class I HDAC inhibition because selective class I HDACI treatment had similar results. However, attenuation of TZD-mediated TNFα antagonism may be specific to TSA and related hydroxamate-based HDACI rather than to HDAC inhibition. Consistently, corepressor depletion did not affect TZD-mediated suppression. Interestingly, TSA treatment greatly reduced PPARγ levels in differentiated adipocytes. Finally, extracellular signal-related kinase 1/2 (ERK1/2) mediated TNFα-induced lipolysis, and TZDs suppressed TNFα-induced ERK phosphorylation. We determined that TSA increased basal ERK phosphorylation, and attenuated TZD-mediated suppression of TNFα-induced ERK phosphorylation, consistent with TSA's effects on lipolysis. These studies suggest that TSA, through down-regulating PPARγ, attenuates TZD-mediated suppression of TNFα-induced ERK phosphorylation and lipolysis in adipocytes. 23501114 Coumarins hinged directly on benzimidazoles and their ribofuranosides to inhibit hepatitis C virus. A new compound library that contained 20 hinged benzimidazole-coumarin hybrids and their β-d-ribofuranosides was established. The anti-hepatitis C virus (HCV) activity of all novel coumarin derivatives, which were obtained by use of organic synthetic methods, was tested. Two of these hybrids exhibited appealing EC50 values of as low as 3.0 and 5.5 μM. The best selectivity index was 14. The incorporation of a d-ribofuranose into the hinged hybrids provided the corresponding nucleosides with the β configuration, one of which inhibited HCV replication with an EC50 value of 20 μM. Additionally, the structure-activity relationship is elucidated on the basis of the functional groups that were attached to the nuclei of benzimidazole, coumarin, and ribofuranose of the hybrids. 23590179 Concentration-Dependent Supramolecular Engineering of Hydrogen-Bonded Nanostructures at Surfaces: Predicting Self-Assembly in 2D. We report a joint computational and experimental study on the concentration-dependent self-assembly of a flat C3-symmetric molecule at surfaces. As a model system we have chosen a rigid molecular module, 1,3,5-tris(pyridine-4-ylethynyl)benzene, which can undergo self-association via hydrogen bonding (H-bonding) to form ordered 2D nanostructures. In particular, the lattice Monte Carlo method, combined with density functional calculations, was employed to explore the spontaneous supramolecular organization of this tripod-shaped molecule under surface confinement. We analyzed the stability of different weak H-bonded patterns and the influence of the concentration of the starting molecule on the 2D supramolecular packing. We found that ordered, densely packed monolayers and 2D porous networks are obtained at high and low concentrations, respectively. A concentration-dependent scanning tunneling microscopy investigation of the molecular self-assembly at a graphite-solution interface revealed supramolecular motifs, which are in perfect agreement with those obtained by simulations. Therefore, our computational approach represents a step forward toward the deterministic prediction of molecular self-assembly at surfaces and interfaces. 23509611 Synthesis and evaluation of stable substrate analogs as potential modulators of cyclodiphosphate synthase IspF. Stable IspF substrate analogs were synthesized. In the presence of substrate analogs, the E. coli IspF-MEP complex shows activities distinct from IspF, and bisphosphonates (BP) behave differently than their diphosphate (DP) counterparts. Bisphosphonate analogs activate and/or stabilize IspF, and only the closest structural substrate analog weakly inhibits the IspF-MEP complex. 23822769 GPER 1: trials and tribulations of a Membrane Oestrogen Receptor. Oestrogens are now recognised to be able to initiate rapid, fast responses, in addition to their classical, longer term actions. There is a growing appreciation of the potential implications of this mode of action for oestrogenic signalling in both neuronal and non-neuronal systems. As such there has been much effort to determine the mechanisms that are critical for transducing these rapid effects into cellular responses. Recently, an orphan G-protein coupled receptor (GPCR), termed GPR30, was identified as an oestrogen sensitive receptor in cancer cells. This receptor, now term G-protein estrogen receptor 1 (GPER1) has been the subject of many investigations, and a role for this receptor in the nervous system is now emerging. In this review, we wish to highlight some of the more recent advances in our understanding of the distribution and subcellular localisation of this receptor in the brain, as well as some of the evidence for the potential role that this receptor may play in the brain. We will then go on to discuss some of the controversies surrounding the pharmacology of this receptor, and attempt to reconcile them by suggesting that the "agonist-specific coupling" model of GPCR function may provide a potential explanation for some of the divergent reports of GPER1 pharmacology. This article is protected by copyright. All rights reserved. 23736381 Pluripotent stem cell transcription factors during human odontogenesis. Stem cells are capable of generating various cell lines and can be obtained from adult or embryonic tissues for clinical therapies. Stem cells from deciduous dental pulp are among those that are easily obtainable from adult tissues and have been widely studied because of their ability to differentiate into a variety of cell lines in the presence of various chemical mediators. We have analyze the expression of several proteins related to the differentiation and proliferative potential of cell populations that compose the tooth germ of human fetuses. We evaluate 20 human fetuses of both genders. After being paraffin-embedded, cap and bell stages of tooth germ development were subjected to immunohistochemistry for the following markers: Oct-4, Nanog, Stat-3 and Sox-2. The studied antibodies showed nuclear or cytoplasmic immunnostaining within various anatomical structures and with various degrees of expression, indicating the action of these proteins during tooth development. We conclude that the interrelationship between these transcription factors is complex and associated with self-renewal and cell differentiation. Our results suggest that the expression of Oct-4, Nanog, Sox-2 and Stat-3 are related to differentiation in ameloblasts and odontoblasts. 23340983 The effects of anesthetic technique and ambient temperature on thermoregulation in lower extremity surgery. The purpose of our study was to determine the effects of anesthetic technique and ambient temperature on thermoregulation for patients undergoing lower extremity surgery. Our study included 90 male patients aged 18-60 years in American Society of Anesthesiologists Physical Status groups I or II who were scheduled for lower extremity surgery. Patients were randomly divided into three groups according to anesthetic technique: general anesthesia (GA), epidural anesthesia (EA), and femoral-sciatic block (FS). These groups were divided into subgroups according to room temperature: the temperature for group I was 20-22 °C and that for group II was 23-25 °C. Therefore, we labeled the groups as follows: GA I, GA II, EA I, EA II, FS I, and FS II. Probes for measuring tympanic membrane and peripheral temperature were placed in and on the patients, and mean skin temperature (MST) and mean body temperature (MBT) were assessed. Postoperative shivering scores were recorded. During anesthesia, tympanic temperature and MBT decreased whereas MST increased for all patients. There was no significant difference between tympanic temperatures in either the room temperature or anesthetic method groups. MST was lower in group GA I than in group GA II after 5, 10, 15, 20, 60 and 90 min whereas MBT was significantly lower at the basal level (p < 0.05). MST after 5 min was significantly lower in group GA I than in group FS I (p < 0.05). Shivering score was significantly higher in group GA I (p < 0.05). There were no significant differences in thermoregulation among anesthetic techniques. Room temperature affected thermoregulation in Group GA. 23821127 Microbicidal and anti-inflammatory effects of Actinomadura spadix (EHA-2) active metabolites from Himalayan soils, India. Actinomycetes play an essential role in producing several bioactive compounds. In the present study, microbicidal and anti-inflammatory effects of metabolites from actinomycetes were investigated. Actinomycetes were isolated from north eastern Himalayan soil samples, India. The actinomycetes were investigated for their microbicidal property by conventional method and the active actinomycetes were identified by 16s rDNA sequence analyses. Further the metabolites were extracted and fractionated to evaluate the antimicrobial potency; they were subjected to GC-MS analysis. The active fraction was evaluated for selective toxicity and anti-inflammatory potential. Among isolated actinomycetes, EHA-2 showed potent antimicrobial activity and was identified as Actinomadura spadix. Fraction-8 from ethyl acetate extract of EHA-2 showed 100 % inhibition against Candida sp. (MIC-80 Î¼g/mL) and Enterococcus faecalis (MIC-80 Î¼g/mL). The expression of GAPDH in primary cells and 16s rRNA levels on E. faecalis treated with fraction-8 revealed no toxicity to the primary cells. Fraction-8 also suppressed the paw thickness on carrageenan induced animals and also controlled the release of NO, TNFα and IL-1β levels on LPS induced RAW 264.7 cell lines. GC-MS profile of fraction-8 showed the presence of an antimicrobial agent 3,6 di-isobutyl 2,5 piperazinedione, which is the first report in A. spadix. The actinomycetes isolate EHA-2 can be proceed further to produce antibiotics. 23745796 Interactions and Stabilities of the UV RESISTANCE LOCUS8 (UVR8) Protein Dimer and Its Key Mutants. The dimeric UVR8 protein is an ultraviolet-B radiation (280-315 nm) photoreceptor responsible for the first step in UV-B regulation of gene expression in plants. Its action comprises the actual absorption of the UV quanta by a tryptophan array at the protein-protein interface, followed by monomerization and subsequent aggregation with downstream signaling components. A crystal structure of the Arabidopsis thaliana tryptophan-rich wild type UVR8 protein dimer was recently published, showing the presence of several salt bridges involving arginines R146, R286, R338, and R354. In this work, molecular dynamics simulations in conjunction with umbrella sampling were used to calculate the binding free energy for the wild type UVR8 dimer and three of its mutants (R286A, R338A, and R286A/R338A), in order to verify whether the key mutants are able to disrupt the dimeric structure as indicated experimentally. 23913257 Adding an unnatural covalent bond to proteins through proximity-enhanced bioreactivity. Natural proteins often rely on the disulfide bond to covalently link side chains. Here we genetically introduce a new type of covalent bond into proteins by enabling an unnatural amino acid to react with a proximal cysteine. We demonstrate the utility of this bond for enabling irreversible binding between an affibody and its protein substrate, capturing peptide-protein interactions in mammalian cells, and improving the photon output of fluorescent proteins. 23835078 Dental age assessment validity of radiographic methods on Serbian children population. In order to establish reliable age estimation method based on dental development, various correlations between chronological age and real growth were tested. Demirjian's scheme was mostly used, but lately the Willems' method has been found to be more reliable. The aim of this study was to evaluate the accuracy of Demirjian's and Willems' methods for dental age estimation in Serbian children population. The study sample encompassed panoramic radiographs of 686 children (322 boys and 364 girls) with age range from 4 to 15 years. The dental age was assed using Demirjian's and Willems' maturity scores. Statistical analysis was performed to test the accuracy of investigated methods by comparing the mean chronological and mean estimated age in total sample, as well as in each group comprising individuals within one-year-age-interval. Both methods showed discrepancy between obtained and chronological age. The Demirjian's method overestimated age with a mean accuracy of 0.45 in boys and 0.42 in girls, while Willems' method showed lower discrepancy (0.12 and 0.16 in boys and girls, respectively). Overall, both methods were unsatisfactory in some age groups, however, Willems' method provided more accurate age estimation in majority of categories. In summary, our results suggest that Willem's method was more accurate for estimating dental age in contemporary Serbian children population. 23802937 Pathophysiologic and anesthetic considerations for patients with myotonia congenita or periodic paralyses. Myotonia congenita and periodic paralyses are hereditary skeletal muscle channelopathies. In these disorders, various channel defects in the sarcolemma lead to a severely disturbed membrane excitability of the affected skeletal muscles. The clinical picture can range from severe myotonic reactions (e.g., masseter spasm, opisthotonus) to attacks of weakness and paralysis. Provided here is a short overview of the pathomechanisms behind such wide-ranging phenotypic presentations in these patients, followed by recommendations concerning the management of anesthesia in such populations. 23380499 Neonatal neurological examination of late preterm babies. Healthy late-preterm (LP) infants examined at term equivalent age showed wider median and range of neurological scores than full-term infants; differences between infants born at 34 and those born at 35-36 weeks were also observed. The aim of this study is to establish the range and frequency distribution of neonatal neurological scores in a cohort of low risk LP infants assessed during the first 3 days from birth. 118 low-risk infants born between 34 and 36 weeks of gestational age (GA) were assessed between 48 and 72 h from birth. The full version of the Hammersmith Neonatal Neurologic Assessment and the screening proforma were used to assess all the infants. The raw scores obtained were compared to those of full-term infants using the same examination. The distribution of neurological scores was similar among the 3 GAs for 26 items, with different median scores among LP infants born at 36 weeks and those born at 34 and 35 in only 2 items. LP infants showed a wider range of findings for each item than that of full term infants assessed soon after birth. Using the screening proforma, in our cohort, for each item the findings falling outside the 90% level were identical to those found in term-born and very preterm infants assessed at term age. The neurological scores obtained in our cohort could help as reference data when examining LP infants at birth compared to age matched low risk infants. 23410587 Benchmark dose for estimation of cadmium reference level for osteoporosis in a Chinese female population. In this study, the reference level of cadmium in urine and blood related with bone damage was assessed using benchmark dose in a Chinese female population. Total of 338 women was recruited, and urine and blood samples were collected from each individual for determination of cadmium in urine (UCd) and blood (BCd). Bone mineral density was measured by dual energy X-ray absorptiometry. BMD and BMDL were calculated corresponding to additional risk of 5% and 10%. With benchmark response (BMR) of 5%/10%, the BMD of BCd, UCd related with osteoporosis was 1.88μg/L/3.23μg/L and 5.30μg/g crea/9.06μg/g crea, and the BMDL-05 was 1.39μg/L/2.38μg/L and 3.78μg/g crea/6.36μg/g crea; the BMD of BCd, UCd related with low bone mass was 0.95μg/L/3.12μg/L and 3.12μg/g crea/5.87μg/g crea, and the BMDL-05 was 0.72μg/L/1.35μg/L and 2.14μg/g crea/3.99μg/g crea. The BMD of UCd in people over 60years old was much lower than that of people less than 60years old. BMD value was related with ages and effects biomarkers. Our data showed that BMD of UCd associated with osteoporosis was lower than that previously estimated. 23933513 Molecular cloning and functional characterization of a short peptidoglycan recognition protein (HcPGRPS1) from the freshwater mussel, Hyriopsis cumingi. Peptidoglycan recognition proteins (PGRPs), which are evolutionarily conserved from invertebrates to vertebrates, function as pattern-recognition and effector molecules in innate immunity. In the present study, a short-form PGRP, designated as HcPGRPS1 was identified from freshwater mussel Hyriopsis cumingi. The deduced amino acid sequence of HcPGRPS1 is composed of 235 residues which contains a conserved PGRP domain at the C-terminus. Sequence analysis showed that HcPGRPS1 shared high identities with other known PGRPs. The mRNA of HcPGRPS1 is constitutively expressed in a wide range of all tested tissues, with highest expression level in hepatopancreas, and its expression in tissues (gonad, nephridium, gill and foot) was up-regulated significantly after LPS or PGN stimulation (P<0.05). The recombinant protein of HcPGRPS1 exhibited binding activity and peptidoglycan-lytic amidase activity toward Lys-PGN from Staphylococcus aureus and DAP-PGN from Bacillus subtilis. Furthermore, recombinant HcPGRPS1 displayed strong antibacterial activity to both Gram-negative bacteria Escherichia coli, Aeromonas hydrophila, Aeromonas sobria and Gram-positive bacteria S. aureus in the presence of Zn(2+). These results suggested that HcPGRPS1 plays a multifunctional role in the defense and protection mechanisms of mussel innate immunity against infections. 23601640 Biosynthetic conclusions from the functional dissection of oxygenases for biosynthesis of actinorhodin and related streptomyces antibiotics. Actinorhodin (ACT) produced by Streptomyces coelicolor A3(2) belongs to the benzoisochromanequinone (BIQ) class of antibiotics. ActVA-ORF5, a flavin-dependent monooxygenase (FMO) essential for ACT biosynthesis, forms a two-component enzyme system in combination with a flavin:NADH oxidoreductase, ActVB. The genes for homologous two-component FMOs are found in the biosynthetic gene clusters for two other BIQs, granaticin (GRA) and medermycin (MED), and a closely related antibiotic, alnumycin (ALN). Our functional analysis of these FMOs (ActVA-ORF5, Gra-ORF21, Med-ORF7, and AlnT) in S. coelicolor unambiguously demonstrated that ActVA-ORF5 and Gra-ORF21 are bifunctional and capable of both p-quinone formation at C-6 in the central ring and C-8 hydroxylation in the lateral ring, whereas Med-ORF7 catalyzes only p-quinone formation. No p-quinone formation on a BIQ substrate was observed for AlnT, which is involved in lateral p-quinone formation in ALN. 23903894 Vorinostat in combination with bortezomib in patients with advanced malignancies directly alters transcription of target genes. Vorinostat is a small molecule inhibitor of class I and II histone deacetylase enzymes which alters the expression of target genes including the cell cycle gene p21, leading to cell cycle arrest and apoptosis. Patients enrolled in a phase I trial were treated with vorinostat alone on day 1 and vorinostat and bortezomib in combination on day 9. Paired biopsies were obtained in eleven subjects. Blood samples were obtained on days 1 and 9 of cycle 1 prior to dosing and 2 and 6 h post-dosing in all 60 subjects. Gene expression of p21, HSP70, AKT, Nur77, ERB1, and ERB2 was evaluated in peripheral blood mononuclear cells and tissue samples. Chromatin immunoprecipitation of p21, HSP70, and Nur77 was also performed in biopsy samples. In peripheral blood mononuclear cells, Nur77 was significantly and consistently decreased 2 h after vorinostat administration on both days 1 and 9, median ratio of gene expression relative to baseline of 0.69 with interquartile range 0.49-1.04 (p < 0.001); 0.28 (0.15-0.7) (p < 0.001), respectively, with more pronounced decrease on day 9, when patients received both vorinostat and bortezomib. p21, a downstream target of Nur77, was significantly decreased on day 9, 2 and 6 h after administration of vorinostat and bortezomib, 0.67 (0.41-1.03) (p < 0.01); 0.44 (0.25-1.3) (p < 0.01), respectively. The ChIP assay demonstrated a protein-DNA interaction, in this case interaction of Nur77, HSP70 and p21 with acetylated histone H3, at baseline and at day 9 after treatment with vorinostat in tissue biopsies in most patients. Vorinostat inhibits Nur77 expression, which in turn may decrease p21 and AKT expression in PBMCs. The influence of vorinostat on target gene expression in tumor tissue was variable; however, most patients demonstrated interaction of acetylated H3 with Nur77, HSP70, and p21 which provides evidence of interaction with the transcriptionally active acetylated H3. 23188070 Element content of propolis collected from different areas of South Spain. The aim of this work is to determine the content of essential and toxic elements in 25 raw propolis samples, when considering pollution agents and geographical and botanical factors. The microwave-assisted digestion was the most reliable and accurate method for determination of inorganic elements in propolis samples. The results were obtained using certified reference materials in a good agreement with certified values. Inductively coupled plasma atomic emission spectroscopy was used for the determination of 23 macro- and microelements (Ag, Al, As, B, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, P, Pb, S, Sb, Se, Si, Sn, and Zn). A Mercury analyzer was also utilized for the detection of the total Hg. Among the analyzed metals, Ca, K, Mg, Zn, Si, S, Fe, Al, P, and Na were found to be the most predominant. Heavy metals (As, Cd, Hg, and Pb) were determined in minimal concentration, and Pb was the highest mean contained toxic (<3.80 mg/kg), without influence on provisional tolerable weekly intake values. The method can be applied for routine analysis and quality and environmental pollution controls of toxic elements in propolis samples. The results obtained indicate no pollution of the collection areas and naturally high concentration of Al (460 ±â€‰62.2 mg/kg). 23909386 Air-Drying Beds Reduce the Quantities of Antibiotic Resistance Genes and Class 1 Integrons in Residual Municipal Wastewater Solids. This study investigated whether air-drying beds reduce antibiotic resistance gene (ARG) concentrations in residual municipal wastewater solids. Three laboratory-scale drying beds were operated for a period of nearly 100 days. Real-time PCR was used to quantify 16S rRNA genes, 16S rRNA genes specific to fecal bacteria (AllBac) and human fecal bacteria (HF183), the integrase gene of class 1 integrons (intI1), and five ARGs representing a cross-section of antibiotic classes and resistance mechanisms (erm(B), sul1, tet(A), tet(W), and tet(X)). Air-drying beds were capable of reducing all gene target concentrations by 1 to 5 orders of magnitude, and the nature of this reduction was consistent with both a net decrease in the number of bacterial cells and a lack of selection within the microbial community. Half-lives varied between 1.5 d (HF183) and 5.4 d (tet(X)) during the first 20 d of treatment. After the first 20 d of treatment, however, half-lives varied between 8.6 d (tet(X)) and 19.3 d (AllBac), and 16S rRNA gene, intI1, and sul1 concentrations did not change (P > 0.05). These results demonstrate that air-drying beds can reduce ARG and intI1 concentrations in residual municipal wastewater solids within timeframes typical of operating practices. 23928607 Clinician and simulated patient scoring - the psychometrics of a national programme recruiting dentists to DF1 training posts. Introduction In 2012 a national, standardised approach was taken to UK Dental Foundation 1 recruitment. Prior to that recruitment method was at the discretion of individual Deaneries. The new national system is interactive, including simulated patients to see how applicants perform in a clinical communication context. A question was whether simulated patient scores could/should be awarded as well as clinicians' scores. This paper presents score data collected in the first round of national DF1 recruitment centres, with focus on how clinical examiners and trained simulated patients rated applicants.Method At the live recruitment events across four national centres score data were collected from observing clinical assessors and simulated patients on the communication station. On this occasion only the clinician awarded scores 'counted', but all simulated patients completed marking sheets to enable the process to be evaluated. Data were retrospectively analysed to test the hypotheses that there would be no significant scoring differences between centres and that inter-rater reliability, by applicant, between paired clinicians, and between clinicians and simulated patients would be strong.Results Results showed encouraging consistency between assessors, with some differences between centres. Clinicians were more likely to offer a borderline score. In communication analyses empathy had the weakest correlation with the overall score, while professional attitude had the strongest correlation. Data supported the hypothesis that trained simulated patients can be considered as assessors. Their future inclusion offers candidates a dual perspective (clinical and non-clinical) on performance, and saves clinical time.Discussion Simulated patients scored consistently and value can be added by including different perspectives in interactive assessment. Robust training is needed in all assessor training.Conclusion Simulated patients can usefully contribute to scoring in national dental recruitment centres. Lessons learned here can inform other dental assessments where stakeholders are already using, or considering using, simulated patients as assessors or co-assessors. 23443636 The impact of station location on water quality characterization in the Loxahatchee National Wildlife Refuge. Water quality was monitored in the Loxahatchee National Wildlife Refuge based on the Consent Decree (CDN), the Enhanced Refuge (ERN), the four-part Test impacted (FPTIN), and the four-part test unimpacted (FPTUN) networks. Alkalinity, dissolved organic carbon, total organic carbon, dissolved oxygen, total dissolved solids, total suspended solids, turbidity, pH, specific conductivity, calcium, chloride, silicon, sulfate, and total phosphorus (TP) were measured from 2005 through 2009. When the ERN was used, the 10 Î¼g TP L(-1) Consent Decree limit would have been exceeded and would have ranged from a low of 2 months in 2009 to a high of 9 months in 2005. Based on the CDN, the limit exceeded only for 1 month in each year from 2006 through 2008. Based on the FPTIN, the 10 Î¼g TP L(-1) limit would have been exceeded and would have ranged from a low of 1 month in 2007 to a high of 7 months in 2005 and 2008. Based on the CDN, the limit only exceeded for 1 month in each year from 2006 through 2008. Since TP is rapidly removed from canal water intruded into the Refuge marsh, one cannot expect a water quality sampling station located 2 km from the source to reliably detect violations. This may be the primary reason why there have been very few months when TP concentration has exceeded the limit since 1992 or part four of the four-part test annual 15 Î¼g L(-1) limit since 2006. 23819679 Salivary adenoid cystic carcinoma with an early phase of high-grade transformation: case report with an immunohistochemical analysis. The early phase of salivary gland carcinomas with high-grade transformation (HGT) is extremely rare. We reported one case of adenoid cystic carcinoma (AdCC) with early HGT, herein. The patient was a 27-year-old Japanese woman who suffered from swelling of the left parotid region. Most of this tumor consisted of typical AdCC histology, whereas the central area of this tumor was composed of solid growth component by atypical cells with clear cytoplasm and marked nuclear atypia. Immunohistochemically, this area was strongly and diffusely positive for epithelial membrane antigen, p53, p16, Her-2, cyclin A and cyclin B1. The Ki-67 labeling index of this area was high, entirely different from that of AdCC area. Overall, this area was an early phase of AdCC-HGT. This case is the second case of early AdCC-HGT. We discuss the development of salivary gland carcinoma with HGT. http://www.diagnosticpatology.diagnomx.eu/vx/1598278104895730. 23838544 Validation of a pediatric obstructive sleep apnea screening tool. Pediatric obstructive sleep apnea (OSA) is a prevalent but under-diagnosed disease. The importance of screening for OSA in every child has been recently re-emphasized by the American Academy of Pediatrics Guidelines. Although several screening questionnaires are available for pediatric OSA, they are either complicated to use or not sensitive enough, and therefore OSA is seldom screened in primary care settings. Here, we validated a previously developed short (6-item) hierarchically-based screening questionnaire tool for pediatric OSA. Parents of 85 children referred for a sleep study at a pediatric community-based sleep clinic completed the questionnaire and their children underwent an overnight PSG. Receiver operator curve analyses and other predictive scales were assessed. The 6-item questionnaire exhibited favorable sensitivity and fair specificity for diagnosis of OSA, which varied depending on the apnea-hypopnea index used for OSA definition. A 6-item questionnaire is a sensitive and easy-to-use screening tool for pediatric OSA in a pediatric sleep clinic setting. 23085437 Growth differentiation factor 15 stimulates rapamycin-sensitive ovarian cancer cell growth and invasion. Identification of novel molecular markers and therapeutic targets may improve survival rates for patients with ovarian cancer. In the current study, immunohistochemical (IHC) analysis of two human ovarian tumor tissue arrays showed high staining for GDF15 in a majority of tissues. Exogenous stimulation of ovarian cancer cell lines with recombinant human GDF15 (rhGDF15) or stable over-expression of a GDF15 expression plasmid promoted anchorage-independent growth, increased invasion, and up-regulation of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF). MMP inhibition suppressed GDF15-mediated invasion. In addition, IHC analysis of human ovarian tumor tissue arrays indicated that GDF15 expression correlated significantly with high MMP2 and MMP9 expression. Exogenous and endogenous GDF15 over-expression stimulated phosphorylation of p38, Erk1/2, and Akt. Pharmacologic inhibition of p38, MEK, or PI3K suppressed GDF15-stimulated growth. Further, proliferation, growth, and invasion of GDF15 stable clones were blocked by rapamycin. IHC analysis demonstrated significant correlation between GDF15 expression and phosphorylation of mTOR. Finally, knockdown of endogenous GDF15 or neutralization of secreted GDF15 suppressed invasion and growth of a GDF15-over-expressing ovarian cancer cell line. These data indicate that GDF15 over-expression, which occurred in a majority of human ovarian cancers, promoted rapamycin-sensitive invasion and growth of ovarian cancer cells. Inhibition of mTOR may be an effective therapeutic strategy for ovarian cancers that over-express GDF15. Future studies should examine GDF15 as a novel molecular target for blocking ovarian cancer progression. 23883243 Cystic renal cell carcinomas: do they grow, metastasize, or recur? OBJECTIVE. The purpose of this study is to evaluate the interval growth, tumor recurrence, and metastatic disease occurrence of cystic renal cell carcinoma (RCC). MATERIALS AND METHODS. Pre-and posttreatment imaging of 47 histologically proven cystic RCCs, with at least 6 months of pretreatment imaging monitoring or at least 2 years of posttreatment imaging follow-up, or both, was retrospectively reviewed. Tumor morphologic features, preoperative growth, histologic typing and grading, and the incidence of tumor recurrence or metastasis were evaluated. Growth rate of tumors were compared among various histologic subtypes and Fuhrman grades. RESULTS. Of 47 tumors, 27 (57.5%) were clear cell RCCs, 12 (25.5%) were multilocular RCCs, and eight (17%) were papillary cystic RCCs. Overall, 26 (55.3%) tumors were graded as Fuhrman grade 2, 17 (36.1%) were Fuhrman grade 1, and one tumor was Fuhrman grade 3. Of the 26 tumors with a minimum of 6 months of pretreatment imaging monitoring, 19 (73%) did not show a significant increase in tumor size. The differences in mean growth among the Fuhrman grades and different subtypes were not statistically significant. The average duration of posttreatment follow-up was 51 months. There were no local recurrences among the 43 patients who underwent posttreatment imaging, except for one patient who had metastasis at preoperative clinical presentation. CONCLUSION. Cystic RCCs exhibit slow indolent growth, if any, and show no significant metastatic or recurrence potential, with excellent clinical outcomes. We raise the need for revisiting current imaging protocols that may involve frequent pre-and posttreatment imaging in cystic RCCs. 23122148 Infusion and decoction of wild German chamomile: bioactivity and characterization of organic acids and phenolic compounds. Natural products represent a rich source of biologically active compounds and are an example of molecular diversity, with recognised potential in drug discovery. Herein, the methanol extract of Matricaria recutita L. (German chamomile) and its decoction and infusion (the most consumed preparations of this herb) were submitted to an analysis of phytochemicals and bioactivity evaluation. The antioxidant activity was determined by free radicals scavenging activity, reducing power and inhibition of lipid peroxidation; the antitumour potential was tested in human tumour cell lines (breast, lung, colon, cervical and hepatocellular carcinomas), and the hepatotoxicity was evaluated using a porcine liver primary cell culture (non-tumour cells). All the samples revealed antioxidant properties. The decoction exhibited no antitumour activity (GI(50)>400 μg/mL) which could indicate that this bioactivity might be related to compounds (including phenolic compounds) that were not extracted or that were affected by the decoction procedure. Both plant methanol extract and infusion showed inhibitory activity to the growth of HCT-15 (GI(50) 250.24 and 298.23 μg/mL, respectively) and HeLa (GI(50) 259.36 and 277.67 μg/mL, respectively) cell lines, without hepatotoxicity (GI(50)>400 μg/mL). Infusion and decoction gave higher contents of organic acids (24.42 and 23.35 g/100g dw). Otherwise, the plant methanol extract contained the highest amounts of both phenolic acids (3.99 g/100g dw) and flavonoids (2.59 g/100g dw). The major compound found in all the preparations was luteolin O-acylhexoside. Overall, German chamomile contains important phytochemicals with bioactive properties (mainly antitumour potential selective to colon and cervical carcinoma cell lines) to be explored in the pharmaceutical, food and cosmetics industries. 22796105 Role of metabotropic glutamate receptor 1 in the basolateral amygdala-driven prefrontal cortical deactivation in inflammatory pain in the rat. Plastic changes in the amygdala and limbic cortex networks have been widely shown in chronic pain. We have here investigated the role of group I metabotropic glutamate receptors (mGluRs) in the basolateral amygdala (BLA) pre-infra-limbic (PL-IL) divisions of the medial prefrontal cortex (mPFC) neuron connections after carrageenan-induced inflammatory pain in the rat. Intra-plantar injection of carrageenan decreased either spontaneous or mechanically/electrically evoked activity of PL cortex pyramidal neurons which responded with excitation in a way prevented by CPCOOEt, a selective mGluR1 antagonist, though not by MPEP, a selective mGluR5 antagonist. Accordingly, intra-BLA microinjection of DHPG, a group I mGluR agonist, caused PL cortex neuron activity depression, antagonized by CPCCOEt. CPCOOEt, but not MPEP, reduced also carrageenan-induced mechanical allodynia. The PL cortex cell deactivation in inflammatory pain condition was associated with increased GABA (conversely glutamate was decreased) in the PL/IL cortex. The local application of bicuculline, a GABA(A) receptor selective antagonist, reduced mechanical allodynia. An over-expression of mGluR1, but not mGluR5, have been observed in the PL-IL cortex after inflammatory pain suggesting an increased mGluR1-dependent cross-talk among BLA and IL-PL cortex neurons in inflammatory pain conditions. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23969149 Lipoma arborescens: Comparison of typical and atypical disease presentations. To determine whether the aetiology differed between typical cases of lipoma arborescens with unilateral knee involvement and atypical cases involving joints other than the knee, polyarticular disease, and disease outside of the knee joint. Cases of lipoma arborescens involving the knee joint were evaluated for the distribution of the disease and severity of degenerative arthritis. Joints other than the knee were evaluated for the presence and severity of degenerative arthritis, and the distribution was classified as either intra-articular, extra-articular, or both. Clinical history was reviewed for patient age at presentation, a history of inflammatory arthritis, diabetes mellitus, and known steroid use. Fisher's exact test was used to determine whether there was a statistically significant difference between typical and atypical presentations of the disease. Lipoma arborescens was identified in 45 joints in 39 patients. Twenty-eight patients were classified as "typical" and 11 patients had "atypical" disease. There was no significant difference in age at presentation, presence of degenerative arthritis, or known inflammatory arthritis when comparing typical and atypical presentations of the disease. Twenty-eight percent of patients in the present study had atypical presentation of lipoma arborescens with multifocal lipoma arborescens or disease in joints other than the knee. There was no significant difference in age at presentation, presence of degenerative arthritis, or known inflammatory arthritis when comparing typical and atypical presentations of the disease. Of the 39 patients, only three had no evidence of degenerative arthritis, which suggests that many cases of lipoma arborescens are secondary to chronic reactive change in association with degenerative arthritis. 23461806 Redox regulation of protein kinases. Reactive oxygen species (ROS) have been long regarded as by-products of a cascade of reactions stemming from cellular oxygen metabolism, which, if they accumulate to toxic levels, can have detrimental effects on cellular biomolecules. However, more recently, the recognition of ROS as mediators of cellular communications has led to their classification as signalling mediators in their own right. The prototypic redox-regulated targets downstream of ROS are the protein tyrosine phosphatases, and the wealth of research that has focused on this area has come to shape our understanding of how redox-signalling contributes to and facilitates protein tyrosine phosphorylation signalling cascades. However, it is becoming increasingly apparent that there is more to this system than simply the negative regulation of protein tyrosine phosphatases. Identification of redox-sensitive kinases such as Src led to the slow emergence of a role for redox regulation of tyrosine kinases. A flow of evidence, which has increased exponentially in recent times as a result of the development of new methods for the detection of oxidative modifications, demonstrates that, by concurrent oxidative activation of tyrosine kinases, ROS fine tune the duration and amplification of the phosphorylation signal. A more thorough understanding of the complex regulatory mechanism of redox-modification will allow targeting of both the production of ROS and their downstream effectors for therapeutic purposes. The present review assesses the most relevant recent literature that demonstrates a role for kinase regulation by oxidation, highlights the most significant findings and proposes future directions for this crucial area of redox biology. 23790774 Interfractional position variation of pancreatic tumors quantified using intratumoral fiducial markers and daily cone beam computed tomography. The aim of this study was to quantify interfractional pancreatic position variation using fiducial markers visible on daily cone beam computed tomography (CBCT) scans. In addition, we analyzed possible migration of the markers to investigate their suitability for tumor localization. For 13 pancreatic cancer patients with implanted Visicoil markers, CBCT scans were obtained before 17 to 25 fractions (300 CBCTs in total). Image registration with the reference CT was used to determine the displacement of the 2 to 3 markers relative to bony anatomy and to each other. We analyzed the distance between marker pairs as a function of time to identify marker registration error (SD of linear fit residuals) and possible marker migration. For each patient, we determined the mean displacement of markers relative to the reference CT (systematic position error) and the spread in displacements (random position error). From this, we calculated the group systematic error, Σ, and group random error, σ. Marker pair distances showed slight trends with time (range, -0.14 to 0.14 mm/day), possibly due to tissue deformation, but no shifts that would indicate marker migration. The mean SD of the fit residuals was 0.8 mm. We found large interfractional position variations, with for 116 of 300 (39%) fractions a 3-dimensional vector displacement of >10 mm. The spread in displacement varied significantly (P<.01) between patients, from a vector range of 9.1 mm to one of 24.6 mm. For the patient group, Σ was 3.8, 6.6, and 3.5 mm; and σ was 3.6, 4.7 and 2.5 mm, in left-right, superior-inferior, and anterior-posterior directions, respectively. We found large systematic displacements of the fiducial markers relative to bony anatomy, in addition to wide distributions of displacement. These results for interfractional position variation confirm the potential benefit of using fiducial markers rather than bony anatomy for daily online position verification for pancreatic cancer patients. 23277430 Immunohistochemical distribution of cocaine- and amphetamine-regulated transcript peptide - like immunoreactive (CART-LI) nerve fibers and various degree of co-localization with other neuronal factors in the circular muscle layer of human descending colon. Cocaine- and amphetamine-regulated transcript peptide (CART) is a neuromediator and/or neuromodulator in nerve structures within the gastrointestinal tract, but knowledge about its distribution, functions and co-localisation with other neuronal factors, especially in humans, is very scarce. During the present investigation the distribution and immunohistochemical reaction (IR) of CART - like immunoreactive (CART-LI) nerve fibers in the circular muscle layer of human descending colon were studied. Fragments of human colon were processed for double labelling immunofluorescence using a mixture of anti-CART antibodies with antibodies against vesicular acetylocholine transporter (VAChT), vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase - activating peptide (PACAP), substance P (SP), galanin (GAL) and nitric oxide synthase (NOS). Thick CART-LI nerve fibers formed a very dense meshwork within the colonic circular muscle layer in all patients studied. The highest number of CART - positive nerves also contained VAChT and/or VIP. A slightly lower level of co-localisation was observed in the case of CART and PACAP or CART and NOS. Only single nerve fibers were concurrently immunoreactive to CART and SP or CART and GAL. The present study reports for the first time a detailed description of the IR of CART-LI nerve fibers in the circular muscle layer within adult human descending colon. 23628403 In vitro-in vivo evaluation of nanosuspension release from subcutaneously implantable osmotic pumps. Utilizing poorly soluble drug candidates in pharmacokinetic studies remains challenging in preclinical drug development. We investigated a nanosuspension-based delivery system to achieve constant drug plasma levels by applying the nanoparticles via subcutaneously implanted micro-osmotic pumps. Various nanosuspension formulations were characterized in vitro prior to Alzet® pump release by means of dynamic light scattering (DLS), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and rheological measurements. In vitro formulation release was checked by HPLC/UV. The in vivo experiments compared plasma-concentration time profiles of subcutaneously injected nanosuspensions with those of formulations delivered by pumps. Two Poloxamer 338 containing nanosuspensions with different viscosities were found to be stable over observation time, physically resistant against biorelevant media and showed only a low amorphous part after preparation. The more viscous nanosuspension with 31.65 mPas revealed in vitro the expected zero-order release, while the low viscous formulation with 2.18 mPas showed first order release. In in vivo experiments, the higher viscous nanosuspension released from osmotic pumps exhibited elevated plasma levels compared to the lower viscous formulation. Compared to bolus injected nanosuspensions constant plasma levels could be maintained by adapting the viscosity of the nanosuspension. Subcutaneously implanted osmotic pumps prove to be a valuable delivery system for nanosuspensions in pharmacokinetic studies by consideration of the key parameter viscosity in release kinetics. 23893311 Community composition and cellulase activity of cellulolytic bacteria from forest soils planted with broad-leaved deciduous and evergreen trees. Cellulolytic bacteria in forest soil provide carbon sources to improve the soil fertility and sustain the nutrient balance of the forest ecological system through the decomposition of cellulosic remains. These bacteria can also be utilized for the biological conversion of biomass into renewable biofuels. In this study, the community compositions and activities of cellulolytic bacteria in the soils of forests planted with broad-leaved deciduous (Chang Qing Garden, CQG) and broad-leaved evergreen (Forest Park, FP) trees in Wuhan, China were resolved through restriction fragment length polymorphism (RFLP) and sequencing analysis of the 16S rRNA gene. All of the isolates exhibited 35 RFLP fingerprint patterns and were clustered into six groups at a similarity level of 50 %. The phylogeny analysis based on the 16S rRNA gene sequence revealed that these RFLP groups could be clustered into three phylogenetic groups and further divided into six subgroups at a higher resolution. Group I consists of isolates from Bacillus cereus, Bacillus subtilis complex (I-A) and from Paenibacillus amylolyticus-related complex (I-B) and exhibited the highest cellulase activity among all of the cellulolytic bacteria isolates. Cluster II consists of isolates belonging to Microbacterium testaceum (II-A), Chryseobacterium indoltheticum (II-B), and Flavobacterium pectinovorum and the related complex (II-C). Cluster III consists of isolates belonging to Pseudomonas putida-related species. The community shift with respect to the plant species and the soil properties was evidenced by the phylogenetic composition of the communities. Groups I-A and I-B, which account for 36.0 % of the cellulolytic communities in the CQG site, are the dominant groups (88.4 %) in the FP site. Alternatively, the ratio of the bacteria belonging to group III (P. putida-related isolates) shifted from 28.0 % in CQG to 4.0 % in FP. The soil nutrient analysis revealed that the CQG site planted with deciduous broad-leaved trees has a richer organic nutrient (total organic carbon and total nitrogen) than the FP site planted with evergreen broad-leaved trees. Against this background, the population density and the diversity of cellulolytic bacteria in the CQG site are clearly higher than those in the FP site, and the latter was dominated with high-cellulase-activity Bacillus- and Paenibacillus-related bacteria. The canonical correspondence analysis further indicated that the distribution of these groups is correlated with the FP site, whereas groups II and III are correlated with the organic nutrient-rich CQG site. 23374145 Enhanced cross-priming of naive CD8+ T cells by dendritic cells treated by the IMiDs® immunomodulatory compounds lenalidomide and pomalidomide. The IMiDs(®) immunomodulatory compounds lenalidomide and pomalidomide are agents with anti-inflammatory, immunomodulatory and anti-cancer activity. An excellent success rate has been shown for multiple myeloma in phase I/II clinical trials leading to Food and Drug Administration approval of lenalidomide. One mechanism by which these drugs could enhance anti-tumour immunity may be through enhanced dendritic cell (DC) function. Thalidomide, a compound structurally related to lenalidomide and pomalidomide, is known to enhance DC function, and we have investigated whether its analogues, pomalidomide and lenalidomide, also have functional effects on DCs. We used mouse bone marrow-derived DCs treated with 5 or 10 μm pomalidomide, or lenalidomide from day 1 of culture. Treatment with IMiD(®) immunomodulatory compounds increased expression of Class I (H2-Kb), CD86, and pomalidomide also increased Class II (I-Ab) expression in bone marrow-derived DCs, as measured by flow cytometry. Fluorescent bead uptake was increased by up to 45% when DCs were treated with 5 or 10 μm pomalidomide or lenalidomide compared with non-treated DCs. Antigen presentation assays using DCs primed with ovalbumin, and syngeneic T cells from transgenic OTI and OTII mice (containing MHC restricted, ovalbumin-specific, T cells) showed that both pomalidomide and lenalidomide effectively increased CD8(+) T-cell cross-priming (by up to 47%) and that pomalidomide alone was effective in increasing CD4(+) T-cell priming (by 30%). Our observations suggest that pomalidomide and lenalidomide enhance tumour antigen uptake by DCs with an increased efficacy of antigen presentation, indicating a possible use of these drugs in DC vaccine therapies. 23815317 Characterization of the mitochondrial genome of Rousettus leschenaulti. Abstract We present a complete sequence of mitochondrial genome of echolocating megabat Rousettus leschenaulti (16,704 nt, GenBank record KC702803) and provide its annotation. We also show that phylogenetic analysis based on mitochondrial genomes of eighteen bat species, including R. leschenaulti, supports division of Chiroptera into Yinpterochiroptera and Yangochiroptera. 23709685 Current management of sickle cell anemia. Proper management of sickle cell anemia (SCA) begins with establishing the correct diagnosis early in life, ideally during the newborn period. The identification of affected infants by neonatal screening programs allows early initiation of prophylactic penicillin and pneumococcal immunizations, which help prevent overwhelming sepsis. Ongoing education of families promotes the early recognition of disease-released complications, which allows prompt and appropriate medical evaluation and therapeutic intervention. Periodic evaluation by trained specialists helps provide comprehensive care, including transcranial Doppler examinations to identify children at risk for primary stroke, plus assessments for other parenchymal organ damage as patients become teens and adults. Treatment approaches that previously highlighted acute vaso-occlusive events are now evolving to the concept of preventive therapy. Liberalized use of blood transfusions and early consideration of hydroxyurea treatment represent a new treatment paradigm for SCA management. 23582213 The floral scent of Taccarum ulei (Araceae): Attraction of scarab beetle pollinators to an unusual aliphatic acyloin. The strongly fragrant thermogenic inflorescences of Taccarum ulei (Araceae) are highly attractive to night-active scarab beetles of Cyclocephala celata and C. cearae (Scarabaeidae, Cyclocephalini), which are effective pollinators of plants in the wild in northeastern Brazil. GC-MS analysis of headspace floral scent samples of T. ulei established that two constituents, (S)-2-hydroxy-5-methyl-3-hexanone (an aliphatic acyloin rarely detected in flowers) and dihydro-β-ionone (an irregular terpene) accounted for over 96% of the total scent discharge. Behavioral tests (in both field and cages) showed that male and female C. celata and C. cearae were attracted to traps baited with a synthetic mixture of both compounds; however, they were also responsive to (S)-2-hydroxy-5-methyl-3-hexanone alone, which thus functions as a specific attractive cue. These findings support other recent research in suggesting that angiosperms pollinated by cyclocephaline scarab beetles release floral odors of limited complexity in terms of numbers of compounds, but often dominated by unusual compounds that may ensure attraction of specific pollinator species. 23912310 The effects of advanced paternal age on fertility. Modern societal pressures and expectations over the past several decades have resulted in the tendency for couples to delay conception. While women experience a notable decrease in oocyte production in their late thirties, the effect of age on spermatogenesis is less well described. While there are no known limits to the age at which men can father children, the effects of advanced paternal age are incompletely understood. This review summarizes the current state of knowledge regarding advanced paternal age and its implications on semen quality, reproductive success and offspring health. This review will serve as a guide to physicians in counseling men about the decision to delay paternity and the risks involved with conception later in life.Asian Journal of Andrology advance online publication, 5 August 2013; doi:10.1038/aja.2013.92. 23568049 High- versus low-volume polyethylene glycol plus laxative versus sennosides for colonoscopy preparation in children. Many protocols of bowel preparation are available for use in children; however, none of them is commonly accepted. The aim of the study was to evaluate the efficacy and acceptability of high-volume polyethylene glycol (PEG) versus low-volume PEG combined with bisacodyl (BPEG) versus sennosides for colonoscopy preparation in children. Participants ages 10 to 18 years were randomly assigned to receive either PEG 60 or PEG 30 mL kg day plus oral bisacodyl 10 to 15 mg/day or sennosides 2 mg kg day for 2 days. A blinded assessment of bowel cleansing was made by the endoscopist according to the Aronchick and Ottawa scales. Patient acceptability was evaluated with the visual-analog scale. Analysis was done on an available case analysis basis. Of 240 patients enrolled in the study 234 patients were available for analysis of the efficacy of colon cleansing. There were no significant differences found among the 3 groups for the proportions of participants with excellent/good (PEG: 35/79, BPEG: 26/79, sennosides 25/76) and poor/inadequate (PEG: 20/79, BPEG: 28/79, sennosides 28/76) bowel preparation evaluated with the Aronchick scale and for the mean Ottawa total score (PEG: 5.47 ± 3.63, BPEG: 6.22 ± 3.3, sennosides: 6.18 ± 3.53). Acceptability of bowel cleansing protocol was similar in all of the groups (P = 0.8). All 3 cleansing methods showed similar efficacy and tolerability; however, none of them was satisfactory. 23922116 Donor-Acceptor (D-A)-Substituted Polyyne Chromophores: Modulation of Their Optoelectronic Properties by Varying the Length of the Acetylene Spacer. A series of donor-acceptor-substituted alkynes, 2 a-f, was synthesized in which the length of the π-conjugated polyyne spacer between the N,N-diisopropylanilino donor and the 1,1,4,4-tetracyanobuta-1,3-diene (TCBD) acceptor was systematically changed. The effect of this structural change on the optoelectronic properties of the molecules and, ultimately, their third-order optical nonlinearity was comprehensively investigated. The branched N,N-diisopropyl groups on the anilino donor moieties combined with the nonplanar geometry of 2 a-f imparted exceptionally high solubility to these chromophores. This important property allowed for performing INADEQUATE NMR measurements without (13) C labeling, which, in turn, resulted in a complete assignment of the carbon skeleton in chromophores 2 a-f and the determination of the (13) C-(13) C coupling constants. This body of data provided unprecedented insight into characteristic (13) C chemical shift patterns in push-pull-substituted polyynes. Electrochemical and UV/Vis spectroscopic studies showed that the HOMO-LUMO energy gap decreases with increasing length of the polyyne spacer, while this effect levels off for spacers with more than four acetylene units. The third-order optical nonlinearity of this series of molecules was determined by measuring the rotational averages of the third-order polarizabilities (γrot ) by degenerate four-wave mixing (DFWM). These latter studies revealed high third-order optical nonlinearities for the new chromophores; most importantly, they provided fundamental insight into the effect of the conjugated spacer length in D-A polyynes, that can be exploited in the future design of suitable charge-transfer chromophores for applications in optoelectronic devices. 23970423 Phenolic Compounds with In Vitro Activity against Respiratory Syncytial Virus from the Nigerian Lichen Ramalina farinacea. The extract of the Nigerian lichen Ramalina farinacea showed inhibitory activity against the respiratory syncytial virus in a preliminary assay. A follow-up chemical investigation of this lichen led to the isolation of thirteen phenolic compounds (1-13), including one new hydroquinone depside, designated 5-hydroxysekikaic acid (1), and one new orsellinic acid derivative, 2,3-dihydroxy-4-methoxy-6-pentylbenzoic acid (8). Their structures were unambiguously determined by analysis of 1D and 2D NMR and mass spectroscopic data, as well as by comparison with literature data. Compound 1 was found to partially convert to a 1,4-benzoquinone derivative (1a) during storage. The antiviral activities of the isolated compounds were evaluated against the respiratory syncytial virus. Among them, sekikaic acid (2) showed potent inhibition towards a recombinant strain rg respiratory syncytial virus (IC50 5.69 µg/mL) and respiratory syncytial virus A2 strain (IC50 7.73 µg/mL). The effect of sekikaic acid on the cell viability of HEp2 and Vero cell lines was investigated, and the time of addition assay revealed that sekikaic acid clearly interferes with viral replication at a viral post-entry step, which is over 1.3-fold more active than the control ribavirin at 4 hours postinfection addition. Furthermore, sekikaic acid did not display virucidal activity at concentrations below the TC50, whereas the parental extract did. 23223382 Plasma electrochemistry: voltammetry in a flame plasma electrolyte. In this paper we present detailed dynamic electrochemical measurements in a flame plasma electrolyte in the presence of tungsten oxide salts. Defined reproducible redox processes are measured using conventional cyclic voltammetry in an operational potential window between 1 and -9 V. This wide potential window is possible due to the absence of solvent and its associated limits due to solvent electrolysis at high over potentials. The measurements were enabled through the development of a new reference electrode, composed of yttria stabilised zirconia (YSZ) which maintains a stable potential at 1100 K. In this paper we focus on developing a phenomenological understanding of electron transfer at the solid-gas interface, using cyclic voltammetry. The effect of working electrode surface area and material, as well as potential scan rate on the voltammetric redox features is presented. We discuss the physical origin of the observed Faradaic current peaks measured in a flame plasma electrolyte, and propose a simple model to describe the redox processes occurring. We conclude that redox processes at the solid-gas interface are actually similar to the analogous processes at the solid-liquid interface described by conventional electrochemical theory; the departures are mainly due to the mass transport processes that dominate in the gas phase. We associate migration effects with the total absence of any oxidation processes. 23968570 Getting the skinny on thick filament regulation in cardiac muscle biology and disease. Thin (actin) filament accessory proteins are thought to be the regulatory force for muscle contraction in cardiac muscle; however, compelling new evidence suggests that thick (myosin) filament regulatory proteins are emerging as having independent and important roles in regulating cardiac muscle contraction. Key to these new findings is a growing body of evidence that point to an influential and, more recently, direct role for ventricular myosin light chain-2 (MLC2v) phosphorylation in regulating cardiac muscle contraction, function, and disease. This includes the discovery and characterization of a cardiac-specific myosin light chain kinase capable of phosphorylating MLC2v as well as a myosin phosphatase that dephosphorylates MLC2v in the heart, which provides added mechanistic insights on MLC2v regulation within cardiac muscle. Here, we review evidence for an emerging and critical role for MLC2v phosphorylation in regulating cardiac myosin cycling kinetics, function, and disease, based on recent studies performed in genetic mouse models and humans. We further provide new perspectives on future avenues for targeting these pathways as therapies in alleviating cardiac disease. 23439619 Circulating Levels of Neutrophil Gelatinase-Associated Lipocalin (NGAL) Correlate With the Presence and Severity of Preeclampsia. Objective: Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as a reliable marker of acute renal injury and is produced at the maternal-fetal interface but its role in preeclampsia has not been systematically examined. This study investigated whether plasma NGAL concentrations changed in patients with preeclampsia at diagnosis compared to normotensive controls. Study Design: A case-control study was performed. Plasma was collected from women with preeclampsia and normotensive controls matched for age, gestational age, and body mass index. Plasma NGAL concentrations were measured by specific enzyme-linked immunosorbent assay. Results: Patients with preeclampsia had significantly higher NGAL concentrations than controls (median [range]: 203.8 ng/mL [66.1-575.4] vs 122.8 ng/mL [7.0-669.7]; P = .047). In subgroup analysis, patients with severe preeclampsia had significantly higher NGAL concentrations than those with mild preeclampsia. Plasma NGAL concentrations were positively correlated with the amount of proteinuria in women with preeclampsia (P = .003). Conclusions: Plasma NGAL concentrations were significantly elevated in women with preeclampsia versus normotensive controls, and concentrations appear to be associated with the severity of the disease. 23901968 Entanglement dynamics of two qubits coupled individually to Ohmic baths. Developed originally for the Holstein polaron, the Davydov D1 ansatz is an efficient, yet extremely accurate trial state for time-dependent variation of the spin-boson model [N. Wu, L. Duan, X. Li, and Y. Zhao, J. Chem. Phys. 138, 084111 (2013)]. In this work, the Dirac-Frenkel time-dependent variational procedure utilizing the Davydov D1 ansatz is implemented to study entanglement dynamics of two qubits under the influence of two independent baths. The Ohmic spectral density is used without the Born-Markov approximation or the rotating-wave approximation. In the strong coupling regime finite-time disentanglement is always found to exist, while at the intermediate coupling regime, the entanglement dynamics calculated by Davydov D1 ansatz displays oscillatory behavior in addition to entanglement disappearance and revival. 23680598 Activity and crystal structure of human thymine DNA glycosylase mutant N140A with 5-carboxylcytosine DNA at low pH. The mammalian thymine DNA glycosylase (TDG) excises 5-carboxylcytosine (5caC) when paired with a guanine in a CpG sequence, in addition to mismatched bases. Here we present a complex structure of the human TDG catalytic mutant, asparagine 140 to alanine (N140A), with a 28-base pair DNA containing a G:5caC pair at pH 4.6. TDG interacts with the carboxylate moiety of target nucleotide 5caC using the side chain of asparagine 230 (N230), instead of asparagine 157 (N157) as previously reported. Mutation of either N157 or N230 residues to aspartate has minimal effect on G:5caC activity while significantly reducing activity on G:U substrate. Combination of both the asparagine-to-aspartate mutations (N157D/N230D) resulted in complete loss of activity on G:5caC while retaining measurable activity on G:U, implying that 5caC can adopt alternative conformations (either N157-interacting or N230-interacting) in the TDG active site to interact with either of the two asparagine side chain for 5caC excision. 23880897 Predictive value of interim 18F-FDG-PET/CT for event-free survival in patients with diffuse large B-cell lymphoma homogenously treated in a phase II trial with six cycles of R-CHOP-14 plus pegfilgrastim as first-line treatment. The predictive value of interim PET/computed tomography (I-PET/CT) in diffuse large B-cell lymphoma (DLBCL) is controversial. Our aim was to evaluate the predictive value of I-PET/CT for an event-free survival. We analyzed patients with DLBCL included in a prospective clinical trial who were treated with six cycles of dose-dense R-CHOP followed by pegfilgrastim and who had undergone an I-PET/CT (after two cycles) and a final PET [F-PET/CT (60 days after the sixth cycle)]. Event was defined as nonresponse, relapse, or death. A total of 69 patients were included. Their median age was 60 years; 54% were male, 25% had bulky disease, and 67% had an International Prognostic Index of 0-2. The median follow-up duration was 28.8 months. I-PET/CT was positive in 34 (49%) patients and F-PET/CT was positive in 12 (17.4%). The 3-year event-free survival was 86% for patients who were I-PET/CT negative as against 64% for those who were I-PET/CT positive (P=0.036). The negative and positive predictive values, sensitivity, and specificity of I-PET/CT for an event were 83, 32, 65, and 56%, respectively. In a multivariate analysis including baseline characteristics, I-PET/CT, and F-PET/CT, F-PET/CT was the only significant predictor (P<0.0005). In patients with DLBCL treated with dose-dense R-CHOP plus pegfilgrastim, a negative I-PET/CT is highly predictive of a favorable outcome and a positive I-PET/CT is of limited clinical value. These results do not support treatment intensification after a short course of chemotherapy based solely on a positive I-PET/CT. 23855954 Acute refractory hypoxemia after chest trauma reversed by high-frequency oscillatory ventilation: a case report. Polytrauma often results in significant hypoxemia secondary to direct lung contusion or indirectly through atelectasis, systemic inflammatory response, large volume fluid resuscitation and blood product transfusion. In addition to causing hypoxemia, atelectasis and acute lung injury can lead to right ventricular failure through an acute increase in pulmonary vascular resistance. Mechanical ventilation is often applied, accompanied with recruitment maneuvers and positive end-expiratory pressure in order to recruit alveoli and reverse atelectasis, while preventing excessive alveolar damage. This strategy should lead to the reversal of the hypoxemic condition and the detrimental heart-lung interaction that may occur. However, as described in this case report, hemodynamic instability and intractable alveolar atelectasis sometimes do not respond to conventional ventilation strategies. We describe the case of a 21-year-old Caucasian man with severe chest trauma requiring surgical interventions, who developed refractory hypoxemia and overt right ventricular failure. After multiple failed attempts of recruitment using conventional ventilation, the patient was ventilated with high-frequency oscillatory ventilation. This mode of ventilation allowed the reversal of the hemodynamic effects of severe hypoxemia and of the acute cor pulmonale. We use this case report to describe the physiological advantages of high-frequency oscillatory ventilation in patients with chest trauma, and formulate the arguments to explain the positive effect observed in our patient. High-frequency oscillatory ventilation can be used in the context of a blunt chest trauma accompanied by severe hypoxemia due to atelectasis. The positive effect is due to its capacity to recruit the collapsed alveoli and, as a result, the relief of increased pulmonary vascular resistance and subsequently the reversal of acute cor pulmonale. This approach may represent an alternative in case of failure of the conventional ventilation strategy. 23444145 Rapamycin inhibits BMP-7-induced osteogenic and lipogenic marker expressions in fetal rat calvarial cells. Bone morphogenetic proteins (BMPs) promote osteoblast differentiation and bone formation in vitro and in vivo. BMPs canonically signal through Smad transcription factors, but BMPs may activate signaling pathways traditionally stimulated by growth factor tyrosine kinase receptors. Of these, the mTOR pathway has received considerable attention because BMPs activate P70S6K, a downstream effector of mTOR, suggesting that BMP-induced osteogenesis is mediated by mTOR activation. However, contradictory effects of the mTOR inhibitor rapamycin (RAPA) on bone formation have been reported. Since bone formation is thought to be inversely related to lipid accumulation and mTOR is also important for lipid synthesis, we postulated that BMP-7 may stimulate lipogenic enzyme expression in a RAPA-sensitive mechanism. To test this hypothesis, we determined the effects of RAPA on BMP-7-stimulated expression of osteogenic and lipogenic markers in cultured fetal rat calvarial cells. Our study showed that BMP-7 promoted the expression of osteogenic and lipogenic markers. The effect of BMP-7 on osteogenic markers was greater in magnitude than on lipogenic markers and was temporally more sustained. RAPA inhibited basal and BMP-7-stimulated osteogenic and lipogenic marker expression and bone nodule mineralization. The acetyl CoA carboxylase inhibitor TOFA stimulated the expression of osteoblast differentiation markers, whereas palmitate suppressed their expression. We speculate that the BMP-7-stimulated adipogenesis is part of the normal anabolic response to BMPs, but that inappropriate activation of the lipid biosynthetic pathway by mTOR could have deleterious effects on bone formation and could explain paradoxical effects of RAPA to promote bone formation. 23540769 Technology use for health education to caregivers: An integrative review of nursing literature. Providing caregivers with health education through educational technologies enhances safe care; and stimulates the decision process and communication among professionals, caregivers and patients. This article is an integrative review to identify what educational technologies have been used for health education to caregivers. The databases Web of Science, Bireme and Scopus were consulted. The inclusion criteria are as follows: full papers, published between 2001 and 2011, in English, Portuguese or Spanish. The descriptors used are the following: educational technology, health education and caregivers. Thirty-four papers were found, 27 of which were excluded because they did not comply with the inclusion criteria, resulting in a final sample of 7 papers. The results evidenced the use of light and hard technologies in health education for caregivers, aimed at the therapeutic discussion of care as well as telehealth service delivery. Research is needed which uses and assesses the use of hard educational technologies in health education for caregivers. 23893953 A phase I study of histone deacetylase inhibitor, pracinostat (SB939), in pediatric patients with refractory solid tumors: IND203 a trial of the NCIC IND program/C17 pediatric phase I consortium. Pracinostat (SB939) is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDAC). The adult recommended phase II dose (RP2D) is 60 mg po three times per week (t.i.w.) for 3 weeks every 4 weeks. This study assessed the toxicities and pharmacokinetics of pracinostat and determined the RP2D in children with refractory solid tumors. Pediatric patients with refractory solid tumors were treated with oral pracinostat t.i.w. for 3 consecutive weeks, followed by 1 week off dosing. Three dose levels-25, 35, and 45 mg/m(2) were evaluated using a standard 3 + 3 cohort design. Pharmacokinetic (PK) studies were optional. Twelve patients were enrolled. The most common diagnosis was Ewing sarcoma. Most adverse events (AEs) were hematological with five (40%) patients experiencing grade 3 neutropenia. Non-hematological AEs were generally grade 1. No dose limiting toxicities occurred. More hematological and non-hematological AEs occurred at 45 mg/m(2) : Two of five patients experienced Grade 3 neutropenia and one each Grade 3 thrombocytopenia and leucopenia, Grade 1 fatigue and anorexia occurred in three. The RP2D was declared to be 45 mg/m(2) (comparable to an adult dose of 80 mg). One patient had a best response of stable disease (duration of 2.9 months). Three patients on 25 mg/m(2) and one each on 35 and 45 mg/m(2) participated in the PK study. No dose related changes in Cmax or AUC occurred. Pracinostat is reasonably well tolerated in children with refractory solid tumors. The RP2D is 45 mg/m(2) . Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc. 23183785 The association between serum uric acid and renal damage in a community-based population: the Takahata study. Hyperuricemia is a risk factor for end-stage renal disease. This study examined the association between serum uric acid and renal damage in a community-based population. In this study 3126 subjects without renal insufficiency were recruited at baseline and were followed for one year. The urinary albumin-creatinine ratio (UACR) and β2-microglobulin-creatinine ratio (UBCR) in morning spot urine samples were used as indices of either glomerular (UACR) or tubular (UBCR) damage. The mean value of serum uric acid (mg/dL) was 5.8 ± 1.3 (SD) in men and 4.5 ± 1.1 in women. In cross-sectional analysis the increased serum uric acid levels were accompanied by higher UACR values in both men and women (P < 0.01). In contrast, UBCR values were reduced when uric acid levels increased in both men and women (P < 0.01). Multivariate analysis revealed that albuminuria (UACR â‰¥ 30 mg/g) was significantly associated with increased uric acid (≥7 mg/dL for men, ≥6 mg/dL for women). High UBCR (≥300 Î¼g/g) was negatively associated with uric acid in men, but not in women, after adjustment for possible confounders. In longitudinal analysis in 1388 subjects multiple linear regression analysis showed that uric acid at baseline was an independent factor for one-year increase of UACR [coefficient 4.80 (95 % confidence interval 0.40-9.33) (mg/g) per 1 mg/dL increase in uric acid, P = 0.033]. This study showed that serum uric acid concentration was positively associated with UACR, suggesting that uric acid may be related to glomerular damage in a community-based population. 23886781 Safety in Numbers: Are Major Cities the Safest Places in the United States? Many US cities have experienced population reductions, often blamed on crime and interpersonal injury. Yet the overall injury risk in urban areas compared with suburban and rural areas has not been fully described. We begin to investigate this evidence gap by looking specifically at injury-related mortality risk, determining the risk of all injury death across the rural-urban continuum. A cross-sectional time-series analysis of US injury deaths from 1999 to 2006 in counties classified according to the rural-urban continuum was conducted. Negative binomial generalized estimating equations and tests for trend were completed. Total injury deaths were the primary comparator, whereas differences by mechanism and age were also explored. A total of 1,295,919 injury deaths in 3,141 US counties were analyzed. Injury mortality increased with increasing rurality. Urban counties demonstrated the lowest death rates, significantly less than rural counties (mean difference=24.0 per 100,000; 95% confidence interval 16.4 to 31.6 per 100,000). After adjustment, the risk of injury death was 1.22 times higher in the most rural counties compared with the most urban (95% confidence interval 1.07 to 1.39). Using total injury death rate as an overall safety metric, US urban counties were safer than their rural counterparts, and injury death risk increased steadily as counties became more rural. Greater emphasis on elevated injury-related mortality risk outside of large cities, attention to locality-specific injury prevention priorities, and an increased focus on matching emergency care needs to emergency care resources are in order. 23872096 Cadmium-induced glutathionylation of actin occurs through a ROS-independent mechanism: Implications for cytoskeletal integrity. Cadmium disrupts the actin cytoskeleton in rat mesangial cells, and we have previously shown that this involves a complex interplay involving activation of kinase signaling, protein translocation, and disruption of focal adhesions. Here we investigate the role that glutathionylation of actin plays in Cd(2+)-associated cytoskeletal reorganization. Low concentrations of Cd(2+) (0.5-2μM) caused an increase in actin glutathionylation by 6h, whereas at higher concentrations glutathionylation remained at basal levels. Although oxidation with diamide increased glutathionylation, reactive oxygen species (ROS) were not involved in the Cd(2+)-dependent effect, as only Cd(2+) concentrations above 2μM were sufficient to increase ROS. However, low [Cd(2+)] increased total glutathione levels without affecting the ratio of reduced/oxidized glutathione, and inhibition of glutathione synthesis suppressed actin glutathionylation. Cadmium increased the activity of the enzyme glutaredoxin, which influences the equilibrium between glutathionylated and deglutathionylated proteins and thus may influence levels of glutathionylated actin. Together these observations show that cadmium-dependent effects on actin glutathionylation are affected by glutathione metabolism and not by direct effects of ROS on thiol chemistry. In vitro polymerization assays with glutathionylated actin show a decreased rate of polymerization. In contrast, immunofluorescence of cytoskeletal structure in intact cells suggests that increases in actin glutathionylation accompanying increased glutathione levels occurring under low Cd(2+) exposure are protective in vivo, with cytoskeletal disruption ensuing only when higher Cd(2+) concentrations increase ROS levels and prevent an increase in actin-glutathione conjugates. 23957890 R.A. Fisher's gene-centred view of evolution and the Fundamental Theorem of Natural Selection. The background to R.A. Fisher's enunciation of his Fundamental Theorem of Natural Selection in 1930 is traced and the Theorem in its original form explained. It can now be seen as the centrepiece of Fisher's introduction of the gene-centred approach to evolutionary biology. Although this paper is a sequel to Edwards (1994) it is not a review of the recent literature on the Theorem, to which, however, reference is made at the end. 23919684 A new kaempferol trioside from Silphium perfoliatum. A new apiose-containing kaempferol trioside, kaempferol-3-O-α-l-rhamnosyl-(1‴ â†’ 6″)-O-β-d-galactopyranosyl-7-O-β-d-apiofuranoside, along with 16 known compounds, were isolated from 50% acetone extract of Silphium perfoliatum L. Their structures were elucidated by acid hydrolysis and spectroscopic techniques including UV, IR, MS, (1)H, (13)C, and 2D-NMR. In addition, the pharmacological activity of compound 1 was tested with HepG2 and Balb/c mice (splenic lymphocytes and thymic lymphocytes) in vitro, and it exhibited inhibitory effect on the proliferation of HepG2 cells and showed the immunosuppressive activity. 23904297 A mouse model of shigellosis by intraperitoneal infection. In human and non-human primates, Shigella spp. cause bacillary dysentery by invading colon epithelium and promoting a strong inflammatory response; however, adult mice are resistant to oral Shigella infection. In this study, intraperitoneal (i.p.) challenge with virulent Shigella (S.) flexneri 2a (YSH6000) resulted in diarrhea and severe body weight loss in adult B6 mice. Of note, virulent S. flexneri 2a could invade and colonize not only systemic tissues but also the serosa and lamina propria region of the large intestine. In addition, epithelial shedding, barrier integrity, and goblet cell hyperplasia were found in the large intestine by 24 hours post i.p. Shigella infection. Of note, predominant expression of proinflammatory cytokines and chemokines were found in the large intestine after i.p. challenge. Monocytes played a critical role in attenuating diarrhea and in providing protective efficacy against i.p. Shigella infection. Most importantly, mice pre-vaccinated with attenuated S. flexneri 2a (SC602) strain were protected against i.p. challenge with YSH6000. When taken together, these findings show that i.p. challenge with virulent S. flexneri 2a can provoke bacillary dysentery and severe pathogenesis in adult mice. This model may be helpful for understanding the induction mechanism of bacillary dysentery and for evaluating Shigella vaccine candidates. 23907855 Aroma Chemistry of African Oryza glaberrima and Oryza sativa Rice and Their Interspecific Hybrids. To increase rice production in Africa, considerable research has focused on creating interspecific hybrids between African (Oryza glaberrima Steud.) and Asian (O. sativa L.) in an attempt to obtain the positive attributes of each in new cultivars. Since flavor is a key criterion in consumer acceptance of rice, as an initial inquiry we characterized and compared the aroma chemistry of selected cultivars of African O. sativa ssp. japonica, O. sativa ssp. indica, O. glaberrima, and their interspecific hybrids grown in West Africa using gas chromatography-mass spectrometry, gas chromatography-olfactometry and descriptive sensory analysis. Of 41 volatiles identified across seven representative rice cultivars grown in West Africa, 3,5,5-trimethyl-2-cyclopenten-1-one, styrene, eucalyptol, linalool, myrtenal and L-α-terpineol had not been previously reported in rice. Thirty-three odor-active compounds were characterized. 4-Ethylphenol and (E,E)-2,4-heptadienal were unique to O. glaberrima and pyridine, eucalyptol and myrtenal were described only in an interspecific hybrid. Descriptive sensory analysis indicated 'cooked grain', 'barny', and 'earthy' attributes were statistically different among the cultivars. The aroma chemistry data suggest that it should be possible to separate African cultivars into distinct flavor types whereby facilitating selection of new cultivars with superior flavor in African rice breeding programs. 23784666 A mild, one-pot stadler-ziegler synthesis of arylsulfides facilitated by photoredox catalysis in batch and continuous-flow. Visible advance: A mild, one-pot Stadler-Ziegler process for CS bond formation has been developed. The method employs the photoredox catalyst [Ru(bpy)3 Cl2 ]⋅6 H2 O irradiated with visible light. A variety of aryl-alkyl and diaryl sulfides were prepared from readily available arylamines and aryl/alkylthiols in good yields. The use of a photo microreactor led to a significant improvement with respect to safety and efficiency. 23951005 Gadd153 and NF-κB Crosstalk Regulates 27-Hydroxycholesterol-Induced Increase in BACE1 and β-Amyloid Production in Human Neuroblastoma SH-SY5Y Cells. β-amyloid (Aβ) peptide, accumulation of which is a culprit for Alzheimer's disease (AD), is derived from the initial cleavage of amyloid precursor protein by the aspartyl protease BACE1. Identification of cellular mechanisms that regulate BACE1 production is of high relevance to the search for potential disease-modifying therapies that inhibit BACE1 to reduce Aβ accumulation and AD progression. In the present study, we show that the cholesterol oxidation product 27-hydroxycholesterol (27-OHC) increases BACE1 and Aβ levels in human neuroblastoma SH-SY5Y cells. This increase in BACE1 involves a crosstalk between the two transcription factors NF-κB and the endoplasmic reticulum stress marker, the growth arrest and DNA damage induced gene-153 (gadd153, also called CHOP). We specifically show that 27-OHC induces a substantial increase in NF-κB binding to the BACE1 promoter and subsequent increase in BACE1 transcription and Aβ production. The NF-κB inhibitor, sc514, significantly attenuated the 27-OHC-induced increase in NF-κB-mediated BACE1 expression and Aβ genesis. We further show that the 27-OHC-induced NF-κB activation and increased NF-κB-mediated BACE1 expression is contingent on the increased activation of gadd153. Silencing gadd153 expression with siRNA alleviated the 27-OHC-induced increase in NF-κB activation, NF-κB binding to the BACE1 promoter, and subsequent increase in BACE1 transcription and Aβ production. We also show that increased levels of BACE1 in the triple transgenic mouse model for AD is preceded by gadd153 and NF-κB activation. In summary, our study demonstrates that gadd153 and NF-κB work in concert to regulate BACE1 expression. Agents that inhibit gadd153 activation and subsequent interaction with NF-κB might be promising targets to reduce BACE1 and Aβ overproduction and may ultimately serve as disease-modifying treatments for AD. 23622867 Preparation of magnesium ferrite nanoparticles by ultrasonic wave-assisted aqueous solution ball milling. Magnesium ferrite, MgFe2O4 nanoparticles with high saturation magnetization were successfully synthesized using ultrasonic wave-assisted ball milling. In this study, the raw materials were 4MgCO3·Mg(OH)2·5H2O and Fe2O3 powders and the grinding media was stainless steel ball. The average particle diameter of the product MgFe2O4 powders was 20 nm and the saturation magnetization of them reached 54.8 emu/g. The different results of aqueous solution ball milling with and without ultrasonic wave revealed that it was the coupling effect of ultrasonic wave and mechanical force that played an important role during the synthesis of MgFe2O4. In addition, the effect of the frequency of the ultrasonic wave on the ball milling process was investigated. 23859734 Gender and migration on the labour market: Additive or interacting disadvantages in Germany? Despite substantial differences in labour market attainment according to gender and migration status, gender and ethnic differences in labour market behaviour are most often studied separately. In contrast, this study describes and analyses interactions between gender, ethnic background and immigrant generation with regard to labour market participation, part-time work, and occupational status. The double comparison aims to reveal whether gender gaps in these labour market outcomes among the majority population generalise to ethnic minorities. Moreover, we ask whether variation in gender gaps in labour market behaviour follows the patterns in migrants' origin countries, and whether gender gaps show signs of intergenerational assimilation. Our heterogeneous choice and OLS regressions of 2009 German Microcensus data reveal considerable variation in gender gaps in labour market behaviour between East and West Germany, across ethnic groups and across generations. Intergenerational comparisons show that most ethnic minorities assimilate towards German patterns of gendered labour market attainment. 23625800 Congenital amegakaryocytic thrombocytopenia (CAMT) presenting as severe pancytopenia in the first month of life. Congenital amegakaryocytic thrombocytopenia (CAMT) is characterised by neonatal thrombocytopenia, with reduced or absent bone marrow megakaryocytes, leading eventually to pancytopenia. The mean age for progression to bone marrow failure is four years, with the earliest reported being six months. We describe a CAMT patient with compound heterozygous mutations of the causative MPL gene (one being a previously unreported splice site mutation in intron 11) who developed pancytopenia within the first month of life. This report emphasises the importance of considering CAMT in the differential diagnosis of congenital aplastic anaemia or idiopathic aplastic anaemia in babies. Pediatr Blood Cancer 2013;60:E94-E96. © 2013 Wiley Periodicals, Inc. 23801592 Overcoming bottlenecks of enzymatic biofuel cell cathodes: crude fungal culture supernatant can help to extend lifetime and reduce cost. Enzymatic biofuel cells (BFCs) show great potential for the direct conversion of biochemically stored energy from renewable biomass resources into electricity. However, enzyme purification is time-consuming and expensive. Furthermore, the long-term use of enzymatic BFCs is hindered by enzyme degradation, which limits their lifetime to only a few weeks. We show, for the first time, that crude culture supernatant from enzyme-secreting microorganisms (Trametes versicolor) can be used without further treatment to supply the enzyme laccase to the cathode of a mediatorless BFC. Polarization curves show that there is no significant difference in the cathode performance when using crude supernatant that contains laccase compared to purified laccase in culture medium or buffer solution. Furthermore, we demonstrate that the oxygen reduction activity of this enzymatic cathode can be sustained over a period of at least 120 days by periodic resupply of crude culture supernatant. This is more than five times longer than control cathodes without the resupply of culture supernatant. During the operation period of 120 days, no progressive loss of potential is observed, which suggests that significantly longer lifetimes than shown in this work may be possible. Our results demonstrate the possibility to establish simple, cost efficient, and mediatorless enzymatic BFC cathodes that do not require expensive enzyme purification procedures. Furthermore, they show the feasibility of an enzymatic BFC with an extended lifetime, in which self-replicating microorganisms provide the electrode with catalytically active enzymes in a continuous or periodic manner. 23935758 Progesterone attenuates cerebral edema in neonatal rats with hypoxic-ischemic brain damage by inhibiting the expression of matrix metalloproteinase-9 and aquaporin-4. The aim of this study was to investigate the effects of progesterone (PROG) on blood-brain barrier (BBB) permeability, cerebral edema and the expression of matrix metalloproteinase-9 (MMP-9) and aquaporin-4 (AQP-4) in neonatal rats with hypoxic-ischemic brain damage (HIBD) and to explore the mechanism of its neuroprotective effect. Sixty 7-day-old Wistar rats were divided into sham surgery, hypoxic ischemia (HI) and drug prophylaxis (PROG) groups. HIBD animal models were established. All the animals were sacrificed after 24 h. The BBB was assessed using Evans blue. Cerebral moisture capacity was determined using the dry-wet method. MMP-9 was detected in the brain tissues using enzyme-linked immunosorbent assay. The expression of AQP-4 and MMP-9 in the cerebral cortex was observed using immunohistochemistry and real-time polymerase chain reaction. The MMP-9 levels in the cortex, BBB permeability, cerebral moisture capacity and expression of AQP-4 and MMP-9 in the HI group were significantly higher compared with those in the sham surgery group (P<0.01), and they were significantly lower in the drug prophylaxis group compared with those in the HI group (P<0.05). In conclusion, PROG reduces BBB damage and cerebral edema and inhibits MMP-9 generation to protect rat brains against HIBD. The protective effect of PROG may be correlated with downregulated expression of AQP-4 and MMP-9 in the cerebral cortex. 23836857 Comparative effectiveness of angiotensin-receptor blockers for preventing macrovascular disease in patients with diabetes: a population-based cohort study. BACKGROUND:Telmisartan, unlike other angiotensin-receptor blockers, is a partial agonist of peroxisome proliferator-activated receptor-γ, a property that has been associated with improvements in surrogate markers of cardiovascular health in small trials involving patients with diabetes. However, whether this property translates into a reduced risk of cardiovascular events and death in these patients is unknown. We sought to explore the risk of myocardial infarction, stroke and heart failure in patients with diabetes who were taking telmisartan relative to the risk of these events occurring in patients taking other angiotensinreceptor METHODS:We conducted a populationbased, retrospective cohort study of Ontario residents with diabetes aged 66 years and older who started treatment with candesartan, irbesartan, losartan, telmisartan or valsartan between Apr. 1, 2001, and Mar. 31, 2011. Our primary outcome was a composite of admission to hospital for acute myocardial infarction, stroke or heart failure. We examined each outcome individually in secondary analyses, in addition to all-cause mortality. RESULTS:We identified 54 186 patients with diabetes who started taking an angiotensinreceptor blocker during the study period. After multivariable adjustment, patients who took either telmisartan (adjusted hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.74-0.97) or valsartan (adjusted HR 0.86, 95% CI 0.77-0.95) had a lower risk of the composite outcome compared with patients who took irbesartan. In contrast, no significant difference in risk was seen between other angiotensin-receptor blockers and irbesartan. In secondary analyses, we found a reduced risk of admission to hospital for heart failure with telmisartan compared with irbesartan (adjusted HR 0.79, 95% CI 0.66- 0.96), but no significant differences in risk were seen between angiotensin-receptor blockers in our other secondary analyses. INTERPRETATION:Compared with other angiotensin-receptor blockers, telmisartan and valsartan were both associated with a lower risk of admission to hospital for acute myocardial infarction, stroke or heart failure among older adults with diabetes and hypertension. Telmisartan and val sartan may therefore be the preferred angiotensin-receptor blockers for use in these patients. 23944789 World in brief. What's happening in nursing across the globe. 23754316 Tetraspanin 1 promotes invasiveness of cervical cancer cells. Tetraspanins are a heterogeneous group of 4-transmembrane proteins that segregate into so-called tetraspanin-enriched microdomains (TEMs) along with other cell surface proteins such as integrins. TEMs of various types are reportedly involved in the regulation of cell growth, migration and invasion of several tumour cell types, both as suppressors or supporting structures. Tetraspanin 1 (Tspan1, NET-1), a member of the transmembrane 4 superfamily (TM4SF) of tetraspanins, is overexpressed in high-grade cervical intraepithelial neoplasia (CIN) and terminal carcinomas but its precise function in the context of carcinoma of the cervix uteri is not known. Here, we present a comprehensive investigation of the role of tetraspanin 1 in the cervical cancer cell lines SiHa and HeLa. We document that tetraspanin 1 increases the invasive potential of cervical cancer cells, whereas proliferation, growth in soft agar and adhesion are largely unaffected. In line with the latter findings, our data exclude the participation of testraspanin in integrin-mediated activation of focal adhesion kinase (FAK), paxillin and phosphoinositide-3-kinase (PI3K) and in EGFR-dependent signalling to the Ras/Erk pathway. In conclusion, our data argue against a role for tetraspanin 1 as a genuine mediator of cell surface receptor signalling but rather document a role for tetraspanin 1 in the control of cervical cancer cell motility and invasion. 23788199 Prognostic role of station 3A mediastinal nodes for non-small-cell lung cancers. Station 3A nodes have been commonly neglected in surgical practice. This retrospective study collected information on the incidence and risk factors of Station 3A node to ascertain the prognostic role of 3A nodal involvement. A total of 180 consecutive pN2 (stage IIIa) non-small-cell lung cancer (NSCLC) cases who underwent systemic lymphadenectomy and contained Station 3A nodes were enrolled. Survival rates were calculated according to the final pathology of Station 3A lymph node: Station 3A node (+) and Station 3A node (-). Statistical analysis was conducted using Kaplan-Meier and Cox regression models. Station 3A nodal metastasis was validated in 32 cases, and the incidence of Station 3A node involvement was 17.8%. Station 3A nodes involvement was strongly associated with the metastatic status of Station 4R nodes and histological nature of pulmonary cancer. The overall 3-year survival was 53% and median survival time was 40.6 months. The 3-year survival difference was significant between Station 3A node (-) and Station 3A node (+) (63 vs 22%, χ(2) = 16.426, P < 0.001). Moreover, the overall 3-year survival was closely related with the number of involved nodal zones (χ(2) = 31.156, P < 0.001). Multivariate analysis showed two statistically significant risk factors for survival including metastasis of Station 3A node and the number of positive nodal zones (hazard ratios [HR]: 2.702; 95% confidence intervals [CI]: 1.008-7.242; P = 0.027; and HR: 7.404; 95% CI: 3.263-16.936, P < 0.001, respectively). The involvement of Station 3A lymph nodes predicts poor prognosis of right-sided stage pIIIa-N2 NSCLC patients. Therefore, systemic lymphadenectomy for right-sided cancers should include Station 3A nodes when ascertaining a complete resection. 22510954 Evaluation of a MEMS-Based Dual Metal-Layer Thin-Film Microelectrode Array for Suprachoroidal Electrical Stimulation. A double metal-layer thin-film platinum microelectrode array was fabricated for implantation between sclera and choroid based on MEMS processing techniques and photosensitive polyimide material. The array was composed of 60 stimulating sites (6 × 10) and four selectable returning electrodes. The diameter of each stimulating electrode was 350 μ m with a center-to-center spacing of 750 μm. The transient voltage responses of the electrode to current pulse stimulation indicated a charge-injection capacity greater than 52.1 μ C/cm (2) . Acute in vivo animal experiments showed that the implicit time of electrically evoked potentials (EEPs) was 17.09±1.45 ms at a threshold current of 25.55 ±5.43 μA for a full-row of simultaneously stimulated electrodes (i.e., current applied simultaneously to each of the 10 electrodes). Individual electrode stimulation threshold was 48.57 ±6.90 μA. The corresponding threshold charge densities were 13.28 ±2.82 μC/cm (2) and 25.24 ±3.59 μC/cm (2) , respectively. The spatial spread of the maximally recorded P1 response in the EEPs indicated a correspondence between the retinal stimulation site and the focal response location in the cortex. This method of array fabrication is suitable for acute suprachoroidal stimulation, and has a potential use for the fabrication of a visual prosthesis. 23588935 Natural immune responses against eight oncogenic human papillomaviruses in the ASCUS-LSIL Triage Study. Only a subset of women with human papillomavirus (HPV) infections will become seropositive, and the factors influencing seroconversion are not well understood. We used a multiplex serology assay in women with mildly abnormal cytology results to examine seroreactivity to oncogenic HPV genotypes. An unbiased subset of women in the atypical squamous cell of undetermined significance /low-grade squamous intraepithelial lesion Triage Study provided blood samples at trial enrollment for serological testing. A Luminex assay based on glutathione s-transferase-L1 fusion proteins as antigens was used to test seroreactivity against eight carcinogenic HPV genotypes (16, 18, 31, 33, 35, 45, 52 and 58). We analyzed the relationship between seroprevalence in women free of precancer (N = 2,464) and HPV DNA status, age, sexual behavior and other HPV-related risk factors. The overall seroprevalence was 24.5% for HPV16 L1 and ∼20% for 18L1 and 31L1. Among women free of precancer, seroprevalence peaked in women less than 29 years and decreased with age. Type-specific seroprevalence was associated with baseline DNA detection for HPV16 (OR = 1.36, 95%CI: 1.04-1.79) and HPV18 (OR = 2.31, 95%CI: 1.61-3.32), as well as for HPV52 and HPV58. Correlates of sexual exposure were associated with increased seroprevalence across most genotypes. Women who were current or former smokers were less likely to be seropositive for all eight of the tested oncogenic genotypes. The multiplex assay showed associations between seroprevalence and known risk factors for HPV infection across nearly all tested HPV genotypes but associations between DNA- and serostatus were weak, suggesting possible misclassification of the participants' HPV serostatus. 23864648 Pseudomonas in augmented care: should we worry? The problem of Pseudomonas as a nosocomial pathogen is not new, with some authors dating its onset to the start of the antimicrobial era, although other factors, such as the growth of intensive or augmented care, have a part to play. This paper outlines the historical and environmental issues that may be associated with a potential increase in the incidence of this difficult-to-treat pathogen. 23930753 Infection of chickens with antimicrobial-resistant Salmonella enterica Typhimurium DT193 and monophasic Salmonella Typhimurium-like variants: an emerging risk to the poultry industry? Antimicrobial-resistant Salmonella enterica poses a particular risk to public health, and in particular isolates belonging to clonal lineages such as Salmonella Typhimurium DT104 cause epidemics across species including poultry. In recent years, antimicrobial-resistant S. Typhimurium DT193 and specifically the monophasic S. Typhimurium-like variants of this phage type, serotypes 4,12:i:- and 4,5,12:i:-, have become an increasing risk to public health in Europe and the USA and now account for nearly one-half of human S. Typhimurium infections in the UK. Unlike S. Typhimurium that possesses two forms of flagella which can vary between phase 1 and phase 2 during infection, monophasic variants possess only phase 1 flagella. These monophasic antimicrobial-resistant variants have become a major problem in pig production but human cases have also been associated with poultry consumption and have been found in UK flocks through surveillance schemes since 2010. In this study we determined the ability of antimicrobial-resistant DT193 serotype 4,12:i:- and 4,5,12:i:- isolates from pigs to infect chickens. All isolates were found to colonize the caeca and liver. All but one isolate of serotype 4,5,12:i:- also infected the spleen. Levels of infection and pathology were comparable with those found with the virulent S. Typhimurium isolate 4/74. These findings indicate that both S. Typhimurium DT193 and monophasic variants of this phage type usually associated with pigs are capable of colonizing the chicken. This shows that both S. Typhimurium DT193 and monophasic variants represent a significant and potential emerging threat to poultry production from "spill-over" of these isolates from the pig industry or other sources. 23944784 News in brief. A roundup of the latest nursing news. 23665382 NFATc2 recruits cJun homodimers to an NFAT site to synergistically activate interleukin-2 transcription. Transcription of interleukin-2 (IL-2), a pivotal cytokine in the mammalian immune response, is induced by NFAT and AP-1 transcriptional activators in stimulated T cells. NFATc2 and cJun drive high levels of synergistic human IL-2 transcription, which requires a unique interaction between the C-terminal activation domain of NFATc2 and cJun homodimers. Here we studied the mechanism by which this interaction contributes to synergistic activation of IL-2 transcription. We found that NFATc2 can recruit cJun homodimers to the -45 NFAT element, which lacks a neighboring AP-1 site. The bZip domain of cJun is sufficient to interact with the C-terminal activation domain of NFATc2 in the absence of DNA and this interaction is inhibited by AP-1 DNA. When the -45 NFAT site was replaced by either an NFAT/AP-1 composite site or a single AP-1 site the specificity for cJun homodimers in synergistically activating IL-2 transcription was lost, and cJun/cFos heterodimers strongly activated transcription. These studies support a model in which IL-2 transcriptional synergy is mediated by the unique recruitment of a cJun homodimer to the -45 NFAT site by NFATc2, where it acts as a co-activator for IL-2 transcription. 23598454 HIV Cure: Knocking on the Door. Although major advances in drug development and public health are helping to control the HIV/AIDS epidemic, there is a strong rationale for pursuing a more definitive cure. Several bold but unproven strategies for HIV eradication are reviewed in this issue of CPT, including novel drugs, gene therapy, and bone marrow transplantation (BMT). Early results, including one probable case of HIV eradication in a leukemia patient, are intriguing but raise many questions. 23837699 Morphology and composition of the spider major ampullate gland and dragline silk. Spider silk is made of unique proteins-spidroins-secreted and stored as a protein solution (dope) in specialized glands. The major ampullate gland, source of the dragline silk, is composed of a tail, a sac and an elongated duct. For this gland, several different types of epithelial cells and granules have been described, but it is largely unknown how they correlate with spidroin production. It is also not settled what parts of the large spidroins end up in the final silk, and it has been suggested that the N-terminal domain (NT) is lacking. Here we show that NT is present in the dope and throughout dragline silk fibers, including the skin layer, and that the major ampullate tail and sac consist of three different and sharply demarcated zones (A-C), each with a distinct epithelial cell type. Finally, we show that spidroins are produced in the A and B zone epithelia, while the C zone granules lack spidroins. 23842200 Cognitive deficits in unipolar old-age depression: a population-based study. There is substantial variability in the degree of cognitive impairment among older depressed persons. Inconsistencies in previous findings may be due to differences in clinical and demographic characteristics across study samples. We assessed the influence of unipolar depression and severity of depression on cognitive performance in a population-based sample of elderly persons aged ⩾60 years. Method Eighty-nine persons fulfilled ICD-10 criteria for unipolar depression (mild, n = 48; moderate, n = 38; severe, n = 3) after thorough screening for dementia (DSM-IV criteria), psychiatric co-morbidities and antidepressant pharmacotherapy. Participants (n = 2486) were administered an extensive cognitive test battery. Moderate/severe unipolar depression was associated with poorer performance on tasks assessing processing speed, attention, executive function, verbal fluency, episodic memory and vocabulary. Mild depression was associated with poorer performance in processing speed, and few differences between mild and moderate/severe depression were observed. No association between depression and short-term memory, general knowledge or spatial ability was observed. Increasing age did not exacerbate the depression-related cognitive deficits, and the deficits remained largely unchanged after excluding persons in a preclinical phase of dementia. Furthermore, depression-related cognitive deficits were not associated with other pharmacological treatments that may affect cognitive performance. Cognitive deficits in unipolar old-age depression involve a range of domains and the cognitive deficits seem to follow the spectrum of depression severity. The finding that mild depression was also associated with poorer cognitive functioning underscores the importance of detecting mild depression in elderly persons. 23824487 Asymmetric pedunculopontine network connectivity in parkinsonian patients with freezing of gait. Freezing of gait is one of the most debilitating symptoms in Parkinson's disease as it causes falls and reduces mobility and quality of life. The pedunculopontine nucleus is one of the major nuclei of the mesencephalic locomotor region and has neurons related to anticipatory postural adjustments preceding step initiation as well as to the step itself, thus it may be critical for coupling posture and gait to avoid freezing. Because freezing of gait and postural impairments have been related to frontal lesions and frontal dysfunction such as executive function, we hypothesized that freezing is associated with disrupted connectivity between midbrain locomotor regions and medial frontal cortex. We used diffusion tensor imaging to quantify structural connectivity of the pedunculopontine nucleus in patients with Parkinson's disease with freezing of gait, without freezing, and healthy age-matched controls. We also included behavioural tasks to gauge severity of freezing of gait, quantify gait metrics, and assess executive cognitive functions to determine whether between-group differences in executive dysfunction were related to pedunculopontine nucleus structural network connectivity. Using seed regions from the pedunculopontine nucleus, we were able to delineate white matter connections between the spinal cord, cerebellum, pedunculopontine nucleus, subcortical and frontal/prefrontal cortical regions. The current study is the first to demonstrate differences in structural connectivity of the identified locomotor pathway in patients with freezing of gait. We report reduced connectivity of the pedunculopontine nucleus with the cerebellum, thalamus and multiple regions of the frontal cortex. Moreover, these structural differences were observed solely in the right hemisphere of patients with freezing of gait. Finally, we show that the more left hemisphere-lateralized the pedunculopontine nucleus tract volume, the poorer the performance on cognitive tasks requiring the initiation of appropriate actions and/or the inhibition of inappropriate actions, specifically within patients with freezing. These results support the notion that freezing of gait is strongly related to structural deficits in the right hemisphere's locomotor network involving prefrontal cortical areas involved in executive inhibition function. 23895601 Maximizing engagement in the American Psychological Association and its affiliated professional associations: 2012 annual report of the Policy and Planning Board. APA Bylaws Article XI.7 requires that the Policy and Planning Board report annually by publication to the membership and review the structure and function of the Association as a whole every fifth year. This report offers a framework for how to strategically and systematically provide a range of high-value engagement opportunities across membership cohorts and activities. The first section provides a selected overview of literature related to engagement and offers some general considerations for incorporating research into evaluating and refining member engagement activities. Next, survey findings on why individuals join membership organizations are reviewed. Finally, 10 engagement domains as a framework for designing, evaluating, and monitoring the impact of engagement initiatives and activities are presented. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23850004 Adiponectin in inflammatory and immune-mediated diseases. Circulating levels of adiponectin (APN) are reduced in obesity and associated comorbidities, with inflammation playing an important role in downregulating APN production. In contrast to obesity and metabolic disease, elevated systemic and local levels of APN are present in patients with inflammatory and immune-mediated diseases, including autoimmune and pulmonary conditions, heart and kidney failure, viral hepatitis, organ transplantation and perhaps critical illness. A positive association between inflammation and APN is usually reported in inflammatory/immune pathologies, in contrast with the negative correlation typical of metabolic disease. This review discusses the role of APN in modulation of inflammation and immunity and the potential mechanisms leading to increased levels of APN in inflammatory/immune diseases, including modification of adipose tissue physiology; relative contribution of different tissues and adipose depots; hormonal, pharmacological, nutritional and life style factors; the potential contribution of the microbiota as well as the role of altered APN clearance and release from T-cadherin-associated tissue reservoirs. Potential reasons for some of the apparently contradictory findings on the role of APN as a modulator of immunity and inflammation are also discussed, including a comparison of types of recombinant APN used for in vitro studies and strain-dependent differences in the phenotype of APN KO mice. 23558507 Controlled-dose versus fixed-dose mycophenolate mofetil for kidney transplant recipients: a systematic review and meta-analysis of randomized controlled trials. Although mycophenolate mofetil (MMF) is recommended at a fixed dose, there is increasing interest in controlled-dose (CD) MMF based on therapeutic drug monitoring. We systematically evaluated published randomized controlled trials (RCTs) on the efficacy and safety of CD versus fixed-dose MMF for kidney transplant recipients. The electronic databases Medline, Embase, and Cochrane Library (up to June 2012) were searched to identify relevant RCTs. Two reviewers independently applied the study selection criteria, examined the study quality, and extracted the data. Dichotomous measures were expressed as relative risk (RR) and continuous outcomes were expressed as weighted mean difference, both with 95% confidence intervals (CIs). All statistical analyses were performed using Review Manager 5.1.6. Four RCTs met our selection criteria and included 1755 de novo recipients. The differences between CD and fixed-dose MMF in treatment failure (RR, 0.95; 95% CI, 0.82-1.10; P=0.52), serum creatinine clearance (weighted mean difference, 2.46; 95% CI, -1.15 to 6.07; P=0.18), total gastrointestinal adverse events (RR, 1.23; 95% CI, 0.65-2.35; P=0.53), diarrhea (RR, 1.08; 95% CI, 0.92-1.25; P=0.35), anemia (RR, 1.24; 95% CI, 0.95-1.64; P=0.12), leukopenia (RR, 1.12; 95% CI, 0.93-1.35; P=0.25), thrombocytopenia (RR, 0.80; 95% CI, 0.47-1.36; P=0.41), and malignancy (RR, 0.61; 95% CI, 0.27-1.38; P=0.23) were not statistically significant. Furthermore, total infections were more frequent in the CD group (36.0% vs. 30.9%; RR, 1.16; 95% CI, 1.03-1.30; P=0.01). Based on current evidence, CD MMF administration cannot be recommended as routine practice for kidney transplant recipients. Therapeutic drug monitoring for MMF may be targeted toward high-risk recipients, who should be identified in future studies. 23385876 Selenite and tellurite form mixed seleno- and tellurotrisulfides with CstR from Staphylococcus aureus. Staphylococcus aureus CstR (CsoR-like sulfur transferase repressor) is a member of the CsoR family of transition metal sensing metalloregulatory proteins. Unlike CsoR, CstR does not form a stable complex with transition metals but instead reacts with sulfite to form a mixture of di- and trisulfide species, CstR2(RS-SR') and CstR2(RS-S-SR')n)n=1 or 2, respectively. Here, we investigate if CstR performs similar chemistry with related chalcogen oxyanions selenite and tellurite. In this work we show by high resolution tandem mass spectrometry that CstR is readily modified by selenite (SeO3(2-)) or tellurite (TeO3(2-)) to form a mixture of intersubunit disulfides and selenotrisulfides or tellurotrisulfides, respectively, between Cys31 and Cys60'. Analogous studies with S. aureus CsoR reveals no reaction with selenite and minimal reaction with tellurite. All cross-linked forms of CstR exhibit reduced DNA binding affinity. We show that Cys31 initiates the reaction with sulfite through the formation of S-sulfocysteine (RS-SO3(2-)) and Cys60 is required to fully derivatize CstR to CstR2(RS-SR') and CstR2(RS-S-SR'). The modification of Cys31 also drives an allosteric switch that negatively regulates DNA binding while derivatization of Cys60 alone has no effect on DNA binding. These results highlight the differences between CstRs and CsoRs in chemical reactivity and metal ion selectivity and establish Cys31 as the functionally important cysteine residue in CstRs. 23871165 Analysis of HHV-6 mutations in solid organ transplant recipients at the onset of cytomegalovirus disease and following treatment with intravenous ganciclovir or oral valganciclovir. Human herpesvirus 6 (HHV-6) and human cytomegalovirus (HCMV) are major opportunistic pathogens in solid organ transplant (SOT) recipients. The use of antivirals for the treatment of HCMV disease can result in the development of drug resistance mutations in HCMV and also potentially in HHV-6. The emergence of HHV-6 drug resistance mutations was evaluated in SOT recipients at the onset of HCMV disease and following treatment with ganciclovir (GCV) or valganciclovir (VGCV). Detection of HHV-6 was performed by real-time PCR from whole blood samples serially obtained from SOT recipients treated for HCMV disease with an induction dose of intravenous GCV or oral VGCV for 21 days followed by VGCV maintenance for 28 days in both arms. Baseline and last positive HHV-6 samples were tested for mutations in the genes encoding the protein kinase (U69) and the DNA polymerase (U38). The rate of HHV-6 viraemia among SOT patients with HCMV disease at baseline was 3.2% (5/155). All isolates belonged to the HHV-6B species. Mutations L213I and Y479H were detected at baseline and at later times in the U69 kinase. Mutation L213I was previously reported as polymorphism whereas the role of mutation Y479H in drug resistance is unknown. Mutations D854E and E855Q found in the DNA polymerase were known as natural variants. The incidence of HHV-6 viraemia in SOT recipients with established HCMV disease before initiation of antiviral therapy was low. Treatment with GCV or VGCV did not induce the emergence of HHV-6 drug resistance mutations. 23439383 Long-term potentiation: Peeling the onion. Since the discovery of long-term potentiation (LTP), thousands of papers have been published on this phenomenon. With this massive amount of information, it is often difficult, especially for someone not directly involved in the field, not to be overwhelmed. The goal of this review is to peel away as many layers as possible, and probe the core properties of LTP. We would argue that the many dozens of proteins that have been implicated in the phenomenon are not essential, but rather modulate, often in indirect ways, the threshold and/or magnitude of LTP. What is required is NMDA receptor activation followed by CaMKII activation. The consequence of CaMKII activation is the rapid recruitment of AMPA receptors to the synapse. This recruitment is independent of AMPA receptor subunit type, but absolutely requires an adequate pool of surface receptors. An important unresolved issue is how exactly CaMKII activation leads to modifications in the PSD to allow rapid enrichment. This article is part of a Special Issue entitled 'GluR-dep synaptic plasticity'. 23841578 Signatures of Isomerization in Photodissociation of trans- Crotonaldehyde Probed by Multiphoton Ionization Mass Spectrometry. We report the observation of new isomerization effects in the UV-photodissociation of trans-crotonaldehyde upon multiphoton excitation by the third harmonic (355 nm) pulses of a Nd:YAG laser. A time-of-flight mass spectrometric analysis reveals formation of acetaldehyde, acetyl, and methoxy radical cations as signatures of isomerization processes. A small segment of the multiphoton ionization spectrum of jet-cooled crotonaldehyde is recorded by tuning the laser frequency around 355 nm. An oxetene type transient intermediate in the ground state has been considered for acetaldehyde formation following a photochemical model suggested earlier ( Reguero ; et al. J. Am. Chem. Soc. 1994 , 116 , 2101 - 2114 ) for such compounds. Likewise, for methoxy radical formation, a trans-cis isomerization about the C═C double bond has been considered in a triplet surface. Electron ionization mass spectra of the compound are also recorded by varying the electron kinetic energy in the range 11-70 eV. Ionic fragments in the mass spectra of the two ionization processes are dramatically different. Our suggested mechanisms for isomerization and fragmentation channels are substantiated by density functional theory calculations. Combined experimental and calculated data lead us conclude that isomerization occurs in neutral potential energy surfaces prior to dissociation and photoionization. 23842134 Variations at multiple genes improve interleukin 28b genotype predictive capacity for response to therapy against hepatitis c genotype 1 or 4 infection. To identify genetic factors that predict sustained virological response (SVR) to pegylated interferon (Peg-IFN)/ribavirin (RBV) in HIV/hepatitis C virus (HCV) genotype 1 or 4-coinfected patients and that enhance the predictive capacity of IL28B genotype in this population. Prospective cohort study. Five tertiary care centers in Spain. 205 HIV/HCV genotype 1 or 4-coinfected patients who received a complete course of Peg-IFN/RBV for 48 weeks. All individuals were genotyped for 144 SNPs.Results: One hundred sixty-two (79%) patients bore HCV genotype 1. Overall SVR was achieved by 73 (36%) individuals. SNPs at the following genes were associated with SVR: IL28B, low-density lipoprotein receptor (LDLR), transforming growth factor β (TGF-β), aquaporine 2 (AQP-2), very-low-density lipoprotein receptor, Sp110 nuclear body protein, interferon alpha/beta receptor 1, 2'-5'-oligoadenylate synthase 1 and apolipoprotein B. There was a strong synergy between SNPs at IL28B, TGF-β and AQP-2 genes: the number of patients reaching SVR with all three favorable genotypes versus unfavorable genotypes were 22 (78.6%) versus 1 (7.1%) (p = 2.1*10). HCV baseline viral load, IL28B, TGF-β, AQP-2 and LDLR haplotypes were independently associated with SVR.Conclusion: A number of genetic factors modify the predictive capacity of IL28B genotype. These can be used to identify HCV genotype 1 or 4 infected patients with a very high or a very low probability to respond to bitherapy with Peg-IFN/RBV. Predictive models based on these factors could be helpful to tailor direct acting antiviral-based therapy. 23801091 A case of instantaneous rigor? The question of whether instantaneous rigor mortis (IR), the hypothetic sudden occurrence of stiffening of the muscles upon death, actually exists has been controversially debated over the last 150 years. While modern German forensic literature rejects this concept, the contemporary British literature is more willing to embrace it. We present the case of a young woman who suffered from diabetes and who was found dead in an upright standing position with back and shoulders leaned against a punchbag and a cupboard. Rigor mortis was fully established, livor mortis was strong and according to the position the body was found in. After autopsy and toxicological analysis, it was stated that death most probably occurred due to a ketoacidotic coma with markedly increased values of glucose and lactate in the cerebrospinal fluid as well as acetone in blood and urine. Whereas the position of the body is most unusual, a detailed analysis revealed that it is a stable position even without rigor mortis. Therefore, this case does not further support the controversial concept of IR. 23826821 The significance of diagnosing associated clonal mast cell diseases in patients with venom-induced anaphylaxis and the role of bone marrow investigation. Hymenoptera venom allergy (HVA) represents a particular risk for exceptionally severe anaphylactic sting reactions in patients with clonal mast cell disorders (CMD). Nevertheless, conventional investigations are not sufficient to do accurate risk assessments. Increased levels of baseline serum tryptase (sBT) (>11.4 μg/L) is highly associated with severe anaphylactic reactions and with a possible underlying CMD. The measurement of baseline serum tryptase, thus, has opened the possibility to screen for CMD. In the present study, we sought to investigate whether bone marrow evaluation provides more accurate diagnosis in patients with HVA.Three patients of the same sex and similar age with HVA were enrolled in this clinical study. The patients underwent comprehensive allergy work-up including skin prick testing, measurements of serum total IgE concentrations and baseline serum tryptase. Bone-marrow biopsies were also performed in all three patients to assess underlying CMD.We evaluated characteristics of the bone marrow mast cells by pathology, flow cytometry and detection of D816V mutation by using current WHO-criteria, which led to changes in the final diagnosis compared to the assessments done by classical allergy work-up and measurements of sBT. Three distinct diagnostic outcomes including systemic mastocytosis, monoclonal mast cell activation syndrome and non-clonal HVA were revealed.We conclude that a bone marrow investigation is required for the correct diagnosis of hymenoptera venom-induced anaphylactic reactions in patients with elevated baseline tryptase levels (>11.4 μg/L), and this has important implications for management strategies. 23643630 Tradeoffs between the strength of conformity and number of conformists in variable environments. Organisms often respond to environmental change phenotypically, through learning strategies that enhance fitness in variable and changing conditions. But which strategies should we expect in population exposed to those conditions? We address this question by developing a mathematical model that specifies the consequences of different mixtures of individual and social learning strategies on the frequencies of different cultural variants in temporally and spatially changing environments. Assuming that alternative cultural variants are differently well-adapted to diverse environmental conditions, we are able to evaluate which mixture of learning strategies maximises the mean fitness of the population. We find that, even in rapidly changing environments, a high proportion of the population will always engage in social learning. In those environments, the highest adaptation levels are achieved through relatively high fractions of individual learning and a strong conformist bias. We establish a negative relationship between the proportion of the population learning socially and the strength of conformity operating in a population: strong conformity requires fewer conformists (i.e. larger proportion of individual learning), while many conformists can only be found when conformist transmission is weak. Investigations of cultural diversity show that in frequently changing environments high levels of adaptation require high level of cultural diversity. Finally, we demonstrate how the developed mathematical framework can be applied to time series of usage or occurrence data of cultural traits. Using Approximate Bayesian Computation we are able to infer information about the underlying learning processes that could have produced observed patterns of variation in the dataset. 23008002 Extractive biodecolorization of triphenylmethane dyes in cloud point system by Aeromonas hydrophila DN322p. The biological treatment of triphenylmethane dyes is an important issue. Most microbes have limited practical application because they cannot completely detoxicate these dyes. In this study, the extractive biodecolorization of triphenylmethane dyes by Aeromonas hydrophila DN322p was carried out by introducing the cloud point system. The cloud point system is composed of a mixture of nonionic surfactants (20 g/L) Brij 30 and Tergitol TMN-3 in equal proportions. After the decolorization of crystal violet, a higher wet cell weight was obtained in the cloud point system than that of the control system. Based on the results of thin-layer chromatography, the residual crystal violet and its decolorized product, leuco crystal violet, preferred to partition into the coacervate phase. Therefore, the detoxification of the dilute phase was achieved, which indicated that the dilute phase could be discharged without causing dye pollution. The extractive biodecolorization of three other triphenylmethane dyes was also examined in this system. The decolorization of malachite green and brilliant green was similar to that of crystal violet. Only ethyl violet achieved a poor decolorization rate because DN322p decolorized it via adsorption but did not convert it into its leuco form. This study provides potential application of biological treatment in triphenylmethane dye wastewater. 23915002 Multilocus patterns of genetic variation across Cryptosporidium species suggest balancing selection at the gp60 locus. Cryptosporidium is an apicomplexan protozoan that lives in most vertebrates, including humans. Its gp60 gene is functionally involved in its attachment to host cells, and its high level of genetic variation has made it the reference marker for sample typing in epidemiological studies. To understand the origin of such high diversity and to determine the extent to which this classification applies to the rest of the genome, we analysed the patterns of variation at gp60 and nine other nuclear loci in isolates of three Cryptosporidium species. Most loci showed low genetic polymorphism (πS <1%) and similar levels of between-species divergence. Contrastingly, gp60 exhibited very different characteristics: (i) it was nearly ten times more variable than the other loci; (ii) it displayed a significant excess of polymorphisms relative to between-species differences in a maximum-likelihood Hudson-Kreitman-Aguadé test; (iii) gp60 subtypes turned out to be much older than the species they were found in; and (iv) showed a significant excess of polymorphic variants shared across species from random expectations. These observations suggest that this locus evolves under balancing selection and specifically under negative frequency-dependent selection (FDS). Interestingly, genetic variation at the other loci clusters very well within the groups of isolates defined by gp60 subtypes, which may provide new tools to understand the genome-wide patterns of genetic variation of the parasite in the wild. These results suggest that gp60 plays an active and essential role in the life cycle of the parasite and that genetic variation at this locus might be essential for the parasite's long-term success. 23907777 Application of the anatomical method to estimate the maximum adult stature and the age-at-death stature. This study focuses on the age adjustment of statures estimated with the anatomical method. The research material includes 127 individuals from the Terry Collection. The cadaveric stature (CSTA)-skeletal height (SKH) ratios indicate that stature loss with age commences before SKH reduction. Testing three equations to estimate CSTA at the age at death and CSTA corrected to maximum stature from SKH indicates that the age correction of stature should reflect the pattern of age-related stature loss to minimize estimation error. An equation that includes a continuous and linear age correction through the entire adult age range [Eq. (1)] results in curvilinear stature estimation error. This curvilinear stature estimation error can be largely avoided by applying a second linear equation [Eq. (2)] to only individuals older than 40 years. Our third equation [Eq. (3)], based on younger individuals who have not lost stature, can be used to estimate maximum stature. This equation can also be applied to individuals of unknown or highly uncertain age, because it provides reasonably accurate estimates until about 60/70 years at least for males. Am J Phys Anthropol, 2013. © 2013 Wiley Periodicals, Inc. 23237625 Enhancement of electrical and thermomechanical properties of silver nanowire composites by the introduction of nonconductive nanoparticles: experiment and simulation. Electrically conductive polymer nanocomposites have been applied extensively in many fields to develop the next generation of devices. Large amounts of conductive nanofillers in polymer matrices are, however, often required for a sufficiently high electrical conductivity, which in turn deteriorates the desired thermomechanical properties. We illustrate a novel but facile strategy to improve the electrical conductivity and the thermomechanical property of silver nanowire/polymer nanocomposites. We find that one may increase the electrical conductivity of silver nanowire/polymer nanocomposites by up to about 8 orders of magnitude by introducing silica nanoparticles with nanocomposites. The electrical percolation threshold volume fraction of silver nanowires decreases from 0.12 to 0.02. Thermomechanical properties also improve as silica nanoparticles are introduced. We carry out extensive Monte Carlo simulations to elucidate the effects of silica nanoparticles at a molecular level and find that van der Waals attractive interaction between silica nanoparticles and silver nanowires dominates over the depletion-induced interaction between silver nanowires, thus improving the dispersion of silver nanowires. Without silica nanoparticles, silver nanowires tend to aggregate, which is why additional silver nanowires are required for a desired electrical conductivity. On the other hand, with silica nanoparticles mixed, the electrical percolating network is likely to form at a smaller volume fraction of silver nanowires. 23319051 Impaired in vitro erythropoiesis following deletion of the Scl (Tal1) +40 enhancer is largely compensated for in vivo despite a significant reduction in expression. The Scl (Tal1) gene encodes a helix-loop-helix transcription factor essential for hematopoietic stem cell and erythroid development. The Scl +40 enhancer is situated downstream of Map17, the 3' flanking gene of Scl, and is active in transgenic mice during primitive and definitive erythropoiesis. To analyze the in vivo function of the Scl +40 enhancer within the Scl/Map17 transcriptional domain, we deleted this element in the germ line. Scl(Δ40/Δ40) mice were viable with reduced numbers of erythroid CFU in both bone marrow and spleen yet displayed a normal response to stress hematopoiesis. Analysis of Scl(Δ40/Δ40) embryonic stem (ES) cells revealed impaired erythroid differentiation, which was accompanied by a failure to upregulate Scl when erythropoiesis was initiated. Map17 expression was also reduced in hematopoietic tissues and differentiating ES cells, and the Scl +40 element was able to enhance activity of the Map17 promoter. However, only Scl but not Map17 could rescue the Scl(Δ40/Δ40) ES phenotype. Together, these data demonstrate that the Scl +40 enhancer is an erythroid cell-specific enhancer that regulates the expression of both Scl and Map17. Moreover, deletion of the +40 enhancer causes a novel erythroid phenotype, which can be rescued by ectopic expression of Scl but not Map17. 23645163 Possible involvement of PPAR-γ in the anticonvulsant effect of Aegle marmelos (L.) Correa. Aegle marmelos is well documented for antihyperglycemic effect and PPAR-γ activation has been suggested to be the molecular mechanism of its action. Also, the plant has been used in Ayurveda as a brain tonic and has been postulated to have antidepressant activities. The present study was designed to investigate the anticonvulsant effects of A. marmelos leaf extract (AME) in pentylenetetrazole and maximal electroshock induced convulsions; involvement of PPAR-γ, nitric oxide pathway and effect of chronic AME treatment on post-ictal depression. AME was administered at doses of 50, 100 and 200 mg kg(-1) in PTZ and MES model. Severity of convulsions was noted in both the models. Pretreatment with bisphenol A diglycidyl ether (BADGE) was used to study the involvement of PPAR-γ and L-arginine and N-nitro-L-arginine methyl ester hydrochloride (L-NAME) to study the involvement of nitric oxide (NO). Chronic treatment with AME interspersed with sub maximal doses of PTZ (50 mg kg(-1)) on every fifth day up to 15 days was given to study post-ictal depression using forced swimming and actophotometer. AME showed significant increase in the onset time and decrease in the duration of convulsions in PTZ and MES models dose dependently. In MES a dose of 100 mg kg(-1) had effect comparable to phenytoin. Pretreatment with BADGE and L-arginine reversed the protective effect while L-NAME did not alter the protective effect, thereby indicating possible involvement of PPAR-γ and inhibition of NO. Chronic AME treatment ameliorated the post-seizure depression significantly as evidenced by increase in the locomotor activity and decrease in the immobility time. 23899749 The ASCOD Phenotyping of Ischemic Stroke (Updated ASCO Phenotyping). ASCO phenotyping (A: atherosclerosis; S: small-vessel disease; C: cardiac pathology; O: other causes) assigns a degree of likelihood of causal relationship to every potential disease (1 for potentially causal, 2 for causality is uncertain, 3 for unlikely causal but the disease is present, 0 for absence of disease, and 9 for insufficient workup to rule out the disease) commonly encountered in ischemic stroke describing all underlying diseases in every patient. In this new evolution of ASCO called ASCOD, we have added a 'D' for dissection, recognizing that dissection is a very frequent disease in young stroke patients. We have also simplified the system by leaving out the 'levels of diagnostic evidence', which has been integrated into grades 9 and 0. Moreover, we have also changed the cutoff for significant carotid or intracranial stenosis from 70% to more commonly used 50% luminal stenosis, and added a cardiogenic stroke pattern using neuroimaging. ASCOD captures and weights the overlap between all underlying diseases present in ischemic stroke patients. © 2013 S. Karger AG, Basel. 23821573 Sugar nucleotide quantification using multiple reaction monitoring liquid chromatography/tandem mass spectrometry. Glycosylation of proteins and lipids is reliant on the availability of monosaccharide-activated donors known as sugar nucleotides. They are responsible for glycosylation in cells. Reliable quantification of these sugar nucleotides might provide an insight into their biological roles and attributes. Herein, a method is described for the quantification of sugar nucleotides using ultra high pressure liquid chromatography (UHPLC) tandem mass spectrometry, allowing selective detection of sugar nucleotides in a biological sample. Seven model sugar nucleotide standards commonly associated with lipid and protein glycosylation were separated on a porous graphitic carbon column using an UHPLC system coupled to a triple stage quadrupole mass spectrometer utilizing a multiple reaction monitoring approach. Successful baseline separation of these metabolites was attained in 6 min using an ammonium formate buffer and acetonitrile, circumventing the use of MS-unfriendly pairing reagents. The linear dynamic range of this procedure was established over almost three orders of magnitude from 20 pg to 1 ng (40 pg to 2 ng for the isomers UDP-GlcNAc/GalNAc). The limit of detection ranged from 15 pg to 30 pg while the limit of quantification ranged from 50 pg to 100 pg. Furthermore, viability of this method was tested using three different breast cancer cell lines (MDA-MB-231, MDA-MB-231-BR, and MDA-MB-361) with the successful identification and quantification of all seven targeted sugar nucleotides. The described method permitted the quantitative analysis of sugar nucleotides in 10 min, thus allowing the practical use of this approach in high-throughput settings. The method was also very effective for the quantification of sugar nucleotides derived from three different breast cancer cell lines. The distribution of sugar nucleotides was different among the different cell lines and unique for each cell line. 23572393 Attenuation of erythrocytic actylcholinesterase by antidepressants: Evidence in an in vitro experiment. The current study was aimed to scrutinize acetylcholinesterase (AchE) inhibitory profile of two antidepressants, diazepam and phenobarbitone. The experimental designed was based on Michaelis-Menten parameters (apparent Michaelis constant (aKm) and apparent maximum velocity (aVm)) that estimate inhibition (%) as well as the type of inhibition (mechanism). The results showed marked inhibition of AchE by diazepam and the values of aKm and aVm were 65.5% and 52.63%, respectively. These values suggested a competitive type of antagonism for diazepam. Similar trend of antagonism was shown by phenobarbitone when it was subjected to the challenge of AchE with aKm and aVm values of 51.99% and 71.80%, respectively. It is concluded that diazepam and phenobarbitone exhibited prominent AchE attenuation apart from their well-established antidepressant activity, which could be more useful in related diseased conditions. 23969894 Comparing the optical properties of soft contact lenses on and off the eye. The purpose of the current study was to examine the on- and off-eye optical performance of two types of soft contact lenses (hydrogel and silicone hydrogel). The monochromatic aberrations (λ = 850 nm) of contact lenses were measured on-eye using a clinical Shack-Hartmann ocular aberrometer. In addition, we used an off-eye single-pass contact lens aberrometer (λ = 540 nm) in which the soft contact lens was placed within a wet cell. Comparison of the lower and higher order aberrations measured with these two methods required compensation for different wavelengths and knowledge of the refractive index of the contact lens materials. The measured on-eye sphere and spherical aberration values were generally similar to those measured off-eye and those specified by the lens manufacturers for both types of soft contact lenses. However, there were notable differences, especially for high plus-powered lenses, which typically exhibited lower sphere power on the eye than expected from the lens specifications and from the off-eye measured powers, both of which were almost identical. Longitudinal spherical aberration varied with lens power in the hydrogel lenses, as expected from geometric optics theory. Longitudinal spherical aberration measurements on- and off-eye, however, deviated significantly from that expected of a thin lens with spherical surfaces due to surface asphericities. The difference between on- and off-eye optics can be modeled as a tear lens or as relative lens thickness changes caused by lens flexure. The results of the current study reveal that the major difference between the on-eye lens optics and the manufacturers' specifications is not due to lens errors but due to eye-lens interactions, which could be either lens flexure or a tear lens forming behind the soft contact lens. 23727557 An electrochemiluminescence assay for gp340 (DMBT1). Gp340 is a member of the scavenger receptor cysteine-rich family of innate immune molecules and also functions as a tumor suppressor. This study describes a picogram-level assay using electrochemiluminescence technology on the MesoScale Discovery platform. Antibodies were evaluated and the best pair was used to assay whole-mouth stimulated saliva and cervical/vaginal lavage. The assay was tested using specimens obtained from healthy volunteers to determine if gp340 concentration in saliva correlates with levels in vaginal lavage fluid. Interestingly, no correlation was determined between gp340 content in these two fluids. 23952326 Comparison of insulin degludec with insulin glargine in insulin-naive subjects with Type 2 diabetes: a 2-year randomized, treat-to-target trial. The aim of this study was to compare long-term safety and efficacy of the basal insulin analogue degludec with glargine in insulin-naive subjects with Type 2 diabetes. This open-label trial included a 52-week core period followed by a 52-week extension. Participants were randomized 3:1 to once-daily degludec or glargine, administered with metformin ± dipeptidyl peptidase-4 inhibitors. Basal insulin was titrated to target pre-breakfast plasma glucose 3.9-4.9 mmol/l. At end of treatment (104 weeks), mean HbA1c reductions were similar for degludec and glargine; estimated treatment difference between degludec and glargine was 1 mmol/mol (95% CI -1 to 3) [0.07% (95% CI -0.07 to 0.22)], P = 0.339 in the extension trial set (degludec 551, glargine 174), comprising subjects who completed core trial and continued into the extension trial. Overall confirmed hypoglycaemia rates (1.72 vs. 2.05 episodes/patient-year), rates of adverse events possibly or probably related to trial product (0.19 events/patient-year), weight gain (2.7 vs. 2.4 kg) and mean daily insulin doses (0.63 U/kg) were similar between treatments in the safety analysis set (degludec 766, glargine 257) comprising all treated subjects. Rates of nocturnal confirmed hypoglycaemia (0.27 vs. 0.46 episodes/patient-year; P = 0.002) and severe hypoglycaemia (0.006 vs. 0.021 episodes/patient-year, P = 0.023) were significantly lower with degludec for the safety analysis set (analysis based on intention-to-treat full analysis set comprising all randomized subjects). In Type 2 diabetes, insulin degludec in combination with oral anti-diabetic drugs, safely and effectively improves long-term glycaemic control, with a significantly lower risk of nocturnal hypoglycaemia as compared with glargine. This article is protected by copyright. All rights reserved. 23796417 Separation of closely eluting chloronaphthalene congeners by two-dimensional gas chromatography/quadrupole mass spectrometry: An advanced tool in the study and risk analysis of dioxin-like chloronaphthalenes. Two capillary columns of different polarity were applied in a two-dimensional gas chromatography system coupled to a quadrupole mass spectrometric detection (GCxGC/qMS) in order to separate and identify all of the possible 22 isomers of tetra-, 14 of penta- and 10 of hexachloronaphthalene that may occur in selected industrial chemicals. The two-dimensional GCxGC separation was achieved using Rt-β DEXcst and DB-WAX phases, and data imaging was done by 2D and 3D mapping. This combination allows for the analysis of all tetra- to hexachloronaphthalene congeners in a single instrumental run without any pre-separation or fractionation of the analytes. The novel methodology described here can assist in the accurate determination and expression of dioxin-like toxicity of tetrachloronaphthalenes to octachloronaphthalene that are usually present as mixtures at least in abiotic materials such as technical chloronaphthalene formulations (e.g. Halowax mixtures), and wastes containing Halowaxes and other CN formulations. 23852674 The Rate of Energy Dissipation Determines Probabilities of Non-equilibrium Assemblies. Outside thermodynamic equilibrium, outcomes of self-assembly can be dictated not by energy but by the energy dissipation rate. Remarkably, non-equilibrium self-assembly can lead to both low- and high-dissipation structures. The latter, thermodynamically more wasteful structures are exponentially less probable with increasing dissipation rate. This dependence is quantified in a Boltzmann-like relation for non-equilibrium systems. 23756260 Synthesis, spectroscopic and structural characterization of 5-benzoyl-4-phenyl-2-methylthio-1H-pyrimidine with theoretical calculations using density functional theory. In this paper, we will report a combined experimental and theoretical investigation of the molecular structure and spectroscopic parameters (FT-IR, (1)H NMR, (13)C NMR) of 5-benzoyl-4-phenyl-2-methylthio-1H-pyrimidine. The compound crystallizes in the triclinic space group P-1 with Z=2. The molecular geometry was also optimized using density functional theory (DFT/B3LYP) method with the 6-311G(d,p) and 6-311++G(d,p) basis sets in ground state and compared with the experimental data. All the assignments of the theoretical frequencies were performed by potential energy distributions using VEDA 4 program. Information about the size, shape, charge density distribution and site of chemical reactivity of the molecules has been obtained by mapping electron density isosurface with electrostatic potential (ESP). Also, non-linear optical properties of the title compound were performed at B3LYP/6-311++G(d,p) level. The theoretical results showed an excellent agreement with the experimental values. 23873766 Introduction of fluorine and fluorine-containing functional groups. Over the past decade, the most significant, conceptual advances in the field of fluorination were enabled most prominently by organo- and transition-metal catalysis. The most challenging transformation remains the formation of the parent CF bond, primarily as a consequence of the high hydration energy of fluoride, strong metal-fluorine bonds, and highly polarized bonds to fluorine. Most fluorination reactions still lack generality, predictability, and cost-efficiency. Despite all current limitations, modern fluorination methods have made fluorinated molecules more readily available than ever before and have begun to have an impact on research areas that do not require large amounts of material, such as drug discovery and positron emission tomography. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field. 23944817 Private finance initiative is to blame for the crisis at barts. I am not surprised that Barts Health NHS Trust - the largest in the UK - is looking to cut its spending on agency nursing (News August 7). It faced a £70 million wage bill for its bank and agency staff last year. 23692689 Activation and involvement of the lateral-posterior nucleus of the thalamus after a single generalized tonic-clonic seizure. The lateral-posterior thalamic nuclei (LP) have been shown to play an important role in controlling epileptic activity. In addition, thalamic atrophy and neuronal loss have been observed in epilepsy. The objective of this study was to investigate whether lateral-posterior neuronal activation may be observed shortly after a single generalized seizure in rats submitted to the pilocarpine model of epilepsy. The results showed an increased lateral-posterior activation as soon as the seizure occurred, suggesting that neuronal loss in the thalamus is not only the consequence of chronic epilepsy. 23786168 pH-Dependent Conformational Ensemble and Polymorphism of Amyloid-β Core Fragment. Characterization of amyloid oligomeric species is important due to its possible responsibility for the toxicity of amyloid proteins, whereas it is difficult to detect by current spectroscopic techniques. The pH-dependent tetramerization and fibrillation of the central hydrophobic segment of Alzheimer amyloid β-peptide (Aβ12-24) were respectively explored by all-atom replica exchange molecular dynamics simulations and by fluorescence and atomic force microscopy measurements. Our combined study shows that more β-sheet structures in the early event of tetramerization is linked directly to the high propensity to form amyloid fibrils in the consequent fibrillation. Both tetramerization and fibrillation are strongly regulated by pH. At pH 5.0, Aβ12-24 has two opposite terminal charges. The electrostatic attraction between the side-chains of His13/His14 and Glu22/Asp23 thus acts as a "pattern keeper", resulting in high propensity of amyloid formation. These results suggest that pH effects most likely by affecting the ionization properties of the Aβ12-24 peptide. Specifically, the pH-dependent equilibrium conformational distribution of different aggregate species are well-investigated in detail. Our findings also give hints to other experimental findings that the kinetics and morphologies of Aβ fibril formation are strongly pH-dependent. 23748423 Nicotine potentiates proatherogenic effects of oxLDL by stimulating and upregulating macrophage CD36 signaling. Cigarette smoking is a major risk factor for atherosclerosis and cardiovascular disease. CD36 mediates oxidized LDL (oxLDL) uptake and contributes to macrophage foam cell formation. We investigated a role for the CD36 pathway in nicotine-induced activation of macrophages and foam cell formation in vitro and in vivo. Nicotine in the same plasma concentration range found in smokers increased the CD36(+)/CD14(+) cell population in human peripheral blood mononuclear cells, increased CD36 expression of human THP1 macrophages, and increased macrophage production of reactive oxygen species, PKCδ phosphorylation, and peroxisome proliferator-activated receptor-γ (PPARγ) expression. Nicotine-induced CD36 expression was suppressed by antioxidants and by specific PKCδ and PPARγ inhibitors, implicating mechanistic roles for these intermediates. Nicotine synergized with oxLDL to increase macrophage expression of CD36 and cytokines TNF-α, monocyte chemoattractant protein-1, IL-6, and CXCL9, all of which were prevented by CD36 small interfering (si)RNA. Incubation with oxLDL (50 μg/ml) for 72 h resulted in lipid deposition in macrophages and foam cell formation. Preincubation with nicotine further increased oxLDL-induced lipid accumulation and foam cell formation, which was also prevented by CD36 siRNA. Treatment of apoE(-/-) mice with nicotine markedly exacerbated inflammatory monocyte levels and atherosclerotic plaque accumulation, effects that were not seen in CD36(-/-) apoE(-/-) mice. Our results show that physiological levels of nicotine increase CD36 expression in macrophages, a pathway that may account at least in part for the known proinflammatory and proatherogenic properties of nicotine. These results identify such enhanced CD36 expression as a novel nicotine-mediated pathway that may constitute an independent risk factor for atherosclerosis in smokers. The results also suggest that exacerbated atherogenesis by this pathway may be an adverse side effect of extended use of high concentrations of nicotine independent of their mode of administration. 22829353 Modeling the connection between primary and metastatic tumors. We put forward a model for cancer metastasis as a migration phenomenon between tumor cell populations coexisting and evolving in two different habitats. One of them is a primary tumor and the other one is a secondary or metastatic tumor. The evolution of the different cell phenotype populations in each habitat is described by means of a simple quasispecies model allowing for a cascade of mutations between the different phenotypes in each habitat. The cell migration event is supposed to be unidirectional and take place continuously in time. The possible clinical outcomes of the model depending on the parameter space are analyzed and the effect of the resection of the primary tumor is studied. 23820667 Adjustable tricuspid annuloplasty. The methods for repairing functional tricuspid regurgitation (TR) are still controversial. A novel concept of tricuspid annuloplasty for functional TR was developed. A flexible annuloplasty band, through which an expanded polytetrafluoroethylene (ePTFE) thread (CV3) was passed inside the cover cloth, was secured to the tricuspid annulus. Both ends of the ePTFE thread were passed through the right atrial wall. The thread was snared from outside the ejecting heart under observation by a transoesophageal echocardiogram after weaning off the cardiopulmonary bypass. We used this technique in 11 patients with functional TR (mean TR grade: 3.4 ± 0.8). The mean circumference of the annulus after snaring was 86.5 ± 4.6 mm (diameter 27.6 ± 1.5 mm). The postoperative TR at discharge was trivial or 0 in 9 patients and Grade 1 in 2. We concluded that this method has the potential to minimize residual regurgitation. 23760245 NS1' Colocalizes with NS1 and Can Substitute for NS1 in West Nile Virus Replication. NS1' is a C-terminally extended form of the NS1 protein produced only by encephalitic flaviviruses from the Japanese encephalitis virus serogroup. Here we show that West Nile virus (WNV) NS1' and NS1 localize to the same cellular compartments when expressed from plasmid DNAs and also colocalize to viral RNA replication sites in infected cells. Using complementation analysis with NS1-deleted WNV cDNA, we demonstrated that NS1' is able to substitute for the crucial function of NS1 in virus replication. 23411228 Hydroxytyrosyl ethyl ether exhibits stronger intestinal anticarcinogenic potency and effects on transcript profiles compared to hydroxytyrosol. The anticarcinogenic activity of hydroxytyrosyl ethyl ether (HTy-Et) compared to its precursor hydroxytyrosol (HTy) has been studied in human Caco-2 colon adenocarcinoma cells. 451 and 977 genes were differentially expressed in Caco-2 cells exposed to HTy or HTy-Et for 24h, respectively, compared with untreated cells (P<0.005; FDR=0), using Affymetrix microarrays. Results showed that both HTy and HTy-Et inhibited cell proliferation and arrested the cell cycle by up-regulating p21 and CCNG2 and down-regulating CCNB1 protein expression. HTy and HTy-Et also altered the transcription of specific genes involved in apoptosis, as suggested by the up-regulation of BNIP3, BNIP3L, PDCD4 and ATF3 and the activation of caspase-3. Moreover, these polyphenols up-regulated xenobiotic metabolizing enzymes UGT1A10 and CYP1A1, enhancing carcinogen detoxification. In conclusion, these results highlight that HTy and its derivative HTy-Et modulate molecular mechanisms involved in colon cancer, with HTy-Et being more effective than HTy. 23837866 Role of hydrophobicity in adhesion of wild yeast isolated from the ultrafiltration membranes of an apple juice processing plant. The role of cell surface hydrophobicity in the adhesion to stainless steel (SS) of 11 wild yeast strains isolated from the ultrafiltration membranes of an apple juice processing plant was investigated. The isolated yeasts belonged to four species: Candida krusei (5 isolates), Candida tropicalis (2 isolates), Kluyveromyces marxianus (3 isolates) and Rhodotorula mucilaginosa (1 isolate). Surface hydrophobicity was measured by the microbial adhesion to solvents method. Yeast cells and surfaces were incubated in apple juice and temporal measurements of the numbers of adherent cells were made. Ten isolates showed moderate to high hydrophobicity and 1 strain was hydrophilic. The hydrophobicity expressed by the yeast surfaces correlated positively with the rate of adhesion of each strain. These results indicated that cell surface hydrophobicity governs the initial attachment of the studied yeast strains to SS surfaces common to apple juice processing plants. 23887713 Prognostic significance of phospho-histone H3 in prostate carcinoma. Prostate cancer is the second most common cancer in men and the sixth most common cause of death from cancer in men worldwide. Currently, a sufficient pathological distinction between patients requiring further treatment and those for which active surveillance remains an option is still lacking, which leads to the problem of overtreatment. Cell proliferation is routinely assessed by detecting Ki-67 antigen. While Ki-67 is expressed throughout the interphase of proliferating cells, phosphorylation of the chromatin constituent histone H3 occurs only during the late G2 phase and mitosis thus providing a more strict assessment of the mitotic activity. We undertook this study to test whether expression of the recently introduced proliferation marker phospho-histone H3 (pHH3) in prostate carcinoma tissue sections exhibits prognostic significance in comparison with Ki-67. Protein expression of pHH3 and Ki-67 was assessed on TMA consisting of paraffin-embedded tissue from men that had undergone radical prostatectomy. The analysis included triplicate tissue cores of a total of 339 tumor foci. Immunohistochemical staining of pHH3 and Ki-67 was performed and analyzed using Definiens imaging software. Prostate cancer tissue exhibited a significantly higher frequency of pHH3-positive cells compared to benign prostate tissue. pHH3 expression was significantly correlated with Ki-67 expression. Furthermore, statistical analysis revealed positive correlation between pHH3 expression and PSA levels at diagnosis and in addition negatively correlated with overall survival. In contrast to Ki-67 staining, pHH3 expression did not correlate with Gleason grade. Our data point to a conceivable role of pHH3 as prognostic biomarker in prostate carcinoma. 23159329 Distinct roles of methamphetamine in modulating spatial memory consolidation, retrieval, reconsolidation and the accompanying changes of ERK and CREB activation in hippocampus and prefrontal cortex. Drugs of abuse modulated learning and memory in humans yet the underlying mechanism remained unclear. The extracellular signal-regulated kinase (ERK) and the transcription factor cAMP response element-binding protein (CREB) were involved in neuroplastic changes associated with learning and memory. In the current study, we used a Morris water maze to examine the effect of methamphetamine (METH) on different processes of spatial memory in mice. We then investigated the status of ERK and CREB in the hippocampus and prefrontal cortex (PFC). We found that 1.0 mg/kg dose of METH facilitated spatial memory consolidation when it was injected immediately after the last learning trial. In contrast, the same dose of METH had no effect on spatial memory retrieval when it was injected 30 min before the test. Furthermore, 1.0 mg/kg dose of METH injected immediately after retrieval had no effect on spatial memory reconsolidation. Activation of both ERK and CREB in the hippocampus was found following memory consolidation but not after retrieval or reconsolidation in METH-treated mouse groups. In contrast, activation of both ERK and CREB in the PFC was found following memory retrieval but not other processes in METH-treated mouse groups. These results suggested that METH facilitated spatial memory consolidation but not retrieval or reconsolidation. Moreover, activation of the ERK and CREB signaling pathway in the hippocampus might be involved in METH-induced spatial memory changes. 23911608 HMGB1 induces an inflammatory response in endothelial cells via the RAGE-dependent endoplasmic reticulum stress pathway. The high mobility group 1B protein (HMGB1) mediates chronic inflammatory responses in endothelial cells, which play a critical role in atherosclerosis. However, the underlying mechanism is unknown. The goal of our study was to identify the effects of HMGB1 on the RAGE-induced inflammatory response in endothelial cells and test the possible involvement of the endoplasmic reticulum stress pathway. Our results showed that incubation of endothelial cells with HMGB1 (0.01-1μg/ml) for 24h induced a dose-dependent activation of endoplasmic reticulum stress transducers, as assessed by PERK and IRE1 protein expression. Moreover, HMGB1 also promoted nuclear translocation of ATF6. HMGB1-mediated ICAM-1 and P-selectin production was dramatically suppressed by PERK siRNA or IRE1 siRNA. However, non-targeting siRNA had no such effects. HMGB1-induced increases in ICAM-1 and P-selectin expression were also inhibited by a specific eIF2α inhibitor (salubrinal) and a specific JNK inhibitor (SP600125). Importantly, a blocking antibody specifically targeted against RAGE (anti-RAGE antibody) decreased ICAM-1, P-selectin and endoplasmic reticulum stress molecule (PERK, eIF2α, IRE1 and JNK) protein expression levels. Collectively, these novel findings suggest that HMGB1 promotes an inflammatory response by inducing the expression of ICAM-1 and P-selectin via RAGE-mediated stimulation of the endoplasmic reticulum stress pathway. 23957329 Therapeutic Effectiveness of Sustained Low-Efficiency Hemodialysis Plus Hemoperfusion and Continuous Hemofiltration Plus Hemoperfusion for Acute Severe Organophosphate Poisoning. There is no report on the effects of sustained low-efficiency dialysis (SLED) plus hemoperfusion (HP) (SLED + HP) in patients with acute severe organophosphate (OP) poisoning (ASOPP). This study was designed to compare the therapeutic effectiveness between SLED + HP and continuous hemofiltration (CHF) plus HP (CHF + HP) in patients with ASOPP. In order to assess the two treatment methods, 56 patients with ASOPP were divided into CHF + HP group and SLED + HP group. The biochemical indicators, in-hospital duration, hemodynamic parameters, Acute Physiology, and Chronic Health Evaluation (APACHE II) score, and survival and mortality rates were compared. In both groups after treatment, the levels of serum creatine kinase isozyme MB, creatine kinase, creatinine, glutamic-oxalacetic transaminease, and glutamate-pyruvate transaminase, and the APACHE II scores on the first, second, and seventh day decreased (P < 0.05), whereas the levels of serum acetylcholinesterase increased. The two groups showed no statistical differences in in-hospital duration, biochemical indicators, APACHE II score, hemodynamic parameters, survival rate, or the mortality rate (P > 0.05). In conclusion, SLED has similar hemodynamic stability to CHF and the two treatment methods have similar effects on ASOPP patients. More importantly, SLED plus HP is relatively economical and convenient for patients with ASOPP in clinical practice. 22804226 Systematic development of pH-independent controlled release tablets of carvedilol using central composite design and artificial neural networks. The purpose of this study was to apply the optimization method incorporating artificial neural network (ANN) using pH-independent release of weakly basic drug, carvedilol from HPMC-based matrix formulation. Because of weakly basic nature of carvedilol, drug shows pH-dependent solubility. The enteric polymer EUDRAGIT L100 was added formulations to overcome pH-dependent solubility of carvedilol. Effects of the Hydroxypropylmethyl cellulose (HPMC) K4M and EUDRAGIT L100 amount on drug release were investigated. For this purpose 13 kinds of formulations were prepared at three different levels of each variables. The optimization of the formulation was evaluated by using ANN method. Two formulation parameters, the amounts of HPMC K4M and Eudragit L100 at three levels (-1, 0, 1) were selected as independent/input variables. In-vitro dissolution sampling times at twelve different time points were selected as dependent/output variables. By using experimental dissolution results and amount of HPMC K4M and EUDRAGIT L100, percentage of dissolved carvedilol was predicted by ANN. Similarity factor (f2) between predicted and experimentally observed profile was calculated and f2 value was found 76.33. This value showed that there was no difference between predicted and experimentally observed drug release profile. As a result of these experiments, it was found that ANNs can be successfully used to optimize controlled release drug delivery systems. 23860124 Molecular epidemiology and virulence markers of Salmonella Infantis isolated over 25years in São Paulo State, Brazil. Infection of humans and animals caused by Salmonella is a major public health problem worldwide. Among the more than 2500 serovars, S. Infantis has been one of the 15 most isolated serovars in the world. Despite its clinical importance, little is known about the molecular characteristics of S. Infantis strains from Brazil. The aims of this study were to type S. Infantis isolates of this country and to assess their pathogenic potential. The molecular epidemiology of 35 S. Infantis strains, isolated from human sources (25) and food items (10) between 1984 and 2009 in São Paulo State, Brazil, were investigated using ERIC-PCR, PFGE and MLST. Furthermore, the presence of some virulence markers from Salmonella pathogenicity islands (SPIs) SPI-1 and SPI-2 and from the virulence plasmid was assessed by PCR. Using ERIC-PCR, 34 S. Infantis strains exhibited a high genetic similarity (⩾93.7%) and using PFGE, 32 strains exhibited a similarity ⩾80.6%. Additionally, MLST showed a high clonal similarity among strains that all presented the same ST32. Thirty-two isolates under investigation contained the virulence markers invA, sopB, sopD, sipA, sipD, ssaR, sifA, flgK, fljB and flgL. In conclusion, the S. Infantis strains studied were genetically similar, suggesting that a prevalent subtype has been causing disease and food contamination during a 25year period in São Paulo State, an important metropolitan region in Brazil. Furthermore, the contamination between strains from food items and sick humans indicates that better control measures for S. Infantis may be needed in this country. 23731732 Role of PCNA and TLS polymerases in D-loop extension during homologous recombination in humans. Homologous recombination (HR) is essential for maintaining genomic integrity, which is challenged by a wide variety of potentially lethal DNA lesions. Regardless of the damage type, recombination is known to proceed by RAD51-mediated D-loop formation, followed by DNA repair synthesis. Nevertheless, the participating polymerases and extension mechanism are not well characterized. Here, we present a reconstitution of this step using purified human proteins. In addition to Pol δ, TLS polymerases, including Pol η and Pol κ, also can extend D-loops. In vivo characterization reveals that Pol η and Pol κ are involved in redundant pathways for HR. In addition, the presence of PCNA on the D-loop regulates the length of the extension tracks by recruiting various polymerases and might present a regulatory point for the various recombination outcomes. 22906044 Associations between airway hyperresponsiveness, obesity and lipoproteins in a longitudinal cohort. Epidemiological data have linked obesity with an increased risk of asthma, but the mechanisms responsible for this relationship remain unknown. One possible mechanism, which has received little attention, could be the effect of cholesterol metabolism on airway smooth muscle function. The present study investigated the association between airway hyperresponsiveness (AHR) to methacholine and body mass index (BMI) and plasma lipoproteins [low-density lipoprotein (LDL), high-density lipoprotein (HDL) and total cholesterol]. Associations between AHR, BMI and plasma lipoproteins were assessed in a population-based cohort at ages 14 and 20 years. In unadjusted analyses, higher LDL cholesterol levels at age 14 were associated with AHR at age 20 in both sexes (P < 0.05). HDL, LDL/HDL ratio and total cholesterol were not associated with AHR. In multiple regression analyses adjusted for sex, lung function, smoking and asthma, only higher levels of BMI at age 14 or 20 years were significantly associated with increased AHR at age 20 years, while neither LDL, HDL and LDL/HDL ratio nor total cholesterol were significantly associated with AHR. We confirmed that in teenagers there is a strong association between BMI and AHR to methacholine. This association seems to be independent of the plasma lipoprotein levels at that age. 23663104 Current treatment of community-acquired pneumonia. Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. Management decisions regarding site of care, extent of assessment and level of treatment are based primarily on disease severity (outpatient, inpatient and ICU admission). Despite the developments in antibiotic therapy, CAP is still the most common infectious cause of death. There are several challenges with the management of CAP, from the accurate diagnosis, decisions about place of therapy and the choice of appropriate antibiotics. An extensive literature review of manuscripts, in PubMed, published in the past 10 years has been performed, using combinations of words and terms appropriate to the concepts of CAP, treatment, guidelines and corticoids. Some empirical antimicrobial regimens, such as macrolides, are still being debated; some new antibiotics and adjunctive therapies (corticoids) have recently been tested. This is a review of current recommended antimicrobials regimens, novel approaches and adjunctive drugs for the treatment of CAP. Effective management of CAP requires risk stratification of patients by severity and proper place of therapy. Additional therapeutic interventions along with antibiotics may help to improve outcome in patients with CAP, especially in severe CAP. 23927894 The metabolic roles of the endosymbiotic organelles of Toxoplasma and Plasmodium spp. The apicoplast and the mitochondrion of Apicomplexa cooperate in providing essential metabolites. Their co-evolution during the ancestral acquisition of a plastid and subsequent loss of photosynthesis resulted in divergent metabolic pathways compared with mammals and plants. This is most evident in their chimerical haem synthesis pathway. Toxoplasma and Plasmodium mitochondria operate canonical tricarboxylic acid (TCA) cycles and electron transport chains, although the roles differ between Toxoplasma tachyzoites and Plasmodium erythrocytic stages. Glutamine catabolism provides TCA intermediates in both parasites. Isoprenoid precursor synthesis is the only essential role of the apicoplast in Plasmodium erythrocytic stages. An apicoplast-located fatty acid synthesis is dispensable in these stages, which instead predominantly salvage fatty acids, while in Plasmodium liver stages and in Toxoplasma tachyzoites fatty acid synthesis is an essential role of the plastid. 23190563 Performance of a novel BD Stem Cell Enumeration Kit on two flow cytometry systems. Hematopoietic stem cell transplantation, which requires accurate enumeration of stem cells, is routinely used in clinical settings. Flow cytometry provides a qualitative and quantitative assessment of CD34(+) cells. Precision, linearity, and stability of the novel BD™ Stem Cell Enumeration (SCE) Kit were evaluated on two flow cytometry platforms using a modified ISHAGE gating strategy and including a viability dye for data acquisition and analysis. Precision and linearity were evaluated on BD FACSCanto™ II and BD FACSCalibur™ systems. Stability was evaluated on the BD FACSCanto II system. Precision was tested using both high and low controls. Linearity was evaluated using dilutions from CD34(+) cell pools, while stability was evaluated using fresh leukapheresis specimens. Both systems showed precision with limited variability in absolute counts and percentages of viable CD34(+) cells. The linearity range of viable CD34(+) cells in both systems was established at 0-1000 cells/μL, showing a linear relationship (R(2)  = 0.99). Stability of CD34(+) cells in mobilized leukapheresis samples was confirmed up to 24 h after collection and up to 60 min after the end of stain/lyse procedures. The BD SCE Kit on both flow cytometry systems shows consistent and reproducible results. 23935478 Parameter trajectory analysis to identify treatment effects of pharmacological interventions. The field of medical systems biology aims to advance understanding of molecular mechanisms that drive disease progression and to translate this knowledge into therapies to effectively treat diseases. A challenging task is the investigation of long-term effects of a (pharmacological) treatment, to establish its applicability and to identify potential side effects. We present a new modeling approach, called Analysis of Dynamic Adaptations in Parameter Trajectories (ADAPT), to analyze the long-term effects of a pharmacological intervention. A concept of time-dependent evolution of model parameters is introduced to study the dynamics of molecular adaptations. The progression of these adaptations is predicted by identifying necessary dynamic changes in the model parameters to describe the transition between experimental data obtained during different stages of the treatment. The trajectories provide insight in the affected underlying biological systems and identify the molecular events that should be studied in more detail to unravel the mechanistic basis of treatment outcome. Modulating effects caused by interactions with the proteome and transcriptome levels, which are often less well understood, can be captured by the time-dependent descriptions of the parameters. ADAPT was employed to identify metabolic adaptations induced upon pharmacological activation of the liver X receptor (LXR), a potential drug target to treat or prevent atherosclerosis. The trajectories were investigated to study the cascade of adaptations. This provided a counter-intuitive insight concerning the function of scavenger receptor class B1 (SR-B1), a receptor that facilitates the hepatic uptake of cholesterol. Although activation of LXR promotes cholesterol efflux and -excretion, our computational analysis showed that the hepatic capacity to clear cholesterol was reduced upon prolonged treatment. This prediction was confirmed experimentally by immunoblotting measurements of SR-B1 in hepatic membranes. Next to the identification of potential unwanted side effects, we demonstrate how ADAPT can be used to design new target interventions to prevent these. 23122075 Lead and cadmium concentrations in goat, cow, sheep, and buffalo milks from different regions of Iran. In total, 137 goat, cow, sheep, and buffalo milk samples were collected in different regions of Iran and analysed to determine concentrations of lead and cadmium by a graphite furnace atomic absorption spectrometric method. The mean recovery of the analytical method was 96.3% and 104% for cadmium and lead, respectively. The mean lead and cadmium contents obtained from 137 samples were 1.93 ± 1.48 (range: 0.18-6.11 ng/ml) and 9.51 ± 4.93 ng/ml (range: 1.84 ng/ml-30.50 ng/ml), respectively. Lead concentration in 8.1% of sheep and 1.9% of cow milk samples was higher than the newly established Codex standard. The mean concentrations of cadmium and lead in animals aged ≤ 3 years (n=80; 1.40 ± 1.05 ng/ml and 7.91 ± 3.60 ng/ml, respectively) were lower than in animals aged >3 years (n=58; 2.69 ± 1.67 ng/ml and 11.8 ± 5.71 ng/ml, respectively). 23767830 Increased serum estrogenic bioactivity in girls with premature thelarche: a marker of environmental pollutant exposure? The aim of the work was to investigate the pathophysiology of isolated premature thelarche (IPT) by determining the impact of pre/postnatal exposure to endocrine disrupting chemicals (EDCs) through evaluation of total serum estrogenic bioactivity (EBA). The pathophysiology remains elusive, although recent investigations suggested the role of EDCs in premature female breast development. We investigated 15 girls with IPT. Plasma estradiol, follicle-stimulating hormone, and luteinizing hormone were measured in basal state and after gonadotropin-releasing hormone testing; bone age and uterine length were also assessed for all patients. Total EBA of patient serum was analyzed with an ultrasensitive bioassay that we previously developed and compared with that of 18 age-matched control girls. Parents were interviewed about their environmental/occupational exposure to EDCs during the patient's prenatal/postnatal life. Nine families reported parental occupational/environmental EDCs exposure during prenatal/postnatal patient life; the mean total EBA found in these 9 IPT girls was significantly elevated (12.31 ± 6.64 pg/mL) in comparison with that of the 6 patients without exposure (2.53 ± 0.73 pg/mL) and the 18 age-matched controls (3.53 ± 2.23 pg/mL; p < 0.01). The significant increase in total EBA in these 9 girls with IPT suggests that premature female breast development may be related in some cases to higher pre/postnatal contamination by EDCs. 23411322 Influences of muscle composition and structure of pork from different breeds on stability and textural properties of cooked meat emulsion. The influences of composition and structure of meats from different pig breeds, including Duroc (D), Large White (LW), Landrace (LR), two-way cross (LR×LW) and three-way cross (D×[LR×LW]) on stability and textural characteristics of cooked meat emulsions were studied by using partial least squares (PLS) regression. Compared to other pig breeds, cooked meat emulsion from LW exhibited superior properties as indicated by lower water and fat released as well as higher chewiness, gumminess, cohesiveness, resilience, springiness and hardness. The univariate analyses of those selected properties indicated a significant correlation with higher contents of myofibrillar and sarcoplasmic proteins, smaller muscle fibre diameter and lower myofibril fragmentation of LW meat, as compared to other breeds. Therefore properties of cooked pork emulsion were influenced by composition and structure of meat, which varied according to the pig breeds. 23906325 Charge and Electric Field Fluctuations in Aqueous NaCl Electrolytes. Crystalloluminescence, the long-lived emission of visible light during the crystallization of certain salts, was first observed over 200 years ago; however, the origin of this luminescence is still not well understood. The observations suggest that the process of crystallization may not be purely classical but also involves an essential electronic structure component. Strong electric field fluctuations may play an important role in this process by providing the necessary driving force for the observed electronic structure changes. The main objective of this work is to provide a basic understanding of the fluctuations in charge, electric potentials, and electric fields for concentrated aqueous NaCl electrolytes. Our charge analysis reveals that the water molecules in the first solvation shell of the ions serve as a sink for electron density originating on Cl(-). We find that the electric fields inside aqueous electrolytes are extremely large (up to several V/Å) and thus may alter the ground and excited electronic states in the condensed phase. Furthermore, our results show that the potential and field distributions are largely independent of concentration. We also find the field component distributions to be Gaussian for the ions and non-Gaussian for the O and H sites (computed in the lab frame of reference), however, these non-Gaussian distributions are readily modeled via an orientationally averaged nonzero mean Gaussian plus a zero mean Gaussian. These calculations and analyses provide the first steps toward understanding the magnitude and fluctuations of charge, electric potentials, and fields in aqueous electrolytes and what role these fields may play in driving charge redistribution/transfer during crystalloluminescence. 23627252 Self-Assembly and Near Perfect Macroscopic Alignment of Fluorescent Triangulenium Salt in Spin Cast Thin Films on PTFE. Highly fluorescent, discotic trioxatriangulenium dyes were aligned by simple spin casting on substrates with friction transferred PTFE layers. The fluorescent crystalline thin films show near perfect macroscopic alignment on centimeter large areas directly from spin casting. Gracing Incidence X-ray Diffraction (GIXD) unambiguously allowed to determine a long range order unit cell as well as its orientation with respect to the PTFE fibers. Further analysis of the X-ray data, in conjunction with polarized absorption spectroscopy, suggest a lamellar packing model with alternating layers of alkyl chains and ionic dyes oriented parallel to the substrate. This structure results in a highly anisotropic electrostatic potential around the cationic chromophore, causing significant shifts in energy and orientation of the optical transitions. Thus, the optical properties of the material are, to a large extent, controlled by the position of the otherwise inert PF6- counter ions. The bright fluorescence from the films is also polarized parallel to the PTFE alignment layer. Doping of the thin films with fluorescent energy acceptor traps shows that efficient exciton migration takes place in the thin films. The excellent exciton transfer capabilities, in conjunction with the perfect alignment, might be of interest in future applications in solar energy harvesting or as thin film sensors. 23932739 The hardware and software implications of hospital birth room design: A midwifery perspective. to explore the impacts of physical and aesthetic design of hospital birth rooms on midwives. the design of a workplace, including architecture, equipment, furnishings and aesthetics, can influence the experience and performance of staff. Some research has explored the effects of workplace design in health care environments but very little research has examined the impact of design on midwives working in hospital birth rooms. a video ethnographic study was undertaken and the labours of six women cared for by midwives were filmed. Filming took place in one birth centre and two labour wards within two Australian hospitals. Subsequently, eight midwives participated in video-reflexive interviews whilst viewing the filmed labour of the woman for whom they provided care. Thematic analysis of the midwife interviews was undertaken. midwives were strongly affected by the design of the birth room. Four major themes were identified: finding a space amongst congestion and clutter; trying to work underwater; creating ambience in a clinical space and being equipped for flexible practice. Aesthetic features, room layout and the design of equipment and fixtures all impacted on the midwives and their practice in both birth centre and labour ward settings. the current design of many hospital birth rooms challenges the provision of effective midwifery practice. Changes to the design and aesthetics of the hospital birth room may engender safer, more comfortable and more effective midwifery practice. 23838185 Neuroligins provide molecular links between syndromic and nonsyndromic autism. Autism is a common and heritable neuropsychiatric disorder that can be categorized into two types: syndromic and nonsyndromic, the former of which are associated with other neurological disorders or syndromes. Molecular and functional links between syndromic and nonsyndromic autism genes were lacking until studies aimed at understanding the role of trans-synaptic adhesion molecule neuroligin, which is associated with nonsyndromic autism, provided important connections. Here, we integrate data from these studies into a model of how neuroligin functions to control synaptic connectivity in the central nervous system and how neuroligin dysfunction may participate in the pathophysiology of autism. Understanding the complex functional interactions between neuroligins and other autism-associated proteins at the synapse is crucial to understand the pathology of autism. This understanding might bring us closer to development of therapeutic approaches for autism. 23337891 Phacomatosis Pigmentokeratotica Is Caused by a Postzygotic HRAS Mutation in a Multipotent Progenitor Cell. Phacomatosis pigmentokeratotica (PPK) is a rare epidermal nevus syndrome characterized by the co-occurrence of a sebaceous nevus and a speckled lentiginous nevus. The coexistence of an epidermal and a melanocytic nevus has been explained by two homozygous recessive mutations, according to the twin spot hypothesis, of which PPK has become a putative paradigm in humans. However, the underlying gene mutations remained unknown. Multiple tissues of six patients with PPK were analyzed for the presence of RAS, FGFR3, PIK3CA, and BRAF mutations using SNaPshot assays and Sanger sequencing. We identified a heterozygous HRAS c.37G>C (p.Gly13Arg) mutation in four patients and a heterozygous HRAS c.182A>G (p.Gln61Arg) mutation in two patients. In each case, the mutations were present in both the sebaceous and the melanocytic nevus. In the latter lesion, melanocytes were identified to carry the HRAS mutation. Analysis of various nonlesional tissues showed a wild-type sequence of HRAS, consistent with mosaicism. Our data provide no genetic evidence for the previously proposed twin spot hypothesis. In contrast, PPK is best explained by a postzygotic-activating HRAS mutation in a multipotent progenitor cell that gives rise to both a sebaceous and a melanocytic nevus. Therefore, PPK is a mosaic RASopathy. 23291036 Dissolution of tablet-in-tablet formulations studied with ATR-FTIR spectroscopic imaging. This work uses ATR-FTIR spectroscopic imaging to study the dissolution of delayed release and pH resistant compressed coating pharmaceutical tablets. Tablets with an inner core and outer shell were constructed using a custom designed compaction cell. The core of the delayed release tablets consisted of hydroxypropyl methylcellulose (HPMC) and caffeine. The shell consisted of microcrystalline cellulose (MCC) and glucose. The core of the pH resistant formulations was an ibuprofen and PEG melt and the shell was constructed from HPMC and a basic buffer. UV/vis spectroscopy was used to monitor the lag-time of drug release and visible optical video imaging was used as a complementary imaging technique with a larger field of view. Two delayed release mechanisms were established. For tablets with soluble shell sections, lag-time was dependent upon rapid shell dissolution. For tablets with less soluble shells, the lag-time was controlled by the rate of dissolution medium ingress through the shell and the subsequent expansion of the wet HPMC core. The pH resistant formulations prevented crystallization of the ibuprofen in the core during dissolution despite an acidic dissolution medium. FTIR imaging produced important information about the physical and chemical processes occurring at the interface between tablet sections during dissolution. 23578655 Residues and dissipation of kresoxim methyl in apple under field condition. The dissipation and residual levels of kresoxim methyl in apple under field condition were determined by using HPLC-DAD with QuEChERS method. At fortification levels of 0.05, 0.1, 0.5 and 1.0mgkg(-1) in apple, it was shown that recoveries were ranged from 91.1% to 96.9% with coefficient variation of the method (CV%) for repeatability ranged from 1.27% to 4.77%. The limit of quantification (LOQ) of the method was 0.05mgkg(-1). The dissipation rates of kresoxim methyl were described by using first-order kinetics and its half-life, as they are ranged from 4.58 to 4.77days in apple. The terminal residues of kresoxim methyl were below the FAO/WHO maximum residue limit (MRL, 0.2mgkg(-1)) in apple when measured 14days after the final application, which suggested that the use of this fungicide was safe for humans. This study would help in providing the basic information for developing regulation to guard a safe use of kresoxim methyl in apple orchard and to prevent health problem from consumers. 23822305 Coupled potential energy surface for the F(2P)+CH4→HF+CH3 entrance channel and quantum dynamics of the CH4·F- photodetachment. An approach to construct vibronically and spin-orbit coupled diabatic potential energy surfaces (PESs) which describe all three relevant electronic states in the entrance channels of the X(P) + CH4 →HX + CH3 reactions (with X=F((2)P), Cl((2)P), or O((3)P)) is introduced. The diabatization relies on the permutational symmetry present in the methane molecule and results in diabatic states which transform as the three p orbitals of the X atom. Spin-orbit coupling is easily and accurately included using the atomic spin-orbit coupling matrix of the isolated X atom. The method is applied to the F + CH4 system obtaining an accurate PES for the entrance channel based on ab initio multi-reference configuration interaction (MRCI) calculations. Comparing the resulting PESs with spin-orbit MRCI calculations, excellent agreement is found for the excited electronic states at all relevant geometries. The photodetachment spectrum of CH4·F(-) is investigated via full-dimensional (12D) quantum dynamics calculations on the coupled PESs using the multi-layer multi-configurational time-dependent Hartree approach. Extending previous work [J. Palma and U. Manthe, J. Chem. Phys. 137, 044306 (2012)], which was restricted to the dynamics on a single adiabatic PES, the contributions of the electronically excited states to the photodetachment spectrum are calculated and compared to experiment. Considering different experimental setups, good agreement between experiment and theory is found. Addressing questions raised in the previous work, the present dynamical calculations show that the main contribution to the second peak in the photodetachment spectrum results from electron detachment into the electronically excited states of the CH4F complex. 23922395 Structure of the processive rubber oxygenase RoxA from Xanthomonas sp. Rubber oxygenase A (RoxA) is one of only two known enzymes able to catalyze the oxidative cleavage of latex for biodegradation. RoxA acts as a processive dioxygenase to yield the predominant product 12-oxo-4,8-dimethyl-trideca-4,8-diene-1-al (ODTD), a tri-isoprene unit. Here we present a structural analysis of RoxA from Xanthomonas sp. strain 35Y at a resolution of 1.8 Å. The enzyme is a 75-kDa diheme c-type cytochrome with an unusually low degree of secondary structure. Analysis of the heme group arrangement and peptide chain topology of RoxA confirmed a distant kinship with diheme peroxidases of the CcpA family, but the proteins are functionally distinct, and the extracellular RoxA has evolved to have twice the molecular mass by successively accumulating extensions of peripheral loops. RoxA incorporates both oxygen atoms of its cosubstrate dioxygen into the rubber cleavage product ODTD, and we show that RoxA is isolated with O2 stably bound to the active site heme iron. Activation and cleavage of O2 require binding of polyisoprene, and thus the substrate needs to use hydrophobic access channels to reach the deeply buried active site of RoxA. The location and nature of these channels support a processive mechanism of latex cleavage. 23617821 Cadmium-Based Quantum Dot Induced Autophagy Formation for Cell Survival via Oxidative Stress. Quantum dots (QDs) are one of most utilized nanomaterials in nanocrystalline semiconductors. QDs emit near-infrared fluorescence and can be applied as probes for detecting vasculature and imaging in biological systems. Since QDs have potential in clinical application, the toxicity of QDs needs to be carefully evaluated. In our present study, we elucidate the cytotoxic mechanisms of QDs using a mouse renal adenocarcinoma (RAG) cell line. QDs in RAG cells increased intracellular reactive oxygen species (ROS) levels and induced autophagy at 6 h, leading to subsequent apoptosis at 24 h. QDs entered the cells and were located within the endoplasmic reticulum (ER), endosome, and lysosome at 6 h and endosome, lysosome, and mitochondria at 24 h. However, QDs only affected mitochondrial function and did not induce ER stress. N-Acetylcysteine, an antioxidant agent, reduced intracellular ROS levels and decreased QD-induced autophagy but enhanced QD-induced cell death. Moreover, 3-methylamphetamine (an autophagy inhibitor) also reduced the cell viability in QD-treated cells. These findings suggest that ROS plays an essential role in the regulation of QD-induced autophagy, which subsequently enhances cell survival. Taken together, these results suggest that oxidative stress-induced autophagy is a defense/survival mechanism against the cytotoxicity of QD. 23770991 Pulse wave imaging in normal, hypertensive and aneurysmal human aortas in vivo: a feasibility study. Arterial stiffness is a well-established biomarker for cardiovascular risk, especially in the case of hypertension. The progressive stages of an abdominal aortic aneurysm (AAA) have also been associated with varying arterial stiffness. Pulse wave imaging (PWI) is a noninvasive, ultrasound imaging-based technique that uses the pulse wave-induced arterial wall motion to map the propagation of the pulse wave and measure the regional pulse wave velocity (PWV) as an index of arterial stiffness. In this study, the clinical feasibility of PWI was evaluated in normal, hypertensive, and aneurysmal human aortas. Radiofrequency-based speckle tracking was used to estimate the pulse wave-induced displacements in the abdominal aortic walls of normal (N = 15, mean age 32.5 ± 10.2 years), hypertensive (N = 13, mean age 60.8 ± 15.8 years), and aneurysmal (N = 5, mean age 71.6 ± 11.8 years) human subjects. Linear regression of the spatio-temporal variation of the displacement waveform in the anterior aortic wall over a single cardiac cycle yielded the slope as the PWV and the coefficient of determination r(2) as an approximate measure of the pulse wave propagation uniformity. The aortic PWV measurements in all normal, hypertensive, and AAA subjects were 6.03 ± 1.68, 6.69 ± 2.80, and 10.54 ± 6.52 m s(-1), respectively. There was no significant difference (p = 0.15) between the PWVs of the normal and hypertensive subjects while the PWVs of the AAA subjects were significantly higher (p < 0.001) compared to those of the other two groups. Also, the average r(2) in the AAA subjects was significantly lower (p < 0.001) than that in the normal and hypertensive subjects. These preliminary results suggest that the regional PWV and the pulse wave propagation uniformity (r(2)) obtained using PWI, in addition to the PWI images and spatio-temporal maps that provide qualitative visualization of the pulse wave, may potentially provide valuable information for the clinical characterization of aneurysms and other vascular pathologies that regionally alter the arterial wall mechanics. 23288054 Evaluation of iodide deficiency in the lactating rat and pup using a biologically based dose-response model. A biologically based dose-response (BBDR) model for the hypothalamic-pituitary thyroid (HPT) axis in the lactating rat and nursing pup was developed to describe the perturbations caused by iodide deficiency on the HPT axis. Model calibrations, carried out by adjusting key model parameters, were used as a technique to evaluate HPT axis adaptations to dietary iodide intake in euthyroid (4.1-39 µg iodide/day) and iodide-deficient (0.31 and 1.2 µg iodide/day) conditions. Iodide-deficient conditions in both the dam and the pup were described with increased blood flow to the thyroid gland, TSH-mediated increase in thyroidal uptake of iodide and binding of iodide in the thyroid gland (organification), and, in general, reduced thyroid hormone production and metabolism. Alterations in thyroxine (T4) homeostasis were more apparent than for triiodothyronine (T3). Model-predicted average daily area-under-the-serum-concentration-curve (nM-day) values for T4 at steady state in the dam and pup decreased by 14-15% for the 1.2 µg iodide/day iodide-deficient diet and 42-52% for the 0.31 µg iodide/day iodide-deficient diet. In rat pups that were iodide deficient during gestation and lactation, these decreases in serum T4 levels were associated with declines in thyroid hormone in the fetal brain and a suppression of synaptic responses in the hippocampal region of the brain of the adult offspring (Gilbert et al. , 2013). 23911901 More than meets the eye: Implicit perception in legally blind individuals. Legally blind participants (uncorrected vision of 20/200+) were able to identify a visual stimulus attribute (clock hand position) in the absence of consciously identifying its presence. Specifically, participants-with their corrective lenses removed-correctly guessed the hour-hand position above chance (8%) on a clockface shown on a computer screen. This occurred both when presented in a 1-clockface display (28%), as well as when shown a display containing 4 clockfaces (21%), in which only 1 face contained a hand. Even more striking, hand identification accuracy in the 4-clockface condition was comparable whether the clockface containing the hand was (21%) or was not (20%) correctly identified. That legally blind individuals are capable of identifying stimulus attributes without conscious awareness provides an additional vehicle for exploring implicit perception. Consistent with previous research, the visualsystem can apparently cope with degraded visual input through information available through a(n unconscious) secondary pathway via the superior colliculi. 23832268 Development of a test for bovine tuberculosis in cattle based on measurement of gamma interferon mRNA by real-time PCR. The infection status of cattle for bovine tuberculosis (bTB) was determined by real-time PCR, comparing the levels of IFN-γ mRNA in blood cultures stimulated with either bovine or avian tuberculin with non-stimulated control (phosphate buffer saline, PBS) blood culture. Totally, 137 cattle were tested to validate the assay, in which 54 were IFN-γ real-time quantitative PCR (RT-qPCR) positive, while the remaining 83 were found negative. Meanwhile, the IFN-γ ELISA test was carried out using the Bovigam IFN-γ detection ELISA kit and these results were used as a standard. The results of the single intradermal tuberculin tests (SIDT) and IFN-γ RT-qPCR tests were compared and revealed that the RT-qPCR correlated better with the ELISA and its accuracy was higher than SIDT. This indicates the RT-qPCR is a useful diagnostic method for bTB in cattle. However, several limitations remain for our approach, such as lack of a TB lesions or postmortem test results as a gold standard. Further improvements should be made in the future to increase accuracy of diagnosis of bTB in cattle. 23825202 Animal activity around the clock with no overt circadian rhythms: patterns, mechanisms and adaptive value. Circadian rhythms are ubiquitous in many organisms. Animals that are forced to be active around the clock typically show reduced performance, health and survival. Nevertheless, we review evidence of animals showing prolonged intervals of activity with attenuated or nil overt circadian rhythms and no apparent ill effects. We show that around-the-clock and ultradian activity patterns are more common than is generally appreciated, particularly in herbivores, in animals inhabiting polar regions and habitats with constant physical environments, in animals during specific life-history stages (such as migration or reproduction), and in highly social animals. The underlying mechanisms are diverse, but studies suggest that some circadian pacemakers continue to measure time in animals active around the clock. The prevalence of around-the-clock activity in diverse animals and habitats, and an apparent diversity of underlying mechanisms, are consistent with convergent evolution. We suggest that the basic organizational principles of the circadian system and its complexity encompass the potential for chronobiological plasticity. There may be trade-offs between benefits of persistent daily rhythms versus plasticity, which for reasons still poorly understood make overt daily arrhythmicity functionally adaptive only in selected habitats and for selected lifestyles. 23587945 Redefining the role of the β-lactamase locus in methicillin-resistant Staphylococcus aureus: β-lactamase regulators disrupt the MecI-mediated strong repression on mecA and optimize the phenotypic expression of resistance in strains with constitutive mecA expression. In response to β-lactam chemotherapy, Staphylococcus aureus has acquired two resistance determinants: blaZ, coding for β-lactamase, which confers resistance to penicillins only, and mecA, coding for an extra cell wall cross-linking enzyme with reduced affinity for virtually all other β-lactams. The transcriptional control of both resistance determinants is regulated by homologous repressors (BlaI and MecI, respectively) and sensor inducers (BlaR1 and MecR1, respectively). There is a cross-talk between the two regulatory systems, and it has been demonstrated that bla regulators stabilize the mecA acquisition. In a recent study, we have unexpectedly observed that in most MRSA strains, there was no significant change in the resistance phenotype upon the overexpression in trans of a MecI repressor, whereas in those few strains negative for the bla locus, there was a massive decrease of resistance (D. C. Oliveira and H. de Lencastre, PLoS One 6:e23287, 2011). Here, we demonstrate that, contrary to what is currently accepted, the bla regulatory system efficiently disrupts the strong MecI-mediated repression on mecA, enabling the optimal expression of resistance. This effect appears to be due to the formation of MecI::BlaI heterodimers that might bind less efficiently to the mecA promoter and become nonfunctional due to the proteolytic inactivation of the BlaI monomer. In addition, we have also observed that the presence of bla regulators may enhance dramatically the expression of β-lactam resistance in MRSA strains with constitutive mecA expression, compensating for the fitness cost imposed by the large β-lactamase plasmid. These observations point to important unrecognized roles of the bla locus for the expression of the methicillin-resistant S. aureus (MRSA) phenotype. 23608238 Decision regret in men undergoing dose-escalated radiation therapy for prostate cancer. Decision regret (DR) is a negative emotion associated with medical treatment decisions, and it is an important patient-centered outcome after therapy for localized prostate cancer. DR has been found to occur in up to 53% of patients treated for localized prostate cancer, and it may vary depending on treatment modality. DR after modern dose-escalated radiation therapy (DE-RT) has not been investigated previously, to our knowledge. Our primary aim was to evaluate DR in a cohort of patients treated with DE-RT. We surveyed 257 consecutive patients with localized prostate cancer who had previously received DE-RT, by means of a validated questionnaire. There were 220 responses (85.6% response rate). Image-guided intensity modulated radiation therapy was given in 85.0% of patients and 3-dimensional conformal radiation therapy in 15.0%. Doses received included 73.8 Gy (34.5% patients), 74 Gy (53.6%), and 76 Gy (10.9%). Neoadjuvant androgen deprivation (AD) was given in 51.8% of patients and both neoadjuvant and adjuvant AD in 34.5%. The median follow-up time was 23 months (range, 12-67 months). In all, 3.8% of patients expressed DR for their choice of treatment. When asked whether they would choose DE-RT or AD again, only 0.5% probably or definitely would not choose DE-RT again, compared with 8.4% for AD (P<.01). Few patients treated with modern DE-RT express DR, with regret appearing to be lower than in previously published reports of patients treated with radical prostatectomy or older radiation therapy techniques. Patients experienced more regret with the AD component of treatment than with the radiation therapy component, with implications for informed consent. Further research should investigate regret associated with individual components of modern therapy, including AD, radiation therapy and surgery. 23904853 Delayed Liver Function Impairment Secondary to Interferon β-1a Use in Multiple Sclerosis. Interferon β-1a is a widely used immunomodulation treatment for multiple sclerosis. Liver function impairment is a common side effect and usually develops in the first 6 months after interferon use. Here, we describe 2 multiple sclerosis patients who developed delayed liver function impairment 5 years after receiving interferon β-1a treatment. Their liver function recovered after discontinuing interferon use, and further detailed hepatological evaluations excluded other etiologies of liver function impairment. Our case reports illustrate that liver function impairment induced by interferon β-1a can be delayed for 5 years after starting treatment and, probably, this is an idiosyncratic reaction. Regular liver function monitoring in multiple sclerosis patients who receive interferon β is necessary even after the first 6 months of treatment, especially in those patients with concomitant use of other liver-toxic medications. 23898230 Practice patterns for lower respiratory tract infections in hospital patients with particular focus on bacteriological examinations and injection antibiotics use. Various types of medical institutions perform treatments for lower respiratory tract infections. However, few studies have assessed and compared practice patterns across different medical institutions in Japan. To assess practice patterns for community-acquired lower respiratory tract infections among patients who needed hospitalization, we examined the use of injection antibiotics and the implementation of bacteriological examinations, and compared these across medical institutions. We then evaluated whether bacteriological examinations were being adequately implemented. A cross-sectional study was conducted using a database of health insurance claims. Subjects were patients (≥16 years old) who received injection antibiotics to treat lower respiratory tract infections, and who were listed among 2004-2007 insurance claims data. For each type of antibiotic, we obtained the dose prescribed, the number of patients treated, and the frequency of bacteriological examinations. A total of 1649 patients were evaluated. The implementation rate of Gram stain and sputum culture was 14% at clinics (<20 beds), approximately 30% at small hospitals (20-99 beds), and 40%-45% at medium-sized (100-499 beds) and large hospitals (≥500 beds). As a whole, beta-lactams were most frequently used, accounting for 80% of all antibiotics used. Among beta-lactams, penicillins comprised 25% of the total amount of drugs used at hospitals with ≥300 beds, but approximately 13% at clinics and small hospitals. Practice patterns varied depending on the size of the medical institution. The implementation rate of bacteriological examinations was not high enough, especially at clinics and small hospitals. 23876342 Role of hepatic resident and infiltrating macrophages in liver repair after acute injury. Treatment of liver disease, caused by hepatotoxins, viral infections, alcohol ingestion, or autoimmune conditions, remains challenging and costly. The liver has a powerful capacity to repair and regenerate, thus a thorough understanding of this tightly orchestrated process will undoubtedly improve clinical means of restoring liver function after injury. Using a murine model of acute liver injury caused by overdose of acetaminophen (APAP), our studies demonstrated that the combined absence of liver resident macrophages (Kupffer cells, KCs), and infiltrating macrophages (IMs) resulted in a marked delay in liver repair, even though the initiation and extent of peak liver injury was not impacted. This delay was not due to impaired hepatocyte proliferation but rather prolonged vascular leakage, which is caused by APAP-induced liver sinusoidal endothelial cell (LSEC) injury. We also found that KCs and IMs express an array of angiogenic factors and induce LSEC proliferation and migration. Our mechanistic studies suggest that hypoxia-inducible factor (HIF) may be involved in regulating the angiogenic effect of hepatic macrophages (Macs), as we found that APAP challenge resulted in hypoxia and stabilization of HIF in the liver and hepatic Macs. Together, these data indicate an important role for hepatic Macs in liver blood vessel repair, thereby contributing to tissue recovery from acute injury. 23722069 Induction of HepG2 cell apoptosis by Irgarol 1051 through mitochondrial dysfunction and oxidative stresses. In this study, HepG2 cells were exposed to 0.04-40mg/L Irgarol 1051. Results show that Irgarol 1051 can damage cell morphology and cause a significant decrease in cell viability. Positive staining by Annexin V, caspase-3 activity enhancement, and the damage in cell ultrastructure indicated an apoptotic mode of cell death for 4.0mg/L Irgarol 1051 treatment. At the same time, caspase-9 was also significantly induced by 0.4 and 4.0mg/L Irgarol 1051 at 72h, which suggests that the intrinsic mitochondria pathway was involved in the apoptosis. The mitochondrial membrane potential decreased significantly after the HepG2 cells were exposed to Irgarol 1051 for 6 and 72h. Especially, the translocation of cytochrome c from mitochondria to cytosol was recorded, supporting the idea that the mitochondrial pathway was involved in the apoptosis signal pathways induced by Irgarol 1051. The significantly increased levels of intracellular reactive oxygen species (ROS) and an immediate ROS burst were also recorded. The results here may imply that Irgarol 1051 induces HepG2 cell apoptosis through mitochondrial dysfunction and oxidative stresses. Although it is possible that this chemical has no detrimental effects on human health at the environmentally relevant concentration, it may cause problems to top coastal predators due to bio-accumulation through the food chain. 23397175 Selective removal of Cr(VI) from aqueous solution by adsorption on mangosteen peel. Mangosteen peel, rich in polyphenolic compounds, was used to prepare the adsorbent exhibiting highly selective adsorption for Cr(VI) over other metal ions such as Pb(2+), Fe(3+), Zn(2+), Cd(2+), and Cr(3+) at the pH values of 1∼4. The chemical modification method proposed by using calcium hydroxide is quite cost-effective and ecofriendly without using any toxic reagents or causing any secondary pollution. The adsorption isotherm results revealed that the adsorption of Cr(VI) on the gel fit well the Langmuir adsorption model, and the maximum adsorption capacity for Cr(VI) at pH levels 1, 2, 3, and 4 was evaluated to be 2.46, 2.44, 1.99, and 2.14 mol/kg, respectively. The adsorption mechanism for Cr(VI) on the saponified gel was verified to follow an esterifiaction reaction coupled with the reduction of Cr(VI) to Cr(III) in which H(+) plays a role of promoter. Thus, modified mangosteen peel gel has the prominent selectivity and low cost for Cr(VI) removal. 23832617 Computed tomography pulmonary findings in healthy older adult aspirators versus nonaspirators. In previous studies, we consistently found that approximately 30% of asymptomatic healthy older adults silently aspirated liquids during a flexible endoscopic evaluation of swallowing (FEES) and that their aspiration status was stable for the following year. However, no studies have systematically evaluated effects of silent aspiration on lung parenchyma and airways. We used computed tomography (CT) to compare lungs of healthy older adult aspirators versus nonaspirators. We hypothesized that CT images would show pulmonary differences in healthy older adult aspirators versus nonaspirators. Prospective study. Fifty healthy older adults (25 aspirators and 25 nonaspirators) who participated in a previous FEES were randomly selected. CT scans were performed; on inspiration, lung views were taken at 1.25 mm and 2.5 mm windows, and on expiration, lung views were taken at 2.5 mm. CT scans were reviewed by radiologists blinded to group assignment. Outcomes included bronchiectasis, bronchiolectasis, bronchial wall thickening, parenchymal band, fibrosis, air trapping, intraluminal airway debris, and tree-in-bud pattern. χ(2) analyses between aspirators and nonaspirators found no statistically significant differences between aspirators and nonaspirators for any outcomes (P > .05). Logistic regression analyses adjusted for smoking did not change the results. There were no differences in pulmonary CT findings between healthy older adult aspirators and nonaspirators. This study adds to the evidence that some aspiration may be within the range of normal for older adults, or at least does not contribute to a change in pulmonary appearance on CT images. 3b Laryngoscope, 2013. 23860006 Validation of RiskCheck Bladder Cancer ©, Version 5.0 for Risk-Adapted Screening of Bladder Cancer. Introduction: The aim of the study was to assess the strength of the online tool RiskCheck Bladder Cancer©, version 5.0 (RCBC) for early detection of bladder cancer (BC). Materials and Methods: RCBC was evaluated retrospectively based on the data of 241 patients, of which 141 were suffering from BC. Statistical analysis was performed by descriptive statistics, nonparametric group comparison, classification tree analysis and ROC analysis. Results: ROC analysis of the risk classification showed a sensitivity of 71.6%, a specificity of 56.5%, a positive predictive value of 67.8%, a negative predictive value of 52% and an accuracy of 63.5%. BC risk factors ranked by importance are time of smoking (p < 0.0001), gender (within the nonsmoking group: p < 0.009), occupational toxin exposure (within the group <35 years of smoking: p < 0.048) and amount of consumed cigarettes resulting in a 95% association with BC (within the group >35 years of smoking: p < 0.0001). Conclusions: The high predictive power of RCBC for the identification of asymptomatic patients living under risk could be demonstrated. 23730924 Pharmaceutical applications of the Calu-3 lung epithelia cell line. Introduction: The Calu-3 lung cell line has been shown to be a promising in vitro model of airway epithelia due to its similarity to in vivo physiology. Hence, over the past decade, it has found increasing applications in the pharmaceutical industry. Areas covered: This review focuses on the pharmaceutical applications of the Calu-3 cell line in areas such as mechanisms of drug transport, studying aerosol deposition, controlled release studies and identification of possible drug-drug interactions. The main findings of various studies, as well as the predictive potential of this model, are presented and discussed in this review. Expert opinion: There is still a lack of mechanistic knowledge regarding transport of inhaled therapeutics across the lungs. Cell culture models such as Calu-3 provide a simple and reproducible system to study the underlying mechanisms by which inhaled therapeutics interact with the lungs. However, more complex systems that integrate particle deposition onto different cell culture systems may be useful in addressing some fundamental questions to generate a better understanding of determinants that influences pulmonary drug dissolution, absorption, metabolism and efficacy. Ultimately the use of the Calu-3 cell line provides a basic research tool that enables the development of safer and more effective inhaled therapeutics. 23257906 Electrophoresis of randomly and vertically embedded graphene nanosheets in activated carbon film as a counter electrode for dye-sensitized solar cells. A new approach has been developed to randomly and vertically embed the graphene nanosheets (GNs) in the activated carbon (AC) film in an applied electric field. The activated carbon (AC) nanoparticles in suspension during electrophoresis play an important role in supporting the GNs perpendicular to the FTO (fluorine-doped tin oxide) glass. Insufficient amount of AC nanoparticles might result in a deposition of GNs parallel to the FTO glass, leading to incomplete utilization of the surface area accessible to electrolyte ions. An AC cathode with randomly and vertically embedded GNs facilitated electrolyte penetration and electron conduction. The photoelectron conversion efficiency of the cell was increased to 7.50% by employing the AC cathode with randomly and vertically embedded GNs. 23842126 Discrepant coagulation profile in HIV infection: elevated D-dimer but impaired platelet aggregation and clot initiation. In HIV infection, cardiovascular disease (CVD) has emerged as a clinical problem, and elevated D-dimer has been reported. The pathophysiologic mechanisms underlying this remain unclear. We aimed to investigate whether untreated HIV-infected individuals display evidence of functional coagulopathy and whether this was associated with microbial translocation. The study population consisted of 50 HIV-infected untreated individuals and 50 HIV-infected individuals on combination antiretroviral therapy (cART). Groups were matched for age, sex and current CD4 cell count. Coagulation analyses included D-dimer and the functional haemostatic whole blood tests, thromboelastography (TEG) and platelet aggregation (Multiplate, impedance aggregometry). Microbial translocation was assessed by plasma levels of lipopolysaccharide (LPS). A larger proportion of untreated individuals compared with treated individuals had D-dimer above normal reference range (27.7 vs. 2.2%, P = 0.001). In both treated and untreated individuals, delayed clot initiation with TEG R-time above upper reference range (18 and 28%, respectively, both P < 0.001) and TEG angle below lower reference range [14% (P = 0.004) and 24% (P < 0.001), respectively] was found. In untreated individuals, 64.6% had aggregation response below threshold in at least two of four tests compared with 36.7% in treated individuals (P = 0.010). Untreated individuals with increased D-dimer levels were relatively hypercoagulable by thromboelastography. Furthermore, in untreated patients, a negative association between microbial translocation and platelet aggregation was found. Elevated D-dimer in untreated HIV-infected individuals was confirmed. However, in both untreated and treated individuals, reduced platelet aggregation and clot initiation was found. The impact of reduced platelet function in HIV infection and a potential role of microbial translocation warrant further investigation. 23822876 Foxa2 Regulates Leukotrienes to Inhibit Th2-mediated Pulmonary Inflammation. Foxa2 is a member of the forkhead family of nuclear transcription factors that is highly expressed in respiratory epithelial cells of the developing and mature lung. Foxa2 is required for normal airway epithelial differentiation, its deletion causing goblet cell metaplasia and Th2-mediated pulmonary inflammation during postnatal development. Foxa2 expression is inhibited during aeroallergen sensitization, and after stimulation with Th2 cytokines, where its loss is associated with goblet cell metaplasia. Mechanisms by which Foxa2 controls airway epithelial differentiation and Th2 immunity are incompletely known. During the first two weeks after birth, loss of Foxa2 increased the production of leukotrienes (LTs) and Th2 cytokines in the lung of Foxa2 gene targeted mice. Foxa2 expression inhibited Alox15 and increased Alox5 transcription, each encoding key lipoxygenases associated with asthma. Inhibition of the cysteinyl LTs (CysLTs) signaling pathway by Montelukast inhibited interleukin (IL)-4, IL-5, eotaxin-2, and RANTES expression in the developing lung of Foxa2 gene targeted mice. Montelukast inhibited expression of genes regulating mucous metaplasia, including Spdef, Muc5ac, Foxa3, and Arg2. Foxa2 plays a cell autonomous role in the respiratory epithelium and is required for suppression of Th2 immunity and mucus metaplasia in the developing lung in a process regulated in part by its regulation of the CysLT pathway. 23590275 Asbestos, asbestosis, smoking, and lung cancer. New findings from the North American insulator cohort. Asbestos, smoking, and asbestosis increase lung cancer risk in incompletely elucidated ways. Smoking cessation among asbestos-exposed cohorts has been little studied. To measure the contributions of asbestos exposure, asbestosis, smoking, and their interactions to lung cancer risk in an asbestos-exposed cohort and to describe their reduction in lung cancer risk when they stop smoking. We examined lung cancer mortality obtained through the National Death Index for 1981 to 2008 for 2,377 male North American insulators for whom chest X-ray, spirometric, occupational, and smoking data were collected in 1981 to 1983 and for 54,243 non-asbestos-exposed blue collar male workers from Cancer Prevention Study II for whom occupational and smoking data were collected in 1982. Lung cancer caused 339 (19%) insulator deaths. Lung cancer mortality was increased by asbestos exposure alone among nonsmokers (rate ratio = 3.6 [95% confidence interval (CI), 1.7-7.6]), by asbestosis among nonsmokers (rate ratio = 7.40 [95% CI, 4.0-13.7]), and by smoking without asbestos exposure (rate ratio = 10.3 [95% CI, 8.8-12.2]). The joint effect of smoking and asbestos alone was additive (rate ratio = 14.4 [95% CI, 10.7-19.4]) and with asbestosis, supra-additive (rate ratio = 36.8 [95% CI, 30.1-45.0]). Insulator lung cancer mortality halved within 10 years of smoking cessation and converged with that of never-smokers 30 years after smoking cessation. Asbestos increases lung cancer mortality among nonsmokers. Asbestosis further increases the lung cancer risk and, considered jointly with smoking, has a supra-additive effect. Insulators benefit greatly by quitting smoking. 23929037 Lens density tracking in mice by Scheimpflug imaging. Scheimpflug imaging has recently been established for in vivo imaging of the anterior eye segment and quantitative determination of lens transparency in the mouse. This enables more effective investigations of cataract formation with the mouse model, including longitudinal studies. In order to enable recognition of disease-associated irregularities, we performed Scheimpflug measurements with the common laboratory inbred lines C57BL/6J, C3HeB/FeJ, FVB/NCrl, BALB/cByJ, and 129/SvJ in a period between 2 and 12 months of age. C57BL/6J mice showed lowest mean lens densities during the test period. Progressive cortical lens opacification was generally observed, with the earliest onset in C57BBL/6J, C3HeB/FeJ, and 129/SvJ, between 2 and 6 months after birth. Moreover, lenses of these inbred lines developed nuclear opacities. Calculated mean lens density significantly increased between 6 and 12 months of age in all inbred strains except 129/SvJ. Lens densities (and the corresponding standard deviations) of FVB/NCrl and 129/SvJ increased most likely because of differences in the genetic background. Albinism as confounder might be excluded since the albino Balb/cByJ mice are more similar to the C57BL/6J or C3Heb/FeJ mice. We further identified strain-specific anterior lens opacities (C57BL/6J) and cloudy corneal lesions (C57BL/6J, FVB/NCrl, and BALB/cByJ) at later stages. In conclusion, our results indicate that there are lifelong opacification processes in the mouse lens. The highest lens transparency and a dark coat color, which prevents interference from light reflections, make mice with the C57BL/6J background most suitable for cataract research by Scheimpflug imaging. We show that lens densitometry by Scheimpflug imaging in mouse eyes can resolve differences of less than 1 %, making it possible to detect differences in cataract development in different mouse strains, even if they are small. 23756337 Current thoughts and developments in facial nerve reanimation. To present the most current literature regarding the management of acute and chronic facial paralysis. This review will focus primarily on smile reanimation in the setting of acute and chronic facial paralysis. The management of the flaccid and the hypertonic face will be discussed. Recent developments include advances in neural repair with fibrin glue and the use of cadaveric nerve grafts as interposition grafts. Advances in nerve substitutes have been shown to limit donor-site morbidity and provide similar outcomes to autografts. Techniques for muscle transfer continue to evolve to improve smile outcomes. The goal of facial reanimation surgery is to restore meaningful facial movement. The goal should be to have quality-driven clinical practice guidelines to better facilitate patient care. This process must be initiated by facial reanimation surgeons deciding to use consistent outcome measures to report their results. Currently, it is impossible to make a direct comparison between different surgical techniques because of inconsistent methods of evaluation. Despite the lack of consistent quantitative evaluation, there have been many exciting advances in the field. 23102537 Executive attention deficits in schizophrenia: Putative mandatory and differential cognitive pathology domains in medicated schizophrenia patients. Executive attention (EA) is a core-construct of working memory (WM) capacity. EA performance is directly related to dorsolateral prefrontal cortex (DLPFC) activation, a neural mechanism that is dysfunctional in schizophrenia. We examined the differences in particular types of EA failure in schizophrenia patients and healthy controls. We evaluated executive attention in 60 medicated schizophrenia patients and 60 matched healthy individuals. We used a standard WM task, a verbal n-Back task, to measure executive attention (WM accuracy). Our standard-version WM task (control block, 10min long) was designed to examine baseline executive attention function and was followed by one out of three different experimental blocks (revised n-Back tasks). Baseline executive attention performance was significantly related to psychosis severity and functional capacity in the psychiatric group. In both healthy and psychiatric groups, experimental-block conditions revealed that domain-general recall had a differential effect on WM scores, and was related to the patient's clinical condition. Only in the psychiatric group domain-specific recall impairments were mandatory, most severe, and independent of baseline WM scores. The results revealed the importance of domain-general recall WM scores in the evaluation of executive attention deficits in patients and controls. Disruption in domain-specific recall may represent a specifier of cognitive impairment in schizophrenia spectrum disorders. 23352690 Menopause, atherosclerosis, and coronary artery disease. Women have coronary heart disease (CHD) later than men. This review describes studies of CHD risk factors or outcomes based on studies of premenopausal women followed through the menopause transition, and prospective cohort studies of younger or older women with CHD risk markers or disease outcomes in the context of their menopause history. Major early reports from both types of studies are included in order to put more recent work in context. Most attention has been paid to the Healthy Women Study (HWS), Study of Women's Health across the Nation (SWAN), the Nurses' Health Study (NHS), and the Rancho Bernardo Study (RBS) because they continue to produce recent publications designed to distinguish the effect of age from the effect of menopause. Understanding these differences has important implications for women's cardiovascular health, but remains incomplete. Transition studies have relatively short (<10 years) follow-up and exclude women with surgical menopause. Cohort studies suggest that women with oophorectomy are at greater risk for CHD than intact women, pointing to a greater risk from testosterone deficiency than from estradiol levels. 23879409 Stochastic lindemann kinetics for unimolecular gas-phase reactions. Lindemann, almost a century ago, proposed a schematic mechanism for unimolecular gas-phase reactions. Here, we present a new semiempirical method to calculate the effective rate constant in unimolecular gas-phase kinetics through a stochastic reformulation of Lindemann kinetics. Considering the rate constants for excitation and de-excitation steps in the Lindemann mechanism as temperature dependent empirical parameters, we construct and solve a chemical master equation for unimolecular gas-phase kinetics. The effective rate constant thus obtained shows excellent agreement with experimental data in the entire concentration range in which it is reported. The extrapolated values of the effective rate constant for very low and very high concentrations of inert gas molecules are in close agreement with values obtained using the Troe semiempirical method. Stochastic Lindemann kinetics, thus, provides a simple method to construct the full falloff curves and can be used as an alternative to the Troe semiempirical method of kinetic data analysis for unimolecular gas-phase reactions. 23815651 Operational sex ratio but not density affects sexual selection in a fish. The operational sex ratio (OSR) and density are considered important factors affecting the strength of sexual selection. Although there is increasing evidence that OSR and density affect the potential for sexual selection, few studies have addressed whether this is realized in phenotypic selection and how the two factors interact. We manipulated OSR (three levels) and male density (two levels) in 36 experimental breeding populations of Gobiusculus flavescens-a fish with paternal care. We measured mating competition behavior, the opportunity for selection (I), and selection on four morphological traits in males. We found sexual selection on two male traits, with the strongest selection being 20% of I. As predicted from OSR theory, increasing female scarcity caused males to become more competitive, concomitant with an increase in I and selection on morphological traits. Model simulations of I based on random mating (Imin ) and maximum mate monopolization (Imax ) demonstrated that the potential for sexual selection was close to its theoretical maximum across the range of OSRs. However, male density and its interaction with the OSR did not affect sexual selection. We argue that a multifaceted approach, combining mating behavior and selection analyses, can help us to understand how ecological factors affect sexual selection. 23833004 Upper oesophageal foreign body with acute respiratory distress. Foreign body (FB) ingestion, a common and serious problem in children can present with a wide variety of symptoms. Oesophageal FB leading to severe acute respiratory distress is uncommon and requires urgent surgical intervenetion. We report an 8-month-old female child who presented with severe respiratory distress to casualty and was found to have a FB in her upper oesophagus. 23624108 Association Between Variants of PRDM1 and NDP52 and Crohn's Disease, Based on Exome Sequencing and Functional Studies. Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies. We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems. We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 Ã— 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 Ã— 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor κB activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways. We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD. 23101934 The effect of oxygen heteroatoms on the single molecule conductance of saturated chains. Single molecule conductance measurements on alkanedithiols and alkoxydithiols (dithiolated oligoethers) were performed using the STM-controlled break junction method in order to ascertain how the oxygen heteroatoms in saturated linear chains impact the molecular conductance. The experimental results show that the difference in conductance increases with chain length, over the range studied. Comparisons with electronic structure calculations and previous work on alkanes indicate that the conductance of the oligoethers is lower than that of alkane chains with the same length. Electronic structure calculations allow the difference in the conductance of these two families of molecules to be traced to differences in the spatial distribution of the molecular orbitals that contribute most to the conductance. A pathway analysis of the electronic coupling through the chain is used to explain how the difference in conductance between the alkane and oligoether molecules depends on the chain length. 23760213 Urgent best medical therapy may obviate the need for urgent surgery in patients with symptomatic carotid stenosis. The purpose of this study was to analyze the 30-day outcome after introduction of a rapid carotid endarterectomy (CEA) program. Reasons for delay in CEA and the incidence of early recurrence neurological symptoms were recorded. This is a prospective population-based study of delays to CEA and 30-day outcome in patients with symptomatic carotid stenosis. Neurological recurrence (NR) rate was determined after initiation of urgent best medical treatment (loading dose aspirin/clopidogrel and duel therapy with aspirin plus clopidogrel with a statin) until CEA and compared with NR ≤90 days prior index event. Of a total of 4905 (transient ischemic attack/ischemic stroke, and ocular events) patients, 115 symptomatic patients underwent CEA, 42% within 14 days of the index event and 99% within 14 days of surgical referral. The overall NR from index event to CEA in symptomatic carotid stenosis patients was significantly lower (2.5% [95% confidence interval, 1%-6%]) after best medical treatment when compared with NR ≤90 days in those before referral to a stroke clinic (29% [95% confidence interval, 22%-37%]; P<0.00001). There were no significant differences in outcomes among 48 early (<14 days), 46 intermediate (14-30 days), and 21 delayed (>30 days) CEAs. CEA can be performed in the subacute period without significantly increasing the operative risk. The urgent best medical treatment was associated with significant reduction in the risk of early NR in CEA patients. It seems that urgent aggressive best medical treatment may obviate the need for urgent CEA. 23883595 Interferon regulatory factor 5 and autoimmune lupus. Systemic lupus erythematosus (SLE) is a severe multi-system autoimmune disease, whereas interferon regulatory factor (IRF) 5 belongs to the family of transcription factors that modulate immune system activities. Recently, many lines of investigations suggested that IRF5 gene polymorphisms are closely associated with the disease onset of SLE. Indeed, expressed in B cells, dendritic cells (DCs), monocytes and macrophages, IRF5 could significantly affect these immune cells participating in the pathogenesis of SLE, and numerous studies implied that this transcription factor is mechanistically linked to the disease progression. Here, we comprehensively review the updated evidence indicating the roles of IRF5 in autoimmune lupus. Hopefully, the information obtained will lead to a better understanding of the pathogenesis and development of novel therapeutic strategies for the systemic autoimmune disease. 23419072 Laponite nanodisks as an efficient platform for Doxorubicin delivery to cancer cells. We report a facile approach to using laponite (LAP) nanodisks as a platform for efficient delivery of doxorubicin (DOX) to cancer cells. In this study, DOX was encapsulated into the interlayer space of LAP through an ionic exchange process with an exceptionally high loading efficiency of 98.3 ± 0.77%. The successful DOX loading was extensively characterized via different methods. In vitro drug release study shows that the release of DOX from LAP/DOX nanodisks is pH-dependent, and DOX is released at a quicker rate at acidic pH condition (pH = 5.4) than at physiological pH condition. Importantly, cell viability assay results reveal that LAP/DOX nanodisks display a much higher therapeutic efficacy in inhibiting the growth of a model cancer cell line (human epithelial carcinoma cells, KB cells) than free DOX drug at the same DOX concentration. The enhanced antitumor efficacy is primarily due to the much more cellular uptake of the LAP/DOX nanodisks than that of free DOX, which has been confirmed by confocal laser scanning microscope and flow cytometry analysis. The high DOX payload and enhanced antitumor efficacy render LAP nanodisks as a robust carrier system for different biomedical applications. 23833270 Interaction of 11C-Tariquidar and 11C-Elacridar with P-Glycoprotein and Breast Cancer Resistance Protein at the Human Blood-Brain Barrier. The adenosine triphosphate-binding cassette transporters P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) are 2 major gatekeepers at the blood-brain barrier (BBB) that restrict brain distribution of several clinically used drugs. In this study, we investigated the suitability of the radiolabeled Pgp/BCRP inhibitors (11)C-tariquidar and (11)C-elacridar to assess Pgp density in the human brain with PET. Healthy subjects underwent a first PET scan of 120-min duration with either (11)C-tariquidar (n = 6) or (11)C-elacridar (n = 5) followed by a second PET scan of 60-min duration with (R)-(11)C-verapamil. During scan 1 (at 60 min after radiotracer injection), unlabeled tariquidar (3 mg/kg) was intravenously administered. Data were analyzed using 1-tissue 2-rate-constant (1T2K) and 2-tissue 4-rate-constant (2T4K) compartment models and either metabolite-corrected or uncorrected arterial input functions. After injection of (11)C-tariquidar or (11)C-elacridar, the brain PET signal corrected for radioactivity in the vasculature was low (∼0.1 standardized uptake value), with slow washout. In response to tariquidar injection, a moderate but statistically significant rise in brain PET signal was observed for (11)C-tariquidar (+27% ± 15%, P = 0.014, paired t test) and (11)C-elacridar (+21% ± 15%, P = 0.014) without changes in plasma activity concentrations. Low levels of radiolabeled metabolites (<25%) were detected in plasma up to 60 min after injection of (11)C-tariquidar or (11)C-elacridar. The 2T4K model provided better data fits than the 1T2K model. Model outcome parameters were similar when metabolite-corrected or uncorrected input functions were used. There was no significant correlation between distribution volumes of (11)C-tariquidar or (11)C-elacridar and distribution volumes of (R)-(11)C-verapamil in different brain regions. The in vivo behavior of (11)C-tariquidar and (11)C-elacridar was consistent with that of dual Pgp/BCRP substrates. Both tracers were unable to visualize cerebral Pgp density, most likely because of insufficiently high binding affinities in relation to the low density of Pgp in human brain (∼1.3 nM). Despite their inability to visualize Pgp density, (11)C-tariquidar and (11)C-elacridar may find use as a new class of radiotracers to study the interplay of Pgp and BCRP at the human BBB in limiting brain uptake of dual substrates. 23253819 The applause sign and neuropsychological profile in progressive supranuclear palsy and Parkinson's disease. The applause sign has been associated with various neurodegenerative diseases. We investigate its validity in the differential diagnosis of progressive supranuclear palsy and Parkinson's disease, and its relationship with neuropsychological tests. 23 patients with progressive supranuclear palsy and 106 patients with Parkinson's disease were included and administered the following scales: progressive supranuclear palsy rating scale, unified Parkinson's disease rating scale (UPDRS), mini-mental state examination (MMSE), frontal assessment battery (FAB), neuropsychiatric inventory and three-clap test. 73.9% with progressive supranuclear palsy and 21.7% with Parkinson's disease showed a positive applause sign. Only a positive applause sign, UPDRS II score and disease duration were found to be predictors of progressive supranuclear palsy. Both patient-groups showed statistically significant correlations between the applause sign and neuropsychological tests: in progressive supranuclear palsy patients MMSE correlation coefficient: 0.62 (p: 0.002) and FAB correlation coefficient: 0.48 (p: 0.02), and in Parkinson's disease patients MMSE correlation coefficient: 0.47 (p<0.001) and FAB correlation coefficient: 0.43 (p<0.001). Verbal fluency and inhibitory control (FAB) and writing and orientation in time (MMSE) discriminated between patients with normal and positive applause sign. A positive applause sign is not specific to progressive supranuclear palsy and may also be observed in Parkinson's disease patients with altered cognition, and it's related to cortical frontal abnormalities such as language disorders and inhibitory control. 23954695 Molecular characterization and expression analysis of three membrane-bound complement regulatory protein isoforms in the ginbuna crucian carp Carassius auratus langsdorfii. Regulators of complement activation (RCA) play a role in protecting cells from excessive complement activation in humans. cDNA corresponding to three isoforms of teleost membrane-bound RCA protein (gTecrem) have been identified in the ginbuna crucian carp. gTecrem-1 consists of seven short consensus repeats (SCRs), whereas gTecrem-2 and gTecrem-3 have four SCRs. While gTecrem-1 possesses a tyrosine phosphorylation site in its cytoplasmic region, gTecrem-2 and gTecrem-3 lack the site. Tissue distribution analysis showed that gTecrem-1 and gTecrem-2 mRNAs were expressed in almost all tissues examined, whereas gTecrem-2 expression was not significantly detected in gill, liver, or intestine. Furthermore, analysis showed that gTecrem-1 was expressed in both peripheral blood leukocytes (PBLs) and erythrocytes and was also expressed in T cell subsets such as CD4(+), CD8(+) T cells, and IgM(+) B cells. gTecrem-2 expression was not detected in either PBLs or erythrocytes, whereas gTecrem-3 was expressed only in erythrocytes. These results suggested that gTecrem isoforms may serve different functional roles; gTecrem-1, which is expressed in T cells and possesses a tyrosine phosphorylation site, may act as a complement regulator and a cellular receptor in adaptive immunity. 23582344 Perioperative haemorrhage in endovascular abdominal aneurysm repair affects outcome. This study aimed to evaluate the outcome and predisposing factors related to perioperative bleeding in patients treated with endovascular aneurysm repair (EVAR) for ruptured and non-ruptured abdominal aortic aneurysm (AAA). This was a retrospective cohort study. A total of 525 consecutive patients (73% elective) with AAA underwent EVAR at two vascular centres from 2008 to 2011. From registry data perioperative bleeding was analysed in relation to outcome and preoperative data. A total of 453 (86%) patients presented with a perioperative bleeding <1000 ml, 42 (8%) patients 1000-1999 ml, 19 (4%) patients 2000-5000 ml and 11 (2%) >5000 ml. Other than ruptured AAA (n = 90), no preoperative risk factors for increased perioperative bleeding were found. Open femoral artery access (n = 101), branched (n = 18) and uni-iliacal endografts (n = 18) and introducer size were associated with increased perioperative bleeding (P < 0.001). In multivariable logistic regression only rupture and perioperative bleeding >2000 ml were significantly related to 30-day mortality (odds ratio 10.6 (range 3.8-29.6) and 13.4 (range 4.8-37.4), respectively). Postoperative renal failure, multi-organ failure, >5 days at intensive care unit, bowel ischaemia and abdominal compartments syndrome were significantly related to perioperative bleeding >2000 ml (P < 0.001). Large perioperative bleeding during EVAR is a clinical problem that affects outcome. About 10% of elective AAA patients and 34% of patients with ruptured AAA, undergoing EVAR, present a perioperative blood loss exceeding 1 l. In our study, a perioperative blood loss exceeding 2 l was independently associated with increased mortality and morbidity in both acute and elective AAA patients. Open femoral access, branched EVAR and larger diameter introducers were associated with increased perioperative blood loss. ETHICAL APPLICATION: 2011/664-31/3 (approved). 22980521 A prospective pilot study of repetitive transcranial magnetic stimulation for gait dysfunction in vascular parkinsonism. Vascular Parkinsonism (VP) causes significant gait dysfunction in patients who otherwise have good lower limb strength. Its pathophysiology is not clearly understood, and current treatment with physical therapy remains unsatisfactory. The study explores repetitive transcranial magnetic stimulation (rTMS) as a potential new and safe therapy for VP. We prospectively applied 5 Hz rTMS treatment to 5 patients who satisfied all the criteria for VP. Repetitive TMS was performed on 5 consecutive days and patients were assessed on (1) timed 10 m walk (T10MW), (2) Unified Parkinson's Disease Rating Scale (UPDRS) motor subsection, (3) Clinician's Global Impression of Change (CGIC), and (4) Patient's Global Impression of Change (PGIC), for up to 6 weeks post-rTMS. All the outcome measures were found to have improved ratings post-rTMS when compared with baseline, and were statistically significant. The T10MW showed significant improvement at 4 weeks post-rTMS with a trend towards improvement at 2 weeks post-rTMS. The UPDRS motor subscores was significantly reduced at 2 weeks, 4 weeks and 6 weeks post-rTMS. The PGIC and CGIC scores were significantly better post-rTMS. The treatment was well-tolerated and all patients completed the study. This study demonstrated for the first time that 5 sessions of rTMS could improve gait in a measurable way for up to 6 weeks without any significant side-effects. Repetitive TMS could be a potentially useful adjunct in rehabilitation of VP patients and further research is warranted. 23325369 Increases in triglyceride levels are associated with clinical response to clozapine treatment. Increases in serum triglyceride (TG) levels are associated with clinical response to clozapine treatment. Clozapine is the most efficacious therapy for treatment of refractory schizophrenia, although its use is well recognised to be associated with substantial metabolic dysfunction. Interestingly, there is some evidence that the therapeutic benefit of clozapine is associated with treatment-emergent weight gain and dyslipidaemia, specifically hypertriglyceridaemia. In this prospective observational study, we examine associations between therapeutic response to clozapine in 49 patients with treatment-resistant schizophrenia and lipid dysregulation. An increase in TG levels was strongly predictive of clinical improvement (B=9.33, t =3.56, df=4, p<0.001) and of improvement in positive PANSS scores (B=2.85, t=3.61, df=4, p=0.001) as well as negative PANSS scores (B=1.93, t=2.36, df=4, p=0.02), when controlling for potential confounds of weight gain, change in waist circumference, baseline antipsychotic polypharmacy and serum clozapine levels. This finding suggests that clozapine's therapeutic efficacy is linked to serum lipid changes. Hypertriglyceridaemia as a predictor of clinical response in patients treated with clozapine merits further investigation in order to better elucidate its effect on the pharmacological activity of clozapine. 23902708 Insights into the prognostic value of DJ-1 and MIB-1 in astrocytic tumors. The histological grade is the gold standard for the evaluation of prognosis of astrocytic tumors. Nevertheless, morphologic criteria are not always accurate prognostic indicators. Aim: The research investigates the expression of MIB-1 and DJ-1 in different grades of astrocytomas and evaluates the possible prognostic role of DJ-1 in these tumors in relation to other prognostic parameters including the MIB-1 labeling index Materials and methods: Immunohistochemical expression of MIB-1 and DJ-1 was evaluated in 111 samples of astrocytic tumors comprising 28 diffuse astrocytomas, 38 anaplastic astrocytomas and 45 glioblastomas. The univariate survival analysis was done using the Kaplan-Meier method and the multivariate survival analysis was done using Cox proportional hazard model. The statistical analysis revealed a significant correlation between each of DJ-1 and MIB-1 and the histological grade of astrocytomas. The univariate analysis showed that high grade, high DJ-1 score and MIB-1 labeling index [greater than or equal to] 10.1 were associated with poor survival. Multivariate analysis for all the studied astrocytomas proved the independent prognostic significance of the histological grade and DJ-1 score. Meanwhile, the multivariate analysis for each grade emphasized that DJ-1 was the only independent prognostic indicator in high-grade astrocytomas. This study emphasized the effectiveness of high DJ-1 expression in predicting poor survival of astrocytoma patients, when compared to MIB-1. DJ-1 could be particularly important in cases with discrepancies between the morphologic criteria and clinical parameters. Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1070116023943146. 23969309 Biological and Clinical Features of Trisomy 21 in Adult Patients With Acute Myeloid Leukemia. Trisomy 21 is frequently noted in patients with AML. In adults, +21 has traditionally been considered an intermediate-risk cytogenetic aberration. We analyzed 90 patients with newly diagnosed AML harboring +21. Four cytogenetic subgroups were defined based on associated cytogenetic abnormalities: +21 alone, +21 with favorable, +21 with intermediate, and +21 with unfavorable cytogenetics. Fifty-four percent of patients with +21 AML achieved a complete remission (CR) or CR with incomplete platelet recovery (CRp) after induction therapy with a trend toward improved CR/CRp rates in patients with +21 alone/+21 with favorable cytogenetics compared with patients with +21 with intermediate/+21 with unfavorable cytogenetics (76% vs. 50%; P = .057). Time to progression (TTP) was 12 months (range, 5-19) and overall survival (OS) was 9 months (range, 7-11) for the entire group. TTP was longer for patients with +21 alone (not reached) or with +21 with favorable cytogenetics (101 months) compared with those with +21 with intermediate cytogenetics (2 months) or +21 with unfavorable cytogenetics (11 months) (P = .02). Similarly, OS was improved in patients with +21 with favorable cytogenetics (not reached) or +21 alone (107 months), compared with +21 with unfavorable cytogenetics (9 months) or +21 with intermediate cytogenetics (8 months) (P < .001). The differences in TTP and OS were maintained on multivariate analysis (P = .04 and P = .001; respectively). Isolated +21 hitherto classified as intermediate-risk cytogenetics might actually behave as a favorable-risk cytogenetics in adult AML patients. 23595200 Strategies to ameliorate abiotic stress-induced plant senescence. The plant senescence syndrome resembles, in many molecular and phenotypic aspects, plant responses to abiotic stresses. Both processes have an enormous negative global agro-economic impact and endanger food security worldwide. Premature plant senescence is the main cause of losses in grain filling and biomass yield due to leaf yellowing and deteriorated photosynthesis, and is also responsible for the losses resulting from the short shelf life of many vegetables and fruits. Under abiotic stress conditions the yield losses are often even greater. The primary challenge in agricultural sciences today is to develop technologies that will increase food production and sustainability of agriculture especially under environmentally limiting conditions. In this chapter, some of the mechanisms involved in abiotic stress-induced plant senescence are discussed. Recent studies have shown that crop yield and nutritional values can be altered as well as plant stress tolerance through manipulating the timing of senescence. It is often difficult to separate the effects of age-dependent senescence from stress-induced senescence since both share many biochemical processes and ultimately result in plant death. The focus of this review is on abiotic stress-induced senescence. Here, a number of the major approaches that have been developed to ameliorate some of the effects of abiotic stress-induced plant senescence are considered and discussed. Some approaches mimic the mechanisms already used by some plants and soil bacteria whereas others are based on development of new improved transgenic plants. While there may not be one simple strategy that can effectively decrease all losses of crop yield that accrue as a consequence of abiotic stress-induced plant senescence, some of the strategies that are discussed already show great promise. 23945733 Profile of Ospemifene in the Breast. Vulvar and vaginal atrophy (VVA) is a chronic, progressive medical condition prevalent among postmenopausal women, which produces symptoms such as dyspareunia, vaginal dryness, and vaginal irritation. Currently, the only prescription options are systemic and vaginal estrogen therapies that may be limited by concerns about long-term safety and breast cancer risk. Ospemifene is a tissue-selective estrogen agonist/antagonist (a selective estrogen receptor modulator) recently approved by the US Food and Drug Administration for treatment of dyspareunia, a symptom of VVA, due to menopause. Ospemifene, the first nonestrogen oral treatment for this indication, may provide an alternative to treatment with estrogen. Animal models with ospemifene suggest an inhibitory effect on growth of malignant breast tissue, but animal data cannot necessarily be extrapolated to humans. Clinical trials, including 3 long-term studies assessing the overall safety of ospemifene, support that ospemifene is generally well tolerated, with beneficial effects on the vagina, neutral effects on the breast, and minimal effects on the endometrium. 23832166 Outcome after total ankle arthroplasty-results and findings from worldwide arthroplasty registers. The data currently available concerning total ankle arthroplasty (TAA) does not allow valid conclusions in several clinically relevant areas. Total ankle arthroplasty imposes special requirements on the methodology of data collection, evaluation, publication and the assessment of register data. We undertook a structured and descriptive analysis of all outcome data available from high-quality national arthroplasty registers worldwide. Register data from Sweden, Finland, Norway, New Zealand and Australia were included in the analysis. There are marked differences between Europe and Oceania with respect to indications. All data sets show revision rates of approximately 10 % at five years, of which about 40 % of cases are for aseptic loosening. Inlay fractures are relatively common, which indicates potential for the improvement of implants. The documentation of intraoperative surgical errors leading to revision surgery varies significantly among registers. A relevant number of complications are treated without an implant component being exchanged and therefore not covered by a register. The results of TAA are promising, but the revision rate is higher than for total hip or knee arthroplasty. TAA outcome measurement by means of registers has several specific requirements necessitating additional documentation beyond the basic data set. For methodological reasons the evaluation of results is more complex than for hip or knee arthroplasty. It will therefore be essential to standardise data collection and evaluation and develop a methodology addressing the specific needs of TAA. 23889886 The Gait Variability Index: A new way to quantify fluctuation magnitude of spatiotemporal parameters during gait. This article describes a conglomerate measure of gait variability based on nine spatiotemporal parameters: the Gait Variability Index (GVI). Concurrent validity, inter-session reliability and minimum detectable change (MDC) were evaluated in 31 patients with Friedreich's Ataxia (FRDA), through comparisons with classically used evaluation tools such as the International Cooperative Ataxia Rating Scale (ICARS). GVI scores for the healthy population were 100.3±8.6 and were significantly reduced in FRDA patients (70.4±7.9). The GVI was correlated with the global ICARS score and was sensitive enough to differentiate between groups of FRDA patients categorized by the Posture and Gait Disturbances sub-score. The GVI was found to have a high inter-session reliability with an intraclass correlation coefficient of 0.91. A MDC of 8.6 points was found necessary to ensure that a change in GVI reflects a true change rather than measurement error. The GVI provides a quantitative measure of variability which behaves well statistically in both HP and patients with FRDA. It can be easily implemented using the supplemental data provided with this article. Complementary work is necessary to strengthen the GVI validation. 23758706 A stream-based methane monitoring approach for evaluating groundwater impacts associated with unconventional gas development. Gaining streams can provide an integrated signal of relatively large groundwater capture areas. In contrast to the point-specific nature of monitoring wells, gaining streams coalesce multiple flow paths. Impacts on groundwater quality from unconventional gas development may be evaluated at the watershed scale by the sampling of dissolved methane (CH4 ) along such streams. This paper describes a method for using stream CH4 concentrations, along with measurements of groundwater inflow and gas transfer velocity interpreted by 1-D stream transport modeling, to determine groundwater methane fluxes. While dissolved ionic tracers remain in the stream for long distances, the persistence of methane is not well documented. To test this method and evaluate CH4 persistence in a stream, a combined bromide (Br) and CH4 tracer injection was conducted on Nine-Mile Creek, a gaining stream in a gas development area in central Utah. A 35% gain in streamflow was determined from dilution of the Br tracer. The injected CH4 resulted in a fivefold increase in stream CH4 immediately below the injection site. CH4 and δ(13) CCH4 sampling showed it was not immediately lost to the atmosphere, but remained in the stream for more than 2000 m. A 1-D stream transport model simulating the decline in CH4 yielded an apparent gas transfer velocity of 4.5 m/d, describing the rate of loss to the atmosphere (possibly including some microbial consumption). The transport model was then calibrated to background stream CH4 in Nine-Mile Creek (prior to CH4 injection) in order to evaluate groundwater CH4 contributions. The total estimated CH4 load discharging to the stream along the study reach was 190 g/d, although using geochemical fingerprinting to determine its source was beyond the scope of the current study. This demonstrates the utility of stream-gas sampling as a reconnaissance tool for evaluating both natural and anthropogenic CH4 leakage from gas reservoirs into groundwater and surface water. 23681739 Integrated ecotoxicological assessment of marine sediments affected by land-based marine fish farm effluents: physicochemical, acute toxicity and benthic community analyses. An integrated ecotoxicological assessment of marine sediments affected by land-based marine fish farm effluents was developed using physicochemical and benthic community structure analyses and standardised laboratory bioassays with bacteria (Vibrio fischeri), amphipods (Ampelisca brevicornis) and sea urchin larvae (Paracentrotus lividus). Intertidal sediment samples were collected at five sites of the Rio San Pedro (RSP) creek, from the aquaculture effluent to a clean site. The effective concentration (EC50) from bacterial bioluminescence and A. brevicornis survival on whole sediments and P. lividus larval developmental success on sediment elutriates were assessed. Numbers of species, abundance and Shannon diversity were the biodiversity indicators measured in benthic fauna of sediment samples. In parallel, redox potential, pH, organic matter and metal levels (Cd, Cu, Ni, Pb and Zn) in the sediment and dissolved oxygen in the interstitial water were measured in situ. Water and sediment physicochemical analysis revealed the exhibition of a spatial gradient in the RSP, evidenced by hypoxia/anoxia, reduced and acidic conditions, high organic enrichment and metal concentrations at the most contaminated sites. Whereas, the benthic fauna biodiversity decreased the bioassays depicted decreases in EC50, A. brevicornis survival, P. lividus larval success at sampling sites closer to the studied fish farms. This study demonstrates that the sediments polluted by fish farm effluents may lead to alterations of the biodiversity of the exposed organisms. 23807269 Rapid HIV self-testing: long in coming but opportunities beckon. The recent approval by the United States Food and Drug Administration of a rapid HIV self-test marks a significant milestone in the evolution of HIV testing approaches. With nearly one in five people living with HIV in the United States still undiagnosed and an even higher proportion unaware of their infection globally, this decision reflects a new willingness to offer diverse options to get tested for HIV. Rapid self-testing offers several distinct opportunities to improve testing among those with undiagnosed HIV: to encourage testing among those who might not otherwise be tested, to increase the frequency of testing among persons at highest risk for new infection, and to facilitate mutual HIV testing with sex partners. To date, the path to regulatory approval has been long but instructive. The studies and clinical trials required for regulatory approval in the United States provide insight into the performance and potential implications of HIV self-tests as they become available for sale directly to consumers. Although some persistent reservations about self-testing for HIV remain, including the 'window period' of the current test kit, its cost, and its effectiveness for facilitating entry to medical care, others have been dispelled. Self-testing in resource-constrained settings is also promising, including self-testing of health professionals. At present, although the impact has yet to be determined, availability of this new option might offer potential opportunities to improve HIV diagnosis and facilitate both treatment and prevention. 23603919 Correlation between HPV sperm infection and male infertility. Human papillomavirus (HPV) is one of the most common sexually transmitted diseases which comprises a group of small DNA viruses that infect both cutaneous and mucous squamous epithelia. Liquid bead microarray technology (LBMA) were used to evaluate 24 HPV genotypes in confirmed fertile and infertile males of North China so that the effects of HPV infection on semen parameters and relationship with male infertility could be discussed. A total of 1138 subjects were recruited in this study; 142 were HPV-positive (12.48%). Among 523 confirmed fertile males, only 35 were HPV-positive (6.70%), and two of them had multiple infections. Among 615 infertile males, 107 were HPV-positive (17.4%), and 29 of them had multiple infections. Infertile males had a relatively high HPV infection rate compared with confirmed fertile males. Sperm progressive motility (PR) and the normal morphology rate were significantly decreased in HPV-positive subjects. HPV-45, HPV-52, HPV-18, HPV-59 and HPV-16 infections were more frequently in infertile males. Hence, HPV infection is closely related to male infertility which will decrease sperm PR and morphology. HPV-45, HPV-52, HPV-18, HPV-59 and HPV-16 infection seems to be major risk factors. 23435216 Fluctuating charge-density waves in a cuprate superconductor. Cuprate materials hosting high-temperature superconductivity (HTS) also exhibit various forms of charge and spin ordering whose significance is not fully understood. So far, static charge-density waves (CDWs) have been detected by diffraction probes only at particular doping levels or in an applied external field . However, dynamic CDWs may also be present more broadly and their detection, characterization and relationship with HTS remain open problems. Here we present a method based on ultrafast spectroscopy to detect the presence and measure the lifetimes of CDW fluctuations in cuprates. In an underdoped La1.9Sr0.1CuO4 film (Tc = 26 K), we observe collective excitations of CDW that persist up to 100 K. This dynamic CDW fluctuates with a characteristic lifetime of 2 ps at T  =  5 K that decreases to 0.5 ps at T  =  100 K. In contrast, in an optimally doped La1.84Sr0.16CuO4 film (Tc  =  38.5 K), we detect no signatures of fluctuating CDWs at any temperature, favouring the competition scenario. This work forges a path for studying fluctuating order parameters in various superconductors and other materials. 23911649 Localization of type-III sodium-dependent phosphate transporter 2 in the mouse brain. Type-III sodium-dependent phosphate transporters 1 and 2 (PiT-1 and PiT-2, respectively) are proteins encoded by SLC20A1 and SLC20A2, respectively. The ubiquitous distribution of PiT-1 and PiT-2 mRNAs in mammalian tissues is in agreement with the housekeeping maintenance of homeostasis of intracellular inorganic phosphate (Pi), which is absorbed from interstitial fluid for normal cellular functions. Recently, mutations of SLC20A2 have been found in patients with idiopathic basal ganglia calcification (IBGC), also known as Fahr's disease. However, the localization of PiT-2 in the brain has not been clarified yet. Therefore, the aim of this study is to clarify the distribution of PiT-2 expression in the mouse brain. Our biochemical and immunohistochemical analyses using a polyclonal antibody (Ab) and a monoclonal Ab showed that PiT-2 was ubiquitously expressed throughout the brain. In terms of the cellular type, PiT-2 was predominantly detected in neurons; it colocalized with β-tubulin III in the cerebral cortex and with calbindin D-28K in Purkinje cells. Additionally, PiT-2 immunopositivity was detected in the microtubule-associated protein 2-positive neuronal dendrites in the cerebral cortex. However, colocalization with PiT-2 immunopositivity was not observed in the synaptophysin-positive nerve terminals. PiT-2 was also expressed in astrocytes and vascular endothelial cells. Our results indicate that PiT-2 plays an important role in the maintenance of cellular Pi homeostasis in neurons, astrocytes, and endothelial cells. This finding is a milestone in the study of the function of PiT-2 in the normal mouse brain and particularly in the brains of patients with Fahr's disease. 23960026 Muscle mass predicts outcomes following liver transplantation. For patients with end-stage liver disease, commonly used indices of nutritional status (ie, body weight and body mass index) are often inflated because of fluid overload (ie, ascites and peripheral edema), and this results in an underdiagnosis of malnutrition. Because muscle is the largest protein reservoir in the body, an estimate of the muscle mass may be a more reliable and valid estimate of nutritional status. Therefore, we used pretransplant computed tomography data for 338 liver transplantation (LT) candidates to identify muscle and fat mass on the basis of a specific abdominal transverse section commonly used in body composition analyses, and we investigated the contribution of this measure to specific post-LT outcomes. We found that the majority of our patients (68%) could be defined as cachectic. For men, muscle mass predicted many important posttransplant outcomes, including intensive care unit (ICU) stay, total length of stay (LOS), and days of intubation. Muscle mass was a significant predictor of survival and also predicted disposition to home versus another facility. For women, muscle mass predicted ICU stay, total LOS, and days of intubation, but the effect was modest. Muscle mass did not predict survival or disposition for women. In conclusion, because pretransplant muscle mass is associated with many important postoperative outcomes, we discuss these findings in the context of possible pretransplant interventions for either improving or sustaining muscle mass before surgery. Liver Transpl 000:000-000, 2013. © 2013 AASLD. 23883158 Modelling the effects of environmental conditions on HT2 andT2 toxin accumulation in field oat grains. Fusarium head blight (FHB) of wheat and barley has been extensively researched worldwide; in contrast, there is limited information on the effects of environmental conditions on Fusarium toxin accumulation in oat grains. More than 300 samples of oat grain from various regions of the UK from 2006-2008 were analysed for mycotoxin contamination due to infection by Fusarium species. HT2 and T2 toxins were the two most commonly detected, and their concentrations in individual samples were highly correlated. Hourly weather data were obtained from meteorological recording stations near most of the sampling sites. Statistical modelling were applied to both the original toxin (HT2 plus T2) data and the toxin data adjusted for oat cultivars and number of cereal crops in the previous four seasons. Accumulation of HT2 and T2 toxin was positively correlated with warm/wet conditions during the early May and dry conditions thereafter. Using a collection of 51 environmental variables summarised over three lengths (10-, 15- and 20-days) of time periods encompassing the early May, late May and early July, all-subsets regression showed that many models, consisting of three-to-six predictor variables, could be identified with similar explanatory strength for the effect of environmental conditions on toxin accumulation. Most important predictor variables were related to wet conditions during the early-May period, which was before anthesis. These results suggest that the predominant period for F. langsethiae infection of oats is likely to be before, rather than during, anthesis as for other head blight pathogens. These empirical models may be further improved by using quantified pathogen biomass within the grains and weather predictor variables summarised in relation to plant growth stages [instead of calendar times]. 23149809 Ferulic acid modulates fluoride-induced oxidative hepatotoxicity in male Wistar rats. The present study is aimed to evaluate the protective effect of ferulic acid (FA) on fluoride-induced oxidative hepatotoxicity in male Wistar rats. Fluoride (25 mg/L) was given orally to induce hepatotoxicity for 12 weeks. Hepatic damage were assessed using status of pathophysiological markers like serum marker enzymes like aspartate transaminase, alanine transaminase, alkaline phosphatase, acid phosphatase, gamma glutamyl transferase, lactate dehydrogenase, bilirubin, lipid profile, total protein content levels, and histopathological studies. Treatment with FA significantly reduced the degree of histological aberrations and rescued lipid peroxidation, as observed from reduced levels of lipid hydroperoxides, nitric oxide, restored levels of enzymic and non-enzymic antioxidants, and total protein content, with a concomitant decline in the levels of marker enzymes and lipid profile in fluoride-induced rats. These results suggest that ferulic acid has the ability to protect fluoride-induced hepatic damage. 23673013 Implementing acute care surgery at a level I trauma center: 1-year prospective evaluation of the impact of this shift on trauma volumes and outcomes. The purpose of this study was to evaluate the impact of the transition to acute care surgery (ACS) on trauma volumes and outcomes. All admissions from 2 1-year periods from June 2008 to May 2010 (1 year before ACS and 1 year after ACS) to the LAC+USC Medical Center were prospectively collected. In anticipation of this change, trauma patient demographics, clinical data, and outcomes (trauma volume and preventable and potentially preventable deaths and complications) were prospectively collected. Before ACS, there were 5,378 trauma admissions. After ACS, there were 5,726 (66.5%) trauma and 2,886 (33.5%) nontrauma admissions. There were no demographic or clinical differences between trauma patients in the 2 groups. There was no significant difference in overall mortality (3.8% before ACS vs 3.3% after ACS, P = .292). Similarly, there were no differences in the rates of preventable and potentially preventable deaths or complications observed (1.2% vs 1.0%, P = .374) during the study period. Despite a 60% increase in total patient volume and a 233% increase in operative volume over the study period, the addition of emergency surgery to a trauma service did not compromise trauma patient outcomes. 23877852 Predictors of hypertension control in Turkey: the MELEN study. Hypertension is one of the most common causes of atherosclerosis, morbidity and mortality in adults. A total of 11 million hypertensive patients were estimated in Turkey. The aim of this study was to investigate the prevalence, awareness and control of hypertension in Duzce and compare the current data with the literature. The visits were carried out in May and June, 2010 in Yigilca town health centre on 2298 participants (1471 female, 827 male with a mean age of 50). Data were obtained by a simple form, physical examination and sampling of blood. Hypertension was defined as a blood pressure 140 mmHg and/or 90 mmHg, and/or use of antihypertensive medication. The data of patients under control were compared with the patients who were not under control. Hypertension was detected in 964 participants. General prevalence was 42%. Hypertension awareness ratio was 70%, use of antihypertensive medication was 39% and the ratio of patients under control was 28%. Antihypertensive drug use, age and awareness were lower in the uncontrolled group. Logistic regression analysis revealed that only antihypertensive drug use and BMI < 30 were the independent predictors of hypertension under control [Odd's ratio (OR) = 3.43; 95% confidence interval (CI) = 2.54-4.64, p < 0.001 and OR = 1.69; 95% CI = 1.23- 2.32, p = 0.01; respectively]. Hypertension is one of the most important public health problems in Turkey. According to the literature data the awareness of hypertension was increased significantly in the last five years. On the other hand, control ratio was increased very little compared with the previous studies. 23409829 Human T cell lymphotropic virus type 1 infection among U.S. thalassemia patients. Thalassemia is an inherited genetic disorder requiring multiple transfusions to treat anemia caused by low hemoglobin levels. Thus, thalassemia patients are at risk for infection with blood-borne pathogens, including human T cell lymphotropic viruses (HTLV) that are transmitted by transfusion of cellular blood products. Here, we examined the prevalence of HTLV among 234 U.S. thalassemia patients using sera collected in 2008. Sera were tested for antibodies to HTLV-1/2 using enzyme immunoassay (EIA) and a confirmatory western blot (WB) that differentiates between HTLV-1 and HTLV-2. Demographic information and clinical information were collected at study enrollment, including HIV and hepatitis C virus (HCV) status. Three patients (1.3%) were WB positive; two were HTLV-1 and one could not be serotyped as HTLV-1/2. All three HTLV-positive persons were HIV-1 negative and one was HCV seropositive. The HTLV seroprevalence was higher than that of HIV-1 (0.85%) and lower than HCV (18.8%) in this population. All three patients (ages 26-46 years) were diagnosed with β-thalassemia shortly after birth and have since been receiving multiple transfusions annually. Two of the HTLV-positive patients confirmed receiving transfusions before HTLV blood screening was implemented in 1988. We identified a substantial HTLV-1 seroprevalence in U.S. thalassemia patients that is much greater than that seen in blood donors. Our findings highlight the importance of HTLV testing of patients with thalassemia and other diseases requiring multiple transfusions, especially in recipients of unscreened transfusions. In addition, appropriate counseling and follow-up of HTLV-infected patients are warranted. 23948571 Managing End Stage Lung Disease in Children. Over the course of a career most physicians will manage only a handful of children through End Stage Lung Disease. Nonetheless, the approach of the physician to this challenge will have a profound impact on the children and families they encounter. Managing the end of life well can bring personal growth and professional satisfaction. In this review we highlight aspects of the Palliative Care approach and its integration with restorative and life-prolonging care. We review the role of active treatment, respiratory support, symptom management and psychosocial aspects of the management of End Stage Lung Disease. 23928006 Scientific Globish versus scientific English. The proposed adoption of 'scientific Globish' as a simplified language standard for scholarly communication may appeal to authors who have difficulty with English proficiency. However, Globish might not justify the hopes being pinned on it and might open the door to further deterioration of the quality of English-language scientific writing. 23532998 SpecDis: quantifying the comparison of calculated and experimental electronic circular dichroism spectra. This article outlines theory and practice of the comparison of calculated and experimental electronic circular dichroism (ECD) curves to determine the absolute configuration of chiral molecules. The focus is on the evaluation of excited-state calculations giving hints at the identification of the correct bandwidth and the application of the so-called "UV shift" as a correction factor. A similarity factor is introduced, which helps to quantify the degree of matching of curves. In addition, a few common errors are described that can be made during the measurements of ECD and UV spectra-and advice is given of how to avoid these mistakes. All equations mentioned in the article are implemented in our SpecDis software, which has been developed to rapidly compare calculated ECD and UV curves with experimental ones, and to produce graphics in publication quality. 23834556 A Case of 22q11.2 Deletion Syndrome with Right Microphthalmia and Left Corneal Staphyloma. Abstract Background: A microdeletion in the chromosome 22q11.2 (DiGeorge or velocardiofacial syndrome) is the most common human deletion syndrome. Patients with 22q11.2 deletion may have a wide range of ocular findings but severe ocular involvement is uncommon. Here, we describe a 2-year-old boy who had growth retardation, developmental delay, right renal agenesis, ventricular septal defect and severe bilateral ocular anomalies. Materials and methods: The systemic and ocular findings and cranial magnetic resonance imaging study results were reviewed. Fluorescence in situ hybridization analysis was performed on his peripheral blood. Results: The patient presented with the oculodigital sign. On examination, he had severe right microphthalmia with no light perception and his left eye could not fix and follow. The left eye had anterior segment dysgenesis, mild sclerocornea, corneal staphyloma and congenital aphakia. Systemic findings included growth deficiency, microcephaly, micrognathia, ventricular septal defect, atrial septal defect and right renal agenesis. Fluorescence in situ hybridization analysis of this patient was significant for a heterozygous deletion covering DiGeorge critical region 2 and spanning a 250 kb region in the 22q11.2 locus. Conclusion: The 22q11.2 deletion syndrome may be associated with severe bilateral ocular malformations including microphthalmia, sclerocornea, corneal staphyloma, anterior segment dysgenesis and congenital aphakia. Corneal staphyloma might have resulted from the oculodigital phenomenon or increased intraocular pressure. 23950950 Prolonged Mechanical Ventilation Alters the Expression Pattern of Angio-neogenetic Factors in a Pre-Clinical Rat Model. Mechanical ventilation (MV) is a life saving intervention for patients with respiratory failure. Even after 6 hours of MV, diaphragm atrophy and dysfunction (collectively referred to as ventilator-induced diaphragmatic dysfunction, VIDD) occurs in concert with a blunted blood flow and oxygen delivery. The regulation of hypoxia sensitive factors (i.e. hypoxia inducible factor 1α, 2α (HIF-1α,-2α), vascular endothelial growth factor (VEGF)) and angio-neogenetic factors (angiopoietin 1-3, Ang) might contribute to reactive and compensatory alterations in diaphragm muscle. Male Wistar rats (n = 8) were ventilated for 24 hours or directly sacrificed (n = 8), diaphragm and mixed gastrocnemius muscle tissue was removed. Quantitative real time PCR and western blot analyses were performed to detect changes in angio-neogenetic factors and inflammatory markers. Tissues were stained using Isolectin (IB 4) to determine capillarity and calculate the capillary/fiber ratio. MV resulted in up-regulation of Ang 2 and HIF-1α mRNA in both diaphragm and gastrocnemius, while VEGF mRNA was down-regulated in both tissues. HIF-2α mRNA was reduced in both tissues, while GLUT 4 mRNA was increased in gastrocnemius and reduced in diaphragm samples. Protein levels of VEGF, HIF-1α, -2α and 4 did not change significantly. Additionally, inflammatory cytokine mRNA (Interleukin (IL)-6, IL-1β and TNF α) were elevated in diaphragm tissue. The results demonstrate that 24 hrs of MV and the associated limb disuse induce an up-regulation of angio-neogenetic factors that are connected to HIF-1α. Changes in HIF-1α expression may be due to several interactions occurring during MV. 23147680 Spontaneous electric fields in films of CF3Cl, CF2Cl2 and CFCl3. Data are presented showing the spontaneous formation of electric fields within solid films of the chlorofluorocarbons (CFCs) CF(3)Cl, CF(2)Cl(2) and CFCl(3) as a function of film deposition temperature from 40 K and above. Electric fields, which arise through dipole alignment and lie in the range of a few times 10(7) V m(-1) to a few times 10(6) V m(-1), decrease as the degree of chlorination increases. Maximum deposition temperatures for display of an electric field lie at ~50 K, ~65 K and ~52 K for CF(3)Cl, CF(2)Cl(2) and CFCl(3) respectively. CFCl(3) films possess electric fields which show an onset of temporal metastability between deposition temperatures of 46 K and 50 K. CF(3)Cl and CF(2)Cl(2) demonstrate temperatures of ~65 K and ~80 K at which the electric field in the film is removed by heating, so-called Curie points, with decay of the field spread over more than 10 K. CFCl(3) displays a comparatively sharp Curie point at 55 K. This variety of behaviour arises despite the resemblance of these three species in terms of electronic structure and gas phase dipole moment, emphasising the requirement for detailed chemical models of this phenomenon. 23771566 Preparation of a semicovalent, molecularly surface imprinted polymer for the rapid determination of trace acid orange II in food and environmental samples. In this work, molecularly imprinted polymer (MIP) particles were synthesized using a semicovalent method based on a specific thermally reversible bond, and these particles were used for the rapid detection of the azo dye acid orange II. The imprinted polymers-which were prepared via the covalent reaction of 3-(triethoxysilyl)propyl isocyanate with the template molecules-were attached to the surface of silica-coated magnetic nanoparticles, and a simple thermal reaction was then performed to remove the templates, leaving spaces with specific noncovalent bonds for target re-recognition. The conditions for the synthesis of the MIP were optimized during the polymerization experiments to improve the adsorption capacity and selectivity. The resulting polymers were characterized using Fourier transform infrared spectroscopy, scanning electron microscopy, and transmission electron microscopy to confirm their structure. The MIPs were subjected to an online solid-phase extraction and a magnetic molecularly imprinted solid-phase extraction procedure. For both methods, all samples were prepared with spiking levels of 5.0, 10.0, and 15.0 μg kg(-1) using high-performance liquid chromatography with UV/vis detection; after the preconcentration of 50-mL sample solutions, the enhancement factors reached 710 and 629. The limits of detection (signal-to-noise ratio of 3) were 9.83 and 17.41 ng L(-1), with relative standard deviations (n = 9) of 6.72% and 8.25%, respectively, for a 4.0 μg L(-1) standard template solution. These two methods were developed to quantify trace acid orange II contents in food and environmental samples; the recoveries ranged from 72 to 105% and from 70 to 94%, respectively. 23953669 Allostatic load amplifies the effect of blood lead levels on elevated blood pressure among middle-aged U.S. adults: a cross-sectional study. Scientists and regulators have sought to understand whether and how physiologic dysregulation due to chronic stress exposure may enhance vulnerability to the adverse health effects of toxicant exposures. We conducted a cross-sectional study to determine whether allostatic load (AL), a composite measure of physiologic response to chronic exposure to stress, amplifies the effect of lead exposure on blood pressure among middle-aged adults. We analyzed associations between blood lead levels and blood pressure in a nationally representative sample of 8,194 U.S. adults (aged 40-65 years) participating in the National Health and Nutritional Examination Survey, 1999--2008. Outcomes were elevated systolic (>= 140 mm Hg) and diastolic (>= 90 mm Hg) blood pressure. AL was defined as the aggregate score of seven components, reflecting dysregulation of the cardiovascular, inflammatory, and endocrine systems. Logistic regression models showed a linear dose-response relationship for quintiles of blood lead and elevated systolic blood pressure in the high AL group (p = 0.03) but not the low AL group (p = 0.24). Similarly, the relationship between lead exposure and elevated diastolic blood pressure was stronger among the high AL group than the low AL group. Within the high AL group, the fourth and fifth quintiles had significantly elevated odds of elevated blood pressure compared to lowest quintile [OR = 1.92, (95% CI, 1.07, 3.47) and OR =2.28 (95% CI, 1.33, 3.91), respectively]. In the low AL group, none of the quintile effects were significantly different than the referent group although there was evidence of a linear trend (p =0.03). The lead by AL interaction term was not statistically significant for either systolic or diastolic blood pressure models. Results suggest that higher AL may amplify the adverse effects of lead on blood pressure . Future research should assess the implications of cumulative exposures to environmental and social stressors for regulatory decision-making. 23935720 Effect of ouabain on myocardial remodeling in rats. The aim of this study was to investigate the effect of ouabain (EO) on myocardial remodeling. Twenty-two adult male Sprague-Dawley rats were randomly divided into two groups: the rats in the EO group (n=12) were intraperitoneally injected with EO daily and those in the control group (n=10) were injected with physiological saline daily. After 8 weeks the rats were sacrificed. The ultrastructural changes in the myocardium were observed. The expression levels of voltage-gated potassium channel 4.2 (KV4.2) were detected by real-time quantitative reverse transcription-polymerase chain reaction. The effects of EO on the myocardial action potential and transient potassium efflux (Ito) were measured by patch clamping. The systolic blood pressure (SBP) of 10 of the 12 rats in the EO group, designated as the EO-sensitive (OS) rats, began to increase from the fifth week of treatment and was significantly higher compared with that of the control group 6 weeks later (P<0.01). The remaining 2 rats in the EO group that presented no increase in SBP following 8 weeks of treatment (P>0.05) were designated as EO-resistant (OR) rats. Pathological ultrastructural changes were significant in the apical mid-myocardium of the OS rats. No significant differences in KV4.2 expression were observed among the OS, OR and control rats. The patch clamp results revealed that EO prolongs the action potential duration, reduces Ito and triggers the electrical remodeling of the myocardium. EO induces a blood pressure increase and triggers structural and electrical remodeling. 23746983 Production, quality and quality assurance of Refuse Derived Fuels (RDFs). This contribution describes characterization, classification, production, application and quality assurance of Refuse Derived Fuels (RDFs) that are increasingly used in a wide range of co-incineration plants. It is shown in this paper, that the fuel-parameter, i.e. net calorific value [MJ/kgOS], particle size d90 or d95 [mm], impurities [w%], chlorine content [w%], sulfur content [w%], fluorine content [w%], ash content [w%], moisture [w%] and heavy metals content [mg/kgDM], can be preferentially used for the classification of different types of RDF applied for co-incineration and substitution of fossil-fuel in different industial sectors. Describing the external production of RDF by processing and confectioning of wastes as well as internal processing of waste at the incineration plant, a case study is reported on the application of RDF made out of different household waste fractions in a 120,000t/yr Waste to Energy (WtE) circulating fluidized bed (CFB) incinerator. For that purpose, delivered wastes, as well as incinerator feedstock material (i.e. after internal waste processing) are extensively investigated. Starting with elaboration of sampling plan in accordance with the relevant guidelines and standards, waste from different suppliers was sampled. Moreover, manual sorting analyses and chemical analyses were carried out. Finally, results of investigations are presented and discussed in the paper. 23945609 Nutrition as a link between obesity and cardiovascular disease: how can we stop the obesity epidemic? Overweight and obesity are associated with excess cardiovascular risk. To reduce cardiovascular risk at the population level, the prevention of overweight and obesity is key. This requires adoption of a healthy lifestyle, including less inactivity and more moderate-to-vigorous physical activity, and a healthy diet. Diet composition may facilitate weight gain prevention and weight loss. Effects of dietary fats, carbohydrates and proteins will be discussed in this context. Current evidence indicates that moderation of the intake of (saturated) fat, a moderate increase in protein content of the diet, a replacement of refined grain/high glucose index (GI) by whole-grain/low GI carbohydrates and limitation of the consumption of calorically-sweetened beverages are likely to facilitate weight control. 23564482 Shugoshin1 enhances multidrug resistance of gastric cancer cells by regulating MRP1, Bcl-2, and Bax genes. Multidrug resistance (MDR) is a major clinical obstacle in treatment of gastric cancer (GC) and it accounts for the majority of cancer-related mortalities. Shugoshin1 (SGO1) is an important player in appropriate chromosome segregation and is involved in tumorigenesis. In this study, we found endogenous SGO1 overexpression in the multidrug-resistant GC cell lines SGC7901/VCR and SGC7901/ADR compared with their parental cell line SGC7901. By enhancing expression of SGO1, sensitivity of SGC7901 cells to vincristine (VCR), adriamycin, 5-fluorouracil (5-FU), and cisplatin (CDDP) was significantly diminished. Silencing its expression resulted in enhanced sensitivity of SGC7901/VCR and SGC7901/ADR cells to these antitumor drugs. Additionally, we confirmed that SGO1 increased capacity of cells to enable adriamycin (ADR) efflux and inhibit drug-induced apoptosis by regulating MRP 1, Bcl-2, and Bax genes so as to confer a MDR phenotype to GC cells. In brief, these findings suggest that SGO1 promotes MDR of GC cells and may be useful as a novel therapeutic target for preventing or reversing MDR. 23832622 Allergic Reaction to Peanuts: Can We Predict Reaction Severity in the Wild? Peanut allergy (PNA) is the main cause of food-induced anaphylaxis. Severe allergic reactions are more likely to occur in older patients and those with underlying asthma. Skin prick testing and measuring serum-specific IgE and recombinant peanut protein levels have been shown to be useful in the diagnosis of PNA and prediction of reactivity, but these tests are less consistent and reliable in terms of predicting the severity of reactions. Recent research has examined the role of biological mediators in allergic reactions such as platelet-activating factor. These may provide a future tool in predicting those at risk of severe reactions. Currently, there are no parameters that can predict with certainty those at risk of anaphylaxis, and management of PNA should continue to focus on patient and family education. 23901295 Validation of 14,500 operated knees registered in the Danish Knee Ligament Reconstruction Register: registration completeness and validity of key variables. The aim of this study was to validate the registration in the Danish Knee Ligament Reconstruction Register (DKRR) by assessing the registration completeness of the anterior cruciate ligament (ACL) reconstruction code and detecting the validity of important key variables. Furthermore, we assessed data quality of patient-related outcome scores. All operation codes for ACL reconstruction from 2005-2011 were identified in the Danish National Registry of Patients and were compared with the cases registered in the DKRR to compute the completeness of registration. We also assessed the validity of key variables in the DKRR using medical records as a reference standard to compute the positive predictive value. Finally, we assessed potential differences between responders and nonresponders to subjective patient-related outcome scores (Knee Injury and Osteoarthritis Outcome Score [KOOS] and Tegner scores) 1 year after surgery. The completeness of the registration of patients in the DKRR increased from 60% (2005) to 86% (2011). Large-volume hospitals had a higher completeness than small-volume hospitals. With a positive predictive value between 85%-100%, the validity of key variables was good. KOOS scores versus Tegner scores for responders and nonresponders were comparable. The results show a good registration of ACL reconstruction procedures in the DKRR, but there is room for improvement mainly at small-volume hospitals. Overall, the validity of the key variables in the DKRR was good and no difference was found in KOOS and Tegner scores for responders versus nonresponders. Therefore, we conclude that the DKRR is a valid source for future research. 23915378 Chronic disease mortality in rural and urban residents in Hubei Province, China, 2008-2010. Chronic non-communicable diseases have become the major cause of death in China. This study describes and compares chronic disease mortality between urban and rural residents in Hubei Province, central China. Death records of all individuals aged 15 years and over who died from 2008 through 2010 in Hubei were obtained from the Disease Surveillance Points system maintained by the Hubei Province Centers for Disease Control and Prevention. Average annual mortality, standardized death rates, years of potential life lost (YLL), average years of potential life lost (AYLL) and rates of life lost were calculated for urban and rural residents. Standardized rate ratios (SRR) were calculated to compare the death rates between urban and rural areas. A total of 86.2% of deaths were attributed to chronic non-communicable diseases in Hubei. Cerebrovascular diseases, ischemic heart disease and neoplasms were the main leading causes in both urban and rural areas, and the mortality rates were higher among rural residents. Lung cancer was the principal cause of mortality from cancer among urban and rural residents, and stomach cancer and liver cancer were more common in rural than urban areas. Breast cancer mortality among women in rural areas was lower than in urban areas (SRR=0.73, 95% CI=0.63-0.85). The standardized mortality for chronic lower respiratory disease among men in rural areas was higher than in urban areas (SRR=4.05, 95% CI=3.82-4.29). Among men, total AYLL from liver cancer and other diseases of liver were remarkably higher than other causes in urban and rural areas. Among women the highest AYLL were due to breast cancer in both urban and rural areas. Chronic diseases were the major cause of death in Hubei Province. While circulatory system diseases were the leading causes in both urban and rural areas, our study highlights that attention should also be paid to breast cancer among women and chronic lower respiratory disease among rural residents. It is important that governments focus on this public health issue and develop preventive strategies to reduce morbidity and premature mortality from chronic non-communicable diseases. 23607932 Antimicrobial and demelanizing activity of Ganoderma lucidum extract, p-hydroxybenzoic and cinnamic acids and their synthetic acetylated glucuronide methyl esters. Mushroom extracts or isolated compounds may be useful in the search of new potent antimicrobial agents. Herein, it is described the synthesis of protected (acetylated) glucuronide derivatives of p-hydroxybenzoic and cinnamic acids, two compounds identified in the medicinal mushroom Ganoderma lucidum. Their antimicrobial and demelanizing activities were evaluated and compared to the parent acids and G. lucidum extract. p-Hydroxybenzoic and cinnamic acids, as also their protected glucuronide derivatives revealed high antimicrobial (antibacterial and antifungal) activity, even better than the one showed by commercial standards. Despite the variation in the order of parent acids and the protected glucuronide derivatives, their antimicrobial activity was always higher than the one revealed by the extract. Nevertheless, the extract was the only one with demelanizing activity against Aspergillus niger. The acetylated glucuronide derivatives could be deprotected to obtain glucuronide metabolites, which circulate in the human organism as products of the metabolism of the parent compounds. 22926523 GAB2 induces tumor angiogenesis in NRAS-driven melanoma. GAB2 is a scaffold protein with diverse upstream and downstream effectors. MAPK and PI3K signaling pathways are known effectors of GAB2. It is amplified and overexpressed in a variety of human tumors including melanoma. Here we show a previously undescribed role for GAB2 in NRAS-driven melanoma. Specifically, we found that GAB2 is co-expressed with mutant NRAS in melanoma cell lines and tumor samples and its expression correlated with metastatic potential. Co-expression of GAB2(WT) and NRAS(G12D) in melanocytes and in melanoma cells increased anchorage-independent growth by providing GAB2-expressing cells a survival advantage through upregulation of BCL-2 family of anti-apoptotic factors. Of note, collaboration of GAB2 with mutant NRAS enhanced tumorigenesis in vivo and led to an increased vessel density with strong CD34 and VEGFR2 activity. We found that GAB2 facilitiated an angiogenic switch by upregulating HIF-1α and VEGF levels. This angiogenic response was significantly suppressed with the MEK inhibitor PD325901. These data suggest that GAB2-mediated signaling cascades collaborate with NRAS-driven downstream activation for conferring an aggressive phenotype in melanoma. Second, we show that GAB2/NRAS signaling axis is non-linear and non-redundant in melanocytes and melanoma, and thus are acting independent of each other. Finally, we establish a link between GAB2 and angiogenesis in melanoma for the first time. In conclusion, our findings provide evidence that GAB2 is a novel regulator of tumor angiogenesis in NRAS-driven melanoma through regulation of HIF-1α and VEGF expressions mediated by RAS-RAF-MEK-ERK signaling. 23575200 Breast milk as a possible route of vertical transmission of dengue virus? We report a case of vertical transmission of dengue infection. The virus was detected and quantified by reverse-transcription polymerase chain reaction in sequential blood samples from mother and child as well as in breast milk, but not in cord blood. This case poses questions about the risk of breastfeeding transmission of dengue virus. 23089945 Biological and biomedical applications of engineered nucleases. The development of engineered nucleases is the fruit of a new technological approach developed in the last two decades which has led to significant benefits on genome engineering, particularly on gene therapy. These applications enable efficient and specific genetic modifications via the induction of a double-strand break (DSB) in a specific genomic target sequence, followed by the homology-directed repair (HDR) or non-homologous end joining (NHEJ) pathways. In addition to the application on gene modification in cells and intact organisms, a number of recent papers have reported that this gene editing technology can be applied effectively to human diseases. With the promising data obtained using engineered endonucleases in gene therapy, it appears reasonable to expect that more diseases could be treated and even be cured in this new era of individualized medicine. This paper first brief introduces the development of engineered nucleases with a special emphasis on zinc-finger nucleases (ZFNs) and transcription activator-like effector (TALE) nucleases (TALENs), and then takes CCR5-based gene therapy as an example to discuss the therapeutic applications of engineered nucleases. 23965968 Decreased Expression of Alpha-L-Fucosidase Gene FUCA1 in Human Colorectal Tumors. In previous studies we described a decreased alpha-L-fucosidase activity in colorectal tumors, appearing as a prognostic factor of tumoral recurrence. The aim of this work was to extend the knowledge about tissue alpha-L-fucosidase in colorectal cancer by quantifying the expression of its encoding gene FUCA1 in tumors and healthy mucosa. FUCA1 mRNA levels were measured by RT-qPCR in paired tumor and normal mucosa tissues from 31 patients. For the accuracy of the RT-qPCR results, five candidate reference genes were validated in those samples. In addition, activity and expression of alpha-L-fucosidase in selected matched tumor and healthy mucosa samples were analyzed. According to geNorm and NormFinder algorithms, RPLP0 and HPRT1 were the best reference genes in colorectal tissues. These genes were used for normalization of FUCA1 expression levels. A significant decrease of more than 60% in normalized FUCA1 expression was detected in tumors compared to normal mucosa (p = 0.002). Moreover, a gradual decrease in FUCA1 expression was observed with progression of disease from earlier to advanced stages. These findings were confirmed by Western blot analysis of alpha-L-fucosidase expression. Our results demonstrated diminished FUCA1 mRNA levels in tumors, suggesting that expression of tissue alpha-L-fucosidase could be regulated at transcriptional level in colorectal cancer. 23546396 Randomly amplified polymorphic-DNA analysis for detecting genotoxic effects of Boron on maize (Zea mays L.). This study was carried out to investigate the genotoxic effect of boron (B) on maize using randomly amplified polymorphic DNA (RAPD) method. Experimental design was conducted under 0, 5, 10, 25, 50, 100, 125, and 150 ppm B exposures, and physiological changes have revealed a sharp decrease in root growth rates from 28% to 85%, starting from 25 ppm to 150 ppm, respectively. RAPD-polymerase chain reaction (PCR) analysis shows that DNA alterations are clearly observed from beginning to 100 ppm. B-induced inhibition in root growth had a positive correlation with DNA alterations. Total soluble protein, root and stem lengths, and B content analysis in root and leaves encourage these results as a consequence. These preliminary findings reveal that B causes chromosomal aberration and genotoxic effects on maize. Meanwhile, usage of RAPD-PCR technique is a suitable biomarker to detect genotoxic effect of B on maize and other crops for the future. 23922762 Assessing gibberellins oxidase activity by anion exchange/hydrophobic polymer monolithic capillary liquid chromatography-mass spectrometry. Bioactive gibberellins (GAs) play a key regulatory role in plant growth and development. In the biosynthesis of GAs, GA3-oxidase catalyzes the final step to produce bioactive GAs. Thus, the evaluation of GA3-oxidase activity is critical for elucidating the regulation mechanism of plant growth controlled by GAs. However, assessing catalytic activity of endogenous GA3-oxidase remains challenging. In the current study, we developed a capillary liquid chromatography - mass spectrometry (cLC-MS) method for the sensitive assay of in-vitro recombinant or endogenous GA3-oxidase by analyzing the catalytic substrates and products of GA3-oxidase (GA1, GA4, GA9, GA20). An anion exchange/hydrophobic poly([2-(methacryloyloxy)ethyl]trimethylammonium-co-divinylbenzene-co-ethylene glycol dimethacrylate)(META-co-DVB-co-EDMA) monolithic column was successfully prepared for the separation of all target GAs. The limits of detection (LODs, Signal/Noise = 3) of GAs were in the range of 0.62-0.90 fmol. We determined the kinetic parameters (K m) of recombinant GA3-oxidase in Escherichia coli (E. coli) cell lysates, which is consistent with previous reports. Furthermore, by using isotope labeled substrates, we successfully evaluated the activity of endogenous GA3-oxidase that converts GA9 to GA4 in four types of plant samples, which is, to the best of our knowledge, the first report for the quantification of the activity of endogenous GA3-oxidase in plant. Taken together, the method developed here provides a good solution for the evaluation of endogenous GA3-oxidase activity in plant, which may promote the in-depth study of the growth regulation mechanism governed by GAs in plant physiology. 23939468 Novel SLC20A2 mutations identified in southern Chinese patients with idiopathic basal ganglia calcification. Idiopathic basal ganglia calcification (IBGC) is a rare neuropsychiatric disorder characterized by bilateral and symmetric cerebral calcifications. Recently, SLC20A2 was identified as a causative gene for familial IBGC, and three mutations were reported in a northern Chinese population. Here, we aimed to explore the mutation spectrum of SLC20A2 in a southern Chinese population. Sanger sequencing was employed to screen mutations within SLC20A2 in two IBGC families and 14 sporadic IBGC cases from a southern Han Chinese population. Four novel mutations (c.82G>A p.D28N, c.185T>C p.L62P, c.1470_1478delGCAGGTCCT p.Q491_L493del and c.935-1G>A) were identified in two families and two sporadic cases, respectively; none were detected in 200 unrelated controls. No mutation was found in the remaining 12 patients. Different mutations may result in varied phenotypes, including brain calcification and clinical manifestations. Our study supports the hypothesis that SLC20A2 is a causative gene of IBGC and expands the mutation spectrum of SLC20A2, which facilitates the understanding of the genotype-phenotype correlation of IBGC. 23053786 Environmentally relevant concentrations of a common insecticide increase predation risk in a freshwater gastropod. Ecological receptors are faced with a multitude of stressors that include abiotic and biotic factors creating a challenge for assessing risk of chemical exposure. Of particular interest and importance are the effects of contaminants on inter-species interactions such as competition and predator-prey relationships. The objective of this study was to determine whether environmentally relevant concentrations of the commonly used insecticide, malathion, would alter predator avoidance behavior in a freshwater gastropod that could translate to increased predation risk. We exposed adult Physa pomilia snails to 0, 0.25, or 1.0 mg/L malathion for 2, 24, or 48 h and evaluated predator avoidance using a behavioral assay in which snails were exposed to cues from predatory crayfish. We found a significant reduction in predator avoidance in snails exposed to both concentrations of malathion after 48 h of exposure. To evaluate whether observed effects of malathion on predator avoidance actually increased susceptibility of snails to predators, we conducted a predator challenge experiment. Snails exposed to 0.25 mg/L malathion for 48 h were significantly more susceptible to predation. That increased predation risk was evident 48 h after initial malathion exposures is a unique result because most studies have evaluated behavioral responses soon after (<12 h) initiation of pesticide exposure. The extent to which the observed interactions affect natural populations, and the mechanisms through which they are mediated are largely unexplored. However, our study is the first to show that a commonly used insecticide decreases predator avoidance and may actually increase predation susceptibility in gastropods at concentrations several orders of magnitude below acute toxicity levels. 23471352 Resveratrol protects against arsenic trioxide-induced nephrotoxicity by facilitating arsenic metabolism and decreasing oxidative stress. Arsenic trioxide (As2O3) is an environmental toxicant and a potent antineoplastic agent. Exposure to arsenic causes renal cancer. Resveratrol is a well-known polyphenolic compound that is reported to reduce As2O3-induced cardiotoxicity. The present study aimed to investigate the effect of resveratrol on As2O3-induced nephrotoxicity and arsenic metabolism. Chinese Dragon-Li cats were injected with 1 mg/kg As2O3 on alternate days; resveratrol (3 mg/kg) was administered via the forearm vein 1 h before the As2O3 treatment. On the sixth day, the cats were killed to determine the histological renal damage, renal function, the accumulation of arsenic, and antioxidant activities in the kidney. Urine samples were taken for arsenic speciation. In the resveratrol + As2O3-treated group, activities of glutathione peroxidase, catalase, and superoxide dismutase, the ratio of reduced glutathione to oxidized glutathione, the total arsenic concentrations, and the percentage of methylated arsenic in urine were significantly increased. The concentrations of renal malondialdehyde, reactive oxygen species, 8-hydroxydeoxyguanosine, serum creatinine, blood urea nitrogen, and renal arsenic accumulation were significantly decreased and reduced renal morphologic injury was observed compared with the As2O3-treated group. These results demonstrate that resveratrol could significantly scavenge reactive oxygen species, inhibit As2O3-induced oxidative damage, and significantly attenuate the accumulation of arsenic in renal tissues by facilitating As2O3 metabolism. These data suggest that use of resveratrol as postremission therapy for acute promyelocytic leukemia as well as adjunctive therapy in patients with exposure to arsenic may decrease arsenic nephrotoxicity. 23589262 Metal extractability patterns to evaluate (potentially) mobile fractions in periurban calcareous agricultural soils in the Mediterranean area-analytical and mineralogical approaches. A set of periurban calcareous agricultural Mediterranean soils was spiked with a mixture of Cd, Cu, Pb and Zn at two levels within the limit values proposed by current European legislation, incubated for up to 12 months, and subjected to various one-step extraction procedures to estimate mobile (neutral salts) and potentially mobile metal fractions (complexing and acidic extraction methods). The results obtained were used to study metal extractability patterns according to the soil characteristics. The analytical data were coupled with mineralogical investigations and speciation modelling using the Visual Minteq model. The formation of soluble metal-complexes in the complexing extracts (predicted by the Visual Minteq calculations) led to the highest extraction efficiency with complexing extractants. Metal extractability patterns were related to both content and composition of carbonate, organic matter, Fe oxide and clay fractions. Potentially mobile metal fractions were mainly affected by the finest soil fractions (recalcitrant organic matter, active lime and clay minerals). In the case of Pb, scarce correlations between extractable Pb and soil constituents were obtained which was attributed to high Pb retention due to the formation of 4PbCO3·3PbO (corroborated by X-ray diffraction). In summary, the high metal proportion extracted with complexing agents highlighted the high but finite capacity to store potentially mobilizable metals and the possible vulnerability of these soils against environmental impact from metal accumulation. 23969946 What holds paper together: Nanometre scale exploration of bonding between paper fibres. Paper, a man-made material that has been used for hundreds of years, is a network of natural cellulosic fibres. To a large extent, it is the strength of bonding between these individual fibres that controls the strength of paper. Using atomic force microscopy, we explore here the mechanical properties of individual fibre-fibre bonds on the nanometre scale. A single fibre-fibre bond is loaded with a calibrated cantilever statically and dynamically until the bond breaks. Besides the calculation of the total energy input, time dependent processes such as creep and relaxation are studied. Through the nanometre scale investigation of the formerly bonded area, we show that fibrils or fibril bundles play a crucial role in fibre-fibre bonding because they act as bridging elements. With this knowledge, new fabrication routes can be deduced to increase the strength of an ancient product that is in fact an overlooked high-tech material. 23665987 Can single cIMT measurement during echocardiography affect further investigation decision for coronary artery disease? This study was aimed to evaluate whether there is any potential role of the measurement of the carotid intima-media thickness (cIMT) in patients with suspected coronary artery disease (CAD) during the echocardiography session on decision-making to refer patients for further diagnostic evaluation such as gated myocardial perfusion imaging (gMPI). cIMT of 199 consecutive patients was measured during the echocardiography session and all patients underwent gMPI. According to gMPI results, patients were divided into two groups as CAD and normal groups and according to cIMT measurements patients were divided into four subgroups. Although, there was a good correlation between the age and cIMT values of the patients (r=0.546, p<0.001), the correlation between the summed stress scores and the age of the patients was very weak (r=0.142, p=0.045) and the correlation between the summed stress scores and the cIMT values was very weak (r=0.107, p=0.131). The cIMT measurements of the CAD group (0.74±0.17 mm) were significantly higher than those of the normal group (0.67±0.16 mm) (p=0.012), but after the age correction, the significance between the cIMT measurements of the CAD and the normal groups was not found (p=0.131). Besides, the relationship between the categorical cIMT values of both the CAD and the normal groups was insignificant (p=0.059) and the correlation between the increasing cIMT values and the presence of detectable CAD was also very weak (r=0.187, p=0.08). cIMT can predict occurrence of cardiovascular events in subjects, but single cIMT measurement during echocardiographic examination does not seem to have potential role on decision making for further investigation in patients with suspected CAD. 23954170 Nardilysin prevents amyloid plaque formation by enhancing α-secretase activity in an Alzheimer's disease mouse model. Amyloid beta (Aβ) peptide, the main component of senile plaques in patients with Alzheimer's disease (AD), is derived from proteolytic cleavage of amyloid precursor protein (APP) by β- and γ-secretases. Alpha-cleavage of APP by α-secretase has a potential to preclude the generation of Aβ because it occurs within the Aβ domain. We previously reported that a metalloendopeptidase, nardilysin (N-arginine dibasic convertase; NRDc) enhances α-cleavage of APP, which results in the decreased generation of Aβ in vitro. To clarify the in vivo role of NRDc in AD, we intercrossed transgenic mice expressing NRDc in the forebrain with an AD mouse model. Here we demonstrate that the neuron-specific overexpression of NRDc prevents Aβ deposition in the AD mouse model. The activity of α-secretase in the mouse brain was enhanced by the overexpression of NRDc, and was reduced by the deletion of NRDc. However, reactive gliosis adjacent to the Aβ plaques, one of the pathological features of AD, was not affected by the overexpression of NRDc. Taken together, our results indicate that NRDc controls Aβ formation through the regulation of α-secretase. 23948798 Quantitative PCR analysis used to characterize physiological changes in brain tissue of senescent sockeye salmon. Senescence varies considerably among fishes, and understanding the evolutionary basis for this diversity has become an important area of study. For rapidly senescing species such as Pacific salmon, senescence is a complex process as these fish are initiating anorexia while migrating to natal spawning grounds, and die within days of reproduction. To better understand senescence in Pacific salmon we examined expression patterns for a suite of genes in brain tissue of pre-senescent and senescent sockeye salmon. Interestingly, a significant increase in expression of genes involved in telomere repair and immune activity was observed in senescent salmon. These data provide insight into physiological changes in salmon undergoing senescence and the factors contributing to variation in observed senescence rates among individuals and populations. 23853710 Apical targeting of the formin Diaphanous in Drosophila tubular epithelia. Apical secretion from epithelial tubes of the Drosophila embryo is mediated by apical F-actin cables generated by the formin-family protein Diaphanous (Dia). Apical localization and activity of Dia are at the core of restricting F-actin formation to the correct membrane domain. Here we identify the mechanisms that target Dia to the apical surface. PI(4,5)P2 levels at the apical membrane regulate Dia localization in both the MDCK cyst model and in Drosophila tubular epithelia. An N-terminal basic domain of Dia is crucial for apical localization, implying direct binding to PI(4,5)P2. Dia apical targeting also depends on binding to Rho1, which is critical for activation-induced conformational change, as well as physically anchoring Dia to the apical membrane. We demonstrate that binding to Rho1 facilitates interaction with PI(4,5)P2 at the plane of the membrane. Together these cues ensure efficient and distinct restriction of Dia to the apical membrane. DOI:http://dx.doi.org/10.7554/eLife.00666.001. 23852115 Bidirectional NMDA receptor plasticity controls CA3 output and heterosynaptic metaplasticity. NMDA receptors (NMDARs) are classically known as coincidence detectors for the induction of long-term synaptic plasticity and have been implicated in hippocampal CA3 cell-dependent spatial memory functions that likely rely on dynamic cellular ensemble encoding of space. The unique functional properties of both NMDARs and mossy fiber projections to CA3 pyramidal cells place mossy fiber NMDARs in a prime position to influence CA3 ensemble dynamics. By mimicking presynaptic and postsynaptic activity patterns observed in vivo, we found a burst timing-dependent pattern of activity that triggered bidirectional long-term NMDAR plasticity at mossy fiber-CA3 synapses in rat hippocampal slices. This form of plasticity imparts bimodal control of mossy fiber-driven CA3 burst firing and spike temporal fidelity. Moreover, we found that mossy fiber NMDARs mediate heterosynaptic metaplasticity between mossy fiber and associational-commissural synapses. Thus, bidirectional NMDAR plasticity at mossy fiber-CA3 synapses could substantially contribute to the formation, storage and recall of CA3 cell assembly patterns. 23903871 Vulnerability of polar oceans to anthropogenic acidification: comparison of arctic and antarctic seasonal cycles. Polar oceans are chemically sensitive to anthropogenic acidification due to their relatively low alkalinity and correspondingly weak carbonate buffering capacity. Here, we compare unique CO2 system observations covering complete annual cycles at an Arctic (Amundsen Gulf) and Antarctic site (Prydz Bay). The Arctic site experiences greater seasonal warming (10 vs 3°C), and freshening (3 vs 2), has lower alkalinity (2220 vs 2320 μmol/kg), and lower summer pH (8.15 vs 8.5), than the Antarctic site. Despite a larger uptake of inorganic carbon by summer photosynthesis, the Arctic carbon system exhibits smaller seasonal changes than the more alkaline Antarctic system. In addition, the excess surface nutrients in the Antarctic may allow mitigation of acidification, via CO2 removal by enhanced summer production driven by iron inputs from glacial and sea-ice melting. These differences suggest that the Arctic system is more vulnerable to anthropogenic change due to lower alkalinity, enhanced warming, and nutrient limitation. 23669792 A strategy for in vitro safety testing of nanotitania-modified textile products. Titanium dioxide nanomaterials are extensively used in many applications, also for modification of textile materials. Toxicological assessment of such textile materials is currently seldom performed, mainly because of lack of appropriate guidelines. The aim of the study was to assess cytotoxic and genotoxic potential of commercially available TiO2 and TiO2/Ag NMs in pristine form as well as polypropylene fibers modified with the NMs. Both titania NMs showed a cytotoxic effect on BALB/3T3 clone A31 and V79 fibroblasts after 72-h exposure. Both NMs induced a weak genotoxic effect in comet assay, with TiO2/Ag being more active. In vitro micronucleus test on human lymphocytes revealed a weak mutagenic effect of both materials after 24h of exposure. In contrast, no significant increase in micronuclei frequency was observed in the in vitro micronucleus test on V79 fibroblasts. The 24-h extracts prepared from polypropylene fibers modified with TiO2/Ag induced a cytotoxic effect on BALB/3T3 cells which strongly depended on the mode of the fibers manufacturing. The study presents a comprehensive approach to toxicity assessment of textile fibers modified with NMs. Proposed approach may form a good "starting point" for improved future testing strategies. 23945422 Screening for Sexually Transmitted Diseases in Short-Term Correctional Institutions: Summary of Evidence Reviewed for the 2010 Centers for Disease Control and Prevention Sexually Transmitted Diseases Treatment Guidelines. Young persons entering US jails and youth detention facilities have high rates of sexually transmitted diseases (STDs). The Centers for Disease Control and Prevention added STD screening guidelines specific to correctional settings to the 2010 STD Treatment Guidelines. This article summarizes published evidence from 1990 to 2009 used to develop the recommendations. The literature supports routine screening of adolescents and young women (aged ≤35 years, or on the basis of local institutional prevalence data) for chlamydia and gonorrhea because of high prevalence and the subsequent risk of adverse reproductive outcomes. Chlamydia positivity among young women (aged <20 years) in juvenile detention facilities and adult facilities is more than 14%. Men in correctional settings are also at high risk for chlamydia and gonorrhea. Among boys in juvenile detention facilities, chlamydia positivity is estimated at 6.6%; among young men in adult facilities, positivity is 16.6%. Screening men (to reduce sequelae among women) should be considered based on local epidemiology and resource availability. Syphilis screening is not strongly supported in published literature because of low prevalence and is not routinely recommended; however, some screening may be warranted based on local prevalence. Although there is a great diversity in the organization of correctional facilities, implementation of screening recommendations is possible owing to improvements in test technology (urine specimens) and through integration of a standard screening protocol. Based on the high burden of disease and substantial opportunities to reach a high-risk population, correctional facilities are important venues to target efforts to control STDs. 23872153 When size does matter: organelle size influences the properties of transport mediated by molecular motors. Organelle transport is driven by the action of molecular motors. In this work, we studied the dynamics of organelles of different sizes with the aim of understanding the complex relation between organelle motion and microenvironment. We used single particle tracking to obtain trajectories of melanosomes (pigmented organelles in Xenopus laevis melanophores). In response to certain hormones, melanosomes disperse in the cytoplasm or aggregate in the perinuclear region by the combined action of microtubule and actin motors. Melanosome trajectories followed an anomalous diffusion model in which the anomalous diffusion exponent (α) provided information regarding the trajectories' topography and thus of the processes causing it. During aggregation, the directionality of big organelles was higher than that of small organelles and did not depend on the presence of either actin or intermediate filaments (IF). Depolymerization of IF significantly reduced α values of small organelles during aggregation but slightly affect their directionality during dispersion. Our results could be interpreted considering that the number of copies of active motors increases with organelle size. Transport of big organelles was not influenced by actin or IF during aggregation showing that these organelles are moved processively by the collective action of dynein motors. Also, we found that intermediate filaments enhance the directionality of small organelles suggesting that this network keeps organelles close to the tracks allowing their efficient reattachment. The higher directionality of small organelles during dispersion could be explained considering the better performance of kinesin-2 vs. dynein at the single molecule level. 23768967 Glycogen synthase kinase-3β (GSK-3β) and its dysregulation in glioblastoma multiforme. Glioblastoma multiforme (GBM) is the most frequently occurring and devastating human brain malignancy, retaining almost universal mortality and a median survival of only 14months, even with recent advances in multimodal treatments. Gliomas are characterised as being both highly resistant to chemo- and radiotherapy and highly invasive, rendering conventional interventions palliative. The continual dismal prognosis for GBM patients identifies an urgent need for the evolutionary development of new treatment modalities. This includes molecular targeted therapies as many signaling molecules and associated pathways have been implicated in the development and survival of malignant gliomas including the protein kinase, glycogen synthase kinase 3 beta (GSK-3β). Here we review the activity and function of GSK-3β in a number of signaling pathways and its role in gliomagenesis. 23452942 Addiction: failure of control over maladaptive incentive habits. Drug addiction may be associated with a loss of executive control over maladaptive incentive habits. We hypothesize that these incentive habits result from a pathological coupling of drug-influenced motivational states and a rigid stimulus-response habit system by which drug-associated stimuli through automatic processes elicit and maintain drug seeking. Neurally, incentive habits may depend upon an interaction between the basolateral amygdala and nucleus accumbens core, together with the progressive development of a ventral-to-dorsolateral striatum functional coupling through the recruitment of striato-nigro-striatal dopamine-dependent loop circuitry. Recent evidence suggests that both ventral striatal and central nucleus pathways from the amygdala may be required for the recruitment of DLS-dependent control over habitual behavior. 23414439 Alcohol dehydrogenase-1B genotype (rs1229984) is a strong determinant of the relationship between body weight and alcohol intake in Japanese alcoholic men. The calories in alcoholic beverages consumed by alcoholics are a major energy source and a strong modifier of their body weight. Genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) affect susceptibility to alcoholism and may affect body weight via gene-associated differences in fuel utilization in alcoholics. We evaluated associations between ADH1B/ALDH2 genotypes and the body weight and body mass index (BMI) of 1,301 Japanese alcoholic men at the time of their first visit to an addiction center. Median (25th to 75th) caloric intake in the form of alcoholic beverages was 864 (588 to 1,176) kcal/d. Age-adjusted caloric intake did not differ according to ADH1B/ALDH2 genotypes. The body weight and BMI values showed that the ADH1B*2/*2 and *1/*2 carriers (n = 939) were significantly leaner than the ADH1B*1/*1 carriers (n = 362) irrespective of age, drinking, smoking, and dietary habits. The age-adjusted body weight values of the ADH1B*2/*2, ADH1B*1/*2, and ADH1B*1/*1 carriers were 58.4 ± 0.4, 58.7 ± 0.5, and 63.6 ± 0.5 kg, respectively (ADH1B*2 vs. ADH1B*1/*1 carriers, p < 0.0001), and the corresponding BMI values were 21.0 ± 0.1, 21.0 ± 0.1, and 22.9 ± 0.2 kg/m(2) , respectively (ADH1B*2 vs. ADH1B*1/*1 carriers, p < 0.0001). No effects of inactive ALDH2 on body weight or BMI were observed. A multivariate analysis showed that BMI decreased by 0.35 per 10-year increase in age, by 1.73 in the presence of the ADH1B*2 allele, by 1.55 when the preferred beverage was whiskey, and by 0.19 per +10 cigarettes/d and that it increased by 0.10 per +22 g ethanol (EtOH)/d and by 0.41 per increase in category of frequency of milk intake (every day, occasionally, rarely, and never). The increase in BMI as alcohol consumption increased was significantly smaller in the ADH1B*2 group than in the ADH1B*1/*1 group (p = 0.002). ADH1B genotype was a strong determinant of body weight in the alcoholics. The more rapid EtOH elimination associated with the ADH1B*2 allele may result in less efficient utilization of EtOH as an energy source in alcoholics. 22498419 Association between gamma-glutamyltransferase and coronary artery calcification. The exact mechanisms behind the association between atherosclerosis and gamma-glutamyltransferase (GGT) are unclear. Coronary artery calcification (CAC) detected by computerized tomography is an important marker of atherosclerosis and its severity correlates with coronary plaque burden. The aim of this study was to investigate if serum GGT levels are associated with CAC in patients without known coronary heart disease (CHD) who had low-intermediate risk for CHD. Two hundred and seventy two patients who had low-intermediate risk for coronary artery disease were included in the study. Serum GGT levels were measured spectrophotometrically. CACS (Agatston method) were performed using a 64-slice computerized tomography scanner. The patients were grouped according to their GGT values in four quartiles. Patients in higher GGT quartiles had elevated CAC score (P<0.001). Patients in higher GGT quartiles were predominantly males (P<0.001) and were more likely to be smoking (P=0.004), and have elevated uric acid (P<0.001), fasting blood glucose (P<0.001), CRP levels (P=0.003) and 10-year total cardiovascular risk (P=0.007) and low HDL levels (P<0.001). Positive correlations were found between log GGT and CAC (r=0.233, P<0.001). In the multivariate analysis GGT, age, smoking and serum uric acid levels appeared as independent factors predictive of presence of CAC. We demonstrated a significant correlation between serum GGT levels and CAC and CHD risk factors. Serum GGT level was an independent marker of CAC. 23565916 Clinical assessment and crisis intervention for the suicidal bipolar disorder patient. Suicidal behaviour is common in people suffering with bipolar disorder, and suicide is a leading cause of death in this group. Our aim in this review is to provide an overview of key assessment and management strategies, highlight research findings relevant to suicide prevention, and identify important areas for future research. We reviewed the published literature regarding the risk factors for and management of suicida\l behaviour in individuals with bipolar disorder using the Pubmed and PsychINFO databases. Where available, we focused our search on systematic reviews. Suicide is usually associated with a depressive phase, although mixed affective states also convey increased risk. All individuals with bipolar disorder should have an up-to-date crisis management plan which outlines the action to be taken should suicidal behaviour emerge. Timely clinical assessment is essential in ensuring that those at high risk are identified. This should include mental state examination, consideration of risk factors, and evaluation of issues such as access to means, preparatory acts before suicide, and also protective factors. While pharmacological approaches are the mainstay of management, less specific measures, such as the removal of access to means, are also important in ensuring safety in the acute situation. Intensifying the clinical support of both patients and relatives, and the sharing of risk information with other health agencies are essential in management. Specific psychological treatments are likely to be helpful in preventing crises, although the evidence base is limited. The aetiology of suicidal behaviour in bipolar disorder is multifactorial and requires proactive crisis planning and management. A range of issues need to be addressed in the assessment of at-risk patients. Determining the efficacy of interventions specific to reducing suicidality in bipolar disorder should be a research priority. 22884720 In vitro characterisation of the novel positive allosteric modulators of the mGlu₅ receptor, LSN2463359 and LSN2814617, and their effects on sleep architecture and operant responding in the rat. The demonstrated functional interaction of metabotropic glutamate 5 (mGlu₅) receptors with N-methyl-d-aspartate (NMDA) receptors has prompted speculation that their activation may offer a potential treatment for aspects of schizophrenia. Development of selective mGlu₅ agonists has been difficult, but several different positive allosteric modulator (PAM) molecules have now been identified. This study describes two novel mGlu₅ PAMs, LSN2463359 (N-(1-methylethyl)-5-(pyridin-4-ylethynyl)pyridine-2-carboxamide) and LSN2814617 [(7S)-3-tert-butyl-7-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-A]pyridine], which are useful tools for this field of research. Both compounds are potent and selective potentiators of human and rat mGlu₅ receptors in vitro, displaying curve shift ratios of two to three fold in the concentration-response relationship to glutamate or the glutamate receptor agonist, DHPG, with no detectable intrinsic agonist properties. Both compounds displaced the mGlu₅ receptor antagonist radioligand, [³H]MPEP in vitro and, following oral administration reached brain concentrations sufficient to occupy hippocampal mGlu₅ receptors as measured in vivo by dose-dependent displacement from the hippocampus of intravenously administered MPEPy. In vivo EEG studies demonstrated that these mGlu₅ PAMs have marked wake-promoting properties but little in the way of rebound hypersomnolence. In contrast, the previously described mGlu₅ PAMs CDPPB and ADX47273 showed relatively poor evidence of in vivo target engagement in either receptor occupancy assays or EEG disturbance. Wake-promoting doses of LSN2463359 and LSN2814617 attenuated deficits in performance induced by the competitive NMDA receptor antagonist SDZ 220,581 in two tests of operant behaviour: the variable interval 30 s task and the DMTP task. These effects were lost if the dose of either compound extended into the range which disrupted performance in the baseline DMTP task. However, the improvements in response accuracy induced by the mGlu₅ potentiators in SDZ 220,581-treated rats were not delay-dependent and, therefore, perhaps more likely reflected optimization of general arousal than specific beneficial effects on discrete cognitive processes. The systematic profiling of LSN2463359 and LSN2814617 alongside other previously described molecules will help determine more precisely how mGlu₅ potentiator pharmacology might provide therapeutic benefit. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23834665 Wetting reversal at gelation transition freezes thermodynamically unstable States. The contact angle of a drop of gelling solution on a flat, solid surface was monitored as the hot solution was allowed to cool. When a solvent with a high cohesive energy and a wettable solid surface was used, a wetting solution turned into a dewetting solid at the gelation transition. The density profiles in gel as probed by confocal Raman microscopy reveal that the adsorption of both gelator and solvent shifts at the transition and the solvent is severely depleted from the interfacial region. Thus, the wetting reversal is accompanied by the interfacial desolvation. As a result of the adsorption shift during the gelation process in progress, a locally concentrated region of the gelator is frozen in space far away from the surface. This is a thermodynamically unstable state but can be realized reproducibly. The profile analysis also shows that the effect of the surface extends out to a few hundred micrometers, 2 orders of magnitude larger than the bulk correlation length. 23501490 The protective role of l-carnitine against cylindrospermopsin-induced oxidative stress in tilapia (Oreochromis niloticus). Cylindrospermopsin (CYN) is one of the most important cyanotoxins in terms of both human health and environmental quality and is produced by several different species of cyanobacteria, including Aphanizomenon ovalisporum. The principal mechanisms of action of CYN involve inhibition of protein and glutathione synthesis. In addition, CYN-mediated genotoxicity results from DNA fragmentation. The results of both in vivo and in vitro studies suggest that oxidative stress also plays a significant role in CYN pathogenesis in fish. We investigated the protective effects of l-carnitine (LC) pre-treatment on A. ovalisporum-induced oxidative stress in cells containing CYN and deoxy-CYN, or pure standard CYN, in tilapia (Oreochromis niloticus) that had been acutely exposed via oral administration. Various oxidative stress markers, including lipid peroxidation (LPO), protein oxidation, DNA oxidation, and the ratio of reduced glutathione to oxidised glutathione (GSH/GSSG), and the activities of NADPH oxidase, superoxide dismutase (SOD), catalase (CAT), and gamma-glutamyl-cysteine synthetase (γ-GCS), were evaluated in the livers and kidneys of fish in the absence and presence of 400 or 880mgLC/kgfish/day during a 21 day period prior to CYN-intoxication. The results of our study demonstrated for the first time the beneficial antioxidant effects of LC dietary supplementation on oxidative stress status in fish. No pro-oxidant effects were detected at any of the LC doses assayed, suggesting that LC is a chemoprotectant that reduces hepatic and renal oxidative stress and may be effective when used for the prophylaxis and treatment of CYN-related intoxication in fish. 23224299 Advanced gecko-foot-mimetic dry adhesives based on carbon nanotubes. Geckos can run freely on vertical walls and even ceilings. Recent studies have discovered that gecko's extraordinary climbing ability comes from a remarkable design of nature with nanoscale beta-keratin elastic hairs on their feet and toes, which collectively generate sufficiently strong van der Waals force to hold the animal onto an opposing surface while at the same time disengaging at will. Vertically aligned carbon nanotube (VA-CNT) arrays, resembling gecko's adhesive foot hairs with additional superior mechanical, chemical and electrical properties, have been demonstrated to be a promising candidate for advanced fibrillar dry adhesives. The VA-CNT arrays with tailor-made hierarchical structures can be patterned and/or transferred onto various flexible substrates, including responsive polymers. This, together with recent advances in nanofabrication techniques, could offer 'smart' dry adhesives for various potential applications, even where traditional adhesives cannot be used. A detailed understanding of the underlying mechanisms governing the material properties and adhesion performances is critical to the design and fabrication of gecko inspired CNT dry adhesives of practical significance. In this feature article, we present an overview of recent progress in both fundamental and applied frontiers for the development of CNT-based adhesives by summarizing important studies in this exciting field, including our own work. 23959850 The aetiology of myocardial injury after non-cardiac surgery. Recognition of myocardial injury after non-cardiac surgery is difficult, since strong analgesics (e.g. opioids) can mask anginal symptoms, and ECG abnormalities are subtle or transient. Thorough knowledge of the pathophysiological mechanisms is therefore essential. These mechanisms can be subdivided into four groups: type I myocardial infraction (MI), type II MI, non-ischaemic cardiac pathology, and non-cardiac pathology. The incidence of type I MI in patients with a clinical suspicion of perioperative acute coronary syndrome (ACS) is 45-57 %. This percentage is higher in patients with a high likelihood of MI such as patients with ST-elevation ACS. Of note, the generalisability of this statement is limited due to significant study limitations. Non-ischaemic cardiac pathology and non-cardiac pathology should not be overlooked as a cause of perioperative myocardial injury (PMI). Especially pulmonary embolism and dysrhythmias are a common phenomenon, and may convey important prognostic value. Implementation of routine postoperative troponin assessment and accessible use of minimally invasive imaging should be considered to provide adequate individualised therapy. Also, addition of preoperative imaging may improve the stratification of high-risk patients who may benefit from preoperative or perioperative interventions. 23965215 Predicting the appropriate uncuffed endotracheal tube size for children: a radiograph-based formula versus two age-based formulas. To determine whether a radiograph-based formula using the tracheal diameter from a chest radiograph predicted the appropriate endotracheal tube (ETT) size in children, and to compare these results with those produced using age-based formulas. Retrospective, observational study. Medical record review. Data from 537 pediatric patients, aged 3 to 6 years, who underwent orotracheal intubation with an uncuffed ETT, were randomly divided into two datasets: one was used to derive a formula and the other was for validation. A radiograph-based formula was obtained by linear regression modeling between the tracheal diameter at the seventh cervical vertebra (C7) on chest radiography and the appropriate ETT size from the estimation dataset (n=268). The appropriate size was defined as the ETT size when air leak pressure was 10 to 30 cmH2O. The predictive ability of this equation was evaluated using the validation dataset (n=269). The primary outcome was the success rate of the prediction. The following radiograph-based formula was obtained: ID = 3 + 0.3 × (tracheal diameter at C7). The success rate of the radiograph-based formula was 57%, which is higher than the 32% (P < 0.001) of the standard age-based formula (ID = 4 + age/4) or 43% (P = 0.002) of Penlington's formula (ID = 4.5 + age/4). An underestimation of the actual tracheal size occurred in 65% of cases using the age-based formulas, but in only 19% with the radiograph-based formula (P < 0.001). The radiograph-based formula may be useful for predicting the appropriate ETT size in children aged 3 to 6 years. 23373751 Electrochemiluminescence biosensor based on conducting poly(5-formylindole) for sensitive detection of Ramos cells. A signal-on electrochemiluminescence (ECL) biosensor devoted to the detection of Ramos cells was fabricated based on a novel conducting polymer, poly(5-formylindole) (P5FIn), which was synthesized electrochemically by direct anodic oxidation of 5-formylindole (5FIn). This ECL platform was presented by covalently coupling the 18-mer amino-substituted oligonucleotide (ODN) probes with aldehyde groups that are strongly reactive toward a variety of nucleophiles on the surface of solid substrates. The specific identification and high-affinity between aptamers and target cells, gold nanoparticles (AuNPs) enhanced ECL nanoprobes, along with P5FIn induced ECL quenching contributed greatly to the sensitivity and selectivity. The ECL signals were logarithmically linear with the concentration of Ramos cells in a wide determination range from 500 to 1.0 × 10(5) cells mL(-1), and the corresponding detection limit was 300 cells mL(-1). 23815980 Transcriptome analysis of human tissues and cell lines reveals one dominant transcript per gene. RNA sequencing has opened new avenues for the study of transcriptome composition. Significant evidence has accumulated showing that the human transcriptome contains in excess of a hundred thousand different transcripts. However, it is still not clear to what extent this diversity prevails when considering the relative abundances of different transcripts from the same gene. Here we show that, in a given condition, most protein coding genes have one major transcript expressed at significantly higher level than others, that in human tissues the major transcripts contribute almost 85 percent to the total mRNA from protein coding loci, and that often the same major transcript is expressed in many tissues. We detect a high degree of overlap between the set of major transcripts and a recently published set of alternatively spliced transcripts that are predicted to be translated utilizing proteomic data. Thus, we hypothesize that although some minor transcripts may play a functional role, the major ones are likely to be the main contributors to the proteome. However, we still detect a non-negligible fraction of protein coding genes for which the major transcript does not code a protein. Overall, our findings suggest that the transcriptome from protein coding loci is dominated by one transcript per gene and that not all the transcripts that contribute to transcriptome diversity are equally likely to contribute to protein diversity. This observation can help to prioritize candidate targets in proteomics research and to predict the functional impact of the detected changes in variation studies. 23783399 Evaluation of the adjuvant effect of pidotimod on the immune protection induced by UV-attenuated Toxoplasma gondii in mouse models. The current anti-Toxoplasma gondii drugs have many shortcomings and effective vaccines against T. gondii may contribute to the control of this pathogen. Pidotimod is a synthetic substance capable of stimulating both cellular and humoral immunity. To investigate the possible adjuvant effect of pidotimod on the immune response to T. gondii in Kunming mice induced by ultraviolet-attenuated T. gondii (UV-T.g), in this study, mice were immunized intraperitoneal (i.p.) with UV-T.g or UV-T.g co-administered with pidotimod (UV-T.g + PT). After infection or challenge by i.p. injection of 10(2) RH tachyzoites, the animal survival rate, parasite burden in peritoneal lavage fluids, liver histopathology, the level of serum anti-toxoplasma IgG antibody, and the mRNA expressions of IL-2, IFN-γ, and TNF-α from spleen analyzed using real-time PCR, were compared among different groups. The results showed that, compared with infected controls, infected mice treated with pidotimod had significantly increased survival rate and extended survival time, decreased parasite burden, improved liver histopathology, increased level of anti-toxoplasma IgG antibody, and increased mRNA expressions of Th1-type cytokine (IL-2, IFN-γ, and TNF-α) (P < 0.01), while mice vaccinated with UV-T.g and then challenged had even significantly increased survival rate and extended survival time, decreased parasite burden, improved liver histopathology, and increased mRNA expressions of Th1-type cytokines (IL-2, IFN-γ, and TNF-α) (P < 0.01); furthermore, vaccinated mice co-administered with pidotimod had even more lower parasite burden, milder liver histopathology, and higher levels of Th1-type cytokine and anti-toxoplasma IgG antibody (P < 0.01). Our data demonstrated that pidotimod in vivo could promote strong and specific humoral and cellular immune response to T. gondii challenge infection when co-administered with UV-attenuated T. gondii. It suggests that pidotimod may have the potential to be used as an effective vaccine adjuvant. 23830884 Mortality and incidence of new primary cancers in men with prostate cancer: A Danish population-based cohort study. Background: Prostate cancer (PC) survivors may have an increased risk of new primary cancers (NPCs) due to shared risk factors or PC-directed treatments. Methods: Using Danish registries, we conducted a cohort study of men with (n=30,220) and without PC (n=151,100) (comparators), matched 1:5 on age and PC diagnosis/index date. We computed incidence rates of NPCs per 10,000 person years (PY) and associated 95% confidence intervals (CI), and used Cox proportional hazards regression to compute hazard ratios (HRs) and 95%CI, adjusting for comorbidities. In order to obviate any impact of shorter survival among prostate cancer patients, we censored comparator patients when the matched prostate cancer patient died or was censored. Results: Follow-up spanned 113,487PY and 462,982PY in the PC and comparison cohorts, respectively. 65% of the cohorts were aged >70 years at diagnosis. Among PC patients, 51% had distant/unspecified stage, and 63% had surgery as primary treatment. The PC cohort had lower incidence of NPCs than their comparators. The adjusted HR of NPC among men with PC versus the comparators was 0.84 (95%CI=0.80, 0.88). Lowest HRs were among older men, those with distant stage, and were particularly evident for cancers of the brain, liver, pancreas, respiratory, upper gastrointestinal, and urinary systems. Conclusions: We find no evidence of an increased risk of NPCs among men with PC. The deficit of NPCs among men with PC may be a true effect but is more likely due to lower levels of risk factors (e.g., smoking) in PC patients versus comparators, clinical consideration of cancers at new organs as metastases rather than new primaries, or under-recording/under-reporting of NPCs among PC patients. 23897335 Fate of Adipose-Derived Stromal Vascular Fraction Cells after Co-implantation with Fat Grafts: Evidence of Cell Survival and Differentiation in Ischemic Adipose Tissue. Some studies have suggested that adipose-derived stromal vascular fraction is a potential cell source responsible for the improved quality and long-term retention of fat grafts, but studies that have clearly demonstrated the survival and differentiation potential of the implanted stromal vascular fraction cells as being dynamic phenomena have not been widely reported. The authors isolated stromal vascular fraction cells from C57BL/6J-GFP mice. Green fluorescence protein-positive stromal vascular fraction cells were mixed with minced inguinal adipose tissue harvested from C57BL/6J mice and then co-implanted into BALB/c nude mice. The survival of implanted green fluorescence protein-positive stromal vascular fraction cells was tracked by in vivo fluorescence imaging for 56 days. Immunofluorescence staining was used to analyze the differentiation of green fluorescence protein-positive stromal vascular fraction cells occurring in ischemic adipose tissue at 7, 14, 28, 35, 42, or 56 days. The fluorescence signal intensity fell drastically within the first 14 days after co-implantation and continued to decrease thereafter, with 17.3 percent signal intensity (relative to day 1) at 56 days. Immunofluorescence staining revealed that some green fluorescence protein-positive cells can spontaneously differentiate into adipocytes from day 7, and some of the implanted stromal vascular fraction cells can incorporate into new blood vessels. The authors show convincing evidence for dynamic changes of stromal vascular fraction cells after co-implantation with fat grafts. The results prove the principle that implanted stromal vascular fraction cells can survive in the ischemic microenvironment of fat grafts and participate in the process of adipogenesis and angiogenesis. 23452875 Inferior vena cava filters: what radiologists need to know. Inferior vena cava (IVC) filters are a controversial mechanical adjunct in the prevention of pulmonary embolism, the most serious result of venous thromboembolism. Despite modern IVC filters being in clinical use for more than 45 years, there is still uncertainty amongst many radiologists about the indications for IVC filter placement and their removal, particularly the more recent prophylactic use in patients without confirmed deep vein thrombosis (DVT) or pulmonary embolism (PE). Recently published guidelines on filter use from the National Institute of Health and Clinical Excellence (NICE) and other professional bodies are discussed. The vast majority of IVC filters in the UK are inserted by interventional radiologists, so radiologists may be the first point of contact for information requested by other clinicians. The increasing use of filters means that radiologists will encounter filters increasingly often during abdominal cross-sectional imaging. Awareness of common filter-related complications, such as tilting, thrombosis, and caval perforation, is useful to reassure or alert other clinicians. The potential role of filters in upper extremity DVT and requirement for concomitant anticoagulation is discussed. 23601399 Nutrients and bioactive compounds of Thai indigenous fruits. This study determined the nutritional potential of Thai indigenous fruits in terms of nutrients, bioactive compounds, and antioxidant activities. Three indigenous fruits were collected at two conservation areas in Kanchanaburi province, Thailand. The results showed that Phyllanthus emblica L. exhibited the highest levels of vitamin C (575±452mg/100g), total phenolics (TP) (3703±1244mGAE/100g), and antioxidant activities, as measured by DPPH, FRAP and ORAC assays. Compared to the other two fruits, Antidesma velutinosum Blume contained higher levels of most nutrients and dietary fibre (15.6±5.9g/100g), as well as carotenoids (335±98μg/100g) and phytosterols (22.1±3.9mg/100g). Spondias pinnata (L.f.) Kurz was high in total phenolics (3178±887mGAE/100g) and antioxidant activity. Moreover, high correlations were found between TP and antioxidant activities (r>0.9). These Thai indigenous fruits are potentially good sources of nutrients, bioactive compounds, and antioxidant activities. Conservation and utilisation should be promoted for food security and consumption as part of a healthy diet. 23370777 Vaspin inhibits kallikrein 7 by serpin mechanism. The molecular target of the adipokine vaspin (visceral adipose tissue-derived serpin; serpinA12) and its mode of action are unknown. Here, we provide the vaspin crystal structure and identify human kallikrein 7 (hK7) as a first protease target of vaspin inhibited by classical serpin mechanism with high specificity in vitro. We detect vaspin-hK7 complexes in human plasma and find co-expression of both proteins in murine pancreatic β-cells. We further demonstrate that hK7 cleaves human insulin in the A- and B-chain. Vaspin treatment of isolated pancreatic islets leads to increased insulin concentration in the media upon glucose stimulation without influencing insulin secretion. By application of vaspin and generated inactive mutants, we find the significantly improved glucose tolerance in C57BL/6NTac and db/db mice treated with recombinant vaspin fully dependent on the vaspin serpin activity and not related to vaspin-mediated changes in insulin sensitivity as determined by euglycemic-hyperinsulinemic clamp studies. Improved glucose metabolism could be mediated by increased insulin plasma concentrations 150 min after a glucose challenge in db/db mice, supporting the hypothesis that vaspin may inhibit insulin degradation by hK7 in the circulation. In conclusion, we demonstrate the inhibitory serpin nature and the first protease target of the adipose tissue-derived serpin vaspin, and our findings suggest hK7 inhibition by vaspin as an underlying physiological mechanism for its compensatory actions on obesity-induced insulin resistance. 23876315 NMR binding and crystal structure reveal that intrinsically-unstructured regulatory domain auto-inhibits PAK4 by a mechanism different from that of PAK1. Six human PAK members are classified into groups I (PAKs 1-3) and II (PAK4-6). Previously, only group I PAKs were thought to be auto-inhibited but very recently PAK4, the prototype of group II PAKs, has also been shown to be auto-inhibited by its N-terminal regulatory domain. However, the complete auto-inhibitory domain (AID) sequence remains undefined and the mechanism underlying its auto-inhibition is largely elusive. Here, the N-terminal regulatory domain of PAK4 sufficient for auto-inhibiting and binding Cdc42/Rac was characterized to be intrinsically unstructured, but nevertheless we identified the entire AID sequence by NMR. Strikingly, an AID peptide was derived by deleting the binding-unnecessary residues, which has a Kd of 320nM to the PAK4 catalytic domain. Consequently, the PAK4 crystal structure complexed with the entire AID has been determined, which reveals that the complete kinase cleft is occupied by 20 AID residuescomposed of an N-terminal α-helix and a previously-identified pseudosubstrate motif, thus achieving auto-inhibition. Our study reveals that PAK4 is auto-inhibited by a novel mechanism which is completely different from that for PAK1, thus bearing critical implications for design of inhibitors specific for group II PAKs. 23827229 A pair of identified giant visual projection neurons demonstrates rhythmic activities before eclosion. A small set of neurons acting as an internal clock in the Drosophila brain is critical for regulating circadian activities behavior and pre-adult development. However, the cell basis for the circadian rhythm in correlation with light sensitivity is not fully understood. Here we identified a pair of giant visual projection neurons located laterally to the calyx of the mushroom bodies, and investigated their electrophysiological, morphological characteristics, as well as the development pathways during eclosion. The typical morphology of these giant neurons showed the size of the soma (16.0±0.6 microns in diameter) and its processes. Interestingly during development, the three major branches shrunk significantly along with gradually decreased rhythmic spikes. Furthermore, the electrical activity of the giant visual projection neurons is circadian-regulated, shown with significantly higher resting membrane potential, increase in frequency of spontaneous action potential firing, and burst firing pattern during circadian day and night time. The similarities in the morphological characteristics with other visual projection neurons highly suggest that this neuron is a type of novel visual projection neurons in this area, which has special properties in light sensitivities and rhythmic activities. Our data provided supporting evidence for the visual projection neurons with light sensitivities, and pointed to the potential correlation of visual projection neurons and circadian rhythms during the eclosion period or an adaptive development for higher sensitivity of light in adult visual systems. 23623512 Long-term outcomes of pediatric sinus bradycardia. To delineate the long-term outcomes and mechanisms of pediatric sinus bradycardia. Participants with sinus bradycardia who were identified from a survey of 432 166 elementary and high school students, were enrolled 10 years after the survey. The clinical course, heart rate variability, and hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4) gene were assessed. A total of 104 (male:female was 60:44; prevalence, 0.025%) participants were observed to have sinus bradycardia at age 15.5 ± 0.2 years with a mean heart rate of 48.4 ± 0.4 beats per minute; 86 study participants (83%) responded to clinical assessment and 37 (36%) underwent laboratory assessment. Athletes composed 37.8% of the study participants. During the extended 10-year follow-up, 15 (17%) of the participants had self-limited syncopal episodes, but none had experienced life-threatening events. According to Holter recordings, none of the participants had heart rate <30 beats per minute or a pause longer than 3 seconds. Compared with 67 age- and sex-matched controls, the variables of heart rate based on the spectral and time domain analysis of the participants with sinus bradycardia were all significantly higher, indicating higher parasympathetic activity. The results of mutation analysis were negative in the HCN4 gene in all of our participants. The long-term outcomes of the children and adolescents with sinus bradycardia identified using school electrocardiographic survey are favorable. Parasympathetic hyperactivity, instead of HCN4 gene mutation, is responsible for the occurrence of sinus bradycardia. 23812893 The association between ß-glucocerebrosidase mutations and parkinsonism. Mutations in the ß-glucocerebrosidase gene (GBA), which encodes the lysosomal enzyme ß-glucocerebrosidase, have traditionally been implicated in Gaucher disease, an autosomal recessive lysosomal storage disorder. Yet the past two decades have yielded an explosion of epidemiological and basic-science evidence linking mutations in GBA with the development of Parkinson disease (PD) as well. Although the specific contribution of mutant GBA to the pathogenesis of parkinsonism remains unknown, evidence suggests that both loss of function and toxic gain of function by abnormal ß-glucocerebrosidase may be important, and implicates a close relationship between ß-glucocerebrosidase and α-synuclein. Furthermore, multiple lines of evidence suggest that although GBA-associated PD closely mimics idiopathic PD (IPD), it may present at a younger age, and is more frequently complicated by cognitive dysfunction. Understanding the clinical association between GBA and PD, and the relationship between ß-glucocerebrosidase and α-synuclein, may enhance understanding of the pathogenesis of IPD, improve prognostication and treatment of GBA carriers with parkinsonism, and furthermore inform therapies for IPD not due to GBA mutations. 23846418 Memory, Imagination, and Predicting the Future: A Common Brain Mechanism? On the face of it, memory, imagination, and prediction seem to be distinct cognitive functions. However, metacognitive, cognitive, neuropsychological, and neuroimaging evidence is emerging that they are not, suggesting intimate links in their underlying processes. Here, we explore these empirical findings and the evolving theoretical frameworks that seek to explain how a common neural system supports our recollection of times past, imagination, and our attempts to predict the future. 23967044 Correction: Pyrolytic and Kinetic Characteristics of the Thermal Decomposition of Perilla frutescens Polysaccharide. [This corrects the article on p. e52597 in vol. 7.]. 23891179 Smoothly Clipped Absolute Deviation (SCAD) regularization for compressed sensing MRI Using an augmented Lagrangian scheme. Compressed sensing (CS) provides a promising framework for MR image reconstruction from highly undersampled data, thus reducing data acquisition time. In this context, sparsity-promoting regularization techniques exploit the prior knowledge that MR images are sparse or compressible in a given transform domain. In this work, a new regularization technique was introduced by iterative linearization of the non-convex smoothly clipped absolute deviation (SCAD) norm with the aim of reducing the sampling rate even lower than it is required by the conventional l1 norm while approaching an l0 norm. The CS-MR image reconstruction was formulated as an equality-constrained optimization problem using a variable splitting technique and solved using an augmented Lagrangian (AL) method developed to accelerate the optimization of constrained problems. The performance of the resulting SCAD-based algorithm was evaluated for discrete gradients and wavelet sparsifying transforms and compared with its l1-based counterpart using phantom and clinical studies. The k-spaces of the datasets were retrospectively undersampled using different sampling trajectories. In the AL framework, the CS-MRI problem was decomposed into two simpler sub-problems, wherein the linearization of the SCAD norm resulted in an adaptively weighted soft thresholding rule with a sparsity enhancing effect. It was demonstrated that the proposed regularization technique adaptively assigns lower weights on the thresholding of gradient fields and wavelet coefficients, and as such, is more efficient in reducing aliasing artifacts arising from k-space undersampling, when compared to its l1-based counterpart. The SCAD regularization improves the performance of l1-based regularization technique, especially at reduced sampling rates, and thus might be a good candidate for some applications in CS-MRI. 23296256 Graphene oxide for effective radionuclide removal. Here we show the efficacy of graphene oxide (GO) for rapid removal of some of the most toxic and radioactive long-lived human-made radionuclides from contaminated water, even from acidic solutions (pH < 2). The interaction of GO with actinides including Am(III), Th(IV), Pu(IV), Np(V), U(VI) and typical fission products Sr(II), Eu(III) and Tc(VII) were studied, along with their sorption kinetics. Cation/GO coagulation occurs with the formation of nanoparticle aggregates of GO sheets, facilitating their removal. GO is far more effective in removal of transuranium elements from simulated nuclear waste solutions than other routinely used sorbents such as bentonite clays and activated carbon. These results point toward a simple methodology to mollify the severity of nuclear waste contamination, thereby leading to effective measures for environmental remediation. 23444138 Coactivators enable glucocorticoid receptor recruitment to fine-tune estrogen receptor transcriptional responses. Nuclear receptors (NRs) are central regulators of pathophysiological processes; however, how their responses intertwine is still not fully understood. The aim of this study was to determine whether and how steroid NRs can influence each other's activity under co-agonist treatment. We used a unique system consisting of a multicopy integration of an estrogen receptor responsive unit that allows direct visualization and quantification of estrogen receptor alpha (ERα) DNA binding, co-regulator recruitment and transcriptional readout. We find that ERα DNA loading is required for other type I nuclear receptors to be co-recruited after dual agonist treatment. We focused on ERα/glucocorticoid receptor interplay and demonstrated that it requires steroid receptor coactivators (SRC-2, SRC-3) and the mediator component MED14. We then validated this cooperative interplay on endogenous target genes in breast cancer cells. Taken together, this work highlights another layer of mechanistic complexity through which NRs cross-talk with each other on chromatin under multiple hormonal stimuli. 23851651 Complete genome sequence of marine bacterium Pseudoalteromonas phenolica bacteriophage TW1. For molecular study of marine bacteria Pseudoalteromonas phenolica using bacteriophage, a novel bacteriophage, TW1, belonging to the family Siphoviridae, was isolated, and its genome was completely sequenced and analyzed. The phage TW1 genome consists of 39,940-bp-length double-stranded DNA with a GC content of 40.19 %, and it was predicted to have 62 open reading frames (ORFs), which were classified into functional groups, including phage structure, packaging, DNA metabolism, regulation, and additional function. The phage life style prediction using PHACTS showed that it may be a temperate phage. However, genes related to lysogeny and host lysis were not detected in the phage TW1 genome, indicating that annotation information about P. phenolica phages in the genome databases may not be sufficient for the functional prediction of their encoded proteins. This is the first report of a P. phenolica-infecting phage, and this phage genome study will provide useful information for further molecular research on P. phenolica and its phage, as well as their interactions. 23611356 Resection margins in conservative breast cancer surgery. Conservative breast cancer surgery is facing a new problem: the potential tumour involvement of resection margins. This eventuality has been closely and negatively associated with disease-free survival. Various factors may influence the likelihood of margins being affected, mostly related to the characteristics of the tumour, patient or surgical technique. In the last decade, many studies have attempted to find predictive factors for margin involvement. However, it is currently the new techniques used in the study of margins and tumour localisation that are significantly reducing reoperations in conservative breast cancer surgery. 23770707 Regulation of food intake after surgery and the gut brain axis. To highlight recent developments relating control of food intake after surgery and the gut-brain axis by reviewing clinically relevant English language articles mainly from January 2011 to March 2013. The gut-brain axis involves a number of complex interactions between hypothalamic nuclei and the gastrointestinal tract. In the postoperative period, release of cytokines and neuromodulators are involved in the control of food intake. Analogues of neuromodulators have been developed and tested in animal studies. The emerging field of metabolic surgery has allowed study of these mechanisms in greater detail. The current epidemic of worldwide obesity demands further research into the mechanisms underlying control of food intake. 23925564 Tuning 'de Vries-like' properties in binary mixtures of liquid crystals with different molecular lengths. Smectic liquid crystals with 'de Vries-like' properties are characterized by a maximum layer contraction of ≤1% upon transition from the orthogonal SmA phase to the tilted SmC phase. We show that binary mixtures of 'de Vries-like' and conventional SmC mesogens with a molecular length ratio of 1.34 undergo a SmA-SmC phase transition with a maximum layer contraction ranging from 1.0 to 1.9% depending on the mixture composition. 23471746 Re-cycling Paradigms: Cell Cycle Regulation in Adult Hippocampal Neurogenesis and Implications for Depression. Since adult neurogenesis became a widely accepted phenomenon, much effort has been put in trying to understand the mechanisms involved in its regulation. In addition, the pathophysiology of several neuropsychiatric disorders, such as depression, has been associated with imbalances in adult hippocampal neurogenesis. These imbalances may ultimately reflect alterations at the cell cycle level, as a common mechanism through which intrinsic and extrinsic stimuli interact with the neurogenic niche properties. Thus, the comprehension of these regulatory mechanisms has become of major importance to disclose novel therapeutic targets. In this review, we first present a comprehensive view on the cell cycle components and mechanisms that were identified in the context of the homeostatic adult hippocampal neurogenic niche. Then, we focus on recent work regarding the cell cycle changes and signaling pathways that are responsible for the neurogenesis imbalances observed in neuropathological conditions, with a particular emphasis on depression. 23811720 The correlation between crestal bone resorption and implant stability during healing period using resonance frequency analysis. To detect the correlation between crestal bone resorption and implant stability during healing period using resonance frequency analysis (RFA). Twenty-two International Team for Implantology Straumann implants were placed in the posterior maxilla or mandible in 9 patients. RFA reading was taken immediately after implant placement. Periapical radiographs were taken, and the distance from the shoulder of the healing cap to the first bone-implant contact was measured, and the average mesial and distal distances were taken. Patients were followed up at 6 and 12 weeks for data collection. At 6 weeks, the correlation between crestal bone resorption and implant stability was significant (Spearman correlation test, P < 0.05) and negative correlation coefficient (r) was -0.522. At 12 weeks, the correlation between crestal bone resorption and implant stability was not significant (Spearman correlation test, P > 0.05) and negative correlation coefficient (r) was -0.119. There was a significant negative correlation between the crestal bone resorption and implant stability at 6 weeks, whereas the negative correlations between the crestal bone resorption and implant stability at 12 weeks were nonsignificant. 23693077 Induction of DNA damage and ATF3 by retigeric acid B, a novel topoisomerase II inhibitor, promotes apoptosis in prostate cancer cells. Retigeric acid B (RB) has been reported to exhibit its anti-tumor activity in vitro and in vivo. Here, we found that RB significantly inhibited activity of topoisomerase IIα (Topo IIα), leading to remarkable DNA damage in prostate cancer (PCa) cells as evidenced by a strong induction of γH2AX and DNA fragmentation. Activation of ATM and ATR sequentially led to induction of phospho-Chk1/2 and phospho-Cdc25 in response to RB. Blockade of ATM/ATR signaling resulted in the attenuation of RB-induced γH2AX, and partially rescued RB-mediated cell death. RB treatment also resulted in inactivation of DNA repair proteins such as phospho-BRCA1, impairment of HR, and NHEJ repair as indicated by DNA end-joining assays. Meanwhile, a stress-responsive gene activating transcription factor 3 (ATF3) was noted for its predominant expression in response to RB-induced DNA damage. Knockdown of ATF3 inhibited the RB-induced expression changes of cell cycle- and apoptosis-related genes such as DR5, DDIT4, CDC25A, GADD45A, and partially blocked RB-mediated inhibition on cell proliferation and induction of apoptosis, suggesting the crucial involvement of ATF3 in this event. Microarray data displayed that RB caused changes of genes required for damaged-DNA binding and repair, as well as ATF3 and its target genes. Our data firstly demonstrated that RB was a novel DNA Topo II inhibitor and triggered cell death by inducing DNA damage and stress-response, suggesting a promising anticancer agent. 23950866 Annexin A2 Promotes the Migration and Invasion of Human Hepatocellular Carcinoma Cells In Vitro by Regulating the Shedding of CD147-Harboring Microvesicles from Tumor Cells. It has been reported that Annexin A2 (ANXA2) is up-regulated in hepatocellular carcinoma (HCC), but the roles of ANXA2 in the migration and invasion of HCC cells have not been determined. In this study, we found that ANXA2-specific siRNA (si-ANXA2) significantly inhibited the migration and invasion of HCC cells co-cultured with fibroblasts in vitro. In addition, the production of MMP-2 by fibroblasts cultured in supernatant collected from si-ANXA2-transfected HCC cells was notably down-regulated. ANXA2 was also found to be co-localized and co-immunoprecipitated with CD147. Further investigation revealed that the expression of ANXA2 in HCC cells affected the shedding of CD147-harboring membrane microvesicles, acting as a vehicle for CD147 in tumor-stromal interactions and thereby regulating the production of MMP-2 by fibroblasts. Together, these results suggest that ANXA2 enhances the migration and invasion potential of HCC cells in vitro by regulating the trafficking of CD147-harboring membrane microvesicles. 23508555 Diurnal pituitary-adrenal activity during schedule-induced polydipsia of water and ethanol in cynomolgus monkeys (Macaca fascicularis). RATIONALE: Intermittent delivery of an important commodity (e.g., food pellets) generates excessive behaviors as an adjunct to the schedule of reinforcement (adjunctive behaviors) that are hypothesized to be due to conflict between engaging and escaping a situation where reinforcement is delivered, but at suboptimal rates. OBJECTIVES: This study characterized the endocrine correlates during schedule-induced polydipsia of water and ethanol using a longitudinal approach in non-human primates. METHODS: Plasma adrenocorticotropic hormone (ACTH) and cortisol were measured in samples from awake cynomolgus monkeys (Macaca fascicularis, 11 adult males) obtained at the onset, mid-day, and offset of their 12-h light cycle. The monkeys were induced to drink water and ethanol (4 % w/v, in water) using a fixed time (FT) 300-s interval schedule of pellet delivery. The induction fluid changed every 30 sessions in the following order: water, 0.5 g/kg ethanol, 1.0 g/kg ethanol, and 1.5 g/kg ethanol. Following induction, ethanol and water were concurrently available for 22 h/day. RESULTS: The FT 300-s schedule gradually increased ACTH, but not cortisol, during water induction to a plateau sustained throughout ethanol induction in every monkey. Upon termination of the schedule, ACTH decreased to baseline and cortisol below baseline. Diurnal ACTH and cortisol were unrelated to the dose of ethanol, but ACTH rhythm flattened at 0.5 g/kg/day and remained flattened. CONCLUSIONS: The coincidence of elevated ACTH with the initial experience of drinking to intoxication may have altered the mechanisms involved in the transition to heavy drinking. 23647338 Thermospermine levels are controlled by an auxin-dependent feedback loop mechanism in Populus xylem. Polyamines are small polycationic amines that are widespread in living organisms. Thermospermine, synthesized by thermospermine synthase ACAULIS5 (ACL5), was recently shown to be an endogenous plant polyamine. Thermospermine is critical for proper vascular development and xylem cell specification, but it is not known how thermospermine homeostasis is controlled in the xylem. We present data in the Populus model system supporting the existence of a negative feedback control of thermospermine levels in stem xylem tissues, the main site of thermospermine biosynthesis. While over-expression of the ACL5 homologue in Populus, POPACAULIS5, resulted in strong up-regulation of ACL5 expression and thermospermine accumulation in leaves, the corresponding levels in the secondary xylem tissues of the stem were similar or lower than those in the wild-type. POPACAULIS5 over-expression had a negative effect on accumulation of indole-3-acetic acid, while exogenous auxin had a positive effect on POPACAULIS5 expression, thus promoting thermospermine accumulation. Further, over-expression of POPACAULIS5 negatively affected expression of the class III homeodomain leucine zipper (HD-Zip III) transcription factor gene PttHB8, a homologue of AtHB8, while up-regulation of PttHB8 positively affected POPACAULIS5 expression. These results indicate that excessive accumulation of thermospermine is prevented by a negative feedback control of POPACAULIS5 transcript levels through suppression of indole-3-acetic acid levels, and that PttHB8 is involved in the control of POPACAULIS5 expression. We propose that this negative feedback loop functions to maintain steady-state levels of thermospermine, which is required for proper xylem development, and that it is dependent on the presence of high concentrations of endogenous indole-3-acetic acid, such as those present in the secondary xylem tissues. 23643467 Influence of the knee flexion on muscle activation and transmissibility during whole body vibration. The influence of the knee flexion on muscle activation and transmissibility during whole body vibration is controversially discussed in the literature. In this study, 34 individuals had electromyography activity (EMG) of the vastus lateralis and the acceleration assessed while squatting with 60° and 90° of knee flexion either with or without whole-body vibration (WBV). The conditions were maintained for 10s with 1min of rest between each condition. The main findings were (1) the larger the angle of knee flexion (90° vs. 60°), the greater the EMG (p<0.001), with no difference on acceleration transmissibility; (2) for both angles of knee flexion, the addition of WBV produced no significant difference in EMG and higher acceleration compared to without WBV (p<0.001). These results suggest that the larger the knee flexion angle (60° vs. 90°), the greater the muscle activation without acceleration modification. However, the addition of WBV increases the transmissibility of acceleration in the lower limbs without modification in EMG of vastus lateralis. 23828221 Slow magnetic relaxation in tris(diphosphanylamido) and tetra(phosphanoamido) dysprosium complexes. Two homoleptic phosphanylamido dysprosium complexes [Li(THF)4][(Ph2PNPh)4Dy] and [Dy{N(PPh2)2}3] have been synthesized. Both have a highly symmetric arrangement of the ligand which is only slightly broken in the solid state by steric and packing effects as a result of the weak coordination of phosphorus atoms to the metal centre. Magnetic properties of these two compounds are similar with both showing slow magnetic relaxation. 23870939 A NMR metabolomics study of the ripening process of the Fiore Sardo cheese produced with autochthonous adjunct cultures. Fiore Sardo (FS) is a traditional Italian raw ewe's milk cheese carrying a Protected Designation of Origin (PDO). This study investigated the kinetics of FS cheese ripening by physicochemical parameters, microbial counting, and NMR metabolomics using aqueous extracts. Four Fiore Sardo cheeses, manufactured from milk with deliberately added autochthonous lactic acid bacteria (LAB) or commercial starters were studied during a period of 90days of ripening. Major differences in the metabolic profiles were observed amongst the samples as a function of the adjunct culture utilised. (1)H NMR metabolomics in combination with multivariate data analysis was able to classify cheese samples on the basis of their maturation age and the type of added cultures. These findings lay the metabolic basis for the authentication of Fiore Sardo cheese produced in compliance with PDO specifications which allow the use of only native LAB cultures. 23530815 Multitarget Global Sensitivity Analysis of n-Butanol Combustion. A model for the combustion of butanol is studied using a recently developed theoretical method for the systematic improvement of the kinetic mechanism. The butanol mechanism includes 1446 reactions, and we demonstrate that it is straightforward and computationally feasible to implement a full global sensitivity analysis incorporating all the reactions. In addition, we extend our previous analysis of ignition-delay targets to include species targets. The combination of species and ignition targets leads to multitarget global sensitivity analysis, which allows for a more complete mechanism validation procedure than we previously implemented. The inclusion of species sensitivity analysis allows for a direct comparison between reaction pathway analysis and global sensitivity analysis. 23966449 Physical Activity and Trial-by-Trial Adjustments of Response Conflict. The relationship of physical activity to trial-by-trial adjustments of response conflict was assessed using behavioral task performance, the N2 event-related brain potential component, and phase-locking values (PLVs) in a lower gamma band during a perceptual conflict task. Nineteen physically active and 19 inactive young adults (mean age = 21.3 years) performed a Navon task, using a global letter made up of local letters of either the same kind (congruent trials) or a different kind (incongruent trials). Findings revealed that active individuals exhibited smaller N2 amplitudes and greater PLVs on incongruent trials that were preceded by incongruent trials compared with those preceded by congruent trials. Such phenomena were not observed for inactive individuals. These results suggest that greater physical activity is associated with larger trial-by-trial adjustments of response conflict, which we attribute to upregulation of top-down cognitive control and reductions in response conflict. 22575593 Magnetic resonance imaging characteristics of primary intraspinal peripheral primitive neuroectodermal tumour. The purpose of our study was to describe the salient magnetic resonance imaging (MRI) findings in primary intraspinal peripheral primitive neuroectodermal tumour (PNET). A retrospective review of the clinical and MRI images of 7 pathologically proven cases of intraspinal peripheral PNETs was performed. The various parameters, such as vertebral level of involvement; tumour location, size, focality, and margin; signal intensity of the lesion; the presence of hemorrhage or calcification; any signal voids; assessment of the adjacent cord for cord compression; cord dilatation; the presence of paraspinal tissue mass; or vertebral or other bony changes, were analysed. All 7 patients had lesions in the thoracolumbar region. Three patients had extradural lesions, 4 had intradural extramedullary lesions, and none had intramedullary lesions. Six lesions were well circumscribed. Only 1 patient had multifocal involvement. All lesions were of hypointense or isointense signal on T1-weighted imaging, whereas all but one were hyperintense on T2-weighted imaging. Lesions enhanced heterogeneously except 1 intradural extramedullary lesion, which enhanced homogeneously. A paraspinal mass was noticed in 2 patients. Vertebral collapse was present in 1 patients. Intraspinal peripheral PNETs are rare spinal tumours. Although imaging characteristics are not specific, a focal circumscribed lesion in a young individual at the intramedullary, extramedullary intradural, or extradural spinal location that shows hypointense and hyperintense signal on T1- and T2-weighted images, respectively, requires PNET to be considered in the differentials. 23907408 Retinal single-layer analysis in Parkinsonian syndromes: an optical coherence tomography study. We report a newly developed analysis algorithm for optical coherence tomography (OCT) that makes a retinal single-layer analysis with calculation of the average thickness of retinal layers possible. The aim of the study was to examine specific patterns of retinal layer pathology as a potential marker of neurodegeneration in Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). Spectral domain OCT with a semiautomatic algorithm to calculate the average thickness of single retinal layers was applied to foveal scans of 65 PD, 16 PSP, and 12 MSA patients as well as 41 matched controls. Demographic and clinical data were collected for correlation analysis. Only PSP and MSA showed a significant reduction of retinal layers in comparison to controls. In PD, there were no significant findings in single retinal layer measurement. Most remarkably, the thickening of the outer nuclear layer in PSP and the outer plexiform layer in MSA was highly specific for these disease entities and allowed differentiating PSP from MSA with high sensitivity and specificity. With this analysis algorithm of OCT data, disease-specific retinal layer changes could be observed. Despite a general tendency to whole retinal and single retinal layer thinning that may reflect neurodegeneration in all Parkinsonian syndromes, the specific findings in MSA and PSP may serve as a highly sensitive and specific differential diagnostic tool and as a progression marker in these disease entities. Upcoming studies with a longitudinal setting will have to prove this assumption. 23968273 Intraventricular haemorrhage in preterm infants - Can we improve outcome by addressing coagulation? Abstract During the last few decades, the survival of preterm infants has increased dramatically. Nevertheless, with the increasing number of very young and extremely low birth weight infants, morbidity is still a major problem. Intraventricular Haemorrhage (IVH) is a major complication of preterm birth, and large haemorrhages or haemorrhages associated with parenchymal brain lesions may yield a high rate of future disability. IVH is a complex, multi-factorial disorder. Prematurity and low birth weight remain as its most important risk factors, affecting vulnerability of the germinal matrix as well as the coagulation system. Approximately 80% of IVHs occur by 72 h after birth, but a considerable proportion of IVH is already visible on the first cranial ultrasound scan within a few hours of birth. The hypothesis that a severe coagulation deficiency in the premature newborn could be a major contributing factor to IVH has been suggested, and small open label interventional studies targeting the premature coagulation system have been conducted with ethamsylate, vitamin K, fresh frozen plasma, recombinant activated factor VII and prothrombin complex concentrate. The outcome of these studies will be reviewed. 23803465 Reprogramming the chromatin landscape: interplay of the estrogen and glucocorticoid receptors at the genomic level. Cross-talk between estrogen receptors (ER) and glucocorticoid receptors (GR) has been shown to contribute to the development and progression of breast cancer. Importantly, the ER and GR status in breast cancer cells is a significant factor in determining the outcome of the disease. However, mechanistic details defining the cellular interactions between ER and GR are poorly understood. We investigated genome-wide binding profiles for ER and GR upon coactivation and characterized the status of the chromatin landscape. We describe a novel mechanism dictating the molecular interplay between ER and GR. Upon induction, GR modulates access of ER to specific sites in the genome by reorganization of the chromatin configuration for these elements. Binding to these newly accessible sites occurs either by direct recognition of ER response elements or indirectly through interactions with other factors. The unveiling of this mechanism is important for understanding cellular interactions between ER and GR and may represent a general mechanism for cross-talk between nuclear receptors in human disease. Cancer Res; 73(16); 5130-9. ©2013 AACR. 23860505 Nature of spatial coupling in children with and without developmental coordination disorder in ball catching. The nature of intra- and interlimb (bimanual) coordination was examined in ten boys with (M = 10.5 years, SD = 1.0) and without DCD (M = 10.8 years, SD = .9) in a two-handed catching task. Children with developmental coordination disorder (DCD) caught significantly fewer balls (MDCD = 56%, SD = 17.6 vs. MnoDCD = 93%, SD = 7.5), and both groups solved the "degrees of freedom problem" differently at intralimb level of coordination. Typically developing children coupled and decoupled the respective spatial relations, whereas the majority of children with DCD segmented their actions. At interlimb level, both groups exhibited a comparable degree of spatial symmetry. However, individual profiles also showed that children with varying degrees of movement issues exhibited movement patterns that were qualitatively and functionally diverse. Overall, in the context of previous research on interlimb coordination it appears that spatial, in addition to temporal organization, may be jeopardized in at least some children with DCD. 23831519 Development and in vitro evaluation of a novel lipid nanocapsule formulation of etoposide. Small cell lung cancer (SCLC) is the most aggressive carcinoma in thoracic oncology, unfortunately, despite chemotherapy, relapse is constant. The effect of etoposide, a major drug used against SCLC, can potentially be enhanced after its encapsulation in nanocarriers. The aim of this study was to use the technology of lipid nanocapsules (LNCs) to obtain nanocarriers with drug loadings compatible with clinical use and with an industrial process. Solubility studies with different co-solvent were first performed, then several process were developed to obtain LNCs. LNCs were then characterized (size, zeta potential, and drug loading). The best formulation called Ω-LNCs had a size of 54.1±2.0nm and a zeta potential of -5.8±3.5mV and a etoposide drug loading of 5.7±0.3mg/g. The characteristics of this formulation were maintained after freeze drying and after a 15× scale-up. Release studies in a media mimicking plasma composition showed that 40% of the drug was released from the LNCs after 48h. Moreover the activity of etoposide after encapsulation was enhanced on H209 cells, IC50 was 100μM and 2.5μM for etoposide and etoposide LNCs respectively. Unfortunately the formulation failed to be more cytotoxic than etoposide alone on H69AR cells that are resistant to etoposide. This study showed that is was possible to obtain a new etoposide nanocarrier without the use of organic solvent, that the process is suitable for scale-up and freeze drying and finally that etoposide activity is maintained which is very promising for future treatment of SCLC. 23159914 The determination of exogenous formaldehyde in blood of rats during and after inhalation exposure. Formaldehyde (FA) is suspected of being associated with the development of leukemia. An inhalation experiment with FA was performed in rats to study whether FA can enter the blood and could thus cause systemic toxicity in remote tissues such as the bone marrow. Therefore, a sophisticated analytical method was developed to detect blood concentrations of FA during and after single 6-h exposure by inhalation. In order to differentiate between exogenous and endogenous FA the rats were exposed to stable isotope ((13)C) labeled FA by inhalation. During and after exposure of the rats to (13)C-FA their blood was analyzed to determine the ratio between labeled and natural FA in blood and the total blood concentration of FA. With respect to sensitivity, with the applied method exogenous (13)C-FA could have been detected in blood at a concentration approximately 1.5% of the endogenous FA blood concentration. Exogenous (13)C-FA was not detectable in the blood of rats either during or up to 30 min after the exposure. It was concluded that the inhalation of (13)C-FA at 10 ppm for 6h did not result in an increase of the total FA concentration in blood. 23475029 Effects of s-ketamine as an anesthetic adjuvant to propofol on treatment response to electroconvulsive therapy in treatment-resistant depression: a randomized pilot study. Ketamine in electroconvulsive therapy (ECT) anesthesia has been reported to be associated with better seizure quality and longer duration compared with methohexital anesthesia. Furthermore, ketamine may enhance the efficacy of ECT while having rapid independent antidepressant properties itself. However, data on the effects of ketamine with ECT are inconsistent, and there are no reports of S-ketamine. The aim of the present pilot study was to explore the effects of S-ketamine as an adjuvant to propofol on the efficacy, seizure duration, and quality of electroencephalography in patients with treatment-resistant depression. Thirty-two patients with a recurrent severe or psychotic major depressive disorder with treatment resistance to antidepressants were included in the study. For induction of anesthesia, the patients were randomized into 2 study groups. The S-ketamine group first received S-ketamine (0.4 mg/kg) as a bolus and then propofol. The treatment-as-usual group first received saline and then propofol. A statistically significant and clinically relevant reduction in the depression symptom scores was found in both study groups during ECT. There was no difference in the magnitude or speed of response between the study groups, nor was there any difference in the numbers of ECT treatments, seizure thresholds, seizure durations, and the electrical doses either. The patients recovered from anesthesia equally, but the degree of posttreatment disorientation and restlessness was more marked in the S-ketamine group. In conclusion, a subanesthetic adjuvant dose of S-ketamine with propofol may not increase the effects of ECT in patients with treatment-resistant depression. However, S-ketamine was associated with increased posttreatment disorientation and restlessness. 23788683 Predictors of Dislocation and Revision After Shoulder Stabilization in Ontario, Canada, From 2003 to 2008. BACKGROUND:Factors contributing to recurrent dislocation, revision stabilization, and complications requiring reoperation after an initial shoulder stabilization procedure for instability have not been evaluated on a population level. PURPOSE:(1) To define the rate of ipsilateral revision stabilization, contralateral primary stabilization, postoperative dislocation, and complications after primary shoulder stabilization in a population cohort. (2) To understand which risk factors among patient, surgical, and provider factors influence these outcomes. STUDY DESIGN:Cohort study; Level of evidence, 3. METHODS:All residents of Ontario, Canada, aged 16 to 60 years undergoing primary shoulder stabilization between July 2003 and December 2008 were identified from billing and hospital databases. Separate Cox proportional hazards survivorship models were built for the outcomes revision stabilization and postoperative physician-documented shoulder relocation (minimum 2-year follow-up). Model covariates included patient demographics (age, sex, preoperative dislocations), provider characteristics (surgeon volume, hospital academic status), and type of surgery (open, arthroscopic). The frequency and risk factors for contralateral stabilization were identified. RESULTS:A total of 5904 patients (80.6% male; median age, 29 years) were identified. Arthroscopic stabilization was used in ~60% of cases in 2003, increasing to ~80% in 2008. The rates of postoperative dislocation were 6.9%, revision stabilization 4%, and contralateral primary stabilization 3.9%. Patients aged younger than 20 years had a 7.7% revision rate (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.7-4.2; P < .0001) and a 12.6% rate of postoperative physician-documented dislocation (HR, 2.4; 95% CI, 1.8-3.4; P < .0001), compared with 2.8% and 5.5%, respectively, in patients 29 years old (median cohort age). Patients with 3 or more preoperative dislocations in Ontario had an increased risk of revision (HR, 2.1; 95% CI, 1.5-3.0; P < .0001) and postoperative dislocation (HR, 10.6; 95% CI, 8.1-14.0; P < .0001). Revision was more common after arthroscopic (4.3%) compared with open (3.5%) stabilization (HR, 1.4; 95% CI, 1.02-1.98; P = .04). No provider factor was predictive, including surgeon volume. Reoperation rate for complications not related to recurrent instability was 0.23% (infection, 0.07%; manipulation under anesthesia, 0.15%). CONCLUSION:The risks of revision stabilization and postoperative (either shoulder) dislocation were most influenced by young age (<20 years) and having had 3 or more preoperative dislocations. Complications requiring surgery are rare. 23949065 Using multiple views of family dynamics to predict the mental health of individuals with TBI and their caregivers in Mexico. To examine differences in ratings of family dynamics between individuals with traumatic brain injury (TBI) and their family caregivers in Mexico, as well as differences in the prediction of caregiver and patient mental health outcomes from those ratings. Forty-two patient-caregiver dyads (n = 84) from the National Institute of Rehabilitation in México City participated in a comprehensive evaluation of their family dynamics and mental health. Patients' and caregivers' ratings of family dynamics were significantly correlated and did not differ across five of six types of family dynamics, but caregivers rated their family's level of empathy higher than patients, p < 0.001. Additionally, all patient and caregiver ratings of family dynamics were significantly correlated. Patients', caregivers', and combined (using structural equation modeling latent constructs) ratings of family dynamics robustly predicted four times as many caregiver mental health outcomes as patient mental health outcomes. Family dynamics influence both TBI patient and caregiver mental health but much more so in caregivers. Research on families of individuals with TBI in Mexico should incorporate both patient and caregiver perspectives to more comprehensively depict the environment in which TBI rehabilitation occurs. 23887235 Calcium Supplementation During Sepsis Exacerbates Organ Failure and Mortality via Calcium/Calmodulin-Dependent Protein Kinase Kinase Signaling. Calcium plays an essential role in nearly all cellular processes. As such, cellular and systemic calcium concentrations are tightly regulated. During sepsis, derangements in such tight regulation frequently occur, and treating hypocalcemia with parenteral calcium administration remains the current practice guideline. We investigated whether calcium administration worsens mortality and organ dysfunction using an experimental murine model of sepsis and explored the mechanistic role of the family of calcium/calmodulin-dependent protein kinases in mediating these physiological effects. To highlight the biological relevance of these observations, we conducted a translational study of the association between calcium administration, organ dysfunction, and mortality among a cohort of critically ill septic ICU patients. Prospective, randomized controlled experimental murine study and observational clinical cohort analysis. University research laboratory and eight ICUs at a tertiary care center. A cohort of 870 septic ICU patients. C57Bl/6 and CaMKK mice. Mice underwent cecal ligation and puncture polymicrobial sepsis and were administered with calcium chloride (0.25 or 0.25 mg/kg) or normal saline. Administering calcium chloride to septic C57Bl/6 mice heightened systemic inflammation and vascular leak, exacerbated hepatic and renal dysfunction, and increased mortality. These events were significantly attenuated in CaMKK mice. In a risk-adjusted analysis of septic patients, calcium administration was associated with an increased risk of death, odds ratio 1.92 (95% CI, 1.00-3.68; p = 0.049), a significant increase in the risk of renal dysfunction, odds ratio 4.74 (95% CI, 2.48-9.08; p < 0.001), and a significant reduction in ventilator-free days, mean decrease 3.29 days (0.50-6.08 days; p = 0.02). Derangements in calcium homeostasis occur during sepsis that is sensitive to calcium administration. This altered calcium signaling, transduced by the calmodulin-dependent protein kinase kinase cascade, mediates heightened inflammation and vascular leak that culminates in elevated organ dysfunction and mortality. In the clinical management of septic patients, calcium supplementation provides no benefit and may impose harm. 23485614 Protective effect of bark and empty pod extracts from Acacia auriculiformis against paracetamol intoxicated liver injury and alloxan induced type II diabetes. The present study is designed to decipher a clinical evidence and biochemical support for hepatoprotective and antidiabetic efficacy of Acacia auriculiformis by its bark and empty pods. Animal models with paracetamol intoxicated liver injury and alloxan induced diabetes were used in a 7 and 14days trial respectively. The interventions were tested at 200 and 400mg/kg b.w. for bark extract; 100 and 200mg/kg b.w. for empty pod extract. Both interventions restored the liver function markers (alanine transaminase: ALT, aspartate transaminase: AST, alkaline phosphatase: ALP, total bilirubin and total protein) and hepatic antioxidants (superoxide dismutase: SOD, catalase: CAT, reduced glutathione: GSH and glutathione peroxidase: GPx) to the normal levels than elevated levels noticed on paracetamol control at P<0.001. Reversal of hepatoarchitecture has also been registered and the hepatoprotection is comparable to the reference drug silymarin. Similarly, substantial elevations of blood glucose, distorted lipid profile (total cholesterol: TC, triglycerides: TGs, high density lipoprotein cholesterol: HDL-C and low density lipoprotein cholesterol: LDL-C) and kidney function signs (creatinine and urea) have been refurbished to the desirable levels on par with the standard antidiabetic glibenclamide. The results signify the importance of bark and empty pod extracts of A. auriculiformis as good therapeutic candidates for liver injury and diabetes. 23252609 Low-dose pegylated interferon-alpha-2a monotherapy in elderly and/or cirrhotic patients infected with hepatitis C virus genotype-2 or genotype-1 low level infection. Elderly and/or cirrhotic patients with hepatitis C virus (HCV) are at high risk of adverse effects during interferon therapy. The aim of the present study was to evaluate the efficacy, safety and predictive factors for sustained virological response (SVR) of low-dose pegylated interferon-α-2a (PEG IFN-α-2a) monotherapy in elderly and/or cirrhotic patients with HCV genotype-2 or genotype-1 low level infection. Sixty-four elderly (≥65 years) and/or cirrhotic patients with HCV genotype-2 or genotype-1 low level (<5 logIU/mL) infection underwent low-dose PEG IFN-α-2a (90 μg/week) monotherapy for 24 weeks. Sixty patients were available for efficacy assessment. SVR was achieved in 78.3%. SVR rates according to genotype-1 low, genotype-2 low and genotype-2 high viral load were 90.0%, 87.1% and 57.9%, respectively. The discontinuation rate was 12.5%. PEG IFN-α-2a was interrupted or discontinued in four patients because of severe thrombocytopenia (<25 000/mm(3) ). The baseline platelet counts of all these patients were less than 70 000/mm(3) . On univariate analysis of factors contributing to SVR, significant differences were noted in viral load, platelet count, γ-glutamyltransferase, ferritin, α-fetoprotein level and rapid viral response (RVR). On multivariate analysis, RVR was the only independent factor (P = 0.010, odds ratio = 47.27). The positive and negative SVR-predictive values based on RVR were 95% and 82%, respectively. Low-dose PEG IFN-α-2a monotherapy was effective and tolerable in elderly and/or cirrhotic patients with genotype-2 or genotype-1 low HCV level infection. However, a baseline platelet count of more than 70 000/mm(3) is needed for safety. RVR can predict SVR accurately. 23529932 High-Purity Prostate Circulating Tumor Cell Isolation by a Polymer Nanofiber-Embedded Microchip for Whole Exome Sequencing. Handpick single cancer cells: A modified NanoVelcro Chip is coupled with ArcturusXT laser capture microdissection (LCM) technology to enable the detection and isolation of single circulating tumor cells (CTCs) from patients with prostate cancer (PC). This new approach paves the way for conducting next-generation sequencing (NGS) on single CTCs. 23515895 Extraction of ginsenosides from fresh ginseng roots (Panax ginseng C.A. Meyer) using commercial enzymes and high hydrostatic pressure. A combination of high hydrostatic pressure (HHP) and enzymatic hydrolysis (HHP-EH) was applied for the extraction of ginsenosides from fresh ginseng roots (Panax ginseng C.A. Myer). The highest yield of ginsenosides was obtained by using a mixture of three enzymes (Celluclast + Termamyl + Viscozyme) along with HHP (100 MPa, at 50 °C for 12 h) in comparison to control samples (no enzymes, atmosphere pressure, P < 0.05). Total ginsenosides increased by 184% while Rg1 + Rb1 increased by 273%. Application of these conditions significantly increased total ginsenosides by 49% and Rg1 + Rb1 by 103% compared to HHP treatment alone (P < 0.05). The effect of HHP on increased yield of ginsenosides is likely due in part, to acceleration of enzyme activity. Thus HHP-EH significantly improves the extraction of ginsenosides from fresh ginseng roots. 23830475 Immediate Post-Transurethral Resection of Bladder Tumor Intravesical Chemotherapy Prevents Non-Muscle-invasive Bladder Cancer Recurrences: An Updated Meta-analysis on 2548 Patients and Quality-of-Evidence Review. Non-muscle-invasive bladder cancer (NMIBC) commonly recurs, requiring invasive and costly transurethral resection of bladder tumor (TURBT). A meta-analysis of seven trials published in 2004 demonstrated that intravesical chemotherapy (IVC) following TURBT reduces recurrences. Despite European Association of Urology endorsement, adoption of this practice has been modest. To investigate whether immediate postoperative IVC prolongs the recurrence-free interval (RFI) and early recurrences (ERs) in light of new trial data and to explore the quality of evidence supporting its use. A systematic literature review of random controlled trials (RCTs) published before March 2013 was performed using the Medline, Embase, and Cochrane databases. Trials examining NMIBC recurrence for adults receiving IVC immediately following TURBT were included. RFI was estimated by hazard ratio (HR), and ER was estimated by absolute risk reduction (ARR) of recurrences within 1 yr of TURBT. Both outcomes were synthesized using random-effects models. Risk of bias was assessed using the Cochrane Collaboration risk-of-bias tool, and quality of evidence for each outcome was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation system. Thirteen studies with 2548 patients were included. IVC prolonged RFI by 38% (HR: 0.62; 95% confidence interval [CI], 0.50-0.77; p<0.001; I(2): 69%), and ERs were 12% less likely in the intervention population (ARR: 0.12; 95% CI, -0.18 to -0.06; p<0.001, I(2): 0%). The number needed to treat to prevent one ER was 9 (95% CI, 6-17 patients). There was high risk of bias present in 12 of 13 publications. Quality of evidence for RFI was very low and low for ERs. Our updated meta-analysis supports that IVC prolongs RFI and reduces ERs of NMIBC when administered immediately after TURBT. However, contemporary methodology suggests low evidence quality for examined outcomes. Thus RCTs with careful randomization and blinding are still warranted to clarify the usefulness of immediate postoperative IVC in this population. 23876413 Design, construction and characterisation of a synthetic promoter library for fine-tuned gene expression in actinomycetes. We developed a synthetic promoter library for actinomycetes based on the -10 and -35 consensus sequences of the constitutive and widely used ermEp1 promoter. The sequences located upstream, in between and downstream of these consensus sequences were randomised using degenerate primers and cloned into an integrative plasmid upstream of the gusA reporter gene. Using this system, we created promoters with strengths ranging from 2% to 319% compared with ermEp1. The strongest synthetic promoter was used in a proof-of-principle approach to achieve the overexpression of a natural type III polyketide synthase. We observed high correlation between the number of gusA reporter gene RNA-Seq reads and the GusA reporter protein activity, indicating that GusA is indeed a transcription-level reporter system. 23925958 Pre-trial reported defendants in the Netherlands with intellectual disability, borderline and normal intellectual functioning. Intellectually disabled offenders may have different characteristics than offenders with average intellectual functioning. We therefore compared pre-trial reported defendants with an IQ score ≤70, 71-84 and ≥85 points. Nationwide database of pre-trial psychiatric reports requested by Dutch courts between 2000 and 2006 with a reported level of intellectual functioning (n = 12 186). Defendants with an IQ score between 71 and 84 (n = 2 439 reports; 20.0%) and ≤70 (n = 539 reports; 4.4%) were younger, more often from an ethnic minority and more often diagnosed with psycho-organic syndromes, developmental and conduct disorders as compared with defendants with an IQ score of 85 or higher. In addition, there was an increased risk of attention deficit hyperactivity disorder and rape as indicted crime and a decreased odds ratio of having a steady job and cannabis abuse in defendants with an IQ score of 71-84. Intellectually disabled defendants have different characteristics than defendants without intellectually disability. 23883649 Acute sphenoid sinusitis leading to contralateral cavernous sinus thrombosis: a case report. Introduction: The objective of this article was to report a case of isolated, acute, right-sided sphenoid sinusitis that progressed to contralateral cavernous sinus thrombosis in an 18-year-old male patient. We describe the atypical presentation of this case and discuss the relevant anatomy, pathogenesis, presentation, diagnostic evaluation and treatment. Case report: A case report of sphenoid sinusitis leading to contralateral cavernous sinus thrombosis was reviewed and presented along with a comprehensive literature review of the relevant anatomy, pathophysiology, microbiology, diagnostic work-up and treatment options. Conclusion: Cavernous sinus thrombosis is a rare clinical entity in the antibiotic era. However, limited sphenoid sinusitis may progress to cavernous sinus thrombosis in spite of maximal medical treatment, as highlighted in this case report. The mainstay of treatment includes early diagnosis allowing aggressive intravenous antibiotics and appropriate surgical management. 23828833 PREDICT-PD: Identifying risk of Parkinson's disease in the community: methods and baseline results. To present methods and baseline results for an online screening tool to identify increased risk for Parkinson's disease (PD) in the UK population. Risk estimates for future PD were derived from the results of a systematic review of risk factors and early features of PD. Participants aged 60-80 years without PD were recruited by self-referral. They completed an online survey (including family history, non-motor symptoms and lifestyle factors), a keyboard-tapping task and the University of Pennsylvania Smell Identification Test. Risk scores were calculated based on survey answers. Preliminary support for the validity of this algorithm was assessed by comparing those estimated to be higher risk for PD with those at lower risk using proxies, including smell loss, REM-sleep behaviour disorder and reduced tapping speed, and by assessing associations in the whole group. 1324 eligible participants completed the survey and 1146 undertook the keyboard-tapping task. Smell tests were sent to 1065 participants. Comparing the 100 highest-risk participants and 100 lowest-risk participants, median University of Pennsylvania Smell Identification Test scores were 30/40 versus 33/40 (p<0.001), mean number of key taps in 30 s were 55 versus 58 (p=0.045), and 24% versus 10% scored above cut-off for REM-sleep behaviour disorder (p=0.008). Regression analyses showed increasing risk scores were associated with worse scores in the three proxies across the whole group (p≤0.001). PREDICT-PD is the first study to systematically combine risk factors for PD in the general population. Validity to predict risk of PD will be tested through longitudinal follow-up of incident PD diagnosis. 23561210 Non-enzymatic glycation of natural actomyosin (NAM) with glucosamine in a liquid system at moderate temperatures. Muscle protein functionality plays an important role in routine applications in the food industry. Glycation by the Maillard reaction is a naturally occurring process, which can be used to develop new ingredients with improved functionality using a food grade approach. Actomyosin was conjugated with glucose or glucosamine in a liquid system at moderate temperatures (40°C). Sugar to protein conjugation was evident by UV-Vis spectral changes, with the glycation level determined by matrix assisted laser desorption/ionisation mass spectrometry. Parameters for glycation of muscle protein were optimised using the bidimensional hierarchical clustering analyses. The best glycation conditions were 40°C for 8h at 1:3 protein:sugar ratio. Solubility and emulsifying properties of glycoconjugates were significantly improved as compared to non-glycated proteins. At pH 7 glycated actomyosin was on average 31% more soluble compared to non-treated protein. Glucosamine was found to be more effective for glycation and provided higher protein functionality as compared to glucose. 23851679 Oat β-glucan inhibits lipopolysaccharide-induced nonalcoholic steatohepatitis in mice. Nonalcoholic steatohepatitis (NASH) is part of the spectrum of nonalcoholic fatty liver disease. However, there are few suitable animal models to study the pathogenesis of NASH or very limited advances in the prevention. Our aims were to establish a mouse model of NASH by intraperitoneally injecting lipopolysaccharide (LPS) at a dose of 1.5 mg per kg body weight per day for 6 weeks and to investigate the potential inhibitory effects of oat β-glucan (1%, 5%, or 10%) added to a specific pathogen-free diet. Intraperitoneal injection of LPS for 6 weeks increased serum LPS levels; decreased serum glucagon-like peptide-2 levels; triggered abnormal aminotransferase activity, glucose intolerance, and insulin resistance; and increased hepatic proinflammatory cytokines (tumor necrosis factor-α, interleukin-6, interleukin-1β), triglyceride, and malonyl dialdehyde levels; but reduced hepatic superoxide dismutase activity. Histologic evaluation revealed evidence of hepatic steatosis, inflammation, and mild necrosis in LPS-treated mice. Dietary supplementation of oat β-glucan prevented most of the LPS-induced metabolic disorders, and improved hepatic steatosis and inflammation, although a dose-dependent effect was not observed. In conclusion, oat β-glucan could inhibit LPS-induced NASH in mice. 23508009 Quantitative and qualitative differences in use and trends of hematopoietic stem cell transplantation: a Global Observational Study. Fifty-five years after publication of the first hematopoietic stem cell transplantation this technique has become an accepted treatment option for defined hematologic and non-hematologic disorders. There is considerable interest in understanding differences in its use and trends on a global level and the macro-economic factors associated with these differences. Data on the numbers of hematopoietic stem cell transplants performed in the 3-year period 2006-2008 were obtained from Worldwide Network for Blood and Marrow Transplantation member registries and from transplant centers in countries without registries. Population and macro-economic data were collected from the World Bank and from the International Monetary Fund. Transplant rates were analyzed by indication, donor type, country, and World Health Organization regional offices areas and related to selected health care indicators using single and multiple linear regression analyses. Data from a total of 146,808 patients were reported by 1,411 teams from 72 countries over five continents. The annual number of transplants increased worldwide with the highest relative increase in the Asia Pacific region. Transplant rates increased preferentially in high income countries (P=0.02), not in low or medium income countries. Allogeneic transplants increased for myelodysplasia, chronic lymphocytic leukemia, acute leukemias, and non-malignant diseases but decreased for chronic myelogenous leukemia. Autologous transplants increased for autoimmune and lymphoproliferative diseases but decreased for leukemias and solid tumors. Transplant rates (P<0.01), donor type (P<0.01) aand disease indications (P<0.01) differed significantly between countries and regions. Transplant rates were associated with Gross National Income/capita (P<0.01) but showed a wide variation of explanatory content by donor type, disease indication and World Health Organization region. Hematopoietic stem cell transplantation activity is increasing worldwide. The preferential increase in high income countries, the widening gap between low and high income countries and the significant regional differences suggest that different strategies are required in individual countries to foster hematopoietic stem cell transplantation as an efficient and cost-effective treatment modality. 23747546 Expression of a truncated hepatitis E virus capsid protein in the protozoan organism Leishmania tarentolae and its application in a serological assay. Zoonotic infections with hepatitis E virus (HEV) genotype 3 are presumably transmitted via contaminated pig meat products, which raises the necessity for enhanced serological surveillance of pig herds. The aim of the study was to set up a novel protein expression system to overcome the well-known problems in (HEV-) protein expression using the standard Escherichia coli tools such as inclusion body formation and loss of protein conformation. A recombinant strain of the protozoan organism Leishmania tarentolae (L. tarentolae) was therefore established. A fragment of HEV ORF2 coding for a truncated capsid protein of a porcine HEV strain was cloned and parts of the plasmid DNA were introduced into the Leishmania genome, resulting in stably transformed cells. Via a C-terminal His-tag the recombinant HEVΔORF2 protein could be purified and concentrated directly from the medium, resulting in a total protein amount of approximately 1.4mg/l Leishmania culture. The recombinant protein was coated on ELISA plates and was proven to be highly reactive and well-suited to be applied in a serological assay. By investigating 144 porcine sera, the in-house assay detected specific antibodies in 43.1% of the samples and demonstrated a higher sensitivity than a commercially available antibody test. Taken together, it was shown that L. tarentolae exhibits a remarkable alternative expression strategy for viral antigens with considerable advantages of a eukaryotic protein expression host. 23525734 Hepatic Arterial Infusion with Oxaliplatin and 5-FU/Folinic Acid for Advanced Biliary Tract Cancer: A Phase II Study. Effective and tolerable chemotherapy with gemcitabine and cisplatin for advanced biliary tract cancer (BTC) has been established recently. However, overall prognosis is still poor, and additional therapeutic approaches are needed for patients with locally advanced, irresectable and/or pretreated tumors. Hepatic arterial infusion (HAI) of chemotherapy represents a safe and well-established treatment modality, but data on its use in patients with BTC are still sparse. Patients with irresectable BTC predominant to the liver were included in a prospective, open phase II study investigating HAI provided through interventionally implanted port catheters. Intraarterial chemotherapy consisted of biweekly oxaliplatin (O) 85 mg/m(2) and folinic acid (F) 170 mg/m(2) with 5-FU (F) 600 mg/m(2). Between 2004 and 2010, 37 patients were enrolled. A total of 432 cycles of HAI were applied with a median of 9 (range 1-46) cycles. Objective response rate was 16 %, and tumor control was achieved in 24 of 37 (65 %) patients. Median progression-free survival was 6.5 months (range 0.5-26.0; 95 % CI 4.3-8.7), median overall survival was 13.5 (range 0.9-50.7; 95 % CI 11.1-15.9) months. The most frequent adverse event was sensory neuropathy grade 1/2 in 10/14 patients. Using a minimal invasive technique, repetitive HAI with OFF is feasible and results in clinically relevant tumor control with low toxicity in patients with liver predominant advanced BTC. 23194527 Monitoring of Escherichia coli O157:H7 in food samples using lectin based surface plasmon resonance biosensor. A novel surface plasmon resonance (SPR) biosensor using lectin as bioreceptor was developed for the rapid detection of Escherichia coli (E. coli) O157:H7. The selective interaction of lectins with carbohydrate components from bacterial cells surface was used as the recognition principle for the detection. Five types of lectins from Triticum vulgaris, Canavailia ensiformis, Ulex europaeus, Arachis hypogaea, and Maackia amurensis, were employed to evaluate the selectivity of the approach for binding E. coli O157:H7 effectively. A detection limit of 3×10(3) cfu mL(-1) was obtained for determination of E. coli O157:H7 when used the lectin from T. vulgaris as the binding molecule. Furthermore, the proposed biosensor was used to detect E. coli O157:H7 in real food samples. Results showed that the lectin based SPR biosensor was sensitive, reliable and effective for detection of E. coli O157:H7, which hold a great promise in food safety analysis. 23748480 Synthesis and characterization of coordinatively unsaturated nickel(II) and manganese(II) alkyl complexes supported by the hydrotris(3-phenyl-5-methylpyrazolyl)borate (Tp(Ph,Me)) ligand. The synthesis of several nickel(II) and manganese(II) alkyl complexes supported by hydrotris(3-phenyl-5-methylpyrazolyl)borate (Tp(Ph,Me)) ligand is reported. The metal halide complexes Tp(Ph,Me)MnCl(CH3CN) (1) and Tp(Ph,Me)NiCl (4) were used as precursors for synthesis of Tp(Ph,Me)MnCH2Si(Me)3 (2), Tp(Ph,Me)MnCH2Ph (3), Tp(Ph,Me)NiCH2Si(Me)3 (5) and Tp(Ph,Me)NiCH2Ph (6). The resulting Mn(II) and Ni(II) alkyl complexes, 2-3 and 5-6, were characterized by X-ray crystallography, NMR spectroscopy, and FT-IR spectroscopy. X-ray crystallographic analysis revealed distorted tetrahedral geometries for complexes 2-3 and 5 with a κ(3)-Tp(Ph,Me). Complex 6, on the other hand, was found to have a distorted square planar geometry with κ(2)-Tp(Ph,Me) and an η(3)-benzyl ligand. Transformations of 4 and Tp(Ph,Me)CoCl (10) via treatment with NaN3 to yield Tp(Ph,Me)NiN3 (11), Tp(Ph,Me)CoN3 (12), along with the synthesis of (Tp(Ph,Me))2Ni (8) and Tp(Ph,Me)NiCl(3-Ph-5MepzH) (9) are also reported. 23732534 Ternary system of dihydroartemisinin with hydroxypropyl-β-cyclodextrin and lecithin: simultaneous enhancement of drug solubility and stability in aqueous solutions. The purpose of this study was to simultaneously improve the solubility and stability of dihydroartemisinin (DHA) in aqueous solutions by a ternary cyclodextrin system comprised of DHA, hydroxypropyl-β-cyclodextrin (HP-β-CD) and a third auxiliary substance. Solubility and phase solubility studies were carried out to evaluate the solubilizing efficiency of HP-β-CD in association with various auxiliary substances. Then, the solid binary (DHA-HP-β-CD or DHA-lecithin) and ternary systems were prepared and characterized by Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC) and power X-ray diffraction (PXRD). The effect of the ternary system on the solubility, dissolution and stability of DHA in aqueous solutions was also investigated. As a result, the soybean lecithin was found to be the most promising third component in terms of solubility enhancement. For the solid characterization, the disappearance of the drug crystallinity indicated the formation of new solid phases, implicating the formation of the ternary system. The dissolution rate of the solid ternary system was much faster than that of the drug alone and binary systems. Importantly, compared with binary systems, the ternary system showed a significant improvement in the stability of DHA in Hank's balanced salt solutions (pH 7.4). The solubility and stability of DHA in aqueous solutions were simultaneously enhanced by the ternary system, which might be attributed to the possible formation of a ternary complex. For the ternary interactions, results of molecular docking studies further indicated that the lecithin covered the top of the wide rim of HP-β-CD and surrounded around the peroxide bridging of DHA, providing the possibility for the ternary complex formation. In summary, the ternary system prepared in our study, with simultaneous enhancement of DHA solubility and stability in aqueous solutions, might have an important pharmaceutical potential in the development of a better oral formulation of DHA. 23896583 Fourth International Conference: Modern Vaccines/Adjuvants Formulation-Impact On Future Development: May 15-17 2013, CHUV, Lausanne, Switzerland. On the 15-17th of May 2013, about 120 scientists, postdoctoral fellows and professors representing renowned academic institutes and senior scientists and executives from small biotechs, contract research organizations (CROs) and Big Pharma companies, gathered at the Centre Hospitalier Universitaire Vaudois (CHUV) in Lausanne, Switzerland for the 4th international conference on Modern Vaccines and Adjuvants Formulation. Despite this relative small number, the speakers and attendees covered together a very broad field of expertise. Indeed, experts in microbiology, immunology, biochemistry, formulation, virus and nanoparticle characterization, vaccine production, quality control as well as regulatory professionals attended the conference and were able to present their works and discuss new developments within the field of vaccine and adjuvant development, characterization and approval process. This broad diversity was a highpoint of the conference and allowed for a stimulating environment and underlined the complexity of the challenges that the field currently faces in order to develop better or completely new vaccines and adjuvants. 23870398 Three-dimensional computed tomography angiography for the preoperative evaluation of coronary artery disease in lung cancer patients. The number of elderly patients undergoing surgery for lung cancer is increasing. In this study, we assessed the usefulness of three-dimensional computed tomographicangiography (3D-CTA) for the detection of coronary disease in the elderly before surgical intervention for lung cancer. One hundred twenty patients admitted to our institution for lung cancer resection were enrolled in the study. 3D-CTA was performed in all 120 patients. Seventy-one patients had normal findings, and forty-nine patients showed coronary stenosis on 3D-CTA examination. Among the latter 49 patients, 24 with slight stenosis underwent lung tumor resection, 23 had coronary angiography for severe stenosis before lung surgery and 2 were not eligible for lung resection because of very severe coronary stenosis. The diagnostic value of 3D-CTA was better than conventional CT. This study suggests the usefulness of 3D-CTA for the preoperative diagnosis of coronary ischemic disease in elderly lung cancer patients. 23714714 Developmental relationship between language and joint attention in late talkers. The article examines the relationship between expressive and receptive language and joint attention (JA) bids during language acquisition in late-talking children. The research was designed to be a longitudinal study with a first test followed by two retests every five months for a period of 10 months, in which we compared late-talking (LT) children aged 26 months (N=25) to a group of five-month-younger typically developing (TD) children (N=25). The results showed that LT children did not differ from TD children in frequency of JA bids at any time point. However, in contrast to TD children, in which a positive relationship between JA bids of high levels and language function was found, in the LT group, JA bids were not related to language comprehension and production. These data indicate that TD children use nonverbal and verbal means jointly for communication purposes, whereas LT children switch between nonverbal and verbal means in concrete communicational acts. The results are discussed within the development of language as a semiotic functional framework. 23240892 Acid-degradable cationic poly(ketal amidoamine) for enhanced RNA interference in vitro and in vivo. Efficient delivery of small interfering RNA (siRNA) is one of major challenges in the successful applications of siRNA in clinic. In the present study, we report a new acid-degradable poly(ketal amidoamine) (PKAA) as a siRNA carrier, which has high delivery efficiency and low cytotoxicity. PKAA was designed to have acid-cleavable ketal linkages in the backbone of cationic biodegradable poly(amidoamine). PKAA efficiently self-assembled with siRNA to form nanocomplexes with a diameter of ~200 nm and slightly positive charges, which are stable under physiological conditions, but rapidly release siRNA at acidic pH. PKAA exhibited sufficient buffering capability and endosomolytic activity due mainly to the presence of secondary amine groups in its backbone and rapid degradation in acidic endosomes, leading to the enhanced release of siRNA to cytoplasm. Cell culture studies demonstrated that PKAA is capable of delivering anti-TNF (tumor necrosis factor)-α siRNA to lipopolysaccharide (LPS)-stimulated macrophages and significantly inhibits the expression of TNF-α. A mouse model of acetaminophen (APAP)-induced acute liver failure was used to evaluate in vivo siRNA delivery efficacy of PKAA. PKAA/anti-TNF-α siRNA nanocomplexes significantly reduced the ALT (alanine transaminase) and the hepatic cellular damages in APAP-intoxicated mice. We anticipate that acid-degradable PKAA has great potential as siRNA carriers based on its excellent biocompatibility, pH sensitivity, potential endosomolytic activity, and high delivery efficiency. 23819896 Integrated medical school ultrasound: development of an ultrasound vertical curriculum. Physician-performed focused ultrasonography is a rapidly growing field with numerous clinical applications. Focused ultrasound is a clinically useful tool with relevant applications across most specialties. Ultrasound technology has outpaced the education, necessitating an early introduction to the technology within the medical education system. There are many challenges to integrating ultrasound into medical education including identifying appropriately trained faculty, access to adequate resources, and appropriate integration into existing medical education curricula. As focused ultrasonography increasingly penetrates academic and community practices, access to ultrasound equipment and trained faculty is improving. However, there has remained the major challenge of determining at which level is integrating ultrasound training within the medical training paradigm most appropriate. The Ohio State University College of Medicine has developed a novel vertical curriculum for focused ultrasonography which is concordant with the 4-year medical school curriculum. Given current evidenced-based practices, a curriculum was developed which provides medical students an exposure in focused ultrasonography. The curriculum utilizes focused ultrasonography as a teaching aid for students to gain a more thorough understanding of basic and clinical science within the medical school curriculum. The objectives of the course are to develop student understanding in indications for use, acquisition of images, interpretation of an ultrasound examination, and appropriate decision-making of ultrasound findings. Preliminary data indicate that a vertical ultrasound curriculum is a feasible and effective means of teaching focused ultrasonography. The foreseeable limitations include faculty skill level and training, initial cost of equipment, and incorporating additional information into an already saturated medical school curriculum. Focused ultrasonography is an evolving concept in medicine. It has been shown to improve education and patient care. The indications for and implementation of focused ultrasound is rapidly expanding in all levels of medicine. The ideal method for teaching ultrasound has yet to be established. The vertical curriculum in ultrasound at The Ohio State University College of Medicine is a novel evidenced-based training regimen at the medical school level which integrates ultrasound training into medical education and serves as a model for future integrated ultrasound curricula. 23347285 Assessment of left atrial function after percutaneous closure of patent foramen ovale. Τhe influence of atrial septal occluders in left atrial (LA) function after percutaneous closure of patent foramen ovale (PFO) has not been thoroughly studied. Twenty-five patients (mean age 40.7 ± 12 years) undergoing percutaneous PFO closure were enrolled in this study. Transthoracic echocardiogram (TTE) was performed 3 and 6 months before the procedure. Volumetric indices (active emptying fraction: LA AEF, expansion index: LA EI, and passive emptying fraction: LA PEF), strain and strain rate (SR), were calculated during the contractile, reservoir, and conduit LA phases for the lateral, anterior, and inferior LA walls with TTE. After 3 months, a decrease in the SR of the LA anterior wall was observed (from 2.12 ± 0.22 to 1.66 ± 0.26, P < 0.045), while the LA lateral wall strain was found to be increased (from 0.708 ± 0.15 to 0.783 ± 0.159, P < 0.001). Moreover, simultaneously LA AEF was greater compared with baseline (from 31.0 ± 1.6 to 34.0 ± 1.6, P < 0.004). However, all these alterations reversed at 6 months. Segmental LA function is altered transiently after percutaneous PFO closure with a septal occlude. The LA anterior wall SR decreases, while the lateral wall strain increases. The impact of these alterations needs further clarification. 23351956 Measurement of lower limb volume: Agreement between the vertically oriented perometer and a tape measure method. To investigate the agreement between lower limb volume measurements for the vertically oriented perometer and a tape measure method. Between-methods agreement and test-retest reliability study. University setting. Thirty university staff and students were recruited using convenience sampling with no participant drop-outs. All participants' dominant lower limb volumes were measured using the vertically oriented perometer and a tape measure method. The Bland-Altman difference plot was reported for determining the bias between the two methods and its 95% confidence interval. Test-retest reliability and the measurement error for the perometer method were determined using the ICC(2,1) model and within-subject standard deviation (sw) respectively. There was a lack of agreement between the tape measure and perometer method. The Bland-Altman difference plot showed that the tape measure method overestimated limb volume by 157ml compared to the perometer method. A 95% confidence interval of -834ml to 519ml was observed. The test-retest reliability of the perometer method was ICC(2,1)=0.99. The measurement error of the perometer method was clinically acceptable (sw=121ml). There was a lack of agreement between the two methods investigated. Therefore the perometer and tape measure methods are not interchangeable. It is recommended that future validity and reliability studies for the vertically oriented perometer are conducted on clinical populations. 23916554 Time to arousal and neurologic outcome in therapeutic hypothermia-treated cardiac arrest patients. Therapeutic hypothermia (TH) has been shown to improve outcomes in comatose Post-Cardiac Arrest Syndrome (PCAS) patients. It is unclear how long it takes these patients to regain neurologic responsiveness post-arrest. We sought to determine the duration to post-arrest awakening and factors associated with times to such responsiveness. We performed a retrospective chart review of consecutive TH-treated PCAS patients at three hospitals participating in a US cardiac arrest registry from 2005 to 2011. We measured the time from arrest until first documentation of "awakening", defined as following commands purposefully. We included 194 consecutive TH-treated PCAS patients; mean age was 57±16 years; 59% were male; 40% had an initial shockable rhythm. Mean cooling duration was 24±8h and mean rewarming time was 14±13h. Survival to discharge was 44%, with 78% of these discharged with a good neurologic outcome. Of the 85 patients who awakened, median time to awakening was 3.2 days (IQR 2.2, 4.5) post-cardiac arrest. Median time to awakening for a patient discharged in good neurological condition was 2.8 days (IQR 2.0, 4.5) vs. 4.0 days (IQR 3.5, 7.6) for those who survived to discharge without a good neurological outcome (p=0.035). There was no significant association between initial rhythm, renal insufficiency, paralytic use, post-arrest seizure, or location of arrest and time to awakening. In TH-treated PCAS patients, time to awakening after resuscitation was highly variable and often longer than three days. Earlier awakening was associated with better neurologic status at hospital discharge. 23660272 A test of the cognitive self-medication hypothesis of tobacco smoking in schizophrenia. Heavier tobacco smoking among people with schizophrenia (SCZ) has been suggested to reflect self-medication of cognitive deficits. The idea that cognitive-enhancing effects of nicotine are a primary motivator of tobacco consumption in SCZ and that abstinence would deprive SCZ of such beneficial effects might explain hesitation among providers to pursue smoking cessation in SCZ. This study tested predictions of the cognitive self-medication hypothesis. In three counterbalanced sessions, 17 SCZ and 17 healthy control subjects (HCS), all smokers, were tested under ad libitum smoking or 3.5 hours after abstaining and receiving a nicotine (14 mg/24 hours) or placebo patch. Attention task performance was improved by transdermal nicotine relative to placebo, with intermediate performance by ad libitum smoking. These effects were of similar size in SCZ and HCS and did not reflect remediation of functions disproportionately impaired in SCZ. Although more SCZ reported that the need to concentrate influenced their smoking, this was not reflected by the actual behavior of these patients. Self-reported ability to concentrate changed with nicotine status in HCS but not SCZ, suggesting insensitivity of SCZ to nicotine-derived performance benefits. Nicotine plasma concentrations after ad libitum smoking were not associated with performance benefits but instead with the propensity to experience nicotine withdrawal upon abstinence. This association was seen selectively in SCZ, suggesting a possible reason for heavier smoking. These findings suggest that subjective or objective attentional benefits are unlikely the primary driving force of tobacco consumption in SCZ and should not discourage providers from supporting quit attempts. 23945156 Antibody secreting cell responses after Vibrio cholerae O1 infection and oral cholera vaccination in adults in Bangladesh. Infection with V. cholerae and oral cholera vaccines (OCVs) induce transient circulating plasmablast responses that peak approximately within 7 days after infection or vaccination. We previously demonstrated that plasmablast responses strongly correlate with subsequent levels of V. cholerae-specific duodenal antibodies up to 6 months after cholera. Hence, plasmablast responses provide an early window into immunologic memory at the mucosal surface. In this study, we characterized plasmablast responses following cholera using a flow cytometrically defined population, and compared V. cholerae-specific responses in adult patients with V. cholerae O1 infection and vaccinees who received the OCV Dukoral. Among flow cytometrically sorted populations of gut homing plasmablasts, almost 50% of the cells recognized either cholera toxin B subunit (CtxB) or V. cholerae O1 lypopolysaccharide (LPS). Using a traditional ELISPOT method, we found that infection with V. cholerae O1 and OCV induce similar responses to the protein antigen CtxB, but responses to LPS were diminished after OCV compared to natural V. cholerae infection. A second dose of OCV on day 14 failed to boost circulating V. cholerae-specific plasmablast responses in Bangladeshi adults. Our results differ from studies in areas where cholera is not endemic, in which a second vaccination on day 14 significantly boosts plasmablast responses. Given these results, it is likely that optimal boosting strategies for OCV differ significantly between endemic and non-endemic areas. 23900774 Hypothyroidism in patients with colorectal carcinoma treated with fluoropyrimidines. Targeted therapy with tyrosine kinase inhibitors, including vascular endothelial growth factor receptors, has been demonstrated to induce hypothyroidism and thyroid dysfunction. Cancer patients with thyroid dysfunction may be underdiagnosed and undertreated. Thyroid function in colorectal cancer patients receiving fluoropyrimidine‑based chemotherapy with or without bevacizumab was evaluated at baseline and monthly. In the present study, 3 of 27 (11.1%) patients who received fluoropyrimidine‑based chemotherapy developed a thyroid-stimulating hormone (TSH) level >10 µU/ml, and 13 (48.1%) developed an elevation above the upper limit of the normal range. No difference in TSH elevation was noted between the bevacizumab and chemotherapy-alone group (50 vs. 45%; P=1.00, respectively). Three (11.1%) patients developed a TSH level >10 µU/ml and 2 with hypothyroidism were treated with thyroid hormone replacement therapy. We demonstrated that bevacizumab does not affect thyroid function but fluoropyrimidines may induce thyroid dysfunction in patients with colorectal cancer. Further investigation is required to clarify the mechanism of fluoropyrimidine-induced thyroid dysfunction. 23350710 Sulfated Small Molecules Targeting EBV in Burkitt Lymphoma: From In Silico Screening to the Evidence of In Vitro Effect on Viral Episomal DNA. Epstein-Barr virus (EBV) infects more than 90% of the world population. Following primary infection, Epstein-Barr virus persists in an asymptomatic latent state. Occasionally, it may switch to lytic infection. Latent EBV infection has been associated with several diseases, such as Burkitt lymphoma (BL). To date, there are no available drugs to target latent EBV, and the existing broad-spectrum antiviral drugs are mainly active against lytic viral infection. Thus, using computational molecular docking, a virtual screen of a library of small molecules, including xanthones and flavonoids (described with potential for antiviral activity against EBV), was carried out targeting EBV proteins. The more interesting molecules were selected for further computational analysis, and sub-sequently, the compounds were tested in the Raji (BL) cell line, to evaluate their activity against latent EBV. This work identified three novel sulfated small molecules capable of decreasing EBV levels in a BL. Therefore, the in silico screening presents a good approach for the development of new anti-EBV agents. 23396419 Involvement of organic anion-transporting polypeptides in the hepatic uptake of dioscin in rats and humans. The objective of this study was to clarify the mechanism underlying hepatic uptake of dioscin (diosgenyl 2,4-di-O-a-L-rhamnopyranosyl-p-D-glucopyranoside), an herbal ingredient with antihepatitis activity, in rats and humans. The liver uptake index (LUI) in vivo, perfused rat liver in situ, rat liver slices, isolated rat hepatocytes, and human organic anion-transporting polypeptide (OATP)-transfected cells in vitro were used to evaluate hepatic uptake of dioscin. Values of 11.9% ± 1.6% and 15.0% ± 0.9% of dose for uptake of dioscin were observed by LUI in vivo and perfused rat livers in situ, respectively. The time course of dioscin uptake by rat liver slices was temperature-dependent. Uptake of dioscin by rat liver slices and isolated rat hepatocytes was inhibited significantly by Oatp modulators, such as ibuprofen (Oatp1a1 inhibitor), digoxin (Oatp1a4 substrate), and glycyrrhizic acid (Oatp1b2 inhibitor), but not by TEA or p-aminohippurate. Uptake of dioscin in rat hepatocytes and OATP1B3-human embryonic kidney (HEK) 293 cells indicated a saturable process with a Km of 3.75 ± 0.51 μM and 2.08 ± 0.27 μM, respectively. (-)-Epigallocatechin gallate, cyclosporin A, rifampicin, and telmisartan inhibited transport of dioscin in OATP1B3-HEK293 cells. However, transcellular transport of dioscin in OATP1B1- or OATP1B1/multidrug resistance-associated protein 2-Madin-Darby canine kidney strain II cells was not observed. These results indicate that hepatic uptake of dioscin is involved in OATP1B3 in humans, and multiple Oatps might participate in this process in rats. 23879974 Polycomblike protein PHF1b: a transcriptional sensor for GABA receptor activity. The γ-aminobutyric acid (GABA) type A receptor (GABA(A)R) contains the recognition sites for a variety of agents used in the treatment of brain disorders, including anxiety and epilepsy. A better understanding of how receptor expression is regulated in individual neurons may provide novel opportunities for therapeutic intervention. Towards this goal we have studied transcription of a GABA(A)R subunit gene (GABRB1) whose activity is autologously regulated by GABA via a 10 base pair initiator-like element (β(1)-INR). By screening a human cDNA brain library with a yeast one-hybrid assay, the Polycomblike (PCL) gene product PHD finger protein transcript b (PHF1b) was identified as a β(1)-INR associated protein. Promoter/reporter assays in primary rat cortical cells demonstrate that PHF1b is an activator at GABRB1, and chromatin immunoprecipitation assays reveal that presence of PHF1 at endogenous Gabrb1 is regulated by GABA(A)R activation. PCL is a member of the Polycomb group required for correct spatial expression of homeotic genes in Drosophila. We now show that PHF1b recognition of β(1)-INR is dependent on a plant homeodomain, an adjacent helix-loop-helix, and short glycine rich motif. In neurons, it co-immunoprecipitates with SUZ12, a key component of the Polycomb Repressive Complex 2 (PRC2) that regulates a number of important cellular processes, including gene silencing via histone H3 lysine 27 trimethylation (H3K27me3). The observation that chronic exposure to GABA reduces PHF1 binding and H3K27 monomethylation, which is associated with transcriptional activation, strongly suggests that PHF1b may be a molecular transducer of GABA(A)R function and thus GABA-mediated neurotransmission in the central nervous system. 23959861 Treatment with suboptimal doses of raltegravir leads to aberrant HIV-1 integrations. Integration of the DNA copy of the HIV-1 genome into a host chromosome is required for viral replication and is thus an important target for antiviral therapy. The HIV-encoded enzyme integrase (IN) catalyzes two essential steps: 3' processing of the viral DNA ends, followed by the strand transfer reaction, which inserts the viral DNA into host DNA. Raltegravir binds to IN and blocks the integration of the viral DNA. Using the Rous sarcoma virus-derived vector RCAS, we previously showed that mutations that cause one viral DNA end to be defective for IN-mediated integration led to abnormal integrations in which the provirus had one normal and one aberrant end, accompanied by rearrangements in the host genome. On the basis of these results, we expected that suboptimal concentrations of IN inhibitors, which could block one of the ends of viral integration, would lead to similar aberrant integrations. In contrast to the proviruses from untreated cells, which were all normal, ∼10-15% of the proviruses isolated after treatment with a suboptimal dose of raltegravir were aberrant. The aberrant integrations were similar to those seen in the RCAS experiments. Most of the aberrant proviruses had one normal end and one aberrant end and were accompanied by significant rearrangements in the host genome, including duplications, inversions, deletions and, occasionally, acquisition of sequences from other chromosomes. The rearrangements of the host DNA raise concerns that these aberrant integrations might have unintended consequences in HIV-1-infected patients who are not consistent in following a raltegravir-containing treatment regimen. 23212989 Bioengineered chimeric spider silk-uranium binding proteins. Heavy metals constitute a source of environmental pollution. Here, novel functional hybrid biomaterials for specific interactions with heavy metals are designed by bioengineering consensus sequence repeats from spider silk of Nephila clavipes with repeats of a uranium peptide recognition motif from a mutated 33-residue of calmodulin protein from Paramecium tetraurelia. The self-assembly features of the silk to control nanoscale organic/inorganic material interfaces provides new biomaterials for uranium recovery. With subsequent enzymatic digestion of the silk to concentrate the sequestered metals, options can be envisaged to use these new chimeric protein systems in environmental engineering, including to remediate environments contaminated by uranium. 23802180 Glycoproteomic Analysis of Bronchoalveolar Lavage (BAL) Fluid Identifies Tumor-Associated Glycoproteins from Lung Adenocarcinoma. Cytological examination of cells from bronchoalveolar lavage (BAL) is commonly used for the diagnosis of lung cancer. Proteins released from lung cancer cells into BAL may serve as biomarkers for cancer detection. In this study, N-glycoproteins in eight cases of BAL fluid, as well as eight lung adenocarcinoma tissues and eight tumor-matched normal lung tissues, were analyzed using the solid-phase extraction of N-glycoprotein (SPEG), iTRAQ labeling, and liquid chromatography tandem mass spectrometry (LC-MS/MS). Of 80 glycoproteins found in BAL specimens, 32 were identified in both cancer BAL and cancer tissues, with levels of 25 glycoproteins showing at least a 2-fold difference between cancer and benign BAL. Among them, eight glycoproteins showed greater than 2-fold elevations in cancer BAL, including Neutrophil elastase (NE), Integrin alpha-M, Cullin-4B, Napsin A, lysosome-associated membrane protein 2 (LAMP2), Cathepsin D, BPI fold-containing family B member 2, and Neutrophil gelatinase-associated lipocalin. The levels of Napsin A in cancer BAL were further verified in independently collected 39 BAL specimens using an ELISA assay. Our study demonstrates that potential protein biomarkers in BAL fluid can be detected and quantified. 23859593 Synthetic ePTFE Grafts Coated with an Anti-CD133 Antibody-Functionalized Heparin/Collagen Multilayer with Rapid in vivo Endothelialization Properties. An anti-CD133 antibody multilayer functionalized by heparin/collagen on an expanded polytetrafluoroethylene (ePTFE) graft was developed to accelerate early endothelialization. The surface modification of ePTFE grafts demonstrated that the multilayer is stable in static incubation and shaking conditions and that the anti-CD133 antibodies were successfully cross-linked onto the surface. Blood compatibility tests revealed that the coimmobilized heparin/collagen films in the presence or absence of anti-CD133 antibodies prolonged the blood coagulation time and that there was less platelet activation and aggregation, whereas the hemolysis rate was comparable with the bare ePTFE grafts. Cellular proliferation was not inhibited, as the heparin/collagen synthetic vascular grafts coated with CD133 antibody showed little cytotoxicity. The endothelial cells adhered well to the modified ePTFE grafts during a cell adhesion assay. A porcine carotid artery transplantation model was used to evaluate the modified ePTFE grafts in vivo. The results of histopathological staining and scanning electron microscopy indicated that the anti-CD133 antibody was able to accelerate the attachment of vascular endothelial cells onto the ePTFE grafts, resulting in early rapid endothelialization. The success of the anti-CD133 antibody-functionalized heparin/collagen multilayer will provide an effective selection system for the surface modification of synthetic vascular grafts and improve their use in clinical applications. 23647370 Cardiovascular event rates in atorvastatin patients versus patients switching from atorvastatin to simvastatin. Statin dose, adherence, and cardiovascular (CV) outcomes are important factors when considering switching statin therapies. The objective of the study was to compare CV event rates and risk in managed care patients receiving atorvastatin versus those switched to simvastatin from atorvastatin. Patients 18-64 years, with ≥3 continuous pharmacy claims for atorvastatin between 1/1/05-11/30/07 and ≥12 months pre- and ≥3 months post-index continuous eligibility were identified using HealthCore Integrated Research Database (HIRD). Patients were stratified into two cohorts: one continued atorvastatin without interruption and the other switched to simvastatin. Patients were matched 1:10 (continue atorvastatin/switch simvastatin) on five variables, excluding lipid parameters due to limited data availability. Descriptive statistics were reported for sample characteristics. A multivariate Cox proportional hazards model was developed to evaluate adjusted CV risk. In total 73,960 atorvastatin patients and 7396 simvastatin-switch patients were analyzed. The mean age was 54 ± 7 years (both cohorts). Mean follow-up was 440 days for atorvastatin patients and 237 days for simvastatin-switch patients. Mean dose and therapy duration for atorvastatin was 20 mg and 321 days compared with 33 mg and 195 days for simvastatin-switch, respectively. Of the simvastatin-switch patients, 32% were switched to a less potent simvastatin dose (<2× prior atorvastatin dose). After adjusting for demographic/clinical characteristics, no significant differences were found in CV risk between cohorts. Limitations include use of administrative claims data without lipid level laboratory results data and the length of follow-up which may not have been sufficient to demonstrate significant differences in event rates between groups. In this managed care population, no significant differences were found in risk of CV events among patients switching to simvastatin compared to patients continuing atorvastatin. Switched patients may differ from controls for reasons not captured in the database. 23672879 Low-dose of oral factor Xa inhibitors in patients with a recent acute coronary syndrome: A systematic review and meta-analysis of randomized trials. Recently, randomized controlled trials (RCTs) have shown that therapy with new oral activated factor X (Xa) inhibitors in acute coronary syndrome (ACS) yielded a reduction of ischemic events. However, this therapy was associated with a dose-related increase in major bleeding complications. We aimed to perform a systematic review and meta-analysis to appraise the clinical efficacy and safety of the lowest doses of oral factor Xa inhibitors compared with placebo in patients after a recent ACS. The primary endpoint was cardiovascular mortality. The rate of new myocardial infarction (MI) was the secondary efficacy endpoint, whereas major bleeding complications were recorded as a safety endpoint. Five RCTs were included in the meta-analysis enrolling a total of 25,643 patients. There was no significant difference in mortality between patients treated with new antithrombotics compared with those receiving the standard therapy: odds ratio (OR), [95% confidence interval (CI)] = 0.97 [0.72-1.31], p = 0.86. Recurrent MI rates were decreased in the anti-Xa group: OR [95%CI] = 0.86 [0.76-0.98], p = 0.02, number needed to treat (NNT) = 189. The administration of new oral anticoagulants was associated with a strongly increased risk of major bleedings compared with the standard treatment: OR [95%CI] = 3.24 [2.29-4.59], p < 0.001, number needed to harm (NNH) = 104; similarly, intracranial bleeding rates were significantly higher in the anti-Xa arm. The addition of the new oral anticoagulants on top of standard therapy in the setting of ACS results in an excessive risk of major bleedings without any clear evidence of outweighing clinical benefits. 23473803 Chemical informatics uncovers a new role for moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4). PDE4 is one of eleven known cyclic nucleotide phosphodiesterase families and plays a pivotal role in mediating hydrolytic degradation of the important cyclic nucleotide second messenger, cyclic 3'5' adenosine monophosphate (cAMP). PDE4 inhibitors are known to have anti-inflammatory properties, but their use in the clinic has been hampered by mechanism-associated side effects that limit maximally tolerated doses. In an attempt to initiate the development of better-tolerated PDE4 inhibitors we have surveyed existing approved drugs for PDE4-inhibitory activity. With this objective, we utilised a high-throughput computational approach that identified moexipril, a well tolerated and safe angiotensin-converting enzyme (ACE) inhibitor, as a PDE4 inhibitor. Experimentally we showed that moexipril and two structurally related analogues acted in the micro molar range to inhibit PDE4 activity. Employing a FRET-based biosensor constructed from the nucleotide binding domain of the type 1 exchange protein activated by cAMP, EPAC1, we demonstrated that moexipril markedly potentiated the ability of forskolin to increase intracellular cAMP levels. Finally, we demonstrated that the PDE4 inhibitory effect of moexipril is functionally able to induce phosphorylation of the small heat shock protein, Hsp20, by cAMP dependent protein kinase A. Our data suggest that moexipril is a bona fide PDE4 inhibitor that may provide the starting point for development of novel PDE4 inhibitors with an improved therapeutic window. 23410043 Antimalarial activities of 6-iodouridine and its prodrugs and potential for combination therapy. Resistance by Plasmodium falciparum to almost all clinically used antimalarial drugs requires the development of new classes of antimalarials. 6-Iodouridine (15), a novel and potent inhibitor of orotidine 5'-monophosphate decarboxylase (ODCase), exhibited efficacy in a mouse model infected by P. chabaudi chabaudi. Compound 15 exhibited promising antimalarial activity against P. falciparum, including drug-resistant isolates, and no rapid drug-resistant populations of the parasite were observed when challenged with 15. Uridine provided options to overcome any toxicity in the host but still suppressing the parasite load when treated with 15. In drug combination studies, compound 15 showed good efficacy in vivo with artemisinin and azithromycin. The propionyl ester of 15 exhibited superior antimalarial efficacy. Antimalarial activities of 15 and its prodrugs and potential for combination therapy are discussed in the context of novel strategies. 23844697 Advancing human health risk assessment: Integrating recent advisory committee recommendations. Abstract Over the last dozen years, many national and international expert groups have considered specific improvements to risk assessment. Many of their stated recommendations are mutually supportive, but others appear conflicting, at least in an initial assessment. This review identifies areas of consensus and difference and recommends a practical, biology-centric course forward, which includes: (1) incorporating a clear problem formulation at the outset of the assessment with a level of complexity that is appropriate for informing the relevant risk management decision; (2) using toxicokinetics and toxicodynamic information to develop Chemical Specific Adjustment Factors (CSAF); (3) using mode of action (MOA) information and an understanding of the relevant biology as the key, central organizing principle for the risk assessment; (4) integrating MOA information into dose-response assessments using existing guidelines for non-cancer and cancer assessments; (5) using a tiered, iterative approach developed by the World Health Organization/International Programme on Chemical Safety (WHO/IPCS) as a scientifically robust, fit-for-purpose approach for risk assessment of combined exposures (chemical mixtures); and (6) applying all of this knowledge to enable interpretation of human biomonitoring data in a risk context. While scientifically based defaults will remain important and useful when data on CSAF or MOA to refine an assessment are absent or insufficient, assessments should always strive to use these data. The use of available 21st century knowledge of biological processes, clinical findings, chemical interactions, and dose-response at the molecular, cellular, organ and organism levels will minimize the need for extrapolation and reliance on default approaches. 23143040 Differential responses in ammonia excretion, sodium fluxes and gill permeability explain different sensitivities to acute high environmental ammonia in three freshwater teleosts. We examined the acute physiological responses to high environmental ammonia (HEA), particularly the linkages between branchial ammonia fluxes and unidirectional Na(+) fluxes, as well as urea excretion, cortisol, and indicators of gill permeability in three freshwater teleosts differing in their sensitivities to ammonia; the highly sensitive salmonid Oncorhynchus mykiss (rainbow trout), the less sensitive cyprinid Cyprinus carpio (common carp) and the highly resistant cyprinid Carassius auratus (goldfish). Fish were acutely exposed to two sub-lethal ammonia concentrations (as NH(4)HCO(3)) at pH 7.9: 1 mM for a period of 12 h, identical for all species, and 5 mM for the cyprinids and 1.4 mM for the trout for 3 h. Elevation of plasma cortisol at both levels of HEA was apparent in all species. At 1 mM, ammonia excretion (J(amm)) was inhibited to a greater extent in trout than cyprinids and concurrently a significantly higher plasma ammonia level was evident in trout. However J(amm) was reversed in all species at 5 or 1.4 mM. Goldfish showed a significant increase in urea excretion rate (J(urea)) during HEA exposure. In carp and trout, neither level of HEA elevated J(urea) but urea production was increased as evidenced by a considerable elevation of plasma urea. At 1mM HEA, Na(+) imbalance became progressively more severe in trout and carp due to a stimulation of unidirectional Na(+) efflux (J(out)(Na)) without a concomitant increase in unidirectional Na(+) influx (J(in)(Na)). Additionally, a transient reduction of J(in)(Na) was evident in trout. Goldfish showed an opposite trend for J(out)(Na) with reduced efflux rates and a positive Na(+) balance during the first few hours of HEA. However, after 12 h of exposure, both J(in)(Na) and J(out)(Na) were also increased in both carp and goldfish, whereas only J(out)(Na) was increased in trout, leading to a net Na(+) loss. Na(+) homeostasis was entirely disrupted in all three species when subjected to the 5 or 1.4 mM ammonia for 3 h: J(in)(Na) was significantly inhibited while considerable activation of J(out)(Na) was observed. Diffusive water efflux rates and net K(+) loss rates across the gills were enhanced during HEA only in trout, indicating an increment in gill transcellular permeability. Transepithelial potential was increased in all the species during ammonia exposure, but to the least extent in goldfish. Overall, for several different physiological systems, trout were most disturbed, and goldfish were least disturbed by HEA, helping to explain the differential ammonia tolerance of the three species. 23797173 Molecular pathogenesis of the obligate intracellular bacterium Coxiella burnetii. The agent of Q fever, Coxiella burnetii, is an obligate intracellular bacterium that causes acute and chronic infections. The study of C. burnetii pathogenesis has benefited from two recent fundamental advances: improved genetic tools and the ability to grow the bacterium in extracellular media. In this Review, we describe how these recent advances have improved our understanding of C. burnetii invasion and host cell modulation, including the formation of replication-permissive Coxiella-containing vacuoles. Furthermore, we describe the Dot/Icm (defect in organelle trafficking/intracellular multiplication) system, which is used by C. burnetii to secrete a range of effector proteins into the host cell, and we discuss the role of these effectors in remodelling the host cell. 23831610 An efficient single prime protocol for the induction of antigen-induced airways inflammation. There are a number of mouse models of allergic airway inflammation used to delineate various aspects of asthma. One of the hurdles with using mice is their natural resistance to developing a Th2 allergic response. This is often overcome by double priming with the allergen and an adjuvant. Here we report on an efficient 11day, single antigen/alum priming protocol that is sufficient to sensitise mice for the development of Th2-mediated inflammation in the lung following antigen challenge. 23585691 Activation-dependent plasticity of polarized GPCR distribution on the neuronal surface. Directionality of information flow through neuronal networks is sustained at cellular level by polarized neurons. However, specific targeting or anchoring motifs responsible for polarized distribution on the neuronal surface have only been identified for a few neuronal G-protein-coupled receptors (GPCRs). Here, through mutational and pharmacological modifications of the conformational state of two model GPCRs, the axonal CB1R cannabinoid and the somatodendritic SSTR2 somatostatin receptors, we show important conformation-dependent variations in polarized distribution. The underlying mechanisms include lower efficiency of conformation-dependent GPCR endocytosis in axons, compared with dendrites, particularly at moderate activation levels, as well as endocytosis-dependent transcytotic delivery of GPCRs from the somatodendritic domain to distal axonal portions, shown by using compartmentalized microfluidic devices. Kinetic modeling predicted that GPCR distribution polarity is highly regulated by steady-state endocytosis, which is conformation dependent and is able to regulate the relative amount of GPCRs targeted to axons and that axonally polarized distribution is an intermediary phenotype that appears at moderate basal activation levels. Indeed, we experimentally show that gradual changes in basal activation-dependent endocytosis lead to highly correlated shifts of polarized GPCR distribution on the neuronal surface, which can even result in a fully reversed polarized distribution of naturally somatodendritic or axonal GPCRs. In conclusion, polarized distribution of neuronal GPCRs may have a pharmacologically controllable component, which, in the absence of dominant targeting motifs, could even represent the principal regulator of sub-neuronal distribution. Consequently, chronic modifications of basal GPCR activation by therapeutic or abused drugs may lead to previously unanticipated changes in brain function through perturbation of polarized GPCR distribution on the neuronal surface. 23325523 Prosaposin expression in the regenerated muscles of mdx and cardiotoxin-treated mice. The trophic factor prosaposin (PS) is strongly expressed in skeletal muscle, and reportedly, a PS-derived peptide attenuates loss of muscle mass after nerve injury in vivo and increases myoblast fusion into myotubes in vitro. However, few studies have focused on the role of PS during muscle regeneration. We examined the expression of PS in the skeletal muscles in normal, mdx, and cardiotoxin (CTX)-treated mice using immunofluorescence staining, Western blotting, and in situ hybridisation. Immunofluorescence showed intense PS immunoreactivity in the peripheral cytoplasm of uninjured myofibres of normal mice and regenerated myofibres of 8 weeks post-CTX-injection mice. In early stage CTX-treated mice (14 days and earlier), intense PS immunoreactivity was also detected in the immune cells that infiltrated damaged muscle, but it was weak for regenerating myofibres. Western blot confirmed these findings. In contrast, PS was continuously low in mdx mice in both immunofluorescence and Western blotting. In situ hybridisation confirmed the decrease of PS mRNA in regenerated myofibres and revealed the main form of PS mRNA as Pro+0 without a 9-base insertion both in normal and mdx mice. The embryonic myosin (MYH3) was clearly localized in the newly regenerated myofibres at 3, 7, and 14 days of post-CTX-injection and mdx mice, but was lower in the late stage of regenerated myofibres (28 and 56 days post-CTX injection). The inverse distribution of MYH3 and PS indicates that the PS expression is closely related to the differentiation of regenerated myofibres. Investigation of the mitogen-activated protein (MAP) kinase signal pathway showed the inversely synchronous correlation of phosphorylated ERK1/2 with myofibre PS and the synchronous correlation of phosphorylated p-38 with myofibre PS. These data suggest that PS is involved in the regulation of muscle differentiation of regenerated fibres. 23832135 Conventional and complementary approaches to chronic widespread pain and its comorbidities. The concept of comorbidities as a challenge for healthcare systems has recently been given increasing attention in leading medical journals. Many patients suffering from chronic pain, especially those who are older or poorer, have more than one pathology (multimorbidity) or more than one set of manifestation of one pathology (comorbidity). These patients present a difficult problem in industrialised societies, with services that are highly specialised and compartmentalised. Systematic reviews of interventions for patients of this kind do not mention acupuncture. Acupuncturists claim that their treatment promotes general well-being and can help with multiple symptoms, but evidence for this claim is currently lacking. Longitudinal research with prospective data collection regarding the effect on morbidity burden is needed. 23937924 Surgeon Delivered Psoas Compartment Block in Total Hip Arthroplasty. Total hip arthroplasty is associated with significant postoperative pain. A psoas compartment block is superior to other regional techniques in analgesia post THA. However, traditional methods of delivery are associated with serious complications. We present a technique of a surgeon delivered lumbar plexus block through injection at the portion of the iliopsoas seen intraoperatively. We randomised fifty-three consecutive patients into two groups. The group that received the block had an increased period prior to requesting supplementary analgesia and lower overall pain scores. There were no adverse effects. We have demonstrated the analgesic efficacy of Psoas Compartment Block performed during surgical access for total hip arthroplasty. This technique should be considered in the analgesic regimen for total hip arthroplasty. 22323474 Effects of maternally exposed colouring food additives on cognitive performance in rats. Artificial food colourings and additives (AFCAs) have long been suggested to adversely affect the learning and behaviour in children. In this study, we aimed to provide additional data to clarify the possible side effects of colouring additives on behaviour and memory. We administered acceptable daily intake values of AFCAs as a mixture (Eritrosin, Ponceau 4R, Allura Red AC, Sunset Yellow FCF, Tartrazin, Amaranth, Brilliant Blue, Azorubin and Indigotin) to female rats before and during gestation and then tested their effects on behaviour and on spatial working memory in their offspring. Effects on spatial learning and memory were evaluated by Morris water maze, behavioural effects were evaluated by open-field test and forced swim test. Our results showed that commonly used artificial food colourings have no adverse effects on spatial working memory and did not create a depressive behaviour in offspring. But they showed a few significant effects on locomotor activity as AFCAs increased some parameters of locomotor activity. 23240893 Informants' Traits Weigh Heavily in Young Children's Trust in Testimony and in Their Epistemic Inferences. This study examined how informants' traits affect how children seek information, trust testimony, and make inferences about informants' knowledge. Eighty-one 3- to 6-year-olds and 26 adults completed tasks where they requested and endorsed information provided by one of two informants with conflicting traits (e.g., honesty vs. dishonesty). Participants also completed tasks where they simultaneously considered informants' traits and visual access to information when inferring their knowledge and trusting their testimony. Children and adults preferred to ask and endorse information provided by people who are nice, smart, and honest. Moreover, these traits influenced the knowledge that young children attributed to informants. Children younger than 5 years of age reported that people with positive traits were knowledgeable even when they lacked access to relevant information. 23763860 Correlation between computed tomographic and magnetic resonance imaging findings of parenchymal lung diseases. Computed tomography (CT) is considered to be the gold standard method for the assessment of morphological changes in the pulmonary parenchyma. Although its spatial resolution is lower than that of CT, MRI offers the advantage of characterizing different aspects of tissue based on the degree of contrast on T1-weighted image (WI) and T2-WI. In this article, we describe and correlate the MRI and CT features of several common patterns of parenchymal lung disease (air trapping, atelectasis, bronchiectasis, cavitation, consolidation, emphysema, ground-glass opacities, halo sign, interlobular septal thickening, masses, mycetoma, nodules, progressive massive fibrosis, reverse halo sign and tree-in-bud pattern). MRI may be an alternative modality for the collection of morphological and functional information useful for the management of parenchymal lung disease, which would help reduce the number of chest CT scans and radiation exposure required in patients with a variety of conditions. 23870826 Immunomodulatory approaches for prevention and treatment of infectious diseases. With increasing pathogen resistance to antibiotics, population ageing, and threat of pandemics there is a strong interest in the development of new approaches for the treatment of infectious diseases. Immunomodulatory therapies are defined as interventions that target the host rather than the pathogen, modulating the immune response with the aim of disease prevention or treatment. Our growing understanding of the immune system continues to offer novel drug targets and approaches for immunomodulatory interventions. In this review we will cover prominent examples of immunomodulatory therapies already in clinical use, as well as the recent advances in the development of new immunomodulators in ongoing clinical trials. 23653369 Differential Effects of a 5% lidocaine medicated patch in peripheral nerve injury. We examined the effect of topical lidocaine on the function of small and large fibers in patients with peripheral neuropathic pain due to traumatic or postoperative nerve injury. In an open-label study, 24 patients were treated with a 5% lidocaine patch for up to 12 weeks. We recorded contact heat evoked potentials (CHEPs) and performed quantitative sensory testing (QST) before and after treatment with the contralateral side as control. Twenty-one patients (mean age 47.6 ± 13.5 years) completed the study. Lidocaine increased cold pain threshold (P = 0.04) and reduced CHEP amplitude (P = 0.007) with no effect on other QST parameters. Patients responding to treatment had less cold detection deficit on the affected side and had a larger increase in cold pain detection threshold following treatment than nonresponders. Controlled trials are warranted to further understand the mechanisms mediating the effects of topical lidocaine. Muscle Nerve, 48: 265-271, 2013. 23813665 Atomoxetine for attention deficit hyperactivity disorder in the adulthood: a meta-analysis and meta-regression. Atomoxetine is a non-stimulant drug that could be an alternative to methylphenidate, whose benefit : risk balance for the treatment of adults with attention deficit hyperactivity disorder (ADHD) has recently been shown to be unclear. This study aimed to compare all-cause discontinuation rate between atomoxetine and placebo in adults with ADHD. Secondarily, efficacy and safety were investigated. Systematic review and meta-analysis of randomized controlled trials comparing atomoxetine with placebo in adults with ADHD were performed. All-cause treatment discontinuation was the primary endpoint. Efficacy in reducing ADHD symptoms and safety were the secondary endpoints. Odds ratio (OR) and the standardized mean difference (SMD) were calculated for dichotomous and continuous outcomes, respectively. Data were pooled using the fixed and random effects model. The influence of study design-related, intervention-related and patient-related co-variables over the primary endpoint was investigated by means of meta-regression. This study is registered with the international prospective register of systematic reviews (PROSPERO): CRD 42012002042. Twelve studies (3375 patients) were included. Treatment discontinuation was larger with atomoxetine than with placebo (OR = 1.39). No co-variable was found to modify the effect of atomoxetine over treatment discontinuation. Atomoxetine showed modest efficacy in reducing ADHD symptoms irrespective of the assessor: patient (SMD = -0.33); clinician (SMD = -0.40). The rate of adverse events-induced discontinuation was higher with atomoxetine than with placebo (OR = 2.57). This study suggests that atomoxetine has a poor benefit-risk balance for the treatment of adults with ADHD. The recommendation of atomoxetine use in this population is weak. Copyright © 2013 John Wiley & Sons, Ltd. 23571002 An amelogenin-chitosan matrix promotes assembly of an enamel-like layer with a dense interface. Biomimetic reconstruction of tooth enamel is a significant topic of study in materials science and dentistry as a novel approach to the prevention, restoration, and treatment of defective enamel. We have developed a new amelogenin-containing chitosan hydrogel for enamel reconstruction that works through amelogenin supramolecular assembly, stabilizing Ca-P clusters and guiding their arrangement into linear chains. These amelogenin Ca-P composite chains further fuse with enamel crystals and eventually evolve into enamel-like co-aligned crystals, anchored to the natural enamel substrate through a cluster growth process. A dense interface between the newly grown layer and natural enamel was formed and the enamel-like layer improved the hardness and elastic modulus compared with etched enamel. We anticipate that this chitosan hydrogel will provide effective protection against secondary caries because of its pH-responsive and antimicrobial properties. Our studies introduce an amelogenin-containing chitosan hydrogel as a promising biomaterial for enamel repair and demonstrate the potential of applying protein-directed assembly to biomimetic reconstruction of complex biomaterials. 23419159 Exploratory study to identify the process used by pharmacy staff to verify the accuracy of dispensed medicines. To determine the common stages and strategies involved in the dispensing accuracy-checking process used by pharmacy staff and to determine the training activities used by these staff to gain the knowledge and skills for accuracy checking. Face-to-face tape-recorded ethnographic interviews (n = 28) were undertaken in 2009-2010 at two large teaching hospitals with a purposive sample of pharmacists and accredited checking technicians qualified to undertake the final accuracy check on dispensed medicines. Participants described their accuracy-checking process, strategies used to aid checking using anonymised prescriptions and accurate dispensing of medicines to aid discussion. The range of training activities undertaken to develop this skill were discussed. Qualitative data were analysed in accordance with the principles of grounded theory to identify themes. The accuracy-checking process was described as a cognitive and systematic process. The order in which accuracy checking was executed was found to follow two pathways, with all participants checking the prescription first before verifying either the label or dispensed product. Various physical and sensory aids were used to assist in this verification process. There were inconsistencies in the level of accuracy-checking training received by pharmacists and accredited checking technicians, with many pharmacists reporting no training. Although an important medication-error prevention strategy, until this study little was known about the process used by pharmacy staff when verifying the accuracy of dispensed medicines. Accuracy checking is a complex cognitive task involving verification of the product and label with the prescription. Strategies obtained during past experience and in training were used to aid checking. The study highlighted that pharmacy staff training to undertake this task was variable. Application of strategies identified in this study may allow individuals to adopt further safeguards to improve patient safety. 23632435 Hyperbaric oxygen does not improve cerebral function when started 2 or 4 hours after cerebral arterial gas embolism in swine. Hyperbaric oxygenation is the accepted treatment for cerebral arterial gas embolism. Although earlier start of hyperbaric oxygenation is associated with better outcome, it is unknown how much delay can be tolerated before start of hyperbaric oxygenation. This study investigates the effect of hyperbaric oxygenation on cerebral function in swine when initiated 2 or 4 hours after cerebral arterial gas embolism. Prospective interventional animal study. Surgical laboratory and hyperbaric chamber. Twenty-two Landrace pigs. Under general anesthesia, probes to measure intracranial pressure, brain oxygen tension (PbtO2), and brain microdialysis, and electrodes for electroencephalography were placed. The electroencephalogram (quantified using temporal brain symmetry index) was suppressed during 1 hour by repeated injection of air boluses through a catheter placed in the right ascending pharyngeal artery. Hyperbaric oxygenation was administered using U.S. Navy Treatment Table 6 after 2- or 4-hour delay. Control animals were maintained on an inspiratory oxygen fraction of 0.4. Intracranial pressure increased to a mean maximum of 19 mm Hg (SD, 4.5 mm Hg) due to the embolization procedure. Hyperbaric oxygenation significantly increased PbtO2 in both groups treated with hyperbaric oxygenation (mean maximum PbtO2, 390 torr; SD, 177 torr). There were no significant differences between groups with regard to temporal brain symmetry index (control vs 2-hr delay, p = 0.078; control vs 4-hr delay, p = 0.150), intracranial pressure, and microdialysis values. We did not observe an effect of hyperbaric oxygenation on cerebral function after a delay of 2 or 4 hours. The injury caused in our model could be too severe for a single session of hyperbaric oxygenation to be effective. Our study should not change current hyperbaric oxygenation strategies for cerebral arterial gas embolism, but further research is necessary to elucidate our results. Whether less severe injury benefits from hyperbaric oxygenation should be investigated in models using smaller amounts of air and clinical outcome measures. 23874904 Dimensions and determinants of trust in health care in resource poor settings - a qualitative exploration. Trust in health care has been intensely researched in resource rich settings. Some studies in resource poor settings suggest that the dimensions and determinants of trust are likely to be different. This study was done as a qualitative exploration of the dimensions and determinants of trust in health care in Tamil Nadu, a state in south India to assess the differences from dimensions and determinants in resource rich settings. The participants included people belonging to marginalized communities with poor access to health care services and living in conditions of resource deprivation. A total of thirty five in depth interviews were conducted. The interviews were summarized and transcribed and data were analyzed following thematic analysis and grounded theory approach. The key dimensions of trust in health care identified during the interviews were perceived competence, assurance of treatment irrespective of ability to pay or at any time of the day, patients' willingness to accept drawbacks in health care, loyalty to the physician and respect for the physician. Comfort with the physician and health facility, personal involvement of the doctor with the patient, behavior and approach of doctor, economic factors, and health awareness were identified as factors determining the levels of trust in health care. The dimensions and determinants of trust in health care in resource poor settings are different from that in resource rich settings. There is a need to develop scales to measure trust in health care in resource poor settings using these specific dimensions and determinants. 23830352 Venous thromboembolism in ovarian cancer: incidence, risk factors and impact on survival. Ovarian cancer has a higher incidence of venous thromboembolism (VTE) than other cancers. Clear cell cancers carry the highest risk at 11-27%. The aim of this study was to identify the predisposing factors for VTE in a population of ovarian cancer patients and to determine the influence of VTE on overall survival. VTE events were identified from hospital and general practice/community care records for all patients with ovarian cancer who were diagnosed and treated in a tertiary cancer center between 2006 and 2010. The overall incidence of VTE was 9.7% (33) in 344 patients. Sixteen (48%) had pulmonary embolism. Six (18%) presented with VTE. Five (15%) had VTE diagnosed during pre-treatment routine CT scanning. Eleven (33%) developed VTE following surgery and eleven (33%) developed VTE during chemotherapy. Risk factors associated with the occurrence of VTE were BMI≥30 (p<0.01), clear cell carcinoma (p<0.05), advanced stage (p<0.01), high grade (p<0.01) and CA125>500IU/ml (p<0.001). The occurrence of VTE was associated with decreased overall survival time (p<0.001). The incidence of VTE is high in ovarian cancer especially in the clear cell subtype. VTE adversely affects survival in ovarian cancer. Obesity, high grade and stage of cancer, clear cell subtype and high CA 125 level should be incorporated into protocols of VTE prophylaxis in women with ovarian cancer. 23835677 Pharmacodynamic modeling of cell cycle and apoptotic effects of gemcitabine on pancreatic adenocarcinoma cells. The standard of care for treating patients with pancreatic adenocarcinomas includes gemcitabine (2',2'-difluorodeoxycytidine). Gemcitabine primarily elicits its response by stalling the DNA replication forks of cells in the S phase of the cell cycle. To provide a quantitative framework for characterizing the cell cycle and apoptotic effects of gemcitabine, we developed a pharmacodynamic model in which the activation of cell cycle checkpoints or cell death is dependent on gemcitabine exposure. Three pancreatic adenocarcinoma cell lines (AsPC-1, BxPC-3, and MiaPaca-2) were exposed to varying concentrations (0-100,000 ng/mL) of gemcitabine over a period of 96 h in order to quantify proliferation kinetics and cell distributions among the cell cycle phases. The model assumes that the drug can inhibit cycle-phase transitioning in each of the 3 phases (G1, S, and G2/M) and can cause apoptosis of cells in G1 and G2/M phases. Fitting was performed using the ADAPT5 program. The time course of gemcitabine effects was well described by the model, and parameters were estimated with good precision. Model predictions and experimental data show that gemcitabine induces cell cycle arrest in the S phase at low concentrations, whereas higher concentrations induce arrest in all cell cycle phases. Furthermore, apoptotic effects of gemcitabine appear to be minimal and take place at later time points. The pharmacodynamic model developed provides a quantitative, mechanistic interpretation of gemcitabine efficacy in 3 pancreatic cancer cell lines, and provides useful insights for rational selection of chemotherapeutic agents for combination therapy. 23525760 Development of somatic hybrids Solanum Ã— michoacanum Bitter. (Rydb.) (+) S. tuberosum L. and autofused 4x S. Ã— michoacanum plants as potential sources of late blight resistance for potato breeding. Phytophthora infestans resistant somatic hybrids of S. Ã— michoacanum (+) S. tuberosum and autofused 4 x S. Ã— michoacanum were obtained. Our material is promising to introgress resistance from S. Ã— michoacanum into cultivated potato background. Solanum Ã— michoacanum (Bitter.) Rydb. (mch) is a wild diploid (2n = 2x = 24) potato species derived from spontaneous cross of S. bulbocastanum and S. pinnatisectum. This hybrid is a 1 EBN (endosperm balance number) species and can cross effectively only with other 1 EBN species. Plants of mch are resistant to Phytophthora infestans (Mont) de Bary. To introgress late blight resistance genes from mch into S. tuberosum (tbr), genepool somatic hybridization between mch and susceptible diploid potato clones (2n = 2x = 24) or potato cultivar Rywal (2n = 4x = 48) was performed. In total 18,775 calli were obtained from postfusion products from which 1,482 formed shoots. The Simple Sequence Repeat (SSR), Cleaved Amplified Polymorphic Sequences (CAPS) and Random Amplified Polymorphic DNA (RAPD) analyses confirmed hybrid nature of 228 plants and 116 autofused 4x mch. After evaluation of morphological features, flowering, pollen stainability, tuberization and ploidy level, 118 somatic hybrids and 116 autofused 4x mch were tested for late blight resistance using the detached leaf assay. After two seasons of testing three somatic hybrids and 109 4x mch were resistant. Resistant forms have adequate pollen stainability for use in crossing programme and are a promising material useful for introgression resistance from mch into the cultivated potato background. 23939511 The efficacy and biobehavioural basis of baclofen in the treatment of alcoholic liver disease (BacALD): Study protocol for a randomised controlled trial. Effective treatments for alcohol use disorders in those with significant liver disease are critically lacking. The primary aim of the current study is to explore the effectiveness and biobehavioural basis of low and high dose baclofen in improving treatment outcomes for alcohol dependence in people with alcoholic liver disease (The BacALD study). This double-blind, placebo-controlled study will randomize 180 participants to a 12-week regime of either baclofen (30mg/day baclofen, 75mg/day baclofen) or placebo. Participants must meet the ICD-10 criteria for alcohol dependence in addition to alcoholic liver disease (ALD) defined as the presence of symptoms and/or signs referable to liver disease or its complications with or without cirrhosis. Primary outcome measures will include total abstinence duration, and time to lapse and relapse. Furthermore, 60 of the ALD patients enrolled in the trial will also participate in a pharmacokinetic and cue-reactivity component along with an additional 30 healthy volunteers matched for age and gender randomised to either 1week regime of 30mg/day baclofen or 75mg/day baclofen. At week 1, plasma levels of baclofen and β-p-chlorophenol-γ-hydroxybutric acid will be measured at 0, 1 and 4h following baclofen administration and psychophysiological responses to alcohol-associated stimuli will be assessed in a cue reactivity paradigm. Recruitment commenced in late March 2013. This trial will demonstrate the efficacy and safety of two doses of baclofen in patients with alcoholic liver disease and will explore the biobehavioural mechanisms of the treatment effect. 23835443 Blockade of VEGF receptor-3 aggravates inflammatory bowel disease and lymphatic vessel enlargement. In contrast to the prominent function of the blood vasculature in promoting tissue inflammation, the role of lymphatic vessels in inflammation has been scarcely studied in vivo. To investigate whether modulating lymphatic vessel function might affect the course of chronic inflammation, the major lymphangiogenic receptor, vascular growth factor receptor 3 (VEGFR-3, FLT4), was blocked in an established model of inflammatory bowel disease. Interleukin 10 (IL10)-deficient mice that spontaneously develop inflammatory bowel disease were treated with a blocking antibody to VEGFR-3 for 18 days, and the inflammatory changes in colon tissue and the blood and lymphatic vascularization were quantitatively analyzed. We found a significant increase in the severity of colon inflammation in anti-VEGFR-3-treated mice. This was accompanied by an increased number of enlarged and tortuous lymphatic vessels and edema in colon submucosa, indicating impaired lymphatic function. In contrast, no major effects of the treatment on the blood vasculature were observed. These results indicate that therapies aimed at promoting lymphatic function, e.g., with prolymphangiogenic factors, such as VEGF-C, might provide a novel strategy for the treatment of inflammatory conditions, such as inflammatory bowel disease. 23434602 Intensity integrated Laplacian-based thickness measurement for detecting human metaphase chromosome centromere location. Accurate detection of the human metaphase chromosome centromere is an important step in many chromosome analysis and medical diagnosis algorithms. The centromere location can be utilized to derive information such as the chromosome type, polarity assignment, etc. Methods available in the literature yield unreliable results mainly due to high variability of morphology in metaphase chromosomes and boundary noise present in the image. In this paper, we have proposed a multistaged algorithm which includes the use of discrete curve evolution, gradient vector flow active contours, functional approximation of curve segments, and support vector machine classification. The standard Laplacian thickness measurement algorithm was enhanced to incorporate both contour information as well as intensity information to obtain a more accurate centromere location. In addition to segmentation and width profile measurement, the proposed algorithm can also correct for sister chromatid separation in cell images. The proposed method was observed to be more accurate and statistically significant as compared to a centerline-based method when tested with 226 human metaphase chromosomes. 23723056 Taxonomic composition of the particle-attached and free-living bacterial assemblages in the Northwest Mediterranean Sea analyzed by pyrosequencing of the 16S rRNA. Free-living (FL) and particle-attached (PA) bacterial assemblages in the Northwest Mediterranean Sea were studied using pyrosequencing data of the 16S rRNA. We have described and compared the richness, the distribution of Operational Taxonomic Units (OTUs) within the two fractions, the spatial distribution, and the taxonomic composition of FL and PA bacterial assemblages. The number of OTUs in the present work was two orders of magnitude higher than in previous studies. Only 25% of the total OTUs were common to both fractions, whereas 49% OTUs were exclusive to the PA fraction and 26% to the FL fraction. The OTUs exclusively present in PA or FL assemblages were very low in abundance (6% of total abundance). Detection of the rare OTUs revealed the larger richness of PA bacteria that was hidden in previous studies. Alpha-Proteobacteria dominated the FL bacterial assemblage and gamma-Proteobacteria dominated the PA fraction. Bacteroidetes were important in the PA fraction mainly at the coast. The high number of sequences in this study detected additional phyla from the PA fraction, such as Actinobacteria, Firmicutes, and Verrucomicrobia. 23953180 25-Hydroxyvitamin D [25(OH)D] levels and diabetic foot ulcer: Is there any relationship? In recent years, there has been an effort to understand possible roles of 25(OH)D, including its role in the immune system particularly on T cell medicated immunity, pancreatic insulin secretion and insulin action. 25(OH)D stimulates the cell differentiation and reduces cell proliferation, which is essential for cell growth and wound healing. However, data on the association between low level of plasma 25(OH)D and diabetic foot syndrome are scarce. Circulating plasma levels of 25(OH)D were measured in diabetic patients with ulcer (n=162) and without ulcer (n=162) in a prospective cohort hospital based study. Of these patients, 85.1% had type 2 diabetes. Subjects with diabetic foot ulcer showed lower median plasma level of 25(OH)D [6.3(4.2-11.1) vs 28.0(21.4-37.0)] ng/ml after adjusting the age and BMI. Regardless of the low levels of 25(OH)D in cases and controls, it was associated with neuropathy, sex (female), duration of ulcer healing, and smoking status and independent of confounding factors, including BMI (kg/m(2)), A1c (%), hypertension, nephropathy, foot ulcer, retinopathy, CAD, PAD, HDL-C (mg/dl) and LDL-C (mg/dl). The factors which predict the risk of developing ulcer independent of 25(OH)D status were A1c (>6.9%) [OR 4.37; RR 1.77], HDL-C (<40mg/dl) [OR 1.16; RR 1.07], LDL-C (>100mg/dl) [OR 1.07; RR 1.03], triglycerides (>200mg/dl) [OR 1.40; RR 1.19], neuropathy [OR 6.88; RR 3.12], retinopathy [OR 3.34; RR 1.91], hypertension [OR 1.64; RR 1.28], nephropathy [OR 3.12; RR 1.87] and smoking [OR 4.53; RR 2.99] using odds and risk ratios. It is not clear whether the suppression of delayed wound healing seen during 25(OH)D deficiency is due to the secondary effect or is a direct action of vitamin D on certain components of the immune system. Long-term randomized trials are needed to see the impact of vitamin D supplementation on the outcome of diabetic foot patients. 23909275 Phosphinate Chemistry in the 21st Century: A Viable Alternative to the Use of Phosphorus Trichloride in Organophosphorus Synthesis. Organophosphorus compounds are important in everyday applications ranging from agriculture to medicine and are used in flame retardants and other materials. Although organophosphorus chemistry is known as a mature and specialized area, researchers would like to develop new methods for synthesizing organophosphorus compounds to improve the safety and sustainability of these chemical processes. The vast majority of compounds that contain a phosphorus-carbon bond are manufactured using phosphorus trichloride (PCl3) as an intermediate. However, these reactions require chlorine, and researchers would like to avoid the use of PCl3 and develop safer chemistry that also decreases energy consumption and minimizes waste. Researchers have already proposed and discussed two primary strategies based on elemental phosphorus (P4 or Pred) or on phosphine (PH3) as alternatives to PCl3. However, phosphinates, an important class of phosphorus compounds defined as any compound with a phosphorus atom attached to two oxygens, R(1)R(2)P(O)(OR) (R(1)/R(2) = hydrogen/carbon), offer another option. This Account discusses the previously neglected potential of these phosphinates as replacements of PCl3 for the preparation of organophosphorus compounds. Because of their strong reductive properties, industry currently uses the simplest members of this class of compounds, hypophosphites, for one major application: electroless plating. In comparison with other proposed PCl3 surrogates, hypophosphorous derivatives can offer improved stability, lower toxicity, higher solubility, and increased atom economy. When their reducing power is harnessed to form phosphorus-carbon or phosphorus-oxygen bonds, these compounds are also rich and versatile precursors to organophosphorus compounds. This Account examines the use of transition metal-catalyzed reactions such as cross-coupling and hydrophosphinylation for phosphorus-carbon bond formation. Because the most important industrial organophosphorus compounds include compounds triply or quadruply bound to oxygen, I also discuss controlled transfer hydrogenation for phosphorus-oxygen bond formation. I hope that this Account will further promote research in this novel and exciting yet much underdeveloped area of phosphinate activation. 23871123 A rare lysosomal enzyme gene SMPD1 variant (p.R591C) associates with Parkinson's disease. To investigate the role of mutations in the sphingomyelin phosphodiesterase (SMPD1) gene in Parkinson's disease (PD) we sequenced all the exons of this gene in 198 Chinese PD cases and matched healthy control subjects. We identified 4 rare variants in SMPD1 (p.P332R, p.Y500H, p.P533L, and p.R591C) that were present only in cases and not in control subjects. Interestingly, 2 of these variants were previously reported in Chinese Niemann-Pick disease patients. Next, we genotyped these variants in another 806 PD cases and 7481 control subjects. We identified a novel, rare SMPD1 variant (p.R591C) which increased the risk of PD (p = 0.009). 23817755 Aspirin: An Alternative for Pulmonary Embolism Prophylaxis After Arthroplasty? The most effective agent for prophylaxis against venous thromboembolic disease after total joint arthroplasty (TJA) remains unknown. The paucity of literature comparing different methods of pulmonary embolism (PE) prophylaxis and fear of litigation make it difficult for surgeons to abandon the use of aggressive chemical prophylaxis. We compared the (1) overall frequency of symptomatic PE, (2) risk of symptomatic PE after propensity matching that adjusted for potentially confounding variables, and (3) other complications and length of stay before and after propensity matching in patients undergoing TJA at our institution who received either aspirin or warfarin prophylaxis. A total of 28,923 patients underwent TJA between January 2000 and June 2012 at our institution, had either aspirin (325 mg twice daily; 2800 patients) or warfarin prophylaxis (26,123 patients), and were registered in our institutional electronic database. The incidence of symptomatic PE, symptomatic deep vein thrombosis (DVT), hematoma formation, infection, wound complications, and mortality up to 90 days postoperatively was collected from the database. We performed multivariate analysis and 3:1 and 5:1 propensity score matching for comorbid and demographic variables. The overall symptomatic PE rate was lower (p < 0.001) in patients receiving aspirin (0.14%) than in the patients receiving warfarin (1.07%). This difference did not change after matching. The aspirin group also had significantly fewer symptomatic DVTs and wound-related problems and shorter hospital stays, which did not change after matching. After publication of the American Academy of Orthopaedic Surgeons' guidelines, some surgeons have utilized aspirin as thromboprophylaxis after TJA. Based on our findings from a large institutional database, aspirin offers suitable prophylaxis against symptomatic PE in selected patients. Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. 23498341 The role of monocyte subsets in myocutaneous revascularization. The controlled recruitment of monocytes from the circulation to the site of injury and their differentiation into tissue macrophages are critical events in the reconstitution of tissue integrity. Subsets of monocytes/macrophages have been implicated in the pathogenesis of atherosclerosis and tumor vascularity; however, the significance of monocyte heterogeneity in physiologic neovascularization is just emerging. A cranial-based, peninsular-shaped myocutaneous flap was surgically created on the dorsum of wild-type mice (C57BL6) and populations of mice with genetic deletion of subset-specific chemokine ligand-receptor axes important in monocyte trafficking and function (CCL2(-/-) and CX3CR1(-/-)) (n=36 total; 12 mice per group, nine with flap and three unoperated controls). Planimetric analysis of digital photographic images was utilized to determine flap surface viability in wild-type and knockout mice. Real-time myocutaneous flap perfusion and functional revascularization was determined by laser speckle contrast imaging. Image analysis of CD-31 immunostained sections confirmed flap microvascular density and anatomy. Macrophage quantification and localization in flap tissues was determined by F4/80 gene and protein expression. Quantitative reverse transcription-polymerase chain reaction was performed on nonoperative back skin and postoperative flap tissue specimens to determine local gene expression. Myocutaneous flaps created on wild type and CX3CR1(-/-) mice were engrafted to the recipient site, resulting in viability. In contrast, distal full thickness cutaneous necrosis and resultant flap dehiscence was evident by d 10 in CCL2(-/-) mice. Over 10 d, laser speckle contrast imaging documented immediate graded flap ischemia in all three groups of mice, functional flap revascularization in wild type and CX3CR1(-/-) mice, and lack of distal flap reperfusion in CCL2(-/-) mice. Immunostaining of serial histologic specimens confirmed marked increases in microvascular density and number of macrophages in wild type mice, intermediate increases in CX3CR1(-/-) mice, and no significant change in vessel count or macrophage quantity in CCL2(-/-) mice over the study interval. Finally, quantitative reverse transcriptase polymerase chain reaction demonstrated that the loss of function of chemokine ligand and receptor genes influenced the transcription of local genes involved in monocyte chemotaxis and wound angiogenesis. In a graded-ischemia wound healing model, monocyte recruitment was severely impaired in CCL2(-/-) mice, resulting in failure of flap revascularization and concomitant cutaneous necrosis. Analysis of CX3CR1-deficient mice revealed adequate monocyte recruitment and revascularization for flap survival; however, the myeloid cell response and magnitude of neovascularization were dampened compared with wild type mice. 23952553 Assessment of Coagulation and Potential Biochemical Markers for Hypercoagulability in Canine Hyperadrenocorticism. Anecdotal accounts and limited research suggest that dogs with spontaneous hyperadrenocorticism (HAC) are at risk of developing thromboembolic complications. Detailed description of coagulation status and identification of subsets of dogs at greatest risk would impact therapeutic recommendations for these patients. Hypothesis: A subset of dogs with HAC will have a hypercoagulable tendency as identified by increased procoagulant activity, decreased fibrinolysis, or both. Objective 1: To document the existence of this hypercoagulable tendency in HAC dogs using assays of individual coagulation factors, fibrinolytic activity, and systemic coagulation. Objective 2: To evaluate clinical and biochemical markers in HAC dogs to identify a subset of HAC patients at increased risk of this hypercoagulable tendency. Seventeen dogs newly diagnosed with HAC. Prospective study. Medical history, physical examination findings, routine diagnostic tests, and comprehensive coagulation testing were performed at the time of HAC diagnosis. Coagulation parameters were assessed individually and as panels for each dog. Historical and clinical variables were correlated with coagulation parameters to identify risk factors. The majority (88.2%) of HAC dogs exhibited a hypercoagulable tendency. Abnormalities in 1 coagulation assay did not predict abnormalities in others. Duration of clinical signs of HAC did not predict hypercoagulability. Comorbid conditions or abnormal clinicopathologic parameters that predicted hypercoagulability were not identified. Although HAC dogs may demonstrate a hypercoagulable tendency individually and as a group, comorbid conditions or biochemical variables that would predict more severe coagulation abnormalities were not identified. 23570748 Different levels of prenatal zinc and selenium had different effects on neonatal neurobehavioral development. Either deficient or excessive of essential nutrients had adverse effects. Effects of different levels of prenatal zinc (Zn) and selenium (Se) on fetal neurobehavioral development remain unclear. To determine the effects of different cord serum levels of Zn and Se on neurobehavioral development in neonates and to explore possible threshold level of Zn and Se based on fetal neurodevelopment, we conducted this epidemiological research. In the multi-center study, we investigated these questions in 927 mother-newborn pairs in Shanghai, China, from 2008 through 2009. Umbilical cord serum concentrations of Zn and Se were measured and Neonatal Behavioral Neurological Assessment (NBNA) tests were conducted. The median cord serum Zn and Se concentrations were 794.3μg/L and 63.1μg/L, respectively. A nonlinear relationship was observed between cord serum Zn and NBNA after adjusting for potential confounders. NBNA score decreased with increasing Zn levels after 794.3μg/L (adjusted β=-3.0, 95% CI: -3.6 to -2.4, p<0.001). Additionally, an invert U-shape with a threshold Se of 100μg/L was observed between cord serum Se and NBNA. The adjusted regression coefficient was 4.4 (95% CI: 3.6-5.2, p<0.001) for Se<100μg/L while -3.6 (95% CI: -6.1 to -1.1, p<0.01) for Se≥100μg/L. Of the 927 infants, 50% had a high level Zn (≥794.3μg/L) and 8.6% had a high level Se (≥100μg/L). High levels of both Zn and Se mainly had adverse effects on behavior and passive tone (p<0.001). Taken together, our study suggested that a threshold of cord blood Zn and Se was existed for fetal neurodevelopment and the prevalence of excessive Zn was high. Thus, the supplementation of Zn during pregnancy should be considered with caution in Shanghai, China. 23924736 Accelerated Degradation of Exogenous Indole by Burkholderia unamae Strain CK43B Exposed to Pyrogallol-Type Polyphenols. In modified Winogradsky's (MW) medium supplemented with excessive indole (1), Burkholderia unamae strain CK43B isolated from polyphenol-rich Shorea rhizosphere showed almost no cell growth, but it showed drastic cell growth given further supplementation of gallic acid, a simple plant polyphenol. This active cell growth of B. unamae CK43B was due to the stimulating effect of gallic acid on 1-degradation of bacterial cells, which acquired a nitrogen source in 1. Under aerobic culture conditions with appropriate concentrations (0.5-2.0 mM) of gallic acid, B. unamae CK43B started to decompose exogenous 1 in a dose-dependent manner, and finally accumulated catechol (5) via anthranilic acid (4). Pyrogallol also showed a cometabolic effect on decarboxylation-coupled oxidative deamination of B. unamae CK43B, producing 5 from 4, as gallic acid did. These results suggest that pyrogallol-type plant polyphenols act as stimulators on B. unamae CK43B, causing it to degrade an N-heterocyclic aromatic compound (NHAC) including nitrogen-containing humic substances. 23926880 Enhanced antimicrobial activity of peptide-cocktails against common bacterial contaminants of ex vivo stored platelets. Bacterial contamination of blood components such as ex vivo-stored platelets is a major safety risk in transfusion medicine. We have recently shown that synthetic antimicrobial peptides named PD1-PD4 derived from the thrombin-induced human platelet-derived antimicrobial proteins, and repeats of Arg-Trp (RW1-RW5) demonstrate microbicidal activity against selected bacteria and viruses. In the present study, we selected PD3, PD4, RW2, RW3 and RW4 and evaluated each individual peptide and their various combinations to see whether the cocktail regimen enhances the antimicrobial activity above and over the individual peptides. Stored platelet or plasma samples spiked with known titres of Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Bacillus cereus were treated with either individual peptides or with peptides in various combinations. Analyses revealed that individual peptides show moderate microbicidal activity (10- to 100-fold reduction) against the tested bacteria relative to their combined regimen. The peptide combinations (RW2 + RW4, RW2 + RW3 + RW4 and PD4 + RW3 + RW4) on the other hand enhanced the microbicidal activity (c.10 000-fold reduction) and revealed a minimal inhibitory concentration of 5 Î¼M. Time-kill kinetics indicated that these three peptide combinations exhibited enhanced antimicrobial activity bringing about a 100-fold reduction of bacterial titres within 20 min of incubation. The present study therefore demonstrates the synergistic effect of antimicrobial peptides when used in combinations and provides a proof-of-concept of its potential application as a molecular tool towards pathogen reduction and further extends the possibility of using peptide combinatorial therapeutics as broad-spectrum antibiotics or as alternatives to combat drug-resistant bacteria. 23851276 Nitroxyl donors retain their depressor effects in hypertension. Nitroxyl (HNO), the redox congener of nitric oxide (NO•), has numerous vasoprotective actions including an ability to induce vasodilation and inhibit platelet aggregation. Given HNO is resistant to scavenging by superoxide and does not develop tolerance, we hypothesised that HNO would retain its in vivo vasodilatory action in the setting of hypertension. The in vitro and in vivo vasodilator properties of the HNO donors, Angeli's salt (AS) and isopropylamine/NONOate (IPA/NO) were compared to the NO• donor, diethylamine/NONOate (DEA/NO) in spontaneously hypertensive (SHR) and normotensive (WKY) rats. AS (10, 50 & 200μg/kg), IPA/NO (10, 50 & 200μg/kg) and DEA/NO (1, 5 & 20μg/kg) caused dose-dependent depressor responses in conscious WKY rats of similar magnitude. Depressor responses to AS and IPA/NO were significantly attenuated (P<0.01) following infusion of the HNO scavenger N-acetyl-L-cysteine (NAC) confirming that AS and IPA/NO function as HNO donors in vivo. In contrast, responses to DEA/NO were unchanged following NAC infusion. Depressor responses to AS and IPA/NO in conscious SHR retained their sensitivity to the inhibitory effects of NAC (P<0.01), yet those to DEA/NO in SHR were significantly (P<0.05) enhanced following NAC infusion. Importantly, depressor responses to AS, IPA/NO and DEA/NO were preserved in hypertension and vasorelaxation responses to AS and DEA/NO, in isolated aortae, unchanged in SHR as compared with WKY rats. This study has shown for the first time that HNO donors exert antihypertensive effects in vivo, and may therefore offer a therapeutic alternative to traditional nitrovasodilators in the treatment of cardiovascular disorders such as hypertension. 23534828 How do nurse practitioners in acute care affect perceptions of team effectiveness? To describe how acute care nurse practitioners affect perceptions of team effectiveness. Acute care nurse practitioners provide safe and effective care to patients. There is limited evidence of the effects of acute care nurse practitioner roles on healthcare teams, and many of the findings are contradictory. Research is lacking to describe how nurse practitioners affect perceptions of team effectiveness. A descriptive multiple-case study undertaken in two university-affiliated teaching hospitals in Canada. Data were collected from March-May 2009. Data sources included interviews (n = 59), time and motion study, non-participant observations, documents and field notes. Interviews were conducted individually or in groups using a semi-structured interview guide. Data were analysed within and across the cases to identify similarities and differences in perceptions of team effectiveness. Team members believed the nurse practitioners improved the team's effectiveness. They identified six team processes they believed were improved by the addition of the nurse practitioners to the teams. The processes included decision-making, communication, cohesion, care coordination, problem-solving and focus on patients and families. The study contributes to our understanding of how nurse practitioners affect perceptions of team effectiveness. Improved team communication and care coordination were believed to be particularly important. Nurse practitioner can facilitate patient- and family-centred care in healthcare teams. Nurse practitioners improve perceptions of team effectiveness. Further work is needed in different contexts and with patients and families to determine their perceptions of team effectiveness. The nurse practitioner role was believed to be particularly important to improve team communication and care coordination. This constitutes an added value of acute care nurse practitioners roles in healthcare teams. Nurse practitioner roles contribute to patient-centred care and can improve the quality and safety of the care provided to patients and families. 23954634 Influenza A virus (H1N1) increases airway epithelial cell secretion by up-regulation of potassium channel KCNN4. Influenza infects the epithelial cells lining the airways. Normally epithelial cells move solutes through ion channels to create the osmotic drive to hydrate the airways. Viral alteration of this process could explain, in part, the fluid imbalance in the lungs and the resulting pulmonary edema that occurs during severe influenza infections. Using western blot and RT-qPCR, we measured ion channel and cytokine expression in the Calu3 airway cell line after infection with influenza virus (H1N1) for 48h. We simultaneously measured chloride and potassium channel function by means of a short-circuit current (Isc) produced in an Ussing chamber. At a multiplicity of infection (MOI) of 10, viral M1 protein and pro-inflammatory cytokine expression was observed 24h post-infection, despite a lack of measurable change in Isc. However, we observed a decreased secretory response in cAMP- and calcium-induced Isc 48h post-infection. This correlated with a decrease in CFTR and KCNN4 protein levels. Interestingly, a viral dose of an MOI 0.6 revealed an increased secretory response that correlated with pro-inflammatory cytokine expression. This increased secretory response seemed to be primarily driven through KCNN4. We detected an increase inKCNN4 mRNA and protein, while CFTR function and expression remained unchanged. Furthermore, inhibition of the KCNN4-stimulated Isc with TRAM-34, a specific inhibitor, ameliorated the response, implicating KCNN4 as the main driving force behind the secretory phenotype. 23818223 Characterization of the 5'-flanking region of the mouse asparagine-linked glycosylation 12 homolog gene. Recently, we characterized multiple roles of the endoplasmic reticulum stress responsive element (ERSE) in the promotion of a unique headto-head gene pair: mammalian asparagine-linked glycosylation 12 homolog (ALG12) and cysteine-rich with EGF-like domains 2 (CRELD2). This bidirectional promoter, which consists of fewer than 400 base pairs, separates the two genes. It has been demonstrated that the ALG12 promoter shows less transcriptional activity through ERSE, but its basic regulatory mechanism has not been characterized. In this study, we focused on well-conserved binding elements for the transcription factors for ATF6, NF-Y and YY1 and the Sp1 and Ets families in the 5'-flanking region of the mouse ALG12 gene. We characterized their dominant roles in regulating ALG12 promoter activities using several deletion and mutation luciferase reporter constructs. The ALG12 gene is expressed in three distinct cell lines: Neuro2a, C6 glioma and HeLa cells. The reporter activity in each cell line decreased similarly with serial deletions of the mouse ALG12 promoter. Mutations in the ERSE and adjacent NF-Y-binding element slightly affected reporter activity. Each of the mutations in the GC-rich sequence and YY1-binding element reduced ALG12 promoter activity, and the combination of these mutations additively decreased reporter activity. Each mutation in the tandem-arranged Ets-family consensus sequences partially attenuated ALG12 promoter activity, and mutations of all three Ets-binding elements decreased promoter activity by approximately 40%. Mutation of the three conserved regulatory elements (GC-rich, YY1 and Ets) in the ALG12 promoter decreased reporter activity by more than 90%. Our results suggest that the promoter activity of the mouse ALG12 gene is regulated in a similar manner in the three cell lines tested in this study. The well-conserved consensus sequences in the promoter of this gene synergistically contribute to maintaining basal gene expression. 23670890 Effects of gamma irradiation and 15 days of subsequent ex vivo storage on the cytosolic red blood cell proteome analyzed by 2D-DIGE and Orbitrap MS. Gamma irradiation of red blood cell (RBC) concentrates is routinely used to prevent transfusion-associated graft-versus-host disease. So far, the effects of ionizing radiation on RBC structure and function and especially the proteome are not fully understood. RBC concentrates were irradiated with 30 Gy and stored for 1 or 15 days at 4 ± 2°C. Following cell lysis and hemoglobin depletion, 2D-DIGE was used to examine the changes of the cytosolic RBC proteome. Significantly altered spots were analyzed using bottom-up proteomic approaches and selected marker proteins validated by western blotting. Gamma irradiation was found to enhance conventional RBC storage lesions. Following 15 days of postirradiation storage, the abundances of a total of 27 spots were significantly altered and 3 out of 13 identified proteins were selected and validated as potential marker proteins for the assessment of irradiation-induced cytosolic RBC lesions. Gamma irradiation and subsequent ex vivo storage according to the Council of Europe guidelines were found to affect RBC protein structures. The validated marker proteins can serve as a basis for the development of a screening assay to monitor the quality of irradiated RBC concentrates during ex vivo storage. 23149839 Sedimentation and remobilization of radiocesium in the coastal area of Ibaraki, 70 km south of the Fukushima Dai-ichi Nuclear Power Plant. Sedimentation and remobilization processes of radiocesium were investigated from time-series observations at nine stations in the coastal area of Ibaraki, 70-110 km south of the Fukushima Dai-ichi Nuclear Power Plant (1FNPP). Sediment samples were collected four times between June 2011 and January 2012, and concentrations of radiocesium as well as sediment properties such as grain size and elemental compositions were analyzed. Cumulative inventory of (137)Cs in sediment (0-10 cm) ranged between 4 × 10(3) and 3 × 10(4) Bq/m(2) as of January 2012. This amount was generally higher at stations nearer 1FNPP and has remained at the same level since August 2011. From these results, it can be inferred that dissolved radiocesium advected southward from the region adjacent to the 1FNPP and was deposited to the sediment of the study area in the early stage after the accident. The incorporation of radiocesium into sediments was almost irreversible, and higher concentrations of (137)Cs were obtained from the finer-grained fraction of sediments. In the northern offshore stations, resuspension of the fine-grained sediments formed a high-turbidity layer 10-20 m above the seabed. These results indicate that radiocesium-enriched fine particles were transported from the coast to offshore regions through the bottom high-turbidity layer. 23841912 Alternate virtual populations elucidate the type I interferon signature predictive of the response to rituximab in rheumatoid arthritis. Mechanistic biosimulation can be used in drug development to form testable hypotheses, develop predictions of efficacy before clinical trial results are available, and elucidate clinical response to therapy. However, there is a lack of tools to simultaneously (1) calibrate the prevalence of mechanistically distinct, large sets of virtual patients so their simulated responses statistically match phenotypic variability reported in published clinical trial outcomes, and (2) explore alternate hypotheses of those prevalence weightings to reflect underlying uncertainty in population biology. Here, we report the development of an algorithm, MAPEL (Mechanistic Axes Population Ensemble Linkage), which utilizes a mechanistically-based weighting method to match clinical trial statistics. MAPEL is the first algorithm for developing weighted virtual populations based on biosimulation results that enables the rapid development of an ensemble of alternate virtual population hypotheses, each validated by a composite goodness-of-fit criterion. Virtual patient cohort mechanistic biosimulation results were successfully calibrated with an acceptable composite goodness-of-fit to clinical populations across multiple therapeutic interventions. The resulting virtual populations were employed to investigate the mechanistic underpinnings of variations in the response to rituximab. A comparison between virtual populations with a strong or weak American College of Rheumatology (ACR) score in response to rituximab suggested that interferon β (IFNβ) was an important mechanistic contributor to the disease state, a signature that has previously been identified though the underlying mechanisms remain unclear. Sensitivity analysis elucidated key anti-inflammatory properties of IFNβ that modulated the pathophysiologic state, consistent with the observed prognostic correlation of baseline type I interferon measurements with clinical response. Specifically, the effects of IFNβ on proliferation of fibroblast-like synoviocytes and interleukin-10 synthesis in macrophages each partially counteract reductions in synovial inflammation imparted by rituximab. A multianalyte biomarker panel predictive for virtual population therapeutic responses suggested population dependencies on B cell-dependent mediators as well as additional markers implicating fibroblast-like synoviocytes. The results illustrate how the MAPEL algorithm can leverage knowledge of cellular and molecular function through biosimulation to propose clear mechanistic hypotheses for differences in clinical populations. Furthermore, MAPEL facilitates the development of multianalyte biomarkers prognostic of patient responses in silico. 23913478 Determinants of the combined use of external beam radiotherapy and brachytherapy for low-risk, clinically localized prostate cancer. Prostate cancer treatment choices have been shown to vary by physician and patient characteristics. For patients with low-risk, clinically localized prostate cancer, the authors examined the impact of their clinical, sociodemographic, and radiation oncologists' (RO) characteristics on the likelihood that the patients would receive combined external beam radiotherapy and brachytherapy, a treatment regimen that is at variance with clinical guidelines. The Surveillance, Epidemiology and End Results (SEER)-Medicare linked database and the American Medical Association Physician Masterfile were used in a retrospective analysis of 5531 patients with low-risk, clinically localized prostate cancer who were diagnosed between 2004 and 2007, and the 708 ROs who treated them. Hierarchical logistic regression analyses were used to evaluate the relationship between patient and RO characteristics and the use of combined therapy within 6 months of diagnosis. Overall, 356 patients (6.4%) received combined therapy. Nonclinical factors were found to be associated with combined therapy. After adjusting for patient and RO characteristics, the odds of receiving combined therapy for patients residing in Georgia were found to be significantly greater than for all other SEER regions. Black patients were significantly less likely to receive combined therapy (odds ratio, 0.62; 95% confidence interval, 0.40-0.96 [P = .03]) compared with white patients. In addition, ROs accounted for 36.6% of the variation in patients receiving combined therapy. Geographic and sociodemographic factors were found to be significantly associated with guideline-discordant combined therapy for patients diagnosed with low-risk, clinically localized prostate cancer. Which RO a patient consults is important in determining whether they receive combined therapy. Cancer 2013. © 2013 American Cancer Society. 23783093 The Rise of Soluble TWEAK Levels in Severely Obese Subjects After Bariatric Surgery May Affect Adipocyte-Cytokine Production Induced by TNFα. Context: Soluble TNF-like weak inducer of apoptosis (sTWEAK) is generated by the intracellular proteolytic cleavage of full-length membrane-bound TNF-like weak inducer of apoptosis (mTWEAK). sTWEAK levels are reduced in diseases with an inflammatory component. Additionally, sTWEAK hampers TNFα activity in human cells. Objectives: The objectives of the study were as follows: 1) to determine circulating sTWEAK in severe obesity and after bariatric surgery; 2) to study m/sTWEAK and its receptor fibroblast growth factor-inducible 14 (Fn14) protein expression in sc adipose tissue (SAT) of severely obese subjects, in SAT stromal vascular fraction (SVF), and isolated adipocytes and in human monocyte-derived macrophages; and 3) to explore, on human adipocytes, the sTWEAK effect on TNFα proinflammatory activity. Design: sTWEAK levels were measured in cohort 1: severely obese subjects (n = 23) and a control group (n = 35); and in cohort 2: (n = 23) severely obese subjects before and after surgery. The m/sTWEAK and Fn14 expressions were determined in SAT biopsies, SVF, and isolated adipocytes from severely obese and control subjects and in human monocyte-derived macrophages. In human primary cultured adipocytes, sTWEAK pretreated and TNFα challenged, IL-6, IL-8, and adiponectin protein and gene expressions were determined and nuclear factor-κ B and MAPK signaling analyzed. Results: sTWEAK levels were reduced in severely obese subjects. After surgery, sTWEAK levels rose in 69% of patients. mTWEAK protein expression was increased in SAT and SVF of severely obese subjects, whereas Fn14 was up-regulated in isolated adipocytes. M2 human monocyte-derived macrophages overexpress mTWEAK. In human adipocytes, sTWEAK down-regulates TNFα cytokine production by hampering TNFα intracellular signaling events. Conclusion: The decrease of sTWEAK in severely obese patients may favor the proinflammatory activity elicited by TNFα. 23951387 Perspectives of gene combinations in phenotype presentation. Cells exhibit a variety of phenotypes in different stages and diseases. Although several markers for cellular phenotypes have been identified, gene combinations denoting cellular phenotypes have not been completely elucidated. Recent advances in gene analysis have revealed that various gene expression patterns are observed in each cell species and status. In this review, the perspectives of gene combinations in cellular phenotype presentation are discussed. Gene expression profiles change during cellular processes, such as cell proliferation, cell differentiation, and cell death. In addition, epigenetic regulation increases the complexity of the gene expression profile. The role of gene combinations and panels of gene combinations in each cellular condition are also discussed. 23796880 Beyond metaphor: contrasting mechanisms of social and physical pain. Physical pain can be clearly distinguished from other states of distress. In recent years, however, the notion that social distress is experienced as physically painful has permeated the scientific literature and popular media. This conclusion is based on the overlap of brain regions that respond to nociceptive input and sociocultural distress. Here we challenge the assumption that underlies this conclusion - that physical pain can be easily inferred from a particular pattern of activated brain regions - by showing that patterns of activation commonly presumed to constitute the 'pain matrix' are largely unspecific to pain. We then examine recent analytical advances that may improve the specificity of imaging for parsing pain from a broad range of perceptually unique human experiences. 23924213 Persistence of Acetonitrile Bilayers at the Interface of Acetonitrile/Water Mixtures with Silica. Previous experiments and simulations have shown that acetonitrile organizes into a lipid-like bilayer at the liquid/silica interface. Recent simulations have further suggested that this bilayer structure persists in mixtures of acetonitrile with water, even at low acetonitrile concentrations. This behavior is indicative of microscopic phase separation of these liquids near silica interfaces and may have important ramifications for the use of acetonitrile in chromatography and heterogeneous catalysis. To explore this phenomenon, we have used vibrational sum-frequency-generation spectroscopy to probe acetonitrile/water mixtures at a silica interface. Our spectra provide evidence that acetonitrile partitions to the hydrated silica interface even when the mole fraction of acetonitrile is as low as 10%. A blue shift is observed in the spectrum of the methyl symmetric stretch upon increasing water mole fraction, in agreement with vibrational spectra of bulk mixtures. Line shape analysis suggests that acetonitrile may exist in the form of bilayer patches at high water mole fractions. 22956166 Measurement of lateral plateau depression and lateral plateau widening in a Schatzker type II fracture can predict a lateral meniscal injury. The purpose of this study is to determine the plain radiographic signs that can be indicative of meniscal injuries in Schatzker type II tibial plateau fractures. The lateral plateau depression and lateral plateau widening were measured on anteroposterior knee radiographs in 20 patients with Schatzker type II tibial plateau fracture. Meniscal injury was present in 12 patients (three, meniscal tears; nine, peripheral meniscal detachments). The lateral plateau depression and lateral plateau widening measurements were compared between those who had meniscal injury (Group 1) and those who did not (Group 2). In Group 1, the median lateral plateau depression was 20 mm (IQR: 14-25) and the median lateral plateau widening was 12 mm (IQR: 10-14). In Group 2, the respective values were 10 mm (IQR: 5-17) and 6 mm (IQR: 2-10). There was a statistically significant difference in both parameters when the two groups were compared (p = 0.001). A plain anteroposterior radiograph depicting a lateral plateau depression ≥14 mm and/or a lateral plateau widening ≥10 mm is associated with a significantly increased risk of meniscal injury in Schatzker type II tibial plateau fractures. These parameters can be used to predict the probable presence of lateral meniscal injury in such patients in routine clinical practice. Retrospective comparative study, Level III. 23899673 CaCO3 biomineralization on cyanobacterial surfaces: Insights from experiments with three Synechococcus strains. In the present paper, the impact of freshwater (ARC21 and LS0519) and marine (PCC8806) Synechococcus cyanobacteria on calcium carbonate (CaCO3) precipitation has been examined in respect of the formation rates and morphology of crystals. Acid-base potentiometric titrations were employed to study surface functional groups, while CaCO3 experiments have been carried out in presence and absence of cells at low to near-equilibrium conditions in respect to CaCO3. During these experiments, the pH values have been monitored, Ca and alkalinity were measured and precipitates have been investigated by Raman spectroscopy and Atomic Force and Scanning Electron microscopy. Our results showed that the Synechococcus strains exhibited different surface reactivity with total concentration of surface functional groups of 0.342 and 0.350mMg(-1) of dry bact. for freshwater strains, and 0.662mMg(-1) of dry bact. for the marine strain, which are on the same order of magnitude as that reported for bacterial cell surfaces. The marine strain showed the highest CaCO3 formation rate with Ca(2+) removal of 18mMg(-1) dry bact. compared to 6-7mMg(-1) dry bact. for freshwater strains. The morphological diversity in crystals has been linked to presence of specific functional groups. The linking cell surface properties to crystal morphologies and precipitation rates propose that bacterial surfaces may modulate CaCO3 formation. Results of this work should allow better understanding of biominiralization in marine and freshwater systems as they define the precipiatation rates in typical range of pH necessary for estimation of CaCO3 formation by cyanobacterial communities. 23929147 Prognostic factors in sudden sensorineural hearing loss: a retrospective study using interaction effects. The prognostic significance of vertigo in patients with idiopathic sudden sensorineural hearing loss (SSNHL) remains a matter of debate. This paper aims to verify the difference between a group with vertigo and a group without vertigo, and to analyze vertigo's validation as a prognostic factor in patients with SSNHL. This study involved 183 patients with SSNHL. A t-test was used to compare group A (SSNHL with vertigo, n = 31) and group B (SSNHL without vertigo, n = 152). Also we want to verify the interaction effects between vertigo and other prognostic factors using multiple regression analysis. There was a significant difference between group A and group B: the initial hearing level of group A was lower than group B, and their treatment onset was also shorter. In addition, vertigo itself didn't affect hearing improvement, but the interaction variable between vertigo and initial hearing level did affect hearing improvement significantly. The clinical characteristics of patients with vertigo did not directly affect hearing improvement with SSNHL; however, vertigo had an influence on SSNHL though its interaction with the initial hearing levels. 23411187 Nutritional value and antioxidant activity of honeys produced in a European Atlantic area. One hundred eighty-seven honey samples from an Atlantic European area were studied to determine their nutritional compositions and antioxidant capacities, as well as the relationships between them. The results showed that heather, polyfloral, blackberry, and eucalyptus honeys had the highest carbohydrate contents, whereas honeydew and chestnut honeys had the lowest. There were some important differences among the honey types, which were related to the presence of minor components. The protein contents were significantly higher in honeydew and chestnut honeys, and the same results were obtained for mineral contents. Related to the presence of several antioxidant compounds, heather honey had the highest phenolic content, whereas honeydew and chestnut honeys had the highest flavonoid contents. Multivariate analysis showed that some variables, such as the amounts of flavonoids, minerals, proteins, and phenols, were significantly correlated with antioxidant activity. The regression analysis produced a significant model (R(2)=0.716; F=154.680; P<0.001) that related the antioxidant activity and the flavonoids, K, and P contents. 23933121 Nanomolar ouabain elicits apoptosis through a direct action on HeLa cell mitochondria. The steroid Na(+)/K(+) ATPase (NKA) blocker ouabain has been shown to exhibit pro-apoptotic effects in various cell systems; however, the mechanism involved in those effects is unclear. Here, we have demonstrated that incubation of HeLa cells during 24h with nanomolar concentrations of ouabain or digoxin causes apoptotic death of 30-50% of the cells. Ouabain caused the activation of caspases-3/7 and -9; however, caspase-8 was unaffected. The fact that compound Z-LEHD-FMK reduced both apoptosis and caspase-9 activation elicited by ouabain, suggest a mitochondrially-mediated pathway. This was strengthened by the fact that ouabain caused ATP depletion and the release of mitochondrial cytochrome c into the cytosol. Furthermore, upon ouabain treatment mitochondrial disruption and redistribution into the cytosol were observed. A mitochondrial site of action for ouabain was further corroborated by tight co-localisation of fluorescent ouabain with mitochondria. Finally, in ouabain-treated cells the histamine-elicited elevation of cytosolic Ca(2+) concentration ([Ca(2+)]c) suggests an additional effect on the endoplasmic reticulum (ER) leading to Ca(2+) store depletion. We conclude that fluorescent ouabain is taken up and tightly co-localises with mitochondria of HeLa cells. This indicates that apoptosis may be triggered by a direct action of ouabain on mitochondria. 23223497 Alteration of the expression of pesticide-metabolizing enzymes in pregnant mice: potential role in the increased vulnerability of the developing brain. Studies on therapeutic drug disposition in humans have shown significant alterations as the result of pregnancy. However, it is not known whether pesticide metabolic capacity changes throughout pregnancy, which could affect exposure of the developing brain. We sought to determine the effect of pregnancy on the expression of hepatic enzymes involved in the metabolism of pesticides. Livers were collected from virgin and pregnant C57BL/6 mice at gestational days (GD)7, GD11, GD14, GD17, and postpartum days (PD)1, PD15, and PD30. Relative mRNA expression of several enzymes involved in the metabolism of pesticides, including hepatic cytochromes (Cyp) P450s, carboxylesterases (Ces), and paraoxonase 1 (Pon1), were assessed in mice during gestation and the postpartum period. Compared with virgin mice, alterations in the expression occurred at multiple time points, with the largest changes observed on GD14. At this time point, the expression of most of the Cyps involved in pesticide metabolism in the liver (Cyp1a2, Cyp2d22, Cyp2c37, Cyp2c50, Cyp2c54, and Cyp3a11) were downregulated by 30% or more. Expression of various Ces isoforms and Pon1 were also decreased along with Pon1 activity. These data demonstrate significant alterations in the expression of key enzymes that detoxify pesticides during pregnancy, which could alter exposure of developing animals to these chemicals. 23751315 Inhibiting the motility and invasion of cancer cells by biomineralization. Many kinds of cancer are difficult to treat because of their highly metastatic abilities. Thus, seeking new anticancer drugs or therapy strategies, which could reduce the motility of cancer cells or inhibit the migration and invasion of the cells, is an urgent affair. Several recent reports suggest various techniques (such as layer-by-layer assembly and biomimetic mineralization) aimed to functionalize human cells and microbial with polyelectrolytes, nanoparticles, or mineral coatings. Inspired by these studies, an artificial mineral shell could be formed to enclose cancer cells under the regulation of SIBLINGs-like proteins. Consequently, the connection between the cancer cell and substrate would be interfered or inhibited. Therefore, the motility of cancer cells would be weakened or inhibited due to the restriction of the artificial mineral shell. This hypothetical strategy might be as a new concept for cancer therapy. 23348715 Expression of the ghrelin receptor gene in neurons of the medulla oblongata of the rat. There is ambiguity concerning the distribution of neurons that express the ghrelin receptor (GHSR) in the medulla oblongata. In the current study we used a sensitive nonradioactive method to investigate GHSR mRNA distribution by in situ hybridization. Strong expression of the GHSR gene was confirmed in neurons of the facial nucleus (FacN, 7), the dorsal vagal complex (DVC), and the semicompact (but not compact) nucleus ambiguus (AmbSC and AmbC). In addition, expression of GHSR was found in other regions, where it had not been described before. GHSR-positive neurons were observed in the gustatory rostral nucleus tractus solitarius and in areas involved in vestibulo-ocular processing (such as the medial vestibular nucleus and the nucleus abducens). GHSR expression was also noted in ventral areas associated with cardiorespiratory control, including the gigantocellular reticular nucleus, the lateral paragigantocellular nucleus, the rostral and caudal ventrolateral medulla, the (pre)-Bötzinger complex, and the rostral and caudal ventrolateral respiratory group. However, GHSR-positive neurons in ventrolateral areas did not express markers for cardiovascular presympathetic vasomotor neurons, respiratory propriobulbar rhythmogenic neurons, or sensory interneurons. GHSR-positive cells were intermingled with catecholamine neurons in the dorsal vagal complex but these populations did not overlap. Thus, the ghrelin receptor occurs in the medulla oblongata in 1) second-order sensory neurons processing gustatory, vestibulo-ocular, and visceral sensation; 2) cholinergic somatomotor neurons of the FacN and autonomic preganglionic neurons of the DMNX and AmbSC; 3) cardiovascular neurons in the DVC, Gi, and LPGi; 4) neurons of as yet unknown function in the ventrolateral medulla. 23902274 Stereotactic body radiation therapy versus conventional radiation therapy in patients with early stage non-small cell lung cancer: An updated retrospective study on local failure and survival rates. Introduction. Stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) is now an accepted and patient friendly treatment, but still controversy exists about its comparability to conventional radiation therapy (RT). The purpose of this single-institutional report is to describe survival outcome for medically inoperable patients with early stage NSCLC treated with SBRT compared with high dose conventional RT. Material and methods. From August 2005 to June 2012, 100 medically inoperable patients were treated with SBRT at Odense University Hospital. The thoracic RT consisted of 3 fractions (F) of 15-22 Gy delivered in nine days. For comparison a group of 32 medically inoperable patients treated with conventional RT with 80 Gy/35-40 F (5 F/week) in the period of July 1998 to August 2011 were analyzed. All tumors had histological or cytological proven NSCLC T1-2N0M0. Results. The median overall survival was 36.1 months versus 24.4 months for SBRT and conventional RT, respectively (p = 0.015). Local failure-free survival rates at one year were in SBRT group 93% versus 89% in the conventional RT group and at five years 69% versus 66%, SBRT and conventional RT respectively (p = 0.99). On multivariate analysis, female gender and performance status of 0-1 and SBRT predicted improved prognosis. Conclusion. In a cohort of patients with NSCLC there was a significant difference in overall survival favoring SBRT. Performance status of 0-1, female gender and SBRT predicted improved prognosis. However, staging procedure, confirmation procedure of recurrence and technical improvements of radiation treatment is likely to influence outcomes. However, SBRT seems to be as efficient as conventional RT and is a more convenient treatment for the patients. 23946336 Comparison Between Southern Blots and qPCR Analysis of Leukocyte Telomere Length in the Health ABC Study. Only a few studies, primarily limited to small samples, have examined the relationship between leukocyte telomere length (LTL) data generated by Southern blots, expressed in kilobases, versus quantitative PCR data, expressed in the telomere product/a single gene product (T/S). In the present study, we compared LTL data generated by the two methods in 681 elderly participants (50% African Americans, 50% of European origin, 49.2% women, mean age 73.7±2.9 years) in the Health Aging and Body Composition Study. The correlation between the data generated by the two methods was modest (R(2) = .27). Both methods captured the age effect on LTL and the longer LTL in women than in men. However, only the Southern blot method showed a significantly longer LTL in African Americans than in European decent individuals, which might be attributed to the larger measurement error of the quantitative PCR-based method than the Southern blots. 23841484 Epigenetic mechanisms may underlie the etiology of sex differences in mental health risk and resilience. In this review, we propose that experiential and hormonal influences on biological sex during development may produce differences in the epigenome, and that these differences play an important role in gating risk or resilience to a number of neurological and psychiatric disorders. One intriguing hypothesis is that the framework belying sex differences in the brain creates differences in methylation and demethylation patterns, and these in turn confer risk and resilience to mental health disorders. Herein we discuss these concepts with regard to social behavior in rodent models and briefly discuss their possible relevance to human disease. This article is protected by copyright. All rights reserved. 23849163 Oseltamivir use and outcomes during the 2009 influenza A H1N1 pandemic in Taiwan. The Taiwan CDC provided free oseltamivir to all patients with influenza infections confirmed by rapid testing or who had clinical warning symptoms during the 2009 H1N1 influenza pandemic in Taiwan. However, oseltamivir utilization patterns, cost, and outcomes among oseltamivir-treated patients remained unclear. A population-level, observational cohort study was conducted using the Taiwan National Health Insurance Database from January to December 2009 to describe the use of oseltamivir. Prescription trend over weeks increased after a change in government policy and responded to the influenza virus activity. The overall prescription rate was 22.33 per 1000 persons, with the highest prescription rate of 116.5 for those aged 7-12 years, followed by 69.0 for those aged 13-18 years, while the lowest rate was 1.7 for those aged ≥ 65 years. As influenza virus activity increased, the number of prescriptions for those aged ≤18 years rose significantly, whereas no substantial change was observed for those aged ≥65 years. There were also regional variations in terms of oseltamivir utilization and influenza complication rates. Oseltamivir was widely used in the 2009 H1N1 influenza pandemic in Taiwan, particularly in those aged 7-18 years. The number of prescriptions for oseltamivir increased with a change in government policy and with increasing cases of pandemic influenza. Further study is needed to examine whether there is an over- or under-use of anti-influenza drugs in different age groups or regions and to examine the current policy of public use of anti-influenza drugs to reduce influenza-associated morbidity and mortality. 23955752 Nonlocal Hierachical Dictionary Learning Using Wavelets for Image Denoising. Exploiting the sparsity within representation models for images is critical for image denoising. The best currently available denoising methods take advantage of the sparsity from image self-similarity, pre-learned and fixed representations. However, most of these methods still have difficulties in tackling high noise levels or noise models other than Gaussian. In this paper, the multi-resolution structure and sparsity of wavelets are employed by nonlocal dictionary learning in each decomposition level of the wavelets. Experimental results show that our proposed method outperforms two state-of-the-art image denoising algorithms on higher noise levels. Furthermore, our approach is more adaptive to the less extensively studied uniform noise. 23934015 Localized cell stiffness measurement using axial movement of an optically trapped microparticle. ABSTRACT. A simple optical tweezers design is proposed to manipulate particles in the axial direction and estimate particle position with nanometer sensitivity. Balb3T3 cell is probed using two different-sized particles, and the localized cell stiffness is evaluated using Hertz model. A series of experiments are performed to obtain the necessary parameters for the cell stiffness computation: particle displacement, trapping stiffness, force exertion, and cell deformation. The computed cell stiffness measurements are 17 and 40 Pa using 4 Î¼m- and 2 Î¼m-sized particles, respectively. Results suggest that the proposed optical tweezers scheme can measure the stiffness of a particular cell locale using Hertz model, offering insights about how cells respond to outside mechanical stimulus. 23651098 Dermal pleomorphic liposarcoma resembling pleomorphic fibroma: report of a case and review of the literature. Pleomorphic liposarcoma (PLPS) is a rare, high-grade sarcoma defined by the presence of pleomorphic lipoblasts. Constituting 5% of all liposarcomas, PLPS usually arises in deep soft tissues of the extremities, with rare occurrences in the dermis and subcutis. We describe a unique case of an 85-year-old Caucasian gentleman with a 1 year history of a pedunculated, pink, non-tender papule on the dorsum of his left arm, measuring 1.0 cm in maximum dimension. Biopsy revealed a dermal collection of atypical epithelioid and spindle cells superimposed on a sclerotic background, resembling a pleomorphic fibroma on low power. On high power, a central focus of discrete adipocytic differentiation with pleomorphic lipoblasts was present. Tumor cells were positive for S-100 and negative for desmin, actin, CD68, keratin, MART-1 and CD34. Clinicopathologic findings were consistent with PLPS and the diagnosis was made. PLPS is rarely localized to the dermis and one with low power features resembling a pleomorphic fibroma has not been previously described in the literature. 23932357 Increase in stearidonic acid by increasing the supply of histidine to oleaginous Saccharomyces cerevisiae. Increasing concentration of histidine significantly increased stearidonic acid production and cell growth in oleaginous Saccharomyces cerevisiae that has been genetically modified by Δsnf2 disruption, DGA1 and Δ6 desaturase gene overexpression, and LEU2 expression. High concentration of histidine in wild-type transformant and HIS3 expression in Δsnf2 transformant also increased stearidonic acid. 22963505 HSP65-PRA identification of non-tuberculosis mycobacteria from 4892 samples suspicious for mycobacterial infections. Various molecular methods have been used for the rapid identification of mycobacterial species. In this survey, evaluation of antibiotic resistance and PCR-restriction fragment length polymorphism analysis (PRA) of the hsp65 gene was carried out for identification of non-tuberculosis mycobacteria (NTM) isolates from different clinical specimens. Forty-eight different mycobacterial isolates were selected and followed by the conventional and PRA of hsp65 for species identification. The antibiotic susceptibility test was carried out according to standard methods. A 439 bp PCR product of hsp65 in all selected isolates was amplified and digested with the BstEII and HaeIII restriction enzymes. The restriction fragment length polymorphism (RFLP) patterns were analyzed for species identification. Using PRA for 48 mycobacterial selected isolates, including 15 M. tuberculosis, one M. bovis and all 32 isolates of NTM, revealed 11 different species among the NTM isolates. The most frequent NTM isolates were M. kansasii, M. gordonae III, M. marinum, M. chelonae, M. scrofluaceum and M. gastri. In most cases, the PRA results were perfectly in accordance with the classical biochemical method. Combination of resistance to rifampin and isoniazid was present among M. kansasi, M. gordoniae III, M. scrofluaceum, M. chelonae, M. marinum, M. gastri, M. gordoniae II and M. trivale isolates. A high incidence of co-resistance to six, five, four and three anti-TB drugs was observed in 18.5%, 9.1%, 6.6% and 11.7% of all NTM isolates, respectively. Our results showed that PRA, in comparison with classical methods, is rapid and accurate enough for the identification of mycobacterial species from LJ medium. Additionally, we found that in Iran we have a highly diverse population of NTM isolates among patients suspected of having TB. 23406293 The secretome of Helicobacter trogontum. Helicobacter trogontum is a putative enterohepatic pathogen, which following infection of IL-10 knock-out mice, results in severe clinical signs and typhlocolitis. The pathogenic potential of H. trogontum Type strain LRB 8581 was investigated using proteomics coupled with mass spectrometry to characterize the secretome of H. trogontum and scanning electron microscopy to visualize H. trogontum adherence and invasion. One hundred and four proteins were identified and bioinformatically predicted to be secreted. Further functional classifications revealed proteins involved in motility, virulence, and colonization factors and the type VI secretion system. Microscopy showed that H. trogontum can adhere to host cells through flagella-microvillus interactions and invade causing a membrane ruffling-like effect and severe cell damage. This indicated H. trogontum has the ability to adhere to and invade human cells and secrete factors that may contribute to disease development. 23939706 Climate and Leishmaniasis in French Guiana. To study the link between climatic variables and the incidence of leishmaniasis a study was conducted in Cayenne, French Guiana. Patients infected between January 1994 and December 2010. Meteorological data were studied in relation to the incidence of leishmaniasis using an ARIMA model. In the final model, the infections were negatively correlated with rainfall (with a 2-month lag) and with the number of days with rainfall > 50 mm (lags of 4 and 7 months). The variables that were positively correlated were temperature and the Multivariate El Niño Southern Oscillation Index with lags of 8 and 4 months, respectively. Significantly greater correlations were observed in March for rainfall and in November for the Multivariate El Niño/Southern Oscillation Index. Climate thus seems to be a non-negligible explanatory variable for the fluctuations of leishmaniasis. A decrease in rainfall is linked to increased cases 2 months later. This easily perceptible point could lead to an interesting prevention message. 23517912 Fisetin regulates obesity by targeting mTORC1 signaling. Fisetin, a flavonol present in vegetables and fruits, possesses antioxidative and anti-inflammatory properties. In this study, we have demonstrated that fisetin prevents diet-induced obesity through regulation of the signaling of mammalian target of rapamycin complex 1 (mTORC1), a central mediator of cellular growth, cellular proliferation and lipid biosynthesis. To evaluate whether fisetin regulates mTORC1 signaling, we investigated the phosphorylation and kinase activity of the 70-kDa ribosomal protein S6 kinase 1 (S6K1) and mTORC1 in 3T3-L1 preadipocytes. Fisetin treatment of preadipocytes reduced the phosphorylation of S6K1 and mTORC1 in a time- and concentration-dependent manner. To further our understanding of how fisetin negatively regulates mTORC1 signaling, we analyzed the phosphorylation of S6K1, mTOR and Akt in fisetin-treated TSC2-knockdown cells. The results suggested that fisetin treatment inhibits mTORC1 activity in an Akt-dependent manner. Recent studies have shown that adipocyte differentiation is dependent on mTORC1 activity. Fisetin treatment inhibited adipocyte differentiation, consistent with the negative effect of fisetin on mTOR. The inhibitory effect of fisetin on adipogenesis is dependent of mTOR activity, suggesting that fisetin inhibits adipogenesis and the accumulation of intracellular triglycerides during adipocyte differentiation by targeting mTORC1 signaling. Fisetin supplementation in mice fed a high-fat diet (HFD) significantly attenuated HFD-induced increases in body weight and white adipose tissue. We also observed that fisetin efficiently suppressed the phosphorylation of Akt, S6K1 and mTORC1 in adipose tissue. Collectively, these results suggest that inhibition of mTORC1 signaling by fisetin prevents adipocyte differentiation of 3T3-L1 preadipocytes and obesity in HFD-fed mice. Therefore, fisetin may be a useful phytochemical agent for attenuating diet-induced obesity. 23460590 Efficacy and toxicity of plerixafor for peripheral blood stem cell mobilization in children with high-risk neuroblastoma. Six patients with high-risk neuroblastoma underwent the second stem cell collection round with G-CSF (5 μg/kg/day) + plerixafor (0.24 mg/kg/day) because the amount of CD34(+) cells collected during the first collection round with G-CSF alone was insufficient. The number of CD34(+) cells collected in the second collection round was higher in four patients and lower in two patients than in the first collection round. Four of the six patients experienced nightmares, nyctophobia, and visual hallucinations with G-CSF + plerixafor, which were not observed with G-CSF alone. Our findings suggest that plerixafor needs to be used with caution in children. 23625320 Influence of acid-etching after grit-blasted on osseointegration of titanium dental implants: in vitro and in vivo studies. Rough implant surfaces have shown improved osseointegration rates. In a majority of dental implants, the microrough surfaces are obtained by grit blasting and/or acid-etching. The aim of this contribution was to evaluate the effects of acid-etching, after the grit-blasted treatment in titanium dental implants, on surface wettability, surface energy, osteoblast responses and its osseointegration behavior. Four surfaces were studied: as-machined, acid-etched, micro-rough by grit-blasting and the combination grit-blasted surface with acid-etched. The surfaces with increasing roughness show more osteoblastic adhered cells. This effect was most pronounced on samples blasted and blasted with acid-etching. The roughness obtained by grit-blasting is the main factor in comparison with the acid etching treatment in the biological response. These results were confirmed in vivo tests and histological analysis. The results demonstrated that the combination of the grit-blasted and acid-etched accelerated lightly bone regeneration at the different periods of implantation in comparison with the grit-blasted implants. 23379719 Diversification in a biodiversity hot spot: landscape correlates of phylogeographic patterns in the African spotted reed frog. The Eastern Afromontane Biodiversity Hotspot is known for microendemism and exceptional population genetic structure. The region's landscape heterogeneity is thought to limit gene flow between fragmented populations and create opportunities for regional adaptation, but the processes involved are poorly understood. Using a combination of phylogeographic analyses and circuit theory, I investigate how characteristics of landscape heterogeneity including regional distributions of slope, rivers and streams, habitat and hydrological basins (drainages) impact genetic distance among populations of the endemic spotted reed frog (Hyperolius substriatus), identifying corridors of connectivity as well as barriers to dispersal. Results show that genetic distance among populations is most strongly correlated to regional and local hydrologic structure and the distribution of suitable habitat corridors, not isolation by distance. Contrary to expectations, phylogeographic structure is not coincident with the two montane systems, but instead corresponds to the split between the region's two major hydrological basins (Zambezi and East Central Coastal). This results in a paraphyletic relationship for the Malawian Highlands populations with respect to the Eastern Arc Mountains and implies that the northern Malawian Highlands are the diversity centre for H. substriatus. Although the Malawian Highlands collectively hold the greatest genetic diversity, individual populations have lower diversity than their Eastern Arc counterparts, with an overall pattern of decreasing population diversity from north to south. Through the study of intraspecific differentiation across a mosaic of ecosystem and geographic heterogeneity, we gain insight into the processes of diversification and a broader understanding of the role of landscape in evolution. 23953462 Simulated single-cycle kinetics improves the design of surface plasmon resonance assays. Instruments based on the surface plasmon resonance (SPR) principle are widely used to monitor in real time molecular interactions between a partner, immobilized on a sensor chip surface and another one injected in a continuous flow of buffer. In a classical SPR experiment, several cycles of binding and regeneration of the surface are performed in order to determine the rate and the equilibrium constants of the reaction. In 2006, Karlsson and co-workers introduced a new method named single-cycle kinetics (SCK) to perform SPR assays. The method consists in injecting sequentially increasing concentrations of the partner in solution, with only one regeneration step performed at the end of the complete binding cycle. A 10 base-pair DNA duplex was characterized kinetically to show how simulated sensorgrams generated by the BiaEvaluation software provided by Biacore(™) could really improve the design of SPR assays performed with the SCK method. The DNA duplex was investigated at three temperatures, 10, 20 and 30°C, to analyze fast and slow rate constants. The results show that after a short obligatory preliminary experiment, simulations provide users with the best experimental conditions to be used, in particular, the maximum concentration used to reach saturation, the dilution factor for the serial dilutions of the sample injected and the duration of the dissociation and association phases. The use of simulated single-cycle kinetics saves time and reduces sample consumption. Simulations can also be used to design SPR experiments with ternary complexes. 23893657 Transcriptional responses, metabolic activity and mouthpart deformities in natural populations of chironomus riparius larvae exposed to environmental pollutants. Biomarkers are an important tool in laboratory assays that link exposure or effect of specific toxicants to key molecular and cellular events, but they have not been widely used in invertebrate populations exposed to complex mixtures of environmental contaminants in their natural habitats. The present study focused on a battery of biomarkers and their comparative analysis in natural populations of the benthic larvae of Chironomus riparius (Diptera), sampled in three differentially polluted rivers (the Con, Sar, and Louro in Galicia, Spain). In our study, some parameters were identified, such as hsp70 gene activity, GST enzymatic activity, total glycogen content and mouthpart deformities, which showed significant differences among populations from the three rivers that differed in the levels and types of sedimentary contaminants analyzed (metals, organic-chlorine pesticides, alkylphenols, pharmaceutical, and personal care products). In contrast to these sensitive biomarkers, other parameters showed no significant differences (hsc70 gene, EcR gene, P450 gene, RNA:DNA ratio, total protein content), and were stable even when comparing field and nonexposed laboratory populations. The hsp70 gene seems to be particularly sensitive to conditions of pollutant exposure, while its constitutive counterpart hsc70 showed invariable expression, suggesting that the hsc70/hsp70 ratio may be a potential indicator of polluted environments. Although further studies are required to understand the correlation between molecular responses and the ecological effects of pollutants on natural populations, the results provide new data about the biological responses to multiple-stressor environments. This field study adds new molecular endpoints, including gene expression, as suitable tools that, complementing other ecotoxicological parameters, may help to improve the methodologies of freshwater monitoring under the increasing burden of xenobiotics. © 2013 Wiley Periodicals, Inc. Environ Toxicol, 2013. 23665088 Endocervical glandular involvement, multicentricity, and extent of the disease are features of high-grade cervical intraepithelial neoplasia. This study aimed to evaluate the rate of endocervical glandular involvement, positive surgical margins, multicentricity, and disease extent between low-grade and high-grade cervical intraepithelial lesions after loop electrosurgical excision procedure (LEEP). Pathology medical records of patients who underwent LEEP were reviewed retrospectively. Patients with negative LEEP results were excluded. Loop electrosurgical excision procedure reports of patients with cervical intraepithelial neoplasia (CIN) 1, 2, and 3 were compared. There was no statistically significant difference between patients with CIN 1 (n = 24), CIN 2 (n = 27), and CIN 3 (n = 64) when age and surgical margin positivity were considered. Endocervical glandular involvement, multicentricity, and disease extent were higher in patients with CIN 3 (P = .001, P = .002, and P = .001, respectively). In conclusion, we recommend that patients with endocervical glandular involvement, lesions involving more than two-thirds of the LEEP specimen, and multicentricity be followed up more closely. 23929742 Kinetics of sulforaphane in mice after consumption of sulforaphane-enriched broccoli sprout preparation. Sulforaphane (SF) is a natural isothiocyanate in broccoli sprouts with cancer chemopreventive activity. This study is aimed to use different methods to develop broccoli sprout preparations to compare their ability to deliver SF to the mice and to evaluate the kinetics and biodistribution of SF. The SF-enriched sprout preparation generated by two-step procedure (quick-steaming followed by myrosinase treatment) contained the highest level of SF, which was 11 and 5 times higher than the freeze-dried fresh broccoli sprouts and the quick-steamed, freeze-dried broccoli sprouts, respectively. After oral administration of 2.5 mg/g body weight of the broccoli sprout preparations, SF was quickly absorbed and distributed throughout the tissues. The SF-rich preparation resulted in the highest exposure, with peak plasma SF concentration of 337 ng/mL, which is 6.0 times and 2.6 times higher compared to the other two preparations. A whole body physiologically based pharmacokinetic model (developed with ADAPT 5 software) suggests that distribution of SF is perfusion-limited in all organs. This study provides a broccoli sprout preparation that can serve as a good source of SF, and the model can be utilized to guide the dose designed for the use of broccoli sprout preparation in chemoprevention. 23930140 Biological Sex and Mechanisms of Ischemic Brain Injury. Cerebrovascular disease is a leading cause of death-from-disease and of disability worldwide, affecting some 15 million people. The incidence of stroke or "brain attack" is unlikely to recede for a decade at minimum by most predictions, despite large public health initiatives in stroke prevention. It has been well established that stroke is also one of the most strikingly sex-specific diseases in its epidemiology, and in some cases, in patient outcomes. For example, women sustain lower rates of ischemic stroke relative to men, even beyond their menopausal years. In contrast, outcomes are worse in women in many clinical studies. The biological basis for this sexual dimorphism is a compelling story, and both hormone-dependent and hormone-independent factors are involved, the latter of which is the subject of this brief review. Understanding the molecular and cell-based mechanisms underlying sex differences in ischemic brain injury is an important step toward personalized medicine and effective therapeutic interventions in patients of both sexes. 23433938 LOX-1 is a novel marker for peripheral artery disease in patients with type 2 diabetes. OBJECTIVE: The aim of this study was to investigate whether serum soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1), which mediates initiation and progression of atherosclerosis in endothelial cells, could be a novel marker for peripheral artery disease (PAD) in patients with type 2 diabetes. METHODS: We evaluated relationships of serum sLOX-1 to ankle-brachial index (ABI) and examined the association of serum sLOX-1 with PAD in 410 patients with type 2 diabetes. RESULTS: Serum sLOX-1 was inversely correlated with ABI (r=-0.197, P<0.0001). Stepwise regression analysis demonstrated that serum sLOX-1 (β=-0.168, F=5.571, P<0.05) was independently associated with ABI, and multiple logistic regression analysis demonstrated that serum sLOX-1 (16.254 (1.237-213.651), P=0.0339) was independently associated with PAD. CONCLUSIONS: Serum sLOX-1 is associated with ABI and it could be a novel marker for PAD in patients with type 2 diabetes. 23611293 Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Understanding potential health risks is a significant challenge due to large numbers of diverse chemicals with poorly characterized exposures and mechanisms of toxicities. The present study analyzes 976 chemicals (including failed pharmaceuticals, alternative plasticizers, food additives, and pesticides) in Phase I and II of the U.S. EPA's ToxCast™ project across 331 cell-free enzymatic and ligand-binding high-throughput screening (HTS) assays. Half-maximal activity concentrations (AC50) were identified for 729 chemicals in 256 assays (7,135 chemical-assay pairs). Some of the most commonly affected assays were CYPs (CYP2C9, CYP2C19), transporters (mitochondrial TSPO, norepinephrine, dopaminergic), and GPCRs (aminergic). Heavy metals, surfactants, and dithiocarbamate fungicides showed promiscuous, but distinctly different patterns of activity whereas many of the pharma compounds showed promiscuous activity across GPCRs. Literature analysis confirmed >50% of the activities for the most potent chemical-assay pairs (56), but also revealed 10 missed interactions. Twenty-two chemicals with known estrogenic activity were correctly identified for the majority (77%), missing only the weaker interactions. In many cases, novel findings for previously unreported chemical-target combinations clustered with known chemical-target interactions. Results from this large inventory of chemical-biological interactions can inform read-across methods as well as to link potential targets to molecular initiating events in adverse outcome pathways for diverse toxicities. This abstract does not necessarily reflect U.S. EPA policy. 23507385 Differential connectivity within the Parahippocampal Place Area. The Parahippocampal Place Area (PPA) has traditionally been considered a homogeneous region of interest, but recent evidence from both human studies and animal models has suggested that PPA may be composed of functionally distinct subunits. To investigate this hypothesis, we utilize a functional connectivity measure for fMRI that can estimate connectivity differences at the voxel level. Applying this method to whole-brain data from two experiments, we provide the first direct evidence that anterior and posterior PPA exhibit distinct connectivity patterns, with anterior PPA more strongly connected to regions in the default mode network (including the parieto-medial temporal pathway) and posterior PPA more strongly connected to occipital visual regions. We show that object sensitivity in PPA also has an anterior-posterior gradient, with stronger responses to abstract objects in posterior PPA. These findings cast doubt on the traditional view of PPA as a single coherent region, and suggest that PPA is composed of one subregion specialized for the processing of low-level visual features and object shape, and a separate subregion more involved in memory and scene context. 23754625 Amphipatic molecules affect the kinetic profile of Pseudomonas putida chlorocatechol 1,2-dioxygenase. Dioxygenases are nonheme iron enzymes that biodegrade recalcitrant compounds, such as catechol and derivatives, released into the environment by modern industry. Intradiol dioxygenases have attracted much attention due to the interest in their use for bioremediation, which has demanded efforts towards understanding their action mechanism and also how to control it. The role of unexpected amphipatic molecules, observed in crystal structures of intradiol dioxygenases, during catalysis has been poorly explored. We report results obtained with the intradiol enzyme chlorocatechol 1,2-dioxygenase (1,2-CCD) from Pseudomonas putida subjected to delipidation. The delipidated enzyme is more stable and shows more cooperative thermal denaturation. The kinetics changes from Michaelis-Menten to a cooperative scheme, indicating that conformational changes propagate between monomers in the absence of amphipatic molecules. Furthermore, these molecules inhibit catalysis, yielding lower v max values. To the best of our knowledge, this is the first report concerning the effects of amphipatic molecules on 1,2-CCD function. 23777186 Quantitative interpretation of anomalous coagulation behavior of colloidal silica using a swellable polyelectrolyte gel model of electrical double layer. Electrolyte-induced coagulation of colloidal dispersions of silica has remained a puzzle for many decades, and it is widely considered anomalous from the viewpoint of traditional Gouy-Chapman theory of diffuse double layer and ζ-potential at ideal surfaces and of their electrostatic interaction (Derjaguin-Landau-Verwey-Overbeek, DLVO theory). It is suggested that this anomaly is caused by the fact that silica particles are covered with swellable gel layers. Theoretical stability ratios are calculated combining the attractive van der Waals and repulsive electrosteric interactions between core-shell (soft) model spheres with homogeneously distributed fixed charges in the shells and matched with the experimental ones measured for nonporous silica microspheres of different diameters (50, 150, and 320 nm) in an univalent electrolyte (KCl) of increasing concentration and pH (2.6, 4, 6, and 8). The variation in the shell thickness with the KCl concentration (mimicking the charged gel layer swelling) as the only adjustable parameter, deduced in such a way from data at pH 6 and 8, not only can explain the parallel experimental electrophoretic mobilities but also conforms itself to a scaling law derived from the thermodynamic theory of polyelectrolyte hydrogels. A resulting inapplicability of the DLVO theory and the ζ-potential concept for a quantitative predicting the coagulation kinetics of gel layer-covered colloids is discussed. 23729731 Membrane cholesterol modulates the hyaluronan-binding ability of CD44 in T lymphocytes and controls rolling under shear flow. The adhesion of circulating lymphocytes to the surface of vascular endothelial cells is important for their recruitment from blood to secondary lymphoid organs and to inflammatory sites. CD44 is a key adhesion molecule for this interaction and its ligand-binding ability is tightly regulated. Here we show that the hyaluronan-binding ability of CD44 in T cells is upregulated by the depletion of membrane cholesterol with methyl-β-cyclodextrin (MβCD), which disintegrates lipid rafts, i.e. cholesterol- and sphingolipid-enriched membrane microdomains. Increasing concentrations of MβCD led to a dose-dependent decrease in cellular cholesterol content and to upregulation of hyaluronan binding. Additionally, a cholesterol-binding agent filipin also increased hyaluronan binding. Cholesterol depletion caused CD44 to be dispersed from cholesterol-enriched membrane microdomains. Cholesterol depletion also increased the number of cells undergoing rolling adhesion under physiological flow conditions. Our results suggest that the ligand-binding ability of CD44 is governed by its cholesterol-dependent allocation to membrane microdomains at the cell surface. These findings provide novel insight into the regulation of T cell adhesion under blood flow. 23710105 Texture Representations Using Subspace Embeddings. In this paper, we propose a texture representation framework to map local texture patches into a low-dimensional texture subspace. In natural texture images, textons are entangled with multiple factors, such as rotation, scaling, viewpoint variation, illumination change, and non-rigid surface deformation. Mapping local texture patches into a low-dimensional subspace can alleviate or eliminate these undesired variation factors resulting from both geometric and photometric transformations. We observe that texture representations based on subspace embeddings have strong resistance to image deformations, meanwhile, are more distinctive and more compact than traditional representations. We investigate both linear and non-linear embedding methods including Principle Component Analysis (PCA), Linear Discriminant Analysis (LDA), and Locality Preserving Projections (LPP) to compute the essential texture subspace. The experiments in the context of texture classification on benchmark datasets demonstrate that the proposed subspace embedding representations achieve the state-of-the-art results while with much fewer feature dimensions. 23892718 Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential. B-precursor acute lymphoblastic leukemia (B-pre ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. The prognosis of B-pre ALL has improved in pediatric patients, but the outcome is much less successful in adults. Constitutive activation of the phosphatidylinositol 3-kinase (PI3K), Akt and the mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) network is a feature of B-pre ALL, where it strongly influences cell growth and survival. RAD001, a selective mTORC1 inhibitor, has been shown to be cytotoxic against many types of cancer including hematological malignancies. To investigate whether mTORC1 could represent a target in the therapy of B-pre ALL, we treated cell lines and adult patient primary cells with RAD001. We documented that RAD001 decreased cell viability, induced cell cycle arrest in G0/G1 phase and caused apoptosis in B-pre ALL cell lines. Autophagy was also induced, which was important for the RAD001 cytotoxic effect, as downregulation of Beclin-1 reduced drug cytotoxicity. RAD001 strongly synergized with the novel allosteric Akt inhibitor MK-2206 in both cell lines and patient samples. Similar results were obtained with the combination CCI-779 plus GSK 690693. These findings point out that mTORC1 inhibitors, either as a single agent or in combination with Akt inhibitors, could represent a potential therapeutic innovative strategy in B-pre ALL.Leukemia advance online publication, 23 August 2013; doi:10.1038/leu.2013.226. 22560949 Missing, unreplaced teeth and risk of all-cause and cardiovascular mortality. A dentition of at least 20 teeth is associated with sufficient masticatory efficiency and is a stated health goal of the World Health Organisation. We examined whether subjects with missing, unreplaced teeth had an increased mortality risk. We used data prospectively collected from those participants in the population-based Study of Health in Pomerania who had fewer than 20 remaining teeth, resulting in a sample of 1803 participants with a median age of 64years. Of those, 188 subjects had 9 or more unreplaced teeth. During a median follow-up period of 9.9years, 362 subjects died, 128 of whom of cardiovascular causes. We found that having 9 or more unreplaced teeth was related to all-cause mortality (rate ratio 1.53, 95% CI: 1.11-2.10; adjusted for variables according to causal diagrams: remaining teeth, age, sex, education, income, marital status, partnership, and oral health behaviour) and cardiovascular mortality (rate ratio 1.94, 95% CI: 1.15-3.25). When adjusting not only for the variables according to causal diagrams but also for smoking, alcohol consumption, physical activity, obesity, hypertension, diabetes, and dyslipidemia, the rate ratio was 1.43 (95% CI: 1.05-1.96) for all-cause mortality and 1.88 (95% CI: 1.10-3.21) for cardiovascular mortality. A reduced, unrestored dentition is associated with increased mortality risk. Thus, clinicians and dietitians have a responsibility to consider individual chewing ability in nutritional recommendations. 23872237 Inflammation is an Independent Risk Factor for Colonic Neoplasia in Patients With Ulcerative Colitis: A Case-control Study. An association between inflammatory activity and colorectal neoplasia (CRN) has been documented in patients with ulcerative colitis (UC). However, previous studies did not address the duration of inflammation or the effects of therapy on risk for CRN. We investigated the effects of inflammation, therapies, and characteristics of patients with UC on their risk for CRN. We collected data from 141 patients with UC without CRN (controls) and 59 matched patients with UC who developed CRN (cases), comparing disease extent and duration and patients' ages. We used a new 6-point histologic inflammatory activity (HIA) scale to score biopsy fragments (n = 4449). Information on medications, smoking status, primary sclerosing cholangitis, and family history of CRN were collected from the University of Chicago Inflammatory Bowel Disease Endoscopy Database. Relationships between HIA, clinical features, and CRN were assessed by conditional logistic regression. Cases and controls were similar in numbers of procedures and biopsies, exposure to steroids or mesalamine, smoking status, and family history of CRN. They differed in proportion of men vs women, exposure to immune modulators, and primary sclerosing cholangitis prevalence. In univariate analysis, HIA was positively associated with CRN (odds ratio [OR], 2.56 per unit increase; P = .001), whereas immune modulators (including azathioprine, 6-mercaptopurine, and methotrexate) reduced the risk for CRN (OR, 0.35; P < .01). HIA was also associated with CRN in multivariate analysis (OR, 3.68; P = .001). In a case-control study, we associated increased inflammation with CRN in patients with UC. Use of immune modulators reduced the risk for CRN, indicating that these drugs have chemoprotective effects. On the basis of these data, we propose new stratified surveillance and treatment strategies to prevent and detect CRN in patients with UC. 23957947 Current Perspectives in the Use of Molecular Imaging To Target Surgical Treatments for Genitourinary Cancers. Molecular imaging (MI) entails the visualisation, characterisation, and measurement of biologic processes at the molecular and cellular levels in humans and other living systems. Translating this technology to interventions in real-time enables interventional MI/image-guided surgery, for example, by providing better detection of tumours and their dimensions. To summarise and critically analyse the available evidence on image-guided surgery for genitourinary (GU) oncologic diseases. A comprehensive literature review was performed using PubMed and the Thomson Reuters Web of Science. In the free-text protocol, the following terms were applied: molecular imaging, genitourinary oncologic surgery, surgical navigation, image-guided surgery, and augmented reality. Review articles, editorials, commentaries, and letters to the editor were included if deemed to contain relevant information. We selected 79 articles according to the search strategy based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis criteria and the IDEAL method. MI techniques included optical imaging and fluorescent techniques, the augmented reality (AR) navigation system, magnetic resonance imaging spectroscopy, positron emission tomography, and single-photon emission computed tomography. Experimental studies on the AR navigation system were restricted to the detection and therapy of adrenal and renal malignancies and in the relatively infrequent cases of prostate cancer, whereas fluorescence techniques and optical imaging presented a wide application of intraoperative GU oncologic surgery. In most cases, image-guided surgery was shown to improve the surgical resectability of tumours. Based on the evidence to date, image-guided surgery has promise in the near future for multiple GU malignancies. Further optimisation of targeted imaging agents, along with the integration of imaging modalities, is necessary to further enhance intraoperative GU oncologic surgery. 23560456 Tissue Factor Activity and ECM-Related Gene Expression in Human Aortic Endothelial Cells Grown on Electrospun Biohybrid Scaffolds. All blood vessels are lined with a quiescent endothelium, which aids in regulating regular blood flow and avoiding thrombus formation. Current attempts at replacing diseased blood vessels frequently fail due to the intrinsic thrombogenicity of the materials used as vascular grafts. In extending our previous work where we introduced a new candidate scaffolds for vascular grafts electrospun from a blend solution of PLGA, gelatin, and elastin (PGE), this study aimed to evaluate the potential of PGE scaffolds to support nonthrombogenic monolayers of primary isolates of human aortic endothelial cells (HAECs), as assessed by a combination of biochemical, molecular, and bioinformatics-based analyses. After 24 h of culture on 3-D fibrous PGE scaffolds, HAECs formed a confluent, nonthrombogenic, and physiologically competent monolayer, as assessed by tissue factor (TF) gene expression and protein activity assays. The levels of TF mRNA/protein activity in HAECs grown on PGE scaffolds were similar to those on gelatin or collagen IV-coated 2-D surfaces. In addition, bioinformatics-based analysis of a focused microarray containing 84 ECM-related cDNA probes demonstrated that HAECs essentially expressed a histotypic ECM-related "transcriptome" on PGE scaffolds, where cells were more quiescent than cells cultured on 2-D coverslips coated with gelatin (a well-known "inert" substrate for conventional EC culture), but less so than on 2-D PGE films. These data suggest an important role for nanorough substrates (PGE films) in passivating endothelial cells and confirm the crucial effect of substrate composition in this process. Principal component analysis of microarray data on the above substrates (including collagen IV) implied that substrate composition plays a greater role than surface topography in affecting the endothelial ECM-related "transcriptome". Taken together, our findings suggest that electrospun PGE scaffolds are potentially suitable for application in small diameter vascular tissue engineering. 23933044 Change-related auditory P50: A MEG study. Changes in continuous sounds elicit a preattentive component that peaks at around 100ms (Change-N1m) on electroencephalograms or magnetoencephalograms (MEG). Change-N1m is thought to reflect brain activity relating to the automatic detection of changes, which facilitate processes for the execution of appropriate behavior in response to new environmental events. The aim of the present MEG study was to elucidate whether a component relating to auditory changes existed earlier than N1m. Change-related cortical responses were evoked by abrupt sound movement in a train of clicks at 100Hz. Sound movement was created by inserting an interaural time delay (ITD) of 0.15, 0.25, 0.35, and 0.45ms into the right ear. Ten out of 12 participants exhibited clear change-related cortical responses earlier than Change-N1m at around 60ms (Change-P50m). The results of source analysis showed that Change-P50m originated from the superior temporal gyrus of both hemispheres and that its location did not differ significantly from dipoles for the response to the sound onset. The magnitude of Change-P50m increased and the peak latency shortened with an increase in the ITD, similar to those of Change-N1m. These results suggest that change-related cortical activity is present as early as its onset latency at around 50ms. 23603317 Neutralizing activity and protective immunity to ricin toxin conferred by B subunit (RTB)-specific Fab fragments. SylH3 and 24B11 are murine monoclonal antibodies directed against different epitopes on ricin toxin's binding (RTB) subunit that have been shown to passively protect mice against ricin challenge. Here we report that Fab fragments of SylH3 and 24B11 neutralize ricin in a cell based assay, and in a mouse challenge model as effectively as their respective full length parental IgGs. These data demonstrate that immunity to ricin can occur independent of Fc-mediated clearance. 23927043 Independent and joint associations of TV viewing time and snack food consumption with the metabolic syndrome and its components; a cross-sectional study in Australian adults. Television (TV) viewing time is positively associated with the metabolic syndrome (MetS) in adults. However, the mechanisms through which TV viewing time is associated with MetS risk remain unclear. There is evidence that the consumption of energy-dense, nutrient poor snack foods increases during TV viewing time among adults, suggesting that these behaviors may jointly contribute towards MetS risk. While the association between TV viewing time and the MetS has previously been shown to be independent of adult's overall dietary intake, the specific influence of snack food consumption on the relationship is yet to be investigated. The purpose of this study was to examine the independent and joint associations of daily TV viewing time and snack food consumption with the MetS and its components in a sample of Australian adults. Population-based, cross-sectional study of 3,110 women and 2,572 men (>35 years) without diabetes or cardiovascular disease. Participants were recruited between May 1999 and Dec 2000 in the six states and the Northern Territory of Australia. Participants were categorised according to self-reported TV viewing time (low: 0-2 hr/d; high: >2 hr/d) and/or consumption of snack foods (low: 0-3 serves/d; high: >3 serves/d). Multivariate odds ratios [95% CI] for the MetS and its components were estimated using gender-specific, forced entry logistic regression. OR [95%CI] for the MetS was 3.59 [2.25, 5.74] (<= 0.001) in women and 1.45 [1.02, 3.45] (p = 0.04) in men who jointly reported high TV viewing time and high snack food consumption. Obesity, insulin resistance and hypertension (women only) were also jointly associated with high TV viewing time and high snack food consumption. Further adjustment for diet quality and central adiposity maintained the associations in women. High snack food consumption was also shown to be independently associated with MetS risk [OR: 1.94 (95% CI: 1.45, 2.60), p < 0.001] and hypertension [OR: 1.43 (95% CI: 1.01, 2.02), p = 0.05] in women only. For both men and women, high TV viewing time was independently associated with the MetS and its individual components (except hypertension). TV viewing time and snack food consumption are independently and jointly associated with the MetS and its components, particularly in women. In addition to physical activity, population strategies targeting MetS prevention should address high TV time and excessive snack food intake. 23943735 Nasal and paranasal involvement in primary Sjogren`s syndrome. The aim of this study is to investigate nasal and paranasal signs and symptoms of the primary Sjogren`s syndrome patients and compare them with healthy controls. Seventy-seven (7 M, 70 F) primary Sjogren`s syndome patients and 77 healthy controls were included in the study. Anterior rhinoscopy, nasal endoscopy, 5 component smell discrimination test, nasal clearance analysis with saccharin test and electrorhinomanometer were performed. Nasal crusting was present in 31 and 24 individuals in patient and control groups, respectively. Sinusitis was present in 2 and 1 individuals in patient and control groups, respectively. Nasal polyposis was present in 7 and 1 individuals in patient and control groups, respectively. These differences were not statistically different. Although there were some findings in a few patients, nasal findings were insignificant and mild even in patients with severe oral or ocular findings. Rhinomanometry, nasal clearance determination or smell discrimination tests have very little value in the diagnosis or management of primary Sjogren`s syndrome. Nasal polyposis was higher in the patient group, though it did not reach a significant level. Nasal glandular involvement is mild and insignificant in primary Sjogren`s syndrome. 23888321 Association between glutathione S-transferases M1 and T1 gene polymorphisms and prostate cancer risk: a systematic review and meta-analysis. Genetic polymorphisms in glutathione S-transferases M1 (GSTM1) and T1 (GSTT1) genes have been widely reported and considered to have a significant effect on prostate cancer (PCa) risk, but the results are inconsistent. To evaluate the impact of the GSTM1 and GSTT1 polymorphism on PCa risk, we conducted a comprehensive meta-analysis based on 18 eligible studies. A total of 18 studies, including 7,119 subjects for GSTM1 and 6,454 subjects for GSTT1 between 1999 and 2012 were identified through researching MEDLINE, PubMed, Web of Science, EMBASE, Chinese National Knowledge Infrastructure database, and Chinese Biomedical Literature database. A meta-analysis was performed to obtain summary-estimated odd ratios and 95 % confidence intervals of GSTM1 and GSTT1 polymorphisms for PCa, with attention to study quality and publication bias. Overall, there is a significant association between GSTM1 (odds ratio (OR) = 1.407, 95 % confidence intervals (95 % CI) = 1.147-1.727, I (2) = 73.2 %, P = 0.001) genotypes and PCa susceptibility. Significant associations were also observed in subgroups of Caucasian populations (OR = 1.262, 95 % CI = 1.055-1.511, I (2) = 48.7 %, P = 0.011) and Asian populations (OR = 1.776, 95 % CI = 1.134-2.781, I (2) = 83.4 %, P = 0.012). However, no significant association was found (OR = 1.776, 95 % CI = 1.134-2.781, P = 0.243) in African-American populations when stratified by ethnicity. While, there was no significant association seen between GSTT1 (OR = 1.003, 95 % CI = 0.823-1.298, I (2) = 68.8 %, P = 0.778) genotypes and PCa risk. However, no significant associations were observed in subgroups of Caucasian populations (OR = 1.086, 95 % CI = 0.801-1.471, I (2) = 72.1 %, P = 0.597) and Asian populations (OR = 0.961, 95 % CI = 0.644-1.434, I (2) = 73.0 %, P = 0.846), and similar result was found among African-American populations (OR = 0.802, 95 % CI = 0.194-3.321, P = 0.761) when stratified by ethnicity. Our results suggest that the GSTM1 gene polymorphism contributes to PCa susceptibility, while GSTT1 gene polymorphism is not associated with PCa in our study. 23809968 Iodine deficiency in Danish pregnant women. Maternal iodine requirements increase during pregnancy. Studies performed before the introduction of mandatory iodine fortification of salt in Denmark in 2000 showed that pregnant women with no intake of iodine-containing supplements were moderately iodine-deficient and showed signs of thyroidal stress. We investigated the intake of iodine-containing supplements and urinary iodine excretion in Danish pregnant women after the introduction of iodine fortification of salt. We conducted a cross-sectional study between June and August 2012 in an area of Denmark where iodine deficiency had previously been moderate. Pregnant women coming to Aalborg University Hospital for obstetric ultrasound were recruited consecutively. Participants filled in a questionnaire and handed in a spot urine sample for measurement of iodine and creatinine. Among the pregnant women included (n = 245) 84.1% reported an intake of iodine-containing supplements, and compared with those not taking iodine supplements the median urinary iodine concentration was significantly higher in this group: 109 g/l (25th-75th percentile: 66-191 µg/l). On the other hand, the median urinary iodine concentration was considerably below the recommended level, even for the non-pregnant state in pregnant women with no iodine supplement intake: 68 µg/l (35-93 µg/l), p < 0.001. The majority of pregnant women took iodine-containing supplements, but the subgroup of non-users was still iodine-deficient after the introduction of iodine fortification of salt. Iodine supplement intake during pregnancy in Denmark should be officially recommended. The study was supported by a grant from Musikforlæggerne Agnes og Knut Mørks Fond and from Speciallæge Heinrich Kopps Legat. not relevant. 23832963 Does adding noradrenaline reuptake inhibition to selective serotonin reuptake inhibition improve efficacy in patients with depression? A systematic review of meta-analyses and large randomised pragmatic trials. Selective serotonin reuptake inhibitors (SSRIs) are recommended as first-line pharmacological treatment for depression and are the most commonly prescribed class of antidepressants. However, there is substantial evidence that noradrenaline has a role in the pathogenesis and treatment of depression. This review aims to examine the evidence of including noradrenaline reuptake inhibition with serotonin reuptake inhibition with respect to increasing efficacy in the treatment of depression. Evidence from meta-analysis of randomised controlled trials (RCTs) and randomised pragmatic trials was found in support of greater efficacy of the serotonin noradrenaline reuptake inhibitors (SNRIs), venlafaxine and duloxetine, in moderate to severe depression compared to SSRIs but no evidence was found for superiority of milnacipran. There is sufficient current evidence that demonstrates an increase in efficacy, when noradrenaline reuptake is added to serotonin (5-HT) reuptake, to suggest that patients with severe depression or those who have failed to reach remission with a SSRI may benefit from treatment with a SNRI. However, as these conclusions are drawn from the evidence derived from meta-analyses and pragmatic trials, large adequately powered RCTs using optimal dosing regimens and clinically relevant outcome measures in severe depression and SSRI treatment failures are still required to confirm these findings. 23893839 Comparative digestibility of energy and nutrients and fermentability of dietary fiber in eight cereal grains fed to pigs. Cereal grains provide a large portion of caloric intake in diets for humans, but not all cereal grains provide the same amount of energy. Therefore, an experiment was conducted to determine and compare the metabolizable energy (ME), the apparent ileal digestibility (AID), and the apparent total tract digestibility (ATTD) of gross energy (GE) and nutrients in eight cereal grains when fed to pigs. Rice had greater (P < 0.05) AID of GE than other cereal grains, greater (P < 0.05) AID of starch than yellow dent corn, dehulled barley, rye, and wheat, and greater (P < 0.05) ATTD of GE than yellow dent corn, rye, sorghum, and wheat. Dehulled barley, rye, and sorghum had less (P < 0.05) AID of starch than other cereal grains. Dehulled barley had greater (P < 0.05) ATTD of GE than rye. Dehulled oats had the greatest (P < 0.05) ME compared with other cereal grains, whereas rye had the least (P < 0.05) ME. Dehulled oats provide more energy to diets and should be used if the goal is to increase caloric intake. In contrast, sorghum and rye may be more suitable to control diabetes and manage body weight of humans. © 2013 Society of Chemical Industry. 22827850 Extra-facial melasma: clinical, histopathological, and immunohistochemical case-control study. Background  Extra-facial melasma is a prevalent dermatosis in some populations with special characteristics in relation to its clinical aspects and probable etiopathogenic factors. Few studies have attempted to address this alteration of pigmentation, which has become a challenge in clinical Dermatology. Objective  To assess the clinical histopathological and immunohistochemical characteristics of extra-facial melasma, comparing affected, and unaffected sites. Methods  Case-control study with 45 patients in each group (melasma and disease-free volunteers), assessing their clinical characteristics. In 36 patients, biopsies were performed on the lesion and the normal perilesional skin. Specimens were stained with HE and Fontana-Masson, and melanocytes analysed by immunohistochemistry. Objective measurements were accomplished by a specifically designed image analysis software. Results  The melasma group had a mean age ± SD of 56.67 ± 8 years, the majority of them were women (86.7%) and 82.1% of the female cases had reached menopause. There were no significant differences between groups in terms of presence of comorbidities, use of medications or hormone therapies. For extra-facial melasma patients, family history of this dermatose and of previous facial melasma was significantly higher than in the control group (P < 0.05). The HE staining showed increased rectification and basal hyperpigmentation, solar elastosis, and collagen degeneration in the pigmented area (P < 0.05). There was a significant increase in melanin density in melasma biopsies, but the immunohistochemical tests did not detect a difference between the groups in terms of number of melanocytes. Conclusion  Extra-facial melasma appears to be related to menopause, family history, and personal history of facial melasma, in the studied population. Histopathology revealed a pattern similar to what has been described for facial melasma, with signs of solar degeneration, and a similar number of melanocytes, when comparing patients, and controls, suggesting that the hyperpigmentation is most likely the result of abnormal melanin production or distribution. 23810972 White matter microstructure correlates of narrative production in typically developing children and children with high functioning autism. This study investigated the relationship between white matter microstructure and the development of morphosyntax in a spoken narrative in typically developing children (TD) and in children with high functioning autism (HFA). Autism is characterized by language and communication impairments, yet the relationship between morphosyntactic development in spontaneous discourse contexts and neural development is not well understood in either this population or typical development. Diffusion tensor imaging (DTI) was used to assess multiple parameters of diffusivity as indicators of white matter tract integrity in language-related tracts in children between 6 and 13 years of age. Children were asked to spontaneously tell a story about at time when someone made them sad, mad, or angry. The story was evaluated for morphological accuracy and syntactic complexity. Analysis of the relationship between white matter microstructure and language performance in TD children showed that diffusivity correlated with morphosyntax production in the superior longitudinal fasciculus (SLF), a fiber tract traditionally associated with language. At the anatomical level, the HFA group showed abnormal diffusivity in the right inferior longitudinal fasciculus (ILF) relative to the TD group. Within the HFA group, children with greater white matter integrity in the right ILF displayed greater morphological accuracy during their spoken narrative. Overall, the current study shows an association between white matter structure in a traditional language pathway and narrative performance in TD children. In the autism group, associations were only found in the ILF, suggesting that during real world language use, children with HFA rely less on typical pathways and more on alternative ventral pathways that possibly mediate visual elements of language. 23376121 Catalytic-site conformational equilibrium in nerve-agent adducts of acetylcholinesterase: Possible implications for the HI-6 antidote substrate specificity. Nerve agents such as tabun, cyclosarin and Russian VX inhibit the essential enzyme acetylcholinesterase (AChE) by organophosphorylating the catalytic serine residue. Nucleophiles, such as oximes, are used as antidotes as they can reactivate and restore the function of the inhibited enzyme. The oxime HI-6 shows a notably low activity on tabun adducts but can effectively reactivate adducts of cyclosarin and Russian VX. To examine the structural basis for the pronounced substrate specificity of HI-6, we determined the binary crystal structures of Mus musculus AChE (mAChE) conjugated by cyclosarin and Russian VX and found a conformational mobility of the side chains of Phe338 and His447. The interaction between HI-6 and tabun-adducts of AChE were subsequently investigated using a combination of time resolved fluorescence spectroscopy and X-ray crystallography. Our findings show that HI-6 binds to tabun inhibited Homo sapiens AChE (hAChE) with an IC50 value of 300μM and suggest that the reactive nucleophilic moiety of HI-6 is excluded from the phosphorus atom of tabun. We propose that a conformational mobility of the side-chains of Phe338 and His447 is a common feature in nerve-agent adducts of AChE. We also suggest that the conformational mobility allow HI-6 to reactivate conjugates of cyclosarin and Russian VX while a reduced mobility in tabun conjugated AChE results in steric hindrance that prevents efficient reactivation. 23815857 Crystal structure of the C-terminal globular domain of the third paralog of the Archaeoglobus fulgidus oligosaccharyltransferases. Protein N-glycosylation occurs in the three domains of life. Oligosaccharyltransferase (OST) transfers an oligosaccharide chain to the asparagine residue in the N-glycosylation sequons. The catalytic subunits of the OST enzyme are STT3 in eukaryotes, AglB in archaea and PglB in eubacteria. The genome of a hyperthermophilic archaeon, Archaeoglobus fulgidus, encodes three paralogous AglB proteins. We previously solved the crystal structures of the C-terminal globular domains of two paralogs, AglB-Short 1 and AglB-Short 2. We determined the crystal structure of the C-terminal globular domain of the third AglB paralog, AglB-Long, at 1.9 A resolutions. The crystallization of the fusion protein with maltose binding protein (MBP) afforded high quality protein crystals. Two MBP-AglB-L molecules formed a swapped dimer in the crystal. Since the fusion protein behaved as a monomer upon gel filtration, we reconstituted the monomer structure from the swapped dimer by exchanging the swapped segments. The C-terminal domain of A. fulgidus AglB-L includes a structural unit common to AglB-S1 and AglB-S2. This structural unit contains the evolutionally conserved WWDYG and DK motifs. The present structure revealed that A. fulgidus AglB-L contained a variant type of the DK motif with a short insertion, and confirmed that the second signature residue, Lys, of the DK motif participates in the formation of a pocket that binds to the serine and threonine residues at the +2 position of the N-glycosylation sequon. The structure of A. fulgidus AglB-L, together with the two previously solved structures of AglB-S1 and AglB-S2, provides a complete overview of the three AglB paralogs encoded in the A. fulgidus genome. All three AglBs contain a variant type of the DK motif. This finding supports a previously proposed rule: The STT3/AglB/PglB paralogs in one organism always contain the same type of Ser/Thr-binding pocket. The present structure will be useful as a search model for molecular replacement in the structural determination of the full-length A. fulgidus AglB-L. 23801759 Structure of the C-terminal region of an ERG channel and functional implications. The human ether-à-go-go-related gene (hERG) encodes a K(+) channel crucial for repolarization of the cardiac action potential. EAG-related gene (ERG) channels contain a C-terminal cyclic nucleotide-binding homology domain coupled to the pore of the channel by a C-linker. Here, we report the structure of the C-linker/cyclic nucleotide-binding homology domain of a mosquito ERG channel at 2.5-Å resolution. The structure reveals that the region expected to form the cyclic nucleotide-binding pocket is negatively charged and is occupied by a short β-strand, referred to as the intrinsic ligand, explaining the lack of direct regulation of ERG channels by cyclic nucleotides. In hERG channels, the intrinsic ligand harbors hereditary mutations associated with long-QT syndrome (LQTS), a potentially lethal cardiac arrhythmia. Mutations in the intrinsic ligand affected hERG channel gating and LQTS mutations abolished hERG currents and altered trafficking of hERG channels, which explains the LQT phenotype. The structure also reveals a dramatically different conformation of the C-linker compared with the structures of the related ether-à-go-go-like K(+) and hyperpolarization-activated cyclic nucleotide-modulated channels, suggesting that the C-linker region may be highly dynamic in the KCNH, hyperpolarization-activated cyclic nucleotide-modulated, and cyclic nucleotide-gated channels. 23842997 Late-stage diagnosis of HIV infection in Brazilian children: evidence from two national cohort studies. This study analyzed data from two consecutive retrospective cohort samples (1983 to 1998 and 1999 to 2002) of Brazilian children with AIDS (N = 1,758) through mother-to-child-transmission. Late-stage diagnosis (CDC category C) was investigated in relation to the following variables: year of birth, year of HIV diagnosis, and time periods related to changes in government treatment guidelines. Late-stage diagnosis occurred in 731 (41.6%) of cases and was more prevalent in infants under 12 months of age. The rate of late-stage diagnosis decreased from 48% to 36% between the two periods studied. We also observed a reduction in the proportion of late-stage diagnoses and the time lapse between HIV diagnosis and ART initiation. A significant association was found between timely diagnosis and having been born in recent years (OR = 0.62; p = 0.009) and year of HIV diagnosis (OR = 0.72; p = 0.002/OR = 0.62; p < 0.001). Infants under the age of 12 months were more likely to be diagnosed at a late stage than older children (OR = 1.70; p = 0.004). Despite advances, there is a need to improve the effectiveness of policies and programs focused on improving early diagnosis and management of HIV/AIDS. 23917402 Role of microRNA-mediated MMP regulation in the treatment and diagnosis of malignant tumors. Matrix metalloproteinases (MMPs) play important roles in tumor cell proliferation and apoptosis and contribute to tumor growth, angiogenesis, migration, and invasion primarily via extracellular matrix (ECM) degradation and/or the activation of pre-pro-growth factors. Recently, there has been considerable interest in the posttranscriptional regulation of MMPs via microRNAs (miRs). In this review, we highlight the complicated interactive network comprised of different MMPs and their regulating microRNAs, as well as the ways in which these interactions influence cancer development, including tumor angiogenesis, growth, invasion, and metastasis. Based on the conclusive roles that microRNAs play in the regulation of MMPs during cancer progression, we discuss the potential use of microRNA-mediated MMP regulation in the diagnosis and treatment of tumors from the clinical perspective. In particular, microRNA-mediated MMP regulation may lead to the development of promising new MMP inhibitors that target MMPs more selectively, and this approach may also target multiple molecules in a network, leading to the efficient regulation of distinct biological processes relevant to malignant tumors. A thorough understanding of the mechanisms underlying microRNA-mediated MMP regulation during tumor progression will help to provide new insights into the diagnosis and treatment of malignant tumors. 23210849 Cantharidin as an antitumor agent: a retrospective review. This review summarizes the progress that has been made recently in the medicinal chemistry of cantharidin, a potent antitumor agent from traditional Chinese medicine. Thousands of analogs have been synthesized on the basis of cantharidin, a part of which shows excellent properties, in particular, norcantharidin and norcantharimide. Despite the enormous efforts made, the intriguing bioactivities, mechanism, indications, and their interplay are still ill-defined. This review provides our up-to-date understanding in connection with the therapeutic use, mechanism, structure-activity relationship (SAR) and interesting properties of cantharidin analogs. Considerable development in the design of cantharidin analogs, in combination with mechanistic studies, has laid a foundation for transforming novel antitumor drugs into the clinic. 23683535 The optimal duration of vitamin supplementation prior to the first dose of pemetrexed in patients with non-small-cell lung cancer. Although folic acid and vitamin B12 supplements are recommended during pemetrexed therapy, the optimal duration for supplementation prior to the first dose of pemetrexed has not been defined. We analyzed adverse events during the first cycle of pemetrexed therapy in 350 patients with advanced non-small-cell lung cancer (NSCLC) who had received pemetrexed monotherapy. Patients were divided into two groups: group A and group B included patients who started vitamin supplements 5-14 days versus within 4 days before the first dose of pemetrexed, respectively. Groups A and B included 294 (84.0%) and 56 (16.0%) patients, respectively. The median number of cycles of pemetrexed was three in both groups. Patients in group A and B showed similar rates of leukopenia (6.1% vs. 5.4%, respectively, P = 1.00), neutropenia (5.1% vs. 3.6%, P = 1.00), thrombocytopenia (3.1% vs. 7.1%, P = 0.14), neutropenic fever (0.7% vs. 0%, P = 1.00), fatigue (20.1% vs. 19.6%, P = 0.94), and anorexia (15.0% vs. 21.4%, P = 0.23) during the first cycle of pemetrexed therapy. There were no significant differences in terms of hospitalization (4.4% vs. 5.4%, P = 0.73) or unscheduled visits due to pemetrexed-related adverse events (8.2% vs. 12.5%, P = 0.31) between groups A and B, respectively. Multivariate logistic regression analysis demonstrated that an age of ≥ 65 years (odds ratio, 3.49; 95% CI 1.12-10.86) and poor performance status (odds ratio, 3.96; 95% CI 1.12-14.03) were statistically significant predictive factors for grade 3 or 4 hematologic toxicity. The duration of vitamin supplementation before the first dose of pemetrexed did not affect the development of pemetrexed-related toxicities, suggesting that the initiation of pemetrexed-based chemotherapy does not have to be delayed to accommodate a vitamin supplementation schedule. 23911205 Neonatal modulation of serum cytokine profiles by a specific mixture of anti-inflammatory neutral and acidic oligosaccharides in preterm infants. Infections are common in preterm infants and cause differences in cytokine levels. Aim of this study was to measure cytokine levels in preterm infants during the first year of life and to determine the effect of feeding a specific non-digestible carbohydrate mixture (scGOS/lcFOS/pAOS). Furthermore, other perinatal factors in relation to these cytokine levels were analysed. In a randomized controlled trial, preterm infants (GA <32weeks and/or birth weight <1500g) received a scGOS/lcFOS/pAOS mixture or a placebo (maltodextrin) between days 3 and 30 of life. Cytokine levels (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17, IFN-γ, and TNF-α) were analysed at 5 time points during the study: before start of the study, at day 7, at day 14 and at 5 and 12months after the start of the intervention. In total, 55 preterm infants in the scGOS/lcFOS/pAOS group and 58 in the placebo group were included. During the neonatal period cytokine levels increased, followed by a decrease at 5months and 12months. Enteral supplementation of the non-digestible oligosaccharides decreased cytokine levels at day 7 but not at day 14, indicating a temporarily anti-inflammatory effect. In the neonatal period, serious infection before sampling increased all cytokine levels. In conclusion, enteral supplementation of this specific non-digestible oligosaccharide mixture decreased cytokine levels in preterm infants at day 7 of life, although this effect disappeared thereafter. 23861074 Hippocampal expression of aryl hydrocarbon receptor nuclear translocator 2 and neuronal PAS domain protein 4 in a rat model of depression. The transcription factors aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) and neuronal PAS domain protein 4 (NPAS4) may influence emotion and cognitive function by regulating brain-derived neurotrophic factor expression in the hippocampus. We estimated hippocampal ARNT2 and NPAS4 expression in chronic unexpected mild stress (CUMS) rat model. The possible association was investigated between expression of these transcription factors and depressive behaviors. Behavioral tests were conducted before, during, and after 28 days of group housing or isolation plus CUMS. The sucrose solution consumption test was used to assess changes in interest and pleasure-seeking, and the open field test (OFT) was conducted to measure spontaneous activity and exploratory behavior. Expression levels of ARNT2 and NPAS4 were estimated by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Compared to controls, rats subjected to isolation plus CUMS exhibited significantly reduced weight gain (t = 9.317, P = 0.000), sucrose consumption (t = 3.756, P = 0.003), horizontal ambulation (t = 2.362, P = 0.041), and number of rearings (vertical motion) (t = 2.268, P = 0.040). Relative hippocampal NPAS4 expression was significantly lower in depression model rats compared to controls (t = 2.995, P = 0.010) but there was no significant difference in hippocampal ARNT2 expression between groups (t = 0.091, P = 0.929). The relationship between the CUMS model of depression and NPAS4 expression requires further exploration. 23891008 Newly Developed Central Diabetes Insipidus Following Kidney Transplantation: A Case Report. Polyuria after kidney transplantation is a common, usually self-limiting disorder. However, persistent polyuria can cause not only patient discomfort, including polyuria and polydipsia, but also volume depletion that can produce allograft dysfunction. Herein, we have report a case of central diabetes insipidus newly diagnosed after kidney transplantation. A 45-year-old woman with end-stage kidney disease underwent deceased donor kidney transplantation. Two months after the transplantation, she was admitted for persistent polyuria, polydipsia, and nocturia with urine output of more than 4 L/d. Urine osmolarity was 100 mOsm/kg, which implied that the polyuria was due to water rather than solute diuresis. A water deprivation test was compatible with central diabetes insipidus; desmopressin treatment resulted in immediate symptomatic relief. Brain magnetic resonance imaging (MRI) demonstrated diffuse thickening of the pituitary stalk, which was considered to be nonspecific finding. MRI 12 months later showed no change in the pituitary stalk, although the patient has been in good health without polyuria or polydipsia on desmopressin treatment. The possibility of central diabetes insipidus should be considered in patients presenting with persistent polyuria after kidney transplantation. 23317016 Relation of excess body weight and survival in patients with esophageal adenocarcinoma: a meta-analysis. Excess body weight (body mass index >25 kg/m(2) ) is common in patients with esophageal adenocarcinoma. In this study, a meta-analysis was performed by searching PubMed, Cochrane Library, EMBASE, and Science Direct databases from 1960 to June 2012. Data were extracted from studies comparing survival in obese (body mass index >30), overweight (body mass index 25-29), and normal-weight (body mass index 20-24) patients undergoing esophagectomy. A total of six studies with 1988 cases were suitable for this global meta-analysis. Compared with patients of normal weight, the hazard ratio of postoperational survival for overweight and obese patients was 0.79 (95% confidence interval 0.65-0.95, P = 0.108) and 0.80 (95% confidence interval 0.68-0.93, P = 1.00), respectably. Taken together, the excess body weight did not have the value of predicting survival for patients with esophageal adenocarcinoma. 23810135 A scientometrics approach to schizophrenia research in India: an analysis of publications output during 2002-11. This study analyses the research output of India in schizophrenia research during 2002-11 on several parameters including the growth, rank and global publications share, citation impact, share of international collaborative papers, contribution of major collaborative partner countries, contribution of various subject-fields, contribution and impact of most productive institutions and authors, media of communication and characteristics of high cited papers. The Scopus Citation Database has been used to retrieve the data for 10 years (2002-11) by searching the keywords schizophrenia research in the combined Title, Abstract and Keywords fields. Among the top 20 most productive countries in schizophrenia research, India ranks at 15th position (with 882 papers) with a global publication share of 1.58% and an annual average publication growth rate of 21.80% during 2002-11. Its citation impact per paper was 3.60 international collaborative publications share was 26.98% during 2002-11. Concludes that India needs to increase both the quantity and quality of research and also increase the international collaborative research, besides strengthening and modernizing its research infrastructure. There is need to treat schizophrenia as a priority area in the current and future national S & T plans of India. 23477570 In situ forming reduction-sensitive degradable nanogels for facile loading and triggered intracellular release of proteins. In situ forming reduction-sensitive degradable nanogels were designed and developed based on poly(ethylene glycol)-b-poly(2-(hydroxyethyl) methacrylate-co-acryloyl carbonate) (PEG-P(HEMA-co-AC)) block copolymers for efficient loading as well as triggered intracellular release of proteins. PEG-P(HEMA-co-AC) copolymers were prepared with controlled Mn of 9.1, 9.5, and 9.9 kg/mol and varying numbers of AC units per molecule of 7, 9 and 11, respectively (denoted as copolymer 1, 2, and 3) by reversible addition-fragmentation chain transfer copolymerization. These copolymers were freely soluble in phosphate buffer but formed disulfide-cross-linked nanogels with defined sizes ranging from 72.5 to 124.1 nm in the presence of cystamine via ring-opening reaction with cyclic carbonate groups. The sizes of nanogels decreased with increasing AC units as a result of increased cross-linking density. Dynamic light scattering studies showed that these nanogels though stable at physiological conditions were rapidly dissociated in response to 10 mM dithiothreitol (DTT). Interestingly, FITC-labeled cytochrome C (FITC-CC) could be readily loaded into nanogels with remarkable loading efficiencies (up to 98.2%) and loading contents (up to 48.2 wt.%). The in vitro release studies showed that release of FITC-CC was minimal under physiological conditions but significantly enhanced under reductive conditions in the presence of 10 mM DTT with about 96.8% of FITC-CC released in 22 h from nanogel 1. In contrast, protein release from 1,4-butanediamine cross-linked nanogels (reduction-insensitive control) remained low under otherwise the same conditions. MTT assays showed that these nanogels were nontoxic to HeLa cells up to a tested concentration of 2 mg/mL. Confocal microscopy results showed that nanogel 1 delivered and released FITC-CC into the perinuclei region of HeLa cells following 8 h incubation. CC-loaded reductively degradable nanogels demonstrated apparently better apoptotic activity than free CC as well as reduction-insensitive controls. These in situ forming, surfactant and oil-free, and reduction-sensitive degradable nanogels are highly promising for targeted protein therapy. 23937598 A human alcohol self-administration paradigm to model individual differences in impaired control over alcohol use. We developed an alcohol self-administration paradigm to model individual differences in impaired control. The paradigm includes moderate drinking guidelines meant to model limits on alcohol consumption, which are typically exceeded by people with impaired control. Possible payment reductions provided a disincentive for excessive drinking. Alcohol use above the guideline, despite possible pay reductions, was considered to be indicative of impaired control. Heavy-drinking 21- to 25-year-olds (n = 39) were randomized to an experimental condition including the elements of the impaired control paradigm or to a free-drinking condition without these elements. Alcohol self-administration was compared between these two conditions to establish the internal validity of the experimental paradigm. In both conditions, participants self-administered beer and nonalcoholic beverages for 3 hours in a bar setting with 1-3 other participants. Experimental condition participants self-administered significantly fewer beers and drank to lower blood-alcohol concentrations (BACs) on average than those in the free-drinking condition. Experimental condition participants were more likely than free-drinking condition participants to intersperse nonalcoholic beverages with beer and to drink at a slower pace. Although experimental condition participants drank more moderately than those in the free-drinking condition overall, their range of drinking was considerable (BAC range = .024-.097), with several participants drinking excessively. A lower initial subjective response to alcohol and earlier age of alcohol use onset were associated with greater alcohol self-administration in the experimental condition. Given the variability in response, the impaired control laboratory paradigm may have utility for preliminary tests of novel interventions in future studies and for identifying individual differences in problem-drinking risk. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23906847 Can carotenoids attenuate vascular aging? One of the main manifestations of vascular aging is the development of atherosclerotic lesions. These lesions become unstable and prone to rupture due to the formation of reactive oxygen species (ROS) that are produced by the inflammatory milieu in the atherosclerotic plaque. The carotenoids are a group of red, orange, or yellow pigmented polyisoprenoid hydrocarbons synthesized by prokaryotes and higher plants. Lycopene, lutein, and other carotenoids have anti-oxidant activity that attenuates the inflammatory atherosclerotic process and delays vascular aging. This ability improves endothelial function due to the increase in bioavailability of NO. Carotenoid consumption also improves the metabolic profile, decreasing the incidence of diabetes, lowering LDL levels, and improving blood pressure control. The beneficial metabolic effect is translated to improvement in atherosclerosis, which is characterized by a decrease in carotid intima-media thickness. The favorable anti-atherosclerotic effect of carotenoids was also demonstrated in cross-sectional population studies showing a positive correlation between low carotenoid levels and adverse cardiovascular outcome. However, carotenoid utilization failed to decrease major cardiovascular and cerebrovascular events in randomized control double blind trials. The main still unanswered question is: What is the therapeutic role of carotenoids in atherosclerotic disease? Is their anti-atherosclerotic effect restricted to primary prevention or can it alter the prognosis of existing cardiovascular and cerebrovascular diseases? 23859800 Physiology of incretins and loss of incretin effect in type 2 diabetes and obesity. Abstract An important role in the regulation of glucose homeostasis is played by incretins, which are gut-derived hormones released in response to nutrient ingestion. In humans, the major incretin hormones are glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), and together they fully account for the incretin effect (that is, higher insulin release in response to an oral glucose challenge compared to an equal intravenous glucose load). Studies have shown that GLP-1 and GIP levels and actions may be perturbed in disease states, and the loss of incretin effect is likely to contribute importantly to the postprandial hyperglycaemia in type 2 diabetes. However, the specific cause-effect relationship between disease and incretins is still unclear. This review focuses on several key studies elucidating the association of defective incretin action with obesity and T2DM and the effects of metformin and other anti-diabetic agents on the incretin system. 23947912 High-Resolution MS, MS/MS, and UV Database of Fungal Secondary Metabolites as a Dereplication Protocol for Bioactive Natural Products. A major problem in the discovery of new biologically active compounds from natural products is the reisolation of known compounds. Such reisolations waste time and resources, distracting chemists from more promising leads. To address this problem, dereplication strategies are needed that enable crude extracts to be screened for the presence of known compounds before isolation efforts are initiated. In a project to identify anticancer drug leads from filamentous fungi, a significant dereplication challenge arises, as the taxonomy of the source materials is rarely known, and, thus, the literature cannot be probed to identify likely known compounds. An ultraperformance liquid chromatography-photodiode array-high-resolution tandem mass spectrometric (UPLC-PDA-HRMS-MS/MS) method was developed for dereplication of fungal secondary metabolites in crude culture extracts. A database was constructed by recording HRMS and MS/MS spectra of fungal metabolites, utilizing both positive- and negative-ionization modes. Additional details, such as UV-absorption maxima and retention times, were also recorded. Small-scale cultures that showed cytotoxic activities were dereplicated before engaging in the scale-up or purification processes. Using these methods, approximately 50% of the cytotoxic extracts could be eliminated from further study after the confident identification of known compounds. The specific attributes of this dereplication methodology include a focus on bioactive secondary metabolites from fungi, the use of a 10 min chromatographic method, and the inclusion of both HRMS and MS/MS data. 23886582 Prediction and Stability of Reading Problems in Middle Childhood. The longitudinal prediction of reading problems from fourth grade to sixth grade was investigated with a sample of 173 students. Reading problems at the end of sixth grade were defined by significantly below average performance (≤ 15th percentile) on reading factors defining word reading, fluency, and reading comprehension. Sixth grade poor reader status was predicted by fall of fourth grade passage reading fluency, spelling fluency, and the number of reading problems identified by teachers. Reading fluency and spelling fluency were significant predictors in logistic regression equation that combined to yield a screening battery with an area under the curve of .91. These results suggest that brief assessments of reading and spelling fluency in fourth grade may be able to identify students in middle childhood who have a reading problem or who are at risk for experiencing reading problems in sixth grade. 23727572 Sex hormonal modulation of interhemispheric transfer time. It is still a matter of debate whether functional cerebral asymmetries (FCA) of many cognitive processes are more pronounced in men than in women. Some evidence suggests that the apparent reduction in women's FCA is a result of the fluctuating levels of gonadal steroid hormones over the course of the menstrual cycle, making their FCA less static than for men. The degree of lateralization has been suggested to depend on interhemispheric communication that may be modulated by gonadal steroid hormones. Here, we employed visual-evoked EEG potentials to obtain a direct measure of interhemispheric communication during different phases of the menstrual cycle. The interhemispheric transfer time (IHTT) was estimated from the interhemispheric latency difference of the N170 component of the visual-evoked potential from either left or right visual field presentation. Nineteen right-handed women with regular menstrual cycles were tested twice, once during the menstrual phase, when progesterone and estradiol levels are low, and once during the luteal phase when progesterone and estradiol levels are high. Plasma steroid levels were determined by blood-based immunoassay at each session. It was found that IHTT, in particular from right-to-left, was generally longer during the luteal phase relative to the menstrual phase. This effect occurred as a consequence of a slowed absolute N170 latency of the indirect pathway (i.e. left hemispheric response after LVF stimulation) and, in particular, a shortened latency of the direct pathway (i.e. right hemispheric response after LVF stimulation) during the luteal phase. These results show that cycle-related effects are not restricted to modulation of processes between hemispheres but also apply to cortical interactions, especially within the right hemisphere. The findings support the view that plastic changes in the female brain occur during relatively short-term periods across the menstrual cycle. 23521495 Controlled Assembly of Gold Nanoparticles through Antibody Recognition: Study and Utilizing the Effect of Particle Size on Interparticle Distance. An assembly of gold nanoparticle through the recognition of unmodified antibody was developed. The use of peptide (Cys-Ala-Leu-Asn-Asn) as ligands to stabilize and functionalize gold nanoparticles provides technical and operational convenience. These peptide-capped particles in different sizes are recognized by antibody and assembly to form dimers and expanded hybrid material by controlling the conditions. The interparticle spacing of these assemblies was well studied with small-angle X-ray scattering measurements, and it was found that the interparticle spacing is inversely dependent on the particle size. This relationship of interparticle spacing and particle size is closely related to the structure of antibody linker. Therefore, analyzing the interparticle spacing of assemblies can reveal the equilibrium configuration of IgG. Based on the investigation, the Fab-Fab angle of IgG is obtained to be ≈102° and the Fab arms are ≈7.8 nm. These results provide new experimental data on the structure of flexible IgG. 23878214 Universal collapse of stress and wrinkle-to-scar transition in spherically confined crystalline sheets. Imposing curvature on crystalline sheets, such as 2D packings of colloids or proteins, or covalently bonded graphene leads to distinct types of structural instabilities. The first type involves the proliferation of localized defects that disrupt the crystalline order without affecting the imposed shape, whereas the second type consists of elastic modes, such as wrinkles and crumples, which deform the shape and also are common in amorphous polymer sheets. Here, we propose a profound link between these types of patterns, encapsulated in a universal, compression-free stress field, which is determined solely by the macroscale confining conditions. This "stress universality" principle and a few of its immediate consequences are borne out by studying a circular crystalline patch bound to a deformable spherical substrate, in which the two distinct patterns become, respectively, radial chains of dislocations (called "scars") and radial wrinkles. The simplicity of this set-up allows us to characterize the morphologies and evaluate the energies of both patterns, from which we construct a phase diagram that predicts a wrinkle-scar transition in confined crystalline sheets at a critical value of the substrate stiffness. The construction of a unified theoretical framework that bridges inelastic crystalline defects and elastic deformations opens unique research directions. Beyond the potential use of this concept for finding energy-optimizing packings in curved topographies, the possibility of transforming defects into shape deformations that retain the crystalline structure may be valuable for a broad range of material applications, such as manipulations of graphene's electronic structure. 22776507 Nicotine improves performance in an attentional set shifting task in rats. A large number of studies in both humans and experimental animals have demonstrated nicotine-induced improvements in various aspects of cognitive function, including attention and memory. The prefrontal cortex (PFC) is thought to be critically involved in the modulation of executive function and these attentional processes are enhanced by nicotine acting at nicotinic acetylcholine receptors. The involvement of nicotinic processes on cognitive flexibility in particular has not been specifically investigated. The effects of nicotine on attentional flexibility were therefore evaluated using the rodent attentional set shifting task in rats. Nicotine injected both acutely and following repeated pre-exposure significantly improved both intradimensional and extradimensional set shifting performance in the task. Further investigation of the acute effects of nicotine demonstrated this improvement in attentional flexibility to be dose-dependent. These results implicate the nicotinic receptor system in the mediation of processes underlying cognitive flexibility and suggest that nicotine improves attentional flexibility in rats, both within and between perceptual dimensions of a compound stimulus. Nicotine-induced alterations in prefrontal circuitry may underlie these effects on cognitive flexibility. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23965106 Regulation moves a step closer. In her independent review of healthcare assistants (HCAs) and support workers, Times journalist Camilla Cavendish examined the issues of recruitment, training, supervision, support and public confidence. But she was instructed to exclude the contentious issue of regulation. 23916785 Arg kinase signaling in dendrite and synapse stabilization pathways: Memory, cocaine sensitivity, and stress. The Abl2/Arg nonreceptor tyrosine kinase is enriched in dendritic spines where it is essential for maintaining dendrite and synapse stability in the postnatal mouse brain. Arg is activated downstream of integrin α3β1 receptors and it regulates the neuronal actin cytoskeleton both by directly binding F-actin and via phosphorylation of substrates including p190RhoGAP and cortactin. Neurons in mice lacking Arg or integrin α3β1 develop normally through postnatal day 21 (P21), however by P42 mice exhibit major reductions in dendrite arbor size and complexity, and lose dendritic spines and synapses. As a result, mice with loss of Arg and Arg-dependent signaling pathways have impairments in memory tasks, heightened sensitivity to cocaine, and vulnerability to corticosteroid-induced neuronal remodeling. Therefore, understanding the molecular mechanisms of Arg regulation may lead to therapeutic approaches to treat human psychiatric and neurodegenerative diseases in which neuronal structure is destabilized. 23819876 T-Shaped Donor-Acceptor Molecules for Low-Loss Red-Emission Optical Waveguide. A series of T-shaped polycyclic molecules with high fluorescence were developed as optical waveguide materials. Their emissions covered almost the whole visible range from 450 to 800 nm. Compound 3-1 showed an optical loss coefficient about 0.29 dB/μm in red-emission waveguide. Our investigations demonstrated that these molecules held great potential for organic optical waveguide due to the high fluorescence quantum efficiency and large Stokes' shift. 21917488 Should the presence of a culture positive urinary tract infection exclude patients from rapid evaluation hematuria protocols? Current rapid evaluation protocols for patients with hematuria tend to exclude those with urinary tract infection since this is assumed to be evidence of a benign treatable cause. The likelihood of a urinary tract cancer in such patients is, however, uncertain, and we have therefore analyzed a prospective hematuria clinic database to determine risk. A total of 1,740 patients were enrolled prospectively in this study at our unit's one stop fast track hematuria clinic between April 2003 and March 2006. Evaluation of patients consisted of basic demographics, history and examination, urinalysis, urine culture, urine cytology, and serum creatinine. All patients then underwent a renal ultrasound, intravenous urogram, and cystoscopy. A total of 1,067 males and 673 females with a mean (range) age of 60.8 (16-96) years were included in the study. One hundred sixty-one patients had a positive mid-stream urine (MSU) on a specimen collected at the hematuria clinic. Amongst this group 20% (32) patients had a urologic malignancy diagnosed, of whom 12% (4) had metastatic disease at presentation. Only 1% (3) of patients had a urologic malignancy with a previous history of a treated urinary tract infection (UTI) and negative MSU at the clinic. The risk of urologic malignancy was 24% (303) in the remaining 1,249 patients with no history of a UTI prior to presentation and a negative MSU on a specimen collected at the one stop fast track hematuria clinic. Despite selection bias inherent in this analysis, it appears that the presence of UTI does not decrease the likelihood of having a urologic malignancy diagnosed. Hence, there is no indication to delay prompt evaluation in patients with hematuria and a positive urine culture collected at the hematuria clinic. 23895689 A functional scaffold in Marine Alkaloid: An anticancer moiety for human. Marine organisms have been developed as a new source of naturally occurring alkaloids. The bioactive scaffolds of marine alkaloids govern the cross-kingdom actions, possessing "unexpectedly" cytotoxic-related antitumor activities against human cancer cell lines. And the actions of marine alkaloids toward mammalian cells have been well substantiated by the recognition of their analogues as antitumor and enzyme modulatory agents. Different moieties of alkaloids target different cellular pathways. Structure-activity studies and docking analysis of marine alkaloids analogs attached importance to certain privileged moieties, and illustrated the mechanism of alkaloids' functionalization in mammals. The fascinating observations prompted us to review five kinds of alkaloid-like moieties including thiazole, pyrroloquinon, oxazole, pyridine and indole, and illuminate suggestively their various roles in common cellular processes of human beings. Meanwhile, an hypothesis was made correlatively to explain the different mechanisms of their anticancer activities in human cell lines. 23945463 Prevalence of cardiovascular risk factors among Latin American adolescents: a multilevel analysis. High blood pressure (HBP) and obesity is a well-established major risk factor for stroke and coronary heart disease. However, the literatures are scarce about these informations in adolescents from low-and-middle income countries. This school-based survey was carried out among students from Maringá (Brazil) and Buenos Aires (Argentina) selected random sampling. We studied 991 Brazilian adolescents (54.5% girls) in the age range of 14-18 years. In Argentina, we studied 933 adolescents (45.9% female) in the age range of 11-17 years. The outcomes of this study are general obesity, abdominal obesity and HBP. The associated factors analysed were gender, age and health behaviours. The prevalence of obesity was 5.8% in Brazil and 2.8% in Argentina, the prevalence of abdominal obesity was 32.7% in Brazil and 11.1% in Argentina, the prevalence of HBP was 14.9% in Brazil and 13.5% in Argentina. The multilevel analysis showed that older adolescents (>14 years old) have a little likelihood of being overweight, whereas male adolescents are more likely to be obese and have HBP. The abdominal obesity in both indicators were not associated with the independent variables. The prevalence of cardiovascular risk factors is high in Latin American adolescents independent of each country, and was associated with male gender.Journal of Human Hypertension advance online publication, 15 August 2013; doi:10.1038/jhh.2013.74. 23410129 Recurrent rearrangements in prostate cancer: causes and therapeutic potential. DNA damage and genetic rearrangements are hallmarks of cancer. However, gene fusions as driver mutations in cancer have classically been a distinction in leukemia and other rare instances until recently with the discovery of gene fusion events occurring in 50 to 75% of prostate cancer patients. The discovery of the TMPRSS2-ERG fusion sparked an onslaught of discovery and innovation resulting in a delineation of prostate cancer via a molecular signature of gene fusion events. The increased commonality of high-throughput sequencing data coupled with improved bioinformatics approaches not only elucidated the molecular underpinnings of prostate cancer progression, but the mechanisms of gene fusion biogenesis. Interestingly, the androgen receptor (AR), already known to play a significant role in prostate cancer tumorigenesis, has recently been implicated in the processes resulting in gene fusions by inducing the spatial proximity of genes involved in rearrangements, promoting the formation of double-strand DNA breaks (DSB), and facilitating the recruitment of proteins for non-homologous end-joining (NHEJ). Our increased understanding of the mechanisms inducing genomic instability may lead to improved diagnostic and therapeutic strategies. To date, the majority of prostate cancer patients can be molecularly stratified based on their gene fusion status thereby increasing the potential for tailoring more specific and effective therapies. 23756745 Intracranial aneurysms occur more frequently at bifurcation sites that typically experience higher hemodynamic stresses. Intracranial aneurysms (IAs) occur more frequently at certain bifurcations than at others. Hemodynamic stress, which promotes aneurysm formation in animal models, also differs among bifurcations, depending on flow and vessel geometry. To determine whether locations that are more likely to develop IAs experience different hemodynamic stresses that might contribute to higher IA susceptibility. We characterized the hemodynamic microenvironment at 10 sites in or around the circle of Willis where IAs commonly occur and examined statistical relationships between hemodynamic factors and the tendency for a site to form IAs. The tendency for each site to develop IAs was quantified on the basis of the site distribution from systematic literature analysis of 19 reports including 26 418 aneurysms. Hemodynamic parameters for these sites were derived from image-based computational fluid dynamics of 114 cerebral bifurcations from 31 individuals. Wall shear stress and its spatial gradient were calculated in the impact zone surrounding the bifurcation apex. Linear and exponential regression analyses evaluated correlations between the tendency for IA formation and the typical hemodynamics of a site. IA susceptibility significantly correlated with the magnitudes of wall shear stress and positive wall shear stress gradient within the hemodynamic impact zone calculated for each site. IAs occur more frequently at cerebral bifurcations that typically experience higher hemodynamic shear stress and stronger flow acceleration, conditions previously shown to promote aneurysm initiation in animals. CFD, computational fluid dynamicsIA, intracranial aneurysmMCA, middle cerebral arteryWSS, wall shear stressWSSG, wall shear stress gradient. 23288712 Materials for the active layer of organic photovoltaics: ternary solar cell approach. Power conversion efficiencies in excess of 7% have been achieved with bulk heterojunction (BHJ)-type organic solar cells using two components: p- and n-doped materials. The energy level and absorption profile of the active layer can be tuned by introduction of an additional component. Careful design of the additional component is required to achieve optimal panchromatic absorption, suitable energy-level offset, balanced electron and hole mobility, and good light-harvesting efficiency. This article reviews the recent progress on ternary organic photovoltaic systems, including polymer/small molecule/functional fullerene, polymer/polymer/functional fullerene, small molecule/small molecule/functional fullerene, polymer/functional fullerene I/functional fullerene II, and polymer/quantum dot or metal/functional fullerene systems. 23832699 Human induced pluripotent stem cell derived cardiomyocytes exhibit temporal changes in phenotype. Human induced pluripotent stem cell derived cardiomyocytes, hiPS-CM, have been recently derived and are used for basic research, cardiotoxicity assessment and phenotypic screening. However, the hiPS-CM phenotype is dependent on their derivation, age and culture conditions, and there is disagreement as to what constitutes a functional hiPS-CM. The aim of the present study was to characterize the temporal changes in hiPS-CM phenotype by examining five determinants of cardiomyocyte function: gene expression, ion channel functionality, calcium cycling, metabolic activity, and responsiveness to cardioactive compounds. Based on both gene expression and electrophysiological properties, at day 30 of differentiation, hiPS-CM are immature cells which, with time in culture, progressively develop a more mature phenotype without signs of dedifferentiation. This phenotype is characterized by adult-like gene expression patterns, action potentials exhibiting ventricular atrial and nodal properties, coordinated calcium cycling and beating suggesting the formation of a functional syncytium. Pharmacological responses to pathologic (ET-1), physiologic (IGF-1) and autonomic (isoproterenol) stimuli similar to those characteristic of isolated adult cardiac myocytes are present in maturing hiPS-CM. In addition, thyroid hormone treatment of hiPS-CM attenuated the fetal gene expression in favor of a more adult-like pattern. Overall, hiPS-CM progressively acquire functionality when maintained in culture for a prolonged period of time. The description of this evolving phenotype helps to identify optimal use of hiPS-CM for a range of research applications. 23147417 Orexin A regulates cardiovascular responses in stress-induced hypertensive rats. Several pieces of evidence indicate that the rostral ventrolateral medulla (RVLM) is probably one of the key neural structures mediating the pressor effects of orexins in the brain. Nitric oxide synthase/nitric oxide (NOS/NO) system in the RVLM modulates cardiovascular activities. Our experiments were designed to test the hypothesis that orexin-A (OXA) is involved in the mechanism of stress-induced hypertension (SIH) by adjusting NOS/NO system in the RVLM. The stress-induced hypertensive rats (SIHR) model was established by electric foot-shocks and noises. Here we examined the expression of OXA immunoreactive (OXA-IR) cells in the lateral hypothalamus (LH) and the protein level of orexin 1 receptor (OX1R) in the RVLM of SIHR, and we found that the expressions of OXA-IR and OX1R were higher than those of the control group. The double-staining immunohistochemical evidence showed that OX1R immunoreactive (OX1R-IR) cells and neuronal nitric oxide synthase (nNOS) or inducible nitric oxide synthase (iNOS) immunoreactive (IR) cells were co-localizated in the RVLM. Microinjection of OXA (10, 50, 100 pmol/100 nl) into the unilateral (right) RVLM of control rats or SIHR produced pressor and tachycardiac effects in a dose-dependent manner. SB-408124 (100 pmol/100 nl, an antagonist of OX1R) or TCS OX2 29 (100 pmol/100 nl, an antagonist of OX2R) partly abolished the cardiovascular effects of exogenously-administrated OXA into the RVLM of control rats and SIHR, and lowered the increased systolic blood pressure (SBP) and heart rate (HR) of SIHR, with no difference in statistical significance between the two antagonists' effects. Microinjection into the RVLM of both control and SIHR groups of 7-Ni (0.05 pmol/100 nl, nNOS inhibitor) or Methylene Blue [100 pmol/100 nl, an inhibitor of soluble guanylate cyclase (sGC)] suppressed the OXA-induced increase of SBP and HR, whereas microinjection of AG (1, 10, 100 pmol/100 nl) had no obvious effects on the OXA-induced increase of SBP and HR. Our results indicate that OXA in the RVLM may participate in the central regulation of cardiovascular activities in SIHR, and OX1R and OX2R both have important roles in it. The cardiovascular effects of OXA in the RVLM may be induced by nNOS-derived NO, which activated sGC-associated signaling pathway. 23843947 Avian WNT4 in the female reproductive tracts: potential role of oviduct development and ovarian carcinogenesis. The wingless-type MMTV integration site family of proteins (WNTs) is highly conserved secreted lipid-modified signaling molecules that play a variety of pivotal roles in developmental events such as embryogenesis, tissue homeostasis and cell polarity. Although, of these proteins, WNT4 is known to be involved in genital development in fetuses of mammalian species, its role is unknown in avian species. Therefore, in this study, we investigated expression profiles, as well as hormonal and post-transcriptional regulation of WNT4 expression in the reproductive tract of female chickens. Results of this study demonstrated that WNT4 is most abundant in the stromal and luminal epithelial cells of the isthmus and shell gland of the oviduct, respectively. WNT4 is also most abundant in the glandular epithelium of the shell gland of the oviduct of laying hens at 3 h post-ovulation during the laying cycle. In addition, treatment of young chicks with diethylstilbestrol (DES, a synthetic estrogen agonist) stimulated WNT4 only in the glandular epithelial cells of the isthmus and shell gland of the oviduct. Moreover, results of our study demonstrated that miR-1786 influences WNT4 expression via specific binding sites in its 3'-UTR. On the other hand, our results also indicate that WNT4 is expressed predominantly in the glandular epithelium of cancerous ovaries, but not in normal ovaries of hens. Collectively, these results indicate cell-specific expression of WNT4 in the reproductive tract of chickens and that it likely has crucial roles in development and function of oviduct as well as initiation of ovarian carcinogenesis in laying hens. 23867340 Improved genome-wide mapping of uncapped and cleaved transcripts in eukaryotes-GMUCT 2.0. The advent of high-throughput sequencing has led to an explosion of studies into the diversity, expression, processing, and lifespan of RNAs. Recently, three different high-throughput sequencing-based methods have been developed to specifically study RNAs that are in the process of being degraded. All three methods-genome-wide mapping of uncapped and cleaved transcripts (GMUCT), parallel analysis of RNA ends (PARE), and degradome sequencing-take advantage of the fact that Illumina sequencing libraries use T4 RNA ligase 1 to ligate an adapter to the 5' end of RNAs that have a free 5'-monophosphate. This condition for T4 RNA ligase 1 substrates means that mature mRNAs are not substrates of the enzyme because they have a 5'-cap moiety. As a result, these sequencing libraries are specifically made up of clones of decapped or degrading mRNAs resulting from 5'-to-3' or nonsense-mediated decay (NMD) and the 3' fragment of cleaved microRNA (miRNA) and small interfering RNA (siRNA) target RNAs. Here, we present a massively streamlined protocol for GMUCT that takes 2-3days, can be initiated with as little as 5μg of starting total RNA, and involves only one gel size-selection step. We show that the resulting datasets are similar to those produced using the previous GMUCT and PARE protocols. In total, our results suggest that this method will be the preferable approach for future studies of RNA degradation intermediates and small RNA-mediated cleavage in eukaryotic transcriptomes. 23002036 Resistin knockout mice exhibit impaired adipocyte glucose-dependent insulinotropic polypeptide receptor (GIPR) expression. Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that also plays a regulatory role in fat metabolism. In 3T3-L1 cells, resistin was demonstrated to be a key mediator of GIP stimulation of lipoprotein lipase (LPL) activity, involving activation of protein kinase B (PKB) and reduced phosphorylation of liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK). The current study was initiated to determine whether resistin has additional roles in GIP-regulated adipocyte functions. Analysis of primary adipocytes isolated from Retn(-/-), Retn(+/-), and Retn(+/+) mice found that GIP stimulated the PKB/LKB1/AMPK/LPL pathway and fatty acid uptake only in Retn(+/+) adipocytes, suggesting that GIP signaling and/or GIP responsiveness were compromised in Retn(+/-) and Retn(-/-) adipocytes. GIP receptor (GIPR) protein and mRNA were decreased in Retn(+/-) and Retn(-/-) adipocytes, but resistin treatment rescued LPL responsiveness to GIP. In addition, genes encoding tumor necrosis factor (TNF), TNF receptor 2 (TNFR2), and the signaling proteins stress-activated protein kinase (SAPK)/Jun NH(2)-terminal kinase (JNK), were downregulated, and phosphorylated levels of SAPK/JNK/c-Jun were decreased in Retn(-/-) mice. Chromatin immunoprecipitation assays were used to identify a 12-O-tetradecanoylphorbol-13-acetate (TPA)-response element (TRE-III) responsible for c-Jun-mediated transcriptional activation of Gipr. Blunted GIP responsiveness in Retn(+/-) and Retn(-/-) adipocytes was therefore largely due to the greatly reduced GIPR expression associated with decreased c-Jun-mediated transcriptional activation of Gipr. 23764192 Detection of potential chronic kidney disease markers in breath using gas chromatography with mass-spectral detection coupled with thermal desorption method. The analytical potential of chromatographic breath analysis towards detection of compounds suggested as markers of chronic kidney disease (CKD) was tested. Until now, trimethylamine (TMA) considered as a potential marker of renal disorder was detected mainly in plasma. Detection of TMA in breath was rarely undertaken due to analytical difficulties associated with amines' properties. The results of our investigations confirmed that an application of thermal desorption (TD) and gas chromatography with mass-spectral detection (GC/MS) allows direct detection of TMA in breath. The preliminary studies allowed to determine the breath composition in case of patients suffering from CKD and to compare the obtained results to a control group. Breath samples were collected from 14 patients and 9 healthy volunteers. TMA was detected in all patients suffering from CKD in the range 1.76-38.02ppb, but not in the control group. Acetone and isoprene were present in the exhaled air of all examined persons. The concentration of acetone was in the range of 26.52-329.46ppb in the patient group and 73.11-437.14ppb in the control group. Isoprene was detected in the range 57.17-329.8ppb among CKD patients and 27.99-143.77ppb in healthy volunteers. Additionally aliphatic hydrocarbons and sulfur compounds were determined in breath as compounds which could be essential in case of diseases coexisting with CKD. Apart from TMA and pentane no statistically significant differences were found using our analytical technique. TMA was detected in the breath of all patients with CKD and in none of breath samples in control group. TMA seems to be a promising marker of CKD. 23578358 Janus-like role of fibroblast growth factor 2 in arteriosclerotic coronary artery disease: atherogenesis and angiogenesis. Angiogenic stimulation is a promising new strategy for treating patients with arteriosclerotic coronary artery disease. This strategy aims to ameliorate cardiac function by improving myocardial perfusion and lowering the risk of myocardial infarction. However, angiogenesis may contribute to the growth of atherosclerotic lesions. Atherogenesis is also a potential side effect of angiogenic therapy. Early clinical trials were performed using fibroblast growth factor 2 (FGF2) protein, which enhances the formation of new collateral vessels to reduce ischaemic symptoms. Conversely, angiogenic stimulation by FGF2 is a dilemma because it could cause negative angiogenic effects, such as atherosclerosis. Thus far, clinical trials in patients with recombinant FGF2 protein therapy have not yet yielded undisputable beneficial effects. Future trials should determine whether an improvement can be obtained in patients with coronary artery disease using a combination of FGF2 and other growth factors or a combination of the FGF2 gene and stem cell therapy. This review summarises the multiple roles of FGF2 in the progression of atherosclerosis, its effect on pro-angiogenesis and improvement of cardiac function in coronary artery disease, and the potentially unfavourable effect of angiogenesis on the prevention and treatment of atherogenesis. 23207801 Expression of antagonists of WNT and BMP signaling after non-rigid fixation of osteotomies. Delayed fracture healing and non-unions represent rare but severe complications in orthopedic surgery. Further knowledge on the mechanisms of the bone repair process and of the development of a pseudoarthrosis is essential to predict and prevent impaired healing of fractures. The present study aimed at elucidating differences in gene expression during the repair of rigidly and non-rigidly fixed osteotomies. For this purpose, the MouseFix™ and the FlexiPlate™ systems (AO Development Institute, Davos, CH), allowing the creation of well defined osteotomies in mouse femora, were employed. A time course following the healing process of the osteotomy was performed and bones and periimplant tissues were analyzed by high-resolution X-ray, MicroCT and by histology. For the assessment of gene expression, Low Density Arrays (LDA) were done. In animals with rigid fixation, X-ray and MicroCT revealed healing of the osteotomy within 3 weeks. Using the FlexiPlate™ system, the osteotomy was still visible by X-ray after 3 weeks and a stabilizing cartilaginous callus was formed. After 4.5 weeks, the callus was remodeled and the osteotomy was, on a histological level, healed. Gene expression studies revealed levels of transcripts encoding proteins associated with inflammatory processes not to be altered in tissues from bones with rigid and non-rigid fixation, respectively. Levels of transcripts encoding proteins of the extracellular matrix and essential for bone cell functions were not increased in the rigidly fixed group when compared to controls without osteotomy. In the FlexiPlate™ group, levels of transcripts encoding the same set of genes were significantly increased 3 weeks after surgery. Expression of transcripts encoding BMPs and BMP antagonists was increased after 3 weeks in repair tissues from bones fixed with FlexiPlate™, as were inhibitors of the WNT signaling pathways. Little changes only were detected in transcript levels of tissues from rigidly fixed bones. The data of the present study suggest that rigid fixation enables accelerated healing of an experimental osteotomy as compared to non-rigid fixation. The changes in the healing process after non-rigid fixation are accompanied by an increase in the levels of transcripts encoding inhibitors of osteogenic pathways and, probably as a consequence, by temporal changes in bone matrix synthesis. 23516962 Major similarities in the bacterial communities associated with lesioned and healthy Fungiidae corals. Cultivation-based studies have demonstrated that yellow-band disease (YBD), a lesion-producing ailment affecting diverse species of coral, is caused by a consortium of Vibrio spp. This study takes the first cultivation-independent approach to examine the whole bacterial community associated with YBD-like lesioned corals. Two species of Fungiidae corals, Ctenactis crassa and Herpolitha limax, displaying YBD-like lesions were examined across diverse reefs throughout the Red Sea. Using a pyrosequencing approach targeting the V1-V3 regions of the SSU rRNA gene, no major differences in bacterial community composition or diversity were identified between healthy and lesioned corals of either species. Indicator species analysis did not find Vibrio significantly associated with the lesioned corals. However, operational taxonomic units belonging to the Ruegeria genus of Alphaproteobacteria and NS9 marine group of Flavobacteria were significantly associated with the lesioned corals. The most striking trend of this dataset was that reef location was found to be the most significant influence on the coral-bacterial community. It is possible that more pronounced lesion-specific bacterial signatures might have been concealed by the strong influence of environmental conditions on coral-bacteria. Overall, this study demonstrates inconsistencies between cultivation-independent and cultivation-based studies regarding the role of specific bacteria in coral diseases. 23963818 Automatically Purification of Aqueous CdTe Nanocrystals in Water-ethanol Co-environment. Purification is a separated post-treatment step after the synthesis of nanocrystals (NCs) in order to exclude excess ligands and monomers in NC solution. The common purification process involves many manipulations, such as concentrating, addition of anti-solvents and centrifugation, which are troublesome and time consuming. In this work, we originally integrate NC synthesis and NC purification in one-pot via selecting water-ethanol co-environment for NC synthesis and NC purification. Our research shows that NCs can grow in water-ethanol mixture. When growing into critical size, NCs will automatically precipitate from the solution. Element analysis demonstrates that precipitates fraction fits well with stoichiometric of ligand-capped NCs. Excess monomers are left in supernatant, and thus achieving automatically purification of NCs in the water-ethanol co-environment. By adjusting the volume ratios of water and ethanol in bi-solvent system, different-sized purified NCs can be controlled. Besides, this water-ethanol co-environment can be used in both thermal-promoted and hydrazine-promoted growth. 23331245 Crystal and magnetic structures and physical properties of a new pyroxene NaMnGe2O6 synthesized under high pressure. A new pyroxene compound, NaMnGe(2)O(6), has been synthesized at 3 GPa and 800 °C and fully characterized by X-ray single-crystal diffraction, neutron powder diffraction, and measurements of magnetization and specific heat. NaMnGe(2)O(6) crystallizes into a monoclinic C2/c structure with unit-cell parameters a = 9.859(2) Å, b = 8.7507(18) Å, c = 5.5724(11) Å, and β = 105.64(3)° at 153 K. A cooperative Jahn-Teller distortion is formed by an ordering of the longest Mn-O bonds between two neighboring octahedra along the chain direction. This feature distinguishes NaMnGe(2)O(6) from other pyroxene compounds without Jahn-Teller active cations and suggests that the Jahn-Teller distortion competes with the intrinsic local distortion in the pyroxene structure. No orbital order-disorder transition has been found up to 750 K. Like other alkali-metal pyroxenes with S > (1)/(2), NaMnGe(2)O(6) (S = 2) was found to undergo a long-range antiferromagnetic (AF) ordering at T(N) = 7 K due to intrachain and interchain exchange interactions. Due to the peculiar structural features and the corresponding magnetic coupling, the weak AF spin ordering gives way to a ferromagnetic-like state at a sufficiently high magnetic field. Specific-heat measurements demonstrated that a large portion of the magnetic entropy, >60%, has been removed above T(N) as a result of strong spin correlations within the quasi-one-dimensional Mn(3+)-spin chains. The Reitveld refinement of neutron powder diffraction data gives a commensurate magnetic structure defined by k = [0 0 0.5] with Mn moments aligned mainly along the c-axis with a small component along both a- and b-axes. 23749094 One-step fabrication of micro/nanotunnels in metal interlayers. A micro/nanotunnel is a very useful structure, which has been used as an interconnected pass in various micro/nano systems. Here, a novel micro/nanotunnel fabrication method in a metal interlayer ZnS-SiO2/Sn/ZnS-SiO2 sandwich structure is proposed based on a laser direct writing (LDW) technique. The experimental results show that the arched tunnel is 170 nm in width and 50 nm in height, far beyond the diffraction limit of the LDW system with a 533 nm laser and 0.9 NA objective lens. In only one step, an arbitrary tunnel can be fabricated, exhibiting its simple, designable and practical features, and providing a new route for micro/nanotunnel fabrication. 23926035 Accounting for direction and speed of the eye motion in planning visually guided manual tracking. Accurate motor planning in a dynamic environment is a critical skill for humans because we are often required to react quickly and adequately to the visual motion of objects. Moreover, we are often in motion ourselves and this complicates motor planning. Indeed, the retinal and spatial motions of an object are different because of the retinal motion component induced by self-motion. Many studies investigated motion perception during smooth pursuit and concluded that eye velocity is partially taken into account by the brain. Here we investigate whether the eye velocity during ongoing smooth pursuit is taken into account for the planning of visually guided manual tracking. We had ten human participants manually track a target while in steady state smooth pursuit towards another target such that the difference between the retinal and spatial target motion directions could be large, depending both on the direction and speed of the eye. We used a measure of initial arm movement direction to quantify whether motor planning occurred in retinal coordinates (not accounting for eye motion) or was spatially correct (incorporating eye velocity). Results showed that the eye velocity was nearly fully taken into account by the neuronal areas involved in the visuomotor velocity transformation (between 75% and 102%). In particular, these neuronal pathways accounted for the non-linear effects due to the relative velocity between the target and the eye. In conclusion, the brain network transforming visual motion into a motor plan for manual tracking adequately uses extra-retinal signals about eye velocity. 23792422 Aging affects high-density lipoprotein composition and function. Most coronary deaths occur in patients older than 65years. Age associated alterations in the composition and function of high-density lipoproteins (HDL) may contribute to cardiovascular mortality. The effect of advanced age on the composition and function of HDL is not well understood. HDL was isolated from healthy young and elderly subjects. HDL composition, cellular cholesterol efflux/uptake, anti-oxidant properties and paraoxonase activity were assessed. We observed a 3-fold increase of the acute phase protein serum amyloid A, an increased content of complement C3 and proteins involved in endopeptidase/protease inhibition in HDL of elderly subjects, whereas levels of apolipoprotein E were significantly decreased. HDL from elderly subjects contained less cholesterol but increased sphingomyelin. Most importantly, HDL from elderly subjects showed defective antioxidant properties, lower paraoxonase 1 activity and was more rapidly taken up by macrophages, whereas cholesterol efflux capability was not altered. These findings suggest that aging alters HDL composition, resulting in functional impairment that may contribute to the onset/progression of cardiovascular disease. 23286367 Design and implementation of two-dimensional polymer adsorption models: evaluating the stability of Candida antarctica lipase B/solid-support interfaces by QCM-D. A two-dimensional model of a solid-supported enzyme catalyst bead is fabricated on a quartz crystal microbalance with dissipation monitoring (QCM-D) sensor to measure in situ interfacial stability and mechanical properties of Candida antarctica Lipase B (CAL B) under varied conditions relating to ring-opening polymerization. The model was fabricated using a dual photochemical approach, where poly(methyl methacrylate) (PMMA) thin films were cross-linked by a photoactive benzophenone monolayer and blended cross-linking agent. This process produces two-dimensional, homogeneous, rigid PMMA layers, which mimic commercial acrylic resins in a QCM-D experiment. Adsorption of CAL B to PMMA in QCM-D under varied buffer ionic strengths produces a viscoelastic enzyme surface that becomes more rigid as ionic strength increases. The rigid CAL B/PMMA interface demonstrates up to 20% desorption of enzyme with increasing trace water content. Increased polycaprolactone (PCL) binding at the enzyme surface was also observed, indicating greater PCL affinity for a more hydrated enzyme surface. The enzyme layer destabilized with increasing temperature, yielding near complete reversible catalyst desorption in the model. 23876139 Enzymatic surface hydrolysis of polyamide 6,6 with mixtures of proteolytic and lipolytic enzymes. This study investigated the changes induced on nylon 6,6 fabric by a mixture of proteolytic and lipolytic enzymes. Technical measurements were studied including those of Fourier-transform infrared spectroscopy (FTIR), thermal gravimetric analysis (TGA), weight loss (WL), bending lengths (BL), scanning electron microscopy (SEM), moisture absorbency (MA), and reflectance spectroscopy (RS). For this purpose, nylon 6,6 fabrics were treated separately with different concentrations of protease and lipase mixtures in solution. The dyeing process was then carried out on the treated fabrics with two reactive and acid dyes. The intensity of major peaks in the FTIR spectra of the protease-treated samples is in favor of chemical changes the polypeptide functional groups in the fabrics. Thermal studies also show a significant decrease in the thermal degradation temperature of the treated polymer at temperatures higher than 400°C. The protease and lipase mixtures decreased the sample weight, while lipase intensified the weight loss comparing with protease. It was observed that the concentration of lipase enzyme had a direct influence on the darkness of dyed samples. 23427025 Is retention of zoledronic acid onto bone different in multiple myeloma and breast cancer patients with bone metastasis? Zoledronic acid (Zol) is used to treat bone disease in both multiple myeloma (MM) and breast cancer patients with bone metastasis (BC). However, bones of MM and BC patients show a difference in retention of the bisphosphonate used for bone scintigraphy. Therefore, we hypothesized that disease-specific factors may differently influence Zol retention in MM and BC patients. We tested this hypothesis in an investigator initiated phase II clinical trial in which we compared the whole-body retention (WBrt) of Zol in a cohort of 30 multiple myeloma (MM) and 30 breast cancer (BC) (20 Zol naive and 40 with six or more previous administrations). On average, 62% of the administered Zol was retained in the skeleton of both MM and BC patients and independently of the number of treatments. WBrt of Zol did not correlate with cross-linked C-telopeptide (CTX) levels, but linear regression analyses showed that WBrt of Zol correlated with bone-specific alkaline phosphatase (bALP) levels in BC (p = 0.001), and with CTX/bALP in Zol naive MM patients (p = 0.012). Especially in BC patients, WBrt correlated with age (p = 0.014) independently of kidney function. In MM patients WBrt was found to primarily correlate with the extent of bone disease (p = 0.028). Multivariate linear regression analyses of the entire cohort pointed out that WBrt of Zol was best predicted by age (p < 0.000), osseous lesions (p < 0.001), and the preceding Zol dosing (p < 0.005) (r(2)  = 0.97). Comparing bone scintigrams with CT/X-ray images showed a poor correlation between sites of active bone disease and binding of scintigraphy bisphosphonate in 36% of MM patients and in 13% of BC patients. We conclude that WBrt of Zol is primarily determined by two non-disease related factors and only one disease related, but that there may be differences in retention or drug delivery at individual sites of bone disease between MM and BC patients. In order to find the optimal dosing of Zol, these observations should be taken into account. 23002250 'Avoidable' mortality: a measure of health system performance in the Czech Republic and Slovakia between 1971 and 2008. BACKGROUND Post-communist health care reforms and the break-up of Czechoslovakia have been studied from various perspectives, but little research has addressed the impact on health system performance. This paper investigates the quality and performance of the Slovak and Czech health systems before and after 1989, including the year of separation in 1993, using the concept of 'avoidable' mortality. METHODS Age-standardized mortality rates for mortality from 'avoidable' and other (non-avoidable) causes have been calculated through indirect standardization to study national and regional trends between 1971 and 2008. RESULTS The paper shows that 'avoidable' mortality in both countries has been continuously decreasing while mortality from other causes has remained unchanged or increased slightly. For some 'avoidable' conditions, mortality rates of the two countries converge while for others divergence can be observed, with either the Czech Republic or Slovakia performing better. CONCLUSION Declines in overall 'avoidable' mortality suggest improvements in the health system's performance and quality of care in both countries, compared with mortality from other causes where factors outside the control of the health care system may be stronger determinants. For conditions where 'avoidable' mortality rates stagnate or increase, more in-depth research should be carried out to identify problems in the delivery of timely and effective prevention and treatment, and to establish steps that would reduce the numbers of unnecessary deaths. 23904446 Wood anatomical correlates with theoretical conductivity and wood density across China: evolutionary evidence of the functional differentiation of axial and radial parenchyma. Background and Aims In recent years considerable effort has focused on linking wood anatomy and key ecological traits. Studies analysing large databases have described how these ecological traits vary as a function of wood anatomical traits related to conduction and support, but have not considered how these functions interact with cells involved in storage of water and carbohydrates (i.e. parenchyma cells). Methods We analyzed, in a phylogenetic context, the functional relationship between cell types performing each of the three xylem functions (conduction, support and storage) and wood density and theoretical conductivity using a sample of approx. 800 tree species from China. Key Results Axial parenchyma and rays had distinct evolutionary correlation patterns. An evolutionary link was found between high conduction capacity and larger amounts of axial parenchyma that is probably related to water storage capacity and embolism repair, while larger amounts of ray tissue have evolved with increased mechanical support and reduced hydraulic capacity. In a phylogenetic principal component analysis this association of axial parenchyma with increased conduction capacity and rays with wood density represented orthogonal axes of variation. In multivariate space, however, the proportion of rays might be positively associated with conductance and negatively with wood density, indicating flexibility in these axes in species with wide rays. Conclusions The findings suggest that parenchyma types may differ in function. The functional axes represented by different cell types were conserved across lineages, suggesting a significant role in the ecological strategies of the angiosperms. 23518007 FMRI analysis of contrast polarity in face-selective cortex in humans and monkeys. Recognition is strongly impaired when the normal contrast polarity of faces is reversed. For instance, otherwise-familiar faces become very difficult to recognize when viewed as photographic negatives. Here, we used fMRI to demonstrate related properties in visual cortex: 1) fMRI responses in the human Fusiform Face Area (FFA) decreased strongly (26%) to contrast-reversed faces across a wide range of contrast levels (5.3-100% RMS contrast), in all subjects tested. In a whole brain analysis, this contrast polarity bias was largely confined to the Fusiform Face Area (FFA; p<0.0001), with possible involvement of a left occipital face-selective region. 2) It is known that reversing facial contrast affects three image properties in parallel (absorbance, shading, and specular reflection). Here, comparison of FFA responses to those in V1 suggests that the contrast polarity bias is produced in FFA only when all three component properties were reversed simultaneously, which suggests a prominent non-linearity in FFA processing. 3) Across a wide range (180°) of illumination source angles, 3D face shapes without texture produced response constancy in FFA, without a contrast polarity bias. 4) Consistent with psychophysics, analogous fMRI biases for normal contrast polarity were not produced by non-face objects, with image statistics similar to the face stimuli. 5) Using fMRI, we also demonstrated a contrast polarity bias in awake behaving macaque monkeys, in the cortical region considered homologous to human FFA. Thus common cortical mechanisms may underlie facial contrast processing across ~25 million years of primate evolution. 23752083 Ductal carcinoma in situ: morphology-based knowledge and molecular advances. Ductal carcinoma in situ (DCIS) is an established precursor of invasive breast carcinoma. Immunoperoxidase stains for selected markers can assist pathologists in the diagnosis of challenging ductal epithelial proliferations, but they cannot replace morphologic evaluation as the primary and critical assessment of this disease. Molecular studies provide further insight into how DCIS progresses to invasive carcinoma and also confirm the heterogeneity of this lesion. Morphology-based knowledge, immunohistochemistry, and molecular advances in DCIS are the subjects of this review. 23736379 ICAM-2 and lipid rafts disappear from the basal plasma membrane of uterine epithelial cells during early pregnancy in rats. Adhesion molecules are redistributed in rat uterine epithelial cells (UECs) during early pregnancy for endometrial receptivity and implantation. Intercellular adhesion molecule-2 (ICAM-2) is located as an oligomer on the basal plasma membrane of non-receptive UECs on day 1 of pregnancy and colocalizes with the lipid raft marker flotillin-2. At the time of implantation in rats and in ovariectomized rats primed with progesterone, ICAM-2 disappears from the basal plasma membrane and lipid rafts redistribute to the apical membrane. The loss of ICAM-2 might render UECs less adherent to the underlying basal lamina and more prone to apoptosis. Flotillin-2 in the apical plasma membrane at the time of implantation might provide an anchoring point for several adhesion molecules that are known to localize to this region at this time. We suggest that flotillin-2 is involved with adhesion between UECs and the implanting blastocyst, whereas ICAM-2 is associated with the ability for UECs to be removed at the time of implantation. 23558577 Neutrophilic bacterial meningitis: pathology and etiologic diagnosis of fatal cases. The frequency of fatalities due to acute bacterial meningitis has decreased significantly due to vaccinations, early diagnoses, and treatments. We studied brain tissues of patients with fatal neutrophilic meningitis referred to the Centers for Disease Control for etiologic diagnosis from 2000-2009 to highlight aspects of the disease that may be preventable or treatable. Demographic, clinical, and laboratory data were extracted from records. Of 117 cases in the database with a diagnosis of meningitis or meningoencephalitis, 39 had neutrophilic inflammation in the meninges. Inflammatory cells infiltrated the superficial cortex in 16 of 39 (41%) cases. Bacteria were found using Gram and bacterial silver stains in 72% of cases, immunohistochemistry in 69% (including two cases where the meningococcus was found outside the meninges), and PCR in 74%. Streptococcus pneumoniae was the cause of the meningitis in 14 patients and Neisseria meningitidis in 9. In addition, Streptococcus spp. were found to be the cause in six cases, while Staphylococcus aureus, Staphylococcus spp., Enterococcus spp., and Fusobacterium were the cause of one case each. There were six cases in which no specific etiological agent could be determined. The mean age of the patients with S. pneumoniae was 39 years (range 0-65), with N. meningitidis was 19 years (range 7-51), whereas that for all others was 31 years (range 0-68). In summary, our study shows that S. pneumoniae continues to be the most frequent cause of fatal neutrophilic bacterial meningitis followed by N. meningitidis, both vaccine preventable diseases. 23728908 Correlation of 99mTc-DMSA scan with radiological and laboratory examinations in childhood acute pyelonephritis: a time-series study. Urinary tract infections are one of the most common diseases in children. They may lead to hypertension and renal failure later in life. Renal scintigraphy with technetium-99m dimercaptosuccinic acid (99mTc-DMSA) is one method used to diagnose acute pyelonephritis (APN) and renal parenchymal scars. The aim of the present study was to determine the ideal time to perform a follow-up 99mTc-DMSA scan to detect renal scars and also to evaluate the factors predicting the development of permanent renal damage after APN. Sixty-four children with a first episode of APN underwent a 99mTc-DMSA scan. If there were abnormal findings on this scan, another scan was performed 6 and 12 months later. The baseline 99mTc-DMSA scan showed cortical changes in 35 patients (54.7 %). One the 6- and 12-month follow-up scans, 25 patients (39.06 %) and 21 patients (32.8 %), respectively, had cortical lesions. In multiple logistic regressions with the final 99mTc-DMSA scan results as the dependent variable, only the age range of the patients (β = 1.062; 95 % CI 1.014-1.113; p = 0.01) showed an independent and significant association. Gender, therapeutic delay time, ultrasonography, and voiding cystourethrogram results, as well as laboratory test results including the erythrocyte sedimentation rate, C-reactive protein level, white blood cell counts, and type of bacteria in the urine, did not show such an association (p > 0.05). There is not a significant difference between the results of 6- and 12-month 99mTc-DMSA follow-up scans. A follow-up 99mTc-DMSA scan should be performed 12 months after the acute scan to yield a more accurate diagnosis of permanent renal damage. If present, long-term follow-up of patients is necessary. 23891292 Desmosome assembly and dynamics. Desmosomes are intercellular junctions that anchor intermediate filaments (IFs) to the plasma membrane, forming a supracellular scaffold that provides mechanical resilience to tissues. This anchoring function is accomplished by specialized members of the cadherin family and associated cytoskeletal linking proteins, which together form a highly organized membrane core flanked by mirror-image cytoplasmic plaques. Due to the biochemical insolubility of desmosomes, the mechanisms that govern assembly of these components into a functional organelle remained elusive. Recently developed molecular reporters and live cell imaging approaches have provided powerful new tools to monitor this finely tuned process in real time. Here we discuss studies that are beginning to decipher the machinery and regulation governing desmosome assembly and homeostasis in situ and how these mechanisms are affected during disease pathogenesis. 23053593 Morphology-elasticity relationships using decreasing fabric information of human trabecular bone from three major anatomical locations. With improving clinical CT scanning technology, the accuracy of CT-based finite element (FE) models of the human skeleton may be ameliorated by an enhanced description of apparent level bone mechanical properties. Micro-finite element (μFE) modeling can be used to study the apparent elastic behavior of human cancellous bone. In this study, samples from the femur, radius and vertebral body were investigated to evaluate the predictive power of morphology-elasticity relationships and to compare them across different anatomical regions. Î¼FE models of 701 trabecular bone cubes with a side length of 5.3 mm were analyzed using kinematic boundary conditions. Based on the FE results, four morphology-elasticity models using bone volume fraction as well as full, limited or no fabric information were calibrated for each anatomical region. The 5 parameter Zysset-Curnier model using full fabric information showed excellent predictive power with coefficients of determination ([Formula: see text]) of 0.98, 0.95 and 0.94 of the femur, radius and vertebra data, respectively, with mean total norm errors between 14 and 20%. A constant orthotropy model and a constant transverse isotropy model, where the elastic anisotropy is defined by the model parameters, yielded coefficients of determination between 0.90 and 0.98 with total norm errors between 16 and 25%. Neglecting fabric information and using an isotropic model led to [Formula: see text] between 0.73 and 0.92 with total norm errors between 38 and 49%. A comparison of the model regressions revealed minor but significant (p<0.01) differences for the fabric-elasticity model parameters calibrated for the different anatomical regions. The proposed models and identified parameters can be used in future studies to compute the apparent elastic properties of human cancellous bone for homogenized FE models. 23945377 Gap junctions, dendrites and resonances: a recipe for tuning network dynamics. Gap junctions, also referred to as electrical synapses, are expressed along the entire central nervous system and are important in mediating various brain rhythms in both normal and pathological states. These connections can form between the dendritic trees of individual cells. Many dendrites express membrane channels that confer on them a form of sub-threshold resonant dynamics. To obtain insight into the modulatory role of gap junctions in tuning networks of resonant dendritic trees we generalise the ``sum-over-trips'' formalism for calculating the response function of a single branching dendrite to a gap junctionally coupled network. Each cell in the network is modelled by a soma connected to an arbitrary structure of dendrites with resonant membrane. The network is treated as a single extended tree structure with dendro-dendritic gap junction coupling. We present the generalised ``sum-over-trips'' rules for constructing the network response function in terms of a set of coefficients defined at special branching, somatic, and gap-junctional nodes. Applying this framework to a two-cell network we construct compact closed form solutions for the network response function in the Laplace (frequency) domain and study how a preferred frequency in each soma depends on the location and strength of the gap junction. 23583020 Sleep disordered breathing in a cohort of patients with sporadic inclusion body myositis. The aims of the study were: (1) to evaluate subjective sleep quality and daytime sleepiness in patients affected by sporadic inclusion-body myositis (IBM); (2) to define the sleep and sleep-related respiratory pattern in IBM patients. Thirteen consecutive adult patients affected by definite IBM were enrolled, six women and seven men, mean age 66.2±11.1years (range: 50-80). Diagnosis was based on clinical and muscle biopsy studies. All patients underwent subjective sleep evaluation (Pittsburgh Sleep Quality Index, PSQI and Epworth Sleepiness Scale, ESS), oro-pharingo-esophageal scintigraphy, pulmonary function tests, psychometric measures, anatomic evaluation of upper airways, and laboratory-based polysomnography. Findings in IBM patients were compared to those obtained from a control group of 25 healthy subjects (13 men and 12 women, mean age 61.9±8.6years). Disease duration was >10years in all. Mean IBM severity score was 28.8±5.4 (range 18-36). Dysphagia was present in 10 patients. Nine patients had PSQI scores⩾5; patients had higher mean PSQI score (IBM: 7.2±4.7, Controls: 2.76±1.45, p=0.005); one patient (and no controls) had EES>9. Polysomnography showed that IBM patients, compared to controls, had lower sleep efficiency (IBM: 78.8±12.0%, Controls: 94.0±4.5%, p<0.001), more awakenings (IBM: 11.9±11.0, Controls: 5.2±7.5, p=0.009) and increased nocturnal time awake (IBM: 121.2±82.0min., Controls: 46.12±28.8min., p=0.001). Seven Patients (and no controls) had polysomnographic findings consistent with sleep disordered breathing (SDB). Data suggest that sleep disruption, and in particular SDB, might be highly prevalent in IBM. Data indicate that IBM patients have poor sleep and high prevalence of SDB. 23913871 A Rapid Route to Aminocyclopropanes via Carbamatoorganozinc Carbenoids. Easy as 1,2,3: Reaction of methyl carbamate, triethyl orthoformate, and readily available alkenes provides a highly practical preparation of protected aminocyclopropanes. The reaction proceeds with preferential cis addition to alkenes, and cleavage of the methyl carbamate gives the free aminocyclopropanes as their HI salts. 23912125 Wg and Wnt4 provide long-range directional input to planar cell polarity orientation in Drosophila. Planar cell polarity (PCP) is cellular polarity within the plane of an epithelial tissue or organ. PCP is established through interactions of the core Frizzled (Fz)/PCP factors and, although their molecular interactions are beginning to be understood, the upstream input providing the directional bias and polarity axis remains unknown. Among core PCP genes, Fz is unique as it regulates PCP both cell-autonomously and non-autonomously, with its extracellular domain acting as a ligand for Van Gogh (Vang). We demonstrate in Drosophila melanogaster wings that Wg (Wingless) and dWnt4 (Drosophila Wnt homologue) provide instructive regulatory input for PCP axis determination, establishing polarity axes along their graded distribution and perpendicular to their expression domain borders. Loss-of-function studies reveal that Wg and dWnt4 act redundantly in PCP determination. They affect PCP by modulating the intercellular interaction between Fz and Vang, which is thought to be a key step in setting up initial polarity, thus providing directionality to the PCP process. 23276254 Besting vitamin E: sidechain substitution is key to the reactivity of naphthyridinol antioxidants in lipid bilayers. A series of naphthyridinol analogs of α-tocopherol (α-TOH, right) with varying sidechain substitution was synthesized to determine how systematic changes in the lipophilicity of these potent antioxidants impact their radical-trapping activities in lipid bilayers, regenerability by water-soluble reductants, and binding to human tocopherol transport protein (TTP). The activities of the naphthyridinols were assayed in phosphatidylcholine unilamellar liposomes using a recently developed high-throughput assay that employs a boron dipyrromethene conjugate of α-TOH (H(2)B-PMHC) that undergoes fluorescence enhancement upon oxidation. The naphthyridinols afforded a dose-dependent protection of H(2)B-PMHC consistent with unprecedented peroxyl radical-trapping activity in lipid bilayers. While sidechain length and/or branching had no effect on their apparent reactivity, it dramatically impacted reaction stoichiometry, with more lipophilic compounds trapping two peroxyl radicals and more hydrophilic compounds trapping significantly less than one. It is suggested that the less lipophilic compounds autoxidize rapidly in the aqueous phase and that preferential partitioning of the more lipophilic compounds to the bilayer protects them from autoxidation. The cooperativity of a lipophilic naphthyridinol with water-soluble reducing agents was also studied in liposomes using H(2)B-PMHC and revealed superior regenerability by each of ascorbate, N-acetylcysteine, and urate when compared to α-TOH. Binding assays with human TTP, a key determinant of the bioavailability of the tocopherols, reveal that the naphthyiridinols can be very good ligands for the protein. In fact, naphthyridinols with sidechains of eight or more carbons had affinities for TTP which were similar to, and in one case 10-fold better than, α-TOH. 23131864 The evolving ethics of infant dialysis. In this paper, we review ethical issues that arise when families and doctors face clinical decisions about renal replacement therapy for an infant with end-stage renal disease (ESRD). Over the last 20 years, many centers have begun to routinely offer renal replacement therapy. However, doctors and nurses both continue to view such therapy as optional, rather than mandatory. We speculate that the burdens of therapy on the family, and the uncertainties about satisfactory outcomes have led to a situation in which renal replacement therapy remains desirable, but non-obligatory. We discuss the reasons why this is likely to remain so, and the ways in which renal replacement therapy for infants with ESRD is similar to, or different from, other clinical situations in pediatrics. Finally, we propose a research agenda to answer questions that are crucial to making good ethical decisions about infant dialysis. 23818662 Immunoblotting histones from yeast whole-cell protein extracts. Histones are small basic proteins that are core components of chromatin. As such, they are essential for cell viability and genomic stability and their levels are tightly controlled. In addition, histone tails are subject to extensive posttranslational modifications, including acetylation, methylation, phosphorylation and ubiquitylation, that play critical roles in many cellular processes. To quickly screen for alterations in histone levels and/or their modifications in yeast mutants under different growth conditions, we present a fast and reliable protocol for whole-cell protein extract preparation and immunoblotting. 23754694 Identification of optimal concentrations and incubation times for the study of in vitro effects of pb in ram spermatozoa. In vitro effects of lead (Pb) on ram (Ovis aries) spermatozoa were studied to establish a threshold level that affects sperm function. Spermatozoa were incubated between 15 and 180 min with Pb concentrations ranging from 0 to 5,000 ng/mL. Sperm motility, acrosome integrity, membrane functionality and sperm viability were all negatively affected by Pb and incubation time. Acrosome integrity was linearly affected by Pb levels at an incubation time of 30 min, and 50 ng/mL was the lowest Pb level producing such effect. These experimental conditions can be appropriate for in vitro studies of the mechanisms of action of Pb on spermatozoa. 23549663 Functional block copolymer assemblies responsive to tumor and intracellular microenvironments for site-specific drug delivery and enhanced imaging performance. Self-assembled nanostructures of amphiphilic and double hydrophilic block copolymers have been increasingly utilized as potent polymeric nanocarriers of therapeutic drugs, genes, bioactive molecules, and imaging/contrast agents due to improved water solubility, bioavailability, and extended blood circulation duration. Though passive and active targeted drug delivery strategies have long been proposed to promote desirable drug accumulation specifically at the disease sites, the introduction of stimuli-responsiveness into self-assembled block copolymer nanocarriers can additionally lead to controlled/triggered release of therapeutic/imaging agents into target pathological tissues and cells, with concomitant advantages of enhanced delivery efficiency and therapeutic efficacy. Appropriately designed stimuli-responsive block copolymer assemblies can exhibit chemical structure transformation, microstructural rearrangement and inversion, or even disassembly into unimers or smaller ones under external stimuli such as pH, temperature, ion strength, redox potential, light, electric, and magnetic fields, and specific bioactive molecules and metabolites. Compared to normal tissues, pathological sites such as tumor tissues typically exhibit vascular abnormalities, weak acidity (∼pH 6.8), abnormal temperatures, over-expressed proteins and enzymes, hypoxia, high levels of metabolites and reactive small molecule species, etc. Moreover, upon cellular uptake, drug-loaded polymeric nanocarriers will be subjected to intracellular pH gradients (pH 5.9-6.2 in early endosomes and pH 5.0-5.5 in late endosomes and lysosomes) and redox and H2O2 gradients within different cell organelles and the cytosol. Thus, block copolymer nanocarriers responsive to the above described bio-relevant stimuli or biochemical signals characteristic of pathologic tissues and cells will provide an alternative type of "active targeting" strategy, which can be utilized to further boost therapeutic efficacy and imaging sensitivity via disease site-specific delivery and controlled release. A variety of extracellular or intracellular stimuli innate to disease sites, such as mildly acidic pH, temperature, enzymes (matrix metalloproteinase, β-glucuronidase, and phosphatase), oxidative/reductive microenvironments, and abnormal levels of bioactive molecules or metabolites, have been utilized for this purpose. In this review, we summarize recent advances in stimuli-responsive block copolymer assemblies which are responsive to tumor and intracellular microenvironments and their applications in anticancer drug delivery and enhanced imaging sensitivity. 23804810 LDL particle core enrichment in cholesteryl oleate increases proteoglycan binding and promotes atherosclerosis. Several studies in humans and animals suggest that LDL particle core enrichment in cholesteryl oleate (CO) is associated with increased atherosclerosis. Diet enrichment with MUFAs enhances LDL CO content. Steroyl O-acyltransferase 2 (SOAT2) is the enzyme that catalyzes the synthesis of much of the CO found in LDL, and gene deletion of SOAT2 minimizes CO in LDL and protects against atherosclerosis. The purpose of this study was to test the hypothesis that the increased atherosclerosis associated with LDL core enrichment in CO results from an increased affinity of the LDL particle for arterial proteoglycans. ApoB-100-only Ldlr(-/-) mice with and without Soat2 gene deletions were fed diets enriched in either cis-MUFA or n-3 PUFA, and LDL particles were isolated. LDL:proteogylcan binding was measured using surface plasmon resonance. Particles with higher CO content consistently bound with higher affinity to human biglycan and the amount of binding was shown to be proportional to the extent of atherosclerosis of the LDL donor mice. The data strongly support the thesis that atherosclerosis was induced through enhanced proteoglycan binding of LDL resulting from LDL core CO enrichment. 22975263 Relevance of non-guideline studies for risk assessment: the coverage model based on most frequent targets in repeated dose toxicity studies. A common challenge for human risk assessment is the quality of the available animal studies. Non-guideline studies are often limited for different aspects of study design and documentation. Within this publication the relevance of a limited scope of examination is discussed. Preliminary analyses of the RepDose database have shown that liver, body weight, kidney and clinical symptoms are frequently affected in oral repeated dose toxicity in rats and mice (Bitsch et al., 2006), while many other targets are seldom affected. As most of these targets are investigated frequently also in non-guideline studies, it is likely that they provide a reliable NOEL, although the full spectrum of endpoints has not been covered. Based on RepDose data we investigate the relevance of individual targets for determining the LOEL and the consequences for risk assessment. The resulting coverage model for subchronic oral rat studies includes up to six targets and an additional assessment factor for LOEL extrapolation. It can be applied to assess the reliability of non-guideline studies with respect to the scope of examination. Furthermore the application of the coverage model to other databases will increase and/or specify the chemical domain and reveal respective targets as well as effects. 23936074 Telomeric Repeats Facilitate CENP-A(Cnp1) Incorporation via Telomere Binding Proteins. The histone H3 variant, CENP-A, is normally assembled upon canonical centromeric sequences, but there is no apparent obligate coupling of sequence and assembly, suggesting that centromere location can be epigenetically determined. To explore the tolerances and constraints on CENP-A deposition we investigated whether certain locations are favoured when additional CENP-A(Cnp1) is present in fission yeast cells. Our analyses show that additional CENP-A(Cnp1) accumulates within and close to heterochromatic centromeric outer repeats, and over regions adjacent to rDNA and telomeres. The use of minichromosome derivatives with unique DNA sequences internal to chromosome ends shows that telomeres are sufficient to direct CENP-A(Cnp1) deposition. However, chromosome ends are not required as CENP-A(Cnp1) deposition also occurs at telomere repeats inserted at an internal locus and correlates with the presence of H3K9 methylation near these repeats. The Ccq1 protein, which is known to bind telomere repeats and recruit telomerase, was found to be required to induce H3K9 methylation and thus promote the incorporation of CENP-A(Cnp1) near telomere repeats. These analyses demonstrate that at non-centromeric chromosomal locations the presence of heterochromatin influences the sites at which CENP-A is incorporated into chromatin and, thus, potentially the location of centromeres. 23846422 Treatment outcomes of pulmonary tuberculosis in the past decade in the mainland of China: a meta-analysis. Due to the implementation of directly observed treatment strategy (DOTS), China has made a significant achievement in tackling the tuberculosis (TB) epidemic in the 1990s. However, only half of regions in China met or exceeded the 85% rate of treatment success target. The aim of the present study is to summarize the treatment outcomes of smear-positive pulmonary TB in the mainland of China in the past decade using meta-analysis based on systematic review of published observational studies. A total of 50 eligible articles (58 studies) were identified and included in this study. The summarized treatment success rates were 93.9% (95% CI, 92.8%-94.7%) for new cases and 85.4% (95% CI, 83.0%-87.6%) for previously treated cases, and the summarized cured rate were 92.2% (95% CI, 90.9%-93.3%) and 81.2% (95% CI, 79.1%-83.1%), respectively. A remarkable increase of rates for treatment success and cure was observed in the 1990s. After 2000, the summarized treatment outcomes were tending towards stability. In addition, geographic areas, type of the data and administrative level of the hospital were also found to influence the estimates of the treatment outcomes. Results of the present study clearly show, in general, that the pulmonary TB treatment achieved significant success in the past decade in the mainland of China. However, it needs to be further strengthened in the central and west areas. 23809970 Elective surgery after successful endoscopic decompression of sigmoid volvulus may be considered. Volvulus is an axial twist of any part of the gastrointestinal tract along its mesentery. If it goes unattended, it will cause bowel obstruction and bowel ischaemia with gangrene and perforation. The primary treatment is endoscopic desufflation, but the place for elective surgery is controversial. Volvulus is a rare condition in Western Europe and North America that most often affects elderly of either gender. We reviewed all records on patients admitted to our hospital during an 11-year period. Age at first admission, co-morbidity and number of readmissions were registered. The results of primary endoscopic treatment and any surgery were registered together with complications, 30-day and one-year moratality rates. A total of 41 patients were treated. The mean age at first admission was 70 years. Significant co-morbidity was found in 33 patients (81%). Thirty patients (73%) were treated for recurrence. Fourteen patients were treated with decompression alone, and 27 patients were operated (14 acute and 13 elective cases). The 30-day mortality was 43% after acute operation and 8% after elective operation (p < 0.05). In the group of patients with decompression alone, the one-year mortality was 50%. Elective surgery should be considered because of a high recurrence rate and one-year mortality after initially successful decompression. not relevant. not relevant. 23222847 DAXX-dependent supply of soluble (H3.3-H4) dimers to PML bodies pending deposition into chromatin. Replication-independent chromatin deposition of histone variant H3.3 is mediated by several chaperones. We report a multistep targeting of newly synthesized epitope-tagged H3.3 to chromatin via PML bodies. H3.3 is recruited to PML bodies in a DAXX-dependent manner, a process facilitated by ASF1A. DAXX is required for enrichment of ATRX, but not ASF1A or HIRA, with PML. Nonetheless, the chaperones colocalize with H3.3 at PML bodies and are found in one or more complexes with PML. Both DAXX and PML are necessary to prevent accumulation of a soluble, nonincorporated pool of H3.3. H3.3 targeting to PML is enhanced with an (H3.3-H4)2 tetramerization mutant of H3.3, suggesting H3.3 recruitment to PML as an (H3.3-H4) dimer rather than as a tetramer. Our data support a model of DAXX-mediated recruitment of (H3.3-H4) dimers to PML bodies, which may function as triage centers for H3.3 deposition into chromatin by distinct chaperones. 23804568 Median infectious dose of human norovirus GII.4 in gnotobiotic pigs is decreased by simvastatin treatment and increased by age. Human noroviruses (NoVs), a major cause of viral gastroenteritis, are difficult to study due to the lack of a cell-culture and a small-animal model. Pigs share with humans the types A and H histo-blood group antigens on the intestinal epithelium and have been suggested as a potential model for studies of NoV pathogenesis, immunity and vaccines. In this study, the effects of age and a cholesterol-lowering drug, simvastatin, on the susceptibility of pigs to NoV infection were evaluated. The median infectious dose (ID50) of a genogroup II, genotype 4 (GII.4) 2006b variant was determined. The ID50 in neonatal (4-5 days of age) pigs was ≤2.74×10(3) viral RNA copies. In older pigs (33-34 days of age), the ID50 was 6.43×10(4) but decreased to <2.74×10(3) in simvastatin-fed older pigs. Evidence of NoV infection was obtained by increased virus load in the intestinal contents, cytopathological changes in the small intestine, including irregular microvilli, necrosis and apoptosis, and detection of viral antigen in the tip of villi in duodenum. This GII.4 variant was isolated in 2008 from a patient from whom a large volume of stool was collected. GII.4 NoVs are continuously subjected to selective pressure by human immunity, and antigenically different GII.4 NoV variants emerge every 1-2 years. The determination of the ID50 of this challenge virus is valuable for evaluation of protection against different GII.4 variants conferred by NoV vaccines in concurrence with other GII.4 variants in the gnotobiotic pig model. 23851486 A soft cortex is essential for asymmetric spindle positioning in mouse oocytes. At mitosis onset, cortical tension increases and cells round up, ensuring correct spindle morphogenesis and orientation. Thus, cortical tension sets up the geometric requirements of cell division. On the contrary, cortical tension decreases during meiotic divisions in mouse oocytes, a puzzling observation because oocytes are round cells, stable in shape, that actively position their spindles. We investigated the pathway leading to reduction in cortical tension and its significance for spindle positioning. We document a previously uncharacterized Arp2/3-dependent thickening of the cortical F-actin essential for first meiotic spindle migration to the cortex. Using micropipette aspiration, we show that cortical tension decreases during meiosis I, resulting from myosin-II exclusion from the cortex, and that cortical F-actin thickening promotes cortical plasticity. These events soften and relax the cortex. They are triggered by the Mos-MAPK pathway and coordinated temporally. Artificial cortex stiffening and theoretical modelling demonstrate that a soft cortex is essential for meiotic spindle positioning. 23934853 SERCA cysteine-674 sulphonylation and inhibition of L-type calcium influx contribute to cardiac dysfunction in endotoxemic mice, independently of cGMP synthesis. The goal of this study was to identify the cellular mechanisms responsible for cardiac dysfunction in endotoxemic mice. We aimed to differentiate the roles of cGMP (produced by soluble guanylyl cyclase, sGC) vs. oxidative post-translational modifications (OPTM) of calcium (Ca(2+)) transporters. C57BL/6 mice (wild type, WT) were administered lipopolysaccharide (LPS, 25 μg/g, intraperitoneal) and euthanized 12 h later. Cardiomyocyte sarcomere shortening and Ca(2+) transients (ΔCai) were depressed in LPS-challenged mice vs. baseline. The time constant (τCa) of Ca(2+) decay was prolonged, and sarcoplasmic reticulum (SR) Ca(2+) load (CaSR) was depressed in LPS-challenged mice (vs. baseline), indicating decreased activity of SR Ca(2+) ATP-ase (SERCA). L-Type Ca(2+) channel (LTCC) current (ICa,L) was also decreased after LPS challenge, while Na(+)/Ca(2+) exchange activity, ryanodine receptors leak flux or myofilament sensitivity for Ca(2+) were unchanged. All Ca(2+) handling abnormalities induced by LPS (the decrease in sarcomere shortening, ΔCai, CaSR, ICa,L and τCa prolongation) were more pronounced in mice deficient in sGC main isoform (sGCα1(-/-)) vs. WT. LPS did not alter protein expression of SERCA and phospholamban (PLB) in either genotype. After LPS, PLB phosphorylation at Ser-16 and Thr-17 was unchanged in WT mice, and was increased in sGCα1(-/-) mice. LPS caused sulphonylation of SERCA cysteine-674 (as measured immunohistochemically and supported by iodoacetamide labeling), which was greater in sGCα1(-/-) vs. WT mice. Taken together, these results suggest that cardiac Ca(2+) dysregulation in endotoxemic mice is mediated by a decrease in LTCC function and OPTM of SERCA cysteine-674, the later (at least) being opposed by sGC-released cGMP. 23647815 Acute Pain Control Challenges with Buprenorphine/Naloxone Therapy in a Patient with Compartment Syndrome Secondary to McArdle's Disease: A Case Report and Review. We report the first case of non-iatrogentic exertional rhabdomyolysis leading to acute compartment syndrome in a patient with McArdle's disease. We describe considerations of concurrent buprenorphine/naloxone therapy during episodes of severe acute pain. Case report. A 50-year-old male with a history of McArdle's disease, taking buprenorphine/naloxone for chronic pain and opioid dependence, presented to the Emergency Department with severe bilateral anterior thigh pain. Over the following 8 hours, he was given a total of 12 mg of intravenous hydromorphone with minimal pain relief. The decision was made to initiate patient-controlled analgesia (PCA) with hydromorphone started at 0.5 mg as needed with a 15-minute lockout. Subsequently, the patient's anterior thighs were found to be extremely tense. His creatine kinase level rose to 198,688 units/L and compartment pressures were greater than 90 mm Hg bilaterally. The patient was taken for emergent bilateral fasciotomies. The hydromorphone PCA was increased to 0.8 mg as needed with a 15-minute lockout and a basal rate of 0.5 mg/h. The patient's reported pain plateaued at 3/10 intensity 2 days after surgery, and he was transitioned to oxycodone and hydrocodone/acetaminophen. He followed up with his pain management physician 2 months later who restarted suboxone and a buphrenorphine transdermal patch. Buprenorphine/naloxone is being prescribed off-label with increasing frequency for pain management in patients with or without a history of opioid abuse. Severe acute pain is more difficult to control with opioid analgesics in patients taking buprenorphine/naloxone, requiring higher than usual doses. If buprenorphine/naloxone is discontinued to better treat acute pain with other opioids, monitoring for overdose must take place for at least 72 hours. 23643543 Pharmacokinetic study of four flavones of Glycyrrhiza in rat plasma using HPLC-MS. AIM OF THE STUDY: This study aimed to develop a specific HPLC-MS method for simultaneous quantification of four flavones of Glycyrrhiza in rat plasma after oral administration and to describe the pharmacokinetics of four flavones in rat plasma. MATERIALS AND METHODS: A simple, sensitive and selective method for simultaneous determination of four flavones of Glycyrrhiza in rat plasma, i.e., liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin, by high performance liquid chromato-graphy-tandem mass spectrometry (HPLC-MS) with negative electrospray ionization mode, was developed and validated. The method was applied to investigate the pharmacokinetics of four flavones in rat plasma after oral administration of Glycyrrhiza flavones. Chromatographic separation was accomplished on an Agilent TC-C18 column (4.6mm×250mm, 5μm), with gradient elution by using a mixture of methanoic acid (A) and acetonitrile (B) as the mobile phase at a flow rate of 0.8mL/min. RESULTS: The calibration curves for four flavones had good linearity in the measured range with higher than 0.997. Relative standard deviations (RSDs) of the intra- and inter-day precision at different levels were all less than 4.8%. The pharmacokinetic profile of four flavones in rat plasma was fitted with a two-compartment model detected by a simple, rapid and accurate HPLC-MS method. Time (h) to reach peak concentration (μg/mL) of liquiritin (2.69±0.04), isoliquiritin (10.16±0.02), liquiritigenin (2.83±0.02), isoliquiritigenin (0.28±0.01) were 2.02±0.23, 1.97±0.20, 0.48±0.02, 1.93±0.36, respectively. The distribution and elimination half-life (h) and area under the concentration-time curve (μg/mL⁎h) from t=0 to last time of liquiritin, isoliquiritin, liquiritigenin, isoliquiritigenin were 1.02±0.48/2.27±0.53/16.97±0.43, 2.04±1.01/2.38±0.80/69.20±5.24, 0.35±0.10/4.26±0.16/14.83±0.11, 1.18±0.32/3.04, ±0.22/2.10±0.09, respectively. Isoliquiritin presented the phenomenon of double peaks and the others appeared together in a single and plateau absorption phase. Isoliquiritigenin had the lowest oral bioavailability because of Cmax and AUC0-∞. Liquiritigenin had the fastest absorption and distribution rate and the lowest elimination rate according to Tmax, t1/2α, t1/2β. CONCLUSIONS: This paper first reported on identification and determination of four flavones of Glycyrrhiza in rat plasma and their respective pharmacokinetic characteristics. The results provided a meaningful basis for better understanding the absorption mechanism of Glycyrrhiza and evaluating the clinical application of this medicine. 23932022 The development of rapid online control in children aged 6-12years: Reaching performance. Rapid online control during reaching has an important bearing on movement accuracy and flexibility. It is surprising then that few studies have investigated the development of rapid online control in children. In this study, we were particularly interested in age-related changes in the nature of motor control in response to visual perturbation. We compared the performance of younger (6-7years of age), mid-aged (8-9), and older (10-12) children, as well as healthy young adults using a double-step reaching task. Participants were required to make target-directed reaching movements in near space, while also responding to visual perturbations that occurred at movement onset for a small percentage of trials. Results showed that both the older and mid-aged children corrected their reaching in response to the unexpected shifts in target location significantly faster than younger children, manifest by reduced time to correction. In turn, the responses of adults were faster than older children in terms of movement time and on kinematic measures such as time to correction and time to peak velocity. These results indicate that the capacity to utilize forward estimates of limb position in the service of online control of early perturbations to ballistic (or rapid) reaching develops in a non-linear fashion, progressing rapidly between early and middle childhood, showing a degree of stability over mid and later childhood, but then evidence for continued refinement between childhood and young adulthood. The pattern of change after childhood and into early adolescence requires further investigation, particularly during the rapid phase of physical growth that accompanies puberty. 23881571 Synthesis of a Strained Acetylenic Macrocycle Incorporating a para-Oligo[2]cruciform Bridge Bent over Nanoscopic Dimensions: Structural, Electronic, Spectroscopic, and Ion-Sensing Properties. An Eglinton-Galbraith diethyne cyclization preferentially yielded a structurally unusual macrocycle, comprising a strained conjugated oligo[2]cruciform wire, forced into a 2.2 nm bow-shape by a terpyridine rein or tether, and stabilized towards light and heat by four insulating triisopropylsilylacetylene (TIPSA) substituents. Spectroscopic ion-binding studies revealed the macrocycle to exhibit a particularly high UV/Vis selectivity for Pd(II) in dilute solution, and one of its precursors to afford a variety of luminescence quenching and color responses to particular metals, suggestive of promising ion-sensor applications. Under more concentrated conditions, the new macrocycle is able to bind specific metals (e.g., Au(I) ) within its cavity despite the steric constraints. Intriguingly, variable-temperature (VT) UV/Vis/(1) H NMR investigations showed the TIPSA substituents to undergo restricted intramolecular motions along with reversible changes in the spectroscopic bandgap of the compound with temperature. In line with the theoretical calculations, the VT UV/Vis observations are consistent with a thermal modulation of the electronic conjugation through the strained oligo[2]cruciform bridge, which is coupled with redistributions within a mixture of conformational isomers of the macrocycle with differing relative twisting between the TIPSA-substituted phenyl rings. Overall, the generation of a para-oligo[2]cruciform, bent and flexed over nanoscopic dimensions through conformational tethering within the macrocyclic ring is noteworthy, and suggests a general approach to nanosized, curved, and strained, yet heat- and light-stable, para-phenyleneethynylene oligomers with unique physicochemical properties and challenging theoretical possibilities. 23535876 Physician recommendations and patient adherence after inadequate bowel preparation on screening colonoscopy. It has been suggested that bowel preparation quality may influence decision-making about appropriate follow-up interval after screening colonoscopy. We sought: (1) to assess physician recommendations for timing of subsequent colonoscopy in average-risk patients with inadequate bowel preparation on initial screening, and (2) to measure the association between physician recommendations and patient adherence to repeat colonoscopy. Patients undergoing average-risk screening colonoscopy from 2004 to 2009 found to have inadequate bowel preparation were identified. Physician recommendations for timing of subsequent colonoscopy and patient adherence to repeat colonoscopy were assessed through examination of endoscopy records. Data from repeat colonoscopies were collected through August 2010. There were 373 patients with inadequate bowel preparation on initial screening colonoscopy. There was a wide range of physician recommendations for timing of repeat colonoscopy: next day (4.6 % of patients), 2 days to 6 months (9.9 %), 7 months to 1 year (34.0 %), 2-5 years (38.3 %), 6-10 years (5.1 %), and timing not specified (8.0 %). Physicians were significantly more likely to recommend repeat colonoscopy within 1 year if any polyps were detected (OR = 2.2, p = 0.001). Patients instructed to have next day follow-up were significantly more likely to adhere to the recommendation compared to patients who were instructed to return after longer intervals (OR 4.4, p = 0.005). Patients with inadequate bowel preparation on screening colonoscopy were subject to a wide range of physician recommendations for follow-up. Patient adherence to physician recommendations was significantly higher when repeat colonoscopy was recommended the next day. 23919424 Correlative Assessment of Fecal Indicators using Human Mitochondrial DNA as a Direct Marker. Identifying the source of surface water fecal contamination is paramount to mitigating pollution and risk to human health. Fecal bacteria such as E. coli have been staple indicator organisms for over a century, however there remains uncertainty with E. coli-based metrics since these bacteria are abundant in the environment. The relationships between the presence of direct indicator of human waste (human mitochondrial DNA), human-specific Bacteroidales, and E. coli were studied for water samples taken from an urban creek system (Duck Creek Watershed, Cincinnati, OH) impacted by combined sewer overflows. Logistic regression analysis shows that human-specific Bacteroidales correlates much more closely to human mitochondrial DNA (R = 0.62) relative to E. coli (R = 0.33). We also examine the speciation of Bacteroidales within the Duck Creek Watershed using next-generation sequencing technology (Ion Torrent) and show the most numerous populations to be associated with sewage. Here we demonstrate that human-specific Bacteroidales closely follow the dynamics of human mitochondrial DNA concentration changes, indicating that these obligate anaerobes are more accurate than E. coli for fecal source tracking, lending further support to risk overestimation using coliforms, especially fecal coliforms and E. coli. 23843273 Self-Assembly of Semiconducting Single-Walled Carbon Nanotubes into Dense, Aligned Rafts. Highly pure semiconducting single-walled carbon nanotubes (SWNTs) are separated from bulk materials and self-assembled into densely aligned rafts. Microscopy and spectroscopy reveals ∼100 SWNTs per micrometer within the rafts. Short channel field-effect transistors (FETs) from tens of purely semiconducting SWNTs within a submicrometer channel width achieve unprecedented on-currents (up to 121 μA) with high on/off ratios. The results demonstrate densely aligned semiconducting SWNTs for high-performance nanoelectronics. 23819730 Percutaneous cervical cordotomy for the management of pain from cancer: a prospective review of 45 cases. Abstract Background: Percutaneous cervical cordotomy (PCC) is a well recognized but infrequently performed procedure for the relief of unilateral intractable pain from malignancy. There is a paucity of data regarding efficacy and safety of PCC. Objectives: The study's objectives were to demonstrate the efficacy and safety of PCC in cancer pain. Design: The study was a prospective review of 45 cases undergoing PCC at a tertiary referral center over a three-year period. Settings/Subjects: All patients were suffering from severe, refractory unilateral pain secondary to malignancy with poor pain relief or intolerable side effects of conventional analgesics including opioids and adjuvants. Measurements: Variables recorded preprocedure, at 2 days, and at 28 days postprocedure were numerical rating scale for maximum and average pain, oral morphine equivalent dose, and global impression of change. Adverse events and survival postprocedure were recorded. Results: Prospective data was obtained in 45 patients. Survival postprocedure ranged from 7 days to 33 months. There was a significant reduction from baseline in pain scores at 2 days and at 28 days postprocedure. Thirty-two patients experienced significant pain relief-average numerical rating scale (NRS) of zero-on day 2. Improvement in pain scores was sustained at 28 days. There were no serious adverse events observed such as respiratory failure. Conclusions: PCC is a safe and highly effective procedure to treat intractable unilateral cancer pain. It offers significant advantages over other pain control methods. Patient selection and attention to detail is paramount for a successful outcome. 23931032 Chronobiology of the renin-angiotensin-aldosterone system in dogs: relation to blood pressure and renal physiology. The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the regulation of blood pressure and volume homeostasis. Its contribution to the development of cardiovascular diseases has long been recognized. Extensive literature has shown that peptides of the RAAS oscillate with a circadian periodicity in humans, under strong influence of posture, sleep, and age. Although observations of time-variant changes in the renin cascade are available in dogs, no detailed chronobiological investigation has been conducted so far. The present studies were designed to explore the circadian variations of plasma renin activity (RA) and urinary aldosterone-to-creatinine ratio (UA:C) in relation to blood pressure (BP), sodium (UNa, UNa,fe), and potassium (UK, UK,fe) renal handling. Data derived from intensive blood and urine sampling, as well as continuous BP monitoring, were collected throughout a 24-h time period, and analyzed by means of nonlinear mixed-effects models. Differences between the geometric means of day and night observations were compared by parametric statistics. Our results show that variables of the renin cascade, BP, and urinary electrolytes oscillate with significant day-night differences in dogs. An approximately 2-fold (1.6-3.2-fold) change between the average day and night measurements was found for RA (p < 0.001), UA:C (p = 0.01), UK,fe (p = 0.01), and UNa (p = 0.007). Circadian variations in BP, albeit small (less than 10 mm Hg), were statistically significant (p < 0.01) and supported by the model-based analysis. For all variables but UNa and UNa,fe, the levels were higher at night than during the day. The data also indicate that blood pressure oscillates in parallel to the RAAS, such that, as opposed to healthy humans, BP does not drop at night in dogs. The postprandial decrease in RA is assumed to be related to body fluid volume expansion secondary to water and sodium intake, whereas the reduction of UA:C reflects aldosterone-stimulated secretion by the renin-angiotensin II pathway. UNa and UNa,fe peaked in the afternoon, about 7-8 h after food intake, which is consistent with the "impulse-response pattern" of sodium excretion described in previous publications. Finally, UK and UK,fe mirrored aldosterone-mediated potassium secretion in the kidney tubules. To describe the circadian variations of the various variables, two different mathematical representations were applied. A cosine model with a fixed 24-h period was found to fit the periodic variations of RA, UA:C, UK, UK,fe, and BP well, whereas changes in UNa and UNa,fe were best characterized by a surge model. The use of nonlinear mixed effects allowed estimation of population characteristics that can influence the periodicity of the RAAS. Specifically, sodium intake was found to interact with the tonic and the phasic secretion of renin, suggesting that varying feeding time could also impact the chronobiology of the renin cascade. (Author correspondence: jonathan.mochel@novartis.com). 23483519 Assembling an ion channel: ORF 3a from SARS-CoV. Protein 3a is a 274 amino acid polytopic channel protein with three putative transmembrane domains (TMDs) encoded by severe acute respiratory syndrome corona virus (SARS-CoV). Synthetic peptides corresponding to each of its three individual transmembrane domains (TMDs) are reconstituted into artificial lipid bilayers. Only TMD2 and TMD3 induce channel activity. Reconstitution of the peptides as TMD1 + TMD3 as well as TMD2 + TMD3 in a 1 : 1 mixture induces membrane activity for both mixtures. In a 1 : 1 : 1 mixture, channel like behavior is almost restored. Expression of full length 3a and reconstitution into artificial lipid bilayers reveal a weak cation selective (PK ≈ 2 PCl ) rectifying channel. In the presence of nonphysiological concentration of Ca-ions the channel develops channel activity. © 2013 Wiley Periodicals, Inc. Biopolymers 99:628-635, 2013. 23461648 Fengycin C Produced by Bacillus subtilis EA-CB0015. Bacillus subtilis EA-CB0015 was isolated from the phyllosphere of a banana plant and tested for its potential to produce bioactive compounds against Mycosphaerella fijiensis. Using a dual plate culture technique the cell-free supernatant of B. subtilis EA-CB0015 produced inhibition values of 89 ± 1%. The active compounds were purified by solid-phase extraction and HPLC, and their primary structures determined using mass spectrometry and amino acid analysis. A new fengycin isoform, fengycin C, with the amino acid sequence Glu-Orn-Tyr-Thr-Glu-Val-Pro-Gln-Thr-Ile was isolated. The peptidic moiety differs from fengycin B at position 9 and from fengycin A at positions 6 and 9. The β-hydroxy fatty acyl chain is connected to the N-terminal of the decapeptide and can be saturated or unsaturated, ranging from 14 to 18 carbons. The C-terminal residue of the peptidic moiety is linked to the tyrosine residue at position 3, forming the branching point of the acyl peptide and the eight-membered cyclic lactone. 23770644 Coping style and ecstasy use motives as predictors of current mood symptoms in ecstasy users. Elevated depressive and anxiety symptoms during childhood and adolescence have been associated with greater risk of later ecstasy use. Ecstasy users have reported using ecstasy to reduce depression or worry, or to escape. While these findings suggest that some people use ecstasy as a form of self-medication, limited research has been conducted examining the relationship between affective symptoms, coping styles and drug use motives in ecstasy users. This cross-sectional study aimed to determine if coping style and/or ecstasy use motives are associated with current mood symptoms in ecstasy users. A community sample (n=184) of 18-35year olds who had taken ecstasy at least once in the past 12months completed self-report measures of depression, anxiety, ecstasy use motives and coping styles. Timeline followback methods were used to collect information on lifetime ecstasy, recent drug use and life stress. Trauma exposure was measured using the Composite International Diagnostic Interview-Trauma List. Coping motives for ecstasy use and an emotion-focused coping style were significantly associated with current depressive and anxiety symptoms. Emotion-focused coping mediated the relationship between a history of trauma and current anxiety symptoms and moderated the relationship between recent stressful life events and current depressive symptoms. These findings highlight the importance of interventions targeting motives for ecstasy use, and providing coping skills training for managing stressful life events among people with co-occurring depressive/anxiety symptoms and ecstasy use. 23868210 Peptide antagonists of the calcitonin gene-related peptide (CGRP) receptor with improved pharmacokinetics and pharmacodynamics. Antagonism of the calcitonin gene-related peptide (CGRP) receptor may be a useful approach for migraine treatment. Selective PEGylated peptide antagonists to the CGRP receptor are described, derived from CGRP(8-37) with polymer derivatization at an engineered lysine-25 residue. Potent PEGylated peptides with improved pharmacokinetics were identified through peptide side-chain modification to mitigate metabolic liabilities. PEGylated Ac-Trp-[Cit(11,18) ,hArg(24) ,Lys(25) ,Asp(31) ,Pro(34) ,1-Nal(35) ]CGRP(8-37)-NH2 , 9, elicits a dose-dependent reduction of intradermal CGRP-induced local blood flow in rodents with an ED50 of 0.52 mg kg(-1) without any overt adverse effects. © 2013 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 100: 422-430, 2013. 23829604 Musculoskeletal health profile for elite female footballers versus untrained young women before and after 16 weeks of football training. Abstract We investigated the musculoskeletal health profile of elite female football players (ET) in comparison to untrained (UT) young women subjected to 16 weeks of football training (2 Ã— 1 h per week). DXA scans, blood sampling, sprint testing and Flamingo postural balance testing were carried out for 27 Danish national team players and 28 untrained women, with eight women being tested after training. At baseline total BMD and BMC were 13% (1.305 ± 0.050 versus 1.159 ± 0.056 g · cm(-2)) and 23% (3047 ± 235 versus 2477 ± 526 g) higher (P <0.001) and leg BMD and BMC were 24 and 28% higher (P <0.01) in ET than in UT. Resting plasma osteocalcin was 45% higher in ET than in UT (28.8 ± 10.9 versus 19.9 ± 9.9 µg · L(-1), P <0.05). Total lean body mass was 14% higher (50.4 ± 3.3 versus 44.3 ± 4.0 kg) in ET compared with UT, with no difference in total body mass. The number of Flamingo test falls was 56-63% less (P <0.01) and 30 m sprinting speed was 31% faster (P <0.001) in ET than UT. After 16 weeks of football training for UT, lean body mass increased by 1.4 ± 0.5 kg and the number of left leg falls decreased by 29% (P <0.05). No significant changes occurred in BMD or BMC, but plasma osteocalcin increased (P <0.05) by 37%. In summary, elite women footballers have an impressive musculoskeletal health profile compared with untrained controls, but short-term football training seems to reduce the risk of falls and increase bone formation. 23624531 Cause-specific mortality in Scottish patients with colorectal cancer with and without type 2 diabetes (2000-2007). The objective of this study was to use Scottish national data to assess the influence of type 2 diabetes on (1) survival (overall and cause-specific) in multiple time intervals after diagnosis of colorectal cancer and (2) cause of death. Data from the Scottish Cancer Registry were linked to data from a population-based national diabetes register. All people in Scotland diagnosed with non-metastatic cancer of the colon or rectum in 2000-2007 were included. The effect of pre-existing type 2 diabetes on survival over four discrete time intervals (<1, 1-2, 3-5 and >5 years) after cancer diagnosis was assessed by Cox regression. Cumulative incidence functions were calculated representing the respective probabilities of death from the competing causes of colorectal cancer, cardiovascular disease, other cancers and any other cause. Data were available for 19,505 people with colon or rectal cancer (1,957 with pre-existing diabetes). Cause-specific mortality analyses identified a stronger association between diabetes and cardiovascular disease mortality than that between diabetes and cancer mortality. Beyond 5 years after colon cancer diagnosis, diabetes was associated with a detrimental effect on all-cause mortality after adjustment for age, socioeconomic status and cancer stage (HR [95% CI]: 1.57 [1.19, 2.06] in men; 1.84 [1.36, 2.50] in women). For patients with rectal cancer, diabetes was not associated with differential survival in any time interval. Poorer survival observed for colon cancer associated with type 2 diabetes in Scotland may be explained by higher mortality from causes other than cancer. 23846024 Conjugated microporous polymers: design, synthesis and application. Conjugated microporous polymers (CMPs) are a class of organic porous polymers that combine π-conjugated skeletons with permanent nanopores, in sharp contrast to other porous materials that are not π-conjugated and with conventional conjugated polymers that are nonporous. As an emerging material platform, CMPs offer a high flexibility for the molecular design of conjugated skeletons and nanopores. Various chemical reactions, building blocks and synthetic methods have been developed and a broad variety of CMPs with different structures and specific properties have been synthesized, driving the rapid growth of the field. CMPs are unique in that they allow the complementary utilization of π-conjugated skeletons and nanopores for functional exploration; they have shown great potential for challenging energy and environmental issues, as exemplified by their excellent performance in gas adsorption, heterogeneous catalysis, light emitting, light harvesting and electrical energy storage. This review describes the molecular design principles of CMPs, advancements in synthetic and structural studies and the frontiers of functional exploration and potential applications. 23818328 Nutritional lipidomics: Molecular metabolism, analytics, and diagnostics. The field of lipidomics is providing nutritional science a more comprehensive view of lipid intermediates. Lipidomics research takes advantage of the increase in accuracy and sensitivity of mass detection of MS with new bioinformatics toolsets to characterize the structures and abundances of complex lipids. Yet, translating lipidomics to practice via nutritional interventions is still in its infancy. No single instrumentation platform is able to solve the varying analytical challenges of the different molecular lipid species. Biochemical pathways of lipid metabolism remain incomplete and the tools to map lipid compositional data to pathways are still being assembled. Biology itself is dauntingly complex and simply separating biological structures remains a key challenge to lipidomics. Nonetheless, the strategy of combining tandem analytical methods to perform the sensitive, high-throughput, quantitative, and comprehensive analysis of lipid metabolites of very large numbers of molecules is poised to drive the field forward rapidly. Among the next steps for nutrition to understand the changes in structures, compositions, and function of lipid biomolecules in response to diet is to describe their distribution within discrete functional compartments lipoproteins. Additionally, lipidomics must tackle the task of assigning the functions of lipids as signaling molecules, nutrient sensors, and intermediates of metabolic pathways. 23872542 Treatment of multicentric reticulohistiocytosis with tocilizumab. Multicentric reticulohistiocytosis (MRH) is a rare multisystem, granulomatous debilitating disease. It affects the skin with a nodular diffuse dermatitis and the joints with a severe, potentially deforming, and handicapping arthritis. No standardized therapy exists, it is a disease with heterogeneous severity, and therefore, a diversity of therapeutic responses has been published.Current experience with anti-tumor necrosis factor agents in disease-modifying antirheumatic drug-refractory MRH cases is encouraging, and other agents such as bisphosphonates have proven effective as well. Histological analysis of the granulomatous inflammatory lesions have shown the presence of cytokines including tumor necrosis factor α, interleukin 1, and interleukin 6; the presence of the latter makes tocilizumab a plausible alternative.In this article, we report a 35-year-old woman with MRH refractory to a combined scheme of prednisone and methotrexate, both at high doses, and who received tocilizumab achieving remission on both cutaneous and articular symptoms. Our patient markedly improved by the second infusion (8 mg/kg monthly), and after 9 infusions, she remained asymptomatic; no toxicity was detected. Tocilizumab could be an alternative for disease-modifying antirheumatic drug-refractory MRH. 23638693 Clinical utility of viscoelastic tests of coagulation in patients with liver disease. The prothrombin time (PT) and international normalised ratio (INR) are used in scoring systems (Child-Pugh, MELD, UKELD) in chronic liver disease and as a prognostic tool and for dynamic monitoring of hepatic function in acute liver disease. These tests are known to be poor predictors of bleeding risk in liver disease; however, they continue to influence clinical management decisions. Recent work on coagulation in liver disease, in particular thrombin generation studies, has led to a paradigm shift in our understanding and it is now recognised that haemostasis is relatively well preserved. Whole blood global viscoelastic tests (TEG(®) /ROTEM(®) ) produce a composite dynamic picture of the entire coagulation process and have the potential to provide more clinically relevant information in patients with liver disease. We performed a systematic review of all relevant studies that have used viscoelastic tests (VET) of coagulation in patients with liver disease. Although many studies are observational and small in size, it is clear that VET provide additional information that is in keeping with the new concepts of how coagulation is altered in these patients. This review provides the basis for large scale, prospective outcome studies to establish the clinical value of these tests. 23951048 Chronic Alcohol-Induced microRNA-155 Contributes to Neuroinflammation in a TLR4-Dependent Manner in Mice. Alcohol-induced neuroinflammation is mediated by pro-inflammatory cytokines and chemokines including tumor necrosis factor-α (TNFα), monocyte chemotactic protein-1 (MCP1) and interleukin-1-beta (IL-1β). Toll-like receptor-4 (TLR4) pathway induced nuclear factor-κB (NF-κB) activation is involved in the pathogenesis of alcohol-induced neuroinflammation. Inflammation is a highly regulated process. Recent studies suggest that microRNAs (miRNAs) play crucial role in fine tuning gene expression and miR-155 is a major regulator of inflammation in immune cells after TLR stimulation. To evaluate the role of miR-155 in the pathogenesis of alcohol-induced neuroinflammation. Wild type (WT), miR-155- and TLR4-knockout (KO) mice received 5% ethanol-containing or isocaloric control diet for 5 weeks. Microglia markers were measured by q-RTPCR; inflammasome activation was measured by enzyme activity; TNFα, MCP1, IL-1β mRNA and protein were measured by q-RTPCR and ELISA; phospho-p65 protein and NF-κB were measured by Western-blotting and EMSA; miRNAs were measured by q-PCR in the cerebellum. MiR-155 was measured in immortalized and primary mouse microglia after lipopolysaccharide and ethanol stimulation. Chronic ethanol feeding up-regulated miR-155 and miR-132 expression in mouse cerebellum. Deficiency in miR-155 protected mice from alcohol-induced increase in inflammatory cytokines; TNFα, MCP1 protein and TNFα, MCP1, pro-IL-1β and pro-caspase-1 mRNA levels were reduced in miR-155 KO alcohol-fed mice. NF-κB was activated in WT but not in miR-155 KO alcohol-fed mice. However increases in cerebellar caspase-1 activity and IL-1β levels were similar in alcohol-fed miR-155-KO and WT mice. Alcohol-fed TLR4-KO mice were protected from the induction of miR-155. NF-κB activation measured by phosphorylation of p65 and neuroinflammation were reduced in alcohol-fed TLR4-KO compared to control mice. TLR4 stimulation with lipopolysaccharide in primary or immortalized mouse microglia resulted in increased miR-155. Chronic alcohol induces miR-155 in the cerebellum in a TLR4-dependent manner. Alcohol-induced miR-155 regulates TNFα and MCP1 expression but not caspase-dependent IL-1β increase in neuroinflammation. 23935585 Language influences on numerical development-Inversion effects on multi-digit number processing. In early numerical development, children have to become familiar with the Arabic number system and its place-value structure. The present review summarizes and discusses evidence for language influences on the acquisition of the highly transparent structuring principles of digital-Arabic digits by means of its moderation through the transparency of the respective language's number word system. In particular, the so-called inversion property (i.e., 24 named as "four and twenty" instead of "twenty four") was found to influence number processing in children not only in verbal but also in non-verbal numerical tasks. Additionally, there is first evidence suggesting that inversion-related difficulties may influence numerical processing longitudinally. Generally, language-specific influences in children's numerical development are most pronounced for multi-digit numbers. Yet, there is currently only one study on three-digit number processing for German-speaking children. A direct comparison of additional new data from Italian-speaking children further corroborates the assumption that language impacts on cognitive (number) processing as inversion-related interference was found most pronounced for German-speaking children. In sum, we conclude that numerical development may not be language-specific but seems to be moderated by language. 23932032 Mixed-mode chromatography with zwitterionic phosphopeptidomimetic selectors from Ugi multicomponent reaction. In the present contribution a novel Ugi multicomponent reaction (MCR) was used to generate zwitterionic chromatographic selectors with capability for application in mixed-mode chromatography featuring complementary selectivities in reversed-phase (RP) and hydrophilic interaction liquid chromatography (HILIC). Aminophosphonate zwitterionic chromatographic ligands were synthesized adopting a one pot microwave assisted three-component UGI-MCR synthesis and, after purification, were immobilized by thiol-ene click chemistry on silica beads. Chromatographic characteristics of these stationary phases were evaluated by variation of experimental conditions for a set of diverse analytes with neutral, acidic, basic and zwitterionic character revealing the presence of multimodal retention capabilities (i.e. tunable retention increments from ion exchange, hydrophobic and hydrophilic interaction were observed). To further investigate and classify the retention properties of the novel stationary phases we performed a comparative chromatographic study with commercially available mixed mode, HILIC and RP columns. The resultant chromatographic data were analyzed by principal component analysis (PCA). PCA revealed that the new reversed-phase/zwitterionic ion-exchangers (RP/ZWIX) are complementary to common RP, HILIC and mixed-mode phases on the market and could be a promising alternative in impurity profiling and 2D-HPLC concepts. Moreover, the adopted synthetic approach offers the capability to generate chemical diversity simply by the variation of the starting aldehyde, aminophosphonic acid and/or isonitrile components. This unique characteristics offer great possibility for the design of novel selectors for mixed mode chromatography like RP/ZWIX, HILIC, affinity and chiral chromatography. 23861795 An Observational Study of Circulating Tumor Cells and (18)F-FDG PET Uptake in Patients with Treatment-Naive Non-Small Cell Lung Cancer. We investigated the relationship of circulating tumor cells (CTCs) in non-small cell lung cancer (NSCLC) with tumor glucose metabolism as defined by (18)F-fluorodeoxyglucose (FDG) uptake since both have been associated with patient prognosis. We performed a retrospective screen of patients at four medical centers who underwent FDG PET-CT imaging and phlebotomy prior to a therapeutic intervention for NSCLC. We used an Epithelial Cell Adhesion Molecule (EpCAM) independent fluid biopsy based on cell morphology for CTC detection and enumeration (defined here as High Definition CTCs or "HD-CTCs"). We then correlated HD-CTCs with quantitative FDG uptake image data calibrated across centers in a cross-sectional analysis. We assessed seventy-one NSCLC patients whose median tumor size was 2.8 cm (interquartile range, IQR, 2.0-3.6) and median maximum standardized uptake value (SUVmax) was 7.2 (IQR 3.7-15.5). More than 2 HD-CTCs were detected in 63% of patients, whether across all stages (45 of 71) or in stage I disease (27 of 43). HD-CTCs were weakly correlated with partial volume corrected tumor SUVmax (r = 0.27, p-value = 0.03) and not correlated with tumor diameter (r = 0.07; p-value = 0.60). For a given partial volume corrected SUVmax or tumor diameter there was a wide range of detected HD-CTCs in circulation for both early and late stage disease. CTCs are detected frequently in early-stage NSCLC using a non-EpCAM mediated approach with a wide range noted for a given level of FDG uptake or tumor size. Integrating potentially complementary biomarkers like these with traditional patient data may eventually enhance our understanding of clinical, in vivo tumor biology in the early stages of this deadly disease. 23639228 Bioequivalence evaluation of two formulations of pidotimod using a limited sampling strategy. The aim of this study was to develop a limited sampling strategy (LSS) to assess the bioequivalence of two formulations of pidotimod. A randomized, two-way, cross-over study was conducted in healthy Chinese volunteers to compare two formulations of pidotimod. A limited sampling model was established using regression models to estimate the pharmacokinetic parameters and assess the bioequivalence of pidotimod. The model was internally validated by the Jack-knife method and graphical methods. The traditional non-compartmental method was also used to analyze the data and compared with LSS method. The results indicate that following oral administration of a single 800mg dose, the plasma AUC0-12h and Cmax of pidotimod can be predicted accurately using only two to four plasma samples. The bioequivalence assessment based on the LSS models provided results very similar to that obtained using all the observed concentration-time data points and indicate that the two pidotimod formulations were bioequivalent. A LSS method for assessing the bioequivalence of pidotimod formulations was established and proved to be applicable and accurate. This LSS method could be considered appropriate for a pidotimod bioequivalence study, providing an inexpensive cost of sampling acquisition and analysis. And the methodology presented here may also be applicable to bioequivalence evaluation of other medications. 23892736 Outcomes in obstetric fistula care: a literature review. To highlight the lack of consistency in the terminology and indicators related to obstetric fistula care and to put forward a call for consensus. Recent studies show at least some degree of statistical correlation between outcome and the following clinical factors: degree of scarring/fibrosis, fistula location, fistula size, damage to the urethra, presence of circumferential fistula, bladder capacity, and prior attempt at fistula repair. Consensus about basic definitions of clinical success does not yet exist. Opinions vary widely about the prognostic parameters for success or failure. Commonly agreed upon definitions and outcome measures will help ensure that site reviews are accurate and conducted fairly. To properly compare technical innovations with existing methods, agreement must be reached on definitions of success. Standardized indicators for mortality and morbidity associated with fistula repair will improve the evidence base and contribute to quality of care. 23895452 Circadian phase-dependent effect of nitric oxide on L-type voltage-gated calcium channels in avian cone photoreceptors. Nitric oxide (NO) plays an important role in phase-shifting of circadian neuronal activities in the suprachiasmatic nucleus and circadian behavior activity rhythms. In the retina, NO production is increased in a light-dependent manner. While endogenous circadian oscillators in retinal photoreceptors regulate their physiological states, it is not clear whether NO also participates in the circadian regulation of photoreceptors. In this study, we demonstrate that NO is involved in the circadian phase-dependent regulation of L-type voltage-gated calcium channels (L-VGCCs). In chick cone photoreceptors, the L-VGCCα1 subunit expression and the maximal L-VGCC currents are higher at night, and both Ras-mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (Erk) and Ras-phosphatidylinositol 3 kinase (PI3K)-protein kinase B (Akt) are part of the circadian output pathways regulating L-VGCCs. The NO-cGMP-protein kinase G (PKG) pathway decreases L-VGCCα1 subunit expression and L-VGCC currents at night, but not during the day, and exogenous NO donor or cGMP decreases the phosphorylation of Erk and Akt at night. The protein expression of neural NO synthase (nNOS) is also under circadian control, with both nNOS and NO production being higher during the day. Taken together, NO/cGMP/PKG signaling is involved as part of the circadian output pathway to regulate L-VGCCs in cone photoreceptors. In cone photoreceptors, the protein expression of neural nitric oxide synthase (nNOS) and NO production are under circadian control. NO-cGMP-protein kinase G (PKG) signaling serves in the circadian output pathway to regulate the circadian rhythms of L-type voltage-gated calcium channels (L-VGCCs) in part through regulating the phosphorylation states of extracellular-signal-regulated kinase (Erk) and protein kinase B (Akt). 23954545 Investigation of the inclusion interaction of p-sulfonatocalix[6]arene with triamterene. The inclusion complexation behavior of p-sulfonatocalix[6]arene (SCX6) with triamterene (TA) was investigated by fluorescence spectroscopy, UV-Vis spectroscopy, (1)H and 2D NMR, FT-IR, SEM and DSC. The results indicate that TA is able to form an inclusion complex with SCX6. The inclusion complex has a stoichiometry of 1:1 at pH 6.50. In addition, the water solubility of TA was obviously increased in the inclusion complex with SCX6. 23869185 The effect of intraoperative use of high-dose remifentanil on postoperative insulin resistance and muscle protein catabolism: a randomized controlled study. Objective: We investigated the effect of the intraoperative use of a high dose remifentanil on insulin resistance and muscle protein catabolism. Design: Randomized controlled study. Patients and Intervention: Thirty-seven patients undergoing elective gastrectomy were randomly assigned to 2 groups that received remifentanil at infusion rates of 0.1 μg·kg(-1)·min(-1) (Group L) and 0.5 μg·kg(-1)·min(-1) (Group H). Main outcome measures: Primary efficacy parameters were changes in homeostasis model assessment as an index of insulin resistance (HOMA-IR) and 3-methylhistidine/creatinine (3-MH/Cr). HOMA-IR was used to evaluate insulin resistance, and 3-MH/Cr was used to evaluate the progress of muscle protein catabolism. Intraoperative stress hormones, insulin, and blood glucose were assessed as secondary endpoints. Results: Eighteen patients in Group L and 19 in Group H were examined. HOMA-IR values varied within normal limits in both groups during surgery, exceeding normal limits at 12 h after surgery and being significantly elevated in Group L. There were no significant differences in the 3-MH/Cr values between the 2 groups at any time point. The stress hormones (adrenocorticotropic hormone, cortisol, and adrenaline) were significantly elevated in Group L at 60 min after the start of surgery and at the initiation of skin closure. There were no significant differences in insulin values, but blood glucose was significantly elevated in Group L at 60 min after the start of surgery and at the start of skin closure. Conclusion: Use of high-dose remifentanil as intraoperative analgesia during elective gastrectomy reduced postoperative insulin resistance, although it did not reduce postoperative muscle protein catabolism. 23893030 Sodium dodecyl sulfate (SDS) effect on the thermal stability of oxy-HbGp: Dynamic light scattering (DLS) and small angle X-ray scattering (SAXS) studies. Glossoscolex paulistus (HbGp) hemoglobin is an oligomeric protein, presenting a quaternary structure constituted by 144 globin and 36 non-globin chains (named linkers) with a total molecular mass of 3.6MDa. SDS effects on the oxy-HbGp thermal stability were studied, by DLS and SAXS, at pH 5.0, 7.0 and 9.0. DLS and SAXS data show that the SDS-oxy-HbGp interactions induce a significant decrease of the protein thermal stability, with the formation of larger aggregates, at pH 5.0. At pH 7.0, oxy-HbGp undergoes complete oligomeric dissociation, with increase of temperature, in the presence of SDS. Besides, oxy-HbGp 3.0mg/mL, pH 7.0, in the presence of SDS, has the oligomeric dissociation process reduced as compared to 0.5mg/mL of protein. At pH 9.0, oxy-HbGp starts to dissociate at 20°C, and the protein is totally dissociated at 50°C. The thermal dissociation kinetic data show that oxy-HbGp oligomeric dissociation at pH 7.0, in the presence of SDS, is strongly dependent on the protein concentration. At 0.5mg/mL of protein, the oligomeric dissociation is complete and fast at 40 and 42°C, with kinetic constants of (2.1±0.2)×10(-4) and (5.5±0.4)×10(-4)s(-1), respectively, at 0.6mmol/L SDS. However, at 3.0mg/mL, the oligomeric dissociation process starts at 46°C, and only partial dissociation, accompanied by aggregates formation is observed. Moreover, our data show, for the first time, that, for 3.0mg/mL of protein, the oligomeric dissociation, denaturation and aggregation phenomena occur simultaneously, in the presence of SDS. Our present results on the surfactant-HbGp interactions and the protein thermal unfolding process correspond to a step forward in the understanding of SDS effects. 23157341 Antitumor properties of natural compounds and related molecules. Cancer is the main cause of death in developing countries. Its development requires multiple steps in which the occurrence of certain events determines the state transition from a normal to a tumor cell. These events are related to the loss of mechanisms that control various biological processes, which results from the accumulation of genetic alterations, including mutations, chromosomal rearrangements, and variations in gene copy number, as well as from epigenetic alterations. In general, chemotherapeutic agents used for toxicity treatments have shown limited antitumor activity, with a high recurrence rate. This has prompted major research efforts to identify novel effective and selective anti-tumor compounds. In this article, we review recent patents that protect the antitumor properties of natural compounds and related molecules derived from plants, animals, or microorganisms. We consider their structure, mechanism of action, molecular targets and, in some cases, the clinical trial phase reached. We also report on various natural agents that appear to prevent cancer development. 23856713 Vaccination of healthy children against seasonal influenza: a European perspective. Despite ample evidence for the great burden that annual influenza epidemics place on children and society in general, few European countries currently recommend influenza vaccination of healthy children of any age. The most frequently cited reasons for reluctance to extend general vaccine recommendations to children include the view that influenza is a mild illness of limited clinical importance, lack of country-specific data on disease burden, uncertainty about the efficacy and safety of influenza vaccines in children and inadequate evidence of cost-effectiveness of vaccinating children. In recent years, several clinical studies have provided new and important information that help address many of these areas of question and concern. In light of this newly available scientific evidence, influenza vaccine recommendations for children should be properly reevaluated in all European countries. Furthermore, to allow for variation in costs and patterns of healthcare delivery between different countries, cost-effectiveness analyses of influenza vaccination of healthy children should be performed in each country or region. Finally, increased efforts should be made to educate both healthcare professionals and the great public about recent findings and advances in the field of pediatric influenza. 23770447 Potentiating 1-(2-hydroxypropyl)-2-styryl-5-nitroimidazole derivatives against antibacterial agents: Design, synthesis and biology analysis. A series of novel 1-(2-hydroxypropyl)-2-styryl-5-nitroimidazole derivatives had been designed, synthesized, isolated and evaluated as potentiators of antibacterial agents. All these synthesized compounds were determined by elemental analysis, (1)H NMR, and MS. Their biological activities were also evaluated against two Gram-negative bacterial strains: Escherichia coli and Pseudomonas aeruginosa and two Gram-positive bacterial strains: Bacillus thuringiensis and Bacillus subtilis by MTT method as potential FabH inhibitory. The results showed that compound 30 exhibited the most potent E. coli FabH inhibitory activity with IC50 of 4.6 Î¼M. Molecular modeling simulation studies were performed in order to predict the biological activities of the proposed compounds. All compounds have been tested for toxicity by MTT assay on human macrophage. 23397055 Impaired function of prejunctional adenosine A1 receptors expressed by perivascular sympathetic nerves in DOCA-salt hypertensive rats. Increased sympathetic nervous system activity contributes to deoxycorticosterone acetate (DOCA)-salt hypertension in rats. ATP and norepinephrine (NE) are coreleased from perivascular sympathetic nerves. NE acts at prejunctional α2-adrenergic receptors (α2ARs) to inhibit NE release, and α2AR function is impaired in DOCA-salt rats. Adenosine, an enzymatic ATP degradation product, acts at prejunctional A1 adenosine receptors (A1Rs) to inhibit NE release. We tested the hypothesis that prejunctional A1R function is impaired in sympathetic nerves supplying mesenteric arteries (MAs) and veins (MVs) of DOCA-salt rats. Electrically evoked NE release and constrictions of blood vessels were studied in vitro with use of amperometry to measure NE oxidation currents and video microscopy, respectively. Immunohistochemical methods were used to localize tyrosine hydroxylase (TH) and A1Rs in perivascular sympathetic nerves. TH and A1Rs colocalized to perivascular sympathetic nerves. Adenosine and N(6)-cyclopentyl-adenosine (CPA, A1R agonist) constricted MVs but not MAs. Adenosine and CPA (0.001-10 µM) inhibited neurogenic constrictions and NE release in MAs and MVs. DOCA-salt arteries were resistant to adenosine and CPA-mediated inhibition of NE release and constriction. The A2A adenosine receptor agonist CGS21680 (C23H29N7O6.HCl.xH2O) (0.001-0.1 μM) did not alter NE oxidation currents. We conclude that there are prejunctional A1Rs in arteries and both pre- and postjunctional A1Rs in veins; thus, adenosine selectively constricts the veins. Prejunctional A1R function is impaired in arteries, but not veins, from DOCA-salt rats. Sympathetic autoreceptor dysfunction is not specific to α2ARs, but there is a more general disruption of prejunctional mechanisms controlling sympathetic neurotransmitter release in DOCA-salt hypertension. 23707191 Cytotoxic interaction between amiodarone and desethylamiodarone in human peripheral lung epithelial cells. The potent and efficacious anti-dysrhythmic agent amiodarone (AM) can cause potentially life-threatening lung damage (amiodarone-induced pulmonary toxicity; AIPT), which is characterized by cell death in the lungs, followed by inflammation and fibrosis. AM's major metabolite, desethylamiodarone (DEA), has a greater toxic potency than AM and it has been suggested that DEA may act synergistically with AM to cause lung toxicity. The objective of this study was to determine the type of cytotoxic interaction between AM and DEA in HPL1A human peripheral lung epithelial cells. Cytotoxicity was measured by lactate dehydrogenase release. AM and DEA caused concentration-dependent cytotoxicity in HPL1A cells. The concentration of drug causing 50% cell death (LC50) and the Hill slope factor, which represents steepness of the concentration-cell death curve, were significantly different between AM and DEA (12.4μM and 1.98; 5.07μM and 5.43, for AM and DEA, respectively) indicating that they may induce cytotoxicity through different mechanisms. A combined concentration of 7.13μM AM plus DEA, equivalent to 41% of each compound's individual LC50 value, resulted in 50% cell death. Isobolographic analysis revealed this effect to be additive, although the combined concentrations were only slightly higher than the concentrations that defined the threshold of synergy (threshold of synergy=4.21±1.98μM AM plus 1.73±1.05μM DEA; experimental data point=5.06±0.47μM AM plus 2.07±0.47μM DEA). The cytotoxic interaction between AM and DEA may be clinically relevant in the development of AIPT. 23896185 Efficacy of Flow Restrictors in Limiting Access of Liquid Medications by Young Children. To assess whether adding flow restrictors (FRs) to liquid medicine bottles can provide additional protection against unsupervised medication ingestions by young children, even when the child-resistant closure is not fully secured. In April and May 2012, we conducted a block randomized trial with a convenience sample of 110 3- and 4-year-old children from 5 local preschools. Participants attempted to remove test liquid from an uncapped bottle with an FR and a control bottle without an FR (with either no cap or an incompletely closed cap). All but 1 (96%; 25 of 26) of the open control bottles and 82% (68 of 83) of the incompletely closed control bottles were emptied within 2 minutes. Only 6% (7 of 110) of the bottles with FRs were emptied during the 10-minute testing period, none before 6 minutes. Overall, children removed less liquid from the bottles with FRs than from the open or incompletely closed control bottles without FRs (both P < .001). All children assigned open control bottles and 90% of those assigned incompletely closed control bottles removed ≥25 mL of liquid. In contrast, 11% of children removed ≥25 mL of liquid from uncapped bottles with FRs. Older children (aged 54-59 months) were more successful than younger children at removing ≥25 mL of liquid (P = .002) from bottles with FRs. Our findings suggest that adding FRs to liquid medicine bottles limits the accessibility of their contents to young children and could complement the safety provided by current child-resistant packaging. 23684899 The most precise computations using Euler's method in standard floating-point arithmetic applied to modelling of biological systems. The explicit Euler's method is known to be very easy and effective in implementation for many applications. This article extends results previously obtained for the systems of linear differential equations with constant coefficients to arbitrary systems of ordinary differential equations. Optimal (providing minimum total error) step size is calculated at each step of Euler's method. Several examples of solving stiff systems are included. 23636851 Economic inequality in presenting near vision acuity in a middle-aged population: a Blinder-Oaxaca decomposition. To investigate economic inequality and its determinants in near vision, in a middle-aged population. In this population-based study, the presenting near vision in the better eye was investigated as the main outcome. If this vision revealed a value ≥1.6 M, the participant was considered to have presenting near vision impairment (PNVI). The effect of variables studied on PNVI was investigated using logistic regression. Economic inequality in PNVI was investigated using the Oaxaca-Blinder decomposition method. PNVI in the better eye was observed in 18.2% (95% CI 16.8 to 19.6) of participants. The prevalence of PNVI in the high and low economic groups was 11.7% (95% CI 10.3 to 13.0) and 28.5% (95% CI 26.0 to 31.0), respectively. Age and education were observed as the main factors in the explained portion of this gap and were in favour of the high economic group. Gender and eye care utilisation were factors affecting the unexplained portion of this gap and were in favour of the low economic group. Economic inequality plays a significant role in PNVI, while age and education are among the main factors affecting this gap. The effect caused by any change in these two factors was found to have a greater effect on women with low economic status. 23841602 The complete mitochondrial genome of Quasipaa boulengeri (Anura: Dicroglossidae). Abstract Quasipaa boulengeri, an Asian spiny frog that belongs to Neobatrachia, has been reported as a de novo case of chromosomal rearrangements. In this paper, we determined the whole mitochondrial DNA (mtDNA) sequence of Q. boulengeri. The complete mtDNA sequence of Q. boulengeri is 17,741 bp in length, which contains 13 protein-coding genes (PCGs), two rRNAs, 23 tRNAs and one control region. The overall nucleotides base composition of the complete mtDNA is A (28.86%), G (14.43%), C (26.09%), T (30.62%), with a much higher A + T content. Compared to other Neobatrachia species, the mtDNA genome of Q. boulengeri shows a novel gene order at WANCY region. 23681396 Predictors of self-reported health-related quality of life in systemic lupus erythematosus. Objective. The Medical Outcomes Short Form-36 Survey (SF-36) has been widely used as a measure of health-related quality of life (HRQOL) in different populations. SLE patients have consistently reported lower scores compared with the general population. The objective of our study was to identify predictors of HRQOL using SF-36 among patients with SLE enrolled in a 2-year randomized controlled trial (RCT). Methods. We analysed 200 SLE patients enrolled in the Lupus Atherosclerosis Prevention Study (LAPS), an RCT of atorvastatin vs placebo, who completed SF-36 at qualifying, 12- and 24-month (final) visits. Results. At baseline, mean SF-36 domain scores were lower than those of age- and gender-matched population norms. There was no statistical difference reported between Physical Component Summary (PCS), Mental Component Summary and eight domain scores in the atorvastatin vs placebo group at 2 years. In multiple regression analyses, African American patients reported significantly lower scores in Physical Functioning compared with Caucasians. The presence of FM was significantly associated with lower scores in physical functioning, role physical, bodily pain, general health, vitality, social functioning and lower overall mean PCS scores. The Physician's Global Assessment of disease activity was associated with multiple SF-36 domains in univariate analysis. Conclusion. This longitudinal study confirmed lower scores reported across all SF-36 domains. No one explanatory variable was independently associated with all domain scores. FM was independently associated with poorer HRQOL in most domains, underscoring the need for effective treatments for FM in SLE. 23823852 Regional Variation in Survival Following Pediatric Out-of-Hospital Cardiac Arrest. Background: Although regional variation in outcome after adult out-of-hospital cardiac arrest (OHCA) is known, no clinical studies have assessed this in pediatric OHCA. Methods and Results: This nationwide, prospective, population-based observation of the whole of Japan included consecutive OHCA patients with resuscitation attempt from January 2005 through December 2009. Primary outcome was 1-month survival with neurologically favorable outcome. Japan was divided into the following 7 regions as the largest administrative units: Hokkaido-Tohoku, Kanto, Tokai-Hokuriku, Kinki, Chugoku, Shikoku, and Kyushu-Okinawa. The outcome of pediatric OHCA was then compared between the regions. Multiple logistic regression analysis was used to adjust for other factors that were considered to influence the relationship between region and outcome. A total of 8,240 pediatric OHCA patients were registered during the study period. One-month survival with neurologically favorable outcome significantly differed by region: 2.5% (24/967) in Hokkaido-Tohoku (adjusted odds ratio [AOR], 1.65; 95% confidence interval [CI]: 0.94-2.90), 2.9% (47/1614) in Tokai-Hokuriku (AOR, 2.06; 95% CI: 1.28-3.31), 2.1% (26/1239) in Kinki (AOR, 1.45; 95% CI: 0.84-2.51), 3.4% (16/465) in Chugoku (AOR, 3.11; 95% CI: 1.62-6.00), 1.5% (4/259) in Shikoku (AOR, 0.79; 95% CI: 0.26-2.43), and 2.8% (27/974) in Kyushu-Okinawa (AOR, 2.15; 95% CI: 1.24-3.74) referred to Kanto (1.4%, 37/2722). Conclusions: According to Japanese nationwide OHCA registry data there are significant regional variations in the outcome of pediatric OHCA. 23914944 The Swedish Primary Care Cardiovascular Database (SPCCD): 74 751 hypertensive primary care patients. Objective. To describe the Swedish Primary Care Cardiovascular Database, SPCCD. Design. Longitudinal data from electronic medical records, linked to national registers. Setting. 48 primary healthcare centres in urban (south-western Stockholm) and rural (Skaraborg) regions in Sweden. Subjects. Patients diagnosed with hypertension 2001-2008. Main outcome measures. Blood pressure (BP) and impact of retrieval of data on BP levels, clinical characteristics, co-morbidity and pharmacological treatment. Results. The SPCCD contains 74 751 individuals, 56% women. Completeness of data ranged from > 99% for drug prescriptions to 34% for smoking habits. BP was recorded in 98% of patients during 2001-2008 and in 63% in 2008. Mean BP based on the last recorded value in 2008 was 142 ± 17/80 ± 13 mmHg. Digit preference in BP measurements differed between the two regions, p < 0.001. Antihypertensive drugs were prescribed in primary healthcare to 88% of the patients in 2008; however, when all prescribers were included 96% purchased their drugs. Cardiovascular co-morbidity and diabetes mellitus were present in 28% and 22%, respectively. Conclusion. This large and representative database shows that there is room for improvement of BP control in Sweden. The SPCCD will provide a rich source for further research of hypertension and its complications. 23966935 The potential of the human connectome as a biomarker of brain disease. The human connectome at the level of fiber tracts between brain regions has been shown to differ in patients with brain disorders compared to healthy control groups. Nonetheless, there is a potentially large number of different network organizations for individual patients that could lead to cognitive deficits prohibiting correct diagnosis. Therefore changes that can distinguish groups might not be sufficient to diagnose the disease that an individual patient suffers from and to indicate the best treatment option for that patient. We describe the challenges introduced by the large variability of connectomes within healthy subjects and patients and outline three common strategies to use connectomes as biomarkers of brain diseases. Finally, we propose a fourth option in using models of simulated brain activity (the dynamic connectome) based on structural connectivity rather than the structure (connectome) itself as a biomarker of disease. Dynamic connectomes, in addition to currently used structural, functional, or effective connectivity, could be an important future biomarker for clinical applications. 23890179 Human rhinovirus infections of the lower respiratory tract in hematopoietic stem cell transplant recipients. Human rhinoviruses (HRVs) are a common cause of upper respiratory infection (URI) in hematopoietic stem cell transplant (HSCT) recipients; yet, their role in lower respiratory illness is not well understood. We performed a retrospective chart review of HSCT recipients with HRV infection from the time molecular detection methods were implemented at our institution in 2008. Factors associated with proven or possible HRV pneumonia at the first HRV detection were evaluated by univariate and multivariate analysis. We then characterized all episodes of proven and possible HRV pneumonia from the initial HRV infection through a 1-year follow-up period. Between 2008 and 2011, 63 HSCT recipients had ≥1 documented HRV infections. At first HRV detection, 36 (57%) patients had HRV URI and 27 (43%) had proven or possible HRV pneumonia; in multivariate analysis, hypoalbuminemia (odds ratio [OR] 9.5, 95% confidence interval [CI] 1.3-71.7; P = 0.03) and isolation of respiratory co-pathogen(s) (OR 24.2, 95% CI 2.0-288.4; P = 0.01) were independently associated with pneumonia. During the study period, 22 patients had 25 episodes of proven HRV pneumonia. Fever (60%), cough (92%), sputum production (61%), and dyspnea (60%) were common symptoms. Fifteen (60%) episodes demonstrated bacterial (n = 7), fungal (n = 5), or viral (n = 3) co-infection. Among the remaining 10 (40%) cases of HRV monoinfection, patients' oxygen saturations ranged from 80% to 97% on ambient air, and computed tomography scans showed peribronchiolar, patchy, ground glass infiltrates. HRV pneumonia is relatively common after HSCT and frequently accompanied by bacterial co-infection. As use of molecular assays for respiratory viral diagnosis becomes widespread, HRV will be increasingly recognized as a significant cause of pneumonia in immunocompromised hosts. 23348406 The effect of apricots on the experimental cataract model formed by sodium selenite. This study was designed in order to investigate whether sun dried apricots have a preventive effect on the experimental cataract model formed by sodium selenite in rats. Fifty-nine Spraque-Dawley rat pups were divided into three groups. Group 1 (control group) consisted of twenty rat pups, born from the rats nourished ad libitum. Group 2 consisted of 18 newborn rats, born from the rats nourished ad libitum with 10% sun dried natural apricots. Group 3 consisted of 21 newborn rats, born from the rats nourished ad libitum. Subcutaneous (30nmol/gr) sodium selenite injection was applied to all the newborn rats except the control group (Group 1) on postpartum day 10. Cataract development was graded by slit-lamp examination and photography. Encapsulated lenses were analyzed for reduced glutathione (GSH) and malondialdehyde (MDA), a marker of lipid per oxidation. Lenses were also analyzed for total nitrite (TN). The presence of oxidative stress in selenite cataract development and its prevention by sun dried apricots. 23291896 Streptomyces halophytocola sp. nov., an endophytic actinomycete isolated from the surface-sterilized stems of a coastal halophyte Tamarix chinensis Lour. A novel actinomycete, designated KLBMP 1284(T), was isolated from the surface-sterilized stems of a coastal halophyte Tamarix chinensis Lour. collected from the city of Nantong, Jiangsu Province, east China. The strain was found to have morphological and chemotaxonomic characteristics typical of members of the genus Streptomyces. Analysis of the 16S rRNA gene sequence of strain KLBMP 1284(T) revealed that the strain formed a distinct clade within the phylogenetic tree based on 16S rRNA gene sequences and the highest sequence similarity (99.43 %) was to Streptomyces sulphureus NRRL B-1627(T). 16S rRNA gene sequence similarity to other species of the genus Streptomyces was lower than 97 %. Based on DNA-DNA hybridization values and comparison of morphological and phenotypic data, KLBMP 1284(T) could be distinguished from the closest phylogenetically related species, Streptomyces sulphureus NRRL B-1627(T). Thus, based on these data, it is evident that strain KLBMP 1284(T) represents a novel species of the genus Streptomyces, for which the name Streptomyces halophytocola sp. nov. is proposed. The type strain is KLBMP 1284(T) ( = KCTC 19890(T) = NBRC 108770(T)). 23892686 Relationship Between Neutrophil to Lymphocyte Ratio and Slow Coronary Flow. Objectives: We evaluated the relationship between neutrophil to lymphocyte ratio (NLR) and slow coronary flow (SCF). Methods: A total of 180 participants were recruited to the present study. Of all the participants, 82 patients were with SCF and 98 participants were with normal coronary arteries. Basal characteristics were recorded. Coronary flow was quantified by thrombolysis in myocardial infarction frame count. Results: Basal characteristics were similar between the 2 groups. The NLR was significantly higher in the SCF group when compared to the control group (2.3 ± 0.8 and 1.5 ± 0.4 respectively, P < .001). In multiple logistic regression analysis, NLR remained as the independent predictor of SCF (P < 0.001). Conclusions: Our findings showed that NLR was significantly higher in the SCF group when compared to the control group with normal coronary arteries. We also showed that NLR was related to the presence of SCF rather than the extent of SCF. Besides these findings, we also showed the NLR as an independent predictor of SCF. 23401473 Interaction of silymarin flavonolignans with organic anion-transporting polypeptides. Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC50 values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC50 values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC50 values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC50 values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC50 values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients. 23913860 Crystal structure of full-length human collagenase 3 (MMP-13) with peptides in the active site defines exosites in the catalytic domain. Matrix metalloproteinase (MMP)-13 is one of the mammalian collagenases that play key roles in tissue remodelling and repair and in progression of diseases such as cancer, arthritis, atherosclerosis, and aneurysm. For collagenase to cleave triple helical collagens, the triple helical structure has to be locally unwound before hydrolysis, but this process is not well understood. We report crystal structures of catalytically inactive full-length human MMP-13(E223A) in complex with peptides of 14-26 aa derived from the cleaved prodomain during activation. Peptides are bound to the active site of the enzyme by forming an extended β-strand with Glu(40) or Tyr(46) inserted into the S1' specificity pocket. The structure of the N-terminal part of the peptides is variable and interacts with different parts of the catalytic domain. Those areas are designated substrate-dependent exosites, in that they accommodate different peptide structures, whereas the precise positioning of the substrate backbone is maintained in the active site. These modes of peptide-MMP-13 interactions have led us to propose how triple helical collagen strands fit into the active site cleft of the collagenase.-Stura, E. A., Visse, R., Cuniasse, P., Dive, V., Nagase, H. Crystal structure of full-length human collagenase 3 (MMP-13) with peptides in the active site defines exosites in the catalytic domain. 23806242 Factors associated with vaccination for hepatitis B, pertussis, seasonal and pandemic influenza among French general practitioners: A 2010 survey. Our objectives were to describe the vaccine coverage (VC(1)) for some occupational vaccines (hepatitis B, pertussis, seasonal and pandemic influenza) among French General Practitioners (GPs(2)) and to study the factors associated with being vaccinated for each of these four diseases. We surveyed a representative national sample of 1431 self-employed GPs in France. Self-reported VC was 76.9% for 2009/10 seasonal influenza, 73.0% for hepatitis B, 63.9% for pertussis and 60.8% for A/H1N1 pandemic influenza. The factors associated with reporting being vaccinated were quite different from one vaccine to another. For some or all four vaccines, we found a significant positive association (p<0.05) with the following factors in the multivariate analysis: GP's male gender, high volume of activity, no particular mode of exercise (e.g. homoeopathy), no use of Internet at the practice, Continuing Medical Education sessions, discussing the benefits and risks of vaccination with the patients and performing prevention investigations for oneself (lipid profile). Being vaccinated for one vaccine also increased the VC for some or all three other studied vaccines. All these findings argue for public health campaigns using messages adapted to each vaccine. 23917208 Orexin receptors: Multi-functional therapeutic targets for sleeping disorders, eating disorders, drug addiction, cancers and other physiological disorders. The orexin peptides (orexin A, orexin B) and their receptors (orexin receptor type 1, orexin receptor type 2) are involved in multiple physiological processes such as the regulation of sleep/wakefulness state, energy homeostasis and reward seeking. A result of this has been the development of small-molecule orexin receptor antagonists as novel therapies for the treatment of insomnia and drug addiction. Increased levels of signaling via the orexin peptide/receptor system may protect against obesity, while somewhat unexpectedly, orexins acting at orexin receptors induce dramatic apoptosis resulting in the significant reduction of cell growth in various cancer cell lines. Meanwhile, the orexin peptide/receptor system is also involved in cardiovascular modulation, neuroendocrine and reproduction regulation. This review summarizes the latest developments in deciphering the biology of orexin signaling as well as efforts to manipulate orexin signaling pharmacologically. 23692528 Functional improvement of Saccharomyces cerevisiae to reduce volatile acidity in wine. Control of volatile acidity (VA) is a major issue for wine quality. In this study, we investigated the production of VA by a deletion mutant of the fermentation stress response gene AAF1 in the budding yeast Saccharomyces cerevisiae. Fermentations were carried out in commercial Chardonnay grape must to mimic industrial wine-making conditions. We demonstrated that a wine yeast strain deleted for AAF1 reduced acetic acid levels in wine by up to 39.2% without increasing the acetaldehyde levels, revealing a potential for industrial application. Deletion of the cytosolic aldehyde dehydrogenase gene ALD6 also reduced acetic acid levels dramatically, but increased the acetaldehyde levels by 41.4%, which is not desired by the wine industry. By comparison, ALD4 and the AAF1 paralog RSF2 had no effects on acetic acid production in wine. Deletion of AAF1 was detrimental to the growth of ald6Δ and ald4Δald6Δ mutants, but had no effect on acetic acid production. Overexpression of AAF1 dramatically increased acetic acid levels in wine in an Ald6p-dependent manner, indicating that Aaf1p regulates acetic acid production mainly via Ald6p. Overexpression of AAF1 in an ald4Δald6Δ strain produced significantly more acetic acid in wine than the ald4Δald6Δ mutant, suggesting that Aaf1p may also regulate acetic acid synthesis independently of Ald4p and Ald6p. 23719857 Evolution and function of chemokine receptors in the immune system of lower vertebrates. Chemokine receptors and their counterpart ligands are one of the evolutionary innovations of vertebrates. They play a guiding role in the coordination of cell trafficking in many biological processes. Comparative syntenic and phylogenetic analyses provide insight into the evolution of chemokine receptors and suggest that the repertoire of chemokine receptors varies in each species, regardless of the evolutionary position of the species. Despite the rapid evolution of chemokine receptors, the expression and function of orthologous chemokine receptors in lower and higher vertebrates are very similar. This is also true for the chemokine ligands that have been examined so far, such as CXCL8, CXCL12, and CCL25. As examples, this review will discuss how the evolution of the chemokine receptor CXCR4 is coincident with the emergence of lymphocytes in jawless vertebrates (lamprey); and that, in jawed vertebrates, CXCR4 and CCR9 are involved in thymus colonization. In myeloid cells, the function of CXCR1 in neutrophils and the expression of CXCR3 in macrophages and DCs are evolutionarily conserved between fish and mammals. In this context, medaka and zebrafish are outstanding models for studying the function of chemokines and their receptors. 23893110 Identification of a ligand on the Wip1 bacteriophage highly specific for a receptor on B. anthracis. Tectiviridae is a family of tailless bacteriophages with gram-negative and gram-positive hosts. The family model PRD1 and its close relatives all infect a broad range of enterobacteria by recognizing a plasmid-encoded conjugal transfer complex as a receptor. In contrast, tectiviruses with gram-positive hosts are highly specific to only a few hosts within the same bacterial species. The cellular determinants that account for the observed specificity remain so far unknown. Here we present the genome sequence of Wip1, a tectivirus that infects the pathogen Bacillus anthracis. The Wip1 genome is related to other tectiviruses with gram-positive hosts, notably AP50, but displays some interesting differences in its genome organization. We identified Wip1 candidate genes for the viral spike complex, the structure located at the capsid vertices and involved in host receptor binding. Phage adsorption and inhibition tests were combined with immunofluorescence microscopy to show that the Wip1 gene product p23 is a receptor binding protein. His-p23 also formed a stable complex with the p24, a Wip1 protein of unknown function, suggesting that the latter is involved with p23 in host cell recognition. The narrow host range of phage Wip1 and the identification of p23 as a receptor binding protein offer a new range of suitable tools for the rapid identification of B. anthracis. 23964864 Population-based incidence and comparative demographics of community-associated and healthcare-associated Escherichia coli bloodstream infection in Auckland, New Zealand, 2005 -- 2011. Escherichia coli is a major human pathogen, both in community and healthcare settings. To date however, relatively few studies have defined the population burden of E. coli bloodstream infections. Such information is important in informing strategies around treatment and prevention of these serious infections. Against this background, we performed a retrospective, population-based observational study of all cases of E. coli bacteremia in patients presenting to our hospital between January 2005 and December 2011. Auckland District Health Board is a tertiary-level, university-affiliated institution serving a population of approximately 500,000, within a larger metropolitan population of 1.4 million. We identified all patients with an episode of bloodstream infection due to E. coli over the study period. A unique episode was defined as the first positive E. coli blood culture taken from the same patient within a thirty-day period. Standard definitions were used to classify episodes into community- or healthcare-associated E. coli bacteremia. Demographic information was obtained for all patients, including: age; gender; ethnicity; length of stay (days); requirement for intensive care admission and all-cause, in-patient mortality. A total of 1507 patients had a unique episode of E. coli bacteremia over the study period. The overall average annual incidence of E. coli bacteremia was 52 per 100,000 population, and was highest in the under one year and over 65-year age groups. When stratified by ethnicity, rates were highest in Pacific Peoples and Maori (83 and 62 per 100,000 population respectively). The incidence of community-onset E. coli bacteremia increased significantly over the study period. The overall in-hospital mortality rate was 9% (135/1507), and was significantly higher in patients who had a hospital-onset E. coli bacteremia. Our work provides valuable baseline data on the incidence of E. coli bacteremia in our locale. The incidence was higher that that described from other developed countries, with significant demographic variation, most notably in ethnic-specific incidence rates. Future work should assess the possible reasons for this disparity. 23818638 Activation of dimeric ABA receptors elicits guard cell closure, ABA-regulated gene expression, and drought tolerance. Abscisic acid (ABA) is an essential molecule in plant abiotic stress responses. It binds to soluble pyrabactin resistance1/PYR1-like/regulatory component of ABA receptor receptors and stabilizes them in a conformation that inhibits clade A type II C protein phosphatases; this leads to downstream SnRK2 kinase activation and numerous cellular outputs. We previously described the synthetic naphthalene sulfonamide ABA agonist pyrabactin, which activates seed ABA responses but fails to trigger substantial responses in vegetative tissues in Arabidopsis thaliana. Here we describe quinabactin, a sulfonamide ABA agonist that preferentially activates dimeric ABA receptors and possesses ABA-like potency in vivo. In Arabidopsis, the transcriptional responses induced by quinabactin are highly correlated with those induced by ABA treatments. Quinabactin treatments elicit guard cell closure, suppress water loss, and promote drought tolerance in adult Arabidopsis and soybean plants. The effects of quinabactin are sufficiently similar to those of ABA that it is able to rescue multiple phenotypes observed in the ABA-deficient mutant aba2. Genetic analyses show that quinabactin's effects in vegetative tissues are primarily mediated by dimeric ABA receptors. A PYL2-quinabactin-HAB1 X-ray crystal structure solved at 1.98-Å resolution shows that quinabactin forms a hydrogen bond with the receptor/PP2C "lock" hydrogen bond network, a structural feature absent in pyrabactin-receptor/PP2C complexes. Our results demonstrate that ABA receptors can be chemically controlled to enable plant protection against water stress and define the dimeric receptors as key targets for chemical modulation of vegetative ABA responses. 23329204 Neurology of volition. Neurological disorders of volition may be characterized by deficits in willing and/or agency. When we move our bodies through space, it is the sense that we intended to move (willing) and that our actions were a consequence of this intention (self-agency) that gives us the sense of voluntariness and a general feeling of being "in control." While it is possible to have movements that share executive machinery ordinarily used for voluntary movement but lack a sense of voluntariness, such as psychogenic movement disorders, it is also possible to claim volition for presumed involuntary movements (early chorea) or even when no movement is produced (anosognosia). The study of such patients should enlighten traditional models of how the percepts of volition are generated in the brain with regard to movement. We discuss volition and its components as multi-leveled processes with feedforward and feedback information flow, and dependence on prior expectations as well as external and internal cues. 23959630 Bone histomorphometry of transiliac paired bone biopsies after 6 or 12 months of treatment with oral strontium ranelate in 387 osteoporotic women. Randomized comparison to alendronate. Preclinical studies indicate that strontium ranelate (SrRan) induces opposite effects on bone osteoblasts and osteoclasts, suggesting that SrRan may have a dual action on both formation and resorption. By contrast, alendronate (ALN) is a potent antiresorptive agent. In this multicenter, international, double-blind, controlled study, conducted in 387 postmenopausal women with osteoporosis, transiliac bone biopsies were performed at baseline and after 6 or 12 months of treatment with either SrRan 2 g per day (n = 256) or alendronate 70 mg per week (n = 131). No deleterious effect on mineralization of SrRan or ALN was observed. In the intention-to-treat (ITT) population (268 patients with paired biopsy specimens), changes in static and dynamic bone formation parameters were always significantly higher with ALN compared to SrRan at M6 and M12. Static parameters of formation were maintained between baseline and the last value with SrRan, except for Ob.S/BS, which decreased at M6. Significant decreases in the dynamic parameters of formation (MS/BS, BFR/BS, Aj.AR, Ac.f) were noted at M6 and M12 in SrRan. Compared with ALN, the bone formation parameters at M6 and M12 were always significantly higher (p < 0.001) with SrRan. ALN, but not SrRan, decreased resorption parameters. Compared to the baseline paired biopsy specimens, W.Th was significantly decreased at M6 but not at M12 and cancellous bone structure parameters (BV/TV, Tb.Th, Tb.N, Nd.N/TV) were significantly decreased at M12 with SrRan; none of these changes was significantly different from ALN. In conclusion, this large controlled paired-biopsy study over one year shows that the bone formation remains higher with a lower diminution of the bone remodeling with SrRan versus ALN. From these results SrRan did not show a significant anabolic action on bone remodeling. 23878065 Identification of a recurrent transforming UBR5-ZNF423 fusion gene in EBV-associated nasopharyngeal carcinoma. Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer which is prevalent in Southern China, Southeast Asia and North Africa. The development and stepwise progression of NPC involves accumulation of multiple gross genetic changes during the clonal expansion of EBV-infected nasopharyngeal epithelial cell population. Here, using paired-end whole-transcriptome sequencing, we discovered a number of chimeric fusion transcripts in a panel of EBV-positive tumor lines. Among these transcripts, a novel fusion of UBR5 (ubiquitin protein ligase E3 component n-recognin 5) on 8q22.3 and ZNF423 (zinc finger protein 423) on 16q12.1 identified from the NPC cell line C666-1 was recurrently detected in 12/144 (8.3%) of primary tumors. The fusion gene contains exon 1 of UBR5 and exon 7-9 of ZNF423 and produces a 94aa chimeric protein including the original C-terminal EBF binding domain (ZF29-30) of ZNF423. Notably, the growth of NPC cells with UBR5-ZNF423 rearrangement is dependent on expression of this fusion protein. Knockdown of UBR5-ZNF423 by fusion-specific siRNA significantly inhibited the cell proliferation and colony forming ability of C666-1 cells. The transforming ability of UBR5-ZNF423 fusion was also confirmed in NIH3T3 fibroblasts. Constitutive expression of UBR5-ZNF423 in NIH3T3 fibroblasts significantly enhanced its anchorage-independent growth in soft agar and induced tumor formation in the nude mice model. These findings suggest that expression of UBR5-ZNF423 protein might contribute to the transformation of a subset of NPC, possibly by altering the activity of EBFs (early B-cell factors). Identification of the oncogenic UBR5-ZNF423 provides new potential opportunities for therapeutic intervention in NPC. 23458967 Artificial neural network analysis of data from multiple in vitro assays for prediction of skin sensitization potency of chemicals. In order to develop in vitro risk assessment systems for skin sensitization, it is important to predict a threshold from the murine local lymph node assay (LLNA). We first confirmed that the combination of the human Cell Line Activation Test (h-CLAT) and the SH test improved the accuracy and sensitivity of prediction of LLNA data compared with each individual test. Next, we assessed the mutual correlations among maximum amount of change of cell-surface thiols (MAC value) in the SH test, CV75 value (concentration giving 75% cell viability) in a cytotoxicity assay, EC150 and EC200 values (thresholds concentrations of CD86 and CD54 expression, respectively) in h-CLAT and published LLNA thresholds of 64 chemicals. Based on the results, we selected MAC value and the minimum of CV75, EC150 (CD86) and EC200 (CD54) as descriptors for the input layer of an artificial neural network (ANN) system. The ANN-predicted values were well correlated with reported LLNA thresholds. We also found a correlation between the SH test and the peptide-binding assay used to evaluate hapten-protein complex formation. Thus, this model, which we designate as the "iSENS ver. 1", may be useful for risk assessment of skin sensitization potential of chemicals from in vitro test data. 23969331 A new ionic liquid-water-organic solvent three phase microextraction for simultaneous preconcentration flavonoids and anthraquinones from traditional Chinese prescription. A novel technique, ionic liquid-water-organic solvent three phase microextraction (ILWOS-3p-ME) was developed and introduced for simultaneous preconcentration and determination of flavonoids and anthraquinones in Chinese herbal formula and its preparations. This technique was performed in one step by using a syringe. High performance liquid chromatography with an UV-detector (HPLC/UV) was subsequently conducted. Two solvents with different densities (organic solvent and ionic liquid with densities less than and higher than water, respectively) were separately placed in a syringe, which was used as an extraction device. A cloudy emulsion was formed by manually shaking the syringe. The mixture was allowed to stand for several minutes; afterward, the emulsion readily separated into three phases: an upper organic solvent extraction phase; a middle aqueous sample phase; and a lower ionic liquid extraction phase. Both the upper and lower layers were transferred to a small Eppendorf (EP) tube. Conducting ILWOS-3P-ME with HPLC/UV, we simultaneously determined the bioactive components of flavonoids and anthraquinones in traditional Chinese medicine. ILWOS-3P-ME is a simple, rapid, practical, and effective method to extract and preconcentrate of different types of trace bioactive components from traditional Chinese medicine simultaneously. 23628394 Neem leaf glycoprotein overcomes indoleamine 2,3 dioxygenase mediated tolerance in dendritic cells by attenuating hyperactive regulatory T cells in cervical cancer stage IIIB patients. Tolerogenic dendritic cells (DCs) are a subset of DCs characterized by abundant indoleamine 2,3 dioxygenase (IDO) expressions. IDO may be co-operatively induced in DCs by regulatory T (Tregs) cells and various DC maturation agents. Tregs are markedly amplified in the physiological system of cancer patients, inducing over tolerance in DCs that leads to the hyper accumulation of immunosuppressive IDO in tumor microenvironment, thereby, hampering anti-tumor immunity. Consequently, a major focus of current immunotherapeutic strategies in cancer is to minimize IDO, which is possible by reducing Tregs and using various IDO inhibitors. Neem leaf glycoprotein (NLGP), a natural and nontoxic immunomodulator, demonstrated several unique immunoregulatory activities. Noteworthy activities of NLGP are to mature DCs and to inhibit Tregs. As Tregs are inducer of IDO in DCs and hyperactive Tregs is a hallmark of cancer, we anticipated that NLGP might abrogate IDO induction in DCs by inhibiting Tregs. Evidences are presented here that in a co-culture of DCs and Tregs isolated from cervical cancer stage IIIB (CaCx-IIIB) patients, NLGP does inhibit IDO induction in DCs by curtailing the over expression of Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) on Tregs and concomitantly induces optimal DC maturation. In contrast, in the presence of LPS as maturation agent the DCs displays a tolerogenic profile. This finding suggests the reduction of tolerogenecity of DCs in CaCx-IIIB patients by reducing the IDO pool using NLGP. Accordingly, this study sheds more light on the diverse immunomodulatory repertoire of NLGP. 23527578 Broken Symmetry Quantum Hall States in Dual-Gated ABA Trilayer Graphene. ABA-stacked trilayer graphene is a unique 2D electron system with mirror reflection symmetry and unconventional quantum Hall effect. We present low-temperature transport measurements on dual-gated suspended trilayer graphene in the quantum Hall (QH) regime. We observe QH plateaus at filling factors ν = -8, -2, 2, 6, and 10, which is in agreement with the full-parameter tight binding calculations. In high magnetic fields, odd-integer plateaus are also resolved, indicating almost complete lifting of the 12-fold degeneracy of the lowest Landau level (LL). Under an out-of-plane electric field E⊥, we observe degeneracy breaking and transitions between QH plateaus. Interestingly, depending on its direction, E⊥ selectively breaks the LL degeneracies in the electron-doped or hole-doped regimes. Our results underscore the rich interaction-induced phenomena in trilayer graphene. 23834012 Novel Antioxidant Peptide Derived from the Ultrafiltrate of Ovomucin Hydrolysate. The techno-functional properties of ovomucin as a gel-forming agent and its biological properties are well-known. The aim of the present study was to investigate antioxidant activity in ovomucin hydrolysate using radical scavenging assays. Electrophoresis showed that ovomucin isolated from whole egg was well separated. Ovomucin hydrolysis was carried out using microbial protease according to different incubation times. These ovomucin hydrolysates exhibited 85% antioxidant activity as measured by the 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) assay after a 2 h incubation with protease and retained 90% activity until 24 h. At an incubation time of 4 h, the activity of ovomucin hydrolysates reached approximately 90%, corresponding to 115 μM gallic acid equivalent, regardless of the proteases used. The partially purified fraction of the hydrolysate by ultrafiltration and reverse-phase high-performance liquid chromatography was collected and then analyzed by liquid chromatography electrospray ionization mass spectrometry. Two peptides, LDEPDPL and NIQTDDFRT, in this fraction were identified. The antioxidant activities of these two synthesized peptides were measured to be 51.8 and 24.7% by the 2,2-diphenyl-1-picrylhydrazyl assay. 23874322 Utility of TMS to understand the neurobiology of speech. According to a traditional view, speech perception and production are processed largely separately in sensory and motor brain areas. Recent psycholinguistic and neuroimaging studies provide novel evidence that the sensory and motor systems dynamically interact in speech processing, by demonstrating that speech perception and imitation share regional brain activations. However, the exact nature and mechanisms of these sensorimotor interactions are not completely understood yet. Transcranial magnetic stimulation (TMS) has often been used in the cognitive neurosciences, including speech research, as a complementary technique to behavioral and neuroimaging studies. Here we provide an up-to-date review focusing on TMS studies that explored speech perception and imitation. Single-pulse TMS of the primary motor cortex (M1) demonstrated a speech specific and somatotopically specific increase of excitability of the M1 lip area during speech perception (listening to speech or lip reading). A paired-coil TMS approach showed increases in effective connectivity from brain regions that are involved in speech processing to the M1 lip area when listening to speech. TMS in virtual lesion mode applied to speech processing areas modulated performance of phonological recognition and imitation of perceived speech. In summary, TMS is an innovative tool to investigate processing of speech perception and imitation. TMS studies have provided strong evidence that the sensory system is critically involved in mapping sensory input onto motor output and that the motor system plays an important role in speech perception. 23254544 The effect of squat depth on multiarticular muscle activation in collegiate cross-country runners. Gorsuch, J, Long, J, Miller K, Primeau, K, Rutledge, S, Sossong, A, and Durocher, JJ. The effect of squat depth on multiarticular muscle activation in collegiate cross-country runners. J Strength Cond Res 27(9): 2619-2625, 2013-The squat is a closed-chain lower body exercise commonly performed by many athletes. Muscle activity has been examined during partial and parallel squats in male weightlifters, but not in male and female runners. Therefore, this study measured muscle activity with surface electromyography (EMG) during partial and parallel squats in 20 Division I collegiate cross-country runners (10 males and 10 females) in a randomized crossover design. We hypothesized the parallel squat would increase extensor muscle activitation (i.e. hamstrings and erector spinae). Furthermore, we sought to determine if changes in muscle activity were different between males and females. Participants performed 6 repetitions using their 10 repetition maximum loads for each condition during EMG testing. EMG was performed on the right rectus femoris, biceps femoris, lumbar erector spinae, and lateral head of the gastrocnemius. Rectus femoris activity (0.18 ± 0.01 vs. 0.14 ± 0.01 mV) and erector spinae activity (0.16 ± 0.01 vs. 0.13 ± 0.01 mV) were significantly higher (p < 0.05) during the parallel squat than during the partial squat condition. This increase in muscle activity may be attributed to greater ranges of motion at the hip and knee joints. Biceps femoris and gastrocnemius activity were similar between conditions. No significant differences existed between males and females (squat condition × gender; p > 0.05). During preliminary isokinetic testing, both male and female runners demonstrated deficient hamstrings-to-quadriceps ratios, which would not likely improve by performing parallel squats based on our EMG findings. Despite the reduced load of the parallel squat, rectus femoris and erector spinae activity were elevated. Thus, parallel squats may help runners to train muscles vital for uphill running and correct posture, while preventing injury by using lighter weights through a larger range of motion. 23876928 Some new [(thione)2Au(diamine)]Cl3 complexes: Synthesis, spectroscopic characterization, computational and in vitro cytotoxic studies. Recent advances in oncology are focused on developing new complexes of gold(III) with various ligands that show augmented anti-proliferative potential and reduced toxicity as compared to cis-platin. In this study, new Au(III) complexes of the type [(thione)2Au(diamine)]Cl3 are reported, where thione=1,3-imidazolidine-2-thione (Imt), 1,3-Diazinane-2-thione (Diaz) and diamine=1,2-diaminoethane (en), 1,3-diaminopropane (pn) or 1,4-diaminobutane (bn). The solid state IR as well as (13)C and (15)N NMR data indicate that Au(III) center is bonded via sulfur of thiocarbonyl SC site of the thiones and also chelated by the diamines from the trans side of coordinated thiones. Spectroscopic data are evaluated by comparisons with calculated data from the built and optimized structure by GAUSSIAN 09 at the RB3LYP level with LanL2DZ bases set. These new Au(III) complexes based on mixed thione and diamine ligands are very similar to the square planar structure of tetracoordinate [Au(en)2]Cl3complex. In this study, cytotoxicity data for these gold(III) complexes against C6 glioma cell lines are also reported, and the results indicate some complexes have cytotoxicity comparable to cis-platin. 23639725 Widespread but tissue-specific patterns of interferon-induced transmembrane protein 3 (IFITM3, FRAGILIS, MIL-1) in the mouse gastrula. Interferon-induced transmembrane protein 3 (IFITM3; FRAGILIS; MIL-1) is part of a larger family of important small interferon-induced transmembrane genes and proteins involved in early development, cell adhesion, and cell proliferation, and which also play a major role in response to bacterial and viral infections and, more recently, in pronounced malignancies. IFITM3, together with tissue-nonspecific alkaline phosphatase (TNAP), PRDM1, and STELLA, has been claimed to be a hallmark of segregated primordial germ cells (PGCs) (Saitou et al., 2002). However, whether IFITM3, like STELLA, is part of a broader stem/progenitor pool that builds the posterior region of the mouse conceptus (Mikedis and Downs, 2012) is obscure. To discover the whereabouts of IFITM3 during mouse gastrulation (~E6.5-9.0), systematic immunohistochemical analysis was carried out at closely spaced 2-4-h intervals. Results revealed diverse, yet consistent, profiles of IFITM3 localization throughout the gastrula. Within the putative PGC trajectory and surrounding posterior tissues, IFITM3 localized as a large cytoplasmic spot with or without staining in the plasma membrane. IFITM3, like STELLA, was also found in the ventral ectodermal ridge (VER), a posterior progenitor pool that builds the tailbud. The large cytoplasmic spot with plasma membrane staining was exclusive to the posterior region; the visceral yolk sac, non-posterior tissues, and epithelial tissues exhibited spots of IFITM3 without cell surface staining. Colocalization of the intracellular IFITM3 spot with the endoplasmic reticulum, Golgi apparatus, or endolysosomes was not observed. That relatively high levels of IFITM3 were found throughout the posterior primitive streak and its derivatives is consistent with evidence that IFITM3, like STELLA, is part of a larger stem/progenitor cell pool at the posterior end of the primitive streak that forms the base of the allantois and builds the fetal-umbilical connection, thus further obfuscating practical phenotypic distinctions between so-called PGCs and surrounding soma. 23159985 Analysis of microRNA and gene expression profiling in triazole fungicide-treated HepG2 cell line. MicroRNA (miRNA) plays an important role in various diseases and in cellular and molecular responses to toxicants. In the present study, we investigated differential expression of miRNAs in response to three triazole fungicides (myclobutanil, propiconazole, and triadimefon). The human hepatoma cell line (HepG2) was treated with the above triazoles for 3 h or 48 h. miRNA-based microarray experiments were carried out using the Agilent human miRNA v13 array. At early exposure (3h), six miRNAs were differentially expressed and at late exposure (48 h), three miRNAs were significantly expressed. Overall, this study provides an array of potential biomarkers for the above triazole fungicides. Furthermore, these miRNAs induced by triazoles could be the foundation for the development of a miRNA-based toxic biomarker library that can predict environmental toxicity. 23962274 Poly (L-lactic acid) Crystallization in a Confined Space Containing Graphene Oxide Nanosheets. The semicrystalline polymer incorporated with nanofillers frequently exhibits complicated crystallization behavior, which is probably attributed to the nanofiller-constructed complex crystalline circumstance, especially a confined space. In the present work, in order to have a thorough understanding of biodegradable poly(L-lactic acid) (PLLA) crystallization behavior on the dependence of graphene oxide nanosheet (GONS) loadings, in particular the relatively high GONS loading, a set of GONS/PLLA nanocomposites with different GONS loadings ranging from 0 to 4.0 wt% were investigated in terms of isothermal crystallization behaviors by differential scanning calorimetry (DSC) and time-resolved Fourier-transform infrared spectroscopy (FTIR) techniques. The results indicated that GONSs not only served as heterogeneous nucleating agents for PLLA crystallization, but also restricted the mobility and diffusion of PLLA chains. At low GONS concentrations of 0.25 and 0.5 wt%, GONSs acted as a temple for PLLA chains to land on due to extremely high specific surface area, thus promoting the conformational ordering and reducing the nucleating barrier. Nucleation effect of GONSs was dominant to achieve accelerated overall crystallization kinetics. As the GONS concentration rose up to 1.0 wt%, GONS network was formed in PLLA matrix, which was verified by solid-like rheological behavior at low frequencies in rheological measurement. The nanofiller network significantly constrained the mobility and diffusion of PLLA chains and offset the nucleation effect of GONSs, giving rise to a turning point from promotion to restriction. Furthermore, a severely confined space was constructed by the more crowded and denser GONS networks at a higher GONS concentration of 4.0 wt%, compelling PLLA lamellae to grow in a two-dimensional mode. The unusual crystallization behavior of PLLA from promotion to restriction was also understood by the four-region model, in which the semi-quantitatively description of crystalline circumstance was provided. These results pave an effective way to further reveal the crystallization behavior of polymer at a relatively high nanofiller loading. 23959831 Burkholderia humi sp. nov., Burkholderia choica sp. nov., Burkholderia telluris sp. nov., Burkholderia terrestris sp. nov., and Burkholderia udeis sp. nov.: Burkholderia glathei-like bacteria from soil and rhizosphere soil. Analysis of partial gyrB gene sequences revealed six taxa in a group of 17 Burkholderia glathei-like isolates that were further examined by (GTG)5-PCR fingerprinting, 16S rRNA sequence analysis, DNA-DNA hybridisations, determination of the mol% G+C content, whole cell fatty acid analysis and an analysis of cell and colony morphology and 155 biochemical characteristics. The results demonstrate that one taxon consisting of three human clinical isolates represents Burkholderia zhejiangensis, a recently described methyl-parathion-degrading bacterium isolated from a wastewater-treatment system in China. The remaining taxa represent five novel species isolated from soil or rhizosphere soil samples, and can be distinguished by both genotypic and phenotypic characteristics. We therefore propose to formally classify these bacteria as Burkholderia humi sp. nov. (with strain LMG 22934T [= CCUG 63059T] as the type strain), Burkholderia choica sp. nov. (with strain LMG 22940T [= CCUG 63063T] as the type strain), Burkholderia telluris sp. nov. (with strain LMG 22936T [= CCUG 63060T] as the type strain), Burkholderia udeis sp. nov. (with strain LMG 27134T [= CCUG 63061T] as the type strain), and Burkholderia terrestris sp. nov. (with strain LMG 22937T [= CCUG 63062T] as the type strain). 23950735 Global analysis of fission yeast mating genes reveals new autophagy factors. Macroautophagy (autophagy) is crucial for cell survival during starvation and plays important roles in animal development and human diseases. Molecular understanding of autophagy has mainly come from the budding yeast Saccharomyces cerevisiae, and it remains unclear to what extent the mechanisms are the same in other organisms. Here, through screening the mating phenotype of a genome-wide deletion collection of the fission yeast Schizosaccharomyces pombe, we obtained a comprehensive catalog of autophagy genes in this highly tractable organism, including genes encoding three heretofore unidentified core Atg proteins, Atg10, Atg14, and Atg16, and two novel factors, Ctl1 and Fsc1. We systematically examined the subcellular localization of fission yeast autophagy factors for the first time and characterized the phenotypes of their mutants, thereby uncovering both similarities and differences between the two yeasts. Unlike budding yeast, all three Atg18/WIPI proteins in fission yeast are essential for autophagy, and we found that they play different roles, with Atg18a uniquely required for the targeting of the Atg12-Atg5·Atg16 complex. Our investigation of the two novel factors revealed unforeseen autophagy mechanisms. The choline transporter-like protein Ctl1 interacts with Atg9 and is required for autophagosome formation. The fasciclin domain protein Fsc1 localizes to the vacuole membrane and is required for autophagosome-vacuole fusion but not other vacuolar fusion events. Our study sheds new light on the evolutionary diversity of the autophagy machinery and establishes the fission yeast as a useful model for dissecting the mechanisms of autophagy. 23106504 The effects of a novel botanical agent on lipopolysaccharide-induced alveolar bone loss in rats. Background: The development of host-modulatory agents with low risk of adverse effects has been needed to treat periodontitis, a chronic inflammatory disease. A botanical mixture of extracts from two natural substances, Panax notoginseng and Rehmannia glutinosa Libosch, was developed as a novel botanical agent synthesized with anti-inflammatory effect. The aim of this study is to evaluate the effects of the botanical mixture on the release of inflammatory cytokines and its inhibitory effect on lipopolysaccharide (LPS)-induced alveolar bone loss (ABL) in a rat model. Methods: Cytotoxicity was assessed by 3-(4,5-dimethylthiazol-2yl)-5(3-carboxymethoxyphenol)-2-(4-sulfophenyl)-2H-tetrazolium assay using human gingival fibroblast (hGF) and human periodontal ligament (hPDL) cells. Human acute monocytic leukemia cell line and hGF cells were cultured to assay tumor necrosis factor (TNF)-α and interleukin (IL)-6, respectively. Microcomputed tomography analysis and immunofluoresence analysis were performed to evaluate the efficacy of the botanical mixture to inhibit the destruction of alveolar bone and connective tissue in a rat model. Results: The botanical mixture is cytotoxic at concentrations exceeding 2.5 mg/mL (P <0.05). Based on the results from cytotoxicity assay, it can be determined that the pharmacologic ranges of the botanical mixture to be used in all subsequent in vitro and in vivo experiments. The botanical mixture reduced the release of TNF-α and IL-6 from human monocytic cells and hGF cells in a dose-dependent manner (P <0.05). The administration of the botanical mixture significantly reduced the alveolar bone loss in a rat model (P <0.05). In groups treated with the botanical mixture, matrix metalloproteinase (MMP)-9 was detected along the alveolar bone crest (ABC), but not around the gingival connective tissue, while in the group with LPS-induced ABL, pronounced expression of MMP-9 around the ABC, periodontal ligament, and gingival connective tissue was found. Conclusions: The botanical mixture showed a potential adjunctive effect in the treatment of periodontitis. However, the present findings are obtained in vitro and in a rat model, so further clinical study is needed for its clinical application. 23939656 Psychosocial work characteristics and sleep quality: a systematic review of longitudinal and intervention research. The objective of this study was to review longitudinal and intervention studies examining the association between psychosocial work characteristics (eg, job demands, job control, and social support) and sleep quality. Our main research aims were to examine whether (i) psychosocial work characteristics are a predictor of sleep quality, and (ii) sleep quality, in turn, is a predictor of psychosocial work characteristics. A systematic literature search resulted in 20 relevant papers, of which 16 were longitudinal studies and 3 were intervention studies (1 study was discussed in separate papers). To quantify results, we assessed the strength of evidence of all examined associations and subsequently evaluated the studies' research quality based on predefined quality criteria. Three longitudinal and one intervention studies were categorized as being of high-quality. In longitudinal studies, we found consistent and strong evidence for a negative relation between job demands and sleep quality as well as evidence for a positive relation between job control and sleep quality. Other psychosocial work characteristics were examined in an insufficient number of (high-quality) studies. Moreover, both intervention studies as well as studies investigating reversed and reciprocal relations are rare, which further limits the possibility of drawing conclusions on causality. Based on the current literature, it can be concluded that high job demands and low job control are predictors of poor sleep quality. More high-quality research is needed to examine the possible causal relationship between these and other psychosocial work characteristics with sleep quality, in addition to research focusing on reversed and reciprocal relations. 23161166 Accelerometry reveals differences in gait variability between patients with multiple sclerosis and healthy controls. Variability of movement reflects important information for the maintenance of the health of the system. For pathological populations, changes in variability during gait signal the presence of abnormal motor control strategies. For persons with multiple sclerosis (PwMS), extensive gait problems have been reported including changes in gait variability. While previous studies have focused on footfall variability, the present study used accelerometers on the trunk to measure variability during walking. Thus, the purpose of this study was to examine the variability of the acceleration pattern of the upper and lower trunk in PwMS compared to healthy controls. We extracted linear and nonlinear measures of gait variability from 30 s of steady state walking for 15 PwMS and 15 age-matched healthy controls. PwMS had altered variability compared to controls with greater Lyapunov exponent in the ML (p < 0.001) and AP (p < 0.001) directions, and greater frequency dispersion in the ML direction (p = 0.034). PwMS also demonstrated greater mean velocity in the ML direction (p = 0.045) and lower root mean square of acceleration in the AP direction (p = 0.040). These findings indicate that PwMS have altered structure of variability of the trunk during gait compared to healthy controls and agree with previous findings related to changes in gait variability in PwMS. 23955500 Molecular characterization and phylogenetic analysis of new variants of the porcine epidemic diarrhea virus in gansu, china in 2012. Between January 2012 and March 2012, the infection rates of porcine epidemic diarrhea virus (PEDV) increased substantially in vaccinated swine herds in many porcine farms in Gansu Province, China. The spike (S) glycoprotein is an important determinant for PEDV biological properties. To determine the distribution profile of PEDV outbreak strains, we sequenced the full-length S gene of five samples from two farms where animals exhibited severe diarrhea and high mortality rates. Five new PEDV variants were identified, and the molecular diversity, phylogenetic relationships, and antigenicity analysis of Gansu field samples with other PEDV reference strains were investigated. A series of insertions, deletions, and mutations in the S gene was found in five PEDV variants compared with classical and vaccine strains. These mutations may provide stronger pathogenicity and antigenicity to the new PEDV variants that influenced the effectiveness of the CV777-based vaccine. Our results suggest that these new PEDV variant strains in Gansu Province might be from South Korean or South China, and the effectiveness of the CV777-based vaccine needs to be evaluated. 23394846 Comparing lidocaine, bupivacaine and a lidocaine-bupivacaine mixture as a metacarpal block in sheep. Mechanical sensory blocking effects in the metacarpi of rams were compared following perineural injection of saline, 2% lidocaine (LIDO), 0.5% bupivacaine (BUPI), and a 1:1 (volume/volume) mixture of LIDO-BUPI. Saline was also administered in the contralateral metacarpi. Compared with the saline treatment and contralateral controls, the various treatments induced larger area under the curve (AUC) values 0-60min post-treatment (AUC0-60). Administration of BUPI and LIDO-BUPI also induced larger AUC60-120 values (P<0.01). The AUC0-60 and AUC60-120 values with LIDO were less than those achieved with LIDO-BUPI and BUPI (P<0.001), and AUC60-120 values with LIDO-BUPI were less than those obtained with BUPI (P<0.05). Anaesthesia occurred within 5min following the administration of all local anaesthetics and lasted longer in the case of BUPI (110.0±47.3min) than with LIDO (40.0±13.2min) (P<0.01). The duration of anaesthesia was 86.9±66.0min with the LIDO-BUPI combination. Thus this combination offered no apparent advantages over the use of BUPI alone. 22890749 Theoretical study of the decomposition of ethyl and ethyl 3-phenyl glycidate. The mechanism of the decomposition of ethyl and ethyl 3-phenyl glycidate in gas phase was studied by density functional theory (DFT) and MP2 methods. A proposed mechanism for the reaction indicates that the ethyl side of the ester is eliminated as ethylene through a concerted six-membered cyclic transition state, and the unstable intermediate glycidic acid decarboxylates rapidly to give the corresponding aldehyde. Two possible pathways for glycidic acid decarboxylation were studied: one via a five-membered cyclic transition state, and the other via a four-membered cyclic transition state. The results of the calculations indicate that the decarboxylation reaction occurs via a mechanism with five-membered cyclic transition state. 23872145 Intestinal absorption of lysozyme, an egg-white allergen, in rats: Kinetics and effect of NSAIDs. The absorption pathway(s) of a representative food allergen, lysozyme, and the mechanisms of lysozyme absorption facilitated by non-steroidal anti-inflammatory drugs were examined by intestinal closed-loop and re-circulating perfusion methods in rats. The absorption rate of fluorescein isothiocyanate (FITC)-labeled lysozyme in the proximal intestine was higher than that for a marker of non-specific absorption, FD-10, and was suppressed by colchicine (endocytosis inhibitor). Aspirin increased the absorption of FITC-lysozyme in the proximal intestine with no effects on tissue accumulation. Diclofenac facilitated FITC-lysozyme absorption, but meloxicam and loxoprofen exerted no effects on absorption. Co-administration of misoprostol (synthetic prostaglandin-E1 analog) with aspirin significantly ameliorated the aspirin-facilitated absorption of FITC-lysozyme to the same level as that seen with controls. Thus, lysozyme absorption was mediated by endocytic and paracellular pathways in the proximal intestine, and was facilitated by aspirin and diclofenac after impairment of the paracellular pathway. Misoprostol may suppress the allergen absorption facilitated by aspirin. 23897560 Wrist breadth and homeostasis model assessment of insulin resistance in youth: The fels longitudinal study. There is biological crosstalk between insulin signaling and bone remodeling pathways, and wrist circumference and bone area were recently found to associate with insulin resistance independent of body mass index (BMI) in overweight/obese children. We aimed to expand on this work by using more specific measures of adiposity for adjustment and examining children with broader range of BMI. We used serial data (1,051 total measures) on 313 non-Hispanic white youth (ages 8-18 y) from the Fels Longitudinal Study with homeostasis model assessment of insulin resistance (HOMA-IR) as the outcome. Internal standard deviation score (SDS) for wrist breadth was evaluated as a predictor of HOMA-IR (log-transformed) before and after adjusting for internal-sample SDSs for BMI, waist circumference (WC), and total body fat (TBF) from dual energy X-ray absorptiometry, in addition to age, sex, Tanner stage, and birth year, using generalized estimating equations. Before additional adiposity adjustment, we found a significant positive association between wrist breadth SDS and log-transformed HOMA-IR (β = 0.13; 95%CI: 0.09-0.17), which remained significant after adjusting for TBF SDS (β = 0.09; 95%CI: 0.05-0.13; P < 0.001), BMI SDS (β = 0.06; 95%CI: 0.02-0.10; P = 0.007), and WC SDS (β = 0.06; 95%CI: 0.02-0.09; P = 0.005). Further work is needed to determine whether simple frame size measures such as wrist breadth may be useful markers of metabolic risk. Am. J. Hum. Biol., 2013. © 2013 Wiley Periodicals, Inc. 23165891 Pigmented Necrobiosis Lipoidica Accompanied by Insulin-dependent Diabetes Mellitus Induces CD163 Proinflammatory Macrophages and Interleukin-17-producing Cells. Abstract is missing (Letter). 23847081 Chemotaxonomic Analysis of the Aroma Compounds in Essential Oils of Two Different Ocimum basilicum L. Varieties from Iran. Hydrodistilled essential oils of 21 accessions of Ocimum basilicum L. belonging to two different varieties (var. purpurascens and var. dianatnejadii) from Iran were characterized by GC-FID and GC/MS analyses. The oil yield was found to be between 0.6 and 1.1% (v/w). In total, 49 compounds, accounting for 96.6-99.7% of the oil compositions, were identified. Aromatic compounds, represented mainly by methyl chavicol (33.6-49.1%), and oxygenated monoterpenes, represented by linalool (14.4-39.3%), were the main components in all essential oils. Monoterpene hydrocarbons were present in the essential oils of all accessions of the purpurascens variety, whereas they were completely absent in those of the dianatnejadii variety, indicating that monoterpene hydrocarbons might be considered as marker constituents of the purpurascens variety. The chemotaxonomic value of the essential-oil compositions was discussed according to the results of the cluster analysis (CA). The CA showed a clear separation of the O. basilicum var. purpurascens accessions and the O. basilicum var. dianatnejadii accessions, although the data showed no major chemotype variation between the studied varieties. Indeed, the CA revealed only one principal chemotype (methyl chavicol/linalool) for both varieties. In conclusion, GC/MS analyses in combination with CA showed to be a flexible and reliable method for the characterization of the chemical profiles of different varieties of Ocimum basilicum L. 23146754 Effects of arsenite in astrocytes on neuronal signaling transduction. The main purpose of this study was to test the hypothesis that arsenite induces neurotoxicity via effects on astrocytes. Astrocytes were exposed to 0, 5 or 10 μM arsenite in medium for 24 h, and then astrocyte-conditioned medium (ACM) was collected after incubation with fresh medium for 6 h. Primary neuron cultures were divided into four groups due to ACM, which were neurons without ACM exposure (group I) and neurons exposed to ACM from 0, 5 or 10 μM arsenite treated astrocytes (group II-IV). Protein expression of N-methyl-d-aspartate receptors (NR1, NR2A, NR2B), calmodulin-dependent protein kinase II (CaMKII) and adenylate cyclase (AC) in neurons were measured after incubation with ACM for 4, 8 or 12 h. Morphological changes and synaptic formation were observed after a 72 h-incubation with ACM. Compared to group II, synaptic formation and protein expression of NR2A, NR2B, CaMKII and AC in group III and IV were significantly suppressed. Moreover, synaptic formation and protein expression of CaMKII and AC in group II were significantly enhanced when compared with group I. Taken together, findings from this study suggested that arsenic in astrocytes might impair synaptic formation through disturbing astrocytic effects on neuronal signal transduction. 23790023 Neural correlates of impaired volitional action control in schizophrenia patients. Slowed initiation of volitional but not visually guided saccades indicates impaired volitional action control in schizophrenia patients (SZ). The present study aimed at identifying neural correlates of this specific deficit. Fourteen SZ and 13 healthy control participants (HC) underwent functional magnetic resonance imaging while performing volitional and visually guided saccades. SZ showed increased latencies in volitional but not in visually guided saccades. Brain activation during volitional saccades compared to visually guided saccades was increased in SZ compared to HC in several areas: the supplementary eye fields, suggesting inefficient production of volitional saccades; the prefrontal cortex, pointing to altered top down control on complex eye movements; and the left middle temporal area, suggesting changes in early sensory and attention processing during the volitional control of saccades in SZ. 23662729 Results of combined multispecialty endoscopic dacryocystorhinostomy. To characterize the pre- and post-operative findings in patients undergoing endoscopic dacryocystorhinostomy (eDCR) performed jointly by ophthalmologists and otolaryngologists. Retrospective case series consisting of all the patients who underwent eDCR for nasolacrimal duct obstruction at New York Presbyterian Hospital/Weill Cornell Medical College between the 2009-2012 academic years. Patients were followed post-operatively for at least six months. The primary endpoint assessed in this study was symptom recurrence (epiphora). A total of 20 patients (25 total cases) underwent eDCR within the study interval. Of the 25 cases, 7 (28.0%) represented reoperations due to recurrent symptoms. All 20 patients in the study exhibited sinus pathology, as determined during a pre-operative otolaryngology assessment. As a result, 16 of these patients (80.0%) underwent concurrent sinonasal surgery at the time of eDCR. The success rate in cases without prior DCR was 83.3% (15/18). Only 57.1% of revision cases (4/7) reported resolution of epiphora following surgery. While a joint approach to eDCR did not appear to significantly improve efficacy, it offered the advantage of having an otolaryngologist assess and treat concurrent sinonasal pathology, which was seen in every patient in our series. Given our findings, as well as the technical difficulty often associated with the procedure, there may be great utility in performing eDCR in conjunction with an otolaryngologist. 23830143 Fracture of the shoulder girdle in multiply injured patients - an imperative for a high level of suspicion for associated neurovascular injuries. The combination of a bony injury to the shoulder girdle and damage to the brachial plexus and the subclavian vessels is a rare finding. The cases of this combined injury pattern described in the literature are most notably reported in multiply-injured patients after high velocity trauma. Three cases were admitted to our hospital after motorcycle accidents resulting in a combination of severe bony injuries to the shoulder girdle, to the subclavian artery and a lesion to the brachial plexus. Based on these three clinical cases the patterns of injury, as well as primary and secondary treatment approaches are presented. The early detection of these injuries can be difficult in given acute, life threatening injuries addressed first in these multiply injured patients. A high level of suspicion, in conjunction with standardized ATLS based institutional protocols for secondary and tertiary survey, should increase the likelihood of a timely detection and early management of these rare but potentially devastating injuries. 23929368 Patient satisfaction survey of mandibular two-implant-retained overdentures in a predoctoral program. In response to the Commission of Dental Accreditation (CODA) mandate of a competency in the "replacement of teeth including fixed, removable and implant" prostheses, a predoctoral implant curriculum was implemented at New York University College of Dentistry. The assessment of the success or failure of a program should include an assessment of patient satisfaction with the treatment received in the predoctoral clinics. The purpose of this study was to measure patient satisfaction with the mandibular 2-implant-retained overdenture therapy received in the predoctoral program at New York University College of Dentistry. A telephone survey of patients who received an implant-retained overdenture in the predoctoral clinics at New York University, College of Dentistry (n=101) was conducted. Two of the authors contacted patients for participation in the survey and, using a prepared script, asked about their satisfaction with items such as function, comfort, and esthetics in addition to their overall satisfaction with the treatment they received. Data were analyzed with descriptive statistics. The study revealed that 79% of participants were satisfied with their masticatory ability, 84% were satisfied with the comfort of the prosthesis, and 89% were satisfied with the esthetics of their new prosthesis. Additionally, 85% of participants reported satisfaction with the overall treatment experience, and 90% would recommend that a friend receive the same treatment. The results of this study support the incorporation of treatment with an implant-retained mandibular overdenture as part of the routine care provided in the predoctoral education program to meet the mandates of CODA. 23823726 The Mycobacterium tuberculosis regulatory network and hypoxia. We have taken the first steps towards a complete reconstruction of the Mycobacterium tuberculosis regulatory network based on ChIP-Seq and combined this reconstruction with system-wide profiling of messenger RNAs, proteins, metabolites and lipids during hypoxia and re-aeration. Adaptations to hypoxia are thought to have a prominent role in M. tuberculosis pathogenesis. Using ChIP-Seq combined with expression data from the induction of the same factors, we have reconstructed a draft regulatory network based on 50 transcription factors. This network model revealed a direct interconnection between the hypoxic response, lipid catabolism, lipid anabolism and the production of cell wall lipids. As a validation of this model, in response to oxygen availability we observe substantial alterations in lipid content and changes in gene expression and metabolites in corresponding metabolic pathways. The regulatory network reveals transcription factors underlying these changes, allows us to computationally predict expression changes, and indicates that Rv0081 is a regulatory hub. 23572266 Beta-catenin and survivin expression in keratocystic odontogenic tumor (KCOT). A comparative immunohistochemical study in primary, recurrent and nevoid basal cell carcinoma syndrome (NBCCS)-associated lesions. Aim: To determine the epithelial expression of β-catenin and survivin in sporadic (primary, and recurrent) and nevoid basal cell carcinoma syndrome (NBCCS) keratocystic odontogenic tumour (KCOT) in order to assess activation of the β-catenin pathway and evidence of apoptotic inhibition, processes that may contribute to the known differences in their biological behaviour. Materials and Methods: Sections from 40 cases of KCOT (19 sporadic/primary; 9 sporadic/recurrent and 12 NBCCS-associated) were immunohistochemically stained for β-catenin and survivin. The extent and intensity of immunoreactivity within the lining epithelium was assessed, using semi-quantitative scales, independently by two pathologists who were blinded to the clinical-pathological data. Data were analysed using Kruskal-Wallis test and, for pair-wise comparisons, Mann-Whitney test with Bonferroni correction. Results: All cystic epithelial linings stained for β-catenin and survivin but there were differences in the pattern and intensity of staining among KCOT types. Sporadic primary KCOT showed weaker staining for β-catenin (P=0.0003) and survivin (P≤0.0048) that was restricted to the basal and para-basal layers only, compared to sporadic recurrent and NBCCS-associated KCOT, which showed expression throughout all epithelial layers. There were no differences in β-catenin expression among recurrent and NBCCS-associated KCOT, whereas the intensity of survivin staining was higher in NBCCS-KCOT (P=0.0003). Nuclear staining for β-catenin was found exclusively in recurrent (5/9 cases) and NBCCS-associated (4/12 cases) KCOT. Conclusion: The data demonstrate β-catenin delocalization and survivin over-expression in recurrent sporadic and NBCCS-associated KCOT suggesting that these pathways related to apoptotic inhibition have a role in KCOT growth and recurrence. 23609225 Structural transitions in mixed ternary noble gas clusters. The properties of noble gas systems can be greatly extended by heterogeneous mixtures of elements. The geometrical structures and energies of mixed Ar-Kr-Xe clusters were investigated using ternary Lennard-Jones (TLJ) potential. For the Ar19Kr n Xe19, Ar19Kr19Xe n , and Ar n Kr19Xe19 (n = 0-17) clusters investigated, the results show that only two minimum energy configurations exist, i.e., polytetrahedron and six-fold pancake. The inner core of all these clusters is composed mainly of Ar atoms, and Kr and Xe atoms are distributed on the surface with well mixed pattern for polytetrahedral and segregate pattern for six-fold pancake configurations. The relative stability property of Ar-Kr-Xe clusters with a certain composition is discussed. Moreover, the role of heterogeneity on the strain was investigated, and reduced strain energies in Ar-Kr-Xe clusters were studied to find possible ways of reducing strain. The results showed that the strain energies were affected mainly by Ar-Ar, Ar-Kr, and Xe-Xe bonds. 23810798 MicroRNAs as pharmacological targets in diabetes. Diabetes is characterized by high levels of blood glucose due to either the loss of insulin-producing beta-cells in the pancreas, leading to a deficiency of insulin in type 1 diabetes, or due to increased insulin resistance, leading to reduced insulin sensitivity and productivity in type 2 diabetes. There is an increasing need for new options to treat diabetes, especially type 2 diabetes at its early stages due to an ineffective control of its development in patients. Recently, a novel class of small noncoding RNAs, termed microRNAs (miRNAs), is found to play a key role as important transcriptional and posttranscriptional inhibitors of gene expression in fine-tuning the target messenger RNAs (mRNAs). miRNAs are implicated in the pathogenesis of diabetes and have become an intriguing target for therapeutic intervention. This review focuses on the dysregulated miRNAs discovered in various diabetic models and addresses the potential for miRNAs to be therapeutic targets in the treatment of diabetes. 23126480 Associations between high levels of conduct problems and co-occurring problems among the youngest boys and girls in schools: A cross-sectional study. Abstract Background: Few studies have focused on conduct problems and co-occurring problems among the youngest children in schools, such as social, internalizing and attention problems. In particular, there is a lack of studies that differentiate between boys and girls in terms of such problems. Aim: The aim of the current study was to test associations between conduct problems and social, internalizing and attention problems, as well as adaptive school functioning, which was rated by the teachers of boys and girls in grades 1-3. Methods: In a cross-sectional study, 103 boys and 108 girls in grades 1-3 at six schools participated in a national Norwegian study of child conduct problems in the normal population. Linear regression analysis was used to test the associations between conduct problems, social skills, problems of internalization, attention problems and adaptation to school among boys and girls. Results: There were significant associations between high levels of conduct problems and social skills problems, attention problems and low adaptive school functioning scores among boys and girls. Attention problems had the most powerful associations with conduct problems for both genders. Conclusions: Young schoolchildren with high levels of conduct problems also had co-occurring problems. Schools and teachers need to adopt a comprehensive approach to help these children during their first years in school. 23874768 Glucose-6-phosphate dehydrogenase deficiency in nigerian children. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy and in Sub-Saharan Africa, is a significant cause of infection- and drug-induced hemolysis and neonatal jaundice. Our goals were to determine the prevalence of G6PD deficiency among Nigerian children of different ethnic backgrounds and to identify predictors of G6PD deficiency by analyzing vital signs and hematocrit and by asking screening questions about symptoms of hemolysis. We studied 1,122 children (561 males and 561 females) aged 1 month to 15 years. The mean age was 7.4±3.2 years. Children of Yoruba ethnicity made up the largest group (77.5%) followed by those Igbo descent (10.6%) and those of Igede (10.2%) and Tiv (1.8%) ethnicity. G6PD status was determined using the fluorescent spot method. We found that the overall prevalence of G6PD deficiency was 15.3% (24.1% in males, 6.6% in females). Yoruba children had a higher prevalence (16.9%) than Igede (10.5%), Igbo (10.1%) and Tiv (5.0%) children. The odds of G6PD deficiency were 0.38 times as high in Igbo children compared to Yoruba children (p = 0.0500). The odds for Igede and Tiv children were not significantly different from Yoruba children (p = 0.7528 and 0.9789 respectively). Mean oxygen saturation, heart rate and hematocrit were not significantly different in G6PD deficient and G6PD sufficient children. The odds of being G6PD deficient were 2.1 times higher in children with scleral icterus than those without (p = 0.0351). In conclusion, we determined the prevalence of G6PD deficiency in Nigerian sub-populations. The odds of G6PD deficiency were decreased in Igbo children compared to Yoruba children. There was no association between vital parameters or hematocrit and G6PD deficiency. We found that a history of scleral icterus may increase the odds of G6PD deficiency, but we did not exclude other common causes of icterus such as sickle cell disease or malarial infection. 23865520 The Role of CD133+ Cells in a Recurrent Embryonal Tumor with Abundant Neuropil and True Rosettes (ETANTR). Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is a recently described embryonal neoplasm of the central nervous system, consisting of a well-circumscribed embryonal tumor of infancy with mixed features of ependymoblastoma (multilayer ependymoblastic rosettes and pseudorosettes) and neuroblastoma (neuroblastic rosettes) in the presence of neuropil-like islands. We present the case of a young child with a very aggressive tumor that rapidly recurred after gross total resection, chemotherapy, and radiation. Prominent vascular sclerosis and circumscribed tumor led to the diagnosis of malignant astroblastoma; however, rapid recurrence and progression of this large tumor after gross total resection prompted review of the original pathology. ETANTR is histologically distinct with focal GFAP and synaptophysin expression in the presence of neuronal and ependymoblastic rosettes with focal neuropil islands. These architectural features, combined with unique chromosome 19q.13.42 amplification, confirmed the diagnosis. In this report, we describe tumor stem cell (TSC) marker CD133, CD15, and nestin alterations in ETANTR before and after chemotherapy. We found that TSC marker CD133 was richly expressed after chemotherapy in recurrent ETANTR, while CD15 is depleted compared to that expressed in the original tumor, suggesting that CD133+ cells likely survived initial treatment, further contributing to formation of the recurrent tumor. 23567241 Comparative study on transcriptional activity of 17 parabens mediated by estrogen receptor α and β and androgen receptor. The structure-activity relationships of parabens which are widely used as preservatives for transcriptional activities mediated by human estrogen receptor α (hERα), hERβ and androgen receptor (hAR) were investigated. Fourteen of 17 parabens exhibited hERα and/or hERβ agonistic activity at concentrations of ⩽1×10(-5)M, whereas none of the 17 parabens showed AR agonistic or antagonistic activity. Among 12 parabens with linear alkyl chains ranging in length from C1 to C12, heptylparaben (C7) and pentylparaben (C5) showed the most potent ERα and ERβ agonistic activity in the order of 10(-7)M and 10(-8)M, respectively, and the activities decreased in a stepwise manner as the alkyl chain was shortened to C1 or lengthened to C12. Most parabens showing estrogenic activity exhibited ERβ-agonistic activity at lower concentrations than those inducing ERα-agonistic activity. The estrogenic activity of butylparaben was markedly decreased by incubation with rat liver microsomes, and the decrease of activity was blocked by a carboxylesterase inhibitor. These results indicate that parabens are selective agonists for ERβ over ERα; their interactions with ERα/β are dependent on the size and bulkiness of the alkyl groups; and they are metabolized by carboxylesterases, leading to attenuation of their estrogenic activity. 22762970 Multi-detector CT in the paediatric urinary tract. The use of paediatric multi-slice CT (MSCT) is rapidly increasing worldwide. As technology advances its application in paediatric care is constantly expanding with an increasing need for radiation dose control and appropriate utilization. Recommendations on how and when to use CT for assessment of the paediatric urinary tract appear to be an important issue. Therefore the European Society of Paediatric Radiology (ESPR) uroradiology task force and European Society of Urogenital Radiology (ESUR) paediatric working groups created a proposal for performing renal CT in children that has recently been published. The objective of this paper is to discuss paediatric urinary tract CT (uro-CT) in more detail and depth. The specific aim is not only to offer general recommendations on clinical indications and optimization processes of paediatric CT examination, but also to address various childhood characteristics and phenomena that facilitate understanding the different approach and use of uro-CT in children compared to adults. According to ALARA principles, paediatric uro-CT should only be considered for selected indications provided high-level comprehensive US is not conclusive and alternative non-ionizing techniques such as MR are not available or appropriate. Optimization of paediatric uro-CT protocols (considering lower age-adapted kV and mAs) is mandatory, and the number of phases and acquisition series should be kept as few as possible. 23219337 Anti-tumor and anti-metastatic actions of wogonin isolated from Scutellaria baicalensis roots through anti-lymphangiogenesis. Tumor growth and metastasis are associated with angiogenesis and lymphangiogenesis through the production of vascular endothelial growth factor (VEGF) or VEGF-C in tumors, and the phosphorylation of VEGF receptor (VEGFR)-2 or VEGFR-3 in vascular endothelial cells or lymphatic endothelial cells (LECs). Tumor-associated macrophages (TAMs) play an important role in tumor lymphangiogenesis, and consequently stimulate metastasis through the lymphatic system to lymph nodes. We examined the effects of wogonin isolated from Scutellaria baicalensis roots on tumor growth and metastasis using a highly metastatic model in osteosarcoma LM8-bearing mice. Wogonin (25 and 50 mg/kg, twice daily) reduced tumor growth and metastasis to the lung, liver and kidney, angiogenesis (CD31-positive cells), lymphangiogenesis (LYVE-1-positive cells), and TAM (F4/80-positive cell) numbers in the tumors of LM8-bearing mice. Wogonin (10-100 μM) also inhibited increases in IL-1β production and cyclooxygenase (COX)-2 expression induced by lipopolysaccharide in THP-1 macrophages. Wogonin had no effect on VEGF-C production in LM8 cells, or VEGFR-3 expression in human lymphatic endothelial cells (HLECs), however, it inhibited VEGF-C-induced VEGFR-3 phosphorylation in HLECs. The anti-tumor and anti-metastatic actions of wogonin may be associated with the inhibition of VEGF-C-induced lymphangiogenesis through a reduction in VEGF-C-induced VEGFR-3 phosphorylation by the inhibition of COX-2 expression and IL-1β production in TAMs. 23867007 First two cases of neonatal human parechovirus 4 infection with manifestation of suspected sepsis, Finland. Human parechoviruses are a family of viruses closely related to enteroviruses, and associated with neonatal sepsis-like syndrome, respiratory symptoms and gastrointestinal infection. Here we present clinical details of two neonatal sepsis cases suspected to be caused by HPeV4 infection. The patients were hospitalized in October, 2012. No other causative agents were detected. 23791977 Turning an antiviral into an anticancer drug: Nanoparticle delivery of acyclovir monophosphate. Anti-herpes simplex virus (HSV) drug acyclovir (ACV) is phosphorylated by the viral thymidine kinase (TK), but not the cellular TK. Phosphorylated ACV inhibits cellular DNA synthesis and kills the infected cells. We hypothesize that ACV monophosphate (ACVP), which is an activated metabolite of ACV, should be efficient in killing cells independent of HSV-TK. If so, ACVP should be a cytotoxic agent if properly delivered to the cancer cells. The Lipid/Calcium/Phosphate (LCP) nanoparticles (NPs) with a membrane/core structure were used to encapsulate ACVP to facilitate the targeted delivery of ACVP to the tumor. The LCP NPs showed entrapment efficiency of ~70%, the nano-scaled particle size and positive zeta potential. Moreover, ACVP-loaded LCP NPs (A-LCP NPs) exhibited concentration-dependent cytotoxicity against H460 cells and increased S-phase arrest. More importantly, a significant reduction of the tumor volume over 4days following administration (p<0.05-0.005) of A-LCP NPs, suggests excellent in vivo efficacy. Whereas, two free drugs (ACV and ACVP) and blank LCP NPs showed little or no therapeutic effect. It was also found that the high efficacy of A-LCP NPs was associated with the ability to induce dramatic apoptosis of the tumor cells, as well as significantly inhibit tumor cell proliferation and cell cycle progression. In conclusion, with the help of LCP NPs, monophosphorylation modification of ACV can successfully modify an HSV-TK-dependent antiviral drug into an anti-tumor drug. 23825133 Plant response to a global greenhouse event 56 million years ago. • Premise of the study: The fossil record provides information about the long-term response of plants to CO2-induced climate change. The Paleocene-Eocene Thermal Maximum (PETM), a 200000-yr-long period of rapid carbon release and warming that occurred ∼56 million years ago, is analogous to future anthropogenic global warming. • Methods: We collected plant macrofossils in the Bighorn Basin, Wyoming, United States, from a period spanning the PETM and studied changes in floristic composition. We also compiled and summarized published records of floristic change during the PETM. • Key results: There was radical floristic change in the Bighorn Basin during the PETM reflecting local or regional extirpation of mesophytic plants, notably conifers, and colonization of the area by thermophilic and dry-tolerant species, especially Fabaceae. This floristic change largely reversed itself as the PETM ended, though some immigrant species persisted and some Paleocene species never returned. Less detailed records from other parts of the world show regional variation in floristic response, but are mostly consistent with the Bighorn Basin trends. • Conclusions: Despite geologically rapid extirpation, colonization, and recolonization, we detected little extinction during the PETM, suggesting the rate of climate change did not exceed the dispersal capacity of terrestrial plants. Extrapolating the response of plants from the PETM to future anthropogenic climate change likely underestimates risk because rates of climate change during the PETM may have been an order of magnitude slower than current rates of change and because the abundant, widespread species common as fossils are likely resistant to extinction. 23711752 Patient autonomy in multiple sclerosis--possible goals and assessment strategies. Patient autonomy has been increasingly acknowledged as prerequisite for successful medical decision making in Western countries. In medical decisions with a need to involve a health professional, patient autonomy becomes apparent in the extent of patients' participation in the communication as described in the concept of shared decision making. Patient autonomy can be derived from different perspectives or goals and the focus of evaluation approaches may vary accordingly. Multiple sclerosis (MS) is a paradigmatic disease to study patient autonomy mainly because MS patients are highly disease competent and due to ambiguous evidence on many aspects of disease-related medical decision making. This review gives an overview on measurement issues in studying decision making in MS, categorized according to prerequisites, process measures and outcomes of patient autonomy. As relevant prerequisites role preferences, risk attribution, risk tolerance, and risk knowledge are discussed. Regarding processes, we distinguish intra-psychic and interpersonal aspects. Intra-psychic processes are elucidated using the theory of planned behavior, which guided development of a 30-item scale to capture decisions about immunotherapy. Moreover, a theory of uncertainty management has been created resulting in the development of a corresponding measurement concept. Interpersonal processes evolving between physician and patient can be thoroughly analyzed from different perspectives by use of the newly developed comprehensive MAPPIN'SDM inventory. Concerning outcomes, besides health related outcomes, we discuss match of preferred roles during the decision encounters (preference match), decisional conflict as well as an application of the multidimensional measure of informed choice to decisions of MS patients. These approaches provide an overview on patient-inherent and interpersonal factors and processes modulating medical decision making and health behavior in MS and beyond. 23712678 N-linked glycoproteome profiling of human serum using tandem enrichment and multiple fraction concatenation. N-linked glycosylation is an important protein posttranslational modification that is involved in numerous biological processes. Different methods, including chemical reaction and affinity interaction, have been developed to enrich glycosylated peptides or proteins from biological systems. However, due to the common occurrence of low glycosites occupancy in proteins and the low efficiency of enrichment approaches, only a small fraction of protein glycosites have been reported. In this study, we combined the glycopeptide enrichment strategy for broad analysis of human serum N-glycoproteins using a tandem enrichment method coupling lectin affinity capture with HILIC. This strategy was applied to profile the human serum N-linked glycoproteome, and it resulted in 32 and 14% more N-glycosites than could be identified with the common lectin affinity capture or HILIC approaches, respectively. With an additional dimension of glycopeptides separation using high-pH reversed phase liquid chromatography or off-gel electrophoresis, the number of identified glycosites was increased by 3.1-fold and 1.8-fold, respectively. These results demonstrate that tandem enrichment methods, especially when followed by high-pH reversed-phase prefractionation, can greatly improve the power of N-glycoproteome analysis. In total, 615 N-glycosites from 312 glycoproteins (protein group) were mapped using high-accuracy mass spectrometry. 23350530 Intracellular drug release from curcumin-loaded PLGA nanoparticles induces G2/M block in breast cancer cells. PLGA nanoparticles are among the most studied polymer nanoformulations for several drugs against different kinds of malignant diseases, thanks to their in vivo stability and tumor localization exploiting the well-documented "enhanced permeation and retention" (EPR) effect. In this paper, we have developed uniform curcumin-bearing PLGA nanoparticles by a single-emulsion process, which exhibited a curcumin release following a Fickian-law diffusion over 10 days in vitro. PLGA nanoparticles were about 120 nm in size, as determined by dynamic light scattering, with a surface negative charge of -30 mV. The loading ratio of encapsulated drug in our PLGA nanoformulation was 8 wt%. PLGA encapsulation provided efficient protection of curcumin from environment, as determined by fluorescence emission experiments. Next, we have investigated the possibility to study the intracellular degradation of nanoparticles associated with a specific G2/M blocking effect on MCF7 breast cancer cells caused by curcumin release in the cytoplasm, which provided direct evidence on the mechanism of action of our nanocomplex. This study was carried out using Annexin V-based cell death analysis, MTT assessment of proliferation, flow cytometry, and confocal laser scanning microscopy. PLGA nanoparticles proved to be completely safe, suggesting a potential utilization of this nanocomplex to improve the intrinsically poor bioavailability of curcumin for the treatment of severe malignant breast cancer. 23860274 Morphology and Metal Binding Characteristics of a Natural Polymer-Kondagogu (Cochlospermum gossypium) Gum. Kondagogu (Cochlospermum gossypium) gum (KG), a natural tree exudate, was investigated for its morphological, adsorption and metal interaction behavior with various toxic heavy metals (Pb, Cd, Ni, Cr and Fe). SEM, AFM and TEM techniques were used to study the morphological changes occurring after metal adsorption onto the biopolymer structure. The degree of biosorption of metals on KG biopolymer surfaces was assessed by small-angle X-ray scattering analysis. EDXA spectrum revealed that the ion-exchange mechanism plays a major role in the binding process between KG and metal ions. The higher electron density observed in the KG-Cd complex suggests that Cd is strongly bound to KG compared to the other metals. This work provides a potential platform for developing a hydrocolloid-based nanogel for bioremediation of environmental contaminants. 23968756 Derivation of a clinical prediction rule for bloodstream infection mortality of patients visiting the emergency department based on predisposition, infection, response, and organ dysfunction concept. Bloodstream infection (BSI) is a serious infection with a high mortality. We aimed to construct a predictive scoring system to stratify the severity of patients with BSI visiting the emergency department (ED). We conducted a retrospective cohort study consisting of patients who visited the ED of a tertiary hospital with documented BSI in 2010. The potential predictors of mortality were obtained via chart review. Multivariate logistic regression was utilized to identify predictors of mortality. Penalized maximum likelihood estimation (PMLE) was applied for score development. There were 1063 patients with bacteremia included, with an overall 28-day mortality rate of 13.2% (n = 140). In multiple logistic regression with penalization, the independent predictors of death were "predisposition": malignancy (β-coefficient, 0.65; +2 points); "infection": Staphylococcus aureus (S. aureus) bacteremia (0.69; +2 points), pneumonia (1.32; +4 points), and bacteremia with an unknown focus (0.70; +2 points); "response": body temperature <36°C (1.17; +3 points), band form >5% (1.00; +3 points), and red blood cell distribution width (RDW) >15% (0.63; +2 points); and "organ dysfunction": pulse oximeter oxygen saturation <90% (0.72; +2 points) and creatinine >2 mg/dL (0.69; +2 points). The area under receiver operating characteristic curve (AUROC) for the model was 0.881 [95% confidence interval (CI), 0.848-0.913], with a better performance than the Pitt bacteremia score (AUROC: 0.750; 95% CI 0.699-0.800, p < 0.001). The patients were stratified into four risk groups: (1) low, 0-3 points, mortality rate: 1.5%; (2) moderate, 4-6 points, mortality rate: 10.5%; (3) high, 7-8 points, mortality rate: 28.6%; and (4) very high, ≥9 points, mortality rate: 65.5%. The new scoring system for bacteremia could facilitate the prediction of the risk of 28-day mortality for patients visiting the ED with BSI. 23849816 Efficacy and safety of direct transnasal cholangioscopy with standard ultraslim endoscopes: results of a large cohort study. Direct cholangioscopy (DC) with ultraslim endoscopes and free-hand cannulation of the common bile duct (CBD) is a promising technique for evaluating and treating cholangiopathy. However, its safety and success rates are as yet unclear. To evaluate the overall success rates and adverse events with the procedure. Single-center, prospective cohort study; 12 patients retrospectively enrolled. Academic tertiary referral center. A total of 100 DC procedures in 84 patients with biliary disease were evaluated prospectively. DC performed with the patient under conscious sedation. Overall success rates and adverse events with the procedure. In 34 cases with small- or medium-sized sphincterotomies, sphincteroplasty was performed with a 10-mm dilating balloon before DC. The intraductal area of interest was successfully accessed in 87% of the procedures. The intended interventions were successfully carried out in 81 patients (93.1%), but failed in 6 (6.9%). In patients without significant strictures, intrahepatic exploration of the bile ducts beyond the level of the bifurcation was feasible in only 10.8%. The mean total procedure time was 38.6 ± 12.2 minutes. Adverse events occurred in 12 procedures (12%) and were managed conservatively. All procedures were performed by 1 endoscopist. DC is safe and allows direct, high-resolution examination and a wide range of therapeutic options in the bile ducts in the majority of patients with biliary disease. However, the range of access is limited to the main bile duct. Suspected pathology restricted to the proximal intrahepatic ducts beyond the bifurcation is therefore not a good indication for DC. 23089249 Carbaryl exposure and recovery modify the interrenal and thyroidal activities and the mitochondria-rich cell function in the climbing perch Anabas testudineus Bloch. We examined the effects of carbaryl (1-naphthyl methylcarbamate; sevin), a carbamate pesticide, on interrenal and thyroid activities and mitochondrial rich (MR) cell function in climbing perch to understand the physiological basis of toxicity acclimation in this fish to the chemical stressor. Carbaryl exposure (5-20 mg L(-1)) for 48 h increased cortisol and glucose, but decreased the T(3) level without affecting T(4) concentration in the plasma. These responses of the carbaryl-exposed fish were nullified and a rise in plasma T(4) occurred in these fish when they were kept for 96 h recovery in clean water. A tight plasma mineral control was indicated in the carbaryl-exposed fish as reflected by the unchanged plasma Na, K, Ca and inorganic phosphate levels. The ouabain-sensitive Na(+), K(+)-ATPase activity showed an increase in the gills but the intestinal and renal tissues showed little response to carbaryl treatment. However, substantial increases in the intestinal and renal Na(+), K(+)-ATPase activities occurred in the recovery fish. The MR cells in the branchial epithelia showed a strong Na(+), K(+)-ATPase immunoreactivity to carbaryl treatment indicating an activated MR cell function. The numerical MR cell density remained unchanged, but stretching of secondary gill lamellae as part of gill remodeling occurred during carbaryl exposure. The increased surface of these lamellae with abundant MR cells as a result of its migration into the lamellar surface points to marked structural and functional modifications of these cells in the carbaryl-treated fish which is likely to a target for carbaryl action. The rise in plasma T(4) and the restoration of normal branchial epithelia in the recovery fish indicate a thyroidal involvement in the recovery response and survival. Our data thus provide evidence that carbaryl exposure and its recovery evoke interrenal and thyroid disruption in this fish leading to a modified osmotic response including an altered MR cell function. 23944814 It is time to speak loudly, lobby MPs and respond to poor media coverage. Like nursing student Claire Docherty (Reflections July 31), I am distressed beyond belief that overstretched nurses are being blamed for the deficiencies in the NHS. 22999653 Maintenance of retinal ganglion cell mitochondrial functions as a neuroprotective strategy in glaucoma. Loss of vision in glaucoma occurs because retinal ganglion cells (RGCs) die. RGCs have probably more mitochondria than any other neurone in the CNS. It is proposed that stress to mitochondria of individual RGCs is a major trigger of the disease and also provides an explanation why different RGCs die at different times. Pharmacological agents that can maintain mitochondrial functions, in particular to attenuate oxidative stress and to sustain energy production, might therefore provide a novel way of slowing down RGC death and help in the treatment of glaucoma. 23223176 Cell-based screening identifies paroxetine as an inhibitor of diabetic endothelial dysfunction. We have conducted a phenotypic screening in endothelial cells exposed to elevated extracellular glucose (an in vitro model of hyperglycemia) to identify compounds that prevent hyperglycemia-induced reactive oxygen species (ROS) formation without adversely affecting cell viability. From a focused library of >6,000 clinically used drug-like and pharmacologically active compounds, several classes of active compounds emerged, with a confirmed hit rate of <0.5%. Follow-up studies focused on paroxetine, a clinically used antidepressant compound that has not been previously implicated in the context of hyperglycemia or diabetes. Paroxetine reduced hyperglycemia-induced mitochondrial ROS formation, mitochondrial protein oxidation, and mitochondrial and nuclear DNA damage, without interfering with mitochondrial electron transport or cellular bioenergetics. The ability of paroxetine to improve hyperglycemic endothelial cell injury was unique among serotonin reuptake blockers and can be attributed to its antioxidant effect, which primarily resides within its sesamol moiety. Paroxetine maintained the ability of vascular rings to respond to the endothelium-dependent relaxant acetylcholine, both during in vitro hyperglycemia and ex vivo, in a rat model of streptozotocin-induced diabetes. Thus, the current work identifies a novel pharmacological action of paroxetine as a protector of endothelial cells against hyperglycemic injury and raises the potential of repurposing of this drug for the experimental therapy of diabetic cardiovascular complications. 23884443 The insulator protein Suppressor of Hairy-wing is an essential transcriptional repressor in the Drosophila ovary. Suppressor of Hairy-wing [Su(Hw)] is a DNA-binding factor required for gypsy insulator function and female germline development in Drosophila. The insulator function of the gypsy retrotransposon depends on Su(Hw) binding to clustered Su(Hw) binding sites (SBSs) and recruitment of the insulator proteins Centrosomal Protein 190 kD (CP190) and Modifier of mdg4 67.2 kD (Mod67.2). By contrast, the Su(Hw) germline function involves binding to non-clustered SBSs and does not require CP190 or Mod67.2. Here, we identify Su(Hw) target genes, using genome-wide analyses in the ovary to uncover genes with an ovary-bound SBS that are misregulated upon Su(Hw) loss. Most Su(Hw) target genes demonstrate enriched expression in the wild-type CNS. Loss of Su(Hw) leads to increased expression of these CNS-enriched target genes in the ovary and other tissues, suggesting that Su(Hw) is a repressor of neural genes in non-neural tissues. Among the Su(Hw) target genes is RNA-binding protein 9 (Rbp9), a member of the ELAV/Hu gene family. Su(Hw) regulation of Rbp9 appears to be insulator independent, as Rbp9 expression is unchanged in a genetic background that compromises the functions of the CP190 and Mod67.2 insulator proteins, even though both localize to Rbp9 SBSs. Rbp9 misregulation is central to su(Hw)(-/-) sterility, as Rbp9(+/-), su(Hw)(-/-) females are fertile. Eggs produced by Rbp9(+/-), su(Hw)(-/-) females show patterning defects, revealing a somatic requirement for Su(Hw) in the ovary. Our studies demonstrate that Su(Hw) is a versatile transcriptional regulatory protein with an essential developmental function involving transcriptional repression. 23081933 Analysis of 30 synthetic cannabinoids in oral fluid using liquid chromatography-electrospray ionization tandem mass spectrometry. In recent years, the analysis of synthetic cannabinoids in human specimens has gained enormous importance in the broad field of drug testing. Nevertheless, the considerable structural diversity among synthetic cannabinoids already identified in 'herbal mixtures' hampers the development of comprehensive analytical methods. As the identification of the main metabolites of newly appearing substances is very laborious and time-consuming, the detection of the parent compounds in blood samples is the current approach of choice for drug abstinence testing. Whenever blood sampling is not possible however, the need for alternative matrices arises. In this article, we present a fully validated liquid chromatography-electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method for the analysis of 30 synthetic cannabinoids in oral fluid samples collected with the Dräger DCD 5000 collection device. The method proved to be suitable for the quantification of 28 substances. The limits of detection were in the range from 0.015 to 0.9 ng/ml, while the lower limits of quantification ranged from 0.15 to 3.0 ng/ml. The method was successfully applied to 264 authentic samples during routine analysis. A total of 31 samples (12%) was tested positive for at least one of the following synthetic cannabinoids: AM-694, AM-2201, JWH-018, JWH-019, JWH-081, JWH-122, JWH-203, JWH-210, JWH-250, JWH-307, MAM-2201, and RCS-4. Given that stabilization of the collection pads after sampling is warranted, the collection device provides satisfactory sensitivity. Hence, whenever blood sampling is not possible, the Dräger DCD 5000 collection device offers a good tool for the analysis of synthetic cannabinoids in oral fluid in the broad field of drug testing. Copyright © 2012 John Wiley & Sons, Ltd. 23959874 Protein kinase Cβ as a therapeutic target stabilizing blood-brain barrier disruption in experimental autoimmune encephalomyelitis. Disruption of the blood-brain barrier (BBB) is a hallmark of acute inflammatory lesions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis. This disruption may precede and facilitate the infiltration of encephalitogenic T cells. The signaling events that lead to this BBB disruption are incompletely understood but appear to involve dysregulation of tight-junction proteins such as claudins. Pharmacological interventions aiming at stabilizing the BBB in MS might have therapeutic potential. Here, we show that the orally available small molecule LY-317615, a synthetic bisindolylmaleimide and inhibitor of protein kinase Cβ, which is clinically under investigation for the treatment of cancer, suppresses the transmigration of activated T cells through an inflamed endothelial cell barrier, where it leads to the induction of the tight-junction molecules zona occludens-1, claudin 3, and claudin 5 and other pathways critically involved in transendothelial leukocyte migration. Treatment of mice with ongoing experimental autoimmune encephalomyelitis with LY-317615 ameliorates inflammation, demyelination, axonal damage, and clinical symptoms. Although LY-317615 dose-dependently suppresses T-cell proliferation and cytokine production independent of antigen specificity, its therapeutic effect is abrogated in a mouse model requiring pertussis toxin. This abrogation indicates that the anti-inflammatory and clinical efficacy is mainly mediated by stabilization of the BBB, thus suppressing the transmigration of encephalitogenic T cells. Collectively, our data suggest the involvement of endothelial protein kinase Cβ in stabilizing the BBB in autoimmune neuroinflammation and imply a therapeutic potential of BBB-targeting agents such as LY-317615 as therapeutic approaches for MS. 23702332 Mixed strategy under generalized public goods games. The relationship between group's contribution and public goods produced often exhibits nonlinearity, which constitutes the generalized public goods game. Far less attention has been paid to how the mixed strategy evolves in such generalized games. Here, we study the effects of nonlinear production functions on the evolution of the mixed strategy in finite populations for the first time. When the group size and the population size are comparable, cooperation is doomed irrespective of the production function. Otherwise, nonlinear production functions may induce a convergent evolutionary stable strategy (CESS) or a repeller, but cannot yield the evolutionary branching. Moreover, we particularly consider three representative families of production functions, intriguingly which all display the hysteresis effect. For two families of production functions including concave and convex curves, a unique CESS or a unique repeller may occur even if the group size is two. Whereas for the third class encompassing symmetrically sigmoidal and inverse sigmoidal curves, the coexistence of a CESS and a repeller only occurs if group size is above two, and two saddle-node bifurcations appear. Our work includes some evidently different results by comparing with the evolution of continuous investment or binary strategy. 23877023 Cyclooxygenase-2 mediates induction of the renal stanniocalcin-1 gene by arginine vasopressin. In rats and mice, the renal stanniocalcin-1 (STC-1) gene is expressed in most nephron segments, but is differentially induced in response to dehydration. In cortical segments STC-1 mRNA levels are upregulated by the hypertonicity of dehydration, while hypovolemia causes gene induction in the inner medulla (papilla). In both cases induction is mediated by arginine vasopressin (AVP) acting via the V2 receptor (V2R). The intent of STC-1 gene upregulation during dehydration has yet to be established. Therefore, to narrow down the range of possible actions, we mapped out the pathway by which V2R activation upregulates the gene. V2R occupancy activates two different renal pathways in response to dehydration. The first is antidiuretic in nature and is mediated by direct V2R occupancy. The second pathway is indirect and counter-regulates AVP-mediated antidiuresis. It involves COX-2 (cyclooxygenase-2) and the prostanoids, and is activated by the V2R-mediated rise in medullary interstitial osmolality. The resulting prostanoids counter-regulate AVP-mediated antidiuresis. They also upregulate renal cytoprotective mechanisms. The present studies employed models of COX inhibition and COX gene deletion to address the possible involvement of the COX pathway. The results showed that both general and specific inhibitors of COX-2 blocked STC-1 gene induction in response to dehydration. Gene induction in response to dehydration was also abolished in COX-2 null mice (cortex and papilla), but not in COX-1 null mice. STC-1 gene induction in response to V2R occupancy was also uniquely abolished in COX-2 nulls (both regions). These findings therefore collectively suggest that AVP-mediated elevations in STC-1 gene expression are wholly dependent on functional COX-2 activity. As such, a permissive role for STC-1 in AVP-mediated antidiuresis can be ruled out, and its range of possible actions has been narrowed down to AVP counter-regulation and renal cytoprotection. 23305503 Comparison of antiproliferative effects of metformine and progesterone on estrogen-induced endometrial hyperplasia in rats. Metformin has been shown to inhibit the growth of endometriotic implants, and reverse endometrial hyperplasia when combined with oral contraceptive in a case report. The aim of this study is to compare the antiproliferative effects of medroxyprogesterone acetate (MPA), and metformin in oopherectomized rat endometrium. Forty oopherectomized Wistar-Albino rats were used, and assigned to receive saline, 17 β Estradiol hemihydrate (4 mg/kg), 17 β Estradiol hemihydrate (4 mg/kg) and metformin (50 mg/kg), 17 β Estradiol hemihydrate (4 mg/kg) and MPA (1 mg/day) for 14 days. Histological markers of uterotrophy, including endometrial height, luminal ephitelial cell height and density of endometrial glands on hysterectomy speciments were quantified for each specimen. Rats treated with estradiol had significantly increased in endometrial height, endomerial luminal epithelial height and endometrial gland densitiy than the other groups. Metformin and MPA acetate significantly reduced all parameters indicating endometrial hyperplasia, and uterotrophy with respect to the control group. Antiproliferative effects of metformin, and MPA was found to be comparable for all three parameters. In conclusion, metformin attenuates estrogen-induced endometrial hyperplasia in ooferectomized rats to the same degree as progesterone. 23851343 A fluorescence method to detect and quantitate sterol esterification by lecithin:cholesterol acyltransferase. We describe a simple but sensitive fluorescence method to accurately detect the esterification activity of lecithin:cholesterol acyltransferase (LCAT). The new assay protocol employs a convenient mix, incubate, and measure scheme. This is possible by using the fluorescent sterol dehydroergosterol (DHE) in place of cholesterol as the LCAT substrate. The assay method is further enhanced by incorporation of an amphiphilic peptide in place of apolipoprotein A-I as the lipid emulsifier and LCAT activator. Specific fluorescence detection of DHE ester synthesis is achieved by employing cholesterol oxidase to selectively render unesterified DHE nonfluorescent. The assay accurately detects LCAT activity in buffer and in plasma that is depleted of apolipoprotein B lipoproteins by selective precipitation. Analysis of LCAT activity in plasmas from control subjects and sickle cell disease (SCD) patients confirms previous reports of reduced LCAT activity in SCD and demonstrates a strong correlation between plasma LCAT activity and LCAT content. The fluorescent assay combines the sensitivity of radiochemical assays with the simplicity of nonradiochemical assays to obtain accurate and robust measurement of LCAT esterification activity. 23709598 Ionic bases for electrical remodeling of the canine cardiac ventricle. Emerging evidence suggests that ventricular electrical remodeling (VER) is triggered by regional myocardial strain via mechanoelectrical feedback mechanisms; however, the ionic mechanisms underlying strain-induced VER are poorly understood. To determine its ionic basis, VER induced by altered electrical activation in dogs undergoing left ventricular pacing (n = 6) were compared with unpaced controls (n = 4). Action potential (AP) durations (APDs), ionic currents, and Ca(2+) transients were measured from canine epicardial myocytes isolated from early-activated (low strain) and late-activated (high strain) left ventricular regions. VER in the early-activated region was characterized by minimal APD prolongation, but marked attenuation of the AP phase 1 notch attributed to reduced transient outward K(+) current. In contrast, VER in the late-activated region was characterized by significant APD prolongation. Despite marked APD prolongation, there was surprisingly minimal change in ion channel densities but a twofold increase in diastolic Ca(2+). Computer simulations demonstrated that changes in sarcolemmal ion channel density could only account for attenuation of the AP notch observed in the early-activated region but failed to account for APD remodeling in the late-activated region. Furthermore, these simulations identified that cytosolic Ca(2+) accounted for APD prolongation in the late-activated region by enhancing forward-mode Na(+)/Ca(2+) exchanger activity, corroborated by increased Na(+)/Ca(2+) exchanger protein expression. Finally, assessment of skinned fibers after VER identified altered myofilament Ca(2+) sensitivity in late-activated regions to be associated with increased diastolic levels of Ca(2+). In conclusion, we identified two distinct ionic mechanisms that underlie VER: 1) strain-independent changes in early-activated regions due to remodeling of sarcolemmal ion channels with no changes in Ca(2+) handling and 2) a novel and unexpected mechanism for strain-induced VER in late-activated regions in the canine arising from remodeling of sarcomeric Ca(2+) handling rather than sarcolemmal ion channels. 23719293 Using disability-adjusted life years to set health-based targets: A novel use of an established burden of disease metric. Following the 1990 Global Burden of Disease (GBD) study, Disability-Adjusted Life Years (DALYs) have been used widely to quantify the population health burden of diseases and to prioritise and evaluate the impact of specific public health interventions. In the context of the recent release of the 2010 GBD study, we explore the novel use of DALYS to determine health-based targets (HBTs). As with the more traditional use of DALYs, the main advantage of using DALYs as HBTs is the ability to account for differential disease severity, identify the most appropriate public health interventions, and measure the positive and negative outcomes of these interventions. Australia is currently considering adopting DALYs for setting HBTs for drinking water quality, as recommended by the WHO. Adoption of DALY HBTs could be relevant in other areas, including air quality, food safety, health care-associated infections, and surgical complications. 23375559 A neurodevelopmental basis for BECTS: evidence from structural MRI. BECTS (benign epilepsy with centro-temporal spikes) is one of the most common childhood-onset epilepsy syndromes. We investigated quantitative evidence for brain morphological variation associated with BECTS to provide insights into the neuroanatomical basis of this disorder. Three independent BECTS groups were imaged at different stages: (a) near onset (n=16, mean age 9.3±1.6 years), (b) ~9 years after onset (n=9, mean age 15.8±2.3 years), and (c) ~15 years after onset (n=10, mean age 22.7±2.7 years). Age-matched controls were imaged with each group. Whole brain T1-weighted MRI was acquired. Voxel-based morphometry (groups a-c) and cortical thickness analyses (groups b and c) were undertaken within each group and for the groups combined. The relationship between cortical morphology and age was investigated. The voxel-based morphometry analysis indicated increased bilateral grey matter volume in the superior frontal gyrus, insula and right inferior frontal gyrus regions in BECTS. The magnitude of the increase lessened with age of the cases. Cortical thickness analysis revealed thicker cortex in BECTS along middle and inferior frontal gyri bilaterally, left insula and bilateral supramarginal gyrus in the 9-year-after-onset group, that normalised with age. The rate of cortical thickness changes with age were greater in BECTS cases than in controls. Increased cortical gray matter associated with BECTS was found. The decreasing magnitude of the effect with increasing age parallels the natural history of the disorder. The areas affected are consistent with neurocognitive dysfunction in BECTS. 23352252 Nucleotide-binding oligomerization domain containing 2: Structure, function, and diseases. To systematically review literature about the structure and function of nucleotide-binding oligomerization domain containing 2 (NOD2) and its disease association. The English literature was searched using keywords "NOD2" and "disease". Relevant original and review articles were reviewed. NOD2 is an intracellular protein and shares similar molecular structure with NOD1, pyrin, and cryopyrin. There are more than 100 NOD2 gene mutations, some of which have been linked to diseases such as Crohn disease, Blau syndrome, and NOD2-associated autoinflammatory disease (NAID). The NOD2 variants located in the leucine-rich repeat (LRR) region are susceptible to Crohn disease, and the variants in the nucleotide-binding domain (NBD) and in between the NBD and LRR are associated with Blau syndrome and NAID, respectively. No disease association with the gene variants has been found in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriasis/psoriatic arthritis, adult sarcoidosis, granulomatous polyangiitis, or multiple sclerosis. The potential association of the NOD2 variants with graft-versus-host-disease remains controversial. NOD2 functions mainly through RICK or RIP2 to activate p38 mitogen-activated protein kinases and NF-κB, resulting in inflammatory response, and enhanced autophagic activity. Biologic therapy may be beneficial for NOD2-associated diseases, and new drug development may be realized based upon the signaling pathways. NOD2 gene mutations are associated with several diseases, and some of the mutations are of diagnostic value in Blau disease and NAID. To understand the NOD2 function, disease association, and its pathogenesis is important given the ever increasing clinical significance of NOD2. 23867364 Decontamination efficiency of high power ultrasound in the fruit and vegetable industry, a review. Decontamination of fresh fruits and vegetables is an important unsolved technological problem. The main focus of this review is to summarize and synthesize the results of studies and articles about ultrasonic processing which can be adapted to the wash water decontamination process for fruits and vegetables. This review will also provide an overview about the importance of an effective wash water decontamination process in fruits and vegetables, the increase of foodborne outbreaks caused by fresh fruits and vegetables, microbial inactivation using ultrasound, and an interpretation of the high power ultrasound results in the fruits and vegetable industry. In addition, the limitations of ultrasonic processing in commercial applications have also been introduced. 23963047 In vivo formation of double-stranded T-DNA molecules by T-strand priming. During plant genetic transformation, Agrobacterium transfers a single-stranded DNA (T-strand) into the host cell. Increasing evidence suggests that double-stranded (ds) T-DNA, converted from T-strands, are potent substrates for integration. Nevertheless, the molecular mechanism governing T-strand conversion to dsT-DNA is unknown. Integrated T-DNA molecules typically exhibit deletions at their 3' end as compared with their 5' end. We hypothesize that this may result from asymmetric polymerization of T-DNA's ends. Here we show that β-glucuronidase (GUS) expression from sense T-strands is more efficient than from antisense T-strands, supporting asymmetric conversion. Co-transfection with two partially complementary, truncated GUS-encoding T-strands results in GUS expression, which suggests functional hybridization of the T-strands via complementary annealing and supports the notion that T-strands can anneal with primers. Indeed, red fluorescent protein (RFP) expression from mutated T-strand can be restored by delivery of synthetic DNA and RNA oligonucleotides with partial wild-type RFP sequence, implying the involvement of plant DNA repair machinery. 23288436 Registration of FA and T1-Weighted MRI Data of Healthy Human Brain Based on Template Matching and Normalized Cross-Correlation. In this work, we propose a new approach for three-dimensional registration of MR fractional anisotropy images with T1-weighted anatomy images of human brain. From the clinical point of view, this accurate coregistration allows precise detection of nerve fibers that is essential in neuroscience. A template matching algorithm combined with normalized cross-correlation was used for this registration task. To show the suitability of the proposed method, it was compared with the normalized mutual information-based B-spline registration provided by the Elastix software library, considered a reference method. We also propose a general framework for the evaluation of robustness and reliability of both registration methods. Both registration methods were tested by four evaluation criteria on a dataset consisting of 74 healthy subjects. The template matching algorithm has shown more reliable results than the reference method in registration of the MR fractional anisotropy and T1 anatomy image data. Significant differences were observed in the regions splenium of corpus callosum and genu of corpus callosum, considered very important areas of brain connectivity. We demonstrate that, in this registration task, the currently used mutual information-based parametric registration can be replaced by more accurate local template matching utilizing the normalized cross-correlation similarity measure. 23859134 Real-time instrument detection in minimally invasive surgery using radiofrequency identification technology. A key part of surgical workflow recording is recognition of the instrument in use. We present a radiofrequency identification (RFID)-based approach for real-time tracking of laparoscopic instruments. The system consists of RFID-tagged instruments and an antenna unit positioned on the Mayo stand. For reliability analysis, RFID tracking data were compared with the assessment of the perioperative video data of instrument changes (the reference standard for instrument application detection) in 10 laparoscopic cholecystectomies. When the tagged instrument was on the Mayo stand, it was referred to as "not in use." Once it was handed to the surgeon, it was considered to be "in use." Temporal miscounts (incorrect number of instruments "in use") were analyzed. The surgeons and scrub nurses completed a questionnaire after each operation for individual system evaluation. A total of 110 distinct instrument applications ("in use" versus "not in use") were eligible for analysis. No RFID tag failure occurred. The RFID detection rates were consistent with the period of effective instrument application. The delay in instrument detection was 4.2 ± 1.7 s. The highest percentage of temporal miscounts occurred during phases with continuous application of coagulation current. Surgeons generally rated the system better than the scrub nurses (P = 0.54). The feasibility of RFID-based real-time instrument detection was successfully proved in our study, with reliable detection results during laparoscopic cholecystectomy. Thus, RFID technology has the potential to be a valuable additional tool for surgical workflow recognition that could enable a situation dependent assistance of the surgeon in the future. 23281185 pH-responsive hydrogels with dispersed hydrophobic nanoparticles for the oral delivery of chemotherapeutics. Amphiphilic polymer carriers were formed by polymerizing a hydrophilic, pH-responsive hydrogel composed of poly(methacrylic-grafted-ethylene glycol) (P(MAA-g-EG)) in the presence of hydrophobic PMMA nanoparticles. These polymer carriers were varied in PMMA nanoparticle content to elicit a variety of physiochemical properties which would preferentially load doxorubicin, a hydrophobic chemotherapeutic, and release doxorubicin locally in the colon for the treatment of colon cancers. Loading levels ranged from 49% to 64% and increased with increasing nanoparticle content. Doxorubicin loaded polymers were released in a physiological model where low pH was used to simulate the stomach and then stepped to more neutral conditions to simulate the upper small intestine. P(MAA-g-EG) containing nanoparticles were less mucoadhesive as determined using a tensile tester, polymer samples, and fresh porcine small intestine. The cytocompatibility of the polymer materials were assessed using cell lines representing the GI tract and colon cancer and were noncytotoxic at varying concentrations and exposure times. 23905924 Inter-observer concordance of Ki67 labeling index in breast cancer : Japan Breast Cancer Research Group (JBCRG) Ki67 Ring Study. The standardized assessment of Ki67 labeling index (LI) is of clinical importance to identify the patients with primary breast cancer who could benefit from chemotherapy. In this study, we evaluated the inter-observer concordance of Ki67 LI assessment. Six surgical pathologists participated and all the slides were prepared from archival breast cancer tissues fixed in 10% buffered formalin for 24 hours and stained with MIB-1. Three independent studies were conducted. 1) Thirty stained slides were assessed using two different methods: the scoring system, the positive rate scored from 1 (0-9%) to 10 (90-100%) by visual estimate; the counting method, approximately 1000 cells counted in hot spots. 2) Twenty tumors with Ki67 LI 5 to 25% were assessed. 3) Fifteen printed photographs of stained slides were assessed to avoid variations by selecting different fields. In study 1, the counting system {the intraclass correlation coefficient (ICC), 0.66 (95% confidence interval 0.52-0.78)} demonstrated a better correlation than the scoring system {ICC, 0.57 (0.42-0.72)}. In study 2, the assessment for Ki67 LI of 5 to 25% demonstrated a correlation {ICC, 0.68 (0.50-0.81)} similar to that of study 1 (unrestricted range of Ki67 LI). In study 3, the assessment of Ki67 LI by counting yielded a good concordance {ICC, 0.94 (0.88-0.97)}. In conclusion, the counting system yielded a better concordance and the concordance was high when the assessed field was pre-determined, indicating that the selection of the evaluation area is critical for obtaining reproducible Ki67 LI in breast cancer. This article is protected by copyright. All rights reserved. 23758275 Ultrasensitive fiber enhanced UV resonance Raman sensing of drugs. Fiber enhanced UV resonance Raman spectroscopy is introduced for chemical selective and ultrasensitive analysis of drugs in aqueous media. The application of hollow-core optical fibers provides a miniaturized sample container for analyte flow and efficient light-guiding, thus leading to strong light-analyte interactions and highly improved analytical sensitivity with the lowest sample demand. The Raman signals of the important antimalaria drugs chloroquine and mefloquine were strongly enhanced utilizing deep UV and electronic resonant excitation augmented by fiber enhancement. An experimental design was developed and realized for reproducible and quantitative Raman fiber sensing, thus the enhanced Raman signals of the pharmaceuticals show excellent linear relationship with sample concentration. A thorough model accounts for the different effects on signal performance in resonance Raman fiber sensing, and conclusions are drawn how to improve fiber enhanced Raman spectroscopy (FERS) for chemical selective analysis with picomolar sensitivity. 23722281 Indicators of the standard of care for melanoma: Tuscany data. Formal indicators for the evaluation of the quality of melanoma care are needed. We identified 13 process indicators, which encompassed early diagnosis, pathology reporting and surgical treatment. We evaluated the adherence to these indicators using a population-based series on incident skin melanomas (only primary melanomas) for the year 2004 (687 cases) and for the first semester of 2008 (539 cases). We compared the indicators for these 2 years. The melanoma incidence increased between 2004 and 2008. There were statistically significant increases in the percentage of thin (≤1 mm) melanomas (from 50.7 to 61.3%) and in the number of pathology reports that mentioned ulceration (from 61.4 to 84.6%) and margin status (from 76.8 to 84.3%). The percentage of patients staged by sentinel lymph node biopsy was stable (63%) and was higher for patients younger than 75 years of age (74%). The number of nodes almost invariably exceeded the proposed site-specific cutoff reference and, in 2008, the number of nodes removed was always reported for lymphadenectomy. From 2004 to 2008, surgical and pathological waiting times increased. Collection and analysis of these indicators would enable continuous evaluation of the quality of melanoma care in Tuscany and provide sources for a comparative study between Italy and elsewhere. 23832280 Polymorphism in tropomyosin structure and function. Tropomyosins (Tm) in humans are expressed from four distinct genes and by alternate splicing >40 different Tm polypeptide chains can be made. The functional Tm unit is a dimer of two parallel polypeptide chains and these can be assembled from identical (homodimer) or different (heterodimer) polypeptide chains provided both chains are of the same length. Since most cells express multiple isoforms of Tm, the number of different homo and heterodimers that can be assembled becomes very large. We review the mechanism of dimer assembly and how preferential assembly of some heterodimers is driven by thermodynamic stability. We examine how in vitro studies can reveal functional differences between Tm homo and heterodimers (stability, actin affinity, flexibility) and the implication for how there could be selection of Tm isomers in the assembly on to an actin filament. The role of Tm heterodimers becomes more complex when mutations in Tm are considered, such as those associated with cardiomyopathies, since mutations can appear in only one of the chains. 23868849 A yellow fluorescent protein with reduced chloride sensitivity engineered by loop-insertion. Light it up! We demonstrate a novel way to reduce the chloride sensitivity of yellow fluorescent protein by inserting glycine residues in its loop region. The length and position for the insertion were optimized experimentally, and a plausible underlying mechanism is proposed. 23937275 Ab initio Study of Molecular Interactions in Cellulose Iα Biomass recalcitrance - the resistance of cellulosic biomass to degradation - is due in part to the stability of the hydrogen bond network and stacking forces between the polysaccharide chains in cellulose microfibers. The fragment molecular orbital (FMO) method at the correlated Møller-Plesset second order perturbation level of theory was used on a model of the crystalline cellulose I core with a total of 144 glucose units. These computations show that the intersheet chain interactions are stronger than the intrasheet chain interactions for the crystalline structure, while they are more similar to each other for a relaxed structure. An FMO chain pair interaction energy decomposition analysis for both the crystal and relaxed structures reveals an intricate interplay between electrostatic, dispersion, charge transfer, and exchange repulsion effects. The role of the primary alcohol groups in stabilizing the interchain hydrogen bond network in the inner sheet of the crystal and relaxed structures of cellulose I, where edge effects are absent, was analyzed. The maximum attractive intrasheet interaction is observed for the GT-TG residue pair with one intrasheet hydrogen bond, suggesting that the relative orientation of the residues is as important as the hydrogen bond network in strengthening the interaction between the residues. 23861804 Proteomic profiling of rabbit embryonic stem cells derived from parthenotes and fertilized embryos. Rabbit embryonic stem (rES) cells can be derived from various sources of embryos. However, understanding of the gene expression profile, which distincts embryonic stem (ES) cells from other cell types, is still extremely limited. In this study, we compared the protein profiles of three independent lines of rabbit cells, i.e., fibroblasts, fertilized embryo-derived stem (f-rES) cells, and parthenote-derived ES (p-rES) cells. Proteomic analyses were performed using two-dimensional gel electrophoresis (2-DE) and mass spectrometry. Collectively, the expression levels of 100 out of 284 protein spots differed significantly among these three cell types (p<0.05). Of those differentially expressed spots, 91% were identified in the protein database and represented 63 distinct proteins. Proteins with known identities are mainly localized in the cytoplasmic compartments (48%), nucleus (14%), and cytoskeletal machineries (13%). These proteins were majorly involved in biological functions of energy and metabolic pathways (25%), cell growth and maintenance (25%), signal transduction (14%), and protein metabolisms (10%). When protein expression levels among cell types were compared, six proteins associated with a variety of cellular activities, including structural constituents of the cytoskeleton (tubulins), structural molecule (KRT8), catalytic molecules (α-enolase), receptor complex scaffold (14-3-3 protein sigma), microfilament motor proteins (Myosin-9), and heat shock protein (HSP60), were found highly expressed in p-rES cells. Two proteins related to HSP activity and structural constituent of cytoskeleton in f-rES cells, and one structural molecule activity protein in fibroblasts showed significantly higher expression levels (p<0.05). Marker protein expressions in f-rES and p-rES cells were further confirmed by Western blotting and immunocytochemical staining. This study demonstrated unique proteomic profiles of the three rabbit cell types and revealed some novel proteins differentially expressed between f-rES and p-rES cells. These analyses provide insights into rES cell biology and would invite more in-depth studies toward rES cell applications. 23921454 Synthesis of a 3D graphite microball using a microfluidic droplet generator and its polymer composite with core-shell structure. Spherical 3D graphite microballs (3D GMs) and their nanohybrids (3D GM-Fe3O4 nanoparticles) were synthesized by using a microfluidic droplet generator and a thermal evaporation-induced capillary compression method. Using the 3D GM-Fe3O4 nanoparticle as a support for polymerization, 3D GM-polypyrrole composites were produced with a unique core-shell structure. 23402526 Increased risk of death among uninsured neonates. To estimate the contribution of health insurance status to the risk of death among hospitalized neonates. Kids' Inpatient Databases (KID) for 2003, 2006, and 2009. KID 2006 subpopulation of neonatal discharges was analyzed by weighted frequency distribution and multivariable logistic regression analyses for the outcome of death, adjusted for insurance status and other variables. Multivariable linear regression analyses were conducted for the outcomes mean adjusted length of stay and hospital charges. The death analysis was repeated with KID 2003 and 2009. Of 4,318,121 estimated discharges in 2006, 5.4 percent were uninsured. There were 17,892 deaths; 9.5 percent were uninsured. The largest risks of death were five clinical conditions with adjusted odds ratios (AOR) of 13.7-3.1. Lack of insurance had an AOR of 2.6 (95 percent CI: 2.4, 2.8), greater than many clinical conditions; AOR estimates in alternate models were 2.1-2.7. Compared with insureds, uninsureds were less likely to have been admitted in transfer, more likely to have died in rural hospitals and to have received fewer resources. Similar death outcome results were observed for 2003 and 2009. Uninsured neonates had decreased care and increased risk of dying. 23862752 Influence of Molecular Structure on the Laser-Induced Plasma Emission of the Explosive RDX and Organic Polymers. A series of organic polymers and the military explosive cyclotrimethylenetrinitramine (RDX) were studied using the light emission from a femtosecond laser-induced plasma under an argon atmosphere. The relationship between the molecular structure and plasma emission was established by using the percentages of the atomic species (C, H, N, O) and bond types (C-C, C═C, C-N, and C≡N) in combination with the atomic/molecular emission intensities and decay rates. In contrast to previous studies of organic explosives in which C2 was primarily formed by recombination, for the organic materials in this study the percentage of C-C (and C═C) bonds was strongly correlated to the molecular C2 emission. Time-resolved emission spectra were collected to determine the lifetimes of the atomic and molecular species in the plasma. Observed differences in decay rates were attributed to the differences in both the molecular structure of the organic polymers or RDX and the chemical reactions that occur within the plasma. These differences could potentially be exploited to improve the discrimination of explosive residues on organic substrates with laser-induced breakdown spectroscopy. 23847042 Strange bedfellows: A Russian Prince, A Scottish economist, and the role of empathy in early theories for the evolution of cooperation. From 1888 to his death in 1921, Russian Prince Peter Kropotkin forced biologists to ask themselves whether natural selection inevitably led to a dog-eat-dog world, or whether pro-social behavior could also be a product of the evolutionary process. In this historical vignette, I focus on Kropotkin's theory of "mutual aid," with emphasis on the role that empathy played in that theory, and the unexpected source-economist Adam Smith's 1759 book, The Theory of Moral Sentiments-of Kropotkin's ideas on empathy in animals. J. Exp. Zool. (Mol. Dev. Evol.) 9999B: XX-XX, 2013. © 2013 Wiley Periodicals, Inc. 23857145 The effect of solicitations on grooming exchanges among female Japanese macaques at Katsuyama. In group-living primates, individuals often exchange grooming with not only kin but also non-kin. We investigated the effect of soliciting behaviors on grooming exchanges in a free-ranging Japanese macaque (Macaca fuscata) group at Katsuyama. In this study, we used a focal animal sampling method, targeting 14 females. Data were collected for 15.75 ± 2.67 (mean ± SD) hours per focal female. We classified female-female pairs into three pair types: kin pairs, affiliated non-kin pairs, and unaffiliated non-kin pairs. Females received grooming more frequently when they solicited after grooming their partners than when they did not solicit in all pair types. In addition, females received grooming less frequently when they did not groom their unaffiliated non-kin partners before soliciting; prior grooming was not needed to receive grooming from kin or affiliated non-kin partners. The degree of grooming reciprocity did not differ according to the frequency with which females in kin or affiliated non-kin pairs solicited after grooming. On the other hand, grooming reciprocity between unaffiliated non-kin females was more balanced when they solicited frequently after grooming, as compared with when they did not. In conclusion, our study suggests that soliciting behaviors promote grooming exchanges in female Japanese macaques. 23103613 Chloroacetic acid induced neuronal cells death through oxidative stress-mediated p38-MAPK activation pathway regulated mitochondria-dependent apoptotic signals. Chloroacetic acid (CA), a toxic chlorinated analog of acetic acid, is widely used in chemical industries as an herbicide, detergent, and disinfectant, and chemical intermediates that are formed during the synthesis of various products. In addition, CA has been found as a by-product of chlorination disinfection of drinking water. However, there is little known about neurotoxic injuries of CA on the mammalian, the toxic effects and molecular mechanisms of CA-induced neuronal cell injury are mostly unknown. In this study, we examined the cytotoxicity of CA on cultured Neuro-2a cells and investigated the possible mechanisms of CA-induced neurotoxicity. Treatment of Neuro-2a cells with CA significantly reduced the number of viable cells (in a dose-dependent manner with a range from 0.1 to 3mM), increased the generation of ROS, and reduced the intracellular levels of glutathione depletion. CA also increased the number of sub-G1 hypodiploid cells; increased mitochondrial dysfunction (loss of MMP, cytochrome c release, and accompanied by Bcl-2 and Mcl-1 down-regulation and Bax up-regulation), and activated the caspase cascades activations, which displayed features of mitochondria-dependent apoptosis pathway. These CA-induced apoptosis-related signals were markedly prevented by the antioxidant N-acetylcysteine (NAC). Moreover, CA activated the JNK and p38-MAPK pathways, but did not that ERK1/2 pathway, in treated Neuro-2a cells. Pretreatment with NAC and specific p38-MAPK inhibitor (SB203580), but not JNK inhibitor (SP600125) effectively abrogated the phosphorylation of p38-MAPK and attenuated the apoptotic signals (including: decrease in cytotoxicity, caspase-3/-7 activation, the cytosolic cytochrome c release, and the reversed alteration of Bcl-2 and Bax mRNA) in CA-treated Neuro-2a cells. Taken together, these data suggest that oxidative stress-induced p38-MAPK activated pathway-regulated mitochondria-dependent apoptosis plays an important role in CA-caused neuronal cell death. 23500538 Analysis by liquid chromatography-mass spectrometry of sterols and oxysterols in brain of the newborn Dhcr7(Δ3-5/T93M) mouse: A model of Smith-Lemli-Opitz syndrome. In this study the sterol and oxysterol profile of newborn brain from the Dhcr7(Δ3-5/T93M) mouse model of Smith-Lemli-Opitz syndrome (SLOS) has been investigated. This is a viable mouse model which is compound heterozygous containing one null allele and one T93M mutation on Dhcr7. We find the SLOS mouse has reduced levels of cholesterol and desmosterol and increased levels of 7- and 8-dehydrocholesterol and of 7- and 8-dehydrodesmosterol in brain compared to the wild type. The profile of enzymatically formed oxysterols in the SLOS mouse resembles that in the wild type but the level of 24S-hydroxycholesterol, the dominating cholesterol metabolite, is reduced in a similar proportion to that of cholesterol. A number of oxysterols abundant in the SLOS mouse are probably derived from 7-dehydrocholesterol, however, the mechanism of their formation is unclear. 23643522 Inflammation markers predict zinc transporter gene expression in women with type 2 diabetes mellitus. The pathology of type 2 diabetes mellitus (DM) often is associated with underlying states of conditioned zinc deficiency and chronic inflammation. Zinc and omega-3 polyunsaturated fatty acids each exhibit anti-inflammatory effects and may be of therapeutic benefit in the disease. The present randomized, double-blind, placebo-controlled, 12-week trial was designed to investigate the effects of zinc (40 mg/day) and α-linolenic acid (ALA; 2 g/day flaxseed oil) supplementation on markers of inflammation [interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, C-reactive protein (CRP)] and zinc transporter and metallothionein gene expression in 48 postmenopausal women with type 2 DM. No significant effects of zinc or ALA supplementation were observed on inflammatory marker concentrations or fold change in zinc transporter and metallothionein gene expression. Significant increases in plasma zinc concentrations were observed over time in the groups supplemented with zinc alone or combined with ALA (P=.007 and P=.009, respectively). An impact of zinc treatment on zinc transporter gene expression was found; ZnT5 was positively correlated with Zip3 mRNA (P<.001) only in participants receiving zinc, while zinc supplementation abolished the relationship between ZnT5 and Zip10. IL-6 predicted the expression levels and CRP predicted the fold change of the ZnT5, ZnT7, Zip1, Zip7 and Zip10 mRNA cluster (P<.001 and P=.031, respectively). Fold change in the expression of metallothionein mRNA was predicted by TNF-α (P=.022). Associations among inflammatory cytokines and zinc transporter and metallothionein gene expression support an interrelationship between zinc homeostasis and inflammation in type 2 DM. 23778703 Transporters in drug development and clinical pharmacology. More than 400 membrane transporters in two major superfamilies-ATP-binding cassette (ABC) and solute carrier (SLC)-are annotated in the human genome. Preclinical and clinical studies indicate that transport is an important determinant of drug disposition, as well as therapeutic and adverse drug effects. Importantly, transporters may represent the rate-determining step of drug absorption, distribution, and elimination in the intestine, liver, kidney, and blood-brain barrier (BBB), and they are often the sites of drug-drug interactions. 23712571 Early development of hand preference and language lateralization: Are they linked, and if so, how? It is often taken for granted that, in a large majority of typical persons, hand preference and hemispheric specialization for language are interrelated. In this article, I argue that there is currently little serious evidence to support this view. I contend that the best way to investigate the true relationship between hand preference and language lateralization would be to look at their codevelopment. Since both hand preference and language asymmetries are expressed very early, even before birth, a systematic comparison of the very early development of both behavioral traits is needed to understand this relationship. At present, such data are clearly lacking. I discuss existing data on the development of hand preference and language asymmetry, and on the relations between the two. I conclude that this evidence favors the view that the two asymmetries develop relatively independently. © 2013 Wiley Periodicals, Inc. Dev Psychobiol 55: 596-607, 2013. 23801067 Transgenic Mice for cGMP Imaging. Rationale: Cyclic GMP (cGMP) is an important intracellular signaling molecule in the cardiovascular system, but its spatiotemporal dynamics in vivo is largely unknown. Objective: To generate and characterize transgenic mice expressing the fluorescence resonance energy transfer-based ratiometric cGMP sensor, cGMP indicator with an EC50 of 500 nmol/L (cGi500), in cardiovascular tissues. Methods and Results: Mouse lines with smooth muscle-specific or ubiquitous expression of cGi500 were generated by random transgenesis using an SM22α promoter fragment or by targeted integration of a Cre recombinase-activatable expression cassette driven by the cytomegalovirus early enhancer/chicken β-actin/β-globin promoter into the Rosa26 locus, respectively. Primary smooth muscle cells isolated from aorta, bladder, and colon of cGi500 mice showed strong sensor fluorescence. Basal cGMP concentrations were <100 nmol/L, whereas stimulation with cGMP-elevating agents such as 2-(N,N-diethylamino)-diazenolate-2-oxide diethylammonium salt (DEA/NO) or the natriuretic peptides, atrial natriuretic peptide, and C-type natriuretic peptide evoked fluorescence resonance energy transfer changes corresponding to cGMP peak concentrations of ≈3 µmol/L. However, different types of smooth muscle cells had different sensitivities of their cGMP responses to DEA/NO, atrial natriuretic peptide, and C-type natriuretic peptide. Robust nitric oxide-induced cGMP transients with peak concentrations of ≈1 to >3 µmol/L could also be monitored in blood vessels of the isolated retina and in the cremaster microcirculation of anesthetized mice. Moreover, with the use of a dorsal skinfold chamber model and multiphoton fluorescence resonance energy transfer microscopy, nitric oxide-stimulated vascular cGMP signals associated with vasodilation were detected in vivo in an acutely untouched preparation. Conclusions: These cGi500 transgenic mice permit the visualization of cardiovascular cGMP signals in live cells, tissues, and mice under normal and pathological conditions or during pharmacotherapy with cGMP-elevating drugs. 23857561 Hitching the gallbladder in laparoscopic-assisted cholecysto-cholangiography: a simple technique. Neonatal cholestatic disorder in the late neonatal period requires often cholangiography to differentiate between biliary atresia and other causes of prolonged neonatal jaundice. A simplified method of a laparoscopic-assisted cholecysto-cholangiography is presented. Retrospective chart review was conducted of all patients who from May 2002 to April 2012 underwent a laparoscopic-assisted cholecysto-cholangiography with routine fixation of the fundus of the gallbladder to the lateral aspect of the abdominal wall. A total of 18 infants (8 boys) aged 41-104 (median 64) days underwent laparoscopic-assisted cholecysto-cholangiography for prolonged jaundice. The technique identified ten cases of a patent bile duct system and eight biliary atresias. (Thirty-two cases of suspected biliary atresia were confirmed by laparoscopy alone.) Two cases required suturing of a bile leak at the puncture site. Hitching the gallbladder to the lateral abdominal wall is a simple method allowing an optimal radiographic assessment of the extra- and intra-hepatic bile duct anatomy. 23361316 Emerging lymphae for the fountain of life. The lymphatic system is indispensable for the collection and cycling of tissue-extravasated fluids, macromolecules and immune cells into the bloodstream. Different mechanisms, including sprouting, ballooning and budding of lymphatic endothelial cells from the cardinal vein, have been proposed for lymphatic vessel formation during mammalial embryogenesis. Hägerling et al (2013) now provide a cell-scale model of lymphoangiogenesis by applying selective plane illumination-based ultramicroscopy (Becker et al, 2008) to wholemount-immunostained mouse embryos. They describe VEGFR-3, VEGF-C and CCBE1 as key regulators of lymphatic endothelial cell budding and migration at the early emergence of lymphatics from venous endothelium. 23968046 Trackline and point detection probabilities for acoustic surveys of Cuvier's and Blainville's beaked whales. Acoustic survey methods can be used to estimate density and abundance using sounds produced by cetaceans and detected using hydrophones if the probability of detection can be estimated. For passive acoustic surveys, probability of detection at zero horizontal distance from a sensor, commonly called g(0), depends on the temporal patterns of vocalizations. Methods to estimate g(0) are developed based on the assumption that a beaked whale will be detected if it is producing regular echolocation clicks directly under or above a hydrophone. Data from acoustic recording tags placed on two species of beaked whales (Cuvier's beaked whale-Ziphius cavirostris and Blainville's beaked whale-Mesoplodon densirostris) are used to directly estimate the percentage of time they produce echolocation clicks. A model of vocal behavior for these species as a function of their diving behavior is applied to other types of dive data (from time-depth recorders and time-depth-transmitting satellite tags) to indirectly determine g(0) in other locations for low ambient noise conditions. Estimates of g(0) for a single instant in time are 0.28 [standard deviation (s.d.) = 0.05] for Cuvier's beaked whale and 0.19 (s.d. = 0.01) for Blainville's beaked whale. 23937589 Redox Signaling Mediated by the Gut Microbiota. Abstract The microbiota that occupies the mammalian intestine can modulate a range of physiological functions, including control over immune responses, epithelial barrier function, and cellular proliferation. While commensal prokaryotic organisms are well known to stimulate inflammatory signaling networks, less is known about control over homeostatic pathways. Recent work has shown that gut epithelia contacted by enteric commensal bacteria rapidly generate reactive oxygen species (ROS). While the induced production of ROS in professional phagocytes via stimulation of formyl peptide receptors (FPRs) and activation of NADPH oxidase 2 (Nox2) is a well-studied process, ROS are also similarly elicited in other cell types, including intestinal epithelia, in response to microbial signals via FPRs and the epithelial NADPH oxidase 1 (Nox1). ROS generated by Nox enzymes have been shown to function as critical second messengers in multiple signal transduction pathways via the rapid and transient oxidative inactivation of a distinct class of sensor proteins bearing oxidant-sensitive thiol groups. These redox sensitive proteins include tyrosine phosphatases that serve as regulators of MAP kinase pathways, focal adhesion kinase, as well as components involved NF-κB activation. As microbial-elicited ROS has been shown to stimulate cellular proliferation and motility, and to modulate innate immune signaling, we hypothesize that many of the established effects of the normal microbiota on intestinal physiology may be at least partially mediated by this ROS-dependent mechanism. 23360074 Variety-based variation in the antimutagenic potential of various vegetables and lack of its correlation with their antioxidant capacity. As mutation causes many life-threatening diseases including cancer, a diet enriched with specific vegetables having potential to reduce mutagenesis possesses immense significance. In this study, 41 commonly used vegetables from diverse botanical taxa were evaluated and compared for their relative antimutagenic potential using standard assays [Escherichia coli RNA polymerase β (rpoB)-based Rif(S) â†’ Rif(R) assay and Ames test] against known mutagens (UV, gamma radiation, 4-nitroquinoline-N-oxide and ethylmethanesulphonate). Significant differences in antimutagenicity were observed even among the cultivars within the same species, as well as at other phylogenetic levels such as genus or family. The effect of cooking in terms of boiling (aquathermal treatment), on the antimutagenicity of these vegetables, was also investigated. In majority of the cases, aquathermal treatment did not affect the antimutagenic potential. The antimutagenicity of these vegetables was not found to correlate well with their antioxidant properties. 23484619 Adsorption of Primary Substituted Hydrocarbons onto Solid Gallium Substrates. Adsorption of a series of primary substituted hydrocarbons (RX; C18H37PO(OH)2 (ODPA), C17H35COOH, C18H37OH, C18H37NH2, and C18H37SH) onto solid gallium substrates with and without UV/ozone treatment was studied using contact angle goniometry, spectroscopic ellipsometry, and cyclic voltammetry (CV). UV/ozone treatment offered a hydrophilic surface (water contact angle (θ(water)) less than 10°), reflecting the formation of a surface oxide layer with the maximum thickness of ca. 1 nm and possibly the removal of surface contaminants. Upon immersion in a toluene solution of a RX, θ(water) increased due to adsorption of the RX onto gallium substrates. In particular, UV/ozone-treated gallium substrates (UV-Ga) immersed in an ODPA solution exhibited θ(water) close to 105°. The ellipsometric thickness of the adsorbed ODPA layer was ca. 2.4 nm, and CV data measured in an acetonitrile solution showed significant inhibition of redox reaction on the substrate surface. These results indicate the formation of a densely packed ODPA monolayer on UV-Ga. The coverage of a C17H35COOH layer adsorbed onto UV-Ga was lower, as shown by smaller θ(water) (ca. 99°), smaller ellipsometric thickness (ca. 1.3 nm), and smaller electrode reaction inhibition. Adsorption of the other RX onto UV-Ga was weaker, as indicated by smaller θ(water) (82°-92°). ODPA did not strongly adsorb onto UV-untreated gallium substrates, suggesting that the ODPA adsorption mainly originates from hydrogen bond interaction of a phosphonate group with surface oxide. These results will provide a means for controlling the surface properties of oxide-coated gallium that play an essential role in monolayer conductivity measurements and electroanalytical applications. 23777222 Corroboration of claims algorithm for second-line costs of metastatic colorectal cancer treatment with targeted agents. Abstract Objective: To refine a claims algorithm for identifying second-line systemic regimens for metastatic colorectal cancer (mCRC) based on clinical evidence and to compare costs during second-line treatment by targeted therapy administered. Methods: This retrospective analysis of a large US managed care database identified patients diagnosed with mCRC during 1 July 2007-30 June 2011. A claims-based algorithm was developed to identify patients with at least two lines of therapy (LOT) and the second LOT contained one targeted agent: bevacizumab or any anti-epidermal growth factor receptor (EGFR). Medical chart data from 92 patients were used to corroborate and refine the LOT algorithm. The positive predictive value (PPV) of the initial algorithm and refined algorithm for identification of second LOT are presented. The final algorithm was applied to claims data and two mutually exclusive second-line cohorts were examined: patients with bevacizumab- or cetuximab-containing regimens. Second-line healthcare costs were analyzed with generalized linear models adjusted for demographic and clinical characteristics. Results: The PPV increased from 50.0% (95% CI = 39.4-60.6) for the initial algorithm to 72.1% (95% CI = 59.2-82.9) for the final algorithm. Mean age in the cohorts (n = 569) was 61 years; 58% were men. Days of therapy were similar for the bevacizumab (n = 450) vs cetuximab (n = 119) cohorts, respectively: 131 vs 148 in first LOT and 123 (both cohorts) in second LOT (p ≥ 0.27). Total costs during second-line treatment in the bevacizumab cohort were lower by $12,318 (p = 0.02) and medical costs were lower by $13,809 (p = 0.01). Monthly total and medical costs were lower by $2728 (p = 0.03) and $3133 (p = 0.01), respectively. Results are based on commercially or Medicare-insured patients and may not be generalizable to Medicaid or uninsured patients. Conclusions: Corroboration of claim-based algorithms with medical chart data improved algorithm performance. Second-line total and medical costs were lower for mCRC patients treated with bevacizumab compared with cetuximab. 23847376 Relief of Inhibitory Autophosphorylation Activates RAF. RAF inhibitors paradoxically activate wild-type RAF by blocking inhibitory autophosphorylation. 23583631 Hypoxia inducible factor-1 (HIF-1)-flavin containing monooxygenase-2 (FMO-2) signaling acts in silver nanoparticles and silver ion toxicity in the nematode, Caenorhabditis elegans. In the present study, nanotoxicity mechanism associated with silver nanoparticles (AgNPs) exposure was investigated on the nematode, Caenorhabditis elegans focusing on the hypoxia response pathway. In order to test whether AgNPs-induced hypoxia inducible factor-1 (HIF-1) activation was due to hypoxia or to oxidative stress, depletion of dissolved oxygen (DO) in the test media and a rescue effect using an antioxidant were investigated, respectively. The results suggested that oxidative stress was involved in activation of the HIF-1 pathway. We then investigated the toxicological implications of HIF-1 activation by examining the HIF-1 mediated transcriptional response. Of the genes tested, increased expression of the flavin containing monooxygenase-2 (FMO-2) gene was found to be the most significant as induced by AgNPs exposure. We found that AgNPs exposure induced FMO-2 activation in a HIF-1 and p38 MAPK PMK-1 dependent manner, and oxidative stress was involved in it. We conducted all experiments to include comparison of AgNPs and AgNO3 in order to evaluate whether any observed toxicity was due to dissolution or particle specific. The AgNPs and AgNO3 did not produce any qualitative differences in terms of exerting toxicity in the pathways observed in this study, however, considering equal amount of silver mass, in every endpoint tested the AgNPs were found to be more toxic than AgNO3. These results suggest that Ag nanotoxicity is dependent not only on dissolution of Ag ion but also on particle specific effects and HIF-1-FMO-2 pathway seems to be involved in it. 23583913 Ligand-induced dynamic changes in extended PDZ domains from NHERF1. The multi-domain scaffolding protein NHERF1 modulates the assembly and intracellular trafficking of various transmembrane receptors and ion-transport proteins. The two PDZ (postsynaptic density 95/disk large/zonula occluden 1) domains of NHERF1 possess very different ligand-binding capabilities: PDZ1 recognizes a variety of membrane proteins with high affinity, while PDZ2 only binds limited number of target proteins. Here using NMR, we have determined the structural and dynamic mechanisms that differentiate the binding affinities of the two PDZ domains, for the type 1 PDZ-binding motif (QDTRL) in the carboxyl terminus of cystic fibrosis transmembrane regulator. Similar to PDZ2, we have identified a helix-loop-helix subdomain coupled to the canonical PDZ1 domain. The extended PDZ1 domain is highly flexible with correlated backbone motions on fast and slow timescales, while the extended PDZ2 domain is relatively rigid. The malleability of the extended PDZ1 structure facilitates the transmission of conformational changes at the ligand-binding site to the remote helix-loop-helix extension. By contrast, ligand binding has only modest effects on the conformation and dynamics of the extended PDZ2 domain. The study shows that ligand-induced structural and dynamic changes coupled with sequence variation at the putative PDZ binding site dictate ligand selectivity and binding affinity of the two PDZ domains of NHERF1. 22949391 An assessment of pure, hybrid, meta, and hybrid-meta GGA density functional theory methods for open-shell systems: the case of the nonheme iron enzyme 8R-LOX. The performance of a range density functional theory functionals combined in a quantum mechanical (QM)/molecular mechanical (MM) approach was investigated in their ability to reliably provide geometries, electronic distributions, and relative energies of a multicentered open-shell mechanistic intermediate in the mechanism 8R-Lipoxygenase. With the use of large QM/MM active site chemical models, the smallest average differences in geometries between the catalytically relevant quartet and sextet complexes were obtained with the B3LYP(*) functional. Moreover, in the case of the relative energies between (4) II and (6) II, the use of the B3LYP(*) functional provided a difference of 0.0 kcal mol(-1). However, B3LYP(±) and B3LYP also predicted differences in energies of less than 1 kcal mol(-1). In the case of describing the electronic distribution (i.e., spin density), the B3LYP(*), B3LYP, or M06-L functionals appeared to be the most suitable. Overall, the results obtained suggest that for systems with multiple centers having unpaired electrons, the B3LYP(*) appears most well rounded to provide reliable geometries, electronic structures, and relative energies. 23883152 Development of a disease risk prediction model for downy mildew (Peronospora sparsa) in boysenberry. Downy mildew caused by Peronospora sparsa Berk. has resulted in serious production losses in boysenberry (Rubus hybrid), blackberry (Rubus fruticosus) and rose (Rosa sp.) in New Zealand, Mexico, and the US and the UK, respectively. Development of a model to predict downy mildew risk would facilitate development and implementation of a disease warning system for efficient fungicide spray application in the crops affected by this disease. Because detailed disease observation data were not available, a two-step approach was applied to develop an empirical risk prediction model for P. sparsa. To identify the weather patterns associated with a high incidence of downy mildew berry infections (dryberry disease) and derive parameters for the empirical model, Classification and Regression Tree (CART) analysis was performed. Then, fuzzy sets were applied to develop a simple model to predict the disease risk based on the parameters derived from the CART analysis. High risk seasons with a boysenberry downy mildew incidence > 10% coincided with months when the number of hours per day with temperature between 15-20°C averaged >9.8 over the month and the number of days with rainfall in the month was > 38.7%. A Fuzzy Peronospora sparsa (FPS) model, developed using fuzzy sets, defined relationships among high risk events, temperature and rainfall conditions. In a validation study, the FPS model provided correct identification of both seasons with high downy mildew risk for boysenberry, blackberry, and rose and low risk in seasons when no disease was observed. As a result, the FPS model had a significant degree of agreement between predicted and observed risks of downy mildew for those crops (p = 0.002). 23659972 Correction of ocular shape in retinal optical coherence tomography and effect on current clinical measures. To address the misrepresentation of the eye in retinal optical coherence tomography (OCT) images and to examine the effect of this misrepresentation on retinal thickness measurements. Prospective case series. Five subjects with recent orbital magnetic resonance imaging (MRI) scans and normal eye examinations were consented from the clinics of the Duke Eye Center. Each subject had both eyes imaged using a retinal spectral-domain OCT system and ocular biometry measured. Two types of individualized optical models of the subject eyes-numerical and analytical-were used to determine the spatial paths of the OCT A-scans. These paths were used to reorient the A-scans in the associated retinal OCT images and generate corrected images. Using curvature as a general measure of shape, the radii of curvature of the retinal pigment epithelium in the original and corrected OCT images were compared to the ocular radii of curvature in the MRI images. Differences between the retinal thickness maps derived from the original and corrected OCT images were then determined. The retinal curvatures were substantially flatter in the original OCT than in the MRI images (mean paired difference: 52.8 ± 41.8 mm, P < .001). Correcting the OCT images decreased the paired differences between OCT and MRI (numerical: 1.6 ± 2.3 mm, P = .091; analytical: 1.9 ± 4.3 mm, P = .278). Retinal thickness measurements between the corrected and uncorrected images differed, with a root mean square difference of 5.61 μm over the entire 6-mm extent of the image; this difference was greater peripherally (6.02 Î¼m) than centrally (2.54 Î¼m). Optically based algorithms can be used to correct the shape of the retina as represented in OCT; this correction makes OCT more consistent with other clinical imaging techniques. Resultant retinal thickness maps were minimally affected by the change in shape. Ocular shape correction should be considered in future development of posterior segment OCT-based morphologic measurements. 23183587 Limits of metastability in amorphous ices: 2H-NMR relaxation. The high-frequency reorientation dynamics of O-(2)H bonds is investigated in various amorphous ices including eHDA (expanded high density amorphous ice), LDA-II (low density amorphous ice II) and HGW (hyperquenched glassy water) using (2)H-NMR spin-lattice relaxation as a local probe. Both low density forms, HGW and LDA-II, show similar spin-lattice relaxation but differ in the thermal stability with respect to the transition into crystalline cubic ice I(c). HGW already transforms slightly above 135 K whereas LDA-II crystallizes at 150 K. eHDA is distinguishable from other high density amorphous ices in its thermal stability and spin-lattice relaxation. Its relaxation times are much larger compared to those of VHDA (very high density amorphous ice) and uHDA (unrelaxed high density amorphous ice). eHDA does not show annealing effects, transforms sharply into LDA-II above 123 K and provides higher thermal stability as compared to other high density forms. 23730814 Discovery of high potency, single-chain insulin analogs with a shortened B-chain and nonpeptide linker. A series of novel, single chain insulin analogs containing polyethylene glycol based connecting segments were synthesized by native chemical ligation and tested for biological activity. While the full length single chain insulin analogs exhibited low potency, deletion of amino acids B26-B30 unexpectedly generated markedly higher activity. This observation is unprecedented in all previous studies of single chain insulin analogs and is consistent with the presumption that in the native hormone this sequence must translocate to achieve high potency insulin receptor interaction. Optimization of the sequence yielded an insulin analog with potency and selectivity comparable to that of native insulin. These results establish a basis for discovery of novel higher potency, single chain insulin analogs of shortened length. 23934547 Direct Analysis in Real Time Mass Spectrometry (DART-MS) of Ionic Liquids. Direct analysis in real time mass spectrometry (DART-MS) was used to analyze ionic liquids (ILs) containing either imidazolium or phosphonium cations combined with different types of inorganic and organic anions. Ionic liquids were directly inserted into the ionization source using a glass probe without dissolution into organic solvents. Mass spectra of the ILs were collected in both positive and negative mode with a linear ion-trap instrument. The intact cation of the compound was typically the dominant peak in positive mass spectra and cluster ion formation was present. Some individual anions were not readily observed in the negative mass spectra (based on the type of anion); however, the mass difference of adjacent cluster ions equal the mass of a complete IL and the anion mass could be verified by subtracting the known cation mass. The degree and intensity of the cluster ion formations was found to be dependent on the nature of the specific ILs as well as the DART temperature gas stream. 23833102 A traumatic case of fat embolism. A fit and healthy 47-year-old woman developed type I respiratory failure 2 days following surgical fixation for a left intertrochanteric neck of femur fracture. She presented to the acute trauma unit following a fall off a horse and had a long dynamic hip screw fixation in theatre. Postoperatively, she became confused and hypoxic. Her chest X-ray was inconclusive and her CT pulmonary angiogram showed diffuse patchy ground glass shadowing in keeping with acute respiratory distress syndrome. Following review by intensive care and respiratory physicians, a diagnosis of acute lung injury secondary to fat embolism was reached. The patient made a good recovery on the orthopaedic ward with supportive treatment. 23602804 Comprehensive cloning of patient-derived 9022-bp amplicons of hepatitis C virus. The instability of recombinant clones accommodating large or full-length viral genomes is frequently a technical challenge in RNA virus research. In an attempt to establish a rapid plasmid-based reverse genetics system that utilizes long RT-PCR technique (LRP), similar difficulty was encountered in the cloning of 9022-bp LRP amplicon. All HCV genotype 1a strains used for LRP cloning showed a remarkable difference in terms of cloning stability. Subsequent analysis revealed the predictive value of phylogenetic positions in determining the cloning stability. Putative Escherichia coli promoters on the HCV genome might be responsible for such cloning difference. An exhaustive exploration, testing nearly one hundred cloning protocols, did not reveal a general approach that can achieve stable cloning for all HCV 1a strains. The selection of appropriate strains, guided by phylogenetic analysis, appears to be necessary prior to the construction of infectious HCV 1a clones. These observations are not only valuable for potentially establishing an HCV 1a cell culture model but also have general implications for other RNA viruses due to concern about cloning instability. 23785073 Electroacupuncture modulation of reflex hypertension in rats: role of cholecystokinin octapeptide. Acupuncture or electroacupuncture (EA) potentially offers a nonpharmacological approach to reduce high blood pressure (BP). However, ∼70% of the patients and animal subjects respond to EA, while 30% do not. EA acts, in part, through an opioid mechanism in the rostral ventrolateral medulla (rVLM) to inhibit sympathoexcitatory reflexes induced by gastric distention. CCK-8 opposes the action of opioids during analgesia. Therefore, we hypothesized that CCK-8 in the rVLM antagonizes EA modulation of sympathoexcitatory cardiovascular reflex responses. Male rats anesthetized with ketamine and α-chloralose subjected to repeated gastric distension every 10 min were examined for their responsiveness to EA (2 Hz, 0.5 ms, 1-4 mA) at P5-P6 acupoints overlying median nerve. Repeated gastric distension every 10 min evoked consistent sympathoexcitatory responses. EA at P5-P6 modulated gastric distension-induced responses. Microinjection of CCK-8 in the rVLM reversed the EA effect in seven responders. The CCK1 receptor antagonist devazepide microinjected into the rVLM converted six nonresponders to responders by lowering the reflex response from 21 ± 2.2 to 10 ± 2.9 mmHg (first vs. second application of EA). The EA modulatory action in rats converted to responders with devazepide was reversed with rVLM microinjection of naloxone (n = 6). Microinjection of devazepide in the absence of a second application of EA did not influence the primary pressor reflexes of nonresponders. These data suggest that CCK-8 antagonizes EA modulation of sympathoexcitatory cardiovascular responses through an opioid mechanism and that inhibition of CCK-8 can convert animals that initially are unresponsive to EA to become responsive. 23934280 Vasoactive intestinal peptide regulates sinonasal mucociliary clearance and synergizes with histamine in stimulating sinonasal fluid secretion. Mucociliary clearance (MCC) is the primary physical airway defense against inhaled pathogens and particulates. MCC depends on both proper fluid/mucus homeostasis and epithelial ciliary beating. Vasoactive intestinal peptide (VIP) is a neurotransmitter expressed in the sinonasal epithelium that is up-regulated in allergy. However, the effects of VIP on human sinonasal physiology are unknown, as are VIP's interactions with histamine, a major regulator of allergic disease. We imaged ciliary beat frequency, mucociliary transport, apical Cl(-) permeability, and airway surface liquid (ASL) height in primary human sinonasal air-liquid-interface cultures to investigate the effects of VIP and histamine. VIP stimulated an increase in ciliary beat frequency (EC50 0.5 μM; maximal increase ∼40% compared with control) and cystic fibrosis transmembrane conductance regulator (CFTR)-dependent and Na(+)K(+)2Cl(-) cotransporter-dependent fluid secretion, all requiring cAMP/PKA signaling. Histamine activated Ca(2+) signaling that increased ASL height but not ciliary beating. Low concentrations of VIP and histamine had synergistic effects on CFTR-dependent fluid secretion, revealed by increased ASL heights. An up-regulation of VIP in histamine-driven allergic rhinitis would likely enhance mucosal fluid secretion and contribute to allergic rhinorrhea. Conversely, a loss of VIP-activated secretion in patients with CF may impair mucociliary transport, contributing to increased incidences of sinonasal infections and rhinosinusitis.-Lee, R. J., Chen, B., Doghramji, L., Adappa, N. D., Palmer, J. N., Kennedy, D. W., Cohen, N. A. Vasoactive intestinal peptide regulates sinonasal mucociliary clearance and synergizes with histamine in stimulating sinonasal fluid secretion. 23892512 Theoretical study of local environment of Mn(2+) in two different tetragonal sites in Cs2NaLaCl6 elpasolite. A theoretical method for investigating the inter-relation between the electronic and the molecular structures of a 3d(5) ion in a tetragonal ligand-field has been established on the basis of a 252×252 complete energy matrix. By means of this method, the local lattice structures of Mn(2+) in two different tetragonal sites in Cs2NaLaCl6 elpasolite are determined by the experimental EPR spectra. The Mn(2+)-Cl(-) distances have been obtained as: R1=3.2803Å, R2=2.6495Å for (MnCl6)La cluster, and R1=3.4558Å, R2=2.5111Å for (MnCl6)Na cluster in the Cs2NaLaCl6:Mn(2+) system. And our results show R1>R2 for each cluster, which exhibits an elongation distortion relative to the regular octahedron. And the elongation magnitude of a tetragonal (MnCl6)Na cluster is larger than that of a (MnCl6)La cluster in the Cs2NaLaCl6:Mn(2+) system. Using this method, our calculation values of EPR parameters are well accordant with the experimental values. 23815499 3D Hollow Nanostructures as Building Blocks for Multifunctional Plasmonics. We present an advanced and robust technology to realize 3D hollow plasmonic nanostructures which are tunable in size, shape, and layout. The presented architectures offer new and unconventional properties such as the realization of 3D plasmonic hollow nanocavities with high electric field confinement and enhancement, finely structured extinction profiles, and broad band optical absorption. The 3D nature of the devices can overcome intrinsic difficulties related to conventional architectures in a wide range of multidisciplinary applications. 23855506 Bulk Transport and Interfacial Transfer Dynamics of Photogenerated Carriers in CdSe Quantum Dot Solid Electrodes. Practical solar-to-fuel conversion applications of quantum-confined semiconductor crystals require their integration into electrodes. We show that photogenerated electrons in quantum dot solid electrodes can be transported to the aqueous interface to reduce methyl viologen with 100% quantum efficiency and an effective time constant of 12 ± 2 ps. The charge separated state had a half-life of 200 ± 10 ns, limited by hole transport within the solid. 23568613 Quantitative microfluidic biomolecular analysis for systems biology and medicine. In the postgenome era, biology and medicine are rapidly evolving towards quantitative and systems studies of complex biological systems. Emerging breakthroughs in microfluidic technologies and innovative applications are transforming systems biology by offering new capabilities to address the challenges in many areas, such as single-cell genomics, gene regulation networks, and pathology. In this review, we focus on recent progress in microfluidic technology from the perspective of its applications to promoting quantitative and systems biomolecular analysis in biology and medicine. 23541371 Endothelin-3 Expression in the Subfornical Organ Enhances the Sensitivity of Nax, the Brain Sodium-Level Sensor, to Suppress Salt Intake. Salt homeostasis is essential to survival, but brain mechanisms for salt-intake control have not been fully elucidated. Here, we found that the sensitivity of Nax channels to [Na(+)]o is dose-dependently enhanced by endothelin-3 (ET-3). Nax channels began to open when [Na(+)]o exceeded ∼150 mM without ET-3, but opened fully at a physiological [Na(+)]o (135-145 mM) with 1 nM ET-3. Importantly, ET-3 was expressed in the subfornical organ (SFO) along with Nax, and the level was robustly increased by dehydration. Pharmacological experiments revealed that endothelin receptor B (ETBR) signaling is involved in this modulation of Nax gating through protein kinase C and ERK1/2 activation. ETBR agonists increased the firing rate of GABAergic neurons via lactate in the SFO, and an ETBR antagonist attenuated salt aversion during dehydration. These results indicate that ET-3 expression in the SFO is tightly coupled with body-fluid homeostasis through modulation of the [Na(+)]o sensitivity of Nax. 23877991 Cancer Incidence Among Those Initiating Insulin Therapy With Glargine Versus Human NPH Insulin. OBJECTIVETo add to the evidence on comparative long-term effects of insulin analogue glargine versus human neutral protamine Hagedorn (NPH) insulin on the risk for cancer.RESEARCH DESIGN AND METHODSWe identified cohorts of initiators of glargine and human NPH without an insulin prescription during the prior 19 months among patients covered by the Inovalon MORE(2) Registry between January 2003 and December 2010. Patients were required to have a second prescription of the same insulin within 180 days and to be free of cancer. We balanced cohorts on risk factors for cancer outcomes based on comorbidities, comedication, and health care use during the prior 12 months using inverse probability of treatment weighting. Incident cancer was defined as having two claims for cancer (any cancer) or the same cancer (breast, prostate, colon) within 2 months. We estimated adjusted hazard ratios (HRs) and their 95% CI using weighted Cox models censoring for stopping, switching, or augmenting insulin treatment, end of enrollment, and mortality.RESULTSMore patients initiated glargine (43,306) than NPH (9,147). Initiators of glargine were followed for 1.2 (1.1) years and 50,548 (10,011) person-years; 993 (178) developed cancer, respectively. The overall HR was 1.12 (95% CI 0.95-1.32). Results were consistent for breast cancer, prostate cancer, and colon cancer; various durations of treatment; and sensitivity analyses.CONCLUSIONSPatients initiating insulin glargine rather than NPH do not seem to be at an increased risk for cancer. While our study contributes significantly to our evidence base for long-term effects, this evidence is very limited mainly based on actual dynamics in insulin prescribing. 23888275 Validity and reliability of the FSS in Greek MS patients. The study provided validity and reliability evidence of the Fatigue Severity Scale (FSS) in Greek patients with multiple sclerosis (MS). The FSS was administered to 72 MS patients, without co morbid fatigue and 75 matched paired controls with respect to gender and age. Both groups responded to the FSS, SF-36v2, BDI-II and a demographic questionnaire on two time points separated by a 1-week interval. Exploratory and confirmatory factor analysis was performed to test construct validity, concurrent and divergent validity, internal and test-retest reliability were also examined. Exploratory and confirmatory factor analysis, intercorrelations with BDI-II (r = 0.552, p < 0.01) and SF-36v2 vitality (r = -0.715, p < 0.01) and physical functioning (r = -0.673, p < 0.01) subscales, and differences between patients and non patients (t (145) = 6.007, p < 0.001), revealed sufficient construct, concurrent and divergent validity evidence. The factor analysis demonstrated a unidimensional structure Cronbach alpha (0.953) and ICC (0.889) was high, indicating that the responses of our sample were internally consistent and stable across time. The Greek version of FSS is valid and reliable and may be used by clinicians and researchers to assess fatigue of Greek MS patients. 23900944 Getting a handle on the general practice workforce in Ireland. General practice makes a critical contribution to healthcare in Ireland. However, there is a weak understanding of the general practice workforce in Ireland. The aim of this study is to estimate the number of general practitioners (GPs) and practice nurses in Ireland. A variety of data sources was used to corroborate counts of general practitioners and practice nurses. Capture-recapture methods were used to estimate the hidden population of GPs not identified by the databases included. There are 2,954 general practitioners in Ireland, equivalent to 64.4 per 100,000 population. There are 1,700 practice nurses nationally, equivalent to 37.1 per 100,000 persons. There is substantial regional variation in the number of general practitioners and practice nurses per 100,000. To some extent, deficits in one discipline may be counterbalanced by a surplus in the other. In the absence of a centralised register, it is not possible to track the number of GPs or practice nurses working in Ireland at present. This is despite the fact that there are twice as many general practice visits per annum compared to hospital visits. 23349057 Outcomes of morbidly obese patients receiving invasive mechanical ventilation: a nationwide analysis. Critically ill, morbidly obese patients (BMI ≥ 40 kg/m2) are at high risk of respiratory failure requiring invasive mechanical ventilation (IMV). It is not clear if outcomes of critically ill, obese patients are affected by obesity. Due to limited cardiopulmonary reserve, they may have poor outcomes. However, literature to this effect is limited and conflicted. We used the Nationwide Inpatient Sample from 2004 to 2008 to examine the outcomes of morbidly obese people receiving IMV and compared them to nonobese people. We identified hospitalizations requiring IMV and morbid obesity using International Classification of Diseases, 9th Revision, Clinical Modification codes. Primary outcomes studied were inhospital mortality, rates of prolonged mechanical ventilation (≥ 96 h), and tracheostomy. Multivariable logistic regression was used to adjust for potential confounding variables. We also examined outcomes stratified by number of organs failing. Of all hospitalized, morbidly obese people, 2.9% underwent IMV. Mean age, comorbidity score, and severity of illness were lower in morbidly obese people. The adjusted mortality was not significantly different in morbidly obese people (OR 0.89; 95% CI, 0.74-1.06). When stratified by severity of disease, there was a stepwise increase in risk for mortality among morbidly obese people relative to nonobese people (range: OR, 0.77; 95% CI, 0.58-1.01 for only respiratory failure, to OR, 4.14; 95% CI, 1.11-15.3 for four or more organs failing). Rates of prolonged mechanical ventilation were similar, but rate of tracheostomy (OR 2.19; 95% CI, 1.77-2.69) was significantly higher in patients who were morbidly obese. Morbidly obese people undergoing IMV have a similar risk for death as nonobese people if only respiratory failure is present. When more organs fail, morbidly obese people have increased risk for mortality compared with nonobese people. 23964216 Competitive Trace Theory: A Role for the Hippocampus in Contextual Interference during Retrieval. Much controversy exists regarding the role of the hippocampus in retrieval. The two dominant and competing accounts have been the Standard Model of Systems Consolidation (SMSC) and Multiple Trace Theory (MTT), which specifically make opposing predictions as to the necessity of the hippocampus for retrieval of remote memories. Under SMSC, memories eventually become independent of the hippocampus as they become more reliant on cortical connectivity, and thus the hippocampus is not required for retrieval of remote memories, only recent ones. MTT on the other hand claims that the hippocampus is always required no matter the age of the memory. We argue that this dissociation may be too simplistic, and a continuum model may be better suited to address the role of the hippocampus in retrieval of remote memories. Such a model is presented here with the main function of the hippocampus during retrieval being "recontextualization," or the reconstruction of memory using overlapping traces. As memories get older, they are decontextualized due to competition among partially overlapping traces and become more semantic and reliant on neocortical storage. In this framework dubbed the Competitive Trace Theory (CTT), consolidation events that lead to the strengthening of memories enhance conceptual knowledge (semantic memory) at the expense of contextual details (episodic memory). As a result, remote memories are more likely to have a stronger semantic representation. At the same time, remote memories are also more likely to include illusory details. The CTT is a novel candidate model that may provide some resolution to the memory consolidation debate. 22627687 Measuring treatment motivation in secure juvenile facilities. The present study examined the validity and reliability of the Adolescent Treatment Motivation Questionnaire (ATMQ) in a sample of 264 adolescents in Dutch secure juvenile facilities. Confirmatory factor analysis of a single-factor model of "treatment motivation" showed a close fit to the data, indicating construct validity of the ATMQ. Concurrent validity was supported by significant relations between treatment motivation and living group climate. Internal consistency reliability in terms of Cronbach's alpha was good (.84). The ATMQ proved to be insensitive to the tendency to provide socially acceptable or desirable answers, which supports discriminant validity, and was unrelated to sex, age, and self-reported aggression of the adolescents. The ATMQ is a parsimonious instrument (11 items) enabling future research on treatment motivation in secure juvenile facilities. 23928737 Autologous bone marrow mononuclear cells therapy attenuates activated microglial/macrophage response and improves spatial learning after traumatic brain injury. Autologous bone marrow-derived mononuclear cells (AMNCs) have shown therapeutic promise for central nervous system insults such as stroke and traumatic brain injury (TBI). We hypothesized that intravenous injection of AMNC provides neuroprotection, which leads to cognitive improvement after TBI. A controlled cortical impact (CCI) rodent TBI model was used to examine blood-brain barrier (BBB) permeability, neuronal and glial apoptosis, as well as cognitive behavior. Two groups of rats underwent CCI with (CCI-autologous) or without AMNC treatment (CCI-alone), consisting of 2 million AMNC per kilogram body weight harvested from the tibia and intravenously injected 72 hours after injury. CCI-alone animals underwent sham harvests and received vehicle injections. Ninety-six hours after injury, AMNC significantly reduced the BBB permeability in injured animals, and there was an increase in apoptosis of proinflammatory activated microglia in the ipsilateral hippocampus. At 4 weeks after injury, we examined changes in spatial memory after TBI owing to AMNC treatment. There was a significant improvement in probe testing of CCI-autologous group in comparison with CCI-alone in the Morris Water Maze paradigm. Our data demonstrate that the intravenous injection of AMNC after TBI leads to neuroprotection by preserving early BBB integrity and increasing activated microglial apoptosis. In addition, AMNC also improves cognitive function. 23850709 Male contraceptive efficacy of Ricinus communis L. extract. Ricinus communis L. (Rc), of Euphorbiaceae family is a widespread plant in tropical regions and it is used in traditional medicines as an antifertility agent in India and different parts of the world. The aim of the present study is to revalidate the ethnobotanical knowledge by evaluating the activity of only crude stem bark extracts of Rc. In this study, effects of extracts on male contraceptive efficacy were experimented in vitro with human sperm sample. The work is based on primordial and contemporary therapeutic uses of this plant. In this study, dose of petroleum ether extract, ethyl acetate extract, acetone extract and lyophilised aqueous extract of Rc were added to fresh human semen in 1:1 volumetric ratio. As the aqueous extract showed a promising result in 1:1 ratio, therefore, the Hypo-osmotic swelling test (HOS), Nuclear chromatin decondensation test (NCD) and Acrosomal status and function test (AFT) were also carried out with the aqueous extract of Rc. The sperm immobilisation effects of the extract appeared immediately in a dose-dependent manner when the samples were treated with four different extracts of this plant. At a concentration of 100mg/mL, 100% (p<0.001 and p<0.05) sperms lost their progressive motility. At a concentration of 300mg/mL, 100% (p<0.001 and p<0.05) became immotile when treated with aqueous extract. There was 88% (p<0.001 and p<0.05) morphological deformities in sperm sample due the effect of aqueous extract when they were tested for HOS and 91% (p<0.05) sperms behaved against NCD as compared to control group. Also there was a distinct decline (p<0.05) in AFT with increase in dosage concentration. The findings of the study revealed that aqueous stem bark extract of the plant showed dose dependent loss of sperm motility by influencing the morphological deformation, blockage in nuclear envelope and distinct declination in acrosomal status of spermatozoa. This research, thus, opens up scope for future exploration of bark of the plant as commercial source of new male contraceptive. 23370856 Bone status in adults with early-onset juvenile idiopathic arthritis following 1-year anti-TNFα therapy and discontinuation of glucocorticoids. Juvenile idiopathic arthritis (JIA) is an inflammatory disease associated with bone loss and low bone mineral density (BMD). The treatment involves disease-modifying antirheumatic drugs, glucocorticoids (GCs) and biological agents. The aim of this study was to evaluate effects of 12-month therapy with the anti-tumor necrosis factor alpha (anti-TNFα) preparations on bone mineral density (BMD) and biochemical turnover markers (BTM) in adult patients with JIA who were previously either treated or not treated with glucocorticoids (GC) and to assess effects of the discontinuation of GCs on their bone status. Nineteen adult patients (12 women, 7 men) aged 18-33 years with active JIA were prospectively enrolled to receive the anti-TNFα therapy (infliximab, etanercept or adalimumab). BMD and BTMs were determined at baseline and 1-year follow-up. The anti-TNFα therapy resulted in a significant reduction in disease activity score 28 (DAS28) and C-reactive protein (CRP) and a significant increase in BMD at the lumbar spine and total body and in serum N-terminal propeptide of type I procollagen (PINP, marker of bone formation). No significant changes in serum beta C-terminal telopeptide of type I collagen (βCTX, marker of osteoclastic bone resorption) and osteocalcin (marker of bone remodeling) were found. A significant negative correlation was observed between the change in the DAS28, CRP and serum PINP. The change in serum PINP concentrations positively correlated with the change in lumbar spine BMD. A significant increase in serum PINP was observed only in patients discontinuing GCs during the anti-TNFα treatment. After the initiation of the anti-TNFα therapy in young adults with JIA, the increase in new bone formation can be explained by discontinuation of GCs administration as the patients with the largest reduction in DAS28 and CRP probably are the ones most likely to stop GC. 23830302 High EpCAM expression is linked to proliferation and lauren classification in gastric cancer. The association of EpCAM expression with the progression of gastric cancer remains unclear. Here, we investigated the expression of EpCAM in gastric cancer subtypes and correlated the data to tumor cell proliferation and clinicopathologic factors. The intratumoral expression of EpCAM was assessed in 163 primary gastric cancers (61 diffuse-, 62 intestinal-, 32 mixed-type and 8 unclassified tumors) by immunohistochemistry, using the monoclonal antibody Ber-EP4. Intensity of staining was classified according the HercepTest-score using a standardized scoring system. Ki-67 was used to examine the proliferation in tumor tissue. Strong EpCAM expression was observed in 77% of the tumors and in 85% of the corresponding lymph nodes. Of the primary tumors, 58% (n=74) presented a homogeneous intratumoral EpCAM expression while 42% were characterised by a heterogenous expression pattern. Tumors with high EpCAM expression at the invasive front were associated with significantly (p=0.03) higher proportion of lymph node metastases and lower median overall survival (p=0.001). Diffuse type tumors presented a significantly higher EpCAM expression at the invasion front compared with the tumor centre (p=0.036). Multivariate survival analysis identified high EpCAM expression at the invasive front as an independent prognostic factor.We observed a significant (p=0.001) correlation between high EpCAM expression and higher tumor cell proliferation. High EpCAM expression associates with proliferation and progression of gastric cancer, especially in the diffuse type. Considering the discontenting results of the current adjuvant concepts for gastric cancer patients, EpCAM might be target in the adjuvant therapy of this malignant disease. 23747141 Clinical, hematological and biochemical parameters of dairy cows experimentally infected with Vaccinia virus. Vaccinia virus (VACV) is the etiological agent of bovine vaccinia (BV), an important zoonosis that affects dairy cattle. There are many aspects of the disease that remain unknown, and aiming to answer some of these questions, the clinical, hematological, and biochemical parameters of VACV experimentally infected cows were evaluated. In the first part of the study, lactating cows were infected with VACV-GP2 strain. In the second part, animals previously infected with VACV-GP2 were divided into two treatment groups: Group 1, immunosuppressed cows; and Group 2, re-infected cows. In this study, BV could be experimentally reproduced, with similar lesions as observed in natural infections. Moreover, a short incubation period and local lymphadenopathy were also observed. VACV could be detected by PCR and isolated from scabs taken from teat lesions of all inoculated and re-inoculated animals. Lymphocytosis and neutrophilia were observed in all animals from the first part of the experiment, and lymphopenia and relative neutrophilia were observed in the immunosuppressed animals. Detection of viral DNA in oral mucosa lesions suggests that viral reactivation might occur in immunosuppressed animals. Moreover, clinical disease with teat lesions may occur in previously VACV-infected cows under the experimental conditions of the present study. 23955320 Neuroprotection in Multiple Sclerosis: A Therapeutic Approach. Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that is pathologically characterized by inflammatory demyelination and neurodegeneration. Axonal damage, along with neuronal loss, occurs from disease onset and may lead to progressive and permanent disability. In contrast with the inflammatory pathways, the molecular mechanisms leading to MS neurodegeneration remain largely elusive. With improved understanding of these mechanisms, new potential therapeutic targets for neuroprotection have emerged. We review the current understanding of neurodegenerative processes at play in MS and discuss potential outcome measures and targets for neuroprotection trials. 23385033 Antitumor drug delivery in multicellular spheroids by electropermeabilization. Electrochemotherapy (ECT) is a physical technique that allows cytotoxic molecules to be efficiently released in tumor cells by inducing transient cell plasma membrane permeabilization. The main antitumoral drugs used in ECT are nonpermeant bleomycin and low permeant cisplatin. The method is nowadays applied in clinics as a palliative treatment. In order to improve it, we took advantage of a human 3D multicellular tumor spheroid as a model of tumor to visually and molecularly assess the effect of ECT. We used bleomycin and cisplatin to confirm its relevance and doxorubicin to show its potential to screen new antitumor drug candidates for ECT. Confocal microscopy was used to visualize the topological distribution of permeabilized cells in 3D spheroids subjected to electric pulses. Our results revealed that all cells were efficiently permeabilized, whatever their localization in the spheroid, even those in the core. The combination of antitumor drugs and electric pulses (ECT) led to changes in spheroid macroscopic morphology and cell cohesion, to tumor spheroid growth arrest and finally to its complete apoptosis-mediated dislocation, mimicking previously observed in vivo situations. Taken together, these results indicate that the spheroid model is relevant for the study and optimization of electromediated drug delivery protocols. 23661096 Pesticide exposure impacts not only hatching of dormant eggs, but also hatchling survival and performance in the water flea Daphnia magna. Laboratory ecotoxicity tests and biomonitoring in aquatic systems are currently based on the active component of invertebrate communities. Even though dormant egg banks are crucial for the long term survival and community dynamics of many aquatic organisms, the effects of anthropogenic activities on dormant egg bank dynamics have rarely been studied. In this study we investigated the effects of two pesticides with a different mode of action (carbaryl and fenoxycarb) on hatching of Daphnia magna dormant eggs (ephippia) as well as on survival, growth and reproduction of the hatched neonates. Dormant eggs were exposed to the pesticides simultaneously to incubation under conditions that induce hatching (long daylight and 20 °C). Carbaryl had no negative effects on embryonic development or hatching rate up to concentrations almost 1,000 times the median effect concentration (EC50) of neonate survival in acute tests. Fenoxycarb, however, had a significant dose-related effect by delaying or completely stopping the hatching process and caused severe abnormalities in developing individuals. Both pesticides had significant negative effects on survival and reproduction of the hatchlings. These results indicate that, in addition to inducing mortality of active individuals, pesticides can affect zooplankton communities by altering hatching dynamics and life history traits of hatched individuals. We briefly discuss how such pollution induced changes in the benthic-pelagic coupling could translate into trans-generational effects impacting ecological and evolutionary dynamics. 23916679 Use and Perceived Benefits of Complementary Therapies by Cancer Patients Receiving Conventional Treatment in Italy. In Italy, data regarding the use of complementary therapies (CTs) among patients with cancer are sparse and discordant. The present study aimed to investigate the demographic and psychological characteristics of Italian cancer patients who use CTs and the perceived benefit of users. Eight hundred three patients from six Italian oncology departments were interviewed about CT use and completed two questionnaires to explore psychological distress and the resilience trait called sense of coherence (SOC). Patients included in the study had different primary tumor sites and were in different phases of the disease and care process. At the time of measurement, 37.9% of patients were using one or more types of CTs. The most commonly used CTs were diets and dietary supplements (27.5%), herbs (10.8%), homeopathy (6.4%), and mind-body therapies (5.5%). The Italian context is characterized by a high percentage of patients who informed their physicians about CT use (66.3%) and who experienced benefits (89.6%); 75.2% of the patients had used CTs in the past. Multivariate analysis revealed that young, female patients, who previously used complementary and alternative medicine in the past, appear more likely to use at least one type of CT in the present. Predictors of the use of CTs varied according to the type of CT. Among psychological factors, SOC was positively associated with both past and present CT use. Overall prevalence of CTs among Italian cancer patients is high and is in accordance with the European average. In addition to clinical and sociodemographic factors, the resilience trait SOC also was associated with CT use. 23662738 Genetics of the corneal endothelial dystrophies: an evidence-based review. The aim of this review was to provide an evidenced-based review of the genetic basis of the corneal endothelial dystrophies. A review of the English language peer-reviewed literature describing the molecular genetic basis of posterior polymorphous corneal dystrophy (PPCD), congenital hereditary endothelial dystrophy (CHED), Fuchs endothelial corneal dystrophy (FECD) and X-linked endothelial corneal dystrophy (XECD) was performed. Mutations in several genes have been implicated as playing a pathogenic role in the corneal endothelial dystrophies: VSX1 mutations in PPCD1; COL8A2 mutations in PPCD2 and FECD; ZEB1 mutations in PPCD3 and FECD; and SLC4A11 mutations in CHED2 and FECD. However, linkage, association and familial segregation analyses support a role of only one gene in each corneal endothelial dystrophy: ZEB1 in PPCD3, SLC4A11 in CHED2 and COL8A2 in FECD (early onset). In addition, insufficient evidence exists to consider the autosomal dominant form of CHED (CHED1) as distinct from PPCD. An accurate classification of the corneal endothelial dystrophies requires a critical review of the evidence to support the role of each suggested chromosomal locus, gene and genetic mutation associated with a corneal endothelial dystrophy. Only after the separation of evidence from opinion is performed can a critical examination of the molecular pathways that lead to endothelial dysfunction in each of these disorders be accurately performed. 23665036 Testing monophyly without well-supported gene trees: evidence from multi-locus nuclear data conflicts with existing taxonomy in the snake tribe Thamnophiini. Ideally, existing taxonomy would be consistent with phylogenetic estimates derived from rigorously analyzed data using appropriate methods. We present a multi-locus molecular analysis of the relationships among nine genera in the North American snake tribe Thamnophiini in order to test the monophyly of the crayfish snakes (genus Regina) and the earth snakes (genus Virginia). Sequence data from seven genes were analyzed to assess relationships among representatives of the nine genera by performing multi-locus phylogeny and species tree estimations, and we performed constraint-based tests of monophyly of classic taxonomic designations on a gene-by-gene basis. Estimates of concatenated phylogenies demonstrate that neither genera are monophyletic, and this inference is supported by a species tree estimate, though the latter is less robust. These taxonomic findings were supported using gene tree constraint tests and Bayes Factors, where we rejected the monophyly of both the crayfish snakes (genus Regina) and the earth snakes (genus Virginia); this method represents a potentially useful tool for taxonomists and phylogeneticists when available data is less than ideal. 23866049 Particulate air pollution and health inequalities: a Europe-wide ecological analysis. Environmental disparities may underlie the unequal distribution of health across socioeconomic groups. However, this assertion has not been tested across a range of countries: an important knowledge gap for a transboundary health issue such as air pollution. We consider whether populations of low-income European regions were a) exposed to disproportionately high levels of particulate air pollution (PM10) and/or b) disproportionately susceptible to pollution-related mortality effects. Europe-wide gridded PM10 and population distribution data were used to calculate population-weighted average PM10 concentrations for 268 sub-national regions (NUTS level 2 regions) for the period 2004-2008. The data were mapped, and patterning by mean household income was assessed statistically. Ordinary least squares regression was used to model the association between PM10 and cause-specific mortality, after adjusting for regional-level household income and smoking rates. Air quality improved for most regions between 2004 and 2008, although large differences between Eastern and Western regions persisted. Across Europe, PM10 was correlated with low household income but this association primarily reflected East-West inequalities and was not found when Eastern or Western Europe regions were considered separately. Notably, some of the most polluted regions in Western Europe were also among the richest. PM10 was more strongly associated with plausibly-related mortality outcomes in Eastern than Western Europe, presumably because of higher ambient concentrations. Populations of lower-income regions appeared more susceptible to the effects of PM10, but only for circulatory disease mortality in Eastern Europe and male respiratory mortality in Western Europe. Income-related inequalities in exposure to ambient PM10 may contribute to Europe-wide mortality inequalities, and to those in Eastern but not Western European regions. We found some evidence that lower-income regions were more susceptible to the health effects of PM10. 23917217 N-Palmitoylethanolamide protects the kidney from hypertensive injury in spontaneously hypertensive rats via inhibition of oxidative stress. Hypertension is an important risk factor for kidney failure and renal events in the general population. Palmitoylethanolamide (PEA) is a member of the fatty acid ethanolamine family with profound analgesic and anti-inflammatory effects, resulting from its ability to activate peroxisome proliferator activated receptor (PPAR)α. A role for this nuclear receptor has been addressed in cardiovascular system and PPARα ligands have been shown to protect against inflammatory damage especially resulting from angiotensin II hypertension. In this study, we demonstrated that PEA significantly reduced blood pressure in spontaneously hypertensive rats (SHR) and limited kidney damage secondary to high perfusion pressure. To investigate the mechanisms involved in PEA effect, we found that PEA reduced cytochrome P450 (CYP) hydroxylase CYP4A, epoxygenase CYP2C23 and soluble epoxide hydrolase enzyme expression in the kidney, accompanied by a reduction of 20-hydroxyeicosatetraenoic acid excretion in the urine. Moreover, it markedly reduced kidney oxidative and nitrosative stress accompanied by decreased expression of renal NAD(P)H oxidase and inducible nitric oxide synthase and increased expression of Cu/Zn superoxide dismutase, in the kidney of SHR. Moreover, angiotensin II receptor (AT) evaluation revealed a decrease in AT1 receptor expression and a restoration of AT2 receptor level in the kidney from PEA-treated SHR. Consistently, angiotensin converting enzyme expression was reduced, implying a decrease in angiotensin II synthesis. These results indicate that PEA treatment lowers blood pressure and can protect against hypertensive renal injury by increasing the antioxidant defense and anti-inflammatory response and modulating renin-angiotensin system. 22904154 Multiple domains of health literacy as reflected in breastfeeding promotion practice: A Canadian case study. A model of multiple domains of health literacy was mapped to 30 practitioners' accounts of their breastfeeding promotion practice in a region of Canada. Fundamental/basic literacy themes were consistent with earlier literature regarding practitioners' discomfort in addressing literacy issues with their clients. Scientific literacy was reflected in practitioners' dilemmas about using jargon and scientific evidence when discussing breastfeeding. Cultural literacy themes related to practitioners' understandings of the sociocultural context influencing adoption of breastfeeding. Civic literacy was reflected in the use of advocacy for creating supportive breastfeeding environments. Building capacity for health literacy, however, was not a conscious focus of practice. 23539296 p38 Mitogen Activated Protein Kinase Regulates the Nuclear Receptor CAR to Activate the CYP2B6 Gene. The constitutive active/androstane receptor (CAR) regulates hepatic drug metabolism by activating genes such as cytochrome P450 (CYP) and certain transferases. p38 mitogen activated protein kinase (MAPK) is highly activated in human primary hepatocytes but barely in human hepatoma cell-lines including HepG2 cells. Liganded-CAR induced CYP2B6 mRNA in human primary hepatocytes far more effectively than in HepG2 cells ectopically expressing CAR. Here, we have now found that activation of p38 MAPK by anisomycin potentiated induction of CYP2B6 mRNA by CAR ligand in HepG2 cells to levels observed in ligand-treated human primary hepatocytes. siRNA knockdown of p38 MAPK abrogated the ability of anisomycin to synergistically induce CYP2B6 mRNA. In addition to CYP2B6, anisomycin co-treatment potentiated an increase in CYP2A7 and CYP2C9 mRNAs but not CYP3A4 or UDP-glucuronosyltransferase 1A1 mRNAs. Thus, activated p38 MAPK is required for liganded-CAR to selectively activate a set of genes that encode drug metabolizing enzymes. Our present results suggest that CAR-mediated induction of these enzymes can not be understood by ligand binding alone because the specificity and magnitude of induction are co-determined by a given cell signaling such as p38 MAPK; both physiological and pathophysiological states of cell signaling may have a strong impact in hepatic drug metabolizing capability during therapeutic treatments. 23864584 Is the Association of Diabetes With Uncontrolled Blood Pressure Stronger in Mexican Americans and Blacks Than in Whites Among Diagnosed Hypertensive Patients? Clinical evidence shows that diabetes may provoke uncontrolled blood pressure (BP) in hypertensive patients. However, racial differences in the associations of diabetes with uncontrolled BP outcomes among diagnosed hypertensive patients have not been evaluated. A total of 6,134 diagnosed hypertensive subjects aged ≥20 years were collected from the National Health and Nutrition Examination Survey 1999-2008 with a stratified multistage design. Odds ratios (ORs) and relative ORs of uncontrolled BP and effect differences in continuous BP for diabetes over race/ethnicity were derived using weighted logistic regression and linear regression models. Compared with participants who did not have diabetes, non-Hispanic black participants with diabetes had a 138% higher chance of having uncontrolled BP, Mexican participants with diabetes had a 60% higher chance of having uncontrolled BP, and non-Hispanic white participants with diabetes had a 161% higher chances of having uncontrolled BP. The association of diabetes with uncontrolled BP was lower in Mexican Americans than in non-Hispanic blacks and whites (Mexican Americans vs. non-Hispanic blacks: relative OR = 0.55, 95% confidence interval [CI] = 0.37-0.82; Mexican Americans vs. non-Hispanic whites: relative OR = 0.53, 95% CI = 0.35-0.80) and the association of diabetes with isolated uncontrolled systolic BP was lower in Mexican Americans than in non-Hispanic whites (Mexican Americans vs. non-Hispanic whites: relative OR = 0.62, 95% CI = 0.40-0.96). Mexican Americans have a stronger associaton of diabetes with decreased systolic BP and diastolic BP than non-Hispanic whites, and a stronger association of diabetes with decreased diastolic BP than non-Hispanic blacks. The association of diabetes with uncontrolled BP outcomes is lower despite higher prevalence of diabetes in Mexican Americans than in non-Hispanic whites. The stronger association of diabetes with BP outcomes in whites should be of clinical concern, considering they account for the majority of the hypertensive population in the United States. 23187720 Effect of carotenoid lutein on N-nitrosodiethylamine-induced hepatocellular carcinoma and its mechanism of action. Oxycarotenoid lutein (3,3'-dihydroxy-β,ε-carotene) was checked for anticarcinogenic activity against N-nitrosodiethylamine-induced hepatocellular carcinoma (HCC) in rats. Lutein could significantly reduce the altered morphological and pathological changes in the liver induced by N-nitrosodiethylamine. Biochemical analysis of serum and tissues indicated that alanine transaminase, aspartate transaminase, and alkaline phosphatase were significantly elevated in the control group and significantly reduced in the lutein-treated groups. These enzymes in liver tissue, which were found to be elevated in the control group, were significantly reduced in the lutein-treated groups. Glutathione level was low in the control groups and it was found to be increased in the treated groups. The activity of γ-glutamyl transpeptidase, a marker of cellular proliferation, was found to be significantly elevated in both the serum and the liver in the control group, which was reduced by the administration of lutein. Studies on the mechanism of action of lutein have indicated that it could significantly inhibit cytochrome P450 enzymes in vitro and in vivo in rats. Moreover, lutein could enhance the detoxifying enzymes glutathione-S-transferase and UDP glucuronyl transferase in vivo. Inhibition of carcinogenesis by lutein could be because of a combined effect of its antioxidant activity along with the inhibition of cytochrome P450 enzymes and inducing detoxifying enzymes. Lutein is nontoxic and is one of the prime compounds in the chemoprevention trials of the future. 23554507 Pressor and renal regional hemodynamic effects of urotensin II in neonatal pigs. Renal expression of the peptide hormone urotensin II (UII) and its receptor (UTR) are dependent on kidney maturation and anatomical regions. However, renal regional hemodynamic effects of UII in neonates are unclear. Here, we investigated regional hemodynamic responses to acute intrarenal arterial administration of UII in newborn pigs. Western immunoblotting and immunofluorescence confirmed UTR expression and membrane localization in newborn pig renal afferent arterioles and afferent arteriolar smooth muscle cells respectively. Intrarenal arterial bolus injections of human UII (hUII; 1-100 ng/kg) resulted in a dose-dependent decrease in total renal blood flow (RBF) and an increase in mean arterial pressure (MAP) and renal vascular resistance (RVR) in newborn pigs. Moreover, hUII dose dependently reduced cortical blood flow (CBF) but increased medullary blood flow (MBF) in the piglets. hUII-induced MAP elevation and hemodynamic changes were inhibited by urantide, a UTR antagonist, but not losartan, a type 1 angiotensin II receptor antagonist. U-73122, a phospholipase C (PLC) inhibitor, and 2-aminoethoxydiphenyl borate, an inositol 1,4,5 trisphosphate (IP3) receptor antagonist, attenuated hUII-induced MAP and RVR elevations, RBF and CBF reductions, but not MBF increase. These findings indicate that intrarenal arterial administration of hUII elevates blood pressure and induces region-selective renal hemodynamic changes in newborn pigs. Our data also suggest that the PLC/IP3 signaling pathway contributes to hUII-induced alterations in MAP, RBF, RVR, and CBF but not MBF in newborn pigs. 23968459 Bond Cleavage During Isobutanol Thermal Decomposition and the Breaking of C-C Bonds in Alcohols at High Temperatures. Isobutanol was thermally decomposed in a single pulse shock tube under conditions where chain processes were suppressed. The main reaction is the breaking of C-C bonds. Literature rate expressions, experimentally determined, are found in some cases to be in disagreement. The rate expressions for the decomposition processes at 1090 K to 1240 K and pressures of 1.5 atm to 6 atm are, k(isobutanol → isopropyl+hydroxymethyl) + k(isobutanol → methyl+1-hydroxypropyl-2) = 1016.7±.3exp(-41097±750) s-1 where k(isobutanol → isopropyl + hydroxymethyl) = 1016.45 ±.3 exp(-40910±750/T) s-1 and k(isobutanol → methyl + 1-hydroxypropyl-2) = 1016.38±.3 exp(-41560±750/T) s-1 These values permit comparisons with recent estimates including those from ab initio calculations. A new procedure is presented that uses information on the kinetics of bond breaking reactions of alkanes and the effect of OH substitution to derive rate coefficients for similar reactions of alcohols. This leads to the following rate expression for the smaller alcohols. k(ethanol → methyl + hydroxymethyl) = 1016.42±.3 exp(-43496±750 K/T) s-1 k(isopropanol → methyl + 1-hydroxyethyl) = 1016.54±.3 exp(-42495±750 K/T) s-1 k(n-propanol → ethyl + hydroxymethyl) = 1016.43±.3 exp(-41696±750 K/T) s-1 k(n-propanol → methyl + 2-hydroxymethyl) = 1016.53±.3 exp(-42945±750 K/T) s-1 Extension of this approach to other alcohols is straightforward. The resulting correlations along with the data on dehydration of alcohols provide novel information of the kinetic stability of alcohols. 23624623 Comparative diagnostic accuracy of contrast-enhanced MRI and (18)F-FDOPA PET-CT in recurrent glioma. To compare the diagnostic accuracy of contrast enhanced magnetic resonance imaging (Ce-MRI) and (18)F-fluorodopa ((18)F-FDOPA) positron emission tomography (PET)-computed tomography (CT) for detecting recurrent glioma. In this prospective study, 35 patients (age, 36.62 ±â€‰0.86 years; 80 % male) with histopathologically proven glioma with clinical suspicion of recurrence were evaluated using Ce-MRI and (18)F-FDOPA PET-CT. (18)F-FDOPA PET-CT images were evaluated qualitatively and semi-quantitatively. Combination of clinical follow-up (minimum 1 year), repeat imaging and/or biopsy (when available) was taken as the reference standard. Based on the reference standard, 26 patients were positive and nine were negative for recurrence. The sensitivity, specificity and accuracy of Ce-MRI were 92.3 %, 44.4 % and 80 % respectively, whereas those of (18)F-FDOPA PET-CT were 100 %, 88.89 % and 97.1 % respectively. Results of Ce-MRI and (18)F-FDOPA PET-CT were concordant in 74.3 % (29/35) and discordant in 17.1 % of patients (6/35). On McNemar analysis the difference was not statistically significant overall (P = 0.687), for high-grade tumour (P = 0.5) or low-grade tumours (P = 1.0). However, (18)F-FDOPA PET-CT was more specific than Ce-MRI overall (P = 0.0002), for high-grade tumour (P = 0.006) and low-grade tumours (P = 0.004). F-FDOPA PET-CT shows a high but comparable diagnostic accuracy to Ce-MRI for the detection of recurrent glioma. However, it is more specific than Ce-MRI. • Recurrent glioma in the postoperative site remains a diagnostic dilemma. • (18) F-FDOPA PET-CT shows high diagnostic accuracy for detecting recurrent glioma. • Diagnostic accuracies for (18) F-FDOPA PET-CT and contrast enhanced MRI are comparable. • However, (18) F-FDOPA PET-CT is more specific than Ce-MRI for recurrent glioma. 23790446 Trace element contamination in the estuarine sediments along Tuticorin coast - Gulf of Mannar, southeast coast of India. Sediment samples were collected from Kallar, Korampallam creek and Punnakayal estuaries of Tuticorin coast for assessing the level of contamination by trace elements in these estuarine sediments. The trace element concentration, calcium carbonate, organic carbon and mercury level were analyzed by Inductively Coupled Plasma Atomic Emission Spectrophotometer, Titrimetric method and SnCl2 reduction method. The results reveals that the enrichment factor, metal pollution index and geo-accumulation index of these estuarine sediments were predominantly polluted by Cd, As, Zn, Hg and Pb. The factor analysis revealed the source of trace element accumulation in the estuarine sediments particularly Mn and Fe are from riverine inputs and As and Hg from untreated industrial effluents. Among the selected estuaries, Korampallam creek was found to be highly contaminated by trace elements due to the discharge of effluents from thermal power plant, Tuticorin alkali chemicals, copper smelting, Petrochemical industries and shipping activities. 23536360 Hydrothermal treatment of naturally contaminated maize in the presence of sodium metabisulfite, methylamine and calcium hydroxide; effects on the concentration of zearalenone and deoxynivalenol. Fusarium toxin-contaminated ground maize was hydrothermally treated in the presence of different combinations of chemicals in order to simultaneously reduce zearalenone (ZEA) and deoxynivalenol (DON) concentrations. Treatments were carried out in a laboratory conditioner at 80 °C and 17 % moisture. Six different treatments were performed, consisting of 3 doses of methylamine (MMA; 2.5, 5 and 10 g/kg maize) at a constant dose of 5 g sodium metabisulfite (SBS)/kg, either with or without the addition of 20 g calcium hydroxide (Ca(OH)2)/kg. The used maize was contaminated with approximately 45.99 mg DON/kg and 3.46 mg ZEA/kg. Without the addition of Ca(OH)2, DON reductions reached approximately 82 % after 1-min treatment and the toxin disappeared nearly completely after 10 min when 2.5 or 5 g MMA were applied. ZEA concentrations were only marginally affected. In the presence of Ca(OH)2, reductions in DON concentrations were lower, but were enhanced by increasing doses of MMA. ZEA concentrations were reduced by 72, 85 and 95 % within the first 5 min of the treatment at MMA dosages of 2.5, 5 and 10 g/kg maize, respectively. The application of SBS in combination with a strong alkaline during hydrothermal treatment seems to be a promising approach to simultaneously decontaminate even high amounts of DON and ZEA in ground maize and may contribute to reduce the toxin load of diets. 23611535 Persistence of subsyndromal residual symptoms after remission of major depression in patients without cardiovascular disease may condition maintenance of elevated platelet factor 4 and β-thromboglobulin plasma levels. Depressive patients show a state dependent platelet activation that may heighten their cardiovascular risk, specially when comorbid with Coronary Artery Disease (CAD). We still have little information however on the possibility that residual symptoms that often persist after recovery from a major depressive episode may contribute to drive forward platelet activation, thus extending the exposure to the associated cardiovascular risk. Nineteen major depressed inpatients treated with electroconvulsive therapy (ECT) were enrolled and tested for platelet aggregation by measuring platelet factor-4 (PF4) and β-thromboglobulin (β-TG) plasma levels, and for psychometric evaluation by using the 20-item Hamilton Depression Rating Scale (HDRS) and the Symptom Checklist 90 Revised (SCL-90R). Subjects were tested at the beginning of treatment (baseline) and after clinical remission (endpoint). At baseline the patients showed high HDRS (31±6) and total SCL-90R (200±38) scores, followed by a significant decrease at endpoint. However, even if all patients showed full syndromal recovery, SCL-90R "Hostility" and "Psychoticism" subscores showed no significant reduction from baseline, indicating the persistence of subtle residual symptoms. Baseline PF4 and β-TG plasma levels were found remarkably higher and no significant reduction was observed at the endpoint. Small study population. No follow-up evaluation. Despite of clinical remission obtained with ECT in patients with major depression, persistence of subsyndromal residual symptoms may contribute to maintain a condition of platelet hyperactivation at the endpoint, increasing their cardiovascular risk and making them more vulnerable to develop cardiovascular disease. 23913993 A longitudinal analysis of the impact of family support on the morale of older parents in Japan: does the parent's normative belief in filial responsibilities make a difference? Japan presents a unique social laboratory in which to examine how family support impacts on older adults' psychological wellbeing. This is because of its cultural climate where distinctively different expectations of old-age independence and the traditional norm of filial piety coexist. This study investigated how structural and functional dimensions of the family support of older Japanese parents influence their psychological morale, and whether the impacts of family support on parents' morale vary depending on the parents' belief in the traditional cultural norm of filial piety. Four waves of data from the Nihon University Japanese Longitudinal Study of Aging (NUJLSOA) collected in 1999, 2001, 2003 and 2006 were analysed. Combining the two- or three-year span of longitudinal data between each wave (N=3,882), an ordered logistic regression analysis was undertaken. The results reveal that although parents who were widowed or received emotional support from a child tended to report a lower level of morale, the negative influences of such support tended to be mitigated if the parent agreed with the traditional cultural norm of filial responsibilities. These results imply that the meaning and benefit of family support may differ depending on the degree to which Japanese older parents support the traditional norm of filial responsibilities. 23886785 Effect of ammonia or nitric acid treatment on surface structure, in vitro apatite formation, and visible-light photocatalytic activity of bioactive titanium metal. Ti metal treated with NaOH, NH4OH, and heat and then soaked in simulated body fluid (SBF) showed in vitro apatite formation whereas that treated with NaOH, HNO3, and heat and then soaked in SBF did not. The anatase TiO2 precipitate and/or the fine network structure formed on the surface of the Ti metal treated with NaOH, NH4OH, and heat and then soaked in SBF might be responsible for the formation of apatite on the surface of the metal. The NaOH, NH4OH, and heat treatments might produce nitrogen-doped TiO2 on the surface of the Ti metal, and the concentration of methylene blue (MB) in the Ti metal sample treated with NaOH, NH4OH, and heat decreased more than in the untreated and NaOH- and heat-treated ones. This preliminary result suggests that Ti metal treated with NaOH, NH4OH, and heat has the potential to show photocatalytic activity under visible light. 23771002 Evaluation of system performance and microbial communities of a temperature-phased anaerobic digestion system treating dairy manure: Thermophilic digester operated at acidic pH. A temperature-phased anaerobic digestion system with the thermophilic digester acidified by acidogenesis products (referred to as AT-TPAD) was evaluated to treat high-strength dairy cattle manure at a 15-day retention time. Three temperatures (50, 55, and 60°C) were tested on the thermophilic digester, and 50°C was found to be the optimal temperature for overall performance of the AT-TPAD system, achieving 31% VS removal and 0.22Lmethane/g VS fed. The mesophilic digester contributed significantly more to the overall system performance than the thermophilic digester. The thermophilic and the mesophilic digesters had different microbial communities under all conditions, and both microbial communities exhibited dynamic changes in response to different conditions. Certain microbial groups were found significantly correlated with the system performance. Methanosarcina was the most important methanogen genus of the AT-TPAD system and its population abundance was inversely correlated with high concentrations of volatile fatty acids (VFA). 23087379 Mesoscopic model parametrization of hydrogen bonds and stacking interactions of RNA from melting temperatures. Information about molecular interactions in DNA can be obtained from experimental melting temperature data by using mesoscopic statistical physics models. Here, we extend the technique to RNA and show that the new parameters correctly reproduce known properties such as the stronger hydrogen bonds of AU base pairs. We also were able to calculate a complete set of elastic constants for all 10 irreducible combinations of nearest neighbours (NNs). We believe that this is particularly useful as experimentally derived information about RNA elasticity is relatively scarce. The melting temperature prediction using the present model improves over those from traditional NN model, providing thus an alternative way to calculate these temperatures for RNA. Additionally, we calculated the site-dependent base pair oscillation to explain why RNA shows larger oscillation amplitudes despite having stronger AU hydrogen bonds. 23688470 Inulinase production in a packed bed reactor by solid state fermentation. In this work, production of inulinase was carried out in a packed bed reactor (PBR) under solid state fermentation. Kluyveromyces marxianus var. marxianus was used to produce the inulinase using pressmud as substrate. The parameters like air flow rate, packing density and particle size were optimized using response surface methodology (RSM) to maximize the inulinase production. The optimum conditions for the maximum inulinase production were: air flow rate - 0.82 L/min, packing density - 40 g/L and particle size - 0.0044 mm (mesh - 14/20). At these optimized conditions, the production of inulinase was found to be 300.5 unit/gram of dry substrate (U/gds). 23917478 Wirkungen einer physikalischen Stimulierung der spontanen arteriolären Vasomotion bei Rehabilitanden unterschiedlichen Alters. Zusammenfassung: An zwei Stichproben aus Rehabilitanden unterschiedlicher Alters-gruppen (~38 Jahre und ~51 Jahre) wurde im Rahmen einer placebokontrollierten Untersuchungsreihe anhand repräsentativer Funktionsmerkmale der Mikrozirkulation der komplementär-thera-peutische Erfolg einer Zusatzbehandlung zur biorhythmisch definier-ten physikalischen Vasomotionsstimulation ermittelt. Als Ergebnis zeigte sich, dass bei älteren Rehabilitanden die Beträge der mikrozirkulatorischen Merkmaländerungen größer sind als bei jüngeren Rehabilitanden, sie klingen jedoch nach Beendigung der Zusatzbehandlung rascher als bei diesen ab. 23537048 From Na+/K+-ATPase and Cardiac Glycosides to Cytotoxicity and Cancer Treatment. The cardiac glycosides are a group of compounds isolated from plants and some animals. They have been used in therapy for heart failure for many years. The cytotoxic effect of many cardiac glycosides has been demonstrated, but the mechanism of action is very complicated and complex, and Na+/K+-ATPase surely plays a crucial role in it. On the other hand, Na+/K+-ATPase is regulated by many endogenous factors, such as hormones or FXYD proteins, whose role in regulating the cell cycle has been studied intensively. This review focuses on the role of Na+/K+-ATPase in regulating the cell growth, the cell cycle and the cell proliferation and on the involvement of cardiac glycosides in regulating Na+/K+-ATPase. The cytotoxic effect of cardiac glycosides is discussed with respect to the apoptotic mechanisms possibly induced by these compounds. Novel strategies in cancer therapy based on cardiac glycosides are discussed as are possibilities for counteracting multidrug resistance by using cardiac glycosides. The aim of this review is to present cardiac glycosides not only as pharmaceuticals used in the management of heart failure, but also as potent cytotoxic agents with potential uses in cancer treatment. 23036454 A subchronic dietary toxicity study of rice hull fiber in rats. We conducted a 90-day feeding study to investigate subchronic toxicity of rice hull fiber. Sprague Dawley rats were randomly divided into four groups; each received a diet containing 0%, 2.5%, 3.75% and 5.0% (w/w) rice hull fiber for 90days. Clinical observations were carried out daily, with weekly measurements of body weight and food consumption. We performed ophthalmic and histological examinations at termination. Blood and urine samples were collected to measure hematology and clinical chemistry parameters. No mortality, ophthalmic abnormalities, or adverse treatment-related effects were seen during clinical observations, hematological tests, or analyses of urine. Macroscopic or microscopic examinations of organs revealed no treatment related abnormalities. The only treatment related significant changes were reduced concentrations of fasting blood glucose (up to 17.6%) and cholesterol (up to 22.0%), typical benefits of dietary fiber, in males treated with 3.75 and 5% rice hull fiber. The no-observed-adverse-effect-level (NOAEL) for rice hull fiber was 5.0% for both genders (females, 3.80g/kg body weight/day; males, 4.11g/kg body weight/day). 23903095 Peptide-based carbon nanotubes for mitochondrial targeting. In the present study, we report the design and synthesis of peptide-based-multi-walled carbon nanotubes (MWCNTs) to target mitochondria. Targeting these intracellular organelles might open the way to develop alternative systems to address diseases related to genetic mutations in mitochondrial (mt)-DNA, by delivering therapeutic oligonucleotides. The first step towards mitochondrial delivery of this type of nucleic acid was to target MWCNTs to mitochondria by covalent functionalization with a well-known endogenous mitochondrial targeting sequence (MTS). The subcellular localization of the conjugates, which were fluorescently labeled, in murine RAW 264.7 macrophages and human HeLa cells was then studied using different microscopy techniques, such as wide-field epifluorescence microscopy, confocal laser scanning microscopy (CLSM) and transmission electron microscopy (TEM). The localization of the MTS-MWCNT conjugates into mitochondria was further confirmed by analyzing the isolated organelles using TEM. 23902310 Does female feeding motivation affect the response to a food-mimicking male ornament in the swordtail characin Corynopoma riisei? Female response to various aspects of male trait morphology and the effect of female feeding motivation were investigated in the swordtail characin Corynopoma riisei, a species where males are equipped with a flag-like food-mimicking ornament that grows from the operculum. Unfed females responded more strongly to the male ornament and showed a stronger preference for larger ornaments than did fed females. Females were shown not to discriminate between artificial male ornaments of either undamaged or damaged shape. 23788554 Recent Developments of 19-Nor-1,25-dihydroxyvitamin D3 Analogues. The vitamin D hormone, 1α,25-dihydroxyvitamin D3 [1,25-(OH)2 D3 ], exerts its hormonal effects predominantly on intestine, bone, and kidney, where it plays a crucial role in calcium and phosphorus homeostasis and bone mineralization. In addition to its classical actions, 1,25(OH)2 D3 exerts pleiotropic effects in a wide variety of target tissues and cell types, often in an autocrine/paracrine fashion. These biological activities of 1,25(OH)2 D3 have suggested a multitude of potential therapeutic applications for the vitamin D hormone in the treatment of hyperproliferative disorders (e.g. cancer and psoriasis), immune dysfunction (autoimmune diseases), and endocrine disorders (e.g. hyperparathyroidism). However, the calcemic effects induced by 1,25(OH)2 D3 -hypercalcemia, increased bone resorption, and soft tissue calcification-limit the use of the natural ligand in these clinical applications. Therefore, numerous 1,25(OH)2 D3 analogues have been synthesized with the intent of producing therapeutic agents devoid of hypercalcemic and hyperphosphatemic side effects. To this aim, much attention has been focused on the development of 19-nor-vitamin D3 derivatives that lack the ring-A exocyclic methylene group (C19). In this review, the 19-nor-1,25(OH)2 D3 analogues are classified according to modifications made at the A-ring, the side chain, or both the A-ring and side chain, as well as other positions. The biological activities of these 19-nor-1,25(OH)2 D3 analogues are summarized and their structure-activity relationships and binding features with the vitamin D receptor (VDR) are discussed. 23199207 Tumor-targeting multifunctional micelles for imaging and chemotherapy of advanced bladder cancer. Aim: This work aimed to determine if the treatment outcomes of bladder cancer could be improved by targeting micelles that are decorated with bladder cancer-specific ligands on the surface and loaded with the chemotherapeutic drug paclitaxel. Materials & methods: Targeting efficacy and specificity was determined with cell lines. An in vivo targeting and anti-tumor efficacy study was conducted in mice carrying patient-derived xenografts. Results & discussion: Targeting micelles were more efficient than nontargeting micelles in delivering the drug load into bladder cancer cells both in vitro and in vivo (p < 0.05). The micelle formulation of paclitaxel was less toxic than free paclitaxel in Cremophor(®) (Sigma, MO, USA) and allowed administration of three-times the maximum tolerated dose without increasing the toxicity. Targeting micelles were more effective than the nontargeting micelles in controlling cancer growth (p = 0.0002) and prolonging overall survival (p = 0.002). Conclusion: Targeting micelles loaded with paclitaxel offer strong potential for clinical applications in treating bladder cancer. Original submitted 16 March 2012; Revised submitted 30 August 2012; Published online 2 December 2012. 23470313 Mild hypohydration decreases cycling performance in the heat. Hypohydration exceeding 2% of body mass decreases exercise performance. However, the effects of mild hypohydration (<2%) are not clear. The aim of this study was to determine the effects of mild hypohydration on cycling performance during a simulated-hill circuit course in a warm environment (32.5°C ± 0.5°C). Ten trained male cyclists (age, 30 ± 7 yr; mass, 78.4 ± 9.5 kg; height, 1.80 ± 0.01 m; V˙O2max, 52.4 ± 3.3 mL·min·kg; and Powermax, 355 ± 29 W) performed a cycling circuit three times on a laboratory ergometer consisting of 5 km at 50% of maximum power output and 5 km at an all-out pace, followed by a 5-min rest every 5 km. Subjects started the performance test either euhydrated (EUH) or hypohydrated (HYP), by 0% ± 0% and -1.0% ± 0.1% of body mass, respectively. Mean speed at the first, second, and third 5-km simulated-hill cycling was higher in the EUH (28.1 ± 3.1, 27.7 ± 3, and 27.0 ± 3.6 km·h) than that in the HYP trial (27.0 ± 2.9, 26.1 ± 3.7, and 25.9 ± 3.6 km·h) (P < 0.05). Mean power output at the first, second, and third 5-km simulated-hill cycling was greater in the EUH (284 ± 55, 266 ± 53, and 254 ± 58 W) than that in the HYP trial (272 ± 56, 250 ± 61, and 240 ± 57 W) (P < 0.05). Gastrointestinal temperature at the end of the first, second, and third 5-km simulated-hill cycling was greater in the HYP (38.3°C ± 0.4°C, 38.4°C ± 0.2°C, and 38.6°C ± 0.2°C) than that in the EUH trial (38.1°C ± 0.3°C, 38.1°C ± 0.3, and 38.3°C ± 0.3°C) (P < 0.05). Overall, sweat sensitivity during the circuit course was greater in the EUH (115 ± 58 g·°C·min) versus HYP trial (67 ± 19 g·°C·min) (P < 0.05). Furthermore, RPE and heart rate were similar and near maximal between trials (P > 0.05). The data showed that mild hypohydration decreased cycling performance, possible by inducing greater thermal and cardiovascular strain. 23684668 Hypothalamic neurogenesis in the adult brain. Adult-born new neurons are continuously added to the hippocampus and the olfactory bulb to serve aspects of learning and perceptual functions. Recent evidence establishes a third neurogenic niche in the ventral hypothalamic parenchyma surrounding the third ventricle that ensures the plasticity of specific brain circuits to stabilize physiological functions such as the energy-balance regulatory system. Hypothalamic lesion studies have demonstrated that regions associated with reproduction-related functions are also capable of recruiting newborn neurons to restore physiological functions and courtship behavior. Induced by lesion or other stimulation, elevated neurotrophic factors trigger neurogenic cascades that contribute to remodeling of certain neural circuits to meet specific transient functions. This insight raises the possibility that event-specific changes, such as increased GnRH, may be mediated by courtship-sensitive neurotrophic factors. We will discuss the potentially integral and ubiquitous roles of neurogenesis in physiological and biological phenomena, roles that await future experimental exploration. 23855369 Rupture of renal artery aneurysm during the early post-partum period. Rupture of renal artery aneurysm associated with pregnancy is an uncommon condition. It is known that almost all previously reported cases have occurred during pregnancy. We experienced a case of rupture of renal artery aneurysm during the early post-partum period which was diagnosed by computed tomography and treated by angiographic embolization. To our knowledge, only two cases of rupture of renal artery aneurysm during the post-partum period have been reported in the English-language published work. An early diagnosis of rupture of renal artery aneurysm during the post-partum period is very challenging because the clinical symptoms of this condition are acute abdominal, flank or back pain, which are relatively common signs caused by more common post-partum complications. However, rupture of renal artery aneurysm is a life-threatening emergency condition requiring prompt diagnosis and treatment. The possibility of a rupture of renal artery aneurysm should be considered in any pregnant women with symptoms of an acute abdomen with hemorrhagic shock. 23894024 Selective separation of lambdacyhalothrin by porous/magnetic molecularly imprinted polymers prepared by Pickering emulsion polymerization. Porous/magnetic molecularly imprinted polymers (PM-MIPs) were prepared by a Pickering emulsion polymerization. The reaction was carried out in an oil/water emulsion using magnetic halloysite nanotubes as the stabilizer instead of a toxic surfactant. In the oil phase, the imprinting process was conducted by radical polymerization of functional and crosslinked monomers, and porogen chloroform generated steam under the high reaction temperature, which resulted in some pores decorated with easily accessible molecular binding sites within the as-made PM-MIPs. The characterization demonstrated that the PM-MIPs were porous and magnetic inorganic-polymer composite microparticles with magnetic sensitivity (Ms = 0.7448 emu g(-1) ), thermal stability (below 473 K) and magnetic stability (over the pH range of 2.0-8.0). The PM-MIPs were used as a sorbent for selective binding of lambdacyhalothrin (LC) and rapidly separated under an external magnetic field. The Freundlich isotherm model gave a good fit to the experimental data. The adsorption kinetics of the PM-MIPs was well described by pseudo-second-order kinetics, indicating that the chemical process could be the rate-limiting step in the adsorption of LC. The selective recognition experiments exhibited the outstanding selective adsorption effect of the PM-MIPs for target LC. Moreover, the PM-MIPs regeneration without significant loss in adsorption capacity was demonstrated by at least four repeated cycles. This article is protected by copyright. All rights reserved. 23397052 Impaired cliff avoidance reaction in dopamine transporter knockout mice. RATIONALE: Impulsivity is a key feature of disorders that include attention-deficit/hyperactivity disorder (ADHD). The cliff avoidance reaction (CAR) assesses maladaptive impulsive rodent behavior. Dopamine transporter knockout (DAT-KO) mice display features of ADHD and are candidates in which to test other impulsive phenotypes. OBJECTIVES: Impulsivity of DAT-KO mice was assessed in the CAR paradigm. For comparison, attentional deficits were also assessed in prepulse inhibition (PPI) in which DAT-KO mice have been shown to exhibit impaired sensorimotor gating. RESULTS: DAT-KO mice exhibited a profound CAR impairment compared to wild-type (WT) mice. As expected, DAT-KO mice showed PPI deficits compared to WT mice. Furthermore, the DAT-KO mice with the most impaired CAR exhibited the most severe PPI deficits. Treatment with methylphenidate or nisoxetine ameliorated CAR impairments in DAT-KO mice. CONCLUSION: These results suggest that DAT-KO mice exhibit impulsive CAR behavior that correlates with their PPI deficits. Blockade of monoamine transporters, especially the norepinephrine transporter (NET) in the prefrontal cortex (PFC), may contribute to pharmacological improvement of impulsivity in these mice. 23518286 Neuromodulation of delay discounting, the reflection effect, and cigarette consumption. Cigarette smokers and substance users discount the value of delayed outcomes more steeply than non-users. Higher discounting rates are associated with relapse and poorer treatment outcomes. The left dorsolateral prefontal cortex (DLPFC) exerts an inhibitory influence on impulsive or seductive choices. Greater activity in the prefrontal cortex is associated with lower discounting rates. We hypothesized that increasing activity in the left DLPFC with high frequency repetitive transcranial magnetic stimulation (HF rTMS) would decrease delay discounting and decrease impulsive decision-making in a gambling task as well as decrease cigarette consumption, similar to other studies. In this single-blind, within-subjects design, smokers with no intention to quit (n = 47) and nonsmokers (n = 19) underwent three counterbalanced sessions of HF rTMS (20 Hz, 10 Hz, sham) delivered over the left DLPFC. Tasks were administered at baseline and after each stimulation session. Stimulation decreased discounting of monetary gains (F([3,250]) = 4.46, p < .01), but increased discounting of monetary losses (F([3,246]) = 4.30, p < .01), producing a reflection effect, normally absent in delay discounting. Stimulation had no effect on cigarette consumption. These findings provide new insights into cognitive processes involved with decision-making and cigarette consumption and suggest that like all medications for substance dependence, HF rTMS is likely to be most effective when paired with cognitive-behavioral interventions. 23946503 omiRas: a Web server for differential expression analysis of miRNAs derived from small RNA-Seq data. Small RNA deep sequencing is widely used to characterize non-coding RNAs (ncRNAs) differentially expressed between two conditions, e.g. healthy and diseased individuals and to reveal insights into molecular mechanisms underlying condition-specific phenotypic traits. The ncRNAome is composed of a multitude of RNAs, such as transfer RNA, small nucleolar RNA and microRNA (miRNA), to name few. Here we present omiRas, a Web server for the annotation, comparison and visualization of interaction networks of ncRNAs derived from next-generation sequencing experiments of two different conditions. The Web tool allows the user to submit raw sequencing data and results are presented as: (i) static annotation results including length distribution, mapping statistics, alignments and quantification tables for each library as well as lists of differentially expressed ncRNAs between conditions and (ii) an interactive network visualization of user-selected miRNAs and their target genes based on the combination of several miRNA-mRNA interaction databases.Availability and Implementation: The omiRas Web server is implemented in Python, PostgreSQL, R and can be accessed at: http://tools.genxpro.net/omiras/. rotter@genxpro.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. 23578862 Feasibility and safety of xenon compared with sevoflurane anaesthesia in coronary surgical patients: a randomized controlled pilot study. /st> To date, only limited data exist about the use of xenon as an anaesthetic agent in patients undergoing cardiac surgery. The favourable cardio- and neuroprotective properties of xenon might attenuate postoperative complications, improve outcome, and reduce the incidence of delirium. Thus, the aims of this study were to investigate the feasibility and safety of balanced xenon anaesthesia in patients undergoing cardiac surgery and to gather pilot data for a future randomized multicentre study. /st> Thirty patients undergoing elective coronary artery bypass grafting were enrolled in this randomized, single-blind controlled trial. They were randomized to receive balanced general anaesthesia with either xenon (45-50 vol%) or sevoflurane (1-1.4 vol%). The primary outcome was the occurrence of adverse events (AEs). Secondary outcome parameters were feasibility criteria (bispectral index, perioperative haemodynamic, and respiratory profile) and safety parameters (dosage of study treatments, renal function, intraoperative blood loss, need for inotropic support, regional cerebral tissue oxygenation). Furthermore, at predefined time points, systemic and pulmonary haemodynamics were assessed by the use of a pulmonary artery catheter. /st> There were no patient characteristic differences between the groups. Patients undergoing xenon anaesthesia did not differ with respect to the incidence of AE (6 vs 8, P=0.464) compared with the sevoflurane group. No differences were detected regarding secondary feasibility and safety criteria. The haemodynamic and respiratory profile was comparable between the treatment groups. /st> Balanced xenon anaesthesia is feasible and safe compared with sevoflurane anaesthesia in patients undergoing coronary artery bypass surgery. Acronym CARDIAX: A pre- and post-coronary artery bypass graft implantation disposed application of xenon. Clinical trial registration ClinicalTrials.gov: NCT01285271; EudraCT-number: 2010-023942-63. Approved by the ethics committee 'Ethik-Kommission an der Medizinischen Fakultät der Rheinisch-Westfälischen Technischen Hochschule Aachen (RWTH Aachen)': EK-218/10. 23816327 The Stay-Green Rice like (SGRL) gene regulates chlorophyll degradation in rice. The Stay-Green Rice (SGR) protein is encoded by the SGR gene and has been shown to affect chlorophyll (Chl) degradation during natural and dark-induced leaf senescence. An SGR homologue, SGR-like (SGRL), has been detected in many plant species. We show that SGRL is primarily expressed in green tissues, and is significantly downregulated in rice leaves undergoing natural and dark-induced senescence. As the light intensity increases during the natural photoperiod, the intensity of SGRL expression declines while that of SGR expression increases. Overexpression of SGRL reduces the levels of Chl and Chl-binding proteins in leaves, and accelerates their degradation in dark-induced senescence leaves in rice. Our results suggest that the SGRL protein is also involved in Chl degradation. The relationship between SGRL and SGR and their effects on the degradation of the light-harvesting Chl a/b-binding protein are also discussed. 23832281 The risk of misinterpreting genital signs of sexual abuse in cadavers: a case report. The significance of genital findings in a case of suspected child sexual abuse has been widely debated in the past decades, as shown by the different classifications available in literature. In the case of postmortem examination, the search for signs of sexual abuse is considerably more difficult because of the superimposition of postmortem modifications, which may determine tissue modifications that can be mistaken for traumatic lesions. This study aims at reporting a case where presumed findings of the first autopsy were denied by histological analysis; in detail, what looked like a possible bruise of the hymen was correctly recognized as hypostasis (livor) of the hymenal tissue by histological analysis. This case report suggests caution in the analysis and discussion of genital lesions found during postmortem examination since the superimposition of cadaveric modifications may radically modify the morphology of soft tissues. 23880773 Flexible, linear, tetranuclear palladium complexes supported by tetraphosphine ligands with electron-withdrawing groups. A linearly ordered tetraphosphine containing electron-withdrawing substituent groups on the outer phosphorus atoms, meso-bis[{di(3,5-difluorophenyl)phosphinomethyl}phenylphosphino]methane (dpmppmF2), was prepared and reacted with [Pd2(RNC)6](PF6)2 and Pd(dba)2 to afford tetranuclear palladium complexes, [Pd4(μ-dpmppmF2)2(RNC)3](PF6)2 (R = 2,6-xylyl (Xyl) (), 2,4,6-mesityl (), 2,6-diisopropylphenyl () and tert-butyl ()), which involve an asymmetric {(RNC)Pd4(CNR)2}(2+) core supported by two dpmppmF2 ligands in anti-arrangement. Each terminal of the Pd4 chain was capped by terminal isocyanide and a semi-bridging RNC is introduced into one terminal Pd site. Mechanistic investigation suggested that the dipalladium(i) complex, [Pd2(μ-dpmppmF2)2(RNC)2](PF6)2 (R = Xyl ()), was a key intermediate to trap Pd(0) species by the uncoordinated outer phosphine pendants with electron-withdrawing groups. Variable-temperature UV-vis and (31)P{(1)H}, (1)H NMR spectroscopic studies demonstrated that the tetrapalladium complexes are quite fluxional in the solution state at high temperature (>20 °C) relating to a symmetric structure of [Pd4(μ-dpmppmF2)2(RNC)2](PF6)2, and the asymmetric solid state structures are retained even in the solution at low temperature (<-60 °C). Theoretical calculations with DFT methods on the asymmetric (R = Xyl ()) and symmetric (R = Xyl ()) structures suggested that contribution of Pd(0)→Pd(I)-Pd(0)-Pd(I) with 60 cluster valence electrons (CVEs) would be dominant in , while the symmetric structure of can be recognized as Pd(I)-Pd(0)-Pd(0)-Pd(I) with 58 CVEs. The new tetraphosphine dpmppmF2 was proven very effective in organizing dynamically flexible tetrapalladium chains. 22520269 Profile of intraocular tumour necrosis factor-α and interleukin-6 in diabetic subjects with different degrees of diabetic retinopathy. Purpose:  To assess and correlate the levels of inflammatory mediators in the eyes from non-diabetic and diabetic subjects without retinopathy (NDR), with non-proliferative diabetic retinopathy (NPDR) or with proliferative diabetic retinopathy (PDR) to corresponding erum levels. Methods:  The levels of interleukin 1β, interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were analysed by an ELISA-mimicking technique in the vitreous from 26 diabetic subjects with active PDR and 27 non-diabetic subjects, or by a multiplex bead assay in the aqueous humour from 35 diabetic subjects with NDR/NPDR and 40 non-diabetic subjects. Intraocular protein production was estimated in vitreous specimens by calculating a vitreous/serum ratio. Results:  In the vitreous, IL-6 was higher in diabetic [157.5 (25.0-1401.0) pg/ml; median (min-max)] than in non-diabetic subjects [44.0 (5.0-4425) pg/ml; p = 0.021]. The vitreous/serum ratio was high (55.5:1 and 16:1, respectively), suggesting intraocular production. TNF-α was lower in diabetic [18.0 (8.0-46.0) pg/ml] than in non-diabetic subjects [22.0 (13.0-47.0) pg/ml; p = 0.034], but the vitreous/serum ratio was elevated in both groups (2:1 and 3.4:1, respectively). TNF-α levels were higher in serum from diabetic subjects [9.0 (5.0-53.0) pg/ml versus 6.7 (3.0-11.0) pg/ml; p < 0.001]. Aqueous levels of inflammatory mediators did not differ between diabetic subjects with NDR/NPDR and non-diabetic subjects despite elevated TNF-α in serum [27.8 (6.8-153.7) pg/ml versus 16.4 (4.1-42.4) pg/ml; p = 0.021]. Conclusion:  Intraocular inflammation seems to be involved in PDR but does not seem to be prominent in early retinopathy stages, i.e. NDR or NPDR. Diabetic subjects have an overall increased inflammatory activity compared to non-diabetic subjects, as demonstrated by increased serum levels of TNF-α. 22935067 Pharmacokinetics, pharmacodynamics and clinical use of valganciclovir in newborns with symptomatic congenital cytomegalovirus infection. Congenital cytomegalovirus infection is the most common cause of nonhereditary sensorineural hearing loss and an important cause of psychomotor retardation. Newborns suffering from symptomatic congenital cytomegalovirus infection have been typically treated with i.v. ganciclovir (GCV). Nowadays valganciclovir (V-GCV), a mono-valyl ester pro-drug of GCV, is available as an oral syrup. The existing literature demonstrated that V-GCV is well absorbed from the gastrointestinal tract and is rapidly converted into GCV in the intestinal wall and liver. The mechanism of antiviral action is the same that has been described for GCV. All these characteristics make this formulation particularly suitable for the symptomatic congenitally infected newborns. In neonates, V-GCV oral formulation proved stable and constant GVC plasma concentrations, in the suggested therapeutic range. The syrup demonstrated to be clinically effective and well tolerated and to be appropriate for a prolonged post-discharge therapy avoiding the discomfort of hospitalization, reducing the risk for nosocomial infections and decreasing the cost for the National Health Service. This article reviews all the available literature about V-GCV syrup in the treatment of newborns and infants with congenital CMV infection with the regard to pharmacokinetics, pharmacodynamic properties and clinical use, focussing on new data and on our experience. 23416647 Bioaccessibility of 12 trace elements in marine molluscs. We conducted a large scale investigation of the bioaccessibility of 12 trace elements from 11 marine mollusc species (scallop, oyster, clam, abalone, snail, and mussel) collected from five locations in Chinese coastal waters. The bioaccessibility of all the 12 trace elements was generally high, with the average values ranging from 42.5% to 90.7%. The highest bioaccessibility was observed for As, Cu, Ni and Se, and the lowest for Fe, Co and Pb. Steaming decreased the bioaccessibility of all 12 trace elements and thus diminished their risks. No correlation was observed between the bioaccessibility and the total concentration of the 12 elements. However, there was a significant correlation between the bioaccessibility of the 12 elements and their subcellular distribution. For most trace elements, a significantly negative relationship was demonstrated between the bioaccessibility and the elemental partitioning in the metal-rich granule fraction or in the cellular debris fraction, and a significantly positive correlation was observed between the bioaccessibility and the elemental partitioning in the heat-stable protein fraction and in the trophically available fraction. Hence, the elemental subcellular distribution, especially the elemental partitioning in the trophically available fraction, might be a good predictor of the bioaccessibility and risks of trace elements in molluscs. 23775439 New insights into cytomixis: specific cellular features and prevalence in higher plants. The phenomenon of intercellular migration of nuclei in plant tissues (cytomixis) was discovered over a century ago, which has been followed by numerous attempts to clarify the essence of this process as well as to determine its causes and consequences. Most attention of researchers has been paid to cytomixis in microsporogenesis, since the transfer of part of genetic material between microsporocytes may influence the ploidy level of the produced pollen and, presumably, have an evolutionary significance. This review compiles the data on cytological pattern of cytomixis and proposes a scheme as to how cytomictic channels are formed and function in angiosperms. The prevalence of cytomixis in different plant taxa is analyzed using the published data. The causes, mechanisms, and consequences of the nuclear migration between cells in plant tissues are discussed. 23580072 Nationally representative household survey of surgery and mortality in sierra leone. There is limited evidence to characterize the burden of unmet need of surgical diseases in low- and middle-income countries. The purpose of this study was to determine rate of deaths attributable to a surgical condition and reasons for not seeking surgical care in Sierra Leone. The Surgeons OverSeas Assessment of Surgical Need (SOSAS) is a survey tool developed collaboratively to be used for cross-sectional data collection of the prevalence of surgical conditions in any country. A population-weighted cluster-sample household survey was conducted throughout Sierra Leone in 2012 using the SOSAS survey tool. Total of 1,840 households (11,870 individuals) were sampled, yielding a 98.3 % response rate. Overall, there were 709 total deaths reported (6.0 %). The mean age at death was 36.4 ± 30.1 years: 330 (46.6 %) were female. Most deaths occurred at home (58.1 % vs. 34.1 % in hospitals). Of the 709 deaths, 237 (33.4 %) were associated with conditions included in our predefined surgical disease category. Abdominal distension/pain was the most commonly associated surgical condition (13.9 %) followed by perinatal bleeding/illness (6.0 %). Among the 237 with surgical conditions, 51 (21.9 %) did not seek medical care, most commonly because of a lack of money (35.3 %) or inability to provide timely care (37.3 %). A large proportion of deaths in Sierra Leone was associated with surgical conditions, the majority of which did not undergo surgical intervention. Our results indicate that to remove barriers to effective surgical care in Sierra Leone policymakers should first focus on relieving financial burdens and increasing access to timely surgical care. 23934268 Geographical Clustering of High Risk Sexual Behaviors in "Hot-Spots" for HIV and Sexually Transmitted Infections in Kwazulu-Natal, South Africa. We investigated geographical variations of three sexually transmitted infections (STIs) namely chlamydia, gonorrhea and syphilis in the greater Durban area, so as to optimize intervention strategies. The study population was a cohort of sexually active women who consented to be screened in one of three biomedical studies conducted in Durban. A total of nine local regions collectively formed three clusters at screening, five of which were previously defined as HIV hot-spots. STI cases were geo-coded at the census level based on residence at the time of screening. Spatial SaTScan Statistics software was employed to identify the areas with a disproportionate prevalence and incidence of STI infection when compared to the neighboring areas under study. Both prevalence and incidence of STIs were collectively clustered in several localized areas, and the majority of these locations overlapped with high HIV clusters and shared the same characteristics: younger age, not married/cohabitating and multiple sex partners. 23681792 Tendon mechanobiology: experimental models require mathematical underpinning. Mathematical and computational modeling is in demand to help address current challenges in mechanobiology of musculoskeletal tissues. In particular for tendon, the high clinical importance of the tissue, the huge mechanical demands placed on it and its ability to adapt to these demands, require coupled, multiscale models incorporating complex geometrical and microstructural information as well as time-based descriptions of cellular activity and response.This review introduces the information sources required to develop such multiscale models. It covers tissue structure and biomechanics, cell biomechanics, the current understanding of tendon's ability in health and disease to update its properties and structure and the few already existing multiscale mechanobiological models of the tissue. Finally, a sketch is provided of what such models could achieve ideally, pointing out where experimental data and knowledge are still missing. 23916600 Mitochondrial dysfunction contributes to the cytotoxicity induced by tentacle extract from the jellyfish Cyanea capillata in rat renal tubular epithelial NRK-52E cells. Our previous studies have shown that tentacle extract (TE) from the jellyfish Cyanea capillata could induce a delayed jellyfish envenomation syndrome with severe multiple organ dysfunctions, among which renal injury with tubular necrosis seemed to be most serious. So, in this study, we aimed to explore the toxic effect of TE on rat renal tubular epithelial NRK-52E cells. Based on the previous findings that TE could cause oxidative damage in erythrocytes, the effects of TE on cell oxidative stress conditions, including ROS production and lipid peroxidation, and mitochondrial dysfunction associated with cell death were investigated in NRK-52E cells. The results showed that TE caused cell morphological change and decreased cell viability through induction of apoptosis and necrosis in NRK-52E cells. Meanwhile, ROS overproduction and mitochondrial membrane potential decrease were found before the cell death occurred. It was concluded that TE could induce cytotoxicity, especially apoptosis and necrosis, in NRK-52E cells, and mitochondrial dysfunction and ROS overproduction might play important roles in the process of cell injury and death. 23938056 Phenomenological models of the dynamics of muscle during isotonic shortening. We investigated the effectiveness of simple, Hill-type, phenomenological models of the force-length-velocity relationship for simulating measured length trajectories during muscle shortening, and, if so, what forms of the model are most useful. Using isotonic shortening data from mouse soleus and toad depressor mandibulae muscles, we showed that Hill-type models can indeed simulate the shortening trajectories with sufficiently good accuracy. However, we found that the standard form of the Hill-type muscle model, called the force-scaling model, is not a satisfactory choice. Instead, the results support the use of less frequently used models, the f-max scaling model and force-scaling with parallel spring, to simulate the shortening dynamics of muscle. 23828556 Effect of vitamin E on milk composition of grazing dairy cows supplemented with microencapsulated conjugated linoleic acid. The objective of this study was to evaluate the effect of vitamin E on the fat content and fatty acid profile of grazing dairy cows supplemented with microencapsulated conjugated linoleic acid. Eight New Zealand Holstein cows in a rotational grazing system were used, in a crossover design, randomly assigned to four treatments: control (base diet with microencapsulated conjugated linoleic acid) and three levels of vitamin E (control with 4,000; 8,000; and 12,000 IU/cow per day). All the cows received a supplement apportioning 5 g of cis-9, trans-11, and 5 g of trans-10, cis-12 of conjugated linoleic acid. Moreover, they each received 4-kg dry matter (DM) concentrate and 3.2-kg DM corn silage every day. There were no differences in dry matter intake, milk production, milk composition (fat, protein, and lactose), or fatty acid profile as an effect of vitamin E, and fat content remained under 3 % in all treatments. Therefore, under the conditions that this experiment was carried out, high concentrations of vitamin E in the diet of grazing dairy cows do not inhibit milk fat depression associated with conjugated linoleic acid. It also has no effect on the fatty acid profile of the milk. 23613004 Disposition kinetics of diclofenac in the dual perfused rat liver. This study investigates the hepatic disposition of diclofenac as a function of route of input: portal vein (PV) versus hepatic artery (HA) in the presence of its binding protein, albumin. The in situ dual perfused rat liver was performed using Krebs bicarbonate buffer containing human serum albumin (HSA, 0.25%-1%) at constant PV (12 mL/min) and HA (3 mL/min) flow rates. Bolus doses of [(14) C]-diclofenac and (125) I-labeled HSA were injected randomly into the HA or PV and then, after an appropriate interval, into the alternate vessel. Regardless of route of input and perfusion medium protein concentration, the hepatic outflow profile of diclofenac displayed a characteristic sharp peak followed by a slower eluting tail, indicating that its radial distribution is not instantaneous. Based on the estimated effective permeability-surface area product/blood flow ratio, hepatic uptake of diclofenac is governed by both perfusion and permeability. Fractional effluent recovery (F) increased as unbound diclofenac fraction in the perfusate decreased. Although no significant difference in hepatic clearance of diclofenac as a function of route of delivery at 0.5% and 1% HSA, it was demonstrable at 0.25% HSA (p < 0.001), when the extraction ratio is higher. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3220-3227, 2013. 23541031 Spin system trajectory analysis under optimal control pulses. Several methods are proposed for the analysis, visualization and interpretation of high-dimensional spin system trajectories produced by quantum mechanical simulations. It is noted that expectation values of specific observables in large spin systems often feature fast, complicated and hard-to-interpret time dynamics and suggested that populations of carefully selected subspaces of states are much easier to analyze and interpret. As an illustration of the utility of the proposed methods, it is demonstrated that the apparent "noisy" appearance of many optimal control pulses in NMR and EPR spectroscopy is an illusion - the underlying spin dynamics is shown to be smooth, orderly and very tightly controlled. 23583776 Solid-State (13)C NMR Reveals Annealing of Raft-Like Membranes Containing Cholesterol by the Intrinsically Disordered Protein α-Synuclein. Misfolding and aggregation of the intrinsically disordered protein α-Synuclein (αS) in Lewy body plaques are characteristic markers of late-stage Parkinson's disease. It is well established that membrane binding is initiated at the N-terminus of the protein and affects biasing of conformational ensembles of αS. However, little is understood about the effect of αS on the membrane lipid bilayer. One hypothesis is that intrinsically disordered αS alters the structural properties of the membrane, thereby stabilizing the bilayer against fusion. Here, we used two-dimensional (13)C separated local-field NMR to study interaction of the wild-type α-Synuclein (wt-αS) or its N-terminal (1-25) amino acid sequence (N-αS) with a cholesterol-enriched ternary membrane system. This lipid bilayer mimics cellular raft-like domains in the brain that are proposed to be involved in neuronal membrane fusion. The two-dimensional dipolar-recoupling pulse sequence DROSS (dipolar recoupling on-axis with scaling and shape preservation) was implemented to measure isotropic (13)C chemical shifts and (13)C-(1)H residual dipolar couplings under magic-angle spinning. Site-specific changes in NMR chemical shifts and segmental order parameters indicate that both wt-αS and N-αS bind to the membrane interface and change lipid packing within raft-like membranes. Mean-torque modeling of (13)C-(1)H NMR order parameters shows that αS induces a remarkable thinning of the bilayer (≈6Å), accompanied by an increase in phospholipid cross-sectional area (≈10Å(2)). This perturbation is characterized as membrane annealing and entails structural remodeling of the raft-like liquid-ordered phase. We propose this process is implicated in regulation of synaptic membrane fusion that may be altered by aggregation of αS in Parkinson's disease. 23651556 Degradation and mineralization of DDT by the ectomycorrhizal fungi, Xerocomus chrysenteron. One strain of ectomycorrhizal fungi, Xerocomus chrysenteron, had been investigated for its ability to degrade 1,1,1-trichloro-2,2-bis(4-chlorophe-nyl) ethane (DDT) by measuring unlabeled DDT and identifying its metabolites, and determining the mineralization of [(13)C]DDT in pure cultures. After 45d incubation, about 55% of the added DDT disappeared from the culture system, less than 5% remained in the nutrient solution, and about 44% was retained in the mycelium. Inoculation with mycelium enhanced the degradation of DDT in soil, and alleviated enrichment of DDT in plants. The metabolites identified by gas chromatography-mass spectrometry were 1,1-dichloro-2,2-bis(4-chlorophenyl) ethane (DDD), 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene (DDE), and 4,4'-dichlorobenzophenone (DBP). There were significant differences in the δ(13)C of released CO2 between [(13)C]DDT and DDT cultures, which indicated X. chrysenteron was able to mineralize DDT to CO2. 23835159 Study protocol: the relation of birth weight and infant growth trajectories with physical fitness, physical activity and sedentary behavior at 8-9 years of age - the ABCD study. Low birth weight and accelerated infant growth have been identified as independent risk factors for childhood and adult obesity and cardiovascular disease. This led to the 'Developmental Origins of Health and Disease' (DOHaD) hypothesis, stating that environmental factors during pregnancy and early postnatal life affect disease risk in later life. There is growing evidence that perinatal factors may influence adult health through the programming of energy balance regulation, including sedentary behavior and physical activity. The present study focuses on the influence of birth weight and infant growth on physical fitness, physical activity and sedentary behavior in 8-9 year old children, as this might partly explain the higher obesity and cardiovascular risk associated with low birth weight and accelerated infant growth. In addition, this study provides the opportunity for a validation study of a linguistic and cross-cultural translated physical activity questionnaire compared to accelerometer data. This article describes the study protocol for this study. This is a study embedded in the Amsterdam Born Children and their Development (ABCD) birth cohort. In 200 children of Dutch ethnicity, physical fitness, physical activity and sedentary behavior were assessed at age 8-9. We measured aerobic fitness using the 20 meter multistage shuttle run test, and neuromuscular fitness using the standing broad jump and handgrip strength test. Sedentary behavior and physical activity levels were measured using accelerometry. All children also completed a translated physical activity questionnaire, the scores of which will be compared to accelerometry data to assess the construct validity of the questionnaire in Dutch school-aged children. This study will be the first population-based prospective cohort study to address the association of both prenatal and postnatal growth with physical fitness and objectively-assessed physical activity and sedentary behavior. This will contribute to a better understanding of the way perinatal growth relate to lifestyle and obesity in later life. The results may guide both future studies in the field of DOHaD, and public health strategies in the prevention of childhood obesity. 23454668 The mode of action of juvenile hormone and ecdysone: towards an epi-endocrinological paradigm? In some insect species, two sites of juvenile hormone (JH) synthesis have been reported: the very well documented corpora allata that secrete JH for "general use", and the reproductive system, in particular the male accessory glands, in which the function of the sometimes huge amounts of JH (e.g. in Hyalophora cecropia) remains to be clarified. A recent finding in Schistocerca gregaria, namely that suppression of the ecdysteroid peak preceding a molt by RNAi of the Halloween genes spook, phantom and shade does not impede normal molting, challenges the (never experimentally proven) classical concept that such a peak is causally linked to a molt. Recent developments in epigenetic control of gene expression in both the honey bee and in locusts suggest that, in addition to the classical scheme of hormone-receptor (membrane- and/or nuclear) mode of action, there may be a third way. Upon combining these and other orphan data that do not fit in the commonly accepted textbook schemes, we here advance the working hypothesis that both JH and ecdysone might be important but overlooked players in epigenetic control of gene expression, in particular at extreme concentrations (peak values or total absence). In this review, we put forward how epi-endocrinology can complement classical arthropod endocrinology. 23815567 Insulin oedema and treatment-induced neuropathy occurring in a 20-year-old patient with Type 1 diabetes commenced on an insulin pump. Oedema may occur following initiation or intensification of insulin therapy in patients with Type 1 and Type 2 diabetes. Mild oedema is thought to be not uncommon, but under-reported, whilst generalized oedema with involvement of serous cavities has rarely been described. Multiple pathogenic mechanisms have been proposed, including insulin-induced sodium and water retention. Patients at greater risk for insulin oedema include those with poor glycaemic control. Dramatic improvement in glycaemic control is also associated with sensory and autonomic neuropathy. We describe a case of generalized oedema occurring in a 20-year-old, low body weight patient with Type 1 diabetes with poor glycaemic control 3 days following commencement of an insulin pump; blood sugars had dramatically improved with this treatment. Alternative causes for oedema were excluded. Oedema slowly improved with insulin dose reduction with higher blood sugar targets plus frusemide treatment. Subsequent to oedema resolution, the patient unfortunately developed generalized neuropathic pain, thought to be another manifestation of rapid improvement in glycaemic control. Caution should be taken when a patient with diabetes that is poorly controlled has an escalation in therapy that may dramatically improve their blood sugar levels; this includes the initiation of an insulin pump. Clinicians and patients should be aware of the potential risk of insulin oedema, treatment-induced neuropathy and worsening of diabetic retinopathy in the setting of rapid improvement in glycaemic control. This article is protected by copyright. All rights reserved. 23851588 Contemporary strategy for aortic valve stenosis in octogenarians. The number of patients with aortic stenosis (AS) has been increasing over recent decades with the longer life expectancy of the general population. AS is life-threatening without surgery and since many elderly patients have a variety of comorbid conditions, 30-40 % of those with severe AS have been denied surgery. However, recent data on standard aortic valve replacement (AVR) for octogenarians have revealed excellent outcomes, with 2.4-6.8 % early mortality and similar survival rates of octogenarians who undergo AVR vs. the general population. The reported incidences of postoperative stroke, dialysis, and pacemaker implantation were 2.4, 2.6, and 4.6 %, respectively. Transcatheter aortic valve replacement (TAVR) is the alternative therapy for patients who are not able to undergo standard AVR and it is developing rapidly. The placement of aortic transcatheter valves (PARTNER) trial showed acceptable early outcomes. The mortality rates from any cause were 3.4 % in the TAVR group and 6.5 % in the AVR group at 30 days, 24.2 and 26.8 % at 1 year, and 33.9 and 35.0 % at 2 years, respectively. Stroke rate was higher in the TAVR group than in the AVR group (3.4 vs. 1.9 %). Vascular complications and paravalvular leakage are frequent procedure-related complications, which must be addressed because they are associated with increased mortality. 23881408 Histological analysis of mammary gland remodeling caused by lipopolysaccharide in lactating mice. The mammary alveolus is a highly specialized structure that secretes milk for suckling infants during lactation. The secreting alveolus consists in alveolar epithelial cells (AECs) and myoepithelial cells and is surrounded by microvascular endothelial cells, adipocytes and several immune cell types such as macrophages and neutrophils. During normal lactation, these cells play distinct roles needed to maintain the secretory ability of the mammary alveolus. However, inflammation resulting from pathogenic bacterial infections causes structural and functional regression of the secreting alveolus in the lactating mammary gland. We initiated artificial inflammation in the mammary glands of lactating mice by injecting lipopolysaccharide (LPS), as a mammary inflammation model and investigated, by immunohistochemical analysis, the early response of the cells constituting and surrounding the alveolus. Some AECs sloughed away from the alveolar epithelial layer and showed progression of apoptosis detected by immunostaining of cleaved caspase-3 after LPS injection. Adipocytes exhibited transient shrinkage and re-accumulation of lipid droplets, although the numbers of adipocytes did not demonstrate a significant difference. Activation of F4/80-positive cells around the mammary alveolus was observed 3 h after LPS injection. However, the recruitment of CD11b-positive cells into the alveolar lumen was not observed until 12 h after LPS injection. Myoepithelial cells were contracted after LPS injection. LPS injection around the alveolus did not induce any detectable structural changes in capillaries surrounding the alveolus. Thus, cell-specific behavior and tissue remodeling of the alveolus occur after LPS injection in a time-dependent manner. 23810514 Solving delay differential equations in S-ADAPT by method of steps. S-ADAPT is a version of the ADAPT program that contains additional simulation and optimization abilities such as parametric population analysis. S-ADAPT utilizes LSODA to solve ordinary differential equations (ODEs), an algorithm designed for large dimension non-stiff and stiff problems. However, S-ADAPT does not have a solver for delay differential equations (DDEs). Our objective was to implement in S-ADAPT a DDE solver using the methods of steps. The method of steps allows one to solve virtually any DDE system by transforming it to an ODE system. The solver was validated for scalar linear DDEs with one delay and bolus and infusion inputs for which explicit analytic solutions were derived. Solutions of nonlinear DDE problems coded in S-ADAPT were validated by comparing them with ones obtained by the MATLAB DDE solver dde23. The estimation of parameters was tested on the MATLB simulated population pharmacodynamics data. The comparison of S-ADAPT generated solutions for DDE problems with the explicit solutions as well as MATLAB produced solutions which agreed to at least 7 significant digits. The population parameter estimates from using importance sampling expectation-maximization in S-ADAPT agreed with ones used to generate the data. 23943088 Simultaneous optimal experimental design for in vitro binding parameter estimation. Simultaneous optimization of in vitro ligand binding studies using an optimal design software package that can incorporate multiple design variables through non-linear mixed effect models and provide a general optimized design regardless of the binding site capacity and relative binding rates for a two binding system. Experimental design optimization was employed with D- and ED-optimality using PopED 2.8 including commonly encountered factors during experimentation (residual error, between experiment variability and non-specific binding) for in vitro ligand binding experiments: association, dissociation, equilibrium and non-specific binding experiments. Moreover, a method for optimizing several design parameters (ligand concentrations, measurement times and total number of samples) was examined. With changes in relative binding site density and relative binding rates, different measurement times and ligand concentrations were needed to provide precise estimation of binding parameters. However, using optimized design variables, significant reductions in number of samples provided as good or better precision of the parameter estimates compared to the original extensive sampling design. Employing ED-optimality led to a general experimental design regardless of the relative binding site density and relative binding rates. Precision of the parameter estimates were as good as the extensive sampling design for most parameters and better for the poorly estimated parameters. Optimized designs for in vitro ligand binding studies provided robust parameter estimation while allowing more efficient and cost effective experimentation by reducing the measurement times and separate ligand concentrations required and in some cases, the total number of samples. 23905616 The Use of FDG-PET/CT in Patients With Febrile Neutropenia. Fever is a frequent complication of neutropenia induced by the treatment of various neoplasms. This is referred to as febrile neutropenia, which is considered to be a sign of a potentially life-threatening infectious complication until proven otherwise. However, most infectious foci do not have localizing signs and symptoms owing to the lack of inflammatory infiltrates during neutropenia. At the same time, recent studies also showed that febrile neutropenia is not a specific indicator for infection. An increase in C-reactive protein and fever may initially be caused by inflammation of the digestive tract mucosa due to cytotoxic treatment of hematologic malignancies. Infectious foci can be found in various organ systems, such as the respiratory tract including invasive fungal disease, septic thrombophlebitis in those patients with central venous catheters, metastatic infection including soft tissue abscesses, and the digestive tract, for example, colitis and esophagitis probably associated with mucosal barrier injury. A growing number of studies focus on the use of FDG-PET/CT to detect infection in patients with febrile neutropenia. Studies show that FDG uptake in inflammatory foci seems not to be hampered by the lack of circulating neutrophils. At the same time, the very high negative predictive value of FDG-PET/CT excluding localized infectious foci might facilitate guidance of antimicrobial treatment. However, larger prospective studies are needed before FDG-PET/CT would be embedded in diagnostic guidelines in patients with febrile neutropenia. 23681603 Immunological insights from patients undergoing surgery on ipilimumab for metastatic melanoma. The tumor microenvironment after treatment with ipilimumab is not well described. Furthermore, the safety of surgery for patients being treated with ipilimumab for metastatic melanoma has not been well reported. This study analyzed the safety of surgery and the immune phenotype of tumors resected while on ipilimumab. From our prospective melanoma database, we identified patients undergoing surgery for any indication within 30 days of receiving a dose of induction ipilimumab or while on maintenance ipilimumab therapy. Surgical toxicity was graded 1-5 by the Clavien classification. Tumor-infiltrating lymphocytes were classified by flow cytometry and compared with peripheral blood. 23 patients were identified who underwent 34 operations a median of 27 weeks after initiation of ipilimumab (1-123 weeks). Subcutaneous resections were the most frequent, followed by intra-abdominal and nodal procedures. Grade 1 or 2 wound complications were seen in 22 % of patients. No Grade 3-5 complications were seen. Analysis of the T cell infiltrate and matched peripheral blood from ten patients showed an elevated % of CD4(+)FOXP3(+) T-regulatory cells and a 2.8-fold lower ratio of CD8(+)/CD4(+)FOXP3(+) in the tumor compared with blood (p = 0.02). In addition, all CD8(+) T cells had a higher expression of PD-1 in the tumor, compared with peripheral blood. Surgery for patients on ipilimumab is safe. This study highlights the immunosuppressive phenotype in tumors not responding to immunotherapy. The high percentage of T-regulatory cells and low T-effector cells in progressive tumors suggests a possible mechanism of immune escape. 23628521 Terminating ventricular tachyarrhythmias using far-field low-voltage stimuli: Mechanisms and delivery protocols. Low-voltage termination of ventricular tachycardia (VT) and atrial fibrillation has shown promising results; however, the mechanisms and full range of applications remain unexplored. To elucidate the mechanisms for low-voltage cardioversion and defibrillation and to develop an optimal low-voltage defibrillation protocol. We developed a detailed magnetic resonance imaging-based computational model of the rabbit right ventricular wall. We applied multiple low-voltage far-field stimuli of various strengths (≤1 V/cm) and stimulation rates in VT and ventricular fibrillation (VF). Of the 5 stimulation rates tested, stimuli applied at 16% or 88% of the VT cycle length (CL) were most effective in cardioverting VT, the mechanism being consecutive excitable gap decreases. Stimuli given at 88% of the VF CL defibrillated successfully, whereas a faster stimulation rate (16%) often failed because the fast stimuli did not capture enough tissue. In this model, defibrillation threshold energy for multiple low-voltage stimuli at 88% of VF CL was 0.58% of the defibrillation threshold energy for a single strong biphasic shock. Based on the simulation results, a novel 2-stage defibrillation protocol was proposed. The first stage converted VF into VT by applying low-voltage stimuli at times of maximal excitable gap, capturing large tissue volume and synchronizing depolarization; the second stage terminated VT. The energy required for successful defibrillation using this protocol was 57.42% of the energy for low-voltage defibrillation when stimulating at 88% of VF CL. A novel 2-stage low-voltage defibrillation protocol using the excitable gap extent to time multiple stimuli defibrillated VF with the least energy by first converting VF into VT and then terminating VT. 23670114 Predictors of colorectal cancer screening variation among primary-care providers and clinics. Colorectal cancer (CRC) screening is underutilized. To effect change, we must understand reasons for underuse at multiple levels of the health-care system. We evaluated patient, provider, and clinic factors that predict variation in CRC screening among primary-care clinics and primary-care providers (PCPs). We analyzed electronic medical record (EMR) data for 34,319 adults eligible for CRC screening, 19 clinics, and 97 PCPs in a large, academic physician group. Detailed data on potential patient, provider, and clinic predictors of CRC screening were obtained from the EMR. PCP perceptions of CRC screening barriers were measured via survey. The outcome was completion of CRC screening at the patient level. Multivariate logistic regression with clustering on clinics obtained adjusted odds ratios and 95% confidence intervals for potential predictors of CRC screening at each level. Seventy-one percentage of patients completed CRC screening. Variation in screening rates was seen among clinics (51-80%) and among PCPs (51-82%). Significant predictors of completing CRC screening were identified at all levels: patient (older age, white race, being married, primarily English-speaking, having commercial insurance plans vs. Medicare or Medicaid, and higher health-care resource utilization), provider (larger panel size of patients eligible for CRC screening), and clinic (hospital-owned, shorter distance to nearest optical colonoscopy center). Variation in CRC screening exists among primary-care clinics and providers within a single clinic. Predictors of variation can be identified at patient, provider, and clinic levels. Quality improvement interventions addressing CRC screening need to be directed at multiple levels of the health-care system. 23948523 Phoenix dactylifera L. spathe essential oil: Chemical composition and repellent activity against the yellow fever mosquito. Date palm, Phoenix dactylifera L. (Arecaceae), grows commonly in the Arabian Peninsula and is traditionally used to treat various diseases. The aim of the present study was to identify chemical composition of the essential oil and to investigate the repellent activity. The essential oil of P. dactylifera was obtained by hydrodistillation from the spathe, a specialized leaf structure that surrounds the pollinating organs of the palm. The oil was subsequently analyzed by GC-FID and GC-MS. The oil showed promising repellent activity against yellow fever mosquito - Aedes aegypti. Sixteen components were characterized, constituting 99% of the oil. The main components were 3,4-dimethoxytoluene (73.5%), 2,4-dimethoxytoluene (9.5%), β-caryophyllene (5.5%), p-cresyl methyl ether (3.8%), and caryophyllene oxide (2.4%). The minimum effective dosage (MED) for repellency for the P. dactylifera oil was 0.051mg/cm(2), which had moderately lower potency compared to reference standard N,N-diethyl-3-methylbenzamide, DEET (0.018mg/cm(2)) in the "cloth patch assay". The five major compounds were individually assayed for repellency to determine to what extent each is responsible for repellency from the oil. 3,4-Dimethoxytoluene and 2,4-dimethoxytoluene showed the best repellent activity with the same MED value of 0.063mg/cm(2), respectively. The results indicate that these two constituents which comprise a large proportion of the P. dactylifera oil (83%) are likely responsible for the observed repellent activity. In this aspect, the P. dactylifera spathe oil is sustainable promising new source of natural repellents. 23933197 Assessment of the mutagenic potential of cyanobacterial extracts and pure cyanotoxins. The aim of the study was to assess the mutagenic potential of extracts obtained from the cyanobacterial bloom-forming cells harvested from the water body located in Lubelszczyzna region of southeastern Poland. Three cyanotoxins, microcystin-LR, cylindrospermopsin and anatoxin-a were detected in some of the studied samples in different concentrations. All extracts were assessed for their potential mutagenic effects with the use of a short-term bacterial assay, the Ames test. Mutagenic activity was observed in four of all ten studied extracts, mainly toward the Salmonella typhimurium TA100 strain. On the contrary, the cyanotoxins in purified forms occurred not to be mutagenic or cytotoxic towards S. typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli WP2 uvrA and WP2 [pKM101] up to a concentration of 10 Î¼g/ml. Similarly, there were no effects after bacteria exposure to the mixture of purified toxins. It has been also detected that after fractionation, genotoxic impact of previously mutagenic extracts was weaker and the highest potency in revertant induction possessed fractions containing very hydrophilic compounds. The results indicate, that while tested cyanotoxins were not directly responsible for the observed mutagenicity of the extracts analysed, some synergistic interactions with other unidentified cyanobacterial-derived factors involved in the process are possible. 23871105 Diet Quality of Overweight and Obese Mothers and Their Preschool Children. Children of obese parents are more likely to become obese than children of normal-weight parents. However, there is little information regarding the diet intakes of children of obese parents. Our objective was to determine the diet quality of preschoolers and their overweight/obese mothers, whether maternal and child diet quality were correlated, and predictors of child's diet quality. Results are from baseline measurements from a randomized controlled behavioral intervention. Participants were English-literate, postpartum mothers and their preschoolers (n=177 mother-child dyads) in North Carolina. Visits took place in the Triangle and Triad regions of North Carolina between September 2007 and November 2009. We measured diet quality of mothers and preschoolers using the Healthy Eating Index-2005. Descriptive statistics, χ(2), analysis of variance, Pearson correlations, and stepwise regression models were used. Only 11% of children and 7% of mothers had Healthy Eating Index-2005 scores ≥80. Most children did not meet recommendations for fruits, vegetables, whole grains, meat and beans, sodium, saturated fat, and energy from solid fat and added sugars. Child diet quality was correlated with maternal diet quality (r=0.44; P<0.001). However, children and mothers differed in the proportion that met food-group recommendations: children vs mothers: total fruit (50% vs 14%), whole fruit (46% vs 28%), total vegetables (6% vs 18%), dark green and orange vegetables and legumes (7% vs 19%), total grains (57% vs 71%), milk (63% vs 22%), and meat and beans (33% vs 60%). Maternal diet quality and household income were positively correlated with child diet quality. The diets of children of overweight/obese mothers need improvement in several areas. Mother's diet quality and household income are important contributors to child's diet quality and should be considered in efforts to improve the diets of these children. 23963010 Diagnosis, Heritability and Outcome Assessment in Cervical Myelopathy: A Consensus Statement. This section of the Cervical Spondylotic Myelopathy (CSM) Spine focus issue collates the existing evidence related to diagnosis, outcome assessment and genetics. Given that a variety of different disease states can present similarly, a guide for diagnosing and differentiating CSM from other neurological conditions is initially presented. Although the value of magnetic resonance imaging (MRI) in diagnosing CSM is cemented, its value as a tool to predict future outcome is less well established. To this end, the existing evidence suggests that while increased T2 cord signal is of limited value, the pairing of high T2 signal with low T1 signal, or a high T2 to T1 signal ratio, is associated with a reduced potential for neurological recovery at follow-up. Outcome assessment in CSM is of paramount importance when monitoring patients' clinical course or measuring the efficacy of therapeutic interventions. Here, the main outcome measures that have been used to assess CSM patients are reviewed. At present, we recommend that clinicians acquire the modified Japanese Orthopedic Association (mJOA) scale score and the neck disability index (NDI) on all patients with CSM at presentation and follow-up. Finally, as regards genetics, the existing evidence seems to support the principle of an inherited predisposition to both CSM and ossification of the posterior longitudinal ligament (OPLL). While several genetic polymorphisms have been consistently associated with OPLL, no specific polymorphisms were consistently associated with CSM. 23669397 Bidirectional transcription of trinucleotide repeats: Roles for excision repair. Genomic instability at repetitive DNA regions in cells of the nervous system leads to a number of neurodegenerative and neuromuscular diseases, including those with an expanded trinucleotide repeat (TNR) tract at or nearby an expressed gene. Expansion causes disease when a particular base sequence is repeated beyond the normal range, interfering with the expression or properties of a gene product. Disease severity and onset depend on the number of repeats. As the length of the repeat tract grows, so does the size of the successive expansions and the likelihood of another unstable event. In fragile X syndrome, for example, CGG repeat instability and pathogenesis are not typically observed below tracts of roughly 50 repeats, but occur frequently at or above 55 repeats, and are virtually certain above 100-300 repeats. Recent evidence points to bidirectional transcription as a new aspect of TNR instability and pathophysiology. Bidirectional transcription of TNR genes produces novel proteins and/or regulatory RNAs that influence both toxicity and epigenetic changes in TNR promoters. Bidirectional transcription of the TNR tract appears to influence aspects of its stability, gene processing, splicing, gene silencing, and chemical modification of DNAs. Paradoxically, however, some of the same effects are observed on both the expanded TNR gene and on its normal gene counterpart. In this review, we discuss the possible normal and abnormal effects of bidirectional transcription on trinucleotide repeat instability, the role of DNA repair in causing, preventing, or maintaining methylation, and chromatin environment of TNR genes. 23902757 Brugada Syndrome Behind Complete Right Bundle Branch Block. The characteristic electrocardiogram of BS can be masked by right CRBBB and exposed by resolution of the block or pharmacological or pacing maneuvers. The study consisted of eleven patients who had BS and CRBBB. BS was diagnosed before the development of CRBBB (n=7), on the resolution of CRBBB, or from new characteristic ST changes that could be due to BS (n=4). Structural heart diseases were excluded, and coronary spasm was excluded based on a provocation test at catheterization. In seven patients, BS was diagnosed before the development of CRBBB. In one patient, BS was diagnosed when CRBBB resolved spontaneously. The precipitating cause for the resolution of CRBBB was, however, not apparent. On repeated ECGs, new additional upward-convex ST elevation was found in V2 and/or V3 in three patients. In two patients, new ST elevation was induced by IC drugs. The QRS duration was more prolonged in the patients with BS and CRBBB, compared to the age- and sex-matched controls: 170±13 ms versus 145±15 ms in V1, and 144±19 ms versus 128±7 ms in V5 (both P<0.0001). The amplitude of R in V1 was larger in the BS patients than in the controls (P=0.0323), but that of R' was similar (P=0.0560). BS can coexist behind CRBBB, and CRBBB can completely mask BS. BS might be demonstrated by relief of CRBBB or by spontaneous or drug-induced ST elevation. The prevalence, mechanism and clinical significance of a combination of CRBBB and BS are yet to be determined. 23411222 Hypolipidemic and antioxidant activities of thymoquinone and limonene in atherogenic suspension fed rats. The hypolipidemic and antioxidant actions of thymoquinone (TQ) and limonene (LMN) were investigated by giving 1 ml of 10mg TQ or 200mg LMN suspension, by gavage in two equal doses (morning and evening) of 0.5 ml each for 30 days, in rats, fed an atherogenic suspension. These compounds effectively ameliorated all the altered cardiovascular risk parameters via a reduction in HMG-CoA reductase activity, along with an increase in arylesterase activity. The compounds significantly blocked the shift in buoyancy from less atherogenic lb-LDL to highly atherogenic sd-LDL, restoring the percent distribution of LDL-C and apoB into sd-LDL and lb-LDL to near normal levels. These compounds also blocked basal and maximal formation of CD and malondialdehyde, and lengthened the lag times of LDL, sd-LDL and lb-LDL in the order TQ>LMN. Our results strongly suggest an important therapeutic use of test compounds, especially TQ, in the prevention of cardiovascular disease risks parameters. 23889217 DHEA supplementation positively affects spontaneous pregnancies in women with diminished ovarian function. Abstract The aim of this article is to describe unexpected spontaneous pregnancies in poor responder patients with long-term infertility, when treated with dehydroepiandrosterone (DHEA) supplementation prior to in vitro fertilization (IVF). Our evaluation was carried out in two groups of women. The first group included 39 young women with <40 years, all treated with DHEA because of a previous poor response. The second group included 38 women over 40 years who received DHEA supplementation. Controls for latter group were 24 comparable women who had not been treated with DHEA before the first IVF cycle to evaluate the spontaneous pregnancy rate during preparation to IVF. Three tablets daily of 25 mg micronized DHEA were administered for at least 12 weeks before starting a long stimulation protocol for IVF. Surprisingly, spontaneous pregnancy rate significantly increased after DHEA treatment, allowing to achieve 10 spontaneous pregnancies and 9 spontaneous ongoing pregnancies among young poor responders. Pregnancy rate and ongoing pregnancy rate obtained before starting the IVF cycle were also significantly higher in older women treated with DHEA than in the control group: 21.05% and 13.15% and 4.1% and 0, respectively. Our results show that DHEA supplementation improves the ovarian function in poor responders and in women over 40 years, suggesting that this molecule alone can raise fecundity and fertility treatment success in women with poor prognosis for pregnancy. 23856208 Single-institution, 22-year, follow-up of 786 CarboMedics mechanical valves used for both primary surgery and reoperation. The long-term (>20 years) results for CarboMedics mechanical valves (Sorin Group, Milano, Italy) used for both primary surgery and reoperation have never been reported or compared. Since 1990, a total of 787 CarboMedics valves have been implanted in 694 patients for aortic valve replacement, including 19 redo cases in 220 patients; for mitral valve replacement, including 108 redo cases in 381 patents; and for double (aortic and mitral) valve replacement, including 29 redo cases in 93 patients. The follow-up data were complete for 7201 patient-years in 99.3% of the patients. The hospital mortality rate of the aortic, mitral, and double valve replacement groups was 0.9%, 3.7%, and 4.3%, respectively. The corresponding freedom from valve-related morbidity rates in each group were 66.0%, 40.6%, and 48.0% at 20 years (P = .0206). A higher incidence of paravalvular leakage was observed in the mitral and double valve replacement groups than in the aortic valve replacement group (P = .0019). Of the cases of mitral paravalvular leakage after single mitral valve replacement, 97% occurred after redo single mitral valve replacement; 73% of the cases of mitral paravalvular leakage after double valve replacement occurred after redo double valve replacement. CarboMedics mechanical valves used for both primary surgery and reoperation for aortic, mitral, and double valve replacement can achieve satisfactory early and long-term results, even 20 years after surgery. Care should be taken, however, to prevent paravalvular leakage in the mitral position during reoperation. 23685908 Role of LM23 in cell proliferation and apoptosis and its expression during the testis development. LM23, a gene expressed specifically in the testis in a stage-specific manner, has a diverse range of functions that are important in both the life and death of spermatogenic cells. The aim of this study was to further investigate the expression of LM23 in the developing rat testis and the biological function of LM23 in proliferation and antiapoptosis in vitro. Semiquantitative reverse transcription (RT)-PCR and real-time PCR were used to examine the expression of LM23 in testis at different developmental stages. The results suggested that LM23 mRNA levels in the testis increased progressively after birth. The role of LM23 in proliferation was analyzed with cell counting kit-8 (CCK8), colony-forming efficiency (CFE) and flow cytometry assays. The results indicated that ectopic expression of LM23 in 293T cells significantly promoted cell proliferation by increasing cell numbers in S phase. Several methods were used, including CCK8, annexin V and propidium iodide staining and western blotting, to determine the role of LM23 in apoptosis. The results showed that LM23 played a protective role in H2O2-induced apoptosis of 293T cells, mediated at least in part through the Akt/PI3K signal pathway. Taken together, these results provide new insights into the role of LM23 in the development of the testes and spermatogenesis. 23924715 Development of Gateway Binary Vectors R4L1pGWB Possessing the Bialaphos Resistance Gene (bar) and the Tunicamycin Resistance Gene as Markers for Promoter Analysis in Plants. We have developed a new series of R4L1 Gateway binary vectors (R4L1pGWB), which carry the bialaphos resistance gene (bar) or the UDP-N-acetylglucosamine:dolichol phosphate N-acetylglucosamine-1-P transferase (GPT) gene as selection markers that confer BASTA(®) and tunicamycin resistance on plants respectively. R4L1pGWBs have an attR4-attL1-reporter and can accept an attL4-promoter-attR1 entry clone for easy construction of an attB4-promoter-attB1-reporter clone. The new R4L1pGWBs facilitate promoter:reporter analysis in pre-existing transgenic plants that are resistant to kanamycin or hygromycin. 23873908 Identification and Characterization of Clostridium sordellii Toxin Gene Regulator. Toxigenic Clostridium sordellii causes uncommon but highly lethal infections in humans and animals. Recently, an increased incidence of C. sordellii infections has been reported in women undergoing obstetric interventions. Pathogenic strains of C. sordellii produce numerous virulence factors, including sordellilysin, phospholipase, neuraminidase, and two large clostridial glucosylating toxins, TcsL and TcsH. Recent studies have demonstrated that TcsL toxin is an essential virulence factor for the pathogenicity of C. sordellii. In this study, we identified and characterized TcsR as the toxin gene (tcsL) regulator in C. sordellii. High-throughput sequencing of two C. sordellii strains revealed that tcsR lies within a genomic region that encodes TcsL, TcsH, and TcsE, a putative holin. By using ClosTron technology, we inactivated the tcsR gene in strain ATCC 9714. Toxin production and tcsL transcription were decreased in the tcsR mutant strain. However, the complemented tcsR mutant produced large amounts of toxins, similar to the parental strain. Expression of the Clostridium difficile toxin gene regulator tcdR also restored toxin production to the C. sordellii tcsR mutant, showing that these sigma factors are functionally interchangeable. 23928935 Expression of β-catenin and cyclin D1 in Merkel cell carcinomas of the head and neck. Merkel cell carcinomas (MCC) are very aggressive tumors of the sun-exposed skin with a high potential to metastasize. Little is known about the genesis of MCC and very few prognostic markers have been detected so far. The Wnt pathway protein β-catenin and the cell cycle protein cyclin D1 are two promotors of tumor growth and are expressed in a variety of malignant neoplasms such as lymphomas, thyroid, breast cancer, and many others. Tissue samples of 27 patients with MCC were immunohistochemically stained for β-catenin and cyclin D1 and correlated with overall survival of patients. In addition, western blot analysis was carried out in the two MCC cell lines MCC-13 and MCC-26. β-catenin showed a cytoplasmatic expression of 10-30 % in 11 samples and an expression lower than 10 % in eight samples. Nuclear staining was visible in two samples. None of the 27 samples expressed cyclin D1. Neither cyclin D1 nor β-catenin was expressed in a statistically significant manner, concluding that the development of MCCs is independent of β-catenin and cyclin D1 expression and these proteins are not suitable as prognostic markers. We could describe the expression pattern of cyclin D1 for the first time. 23920120 Effect of temperature on lignin-derived inhibition studied with three structurally different cellobiohydrolases. Non-productive enzyme adsorption onto lignin inhibits enzymatic hydrolysis of lignocellulosic biomass. Three cellobiohydrolases, Trichoderma reesei Cel7A (TrCel7A) and two engineered fusion enzymes, with distinctive modular structures and temperature stabilities were employed to study the effect of temperature on inhibition arising from non-productive cellulase adsorption. The fusion enzymes, TeCel7A-CBM1 and TeCel7A-CBM3, were composed of a thermostable Talaromyces emersonii Cel7A (TeCel7A) catalytic domain fused to a carbohydrate-binding module (CBM) either from family 1 or from family 3. With all studied enzymes, increase in temperature was found to increase the inhibitory effect of supplemented lignin in the enzymatic hydrolysis of microcrystalline cellulose. However, for the different enzymes, lignin-derived inhibition emerged at different temperatures. Low binding onto lignin and thermostable structure were characteristic for the most lignin-tolerant enzyme, TeCel7A-CBM1, whereas TrCel7A was most susceptible to lignin especially at elevated temperature (55°C). 23769731 Fronto-temporal interactions in the theta-band during auditory deviant processing. Mismatch negativity (MMN) is a negative component of event-related potential (ERP) that reflects auditory deviant detection. Previous studies repeatedly suggested that MMN is generated by the fronto-temporal network. However, it is still unclear how the frontal and temporal areas interact. To verify this, we observed the spatiotemporal pattern of inter-regional functional connectivity using phase synchrony and Granger causality, by analyzing event-related electroencephalograms (EEGs) elicited by standard and deviant tones in an oddball paradigm. Strong theta-band phase synchrony and bidirectional Granger causality were observed between the frontal and temporal areas during the processing of auditory deviants, especially at the temporal interval of MMN. Our results support the hypothesis that fronto-temporal interactions are crucial to the generation of MMN during auditory deviant processing. 23905648 Cornelian cherry (cornus MAS L.) juice as a potential source of biological compounds. Abstract Cornelian cherry (Cornus mas L.), apple (Malus domestica Borkh. cultivars Jonagold and Red Boskoop), pear (Pyrus communis cv. Conference), and plum (Prunus domestica L. cv. Common Plum) juices were assayed for their quality, organic acids, polyphenol content, and antioxidant activity (determined as a ferric-reducing antioxidant power [FRAP]). Cornelian cherry juice revealed the highest titratable acidity-2.58 g malic acid/100 g. The highest polyphenol content was also noted for Cornelian cherry-45.6 mg gallic acid (GA)/g. The medium level of polyphenols was proved for Jonagold apple (22.8 mg GA1/g). The lowest level was recorded for Common Plum (9.60 mg GA/g), followed by Conference pear and Red Boskoop apple (12.3 and 21.3 mg GA/g, respectively). The FRAP values were 1.97 mmol Fe/L for Common Plum juice, 2.37 mmol Fe/L for Conference pear juice, and 3.92 mmol Fe/L for both Red Boskoop and Jonagold apple juices. However, the obtained data indicated outstanding antioxidant properties for Cornelian cherry juice. In this case, FRAP reached 23.5 mmol Fe/L. The calculated correlation coefficient FRAP versus polyphenols indicates that the antioxidant status for Cornelian cherry is not only correlated with polyphenols but also with other biological compounds. The obtained results indicated that Cornelian cherry is a valuable source of substances with a high antioxidant activity. 23806825 Procalcitonin ratio as a predictor of successful surgical treatment of severe necrotizing soft tissue infections. Necrotizing soft tissue infections often are characterized by fulminant presentation and lethal outcomes. Besides critical care support and antibiotic therapy, aggressive surgical treatment is important for the therapy of necrotizing fasciitis. The aim of this study was to develop a procalcitonin (PCT) ratio indicating successful surgical intervention. The study group consisted of 38 patients treated with clinical signs of sepsis caused by a necrotizing soft tissue infection. All patients received radical surgical treatment, and serum levels of PCT and C-reactive protein were monitored postoperatively. The ratio of day 1 to day 2 was calculated and correlated with the successful elimination of the infectious source and clinical recovery. An eradication of the infectious focus was successfully performed in 84% of patients, averaging 1.9 operations (range 1 to 6) to achieve an elimination of the infectious source. The PCT ratio was significantly higher in the group of patients with successful surgical intervention (1.665 vs .9, P < .001). A ratio higher than the calculated cutoff of 1.14 indicated successful surgical treatment with a sensitivity of 83.3% and a specificity of 71.4%. The positive predictive value was 75.8%, and the negative predictive value was 80.0%. The PCT ratio of postoperative day 1 to day 2 following major surgical procedures for necrotizing soft tissue infections represents a valuable clinical tool indicating successful surgical eradication of the infectious focus. 23612902 Sagittal geometry of the middle and lower cervical endplates. Construct subsidence is a relatively common complication following anterior cervical fusion. Its occurrence has been revealed to be closely related to endplate-implant contact interface. But current literature focusing on the anatomy of cervical endplate is very scarce. The purpose of this morphometric study was to analyse the sagittal geometry, especially the concavity and slope, of vertebral endplates from C3 to C7 by employing data from CT scans. Reformatted CT scans of 97 individuals were analyzed and endplate concavity depth, endplate concavity apex location, as well as endplate slope were measured in midsagittal plane. Those specific parameters were compared among different age and gender groups. Meanwhile, comparison between superior and inferior endplate of each vertebra was also performed. Age and gender did not influence endplate concavity depth, endplate concavity apex location, or endplate slope significantly (P > 0.05). Endplate concavity depths of superior endplates (range 0.9-1.2 mm) were significantly smaller than those of inferior endplates (range 2.1-2.7 mm). Endplate concavity apex was always located in the posterior half of the endplate, with the superior one ranged from 56 to 67% and the inferior one 52 to 57%. Average endplate slopes of superior endplates were between 4.5° and 9.0°, and average inferior endplate slopes ranged from 4.5° to 7.5°. Among all measured segments, C5 had the largest endplate slope values, while C7 the least. Superior endplate is more flat than its inferior counterpart in middle and lower cervical spine, and the concavity apex is always located in the posterior half of the endplate. Endplate slope is correlated with cervical curvature, greater slope implying more significant lordosis. These sagittal endplate geometrical parameters should be taken into consideration when investigating implant subsidence following anterior cervical fusion. 23689524 Diet therapy for eosinophilic esophagitis: when, why and how. With the increasing recognition of eosinophilic esophagitis (EoE) over the past two decades, pharmacologic and dietary therapies have emerged as primary management options. The effectiveness of the elimination dietary therapy supports the conceptual definition of EoE as an antigen/immune-mediated esophageal disease. This manuscript reviews the three types of dietary therapy: an elemental formula diet with complete elimination of table foods, an allergy testing-directed elimination diet and an empiric elimination diet based on common food allergens. Recent prospective studies have demonstrated symptomatic and histologic response to an elimination diet in adults with EoE that is comparable with response rates previously reported in children. Retrospective, comparative data in pediatric EoE have identified the elemental diet as offering the greatest likelihood of histologic disease remission compared with either allergy testing-directed or empiric elimination diets. The long-term goal of each dietary approach is the eventual identification of a single or limited number of trigger foods, thereby allowing a return to as regular a diet as possible. Studies continue to support dietary therapy as an important and effective therapy for EoE. Although topical steroids continue to be a mainstay of therapy, none are presently Food and Drug Administration-approved for EoE. In addition, many patients are reluctant to utilize pharmacologic therapy on a chronic basis. Further research is necessary to better understand and optimize the use of diet therapy for EoE. 23911054 Intermittently-induced endotoxaemia has no effect on post-challenge plasma metabolites, but increases body temperature and cortisol concentrations in periparturient dairy cows. This study evaluated the responses of plasma cortisol, metabolites and body temperature to intermittently-induced endotoxaemia in periparturient cows. Sixteen Holstein cows were randomly allocated to one of the two treatment groups. Cows were infused intravenously either with saline solution (control) or with the same solution containing 3 increasing doses of lipopolysaccharide (LPS) for 3 consecutive weeks around parturition as follows: 0.01μg LPS/kg body weight (BW) on d -14 and -10 prepartum, 0.05μg LPS/kg BW on d -7 and -3 prepartum, and 0.1μg LPS/kg BW on d 3 and 7 postpartum. Blood samples were measured shortly before and in 8 time-points after (up to 6h) the challenges on d -14, -7, 3, and 7 to evaluate the post-challenge plasma profile. Results showed greater concentrations of plasma cortisol, in particular after the second and third LPS challenge. An increase in body temperature was recorded after administration of the greatest LPS dose, but this effect diminished during the very last LPS challenge. A biphasic response of glucose was observed; a linear increase up to 60min after the second LPS challenge followed by a rapid decrease thereafter. Other plasma variables like lactate, cholesterol, non-esterified fatty acids, and beta-hydroxybutyrate were not affected by treatment. In conclusion, LPS administrations did not notably affect post-challenge metabolic responses in periparturient dairy cows but increased the level of plasma cortisol and the body temperature after the highest LPS challenge. 23949897 Occult pyogenic liver abscess in an adolescent with type 2 diabetes. Pyogenic liver abscess is a rare complication of diabetes, usually seen in adults greater than 50 years of age who have had diabetes for many years. We describe an 18-year-old male with type 2 diabetes found to have a pyogenic liver abscess caused by Klebsiella pneumoniae, and show accompanying images from his evaluation for fever of unknown origin (FUO). We conclude that in a child or adolescent with FUO and diabetes, occult pyogenic liver abscess must be considered. 23397359 Temperature Effects of Sputtering of Langmuir-Blodgett Multilayers. Time-of-flight secondary ion mass spectrometry (TOF-SIMS) and atomic force microscopy (AFM) are employed to characterize a wedge-shaped crater eroded by a 40 keV C(60) (+) cluster ion beam on an organic thin film of 402 nm of barium arachidate (AA) multilayers prepared by the Langmuir-Blodgett (LB) technique. Sample cooling to 90 K was used to help reduce chemical damage, improve depth resolution and maintain constant erosion rate during depth profiling. The film was characterized at 90 K, 135 K, 165 K, 205 K, 265 K and 300 K. It is shown that sample cooling to 205 K or lower helps to inhibit erosion rate decay, whereas at 300 K and 265 K the erosion rate continues to drop after 250 nm of erosion, reaching about half of the initial value after removal of the entire film. Depth profiles are acquired from the SIMS images of the eroded wedge crater. The results suggest that sample cooling only slightly improves the altered layer thickness, but eliminates the decrease in erosion rate observed above 265 K. 23895951 Complexation of chitosan with surfactant like ionic liquids: Molecular interactions and preparation of chitosan nanoparticles. Interactions and behavior of chitosan (Ch) with surface active ionic liquids (ILs)- 1-butyl-3-methylimidazolium octylsulfate, [C4mim][C8OSO3] or 3-methyl-1-octylimidazolium chloride, [C8mim][Cl]-have been probed at the air solution interface and in the bulk in aqueous media at pH 3.0 using a multi-technique approach, viz. tensiometry, conductometry, turbidimetry, dynamic light scattering (DLS), and atomic force microscopy (AFM). At the interface, a strong complexation is observed in Ch-[C4mim][C8OSO3] system. Bulk [C4mim][C8OSO3] interacts with Ch to form Ch-[C4mim][C8OSO3] complexes which precipitate out at higher IL concentrations, whereas comparatively weaker Ch-[C8mim][Cl] complexes remain solubilized in the solution. DLS measurements showed that the Ch chains contract before the cmc and expands after the cmc upon interaction with both the ILs. Interaction of ILs with Ch resulted in facile preparation of uniformly distributed Ch nanoparticles with good sphericity and control which have been verified using DLS, SEM, AFM, and fluorescence microscopy. The present study provides an understanding of forces governing the complexation behavior of Ch with surface active ILs and their efficacy to produce Ch nanoparticles. 23597859 Hemodialysis for the treatment of pulmonary hemorrhage from dabigatran overdose. Dabigatran is an oral direct thrombin inhibitor indicated for thromboembolism prophylaxis in patients with nonvalvular atrial fibrillation. Since its approval in the United States in 2010, dabigatran-associated hemorrhages have garnered much attention because bleeding rates were higher than initially expected. Additionally, reversing anticoagulation remains challenging. Traditional modes of reversing warfarin-associated coagulopathies are ineffective in reversing anticoagulation from dabigatran. Although hemodialysis is proposed as a method to accelerate dabigatran elimination, evidence supporting its clinical utility remains unproved. We report the case of an 80-year-old man who presented with worsening hemoptysis in the setting of unintentional ingestion of excess dabigatran. Despite transfusion of 2 units of fresh frozen plasma, he continued to bleed, although his international normalized ratio improved from 8.8 to 7.2. He underwent hemodialysis, and serum dabigatran concentration decreased from 1,100 to 18 ng/mL over 4 hours, with an initial extraction ratio of 0.97 and blood clearance of 291 mL/min. Although his serum dabigatran concentration rebounded to 100 ng/mL 20 minutes after the cessation of dialysis, his bleeding stopped and he improved clinically. Hemorrhage in the setting of dabigatran anticoagulation remains a therapeutic predicament. Hemodialysis may play an adjunct role in accelerating the elimination of dabigatran in bleeding patients. 23910804 Neonatal lupus erythematosus complicated by improved congenital complete heart block. Complete congenital heart block (CCHB) accompanied with neonatal lupus erythematosus is caused by an immune reaction between maternal anti-Ro/SSA antibodies and the fetal heart and is generally considered an irreversible process. This reaction mostly occurs before 30 weeks' gestation, especially between the 20th and 24th week. Reported here is an atypical case of neonatal lupus erythematosus with CCHB detected after 32 weeks' gestation that showed postnatal improvement in the degree of heart block after preterm delivery and immunoglobulin use. The clinical condition of the infant worsened with an increase in heart rate due to possible cardiomyopathy induced by the immune reaction. 23871158 Leukemia associated mutant Wilms' tumor gene 1 protein promotes expansion of human hematopoietic progenitor cells. The transcription factor Wilms' tumor gene 1 (WT1) is highly expressed in the majority of leukemias, suggesting a role in leukemogenesis. Acquired WT1 mutations are reported as an independent predictor of poor clinical outcome, and mutations resulting in deletion of the entire DNA-binding zinc-finger domain (WT1delZ), is the most common type. The aim of this study was to study cellular effects of WT1(delZ) that may contribute to an oncogenic phenotype. We found that expression of WT1(delZ) supported proliferation of human hematopoietic CD34(+) progenitor cells. Moreover, WT1(delZ) transduced cells expressed erythroid markers, including raised levels of STAT5, independently of addition of erythropoietin. At the global gene expression level, WT1(delZ) caused upregulation of genes related to cell division and genes associated with erythroid maturation, in the absence of added erythropoietin. Our results indicate that WT1(delZ) promotes cell proliferation and expansion of progenitor cells, consistent with a possible role in leukemogenesis. 23160981 The novel Fh8 and H fusion partners for soluble protein expression in Escherichia coli: a comparison with the traditional gene fusion technology. The Escherichia coli host system is an advantageous choice for simple and inexpensive recombinant protein production but it still presents bottlenecks at expressing soluble proteins from other organisms. Several efforts have been taken to overcome E. coli limitations, including the use of fusion partners that improve protein expression and solubility. New fusion technologies are emerging to complement the traditional solutions. This work evaluates two novel fusion partners, the Fh8 tag (8 kDa) and the H tag (1 kDa), as solubility enhancing tags in E. coli and their comparison to commonly used fusion partners. A broad range comparison was conducted in a small-scale screening and subsequently scaled-up. Six difficult-to-express target proteins (RVS167, SPO14, YPK1, YPK2, Frutalin and CP12) were fused to eight fusion tags (His, Trx, GST, MBP, NusA, SUMO, H and Fh8). The resulting protein expression and solubility levels were evaluated by sodium dodecyl sulfate polyacrylamide gel electrophoresis before and after protein purification and after tag removal. The Fh8 partner improved protein expression and solubility as the well-known Trx, NusA or MBP fusion partners. The H partner did not function as a solubility tag. Cleaved proteins from Fh8 fusions were soluble and obtained in similar or higher amounts than proteins from the cleavage of other partners as Trx, NusA or MBP. The Fh8 fusion tag therefore acts as an effective solubility enhancer, and its low molecular weight potentially gives it an advantage over larger solubility tags by offering a more reliable assessment of the target protein solubility when expressed as a fusion protein. 23935729 Correlation between inflammatory factors and post-stroke pneumonia in diabetic patients. Pneumonia is the most common cause of mortality in stroke patients and it has been demonstrated to contribute to mortality and poor functional outcome following stroke in the majority of clinical studies. The risk of infection may be attributed to stroke-induced immunodepression syndrome (SIDS). Cytokine production is increased in SIDS. However, the correlation between biomarkers and the risk of post-stroke pneumonia in patients with diabetes mellitus is not clear. The aim of this study was to determine the correlation between pneumonia and the levels of C-reactive protein (CRP) and interleukin-6 (IL-6), as well as to identify early predictors of pneumonia in acute ischemic stroke patients with diabetes mellitus. Additionally, we investigated the impact of pneumonia on functional outcome after 1 month. A total of 106 ischemic stroke patients with diabetes mellitus who were admitted after the onset of symptoms were included in the study. They were divided into two groups, the pneumonia and non-pneumonia groups. CRP, IL-6, white blood cells (WBCs), mean body temperature and National Institutes of Health Stroke Scale (NIHSS) score were measured at the time of admission. The modified Rankin Scale score was assessed at 30 days. The levels of IL-6, CRP and WBCs, as well as mean body temperature were significantly higher in the patients with pneumonia than in the patients without pneumonia. There were also significant differences between the pneumonia and non-pneumonia groups in age, admission NIHSS score, length of hospital stay and dysphagia. Pneumonia patients had worse outcomes compared with patients without pneumonia at 1 month. Age, NIHSS score and dysphagia were significantly associated with pneumonia. WBCs and mean body temperature were not significant predictors of pneumonia. Older patients with more severe ischemic stroke are more susceptible to the development of pneumonia during the stay in hospital. Pneumonia contributes to poor functional outcome. IL-6, CRP, age, NIHSS score and dysphagia may predict the occurrence of pneumonia on the day of stroke symptom onset. 23924587 Baseline CD4+ T-Cell Counts Predict HBV Viral Kinetics to Adefovir Treatment in Lamivudine-Resistant HBV-Infected Patients with or without HIV Infection. Background: Coinfection with HIV and hepatitis B virus (HBV) substantially alters the course of HBV. Directly acting anti-HBV agents suppress HBV viral levels; however, the kinetics of HBV decline in mono- and coinfected persons have not been evaluated. We investigated the role of baseline CD4+ T-cell counts as a predictor of HBV response to adefovir (ADV) therapy in chronic HBV with and without HIV coinfection. Methods: We conducted a double-blind, randomized, placebo-controlled study of HIV-infected (n = 12) and uninfected (n = 5) chronic HBV patients treated with ADV. Five HIV uninfected patients received ADV; the HIV+ patients received ADV or placebo for a total of 48 weeks. At the end of 48 weeks, all patients received open-label ADV for an additional 48 weeks. HBV, HIV viral loads, CD4+ T-cell counts, and safety labs were performed on days 0, 1, 3, 5, 7, 10, 14, and 28 and then every 4 weeks. Results: Lower HBV slopes were observed among coinfected compared to monoinfected patients (P = .027 at 4 weeks, P = .019 at 24 weeks, and P = .045 at 48 weeks). Using a mixed model analysis, we found a significant difference between the slopes of the 2 groups at 48 weeks (P = .045). Baseline CD4+ T-cell count was the only independent predictor of HBV decline in all patients. Conclusion: HIV coinfection is associated with slower HBV response to ADV. Baseline CD4+ T-cell count and not IL28B genotype is an independent predictor of HBV decline in all patients, emphasizing the role of immune status on clearance of HBV. 23934446 Carcinosarcoma in a White Rhinoceros (Ceratotherium simum simum). In Rhinocerotidae, there are very few reports of tumors and no reports of a mixed tumor. This paper reports the case of a male 33-year-old southern white rhinoceros. Grossly, there were two masses in the coelomic cavity and solid nodules in the liver. Histologically, all tumors had a biphasic pattern that consisted of malignant epithelial cells (cytokeratin- and E-cadherin-positive) and non-epithelial cells (vimentin-positive) with cartilage. In this case, the prostate could not be identified, and instead, the largest tumor mass was present at that site. Furthermore, since structures regarded as the prostate duct remained in this tumor, we considered that this tumor was very likely to be of prostate gland origin. This case is the first report of carcinosarcoma in Rhinocerotidae. 23953436 Identification of selenium-containing proteins in HEK 293 kidney cells using multiple chromatographies, LC-ICPMS and nano-LC-ESIMS. Our previous studies using HeLa and HEK 293 cells demonstrated that selenomethionine, SeMet, exerts more of an antagonistic effect on arsenic than other selenium species. These studies attributed the antagonistic effect of SeMet to decreased levels of reactive oxygen species, ROS, changes in protein phosphorylation and possible incorporation of SeMet into proteins. The present study employs a metallomics approach to identify the selenium-containing proteins in HEK 293 cells raised with SeMet. The proteins were screened and separated using two dimensional high performance liquid chromatography (HPLC)-inductively coupled plasma mass spectrometry (ICPMS), size exclusion chromatography (SEC) and reversed-phase chromatography (RPC). The Se-containing proteins were identified by peptide mapping using nano-HPLC-Chip-electrospray ionization mass spectrometry (ESIMS). 23567036 Commonly used metal and crystalline salts in South African traditional medicine. ETHNOPHARMACOLOGICAL RELEVANCE: Traditional medicines in the form of plants, animals and/or minerals are used by millions of South Africans. There is currently no data regarding the commonly used mineral elements thus the potential benefits or hazards of such products remain unclear. MATERIALS AND METHODS: Metal and crystalline salts were purchased from a rural market (Nongoma, Zululand, South Africa). Information regarding the colloquial name, price and weight was recorded. Energy dispersive X-ray spectroscopy (EDX) was used to quantatively determine the unknown salts. RESULTS: Six widely available salts were analyzed. Ndonya, as it is colloquially known, refers to two products which look identical to the untrained eye-one is dyed table salt and the other is hexavalent chromium. A further product used medicinally, although not widely available, was identified as iron chromite ore. CONCLUSIONS: The array of substances documented, ranging from benign to carcinogenic, stresses the importance of documenting components used in traditional medicine and confirms the necessity to regulate South Africa traditional medicine. Healthcare workers should be aware of the complexities of using such metal salt. 23755936 How do different concentrations of Clostridium perfringens affect the quality of extended boar spermatozoa? Bacteriospermia in boar fresh and extended semen is a frequent finding that produces alterations on sperm quality and, consequently, causes economic losses in artificial insemination (AI) centres. The present study sought to evaluate the effect of different infective concentrations of Clostridium perfringens on boar sperm quality, assessed as sperm motility (CASA), morphology and viability, through 11 days of storage at 15°C (experiment 1), and after 96h of incubation at 37°C (experiment 2). With this purpose, different seminal doses were artificially inoculated with different infective concentrations of C. perfringens, ranging from 10(2) to 10(8)cfumL(-1). The negative controls were non-inoculated doses. Sperm quality was checked after 0, 1, 2, 3, 4, 7, 8, 9, 10 and 11 days of storage at 15°C in experiment 1, and after 0, 24, 48, 72 and 96h at 37°C in the second experiment. Moreover, the presence/absence of bacteria was detected by PCR analyses during both experiments at different time points. In both experiments, sperm morphology of inoculated samples did not differ from the negative control. Conversely, detrimental effects on sperm viability and motility were observed after 24h of incubation/storage at the highest infective concentrations in both experiments. The deleterious effects observed because of the presence of C. perfringens in semen emphasise the relevance of detecting bacteria in extended doses destined to AI. So, this study suggests that the evaluation of bacterial contamination in semen is a procedure that should be routinely applied while assessing sperm quality in AI centres to avoid the use of doses with low sperm quality and the possible spread of bacterial contaminants. 23445460 Magnetic resonance laparoscopy: A new non-invasive technique for the assessment of chronic viral liver disease. Laparoscopy-guided liver biopsy is the most accurate method for assessing liver fibrosis but have several limitations. We designed a non-invasive method, called magnetic resonance laparoscopy (MRL), based on gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging, to assess liver fibrosis in patients with chronic hepatitis B and C virus. We prospectively analyzed 49 patients with normal liver and 353 patients with chronic viral hepatitis, laparoscopic liver biopsy was performed on 109 patients and 244 patients were diagnosed as having liver cirrhosis clinically. The MRL findings of the liver surface were classified into three categories: (i) smooth (essentially smooth surface of the entire liver or with limited areas of depression); (ii) partially irregular (several interconnected depressions on the surface mainly in the left lobe of the liver); and (iii) diffusely irregular (nodules present on the liver surface). Patients with diffusely irregular liver surface was diagnosed as liver cirrhosis. The liver surface changed with the progression of liver fibrosis from smooth, partially irregular to diffusely irregular, irrespective of viral type. The sensitivity, specificity, positive and negative predictive values for the diagnosis of cirrhosis according to the surface findings on MRL were 96%, 100%, 95% and 95%, respectively. The cirrhotic liver showed: (i) disappearance of impression of the right ribs; (ii) enlargement of the lateral segment; and (iii) atrophy of the right lobe according to Child-Pugh classification. Our data indicated that MRL is a potentially useful non-invasive examination for evaluation of liver fibrosis associated with viral hepatitis. 23265485 Characterization of modified high-amylose maize starch-α-naphthol complexes and their influence on rheological properties of wheat starch. Amylose can form inclusion complexes with diverse small molecules. Modified starch has different and unique properties compared with its native counterpart. In this study, chemically/enzymatically modified high-amylose maize starches were used to make inclusion complexes with α-naphthol, and the physical properties of complexes and their influences on the rheology of wheat starch were characterized. The results showed that modification of starch had little influence on the wide angle X-ray diffraction pattern of complex (eightfold single helix), but did so on the complexation index and precipitation yield. Inclusion complexes with chemically modified starch showed a lower range of thermostability and recrystallization temperatures. Addition of complex considerably influenced the rheological properties of wheat starch, and the effect was dependent on the type of modified starch used. It may be concluded that starch inclusion complexes, with a range of properties and potential food applications, may be feasibly prepared by using diverse modified high-amylose maize starches. 23849279 Precursors to overnutrition: The effects of household market food expenditures on measures of body composition among Tsimane' adults in lowland Bolivia. Nutrition transitions are characterized by shifts in diet and activity levels that lead to changes in weight and body fatness over a relatively short time. Research has linked these nutritional shifts to socio-economic factors, including wealth and income. However, few studies have examined household spending patterns on market foods among subsistence populations, which may reveal food access, choice, and indicate household nutritional environment. This paper examines the relation between household monetary expenditures on "market" foods and measures of body composition among Tsimane', a forager-horticulturalist indigenous group in the Bolivian Amazon. Economic and anthropometric surveys were conducted for adults (n = 1199) 16 years or older in 563 households in 40 Tsimane' villages in 2008. Results indicate that overweight status (19% of men and 24% of women) is more common than obesity (1% of men and 4% of women). Sixty-one percent (61%) of households reported purchasing market foods during the previous week. Multiple linear and logistic regressions suggest that men living in households in the top third of monetary expenditures on market foods had significantly higher BMI (0.69 kg/m(2); p = 0.027), weight (1.80 kg; p = 0.048), percent body fat (1.06%; p = 0.025), and probability of being overweight/obese (Odds ratio = 1.83; p = 0.042) than men in households that reported not spending money on market foods in the previous week. We discuss the possibility that the division of labor may help explain the differences between men and women in this sample. This research suggests household expenditures on market foods may mediate the relation between wealth and body composition. 23262269 Phenylethanoid glycosides from the stems of Callicarpa peii (hemostatic drug). Two new trisaccharide intermediates of phenylethanoid glycosides, peiioside A(1)/A(2) (1a/1b) and peiioside B (2), were isolated from the n-BuOH fraction of MeOH extract of the stems of Callicarpa peii H.T. Chang, together with five biogenetic relevant known compounds 3-7. The structures of compounds 1 and 2 were elucidated by extensive spectroscopic methods (especially 2D-NMR techniques) and acid-catalyzed hydrolysis as O-α-l-rhamnopyranosyl-(1″→3')-O-[β-d-apiofuranosyl-(1‴→6')] -4'-O-[(E)-caffeoyl]-d-glucopyranoside] (1a/1b), 3,4-dihydroxy-β-phenylethoxy-O-[β-d-apiofuranosyl-(1‴→6')-α-l-rhamnopyranosyl-(1″→3')-O-β-d-glucopyranoside] (2), respectively. On the basis of the isolated compounds, a presumable biogenetic pathway of the biologically interesting phenylethanoid glycosides about forsythoside B (3) and acteoside (4) isolated from this species was proposed. Isolation of five related intermediates (1-2, 5-7) provided further support for the biogenetic path. This is the first report about phytochemical research on C. peii and the biogenetic hypothesis of forsythoside B and acteoside. 23867757 Zoledronic Acid Inhibits Human Osteoblast Activities. Background: Bisphosphonates are potent inhibitors of bone resorption. These kinds of drugs, which are used for the treatment of osteolytic diseases, have been associated with the occurrence of oral osteonecrosis, especially in patients over 60 years old. Current studies have demonstrated that the cytotoxic effects of bisphosphonates on osteoblasts play an important role in oral osteonecrosis development. Objective: The aim of this study was to evaluate the effect of long-term application of a highly potent bisphosphonate - zoledronic acid (ZA) - on human osteoblasts in vitro. Methods: Human osteoblasts (MG63 cell line) were seeded for 72 h in wells of 24-well plates. The Dulbecco's modified Eagle's medium (DMEM) was then replaced by culture medium without fetal bovine serum (FBS), and the cells were incubated for an additional 24 h, after which ZA was added to the DMEM without FBS and incubated in contact with osteoblasts for 7, 14 or 21 days. Cell viability (CV), total protein production (TPP), alkaline phosphatase (ALP) activity, mineral nodule formation (MNF), and gene expression of ALP and osteocalcin (OCN), as well as cell morphology by scanning electronic microscopy, were evaluated. Data were statistically analyzed by Kruskal-Wallis and Mann-Whitney tests, with a significance level of 5%. Results: The cytotoxic effects of ZA on osteoblasts were characterized by reduction of CV, TPP, ALP and MNF production. In addition, ZA MNF caused a decrease in gene expression of ALP and OCN, as well as intense cell morphology alterations. All these negative effects of ZA were concentration and period dependent. Conclusion: Both concentrations of ZA (1 and 5 μM) caused cytotoxic effects to osteoblasts which reduced the production and expression of proteins that play an important role in bone matrix synthesis and mineralization. © 2013 S. Karger AG, Basel. 23921659 Quantitative interaction screen of telomeric repeat-containing RNA reveals novel TERRA regulators. Telomeres are actively transcribed into telomeric repeat-containing RNA (TERRA), which has been implicated in the regulation of telomere length and heterochromatin formation. Here, we applied quantitative mass spectrometry (MS)-based proteomics to obtain a high confidence interactome of TERRA. Using SILAC-labeled nuclear cell lysates in an RNA pull-down experiment, and two different salt conditions, we distinguished 115 proteins binding specifically to TERRA out of a large set of background binders. While TERRA binders identified in two previous studies showed little overlap, using quantitative mass spectrometry we obtain good overlap to both studies. To test whether novel candidates found here are involved in TERRA regulation, we performed an esiRNA-based interference analysis for 15 of them. Knock-down of ten proteins significantly affected total cellular levels of TERRA and RNAi of five candidates perturbed TERRA recruitment to telomeres. Notably, depletion of SRRT/Ars2, involved in miRNA processing, up-regulated both total and telomere-bound TERRA. Conversely, knock-down of MORF4L2, a component of the NuA4 histone acetyltransferase complex, reduced TERRA levels both globally and for telomere-bound TERRA. We thus identified new proteins involved in the homeostasis and telomeric abundance of TERRA, extending our knowledge of TERRA regulation. 23799802 Ortho- and para-selective ruthenium-catalyzed C(sp2)-H oxygenations of phenol derivatives. Versatile ruthenium catalysts allowed for efficient direct oxygenations of aryl carbamates under remarkably mild reaction conditions. In addition to chelation-assisted C-H activation, the optimized ruthenium catalyst proved amenable to para-selective hydroxylations of anisoles without Lewis basic directing groups. 23063595 Multifunctional targets of dietary polyphenols in disease: a case for the chemokine network and energy metabolism. Chronic, non-acute inflammation is behind conditions that represent most of the disease burden in humans and is clearly linked to immune and metabolic mechanisms. The convergence of pathways involving the immune response, oxidative stress, increased circulating lipids and aberrant insulin signaling results in CCL2-associated macrophage recruitment and altered energy metabolism. The CCL2/CCR2 pathway and the energy sensor AMP-activated protein kinase (AMPK) are attractive therapeutic targets as a part of preventive management of disease. Several effects of polyphenols are useful in this scenario, including a reduction in the activities of cytokines and modulation of cellular metabolism through histone deacetylase inhibitors, AMPK activators, calorie-restriction mimetics or epigenetic regulators. Research is currently underway to develop orally active drugs with these effects, but it is convenient to examine more closely what we are eating. If a lack of relevance in terms of toxicity and substantial effectiveness are confirmed, plant-derived components may provide useful druggable components and dietary supplements. We consider therapeutic actions as a combination of synergistic and/or antagonistic interactions in a multi-target strategy. Hence, improvement in food through enrichment with polyphenols with demonstrated activity may represent a major advance in the design of diets with both industrial and sanitary value. 23625269 Spironolactone inhibits apoptosis in rat mesangial cells under hyperglycaemic conditions via the Wnt signalling pathway. Mesangial cells (MCs) play a crucial role in maintaining structure and function of glomerular tufts, providing structural support for capillary loops and modulating glomerular filtration by their contractility. MCs apoptosis occurs in experimental diabetic nephropathy, and this correlates with worsening albuminuria. Accumulating evidence suggests that mineralocorticoid receptor (MR) blockade effectively reduces proteinuria in diabetic nephropathy; however, it is rarely known whether spironolactone (SPI), a nonspecific MR antagonist, inhibits apoptosis in MCs under hyperglycaemic conditions. The objectives of this study are to determine the relationship between SPI and apoptosis, and investigate the cell signalling pathway by which SPI inhibits apoptosis. Rat MCs were treated with 30 mM D-glucose and 10(-8), 10(-7) or 10(-6) M aldosterone (ALD) for 24 h. In some experiments, MCs were pretreated with 10(-7) M SPI or 10 mM LiCl for 1 h. Apoptosis was evaluated by cell nucleus staining and flow cytometric analyses, and caspase-3 activity was assayed. Gene and protein expression were quantified using quantitative real-time PCR and Western blotting, respectively. SPI directly inhibited high glucose and ALD-induced MCs apoptosis in a caspase-dependent manner. Importantly, SPI inhibited MCs apoptosis via the Wnt signalling pathway. SPI promoted activation of the Wnt signalling pathway in MCs, leading to upregulation of Wnt4 and Wnt5a mRNA expression, decreased GSK-3β protein expression and increased β-catenin protein expression. As a conclusion, this study suggests that SPI may inhibit apoptosis in MCs during hyperglycaemic conditions via the Wnt signalling pathway. Blockade of the ALD system may represent a novel therapeutic strategy to prevent MCs injury under hyperglycaemic conditions. 23947913 pH-Sensitive micelles for targeted drug delivery prepared using a novel membrane contactor method. A novel membrane contactor method was used to produce size-controlled poly(ethylene glycol)-b-polycaprolactone (PEG-PCL) copolymer micelles composed of diblock copolymers with different average molecular weights, Mn (9200 or 10400 Da) and hydrophilic fractions, f (0.67 or 0.59). By injecting 570 l m-2 h-1 of the organic phase (a 1 mg ml-1 solution of PEG-PCL in tetrahydrofuran) through a microengineered nickel membrane with a hexagonal pore array and 200 μm pore spacing into deionized water agitated at 700 rpm, the micelle size linearly increased from 92 nm for a 5-μm pore size to 165 nm for a 40-μm pore size. The micelle size was finely tuned by the agitation rate, transmembrane flux and aqueous to organic phase ratio. An encapsulation efficiency of 89 % and a drug loading of ∼75 % (w/w) were achieved when a hydrophobic drug (vitamin E) was entrapped within the micelles, as determined by ultracentrifugation method. The drug-loaded micelles had a mean size of 146 ± 7 nm, a polydispersity index of 0.09 ± 0.01, and a zeta potential of -19.5 ± 0.2 mV. When drug-loaded micelles where stored for 50 h, a pH sensitive drug release was achieved and a maximum amount of vitamin E (23 %) was released at the pH of 1.9. When a pH-sensitive hydrazone bond was incorporated between PEG and PCL blocks, no significant change in micelle size was observed at the same micellization conditions. 23674393 Comparative analysis of reference gene stability in human mesenchymal stromal cells during osteogenic differentiation. Mesenchymal stromal cells (MSCs) are one of the most frequently used cell sources for tissue engineering strategies. Cultivation of osteogenic MSCs is a prerequisite for cell-based concepts that aim at bone regeneration. Quantitative real time reverse transcription polymerase chain reaction (qRT-PCR) analysis is a commonly used method for the examination of mRNA expression levels. However, data on suitable reference genes for osteogenically cultivated MSCs is scarce. Hence, the aim of the study was to compare the regulation of different potential reference genes in osteogenically stimulated MSCs. Human MSCs were isolated from bone marrow aspirates of N = 6 hematologically healthy individuals, expanded by polystyrene-adherence, and maintained with and without osteogenic supplements for 14 days. Cellular proliferation and osteogenic differentiation were assessed by total DNA quantification, cell-specific alkaline phosphatase (ALP) activity and by qualitative staining for ALP and alizarin red, respectively. mRNA expression levels of N = 32 potential reference genes were quantified using the human Endogenous Control TaqMan® assays. mRNA expression stability was calculated using geNorm. The combined use of the most stable reference genes and DNA-damage-inducible alpha, Pumilio homolog 1, and large ribosomal protein P0 significantly improved gene expression accuracy as compared to the use of the commonly used reference genes beta actin and glyceraldehyde-3-phosphate dehydrogenase during qRT-PCR-based target gene expression analysis of osteogenically stimulated MSCs. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 29:1034-1042, 2013. 22332833 Aromatic profiling of wild and rare species growing in Turkey: hypericum aviculariifolium Jaub. and Spach subsp. depilatum (Freyn and Bornm.) Robson var. depilatum and Hypericum pruinatum Boiss. and Bal. The volatile constituents of the rare species of Hypericum, namely Hypericum pruinatum (as one population) and Hypericum aviculariifolium subp. depilatum var. depilatum (endemic, as two populations namely 'Gümüş' and 'Yeniköy') growing wild in the mountainous parts of Northern Turkey were studied for the first time. The essential oils (EOs) were extracted by hydrodistillation of the air-dried aerial parts and analysed by GC-FID and GC-MS. A total of 56, 49 and 50 EO components representing 98.2%, 96.9% and 99.4% of the total composition were identified respectively from one population for H. pruinatum and two populations for Hypericum aviculariifolium subp. depilatum var. depilatum. GC-MS profiles showed significant compositional variations not only between the two Turkish species, but also between the two populations of the same species highlighting the importance of genetic factors affecting secondary metabolite profile. 23913137 Is approximate numerical judgment truly modality-independent? Visual, auditory, and cross-modal comparisons. The numerosity of any set of discrete elements can be depicted by a genuinely abstract number representation, irrespective of whether they are presented in the visual or auditory modality. The accumulator model predicts that no cost should apply for comparing numerosities within and across modalities. However, in behavioral studies, some inconsistencies have been apparent in the performance of number comparisons among different modalities. In this study, we tested whether and how numerical comparisons of visual, auditory, and cross-modal presentations would differ under adequate control of stimulus presentation. We measured the Weber fractions and points of subjective equality of numerical discrimination in visual, auditory, and cross-modal conditions. The results demonstrated differences between the performances in visual and auditory conditions, such that numerical discrimination of an auditory sequence was more precise than that of a visual sequence. The performance of cross-modal trials lay between performance levels in the visual and auditory conditions. Moreover, the number of visual stimuli was overestimated as compared to that of auditory stimuli. Our findings imply that the process of approximate numerical representation is complex and involves multiple stages, including accumulation and decision processes. 23920242 Novel angiotensin I-converting enzyme inhibitory peptides from enzymatic hydrolysates of goby (Zosterisessor ophiocephalus) muscle proteins. In recent years, food protein-derived bioactive peptides have received considerable attention because of their numerous health benefits. Amongst bioactive peptides, those with antihypertensive activity are receiving special attention due to their role in cardiovascular diseases. Goby protein hydrolysates (GPHs) prepared by treatment with five different crude bacterial proteases were found to exhibit varying degrees of angiotensin I-converting enzyme (ACE) inhibitory activity. The hydrolysate generated by the crude protease from Bacillus mojavensis A21, which displayed the highest ACE inhibitory activity, was further fractionated by size exclusion chromatography on a Sephadex G-25 and reversed-phase high performance liquid chromatography (RP-HPLC). The molecular masses and amino acid sequences of five peptides, in sub-fraction F5-2, which exhibited the highest ACE inhibitory activity, were determined using ESI-MS and ESI-MS/MS, respectively. The structures of these peptides were identified as Ala-Arg-Ser, Val-Val-Ala-Pro-Phe-Ala-His-Gly-Thr, Arg-Ser-Thr-Ala, Phe-Tyr-Pro-Pro, Arg-Cys-Ser-Ala-Gly-Val. Further, the sequences of fifteen peptides in the F5-4 sub-fraction, which exhibited high activity, were determined. Therefore, GPHs have a potential as hypotensive nutraceutical ingredients. Peptides find many outlets of application in the biotechnological field, amongst which are pharmaceutical applications. Progression amongst new small molecules deposited like substance medicamentous blows itself. In this context, large pharmaceutical companies invest in peptide research to open therapeutic new prospects. Even if they are used as therapeutic agents for nearly one century in their natural form, the use of peptides remains parsimonious although we experienced a significant development since a few tens of years, in particular thanks to the clarification of the methods of production, chemical in solid or biological phase such as in phage display. Peptides present many advantages compared to traditional drugs that have small molecules, Generation of bioactive peptides by proteolysis of food proteins, using exogenous proteases, is a new and interesting approach for the production and identification of new and potent specific hypotensive agents. From another side, compared with natural peptides isolated from different sources, there is more diversity in structure and mode of action of the derived bioactive peptides. In fact, proteolysis of protein substrates, having different amino acid composition and sequences, by proteases having different specificities may generate numerous specific peptide inhibitors, with different lengths and amino acid sequences. These bioactive peptides have received considerable attention for their effectiveness in both the prevention and the treatment of hypertension. 23407160 Iatrogenic acute aortic dissection type A: insight from the German Registry for Acute Aortic Dissection Type A (GERAADA). Previous investigators have reported a grave prognosis for iatrogenic acute aortic dissection (iAADA), but such studies are limited by their small sample sizes. The purpose of the current study was to analyse the clinical characteristics, current management and surgical outcomes in a large number of iAADA patients identified through a multicentre registry. Between July 2006 and June 2010, 50 centres participated in the German Registry for Acute Aortic Dissection Type A (GERAADA). Of the 2137 patients included, 100 (5%) had iAADA. We compared the clinical features and 30-day outcomes of patients with iatrogenic and spontaneous acute aortic dissection type A (sAADA). Patients with iAADA were older than those with sAADA (67.7 ± 9.4 vs 60.1 ± 13.7 years, P < 0.0001). Preoperative cardiac tamponade and hemiplegia or hemiparesis were less frequently observed in patients with iAADA (10 vs 21%, P = 0.003; 1 vs 7%, P = 0.04). Aortic dissection extended to the supra-aortic vessels (19 vs 38%, P = 0.0005) and to iliac arteries (7 vs 25%, P = 0.0002) less frequently in iAADA patients. Those with iAADA were less likely to undergo complex aortic surgery with composite graft implantation (8 vs 20%, P = 0.02), hemiarch (38 vs 47%, P = 0.04) or total arch replacement (9 vs 17%, P = 0.07). The rate of new onset of hemiplegia or hemiparesis after surgery was also lower in iAADA patients (4 vs 10%, P = 0.05). Thirty-day mortality did not differ between the two groups (16 vs 17% for iAADA vs sAADA, P = 0.53). Early-term surgical outcomes in current iAADA patients are better than those reported previously. Immediate surgical therapy results in acceptable outcomes similar to those in naturally occurring aortic dissection. 23707924 Development and validation of a quantitation assay for fluorescently tagged HIV-1 virus-like particles. Upon expression, the Gag polyprotein of HIV-1 assembles spontaneously in the vicinity of the plasma membrane giving rise to enveloped virus-like particles (VLPs). These particulate immunogens offer great promise as HIV-1 vaccines. Robust VLP production and purification processes are required to generate VLPs of sufficient quality and quantity for both pre-clinical and clinical evaluation. The availability of simple, fast and reliable quantitation tools is critical to develop, optimize and monitor such processes. Traditionally, enzyme-linked immunosorbent assays (ELISA) are used to quantify p24 antigen concentrations, which reflect tightly virus particle concentrations. However, this quantitation technique is not only time-consuming, laborious and costly but it is also prone to methodological variability. As an alternative, the development and validation of a fluorescence-based quantitation assay for Gag VLPs is presented here. A Gag polyprotein fused to the enhanced green fluorescent protein was used for generation of fluorescent VLPs. A purified standard reference Gag-GFP VLP material was prepared and characterized in house. The method was validated according to ICH guidelines. The validation characteristics evaluated included accuracy, precision, specificity, linearity, range and limit of detection. The method showed to be specific for Gag-GFP. The fluorescence signal correlated well with p24 concentrations measured using a reference p24 ELISA assay. The method showed little variability compared to ELISA and was linear over a 3-log range. The limit of detection was ∼10ng of p24/mL. Finally, fluorescence-based titers were in good agreement with those obtained using transmission electron microscopy and nanoparticle tracking analysis. This simple, rapid and cost-effective quantitation assay should facilitate development and optimization of bioprocessing strategies for Gag-based VLPs. 22750078 The novel phosphodiesterase 10A inhibitor THPP-1 has antipsychotic-like effects in rat and improves cognition in rat and rhesus monkey. Phosphodiesterase 10A (PDE10A) is a novel target for the treatment of schizophrenia that may address multiple symptomatic domains associated with this disorder. PDE10A is highly expressed in the brain and functions to metabolically inactivate the important second messengers cAMP and cGMP. Here we describe effects of a potent and orally bioavailable PDE10A inhibitor [2-(6-chloropyridin-3-yl)-4-(2-methoxyethoxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl](imidazo[1,5-a]pyridin-1-yl)methanone] (THPP-1) on striatal signaling pathways, in behavioral tests that predict antipsychotic potential, and assays that measure episodic-like memory in rat and executive function in rhesus monkey. THPP-1 exhibits nanomolar potency on the PDE10A enzyme, demonstrates excellent pharmacokinetic properties in multiple preclinical animal species, and is selective for PDE10A over other PDE families of enzymes. THPP-1 significantly increased phosphorylation of proteins in the striatum involved in synaptic plasticity, including the a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor (AMPA) GluR1 subunit, extracellular receptor kinase (ERK), and cAMP-response element binding protein (CREB). THPP-1 produced dose-dependent effects in preclinical assays predictive of antipsychotic activity including attenuation of MK-801-induced psychomotor activation and condition avoidance responding in rats. At similar plasma exposures, THPP-1 significantly increased object recognition memory in rat and attenuated a ketamine-induced deficit in the object retrieval detour task in rhesus monkey. These findings suggest that PDE10A inhibitors have the potential to impact multiple symptomatic domains of schizophrenia including positive symptoms and cognitive impairment. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23954711 Relationship between plasma mid-regional pro-adrenomedullin level and resistance to antihypertensive therapy in stable kidney transplant recipients. We investigated the relationship between plasma mid-regional pro-adrenomedullin (MR-proADM)-like immunoreactive substance (IS) level and clinical characteristics associated with renal failure or resistance to antihypertensive therapy in stable kidney transplant recipients. Forty-six Japanese kidney transplant recipients who underwent transplantation more than 90 days prior to the study were included. To evaluate resistance to antihypertensive therapy, we calculated the treatment intensity score of the antihypertensive drugs in each recipient. Morning blood samples were collected and plasma MR-proADM-IS levels were measured using an enzyme immunoassay. A significant correlation was observed between plasma MR-proADM-IS level with creatinine clearance or treatment intensity score. Multiple regression analysis identified plasma MR-proADM level and body mass index as significant independent factors associated with treatment intensity score. Plasma MR-proADM level may be a useful biomarker indicating the degree of resistance to antihypertensive therapy. 23851037 "Can you send an ambulance please?": a comparison of callers' requests for emergency medical dispatch in non-stroke and stroke calls. Identifying 'true stroke' from an emergency medical services (EMS) call is challenging, with over 50% of strokes being misclassified. In a previous study, we examined the relationship between callers' descriptions of stroke symptoms to the emergency medical dispatcher and the subsequent classification and prioritisation of EMS response. The aim of this subsequent study was to explore further the use of keywords by callers when making emergency calls, comparing stroke and non-stroke calls. All non-stroke calls to one EMS dispatch centre between 8 March 2010 and 14 March 2010 were analysed. These were compared with the stroke calls made to one EMS dispatch centre between 1 October 2006 and 30 September 2007. Content analysis was used to explore the problems described by the caller, and findings were compared between non-stroke and stroke calls. 277 non-stroke calls were identified. Only eight (3%) callers mentioned stroke, 12 (4%) and 11 (4%) mentioned limb weakness and speech problems, respectively, while no caller mentioned more than one classic stroke symptom. This contrasted with 473 stroke calls, where 188 (40%) callers mentioned stroke, 70 (15%) limb weakness and 72 (15%) speech problems, and 14 (3%) mentioned more than one classic stroke symptom. People who contact the EMS about non-stroke conditions rarely say stroke, limb weakness, speech problems or facial weakness. These words are more frequently used when people contact the EMS about stroke, although many calls relating to stroke patients do not mention any of these keywords. 23962203 Host signature effect on plant root-associated microbiomes revealed through analyses of resident vs. active communities. Plant roots create specific microbial habitat in the soil - the rhizosphere. In this study, we characterized the rhizosphere microbiome of four host plant species to get insight into the impact of the host (host signature effect) on resident vs. active communities. Results show a distinct plant host specific signature found among wheat, maize, tomato and cucumber, based on the following three parameters: (i) each plant promoted the activity of a unique suite of soil bacterial populations; (ii) significant variations were observed in the number and the degree of dominance of active populations; and (iii) the level of contribution of active (rRNA-based) populations to the resident (DNA-based) community profiles. In the rhizoplane of all four plants, a significant reduction of diversity was observed, relative to the bulk soil. Moreover, an increase in DNA-RNA correspondence indicated higher representation of active bacterial populations in the residing rhizoplane community. This study demonstrates that the host plant determines the bacterial community composition in its immediate vicinity, especially with respect to the active populations. 23969949 Effect of Temozolomide in Patients with Metastatic Bronchial Carcinoids. Introduction: Metastatic bronchial carcinoids are rare neoplasms, where efforts of medical treatment so far have been disappointing. A previous study from our center indicated that temozolomide might be of value. Materials and Methods: All patients with progressive metastatic bronchial carcinoid treated with temozolomide as monotherapy at our center between 2004 and 2010 (n = 31) were included in this retrospective study. 14 tumors were classified as typical and 15 as atypical carcinoids, whereas 2 tumors could not be classified. Temozolomide was given on 5 consecutive days every 4 weeks. Toxicity was evaluable in 28 of 31 patients, and 22 patients were evaluable by RECIST 1.1. Results: There were no complete responses. A partial response was seen in 3 patients (14%), stable disease in 11 (52%) and progressive disease in 7 patients (33%). Median progression-free survival was 5.3 months and median overall survival was 23.2 months from the start of temozolomide. Toxicities grade 3-4 were noted in 4 patients, thrombocytopenia (n = 3) and leukopenia (n = 1). Conclusion: Temozolomide as monotherapy shows activity in metastatic bronchial carcinoids. Regimens combining temozolomide with other agents (e.g. capecitabine and/or bevacizumab, everolimus, radiolabeled somatostatin analogues) should be further studied in these patients. © 2013 S. Karger AG, Basel. 23852797 Assessment of Factors Influencing the Agrobacterium-mediated in planta Seed Transformation of Brinjal (Solanum melongena L.). An efficient and reproducible in planta transformation method was developed for brinjal using seed as an explant. The brinjal seeds were infected with Agrobacterium tumefaciens EHA 105 harbouring pCAMBIA 1301-bar plasmid, and the transformants were selected against BASTA®. Several parameters influencing the in planta seed transformation such as pre-culture duration, acetosyringone concentration, surfactants, duration of sonication, vacuum pressure and vacuum duration have been evaluated. The putatively transformed (T 0) brinjal plants were screened by GUS histochemical analysis. Among the different combinations and concentrations tested, when the 18-h pre-cultured brinjal seeds were sonicated for 20 min and vacuum infiltered for 3 min at 500 mm of Hg in Agrobacterium suspension containing 100 Î¼M acetosyringone, 0.2 % Silwett L-77 favoured the Agrobacterium infection and showed maximum transformation efficiency. Among the five brinjal varieties evaluated, Arka Samhitha showed maximum transformation efficiency at 45.66 %. The transgene was successfully transmitted to progeny plants (T 1) which was evidenced by GUS histochemical analysis, polymerase chain reaction and Southern hybridisation. The in planta protocol developed in the present study would be beneficial to transfer the economically and nutritionally important genes into different varieties of brinjal, and the transgenic brinjal plants can be produced in less time (approximately 27 days). 23500089 Accuracy of intraoperative pathological examination of SLN in cervical cancer. Early cervical cancer patients with pelvic lymph node metastasis do not benefit from radical hysterectomy. Assessment of the SLN status is thus crucial before deciding to perform a radical hysterectomy as opposed to aortic dissection only followed by definitive radiation therapy. Accuracy of frozen section of SLN has been questioned and deserves further investigation. Stage IA-IB1 cervical cancer patients who underwent SLN then full pelvic dissection at the Claudius Regaud Cancer Center in Toulouse, France, were included. At least one SLN was identified in all 94 patients. Bilateral detection rate was 80.8%. Ectopic drainage area was found in 19 patients (20.2%). Sentinel lymph node involvement was found in 11 patients (11.7%). Sensitivity and NPV of frozen section pathological examination for the detection of macrometastatic disease was 100%, sensitivity for the detection of macro and micrometastatic disease, excluding ITC, was 88.9%, and NPV was 98.8%. Micrometastasis and isolated tumor cells (ITC) undetected at frozen section examination were found in 1 patient (1.06%) and 2 lymph nodes (1.24%), and in 2 patients (2.13%) and 2 lymph nodes (1.24%), respectively. Final pathology sensitivity of SLN was 100% for both macro and micrometastatic disease, including ITC. In our institution, intraoperative frozen examination of SLN accurately predicts the status of pelvic lymph nodes and is effective for selecting intraoperatively the group of patients who benefit from radical hysterectomy. In addition, our results suggest that patients with small tumors and bilateral detection of SLN can be spared full pelvic lymphadenectomy. 23539232 Glomerular and tubular damage markers in individuals with progressive albuminuria. Albuminuria is associated with risk for renal and cardiovascular disease. It is difficult to predict which persons will progress in albuminuria. This study investigated whether assessment of urinary markers associated with damage to different parts of the nephron may help identify individuals that will progress in albuminuria. Individuals were selected from a prospective community-based cohort study with serial follow-up and defined as "progressors" if they belonged to the quintile of participants with the most rapid annual increase in albuminuria, and reached an albuminuria ≥150 mg/d during follow-up. Patients with known renal disease or macroalbuminuria at baseline were excluded. Each progressor was matched to two control participants, based on baseline albuminuria, age, and sex. Furthermore, damage markers were measured in a separate set of healthy individuals. After a median follow-up of 8.6 years, 183 of 8394 participants met the criteria for progressive albuminuria. Baseline clinical characteristics were comparable between progressors and matched controls (n=366). Both had higher baseline albuminuria than the overall population. Urinary excretion of the glomerular damage marker IgG was significantly higher in progressors, whereas urinary excretion of proximal tubular damage markers and inflammatory markers was lower in these individuals compared with controls. Healthy individuals (n=109) had the lowest values for all urinary damage markers measured. These data suggest that albuminuria associated with markers of glomerular damage is more likely to progress, whereas albuminuria associated with markers of tubulointerstitial damage is more likely to remain stable. 23953721 Protecting the aged heart during cardiac surgery: Use of del Nido cardioplegia provides superior functional recovery in isolated hearts. Aged hearts are particularly vulnerable to ischemia-reperfusion injury. Our objective was to determine if del Nido cardioplegia, which contains lidocaine, less blood, and less calcium than our standard cardioplegia, provides superior protection for aged hearts. We also sought to determine if the lidocaine in del Nido cardioplegia is adequate to prevent Na(+) influx via the window current. Sodium channel kinetics were measured in rat cardiomyocytes with and without lidocaine. Recovery after 60 minutes of cardioplegic arrest was assessed in isolated working senescent rat hearts. Del Nido cardioplegia was delivered as a single dose (n = 8) because it is used clinically, and standard cardioplegia was delivered as an induction dose with re-dosing every 20 minutes (n = 8). After 20 minutes of reperfusion, hearts were switched to working mode for 60 minutes. Flows were indexed to ventricular dry weight. Troponin release was assayed. Sodium channel kinetics indicated that the lidocaine concentration in del Nido cardioplegia minimizes the potential for Na+ influx via the window current. Spontaneous contractions occurred in fewer hearts arrested with del Nido cardioplegia (88% vs 13%; P = .01), and troponin release was reduced (0.24 vs 0.89 ng/mL; P = .017). Cardiac output was approximately 90% of baseline in the del Nido group compared with approximately 50% in the standard group (173 ± 14 vs 86 ± 22 mL · min(-1) · g(-1); P = .0008). Stroke work was higher in the del Nido group (93 ± 6 vs 41 ± 10 mL · mm Hg · g(-1); P = .0002). Del Nido cardioplegia prevents spontaneous contractions during arrest, reduces troponin release, and results in superior myocardial function in isolated aged hearts. Del Nido cardioplegia has the potential to provide superior myocardial protection for older patients undergoing cardiac surgery. 23946347 Extracted Oat and Barley β-Glucans Do Not Affect Cholesterol Metabolism in Young Healthy Adults. β-Glucans are known to exhibit hypocholesterolemic effects. Increased intestinal viscosity is thought to be crucial for cholesterol lowering. It is suggested that concentration, molecular mass, and structure, including the ratio of (1→3) to (1→4) glucan bonds in the molecule, are of importance for β-glucan functionality. This study investigates the effects of 3 different β-glucan sources, incorporated into a beverage and yogurt, on blood lipids and fecal endpoints. Fourteen participants completed this randomized, crossover, single-blinded study with four 3-wk periods: control and 3.3 g/d oat, barley, and barley mutant β-glucans of similar molecular mass. Before and after each period, fasting and postprandial blood samples were drawn and 3-d fecal samples were collected. Treatment did not affect changes in total, LDL, and HDL cholesterol compared with control; however, consumption of 3.3 g/d of oat β-glucans for 3 wk resulted in greater decreases in total (-0.29 ± 0.09 mmol/L, P < 0.01), LDL (-0.23 ± 0.07 mmol/L, P < 0.01), and HDL (-0.05 ± 0.0.3 mmol/L, P < 0.05) cholesterol compared with baseline. Changes in LDL in the β-glucan treatments were not related to β-glucan structure (cellotriosyl:cellotetraosyl). Decreases in fasting triacylglycerol were substantially greater after oat β-glucan treatment compared with control (P = 0.03). Fecal dry and wet weight, stool frequency, fecal pH, and energy excretion were unaffected. The results do not fully support the hypocholesterolemic effects by differently structured oat and barley β-glucans. However, substantial differences compared with baseline suggest a potential for oat β-glucan, presumably due to its higher solubility and viscosity. This underlines the importance of elusive structural β-glucan features for beneficial physiologic effects. 23931704 A Systematic Review of Studies Performing the Hypo-Osmotic Swelling Test to Evaluate the Quality of Canine Spermatozoa. The hypo-osmotic swelling test (HOS test) is a simple and inexpensive test to evaluate the functional integrity of sperm cell membranes. According to the existing literature, its simple applicability has turned it into a valuable additional parameter to standard canine semen analysis. In the recent years, much research has been conducted in this field. The aim of this systematic review was to evaluate the quality of published literature in canine reproduction concerning the HOS test. Using two distinguished databases, 38 articles were detected and analysed subsequently according to various aspects, for example study design, population, semen sampling and implementation concerning the HOS test. Although there are numerous articles available, the diagnostic value of the HOS test remains ambiguous. Until now, neither a recognized test protocol nor reliable reference values have been defined. Most of the trials evaluated show serious methodological flaws and therefore do not permit drawing reliable conclusions. According to our results, approximately half of the studies (n = 20) included a sample size of five or less animals. None of the studies examined the inter- or intraobserver agreement for the HOS test. Further research is warranted including appropriate statistical methods and a sufficient number of animals to establish a standardized test protocol as well as reliable reference values. Most importantly, it is required to clarify a correlation between the HOS test and the fertilizing capacity to determine the diagnostic value of the HOS test. 23863782 Spectral-Domain Optical Coherence Tomography of Retinal Nerve Fiber Layer Thickness in NMO Patients. Neuromyelitis optica (NMO) is a demyelinating syndrome of the central nervous system. NMO might be underdiagnosed at early stages when patients have not yet developed the full spectrum of disease. The aim of this study was to analyze the retinal nerve fiber layer (RNFL) with optical coherence tomography (OCT) and to compare RNFL measurements between NMO patients, patients with relapsing-remitting multiple sclerosis (RRMS), and healthy controls to determine whether differences in RNFL thickness could be an early diagnostic marker for NMO. In a cross-sectional study, eyes of 25 NMO patients, 25 RRMS patients, and 50 healthy controls underwent RNFL measurements by OCT. Clinical parameters were collected by history and chart review. Pairwise Wilcoxon rank sum tests with Holm correction were used to compare means of RNFL thickness among 6 groups (NMO, RRMS, and healthy control) of patients [without or with 1 or more episode of optic neuritis (ON)]. The association between RNFL thickness and patient characteristics for NMO group was examined via linear mixed-effects models (adjusting for within-patient intereye correlations and history of ON, where appropriate). Based on the pairwise Wilcoxon rank sum tests with Holm correction, significant differences were found between NMO with 1 episode of ON and non-ON eyes (mean RNFL 63.7 vs 97.0 µm, P < 0.0001), multiple sclerosis (MS) non-ON eyes, and controls (RNFL 93.2 vs 98.4 µm, P = 0.03). No significant differences were found between NMO and MS with 1 attack of ON eyes (RNFL 63.7 vs 73.9 µm, P = 0.46), NMO non-ON eyes and healthy controls (RNFL 97.0 vs 98.4 µm, P = 0.56), and NMO non-ON and MS non-ON (RNFL 97.0 vs 93.2 µm, P = 0.56). For NMO group, RNFL thickness was associated with a history of ON (P < 0.001) but not with disability or disease duration when adjusting for the history of ON (P > 0.1). RNFL in NMO is not different enough to distinguish NMO ON from MS ON eyes, but the intereye difference in RFNL with a history of unilateral ON may be a better diagnostic marker for NMO. 23132096 Membrane trafficking in neuronal maintenance and degeneration. Defects in membrane trafficking and degradation are hallmarks of most, and maybe all, neurodegenerative disorders. Such defects typically result in the accumulation of undegraded proteins due to aberrant endosomal sorting, lysosomal degradation, or autophagy. The genetic or environmental cause of a specific disease may directly affect these membrane trafficking processes. Alternatively, changes in intracellular sorting and degradation can occur as cellular responses of degenerating neurons to unrelated primary defects such as insoluble protein aggregates or other neurotoxic insults. Importantly, altered membrane trafficking may contribute to the pathogenesis or indeed protect the neuron. The observation of dramatic changes to membrane trafficking thus comes with the challenging need to distinguish pathological from protective alterations. Here, we will review our current knowledge about the protective and destructive roles of membrane trafficking in neuronal maintenance and degeneration. In particular, we will first focus on the question of what type of membrane trafficking keeps healthy neurons alive in the first place. Next, we will discuss what alterations of membrane trafficking are known to occur in Alzheimer's disease and other tauopathies, Parkinson's disease, polyQ diseases, peripheral neuropathies, and lysosomal storage disorders. Combining the maintenance and degeneration viewpoints may yield insight into how to distinguish when membrane trafficking functions protectively or contributes to degeneration. 23194827 The cucurbitacins E, D and I: investigation of their cytotoxicity toward human chondrosarcoma SW 1353 cell line and their biotransformation in man liver. Cucurbitacins are a class of natural compounds known for their numerous potential pharmacological effects. The purpose of this work was to compare the cytotoxicity of three cucurbitacins I, D, E on the chondrosarcoma SW 1353 cancer cell line and to investigate their biotransformation in man. Cucurbitacins I and D showed a very strong cytotoxicity, which was higher than that of cytochalasin D, used as a drug reference. Almost 100% of the cells were apoptotic as observed by DNA fragmentation (TUNEL assay) after 12 h with cucurbitacins I and D (1 μM) and cucurbitacin E (10 μM). In terms of IC(50) values, cucurbitacins I and E presented a higher toxicity compared to that of cucurbitacin D (MTT assay). Cucurbitacin E was readily hydrolyzed by human hepatic microsomes, leading to cucurbitacin I (K(m) 22 μM, V(max) 571 nmol/mg proteins/min). On the other hand, the three cucurbitacins were hydroxylated at a very low extent, but they were sulfated and glucuronidated. In terms of V(max)/K(m), the cucurbitacin E was the best substrate of UDP-glucuronosyltransferases. This study shows that cucurbitacins I, D and E present a potent cytotoxic activity toward the chondrosarcoma SW 1353 cell line and are metabolized as sulfate and glucuronide conjugates. 23928115 RESIDUAL FORCE DEPRESSION FOLLOWING MUSCLE SHORTENING IS EXAGGERATED BY PRIOR ECCENTRIC DROP JUMP EXERCISE. We studied the relation between two common force modifications in skeletal muscle: the prolonged force depression induced by unaccustomed eccentric contractions and the residual force depression (rFD) observed immediately after active shortening. We tested two hypotheses: (I) the magnitude of rFD correlates to the mechanical work performed during shortening; (II) the eccentric contraction-induced force depression and rFD are caused by different, but interacting mechanisms. Nine healthy untrained men (mean age 26 years) participated in the study. rFD was studied in electrically stimulated knee extensor muscles. rFD was defined as the reduction in isometric torque after active shortening as compared to the torque in a purely isometric contraction. Eccentric contractions were performed as 50 repeated drop jumps with active deceleration to 90º knee angle, immediately followed by a maximal upward jump. rFD was assessed before and 5 min to 72 hours after drop jumps. The series of drop jumps caused a prolonged force depression, which was about two times larger at 20 Hz than at 50 Hz stimulation. There was a significant correlation between increasing rFD and increasing mechanical work performed during active shortening both before and after drop jumps. In addition, a given rFD was obtained at a markedly lower mechanical work after drop jumps. The extent of rFD correlates to the mechanical work performed during active shortening. A series of eccentric contractions causes a prolonged reduction of isometric force. In addition, eccentric contractions exaggerate rFD, which further decreases muscle performance during dynamic contractions. 23677206 A victory for global public health in the Indian Supreme Court. On 1 April of this year, the Indian Supreme Court upheld the decision of the Indian Patent Office to refuse the patent grant for Novartis imatinib mesylate (Gleevec). The patent application failed to meet the requirements for patentability under Indian law. The global public health community followed the case closely. Its outcome could affect the Indian generics industry - an important supplier of low cost medicines to the developing world. 23499049 Racial Differences in Estimated GFR Decline, ESRD, and Mortality in an Integrated Health System. Current evidence does not clearly identify the contribution of kidney function decline and mortality to racial disparities in end-stage renal disease (ESRD) incidence. We used observed estimated glomerular filtration rate (eGFR) to project the time of onset of kidney failure and examined mortality to better understand these racial disparities. Retrospective cohort. Adult members of Kaiser Permanente Southern California in 2003-2009 with more than 2 serum creatinine tests and more than 180 days between tests: 526,498 whites, 350,919 Hispanics, 136,923 blacks, and 105,476 Asians. Race/ethnicity. ESRD (dialysis or transplantation); mortality. eGFR decline was modeled using linear regression. Kidney failure was projected based on predicted eGFR <15 mL/min/1.73 m(2) at specified times. Racial differences in projected kidney failure and mortality in those with projected kidney failure were estimated with adjustment for age, sex, and entry eGFR. Blacks had more extreme rates of eGFR decline (1st percentile, -23.6 mL/min/1.73 m(2) per year), followed by Hispanics (-20.9 mL/min/1.73 m(2) per year), whites (-20.1 mL/min/1.73 m(2) per year), and Asians (-17.6 mL/min/1.73 m(2) per year; P < 0.001). There were 25,065 whites, 11,368 Hispanics, 6,785 blacks, and 3,176 Asians with projected kidney failure during the study period. The ORs for projected kidney failure versus whites during CKD stages 3 and 4 were 1.54 (95% CI, 1.46-1.62) in blacks, 1.49 (95% CI, 1.42-1.56) in Hispanics, and 1.41 (95% CI, 1.32-1.51) in Asians. For those with projected kidney failure, the HRs of death versus whites during CKD stages 3 and 4 were 0.82 (95% CI, 0.77-0.88) in blacks, 0.67 (95% CI, 0.63-0.72) in Hispanics, and 0.58 (95% CI, 0.52-0.65) in Asians. Results may not generalize to the uninsured or subgroups within a race. Projected kidney failure was based on linear trends from clinically obtained eGFR. We found more extreme rates of eGFR decline in blacks. Projected kidney failure during CKD stages 3 and 4 was high in blacks, Hispanics, and Asians relative to whites. Mortality for those with projected kidney failure was highest in whites. Differences in eGFR decline and mortality contributed to racial disparities in ESRD incidence. 23756769 A rapid noninvasive assay for the detection of renal transplant injury. The copy number of donor-derived cell-free DNA (dd-cfDNA) in blood correlates with acute rejection (AR) in heart transplantation. We analyzed urinary dd-cfDNA as a surrogate marker of kidney transplant injury. Sixty-three biopsy-matched urine samples (41 stable and 22 allograft injury) were analyzed from female recipients of male donors for chromosome Y (donor)-specific dd-cfDNA. All biopsies were semiquantitatively scored by a single pathologist. Standard statistical measures of correlation and significance were used. There was baseline scatter for urinary dd-cfDNA/μg urine creatinine across different patients, even at the time of stable graft (STA) function (undetected to 12.26 copies). The mean urinary dd-cfDNA in AR (20.5 ± 13.9) was significantly greater compared with STA (2.4 ± 3.3; P<0.0001) or those with chronic allograft injury (CAI; 2.4 ± 2.4; P=0.001) but no different from BK virus nephropathy (BKVN; 20.3±15.7; P=0.98). In AR and BKVN, the intrapatient drift was highly significant versus STA or CAI patients (10.3 ± 7.4 in AR; 12.3 ± 8.4 in BKVN vs. -0.5 ± 3.5 in STA and 2.3 ± 2.6 in CAI; P<0.05). Urinary dd-cfDNA correlated with protein/creatinine ratio (r=0.48; P<0.014) and calculated glomerular filtration rate (r=-0.52; P<0.007) but was most sensitive for acute allograft injury (area under the curve=0.80; P<0.0006; 95% confidence interval, 0.67-0.93). Urinary dd-cfDNA after renal transplantation has patient specific thresholds, reflecting the apoptotic injury load of the donor organ. Serial monitoring of urinary dd-cfDNA can be a surrogate sensitive biomarker of acute injury in the donor organ but lacks the specificity to distinguish between AR and BKVN injury. 23873939 The CLAMP protein links the MSL complex to the X chromosome during Drosophila dosage compensation. The Drosophila male-specific lethal (MSL) dosage compensation complex increases transcript levels on the single male X chromosome to equal the transcript levels in XX females. However, it is not known how the MSL complex is linked to its DNA recognition elements, the critical first step in dosage compensation. Here, we demonstrate that a previously uncharacterized zinc finger protein, CLAMP (chromatin-linked adaptor for MSL proteins), functions as the first link between the MSL complex and the X chromosome. CLAMP directly binds to the MSL complex DNA recognition elements and is required for the recruitment of the MSL complex. The discovery of CLAMP identifies a key factor required for the chromosome-specific targeting of dosage compensation, providing new insights into how subnuclear domains of coordinate gene regulation are formed within metazoan genomes. 23703538 Time-frequency Techniques in Biomedical Signal Analysis. A Tutorial Review of Similarities and Differences. Objectives: This review outlines the methodological fundamentals of the most frequently used non-parametric time-frequency analysis techniques in biomedicine and their main properties, as well as providing decision aids concerning their applications. Methods: The short-term Fourier transform (STFT), the Gabor transform (GT), the S-transform (ST), the continuous Morlet wavelet transform (CMWT), and the Hilbert transform (HT) are introduced as linear transforms by using a unified concept of the time-frequency representation which is based on a standardized analytic signal. The Wigner-Ville distribution (WVD) serves as an example of the 'quadratic transforms' class. The combination of WVD and GT with the matching pursuit (MP) decomposition and that of the HT with the empirical mode decomposition (EMD) are explained; these belong to the class of signal-adaptive approaches. Results: Similarities between linear transforms are demonstrated and differences with regard to the time-frequency resolution and interference (cross) terms are presented in detail. By means of simulated signals the effects of different time-frequency resolutions of the GT, CMWT, and WVD as well as the resolution-related properties of the interference (cross) terms are shown. The method-inherent drawbacks and their consequences for the application of the time-frequency techniques are demonstrated by instantaneous amplitude, frequency and phase measures and related time-frequency representations (spectrogram, scalogram, time-frequency distribution, phase-locking maps) of measured magnetoencephalographic (MEG) signals. Conclusions: The appropriate selection of a method and its parameter settings will ensure readability of the time-frequency representations and reliability of results. When the time-frequency characteristics of a signal strongly correspond with the time-frequency resolution of the analysis then a method may be considered 'optimal'. The MP-based signal-adaptive approaches are preferred as these provide an appropriate time-frequency resolution for all frequencies while simultaneously reducing interference (cross) terms. 23952859 Pulmonary fibrosis in sarcoidosis. Clinical features and outcomes. Sarcoidosis is a systemic inflammatory disease with a predilection for the respiratory system. Although most patients enter remission and have good long-term outcomes, up to 20% develop fibrotic lung disease, whereby granulomatous inflammation evolves to pulmonary fibrosis. There are several radiographic patterns of pulmonary fibrosis in sarcoidosis; bronchial distortion is common, and other patterns, including honeycombing, are variably observed. The development of pulmonary fibrosis is associated with significant morbidity and can be fatal. Dyspnea, cough, and hypoxemia are frequent clinical manifestations. Pulmonary function testing often demonstrates restriction from parenchymal involvement, although airflow obstruction from airway-centric fibrosis is also recognized. Complications of fibrotic pulmonary sarcoidosis include pulmonary hypertension from capillary obliteration and chronic aspergillus disease, with hemoptysis a common and potentially life-threatening manifestation. Immunosuppression is not always indicated in end-stage sarcoidosis. Lung transplantation should be considered for patients with severe fibrotic pulmonary sarcoidosis, as mortality is high in these patients. 23713824 Individual platelet adhesion assay: measuring platelet function and antiplatelet therapies in whole blood via digital quantification of cell adhesion. Widespread monitoring of platelet function and the effect of antiplatelet drugs will improve outcomes in cardiovascular patients, but platelet function testing is not routine in clinical practice. We report a rapid, accurate methodology to quantify platelet-protein interactions: a microarray of contact-printed 6-μm fibrinogen dots on a transparent substrate binds platelets from whole blood, one platelet per dot. The fractional occupancy of an array of fibrinogen dots after a predefined incubation time quantitatively assays platelet adhesion to the protein matrix. We demonstrate this technique by measurement of platelet adhesion to fibrinogen as a means to quantify the effect of the P2Y12 and αIIbβ3 receptor inhibitors cangrelor and abciximab, respectively, both in vitro--by incubating the drug with a freshly drawn blood sample--and in blood from patients treated with antiplatelet agents. The effects of single- and dual-antiplatelet therapy are also assessed. Results from this platelet-binding assay are well correlated with standard techniques including flow cytometry and light transmission aggregometry. This assay technology, readily integrated with microfluidic platforms, is generally applicable to the assay of cell-protein interactions and promises more effective, rapid assay of drug effects in cardiovascular disease patients. 23535188 Mechanisms of the anti-proliferative and anti-inflammatory effects of the herbal fixed combination STW 5 (Iberogast(®)) on colon adenocarcinoma (HT29) cells in vitro. INTRODUCTION: Several conventional pharmaceuticals like non-steroidal anti-inflammatory drugs (NSAIDS) or selective cyclooxygenase-2 (COX-2) inhibitors have been demonstrated to exert anti-proliferative effects and to induce apoptosis in a variety of cell lines, e.g. colon, stomach, or prostate cancer cells. STW 5 (Iberogast(®)), a combination of nine plant extracts, is widely used in the treatment of gastrointestinal disorders, including functional dyspepsia and irritable bowel syndrome for which the involvement of an inflammatory etiology is discussed. To investigate the possible anti-proliferative effects, STW 5 and its components have been tested by using the colon-carcinoma cell line HT-29. The analyses have been performed in comparison to acetylsalicylic acid (ASA) and diclofenac (Diclo), which are well-known to reduce colon carcinoma risk. RESULTS: STW 5 showed significant anti-proliferative and pro-apoptotic effects on HT-29 cancer cells, similar to NSAIDs under test. However, using the LDH assay, STW 5 revealed significantly lower cytotoxicity than Diclo at same concentrations. In contrast to NSAIDs, STW 5 induced COX-1/COX-2, caspase-3 and Bax mRNA expressions in HT-29 and blocked LPS mediated translocation of the NF-κB p65 from the cytoplasm into the nucleus in PMA-differentiated THP-1 macrophages. These effects might be relevant, e.g. for prevention of undesirable side effects like gastric erosions. CONCLUSION: Our data suggest that the pro-apoptotic effect of STW 5 on HT-29 cells is involving multiple targets and is possibly due to an activation of the caspase cascade via mitochondrial destabilization. Active concentrations of STW 5 are, in relation to therapeutic doses, comparable to those of ASA and Diclo, suggesting a similar favorable effect on colon carcinoma risk. 23970485 Evolution and molecular characterization of macrolide-resistant Streptococcus pneumoniae in Canada between 1998 and 2008. Studies were performed to assess resistance mechanisms, multidrug resistance (MDR), genetic relatedness, serotype distribution, heptavalent pneumococcal conjugate vaccine (PCV7) coverage and pili virulence factors among macrolide-resistant Streptococcus pneumoniae (MRSP) isolated from respiratory samples submitted to hospital laboratories across Canada from 1998 to 2008. Isolates of MRSP (n = 1518) collected by the national surveillance studies CROSS (Canadian Respiratory Organism Susceptibility Study; 1998-2006) and CANWARD (Canadian Ward Surveillance Study; 2007-08) were tested using the CLSI broth microdilution method to establish antimicrobial susceptibilities. PCR was used to detect macrolide resistance genes [mef(A) and erm(B)] and pili virulence factors (type 1 pili and type 2 pili), the Quellung reaction was used to identify serotypes and PFGE was used to determine genetic relatedness. The prevalence of MRSP increased from 8% in 1998 to 22% in 2008 (P = 0.0001). MRSP were 51% mef(A) positive, 36% erm(B) positive, 8% dual mef(A) and erm(B) positive and 5% mef(A) and erm(B) negative. Dual mef(A)- and erm(B)-positive isolates increased in prevalence from 3% in 1998 to 19% in 2008 (P = 0.001). The prevalence of PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F and 23F) decreased from 67% in 1998 to 31% in 2008 (P = 0.0072). The prevalence of serotype 19A, a non-PCV7 serotype, increased by 15% from 1998 to 2008; isolates of serotype 19A were MDR, dual mef(A) and erm(B) positive, genetically related by PFGE and associated with the presence of pili virulence factors. From 1998 to 2008, respiratory isolates of MRSP in Canada increased significantly due primarily to the emergence and spread of serotypes 6A, 19A and other non-PCV7 serotypes. 23938116 Whole genomic analyses of equine group A rotaviruses from Japan: Evidence for bovine-to-equine interspecies transmission and reassortment events. Equine group A rotaviruses (RVA) are a major cause of severe diarrhea in foals. The whole genomes of only six common and three unusual equine RVA strains have been analyzed so far. To date, there are no reports on whole genomic analyses of equine RVAs from Asian countries. We report here the whole genomic analyses of three common (strains RVA/Horse-tc/JPN/BI/1981/G3P[12], RVA/Horse-tc/JPN/HH-22/1989/G3P[12] and RVA/Horse-tc/JPN/CH-3/1987/G14P[12]) and an unusual (RVA/Horse-tc/JPN/OH-4/1982/G6P[5]) equine RVA strains isolated from diarrheic foals in Japan. Strains BI, HH-22 and CH-3 shared a largely conserved genotype constellation (G3/G14-P[12]-I2/I6-R2-C2-M3-A10-N2-T3-E2-H7) with each other and with those of common equine RVAs from other continents. Phylogenetically, most of the genes of BI, HH-22 and CH-3 were closely related to those of other common equine RVAs. On the other hand, the NSP2 genes of BI and CH-3 formed a distinct lineage, and were distantly related to the other, major equine RVA cluster within the NSP2-N2 genotype. The NSP4 gene of HH-22 appeared to originate from possible reassortment events involving common equine RVAs and co-circulating bovine or bovine-like equine RVAs, revealing the presence of a bovine RVA-like NSP4 gene on a typical equine RVA genetic backbone. All the 11 gene segments of the unusual equine RVA strain OH-4 were found to be more closely related to those of bovine and bovine-like human RVAs than to those of other RVAs, providing the first conclusive evidence for artiodactyl(likely bovine)-to-equine interspecies transmission events. Taken together, these observations provided important insights into the genetic diversity of equine RVAs. 23933115 New-generation screening assays for the detection of anti-influenza compounds targeting viral and host functions. Current options for influenza antiviral therapy are limited to the neuraminidase inhibitors, and knowledge that high levels of oseltamivir resistance have been seen among previously circulating H1N1 viruses increases the urgency to find new influenza therapeutics. To feed this pipeline, assays that are appropriate for use in high-throughput screens are being developed and are discussed in this review. Particular emphasis is placed on cell-based assays that capture both inhibitors of viral functions as well as the host functions that facilitate optimal influenza virus replication. Success in this area has been fueled by a greater understanding of the genome structure of influenza viruses and the ability to generate replication-competent recombinant viruses that carry a reporter gene, allowing for easy monitoring of viral infection in a high-throughput setting. This article forms part of a symposium in Antiviral Research on "Treatment of influenza: targeting the virus or the host." 23546602 17β-estradiol activates glucose uptake via GLUT4 translocation and PI3K/Akt signaling pathway in MCF-7 cells. The relationship between estrogen and some types of breast cancer has been clearly established. However, although several studies have demonstrated the relationship between estrogen and glucose uptake via PI3K/Akt in other tissues, not too much is known about the possible cross talk between them for development and maintenance of breast cancer. This study was designed to test the rapid effects of 17β-estradiol (E2) or its membrane-impermeable form conjugated with bovine serum albumin (E2BSA) on glucose uptake in a positive estrogen receptor (ER) breast cancer cell line, through the possible relationship between key components of the PI3K/Akt signaling pathway and acute steroid treatment. MCF-7 human breast cancer cells were cultured in standard conditions. Then 10nM of 17β-estradiol or estradiol BSA conjugated were administrated before obtaining the cell lysates. To study the glucose uptake, the glucose fluorescent analogue 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose was used. We report an ER-dependent activation of some of the key steps of the PI3K/Akt signaling pathway cascade that leads cells to improve some mechanisms that finally increase glucose uptake capacity. Our data suggest that both E2 and E2BSA enhance the entrance of the fluorescent glucose analogue 2-NBDG, and also activates s PI3K/Akt signaling pathway, leading to translocation of GLUT4 to the plasma membrane in an ERα dependent manner. E2 enhances ER-dependent rapid signaling triggered, partially in the plasma membrane, allowing ERα-positive MCF-7 breast cancer cells to increase glucose uptake, which could be essential to meet the energy demands of the high rate of proliferation. 23754635 Natural selection in utero: evidence from the Great East Japan Earthquake. Controversy remains over whether declines in male births reported after population stressors result from either or both reduced conception of males or increased selection in utero against male fetuses. We use monthly birth cohorts to determine if Japanese male births following the Great East Japan Earthquake of 2011 fell below levels expected from female births and from history (i.e., autocorrelation) among cohorts exposed to the Earthquake at or after conception. We apply interrupted time-series methods to 69 months (i.e., April, 2006 through December, 2011) of birth data from the most and least affected prefectures as well as from the remainder of Japan. We estimate expected male births from female births and from autocorrelation. Findings varied by distance from the greatest damage but suggest sensitive periods both early and late in gestation when population stressors may induce selection against males in utero. Support for reduced conception of males appeared only in the prefectures most damaged by the Earthquake. Results align with the claim that natural selection has conserved mechanisms that reduce the odds of a male live birth during stressful times by reducing the conception of males and by increasing the rate of spontaneous abortion among male fetuses. 23371304 Mitogen-activated protein kinases as therapeutic targets for rheumatoid arthritis. Rheumatoid arthritis (RA) is a chronic autoimmune disease in which imbalances in pro- and anti-inflammatory cytokines promote the induction of autoimmunity, inflammation and joint destruction. Methotrexate, the standard disease-modifying anti-rheumatic drug (DMARD), has shown a gradual loss of efficacy in a significant proportion of patients, probably due to the onset of drug resistance, and thus it was hoped that the development of biologics would revolutionise RA management. Even though biologics have improved the therapy of patients refractive to DMARDs, they require parenteral administration and may leave patients open to serious infection and cancer. Therefore, attention has also been focused on inhibitors of mitogen-activated protein kinases (MAPKs), signalling enzymes that play key roles in pathogenic cytokine production, and their downstream effector pathways, in order to create safe and effective oral drugs. This article therefore provides an overview of the structure and function of MAPKs and their role in the pathogenesis of RA as context to describing the advances in the development of specific, druggable MAPK inhibitors. Their potential as therapies in the management of RA is also discussed. 23964094 Redistribution of the Lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence. Senescence is a stress-responsive form of stable cell cycle exit. Senescent cells have a distinct gene expression profile, which is often accompanied by the spatial redistribution of heterochromatin into senescence-associated heterochromatic foci (SAHFs). Studying a key component of the nuclear lamina lamin B1 (LMNB1), we report dynamic alterations in its genomic profile and their implications for SAHF formation and gene regulation during senescence. Genome-wide mapping reveals that LMNB1 is depleted during senescence, preferentially from the central regions of lamina-associated domains (LADs), which are enriched for Lys9 trimethylation on histone H3 (H3K9me3). LMNB1 knockdown facilitates the spatial relocalization of perinuclear H3K9me3-positive heterochromatin, thus promoting SAHF formation, which could be inhibited by ectopic LMNB1 expression. Furthermore, despite the global reduction in LMNB1 protein levels, LMNB1 binding increases during senescence in a small subset of gene-rich regions where H3K27me3 also increases and gene expression becomes repressed. These results suggest that LMNB1 may contribute to senescence in at least two ways due to its uneven genome-wide redistribution: first, through the spatial reorganization of chromatin and, second, through gene repression. 23869795 Considering the balance: development of a scale to assess patient views on trade-offs in competing health outcomes. To describe the development of a scale assessing participant attitudes regarding two commonly encountered trade-offs: quality versus quantity of life and present versus future health. Observational cohort study. Community. Three hundred and fifty-seven community-dwelling adults aged 65 and older. An initial set of 20 items rated on a 5-point Likert scale of agreement was reduced using principal components analysis. Construct validity was evaluated through comparison of the scale with other tools addressing the same trade-offs and analysis of participant characteristics associated with attitudes favoring quality over quantity of life and present over future health. Internal consistency was assessed using Cronbach alpha. Test-retest reliability was assessed using intraclass correlation coefficients (ICCs). The scale consists of two subscales, each addressing one trade-off, with a total of 10 items. All factor loadings were 0.5 and greater, and subscale scores were significantly different (P â‰¤ .05) in the expected directions when comparing with other tools and with participant race, education, and religious identity. Internal consistency was good (Cronbach α 0.85 and 0.84), and test-retest reliability was fair (ICCs 0.63 and 0.47). Subscale score medians fell near the middle of each scale, with narrow interquartile ranges, but more than 15% of the sample scored at an extreme of each subscale. This new scale captures views on two common trade-offs in health care. Although test-retest reliability was modest, its high validity suggests that this tool can be used to familiarize people with common trade-offs and further explore influences on attitudes. 23932036 The role of psychosocial factors in exclusive breastfeeding to six months postpartum. to investigate the psychosocial variables associated with the ability to exclusively breastfeed to six months postpartum. Additionally, to evaluate a conceptual model of psychosocial correlates of exclusive breastfeeding duration. online, retrospective questionnaire. the questionnaire was placed online and participants accessed it through social networking sites including groups relating to breastfeeding, motherhood and parenting. Participants were also able to share the link with their own networks. This online setting facilitated recruitment of a wide range of Australian and international participants. 174 women aged 18 years and older who had given birth between six months to two years prior. Participants completed an online questionnaire, which asked them to report on three time points: pre-pregnancy, during pregnancy and during the first six months postpartum. Data were collected from June to December 2011. psychometrically validated tools such as the breastfeeding Self-Efficacy Scale, Body Attitude Questionnaire, Depression Anxiety and Stress Scale, Fetal Health Locus of Control Scale, and the brief COPE scale were used to measure psychosocial variables. Additional scales were developed by the researchers and met scale reliability criteria. correlation analyses, t-tests and path analysis were used to statistically analyse the data. Results showed that women who exclusively breast fed to six months postpartum exhibited higher intention to exclusively breastfeed, breastfeeding self-efficacy, comfort breastfeeding in public, perceived physical strength and reported less perceived breastfeeding difficulties. Path analyses indicated that breastfeeding self-efficacy was a strong significant predictor of both exclusive breastfeeding intention and duration. Maternal attitude towards pregnancy (both during pregnancy and postpartum), psychological adjustment and early breastfeeding difficulties were also found to be significant predictors of exclusive breastfeeding intention and duration. psychosocial factors are likely to play a significant role in the maintenance of exclusive breastfeeding for six months post-birth. Future research should adopt a prospective study design to examine the influence of psychosocial factors systematically and rigorously. longitudinal, prospective studies are needed to further examine the role of psychosocial factors on exclusive breastfeeding outcomes. Interventions, which involve improving psychosocial factors such as breastfeeding self-efficacy, may improve exclusive breastfeeding outcomes. 23807049 Kinetic spectrophotometric H-point standard addition method for the simultaneous determination of diloxanide furoate and metronidazole in binary mixtures and biological fluids. Simple, reliable, and sensitive kinetic spectrophotometric method has been developed for the simultaneous determination of diloxanide furoate and metronidazole using H-point standard addition method (HPSAM). The method is based on the oxidation rate difference of diloxanide and metronidazole by potassium permanganate in basic medium. A green color has been developed and measured at 610nm. Different experimental parameters were carefully optimized. The limiting logarithmic and the initial-rate methods were adopted for the construction of the calibration curve of each individual reaction with potassium permanganate. Under the optimum conditions, Beer's law was obeyed in the range of 1.0-20.0 and 5.0-25.0μgml(-1) for diloxanide furoate and metronidazole, respectively. The detection limits were 0.22μgml(-1) for diloxanide furoate and 0.83μgml(-1) for metronidazole. Correlation coefficients of the regression equations were greater than 0.9970 in all cases. The precision of the method was satisfactory; the maximum value of relative standard deviation did not exceed 1.06% (n=5). The accuracy, expressed as recovery was between 99.4% and 101.4% with relative error of 0.12 and 0.14 for diloxanide furoate and metronidazole, respectively. The proposed method was successfully applied for the simultaneous determination of both drugs in pharmaceutical dosage forms and human urine samples and compared with alternative HPLC method. 23347952 Morphine withdrawal produces ERK-dependent and ERK-independent epigenetic marks in neurons of the nucleus accumbens and lateral septum. Epigenetic changes such as covalent modifications of histone proteins represent complex molecular signatures that provide a cellular memory of previously experienced stimuli without irreversible changes of the genetic code. In this study we show that new gene expression induced in vivo by morphine withdrawal occurs with concomitant epigenetic modifications in brain regions critically involved in drug-dependent behaviors. We found that naloxone-precipitated withdrawal, but not chronic morphine administration, caused a strong induction of phospho-histone H3 immunoreactivity in the nucleus accumbens (NAc) shell/core and in the lateral septum (LS), a change that was accompanied by augmented H3 acetylation (lys14) in neurons of the NAc shell. Morphine withdrawal induced the phosphorylation of the epigenetic factor methyl-CpG-binding protein 2 (MeCP2) in Ser421 both in the LS and the NAc shell. These epigenetic changes were accompanied by the activation of members of the ERK pathway as well as increased expression of the immediate early genes (IEG) c-fos and activity-regulated cytoskeleton-associated protein (Arc/Arg3.1). Using a pharmacological approach, we found that H3 phosphorylation and IEG expression were partially dependent on ERK activation, while MeCP2 phosphorylation was fully ERK-independent. These findings provide new important information on the role of the ERK pathway in the regulation of epigenetic marks and gene expression that may concur to regulate in vivo the cellular changes underlying the onset of the opioid withdrawal syndrome. 23945936 YoeB-ribosome structure: a canonical RNase that requires the ribosome for its specific activity. As a typical endoribonuclease, YoeB mediates cellular adaptation in diverse bacteria by degrading mRNAs on its activation. Although the catalytic core of YoeB is thought to be identical to well-studied nucleases, this enzyme specifically targets mRNA substrates that are associated with ribosomes in vivo. However, the molecular mechanism of mRNA recognition and cleavage by YoeB, and the requirement of ribosome for its optimal activity, largely remain elusive. Here, we report the structure of YoeB bound to 70S ribosome in pre-cleavage state, revealing that both the 30S and 50S subunits participate in YoeB binding. The mRNA is recognized by the catalytic core of YoeB, of which the general base/acid (Glu46/His83) are within hydrogen-bonding distance to their reaction atoms, demonstrating an active conformation of YoeB on ribosome. Also, the mRNA orientation involves the universally conserved A1493 and G530 of 16S rRNA. In addition, mass spectrometry data indicated that YoeB cleaves mRNA following the second position at the A-site codon, resulting in a final product with a 3'-phosphate at the newly formed 3' end. Our results demonstrate a classical acid-base catalysis for YoeB-mediated RNA hydrolysis and provide insight into how the ribosome is essential for its specific activity. 23893112 Copper efflux is induced during anaerobic amino acid limitation in Escherichia coli to protect iron-sulfur cluster enzymes and its biogenesis. Adaptation to changing environments is essential to bacterial physiology. Here we report a unique role of the copper homeostasis system in adapting Escherichia coli to its host-relevant environment of anaerobiosis coupled with amino acid limitation. We found that expression of the copper/silver efflux pump CusCFBA was significantly up-regulated during anaerobic amino acid limitation in E. coli without the supplement of exogenous copper. ICP-MS analysis of the total intracellular copper content combined with transcriptional assay of the PcusC-lacZ reporter in the presence of specific Cu(I) chelators indicated that anaerobic amino acid limitation led to the accumulation of free Cu(I) in the periplasmic space of E. coli, resulting in Cu(I) toxicity. Cells lacking cusCFBA and another copper transporter copA under this condition displayed growth defects and reduced ATP production during fumarate respiration. Ectopic expression of the Fe-S cluster enzyme fumarate reductase (Frd), or supplementing amino acids which biosynthesis involves Fe-S cluster enzymes, rescued the poor growth of ΔcusC cells. Yet, Cu(I) treatment did not impair the Frd activity in vitro. Further studies revealed that the alternative Fe-S cluster biogenesis system Suf was induced during the anaerobic amino acid limitation and ΔcusC enhanced this up-regulation, indicating the impairment of the Fe-S cluster assembly machinery and the increased Fe-S cluster demands under this condition. Taken together, we conclude that the copper efflux system CusCFBA was induced during anaerobic amino acid limitation to protect Fe-S cluster enzymes and its biogenesis from the endogenously originated Cu(I) toxicity, thus facilitating the physiological adaptation of E. coli. 23878201 Efficacy of birth ball exercises on labour pain management. OBJECTIVES. To evaluate the efficacy of a birth ball exercise programme conducted by physiotherapists on pain relief, psychological care, and facilitation of the labour process at a labour ward in a regional hospital. DESIGN. Case series with before-after comparisons. SETTING. Kwong Wah Hospital, Hong Kong. PARTICIPANTS. Chinese women admitted to the labour ward for spontaneous vaginal delivery between April and August 2012 were recruited. Physiotherapists taught birth ball exercises in groups or individually for 30 minutes. Labour pain intensity, back pain intensity, frequency of labour pain, stress and anxiety levels, and subjective pressure level over the lower abdomen were captured before and after birth ball exercises. Most of the parameters were measured using self-reported visual analogue scales. After the exercise session, physiotherapists measured the women's satisfaction level. Midwives recorded pethidine usage. RESULTS. A total of 203 pregnant women participated in this programme; 181 were in the latent phase group, whereas 22 were categorised into the no-labour-pain group. In both groups, there were statistically and clinically significant differences in back pain level, stress and anxiety levels, as well as pressure level over the lower abdomen before and after the exercise (P<0.05). In the latent phase group, significant decreases in labour pain and frequency of labour pain were demonstrated. Mean satisfaction scores were high, with visual analogue scale scores higher than 8.2 in both groups. Pethidine usage showed a further decreasing trend (6.4%) compared with the past 2 years. CONCLUSION. Birth ball exercise could be an alternative means of relieving back pain and labour pain in the labour ward, and could decrease pethidine consumption in labouring women. 23889352 Clinical significance and limitations of repeat resection for pediatric malignant neuroepithelial tumors. Object Maximized tumor resection and minimized surgical morbidity are extremely important in the treatment of children with malignant neuroepithelial tumors. However, the indications for repeat surgery for these tumors remain unclear. The present study investigated the clinical significance and limitations of repeat resection for these tumors. Methods This study included 61 consecutive pediatric patients with malignant neuroepithelial tumor, histologically diagnosed as WHO Grades III and IV. All patients were initially treated between January 1997 and March 2011 and had follow-up of more than 2 years. The number of surgeries, presence of leptomeningeal dissemination, survival, WHO grade, and Eastern Cooperative Oncology Group performance status before and after surgery were retrospectively reviewed. Results Repeat resections were performed for 21 patients (34.4%). Eastern Cooperative Oncology Group performance status was not aggravated by surgery, even after multiple operations. The 5-year survival rates of patients who received single and repeat surgery were 58.6% and 38.7%, respectively (p = 0.12). The mean interval between initial surgery and leptomeningeal dissemination detection was 331 ± 108 days in the single-surgery group and 549 ± 122 days in the repeat-surgery group (p = 0.19). The median survival time after leptomeningeal dissemination was 580 days in the single-surgery group and 890 days in the repeat-surgery group (p = 0.74). Conclusions Repeat resection with minimized surgical morbidity is an effective method to achieve better local control of pediatric malignant neuroepithelial tumors. Leptomeningeal dissemination was a leading cause of death, but repeat surgery did not increase the frequency of death. 23844071 Membrane elastic properties and cell function. Recent studies indicate that the cell membrane, interacting with its attached cytoskeleton, is an important regulator of cell function, exerting and responding to forces. We investigate this relationship by looking for connections between cell membrane elastic properties, especially surface tension and bending modulus, and cell function. Those properties are measured by pulling tethers from the cell membrane with optical tweezers. Their values are determined for all major cell types of the central nervous system, as well as for macrophage. Astrocytes and glioblastoma cells, which are considerably more dynamic than neurons, have substantially larger surface tensions. Resting microglia, which continually scan their environment through motility and protrusions, have the highest elastic constants, with values similar to those for resting macrophage. For both microglia and macrophage, we find a sharp softening of bending modulus between their resting and activated forms, which is very advantageous for their acquisition of phagocytic functions upon activation. We also determine the elastic constants of pure cell membrane, with no attached cytoskeleton. For all cell types, the presence of F-actin within tethers, contrary to conventional wisdom, is confirmed. Our findings suggest the existence of a close connection between membrane elastic constants and cell function. 23642203 Prevention of chronic diseases by tea: possible mechanisms and human relevance. Tea, made from leaves of the plant Camellia sinensis, Theaceae, has been used by humans for thousands of years, first as a medicinal herb and then as a beverage that is consumed widely. For the past 25 years, tea has been studied extensively for its beneficial health effects, including prevention of cancer, reduction of body weight, alleviation of metabolic syndrome, prevention of cardiovascular diseases, and protection against neurodegenerative diseases. Whether these effects can be produced by tea at the levels commonly consumed by humans is an open question. This review examines these topics and elucidates the common mechanisms for these beneficial health effects. It also discusses other health effects and possible side effects of tea consumption. This article provides a critical assessment of the health effects of tea consumption and suggests new directions for research in this area. 23339853 Antivenom therapy of carpet viper (Echis ocellatus) envenoming: Effectiveness and strategies for delivery in West Africa. In West Africa, response to specific, geographically appropriate, antivenom is often dramatic following carpet viper (Echis ocellatus) envenoming with rapid restoration of blood coagulability and resolution of spontaneous haemorrhage. Envenoming from Australasian snakes causing similar coagulopathies may respond less dramatically and the effectiveness of antivenom is being questioned. Here we have reviewed and re-analysed all published preclinical and clinical studies on envenoming and antivenom therapy conducted in West Africa to determine the effectiveness of antivenom. 22 studies provided relevant information: 12 observational studies, 4 RCTs and 6 preclinical studies. Four comparative studies confirmed statistically significant protection against mortality ranging from 57 to 87% using specific antivenoms compared to non-specific or no antivenoms. Meta-analysis estimated combined Odds Ratio (95% CI) of 0.25 (0.14-0.45) of dying among those treated with specific antivenom or 75% (95% CI: 55-86%) protection against death. Mortality more than doubled during times when stocks of reliable antivenoms ran out, with Relative Risk (95% CI)] of 2.33 (1.26-4.06). Serum kinetics of venom antigen/antivenom levels also confirmed that decline of venom antigen levels coincided with resolution of coagulopathy while decline of antivenom levels was associated with venom antigen reappearance and recurrence of coagulopathy. Preclinical and antivenomics analysis confirmed efficacy of regionally appropriate antivenoms against E. ocellatus and related species' venoms in Sub-Saharan Africa but not against Asian Echis carinatus venom. Antivenoms raised against E. carinatus were ineffective in human studies. In West Africa, specific antivenom is effective in managing carpet viper envenoming. A centralized hub-and-spoke strategy is suggested for broadening antivenom access to endemic rural areas together with instituting quality assurance, standardization and manpower training. Benefits, risks, cost-effectiveness and feasibility of the approach should be formally assessed. 23955035 Determination of nanostructure of liposomes containing two model drugs by X-ray scattering from a synchrotron source. Small-angle X-ray scattering has been employed to study how the introduction of paracetamol and acetylsalicylic acid into a liposome bilayer system affects the system's nanostructure. An X-ray scattering model, developed for multilamellar liposome systems [Pabst et al. (2000), Phys. Rev. E, 62, 4000-4009], has been used to fit the experimental data and to extract information on how structural parameters, such as the number and thickness of the bilayers of the liposomes, thickness of the water layer in between the bilayers, size and volume of the head and tail groups, are affected by the drugs and their concentration. Even though the experimental data reveal a complicated picture of the drug-bilayer interaction, they clearly show a correlation between nanostructure, drug and concentration in some aspects. The localization of the drugs in the bilayers is discussed. 23863074 Factors associated with clinically significant insomnia among pregnant low-income latinas. Abstract Background: Poor sleep, common during pregnancy, is associated with negative health risks. The study aimed to identify predictors of clinically significant insomnia among pregnant Latinas. Methods: A total of 1289 pregnant Latinas recruited from obstetric clinics completed the Insomnia Severity Index (ISI) and questions about demographics and sleep. Results: Clinically significant insomnia (ISI≥10) was present among 17% of participants. Significant correlates of clinically significant insomnia were higher scores on the Edinburgh Postnatal Depression Scale (EPDS) after removing the sleep item (47% of women with EPDS≥9 and 9% with EPDS<9), completing measures in English (rather than Spanish: 26% versus 13%), and income but not pregnancy week, age, highest education level, or marital status. The highest percentage of clinically significant insomnia (59%) was experienced by women with EPDS≥9 who completed measures in English. The lowest percentage of clinically significant insomnia (6.2%) was experienced by women with EPDS<9 who completed measures in Spanish. Conclusions: In this sample of low-income, mostly Spanish-speaking pregnant Latinas, rates of clinically significant insomnia appear to be higher than rates among nonpregnant Latinas. Rates of clinically significant insomnia are particularly high among Latinas with elevated depressive symptom severity, a known risk for insomnia. Acculturation, as indicated by completing measures in English, may be another risk specific to Latinas, possibly owing to loss of some ethnicity-specific protective factors (e.g., social support, strong family ties, and group identity). It will be important to directly test this explanation in future research. 23944967 Synthesis of Chromeno[2,3-d]imidazol-9(1H)-ones via Tandem Reactions of 3-Iodochromones with Amidines Involving Copper-Catalyzed C-H Functionalization and C-O Bond Formation. A novel six-membered heterocyclic skeleton of imidazochromone was prepared via an efficient one-pot reaction including a key step of copper-catalyzed aerobic C-H intramolecular cycloetherification. Notably, this process does not require the presence of strong para electron-withdrawing groups on the phenol component. Also, the results of this effort show that acyl phenols containing electron-rich heterocycles participate in an efficient C-H activation/C-O formation process. 23838039 Mechanisms of photosynthetic inactivation on growth suppression of Microcystis aeruginosa under UV-C stress. This study aims to investigate the effects of UV-C irradiation on photosynthetic processes of Microcystis aeruginosa to unravel the mechanism(s) involved in how and in what ways UV-C mediates growth suppression and cellular recovery. Changes in the concentration of photosynthetic pigments, photochemical efficiency, PS II core protein (D1) content, and the coding genes expressions were measured. The results indicate that UV-C doses at 20-200mJcm(-2) lead to rapid reduction in gene expression of both psbA (for D1) and cpc (for phycocyanin), but the suppression was short term and recoverable within 3 d of post-UV incubation. Conversely, UV-C doses at ⩾50mJcm(-2) could induce marked decline in photochemical efficiency (represented by the optimal PS II quantum yield, FV/FM, and the effective PS II quantum yield, Y) as well as decreases in D1 content and water soluble pigments (phycoerythrins, phycocyanins, allophycocyanins) in M. aeruginosa during the post UV-C incubation period. The results suggest that interruption of both the light energy harvesting apparatus (especially the water soluble pigments) and the photochemical process mainly accounted for the growth suppression effect in UV-C irradiated M. aeruginosa. 23052250 Secular trends in the association between nativity/length of US residence with body mass index and waist circumference among Mexican-Americans, 1988-2008. We investigated whether associations between nativity/length of US residence and body mass index (BMI) and waist circumference (WC) varied over the past two decades. Mexican-Americans aged 20-64 years from the National Health and Nutrition Survey (NHANES) III (1988-1994), and NHANES (1999-2008). Sex-stratified multivariable linear regression models further adjusted for age, education, and NHANES period. We found no evidence of secular variation in the nativity/length of US residence gradient for men or women. Foreign-born Mexican-Americans, irrespective of residence length, had lower mean BMI and WC than their US-born counterparts. However among women, education modified secular trends in nativity differentials: notably, in less-educated women, nativity gradients widened over time due to alarming increases in BMI among the US-born and little increase in the foreign-born. Associations between nativity/length of US residence and BMI/WC did not vary over this 20-year period, but we noted important modifications by education in women. Understanding these trends is important for identifying vulnerable subpopulations among Mexican-Americans and for the development of effective health promotion strategies in this fast-growing segment of the population. 23905603 A learner developed longitudinal interprofessional education curriculum. Abstract Increased patient safety requires interprofessional collaboration, now critical given rising healthcare costs and an aging population with complex and chronic conditions. One way in which to educate future health care team members about team dynamics is to have them learn through active participation on a team. Six students representing the five health professions programs at the University of California, San Francisco formed a curriculum development team that created a novel yearlong interprofessional education curriculum and assessed its impact on knowledge, skills and attitudes of first-year learners in medicine, physical therapy, dentistry, nursing, and pharmacy (n = 480). Through their participation on the curriculum development team and reflection on their roles, responsibilities, communication and negotiation, the six students developed the inter-personal and intra-personal skills required for successful interprofessional collaboration. 23661264 Novel pathways and molecular targets for the treatment of sarcoma. Sarcomas collectively represent over 100 different subtypes of bone and soft tissue tumors of mesenchymal origin. The low response rate to cytotoxic chemotherapies has necessitated the need for development of either histologically driven or pathway-specific targeted therapies. As our understanding of the molecular mechanisms driving certain subtypes is rapidly advancing, the number of targeted therapies is also increasing. Recently identified novel druggable targets include the MDM2 amplifications in well-differentiated and dedifferentiated liposarcomas, the new translocation NAB2:STAT6 of solitary fibrous tumors, the angiopoeitin-TIE2 pathway in angiosarcoma, the suppression of Mcl1 in X:18/synovial sarcomas, the mTOR pathway in malignant peripheral nerve sheath tumors, CDK4 in alveolar rhabdomyosarcoma, cMET regulation in alveolar soft parts sarcoma, the metabolic abnormalities in wild-type/SHD GIST, and the lack of argininosuccinate synthetase 1 expression seen in most sarcomas. It is through a fundamental understanding of sarcoma biology that clinical trials based on molecular targets can be developed. 23631672 Spectroscopic Study of the Light-Harvesting CP29 Antenna Complex of Photosystem II - Part I. Recent structural data revealed that the CP29 protein of higher plant Photosystem II (PSII) contains 13 chlorophylls (Chls) per complex [Pan et al., Nat. Struct. Mol. Biol. 2011, 18, 309], i.e., five Chls more than in the predicted CP29 homology-based structure model [Bassi et al., Proc. Natl. Acad. Sci. USA 1999, 96, 10056]. This lack of consensus presents a constraint on the interpretation of CP29 optical spectra and their underlying electronic structure. To address this problem, we present new low-temperature (5 K) absorption, fluorescence, and hole-burned (HB) spectra for CP29 proteins from spinach, which are compared with the previously reported data. We focus on excitation energy transfer (EET) and the nature of the lowest-energy state(s). We argue that CP29 proteins previously studied by HB spectroscopy lacked at least one Chl a molecule (i.e., a615 or a611), which along with Chl a612 contribute to the lowest energy state in more intact CP29, and one Chl b (most likely b607). This is why the low-energy state and fluorescence maxima reported by Pieper et al. [Photochem. Photobiol. 2000, 71, 574] were blueshifted by ~ 1 nm, the low-energy state appeared to be highly localized on a single Chl a molecule, and the position of the low-energy state was independent of burning fluence. In contrast, the position of the nonresonant HB spectrum shifts blue with increasing fluence in intact CP29, as this state is strongly contributed to by several pigments (i.e., a611, a612, a615 and a610). Zero-phonon hole widths obtained for the Chl b band at 638.5 nm (5 K) revealed two independent Chl b → Chl a EET times, i.e., 4 ± 0.5 ps and 0.4 ± 0.1 ps. The latter value is a factor of two faster than previously observed by HB spectroscopy and very similar to the one observed by Gradinaru et al. [J. Phys. Chem. B 2000, 104, 9330] in pump-probe experiments. EET time from 650 nm Chl b → Chl a and downward EET from Chl(s) a state(s) at 665 nm occurs in 4.9 ± 0.7 ps. These findings provide important constraints for excitonic calculations that are discussed in the accompanying paper (Part II). 22625220 Rapid characterisation of flavonoids from Sophora alopecuroides L. by HPLC/DAD/ESI-MSn. An HPLC/DAD/ESI-MSn method was established to characterise flavonoids in the seeds of Sophora alopecuroides L. All the flavonoids exhibited abundant [M-H]- ions, which triggered data-dependent multistage mass spectrometry fragmentations. Characteristic UV spectra were used to confirm flavonoid subtypes. In total, 22 flavonoids and two phenolic compounds were detected and identified. Five of them were identified by comparing with reference standards, and the others were characterised based on the retention behaviour, multistage fragmentation feature and UV absorption. A total of 19 compounds were reported from S. alopecuroides for the first time. This method accomplished rapid profiling of flavonoid constituents in S. alopecuroides L. 23826834 Fundus Fluorescein Angiographic Findings in Patients Who Underwent Ventricular Assist Device Implantation. Disruption of microcirculation in various tissues as a result of deformed blood rheology due to ventricular assist device (VAD) implantation causes novel arteriovenous malformations. Capillary disturbances and related vascular leakage in the retina and choroidea may also be seen in patients supported by VADs. We aimed to evaluate retinal vasculature deteriorations after VAD implantation. The charts of 17 patients who underwent VAD implantation surgery for the treatment of end-stage heart failure were retrospectively reviewed. Eight cases (47.1%) underwent pulsatile pump implantation (Berlin Heart EXCOR, Berlin Heart Mediprodukt GmbH, Berlin, Germany); however, nine cases (52.9%) had continuous-flow pump using centrifugal design (HeartWare, HeartWare Inc., Miramar, FL, USA). Study participants were selected among the patients who had survived with a VAD for at least 6 months, and results of detailed ophthalmologic examinations including optic coherence tomography (OCT) and fundus fluorescein angiography (FA) were documented. All of the 17 patients were male, with a mean age of 48.5 ± 14.8 years (15-67 years). Detailed ophthalmologic examinations including the evaluation of retinal vascular deteriorations via FA were performed at a mean of 11.8 ± 3.7 months of follow-up (6-18 months). Mean best-corrected visual acuity and intraocular pressure were found as logMAR 0.02 ± 0.08 and 14.6 ± 1.9 mm Hg, respectively in the study population. Dilated fundoscopy revealed severe focal arteriolar narrowing in two patients (11.8%), and arteriovenous crossing changes in four patients (23.5%); however, no pathological alteration was present in macular OCT scans. In patients with continuous-flow blood pumps, mean arm-retina circulation time (ARCT) and arteriovenous transit time (AVTT) were found to be 16.8 ± 3.0 and 12.4 ± 6.2 s, respectively; whereas those with pulsatile-flow blood pumps were found to be 17.4 ± 3.6 and 14.0 ± 2.1 s in patients (P = 0.526 and P = 0.356, respectively). FA also revealed a tendency for increased frequency of dye leakage from the optic disc in our study population. Except for remarkable delays in both ARCT and AVTT as well as a tendency for increased frequency of dye leakage from the optic disc, ophthalmologic evaluations revealed no other significant pathology or vascular deterioration in the retina that could be attributed to artificial heart systems. 23954516 Integrative commentary: Implications of blunted reactivity. The previous issue of the International Journal of Psychophysiology was a special issue that collected some of the latest emerging evidence on blunted reactivity and its relationships with a variety of negative health outcomes. This commentary on the special issue briefly reviews each of the contributions and then provides some thoughts on the general themes that run through these papers. The findings from the special issue suggest that both lower and higher than expected cardiovascular and neuroendocrine responses to active psychological challenges may be maladaptive and differentially associated with adverse health sequelae. 23814079 Dual Roles of the Transcription Factor Grainyhead-like 2 (GRHL2) in Breast Cancer. Using a retrovirus-mediated cDNA expression cloning approach, we identified the grainyhead-like 2 (GRHL2) transcription factor as novel protooncogene. Overexpression of GRHL2 in NIH3T3 cells induced striking morphological changes, an increase in cell proliferation, anchorage-independent growth, and tumor growth in vivo. By combining a microarray analysis and a phylogenetic footprinting analysis with various biochemical assays, we identified the epidermal growth factor receptor family member Erbb3 as a novel GRHL2 target gene. In breast cancer cell lines, shRNA-mediated knockdown of GRHL2 expression or functional inactivation of GRHL2 using dominant negative GRHL2 proteins induces down-regulation of ERBB3 gene expression, a striking reduction in cell proliferation, and morphological and phenotypical alterations characteristic of an epithelial-to-mesenchymal transition (EMT), thus implying contradictory roles of GRHL2 in breast carcinogenesis. Interestingly, we could further demonstrate that expression of GRHL2 is directly suppressed by the transcription factor zinc finger enhancer-binding protein 1 (ZEB1), which in turn is a direct target for repression by GRHL2, suggesting that the EMT transcription factors GRHL2 and ZEB1 form a double negative regulatory feedback loop in breast cancer cells. Finally, a comprehensive immunohistochemical analysis of GRHL2 expression in primary breast cancers showed loss of GRHL2 expression at the invasive front of primary tumors. A pathophysiological relevance of GRHL2 in breast cancer metastasis is further demonstrated by our finding of a statistically significant association between loss of GRHL2 expression in primary breast cancers and lymph node metastasis. We thus demonstrate a crucial role of GRHL2 in breast carcinogenesis. 22960936 Analysis of Reserve Capacity and Subsequent Stenting in a Case of Subacute Occlusion of the Internal Carotid Artery. While acute internal carotid artery (ICA) occlusions are increasingly being treated with carotid angioplasty and stenting (CAS), the utility of CAS in subacute stages is unclear. A 65-year-old patient with an acute left ICA occlusion and pre-existing occlusion on the right side presented with dysarthria and central right-sided facial palsy. Carbon dioxide (CO2) reactivity within the left hemisphere was markedly reduced. Due to acute deterioration despite maximal conservative therapy CAS was performed 8 days after the initial event with an excellent result and symptoms subsided. CAS in subacute ICA occlusion is possible. Patients should be selected carefully. Assessment of cerebrovascular CO2 reactivity might provide valuable information. 23818044 Directed manipulation of a flavoprotein photocycle. Tamed electrons: To manipulate a protein photocycle in a directed manner, the flavoprotein dodecin was endoscopically modified at its key amino acid tryptophan with substituents carefully selected by their structural and electronic influence. The approach is ideal in the precision of rational protein engineering, and allows correlating tryptophan ionization potentials and electron transfer rates in a Marcus model. 23198807 Downregulation of tumor growth and invasion by redox-active nanoparticles. Abstract Aims: Melanoma is the most aggressive type of malignant skin cancer derived from uncontrolled proliferation of melanocytes. Melanoma cells possess a high potential to metastasize, and the prognosis for advanced melanoma is rather poor due to its strong resistance to conventional chemotherapeutics. Nanomaterials are at the cutting edge of the rapidly developing area of nanomedicine. The potential of nanoparticles for use as carrier in cancer drug delivery is infinite with novel applications constantly being tested. The noncarrier use of cerium oxide nanoparticles (CNPs) is a novel and promising approach, as those particles per se show an anticancer activity via their oxygen vacancy-mediated chemical reactivity. Results: In this study, the question was addressed of whether the use of CNPs might be a valuable tool to counteract the invasive capacity and metastasis of melanoma cells in the future. Therefore, the effect of those nanoparticles on human melanoma cells was investigated in vitro and in vivo. Concentrations of polymer-coated CNPs being nontoxic for stromal cells showed a cytotoxic, proapoptotic, and anti-invasive capacity on melanoma cells. In vivo xenograft studies with immunodeficient nude mice showed a decrease of tumor weight and volume after treatment with CNPs. Innovation: In summary, the redox-active CNPs have selective pro-oxidative and antioxidative properties, and this study is the first to show that CNPs prevent tumor growth in vivo. Conclusion: The application of redox-active CNPs may form the basis of new paradigms in the treatment and prevention of cancers. Antioxid. Redox Signal. 19, 765-778. 23615500 The calcium sensing receptor modulates fluid reabsorption and acid secretion in the proximal tubule. The proximal tubule uses a complex process of apical acid secretion and basolateral bicarbonate absorption to regulate both luminal acidification and fluid absorption. One of the primary regulators of apical acid secretion is the luminal sodium-hydrogen exchanger expressed along the apical membrane of the proximal tubule. Similarly, the calcium-sensing receptor (CaSR) is also located along the luminal membrane of the proximal tubule. Here we investigated the role of CaSR in proton secretion and fluid reabsorption in proximal tubules by modulating luminal calcium concentration, using both in vivo micropuncture in rats and in vitro perfused mouse proximal tubules. Using CaSR knockout mice and a calcimimetic agent, we found that increased proton secretion and fluid reabsorption were CaSR dependent. Activating CaSR by either raising the luminal calcium ion concentration or by the calcimimetic caused a concomitant increase in sodium-dependent proton extrusion and fluid reabsorption, whereas in proximal tubules isolated from CaSR knockout mice varying calcium ion concentration had no effect. Application of a calcimimetic in lower concentrations of calcium ion stimulated these processes in vitro and in vivo. Thus, in both rats and mice, increased luminal calcium concentration leads to enhanced fluid reabsorption in the proximal tubule, a process related to activation of CaSR. 23357402 Towards the validation of a lung tumorigenesis model with mainstream cigarette smoke inhalation using the A/J mouse. A generally accepted and validated laboratory model for smoking-associated pulmonary tumorigenesis would be useful for both basic and applied research applications, such as the development of early diagnostic endpoints or the evaluation of modified risk tobacco products, respectively. The A/J mouse is susceptible for developing both spontaneous and induced lung adenomas and adenocarcinomas, and increased lung tumor multiplicities were also observed in previous cigarette smoke inhalation studies. The present study was designed to collect data useful towards the validation of an 18-month mainstream smoke (MS) inhalation model. Male and female A/J mice were exposed whole-body at three MS concentration levels for 6h/day, and the results were compared to a previous study in the same laboratory and with a similar design. A linear MS concentration-dependent increase in lung tumorigenesis was observed with similar slopes for both sexes and both studies and a maximal 5-fold increase in multiplicity beyond sham control. The minimal detectable difference in lung tumor multiplicity for the current study was 37%. In the larynx, papillomas were detectable in all MS-exposed groups in a non-concentration dependent manner. No other extra-pulmonary MS-dependent neoplastic lesions were found. Gene expression signatures of lung tumor tissues allowed a clear differentiation of sham- and high dose MS-exposed mice. In combination with data from previous smoke inhalation studies with A/J mice, the current data suggest that this model for MS inhalation-induced pulmonary tumorigenesis is reliable and relevant, two crucial requirements towards validation of such a model. 23916735 The cell adhesion molecule L1 regulates the expression of FGF21 and enhances neurite outgrowth. L1 plays a role in neural development. However, it remains unclear how L1 plays this role. In the present study, we have shown extensive outgrowth of long neurites in cerebellar neurons after treatment with either L1 or L1 antibody. Notably, the mRNA level of FGF21 was significantly increased in both L1 and L1 antibody treated neurons compared to control group. Consistently, the neurite outgrowth promoted by L1 was strongly inhibited by siRNA against FGF21 gene or a treatment of cells with FGFR inhibitor. These results demonstrate that FGF21/FGFR signaling promotes the neurite outgrowth in a L1-dependent manner. 23826865 Transcriptional analysis of intramuscular fatty acid composition in the longissimus thoracis muscle of Iberian Ã— Landrace back-crossed pigs. This study aimed at identifying differential gene expression conditional on the fatty acid profile of the longissimus thoracis (Lt) muscle, a prime cut of economic relevance for fresh and cured pork production. A population of 110 Iberian (25%) Ã— Landrace (75%) back-crossed pigs was used, because these two breeds exhibit extreme profiles of intramuscular saturated fatty acid, monounsaturated fatty acid (MUFA) and polyunsaturated fatty acid (PUFA) contents. Total RNA from Lt muscle was individually hybridized to GeneChip Porcine Genome arrays (Affymetrix). A principal component analysis was performed with data from the 110 animals to select 40 extreme animals based on the total fatty acid profile and the MUFA composition (MAP). Comparison of global transcription levels between extreme fatty acid profile pigs (n = 40) resulted in 219 differentially expressed probes (false discovery rate <0.10). Gene ontology, pathway and network analysis indicated that animals with higher percentages of PUFA exhibit a shift toward a more oxidative muscular metabolism state, with a raise in mitochondria function (PPARGC1A, ATF2), fatty acid uptake and oxidation (FABP5, MGLL). On the other hand, 87 probes were differentially expressed between MUFA composition groups (n = 40; false discovery rate <0.10). In particular, muscles rich in n-7 MUFA expressed higher levels of genes involved in lipid metabolism (GLUL, CRAT, PLA2G15) and lower levels of fatty acid elongation genes (ELOVL5). Moreover, the chromosomal position of FABP5, PAQR3, MGLL, PPARGC1A, GLUL and ELOVL5 co-localized with very relevant QTL for fat deposition and composition described in the same resource population. This study represents a complementary approach to identifying genes underlying these QTL effects. 23850695 Application of real-time RT-PCR in vector surveillance and assessment of replication kinetics of an emerging novel ECSA genotype of Chikungunya virus in Aedes aegypti. Chikungunya has emerged as one of the most important arboviral infection of global significance. Expansion of Chikungunya virus endemic areas can be ascribed to naive population, increasing vector population and adaptability of virus to new vector. In this study, a SYBR Green I based quantitative RT-PCR assay was developed. The assay was found to be 10-fold more sensitive than conventional RT-PCR and no cross reactivity was observed with related alphaviruses and flaviviruses. The detection efficiency of the assay was impervious to mosquitoes of different pool sizes. Vector surveillance has resulted in detection of CHIKV RNA in Aedes aegypti, confirming its vectorial potential for CHIKV in northern India. The assessment of the assay was further carried out by studying the competence of Indian Ae. aegypti for CHIKV, which revealed 100% infection rate and dissemination rate with 60% transmission rate. The replication kinetics of CHIKV in different anatomical sites of Ae. aegypti revealed highest titre at day 6 post infection in midgut and at day 10 post infection in saliva, legs and wings. The implementation of the assay in detecting lower viral load makes it a remarkable tool for surveillance of virus activity in mosquitoes. 23943795 Fertility drugs and endometrial cancer risk: results from an extended follow-up of a large infertility cohort. Do fertility drugs influence the subsequent risk of endometrial cancer in a manner that is independent of other risk predictors, such as parity? In this follow-up of a large cohort of women evaluated for infertility and for whom information was captured on fertility drugs, indications for usage and other risk factors that might influence cancer risk, we found no evidence for a substantial relationship between fertility drug use and endometrial cancer risk. Although the hormonal etiology of endometrial cancer has been well established, it remains unclear whether the use of fertility drugs has an influence on risk. Results regarding the effects of fertility drugs on endometrial cancer risk have been inconsistent, although several studies have shown some evidence for possible increases in risk. The relationship is of particular interest given that clomiphene, a commonly prescribed drug, is a selective estrogen receptor modulator, with chemical properties similar to tamoxifen, another drug linked to an increase in endometrial cancer risk. In a retrospective cohort of 12 193 women evaluated for infertility between 1965 and 1988 at five US sites, follow-up was pursued through 2010 via both passive as well as active (questionnaire) means. Among the 9832 subjects for whom follow-up was allowed and achieved, 259 346 at-risk person-years (i.e. prior to hysterectomy) were accrued, and 118 invasive endometrial cancers identified. Cox regression determined hazard ratios (HRs) and 95% confidence intervals (CIs) for fertility treatments adjusted for endometrial cancer risk factors and causes of infertility. Although we observed slight increases in endometrial cancer risk associated with clomiphene (HR = 1.39, 95% CI: 0.96-2.01) and the less commonly prescribed gonadotrophins (1.34, 0.76-2.37), there were no convincing relationships of risk with either cycles of use or cumulative exposures for either drug. A statistically significant risk associated with the use of clomiphene among women who began use at younger ages (<30) (1.93, 1.24-3.00) may have reflected indications for drug usage rather than the effect of the drug itself. Women who received clomiphene followed by gonadotrophins were at a non-significantly elevated risk (1.77, 0.98-3.19). Like most studies of endometrial cancer, we were limited by sample sizes, particularly for evaluating subgroup associations. We were also unable to follow all women and were not able to obtain complete risk factor information (including hysterectomy status) for the entire cohort. Although we found no support for a relationship between fertility drugs and endometrial cancer risk, the association should continue to be monitored given that our study population was still young and had not yet reached the age of peak endometrial cancer incidence. This project was supported in part by funds from the intramural research program of the National Cancer Institute, National Institutes of Health. None of the authors has any conflicting interests to declare. 23948479 Segment-specific and state-dependent targeting accuracy of the stick insect. In its natural habitat, Carausius morosus climbs on the branches of bushes and trees. Previous work suggested that stick insects perform targeting movements with their hind legs to find support more easily. It has been assumed that the animals use position information from the anterior legs to control the touchdown position of the ipsilateral posterior legs. Here we address the questions if not only the hind but also the middle leg performs targeting, and if targeting is still present in a walking animal when influences of mechanical coupling through the ground are removed. If this were the case, it would emphasize the role of underlying neuronal mechanisms. We studied whether targeting occurred in both legs, when the rostral neighboring leg, i.e. either middle- or front leg, was placed at defined positions relative to the body, and analyzed targeting precision for dependency on the targeted position. Under these conditions, the touchdown positions of the hind legs show correlation to the position of the middle leg parallel and perpendicular to the body axis while only weak correlation exists between the middle and front legs, and only in parallel to the body axis. In continuously walking tethered animals targeting accuracy of hind and middle legs parallel to the body axis was barely different. However, targeting became significantly more accurate perpendicular to the body axis. Our results suggest that a neural mechanism exists for controlling the touchdown position of the posterior leg but that the strength of this mechanism is segment-specific and dependent on the behavioral context in which it is used. 23940230 Explicit Prognostic Information and Reassurance About Nonabandonment When Entering Palliative Breast Cancer Care: Findings From a Scripted Video-Vignette Study. When discussing the transition to palliative care for patients with breast cancer, oncologists have to find a balance between giving explicit information while not overwhelming patients and being realistic while remaining hopeful. It is unclear whether patients prefer more or less explicit prognostic information, and reassuring patients that they will not be abandoned may provide realistic hope. We assessed the effect of explicit prognostic information and reassurance about nonabandonment at the transition to palliative care. An experimental 2 × 2 study was used. Four scripted videos of a bad news conversation were created that differed only in the level of "explicitness of prognosis" and "reassurance about nonabandonment" (high v low). Patients with and survivors of breast cancer (n = 51) and healthy women (n = 53) watched the video-vignettes. The effects of the different communications on participants' anxiety, uncertainty, self-efficacy, and satisfaction were assessed by using multilevel analyses that explored the moderating influences of monitoring/blunting scores. The highly explicit/highly reassuring video yielded the most positive outcomes, and the less explicit/less reassuring video, the most negative (P ≤ .05 for all outcome measures except anxiety). The main effects found were that explicitness and reassurance decreased participants' uncertainty (P < .001 and P = .002, respectively) and anxiety (only after reassurance; P = .001) while increasing self-efficacy (P = .004 and P < .001, respectively) and satisfaction (P < .001 and P < .001, respectively). High monitors seemed least positive, mainly following explicitness. Explicit prognostic information may lead to better outcomes than general information. In addition, reassurance about nonabandonment might provide realistic hope but should be lived up to. More research is needed to translate these findings into clinical care. 23933981 Endothelial TWIK-related potassium channel-1 (TREK1) regulates immune-cell trafficking into the CNS. The blood-brain barrier (BBB) is an integral part of the neurovascular unit (NVU). The NVU is comprised of endothelial cells that are interconnected by tight junctions resting on a parenchymal basement membrane ensheathed by pericytes, smooth muscle cells and a layer of astrocyte end feet. Circulating blood cells, such as leukocytes, complete the NVU. BBB disruption is common in several neurological diseases, but the molecular mechanisms involved remain largely unknown. We analyzed the role of TWIK-related potassium channel-1 (TREK1, encoded by KCNK2) in human and mouse endothelial cells and the BBB. TREK1 was downregulated in endothelial cells by treatment with interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Blocking TREK1 increased leukocyte transmigration, whereas TREK1 activation had the opposite effect. We identified altered mitogen-activated protein (MAP) kinase signaling, actin remodeling and upregulation of cellular adhesion molecules as potential mechanisms of increased migration in TREK1-deficient (Kcnk2(-/-)) cells. In Kcnk2(-/-) mice, brain endothelial cells showed an upregulation of the cellular adhesion molecules ICAM1, VCAM1 and PECAM1 and facilitated leukocyte trafficking into the CNS. Following the induction of experimental autoimmune encephalomyelitis (EAE) by immunization with a myelin oligodendrocyte protein (MOG)35-55 peptide, Kcnk2(-/-) mice showed higher EAE severity scores that were accompanied by increased cellular infiltrates in the central nervous system (CNS). The severity of EAE was attenuated in mice given the amyotrophic lateral sclerosis drug riluzole or fed a diet enriched with linseed oil (which contains the TREK-1 activating omega-3 fatty acid α-linolenic acid). These beneficial effects were reduced in Kcnk2(-/-) mice, suggesting TREK-1 activating compounds may be used therapeutically to treat diseases related to BBB dysfunction. 23899048 Motor learning in children with hemiplegic cerebral palsy and the role of sensation in short-term motor training of goal-directed reaching. Our aim was to determine if improved upper limb kinematics in children with cerebral palsy (CP) during a reach-to-grasp task could be retained and transferred to a similar task. We also characterized the relationship between sensation and motor learning. We used a prospective, single-participant research design with 16 children (seven males, nine females; mean/median age 8.6/9y; age range 6-11y) with spastic hemiparesis (Manual Ability Classification System levels II-IV). Children were randomly allocated to one of two groups: (1) task-oriented training with or (2) without trunk restraint. The intervention consisted of three 1-hour sessions per week for 5 weeks (total 15h). Evaluations consisted of sensory modalities (tactile threshold, touch, proprioception, stereognosis) and upper limb kinematics during reach-to-grasp of an object located near and far from the body (five assessments: three pre-intervention, immediately post-intervention and 3mo post-intervention). Motor improvements could be retained 3 months after the intervention and transferred to a similar task in children with CP. Proprioception and tactile thresholds were associated with retention of improvements in endpoint velocity (F2,13 =4.832, p=0.027). Practice of activities aimed at improving upper limb kinematics led to better learning and retention of movement patterns in children with CP. Our results underline the importance of sensation for motor learning in children with CP. 23929528 Extreme thermal noxious stimuli induce pain responses in zebrafish larvae. Exposing tissues to extreme high or low temperature leads to burns. Burned animals sustain several types of damage, from the disruption of the tissue to degeneration of axons projecting through muscle and skin. Such damage causes pain due to both inflammation and axonal degeneration (neuropathic-like pain). Thus, the approach to cure and alleviate the symptoms of burns must be twofold: rebuilding the tissue that has been destroyed and alleviating the pain derived from the burns. While tissue regeneration techniques have been developed, less is known on the treatment of the induced pain. Thus, appropriate animal models are necessary for the development of the best treatment for pain induced in burned tissues. We have developed a methodology in the zebrafish aimed to produce a new animal model for the study of pain induced by burns. Here we show that two events linked to the onset of burn-induced inflammation and neuropathic-like pain in mammals, degeneration of axons innervating the affected tissues and over-expression of specific genes in sensory tissues, are conserved from zebrafish to mammals. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc. 23536131 Heterozygous non-synonymous ROBO2 variants are unlikely to be sufficient to cause familial vesicoureteric reflux. ROBO2, the receptor of SLIT2, is one of many genes/proteins that regulate the outgrowth of the ureteric bud, which is the first step in the development of the metanephric urinary system. Non-synonymous variants in ROBO2 have been found in a small proportion of patients with primary vesicoureteric reflux (VUR) in various countries. Here we sequenced 1 kb of promoter and all exons of ROBO2b with intronic margins in 227 index cases with primary VUR in an Irish population and found 55 variants, of which 20 were novel. We assessed the variants for evolutionary conservation and investigated novel and uncommon known conserved variants in 23 further index cases and family members of all index cases (to check for segregation with VUR), and then in healthy controls if we found segregation of the variants with VUR. Apart from one non-synonymous variant that was previously found in controls, we did not find any of the six other previously reported non-synonymous variants, but found four new non-synonymous variants. Of those, only two segregated with the disorder (p.Pro522Thr and p.Val799Ile). The former was not present in any of 592 healthy controls; the latter was present in one control. There are now 35 reported non-synonymous coding variants of ROBO2b. The predicted pathogenicity of those that have so far been found exclusively in VUR patients does not differ from that predicted for those variants also found in controls. Thus, our finding does not completely rule out that some variants may be the sole cause of VUR, but it is clear from the overall frequency that most of them cannot be. However, it is possible that some of these variants may cause VUR in combination with a mutation in another gene. 23912085 New synthesis of silver phosphonate complexes from polymeric silver phenylethynide as a structure-directing precursor. Three new silver(i) phosphonate complexes have been synthesized from silver phenylethynide as a structure-directing precursor. Ag2(PhPO3)(H2O) displays a layer-type coordination network, Ag(3,5-dimethylpyrazole)2(PhPO3H) contains a dimeric unit, and {Ag8(dppm)4((t)BuPO3)2(ClO4)(NO3)0.67(H2O)1.33}·(ClO4)2.33·(CH3OH)6.67 features an octanuclear composite cluster. We have also isolated the pyrophenylphosphonate complex Ag2[PhPO2(O)O2PPh](CH3CN), which exhibits an infinite-chain structure. 23949893 Error processing in current and former cocaine users. Deficits in response inhibition and error processing can result in maladaptive behavior, including failure to use past mistakes to inform present decisions. A specific deficit in inhibiting a prepotent response represents one aspect of impulsivity and is a prominent feature of addictive behaviors in general, including cocaine abuse/dependence. Brain regions implicated in cognitive control exhibit reduced activation in cocaine abusers. The purposes of the present investigation were (1) to identify neural differences associated with error processing in current and former cocaine-dependent individuals compared to healthy controls and (2) to determine whether former, long-term abstinent cocaine users showed similar differences compared with current users. The present study used an fMRI Go/No-Go task to investigate differences in BOLD response to correct rejections and false alarms between current cocaine users (n = 30), former cocaine users (n = 29), and healthy controls (n = 35). Impulsivity trait measures were also assessed and compared with BOLD activity. Nineteen regions of interest previously implicated in errors of disinhibition were queried. There were no group differences in the correct rejections condition, but both current and former users exhibited increased BOLD response relative to controls for false alarms. In current users, the pregenual cingulate gyrus and left angular/supramarginal gyri overactivated. In former users, the right middle frontal/precentral gyri, right inferior parietal lobule, and left angular/supramarginal gyri overactivated. Overall, our results support a hypothesis that neural activity in former users differs more from healthy controls than that of current users due to cognitive compensation that facilitates abstinence. 23270976 Reduced social interaction, behavioural flexibility and BDNF signalling in the BTBR T+tf/J strain, a mouse model of autism. Autism is a neurodevelopmental disorder characterized by social and communication impairments and repetitive behaviours. The inbred BTBR T+tf/J (BTBR) strain, a putative mouse model of autism, exhibits lower social interactions, higher repetitive self-grooming levels and unusual pattern of vocalizations as compared to C57BL/6J strain. First aim of the present study was to evaluate at adolescence (postnatal days 30-35) male BTBR and C57BL/6J performances in two different tasks involving either investigation of social cues (same strain partners) or non social ones (inanimate objects). In the social interaction test, BTBR mice showed a reduction of investigation of the social partner, due to a selective reduction of head sniffing, associated with a decrease in ultrasonic vocalizations. By contrast, no strain differences were detected in object investigations. Second aim of the study was to evaluate adult male BTBR and C57BL/6J performances in a fear conditioning task. Strain differences were evident during contextual retest: these strain differences primarily suggested a lack of behavioural flexibility in BTBR mice (i.e. realizing the occurrence of changes in the experimental paradigm). Subsequent electrophysiological analysis in hippocampal slices from adult BTBR and C57BL/6J mice revealed a significant reduction of Brain Derived Neurotrophic Factor (BDNF)-induced potentiation of synaptic transmission in BTBR mice. BDNF and tyrosine kinase B (TrkB) protein levels measured in the hippocampal region were also lower in BTBR as compared to C57BL/6J mice. These data confirm the presence of low levels of direct interaction with social stimuli in BTBR mice at adolescence, in the absence of any strain difference as for investigation of physical objects. At adulthood in BTBR mice clear signs of behavioural inflexibility were evident whereas both biochemical and electrophysiological data point to decreased BDNF signalling (likely due to a reduction in TrkB levels) in the hippocampus of this mouse strain. 23643987 Event-related potentials indicating impaired emotional attention in cerebellar stroke-A case study. The cerebellum has been implicated in affective and attentional processes, but little is known about corresponding neural signatures. We investigated early and late components of event-related potentials (ERPs) to emotionally arousing pictures, with and without competing attentional tasks, in a patient with an ischemic right posterior cerebellar infarction, at two months post infarct and two year follow-up. The early posterior negativity (EPN) response to highly arousing emotional cues in the competing visual attention condition revealed that the augmentation over occipital areas, as typically seen in normals, was absent post-infarct but was restored after two years. The late positive potentials (LPP) response to highly arousing emotional cues showed augmentation over frontal areas post-infarct, and over centro-parietal regions after two years. These ERP findings suggest a specific pattern of disruption of neural function associated with emotional-behavioral disturbances following cerebellar lesions, which can revert to normal with long term recovery. 23526496 Proteome-wide analyses of human hepatocytes during differentiation and dedifferentiation. Failure to predict hepatotoxic drugs in preclinical testing makes it imperative to develop better liver models with a stable phenotype in culture. Stem cell-derived models offer promise, with differentiated hepatocyte-like cells currently considered to be "fetal-like" in their maturity. However, this judgment is based on limited biomarkers or transcripts and lacks the required proteomic datasets that directly compare fetal and adult hepatocytes. Here, we quantitatively compare the proteomes of human fetal liver, adult hepatocytes, and the HepG2 cell line. In addition, we investigate the proteome changes in human fetal and adult hepatocytes when cultured in a new air-liquid interface format compared to conventional submerged extracellular matrix sandwich culture. From albumin and urea secretion, and luciferase-based cytochrome P450 activity, adult hepatocytes were viable in either culture model over 2 weeks. The function of fetal cells was better maintained in the air-liquid interface system. Strikingly, the proteome was qualitatively similar across all samples but hierarchical clustering showed that each sample type had a distinct quantitative profile. HepG2 cells more closely resembled fetal than adult hepatocytes. Furthermore, clustering showed that primary adult hepatocytes cultured at the air-liquid interface retained a proteome that more closely mimicked their fresh counterparts than conventional culture, which acquired myofibroblast features. Principal component analysis extended these findings and identified a simple set of proteins, including cytochrome P450 2A6, glutathione S transferase P, and alcohol dehydrogenases as specialized indicators of hepatocyte differentiation. Conclusion: Our quantitative datasets are the first that directly compare multiple human liver cells, define a model for enhanced maintenance of the hepatocyte proteome in culture, and provide a new protein "toolkit" for determining human hepatocyte maturity in cultured cells. (Hepatology 2013;58:799-809). 23886360 Clinical course of pars planitis in patients treated with selective photocoagulation. Pars planitis is an intermediate uveitis with bilateral and asymmetric presentation. The etiology is unknown and pathogenesis is unclear. Treatment follows the algorithm of Foster, which includes selective photocoagulation. The mechanism of action of photocoagulation is still unknown. An observational, longitudinal, ambispective cohort study was performed with the objective of evaluating the course of inflammation in patients with pars planitis treated with a selective argon laser. The study included 29 patients (10 female and 19 male) diagnosed with pars planitis and were treated with selective laser. The mean age of onset was 11.77 years. Eighteen (62.1%) patients were not immunosuppressed at the time of receiving the selective laser, and 11 (37.9%) were taking immunosuppressants. Indications for selective laser were; following the algorithm, 19 (65.55%), vitreous hemorrhage 7 (24.1%), vitrectomy 2 (6.98%), and neovascularization 1 (3.4%). The mean time for inflammation reduction was 5.9 months, and 17 patients (58.6%) had no relapse. Visual acuity showed improvement post-laser (OD P=.025 and OI P=.022). There was also an improvement in vitreous cells. Selective laser was effective in 58.6%% of patients. 23869053 Characterization of CXCR4-using HIV-1 during primary infection by ultra-deep pyrosequencing. R5 viruses have long been thought to account for almost all strains present in primary HIV-1 infections (PHIs), but recent studies using sensitive phenotypic assays have revealed that 3%-6.4% of subjects also harbour CXCR4-using viruses. Phenotypic assays provide only qualitative results: the presence or absence of CXCR4-using viruses. We have therefore used ultra-deep pyrosequencing (UDS) to determine the frequency of CXCR4-using viruses among HIV-1 quasispecies. We first screened 200 patients for HIV-1 tropism using a sensitive phenotypic assay during PHI and identified 11 infected with an R5X4 dual/mixed (D/M) virus population. We then used UDS of the V3 env region with the geno2pheno algorithm (false positive rate = 5.75) to identify the HIV-1 quasispecies. CXCR4-using viruses were detected in all but 1 of the 11 patients by UDS, and accounted for 0.2%-100% of the virus populations. The frequency of CXCR4-using viruses was <20% in six subjects and 100% in four subjects. Virus populations containing 100% CXCR4-using variants during PHI persisted for at least 1-2 years after the acute phase. The CCR5 Δ32 heterozygous genotype was similarly prevalent in patients infected with D/M (27%) and R5 (15%) viruses. UDS and the phenotype were concordant for determining HIV-1 coreceptor usage. UDS analysis indicated large differences in the percentage of CXCR4-using viruses in the HIV-1 quasispecies during PHI. Further studies should examine the impact of the proportion of CXCR4-using viruses on disease prognosis. 23924260 A Coupled Modeling and Molecular Biology Approach to Microbial Source Tracking at Cowell Beach, Santa Cruz, CA, United States. Consistently high levels of bacterial indicators of fecal pollution rank Cowell Beach as the most polluted beach in California. High levels of fecal indicator bacteria (FIB), E. coli and enterococci, are measured throughout the summer, resulting in beach advisories with social and economic consequences. The source of FIB, however, is unknown. Speculations have been made that the wrack accumulating on the beach is a major source of FIB to the surf zone. The present study uses spatial and temporal sampling coupled with process-modeling to investigate potential FIB sources and the relative contributions of those sources. Temporal sampling showed consistently high FIB concentrations in the surf zone, sand, and wrack at Cowell Beach, and ruled out the storm drain, the river, the harbor, and the adjacent wharf as the sources of the high concentrations observed in the surf zone. Spatial sampling confirmed that the source of FIB to the beach is terrestrial rather than marine. Modeling results showed two dominant FIB sources to the surf zone: sand for enterococci and groundwater for E. coli. FIB from wrack represented a minor contribution to bacterial levels in the water. Molecular source tracking methods indicate the FIB at the beach is of human and bird origin. The microbial source tracking (MST) approach presented here provides a framework for future efforts. 23969395 Joint histogram-based cost aggregation for stereo matching. This paper presents a novel method for performing efficient cost aggregation in stereo matching. The cost aggregation problem is reformulated from the perspective of a histogram, giving us the potential to reduce the complexity of the cost aggregation in stereo matching significantly. Differently from previous methods which have tried to reduce the complexity in terms of the size of an image and a matching window, our approach focuses on reducing the computational redundancy that exists among the search range, caused by a repeated filtering for all the hypotheses. Moreover, we also reduce the complexity of the window-based filtering through an efficient sampling scheme inside the matching window. The tradeoff between accuracy and complexity is extensively investigated by varying the parameters used in the proposed method. Experimental results show that the proposed method provides high-quality disparity maps with low complexity and outperforms existing local methods. This paper also provides new insights into complexity-constrained stereo-matching algorithm design. 23836714 An expanded tool kit for the auxin-inducible degron system in budding yeast. Fusion of inducible degradation signals, so-called degrons, to cellular proteins is an elegant method of controlling protein levels in vivo. Recently, a degron system relying on the plant hormone auxin has been described for use in yeast and vertebrate cells. We now report the construction of a series of vectors that significantly enhance the versatility of this auxin-inducible degron (AID) system in Saccharomyces cerevisiae. We have minimized the size of the degron and appended a series of additional epitope tags, allowing detection by commercial antibodies or fluorescence microscopy. The vectors are compatible with PCR-based genomic tagging strategies, allow for C- or N-terminal fusion of the degron, and provide a range of selection markers. Application to a series of yeast proteins, including essential replication factors, provides evidence for a general usefulness of the system. © 2013 The Authors. Yeast published by John Wiley & Sons, Ltd. 23878147 Academy on Violence and Abuse: Highlights of Proceedings From the 2011 Conference, "Toward a New Understanding" In April 2011, the Academy on Violence Abuse (http://www.avahealth.org/) convened a network of experts for its second annual conference, "Developing the Science of Violence and Abuse: Toward a New Understanding." The conference served as a forum for highlighting the growing body of research regarding the biological consequences and adverse health consequences of abuse. In doing so, it underscored an important scientific premise: By evaluating the impact of violence and abuse from birth to death, one can better evaluate the social, behavioral, psychological, and biological context and pathways that result in the morbidity, mortality, and quality of life of all affected individuals and communities. In this article, we summarize content presented by the conference's keynote speakers and provide citations that speakers have submitted to support their statements. 23748109 Immunofluorescent detection of S-nitrosoproteins in cell culture. The role of S-nitrosylation in cellular signaling has been clearly demonstrated. There a number of mechanisms whereby this post-translational modification can occur and the number of protein targets continue to expand. The need to be able to monitor when this important signaling process occurs within cells is increasingly important. Previously we have identified immunohistochemistry approaches effective for monitoring S-nitrosylation within fixed tissue. Within this paper we show how these techniques can be adapted to use in a cell culture system using immunofluorescence. We have used this protocol to detect S-nitrosoprotein formation within LPS stimulated microglial cells using both transformed and primary cultured cells. 23159773 Cav1.3 and Cav1.2 channels of adrenal chromaffin cells: emerging views on cAMP/cGMP-mediated phosphorylation and role in pacemaking. Voltage-gated Ca²⁺ channels (VGCCs) are voltage sensors that convert membrane depolarizations into Ca²⁺ signals. In the chromaffin cells of the adrenal medulla, the Ca²⁺ signals driven by VGCCs regulate catecholamine secretion, vesicle retrievals, action potential shape and firing frequency. Among the VGCC-types expressed in these cells (N-, L-, P/Q-, R- and T-types), the two L-type isoforms, Ca(v)1.2 and Ca(v)1.3, control key activities due to their particular activation-inactivation gating and high-density of expression in rodents and humans. The two isoforms are also effectively modulated by G protein-coupled receptor pathways delimited in membrane micro-domains and by the cAMP/PKA and NO/cGMP/PKG phosphorylation pathways which induce prominent Ca²⁺ current changes if opposingly regulated. The two L-type isoforms shape the action potential and directly participate to vesicle exocytosis and endocytosis. The low-threshold of activation and slow rate of inactivation of Ca(v)1.3 confer to this channel the unique property of carrying sufficient inward current at subthreshold potentials able to activate BK and SK channels which set the resting potential, the action potential shape, the cell firing mode and the degree of spike frequency adaptation during spontaneous firing or sustained depolarizations. These properties help chromaffin cells to optimally adapt when switching from normal to stress-mimicking conditions. Here, we will review past and recent findings on cAMP- and cGMP-mediated modulations of Ca(v)1.2 and Ca(v)1.3 and the role that these channels play in the control of chromaffin cell firing. This article is part of a Special Issue entitled: Calcium channels. 23903108 Polarization independent varifocal lens using KTN crystals. We fabricated a polarization-independent varifocal lens using KTa1-xNbxO3 (KTN) crystals. The polarization dependence of the KTN crystal is effectively compensated for by combining a pair of KTN lenses and a half-wave plate. This compensation is achieved by a total electro-optic effect, which consists of the Kerr effect and the elasto-optic effects via the electrostrictive and elastic strains in the KTN crystal. 23898884 Clinical implications of DLL4 expression in gastric cancer. Delta-like ligand 4 (DLL4)-Notch signaling plays a key role in tumor neovascular development and angiogenesis during tumor growth. The clinical significance of DLL4 expression in gastric cancer has not been clarified. Gastric cancer cell lines and 180 gastric cancer patients were enrolled. DLL4 expression in gastric cancer cells and stroma was identified and evaluated immunohistochemically. The association between DLL4 and clinicopathological factors was also assessed. DLL4 expression was identified in the cellular membrane and cytoplasm of gastric cancer cells by immunoblotting and immunohistochemical staining. DLL4 positivity in cancer cells and stroma was found in 88 (48%) and 41 (22%) of the 180 gastric cancer patients respectively. Both cancer and stromal DLL4 expression significantly correlated with more advanced tumor depth, nodal involvement, and lymphatic and venous invasion. A strongly positive association between cancerous and stromal DLL4 expression was identified (p < 0.01). Both cancerous and stromal DLL4 expression were prognostic markers in gastric cancer as determined by univariate analysis. Cancerous and stromal DLL4 expression was found in 48% and 22% in gastric cancer, and significantly affected postoperative clinical outcomes. Cancerous and stromal DLL4 expression may be an effective target of anti-DLL4 treatment in gastric cancer. 23838744 Nanostructure-induced DNA condensation. The control of the DNA condensation process is essential for compaction of DNA in chromatin, as well as for biological applications such as nonviral gene therapy. This review endeavours to reflect the progress of investigations on DNA condensation effects of nanostructure-based condensing agents (such as nanoparticles, nanotubes, cationic polymer and peptide agents) observed by using atomic force microscopy (AFM) and other techniques. The environmental effects on structural characteristics of nanostructure-induced DNA condensates are also discussed. 23561111 Structural characterisation of partially glycosylated whey protein as influenced by pH and heat using surface-enhanced Raman spectroscopy. Maillard-induced glycosylation of whey protein improves solubility and thermal stability over a wide pH range. However, the relationship between structural changes and functional enhancement upon glycosylation is not well-characterized. Therefore, our objective was to characterise these structural changes and determine the protein conformation at various pH and thermal treatments, using surface-enhanced Raman-spectroscopy. The spectra of glycosylated protein revealed a new peak at 983cm(-1) that can be used as a Raman marker for the early stage glycosylation. Upon glycosylation, structural variations were significant at the disulfide, hydrophobic, amide III, amide II, and amide I regions. Ionisation of carboxyl groups at all tested pH values, and increased β-sheet configuration were also observed. The noted structural modifications imparted molecular rigidity and a consequent resistance to denaturation upon thermal treatment over a wide pH range. These findings can be used to explain various functional enhancements of whey protein upon glycosylation. 23892735 Simulation and assessment of realistic breast lesions using fractal growth models. A new method of generating realistic three dimensional simulated breast lesions known as diffusion limited aggregation (DLA) is presented, and compared with the random walk (RW) method. Both methods of lesion simulation utilize a physics-based method for inserting these simulated lesions into 2D clinical mammogram images that takes into account the polychromatic x-ray spectrum, local glandularity and scatter. DLA and RW masses were assessed for realism via a receiver operating characteristic (ROC) study with nine observers. The study comprised 150 images of which 50 were real pathology proven mammograms, 50 were normal mammograms with RW inserted masses and 50 were normal mammograms with DLA inserted masses. The average area under the ROC curve for the DLA method was 0.55 (95% confidence interval 0.51-0.59) compared to 0.60 (95% confidence interval 0.56-0.63) for the RW method. The observer study results suggest that the DLA method produced more realistic masses with more variability in shape compared to the RW method. DLA generated lesions can overcome the lack of complexity in structure and shape in many current methods of mass simulation. 23856783 DNA-Microarray for genotyping antibiotic resistance determinants in Acinetobacter baumannii clinical isolates. Within the last decades, Acinetobacter baumannii has emerged to an organism of great concern due to its capability to accumulate antibiotic resistances. In order to improve diagnosis of resistance determinants in A. baumannii in terms of lead time and accuracy, we developed a microarray that can be used to detect 91 target sequences associated with antibiotic resistance within four hours from bacterial culture to result. The array was validated with 60 multi-drug-resistant strains of A. baumannii in a blinded, prospective study. The results were compared to phenotype determined by the automated susceptibility testing system VITEK2. Antibiotics considered were piperacillin/tazobactam, ceftazidime, imipenem, meropenem, trimethoprim/sulfamethoxazole, amikacin, gentamicin, tobramycin, ciprofloxacin, and tigecycline. The average positive predictive value, negative predictive value, sensitivity, and specificity were 98%, 98%, 99%, and 94%, respectively. Regarding carbapenemase genes, the array results were compared to singleplex-PCR results provided by the German National Reference Center for Gram-Negative Pathogens, and results were in complete accordance. The presented array is able to detect all relevant resistance determinants of A. baumanii in parallel. The short handling time of four hours from culture to result helps to provide fast results in order to initiate an adequate anti-infective therapy of critical-ill patients. Another application would be data acquisition for epidemiologic surveillance. 23103565 Platelet-derived growth factor triggers PKA-mediated signalling by a redox-dependent mechanism in rat renal mesangial cells. Inflammatory glomerular kidney diseases are often accompanied with a massive production of reactive oxygen species (ROS) that affect the function of the glomerular filtration barrier and contribute to mesangiolysis via the induction of cell death in mesangial cells. Intriguingly, ROS also trigger fine-tuned signalling processes that affect gene expression and cell proliferation or migration. To define such redox-driven signalling devices, a proteomics approach was performed to identify the formation of protein complexes induced by ROS. To this end, protein lysates of human podocytes were treated with or without hydrogen peroxide (250 μM). Thereafter cell lysates were subjected to diagonal 2D gel electrophoresis and putative redox-affected proteins were analysed by MS/MS analysis. Among others, the regulatory subunit of protein kinase A (PKA) could be identified that forms homodimers under oxidative conditions. To evaluate whether ROS dependent dimerization of PKA also occurs in a more physiological setting, rat mesangial cells were treated with platelet-derived growth factor-BB (PDGF-BB) to induce ROS formation. This regimen resulted in a redox dependent dimerization of the R-subunits of PKA. To demonstrate whether PDGF-BB induced ROS formation affects PKA dependent pathways, the effects of PDGF-BB on phosphorylation of serine 157 of vasodilator stimulated protein (VASP) a classical target of PKA were analysed. Interestingly PDGF-BB induced VASP phosphorylation in a ROS dependent manner but independent of changes in cAMP levels. Taken together, we demonstrate a redox-mediated activation of PKA by PDGF-BB thus highlighting a physiological role of ROS as regulator of PKA activity in rat mesangial cells. 23570324 Rehabilitation of surgically relocated integrated dental implants with and without bone morphogenesis protein-2. In the following case report, three osseointegrated implants placed in a dysfunctional and nonaesthetic position were successfully relocated with innovative surgical techniques were followed by a comprehensive dental rehabilitation. The goal of this report is to communicate the surgical techniques used to successfully relocate dental implants rather than replace them. Two techniques were used for these implants relocation. One technique consisted of displacing the integrated implant with some similarity to the alveolar distraction osteogenesis but without using the distraction device. The second surgical technique involved the displacement of the 2 adjacent implants, similarly to the first approach, except that an osseoinductive molecule, recombinant human bone morphogenetic protein-2, was used for guided bone growth. It was possible to relocate dental implants within bone blocs and rehabilitate them to adopt new dental abilities by complying with bone regeneration parameters. However, advanced treatment planning with computerized tomography scans, parametric software, and stereolithography models as well as guided surgery and bone regeneration products were used. 23857724 Non-Porous Low-k Dielectric Films Based on a New Structural Amorphous Fluoropolymer. A non-porous and amorphous fluoropolymer PFN with low dielectric constant of 2.33 and dielectric loss less than 1.2 × 10(-3) is reported here. PFN also exhibits good mechanical properties and high thermostability. This study is a new example of a fully dense material showing a low k value and having good thermo/mechanical properties. 23543324 Enzymatic synthesis of glutathione using engineered Saccharomyces cerevisiae. Two single gene cassettes, each containing one of the individual gene (γ-glutamylcysteine synthetase gene GSH1 or glutathione synthetase gene GSH2), were constructed under the control of alcohol dehydrogenase (ADH1) promoter and their respective native terminators. The recombinant plasmids constructed with Kan (r) or Hyg (r) as the selective markers and were transformed into Saccharomyces cerevisiae separately and jointly. Three engineered strains, GSH1-enhanced strain S.TS013/GSH1, GSH2-enhanced strain S.TS013/GSH2 and GSH1+GSH2 double-enhanced strain S.TS013/GSH1+GSH2, were constructed. Glutathione production using the recombinant strains to improve was then determined. By the cell dosage proportions of two engineered strains (S.TS013/GSH1, S.TS013/GSH2) and a two-stage reaction, GSH productivity increased by 84 and 59 % over that of the host strain and the S.TS013/GSH1+GSH2 strain, respectively. 23906996 Childhood physical abuse, non-suicidal self-harm and attempted suicide amongst regular injecting drug users. Childhood physical abuse (CPA), non-suicidal self-harm and attempted suicide are all highly prevalent amongst injecting drug users (IDU). This paper reported on the association of CPA with self-harm and attempted suicide. Cross-sectional study, with 300 IDU administered a structured interview examining the prevalence of CPA, non-suicidal self-harm and suicide attempts. CPA was reported by 74.3%, and severe CPA by 40.3%. A history of non-suicidal self-harm was reported by 23.7%, and 25.7% had attempted suicide. Non-suicidal self-harm preceded the suicide attempt in 83.3% of cases where both had occurred. Independent correlates of non-suicidal self-harm were: female gender (OR 3.62), avoided home due to conflict (OR 2.28) and more extensive polydrug use (OR 1.32). Independent correlates of attempted suicide were: severe CPA (OR 3.18), frequent CPA (OR 2.54), avoided home due to conflict (OR 3.95), female gender (OR 2.99), a positive screen for Conduct Disorder (OR 3.53), and more extensive polydrug use (OR 1.52). Those presenting to treatment agencies are highly likely to have a history of CPA, that may still influence their behaviours. Screening for histories of CPA and non-suicidal self-harm appears warranted when determining suicide risk for this population. At the population level, reductions in the rate of CPA, could possibly reduce the rate of subsequent suicidality. 23818486 Overexpression of the Escherichia coli TolQ protein leads to a null-FtsN-like division phenotype. Mutations involving the Tol-Pal complex of Escherichia coli result in a subtle phenotype in which cells chain when grown under low-salt conditions. Here, the nonpolar deletion of individual genes encoding the cytoplasmic membrane-associated components of the complex (TolQ, TolR, TolA) produced a similar phenotype. Surprisingly, the overexpression of one of these proteins, TolQ, resulted in a much more overt phenotype in which cells occurred as elongated rods coupled in long chains when grown under normal salt conditions. Neither TolR nor TolA overexpression produced a phenotype, nor was the presence of either protein required for the TolQ-dependent phenotype. Consistent with their native membrane topology, the amino-terminal domain of TolQ specifically associated in vivo with the periplasmic domain of FtsN in a cytoplasm-based two-hybrid analysis. Further, the concomitant overexpression of FtsN rescued the TolQ-dependent phenotype, suggesting a model wherein the overexpression of TolQ sequesters FtsN, depleting this essential protein from the divisome during Gram-negative cell division. The role of the Tol-Pal system in division is discussed. 23383985 Femtosecond Dynamics of Excitons and Hole-Polarons in Composite P3HT/PCBM Nanoparticles. The dynamics of charge separation in aqueous suspensions of regioregular P3HT nanoparticles containing PCBM were investigated for the first time using femtosecond transient absorption spectroscopy. This investigation is supported by the recently reported use of regioregular P3HT/PCBM nanoparticles as charge trapping and storage devices. In this study, the presence of excited-state and charge-separated species, including singlet excitons, polymer polarons and free charges, generated in rr-P3HT/PCBM nanoparticles was identified through visible pump and visible/near-infrared probe femtosecond transient absorption spectroscopy at a range of electron acceptor concentrations. The decrease of the singlet exciton lifetime by charge transfer to PCBM is well described by a one-dimensional diffusion model with a P3HT domain size of approximately 5 nm for 5-50 wt % PCBM. This model also indicates that bimolecular recombination is the dominant charge recombination mechanism at 20 wt % PCBM and above. 23570945 A simple skin blister technique for the study of in vivo transmigration of human leukocytes. The study of human leukocytes is almost exclusively conducted using cells isolated from peripheral blood. This is especially true for neutrophils, despite the fact that these cells are of main (pathological) importance in extravascular tissues upon e.g., infection and/or tissue damage. The journey from circulation to tissue is typically associated with a number of cellular changes, making the cells primed, or hyper-responsive, and in many aspects distinct from the cells present in circulation. Models to obtain in vivo transmigrated leukocytes from human tissue are available, but not widely used. We describe here an easy-to-use model for the study of local inflammation, stemming from limited tissue damage, which can be used to isolate viable and functional leukocytes. The model is based on the generation of aseptic skin blisters, formed by the application of negative pressure, and allows for investigations of the cellular infiltrate as well as of soluble mediators present in the exudate. We believe that this method, combined with modern analysis equipment suitable for small volumes and cell numbers, could be of great use for increasing our understanding of the nature and function of leukocytes that have left circulation and transmigrated to inflamed tissues. 23603434 Inactivation of PTEN increases ABCG2 expression and the side population through the PI3K/Akt pathway in adult acute leukemia. Both the occurrence and recurrence of acute leukemia (AL) might suggest the presence of leukemia stem cells. Side population (SP) cells, exhibiting stem cell-like properties, express ABCG2 (breast cancer resistance protein [BCRP]). This study revealed that over-expression of ABCG2 in Jurkat and HL60 cells led to an increased SP fraction, up-regulated levels of phosphorylated-PI3K and phosphorylated-Akt, and enhanced drug resistance, all of which could be attenuated by treatment with either the PI3K inhibitor LY294002 or the mTOR inhibitor rapamycin. ABCG2 expression and SP cell counts were further characterized in 222 adult AL patients at three disease stages: upon diagnosis, at remission and at refractory/relapse (R/R), while 10 healthy donors served as the normal controls. Only a small fraction of the ABCG2+population (0.05-12.3%) and SP cells (0.02-1.60%) were observed in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. In the normal control population, the SP cell fraction represented a statistically higher percentage of total cells compared to the fraction of SP cells upon diagnosis or relapse in both AML and ALL. In addition, we demonstrated that ABCG2 expression and SP cell ratios can be upregulated by the inactivation of phosphatase and tensin homolog (PTEN) protein, achieved in this study by removing inhibition of the PI3K/Akt pathway. Collectively, this study suggests that the PTEN/PI3K/Akt pathway up-regulates ABCG2 expression and the SP cell population and is a potential AL-specific treatment target worth investigating further. 23925535 Application of micro-segmented flow for two-dimensional characterization of the combinatorial effect of zinc and copper ions on metal-tolerant Streptomyces strains. The cultivation and growth behavior of metal-tolerant strains of Streptomyce acidiscabies E13 and Streptomyces sp. F4 were studied under droplet-based microfluidics conditions. It was shown that the technique of micro segmented flow is well suited for the investigation of dependence of bacterial growth on different concentrations of either single metal ions or combinations of them. This study confirms higher tolerance to Zn than to Cu by our test organism. The highly resolved dose-response curves reflect two transitions between the different growth behaviors, separating initial responses to Cu concentration ranges into those with (a) intense growth, (b) moderate growth, and (c) growth inhibition. For Streptomyces sp. F4, an initial stimulation was shown in the sublethal range of zinc sulfate. Two-dimensional screenings using computer-controlled fluid actuation and in situ micro flow-through fluorimetry reflected a strong growth stimulation of strain F4 by zinc sulfate in the presence of sublethal Cu concentrations. This stimulatory effect on binary mixtures may be useful in providing optimal growth conditions in bioremediation procedures. 23719208 Effects of postural threat on spinal stretch reflexes: evidence for increased muscle spindle sensitivity? Standing balance is often threatened in everyday life. These threats typically involve scenarios in which either the likelihood or the consequence of falling is higher than normal. When cats are placed in these scenarios they respond by increasing the sensitivity of muscle spindles imbedded in the leg muscles, presumably to increase balance-relevant afferent information available to the nervous system. At present, it is unknown whether humans also respond to such postural threats by altering muscle spindle sensitivity. Here we present two studies that probed the effects of postural threat on spinal stretch reflexes. In study 1 we manipulated the threat associated with an increased consequence of a fall by having subjects stand at the edge of an elevated surface (3.2 m). In study 2 we manipulated the threat by increasing the likelihood of a fall by occasionally tilting the support surface on which subjects stood. In both scenarios we used Hoffmann (H) and tendon stretch (T) reflexes to probe the spinal stretch reflex circuit of the soleus muscle. We observed increased T-reflex amplitudes and unchanged H-reflex amplitudes in both threat scenarios. These results suggest that the synaptic state of the spinal stretch reflex is unaffected by postural threat and that therefore the muscle spindles activated in the T-reflexes must be more sensitive in the threatening conditions. We propose that this increase in sensitivity may function to satisfy the conflicting needs to restrict movement with threat, while maintaining a certain amount of sensory information related to postural control. 23960015 The role of the Saccharomyces cerevisiae lipoate protein ligase homologue, Lip3, in lipoic acid synthesis. The covalent attachment of lipoate to the lipoyl domains (LDs) of the central metabolism enzymes pyruvate dehydrogenase (PDH) and oxoglutarate dehydrogenase (OGDH) is essential for their activation and thus for respiratory growth in Saccharomyces cerevisiae. A third lipoate-dependent enzyme system, the glycine cleavage system (GCV), is required for utilization of glycine as a nitrogen source. Lipoate is synthesized by extraction of it precursor, octanoyl-acyl carrier protein (ACP) from the pool of fatty acid biosynthetic intermediates. Alternatively, lipoate is salvaged from previously modified proteins or from growth media by lipoate protein ligases (Lpls). The first Lpl to be characterized, LplA of Escherichia coli, catalyzes two partial reactions: activation of the acyl chain by formation of acyl-AMP, followed by transfer of the acyl chain to LDs. There is a surprising diversity within the Lpl family of enzymes, several of which catalyze reactions other than ligation reactions. For example, the Bacillus subtils Lpl homologue LipM is an octanoyltransferase that transfers the octanoyl moiety from octanoyl-ACP to GCV. Another B. subtils Lpl homologue, LipL, transfers octanoate from octanoyl-GCV to other LDs in an amidotransfer reaction. Study of eukaryotic Lpls has lagged behind studies of the bacterial enzymes. We report that the Lip3 Lpl homologue of the yeast S. cerevisiae has octanoyl-CoA: protein transferase activity and discuss implications of this activity on the physiological role of Lip3 in lipoate synthesis. This article is protected by copyright. All rights reserved. 23402432 Effects of hydrogen bonding on internal conversion of GFP-like chromophores. II. The meta-amino systems. To rationalize the efficient quenching of the fluorescence and the Z → E photoisomerization of m-ABDI, the meta-amino analogue of the green fluorescent protein (GFP) chromophore, in protic solvents, the femtosecond time-resolved fluorescence and transient infrared (TRIR) spectra of m-ABDI in CD3CN, CH3OH, and CD3OD are determined. For solutions in CD3CN, the fluorescence decay lifetime is ∼7.9 ns and IR absorption lines near 1513, 1531, 1557, and 1613 cm(-1) of m-ABDI in its electronically excited state were observed with a decay time >5 ns. For solutions in CH3OH, the fluorescence decay is double exponential with time constants of ∼16 and 62 ps. In addition to IR absorption lines of m-ABDI in its electronically excited state with a decay time of ∼16 ps, new features near 1513, 1532, 1554, and 1592 cm(-1) were observed to have a rise time of ∼19 ps and a decay constant of ∼58 ps, indicating formation of an intermediate. The assignments for the IR spectra of the ground and excited states were assisted with DFT and TDDFT calculations, respectively. We conclude that the torsion of the exocyclic C═C bond (the τ torsion) is responsible for the nonradiative decay of electronically excited m-ABDI in CD3CN. However, in CH3OH and CD3OD, the solute-solvent hydrogen bonding (SSHB) interactions diminish significantly the barrier of the τ torsion and induce a new pathway that competes successfully with the τ torsion, consistent with the efficient fluorescence quenching and the diminished yield for Z → E photoisomerization. The new pathway is likely associated with excited-state proton transfer (ESPT) from the solvent to m-ABDI, particularly the carbonyl group, and generates an intermediate (ESPT*) that is weakly fluorescent. 23830937 The p7 protein of hepatitis C virus is degraded via the proteasome-dependent pathway. The p7 protein of hepatitis C virus (HCV) is a multifunctional, integral membrane protein that plays a critical role in virus life cycle. This study demonstrated that the p7 proteins from different HCV genotypes (GTs) were unstable and degraded via the proteasome-dependent pathway. Mutagenesis analysis of the one and only lysine in JFH1 p7 (K4), the exclusive substrate for ubiquitination, did not stabilize p7 in human hepatoma cells. Collectively, this report demonstrated that p7 is degraded via the proteasome-dependent pathway, and provided evidence suggesting that p7 degradation is an ubiquitin-independent process. 23912261 Resource competition induces heterogeneity and can increase cohort survivorship: selection-event duration matters. Determining when resource competition increases survivorship can reveal processes underlying population dynamics and reinforce the importance of heterogeneity among individuals in conservation. We ran an experiment mimicking the effects of competition in a growing season on survivorship during a selection event (e.g., overwinter starvation, drought). Using a model fish species (Poecilia reticulata), we studied how food availability and competition affect mass in a treatment stage, and subsequently survivorship in a challenge stage of increased temperature and starvation. The post-treatment mean mass was strongly related to the mean time to mortality and mass at mortality at all levels of competition. However, competition increased variance in mass and extended the right tail of the survivorship curve, resulting in a greater number of individuals alive beyond a critical temporal threshold ([Formula: see text]) than without competition. To realize the benefits from previously experienced competition, the duration of the challenge ([Formula: see text]) following the competition must exceed the critical threshold [Formula: see text] (i.e., competition increases survivorship when [Formula: see text]). Furthermore, this benefit was equivalent to increasing food availability by 20 % in a group without competition in our experiment. The relationship of [Formula: see text] to treatment and challenge conditions was modeled by characterizing mortality through mass loss in terms of the stochastic rate of loss of vitality (individual's survival capacity). In essence, when the duration of a selection event exceeds [Formula: see text], competition-induced heterogeneity buffers against mortality through overcompensation processes among individuals of a cohort. Overall, our study demonstrates an approach to quantify how early life stage heterogeneity affects survivorship. 23961901 Multivalency of non-peptide integrin αVβ3 antagonist slows tumor growth. Multivalency is a powerful strategy for achieving high-affinity molecular binding of compounds to increase their therapeutic potency or imaging potential. In our study, multivalent non-peptide integrin αvβ3 antagonists (IA) were designed for anti-tumor therapy. Docking and molecular dynamics were employed to explore the binding modes of IA monomer, dimer and trimer. In silico, one IA unit binds tightly in the active site with similar pose to native ligand RGD and other parts of dimer and trimer contribute extra binding affinities by interacting with residues in vicinity of the original site. In vitro studies demonstrated that increasing valency results in increasing anti-proliferative and anti-organizational effects against endothelial cells (HUVECs), and a much weaker effect on melanoma B16F10 cells. The anti-tumor efficacies of the IA multivalent compounds were evaluated in subcutaneous B16F10 melanoma tumor-bearing mice. At 30 mg/kg dose, the mean masses of tumors harvested 18 days after inoculation were significantly reduced (p<10-7) by 36±9 %, 49±8 %, and 71±7 % for the IA-monomer, dimer, and trimer groups, relative to control. The importance of multivalency was demonstrated to be highly significant beyond the additive effect of the extra pharmacological sites (p=0.00011). These results suggest that the major target of these anti-αvβ3 compounds is the neovasculature rather than the cancer cells, and the success of a multivalent strategy depends on the details of the components and linker. This is the first integrin αvβ3 multivalent ligand showing clear enhancement in anti-tumor effectiveness. 23569205 Molecular Identification and Characterization of an Essential Pyruvate Transporter from Trypanosoma brucei. Pyruvate export is an essential physiological process for the bloodstream form of T. brucei as the parasite would otherwise accumulate this end product of glucose metabolism to toxic levels. In the studies reported here genetic complementation in Saccharomyces cerevisiae has been employed to identify a gene (TbPT0) that encodes this vital pyruvate transporter from T. brucei. Expression of TbPT0 in S. cerevisiae reveals that TbPT0 is a high affinity pyruvate transporter. TbPT0 belongs to a clustered multigene family consisting of five members, whose expression is up-regulated in the bloodstream form. Interestingly, TbPT family permeases are related to polytopic proteins from plants but not to characterized monocarboxylate transporters from mammals. Remarkably, inhibition of the TbPT gene family expression in bloodstream parasites by RNAi is lethal, confirming the physiological relevance of these transporters. The discovery of TbPT0 reveals for the first time the identity of the essential pyruvate transporter and provides a potential drug target against the mammalian life cycle stage of T. brucei. 23623923 CD147 mediates chemoresistance in breast cancer via ABCG2 by affecting its cellular localization and dimerization. CD147 and ABCG2 both have been reported to mediate Multidrug resistance (MDR) in breast cancer. Recent study demonstrates that CD147 could form a complex with ABCG2 on the cell membrane in primary effusion lymphoma. However, whether these two molecules regulate each other in breast cancer and result in MDR is not clear. We established four MCF-7 cell lines transfected with CD147 and/or ABCG2 and found that CD147 could increase the expression and dimerization of ABCG2, affect its cellular localization and regulate its drug transporter function. The findings derived from cells were confirmed subsequently in clinic samples of chemotherapy-sensitive/resistant breast cancer. 23519265 Aspirin protects human coronary artery endothelial cells against atherogenic electronegative LDL via an epigenetic mechanism: a novel cytoprotective role of aspirin in acute myocardial infarction. L5 is the most negatively charged subfraction of human low-density lipoprotein (LDL) and is the only subfraction of LDL capable of inducing apoptosis in cultured vascular endothelial cells (ECs) by inhibiting fibroblast growth factor-2 (FGF2) transcription. We examined whether plasma L5 levels are elevated in patients with ST-segment elevation myocardial infarction (STEMI) and whether aspirin provides epigenetic protection of human coronary artery ECs (HCAECs) exposed to L5. Plasma L5 levels were compared between patients with STEMI (n = 10) and control subjects with chest pain syndrome but a normal coronary arteriogram (n = 5). L5 was isolated from the plasma of STEMI patients and control subjects, and apoptosis, FGF2 expression, and FGF2 promoter methylation were examined in HCAECs treated with L5 and aspirin. Plasma L5 levels were significantly higher in STEMI patients than in control subjects (P < 0.001). Treatment of HCAECs with L5 resulted in reduced survival and FGF2 expression and increased CpG methylation of the FGF2 promoter. Co-treatment of HCAECs with L5 and a physiologically relevant, low concentration of aspirin (0.2 mM) attenuated the adverse effects of L5 on HCAEC survival, FGF2 expression, and FGF2 promoter methylation. In contrast, high concentrations of aspirin (≥1.0 mM) accentuated the effects of L5. Our results show that L5 levels are significantly increased in STEMI patients. Furthermore, L5 impairs HCAEC function through CpG methylation of the FGF2 promoter, which is suppressed in the presence of low-concentration aspirin. Our results provide evidence of a novel mechanism of aspirin in the prevention of MI. 23906601 Molecular phylogeny based on increased number of species and genes revealed more robust family-level systematics of the order Euryalida (Echinodermata: Ophiuroidea). Previous molecular analysis of the order Euryalida (Echinodermata: Ophiuroidea), has identified three monophyletic families, the Euryalidae, Asteronychidae and Gorgonocephalidae. However, family-level relationships have remained unresolved due to inadequate taxon sampling and insufficient molecular markers. Here, we present a family-level revision of the Euryalida based on sequences from mitochondrial genes (16S rRNA and COI) and a nuclear gene (18S rRNA) from 83 euryalid ophiuroids. The monophyly of the three families, Euryalidae, Asteronychidae and Gorgonocephalidae is confirmed. The Euryalidae and Asteronychidae+Gorgonocephalidae are assigned to superfamilies, the Euryalidea and the Gorgonocephalidea, respectively. Three subclades within the family Gorgonocephalidae are identified and assigned to three subfamilies; Astrotominae includes Astrocrius, Astrohamma and Astrotoma, Astrothamninae (subfamily nov.) includes Astrothamnus and Astrothrombus with Gorgonocephalinae including the remaining genera. Morphological characters are consistent with the newly recognised superfamilies and subfamilies. 23944934 Coarsening of Silver Nanoparticles in Polyelectrolyte Multilayers. In polyelectrolyte multilayer (PEM) films assembled from poly(diallyldimethylammonium chloride) and poly(styrene sulfonate) via the layer-by-layer deposition technique, the counterions were exchanged with silver ions, which were subsequently reduced in situ to produce silver (Ag) nanoparticles. The Ag nanoparticles embedded in the PEMs were found to undergo an interesting coarsening process over time, through which smaller Ag nanoparticles coalesce into larger ones until reaching an equilibrium. The process was investigated by monitoring the localized surface plasmon resonance of the Ag nanoparticles using UV-vis extinction spectroscopy, and the spectral evolution revealed an increase in nanoparticle size with time, a trend in qualitative agreement with theoretical calculation and further confirmed by transmission electron microscopy. The kinetics of the coarsening process and the size of Ag nanoparticles at equilibrium were found to be affected by the PEM structure as well as the temperature and relative humidity the PEM was exposed to, and coalescence was identified to be the mechanism. 23575197 Evolution of treatment-emergent resistant variants in telaprevir phase 3 clinical trials. Telaprevir (TVR), a hepatitis C virus (HCV) NS3/4A protease inhibitor, has been approved to treat genotype 1 HCV. To understand the clinical impact of TVR-resistant variants, we analyzed samples from patients in phase 3 clinical trials to determine the frequency and retention of TVR-resistant variants in patients who did not achieve sustained virologic response (SVR). A total of 1797 patients were treated with TVR. Resistant variants (V36A/G/I/L/M, T54A/S, I132V [subtype 1a only], R155G/K/T/M, A156F/N/S/T/V, and D168N) were identified after treatment failure and at visits thereafter, by direct (population) sequencing of the NS3/4A region. Kaplan-Meier analysis was used to determine median time to loss of these variants. Resistant variants were observed in 77% (299/388) of patients who did not achieve SVR. Resistance occurred more commonly in subtype 1a (86%; 232/269) than subtype 1b infections (56%; 67/119). After treatment failure, 355 patients had at least 1 follow-up visit (median follow-up period: 9.6 months). Of patients with resistance at time of failure and at least 1 follow-up visit, 60% (153/254) lost resistance. Kaplan-Meier analysis, including all patients with any sequence data after treatment failure, indicated that median time to wild type was 10.6 months (95% confidence interval [CI], 9.47-12.20) in subtype 1a and 0.9 months (95% CI, 0.00-2.07) in subtype 1b infections. After failure to achieve SVR with TVR-based treatment, resistant variants are observed in most patients. However, presumably due to the lower fitness of those variants, they tend to be replaced with wild-type virus over time. 23934578 Preparation of reduced graphene oxide by infrared irradiation induced photothermal reduction. We present a green and scalable route toward the formation of reduced graphene oxide (r-GO) by photothermal reduction induced by infrared (IR) irradiation, utilizing a bathroom IR lamp as the source of IR light. Thermogravimetric analysis, Raman, Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy confirm the reduction of r-GO by IR light. Ultraviolet-visible-infrared spectra indicate that adsorption of IR light by original GO films is less than that of UV and visible light; but when GO is exposed to IR light, its adsorption of IR light increases very rapidly with time. The influence of the power density of the IR light on the structure and properties of r-GO was investigated. At high IR power density, the reduction reaction was so fierce that r-GO became highly porous due to the rapid degassing and exfoliation of GO sheets. The r-GO powder revealed good performance as the anode material for lithium ion batteries. At relatively low IR power density, the reduction process was found to be mild but relatively slow. Crack-free and uniform conductive r-GO thin films with a volume conductivity of 1670 S m(-1) were then prepared by two-step IR irradiation, i.e. first at low IR power density and then at high IR power density. Moreover, the r-GO films were also observed to exhibit obvious and reversible IR light-sensing behavior. 23424204 Effect of bisphenol-A on insulin signal transduction and glucose oxidation in skeletal muscle of adult male albino rat. The estrogenic monomer bisphenol-A (BPA) is an endocrine-disrupting chemical used in the production of epoxy resins, plastic food and beverage containers, leading to ubiquitous human exposure. Environmentally relevant doses of BPA have profound effects on mice endocrine pancreas. It increases pancreatic insulin content and favors postprandial hyperinsulinemia and insulin resistance in male mice. Skeletal muscle plays a crucial role in maintaining systemic glucose metabolism. In the present study, we investigated the possible effects of BPA on insulin-signaling molecules and glucose oxidation in skeletal muscle of male rat. Adult male Wistar albino rats were divided into three groups. Group I: control (vehicle treated) and groups II and III were administered with BPA orally (20 and 200 mg/kg bw/day, respectively). Although there was no change in the levels of insulin receptor (IR), Akt (protein kinase B) and glucose transporter-4 (GLUT4) messenger RNA, BPA significantly decreased the IR, Akt and GLUT4 protein levels (both plasma membrane and cytosolic fraction) of the gastrocnemius muscle. There was an increase in serum insulin and decrease in serum testosterone levels but fasting blood glucose level remained unaltered. In conclusion, BPA has adverse effects on phosphorylation of Akt, GLUT4 translocation and (14)C-glucose oxidation. 23402727 Innate immune response and programmed cell death following carrier-mediated delivery of unmodified mRNA to respiratory cells. In this report we show that carrier-mediated delivery of mRNA may activate TLR3 signaling in respiratory cells. This activation of the innate immune system was accompanied with a massive production of type 1 interferons and other immunostimulating cytokines. The recognition of mRNA by the innate immune system was also associated with cell death, which proceeded in human respiratory cells via pyroptosis, a form of programmed cell death mediated by substantial overexpression of caspase-1. This indicated that the delivered mRNA is most likely also recognized by NOD-like receptors which regulate caspase-1 production. The viability of murine respiratory cells was less affected by mRNA transfection, which is in line with the lower transfection efficiency, lower innate immune response and the absence of a massive caspase-1 upregulation in these cells. Finally, we also demonstrated that the recognition of the delivered mRNA by the innate immune system had a negative effect on mRNA translation. 23857415 Distinguishing multi-voxel patterns and mean activation: Why, how, and what does it tell us? The introduction of multi-voxel pattern analysis (MVPA) to the functional magnetic resonance imaging (fMRI) community has brought a deeper appreciation for the diverse forms of information that can be present within fMRI activity. The conclusions drawn from MVPA investigations are frequently influenced by both the ability to decode information from multi-voxel patterns and mean activation levels. In practice, MVPA studies vary widely in why and how they test for differing overall response levels. In this article, I examine the place of univariate information in MVPA investigations. I first discuss the variety of interpretations given to finding univariate response differences. I go on to discuss some of the analysis approaches used to investigate and compare univariate and multivariate sources of information, which can illuminate their respective contributions. It will be important for the MVPA and general fMRI community to continue to discuss and debate these important issues. 23339625 Time-dependent changes in hepatic and intestinal induction of cytochrome P450 3A after administration of dexamethasone to rats. Abstract 1. We investigated the effects of the dose of and the number of times an inducer was administered and the duration of induction of hepatic and intestinal cytochrome P450 3A (CYP3A) in rats using dexamethasone 21-phosphate (DEX-P) and midazolam (MDZ) as an inducer and a substrate to CYP3A, respectively. 2. The number of times DEX-P was administered was not a significant factor in the induction of either hepatic or intestinal CYP3A; however, administration of DEX-P multiple times markedly decreased the bioavailability of DEX-P by self-induction of CYP3A. 3. CYP3A induction in the liver increased depending on the dose of DEX-P, whereas that in intestine showed a mild increase, but the induction level was almost constant regardless of the dose of DEX-P. 4. Administration of a single dose of DEX-P showed a temporal increase in CYP3A activity in both tissues and the induction ratios reached maximum values at 12 h after DEX-P administration. On the other hand, a mild increase of CYP3A activity, which lasted for at least 48 h, was observed in both tissues after administration of multiple doses. 5. Some physiological compounds such as cytokines might be involved in decreasing the CYP3A activity to maintain homeostasis of the body. 23392339 Estimating skeletal muscle fascicle curvature from B-mode ultrasound image sequences. We address the problem of tracking in vivo muscle fascicle shape and length changes using ultrasound video sequences. Quantifying fascicle behavior is required to improve understanding of the functional significance of a muscle's geometric properties. Ultrasound imaging provides a noninvasive means of capturing information on fascicle behavior during dynamic movements; to date however, computational approaches to assess such images are limited. Our approach to the problem is novel because we permit fascicles to take up nonlinear shape configurations. We achieve this using a Bayesian tracking framework that is: 1) robust, conditioning shape estimates on the entire history of image observations; and 2) flexible, enforcing only a very weak Gaussian Process shape prior that requires fascicles to be locally smooth. The method allows us to track and quantify fascicle behavior in vivo during a range of movements, providing insight into dynamic changes in muscle geometric properties which may be linked to patterns of activation and intramuscular forces and pressures. 23851636 Magnetic isotope and magnetic field effects on the DNA synthesis. Magnetic isotope and magnetic field effects on the rate of DNA synthesis catalysed by polymerases β with isotopic ions (24)Mg(2+), (25)Mg(2+) and (26)Mg(2+) in the catalytic sites were detected. No difference in enzymatic activity was found between polymerases β carrying (24)Mg(2+) and (26)Mg(2+) ions with spinless, non-magnetic nuclei (24)Mg and (26)Mg. However, (25)Mg(2+) ions with magnetic nucleus (25)Mg were shown to suppress enzymatic activity by two to three times with respect to the enzymatic activity of polymerases β with (24)Mg(2+) and (26)Mg(2+) ions. Such an isotopic dependence directly indicates that in the DNA synthesis magnetic mass-independent isotope effect functions. Similar effect is exhibited by polymerases β with Zn(2+) ions carrying magnetic (67)Zn and non-magnetic (64)Zn nuclei, respectively. A new, ion-radical mechanism of the DNA synthesis is suggested to explain these effects. Magnetic field dependence of the magnesium-catalysed DNA synthesis is in a perfect agreement with the proposed ion-radical mechanism. It is pointed out that the magnetic isotope and magnetic field effects may be used for medicinal purposes (trans-cranial magnetic treatment of cognitive deceases, cell proliferation, control of the cancer cells, etc). 23965608 Electroconvulsive therapy and klinefelter syndrome. Klinefelter syndrome is a common sex chromosome disorder characterized by the presence of 1 or more extra X chromosomes, and the most prevalent karyotype is 47,XXY. Epidemiological studies have showed that patients with Klinefelter syndrome had a significantly increased risk of psychosis. We presented a case of a patient with Klinefelter syndrome who was characterized by psychiatric symptoms. The patients had been refractory to clozapine and sodium valproate, but a remarkable improvement occurred after a cycle of 11 sessions of modified electroconvulsive therapy. 22695677 Genetic determinants of neuronal vulnerability to apoptosis. Apoptosis is a common mode of cell death that contributes to neuronal loss associated with neurodegeneration. Single-nucleotide polymorphisms (SNPs) in chromosomal DNA are contributing factors dictating natural susceptibility of humans to disease. Here, the most common SNPs affecting neuronal vulnerability to apoptosis are reviewed in the context of neurological disorders. Polymorphic variants in genes encoding apoptotic proteins, either from the extrinsic (FAS, TNF-α, CASP8) or the intrinsic (BAX, BCL2, CASP3, CASP9) pathways could be highly valuable in the diagnosis of neurodegenerative diseases and stroke. Interestingly, the Arg72Pro SNP in TP53, the gene encoding tumor suppressor p53, was recently revealed a biomarker of poor prognosis in stroke due to its ability to modulate neuronal apoptotic death. Search for new SNPs responsible for genetic variability to apoptosis will ensure the implementation of novel diagnostic and prognostic tools, as well as therapeutic strategies against neurological diseases. 23925966 Face recognition and description abilities in people with mild intellectual disabilities. People with intellectual disabilities (ID) are as likely as the general population to find themselves in the situation of having to identify and/or describe a perpetrator's face to the police. However, limited verbal and memory abilities in people with ID might prevent them to engage in standard police procedures. Two experiments examined face recognition and description abilities in people with mild intellectual disabilities (mID) and compared their performance with that of people without ID. Experiment 1 used three old/new face recognition tasks. Experiment 2 consisted of two face description tasks, during which participants had to verbally describe faces from memory and with the target in view. Participants with mID performed significantly poorer on both recognition and recall tasks than control participants. However, their group performance was better than chance and they showed variability in performance depending on the measures introduced. The practical implications of these findings in forensic settings are discussed. 23886961 Paradoxical Hypoglycaemia Associated with Diazoxide Therapy for Hyperinsulinaemic Hypoglycaemia. Background/Aims: Hyperinsulinaemic hypoglycaemia (HH) is the most common cause of severe and persistent hypoglycaemia in the neonatal period. Diazoxide, a KATP channel activator, is the first line of treatment for patients with HH. Methods: We present 2 cases diagnosed with HH in the neonatal period. Both were started on diazoxide as the first line of treatment and the dose was titrated in order to achieve euglycaemia. Results: When the dose of diazoxide was increased to 15 mg/kg/day, we noted that both infants had increased frequency of hypoglycaemic episodes associated with an increase in the intravenous glucose infusion rate required to maintain normoglycaemia. When the diazoxide was stopped, the intravenous glucose infusion rate decreased and the frequency of hypoglycaemic episodes significantly reduced. The period between the increase in the dose of diazoxide and the onset of increased episodes of hypoglycaemia varied from 12 to 48 h. Conclusion: We report for the first time that diazoxide can cause paradoxical hypoglycaemia when used in moderate to high doses in infants with HH. Our clinical observations support the recent in vitro observations on pancreatic tissue isolated from patients with HH, where diazoxide caused an unanticipated increase in insulin secretion. These observations have important implications for managing patients with HH. 23939719 Nursing interventions for smoking cessation. Healthcare professionals, including nurses, frequently advise people to improve their health by stopping smoking. Such advice may be brief, or part of more intensive interventions. To determine the effectiveness of nursing-delivered smoking cessation interventions. We searched the Cochrane Tobacco Addiction Group specialized Register and CINAHL in June 2013. Randomized trials of smoking cessation interventions delivered by nurses or health visitors with follow-up of at least six months. Two authors extracted data independently. The main outcome measure was abstinence from smoking after at least six months of follow-up. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. Where statistically and clinically appropriate, we pooled studies using a Mantel-Haenszel fixed-effect model and reported the outcome as a risk ratio (RR) with a 95% confidence interval (CI). Forty-nine studies met the inclusion criteria. Pooling 35 studies (over 17,000 participants) comparing a nursing intervention to a control or to usual care, we found the intervention to increase the likelihood of quitting (RR 1.29; 95% CI 1.20 to 1.39). In a subgroup analysis the estimated effect size was similar for the group of seven studies using a particularly low intensity intervention but the confidence interval was wider. There was limited indirect evidence that interventions were more effective for hospital inpatients with cardiovascular disease than for inpatients with other conditions. Interventions in non-hospitalized adults also showed evidence of benefit. Eleven studies comparing different nurse-delivered interventions failed to detect significant benefit from using additional components. Six studies of nurse counselling on smoking cessation during a screening health check or as part of multifactorial secondary prevention in general practice (not included in the main meta-analysis) found nursing intervention to have less effect under these conditions. The results indicate the potential benefits of smoking cessation advice and/or counselling given by nurses, with reasonable evidence that intervention is effective. The evidence for an effect is weaker when interventions are brief and are provided by nurses whose main role is not health promotion or smoking cessation. The challenge will be to incorporate smoking behaviour monitoring and smoking cessation interventions as part of standard practice so that all patients are given an opportunity to be asked about their tobacco use and to be given advice and/or counselling to quit along with reinforcement and follow-up. 23642079 Simulations of droplet coalescence in simple shear flow. Simulating droplet coalescence is challenging because small-scale (tens of nanometers) phenomena determine the behaviour of much larger (micron- to millimetre-scale) droplets. In general, liquid droplets colliding in a liquid medium coalesce when the capillary number is less than a critical value. We present simulations of droplet collisions and coalescence in simple shear flow using the free-energy binary-liquid lattice Boltzmann method. In previous simulations of low-speed collisions, droplets coalesced at unrealistically high capillary numbers. Simulations of non-coalescing droplets have not been reported, and therefore the critical capillary number for simulated collisions was unknown. By simulating droplets with radii up to 100 lattice nodes, we determine the critical capillary number for coalescence and quantify the effects of several numerical and geometric parameters. The simulations were performed with a well-resolved interface, a Reynolds number of one, and capillary numbers from 0.01 to 0.2. The ratio of the droplet radius and interface thickness has the greatest effect on the critical capillary number. As in experiments, the critical capillary number decreases with increasing droplet size. A second numerical parameter, the interface diffusivity (Peclet number) also influences the conditions for coalescence: coalescence occurs at higher capillary numbers with lower Peclet numbers (higher diffusivity). The effects of the vertical offset between the droplets and the confinement of the droplets were also studied. Physically reasonable results were obtained and provide insight into the conditions for coalescence. Simulations that match the conditions of experiments reported in the literature remain computationally impractical. However, the scale of the simulations is now sufficiently large that a comparison with experiments involving smaller droplets (~10 μm) and lower viscosities (10(-6) m(2)/s, the viscosity of water) may be possible. Experiments at these conditions are therefore needed to determine the interface thickness and Peclet number that should be used for predictive simulations of coalescence phenomena. 23723018 Geodermatophilus africanus sp. nov., a halotolerant actinomycete isolated from Saharan desert sand. A novel Gram-strain positive, aerobic, actinobacterial strain, designated CF11/1(T), was isolated from a sand sample obtained in the Sahara Desert, Chad. The black-pigmented isolate was aerobic and exhibited optimal growth from 25 to 35 °C at pH 6.0-8.0 and with 0-8 % (w/v) NaCl, indicating that it is a halotolerant mesophile. Chemotaxonomic and molecular characteristics of the isolate matched those described for members of the genus Geodermatophilus. The G+C content in the genome was 74.4 mol%. The peptidoglycan contained meso-diaminopimelic acid as diagnostic diaminoacid. The main phospholipids were diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and a minor fraction of phosphatidylglycerol; MK-9(H4) was the dominant menaquinone, and galactose was detected as a diagnostic sugar. The major cellular fatty acid was branched-chain saturated acid iso-C16:0. Analysis of 16S rRNA gene sequences showed 95.3-98.6 % pairwise sequence identity with the members of the genus Geodermatophilus. Based on phenotypic and chemotaxonomic properties, as well as phylogenetic distinctiveness, the isolate represents a novel species, Geodermatophilus africanus, with the type strain CF11/1(T) (DSM 45422 = CCUG 62969 = MTCC 11556). 23937222 Expression patterns of key iron and oxygen metabolism genes during magnetosome formation in Magnetospirillum gryphiswaldense MSR-1. To evaluate the expression patterns of genes involved in iron and oxygen metabolism during magnetosome formation, the profiles of 13 key genes in Magnetospirillum gryphiswaldense MSR-1 cells cultured under high-iron vs. low-iron conditions were examined. Cell growth rates did not differ between the two conditions. Only the high-iron cells produced magnetosomes. TEM observations revealed that magnetosome formation began at 6 h and crystal maturation occurred from 10 to 18 h. Real-time PCR analysis showed that expression of these genes increased during cell growth and magnetosome synthesis, particularly for ferric reductase gene (fer6) and ferrous transport system-related genes feoAB1, feoAB2, sodB, and katG. The low-iron cells showed increased expression of feoAB1 and feoB2 from 12 to 18 h but no clear expression changes for the other genes. Expression patterns of the genes were divided by hierarchical clustering into four clusters for the high-iron cells and three clusters for the low-iron cells. Each cluster included both iron and oxygen metabolism genes showing similar expression patterns. The findings indicate the coordination and co-dependence of iron and oxygen metabolism gene activity to achieve a balance during the biomineralization process. Future transcriptome analysis will help elucidate the mechanism of biomineralization in MSR-1 magnetosome formation. This article is protected by copyright. All rights reserved. 23788371 Pro-inflammatory cytokines in glaucomatous aqueous and encysted molteno implant blebs and their relationship to pressure. To ascertain the presence of additional pro-inflammatory cytokines in glaucomatous aqueous, and their relationship with IOP. To quantify the levels of 23 pro-inflammatory cytokines, and correlate levels with IOP, aqueous humor samples were analyzed from 23 eyes with open angle glaucoma (OAG) undergoing glaucoma filtration procedures, and from 24 Molteno blebs during the hypertensive phase. Control aqueous was derived from 13 eyes without glaucoma undergoing cataract removal. A significant difference (P < 0.05) was noted between hypertensive bleb aqueous and controls in the amount TGF-β2, interleukins IL-6, IL-10, and chemokine (C-X-C motif) ligand 1 (CXCL1; GROα). The levels of these cytokines were higher in the glaucomatous aqueous, but not significantly so. A significant difference was noted in levels of chemokine (C-C motif) ligand 2 (CCL2; MCP-1, monocyte chemotactic protein-1) in the glaucoma eye and bleb aqueous compared with controls. Of the 23 cytokines tested for, 19 were found in the bleb group, 14 in the glaucoma group, and 16 in the control group. Compared with controls, all cytokines levels were higher in the glaucoma group and highest in the bleb group. The study confirms the well documented presence of TGF-β2 in glaucomatous aqueous. The presence of significant levels of CCL2 in glaucomatous aqueous is a new finding. The finding of higher levels of all the cytokines in the aqueous from the encysted blebs, in which the IOP was the highest, suggests that their levels increase with an increase in IOP, as well as the possibility that encysted blebs form cytokines. 23850550 Stem Cell Origin of Testicular Seminoma. A major question concerning cancer is its cells of origin. We hypothesized that distinct cancer subtypes arise from unique cancer-initiating cells. By performing a microarray meta-analysis of seminomas and spermatogonial stem cells, we investigated a putative cell of origin for seminoma. We obtained published microarray data for 6 human adult germ cell lines, 16 embryonic stem cell lines, 3 normal testicular tissue samples, and 40 seminomas from the Gene Expression Omnibus database. By assessing correlations between various tissue microarrays, we determined the number of transitional events and the distance between seminomas and human spermatogonial stem cells. Our meta-analysis showed that spermatogonial stem cells correlated similarly with seminoma (95% CI of Spearman ρ, 0.33-0.44) and with normal somatic testicular tissue cells (95% CI, 0.39-0.40), which suggests parallel paths of cellular origins. Analysis of our results suggests that a unique cancer subtype, namely seminoma, may have originated from an undifferentiated cell with stemness features rather than from a differentiated cell that acquired stemness features. 23951202 Bilateral bi-cephalic tdcs with two active electrodes of the same polarity modulates bilateral cognitive processes differentially. Transcranial direct current stimulation (tDCS) is an innovative method to explore the causal structure-function relationship of brain areas. We investigated the specificity of bilateral bi-cephalic tDCS with two active electrodes of the same polarity (e.g., cathodal on both hemispheres) applied to intraparietal cortices bilaterally using a combined between- and within-task approach. Regarding between-task specificity, we observed that bilateral bi-cephalic tDCS affected a numerical (mental addition) but not a control task (colour word Stroop), indicating a specific influence of tDCS on numerical but not on domain general cognitive processes associated with the bilateral IPS. In particular, the numerical effect of distractor distance was more pronounced under cathodal than under anodal stimulation. Moreover, with respect to within-task specificity we only found the numerical distractor distance effect in mental addition to be modulated by direct current stimulation, whereas the effect of target identity was not affected. This implies a differential influence of bilateral bi-cephalic tDCS on the recruitment of different processing components within the same task (number magnitude processing vs. recognition of familiarity). In sum, this first successful application of bilateral bi-cephalic tDCS with two active electrodes of the same polarity in numerical cognition research corroborates the specific proposition of the Triple Code Model that number magnitude information is represented bilaterally in the intraparietal cortices. 23397966 Treatment of pretibial myxedema with dexamethazone injected subcutaneously by mesotherapy needles. Pretibial myxedema (PTM) is a rare extrathyroidal manifestation of Graves' disease that requires treatment when the clinical picture is markedly evident. In addition to topical treatment with steroid ointments, there have been previous reports of subcutaneous injections of steroids. This procedure may cause nodular degeneration of the skin due to fat atrophy when standard needles are used. In the present study, we have tried a novel modality of treatment of PTM by injecting a solution of dexamethasone in the subcutaneous tissue using needles employed for mesotherapy. These needles are ≤4 mm long and deliver the medication within the dermis or the first layer of the subcutaneous fat. We have treated five patients, four with diffuse and one with elephanthiasic PTM. We utilized multiple injections of a solution of dexamethasone, lidocaine, and saline in the PTM plaque and in the pretibial area, both in the PTM plaque and in the area surrounding the lesions, once a week for three consecutive weeks. Two patients with a more severe form of PTM underwent another two cycles four to six weeks after initial treatment. Patients were studied before and after treatment by clinical assessment and ultrasound of the pretibial skin. The treatment was well-tolerated, with only moderate pain upon injection of the solution. One month after treatment, all patients showed improvement of PTM at clinical assessment and a reduction of the thickness of the lesions at ultrasound of ∼15%, involving mostly the dermis. Moreover, all patients reported amelioration of the leg appearance. The present study, although preliminary, shows that intralesion steroid injection with mesotherapy needles in PTM is effective and well tolerated, and does not cause undesired long-term modifications of the skin. More studies are warranted to standardize such treatment in larger groups of patients. 23857975 High-Risk Medulloblastoma: A Pediatric Oncology Group Randomized Trial of Chemotherapy Before or After Radiation Therapy (POG 9031). PURPOSE To compare event-free survival (EFS) in children with high-risk medulloblastoma randomly assigned to receive either chemotherapy before radiation or chemotherapy after radiation. PATIENTS AND METHODS One hundred twelve patients were randomly assigned to each arm. Criteria used to categorize patients as high risk included M1-4 disease by modified Chang staging classification, T3b/T4 disease, or greater than 1.5 cm(3) of residual tumor after surgery. Postoperatively, children with high-risk medulloblastoma were randomly assigned to two arms, either chemotherapy entailing three cycles of cisplatin and etoposide before radiation (chemotherapy first [CT1]) or the same chemotherapy regimen after radiation (radiation therapy first [RT1]). Both groups received consolidation chemotherapy consisting of vincristine and cyclophosphamide. Results The median follow-up time was 6.4 years. Five-year EFS was 66.0% in the CT1 arm and 70.0% in the RT1 arm (P = .54), and 5-year overall survival in the two groups was 73.1% and 76.1%, respectively (P = .47). In the CT1 arm, 40 of the 62 patients with residual disease achieved either complete or partial remission. CONCLUSION Five-year EFS did not differ significantly whether, after surgery, patients received chemotherapy before or after radiotherapy. 23200243 Fluorescent ligands for adenosine receptors. Interest is increasing in developing fluorescent ligands for characterization of adenosine receptors (ARs), which hold a promise of usefulness in the drug discovery process. The size of a strategically labeled AR ligand can be greatly increased after the attachment of a fluorophore. The choice of dye moiety (e.g. Alexa Fluor 488), attachment point and linker length can alter the selectivity and potency of the parent molecule. Fluorescent derivatives of adenosine agonists and antagonists (e.g. XAC and other heterocyclic antagonist scaffolds) have been synthesized and characterized pharmacologically. Some are useful AR probes for flow cytometry, fluorescence correlation spectroscopy, fluorescence microscopy, fluorescence polarization, fluorescence resonance energy transfer, and scanning confocal microscopy. Thus, the approach of fluorescent labeled GPCR ligands, including those for ARs, is a growing dynamic research field. 23846391 Rh-BMP-2 for L5-S1 arthrodesis in long fusions to the pelvis for neuromuscular spinal deformity in the pediatric age group: analysis of 11 patients. Neuromuscular scoliosis is a challenging pathology to treat with high incidence of complications and failure of surgical fusion. Surgical correction can entail long fusion constructs extending to the pelvis. We report our experience in the use of bone morphogenetic protein (BMP) to augment L5-S1 arthrodesis in long segment fusions in pediatric patients with neuromuscular scoliosis. Retrospective review of 11 pediatric patients with neuromuscular spinal deformity (mean, age 13.7 years; range, 10-20 years) who underwent long (mean, 15 levels; range, 10-18 levels) spinal instrumentation and fusion to the pelvis at a single institution from 2007 to 2012 with an average follow-up of 34 months (range, 11-62 months). Of the 11 patients, one had pseudoarthrosis at L5-S1. The average coronal Cobb angle measured 59° before surgery and 42° immediately after surgery. The average preoperative thoracic kyphosis and lumbar sagittal lordosis measured 34 and 59°, respectively. Immediately after surgery, the thoracic and lumbar angles measured 28 and 39°, respectively. At last follow-up, the average coronal Cobb angle was maintained at 43° and the thoracic and lumbar sagittal angles were 28 and 44°, respectively. An average of 14.2 mg of recombinant human bone morphogenetic protein-2 (rh-BMP-2) was used for each case. L5-S1 arthrodesis may be effectively achieved in long fusions for pediatric neuromuscular spinal deformity with posterolateral fusion supplemented with rh-BMP-2. This surgical strategy may be associated with lower complication rates, decreased blood loss, and shorter operative times than circumferential fusion, which is particularly important in this complex fragile patient population. 23792564 Promoter directionality is controlled by U1 snRNP and polyadenylation signals. Transcription of the mammalian genome is pervasive, but productive transcription outside of protein-coding genes is limited by unknown mechanisms. In particular, although RNA polymerase II (RNAPII) initiates divergently from most active gene promoters, productive elongation occurs primarily in the sense-coding direction. Here we show in mouse embryonic stem cells that asymmetric sequence determinants flanking gene transcription start sites control promoter directionality by regulating promoter-proximal cleavage and polyadenylation. We find that upstream antisense RNAs are cleaved and polyadenylated at poly(A) sites (PASs) shortly after initiation. De novo motif analysis shows PAS signals and U1 small nuclear ribonucleoprotein (snRNP) recognition sites to be the most depleted and enriched sequences, respectively, in the sense direction relative to the upstream antisense direction. These U1 snRNP sites and PAS sites are progressively gained and lost, respectively, at the 5' end of coding genes during vertebrate evolution. Functional disruption of U1 snRNP activity results in a dramatic increase in promoter-proximal cleavage events in the sense direction with slight increases in the antisense direction. These data suggest that a U1-PAS axis characterized by low U1 snRNP recognition and a high density of PASs in the upstream antisense region reinforces promoter directionality by promoting early termination in upstream antisense regions, whereas proximal sense PAS signals are suppressed by U1 snRNP. We propose that the U1-PAS axis limits pervasive transcription throughout the genome. 23808469 Direct thrombin inhibitors and factor xa inhibitors can influence the diluted prothrombin time used as the initial screen for lupus anticoagulant. Lupus anticoagulant (LA) is a heterogeneous group of antiphospholipid antibodies. Among others, diluted prothrombin time (dPT) is a sensitive screening test for LA; however, the interpretation of LA tests is difficult in patients treated with anticoagulants. The effect of different types of anticoagulants on the result of LA tests, particularly on dPT, has not been studied extensively. To determine whether the direct thrombin inhibitors lepirudin and argatroban and the predominantly factor Xa inhibitors enoxaparin, danaparoid, and fondaparinux could interfere with LA screening based on dPT. Each drug was added to normal and LA-positive plasmas in clinically relevant concentrations. Each sample was tested for dPT. Samples with factor Xa inhibitors were investigated before and after addition of heparinase. Mixing and confirmatory tests for LA were not performed. In the presence of lepirudin or argatroban, dPT increased notably and the dPT ratio exceeded the cutoff value even at subtherapeutic concentrations resulting in false positivity. With increasing factor Xa inhibitor concentrations, a linear increase of dPT ratios and false-positive results were also demonstrated. Although heparinase could almost completely neutralize the anti-Xa effect of all investigated factor Xa inhibitors, dPT ratio returned to the basal level only in case of enoxaparin. Here we provide evidence that both the direct thrombin and indirect factor Xa inhibitors influence dPT assay for LA, causing false positivity. This should be considered when interpreting LA results during anticoagulant therapy. However, dPT seems to be a reliable test for LA screening under enoxaparin therapy after neutralization by heparinase. 23805914 Engineering chiral polyoxometalate hybrid metal-organic frameworks for asymmetric dihydroxylation of olefins. Chiral metal-organic frameworks (MOFs) with porous and tunable natures have made them feasible for performing a variety of chemical reactions as heterogeneous asymmetric catalysts. By incorporating the oxidation catalyst [BW12O40](5-) and the chiral group, l- or d-pyrrolidin-2-ylimidazole (PYI), into one single framework, the two enantiomorphs Ni-PYI1 and Ni-PYI2 were obtained via self-assembly, respectively. The channels of Ni-PYIs were enlarged through a guest exchange reaction to remove the cationic chiral templates and were well modulated with hydrophilic/hydrophobic properties to allow molecules of both H2O2 and olefin ingress and egress. The coexistence of both the chiral directors and the oxidants within a confined space provided a special environment for the formation of reaction intermediates in a stereoselective fashion with high selectivity. The resulting MOF acted as an amphipathic catalyst to prompt the asymmetric dihydroxylation of aryl olefins with excellent stereoselectivity. 23830871 Learning from rejection: What transplantation teaches us about (other) vascular pathologies. Allograft vasculopathy is an accelerated intimal hyperplastic lesion leading to progressive vascular stenosis; it represents the major long-term limitation to successful solid organ transplant. Although allograft vasculopathy is not formally an autoimmune disease, nor does it constitute a major cause of cardiovascular disease on a purely numerical basis, its pathogenesis provides an important window on the mechanisms by which immune injury can drive more common vascular pathologic entities. Thus, insights gleaned from vascularized solid organ transplants can shed new mechanistic (and therapeutic) light on: 1) the intimal vascular responses accompanying typical atherosclerosis and other inflammatory vessel diseases (e.g., scleroderma); 2) the pathogenesis of vascular stenosis versus aneurysm formation; 3) the sources of intimal smooth muscle cells in the healing of any vascular injury; and 4) the mechanisms by which smooth muscle cells are recruited into intimal lesions. Indeed, research on allograft vasculopathy has led to the understanding that interferon-γ plays a similar pathogenic role in a host of vascular stenosing lesions-and that Th2 cytokines can drive vascular remodeling and aneurysm formation. Moreover, circulating precursors (and not just medial smooth muscle cells) contribute to the intimal hyperplasia seen in atherosclerosis and in-stent restenosis. That non-vessel smooth muscle cells can be recruited to sites of vessel injury further suggests that chemokine and adhesion molecule interactions may be viable targets to limit vascular stenosis in a wide range of vascular lesions. This review will describe the pathogenesis of allograft vasculopathy, and will relate how understanding the underlying pathways informs our understanding of both human transplant-associated disease, as well as other human vascular pathologies. 23851222 Transcriptome analysis of venom glands from a single fishing spider Dolomedes mizhoanus. The spider venom is a large pharmacological repertoire composed of different types of bioactive peptide toxins. Despite the importance of spider toxins in capturing terrestrial prey and defending themselves against predators, we know little about the venom components from the spider acting on the fish. Here we constructed a cDNA library of a pair of venomous glands from a single fish-hunting spider Dolomedes mizhoanus. A total of 356 high-quality expressed sequence tags (ESTs) were obtained from the venom gland cDNA library and analyzed. These transcripts were further classified into 45 clusters (19 contigs and 26 singletons), most of which encoded cystine knot toxins (CKTs) and non-CKTs. The ESTs coding for 53 novel CKT precursors were abundant transcripts in the venom glands of the spider D. mizhoanus, accounting for 76% of the total ESTs, the precursors of which were grouped into six families based on the sequence identity and the phylogenetic analysis. In addition, the non-CKTs deduced from 21% of the total ESTs were annotated by Gene Ontology terms and eukaryotic orthologous groups. Fifty-five CKT precursors deduced from 273 ESTs are the largest dataset for a single spider specimen to date. The results may contribute to discovering novel potential drug leads from spider venoms and a better understanding of the evolutionary relationship of the spider toxin. 23824950 Titanium Salalen Catalysts Based on cis-1,2-Diaminocyclohexane: Enantioselective Epoxidation of Terminal Non-Conjugated Olefins with H2 O2. Help for the neglected: Terminal, non-conjugated olefins, such as 1-octene, are difficult to epoxidize asymmetrically. Ti salalen complexes based on cis-1,2-diaminocyclohexane catalyze this demanding reaction giving high yields and enantioselectivities (up to 95 % ee), with H2 O2 as the oxidant. The X-ray structures of the μ-oxo and peroxo complexes shed light on the coordination behavior of this novel class of ligands. 23804329 Initial Human PET Studies of Metabotropic Glutamate Receptor Type 1 Ligand 11C-ITMM. N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4-(11)C-methoxy-N-methylbenzamide ((11)C-ITMM) is a potential radioligand for mapping metabotropic glutamate receptor type 1 (mGluR1) in the brain by PET. The present study was performed to determine the safety, distribution, radiation dosimetry, and initial brain imaging of (11)C-ITMM in healthy human subjects. The multiorgan biodistribution and radiation dosimetry of (11)C-ITMM were assessed in 3 healthy human subjects, who underwent 2-h whole-body PET scans. Radiation dosimetry was estimated from the normalized number of disintegrations of source organs using the OLINDA/EXM program. Five healthy human subjects underwent 90-min dynamic (11)C-ITMM scans of brain regions with arterial blood sampling. For anatomic coregistration, T1-weighted MR imaging was performed. Metabolites in plasma and urine samples were analyzed by high-performance liquid chromatography. (11)C-ITMM uptake was assessed quantitatively using a 2-tissue-compartment model. There were no serious adverse events in any of the subjects throughout the study period. (11)C-ITMM PET demonstrated high uptake in the urinary bladder and gallbladder, indicating both urinary and fecal excretion of radioactivity. The absorbed dose (μGy/MBq) was highest in the urinary bladder wall (13.2 ± 3.5), small intestine (9.8 ± 1.7), and liver (9.1 ± 2.0). The estimated effective dose for (11)C-ITMM was 4.6 ± 0.3 μSv/MBq. (11)C-ITMM showed a gradual increase of radioactivity in the cerebellar cortex. The total distribution volume in the brain regions ranged from 2.61 ± 0.30 (cerebellar cortex) to 0.52 ± 0.17 (pons), and the rank order of the corresponding total distribution volume of (11)C-ITMM was cerebellar cortex > thalamus > frontal cortex > striatum ≈ pons, which was consistent with the known distribution of mGluR1 in the primate brain. The rate of (11)C-ITMM metabolism in plasma was moderate: at 60 min after injection, 62.2% ± 8.2% of the radioactivity in plasma was intact parent compound. The initial findings of the present study indicated that (11)C-ITMM PET is feasible for imaging of mGluR1 in the brain. The low effective dose will permit serial examinations in the same subjects. 23750020 HAMI 3379, a CysLT2 Receptor Antagonist, Attenuates Ischemia-Like Neuronal Injury by Inhibiting Microglial Activation. The cysteinyl leukotrienes (CysLTs) are inflammatory mediators closely associated with neuronal injury after brain ischemia through the activation of their receptors, CysLT1R and CysLT2R. Here we investigated the involvement of both receptors in oxygen-glucose deprivation/recovery (OGD/R)-induced ischemic neuronal injury and the effect of the novel CysLT2R antagonist HAMI 3379 [3-({[(1S,3S)-3- carboxycyclohexyl]amino}carbonyl)-4-(3-{4-[4-(cyclo-hexyloxy)butoxy]phenyl}propoxy)benzoic acid] in comparison with the CysLT1R antagonist montelukast. In primary neurons, neither the nonselective agonist leukotriene D4 (LTD4) nor the CysLT2R agonist N-methyl-leukotriene C4 (NMLTC4) induced neuronal injury, and HAMI 3379 did not affect OGD/R-induced neuronal injury. However, in addition to OGD/R, LTD4 and NMLTC4 induced cell injury and neuronal loss in mixed cultures of cortical cells, and neuronal loss and necrosis in neuron-microglial cocultures. Moreover, they induced phagocytosis and cytokine release (interleukin-1β and tumor necrosis factor-α) from primary microglia, and conditioned medium from the treated microglia induced neuronal necrosis. HAMI 3379 inhibited all of these responses, and its effects were the same as those of CysLT2R interference by CysLT2R short hairpin RNA, indicating CysLT2R dependence. In comparison, montelukast moderately inhibited OGD/R-induced primary neuronal injury and most OGD/R- and LTD4-induced (but not NMLTC4-induced) responses in mixed cultures, cocultures, and microglia. The effects of montelukast were both dependent and independent of CysLT1Rs because interference by CysLT1R small interfering RNA had limited effects on neuronal injury in neuron-microglial cocultures and on cytokine release from microglia. Our findings indicated that HAMI 3379 effectively blocked CysLT2R-mediated microglial activation, thereby indirectly attenuating ischemic neuronal injury. Therefore, CysLT2R antagonists may represent a new type of therapeutic agent in the treatment of ischemic stroke. 23856236 Look now and hear what's coming: On the functional role of cross-modal phase reset. In our multisensory environment our sensory systems are continuously receiving information that is often interrelated and must be integrated. Recent work in animals and humans has demonstrated that input to one sensory modality can reset the phase of ambient cortical oscillatory activity in another. The periodic fluctuations in neuronal excitability reflected in these oscillations can thereby be aligned to forthcoming anticipated sensory input. In the auditory domain, the example par excellence is speech, because of its inherently rhythmic structure. In contrast, fluctuations of oscillatory phase in the visual system are argued to reflect periodic sampling of the environment. Thus rhythmic structure is imposed on, rather than extracted from, the visual sensory input. Given this distinction, we suggest that cross-modal phase reset subserves separate functions in the auditory and visual systems. We propose a modality-dependent role for cross-modal input in temporal prediction whereby an auditory event signals the visual system to look now, but a visual event signals the auditory system that it needs to hear what is coming. This article is part of a Special Issue entitled . 23910988 Identification of 2,3-disubstituted pyridines as potent, orally active PDE4 inhibitors. A series of 2,3-disubstituted pyridines were synthesized and evaluated for their PDE4 inhibitory activity. We successfully modified undesirable cyano group of initial lead compound 2 to 4-pyridyl group with improvement of in vitro efficacy and optimized the position of nitrogen atoms in pyridine moiety and alkylene linker. The most potent compound showed significant efficacy in animal models of asthma and inflammation. 23904151 The High Sensitive and Selective "Off-On" Fluorescent Zn(2+) Sensor Based on the Bis(2,4,7,8,9-pentamethyldipyrrolylmethene-3-yl)methane. A fluorescent chemosensor based on the 3,3'-bis(dipyrrin) bearing two chromophoric dipyrrin units was synthesized, which showed a strongly enhanced fluorescent intensity in the presence of Zn(2+) ions and a high selectivity toward Zn(2+) ions over a wide range of tested metal ions in organic solvents. 23970296 Nurses' perspectives on the discharge of cancer patients with palliative care needs from a gastroenterology ward. Background: People with cancer usually like to spend as much time as possible at home rather than in the hospital. Nurses have a pivotal role when patients are discharged to a unit in hospital or from hospital to the community health-care system. Aim: To explore how frontline surgical nurses assess patients with gastrointestinal cancer receiving palliative care and the implications of their assessment and competency for the patients' discharge destinations. Methods: A descriptive exploratory approach was used involving focus group interviews with a purposive sample of ten nurses from an inpatient gastroenterology surgical ward at a university hospital in Norway. Transcriptions of the interviews were analysed using Kvale and Brinkman's thematic approach. Results: Two overall themes emerged that had implications for the nurses' recommendations for optimal patient follow-up care after discharge: 'the complexity of and fluctuations in the patients' health status' and 'considering the competency of the nurses at the discharge destinations'. Conclusions: This study illustrates surgical nurses' perspectives on the discharge destinations of cancer patients receiving palliative care. The findings have implications for initiatives aimed at providing more home-based palliative care. 23606216 Variation in scrotal color among widely distributed vervet monkey populations (chlorocebus aethiops pygerythrus and chlorocebus aethiops sabaeus). Vervet monkeys (Chlorocebus aethiops) exhibit bright blue scrotal skin which may function to mediate social interactions by acting as a socio-sexual signal. Previous research on scrotal coloration among vervet monkeys was limited to experimental work on captive Ch. a. sabaeus, the least colorful vervet subspecies, and two field studies of the more colorful Ch. a. pygerythrus. In a study of free-ranging and captive vervet monkeys in South Africa (Ch. pygerythrus), West Africa (Ch. a. sabaeus) and the Caribbean (Ch. a. sabaeus), we examined scrotal color variation across geographically distant subspecies. We provide an exploration of how digital photographs may be used to quantify and analyze blue and green skin coloration by examining the blue-yellow opponency channel and luminance channel as color measures. We found that that at all ages the scrotal color of Ch. a. pygerythrus males was always bluer and darker than that of Ch. a. sabaeus males. Among Ch. a. pygerythrus scrotal color becomes bluer and lightens with increasing age, while the color of Ch. a. sabaeus males also lightens, but becomes less blue with increasing age. We suggest that color variation is related to maturation and may function as an age-related signal among Ch. a. pygerythrus and Ch. a. sabaeus. We also found color was related to three morphological features among adults. For Ch. a. pygerythrus, higher body weight is associated with more blue color and longer canine length is associated with lighter color. Lighter color was associated with longer body lengths among Ch. a. sabaeus. Future studies focused on color variation within age classes are needed to examine the potential signal content of color in this species. 23925801 Fabrication of thermally stable and active bimetallic Au-Ag nanoparticles stabilized on inner wall of mesoporous silica shell. A general method has been developed for the fabrication of highly dispersed and thermally stable bimetallic Au-Ag nanoparticles (NPs) stabilized on the inner wall of a mesoporous silica shell. In our approach, gold particles were formed in the first step on carbon spheres decorated with Sn(2+) cations. Upon Ag(+) adsorption and reduction by l-ascorbic acid in the second step, specific nanoparticles with a gold-silver alloy core and a silver nanoshell have been formed. Important evidence of the core-shell configurations of the bimetallic Au-Ag nanoparticles were clearly characterized by UV-vis, TEM and HAADF-STEM observations combined with elemental mapping and line scans. The mesoporous silica outer shell was obtained through the hydrolysis and condensation of the precursors tetraethoxysilane (TEOS) in a basic condition and cetyltrimethylammonium bromide (CTAB) as a structure-directing agent. On this basis, the nanoreactors were fabricated after calcination, which further serves as a nanoreactor for the reduction of p-nitrophenol. Furthermore, such particles have been found to be thermally stable and their sizes remain substantially unchanged even upon calcination in air at 500 °C and a reduction treatment in H2. Potentially, the method can be developed into a general approach to synthesize other highly dispersed and thermally stable bimetallic nanoparticles stabilized on the inner wall of a mesoporous silica shell. 23720772 Metformin increases mitochondrial energy formation in l6 muscle cell cultures. A popular hypothesis for the action of metformin, the widely used anti-diabetes drug, is the inhibition of mitochondrial respiration, specifically at complex I. This is consistent with metformin stimulation of glucose uptake by muscle and inhibition of gluconeogenesis by liver. Yet, mitochondrial inhibition is inconsistent with metformin stimulation of fatty acid oxidation in both tissues. In this study, we measured mitochondrial energy production in intact cells adapting an in vivo technique of phosphocreatine (PCr) formation following energy interruption ("PCr recovery") to cell cultures. Metformin increased PCr recovery from either dinitrophenol (DNP) or azide in L6 cells. We found that metformin alone had no effect on cell viability as measured by total ATP concentration, trypan blue exclusion, or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction. However, treatments with low concentrations of DNP or azide reversibly decreased ATP concentration. Metformin increased 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction during recovery from either agent. Viability measured by trypan blue exclusion indicated that cells were intact under these conditions. We also found that metformin increased free AMP and, to a smaller extent, free ADP concentrations in cells, an action that was duplicated by a structurally unrelated AMP deaminase inhibitor. We conclude that, in intact cells, metformin can lead to a stimulation of energy formation, rather than an inhibition. 23787792 High quantum-yield CdSexS1-x/ZnS core/shell quantum dots for warm white light-emitting diodes with good color rendering. Composition-controllable ternary CdSe(x)S(1-x) quantum dots (QDs) with multiple emission colors were obtained via a hot-injection-like method at a relatively low injection temperature (230 ° C) in octadecene. Then highly fluorescent CdSe(x)S(1-x)/ZnS core/shell (CS) QDs were synthesized by a facile single-molecular precursor approach. The fluorescent quantum yield of the resulting green (λ(em) = 523 nm), yellow (λ(em) = 565 nm) and red (λ(em) = 621 nm) emission of CS QDs in toluene reached up to 85%, 55% and 39%, respectively. Moreover, a QDs white light-emitting diode (QDs-WLED) was fabricated by hybridizing green-, yellow- and red-emitting CdSe(x)S(1-x)/ZnS CS QDs/epoxy composites on a blue InGaN chip. The resulting four-band RYGB QDs-WLED showed good performance with CIE-1931 coordinates of (0.4137, 0.3955), an R(a) of 81, and a T(c) of 3360 K at 30 mA, which indicated the combination of multiple-color QDs with high fluorescence QYs in LEDs as a promising approach to obtain warm WLEDs with good color rendering. 23436254 Microporous carbon nanoplates from regenerated silk proteins for supercapacitors. Novel carbon-based microporous nanoplates containing numerous heteroatoms (H-CMNs) are fabricated from regenerated silk fibroin by the carbonization and activation of KOH. The H-CMNs exhibit superior electrochemical performance, displaying a specific capacitance of 264 F/g in aqueous electrolytes, a specific energy of 133 Wh/kg, a specific power of 217 kW/kg, and a stable cycle life over 10000 cycles. 23910447 Experimental and Monte Carlo evaluation of Eclipse treatment planning system for effects on dose distribution of the hip prostheses. The present study aimed to investigate the effects of titanium, titanium alloy, and stainless steel hip prostheses on dose distribution based on the Monte Carlo simulation method, as well as the accuracy of the Eclipse treatment planning system (TPS) at 6 and 18MV photon energies. In the present study the pencil beam convolution (PBC) method implemented in the Eclipse TPS was compared to the Monte Carlo method and ionization chamber measurements. The present findings show that if high-Z material is used in prosthesis, large dose changes can occur due to scattering. The variance in dose observed in the present study was dependent on material type, density, and atomic number, as well as photon energy; as photon energy increased back scattering decreased. The dose perturbation effect of hip prostheses was significant and could not be predicted accurately by the PBC method for hip prostheses. The findings show that for accurate dose calculation the Monte Carlo-based TPS should be used in patients with hip prostheses. 23526644 Inhibition of Ebola Virus Infection: Identification of Niemann-Pick C1 as the Target by Optimization of a Chemical Probe. A high throughput screen identified adamantane dipeptide 1 as an inhibitor of Ebola virus (EboV) infection. Hit-to-lead optimization to determine the structure-activity relationship (SAR) identified the more potent EboV inhibitor 2 and a photoaffinity labeling agent 3. These anti-viral compounds were employed to identify the target as Niemann-Pick C1 (NPC1), a host protein that binds the EboV glycoprotein and is essential for infection. These studies establish NPC1 as a promising target for anti-viral therapy. 23934893 Precise and Heritable Genome Editing in Evolutionarily Diverse Nematodes Using TALENs and CRISPR/Cas9 to Engineer Insertions and Deletions. Exploitation of custom-designed nucleases to induce DNA double-strand breaks (DSBs) at genomic locations of choice has transformed our ability to edit genomes, regardless of their complexity. DSBs can trigger either error-prone repair pathways that induce random mutations at the break sites or precise homology-directed repair pathways that generate specific insertions or deletions guided by exogenously supplied DNA. Prior editing strategies using site-specific nucleases to modify the C. elegans genome achieved only the heritable disruption of endogenous loci through random mutagenesis by error-prone repair. Here we report highly effective strategies using TALE nucleases and RNA-guided CRISPR/Cas9 nucleases to induce error-prone repair and homology-directed repair to create heritable, precise insertion, deletion, or substitution of specific DNA sequences at targeted endogenous loci. Our robust strategies are effective across nematode species diverged by 300 million years, including necromenic nematodes (P. pacificus), male/female species (Caenorhabditis species 9), and hermaphroditic species (C. elegans). Thus, genome-editing tools now exist to transform non-model nematode species into genetically tractable model organisms. We demonstrate the utility of our broadly applicable genome-editing strategies by creating reagents generally useful to the nematode community and reagents specifically designed to explore the mechanism and evolution of X-chromosome dosage compensation. By developing an efficient pipeline involving germline injection of nuclease mRNAs and single-stranded DNA templates, we engineered precise, heritable nucleotide changes both close to and far from DSBs to gain or lose genetic function, to tag proteins made from endogenous genes, and to excise entire loci through targeted FLP-FRT recombination. 23768064 Blocking of L-type calcium channels protects hippocampal and nigral neurons against iron neurotoxicity. Iron plays an important role in maintaining normal brain function. However, iron overload and enhanced hydroxyl radical formation have been implicated as the causative factors of some neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Calcium is also required for diverse physiological process including secretion of neurotransmitters, synaptic plasticity, gene expression and axonal growth. Iron and calcium are essential for neuronal function but, when present in excessive level, they induce neuronal damage and may even cause neuronal death. Some reports suggest that voltage gated calcium channels (VGCCs) are an alternate route for iron entry into neuronal cell lines under conditions of iron overload. The aim of the present study was to investigate the effects of L-type VGCCs on iron-induced neurotoxicity. Iron neurotoxicity was generated by intracerebroventricular FeCl3 injection. Nicardipine treatment (10 mg/kg/d) was applied to block L-type VGCCs for 10 d. Rats were perfused intracardially under deep urethane anaesthesia after treatment period. Removed brains were processed using the standard histological techniques. The numbers of neurons in hippocampus and substantia nigra of all rats were estimated by stereological techniques. Results of present study show that nicardipine decreased hippocampal and nigral neuron loss from 43.9% to 18.4% and 41.0% to 12.1%, respectively. Outcomes of the present study propose that blocking of L-type VGCCs may reduce the neurotoxic effects of iron by inhibiting the cellular influx of excessive calcium and/or iron ions. 23617888 Enhanced inhibition of Aspergillus niger on sedge (Lepironia articulata) treated with heat-cured lime oil. This study aimed to examine heat curing effect (30-100°C) on antifungal activities of lime oil and its components (limonene, p-cymene, β-pinene and α-pinene) at concentrations ranging from 100 to 300 Î¼l ml(-1) against Aspergillus niger in microbiological medium and to optimize heat curing of lime oil for efficient mould control on sedge (Lepironia articulata). Broth dilution method was employed to determine lime oil minimum inhibitory concentration, which was at 90 Î¼l ml(-1) with heat curing at 70°C. Limonene, a main component of lime oil, was an agent responsible for temperature dependencies of lime oil activities observed. Response surface methodology was used to construct the mathematical model describing a time period of zero mould growth on sedge as functions of heat curing temperature and lime oil concentration. Heat curing of 90 Î¼l ml(-1) lime oil at 70°C extended a period of zero mould growth on sedge to 18 weeks under moist conditions. Heat curing at 70°C best enhanced antifungal activity of lime oil against A. niger both in medium and on sedge. Heat curing of lime oil has potential to be used to enhance the antifungal safety of sedge products. 22320163 Steroids and phenolic constituents from the fruiting bodies of the basidiomycete Sarcodon joedes. Nine secondary metabolites, including four steroids, four phenolics and one cerebroside, were isolated from the methanol extract of the fruiting bodies of the basidiomycete Sarcodon joedes. The isolated compounds were identified by spectroscopic analyses as (22E,24R)-6β-methoxyergosta-7,22-diene-3β,5α-diol (1), 2',3'-diacetoxy-3,4,5',6',4″-pentahydroxy-p-terphenyl (2), cerebroside B (3), ergosta-7,22-dien-3β-ol (4), ergosterol peroxide (5), (22E,24R)-3β-hydroxy-ergosta-5,22-dien-7-one (6), benzoic acid (7), methyl p-hydroxybenzoate (8) and 3,4-dihydroxybenzoic acid (9). The cytotoxic activities of these compounds were evaluated. All these compounds were isolated from this fungus for the first time. 23803469 Cake: a bioinformatics pipeline for the integrated analysis of somatic variants in cancer genomes. We have developed Cake, a bioinformatics software pipeline that integrates four publicly available somatic variant-calling algorithms to identify single nucleotide variants with higher sensitivity and accuracy than any one algorithm alone. Cake can be run on a high-performance computer cluster or used as a stand-alone application. Availabilty: Cake is open-source and is available from http://cakesomatic.sourceforge.net/ da1@sanger.ac.uk Supplementary data are available at Bioinformatics online. 23950630 Pattern of pathogens and their sensitivity isolated from surgical site infections at the aga khan university hospital, nairobi, kenya. In low income countries, surgical site infections (SSIs) are costly and impose a heavy and potentially preventable burden on both patients and healthcare providers. This study aimed to determine the occurrence of SSI, pathogens associated with SSI, the antibiogram of the causative pathogens and specific risk factors associated with SSI at the hospital. Two hundred and sixty-eight respondents admitted for general surgical procedures (other than neurological and cardiothoracic surgeries) at the Aga Khan University Hospital were eligible to take part in the study. Post-surgery patients were observed for symptoms of infection. Follow ups were done through the consulting clinics, breast clinic and casualty dressing clinic by a team of surgeons. In cases of infection, pus swabs were collected for culture. SSI incidence rate was 7.0%, pathogens isolated from SSI included gram negative enteric bacilli and S. aureus which was the most prevalent bacterial isolate. Only one isolate of MRSA was found and all staphylococci were susceptible to Vancomycin. Preoperative stay ≥ 2 days and wound class were the risk factors associated with SSI. The SSI incidence rates (7.0%) observed in this study were relatively lower than the ones documented in other studies in Kenya. S. aureus is the most prevalent pathogen associated with SSI. Similar to findings from other studies done in the region; prolonged hospital stay and dirty wounds were the risks associated with postsurgical sepsis at the hospital. 23509955 Treatment of preoperatively diagnosed colorectal adenomas by transanal endoscopic microsurgery: The experience in China. Colorectal adenoma is a recognized precancerous lesion that has the potential for malignant transformation. Surgical resection of colorectal adenomas is required for exact diagnosis and treatment. The aim of this study is to assess the safety and therapeutic effect of transanal endoscopic microsurgery for preoperatively diagnosed colorectal adenomas. From September 2006 to February 2011, 45 patients with preoperatively diagnosed colon and rectal adenomas underwent transanal endoscopic microsurgery. The clinical data of these patients were reviewed. The mean tumor diameter was 2.2 cm, mean operative time was 65 min, and the mean estimated blood loss was less than 10 mL. There was no conversion to transabdominal procedure. The mean tumor distance from the anal verge was 8.2 cm. Four patients had perforation into the peritoneal cavity during full-thickness resection; these were repaired by continuous suturing, and there was no postoperative leakage after 1 week of fasting. The surgical margins of specimens were negative in 44 patients. Complications included rectal bleeding in one patient, acute urinary retention in one patient and pulmonary infection in one patient. The mean postoperative hospital stay was 4.5 days. Only one patient experienced incontinence of hard stool 6 months after surgery. The patients were followed up for a median period of 42 months, with four cases of tumor recurrence observed. Transanal endoscopic microsurgery is a safe and effective technique for excising large adenomas in the mid and upper rectum and in the lower sigmoid colon. It is also an oncologically preferred method for T1 focal carcinomas that develop from villous adenomas. 23704120 Long-term Outcomes of a Cell Phone-Delivered Intervention for Smokers Living With HIV/AIDS. Background. People living with human immunodeficiency virus (HIV)/AIDS (PLWHA) have a substantially higher prevalence of cigarette smoking compared to the general population. In addition, PLWHA are particularly susceptible to the adverse health effects of smoking. Our primary objective was to design and test the efficacy over 12 months of a smoking cessation intervention targeting PLWHA. Methods. Participants were enrolled from an urban HIV clinic with a multiethnic and economically disadvantaged patient population. Participants received smoking cessation treatment either through usual care (UC) or counseling delivered by a cell phone intervention (CPI). The 7-day point prevalence abstinence was evaluated at 3, 6, and 12 months using logistic regression and generalized linear mixed models. Results. We randomized 474 HIV-positive smokers to either the UC or CPI group. When evaluating the overall treatment effect (7-day abstinence outcomes from 3-, 6-, and 12-month follow-ups), participants in the CPI group were 2.41 times (P = .049) more likely to demonstrate abstinence compared to the UC group. The treatment effect was strongest at the 3-month follow-up (odds ratio = 4.3, P < .001), but diminished at 6 and 12 months (P > .05). Conclusions. Cell phone-delivered smoking cessation treatment has a positive impact on abstinence rates compared to a usual care approach. Future research should focus on strategies for sustaining the treatment effect in the long term. 23821534 Severe systemic reaction from calcium hydroxylapatite vocal fold filler. We describe a severe systemic reaction that occurred following injection augmentation with calcium hydroxylapatite vocal fold filler. The reaction occurred within 30 minutes of the procedure and consisted of diffuse itching, hives, edematous face and eyelids, and voice changes indicating glottic edema. It is classified as a grade 3 systemic reaction. Consideration is given to possible etiologies and at risk patients are discussed. We recommend a postprocedure observation time of at least 30 minutes to monitor for such reactions. 23303709 Synthesis and characterization of an MRI Gd-based probe designed to target the translocator protein. DPA-713 is the lead compound of a recently reported pyrazolo[1,5-a]pyrimidineacetamide series, targeting the translocator protein (TSPO 18 kDa), and as such, this structure, as well as closely related derivatives, have been already successfully used as positron emission tomography radioligands. On the basis of the pharmacological core of this ligands series, a new magnetic resonance imaging probe, coded DPA-C(6)-(Gd)DOTAMA was designed and successfully synthesized in six steps and 13% overall yield from DPA-713. The Gd-DOTA monoamide cage (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) represents the magnetic resonance imaging reporter, which is spaced from the phenylpyrazolo[1,5-a]pyrimidineacetamide moiety (DPA-713 motif) by a six carbon-atom chain. DPA-C(6)-(Gd)DOTAMA relaxometric characterization showed the typical behavior of a small-sized molecule (relaxivity value: 6.02 mM(-1) s(-1) at 20 MHz). The good hydrophilicity of the metal chelate makes DPA-C(6)-(Gd)DOTAMA soluble in water, affecting thus its biodistribution with respect to the parent lipophilic DPA-713 molecule. For this reason, it was deemed of interest to load the probe to a large carrier in order to increase its residence lifetime in blood. Whereas DPA-C(6)-(Gd)DOTAMA binds to serum albumin with a low affinity constant, it can be entrapped into liposomes (both in the membrane and in the inner aqueous cavity). The stability of the supramolecular adduct formed by the Gd-complex and liposomes was assessed by a competition test with albumin. 22753268 Emergent stent-assisted angioplasty of extracranial internal carotid artery and intracranial stent-based thrombectomy in acute tandem occlusive disease: technical considerations. Tandem occlusions of the internal carotid artery (ICA) and a major intracranial artery respond poorly to intravenous thrombolytic therapy, and are usually managed by endovascular means. This study describes experience with stent-assisted endovascular ICA revascularization and stent-based thrombectomy. In patients with tandem ICA-middle cerebral artery (MCA)/distal ICA occlusion, the carotid occlusion was recanalized by primary angioplasty and stent implantation, and the distal occlusion by stent-based thrombectomy. Two variant techniques are described. Seven consecutive patients, mean age 64.1 years (range 49-75) and mean admission National Institutes of Health Stroke Scale score of 23, were included. Occlusion sites were tandem proximal ICA and MCA trunk (six patients) and tandem proximal left ICA and ICA terminus (one patient). Complete recanalization with complete perfusion (Thrombolysis in Myocardial Infarction [TIMI] 3, Thrombolysis in Cerebral Infarction [TICI] 3) was achieved in six patients and partial recanalization with partial perfusion (TIMI 2, TICI 2A) in one. Mean time to therapy was 4.9 h (range 3-6.5); mean time to recanalization was 55 min (range 38-65 min). CT performed 1 day after recanalization showed cortical sparing (>90% of the cortex at risk) in seven patients. Five patients (72%) presented with good clinical outcome (modified Rankin Scale (mRS) score 0-2) at 1 month; one patient (patient No 7) reached an mRS score of 3 and one patient died. In selected cases of acute ICA occlusion and concomitant major vessel embolic stroke, angioplasty and stenting of the proximal occlusion and stent-based thrombectomy of the intracranial occlusion may be feasible, effective and safe, and provide early neurological improvement. Further experience and prospective studies are warranted. 23847645 Dynamics of soil exploration by fine roots down to a depth of 10 m throughout the entire rotation in Eucalyptus grandis plantations. Although highly weathered soils cover considerable areas in tropical regions, little is known about exploration by roots in deep soil layers. Intensively managed Eucalyptus plantations are simple forest ecosystems that can provide an insight into the belowground growth strategy of fast-growing tropical trees. Fast exploration of deep soil layers by eucalypt fine roots may contribute to achieving a gross primary production that is among the highest in the world for forests. Soil exploration by fine roots down to a depth of 10 m was studied throughout the complete cycle in Eucalyptus grandis plantations managed in short rotation. Intersects of fine roots, less than 1 mm in diameter, and medium-sized roots, 1-3 mm in diameter, were counted on trench walls in a chronosequence of 1-, 2-, 3.5-, and 6-year-old plantations on a sandy soil, as well as in an adjacent 6-year-old stand growing in a clayey soil. Two soil profiles were studied down to a depth of 10 m in each stand (down to 6 m at ages 1 and 2 years) and 4 soil profiles down to 1.5-3.0 m deep. The root intersects were counted on 224 m(2) of trench walls in 15 pits. Monitoring the soil water content showed that, after clear-cutting, almost all the available water stored down to a depth of 7 m was taken up by tree roots within 1.1 year of planting. The soil space was explored intensively by fine roots down to a depth of 3 m from 1 year after planting, with an increase in anisotropy in the upper layers throughout the rotation. About 60% of fine root intersects were found at a depth of more than 1 m, irrespective of stand age. The root distribution was isotropic in deep soil layers and kriged maps showed fine root clumping. A considerable volume of soil was explored by fine roots in eucalypt plantations on deep tropical soils, which might prevent water and nutrient losses by deep drainage after canopy closure and contribute to maximizing resource uses. 23841895 Rapid assessment of avoidable blindness in bhutan. Abstract Aim: To conduct a rapid assessment of avoidable blindness survey in Bhutan to obtain estimates of blindness, visual impairment, and cataract surgical coverage, outcomes and barriers among persons ≥50 years old. Methods: A total of 82 clusters of 50 people ≥50 years were selected using probability proportionate to size sampling. Eligible participants were selected from households using compact segment sampling, and underwent ophthalmic examination for visual acuity, followed by penlight and direct ophthalmoscopy. Participants with cataract were interviewed regarding surgical outcomes and barriers to surgery. Results: Overall, 4046 of 4100 persons enumerated (98.7%) underwent ophthalmic examination. Adjusting for age and sex, the prevalence of bilaterally blind persons with available correction was 1.5% (95% confidence interval 1.09-1.89). Most blindness (67.1%) and severe visual impairment (74.1%) resulted from cataract, but 22.1% resulted from posterior segment pathology. Cataract surgical coverage for bilaterally blind persons was 72.7%. Almost 90% of patients reported moderate or good satisfaction, despite poor surgical outcomes in 23.6%. Conclusions: The prevalence of blindness in people aged ≥50 years in Bhutan was relatively low when compared with neighboring countries and World Health Organization sub-region estimates. Areas for improvement include community outreach, surgical outcomes, and posterior segment diseases. 23122164 Structure and composition of model cheeses influence sodium NMR mobility, kinetics of sodium release and sodium partition coefficients. The mobility and release of sodium ions were assessed in model cheeses with three different lipid/protein ratios, with or without added NaCl. The rheological properties of the cheeses were analysed using uniaxial compression tests. Microstructure was characterised by confocal laser scanning microscopy. (23)Na nuclear magnetic resonance (NMR) spectroscopy was used to study the molecular mobility of sodium ions in model cheeses through measurements of the relaxation and creation times. Greater mobility was observed in cheeses containing a lower protein content and with added NaCl. The kinetics of sodium release from the cheese to an aqueous phase was correlated with the mobility of sodium ions. The highest rates of sodium release were observed with a lower protein content and with added NaCl. The water/cheese partition coefficients of sodium increased when NaCl was added or the protein content was higher. The study highlighted the effect of model cheese characteristics on molecular and macroscopic behaviours of sodium. 23833029 Validation of the French version of the Hospital Survey on Patient Safety Culture questionnaire. /st> To assess the psychometric properties of the French version of the Hospital Survey on Patient Safety Culture questionnaire (HSOPSC) and study the hierarchical structure of the measured dimensions. /st> Cross-sectional survey of the safety culture. /st> 18 acute care units of seven hospitals in South-western France. /st> Full- and part-time healthcare providers who worked in the units. /st> None. /st> Item responses measured with 5-point agreement or frequency scales. Data analyses A principal component analysis was used to identify the emerging components. Two structural equation modeling methods [LInear Structural RELations (LISREL) and Partial Least Square (PLS)] were used to verify the model and to study the relative importance of the dimensions. Internal consistency of the retained dimensions was studied. A test-retest was performed to assess reproducibility of the items. /st> Overall response rate was 77% (n = 401). A structure in 40 items grouped in 10 dimensions was proposed. The LISREL approach showed acceptable data fit of the proposed structure. The PLS approach indicated that three dimensions had the most impact on the safety culture: 'Supervisor/manager expectations & actions promoting safety' 'Organizational learning-continuous improvement' and 'Overall perceptions of safety'. Internal consistency was above 0.70 for six dimensions. Reproducibility was considered good for four items. /st> The French HSOPSC questionnaire showed acceptable psychometric properties. Classification of the dimensions should guide future development of safety culture improving action plans. 23965637 Continuous Renal Replacement Therapy With an Automated Monitor Is Superior to a Free-Flow System During Extracorporeal Life Support. To determine whether integrated continuous renal replacement therapy provides more accurate fluid management than IV pump free-flow ultrafiltration in pediatric patients on extracorporeal life support. Retrospective study. PICU and neonatal ICU in a tertiary academic center. Infants and children less than 18 years old. Extracorporeal membrane oxygenation and continuous renal replacement therapy. Clinical data collected on patients who received free-flow or integrated renal replacement therapy while on extracorporeal life support. Normalized ultrafiltration error was calculated as: (physician specified fluid loss per 24-hr period - actual fluid loss per 24-hr period) divided by patient body weight (kg). Mixed linear regression analyses were used to model longitudinal ultrafiltration error trajectories within each mode of ultrafiltration. Based on an analysis of 458 serial ultrafiltration fluid balance measurements, integrated ultrafiltration was significantly more accurate than free-flow ultrafiltration (normalized ultrafiltration error of 1.2 vs 13.1 mL; p < 0.001). After adjusting for patient factors and time, integrated ultrafiltration was associated with a significantly lower normalized ultrafiltration error (variable estimate, -24 ± 6; p < 0.001). The use of integrated ultrafiltration was associated with shorter duration of extracorporeal life support (384 vs 583 hr, p < 0.001) and renal replacement therapy (185 vs 477 hr, p < 0.001) than free-flow patients. Overall ICU and hospital length of stay and in-hospital mortality were similar between the groups. While free-flow ultrafiltration has the advantages of simplicity and low cost, integrated renal replacement therapy provides more accurate fluid management during extracorporeal life support. Better fluid status management with integrated renal replacement therapy may contribute to shorter duration of extracorporeal life support. 23881873 Cost implications of treatment non-completion in a forensic personality disorder service. A high proportion of individuals admitted to specialist secure hospital services for treatment of personality disorder do not complete treatment. Non-completion has been associated with poorer treatment outcomes and increased rates of recidivism and hospital readmission, when compared with individuals who do complete treatment or who do not receive treatment at all. In this study, we sought to determine the economic consequences of non-completion of treatment, using case study data from a secure hospital sample. Both health and criminal justice service perspectives were taken into account. Data were collected from a medium secure hospital personality disorder unit. A probabilistic decision-analytic model was constructed, using a Markov cohort simulation with 10,000 iterations. The expected cost differential between those who do and those who do not complete treatment was estimated, as was the probability of a cost differential over a 10-year post-admission time horizon. On average, in the first 10 years following admission, those who do not complete treatment go on to incur £52,000 more in costs to the National Health Service and criminal justice system than those who complete treatment. The model estimates that the probability that non-completers incur greater costs than completers is 78%. It is possible that an improvement in treatment completion rates in secure hospital personality disorder units would lead to some cost savings. This might be achievable through better selection into treatment or improved strategies for engagement and retention. Our study highlights a financial cost to society of individuals discharged from secure hospital care when incompletely treated. We suggest that it could, therefore, be useful for secure hospitals to introduce routine monitoring of treatment completion. Copyright © 2013 John Wiley & Sons, Ltd. 23319549 The pharmacology of L-DOPA-induced dyskinesia in Parkinson's disease. L-3,4-Dihydroxyphenylalanine (L-DOPA) remains the most effective symptomatic treatment of Parkinson's disease (PD). However, long-term administration of L-DOPA is marred by the emergence of abnormal involuntary movements, i.e., L-DOPA-induced dyskinesia (LID). Years of intensive research have yielded significant progress in the quest to elucidate the mechanisms leading to the development and expression of dyskinesia and maintenance of the dyskinetic state, but the search for a complete understanding is still ongoing. Herein, we summarize the current knowledge of the pharmacology of LID in PD. Specifically, we review evidence gathered from postmortem and pharmacological studies, both preclinical and clinical, and discuss the involvement of dopaminergic and nondopaminergic systems, including glutamatergic, opioid, serotonergic, γ-aminobutyric acid (GABA)-ergic, adenosine, cannabinoid, adrenergic, histaminergic, and cholinergic systems. Moreover, we discuss changes occurring in transcription factors, intracellular signaling, and gene expression in the dyskinetic phenotype. Inasmuch as a multitude of neurotransmitters and receptors play a role in the etiology of dyskinesia, we propose that to optimally alleviate this motor complication, it may be necessary to develop combined treatment approaches that will target simultaneously more than one neurotransmitter system. This could be achieved via three ways as follows: 1) by developing compounds that will interact simultaneously to a multitude of receptors with the required agonist/antagonist effect at each target, 2) by targeting intracellular signaling cascades where the signals mediated by multiple receptors converge, and/or 3) to regulate gene expression in a manner that has effects on signaling by multiple pathways. 23009272 Development of a live tissue microtome: reflections of an amateur machinist. Live circular tissue slices of nearly identical diameter and thickness can be generated from most tissues by the use of two instruments; a coring tool to cut cylindrical tissue cores which are subsequently sliced by a microtome into thin circular sections 5-8 mm in diameter and 50-300 microns thick. The sections are of very similar geometry permitting direct comparisons without normalization. Both instruments operate submerged in a cold isotonic medium that caries the cut slices outside the microtome. The slices are cut by a rapidly oscillating disposable Gillette blade mounted at an angle of 20 degrees to the vertical main axis of the tissue core. The latter is advanced against the oscillating blade by a weighted plunger pushing it against a screw adjustable limit plate that defines the desired slice thickness. Both instruments can be sterilized and slices can be obtained at a rate of approximately one every ten seconds. 23477304 Characteristics of an Ambulatory Palliative Care Clinic for HIV-Infected Patients. Abstract Background: Many HIV-infected patients in the current treatment era have substantial symptom burden, but few HIV palliative care clinics have been described. Our objective was to describe the University of Alabama at Birmingham (UAB) HIV palliative care clinic (HPCC) and compare it to the overall HIV clinic. Methods: We conducted a chart review of patients referred to the HPCC between April 2008 and June 2011. We evaluated the reason for referral and other issues addressed during palliative care visits. Patient Reported Outcome (PRO) data was used to assess depression (PHQ-9), anxiety (PHQ-A), and substance abuse (ASSIST). Results: Among 124 patients, mean age was 44 (range 27-64), and median CD4 count was 352 cells/mm(3) (IQR 209-639). Depression (43, 35%), anxiety (40, 32%), and current 8 (7%) or prior 68 (56%) substance abuse occurred at higher rates than in the overall HIV clinic (p<0.05). Pain was the most common reason for referral (118, 95%); most was chronic (113, 90%) and included back pain (26, 21%) and neuropathic pain (15, 12%). Other problems commonly addressed by the palliative team included nonpain symptoms such as depression (39, 48%) and anxiety (17, 21%), insomnia (25, 30%), and constipation (26, 32%). Conclusions: This is the first description of a palliative care clinic embedded within an HIV primary care clinic in a developed country that sees patients at all stages of illness. Chronic pain and nonpain symptom management in patients with psychiatric and substance abuse comorbidities are important components of ambulatory palliative care for HIV-infected patients. 23864595 Travelling light: white sharks (Carcharodon carcharias) rely on body lipid stores to power ocean-basin scale migration. Many species undertake long-distance annual migrations between foraging and reproductive areas. Such migrants depend on the efficient packaging, storage and utilization of energy to succeed. A diverse assemblage of organisms accomplishes this through the use of lipid reserves; yet, it remains unclear whether the migrations of elasmobranchs, which include the largest gill breathers on Earth, depend on such a mechanism. We examine depth records from pop-up satellite archival tags to discern changes in buoyancy as a proxy for energy storage in Eastern Pacific white sharks, and assess whether lipid depletion fuels long-distance (approx. 4000 km) migrations. We develop new algorithms to assess body condition, buoyancy and drift rate during drift dives and validate the techniques using a captive white shark. In the wild, we document a consistent increase in drift rate over the course of all migrations, indicating a decrease in buoyancy caused by the depletion of lipid reserves. These results comprise, to our knowledge, the first assessment of energy storage and budgeting in migrating sharks. The methods provide a basis for further insights into using electronic tags to reveal the energetic strategies of a wide range of elasmobranchs. 23887813 The man who feels two hearts: the different pathways of interoception. Recent advances in neuroscience have provided new insights into the understanding of heart-brain interaction and communication. Cardiac information to the brain relies on two pathways, terminating in the insular cortex (IC) and anterior cingulate cortex (ACC), along with the somatosensory cortex (S1-S2). Interoception relying on these neuroanatomical pathways has been shown to modulate social cognition. We report the case study of C.S., a patient with an 'external heart' (an extracorporeal left-univentricular cardiac assist device, LVAD). The patient was assessed with neural/behavioral measures of cardiac interoception complemented by neuropsychological and social cognition measures. The patient's performance on the interoception task (heartbeat detection) seemed to be guided by signals from the artificial LVAD, which provides a somatosensory beat rather than by his endogenous heart. Cortical activity (HEP, heartbeat-evoked potential) was found decreased in comparison with normal volunteers, particularly during interoceptive states. The patient accurately performed several cognitive tasks, except for interoception-related social cognition domains (empathy, theory of mind and decision making). This evidence suggests an imbalance in the patient's cardiac interoceptive pathways that enhances sensation driven by the artificial pump over that from the cardiac vagal-IC/ACC pathway. A patient with two hearts, one endogenous and one artificial, presents a unique opportunity to explore models of interoception and heart-brain interaction. 23895727 Novel Interactions between Mitochondrial Superoxide Dismutases and the Electron Transport Chain. The processes that control aging remain poorly understood. We have exploited mutants in the nematode, C. elegans, that compromise mitochondrial function and scavenging of reactive oxygen species (ROS) to understand their relation to lifespan. We discovered unanticipated roles and interactions of the mitochondrial superoxide dismutases (mtSODs), SOD-2 and SOD-3. Both SODs localize to mitochondrial supercomplex I:III:IV. Loss of SOD-2 specifically: 1) decreases the activities of complexes I and II; complexes III, and IV remain normal, 2) increases the lifespan of animals with a complex I defect, but not the lifespan of animals with a complex II defect, and kills an animal with a complex III defect, 3) induces a presumed pro-inflammatory response. Knockdown of a molecule that may be a pro-inflammatory mediator very markedly extends lifespan and health of certain mitochondrial mutants. The relationship between the electron transport chain, ROS and lifespan is complex, and defects in mitochondrial function have specific interactions with ROS scavenging mechanisms. We conclude that mtSODs are embedded within the supercomplex I:III:IV, and stabilize or locally protect it from reactive oxygen species (ROS) damage. The results call for a change in the usual paradigm for the interaction of electron transport chain function, ROS release, scavenging and compensatory responses. This article is protected by copyright. All rights reserved. 23908472 Distinct pathways regulated by menin and by MLL1 in hematopoietic stem cells and developing B-cells. MLL1 translocations encode fusion proteins retaining the N-terminus of MLL1, which interacts with the tumor suppressor, menin. This interaction is essential for leukemogenesis, thus is a promising drug target. However, wild-type MLL1 plays a critical role in sustaining hematopoietic stem cells (HSCs), therefore disruption of an essential MLL1 cofactor would be expected to obliterate normal hematopoiesis. Here we show that rather than working together as a complex, menin and MLL1 regulate distinct pathways during normal hematopoiesis, particularly in HSCs and B-cells. We demonstrate the lack of genetic interaction between menin and MLL1 in steady-state or regenerative hematopoiesis and in B-cell differentiation despite the fact that MLL1 is critical for these processes. In B-cells, menin- or MLL1-regulated genes can be classified into three categories: 1) a relatively small group of co-regulated genes including previously described targets Hoxa9 and Meis1 but also Mecom and Eya1, and much larger groups of 2) exclusively menin-regulated and 3) exclusively MLL1-regulated genes. Our results highlight the large degree of independence of these two proteins and demonstrate that menin is not a requisite cofactor for MLL1 during normal hematopoiesis. Furthermore, our data support the development of menin-MLL1 disrupting drugs as safe and selective leukemia targeting agents. 23944704 Label-Free Fluorescence Detection of Aromatic Compounds in Chip Electrophoresis Applying Two-Photon Excitation and Time-Correlated Single-Photon Counting. In this study, we introduce time-resolved fluorescence detection with two-photon excitation at 532 nm for label-free analyte determination in microchip electrophoresis. In the developed method, information about analyte fluorescence lifetimes is collected by time-correlated single-photon counting, improving reliable peak assignment in electrophoretic separations. The determined limits of detection for serotonin, propranolol, and tryptophan were 51, 37, and 280 nM, respectively, using microfluidic chips made of fused silica. Applying two-photon excitation microchip separations and label-free detection could also be performed in borosilicate glass chips demonstrating the potential for label-free fluorescence detection in non-UV-transparent devices. Microchip electrophoresis with two-photon excited fluorescence detection was then applied for analyses of active compounds in plant extracts. Harmala alkaloids present in methanolic plant extracts from Peganum harmala could be separated within seconds and detected with on-the-fly determination of fluorescence lifetimes. 23897164 Functional influence of human CYP2D6 allelic variations: P34S, E418K, S486T, and R296C. CYP2D6 is responsible for the oxidative metabolism of 20-25 % of clinical drugs and its genetic polymorphisms can significantly influence the drug metabolism. In this study, we analyzed the functional activities of four nonsynonymous single nucleotide polymorphisms from CYP2D6*52 allele, which were recently found, and one found frequently in CYP2D6 alleles. Recombinant variant enzymes of E418K, S486T, and R296C were successfully expressed in Escherichia coli and purified. However, a CYP holoenzyme spectrum of P34S variant was not detected in E. coli whole cell level. Structural analysis indicated that P34S mutation seemed to perturb a highly conserved proline-rich N-terminus of CYP2D6. Steady state kinetic analyses showed the significant reductions of enzymatic activities in E418K and R296C variants. In the case of bufuralol 1'-hydroxylation, a novel mutant, E418K, showed 32 % decrease in catalytic efficiency (k cat/K m) mainly due to the decrease of k cat value. R296C showed much greater reduction in the catalytic efficiency (9 % of wild-type) due to both of a decrease of k cat value and an increase of K m value. In the case of dextromethorphan O-demethylation, E418K showed both of a decrease of k cat value and an increase K m value to result in ~43 % reduction of catalytic efficiency. A highly decreased catalytic efficiency (~6 % of wild-type) in the mutant of R296C also was observed mainly due to the dramatic change of k cat value of dextromethorphan O-demethylation. These results suggested that individuals carrying these allelic variants are likely to have the altered metabolic abilities of many clinical drugs therefore, these polymorphisms of CYP2D6 should be much concerned for reliable drug treatment. 22749643 Structure-based optimization of oxadiazole-based GSK-3 inhibitors. Inhibition of glycogen synthase kinase-3 (GSK-3) induces neuroprotective effects, e.g. decreases β-amyloid production and reduces tau hyperphosphorylation, which are both associated with Alzheimer's disease (AD). The two isoforms of GSK-3 in mammalians are GSK-3α and β, which share 98% homology in their catalytic domains. We investigated GSK-3 inhibitors based on 2 different scaffolds in order to elucidate the demands of the ATP-binding pocket [1]. Particularly, the oxadiazole scaffold provided potent and selective GSK-3 inhibitors. For example, the most potent inhibitor of the present series, the acetamide 26d, is characterized by an IC50 of 2 nM for GSK-3α and 17 nM for GSK-3β. In addition, the benzodioxane 8g showed up to 27-fold selectivity for GSK-3α over GSK-3β, with an IC50 of 35 nM for GSK-3α. Two GSK-3 inhibitors were further profiled for efficacy and toxicity in the wild-type (wt) zebrafish embryo assay to evaluate simultaneously permeability and safety. 23664840 regEfmtool: speeding up elementary flux mode calculation using transcriptional regulatory rules in the form of three-state logic. Despite the considerable progress made in recent years, the computation of the complete set of elementary flux modes of large or even genome-scale metabolic networks is still impossible. We present regEfmtool which is an extension to efmtool that utilizes transcriptional regulatory networks for the computation of elementary flux modes. The implemented extension significantly decreases the computational costs for the calculation of elementary flux modes, such as runtime, memory usage and disk space by omitting biologically infeasible solutions. Hence, using the presented regEfmtool pushes the size of metabolic networks that can be studied by elementary flux modes to new limits. 23825184 Correlation of MRI grading of bone stress injuries with clinical risk factors and return to play: a 5-year prospective study in collegiate track and field athletes. Bone stress injuries are common in track and field athletes. Knowledge of risk factors and correlation of these to magnetic resonance imaging (MRI) grading could be helpful in determining recovery time. To examine the relationships between MRI grading of bone stress injuries with clinical risk factors and time to return to sport in collegiate track and field athletes. Cohort study (prognosis); Level of evidence, 2. A total of 211 male and female collegiate track and field and cross-country athletes were followed prospectively through their competitive seasons. All athletes had preparticipation history, physical examination, and anthropometric measurements obtained annually. An additional questionnaire was completed regarding nutritional behaviors, menstrual patterns, and prior injuries, as well as a 3-day diet record. Dual-energy X-ray absorptiometry was performed at baseline and each year of participation in the study. Athletes with clinical evidence of bone stress injuries had plain radiographs. If radiograph findings were negative, MRI was performed. Bone stress injuries were evaluated by 2 independent radiologists utilizing an MRI grading system. The MRI grading and risk factors were evaluated to identify predictors of time to return to sport. Thirty-four of the athletes (12 men, 22 women) sustained 61 bone stress injuries during the 5-year study period. The mean prospective assessment for participants was 2.7 years. In the multiple regression model, MRI grade and total-body bone mineral density (BMD) emerged as significant and independent predictors of time to return to sport. Specifically, the higher the MRI grade (P = .004) and lower the BMD (P = .030), the longer the recovery time. Location of the bone injury at predominantly trabecular sites of the femoral neck, pubic bone, and sacrum was also associated with a prolonged time to return to sport. Female athletes with oligomenorrhea and amenorrhea had bone stress injuries of higher MRI grades compared with eumenorrheic athletes (P = .009). Higher MRI grade, lower BMD, and skeletal sites of predominant trabecular bone structures were associated with a delayed recovery of bone stress injuries in track and field athletes. Knowledge of these risk factors, as well as nutritional and menstrual factors, can be clinically useful in determining injury severity and time to return to sport. 23958448 Active DNA demethylation in post-mitotic neurons: A reason for optimism. Over the last several years proteins involved in base excision repair (BER) have been implicated in active DNA demethylation. We review the literature supporting BER as a means of active DNA demethylation, and explain how the various components function and cooperate to remove the potentially most enduring means of epigenetic gene regulation. Recent evidence indicates that the same pathways implicated during periods of widespread DNA demethylation, such as the erasure of methyl marks in the paternal pronucleus soon after fertilization, are operational in post-mitotic neurons. Neuronal functional identities, defined here as the result of a combination of neuronal subtype, location, and synaptic connections are largely maintained through DNA methylation. Chronic mental illnesses, such as schizophrenia, may be the result of both altered neurotransmitter levels and neurons that have assumed dysfunctional neuronal identities. A limitation of most current psychopharmacological agents is their focus on the former, while not addressing the more profound latter pathophysiological process. Previously, it was believed that active DNA demethylation in post-mitotic neurons was rare if not impossible. If this were the case, then reversing the factors that maintain neuronal identity, would be highly unlikely. The emergence of an active DNA demethylation pathway in the brain is a reason for great optimism in psychiatry as it provides a means by which previously pathological neurons may be reprogrammed into a more favorable role. Agents targeting epigenetic processes have shown much promise in this regard, and may lead to substantial gains over traditional pharmacological approaches. 23874920 A pharmacological screening approach for discovery of neuroprotective compounds in ischemic stroke. With the availability and ease of small molecule production and design continuing to improve, robust, high-throughput methods for screening are increasingly necessary to find pharmacologically relevant compounds amongst the masses of potential candidates. Here, we demonstrate that a primary oxygen glucose deprivation assay in primary cortical neurons followed by secondary assays (i.e. post-treatment protocol in organotypic hippocampal slice cultures and cortical neurons) can be used as a robust screen to identify neuroprotective compounds with potential therapeutic efficacy. In our screen about 50% of the compounds in a library of pharmacologically active compounds displayed some degree of neuroprotective activity if tested in a pre-treatment toxicity assay but just a few of these compounds, including Carbenoxolone, remained active when tested in a post-treatment protocol. When further examined, Carbenoxolone also led to a significant reduction in infarction size and neuronal damage in the ischemic penumbra when administered six hours post middle cerebral artery occlusion in rats. Pharmacological testing of Carbenoxolone-related compounds, acting by inhibition of 11-β-hydroxysteroid dehydrogenase-1 (11β-HSD1), gave rise to similarly potent in vivo neuroprotection. This indicates that the increase of intracellular glucocorticoid levels mediated by 11β-HSD1 may be involved in the mechanism that exacerbates ischemic neuronal cell death, and inhibiting this enzyme could have potential therapeutic value for neuroprotective therapies in ischemic stroke and other neurodegenerative disorders associated with neuronal injury. 23172777 3D-QSAR-assisted drug design: identification of a potent quinazoline-based Aurora kinase inhibitor. We describe the 3D-QSAR-assisted design of an Aurora kinase A inhibitor with improved physicochemical properties, in vitro activity, and in vivo pharmacokinetic profiles over those of the initial lead. Three different 3D-QSAR models were built and validated by using a set of 66 pyrazole (Model I) and furanopyrimidine (Model II) compounds with IC(50) values toward Aurora kinase A ranging from 33 nM to 10.5 μM. The best 3D-QSAR model, Model III, constructed with 24 training set compounds from both series, showed robustness (r(2) (CV) =0.54 and 0.52 for CoMFA and CoMSIA, respectively) and superior predictive capacity for 42 test set compounds (R(2) (pred) =0.52 and 0.67, CoMFA and CoMSIA). Superimposition of CoMFA and CoMSIA Model III over the crystal structure of Aurora kinase A suggests the potential to improve the activity of the ligands by decreasing the steric clash with Val147 and Leu139 and by increasing hydrophobic contact with Leu139 and Gly216 residues in the solvent-exposed region of the enzyme. Based on these suggestions, the rational redesign of furanopyrimidine 24 (clog P=7.41; Aurora A IC(50) =43 nM; HCT-116 IC(50) =400 nM) led to the identification of quinazoline 67 (clog P=5.28; Aurora A IC(50) =25 nM; HCT-116 IC(50) =23 nM). Rat in vivo pharmacokinetic studies showed that 67 has better systemic exposure after i.v. administration than 24, and holds potential for further development. 23905953 Flexion-distraction injuries of the thoracolumbar spine: open fusion versus percutaneous pedicle screw fixation. Object Flexion-distraction injuries occur due to distractive forces causing disruption of the posterior and middle spinal columns. These fractures classically consist of a fracture line through the posterior bony elements; involvement of the posterior ligamentous complex is, however, common. Surgical treatment is often required for these unstable injuries to avoid neurological deterioration and posttraumatic kyphosis, and the surgery traditionally consists of an open posterior approach with instrumented fusion. Percutaneous pedicle screw fixation for these injuries, with the goal of minimal tissue disruption and preservation of normal anatomy while achieving adequate stabilization, has recently been reported in the literature, but to date, a direct comparative study comparing open and percutaneous fixation has not been reported. The authors report their experience treating these fractures with both techniques and review the available literature. Methods Patients with flexion-distraction injury who were treated between May 2003 and March 2013 were prospectively followed. American Spinal Injury Association scores and degree of kyphotic angulation were recorded at admission, discharge, and follow-up. Data regarding intraoperative blood loss and operative time were obtained from a chart review. Patients treated with open versus minimally invasive procedures were compared. Results The authors identified 39 patients who suffered flexion-distraction injuries and were treated at their institution during the specified period; one of these patients declined surgery. All had injury to the posterior ligamentous complex. Open surgical procedures with pedicle screw fixation and posterolateral fusion were performed in 27 patients, while 11 patients underwent minimally invasive pedicle screw placement. Overall, there was improvement in kyphotic angulation at the time of discharge as well as most recent follow-up in both the open surgery and minimally invasive surgery (MIS) groups. The authors found no significant difference in American Spinal Injury Association score or the degree of kyphotic angulation between the MIS and open surgery groups. There was a trend toward shorter operative time for the MIS group, and patients who underwent minimally invasive procedures had significantly less blood loss. Conclusions Minimally invasive percutaneous pedicle screw fixation appears to have similar efficacy in the treatment of flexion-distraction injuries and it allows for reduced blood loss and tissue damage compared with open surgical techniques. Therefore it should be considered as an option for the treatment of this type of injury. 23810905 The Role of Aromatic-Aromatic Interactions in Strand-Strand Stabilization of β-Sheets. Aromatic-aromatic interactions have long been believed to play key roles in protein structure, folding, and binding functions. However, we still lack full understanding of the contributions of aromatic-aromatic interactions to protein stability and the timing of their formation during folding. Here, using an aromatic ladder in the β-barrel protein, cellular retinoic acid-binding protein 1 (CRABP1), as a case study, we find that aromatic π stacking plays a greater role in the Phe65-Phe71 cross-strand pair, while in another pair, Phe50-Phe65, hydrophobic interactions are dominant. The Phe65-Phe71 pair spans β-strands 4 and 5 in the β-barrel, which lack interstrand hydrogen bonding, and we speculate that it compensates energetically for the absence of strand-strand backbone interactions. Using perturbation analysis, we find that both aromatic-aromatic pairs form after the transition state for folding of CRABP1, thus playing a role in the final stabilization of the β-sheet rather than in its nucleation as had been earlier proposed. The aromatic interaction between strands 4 and 5 in CRABP1 is highly conserved in the intracellular lipid-binding protein (iLBP) family, and several lines of evidence combine to support a model wherein it acts to maintain barrel structure while allowing the dynamic opening that is necessary for ligand entry. Lastly, we carried out a bioinformatics analysis and found 51 examples of aromatic-aromatic interactions across non-hydrogen-bonded β-strands outside the iLBPs, arguing for the generality of the role played by this structural motif. 23893643 MALDI mass spectrometry-based sequence analysis of arginine-containing glycopeptides: improved fragmentation of glycan and peptide chains by modifying arginine residue. This paper describes an improved method for the sequence analysis of Arg-containing glycopeptide by MALDI mass spectrometry (MS). The method uses amino group derivatization (4-aza-6-(2,6-dimethyl-1-piperidinyl)-5-oxohexanoic acid N-succinimidyl ester) and removal (carboxypeptidase B) or modification (peptidylarginine deiminase 4) of the arginine residue of the peptide. The derivatization attaches a basic tertiary amine moiety onto the peptides, and the enzymatic treatment removes or modifies the arginine residue. Fragmentation of the resulting glycopeptide under low-energy collision-induced dissociation yielded a simplified ion series of both the glycan and the peptide that can facilitate their sequencing. The feasibility of the method was studied using α1 -acid glycoprotein-derived N-linked glycopeptides, and glycan and peptide in each glycopeptide were successfully sequenced by MALDI tandem MS (MS/MS). Copyright © 2013 John Wiley & Sons, Ltd. 22847251 The limiting behaviour of a stochastic patch occupancy model. Metapopulation models have been used to better understand the conditions necessary for the persistence of the metapopulation. In this paper, we study a stochastic patch occupancy model that incorporates variation in quality and connectivity of the habitat patches. Two important assumptions are imposed in our analysis. Firstly, the distance between patches has a special form. This amounts to assuming that migrating individuals follow certain pathways. Secondly, the area of the habitat patches is assumed to scale with the number of patches in the metapopulation. Under these assumptions, a deterministic limit is obtained as the number of patches goes to infinity. Using the deterministic limiting process, a condition for persistence of the metapopulation is derived. 23707666 Survivorship planning in gynecologic cancer patients. There are over one million survivors from gynecologic malignancies currently living in the United States and this population is expected to increase by 33% over the next decade. Identifying the needs of these cancer survivors is often understudied and overlooked. A literature review using MEDLINE was searched for research articles published in English from 1967 to 2013 focusing on survivorship care in women with gynecologic malignancies. For women with gynecologic malignancies, the survivorship period requires management of several aspects of care. Improved coordination of care between providers that may be addressed with the use of survivorship care plans and should include surveillance recommendations. Providers should conduct a focused evaluation of late and long-term effects of cancer that may continue to effect patients during and after treatment. Opportunities to improve lifestyle behaviors and continue general health maintenance should also be maximized. The survivorship period incorporates the following: prevention of new cancer diagnoses, surveillance for recurrence, assessment and management of side effects from cancer and cancer treatment, and the coordination of care between patients and healthcare providers. Focusing on these components may improve quality of life as it allows for a seamless transition for cancer survivors and their caregivers. 23954303 Effects of cue frequency and repetition on prospective memory: An ERP investigation. Prospective memory involves the formation and completion of delayed intentions and is essential for independent living. In this study (n=33), event-related potentials (ERPs) were used to systematically evaluate the effects of PM cue frequency (10% versus 30%) and PM cue repetition (high versus low) on ERP modulations. PM cues elicited prospective positivity and frontal positivity but not N300, perhaps due to the semantic nature of the task. Results of this study revealed an interesting interaction between PM cue frequency and PM cue repetition for prospective positivity and frontal positivity, highlighting the importance of taking both factors into account when designing future studies. 23877754 Endoscopic Reconstruction of Partial Mastectomy Defects Using Latissimus Dorsi Muscle Flap Without Causing Scars on the Back. Results obtained with breast-conserving therapy are not always satisfactory. Reconstruction with a pure latissimus dorsi muscle flap is a useful option. The techniques described for endoscopic dissection of the flap create several scars on the back. As a result, they do not improve on the open approach, which causes a horizontal scar at the level of the bra strap. The authors' technique avoids all scars on the back using a single incision in the highest folds of the axilla, which also is used for the sentinel node biopsy or lymphadectomy and quadrantectomy. The study was performed with 23 patients. The tumor was extracted via a clockwise downward periareolar incision and via another incision in a fold of the axilla. Through this axillary incision, the sentinel lymph node biopsy or lymphadectomy was performed, and the external part of the latissimus dorsi muscle was harvested endoscopically for the reconstruction. Both the medical team and the patients reported high satisfaction with the aesthetic and functional results due to the preservation of the breast shape and the absence of any scarring on the back. Endoscopy-assisted techniques make either three small scars on the back or one long scar, with the muscle sectioned distally, or a vertical incision in the midaxillary line, which may form a hypertrophic or keloid scar. The authors' approach avoids the creation of these scars on the back because the endoscopy and the distal sectioning of the muscle flap are performed through the single axillary incision. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . 23811484 Impedimetric immunosensor based on gold nanoparticles modified graphene paper for label-free detection of Escherichia coli O157:H7. In this study, a low-cost and robust impedimetric immunosensor based on gold nanoparticles modified free-standing graphene paper electrode for rapid and sensitive detection of Escherichia coli O157:H7 (E. coli O157:H7) was developed. Graphene paper was prepared by chemical reduction of graphene oxide paper obtained from vacuum filtration method. Scanning electron microscope, Raman spectroscopy and X-ray diffraction techniques were employed to investigate the surface morphology and crystal structure of the prepared graphene paper. The gold nanoparticles were grown on the surface of graphene paper electrode by one-step electrodeposition technique. The immobilization of anti-E. coli O157:H7 antibodies on paper electrode were performed via biotin-streptavidin system. Electrochemical impedance spectroscopy was used to detect E. coli O157:H7 captured on the paper electrode. Results show that the developed paper immunosensor possesses greatly enhanced sensing performance, such as wide linear range (1.5×10(2)-1.5×10(7)cfumL(-1)), low detection limit (1.5×10(2)cfumL(-1)), and excellent specificity. Furthermore, flexible test demonstrate the graphene paper based sensing device has high tolerability to mechanical stress. The strategy of structurally integrating metal nanomaterials, graphene paper, and biorecognition molecules would provide new insight into design of flexible immunosensors for routine sensing applications. 23912154 Discrimination of cis-trans isomers by dinuclear metal cryptates at physiological pH: selectivity for fumarate vs. maleate. Cryptand ( = N[(CH2)2NHCH2(2,6-C10H6)CH2NH(CH2)2]3N) and its dinuclear metal cryptates [Zn2L](NO3)4 () and [Cu2L](ClO4)4 () have been prepared, and the binding properties of the cryptates with fumarate and its cis isomer maleate were investigated using fluorescent spectra, (1)H NMR titrations and single crystal X-ray diffraction analysis for [(Cu2L)(fum)][ClO4]2 () (fum = fumarate). Thanks to the size and shape matching effect, the cryptates can selectively recognize fumarate at physiological pH, with an association constant almost 18-fold larger than that of maleate, forming a cradle-like cascade complex. 23803303 Examining language functions: a reassessment of Bastian's contribution to aphasia assessment. Henry Charlton Bastian (1837-1915) developed his network model of language processing, modality deficits and correlated lesion localizations in the 1860s and was a leading clinical authority for over four decades. Although his ideas are little referenced today, having been overshadowed by his more eminent Queen Square colleague John Hughlings Jackson, his work on aphasia and paralysis was highly regarded by contemporaries. This paper traces Bastian's lasting but largely unattributed contribution to the development of standardized clinical assessment of language disorders. From 1867 onwards, Bastian trained generations of medical students in neurology. In his 1875 book On Paralysis there is evidence in his case descriptions that Bastian had already implemented a detailed set of procedures for examining aphasic patients. In 1886, Bastian published a 'Schema for the Examination of Aphasic and Amnesic Persons'. Bastian insisted on the utility of this battery for diagnosis, classification and lesion localization; he argued that its consistent use would allow the development of a patient corpus and the comparison of cases from other hospitals. In 1898 his Treatise on Aphasia included a list of 34 questions that were to be used to examine all patients to provide detailed and systematic evidence of spared and impaired abilities in all receptive and expressive modalities. Bastian's contribution to the development of standardized clinical aphasia assessment is reassessed through detailed analysis of his publications and those of his contemporaries as well as new material from archives and casebooks. This evidence demonstrates that his approach to diagnosis of language and other cognitive impairments has propagated through the decades. His legacy can be seen in the approach to standardized aphasia testing developed in the latter 20th century through to today. 23915212 Interdisciplinary decision making in prostate cancer therapy - 5-years' time trends at the Interdisciplinary Prostate Cancer Center (IPC) of the Charité Berlin. Patients with prostate cancer face the difficult decision between a wide range of therapeutic options. These men require elaborate information about their individual risk profile and the therapeutic strategies´ risks and benefits to choose the best possible option. In order to detect time trends and quality improvements between an early patient population (2003/2004) and a later reference group (2007/2008) data was analysed with regards to epidemiologic parameters, differences in diagnostics and the type and ranking of the recommended therapies taking into account changes to Gleason Grading System and implementation of new therapeutic strategies, particularly Active surveillance, in 2005. Data from all 496 consecutive patients who received consultation in 2003/2004 (n = 280) and 2007/2008 (n = 216) was retrospectively evaluated. Categorical variables were compared using the Chi-square test. Dependent variables were analysed using the unpaired Students´ t-test and the Mann-Whitney U-test. The cohorts were comparable concerning clinical stage, initial PSA, prostate volume, comorbidities and organ confined disease. Patients in Cohort I were younger (66.44 vs. 69.31y; p < .001) and had a longer life expectancy (17.22 vs. 14.75y; p < .001). 50.9%, 28.2% and 20.9% in Cohort I and 37.2%, 39.6% and 23.2% in Cohort II showed low-, intermediate- and high-risk disease (D´Amico) with a trend towards an increased risk profile in Cohort II (p = .066). The risk-adapted therapy recommended as first option was radical prostatectomy for 91.5% in Cohort I and 69.7% in Cohort II, radiation therapy for 83.7% in Cohort I and 50.7% in Cohort II, and other therapies (brachytherapy, Active surveillance, Watchful waiting, high-intensity focused ultrasound) for 6.5% in Cohort I and 6.9% in Cohort II (p < .001). Radiation therapy was predominant in both cohorts as second treatment option (p < .001). Time trends showing quality improvement involved an increase in biopsy cores (9.95 ± 2.38 vs. 8.43 ± 2.29; p < .001) and an increased recommendation for bilateral nerve sparing (p < .001). In the earlier years, younger patients with a more favourable risk profile presented for interdisciplinary consultation. A unilateral recommendation for radical prostatectomy and radiation therapy was predominant. In the later years, the patient population was considerably older. However, this group may have benefitted from optimised diagnostic possibilities and a wider range of treatment options. 23293133 Serum mineral status of long-term cigarette smokers. This study was carried out to investigate comparatively some serum mineral levels of cigarette smokers. A total of 25 nonsmokers (control group) and 50 long-term cigarette smokers (smoking for at least 15 years; smoker group) were participated in the study. Subjects were between 25 and 40 years old. Control and smoker groups were matched for age, sex and body mass index status. The blood samples were taken from smokers and nonsmokers after 12 h of fasting period. The levels of zinc (Zn), copper (Cu), iron (Fe), magnesium (Mg), calcium (Ca), potassium (K), chlorine (Cl), sodium (Na) and phosphorus (P) were measured by autoanalyzer using commercial kits. Student's t test was used to compare the control and smoker groups, and p < 0.05 indicated a significant difference. Pearson's correlation coefficient was used to demonstrate the relationship among parameters in smoker and control groups. Although there was no statistical difference (p > 0.05) between the groups regarding the levels of K, P, Mg, Na, Cl, Zn, Fe, Ca and Cu, some positive correlations were observed in controls but not in smokers. Therefore, it was concluded that smoking does not affect the serum mineral levels. However, it may negatively affect some important positive correlations among minerals observed in healthy individuals. 18394845 Characterization of ST80 Panton-Valentine leukocidin-positive community-acquired methicillin-resistant Staphylococcus aureus clone in Tunisia. The spread of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has been reported in communities worldwide. In this study, we characterized 64 Tunisian CA-MRSA by agr typing, polymerase chain reaction assay for 20 virulence genes, staphylococcal chromosomal cassette mec (SCCmec) typing, pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and protein A gene (spa) typing. All our isolates were lukS-PV-lukF-PV positive, etd positive, and edin positive. They harbored SCCmec type IV and belonged to agr group 3. PFGE typing showed that our isolates were distributed in 11 different pulsotypes. spa typing and MLST, performed with isolates representative of each PFGE pattern, revealed that all isolates had a unique spa type (t044) and a common sequence type (ST80). The isolates showed susceptibility to the majority of antibiotics, and resistance to kanamycin, erythromycin, and tetracycline, but intermediate resistance to fusidic acid. Full analysis of our results revealed that our isolates were nonmultiresistant and belonged to a single clonal type ST80. 23931033 Bipolar Disorder with Seasonal Pattern: Clinical Characteristics and Gender Influences. Bipolar disorder (BD) has a multifactorial etiology with heterogeneous clinical presentations. Around 25% of BD patients may present with a depressive seasonal pattern (SP). However, there are limited scientific data on the prevalence of SP, its clinical manifestations, and any gender influence. Four hundred and fifty-two BD I and II cases (62% female), recruited from three French university-affiliated psychiatric departments, were assessed for SP. Clinical, treatment, and sociodemographic variables were obtained from structured interviews. One hundred and two (23%) cases met DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) criteria for SP, with similar frequency according to gender. Multivariate analysis showed a significant association between SP and BD II (odds ratio [OR] = 1.99, p = 0.01), lifetime history of rapid cycling (OR = 2.05, p = 0.02), eating disorders (OR = 2.94, p = 0.003), and total number of depressive episodes (OR = 1.13, p = 0.002). Seventy-one percent of cases were correctly classified by this analysis. However, when stratifying the analyses by gender, SP was associated with BD II subtype (OR = 2.89, p = 0.017) and total number of depressive episodes (OR = 1.21, p = 0.0018) in males but with rapid cycling (OR = 3.02, p = 0.0027) and eating disorders (OR = 2.60, p = 0.016) in females. This is the first study to identify different associations between SP and clinical characteristics of BD according to gender. The authors suggest that SP represents a potentially important specifier of BD. These findings indicate that seasonality may reflect increased severity or complexity of disorder. 23876764 Local behavioral rules sustain the cell allocation pattern in the combs of honey bee colonies (Apis mellifera). In the beeswax combs of honey bees, the cells of brood, pollen, and honey have a consistent spatial pattern that is sustained throughout the life of a colony. This spatial pattern is believed to emerge from simple behavioral rules that specify how the queen moves, where foragers deposit honey/pollen and how honey/pollen is consumed from cells. Prior work has shown that a set of such rules can explain the formation of the allocation pattern starting from an empty comb. We show that these rules cannot maintain the pattern once the brood start to vacate their cells, and we propose new, biologically realistic rules that better sustain the observed allocation pattern. We analyze the three resulting models by performing hundreds of simulation runs over many gestational periods and a wide range of parameter values. We develop new metrics for pattern assessment and employ them in analyzing pattern retention over each simulation run. Applied to our simulation results, these metrics show alteration of an accepted model for honey/pollen consumption based on local information can stabilize the cell allocation pattern over time. We also show that adding global information, by biasing the queen's movements towards the center of the comb, expands the parameter regime over which pattern retention occurs. 23898848 Functional dysconnectivity in schizophrenia and its relationship to neural synchrony. Schizophrenia is a debilitating disorder of unknown cause. There is increasing momentum to consider functional dysconnectivity as an endophenotype of schizophrenia, and in particular, how it relates to cognition as a core feature of the disorder. Here, the authors review the conceptual models of functional dysconnectivity in schizophrenia to date, the evidence they are based on and some of the limitations of these models. The authors then propose 'neural synchrony' as a potential mechanism for functional dysconnectivity and review the current state of evidence for a link between neural synchrony and cognition in schizophrenia across behavioral, physiological, brain imaging, neurochemical and neurogenetic units of enquiry. The authors conclude by outlining the unmet needs in this field and give an outlook on how to fill these gaps. 23512583 Edge-to-Edge Assembled Graphene Oxide Aerogels with Outstanding Mechanical Performance and Superhigh Chemical Activity. Aerogels, an extremely important aggregation state of various self-assembled nanoscale building blocks, have great potential in fields ranging from energy storage to thermal insulation. However, the porosity of aerogels makes them mechanically weak in most cases, and the chemical activity of the resulting aerogel needs consideration. Herein, chemically crosslinked graphene oxide (GO) 3D aerogels with large specific surface areas (up to 850 m(2) g(-1) ), outstanding mechanical performance (up to 20 MPa Young's modulus, 1 MPa yield strength and 45 J g(-1) specific energy adsorption), and superhigh chemical activity (toward some reducing gases such as H2 S, HI, and SO2 ), are fabricated by assembling 2D GO sheets edge-to-edge into uniform, 3D hydrogel networks with subsequent supercritical fluid drying. These aerogels are superior to other 3D frameworks (e.g. graphene aerogels) assembled via partial overlapping of the basal planes of the 2D building blocks. 23558431 Prenatal and postnatal inflammation in relation to cortisol levels in preterm infants at 18 months corrected age. Objective:To examine whether early inflammation is related to cortisol levels at 18 months corrected age (CA) in children born very preterm.Study Design:Infants born 32 weeks of gestational age were recruited in the neonatal intensive care unit (NICU), and placental histopathology, magnetic resonance imaging (MRI) and chart review were obtained. At 18 months CA, developmental assessment and collection of three salivary cortisol samples were carried out. Generalized least squares was used to analyze data from 85 infants providing 222 cortisol samples.Result:Infants exposed to chorioamnionitis with funisitis had a significantly different pattern of cortisol across the samples compared with infants with chorioamnionitis alone or no prenatal inflammation (F(4, 139)=7.3996, P<0.0001). Postnatal infections, necrotizing enterocolitis and chronic lung disease were not significantly associated with the cortisol pattern at 18 months CA.Conclusion:In children born very preterm, prenatal inflammatory stress may contribute to altered programming of the hypothalamic-pituitary-adrenal (HPA) axis. 23891560 Prevalence and Clinical Significance of Incidental and Clinically Suspected Venous Thromboembolism in Lung Cancer Patients. It is unclear what proportion of VTE events in lung cancer patients are incidentally discovered and whether incidental events affect mortality. We conducted a retrospective cohort study of lung cancer patients seen at the University of Rochester between January 1, 2006 and December 31, 2008 with the goal of quantifying and characterizing VTE events. Multiple clinical variables and mortality outcomes were compared using Kaplan-Meier survival analysis and multivariate Cox proportional hazards. The study population consisted of 207 subjects with lung cancer. The median age was 66 years and 55% were female (n = 115). Thirty-one patients (14.9%) experienced at least 1 VTE event with 32.2% (10/31) of these incidentally discovered. Incidental events comprised 29.4% (n = 5) of pulmonary embolisms, 11.1% (n = 2) of deep vein thrombosis, and 100% (n = 3) of visceral events. The median survival for patients with incidental VTE was 23.4 months (95% confidence interval [CI], 4.8-32.1) compared with 45.8 months (95% CI, 34.1-56.8) in patients without VTE (HR 2.4; 95% CI, 1.2-4.9; P = .01), but in a subgroup analysis of stage IV patients overall survival was not significantly different (HR, 0.94; P = .33). Patients with clinically suspected VTE had the lowest median survival at 13.1 months (95% CI, 6.4-18.9) which was significantly lower than patients without VTE (HR, 2.7; 95% CI, 1.6-4.5; P = .002), but not significantly different from patients with incidental VTE (HR, 1.2; 95% CI, 0.4-2.0; P = .7). In multivariate analysis, occurrence of VTE (HR, 2.3; 95% CI, 1.3-3.8; P = .002) was significantly associated with mortality when adjusting for age, stage, and histology. One-third of VTE events in lung cancer patients are incidentally discovered and VTE has negative clinical effect in lung cancer patients. 23839910 In situ UV-crosslinking gelatin electrospun fibers for tissue engineering applications. Electrospun fibers of natural polymers are desirable for biomedical applications such as tissue engineering. Crosslinking of electrospun fibers of natural polymers is needed to prevent dissolution in water and to enhance mechanical strength. In this study, an in situ UV-crosslinking method was developed for crosslinking of gelatin electrospun fibers (GESFs) and water-soluble synthetic polymers. A mixture of gelatin and phenylazide-conjugated poly(acrylic acids) was electrospun under UV irradiation. The UV-crosslinked GESFs were not dissolved in water with improved mechanical strength. Compared to traditional crosslinking by glutaraldehyde vapor, the GESFs crosslinked by our method are superior in terms of retention of GESF morphology, uniform crosslinking throughout the fibers, low cytotoxic and retention of biofunctionality. L929 cells grew better on the UV-crosslinked GESF scaffolds compared to glutaraldehyde-crosslinked ones. Furthermore, bioactive nanoparticles, e.g. hydroxyapatite, could be incorporated into GESFs for enhancing osteoconductivity, which possess a great potential in bone tissue engineering. 23833130 Complete Genome Sequence of the Thermophilic and Facultatively Chemolithoautotrophic Sulfate Reducer Archaeoglobus sulfaticallidus Strain PM70-1T. Dissimilatory sulfate-reducing archaea of the genus Archaeoglobus display divergent preferences in the use of energy sources and electron acceptors. Here we present the complete genome sequence of the thermophilic Archaeoglobus sulfaticallidus strain PM70-1(T), which distinctly couples chemolithoautotrophic growth on H2/CO2 to sulfate reduction in addition to heterotrophic growth. 23909506 Addressing Biogenic Greenhouse Gas Emissions from Hydropower in LCA. The ability of hydropower to contribute to climate change mitigation is sometimes questioned, citing emissions of methane and carbon dioxide resulting from the degradation of biogenic carbon in hydropower reservoirs. These emissions are, however, not always addressed in life cycle assessment, leading to a bias in technology comparisons, and often misunderstood. The objective of this paper is to review and analyze the generation of greenhouse gas emissions from reservoirs for the purpose of technology assessment, relating established emission measurements to power generation. A literature review, data collection, and statistical analysis of methane and CO2 emissions are conducted. In a sample of 82 measurements, methane emissions per kWh hydropower generated are log-normally distributed, ranging from micrograms to 10s of kg. A multivariate regression analysis shows that the reservoir area per kWh electricity is the most important explanatory variable. Methane emissions flux per reservoir area are correlated with the natural net primary production of the area, the age of the power plant, and the inclusion of bubbling emissions in the measurement. Even together, these factors fail to explain most of the variation in the methane flux. The global average emissions from hydropower are estimated to be 85 gCO2/kWh and 3 gCH4/kWh, with a multiplicative uncertainty factor of 2. GHG emissions from hydropower can be largely avoided by ceasing to build hydropower plants with high land use per unit of electricity generated. 23552832 Soluble Receptor for Advanced Glycation End-Product (sRAGE)/Pentosidine Ratio: A Potential Risk Factor Determinant for Type 2 Diabetic Retinopathy. This study aims to investigate potential diabetic retinopathy (DR) risk factors by evaluating the circulating levels of pentosidine, soluble receptor for advanced glycation end-product (sRAGE), advanced oxidation protein product (AOPP) as well as glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities in DR patients. A total of 235 healthy controls, 171 type 2 diabetic without retinopathy (DNR) and 200 diabetic retinopathy (DR) patients were recruited. Plasma was extracted for the estimation of pentosidine, sRAGE, AOPP levels and GPx activity whereas peripheral blood mononuclear cells were disrupted for SOD activity measurement. DNR and DR patients showed significantly higher levels of plasma pentosidine, sRAGE and AOPP but lower GPx and SOD activities when compared to healthy controls. The sRAGE/pentosidine ratio in DR patients was significantly lower than the ratio detected in DNR patients. Proliferative DR patients had significantly higher levels of plasma pentosidine, sRAGE, AOPP and sRAGE/pentosidine ratio than non-proliferative DR patients. High HbA1c level, long duration of diabetes and low sRAGE/pentosidine ratio were determined as the risk factors for DR. This study suggests that sRAGE/pentosidine ratio could serve as a risk factor determinant for type 2 DR as it has a positive correlation with the severity of DR. 23884847 The "bespoke" upper eyelid blepharoplasty and brow rejuvenation. Blepharoplasty of the upper eyelids is one of the most commonly performed procedures in aesthetic plastic surgery. In this article, we describe our approach to the patient with aging of the periorbita. At all times, the approach is tailored to the individual's needs, trying to achieve a natural result that will not in any way affect the function of the eyelid. Our current approach and techniques for upper eyelid blepharoplasty and brow lifting are described. 23706810 Construction and characterization of infectious hepatitis C virus chimera containing structural proteins directly from genotype 1b clinical isolates. HCV genotype is a major determinant of clinical outcome, and GT1b HCV infection is the most difficult to treat and also the predominant genotype in East Asia and Europe. We developed 1b/JFH-1 inter-genotypic recombinants containing the structural genes (Core, E1, E2), p7 and the 1stTMD of NS2 directly from GT1b clinical isolates. Through a cloning selection strategy, we obtained 4 functional clones from 3 cases of GT1b patients' sera, which could produce infectious viruses in Huh7.5.1 cells. Sequencing analysis of recovered viruses from serial passage and reverse genetics revealed that adaptive mutations in the GT1b-originated region were enough for the enhancement of infectivity. A monoclonal antibody to E2 and original patient sera could efficiently block 3 of the viruses (26C3mt, 52B6mt and 79L9) while had little effect on 26C6mt viruses. The availability of 1b/JFH-1 chimeric viruses will be important for studies of isolate-specific neutralization and useful in evaluating antiviral therapies. 23685172 Accurate measurement of Atomic Force Microscope cantilever deflection excluding tip-surface contact with application to force calibration. Considerable attention has been given to the calibration of AFM cantilever spring constants in the last 20 years. Techniques that do not require tip-sample contact are considered advantageous since the imaging tip is not at risk of being damaged. Far less attention has been directed toward measuring the cantilever deflection or sensitivity, despite the fact that the primary means of determining this factor relies on the AFM tip being pressed against a hard surface, such as silicon or sapphire; which has the potential to significantly damage the tip. A recent method developed by Tourek et al. in 2010 involves deflecting the AFM cantilever a known distance from the imaging tip by pressing the cantilever against a sharpened tungsten wire. In this work a similar yet more precise method is described, whereby the deflection of the cantilever is achieved using an AFM probe with a spring constant much larger than the test cantilever, essentially a rigid cantilever. The exact position of loading on the test cantilever was determined by reverse AFM imaging small spatial markers that are milled into the test cantilever using a focussed ion beam. For V shaped cantilevers it is possible to reverse image the arm intersection in order to determine the exact loading point without necessarily requiring FIB milled spatial markers, albeit at the potential cost of additional uncertainty. The technique is applied to tip-less, beam shaped and V shaped cantilevers and compared to the hard surface contact technique with very good agreement (on average less than 5% difference). While the agreement with the hard surface contact technique was very good the error on the technique is dependent upon the assumptions inherent in the method, such as cantilever shape, loading point distance and ratio of test to rigid cantilever spring constants. The average error ranged between 2 to 5% for the majority of test cantilevers studied. The sensitivity derived with this technique can then be used to calibrate the cantilever spring constant using the thermal noise method, allowing complete force calibration to be accurately performed without tip-sample contact. 23758292 Assessing the State of Chronic Spinal Cord Injury Using Diffusion Tensor Imaging. Abstract The aim of this study was to quantify the association between diffusion tensor imaging (DTI) parameters of the cervical spinal cord and neurological disability in patients with chronic traumatic spinal cord injury (SCI). A cervical spinal cord 3T magnetic resonance imaging (MRI) with DTI sequences was performed on 28 patients with chronic traumatic SCI and 40 healthy control subjects. DTI metrics, including fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD), and radial diffusivity (RD), were calculated within the normal-appearing spinal cord area at levels C2 or C3. Clinical assessment of the patients was performed according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) and the motor subscale of the Functional Independence Measure (FIM). The FA values of the patients with SCI were significantly lower than those of healthy control subjects (p<0.000001). In contrast, the ADC and RD values of these patients were significantly higher than those of control subjects (ADC p<0.0001, RD p<0.00001). In patients with SCI, the FA values were positively correlated with the motor (pr=0.56, p<0.01) and sensory (pr=0.66, p<0.001) scores of ISNCSCI and with the motor subscale of FIM (pr=0.51, p<0.01). DTI revealed spinal cord pathology, which was undetectable using conventional MRI. DTI changes in regions that were remote from the site of primary injury were most likely the result of secondary degeneration of white matter tracts. Decreased FA values were correlated with poorer motor and sensory function, as well as a lack of independence in daily living. DTI is a promising quantitative and objective tool that may be used in the clinical assessment of patients with SCI. 23339449 Risk factors of central nervous system relapse in mantle cell lymphoma. Abstract Central nervous system (CNS) relapse has not been extensively studied in mantle cell lymphoma (MCL). We retrospectively analyzed the risk factors and pattern of CNS relapse in consecutive patients with MCL. We identified 142 cases of MCL treated from 1980 to 2011. Median age at diagnosis was 68 years; 82% of patients had advanced stage; extranodal disease was reported in 89% of cases and high serum lactate dehydrogenase (LDH) in 40%. Fourteen patients (10%) did not receive treatment at diagnosis. Chemotherapy was administered to 125 patients (88%), in 21 cases (15%) including drugs penetrating into the CNS or given intrathecally; 49 patients (35%) had rituximab. Ten patients had front-line autologous transplant. After a median follow-up of 7.9 years, CNS relapse occurred in 11 cases (7.8%) at a median of 13.8 months. Actuarial risk of CNS relapse was higher in patients with elevated LDH (p = 0.002), higher International Prognostic Index (IPI) score (p = 0.018) and blastoid histology (p < 0.0001). Blastoid histology retained significance at multivariate analysis. Median survival after CNS relapse was 6.3 months. No front-line treatment reduced the risk of CNS relapse. Our analysis confirms the poor outcome of MCL after CNS relapse and may allow the identification of patients needing prophylaxis of CNS relapse. 23506025 Quorum sensing inhibitors: a patent review. Quorum sensing (QS) is a cell-to-cell communication that regulates gene expression and coordinates their behavior in accordance with the cell population density as a result of discerning molecules termed autoinducers (AIs). The processes that QS governed include biofilm formation, bacterial virulence, antibiotic production, competence, conjugation, swarming motility and sporulation. Three main QS AIs are acyl-homoserine lactones, AI-2 and AI peptides. The attractive study of QS leads to an expansive number of QS inhibitors and approaches interfering with QS appearing. This review summarized the recent QS inhibitor-related patents published from 2009 to 2012. The authors have analyzed these patents and have provided an overview of QS inhibitors and their application. The main strategies for QS inhibition related to the patents are disruption of the AI synthase, inactivation of the signal molecule, antagonism of the receptor and promotion of immune response to AI. Some of the natural or synthetic QS inhibitors display excellent activity to manipulate bacterial pathogenicity to offer significant potential in clinical therapy. However, more efforts are needed to be conducted to determine this form of communication to guide the development of QS inhibitors. Overall, QS is a suitable target for antimicrobial therapy and QS inhibitors are likely to lead to a renaissance of anti-virulence drugs without tolerance, which is the ultimate goal expected to achieve in this field. 23899444 Nanoparticle drug loading as a design parameter to improve docetaxel pharmacokinetics and efficacy. Nanoparticle (NP) drug loading is one of the key defining characteristics of an NP formulation. However, the effect of NP drug loading on therapeutic efficacy and pharmacokinetics has not been thoroughly evaluated. Herein, we characterized the efficacy, toxicity and pharmacokinetic properties of NP docetaxel formulations that have differential drug loading but are otherwise identical. Particle Replication in Non-wetting Templates (PRINT(®)), a soft-lithography fabrication technique, was used to formulate NPs with identical size, shape and surface chemistry, but with variable docetaxel loading. The lower weight loading (9%-NP) of docetaxel was found to have a superior pharmacokinetic profile and enhanced efficacy in a murine cancer model when compared to that of a higher docetaxel loading (20%-NP). The 9%-NP docetaxel increased plasma and tumor docetaxel exposure and reduced liver, spleen and lung exposure when compared to that of 20%-NP docetaxel. 23897840 Possibilities and Implications of Using the ICF and Other Vocabulary Standards in Electronic Health Records. There is now widespread recognition of the powerful potential of electronic health record (EHR) systems to improve the health-care delivery system. The benefits of EHRs grow even larger when the health data within their purview are seamlessly shared, aggregated and processed across different providers, settings and institutions. Yet, the plethora of idiosyncratic conventions for identifying the same clinical content in different information systems is a fundamental barrier to fully leveraging the potential of EHRs. Only by adopting vocabulary standards that provide the lingua franca across these local dialects can computers efficiently move, aggregate and use health data for decision support, outcomes management, quality reporting, research and many other purposes. In this regard, the International Classification of Functioning, Disability, and Health (ICF) is an important standard for physiotherapists because it provides a framework and standard language for describing health and health-related states. However, physiotherapists and other health-care professionals capture a wide range of data such as patient histories, clinical findings, tests and measurements, procedures, and so on, for which other vocabulary standards such as Logical Observation Identifiers Names and Codes and Systematized Nomenclature Of Medicine Clinical Terms are crucial for interoperable communication between different electronic systems. In this paper, we describe how the ICF and other internationally accepted vocabulary standards could advance physiotherapy practise and research by enabling data sharing and reuse by EHRs. We highlight how these different vocabulary standards fit together within a comprehensive record system, and how EHRs can make use of them, with a particular focus on enhancing decision-making. By incorporating the ICF and other internationally accepted vocabulary standards into our clinical information systems, physiotherapists will be able to leverage the potent capabilities of EHRs and contribute our unique clinical perspective to other health-care providers within the emerging electronic health information infrastructure. Copyright © 2013 John Wiley & Sons, Ltd. 23763968 Use of the intrauterine device among adolescent and young adult women in the United States from 2002 to 2010. Long-acting contraceptives, such as the intrauterine device (IUD), show potential for decreasing the incidence of unintended pregnancy. However, use among adolescent and young adult women remains low. We determined factors associated with IUD use among young women. We conducted an analysis of nationally representative, cross-sectional data from the 2002 and 2006-2010 National Surveys of Family Growth. We included sexually active women 15-24 years old. We used bivariate analysis to compare proportions of ever-use of any type of IUD in 2002 and in 2006-2010 and multivariable logistic regression to identify correlates of ever-use in 2006-2010. We found an increase in IUD use in teens 15-19 years old, from .2% to 2.5% (p < .001), and among women 20-24 years old, 2.0% to 5.4% (p < .001). Use increased among nearly all subgroups of respondents. Compared with nulliparous young women, those with one prior delivery and with two or more deliveries were substantially more likely to have used an IUD (adjusted OR 11.43, 95% CI 3.61-36.16, and adjusted OR 13.60, 95% CI 4-46.48, respectively). Young black women were less likely to report IUD use (adjusted OR .32, 95% CI .16-.66), and women whose mothers received at least a high school education were more likely to report use (adjusted OR 2.56, 95% CI 1.22-5.43). IUD use is increasing among adolescent and young adult women overall and among almost all sociodemographic subgroups. Nonetheless, use remains low, and nulliparous young women are highly unlikely to use the IUD. 23348842 Kava for the Treatment of Generalized Anxiety Disorder RCT: Analysis of Adverse Reactions, Liver Function, Addiction, and Sexual Effects. Presently, little is known about a number issues concerning kava (Piper methysticum), including (i) whether kava has any withdrawal or addictive effects; (ii) if genetic polymorphisms of the cytochrome (CYP) P450 2D6 liver enzyme moderates any potential adverse effects; and (iii) if medicinal application of kava has any negative or beneficial effect on sexual function and experience. The study design was a 6-week, double-blind, randomized controlled trial (n = 75) involving chronic administration of kava (one tablet of kava twice per day; 120 mg of kavalactones per day, titrated in non-response to two tablets of kava twice per day; 240 mg of kavalactones) or placebo for participants with generalized anxiety disorder. Results showed no significant differences across groups for liver function tests, nor were there any significant adverse reactions that could be attributed to kava. No differences in withdrawal or addiction were found between groups. Interesting, kava significantly increased female's sexual drive compared to placebo (p = 0.040) on a sub-domain of the Arizona Sexual Experience Scale (ASEX), with no negative effects seen in males. Further, it was found that there was a highly significant correlation between ASEX reduction (improved sexual function and performance) and anxiety reduction in the whole sample. Copyright © 2013 John Wiley & Sons, Ltd. 23208978 Novel Three-Dimensional Nanoporous Alumina as a Template for Hierarchical TiO2 Nanotube Arrays. Hierarchical micro-/nano-structures made easy. By using extremely rough, chemically etched microstructured aluminium foils, anodization in phosphoric acid under very harsh conditions, e.g., 10 wt% phosphoric acid and room temperature, can be repeatedly accomplished without suffering from breakdown. As a result, an alumina membrane with a three-dimensionally distributed nanopore structure is formed, which can be used as a general template to fabricate hierarchical micro-/nano-structures. 23904173 In vitro fracture load of monolithic lithium disilicate ceramic molar crowns with different wall thicknesses. The objective of this in vitro study was to assess the effect of wall thickness on the fracture loads of monolithic lithium disilicate molar crowns. Forty-eight extracted molars were prepared by use of a standardized preparation design. Lithium disilicate crowns (e.max CAD, Ivoclar/Vivadent, Schaan, Liechtenstein) of different wall thicknesses (d = 0.5, 1.0, and 1.5 mm; n = 16 for each series) were then constructed and milled (Cerec MC-XL, Sirona, Bensheim, Germany). After placement of the teeth in acrylic blocks (Technovit, Heraeus Kulzer, Hanau, Germany), the crowns were adhesively luted (Multilink, Ivoclar Vivadent). In each series, eight crowns were loaded without artificial aging whereas another eight crowns underwent thermocycling (10,000 cycles, THE-1100, SD Mechatronik) and chewing simulation (1.2 million cycles, Willytec CS3, SD Mechatronik, F max = 108 N). All specimens were loaded until fracture on one cusp with a tilt of 30° to the tooth axis in a universal testing machine (Z005, Zwick/Roell). Statistical assessment was performed by use of SPSS 19.0. Crowns with d = 1.0 and 1.5 mm wall thickness did not crack during artificial aging whereas two of the crowns with d = 0.5 mm wall thickness did. The loads to failure (F u) of the crowns without aging (with aging) were 470.2 ±â€‰80.3 N (369.2 ±â€‰117.8 N) for d = 0.5 mm, 801.4 ±â€‰123.1 N (889.1 ±â€‰154.6 N) for d = 1.0 mm, and 1107.6 ±â€‰131.3 N (980.8 ±â€‰115.3 N) for d = 1.5 mm. For aged crowns with d = 0.5 mm wall thickness, load to failure was significantly lower than for the others. However, differences between crowns with d = 1.0 mm and d = 1.5 mm wall thickness were not significant. Fracture loads for posterior lithium disilicate crowns with 0.5 mm wall thickness were too low (F u < 500 N) to guarantee a low complication rate in vivo, whereas all crowns with 1.0 and 1.5 mm wall thicknesses showed appropriate fracture resistances F u > 600 N. The wall thickness of posterior lithium disilicate crowns might be reduced to 1 mm, thus reducing the invasiveness of the preparation, which is essential for young patients. 23771017 Advances of lab-on-a-chip in isolation, detection and post-processing of circulating tumour cells. Circulating tumour cells (CTCs) are shed by primary tumours and are found in the peripheral blood of patients with metastatic cancers. Recent studies have shown that the number of CTCs corresponds with disease severity and prognosis. Therefore, detection and further functional analysis of CTCs are important for biomedical science, early diagnosis of cancer metastasis and tracking treatment efficacy in cancer patients, especially in point-of-care applications. Over the last few years, there has been an increasing shift towards not only capturing and detecting these rare cells, but also ensuring their viability for post-processing, such as cell culture and genetic analysis. High throughput lab-on-a-chip (LOC) has been fuelled up to process and analyse heterogeneous real patient samples while gaining profound insights for cancer biology. In this review, we highlight how miniaturisation strategies together with nanotechnologies have been used to advance LOC for capturing, separating, enriching and detecting different CTCs efficiently, while meeting the challenges of cell viability, high throughput multiplex or single-cell detection and post-processing. We begin this survey with an introduction to CTC biology, followed by description of the use of various materials, microstructures and nanostructures for design of LOC to achieve miniaturisation, as well as how various CTC capture or separation strategies can enhance cell capture and enrichment efficiencies, purity and viability. The significant progress of various nanotechnologies-based detection techniques to achieve high sensitivities and low detection limits for viable CTCs and/or to enable CTC post-processing are presented and the fundamental insights are also discussed. Finally, the challenges and perspectives of the technologies are enumerated. 23917430 Neural Correlates of Reward-Based Spatial Learning in Persons with Cocaine Dependence. Dysfunctional learning systems are thought to be central to the pathogenesis of and impair recovery from addictions. The functioning of the brain circuits for episodic memory or learning that support goal-directed behavior has not been studied previously in persons with cocaine dependence (CD). Thirteen abstinent CD and 13 healthy participants underwent MRI scanning while performing a task that requires the use of spatial cues to navigate a virtual-reality environment and find monetary rewards, allowing the functional assessment of the brain systems for spatial learning, a form of episodic memory. Whereas both groups performed similarly on the reward-based spatial learning task, we identified disturbances in brain regions involved in learning and reward in CD participants. In particular, CD was associated with impaired functioning of medial temporal lobe (MTL), a brain region that is crucial for spatial learning (and episodic memory) with concomitant recruitment of striatum (which normally participates in stimulus-response, or habit, learning), and prefrontal cortex. CD was also associated with enhanced sensitivity of the ventral striatum to unexpected rewards but not to expected rewards earned during spatial learning. We provide evidence that spatial learning in CD is characterized by disturbances in functioning of an MTL-based system for episodic memory and a striatum-based system for stimulus-response learning and reward. We have found additional abnormalities in distributed cortical regions. Consistent with findings from animal studies, we provide the first evidence in humans describing the disruptive effects of cocaine on the coordinated functioning of multiple neural systems for learning and memory.Neuropsychopharmacology accepted article preview online, 6 August 2013. doi:10.1038/npp.2013.189. 23465411 Effect of dentine matrix proteins on human endometrial adult stem-like cells: in vitro regeneration of odontoblasts cells. Human endometrium has enormous regenerative capacity due to the presence of endometrial stem cells. The present study sought to assess the possibility of differentiation of these cells into odontoblast-like cells by in vitro induction. Endometrial stem-like cells were obtained using enzymatic digestion of the biopsy samples of the endometrium after hysterectomy and cultured in Dulbecco's Modified Eagle's Medium (DMEM) which contained dentine non-collagenous proteins (dNCPs). The results were evaluated using the following assays: analysis of morphology, enzymatic assay for measuring alkaline phosphatase activity, Alizarin Red staining to detect in vitro formation of mineralized nodules, immunofluorescence for detection of dentine sialoprotein (DSP) and dentine-matrix protein (DMP1), and Western blotting for DMP1 expression. Following induction, endometrial stem-like cells demonstrated high alkaline phosphatase activity, and expression of DSP and DMP1 confirmed the odontoblast phenotype. DMP1 level increased in samples treated with dNCPs. Study results indicated that odontoblastic differentiation of endometrial stem cells can be induced by extracellular matrix proteins (e.g. dNCPs). The capacity of endometrial stem-like cells to differentiate into odontoblast-like cells under specific conditions gives new insights into the mechanism of odontogenesis and highlights the potential of such approaches for further research on dental tissue regeneration. 23892184 Anemia and type 2 diabetes mellitus associated with peripheral arterial disease progression in Chinese male patients. Peripheral arterial disease (PAD) is a chronic occlusive disease mainly occurred in elderly adults. Arteriosclerosis obliterans (ASO) mainly occurring from small or medium sized arteries of the lower extremities is one of the most common causes of PAD. The gender-related differences of circulating risk factors in diabetic patients with ASO in China remain unknown. The aim of this study is to investigate the gender-related differences in the pattern of several potential risk factors between male and female patients with ASO and type 2 diabetes mellitus (T2D). Clinical profiles and risk factors were analyzed in 323 Chinese patients with ASO and 112 patients were confirmed with T2D. Severities of limb ischemia were staged according to Fontaine classification. The significant inverse correlation was seen between the increased age and hemoglobin. The significant positive correlation was seen between the increased age, urea and creatinine both in the non-diabetic and diabetic male patients. The expression levels of hemoglobin significantly correlate with the classification of Fontaine clinical symptoms in Chinese male patients with T2D/ASO. The study is the first report indicating that the gender-related differences of circulating risk factors are associated with T2D patients with ASO in China. Anemia in Chinese male patients with T2D/ASO may play an important role in peripheral arterial disease progression. 23746269 Analysis of putative nonulosonic acid biosynthesis pathways in Archaea reveals a complex evolutionary history. Sialic acids and the other nonulosonic acid sugars, legionaminic acid and pseudaminic acid, are nine carbon-containing sugars that can be detected as components of the glycans decorating proteins and other molecules in Eukarya and Bacteria. Yet, despite the prevalence of N-glycosylation in Archaea and the variety of sugars recruited for the archaeal version of this post-translational modification, only a single report of a nonulosonic acid sugar in an archaeal N-linked glycan has appeared. Hence, to obtain a clearer picture of nonulosonic acid sugar biosynthesis capability in Archaea, 122 sequenced genomes were scanned for the presence of genes involved in the biogenesis of these sugars. The results reveal that while Archaea and Bacteria share a common route of sialic acid biosynthesis, numerous archaeal nonulosonic acid sugar biosynthesis pathway components were acquired from elsewhere via various routes. Still, the limited number of Archaea encoding components involved in the synthesis of nonulosonic acid sugars implies that such saccharides are not major components of glycans in this domain. 23642132 Developmental mechanisms of topographic map formation and alignment. Brain connections are organized into topographic maps that are precisely aligned both within and across modalities. This alignment facilitates coherent integration of different categories of sensory inputs and allows for proper sensorimotor transformations. Topographic maps are established and aligned by multistep processes during development, including interactions of molecular guidance cues expressed in gradients; spontaneous activity-dependent axonal and dendritic remodeling; and sensory-evoked plasticity driven by experience. By focusing on the superior colliculus, a major site of topographic map alignment for different sensory modalities, this review summarizes current understanding of topographic map development in the mammalian visual system and highlights recent advances in map alignment studies. A major goal looking forward is to reveal the molecular and synaptic mechanisms underlying map alignment and to understand the physiological and behavioral consequences when these mechanisms are disrupted at various scales. 23917782 Widespread Hypermetabolic Lesions Due to Multicentric Form of Castleman Disease as the Cause of Fever of Unknown Origin Revealed by FDG PET/CT. A 46-year-old male patient presented with fever for over 5 months. An FDG PET/CT was acquired to evaluate the source of the fever. The images showed many hypermetabolic foci throughout the imaged regions, which mainly corresponded to enlarged lymph nodes. Pathological examination demonstrated that the patient suffered from a multicentric form of Castleman disease. 22023252 Craniofacial and dental features in kabuki syndrome patients. Objective : To describe oral manifestations in Brazilian individuals with Kabuki syndrome, a multiple congenital anomaly/mental retardation syndrome. Study Design : A total of 16 Kabuki syndrome individuals, aged between 8 to 24 years and of both sexes, were referred by the Department of Clinical Genetics for oral treatment and follow-up to the Oral Care Center for Inherited Diseases, University Hospital of Brasília, Brasília, Brazil. Each individual underwent complete physical examination, as well as intraoral and radiographic examinations. Results : Craniofacial and dental alterations were observed in all Kabuki syndrome patients examined. In addition, atypical shape of the molars' crowns, occlusal convergence of the premolars' crowns, and root dilaceration were also observed. Enamel diffuse opacities were observed in permanent dentition (n  =  10). Conclusion : A great clinical heterogeneity was observed in Kabuki syndrome individuals in line with previous studies in the literature. Further clinical and molecular studies are necessary in order to better understand the presence of dental anomalies in this syndrome. 23915716 Selective ablation of mast cells or basophils reduces peanut-induced anaphylaxis in mice. Studies with c-kit mutant mast cell (MC)-deficient mice and antibody-mediated depletion of basophils suggest that both MCs and basophils can contribute to peanut-induced anaphylaxis (PIA). However, interpretation of data obtained by using such approaches is complicated because c-kit mutant mice have several phenotypic abnormalities in addition to MC deficiency and because basophil-depleting antibodies can also react with MCs. We analyzed (1) the changes in the features of PIA in mice after the selective and inducible ablation of MCs or basophils and (2) the possible importance of effector cells other than MCs and basophils in the PIA response. Wild-type and various mutant mice were orally sensitized with peanut extract and cholera toxin weekly for 4 weeks and challenged intraperitoneally with peanut extract 2 weeks later. Peanut-challenged, MC-deficient Kit(W-sh/W-sh) mice had reduced immediate hypothermia, as well as a late-phase decrease in body temperature that was abrogated by antibody-mediated depletion of neutrophils. Diphtheria toxin-mediated selective depletion of MCs or basophils in Mcpt5-Cre;iDTR and Mcpt8(DTR) mice, respectively, and treatment of wild-type mice with the basophil-depleting antibody Ba103 significantly reduced peanut-induced hypothermia. Non-c-kit mutant MC- and basophil-deficient Cpa3-Cre;Mcl-1(fl/fl) mice had reduced but still significant responses to peanut. Inducible and selective ablation of MCs or basophils in non-c-kit mutant mice can significantly reduce PIA, but partial responses to peanut can still be observed in the virtual absence of both cell types. The neutrophilia in Kit(W-sh/W-sh) mice might influence the responses of these mice in this PIA model. 23731666 Sphingosine-1-phosphate inhibits ceramide-induced apoptosis during murine preimplantation embryonic development. Sphingolipids are a complex family of naturally occurring molecules enriched with lipid rafts that contribute to their unique biochemical properties. Sphingolipid metabolites, including ceramide (Cer) and sphingosine-1-phosphate (S1P), are bioactive signaling molecules that regulate cell movement, differentiation, survival, and apoptosis, but their effects on preimplantation development of murine embryos are not well-characterized. In this study, murine zygotes were collected, cultured in vitro, and treated with 50 μM C2-Cer plus various concentrations of S1P. The blastocyst formation rate was decreased in the C2-Cer-treated group, compared with that in the control group and the group treated with 50 μM C2-Cer plus 25, 50, or 100 nM S1P (P < 0.05), respectively. The total cell number of the blastocysts from various treatment groups was similar at 110 hours post-hCG treatment, but that from the group treated with 50 μM C2-Cer was significantly decreased at 120 hours post-hCG treatment, compared with the control group and the group treated with 50 μM C2-Cer plus 50 nM S1P. However, the apoptotic cell number of blastocysts from the group treated with 50 μM C2-Cer was significantly increased at 110 and 120 hours post-hCG treatment, compared with the control group and the group treated with 50 μM C2-Cer plus 50 nM S1P. Moreover, expression of p53 in the group treated with 50 μM C2-Cer was higher than that in the control group and the group treated with 50 μM C2-Cer plus 50 nM S1P (P < 0.05). In conclusion, Cer decreases the blastocyst formation rate and induces embryonic cell apoptosis, but S1P partly inhibits the effects of Cer during preimplantation development of murine embryos. 23448129 Glutathione dimerization-based plasmonic nanoswitch for biodetection of reactive oxygen and nitrogen species. Reactive oxygen and nitrogen species (ROS and RNS) are continuously produced in the cellular systems and are controlled by several antioxidant mechanisms. Here, we developed a straightforward, sensitive, and quantitative assay for the colorimetric and spectroscopic detection of various ROS and RNS such as H2O2, ·OH, (-)OCl, NO·, and O2(-) using glutathione-modified gold nanoparticles (GSH-AuNPs). A basic principle here is that the GSHs on the AuNP surface can be readily detached via the formation of glutathione disulfides upon the addition of ROS and RNS, and destabilized particles can aggregate to generate the plasmonic couplings between plasmonic AuNPs that trigger the red shift in UV-vis spectrum and solution color change. For nonradical species such as H2O2, this process can be more efficiently achieved by converting them into radical species via the Fenton reaction. Using this strategy, we were able to rapidly and quantitatively distinguish among cancerous and normal cells based on ROS and RNS production. 23899019 Cluster-assembled metallic glasses. A bottom-up approach to nanofabricate metallic glasses from metal clusters as building blocks is presented. Considering metallic glasses as a subclass of cluster-assembled materials, the relation between the two lively fields of metal clusters and metallic glasses is pointed out. Deposition of selected clusters or collections of them, generated by state-of-the-art cluster beam sources, could lead to the production of a well-defined amorphous material. In contrast to rapidly quenched glasses where only the composition of the glass can be controlled, in cluster-assembled glasses, one can precisely control the structural building blocks. Comparing properties of glasses with similar compositions but differing in building blocks and therefore different in structure will facilitate the study of structure-property correlation in metallic glasses. This bottom-up method provides a novel alternative path to the synthesis of glassy alloys and will contribute to improving fundamental understanding in the field of metallic glasses. It may even permit the production of glassy materials for alloys that cannot be quenched rapidly enough to circumvent crystallization. Additionally, gaining deeper insight into the parameters governing the structure-property relation in metallic glasses can have a great impact on understanding and design of other cluster-assembled materials. 23931703 Correlations between Milk and Plasma Levels of Amino and Carboxylic Acids in Dairy Cows. The objective of this study was to investigate the relationship between the concentrations of 19 amino acids, glucose, and seven carboxylic acids in the blood and milk of dairy cows and their correlations with established markers of ketosis. To that end, blood plasma and milk specimens were collected throughout lactation in two breeds of dairy cows of different milk yield. Plasma concentrations of glucose, pyruvate, lactate, α-aminobutyrate, β-hydroxybutyrate (BHBA), and most amino acids, except for glutamate and aspartate, were on average 9.9-fold higher than their respective milk levels. In contrast, glutamate, aspartate, and the Krebs cycle intermediates succinate, fumarate, malate, and citrate were on average 9.1-fold higher in milk than in plasma. For most metabolites, with the exception of BHBA and threonine, no significant correlations were observed between their levels in plasma and milk. Additionally, milk levels of acetone showed significant direct relationships with the glycine-to-alanine ratio and the BHBA concentration in plasma. The marked decline in plasma concentrations of glucose, pyruvate, lactate, and alanine in cows with plasma BHBA levels above the diagnostic cutoff point for subclinical ketosis suggests that these animals fail to meet their glucose demand and, as a consequence, rely increasingly on ketone bodies as a source of energy. The concomitant increase in plasma glycine may reflect not only the excessive depletion of protein reserves but also a potential deficiency of vitamin B6. 23198719 Predictors of grade ≥ 2 and grade ≥ 3 radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with three-dimensional conformal radiotherapy. Abstract Grade ≥ 3 radiation pneumonitis (RP) is generally severe and life-threatening. Predictors of grade ≥ 2 are usually used for grade ≥ 3 RP prediction, but it is unclear whether these predictors are appropriate. In this study, predictors of grade ≥ 2 and grade ≥ 3 RP were investigated separately. The increased risk of severe RP in elderly patients compared with younger patients was also evaluated. Material and methods. A total of 176 consecutive patients with locally advanced non-small cell lung cancer were followed up prospectively after three-dimensional conformal radiotherapy. RP was graded according to Common Terminology Criteria for Adverse Events version 3.0. Results. Mean lung dose (MLD), mean heart dose, ratio of planning target volume to total lung volume (PTV/Lung), and dose-volume histogram comprehensive value of both heart and lung were associated with both grade ≥ 2 and grade ≥ 3 RP in univariate analysis. In multivariate logistic regression analysis, age and MLD were predictors of both grade ≥ 2 RP and grade ≥ 3 RP; receipt of chemotherapy predicted grade ≥ 3 RP only; and sex and PTV/Lung predicted grade ≥ 2 RP only. Among patients who developed high-grade RP, MLD and PTV/Lung were significantly lower in patients aged ≥ 70 years than in younger patients (p < 0.05 for both comparisons). Conclusions. The predictors were not completely consistent between grade ≥ 2 RP and grade ≥ 3 RP. Elderly patients had a higher risk of severe RP than younger patients did, possibly due to lower tolerance of radiation to the lung. 23936120 Blueberry Peel Extracts Inhibit Adipogenesis in 3T3-L1 Cells and Reduce High-Fat Diet-Induced Obesity. This study examined the anti-obesity effect and mechanism of action of blueberry peel extracts (BPE) in 3T3-L1 cells and high-fat diet (HFD)-induced obese rats. The levels of lipid accumulation were measured, along with the changes in the expression of genes and proteins associated with adipocyte differentiation in 3T3-L1 cells. Evidenced by Oil-red O staining and triglyceride assay, BPE dose-dependently inhibited lipid accumulation at concentrations of 0, 50, and 200 µg/ml. BPE decreased the expression of the key adipocyte differentiation regulator C/EBPβ, as well as the C/EBPα and PPARγ genes, during the differentiation of preadipocytes into adipocytes. Moreover, BPE down-regulated adipocyte-specific genes such as aP2 and FAS compared with control adipocytes. The specific mechanism mediating the effects of BP revealed that insulin-stimulated phosphorylation of Akt was strongly decreased, and its downstream substrate, phospho-GSK3β, was downregulated by BPE treatment in 3T3-L1 cells. Together, these data indicated that BP exerted anti-adipogenic activity by inhibiting the expression of PPARγ and C/EBPβ and the Akt signaling pathway in 3T3-L1 adipocytes. Next, we investigated whether BP extracts attenuated HFD-induced obesity in rats. Oral administration of BPE reduced HFD-induced body weight gain significantly without affecting food intake. The epididymal or perirenal adipose tissue weights were lower in rats on an HFD plus BPE compared with the tissue weights of HFD-induced obese rats. Total cholesterol and triglyceride levels in the rats fed BPE were modestly reduced, and the HDL-cholesterol level was significantly increased in HFD plus BP-fed rats compared with those of HFD-fed rats. Taken together, these results demonstrated an inhibitory effect of BP on adipogenesis through the down-regulation of C/EBPβ, C/EBPα, and PPARγ and the reduction of the phospho-Akt adipogenic factor in 3T3-L1 cells. Moreover, BPE reduced body weight gain and inhibited fat accumulation in an HFD-induced animal model of obesity. 23860422 Alpha lipoic acid and superoxide dismutase in the treatment of chronic low back pain. Background: Neuropathic mechanisms largely contribute to low back pain (LBP) and oxidative stress is acknowledged as one of the causes of nerve damage typical of neuropathic pain: antioxidant agents may be a useful choice in the multimodal treatment strategy for chronic LBP patients. Aim: The aim of this study was to detect changes in perceived pain, functional activity and in the assumption of analgesics in patients with chronic LBP treated with a combination of alpha-lipoic acid (ALA) and superoxide dismutase (SOD). Design: Prospective non-randomized open-label study. Setting: Outpatient at TAMMEF (Therapeutic Application of Musically Modulated Electromagnetic Fields) Centre of the University of Siena. Population: The study enrolled 98 adult patients with chronic (≥12 weeks) LBP with or without radiculopathy and without neoplastic or inflammatory pathologies. Methods: Patients were treated for 60 days with 600 mg ALA and 140 UI SOD/die. The Roland Morris Disability Questionnaire and Pain Rating Scale were used and concomitant use of medications (with particular attention to analgesics) and adverse events (toxicity) were recorded during treatment. Differences between all the study time points were calculated for the scores of the two tools and for the need of concomitant treatment with analgesics. Results: At the end of the study only 8% of patients still used analgesics versus 73.5% registered at baseline (P<0.01). Regarding self-reported tools, a statistically significant improvement both for perceived pain and functional disabilities occurred: pain ameliorated after 40 days of therapy and the improvement was significant both statistically (P<0.05) and clinically. Only 4 patients stopped the treatment due to unacceptable pain (not related to the treatment). Conclusion: Oral treatment with ALA and SOD improves functionality and reduces the use of analgesics in chronic LBP patients. Clinical Rehabilitation Impact: Oral combination of ALA and SOD may be a powerful adjuvant in multimodal therapy of chronic LBP patients. 23918965 Pattern of iron distribution in maternal and filial tissues in wheat grains with contrasting levels of iron. Iron insufficiency is a worldwide problem in human diets. In cereals like wheat, the bran layer of the grains is an important source of iron. However, the dietary availability of iron in wheat flour is limited due to the loss of the iron-rich bran during milling and processing and the presence of anti-nutrients like phytic acid that keep iron strongly chelated in the grain. The present study investigated the localization of iron and phosphorus in grain tissues of wheat genotypes with contrasting grain iron content using synchrotron-based micro-X-ray fluorescence (micro-XRF) and micro-proton-induced X-ray emission (micro-PIXE). X-ray absorption near-edge spectroscopy (XANES) was employed to determine the proportion of divalent and trivalent forms of Fe in the grains. It revealed the abundance of oxygen, phosphorus, and sulphur in the local chemical environment of Fe in grains, as Fe-O-P-R and Fe-O-S-R coordination. Contrasting differences were noticed in tissue-specific relative localization of Fe, P, and S among the different genotypes, suggesting a possible effect of localization pattern on iron bioavailability. The current study reports the shift in iron distribution from maternal to filial tissues of grains during the evolution of wheat from its wild relatives to the present-day cultivated varieties, and thus suggests the value of detailed physical localization studies in varietal improvement programmes for food crops. 23060635 Intermittent hypoxia-activated cyclooxygenase pathway: role in atherosclerosis. Intermittent hypoxia, the main stimulus of obstructive sleep apnoea (OSA), induces inflammation, leading to early atherosclerosis. Whether the cyclooxygenase (COX) pathway contributes to intermittent hypoxia-induced atherosclerosis remains to be determined. We studied the effects of 8-weeks of intermittent hypoxia exposure on COX-pathway gene expression and atherosclerosis, and the influence of COX-1 inhibition by SC-560 on atherosclerosis progression in aortas of apolipoprotein E(-/-) mice. Urinary 11-dehydrothromboxane B2 (11-dTXB2) was assessed in 50 OSA subjects free of cardiovascular risk factor matched for age and body mass index with 25 controls, and 56 OSA with cardiovascular risk factor. Intermittent hypoxia significantly increased atherosclerotic lesion sizes, mRNA levels of COX-1 and thromboxane synthase (TXBS). Lesion sizes correlated to COX-1 (r = 0.654, p = 0.0003) and TXBS (r = 0.693, p<0.0001) mRNA levels. COX-1 inhibition reduced lesion progression in intermittent hypoxia mice only (p = 0.04). Urinary 11-dTXB2 was similar in OSA subjects free of cardiovascular risk factor and controls, but was increased by 13% (p = 0.007) in OSA subjects with cardiovascular risk factor compared with those without. Although OSA itself was not associated with increased urinary 11-dTXB2 concentration, the COX-1 pathway was activated in intermittent hypoxia-exposed mice and in OSA subjects presenting with cardiovascular risk factor, and may contribute to intermittent hypoxia-induced atherogenesis. COX-1 inhibition could be of clinical interest in the prevention of cardiovascular morbidity in OSA. 23896699 Microwave sensing and heating of individual droplets in microfluidic devices. Droplet-based microfluidics is an emerging high-throughput screening technology finding applications in a variety of areas such as life science research, drug discovery and material synthesis. In this paper we present a cost-effective, scalable microwave system that can be integrated with microfluidic devices enabling remote, simultaneous sensing and heating of individual nanoliter-sized droplets generated in microchannels. The key component of this microwave system is an electrically small resonator that is able to distinguish between materials with different electrical properties (i.e. permittivity, conductivity). The change in these properties causes a shift in the operating frequency of the resonator, which can be used for sensing purposes. Alternatively, if microwave power is delivered to the sensing region at the frequency associated with a particular material (i.e. droplet), then only this material receives the power while passing the resonator leaving the surrounding materials (i.e. carrier fluid and chip material) unaffected. Therefore this method allows sensing and heating of individual droplets to be inherently synchronized, eliminating the need for external triggers. We confirmed the performance of the sensor by applying it to differentiate between various dairy fluids, identify salt solutions and detect water droplets with different glycerol concentrations. We experimentally verified that this system can increase the droplet temperature from room temperature by 42 °C within 5.62 ms with an input power of 27 dBm. Finally we employed this system to thermally initiate the formation of hydrogel particles out of the droplets that are being heated by this system. 23960222 Complexity in electro-optic delay dynamics: modelling, design and applications. Nonlinear delay dynamics have found during the last 30 years a particularly prolific exploration area in the field of photonic systems. Besides the popular external cavity laser diode set-ups, we focus in this article on another experimental realization involving electro-optic (EO) feedback loops, with delay. This approach has strongly evolved with the important technological progress made on broadband photonic and optoelectronic devices dedicated to high-speed optical telecommunications. The complex dynamical systems performed by nonlinear delayed EO feedback loop architectures were designed and explored within a huge range of operating parameters. Thanks to the availability of high-performance photonic devices, these EO delay dynamics led also to many successful, efficient and diverse applications, beyond the many fundamental questions raised from the observation of experimental behaviours. Their chaotic motion allowed for a physical layer encryption method to secure optical data, with a demonstrated capability to operate at the typical speed of modern optical telecommunications. Microwave limit cycles generated in similar EO delay oscillators showed significantly improved spectral purity thanks to the use of a very long fibre delay line. Last but not least, a novel brain inspired computational principle has been recently implemented physically in photonics for the first time, again on the basis of an EO delay dynamical system. In this latter emerging application, the computed result is obtained by a proper 'read-out' of the complex nonlinear transients emerging from a fixed point, the transient being issued by the injection of the information signal to be processed. 23892952 Conductive microemulsions for template CoNi electrodeposition. Microemulsions have been revealed as feasible templates to grow magnetic nanostructures using an electrodeposition method. Reducing agents are not required and the applied potential has been used as driving force of the nanostructure growth. A systematic study of conductive microemulsion systems to allow the CoNi electrodeposition process has been performed. Different surfactants and organic components have been tested to form microemulsions with a CoNi electrolytic bath as an aqueous component in order to define the microemulsions showing enough conductivity to perform an electrodeposition process from the aqueous component. By using microemulsions of the aqueous electrolyte solution-Triton X-100-diisopropyl adipate system, CoNi electrodeposition has been achieved, the structure of the deposits being dependent on the composition and structure of the microemulsion, which can act as a soft-template to obtain different discontinuous deposits. The magnetic properties of the CoNi deposits vary with their structure. 23778639 Amount of Hispanic youth exposure to food and beverage advertising on spanish- and english-language television. IMPORTANCE Exposure to large numbers of television advertisements for foods and beverages with little or no nutritional value likely contributes to poor diet among youth. Given higher rates of obesity and overweight for Hispanic youth, it is important to understand the amount and types of food advertising they view. OBJECTIVE To quantify the amount of food and beverage advertising viewed by Hispanic youth on Spanish- and English-language television and compare it with the amount of food and beverage advertising viewed by non-Hispanic youth. DESIGN, SETTING, AND PARTICIPANTS Data on gross rating points that measured advertising viewed on national broadcast and cable television in 2010 using a Nielsen panel of television-viewing households of Hispanic and non-Hispanic preschoolers (2-5 years), children (6-11 years), and adolescents (12-17 years). MAIN OUTCOMES AND MEASURES Food and beverage television advertisements viewed on English- and Spanish-language television by product category and television-viewing times by age and language preference. EXPOSURE Food and beverage advertising on Spanish- and English-language television. RESULTS In 2010, Hispanic preschoolers, children, and adolescents viewed, on average, 11.6 to 12.4 television food ads per day; the majority of these ads (75%-85%) appeared on English-language television. Fast food represented a higher proportion of food ads on Spanish-language television. Consistent with television-viewing patterns, Hispanic preschoolers saw more Spanish-language food advertisements than did Hispanic children and adolescents. Owing to somewhat less food advertising on Spanish-language television, Hispanic children and adolescents viewed 14% and 24% fewer food ads overall, respectively, compared with non-Hispanic youth. Spanish-language television viewing was highly concentrated among youth who primarily speak Spanish. CONCLUSIONS AND RELEVANCE Both Hispanic and non-Hispanic youth view large numbers of television advertisements for nutrient-poor categories of food and beverage. Although Hispanic children and adolescents see somewhat fewer of these ads, the higher obesity rates among Hispanic youth, the greater exposure by Hispanic preschoolers, and the potential enhanced effects of targeted advertising on Hispanic youth suggest that this exposure may pose additional risks for Hispanic youth. Continued monitoring is warranted owing to food companies' stated intentions to increase marketing to Hispanics. 23928109 Cancer markers: Integratively annotated classification. Translational cancer genomics research aims to ensure that experimental knowledge is subject to computational analysis, and integrated with a variety of records from omics and clinical sources. The data retrieval from such sources is not trivial, due to their redundancy and heterogeneity, and the presence of false evidence. In silico marker identification, therefore, remains a complex task that is mainly motivated by the impact that target identification from the elucidation of gene co-expression dynamics and regulation mechanisms, combined with the discovery of genotype-phenotype associations, may have for clinical validation. Based on the reuse of publicly available gene expression data, our aim is to propose cancer marker classification by integrating the prediction power of multiple annotation sources. In particular, with reference to the functional annotation for colorectal markers, we indicate a classification of markers into diagnostic and prognostic classes combined with susceptibility and risk factors. 23611514 Therapeutic potential of hematopoietic cells derived from pluripotent stem cells. Several challenges must be overcome before hematopoietic cells derived from pluripotent stem cells (PSCs) can be tested in the clinics. Pre-existing genetic mutations in somatic cells are a major concern for the production of iPSCs (induced pluripotent stem cells). This raises the question of what is the best somatic cell source to reprogram into iPSCs. Adult stem cells such as germ cell precursors and hematopoietic stem cells (HSCs) which are believed to be protected from somatic mutation accumulation are good candidates. Three gene editing methods have now been developed for human cells. Careful comparison of these methods is needed to determine the most appropriate for clinical applications. Differentiation of PSCs generally recapitulates early development. Therefore, cells produced from PSCs have an embryonic phenotype. Because transplantable HSCs and red blood cells expressing adult hemoglobin arise late in development, long after gastrulation, they have been difficult to produce from PSCs. The most difficult challenge is perhaps the development of methods to produce cells with an adult phenotype. Interestingly, recent reports suggest that primitive hematopoietic cells might make important contributions to adult hematopoiesis. Production of primitive hematopoietic cells might therefore have clinical applications. 23538115 Discovery of adamantane based highly potent HDAC inhibitors. Herein, we report the development of highly potent HDAC inhibitors for the treatment of cancer. A series of adamantane and nor-adamantane based HDAC inhibitors were designed, synthesized and screened for the inhibitory activity of HDAC. A number of compounds exhibited GI50 of 10-100 nM in human HCT116, NCI-H460 and U251 cancer cells, in vitro. Compound 32 displays efficacy in human tumour animal xenograft model. 23729807 DcR3 Mutations in Patients with Juvenile-onset Systemic Lupus Erythematosus Lead to Enhanced Lymphocyte Proliferation. Previous studies suggested a role for the death decoy receptor 3 (DcR3) in the pathogenesis of adult systemic lupus erythematosus (SLE). We investigated the role of DcR3 in juvenile-onset SLE, to identify polymorphisms that might alter the function of this protein. DcR3 was measured in the serum of 61 patients with juvenile SLE. The coding region of the DcR3 gene was sequenced in 100 juvenile and 103 adult patients with SLE, together with 500 healthy controls. DcR3 was elevated in the serum of juvenile patients with active SLE disease (440.8 ± 169.1 pg/ml), compared to patients with inactive disease (122.6 ± 28.05 pg/ml; p = 0.0014) and controls (69.27 ± 20.23 pg/ml; p = 0.0009). DNA sequencing identified 2 novel missense mutations: c.C167T (p.T56I) in an adult SLE patient and c.C364T (p.H122Y) in a juvenile patient. Recombinant proteins containing these mutations exhibited altered binding kinetics to FasL and they significantly increased lymphocyte proliferation, compared to the wild-type protein (p < 0.05). The adult patient with SLE carrying the p.T56I mutation had significantly increased lymphocyte proliferation compared to 3 SLE controls matched for age, sex, and disease severity. DcR3 may play an etiologic role in SLE through either elevated serum levels of wild-type DcR3 or normal levels of gain-of-function DcR3 proteins that increase lymphocyte proliferation. 23839277 Clinical effects of intrathecal fentanyl on shoulder tip pain in laparoscopic total extraperitoneal inguinal hernia repair under spinal anaesthesia: A double-blind, prospective, randomized controlled trial. The study evaluated the clinical intraoperative effects of intrathecal administration of fentanyl on shoulder tip pain in patients undergoing laparoscopic total extraperitoneal inguinal hernia repair (TEP) under spinal anaesthesia. Patients undergoing TEP were allocated in a double-blinded, prospective, randomized manner to two groups. Spinal anaesthesia was induced by intrathecal administration of 2.8 ml of 0.5% hyperbaric bupivacaine (14 mg) in the control group and with 2.6 ml of 0.5% hyperbaric bupivacaine (13 mg) and 10 µg fentanyl (0.2 ml) in the experimental group. The quality of muscle relaxation, adequacy of operative space and incidence of pneumoperitoneum were similar in the two groups (n = 36 per group). Compared with the control group, the experimental group had significantly fewer cases of hypotension (12 [33.3%]) versus 23 [63.9%]) and shoulder tip pain (nine [25%] versus 18 [50%]). Intraoperative shoulder tip pain was more severe in the control group than in the experimental group. Addition of intrathecal fentanyl to local anaesthetic can relieve shoulder tip pain with no change in complications, especially hypotension, during TEP under spinal anaesthesia. 23942544 Development and Validation of a High-Performance Liquid Chromatography Ultraviolet Method for Lapatinib Quantification in Human Plasma. : A selective and precise high-performance liquid chromatography ultraviolet method was developed and validated for the determination of lapatinib in human plasma. After protein precipitation with acetonitrile, lapatinib and sorafenib were separated using isocratic elution (on a C18 Ultrabase column using a mobile phase of acetonitrile/20 mM ammonium acetate in a proportion 53:47 (v/v) pumped at a constant flow rate of 1.2 mL/min). Quantification was performed at 260 nm. Calibration curves were linear over the range 0.2-10 µg/mL. Inter- and intraday coefficients of variation were less than 7%. The limit of detection and the lower limit of quantification were 0.1 and 0.2 µg/mL, respectively. Recoveries of lapatinib from plasma were higher than 86.7% in all cases. The assay was applied to the determination of the drug in the plasma of 2 cancer patients receiving lapatinib, 1000 and 1250 mg orally, and could be useful for therapeutic drug monitoring of lapatinib in routine clinical practice. 23410126 Genome-wide integrated analyses of androgen receptor signaling in prostate cancer based on high-throughput technology. The androgen receptor (AR) is a steroid hormone receptor that functions as a ligand-dependent transcriptional factor, which plays a key role in the development and progression of prostate cancer. Recent advancement in high throughput technologies including microarrays and deep-sequencing provides unbiased genome-wide knowledge on the AR signaling including datasets for androgen-regulated gene expression and genomic binding sites for AR. In the present review, we will briefly summarize the main features of the AR signaling as well as the individual AR target genes identified by the integration of multiple datasets in prostate cancer. Cap analysis gene expression (CAGE) is also featured as a unique transcriptome method, which particularly determines the androgen-dependent transcription start points in prostate cancer. 23689688 MPR realignment increases accuracy when measuring femoral neck anteversion angle. To compare two methods of measuring femoral neck anteversion angle (FNA): A 2D method used at Odense University Hospital until 2010, and a method labeled 3D-OUH. The latter method makes corrections to compensate for errors introduced by the individual placement of patients in the CT scanner. Twenty-six CT-examined patients were included: nine men and 17 women. The right side FNA was measured twice with each method by one observer, measuring intraobserver variability. Both methods are based on the following anatomy: femoral head center, center at the level of lesser trochanter and posterior apex of the femoral condyles. The 3D-OUH method corrects for the individual orientation of femur by realigning it prior to measurement, in accordance to Murphy et al.'s original definition of FNA. The intercondylar notch center of the knee and center at lesser trochanter was used in the realignment. The 2D method significantly overestimated FNA compared to 3D-OUH by 4.2° (95 % CI: 2.8°; 5.6°), p < 0.0001. All measurements with the 3D method needed clock-wise correction in the coronal plane, suggesting patient positioning as a consistent source of overestimation by the 2D method. The 3D-OUH method had a lower intraobserver variability with a limit of agreement (LOA) of -2.4° to 2.1° against that of the 2D method of -3.4° to 3.8° Mean anteversion was 4.2° (95 % CI: 2.8°; 5.6°) lower with the 3D-OUH method than with the 2D method. The 3D-OUH method eliminated an obvious source of error, namely the individual orientation of femur during CT-examination. Moreover, intraobserver variability was improved with the 3D-OUH method. 23778052 Can the L5178Y Tk(+/-) mouse lymphoma assay detect epigenetic silencing? The mouse lymphoma L5178Y Tk(+/-) assay is broadly used in toxicology to assess genotoxicity because of its known sensitivity to genotoxicants that act through a variety of mechanisms, which may include epigenetic DNA methylation. This brief article highlights the studies that have contributed to this conjecture and suggests an addition to the experimental design that could identify if the test substance is a potential epimutagen acting via hypermethylation. 23903335 The Role of the Major Histocompatibility Complex Region in Cognition and Brain Structure: A Schizophrenia GWAS Follow-Up. OBJECTIVE The authors investigated the effects of recently identified genome-wide significant schizophrenia genetic risk variants on cognition and brain structure. METHOD A panel of six single-nucleotide polymorphisms (SNPs) was selected to represent genome-wide significant loci from three recent genome-wide association studies (GWAS) for schizophrenia and was tested for association with cognitive measures in 346 patients with schizophrenia and 2,342 healthy comparison subjects. Nominally significant results were evaluated for replication in an independent case-control sample. For SNPs showing evidence of association with cognition, associations with brain structural volumes were investigated in a large independent healthy comparison sample. RESULTS Five of the six SNPs showed no significant association with any cognitive measure. One marker in the major histocompatibility complex (MHC) region, rs6904071, showed independent, replicated evidence of association with delayed episodic memory and was significant when both samples were combined. In the combined sample of up to 3,100 individuals, this SNP was associated with widespread effects across cognitive domains, although these additional associations were no longer significant after adjusting for delayed episodic memory. In the large independent structural imaging sample, the same SNP was also associated with decreased hippocampal volume. CONCLUSIONS The authors identified a SNP in the MHC region that was associated with cognitive performance in patients with schizophrenia and healthy comparison subjects. This SNP, rs6904071, showed a replicated association with episodic memory and hippocampal volume. These findings implicate the MHC region in hippocampal structure and functioning, consistent with the role of MHC proteins in synaptic development and function. Follow-up of these results has the potential to provide insights into the pathophysiology of schizophrenia and cognition. 23868487 Developmental milestones across the programmatic life cycle: Implementing the CDC's Colorectal Cancer Screening Demonstration Program. In 2005 through 2009, the Centers for Disease Control and Prevention (CDC) funded 5 sites to implement a colorectal cancer screening program for uninsured, low-income populations. These 5 sites composed a demonstration project intended to explore the feasibility of establishing a national colorectal cancer screening program through various service delivery models. A longitudinal, multiple case study was conducted to understand and document program implementation processes. Using metaphor as a qualitative analytic technique, evaluators identified stages of maturation across the programmatic life cycle. Analysis rendered a working theory of program development during screening implementation. In early stages, program staff built relationships with CDC and local partners around screening readiness, faced real-world challenges putting program policies into practice, revised initial program designs, and developed new professional skills. Midterm implementation was defined by establishing program cohesiveness and expanding programmatic reach. In later stages of implementation, staff focused on sustainability and formal program closeout, which prompted reflection about personal and programmatic accomplishments. Demonstration sites evolved through common developmental stages during screening implementation. Findings elucidate ways to target technical assistance to more efficiently move programs along their maturation trajectory. In practical terms, the time and cost associated with guiding a program to maturity may be potentially shortened to maximize return on investment for both organizations and clients receiving service benefits. Cancer 2013;119(15 suppl):2926-39. © 2013 American Cancer Society. 23749233 Facile Fabrication of Hierarchically Porous CuFe2O4 Nanospheres with Enhanced Capacitance Property. In this work, CuFe2O4 nanospheres with hierarchically porous structure have been synthesized via a facile solvothermal procedure. The superstructures consist of the textured aggregations of nanocrystals with high specific surface area, pore volume, and uniform pore size distribution.To figure out the formation mechanism, we discussed in detail the effects of a series of experimental parameters, including the concentrations of the precipitation agent, stabilizer agent, and reaction temperature and time on the size and morphology of the resulting products. Furthermore, the electrochemical properties of CuFe2O4 nanospheres were evaluated by cyclic voltammetry and galvanostatic charge-dischrge studies. The results demonstrate that the as-prepared CuFe2O4 nanospheres are excellent electrode material in supercapacitor with high specific capacitance and good retention. The hierarchically CuFe2O4 nanospheres show the highest capacitance of 334F/g, and 88% of which can still be maintained after 600 charge-discharge cycles. 23625663 Modelling the effects of climate change on the distribution and production of marine fishes: accounting for trophic interactions in a dynamic bioclimate envelope model. Climate change has already altered the distribution of marine fishes. Future predictions of fish distributions and catches based on bioclimate envelope models are available, but to date they have not considered interspecific interactions. We address this by combining the species-based Dynamic Bioclimate Envelope Model (DBEM) with a size-based trophic model. The new approach provides spatially and temporally resolved predictions of changes in species' size, abundance and catch potential that account for the effects of ecological interactions. Predicted latitudinal shifts are, on average, reduced by 20% when species interactions are incorporated, compared to DBEM predictions, with pelagic species showing the greatest reductions. Goodness-of-fit of biomass data from fish stock assessments in the North Atlantic between 1991 and 2003 is improved slightly by including species interactions. The differences between predictions from the two models may be relatively modest because, at the North Atlantic basin scale, (i) predators and competitors may respond to climate change together; (ii) existing parameterization of the DBEM might implicitly incorporate trophic interactions; and/or (iii) trophic interactions might not be the main driver of responses to climate. Future analyses using ecologically explicit models and data will improve understanding of the effects of inter-specific interactions on responses to climate change, and better inform managers about plausible ecological and fishery consequences of a changing environment. 23860000 Drinking water contributes to excessive iodine intake among children in Hebei, China. Background/objectives:In Hebei province, China, over six million people are potentially exposed to excessive iodine through consumption of high iodine underground drinking water and consumption of iodized salt. The aim of this study is to evaluate the contributions of drinking water and iodized salt on children's iodine nutrition in one area of Hebei province in order to refine strategies to correct the excessive iodine intake in these areas.Subjects/methods:To investigate the relationships between iodine content in water, iodized salt and urinary iodine content (UIC) in children (8-10 years), we randomly sampled three towns with a known median water iodine (MWI) of 150-300 μg/l in Hengshui City, Hebei province and collected water, salt and urine samples.Results:The median UIC was 518.1 μg/l, the overall MWI was 247.0 μg/l, and 83% of children sampled were found to have urinary iodine concentrations higher than the WHO criterion of 300 μg/l. There was a significant and positive correlation between the median UIC of the children and the MWI in the 12 villages where the children lived (Spearman R=0.79, P=0.002), but the UIC was not significantly correlated with the median salt intake (MSI) (Spearman R=-0.17, P=0.6). A multiple linear regression analysis indicated that 68.7% of the variability in median UIC is associated with variability in MWI in the 12 villages.Conclusions:Iodine in drinking water was identified to be the key contributor to this excessive iodine in children indicating that in these areas, intervention should focus on providing alternative drinking water supplies.European Journal of Clinical Nutrition advance online publication, 17 July 2013; doi:10.1038/ejcn.2013.127. 23925863 The impact of poultry litter application on sediment chemistry of the Broadkill River estuary system, Delaware. This project examined the impact of long-term poultry litter application on the chemical signatures of As, Cu, Zn, and P in stream sediments of the Broadkill River watershed within the Delmarva Peninsula, a region of intense poultry production. Thirty-seven sediment samples were collected from Broadkill River drainage systems and analyzed for litter-derived elements (As, Cu, Zn, P) and basic soil parameters such as particle size distribution, organic matter, and soluble salts. Results showed that concentrations of elements in stream sediments are approximately log-normally distributed. Spatial variability in concentrations of elements was evident, with most elements increasing in concentration and enrichment from upgradient headwaters to downgradient reaches draining predominantly agricultural areas. Results of correlation analyses showed positive significant correlation among elements; elements were also positively correlated with percent clay and silt in the sediment. Using GIS maps with overlays of hydrology and land use activities, statistical correlations between As, Cu, Zn, and P enrichment factors and land use were examined. Results showed statistically significant relationships between As, Mn, and Zn enrichment factors and residential areas within the watershed, but did not show a statistically significant relationship between element enrichment factors and agricultural land use. Factors that complicate this type of landscape-scale study include the presence of poultry processing plants, impoundments, changes in land use over time, and the influence of tides, all of which can have direct and indirect influences on element mobility. 23625986 The utility of sildenafil in pulmonary hypertension: a focus on bronchopulmonary dysplasia. The treatment of pulmonary hypertension (PH) secondary to bronchopulmonary dysplasia (BPD) in infants has evolved in recent years, improving both quality of life and survival for patients. One of the potential agents for this condition is sildenafil, a phosphodiesterase-V inhibitor with proven efficacy within the idiopathic PH population. However, only limited evidence exists for its use as either monotherapy or part of a combination approach towards the management of PH in BPD. This review summarises the evidence base for sildenafil alone and in combination with other recognised therapeutic agents for ameliorating paediatric PH in the presence of BPD. It also examines the suitability for current practice with the aim of clarifying regimens that produce improved patient outcomes. We conclude that sildenafil is both safe and effective in this utility. Doses should be started at 0.5 mg/kg every 8 h before titrating up towards 2 mg/kg every 6 h to effect reductions in pulmonary vascular resistance and arterial pressure. Evidence suggests that if continued until PH resolution, this improves survival from 61% to 81% at 12 months. Furthermore, there are also data suggesting that in treatment refractory PH cases, the addition of endothelin antagonists and prostacyclin analogues to sildenafil therapy can also be considered. 23788532 Is intracytoplasmic morphologically selected sperm injection (IMSI) beneficial in the first ART cycle? A multicentric randomized controlled trial. Intracytoplasmic morphologically selected sperm injection (IMSI), by selecting spermatozoa at high magnification improves the outcome of intracytoplasmic sperm injection (ICSI) mainly after several failures. However, only few monocentric randomized studies are available and they do not analyse results as a function of sperm characteristics. In 255 couples attempting their first assisted reproductive technology (ART) attempt for male infertility (motile sperm count <1×10(6) after sperm selection, but at least 3×10(6) spermatozoa per ejaculate to allow a detailed analysis of sperm characteristics), a prospective randomized trial was performed to compare the clinical outcomes of IMSI and ICSI and to evaluate the influence of sperm characteristics on these outcomes. IMSI did not provide any significant improvement in the clinical outcomes compared with ICSI neither for implantation (24% vs. 23%), nor clinical pregnancy (31% vs. 33%) nor live birth rates (27% vs. 30%). Moreover, the results of IMSI were similar to the ICSI ones whatever the degree of sperm DNA fragmentation, nuclear immaturity and sperm morphology. These results show that IMSI instead of ICSI has no advantage in the first ART attempts. However, this does not rule out IMSI completely and more randomized trials must be performed especially regarding patients carrying severe teratozoospermia, or high sperm DNA fragmentation levels or having previous ICSI failures. 23868131 Draft Genome Sequences of Two Yersinia pseudotuberculosis ST43 (O:1b) Strains, B-7194 and B-7195. We report the first draft genome sequences of two Yersinia pseudotuberculosis sequence type 43 (ST43) (O:1b) strains, B-7194 and B-7195, isolated in Russia. The total lengths of the assemblies are 4,427,121 bp and 4,608,472 bp, and 3,819 and 4,018 coding sequences, respectively, were predicted within the genomes. 23640503 Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age: an update. Epilepsies occur across the entire age range, and their incidence peaks in the first years of life and in the elderly. Therefore, antiepileptic drugs (AEDs) are commonly used at the extremes of age. Rational prescribing in these age groups requires not only an understanding of the drugs' pharmacodynamic properties, but also careful consideration of potential age-related changes in their pharmacokinetic profile. The present article, which updates a review published in 2006 in this journal, focuses on recent findings on the pharmacokinetics of new-generation AEDs in neonates, infants, children, and the elderly. Significant new information on the pharmacokinetics of new AEDs in the perinatal period has been acquired, particularly for lamotrigine and levetiracetam. As a result of slow maturation of the enzymes involved in glucuronide conjugation, lamotrigine elimination occurs at a particularly slow rate in neonates, and becomes gradually more efficient during the first months of life. In the case of levetiracetam, elimination occurs primarily by renal excretion and is also slow at birth, but drug clearance increases rapidly thereafter and can even double within 1 week. In general, infants older than 2-3 months and children show higher drug clearance (normalized for body weight) than adults. This pattern was confirmed in recent studies that investigated the pediatric pharmacokinetics of several new AEDs, including levetiracetam, rufinamide, stiripentol, and eslicarbazepine acetate. At the other extreme of age, in the elderly, drug clearance is generally reduced compared with younger adults because of less efficient drug-metabolizing activity, decreased renal function, or both. This general pattern, described previously for several AEDs, was confirmed in recent studies on the effect of old age on the clearance of felbamate, levetiracetam, pregabalin, lacosamide, and retigabine. For those drugs which are predominantly eliminated by renal excretion, aging-related pharmacokinetic changes could be predicted by measuring creatinine clearance (CLCR). Overall, most recent findings confirm that age is a major factor influencing the pharmacokinetic profile of AEDs. However, pharmacokinetic variability at any age can be considerable, and the importance of other factors should not be disregarded. These include genetic factors, co-morbidities, and drug interactions, particularly those caused by concomitantly administered AEDs which induce or inhibit drug-metabolizing enzymes. 23878135 Cytokine profiling reveals decreased serum levels of CCL2 in active ocular toxoplasmosis. Toxoplasma gondii infection is an important cause of ocular disease. Although parasite-mediated host cell lysis is probably the principal cause of tissue destruction in immunodeficiency states, hypersensitivity and inflammatory responses may underlie severe disease in otherwise immunocompetent individuals. The purpose of the current investigation was to study the cytokine profiles in serum from patients with ocular toxoplasmosis and to compare them with those obtained from healthy control subjects. Using a multiplex assay, we determined the serum concentration of granulocyte colony-stimulating factor (GCSF), interferon γ (IFNγ), interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, chemokine (C-C motif) ligand 2 (CCL2) and tumour necrosis factor α (TNFα) in patients with inactive ocular toxoplasmosis (n=48), active ocular toxoplasmosis (n=21), and an age-matched and sex-matched healthy control group (n=25). In a subgroup of 17 patients with active disease, a second serum sample was obtained when the disease was inactive. Cytokine profiles were correlated with disease activity, severity and visual outcome. Levels of CCL2 were significantly reduced in patients with active ocular toxoplasmosis compared to the control group (564±42 pg/mL vs 455±35 pg/mL, p<0.05). Moreover, CCL2 levels were significantly lower during active ocular toxoplasmosis compared to inactive disease (569±32 pg/mL vs 433±32 pg/mL, p<0.01). GCSF and TNFα were elevated in patients with toxoplasmosis with poor visual outcome. No significant correlations were found with specific cytokine profiles and disease severity. Decreased serum levels of CCL2 may be associated with active ocular toxoplasmosis and could therefore serve as a marker of disease activity. 23836332 Heterogeneous phenotype of human glioblastoma. In vitro study. Glioblastomas (GBMs) are the most lethal primary brain tumours. Increasing evidence shows that brain tumours contain the population of stem cells, so-called cancer stem cells (CSCs). Stem cell marker CD133 was reported to identify CSC population in GBM. Further studies have indicated that CD133 negative cells exhibiting similar properties and are able to initiate the tumour, self-renew and undergo multilineage differentiation. GBM is a highly heterogeneous tumour and may contain different stem cell populations with different functional properties. We characterized five GBM cell lines, established from surgical samples, according to the marker expression, proliferation and differentiation potential. CD133 positive cell lines showed increased proliferation rate in neurosphere condition and marked differentiation potential towards neuronal lineages. Whereas two cell lines low-expressing CD133 marker showed mesenchymal properties in vitro, that is high proliferation rate in serum condition and differentiation in mesenchymal cell types. Further, we compared therapy resistance capacity of GBM cell lines treated with hydroxyurea. Our results suggest that CSC concept is more complex than it was believed before, and CD133 could not define entire stem cell population within GBM. At least two different subtypes of GBM CSCs exist, which may have different biological characteristics and imply different therapeutic strategies. Copyright © 2013 John Wiley & Sons, Ltd. 23629394 Suicide due to four speargun shots: a case report. In the literature, only a few cases of deaths related to the use of atypical firearms are present and even more rare are cases of suicide due to multiple lesions.In the present case, the authors report a rare occurrence of suicide due to 4 speargun shots, 3 to the chest and 1 to the head.A complete forensic approach led to attribute the death to acute cardiac failure due to hemopericardium after the injury of the left coronary artery.Scene investigation and autoptic findings allowed authors to hypothesize that injury to the head was a last attempt of suicide, elapsed during the progression of cardiac tamponade.With this report, the authors would like to share knowledge with the forensic community about speargun-related lesions distinguishing them from the very similar ones produced by cold steels.It also shows how it is possible to survive for some time after being shot by such a weapon. 23884136 In-Solution Conformational Analysis of the XCYCH3 Moiety for Small Esters and Ethers with all Combinations of X, Y = O, S. Favorable steric and electrostatic fit of a ligand to a receptor is of central interest in theoretical drug design. This paper considers the effects of non-protic solvents, in comparison with the gas phase, on the preferred conformation of the XCYCH3 moiety of simple aliphatic esters and heterocyclic methyl ethers with all combinations of the X and Y atoms as oxygen and sulfur. An IEF-PCM/B97D/aug-cc-pv(t+d)z continuum dielectric solvent study in chloroform and acetonitrile explores the through-space polarization effect of the environment on the conformational preference, not affected by possible solute-solvent hydrogen bond formation. The inherently favored structure for the present molecules is important, since the hypothetical oxygen and sulfur lone-pairs point approximately in opposite directions in the cis conformation of esters, whereas the trans and gauche conformations for the methyl group in ethers define nearly parallel or perpendicular directionality for the lone pairs of the ring heteroatoms and the O or S atoms connecting to the ring. These different preferences for the studied two families of compounds allow for designing formation of hydrogen bonds with a protein in fairly different regions of the latter still within the ligand-binding cavity. For a fine-tuning of these hydrogen bonds, a replacement of an oxygen atom of the ligand by a sulfur atom could be a straightforward possibility. 23909324 Manipulating polarization and impedance signature: a reciprocal field transformation approach. We introduce a field transformation method for wave manipulation based on completely reciprocal and passive materials. While coordinate transformations in transformation optics (TO) change the size and shape of an object, field transformations give us direct control on the impedance and polarization signature of an object. Using our approach, a new type of perfect conductor can be realized to completely convert between transverse electric and transverse magnetic polarizations at any incidence angles and a perfect magnetic conductor of arbitrary shape can be mimicked by using anisotropic materials. The approach can be further combined with TO to enhance existing TO devices. For example, a dielectric cylinder can become completely transparent for both polarizations using bianisotropic materials. 23859853 Antecedents of perinatal cerebral white matter damage with and without intraventricular hemorrhage in very preterm newborns. Isolated periventricular leukomalacia, defined as periventricular leukomalacia unaccompanied by intraventricular hemorrhage, is reportedly increased in newborns with systemic hypotension and in infants who received treatment for systemic hypotension or a patent ductus arteriosus. This study sought to determine if the risk profile of one or more hypoechoic lesions unaccompanied by intraventricular hemorrhage, our surrogate for isolated periventricular leukomalacia, differs from that of one or more hypoechoic lesions preceded or accompanied by intraventricular hemorrhage. We compared extremely preterm infants (i.e., gestation 23-27 weeks) with each of these entities to 885 extremely preterm infants who had neither an isolated hypoechoic lesion nor a hypoechoic lesion preceded or accompanied by intraventricular hemorrhage. The risk of a hypoechoic lesion with intraventricular hemorrhage (N = 61) was associated with gestation <25 weeks, high Score for Acute Neonatal Physiology, early recurrent or prolonged acidemia, analgesic exposure, and mechanical ventilation 1 week after birth. In this large, multicenter sample of extremely low gestational age newborns, the risk profile of a hypoechoic lesion unaccompanied by intraventricular hemorrhage differed from that of a hypoechoic lesion with intraventricular hemorrhage. This suggests that hypoechoic lesions accompanied or preceded by intraventricular hemorrhage (our surrogate for periventricular hemorrhagic infarction) may have a different causal pathway than hypoechoic lesions without intraventricular hemorrhage, our surrogate for periventricular leukomalacia. 23499419 Safety and feasibility of femoral catheters during physical rehabilitation in the intensive care unit. Femoral catheters pose a potential barrier to early rehabilitation in the intensive care unit (ICU) due to concerns, such as catheter removal, local trauma, bleeding, and infection. We prospectively evaluated the feasibility and safety of physical therapy (PT) in ICU patients with femoral catheters. We evaluated consecutive medical ICU patients who received PT with a femoral venous, arterial, or hemodialysis catheter(s) in situ. Of 1074 consecutive patients, 239 (22%) received a femoral catheter (81% venous, 29% arterial, 6% hemodialysis; some patients had >1 catheter). Of those, 101 (42%) received PT interventions, while the catheter was in situ, for a total of 253 sessions over 210 medical ICU (MICU) days. On these 210 MICU days, the highest daily activity level achieved was 49 (23%) standing or walking, 57 (27%) sitting, 25 (12%) supine cycle ergometry, and 79 (38%) in-bed exercises. During 253 PT sessions, there were no catheter-related adverse events giving a 0% event rate (95% upper confidence limit of 2.1% for venous catheters). Physical therapy interventions in MICU patients with in situ femoral catheters appear to be feasible and safe. The presence of a femoral catheter should not automatically restrict ICU patients to bed rest. 23867366 Carbon Dioxide Insufflation During Endoscopic Retrograde Cholangiopancreatography: A Review and Meta-Analysis. The role of carbon dioxide (CO2) insufflation during endoscopic retrograde cholangiopancreatography (ERCP) is debated. A meta-analysis was performed to evaluate the efficacy and safety of CO2 insufflation for ERCP. Searches were conducted in multiple databases composed of Pub-Medline, EMBASE, the Cochrane Library, science citation index expanded, Google scholar, and CNKI China series full-text database. Outcome measurements are listed below: ERCP procedural data, post-ERCP abdominal discomfort, radiographic evaluation of bowel gas volume, and CO2 safety data concerning CO2 elimination. Seven published randomized clinical trials involving 756 patients fulfilling the inclusion criteria were selected for meta-analysis, almost all of high quality. The incidence of ERCP-related complications was reduced by CO2 insufflation, so were the events of 1-hour, 3-hour, and 6-hour post-ERCP abdominal pain, based on their corresponding statistical results. Besides, CO2 insufflation was associated with less gas volume in the bowel lumen after the procedure. There were no significant differences between CO2 and air insufflation in total procedure time, the success rate of selective cannulation, post-ERCP abdominal distension, respectively. Subsequent sensitivity and subgroup analyses produced conflicting results. Compared with air insufflation, CO2 insufflation during ERCP reduces post-ERCP abdominal pain, post-ERCP bowel remnant gas volume, and ERCP-related complications, without clinically significant systematic CO2 retention. 23703457 PET/MR in prostate cancer: technical aspects and potential diagnostic value. PET/MR is a new multimodal imaging technique that is expected to improve diagnostic performance of imaging in conditions in which assessment of changes in soft tissue is important such as prostate cancer. Despite substantial changes in PET technology compared to PET/CT, initial studies have demonstrated that integrated PET/MR provides comparable image quality to that of PET/CT, retaining PET quantification efficacy. In this review we briefly describe technological changes compared to PET/CT that made integrated PET/MR possible, propose acquisition protocols for evaluation of prostate cancer with this new multimodal approach, present initial results concerning the application of PET/MR in prostate cancer, and outline the potential for further clinical applications, focusing on potential incremental value compared to present diagnostic performance. 22796337 Emerging role of AMP-activated protein kinase in endocrine control of metabolism in the liver. This review summarizes the emerging role of AMP-activated protein kinase (AMPK) in mediating endocrine regulation of metabolic fluxes in the liver. There are a number of hormones which, when acting on the liver, alter AMPK activation. Here we describe those hormones associated with activation and de-activation of AMPK and the potential mechanisms for changes in AMPK activation state. The actions of these hormones, in many cases, are consistent with downstream effects of AMPK signaling thus strengthening the circumstantial case for AMPK-mediated hormone action. In recent years, genetic mouse models have also been used in an attempt to establish the role of AMPK in hormone-stimulated metabolism in the liver. Few experiments have, however, firmly established a causal relationship between hormone action at the liver and AMPK signaling. 23834457 Effect of a mixture of bovine milk oligosaccharides, Lactobacillus rhamnosus NCC4007 and long-chain polyunsaturated fatty acids on catch-up growth of intra-uterine growth-restricted rats. To investigate the effect of a nutritional mixture (bovine milk oligosaccharides, Lactobacillus rhamnosus NCC4007, arachidonic and docosahexaenoic acid) on growth of intrauterine growth-restricted (IUGR) rats. IUGR was induced by maternal food restriction. The offspring (males and females) were assigned to: REF (non-IUGR, no mixture), IUGRc (IUGR, no mixture), or IUGRmx (IUGR, mixture). The mixture was given from day 7 to day 58, when tissues and plasma from half of the animals were collected for hormones, metabolites and microarray analysis. The rest received a high-fat diet (HFD) until day 100. Glucose tolerance was measured at 56 and 98 days, and body fat content at 21, 52 and 97 days. IUGRmx had the greatest growth during lactation, but from day 22 to day 54, both IUGR groups gained less body weight than the REF (P < 0.05). In the short-term (58 days), IUGRmx tended to be longer (P = 0.06) and had less body fat (P = 0.03) than IUGRc. These differences were not seen after HFD. Microarray analysis of hepatic mRNA expression at 58 and 100 days revealed a gender-dependent treatment effect, and expression of genes related to lipid metabolism was the most affected. Twelve of these genes were selected for studying differences in DNA methylation in the promoter region, for some, we observed age- and gender-related differences but none because of treatment. The nutritional intervention promoted catch-up growth and normalized excessive adiposity in IUGR animals at short-term. The benefits did not extend after a period of HFD. IUGR and early diet had gender-dependent effects on hepatic gene expression. 23872896 Visible light photocatalytic water disinfection and its kinetics using Ag-doped titania nanoparticles. The UN estimated about five million deaths every year due to water-borne diseases, accounting from four billion patients. Keeping in view, the ever increasing health issues and to undermine this statistics, a reliable and sustainable water-treatment method has been developed using visible light for water treatment. titania nanoparticles (NPs) have been synthesized successfully by a more applicable method Viz: liquid impregnation (LI) method. The bacterial death rate by photocatalysis under visible light was studied by employing a typical fluorescent source and was found to follow pseudo first-order reaction kinetics. The nanoparticles were characterized using X-ray diffraction (XRD), scanning electron microscopy, and energy-dispersive X-ray spectroscopy to deduce their size range, surface morphology, and elemental compositions, respectively. Among all the prepared grades, 1 % Ag-TiO2 was found to be a very effective photocatalytic agent against Escherichia coli. The resulted photoinactivated data were also evaluated by different empirical kinetic models for bacterial inactivation. Hom, Hom-power, Rational, and Selleck models were not able to explain the disinfection kinetics but modified-Hom model fitted best with the experimentally obtained data by producing a shoulder, log-linear, and a tail region. 23360249 Parallel nanometric 3D tracking of intracellular gold nanorods using multifocal two-photon microscopy. We report a novel technique for long-term parallel three dimensional (3D)-tracking of gold nanorods in live cells with nanometer resolution. Gold nanorods feature a strong plasmon-enhanced two-photon luminescence, can be easily functionalized, and have been shown to be nontoxic. These properties make gold nanorods very suitable for in vivo two-photon luminescence microscopy. By rapid multifocal scanning, we combine the advantages of 3D molecular tracking methods using wide-field imaging with the advantages of two-photon microscopy. Isolated gold nanorods can be localized with a resolution of 4 nm in the xy-plane and 8 nm in the z-direction. The polarization-dependence of the two-photon luminescence signal can be used to resolve the angular orientation, even when two gold nanorods are separated by less than the diffraction limit. Individual nanorods in live U2OS cells could be followed in 3 dimensions for over 30 min, with a photon noise limited accuracy, and a time resolution of 50 ms in 2D and 500 ms in 3D. 23870484 Release and uptake of volatile organic compounds by human hepatocellular carcinoma cells (HepG2) in vitro. Volatile organic compounds (VOCs) emitted by human body offer a unique insight into biochemical processes ongoing in healthy and diseased human organisms. Unfortunately, in many cases their origin and metabolic fate have not been yet elucidated in sufficient depth, thus limiting their clinical application. The primary goal of this work was to identify and quantify volatile organic compounds being released or metabolized by HepG2 hepatocellular carcinoma cells. The hepatocellular carcinoma cells were incubated in specially designed head-space 1-L glass bottles sealed for 24 hours prior to measurements. Identification and quantification of volatiles released and consumed by cells under study were performed by gas chromatography with mass spectrometric detection (GC-MS) coupled with head-space needle trap device extraction (HS-NTD) as the pre-concentration technique. Most of the compounds were identified both by spectral library match as well as retention time comparison based on standards. A total of nine compounds were found to be metabolised and further twelve released by the cells under study (Wilcoxon signed-rank test, p<0.05). The former group comprised 6 aldehydes (2-methyl 2-propenal, 2-methyl propanal, 2-ethylacrolein, 3-methyl butanal, n-hexanal and benzaldehyde), n-propyl propionate, n-butyl acetate, and isoprene. Amongst the released species there were five ketones (2-pentanone, 3-heptanone, 2-heptanone, 3-octanone, 2-nonanone), five volatile sulphur compounds (dimethyl sulfide, ethyl methyl sulfide, 3-methyl thiophene, 2-methyl-1-(methylthio)- propane and 2-methyl-5-(methylthio) furan), n-propyl acetate, and 2-heptene. The emission and uptake of the aforementioned VOCs may reflect the activity of abundant liver enzymes and support the potential of VOC analysis for the assessment of enzymes function. 23793800 Effect of moisture, organic matter, microbial population and fortification level on dissipation of pyraclostrobin in soils. The dissipation of pyraclostrobin, a strobilurin fungicide, in soil was found to be influenced by soil moisture, organic matter content and microbial population. Among the different moisture regimes, dissipation was faster under submerged condition (T1/2 10 days) followed by field capacity (T1/2 28.7 days) and in dry soil (T1/2 41.8 days). Use of sludge at 5 % level to Inceptisol favoured a faster dissipation of pyraclostrobin, whereas a slower rate of dissipation was observed in partial organic matter removed soil as compared to normal soil. Slower rate of dissipation was also observed in sterile soil (T1/2 47 days) compared to normal soil. Pyraclostrobin dissipated faster in Vertisol (T1/2 21.8 days) than in Inceptisol (T1/2 28.7 days). No significant difference in the dissipation rate was observed at 1 and 10 Î¼g g(-1) fortification levels. 23814675 Rhinovirus-Infected Epithelial Cells Produce More IL-8 and RANTES Compared With Other Respiratory Viruses. The environmental factors human rhinoviruses (HRVs) and house dust mites (HDMs) are the most common causes of acute exacerbations of asthma. The aim of this study was to compare the chemokine production induced by HRVs in airway epithelial cells with that induced by other respiratory viruses, and to investigate synergistic interactions between HRVs and HDMs on the induction of inflammatory chemokines in vitro. A549 human airway epithelial cells were infected with either rhinovirus serotype 7, respiratory syncytial virus (RSV)-A2 strain, or adenovirus serotype 3 and analyzed for interleukin (IL)-8 and regulated on activation, normal T-cell expressed and secreted (RANTES) release and mRNA expression. Additionally, activation of nuclear factor (NF)-κB and activator protein (AP)-1 were evaluated. The release of IL-8 and RANTES was also measured in cells stimulated simultaneously with a virus and the HDM allergen, Der f1. HRV caused greater IL-8 and RANTES release and mRNA expression compared with either RSV or adenovirus. NF-κB and AP-1 were activated in these processes. Cells incubated with a virus and Der f1 showed an increased IL-8 release. However, compared with cells incubated with virus alone as the stimulator, only HRV with Der f1 showed a statistically significant increase. IL-8 and RANTES were induced to a greater extent by HRV compared with other viruses, and only HRV with Der f1 acted synergistically to induce bronchial epithelial IL-8 release. These findings may correspond with the fact that rhinoviruses are identified more frequently than other viruses in cases of acute exacerbation of asthma. 23793604 Functional MDM4 rs4245739 genetic variant, alone and in combination with P53 Arg72Pro polymorphism, contributes to breast cancer susceptibility. The oncoprotein MDM4 plays an essential role in P53 tumor suppressor pathway through negative regulation of P53 function. It has been reported that the rs4245739 A > C polymorphism located in the MDM4 3'-untranslated region creates a miR-191 target site and results in decreased MDM4 expression. Therefore, we investigated the association of the MDM4 rs4245739 polymorphism as well as the P53 Arg72Pro genetic variant with the breast cancer risk. Genotypes were determined in two independent case-control sets consisting of 1100 breast cancer cases and 1400 controls from two regions of China. Odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated by logistic regression. Our results demonstrated that the MDM4 rs4245739 AC and CC genotypes were significantly associated with decreased breast cancer risk compared to the AA genotype in both the case-control sets (Jinan set: OR = 0.55, 95 % CI 0.40-0.76, P = 2.3 Ã— 10(-4); Huaian set: OR = 0.41, 95 % CI 0.25-0.67, P = 3.1 Ã— 10(-4)). The P53 Arg/Pro genotype or Pro/Pro genotype was significantly associated with an increased risk of developing breast cancer, compared to the P53 Arg/Arg genotype in both the case-control sets (all P < 0.05). Interestingly, we observed a combinational effect between MDM4 rs4245739 and P53 Arg72Pro variants in attenuating breast cancer risk, highlighting the importance of the P53 tumor suppressor pathway genes during malignant transformation. Our results also support the hypothesis that genetic variants interrupting miRNA-mediated gene regulation might be important genetic modifiers of breast cancer risk. 23440358 Sclerosing angiomatoid nodular transformation of the spleen related to IgG4-associated disease: report of a case. Sclerosing angiomatoid nodular transformation (SANT) of the spleen is a rare benign vascular mass, with fewer than 100 cases documented. It is generally recognized as a vascular lesion that develops in the red pulp of the spleen; however, its pathogenesis is not clearly defined. We report a case of SANT of the spleen, which presents evidence to support the hypothesis that this disease entity is associated with IgG4-associated disease. Microscopically, the tumor was composed of multiple vascular structures separated by fibrous connective tissue and immunohistochemical examination revealed positive staining for CD31, CD34, factor VIII, and IgG4. Further research based on large number of cases is warranted to clarify the pathogenesis of this tumor. 23524149 Efficacy of intraoperative dexmedetomidine infusion on emergence agitation and quality of recovery after nasal surgery. /st> Emergence agitation is common after nasal surgery. We investigated the effects of intraoperative dexmedetomidine infusion on emergence agitation and quality of recovery after nasal surgery in adult patients. /st> One hundred patients undergoing nasal surgery were randomized into two groups. The dexmedetomidine group (Group D, n=50) received dexmedetomidine infusion at a rate of 0.4 μg kg(-1) h(-1) from induction of anaesthesia until extubation, while the control group (Group C, n=50) received volume-matched normal saline infusion as placebo. Propofol (1.5-2 mg kg(-1)) and fentanyl (1 μg kg(-1)) were used for induction of anaesthesia, and desflurane was used for maintenance of anaesthesia. The incidence of agitation, haemodynamic parameters, and recovery characteristics were evaluated during emergence. A 40-item quality-of-recovery questionnaire (QoR-40) was provided to patients 24 h after surgery. /st> The incidence of agitation was lower in Group D than Group C (28 vs 52%, P=0.014). Mean arterial pressure and heart rate were more stable in Group D than in Group C during emergence (P<0.05). Time to extubation, bispectral index, and respiratory rate at extubation were similar between the groups. Global QoR-40 score at 24 h after surgery was higher in Group D (median [range], 183 [146 -198]) compared with Group C (178 [133-196]) (P=0.041). /st> Intraoperative infusion of dexmedetomidine provided smooth and haemodynamically stable emergence. It also improved quality of recovery after nasal surgery. 23542729 Liver X receptors: Emerging therapeutic targets for Alzheimer's disease. Alzheimer's disease (AD) is a complex neurodegenerative disorder, typified by the pathological accumulation of ß-amyloid peptides (Aß) and neurofibrillary tangles within the brain, culminating to cognitive impairment. Epidemiological and biochemical data have suggested a link between cholesterol content, APP (amyloid precursor protein) processing, Aß, inflammation and AD. The intricacy of the disease presents considerable challenges for the development of newer therapeutic agents. Liver X receptors (LXRa and LXRß) are oxysterol activated nuclear receptors that play essential role in lipid and glucose homeostasis, steroidogenesis and inflammatory responses. LXR signalling impacts the development of AD pathology through multiple pathways. Reports indicate that genetic loss of either lxra or lxrß in APP/PS1 transgenic mice results in increased amyloid plaque load. Studies also suggest that ligand activation of LXRs in Tg2576 mice enhanced, the expression of genes linked with cholesterol efflux e.g. apoe, abca-1, down regulated APP processing and Aß production with significant improvement in memory functions. LXR agonists have also depicted to inhibit neuroinflammation through modulation of microglial phagocytosis and by repressing the expression of cox2, mcp1 and iNos in glial cells. This review summarizes in brief the biology of LXRs, with an emphasis on their probable pathophysiological mechanisms that may elicit the defending role of these receptors in brains of AD patients. 23771521 Grape seeds: ripe for cancer chemoprevention. A wide variety of phytochemicals, mostly flavonoids or polyphenolics, have been shown to possess anticarcinogenic activities. Among these are the grape seed proanthocyanidins (GSPs), which are the active ingredients of grape seed extract (GSE). Substantial in vitro and preclinical in vivo studies have shown the chemopreventive efficacy of GSPs against various forms of cancers in different tumor models. In this issue of the journal, Derry and colleagues show that administration of GSE in the diet reduces azoxymethane-induced colon carcinogenesis in an A/J mouse model. The results of this innovative and comprehensive study indicate that inhibition of azoxymethane-induced colon cancer by dietary GSE is mediated through the induction of apoptosis that is associated with alterations in microRNA (miRNA) and cytokine expression profiles as well as β-catenin signaling. Notably, the demonstration that miRNA expression is affected by dietary GSE suggests a novel underlying mechanism for the chemopreventive action of GSE in colon cancer and, potentially, other cancers. 23823328 Unique structural, dynamical, and functional properties of k11-linked polyubiquitin chains. K11-linked polyubiquitin chains play important signaling and regulatory roles in both degradative and nonproteolytic pathways in eukaryotes. To understand the structural basis of how these chains are recognized and distinguished from other polyubiquitins, we determined solution structures of K11-linked diubiquitin (K11-Ub2) in the absence and presence of salt. These structures reveal that K11-Ub2 adopts conformations distinct from those of K48-linked or K63-linked chains. Importantly, our solution NMR and SANS data are inconsistent with published crystal structures of K11-Ub2. We found that increasing salt concentration compacts K11-Ub2 and strengthens interactions between the two Ub units. Binding studies indicate that K11-Ub2 interacts with ubiquitin-receptor proteins from both proteasomal and nonproteasomal pathways but with intermediate affinity and different binding modes than either K48-linked or K63-linked diubiquitin. Our data support the hypothesis that polyubiquitin chains of different linkages possess unique conformational and dynamical properties, allowing them to be recognized differently by downstream receptor proteins. 23845879 Disconnected panreatic duct syndrome. Disconnected pancreatic duct syndrome (DPDS) is characterized by disruption of the main pancreatic duct with a loss of continuity between the pancreatic duct and the gastrointestinal tract caused by ductal necrosis after severe acute necrotizing pancreatitis treated medically, by percutaneous drainage, or necrosectomy. There are no clear epidemiological data on the real incidence of DPDS; approximately 10 to 30% of patients with severe acute pancreatitis could develop DPDS. The existing literature is scarce, the terminology is confusing and therapeutic algorithms are not clearly defined. Both endoscopic and surgical management have been described. We have performed a sytematic review of the literature on DPDS. 23510409 Allopregnanolone induces a diurnally dependent hyperphagic effect and alters feeding latency and duration in male Wistar rats. Gamma-aminobutyric acid (GABA)-ergic transmission from the hypothalamus is essential for normal feeding regulation, and hyperphagia can be induced by local application of GABAA -receptor agonists to different feeding-associated brain areas. The food intake in rats varies diurnally and that may influence the effect of GABAA -receptor active compounds. The progesterone metabolite allopregnanolone is a highly potent endogenous positive modulator of the GABAA receptor. Therefore, it is easy to envisage that allopregnanolone would have a hyperphagic effect, but earlier reports in rat have given ambiguous results. However, a contributing factor for the discrepancy may be the time point of the diurnal cycle in which the experiments were performed. The aim of this study was to investigate the effect of allopregnanolone on intake of standard chow in male Wistar rats at different time points of the day. Chow intake was measured after acute administration of allopregnanolone, and feeding behaviour was analysed to detect meal patterns. We found that allopregnanolone increased chow intake by up to four times in the dark part of the 24-h cycle. The rats ate significantly more, and the effect of allopregnanolone was more prominent in the active (dark) compared with the inactive (light) period. Allopregnanolone also reduced feeding latency and prolonged the meal duration compared with vehicle. Allopregnanolone seems to act at several levels of feeding regulation, that is, to initiate feeding and to prolong the duration of a meal, thereby increasing the meal size, especially in the dark period of the 24-h cycle. 23932550 New LDL-Cholesterol Lowering Therapies: Pharmacology, Clinical Trials, and Relevance to Acute Coronary Syndromes. Reduction in plasma low-density lipoprotein cholesterol (LDL-C) is a fundamental treatment for the prevention of acute coronary syndromes (ACS). Although statin therapy confers significant protection against ACS in both primary and secondary prevention, a considerable residual risk remains after intensive therapy. In addition, a significant proportion of high-risk patients do not achieve the optimal LDL-C goal recommended in the current guidelines (<1.8 mmol/L). Hence, novel LDL-C-lowering agents that act via mechanisms distinct from HMG-CoA reductase inhibition are under investigation. We reviewed the recent literature on the development of novel LDL-C-lowering agents that could potentially be used as an alternative or adjunct to statin therapy in high-risk coronary patients. PubMed and Scopus databases were searched to retrieve studies on the efficacy and/or tolerability of novel LDL-C-lowering agents in animals and humans. Agents that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein (apo) B, and microsomal triglyceride transfer protein (MTTP) are the most promising therapies. Inhibition of PCSK9, apoB, and MTTP has been achieved mostly via fully humanized monoclonal antibodies (mAbs), antisense oligonucleotides, and synthetic compounds, respectively. PCSK9 inhibitors increase the hepatic uptake of LDL-C, while apoB and MTTP inhibitors decrease the synthesis and secretion of apoB-containing lipoproteins. These 3 mechanisms lead to marked reductions in plasma LDL-C in patients with hypercholesterolemia at risk for ACS, particularly those with familial hypercholesterolemia. Moreover, these agents can exert additional benefits by decreasing plasma levels of apoB, triglycerides, and lipoprotein(a). Mipomersen and lomitapide have been approved by the United States Food and Drug Administration (US FDA) for use in patients with homozygous familial hypercholesterolemia. PCSK9 inhibitors are currently under final evaluation in clinical outcomes studies and are anticipated to find wide application either as monotherapy or as an adjunct to statins. A main safety concern is the risk for hepatic steatosis with apoB and MTTP inhibitors, which needs to be explored in prospective, long-term trials. PCSK9, apoB, and MTTP inhibitors can exert potent reductions in plasma LDL-C and apoB concentrations, either as monotherapy or in combination with statins. These effects are particularly relevant to high-risk individuals with marked hypercholesterolemia, such as those with familial hypercholesterolemia. Although the use of mipomersen and lomitapide is limited to severe familial hypercholesterolemia as a replacement for LDL-apheresis, PCSK9 inhibitors are likely to be more widely prescribed in patients at high risk for CVD, especially those who are resistant to or intolerant of high-intensity statin therapy. PCSK9 mAbs are efficacious and have an excellent safety profile, but their long-term impact on cardiovascular events is currently under investigation. Whether PCSK9 mAbs decrease the rates of recurrent cardiovascular events within 3 months following ACS is questionable; however, these agents, unlike statins, may not have pleiotropic benefits on the unstable plaque. 23884224 B-cell activating factor promoter polymorphisms in egyptian patients with systemic lupus erythematosus. Background Systemic lupus erythematosus (SLE) is a heterogonous autoimmune disease involving most immune cells. Studies have revealed a number of cytokine pathways that play important roles in the disease process. Among these is B- cell activating factor (BAFF), which regulates B-cell maturation, survival, and function. Objective To study the association between BAFF promoter polymorphism and systemic lupus erythematosus (SLE). Methods Single nucleotide polymorphisms in the BAFF promoter region; -2841 (T>C), -2701 (T>A), -871 (C>T) were investigated by PCR-RFLP genotyping in fifty Egyptian SLE patients and thirty normal controls. Results The frequency of mutant alleles of both -871C>T and -2701 T>A was higher among SLE patients than controls (p-value <0.001 and 0.000 respectively). There was a highly significant relationship between -871 C>T polymorphism and SLE (P<0.001), with the sensitivity and the specificity of the test being 100 %, and 70%, respectively. Patients expressing the -2701 T>A allele were seven times more prone to SLE than those with the T/T wild genotype (sensitivity of the test = 78%, specificity = 66.7%, odds ratio = 7.09, C.I at 95% = 2.29-22.64). Conclusion Polymorphisms in the regulatory region of the BAFF gene do contribute to the susceptibility to SLE in Egyptian patients, which indicates BAFF as a potential therapeutic target. 23147807 Toxicity of diesel contaminated soils to the subantarctic earthworm Microscolex macquariensis. Several fuel spills have occurred on subantarctic Macquarie Island (54°30' S 158°57' E) associated with storing fuel and generating power for the island's research station. The Australian Antarctic Division began full-scale, on-site remediation of these sites in 2009. To develop appropriate target concentrations for remediation, acute and chronic tests were developed with the endemic earthworm, Microscolex macquariensis, using avoidance, survival, and reproduction as endpoints. Uncontaminated low (3%), medium (11%), and high (38-48%) carbon content soils from Macquarie Island were used to examine the influence of soil carbon on toxicity. Soils were spiked with Special Antarctic Blend (SAB) diesel and used either immediately to simulate a fresh spill or after four weeks to simulate an aged spill. Earthworms were sensitive to fresh SAB, with significant avoidance at 181 mg/kg; acute 14-d survival median lethal concentration (LC50) of 103 mg/kg for low carbon soil; and juvenile production median effective concentration (EC50) of 317 mg/kg for high carbon soil. Earthworms were less sensitive to aged SAB than to fresh SAB in high carbon soil for juvenile production (EC50 of 1,753 and 317 mg/kg, respectively), but were more sensitive for adult survival (LC50 of 2,322 and 1,364 mg/kg, respectively). Using M. macquariensis as a surrogate for soil quality, approximately 50 to 200 mg SAB/kg soil would be a sufficiently protective remediation target. 23379996 DNA delivery with hyperbranched polylysine: A comparative study with linear and dendritic polylysine. PEI and polylysine are among the most investigated synthetic polymeric carriers for DNA delivery. Apart from their practical use, these 2 classes of polymers are also of interest from a fundamental point of view as they both can be prepared in different architectures (linear and branched/dendritic) and in a wide range of molecular weights, which is attractive to establish basic structure-activity relationships. This manuscript reports the results of an extensive study on the influence of molecular weight and architecture of a library of polylysine variants that includes linear, dendritic and hyperbranched polylysine. Hyperbranched polylysine is a new polylysine-based carrier that is structurally related to dendritic polylysine but possesses a randomly branched structure. Hyperbranched polylysine is attractive as it can be prepared in a one-step process on a large scale. The performance of these 3 classes of polylysine analogs was evaluated by assessing eGFP and IgG production in transient gene expression experiments with CHO DG44 cells, which revealed that protein production generally increased with increasing molecular weight and that at comparable molecular weight, the hyperbranched analogs were superior as compared to the dendritic and linear polylysines. To understand the differences between the gene delivery properties of the hyperbranched polylysine analogs on the one hand and the dendritic and linear polylysines on the other hand, the uptake and trafficking of the corresponding polyplexes were investigated. These experiments allowed us to identify (i) polyplex-external cell membrane binding, (ii) free, unbound polylysine coexisting with polyplexes as well as (iii) polymer buffer capacity as three possible factors that may contribute to the superior transfection properties of the hyperbranched polylysines as compared to their linear and dendritic analogs. Altogether, the results of this study indicate that hyperbranched polylysine is an interesting, alternative synthetic gene carrier. Hyperbranched polylysine can be produced at low costs and in large quantities, is partially biodegradable, which may help to prevent cumulative cytotoxicity, and possesses transfection properties that can approach those of PEI. 23884123 In Vitro Antimicrobial Activity of Plant-Derived Diterpenes against Bovine Mastitis Bacteria. We evaluated the antibacterial activity of three diterpenes isolated from natural sources against a panel of microorganisms responsible for bovine mastitis. ent-Copalic acid (CA) was the most active metabolite, with promising MIC values (from 1.56 to 6.25 µg mL-1) against Staphylococcus aureus (ATCC and clinical isolate), Staphylococcus epidermidis, Streptococcus agalactiae, and Streptococcus dysgalactiae. We conducted time-kill assays of CA against S. aureus, a commensal organism considered to be a ubiquitous etiological agent of bovine mastitis in dairy farms worldwide. In the first 12 h, CA only inhibited the growth of the inoculums (bacteriostatic effect), but its bactericidal effect was clearly noted thereafter (between 12 and 24 h). In conclusion, CA should be considered for the control of several Gram-positive bacteria related to bovine mastitis. 23857644 Anticardiolipin in Porphyromonas gingivalis Antisera Causes Fetal Loss in Mice. β2-glycoprotein I (β2GPI)-dependent anticardiolipin autoantibodies (aCl) are associated with thrombosis and fetal loss. Some microbial pathogens can induce pathogenic antibodies cross-reactive with β2GPI. Sera from a significant percentage of periodontitis patients contain aCl, and some periodontal pathogens contain antigens with peptide sequences having homology to β2GPI. We hypothesized that antibodies raised against P. gingivalis (aPg) contain pathogenic aCl that induce fetal resorption. We immunized mice with β2GPI, P. gingivalis W83, or an arg-gingipain-defective mutant of P. gingivalis (HF18). IgG fractions of aPg were immunoabsorbed to remove aCl-like antibodies (abs-aPg). IgG fractions were administered intravenously into tail veins of mated BALB/c females at day 0 of pregnancy. At day 15, the proportions of fetal resorptions were evaluated. The prevalence of fetal loss was significantly greater in the aPg group than in the control IgG group (21.2% vs. 5.3%, p = .001), and greater in the aPg group than in the abs-aPg group (21.2% vs. 12%, p < .05). There were no fetal resorptions observed in the aPgHF18 group (p = .0005 compared with aPg, p = .17 compared with control). aPg antibody contains activity consistent with pathogenic aCl, and the antigen inducing the antibodies that cause increased fetal loss may be on the arg-gingipain protease of P. gingivalis. 23611117 Diversity in Structural Consequences of MexZ Mutations in Pseudomonas aeruginosa. Pseudomonas aeruginosa is the major cause of morbidity and mortality in patients with cystic fibrosis. The high level of intrinsic and acquired antibiotic resistance of P. aeruginosa is attributable to the low permeability of its outer membrane in combination with the expression of several multidrug resistance efflux systems. MexZ, the negative regulator of the MexXY efflux pump, is found to be the most frequently mutated gene in P. aeruginosa isolated from cystic fibrosis patient lungs, confirming its importance in multidrug resistance. Structural consequences of four MexZ mutations, including L25P, G46V, P151L, and S202F, have been explored based on the known structure of MexZ using both molecular modeling and molecular dynamics methods. According to obtained results, G46V mutation, which completely abolishes the ability of MexZ binding to DNA, occurs in a specific evolutionary conserved region of MexZ. In addition, the most fluctuation values occur in DNA-binding domain and Helix4. The obtained results explore details of diversity in structural consequences of MexZ mutations in P. aeruginosa. 23780746 Environment-sensitive fluorescent turn-on probes targeting hydrophobic ligand-binding domains for selective protein detection. Bind and shine: An approach for the selective detection of both enzymes and non-enzymatic proteins using an environment-sensitive fluorescent turn-on probe is described. This approach targets the hydrophobic ligand-binding domain of the target protein to trigger the fluorescence turn-on and was shown to be specific for the targeted protein. 23887948 Development of an In-house Endoanal Ultrasound Teaching Phantom. Objectives- The aim of this study was to construct an anatomically correct phantom for visualization of anal sphincter complex structures. Methods- To make an endoanal ultrasound phantom, we experimented with a variety of commercially available materials to simulate hyperechoic, hypoechoic, and isoechoic tissue consistency. We created external anal sphincter muscle and the levator plate using stand-alone density gel and microbubbles to simulate the echogenicity of the muscles. A mold was created in a container, the muscles were inserted, and the mold was filled with high-density clear gel and allowed to fill. Once finished, the container was sealed tightly and stored for later use. To evaluate the accuracy of the model, 6 ultrasound imaging raters from different disciplines were included. The raters were administered a 6-item Internet-based interactive test using 2-dimensional images obtained from scanning the phantom. Rater agreement was determined. The Fleiss κstatistic was calculated to determine inter-rater reliability. Results- The raters identified the structures in 32 (89%) of 36 test questions. There was good to excellent agreement among the readers. Agreement rates for visualization of the external anal sphincter, perineal body, and internal anal sphincter were 67%, 83%, and 100%, respectively. Conclusions- An endoanal phantom can be constructed as a simulator for endoanal sonography. 23835338 Cyclodextrin protects podocytes in diabetic kidney disease. Diabetic kidney disease remains the most common cause of end-stage kidney disease despite multifactorial intervention. We demonstrated that increased cholesterol in association with down-regulation of ATP-binding cassette transporter ABCA1 occurs in normal human podocytes exposed to the sera of patients with type 1-diabetes and albuminuria (DKD+) when compared to diabetic patients with normoalbuminuria (DKD-) and similar duration of diabetes and lipid profile. Glomerular down-regulation of ABCA1 was confirmed in biopsies from patients with early DKD (n=70) when compared to normal living donors (n=32). Induction of cholesterol efflux with cyclodextrin (CD) but not inhibition of cholesterol synthesis with simvastatin prevented podocyte injury observed in vitro after exposure to patient sera. Subcutaneous administration of CD to diabetic BTBR ob/ob mice was safe and reduced albuminuria, mesangial expansion, kidney weight and cortical cholesterol content. This was followed by an improvement of fasting insulin, blood glucose, body weight, glucose tolerance in vivo and improved glucose stimulated insulin release in human islets in vitro. Our data suggest that impaired reverse cholesterol transport characterizes clinical and experimental DKD and negatively influences podocyte function. Treatment with CD is safe and effective in preserving podocyte function in vitro and in vivo and may improve the metabolic control of diabetes. 23543418 Reason for revision TKA predicts clinical outcome: prospective evaluation of 150 consecutive patients with 2-years followup. There is limited knowledge regarding the relationship between the reason for revising a TKA and the clinical outcome in terms of satisfaction, pain, and function with time. In a cohort of patients receiving a fully revised TKA, we hypothesized (1) outcomes would differ according to reason for revision at 2 years, (2) outcomes would improve gradually during those 2 years, (3) rates of complications differ depending on the reason for revision, and (4) patients with complications have lower scores. We studied a prospective cohort of 150 patients receiving a fully revised TKA using a single implant system in two high-volume centers at 24 months of followup. VAS satisfaction, VAS pain, The Knee Society Scoring System(©) (KSS) clinical and functional scores, and complication rate were correlated with their reasons for revision, including septic loosening, aseptic loosening, component malposition, instability, and stiffness. The aseptic loosening group showed better outcomes compared with the instability, malposition, and septic loosening groups, which showed intermediate results (p < 0.05). The stiffness group performed significantly worse on all outcome measures. The outcome for patients with a complication, after treatment of the complication, was less favorable. The reason for revision TKA predicts clinical outcomes. Satisfaction, pain reduction, and functional improvement are better and complication rates are lower after revision TKA for aseptic loosening than for other causes of failure. For component malposition, instability, and septic loosening groups, there may be more pain and a higher complication rate. For stiffness, the outcomes are less favorable in all scores. Level III, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. 23526361 miRNA expression profiling of inflammatory breast cancer identifies a 5-miRNA signature predictive of breast tumor aggressiveness. IBC (inflammatory breast cancer) is a rare but very aggressive form of breast cancer with a particular phenotype. The molecular mechanisms responsible for IBC remain largely unknown. In particular, genetic and epigenetic alterations specific to IBC remain to be identified. MicroRNAs, a class of small noncoding RNAs able to regulate gene expression, are deregulated in breast cancer and may therefore serve as tools for diagnosis and prediction. This study was designed to determine miRNA expression profiling (microRNAome) in IBC. Quantitative RT-PCR was used to determine expression levels of 804 miRNAs in a screening series of 12 IBC compared to 31 non-stage-matched non-IBC and 8 normal breast samples. The differentially expressed miRNAs were then validated in a series of 65 IBC and 95 non-IBC. From a set of 18 miRNAs of interest selected from the screening series, 13 were differentially expressed with statistical significance in the validation series of IBC compared to non-IBC. Among these, a 5-miRNA signature comprising miR-421, miR-486, miR-503, miR-720 and miR-1303 was shown to be predictive for IBC phenotype with an overall accuracy of 89%. Moreover, multivariate analysis showed that this signature was an independent predictor of poor Metastasis-Free Survival in non-IBC patients. 23915072 Smoothened inhibition leads to decreased proliferation and induces apoptosis in esophageal adenocarcinoma cells. The Hedgehog (Hh) pathway is known to be active in Barrett's carcinogenesis. Therefore, we evaluated the efficacy and underlying mechanisms of inhibition of cancer cell growth by the smoothened (Smo) antagonist BMS-833923 in esophageal adenocarcinoma (EAC) cell lines. Cell proliferation and apoptosis were evaluated by flow cytometry, Western blotting, immunofluorescence, and quantitative reverse transcription polymerase chain reactions. Results showed that the Smo antagonist led to reduced Hh pathway activity, resulting in decreased cell proliferation and induction of apoptosis via the intrinsic pathway in the esophageal cancer cells. In conclusion, the Smo antagonist may have application as an EAC chemotherapeutic agent. 23137166 Treatment with finasteride and prostate cancer survival. Abstract Objective. This study compared survival after diagnosis of prostate cancer (PC) in men previously treated with finasteride, in men previously treated with α-adrenoceptor antagonists, in men treated with both, and in men who had received neither type of medication. Material and methods. In total, 3791 men diagnosed with PC in northern Denmark were identified. The region's prescription database was used to identify all men prescribed finasteride and α-adrenoceptor antagonists and those who had received neither medication during the period 1989-2001. Among men with a diagnosis of PC, overall survival and disease-specific survival were assessed after diagnosis using Cox proportional hazards regression. The risk of being diagnosed with non-localized PC was estimated using conditional logistic regression. Results. The adjusted hazard ratio (HR) for PC death and overall death after treatment with finasteride was 0.93 [95% confidence interval (CI) 0.76-1.14] and 0.92 (95% CI 0.77-1.10), respectively. Treatment with α-adrenoceptor antagonists was associated with a reduced risk of PC death and overall death (HR 0.78, 95% CI 0.67-0.90, and 0.82, 95% CI 0.73-0.93, respectively. The risk of being diagnosed with non-localized PC was increased for men taking finasteride (odds ratio 1.14, 95% CI 1.01-1.29) per 100 defined daily doses. Conclusions. Treatment with finasteride prior to a diagnosis of PC did not affect PC-specific survival, but increased the risk of being diagnosed with non-localized disease. Treatment with α-adrenoceptor antagonists was associated with better cause-specific survival and lower risk of non-localized disease. 23934068 A New Isolate from Fusarium proliferatum (AUF-2) for Efficient Nitrilase Production. A fungal isolate from Fusarium proliferatum strain AUF-2 has been found to have a high nitrilase activity (≥1,000 U/l culture). The present work describes optimization of growth conditions and production medium to achieve maximum nitrilase production. The most effective carbon and nitrogen sources for nitrilase production were glucose and sodium nitrate, respectively. ε-Caprolactam was found to be the best inducer for maximum nitrilase production with 80 g/l wet cell biomass and 26 U/g nitrilase activity. An overall nitrilase activity of ≥2,000 U/l culture was obtained in this study, which is one of the best activities reported so far in any Fusarium strain. Chemo-profiling has shown that the strain is versatile in its ability to hydrolyze both aliphatic as well as aromatic nitriles. Efforts are being made to use the strain for biotransformation of pharmaceutical substrates. 23568676 Better quality of life after medial versus lateral unicondylar knee arthroplasty. The number of unicompartmental knee arthroplasties (UKAs) is growing worldwide. Because lateral UKAs are performed much less frequently than medial UKAs, the limited information leaves unclear whether UKAs have comparable survival and health-related quality of life (HRQoL) of the lateral UKA to medial UKAs. We therefore compared the (1) survivorship and (2) HRQoL after lateral versus medial cemented mobile-bearing UKAs and (3) determined whether there is an association of survival to modifications of surgical technique in one of three phases. We retrospectively reviewed 558 patients who underwent mobile-bearing UKAs from 2002 to 2009. From the records we determined revision of the joint for any reason and revision for aseptic loosening. Patients reported their physical function, pain, and stiffness as measured by the WOMAC, SF-36 physical-component summary (PCS), and Lequesne knee score. Information regarding implant survival was collected for 93% of the patients. We analyzed the patients separately by three phases based on surgical changes associated with each phase (1: initial technique; 2: improved cementing; 3: additional bone resection to ensure backward sliding of the inlay without impingement). The minimum followup was 2.1 years (mean, 6 years; range, 2.1-9.8 years). Implant survival was 88% at 9 years. We found similar implant survival rates for medial (90%) and lateral UKAs (83%). In all HRQoL measures, patients receiving a medial UKA had better mean scores compared with patients who had a lateral UKA: WOMAC physical function (23 versus 34, respectively) and pain (21 versus 34) and SF-36 PCS (41 versus 38). There were no survival differences by surgical phase. Our observations suggest a medial UKA is associated with superior HRQoL when compared with a lateral UKA, although implant survival is similar. Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. 23764989 Late in-the-bag intraocular lens dislocation requiring explantation: risk factors and outcomes. PurposeTo study the predisposing factors for late in-the-bag intraocular lens (IOL) dislocation and to analyze the outcomes after explantation surgery.MethodsIn this retrospective multicentre study, 61 eyes were enrolled. The main inclusion criterion was in-the-bag spontaneous IOL dislocation after uneventful phacoemulsification cataract extraction. Only eyes with serious dislocation that required IOL explantation were eligible. Follow-up after explantation surgery of at least 3 months was required. Exclusion criteria were complicated cataract surgery, out-of-the-bag IOL dislocation, and dislocations that occurred in the first year after the cataract surgery. The main outcome measures were predisposing factors for dislocation, interval between cataract surgery and dislocation, surgical treatment at the time of explantation, preoperative and postoperative corrected distance visual acuity (CDVA), and postoperative complications.ResultsHigh myopia was detected in 12 cases (19.7%) and it was the main predisposing factor. Mean time interval from cataract surgery to dislocation was 7.5 (SD 5.2) years. The dislocated in-the-bag IOL was replaced with a scleral fixated IOL (36.1%), angle-supported anterior chamber IOL (31.1%), sulcus repositioning (18%), or posterior chamber iris sutured IOL (4.9%). Finally, 9.8% of the patients were left aphakic. Mean CDVA improved significantly after surgery (P=0.005). Final CDVA of 20/40 or better was achieved in 29 cases (47.5%).ConclusionsHigh myopia was the main risk factor for late in-the-bag IOL dislocation. Surgical treatment significantly improved the CDVA in our sample and was associated with a low complication rate. 23857547 In-Hospital and 1-Year Mortality in Patients Undergoing Early Surgery for Prosthetic Valve Endocarditis. IMPORTANCE There are limited prospective, controlled data evaluating survival in patients receiving early surgery vs medical therapy for prosthetic valve endocarditis (PVE). OBJECTIVE To determine the in-hospital and 1-year mortality in patients with PVE who undergo valve replacement during index hospitalization compared with patients who receive medical therapy alone, after controlling for survival and treatment selection bias. DESIGN, SETTING, AND PARTICIPANTS Participants were enrolled between June 2000 and December 2006 in the International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS), a prospective, multinational, observational cohort of patients with infective endocarditis. Patients hospitalized with definite right- or left-sided PVE were included in the analysis. We evaluated the effect of treatment assignment on mortality, after adjusting for biases using a Cox proportional hazards model that included inverse probability of treatment weighting and surgery as a time-dependent covariate. The cohort was stratified by probability (propensity) for surgery, and outcomes were compared between the treatment groups within each stratum. INTERVENTIONS Valve replacement during index hospitalization (early surgery) vs medical therapy. MAIN OUTCOMES AND MEASURES In-hospital and 1-year mortality. RESULTS Of the 1025 patients with PVE, 490 patients (47.8%) underwent early surgery and 535 individuals (52.2%) received medical therapy alone. Compared with medical therapy, early surgery was associated with lower in-hospital mortality in the unadjusted analysis and after controlling for treatment selection bias (in-hospital mortality: hazard ratio [HR], 0.44 [95% CI, 0.38-0.52] and lower 1-year mortality: HR, 0.57 [95% CI, 0.49-0.67]). The lower mortality associated with surgery did not persist after adjustment for survivor bias (in-hospital mortality: HR, 0.90 [95% CI, 0.76-1.07] and 1-year mortality: HR, 1.04 [95% CI, 0.89-1.23]). Subgroup analysis indicated a lower in-hospital mortality with early surgery in the highest surgical propensity quintile (21.2% vs 37.5%; P = .03). At 1-year follow-up, the reduced mortality with surgery was observed in the fourth (24.8% vs 42.9%; P = .007) and fifth (27.9% vs 50.0%; P = .007) quintiles of surgical propensity. CONCLUSIONS AND RELEVANCE Prosthetic valve endocarditis remains associated with a high 1-year mortality rate. After adjustment for differences in clinical characteristics and survival bias, early valve replacement was not associated with lower mortality compared with medical therapy in the overall cohort. Further studies are needed to define the effect and timing of surgery in patients with PVE who have indications for surgery. 23887184 Surface changes and polymyxin interactions with a resistant strain of Klebsiella pneumoniae. This study examines the interaction of polymyxin B and colistin with the surface and outer membrane components of a susceptible and resistant strain of Klebsiella pneumoniae. The interaction between polymyxins and bacterial membrane and isolated LPS from paired wild type and polymyxin-resistant strains of K. pneumoniae were examined with N-phenyl-1-naphthylamine (NPN) uptake, fluorometric binding and thermal shift assays, lysozyme and deoxycholate sensitivity assays, and by (1)H NMR. LPS from the polymyxin-resistant strain displayed a reduced binding affinity for polymyxins B and colistin in comparison with the wild type LPS. The outer membrane NPN permeability of the resistant strain was greater compared with the susceptible strain. Polymyxin exposure enhanced the permeability of the outer membrane of the wild type strain to lysozyme and deoxycholate, whereas polymyxin concentrations up to 32 mg/ml failed to permeabilize the outer membrane of the resistant strain. Zeta potential measurements revealed that mid-logarithmic phase wild type cells exhibited a greater negative charge than the mid-logarithmic phase-resistant cells. Taken together, our findings suggest that the resistant derivative of K. pneumoniae can block the electrostatically driven first stage of polymyxin action, which thereby renders the hydrophobically driven second tier of polymyxin action on the outer membrane inconsequential. 22521336 The role of inflammation in epileptogenesis. One compelling challenge in the therapy of epilepsy is to develop anti-epileptogenic drugs with an impact on the disease progression. The search for novel targets has focused recently on brain inflammation since this phenomenon appears to be an integral part of the diseased hyperexcitable brain tissue from which spontaneous and recurrent seizures originate. Although the contribution of specific proinflammatory pathways to the mechanism of ictogenesis in epileptic tissue has been demonstrated in experimental models, the role of these pathways in epileptogenesis is still under evaluation. We review the evidence conceptually supporting the involvement of brain inflammation and the associated blood-brain barrier damage in epileptogenesis, and describe the available pharmacological evidence where post-injury intervention with anti-inflammatory drugs has been attempted. Our review will focus on three main inflammatory pathways, namely the IL-1 receptor/Toll-like receptor signaling, COX-2 and the TGF-β signaling. The mechanisms underlying neuronal-glia network dysfunctions induced by brain inflammation are also discussed, highlighting novel neuromodulatory effects of classical inflammatory mediators such as cytokines and prostaglandins. The increase in knowledge about a role of inflammation in disease progression, may prompt the use of specific anti-inflammatory drugs for developing disease-modifying treatments. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'. 23863220 Sex-specific assessment of reduced coronary sinus flow in non-hypertensive patients with coronary artery disease at rest. Access to data on the coronary flow in the coronary sinus (CS) can aid in the diagnosis of coronary artery disease (CAD). We tested the hypothesis that assessing the CS flow by transthoracic Doppler echocardiography (TTE) at rest can detect coronary artery stenosis in non-hypertensive patients. The antegrade phase of coronary flow in the CS was analyzed and compared in 140 male and 135 female non-hypertensive subjects who had all undergone coronary angiography. There were statistically significant differences noted between males and females for the CS flow both in normal subjects and patients with CAD. Compared with normal subjects, patients with CAD had significantly lower blood flow in the CS both in males (196.6±174.31 vs. 367.65±168.04 ml/min, P<0.01) and females (183.04±65.46 vs. 244.13±135.43 ml/min P<0.01). For males, the diagnostic sensitivity, specificity, and accuracy of the cutoff value of the CS flow (206 ml/min) for predicting a significant coronary artery stenosis (>70%) were 91.67%, 81.25%, and 85.71%, respectively. For females, those of the cutoff value of the CS flow (195 ml/min) were 85.71%, 75%, and 80%, respectively. TTE can effectively detect coronary hemodynamically significant stenosis in non-hypertensive male and female patients at different cutoff values. 23895050 Neuronal Assembly Dynamics in Supervised and Unsupervised Learning Scenarios. The dynamic formation of groups of neurons-neuronal assemblies-is believed to mediate cognitive phenomena at many levels, but their detailed operation and mechanisms of interaction are still to be uncovered. One hypothesis suggests that synchronized oscillations underpin their formation and functioning, with a focus on the temporal structure of neuronal signals. In this context, we investigate neuronal assembly dynamics in two complementary scenarios: the first, a supervised spike pattern classification task, in which noisy variations of a collection of spikes have to be correctly labeled; the second, an unsupervised, minimally cognitive evolutionary robotics tasks, in which an evolved agent has to cope with multiple, possibly conflicting, objectives. In both cases, the more traditional dynamical analysis of the system's variables is paired with information-theoretic techniques in order to get a broader picture of the ongoing interactions with and within the network. The neural network model is inspired by the Kuramoto model of coupled phase oscillators and allows one to fine-tune the network synchronization dynamics and assembly configuration. The experiments explore the computational power, redundancy, and generalization capability of neuronal circuits, demonstrating that performance depends nonlinearly on the number of assemblies and neurons in the network and showing that the framework can be exploited to generate minimally cognitive behaviors, with dynamic assembly formation accounting for varying degrees of stimuli modulation of the sensorimotor interactions. 23614676 Yeast as a Biosensor of Detoxification: A Tool for Identifying New Compounds that Revert Multidrug Resistance. During tumour progression, cells accumulate secondary mutations and/or chromosomal aberrations that generate genetic diversity within the tumour cell population. This may result in the acquisition of new properties that increase tumour malignancy, such as invasiveness or resistance to chemotherapy. One of the important mechanisms of chemotherapy resistance is overexpression or biochemical activation of ABC family transporters. ABC transporters remove anti tumour drugs from the cell, reducing their intracellular concentration and producing resistance against a wide range of chemically unrelated drugs, known as multidrug resistant phenotype (MDR). During recent decades, much effort has been devoted to the isolation of compounds able to inhibit the activity of these transporters. However, few such compounds have reached clinical practice and MDR remains a serious complication in cancer therapy. In an innovative approach to finding new ABC inhibitors, we propose using fission yeast Schizosaccharomyces pombe as a biosensor of detoxification that would enable cost-efficient screening of natural compounds and chemical libraries for molecules that revert the MDR phenotype. Existing fission yeast tools provide genetic, biochemical and cell biological analysis, thereby facilitating identification of drug targets. Putative inhibitors and modulators of ABC transporters could be used in combination with chemotherapeutic drugs for the treatment of multidrug resistant tumours. 23870943 Determination of amino acid contents of manketti seeds (Schinziophyton rautanenii) by pre-column derivatisation with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate and RP-HPLC. Defatted kernel flour from manketti seed kernels (Schinziophyton rautanenii) is an underutilised natural product. The plant grows in the wild, on sandy soils little used for agriculture in Southern Africa. The kernels are rich in protein and have a great potential for improving nutrition. The protein content and amino acid profile of manketti seed kernel were studied, using a new analytical method, in order to evaluate the nutritional value. The crude protein content of the press cake and defatted kernel flour was 29.0% and 67.5%, respectively. Leucine and arginine were found to be the most abundant essential and non-essential amino acids, respectively. The seed kernel contained 4.77g leucine and 12.34g arginine/100g of defatted seed kernel flour. Methionine and proline were the least abundant essential and non-essential amino acids to with 0.23g methionine and 0.36g proline/100g of defatted seed kernel flour, respectively. Validation of the pre-column derivatisation procedure with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) for the determination of amino acids was carried out. The analytical parameters were determined: linearity (0.0025-0.20mM), accuracy of the derivatisation procedure: 86.7-109.8%, precision (method: 0.72-5.04%, instrumental: 0.14-1.88% and derivatisation: 0.15-2.94% and 0.41-4.32% for intraday and interday, respectively). Limits of detection and quantification were 6.80-157mg/100g and 22.7-523mg/100g kernel flour, respectively. 23684928 Molecular interplay between cdk4 and p21 dictates G0/G1 cell cycle arrest in prostate cancer cells. This study examined the effect of 3, 9-dihydroxy-2-prenylcoumestan (pso), a furanocoumarin, on PC-3 and C4-2B castration-resistant prostate cancer (CRPC) cell lines. Pso caused significant G0/G1 cell cycle arrest and inhibition of cell growth. Molecular analysis of cyclin (D1, D2, D3, and E), cyclin-dependent kinase (cdk) (cdks 2, 4, and 6), and cdk inhibitor (p21 and p27) expression suggested transcriptional regulation of the cdk inhibitors and more significant downregulation of cdk4 than of cyclins or other cdks. Overexpression of cdk4, or silencing of p21 or p27, overcame pso-induced G0/G1 arrest, suggesting that G0/G1 cell cycle arrest is a potential mechanism of growth inhibition in CRPC cells. 23956446 Criteria and prediction models for mismatch repair gene mutations: a review. One of the strongest predictors of colorectal cancer risk is carrying a germline mutation in a DNA mismatch repair (MMR) gene. Once identified, mutation carriers can be recommended for intensive screening that will substantially reduce their high colorectal cancer risk. Conversely, the relatives of carriers identified as non-carriers can be relieved of the burden of intensive screening. Criteria and prediction models that identify likely mutation carriers are needed for cost-effective, targeted, germline testing for MMR gene mutation. We reviewed 12 criteria/guidelines and 8 prediction models (Leiden, Amsterdam-plus, Amsterdam-alternative, MMRpro, PREMM1,2,6, MMRpredict, Associazione Italiana per lo studio della Familiarità ed Ereditarietà dei tumori Gastrointestinali (AIFEG) and the Myriad Genetics Prevalence table) for identifying mutation carriers. While criteria are only used to identify individuals with colorectal cancer (yes/no for screening followed by germline testing), all prediction models except MMRpredict and Myriad tables can predict the probability of carrying mutations for individuals with or without colorectal cancer. We conducted a meta-analysis of the discrimination performance of 17 studies that validated the prediction models. The pooled estimate for the area under curve was 0.80 (95% CI 0.72 to 0.88) for MMRpro, 0.81 (95% CI 0.73 to 0.88) for MMRpredict, 0.84 (95% CI 0.81 to 0.88) for PREMM, and 0.85 (95% CI 0.78 to 0.91) for Leiden model. Given the high degree of overlap in the CIs, we cannot state that one model has a higher discrimination than any of the others. Overall, the existing statistical models have been shown to be sensitive and specific (at a 5% cut-off) in predicting MMR gene mutation carriers. Future models may need to: provide prediction of PMS2 mutations, take into account a wider range of Lynch syndrome-associated cancers when assessing family history, and be applicable to all people irrespective of any cancer diagnosis. 23795939 11β-HSD1 Inhibitors from Walsura cochinchinensis. A search for inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) from Walsura cochinchinensis yielded 10 new limonoids, cochinchinoids A-J (1-10), and two new triterpenoids, 3-epimesendanin S (11) and cochinchinoid K (12). Their structures were assigned on the basis of spectroscopic data, with the absolute configurations of 1 and 12 being established by X-ray diffraction analysis. Of these compounds, cochinchinoid K (12) displayed inhibitory activity against mouse 11β-HSD1 with an IC50 value of 0.82 μM. 23933652 Inhibitory effects of rosiglitazone on paraquat-induced acute lung injury in rats. Aim:To investigate the effects of the PPAR-γ agonist rosiglitazone on acute lung injury induced by the herbicide paraquat (PQ) and the underlying mechanisms of action.Methods:Male Sprague-Dawley rats were injected with PQ (20 mg/kg, ip). Rosiglitazone (3 or 10 mg/kg, ip) was administered 1 h before PQ exposure. Peripheral blood was collected at 4, 8, 24 and 72 h after PQ exposure for measuring the levels of MDA, TNF-α and IL-1β, and the SOD activity. Lung tissues were collected at 72 h after PQ exposure to determine the wet-to-dry (W/D) ratios and lung injury scores, as well as the protein levels of NF-κBp65, PPAR-γ, Nrf2, IκBα and pIκBα.Results:At 72 h after PQ exposure, the untreated rats showed a 100% cumulative mortality, whereas no death was observed in rosiglitazone-pretreated rats. Moreover, rosiglitazone pretreatment dose-dependently attenuated PQ-induced lung edema and lung histopathological changes. The pretreatment significantly reduced the levels of TNF-α, IL-1β and MDA, increased SOD activity in the peripheral blood of PQ-treated rats. The pretreatment also efficiently activated PPAR-γ, induced Nrf2 expression and inhibited NF-κB activation in the lung tissues of PQ-treated rats. Furthermore, the pretreatment dose-dependently inhibited IκB-α degradation and phosphorylation, thus inhibiting NF-κB activation.Conclusion:Pretreatment with rosiglitazone protects rats against PQ-induced acute lung injury by activating PPAR-γ, inducing Nrf2 expression and inhibiting NF-κB activation. 23863955 Memory suppression trades prolonged fear and sleep-dependent fear plasticity for the avoidance of current fear. Sleep deprivation immediately following an aversive event reduces fear by preventing memory consolidation during homeostatic sleep. This suggests that acute insomnia might act prophylactically against the development of posttraumatic stress disorder (PTSD) even though it is also a possible risk factor for PTSD. We examined total sleep deprivation and memory suppression to evaluate the effects of these interventions on subsequent aversive memory formation and fear conditioning. Active suppression of aversive memory impaired retention of event memory. However, although the remembered fear was more reduced in sleep-deprived than sleep-control subjects, suppressed fear increased, and seemed to abandon the sleep-dependent plasticity of fear. Active memory suppression, which provides a psychological model for Freud's ego defense mechanism, enhances fear and casts doubt on the potential of acute insomnia as a prophylactic measure against PTSD. Our findings bring into question the role of sleep in aversive-memory consolidation in clinical PTSD pathophysiology. 23927092 Non-paraxial model for a parametric acoustic array. This study is concerned with parametric radiation from an arbitrary axisymmetric planar source with a special focus on low-frequency difference-frequency fields. As a model equation accounting for nonlinearity, diffraction, and dissipation, the Westervelt equation is used. The difference-frequency-field patterns are calculated in the quasi-linear approximation by the method of successive approximations. A multi-layer integral for calculation of the acoustic field is reduced to a three-dimensional one by employing an approximate analytical description of the primary field with the use of a multi-Gaussian beam expansion. This integral is subsequently reduced in the paraxial approximation to a one-dimensional form which has previously been published in literature and which represents a means for fast calculations of secondary acoustic fields. The three-dimensional integral is calculated numerically and the numerical results predict nonzero amplitude of the low-frequency field in the vicinity of the source which is an effect that cannot be correctly encompassed in the paraxial approximation. 23757474 Preoperative carbohydrate loading in patients undergoing coronary artery bypass or spinal surgery. Surgical stress creates a state of insulin resistance which may contribute to the development of hyperglycemia and, subsequently, postoperative complications. Consumption of an oral carbohydrate supplement before surgery may improve insulin sensitivity and reduce hyperglycemia. In this trial, we investigated the effects of carbohydrate supplementation on insulin resistance in coronary artery bypass graft and spinal decompression and fusion surgical patients. Twenty-six patients undergoing coronary artery bypass graft and 12 undergoing spine surgery were randomized to receive 800 mL of an oral carbohydrate supplement the evening before and 400 mL 2 hours before surgery (CHO) or to fasting per standard hospital protocol (FAST). Baseline and postoperative measurements of insulin sensitivity were assessed using the short insulin tolerance test and homeostasis model assessment (HOMA). Interleukin-6, C-reactive protein, and free fatty acid levels were determined at baseline, postoperatively, and 24, 48, and 72 hours after surgery. Adiponectin was measured at baseline. Subjective feelings of well-being were measured immediately before surgery, and intra- and postoperative outcomes were documented. Postoperative insulin sensitivity did not differ significantly between the FAST and CHO groups whether measured by the short insulin tolerance test (rate of disappearance of blood glucose: 0.29%/min vs 0.38%/min; 99% confidence interval [CI] for difference, -0.17 to 0.32, P = 0.41) or HOMA (insulin resistance at values >1: 2.3 vs 3.3; 99% CI for difference, -0.8 to 2.8, P = 0.14). Circulating blood glucose levels after surgery in the CHO group, 6.2 mmol/L, tended to be lower than the FAST group, 6.9 mmol/L (99% CI for difference, -1.7 to 0.25, P = 0.05) and postoperative β-cell function, measured by HOMA-β (impaired β-cell function at values <100%), tended to be higher in the CHO group, 87%, vs 47.5% in the FAST group (99% CI for difference, -9.4 to 88.4), but these differences were not significant. Adiponectin levels were not different between groups at baseline, and levels of free fatty acid, interleukin-6 and C-reactive protein were not affected by treatment. Preoperative carbohydrate loading did not improve postoperative insulin sensitivity. However, the observed postoperative blood glucose levels and β-cell function as well as secondary outcomes warrant further study to reevaluate traditional fasting practices in surgical patients. 23501055 Gambogic acid inhibits angiogenesis through inhibiting PHD2-VHL-HIF-1α pathway. Our previous studies revealed that gambogic acid (GA), the major active ingredient of gamboge, possessed antiangiogenic activities. In this study, we further explored the mechanism of inhibition effects of GA in tumor angiogenesis. The results of luciferase, RT-PCR, and ELISA assays indicated that GA significantly decreased transcription activation, mRNA expression, and secretion of VEGF in hypoxia. We detected that GA had no effect on mRNA level of HIF-1α which targets VEGF gene, but the increase of HIF-1α protein expression in hypoxia was repressed by GA, which can be reversed by proteasomal inhibitor MG132 and siRNA of VHL. But GA exhibited no effect on expression of VHL both in normoxia and hypoxia. HIF prolyl hydroxylases (PHD enzymes) act as oxygen sensors regulating HIF, and hence angiogenesis. Our results showed that GA potentially enhanced level of PHD2, the most important HIF hydroxylase, and showed no effect on PHD1 and PHD3. Transient transfection of siRNA of PHD2 could eliminate GA-induced VEGF secretion increase. Growth of HepG2 xenografts in BALB/cA nude mice was inhibited by GA and angiogenesis was repressed significantly in tumor xenografts by immunohistochemical staining of CD-31, a vascular endothelial marker, accompanied with decrease of HIF-1α and increase of PHD2 expression in tissue extracts. This work provides the demonstration that GA shows anti-angiogenic effects via inhibiting PHD2-VHL-HIF-1α pathway. 23819549 Hyperparasites influence population structure of the chestnut blight pathogen, Cryphonectria parasitica. Vegetative compatibility (VC) is commonly used to characterize structure and diversity in fungal populations. In the chestnut blight fungus, Cryphonectria parasitica, high VC diversity is hypothesized to be responsible for the failure of hyperparasitic mycoviruses to spread through pathogen populations in North America. To test this hypothesis, we assessed VC diversity at three recovering sites in Michigan where mycoviruses had invaded and compared them with four epidemic populations where mycoviruses were absent. VC diversity was assessed for samples collected in 1996 and 2009, which allowed us to determine how C. parasitica populations changed with time. Twelve VC types were found in 1996 while thirty were found in 2009; 75% of types overlapped between the sample dates. Sites where mycoviruses were present had unique VC structures with the exception of the recovering population site at County Line where the main VC group was also detected at two epidemic sites. More VC groups were detected at epidemic sites than recovering (with one exception) and were more diverse. Mating type analyses of blight populations revealed that two of three recovering populations were significantly skewed for MAT2 suggesting asexual reproduction, while epidemic sites with a long history of blight infection had ratios near 50:50 suggesting sexual reproduction. We propose that selection in the largely asexual C. parasitica populations at two recovering sites favors the most-fit fungal genotype by mycovirus combination and results in reduced diversity relative to the sexually reproducing pathogen populations at epidemic sites. 23871203 Inhibition of larval swimming activity of the coral (Platygyra acuta) by interactive thermal and chemical stresses. This study examined the interactive effects of copper and elevated temperature and subsequent depuration on Platygyra acuta coral larvae. Larval mortality and motility were significantly affected by copper alone (70% and 100% inhibition respectively). Their respective lethal/inhibitory concentration (LC50/IC50) were 10-130% and 86-193% higher than those reported for other larvae. Temperature (ambient, 27°C and elevated, 30°C) alone and the combination of temperature and copper did not significantly affect both endpoints. This study provides the first quantitative data on depuration effect on resumption of larval motility after copper exposure, although no sign of larval recovery was observed. These findings suggest that the effects of copper pollution outweigh the thermal tolerance of coral larvae. High LC50 and IC50 recorded may be unique for corals from marginal reefs like Hong Kong which have already been exposed to high levels of copper pollution. 23877533 Linking ecosystem services and human health: the Eco-Health Relationship Browser. Ecosystems provide multiple services, many of which are linked to positive health outcomes. Review objectives were to identify the set of literature related to this research topic, and to design an interactive, web-based tool highlighting the weight of evidence, thus making the information more accessible. A systematic review was conducted to create the Eco-Health Relationship Browser ( http://www.epa.gov/research/healthscience/browser/introduction.html ). The search was conducted in four stages utilizing Google Scholar, PubMed and Science Direct, targeted journals, and targeted keywords; search results were limited to peer-reviewed journal articles published in English from 1 January 1990 to 31 December 2012. The review identified 344 relevant articles; a subset of 169 articles was included in the Browser. Articles retrieved during the search focused on the buffering and health-promotional aspects of ecosystem services. Landscape and Urban Planning, Urban Forestry and Urban Greening, and Health and Place yielded the most articles relevant to this search. Results from the systematic review were used to populate the Browser, which organizes the diverse literature and allows users to visualize the numerous connections between ecosystem services and human health. 23635319 Piezotronic Effect in Solution-Grown p-Type ZnO Nanowires and Films. Investigating the piezotronic effect in p-type piezoelectric semiconductor is critical for developing a complete piezotronic theory and designing/fabricating novel piezotronic applications with more complex functionality. Using a low temperature solution method, we were able to produce ultralong (up to 60 μm in length) Sb doped p-type ZnO nanowires on both rigid and flexible substrates. For the p-type nanowire field effect transistor, the on/off ratio, threshold voltage, mobility, and carrier concentration of 0.2% Sb-doped sample are found to be 10(5), 2.1 V, 0.82 cm(2)·V(-1)·s(-1), and 2.6 × 10(17) cm(-3), respectively, and the corresponding values for 1% Sb doped samples are 10(4), 2.0 V, 1.24 cm(2)·V(-1)·s(-1), and 3.8 × 10(17) cm(-3). We further investigated the universality of piezotronic effect in the as-synthesized Sb-doped p-type ZnO NWs and reported for the first time strain-gated piezotronic transistors as well as piezopotential-driven mechanical energy harvesting based on solution-grown p-type ZnO NWs. The results presented here broaden the scope of piezotronics and extend the framework for its potential applications in electronics, optoelectronics, smart MEMS/NEMS, and human-machine interfacing. 23842470 A year in transition: a qualitative study examining the trajectory of first year residents' well-being. It is generally understood that trainees experience periods of heightened stress during first year residency, yet there is little information on variations in stress and well-being over the transition period or those factors that contribute to these variations. This qualitative study explored the trajectory of well-being described by first year residents in the context of challenges, supports and adaptations over time. In-depth interviews were conducted face-to-face with 17 first year residents at the University of Toronto. Participants drew a graph of their well-being over the course of their first year and described critical periods of challenge and adaptation. Interviews were audio-taped and transcribed. Results were organized into a thematic analysis using NVivo software. Residents described a pattern of well-being that varied in accordance with changes in rotations. Well-being increased when residents perceived high levels of team support, felt competent and experienced valued learning opportunities. Well-being decreased with low team support, heavy work demands, few learning opportunities and poor orientations. Anxiety and excitement in the beginning of the year gave way to heightened confidence but increased fatigue and apathy towards the year's end. Residents used a number of cognitive, behavioural and self-care strategies to cope with transitional challenges. Residents experienced a pattern of highly fluctuating well-being that coincided with changes in rotations. Residents' well-being varied according to levels of supervisor and colleague support, learning opportunities, and work demands. Residents' well-being may be improved by program interventions that facilitate better team and supervisory supports, maintain optimal service to learning ratios, establish effective fatigue and risk management systems, offer wellness support services and integrate skills based resiliency training into the curriculum. 23929814 pH-Switchable Ampholytic Supramolecular Copolymers. β-sheet-encoded anionic and cationic dendritic peptide amphiphiles form supramolecular copolymers when self-assembled in a 1:1 feed ratio of the monomers. These ampholytic materials have been designed for on-off polymerization in response to pH triggers. The cooperative supramolecular self-assembly process is switched on at a physiologically relevant pH value and can be switched off by increasing or decreasing the pH value. 23884576 Is Magnetic Resonance Imaging Assessment of the Size of Articular Cartilage Defects Accurate? The purpose of this study was to systematically review the literature relative to the following question: Is preoperative magnetic resonance imaging (MRI) an accurate instrument for the assessment of the size of knee articular cartilage defects compared with arthroscopy? A systematic search was performed in September 2011 using PubMed MEDLINE (from 1966), CINAHL (from 1982), SPORTDiscus (from 1985), SCOPUS (from 1996), and EMBASE (from 1974) databases. Four studies (one study of Level II and three studies of Level III) were identified that met the predetermined inclusion and exclusion criteria. The ability of MRI to preoperatively assess the size of cartilage lesions was highly variable. As a result of inconsistencies between imaging techniques, the methodological variability and shortcomings of the studies, and the limited amount of data available, a meta-analysis was not performed. There is some evidence that MRI is an accurate tool for preoperatively assessing the dimensions of articular cartilage defects. However, because of the heterogeneity of MRI sequences and the paucity of literature related to preoperative sizing, it is not possible to make definitive conclusions regarding the global clinical utility of MRI for guiding the selection of therapeutic strategies. 23318644 Elevated vaspin and leptin levels are associated with obesity in prepubertal Korean children. Adipokines are associated with obesity. However, the relationships between adipokines, specifically vaspin, obesity, and obesity-related variables remain controversial, and only a few studies have been conducted which examines them in children. We investigated the relationships between obesity in prepubertal Korean children and three types of adipokines: vaspin, leptin, and visfatin. In this cross-sectional study, 168 nine-year-old boys and 176 nine-year-old girls participated in a school-based health examination program. Children were classified as overweight using the Korean Pediatric Society 2007 guidelines. Overweight boys and girls had higher leptin and vaspin levels than both boys and girls of normal weight, whereas only overweight boys had higher visfatin levels than normal weight boys. Leptin, visfatin and vaspin concentrations were correlated with obesity-related variables. A multiple logistic regression analysis showed that systolic blood pressure (SBP), total cholesterol (TC), alanine aminotransferase (ALT), homeostasis model assessment of insulin resistance (HOMA-IR), leptin, and vaspin were associated with an increased risk of being overweight, whereas high-density lipoprotein (HDL) cholesterol was associated with a decreased risk of being overweight. Elevated vaspin and leptin levels are associated with obesity in prepubertal Korean children. 23969307 Five Parameters You Must Understand to Master Control of Your Laser/Light-Based Devices. In this article, the authors review basic fundamental principles of light characteristics and their interaction with the target tissue. It is imperative for the practitioner to understand these concepts to deliver appropriate, efficacious, and safe phototherapeutic treatment for their patients. Once a diagnosis is made and a laser is chosen as a treatment tool, a basic knowledge and understanding of the physics and properties of light/tissue interaction is essential to allow practitioners to provide their patients with optimal results. 23194826 Effect of blood-retinal barrier development on formation of selenite nuclear cataract in rat. Selenite cataract, as an experimental animal model of nuclear cataract to mimic human senile cataract, is produced only when overdose selenite is injected to neonatal rats before eyelid opening. To clarify the cause of age differences on selenite cataract formation in rats, mRNA expression of GPx1, MsrA and MsrB1, as well as GPx activity in Wistar rat lens at different ages were assayed, level of lipid peroxidation, extent of lens damage induced by sodium selenite and barricade function of blood-retinal barrier (BRB) were investigated. The results showed that mRNA expressions and activity of antioxidant enzymes in neonatal rat lens before eyelid opening were the highest and then decreased with age, and revealed by transmission electron microscopy (TEM) using lanthanum hydroxide as tracer that higher selenite content entering eyes injured lens and resulted in cataract formation for immature BRB before eyelid opening, moreover, a little selenite content entering eyes was not enough to induce cataract formation after eyelid opening because of mature BRB. 23142712 Yuwen02f1 suppresses LPS-induced endotoxemia and adjuvant-induced arthritis primarily through blockade of ROS formation, NFkB and MAPK activation. Phagocytes release inflammatory mediators to defense harmful stimuli upon bacterial invasion, however, excessive inflammatory reaction leads to tissue damage and manifestation of pathological states. Therefore, targeting on uncontrolled inflammation seems feasible to control numerous inflammation-associated diseases. Under the drug screening process of synthetic diphenylpyrazole derivatives, we discovered compound yuwen02f1 possesses anti-inflammatory effects in decreasing the release of pro-inflammatory cytokines including TNFα and IL-6, nitric oxide, reactive oxygen species (ROS) as well as inhibiting migration of LPS-stimulated phagocytes. In addition, we observed that the molecular mechanism of yuwen02f1-mediated anti-inflammation is associated with decreasing phosphorylation of MAPK molecules including ERK1/2, JNK and p38, and attenuating translocation of p47(phox) and p67(phox) to the cell membrane. Yuwen02f1 also reverses IκBα degradation and attenuates the expression of NFκB-related downstream inducible enzymes like iNOS and COX-2. Furthermore, we found that yuwen02f1 attenuates some pathological syndromes of LPS-induced sepsis and adjuvant-induced arthritis in mice, as evidenced by decreasing the cytokine production, reversing thrombocytopenic syndrome, protecting the mice from tissue injury in septic mice, and attenuating paw edema in arthritic mice as well. These results suggest that yuwen02f1 is a potential anti-inflammatory agent for alleviating syndromes of acute and chronic inflammatory diseases as evidenced by attenuating the generation of cytokines and down-regulating the expression of iNOS and COX-2 through the blockade of ROS generation and NADPH oxidase, NFκB and MAPK activation pathways in LPS-stimulated phagocytes. 23512105 Confirming genes influencing risk to cleft lip with/without cleft palate in a case-parent trio study. A collection of 1,108 case-parent trios ascertained through an isolated, nonsyndromic cleft lip with or without cleft palate (CL/P) was used to replicate the findings from a genome-wide association study (GWAS) conducted by Beaty et al. (Nat Genet 42:525-529, 2010), where four different genes/regions were identified as influencing risk to CL/P. Tagging SNPs for 33 different genes were genotyped (1,269 SNPs). All four of the genes originally identified as showing genome-wide significance (IRF6, ABCA4 and MAF, plus the 8q24 region) were confirmed in this independent sample of trios (who were primarily of European and Southeast Asian ancestry). In addition, eight genes classified as 'second tier' hits in the original study (PAX7, THADA, COL8A1/FILIP1L, DCAF4L2, GADD45G, NTN1, RBFOX3 and FOXE1) showed evidence of linkage and association in this replication sample. Meta-analysis between the original GWAS trios and these replication trios showed PAX7, COL8A1/FILIP1L and NTN1 achieved genome-wide significance. Tests for gene-environment interaction between these 33 genes and maternal smoking found evidence for interaction with two additional genes: GRID2 and ELAVL2 among European mothers (who had a higher rate of smoking than Asian mothers). Formal tests for gene-gene interaction (epistasis) failed to show evidence of statistical interaction in any simple fashion. This study confirms that many different genes influence risk to CL/P. 23069477 Pharmacological management of ocular hypertension: current approaches and future prospective. Elevated eye pressure is the main risk factor for glaucoma, and intraocular pressure rises when the balance between aqueous humor formation and outflow resistance is compromised. In a normal eye there is a precise tune of aqueous outflow under the fine control of ciliary body and trabecular meshwork. Current pharmacological therapies for lowering the intraocular pressure in glaucoma include increasing aqueous humor outflow and suppression of aqueous humor production. However, most of antiglaucoma drugs currently on the market do not target the trabecular meshwork that represents the site of the pathology. This review focuses on pharmacological management of ocular hypertension with a particular attention to the future pharmacotherapy scenario. 23929935 Age-dependent labeling and imaging of insulin secretory granules. Insulin is stored within the secretory granules of pancreatic beta cells and impairment of its release is the hallmark of type 2 diabetes. Preferential exocytosis of newly synthesized insulin suggests that granule aging is a key factor influencing insulin secretion. Here we illustrate a technology that enables the study of granule aging in insulinoma cells and beta cells of knock-in mice through the conditional and unequivocal labeling of insulin fused to the SNAP tag. This approach, which overcomes the limits encountered with previous strategies based on radiolabeling or fluorescence timer proteins, allowed us to formally demonstrate the preferential release of newly-synthesized insulin and reveal that the motility of cortical granules significantly changes over time. Exploitation of this approach may enable the identification of molecular signatures associated with granule aging and unravel possible alterations of granule turnover in diabetic beta cells. Furthermore, the method is of general interest for the study of membrane traffic and aging. 23735847 Hyperkalemic paralysis: an elective abortion gone wrong. Commonly used abortion agents carry potentially serious side effects for the mother. It is important for emergency physicians to be aware of the medications used in elective abortions from the late first trimester to term. If digoxin is used as an abortifacient, it is injected intrafetally or intraplacentally. With this method there is a chance of extraplacental injection, resulting in maternal systemic digoxin toxicity and serious morbidity or death. This report presents a case report, discusses the risks of digoxin-induced abortion, and teaches the reader about the abortifacient agents currently in use, along with their associated complications. This is a case of a 28-year-old pregnant woman of approximately 20 weeks gestation, who presented with severe muscular weakness and respiratory failure requiring intubation. She was subsequently found to have hyperkalemic paralysis from digoxin toxicity after an extraplacental injection during the first step of a two-part elective abortion. It is important for emergency physicians to be aware of the various late first-trimester to term abortifacient agents and procedures being used in obstetrical/gynecological practice, and the potential risks of these interventions. Digoxin toxicity or hyperkalemia should be suspected when a patient presents with severe weakness and respiratory distress after an attempted abortion. 23848344 The interacting effect of the BDNF Val66Met polymorphism and stressful life events on adolescent depression is not an artifact of gene-environment correlation: evidence from a longitudinal twin study. Confounding introduced by gene-environment correlation (rGE) may prevent one from observing a true gene-environment interaction (G Ã— E) effect on psychopathology. The present study investigated the interacting effect of the BDNF Val66Met polymorphism and stressful life events (SLEs) on adolescent depression while controlling for the rGE by two means: separating pure environmental factors (independent SLEs) from the environmental factors under partial genetic control (dependent SLEs) and adopting a prospective longitudinal design. A total of 780 pairs of Chinese twins, aged 11-17 years (mean = 13.6, SD = 1.8) at intake, were followed up twice. Self-reported depression symptoms at Time 1 and Time 2 were assessed by the Children's Depression Inventory (CDI). SLEs occurring between Time 1 and Time 2 were assessed by a self-reported checklist. SLEs were differentiated into independent and dependent ones and were validated by heritability analyses using twin design. The interacting effects between the BDNF Val66Met polymorphism and numbers of SLEs (total SLEs and independent SLEs) on intraindividual change of depression symptoms were examined. After controlling for sex, age, age square, and Time 1 depression, both total SLEs × BDNF Val66Met genotype and independent SLEs × BDNF Val66Met genotype significantly predicted Time 2 depression. Val allele carriers (Val/Val and Val/Met) were more susceptible to the detrimental effects of stress. There is a true G Ã— E effect underlying the observed interaction between BDNF Val66Met polymorphism and environmental stress on depression. 23866158 Solifenacin-induced delirium and hallucinations. Solifenacin-induced cognitive adverse effects have not been reported frequently, but solifenacin-induced delirium and hallucinations with successful switching to darifenacin, without additional drug, have not been reported in the literature. In this case report, we present an 80-year-old Caucasian male with insomnia and anxiety symptoms and overactive bladder who developed delirium and hallucinations when treated with solifenacin and trazodone. After solifenacin discontinuation and switching to darifenacin, symptoms significantly improved immediately. Such a case has not yet been described in literature; however, an adverse effect associated with solifenacin can occur, as this report clearly demonstrates. 23936181 Task and spatial frequency modulations of object processing: an EEG study. Visual object processing may follow a coarse-to-fine sequence imposed by fast processing of low spatial frequencies (LSF) and slow processing of high spatial frequencies (HSF). Objects can be categorized at varying levels of specificity: the superordinate (e.g. animal), the basic (e.g. dog), or the subordinate (e.g. Border Collie). We tested whether superordinate and more specific categorization depend on different spatial frequency ranges, and whether any such dependencies might be revealed by or influence signals recorded using EEG. We used event-related potentials (ERPs) and time-frequency (TF) analysis to examine the time course of object processing while participants performed either a grammatical gender-classification task (which generally forces basic-level categorization) or a living/non-living judgement (superordinate categorization) on everyday, real-life objects. Objects were filtered to contain only HSF or LSF. We found a greater positivity and greater negativity for HSF than for LSF pictures in the P1 and N1 respectively, but no effects of task on either component. A later, fronto-central negativity (N350) was more negative in the gender-classification task than the superordinate categorization task, which may indicate that this component relates to semantic or syntactic processing. We found no significant effects of task or spatial frequency on evoked or total gamma band responses. Our results demonstrate early differences in processing of HSF and LSF content that were not modulated by categorization task, with later responses reflecting such higher-level cognitive factors. 23507144 Tau hyperphosphorylation and increased BACE1 and RAGE levels in the cortex of PPARβ/δ-null mice. The role of peroxisome proliferator activator receptor (PPAR)β/δ in the pathogenesis of Alzheimer's disease has only recently been explored through the use of PPARβ/δ agonists. Here we evaluated the effects of PPARβ/δ deficiency on the amyloidogenic pathway and tau hyperphosphorylation. PPARβ/δ-null mice showed cognitive impairment in the object recognition task, accompanied by enhanced DNA-binding activity of NF-κB in the cortex and increased expression of IL-6. In addition, two NF-κB-target genes involved in β-amyloid (Aβ) synthesis and deposition, the β site APP cleaving enzyme 1 (Bace1) and the receptor for advanced glycation endproducts (Rage), respectively, increased in PPARβ/δ-null mice compared to wild type animals. The protein levels of glial fibrillary acidic protein (GFAP) increased in the cortex of PPARβ/δ-null mice, which would suggest the presence of astrogliosis. Finally, tau hyperphosphorylation at Ser199 and enhanced levels of PHF-tau were associated with increased levels of the tau kinases CDK5 and phospho-ERK1/2 in the cortex of PPARβ/δ(-/-) mice. Collectively, our findings indicate that PPARβ/δ deficiency results in cognitive impairment associated with enhanced inflammation, astrogliosis and tau hyperphosphorylation in the cortex. 23913275 Oxytocin enhances hippocampal spike transmission by modulating fast-spiking interneurons. Neuromodulatory control by oxytocin is essential to a wide range of social, parental and stress-related behaviours. Autism spectrum disorders (ASD) are associated with deficiencies in oxytocin levels and with genetic alterations of the oxytocin receptor (OXTR). Thirty years ago, Mühlethaler et al. found that oxytocin increases the firing of inhibitory hippocampal neurons, but it remains unclear how elevated inhibition could account for the ability of oxytocin to improve information processing in the brain. Here we describe in mammalian hippocampus a simple yet powerful mechanism by which oxytocin enhances cortical information transfer while simultaneously lowering background activity, thus greatly improving the signal-to-noise ratio. Increased fast-spiking interneuron activity not only suppresses spontaneous pyramidal cell firing, but also enhances the fidelity of spike transmission and sharpens spike timing. Use-dependent depression at the fast-spiking interneuron-pyramidal cell synapse is both necessary and sufficient for the enhanced spike throughput. We show the generality of this novel circuit mechanism by activation of fast-spiking interneurons with cholecystokinin or channelrhodopsin-2. This provides insight into how a diffusely delivered neuromodulator can improve the performance of neural circuitry that requires synapse specificity and millisecond precision. 23947918 Evaluating using ATR-FTIR spectroscopy the binding mechanisms of ZnO nanoparticles and Zn2+ to Chelex®-100 and Metsorb™ Advancements in nanotechnology and the expected increase in production of commercial products with incorporated manufactured nanomaterials will very likely lead to increasing contamination of nanoparticles (NPs) in the environment. Though studying adverse impacts of NPs in the environment and their ecotoxicological fate and behaviour is not new, limited information is available. A major challenge in this respect is the lack of a proper sampling technique that could provide data about concentrations of these agents in the environment. Diffusive gradient in thin-films (DGT) is a well-established method that is able to measure available concentration of trace metals in soil and water. Using this approach, different binding resins are employed as a sink to collect targeted chemicals during known times. Here, we examine the suitability of two common types of the DGT binding agents, commercially available Chelex®-100 and Metsorb™, to investigate whether these materials could irreversibly retain a model nanoparticle, ZnO, and if so, what would be the difference between bound ZnO NP and Zn2+ ion. Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy was used to study the binding materials before and after exposure to ZnO NP and Zn2+. Based on computational analysis using principal component analysis and linear discriminant analysis (PCA-LDA), it was determined that both Chelex®-100 and Metsorb™ form chemical bonds with ZnO NP and Zn2+, however the binding mechanisms of these zinc species as inferred from their infrared (IR) spectra are statistically different (95% confidence level). The experimental results suggest that the binding resins hold ZnO NP with fewer and weaker chemical bonds compared to Zn2+. This research demonstrates the potential of DGT method to measure available concentrations of nanoparticles in the environment and highlights a potential role for ATR-FTIR spectroscopy when used with computational analysis to differentiate between chemical bond formations. 23823131 Alginate-chitosan-PLGA composite microspheres induce both innate and adaptive immune response through parenteral immunization in fish. Alginate-chitosan-PLGA composite microspheres encapsulating outer membrane protein antigen of Aeromonas hydrophila as an antigen carrier was explored for the first time in a fish model. This composite microsphere showed distinct advantages over the conventional PLGA microparticles in aspects of the high encapsulation efficiency due to the protein-friendly microenvironment created by the hydrophilic alginate-chitosan cores of the composite microspheres, preventing initial burst release and the elimination of lyophilizing process. The antibody responses significantly increased and persist up to 9 weeks in composite microspheres unlike that PLGA microsphere, native OMP and FIA adjuvant. Moreover, several innate immune parameters as respiratory burst, lysozyme and complement activity were significantly increased in both composite and PLGA microspheres up to 9 weeks than other treated groups. It also gives protection from A. hydrophila infection and brought some hope, for its application in replacement with conventional PLGA microparticle for antigen delivery in fish. 23925342 Excitotoxic injury to thoracolumbar gray matter alters sympathetic activation and thermal pain sensitivity. Studies of humans, monkeys and rodents have implicated combined gray and white matter damage as important for development of chronic pain following spinal cord injury (SCI). Below-level chronic pain and hyperalgesia following injury to the spinal white matter, including the spinothalamic tract (STT), can be enhanced by excitotoxic influences within the gray matter at the site of SCI. Also, excitotoxic injury of thoracic gray matter without interruption of the STT results in below-level heat hyperalgesia. The present study evaluates the possibility that thoracolumbar gray matter injury increases sensitivity to nociceptive heat stimulation by altering spinal sympathetic outflow. Thermal preferences of rats for heat (45 °C) versus cold (15 °C) were evaluated before and after thoracolumbar injections of quisqualic acid (QUIS). A pre-injury preference for heat changed to a post-injury preference for cold. Systemic activation of the sympathetic nervous system by restraint stress decreased the heat preference pre-injury and increased the cold preference post-injury. The heat aversive effect of stress was magnified and prolonged post-injury, compared to pre-injury. Also, peripheral sympathetic activation by nociceptive stimulation was evaluated pre- and post-injury by measuring thermal transfer through a hindpaw during stimulation with 44.5 °C. Skin temperature recordings revealed enhanced sympathetic activation by nociceptive heat stimulation following spinal QUIS injury. However, increased sympathetic activation with peripheral vasoconstriction should enhance cold aversion, in contrast to the observed increase in heat aversion. Thus, peripheral sympathetic vasoconstriction can be ruled out as a mechanism for heat hyperalgesia following excitotoxic gray matter injury. 23882067 Congenital heart disease beyond the age of 60: emergence of a new population with high resource utilization, high morbidity, and high mortality. The population of adults with congenital heart disease (ACHD) is growing and ageing. Limited information about the diagnostic spectrum of this emerging population, its resource utilization at tertiary ACHD centres, and especially about prognostic parameters is available. Retrospective cohort study on all ACHD patients ≥60 years of age under active follow-up. All-cause mortality was the primary outcome measure. Out of a total population of 7315 ACHD patients, 375 [190 females (50.7%), mean age 64.8 ± 5.9 years] fulfilled the inclusion criteria. During a median follow-up of 5.5 (IQR 3.1-8.6) years, 55 of the 375 patients died. The number of interventions (P = 0.0006), the number and length of hospitalization (P < 0.0001), and the number of outpatient clinic visits (P < 0.0001) were significantly higher in patients ≥60 compared with patients aged between 20 and 60 years. Patients ≥60 years of age with moderate or severe congenital heart defects had worse survival prospects than their age- and gender-matched comparison population. On multivariate Cox analysis, coronary artery disease [hazard ratio (HR): 5.04; 95%CI: 1.88-13.51, P = 0.0014], symptoms of heart failure (HR: 2.36; 95%CI: 1.05-5.29, P < 0.05), NYHA class (HR: 1.96; 95%CI: 1.18-3.26, P < 0.01), and moderate to severe reduction in systemic ventricular systolic function (HR: 1.90; 95%CI: 1.20-2.99, P < 0.001) were the strongest prognostic factors. There is a growing number of elderly ACHD patients with high mortality rates and a higher utilization of healthcare resources compared with younger patients. Acquired morbidities, such as coronary artery disease, seem to be key determinants of outcome in this older population in conjunction with the underlying congenital heart disease. 23862919 Communication: Spin-free quantum computational simulations and symmetry adapted states. The ideas of digital simulation of quantum systems using a quantum computer parallel the original ideas of numerical simulation using a classical computer. In order for quantum computational simulations to advance to a competitive point, many techniques from classical simulations must be imported into the quantum domain. In this article, we consider the applications of symmetry in the context of quantum simulation. Building upon well established machinery, we propose a form of first quantized simulation that only requires the spatial part of the wave function, thereby allowing spin-free quantum computational simulations. We go further and discuss the preparation of N-body states with specified symmetries based on projection techniques. We consider two simple examples, molecular hydrogen and cyclopropenyl cation, to illustrate the ideas. The methods here are the first to explicitly deal with preparing N-body symmetry-adapted states and open the door for future investigations into group theory, chemistry, and quantum simulation. 23211714 Effects of probiotic Lactobacillus rhamnosus GG and Propionibacterium freudenreichii ssp. shermanii JS supplementation on intestinal and systemic markers of inflammation in ApoE*3Leiden mice consuming a high-fat diet. A high-fat diet disturbs the composition and function of the gut microbiota and generates local gut-associated and also systemic responses. Intestinal mast cells, for their part, secrete mediators which play a role in the orchestration of physiological and immunological functions of the intestine. Probiotic bacteria, again, help to maintain the homeostasis of the gut microbiota by protecting the gut epithelium and regulating the local immune system. In the present study, we explored the effects of two probiotic bacteria, Lactobacillus rhamnosus GG (GG) and Propionibacterium freudenreichii spp. shermanii JS (PJS), on high fat-fed ApoE*3Leiden mice by estimating the mast cell numbers and the immunoreactivity of TNF-α and IL-10 in the intestine, as well as plasma levels of several markers of inflammation and parameters of lipid metabolism. We found that mice that received GG and PJS exhibited significantly lower numbers of intestinal mast cells compared with control mice. PJS lowered intestinal immunoreactivity of TNF-α, while GG increased intestinal IL-10. PJS was also observed to lower the plasma levels of markers of inflammation including vascular cell adhesion molecule 1, and also the amount of gonadal adipose tissue. GG lowered alanine aminotransferase, a marker of hepatocellular activation. Collectively, these data demonstrate that probiotic GG and PJS tend to down-regulate both intestinal and systemic pro-inflammatory changes induced by a high-fat diet in this humanised mouse model. 23743002 National Trends in Pelvic Inflammatory Disease Among Adolescents in the Emergency Department. In 2002, the Centers for Disease Control and Prevention (CDC) broadened the pelvic inflammatory disease (PID) diagnostic criteria to increase detection and prevent serious sequelae of untreated PID. The impact of this change on PID detection is unknown. Our objectives were to estimate trends in PID diagnosis among adolescent emergency department (ED) patients before and after the revised CDC definition and to identify factors associated with PID diagnoses. We performed a retrospective repeated cross-sectional study using the National Hospital Ambulatory Medical Care Survey from 2000 to 2009 of ED visits by 14- to 21-year-old females. We calculated national estimates of PID rates and performed multivariable logistic regression analyses and tests of trends. During 2000-2009, of the 77 million female adolescent ED visits, there were an estimated 704,882 (95% confidence interval [CI], 571,807-837,957) cases of PID. After the revised criteria, PID diagnosis declined from 5.4 cases per 1,000 United States adolescent females to 3.9 cases per 1,000 (p = .03). In a multivariable model, age ≥17 years (odds ratio, 2.14; 95% CI, 1.25-3.64) and black race (odds ratio, 2.04; 95% CI, 1.36-3.07) were associated with PID diagnosis. Despite broadened CDC diagnostic criteria, PID diagnoses did not increase over time. This raises concern about awareness and incorporation of the new guidelines into clinical practice. 23870864 Protective role of Punica granatum (pomegranate) peel and seed oil extracts on diethylnitrosamine and phenobarbital-induced hepatic injury in male rats. The present study is an attempt to reveal the protective role of Punica granatum peel and seed oil extracts against diethylnitrosamine (DEN) and phenobarbital (PB) induced hepatic injury in rats. DEN administration increased the levels of malondialdehyde (MDA), DNA fragmentation, caspase-3 and glutathione reductase (GSR) activities, while the level of reduced glutathione (GSH) and the activities of superoxide dismutase (SOD), glutathione S-transferase (GST) and total glutathione peroxidase (t-GPx) were decreased compared with the control. Treatment with peel and seed oil extracts pre, during and post DEN administration improved liver functions, decreased the levels of MDA, DNA fragmentation, caspase-3 and GSR activities with an elevation in levels of GSH, SOD, GST and t-GPx activities. This indicates that these extracts reduced the oxidative stress and apoptosis induced by DEN. Also the effect of administration of PE and SOE separately for a long time (23weeks) on healthy rats was studied. 23946840 Hypervalent iodine/TEMPO-mediated oxidation in flow systems: a fast and efficient protocol for alcohol oxidation. Hypervalent iodine(III)/TEMPO-mediated oxidation of various aliphatic, aromatic and allylic alcohols to their corresponding carbonyl compounds was successfully achieved by using microreactor technology. This method can be used as an alternative for the oxidation of various alcohols achieving excellent yields and selectivities in significantly shortened reaction times. 23858469 Oxygen-sensitive mitochondrial accumulation of cystathionine β-synthase mediated by Lon protease. Oxygen-sensitive accumulation and degradation, two opposite but intrinsically linked events, of heme proteins in mitochondria affect mitochondrial functions, including bioenergetics and oxygen-sensing processes. Cystathionine β-synthase (CBS) contains a prosthetic heme group and catalyzes the production of hydrogen sulfide in mammalian cells. Here we show that CBS proteins were present in liver mitochondria at a low level under normoxia conditions. Ischemia/hypoxia increased the accumulation of CBS proteins in mitochondria. The normalization of oxygen partial pressure accelerated the degradation of CBS proteins. Lon protease, a major degradation enzyme in mitochondrial matrix, recognized and degraded mitochondrial CBS by specifically targeting at the oxygenated heme group of CBS proteins. The accumulation of CBS in mitochondria increased hydrogen sulfide production, which prevented Ca(2+)-mediated cytochrome c release from mitochondria and decreased reactive oxygen species generation. Mitochondrial accumulation of heme oxygenase-1, another heme protein, was also regulated by oxygen level and Lon protease in the same mechanism as for CBS. Our findings provide a fundamental and general mechanism for oxygen-sensitive regulation of mitochondrial functions by linking oxygenation level to the accumulation/degradation of mitochondrial heme proteins. 23738828 Toroid formation through self-assembly of graft copolymer and homopolymer mixtures: experimental studies and dissipative particle dynamics simulations. Self-assembly of mixture systems containing poly(acrylic acid)-g-poly(γ-benzyl-L-glutamate) graft copolymers (PAA-g-PBLG) and PBLG homopolymers in aqueous solution was investigated by both experiments and computer simulations. It was found that the aggregate morphologies, such as rods, curved rods, and toroids, could be tuned by the homopolymer content. The toroidal micelles with uniform size were formed when the homopolymer content in the hybrid aggregates is higher. The effect of added water content on the toroid formation process was studied. Rods and curved rods were observed sequentially before formation of toroids. We also performed dissipative particle dynamics (DPD) simulations to verify the structure transition and explore the formation mechanism of the toroidal aggregates. The DPD results are in good agreement with the experimental findings and provide additional information such as chain distribution in aggregates, which is difficult to be gained through experiments. On the basis of the experimental and simulation results, the formation mechanism of the toroidal micelles was suggested. 23969359 Changing the Culture of Academic Medicine to Eliminate the Gender Leadership Gap: 50/50 by 2020. Central to the daily struggles that successful working women face is the misalignment of the current work culture and the values of the workforce. In addition to contributing to work-life integration conflicts, this disconnect perpetuates the gender leadership gap. The dearth of women at the highest ranks of academic medicine not only sends a clear message to women that they must choose between career advancement and their personal life but also represents a loss of talent for academic health centers as they fail to recruit and retain the best and the brightest. To close the gender leadership gap and to meet the needs of the next generation of physicians, scientists, and educators, the authors argue that the culture of academic medicine must change to one in which flexibility and work-life integration are core parts of the definition of success. Faculty must see flexibility policies, such as tenure clock extensions and parental leaves, as career advancing rather than career limiting. To achieve these goals, the authors describe the Stanford University School of Medicine Academic Biomedical Career Customization (ABCC) model. This framework includes individualized career plans, which span a faculty member's career, with options to flex up or down in research, patient care, administration, and teaching, and mentoring discussions, which ensure that faculty take full advantage of the existing policies designed to make career customization possible. The authors argue that with vision, determination, and focus, the academic medicine community can eliminate the gender leadership gap to achieve 50/50 by 2020. 23952611 NMR Spectroscopic Approach Reveals Metabolic Diversity of Human Blood Plasma Associated with Protein-Drug Interaction. Although blood plasma has been used to diagnose diseases and to evaluate physiological conditions, it is not easy to establish a global normal concentration range for the targeting components in the plasma due to the inherent metabolic diversity. We showed here that NMR spectroscopy coupled with principal component analysis (PCA) may provide a useful method for quantitatively characterizing metabolic diversity of human blood plasma. We analyzed 70 human blood plasma samples with and without addition of ibuprofen. By defining the PC score values as diversity index (Idiv) and the drug induced PC score value change as interaction index (Idist), we find that the two indexes are highly correlated (P<0.0001). Triglycerides, choline contained phospholipids, lactate and pyruvate are associated with both indexes (P<0.0001), respectively. In addition, significant amount of lactate and pyruvate are in the NMR "invisible" bound forms and can be replaced by ibuprofen. The diffusion and transverse relaxation time weighted NMR approaches give rise to a better characterization of the diversity and the interaction than that of the one acquired using NOESYPR1D with 100 ms mixing time. These results might be useful for understanding the blood plasma-drug interaction and personalized therapy. 23575191 Critical concepts in elder abuse research. This paper identifies core elements in principal definitions of elder abuse or mistreatment of older adults (EA/MOA) and discusses the relevance of four crucial concepts: age, vulnerability, trust, and power balance in relationships. A critical analysis of selected literature in EA/MOA with a focus on works from the last 10 years. Current definitions of EA/MOA share commonalities regarding an understanding of elder abuse as a status offence, the inclusion of both acts and omissions, and the consideration of multiple levels of behavior and its effects. Definitions differ with regard to aspects as crucial as the intentionality of an abusive action and its actual or potential harmful effects. EA/MOA can be considered as a complex subtype of victimization in later life limited to victim-perpetrator relationships, where the perpetrator has assumed responsibility for the victim, the victim puts trust in the offender, or the role assigned to the offending person creates the perception and expectation that the victim may trust the perpetrator. Vulnerability is identified as a key variable in EA/MOA theory and research. With regard to neglect, the mere possibility of being neglected presupposes a heightened level of vulnerability. Power imbalance often characterizes victim - perpetrator relationships but is not a necessary characteristic of abuse. Research on EA/MOA needs conceptual development. Confining phenomena of EA/MOA to specific relationships and tying them to notions of vulnerability has implications for research design and sampling and points to the limits of population-based victimization surveys. 23515495 Transforming growth factor beta 1 and monocyte chemoattractant protein-1 as prognostic markers of diabetic nephropathy. We aimed to find the relationship between serum transforming growth factor beta 1(TGF-β1) and urinary monocyte chemoattractant protein-1 (MCP-1) throughout the course of diabetic nephropathy (DN) and to assess the relationship between both levels and other parameters of renal injury such as albumin/creatinine ratio and estimated glomerular filtration rate (eGFR). Serum TGF-β1, urinary MCP-1, eGFR, and glycosylated hemoglobin (HbA1c) were measured in 60 patients with type II diabetes mellitus with different degrees of nephropathy (20 patients with normoalbuminuria, 20 patients with microalbuminuria, and 20 patients with macroalbuminuria) and compared with 20 matched healthy control subjects. Both the levels of serum TGF-β1 and urinary MCP-1 were significantly higher in patients with micro- and macroalbuminuria (137.8 ± 69.5 and 329.25 ± 41.46 ng/dl, respectively, for TGF-β1 and 167.41 ± 50.23 and 630.87 ± 318.10 ng/g creatinine, respectively, for MCP-1) compared with normoalbuminuric patients and healthy controls (33.25 ± 17.5 and 29.64 ± 10.57 ng/dl, respectively, for TGF-β1 and 63.85 ± 21.15 and 61.50 ± 24.81 ng/g creatinine, respectively, for MCP-1; p < 0.001). There was a positive significant correlation between the levels of serum TGF-β1 and those of urinary MCP-1 (r = 0.73, p < 0.001). Also, serum TGF-β1 and urinary MCP-1 correlated positively with HbA1c (r = 0.49 and 0.55, respectively, p < 0.05 for both) and inversely with eGFR (r = -0.69 and -0.60, respectively, p < 0.001 for both). We can conclude that serum TGF-β1 and urinary MCP-1 can be used as the markers for detection of progression of DN. Antagonizing TGF-β1 and MCP-1 might be helpful in attenuating the progression of nephropathy in diabetic patients. 23684811 Immune responses during the larval stages of Mytilus galloprovincialis: metamorphosis alters immunocompetence, body shape and behavior. We investigated the development of the immune system during the larval stages of the mussel Mytilus galloprovincialis. The ability of trochophore and veliger larvae to phagocytose foreign particles (Escherichia coli and zymosan) was measured. Phagocytosis was detected as early as 24 h post-fertilization (hpf) using flow cytometry and fluorescence microscopy. However, although there was a high basal production of reactive oxygen and nitrogen species (ROS and NRS), the phagocytosis of zymosan did not trigger an associated increase in radical production. In addition, a panel of immune-related mussel genes (Myticin B, Myticin C, Mytilin B, Mytimycin precursor 1, Macrophage migration inhibition factor, lysozyme, C1q, membrane attack complex protein and fibrinogen-related protein) was selected for expression profile analysis throughout the different developmental stages (trochophore, veliger, metamorphosis, post-settlement and spat). The expression of these genes increased during the transition from trochophore to spat, and the level of expression was higher in oocytes than in trochophores, suggesting that gene expression during the first larval stages might be maternal in origin. Metamorphosis was identified as a crucial stage when larvae increased the expression of immune-related genes and responded to environmental signals. Whole-mount in situ hybridization studies showed the mantle edge as an important area in the development of immunocompetence in bivalve larvae. Larvae responded to both live and heat-inactivated bacteria by modulating expression of immune-related genes. Altogether, our results support that during the early stages of M. galloprovincialis development, immune mechanisms emerge to aid larvae in managing infections. 23832020 Pyloric atresia with epidermolysis bullosa: fetal MRI diagnosis with postnatal correlation. Pyloric atresia is an uncommon congenital gastric outlet obstruction, accounting for only 1% of gastrointestinal atresias. Up to 55% of cases have associated anomalies, the most common of which is epidermolysis bullosa. Fetal MRI findings of the epidermolysis bullosa-pyloric atresia association have not been previously reported. We present a case of this association diagnosed by prenatal MRI with corroborative postnatal imaging and surgical findings. 23738985 Occupational exposures of airborne trichloramine at indoor swimming pools in Taipei. Ten indoor swimming pools in Taipei, Taiwan were included in the study to assess the exposure of people to airborne trichloramine (NCl3) and also to discover the factors that might affect the associated concentrations. An active air sampling method was performed to determine the levels of NCl3, while questionnaires were administered to swimming pool workers, including lifeguards, swimming instructors, and management employees. The results show that the concentrations of trichloramine ranged from 0.017 to 0.15mgm(-3), which were generally lower than what have been reported from other studies. Symptoms of sore throat and phlegm were more frequent among lifeguards and swimming instructors (exposure group) than management employees (reference group) (odds ratios were 11.28 and 4.22 for sore throat and phlegm, respectively). It seems that the current exposure limit for airborne NCl3, which was recommended by WHO, was not lower enough to protect the health of pool attendants. Regulated level of free available chlorine in Taipei (i.e., 0.3-0.7ppm) is lower than what is required in other countries (e.g., 1-3ppm in the UK). This might be the main reason why the concentrations of NCl3 reported elsewhere were higher than what were found in this research. Further international comparisons will help to elucidate if low free chlorine concentration should be adopted as an operating standard. For the indoor swimming pools in Taipei, the air quality is suggested to be improved, since even with the low concentrations of NCl3, higher respiratory ailments among pool workers were observed. 23536525 Distinct set of kinases induced after retrieval of spatial memory discriminate memory modulation processes in the mouse hippocampus. Protein phosphorylation and dephosphorylation events play a key role in memory formation and various protein kinases and phosphatases have been firmly associated with memory performance. Here, we determined expression changes of protein kinases and phosphatases following retrieval of spatial memory in CD1 mice in a Morris Water Maze task, using antibody microarrays and confirmatory Western blot. Comparing changes following single and consecutive retrieval, we identified stably and differentially expressed kinases, some of which have never been implicated before in memory functions. On the basis of these findings we define a small signaling network associated with spatial memory retrieval. Moreover, we describe differential regulation and correlation of expression levels with behavioral performance of polo-like kinase 1. Together with its recently observed genetic association to autism-spectrum disorders our data suggest a role of this kinase in balancing preservation and flexibility of learned behavior. © 2013 Wiley Periodicals, Inc. 23872124 Can proton pumping by SERCA enhance the regulatory role of phospholamban and sarcolipin? The effect of the incorporation of phosphorylated phospholamban (pPLN) and sarcolipin (SLN) in mercury-supported self-assembled lipid monolayers and in lipid bilayers tethered to mercury via a hydrophilic spacer was investigated by voltammetric techniques and electrochemical impedance spectroscopy. It was shown that pPLN and SLN do not permeabilize lipid bilayers toward ions at physiological pH. However, they exert a permeabilizing action toward inorganic monovalent cations such as K(+) and Tl(+), but not toward divalent cations such as Ca(2+) and Cd(2+), following a small decrease in pH. This behavior can be associated with their regulatory action on the Ca-ATPase of the sarcoplasmic reticulum (SERCA). SERCA pumps two Ca(2+) ions from the cytosol to the lumen of the sarcoplasmic reticulum (SR) and two protons in the opposite direction, causing a transient decrease of pH in the immediate vicinity of its cytoplasmic domain. This decrease is expected to activate the liberated pPLN molecules and SLN to make the SR membrane leakier toward K(+) and Na(+) and the SLN ion channel to translocate small inorganic anions, such as Cl(-). The effect of pPLN and SLN, which becomes synergic when they are both present in the SR membrane, is expected to favor a rapid equilibration of ions on both sides of the membrane. 23727906 Temperature-responsive enzyme-polymer nanoconjugates with enhanced catalytic activities in organic media. A general approach for preparing enzyme-polymer nanoconjugates that respond to temperature in organic media is presented. These nanoconjugates readily dissolve in organic solvents for homogenous catalysis at 40 °C and showed greatly enhanced apparent catalytic activities. The recovery of the soluble enzyme-polymer nanoconjugates is accomplished by temperature-induced precipitation. 23459935 Exclusive skeletal muscle correction does not modulate dystrophic heart disease in the aged mdx model of Duchenne cardiomyopathy. Duchenne muscular dystrophy (DMD) is characterized by severe degeneration and necrosis of both skeletal and cardiac muscle. While many experimental therapies have shown great promise in treating skeletal muscle disease, an effective therapy for Duchenne cardiomyopathy remains a challenge in large animal models and human patients. The current views on cardiac consequences of skeletal muscle-centered therapy are controversial. Studies performed in young adult mdx mice (a mild DMD mouse model) have yielded opposing results. Since mdx mice do not develop dystrophic cardiomyopathy until ≥21 months of age, we reasoned that old mdx mice may represent a better model to assess the impact of skeletal muscle rescue on dystrophic heart disease. Here, we aged skeletal muscle-specific micro-dystrophin transgenic mdx mice to 23 months and examined the cardiac phenotype. As expected, transgenic mdx mice had minimal skeletal muscle disease and they also outperformed original mdx mice on treadmill running. On cardiac examination, the dystrophin-null heart of transgenic mdx mice displayed severe cardiomyopathy matching that of non-transgenic mdx mice. Specifically, both the strains showed similar heart fibrosis and cardiac function deterioration in systole and diastole. Cardiac output and ejection fraction were also equally compromised. Our results suggest that skeletal muscle rescue neither aggravates nor alleviates cardiomyopathy in aged mdx mice. These findings underscore the importance of treating both skeletal and cardiac muscles in DMD therapy. 23570985 Development and evaluation of novel solid nanodispersion system for oral delivery of poorly water-soluble drugs. The aim of the present study was to develop and evaluate a novel drug solubilization platform (so-called solid nanodispersion) prepared by a simple co-grinding and solvent-free process. Using structurally diverse model compounds from the Pfizer drug library, including ingliforib, furosemide and celecoxib, we successfully prepared stable solid nanodispersions (SNDs) without the use of solvent or heat. Stable colloidal particles (<350nm) containing drug, polyvinylpyrrolidone (PVP) K12 and sodium dodecyl sulfate (SDS) in 1:2.75:0.25 ratio were produced after 2h of co-grinding. The composition and particle size of SNDs were optimized by varying the grinding media size, powder-to-grinding media ratio, milling speed and milling time. The resulting formulations contained crystalline drug and were stable at room temperature for over one month. Greater than 80% of the drug was released from the SND in less than 30min, with sustained supersaturation over 4h. Using furosemide (BCS class IV compound) as a model compound, we conducted transport studies with Madin-Darby canine kidney cells transfected with human MDR1 gene (MDCK/MDR1), followed by pharmacokinetics studies in rats. Results showed that the SND formulation enhanced the absorptive flux of furosemide by more than 3-fold. In the pharmacokinetics studies, the SND formulation increased Cmax and AUC of furosemide by 36.6 and 43.2 fold respectively, relative to Methocel formulation. Interestingly, physical mixture containing furosemide, PVP K12 and SDS produced a similar level of oral exposure as the SNDs, albeit with a longer Tmax than the SND formulation. The results suggest that PVP K12 and SDS were able to increase the furosemide free fraction available for oral absorption. Low solubility, poor permeability, and high first-pass effect of furosemide may also have produced the effect that small improvements in solubilization resulted in significant potentiation of the oral exposure of the physical mixture. However the use of a physical mixture of drug, polymer and surfactant, to increase drug bioavailability cannot be generalized to all drugs. There are only a few reported cases of such phenomenon. While SNDs may not be the only option to solubilize compounds in every case, SNDs are expected to be applicable to a broader chemical space of pharmaceutical compounds compared to a physical mixture. Ultimately, formulation scientists have to exercise judgment in choosing the appropriate formulation strategy for the compound of interest. SNDs represent a significant improvement over current enabling technologies such as nanocrystal and spray-dried dispersion technologies, in that SNDs are simple, do not require solvent or heat, are applicable to a structurally diverse chemical space, and are amenable to the development of solid dosage forms. 23911822 α1β1 Integrin/Rac1-Dependent Mesangial Invasion of Glomerular Capillaries in Alport Syndrome. Alport syndrome, hereditary glomerulonephritis with hearing loss, results from mutations in type IV collagen COL4A3, COL4A4, or COL4A5 genes. The mechanism for delayed glomerular disease onset is unknown. Comparative analysis of Alport mice and CD151 knockout mice revealed progressive accumulation of laminin 211 in the glomerular basement membrane. We show mesangial processes invading the capillary loops of both models as well as in human Alport glomeruli, as the likely source of this laminin. l-NAME salt-induced hypertension accelerated mesangial cell process invasion. Cultured mesangial cells showed reduced migratory potential when treated with either integrin-linked kinase inhibitor or Rac1 inhibitor, or by deletion of integrin α1. Treatment of Alport mice with Rac1 inhibitor or deletion of integrin α1 reduced mesangial cell process invasion of the glomerular capillary tuft. Laminin α2-deficient Alport mice show reduced mesangial process invasion, and cultured laminin α2-null cells showed reduced migratory potential, indicating a functional role for mesangial laminins in progression of Alport glomerular pathogenesis. Collectively, these findings predict a role for biomechanical insult in the induction of integrin α1β1-dependent Rac1-mediated mesangial cell process invasion of the glomerular capillary tuft as an initiation mechanism of Alport glomerular pathology. 23524017 Bronchodilation and safety of supratherapeutic doses of salbutamol or ipratropium bromide added to single dose GSK961081 in patients with moderate to severe COPD. There are few data on the bronchodilatory effects of adding short-acting bronchodilators (SABA) to maintenance, long-acting bronchodilator therapy. This study assessed the additional bronchodilation and safety of adding supratherapeutic doses of salbutamol (SALB) or ipratropium bromide (IPR) to the novel bi-functional molecule (or dual pharmacophore) GSK961081 400 Î¼g (MABA 400) or 1200 Î¼g (MABA 1200). This randomised, double-blind, complete, crossover study in 44 patients with moderate to severe COPD, evaluated 6 treatments with a washout of at least 7 days between treatments: single doses of MABA 400 or MABA 1200 followed by cumulative doses of either SALB (3× 200 Î¼g at 20 min intervals), IPR (20 Î¼g, 20 Î¼g and 40 Î¼g at 20 min intervals) or placebo (PLA) (three doses at 20 min intervals) at 1 h, 12 h and 24 h post-MABA dose. The primary endpoint was maximal increase in FEV1, from pre-dose bronchodilator (SABA/PLA), measured 15 min after each cumulative dose of SALB, IPR or PLA. Systemic pharmacodynamics (potassium, heart rate, glucose and QTc), adverse events and systemic pharmacokinetics were also assessed. The additional bronchodilatory effects at 12 h and 24 h for both SALB and IPR were of a similar magnitude and statistically significant relative to PLA; mean differences (SE) (L) following MABA 400 dosing: 0.139 (0.023) after SALB at 12 h; 0.123 (0.022) after SALB at 24 h; 0.124 (0.023) after IPR at 12 h; 0.141 (0.021) after IPR at 24 h; and after MABA 1200 dosing: 0.091 (0.023) after SALB at 12 h; 0.126 (0.022) after SALB at 24 h; 0.055 (0.023) after IPR at 12 h; 0.122 (0.022) after IPR at 24 h. Any additional bronchodilator effects at 1 h were small and not clinically significantly different from PLA. There were small, non-clinically significant increases in mean heart rate after both MABA doses plus SALB, and decreased potassium levels in four patients after MABA 1200 plus SALB (×3) or PLA (×1) were observed but overall all treatments were well tolerated and raised no significant safety signals. The additional bronchodilation achieved following supratherapeutic doses of SALB and IPR on top of single doses of MABA 400 or 1200 was comparable for the two agents and neither were associated with any clinically relevant systemic pharmacodynamic effects other than the small transient hypokalemic effect in a 3 out of 41 patients receiving additional high dose salbutamol and MABA 1200. Either short-acting bronchodilator could potentially be used as rescue medication on top of MABA therapy. 23908459 Does income inequality get under the skin? A multilevel analysis of depression, anxiety and mental disorders in Sao Paulo, Brazil. Test the original income inequality theory, by analysing its association with depression, anxiety and any mental disorders. We analysed a sample of 3542 individuals aged 18 years and older selected through a stratified, multistage area probability sample of households from the São Paulo Metropolitan Area. Mental disorder symptoms were assessed using the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Bayesian multilevel logistic models were performed. Living in areas with medium and high-income inequality was statistically associated with increased risk of depression, relative to low-inequality areas (OR 1.76; 95% CI 1.21 to 2.55, and 1.53; 95% CI 1.07 to 2.19, respectively). The same was not true for anxiety (OR 1.25; 95% CI 0.90 to 1.73, and OR 1.07; 95% CI 0.79 to 1.46). In the case of any mental disorder, results were mixed. In general, our findings were consistent with the income inequality theory, that is, people living in places with higher income inequality had an overall higher odd of mental disorders, albeit not always statistically significant. The fact that depression, but not anxiety, was statistically significant could indicate a pathway by which inequality influences health. 23095322 Subclinical Cardiomyopathy and Long QT Syndrome: An Echocardiographic Observation. Long QT syndrome (LQTS) is a cardiac channelopathy predisposing to syncope and sudden death secondary to LQT-triggered ventricular arrhythmias. Long QT syndrome has been regarded as a purely electrical disease. Recent reports have shown by echocardiography that LQTS patients have contraction abnormalities that are associated with cardiac arrhythmias. The purpose of this study was to determine the spectrum and prevalence of echocardiographic anomalies in a large cohort of patients diagnosed genetically and/or clinically with LQTS. Two-dimensional and Doppler echocardiographic studies performed during medical evaluation in Mayo's LQTS Clinic were reviewed for 216 LQTS patients. Echocardiograms were evaluated for morphologic abnormalities and atrial and ventricular size and function. Left atrial volume was indexed by body mass. Arrhythmic events were defined as a history of aborted cardiac arrest, documented ventricular tachycardia or fibrillation, and syncope. While 75% of patients had normal standard echocardiograms, 54 patients (25%) had at least one abnormal echocardiographic finding. Most common were subclinical cardiomyopathic changes, including increased left atrial volume index (n = 25), left or right ventricular enlargement (n = 7), and grade I-II diastolic dysfunction (n = 7). Left atrial volume index was higher in LQTS patients with arrhythmic events compared with those without (24.4 ± 5.5 mL/m(2) vs. 22.3 ± 6.1 mL/m(2) , P =.02). Corrected QT intervals and left atrial volume index correlated significantly albeit weakly (r(2) = 0.04, P <.01). Concomitant congenital heart disease was found in two patients. Subclinical cardiomyopathic changes were found in nearly 20% of LQTS patients. Left atrial enlargement was the most common finding and was associated with prolonged corrected QT and arrhythmic events. These changes may stem from underlying contraction abnormalities caused by ion channel dysfunction. 23900942 Free-breathing phase contrast MRI with near 100% respiratory navigator efficiency using k-space-dependent respiratory gating. To investigate the efficacy of a novel respiratory motion scheme, where only the center of k-space is gated using respiratory navigators, versus a fully respiratory-gated acquisition for three-dimensional flow imaging. Three-dimensional flow images were acquired axially using a gradient echo sequence in a volume, covering the ascending and descending aorta, and the pulmonary artery bifurcation in 12 healthy subjects (33.2 ± 15.8 years; five men). For respiratory motion compensation, two gating and tracking strategies were used with a 7-mm gating window: (1) All of k-space acquired within the gating window (fully gated) and (2) central k-space acquired within the gating window, and the remainder of k-space acquired without any gating (center gated). Each scan was repeated twice. Stroke volume, mean flow, peak velocity, and signal-to-noise-ratio measurements were performed both on the ascending and on the descending aorta for all acquisitions, which were compared using a linear mixed-effects model and Bland-Altman analysis. There were no statistical differences between the fully gated and the center-gated strategies for the quantification of stroke volume, peak velocity, and mean flow, as well as the signal-to-noise-ratio measurements. Furthermore, the proposed center-gated strategy had significantly shorter acquisition time compared to the fully gated strategy (13:19 ± 3:02 vs. 19:35 ± 5:02, P < 0.001). The proposed novel center-gated strategy for three-dimensional flow MRI allows for markedly shorter acquisition time without any systematic variation in quantitative flow measurements in this small group of healthy volunteers. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc. 23657530 Successful substitution of fetal calf serum by human plasma for bulk cultivation of Leishmania donovani promastigotes. The potential of human plasma (HP) or serum (HS) as a replacement for fetal calf serum (FCS) was evaluated in a liver infusion tryptose (LIT) medium for bulk cultivation of Leishmania donovani promastigotes. The promastigote yield with the LIT-FCS standard medium was 0.4-1.8×10(7) ml(-1), and yields of 0.5-3.4×10(7) (P = 0.527) and 0.4-2.4×10(7) (P = 0.062) were recorded for two LIT medium variants containing HP or HS as supplement instead of FCS. Significantly, higher promastigote yields of 1.3-4.9×10(7) ml(-1) were demonstrated when LIT medium was supplemented with HP of blood group O but not A, B, AB or equally pooled ABO (P = 0.007-0.020). Matching (P = 0.56) strong positive (1 : 10 2400 to ≥1 : 262 144 00) and weak negative (1 : 5-1 : 160) direct agglutination test (DAT) titres, respectively, were demonstrated in 24 visceral leishmaniasis (VL) and 45 non-VL sera for both standard LIT-FCS and alternative LIT-HP derived antigens. Our findings indicate strong potential for sustainable production of promastigotes for important diagnostic procedures such as DAT in the VL affected areas. 23750492 Obesity portends increased morbidity and earlier recurrence following liver transplantation for hepatocellular carcinoma. Obesity has been associated with poor oncologic outcomes following pancreatoduodenectomy for pancreatic cancer. However, there is a paucity of evidence on the impact of obesity on postoperative complications, oncologic outcome and survival in patients with hepatocellular carcinoma (HCC) undergoing orthotopic liver transplantation (OLT). From a database of over 1000 patients who underwent OLT during 1996-2008, 159 patients with a diagnosis of HCC were identified. Demographic data, body mass index (BMI), perioperative parameters, recurrence and survival were obtained. Complications were grouped according to Clavien-Dindo grading (Grades I-V). There were increased incidences of life-threatening complications in overweight (58%) and obese (70%) patients compared with the non-obese patient group (41%) (P < 0.05). Furthermore, the incidence of recurrence of HCC was doubled in the presence of overweight (15%) and obesity (15%) compared with non-obesity (7%) (P < 0.05). Time to recurrence also decreased significantly. Differences in mean ± standard deviation survival in the overweight (45 ± 3 months) and obese (41 ± 4 months) groups compared with the non-obese group (58 ± 6 months) did not reach statistical significance. These findings indicate that BMI is an important surrogate marker for obesity and portends an increased risk for complications and a poorer oncologic outcome following OLT for HCC. 22643566 Increasing Use of Elective Mastectomy and Contralateral Prophylactic Surgery Among Breast Conservation Candidates: A 14-year Report From a Comprehensive Cancer Center. First-line surgical options for early-stage breast cancer include breast-conserving surgery (BCS) or mastectomy. We analyzed factors that influence the receipt of mastectomy and resultant trends over time. We analyzed the rates of mastectomy and BCS for 1634 women who underwent upfront surgical treatment for AJCC stage 0, I, or II breast cancer between 1995 and 2008 using data from the University of Louisville James Graham Brown Cancer Center Tumor Registry. We examined the trend of treatment over time and assessed the probability of receiving mastectomy using multivariate logistic regression. Overall, 65.9% of women received BCS, and 34.1% received mastectomy over a 14-year period (annual BCS rate range, 38.6% to 77.7%). The mastectomy rate substantially decreased from 43.5% in 1995 to 22.5% in 2004 (P=0.0007) but then increased to 51.7% in 2008 (P<0.0001). During the years between 2004 and 2008 (vs. 1995 to 2003), there was a significant increase in the rates of mastectomy performed in conjunction with immediate reconstruction (IR: 35.7% vs. 8.4%; P<0.0001) and/or contralateral prophylactic mastectomy (CPM: 22.9% vs. 3.3%; P<0.0001). On the basis of the multivariate analysis, the rate of receiving mastectomy was drastically higher for patients treated since 2004 (vs. before 2004), uninsured and government-insured (vs. privately insured) patients, patients with pT2 disease (vs. pTis or pT1), patients with pN1 disease (vs. pNX or pN0). In this longitudinal registry study, major independent determinants of mastectomy for early-stage breast cancer include year of diagnosis, insurance status, and stage. Mastectomy rates declined until 2004, but have since increased in conjunction with immediate reconstruction and contralateral prophylactic mastectomy. Additional study is needed to identify the underlying reasons for and unintended consequences of the reemergence of radical surgery for early-stage breast cancer in the era of multidisciplinary care. 23949998 Abundance and community structure of ammonia-oxidizing microorganisms in reservoir sediment and adjacent soils. Ammonia oxidation is an important process for global nitrogen cycling. Both ammonia-oxidizing bacteria (AOB) and archaea (AOA) can be the important players in nitrification process. However, their relative contribution to nitrification remains controversial. This study investigated the abundance and community structure of AOA and AOB in sediment of Miyun Reservoir and adjacent soils. Quantitative PCR assays indicated that the highest AOA abundance occurred in unplanted riparian soil, followed by reservoir sediment, reed-planted riparian soil and agricultural soil. The AOB community size in agricultural soil was much larger than that in the other habitats. Large variations in the structures of AOA and AOB were also observed among the different habitats. The abundance of Nitrosospira-like AOB species were detected in the agricultural soil and reservoir sediment. Pearson's correlation analysis showed the AOB diversity had positive significant correlations with pH and total nitrogen, while the AOA diversity might be negatively affected by nitrate nitrogen and ammonia nitrogen. This work could add new insights towards nitrification in aquatic and terrestrial ecosystems. 23453306 Cytotoxic effect of leaf essential oil of Lippia gracilis Schauer (Verbenaceae). Medicinal plants are one of the most important sources of drugs used in the pharmaceutical industry. Among traditional medicinal plants, Lippia gracilis Schauer (Verbenaceae) had been used for several medicinal purposes in Brazilian northeastern. In this study, leaf essential oil (EO) of L. gracilis was prepared using hydrodistillation. Followed by GC-MS analysis, its composition was characterized by the presence of thymol (55.50%), as major constituent. The effects of EO on cell proliferation and apoptosis induction were investigated in HepG2 cells. Furthermore, mice bearing Sarcoma 180 tumor cells were used to confirm its in vivo effectiveness. EO and its constituents (thymol, p-cymene, γ-terpinene and myrcene) displayed cytotoxicity to different tumor cell lines. EO treatment caused G1 arrest in HepG2 cells accompanied by the induction of DNA fragmentation without affecting cell membrane integrity. Cell morphology consistent with apoptosis and a remarkable activation of caspase-3 were also observed, suggesting induction of caspase-dependent apoptotic cell death. In vivo antitumor study showed tumor growth inhibition rates of 38.5-41.9%. In conclusion, the tested essential oil of L. gracilis leaves, which has thymol as its major constituent, possesses significant in vitro and in vivo antitumor activity. These data suggest that leaf essential oil of L. gracilis is a potential medicinal resource. 23900888 Clinical Potential of a Silk Sericin-Releasing Bioactive Wound Dressing for the Treatment of Split-Thickness Skin Graft Donor Sites. An ethyl alcohol-precipitated silk sericin/PVA scaffold that controlled the release of silk sericin was previously developed and applied for the treatment of full-thickness wounds in rats and demonstrated efficient healing. In this study, we aimed to further evaluate the clinical potential of this scaffold, hereafter called "silk sericin-releasing wound dressing", for the treatment of split-thickness skin graft donor sites by comparison with the clinically available wound dressing known as "Bactigras®". In vitro characterization and in vivo evaluation for safety of the wound dressings were performed. A clinical trial of the wound dressings was conducted according to standard protocols. The sericin released from the wound dressing was not toxic to HaCat human keratinocytes. A peel test indicated that the silk sericin-releasing wound dressing was less adhesive than Bactigras®, potentially reducing trauma and the risk of repeated injury upon removal. There was no evidence of skin irritation upon treatment with either wound dressing. When tested in patients with split-thickness skin graft donor sites, the wounds treated with the silk sericin-releasing wound dressing exhibited complete healing at 12 ±â€‰5.0 days, whereas those treated with Bactigras® were completely healed at 14 ±â€‰5.2 days (p = 1.99 × 10(-4)). In addition, treatment with the silk sericin-releasing wound dressing significantly reduced pain compared with Bactigras® particularly during the first 4 postoperative days (p = 2.70 × 10(-5) on day 1). We introduce this novel silk sericin-releasing wound dressing as an alternative treatment for split-thickness skin graft donor sites. 23706622 The role of abstinence and activity in the quality of life of drug users engaged in treatment. There is increasing interest in understanding factors that enhance the quality of life of substance users in treatment, however limited research has been conducted to date. Measures of physical and psychological health, overall quality of life, drug use, and meaningful activity (education, training or employment) were collected at treatment entry and review in two areas of England as part of routine monitoring. Analysis was performed on an initial sample of 10,470 cases in one site and a more targeted assessment of 783 cases (with repeated measures for 528 of these) in the second site. Women reported lower satisfaction with their physical and psychological health at treatment entry compared with men, but these differences were not present at treatment review. Individuals who reported engagement in meaningful activities had significantly higher quality of life than those that did not. Clients in treatment who reported abstinence and engagement in meaningful activity demonstrated the highest quality of life. A holistic approach to supporting problematic substance users that acknowledges the importance of participation in meaningful activity is likely to be beneficial. 23872870 Controlled synthesis of ultrathin lamellar Eu2O3 nanocrystals: self-assembly of 1D nanowires to 2D nanosheets. By using 1,5-pentanediol as a capping and structure directing agent, ultrathin Eu2O3 nanosheets (<1 nm) have been synthesized and assembled into a layered structure. The lateral dimensions of the nanosheets can be tuned by simply controlling the reaction time. These layered structures exhibit a strong quantum size effect due to the extremely small thickness of the assembled nanosheets. 23583543 On the problem-size effect in small additions: can we really discard any counting-based account? The problem-size effect in simple additions, that is the increase in response times (RTs) and error rates with the size of the operands, is one of the most robust effects in cognitive arithmetic. Current accounts focus on factors that could affect speed of retrieval of the answers from long-term memory such as the occurrence of interference in a memory network or the strength of memory traces that would differ from problem to problem. The present study analyses chronometric data from a sample of 91 adults solving very small additions (operands from 1 to 4) that are generally considered as being solved by retrieval. The results reveal a monotonic linear increase in RTs with the magnitude of both operands. This pattern is at odds with the retrieval-based accounts of the problem-size effect and challenges the well-established view that small additions are solved through retrieval of the answer from long-term memory. Our results are more compatible with the hypothesis that even very small additions are solved using compacted fast procedures that scroll an ordered representation such as a number line or a verbal number sequence. This interpretation is corroborated by the analysis of individual differences. 23905645 Comparison of the antitumor efficacy of transcatheter arterial chemoembolization with a miriplatin-iodized oil suspension and a cisplatin-iodized oil suspension for hepatocellular carcinoma. To retrospectively compare the short-term antitumor efficacy and safety of transcatheter arterial chemoembolization (TACE) with a cisplatin-iodized oil suspension (C-IS) and a miriplatin-iodized oil suspension (M-IS) for hepatocellular carcinoma (HCC). Of patients who underwent TACE for unresectable HCC between January 2010 and August 2011, 25 and 21 patients received C-IS and M-IS, respectively. The short-term therapeutic efficacy of both groups was evaluated by the treatment effect seen on dynamic enhanced computed tomography or magnetic resonance imaging of tumor nodules 3 months after treatment. Adverse events were evaluated to compare C-IS and M-IS. After TACE using C-IS and M-IS, 100% necrosis or tumor size reduction was achieved in 30 and 18 tumor nodules, respectively (81% vs 53%; P = 0.006). Objective responses were achieved in 30 nodules exposed to TACE using C-IS and 17 exposed to TACE using M-IS (81% vs 50%; P = 0.011). Disease control was achieved in 36 nodules exposed to C-IS and 27 exposed to M-IS (97% vs 79%; P = 0.017). The percentage of patients attaining a complete response, an objective response and disease control was significantly greater in the C-IS group than in the M-IS group. No significant differences were found in the aspartate aminotransferase, alanine aminotransferase, total bilirubin and creatinine levels between the two groups either before treatment or 1 month after treatment. The short-term antitumor effects of TACE with C-IS may be superior to those with M-IS in terms of the complete response, objective response and disease control rates. 23688827 With how many users should you test a medical infusion pump? Sampling strategies for usability tests on high-risk systems. Usability testing is recognized as an effective means to improve the usability of medical devices and prevent harm for patients and users. Effectiveness of problem discovery in usability testing strongly depends on size and representativeness of the sample. We introduce the late control strategy, which is to continuously monitor effectiveness of a study towards a preset target. A statistical model, the LNBzt model, is presented, supporting the late control strategy. We report on a case study, where a prototype medical infusion pump underwent a usability test with 34 users. On the data obtained in this study, the LNBzt model is evaluated and compared against earlier prediction models. The LNBzt model fits the data much better than previously suggested approaches and improves prediction. We measure the effectiveness of problem identification, and observe that it is lower than is suggested by much of the literature. Larger sample sizes seem to be in order. In addition, the testing process showed high levels of uncertainty and volatility at small to moderate sample sizes, partly due to users' individual differences. In reaction, we propose the idiosyncrasy score as a means to obtain representative samples. Statistical programs are provided to assist practitioners and researchers in applying the late control strategy. 23685219 Profiling celiac disease antibody repertoire. The aim of this study was to dissect the autoantibody response in celiac disease (CD) that remains largely unknown, with the goal of identifying the disease-specific autoantigenic protein pattern or the so called epitome. Sera from CD patients were used to select immunoreactive antigens from a cDNA phage-display library. Candidate genes were identified, the corresponding proteins produced and their immunoreactivity validated with sera from CD patients and controls. Thirteen CD-specific antigens were identified and further validated by protein microarray. The specificity for 6 of these antigens was confirmed by ELISA. Furthermore we showed that this antibody response was not abolished on a gluten free diet and was not shared with other autoimmune diseases. These antigens appear to be CD specific and independent of gluten induction. The utility of this panel extends beyond its diagnostic value and it may drive the attention to new targets for unbiased screens in autoimmunity research. 23877300 Epitaxial growth and lithium ion conductivity of lithium-oxide garnet for an all solid-state battery electrolyte. Epitaxial thin films of Al-doped Li7La3Zr2O12 (LLZO) with a cubic garnet-type structure were successfully synthesized using pulsed laser deposition to investigate the lithium ion conduction in grains. Two orientations of the films were obtained depending on the Gd3Ga5O12 (GGG) substrate orientation, LLZO(001)/GGG(001) and LLZO(111)/GGG(111). The ionic conductivities in the grains of the (001) and (111) films were 2.5 × 10(-6) and 1.0 × 10(-5) S cm(-1) at 298 K, respectively, which were lower than those of polycrystalline LLZO of over 10(-4) S cm(-1). X-ray reflectometry and inductively coupled plasma mass spectrometry revealed a large amount of Al(3+) of over 0.6 moles substituted for Li(+). These results indicate that the Al(3+) substitution in the LLZO lattice decreases the number of movable lithium ions and blocks the three-dimensional lithium migration pathway. The lattice mismatch between the film and the substrate induced the lattice distortion of the LLZO, resulting in different conductivities between the (001) and (111) films. The epitaxial-film model system directly clarified a substantial impact of the Al substitution and the lattice distortion on the lithium ion conductivity in the LLZO. 23523531 Characterization of the first K(+) channel blockers from the venom of the Moroccan scorpion Buthus occitanus Paris. The availability of a large variety of specific blockers, which inhibit different K(+) currents, would help to elucidate their differences in physiological function. Short peptide toxins isolated from scorpion venoms are able to block voltage-dependent or Ca(2+)-activated K(+) channels. Here, we have studied the venom of the Moroccan scorpion Buthus occitanus Paris (BoP) in order to find new peptides, which could enlarge our structure-function relationship knowledge on the Kv1.3 blocker Kaliotoxin (KTX) that belongs to the α-KTx3.1 family. Indeed and since more a decade, KTX is widely used by international investigators because it exhibits a quite sharp specificity and a high-affinity for the Kv1.3 channel, which is not only a neuronal channel but also a therapeutic target for diverse autoimmune diseases such as multiple sclerosis, type 1 diabetes, and rheumatoid arthritis. The BoP venom was first investigated using HPLC and MALDI-TOF/MS. Further, the HPLC fractions were screened by ELISA with antibodies raised against KTX. These antibodies recognized at least three components toxic in mice by intracerebroventricular injection. They were further pharmacologically characterized by competition using (125)I-KTX bound to its specific binding sites on rat brain synaptosomes. A single component (4161 Da) inhibited totally the (125)I-KTX binding and with high-affinity (IC50 = 0.1 nM), while the two other components poorly competed with (IC50 > 100 nM). These toxins were sequenced in full by Edman's degradation. The high-affinity ligand (BoPKTX) shares 86% sequence identity with KTX and was classified as toxin α-KTx3.17. The two others peptides (BoP1 and BoP2, 4093 Da and 4121 Da, respectively) only differ by a Lys/Arg mutation. Their amino acid sequences were related to Martentoxin, which has been characterized from the Chinese scorpion Buthus martenzi Karch and described as both a BKCa and Kv1.3 blocker. Accordingly, they belong to the α-KTx16 family. 23836909 Neutralizing Nanobodies targeting diverse chemokines effectively inhibit chemokine function. Chemokine receptors and their ligands play a prominent role in immune regulation but many have also been implicated in inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, allograft rejection after transplantation, and also in cancer metastasis. Most approaches to therapeutically target the chemokine system involve targeting of chemokine receptors with low molecular weight antagonists. Here we describe the selection and characterization of an unprecedented large and diverse panel of neutralizing Nanobodies (single domain camelid antibodies fragment) directed against several chemokines. We show that the Nanobodies directed against CCL2 (MCP-1), CCL5 (RANTES), CXCL11 (I-TAC) and CXCL12 (SDF-1α) bind the chemokines with high affinity (at nanomolar concentration), thereby blocking receptor binding, inhibiting chemokine-induced receptor activation as well as chemotaxis. Together, we show that neutralizing Nanobodies can be selected efficiently for effective and specific therapeutic treatment against a wide range of immune and inflammatory diseases. 23777322 Water vapor sorption thermodynamics of the nafion ionomer membrane. The water interactions of polymer electrolyte membranes are of significant interest when these materials are used in, for example, fuel cells. We have therefore studied the sorption thermodynamics of Nafion with a sorption calorimeter that simultaneously measures the sorption isotherm and the mixing (sorption) enthalpy. This unique method is suitable for investigating the sorption thermodynamics of ionic polymers. The measurements were made at 25 °C on a series of samples dried at different temperatures from 25 to 120 °C. The sorption isotherms indicate that the samples dried at 120 °C lost about 0.8 more water molecules per sulfonic group during the drying than did the samples dried at 25 °C, and this result was verified gravimetrically. The mixing enthalpies showed several peaks or plateaus for the samples dried at 60-120 °C. This behavior was seen up to about 2 water molecules per sulfonic group. As these peaks were not directly related to any feature in the sorption isotherm, they probably have their origin in a secondary process, such as a reorganization of the polymer. 23430006 Cryoballoon ablation for atrial fibrillation guided by real-time three-dimensional transoesophageal echocardiography: a feasibility study. Cryoballoon ablation (CBA; Arctic Front, Medtronic) has proven very effective in achieving pulmonary vein isolation. Real-time three-dimensional transoesophageal echocardiography (RT 3D TEE) is a novel technology, which permits detailed visualization of cardiac structures in a 3D perspective. The aim of the present study was to assess the feasibility, advantages, and safety of RT 3D TEE in guiding CBA in a series of patients affected by paroxysmal atrial fibrillation. Forty-five patients (34 males, mean age: 63 ± 12 years) underwent CBA guided by 3D TEE. A total of 190 veins could be documented by TEE. Real-time three-dimensional transoesophageal echocardiography successfully guided the operator to position the CB in the pulmonary vein (PV) ostium and obtain complete occlusion in all 190 (100%) veins. Transoesophageal echocardiography identified leakages in 25 (13%) veins led to successful elimination of PV-left atrium (LA) backflow by guiding correct balloon repositioning. In four (2%) veins, this imaging tool led to perform successful pull-down manoeuvres. After a mean 2.6 ± 1.4 applications, isolation could be documented in 190 (100%) PVs. Median procedural and fluoroscopy times were 145 and 24 min. During a median follow-up of 278 days, 37 (82%) patients did not experience atrial fibrillation recurrence following a 3-month blanking period. Cryoballoon ablation is safe and feasible under RT 3D TEE guidance. This imaging tool permits perfect visualization of all PV ostia and neighbouring LA structures. Most importantly, it proved very efficient in guiding the operator to achieve complete occlusion and successful isolation in all veins. 23836784 Advancing the long view of ecological change in tundra systems. Despite uncertainties related to sustained funding, ideological rivalries and the turnover of research personnel, long-term studies and studies espousing a long-term perspective in ecology have a history of contributing landmark insights into fundamental topics, such as population- and community dynamics, species interactions and ecosystem function. They also have the potential to reveal surprises related to unforeseen events and non-stationary dynamics that unfold over the course of ongoing observation and experimentation. The unprecedented rate and magnitude of current and expected abiotic changes in tundra environments calls for a synthetic overview of the scope of ecological responses these changes have elicited. In this special issue, we present a series of contributions that advance the long view of ecological change in tundra systems, either through sustained long-term research, or through retrospective or prospective modelling. Beyond highlighting the value of long-term research in tundra systems, the insights derived herein should also find application to the study of ecological responses to environmental change in other biomes as well. 23603808 Impairment of proteostasis network in Down syndrome prior to the development of Alzheimer's disease neuropathology: redox proteomics analysis of human brain. DS is the most frequent genetic cause of intellectual disability characterized by the anomalous presence of three copies of chromosome 21. One of the peculiar features of DS is the onset of Alzheimer's disease neuropathology after the age of 40years characterized by deposition of senile plaques and neurofibrillary tangles. Growing studies demonstrated that increased oxidative damage, accumulation of unfolded/damaged protein aggregates and dysfunction of intracellular degradative system are key players in neurodegenerative processes. In this study, redox proteomics approach was used to analyze the frontal cortex from DS subjects under the age of 40 compared with age-matched controls, and proteins found to be increasingly carbonylated were identified. Interestingly, our results showed that oxidative damage targets specifically different components of the intracellular quality control system such as GRP78, UCH-L1, V0-ATPase, cathepsin D and GFAP that couples with decreased activity of the proteasome and autophagosome formation observed. We also reported a slight but consistent increase of Aβ 1-42 SDS- and PBS-soluble form and tau phosphorylation in DS versus CTR. We suggest that disturbance in the proteostasis network could contribute to the accumulation of protein aggregates, such as amyloid deposits and NFTs, which occur very early in DS. It is likely that a sub-optimal functioning of degradative systems occur in DS neurons, which in turn provide the basis for further accumulation of toxic protein aggregates. The results of this study suggest that oxidation of protein members of the proteostatis network is an early event in DS and might contribute to neurodegenerative phenomena. 23602385 Systematic cochrane reviews in neonatology: a critical appraisal. There is a lack of up-to-date, systematic reviews that critically assess the role and potential limitations of evidence-based medicine (EBM) and systematic reviews in neonatology. We performed a systematic literature review of all Cochrane reviews published between 1996 and 2010 by the Cochrane Neonatal Review Group (CNRG). Main outcome parameter: assessment of the percentage of reviews that concluded that a certain intervention provides a benefit, the percentage of reviews that concluded that no benefit was seen, and the percentage of studies that concluded that the current level of evidence is inconclusive. In total, 262 reviews were assessed, most of which included exclusively preterm infants (146/262). The majority of reviews assessed pharmacological interventions (145/262); other important fields included nutritional (46/262), and ventilatory issues (27/262). In 42/262 reviews, a clear recommendation in favor of a specific intervention was given, whereas 98/262 reviews concluded that certain interventions should not be performed. However, the largest proportion of reviews was inconclusive (122/262) and did not issue specific recommendations. The proportion of inconclusive reviews increased from 30% (1996-2000), to 50% (2001-2005), and finally to 58% for the years 2006-2010. Common reasons for inconclusive reviews were the small number of patients (105), insufficient data (94), insufficient methodological quality (87), and heterogeneity of studies (69). There is an ongoing need for high-quality research in order to reduce the proportion of inconclusive meta-analyses in the field of neonatology. Funding and research agencies will play a vital role in selecting the most appropriate research programs. 23847607 Diversity and phylogenetic analyses of bacteria from a shallow-water hydrothermal vent in Milos island (Greece). Studies of shallow-water hydrothermal vents have been lagging behind their deep-sea counterparts. Hence, the importance of these systems and their contribution to the local and regional diversity and biogeochemistry is unclear. This study analyzes the bacterial community along a transect at the shallow-water hydrothermal vent system of Milos island, Greece. The abundance and biomass of the prokaryotic community is comparable to areas not affected by hydrothermal activity and was, on average, 1.34 × 10(8) cells g(-1). The abundance, biomass and diversity of the prokaryotic community increased with the distance from the center of the vent and appeared to be controlled by the temperature gradient rather than the trophic conditions. The retrieved 16S rRNA gene fragments matched sequences from a variety of geothermal environments, although the average similarity was low (94%), revealing previously undiscovered taxa. Epsilonproteobacteria constituted the majority of the population along the transect, with an average contribution to the total diversity of 60%. The larger cluster of 16S rRNA gene sequences was related to chemolithoautotrophic Sulfurovum spp., an Epsilonproteobacterium so far detected only at deep-sea hydrothermal vents. The presence of previously unknown lineages of Epsilonproteobacteria could be related to the abundance of organic matter in these systems, which may support alternative metabolic strategies to chemolithoautotrophy. The relative contribution of Gammaproteobacteria to the Milos microbial community increased along the transect as the distance from the center of the vent increased. Further attempts to isolate key species from these ecosystems will be critical to shed light on their evolution and ecology. 23417705 Oviposition behaviour of the soil mite Pergamasus brevicornis (Acari: Parasitidae). We observed the oviposition behaviour of the soil mite Pergamasus brevicornis Berlese (Acari: Parasitidae) using continuous video-monitoring. Oviposition consisted of six sequential phases. The first phase (I) involved inspection of the substrate. In the second phase (II) there were rhythmic movements of the first pair of legs and slight reciprocating movements of the body. The third (III) was a resting phase. In the fourth phase (IV) the gnathosoma was lowered and the body was raised. In the next phase (V) there were two sub-phases. During the first (Va), the female held the egg below the gnathosoma. In the second sub-phase (Vb), the gnathosoma moved up holding the egg, which was then placed on the substrate. The last phase (VI) involved intense 'cleaning' movements of the chelicerae and palps. During Va a protective external eggshell structure is gradually formed, involving a phase where the egg shell is sticky. After moving the egg to the substrate, the female freed her palps and chelicerae from the sticky egg shell and cleaned her gnathosomal appendages. Phases II-V took on average 207 ± 69 s. 23952399 Signatures of nonlinear cavity optomechanics in the weak coupling regime. We identify signatures of the intrinsic nonlinear interaction between light and mechanical motion in cavity optomechanical systems. These signatures are observable even when the cavity linewidth exceeds the optomechanical coupling rate. A strong laser drive red detuned by twice the mechanical frequency from the cavity resonance frequency makes two-phonon processes resonant, which leads to a nonlinear version of optomechanically induced transparency. This effect provides a new method of measuring the average phonon number of the mechanical oscillator. Furthermore, we show that if the strong laser drive is detuned by half the mechanical frequency, optomechanically induced transparency also occurs due to resonant two-photon processes. The cavity response to a second probe drive is in this case nonlinear in the probe power. These effects should be observable with optomechanical coupling strengths that have already been realized in experiments. 23878015 Corticosteroids directly reduce staphylococcus aureus biofilm growth: An in vitro study. Clinical improvement in patients with chronic rhinosinusitis (CRS) treated with steroids alone has previously been ascribed to the steroids' anti-inflammatory properties rather than any direct effect on the bacteria. The aim of this study was to determine if commonly used intranasal steroids directly reduce bacterial biofilm production in vitro. In vitro comparative controlled trial. Staphylococcus aureus biofilms were grown on minimum biofilm eradication concentration device pegs and treated with the commonly prescribed CRS topical steroids fluticasone, mometasone, or budesonide. These were dissolved in vehicle solvents and added to cerebrospinal fluid (CSF) broth. Concentrations (including therapeutic doses) tested for fluticasone and mometasone ranged from 25 μg/200 μL to 400 μg/200 μL, and from 16 μg/200 μL to 2000 μg/200 μL for budesonide. Control pegs were exposed to equivalent volumes of the appropriate solvent/CSF. Confocal scanning laser microscopy and COMSTAT software were used to quantify biofilms at 24 hours after treatment. Significant differences from control were found for fluticasone at 400 μg/200 μL (difference = -0.3065 μm(3) /μm(2) , P = .007), mometasone at 300 μg/200 μL and 400 μg/200 μL (difference = -0.15 μm(3) /μm(2) , P = .006, and difference = -0.9193 μm(3) /μm(2) , P = .034, respectively), and budesonide at 750 μg/200 μL, 1000 μg/200 μL and 2000 μg/200 μL (difference = -1.0137 μm(3) /μm(2) , P = .038, difference = -0.6164, P = .009, and difference = -0.1906 μm(3) /μm(2) , P = .029, respectively). The concentrations of 400 μg/200 μL of fluticasone, 300 μg and 400 μg/200 μL of mometasone, and 750 μg, 1,000μg, and 2,000 μg/200 μL of budesonide directly reduce biofilm production in vitro, outside of the inflammatory milieu. Laryngoscope, 2013. 23804245 Domino cycloaddition organocascades of dendralenes. Hooray Horeau! Highly enantioselective organocatalyzed Diels-Alder reaction cascades are disclosed for the first time. The reaction enables the efficient and rapid construction of enantiopure polycycles from simple achiral, acyclic polyenes. 23821354 Meeting Report: Metabolites in Safety Testing (MIST) Symposium-Safety Assessment of Human Metabolites: What's REALLY Necessary to Ascertain Exposure Coverage in Safety Tests? In the 2012 AAPS metabolites in safety testing (MIST) symposium held in Chicago, IL, USA, on October 15, 2012, regulatory experts and industrial scientists joined together to discuss their perspectives and strategies in addressing contemporary MIST recommendations (FDA 2008, International Conference on Harmonization (ICH) M3(R2), ICH M(R2) Q&A). Overall, these regulatory guidances indicate that metabolites identified in human plasma should circulate at similar or greater concentrations in at least one of the animal species used in nonclinical safety assessment of the parent drug. However, synthetic standards for the metabolites often do not exist or they are intractable to synthesize, thus introducing multiple challenges in drug development for the quantitative comparison of metabolites between human and animals. A tiered bioanalytical strategy for metabolite analysis is a prevalent approach to demonstrate coverage in animals. Recent developments in bioanalytical methodology have yielded several time- and resource-sparing strategies to provide fit-for-purpose approaches that can enable critical decisions related to metabolite quantification and monitoring in plasma. This report summarizes the presentations and panel discussions at the symposium. 23844042 Trends of mortality due to septicemia in Greece: an 8-year analysis. Infectious diseases are among the major causes of death worldwide. We evaluated the trends of mortality due to septicemia in Greece and compared it with mortality due to other infections. Data on mortality stratified by cause of death during 2003-2010 was obtained from the Hellenic Statistical Authority. Deaths caused by infectious diseases were grouped by site of infection and analyzed using SPSS 17.0 software. 45,451 deaths due to infections were recorded in Greece during the 8-year period of time, among which 12.2% were due to septicemia, 69.7% pneumonia, 1.5% pulmonary tuberculosis, 0.2% influenza, 0.5% other infections of the respiratory tract, 7.9% intra-abdominal infections (IAIs), 2.5% urinary tract infections (UTIs), 2.2% endocarditis or pericarditis or myocarditis, 1.6% hepatitis, 1% infections of the central nervous system, and 0.7% other infections. A percentage of 99.4% of deaths due to septicemia were caused by bacteria that were not reported on the death certificate (noted as indeterminate septicemia). More deaths due to indeterminate septicemia were observed during 2007-2010 compared to 2003-2006 (3,558 versus 1,966; p<0.05). Despite the limitations related to the quality of death certificates, this study shows that the mortality rate due to septicemia has almost doubled after 2007 in Greece. Proportionally, septicemia accounted for a greater increase in the mortality rate within the infectious causes of death for the same period of time. The emergence of resistance could partially explain this alarming phenomenon. Therefore, stricter infection control measures should be urgently applied in all Greek healthcare facilities. 23880660 Carboxy terminal modifications of the P0 protein reveal alternative mechanisms of nuclear ribosomal stalk assembly. The P0 scaffold protein of the ribosomal stalk is mainly incorporated into pre-ribosomes in the cytoplasm where it replaces the assembly factor Mrt4. In analyzing the role of the P0 carboxyl terminal domain (CTD) during ribosomal stalk assembly, we found that its complete removal yields a protein that is functionally similar to Mrt4, whereas a chimeric Mrt4 containing the P0 CTD behaves more like P0. Deleting the P0 binding sites for the P1 and P2 proteins provoked the nuclear accumulation of P0ΔAB induced by either leptomycin B-mediated blockage of nuclear export or Mrt4 deletion. This effect was reversed by removing P1/P2 from the cell, whereas nuclear accumulation was restored on reintroduction of these proteins. Together, these results indicate that the CTD determines the function of the P0 in stalk assembly. Moreover, they indicate that in cells lacking Mrt4, P0 and its stalk base partner, the L12 protein, bind to pre-ribosomes in the nucleus, a complex that is then exported to the cytoplasm by a mechanism assisted by the interaction with P1/P2 proteins. Furthermore, in wild-type cells, the presence of nuclear pre-ribosome complexes containing P0 but not L12 is compatible with the existence of an alternative stalk assembly process. 23719719 Brentuximab vedotin does not cause clinically relevant QTc interval prolongation in patients with CD30-positive hematologic malignancies. Brentuximab vedotin (ADCETRIS®), an antibody-drug conjugate, comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). In vitro studies showed that MMAE does not interfere with hERG K+ channels at clinically relevant concentrations. In pivotal phase 2 clinical trials in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, brentuximab vedotin has shown substantial efficacy and an acceptable safety profile. This phase 1 open-label study was designed to evaluate the effect of brentuximab vedotin on the duration of cardiac ventricular repolarization. Patients with CD30-positive hematologic malignancies were treated with 1.8 mg/kg brentuximab vedotin by intravenous infusion every 3 weeks for up to 16 cycles. The primary endpoint was the change from baseline to Cycle 1 Days 2, 3, and 4 in the duration of ventricular repolarization using Fridericia's corrected QT interval (QTcF). There was no clinically meaningful change from baseline in the duration of ventricular repolarization as measured by QTcF in the 46 evaluable patients out of 52 total patients treated with brentuximab vedotin. There was no evidence of treatment-emergent cardiac safety abnormalities. Brentuximab vedotin was generally well tolerated with a response rate and an adverse event profile consistent with prior studies. There is no significant prolongation of the QT/QTc interval with brentuximab vedotin in patients with CD30-positive hematologic malignancies. 23691951 Coagulation and metastasis: what does the experimental literature tell us? Inhibition of coagulation greatly limits cancer metastasis in many experimental models. Cancer cells trigger coagulation, through expression of tissue factor or P-selectin ligands that have correlated with worse prognosis in human clinical studies. Cancer cells also affect coagulation through expression of thrombin and release of microparticles that augment coagulation. In the cancer-bearing host, coagulation facilitates tumour progression through release of platelet granule contents, inhibition of Natural Killer cells and recruitment of macrophages. We are revisiting this literature in the light of recent studies in which treatment of clinical cohorts with anticoagulant drugs led to diminished metastasis. 23841584 In vivo robotics: the automation of neuroscience and other intact-system biological fields. Robotic and automation technologies have played a huge role in in vitro biological science, having proved critical for scientific endeavors such as genome sequencing and high-throughput screening. Robotic and automation strategies are beginning to play a greater role in in vivo and in situ sciences, especially when it comes to the difficult in vivo experiments required for understanding the neural mechanisms of behavior and disease. In this perspective, we discuss the prospects for robotics and automation to influence neuroscientific and intact-system biology fields. We discuss how robotic innovations might be created to open up new frontiers in basic and applied neuroscience and present a concrete example with our recent automation of in vivo whole-cell patch clamp electrophysiology of neurons in the living mouse brain. 23660295 The orphan nuclear receptor TR3/Nur77 regulates ER stress and induces apoptosis via interaction with TRAPγ. The orphan nuclear receptor TR3 (also known as Nur77) belongs to the steroid/thyroid/retinoid nuclear receptor superfamily and plays important roles in regulating cell proliferation, differentiation and apoptosis. No physiological ligand for TR3 has been found thus far; the determination of its binding partners is therefore important to clarify the biological functions of TR3. Here, we identified translocon-associated protein subunit γ (TRAPγ) as a novel TR3 binding partner using a tandem affinity purification method. This interaction between TR3 and TRAPγ was further confirmed, and the interacting regions were mapped. The ligand-binding domain of TR3 was required for TRAPγ binding, and the C terminus of TRAPγ was responsible for its interaction with TR3. When stimulated with 12-O-tetradecanoylphorbol 13-acetate (TPA) or CD437, this TR3-TRAPγ interaction not only induced Ca(2+) depletion in the endoplasmic reticulum (ER) but also promoted the expression of the proapoptotic transcriptional regulator CHOP. Notably, both TR3 and TRAPγ were required for ER stress-induced apoptosis in HepG2 cells. Overall, this study demonstrated a novel, TR3-initiated signaling pathway in which TR3 regulates ER stress and induces apoptosis of hepatoma cells through its interaction with TRAPγ. 23775353 Can anti-mullerian hormone predict the diagnosis of polycystic ovary syndrome? A systematic review and meta-analysis of extracted data. Context: Existing biochemical tests for polycystic ovary syndrome (PCOS) have poor sensitivity and specificity. Many women with PCOS have high anti-Müllerian hormone (AMH) concentrations; thus, this may be a useful addition to the diagnostic criteria. Objective: A systematic literature review was performed to assess the true accuracy of AMH in the prediction of PCOS and to determine the optimal diagnostic threshold. Data Sources: Published and gray literature were searched for all years until January 2013. Study Selection: Observational studies defining PCOS according to the Rotterdam criteria and assessing the value of AMH in diagnosing PCOS were selected. Ten studies of the initial 314 hits reporting AMH values in the diagnosis of PCOS were included in the meta-analysis and the construction of the summary receiver-operating characteristic curve. Four studies that plotted individual AMH serum levels of women with PCOS and controls on graphs were selected for individual data extraction. Data Extraction: Two researchers independently assessed the abstracts resulted from the initial search against the inclusion criteria, graded the papers for selection and verification biases, and selected the papers that assessed the value of AMH in diagnosing PCOS. Data were extracted from 4 studies with the plotted individual data on graphs with the help of computer software. Data Synthesis: The meta-analysis of the extracted data demonstrated the specificity and sensitivity in diagnosing PCOS in the symptomatic women of 79.4% and 82.8%, respectively, for a cutoff value of AMH of 4.7 ng/mL. The area under the curve was 0.87 (95% confidence interval 0.83-0.92), identical with the area under the curve of 0.87 for the summary receiver-operating characteristic curve involving 10 separate studies. Conclusions: AMH may be a useful initial diagnostic test for PCOS subject to validation in prospective population cohorts. 23528610 Reversal of Morphine Analgesic Tolerance by Ethanol in the Mouse. The chronic use of opioids in humans, accompanied by the development of tolerance, is a dangerous phenomenon in its own right. However chronic opioid use is often made more dangerous by the co-consumption of other substances. It has been observed that the blood level of opioids in postmortem analyses of addicts, who consumed ethanol along with the opioid, was much less than that observed in individuals that died from opioids alone. This relationship between ethanol and opioids led us to investigate the hypothesis that ethanol alters tolerance to opioids. In the present study, we report that ethanol significantly and dose-dependently reduced the antinociceptive tolerance produced by morphine and the cross tolerance between DAMGO and morphine in the mouse tail-flick test. The reversal of morphine tolerance was partially blocked by both the GABAA receptor blocker bicuculline and by the GABAB receptor blocker phaclofen and the administration of both inhibitors completely reversed the effects of ethanol on morphine tolerance. Diazepam, like ethanol, decreased morphine tolerance. However, this inhibition was reversed by the GABAA antagonist bicuculline but not by the GABAB antagonist phaclofen. These findings have important implications for individuals who abuse opioids and ethanol as well as suggest a mechanism to reduce the amount of opioid needed in chronic pain treatment. 23375671 Disordered gambling: a behavioral addiction. Developments in psychiatry have ratified the existence of behavioral addictions, that certain activities such as gambling or video-game play may be considered addictive in the absence of exogenous (i.e. drug-induced) stimulation of brain reinforcement circuitry. This article describes recent advances in understanding the neurobiological basis of behavioral addiction, with a focus on pathological gambling as the prototypical disorder. We describe positron emission tomography (PET) studies characterizing dopaminergic transmission, and functional imaging studies of reward processing and gambling-related cognitive distortions. The current evidence not only indicates changes in pathological gamblers in core circuitry implicated in drug addiction, but also highlights some subtle differences. Behavioral addictions can also provide experimental traction on distinguishing vulnerability markers for addictions from the active detrimental effects of chronic drug use. 22064666 Endothelial nitric oxide synthase genotypes and haplotypes modify the responses to sildenafil in patients with erectile dysfunction. Erectile dysfunction (ED) is usually treated with sildenafil. Although genetic polymorphisms in the endothelial nitric oxide synthase (eNOS) gene may impair endogenous NO formation, there is little information about how eNOS polymorphisms and haplotypes affect the responses to sildenafil. We studied 118 patients; 63 patients had ED secondary to radical prostatectomy (PED) and 55 had organic, clinical ED. eNOS genotypes for three eNOS polymorphisms (T(-786)C, rs2070744; a variable number of tandem repeats (VNTR) in intron 4; and Glu298Asp, rs1799983) were determined, and eNOS haplotypes were estimated using PHASE 2.1. The clinical responses to sildenafil were evaluated and the patients were classified as good responders (GR) or poor responders (PR) when their changes in five-item version of International Index for Erectile Function questionnaire were above or below the median value. The TC/CC genotypes and the C allele for the T(-786)C polymorphism were more common in GR, compared with PR patients with PED. However, the 4b4a/4a4a genotypes and the 4a allele for the VNTR polymorphism in intron 4 were more common in GR, compared with PR patients with clinical ED. The C-4a-Glu haplotype was more common in GR than in PR patients with PED. Conversely, the T-4b-Asp haplotype was less common in GR than in PR patients with PED. No other significant differences were found. Our findings show evidence that eNOS polymorphisms affect the responses of PED and clinical ED patients to sildenafil. 23222084 Regional Fat Changes Induced by Localized Muscle Endurance Resistance Training. Ramírez-Campillo, R, Andrade, DC, Campos-Jara, C, Henríquez-Olguín, C, Alvarez-Lepín, C, and Izquierdo, M. Regional fat changes induced by localized muscle endurance resistance training. J Strength Cond Res 27(8): 2219-2224, 2013-The purpose of this study was to examine the effects of a localized muscle endurance resistance training program on total body and regional tissue composition. Seven men and 4 women (aged 23 ± 1 years) were trained with their nondominant leg during 12 weeks, 3 sessions per week. Each session consisted of 1 set of 960-1,200 repetitions (leg press exercise), at 10-30% 1 repetition maximum. Before and after training, body mass, bone mass, bone mineral density (BMD), lean mass, fat mass, and fat percentage were determined by dual-emission x-ray absorptiometry. Energy intakes were registered using a food recall questionnaire. At the whole-body level, body mass, bone mass, BMD, lean mass, or body fat percentage were not significantly changed. However, body fat mass significantly decreased by 5.1% (preexercise: 13.5 ± 6.3 kg; postexercise: 12.8 ± 5.4 kg, p < 0.05). No significant changes in bone mass, lean mass, fat mass, or fat percentage were observed in both the control and trained leg. A significant (p < 0.05) decrease in fat mass was observed in the upper extremities and trunk (10.2 and 6.9%, respectively, p < 0.05). The reduction of fat mass in the upper extremities and trunk was significantly greater (p < 0.05) than the fat mass change observed in the trained leg but not in the control leg. No significant changes were observed in energy intake pre- and postexercise intervention (2,646 ± 444 kcal·d and 2,677 ± 617 kcal·d, respectively). In conclusion, the training program was effective in reducing fat mass, but this reduction was not achieved in the trained body segment. The present results expand the limited knowledge available about the plastic heterogeneity of regional body tissues when a localized resistance training program is applied. 23744746 Ultrathin PtPdTe Nanowires as Superior Catalysts for Methanol Electrooxidation. Ultrathin and ultralong: Highly uniform, ultrathin (diameter 5-7 nm), and ultralong (aspect ratio >10(4) ) PtPdTe nanowires (NWs) were synthesized by using a facile method employing Te NWs as both sacrificial templates and reducing agents. Fine-tuning of the molar ratios of Pt and Pd precursors afforded PtPdTe NWs with different compositions and enhanced electroactivity in the methanol oxidation reaction in comparison with a commercial Pt/C catalyst. 23278282 Concentration of tacrolimus and major metabolites in kidney transplant recipients as a function of diabetes mellitus and cytochrome P450 3A gene polymorphism. Abstract 1. Disposition of tacrolimus and its major metabolites, 13-O-desmethyl tacrolimus and 15-O-desmethyl tacrolimus, was evaluated in stable kidney transplant recipients in relation to diabetes mellitus and genetic polymorphism of cytochrome P450 (CYP) 3A. 2. Steady-state concentration-time profiles were obtained for 12-hour or 2-hour post-dose, in 20 (11 with diabetes) and 32 (24 with diabetes) patients, respectively. In addition, single nucleotide polymorphisms of the following genes: CYP3A4 (CYP3A4: CYP3A4*1B, -392A > G), 3A5 (CYP3A5: CYP3A5*3, 6986A > G) and P-glycoprotein (ABCB1: 3435C > T) were characterized. 3. Dose-normalized concentrations of tacrolimus or metabolites were higher in diabetic patients. CYP3A4*1B carriers and CYP3A5 expressers, independently or when assessed as a combined CYP3A4-3A5 genotype, had significantly lower dose-normalized pre-dose (C(0)/dose) and 2-hour post-dose (C(2)/dose) concentrations of tacrolimus and metabolites. Non-diabetic patients with at least one CYP3A4*1B and CYP3A5*1 allele had lower C(0)/dose as compared to the rest of the population. 4. Genetic polymorphism of CYP3A5 or CYP3A4 influence tacrolimus or metabolites dose-normalized concentrations but not metabolite to parent concentration ratios. The effect of diabetes on tacrolimus metabolism is subject to debate and requires a larger sample size of genetically stratified subjects. 23677434 Influence of ibuprofen addition on the properties of a bioactive bone cement. Bioactive bone cements can promote bone growth and the formation of a strong chemical bond between the implant and bone tissue increasing the lifetime of the prosthesis. This study aims at synthesizing a new bioactive bone cement with different amounts of ibuprofen (5, 10 and 20 wt%) using a low toxicity activator, and investigating its in vitro release profile. The effect of ibuprofen (IB) on the setting parameters, residual monomer and bioactivity in synthetic plasma was also evaluated. It was verified that the different IB contents do not prevent the growth of calcium phosphate aggregates on composite surfaces, confirming that the cements are potentially bioactive. A relevant advantage of these formulations was a significant improvement in their curing parameters with increasing IB amount, associated to a reduction of the peak temperature and an extension of the setting time. The investigated cements released an average of about 20 % of the total incorporated ibuprofen during 30 days test, with IB20 liberating the highest percentage of drug 20.6 %, and IB10 and IB5, respectively 19.1 and 17.6 %. This behavior was attributed to the low solubility of this drug in aqueous media and was also related with the hydrophobic character of the polymer. Regarding the therapeutic concentration sufficient to suppress inflammation, the cement with 10 % of ibuprofen achieved the required release rate for 1 week and the cement with 20 % for 2 weeks. 23935594 New insights into the evolutionary history of biological nitrogen fixation. Nitrogenase, which catalyzes the ATP-dependent reduction of dinitrogen (N2) to ammonia (NH3), accounts for roughly half of the bioavailable nitrogen supporting extant life. The fundamental requirement for fixed forms of nitrogen for life on Earth, both at present and in the past, has led to broad and significant interest in the origin and evolution of biological N2 fixation. One key question is whether the limited availability of fixed nitrogen was a factor in life's origin or whether there were ample sources of fixed nitrogen produced by abiotic processes or delivered through the weathering of bolide impact materials to support this early life. If the latter, the key questions become what were the characteristics of the environment that precipitated the evolution of this oxygen sensitive process, when did this occur, and how was its subsequent evolutionary history impacted by the advent of oxygenic photosynthesis and the rise of oxygen in the Earth's biosphere. Since the availability of fixed sources of nitrogen capable of supporting early life is difficult to glean from the geologic record, there are limited means to get direct insights into these questions. Indirect insights, however, can be gained through phylogenetic studies of nitrogenase structural gene products and additional gene products involved in the biosynthesis of the complex metal-containing prosthetic groups associated with this enzyme complex. Insights gained from such studies, as reviewed herein, challenge traditional models for the evolution of biological nitrogen fixation and provide the basis for the development of new conceptual models that explain the stepwise evolution of this highly complex life sustaining process. 23965305 Structure of an 'open' clamp type II topoisomerase-DNA complex provides a mechanism for DNA capture and transport. Type II topoisomerases regulate DNA supercoiling and chromosome segregation. They act as ATP-operated clamps that capture a DNA duplex and pass it through a transient DNA break in a second DNA segment via the sequential opening and closure of ATPase-, G-DNA- and C-gates. Here, we present the first 'open clamp' structures of a 3-gate topoisomerase II-DNA complex, the seminal complex engaged in DNA recognition and capture. A high-resolution structure was solved for a (full-length ParE-ParC55)2 dimer of Streptococcus pneumoniae topoisomerase IV bound to two DNA molecules: a closed DNA gate in a B-A-B form double-helical conformation and a second B-form duplex associated with closed C-gate helices at a novel site neighbouring the catalytically important β-pinwheel DNA-binding domain. The protein N gate is present in an 'arms-wide-open' state with the undimerized N-terminal ParE ATPase domains connected to TOPRIM domains via a flexible joint and folded back allowing ready access both for gate and transported DNA segments and cleavage-stabilizing antibacterial drugs. The structure shows the molecular conformations of all three gates at 3.7 Å, the highest resolution achieved for the full complex to date, and illuminates the mechanism of DNA capture and transport by a type II topoisomerase. 22391568 Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8. Mutation of the p53 gene is the most common genetic alteration in human cancer and contributes to malignant process by enhancing transformed properties of cells and resistance to anticancer therapy. Mutant p53 is often highly expressed in tumor cells at least, in part, due to its increased half-life. However, whether mutant p53 expression is regulated by other mechanisms in tumors is unclear. Here we found that histone deacetylase (HDAC) inhibitors suppress both wild-type and mutant p53 transcription in time- and dose-dependent manners. Consistent with this, the levels of wild-type and mutant p53 proteins are decreased upon treatment with HDAC inhibitors. Importantly, we found that upon knockdown of each class I HDAC, only HDAC8 knockdown leads to decreased expression of wild-type and mutant p53 proteins and transcripts. Conversely, we found that ectopic expression of wild-type, but not mutant HDAC8, leads to increased transcription of p53. Furthermore, we found that knockdown of HDAC8 results in reduced expression of HoxA5 and consequently, attenuated ability of HoxA5 to activate p53 transcription, which can be rescued by ectopic expression of HoxA5. Because of the fact that HDAC8 is required for expression of both wild-type and mutant p53, we found that targeted disruption of HDAC8 expression remarkably triggers proliferative defect in cells with a mutant, but not wild-type, p53. Together, our data uncover a regulatory mechanism of mutant p53 transcription via HDAC8 and suggest that HDAC inhibitors and especially HDAC8-targeting agents might be explored as an adjuvant for tumors carrying a mutant p53. 23953202 Signal amplification strategy for sensitive immunoassay of prostate specific antigen (PSA) based on ferrocene incorporated polystyrene spheres. A new kind of signal amplification strategy based on ferrocene (Fc) incorporated polystyrene spheres (PS-Fc) was proposed. The synthesized PS-Fc displayed narrow size distribution and good stability. PS-Fc was applied as label to develop immunosensors for prostate specific antigen (PSA) after the typical sandwich immunoreaction by linking anti-PSA antibody (Ab2) onto PS-Fc. After the fabrication of the immunosensor, tetrahydrofuran (THF) was dropped to dissolve PS and release the contained Fc for the following stripping voltammetric detection. PS-Fc as a new electrochemical label prevented the leakage of Fc and greatly amplified the immunosensor signal. In addition, the good biocompatibility of PS could maintain the bioactivity of the antibodies. The response current was linear to the logarithm of PSA concentration in the range from 0.01ngmL(-1) to 20ngmL(-1) with a detection limit of 1pgmL(-1). The immunosensor results were validated through the detection of PSA in serum samples with satisfactory results. 23566551 Robot-assisted laparoscopic nephron sparing surgery for tumors over 4 cm: operative results and preliminary oncologic outcomes from a multicentre French study. To assess operative and pathological results obtained after robot-assisted partial nephrectomy (RAPN) in renal masses over 4 cm. Between 2007 and 2011, 220 robotic nephron-sparing surgeries (NSS) were performed at six French urology departments. Data were prospectively collected: age, BMI, pre and post-operative eGFR (MDRD), operative time (OT), warm ischemia time (WIT), estimated blood loss (EBL), length of hospital stay (LOS), Clavien complications, pathological results and oncologic outcome. Tumor complexity was assessed according to the RENAL nephrometry score. Overall, 54 tumors were included. Median follow up was 26 months. Median age at surgery was 62 years. Median RENAL nephrometry score was 7 (4-10). Median WIT was 23 min (10-59). Median OT and EBL were 180 min (110-425) and 100 cc (0-2500). Blood transfusion occurred in 7 cases (13%). Median tumor size was 45 mm (40-70). Three patients had positive surgical margins. Median LOS was 5 days (2-28). Nine patients presented post-operative complications of which 1/3 were considered as major (Clavien IIIb). Median pre-operative and post-operative eGFR was 88 (36-136) and 75 ml/min (33-122) (p = 0.01), respectively. Two patients developed subsequent metastasis. The 2-year progression free survival (PFS) rate was 90.5%. Our results confirm that RAPN is a useful and acceptable approach for renal masses greater than 4 cm in size. When technically possible, NSS provides promising short-term cancer-specific survival rates with acceptable morbidity. Tumor size is not sufficiently discriminant enough and RENAL nephrometry score should increasingly used to describe tumor complexity. 23664835 Negative feedback regulation of Homer 1a on norepinephrine-dependent cardiac hypertrophy. Homers are scaffolding proteins that modulate diverse cell functions being able to assemble signalling complexes. In this study, the presence, sub-cellular distribution and function of Homer 1 was investigated. Homer 1a and Homer 1b/c are constitutively expressed in cardiac muscle of both mouse and rat and in HL-1 cells, a cardiac cell line. As judged by confocal immunofluorescence microscopy, Homer 1a displays sarcomeric and peri-nuclear localization. In cardiomyocytes and cultured HL-1 cells, the hypertrophic agonist norepinephrine (NE) induces α1-adrenergic specific Homer 1a over-expression, with a two-to-three-fold increase within 1h, and no up-regulation of Homer 1b/c, as judged by Western blot and qPCR. In HL-1 cells, plasmid-driven over-expression of Homer 1a partially antagonizes activation of ERK phosphorylation and ANF up-regulation, two well-established, early markers of hypertrophy. At the morphometric level, NE-induced increase of cell size is likewise and partially counteracted by exogenous Homer 1a. Under the same experimental conditions, Homer 1b/c does not have any effect on ANF up-regulation nor on cell hypertrophy. Thus, Homer 1a up-regulation is associated to early stages of cardiac hypertrophy and appears to play a negative feedback regulation on molecular transducers of hypertrophy. 23800424 Seasonal and spatial variation of trace elements and metals in quasi-ultrafine (PM0.25) particles in the Los Angeles metropolitan area and characterization of their sources. Year-long sampling campaign of quasi-ultrafine particles (PM0.25) was conducted at 10 distinct locations across the Los Angeles south coast air basin and concentrations of trace elements and metals were quantified at each site using high-resolution inductively coupled plasma sector field mass spectrometry. In order to characterize sources of trace elements and metals, principal component analysis (PCA) was applied to the dataset. The major sources were identified as road dust (influenced by vehicular emissions as well as re-suspended soil), vehicular abrasion, residual oil combustion, cadmium sources and metal plating. These sources altogether accounted for approximately 85% of the total variance of quasi-ultrafine elemental content. The concentrations of elements originating from source and urban locations generally displayed a decline as we proceeded from the coast to the inland. Occasional concentration peaks in the rural receptor sites were also observed, driven by the dominant westerly/southwesterly wind transporting the particles to the receptor areas. 23686668 Subnuclear distribution of SSX regulates its function. SSX, a family of genes clustered on the X chromosome, has been identified as a cancer-testis antigen and also forms a part of the SYT-SSX fusion gene found in synovial sarcoma, implying that it has an important role in tumorigenesis. However, knowledge of the molecular regulation of SSX is still limited. In this study, we demonstrate that SSX or its SYT fusion protein is distributed as nuclear speckles, in which it is co-localized with B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi1), which is a core factor of polycomb repressor complex 1. The C-terminal residues of SSX are indispensable for the nuclear speckle distribution, while the N-terminal domain is necessary for the recruitment of Bmi1, indicating that intact SSX must be needed for interaction with Bmi1 both spatially and functionally. In addition, the N-terminus of SSX also proved to contain an intrinsic nucleolar localization signal, which mediates the nucleolar translocation of SSX in particular kinds of cell stress such as the oxidation of hydrogen peroxide or heat shock. This stress-induced translocation is reversible and accompanied by HSP 70 or p14ARF traffic, suggesting that SSX is a stress response gene. It is of note that nucleolar translocation of SSX can result in disassociation of SSX from Bmi1, with consequent down-regulation of Bmi1 activity. These novel findings regarding distinct domains of SSX and its interaction with Bmi1 may shed light on the mechanism by which synovial sarcoma develops and on the up-regulation of SSX in cancer cells. 23716615 Borrelia hermsii Acquisition Order in Superinfected Ticks Determines Transmission Efficiency. Multilocus sequence typing of Borrelia hermsii isolates reveals its divergence into two major genomic groups (GG), but no differences in transmission efficiency or host pathogenicity are associated with these genotypes. To compare GGI and GGII in the tick-host infection cycle, we first determined if spirochetes from the two groups could superinfect the tick vector Ornithodoros hermsi. We infected mice with isolates from each group and fed ticks sequentially on these mice. We then fed the infected ticks on naive mice and measured GGI and GGII spirochete densities in vector and host, using quantitative PCR of genotype-specific chromosomal DNA sequences. Sequential feedings resulted in dual tick infections, showing that GGI or GGII primary acquisition did not block superinfection by a secondary agent. On transmission to naive mice at short intervals after acquisition, ticks with primary GGI and secondary GGII spirochete infections caused mixed GGI and GGII infections in mice. However, ticks with primary GGII and secondary GGI spirochete infections caused only GGII infections with all isolate pairs examined. At longer intervals after acquisition, the exclusion of GGI by GGII spirochetes declined and cotransmission predominated. We then examined GGI and GGII spirochetemia in mice following single inoculation and coinoculation by needle and found that GGI spirochete densities were reduced on multiple days when coinoculated with GGII. These findings indicate that dual GGI-GGII spirochete infections can persist in ticks and that transmission to a vertebrate host is dependent on the order of tick acquisition and the interval between acquisition and transmission events. 23362001 Usefulness of (11)c-choline positron emission tomography for genital chlamydial infection assessment in a BALB/c murine model. The aim of this study is to explore the feasibility of (11)C-Choline PET in the assessment of the degree of inflammation in the Chlamydia muridarum genital infection model. Forty female Balb/c mice received 2.5 mg of medroxyprogesterone acetate i.m. 9 and 2 days prior to the infection: 21 mice were infected by C. muridarum into the vaginal vault, 12 mice were treated with inactivated chlamydiae, and 7 mice were SPG buffer-treated as negative controls. Three healthy control mice were not treated with progesterone. Mice in each category were randomly subdivided in two groups: (1) sacrificed at 5, 10, 15, and 20 days for histological analysis and (2) undergoing (11)C-Choline PET at days 5, 10, and 20 post-infection (20 MBq of (11)C-Choline, uptake time of 10 min, acquisition through a small-animal PET tomograph for 15 min). Infected animals showed a significantly higher standardized uptake value than both controls and animals inoculated with heat-inactivated chlamydiae in each PET scan (P < 0.05). All organs of the infected animals had scores of inflammation ranging between 2 and 3 at day 5, decreasing to 1-2 at day 20. This preliminary result demonstrated that (11)C-Choline PET can highlight a specific proliferation mechanism of inflammatory cells induced by C. muridarum, thanks to a very high sensitivity in detecting very small amounts of tracer in inflammatory cells. 23965928 Thimerosal exposure and the role of sulfation chemistry and thiol availability in autism. Autism spectrum disorder (ASD) is a neurological disorder in which a significant number of the children experience a developmental regression characterized by a loss of previously acquired skills and abilities. Typically reported are losses of verbal, nonverbal, and social abilities. Several recent studies suggest that children diagnosed with an ASD have abnormal sulfation chemistry, limited thiol availability, and decreased glutathione (GSH) reserve capacity, resulting in a compromised oxidation/reduction (redox) and detoxification capacity. Research indicates that the availability of thiols, particularly GSH, can influence the effects of thimerosal (TM) and other mercury (Hg) compounds. TM is an organomercurial compound (49.55% Hg by weight) that has been, and continues to be, used as a preservative in many childhood vaccines, particularly in developing countries. Thiol-modulating mechanisms affecting the cytotoxicity of TM have been identified. Importantly, the emergence of ASD symptoms post-6 months of age temporally follows the administration of many childhood vaccines. The purpose of the present critical review is provide mechanistic insight regarding how limited thiol availability, abnormal sulfation chemistry, and decreased GSH reserve capacity in children with an ASD could make them more susceptible to the toxic effects of TM routinely administered as part of mandated childhood immunization schedules. 23758057 Sorption of Pure N2O to Biochars and Other Organic and Inorganic Materials under Anhydrous Conditions. Suppression of nitrous oxide (N2O) emissions from soil is commonly observed after amendment with biochar. The mechanisms accounting for this suppression are not yet understood. One possible contributing mechanism is N2O sorption to biochar. The sorption of N2O and carbon dioxide (CO2) to four biochars was measured in an anhydrous system with pure N2O. The biochar data were compared to those for two activated carbons and other components potentially present in soils-uncharred pine wood and peat-and five inorganic metal oxides with variable surface areas. Langmuir maximum sorption capacities (Qmax) for N2O on the pine wood biochars (generated between 250 and 500 °C) and activated carbons were 17-73 cm(3) g(-1) at 20 °C (median 51 cm(3) g(-1)), with Langmuir affinities (b) of 2-5 atm(-1) (median 3.4 atm(-1)). Both Qmax and b of the charred materials were substantially higher than those for peat, uncharred wood, and metal oxides [Qmax 1-34 cm(3) g(-1) (median 7 cm(3) g(-1)); b 0.4-1.7 atm(-1) (median 0.7 atm(-1))]. This indicates that biochar can bind N2O more strongly than both mineral and organic soil materials. Qmax and b for CO2 were comparable to those for N2O. Modeled sorption coefficients obtained with an independent polyparameter-linear free-energy relationship matched measured data within a factor 2 for mineral surfaces but underestimated by a factor of 5-24 for biochar and carbonaceous surfaces. Isosteric enthalpies of sorption of N2O were mostly between -20 and -30 kJ mol(-1), slightly more exothermic than enthalpies of condensation (-16.1 kJ mol(-1)). Qmax of N2O on biochar (50000-130000 μg g(-1) biochar at 20 °C) exceeded the N2O emission suppressions observed in the literature (range 0.5-960 μg g(-1) biochar; median 16 μg g(-1)) by several orders of magnitude. Thus, the hypothesis could not be falsified that sorption of N2O to biochar is a mechanism of N2O emission suppression. 23914199 Crop plants as models for understanding plant adaptation and diversification. Since the time of Darwin, biologists have understood the promise of crop plants and their wild relatives for providing insight into the mechanisms of phenotypic evolution. The intense selection imposed by our ancestors during plant domestication and subsequent crop improvement has generated remarkable transformations of plant phenotypes. Unlike evolution in natural settings, descendent and antecedent conditions for crop plants are often both extant, providing opportunities for direct comparisons through crossing and other experimental approaches. Moreover, since domestication has repeatedly generated a suite of "domestication syndrome" traits that are shared among crops, opportunities exist for gaining insight into the genetic and developmental mechanisms that underlie parallel adaptive evolution. Advances in our understanding of the genetic architecture of domestication-related traits have emerged from combining powerful molecular technologies with advanced experimental designs, including nested association mapping, genome-wide association studies, population genetic screens for signatures of selection, and candidate gene approaches. These studies may be combined with high-throughput evaluations of the various "omics" involved in trait transformation, revealing a diversity of underlying causative mutations affecting phenotypes and their downstream propagation through biological networks. We summarize the state of our knowledge of the mutational spectrum that generates phenotypic novelty in domesticated plant species, and our current understanding of how domestication can reshape gene expression networks and emergent phenotypes. An exploration of traits that have been subject to similar selective pressures across crops (e.g., flowering time) suggests that a diversity of targeted genes and causative mutational changes can underlie parallel adaptation in the context of crop evolution. 23644911 The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample. RATIONALE: To improve outcomes for patients undergoing extinction-based therapies (e.g., exposure therapy) for anxiety disorders such as post-traumatic stress disorder (PTSD), there has been interest in identifying pharmaceutical compounds that might facilitate fear extinction learning and recall. Oxytocin (OT) is a mammalian neuropeptide that modulates activation of fear extinction-based neural circuits and fear responses. Little is known, however, about the effects of OT treatment on conditioned fear responding and extinction in humans. OBJECTIVES: The purpose of the present study was to assess the effects of OT in a fear-potentiated startle task of fear conditioning and extinction. METHODS: A double-blind, placebo-controlled study of 44 healthy human participants was conducted. Participants underwent a conditioned fear acquisition procedure, after which they were randomized to treatment group and delivered OT (24 IU) or placebo via intranasal (IN) spray. Forty-five minutes after treatment, participants underwent extinction training. Twenty-four hours later, subjects were tested for extinction recall. RESULTS: Relative to placebo, the OT group showed increased fear-potentiated startle responding during the earliest stage of extinction training relative to placebo; however, all treatment groups showed the same level of reduced responding by the end of extinction training. Twenty-four hours later, the OT group showed significantly higher recall of extinction relative to placebo. CONCLUSIONS: The current study provides preliminary evidence that OT may facilitate fear extinction recall in humans. These results support further study of OT as a potential adjunctive treatment for extinction-based therapies in fear-related disorders. 23862633 The development of mismatch responses to mandarin lexical tones in early infancy. This study examined how maturation and the size of deviance affect the development of mismatch responses to Mandarin lexical tones by a multi-deviant oddball paradigm with both large deviant T1/T3 and small deviant T2/T3 pairs in newborns and 6-month-olds. The T1/T3 pair elicited a positive mismatch response (P-MMR) at birth but an adult-like mismatch negativity (MMN) at 6 months of age. For the T2/T3 pair, no significant MMR was seen in newborns, whereas a P-MMR was found when infants are 6 months old. Results suggest that the developmental trajectories of MMRs are dependent on the neural maturation and the discriminability of tonal changes. 23673987 Tumor cavitation among lung cancer patients receiving first-line chemotherapy at a tertiary care centre in India: association with histology and overall survival. Clinical significance of tumor cavitation (TC) prior to and following first-line chemotherapy of lung cancer is unclear. An evaluation of the incidence and prognostic role of TC among treatment naive lung cancer patients undergoing chemotherapy at a tertiary care institute in North India was undertaken. Retrospective data analysis and radiological review of newly diagnosed lung cancer patients initiated on chemotherapy over a 2-year period were carried out. Demographic characteristics and overall survival (OS) were compared between patients with and without TC at baseline. Patients who received 3 or more cycles of chemotherapy were included in analysis for response rates and new onset TC. Overall, 27 (7.8 %) of 347 patients had baseline TC. Among 271 non-small cell lung cancer (NSCLC) patients with (n = 26) and without (n = 245) baseline TC, histology was the only demographic characteristic that differed significantly [squamous 76.9 vs. 46.9 %; p = 0.004]. Majority (82.7 %) of NSCLC patients had advanced (stage IIIB/IV) disease. NSCLC patients with and without baseline TC alive at 6 months, 1 and 2 years were 34.6 versus 53.9 %, 11.5 versus 25.7 % and 3.8 versus 7.8 %, respectively. NSCLC patients with baseline TC had shorter median OS than those without (174 days [95 % confidence interval (CI) 106-242 days] vs. 235 days [95 % CI 207-263 days]). On multivariate Cox proportional hazard analysis, age [hazard ratio (HR) = 1.02, 95 % CI 1.01-1.04] and baseline TC [HR = 1.66, 95 % CI 1.03-2.69] were found significant. Response rates were similar between the two groups. Patients with TC after chemotherapy differed from those without in frequency of squamous histology (77.8 vs. 38.9 %; p < 0.001) and presence of metastatic disease (19.4 vs. 40.9 %; p = 0.016). Squamous histology has a significant association with presence of baseline TC and of new onset TC after chemotherapy. Presence of baseline TC has an independent association with shorter OS among NSCLC patients undergoing first-line chemotherapy. 23855749 Designing a C84 fullerene as a specific voltage-gated sodium channel blocker. Fullerene derivatives demonstrate considerable potential for numerous biological applications, such as the effective inhibition of HIV protease. Recently, they were identified for their ability to indiscriminately block biological ion channels. A fullerene derivative which specifically blocks a particular ion channel could lead to a new set of drug leads for the treatment of various ion channel-related diseases. Here, we demonstrate their extraordinary potential by designing a fullerene which mimics some of the functions of μ-conotoxin, a peptide derived from cone snail venom which potently binds to the bacterial voltage-gated sodium channel (NavAb). We show, using molecular dynamics simulations, that the C84 fullerene with six lysine derivatives uniformly attached to its surface is selective to NavAb over a voltage-gated potassium channel (Kv1.3). The side chain of one of the lysine residues protrudes into the selectivity filter of the channel, while the methionine residues located just outside of the channel form hydrophobic contacts with the carbon atoms of the fullerene. The modified C84 fullerene strongly binds to the NavAb channel with an affinity of 46 nM but binds weakly to Kv1.3 with an affinity of 3 mM. This potent blocker of NavAb may serve as a structural template from which potent compounds can be designed for the targeting of mammalian Nav channels. There is a genuine need to target mammalian Nav channels as a form of treatment of various diseases which have been linked to their malfunction, such as epilepsy and chronic pain. 23955493 H-loop histidine catalyzes ATP hydrolysis in the E. coli ABC-transporter HlyB. Adenosine triphosphate (ATP)-binding cassette (ABC) transporters form a family of molecular motor proteins that couple ATP hydrolysis to substrate translocation across cell membranes. Each nucleotide binding domain of ABC-transporters contains a highly conserved H-loop histidine residue, whose precise mechanistic role in motor functions has remained elusive. By using combined quantum mechanical and molecular mechanical (QM/MM) calculations, we showed that the conserved H-loop residue H662 in E. coli HlyB, a bacterial ABC-transporter, can act first as a general acid and then as a general base to facilitate proton transfer in ATP hydrolysis. Without the assistance of H662, direct proton transfer from the lytic water to ATP results in a substantially higher barrier height. Our findings suggest that the essential function of the H-loop residue H662 is to provide a "chemical linchpin" that shuttles protons between reactants through a relay mechanism, thereby catalyzing ATP hydrolysis in HlyB. 23909628 Imaging electroluminescence from individual nanoparticles in an array exhibiting room temperature single electron effect. Electroluminescence (EL) from the monolayer of a network of a one-dimensional (1D) necklace of 10 nm Au particles (nano)cemented by CdS is imaged. The EL and photoluminescence (PL) spectra confirm the emission from CdS. The EL emission blinks and is highly specular. The position of the speckles from individual CdS cement sites is independent of magnitude and polarity of the applied bias. The EL is explained by field-assisted ionization of the cement due to high internal fields in the array caused by stationary local charging that also leads to robust single electron effect at room temperature. 22465347 Berberine improves endothelial function by reducing endothelial microparticles-mediated oxidative stress in humans. Circulating endothelial microparticles (EMPs) lead to endothelial dysfunction by increasing oxidative stress. Berberine has a beneficial effect on endothelial function, but no data are available on the EMP-mediated oxidative stress. The present study tests the hypothesis that berberine contributes to the improvement of endothelial function in humans via inhibiting EMP-mediated oxidative stress in vascular endothelium. Twelve healthy subjects received a 1-month berberine therapy and eleven healthy subjects served as control. Endothelium-dependent and -independent function in the brachial artery was assessed by flow-mediated vasodilation (FMD) and sublingual nitroglyceride-mediated vasodilation (NMD). Circulating EMPs and serum malondialdehyde (MDA) were measured before and after therapy. Furthermore, in vitro human umbilical vein endothelial cells (HUVECs) were stimulated by EMPs with or without presence of anti-oxidant compound apocynin or berberine. Intracellular reactive oxygen species (ROS), nitric oxide (NO) production and NADPH oxidase 4 (Nox4) protein expressions were examined, respectively. The levels of serum MDA and circulating CD31+/CD42- MPs were significantly reduced in the berberine group compared with the control group, which were associated with improvement of FMD. The EMPs in vitro facilitated ROS production and Nox4 protein expression and reduced NO synthesis in HUVECs. These alterations can be reversed by the presence of apocynin or berberine, respectively. The present study demonstrated for the first time that EMP-induced upregulation of Nox4 expression may enhance ROS production in HUVECs. Berberine treatment contributes to the amelioration of endothelial function through a partially reducing oxidative stress of vascular endothelium induced by circulating CD31+/CD42- microparticles in humans. 23273319 The effect of admission spontaneous hypothermia on patients with severe traumatic brain injury. Recent information has emerged regarding the harmful effects of spontaneous hypothermia at time of admission in trauma patients. However the volume of evidence regarding the role of spontaneous hypothermia in TBI patients is inadequate. We performed secondary data analysis of 10 years of the Pennsylvania trauma outcome study (PTOS) database. Unadjusted comparisons of the association of admission spontaneous hypothermia with mortality were performed. In addition, full assessment of the association of hypothermia with mortality was conducted using multivariable logistic regressions reporting the odds ratios (OR) with the 95% confidence intervals (CI) and P-values. There were 11,033 patients identified from the PTOS with severe TBI. There were 4839 deaths (43.9%). The proportion of deaths in hypothermic patients was higher than the proportion of deaths in normothermic patients (53.9% vs. 37.4% respectively; P value<0.001). In a multivariable logistic regression model adjusted for demographics, injury characteristics, and information at admission to the trauma centre, the odds of death among patients with hypothermia were 1.70 times the odds of death among patients with normothermia (OR 1.70, 95% CI 1.50-1.93), indicating that the probability of death was significantly higher when patients arrived hypothermic at the trauma centre. The presence of spontaneous hypothermia at hospital admission is associated with a significant increase in the risk of mortality in patients with severe TBI. The benefit of maintaining normothermia in severe TBI patients, the impact of prolonged re-warming in patients with established hypothermia and the introduction of prophylactic measures to complications of hypothermia are key points that require further investigation. 23607610 Competitive processes in cross-situational word learning. Cross-situational word learning, like any statistical learning problem, involves tracking the regularities in the environment. However, the information that learners pick up from these regularities is dependent on their learning mechanism. This article investigates the role of one type of mechanism in statistical word learning: competition. Competitive mechanisms would allow learners to find the signal in noisy input and would help to explain the speed with which learners succeed in statistical learning tasks. Because cross-situational word learning provides information at multiple scales-both within and across trials/situations-learners could implement competition at either or both of these scales. A series of four experiments demonstrate that cross-situational learning involves competition at both levels of scale, and that these mechanisms interact to support rapid learning. The impact of both of these mechanisms is considered from the perspective of a process-level understanding of cross-situational learning. 23922975 The Incidence of First Venous Thromboembolism in and around Pregnancy Using Linked Primary and Secondary Care Data: A Population Based Cohort Study from England and Comparative Meta-Analysis. Recent linkage between primary and secondary care data has provided valuable information for studying heath outcomes that may initially present in different health care settings. The aim of this study was therefore, twofold: to use linked primary and secondary care data to determine an optimum definition for estimating the incidence of first VTE in and around pregnancy; and secondly to conduct a systematic literature review of studies on perinatal VTE incidence with the purpose of comparing our estimates. We used primary care data from the Clinical Practice Research Datalink (CPRD), which incorporates linkages to secondary care contained within Hospital Episode Statistics (HES) between 1997 and 2010 to estimate the incidence rate of VTE in the antepartum and postpartum period. We systematically searched the literature on the incidence of VTE during antepartum and postpartum periods and performed a meta-analysis to provide comparison. Using combined CPRD and HES data and a restrictive VTE definition, the absolute rate during the antepartum period and first six weeks postpartum (early postpartum) were 99 (95%CI 85-116) and 468 (95%CI 391-561) per 100,000 person-years respectively. These were comparable to the pooled estimates from our meta-analysis (using studies after 2005) during the antepartum period (118/100,000 person-years) and early postpartum (424/100,000 person-years). When we used only secondary care data to identify VTE events, incidence was lower during the early postpartum period (308/100,000 person-years), whereas relying only on primary care data lead to lower incidence during the time around delivery, but higher rates during the postpartum period (558/100,000 person-years). Using combined CPRD and HES data gives estimates of the risk of VTE in and around pregnancy that are comparable to the existing literature. It also provides more accurate estimation of the date of VTE diagnosis which will allow risk stratification during specific pregnancy and postpartum periods. 23900517 Formation and structural characterization of a five-membered zirconacycloallenoid. A conjugated enyne reacts with in situ generated zirconocene to yield a five membered zirconacycloallenoid that was characterized by X-ray diffraction. 23880388 A theoretical model of continuity in anxiety and links to academic achievement in disaster-exposed school children. This study tested a theoretical model of continuity in anxious emotion and its links to academic achievement in disaster-exposed youth. An urban school based sample of youths (n = 191; Grades 4-8) exposed to Hurricane Katrina were assessed at 24 months (Time 1) and then again at 30 months (Time 2) postdisaster. Academic achievement was assessed through end of the school year standardized test scores (~31 months after Katrina). The results suggest that the association of traumatic stress to academic achievement was indirect via linkages from earlier (Time 1) posttraumatic stress disorder symptoms that predicted later (Time 2) test anxiety. Time 2 test anxiety was then negatively associated with academic achievement. Age and gender invariance testing suggested strong consistency across gender and minor developmental variation in the age range examined. The model presented advances the developmental understanding of the expression of anxious emotion and its links to student achievement among disaster-exposed urban school children. The findings highlight the importance of identifying heterotypic continuity in anxiety and suggest potential applied and policy directions for disaster-exposed youth. Avenues for future theoretical refinement are also discussed. 23856552 Shared understanding in psychiatrist-patient communication: Association with treatment adherence in schizophrenia. Effective doctor-patient communication, including a shared understanding, is associated with treatment adherence across medicine. However, communication is affected by a diagnosis of schizophrenia and reaching a shared understanding can be challenging. During conversation, people detect and deal with possible misunderstanding using a conversational process called repair. This study tested the hypothesis that more frequent repair in psychiatrist-patient communication is associated with better treatment adherence in schizophrenia. Routine psychiatric consultations involving patients with (DSM-IV) schizophrenia or schizoaffective disorder were audio-visually recorded. Consultations were coded for repair and patients' symptoms and insight assessed. Adherence was assessed six months later. A principal components analysis reduced the repair data for further analysis. Random effects models examined the association between repair and adherence, adjusting for symptoms, consultation length and the amount patients spoke. 138 consultations were recorded, 118 were followed up. Patients requesting clarification of the psychiatrist's talk and the clarification provided by the psychiatrist was associated with adherence six months later (OR 5.82, 95% CI 1.31-25.82, p=0.02). The quality of doctor-patient communication also appears to influence adherence in schizophrenia. Future research should investigate how patient clarification can be encouraged among patients and facilitated by psychiatrists' communication. 23862968 Note: Molecular architecture dependent hydrogen-bonded motifs, entropy change, and dielectric permittivity of alcohols. Our previous studies showed that the static permittivity, ɛs, of some octanol isomers first increased on cooling, then decreased, and finally increased rapidly, and ɛs monotonically increased on compression such that the local minimum in ɛs vanished. Thus, while ɛs is the same at different temperatures and pressures, the density differs. To reconcile these findings with thermodynamic requirements, we propose that hydrogen bonded ring-dimers of near zero dipole moment that form on initial cooling and decrease ɛs, open to form linear-dimers on further cooling (or pressurizing). The H and O atoms at the terminals of the linear dimer form hydrogen bonds with the existing monomers and linear chains, thus extending the length of the H-bonded chains. This mechanism agrees with the enthalpy and entropy of formation of ring-dimer and linear-chain motifs. 23413250 Super-resolution track density imaging of glioblastoma: histopathologic correlation. Super-resolution track density imaging generates anatomic images with submillimeter voxel resolution by using high-angular-resolution diffusion imaging and fiber-tractography. TDI within the diseased human brain has not been previously described. The purpose of this study was to correlate TDI with histopathologic features of GBM. A total of 43 tumor specimens (24 contrast-enhancing, 12 NE, and 7 centrally necrotic regions) were collected from 18 patients with treatment-naïve GBM by use of MR imaging-guided neurosurgical techniques. Immunohistochemical stains were used to evaluate the following histopathologic features: hypoxia, architectural disruption, microvascular hyperplasia, and cellular proliferation. We reconstructed track density maps at a 0.25-mm isotropic spatial resolution by using probabilistic streamline tractography combined with constrained spheric deconvolution (model order, 8; 0.1-mm step size; 1 million seed points). Track density values were obtained from each tissue site. A P value of .05 was considered significant and was adjusted for multiple comparisons by use of the false discovery rate method. Track density was not significantly different between contrast-enhancing and NE regions but was more likely to be elevated within regions demonstrating aggressive histopathologic features (P < .05). Significant correlation between relative track density and hypoxia (odds ratio, 3.52; P = .01), architectural disruption (odds ratio, 3.49; P = .03), and cellular proliferation (odds ratio, 1.70; P = .05) was observed irrespective of the presence or absence of contrast enhancement. Numeric values of track density correlate with GBM biologic features and may be clinically useful for identification of regions of tumor infiltration within both enhancing and NE components of GBM. 23786625 Quantum dot loaded liposomes as fluorescent labels for immunoassay. Liposomes loaded with water-soluble and water-insoluble quantum dots (QD) were for the first time applied as labels in different heterogeneous immunoassays for the determination of food contaminants, using mycotoxin zearalenone (ZEN) as a model. A great deal of work was devoted to the optimal choice of phospholipids for the liposomes preparation and to the factors which are important for the stability and size of obtained liposomes. Thin-film hydration and reverse-phase evaporation techniques were evaluated in terms of stability of the obtained liposomes and their efficiency for QD loading. Conjugation of liposomes with proteins and the influence of cross-linkers to the nonspecific interaction of the obtained liposomes with the surface of microtiter plates and cartridges were investigated and 3-(2-pyridyldithio)propionic acid N-hydroxysuccinimide ester was found as the optimal cross-linker. The limits of detection (LOD) for ZEN of fluorescence-labeled immunosorbent assays were 0.6 μg kg(-1), 0.08 μg kg(-1), and 0.02 μg kg(-1), using QD, liposomes loaded with water-soluble QD, and water-insoluble QD, respectively. Similarly, the developed qualitative on-site tests using the different QD labels and taking into account the EU maximum residues level for ZEN in unprocessed cereals showed cutoff levels of 100, 50, and 20 μg kg(-1). 23913446 Characterization of the Gonadotropin Releasing Hormone Receptor (GnRHR) expression and activity in the Female Mouse Ovary. Gonadotropin releasing hormone agonists (GnRHa) are increasingly used for fertility preservation in women undergoing gonadotoxic chemotherapy. However, the protective mechanisms of action for these compounds have not yet been elucidated. In this study, we aimed to determine whether GnRHa have a direct effect on ovarian granulosa cells. Gonadotropin releasing hormone receptor (GnRHR) expression was determined in mouse somatic and gonadal tissues including granulosa/cumulus cells and oocytes using quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry. Granulosa cells were isolated from mouse ovaries primed with pregnant mare serum gonadotropin (PMSG). Response to GnRHa in cultured granulosa cells was assessed by determining the increase of intracellular cAMP and by assessing phosphorylation of downstream mediators of GnRH signaling: ERK and p38. To measure intracellular cAMP in our system, the cells were transfected with a cAMP-responsive luciferase reporter plasmid and stimulated with GnRHa. For all experiments, pituitary tissue and/or the αT3-1 mouse pituitary cell line were used as controls. GnRHR mRNA and protein were detected in mouse ovaries, granulosa/cumulus cells, and oocytes. Following GnRHa stimulation at various time intervals, we were unable to detect a cAMP increase or activation of the ERK or p38 signaling pathway in cultured primary mouse granulosa cells, while activation was detected in the control αT3-1 mouse pituitary cells. In this study, we have not detected activation of the canonical GnRH signaling pathways in mouse ovarian somatic cells. Our findings suggest that the mechanism of action of GnRHa in the ovary is either below the detection level of our experimental design or is different from that in the pituitary. 23861744 Modes of Action of ADP-Ribosylated Elongation Factor 2 in Inhibiting the Polypeptide Elongation Cycle: A Modeling Study. Despite the fact that ADP-ribosylation of eukaryotic elongation factor 2 (EF2) leads to inhibition of protein synthesis, the mechanism by which ADP-ribosylated EF2 (ADPR•EF2) causes this inhibition remains controversial. Here, we applied modeling approaches to investigate the consequences of various modes of ADPR•EF2 inhibitory actions on the two coupled processes, the polypeptide chain elongation and ADP-ribosylation of EF2. Modeling of experimental data indicates that ADPR•EF2 fully blocks the late-phase translocation of tRNAs; but the impairment in the translocation upstream process, mainly the GTP-dependent factor binding with the pretranslocation ribosome and/or the guanine nucleotide exchange in EF2, is responsible for the overall inhibition kinetics. The reduced ADPR•EF2-ribosome association spares the ribosome to bind and shield native EF2 against toxin attack, thereby deferring the inhibition of protein synthesis inhibition and inactivation of EF2. Minimum association with the ribosome also keeps ADPR•EF2 in an accessible state for toxins to catalyze the reverse reaction when nicotinamide becomes available. Our work underscores the importance of unveiling the interactions between ADPR•EF2 and the ribosome, and argues against that toxins inhibit protein synthesis through converting native EF2 to a competitive inhibitor to actively disable the ribosome. 23770226 Mathematical modeling of drug release from nanostructured porous Si: Combining carrier erosion and hindered drug diffusion for predicting release kinetics. A novel, empirical, macroscopic model is developed to describe the release of a model anticancer drug, Mitoxantrone, from native and chemically modified porous Si (PSi) thin films. Drug release from these carriers results from a combination of two mechanisms, i.e. out-diffusion of the drug molecules and erosion of the Si scaffold. Thus, the proposed mathematical model adapts the Crank model to lump the effects of temporal changes in molecular interactions and carrier scaffold erosion into a comprehensive model of hindered drug diffusion from nanoscale porous systems. Careful characterization of pore size, porosity, surface area, drug loading, as well as Si scaffold degradation profiles, measured over the same time-scale as drug release, are incorporated into the model parameter estimation. A comparison of the experimental and model results shows accurate representation of the data, emphasizing the reliability of the model. The proposed model shows that drug diffusivity values significantly vary with time for the two studied carriers, which are ascribed to the distinctive role of the prevailing physical mechanisms in each system. Finally, secondary validation of the proposed model is demonstrated by showing adequate fit to published data of the release of dexamethasone from similar mesoporous Si carriers. 23899829 Effects of estrogen therapy and aerobic training on sympathetic activity and hemodynamics in healthy postmenopausal women: a double-blind randomized trial. The aim of this study was to evaluate the isolated and associated effects of aerobic training and estrogen therapy on sympathetic nerve activity and hemodynamics in healthy postmenopausal women. Forty-five postmenopausal women (mean [SD] age, 51 [3] y) were randomly divided into four groups: sedentary-placebo (SED-PLA; n = 11), sedentary-estrogen therapy (SED-ET; n = 14), aerobic training-placebo (AT-PLA; n = 12), and aerobic training-estrogen therapy (AT-ET; n = 8). The ET groups received oral estradiol valerate (1 mg/d), whereas the PLA groups received placebo. The AT groups performed aerobic exercise three times a week on a cycle ergometer for 50 minutes, whereas the SED groups remained sedentary. All participants were evaluated before and after 6 months. Muscle sympathetic nerve activity (MSNA; microneurography), forearm blood flow (plethysmography), blood pressure (oscillometry), and heart rate (HR) were measured at rest for 10 minutes. Data were analyzed by three-way analysis of variance. Estrogen administration itself did not change any of the studied parameters. AT improved forearm blood flow (AT-PLA, 2.02 [0.85] vs 2.92 [1.65] mL min 100 mL, P = 0.03; AT-ET, 1.68 [1.11] vs 2.27 [0.76] mL min 100 mL, P = 0.03), reduced MSNA in the AT-PLA group (39 [6] vs 34 [5] bursts/min, P = 0.01), and decreased HR in the AT-ET group (65 [8] vs 62 [7] beats/min, P = 0.01). AT reduces sympathetic nerve activity and improves muscle blood flow in healthy hysterectomized postmenopausal women. Moreover, AT decreases HR when combined with ET. However, ET abolishes the reducing effect of AT on MSNA. 23926243 Whole-exome sequencing identifies a polymorphism in the BMP5 gene associated with SSRI treatment response in major depression. Although antidepressants are widely used in the pharmacotherapy of major depressive disorder (MDD), their efficacy is still insufficient as approximately one-third of the patients do not fully recover even after several treatment trials. Inter-individual genetic differences are thought to contribute to the variability in antidepressant response; however, current findings from pharmacogenetic studies are uncertain or not clearly replicated. Here we report the first application of full exome sequencing for the analysis of pharmacogenomics on antidepressant treatment. After 12 weeks of treatment with the selective serotonin re-uptake inhibitor escitalopram, we selected five clear responders and five clear non-responders for exome sequencing. By comparing the allele counts of previously known single nucleotide polymorphisms and novel polymorphisms we selected 38 markers for further genotyping in two independent patient samples treated with escitalopram (n=116 and n=394). The A allele, carried by approximately 30% of the patients with MDD, of rs41271330 in the bone morphogenetic protein (BMP5) gene showed strong association with worse treatment response in both sample sets (p=0.001), indicating that this is an promising pharmacogenetic marker for prediction of antidepressant therapeutic outcome. 23746389 Influence of oxidation on fulvic acids composition and biodegradability. Oxidation is well-known process of transforming natural organic matter during the treatment of drinking water. Chlorine, ozone, and chlorine dioxide are common oxidants used in water treatment technologies for this purpose. We studied the influence of different doses of these oxidants on by-products formation and changes in biodegradable dissolved organic carbon (BDOC) and molecular weight distribution (MWD) of fulvic acids (FA) with different BDOC content. Chlorination did not significantly change the MWD of FA and disinfection by-products formation. However, higher molecular weight compounds, than those in the initial FA, were formed. It could be a result of chlorine substitution into the FA structure. Chlorine dioxide oxidized FA stronger than chlorine. During ozonation of FA, we found the highest increase of BDOD due to the formation of a high amount of organic acids and aldehydes. FA molecules were transformed into a more biodegradable form. Ozonation is the most preferable process among those observed for pre-treatment of FA before biofiltration. 23894271 Correction: A Versatile Method for Cell-Specific Profiling of Translated mRNAs in Drosophila. [This corrects the article on p. e40276 in vol. 7.]. 23462929 Neuroprotective properties of the excitatory amino acid carrier 1 (EAAC1). Extracellular glutamate should be maintained at low levels to conserve optimal neurotransmission and prevent glutamate neurotoxicity in the brain. Excitatory amino acid transporters (EAATs) play a pivotal role in removing extracellular glutamate in the central nervous system (CNS). Excitatory amino acid carrier 1 (EAAC1) is a high-affinity Na⁺-dependent neuronal EAAT that is ubiquitously expressed in the brain. However, most glutamate released in the synapses is cleared by glial EAATs, but not by EAAC1 in vivo. In the CNS, EAAC1 is widely distributed in somata and dendrites but not in synaptic terminals. The contribution of EAAC1 to the control of extracellular glutamate levels seems to be negligible in the brain. However, EAAC1 can transport not only extracellular glutamate but also cysteine into the neurons. Cysteine is an important substrate for glutathione (GSH) synthesis in the brain. GSH has a variety of neuroprotective functions, while its depletion induces neurodegeneration. Therefore, EAAC1 might exert a critical role for neuroprotection in neuronal GSH metabolism rather than glutamatergic neurotransmission, while EAAC1 dysfunction would cause neurodegeneration. Despite the potential importance of EAAC1 in the brain, previous studies have mainly focused on the glutamate neurotoxicity induced by glial EAAT dysfunction. In recent years, however, several studies have revealed regulatory mechanisms of EAAC1 functions in the brain. This review will summarize the latest information on the EAAC1-regulated neuroprotective functions in the CNS. 23859476 Probing the interaction of individual amino acids with inorganic surfaces using atomic force spectroscopy. This article describes single-molecule force spectroscopy measurements of the interaction between individual amino acid residues and inorganic surfaces in an aqueous solution. In each measurement, there is an amino acid residue, lysine, glutamate, phenylalanine, leucine, or glutamine, and each represents a class of amino acids (positively or negatively charged, aromatic, nonpolar, and polar). Force-distance curves measured the interaction of the individual amino acid bound to a silicon atomic force microscope (AFM) tip with a silcon substrate, cut from a single-crystal wafer, or mica. Using this method, we were able to measure low adhesion forces (below 300 pN) and could clearly determine the strength of interactions between the individual amino acid residues and the inorganic substrate. In addition, we observed how changes in the pH and ionic strength of the solution affected the adsorption of the residues to the substrates. Our results pinpoint the important role of hydrophobic interactions among the amino acids and the substrate, where hydrophobic phenylalanine exhibited the strongest adhesion to a silicon substrate. Additionally, electrostatic interactions also contributed to the adsorption of amino acid residues to inorganic substrates. A change in the pH or ionic strength values of the buffer altered the strength of interactions among the amino acids and the substrate. We concluded that the interplay between the hydrophobic forces and electrostatic interactions will determine the strength of adsorption among the amino acids and the surface. Overall, these results contribute to our understanding of the interaction at the organic-inorganic interface. These results may have implications for our perception of the specificity of peptide binding to inorganic surfaces. Consequently, it would possibly lead to a better design of composite materials and devices. 23958979 Clinical news. Clinical News. 23787348 Graph isomorphisms and automorphisms via spectral signatures. An isomorphism between two graphs is a connectivity preserving bijective mapping between their sets of vertices. Finding isomorphisms between graphs, or between a graph and itself (automorphisms), is of great importance in applied sciences. The inherent computational complexity of this problem is as yet unknown. Here, we introduce an efficient method to compute such mappings using heat kernels associated with the graph Laplacian. While the problem is combinatorial in nature, in practice we experience polynomial runtime in the number of vertices. As we demonstrate, the proposed method can handle a variety of graphs and is competitive with state-of-the-art packages on various important examples. 23968336 Attitudes towards homeless people among emergency department teachers and learners: a cross-sectional study of medical students and emergency physicians. Medical students' attitudes and beliefs about homeless people may be shaped by the attitudes of their teachers and one of the most common sites for learning about homeless patients is the emergency department. The objective of this study was to determine if medical students in the preclinical and clinical years and emergency medicine faculty and residents have different attitudes and beliefs about homeless people. The Health Professional Attitudes Toward the Homeless Inventory (HPATHI), was administered to all medical students, and emergency medicine physicians and residents at a large academic health sciences center in Canada. The HPATHI examines attitudes, interest and confidence on a 5-point Likert scale. Differences among groups were examined using the Kruskal Wallis test and Pearson's chi-square test. The HPATHI was completed by 371 individuals, for an overall response rate of 55%. Analysis of dichotomized median and percentage results revealed 5/18 statements were significant by both methods. On the attitudes subscales physicians and residents as a group were more negative for 2/9 statements and on the confidence subscale more positive for 1/4 statements. The interest subscale achieved overall statistical significance with decreased positive responses among physicians and residents compared to medical students in 2/5 statements. This study revealed divergences in attitudes, interests and beliefs among medical students and emergency medicine physicians and residents. We offer strategies for training interventions and systemic support of emergency faculty. Emergency medicine physicians can examine their role in the development of medical students through both formal and informal teaching in the emergency department. 23962054 ( - )-Arctigenin as a lead compound for anticancer agent. ( - )-Arctigenin, an important active constituent of the traditional Chinese herb Fructus Arctii, was found to exhibit various bioactivities, so it can be used as a good lead compound for further structure modification in order to find a safer and more potent medicine. ( - )-Arctigenin derivatives 1-5 of ( - )-arctingen were obtained by modifying with ammonolysis at the lactone ring and sulphonylation at C (6') and C (6″) and O-demethylation at CH3O-C (3'), CH3O-C (3″) and CH3O-C (4″), and their anticancer bioactivities were examined. 23939588 How Many Molecular Layers of Polar Solvent Molecules Control Chemistry? The Concept of Compensating Dipoles. The extension of the solvent influence of the shell into the volume of a polar medium was examined by means of anti-collinear dipoles on the basis of the ET (30) solvent polarity scale (i.e., the molar energy of excitation of a pyridinium-N-phenolatebetaine dye; generally: ET =28 591 nm kcal mol(-1) /λmax ) where no compensation effects were found. As a consequence, solvent polarity effects are concentrated to a very thin layer of a few thousand picometres around the solute where extensions into the bulk solvent become unimportant. A parallelism to the thin surface layer of water to the gas phase is discussed. 23895262 Small ruminant lentivirus genetic subgroups associate with sheep TMEM154 genotypes. Small ruminant lentiviruses (SRLVs) are prevalent in North American sheep and a major cause of production losses for the U.S. sheep industry. Sheep susceptibility to SRLV infection is influenced by genetic variation within the ovine transmembrane 154 gene (TMEM154). Animals with either of two distinct TMEM154 haplotypes that both encode glutamate at position 35 of the protein (E35) are at greater risk of SRLV infection than those homozygous with a lysine (K35) haplotype. Prior to this study, it was unknown if TMEM154 associations with infection are influenced by SRLV genetic subgroups. Accordingly, our goals were to characterize SRLVs naturally infecting sheep from a diverse U.S. Midwestern flock and test them for associations with TMEM154 E35K genotypes. Two regions of the SRLV genome were targeted for proviral amplification, cloning, sequence analysis, and association testing with TMEM154 E35K genotypes: gag and the transmembrane region of env. Independent analyses of gag and env sequences showed that they clustered in two subgroups (1 and 2), they were distinct from SRLV subtypes originating from Europe, and that subgroup 1 associated with hemizygous and homozygous TMEM154 K35 genotypes and subgroup 2 with hemi- and homozygous E35 genotypes (gag p < 0.001, env p = 0.01). These results indicate that SRLVs in the U.S. have adapted to infect sheep with specific TMEM154 E35K genotypes. Consequently, both host and SRLV genotypes affect the relative risk of SRLV infection in sheep. 23603131 Impedimetric microbial sensor for real-time monitoring of phage infection of Escherichia coli. We describe an impedimetric microbial sensor for real-time monitoring of the non-lytic M13 bacteriophage infection of Escherichia coli cells using a gold electrode covalently grafted with a monolayer of lipopolysaccharide specific antibody. After infection, damage to the lipopolysaccharide layer on the outer membrane of E. coli causes changes to its surface charge and morphology, resulting in the aggregation of redox probe, Fe(CN)6(3-/4-) at the electrode surface and thereby increases its electron-transfer rate. This consequent decrease of electron-transfer resistance in the presence of bacteriophage can be easily monitored using Faradaic impedance spectroscopy. Non-lytic bacterium-phage interaction which is hardly observable using conventional microscopic methods is detected within 3h using this impedimetric microbial sensor which demonstrates its excellent performance in terms of analysis time, ease and reduced reliance on labeling steps during in-situ monitoring of the phage infection process. 23721686 HUWE1 mutation explains phenotypic severity in a case of familial idiopathic intellectual disability. The advent of next-generation sequencing has proven to be a key force in the identification of new genes associated with intellectual disability. In this study, high-throughput sequencing of the coding regions of the X-chromosome led to the identification of a missense variant in the HUWE1 gene. The same variant has been reported before by Froyen et al. (2008). We compare the phenotypes and demonstrate that, in the present family, the HUWE1 mutation segregates with the more severe ID phenotypes of two out of three brothers. The third brother has a milder form of ID and does not carry the mutation. 23831947 Glial and glioneuronal tumors in adults and children: main genetic alterations and towards a histomolecular classification. Glial and glioneuronal tumors in children and adult demonstrate distinctive clinical, neuroradiological and molecular features depending on the pathological subtype and within a same subgroup according to the age. In children, gliomas are mainly located in the infratentorial part of the brain. They are most often benign and circumscribed but infiltrative tumors with dismal prognosis are recorded within the pons (DIGP) or the thalamus. Glioblastomas are very rare in children. In contrast, gliomas in adult mainly occur in the cerebral hemispheres and the most frequent subtype is glioblastoma. Glioneuronal tumors mainly occurred in children and young adults. In addition, although pilocytic astrocytomas, pleomorphic xanthoastrocytomas and gangliogliomas are classified into different subgroups according to the WHO 2007 classification, these tumors demonstrate similar neuroradiological findings: they are cystic with contrast enhancement of a mural nodule. Major advances have been made these last five years in the discovery of some master genes that are involved in gliomagenesis and point out differences between children and adults. In adults, infiltrative gliomas can be classified into two major subgroups depending on the existence or not of IDH mutations. IDH-dependent gliomagenesis encompasses diffuse grade II and grade III (they can also show additional molecular alterations such as TP53 mutation or 1p19q codeletion) and secondary glioblastomas. IDH-independent gliomagenesis include triple negative grade II gliomas, gliomatosis cerebri (grade III) and de novo glioblastomas. Pilocytic astrocytomas, pleomorphic xanthoastrocytomas and gangliogliomas share in common BRAF alterations. However, KIAA1549-BRAF fusion characterizes pilocytic astrocytomas whereas V600E BRAF mutation is mainly recorded in pleomorphic xanthoastrocytomas and gangliogliomas. 23934609 General power and sample size calculations for high-dimensional genomic data. Abstract In the design of microarray or next-generation sequencing experiments it is crucial to choose the appropriate number of biological replicates. As often the number of differentially expressed genes and their effect sizes are small and too few replicates will lead to insufficient power to detect these. On the other hand, too many replicates unnecessary leads to high experimental costs. Power and sample size analysis can guide experimentalist in choosing the appropriate number of biological replicates. Several methods for power and sample size analysis have recently been proposed for microarray data. However, most of these are restricted to two group comparisons and require user-defined effect sizes. Here we propose a pilot-data based method for power and sample size analysis which can handle more general experimental designs and uses pilot-data to obtain estimates of the effect sizes. The method can also handle χ2 distributed test statistics which enables power and sample size calculations for a much wider class of models, including high-dimensional generalized linear models which are used, e.g., for RNA-seq data analysis. The performance of the method is evaluated using simulated and experimental data from several microarray and next-generation sequencing experiments. Furthermore, we compare our proposed method for estimation of the density of effect sizes from pilot data with a recent proposed method specific for two group comparisons. 23928413 Determination of benzothiazole and benzotriazole derivates in tire and clothing textile samples by high performance liquid chromatography-electrospray ionization tandem mass spectrometry. A high performance liquid chromatography-tandem mass spectrometry method utilizing electrospray ionization in positive and negative mode has been developed for the separation and detection of benzothiazole and benzotriazole derivates. Ultra-sonication assisted solvent extraction of these compounds has also been developed and the overall method demonstrated on a selected clothing textile and an automobile tire sample. Matrix effects and extraction recoveries, as well as linearity and limits of detection have been evaluated. The calibration curves spanned over more than two orders of magnitude with coefficients of correlation R(2)>0.99 and the limits of detection and the limits of quantification were in the range 1.7-58pg injected and 18-140pg/g, respectively. The extraction recoveries ranged between 69% and 102% and the matrix effects between 75% and 101%. Benzothiazole and benzotriazole derivates were determined in the textile sample and benzothiazole derivatives determined in the tire sample with good analytical performance. 23689373 Comparison of Predicted Epimerases and Reductases of the Campylobacter jejuni D-altro- and L-gluco-Heptose Synthesis Pathways. Uniquely modified heptoses found in surface carbohydrates of bacterial pathogens are potential therapeutic targets against such pathogens. Our recent biochemical characterization of the GDP-6-deoxy-d-manno- and GDP-6-deoxy-d-altro-heptose biosynthesis pathways has provided the foundation for elucidation of the more complex l-gluco-heptose synthesis pathway of Campylobacter jejuni strain NCTC 11168. In this work we use GDP-4-keto,6-deoxy-d-lyxo-heptose as a surrogate substrate to characterize three enzymes predicted to be involved in this pathway: WcaGNCTC (also known as Cj1427), MlghB (Cj1430), and MlghC (Cj1428). We compare them with homologues involved in d-altro-heptose production: WcaG81176 (formerly WcaG), DdahB (Cjj1430), and DdahC (Cjj1427). We show that despite high levels of similarity, the enzymes have pathway-specific catalytic activities and substrate specificities. MlghB forms three products via C3 and C5 epimerization activities, whereas its DdahB homologue only had C3 epimerase activity along its cognate pathway. MlghC is specific for the double C3/C5 epimer generated by MlghB and produces l-gluco-heptose via stereospecific C4 reductase activity. In contrast, its homologue DdahC only uses the C3 epimer to yield d-altro-heptose via C4 reduction. Finally, we show that WcaGNCTC is not necessary for l-gluco-heptose synthesis and does not affect its production by MlghB and MlghC, in contrast to its homologue WcaG81176, that has regulatory activity on d-altro-heptose synthesis. These studies expand our fundamental understanding of heptose modification, provide new glycobiology tools to synthesize novel heptose derivatives with biomedical applications, and provide a foundation for the structure function analysis of these enzymes. 23864615 The short stalk length of HPAI H5N1 influenza neuraminidase limits transmission of pandemic H1N1 virus in ferrets. H5N1 influenza viruses pose a pandemic threat but have not acquired the ability to support sustained transmission between mammals in nature. The restrictions to transmissibility of avian influenza viruses in mammals are multigenic and overcoming them requires adaptations in HA and PB2 genes. Here we propose that a further restriction to mammalian transmission of the majority of HPAI H5N1 viruses may be the short stalk length of the NA protein. This genetic feature is selected for when influenza viruses adapt to chickens. In our study a recombinant virus, with seven gene segments from a human isolate of the 2009 H1N1 pandemic combined with the NA gene from a typical chicken-adapted H5N1 virus with a short stalk, did not support transmission by respiratory droplet between ferrets. This virus was also compromised in multicycle replication in cultures of human airway epithelium at 32°C. These defects correlated with a reduction in the ability of virus with a short stalk NA to penetrate mucus and de-aggregate virions. The deficiency in transmission and in cleavage of tethered substrates was overcome by increasing the stalk length of the NA protein. These observations suggest that H5N1 viruses that acquire a long stalk NA through reassortment might be more likely to support transmission between humans. Phylogenetic analysis showed that reassortment with long stalk NA occurred sporadically and as recently as 2011. However, all identified H5N1 viruses with a long stalk NA lacked other mammalian adapting features and were thus several genetic steps away from becoming transmissible between humans. 23568856 Non-classical Pharmacology of the Dopamine Transporter: Atypical Inhibitors, Allosteric Modulators and Partial Substrates. The dopamine transporter (DAT) is a sodium-coupled symporter protein responsible for modulating the concentration of extraneuronal dopamine in the brain. The DAT is a principle target of various psychostimulant, nootropic and antidepressant drugs, as well as certain drugs used recreationally, including the notoriously addictive stimulant cocaine. DAT ligands have traditionally been divided into two categories: cocaine-like inhibitors and amphetamine-like substrates. Whereas inhibitors block monoamine uptake by the DAT, but are not translocated across the membrane, substrates are actively translocated and trigger DAT-mediated release of dopamine by reversal of the translocation cycle. As both inhibitors and substrates increase extraneuronal dopamine levels, it is often assumed that all DAT ligands posses an addictive liability equivalent to cocaine. However, the recent development of novel 'atypical' inhibitors and 'partial substrate' ligands with reduced or even a complete lack of cocaine-like rewarding effects suggests that addictiveness is not a constant property of DAT-affecting compounds. These atypical ligands do not conform to the classical preconception that all DAT inhibitors (or substrates) are functionally and mechanistically alike. Instead, they suggest the possibility that the DAT exhibits some of the ligand-specific 'pleiotropic' functional qualities inherent to G-protein-coupled receptors. That is, ligands with different chemical structures induce specific conformational changes in the transporter protein, which can be differentially transduced by the cell, ultimately eliciting unique behavioral and psychical effects. The present overview discusses compounds with conformation-specific activity, useful not only as tools for studying the mechanics of dopamine transport, but also as leads for medication development in addictive disorders. 23806998 Immobilized capillary tyrosinase microreactor for inhibitor screening in natural extracts by capillary electrophoresis. A method for creating an immobilized capillary tyrosinase (TRS) reactor based on a layer-by-layer (LBL) assembly for inhibitor screening is described. Tyrosinase was immobilized on the surface of fused-silica capillary via ionic binding technique with cationic polyelectrolyte hexadimethrine bromide (HDB). Then, HDB solution with the same plug length as the TRS was injected again into the capillary to cover the immobilized enzyme by forming HDB-TRS-HDB sandwich-like structure. Then, the substrate of l-tyrosine was introduced into the capillary and on-line enzyme inhibition study was performed by capillary electrophoresis (CE). The enzyme activity was determined by the quantification of peak area of the product of l-DOPA. Enzyme inhibition can be read out directly from the reduced peak area of the product in comparison with a reference electropherogram obtained in the absence of any inhibitor. The immobilized enzyme could withstand 25 consecutive assays by only losing 12% activity. A known TRS inhibitor, kojic acid was employed as a model compound for the validation of the inhibitor screening method. Finally, screening 19 natural extracts of traditional Chinese drugs was demonstrated. The results indicated that inhibition activity could be straightforwardly identified with the system. 23830697 Synthesis and evaluation of 1-[2-(4-[(11)C]methoxyphenyl)phenyl]piperazine for imaging of the serotonin 5-HT7 receptor in the rat brain. 1-[2-(4-Methoxyphenyl)phenyl]piperazine (4) is a potent serotonin 5-HT7 receptor antagonist (Ki=2.6nM) with a low binding affinity for the 5-HT1A receptor (Ki=476nM). As a potential positron emission tomography (PET) radiotracer for the 5-HT7 receptor, [(11)C]4 was synthesized at high radiochemical yield and specific activity, by O-[(11)C]methylation of 2'-(piperazin-1-yl)-[1,1'-biphenyl]-4-ol (6) with [(11)C]methyl iodide. Autoradiography revealed that [(11)C]4 showed in vitro specific binding with 5-HT7 in the rat brain regions, such as the thalamus which is a region with high 5-HT7 expression. Metabolite analysis indicated that intact [(11)C]4 in the brain exceeded 90% of the radioactive components at 15min after the radiotracer injection, although two radiolabeled metabolites were found in the rat plasma. The PET study of rats showed moderated uptake of [(11)C]4 in the brain (1.2SUV), but no significant regional difference in radioactivity in the brain. Pretreatment with 5-HT7-selective antagonist SB269970 (3) did not decrease the uptake of [(11)C]4 in the rat brain. Further studies are warranted that focus on the development of PET ligand candidates with higher binding affinity for 5-HT7 and higher in vivo stability in brain than 4. 23775396 Sequence-controlled polymerization using dendritic macromonomers: precise chain-positioning of bulky functional clusters. A simple strategy to insert functional dendrons at precise positions along a linear polymer backbone is reported. Sequence controlled copolymerization of styrene and polyester dendrons containing a maleimide unit at their focal points was utilized to yield such polymers. 23842128 Associations between immune depression and cardiovascular events in HIV infection. To consider associations between the latest/nadir CD4 cell count, and time spent with CD4 cell count less than 200 cells/μl (duration of immune depression), and myocardial infarction (MI), coronary heart disease (CHD), stroke, or cardiovascular disease (CVD) (CHD or stroke) in 33 301 HIV-positive individuals. Longitudinal cohort study. Analyses were undertaken using Poisson regression. To investigate whether analyses of stroke were robust to the type of endpoint, we additionally included stroke-like events and rejected strokes into the stroke endpoint. Participants experienced 716 MI, 1056 CHD, 303 stroke, and 1284 CVD events. Whereas there was no evidence of a higher MI/CHD risk in those with lower latest/nadir CD4 cell counts after adjustment [current CD4 <100 cells/μl: relative rate (95% confidence interval) 0.96 (0.62-1.50) for MI, 0.89 (0.30-2.36) for CHD; nadir CD4 <100 cells/μl: 1.36 (0.57-3.23) for MI, 0.98 (0.45-2.16) for CHD], stroke and CVD rates were higher in those with a latest CD4 cell count less than 100 cells/μl [2.26 (1.29-3.94) and 1.14 (0.84-1.56), respectively]. All events occurred less frequently in those who had not experienced immune depression, although evidence for a linear association with duration of immune depression was weak. The association between stroke risk and the latest CD4 cell count strengthened as stroke-like and rejected strokes were included; conversely, associations with established stroke risk factors weakened. We do not find strong evidence that HIV-positive individuals with a low CD4 cell count are more likely to experience MI/CHD. Although strokes appear to occur more commonly at low CD4 cell counts, this may be partly explained by misclassification or other biases. 23618773 Therapeutic effect of praziquantel against Taeniasis asiatica. Eight Japanese adult patients infected with Taenia asiatica were treated with a single 600 mg dose of praziquantel. The patients' body weights ranged from 47 to 87 kg (mean 67.1±12.7 kg). All patients expelled the strobila after taking praziquantel, and all of them were free from proglottids the day after praziquantel administration, hence all patients were considered to be cured. No side effects due to praziquantel were noted. Although the number of patients is small, our results indicate that praziquantel is a drug of choice for the treatment of taeniasis asiatica and that a single dose of 7-13 mg/kg (9.3±1.9 mg/kg) is effective. 23792455 An overall uncertainty approach for the validation of analytical separation methods. The aim of this paper is to recommend a new strategy for the analytical validation based on the uncertainty profile as a graphical decision-making tool, and to exemplify a novel method to estimate the measurement uncertainty. Indeed, the innovative formula that we offer to assess the uncertainty is based on the calculation of the β-content tolerance interval. Three chemometric methodologies are exposed to build the (β, γ) tolerance interval, namely: the Satterthwaite approximation, the GPQ method (generalized pivotal confidence) and the MLS procedure (modified large simple). Furthermore, we illustrate the applicability and flexibility of the uncertainty profile to assess the fitness of the purpose of chromatographic and electrophoretic analytical methods, which use different instrumental techniques such as liquid chromatography (LC-UV, LC-MS), gas chromatography (GC-FID, GC-MS) and capillary electrophoresis (CE, CE-MS). In addition, we demonstrate here that (β, γ) tolerance intervals will provide perfect estimates of the routine uncertainty. In particular, we show that there is no difference statistically between the uncertainties estimated by our methodology as of the validation stage with those obtained from the routine phase. 23462227 Assessment of baseline characteristics, glycemic control and oral antidiabetic treatment in Asian patients with diabetes: The Registry for Assessing OAD Usage in Diabetes Management (REASON) Asia study (、：（REASON）). To assess baseline characteristics, glycemic control, and treatment with oral antidiabetic drugs (OAD) in type 2 diabetes mellitus (T2DM) patients. This multinational, observational study recruited patients ≥21 years of age who were newly diagnosed and/or treated with OAD monotherapy for <6 months but were inadequately controlled. In cross-sectional phase, data on demographics, medical history, diabetic complications and comorbidities, OAD treatment, glycosylated hemoglobin (HbA1c), and fasting blood glucose (FBG) were collected. In longitudinal phase evaluating 6-month follow-up of sulfonylurea (SU)-treated patients, additional data on reasons for not achieving HbA1c targets were collected. Of 1487 patients (mean [±SD] age 52.0 ± 11.6 years; 46.7% men; mean BMI 25.8 ± 4.4 kg/m(2) ) recruited, 75.9% were newly diagnosed, 73.3% had central obesity, 43.8% had hypertension, and 60.5% had dyslipidemia. The mean HbA1c was 9.8 ± 2.4%, and the mean FBG was 11.3 ± 4.3 mmol/L. At T0 (baseline) and T6 (month 6 visit), 99.8% (n = 1066) and 97.1% (n = 830) patients received SU, respectively. There was decrease from T0 to T6 in mean HbA1c (10.2% vs 7.3%, respectively; P < 0.0001) and mean FBG (12.0 vs 7.6 mmol/L, respectively; P < 0.0001). Number of patients with HbA1c <7% increased from T0 (4.5%) to T6 (46.8%). Reasons for not achieving target HbA1c included poor diabetes education (50.7%), non-compliance to OADs (21.4%), and fear of hypoglycemia (19.7%). Marked reductions in HbA1c and FBG are achievable in T2DM patients managed with OADs. However, patient education and compliance are important for achieving and maintaining treatment targets. 23400642 Cone-beam computed tomography and microtomography for alveolar bone measurements. To compare cone-beam computed tomography (CBCT) and microtomography (micro-CT) for alveolar bone measurements. Forty teeth and alveolar bone blocks of five pigs were scanned on a micro-CT with a 9.05 Î¼m pixel size, and on a CBCT device at 0.125 mm voxel size. One height and four thickness measurements were performed twice in standardized slices by two radiologists to verify reliability. Agreement between imaging methods was assessed by correlation coefficients, Bland-Altman plots, and the difference was tested by a Wilcoxon signed-rank test. Regarding intra- and interobserver agreements, all bone measurements presented excellent precision values for micro-CT, but interobserver agreement for CBCT presented good to moderate values. Bone height differed about 0.3 mm, but no statistically significant differences were found for the bone thickness measurements. CBCT underestimated bone height. No statistically significant differences were found for bone thickness. Regions of thin bone tissue may not be visualized on CBCT images. There are risks of underestimating bone measurements with CBCT and assuming bone loss that does not exist clinically. Although the difference of the bone height measurement was small, the clinical relevance must be analyzed on how to interpret CBCT. 23467773 Arbuscular mycorrhizal fungi differ in their ability to regulate the expression of phosphate transporters in maize (Zea mays L.). Previous studies have found that some phosphate (Pi) starvation inducible transporter genes are downregulated and arbuscular mycorrhizal (AM) inducible Pi transporter genes are upregulated in maize roots associated with the fungus Glomus intraradices. However, little is known about the functional diversity of different AM fungal species in influencing the expression of Pi transporters in maize roots. Here, we studied the expression of two Pi transporter genes ZEAma:Pht1;3 (Pi starvation inducible) and ZEAma:Pht1;6 (AM inducible) in maize root colonized by different AM fungal inoculants. Non-mycorrhizal maize, maize colonized by Glomus deserticola (CA113), Glomus intraradices (IA506), Glomus mosseae (CA201), Gigaspora gigantea (MN922A) and the co-inoculation of all four species were established. The expression patterns of the two genes were quantified using real-time, reverse transcription polymerase chain reaction. The expression level of ZEAma:Pht1;6 was 26-135 times higher in AM plants than in non-mycorrhizal maize roots, whereas the expression level of ZEAma:Pht1;3 was five to 44 times lower in AM plants than in non-mycorrhizal plants. Expression of the two genes differed with inoculation treatment, and increasing the diversity of AM fungi in maize roots led to greater expression of ZEAma:Pht1;6 as well as Pi uptake in shoots. The expression of ZEAma:Pht1;6 was significantly positively correlated with AM colonization rate, concentration of AM biomarkers in maize roots, Pi uptake and dry weight of shoot, but negatively correlated with the expression of ZEAma:Pht1;3. Addition of Pi fertilizer at a low concentration significantly increased the expression of ZEAma:Pht1;6 but had no effect on the expression of ZEAma:Pht1;3. 23624851 Novel adenoviral vector induces T-cell responses despite anti-adenoviral neutralizing antibodies in colorectal cancer patients. First-generation, E1-deleted adenovirus subtype 5 (Ad5)-based vectors, although promising platforms for use as cancer vaccines, are impeded in activity by naturally occurring or induced Ad-specific neutralizing antibodies. Ad5-based vectors with deletions of the E1 and the E2b regions (Ad5 [E1-, E2b-]), the latter encoding the DNA polymerase and the pre-terminal protein, by virtue of diminished late phase viral protein expression, were hypothesized to avoid immunological clearance and induce more potent immune responses against the encoded tumor antigen transgene in Ad-immune hosts. Indeed, multiple homologous immunizations with Ad5 [E1-, E2b-]-CEA(6D), encoding the tumor antigen carcinoembryonic antigen (CEA), induced CEA-specific cell-mediated immune (CMI) responses with antitumor activity in mice despite the presence of preexisting or induced Ad5-neutralizing antibody. In the present phase I/II study, cohorts of patients with advanced colorectal cancer were immunized with escalating doses of Ad5 [E1-, E2b-]-CEA(6D). CEA-specific CMI responses were observed despite the presence of preexisting Ad5 immunity in a majority (61.3 %) of patients. Importantly, there was minimal toxicity, and overall patient survival (48 % at 12 months) was similar regardless of preexisting Ad5 neutralizing antibody titers. The results demonstrate that, in cancer patients, the novel Ad5 [E1-, E2b-] gene delivery platform generates significant CMI responses to the tumor antigen CEA in the setting of both naturally acquired and immunization-induced Ad5-specific immunity. 23044926 Glucocorticoid effects on changes in bone mineral density and cortical structure in childhood nephrotic syndrome. The impact of glucocorticoids (GC) on skeletal development has not been established. The objective of this study was to examine changes in volumetric bone mineral density (vBMD) and cortical structure over 1 year in childhood nephrotic syndrome (NS) and to identify associations with concurrent GC exposure and growth. Fifty-six NS participants, aged 5 to 21 years, were enrolled a median of 4.3 (0.5 to 8.1) years after diagnosis. Tibia peripheral quantitative computed tomography (pQCT) scans were obtained at enrollment and 6 and 12 months later. Sex, race, and age-specific Z-scores were generated for trabecular vBMD (TrabBMD-Z), cortical vBMD (CortBMD-Z), and cortical area (CortArea-Z) based on >650 reference participants. CortArea-Z was further adjusted for tibia length-for-age Z-score. Quasi-least squares regression was used to identify determinants of changes in pQCT Z-scores. At enrollment, mean TrabBMD-Z (-0.54 ± 1.32) was significantly lower (p = 0.0001) and CortBMD-Z (0.73 ± 1.16, p < 0.0001) and CortArea-Z (0.27 ± 0.91, p = 0.03) significantly greater in NS versus reference participants, as previously described. Forty-eight (86%) participants were treated with GC over the study interval (median dose 0.29 mg/kg/day). On average, TrabBMD-Z and CortBMD-Z did not change significantly over the study interval; however, CortArea-Z decreased (p = 0.003). Greater GC dose (p < 0.001), lesser increases in tibia length (p < 0.001), and lesser increases in CortArea-Z (p = 0.003) were independently associated with greater increases in CortBMD-Z. Greater increases in tibia length were associated with greater declines in CortArea-Z (p < 0.01); this association was absent in reference participants (interaction p < 0.02). In conclusion, GC therapy was associated with increases in CortBMD-Z, potentially related to suppressed bone formation and greater secondary mineralization. Conversely, greater growth and expansion of CortArea-Z (ie, new bone formation) were associated with declines in CortBMD-Z. Greater linear growth was associated with impaired expansion of cortical area in NS. Studies are needed to determine the fracture implications of these findings. 23682071 The chemopreventive efficacies of nonsteroidal anti-inflammatory drugs: the relationship of short-term biomarkers to long-term skin tumor outcome. The ultraviolet B (UVB) component of sunlight, which causes DNA damage and inflammation, is the major cause of nonmelanoma skin cancer (NMSC), the most prevalent of all cancers. Nonsteroidal anti-inflammatory drugs (NSAID) and coxibs have been shown to be effective chemoprevention agents in multiple preclinical trials, including NMSC, colon, and urinary bladder cancer. NSAIDs, however, cause gastrointestinal irritation, which led to the recent development of nitric oxide (NO) derivatives that may partially ameliorate this toxicity. This study compared the efficacy of several NSAIDs and NO-NSAIDs on UV-induced NMSC in SKH-1 hairless mice and determined whether various short-term biomarkers were predictive of long-term tumor outcome with these agents. Naproxen at 100 (P = 0.05) and 400 ppm (P < 0.01) in the diet reduced tumor multiplicity by 26% and 63%, respectively. The NO-naproxen at slightly lower molar doses shows similar activities. Aspirin at 60 or 750 ppm in the diet reduced tumor multiplicity by 19% and 50%, whereas the equivalent doses (108 and 1,350 ppm) were slightly less effective. Sulindac at 25 and 150 ppm in the diet, doses far below the human equivalent dose was the most potent NSAID with reductions of 50% and 94%, respectively. In testing short-term biomarkers, we found that agents that reduce UV-induced prostaglandin E2 synthesis and/or inhibit UV-induced keratinocyte proliferation yielded long-term tumor efficacy. 23952418 Effects of density conservation and hydrodynamics on aging in nonequilibrium processes. Aging in kinetics of three different phase transitions, viz., magnetic, a binary solid, and a single component fluid, are studied via Monte Carlo and molecular dynamics simulations in three space dimensions with the objective of identifying the effects of order-parameter conservation and hydrodynamics. We observe that the relevant autocorrelations exhibit power-law decay in a ferromagnet and binary solid but with different exponents. At early time the fluid autocorrelation function nicely follows that of the binary solid, the order parameter being conserved for both of them, as opposed to a ferromagnet. At a late time the fluid data crosses over to an exponential decay which we identify as a hydrodynamic effect and we provide analytical justification for this behavior. 23886615 Blastocystis subtypes detected in humans and animals from Colombia. Blastocystis is a common enteric protist colonizing probably more than 1 billion people along with a large variety of non-human hosts. This protist has been linked to symptoms and diseases such as abdominal pain, constipation, diarrhea, flatulence and irritable bowel syndrome (IBS). Remarkable genetic diversity has been observed, leading to the subdivision of the genus into multiple subtypes (ST), some of which are exclusively found in non-human hosts. The aim of this study was to determine the distribution of Blastocystis STs in different Colombian hosts. We obtained fecal samples positive for Blastocystis by microscopy from 277 humans, 52 birds, and 117 mammals (25 cattle, 40 opossums, 40 dogs, 10 rats and 2 howler monkeys). The samples were submitted to DNA extraction, PCR and sequencing using primers targeting the small subunit rRNA gene, and ST identification was performed according to DNA barcoding. We observed the occurrence of ST1 (34%) and ST2 (23%) and lower proportions of STs 3 (11.4%), 4 (0.8%), 6 (19.8%) and 8 (10.5%). Domesticated mammals shared the same STs as those usually seen in humans (ST1, ST2, ST3), while birds and marsupials had STs, which are usually rare in humans (ST6, ST8). Further studies implementing high-resolution molecular markers are necessary to understand the phylodynamics of Blastocystis transmission and the role of this stramenopile in health and disease in Colombian populations, and to expand on the phylogeographic differences observed so far with a view to exploring and understanding host-parasite co-evolution. 23929853 Temporal coherence in image-based visual hull rendering. Image-based visual hull rendering is a method for generating depth maps of a desired viewpoint from a set of silhouette images captured by calibrated cameras. It does not compute a view-independent data representation, such as a voxel grid or a mesh, which makes it particularly efficient for dynamic scenes. When users are captured, the scene is usually dynamic, but does not change rapidly because people move smoothly within a subsecond time frame. Exploiting this temporal coherence to avoid redundant calculations is challenging because of the lack of an explicit data representation. This paper analyzes the image-based visual hull algorithm to find intermediate information that stays valid over time and is, therefore, worth to make explicit. We then derive methods that exploit this information to improve the rendering performance. Our methods reduce the execution time by up to 25 percent. When the user's motions are very slow, reductions of up to 50 percent are achieved. 23845048 Synthesis of a Mycobacterium tuberculosis Tetra-acylated Sulfolipid Analogue and Characterization of the Chiral Acyl Chains Using Anisotropic NAD 2D-NMR Spectroscopy. Tetra-O-acylated sulfolipids are metabolites found in the cell wall of Mycobacterium tuberculosis, the causative agent of tuberculosis. Their role in pathogenesis remains, however, undefined. Here we describe a novel access to model tetra-O-acylated trehalose sulfate derivatives having simple acyl chains. The trehalose core was regioselectively protected using a tandem procedure with catalytic iron(III) chloride hexahydrate and further desymmetrized. Model chiral fatty acids, prepared by a zinc-mediated cross-coupling, were incorporated into the trehalose core. The enantiomeric excess of the chiral fatty acids has been measured by natural abundance deuterium (NAD) 2D-NMR spectroscopy in a polypeptide based chiral liquid crystal. The synthetic approach established for the model compounds can easily be developed for the preparation of other analogues and natural sulfolipids. 23941987 Teaching billing and coding to medical students: a pilot study. Complex billing practices cost the US healthcare system billions of dollars annually. Coding for outpatient office visits [known as Evaluation & Management (E&M) services] is commonly particularly fraught with errors. The best way to insure proper billing and coding by practicing physicians is to teach this as part of the medical school curriculum. Here, in a pilot study, we show that medical students can learn well the basic principles from lectures. This approach is easy to implement into a medical school curriculum. 23834387 Evaluating the Psycholegal Abilities of Young Offenders With Fetal Alcohol Spectrum Disorder. Individuals with a diagnosis of fetal alcohol spectrum disorder (FASD) experience a range of physical, cognitive, and behavioral deficits thought to interfere with their ability to competently navigate the arrest, interrogation, and trial process. This study examined the psycholegal abilities of young offenders with FASD, including their understanding and appreciation of Miranda rights, and adjudication capacities (factual knowledge of criminal procedure, appreciation of the nature and object of the proceedings, ability to participate in a defense and communicate with counsel). Two groups of young offenders (50 with FASD and 50 without prenatal alcohol exposure) completed Grisso's Instruments for Assessing Understanding and Appreciation of Miranda rights and the Fitness Interview Test-Revised to assess overall rates of impairment in youth with FASD, as well as differences between the groups. Potentially important predictors of psycholegal abilities were also evaluated. Results indicated the majority of young offenders with FASD (90%) showed impairment in at least one psycholegal ability, and rates of impairment were significantly higher than the comparison group. However, considerable within-group variability was observed. IQ and reading comprehension emerged as robust predictors of participants' psycholegal abilities, while the FASD diagnosis differentiated participants' scores on the FIT-R. These findings underscore the importance of individualized and comprehensive forensic assessments of psycholegal abilities in this population when warranted. Additional system level strains for this population are discussed, including problems in approaching competency remediation, and the potentially growing need for accommodation and forensic assessments in the face of limited financial and professional resources in legal settings. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23789697 Primary salivary gland-type lung cancer: imaging and clinical predictors of outcome. The objective of our study was to assess whether CT features and FDG up-take of primary salivary gland-type tumors of the lung are associated with tumor type, disease stage, or survival. CT (n = 30) and PET (n = 15) data of 30 consecutive patients with primary salivary gland-type tumors of the lung were retrospectively evaluated for tumor size, location, and homogeneity and the presence of lymphadenopathy, pleural effusions, and metastases. Maximum FDG uptake and volumetric FDG uptake of the tumors were recorded. The Wilcoxon rank sum and Fisher exact tests and univariate Cox regression were used for statistical calculations. Compared with mucoepidermoid carcinomas, adenoid cystic carcinomas (57%) were larger (mean, 3.5 vs 2.2 cm, respectively; p = 0.03), more frequently involved the central airways (94% vs 63%; p = 0.002), and had a higher median FDG uptake (p = 0.0264). Higher FDG uptake of the primary tumor was associated with nodal tumor involvement (p = 0.05). The median overall survival times for patients with adenoid cystic carcinoma and mucoepidermoid carcinoma were 7.7 and 4.0 years, respectively. Imaging features that significantly affected overall survival included the presence of mediastinal or hilar lymphadenopathy (hazard ratio [HR], 4.33; 95% CI, 1.15-16.26; p = 0.03), suspected metastatic disease (HR, 5.10; 95% CI, 1.27-20.47; p = 0.02), and primary tumor heterogeneity (HR, 3.46; 95% CI, 1.04-11.55; p = 0.04). Higher FDG uptake is associated with nodal disease in patients with primary salivary gland-type tumors of the lung but is not predictive of survival, whereas CT features suggestive of advanced disease correlate with worse outcome. 23786620 Metabolic activation of nonpolar sediment extracts results in enhanced thyroid hormone disrupting potency. Traditional sediment risk assessment predominantly considers the hazard derived from legacy contaminants that are present in nonpolar sediment extracts, such as polychlorinated biphenyls (PCBs), dioxins, furans (PCDD/Fs), and polyaromatic hydrocarbons (PAHs). Although in vivo experiments with these compounds have shown to be thyroid hormone disrupting (THD), in vitro their THD potency is not observed in nonpolar sediment extracts. This is hypothesized to be due to the absence of in vitro biotransformation which will result in bioactivation of the lipophilic compounds into THD hydroxyl metabolites. This study reveals that indeed metabolically activated nonpolar contaminants in sediments can competitively bind to thyroid hormone transport proteins. Sediment fractions were incubated with S9 rat microsomes, and the metabolites were extracted with a newly developed method that excludes most of the lipids to avoid interference in the applied nonradioactive 96-well plate TTR competitive binding assay. Metabolic activation increased the TTR binding potency of nonpolar fractions of POP-polluted sediments up to 100 times, resulting in potencies up to 240 nmol T4 equivalents/g sediment equivalent (nmol T4-Eq/g SEQ). This demonstrates that a more realistic in vitro sediment THD risk characterization should also include testing of both polar and medium polar sediment extracts for THD, as well as bioactivated nonpolar sediment fractions to prevent underestimation of its toxic potency. 23865955 Proton pump inhibitors and acute kidney injury: a nested case--control study. Proton pump inhibitors (PPI) are a widely-used class of drugs for the treatment of gastro-esophageal reflux disease and other acid-related disorders of the gastrointestinal tract. As a class, PPIs have demonstrated a favorable safety profile. However, case reports have suggested that this class of drugs may be linked to acute kidney injury, which may in turn lead to chronic injury or failure. The objective of this study was to determine if an association between PPIs and kidney failure exists and to estimate an effect size for the relationship between PPI use and renal disease. A nested case--control study was conducted in a privately insured population in a single Midwestern state including a total of 184,480 patients aged 18 years or older who were continuously enrolled with the insurer for at least 24 months between September 2002 and November 2005.Of the patients eligible for the study, 854 cases were identified as having at least two claims for an acute renal disease diagnosis. Cases were randomly matched with up to four controls (n = 3,289) based on age, gender, county of residence, and date of entry into the cohort. Patient demographic data, PPI use, illnesses, and medications associated with renal disease and a proxy for health status using pre-existing patient comorbidities were collected from inpatient, professional, and prescription claims data. Conditional logistic regression models were used to evaluate the association between renal disease and PPI use. Renal disease was positively associated with PPI use (odds ratio [OR] 1.72, 95% confidence interval [CI] 1.27, 2.32, p < 0.001) even after controlling for potential confounding conditions. After removing patients with potential confounding disease states from the study population, the number of cases (195 of the 854) and controls (607) was lower, but the relationship between renal disease and PPI use remained consistent (OR 2.25, CI 1.09-4.62, p < 0.001). Patients with a renal disease diagnosis were twice as likely to have used a previous prescription for a PPI. Therefore, it is necessary for physicians to increase recognition of patient complaints or clinical manifestations of this potentially harmful event in order to prevent further injury. 23877741 Antioxidant micronutrients and cardiovascular risk in patients with diabetes: a systematic review. Inverse associations between micronutrient intake and cardiovascular outcomes have been previously shown, but did not focus on diabetic patients. To systematically review the role of micronutrients in the development/presence of cardiovascular outcomes in patients with diabetes. We searched Medline, Embase, and Scopus (January/1949-March/2012) for observational studies that evaluated micronutrients and cardiovascular outcomes in patients with diabetes, and then selected and extracted the data (two independent reviewers). From the 15 658 studies identified, five were included, comprising three case-control and two cohorts, with a follow-up of 7-15 years. A meta-analysis was not performed due to the different antioxidant micronutrients (types and measurement methods) and outcomes evaluated. The micronutrients assessed were vitamin C intake in diet and/or supplementation, chromium and selenium in toenail samples, and α-tocopherol and zinc in serum levels. Intake of >300 mg of vitamin C through supplementation was associated with increased risk of cardiovascular disease, coronary artery disease (CAD), and stroke (RR 1.69-2.37). High levels of α-tocopherol in serum were associated with 30% lower CAD risk in another study (HR 0.71; 95%CI 0.53-0.94). Among minerals (zinc, selenium, and chromium), an inverse association between zinc and CAD was observed; levels lower than 14.1 µmol/L were associated with an increased risk for CAD (RR 1.70; 95%CI 1.21-2.38). The information available on this issue is scarce. Further prospective studies are needed to elucidate the role of these nutrients in the cardiovascular risk of patients with diabetes. 23852000 Simulations on the possibility of formation of complexes between fluorouracil drug and cucurbit[n]urils: ab initio van der Waals DFT study. The binding geometry of fluorouracil/cucurbit[n]urils (CB[n]s) complexes with n = 5-8 is investigated using the first-principles van der Waals density functional (vdW-DF) method, involving full geometry optimization. Such host-guest complexes are typically calculated using conventional DFT method, which significantly underestimates non-local dispersion forces (or vdW contributions) and therefore affects interactions between respected entities. We address here the role of vdW forces for the fluorouracil and CB[n]s molecules which can form directional hydrogen bonds with each other. It was found that the inclusion of dispersion interactions significantly affects the host-guest binding properties and the hydrogen bonding between the molecules provides the main binding mechanism, while results in the same geometries for the considered complexes. The 0.84 eV binding energy, for the thermodynamically favorable state, reveals that the interaction of fluorouracil with CB[n]s is an exothermic interaction and typical for strong hydrogen bonding. Furthermore, we have investigated the binding nature of these host-guest systems in aqueous solution with ab initio MD simulations adopting vdW-DF method. These findings afford evidence for the applicability of the vdW-DF approach and provide a realistic benchmark for the investigation of the host-guest complexes. 23415904 11β-Hydroxysteroid dehydrogenase type 1 contributes to the balance between 7-keto- and 7-hydroxy-oxysterols in vivo. 11β-Hydroxysteroid dehydrogenase 1 (11βHSD1; EC 1.1.1.146) generates active glucocorticoids from inert 11-keto metabolites. However, it can also metabolize alternative substrates, including 7β-hydroxy- and 7-keto-cholesterol (7βOHC, 7KC). This has been demonstrated in vitro but its consequences in vivo are uncertain. We used genetically modified mice to investigate the contribution of 11βHSD1 to the balance of circulating levels of 7KC and 7βOHC in vivo, and dissected in vitro the kinetics of the interactions between oxysterols and glucocorticoids for metabolism by the mouse enzyme. Circulating levels of 7KC and 7βOHC in mice were 91.3±22.3 and 22.6±5.7nM respectively, increasing to 1240±220 and 406±39nM in ApoE(-/-) mice receiving atherogenic western diet. Disruption of 11βHSD1 in mice increased (p<0.05) the 7KC/7βOHC ratio in plasma (by 20%) and also in isolated microsomes (2 fold). The 7KC/7βOHC ratio was similarly increased when NADPH generation was restricted by disruption of hexose-6-phosphate dehydrogenase. Reduction and oxidation of 7-oxysterols by murine 11βHSD1 proceeded more slowly and substrate affinity was lower than for glucocorticoids. in vitro 7βOHC was a competitive inhibitor of oxidation of corticosterone (Ki=0.9μM), whereas 7KC only weakly inhibited reduction of 11-dehydrocorticosterone. However, supplementation of 7-oxysterols in cultured cells, secondary to cholesterol loading, preferentially slowed reduction of glucocorticoids, rather than oxidation. Thus, in mouse, 11βHSD1 influenced the abundance and balance of circulating and tissue levels of 7βOHC and 7KC, promoting reduction of 7KC. In health, 7-oxysterols are unlikely to regulate glucocorticoid metabolism. However, in hyperlipidaemia, 7-oxysterols may inhibit glucocorticoid metabolism and modulate signaling through corticosteroid receptors. 23842071 The optimum cut-off value to differentiate Echinococcus granulosus sensu stricto from other species of E. granulosus sensu lato using larval rostellar hook morphometry. Cystic echinococcosis caused by Echinococcus granulosus sensu lato is one of the most important helminth zoonoses in the world; it affects both humans and livestock. The disease is endemic in Argentina and highly endemic in the province of Neuquén. Considerable genetic and phenotypic variation has been demonstrated in E. granulosus, and ten different genotypes (G1-G10) have been identified using molecular tools. Echinococcus granulosus sensu lato may be considered a species complex, comprised of E. granulosus sensu stricto (G1-G3), E. equinus (G4), E. ortleppi (G5) and E. canadensis (G6-G10). In endemic areas, the characterization of cystic echinococcosis molecular epidemiology is important in order to apply adequate control strategies. A cut-off value for larval large hook total length to distinguish E. granulosus sensu stricto isolates from those produced by other species of the complex was defined for the first time. Overall, 1780 larval hooks of 36 isolates obtained from sheep (n= 11, G1), goats (n= 10, G6), cattle (n= 5, G6) and pigs (n= 10, G7) were analysed. Validation against molecular genotyping as gold standard was carried out using the receiver operating characteristic (ROC) curve analysis. The optimum cut-off value was defined as 26.5 Î¼m. The proposed method showed high sensitivity (97.8%) and specificity (91.1%). Since in most endemic regions the molecular epidemiology of echinococcosis includes the coexistence of the widely distributed E. granulosus sensu stricto G1 strain and other species of the complex, this technique could be useful as a quick and economical tool for epidemiological and surveillance field studies, when fertile cysts are present. 23860764 Insulin Resistance Induced by Zymosan as a New Animal Model in Mice. Insulin resistance (IR) is known as a main problem in diabetic disorders. Some animal models for research in IR have been mentioned. Each model shows merit with some disadvantages. Thus, a new animal model for IR is required. The present study used zymosan, a mixture of cell-wall particles from the yeast named Saccharomyces cerevisiae, to establish a new model of IR in mice. Also, we compared the difference of this model with fructose-rich chow-induced model and found some merits of this model. Moreover, we identified that this model induced by zymosan is reversible and IR can be reversed gradually after termination of treatment. Taken together, we suggest zymosan as a useful agent to induce IR through inflammatory pathway in mice. 23359175 Do comorbidity influences acute toxicity and outcome in elderly patients with endometrial cancer treated by adjuvant radiotherapy plus brachytherapy? To correlate comorbidity and acute radiation toxicity in elderly patients treated with adjuvant external beam radiotherapy (EBRT) plus brachytherapy-high dose rate (HDR-BRT) for endometrial cancer (EC). Endometrial cancer patients over 65 were treated and evaluated for comorbidity assessment with ACE-27 and Charlson comorbidity index (CCI). EBRT total dose was 45-50.4 Gy (1.8 Gy/day). The vault vagina boost of dose was performed by HDR-BRT with 2/3 fractions with a total dose of 10-15 Gy. From 2008 to 2011, 35 patients were analyzed. Eighteen patients (51.43 %) had not ACE-27 comorbidity; while 27 patients (77.14 %) had CCI lower than three. During treatment, acute toxicity was mild and not influenced by the comorbidity score. Two-year Progression Free and Overall Survival were 69 and 80 %. ACE-27 and CCI did not affect progression-free survival (p = 0.51, p = 0.3) and OS (p = 0.26, p = 0.5). External beam radiotherapy plus BRT-HDR are well tolerated in EC elderly with good performance status and low comorbidity profile. 23894113 Endocrine abnormalities in townes-brocks syndrome. Townes-Brocks syndrome is a recognizable variable pattern of malformation caused by mutations to the SALL1 gene located on chromosome 16q12.1. Only three known cases of Townes-Brocks syndrome with proven SALL1 gene mutation and concurrent endocrine abnormalities have been previously documented to our knowledge [Kohlhase et al., 1999; Botzenhart et al., 2005; Choi et al., 2010]. We report on two unrelated patients with Townes-Brocks syndrome who share an identical SALL1 mutation (c.3414_3415delAT), who also have endocrine abnormalities. Patient 1 appears to be the first known case of growth hormone deficiency, and Patient 2 extends the number of documented mutation cases with hypothyroidism to four. We suspect endocrine abnormalities, particularly treatable deficiencies, may be an underappreciated component to Townes-Brocks syndrome. © 2013 Wiley Periodicals, Inc. 23947736 Clostridium difficile exposure as an insidious source of infection in healthcare settings: an epidemiological model. Clostridium difficile is the leading cause of infectious diarrhea in hospitalized patients. Its epidemiology has shifted in recent years from almost exclusively infecting elderly patients in whom the gut microbiota has been disturbed by antimicrobials, to now also infecting individuals of all age groups with no recent antimicrobial use. A stochastic mathematical model was constructed to simulate the modern epidemiology of C. difficile in a healthcare setting, and, to compare the efficacies of interventions. Both the rate of colonization and the incidence of symptomatic disease in hospital inpatients were insensitive to antimicrobial stewardship and to the prescription of probiotics to expedite healthy gut microbiota recovery, suggesting these to be ineffective interventions to limit transmission. Comparatively, improving hygiene and sanitation and reducing average length of stay more effectively reduced infection rates. Although the majority of new colonization events are a result of within-hospital ward exposure, simulations demonstrate the importance of imported cases with new admissions. By analyzing a wide range of screening sensitivities, we identify a previously ignored source of pathogen importation: although capturing all asymptomatic as well as symptomatic introductions, individuals who are exposed but not yet colonized will be missed by even a perfectly sensitive screen on admission. Empirical studies to measure the duration of this latent period of infection will be critical to assessing C. difficile control strategies. Moreover, identifying the extent to which the exposed category of individual contributes to pathogen importation should be explicitly considered for all infections relevant to healthcare settings. 23855530 Changes in the histological spectrum of glomerular diseases in the past 16 years in the North-Eastern region of Romania. The aim of this study was to describe the findings of renal biopsies from a large nephrology center in Iasi, Romania, performed between 2005 and 2010. We compared these findings with our previous ones, from 1995 to 2004, as well as with similar reports. We studied retrospectively 239 renal biopsies. The indications for renal biopsy were categorized into: nephrotic syndrome, acute nephritic syndrome, asymptomatic urinary abnormalities, acute kidney injury, and chronic kidney disease of unknown etiology. During the past 16 years, a gradual increase in the annual number of renal biopsies/per million population (p.m.p.)/year was observed, although this incidence remained lower than in other European countries. Nephrotic syndrome was the indication for renal biopsy in over 50% of cases. Glomerulonephritis (GN) was the main histological diagnosis in 91% of cases, of which 56% were primary GN and 35% were secondary GN. The frequency of various types of primary GN was: membranoproliferative GN (MPGN) - 29.3%, membranous nephropathy (MN) -27.5%, focal segmental glomerulosclerosis (FSGS) - 17.2%, mesangial GN (including IgAN) -13.7%, crescentic GN - 9.4%, and minimal change disease (MCD) - 2.5%. Compared to the previously reported period (1994-2004), we observed a significant decrease in the frequency of MPGN and significant increases in the frequency of FSGS and, particularly MN - which more than doubled. We report significant changes in the histological spectrum of GN in North-Eastern Romania in 2005-2010, compared to the previously reported 10-yrs. These changes seem to be following a trend that has also been observed in Western countries a few decades ago, and which may have a socioeconomic explanation. 23620164 Effects of cartilage impact with and without fracture on chondrocyte viability and the release of inflammatory markers. Post-traumatic arthritis (PTA) frequently develops after intra-articular fracture of weight bearing joints. Loss of cartilage viability and post-injury inflammation have both been implicated as possible contributing factors to PTA progression. To further investigate chondrocyte response to impact and fracture, we developed a blunt impact model applying 70%, 80%, or 90% surface-to-surface compressive strain with or without induction of an articular fracture in a cartilage explant model. Following mechanical loading, chondrocyte viability, and apoptosis were assessed. Culture media were evaluated for the release of double-stranded DNA (dsDNA) and immunostimulatory activity via nuclear factor kappa B (NF-κB) activity in Toll-like receptor (TLR) -expressing Ramos-Blue reporter cells. High compressive strains, with or without articular fracture, resulted in significantly reduced chondrocyte viability. Blunt impact at 70% strain induced a loss in viability over time through a combination of apoptosis and necrosis, whereas blunt impact above 80% strain caused predominantly necrosis. In the fracture model, a high level of primarily necrotic chondrocyte death occurred along the fracture edges. At sites away from the fracture, viability was not significantly different than controls. Interestingly, both dsDNA release and NF-κB activity in Ramos-Blue cells increased with blunt impact, but was only significantly increased in the media from fractured cores. This study indicates that the mechanism of trauma determines the type of chondrocyte death and the potential for post-injury inflammation. 23926270 Adrenergic gating of hebbian spike-timing-dependent plasticity in cortical interneurons. In pyramidal cells, the induction of spike-dependent plasticity (STDP) follows a simple Hebbian rule in which the order of presynaptic and postsynaptic firing dictates the induction of LTP or LTD. In contrast, cortical fast spiking (FS) interneurons, which control the rate and timing of pyramidal cell firing, reportedly express timing-dependent LTD, but not timing-dependent LTP. Because a mismatch in STDP rules could impact the maintenance of the excitation/inhibition balance, we examined the neuromodulation of STDP in FS cells of mouse visual cortex. We found that stimulation of adrenergic receptors enables the induction of Hebbian bidirectional STDP in FS cells in a manner consistent with a pull-push mechanism previously characterized in pyramidal cells. However, in pyramidal cells, STDP induction depends on NMDA receptors, whereas in FS cells it depends on mGluR5 receptors. We propose that neuromodulators control the polarity of STDP in different synapses in the same manner, and independently of the induction mechanism, by acting downstream in the plasticity cascade. By doing so, neuromodulators may allow coordinated plastic changes in FS and pyramidal cells. 23822080 Thoracic radiographic findings for dogs with cardiac tamponade attributable to pericardial effusion. To determine the prevalence of various radiographic findings for dogs with cardiac tamponade (CT) attributable to pericardial effusion (PE) and to determine the sensitivity and specificity of such findings for identification of affected dogs. Retrospective, randomized, blinded, controlled study. 50 dogs with CT attributable to PE and 23 control dogs (10 healthy dogs and 13 dogs with cardiac diseases other than CT). Thoracic radiographic images of dogs were evaluated by an observer who was unaware of the dogs' medical histories. For each dog, a vertebral heart score, globoid appearance of the cardiac silhouette, and convexity of the dorsocaudal aspect of the cardiac silhouette were determined. The sensitivity and specificity of enlargement of the cardiac silhouette (vertebral heart score, ≥ 10.7) for identification of dogs with CT attributable to PE were 77.6% and 47.8%, respectively. The sensitivity and specificity of a globoid appearance of the cardiac silhouette for identification dogs with CT were 41.9% and 40.0%, respectively. The sensitivity and specificity of a convex appearance of the dorsocaudal aspect of the cardiac silhouette for identification of dogs with CT were 57.1% and 35.0%, respectively. Results of this study indicated none of the evaluated radiographic variables was highly (> 90%) sensitive or specific for identification of dogs with CT attributable to PE. Thoracic radiographic findings should not be considered reliable for identification of dogs with CT attributable to PE. 23864654 Quantification of mitochondrial acetylation dynamics highlights prominent sites of metabolic regulation. Lysine acetylation is rapidly becoming established as a key post-translational modification (PTM) for regulating mitochondrial metabolism. Nonetheless, distinguishing regulatory sites from among the thousands identified by mass spectrometry and elucidating how these modifications alter enzyme function remain primary challenges. Here, we performed multiplexed quantitative mass spectrometry to measure changes to the mouse liver mitochondrial acetyl-proteome in response to acute and chronic alterations in nutritional status, and integrated these data sets with our compendium of predicted Sirt3 targets. These analyses highlight a subset of mitochondrial proteins with dynamic acetylation sites, including acetyl-CoA acetyltransferase 1 (Acat1) - an enzyme central to multiple metabolic pathways. We performed in vitro biochemistry and molecular modeling to demonstrate that acetylation of Acat1 decreases its activity by disrupting the binding of Coenzyme A. Collectively, our data reveal an important new target of regulatory acetylation, and provide a foundation for investigating the role of select mitochondrial protein acetylation sites in mediating acute and chronic metabolic transitions. 23881867 Reciprocal modulation of C/EBPα and C/EBPβ by IL-13 in activated microglia prevents neuronal death. In response to aggravation by activated microglia, IL-13 can significantly enhance endoplasmic reticulum stress induction, apoptosis, and death via reciprocal signaling through C/EBPα and C/EBPβ. This reciprocal signaling promotes neuronal survival. Since the induction of COX-2 and PPARγ/HO-1 by IL-13 plays a crucial role in the promotion of and protection from activated microglia respectively, here we investigated the role of IL-13 in regulating C/EBPs in activated microglia and determined its correlation with neuronal function. The results revealed that IL-13 significantly enhanced C/EBPα/COX-2 expression and PGE2 production in LPS-treated microglial cells. Paradoxically, IL-13 abolished C/EBPβ/PPARγ/HO-1 expression. IL-13 also enhanced ER stress-evoked calpain activation by promoting the association of C/EBPβ and PPARγ. SiRNA-C/EBPα effectively reversed the combined LPS-activated caspase-12 activation and IL-13-induced apoptosis. In contrast, siRNA-C/EBPβ partially increased microglial cell apoptosis. By NeuN immunochemistry and CD11b staining, there was improvement in the loss of CA3 neuronal cells after intra-hippocampal injection of IL-13. This suggests that IL-13-enhanced PLA2 activity regulates COX-2/PGE2 expression through C/EBPα activation. In parallel, ER stress-related calpain downregulates the PPARγ/HO-1 pathway via C/EBPβ and leads to aggravated death of activated microglia via IL-13, thereby preventing cerebral inflammation and neuronal injury. This article is protected by copyright. All rights reserved. 23893716 Polynitroethyl- and Fluorodinitroethyl Substituted Boron Esters. The reaction of boron oxide with various nitro-substituted ethanols (2-nitroethanol, 2-fluoro-2,2-dinitroethanol, 2,2,2-trinitroethanol) furnished the corresponding nitroethyl borates B(OCH2 CH2 NO2 )3 (1), B(OCH2 CF(NO2 )2 )3 (2), and B(OCH2 C(NO2 )3 )3 (3). Fluorination of the anion [(NO2 )2 CCH2 OH](-) (4) resulted in 2-fluoro-2,2-dinitroethanol (5), a precursor for 2, and was thoroughly characterized. An interesting condensation was observed with the anion 4 to form the unusual dianion [(NO2 )2 CCH2 C(NO2 )2 ](2-) (6). All compounds were fully characterized by multinuclear NMR spectroscopy, vibrational spectroscopy (IR, Raman), mass spectrometry and elemental analysis. The chemical, physical and energetic properties of 1-3 and 5 are reported, as well as quantum chemical calculations at the CBS-4M level of theory to predict the enthalpies and energies of formation. X-ray diffraction studies were performed, and the crystal structures for compounds 1-6 were determined and discussed thoroughly. The boron esters 1-3 are of interest as possible candidates for smoke-free, green colorants in pyrotechnic applications, and in case of 2 and 3 also as promising high energy oxidizers. 23122159 Antioxidant and antihypertensive properties of liquid and solid state fermented lentils. The effect of liquid (LSF) and solid state fermentation (SSF) of lentils for production of water-soluble fractions with antioxidant and antihypertensive properties was studied. LSF was performed either spontaneously (NF) or by Lactobacillus plantarum (LP) while SSF was performed by Bacillus subtilis (BS). Native lactic flora in NF adapted better than L. plantarum to fermentative broth and BS counts increased 4.0 logCFU/g up to 48 h of SSF. LSF water-soluble fractions had higher (P ≤ 0.05) free amino groups, GABA content, antioxidant and angiotensin I-converting enzyme inhibitory (ACEI) activities than SSF. In addition, GABA and ACEI activity of LSF increased in a time-dependent manner. Proteolysis by BS was limited, with slight changes in free amino groups, while GABA, total phenolic compounds and antioxidant capacity increased throughout fermentation. Higher antihypertensive potential was observed in NF (96 h) characterised by the highest GABA content (10.42 mg/g extract), ACE-inhibitory potency (expressed as IC(50)) of 0.18 mg protein/ml and antioxidant capacity of 0.26 mmol Trolox equivalents/g extract. Therefore, water-soluble fermented lentil extracts obtained by LSF are particularly promising as functional ingredients in preventing hypertension. 23891892 Migraine pathophysiology: Anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain. Scientific evidence supports the notion that migraine pathophysiology involves inherited alteration of brain excitability, intracranial arterial dilatation, recurrent activation, and sensitization of the trigeminovascular pathway, and consequential structural and functional changes in genetically susceptible individuals. Evidence of altered brain excitability emerged from clinical and preclinical investigation of sensory auras, ictal and interictal hypersensitivity to visual, auditory, and olfactory stimulation, and reduced activation of descending inhibitory pain pathways. Data supporting the activation and sensitization of the trigeminovascular system include the progressive development of cephalic and whole-body cutaneous allodynia during a migraine attack. In addition, structural and functional alterations include the presence of subcortical white mater lesions, thickening of cortical areas involved in processing sensory information, and cortical neuroplastic changes induced by cortical spreading depression. Here, we review recent anatomical data on the trigeminovascular pathway and its activation by cortical spreading depression, a novel understanding of the neural substrate of migraine-type photophobia, and modulation of the trigeminovascular pathway by the brainstem, hypothalamus and cortex. 23180651 Facile and clean release of vertical Si nanowires by wet chemical etching based on alkali hydroxides. A simple method to release Si nanowires (SiNWs) from a substrate, with their original length almost intact, is demonstrated. By exploiting the unique chemistry involved for the fabrication of vertical arrays of SiNWs in metal-assisted chemical etching (MaCE) based either on HF/AgNO3 or HF/H2O2 chemistries, wet etching with alkali hydroxides such as NaOH or KOH preferentially attacks the bottom part of the vertical SiNWs. A protective layer of Si oxide is found to exist on the outer wall of the SiNWs and to play the key role of etch mask during the release-etching by alkali hydroxides. The clean release of SiNWs also enables the repeated use of the Si substrate for the fabrication of vertical SiNW arrays by MaCE. The released SiNWs are further used for the fabrication of field-effect transistors on a flexible plastic substrate. The method developed here, when combined with a suitable assembling technique, can be very useful in implementing flexible electronics, or in the fabrication of SiNW composites with other functional materials. 23841620 Plumbagin inhibits cytokinesis in Bacillus subtilis by inhibiting FtsZ assembly - a mechanistic study of its antibacterial activity. The assembly of FtsZ plays a central role in construction of the cytokinetic Z-ring that orchestrates bacterial cell division. A naturally occurring naphthoquinone, plumbagin, is known to exhibit antibacterial properties against several types of bacteria. In this study, plumbagin was found to perturb formation of the Z-ring in Bacillus subtilis 168 cells and to cause elongation of these cells without an apparent effect on nucleoid segregation, indicating that it may inhibit FtsZ assembly. Furthermore, it bound to purified B. subtilis FtsZ (BsFtsZ) with a dissociation constant of 20.7 ± 5.6 Î¼m, and inhibited the assembly and GTPase activity of BsFtsZ in vitro. Interestingly, plumbagin did not inhibit either the assembly or GTPase activity of Escherichia coli FtsZ (EcFtsZ) in vitro. Using docking analysis, a putative plumbagin-binding site on BsFtsZ was identified, and the analysis indicated that hydrophobic interactions and hydrogen bonds predominate. Based on the in silico analysis, two variants of BsFtsZ, namely D199A and V307R, were constructed to explore the binding interaction of plumbagin and BsFtsZ. The effects of plumbagin on the assembly and GTPase activity of the variant BsFtsZ proteins in vitro indicated that the residues D199 and V307 may be involved in the binding of plumbagin to BsFtsZ. The results suggest that plumbagin inhibits bacterial proliferation by inhibiting the assembly of FtsZ, and provide insight into the binding site of plumbagin on BsFtsZ, which may help in the design of potent FtsZ-targeted antibacterial agents. 23726883 Investigation on extracellular polymeric substances from mucilaginous cyanobacterial blooms in eutrophic freshwater lakes. Enhanced knowledge on extracellular polymeric substances (EPSs) of mucilaginous cyanobacterial blooms could improve our understanding of its ecological significance. This study for the first time investigated the extraction and fractionation of EPS matrix from cyanobacterial blooms in a eutrophic freshwater lake, and the changes in chemical compositions in EPS matrix during extraction were systematically investigated by two-dimensional correlation spectroscopy (2D-COS). The analyses demonstrated that organic matters were unevenly distributed among the EPS matrix, with most of organic matters being tightly bound to cyanobacterial cells. In addition, the soluble and loosely bound EPS fractions mainly consisted of proteins, while polysaccharides became the predominant compounds in the tightly bound EPS fraction. Heating extraction at 60°C for 30min led to a high EPS yield and low cell lysis when compared with other extraction methods. The 2D-COS results revealed a preferential release of OH in polysaccharides versus amide I in proteins in the initial heating; whereas further extension of heating resulted in EPS degradation, with degradation rates arranging in a decreased order from amide I, amide II, polysaccharides-like substances to polysaccharides. These results obtained would help enhance our insights into EPS characterization from cyanobacterial blooms in eutrophic lakes. 23340797 The first dehydration and the competing reaction pathways of glucose homogeneously and heterogeneously catalyzed by acids. The dehydration mechanisms for glucose in β-pyranose (BP) and in open-chain (OC) forms, catalyzed by acids homogeneously and heterogeneously, were investigated using density functional and two-layer ONIOM calculations. The first dehydration reaction and competing reaction pathways are the main focus of the present study. The energetics of five dehydration and two isomerization pathways were examined for the protonated form of BP in acidic aqueous solutions and the most favorable pathway of these was found to be the dehydration at the anomeric site. No dehydration pathway of OC glucose is favored over its isomerization to BP or to fructose. The relative ease of dehydration over isomerization depends on the selection of the reaction media for the protonated form of BP. These two reaction pathways catalyzed by a surface Brönsted acid site were then examined and the isomerization pathway was found to be more favorable than dehydration at the anomeric site on a surface acid site. These mechanistic insights provide an important guide for the catalyst design/selection of the reaction media for glucose dehydration. 23935040 Functionally essential interaction between Yersinia YscO and the T3S4 domain of YscP. The type III secretion (T3S) system is essential to the virulence of a large number of gram-negative bacterial pathogens, including Yersinia. YscO is required for T3S in Yersinia and is known to interact with several other T3S proteins, including the chaperone SycD and the needle length regulator YscP. To define which interactions of YscO are required for T3S, we pursued model-guided mutagenesis: Three conserved and surface-exposed regions of modeled YscO were targeted for multiple alanine substitutions. Most of the mutations abrogated T3S and did so in a recessive manner, consistent with a loss of function. Both functional and nonfunctional YscO mutant proteins interacted with SycD, indicating that the mutations had not affected protein stability. Likewise, both functional and nonfunctional versions of YscO were exclusively intrabacterial. Functional and nonfunctional versions of YscO were, however, distinguishable with respect to interaction with YscP. This interaction was observed only for wild-type YscO and a T3S-proficient mutant of YscO, but not for the several T3S-deficient YscO mutants of YscO. Evidence is presented that the YscO-YscP interaction is direct, and that the type III secretion substrate specificity switch (T3S4) domain of YscP is sufficient for this interaction. These results provide evidence that the interaction of YscO with YscP, and in particular the T3S4 domain of YscP, is essential to type III secretion. 23628620 Receiver Operating Characteristic Analysis of HLA, CTLA4, and Insulin Genotypes for Type 1 Diabetes. OBJECTIVEThis study assessed the ability to distinguish between type 1 diabetes-affected individuals and their unaffected relatives using HLA and single nucleotide polymorphism (SNP) genotypes.RESEARCH DESIGN AND METHODSEight models, ranging from only the high-risk DR3/DR4 genotype to all significantly associated HLA genotypes and two SNPs mapping to the cytotoxic T-cell-associated antigen-4 gene (CTLA4) and insulin (INS) genes, were fitted to high-resolution class I and class II HLA genotyping data for patients from the Type 1 Diabetes Genetics Consortium collection. Pairs of affected individuals and their unaffected siblings were divided into a "discovery" (n = 1,015 pairs) and a "validation" set (n = 318 pairs). The discriminating performance of various combinations of genetic information was estimated using receiver operating characteristic (ROC) curve analysis.RESULTSThe use of only the presence or absence of the high-risk DR3/DR4 genotype achieved very modest discriminating ability, yielding an area under the curve (AUC) of 0.62 in the discovery set and 0.59 in the validation set. The full model, which included HLA information from the class II loci DPB1, DRB1, DQB1, selected alleles from HLA class I loci A and B, and SNPs from the CTLA4 and INS genes, increased the AUC to 0.74 in the discovery set and to 0.71 in the validation set. A cost-effective alternative is proposed, using genotype information equivalent to typing four SNPs (DR3, DR4-DQB1*03:02, CTLA-4, and INS), which achieved an AUC of 0.72 in the discovery set and 0.69 in the validation set.CONCLUSIONSGenotyping data sufficient to tag DR3, DR4-DQB1*03:02, CTLA4, and INS was shown to distinguish between subjects with type 1 diabetes and their unaffected siblings adequately to achieve clinically utility to identify children in multiplex families to be considered for early intervention. 23656887 Npas4 Is a Novel Activity-Regulated Cytoprotective Factor in Pancreatic β-Cells. Cellular homeostasis requires intrinsic sensing mechanisms to temper function in the face of prolonged activity. In the pancreatic β-cell, glucose is likely a physiological trigger that activates an adaptive response to stimulation, thereby maintaining cellular homeostasis. Immediate early genes (IEGs) are activated as a first line of defense in cellular homeostasis and are largely responsible for transmitting an environmental cue to a cellular response. Here we examine the regulation and function of the novel β-cell IEG, neuronal PAS domain protein 4 (Npas4). Using MIN6 cells, mouse and human islets, as well as in vivo infusions, we demonstrate that Npas4 is expressed within pancreatic islets and is upregulated by β-cell depolarizing agents. Npas4 tempers β-cell function through a direct inhibitory interaction with the insulin promoter and by blocking the potentiating effects of GLP-1 without significantly reducing glucose-stimulated secretion. Finally, Npas4 expression is induced by classical endoplasmic reticulum (ER) stressors and can prevent thapsigargin- and palmitate-induced dysfunction and cell death. These results suggest that Npas4 is a key activity-dependent regulator that improves β-cell efficiency in the face of stress. We posit that Npas4 could be a novel therapeutic target in type 2 diabetes that could both reduce ER stress and cell death and maintain basal cell function. 23871992 Unlocking the secrets of the gatekeeper: Methods for stabilizing and crystallizing GPCRs. G-protein coupled receptors (GPCRs) are integral membrane cell surface receptors with key roles in mediating the cellular responses to a wide range of biologically relevant molecules including hormones, neurotransmitters and importantly the majority of currently available drugs. The first high-resolution, X-ray crystallographic structure of a GPCR, that of rhodopsin, was obtained in 2000. It took a further seven years for the next structure, that of the β2 adrenergic receptor. Remarkably, at the time of writing, there have been an astonishing 18 further independent high-resolution GPCR structures published in the last five years (overall total of 68 structures in different conformations or bound to different ligands). Of particular note is the recent structure of the β2 adrenergic receptor in complex with its cognate heterotrimeric G-protein revealing for the first time molecular details of the interaction between a GPCR and the complete G-protein. Together these structures have provided unprecedented detail into the mechanism of action of these incredibly important proteins. This review describes several key methodological advances that have made such extraordinarily fast progress possible. 23824392 Upper cervical fusion in children with Morquio syndrome: intermediate to long-term results. Paraplegia or death secondary to upper cervical spine instability and spinal cord compression are known consequences of Morquio syndrome. Decompression and fusion of the upper cervical spine are indicated to treat spinal cord compression. The purpose of this study was to report the intermediate to long-term results of upper cervical spine fusion in children with Morquio syndrome. Twenty patients (nine female and eleven male) with Morquio syndrome who underwent upper cervical spine fusion at a mean age of sixty-three months were retrospectively analyzed with use of hospital records. Radiographic and clinical results were reported. The average follow-up period was eight years and ten months. Fusion was achieved in all patients except one; this patient underwent a revision with transarticular C1-C2 screw fixation. Seven patients developed symptomatic instability below the fusion mass that required extension of fusion to lower levels at a mean of ninety-one months after the initial operation. Two patients required decompression and fusion of a site other than the upper cervical spine. Asymptomatic cervicothoracic and thoracolumbar kyphosis was prevalent among our patients. All patients were neurologically stable at the time of the latest follow-up visit. Upper cervical spine fusion provides reliable fusion and a stable neural outcome in patients with Morquio syndrome. However, distal junctional instability is a major problem at long-term follow-up. Kyphotic deformity of the cervicothoracic and thoracolumbar junction may be present in a large number of patients with Morquio syndrome and evaluation for spinal stenosis at these levels should also be considered. 23848523 Use of a Standardized MxA Protein Measurement-Based Assay for Validation of Assays for the Assessment of Neutralizing Antibodies Against Interferon-β Effective monitoring of the development of neutralizing antibodies (NAbs) against IFN-β in multiple sclerosis (MS) patients on IFN-β therapy is important for clinical decision making and disease management. To date, antiviral assays have been the favored approach for NAb determination, but variations in assay conditions between laboratories and the increasing use of novel assays have contributed to the reporting of inconsistent antibody data between laboratories and between products. This study, undertaken at the request of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA), is a joint effort by manufacturers of IFN-β products (approved in Europe) towards harmonization of a NAb assay that facilitates generation of comparable NAb data, which, in conjunction with clinical outcomes, should prove useful for clinicians treating MS patients with IFN-β products. This article describes the standardized cellular myxovirus resistance protein A (MxA) protein measurement-based assay for detection of IFN-β NAbs and its use for the validation of assays used for the quantitative determination of such antibodies. Although titers varied between laboratories and the products used, utilization of IFN-β1a rather than IFN-β1b as the challenge antigen produced more consistent results in the NAb assay. Adoption of the standardized assay improves comparability between laboratories circumventing problems that arise when different, nonstandardized assays are employed for immunogenicity assessment. Based on the data, the EMA recommended for standardization purposes, the use of IFN-β1a in NAb assays, independent of the therapeutic product used for therapy and validation of new NAb procedures against the standardized assay described. 23027679 Measurement Invariance of the Perceived Stress Scale and Latent Mean Differences across Gender and Time. Measurement invariance of the 2-factor model of the Perceived Stress Scale-10-item version (Cohen & Williamson, 1988) was tested across men and women at two time points and in the combined total sample over a 2-year time frame (n = 871). Measurement invariance results indicated that the scale measured the latent factors, stress and counter-stress, equivalently in men and women and over time. With measurement invariance demonstrated, differences in latent means were tested. Results indicated that men had lower levels of frequencies of stressors, and at one time point, higher levels of counter-stress, when compared with women. When examining change in frequencies of stressors and counter-stress over 2 years with the combined male and female sample, stressors remained stable, yet counter-stress increased over time. These findings may aid in the interpretation of results when examining stressors and counter-stress in clinical samples where one would expect stress to increase, whereas positive psychological states decrease. Copyright © 2012 John Wiley & Sons, Ltd. 23404300 Predicting the Optimal Basal Insulin Infusion Pattern in Children and Adolescents on Insulin Pumps. OBJECTIVEWe aimed at developing and cross-validating a mathematical prediction model for an optimal basal insulin infusion pattern for children with type 1 diabetes on continuous subcutaneous insulin infusion therapy (CSII).RESEARCH DESIGN AND METHODSWe used the German/Austrian DPV-Wiss database for quality control and scientific surveys in pediatric diabetology and retrieved all CSII patients <20 years of age (November 2009). A total of 1,248 individuals from our previous study were excluded (dataset 1), resulting in 6,063 CSII patients (dataset 2) (mean age 10.6 ± 4.3 years). Only the most recent basal insulin infusion rates (BRs) were considered. BR patterns were identified and corresponding patients sorted by unsupervised clustering. Logistic regression analysis was applied to calculate the probabilities for each BR pattern. Equations were based on both independent datasets separately, and probabilities for BR patterns were cross-validated using typical test patients.RESULTSOf the 6,063 children, 5,903 clustered in one of four major circadian BR patterns, confirming our previous study. The oldest age-group (mean age 12.8 years) was represented by 2,490 patients (42.18%) with a biphasic dawn-dusk pattern (BC). A broad single insulin maximum at 9-10 p.m. (F) was unveiled by 853 patients (14.45%) (mean age 6.3 years). Logistic regression analysis revealed that age, to a lesser extent duration of diabetes, and partly sex predicted BR patterns. Cross-validation revealed almost identical probabilities for BR patterns BC and F in the two datasets but some variation in the remaining two BR patterns.CONCLUSIONSReconfirmation of four key BR patterns in two very large independent cohorts supports that these patterns are realistic approximations of the circadian distribution of insulin needs in children with type 1 diabetes. Prediction of an optimal pattern a priori can improve initiation and clinical follow-up of CSII in children and adolescents. In addition, these BR patterns represent valuable information for insulin-infusion algorithms in closed-loop CSII. 23567158 Deletion of beta catenin in hypertrophic growth plate chondrocytes impairs trabecular bone formation. In order to elucidate the role of β-catenin in hypertrophic cartilage zone of the growth plate, we deleted the β-catenin gene ctnnb1specifically from hypertrophic chondrocytes by mating ctnnb1(fl/fl) mice with BAC-Col10a1-Cre-deleter mice. Surprisingly, this resulted in a significant reduction of subchondral trabecular bone formation in BACCol10Cre; ctnnb1(Δ/Δ) (referred to as Cat-ko) mice, although Cre expression was restricted to hypertrophic chondrocytes. The size of the Col10a1 positive hypertrophic zone was normal, but qRT-PCR revealed reduced expression of Mmp13, and Vegfa in Cat-ko hypertrophic chondrocytes, indicating impaired terminal differentiation. Immunohistological and in situ hybridization analysis revealed the substantial deficiency of collagen I positive mature osteoblasts, but equal levels of osterix-positive cells in the subchondral bone marrow space of Cat-ko mice, indicating that the supply of osteoblast precursor cells was not reduced. The fact that in Cat-ko mice subchondral trabeculae were lacking including their calcified cartilage core indicated a strongly enhanced osteoclast activity. In fact, TRAP staining as well as in situ hybridization analysis of Mmp9 expression revealed denser occupation of the cartilage erosion zone with enlarged osteoclasts as compared to the control growth plate, suggesting increased RANKL or reduced osteoprotegerin (Opg) activity in this zone. This notion was confirmed by qRT-PCR analysis of mRNA extracted from cultured hypertrophic chondrocytes or from whole epiphyses, showing increased Rankl mRNA levels in Cat-ko as compared to control chondrocytes, whereas changes in OPG levels were not significant. These results indicate that β-catenin levels in hypertrophic chondrocytes play a key role in regulating osteoclast activity and trabecular bone formation at the cartilage-bone interface by controlling RANKL expression in hypertrophic chondrocytes. 23943601 Anomalous Property of Ag(BO2 )2 Hyperhalogen: Does Spin-Orbit Coupling Matter? Hyperhalogens were recently identified as a new class of highly electronagative species which are composed of metals and superhalogens. In this work, high-level theoretical calculations and photoelectron spectroscopy experiments are systematically conducted to investigate a series of coinage-metal-containing hyperhalogen anions, Cu(BO2 )2 (-) , Ag(BO2 )2 (-) , and Au(BO2 )2 (-) . The vertical electron detachment energy (VDE) of Ag(BO2 )2 (-) is anomalously higher than those of Au(BO2 )2 (-) and Cu(BO2 )2 (-) . In quantitative agreement with the experiment, high-level ab initio calculations reveal that spin-orbit coupling (SOC) lowers the VDE of Au(BO2 )2 (-) significantly. The sizable magnitude of about 0.5 eV of SOC effect on the VDE of Au(BO2 )2 (-) demonstrates that SOC plays an important role in the electronic structure of gold hyperhalogens. This study represents a new paradigm for relativistic electronic structure calculations for the one-electron-removal process of ionic Au(I) L2 complexes, which is characterized by a substantial SOC effect. 23857174 Effects of cis-9,trans-11 and trans-10,cis-12 conjugated linoleic acid, linoleic acid, phytanic acid and the combination of various fatty acids on proliferation and cytokine expression of bovine peripheral blood mononuclear cells. Fatty acids may have an impact on immune functions, which is important in times of increased mobilization of body fat, e.g., around parturition. The aim of the present study was to investigate the effects of the CLA isomers cis-9,trans-11 and trans-10,cis-12, phytanic acid (PA), linoleic acid (LA) and a fatty acid (FA) mixture (containing 29.8% palmitic acid, 6.7% palmitoleic acid, 17.4% stearic acid and 46.1% oleic acid) on the proliferation of bovine blood mononuclear cells (PBMC) in vitro using alamar blue (AB) and 5-bromo-2'-deoxyuridine (BrdU) assay. Quantitative real time polymerase chain reaction analyses were performed to evaluate the expression of interleukin (IL)-4, IL-10, interferon (IFN)-γ, tumor necrosis factor (TNF)-α and peroxisome proliferator-activated receptor (PPAR)-γ in response to cis-9,trans-11 and LA. The IC50 values did not differ between the investigated FA, but there were differences within the proliferation in the response of these FA in a concentration range between 20 and 148 µM (e.g., increased proliferation after treatment with lower concentrations of LA). No differences occurred when different FA combinations were tested. ConA stimulation increased the expression of TNF-α and IFN-γ, whereas IL-10 decreased. In general, neither the baseline expression nor the ConA-stimulated mRNA expression of cytokines and PPAR-γ were affected by the FA. In conclusion, all FA inhibit the proliferation of PBMC dose dependently without significantly altering the induced cytokine spectrum of activated bovine PBMC. 23570951 Evaluation of the potential of phase-contrast computed tomography for improved visualization of cancerous human liver tissue. Phase-contrast X-ray computed tomography (PCCT) is currently investigated and developed as a potentially very interesting extension of conventional CT, and can offer several advantages for specific indications in diagnostic imaging. Current absorption-based computed tomography (CT) without the application of contrast material is limited in the detection of minor density differences in soft-tissue. The purpose of this study is to test whether PCCT can improve soft tissue contrast in healthy and tumorous human liver specimens. Two specimens of human liver (one healthy and one metastasized liver sample) were imaged with brilliant X-ray beam at the synchrotron radiation source ESRF in Grenoble, France. For correlation the same specimens were imaged with a magnetic resonance imaging system at 1.5 T. The histopathology confirmed our findings in the corresponding sections of the specimens. In the phase-contrast CT images we observed a significantly enhanced soft-tissue contrast when compared to simultaneously recorded standard absorption CT measurements. Further, we found that the pathological and morphological information in the PCCT reconstructions show significant improvement when compared to those performed on MRI. Based on matching of prominent features, a good correlation between PCCT and the histological section is demonstrated; especially the tumor capsule and the surrounding vascular structures are visible in PCCT. In addition, our study revealed the ability of PCCT to visualize the blood vessels structure in the tumorous liver without the need of any contrast agents. Grating-based PCCT significantly improves the soft-tissue contrast in ex-vivo liver specimens and holds the potential to overcome the need of contrast materials for visualization of the tumor vascularization. 22093085 The effect of ergometer design on rowing stroke mechanics. The effect of rowing ergometer design upon power delivery and coordination patterns of the rowing stroke was analyzed for 14 elite rowers. Rowers were tested in three ergometer conditions: the fixed stretcher Concept2c ergometer, the Concept2c ergometer mounted on sliding rails, and the sliding stretcher RowPerfect ergometer. Ergometers were instrumented to measure the external force generated at the handle and the foot stretcher and a nine-segment inverse dynamics model used to calculate joint and overall power delivery. Peak power generation and absorption at the knee joint was significantly greater, and total power delivered to the ergometer delayed on the fixed stretcher ergometer when compared to the sliding stretcher ergometers. No differences were found in the mechanical energy delivered to the handle of the three ergometers; however, greater joint mechanical energy production of the lower limb reduced mechanical efficiency when rowing the Concept2c fixed ergometer. The fixed foot stretcher on the Concept2c fixed ergometer acts to increase the inertial forces that the rower must overcome at the catch, increasing the moment and power output at the knee, and affecting the coordination pattern during the recovery phase. 23397506 Human applications of submucosal endoscopy under conscious sedation for pure natural orifice transluminal endoscopic surgery. The submucosal endoscopy provide not only a reliable methods of access and closure for peritoneoscopy, but also an endoscopic working space for full-thickness resection. The aim of this study was to report the clinical outcome of submucosal endoscopy for pure natural orifice transluminal endoscopic surgery. We prospectively evaluated 10 patients who received submucosal endoscopies. The indications of submucosal endoscopy were transgastric peritoneoscopy (TGP) and endoscopic full-thickness resection (EFTR) of a gastric subepithelial tumor. All procedures were performed with a standard gastroscope under conscious sedation with the balanced propofol method in the endoscopic unit. After a 40 mm submucosal tunnel was created using an endoscopic submucosal dissection technique, (1) in TGP, balloon dilation of a serosal puncture and intraperitoneal exploration was performed; (2) in EFTR, a full-thickness incision and snaring resection was performed. Closure of the mucosal incision was performed by endoclips. All cases were technically feasible. The mean times for creating the submucosal tunnel, main procedure (peritoneal exploration or resection), and closure were acceptable (10.44 ± 2.42 minutes, 18.80 ± 9.41 minutes, and 5.63 ± 2.17 minutes, respectively). The mean hospital stay was 3.8 ± 1.48 days. All TGPs were diagnostic (4 peritoneal carcinomatosis and 1 tuberculosis). En bloc and complete resections were possible in all EFTRs (3 gastrointestinal stromal tumors and 2 schwannomas; mean tumor size, 20.8 ± 3.27 mm). There were no procedure-related complications, such as significant bleeding or peritonitis. Human applications of submucosal endoscopy under conscious sedation for pure NOTES were feasible and safe. 23870011 Effects of Gestational Age on Physical Findings of Immaturity, Body Weight, and Survival in Neonatal Alpacas (2002-2010). Gestational duration is highly variable in camelids (reference range 330-360 days), and a definition for prematurity has not been established. Anecdotally, it is suggested that crias born outside of this have increased incidence of physical findings of immaturity (tendon laxity, floppy ears, and unerupted teeth) and need increased intensive support in the neonatal period. Low gestational age (<330 days) is associated with physical findings of immaturity, low birth weight, more intensive and expensive care, but not decreased short-term survival. A total of 130 alpacas presented to the University of Wisconsin. Retrospective study of all neonatal crias <1 month of age. Of 130 neonatal alpacas presented, 86 (66%) had gestational age recorded (range 312-393 days). There were 16 (18.6%) crias with gestational age below 330 days. Crias born before 330 days were lighter at birth (mean 6.4 kg, SD 1.3 kg) than those born after 330 days (mean 7.4 kg, SD 1.7 kg, P = .002). Clinically immature crias had lower birth weights (mean 6.5 kg, SD 1.5 kg) than physically mature crias (mean 8.8 kg, SD 3.2 kg, P = .05). Survival rates were similar in all groups (premature 77%, mature 88%, P = .12). However, treatment costs were higher in crias born prior to 330 days with physical findings at birth consistent with immaturity compared with gestationally mature crias and those born prior to 330 days but with a physically mature appearance. Crias born before 330 days and those with physical findings of immaturity have a good prognosis, but require more intensive care, resulting in higher treatment costs. 23871885 Exercise Increases Age-Related Penetrance and Arrhythmic Risk in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Associated Desmosomal Mutation Carriers. To determine how exercise influences penetrance of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) among patients with desmosomal mutations. While animal models and anecdotal evidence suggest exercise is a risk factor for ARVD/C, there have been no systematic human studies. Eighty-seven carriers (46 male, mean age 44±18) were interviewed about regular physical activity from age ten. The relationship of exercise with; 1) sustained ventricular arrhythmia (VT/VF), 2) stage C heart failure (HF), and 3) meeting diagnostic criteria for ARVD/C (TFC) was studied. Endurance athletes (n=56) developed symptoms at a younger age (30.1±13.0 vs. 40.6±21.1 years, p=0.05), were more likely to meet TFC at last follow-up (82% vs. 35%, p<0.001), and had a lower lifetime survival free from VT/VF (p=0.013) and HF (p=0.004). Compared to those who did the least (lowest quartile) exercise per year prior to presentation, those in the second (OR=6.64, p=0.013), third (OR=16.7, p=0.001), and top (OR=25.3, p<0.0001) quartiles were increasingly likely to meet TFC. Among 61 who did not present with VT/VF, the 13 subjects experiencing a first VT/VF event over a mean 8.4±6.7 year follow-up were all endurance athletes (p=0.002). Survival from first VT/VF was lowest among those who exercised most (top quartile) both prior to (p=0.036) and after (p=0.005) clinical presentation. Among individuals in the top quartile, a reduction in exercise decreased VT/VF risk (p=0.04). Endurance exercise and frequent exercise increase risk of VT/VF, HF, and ARVD/C in desmosomal mutation carriers. These findings support exercise restriction for these patients. 23711747 Alternative substrates selective for S-adenosylmethionine synthetases from pathogenic bacteria. S-adenosyl-l-methionine (AdoMet) synthetase catalyzes the production of AdoMet, the major biological methyl donor and source of methylene, amino, ribosyl, and aminopropyl groups in the metabolism of all known organism. In addition to these essential functions, AdoMet can also serve as the precursor for two different families of quorum sensing molecules that trigger virulence in Gram-negative human pathogenic bacteria. The enzyme responsible for AdoMet biosynthesis has been cloned, expressed and purified from several of these infectious bacteria. AdoMet synthetase (MAT) from Neisseria meningitidis shows similar kinetic parameters to the previously characterized Escherichia coli enzyme, while the Pseudomonas aeruginosa enzyme has a decreased catalytic efficiency for its MgATP substrate. In contrast, the more distantly related MAT from Campylobacter jejuni has an altered quaternary structure and possesses a higher catalytic turnover than the more closely related family members. Methionine analogs have been examined to delineate the substrate specificity of these enzyme forms, and several alternative substrates have been identified with the potential to block quorum sensing while still serving as precursors for essential methyl donation and radical generation reactions. 23851351 Aerodynamic forces and flow structures of the leading edge vortex on a flapping wing considering ground effect. The aim of this work is to provide an insight into the aerodynamic performance of the beetle during takeoff, which has been estimated in previous investigations. We employed a scaled-up electromechanical model flapping wing to measure the aerodynamic forces and the three-dimensional flow structures on the flapping wing. The ground effect on the unsteady forces and flow structures were also characterized. The dynamically scaled wing model could replicate the general stroke pattern of the beetle's hind wing kinematics during takeoff flight. Two wing kinematic models have been studied to examine the influences of wing kinematics on unsteady aerodynamic forces. In the first model, the angle of attack is asymmetric and varies during the translational motion, which is the flapping motion of the beetle's hind wing. In the second model, the angle of attack is constant during the translational motion. The instantaneous aerodynamic forces were measured for four strokes during the beetle's takeoff by the force sensor attached at the wing base. Flow visualization provided a general picture of the evolution of the three-dimensional leading edge vortex (LEV) on the beetle hind wing model. The LEV is stable during each stroke, and increases radically from the root to the tip, forming a leading-edge spiral vortex. The force measurement results show that the vertical force generated by the hind wing is large enough to lift the beetle. For the beetle hind wing kinematics, the total vertical force production increases 18.4% and 8.6% for the first and second strokes, respectively, due to the ground effect. However, for the model with a constant angle of attack during translation, the vertical force is reduced during the first stroke. During the third and fourth strokes, the ground effect is negligible for both wing kinematic patterns. This finding suggests that the beetle's flapping mechanism induces a ground effect that can efficiently lift its body from the ground during takeoff. 23916241 Endoscopic ultrasound-guided fine needle aspiration and biopsy using a 22-gauge needle with side fenestration in pancreatic cystic lesions. Cytologic diagnosis by endoscopic ultrasound-guided fine needle aspiration is associated with low sensitivity and adequacy. A newly designed endoscopic ultrasound-guided fine needle biopsy device, endowed with a side fenestration, is now available. We carried out a study with the aim of evaluating the feasibility, safety, and diagnostic yield of the 22-gauge needle with side fenestration for endoscopic ultrasound fine needle aspiration and biopsy of pancreatic cystic lesions. 58 patients with 60 pancreatic cystic lesions consecutively referred for endoscopic ultrasound guided-fine needle aspiration were enrolled in a prospective, dual centre study, and underwent fine needle aspiration and biopsy with the 22-gauge needle with side fenestration. Fine needle aspiration and biopsy was technically feasible in all cases. In 39/60 (65%) pancreatic cystic lesions, the specimens were adequate for cyto-histologic assessment. In lesions with solid components, and in malignant lesions, adequacy was 94.4% (p=0.0149) and 100% (p=0.0069), respectively. Samples were adequate for histologic evaluation in 18/39 (46.1%) cases. There were only 2 (3.3%) mild complications. Fine needle aspiration and biopsy with the 22-gauge needle with side fenestration is feasible, and superior to conventional endoscopic ultrasound-guided fine needle aspiration cytology from cystic fluid, particularly in pancreatic cystic lesions with solid component or malignancy, with a higher diagnostic yield and with no increase in complication rate. 23561221 Flavour profiles of three novel acidic varieties of muskmelon (Cucumis melo L.). Novel acidic varieties of muskmelon (Cucumis melo L.) are emerging onto the UK market. These melons contain almost twice the amount of citric acid compared to standard melons and are described as 'zesty and fresh'. This study compared the flavour components of three acidic varieties with a standard Galia-type melon. The volatile and semivolatile compounds were extracted, using dynamic headspace extraction (DHE) or solid-phase microextraction (SPME) and solid phase extraction (SPE), respectively, followed by gas chromatography-mass spectrometry (GC-MS) and gas chromatography-olfactometry (GC-O). More than 50 volatile and 50 semivolatile compounds were identified in the headspace and the SPE extracts, respectively. GC-O revealed 15 odour-active components in the headspace, with esters being consistently higher in the acidic variety. This study showed quantitative and qualitative differences among all four varieties and key differences between acidic varieties and standard melons. 23296464 The feasibilities of TruScreen for primary cervical cancer screening: a self-controlled study. Screening programs based on cytology testing led to the incidence reduction of cervical cancer mortality of about 70-80 % in industrialized countries. However, these favorable results have not been replicated in developing areas. Thus, we aim to evaluate the efficacy of TruScreen (Polartechnics, Sydney, Australia) in detecting of precancerous lesions in comparison with cervical cytology test. A total of 181 outpatients were screened by TruScreen using the pathological results as the gold standard. The medical records of cytological smear within 6 weeks were obtained from 169 of these participants. The reliability and yield of TruScreen and cytological smear were assessed. The screening results of TruScreen were compared with those obtained from the conventional smear. The sensitivities for histologically confirmed cervical intraepithelial neoplasia (CIN) lesions by TruScreen and Pap, were 67.4 % (95 % CI 53.4-81.5) and 87.9 % (95 % CI 76.7-99.0), respectively. The specificities for histologically confirmed CIN lesions by TruScreen and Pap, were 68.1 % (95 % CI 60.3-75.9) and 74.3 % (95 % CI 70.0-81.4), respectively. In contrast to Pap smear, TruScreen was comparatively efficacious in screening of cervical cancer (χ (2) = 0.0133, P = 0.9081). TruScreen is a potential test for initial cervical screening in developing world regions. 23847091 Occurrence of osteochondromatosis (multiple cartilaginous exostoses) in a domestic pig (Sus scrofa domesticus). Osteochondromatosis is a condition in which multiple benign, cartilage-capped tumors arise from the surface of bones formed by endochondral ossification. The current report describes the presence of 4 prominent exophytic masses, measuring between 4 and 13 cm in diameter, arising from the surface of the ribs, and located within the thoracic cavity, in a 2-year-old female domestic pig (Sus scrofa domesticus). Histological studies revealed that masses were well-differentiated, cartilage-capped proliferations with an orderly pattern of endochondral mineralization toward deeper areas. The observed gross and microscopic findings are characteristic of osteochondromatosis. 23922105 Proanthocyanidins and other flavonoids in relation to endometrial cancer risk: a case-control study in Italy. Background:Because of their antioxidant and antimutagenic properties, flavonoids may reduce cancer risk. Some flavonoids have antiestrogenic effects that can inhibit the growth and proliferation of endometrial cancer cells.Methods:In order to examine the relation between dietary flavonoids and endometrial cancer, we analysed data from an Italian case-control study including 454 incident, histologically confirmed endometrial cancers and 908 hospital-based controls. Information was collected through a validated food-frequency questionnaire. We applied data on food and beverage composition to estimate the intake of flavanols, flavanones, flavonols, anthocyanidins, flavones, isoflavones, and proanthocyanidins. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from multiple logistic regression models conditioned on age and study centre and adjusted for major confounding factors.Results:Women in the highest quartile category of proanthocyanidins with 3 mers vs the first three quartile categories had an OR for endometrial cancer of 0.66 (95% CI=0.48-0.89). For no other class of flavonoids, a significant overall association was found. There was a suggestion of an inverse association for flavanones and isoflavones among women with body mass index <25 kg m(-2), and, for flavanones, among parous or non-users of hormone-replacement therapy women.Conclusion:High consumption of selected proanthocyanidins may reduce endometrial cancer risk.British Journal of Cancer advance online publication, 6 August 2013; doi:10.1038/bjc.2013.447 www.bjcancer.com. 23544891 In Vitro Fertilization outcomes in treated hypothyroidism. Background: Levothyroxine has been shown to enhance pregnancy outcomes in women with hypothyroidism requiring In Vitro Fertilization (IVF). However, the precise magnitude of these benefits remains to be determined. In particular, it has yet to be clarified whether levothyroxine may fully overcome the detrimental effects of hypothyroidism or, conversely, whether affected women remain at reduced prognosis for pregnancy outcomes. Methods: Patients who underwent IVF-ICSI (IVF-intracytoplasmic sperm injection) over a three-year period were reviewed. Cases were deemed eligible if they were diagnosed with clinical or subclinical hypothyroidism and were receiving levothyroxine. Controls were two subsequently age-matched euthyroid women for every case. Both cases and controls were selected only if serum TSH was ≤ 2.5 mIU/L. Results: One hundred thirty-seven women with treated hypothyroidism and 274 controls were included. Baseline characteristics of the two study groups were similar with the exception of BMI, which was slightly higher among the cases (22.9 ± 3.9 versus 21.9 ± 3.3 Kg/m2, p=0.013). Most IVF-ICSI cycle outcome variables were also similar with the exception of a higher rate of cancellation for poor response (3.6% versus 0.7%, p=0.04), a longer duration of stimulation (10.9 ± 2.2 versus 10.1 ± 2.0 days, p=0.001), a higher proportion of women failing to obtain viable embryos (17% versus 7%, p=0.006), and a lower fertilization rate (75% versus 86%, p=0.017) among cases. Conversely, the clinical pregnancy rate per started cycle, the implantation rate and the live birth rate per started cycle did not differ; they were 36% and 34% (p=0.93), 28% and 22% (p=0.11) and 30% and 27% (p=0.50) in cases and controls, respectively. Subgroup analyses comparing women with (n=79) and without (n=58) thyroid autoimmunity and comparing women who were diagnosed with overt hypothyroidism (n=70) or subclinical hypothyroidism (n=67) failed to identify relevant differences. Conclusions: In our population, IVF-ICSI outcome was not significantly hampered in women with adequately treated hypothyroidism. The magnitude of the detected differences in cycle outcome was mild and we failed to document any differences for the most relevant outcomes, i.e. pregnancy rate, implantation rate and delivery rate. In conclusion, adequate levothyroxine treatment maintaining TSH serum levels below 2.5 mIU/L may overcome the detrimental effects of hypothyroidism. 22848037 Sour Cherry Seed Kernel Extract Increases Heme Oxygenase-1 Expression and Decreases Representation of CD3+ TNF-α + and CD3 + IL-8+ Subpopulations in Peripheral Blood Leukocyte Cultures from Type 2 Diabetes Patients. The present study evaluates a hypothesis that sour cherry (Prunus cerasus) seed extracts (SCE) modulate CD3+ T lymphocyte activity in ways predictive of potential for uses of SCE in management of inflammatory diseases. Peripheral blood mononuclear cells (PBMC) from 12 type 2 diabetes (T2DM) patients and eight healthy control subjects were cultured 24 h with 100 ng/ml lipopolysaccharide (LPS) to increase inflammatory signaling and co-incubated with 0.5-100 µg/ml SCE. Cultures were evaluated by two-color flow cytometry for percent representation of CD3+ IL8+ and CD3 + TNF-α + cells which express interleukin-8 (IL-8), and tumor necrosis factor-α, (TNF-α+) respectively, and by enzyme-linked immunoassay for lymphocyte-associated heme oxygenase-1 (HO-1, known to be induced by SCE). SCE dosage ranges of 0.5-100 µg/ml in cell cultures significantly suppressed LPS-increased CD3 + TNF-α + and CD3 + IL8+ representation from all participants (p < 0.05), with greater pharmacological effect noted in suppression of CD3 + TNF-α + noted in cells from T2DM patients versus healthy control subjects. These effects correlated with increased HO-1 expression in SCE-treated PBMC from all subjects (p < 0.05). Since TNF-α and IL-8 are diagnostic/prognostic biomarkers for many inflammatory syndromes, the capacity of SCE to down-regulate representation of cells that express them suggests potential for therapeutic use of SCE in T2DM and other diseases. Copyright © 2012 John Wiley & Sons, Ltd. 23965745 Intact numbers of cerebellar purkinje and granule cells in sudden infant death syndrome: a stereologic analysis and critical review of neuropathologic evidence. Despite much research during recent decades, the etiology and pathogenesis of sudden infant death syndrome (SIDS) remain unknown. Because of the role of the cerebellum in respiratory and cardiovascular control, it has been proposed that it plays an important role in the pathogenesis of SIDS. To date, 5 postmortem studies on the cerebellum of SIDS cases have yielded conflicting results. Using a rigorous design-based stereologic approach, we investigated postmortem cerebella from 9 SIDS patients who died between 2 and 10 months of age and from 9 age- and sex-matched control children. Neither the volumes of the cerebellar external granule cell layer, molecular layer, internal granule cell layer (including the Purkinje cell layer), and white matter nor the total numbers of Purkinje cells, granule cells in the internal granule cell layer, and the number of granule cells per Purkinje cell showed statistically significant differences between the SIDS cases and the controls. Based on these observations, we conclude that structural alterations in cerebellar development are not involved in the etiology and pathogenesis of SIDS. 23659888 Genotoxicity assessment of β-caryophyllene oxide. β-caryophyllene oxide is a biciclic sesquiterpene, occurring naturally in essential oils from various medicinal and edible plants and used as a flavouring agent. Due to its potential hazardous chemical structure, the European Food Safety Authority reported to be pending a safety assessment for this compound. Here, this flavouring agent was tested for its mutagenic effect in the Ames test and micronucleus assay. Furthermore, considering that the penetration of a substance through phospholipid bilayers is determinant for its activity, the ability of β-caryophyllene oxide to be absorbed into cells was evaluated by differential scanning calorimetry (DSC) using multilamellar vesicles of dimyristoylphosphatidylcholine as a biomembrane model. β-caryophyllene oxide was found to be devoid of mutagenic effect, both at gene level (frameshift or base-substitution mutations), and on chromosome (clastogenicity and aneuploidogenicity). Results of DSC analysis highlighted that the substance was strongly absorbed through the membrane bilayer. Present results show that β-caryophyllene oxide, although absorbed through cell membranes and in spite of its potentially reactive chemical structure, is devoid of genotoxic effects, inducing neither point mutations nor chromosomal damages. These negative genotoxic findings will be critical to the safety assessment of β-caryophyllene oxide as used as a flavouring/fragrance ingredient. 23856014 Natural killer cells in human autoimmune disorders. Natural killer (NK) cells are innate lymphocytes that play a critical role in early host defense against viruses. Through their cytolytic capacity and generation of cytokines and chemokines, NK cells modulate the activity of other components of the innate and adaptive immune systems and have been implicated in the initiation or maintenance of autoimmune responses. This review focuses on recent research elucidating a potential immunoregulatory role for NK cells in T-cell and B-cell-mediated autoimmune disorders in humans, with a particular focus on multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematous. A better understanding of the contributions of NK cells to the development of autoimmunity may lead to novel therapeutic targets in these diseases. 23950962 Identification and Characterization of a Novel aac(6')-Iag Associated with the bla IMP-1-Integron in a Multidrug-Resistant Pseudomonas aeruginosa. In a continuing study from Dec 2006 to Apr 2008, we characterized nine multi-drug resistant Pseudomonas aeruginosa strains isolated from four patients in a ward at the Hiroshima University Hospital, Japan. Pulsed-field gel electrophoresis of SpeI-digested genomic DNAs from the isolates suggested the clonal expansion of a single strain; however, only one strain, NK0009, was found to produce metallo-β-lactamase. PCR and subsequent sequencing analysis indicated NK0009 possessed a novel class 1 integron, designated as In124, that carries an array of four gene cassettes: a novel aminoglycoside (AG) resistance gene, aac(6')-Iag, bla IMP-1, a truncated form of bla IMP-1, and a truncated form of aac(6')-Iag. The aac(6')-Iag encoded a 167-amino-acid protein that shows 40% identity with AAC(6')-Iz. Recombinant AAC(6')-Iag protein showed aminoglycoside 6'-N-acetyltransferase activity using thin-layer chromatography (TLC) and MS spectrometric analysis. Escherichia coli carrying aac(6')-Iag showed resistance to amikacin, arbekacin, dibekacin, isepamicin, kanamycin, sisomicin, and tobramycin; but not to gentamicin. A conjugation experiment and subsequent Southern hybridization with the gene probes for bla IMP-1 and aac(6')-Ig strongly suggested In124 is on a conjugal plasmid. Transconjugants acquired resistance to gentamicin and were resistant to virtually all AGs, suggesting that the In124 conjugal plasmid also possesses a gene conferring resistance to gentamicin. 23436211 The role of inhibition in young children's altruistic behaviour. By behaving altruistically, individuals voluntarily reduce their benefits in order to increase their partners'. This deviation from a self-interest-maximizing function may be cognitively demanding, though. This study investigates whether altruistic sharing in 4- to 6-year-old children, assessed by a dictator game (DG), is related to three measures of executive functioning, that is, inhibitory control, working memory, and cognitive flexibility. We found that children who turned out to be altruistic in the DG performed better on an inhibition task than non-altruists did. This finding lends support to the hypothesis that altruistic sharing might be somewhat constrained by the child's ability to inhibit a natural tendency to preserve his or her own resources. Much research is needed to understand the role of inhibitory control in the development of costly sharing and the consolidation of inequity aversion. 23968698 Improved Safety and Reduction in Stent Thrombosis Associated With Biodegradable Polymer-Based Biolimus-Eluting Stents Versus Durable Polymer-Based Sirolimus-Eluting Stents in Patients With Coronary Artery Disease: Final 5-Year Report of the LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) Randomized, Noninferiority Trial. This study sought to report the final 5 years follow-up of the landmark LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) trial. The LEADERS trial is the first randomized study to evaluate biodegradable polymer-based drug-eluting stents (DES) against durable polymer DES. The LEADERS trial was a 10-center, assessor-blind, noninferiority, "all-comers" trial (N = 1,707). All patients were centrally randomized to treatment with either biodegradable polymer biolimus-eluting stents (BES) (n = 857) or durable polymer sirolimus-eluting stents (SES) (n = 850). The primary endpoint was a composite of cardiac death, myocardial infarction (MI), or clinically indicated target vessel revascularization within 9 months. Secondary endpoints included extending the primary endpoint to 5 years and stent thrombosis (ST) (Academic Research Consortium definition). Analysis was by intention to treat. At 5 years, the BES was noninferior to SES for the primary endpoint (186 [22.3%] vs. 216 [26.1%], rate ratio [RR]: 0.83 [95% confidence interval (CI): 0.68 to 1.02], p for noninferiority <0.0001, p for superiority = 0.069). The BES was associated with a significant reduction in the more comprehensive patient-orientated composite endpoint of all-cause death, any MI, and all-cause revascularization (297 [35.1%] vs. 339 [40.4%], RR: 0.84 [95% CI: 0.71 to 0.98], p for superiority = 0.023). A significant reduction in very late definite ST from 1 to 5 years was evident with the BES (n = 5 [0.7%] vs. n = 19 [2.5%], RR: 0.26 [95% CI: 0.10 to 0.68], p = 0.003), corresponding to a significant reduction in ST-associated clinical events (primary endpoint) over the same time period (n = 3 of 749 vs. n = 14 of 738, RR: 0.20 [95% CI: 0.06 to 0.71], p = 0.005). The safety benefit of the biodegradable polymer BES, compared with the durable polymer SES, was related to a significant reduction in very late ST (>1 year) and associated composite clinical outcomes. (Limus Eluted From A Durable Versus ERodable Stent Coating [LEADERS] trial; NCT00389220). 23764343 Undetected multidrug-resistant tuberculosis amplified by first-line therapy in mixed infection. Infections with >1 Mycobacterium tuberculosis strain(s) are underrecognized. We show, in vitro and in vivo, how first-line treatment conferred a competitive growth advantage to amplify a multidrug-resistant M. tuberculosis strain in a patient with mixed infection. Diagnostic techniques that identify mixed tubercle bacilli populations are needed to curb the spread of multidrug resistance. 23435357 Molecular aspects of cancer cell resistance to chemotherapy. Cancer cell resistance to chemotherapy is still a heavy burden that impairs treatment of cancer patients. Both intrinsic and acquired resistance results from the numerous genetic and epigenetic changes occurring in cancer cells. Most of the hallmarks of cancer cells provide general mechanisms to sustain stresses such as the ones induced by chemotherapeutic drugs. Moreover, specific changes in the target bring resistance to specific drugs like modification in nucleotide synthesis enzymes upon anti-metabolite exposure, in microtubule composition upon spindle poison treatment, in topoisomerase activity upon topoisomerase inhibitor incubation or in intracellular signaling pathways when targeting tyrosine kinase receptors. Finally, the stemness properties of a few cancer cells as well as components of the tumor stroma, like fibroblasts and tumor-associated macrophages but also hypoxia, also help tumor to resist to anticancer agents. These processes provide an additional level of complexity to the understanding of the tumor resistance phenomenon. This review aims to describe the different general mechanisms as well as some examples of specific on target modifications inducing cancer cell resistance to chemotherapy at the molecular level. Perspectives to develop more efficient treatment, using genomic signature or more specific biomarkers to characterize putative resistance mechanisms in patients before choosing the more appropriate treatment, will also be discussed. 23941722 Effect of ankle taping or bracing on creating an increased sense of confidence, stability, and reassurance when performing a dynamic-balance task. Clinical Scenario: Ankle taping and bracing are commonly used to reduce the risk of sports-related ankle sprains. Mechanical- and neuromuscular-control facilitation has been the focus of their effectiveness. Another potential advantage to using ankle taping or bracing is an increased sense of confidence, stability, and reassurance that the individual may experience when performing a dynamic-balance activity. Since ankle sprains are one of the most common sport-related injuries treated by clinicians, treatment and prevention of these injuries is a priority for many health care providers. However, the psychological effects of taping or bracing on athletes are still unknown. Researchers have described athletes' emotional responses and psychological reactions after athletic injuries. However, athlete reactions related to adhesive taping or bracing are limited. There is anecdotal evidence showing that football players stated they would tape a body part even if it was not injured as part of a superstitious pregame ritual. Therefore, the purpose of this article was to determine if individuals who have had their ankle taped or braced experience an increased sense of confidence, stability, or reassurance when performing a dynamic-balance activity. Focused Clinical Question: Does ankle taping or bracing create an increased sense of confidence, stability, and reassurance when performing dynamic-balance activity in physically active people? 23766104 Genetic Abnormalities in FOXP1 Are Associated with Congenital Heart Defects. The etiology for the majority of congenital heart defects (CHD) is unknown. We identified a patient with unbalanced atrioventricular septal defect (AVSD) and hypoplastic left ventricle who harbored an ∼0.3 Mb monoallelic deletion on chromosome 3p14.1. The deletion encompassed the first four exons of FOXP1, a gene critical for normal heart development that represses cardiomyocyte proliferation and expression of Nkx2.5. To determine whether FOXP1 mutations are found in patients with CHD, we sequenced FOXP1 in 82 patients with AVSD or hypoplastic left heart syndrome. We discovered two patients who harbored a heterozygous c.1702C>T variant in FOXP1 that predicted a potentially deleterious substitution of a highly conserved proline (p.Pro568Ser). This variant was not found in 287 controls but is present in dbSNP at a 0.2% frequency. The orthologous murine Foxp1 p.Pro596Ser mutant protein displayed deficits in luciferase reporter assays and resulted in increased proliferation and Nkx2.5 expression in cardiomyoblasts. Our data suggest that haploinsufficiency of FOXP1 is associated with human CHD. 23960179 Vertebral Compression Fracture After Spine Stereotactic Body Radiotherapy: A Multi-Institutional Analysis With a Focus on Radiation Dose and the Spinal Instability Neoplastic Score. Vertebral compression fracture (VCF) is increasingly recognized as an adverse event after spine stereotactic body radiotherapy (SBRT). We report a multi-institutional study aimed at clarifying the risk and predictive factors associated with VCF. A total of 252 patients with 410 spinal segments treated with SBRT were included. The primary outcome was the development of VCF (a new VCF or progression of a baseline VCF). In addition to various patient-, treatment-, and tumor-specific factors, the Spinal Instability Neoplastic Scoring (SINS) system was applied to determine predictive value. The median follow-up was 11.5 months (range, 0.03 to 113 months). The median and mean overall survival rates were 16 and 26 months, respectively. We observed 57 fractures (57 of 410, 14%), with 47% (27 of 57) new fractures and 53% (30 of 57) fracture progression. The median time to VCF was 2.46 months (range, 0.03 to 43.01 months), and 65% occurred within the first 4 months. The 1- and 2-year cumulative incidences of fracture were 12.35% and 13.49%, respectively. Multivariable analysis identified dose per fraction (greatest risk for ≥ 24 Gy v 20 to 23 Gy v ≤ 19 Gy), in addition to three of the six original SINS criteria: baseline VCF, lytic tumor, and spinal deformity, as significant predictors of VCF. Caution must be observed when treating with ≥ 20 Gy/fraction, in particular, for patients with lytic tumor, spinal misalignment, and a baseline VCF. Frequent short-term follow-up is required, as nearly two thirds of all VCF occurred within the first 4 months. We also conclude that SINS may have utility in predicting patients at high risk of SBRT-induced VCF. 23550738 Chronic Ethanol (EtOH) Consumption Differentially Alters Gray and White Matter EtOH Methyl (1) H Magnetic Resonance Intensity in the Primate Brain. In vivo magnetic resonance spectroscopy (MRS) has previously been used to directly monitor brain ethanol (EtOH). It has been proposed that the EtOH methyl (1) H resonance intensity is larger in EtOH-tolerant individuals than in sensitive individuals. To characterize the relationship between long-term EtOH exposure and the brain EtOH MRS intensity, we present data from a longitudinal experiment conducted using nonhuman primate subjects. In vivo MRS was used to measure the gray matter (GM) and white matter (WM) EtOH methyl (1) H MRS intensity in 18 adult male rhesus macaques at 4 time points throughout the course of a chronic drinking experiment. Time points were prior to EtOH drinking, following a 3-month EtOH induction procedure, and following 6, and 12 subsequent months of 22 h/d of "open access" to EtOH (4% w/v) and water. The EtOH methyl (1) H MRS intensity, which we observed to be independent of age over the range examined, increased with chronic EtOH exposure in GM and WM. In GM, MRS intensity increased from naïve level following the EtOH induction period (90 g/kg cumulative EtOH intake). In WM, MRS intensity was not significantly different from the EtOH-naïve state until after 6 months of 22-hour free access (110 to 850 g/kg cumulative intake range). The WM MRS intensity in the EtOH-naïve state was positively correlated with future drinking, and the increase in WM MRS intensity was negatively correlated with the amount of EtOH consumed throughout the experiment. Chronic exposure to EtOH is associated with brain changes that result in differential increases in EtOH MRS intensity in GM and WM. The EtOH-naïve WM MRS intensity pattern is consistent with its previously proposed relationship to innate tolerance to the intoxicating effects of EtOH. EtOH-dependent MRS intensity changes in GM required less EtOH exposure than was necessary to produce changes in WM. Within WM, an unexpected, potentially age dependent, enhanced sensitivity to EtOH in light drinkers relative to heavy drinkers was observed. 23789827 Clinical efficacy of the dual-pulsed Q-switched neodymium:yttrium-aluminum-garnet laser: Comparison with conservative mode. The quality (Q)-switched neodymium:yttrium-aluminum-garnet (Nd:YAG) laser is one of the first non-ablative lasers to be used for facial resurfacing and photorejuvenation. Recently, the method of low-fluence Q-switched Nd:YAG lasers known as 'laser toning' has been used for non-ablative skin rejuvenation and for the treatment of melasma in Asian countries. We report our experience of using a novel Q-switched Nd:YAG laser that was operated as a dual pulse at half fluence and 140-μs intervals compared with conservative mode laser. 23390092 Both autologous bone marrow mononuclear cell and peripheral blood progenitor cell therapies similarly improve ischaemia in patients with diabetic foot in comparison with control treatment. The aim of our study was to compare the effect of bone marrow mononuclear cell and peripheral blood progenitor cell therapies in patients with diabetic foot disease and critical limb ischaemia unresponsive to revascularization with conservative therapy. Twenty-eight patients with diabetic foot disease (17 treated by bone marrow cells and 11 by peripheral blood cell) were included into an active group and 22 patients into a control group without cell treatment. Transcutaneous oxygen pressure and rate of major amputation, as the main outcome measures, were compared between bone marrow cells, peripheral blood cell and control groups over 6 months; both cell therapy methods were also compared by the characteristics of cell suspensions. Possible adverse events were evaluated by changes of serum levels of angiogenic cytokines and retinal fundoscopic examination. The transcutaneous oxygen pressure increased significantly (p < 0.05) compared with baseline in both active groups after 6 months, with no significant differences between bone marrow cells and peripheral blood cell groups; however, no change of transcutaneous oxygen pressure in the control group was observed. The rate of major amputation by 6 months was significantly lower in the active cell therapy group compared with that in the control group (11.1% vs. 50%, p = 0.0032), with no difference between bone marrow cells and peripheral blood cell. A number of injected CD34+ cells and serum levels of angiogenic cytokines after treatment did not significantly differ between bone marrow cells and peripheral blood cell. Our study showed a superior benefit of bone marrow cells and peripheral blood cell treatments of critical limb ischaemia in patients with diabetic foot disease when compared with conservative therapy. There was no difference between both cell therapy groups, and no patient demonstrated signs of systemic vasculogenesis. Copyright © 2013 John Wiley & Sons, Ltd. 23411176 Reduction of abdominal fat accumulation in rats by 8-week ingestion of a newly developed sweetener made from high fructose corn syrup. Many studies have shown that ingestion of high-fructose corn syrup (HFCS) may cause an increase in body weight and abdominal fat. We recently developed a new sweetener containing rare sugars (rare sugar syrup; RSS) by slight isomerization of HFCS. Here, the functional effects of RSS on body weight and abdominal fat, and biochemical parameters in Wistar rats were examined. Rats (n=30) were randomly divided into three groups and maintained for 8-weeks on starch, starch+HFCS (50:50), and starch+RSS (50:50) diets. Rats in the Starch and HFCS groups gained significantly more body weight and abdominal fat than the RSS group. Fasting serum insulin in the RSS group was significantly lower than in the Starch and HFCS groups, although serum glucose in the HFCS and RSS groups was significantly lower than that in the Starch group. Thus, the substitution of HFCS with RSS prevents obesity induced by the consumption of HFCS. 23894094 Trisomy 18p caused by a supernumerary marker with a chromosome 13/21 centromere: A possible recurrent chromosome aberration. We present a clinical and molecular cytogenetic characterization of two new patients with a complex supernumerary marker consisting of the entire short arm of chromosome 18 with a chromosome 13/21 centromere. One patient is a girl with a nonsyndromic intellectual disability and the second is a prenatally diagnosed fetus. To our knowledge, these are the fourth and fifth such cases to be described in the literature, suggesting the existence of a possible recurring constitutional structural chromosome abnormality. © 2013 Wiley Periodicals, Inc. 23427187 Improvement of nanoprecipitation technique for preparation of gelatin nanoparticles and potential macromolecular drug loading. An optimum nanoprecipitation technique for gelatin nanoparticles is established, based on aqueous gelatin solution and ethanolic solution containing stabilizer. Crosslinking with glutaraldehyde results in stable gelatine nanoparticles. Several factors such as the surfactant concentration, type of surfactant, type of nonsolvent and gelatin concentration are evaluated. Gelatin nanoparticles with 200-300 nm can be produced using 20-30 mg mL(-1) of gelatin and a minimum of 7% w/v stabilizer (Poloxamer 407 or 188). Furthermore, methanol and ethanol are good nonsolvents, whereas other nonsolvents such as acetone, isopropyl alcohol, and acetonitrile, result in phase separation and visible precipitates. The entrapment efficiency of fluorescein-isothiocyanate (FITC)-dextran as model drug was determined to 50% with no substantial effect on particle size. 80% of the drug is only released after enzymatic digestion. 23362121 Small-molecule-mediated axonal branching in Caenorhabditis elegans. An in vivo system for monitoring small-molecule-mediated neuronal branching has been developed by using C. elegans. Growth-promoting compounds can be detected by visual inspection of GFPlabeled cholinergic neurons, as axonal branching occurs following treatment with neurotrophic agents. Investigation of the structure-activity relationship of the neurotrophic natural product clovanemagnolol (1) led us to a comparable chemically edited derivative. 23500486 On allosteric modulation of P-type Cu(+)-ATPases. P-type ATPases perform active transport of various compounds across biological membranes and are crucial for ion homeostasis and the asymmetric composition of lipid bilayers. Although their functional cycle share principles of phosphoenzyme intermediates, P-type ATPases also show subclass-specific sequence motifs and structural elements that are linked to transport specificity and mechanistic modulation. Here we provide an overview of the Cu(+)-transporting ATPases (of subclass PIB) and compare them to the well-studied sarco(endo)plasmic reticulum Ca(2+)-ATPase (of subclass PIIA). Cu(+) ions in the cell are delivered by soluble chaperones to Cu(+)-ATPases, which expose a putative "docking platform" at the intracellular interface. Cu(+)-ATPases also contain heavy-metal binding domains providing a basis for allosteric control of pump activity. Database analysis of Cu(+) ligating residues questions a two-site model of intramembranous Cu(+) binding, and we suggest an alternative role for the proposed second site in copper translocation and proton exchange. The class-specific features demonstrate that topological diversity in P-type ATPases may tune a general energy coupling scheme to the translocation of compounds with remarkably different properties. 23909825 Several developmental and morphogenetic factors govern the evolution of stomatal patterning in land plants. I. II. III. IV. V. VI. VII. VIII. References SUMMARY: We evaluate stomatal development in terms of its primary morphogenetic factors and place it in a phylogenetic context, including clarification of the contrasting specialist terms that are used by different sets of researchers. The genetic and structural bases for stomatal development are well conserved and increasingly well understood in extant taxa, but many phylogenetically crucial plant lineages are known only from fossils, in which it is problematic to infer development. For example, specialized lateral subsidiary cells that occur adjacent to the guard cells in some taxa can be derived either from the same cell lineage as the guard cells or from an adjacent cell file. A potentially key factor in land-plant evolution is the presence (mesogenous type) or absence (perigenous type) of at least one asymmetric division in the cell lineage leading to the guard-mother cell. However, the question whether perigenous or mesogenous development is ancestral in land plants cannot yet be answered definitively based on existing data. Establishment of 'fossil fingerprints' as developmental markers is critical for understanding the evolution of stomatal patterning. Long cell-short cell alternation in the developing leaf epidermis indicates that the stomata are derived from an asymmetric mitosis. Other potential developmental markers include nonrandom stomatal orientation and a range of variation in relative sizes of epidermal cells. Records of occasional giant stomata in fossil bennettites could indicate development of a similar type to early-divergent angiosperms. 23832487 Intravenous low molecular weight iron dextran in children with iron deficiency anemia unresponsive to oral iron. Iron deficiency anemia (IDA) in children is usually treated with oral iron, yet many respond poorly. Intravenous low molecular weight iron dextran (LMWID) offers the opportunity of employing a single outpatient infusion to correct the anemia and reduce the overall burden of treatment, but its use in children has been limited due to concerns of serious adverse effects. In this study we report our initial experience using LMWID in children with iron deficiency in whom oral iron was ineffective. We performed a case series of LMWID treatment of children with IDA of diverse etiologies who were poorly responsive to oral iron therapy with the aim of measuring its efficacy and adverse effects. LMWID was administered as a total dose infusion over 60 minutes in the outpatient setting. Thirty-one patients age 11 months to 18 years received intravenous LMWID, and 24 were evaluable for hematologic response. Median hemoglobin increments were respectively 3.5, 1.9, and 1.8 g/dl in patients with IDA due to poor nutrition (n = 11), chronic blood loss (n = 13), and miscellaneous causes (n = 7). Two thirds of evaluable patients had a complete hematologic response. Nine of the patients (29%) had mild non-specific adverse effects upon initiation of the LMWID infusion. LMWID as a total dose infusion was well tolerated and effective in a heterogeneous group of children and adolescents with IDA who were refractory to oral iron therapy. Transient reactions were common but not serious. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc. 23818604 Highly multiplexed single-cell analysis of formalin-fixed, paraffin-embedded cancer tissue. Limitations on the number of unique protein and DNA molecules that can be characterized microscopically in a single tissue specimen impede advances in understanding the biological basis of health and disease. Here we present a multiplexed fluorescence microscopy method (MxIF) for quantitative, single-cell, and subcellular characterization of multiple analytes in formalin-fixed paraffin-embedded tissue. Chemical inactivation of fluorescent dyes after each image acquisition round allows reuse of common dyes in iterative staining and imaging cycles. The mild inactivation chemistry is compatible with total and phosphoprotein detection, as well as DNA FISH. Accurate computational registration of sequential images is achieved by aligning nuclear counterstain-derived fiducial points. Individual cells, plasma membrane, cytoplasm, nucleus, tumor, and stromal regions are segmented to achieve cellular and subcellular quantification of multiplexed targets. In a comparison of pathologist scoring of diaminobenzidine staining of serial sections and automated MxIF scoring of a single section, human epidermal growth factor receptor 2, estrogen receptor, p53, and androgen receptor staining by diaminobenzidine and MxIF methods yielded similar results. Single-cell staining patterns of 61 protein antigens by MxIF in 747 colorectal cancer subjects reveals extensive tumor heterogeneity, and cluster analysis of divergent signaling through ERK1/2, S6 kinase 1, and 4E binding protein 1 provides insights into the spatial organization of mechanistic target of rapamycin and MAPK signal transduction. Our results suggest MxIF should be broadly applicable to problems in the fields of basic biological research, drug discovery and development, and clinical diagnostics. 23644824 How does genotype influence disease phenotype in inflammatory bowel disease? : Inflammatory bowel diseases (Crohn's disease and ulcerative colitis) are chronic immunologically mediated diseases of the gut. Advances in genetics have revolutionized our understanding of the pathogenesis of these conditions with 163 risk loci identified, encompassing a variety of immunologic functions. There is substantial heterogeneity in the natural history of these diseases with respect to disease onset, course, and progression to complications. There are also significant variations in response to therapies and susceptibility to therapy-related and disease-related complications. An important need in the field is to identify predictors of disease course, complications, and likelihood of response and adverse events to allow for targeted therapeutic decision making. The genotype of an individual in constant and non-modifiable, and thus could potentially fulfill the role of important predictors of these outcomes. In this review, we discuss the existing literature on the prediction of various disease phenotypes in Crohn's disease and ulcerative colitis using underlying genotype. We also identify gaps in the literature and suggest future directions for research. There is need for large, multi-institutional, and international collaborative consortia with efficient and detailed cohort accrual, phenotypic definition, genotyping, and dynamic assessments of external (e.g., diet) and internal (microbiome) environment to allow us to progress toward personalized and precision medicine in the management of these complex diseases. 23887090 Effects of centrally acting ACE inhibitors on the rate of cognitive decline in dementia. There is growing evidence that antihypertensive agents, particularly centrally acting ACE inhibitors (CACE-Is), which cross the blood-brain barrier, are associated with a reduced rate of cognitive decline. Given this, we compared the rates of cognitive decline in clinic patients with dementia receiving CACE-Is (CACE-I) with those not currently treated with CACE-Is (NoCACE-I), and with those who started CACE-Is, during their first 6 months of treatment (NewCACE-I). Observational case-control study. 2 university hospital memory clinics. 817 patients diagnosed with Alzheimer's disease, vascular or mixed dementia. Of these, 361 with valid cognitive scores were included for analysis, 85 CACE-I and 276 NoCACE-I. Patients were included if the baseline and end-point (standardised at 6 months apart) Standardised Mini-Mental State Examination (SMMSE) or Quick Mild Cognitive Impairment (Qmci) scores were available. Patients with comorbid depression or other dementia subtypes were excluded. The average 6-month rates of change in scores were compared between CACE-I, NoCACE-I and NewCACE-I patients. When the rate of decline was compared between groups, there was a significant difference in the median, 6-month rate of decline in Qmci scores between CACE-I (1.8 points) and NoCACE-I (2.1 points) patients (p=0.049), with similar, non-significant changes in SMMSE. Median SMMSE scores improved by 1.2 points in the first 6 months of CACE treatment (NewCACE-I), compared to a 0.8 point decline for the CACE-I (p=0.003) group and a 1 point decline for the NoCACE-I (p=0.001) group over the same period. Multivariate analysis, controlling for baseline characteristics, showed significant differences in the rates of decline, in SMMSE, between the three groups, p=0.002. Cognitive scores may improve in the first 6 months after CACE-I treatment and use of CACE-Is is associated with a reduced rate of cognitive decline in patients with dementia. 23273646 Serum total cholesterol: a mortality predictor in elderly hospitalized patients. Elevated serum total cholesterol levels are associated with increased risk of cardiovascular mortality among middle aged adults, but not the elderly. We therefore examined whether increased serum total cholesterol reduces mortality risk in the hospitalized elderly. Of 1852 patients consecutively admitted to an acute geriatric department from 1/1/99-12/31/00, only 298 (49.6% males, mean age 81.36 ± 6.3 years) who had measured serum total cholesterol and albumin levels were included in the study and followed until August 31, 2004. Mortality data were extracted from their death certificates. During follow-up of 3.47 ± 1.87 years, 248 patients died. These patients had significantly lower levels of baseline serum total cholesterol (183.3 ± 45.4 vs. 200.2 ± 37.9, p = 0.01) and albumin (3.6 ± 0.5 vs. 3.8 ± 0.3 g/l, p = 0.002) than the survivors. In the Cox regression analysis, serum total cholesterol emerged as a significant, independent predictor of mortality in this cohort. Specifically, each 1 mg/dl increase in serum total cholesterol reduced risk of death by 0.4%. This association persisted even after controlling for serum creatinine, age, body mass index, dementia and congestive heart failure. These factors were also significantly, independently associated with mortality. In very elderly hospitalized subjects, increased levels of serum total cholesterol and albumin may be associated with reduced mortality risk. 23385231 Transcriptional Analysis of Hair Follicle-Derived Keratinocytes from Donors with Atopic Dermatitis Reveals Enhanced Induction of IL32 Gene by IFN-γ. We cultured human hair follicle-derived keratinocytes (FDKs) from plucked hairs. To gain insight into gene expression signatures that can distinguish atopic dermatitis from non-atopic controls without skin biopsies, we undertook a comparative study of gene expression in FDKs from adult donors with atopic dermatitis and non-atopic donors. FDK primary cultures (atopic dermatitis, n = 11; non-atopic controls, n = 7) before and after interferon gamma (IFN-γ) treatment were used for microarray analysis and quantitative RT-PCR. Comparison of FDKs from atopic and non-atopic donors indicated that the former showed activated pathways with innate immunity and decreased pathways of cell growth, as indicated by increased NLRP2 expression and decreased DKK1 expression, respectively. Treatment with IFN-γ induced the enhanced expression of IL32, IL1B, IL8, and CXCL1 in the cells from atopic donors compared to that in cells from non-atopic donors at 24 h after treatment. IL1B expression in FDKs after IFN-γ treatment correlated with IL32 expression. We hypothesized that overexpression of IL32 in hair follicle keratinocytes of patients with atopic dermatitis would lead to the excessive production of pro-IL1β and that the activation of IL1β from pro-IL1β by inflammasome complex, in which NLRP2 protein might be involved, would be augmented. This is the first report to show enhanced induction of cytokine/chemokine genes by IFN-γ in atopic dermatitis using cultured FDKs. 23872067 Oxidative damage associated with obesity is prevented by overexpression of CuZn- or Mn-superoxide dismutase. The development of insulin resistance is the primary step in the etiology of type 2 diabetes mellitus. There are several risk factors associated with insulin resistance, yet the basic biological mechanisms that promote its development are still unclear. There is growing literature that suggests mitochondrial dysfunction and/or oxidative stress play prominent roles in defects in glucose metabolism. Here, we tested whether increased expression of CuZn-superoxide dismutase (Sod1) or Mn-superoxide dismutase (Sod2) prevented obesity-induced changes in oxidative stress and metabolism. Both Sod1 and Sod2 overexpressing mice were protected from high fat diet-induced glucose intolerance. Lipid oxidation (F2-isoprostanes) was significantly increased in muscle and adipose with high fat feeding. Mice with increased expression of either Sod1 or Sod2 showed a significant reduction in this oxidative damage. Surprisingly, mitochondria from the muscle of high fat diet-fed mice showed no significant alteration in function. Together, our data suggest that targeting reduced oxidative damage in general may be a more applicable therapeutic target to prevent insulin resistance than is improving mitochondrial function. 23178255 Synthesis and anti-tumor evaluation of novel 25-hydroxyprotopanaxadiol analogs incorporating natural amino acids. In the current study, derivatives of 25-hydroxyprotopanaxadiol (25-OH-PPD) were prepared and their in vitro anti-tumor activities were tested on six different human tumor cell lines by standard MTT assay. The results showed that combining an ester group combined with the presence of an amino acid moiety led to a 10-fold improved anti-tumor activity. Compound 1c exhibited the best anti-tumor activity in the in vitro assays. Compounds 2c, 3c, 4c, 5c, 6c and 8b showed better anti-tumor activities compared to the parent compound 25-OH-PPD. The current results may provide useful data for researching and developing new anti-cancer agents. 23912018 Implementing Family-Integrated Care in the NICU: Engaging Veteran Parents in Program Design and Delivery. The purpose of this article is to describe and evaluate how "veteran" parents were engaged as experts in the design and implementation of a family-integrated care program in a Canadian neonatal intensive care unit (NICU). Three parents of preterm infants previously discharged from the NICU participated in the design and implementation of a family-integrated care pilot program. The steering committee for the program included 5 staff members (a physician, a NICU nurse, a parent education nurse, a lactation consultant, and a social worker) and the parent volunteers. This article includes a total of 42 mothers of infants born at 35-week gestation or less were enrolled in the pilot program. A detailed description and qualitative evaluation of the engagement of veteran parents in the design and implementation of the family-integrated care program. The effectiveness of engaging veteran parents in developing this model of care was evaluated by written feedback from the veteran parents and the other steering committee members. In addition, a structured interview at discharge with the 42 mothers enrolled in the pilot study was used to assess their experiences of the peer-to-peer support provided by veteran parents. Veteran NICU parents brought a wealth of wisdom and expertise developed through personal experience to the design and implementation of the family-integrated care program. The veteran parents played a significant role in both the initial development of the program and in the provision of peer-to-peer support during program implementation. Engagement of parents with prior experience of the NICU care environment is a critical step in the design and implementation of a program of family-integrated care. 23886364 Excimer laser assisted Descemet stripping endothelial keratoplasty in iridocorneal endothelial syndrome. A 42 year-old female diagnosed with essential iris atrophy complained of visual decrease in the right eye. Examination revealed moderate corneal oedema, folds in Descemet's membrane, polycoria, corectopia, and iris atrophy. Excimer laser assisted Descemet stripping endothelial keratoplasty was performed, with a good corneal transparency and a significant visual improvement being obtained. The results one year after the surgery, with visual acuity of 0.4, clear lens, pachymetry of 580μm and cylinder of 0.5 D, with low endothelial cell loss, suggest that further studies are required to evaluate the efficacy of this technique in patients with iridocorneal endothelial syndrome. 23161550 Phosphorylation of dopamine transporter serine 7 modulates cocaine analog binding. As an approach to elucidating dopamine transporter (DAT) phosphorylation characteristics, we examined in vitro phosphorylation of a recombinant rat DAT N-terminal peptide (NDAT) using purified protein kinases. We found that NDAT becomes phosphorylated at single distinct sites by protein kinase A (Ser-7) and calcium-calmodulin-dependent protein kinase II (Ser-13) and at multiple sites (Ser-4, Ser-7, and Ser-13) by protein kinase C (PKC), implicating these residues as potential sites of DAT phosphorylation by these kinases. Mapping of rat striatal DAT phosphopeptides by two-dimensional thin layer chromatography revealed basal and PKC-stimulated phosphorylation of the same peptide fragments and comigration of PKC-stimulated phosphopeptide fragments with NDAT Ser-7 phosphopeptide markers. We further confirmed by site-directed mutagenesis and mass spectrometry that Ser-7 is a site for PKC-stimulated phosphorylation in heterologously expressed rat and human DATs. Mutation of Ser-7 and nearby residues strongly reduced the affinity of rat DAT for the cocaine analog (-)-2β-carbomethoxy-3β-(4-fluorophenyl) tropane (CFT), whereas in rat striatal tissue, conditions that promote DAT phosphorylation caused increased CFT affinity. Ser-7 mutation also affected zinc modulation of CFT binding, with Ala and Asp substitutions inducing opposing effects. These results identify Ser-7 as a major site for basal and PKC-stimulated phosphorylation of native and expressed DAT and suggest that Ser-7 phosphorylation modulates transporter conformational equilibria, shifting the transporter between high and low affinity cocaine binding states. 23766476 Tear film breakup and structure studied by simultaneous video recording of fluorescence and tear film lipid layer images. The thinning of the precorneal tear film between blinks and tear film breakup can be logically analyzed into contributions from three components: evaporation, flow into the cornea, and tangential flow along the corneal surface. Whereas divergent tangential flow contributes to certain types of breakup, it has been argued that evaporation is the main cause of tear thinning and breakup. Because evaporation is controlled by the tear film lipid layer (TFLL) it should therefore be expected that patterns of breakup should match patterns in the TFLL, and this hypothesis is tested in this study. An optical system is described for simultaneous video imaging of fluorescein tear film breakup and the TFLL. Recordings were made from 85 subjects, including both with healthy and dry eyes. After instillation of 5 μL2% fluorescein, subjects were asked to blink 1 second after the start of the recording and try to maintain their eyes open for the recording length of 30 or 60 seconds. Areas of tear film thinning and breakup usually matched corresponding features in the TFLL. Whereas thinning and breakup were often matched to thin lipid, surprisingly, the corresponding lipid region was not always thinner than the surrounding lipid. Occasionally, a thin lipid region caused a corresponding region of greater fluorescence (thicker aqueous layer), due to convergent tangential flow. Areas of tear thinning and breakup can generally be matched to corresponding regions of the TFLL as would be expected if breakup is largely due to evaporation. Surprisingly, in some examples, the corresponding lipid area was not thinner and possibly thicker than the surrounding lipid. This indicates that the lipid was a poor barrier to evaporation, perhaps because of deficiency in composition and/or structure. For example, bacterial lipases may have broken down esters into component acids and alcohols, causing a defective TFLL structure with increased evaporation. 23790455 Cytokine responses in patients with mild or severe influenza A(H1N1)pdm09. Influenza virus affects millions of people worldwide each year. More severe infection occurs in the elderly, very young and immunocompromised. In 2009, a new variant of swine origin (influenza A(H1N1)pdm09 virus) emerged that produced severe disease in young healthy adults. The aim of this study was to determine whether cytokine concentrations are associated with clinical outcome in patients infected influenza A(H1N1)pdm09 virus. Plasma concentration of 32 cytokines and growth factors were measured using a multiplex bead immunoassay and conventional ELISA in four patient groups. Patients with severe and mild influenza A(H1N1)pdm09 virus infection, rhinovirus infection and healthy volunteers were investigated. In addition, serial samples of respiratory secretions from five patients with severe influenza A(H1N1)pdm09 virus infection were examined. The majority of cytokines measured were elevated in patients with viral respiratory infections compared to the healthy controls. Concentrations of IL-6, IL-10, IL-15, IP-10, IL-2R, HGF, ST2 and MIG were significantly higher (p<0.05) and EGF significantly lower (p=0.0001) in patients with severe influenza A(H1N1)pdm09 virus infection compared to those with mild influenza A(H1N1)pdm09 virus and rhinovirus infection. A number of cytokines were found to be substantially elevated in patients with severe influenza A(H1N1)pdm09 virus infection. This supports and extends other published work suggesting a role for proinflammatory cytokines in influenza-induced lung pathology. Interestingly, EGF was significantly lower in patients with severe infection suggesting it is actively suppressed. As EGF has a role in role in cell proliferation and tissue repair, it may protect the lung from host or virus mediated damage. 22907905 Concurrent primary and metastatic cutaneous head and neck squamous cell carcinoma: Analysis of prognostic factors. There is a small subgroup of patients with head and neck cutaneous squamous cell carcinoma (cSCC) in which nodal metastases present concurrently with the primary lesion. There is evidence that these tumors may represent a more aggressive subset of cSCC. The aim of this study was to determine whether alternative clinicopathologic prognostic factors should be applied to this patient cohort. A retrospective analysis of data from prospective databases of 2 large head and neck cancer units in Sydney, Australia, was performed. Ninety-five patients with concurrent primary and nodal metastatic head and neck cSCC were suitable for inclusion in the study. Univariable analysis was performed for overall survival (OS) and disease-specific survival (DSS). OS was adversely affected by immunosuppression (p = .011) and nodal extracapsular spread (ECS) (p = .006). Similarly, immunosuppression (p = .005) and ECS (p = .005) indicated a worse outcome for DSS. ECS and immunosuppression remained significant in the multivariable analysis. This study found that adverse prognostic factors were similar to the current evidence for nonconcurrent metastatic cSCC. In particular, the primary lesion had no significant influence on survival. © 2012 Wiley Periodicals, Inc. Head Neck, 2013. 23684918 Mosquitofish (Gambusia affinis) responds differentially to a robotic fish of varying swimming depth and aspect ratio. In this study, we explore the feasibility of using bioinspired robotics to influence the behaviour of mosquitofish (Gambusia affinis), a social freshwater fish species that is extensively studied for the ecological issues associated with its diffusion in non-native environments. Specifically, in a dichotomous choice test, we investigate the behavioural response of small shoals of mosquitofish to a robotic fish inspired by mosquitofish in its colouration, shape, aspect ratio, and locomotion. Our results indicate that the swimming depth and the aspect ratio of the robotic fish are both determinants of mosquitofish preference. In particular, we find that mosquitofish are never attracted by a robotic fish whose colouration and shape are inspired by live subjects and that the degree of repulsion varies as a function of the swimming depth and the aspect ratio. 23957590 Long-term treatment with probiotics in primary care patients with irritable bowel syndrome - a randomised, double-blind, placebo controlled trial. Abstract Objective. Meta-analyses have indicated effect of probiotics on irritable bowel syndrome (IBS). However, few long-term trials have been conducted and uncertainty remains as to effectiveness and long-term effect in a primary care setting. We aimed to investigate the effect of probiotics compared with placebo in the management of IBS in primary care during a 6-month treatment period and with a 6-month follow-up. Material and methods. We randomized IBS patients fulfilling Rome III criteria to receive two capsules twice daily either containing placebo or a probiotic mixture of Lactobacillus paracasei ssp paracasei F19, Lactobacillus acidophilus La5 and Bifidobacterium Bb12 in an amount of 1.3 × 10(10) CFU per capsule. Primary endpoint was proportion of responders defined as patients reporting adequate relief (AR) at least 50% of the time in the 6-month treatment period. Secondary outcomes were proportions of patients reporting AR at different time points, and change in gastrointestinal symptoms and health-related quality of life (HrQOL) from baseline to 6 and 12 months. Results. A total of 131 patients were included in this study. The proportion of responders in the treatment period was 52% (35/67) in the probiotic group versus 41% (26/64) in the placebo group, p = 0.18. Overall we found no difference between the groups in change in gastrointestinal symptoms after treatment. Patients improved in HrQOL, but with no statistically significant difference between the groups. Conclusion. During a 6-month treatment period, we were not able to detect a positive effect of probiotic when compared with placebo. 23611246 9,10-Phenanthrenedione biodegradation by a soil bacterium and identification of transformation products by LC/ESI-MS/MS. Transformation of 9,10-phenanthrenedione, a cytotoxic derivative of phenanthrene, was shown to occur by a soil bacterium belonging to the genus Sphingobium. Phenanthrene-grown cells of this strain were exposed to 50mgL(-1) 9,10-phenanthrenedione in liquid cultures, extracted, and extracts were analyzed by liquid chromatography electrospray ionization mass spectrometry in negative ionization mode. Full scan analyses of exposed cells over the range from m/z 50 to m/z 500 were compared to abiotic and biotic controls. Product and precursor ion scan mode analyses indicated that at least three aromatic ring-cleavage transformation products of 9,10-phenanthrenedione were present and structures for these products, corresponding to [M-H](-)=271, [M-H](-)=241, and [M-H](-)=339 were proposed to be 4-(1-hydroxy-3,4-dioxo-2-naphthyl)-2-oxo-but-3-enoic acid, 2,2'-diphenic acid and 2-[(6-carboxy-2,3-dihydroxy-phenyl)-hydroxy-methyl]-5-oxo-hex-3-enedioic acid. The identity of 2,2'-diphenic acid was confirmed by comparison to an authentic standard and when the strain was exposed to 50mgL(-1) 2,2'-diphenic acid in separate assays, a transformation product with a similar mass spectrum as 9,10-phenanthrenedione-derived [M-H](-)=339 was revealed. Based upon these results, pathways for the transformation of 9,10-phenanthrenedione by strain KK22 were proposed. Strain KK22 appeared unable to use 9,10-phenanthrenedione as a growth substrate under these conditions. This is the first report of potential biotransformation pathways of 9,10-phenanthrenedione by a bacterium. 22819456 Pattern of mandibular third molar impaction in the Indian population: a retrospective clinico-radiographic survey. The objective of this study was to study incidence of type of impaction of mandibular third molars in the Indian population. Data of 1200 patients examined during a 5-year period were reviewed, which included status of mandibular third molar for inclination, emergence in oral cavity, and prevalence of caries. Radiographically, angulation of tooth, level of occlusal surface of third molar with respect to second molar, relationship between ascending ramus of mandible and distal surface of third molar, and proximity to inferior alveolar nerve were studied. Of 1200 patient data reviewed, 620 (51.77%) were of men and 580 (48.3%) were women in the age group of 20 to 40 years (26.3 years). Mesioangular impaction was most prevalent followed by distoangular. A strong statistical significance was found between gender and ramus relationship. Fifty percent of cases showed proximity to the inferior alveolar nerve, which was more frequent in males (58.3%). Our study highlights mesioangular impaction as the most frequently encountered angulation in impacted teeth. 23955258 Surgical Technique: Gluteus Maximus and Tensor Fascia Lata Transfer for Primary Deficiency of the Abductors of the Hip. Avulsion of the abductor muscles of the hip may cause severe limp and pain. Limited literature is available on treatment approaches for this problem, and each has shortcomings. This study describes a muscle transfer technique to treat complete irreparable avulsion of the hip abductor muscles and tendons. Ten adult cadaver specimens were dissected to determine nerve and blood supply point of entry in the gluteus maximus and tensor fascia lata (TFL) and evaluate the feasibility and safety of transferring these muscles to substitute for the gluteus medius and minimus. In this technique, the anterior portion of the gluteus maximus and the entire TFL are mobilized and transferred to the greater trochanter such that the muscle fiber direction of the transferred muscles closely matches that of the gluteus medius and minimus. Five patients (five hips) were treated for primary irreparable disruption of the hip abductor muscles using this technique between January 2008 and April 2011. All patients had severe or moderate pain, severe abductor limp, and positive Trendelenburg sign. Patients were evaluated for pain and function at a mean of 28 months (range, 18-60 months) after surgery. All patients could actively abduct 3 months postoperatively. At 1 year postoperatively, three patients had no hip pain, two had mild pain that did not limit their activity, three had no limp, and one had mild limp. One patient fell, fractured his greater trochanter, and has persistent limp and abduction weakness. The anterior portion of the gluteus maximus and the TFL can be transferred to the greater trochanter to substitute for abductor deficiency. In this small series, the surgical procedure was reproducible and effective; further studies with more patients and longer followup are needed to confirm this. Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. 23506527 Effect of Enzyme Concentration of the Morphology and Properties of Enzymatically Triggered Peptide Hydrogels. We have recently shown that thermolysine, a protease enzyme obtained from Bacillus thermoproteolyticus rokko , can be used to trigger the gelation of FEFK (F, phenylalanine; E, glutamic acid; K, lysine) tetrapeptides through reverse hydrolysis and formation of longer peptide sequences, mainly octapeptides, that self-assemble readily. In this article we investigate the effect of enzyme concentration on the morphology and properties of enzymatically triggered peptide hydrogels using HPLC, FTIR, real-time SAXS, TEM, and shear rheology. We have shown that the enzyme concentration, Cenz, does not affect the final composition of the samples. Instead, this is dictated by the initial tetrapeptide concentration, C0, suggesting the existence of a chemical equilibrium. We went on to show that Cenz does not affect the self-assembly of these peptides at a molecular level either nor the structure of the fibrillar network formed at the nanometer scale. Interestingly, the mechanical properties were found to be affected by Cenz, where the shear moduli of the hydrogels were found to increase with increasing Cenz. These results suggest that morphological differences between the hydrogels at the microscale are at the origin of their difference in mechanical properties. In this paper, we propose a morphological model in which denser network regions are found around the enzymes, resulting in the creation of heterogeneous networks. These were confirmed by TEM measurements. The existence of these denser network regions will result in the reinforcement of the hydrogels, thus, explaining the high shear moduli obtained increasing Cenz. 23726122 Comparison of two different thermal techniques for the treatment of hepatocellular carcinoma. To compare the safety and efficacy of radiofrequency ablation (RFA) and microwave ablation (MWA) in treating hepatocellular carcinoma (HCC) while conforming to the Milan criteria. The study was approved by the Institutional Review Board, and informed consent was waived due to the retrospective study design. One hundred ninety-eight patients met the inclusion criteria and were included in the study. Eighty-five patients with 98 lesions received RFA, and 113 patients with 131 lesions underwent MWA. Complete ablation rates, local recurrence rates, disease-free survival rates, cumulative survival rates, and major complications were compared between the two treatment groups. Complete ablation rates were 99.0% for RFA and 98.5% for MWA (P=1.000). Local recurrence rates were 5.2% for RFA and 10.9% for MWA (P=0.127). Disease-free survival rates at 1, 2, 3, and 4 years were 80.3%, 61.8%, 39.5%, and 19.0% in the RFA group and 75.0%, 59.4%, 32.1%, and 16.1% in the MWA group, respectively (P=0.376). Cumulative survival rates at 1, 2, 3, and 4 years were 98.7%, 92.3%, 82.7%, and 77.8% in the RFA group and 98.0%, 90.7%, 77.6%, and 77.6% in the MWA group, respectively (P=0.729). Major complication rates were 2.4% and 2.7% in the RFA group and the MWA group, respectively (P=1.000). There were no patient deaths due to treatment. RFA and MWA have the same clinical value in treating HCC conforming to the Milan criteria. RFA and MWA are both safe and effective techniques for HCC as clinical application. 23911636 Germline genetic variations at 11q13 and 12p11 locus modulate age of onset for renal cell carcinoma. Few risk factors are identified for Renal Cell Carcinoma (RCC). The purpose of this work was to perform a validation study on a population of European background for the most significant variants previously identified in association with RCC risk. We conducted a case-control validation study by recruiting 463 controls and 463 patients with a histologically confirmed diagnosis of clear cell RCC. For each patient and matched control, we performed genotyping of 8 Single Nucleotide Polymorphisms (SNPs) selected from previous studies, to evaluate the association between candidate SNPs and susceptibility to RCC. After adjusting for age, gender, smoking status and body mass index (BMI), the AG+AA genotypes from rs7105934 (11q13) were associated with a decrease in the risk of RCC (OR=0.50; 95% CI=0.33-0.75; p=0.001) and the AC+CC genotypes from rs1049380 (ITPR2) were associated with an increased risk (OR=1.66; 95% CI=1.28-2.16; p<0.001). Moreover, kidney cancer occurred at an older age in case of carriage of the dominant risk allele A for rs7105934 (mean age at diagnosis = 73.1 years vs. 68.9; p=0.002) and at a younger age in case of carriage of the dominant allele C for rs1049380 (mean age at diagnosis = 68.1 years vs. 70.8; p=0.005). In this first validation study of the main 8 SNP variants associated with RCC susceptibility, we confirmed the association of 2 of these SNPs with the risk of RCC. Both variants influence the age at diagnosis of the disease. 23928839 Poor correlation between the removal or deposition of pollen grains and frequency of pollinator contact with sex organs. Pollinators deposit pollen grains on stigmas and remove pollen grains from anthers. The mechanics of these transfers can now be quantified with the use of high-speed video. We videoed hawkmoths, carpenter bees, and swallowtail butterflies pollinating Clerodendrum trichotomum. The number of grains deposited on stigmas did not vary significantly with the number of times pollinators contacted stigmas. In contrast, pollen removal from the anthers increased significantly with the number of contacts to anthers. Pollen removal varied among the three types of pollinators. Also, the three types carried pollen on different parts of their bodies. In hawkmoths and carpenter bees, a large number of contacted body part with anthers differed significantly from the body part that attached a large number of pollen grains. Our results indicate that a large number of contacts by pollinators does not increase either the male or female reproductive success of plants compared to a small number of contacts during a visit. 23714284 Predictors of cardiac allograft vasculopathy in pediatric heart transplant recipients. CAV remains a leading cause of late graft loss and mortality among survivors of pediatric heart transplantation. We sought to define the incidence of CAV and identify its predictors in pediatric heart transplant recipients. The OPTN/UNOS database was analyzed for pediatric recipients who underwent heart transplant between 1987 and 2011. The primary end-point is time from heart transplantation to development of CAV (CAV-free survival). To identify predictors of CAV-free survival, demographic and transplant data were analyzed by the Kaplan-Meier survival method and Cox proportional hazards regression. Of 5211 pediatric heart transplant recipients with at least one-yr follow-up, the incidence of CAV at five, 10, and 15 yr was 13%, 25%, and 54%, respectively. Multivariate analysis found that risk of CAV was associated with the following variables: Recipient age 1-4 yr (HR 1.25), 5-9 yr (1.45), 10-18 yr (1.83), donor age >18 yr (1.34), re-transplantation (2.14), recipient black race (1.55), and donor cigarette use (1.54). Older recipient and donor age, recipient black race, donor cigarette use, and re-transplantation were highly associated with shorter CAV-free survival. 23246435 A SWI/SNF chromatin-remodeling complex acts in noncoding RNA-mediated transcriptional silencing. RNA-mediated transcriptional silencing prevents deleterious effects of transposon activity and controls the expression of protein-coding genes. It involves long noncoding RNAs (lncRNAs). In Arabidopsis thaliana, some of those lncRNAs are produced by a specialized RNA Polymerase V (Pol V). The mechanism by which lncRNAs affect chromatin structure and mRNA production remains mostly unknown. Here we identify the SWI/SNF ATP-dependent nucleosome-remodeling complex as a component of the RNA-mediated transcriptional silencing pathway. We found that SWI3B, an essential subunit of the SWI/SNF complex, physically interacts with a lncRNA-binding protein, IDN2. SWI/SNF subunits contribute to lncRNA-mediated transcriptional silencing. Moreover, Pol V mediates stabilization of nucleosomes on silenced regions. We propose that Pol V-produced lncRNAs mediate transcriptional silencing by guiding the SWI/SNF complex and establishing positioned nucleosomes on specific genomic loci. We further propose that guiding ATP-dependent chromatin-remodeling complexes may be a more general function of lncRNAs. 23884098 Searching and review on the Three Rs information in Korea: time for quality assessment and continued education. Scientists planning research that involves the use of animals are required by international and/or national law to examine the possibilities for the implementation of Replacement, Reduction and/or Refinement (the Three Rs principles of Russell and Burch) in experiments for research, testing, and education. There are two Korean laws legislating humane use of animals and ethical review prior to animal experiments. This report reviews current practice of the literature search by the researchers and protocol review by the Institutional Animal Care and Use Committees on the Replacement, Reduction and Refinement alternatives in Korea. The promotion and protection of the laboratory animals are one of the core competencies of investigators exploring the ethical conduct of research and good science. [BMB Reports 2013; 46(7): 335-337]. 23659929 Significant dermatological side effects of intravenous immunoglobulin. Intravenous immunoglobulin (IVIg) is an essential treatment for many neurological, immunological and haematological conditions. However, the severity of its rare adverse effects is often underrecognised. We report a series of 15 patients receiving IVIg for neurological and immunological disorders who developed severe skin reactions. Despite pre-medication, nearly all patients ceased IVIg due to the severity of the adverse response. Interestingly, the majority of patients were male and two-thirds were receiving treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) or another inflammatory or demyelinating neuropathy. This marked propensity for male patients with CIDP to develop significant dermatological reactions following IVIg administration has not previously been described. Mechanisms involving the underlying autoimmunity inherent to this condition may play a role. 23953885 Hidden genetic nature of epigenetic natural variation in plants. Transcriptional gene silencing (TGS) is an epigenetic mechanism that suppresses the activity of repetitive DNA elements via accumulation of repressive chromatin marks. We discuss natural variation in TGS, with a particular focus on cases that affect the function of protein-coding genes and lead to developmental or physiological changes. Comparison of the examples described has revealed that most natural variation is associated with genetic determinants, such as gene rearrangements, inverted repeats, and transposon insertions that triggered TGS. Recent technical advances have enabled the study of epigenetic natural variation at a whole-genome scale and revealed patterns of inter- and intraspecific epigenetic variation. Future studies exploring non-model species may reveal species-specific evolutionary adaptations at the level of chromatin configuration. 23928767 Microbial Metabolites and Senescence Cytokines Promote Obesity-Induced HCC. Changes in a gut bacterial metabolite stimulate SASP and contribute to obesity-associated HCC. 23654348 Analysis of the latest Austroads guidelines for fitness to drive as promulgated in March 2012. After 9 years, Austroads has published new guidelines for fitness to drive. The guidelines have a preamble, which includes a legal disclaimer denying any culpability for those who designed the guidelines. They also warn of the legal responsibility for health professionals to satisfy their obligations, the need to be current with both relevant medical and legal expectations and if in doubt to seek guidance from Medical Defence Organisations. The guidelines are divided into Parts A and B, with A providing broad overview and background information while B deals with specific entities, such as blackouts, epilepsy or sleep disorders. This paper examines the guidelines and offers an appraisal of their content, their relevance to health practitioners and an assessment of their role in assisting to improve road safety. 23661194 Severe equinus deformity after radiofrequency-induced calf muscle reduction. Radiofrequency-induced calf muscle volume reduction is a commonly used method for cosmetic shaping of the lower leg contour. Functional disabilities associated with the use of the radiofrequency (RF) technique, with this procedure targeting the normal gastrocnemius muscle, still have not been reported. However, the authors have experienced several severe ankle equinus cases after RF-induced calf muscle volume reduction. This study retrospectively reviewed 19 calves of 12 patients who showed more than 20° of fixed equinus even though they underwent physical therapy for more than 6 months. All were women with a mean age of 32 years (range, 23-41 years). Of the 12 patients, 7 were bilateral. All the patients received surgical Achilles lengthening for deformity correction. To evaluate the clinical outcome, serial ankle dorsiflexion was measured, and the American Orthopedic Foot and Ankle Society (AOFAS) score was evaluated at the latest follow-up visit. The presence of soleus muscle involvement and an ongoing lesion that might affect the postoperative results of preoperative magnetic resonance imaging (MRI) were investigated. Statistical analysis was conducted to analyze preoperative factors strongly associated with patient clinical outcomes. The mean follow-up period after surgery was 18.6 months (range, 12-28 months). At the latest follow-up visit, the mean ankle dorsiflexion was 9° (range, 0-20°), and the mean AOFAS score was 87.7 (range, 80-98). On preoperative MRI, 13 calves showed soleus muscle involvement. Seven calves had ongoing lesions. Five of the ongoing lesions were muscle edema, and the remaining two lesions were cystic mass lesions resulting from muscle necrosis. Ankle dorsiflexion and AOFAS scores at the latest follow-up evaluation were insufficient in the ongoing lesions group. Although RF-induced calf muscle reduction is believed to be a safer method than conventional procedures, careful handling is needed because of the side effects that may occur in some instances. The slow progression of fibrosis could be observed after RF-induced calf reduction. Therefore, long-term follow-up evaluation is needed after the procedure. Therapeutic case series. 23891395 Reprogramming of mesenchymal stem cells derived from iPSCs seeded on biofunctionalized calcium phosphate scaffold for bone engineering. Human induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) are a promising choice of patient-specific stem cells with superior capability of cell expansion. There has been no report on bone morphogenic protein 2 (BMP2) gene modification of iPSC-MSCs for bone tissue engineering. The objectives of this study were to: (1) genetically modify iPSC-MSCs for BMP2 delivery; and (2) to seed BMP2 gene-modified iPSC-MSCs on calcium phosphate cement (CPC) immobilized with RGD for bone tissue engineering. iPSC-MSCs were infected with green fluorescence protein (GFP-iPSC-MSCs), or BMP2 lentivirus (BMP2-iPSC-MSCs). High levels of GFP expression were detected and more than 68% of GFP-iPSC-MSCs were GFP positive. BMP2-iPSC-MSCs expressed higher BMP2 levels than iPSC-MSCs in quantitative RT-PCR and ELISA assays (p < 0.05). BMP2-iPSC-MSCs did not compromise growth kinetics and cell cycle stages compared to iPSC-MSCs. After 14 d in osteogenic medium, ALP activity of BMP2-iPSC-MSCs was 1.8 times that of iPSC-MSCs (p < 0.05), indicating that BMP2 gene transduction of iPSC-MSCs enhanced osteogenic differentiation. BMP2-iPSC-MSCs were seeded on CPC scaffold biofunctionalized with RGD (RGD-CPC). BMP2-iPSC-MSCs attached well on RGD-CPC. At 14 d, COL1A1 expression of BMP2-iPSC-MSCs was 1.9 times that of iPSC-MSCs. OC expression of BMP2-iPSC-MSCs was 2.3 times that of iPSC-MSCs. Bone matrix mineralization by BMP2-iPSC-MSCs was 1.8 times that of iPSC-MSCs at 21 d. In conclusion, iPSC-MSCs seeded on CPC were suitable for bone tissue engineering. BMP2 gene-modified iPSC-MSCs on RGD-CPC underwent osteogenic differentiation, and the overexpression of BMP2 in iPSC-MSCs enhanced differentiation and bone mineral production on RGD-CPC. BMP2-iPSC-MSC seeding on RGD-CPC scaffold is promising to enhance bone regeneration efficacy. 23514061 The effect of rabeprazole on les tone in experimental rat model. ABSTRACT Introduction: Despite adequate treatment with proton pump inhibitors (PPIs), symptoms of gastroesophageal reflux disease (GERD) may remain persistent as well as Barrett's esophagus may emerge. It may be proposed that the relaxant effect of PPIs on the smooth muscles may lead to resistance of symptoms. The aim of this study is to investigate effects of rabeprazole on the lower esophageal sphincter (LES) pressure with a rat model. Materials and Methods: Sixteen rats were grouped as control and treatment groups. After obtaining LES tissues followed by a 60 min equilibration period for stabilization, contractile response to carbachol was obtained by application of single dose of carbachol to have a final concentration of 10(-6) M in the organ bath. After the contractions reached a plateau, concentration-response relationships for rabeprazole were obtained in a cumulative manner in the treatment group. Results: In the carbachol contracted LES preparations; 1.5 × 10(-6) and 1.5×10(-5) M of rabeprazole caused 6.08% and 11.34% relaxations respectively which were not statistically significant. However, mean integral relaxation value for 4.5 × 10(-5) M of rabeprazole was 17.34% and this relaxation was significant compared with controls. Conclusions: In the present study, rabeprazole caused no direct significant change in LES tone in the therapeutic dose range applied to the organ bath. However, rabeprazole at the high dose caused a significant decrease in the LES tone. 23401166 Quantum Dot-Based Thermal Spectroscopy and Imaging of Optically Trapped Microspheres and Single Cells. Laser-induced thermal effects in optically trapped microspheres and single cells are investigated by quantum dot luminescence thermometry. Thermal spectroscopy has revealed a non-localized temperature distribution around the trap that extends over tens of micrometers, in agreement with previous theoretical models besides identifying water absorption as the most important heating source. The experimental results of thermal loading at a variety of wavelengths reveal that an optimum trapping wavelength exists for biological applications close to 820 nm. This is corroborated by a simultaneous analysis of the spectral dependence of cellular heating and damage in human lymphocytes during optical trapping. This quantum dot luminescence thermometry demonstrates that optical trapping with 820 nm laser radiation produces minimum intracellular heating, well below the cytotoxic level (43 °C), thus, avoiding cell damage. 23870309 Revisiting caspase-11 function in host defense. Proinflammatory caspases play important roles in innate immunity. Much attention has focused on caspase-1, which acts to eliminate pathogens by obliterating their replicative niches as well as alerting the host to their presence. Now, emerging data have shed light on the lesser-studied proinflammatory caspase-11 in the combat between host and pathogens. Using the new tools available, researchers are further elucidating the mechanisms by which caspase-11 contributes to host defense. Here, we review the emerging understanding of caspase-11 functions and the mechanisms of activation and discuss the implications for human disease. 23827715 Immunolocalization of Smad-4 in developing molar roots of alendronate-treated rats. During root formation, Smad-4 plays a key role during the epithelial-mesenchymal interactions and the Hertwig's epithelial root sheath (HERS) apical proliferation. The root formation and eruption of rat molars is impeded by alendronate treatment due to the inhibition of bone resortion by this drug. The present study aimed to examine the structures affected in the developing root and immunodetect the presence of Smad-4 in rats treated with alendronate. Newborn Wistar rats were daily injected 2.5mg/kg alendronate (ALN) during 9, 12 and 30 days. The controls (CON) were injected with saline. The maxillae were fixed and embedded in paraffin or Spurr resin. Paraffin sections were incubated in Smad-4 antibody that was labelled with DAB. The ultrathin sections were examined in a transmission electron microscope. In ALN, a short portion of root dentine was formed; the epithelial diaphragm (ED) and the dental follicle (DF) were disorganized by the contact of bone trabeculae. The (CON) molar roots developed normally. Smad-4 labelling was detected in the cytoplasm of fibroblasts and cementoblasts adjacent to the cementum in CON; in ALN group, few ED cells presented weak immunolabelling. Ultrastructurally, the ED and DF appeared disrupted due to the presence of thin bone trabeculae between its cells. It resulted in the lack of apical proliferation of HERS and, consequently, arrest of root formation. The immunodetection of Smad-4 in the DF cells of ALN specimens indicates that the signalling for the differentiation of these cells into cementum-forming fibroblasts and cementoblasts occurs, despite the impairment of root elongation. 23850182 Study of crack initiation or damage in very high cycle fatigue using ultrasonic fatigue test and microstructure analysis. Fatigue damage behaviors of four metal materials in the very high cycle fatigue (VHCF) regime have been studied using ultrasonic fatigue test and microstructure analysis. The results show that the fatigue crack initiation in VHCF regime could occur at subsurface non-defect fatigue crack origin (SNDFCO), where the accumulated cyclic strains or damage in the specimens were highly localized, especially in the materials with some softer phase, where the local maximum strain can be eight times higher than the average strain value in the specimen. This high strain localization can cause a local plasticity exhaustion that leads to a stress concentration and consequently fatigue crack initiation, and finally the formation of SNDFCO. For pure single phase austenitic material, strain localization can also occur due to dislocation accumulation at or near grain boundaries, which can become fatigue crack initiation origin in the VHCF regime. The results in this study show that fatigue damage and crack initiation mechanisms in the VHCF regime can be different in different metals due to the mechanisms for local plasticity exhaustion. 23937229 RCircos: an R package for Circos 2D track plots. Circos is a Perl language based software package for visualizing similarities and differences of genome structure and positional relationships between genomic intervals. Running Circos requires extra data processing procedures to prepare plot data files and configure files from datasets, which limits its capability of integrating directly with other software tools such as R. Recently published R Bioconductor package ggbio provides a function to display genomic data in circular layout based on multiple other packages, which increases its complexity of usage and decreased the flexibility in integrating with other R pipelines. We implemented an R package, RCircos, using only R packages that come with R base installation. The package supports Circos 2D data track plots such as scatter, line, histogram, heatmap, tile, connectors, links, and text labels. Each plot is implemented with a specific function and input data for all functions are data frames which can be objects read from text files or generated with other R pipelines. RCircos package provides a simple and flexible way to make Circos 2D track plots with R and could be easily integrated into other R data processing and graphic manipulation pipelines for presenting large-scale multi-sample genomic research data. It can also serve as a base tool to generate complex Circos images. 23756092 Clinical significance of survivin and VEGF mRNA detection in the cell fraction of the peripheral blood in non-small cell lung cancer patients before and after surgery. The aim of this study was to evaluate the predictive and prognostic value of peripheral blood survivin and VEGF mRNA expression levels in non-small cell lung cancer (NSCLC) patients. Fifty-eight patients with stage I-IIIA NSCLC who underwent surgical resection were enrolled in this study. Thirty-six patients with benign lung disease (BLD) entered this study as control group. Quantitative real-time PCR was used to detect survivin and VEGF mRNA levels in the cell fraction of peripheral blood in NSCLC patients before and after surgery and BLD patients. The relationship between blood survivin and VEGF mRNA levels and patients clinicopathologic parameters and prognostic factors were investigated. The levels of survivin and VEGF mRNA were decreased significantly after surgery in NSCLC patients (P = 0.024 and P = 0.012 respectively). Tumor recurrence was significantly more frequent in NSCLC patients with survivin and VEGF mRNA positivity postoperation than in patients without (P = 0.003 and P = 0.006, respectively). Patients with survivin or VEGF mRNA positivity postoperation had markedly shorter disease-free survival (DFS) and overall survival (OS) than patients without (P = 0.023 and P = 0.016 for survivin; P = 0.031 and P = 0.025 for VEGF, respectively). Multivariate analysis showed that survivin positivity preoperation (P = 0.026, P = 0.041, respectively) and postoperation (P = 0.003, P = 0.005, respectively) and VEGF mRNA positivity postoperation (P = 0.007, P = 0.009, respectively) were independently associated with DFS and OS. Although the levels of surviving and VEGF mRNA were decreased significantly after surgery, postoperative detections of survivin and VEGF mRNA by quantitative real-time PCR could be used as tools to monitor tumor recurrence and predict prognosis. 23838360 The angiopoietin:Tie 2 interaction: A potential target for future therapies in human vascular disease. Angiopoietin-1 and -2 are endogenous ligands for the vascular endothelial receptor tyrosine kinase Tie2. Signalling by angiopoietin-1 promotes vascular endothelial cell survival and the sprouting and reorganisation of blood vessels, as well as inhibiting activation of the vascular endothelial barrier to reduce leakage and leucocyte migration into tissues. Angiopoietin-2 generally has an opposing action, and is released naturally at times of vascular growth and inflammation. There is a significant body of emerging evidence that promoting the actions of angiopoietin-1 through Tie2 is of benefit in pathologies of vascular activation, such as sepsis, stroke, diabetic retinopathy and asthma. Similarly, methods to inhibit the actions of angiopoietin-2 are emerging and have been demonstrated to be of preclinical and clinical benefit in reducing tumour angiogenesis. Here the author reviews the evidence for potential benefits of modulation of the interaction of angiopoietins with Tie2, and the potential applications. Additionally, methods for delivery of the complex protein angiopoietin-1 are discussed, as well as potentially deleterious consequences of administering angiopoietin-1. 23965744 Disruption of CDH2/N-Cadherin-Based Adherens Junctions Leads to Apoptosis of Ependymal Cells and Denudation of Brain Ventricular Walls. Disruption/denudation of the ependymal lining has been associated with the pathogenesis of various human CNS disorders, including hydrocephalus, spina bifida aperta, and periventricular heterotopia. It has been traditionally considered that ependymal denudation is a consequence of mechanical forces such as ventricular enlargement. New evidence indicates that ependymal disruption can precede ventricular dilation, but the cellular and molecular mechanisms involved in the onset of ependymal denudation are unknown. Here, we present a novel model to study ependymal cell pathophysiology and demonstrate that selective disruption of N-cadherin-based adherens junctions is sufficient to provoke progressive ependymal denudation. Blocking N-cadherin function using specific peptides that interfere with the histidine-alanine-valine extracellular homophilic interaction domain caused early pathologic changes characterized by disruption of zonula adherens and abnormal intracellular accumulation of N-cadherin. These changes then triggered massive apoptosis of ependymal cells and denudation of brain ventricular walls. Because no typical extrinsic mechanical factors such as elevated pressure or stretching forces are involved in this model, the critical role of N-cadherin-based adherens junctions in ependymal survival/physiology is highlighted. Furthermore, the results suggest that abnormal adherens junctions between ependymal cells should be considered as key components of the pathogenesis of CNS disorders associated with ependymal denudation. 23817308 Synthesis and characterization of the crystal structure and magnetic properties of the hydroxyfluoride MnF2-x(OH)x (x ∼ 0.8). The new compound MnF2-x(OH)x (x ∼ 0.8) was synthesized by a hydrothermal route from a 1 : 1 molar ratio of lithium fluoride and manganese acetate in an excess of water. The crystal structure was determined using the combination of single crystal X-ray and neutron powder diffraction measurements. The magnetic properties of the title compound were characterized by magnetic susceptibility and low-temperature neutron powder diffraction measurements. MnF2-x(OH)x (x ∼ 0.8) crystallizes with orthorhombic symmetry, space group Pnn2 (no. 34), a = 4.7127(18), b = 5.203(2), c = 3.2439(13) Å, V = 79.54(5) Å(3) and Z = 2. The crystal structure is a distorted rutile-type with [Mn(F,O)4] infinite edge-sharing chains along the c-direction. The protons are located in the channels and form O-HF bent hydrogen bonds. The magnetic susceptibility measurements indicate an antiferromagnetic ordering at ∼70 K and the neutron powder diffraction measurements at 3 K show that the ferromagnetic chains with spins parallel to the c-axis are antiferromagnetically coupled to each other, similarly to the magnetic structure of tetragonal rutile-type MnF2 with isoelectronic Mn(2+). MnF2-x(OH)x (x ∼ 0.8) is expected to be of great interest as a positive electrode for Li cells if the protons could be exchanged for lithium. 23832465 Factors influencing the course of acute appendicitis in adults and children. Our aim was to determine predictive factors for the diagnosis and postoperative complications of acute appendicitis. Data sets of 1,439 consecutive adults and children who had an appendectomy between 1999 and 2008 were retrospectively analyzed. A mild acute appendicitis was present in 50 % (n = 722) and a severe acute appendicitis in 25 % (n = 355) of the patients. No signs of any pathology were found in 6 % (n = 82). Gender, white blood count (WBC), C-reactive protein (CRP), and ultrasound (US) examination were important indicators of mild acute and severe acute appendicitis in adults and children. Postoperative complications occurred in 16 % (237/1,439), mainly consisting of wound infections (8 %, n = 122) and bowel dysfunction (5 %, n = 76). Sixty-two patients (4.3 %) required reoperations. One patient died (1/1,439, 0.07 % mortality rate). Age, pathology, and the presence of bacteria in the intraoperative swab were important predictive factors for postoperative complications in adults and children. Time since onset of symptoms and type of operation were also associated with postoperative complications among adults. Complications developed in 21 and 9 % of the adults (155/754 and 10/125) who had open and laparoscopic surgery, respectively. Besides history and clinical examination, WBC, CRP, and US examination remain important factors for diagnosing acute appendicitis. Complications are related to the pathology, presence of bacteria, and type of operation. Early diagnosis within 48 h may be important. A laparoscopic procedure in adults may also cause fewer wound infections. 23774257 Retention of structure, antigenicity, and biological function of pneumococcal surface protein A (PspA) released from polyanhydride nanoparticles. Pneumococcal surface protein A (PspA) is a choline-binding protein which is a virulence factor found on the surface of all Streptococcus pneumoniae strains. Vaccination with PspA has been shown to be protective against a lethal challenge with S. pneumoniae, making it a promising immunogen for use in vaccines. Herein the design of a PspA-based subunit vaccine using polyanhydride nanoparticles as a delivery platform is described. Nanoparticles based on sebacic acid (SA), 1,6-bis-(p-carboxyphenoxy)hexane (CPH) and 1,8-bis-(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG), specifically 50:50 CPTEG:CPH and 20:80 CPH:SA, were used to encapsulate and release PspA. The protein released from the nanoparticle formulations retained its primary and secondary structure as well as its antigenicity. The released PspA was also biologically functional based on its ability to bind to apolactoferrin and prevent its bactericidal activity against Escherichia coli. When the PspA nanoparticle formulations were administered subcutaneously to mice they elicited a high titer and high avidity anti-PspA antibody response. Together these studies provide a framework for the rational design of a vaccine against S. pneumoniae based on polyanhydride nanoparticles. 23710687 Solitary epidermolytic acanthoma. Solitary epidermolytic acanthoma is thought to be an uncommon lesion. It can present as a solitary, localized or disseminated process that is unrelated to the genetic form of icthyosis. A retrospective review of solitary epidermolytic acanthomas was performed at the Ackerman Academy of Dermatopathology, NY, over a 2 year period. The clinical and histopathological features of solitary epidermolytic acanthomas were described in 64 biopsies from 60 individuals. In situ hybridization for human papillomavirus (HPV) was performed on all genital lesions. The incidence of epidermolytic acanthomas in our series was higher than previously reported (27.8/100,000). Genital location was the most common and the incidence of genital lesions was 8/100,000. In situ hybridization showed no evidence of genital HPV types within the lesions. The histological features of solitary epidermolytic acanthoma were re-evaluated. Genital skin was the most common location for solitary epidermolytic acanthoma, but we found no evidence to suggest a role for genital HPV types. A strong male predominance was noted, and the lesions demonstrate a wide range of clinical and pathological findings. 23752618 Expression and characterization of a novel highly glucose-tolerant β-glucosidase from a soil metagenome. A β-glucosidase gene unbgl1A was isolated by the function-based screening of a metagenomic library and the enzyme protein was expressed in Escherichia coli, purified, and biochemically characterized. The enzyme Unbgl1A had a Km value of 2.09 ± 0.31 mM, and a Vmax value of 183.90 ± 9.61 μmol min(-1) mg(-1) under the optimal reaction conditions, which were pH 6.0 at 50°C. Unbgl1A can be activated by a variety of monosaccharides, disaccharides, and NaCl, and exhibits a high level of stability at high concentration of NaCl. Two prominent features for this enzyme are: (i) high glucose tolerance. It can be tolerant to glucose as high as 2000 mM, with Ki = 1500 mM; (ii) high NaCl tolerance. Its activity is not affected by 600 mM NaCl. The enzyme showed transglucosylation activities resulting in the formation of cellotriose from cellobiose. These properties of Unbgl1A should have important practical implication in its potential applications for better industrial production of glucose or bioethanol started from lignocellulosic biomass. 23701192 Urokinase-type plasminogen activator receptor (uPAR) as a promising new imaging target: potential clinical applications. Urokinase-type plasminogen activator receptor (uPAR) has been shown to be of special importance during cancer invasion and metastasis. However, currently, tissue samples are needed for measurement of uPAR expression limiting the potential as a clinical routine. Therefore, non-invasive methods are needed. In line with this, uPAR has recently been identified as a very promising imaging target candidate. uPAR consists of three domains attached to the cell membrane via a glycosylphosphatidylinositol (GPI) anchor and binds it natural ligand uPA with high affinity to localize plasminogen activation at the cell surface. Due to the importance of uPAR in cancer invasion and metastasis, a number of high-affinity ligands have been identified during the last decades. These ligands have recently been used as starting point for the development of a number of ligands for imaging of uPAR using various imaging modalities such as optical imaging, magnetic resonance imaging, single photon emission computer tomography (SPECT) and positron emission topography (PET). In this review, we will discuss recent advances in the development of uPAR-targeted imaging ligands according to imaging modality. In addition, we will discuss the potential future clinical application for uPAR imaging as a new imaging biomarker. 23074081 Solid-state nanopore detection of protein complexes: applications in healthcare and protein kinetics. Protein conjugation provides a unique look into many biological phenomena and has been used for decades for molecular recognition purposes. In this study, the use of solid-state nanopores for the detection of gp120-associated complexes are investigated. They exhibit monovalent and multivalent binding to anti-gp120 antibody monomer and dimers. In order to investigate the feasibility of many practical applications related to nanopores, detection of specific protein complexes is attempted within a heterogeneous protein sample, and the role of voltage on complexed proteins is researched. It is found that the electric field within the pore can result in unbinding of a freely translocating protein complex within the transient event durations measured experimentally. The strong dependence of the unbinding time with voltage can be used to improve the detection capability of the nanopore system by adding an additional level of specificity that can be probed. These data provide a strong framework for future protein-specific detection schemes, which are shown to be feasible in the realm of a 'real-world' sample and an automated multidimensional method of detecting events. 23887695 Nonwage losses associated with occupational injury among health care workers. To examine nonwage losses after occupational injury among health care workers and the factors associated with the magnitude of these losses. Inception cohort of workers filing an occupational injury claim in a Canadian province. Worker self-reports were used to calculate (1) the nonwage economic losses in 2010 Canadian dollars, and (2) the number of quality-adjusted days of life lost on the basis of the EuroQOL Index. Most workers (84%; n = 123) had musculoskeletal injuries (MSIs). Each MSI resulted in nonwage economic losses of Can$3131 (95% confidence interval, Can$3035 to Can$3226), lost wages of Can$5286, and 7.9 quality-adjusted days of life lost within 12 weeks after injury. Losses varied with type of injury, region of the province, and occupation. Non-MSIs were associated with smaller losses. These estimates of nonwage losses should be considered in workers' injury compensation policies and in economic evaluation studies. 23334807 Brief report: difficulty in understanding social acting (but not false beliefs) mediates the link between autistic traits and ingroup relationships. Why do individuals with more autistic traits experience social difficulties? Here we examined the hypothesis that these difficulties stem in part from a challenge in understanding social acting, the prosocial pretense that adults routinely produce to maintain positive relationships with their ingroup. In Study 1, we developed a self-administered test of social-acting understanding: participants read stories in which a character engaged in social acting and rated the appropriateness of the character's response. Adults who scored 26 or higher on the Autism Spectrum Quotient (AQ) questionnaire gave significantly lower ratings than comparison participants (AQ < 26). Study 2 found that difficulty in understanding social acting, but not false beliefs, mediated the link between autistic traits and perceived ingroup relationships. 23232698 Symptomatic lipid storage in carriers for the PNPLA2 gene. Neutral lipid storage disease comprises a heterogeneous group of inherited disorders characterized by severe accumulation of cytoplasmic triglyceride droplets in several tissues and neutrophils. A novel type of autosomal recessive lipid myopathy due to PNPLA2 mutations was recently described with associated cardiac disease, myopathy and frequent infections, but without ichthyosis. Here we describe the clinical and biochemical characteristics of a long surviving patient and report on four carrier family members with diverse clinical involvement. Interestingly, heterozygous patients show neutral lipid storage in muscle and in the keratocytes of the skin, Jordans' bodies, mild myopathy and frequent infections. Biochemical analysis of fibroblasts obtained from patients revealed increased triglyceride storage and reduced lipid droplet-associated triglyceride hydrolase activity. Together, our data implicate that the wild-type allele cannot fully compensate for the mutated dysfunctional allele of PNPLA2 leading to triglyceride accumulation in muscle and mild myopathy in PNPLA2 mutation carriers. The presence of neutral lipid droplets in the skin in PNPLA2 mutation carriers strengthens the link between NLSD and other neutral lipid storage diseases with ichthyosis. 23931748 Mitochondrial Dysfunction Indirectly Elevates ROS Production by the Endoplasmic Reticulum. Mitochondrial dysfunction is often associated with increased reactive oxygen species (ROS) production by the organelle itself. Leadsham et al. (2013) now show that the link between mitochondrial damage and ROS is more complicated, at least in yeast, where signals from damaged mitochondria increase ROS production from the endoplasmic reticulum surface. 23639136 Cutaneous presentation of chronic lymphocytic leukemia as unique extramedullar involvement in a patient with normal peripheral blood lymphocyte count (monoclonal B-cell lymphocytosis). Skin infiltration by chronic lymphocytic leukemia (CLL) is very rare and almost all reported cases occur in advanced stage. We report a patient with no relevant past medical history who presented with cutaneous erythematous plaques. A punch biopsy showed typical CLL morphologic and immunophenotypic features. Subsequent studies revealed a normal lymphocyte count in peripheral blood, and there was no evidence of lymphadenopathy or organomegaly. Flow cytometry demonstrated a clonal B-cell population both in the bone marrow and peripheral blood (1.60 × 10(9) /l) with a CLL phenotype, but it did not fulfill required criteria for CLL diagnosis. Without cutaneous involvement, this case should be classified as monoclonal B-cell lymphocytosis. 23847158 Phase Transitions, Phase Coexistence, and Piezoelectric Switching Behavior in Highly Strained BiFeO3 Films. Highly strained BiFeO3 films transition into a true tetragonal state at 430 °C but remain polar to much higher temperatures (∼800 °C). Piezoelectric switching is only possible up to 300 °C, i.e., at temperatures for which strain stabilizes the stripe-like coexistence of multiple polymorphs. 23898834 Medical crises and therapeutic talk. Coexisting medical traditions operate at different levels of scale. In rural eastern Africa there are diviners and herbalists whose clients are drawn from the immediate neighbourhood. Some develop healing reputations more widely over a region or nation, sometimes with prophetic and witch-finding powers. Biomedical clinics and hospitals are also interlinked regionally, nationally and internationally. Patients or carers may seek healthcare by moving through these different levels, sometimes beginning with a neighbourhood healer and sometimes trying out different therapies simultaneously. Sicknesses and misfortunes are often first discussed within a family or homestead, with concern for the victim extending to all its members. The talk is based on assumed trust among its members. However, if unresolved, the affliction may trigger a crisis that breaks the trust, so that healers beyond the neighbourhood are sought, whether prophetic/witch-finding or biomedical. Taken out of the context of family and homestead intimacy, the talk blames the ailment on the malevolence or negligence of individuals in the community. Talk about sickness among sufferers and between them and healers, is thus transformed from that which seeks resolution in amity to that which seeks culpability and, sometimes, retribution. A similar process of sickness talk changing through its appropriation by wider scale and more powerful medical authority also occurs in western biomedical hospitals and clinics. 23887700 Objectively measured sedentary behavior and physical activity in office employees: relationships with presenteeism. Employee presenteeism is the extent to which health conditions adversely affect at-work productivity. Given the links between health and activity, this study examined associations between objectively measured physical activity, sedentary behavior, and presenteeism. Participants were 108 office employees (70% women, mean age 40.7 ± 11.2 years). Activity was measured using ActiGraph GT3X+ accelerometers to determine sedentary (≤150 counts) and light (151 to 1689 counts) activity; presenteeism with the Work Limitations Questionnaire. Fifty-seven percent of time was spent in sedentary behavior and 38% in light activity. The median Work Limitations Questionnaire Index was 4.38; 6% of participants reported at least moderate impairment. Significant associations were reported for time spent in sedentary behavior before/after work (odds ratio [OR] = 2.58; 95% CI: 1.08 to 6.20) and in light activity, overall (OR = 0.43; 95% CI: 0.19 to 0.97) and during workday lunch hours (OR = 0.34; 95% CI: 0.15 to 0.77), and presenteeism. Future studies should seek greater variation in employee levels of activity and presenteeism to confirm these relationships. 23387444 Synthesis of MoS2 and MoSe2 films with vertically aligned layers. Layered materials consist of molecular layers stacked together by weak interlayer interactions. They often crystallize to form atomically smooth thin films, nanotubes, and platelet or fullerene-like nanoparticles due to the anisotropic bonding. Structures that predominately expose edges of the layers exhibit high surface energy and are often considered unstable. In this communication, we present a synthesis process to grow MoS2 and MoSe2 thin films with vertically aligned layers, thereby maximally exposing the edges on the film surface. Such edge-terminated films are metastable structures of MoS2 and MoSe2, which may find applications in diverse catalytic reactions. We have confirmed their catalytic activity in a hydrogen evolution reaction (HER), in which the exchange current density correlates directly with the density of the exposed edge sites. 23712490 Calculation of nucleation free energy for duplex oligomers in the context of nearest neighbor models. Additive physical properties of DNA double strand polymers have been expanded in terms of 8 irreducible parameters. This provided consistency relations among the corresponding 10 duplex dimer contributions. To allow for oligomer analysis, end parameters were often added, and this would add extra degrees of freedom to the fore mentioned parameters. Statistical mechanics approaches were then connected to the nearest neighbor (NN) approach in the framework of the two-states model. Ad hoc end effects were thus (wrongly) correlated to nucleation phenomena and this lead to a critique for its role in NN modeling. With this motivation, a new NN model is proposed that accommodates the nucleation free energies. The model relates the nucleation free energy to the mean composition of the chain and permits to obtain a good estimate for the free energy associated only to the Watson-Crick base pairings. © 2013 Wiley Periodicals, Inc. Biopolymers 99: 538-547, 2013. 23633482 Cancer stem-like cell marker CD44 promotes bone metastases by enhancing tumorigenicity, cell motility, and hyaluronan production. CD44, an adhesion molecule that binds to the extracellular matrix, primarily to hyaluronan (HA), has been implicated in cancer cell migration, invasion, and metastasis. CD44 has also recently been recognized as a marker for stem cells of several types of cancer. However, the roles of CD44 in the development of bone metastasis are unclear. Here, we addressed this issue by using bone metastatic cancer cell lines, in which CD44 was stably knocked down. Tumor sphere formation and cell migration and invasion were significantly inhibited by CD44 knockdown. Furthermore, the downregulation of CD44 markedly suppressed tumorigenicity and bone metastases in nude mice. Of note, the number of osteoclasts decreased in the bone metastases. Microarray analysis revealed that the expression of HA synthase 2 was downregulated in CD44-knockdown cells. The localization of HA in the bone metastatic tumors was also markedly reduced. We then examined the roles of CD44-HA interaction in bone metastasis using 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis. 4-MU decreased tumor sphere and osteoclast-like cell formation in vitro. Moreover, 4-MU inhibited bone metastases in vivo with reduced number of osteoclasts. These results collectively suggest that CD44 expression in cancer cells promotes bone metastases by enhancing tumorigenicity, cell migration and invasion, and HA production. Our results also suggest the possible involvement of CD44-expressing cancer stem cells in the development of bone metastases through interaction with HA. CD44-HA interaction could be a potential target for therapeutic intervention for bone metastases. 23500672 Donor substrate specificity of bovine kidney gamma-glutamyltransferase. The enzyme γ-glutamyltransferase (GGT) catalyzes the hydrolysis of the γ-glutamyl isopeptide bond of glutathione conjugates (donor substrates), releasing glutamic acid, or the transfer of the donor's γ-glutamyl group to an acceptor substrate, such as a dipeptide. The specificity of GGT for xenobiotic donor substrates has not been fully characterized. The transpeptidation activity of bovine kidney GGT was measured with glycylglycine as the acceptor substrate and several glutathione conjugate donor substrates, representative of detoxication products of polycyclic aromatic xenobiotics. HPLC separation with UV detection was used for quantitation. The commonly-used chromogenic substrate γ-glutamyl-p-nitroanilide was also tested. Michaelis constants (Km) were obtained for 4-nitrobenzylglutathione (0.075mM), 2,4-dinitrophenylglutathione (0.30mM), 4-methylbiphenylylglutathione (0.12mM), 1-menaphthylglutathione (0.23mM), and 9-methylanthracenylglutathione (0.22mM), indicating a trend towards higher values for bulkier substrates. These results provide insight into the capacity of GGT to act in the biotransformation of aromatic compounds, many of which are of toxicological importance. 23305534 Photophysical and electrochemical investigations of the fluorescent probe, 4,4'-bis(2-benzoxazolyl)stilbene. In solution, 4,4'-bis(2-benzoxazolyl)stilbene (BBS) was found to exhibit consistently high absolute fluorescence quantum yields (Φ(fl) ≥ 0.88) and a monoexponential lifetime, both independent of BBS concentration. The BBS steady-state and time-resolved photophysics were investigated by different techniques to understand the various deactivation pathways. Nonradiative deactivation of BBS singlet excited state by intersystem crossing was found to be negligible. Other than fluorescence, the excited state of BBS was found to be deactivated by trans-cis photoisomerization. At low concentrations (≈5 μg/mL), UV spectroscopy and laser flash photolysis showed concordant results that the photoinduced cis isomer gradually replaced the original absorption spectrum of the pure trans isomer. However, at high concentrations (≈0.2 mg/mL), (1)H NMR and DOSY measurements confirmed that irradiating BBS at 350 nm induced a conversion from the trans-BBS into its cis isomer by photoisomerization. It was further found that the stilbene moiety of both isomers was photocleaved. The resulting photoproduct was an aldehyde that was oxidized under ambient conditions to its corresponding carboxylic acid, i.e., 4-(1,3-benzoxazol-2-yl)benzoic acid. The structure of the photoproduct was unequivocally confirmed by X-ray diffraction. Spectroscopic investigation of BBS showed a limited photoisomerization after irradiation at 350 nm of a trans solution. The BBS electrochemistry showed irreversible oxidation, resulting in an unstable and highly reactive radical cation. Similarly, the cathodic process was also found to be irreversible, giving rise to a radical anion and showing its n-doping character. 23160434 M1.3--a small scaffold for DNA origami . The DNA origami method produces programmable nanoscale objects that form when one long scaffold strand hybridizes to numerous oligonucleotide staple strands. One scaffold strand is dominating the field: M13mp18, a bacteriophage-derived vector 7249 nucleotides in length. The full-length M13 is typically folded by using over 200 staple oligonucleotides. Here we report the convenient preparation of a 704 nt fragment dubbed "M1.3" as a linear or cyclic scaffold and the assembly of small origami structures with just 15-24 staple strands. A typical M1.3 origami is large enough to be visualized by TEM, but small enough to show a cooperativity in its assembly and thermal denaturation that is reminiscent of oligonucleotide duplexes. Due to its medium size, M1.3 origami with globally modified staples is affordable. As a proof of principle, two origami structures with globally 5'-capped staples were prepared and were shown to give higher UV-melting points than the corresponding assembly with unmodified DNA. M1.3 has the size of a gene, not a genome, and may function as a model for gene-based nanostructures. Small origami with M1.3 as a scaffold may serve as a workbench for chemical, physical, and biological experiments. 23147414 Linking GABA(A) receptor subunits to alcohol-induced conditioned taste aversion and recovery from acute alcohol intoxication. GABA type A receptors (GABA(A)-R) are important for ethanol actions and it is of interest to link individual subunits with specific ethanol behaviors. We studied null mutant mice for six different GABA(A)-R subunits (α1, α2, α3, α4, α5 and δ). Only mice lacking the α2 subunit showed reduction of conditioned taste aversion (CTA) to ethanol. These results are in agreement with data from knock-in mice with mutation of the ethanol-sensitive site in the α2-subunit (Blednov et al., 2011). All together, they indicate that aversive property of ethanol is dependent on ethanol action on α2-containing GABA(A)-R. Deletion of the α2-subunit led to faster recovery whereas absence of the α3-subunit slowed recovery from ethanol-induced incoordination (rotarod). Deletion of the other four subunits did not affect this behavior. Similar changes in this behavior for the α2 and α3 null mutants were found for flurazepam motor incoordination. However, no differences in recovery were found in motor-incoordinating effects of an α1-selective modulator (zolpidem) or an α4-selective agonist (gaboxadol). Therefore, recovery of rotarod incoordination is under control of two GABA(A)-R subunits: α2 and α3. For motor activity, α3 null mice demonstrated higher activation by ethanol (1 g/kg) whereas both α2 (-/-) and α3 (-/Y) knockout mice were less sensitive to ethanol-induced reduction of motor activity (1.5 g/kg). These studies demonstrate that the effects of ethanol at GABAergic synapses containing α2 subunit are important for specific behavioral effects of ethanol which may be relevant to the genetic linkage of the α2 subunit with human alcoholism. 23962442 Regulation of intraocular pressure in mice: structural analysis of dopaminergic and serotonergic systems in response to cabergoline. Elevated intraocular pressure (IOP) is the main recognized risk factor of glaucoma. To investigate the contribution of dopaminergic and serotonergic systems in IOP regulation, we used cabergoline, a mixed dopamine and serotonin agonist, in C57BL/6J WT and dopamine D3 receptor knock-out (D3R(-/-)) mice with normal eye pressure or steroid-induced ocular hypertension. Furthermore, we studied the structural basis of the cabergoline-mediated activation of the dopaminergic and serotonergic systems by molecular modeling. Topical application of cabergoline, significantly decreased, in a dose-dependent manner, the intraocular pressure in WT mice, both in an ocular normotensive group (-9, -5 and -2mmHg with 5%, 1%, and 0.1%, respectively) and an ocular hypertensive group, with a prolonged effect in this latter group. No change of intraocular pressure was observed after topical application of cabergoline in D3R(-/-) mice. We modeled and optimized, with molecular dynamics, structures of hD3, h5HT1A and h5HT2A-C receptors; thereafter we carried out molecular docking of cabergoline. Docking revealed that binding of cabergoline into D3 and 5HT1A receptors is associated with a better desolvation energy in comparison to 5HT2A-C binding. In conclusion, the present study support the hypothesis that dopaminergic system is pivotal to regulate IOP and that D3R represents an intriguing target in the treatment of glaucoma. Furthermore, the structure-based computational approach adopted in this study is able to build and refine structure models of homologous dopaminergic and serotonergic receptors that may be of interest for structure-based drug discovery of ligands, with dopaminergic selectivity or with multi-pharmacological profile, potentially useful to treat optic neuropathies. 23899002 Improving diversity in cultures of bacteria from an extreme environment. The ikaite columns in the Ikka Fjord in Greenland represent one of the few permanently cold and alkaline environments on Earth, and the interior of the columns is home to a bacterial community adapted to these extreme conditions. The community is characterized by low cell numbers imbedded in a calcium carbonate matrix, making extraction of bacterial cells and DNA a challenge and limiting molecular and genomic studies of this environment. To utilize this genetic resource, cultivation at high pH and low temperature was studied as a method for obtaining biomass and DNA from the fraction of this community that would not otherwise be amenable to genetic analyses. The diversity and community dynamics in mixed cultures of bacteria from ikaite columns was investigated using denaturing gradient gel electrophoresis and pyrosequencing of 16S rDNA. Both medium composition and incubation time influenced the diversity of the culture and many hitherto uncharacterized genera could be brought into culture by extended incubation time. Extended incubation time also gave rise to a more diverse community with a significant number of rare species not detected in the initial community. 23913504 An invertebrate stomach's view on vertebrate ecology: Certain invertebrates could be used as "vertebrate samplers" and deliver DNA-based information on many aspects of vertebrate ecology. Recent studies suggest that vertebrate genetic material ingested by invertebrates (iDNA) can be used to investigate vertebrate ecology. Given the ubiquity of invertebrates that feed on vertebrates across the globe, iDNA might qualify as a very powerful tool for 21st century population and conservation biologists. Here, we identify some invertebrate characteristics that will likely influence iDNA retrieval and elaborate on the potential uses of invertebrate-derived information. We hypothesize that beyond inventorying local faunal diversity, iDNA should allow for more profound insights into wildlife population density, size, mortality, and infectious agents. Based on the similarities of iDNA with other low-quality sources of DNA, a general technical framework for iDNA analyses is proposed. As it is likely that no such thing as a single ideal iDNA sampler exists, forthcoming research efforts should aim at cataloguing invertebrate properties relevant to iDNA retrieval so as to guide future usage of the invertebrate tool box. 23201310 Effect of volume ratio of ultrafiltrate to sample solution on the analysis of free drug and measurement of free carbamazepine in clinical drug monitoring. Traditional ultrafiltration (UF) usually has a large volume ratio of ultrafiltrate to sample solution, and this ratio cannot be well controlled. It can break the balance of protein-binding equilibrium and exert an influence on the analysis of free drug. In the present study, we evaluated the influence of volume ratio of ultrafiltrate to sample solution on the analysis of free drug in human plasma. We used carbamazepine as a model drug and studied the effect of different centrifugation times on ultrafitrate volume and the related effects on unbound carbamazepine measurement. Moreover, we compared the hollow fiber centrifugal ultrafiltration (HFCF-UF) with traditional UF. Our results showed that the ultrafiltrate volume was changed from 40 to 400 μL with the increase of centrifugation time for the traditional UF, and the related changes in unbound concentration were significant. The rate of protein binding (BP) was changed from 40% to 70%. In contrast, a tiny and invariant ultrafiltrate yield (40 μL) was obtained using the HFCF-UF method, and the BP rate was around 72%. In addition, with the HFCF-UF method, the volume ratio of ultrafiltrate to sample solution could be also well controlled by the inner diameters of both the glass tube and hollow fiber. The HFCF-UF method was a more accurate plasma pretreatment procedure, by which the in vivo balance of protein-binding equilibrium was hardly broken. Therefore, this method was successfully employed to quantify the free fraction of carbamazepine in clinical samples. 23695491 Short-term risk of hospitalization for asthma or bronchiolitis in children living near an aluminum smelter. Few studies have measured the effect of short-term exposure to industrial emissions on the respiratory health of children. Here we estimate the risk of hospitalization for asthma and bronchiolitis in young children associated with their recent exposure to emissions from an aluminum smelter. We used a case-crossover design to assess the risk of hospitalization, February 1999-December 2008, in relation to short-term variation in levels of exposure among children 0-4 years old living less than 7.5 km from the smelter. The percentage of hours per day that the residence of a hospitalized child was in the shadow of winds crossing the smelter was used to estimate the effect of wind-borne emissions on case and crossover days. Community-wide pollutant exposure was estimated through daily mean and daily maximum SO2 and PM2.5 concentrations measured at a fixed monitoring site near the smelter. Odds ratios (OR) were estimated using conditional logistic regressions. The risk of same-day hospitalization for asthma or bronchiolitis increased with the percentage of hours in a day that a child's residence was downwind of the smelter. For children aged 2-4 years, the OR was 1.27 (95% CI=1.03-1.56; n=103 hospitalizations), for an interquartile range (IQR) of 21% of hours being downwind. In this age group, the OR with PM2.5 daily mean levels was slightly smaller than with the hours downwind (OR: 1.22 for an IQR of 15.7 μg/m(3), 95% CI=1.03-1.44; n=94 hospitalizations). Trends were observed between hospitalizations and levels of SO2 for children 2-4 years old. Increasing short-term exposure to emissions from a Quebec aluminum smelter was associated with an increased risk of hospitalization for asthma and bronchiolitis in young children who live nearby. Estimating exposure through records of wind direction allows for the integration of exposure to all pollutants carried from the smelter stack. 23787106 Endocrine markers for identifying prolificacy potential and predicting fetal number in goats. Identifying prolificacy potential and determination of fetal number during pregnancy for proper care and management of the pregnant goats bearing multiple fetuses and achieving the benefits out of multiple births are essential for sustainable goat farming. Our objectives were (1) to examine prolificacy potential in goats by using pituitary response to gonadotrophin releasing hormone (GnRH) challenge test, (2) to investigate hormonal profiles for the prediction of fetal number in pregnant goats and (3) to find out the most reliable timing of blood sampling for discriminating prolificacy trait and differentiating the goats bearing single, twin and triplet fetuses. In first experiment (GnRH challenge test), plasma FSH concentrations were significantly higher (P<0.01) among the goats belonging to triplet vs. twin vs. single kidding size groups after GnRH administration. Multivariate stepwise discriminant function analysis recognized that one blood sampling at 220min after GnRH administration can be used to distinguish prolificacy potential in goats. In second experiment, plasma progesterone levels were significantly higher (P<0.01) in goats bearing triplet vs. twin vs. single fetus between day 84 and 21 prior to parturition. Plasma estrone sulphate concentrations were found to be higher (P<0.05) in does bearing multiple fetuses than the does bearing single fetus between day 126 and 28 prior to parturition. A single blood sampling at day 63 prior to parturition was the most probable suitable time for discriminating kidding size by using plasma progesterone as marker. 23859443 Molecular study of congenital erythrocytosis in 70 unrelated patients revealed a potential causal mutation in less than half of the cases (Where is/are the missing gene(s)?). Congenital erythrocytosis can be classified as primary, when the defect is intrinsic to the RBC progenitors and independent of the serum erythropoietin (Epo) concentration, or secondary, when the erythrocytosis is the result of an upregulation of Epo production. Primary erythrocytosis is associated with mutations in the EPOR gene, secondary CE can de due to mutations that stabilize the hemoglobin in the oxygenated form or to mutations in the genes that control the transcriptional activation of the EPO gene - VHL, EGLN1, EPAS1. Chuvash polycythemia, caused by mutations in VHL gene, shares features of both primary and secondary erythrocytosis, with increased Epo production but also hypersensitivity of progenitors to Epo. With the main objective of describing the etiology and molecular basis of CE, we have studied 70 consecutive unrelated patients presenting with idiopathic erythrocytosis from our hematology clinic or referred from other centers. According to a study algorithm, we have sequenced all the genes described as associated with CE. Erythrocytosis molecular etiology was identify in 25 (36%) of the 70 subjects. High-affinity Hb variants were the most common cause, present in 20% of the cases. New mutations were identified in the JAK2, EPOR, VHL, and EGLN1 genes. High-affinity hemoglobin variants are a very rare cause of secondary CE, but it seems likely that their incidence may be underestimated. Our experience shows that in erythrocytosis with a dominant inheritance and normal or inappropriate high Epo levels, the HBB and HBA genes should be the first to be studied. In spite of the seven genes known to be involved in CE, the majority of the cases have unknown etiology. 23499623 Ventricular fibrillation associated with complete right bundle branch block. A substantial number of patients with idiopathic ventricular fibrillation (IVF) present with no specific electrocardiographic (ECG) findings. To evaluate complete right bundle branch block (RBBB) in patients with IVF. Patients with IVF showing complete RBBB were included in the present study. Structural and primary electrical diseases were excluded, and provocation tests were performed to exclude the presence of spastic angina or Brugada syndrome (BrS). The prevalence of complete RBBB and the clinical and ECG parameters were compared either in patients with IVF who did not show RBBB or in the general population and age and sex comparable controls with RBBB. Of 96 patients with IVF, 9 patients were excluded for the presence of BrS. Of 87 patients studied, 10 (11.5%) patients showed complete RBBB. None had structural heart diseases, BrS, or coronary spasms. The mean age was 44 ± 15 years, and 8 of 10 patients were men. Among the ECG parameters, only the QRS duration was different from that of the other patients with IVF who did not show complete RBBB. Ventricular fibrillation recurred in 3:2 in the form of storms, which were well suppressed by isoproterenol. Complete RBBB was found less often in control subjects (1.37%; P < .0001), and the QRS duration was more prolonged in patients with IVF: 139 ± 10ms vs 150 ± 14ms (P = .0061). Complete RBBB exists more often in patients with IVF than in controls. A prolonged QRS complex suggests a conduction abnormality. Our findings warrant further investigation of the role of RBBB in the development of arrhythmias in patients with IVF. 23733013 Microbial effects on the release and attenuation of arsenic in the shallow subsurface of a natural geochemical anomaly. Critical factors leading to arsenic release and attenuation from the shallow subsurface were studied with multidisciplinary approach in the natural gold-arsenic geochemical anomaly at Mokrsko (Czech Republic). The results show that microbial reduction promotes arsenic release from Fe(III) (hydr)oxides and Fe(III) arsenates, thereby enhancing dissolved arsenic in the shallow groundwater at average concentration of 7.76 mg/L. In the organic-rich aggregates and wood particles, however, microbial sulfate reduction triggers the formation of realgar deposits, leading to accumulation of As in the distinct organic-rich patches of the shallow subsurface. We conclude that precipitation of realgar in the shallow subsurface of soil/sediment depends on specific and non-trivial combination of water and rock chemistry, microbial community composition and spatial organisation of the subsurface zone, where speciation in saturated environments varied on a centimeter scale from reduced (decomposed wood, H2S and realgar present) to oxidized (goethite and arsenate minerals are present). 23958965 Nursing Student Control Over Using a Computer Simulation Program About Empowering Discourse. Nurses find empowering discourse as a patient education intervention demanding, so using methods that support the constructive learning of empowering discourse during their education would be helpful. The aim of this descriptive, comparative study was to evaluate student control when using a computer simulation program that facilitates learning about empowering discourse. The study hypothesis was as follows: Students can control the use of an empowering discourse computer simulation program regardless of their sociodemographic background and study orientation. In the study, 69 students completed an educational session culminating in a computer simulation in which the students responded to a simulated patient's statements in their choice of six content areas in three sections by using a multiple-choice method, an open-ended method, or both methods. The students used all the options in the program despite their background and study orientations. The findings provided evidence that nursing students had control over the use of the computer simulation program to manage their own learning and were able to construct personal knowledge about empowering discourse using the computer simulation regardless of their study orientations. 23731201 Comparison of postoperative nausea between benign and malignant brain tumor patients undergoing awake craniotomy: a retrospective analysis. Abstract Background: Benign and malignant brain tumors have different histopathological characteristics, including different degrees of tissue infiltration and inflammatory response. The aim of this retrospective study was to compare the incidence of postoperative nausea between the two categories of brain tumors in patients undergoing awake craniotomy. Methods: After IRB approval, we retrospectively extracted data from perioperative records between January 2005 and December 2010. Patients were divided based on the postoperative histopathological diagnosis into two groups, benign and malignant. The incidence of nausea, rescue anti-emetics, pain scores and postoperative analgesic requirements were compared between the two groups up to 12 hours postoperatively. Intraoperative anti-emetic, anesthetic, and analgesic regimens were also assessed. Limitations of this study include the retrospective design, the arbitrary dichotomization of tumors as benign or malignant, and the inability to gather accurate data regarding vomiting from the medical record. Results: Data from 415 patients were available for analysis, with 115 patients in the benign group and 300 patients in the malignant tumor group. A higher postoperative mean pain score was found in the benign brain tumor group compared to the malignant brain tumor group (P < 0.05). However, there was no difference in the incidence of nausea between the two groups. Conclusion: The different histopathological characteristics of brain tumors have no association with postoperative nausea in patients undergoing awake craniotomy. Patients with benign brain tumors experience more pain than patients with malignant brain tumors. This difference in postoperative pain may be due to the younger age of the patients in the benign group. 23953277 Continuous in situ diffusion of ropivacaine for ambulatory congenital hand disorders surgery in young children. Pediatric ambulatory surgery presents a specific set of challenges to the anesthesiologist. Similarly to adult ambulatory surgery, we report four ambulatory surgical procedures in two young children with congenital hand disorders. For each surgical procedure pain was controlled with continuous in situ infusion of ropivacaine. 22168624 Histologic and histomorphometric evaluation of a synthetic bone substitute for maxillary sinus grafting in humans. The present study investigated the efficacy of a biphasic calcium phosphate as a bone grafting material for maxillary sinus augmentation in humans. Half of the thirty patients selected for sinus augmentation were grafted with biphasic calcium phosphate, whereas the other half were grafted with autogenous bone chips harvested intraorally. After 9 months of healing, bone cores were retrieved from implant sites for histologic and histomorphometric evaluation. The areas augmented with autogenous bone chips showed newly formed bone with a pattern very similar to that of the native area. Histomorphometry demonstrated that the amount of newly formed bone in the autogenous bone group was significantly greater than in the biphasic calcium phosphate group (P < 0.05). In the biphasic calcium phosphate group, less bone formation was observed in the area further away from native bone interface than in the area closer to native bone interface (P < 0.05), whereas no significant differences were observed between both areas in the autogenous group. In both groups, the implant survival rate was 100% with a minimum 1-year follow-up. The data presented in this work confirm the osteoconductive properties of biphasic calcium phosphate, as well as its use in association with maxillary sinus floor augmentation procedures with successful outcomes. 23702417 Pushing spatial and temporal resolution for functional and diffusion MRI in the Human Connectome Project. The Human Connectome Project (HCP) relies primarily on three complementary magnetic resonance (MR) methods. These are: 1) resting state functional MR imaging (rfMRI) which uses correlations in the temporal fluctuations in an fMRI time series to deduce 'functional connectivity'; 2) diffusion imaging (dMRI), which provides the input for tractography algorithms used for the reconstruction of the complex axonal fiber architecture; and 3) task based fMRI (tfMRI), which is employed to identify functional parcellation in the human brain in order to assist analyses of data obtained with the first two methods. We describe technical improvements and optimization of these methods as well as instrumental choices that impact speed of acquisition of fMRI and dMRI images at 3T, leading to whole brain coverage with 2mm isotropic resolution in 0.7s for fMRI, and 1.25mm isotropic resolution dMRI data for tractography analysis with three-fold reduction in total dMRI data acquisition time. Ongoing technical developments and optimization for acquisition of similar data at 7T magnetic field are also presented, targeting higher spatial resolution, enhanced specificity of functional imaging signals, mitigation of the inhomogeneous radio frequency (RF) fields, and reduced power deposition. Results demonstrate that overall, these approaches represent a significant advance in MR imaging of the human brain to investigate brain function and structure. 23144238 Noncompetitive, voltage-dependent NMDA receptor antagonism by hydrophobic anions. NMDA receptor (NMDAR) antagonists are dissociative anesthetics, drugs of abuse, and are of therapeutic interest in neurodegeneration and neuropsychiatric disease. Many well-known NMDAR antagonists are positively charged, voltage-dependent channel blockers. We recently showed that the hydrophobic anion dipicrylamine (DPA) negatively regulates GABA(A) receptor function by a mechanism indistinguishable from that of sulfated neurosteroids. Because sulfated neurosteroids also modulate NMDARs, here we examined the effects of DPA on NMDAR function. In rat hippocampal neurons DPA inhibited currents gated by 300 µM NMDA with an IC(50) of 2.3 µM. Neither onset nor offset of antagonism exhibited dependence on channel activation but exhibited a noncompetitive profile. DPA antagonism was independent of NMDAR subunit composition and was similar at extrasynaptic and total receptor populations. Surprisingly, similar to cationic channel blockers but unlike sulfated neurosteroids, DPA antagonism was voltage dependent. Onset and offset of DPA antagonism were nearly 10-fold faster than DPA-induced increases in membrane capacitance, suggesting that membrane interactions do not directly explain antagonism. Furthermore, voltage dependence did not derive from association of DPA with a site on NMDARs directly accessible to the outer membrane leaflet, assessed by DPA translocation experiments. Consistent with the expected lack of channel block, DPA antagonism did not interact with permeant ions. Therefore, we speculate that voltage dependence may arise from interactions of DPA with the inherent voltage dependence of channel gating. Overall, we conclude that DPA noncompetitively inhibits NMDA-induced current by a novel voltage-dependent mechanism and represents a new class of anionic NMDAR antagonists. 23552953 Dissecting the genotype in syndromic intellectual disability using whole exome sequencing in addition to genome-wide copy number analysis. When a known microimbalance affecting multiple genes is detected in a patient with syndromic intellectual disability, it is usually presumed causative for all observed features. Whole exome sequencing (WES) allows questioning this assumption. In this study of three families with children affected by unexplained syndromic intellectual disability, genome-wide copy number and subsequent analyses revealed a de novo maternal 1.1 Mb microdeletion in the 14q32 imprinted region causing a paternal UPD(14)-like phenotype, and two inherited 22q11.21 microduplications of 2.5 or 2.8 Mb. In patient 1 carrying the 14q32 microdeletion, tall stature and renal malformation were unexplained by paternal UPD(14), and there was no altered DLK1 expression or unexpected methylation status. By WES and filtering with a mining tool, a novel FBN1 missense variant was found in patient 1 and his mother, who both showed clinical features of Marfan syndrome by thorough anthropometric assessment, and a novel EYA1 missense variant as a probable cause of the renal malformation in the patient. In patient 2 with the 22q11.21 microduplication syndrome, skin hypo- and hyperpigmentation and two malignancies were only partially explained. By WES, compound heterozygous BLM stop founder mutations were detected causing Bloom syndrome. In male patient 3 carrying a 22q11.21 microduplication inherited from his unaffected father, WES identified a novel missense variant in the OPHN1 X-linked intellectual disability gene inherited from the unaffected mother as a possible additional cause for developmental delay. Thus, WES seems warranted in patients carrying microdeletions or microduplications, who have unexplained clinical features or microimbalances inherited from an unaffected parent. 23519596 Protein a chromatography at high titers. The large increase in antibody titers over the past two decades has created significant challenges for downstream processes; however, there have been no quantitative studies of the effect of feed concentration on the dynamic binding capacity in Protein A chromatography. Small scale experiments were performed using pre-packed ProSep® Ultra Plus columns over a range of feed flow rates and antibody concentrations. The data clearly demonstrate that the dynamic binding capacity decreases with increasing concentration of the monoclonal antibody at short residence times. This reduction in DBC is due to non-equilibrium mass transfer effects in the porous resin, with the experimental results consistent with predictions of a simple mathematical model based on a linear driving force with solid phase diffusion. These results provide important insights into the behavior of Protein A chromatography and provide a framework for the proper design of Protein A capture steps for high titer products. Biotechnol. Bioeng. 2013; 110:2445-2451. © 2013 Wiley Periodicals, Inc. 23232447 Structure-based optimization of angiostatic agent 6DBF7, an allosteric antagonist of galectin-1. Galectin-1 (gal-1), which binds β-galactoside groups on various cell surface receptors, is crucial to cell adhesion and migration, and is found to be elevated in several cancers. Previously, we reported on 6DBF7, a dibenzofuran (DBF)-based peptidomimetic of the gal-1 antagonist anginex. In the present study, we used a structure-based approach to optimize 6DBF7. Initial NMR studies showed that 6DBF7 binds to gal-1 on one side of the β-sandwich away from the lectin's carbohydrate binding site. Although an alanine scan of 6DBF7 showed that the two cationic groups (lysines) in the partial peptide are crucial to its angiostatic activity, it is the hydrophobic face of the amphipath that appears to interact directly with the surface of gal-1. Based on this structural information, we designed and tested additional DBF analogs. In particular, substitution of the C-terminal Asp for alanine and branched alkyl side chains (Val, Leu, Ile) for linear ones (Nle, Nva) rendered the greatest improvements in activity. Flow cytometry with gal-1(-/-) splenocytes showed that 6DBF7 and two of its more potent analogs (DB16 and DB21) can fully inhibit fluorescein isothiocyanate-gal-1 binding. Moreover, heteronuclear single-quantum coherence NMR titrations showed that the presence of DB16 decreases gal-1 affinity for lactose, indicating that the peptidomimetic targets gal-1 as a noncompetitive, allosteric inhibitor of glycan binding. Using tumor mouse models (B16F10 melanoma, LS174 lung, and MA148 ovarian), we found that DB21 inhibits tumor angiogenesis and tumor growth significantly better than 6DBF7, DB16, or anginex. DB21 is currently being developed further and holds promise for the management of human cancer in the clinic. 23270368 6-acetyl-5H-thiazolo[3,2-a]pyrimidine derivatives as the novel acetylcholinesterase inhibitors: design, synthesis, and biological activity. Acetylcholinesterase inhibitors are the most frequently prescribed anti-Alzheimer's drugs. A series of 6-acetyl- 5H-thiazolo[3,2-a]pyrimidine derivatives as the novel acetylcholinesterase inhibitors were designed based on virtual screening methods. The target compounds which are not reported in the literature were synthesized with Biginelli reaction and Hantzsch-type condensation of dihydropyrimidines with substituted phenacyl chlorides, and were characterized with elemental analysis, IR, MS, 1H-NMR and 13C-NMR. The biological evaluation against human acetylcholinesterase in vitro showed most of the target compounds exhibited varying inhibition at 10 µM using the Ellman method. The results provide a starting point for the development of novel drugs to treat Alzheimer's disease, and a foundation in search for improved acetylcholinesterase inhibitors with the novel scaffolds. The preliminary structure-activity relationships were the 2-hydroxyethoxy group at the phenyl ring at C4 position of the parent nucleus played significant roles in the AChE inhibitory activity of the target compounds. 23965304 Dicodon monitoring of protein synthesis (DiCoMPS) reveals levels of synthesis of a viral protein in single cells. The current report represents a further advancement of our previously reported technology termed Fluorescent transfer RNA (tRNA) for Translation Monitoring (FtTM), for monitoring of active global protein synthesis sites in single live cells. FtTM measures Förster resonance energy transfer (FRET) signals, generated when fluorescent tRNAs (fl-tRNAs), separately labeled as a FRET pair, occupy adjacent sites on the ribosome. The current technology, termed DiCodon Monitoring of Protein Synthesis (DiCoMPS), was developed for monitoring active synthesis of a specific protein. In DiCoMPS, specific fl-tRNA pair combinations are selected for transfection, based on the degree of enrichment of a dicodon sequence to which they bind in the mRNA of interest, relative to the background transcriptome of the cell in which the assay is performed. In this study, we used cells infected with the Epizootic Hemorrhagic Disease Virus 2-Ibaraki and measured, through DiCoMPS, the synthesis of the viral non-structural protein 3 (NS3), which is enriched in the AUA:AUA dicodon. fl-tRNA(Ile)UAU-generated FRET signals were specifically enhanced in infected cells, increased in the course of infection and were diminished on siRNA-mediated knockdown of NS3. Our results establish an experimental approach for the single-cell measurement of the levels of synthesis of a specific viral protein. 23873731 Tetraalkoxyphenanthrene-Fused Dehydroannulenes: Synthesis, Self-Assembly, and Electronic, Optical, and Electrochemical Properties. Novel tetraalkoxyphenanthrene-fused dehydro[12]-, [18]-, and [24]annulenes 1-3 were synthesized by using Cu-mediated or Pd-catalyzed oxidative macrocyclization reactions as key steps, and their electronic, optical, and electrochemical properties have been investigated in detail. X-ray crystallographic analysis of a single crystal of 1 a demonstrated that the molecules were arranged longitudinally in a slipped π-stacked fashion to form a 1D column. (1) H NMR and UV/Vis spectroscopic and cyclic voltammetric analysis in conjugation with nucleus-independent chemical shift (NICS) calculations for 1-3 support that the annulation at the 9,10-positions of phenanthrene to the dehydroannulene ring enhances the tropicity and decreases the HOMO-LUMO gaps of the molecules relative to the benzannulation and that 1 possesses an antiaromatic character. Self-association behavior due to π-π stacking in CDCl3 was observed for 1 and 2 and was quantified by concentration-dependent (1) H NMR spectroscopic measurements. The self-assembly of 1 and 2 into well-defined 1D superstructures with high aspect ratios were obtained, and the morphology and crystallinity of these compounds were investigated by means of SEM and wide-angle X-ray diffraction (WAXD) measurements. Furthermore, it was shown that 1 b and 2 b display liquid-crystalline phases by means of differential scanning calorimetry, polarizing optical microscopy, and variable-temperature WAXD measurements. 23849979 Comparison of gluteal and hamstring activation during five commonly used plyometric exercises. Anterior cruciate ligament injuries occur frequently in athletics, and anterior cruciate ligament injury prevention programs may decrease injury risk. However, previous prevention programs that include plyometrics use a variety of exercises with little justification of exercise inclusion. Because gluteal and hamstring activation is thought to be important for preventing knee injuries, the purpose of this study was to determine which commonly used plyometric exercises produce the greatest activation of the gluteals and hamstrings. EMG (Electromyography) amplitudes of the hamstring and gluteal muscles during preparatory and loading phases of landing were recorded in 41 subjects during 5 commonly used plyometric exercises. Repeated measures ANOVAs (Analysis of Variance) were used on 36 subjects to examine differences in muscle activation. Differences in hamstring (P<.01) and gluteal (P<.01) activities were identified across exercises during the preparatory and landing phases. The single-leg sagittal plane hurdle hops produced the greatest gluteal and hamstring activity in both phases. The 180° jumps did not produce significantly greater gluteal or hamstring activity than any other exercise. Single-leg sagittal plane hurdle hops may be the most effective exercise to activate the gluteals and hamstrings and may be important to include in anterior cruciate ligament injury prevention programs, given the importance of these muscles for limiting valgus loading of the knee. Because 180° jumps do not produce greater gluteal and hamstring activation than other plyometric exercises, their removal from injury prevention programs may be warranted without affecting program efficacy. 23946345 Increasing the Percentage of Energy from Dietary Sugar, Fats, and Alcohol in Adults Is Associated with Increased Energy Intake but Has Minimal Association with Biomarkers of Cardiovascular Risk. The optimal diet composition to prevent obesity and its complications is unknown. Study aims were to determine the association of diet composition with energy intake, homeostatic model assessment-insulin resistance (HOMA-IR), and C-reactive protein (CRP). Data were from the NHANES for eligible adults aged 20-74 y from 2005 to 2006 (n = 3073). Energy intake and diet composition were obtained by dietary recall. HOMA-IR was calculated from fasting insulin and glucose concentrations, and CRP was measured directly. Changes for a 1-point increase in percentage of sugar, saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), and alcohol were determined across their means in exchange for a 1-point decrease in percentage of nonsugar carbohydrates. Regression analyses were performed, and means ± SEs were estimated. Increasing the percentage of sugar was associated with increased energy intake in men (23 ± 5 kcal; P < 0.001) and women (12 ± 3 kcal; P = 0.002). In men, increasing percentages of SFAs (58 ± 13 kcal; P = 0.001) and PUFAs (66 ± 19 kcal; P < 0.001) were associated with increased energy intake. In women, increasing percentages of SFAs (27 ± 10 kcal; P = 0.02), PUFAs (43 ± 6 kcal; P < 0.001), and MUFAs (36 ± 13 kcal; P = 0.01) were associated with increased energy intake. Increasing the percentage of alcohol was associated with increased energy intake in men (38 ± 7 kcal; P < 0.001) and women (25 ± 8 kcal; P = 0.001). Obesity was associated with increased HOMA-IR and CRP in both genders (all P ≤ 0.001). Increasing PUFAs was associated with decreasing CRP in men (P = 0.02). In conclusion, increasing the percentage of calories from sugar, fats, and alcohol was associated with substantially increased energy intake but had minimal association with HOMA-IR and CRP. 23884734 Screening Mammography Recall Rate: Does Practice Site Matter? Purpose:To determine whether the screening mammography recall rate for individual radiologists varies as a function of imaging site.Materials and Methods:Institutional review board-approved, HIPAA-compliant retrospective review of mammography audit data was performed between May 1, 2008, and September 1, 2011, for five radiologists with expertise in breast imaging interpreting mammograms at a community office practice and an academic referral hospital. Informed consent was waived. Both sites used full-field digital mammography and batch screening interpretation. Recall rates were calculated from audit data. Breast density, history of surgery or biopsy, and availability of prior mammograms were compared in a sample of 500 mammograms from each site by using χ(2) and two-sample t tests.Results:Radiologists interpreted a total of 74 297 screening mammograms between both sites during the study. The overall mean recall rate was 7.8% ± 0.2 (standard deviation). Overall recall rate at the community site was significantly lower than at the hospital site (6.9% ± 0.3 vs 8.6% ± 0.3, P < .001). Recall rates for each radiologist were also lower at the community site: 3.7% versus 6.5% (P < .001), 9.6% versus 12.0% (P < .001), 7.5% versus 9.1% (P = .01), 7.6% versus 11.5% (P < .001), and 5.6% versus 8.0% (P = .02). There was a significantly higher proportion of patients at the hospital site with a history of surgery (13.4% vs 5.6%, P < .001) and biopsy (7.0% vs 1.4%, P < .001) but no difference in the percentage with dense breasts or in the percentage with availability of prior mammograms. Mean patient age was lower at the hospital site: 56.1 versus 62.9 years (P < .001).Conclusion:Recall rates were higher at the hospital site, probably primarily caused by patient population factors.© RSNA, 2013. 23849803 Induction of apoptosis associated with chromosomal DNA fragmentation and caspase-3 activation in leukemia L1210 cells by TiO2 nanoparticles. We investigated the effects of nanosized TiO2 particles on the death of mouse leukemia L1210 cells. TiO2 particles suppressed proliferation and induced cell death, as measured by lactate dehydrogenase (LDH) release into the culture medium. Chromatin condensation, which is typical of the initiation of cell death, was observed in approximately 14% cells cultured with titanium dioxide (TiO2) particles for 12 h. Furthermore, giant DNA fragments of approximately 2 Mbp and high-molecular-weight DNA fragments between 100 kbp and 1 Mbp were observed in cells cultured for 18 h with TiO2 particles. These giant and high-molecular-weight DNA fragments were further degraded into smaller DNA fragments, appearing as DNA ladders. Corresponding to the generation of DNA fragments, caspase-3 activity increased in cells treated with TiO2 particles. TiO2 particle-induced LDH release was not inhibited by cytochalasin D, an inhibitor of endocytosis. These results suggest that nanosized TiO2 particles can induce apoptosis associated with DNA fragmentation and caspase-3 activation and that TiO2 particle-induced apoptosis is not caused by endocytosis but is associated with contact of the particles with the cell surface. 23782652 Disruption of JAK2 in Adipocytes Impairs Lipolysis and Improves Fatty Liver in Mice With Elevated GH. Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic expression of the metabolic syndrome, and its prevalence is increasing. The factors that influence the development of fatty liver and its progression to steatohepatitis and cirrhosis are not well understood. The pleiotropic hormone, GH, has been associated with an increased risk of NAFLD in humans and mice. GH is known to have diverse effects on lipid metabolism including decreasing body fat in vivo, presumably through stimulation of lipolysis via an undefined mechanism. Previously we described mice with hepatocyte-specific deletion of the GH signaling mediator, Janus kinase 2 (JAK2L). JAK2L animals have elevated serum GH, reduced body fat, high liver triglyceride content, and increased serum markers of hepatocyte injury (alanine transaminase and aspartate transaminase). We aimed to determine whether the elevation of GH in JAK2L mice contributed to fatty liver by promoting lipolysis directly in adipocytes. We generated mice with adipocyte-specific disruption of JAK2 (JAK2A) and found that GH resistance in adipocytes reduced lipolysis and increased body fat. JAK2A mice were then crossed to JAK2L mice, and the resultant JAK2L/A animals had increased body fat and decreased lipolysis, despite elevated circulating GH. Furthermore, the increased triglyceride content, serum alanine transaminase, and serum aspartate transaminase observed in JAK2L mice were nearly normalized with the additional disruption of JAK2 in adipocytes (JAK2L/A mice). Our results offer novel mechanistic insights into the long-recognized effects of GH on lipid flux and suggest that GH signaling may play an important regulatory role in the development of NAFLD. 23835606 Ferrimagnetism in GdCo12-xFexB6. The effects of iron substitution on the structural and magnetic properties of the GdCo12-xFexB6 (0 â‰¤ x â‰¤ 3) series of compounds have been studied. All of the compounds form in the rhombohedral SrNi12B6-type structure and exhibit ferrimagnetic behaviour below room temperature: TC decreases from 158 K for x = 0 to 93 K for x = 3. (155)Gd Mössbauer spectroscopy indicates that the easy magnetization axis changes from axial to basal-plane upon substitution of Fe for Co. This observation has been confirmed using neutron powder diffraction. The axial to basal-plane transition is remarkably sensitive to the Fe content and comparison with earlier (57)Fe-doping studies suggests that the boundary lies below x = 0.1. 23815686 Electrocapillary instability of magnetic fluid peak. This Article presents an experimental study of the capillary electrostatic instability occurring under the effect of a constant electric field on a magnetic fluid individual peak. The peaks under study occur at disintegration of a magnetic fluid layer applied on a flat electrode surface under the effect of a perpendicular magnetic field. The electrocapillary instability shows itself as an emission of charged drops jets from the peak point in direction of the opposing electrode. The charged drops emission repeats periodically and results in the peak shape pulsations. It is shown that a magnetic field affects the electrocapillary instability occurrence regularities and can stimulate its development. The critical electric and magnetic field strengths at which the instability occurs have been measured; their dependence on the peak size is shown. The hysteresis in the system has been studied; it consists in that the charged drops emission stops at a lesser electric (or magnetic) field strength than that of the initial occurrence. The peak pulsations frequency depending on the magnetic and electric field strengths and on the peak size has been measured. 23258694 Analysing malaria drug trials on a per-individual or per-clone basis: a comparison of methods. There are a variety of methods used to estimate the effectiveness of antimalarial drugs in clinical trials, invariably on a per-person basis. A person, however, may have more than one malaria infection present at the time of treatment. We evaluate currently used methods for analysing malaria trials on a per-individual basis and introduce a novel method to estimate the cure rate on a per-infection (clone) basis. We used simulated and real data to highlight the differences of the various methods. We give special attention to classifying outcomes as cured, recrudescent (infections that never fully cleared) or ambiguous on the basis of genetic markers at three loci. To estimate cure rates on a per-clone basis, we used the genetic information within an individual before treatment to determine the number of clones present. We used the genetic information obtained at the time of treatment failure to classify clones as recrudescence or new infections. On the per-individual level, we find that the most accurate methods of classification label an individual as newly infected if all alleles are different at the beginning and at the time of failure and as a recrudescence if all or some alleles were the same. The most appropriate analysis method is survival analysis or alternatively for complete data/per-protocol analysis a proportion estimate that treats new infections as successes. We show that the analysis of drug effectiveness on a per-clone basis estimates the cure rate accurately and allows more detailed evaluation of the performance of the treatment. 23160855 Practicing physiotherapy in Danish private practice: an ethical perspective. Despite an increasingly growth of professional guidelines, textbooks and research about ethics in health care, awareness about ethics in Danish physiotherapy private practice seen vague. This article explores how physiotherapists in Danish private practice, from an ethical perspective, perceive to practice physiotherapy. The empirical data consists of interviews with twenty-one physiotherapists. The interviews are analysed from a hermeneutic approach, inspired by Ricoeur's textual interpretation of distanciation. The analysis follows three phases: naïve reading, structural analysis and comprehensive analysis. Four main themes are constructed: Beneficence as the driving force; Disciplining the patient through the course of physiotherapy; Balancing between being a trustworthy professional and a businessperson; The dream of a code of practice. Private practice physiotherapy is embedded in a structural frame directed by both political and economical conditions that shape the conditions for practicing physiotherapy. It means that beneficence in practice is a balance between the patient, the physiotherapists themselves and the business. Beneficence towards the patient is expressed as an implicit demand. Physiotherapeutic practice is expressed as being an integration of professionalism and personality which implies that the physiotherapists also have to benefit themselves. Private practice seems to be driven by a paternalistic approach towards the patient, where disciplining the patient is a crucial element of practice, in order to optimise profit. Physiotherapists wish for a more beneficent practice in the future by aiming at bridging 'to be' and 'ought to be'. 23712537 Poloxamer-based hydrogels hardening at body core temperature as carriers for cell based therapies: in vitro and in vivo analysis. Cell-based regenerative therapies for bone defects usually employ bone precursor cells seeded on solid scaffolds. Thermosensitive hydrogels that harden at body core temperature are promising alternative cell carriers as they are applicable minimally invasively. We modified Pluronic(®) P123 with different chain extenders and assessed rheology and biocompatibility of the resulting hydrogels. The best candidate was tested in a rat's femoral defect model. All gels hardened above 25 °C with butane-diisocyanate-hydrogels (BDI-gels) displaying the highest storage moduli. BDI-gels showed the most favourable biocompatibility and did not affect cellular adipogenic or osteogenic differentiation in vitro. Implantation of BDI-hydrogel into femoral defects did not impede bone healing in vivo as evidenced by μCT and histological analysis. We conclude that thermosensitive BDI-gels are promising alternative cell carriers. The gels harden upon injection in vivo without interfering with bone metabolism. Further experiments will assess the gels' capacity to effectively transport living cells into bone defects. 23763754 Multidrug-resistant atypical variants of Shigella flexneri in China. We identified 3 atypical Shigella flexneri varieties in China, including 92 strains with multidrug resistance, distinct pulse types, and a novel sequence type. Atypical varieties were prevalent mainly in developed regions, and 1 variant has become the dominant Shigella spp. serotype in China. Improved surveillance will help guide the prevention and control of shigellosis. 23786444 Aureobasidium pullulans culture supernatant significantly stimulates R-848-activated phagocytosis of PMA-induced THP-1 macrophages. Abstract Toll-like receptors (TLRs), which recognize a wide range of microbial pathogens and pathogen-related products, play important roles in innate immunology. Macrophages have a variety of TLRs, and pathogen binding to TLR resulted in the activation of macrophages. R-848, an immune response modifier, is an analog of imidazoquinoline derivative and binds to an endosome-localized TLR to exert an anti-viral response on leukocytes. In the present study, we verified that co-treatment of R-848 with other TLR agonists would enhance immune response. The culture supernatant of Aureobasidium pullulans (A. pullulans, which contains predominantly soluble β-glucan), which binds to cell membrane-localized TLR, and to C-type lectin receptor Dectin-1, was treated together with R-848 to THP-1 macrophages. Compared to R-848 treatment alone, co-treatment of R-848 with A. pullulans culture supernatant significantly augmented TNF-α and IL-12p40 cytokine expression. Next, we investigated whether or not apoptotic cell uptake would be increased by co-treatment of R-848 with A. pullulans culture supernatant. To detect engulfed apoptotic cells, we induced apoptosis in human lymphoma Jurkat cells by 5-fluorouracil and stained them with fluorescent dye 5(6)-carboxytetramethylrhodamine (TAMRA), whereas THP-1 macrophage was labeled with fluorescein isothiocyanate-anti-CD14 and determined the percentage increase in TAMRA-positive THP-1 macrophages by flow cytometric assay. Since R-848 or A. pullulans treatment alone stimulated THP-1 macrophages to induce phagocytosis, co-treatment of R-848 with A. pullulans culture supernatant significantly augmented phagocytosis of apoptotic Jurkat cells. These results suggest that the activation of several different innate immune receptor pathways may enhance the immune response of R-848 significantly. 23876507 Two-step catalytic hydrodeoxygenation of fast pyrolysis oil to hydrocarbon liquid fuels. Two-step catalytic hydrodeoxygenation (HDO) of fast pyrolysis oil was investigated for translating pyrolysis oil to transportation grade hydrocarbon liquid fuels. At the first mild HDO step, various organic solvents were employed to promote HDO of bio-oil to overcome coke formation using noble catalyst (Ru/C) under mild conditions (300°C, 10MPa). At the second deep HDO step, conventional hydrogenation setup and catalyst (NiMo/Al2O3) were used under severe conditions (400°C, 13MPa) for obtaining hydrocarbon fuel. Results show that the phenomenon of coke formation is effectively eliminated, and the properties of products have been significantly improved, such as oxygen content decreases from 48 to 0.5wt% and high heating value increases from 17 to 46MJkg(-1). GC-MS analysis indicates that the final products include C11C27 aliphatic hydrocarbons and aromatic hydrocarbons. In short, the fast pyrolysis oils were successfully translated to hydrocarbon liquid fuels using a two-step catalytic HDO process. 23739162 Selective solid-phase extraction of naproxen drug from human urine samples using molecularly imprinted polymer-coated magnetic multi-walled carbon nanotubes prior to its spectrofluorometric determination. A drug imprinted polymer based on suspension polymerization on magnetic multi-walled carbon nanotubes (MIPMCNTs) was prepared with a synthesized amidoamine as the functional monomer, ethylene glycol dimethacrylate as the cross-linker, naproxen (NAP) as the template and ammonium persulfate as the initiator. The MIPMCNTs were characterized by TEM, FT-IR and XRD measurements. The prepared magnetic adsorbent can be well dispersed in aqueous media and can be easily separated magnetically from the medium after loading with NAP. All the aspects influencing the adsorption (extraction time, adsorbent dosage and pH) and desorption (desorption time and desorption solvent) of the analyte on the MIPMCNTs have been investigated. The extracted NAP could be easily desorbed with a mixture of methanol/sodium hydroxide aqueous solution and determined spectrofluorometrically at λem = 353 nm (λex = 271 nm). A linear dynamic range was established from 4.0 to 40.0 ng mL(-1) of NAP and the limit of detection (LOD) was found to be 2.0 ng mL(-1). In addition, the equilibrium adsorption data of NAP by imprinted polymer were analyzed by Langmuir and Freundlich isotherm models. The developed method was utilized for the determination of NAP in human urine samples with satisfactory results. 23965395 Influence of dental correction on nociceptive test responses, fecal appearance, body condition score and apparent digestibility coefficient for dry matter of Zamorano-leones donkeys (Equus asinus). The influence of dental correction on nociceptive (pressure) test responses, fecal appearance, body condition score, and apparent digestibility coefficient for DM was studied in 18 Zamorano-Leonés donkeys, an endangered local breed from the Zamora province in Spain. For this purpose, donkeys were divided into 2 homogeneous control and treatment groups based on age, BCS, and dental findings. On d 1, 45, 90, and 135, BCS and nociceptive test responses were evaluated in all donkeys. Feed and fecal samples were collected from all donkeys for 3 consecutive days, starting at each of the aforementioned days. Apparent digestibility coefficient for DM was estimated using ADL as an internal marker. A progressive decrease of positive nociceptive test responses was observed from d 1 up to 90 (P < 0.01) in the treatment group. No difference between groups was observed for BCS. However, BCS at d 90 was greater (P = 0.018) than observed on d 1 or 45, indicating a time influence. Concerning apparent digestibility coefficient for dry matter, There were differences among collection days in apparent digestibility coefficient for DM (P < 0.05). No differences in fecal appearance were observed between treatments or collection days. This study highlighted the importance of regular dental care for not only Zamorano-Leonés donkeys, but also the equid population in general improving their welfare. 23496237 Quality of life in patients with toenail onychomycosis. Onychomycosis is a common, chronic fungal nail infection that can have a significant negative impact on patients' physical and social functioning and emotional well-being. This study was undertaken to assess health-related quality of life (HRQoL) in patients with toenail onychomycosis. The Onychomycosis QoL questionnaire (ONYCHO), as a disease-specific instrument, and the Short Form 36 Health Survey (SF-36) as a generic instrument, were applied in 140 consecutive patients affected by onychomycosis. Women and patients who were experiencing toenail onychomycosis for more than 2 years were reporting worse disease-specific HRQoL. The patients working in blue-collar occupations and patients with greater involvement of individual nails were more affected by onychomycosis regarding symptoms. The results of this study confirm that although onychomycosis is not a life-threatening disease, it can significantly reduce patients' QoL. 23817615 MntABC and MntH Contribute to Systemic Staphylococcus aureus Infection by Competing with Calprotectin for Nutrient Manganese. During infection, vertebrates limit access to manganese and zinc, starving invading pathogens, such as Staphylococcus aureus, of these essential metals in a process termed "nutritional immunity." The manganese and zinc binding protein calprotectin is a key component of the nutrient-withholding response, and mice lacking this protein do not sequester manganese from S. aureus liver abscesses. One potential mechanism utilized by S. aureus to minimize host-imposed manganese and zinc starvation is the expression of the metal transporters MntABC and MntH. We performed transcriptional analyses of both mntA and mntH, which revealed increased expression of both systems in response to calprotectin treatment. MntABC and MntH compete with calprotectin for manganese, which enables S. aureus growth and retention of manganese-dependent superoxide dismutase activity. Loss of MntABC and MntH results in reduced staphylococcal burdens in the livers of wild-type but not calprotectin-deficient mice, suggesting that these systems promote manganese acquisition during infection. During the course of these studies, we observed that metal content and the importance of calprotectin varies between murine organs, and infection leads to profound changes in the anatomical distribution of manganese and zinc. In total, these studies provide insight into the mechanisms utilized by bacteria to evade host-imposed nutrient metal starvation and the critical importance of restricting manganese availability during infection. 21824792 Gender as a significant predictor of intravesical recurrence in patients with urothelial carcinoma of the upper urinary tract following nephroureterectomy. To retrospectively assess the significance of gender as a predictor of intravesical recurrence following nephroureterectomy for urothelial carcinoma of the upper urinary tract (UC-UUT). This study included 502 consecutive patients (360 male and 142 female) who were diagnosed as having clinically localized UC-UUT and underwent nephroureterectomy. Clinicopathologic outcomes of these patients were analyzed focusing on the impact of gender. The incidence of intravesical recurrence in male patients (41.9%) was significantly greater than that in female patients (27.5%). Despite the lack of significant differences in cancer-specific and overall survivals with respect to gender, the intravesical recurrence-free survival in male patients was significantly worse than that in female patients. Of several parameters examined, univariate analysis identified gender, tumor site, and tumor focality as significant predictors of intravesical recurrence following nephroureterectomy. Of these, only gender and tumor site appeared to be independently associated with intravesical recurrence-free survival on multivariate analysis. Furthermore, there was a significant difference in intravesical recurrence-free survival according to positive numbers of these two independent factors; that is, intravesical recurrence occurred in 12 of 55 patients who were negative for both risk factors (21.8%), 96 of 280 positive for a single risk factor (34.3%), and 82 of 167 positive for both risk factors (49.1%). The incidence of intravesical recurrence following nephroureterectomy for UC-UUT is comparatively high. Therefore, it would be potentially important to perform careful follow-up targeting intravesical recurrence for such patients, particularly for male patients and/or patients with tumor located at the ureter. 23616343 Dasatinib inhibits mammary tumour development in a genetically engineered mouse model. Src family kinase activity is elevated in a number of human cancers including breast cancer. This increased activity has been associated with aggressive disease and poor prognosis. Src inhibitors are currently in clinical development with a number of trials currently assessing their activity in breast cancer. However, the results to date have been disappointing and a further evaluation of the preclinical effects of Src inhibitors is required to help establish whether these agents will be useful in the treatment of breast cancer. In this study we investigate the effects of dasatinib, which is a potent inhibitor of Src family kinases, on the initiation and development of breast cancer in a genetically engineered model of the disease. The mouse model utilized is driven by expression of activated ErbB-2 under the transcriptional control of its endogenous promoter coupled with conditional loss of Pten under the control of Cre recombinase expressed by the BLG promoter. We show that daily oral administration of dasatinib delays tumour onset and increases overall survival but does not inhibit the proliferation of established tumours. The striking difference between the dasatinib-treated group of tumours and the vehicle controls was the prominent squamous metaplasia that was seen in six out of 11 dasatinib-treated tumours. This was accompanied by a dramatic up-regulation of both E-cadherin and β-catenin and down-regulation of ErbB-2 in the dasatinib-treated tumours. Dasatinib also inhibited both the migration and the invasion of tumour-derived cell lines in vitro. Together these data support the argument that benefits of Src inhibitors may predominate in early or even pre-invasive disease. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. 23404650 Stratified communities of active archaea in shallow sediments of the Pearl River Estuary, Southern China. Marine subsurface sediments represent a novel archaeal biosphere with unknown physiology. To get to know the composition and ecological roles of the archaeal communities within the sediments of the Pearl River Estuary, Southern China, the diversity and vertical distribution of active archaea in a sediment core were characterized by 16S rRNA phylogenetic analysis of clone libraries derived from RNA. In this study, the archaeal diversity above, within, and beneath the sulfate-methane transition zone (SMTZ) in the Pearl River Estuary sediment core was described. The majority of the clones obtained from the metabolically active fraction of the archaeal community were most closely related to miscellaneous crenarchaeotal group and terrestrial miscellaneous euryarchaeotal group. Notably, although the Pearl River Estuary sediment belong to high methane and high organic carbon environment, sequences affiliated with methanotrophic and methanogenic archaea were detected as minor group in 16S rRNA clone libraries. No obvious evidence suggested that these unknown archaeal phylotypes related directly to anaerobic oxidation of methane in SMTZ. This is the first phylogenetic analysis of the metabolically active fraction of the archaeal community in the coastal sediment environments. 23824795 Endothelial Cell Stimulation Overcomes Restriction and Promotes Productive and Latent HIV-1 Infection of Resting CD4+ T Cells. Highly active antiretroviral therapy (HAART) is able to suppress human immunodeficiency virus type 1 (HIV-1) to undetectable levels in the majority of patients, but eradication has not been achieved because latent viral reservoirs persist, particularly in resting CD4(+) T lymphocytes. It is generally understood that HIV-1 does not efficiently infect resting CD4(+) T cells, and latent infection in those cells may arise when infected CD4(+) T lymphoblasts return to resting state. In this study, we found that stimulation by endothelial cells can render resting CD4(+) T cells permissible for direct HIV infection, including both productive and latent infection. These stimulated T cells remain largely phenotypically unactivated and show a lower death rate than activated T cells, which promotes the survival of infected cells. The stimulation by endothelial cells does not involve interleukin 7 (IL-7), IL-15, CCL19, or CCL21. Endothelial cells line the lymphatic vessels in the lymphoid tissues and have frequent interactions with T cells in vivo. Our study proposes a new mechanism for infection of resting CD4(+) T cells in vivo and a new mechanism for latent infection in resting CD4(+) T cells. 23837823 Decreased prevalence of sepsis but not mild or severe P. falciparum malaria is associated with pre-existing filarial infection. Enhanced inflammatory host responses have been attributed as the cellular basis for development of severe malaria as well as sepsis. In contrast to this, filarial infections have been consistently reported to be associated with an immunological hypo-responsive phenotype. This suggests that successful control of filariasis by employing mass drug administration, could potentially contribute to an increase in incidence of sepsis and cerebral malaria in human communities. A case control study was undertaken to address this critical and urgent issue. Eighty-nine patients with sepsis and one hundred and ninety-six patients with P. falciparum malaria all originating from Odisha, were tested for prevalence of circulating filarial antigens - a quantitative marker of active filarial infection. Antibodies to four stage specific malarial recombinant proteins were measured by solid phase immunoassays and circulating CD4+CD25high T-cells were quantified by flow cytometry with an objective to study if pre-existing filarial infections influence antibody responses to malarial antigens or the levels of circulating T-regulatory cells in P. falciparum infected patients. Prevalence of filarial antigenemia was significantly less in sepsis patients as compared to controls suggesting that pre-existing filariasis could influence development of sepsis. On the other hand, levels of circulating filarial antigen were comparable in severe malaria cases and healthy controls suggesting that development of severe malaria is independent of pre-existing W. bancrofti infections. Plasma TNF-a, RANTES and antibodies to recombinant malarial proteins as well as levels of circulating CD4+ CD25high cells were comparable in malaria patients with or without filarial infections. These observations imply that successful control of filariasis could have adverse consequences on public health by increasing the incidence of sepsis, while the incidence of severe malaria may not adversely increase as a consequence of elimination of filariasis. 23579473 Plasmonic fluorescence enhancement by metal nanostructures: shaping the future of bionanotechnology. This review focuses on metal enhanced fluorescence (MEF) and its current and future applications in biotechnology. The mechanisms of MEF are discussed in terms of the additional radiative and nonradiative decay rates caused by the close proximity of the metal. We then review the current MEF materials and structures that show promise in bioapplications. The use of electromagnetic modelling to predict fluorescent rate enhancement is then considered. We then give particular focus to the recent work carried out in the homogeneous fabrication of metal nanoparticles using colloidal lithography. It is concluded that the use of computational electromagnetic modelling alongside homogeneous fabrication techniques will lead to predictable and controllable MEF, paving the way for increased applications in biotechnology. 23942524 Critical role of interleukin-5 in the development of a mite antigen-induced chronic bronchial asthma model. Asthma is associated with eosinophilic airway inflammation and characterized by enhanced airway sensitivity. Interleukin (IL)-5 plays an important role in the pathogenesis of asthma. The involvement of IL-5 receptor-mediated cellular signals in the pathogenesis of a mite antigen-induced chronic asthma model was investigated. In this study, 48 female C57BL/6J (WT) mice and IL-5 receptor-deficient (IL-5RKO) mice were used. Mite antigen (50 Î¼l) was intranasally administered 13 times to WT and IL-5RKO mice. Airway hypersensitivity (Mch PC200) and specific antigen exposure tests were performed, and lung tissue, bronchoalveolar lavage fluid (BALF), and blood were collected to investigate the asthma pathology and differences in the local pulmonary levels of cytokines and chemokines. Airway sensitivity was enhanced and antigen-specific airway resistance was increased in WT mice. In addition, the number of eosinophils and Th2 cytokine levels in the BALF were increased. In contrast, IL-5RKO mice did not acquire the asthma pathology, such as antigen-specific airway resistance and eosinophilic airway inflammation. Mch PC200 was significantly correlated with cysteinyl leukotriene levels in WT mice. These findings suggested that both IL-5 induced eosinophils and cysteinyl leukotrienes are involved in the pathology of this mite antigen-induced chronic asthma model. 23503627 Xanthohumol attenuates tumour cell-mediated breaching of the lymphendothelial barrier and prevents intravasation and metastasis. Health beneficial effects of xanthohumol have been reported, and basic research provided evidence for anti-cancer effects. Furthermore, xanthohumol was shown to inhibit the migration of endothelial cells. Therefore, this study investigated the anti-metastatic potential of xanthohumol. MCF-7 breast cancer spheroids which are placed on lymphendothelial cells (LECs) induce "circular chemorepellent-induced defects" (CCIDs) in the LEC monolayer resembling gates for intravasating tumour bulks at an early step of lymph node colonisation. NF-κB reporter-, EROD-, SELE-, 12(S)-HETE- and adhesion assays were performed to investigate the anti-metastatic properties of xanthohumol. Western blot analyses were used to elucidate the mechanisms inhibiting CCID formation. Xanthohumol inhibited the activity of CYP, SELE and NF-kB and consequently, the formation of CCIDs at low micromolar concentrations. More specifically, xanthohumol affected ICAM-1 expression and adherence of MCF-7 cells to LECs, which is a prerequisite for CCID formation. Furthermore, markers of epithelial-to-mesenchymal transition (EMT) and of cell mobility such as paxillin, MCL2 and S100A4 were suppressed by xanthohumol. Xanthohumol attenuated tumour cell-mediated defects at the lymphendothelial barrier and inhibited EMT-like effects thereby providing a mechanistic explanation for the anti-intravasative/anti-metastatic properties of xanthohumol. 23664130 Leptomeningeal metastasis of an intradural malignant peripheral nerve sheath tumor. Malignant peripheral nerve sheath tumors (MPNST) are defined as any malignant tumor arising from or differentiating towards the peripheral nerve sheath. Intradural MPNST metastases are very rare. We report, to our knowledge, the first case of leptomeningeal metastasis of a MPNST to the spine and intracranial space. A 56-year-old woman with primary intradural MPNST of the S1 nerve root developed leptomeningeal metastases as well as brain metastases 19months after diagnosis. The patient had a history of non-Hodgkins lymphoma for which she had received irradiation to the spine 15years prior to this presentation. She had no stigmata of neurofibromatosis type 1. Patients with MPNST may also develop leptomeningeal metastases as demonstrated in this patient with intradural post-radiation MPNST. 23819946 Cytometric profiling in various clinical forms of multiple sclerosis with respect to CD21+, CD32+, and CD35+ B and T cells. We aimed to evaluate the frequency of various types of B and T cells expressing CD21, CD32, and CD35 in multiple sclerosis (MS) clinical courses. Peripheral blood mononuclear cell from 30 MS patients (17 relapsing remitting [RRMS], six secondary progressive [SPMS], and seven primary progressive MS [PPMS]) and 18 healthy subjects were analyzed. All patients were in acute attack. Healthy controls were matched for age and gender ratio. The frequencies of various subsets of B and T cells were determined using flow cytometry. The frequency of CD4+T cells was lower in MS patients compared to control subjects (41.14 ± 9.45% vs. 46.88 ± 6.98%, respectively, P < 0.05). The CD32+ fraction of CD4+T cells and the CD21+ fraction of CD8+T cells were higher in MS patients (2.85 ± 3.72% vs. 1.06 ± 0.62% for CD32+CD4+T cells, 2.71 ± 1.86% vs. 1.16 ± 0.99% for CD21+CD8+T cells in MS patients and control subjects, respectively, P < 0.05). After dividing subjects by type of MS course, higher values of these two T cell subsets were found in SPMS patients compared to control subjects (P < 0.05). Further, RRMS patients had lower levels of CD32+CD4+T cells than SPMS patients and also they had lower levels of CD32+CD8+T cells than PPMS patients (P < 0.05). However, neither the expression of CD35 on T cells nor the various B cell subsets were statistically different between the compared groups. Our findings demonstrate that T cell subsets expressing CD21 and CD32 may differ with respect to the presence or clinical forms of MS disease. By contrast, CD35+T cells and different subsets of B cells are not altered in various MS clinical courses. 23398143 Predicting temperature-dependent solid vapor pressures of explosives and related compounds using a quantum mechanical continuum solvation model. Temperature-dependent vapor pressures of solid explosives and their byproducts are calculated to an accuracy of 0.32 log units using a modified form of the conductor-like screening model for real solvents (COSMO-RS). Accurate predictions for solids within COSMO-RS require correction for the free energy of fusion as well as other effects such as van der Waals interactions. Limited experimental data on explosives is available to determine these corrections, and thus we have extended the COSMO-RS model by introducing a quantitative structure-property relationship to estimate a lumped correction factor using only information from standard quantum chemistry calculations. This modification improves the COSMO-RS estimate of ambient vapor pressure by more than 1 order of magnitude for a range of nitrogen-rich explosives and their derivatives, bringing the theoretical predictions to within typical experimental error bars for vapor pressure measurements. The estimated temperature dependence of these vapor pressures also agrees well with available experimental data, which is particularly important for estimating environmental transport and gas evolution for buried explosives or environmentally contaminated locations. This technique is then used to predict vapor pressures for a number of explosives and degradation products for which experimental data is not readily available. 23665108 Homocysteine induces cerebral endothelial cell death by activating the acid sphingomyelinase ceramide pathway. Homocysteine (Hcy) levels may rise after a stroke, but the mechanism of Hcy-induced cerebral endothelial cell (CEC) dysfunction has not been explored. In this study we examined the role of the acid sphingomyelinase (Asm)-ceramide pathway in the molecular mechanism of Hcy-induced CEC dysfunction. Murine CECs were prepared from fresh mouse brains. CECs were treated with 50-500μM Hcy and 30-100μM C2-ceramide for 48h. Sphingomyelinase assays were performed to determine Asm activity. Quantitative assessments of cell survival and death by the MTT reduction and LDH release were conducted. Treatment of murine CECs with Hcy and ceramide caused cell death in a dose-dependent manner as determined by LDH and MTT assays. 250μM Hcy and 50μM C2-ceramide caused 50% cell death. Hcy induced murine CEC death also occurred in a time-dependant manner with substantial cell death noted as early as 24h after Hcy exposure. C2-ceramide-induced murine CEC death occurred earlier than Hcy-induced cell death by about 18h. Hcy treatment increased Asm activity and intracellular ceramide accumulation. This study demonstrated that Hcy and C2-ceramide can cause murine CEC death. Hcy induces CEC death possibly by activating the Asm-ceramide pathway. 23240866 Optimization of brush-like cationic copolymers for nonviral gene delivery. Polyethylenimine (PEI) is one of the most broadly used polycations for gene delivery due to its high transfection efficiency and commercial availability but materials are cytotoxic and often polydisperse. The goal of current work is to develop an alternative family of polycations based on controlled living radical polymerization (CLRP) and to optimize the polymer structure for efficient gene delivery. In this study, well-defined poly(glycidyl methacrylate)(P(GMA)) homopolymers were synthesized using reversible addition-fragmentation chain transfer (RAFT) polymerization followed by decoration using three different types of oligoamines, i.e., tetraethylenepentamine (TEPA), pentaethylenehexamine (PEHA), and tris(2-aminoethyl)amine (TREN), respectively, to generate various P(GMA-oligoamine) homopolycations. The effect of P(GMA) backbone length and structure of oligoamine on gene transfer efficiency was then determined. The optimal polymer, P(GMA-TEPA)(50), provided comparable transfection efficiency but lower cytotoxicity than PEI. P(GMA-TEPA)(50) was then used as the cationic block in diblock copolymers containing hydrophilic N-(2-hydroxypropyl) methacrylamide (HPMA) and oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA). Polyplexes of block copolymers were stable against aggregation in physiological salt condition and in Opti-MEM due to the shielding effect of P(HPMA) and P(OEGMA). However, the presence of the HPMA/OEGMA block significantly decreased the transfection efficacy of P(GMA-TEPA)(50) homopolycation. To compensate for reduced cell uptake caused by the hydrophilic shell of polyplex, the integrin-binding peptide, RGD, was conjugated to the hydrophilic chain end of P(OEGMA)(15)-b-P(GMA-TEPA)(50) copolymer by Michael-type addition reaction. At low polymer to DNA ratios, the RGD-functionalized polymer showed increased gene delivery efficiency to HeLa cells compared to analogous polymers lacking RGD. 23681252 Staff and youth views on autonomy and emancipation from residential care: a participatory research study. The use of participatory approaches in designing services is still relatively uncommon. In this study, we helped design a service to support the transition of youth from residential care to independent living by exploring the perspectives of staff and of youth regarding: (a) the concept and development of autonomy; and (b) key factors in developing this type of service. We gathered the data through 10 interviews with staff (n=10) and 4 focus groups with youth (n=21), and subjected the data to a thematic content analysis. Staff defined autonomy as self-regulation and self-care, and identified three paths to foster autonomy--a sense of normality, meaningful relationships, and planning for emancipation. The staff and youth identified the following important aspects in designing the service: achieving normality (e.g. limited number of residents), promoting youth capacity (e.g. skill-building activities), providing social support (e.g. trust and respect between residents), and assuring guidance and boundaries (e.g. supervision of youth). 23926108 Galectin-3 guides intracellular trafficking of some human serotransferrin glycoforms. Transferrin internalization via clathrin-mediated endocytosis and subsequent recycling after iron delivery has been extensively studied. Here we demonstrate a previously unrecognized parameter regulating this recycling -the binding of galectin-3 to particular glycoforms of transferrin. Two fractions of transferrin, separated by affinity chromatography based on their binding or not to galectin-3, are targeted to kinetically different endocytic pathways in HFL-1 cells expressing galectin-3 but not in SKBR3 cells lacking galectin-3; the SKBR3 cells, however can acquire the ability to target these transferrin glycoforms differently after preloading with exogenously added galectin-3. In all, this study provides the first evidence of a functional role for transferrin glycans, in intracellular trafficking after uptake. Moreover, the galectin-3 bound glycoform increased in cancer, suggesting a pathophysiological regulation. These are novel aspects of transferrin cell biology, which has previously considered only degree of iron loading, but not other forms of heterogeneity. 23685191 The fate of object memory traces under change detection and change blindness. Observers often fail to detect substantial changes in a visual scene. This so-called change blindness is often taken as evidence that visual representations are sparse and volatile. This notion rests on the assumption that the failure to detect a change implies that representations of the changing objects are lost all together. However, recent evidence suggests that under change blindness, object memory representations may be formed and stored, but not retrieved. This study investigated the fate of object memory representations when changes go unnoticed. Participants were presented with scenes consisting of real world objects, one of which changed on each trial, while recording event-related potentials (ERPs). Participants were first asked to localize where the change had occurred. In an additional recognition task, participants then discriminated old objects, either from the pre-change or the post-change scene, from entirely new objects. Neural traces of object memories were studied by comparing ERPs for old and novel objects. Participants performed poorly in the detection task and often failed to recognize objects from the scene, especially pre-change objects. However, a robust old/novel effect was observed in the ERP, even when participants were change blind and did not recognize the old object. This implicit memory trace was found both for pre-change and post-change objects. These findings suggest that object memories are stored even under change blindness. Thus, visual representations may not be as sparse and volatile as previously thought. Rather, change blindness may point to a failure to retrieve and use these representations for change detection. 23830752 Infections in outpatient surgery. In the plastic surgery patient population, outpatient surgery is cost effective and will continue to grow as the preferred arena for performing surgery in healthy patients. Although there is a widespread myth that outpatient surgery centers may suffer from increased infection rates due to lax infection control, the data presented from American Association for Accreditation of Ambulatory Surgery Facilities-accredited facilities prove the contrary. There is a lack of data investigating infection prevention in the perioperative period in plastic surgery patients. As data collection becomes more refined, tracking the postoperative care environment should offer additional opportunities to lower the incidence of postoperative infections. 23561215 Mechanisms of saccharide protection against epigallocatechin-3-gallate deterioration in aqueous solutions. We investigated the mechanisms of the protection conferred by sugars to epigallocatechin-3-gallate (EGCG) against deterioration. Additionally, we present a rapid method for evaluating the deterioration rate of EGCG using absorbance spectroscopy. We found that various sugars provided different levels of protection at identical weight percentage, and the combination of sugars and β-lactoglobulin nanocomplexes provided greater protection for EGCG than each protective component alone. We suggest that the concentration-dependent protection by sugars resulted from a combination of mechanisms, including: (1) reduced aqueous O2 solubility, (2) scavenging of reactive oxygen species, and (3) chelation of traces of transition metal ions, which is suggested to be the main reason for the differences among the sugars. The observed protective effect of sugars can be easily applied by the industry in proper selection of sugars for enrichment of syrups or concentrates with EGCG and for the preparation of enriched beverages and foods for health promotion. 23957963 Impact of the gut microbiome on mucosal inflammation. In the past 10 years it has become increasingly apparent that the gut microbiome has profound effects on the immune system to which it is juxtaposed, the mucosal immune system. Here, I explore recent studies in which the effects of the microbiota expand or facilitate anti-inflammatory or regulatory immunological machinery or which favor development of proinflammatory immunological machinery in this system. I then focus on how these opposing processes play out in inflammatory bowel disease (IBD); a disease in which normal immune homeostasis is disturbed and inflammation takes hold. 22798247 Increased expression of P450scc and CYP17 in development of endogenous hyperandrogenism in a rat model of PCOS. The objective of the present study was to characterize the effect of insulin plus hCG on the expression of steroidogenic enzymes (P450scc and CYP17) in polycystic ovaries of rats. Changes in estrous cycle, ovarian morphology, hormonal levels, and protein levels by immunohistochemistry and western-blot were determined. Rats treated with insulin plus hCG displayed abnormal estrous cycles with increasing androgen biosynthesis. Meanwhile, insulin plus hCG resulted in multiple large cysts with diminished granulosa layers and increased thecal layers and stromal-interstitial tissue. Moreover, there was an increase in the expression of P450scc and CYP17 in thecal and stromal cells in our PCOS rat model compared with control rats. These results indicate that administration of insulin with hCG can synergistically result in endogenous hyperandrogenism which may partially upregulate the expression of steroidogenic enzymes in ovarian tissue. 23816081 Mycotic aneurysm of the aortic arch presenting with left vocal cord palsy. We report a case of a 71-year-old man with a mycotic aneurysm of the aortic arch who presented with progressive hoarseness. Three weeks prior to this event the patient was admitted to an outside hospital in septic condition and was diagnosed with a mycotic abdominal aortic aneurysm. Resection of the infected abdominal aortic aneurysm with right axillofemoral and femoral-femoral bypass grafts was performed and the patient was discharged home on intravenous antibiotics. At our institution, the aortic arch aneurysm was treated with extensive debridement and replaced with a Dacron prosthesis under circulatory arrest with antegrade cerebral perfusion through the axillofemoral bypass. 23915302 Low-Cost Synthesis of Hierarchical V2O5 Microspheres as High-Performance Cathode for Lithium-Ion Batteries. Hierarchical V2O5 microspheres composed of stacked platelets are fabricated through a facile, low-cost, and energy-saving approach. The preparation procedure involves a room-temperature precipitation of precursor microspheres in aqueous solution and subsequent calcination. Because of this unique structure, V2O5 microspheres manifest a high capacity (266 mA h g(-1)), excellent rate capability (223 mA h g(-1) at a current density 2400 mA g(-1)), and good cycling stability (200 mA h g(-1) after 100 cycles) as cathode materials for lithium-ion batteries. 23852036 Intrapelvic pin migration after Salter innominate osteotomy and laparoscopic removal: a case report. Although there are many methods for the treatment of developmental dysplasia of the hip, Salter innominate osteotomy is a surgical technique presently used successfully worldwide. However, several complications can be found after Salter innominate osteotomy. Kirschner (K) wire migration into the pelvic cavity is not a common occurrence and is also rarely reported in the literature. Here, we report the case of a patient who was admitted to the emergency department of our hospital with acute abdominal pain because of K wire migration into the pelvis. We recommend bending the proximal end of the K wires or using threaded K wires to prevent this complication. 23846393 A health food high-peptide meal alleviates immunosuppression induced by hydrocortisone and cyclophosphamide in mice. This study set out to determine the immunomodulatory effects of a health food high-peptide meal in immunodeficient mice that was induced by either hydrocortisone (HY) or cyclophosphamide (CP). Five separate trials were performed in which animals were randomly divided into 5 groups of 12 mice for each experimental trial. Group 1 served as the vehicle control. Animals assigned to groups 3-5 (dose groups), were each administered once daily with 1.67, 3.33 or 6.67 g kg(-1) body weight of a high-peptide meal, respectively, for 30 consecutive days. Animals from groups 2 to 5 that were included in trials 1 to 4, each received an intramuscular administration of HY at 40 mg kg(-1) body weight on days 22, 24, 26, 28, 30. Animals from groups 2-5, in trial 5, each received an intraperitoneal administration of CP at 50 mg kg(-1) body weight, on days 26 and 27. On day 31, all groups of mice were differentially screened for immunomodulatory activity following the conclusion of the above experiments. In HY-treated mice, the high-peptide meal accelerated the recovery of the phagocytic function of both macrophages and the reticuloendothelial system, and restored NK cell activity. In CP-treated mice, the high-peptide meal promoted a humoral immune response to sheep red blood cells (SRBCs). These results demonstrated the immunomodulatory effects of a high-peptide meal. 23856782 Antiviral efficacy of favipiravir against two prominent etiological agents of hantavirus pulmonary syndrome. Hantavirus pulmonary syndrome (HPS) is caused by infection with several Sigmodontinae- and Neotominae-borne hantaviruses and has a case fatality rate of 30-50%. Humans often become infected by inhalation of materials contaminated with virus-laden rodent urine or saliva, though human-to-human transmission has also been documented for Andes virus (ANDV). The capability to transmit via aerosolization, coupled with the high mortality rates and lack of therapeutic options make the development of medical countermeasures against HPS imperative. In the present study we evaluated the efficacy of the broad-spectrum antiviral agent favipiravir (T-705) against Sin Nombre virus (SNV) and ANDV, the predominant causes of HPS in North and South America, respectively. In vitro, T-705 potently inhibited SNV and ANDV as evidenced by decreased detection of viral RNA and reduced infectious titers. For both viruses the 90% effective concentration was estimated at ≤5μg/mL (≤31.8μM). In the lethal ANDV hamster model, daily administration of oral T-705 at 50 or 100mg/kg diminished the detection of viral RNA and antigen in tissue specimens and significantly improved survival rates. Oral T-705 therapy remained protective against HPS when treatment was initiated prior to viremia onset. A disease model for SNV does not exist, however using a hamster-adapted SNV, we found that daily administration of oral T-705 significantly reduced the detection of SNV RNA and antigen in tissues specimens, suggesting the compound would also be effective against HPS in North America. Combined these results suggest T-705 treatment is beneficial for post-exposure prophylaxis against HPS-causing viruses and should be considered for probable exposures. 23821438 Homothorax plays autonomous and nonautonomous roles in proximodistal axis formation and migration of the Drosophila renal tubules. The Drosophila Malpighian tubules (MpTs) serve as a functional equivalent of the mammalian renal tubules. The MpTs are composed of two pairs of epithelial tubes that bud from the midgut-hindgut boundary during embryogenesis. The MpT primordia grow, elongate and migrate through the body cavity to assume their final position and shape. The stereotypic pattern of MpT migration is regulated by multiple intrinsic and extrinsic signals, many of which are still obscure. In this work, we implicate the TALE-class homeoprotein Homothorax (Hth) in MpT patterning. We show that in the absence of Hth the tubules fail to rearrange and migrate. Hth plays both autonomous and nonautonomous roles in this developmental process. Within the tubules Hth is required for convergent extension and for defining distal versus proximal cell identities. The difference between distal and proximal cell identities seems to be required for proper formation of the leading loop. Outside the tubules, wide-range mesodermal expression of Hth is required for directing anterior migration. The nonautonomous effects of Hth on MpT migration can be partially attributed to its effects on homeotic determination along the anterior posterior axis of the embryo and to its effects on stellate cell (SC) incorporation into the MpT. Developmental Dynamics, 2013. © 2013 Wiley Periodicals, Inc. 23943340 CHA2DS 2-VASc versus CHADS2 for stroke risk assessment in low-risk patients with atrial fibrillation: a pilot study from a single center of the NCDR-PINNACLE registry. The CHADS2 score is widely used to assess the risk of stroke in patients with atrial fibrillation (AF). Patients with score of 0 and 1 are considered 'low risk' and are often treated with aspirin. In a Danish Study, the CHA2DS2-VASc score was shown to identify low and high-risk subgroups among patients with CHADS2 score of 0 and 1, with annual risk ranging from 0.84 to 8.18 %. This study seeks to assess whether using CHA2DS2-VASc score will identify high-risk subset of patients with low CHADS2 scores in an American population. This pilot study examined data from our cardiology fellowship ambulatory clinics from January 2009 to May 2012 using the NCDR-PINNACLE registry. Each cardiology fellow entered patients' data using on-line software developed by the American College of Cardiology. Among 2,048 patients followed at our clinics, 478 had AF. Of those, 161 patients had CHADS2 score of 0 (44 patients) or 1 (117 patients). Calculating the CHA2DS2-VASc score in these patients, 12 (7.4 %) had score of 0, 50 (31.1 %) had score of 1, 66(41 %) had score of 2, 31 (19.3 %) had score of 3 and 2 (1.2 %) had score of 4. Using original CHADS2 recommendation, warfarin would not be strongly recommended in any of these patients. Utilizing the CHA2DS2-VASc score, 61.5 % of the 161 patients would have a score of 2 or more signifying increased risk where anticoagulation may be indicated. Compared to CHADS2, CHA2DS2-VASc may more precisely predict the risk of stroke and anticoagulation strategy in low-risk patients with non-valvular AF. 23603225 Hungry in hospital, well-fed in prison? A comparative analysis of food service systems. Meals served in prisons and hospitals are produced in similar ways and have similar characteristics, yet hospital patients are often at risk of being undernourished, while prisoners typically are not. This article examines field notes collected during nutritional studies of prison and hospital food service, which confirmed the difference in nutrient intake claimed by other authors. A comparison of food service processes and systems showed that the production of meals and the quality leaving the kitchen was similar in both types of institution. However, the delivery and service system was found to be much less coherent in hospital than in prison. Transport and service of hospital food were subject to delays and disruptions from a number of sources, including poor communication and the demands of medical professionals. These meant that meals reached hospital patients in a poorer, less appetising condition than those received by prisoners. The findings are discussed in the light of previous work and in terms of hospital food service practice. 23454135 Antiproliferative effect of two novel COX-2 inhibitors on human keratinocytes. Selective COX-2 inhibitors (COXib) belonging to the class of diaryl heterocycles (e.g., celecoxib, rofecoxib, etc.), are devoid of the undesirable effects due to their capacity to inhibit selectively inducible (COX-2), responsible for inflammatory effects but not constitutive cyclooxygenase-1 (COX-1)(COX); responsible for cytoprotective effects on gastric mucosa. In addition, several reports have identified an increased risk of cardiovascular events associated with the use of COXib. We have developed a new series of anti-inflammatory agents (1,5-diarylpyrrole-3-alkoxyethyl esters and ethers). To evaluate the effect of two 1,5-diarylpyrrole-3-alkoxyethyl ethers, VA441 and VA428 (up to 100μM), respectively, in comparison with two well known COXib, celecoxib and rofecoxib, on HaCaT cell (keratinocytes) proliferation and toxicity. Crucial molecules in cell cycle progression, i.e. NFκB and ERK as targets/mediators and cyclin D1 and p21 Cip1/Kip as final effectors were evaluated by Western blot, immunohystochemistry and q-PCR analysis. Both compounds, VA441 and VA428, showed a strong inhibition of cell proliferation, and did not exhibit cytotoxicity. The anti-proliferative effect was accompanied by a strong activation of ERK and induction of the cell cycle inhibitor p21. In addition, there was a clear inhibition of the transcription factor NF-κB and downregulation of cyclin D1, with enforced inhibition of the HaCaT cell cycle progression. These data suggest that compounds VA441 and VA428, along with their role in inhibiting COX-2 and inflammation, could have a possible therapeutic (topical and systemic) use against skin proliferative disorders, such as psoriasis. 23773086 Proximity of term labor deepens the fall of Doppler impedance in the fetal cerebral arteries. ABSTRACT Objective: To determine the existence of Doppler changes in the fetal vertebral, middle cerebral and umbilical arteries prior to term labor. Methods: Five hundred and twenty eight Doppler examinations of the vertebral (VA), middle cerebral (MCA) and umbilical (UA) arteries resistance indices (RI) were performed between 37 and 41 weeks gestation. For each artery, values were converted into multiples of the median (MoM) and were divided into four groups according to the interval to labor and compared using Kruskal-Wallis tests. Subsequently, values were plotted in scattergrams and linear regressions and 95% confidence intervals were calculated. Finally, using multivariate analysis and model averaging, the importance and interrelationship of Doppler measurements in the explanation of the interval to labor was evaluated. Results: Univariate and multivariate analysis confirmed that, independently of gestational age, fetuses examined close to labor presented more intense Doppler changes in the cerebral arteries with a significant reduction of the VA RI and MCA RI. This reduction was larger in the MCA. No significant changes were detected in the UA. Conclusion: Before the onset of term labor, the fetal cerebral flow presents an additional reduction of impedance, which is more intense in the MCA system. 23609209 Sensing of Micellar Microenvironment with Dual Fluorescent Probe, Triazolylpyrene ((TNDMB)Py). We report a dual fluorescent triazolylpyrene ( (TNDMB) Py) as an efficient fluorescent light-up probe of various micellar microenvironments. The absorption spectra of (TNDMB) Py in an aqueous solution of varying surfactant concentration, CTAB, SDS and TX-100 showed that as the surfactant concentration was increased the absorbance increased with no shift in wavelength maxima. The increase of absorbance in each surfactant solution with increase in surfactant concentration was due to the enhanced solubilization of (TNDMB) Py in surfactant solutions. Our investigations based on steady state and time resolved fluorescence techniques showed that the probe reports the microenvironment of ionic surfactant solutions (CTAB and SDS) via dual emission (LE and ICT) at low surfactant concentration. The ICT band showed a blue shifting pattern with enhanced intensity that disappeared as the concentration of surfactant increases (> 1 mM for CTAB and > 3 mM for SDS). In non-ionic surfactant (Triton X-100) solution, the fluorophore showed dual emission with dominant ICT behaviour over LE emission at low concentration (up to 0.35 mM). In reverse micelle we observed a blue shifted ICT band with no LE band with increasing molar concentration of water. We found 100 nm blue shifting when we moved from R = 0 to R = 7, where R is the molar ratio of water to TX-100 (R = [H2O]/[TX-100]). The blue shifting of ICT band is because of the movement of the probe from hydrophilic core to hydrophobic core (surface) of the reverse micelle. Thus from the steady-state fluorescence study it was observed that the ICT band of the probe, (TNDMB) Py was more influenced by the micellar environment in comparison to the LE band. This difference in behaviour of the fluorophore is probably because of varying extent of hydrophobic/hydrogen bonding interactions experienced by the probe and its relative disposition inside the various micellar nanocores. 23925296 Fabrication of artificial toroid nanostructures by modified β-sheet peptides. Facial peptide carrying repeating hydrophobic and hydrophilic residues as well as lysine terminals self-assemble into uniform toroid structures. The sensitive balance between the hydrophobic interactions and electrostatic repulsion dominates the formation of highly curved assemblies. 23852581 Pharmacological validation of a refined burrowing paradigm for prediction of analgesic efficacy in a rat model of sub-chronic knee joint inflammation. Burrowing is an evolutionarily conserved behaviour in rodents. This study validates a refined burrowing paradigm (requiring a reduced number of animals) in a rat model of sub-chronic knee joint inflammation and evaluates its sensitivity and specificity for analgesic drugs. Knee joint inflammation in rats was induced by intra-articular injection with complete Freund's adjuvant (CFA). Burrowing performance was assessed at baseline without study drugs, and in CFA-naive and CFA-injected animals following administration of the analgesic drugs naproxen, pregabalin and morphine, each at three doses, or corresponding vehicle (nine rats per dose group). The specificity of the model was evaluated by also testing the anxiogenic drug yohimbine, the stimulant drug dexamphetamine and the anxiolytic drug chlordiazepoxide in CFA-naive and CFA-injected animals. Percentage maximum possible effect (%MPE) was determined by relating the difference between post-CFA and baseline burrowing performance in each drug dose group to that in the vehicle group in each experiment. Burrowing performance in the vehicle groups was decreased by 39.0-59.8% in CFA-injected animals compared with CFA-naive animals. CFA-induced reductions in burrowing performance were reversed by each of the three analgesic drugs tested. The highest %MPE was 75.2% with naproxen 50 mg/kg, 80.9% with pregabalin 10 mg/kg and 77.0% with morphine 1 mg/kg (all p < 0.05 vs. control). CFA-induced reductions in burrowing performance were not reversed by yohimbine, dexamphetamine or chlordiazepoxide. This study provides pharmacological validation of a refined burrowing paradigm for analgesic efficacy that exhibits good predictive validity, with high sensitivity and specificity. 23648066 Poor reporting quality of key Randomization and Allocation Concealment details is still prevalent among published RCTs in 2011: a review. Randomized controlled trials (RCTs) are powerful tools; it is essential that these trials are not only conducted rigorously, but reported accurately. The aim of this paper was to describe the reporting quality among a set of RCTs published in 2011 on methodological details essential to judging the adequacy of allocation concealment methods employed. Medline was searched using the Ovid platform to identify all those RCTs published in January 2011 in core clinical journals. Methodological details in relation to allocation concealment were extracted from the identified RCTs to allow the reporting quality to be assessed. If the information was not available in the paper the corresponding author was contacted. Eighty-five papers were identified, 74% (n = 63) endorsed the CONSORT statement. 73% (n = 62) required the author to be contacted for further information. Sequence generation methods were ascertained in 74% of trials, allocation concealment method in 41%, details of who recruited participants and who generated the randomization sequence in 38%. There is evidence to suggest that in 2011 key methodological information relating to allocation concealment is still not reported well in RCTs. Authors and journal editors need to ensure explicit and clear methods are reported in RCTs published. 23962463 Global lessons on transforming strategy into action to save mothers' lives. Although many countries remain far from achieving the reduction in maternal mortality stipulated by Millennium Development Goal (MDG) 5, 13 are on track to achieve this goal-despite experiencing similar fiscal, workforce, and other constraints as lower-performing peers. The present article assesses existing literature and successful local examples to allow health leaders to learn from these global success stories. A key lesson is that clinical interventions are not enough. Basic care provision must be supplemented with interventions that stimulate demand for services and ensure that they are both affordable and physically accessible. At US $1-6 per woman, comprehensive programs need not exert unsustainable pressure on health budgets. But perhaps more important is how this "ecosystem" of interventions is implemented. We identify 5 principles that characterize successful implementation: embedding maternal health as a top priority; focusing on targeted effective initiatives; fostering strong local ownership; maximizing efficiency and use of available resources; and creating a tough system of national accountability. Together, they offer policymakers and health leaders principles with which to accelerate progress toward MDG 5. With so many women's lives at stake, there could hardly be a greater incentive to do so. 23927933 Prospective study of acute health effects in relation to exposure to cyanobacteria. We conducted a study to investigate the relationship between exposure to cyanobacteria and microcystins and the incidence of symptoms in humans living in close proximity to lakes affected by cyanobacteria. The design was a prospective study of residents living around three lakes (Canada), one of which has a water treatment plant supplying potable water to local residents. Participants had to keep a daily journal of symptoms and record contact (full or limited) with the water body. Samples were collected to document cyanobacteria and microcystin concentrations. Symptoms potentially associated with cyanobacteria (gastrointestinal: 2 indices (GI1: diarrhea or abdominal pain or nausea or vomiting; GI2: diarrhea or vomiting or [nausea and fever] or [abdominal cramps and fever]); upper and lower respiratory tract; eye; ear; skin; muscle pain; headaches; mouth ulcers) were examined in relation with exposure to cyanobacteria and microcystin by using Poisson regression. Only gastrointestinal symptoms were associated with recreational contact. Globally, there was a significant increase in adjusted relative risk (RR) with higher cyanobacterial cell counts for GI2 (<20,000cells/mL: RR=1.52, 95% CI=0.65-3.51; 20,000-100,000cells/mL: RR=2.71, 95% CI=1.02-7.16; >100,000cells/mL: RR=3.28, 95% CI=1.69-6.37, p-trend=0.001). In participants who received their drinking water supply from a plant whose source was contaminated by cyanobacteria, an increase in muscle pain (RR=5.16; 95% CI=2.93-9.07) and gastrointestinal (GI1: RR=3.87; 95% CI=1.62-9.21; GI2: RR=2.84; 95% CI=0.82-9.79), skin (RR=2.65; 95% CI=1.09-6.44) and ear symptoms (RR=6.10; 95% CI=2.48-15.03) was observed. The population should be made aware of the risks of gastrointestinal symptoms associated with contact (full or limited) with cyanobacteria. A risk management plan is needed for water treatment plants that draw their water from a source contaminated with cyanobacteria. 23894025 Consideration of a new definition of clinically relevant myocardial infarction after coronary revascularization an expert consensus document from the society for cardiovascular angiography and interventions (SCAI). Numerous definitions have been proposed for the diagnosis of myocardial infarction (MI) after coronary revascularization. The Universal Definition for MI designates post procedural biomarker thresholds for defining percutaneous coronary intervention (PCI)-related MI (type 4a) and coronary artery bypass grafting (CABG)-related MI (type 5) which are of uncertain prognostic importance. In addition, for both MI types cTn is recommended as the biomarker of choice, the prognostic significance of which is less well validated than CK-MB. Widespread adoption of a MI definition not clearly linked to subsequent adverse events such as mortality or heart failure may have serious consequences for the appropriate assessment of devices and therapies, may affect clinical care pathways, and may result in misinterpretation of physician competence. Rather than employing an MI definition sensitive for small degrees of myonecrosis (the occurrence of which, based on contemporary large-scale studies, are unlikely to have important clinical consequences), it is instead recommended that a threshold level of biomarker elevation which has been strongly linked to subsequent adverse events in clinical studies be used to define a "clinically relevant MI". The present document introduces a new definition for "clinically relevant MI" after coronary revascularization (PCI or CABG) which is applicable for use in clinical trials, patient care, and quality outcomes assessment. © 2013 Wiley Periodicals, Inc. 23609771 Region-specific regulation of 5-HT1B receptors in the rat brain by chronic venlafaxine treatment. RATIONALE: Venlafaxine is a non-selective serotonin and noradrenaline reuptake inhibitor antidepressant drug for which clinical studies have suggested a high level efficacy and a possible early action onset compared to the classical antidepressants. Its therapeutic effects might be due, at least in part, to adaptive changes in serotonergic neurotransmission, through the activation of the different 5-HT receptor subtypes. 5-HT1B receptors are located in the axon terminals of both serotonergic and non-serotonergic neurons, where they act as inhibitory autoreceptors or heteroreceptors, respectively. However, the information about the involvement of this subtype in the mechanism of action of antidepressants is limited and quite controversial. OBJECTIVES: The aim of this study was to evaluate the effect of venlafaxine (10 mg kg(-1) day(-1), p.o.) after 21 days of treatment on the density of 5-HT1B receptors and their functionality in rat brain. METHODS: Effects of chronic venlafaxine were evaluated at different levels of 5-HT1B receptor by using receptor autoradiography, [(35)S]GTPγS binding, and the regulation of body temperature induced by selective 5-HT1B agonist. RESULTS: Our results show that venlafaxine induced an increase in sensitivity of 5-HT1B receptors in hypothalamus both at G-protein level and the control of core temperature without affecting the receptor density. CONCLUSIONS: These results demonstrate that adaptive changes on 5-HT1B receptors induced by chronic administration of venlafaxine exhibit regional differences suggesting that the hypothalamus might be an important site of drug action. 23841534 Increasing the dynamic range of metal ion affinity changes in zn(2+) photocages using multiple nitrobenzyl groups. Two generations of DiCast photocages that exhibit light-induced decreases in metal ion affinity have been prepared and characterized. Expansion of the common Zn(2+) chelator of N,N-dipicolylaniline (DPA) to include additional aniline ligand provides N,N'-diphenyl-N,N'-bis(pyridin-2-ylmethyl)ethane-1,2-diamine, a tetradentate ligand that was functionalized with two photolabile groups to afford DiCast-1. Uncaging of the nitrobenzhydrol reduces the electron density on two metal-bound aniline ligands, which decreases the Zn(2+) affinity 190-fold. The analogous MonoCast photocage with a single nitrobenzhydrol group only undergoes a 14-fold reduction in affinity after an identical photochemical transformation. A second series of DiCast photocages based on a N,N'-(pyridine-2,6-diylbis(methylene))dianiline scaffold, which allows the introduction of two additional Zn(2+)-binding ligands into a preorganized chelator, expand on the multi-photolabile group strategy. DiCast-2 includes two pyridine ligands while DiCast-3 adds two carboxylate groups. Addition of bridging pyridine to the second generation photocages leads to more stable Zn(2+) complexes, and photolysis of two photolabile groups increases the Zn(2+) affinity changes to 480-fold. The Zn(2+), Cu(2+), and Cd(2+) binding properties were examined in all the DiCast photocages and the corresponding photoproducts using UV-vis spectroscopy. Further insight into the photocage Zn(2+)-binding motifs was obtained by X-ray analysis of DiCast-2 and DiCast-3 model ligands. 23915250 Feasibility and impact of an evidence-based electronic decision support system for diabetes care in family medicine: protocol for a cluster randomized controlled trial. In Belgium, the construction of the national electronic point-of-care information service, EBMPracticeNet, was initiated in 2011 to optimize quality of care by promoting evidence-based decision-making. The collaboration of the government, healthcare providers, Evidence-Based Medicine (EBM) partners, and vendors of Electronic Health Records (EHR) is unique to this project. All Belgian healthcare professionals get free access to an up-to-date database of validated Belgian and nearly 1,000 international guidelines, incorporated in a portal that also provides EBM information from sources other than guidelines, including computerized clinical decision support that is integrated in the EHRs.The EBMeDS system is the electronic evidence-based decision support system of EBMPracticeNet. The EBMeDS system covers all clinical areas of diseases and could play a crucial role in response to the emerging challenge posed by chronic conditions. Diabetes was chosen as the analysis topic of interest. The objective of this study is to assess the effectiveness of EBMeDS use in improving diabetes care. This objective will be enhanced by a formal process evaluation to provide crucial information on the feasibility of using the system in daily Belgian family medicine. The study is a cluster-randomized trial with before/after measurements conducted in Belgian family medicine. Physicians' practices will be randomly assigned to the intervention or control group in a 1:1 ratio, to receive either the EBMeDS reminders or to follow the usual care process. Randomization will be performed by a statistical consultant with an electronic random list generator, anonymously for the researchers. The follow-up period of the study will be 12 months with interim analysis points at 3, 6 and 9 months. Primary outcome is the one-year pre- to post-implementation change in HbA1c. Patients will not be informed about the intervention. Data analysts will be kept blinded to the allocation. The knowledge obtained in this study will be useful for further integration in other Belgian software packages. Users' perceptions and process evaluation will provide information for improving the feasibility of the system.Trial registration: The trial is registered with the ClinicalTrials.gov registry: NCT01830569. 23915136 Thyroid Hormone Analogues - Where do we stand in 2013? Thyroid hormones (TH) are important in development and maintenance of lipid and energy homeostasis. THs act through two closely related TH receptors (TRs α and β), which are conditional transcription factors. Recently TH analogues or thyromimetics with varying degrees of TR subtype and liver uptake selectivity have been developed. These compounds exert beneficial effects of TH excess states without many undesirable TR-dependent side effects. Several selective TR modulators (STRMs) showed exceptionally promising results in lowering serum cholesterol in preclinical animal models and human clinical studies. Moreover, some first generation STRMs elicit other potentially beneficial effects on obesity, glucose metabolism and non-alcoholic fatty liver disease (NAFLD). While it was initially thought that STRMs would be an effective long-term therapy to combat elevated cholesterol, possibly in conjunction with another cholesterol-lowering therapy, the statins, three major first generation STRMs failed to progress beyond early phase 3 human trials. The aim of this review is to discuss how STRMs work, their actions in preclinical animal models and human clinical trials, why they did not progress beyond clinical trials as cholesterol-lowering therapeutics, whether selective TR modulation continues to hold promise for dyslipidemias and whether members of this drug class could be applied to the treatment of other aspects of metabolic syndrome and human genetic disease. 23659306 Comparative host-parasite population genetic structures: obligate fly ectoparasites on Galapagos seabirds. Parasites often have shorter generation times and, in some cases, faster mutation rates than their hosts, which can lead to greater population differentiation in the parasite relative to the host. Here we present a population genetic study of two ectoparasitic flies, Olfersia spinifera and Olfersia aenescens compared with their respective bird hosts, great frigatebirds (Fregata minor) and Nazca boobies (Sula granti). Olfersia spinifera is the vector of a haemosporidian parasite, Haemoproteus iwa, which infects frigatebirds throughout their range. Interestingly, there is no genetic differentiation in the haemosporidian parasite across this range despite strong genetic differentiation between Galapagos frigatebirds and their non-Galapagos conspecifics. It is possible that the broad distribution of this one H. iwa lineage could be facilitated by movement of infected O. spinifera. Therefore, we predicted more gene flow in both fly species compared with the bird hosts. Mitochondrial DNA sequence data from three genes per species indicated that despite marked differences in the genetic structure of the bird hosts, gene flow was very high in both fly species. A likely explanation involves non-breeding movements of hosts, including movement of juveniles, and movement by adult birds whose breeding attempt has failed, although we cannot rule out the possibility that closely related host species may be involved. 23395263 The development of an activity pacing questionnaire for chronic pain and/or fatigue: a Delphi technique. Activity pacing is frequently advised as a coping strategy for the management of chronic conditions (such as chronic low back pain, chronic widespread pain and chronic fatigue syndrome/myalgic encephalomyelitis). Despite anecdotal support for activity pacing, there is limited and conflicting research evidence into the efficacy of this strategy. There is no consensus on the interpretation of 'pacing' due to diverse descriptions, including strategies that encourage both increasing and decreasing activities. Furthermore, at present, there are few validated scales to measure how patients pace their activities. The aim of this study was to undertake the first stage in the development of a comprehensive tool that assesses the multi-faceted nature of pacing among patients with chronic conditions. Three-round Delphi technique. Expert panel based in the UK including patients and clinicians. The 42 participants who completed three rounds of Delphi included 4 patients, 3 nurses, 26 physiotherapists and 9 occupational therapists. The 38 questions that reached consensus to be included in the questionnaire encompassed a number of different facets of pacing, for example, breaking down tasks, not over-doing activities, and gradually increasing activities. To our knowledge, this is the first study that has engaged both patients and clinicians in a Delphi technique to develop an activity pacing questionnaire. In contrast to existing pacing scales, our questionnaire appears to contain a number of distinct facets of pacing. Further study is being undertaken to engage patients in the exploration of the validity, reliability and acceptability of the questionnaire. 23467004 Molecular markers from three organellar genomes unravel complex taxonomic relationships within the coralline algal genus Chiharaea (Corallinales, Rhodophyta). The use of molecular markers in taxonomic studies has become a standard practice in biology. However, consensus on which markers to use at the species level is lacking because evolutionary lineages show differences in divergence rates between organellar genomes. Ideally, researchers use multiple lines of evidence when first describing a species, such as the incorporation of several molecular markers from varied genomes (mitochondrion, plastid and nucleus). This study examined species boundaries in the red algal genus Chiharaea. We used five molecular markers, with at least one marker from each genome, coupled with thorough morphological analyses. We recognized three species in Chiharaea (C.americana, C. rhododactyla sp. nov., C. silvae) and two forms (C. americana f. americana and C. americana f. bodegensis (H.W. Johansen) stat. nov.). For C. americana f. americana and C. americana f. bodegensis differentiation based on morphological data was reflected in the plastid-encoded large subunit of RuBisCO (rbcL), but was not concordant with either the mitochondrial cytochrome c oxidase subunit 1 (COI-5P) or nuclear internal transcribed spacer (ITS) sequence data. We suggest that this discordance is indicative of ongoing hybridization and introgression between populations of C. americana f. americana and C. americana f. bodegensis. In addition, we used a PCR assay with ITS specific primers to amplify multiple ITS variants for collections assignable to C. americana indicating that there is genetic variability within ITS copies most likely due to introgression, crossing over and/or the retention of ancestral variants. 23743342 The Aesthetic Aha: On the pleasure of having insights into Gestalt. Are challenging stimuli appreciated due to perceptual insights during elaboration? Drawing on the literature regarding aesthetic appreciation, several approaches can be identified. For instance, fluency of processing as well as perceptual challenge are supposed to increase appreciation: One group (Reber, Schwarz, & Winkielman, 2004) claims that fluency of processing increases appreciation. Others link aesthetics to engagement: Creation and manipulation of sense itself should be rewarding (Ramachandran & Hirstein, 1999). We experimentally tested the influence of insights during elaboration on liking. Pairs of stimuli - hardly detectable two-tone images including a face (Mooney face) and meaningless stimuli matched for complexity - were presented repeatedly. Having an insight as well as the intensity of the insight predicted subsequent gains in liking. This paper qualifies the role of insight (-aha!) on aesthetic appreciation through the effects of elaboration and problem-solving on understanding the processing of modern art. 23747563 Determining the contributions of caspase-2, caspase-8 and effector caspases to intracellular VDVADase activities during apoptosis initiation and execution. Apoptosis signaling crucially depends on caspase activities. Caspase-2 shares features of both initiator and effector caspases. Opinions are divided on whether caspase-2 activity is established during apoptosis initiation or execution in response to DNA damage, death receptor stimulation, or heat shock. So far, approaches towards measuring caspase-2 activity were restricted to analyses in cell homogenates and extracts, yielded inconsistent results, and were often limited in sensitivity, thereby contributing to controversies surrounding the role of caspase-2 during apoptosis. Furthermore, caspases overlap in substrate specificities, and caspase-8 as well as effector caspases may cleave the optimal VDVAD recognition motif as well. We therefore generated a highly sensitive Förster resonance energy transfer (FRET) substrate to determine the relative contribution of these caspases to VDVADase activity non-invasively inside living cells. We observed limited proteolysis of the substrate during apoptosis initiation in response to death receptor stimulation by FasL, TNFα and TRAIL. However, this activity was attributable to caspase-8 rather than caspase-2. Likewise, no caspase-2-specific activity was detected during apoptosis initiation in response to genotoxic stress (cisplatin, 5-FU), microtubule destabilization (vincristine), or heat shock. The contribution of caspase-2 to proteolytic activities during apoptosis execution was insignificant. Since even residual, ectopically introduced caspase-2 activity could readily be detected inside living cells in our measurements, we conclude, in contrast to several previous studies, that caspase-2 activity does not contribute to apoptosis in the scenarios investigated, and that instead caspase-8 and effector caspases are the most significant VDVADases during canonical apoptosis signaling. 23880199 Inhibition of monocyte chemotaxis by VB-201, a small molecule lecinoxoid, hinders atherosclerosis development in ApoE(-/-) mice. Monocytes are motile cells which sense inflammatory stimuli and subsequently migrate to sites of inflammation. Key players in host defense, monocytes have nevertheless been implicated as requisite mediators of several chronic inflammatory diseases. Inhibition of monocyte chemotaxis is therefore an attractive anti-inflammatory strategy. Oxidized phospholipids (OxPL) are native regulators of inflammation, yet their direct effect on monocyte chemotaxis is poorly defined. In this study, we investigated the direct effect of natural and synthetic phospholipids on monocyte chemotaxis. Exploring various phospholipids using in vitro chemotaxis assays, we found that the natural phospholipid 1-palmitoyl-2-glutaryl phosphatidylcholine (PGPC) can decrease monocyte chemotaxis by 50%, while other tested OxPL had no effect. We generated a library of synthetic OxPL designated lecinoxoids, which was screened for anti-inflammatory properties. VB-201, a small-molecule lecinoxoid, exhibited up to 90% inhibition of monocyte chemotaxis in vitro. Molecular analysis revealed that the effect of VB-201 was not restricted to a specific chemotactic ligand or receptor, and resulted from inhibition of signaling pathways required for monocyte chemotaxis. Interestingly, VB-201 did not inhibit monocyte adhesion or phagocytosis and had no effect on chemotaxis of CD4(+) T-cells or neutrophils. In vivo, oral treatment with VB-201 reduced monocyte migration in a peritonitis model and inhibited atheroma development in ApoE(-/-) mice, without affecting cholesterol or triglyceride levels. Our findings highlight a novel role played by native and synthetic phospholipids in regulation of monocyte chemotaxis. The data strengthen the involvement of phospholipids as key signaling molecules in inflammatory settings and demonstrate their potential therapeutic applicability. 23075165 Substrate effect on the plasmonic sensing ability of hollow nanoparticles of different shapes. Gold hollow nanospheres (AuHSs) and gold hollow nanocubes (AuHCs) were synthesized by the galvanic replacement technique using silver nano templates. Colloidal AuHSs are found to have a higher sensitivity factor than that of AuHCs. This value decreases for both shapes when the nanoparticles are assembled on a quartz substrate by using the Langmuir-Blodgett technique. AuHSs are observed to have the larger effect. It is observed that as the separation gap between AuHCs nanoparticles decreases, their localized surface plasmon resonance band red shifts more than AuHSs. This is accounted for by the discrete dipole approximation (DDA) calculations. The coupling between the plasmon fields of the AuHCs pair is stronger than that between AuHSs pair. Using the DDA calculation, this is found to be due to geometric factors, as well as to the difference in the plasmonic field intensity. The calculation also showed that the plasmon field distributions of both AuHCs and AuHSs were distorted by the quartz substrate in a different manner. It is also observed that the surface-enhanced Raman spectrum of thiophenol is stronger when measured on AuHCs than on AuHSs. This is due to the difference in the plasmon field distribution as well as the fact that the AuHCs have a higher scattering/absorption yield ratio. 23958856 Ejection of a rear facing, golf cart passenger. The following report details the findings of a series of experiments and simulations performed on a commercially available, shuttle style golf cart during several maneuvers involving rapid accelerations of the vehicle. It is determined that the current set of passive restraints on these types of golf carts are not adequate in preventing ejection of a rear facing passenger during rapid accelerations in the forward and lateral directions. Experimental data and simulations show that a hip restraint must be a minimum of 13in. above the seat in order to secure a rear facing passenger during sharp turns, compared to the current restraint height of 5in. Furthermore, it is determined that a restraint directly in front of the rear facing passenger is necessary to prevent ejection. In addressing these issues, golf cart manufacturers could greatly reduce the likelihood of injury due to ejection of a rear facing, golf cart passenger. 23576103 The -590C/T polymorphism in the IL-4 gene and the risk of cancer: a meta-analysis. Interleukin-4 (IL-4) plays an important role in the pathogenesis of cancer. The -590C/T polymorphism in the IL-4 gene has been implicated in susceptibility to cancer, but the results have been inconclusive. The aim of this study was to analyze the association between this polymorphism with the risk of cancer by meta-analysis. PubMed, Embase, CNKI, and Wanfang databases were searched for all publications concerning the association between this polymorphism and cancer risk. Statistical analyses were analyzed by using RevMan 4.2 and STATA10.0 softwares. A total of 8,715 cases and 9,532 controls in 23 case-control studies were included. The results suggested that there was no significant association between IL-4 -590C/T polymorphism and cancer risks (TT + TC vs. CC: OR = 0.97, 95 % CI = 0.90-1.04, P = 0.36). In the subgroup analysis by ethnicity, no significant association was detected in Asians and Caucasians. In the subgroup analysis by cancer types, no significant association was found in gastric cancer and colorectal cancer. The current meta-analysis suggested that the -590C/T polymorphism in the IL-4 gene might not be associated with increased/decreased risk of cancer. The -590C/T polymorphism might be not a risk factor for cancers. 23919569 Environmental monitoring using next generation sequencing: rapid identification of macroinvertebrate bioindicator species. Invertebrate communities are central to many environmental monitoring programs. In freshwater ecosystems, aquatic macroinvertebrates are collected, identified and then used to infer ecosystem condition. Yet the key step of species identification is often not taken, as it requires a high level of taxonomic expertise, which is lacking in most organizations, or species cannot be identified as they are morphologically cryptic or represent little known groups. Identifying species using DNA sequences can overcome many of these issues; with the power of next generation sequencing (NGS), using DNA sequences for routine monitoring becomes feasible. In this study, we test if NGS can be used to identify species from field-collected samples in an important bioindicator group, the Chironomidae. We show that Cytochrome oxidase I (COI) and Cytochrome B (CytB) sequences provide accurate DNA barcodes for chironomid species. We then develop a NGS analysis pipeline to identifying species using megablast searches of high quality sequences generated using 454 pyrosequencing against comprehensive reference libraries of Sanger-sequenced voucher specimens. We find that 454 generated COI sequences successfully identified up to 96% of species in samples, but this increased up to 99% when combined with CytB sequences. Accurate identification depends on having at least five sequences for a species; below this level species not expected in samples were detected. Incorrect incorporation of some multiplex identifiers (MID's) used to tag samples was a likely cause, and most errors could be detected when using MID tags on forward and reverse primers. We also found a strong quantitative relationship between the number of 454 sequences and individuals showing that it may be possible to estimate the abundance of species from 454 pyrosequencing data. Next generation sequencing using two genes was successful for identifying chironomid species. However, when detecting species from 454 pyrosequencing data sets it was critical to include known individuals for quality control and to establish thresholds for detecting species. The NGS approach developed here can lead to routine species-level diagnostic monitoring of aquatic ecosystems. 23583188 Effects of an extremely low-frequency electromagnetic field on stress factors: a study in Dictyostelium discoideum cells. The development of technologies that generate environmental electromagnetic fields (EMFs) has led public opinion and the scientific community to debate upon the existence of possible effects caused by man-made EMFs on the human population and, more generally, on terrestrial ecosystems. Protozoa are known to be excellent bioassay systems in bioelectromagnetic studies because of their features that combine the reliability of in vivo results with the practicality of in vitro ones. For this reason, we examined the possible stressful effects of a 50-Hz, 300-μT extremely low-frequency electromagnetic field (ELF-EMF) on the protozoan Dictyostelium discoideum, which was used as it is included in the eight bioassay alternatives to vertebrate models for the study of human disease by the U.S. National Institutes of Health. Our results show how a 24-h exposure of D. discoideum cells to ELF-EMF can affect the net fission rate, the activity and presence of the pseudocholinesterase as well as the presence of the heat shock protein-70, while no change in the catalase and glutathione peroxidase activities was observed. However, this effect seems to be transient and all the altered parameters returned to their respective control value after a 24-h stay under dummy exposure conditions. 23865422 Bithiazole Correctors Rescue CFTR Mutants by Two Different Mechanisms. Better correctors are needed to repair cystic fibrosis transmembrane conductance regulator (CFTR) processing mutants that cause cystic fibrosis. Determining where the correctors bind to CFTR would aid in the development of new correctors. A recent study reported that the second nucleotide-binding domain (NBD2) was involved in binding of bithiazole correctors. Here, we show that bithiazole correctors could also rescue CFTR mutants that lacked NBD2. These results suggest that bithiazoles rescue CFTR mutants by two different mechanisms. 23576100 Neuroradiological advances detect abnormal neuroanatomy underlying neuropsychological impairments: the power of PET imaging. Medical imaging has made a major contribution to cerebral dysfunction due to inherited diseases, as well as injuries sustained with modern living, such as car accidents, falling down, and work-related injuries. These injuries, up until the introduction of sensitive techniques such as positron emission tomography (PET), were overlooked because of heavy reliance on structural imaging techniques such as MRI and CT. These techniques are extremely insensitive for dysfunction caused by such underlying disorders. We believe that the use of these highly powerful functional neuroimaging technologies, such as PET, has substantially improved our ability to assess these patients properly in the clinical setting, to determine their natural course, and to assess the efficacy of various interventional detections. As such the contribution from the evolution of PET technology has substantially improved our knowledge and ability over the past 3 decades to help patients who are the victims of serious deficiencies due to these injuries. In particular, in recent years the use of PET/CT and soon PET/MRI will provide the best option for a structure-function relationship in these patients. We are of the belief that the clinical effectiveness of PET in managing these patients can be translated to the use of this important approach in bringing justice to the victims of many patients who are otherwise uncompensated for disorders that they have suffered without any justification. Therefore, legally opposing views about the relevance of PET in the court system by some research groups may not be justifiable. This has proven to be the case in many court cases, where such imaging techniques have been employed either for criminal or financial compensation purposes in the past 2 decades. 23444081 Structure and function of mycobacterium glycopeptidolipids from comparative genomics perspective. Glycopeptidolipids (GPLs) attached to the outer surface of the greasy cell envelope, are a class of important glycolipids synthesized by several non-tuberculosis mycobacteria. The deletion or structure change of GPLs confers several phenotypical changes including colony morphology, hydrophobicity, aggregation, sliding motility, and biofilm formation. In addition, GPLs, particular serovar specific GPLs, are important immunomodulators. This review aims to summarize the advance on the structure, function and biosynthesis of mycobacterium GPLs. 23725356 Eph receptor B4 is a regulator of estrogen receptor alpha in breast cancer cells. Abstract Background: Estrogen receptor alpha (ER-α) plays an important role in breast cancer initiation and progression and represents a major target in cancer therapy. The expression and activity of ER-α is regulated by multiple mechanisms at the transcriptional and post-translational level. Interaction of tyrosine kinase receptor-activated signaling pathways with ER-α function has been reported. We previously performed a kinome-wide small interfering RNA high-throughput screen to identify novel protein kinases involved in the regulation of ER-α transcriptional activity in human breast cancer cells. Our screening analysis identified the Eph receptor tyrosine kinases (Eph) as potential positive regulators of ER-α. Results: In this study, we demonstrate Eph receptor B4 (EphB4), a member of Eph kinase family, a positive regulator of ER-α in human breast cancer cell lines (MCF-7, T-47D and BT-474). Down-regulation of EphB4 by RNA interference technology impairs estrogen-dependent ER-α transcriptional activity in breast cancer cells. Decreased activity of ER-α after EphB4 knockdown is the consequence of diminished ER-α messenger RNA and protein expression. Furthermore, phosphorylation of Akt, a downstream mediator of EphB4, is reduced following EphB4 silencing. Conclusions: Our data suggests EphB4 as an upstream regulator of ER-α in human breast cancer cells by modulating ER-α transcription. The results also suggest Akt as a relevant downstream signaling molecule in this novel EphB4-ER-α pathway. 23768737 Inhaled corticosteroid use and risks of lung cancer and laryngeal cancer. Chronic inflammation has been implicated in the pathogenesis of several cancers, including lung and laryngeal cancer. The objective of the study is to elucidate the association between ICS use and diagnosis of lung and laryngeal cancer. A nested case-control study based on the Korean national claims database included new adult users of inhaled medications between January 1, 2007, and December 31, 2010. Patients diagnosed with lung cancer or laryngeal cancer after enrollment were identified as cases and up to five control individuals matched for age, sex, diagnosis of asthma or COPD, Charlson Comorbidity Index scores, number of health care visits, and initiation date were selected. From the 792,687 eligible cohort, 9177 individuals diagnosed with lung cancer were matched with 37,048 controls. Additionally, 408 laryngeal cancer patients and 1651 controls were matched. ICS use was associated with a decreased rate of lung cancer diagnosis [adjusted odds ratio (aOR), 0.79; 95% confidence interval (CI), 0.69-0.90]. The inverse association between ICS use and lung cancer risk was dose dependent (P < 0.0001 for the trend). However, no reduction in the risk of laryngeal cancer among ICS users was identified (aOR, 1.06; 95% CI, 0.62-1.18). The use of ICS is associated with a reduced risk of lung cancer but not of laryngeal cancer. 23100494 Endotoxin levels in homes and classrooms of Dutch school children and respiratory health. Several studies describe indoor pollutant exposure in homes and to a lesser extent in schools. Population studies that include both environments are sparse. This study aims to assess endotoxin levels in primary schools and homes of children. Endotoxin was also studied in relation to asthma and sensitisation. 10 schools with (index) and without (reference) dampness were selected, based on reports and inspections. Cases and controls were selected from 169 homes based on the presence or absence of asthma-like symptoms of children. Classroom and bedroom airborne settled dust was sampled using electrostatic dust fall collectors. Average endotoxin levels in schools ranged from 2178 to 6914 endotoxin units (EU)·m(-2) per week compared with 462-1285 EU·m(-2) per week in homes. After mutual adjustment for home and school endotoxin, school endotoxin was positively associated with nonatopic asthma (OR 1.11, 95% CI 0.97-1.27), while no associations with endotoxin were found at home. The high endotoxin levels in schools compared with homes indicate that exposure at school can contribute considerably to environmental endotoxin exposure of children and teachers. Our results also suggest that endotoxin in schools may be associated with nonatopic asthmatic symptoms in pupils, although the results require reproduction because of the modest sample size. 23499662 The bizarre pharmacology of the ATP release channel pannexin1. Pannexins were originally thought to represent a second and redundant family of gap junction proteins in addition to the well characterized connexins. However, it is now evident that pannexins function as unapposed membrane channels and the major role of Panx1 is that of an ATP release channel. Despite the contrasting functional roles, connexins, innexins and pannexins share pharmacological properties. Most gap junction blockers also attenuate the function of Panx1, including carbenoxolone, mefloquine and flufenamic acid. However, in contrast to connexin based gap junction channels, Panx1 channel activity can be attenuated by several groups of drugs hitherto considered very specific for other proteins. The drugs affecting Panx1 channels include several transport inhibitors, chloride channel blockers, mitochondrial inhibitors, P2X7 receptor ligands, inflammasome inhibitors and malaria drugs. These observations indicate that Panx1 may play an extended role in a wider spectrum of physiological functions. Alternatively, Panx1 may share structural domains with other proteins, not readily revealed by sequence alignments. This article is part of a Special Issue entitled 'Connexin based channels' 23910467 Epidemiology of oral-cavity and oropharyngeal carcinomas: controlling a tobacco epidemic while a human papillomavirus epidemic emerges. Although tobacco prevalence is declining in most developed countries, less developed countries are still experiencing an increase in tobacco use. Thus the future burden of oral-cavity and oropharyngeal cancers in less developed countries is expected to be heavy. The incidence of human papillomavirus (HPV)-associated oropharyngeal cancer is dramatically increasing in the United States and other developed countries, although trends in less developed countries are not clear at present. HPV vaccine compliance in the United States is low, although it continues to increase each year. Increasing the HPV vaccination rate to control future HPV-associated cancer incidence remains a priority. 23780969 Effects of interactions between intestinal microbiota and intestinal macrophages on health. Macrophages reside in every tissue of the body and play an important role in maintaining homeostasis. The intestinal mucosa is the largest immune organ and harbors macrophages in abundance. Dysfunction of intestinal macrophages is characteristic of patients with certain inflammatory bowel diseases. Although intestinal macrophages exhibit hyporesponsiveness to foreign substances, including various bacterial products, their physiological functions are unknown, but may be related to the contribution of intestinal bacteria to the maintenance of various physiological functions of the host. Moreover, recent reports suggest that there are associations between intestinal microbiota and the onset of pathologies, such as diverse metabolic syndromes, depression, and cancer. Evidence indicates that the host's immune response to intestinal microbiota may be etiologically-linked to these diseases; however, the mechanisms are poorly understood. In the present review, we discuss the possibility that intestinal microbiota influence health through the function of intestinal macrophages. 23909906 Saffron (Crocus sativus L.) Powder as an Ingredient of Rye Bread: An Anti-Diabetic Evaluation. Abstract In this study, a most consumer-acceptable rye bread (RB) containing saffron (S) powder (RB+S) was designed to verify its anti-diabetic properties, and to compare these effects with those of RB and S separately, matched to a similar dose of bioactive components, used in the high-fat (HF) diet in streptozotocin (STZ)-induced Wistar rats. After baking, beneficial antioxidant and sensory properties for RB enriched with 0.12% S were achieved. Twenty-four severely diabetic rats (fasting blood glucose (FBG) ≥350 mg·dL(-1)) were randomized to incorporate either 0.08% of pure S, or RB enriched with 0.12% S (the diet provided 0.08% of S), or RB alone into their diet for 5 weeks. As controls, nontreated, HF-feeding STZ-induced rats (positive control-HF/STZ) and rats receiving normal laboratory diet (negative control-C) were used. A significant FBG-lowering effect was observed (47%, 53%, and 54% reduction vs. HF/STZ; P<.05) after S, RB, and RB+S treatment. Improvements in the rats' glycemia were achieved by β-cell regeneration and increases in insulin secretion. Only in the S and RB+S group of rats, a significant (P<.05) increase in relative pancreas (vs. HF/STZ) was noted. A significant (P<.05) reduction in the concentration of thiobarbituric acid-reactive substances (TBARS) was achieved, whereas the ferric-reducing ability of plasma (FRAP) was not changed after S, RB and RB+S treatment (vs. HF/STZ). Triglyceride (TG) concentrations after S, RB, and RB+S treatment were significantly decreased (P<.05) versus HF/STZ. Both S and RB can be used in diabetic therapy, but no additional metabolic effect was achieved after consumption of RB+S. 22851671 Serial high-sensitivity troponin measurements for the rapid exclusion of acute myocardial infarction in low-risk patients. High-sensitivity troponin assays facilitate the rapid exclusion of acute myocardial infarction (AMI). However, elevated results are also seen in other conditions causing myocardial injury. Serial measurements increase the specificity for AMI, helping to rapidly identify patients for whom revascularisation may be appropriate. In this study, we explore a strategy for rapidly excluding AMI in symptomatic patients using serial high-sensitivity troponin measurements. Main findings: (1) all patients presenting more than 3 h after symptom onset with a negative result had a second negative result; (2) AMI was excluded in all patients with two results falling below the lower limit of detection of a standard troponin assay by 8 h post-symptom onset. 23524100 The force of the spontaneously contracting zebrafish heart, in the assessment of cardiovascular toxicity: Application on adriamycin. The heart of the zebrafish has been used extensively to assess the cardiotoxic effect of compounds, using the frequency of heart contractions as the main index of cardiac response to drugs. In this study, the force and the frequency generated by the spontaneously contracting zebrafish heart, isolated in saline, were found to be 0.87±0.05mN and 1.54±0.03Hz (n=6) respectively within the first hour of recording. Both values of force and frequency remained constant for over 8h. The advantage of prolonged vitality in the assessment of cardiovascular toxicity was shown using the well-known anticancer drug adriamycin, which has severe cardiotoxic side effects. At 10.0μM there was a 21.05±4.42% (p=0.02, n=4) decrease in the force of contraction, while the frequency was not affected after 3h treatment (p>0.05). At 50.0 and 100.0μM there was a 33.24±3.0 and 46.6±4.80% irreversible decrease in force (p<0.05, n=4), while a 18.02±4.07% and 16.16±4.07% reversible increase was observed in the frequency (p=0.02, n=4). These contradictory positive chronotropic and negative inotropic responses indicate the strong inhibitory effect of adriamycin on ventricular cardiomyocytes and its excitatory effects on auto-rhythmical pacemaker cells. If heart frequency was the only parameter used to assess the cardiotoxic effect of adriamycin, at the above range of concentrations, this compound would have been classified as non-cardiotoxic. 23850449 Can IGF-I polymorphism affect power and endurance athletic performance? Insulin-like growth factor-I (IGF-I) plays a key role in exercise-associated muscle growth and development. The regulatory region of the promoter of the IGF-I gene is labile, but changes in this region were studied mostly in the elderly and in relation to pathological states. C-1245T (rs35767) is a genetic variation in the promoter region of the IGF-I gene. The minor allele T was found to be associated with higher circulating IGF-I levels, and possibly with increased muscle mass. The aim of the current study was to analyze the frequency distribution of C-1245T SNP in athletic and nonathletic Israeli populations. One hundred and sixty-five athletes (78 endurance-type athletes, and 87 power-type athletes) and 159 nonathletic healthy individuals participated in the current study. Genomic DNA was extracted from peripheral EDTA treated anti-coagulated blood using a standard protocol. Genotyping of the IGF1 C-1245T polymorphism was performed using polymerase chain reaction (PCR). We found that the endurance and power athletes' allele and genotype frequencies were significantly different from those of the control group. Only 4.8% of the athletes were TT carriers, but none of the controls carried this genotype. The T allele was found to be more frequent in the top-level power athletes (international and Olympic level) compared to national level athletes, but such a difference was not found in endurance athletes. Our findings suggest a possible contribution for the relatively rare IGF-I TT genotype to endurance performance, and in particular to power sport excellence in Israeli athletes. 23433701 Near-miss in focused lower-extremity ultrasound for deep venous thrombosis. Focused, proximal compression ultrasound (FPCUS) is a commonly used point-of-care study in the Emergency Department (ED). Pelvic vein deep venous thrombosis (DVT) is a rare presentation, and Emergency Physicians need to be aware of the limitations and pitfalls of FPCUS. A case of external iliac vein DVT diagnosed in the ED is presented, with a focus on subtle signs seen during FPCUS that led to the diagnosis and additional ultrasound techniques to aid in appropriate point-of-care diagnosis. We describe a patient who presented with lower-extremity pain and was subsequently diagnosed with external iliac DVT. A FPCUS study by Emergency Physicians was performed and demonstrated subtle findings that led to further investigation and appropriate diagnosis. Emergency physicians using FPCUS in the evaluation of lower-extremity pain or swelling need to be aware of the pitfalls, limitations, and advanced techniques to avoid misdiagnosis while evaluating for DVT. 23926253 Dopamine modulates risk-taking as a function of baseline sensation-seeking trait. Trait sensation-seeking, defined as a need for varied, complex, and intense sensations, represents a relatively underexplored hedonic drive in human behavioral neuroscience research. It is related to increased risk for a range of behaviors including substance use, gambling, and risky sexual practice. Individual differences in self-reported sensation-seeking have been linked to brain dopamine function, particularly at D2-like receptors, but so far no causal evidence exists for a role of dopamine in sensation-seeking behavior in humans. Here, we investigated the effects of the selective D2/D3 agonist cabergoline on performance of a probabilistic risky choice task in healthy humans using a sensitive within-subject, placebo-controlled design. Cabergoline significantly influenced the way participants combined different explicit signals regarding probability and loss when choosing between response options associated with uncertain outcomes. Importantly, these effects were strongly dependent on baseline sensation-seeking score. Overall, cabergoline increased sensitivity of choice to information about probability of winning; while decreasing discrimination according to magnitude of potential losses associated with different options. The largest effects of the drug were observed in participants with lower sensation-seeking scores. These findings provide evidence that risk-taking behavior in humans can be directly manipulated by a dopaminergic drug, but that the effectiveness of such a manipulation depends on baseline differences in sensation-seeking trait. This emphasizes the importance of considering individual differences when investigating manipulation of risky decision-making, and may have relevance for the development of pharmacotherapies for disorders involving excessive risk-taking in humans, such as pathological gambling. 23943501 The Cdk inhibitor flavopiridol enhances temozolomide-induced cytotoxicity in human glioma cells. The recent progress in chemotherapy for malignant gliomas is attributable to the introduction of the DNA-methylating agent temozolomide (TMZ); however, drug resistance remains a major issue. Previous studies have shown that TMZ induces prolonged arrest of human glioma cells in the G2/M phase of the cell cycle followed by a senescence-like phenomenon or mitotic catastrophe. These findings suggest that the G2 checkpoint is linked to DNA repair mechanisms. We investigated the effect of a cyclin-dependent kinase (Cdk) inhibitor flavopiridol (FP) that inhibits the action of Cdc2, a key protein in the G2 checkpoint pathway, on TMZ-treated glioma cells. Colony formation efficiency revealed that FP potentiated the cytotoxicity of TMZ in glioma cells in a p53-independent manner. This effect was clearly associated with the suppression of key proteins at the G2-M transition, accumulation of the cells exclusively at the G2 phase, and increase in a double-stranded DNA break marker (seen on performing immunoblotting). TMZ-resistant clones showed activation of the G2 checkpoint in response to TMZ, while FP treatment resensitized these clones to TMZ. FP also enhanced the cytotoxicity of TMZ in U87MG-AktER cells. Moreover, administration of TMZ and/or FP to nude mice with xenografted U87MG cells revealed that FP sensitized xenografted U87MG cells to TMZ in these mice. Our findings suggest that TMZ resistance could be promoted by enhanced DNA repair activity in the G2-M transition and that a Cdk inhibitor could suppress this activity, leading to potentiation of TMZ action on glioma cells. 23411278 Absorption and urinary excretion of A-type procyanidin oligomers from Litchi chinensis pericarp in rats by selected ion monitoring liquid chromatography-mass spectrometry. Intervention studies with A-type oligomeric procyanidins from litchi (Litchi chinensis) pericarp (LPOPC) suggested its protective effect against cardiovascular diseases. However, there is no consensus on the absorption and metabolism of LPOPC. It was demonstrated that the main components in LPOPC were (-)-epicatechin, A-type procyanidin dimers, trimers and tetramers. Rats were orally administered different levels of LPOPC (150 and 300 mg/kgbw), the procyanidins and their microbial metabolites in urine were identified by HPLC-MS/MS analysis 18 h post-administration. Data indicated that seven aromatic acid metabolites excreted were significantly increased by 300 mg/kgbw of LPOPC (P<0.01). However, only (-)-epicatechin and its methylated derivatives were detected in rat plasma 1h after 300 mg/kgbw of LPOPC administration. The total EC content absorbed in plasma was only 2.54 ± 0.53 μmol/L, indicating that the biological properties of LPOPC should be probably explained by its microbial degraded phenolic acids. 23413358 Adenosine 2A receptor modulates inflammation and phenotype in experimental abdominal aortic aneurysms. Activation of the adenosine 2A receptor (A(2A)R) reduces inflammation in models of acute injury but contribution in development of chronic abdominal aortic aneurysms (AAAs) is unknown. Elastase perfusion to induce AAA formation in A(2A)R-knockout (A(2A)RKO) and C57BL6/J wild-type (WT) mice resulted in nearly 100% larger aneurysms in A(2A)RKO compared to WT at d 14 (P<0.05), with evidence of greater elastin fragmentation, more immune cell infiltration, and increased matrix metallatoproteinase (MMP) 9 expression (P<0.05). Separately, exogenous A(2A)R antagonism in elastase-perfused WT mice also resulted in larger aneurysms (P<0.05), while A(2A)R agonism limited aortic dilatation (P<0.05). Activated Thy-1.2(+) T lymphocytes from WT mice treated in vitro with A(2A)R antagonist increased cytokine production, and treatment with A(2A)R agonist decreased cytokine production (P<0.05 for all). Primary activated CD4(+) T lymphocytes from A(2A)RKO mice exhibited greater chemotaxis (P<0.05). A(2A)R antagonist increased chemotaxis of activated CD4(+) cells from WT mice in vitro, and A(2A)R agonist reduced this effect (P<0.05). A(2A)R activation attenuates AAA formation partly by inhibiting immune cell recruitment and reducing elastin fragmentation. These findings support augmenting A(2A)R signaling as a putative target for limiting aneurysm formation.-Bhamidipati, C. M., Mehta, G. S., Moehle, C. W., Meher, A. K., Su, G., Vigneshwar, N. G., Barbery, C., Sharma, A. K., Kron, I. L., Laubach, V. E., Owens, G. K., Upchurch Jr., G. R., Ailawadi, G. Adenosine 2A receptor modulates inflammation and phenotype in experimental abdominal aortic aneurysms. 23800629 Effects of CO2 enrichment and nutrients supply intermittency on batch cultures of Isochrysis galbana. Aiming at enhanced performance to increase economic feasibility of microalgae based processes, Isochrysis galbana was grown in three modes of cultivation: batch, intermittent fed batch and semi-continuous. The batch mode was conducted under two regimes of aeration: conventional aeration and CO2 enriched aeration (5% v/v in air). Increased biomass productivity without significant impact on lipid accumulation was observed for CO2 enriched aeration relatively to cultivation aerated with air only. The intermittent fed batch cultivation policy was proven to be useful for lipid accumulation, increasing the lipid content by 19.8%. However, the semi-continuous mode resulted in higher productivity due to increased biomass concentration; the biomass productivity reached 0.51g/(Ld). Fluorescence measurements were performed; the calculated low electron transport rate showed the need to increase the irradiance. The results showed that I. galbana can be grown in semi-continuous condition at high levels of biomass productivity. 23956825 Do positive surgical margins predict biochemical recurrence in all patients without adjuvant therapy after radical prostatectomy? The objective was to study whether positive surgical margins (PSMs) predict biochemical recurrence (BCR) in all patients without adjuvant therapy after radical prostatectomy (RP). We retrospectively reviewed the medical records of patients who underwent RP for prostate cancer at Veterans Health Service Medical Center from 2005 to 2011. BCR was defined by a prostate-specific antigen (PSA) value ≥0.2 ng/mL. The clinicopathological factors of the PSM group were compared with those of the negative surgical margin (NSM) group, and the predictive impact of a PSM for BCR-free survival were evaluated. In addition, we analyzed the prognostic difference for BCR-free survival between solitary and multiple PSMs. A PSM was noted in 167 patients (45.5%). BCR was reported in 101 men in total (27.5%). The BCR-free survival rate of the PSM group was lower than that of the NSM group (p<0.001). In a multivariate analysis for the total patients, PSM was significantly associated with BCR-free survival (p<0.001). After stratification by pathological T stage, Gleason score (GS), and preoperative PSA value, PSM was significantly predictive for BCR-free survival in men with pT2 and/or GS ≤6 or 7 and/or a PSA value <10 or 10-20 ng/mL (all p<0.05). Multiple PSMs were more predictive of BCR-free survival than was a solitary PSM (p=0.001). A PSM is a significant predictor of postoperative BCR in patients with pT2 and/or GS ≤7 and/or preoperative PSA <20 ng/mL. Multiple PSMs are considered a stronger prognostic factor for prediction of BCR than is a solitary PSM. 23896377 New clinical, pathological and molecular prognostic models and calculators in patients with locally diagnosed anaplastic oligodendroglioma or oligoastrocytoma. A prognostic factor analysis of European Organisation for Research and Treatment of Cancer Brain Tumour Group Study 26951. The prognosis of patients with anaplastic oligodendrogliomas (AOD) and oligoastrocytomas (AOA) is variable. Biomarkers might be helpful to identify more homogeneous disease subtypes and improve therapeutic index. The aim of this study is to develop new clinical, pathological and molecular prognostic models for locally diagnosed anaplastic gliomas with oligodendroglial features (AOD or AOA). Data from 368 patients with AOD or AOA recruited in The European Organisation for Research and Treatment of Cancer (EORTC) trial 26951 on adjuvant PCV (Procarbazine, CCNU, Vincristine) chemotherapy in anaplastic oligodendroglial tumours were used to develop multifactor models to predict progression free survival (PFS) and overall survival (OS). Different models were compared by their percentage of explained variation (PEV). Prognostic calculators were derived from these new models. Treatment (for PFS only), younger age, confirmed absence of residual tumour on imaging, frontal location, good World Health Organisation (WHO) performance status, absence of endothelial abnormalities and/or necrosis, 1p/19q codeletion and Isocitrate dehydrogenase 1 (IDH1) mutation were independent factors that predicted better PFS and OS. We identified important prognostic factors for AOD and AOA and showed that molecular markers added a major contribution to clinical and pathological factors in explaining PFS and OS. With a positive predictive value of 92% for PFS and 94% for OS, our models allow physicians to precisely identify high risk patients and aid in making therapeutic decisions. 23902134 MicroRNA-Specific Argonaute 2 Protein Inhibitors. As microRNA silencing processes are mediated by the protein Argonaute 2 and for target RNA binding only a short sequence at the microRNA's 5' end (seed region) is crucial, we report a novel inhibitor class: the microRNA-specific Argonaute 2 protein inhibitors that not only block this short recognition sequence but also bind to the protein's active site. We developed a model for rational drug design, enabling the identification of Argonaute 2 active site binders and their linkage with a peptide nucleic acid sequence (PNA), which addresses the microRNA of interest. The designed inhibitors targeting microRNA-122, a hepatitis C virus drug target, had an IC50 of 100 nM, 10-fold more active than the simple PNA sequence (IC50 of 1 μM), giving evidence that the strategy has potential. Due to their lower molecular weight, these inhibitors may show better pharmacokinetic properties than reported oligonucleotide inhibitors, enabling them for potential therapeutic use. 23831765 Magnetic field directed fabrication of conducting polymer nanowires. The self-assembly of nanoparticles is an efficient and precise method to fabricate nanoscale devices. By manipulating iron oxide nanoparticles in suspension with an external field to form magnetically directed linear assemblies, we demonstrate the feasibility of using this structure to template the synthesis of PEDOT:PSS conducting polymer nanowires in suspension. Furthermore these conducting wires can be assembled on interdigitated electrodes to form an array of conducting nanowires. 23560608 Adolescent attachment security, family functioning, and suicide attempts. Theories of suicidal behavior suggest that the desire to die can arise from disruption of interpersonal relationships. Suicide research has typically studied this from the individual's perspective of the quality/frequency of their social interactions; however, the field of attachment may offer another perspective on understanding an individual's social patterns and suicide risk. This study examined attachment along with broader family functioning (family adaptability and cohesion) among 236 adolescent psychiatric inpatients with (n = 111) and without (n = 125) histories of suicide attempts. On average, adolescents were 14 years of age and Hispanic (69%). Compared to those without suicide attempts, adolescent attempters had lower self-reported maternal and paternal attachment and lower familial adaptability and cohesion. When comparing all three types of attachment simultaneously in the logistic regression model predicting suicide attempt status, paternal attachment was the only significant predictor. Suicide attempt group was also significantly predicted by self-rated Cohesion and Adaptability; neither of the parent ratings of family functioning were significant predictors. These findings are consistent with the predictions of the Interpersonal Theory of Suicide about social functioning and support the efforts to develop attachment-based interventions as a novel route towards suicide prevention. 23192554 Motion analysis using 3D high-resolution frequency analysis. The spatiotemporal spectra of a video that contains a moving object form a plane in the 3D frequency domain. This plane, which is described as the theoretical motion plane, reflects the velocity of the moving objects, which is calculated from the slope. However, if the resolution of the frequency analysis method is not high enough to obtain actual spectra from the object signal, the spatiotemporal spectra disperse away from the theoretical motion plane. In this paper, we propose a high-resolution frequency analysis method, described as 3D nonharmonic analysis (NHA), which is only weakly influenced by the analysis window. In addition, we estimate the motion vectors of objects in a video using the plane-clustering method, in conjunction with the least-squares method, for 3D NHA spatiotemporal spectra. We experimentally verify the accuracy of the 3D NHA and its usefulness for a sequence containing complex motions, such as cross-over motion, through comparison with 3D fast Fourier transform. The experimental results show that increasing the frequency resolution contributes to high-accuracy estimation of a motion plane. 23371415 Genotoxicity and carcinogenicity of the light emitted by artificial illumination systems. The light delivered by artificial illumination systems, and in particular by halogen quartz bulbs, contains UVA, UVB, and UVC radiation, is genotoxic to both bacterial and human cells and is potently carcinogenic to hairless mice. Since IARC has classified UV radiation in Group 1, any source of UV light poses a carcinogenic hazard to humans. Suitable regulations would be needed in order to control the safety of the light emitted by artificial light sources. 23466277 Comparison of polyurethane foam and XAD-2 sampling matrices to measure airborne organophosphorus pesticides and their oxygen analogs in an agricultural community. Side-by-side active air sampling for the organophosphorus (OP) pesticide, chlorpyrifos (CPF) and its oxygen analog, chlorpyrifos-oxon (CPF-O) was conducted with two recommended air sampling matrices: OSHA Versatile Sampling (OVS) tubes with XAD-2 resin, polyurethane foam (PUF) tubes, and passive PUF deposition disks. The study compared the proportion of artificially transformed CPF-O in the laboratory and in the field during a tree fruit application in Washington State. Lab results demonstrated that the NIOSH-recommended OVS tubes artificially transformed up to 32% of CPF to CPF-O during the sampling process, whereas PUF tubes had little to no artificial transformation (⩽0.1%). In the field, the proportion of CPF-O in the sample was significantly higher on OVS tubes than on PUF tubes (p<0.001), confirming that OVS tubes were converting a significant portion of CPF to CPF-O. In addition, PUF tubes reported measurable levels CPF-O in the field even when no artificial transformation was expected. We conclude that the PUF matrix is the superior sampling medium for OP oxygen analogs when compared to XAD-two resin. Community-located PUF tube samples 24h post-application had considerably higher levels CPF-O (16-21ngm(-3)) than near field samples during application (2-14ngm(-3)), suggesting that the oxygen analog is volatile and formed during atmospheric transport. It is recommended that worker and community risk assessments begin to take into consideration the presence of the more toxic oxygen analogs when measuring for OP pesticide mixtures. 23928630 Communicating new policy on antibiotic prophylaxis with patients: a randomised controlled trial. Objectives This trial aimed to assess the effectiveness of two different communication tools on the levels of anxiety and concern when a change in patients' treatment was introduced.Method Patients previously advised to have antibiotic prophylaxis before their dental treatments were randomised to receive information about the new policy either through a video accompanied by a written leaflet or just the leaflet. All patients completed a questionnaire to assess anxiety and concern as well as intentions regarding accepting dental treatment without antibiotic prophylaxis at enrolment point, after intervention and after meeting the cardiologist.Results Ninety questionnaires were analysed (45 in each group). The mean level of anxiety and concern scores were significantly reduced after the intervention point (p <0.05). The ANOVA model revealed a significant reduction in the levels of anxiety and concern during the trial (p <0.001). However, the main effect of group (intervention versus control) and the interaction term were not significant. At the end of trial there was no difference in the number of patients accepting dental treatment without cover in the two groups.Conclusion Patients appear more likely to accept a change if it is communicated directly to them by their practitioners via face to face consultation compared with video or leaflet. When there is a lack of time for in-depth consultation, video could be a more effective method than leaflet alone. 23785011 Synthesis and Radiopharmacological Characterisation of a Fluorine-18-Labelled Azadipeptide Nitrile as a Potential PET Tracer for in vivo Imaging of Cysteine Cathepsins. A fluorinated cathepsin inhibitor based on the azadipeptide nitrile chemotype was prepared and selected for positron emission tomography (PET) tracer development owing to its high affinity for the oncologically relevant cathepsins L, S, K and B. Labelling with fluorine-18 was accomplished in an efficient and reliable two-step, one-pot radiosynthesis by using 2-[(18) F]fluoroethylnosylate as a prosthetic agent. The pharmacokinetic properties of the resulting radiotracer compound were studied in vitro, ex vivo and in vivo in normal rats by radiometabolite analysis and small-animal positron emission tomography. These investigations revealed rapid conjugate formation of the tracer with glutathione in the blood, which is associated with slow blood clearance. The potential of the developed (18) F-labelled probe to image tumour-associated cathepsin activity was investigated by dynamic small-animal PET imaging in nude mice bearing tumours derived from the human NCI-H292 lung carcinoma cell line. Computational analysis of the obtained image data indicated the time-dependent accumulation of the radiotracer in the tumours. The expression of the target enzymes in the tumours was confirmed by immunohistochemistry with specific antibodies. This indicates that azadipeptide nitriles have the potential to target thiol-dependent cathepsins in vivo despite their disadvantageous pharmacokinetics. 23845429 Excitability modulation of the motor system induced by transcranial direct current stimulation: A multimodal approach. Anodal and cathodal transcranial direct current stimulations (tDCS) are both established techniques to induce cortical excitability changes. Typically, in the human motor system, such cortical modulations are inferred through changes in the amplitude of the motor evoked potentials (MEPs). However, it is now possible to directly evaluate tDCS-induced changes at the cortical level by recording the transcranial magnetic stimulation evoked potentials (TEPs) using electroencephalography (EEG). The present study investigated the modulation induced by the tDCS on the motor system. The study evaluates changes in the MEPs, in the amplitude and distribution of the TEPs, in resting state oscillatory brain activity and in behavioral performance in a simple manual response task. Both the short- and long-term tDCS effects were investigated by evaluating their time course at ~0 and 30min after tDCS. Anodal tDCS over the left primary motor cortex (M1) induced an enhancement of corticospinal excitability, whereas cathodal stimulation produced a reduction. These changes in excitability were indexed by changes in MEP amplitude. More interestingly, tDCS modulated the cortical reactivity, which is the neuronal activity evoked by TMS, in a polarity-dependent and site-specific manner. Cortical reactivity increased after anodal stimulation over the left M1, whereas it decreased with cathodal stimulation. These effects were partially present also at long term evaluation. No polarity-specific effect was found either on behavioral measures or on oscillatory brain activity. The latter showed a general increase in the power density of low frequency oscillations (theta and alpha) at both stimulation polarities. Our results suggest that tDCS is able to modulate motor cortical reactivity in a polarity-specific manner, inducing a complex pattern of direct and indirect cortical activations or inhibitions of the motor system-related network, which might be related to changes in synaptic efficacy of the motor cortex. 23817726 Prevention of Recurrent Preterm Birth: Role of the Neonatal Follow-up Program. Preterm birth (PTB) is a public health crisis in need of effective preventative strategies. Multi-disciplinary Neonatal Follow-up Programs (NFPs) provide health services to preterm infants at high risk for developmental problems after discharge from US newborn intensive care units. We aimed to determine whether NFPs are a potentially effective venue for specialized maternal counseling and intervention aimed at reducing the high rate of recurrent PTB in this population. This prospective case series enrolled women with preterm children evaluated in the Utah Department of Health NFP, 2010-2012. Women were interviewed, received Maternal Fetal Medicine (MFM) counseling services, and maternal and neonatal records were abstracted. We assessed maternal demographics, medical history, and characteristics of the index pregnancy. We calculated the proportion of women with knowledge of PTB recurrence risk and available prevention strategies, and assessed current contraceptive use and reproductive plans. Ninety-six women with a history of early PTB (≤26 weeks and/or birth weight < 1,250 g) were evaluated. Nearly 1 in 5 women (19.8 %) evaluated reported sexual activity, desire to avoid pregnancy, and no current contraceptive use, and were therefore at imminent risk of unintended pregnancy. Of women without permanent contraception, only 24.3 % were aware of their individual PTB recurrence risk. Of women with a history of spontaneous PTB, only 4 % were aware of effective pharmacologic preventative strategies. Introduction of MFM consultation as part NFP multi-disciplinary services is a novel approach with the potential to reduce recurrent PTB in an exceptionally high-risk population. 23886412 Comment on 'Performance analysis in football: A critical review and implications for future research' Abstract MacKenzie and Cushion ( 2013 ) recently reviewed performance analysis research in association football (soccer). Their critical review focused on several themes related to methodological approaches such as sample size, match context and operational definitions and the implications of research findings to professional practice. In this response letter, we comment on additional pragmatic concerns regarding these key themes as well as some of the difficulties commonly faced when conducting performance analysis research. 23963016 Application of the Modified Lower Extremity Functional Scale in Low Back Pain. Study Design. This was a cross-sectional study.Objective. We sought to test the psychometric properties of the modified Lower Extremity Functional Scale (LEFS) for low back pain (LBP).Summary of Background Data. Low back and lower extremities are anatomically and functionally related and radiating leg pain is common among patients with LBP. The LEFS is a reliable and valid questionnaire for patients with lower extremity conditions caused by musculoskeletal disorders, although its utility in LBP with or without radiating leg pain has not been tested.Methods. We recruited subjects with LBP who were aged at least 18 years old from physical medicine and rehabilitation outpatient clinics. The evaluation included demographic data, back pain history, pain intensity by the visual analogue scale (VAS), the Roland-Morris Disability Questionnaire (RDQ), and the modified LEFS, in which "lower limb problem" was substituted with "low back/lower limb problem" in the introductory sentence of the questionnaire. Data from 242 patients were analyzed for the psychometric properties of the modified LEFS, including floor and ceiling effects, internal consistency, test-retest reliability, dimensionality, and construct validity.Results. The modified LEFS had no floor or ceiling effects, high internal consistency (Cronbach α: 0.94) and good test-retest reliability (Intraclass correlation coefficient (2,1): 0.86). Principal component analysis identified one major factor that had an eigenvalue of 9.9 and explained 49.6% of the total variance. The correlations between the modified LEFS and RDQ was high (Pearson's correlation coefficient: -0.71). The modified also LEFS discriminated well between the subgroups of LBP with unilateral leg pain and those with bilateral leg pain.Conclusions. The modified LEFS had satisfactory psychometric properties in LBP patients and could serve as a supplementary outcome measure to assess their activity limitations. 23459999 Aminoalkylmethacrylate copolymer E improves oral bioavailability of YM466 by suppressing drug-bile interaction. The aim of this study was to find out polymeric compounds that can inhibit the interaction between YM466, a novel anticoagulant, and bile to improve its oral bioavailability. In vitro ultrafiltration method using extract gall powder was useful to detect the formation of insoluble complex of YM466 with bile and also used to select a polymer that can inhibit the interaction between YM466 and bile. The in vitro studies revealed that aminoalkylmethacrylate (AAM) copolymer E, a polymethacrylate, dose-dependently inhibited the interaction between YM466 and bile and that this polymer could interact with bile salt, but not with YM466, possibly by electrostatic and/or hydrophobic interactions. The coadministration of AAM copolymer E with YM466 to rats dose-dependently increased the plasma concentration of YM466 and it was found that the oral dose of the polymer three times of YM466 (polymer to drug ratio in weight, P-D ratio, 3) significantly increased AUC0-1 h of YM466 to 2.6-fold of that of YM466 alone. Considering the condition of therapeutic use of YM466 and the maximum tolerated dose of the polymer, the formulation of P-D ratio 3 would be clinically practical and promising from the viewpoint of safety. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3128-3135, 2013. 23883403 InAs-mediated growth of vertical InSb nanowires on Si substrates. In this work, InSb nanowires are grown vertically on Si (111) with metal organic chemical vapor deposition using InAs as seed layer, instead of external metal catalyst. Two groups of InSb nanowires are fabricated and characterized: one group presents Indium droplets at the nanowire's free end, while the other, in contrast, ends without Indium droplet but with pyramid-shaped InSb. The indium-droplet-ended nanowires are longer than the other group of nanowires. For both groups of InSb nanowires, InAs layers play an important role in their formation by serving as a template for growing InSb nanowires. The results presented in this work suggest a useful approach to grow catalyst-free InSb nanowires on Si substrates, which is significant for their device applications. 23900406 Working Memory Contributes to Elevated Motor Activity in Adults With ADHD: An Examination of the Role of Central Executive and Storage/Rehearsal Processes. Objective: The relationship between working memory (WM) and objectively measured motor activity was examined in adults with ADHD and healthy controls (HCs). Method: Thirty-five adults (ADHD = 20, HC = 15) were grouped using self-report and collateral-report measures in addition to a semistructured clinical interview. All participants completed control conditions with minimal WM demands, and separate phonological (PH) and visuospatial (VS) WM tasks with recall demands ranging from four to seven stimuli. Results: The ADHD group exhibited significantly more motor activity relative to the HC group, and both groups exhibited greater activity during PH and VS WM tasks, relative to control conditions. Finally, the central executive (CE) and PH storage/rehearsal subsystems were associated with large-magnitude between-group differences in activity. Conclusion: Findings suggest that increased demands on WM, particularly the CE and PH storage/rehearsal, contribute to ADHD-related hyperactivity, though a portion of excessive motor activity in adults with ADHD may occur independently of WM demands. (J. of Att. Dis. 2013; XX(X) 1-XX). 23480726 Killed Bacillus subtilis spores expressing streptavidin: a novel carrier of drugs to target cancer cells. Abstract Carriers of drugs in cancer therapy are required to reduce side-effects of the drugs to normal cells. Here we constructed killed recombinant Bacillus subtilis spores (SA1) that expressed streptavidin as a chimeric fusion to the spore coat protein CotB and used the spores as bioparticle carrier. When bound with biotinylated cetuximab these spores could specifically target to the epidermal growth factor receptor on HT 29 colon cancer cells, thereby delivered paclitaxel to the cells with 4-fold higher efficiency, as indicated by fluorescent intensity of paclitaxel Oregon Green 488 bound to HT29 cells. Based on real-time monitoring of cell index, the IC50 of growth of HT29 cells by paclitaxel-SA1-cetuximab was estimated to be 2.9 nM approximately 5-fold lower than water-soluble paclitaxel (14.5 nM). Instability of DNA content was observed when cells were treated with 16 nM paclitaxel-SA1-cetuximab, resulting in a 2-fold enhancement in polyploidy cells. Thus, by targeting the release of paclitaxel to HT29 cells, spore-associated cetuximab augmented the inhibitory effect of paclitaxel on cell division and proliferation. The SA1 could be used as a "universal" drug carrier to target specific biomarkers on cancer cells by conjugating with suitable biotinylated antibodies. 23689547 How did we arrive at burden of disease estimates for mental and illicit drug use disorders in the Global Burden of Disease Study 2010? The Global Burden of Disease study 2010 (GBD 2010) estimated regional and global burden of 291 diseases and 67 risk factors. Here, we provide an overview of the methodological approach taken to this work, as well as the challenges and limitations encountered in deriving the burden of mental and drug use disorders. GBD 2010 estimated the burden of 11 mental disorders and four drug use disorders for 21 regions. This involved a systematic literature search for epidemiological data; setting lay case definitions; synthesizing available epidemiological data into an internally consistent disease model; and quantifying the associated disability and health outcomes, to derive region, sex, year and age-specific burden estimates. Notable challenges included the difficulty in deriving culturally comparable case definitions for mental and drug use disorders, the paucity of epidemiological data and the difficulty in capturing disability associated with mental and drug use disorders. GBD 2010 findings demonstrated the major public health importance of mental and drug use disorders. The methodology used to estimate burden was more sophisticated than previous GBD studies, with some restrictions required in order to achieve defensible numerical measures of burden for mental and drug use disorders. 23771878 Aerobic biological pretreatment of municipal solid waste with a high content of putrescibles: effect on landfill emissions. The objective of this work was to study the effect of aerobic biological pretreatment on the emissions of municipal solid waste (MSW) with a high content of putrescibles after landfilling. For this purpose, the organic fraction of MSW was simulated by a mixture of food waste and office paper at a 2.4:1 wet weight ratio. MSW was first pretreated aerobically for three different time periods (8, 45 and 90 days) resulting in organic matter reductions equal to 15%, 45% and 81% respectively. MSW were then placed in 160-L air-tight anaerobic bioreactors. The control anaerobic bioreactors contained untreated MSW. Anaerobic experiments lasted from 300 to 550 days. Results showed that the biogas production from untreated MSW was 372 NL dry kg(-1) (average of two replications) after 530 days. The MSW that was pretreated aerobically for 45 days and 90 days yielded 130 and 62 NL dry kg(-1) of biogas after 310 days and 230 days respectively. However, the 8-day (very short-term) pretreatment period led to an increase of the biogas yield (550 NL dry kg(-1) after 340 days) compared with that of raw refuse. All three runs with aerobically pretreated MSW reached the steady methanogenic phase faster than raw MSW. Leachate emissions were significantly lower in the aerobically-pretreated MSWthan the untreated ones. The leachate ammonium concentrations had an increasing trend in all anaerobic reactors and reached a plateau of between 2 and 3.5 g L(-1) at the end of the process. 23910094 Poultry and fish intake and risk of esophageal cancer: A meta-analysis of observational studies. Mixed results regarding the association between white meat (including poultry and fish) intake and the risk of esophageal cancer (EC) have been reported. We performed a meta-analysis to provide a quantitative assessment of this association. Relevant studies were identified in MEDLINE until December 31, 2012. Summary relative risks (SRRs) with 95% confidence intervals (CIs) were pooled with a random-effects model. A total of 20 articles, including 3990 cases with EC, were included in this meta-analysis. Compared to individuals with the lowest level of fish intake, individuals with the highest fish intake were found to have reduced risk of EC (SRRs = 0.69; 95% CIs: 0.57-0.85), while poultry intake was not associated with EC (SRRs = 0.83; 95% CIs: 0.62-1.12). Total fish consumption is associated with reduced esophageal squamous cell carcinoma (ESCC) risk, while poultry consumption was not associated with ESCC risk. Additionally, neither poultry nor fish consumption was associated with esophageal adenocarcinoma risk. Our results suggest that fish consumption may have a potential role in EC prevention, while poultry intake has no effect. However, because the majority of data was from case-control studies, further well-designed prospective studies are warranted. 23454528 Neuropeptide S enhances memory and mitigates memory impairment induced by MK801, scopolamine or Aβ1-42 in mice novel object and object location recognition tasks. Neuropeptide S (NPS), the endogenous ligand of NPSR, has been shown to promote arousal and anxiolytic-like effects. According to the predominant distribution of NPSR in brain tissues associated with learning and memory, NPS has been reported to modulate cognitive function in rodents. Here, we investigated the role of NPS in memory formation, and determined whether NPS could mitigate memory impairment induced by selective N-methyl-d-aspartate receptor antagonist MK801, muscarinic cholinergic receptor antagonist scopolamine or Aβ1-42 in mice, using novel object and object location recognition tasks. Intracerebroventricular (i.c.v.) injection of 1 nmol NPS 5 min after training not only facilitated object recognition memory formation, but also prolonged memory retention in both tasks. The improvement of object recognition memory induced by NPS could be blocked by the selective NPSR antagonist SHA 68, indicating pharmacological specificity. Then, we found that i.c.v. injection of NPS reversed memory disruption induced by MK801, scopolamine or Aβ1-42 in both tasks. In summary, our results indicate that NPS facilitates memory formation and prolongs the retention of memory through activation of the NPSR, and mitigates amnesia induced by blockage of glutamatergic or cholinergic system or by Aβ1-42, suggesting that NPS/NPSR system may be a new target for enhancing memory and treating amnesia. 23881145 Further In-vitro Characterization of an Implantable Biosensor for Ethanol Monitoring in the Brain. Ethyl alcohol may be considered one of the most widespread central nervous system (CNS) depressants in Western countries. Because of its toxicological and neurobiological implications, the detection of ethanol in brain extracellular fluid (ECF) is of great importance. In a previous study, we described the development and characterization of an implantable biosensor successfully used for the real-time detection of ethanol in the brain of freely-moving rats. The implanted biosensor, integrated in a low-cost telemetry system, was demonstrated to be a reliable device for the short-time monitoring of exogenous ethanol in brain ECF. In this paper we describe a further in-vitro characterization of the above-mentioned biosensor in terms of oxygen, pH and temperature dependence in order to complete its validation. With the aim of enhancing ethanol biosensor performance, different enzyme loadings were investigated in terms of apparent ethanol Michaelis-Menten kinetic parameters, viz. IMAX, KM and linear region slope, as well as ascorbic acid interference shielding. The responses of biosensors were studied over a period of 28 days. The overall findings of the present study confirm the original biosensor configuration to be the best of those investigated for in-vivo applications up to one week after implantation. 23902400 Transformation of pd nanocubes into octahedra with controlled sizes by maneuvering the rates of etching and regrowth. Palladium octahedra with controlled edge lengths were obtained from Pd cubes of a single size. The success of this synthesis relies on a transformation involving oxidative etching and regrowth. Because the {100} side faces of the Pd nanocubes were capped by Br(-) ions, Pd atoms were removed from the corners during oxidative etching, and the resultant Pd(2+) ions could be reduced and deposited back onto the nanocubes, but preferentially on the {100} facets. We could control the ratio of the etching and regrowth rates (Retching and Rregrowth) simply by varying the amount of HCl added to the reaction solution. With a large amount of HCl, etching dominated the process (Retching ≫ Rregrowth), resulting in the formation of Pd octahedra with an edge length equal to 70% of that of the cubes. In contrast, with a small amount of HCl, all of the newly formed Pd(2+) ions could be quickly reduced and deposited back onto the Pd cubes. In this case, Retching ≈ Rregrowth, and the resultant Pd octahedra had roughly the same volume as the starting cubes, together with an edge length equal to 130% of that of the cubes. When the amount of HCl was between these two extremes, we obtained Pd octahedra with intermediate edge lengths. This work not only advances our understanding of oxidative etching in nanocrystal synthesis but also offers a powerful means for controlling the shape and size of metal nanocrystals simply by adjusting the rates of etching and regrowth. 22915348 Acute multiple arterial thrombosis after cisplatin in base of tongue carcinoma: Case report. Arterial thromboses following cisplatin-based chemotherapy in head and neck cancers are extremely rare and devastating complication. A 54-year-old male smoker had an acute history of left lower limb pain and calf claudication 3 days following the first cycle of cisplatin-based chemotherapy given concurrently with radiotherapy for squamous cell carcinoma of the base of tongue. CT angiography showed extensive abdominal aortic thrombus along with involvement of left common iliac, saphenopopliteal, and tibeal arteries as well as moderate stenosis in the proximal segments of left anterior descending and right coronary artery. We suggest that endothelial damage and hypercoaguable state secondary to cisplatin may have induced severe arterial and coronary thrombosis. This is the first reported case of acute multiple arterial thrombosis following cisplatin in head and neck cancer. It is a dreaded complication and has a dismal prognosis if not promptly recognized and treated. © 2012 Wiley Periodicals, Inc. Head Neck, 2013. 23640058 Activated α2-macroglobulin induces Muller glial cell migration by regulating MT1-MMP activity through LRP1. In retinal proliferative diseases, Müller glial cells (MGCs) acquire migratory abilities. However, the mechanisms that regulate this migration remain poorly understood. In addition, proliferative disorders associated with enhanced activities of matrix metalloprotease 2 (MMP-2) and MMP-9 also present increased levels of the protease inhibitor α2-macroglobulin (α2M) and its receptor, the low-density lipoprotein receptor-related protein 1 (LRP1). In the present work, we investigated whether the protease activated form of α2M, α2M*, and LRP1 are involved with the MGC migratory process. By performing wound-scratch migration and zymography assays, we demonstrated that α2M* induced cell migration and proMMP-2 activation in the human Müller glial cell line, MIO-M1. This induction was blocked when LRP1 and MT1-MMP were knocked down with siRNA techniques. Using fluorescence microscopy and biochemical procedures, we found that α2M* induced an increase in LRP1 and MT1-MMP accumulation in early endosomes, followed by endocytic recycling and intracellular distribution of MT1-MMP toward cellular protrusions. Moreover, Rab11-dominant negative mutant abrogated MT1-MMP recycling pathway, cell migration, and proMMP-2 activation induced by α2M*. In conclusion, α2M*, through its receptor LRP1, induces cellular migration of Müller glial cells by a mechanism that involves MT1-MMP intracellular traffic to the plasma membrane by a Rab11-dependent recycling pathway.-Barcelona, P. F., Jaldín-Fincati, J. R., Sánchez, M. C., Chiabrando, G. A. Activated α2-macroglobulin induces Müller glial cell migration by regulating MT1-MMP activity through LRP1. 23936193 Gβ-Like CpcB Plays a Crucial Role for Growth and Development of Aspergillus nidulans and Aspergillus fumigatus. Growth, development, virulence and secondary metabolism in fungi are governed by heterotrimeric G proteins (G proteins). A Gβ-like protein called Gib2 has been shown to function as an atypical Gβ in Gpa1-cAMP signaling in Cryptococcus neoformans. We found that the previously reported CpcB (cross pathway control B) protein is the ortholog of Gib2 in Aspergillus nidulans and Aspergillus fumigatus. In this report, we further characterize the roles of CpcB in governing growth, development and toxigenesis in the two aspergilli. The deletion of cpcB results in severely impaired cellular growth, delayed spore germination, and defective asexual sporulation (conidiation) in both aspergilli. Moreover, CpcB is necessary for proper expression of the key developmental activator brlA during initiation and progression of conidiation in A. nidulans and A. fumigatus. Somewhat in accordance with the previous study, the absence of cpcB results in the formation of fewer, but not micro-, cleistothecia in A. nidulans in the presence of wild type veA, an essential activator of sexual development. However, the cpcB deletion mutant cleistothecia contain no ascospores, validating that CpcB is required for progression and completion of sexual fruiting including ascosporogenesis. Furthermore, unlike the canonical GβSfaD, CpcB is not needed for the biosynthesis of the mycotoxin sterigmatocystin (ST) as the cpcB null mutant produced reduced amount of ST with unaltered STC gene expression. However, in A. fumigatus, the deletion of cpcB results in the blockage of gliotoxin (GT) production. Further genetic analyses in A. nidulans indicate that CpcB may play a central role in vegetative growth, which might be independent of FadA- and GanB-mediated signaling. A speculative model summarizing the roles of CpcB in conjunction with SfaD in A. nidulans is presented. 23845253 Bayesian approach for clinical trial safety data using an ising prior. In drug safety, development of statistical methods for multiplicity adjustments has exploited potential relationships among adverse events (AEs) according to underlying medical features. Due to the coarseness of the biological features used to group AEs together, which serves as the basis for the adjustment, it is possible that a single adverse event can be simultaneously described by multiple biological features. However, existing methods are limited in that they are not structurally flexible enough to accurately exploit this multi-dimensional characteristic of an adverse event. In order to preserve the complex dependencies present in clinical safety data, a Bayesian approach for modeling the risk differentials of the AEs between the treatment and comparator arms is proposed which provides a more appropriate clinical description of the drug's safety profile. The proposed procedure uses an Ising prior to unite medically related AEs. The proposed method and an existing Bayesian method are applied to a clinical dataset, and the signals from the two methods are presented. Results from a small simulation study are also presented. 23957576 Droplet-interfaced microchip and capillary electrophoretic separations. Both capillary and chip-based electrophoresis are powerful separation methods widely used for the separation of complex analytical mixtures in the fields of genomics, proteomics, metabolomics and cellular analysis. However their utility as basic tools in high-throughput analysis and multi-dimensional separations has been hampered by inefficient or biased sample injection methods. Herein we address this problem through the development of a simple separation platform that incorporates droplet-based microfluidic module for the encapsulation of analytes prior to the analytical separation. This method allows for the precise and reproducible injection of pL-volume isolated plugs into an electrophoretic separation channel. The developed platform is free from inter sample contamination, allows for a high-throughput analysis, and can provide quantitative analytical information. 23751332 Treatment of micropollutants in municipal wastewater: Ozone or powdered activated carbon? Many organic micropollutants present in wastewater, such as pharmaceuticals and pesticides, are poorly removed in conventional wastewater treatment plants (WWTPs). To reduce the release of these substances into the aquatic environment, advanced wastewater treatments are necessary. In this context, two large-scale pilot advanced treatments were tested in parallel over more than one year at the municipal WWTP of Lausanne, Switzerland. The treatments were: i) oxidation by ozone followed by sand filtration (SF) and ii) powdered activated carbon (PAC) adsorption followed by either ultrafiltration (UF) or sand filtration. More than 70 potentially problematic substances (pharmaceuticals, pesticides, endocrine disruptors, drug metabolites and other common chemicals) were regularly measured at different stages of treatment. Additionally, several ecotoxicological tests such as the Yeast Estrogen Screen, a combined algae bioassay and a fish early life stage test were performed to evaluate effluent toxicity. Both treatments significantly improved the effluent quality. Micropollutants were removed on average over 80% compared with raw wastewater, with an average ozone dose of 5.7mgO3l(-1) or a PAC dose between 10 and 20mgl(-1). Depending on the chemical properties of the substances (presence of electron-rich moieties, charge and hydrophobicity), either ozone or PAC performed better. Both advanced treatments led to a clear reduction in toxicity of the effluents, with PAC-UF performing slightly better overall. As both treatments had, on average, relatively similar efficiency, further criteria relevant to their implementation were considered, including local constraints (e.g., safety, sludge disposal, disinfection), operational feasibility and cost. For sensitive receiving waters (drinking water resources or recreational waters), the PAC-UF treatment, despite its current higher cost, was considered to be the most suitable option, enabling good removal of most micropollutants and macropollutants without forming problematic by-products, the strongest decrease in toxicity and a total disinfection of the effluent. 23937272 Hierarchical NiCo2O4@NiCo2O4 Core/Shell Nanoflake Arrays as High-Performance Supercapacitor Materials. Hierarchical NiCo2O4@NiCo2O4 core/shell nanoflake arrays on nickel foam for high-performance supercapacitors are fabricated by a two-step solution-based method which involves in hydrothermal process and chemical bath deposition. Compared with the bare NiCo2O4 nanoflake arrays, the core/shell electrode displays better pseudocapacitive behaviors in 2 M KOH, which exhibits high areal specific capacitances of 1.55 F cm(-2) at 2 mA cm(-2) and 1.16 F cm(-2) at 40 mA cm(-2) before activation as well as excellent cycling stability. The specific capacitance can achieve a maximum of 2.20 F cm(-2) at a current density of 5 mA cm(-2), which can still retain 2.17 F cm(-2) (98.6% retention) after 4000 cycles. The enhanced pseudocapacitive performances are mainly attributed to its unique core/shell structure, which provides fast ion and electron transfer, a large number of active sites, and good strain accommodation. 23855918 Coring-out fistulectomy with a newly designed 'fistulectome' for complicated perianal fistulae: a retrospective clinical analysis. Conventional surgery for complex anal fistula (AF) is associated with continence disturbance and recurrence. In the hope of reducing these we developed a new mechanical device, the 'fistulectome', to excise the entire fistula tract. Between March 2001 and April 2011, 136 patients underwent surgery for a complex AF using the fistulectome. All fistulae were cryptoglandular in origin. Five patients were lost to follow up and were excluded from the analysis. Of the 131 fistulae, 76 were trans-sphincteric, 14 were suprasphincteric and 16 were extrasphincteric. Seven had a horseshoe extension and 18 were unclassified. Of the 131, 108 had recurred after conventional fistulotomy performed at another centre and 23 were primary. The mean duration of follow up was 34.6 months, the mean hospital stay was 5 days and the healing time was 14 days. Recurrence, flatus incontinence and soiling occurred in 17 (12.9%), four (3.5%) and two (1.52%) patients. The results of this series suggest that coring-out of a fistula using a fistulectome may be a valid treatment for complicated anal fistula. 23963359 Prediction of different types of liver diseases using rule based classification model. Diagnosing different types of liver diseases clinically is a quite hectic process because patients have to undergo large numbers of independent laboratory tests. On the basis of results and analysis of laboratory test, different liver diseases are classified. Hence to simplify this complex process, we have developed a Rule Base Classification Model (RBCM) to predict different types of liver diseases. The proposed model is the combination of rules and different data mining techniques.OBJECTIVE: The objective of this paper is to propose a rule based classification model with machine learning techniques for the prediction of different types of Liver diseases.METHOD: A dataset was developed with twelve attributes that include the records of 583 patients in which 441 patients were male and rests were female. Support Vector Machine (SVM), Rule Induction (RI), Decision Tree (DT), Naive Bayes (NB) and Artificial Neural Network (ANN) data mining techniques with K-cross fold technique are used with the proposed model for the prediction of liver diseases. The performance of these data mining techniques are evaluated with accuracy, sensitivity, specificity and kappa parameters as well as statistical techniques (ANOVA and Chi square test) are used to analyze the liver disease dataset and independence of attributes.RESULT: Out of 583 patients, 416 patients are liver diseases affected and rests of 167 patients are healthy. The proposed model with decision tree (DT) technique provides the better result among all techniques (RI, SVM, ANN and NB) with all parameters (Accuracy 98.46%, Sensitivity 95.7%, Specificity 95.28% and Kappa 0.983) while the SVM exhibits poor performance (Accuracy 82.33%, Sensitivity 68.03%, Specificity 91.28% and Kappa 0.801). It is also found that the best performance of the model without rules (RI, Accuracy 82.68%, Sensitivity 86.34%, Specificity 90.51% and Kappa 0.619) is almost similar to the worst performance of the rule based classification model (SVM, Accuracy 82.33%, Sensitivity 68.03%, Specificity 91.28% and Kappa 0.801 and the accuracy of chi square test is 76.67%.CONCLUSION: This study demonstrates that there is a significant difference between the proposed rules based classification model and the model without rules for the liver diseases prediction and the rule based classification model with decision tree (DT) technique provides most accurate result. This model can be used as a valuable tool for medical decision making. 23921719 Is self-rated health still sensitive for changes in disease and functioning among nonagenarians? Objectives. With age, there is an increasing gap between relatively stable levels of self-rated health (SRH) and actual health status. This study investigates longitudinal changes in SRH and examines its sensitivity to changes in chronic conditions and functioning among people aged 90 and older. In the Vitality 90+ Study, questionnaires were sent to all people aged 90 years and older living in Tampere, Finland. Included were respondents who provided data on the 2001 measurement and at least one follow-up measurement in 2003, 2007, or 2010 (N = 334). Generalized Estimating Equations analyses examined longitudinal change in SRH and the predictive value of number of chronic conditions and a functioning score based on 5 activities. Within 2 years, most people (56.3%) had unchanged SRH, but declined SRH (22.3%) was associated with worse baseline functioning and declined functioning. Clear declines in SRH after 6 and 9 years were associated with increased chronic conditions (odds ratio [OR] = 1.23) and decreased functioning (OR = 1.28). The impact of chronic conditions and functioning was smaller among institutionalized people (chronic conditions OR = 0.90; functioning OR = 1.18) than among people living independently (chronic conditions OR = 1.30; functioning OR = 1.44). Discussion. SRH among nonagenarians was sensitive to changes in the number of chronic conditions and functioning although more pronounced on the longer than on the shorter term. 23934736 Genome-Wide Association Study of a Heart Failure Related Metabolomic Profile Among African Americans in the Atherosclerosis Risk in Communities (ARIC) Study. Both the prevalence and incidence of heart failure (HF) are increasing, especially among African Americans, but no large-scale, genome-wide association study (GWAS) of HF-related metabolites has been reported. We sought to identify novel genetic variants that are associated with metabolites previously reported to relate to HF incidence. GWASs of three metabolites identified previously as risk factors for incident HF (pyroglutamine, dihydroxy docosatrienoic acid, and X-11787, being either hydroxy-leucine or hydroxy-isoleucine) were performed in 1,260 African Americans free of HF at the baseline examination of the Atherosclerosis Risk in Communities (ARIC) study. A significant association on chromosome 5q33 (rs10463316, MAF = 0.358, P-value = 1.92 × 10(-10) ) was identified for pyroglutamine. One region on chromosome 2p13 contained a nonsynonymous substitution in N-acetyltransferase 8 (NAT8) was associated with X-11787 (rs13538, MAF = 0.481, P-value = 1.71 × 10(-23) ). The smallest P-value for dihydroxy docosatrienoic acid was rs4006531 on chromosome 8q24 (MAF = 0.400, P-value = 6.98 × 10(-7) ). None of the above SNPs were individually associated with incident HF, but a genetic risk score (GRS) created by summing the most significant risk alleles from each metabolite detected 11% greater risk of HF per allele. In summary, we identified three loci associated with previously reported HF-related metabolites. Further use of metabolomics technology will facilitate replication of these findings in independent samples. 23927094 Theory of the directionality and spatial coherence of wind-driven ambient noise in a deep ocean with attenuation. Acoustic attenuation in seawater usually has little effect on the spatial statistics of ambient noise in the ocean. This expectation does not hold, however, at higher frequencies, above 10 kHz, and extreme depths, in excess of 6 km, an operating regime that is within the capabilities of the most recently developed acoustic instrument platforms. To quantify the effects of attenuation, theoretical models for the vertical directionality and the spatial coherence of wind-generated ambient noise are developed in this paper, based on a uniform distribution of surface sources above a semi-infinite, homogeneous ocean. Since there are no bottom reflections, all the noise is downward traveling; and the angular width of the directional density function becomes progressively narrower with increasing frequency because sound from the more distant sources experiences greater attenuation than acoustic arrivals from overhead. This narrowing of the noise lobe modifies the spatial coherence, shifting the zeros in the horizontal (vertical) coherence function to higher (lower) frequencies. In addition, the attenuation modifies the amplitudes of the higher-order oscillations in the horizontal and vertical coherence functions, tending to suppress the former and enhance the latter. These effects are large enough to be detectable with the latest deep-diving sensor technology. 23176702 Effector memory T-cell frequencies in relation to tumour stage, location and HPV status in HNSCC patients. The immune system plays an important role in tumour immune surveillance. Head and neck squamous cell carcinoma patients are often immune compromised. To chart the baseline levels of T-cell subpopulation frequencies in patients with cancer prior to treatment. Blood samples of patients were taken at the time of diagnosis, analysed with flowcytometry and compared with blood samples of healthy donors. Compared to healthy donors, a significant shift from naive to effector memory T cells was observed. This effect was most prominent in stage II patients. A similar shift from naive to effector memory T cells was noted in patients with oropharynx or larynx squamous cell carcinomas. Furthermore, the percentage of effector memory and effector T cells was higher in the group of patients with human papillomavirus-positive oropharyngeal squamous cell carcinomas, compared with patients with human papillomavirus-negative tumours, suggestive of virus-induced T-cell activation. Here, we provide a simple and easily implementable tool to document T lymphocyte subsets in the peripheral blood of head and neck cancer patients, which might be useful for prognosis and/or therapy response prediction. 23782455 Identification of the grincamycin gene cluster unveils divergent roles for GcnQ in different hosts, tailoring the L-rhodinose moiety. The gene cluster responsible for grincamycin (GCN, 1) biosynthesis in Streptomyces lusitanus SCSIO LR32 was identified; heterologous expression of the GCN cluster in S. coelicolor M512 yielded P-1894B (1b) as a predominant product. The ΔgcnQ mutant accumulates intermediate 1a and two shunt products 2a and 3a bearing L-rhodinose for L-cinerulose A substitutions. In vitro data demonstrated that GcnQ is capable of iteratively tailoring the two L-rhodinose moieties into L-aculose moieties, supporting divergent roles of GcnQ in different hosts. 23832263 Changes in antiplatelet use prior to incident ischaemic stroke over 7 years in a UK centre and the association with stroke subtype. guidelines have changed in relation to the indication of antiplatelet therapy for the primary and secondary prevention of stroke. Of interest is how the proportion of patients who had or had not taken antiplatelet agents prior to an incident stroke has changed over time, whether the type of antiplatelet agents used has altered and whether prior antiplatelet use is associated with a particular ischaemic stroke subtype. a stroke register was retrospectively examined. All ischaemic stroke patients admitted between January 2004 and March 2011 to a single University Hospital with a catchment population of ∼750,000 were included. We excluded those who were on anticoagulants prior to the ischaemic stroke. a total of 4,307 ischaemic stroke patients [male 47.5%, mean age 77.6 (SD 11.7) years] were included. Of them, 54.7% (SD 2.2%) were not on any antiplatelet therapy prior to their incident stroke. The type and pattern of antiplatelet use prior to stroke did not change significantly during the 7-year study period, and there were no statistically significant differences between different ischaemic stroke subtypes with regards to prior antiplatelet use. our findings highlight the requirement to improve currently available risk prediction scores as well as the potential clinical impact of antiplatelet resistance within the at risk population who are already on antiplatelets. These findings also indicate that targeting of multiple risk factors may be very important in stroke prevention. 23874595 Biological signal processing with a genetic toggle switch. Complex gene regulation requires responses that depend not only on the current levels of input signals but also on signals received in the past. In digital electronics, logic circuits with this property are referred to as sequential logic, in contrast to the simpler combinatorial logic without such internal memory. In molecular biology, memory is implemented in various forms such as biochemical modification of proteins or multistable gene circuits, but the design of the regulatory interface, which processes the input signals and the memory content, is often not well understood. Here, we explore design constraints for such regulatory interfaces using coarse-grained nonlinear models and stochastic simulations of detailed biochemical reaction networks. We test different designs for biological analogs of the most versatile memory element in digital electronics, the JK-latch. Our analysis shows that simple protein-protein interactions and protein-DNA binding are sufficient, in principle, to implement genetic circuits with the capabilities of a JK-latch. However, it also exposes fundamental limitations to its reliability, due to the fact that biological signal processing is asynchronous, in contrast to most digital electronics systems that feature a central clock to orchestrate the timing of all operations. We describe a seemingly natural way to improve the reliability by invoking the master-slave concept from digital electronics design. This concept could be useful to interpret the design of natural regulatory circuits, and for the design of synthetic biological systems. 23868746 Evaluation of cytomegalovirus (CMV)-specific t-cell immunity for the assessment of the risk of active CMV infection in non-immunosuppressed surgical and trauma intensive care unit patients. The current study was designed to assess the predictive value of the evaluation of cytomegalovirus (CMV)-specific T-cell immunity early following admission to the intensive care unit for inferring the risk of active CMV infection in non-immunosuppressed surgical and trauma patients. A total of 31 CMV-seropositive patients were included. Patients were screened for the presence of CMV DNA in plasma and in tracheal aspirates by real-time PCR. Enumeration of CMV pp65 and IE-1-specific IFN-γ CD8(+) and CD4(+) T cells was performed by flow cytometry for intracellular cytokine staining. Virological and immunological monitoring was conducted once or twice a week. Active CMV infection occurred in 17 out of 31 patients. Undetectable levels of pp65 and IE-1-specific IFN-γ CD8(+) and CD4(+) T-cell subsets cells were observed in 10 patients who developed active CMV infection and in one who did not (at a median of 2 days following ICU admission). Peak CMV DNA loads in both tracheal aspirates and plasma were substantially higher (P = 0.018 and P = 0.091, respectively) in patients with undetectable IFN-γ T-cell responses than in patients with detectable responses. The expansion of both CMV-specific T-cell subsets following detection of active CMV infection was demonstrated in 9 out of 14 patients with active CMV infection. In conclusion, the evaluation of CMV pp65 and IE-1-specific IFN-γ-producing CD8(+) and CD4(+) T cells early following ICU admission may allow the identification of patients most at risk of either having or developing an episode of active CMV infection, particularly those associated with high-level virus replication. J Med. Virol. 85:1802-1810, 2013. © 2013 Wiley Periodicals, Inc. 23639539 Synthesis, spectral and antimicrobial evaluation of some novel 1-methyl-3-alkyl-2,6-diphenylpiperidin-4-one oxime carbonates. Synthesis of some novel biologically active piperidin-4-one oxime carbonates from 1-methyl-3alkyl-2,6-diphenylpiperidin-4-one oximes and substituted chloroformates was carried out in the presence of potassium carbonate as base and tetrabutylammonium bromide (TBAB) as catalyst. The newly synthesized compounds were characterized by IR, (1)H, (13)C NMR and LC-mass spectra. Based on the (1)H NMR analysis, all the compounds were found to adopt normal chair conformation with equatorial orientation of all the substituents. For all the synthesized compounds (5a-5l) antimicrobial activity has been tested against bacterial and fungal strains using Streptomycin and Amphotericin B as standards. 23861878 Species Delimitation and Morphological Divergence in the Scorpion Centruroides vittatus (Say, 1821): Insights from Phylogeography. Scorpion systematics and taxonomy have recently shown a need for revision, partially due to insights from molecular techniques. Scorpion taxonomy has been difficult with morphological characters as disagreement exists among researchers with character choice for adequate species delimitation in taxonomic studies. Within the family Buthidae, species identification and delimitation is particularly difficult due to the morphological similarity among species and extensive intraspecific morphological diversity. The genus Centruroides in the western hemisphere is a prime example of the difficulty in untangling the taxonomic complexity within buthid scorpions. In this paper, we present phylogeographic, Ecological Niche Modeling, and morphometric analyses to further understand how population diversification may have produced morphological diversity in Centruroides vittatus (Say, 1821). We show that C. vittatus populations in the Big Bend and Trans-Pecos region of Texas, USA are phylogeographically distinct and may predate the Last Glacial Maximum (LGM). In addition, we suggest the extended isolation of Big Bend region populations may have created the C. vittatus variant once known as C. pantheriensis. 23065917 Prevalence of hypertension in a large cohort of Italian hemodialysis patients: results of a cross-sectional study. Background: Hypertension is very common among patients receiving hemodialysis; however, little is known about its prevalence and control following the publication of the Kidney Disease Outcomes Quality Initiative (KDOQI) recommendations. Methods: This was a multicenter, observational, prospective, cross-sectional study aimed at evaluating the prevalence of hypertension and its awareness in a large sample of hemodialysis patients in Italy, and assessing possible relationships between high blood pressure (BP) values and traditional and nontraditional cardiovascular risk factors. Predialysis hypertension was defined as systolic BP (SBP) / diastolic BP (DBP) =140/90 mm Hg, and postdialysis hypertension as SBP/DBP =130/80 mm Hg or the use of antihypertensive medications. Results: We collected data for 4,022 patients (men/women 2,478/1,544, mean age 67.14 ± 14.08 years) from 77 dialysis centers. Of these, 2,832 patients (70.3%) were defined as having predialysis hypertension. At logistic regression analysis, diabetes, months on dialysis, serum albumin levels and treatment with erythropoiesis-stimulating agent (ESA) were independent factors predicting predialysis hypertension. Antihypertensive agents were used in 57.7% of the patients, leading to adequate BP control in only 40% of them. Factors independently predicting inadequate BP control were diabetes, ESA therapy, high serum cholesterol and higher Kt/V values. Conclusions: Hypertension is highly prevalent in this Italian hemodialysis population; achievement of adequate BP control is inadequate. It is unclear whether this may reflect suboptimal diagnosis or treatment of hypertension or, more likely, the allowance of higher predialysis BP values to try to avoid abrupt BP falls during the dialytic session. 23702418 Advances in diffusion MRI acquisition and processing in the Human Connectome Project. The Human Connectome Project (HCP) is a collaborative 5-year effort to map human brain connections and their variability in healthy adults. A consortium of HCP investigators will study a population of 1200 healthy adults using multiple imaging modalities, along with extensive behavioral and genetic data. In this overview, we focus on diffusion MRI (dMRI) and the structural connectivity aspect of the project. We present recent advances in acquisition and processing that allow us to obtain very high-quality in-vivo MRI data, whilst enabling scanning of a very large number of subjects. These advances result from 2years of intensive efforts in optimising many aspects of data acquisition and processing during the piloting phase of the project. The data quality and methods described here are representative of the datasets and processing pipelines that will be made freely available to the community at quarterly intervals, beginning in 2013. 23871889 Effects of Habitual Coffee Consumption on Cardiometabolic Disease, Cardiovascular Health, and All-cause Mortality. Coffee is the most widely consumed beverage in the United States (US) after water, and is the principal source of caffeine intake among adults. The biological effects of coffee may be substantial and are not limited to the actions of caffeine. Coffee is a complex beverage containing hundreds of biologically-active compounds, and the health effects of chronic coffee intake are wide ranging. From a cardiovascular (CV) standpoint, coffee consumption may reduce the risks of type 2 diabetes mellitus (T2DM) and hypertension (HTN), as well as other conditions associated with CV risk such as obesity and depression; but it may adversely affect lipid profiles depending on how the beverage is prepared. Regardless, a growing body of data suggests that habitual coffee consumption is neutral to beneficial regarding the risks for a variety of adverse CV outcomes including coronary heart disease (CHD), congestive heart failure (CHF), arrhythmias, and stroke. Moreover, large epidemiological studies suggest that regular coffee drinkers have reduced risks for mortality-both CV and all-cause. The potential benefits also include protection against neurodegenerative diseases, improved asthma control, and lower risk of select gastrointestinal diseases. A daily intake of about 2 to 3 cups of coffee appears to be safe and is associated with neutral to beneficial effects for most of the studied health outcomes. However, most of the data on coffee's health effects are based upon observational data, with very few randomized controlled studies, and association does not prove causation. Additionally, the possible advantages of regular coffee consumption have to be weighed against potential risks (which are mostly related to its high caffeine content) including anxiety, insomnia, tremulousness and palpitations, as well as bone loss and possibly increased risk of fractures. 23935071 G-rich VEGF aptamer with locked and unlocked nucleic acid modifications exhibits a unique G-quadruplex fold. The formation of a single G-quadruplex structure adopted by a promising 25 nt G-rich vascular endothelial growth factor aptamer in a K(+) rich environment was facilitated by locked nucleic acid modifications. An unprecedented all parallel-stranded monomeric G-quadruplex with three G-quartet planes exhibits several unique structural features. Five consecutive guanine residues are all involved in G-quartet formation and occupy positions in adjacent DNA strands, which are bridged with a no-residue propeller-type loop. A two-residue D-shaped loop facilitates inclusion of an isolated guanine residue into the vacant spot within the G-quartet. The remaining two G-rich tracts of three residues each adopt parallel orientation and are linked with edgewise and propeller loops. Both 5' with 3 nt and 3' with 4 nt overhangs display well-defined conformations, with latter adopting a basket handle topology. Locked residues contribute to thermal stabilization of the adopted structure and formation of structurally pre-organized intermediates that facilitate folding into a single G-quadruplex. Understanding the impact of chemical modifications on folding, thermal stability and structural polymorphism of G-quadruplexes provides means for the improvement of vascular endothelial growth factor aptamers and advances our insights into driving nucleic acid structure by locking or unlocking the conformation of sugar moieties of nucleotides in general. 23611709 Zenith p-branch standard fenestrated endovascular graft for juxtarenal abdominal aortic aneurysms. This article reports the early clinical outcomes and experiences of Zenith pivot branch device (p-branch) standard fenestrated endovascular graft (Cook, Bloomington, Ind) for treating juxtarenal abdominal aortic aneurysm (AAA) originating below the superior mesenteric artery (SMA). A physician-sponsored investigational device exemption study was used to assess enrolled elective and emergency patients from August 2011 to September 2012 for treatment with an off-the-shelf Zenith p-branch device. Patients were included provided an anatomic seal could be established 4 mm below the SMA and the renal geometry fit the protocol based on reconstructed computed tomography data. The celiac artery was addressed with a scallop and the SMA with an 8-mm fenestration. The renal fenestrations were constructed as a modified design to allow a range of renal locations (7.5 mm radially from the center of the fenestration) to be acceptably treated with a single configuration. Two anatomic configurations were created for renal arteries (origins at the same level, or disparate renal arteries with left lower than right). Outcomes are reported in coherence with endovascular reporting standards documents. The study enrolled 16 patients (94% men; median age, 75 years [range, 59-87 years]) with a mean aneurysm size of 61 mm (range, 52-82 mm). Two were treated for aneurysm rupture. Technical success was achieved in all patients. The median fluoroscopy time was 62 minutes (range, 38-105 minutes), and the amount of contrast media was 69 mL (range, 31-121 mL). There were no aortic-related deaths, aneurysm ruptures, open surgical conversion, or type I/III endoleaks. One right renal artery occluded during follow-up in the setting of a conically shaped visceral aortic segment and was successfully treated with endovascular recanalization. The use of the p-branch device for aneurysms originating infra-SMA is associated with a high rate of technical success and minimal problems during the short follow-up duration. The off-the-shelf design allows for the treatment of ruptures and other urgent situations. Additional patients and more follow-up will be required to further define the risks and benefits of such a treatment strategy. 23541868 The effect of tranexamic Acid on blood loss and transfusion rate in primary total knee arthroplasty. Allogeneic blood transfusions remain common in primary total knee arthroplasty. We reviewed our experience with 2269 consecutive primary total knee arthroplasties in 2069 patients over a 3.5year period. In our cohort, 1838 received no TXA, 330 received TXA via IV infusion, and 130 had TXA applied topically. The need for blood transfusion, as well as hematocrit levels immediately after surgery in the recovery room and the day of discharge were recorded. Tranexamic acid infusion demonstrated a statistically significant decrease in blood transfusion (P=0.001), as did topical application of TXA (P=0.019). The transfusion rate without TXA was 6.5% (120/1839) but only 0.3% (1/330) with TXA infusion. There were no transfusions (0/130) with topical TXA. Statistical differences were also noted in both immediate post operative and day of discharge hematocrit levels in patients having TXA infusion while those values for patients with TXA irrigation failed to obtain statistical significance. No significant change in the rate of symptomatic deep venous thrombosis or pulmonary embolism was noted. 23631841 Group B Streptococcus pilus sortase regulation: a single mutation in the lid region induces pilin protein polymerization in vitro. Gram-positive bacteria build pili on their cell surface via a class C sortase-catalyzed transpeptidation mechanism from pilin protein substrates. Despite the availability of several crystal structures, pilus-related C sortases remain poorly characterized to date, and their mechanisms of transpeptidation and regulation need to be further investigated. The available 3-dimensional structures of these enzymes reveal a typical sortase fold, except for the presence of a unique feature represented by an N-terminal highly flexible loop known as the "lid." This region interacts with the residues composing the catalytic triad and covers the active site, thus maintaining the enzyme in an autoinhibited state and preventing the accessibility to the substrate. It is believed that enzyme activation may occur only after lid displacement from the catalytic domain. In this work, we provide the first direct evidence of the regulatory role of the lid, demonstrating that it is possible to obtain in vitro an efficient polymerization of pilin subunits using an active C sortase lid mutant carrying a single residue mutation in the lid region. Moreover, biochemical analyses of this recombinant mutant reveal that the lid confers thermodynamic and proteolytic stability to the enzyme.-Cozzi, R., Zerbini, F., Assfalg, M., D'Onofrio, M., Biagini, M., Martinelli, M., Nuccitelli, A., Norais, N., Telford, J. L., Maione, D., Rinaudo, C. D. Group B Streptococcus pilus sortase regulation: a single mutation in the lid region induces pilin protein polymerization in vitro. 23934304 Change Patterns of Homeless Individuals with Mental Illness: A Multiple Case Study. This multiple case study illuminates the individual change trajectories of four homeless men with mental illnesses who participated in a manualized life skills intervention to improve housing retention. Readiness-to-change, life skills knowledge and trauma symptoms were measured at baseline, post-intervention and at 3-6 months follow-up. Cluster analysis identified two patterns of readiness-to-change: engaged and pre-engaged. Change is non-linear and baseline readiness is not necessary to benefit from the intervention. Examining individuals' lives in context illuminated the change process and demonstrated that varied patterns can lead to successful outcomes for housing stability and community reintegration. 23800642 Severe obesity and diabetes insipidus in a patient with PCSK1 deficiency. Non-synonymous mutations affecting both alleles of PCSK1 (proprotein convertase 1/3) are associated with obesity and impaired prohormone processing. We report a proband who was compound heterozygous for a maternally inherited frameshift mutation and a paternally inherited 474kb deletion that encompasses PCSK1, representing a novel genetic mechanism underlying this phenotype. Although pro-vasopressin is not a known physiological substrate of PCSK1, the development of central diabetes insipidus in this proband suggests that PCSK1 deficiency can be associated with impaired osmoregulation. 23591749 Protective effects of kaempferol on isoniazid- and rifampicin-induced hepatotoxicity. Isoniazid (INH) and rifampicin (RIF) are the first-line drugs for antituberculosis (anti-TB) chemotherapy. The levels of serum transaminases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] are abnormal in 27% of patients undergoing INH and RIF treatments and in 19% of patients undergoing treatment with INH alone. Cytochrome P450 2E1 (CYP2E1) metabolizes many toxic substrates, including ethanol, carbon tetrachloride, and INH, which ultimately results in liver injury. The objective of this study was to screen for CYP2E1 inhibitors in vitro and investigate whether the selected compound could prevent INH/RIF-induced hepatotoxicity in vivo. We screened 83 known compounds from food and herbal medicines as inhibitors of CYP2E1. The hepatotoxic dose of INH/RIF was 50/100 mg kg(-1) day(-1). Hepatotoxicity was assessed using galactose single-point (GSP) method (a quantitative measurement of liver function), histopathological examination of the liver, malondialdehyde (MDA) assay, and measurement of AST and ALT activities. Kaempferol inhibited CYP2E1 activity in mice by 0.31- to 0.48-fold (p < 0.005). Mice with INH/RIF-induced hepatotoxicity showed significantly abnormal serum levels of AST and ALT, and GSP value, and these values could be decreased by the administration of kaempferol (p < 0.005). Kaempferol significantly reduced the depletion of hepatic glutathione and prevented the increase in MDA formation in mice. Furthermore, kaempferol did not affect the anti-TB effects of INH/RIF. To our knowledge, this is the first report of kaempferol's utility as an adjuvant for preventing CYP2E1-mediated hepatotoxicity induced by drugs such as INH and RIF. 23880114 Marital distress prospectively predicts poorer cellular immune function. Distressed marriages enhance risk for a variety of health problems. Immune dysregulation is one potential mechanism; cross-sectional studies have demonstrated that marital distress is linked to maladaptive immune alterations. The current study filled an important gap in the literature by examining the ability of marital distress to prospectively predict immune alterations over a two-year period. Participants were 90 couples (N=180 individuals; Mage=25.67) married less than a year at the time of their first study visit. Both members of a couple completed a baseline assessment of marital quality and provided blood samples at baseline and two years later. 63 couples (N=123 individuals) completed the follow-up assessment. Spouses in more distressed marriages had larger declines in cellular immune function over time than spouses in less distressed marriages. Furthermore, the results were highly consistent across two different indices, proliferative responses to two mitogens, concanavalin A (Con A) and phytohemagglutinin (PHA). Marital distress has a variety of negative health consequences. The current study provided important evidence that marital distress has longer-term immune consequences. Accordingly, the present results provide a glimpse into the pathways through which marital distress may impact health over time. 23398328 Brand-specific consumption of alcohol among underage youth in the United States. Little is known about brand-specific alcohol consumption among underage youth, as existing information is collected at the level of alcoholic beverage type. This study identifies the alcohol brands consumed by a nationally representative sample of underage youth in the United States. We obtained a national sample of 1,032 underage youth, aged 13 to 20, using a pre-recruited Internet panel maintained by Knowledge Networks. Youth aged 18 to 20 were recruited directly from the panel via email invitation. Teens aged 13 to 17 were identified by asking adult panelists to identify a member of their household. The survey assessed the past 30-day consumption of 898 brands of alcohol among 16 alcoholic beverage types, including the frequency and amount of each brand consumed in the past 30 days. Market share for a given brand was calculated by dividing the total number of drinks for that brand in the past 30 days across the entire sample by the total number of drinks for all identified brands. The alcohol brands with highest prevalence of past 30-day consumption were Bud Light (27.9%, 95% confidence interval [CI] 23.3 to 32.4%), Smirnoff malt beverages (17.0%, 95% CI 12.9 to 21.1%), and Budweiser (14.6%, 95% CI 11.0 to 18.3%). Brand market share was concentrated in a relatively small number of brands, with the top 25 brands accounting for nearly half of all market shares. Underage youth alcohol consumption, although spread out over several alcoholic beverage types, is concentrated among a relatively small number of alcohol brands. This finding has important implications for alcohol research, practice, and policy. 23683834 20(S)-Protopanaxadiol (PPD) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs. Novel 20(S)-protopanoxadiol (PPD) analogues were designed, synthesized, and evaluated for the chemosensitizing activity against a multidrug resistant (MDR) cell line (KBvcr) overexpressing P-glycoprotein (P-gp). Structure-activity relationship analysis showed that aromatic substituted aliphatic amine at the 24-positions (groups V) effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as docetaxel (DOC), vincristine (VCR), and adriamycin (ADM). PPD derivatives 12 and 18 showed 1.3-2.6 times more effective reversal ability than verapamil (VER) for DOC and VCR. Importantly, no cytotoxicity was observed by the active PPD analogues (5μM) against both non-MDR and MDR cells, suggesting that PPD analogues serve as novel lead compounds toward a potent and safe resistance modulator. Moreover, a preliminary mechanism study demonstrated that the chemosensitizing activity of PPD analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells. 23680163 Biases in rhythmic sensorimotor coordination: effects of modality and intentionality. Sensorimotor biases were examined for intentional (tracking task) and unintentional (distractor task) rhythmic coordination. The tracking task involved unimanual tracking of either an oscillating visual signal or the passive movements of the contralateral hand (proprioceptive signal). In both conditions the required coordination patterns (isodirectional and mirror-symmetric) were defined relative to the body midline and the hands were not visible. For proprioceptive tracking the two patterns did not differ in stability, whereas for visual tracking the isodirectional pattern was performed more stably than the mirror-symmetric pattern. However, when visual feedback about the unimanual hand movements was provided during visual tracking, the isodirectional pattern ceased to be dominant. Together these results indicated that the stability of the coordination patterns did not depend on the modality of the target signal per se, but on the combination of sensory signals that needed to be processed (unimodal vs. cross-modal). The distractor task entailed rhythmic unimanual movements during which a rhythmic visual or proprioceptive distractor signal had to be ignored. The observed biases were similar as for intentional coordination, suggesting that intentionality did not affect the underlying sensorimotor processes qualitatively. Intentional tracking was characterized by active sensory pursuit, through muscle activity in the passively moved arm (proprioceptive tracking task) and rhythmic eye movements (visual tracking task). Presumably this pursuit afforded predictive information serving the coordination process. 23910734 The political economy of the public-private mix in heath expenditure: An empirical review of thirteen OECD countries. This study investigates the factors that may have influenced the public-private mix of health expenditure in 13 OECD countries from 1981 to 2007. The degree to which health services are socialized is regarded as the product of a trade-off between the desire to redistribute income through the fiscal system and the losses some citizens will incur when the public health care system expands. The estimation results show that, greater income inequality and population aging are associated with a smaller share of public health expenditure in total health expenditure. The more ideologically left-leaning the electorate is, the larger the share of public health expenditure. Private health insurance tends to erode the political support for the public health care systems in countries with private duplicate health insurance, but not in countries with private primary health insurance. The findings suggest that the role of private sources of funding for health care is likely to grow in developed countries. The expansion of public coverage to include pharmaceuticals and long-term care in some countries may (theoretically) encounter less opposition if the current insurance holders have no duplicate coverage, if the voters as a whole share more left-leaning political ideology, and if low-income voters are more politically mobilized. 23831565 Sampling from the mental number line: How are approximate number system representations formed? Nonsymbolic comparison tasks are commonly used to index the acuity of an individual's Approximate Number System (ANS), a cognitive mechanism believed to be involved in the development of number skills. Here we asked whether the time that an individual spends observing numerical stimuli influences the precision of the resultant ANS representations. Contrary to standard computational models of the ANS, we found that the longer the stimulus was displayed, the more precise was the resultant representation. We propose an adaptation of the standard model, and suggest that this finding has significant methodological implications for numerical cognition research. 23775124 LIM-Only Protein FHL2 Activates NF-κB Signaling in the Control of Liver Regeneration and Hepatocarcinogenesis. Four-and-a-half LIM-only protein 2 (FHL2) is an important mediator in many signaling pathways. In this study, we analyzed the functions of FHL2 in nuclear factor κB (NF-κB) signaling in the liver. We show that FHL2 enhanced tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) activity in transcriptional activation of NF-κB targets by stabilizing the protein. TRAF6 is a binding partner of FHL2 and an important component of the Toll-like receptor-NF-κB pathway. Knockdown of FHL2 in 293-hTLR4/MD2-CD14 cells impaired lipopolysaccharide (LPS)-induced NF-κB activity, which regulates expression of inflammatory cytokines. Indeed, FHL2(-/-) macrophages showed significantly reduced production of TNF and interleukin 6 (IL-6) following LPS stimulation. TNF and IL-6 are the key cytokines that prime liver regeneration after hepatic injury. Following partial hepatectomy, FHL2(-/-) mice exhibited diminished induction of TNF and IL-6 and delayed hepatocyte regeneration. In the liver, NF-κB signaling orchestrates inflammatory cross talk between hepatocytes and hepatic immune cells that promote chemical hepatocarcinogenesis. We found that deficiency of FHL2 reduced susceptibility to diethylnitrosamine-induced hepatocarcinogenesis, correlating with the activator function of FHL2 in NF-κB signaling. Our findings demonstrate FHL2 as a positive regulator of NF-κB activity in liver regeneration and carcinogenesis and highlight the importance of FHL2 in both hepatocytes and hepatic immune cells. 23118328 Evaluation of the relationship between sex, polymorphisms in CYP2C8 and CYP2C9, and pharmacokinetics of angiotensin receptor blockers. Angiotensin II receptor blockers (ARBs) are used to treat hypertension. Most ARBs are metabolized by CYP2C9. The aim of this study is to evaluate the possible association between sex, polymorphisms in the CYP2C8 and CYP2C9 genes, and the pharmacokinetics of losartan, valsartan, candesartan, and telmisartan. The study population comprised 246 healthy volunteers from seven single-dose clinical trials: 64 from two candesartan studies, 43 from a telmisartan study, 36 from a losartan study, and 103 from three valsartan studies. DNA was extracted from blood samples and single-nucleotide polymorphisms in the CYP2C8 (CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP2C8*5) and CYP2C9 (CYP2C9*2, CYP2C9*3) genes were evaluated using real-time polymerase chain reaction. Sex only affected telmisartan pharmacokinetics, since women showed a higher telmisartan C(max) than men (590.5 ± 75.8 ng/ml versus 282.1 ± 30.8 ng/ml; P ≤ 0.01). CYP2C9 variants were associated only with losartan pharmacokinetics: the half-life of losartan was higher in CYP2C9*3 allele carriers (3.1 ± 0.4 hours) than in volunteers with the wild-type genotype (2.3 ± 0.1 hours) (P ≤ 0.05). CYP2C8 polymorphisms were associated only with valsartan pharmacokinetics, since *2 allele carriers showed faster clearance (1.07 ± 0.57 l/h·kg) than those with the wild-type genotype (0.48 ± 0.72 l/h·kg; P ≤ 0.01) and carriers of the *3 allele (0.35 ± 0.49 l/h·kg; P ≤ 0.001). These results suggest that genotypes for CYP2C9 and CYP2C8 are relevant to the pharmacokinetics of losartan and valsartan, respectively, but not the pharmacokinetics of candesartan or telmisartan. 23760279 A Conserved Motif in Tetrahymena thermophila Telomerase Reverse Transcriptase Is Proximal to the RNA Template and Is Essential for Boundary Definition. The ends of linear chromosomes are extended by telomerase, a ribonucleoprotein complex minimally consisting of a protein subunit called telomerase reverse transcriptase (TERT) and the telomerase RNA (TER). TERT functions by reverse transcribing a short template region of TER into telomeric DNA. Proper assembly of TERT and TER is essential for telomerase activity; however, a detailed understanding of how TERT interacts with TER is lacking. Previous studies have identified an RNA binding domain (RBD) within TERT, which includes three evolutionarily conserved sequence motifs: CP2, CP, and T. Here, we used site-directed hydroxyl radical probing to directly identify sites of interaction between the TERT RBD and TER, revealing that the CP2 motif is in close proximity to a conserved region of TER known as the template boundary element (TBE). Gel shift assays on CP2 mutants confirmed that the CP2 motif is an RNA binding determinant. Our results explain previous work that established that mutations to the CP2 motif of TERT and to the TBE of TER both permit misincorporation of nucleotides into the growing DNA strand beyond the canonical template. Taken together, these results suggest a model in which the CP2 motif binds the TBE to strictly define which TER nucleotides can be reverse transcribed. 23359358 Evaluation of Current Eligibility Criteria for Bariatric Surgery: Diabetes prevention and risk factor changes in the Swedish Obese Subjects (SOS) study. OBJECTIVE Patients with a BMI <35 kg/m(2) and patients with a BMI between 35 and 40 kg/m(2) without comorbidities are noneligible by current eligibility criteria for bariatric surgery. We used Swedish obese subjects (SOS) to explore long-term outcomes in noneligible versus eligible patients. RESEARCH DESIGN AND METHODS The SOS study involved 2,010 obese patients who underwent bariatric surgery (68% vertical-banded gastroplasty, 19% banding, and 13% gastric bypass) and 2,037 contemporaneously matched obese controls receiving usual care. At inclusion, the participant age was 37-60 years and BMI was ≥34 kg/m(2) in men and ≥38 kg/m(2) in women. The effect of surgery was assessed in patients that do (n = 3,814) and do not (n = 233) meet current eligibility criteria. The date of analysis was 1 January 2012. The follow-up time was up to 20 years, with a median of 10 years. RESULTS Cardiovascular risk factors were significantly improved both in noneligible and eligible individuals after 10 years of follow-up. Surgery reduced the diabetes incidence in both the noneligible (adjusted hazard ratio 0.33 [95% CI 0.13-0.82], P = 0.017) and eligible (0.27 [0.22-0.33], P < 0.001) groups. We could not detect a difference in the effect of surgery between the groups (adjusted interaction P value = 0.713). CONCLUSIONS Bariatric surgery drastically reduced the incidence of type 2 diabetes both in noneligible and eligible patients and improved cardiovascular risk factors in both groups. Our results show that strict BMI cutoffs are of limited use for bariatric surgery prioritization if the aim is to prevent diabetes and improve cardiovascular risk factors. 23897856 Hepatitis C virus induced up-regulation of microRNA-27: A novel mechanism for hepatic steatosis. MicroRNAs (miRNAs) are small RNAs that post-transcriptionally regulate gene expression. Their aberrant expression is commonly linked with diseased states, including hepatitis C virus (HCV) infection. Herein, we demonstrate that HCV replication induces the expression of miR-27 in cell culture and in vivo HCV infectious models. Overexpression of the HCV proteins core and NS4B independently activates miR-27 expression. Furthermore, we establish that miR-27b overexpression in hepatocytes results in larger and more abundant lipid droplets, as observed by coherent anti-Stokes Raman scattering (CARS) microscopy. This hepatic lipid droplet accumulation coincides with miR-27b's repression of PPAR-α and ANGPTL3, known regulators of triglyceride homeostasis. We further demonstrate that treatment with a PPAR-α agonist, bezafibrate, is able to reverse the miR-27b-induced lipid accumulation in Huh7 cells. This miR-27b mediated repression of PPAR-α signaling represents a novel mechanism of HCV-induced hepatic steatosis. This link was further demonstrated in vivo through the correlation between miR-27b expression levels and hepatic lipid accumulation in HCV infected SCID-beige/Alb-uPa mice. Conclusion: Collectively, our results highlight HCV's up-regulation of miR-27 expression as a novel mechanism contributing to the development of hepatic steatosis. (Hepatology 2013;). 23388168 Drug treatments for schizophrenia: pragmatism in trial design shows lack of progress in drug design. Aims. The introduction of second generation antipsychotic (SGA) medication over a decade ago led to changes in prescribing practices; these drugs have eclipsed their predecessors as treatments for schizophrenia. However, the metabolic side effects of these newer antipsychotics have been marked and there are increasing concerns as to whether these novel drugs really are superior to their predecessors in terms of the balance between risks and benefits. In this article, we review the literature regarding comparisons between first generation antipsychotic (FGA) and SGA in terms of clinical effectiveness. Methods. Large (n > 150) randomized-controlled trials (RCTs) comparing the effectiveness (efficacy and side effects) of FGA and SGA medications other than clozapine were reviewed, as were meta-analyses that included smaller studies. Results. The superiority in efficacy and reduced extrapyramidal side effects (EPSE) of SGAs is modest, especially when compared with low-dose FGAs. However, the high risk of weight gain and other metabolic disturbances associated with certain SGAs such as olanzapine is markedly higher than the risk with FGAs at the doses used in the trials. Conclusions. The efficacy profiles of various FGAs and SGAs are relatively similar, but their side effects vary between and within classes. Overall, large pragmatic trials of clinical effectiveness indicate that the care used in prescribing and managing drug treatments to ensure tolerability may be more important than the class of drug used. 23954176 Some like it pungent and vile. TRPA1 as a molecular target for the malodorous vinyl disulfides from asafoetida. Ferula assa-foetida L. is a major source of asafoetida, a foul-smelling gum-resin of dietary and medicinal relevance. Investigation of the roots and latex of F. assa-foetida afforded various mixed vinyl disulfides, including two novel asadisulfide-type esters (3c and 3d). The reactivity of asadisulfide (3b) was investigated in the cysteamine NMR assay, where it behaved as disulfide shuffling agents due to the high mobility of the vinyl sulfide moiety. In accordance with their transthiolation capacity, these compounds potently activated TRPA1, the target of mustard oil and the pungent sulfur compounds from onion and garlic, qualifying S-alkyl-S-alkenyldisulfides, a rare class of natural products, as a novel class of dietary TRPA1 activators. These observations provide a mechanistic basis for rationalizing some of the sensory properties and potential beneficial health claims associated to the use of asafoetida as a spice and as a medicine. 23824515 Polycyclic aromatic hydrocarbons study in atmospheric fine and coarse particles using diagnostic ratios and receptor model in urban/industrial region. Atmospheric fine and coarse particles were collected in Teflon filters in three cities of the region of the Lower Sinos River Basin of Rio Grande do Sul in the year 2010. The filters were Soxhlet extracted, and 14 priority PAHs were analyzed using a gas chromatograph coupled to a mass spectrometer (GC/MS). The principal emission sources of these compounds were assessed by using diagnostic ratios and receptor model: positive matrix factorization (PMF 3.0) of the US Environmental Protection Agency. The results of PAHs concentration for the studied year showed significant levels of high molecular weight (HMW) PAH, Ind, and BghiP, in PM2.5 in the winter season, showing the influence of mobile sources. The application of receptor model PMF 3.0 revealed that the main sources of PAHs were vehicle fleet (both diesel and gasoline), followed by coal combustion, wood combustion, and resuspension of dust. The results of the receptor modeling are in agreement with the data obtained by the ratio diagnostic. 23152001 A dual role of Se on Cd toxicity: evidences from the uptake of Cd and some essential elements and the growth responses in paddy rice. This study was carried out to investigate the effects of selenium (Se) on the uptake and translocation of cadmium (Cd) and essential elements in paddy rice (Oryza sativa L., Shuangyou 998). Selenium could alleviate/aggravate Cd toxicity in paddy rice, which depended on the dosages of Se and/or Cd. When Cd treatment level was as low as 35.6 μM, ≤12.7 μM Se could inhibit the uptake of Cd in paddy rice and increase the biomass of paddy rice; however, with Cd levels reaching 89-178 μM, the addition of Se resulted in increases in Cd uptake and exacerbated the growth of paddy rice. Cd always inhibited the uptake of Se. Cd alone suppressed the uptake of Ca, Mg, Mn, Cu, and Zn; however, Se reversed the decreases in the concentrations of the said elements, suggesting an element regulation mechanism to relieve Cd toxicity. Without Cd in the solution, low doses of Se increased the biomasses of shoots and roots at the expense of the more or less decreases in the concentrations of Ca, Mg, K, Fe, Mn, Cu, and shoot Zn, indicating an antagonistic effect of Se on these cations. The presence of Cd could also reverse these decreases especially at the highest treatment levels for both Se and Cd, also suggesting an element regulation mechanism responsible for the detoxification of high dosages of Se. Consequently, when Se is used to alleviate Cd toxicity, attention must be paid to the Cd pollution extent and doses of Se supplement. 23775048 Effects of controlled discontinuation of long-term used antipsychotics on weight and metabolic parameters in individuals with intellectual disability. Antipsychotics are frequently prescribed agents in individuals with intellectual disability, often for behavioral symptoms. Efficacy of antipsychotics for this is ambiguous, so discontinuation should be considered. Weight gain and metabolic dysregulation are well-known adverse effects of antipsychotics which increase the risk of the metabolic syndrome. We performed a discontinuation study in 99 adults with intellectual disability, living in residential facilities who used antipsychotics for behavioral symptoms for more than 1 year. The aim of the present study was to investigate the effects of discontinuation of long-term used antipsychotics on weight, body mass index (BMI), and parameters of the metabolic syndrome and to investigate the influence of genetic polymorphisms and medication factors on these outcomes. Discontinuation of antipsychotics led to a mean decrease of 4 cm waist circumference, of 3.5 kg weight, 1.4 kg/m2 BMI, and 7.1 mm Hg systolic blood pressure. In those participants who had not completely discontinued use of antipsychotics we found a decrease in weight and BMI and an increase in fasting glucose. The presence of the C-allele of serotonin 5-hydroxytryptamine receptor polymorphism rs141334 was associated with higher waist circumference and higher plasma levels of triglycerides and lower levels of high-density lipoprotein. Achievement of complete discontinuation predicted a larger decrease in waist circumference and BMI. In conclusion, results of the study show the beneficial effects of discontinuation of long-term used antipsychotics on metabolic outcomes. 23892594 Influences of coal mining water irrigation on the maize losses in the Xingdong Mine area, China. In 2008, a maize underproduction disaster occurred in the Xianyu village after irrigation using the coal mining water from the Xingdong Mine, China. This disaster resulted in about 40 hectare maize underproduction and 20 hectare total loss of the maize yields. In order to study the reason, a total of 25 soil, water and plant samples were taken from the study area. These samples were analysed by inductively coupled plasma mass spectrometry and ion chromatography. The results indicate that the contents of both water-soluble fluorine and total fluorine are very high and resulting of maize underproduction and total loss of production. The possible pollution sources of fluorine in the study area could be from the coal mine water used for irrigation and glass chemical factory near the study area. 23389040 Natural products as a source for treating neglected parasitic diseases. Infectious diseases caused by parasites are a major threat for the entire mankind, especially in the tropics. More than 1 billion people world-wide are directly exposed to tropical parasites such as the causative agents of trypanosomiasis, leishmaniasis, schistosomiasis, lymphatic filariasis and onchocerciasis, which represent a major health problem, particularly in impecunious areas. Unlike most antibiotics, there is no "general" antiparasitic drug available. Here, the selection of antiparasitic drugs varies between different organisms. Some of the currently available drugs are chemically de novo synthesized, however, the majority of drugs are derived from natural sources such as plants which have subsequently been chemically modified to warrant higher potency against these human pathogens. In this review article we will provide an overview of the current status of plant derived pharmaceuticals and their chemical modifications to target parasite-specific peculiarities in order to interfere with their proliferation in the human host. 23909846 Prostaglandin E2 and nitric oxide mediate the acute inflammatory (erythemal) response to topical 5-aminolevulinic acid-photodynamic therapy in human skin. Topical 5-aminolevulinic acid-photodynamic therapy (5-ALA-PDT) causes a clinical inflammatory response in human skin. While histamine mediates the immediate reaction, the mediators of the prolonged erythema are unknown OBJECTIVE: To examine for involvement of pro-inflammatory mediators prostaglandin E2 (PGE2 ) and nitric oxide (NO) in topical PDT-induced erythema in human skin. A series of studies were performed in forearm skin of healthy volunteers (n=35). Following definition of the erythemal time-course and dose-response to 5-ALA-PDT, duplicate 5-ALA dose-series were iontophoresed into the skin of each ventral forearm and exposed to 100J/cm(2) broadband red light. Within subject, arms were randomised to control or treatment with cyclooxygenase and nitric oxide synthase inhibitors, indomethacin and N(ω)-nitro-L-arginine methyl ester (L-NAME), respectively, and impact on 5-ALA-PDT induced erythema quantified. Additionally, release of PGE2 and NO was directly assessed by sampling dermal microdialysate at intervals following 5-ALA-PDT. A 5-ALA dose-related delayed erythema occurred by 3h (r= 0.97, P<0.01), with erythema persisting to 48h post-PDT. Topical indomethacin applied immediately post-PDT reduced the slope of erythemal response at 3 and 24h (P<0.05). Intradermal injection of L-NAME into 5-ALA-PDT treated sites reduced the slope of response at 24h post-PDT (p<0.001) whilst significantly inhibiting erythema from 3-48h post-PDT (P<0.01). Analysis of dermal microdialysate showed release of NO and PGE2 following topical 5-ALA-PDT. Topical 5-ALA-PDT upregulates PGE2 and NO in human skin, where they play a significant role in the clinical inflammatory response. The potential relevance of these mediators to PDT of human cutaneous pathology warrants study. This article is protected by copyright. All rights reserved. 23660966 Intrinsic disorder of the bacterial cell division protein ZipA: coil-to-brush conformational transition. The full-length ZipA protein from Escherichia coli, one of the essential elements of the cell division machinery, was studied in a surface model built as adsorbed monolayers. The interplay between lateral packing and molecular conformation was probed using a combined methodology based on the scaling analysis of the surface pressure isotherms and ellipsometry measurements of the monolayer thickness. The observed behavior is compatible with the one expected for an intrinsically disordered and highly flexible protein that is preferentially structured in a random coil conformation. At low grafting densities, ZipA coils organize in a mushroom-like regime, whereas a coil-to-brush transition occurs on increasing lateral packing. The structural results suggest a functional scenario in which ZipA acts as a flexible tether anchoring bacterial proto-ring elements to the membrane during the earlier stages of division.-López-Montero, I., López-Navajas, P., Mingorance, J., Rivas, G., Vélez, M., Vicente, M., Monroy, F. Intrinsic disorder of the bacterial cell division protein ZipA: coil-to-brush conformational transition. 23963638 Sox transcription factors require selective interactions with Oct4 and specific transactivation functions to mediate reprogramming. The unique ability of Sox2 to cooperate with Oct4 at selective binding sites in the genome is critical for reprogramming somatic cells into induced pluripotent stem cells (iPSCs). We have recently demonstrated that Sox17 can be converted into a reprogramming factor by alteration of a single amino-acid (Sox17EK) within its DNA binding HMG domain. Here we expanded this study by introducing analogous mutations to 10 other Sox proteins and interrogated the role of N-and C-termini on the reprogramming efficiency. We found that point-mutated Sox7 and Sox17 can convert human and mouse fibroblasts into iPSCs, but Sox4, Sox5, Sox6, Sox8, Sox9, Sox11, Sox12, Sox13 and Sox18 cannot. Next we studied regions outside the HMG domain and found that the C-terminal transactivation domain of Sox17 and Sox7 enhances the potency of Sox2 in iPSC assays and confers weak reprogramming potential to the otherwise inactive Sox4EK and Sox18EK proteins. These results suggest that the glutamate (E) to lysine (K) mutation in the HMG domain is necessary, but insufficient to swap the function of Sox factors. Moreover, the HMG domain alone fused to the VP16 transactivation domain is able to induce reprogramming, albeit at low efficiency. By molecular dissection of the C-terminus of Sox17 we found that the β-catenin interaction region contributes to the enhanced reprogramming efficiency of Sox17EK. To mechanistically understand the enhanced reprogramming potential of Sox17EK we analysed ChIP-sequencing and expression data and identified a subset of candidate genes specifically regulated by Sox17EK and not by Sox2. Stem Cells 2013. 23940819 CD200R/CD200 Inhibits Osteoclastogenesis: New Mechanism of Osteoclast Control by Mesenchymal Stem Cells in Human. Bone homeostasis is maintained by the balance between bone-forming osteoblasts and bone-degrading osteoclasts. Osteoblasts have a mesenchymal origin whereas osteoclasts belong to the myeloid lineage. Osteoclast and osteoblast communication occurs through soluble factors secretion, cell-bone interaction and cell-cell contact, which modulate their activities. CD200 is an immunoglobulin superfamilly member expressed on various types of cells including mesenchymal stem cells (MSCs). CD200 receptor (CD200R) is expressed on myeloid cells such as monocytes/macrophages. We assume that CD200 could be a new molecule involved in the control of osteoclastogenesis and could play a role in MSC-osteoclast communication in humans. In this study, we demonstrated that soluble CD200 inhibited the differentiation of osteoclast precursors as well as their maturation in bone-resorbing cells in vitro. Soluble CD200 did not modify the monocyte phenotype but inhibited the receptor activator of nuclear factor kappa-B ligand (RANKL) signaling pathway as well as the gene expression of osteoclast markers such as osteoclast-associated receptor (OSCAR) and nuclear factor of activated T cells cytoplasmic 1 (NFATc1). Moreover, MSCs inhibited osteoclast formation, which depended on cell-cell contact and was associated with CD200 expression on the MSC surface. Our results clearly demonstrate that MSCs, through the expression of CD200, play a major role in the regulation of bone resorption and bone physiology and that the CD200-CD200R couple could be a new target to control bone diseases. 23836123 Laparoscopic versus open repair of parastomal hernias: an ACS-NSQIP analysis of short-term outcomes. Parastomal hernia (PSH) is a frequent complication following the creation of a stoma. While a significant number of cases require operative management, data comparing short-term outcomes of laparoscopic versus open repair of parastomal hernias are limited. The ACS-NSQIP was retrospectively reviewed from 2005 to 2011 for all PSH cases that underwent open or laparoscopic repair. Patients characteristics, operative details, and outcomes were listed for both procedure types. Selected end points were compared on multivariate regression analysis. Among the 2,167 identified parastomal hernia cases, only 222 (10.24 %) were treated laparoscopically. The open and laparoscopic groups were similar with respect to mean patient age (63 vs. 63 years; p = 1) and gender distribution as the majority of patients were females (56.8 %). However, open repair was more likely to be performed in patients with a higher ASA class (III and IV) (p < 0.001). Also, the open approach was more likely to be used emergently (8.64 vs. 3.60 %; p = 0.01) and for recurrent hernias (6.99 vs. 3.15 %; p < 0.05). After adjusting for all potential confounders including age, gender, ASA, emergency designation of the operation, hernia type, and wound class, laparoscopy was associated with shorter operative time (137.5 vs. 153.4 min; p < 0.05), shorter length of hospital stay by 3.32 days (p < 0.001), lower risk of overall morbidity (OR = 0.42; p < 0.001), and a lower risk of surgical site infections (OR = 0.35; p < 0.01) compared to open repair. Mortality rates were similar in the laparoscopic and open groups (0.45 vs. 1.59 %, respectively; p = 0.29). Laparoscopic parastomal hernia repair is safe and appears to be associated with better short-term outcomes compared to open repair in selected cases. Large prospective randomized trials are needed to confirm those results and to assess long-term recurrence rates. 23899658 Childhood Economic Strains in Predicting Substance Use in Emerging Adulthood: Mediation Effects of Youth Self-Control and Parenting Practices. To examine the influence of childhood economic strains on substance use in young adulthood and to assess the mediating roles of self-control as well as positive parenting during adolescence in a nationally representative longitudinal cohort. The study included data from participants (n = 1,285) in the Panel Study of Income Dynamics, Child Development Supplement, and Transition to Adult. Structural equation modeling was used to evaluate the associations among risk factors during childhood and adolescence that predicted substance use in early adulthood. Conditions of economic strains, especially poverty, during childhood were associated with an increased likelihood of regular smoking in adulthood, which was partially mediated by poorer self-control during adolescence. Self-control is negatively affected by economic strains and serves as a mediator between poverty and risk of regular smoking. Additional research is needed to better understand how economic strains effect the development of self-control. 23861830 Regional variations in esophageal cancer rates by census region in the United States, 1999-2008. Assessment of cancer incidence trends within the U.S. have mostly relied upon Surveillance, Epidemiology, and End Results (SEER) data, with implicit inference that such is representative of the general population. However, many cancer policy decisions are based at a more granular level. To help inform such, analyses of regional cancer incidence data are needed. Leveraging the unique resource of National Program of Cancer Registries (NPCR)-SEER, we assessed whether regional rates and trends of esophageal cancer significantly deviated from national estimates. From NPCR-SEER, we extracted cancer case counts and populations for whites aged 45-84 years by calendar year, histology, sex, and census region for the period 1999-2008. We calculated age-standardized incidence rates (ASRs), annual percent changes (APCs), and male-to-female incidence rate ratios (IRRs). This analysis included 65,823 esophageal adenocarcinomas and 27,094 esophageal squamous cell carcinomas diagnosed during 778 million person-years. We observed significant geographic variability in incidence rates and trends, especially for esophageal adenocarcinomas in males: ASRs were highest in the Northeast (17.7 per 100,000) and Midwest (18.1). Both were significantly higher than the national estimate (16.0). In addition, the Northeast APC was 62% higher than the national estimate (3.19% vs. 1.97%). Lastly, IRRs remained fairly constant across calendar time, despite changes in incidence rates. Significant regional variations in esophageal cancer incidence trends exist in the U.S. Stable IRRs may indicate the predominant factors affecting incidence rates are similar in men and women. 23384278 Frequency-multiplication high-output triboelectric nanogenerator for sustainably powering biomedical microsystems. An attractive method to response the current energy crisis and produce sustainable nonpolluting power source is harvesting energy from our living environment. However, the energy in our living environment always exists in low-frequency form, which is very difficult to be utilized directly. Here, we demonstrated a novel sandwich-shape triboelectric nanogenerator to convert low-frequency mechanical energy to electric energy with double frequency. An aluminum film was placed between two polydimethylsiloxane (PDMS) membranes to realize frequency multiplication by twice contact electrifications within one cycle of external force. The working mechanism was studied by finite element simulation. Additionally, the well-designed micro/nano dual-scale structures (i.e., pyramids and V-shape grooves) fabricated atop PDMS surface was employed to enhance the device performance. The output peak voltage, current density, and energy volume density achieved 465 V, 13.4 μA/cm(2), and 53.4 mW/cm(3), respectively. This novel nanogenerator was systematically investigated and also demonstrated as a reliable power source, which can be directly used to not only lighten five commercial light-emitting diodes (LEDs) but also drive an implantable 3-D microelectrode array for neural prosthesis without any energy storage unit or rectification circuit. This is the first demonstration of the nanogenerator for directly driving biomedical microsystems, which extends the application fields of the nanogenerator and drives it closer to practical applications. 23869450 Extent of Sample Loss on the Sampling Device and the Resulting Experimental Biases When Collecting Volatile Fatty Acids (VFAs) in Air Using Sorbent Tubes. Not all volatile organic compounds (VOCs) are suitable for sampling from air onto sorbent tubes (ST) with subsequent analysis by thermal desorption (TD) with gas chromatography (GC). Some compounds (such as C2 hydrocarbons) are too volatile for quantitative retention by sorbents at ambient temperature, while others are too reactive - either for storage stability on the tubes (post-sampling) or for thermal desorption/GC analysis. Volatile fatty acids (VFAs) are one of the compound groups that present a challenge to sorbent tube sampling. In this study, we evaluated sample losses on the inner wall surface of the sorbent tube sampler. The sorptive losses of five VFA (acetic, propionic, n-butyric, i-valeric, and n-valeric acid) were tested using two types of tubes (stainless steel and quartz), each packed with three sorbent beds arranged in order of sorbent strength from the sampling end of the tube (Tenax TA, Carbopack B, and Carbopack X). It showed significantly higher losses of VFAs in both liquid phase and vapor phase when using stainless steel tube samplers. These losses were also seen if vapor-phase fatty acids were passed through empty stainless steel tubing and increased dramatically with increasing molecular weight, e.g., losses of 33.6% (acetic acid) to 97.5% (n-valeric acid). Similar losses of VFAs were also observed from headspace sampling of cheese products. Considering that stainless steel sampling tubes are still used extensively by many researchers, their replacement with quartz tubes is recommended to reduce systematic biases in collecting VFA samples or in their calibration. 23559552 A morpholino-based screen to identify novel genes involved in craniofacial morphogenesis. The regulatory mechanisms underpinning facial development are conserved between diverse species. Therefore, results from model systems provide insight into the genetic causes of human craniofacial defects. Previously, we generated a comprehensive dataset examining gene expression during development and fusion of the mouse facial prominences. Here, we used this resource to identify genes that have dynamic expression patterns in the facial prominences, but for which only limited information exists concerning developmental function. This set of ∼80 genes was used for a high-throughput functional analysis in the zebrafish system using Morpholino gene knockdown technology. This screen revealed three classes of cranial cartilage phenotypes depending upon whether knockdown of the gene affected the neurocranium, viscerocranium, or both. The targeted genes that produced consistent phenotypes encoded proteins linked to transcription (meis1, meis2a, tshz2, vgll4l), signaling (pkdcc, vlk, macc1, wu:fb16h09), and extracellular matrix function (smoc2). The majority of these phenotypes were not altered by reduction of p53 levels, demonstrating that both p53-dependent and -independent mechanisms were involved in the craniofacial abnormalities. This Morpholino-based screen highlights new genes involved in development of the zebrafish craniofacial skeleton with wider relevance to formation of the face in other species, particularly mouse and human. 23898189 Reproductive aging patterns in primates reveal that humans are distinct. Women rarely give birth after ∼45 y of age, and they experience the cessation of reproductive cycles, menopause, at ∼50 y of age after a fertility decline lasting almost two decades. Such reproductive senescence in mid-lifespan is an evolutionary puzzle of enduring interest because it should be inherently disadvantageous. Furthermore, comparative data on reproductive senescence from other primates, or indeed other mammals, remains relatively rare. Here we carried out a unique detailed comparative study of reproductive senescence in seven species of nonhuman primates in natural populations, using long-term, individual-based data, and compared them to a population of humans experiencing natural fertility and mortality. In four of seven primate species we found that reproductive senescence occurred before death only in a small minority of individuals. In three primate species we found evidence of reproductive senescence that accelerated throughout adulthood; however, its initial rate was much lower than mortality, so that relatively few individuals experienced reproductive senescence before death. In contrast, the human population showed the predicted and well-known pattern in which reproductive senescence occurred before death for many women and its rate accelerated throughout adulthood. These results provide strong support for the hypothesis that reproductive senescence in midlife, although apparent in natural-fertility, natural-mortality populations of humans, is generally absent in other primates living in such populations. 23526813 Comprehensive quality of discharge summaries at an academic medical center. Discharge summaries are essential for safe transitions from hospital to home. To conduct a comprehensive quality assessment of discharge summaries. Prospective cohort study. Three hundred seventy-seven patients discharged home after hospitalization for acute coronary syndrome, heart failure, or pneumonia. Discharge summaries were assessed for timeliness of dictation, transmission of the summary to appropriate outpatient clinicians, and presence of key content including elements required by The Joint Commission and elements endorsed by 6 medical societies in the Transitions of Care Consensus Conference (TOCCC). A total of 376 of 377 patients had completed discharge summaries. A total of 174 (46.3%) summaries were dictated on the day of discharge; 93 (24.7%) were completed more than a week after discharge. A total of 144 (38.3%) discharge summaries were not sent to any outpatient physician. On average, summaries included 5.6 of 6 The Joint Commission elements and 4.0 of 7 TOCCC elements. Summaries dictated by hospitalists were more likely to be timely and to include key content than summaries dictated by housestaff or advanced practice nurses. Summaries dictated on the day of discharge were more likely to be sent to outside physicians and to include key content. No summary met all 3 quality criteria of timeliness, transmission, and content. Discharge summary quality is inadequate in many domains. This may explain why individual aspects of summary quality such as timeliness or content have not been associated with improved patient outcomes. However, improving discharge summary timeliness may also improve content and transmission. Journal of Hospital Medicine 2013;8:436-443. © 2013 Society of Hospital Medicine. 23353748 Design, synthesis and biological evaluation of novel hybrid compounds of imidazole scaffold-based 2-benzylbenzofuran as potent anticancer agents. A series of novel hybrid compounds between 2-benzylbenzofuran and imidazole has been prepared and evaluated in vitro against a panel of human tumor cell lines. The results suggest that the existence of benzimidazole ring and substitution of the imidazolyl-3-position with a naphthylacyl or 4-methoxyphenacyl group were vital for modulating cytotoxic activity. In particular, hybrid compounds 46 and 47 were found to be the most potent derivatives against 5 strains human tumor cell lines and more active than cisplatin (DDP), and exhibited cytotoxic activities selectively against breast carcinoma (MCF-7) and myeloid liver carcinoma (SMMC-7721), respectively. 23576019 Golimumab for the Treatment of Rheumatoid Arthritis After the Failure of Previous Disease-Modifying Antirheumatic Drugs: A NICE Single Technology Appraisal. As part of the National Institute for Health and Clinical Excellence (NICE) single technology appraisal (STA) process, the manufacturer of golimumab (Simponi(®); Merck Sharp & Dohme, USA) was invited to submit evidence for its clinical and cost effectiveness for the treatment of rheumatoid arthritis (RA) after the failure of previous disease-modifying antirheumatic drugs (DMARDs). The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at The University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). This article provides details of the manufacturer's initial submission, the ERG's clarification questions and the ERG report submitted to NICE. The decision made by NICE is provided alongside a brief comment on additional results produced from an additional analysis requested by NICE on behalf of the Committee. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based on upon the manufacturer's submission to NICE. The clinical evidence was derived from three randomized controlled trials of golimumab in the treatment of moderate to severe RA: GO-FORWARD and Kay et al. (DMARD-experienced population) and GO-AFTER (tumour necrosis factor [TNF]-α inhibitor-experienced population). The ERG considered that the trials were of reasonable methodological quality and measured a clinically relevant range of outcomes. The trials for golimumab, as well as comparator treatments, were synthesized using mixed-treatment comparison methods for the DMARD-experienced population and an indirect comparison using the Bucher method for the TNF-α inhibitor-experienced population. The trials used were appropriate, although no definitive judgement regarding the comparative efficacy of golimumab with other biologics was possible. The manufacturer provided a DMARD-experienced population model and a TNF-α inhibitor-experienced population model. The models allowed sequences of treatments to be evaluated for each population, although a fully incremental analysis between the use of golimumab following DMARD failure and the use of golimumab following TNF-α inhibitor failure was not possible. Several limitations with the model were identified, and after a request from NICE and suspension of the appraisal, the manufacturer submitted sensitivity analyses with an additional American College of Rheumatology 70 % improvement criteria (ACR70) health state included, using SF-36 data directly from the GO-FORWARD study. The annual rate of the Health Assessment Questionnaire (HAQ) score increase for patients receiving palliative treatment was also changed from 0.09 to 0.06. The further analyses provided highlighted the particular sensitivity of the results to HAQ progression rates and the re-administration frequency for rituximab in the TNF-α inhibitor-experienced population. The Appraisal Committee concluded that golimumab should be recommended in combination with methotrexate as an option for patients with severe active RA who have failed on conventional DMARDs, or who have failed on a TNF-α inhibitor and are contraindicated to or withdrawn from rituximab. 23836107 Terminal oxidase mutants of the cyanobacterium Synechocystis sp. PCC 6803 show increased electrogenic activity in biological photo-voltaic systems. Biological photo-voltaic systems are a type of microbial fuel cell employing photosynthetic microbes at the anode, enabling the direct transduction of light energy to electrical power. Unlike the anaerobic bacteria found in conventional microbial fuel cells that use metals in the environment as terminal electron acceptors, oxygenic photosynthetic organisms are poorly adapted for electron transfer out of the cell. Mutant strains of the cyanobacterium Synechocystis sp. PCC 6803 were created in which all combinations of the three respiratory terminal oxidase complexes had been inactivated. These strains were screened for the ability to reduce the membrane-impermeable soluble electron acceptor ferricyanide, and the results were compared to the performance of the mutants in a biological photo-voltaic system. Deletion of the two thylakoid-localised terminal oxidases, the bd-quinol oxidase and cytochrome c oxidase resulted in a 16-fold increase in ferricyanide reduction rate in the dark compared to the wild-type. A further improvement to a 24-fold increase was seen upon deletion of the remaining "alternative respiratory terminal oxidase". These increases were reflected in the peak power generated in the biological photo-voltaic systems. Inactivation of all three terminal oxidase complexes resulted in a substantial redirection of reducing power; in the dark the equivalent of 10% of the respiratory electron flux was channelled to ferricyanide, compared to less than 0.2% in the wild-type. Only minor improvements in ferricyanide reduction rates over the wild-type were seen in illuminated conditions, where carbon dioxide is preferentially used as an electron sink. This study demonstrates the potential for optimising photosynthetic microbes for direct electrical current production. 23941910 Synthesis of bimetallic platinum nanoparticles for biosensors. The use of magnetic nanomaterials in biosensing applications is growing as a consequence of their remarkable properties; but controlling the composition and shape of metallic nanoalloys is problematic when more than one precursor is required for wet chemistry synthesis. We have developed a successful simultaneous reduction method for preparation of near-spherical platinum-based nanoalloys containing magnetic solutes. We avoided particular difficulties in preparing platinum nanoalloys containing Ni, Co and Fe by the identification of appropriate synthesis temperatures and chemistry. We used transmission electron microscopy (TEM) to show that our particles have a narrow size distribution, uniform size and morphology, and good crystallinity in the as-synthesized condition. Energy dispersive spectroscopy (EDS) and X-ray diffraction (XRD) confirms the coexistence of Pt with the magnetic solute in a face-centered cubic (FCC) solid solution. 23845514 Psychosocial factors and hematopoietic stem cell transplantation: Potential biobehavioral pathways. While psychosocial factors are known to affect cancer progression via biobehavioral pathways in many patient populations, these relationships remain largely unexplored in hematopoietic stem cell transplant (HCT) patients. The purpose of this paper is to critically review the literature regarding psychosocial and endocrine/immune aspects of HCT, with an emphasis on exploring pathways that may mediate the associations between psychosocial factors and disease outcomes. These include the roles of catecholamines, glucocorticoids, inflammation, vascular endothelial growth factor (VEGF), immune reconstitution and infectious susceptibility, as well as the new opportunities available in genomics research. We also discuss the implications for potential immunomodulating psychosocial interventions. Elucidating the biological pathways that account for the associations between psychosocial factors and clinical course could ultimately lead to improved outcomes for this psychologically and immunologically vulnerable population. 22305808 The impact on kinesiophobia (fear of movement) by clinical variables for patients with coronary artery disease. The impact on kinesiophobia (fear of movement) for patients with coronary artery disease (CAD) is not known. The aims were to describe the occurrence of kinesiophobia in patients with CAD, and to investigate the influence on kinesiophobia by clinical variables. In total, 332 patients, mean age, 65 ± 9.1 years diagnosed with CAD at a university hospital were included in the study. The Tampa Scale for Kinesiophobia Heart (TSK-SV Heart) was used to assess kinesiophobia. Comparisons between high versus low levels of kinesiophobia were measured for each variable. Binary logistic regression analyses were performed with a high level of kinesiophobia (TSK-SV Heart>37) as dependent variable, and with the observed variables as independent. The study had an exploratory, cross-sectional design. A high level of kinesiophobia was found in 20% of the patients. The following variables decreased the odds ratio (OR) for a high level of kinesiophobia: Attending cardiac rehabilitation (yes vs no: -56.7%), level of physical activity (medium vs high: -80.8%), Short-Form 36: general health (-4.3%), physical functioning (-1.8%). Two variables increased the OR for a high level of kinesiophobia: heart failure as complication at hospital (yes vs no: 418.7%), anxiety (19.2%). Previous heart failure (yes vs no) was unexpectedly found to reduce kinesiophobia (-88.3%) due to suppression. Several important clinical findings with impact on rehabilitation and prognosis for patients with CAD were found to be associated with a high level of kinesiophobia. Therefore, kinesiophobia needs to be considered in secondary prevention for patients with CAD. 23585667 Immunohistochemical characteristics of hepatocellular carcinoma in non-cirrhotic livers. Hepatocellular carcinoma (HCC) typically develops in cirrhotic livers. In the absence of risk factors, for example, cirrhosis or hepatitis B or C virus infection, HCC diagnosis might be difficult. We aimed to explore the value of immunohistochemical characteristics to diagnostics and prognosis, and whether these immunohistochemical characteristics differ from those of HCC in a cirrhotic liver, possibly indicating an aberrant pathogenetic pathway. Paraffin-embedded, formalin-fixed tissue slides from liver resection specimens of the patients with HCC in a non-cirrhotic liver were analysed. From January 2000 through April 2011, 799 patients with HCC were admitted to our hospital; in total, 47 patients with 50 HCCs in a non-cirrhotic liver were operated. These tumours were stained positive for α-fetoprotein (AFP) in 30%, CD34 in 88%, cytokeratine 7 (CK7) in 44%, CK19 in 12%, glypican-3 (GPC-3) in 40%, glutamine synthetase in 62% and β-catenin in 32%. There was similarity in immunohistochemical expression of several markers comparing HCC in a non-cirrhotic liver with HCC in a cirrhotic liver. Moderate or poorly differentiated HCC more often expressed β-catenin and GPC-3 and showed a higher percentage of MIB-1-positive hepatocytes. A positive AFP immunohistochemical staining was significantly related with a high preoperative AFP serum level (p=0.001). None of the immunohistochemical stainings were associated with a worse overall survival. Of the patients treated with a surgical resection, 17 had recurrence of HCC and these patients more often had a positive CK19 staining (p=0.048). In conclusion, immunohistochemical expression of several markers in HCC in a non-cirrhotic and cirrhotic liver was comparable. Immunohistochemical markers have limited additional value to characterise HCC in non-cirrhoitc livers. 23859207 Small-molecule inhibition of bacterial two-component systems to combat antibiotic resistance and virulence. Infections caused by multidrug-resistant bacteria are a considerable and increasing global problem. The development of new antibiotics is not keeping pace with the rapid evolution of resistance to almost all clinically available drugs, and novel strategies are required to fight bacterial infections. One such strategy is the control of pathogenic behaviors, as opposed to simply killing bacteria. Bacterial two-component system (TCS) signal transduction pathways control many pathogenic bacterial behaviors, such as virulence, biofilm formation and antibiotic resistance and are, therefore, an attractive target for the development of new drugs. This review presents an overview of TCS that are potential targets for such a strategy, describes small-molecules inhibitors of TCS identified to date and discusses assays for the identification of novel inhibitors. The future perspective for the identification and use of inhibitors of TCS to potentially provide new therapeutic options for the treatment of drug-resistant bacterial infections is discussed. 23568545 Atomic force microscopy reveals regional variations in the micromechanical properties of the pericellular and extracellular matrices of the meniscus. Regional variations in the composition and architecture of the extracellular matrix (ECM) and pericellular matrix (PCM) of the knee meniscus play important roles in determining the local mechanical environment of meniscus cells. In this study, atomic force microscopy was used to spatially map the mechanical properties of matched ECM and perlecan-labeled PCM sites within the outer, middle, and inner porcine medial meniscus, and to evaluate the properties of the proximal surface of each region. The elastic modulus of the PCM was significantly higher in the outer region (151.4 ± 38.2 kPa) than the inner region (27.5 ± 8.8 kPa), and ECM moduli were consistently higher than region-matched PCM sites in both the outer (320.8 ± 92.5 kPa) and inner (66.1 ± 31.4 kPa) regions. These differences were associated with a higher proportion of aligned collagen fibers and lower glycosaminoglycan content in the outer region. Regional variations in the elastic moduli and some viscoelastic properties were observed on the proximal surface of the meniscus, with the inner region exhibiting the highest moduli overall. These results indicate that matrix architecture and composition play an important role in the regional micromechanical properties of the meniscus, suggesting that the local stress-strain environment of meniscal cells may vary significantly among the different regions. 23696424 Association between operative approach and complications in patients undergoing Hartmann's reversal. Complications following reversal of Hartmann's procedure are common, with morbidity rates of up to 50 per cent, and a mortality rate as high as 10 per cent. This is based on case series with heterogeneous data collection and analysis. This study determined risk factors for complications following Hartmann's reversal. Patients who underwent elective open and laparoscopic Hartmann's reversal were identified from the American College of Surgeons National Surgical Quality Improvement Program database (2005-2010). The programme collects patient demographics, preoperative medical history, clinical findings and laboratory investigations. Postdischarge data were obtained by a certified reviewer. Complications were categorized as major, septic or incisional. Risk-adjusted 30-day outcomes were assessed by univariable and multivariable analyses, adjusting for patient characteristics, co-morbidity and operative approach. During the study period 7996 patients had a Hartmann's procedure and 2567 cases of Hartmann's reversal were identified, including 336 laparoscopic procedures (13·1 per cent). Major, septic and incisional complication rates were 13·3, 8·5 and 15·7 per cent respectively, with a mortality rate of 0·5 per cent. A laparoscopic approach was found to be independently associated with fewer major (odds ratio (OR) 0·53, 95 per cent confidence interval 0·34 to 0·81), septic (OR 0·48, 0·27 to 0·83) and incisional (OR 0·54, 0·37 to 0·80) complications. A history of chronic obstructive pulmonary disease (OR 1·78-2·00), steroid use (OR 1·75), body mass index at least 30 kg/m² (OR 1·48), diabetes (OR 1·40), smoking (OR 1·33-1·40), American Society of Anesthesiologists fitness grade III and IV (OR 1·46-1·48) and prolonged operating time (OR 1·02) were other factors associated with complications. A laparoscopic approach to Hartmann's reversal was associated with fewer complications than open surgery in this highly selected group of patients. 23942284 Multiple Channeling Improves the Structural Integrity of Rotator Cuff Repair. BACKGROUND:Multiple channeling is a straightforward additional procedure for rotator cuff repair that creates multiple channels in the greater tuberosity, through which bone marrow of the proximal humerus communicates with the repair site. PURPOSE:To investigate the effect of multiple channeling on clinical and structural outcomes of arthroscopic rotator cuff repair. STUDY DESIGN:Cohort study; Level of evidence, 3. METHODS:A total of 124 patients with a full-thickness rotator cuff tear were included in the study. Fifty-seven patients underwent arthroscopic rotator cuff repair with multiple channeling (the multiple channeling group) and 67 without it (the conventional group). Analysis of surface markers was performed to characterize the cells recruited by multiple channeling using flow cytometry. Clinical outcomes were evaluated preoperatively and at a minimum of 2 years after surgery (average, 36.79 ± 13.69 months) with respect to pain, range of motion, muscle strength, overall satisfaction, and commonly used functional scores. At a minimum of 9 months after surgery, structural integrity was assessed by magnetic resonance imaging or computed tomography arthrography. RESULTS:Mesenchymal stem cells (MSCs) positive for CD73, CD90, and CD105 and negative for CD45 could be isolated and cultured from bone marrow mononuclear cells of the proximal humerus. Clinical outcomes, including pain, range of motion, strength, overall satisfaction, and functional scores, showed no statistical difference between the 2 groups (all P > .05). The retear rate of the multiple channeling group (22.2%) was significantly lower than that of the conventional group (45.2%) (P = .023). CONCLUSION:The findings of the study showed that multiple channeling significantly decreased the retear rate after arthroscopic rotator cuff repair, probably via the recruitment of endogenous MSCs from the proximal humerus. Although the results did not show significant differences in the clinical outcomes between the 2 groups, better clinical outcomes might be anticipated in the multiple channeling group via improved structural integrity in a long-term follow-up. 23886757 A systematic review and evaluation of response redirection as a treatment for challenging behavior in individuals with developmental disabilities. Response redirection is widely used in clinical practice as a treatment for repetitive behavior or stereotypy in persons with developmental disabilities. However, to date the procedure has received comparatively little empirical evaluation. The current review sought to examine the literature describing the efficacy of response redirection alone, response interruption and redirection (RIRD), and multi-element treatment packages incorporating response redirection, as interventions for challenging behavior in individuals with developmental disabilities. Additionally, the status of response redirection, and RIRD, as evidence-based practice was evaluated in accordance with Reichow's (2011) recently developed criteria. Results indicated that interventions involving response redirection or RIRD typically led to large decreases in challenging behavior but did not result in behavioral suppression. On the basis of the current literature and in accordance with Reichow's criteria, interventions incorporating response redirection do not yet constitute evidence-based practice. The implications of these findings, for both research and practice, are discussed. 23265540 Characterising protein, salt and water interactions with combined vibrational spectroscopic techniques. In this paper a combination of NIR spectroscopy and FTIR and Raman microspectroscopy was used to elucidate the effects of different salts (NaCl, KCl and MgSO(4)) on structural proteins and their hydration in muscle tissue. Multivariate multi-block technique Consensus Principal Component Analysis enabled integration of different vibrational spectroscopic techniques: macroscopic information obtained by NIR spectroscopy is directly related to microscopic information obtained by FTIR and Raman microspectroscopy. Changes in protein secondary structure observed at different concentrations of salts were linked to changes in protein hydration affinity. The evidence for this was given by connecting the underlying FTIR bands of the amide I region (1700-1600 cm(-1)) and the water region (3500-3000 cm(-1)) with water vibrations obtained by NIR spectroscopy. In addition, Raman microspectroscopy demonstrated that different cations affected structures of aromatic amino acid residues differently, which indicates that cation-π interactions play an important role in determination of the final structure of protein molecules. 23711841 Extraction of bioavailable contaminants from marine sediments: an approach to reducing toxicity using adsorbent parcels. This paper demonstrates an approach to reducing acute toxicity in marine sediments using adsorbent parcels. Acute toxicity tests were carried using the marine amphipod Corophium volutator. Marine sediments were spiked with two know contaminants tributyltin and naphthalene and then treated with adsorbent parcels containing either amberlite XAD4 or activated carbon. Results showed that both types of adsorbent parcels were effective in reducing acute toxicity, not only within spiked sediments containing naphthalene and/or tributyltin, but also in an environmental field samples form an expected contaminated site. Adsorbent parcels such as these could provide a practical approach to remediate areas of contaminated sediment within marine environments. Furthermore adsorbents can be used as an identification tool for problematic contaminants using a toxicity identification evaluation approach. 23727992 SFG analysis of surface bound proteins: a route towards structure determination. The surface of a material is rapidly covered with proteins once that material is placed in a biological environment. The structure and function of these bound proteins play a key role in the interactions and communications of the material with the biological environment. Thus, it is crucial to gain a molecular level understanding of surface bound protein structure. While X-ray diffraction and solution phase NMR methods are well established for determining the structure of proteins in the crystalline or solution phase, there is not a corresponding single technique that can provide the same level of structural detail about proteins at surfaces or interfaces. However, recent advances in sum frequency generation (SFG) vibrational spectroscopy have significantly increased our ability to obtain structural information about surface bound proteins and peptides. A multi-technique approach of combining SFG with (1) protein engineering methods to selectively introduce mutations and isotopic labels, (2) other experimental methods such as time-of-flight secondary ion mass spectrometry (ToF-SIMS) and near edge X-ray absorption fine structure (NEXAFS) to provide complementary information, and (3) molecular dynamic (MD) simulations to extend the molecular level experimental results is a particularly promising route for structural characterization of surface bound proteins and peptides. By using model peptides and small proteins with well-defined structures, methods have been developed to determine the orientation of both backbone and side chains to the surface. 23726865 Ethanol-induced apoptosis in human liver adenocarcinoma cells (SK-Hep1): Fas- and mitochondria-mediated pathways and interaction with MAPK signaling system. For studying molecular mechanisms regulating the fate of ethanol-treated hepatocytes, involvement of Fas in ethanol-induced apoptosis was examined in human liver adenocarcinoma (SK-Hep1) cells in which the function of Fas-associated death domain (FADD) protein was knocked down by transfection. In FADD-knocked down cells, while ethanol-induced increase in generation of reactive oxygen species (ROS) was unaffected, apoptosis was significantly suppressed, demonstrating the involvement of Fas in ethanol-induced hepatocyte apoptosis more directly than in the past reports. On the other hand, effects of mitogen-activated protein kinase (MAPK), which is well known to determine the fate of various cells, on ethanol-induced apoptosis have not been examined in SK-Hep1 cells. Of three major MAPKs, only p38 MAPK and JNK were found activated by 200mM ethanol treatment. When cells were incubated with inhibitors of p38 MAPK and JNK, ethanol-induced apoptosis was decreased while ROS generation was unaffected, and examination of pro-apoptotic Bax and anti-apoptotic Bcl-2 levels showed decrease of the former and increase of the latter. We concluded that oxidative stress inflicted by ROS triggered Fas-mediated and mitochondria-mediated apoptotic pathways in ethanol-treated SK-Hep1 cells, and that p38 MAPK and JNK were promoting mitochondrial pathway, suggesting interaction between apoptosis and MAPK signaling systems. 23239633 Enzyme-catalyzed crosslinking in a partly frozen state: a new way to produce supermacroporous protein structures. In this study a new way to produce supermacroporous protein structures was investigated. Enzyme-mediated crosslinking of gelatin or casein was performed in a partly frozen state, which yielded stable, protein-based cryogels. The reaction kinetics for the formation of cryogels were found to be fairly slow, most likely due to the low temperature (-12 °C) used or due to an increased viscosity owing to the cryo-concentration taking place. The produced cryogels were characterized with regards to their physical properties and in vitro degradation. Furthermore, cryogels produced from gelatin and casein were evaluated as potential scaffolds by fibroblast cultivation to confirm their in vitro biocompatibility. Gelatin- and casein-based scaffolds both supported cell proliferation and migration through the scaffold. 23731867 Cadmium-tolerant bacteria reduce the uptake of cadmium in rice: potential for microbial bioremediation. We selected 24 bacterial isolates that could tolerate up to 2500 µM CdCl2 from the soil of rice fields downstream from a zinc-mineralized area contaminated with a high level of cadmium (Cd). In the presence of 500 µM CdCl2, all isolates grew slower and with a prolonged lag-phase compared to in the absence of Cd. Cd-binding capacity was high and ranged from 6.38 to 9.38 log[Cd(atom)]/cell. The stability of Cd complexes in bacteria was affected by 1mM EDTA. In 500 µM CdCl2, all isolates produced 0.7 to 4.8-fold more inorganic sulfide and 0.6 to 2.2-fold more thio-rich compounds containing SH groups. Out of 24 Cd-tolerant bacterial isolates, KKU2500-3, -8, -9 and -20 were able to promote the growth of Thai jasmine rice (Kao Hom Mali 105) seedlings in the presence of 200 µM CdCl2, and KKU2500-3 produced the highest numbers of fibrous root. Interestingly, these 4 isolates increased Cd tolerance and decreased the accumulation of Cd in rice by 61, 9, 6, and 17% when grown in the presence of 200 µM CdCl2. Of the 4 isolates, KKU2500-3 produced more inorganic sulfide when grown in CdCl2 at 500-2000 µM. XANES analyses indicated that this isolate precipitated a detectable amount of cadmium sulfide (CdS) when grown in 500 µM CdCl2. Thus, the isolate KKU2500-3 could possibly transform toxic, soluble CdCl2 into non-toxic, insoluble CdS. These 4Cd-tolerant bacterial isolates were identified via 16S rDNA sequencing and classified as Cupriavidus taiwanensis KKU2500-3 and Pseudomonas aeruginosa KKU2500-8, -9, and -20. 23856207 Radiologic evaluation for volume and weight of remnant lung in living lung donors. Living-lung donors lose pulmonary function of a right or left lower lobe in exchange for a noble donation; however, Chen and colleagues reported postoperative pulmonary function of the donors was significantly better than the estimated values. The purpose of this study was to investigate if the improvement of postoperative pulmonary function is associated with hypertrophic phenomena of remnant lung. A total of 35 patients who underwent a right or left lower lobectomy for living-donor lobar lung transplantation in Kyoto University Hospital from 2008 to 2011 were evaluated by means of spirometry (forced vital capacity, forced expiratory volume in 1 second, and diffusing capacity for carbon monoxide), and computed tomography scans both before and 1 year after the surgery. Postoperative predictions of pulmonary function and radiologic parameters were made based on the number of resected segments. The average radiologic density of the lung was determined as follows: (mean computed tomography number + 1000)/1000, and weight of the lung was calculated as follows: lung volume (mL) Ã— average radiologic lung density (g/mL). The radiologic analysis was performed on both the surgical and contralateral sides. Postoperative forced vital capacity, forced expiratory volume in 1 second, and diffusing capacity for carbon monoxide were significantly higher than estimated values by 17.3% ± 10.2% (P < .0001), 14.7% ± 10.2% (P < .0001), and 10.9% ± 16. % (P < .002), respectively. Postoperative lung volume and weight of the surgical side were significantly higher than estimated values by 54.4% ± 30.4% (P < .0001) and 28.1% ± 15.7% (P < .0001), respectively. On the contralateral side, the postoperative lung volume was significantly higher than the estimated value by 12.6% ± 15.3% (P < .0001), but postoperative weight was comparable with the estimated value (-2.3% ± 8.8%; P = .07). Hypertrophic change of the ipsilateral remnant lung may be recognized in living lung donors. 23838991 Oral EMG Activation Patterns for Speech Are Similar in Preschoolers Who Do and Do Not Stutter. We determined whether basic patterns of muscle activation for speech were similar in preschool children who stutter and their fluent peers. We recorded right and left lower lip muscle activity during conversational speech and sentence repetition in 64 preschool children (CWS) diagnosed as stuttering and in 40 children who do not stutter (CWNS). Measures of EMG amplitude, right/left asymmetry, and bilateral coordination were computed for fluent speech. The potential presence of tremor-like oscillations during disfluencies of CWS was assessed, and EMG amplitudes of fluent and disfluent speech were compared in CWS. Across both speaking tasks lip muscle activation was similar in CWS and CWNS in overall amplitude, bilateral synchrony, and degree of right/left asymmetry. EMG amplitude was reduced during disfluent compared to fluent conversational speech of CWS, and there was no evidence of tremor in the disfluencies of CWS. These results support the assertion that stuttering in young children arises not from basic features of muscle contraction, but rather from the command signals that control the timing and amplitude of muscle activity. Our results indicate that no frank abnormality is present in muscle activation patterns in preschoolers who stutter. 23663300 Effect of high pressure on the structure and antibacterial activity of bovine lactoferrin treated in different media. The effect of high-pressure treatment (400, 500 and 650 MPa) on the structure and activity of bovine lactoferrin in different iron-saturation forms has been studied by several techniques. The structural changes produced in lactoferrin by high-pressure were analysed by differential scanning calorimetry and fluorescence spectroscopy, and the immunoreactivity by ELISA. The effect of high-pressure was also studied on some biological properties of lactoferrin, such as iron binding capacity, retention of the bound iron, and antibacterial activity against Escherichia coli O157:H7. Results obtained indicate that treatment at 400 MPa does not substantially modify the conformation of lactoferrin, meanwhile treatments at 500 and 650 MPa greatly affect some of its properties. With respect to the antibacterial activity, the apo and native forms of lactoferrin maintain that activity against Esch. coli only after 400 MPa treatment. 23818658 Update on platelet glycoprotein IIb/IIIa inhibitors: recommendations for clinical practice. Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndrome (ACS) and undergoing percutaneous coronary intervention (PCI). Glycoprotein IIb/IIIa receptors mediate platelet aggregation, representing the final common pathway of platelet-mediated thrombosis. Therefore, agents blocking this pathway may be desirable for the treatment of patients with ACS and PCI. Glycoprotein IIb/IIIa receptor inhibitors have been widely investigated and have been key to the pharmacological advancements in the field. However, although GPIs have been important to reduce ischemic complications, their elevated risk of bleeding complications remains a major limitation. The poor prognostic implications, including increased mortality, associated with bleeding complication underscores the need for alternative treatment options. Over the past years there have been several advancements in antithrombotic pharmacology which have led to changes in recommendations for GPI usage in clinical practice. This is an overview of the most recent clinical trial data on GPIs, and provides practical insight on their modern day use in ACS therapy. 23835596 Assessment of Rat Antigen-Induced Arthritis and Its Suppression During Glucocorticoid Therapy by Use of Hemicyanine Dye Probes With Different Molecular Weight in Near-Infrared Fluorescence Optical Imaging. Arthritic joints are ideal disease entities to be assessed via optical imaging. Here, we investigated the selective accumulation behavior of two differently sized hemicyanine optical probes in arthritic joints and its modification during glucocorticoid therapy in the course of inflammation. The well-standardized preclinical antigen-induced arthritis (AIA) model in rats was used. The animals were divided into 3 groups: arthritic, arthritic and dexamethasone-treated, and immunized only. After intravenous coinjection of DY-752 (size, 800 Da) and DY-682-(rat) IgG (size, 150 kDa) probes, spectrally unmixed near-infrared fluorescence images were acquired and analyzed semiquantitatively. Probe organ distribution, joint swelling, blood cell counts, joint vessel density, and histological scoring of arthritis were determined. The local joint accumulation kinetics of the DY-752 probe differed from the DY-682-IgG one. In the course of AIA, probe signaling in arthritic joints was similar between each other. Joint swelling and histological scoring were in accordance with signaling. Dexamethasone treatment of rats with AIA significantly reduced both the near-infrared fluorescence signals and severity of arthritis but did not change the joint vascular density or the uptake of the probes by phagocytes. A differential biodistribution of both probes was encountered, but such an accumulation was prevented by dexamethasone treatment. Near-infrared fluorescence signaling in the course of AIA closely reflects the pathophysiological events of the arthritic joint and the effects of therapy independently of the molecular size of the probe. The results show the suitability of our hemicyanine probes for imaging of arthritis. 23870103 Lymphatic filariasis control in Tanzania: effect of six rounds of mass drug administration with ivermectin and albendazole on infection and transmission. Control of lymphatic filariasis (LF) in most countries of sub-Saharan Africa is based on annual mass drug administration (MDA) with a combination of ivermectin and albendazole, in order to interrupt transmission. We present findings from a detailed study on the effect of six rounds of MDA with this drug combination as implemented by the National Lymphatic Filariasis Elimination Programme (NLFEP) in a highly endemic rural area of north-eastern Tanzania. The effect of treatment on transmission and human infection was monitored in a community- and a school-based study during an 8-year period (one pre-intervention and 7 post-intervention years) from 2003 to 2011. Before intervention, 24.5% of the community population had microfilariae (mf) in the blood, 53.3% had circulating filarial antigens (CFA) and 78.9% had specific antibodies to the recombinant filarial antigen Bm14. One year after the sixth MDA, these values had decreased considerably to 2.7%, 19.6% and 27.5%, respectively. During the same period, the CFA prevalence among new intakes of Standard 1 pupils in 10 primary schools decreased from 25.2% to 5.6%. In line with this, transmission by the three vectors (Anopheles gambiae, An. funestus and Culex quinquefasciatus) as determined by dissection declined sharply (overall vector infectivity rate by 99.3% and mean monthly transmission potential by 99.2% between pre-intervention and fifth post-intervention period). A major shift in vector species composition, from predominantly anopheline to almost exclusively culicine was observed over the years. This may be largely unrelated to the MDAs but may have important implications for the epidemiology of LF in the area. Six MDAs caused considerable decrease in all the measured indices for transmission and human infection. In spite of this, indices were still relatively high in the late period of the study, and it may take a long time to reach the recommended cut-off levels for interruption of transmission unless extra efforts are made. These should include increased engagement of the target population in the control activities, to ensure higher treatment coverage. It is expected that the recent initiative to distribute insecticide impregnated bed nets to every household in the area will also contribute towards reaching the goal of successful LF elimination. 23673372 Short-term Maximal-Intensity Resistance Training Increases Volitional Function and Strength in Chronic Incomplete Spinal Cord Injury: A Pilot Study. Recent research shows that individuals with an incomplete spinal cord injury (SCI) have a reserve of force-generating capability that is observable during repeated intermittent maximal volitional effort contractions. Previous studies suggest that increased neural drive contributes to the enhanced short-term force-generating capabilities. Whether this reserve can be harnessed with repeated training is unclear. The purpose of this pilot study was to investigate the effects of 4 weeks of maximal-intensity resistance training, compared with conventional progressive resistance training, on lower extremity function and strength in chronic incomplete SCI. Using a randomized crossover design, 5 individuals with chronic (> 1 year postinjury) SCI American Spinal Injury Association Impairment Scale classification C or D were tested before and after 4 weeks of both maximal-intensity training and progressive resistance training paradigms. Outcomes measures included the 6-Minute Walk Test, the Berg Balance Scale, and peak isometric torque for strength of lower extremity muscles. Maximal-intensity resistance training was associated with an average increase of 12.19 ± 8.29 m on the 6-Minute Walk Test, 4 ± 1.9 points on the Berg Balance Scale, 4 ± 4.5 points on the lower extremity motor score), while no changes on the above scores were seen with conventional training. Furthermore, significant increases in peak volitional isometric torques (mean increase = 20 ± 8 Nm) were observed following maximal-intensity resistance training when compared with conventional training (mean increase = 0.12 ± 3 Nm, P = 0.03). Maximal-intensity training paradigm may facilitate rapid gains in volitional function and strength in persons with chronic motor-incomplete SCI, using a simple short-term training paradigm.Video Abstract available (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A37) for more insights from the authors. 23444337 A 90-day subchronic toxicity study of neem oil, a Azadirachta indica oil, in mice. To determine the no-observed-adverse-effect level (NOAEL) of exposure and target organs of neem oil for establishing safety criteria for human exposure, the subchronic toxicity study with neem oil in mice was evaluated. The mice (10 per sex for each dose) was orally administered with neem oil with the doses of 0 (to serve as a control), 177, 533 and 1600 mg/kg/day for 90 days. After the treatment period, observation of reversibility or persistence of any toxic effects, mice were continuously fed without treatment for the following 30 days. During the two test periods, the serum biochemistry, organ weight and histopathology were examined. The results showed that the serum biochemistry and organ coefficient in experimental groups had no statistical difference compared with those of the control group. At the 90th day, the histopathological examinations showed that the 1600 mg/kg/day dose of neem oil had varying degrees of damage on each organ except heart, uterus and ovarian. After 30-day recovery, the degree of lesions to the tissues was lessened or even restored. The NOAEL of neem oil was 177 mg/kg/day for mice and the target organs of neem oil were determined to be testicle, liver and kidneys. 23893556 In vivo GABA T2 determination with J-refocused echo time extension at 7 T. A method to measure the T2 relaxation time of GABA with spectral editing techniques is proposed. Spectral editing techniques can be used to unambiguously extract signals of low concentration J-coupled spins such as γ-aminobutyric acid (GABA) from overlapping resonances such as creatine and macromolecules. These sequences, however, generally have fixed and relatively long echo times. Therefore, for the absolute quantification of the edited spectrum, the T2 relaxation time must be taken into account. To measure the T2 relaxation time, the signal intensity has to be obtained at multiple echo times. However, on a coupled spin system such as GABA this is challenging, since the signal intensity of the target resonances is modulated not only by T2 decay but also by the J-coupling, which strongly influences the shapes and amplitudes of the edited signals, depending on the echo time. Here, we propose to refocus the J-modulation of the edited signal at different echo times by using chemical shift selective refocusing. In this way the echo time can be arbitrarily extended while preserving the shape of the edited signal. The method was applied in combination with the MEGA-sLASER editing technique to measure the in vivo T2 relaxation time of GABA (87 ± 11 ms, n = 10) and creatine (109 ± 8 ms, n = 10) at 7 T. The T1 relaxation time of these metabolites in a single subject was also determined (GABA, 1334 ± 158 ms; Cr, 1753 ± 12 ms). The T2 decay curve of coupled spin systems can be sampled in an arbitrary fashion without the need for signal shape correction. Furthermore, the method can be applied with any spectral editing technique. The shortest echo time of the method is limited by the echo time of the spectral editing technique. Copyright © 2013 John Wiley & Sons, Ltd. 23529668 Malignant biliary obstructions: can we predict immediate postprocedural cholangitis after percutaneous biliary drainage? Percutaneous transhepatic biliary drainage (PTBD) is performed for the palliation of malignant biliary obstructions. The purpose of this study was to identify factors related to the occurrence of immediate cholangitis as a complication after PTBD METHODS: We retrospectively assessed 409 apparently stable patients with malignant biliary obstruction who underwent PTBD between January 2008 and December 2010. New onset cholangitis was defined as fever (>38 °C) that arose within 24 h after the intervention. Variables significantly associated with the occurrence of immediate cholangitis were selected and their odds ratio and 95 % confidence interval were calculated using logistic regression analysis. There were 106 (25.9 %) cases of immediate cholangitis following PTBD, and among those 106 cases, 45 (42.5 %) had sepsis. In multivariate analysis, history of cholangitis (OR 4.7, 95 % CI 2.45-9.18), biliary drainage within 6 months (OR 2.3, 95 % CI 1.26-4.15), CRP ≥ 5 mg/dL (OR 2.2, 95 % CI 1.23-4.03), and serum albumin <3 g/dL (OR 1.9, 95 % CI 1.023-3.40) were predictive of immediate cholangitis after PTBD for malignant biliary obstructions. Cholangitis is a common immediate complication after PTBD. Patients should always be given prophylactic antibiotics before the drainage procedures. The results of this study could highlight the patients who require closer follow-up in order to make PTBD a safer procedure. 23774860 Synthetic evaluation of disulphide-bonded sarafotoxin on a poly(oxy ether) grafted dendrimeric poly(alkyl amine) support for polymer assisted organic synthesis. The present paper describes the synthesis, characterization and assessment of a novel class of insoluble polymeric polystyrene supports which combines polar poly(ethylene glycol)dimethacrylate as a cross-linker and poly(ethylene glycol) grafted poly(N,N-bisethylamine) as a dendritic template. Poly(N,N-bisethylamine) dendrimers were generated by a series of reactions such as Schiff base integration, acidolysis, diazotization and thionyl chloride treatment. The same successive sequences of reactions have been followed for second generation dendrimers also and subjected to PEGylation (PEG 600) to achieve the desirable physico-chemical properties. The applicability of the novel PEGylated dendrimer support was demonstrated by synthesizing linear as well as disulfide bonded peptides in high yields and purities. 23038767 PUB-NChIP--"in vivo biotinylation" approach to study chromatin in proximity to a protein of interest. We have developed an approach termed PUB-NChIP (proximity utilizing biotinylation with native ChIP) to purify and study the protein composition of chromatin in proximity to a nuclear protein of interest. It is based on coexpression of (1) a protein of interest, fused with the bacterial biotin ligase BirA, together with (2) a histone fused to a biotin acceptor peptide (BAP), which is specifically biotinylated by BirA-fusion in the proximity of the protein of interest. Using the RAD18 protein as a model, we demonstrate that the RAD18-proximal chromatin is enriched in some H4 acetylated species. Moreover, the RAD18-proximal chromatin containing a replacement histone H2AZ has a different pattern of H4 acetylation. Finally, biotin pulse-chase experiments show that the H4 acetylation pattern starts to resemble the acetylation pattern of total H4 after the proximity of chromatin to RAD18 has been lost. 23933587 Endothelin regulates neural crest deployment and fate to form great vessels through Dlx5/Dlx6-independent mechanisms. Endothelin-1 (Edn1), originally identified as a vasoconstrictor peptide, is involved in the development of cranial/cardiac neural crest-derived tissues and organs. In craniofacial development, Edn1 binds to Endothelin type-A receptor (Ednra) to induce homeobox genes Dlx5/Dlx6 and determines the mandibular identity in the first pharyngeal arch. However, it remains unsolved whether this pathway is also critical for pharyngeal arch artery development to form thoracic arteries. Here, we show that the Edn1/Ednra signaling is involved in pharyngeal artery development by controlling the fate of neural crest cells through a Dlx5/Dlx6-independent mechanism. Edn1 and Ednra knock-out mice demonstrate abnormalities in pharyngeal arch artery patterning, which include persistent first and second pharyngeal arteries, resulting in additional branches from common carotid arteries. Neural crest cell labeling with Wnt1-Cre transgene and immunostaining for smooth muscle cell markers revealed that neural crest cells abnormally differentiate into smooth muscle cells at the first and second pharyngeal arteries of Ednra knock-out embryos. By contrast, Dlx5/Dlx6 knockout little affect the development of pharyngeal arch arteries and coronary arteries, the latter of which is also contributed by neural crest cells through an Edn-dependent mechanism. These findings indicate that the Edn1/Ednra signaling regulates neural crest differentiation to ensure the proper patterning of pharyngeal arch arteries, which is independent of the regional identification of the pharyngeal arches along the dorsoventral axis mediated by Dlx5/Dlx6. 23831865 Derivation of a clinical prediction rule to identify both chronic moderate/severe disability and full recovery following whiplash injury. Recovery following a whiplash injury is varied: approximately 50% of individuals fully recover, 25% develop persistent moderate/severe pain and disability, and 25% experience milder levels of disability. Identification of individuals likely to develop moderate/severe disability or to fully recover may help direct therapeutic resources and optimise treatment. A clinical prediction rule (CPR) is a research-generated tool used to predict outcomes such as likelihood of developing moderate/severe disability or experiencing full recovery from whiplash injury. The purpose of this study was to assess the plausibility of developing a CPR. Participants from 2 prospective, longitudinal studies that examined prognostic factors for poor functional recovery following whiplash injury were used to derive this tool. Eight factors, previously identified as predictor variables of poor recovery, were included in the analyses: initial neck disability index (NDI), initial neck pain (visual analogue scale), cold pain threshold, range of neck movement, age, gender, presence of headache, and posttraumatic stress symptoms (Posttraumatic Diagnostic Scale [PDS]). An increased probability of developing chronic moderate/severe disability was predicted in the presence of older age and initially higher levels of NDI and hyperarousal symptoms (PDS) (positive predictive value [PPV]=71%). The probability of full recovery was increased in younger individuals with initially lower levels of neck disability (PPV=71%). This study provides initial evidence for a CPR to predict both chronic moderate/severe disability and full recovery following a whiplash injury. Further research is needed to validate the tool, determine the acceptability of the proposed CPR by practitioners, and assess the impact of inclusion in practice. 23346902 Screening for X-linked adrenoleukodystrophy among adult men with Addison's disease. X-linked adrenoleukodystrophy is an important cause of Addison's disease in boys, but less is known about its contribution to Addison's disease in adult men. After surveying all known cases of X-linked adrenoleukodystrophy in Norway in a separate study, we aimed to look for any missed cases among the population of adult men with nonautoimmune Addison's disease. Among 153 adult men identified in a National Registry for Addison's Disease (75% of identified male cases of Addison's disease in Norway), those with negative indices for 21-hydroxylase autoantibodies were selected. Additionally, cases with low autoantibody indices (48-200) were selected. Sera from subjects included were analysed for levels of very long-chain fatty acids, which are diagnostic for X-linked adrenoleukodystrophy in men. Eighteen subjects had negative indices and 17 had low indices for 21-hydroxylase autoantibodies. None of those with low indices and only one of those with negative indices were found to have X-linked adrenoleukodystrophy; this subject had already been diagnosed because of the neurological symptoms. Cases of Addison's disease proved to be caused by X-linked adrenoleukodystrophy constitute 1·5% of all adult male cases in Norway; the proportion among nonautoimmune cases was 15%. We found X-linked adrenoleukodystrophy to be an uncommon cause of Addison's disease in adult men. However, this aetiological diagnosis has far-reaching consequences both for the patient and for his extended family. We therefore recommend that all adult men with nonautoimmune Addison's disease be analysed for levels of very long-chain fatty acids. 23922648 Comparison of Different Cells of Haematococcus pluvialis Reveals an Extensive Acclimation Mechanism during its Aging Process: From a Perspective of Photosynthesis. Both biomass dominated green vegetative cells (GV) and astaxanthin-dominated orange resting cells (OR) affect the final astaxanthin yield in industry. Examination of Haematococcus pluvialis revealed that the OR cells greatly varied from the GV cells at both cellular and subcellular levels. In particular, the thylakoid membranes in the OR were disassembled and fragmented. Furthermore, the OR conserved most of the photosynthetic pigments, with elevated concentrations of violaxanthin, antheraxanthin, and neoxanthin. Notably, moderate photosynthesis was detected in OR, even though most of the thylakoid membranes were disassembled, when compared with those in the GV. However, the energy distribution pattern between photosystem I and II (PSI and PSII) in the OR favored PSI, which was also confirmed by 77-K fluorescence. As zeaxanthin was not detected in the OR, we attribute the acclimation role to astaxanthin, instead of xanthophyll cycle. Additionally, proteomic-scale comparison analysis of thylakoids of the OR and GV indicated no photosynthetically remarkable variations. However, an extensive acclimation mechanism of H. pluvialis was proposed, in which proteins in thylakoid of GV were noted to be involved in biomass accumulation and those in OR were involved in stress response. Conclusions of the comparative analysis might provide some physiological background of OR for astaxanthin production by using H. pluvialis. 23911410 Comparative antigen-induced gene expression profiles unveil novel aspects of susceptibility/resistance to adjuvant arthritis in rats. Lewis (LEW) and Wistar Kyoto (WKY) rats of the same major histocompatibility complex (MHC) haplotype (RT.1(l)) display differential susceptibility to adjuvant-induced arthritis (AIA). LEW are susceptible while WKY are resistant to AIA. To gain insights into the mechanistic basis of these disparate outcomes, we compared the gene expression profiles of the draining lymph node cells (LNC) of these two rat strains early (day 7) following a potentially arthritogenic challenge. LNC were tested both ex vivo and after restimulation with the disease-related antigen, mycobacterial heat-shock protein 65. Biotin-labeled fragment cRNA was generated from RNA of LNC and then hybridized with an oligonucleotide-based DNA microarray chip. The differentially expressed genes (DEG) were compared by limiting the false discovery rate to <5% and fold change ≥2.0, and their association with quantitative trait loci (QTL) was analyzed. This analysis revealed overall a more active immune response in WKY than LEW rats. Important differences were observed in the association of DEG with QTL in LEW vs. WKY rats. Both the number of upregulated DEG associated with rat arthritis-QTL and their level of expression were relatively higher in LEW when compared to WKY rat; however, the number of downregulated DEG-associated with rat arthritis-QTL as well as AIA-QTL were found to be higher in WKY than in LEW rats. In conclusion, distinct gene expression profiles define arthritis-susceptible versus resistant phenotype of MHC-compatible inbred rats. These results would advance our understanding of the pathogenesis of autoimmune arthritis and might also offer potential novel targets for therapeutic purposes. 23273521 HCV NS5A replication complex inhibitors. Part 3: discovery of potent analogs with distinct core topologies. In a recent disclosure, we described the discovery of dimeric, prolinamide-based NS5A replication complex inhibitors exhibiting excellent potency towards an HCV genotype 1b replicon. That disclosure dealt with the SAR exploration of the peripheral region of our lead chemotype, and herein is described the SAR uncovered from a complementary effort that focused on the central core region. From this effort, the contribution of the core region to the overall topology of the pharmacophore, primarily vector orientation and planarity, was determined, with a set of analogs exhibiting <10 nM EC(50) in a genotype 1b replicon assay. 23737100 Fluorene-Based Co-polymer with High Hole Mobility and Device Performance in Bulk Heterojunction Organic Solar Cells. A new donor-acceptor polymer based on 9,9-dioctylfluorene is synthesized and tested in organic photovoltaic devices. Results show that the polymer exhibits good solubility in a range of organic solvents and has a high hole mobility. When blended with a PC70 BM acceptor and fabricated into a bulk heterojunction, photovoltaic devices having a maximum power conversion efficiency (PCE) of 6.2% and a peak external quantum efficiency of 74% are created. Such efficiencies are realized without any necessity for solvent additives or thermal annealing protocols. 23907924 The relationship between attentional bias and anxiety in children and adolescents with autism spectrum disorders. Young people with an autism spectrum disorder (ASD) are more likely to have heightened levels of anxiety compared with their typically developing (non-ASD) peers. The reasons for this are poorly understood, and there has been little research investigating the cognitive correlates of anxiety in individuals with ASD. Typically developing youth with anxiety disorders have frequently been found to show an attentional bias toward threatening information. In this study, we examined whether such a bias was also found in young people with ASD and anxiety symptoms. The protocol utilized two versions of the dot-probe paradigm, the first with emotional faces and the second with emotional words. Participants comprised 38 boys with an ASD and 41 typically developing controls aged 10-16 years of age. Those with an ASD displayed higher levels of parent- and child-rated anxiety (both P < 0.001) and depression (P < 0.001) compared with controls. However, there were no significant group differences in attentional bias scores and no significant relationship between anxiety and attentional bias in either the face or word tasks, for either group. Our findings suggest that, for young people with ASD, unlike non-ASD individuals with an anxiety disorder, high levels of anxiety may not be associated with attentional bias to threat. This may indicate that anxiety in ASD has different cognitive correlates from anxiety in the typically developing population. Further conclusions, study limitations, and future directions are discussed. Autism Res 2013, ●●: ●●-●●. © 2013 International Society for Autism Research, Wiley Periodicals, Inc. 23522835 In silico identification of poly(ADP-ribose)polymerase-1 inhibitors and their chemosensitizing effects against cisplatin-resistant human gastric cancer cells. Poly(ADP-ribose)polymerase-1 (PARP-1) enzyme is involved in the repair of DNA damages made by certain anticancer agents. It is suggested that PARP-1 inhibitors potentiate the cytotoxic effects and circumvent the resistance of DNA-modifying anticancer agents such as cisplatin. In this study, we conducted virtual screening of Korea Chemical Bank database targeting PARP-1 and identified several potent PARP-1 inhibitors with submicromolar IC50 values (77-79nM). We then examined the chemosensitization of cisplatin by pre-treatment of PARP-1 inhibitors in cisplatin-resistant human gastric cancer cells. Our results show that PARP-1 inhibitors suppress the formation of poly(ADP-ribose) and enhance the cytotoxicity of cisplatin. 23596176 Impact of fasting on the rhythmic expression of myogenic and metabolic factors in skeletal muscle of adult mice. Circadian rhythms and metabolism are tightly integrated, and rhythmic expression of metabolic factors is common in homeostatic processes. We measured the temporal changes in the expression of myogenic regulatory factors and expression and activity level of molecules involved in protein metabolism in skeletal muscles and livers in mice and examined the impact of fasting. Tissues were collected over 24 h (at zeitgeber times ZT1, ZT5, ZT9, ZT13, ZT17, ZT21, and ZT1 the following day) from adult male C57Bl/6J mice that had been either freely fed or fasted for 24 h. In skeletal muscle, there was a robust rise in the mRNA expression of the myogenic regulatory factors MyoD and myogenin during dark hours which was strongly suppressed by fasting. Circadian pattern was observed for mRNA of MuRF1, Akt1, and ribosomal protein S6 in muscles in fed and fasted mice and for Fbxo32 in fed mice. Activity (phosphorylation) levels of Akt(Ser473) displayed temporal regulation in fasted (but not fed) mice and were high at ZT9. Fasting caused significant reductions in phosphorylation for both Akt and S6 in muscles, indicative of inactivation. Hepatic phosphorylated Akt(Ser473) and S6(Ser235/236) proteins did not exhibit daily rhythms. Fasting significantly reduced hepatic Akt(473) phosphorylation compared with fed levels, although (unlike in muscle) it did not affect S6(Ser235/236) phosphorylation. This in vivo circadian study addresses for the first time the signaling activities of key molecules related to protein turnover and their possible cross-regulation of expression of genes related to protein degradation. 23624394 Developmental toxicity and estrogenic potency of zearalenone in zebrafish (Danio rerio). Zearalenone (ZEA, F2) is one of the most common mycotoxins and the only known mycoestrogen. It enters the food and feed chain from contaminated cereals and infiltrates into sewage or natural waters posing potential threat to exposed livestock, wildlife and humans. Therefore evaluation of its biological effects is of international importance. We performed toxicological tests on zebrafish (Danio rerio) larvae and adults. Developmental toxicity was assessed by an extended (5 days) fish embryo toxicity test (FET). Effects of early ZEA exposure were concentration-dependent with LC50 and LC10 values of 893 and 335μg/L. In larvae exposed to 500μg/L and above, ZEA induced similar phenotype to has (heart-and soul) showing defects in heart and eye development and upward curvature of the body axis. From 250μg/L at 72hpf the gap in the melanophore streak at the base of the tail fin was missing and the fin fold was abnormal, suggesting disturbance in the development of the adult tail fin primordium. Estrogenic potency was measured on the basis of Vitellogenin (Vtg) protein (adults) levels and relative abundance of vitellogenin-1 mRNA (vtg-1) (larvae and adults). qRT-PCR in larvae proved to be sufficient substitute to adult tests and sensitive enough to detect ZEA in 0.1μg/L concentrations, that is close to levels observed in wastewaters. Developmental defects reveal that besides direct estrogenic effects, zearalenone might interact with other ontogenic pathways. 23958682 Two-stage anaerobic membrane bioreactor for the treatment of sugarcane vinasse: Assessment on biological activity and filtration performance. A two-stage submerged anaerobic membrane bioreactor (2-SAnMBR) was designed for the treatment of sugarcane vinasse. For start-up, the flow rate was reduced whenever VFA levels reached critical levels in the methanogenic reactor. After acclimation, the system was operated under a continuous flow. Separation of the stages was observed during the entire period of operation. VFA, COD and DOC levels of raw effluent, acidified effluent and permeate averaged 2141, 3525 and 61mgVFAL(-1) (as acetic acid), 15727, 11512 and 488mgCODL(-1), and, 3544, 3533 and 178mgDOCL(-1), respectively. Overall COD and DOC removal efficiencies of 96.9±0.7% and 95.0±1.1%, respectively, were reached. Methane content of the biogas from the acidogenic and methanogenic reactors ranged 0.1-4.6% and 60.1-70.1%, respectively. Removable fouling strongly affected filtration performance and cake layer formation accounted for most of filtration resistance. Membrane resistance was related to presence of protein-like substances and carbohydrates. 23791762 Maternal corticosterone elevation during egg formation in chickens (Gallus gallus domesticus) influences offspring traits, partly via prenatal undernutrition. The relationship between maternal stress during pregnancy in humans and the subsequent physical and mental health disorders in their children has inspired a wide array of studies on animal models. Almost all of these studies have used mammalian species, but more recently oviparous species in which the embryo develops outside the mother's body have received more attention. These new models facilitate disentangling of the underlying mechanism due to the accessibility of the prenatal environment, the egg. Studies in birds have found that maternal stress during egg formation induces phenotypic alterations in the offspring that hatch from these eggs. However, different offspring traits have been measured in different studies and potential underlying mechanisms are barely addressed. In this study we experimentally manipulated maternal corticosterone levels in laying hens. We found that mothers with experimentally elevated plasma corticosterone levels produced offspring that are smaller at hatching, less competitive, less fearful, have lower immunocompetence and higher plasma testosterone levels, as well as an alteration of visually guided behavioural lateralization. Earlier we have showed that eggs produced by these corticosterone treated mothers were lighter and contained lower concentrations of testosterone and progesterone in the yolk. While yolk hormones showed no correlation with any offspring traits, egg mass correlated positively with offspring's body mass from hatching until 10days of age and hatching mass correlated positively with the offspring's ability to compete for food, indicating that prenatal under nutrition might mediate some effects of maternal stress. 23857287 Interleukin-6 limits influenza-induced inflammation and protects against fatal lung pathology. Balancing the generation of immune responses capable of controlling virus replication with those causing immunopathology is critical for the survival of the host and resolution of influenza-induced inflammation. Based on the capacity of interleukin-6 (IL-6) to govern both optimal T-cell responses and inflammatory resolution, we hypothesised that IL-6 plays an important role in maintaining this balance. Comparison of innate and adaptive immune responses in influenza-infected wild-type control and IL-6-deficient mice revealed striking differences in virus clearance, lung immunopathology and generation of heterosubtypic immunity. Mice lacking IL-6 displayed a profound defect in their ability to mount an anti-viral T-cell response. Failure to adequately control virus was further associated with an enhanced infiltration of inflammatory monocytes into the lung and an elevated production of the pro-inflammatory cytokines, IFN-α and TNF-α. These events were associated with severe lung damage, characterised by profound vascular leakage and death. Our data highlight an essential role for IL-6 in orchestrating anti-viral immunity through an ability to limit inflammation, promote protective adaptive immune responses and prevent fatal immunopathology. 23661010 Interactive applications for sketch-based editable polycube map. In this paper, we propose a sketch-based editable polycube mapping method that, given a general mesh and a simple polycube that coarsely resembles the shape of the object, plus sketched features indicating relevant correspondences between the two, provides a uniform, regular, and user-controllable quads-only mesh that can be used as a basis structure for subdivision. Large scale models with complex geometry and topology can be processed efficiently with simple, intuitive operations. We show that the simple, intuitive nature of the polycube map is a substantial advantage from the point of view of the interface by demonstrating a series of applications, including kit-basing, shape morphing, painting over the parameterization domain, and GPU-friendly tessellated subdivision displacement, where the user is also able to control the number of patches in the base mesh by the construction of the base polycube. 23863574 Infection with hemotropic Mycoplasma sp. in people with and without extensive arthropod and animal contact. PCR amplification targeting the 16S rRNA gene was used to test individuals with and without extensive arthropod and animal contact for the possibility of hemotropic mycoplasma infection. The prevalence of hemotropic mycoplasma infection (4.7%) was significantly greater in previously reported cohorts of veterinarians, veterinary technicians, spouses of veterinary professionals, and others with extensive arthropod exposure and/or frequent animal contact, as compared to a previously reported cohort of patients examined by a rheumatologist because of chronic joint pain or evidence of small vessel disease (0.7%). Based upon DNA sequence analysis, Mycoplasma ovis-like species was the most prevalent organism detected; however, infection with 'Candidatus M. haematoparvum' and a potentially novel, but incompletely characterized hemotropic mycoplasma species was also documented. Historical exposure to animals and arthropod vectors that can harbor hemotropic mycoplasma spp. should be considered during epidemiological investigations and when evaluating individual patients. 23878845 Randomized clinical evaluation of the effect of chlorhexidine on postoperative sensitivity of posterior composite resin restorations. Objectives: Evaluation of postoperative sensitivity in posterior teeth restored with etchand- rinse adhesive and composite resin after application of 2% chlorhexidine solution. Method and Materials: Thirty participants with similar dental caries on both sides of the jaws were selected. After cavity preparation, each tooth was randomized to one of the following restoration methods. Teeth in the control group were restored using etch-and-rinse resin adhesive (Single Bond, 3M ESPE) and universal microhybrid composite resin (Filtek Z250, 3M ESPE). Restoration of teeth in the experimental group was similar to the control group except that 2% chlorhexidine solution (Concepsis, Ultradent) was applied on the etched dentin for 60 seconds. Subjects were recalled for evaluation of postoperative sensitivity at 1 day, 1 week, 1 month, and 6 months. Data were analyzed by Fisher exact test (α = .05). Results: The experimental group showed significantly less postoperative sensitivity (8 teeth) compared with the control group (20 teeth) at the 1-day recall (P < .05; Fisher exact test). Conventional restorations were comparable to teeth treated with chlorhexidine at other recall times (P > .05). Conclusion: Chlorhexidine significantly decreased immediate postoperative sensitivity of posterior teeth restored by composite resin. 23688823 Robust tests for one or more allometric lines. In allometry, the study of how size variables scale against each other, it is often of interest to fit lines to bivariate data and test hypotheses about slope and elevation about one or several lines. The nature of the problem suggests that bivariate techniques related to principal component analysis are more appropriate than linear regression. Inference methods have been developed for this problem and are in widespread use, however, we demonstrate that such methods are not robust to bivariate contamination, and propose alternative approaches which are. The new approaches use Huber's M-estimator via a plug-in approach, where robust test procedures have the same form as classical ones, but where we plug in robust estimators of parameters and standard errors in place of classical estimators. Simulations demonstrate that these new procedures are robust against bivariate contamination, and can make accurate inferences even from small samples. 23818037 A job-exposure matrix for research and surveillance of occupational health and safety in Spanish workers: MatEmESp. In this study we describe a general-population job-exposure matrix (MatEmESp) for Spanish workers covering the period 1996-2005. The Finnish job-exposure matrix (FINJEM) provided the default value estimates for occupational exposure to chemical, physical and biological agents. These estimates were adapted to Spanish working conditions by local experts. Spanish surveys were used to obtain exposure estimates for ergonomic and psychosocial risk factors. Employment and socio-demographic conditions for Spanish workers were obtained from the Spanish National Statistics Institute. MatEmESp provides a large amount of national and occupation-specific data on the major occupational exposures in Spain. As some examples, the data show that the most prevalent occupational hazards are repetitive movements and a lack of support from co-workers. In addition, 10% of the Spanish working population perform night shifts, and bricklayers and concrete workers are the job titles with the highest risk of exposure to quartz dust. MatEmESp can be a useful tool for research and surveillance, and can help set priorities for occupational illness and injury prevention in Spain. Am. J. Ind. Med. © 2013 Wiley Periodicals, Inc. 23903944 Adoption of the ICD-10 Standard in the United States: The Time Is Now. The United States is facing a revolution in the health care system soon when the present coding system (International Classification of Diseases, Ninth Revision) will be replaced with what has for some years been the international standard: International Statistical Classification of Diseases, 10th Revision (ICD-10). The ICD-10 system will provide a tremendous opportunity for better capturing information in the increasingly complex delivery of health care. Although the transition to ICD-10 will undoubtedly result in substantial short-term costs, the long-term benefits make the transition imperative. 23192525 Effective inhibition of mRNA accumulation and protein expression of H5N1 avian influenza virus NS1 gene in vitro by small interfering RNAs. Avian influenza has emerged as a devastating disease and may cross species barrier and adapt to a new host, causing enormous economic loss and great public health threats, and non-structural protein 1 (NS1) is a multifunctional non-structural protein of avian influenza virus (AIV) that counters cellular antiviral activities and is a virulence factor. RNA interference (RNAi) provides a powerful promising approach to inhibit viral infection specifically. To explore the possibility of using RNAi as a strategy against AIV infection, after the fusion protein expression plasmids pNS1-enhanced green fluorescent protein (EGFP), which contain the EGFP reporter gene and AIV NS1 as silencing target, were constructed and NS1-EGFP fusion protein expressing HEK293 cell lines were established, four small interfering RNAs (siRNAs) targeting NS1 gene were designed, synthesized, and used to transfect the stable cell lines. Flow cytometry, real-time quantitative polymerase chain reaction, and Western blot were performed to assess the expression level of NS1. The results suggested that sequence-dependent specific siRNAs effectively inhibited mRNA accumulation and protein expression of AIV NS1 in vitro. These findings provide useful information for the development of RNAi-based prophylaxis and therapy for AIV infection. 23742903 Oral trail making task as a discriminative tool for different levels of cognitive impairment and normal aging. The Trail Making Test (TMT) is a useful measure of executive dysfunction in elderly subjects. This study aims to investigate the discriminative validity of the oral version of the TMT (OTMT), which can be administered to subjects with visual or motor disabilities, in elderly patients with Mild Cognitive Impairment (MCI; n = 30), Alzheimer's disease (AD; n = 30), and healthy controls (HCs; n = 25). The WAIS-R Digit Span Backwards Subscale, written form of the Trail Making Task, the Clock Drawing Test, the AD Assessment Scale-Cognitive Subscale, and the OTMT were also administered to all participants in order to examine the concurrent validity of the OTMT. The OTMT part B discriminated between patients with MCI, AD, and HC correctly. The OTMT completion time was not correlated with age, but was negatively correlated with education. In conclusion, the OTMT (mostly part B) is a valid and practical measurement tool for different levels of cognitive impairment, especially for patients with visual or motor disabilities for whom the classical written form is not feasible. 23488932 RhoA, RhoB and RhoC have different roles in cancer cell migration. Rho GTPases are well known to regulate cell motility through activation of a variety of downstream effector proteins, including enzymes, adaptor proteins and actin nucleators. The three closely related Rho GTPases RhoA, RhoB and RhoC all have the potential to interact with the same downstream effectors, yet they have substantially different effects on cell shape and migratory properties. Here I review the different ways in which RhoA, RhoB and RhoC expression is regulated in cancer and how they play distinct roles in cancer progression. I describe their main effectors known to contribute to cell motility. Recent results from our laboratory and others indicate that RhoA, RhoB and RhoC can be activated by specific stimuli and act through different effectors to control distinct aspects of cancer cell migration and invasion. This suggests that they each make unique contributions to cancer by participating in different protein complexes. 23897426 Regulation of SirT1-NML binding by rRNA coordinates ribosome biogenesis with nutrient availability. Nucleomethylin (NML), a novel nucleolar protein, is important for mediating the assembly of the energy-dependent nucleolar silencing complex (eNoSC) that also contains SirT1 and SUV39H1. The eNoSC complex represses rRNA transcription during nutrient deprivation, thus reducing energy expenditure and improving cell survival. We found that NML is a RNA-binding protein that co-purifies with 5S, 5.8S and 28S rRNA. The SirT1 and RNA binding regions on NML showed partial overlap, and NML-SirT1 interaction is competitively inhibited by rRNA. Nutrient deprivation triggers down regulation of rRNA transcription, reduces the level of NML-associated rRNA, and stimulates NML-SirT1 binding. Assembly of eNoSC complex facilitates repression of pre-rRNA transcription. These results suggest that nascent rRNA generates a positive feedback signal by suppressing the assembly of eNoSC and protecting active rDNA units from heterochromatin formation. This RNA-mediated mechanism enables the eNoSC to amplify the effects of upstream nutrient-responsive regulators. 23643743 Cyclooxygenase activity contributes to the monoaminergic damage caused by serial exposure to stress and methamphetamine. Methamphetamine (Meth) is a widely abused psychostimulant that causes long-term dopamine (DA) and serotonin (5-HT) depletions. Stress and Meth abuse are comorbid events in society and stress exacerbates Meth-induced monoaminergic terminal damage. Stress is also known to produce neuroinflammation. This study examined the role of the neuroinflammatory mediator, cyclooxygenase (COX), in the depletions of monoamines caused by serial exposure to chronic unpredictable stress (CUS) and Meth. CUS produced an increase in COX-2 protein expression and enhanced Meth-induced monoaminergic depletions in the striatum and hippocampus. The enhanced DA and 5-HT depletions in the striatum, but not the hippocampus, were prevented by pretreatment with COX inhibitor, ketoprofen, during stress or during Meth; however, ketoprofen did not attenuate the monoaminergic damage caused by Meth alone. The COX-dependent enhancement by stress of Meth-induced monoaminergic depletions was independent of hyperthermia, as ketoprofen did not attenuate Meth-induced hyperthermia. In addition, the EP1 receptor antagonist, SC-51089, did not attenuate DA or 5-HT depletions caused by stress and Meth. These findings illustrate that COX activity, but not activation of the EP1 receptor, is responsible for the potentiation of Meth-induced damage to striatal monoamine terminals by stress and suggests the use of anti-inflammatory drugs for mitigating the neurotoxic effects associated with the combination of stress and Meth. 23861361 Case Definitions, Diagnostic Algorithms, and Priorities in Encephalitis: Consensus Statement of the International Encephalitis Consortium. Background. Encephalitis continues to result in substantial morbidity and mortality worldwide. Advances in diagnosis and management have been limited, in part, by a lack of consensus on case definitions, standardized diagnostic approaches, and priorities for research. Methods. In March 2012, the International Encephalitis Consortium, a committee begun in 2010 with members worldwide, held a meeting in Atlanta to discuss recent advances in encephalitis and to set priorities for future study. Results. We present a consensus document that proposes a standardized case definition and diagnostic guidelines for evaluation of adults and children with suspected encephalitis. In addition, areas of research priority, including host genetics and selected emerging infections, are discussed. Conclusions. We anticipate that this document, representing a synthesis of our discussions and supported by literature, will serve as a practical aid to clinicians evaluating patients with suspected encephalitis and will identify key areas and approaches to advance our knowledge of encephalitis. 23752348 A green luminescent 1-D helical tubular dipyrazol-bridged cadmium(II) complex: a coordination tube included in a supramolecular tube. A 1-D helical tubular cadmium coordination polymer, [Cd(H2Me4bpz)(H2bidc)2]n (1, H2Me4bpz = 3,3',5,5'-tetramethyl-4,4'-bipyrazole; H3bidc = benzimidazole-5,6-dicarboxylic acid) was hydrothermally synthesized and characterized by means of elemental analyses, PXRD, IR, 2D IR correlation spectra, solid UV, TG analysis, luminescence spectroscopy and single crystal X-ray diffraction. The crystal structure of 1 is a unique example of a 1D helical tube-in-tube structure. Interestingly, the [Cd(H2Me4bpz)] coordination helical tube is included in the [Cd(H2bidc)] supramolecular helical tube with the same handness. The compound displays a green luminescence upon excitation at 397 nm. 23863899 Implications of continued response after autologous stem cell transplantation for multiple myeloma. Patients undergoing autologous stem cell transplantation (ASCT) for multiple myeloma (MM) have disease assessment approximately 100 days later. Some patients continue to experience a decline in their serum or urine monoclonal protein after day 100 in the absence of additional therapy. We evaluated 430 MM patients who underwent ASCT within 12 months of their diagnosis and who had not achieved a complete remission at day 100. Of these patients, 167 (39%) had a continued response after day 100 without additional therapy. When compared to patients who did not (n=263), those experiencing a continued response had a longer progression free survival (35 vs. 13 months, P < 0.001), time to next therapy (43 vs. 16 months, P < 0.001) and overall survival (96 vs. 57 months, P < 0.001). This phenomenon of a continued response maintained prognostic value in a multivariable analysis and should be considered when interpreting post-transplant responses. 23868679 Effects of Different Physical Exercises on Leptin Concentration in Obese Adolescents. In order to compare the effects of leisure physical activity (LPA), aerobic training (AT) and aerobic plus resistance training (AT+RT) as part of a 6-month interdisciplinary therapy in body composition, insulin resistance and leptin concentrations in obese adolescents, 72 volunteers (n=24 in each group) ages 15-19 years were evaluated. Delta (Δ) body mass (kg) and Δ BMI (kg/m2) was different between AT and LPA groups and in AT+RT group compared to both LPA and AT groups; Δ body fat mass (kg and %) was different only in AT+RT group compared to both LPA and AT; Δ body lean mass (%) was different only in AT+RT group; Δ body lean mass (kg) was negative only in AT and positive and different from AT in AT+RT group; ΔHOMA-IR did not differ among groups; Δ leptin (ng/ml) was negative and different from LPA for both AT and AT+RT groups. In conclusion, both AT and AT+RT promoted a reduction on leptin levels, however, the adolescents subjected to AT+RT presented better results in body composition than the AT group. These results highlight the importance of associating aerobic and resistance training with nutritional and psychological approaches in the treatment of obese adolescents. 23447658 Developing a patient measure of safety (PMOS). Tools that proactively identify factors that contribute to accidents have been developed within high-risk industries. Although patients provide feedback on their experience of care in hospitals, there is no existing measure which asks patients to comment on the factors that contribute to patient safety incidents. The aim of the current study was to determine those contributory factors from the Yorkshire Contributory Factors Framework (YCFF) that patients are able to identify in a hospital setting and to use this information to develop a patient measure of safety (PMOS). Thirty-three qualitative interviews with a representative sample of patients from six units in a teaching hospital in the north of England were carried out. Patients were asked either to describe their most recent/current hospital experience (unstructured) or were asked to describe their experience in relation to specific contributory factors (structured). Responses were coded using the YCFF. Face validity of the PMOS was tested with 12 patients and 12 health professionals, using a 'think aloud' approach, and appropriate revisions made. The research was supported by two patient representatives. Patients were able to comment on/identify 13 of the 20 contributory factors contained within the YCFF domains. They identified contributory factors relating to communication and individual factors more frequently, and contributory factors relating to team factors, and support from central functions less frequently. In addition, they identified one theme not included in the YCFF: dignity and respect. The draft PMOS showed acceptable face validity. Patients are able to identify factors which contribute to the safety of their care. The PMOS provides a way of systematically assessing these and has the potential to help health professionals and healthcare organisations understand and identify, safety concerns from the patients' perspective, and, in doing so, make appropriate service improvements. 23868077 Molecular epidemiology of norovirus in Singapore, 2004-2011. Norovirus (NoV) is the most common cause of sporadic and epidemic gastroenteritis, globally. This study aimed to investigate the molecular epidemiology of NoV-associated acute gastroenteritis in Singapore by classifying circulating NoV genotypes and genogroup II, genotype 4 (GII.4) variants between September 2004 and February 2011. The temporal dominance and antigenic variation within the circulating epidemic NoV GII.4 variants was also examined, in order to compare the trends in Singapore to those observed globally during the same period. A total of 312 of 1,060 fecal specimens were positive for NoV RNA, using a quantitative RT-PCR. In a subset (125 of 312) of NoV positive samples, the 5' end of ORF2 (region C) of the GI or GII NoV genome was amplified and sequenced. Subsequent phylogenetic analysis identified GII.4 was the most commonly identified genotype representing 80.8% (101/125) of NoV sequenced in this study. The predominant GII.4 variants in circulation during the 2004-2011 epidemic periods were Hunter 2004 (2004-2005), Den Haag 2006b (2006-2009), and New Orleans 2009 (2009-2011). Amino acid variation within the P2 domain of the major capsid protein, VP1, was followed longitudinally within the GII.4 lineage. A constant turnover of variant-specific amino acid change was observed, particularly within the antigenic epitopes A, C and E. In conclusion, this study has characterized the NoV strains in circulation in Singapore between 2004 and 2011. The molecular epidemiology and persistence of GII.4 pandemic NoV lineages in Singapore was similar to trends seen globally, with a noted absence of the Asia 2003 variant. J Med. Virol. 85:1842-1851, 2013. © 2013 Wiley Periodicals, Inc. 23265530 Physicochemical properties of lard-based diacylglycerols in blends with lard. The objective of the study was to investigate how blending of triacylglycerols and diacylglycerols affected the melting and crystallisation properties in a solid fat system. Lard-based diacylglycerols (DAGs) were blended with lard in various concentrations (0%, 1%, 5%, 10%, 20%, 50%, 60%, 70%, 80%, 90%, and 100%). The melting and crystallisation properties were investigated by the determination of dropping point (DP), solid fat content (SFC), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). In general, the effects of DAGs were found to be dependent on concentration. The DP was significantly (P<0.0001) decreased when DAGs were added to the lard from 5-50%, whereas the DP was increased (P<0.0001) when the blends contained more than 60% DAGs. The DSC thermograms showed that DAGs changed the melting and crystallisation profiles of lard. The crystallisation onset point increased (P<0.05) with increasing the DAG concentrations (10-100%). The melting peaks and off-set points generally shifted slightly towards higher temperatures as the content of DAGs increased above 50%. DAG content of 5% and 10% resulted in lowering of the off-set point. The lard contained both β and β' crystals. The β form was more pronounced in the blends with high concentrations of DAGs. Blending of TAGs and DAGs may serve as a solution to achieve specific functional properties in products containing solid fats. 23773928 Redox modification of proteins as essential mediators of CNS autophagy and mitophagy. Production of cellular reactive oxygen species (ROS) is typically associated with protein and DNA damage, toxicity, and death. However, ROS are also essential regulators of signaling and work in concert with redox-sensitive proteins to regulate cell homeostasis during stress. In this review, we focus on the redox regulation of mitophagy, a process that contributes to energetic tone as well as mitochondrial form and function. Mitophagy has been increasingly implicated in diseases including Parkinson's, Amyotrophic Lateral Sclerosis, and cancer. Although these disease states employ different genetic mutations, they share the common factors of redox dysregulation and autophagic signaling. This review highlights key redox sensitive signaling molecules which can enhance neuronal survival by promoting temporally and spatially controlled autophagic signaling and mitophagy. 23886522 Gelsemine, a principal alkaloid from Gelsemium sempervirens Ait., exhibits potent and specific antinociception in chronic pain by acting at spinal α3 glycine receptors. The present study examined the antinociceptive effects of gelsemine, the principal alkaloid in Gelsemium sempervirens Ait. A single intrathecal injection of gelsemine produced potent and specific antinociception in formalin-induced tonic pain, bone cancer-induced mechanical allodynia, and spinal nerve ligation-induced painful neuropathy. The antinociception was dose-dependent, with maximal inhibition of 50% to 60% and ED50 values of 0.5 to 0.6μg. Multiple daily intrathecal injections of gelsemine for 7days induced no tolerance to antinociception in the rat model of bone cancer pain. Spinal gelsemine was not effective in altering contralateral paw withdrawal thresholds, and had only a slight inhibitory effect on formalin-induced acute nociception. The specific antinociception of gelsemine in chronic pain was blocked dose-dependently by the glycine receptor (GlyR) antagonist strychnine with an apparent ID50 value of 3.8μg. Gelsemine concentration-dependently displaced H(3)-strychnine binding to the membrane fraction of rat spinal cord homogenates, with a 100% displacement and a Ki of 21.9μM. Gene ablation of the GlyR α3 subunit (α3 GlyR) but not α1 GlyR, by a 7-day intrathecal injection of siRNA targeting α3 GlyR or α1 GlyR, nearly completely prevented gelsemine-induced antinociception in neuropathic pain. Our results demonstrate that gelsemine produces potent and specific antinociception in chronic pain states without induction of apparent tolerance. The results also suggest that gelsemine produces antinociception by activation of spinal α3 glycine receptors, and support the notion that spinal α3 glycine receptors are a potential therapeutic target molecule for the management of chronic pain. 23201447 Determination of aflatoxins, deoxynivalenol, ochratoxin A and zearalenone in wheat and oat based bran supplements sold in the Spanish market. The aflatoxins (AFs), deoxynivalenol (DON), ochratoxin A (OTA) and zearalenone (ZEA) are mycotoxins produced by fungal species which can contaminate, alone or simultaneously, cereal-based raw materials. Usually, the higher mycotoxins concentrations in cereals are found in the external layers of the grain (bran). Nowadays bran is increasingly consumed for its high fibre concentration. The objectives of this study were determining the concentration of these mycotoxins in bran samples intended for direct human consumption and to study the influence of some characteristics of the samples that may affect the mycotoxins content, there are not studies about fibre for direct human consumption. 67 bran samples from shops and supermarkets from two different Spanish cities were analyzed, being 37 samples of wheat bran and the remaining of oat bran. The results showed a major presence of DON in the analyzed samples, with levels above the EU legislation in some samples. Presence of DON was more frequent in wheat samples, compared to oats ones (p<0.05). Extruded or toasted samples, subjected to a heat treatment during processing, presented a significantly lower concentration of OTA, and differences between the organically and conventionally produced samples were also detected in OTA, which showed higher levels in the organic samples. Co-occurrence was frequently found between the Fusarium mycotoxins (ZEA and DON). Due to the high levels of DON in the analyzed samples, a calculation of DON intake has been made and it has been demonstrated that bran can account for an important percentage of DON exposure in the total diet. 23833098 CT and MRI findings of renal infestation by a huge active hydatid cyst. Hydatid cysts derived from a type of tapeworm called Echinococcus granulosis larvaes which can situate in various organs or tissues in human body. It encounters as an endemic zoonosis in many regions all over the world including eastern part of Turkey. Renal involvement of hydatid cysts is uncommon even in endemic areas. The imaging properties vary according to the phase of the disease. Although it is a benign condition, the diagnosis of a renal hydatid cyst is critical in managing treatment and complications, such as nephrectomy, medical treatment before surgery and the risk of anaphylaxis or dissemination during intervention. Herein authors reported a case of an isolated involvement of the right kidney by a huge active hydatid cyst in a young man who was treated surgically, emphasising its ultrasound, CT, contrast-enhanced MR and diffusion-weighted imaging findings. 23959312 Mevalonate auxotrophic mutant of Staphylococcus aureus can adapt to mevalonate depletion. In this study we attempted to adopt the auxotrophic mevalonate synthase mutant (ΔmvaS) of Staphylococcus aureus to study whether a non-growing but viable cell population is tolerant to bactericidal antibiotics. The mevalonate-depleted non-growing ΔmvaS was found tolerant to antibiotics. Surprisingly, after prolonged cultivation we obtained stable ΔmvaS variants that were able to grow without mevalonate, which suggested unknown mechanisms for compensating undecaprenyl pyrophosphate production without mevalonate in S. aureus. 23220608 Anti-inflammatory properties of fruit juices enriched with pine bark extract in an in vitro model of inflamed human intestinal epithelium: the effect of gastrointestinal digestion. Enrichment of fruit juices with pine bark extract (PBE) could be a strategy to compensate for phenolic losses during the gastrointestinal digestion. A coculture system with Caco-2 cells and RAW 264.7 macrophages was established as an in vitro model of inflamed human intestinal epithelium for evaluating the anti-inflammatory capacity of fruit juices enriched with PBE (0.5 g L(-1)) before and after in vitro digestion. The digestion of both PBE-enriched pineapple and red fruit juice led to significant changes in most of the analysed phenolic compounds. The in vitro inflammatory state showed cell barrier dysfunction and overproduction of IL-8, nitric oxide (NO) and reactive oxygen species (ROS). In the inflamed cells, incubation with nondigested samples reduced (P<0.05) the production of IL-8 and NO compared with digested samples. ROS production increased in the inflamed cells exposed to digested commercial red fruit juice (86.8±1.3%) compared with fresh juice (77.4±0.8%) and increased in the inflamed cells exposed to digested enriched red fruit juice (82.6±1.6%) compared with the fresh enriched juice (55.8±6%). The anti-inflammatory properties of PBE-enriched fruit juices decreased after digestion; further research on the bioavailability of the assayed compounds is needed to properly assess their usefulness for the treatment of gut inflammation. 23684728 Anti-Aspergillus activity of green coffee 5-O-caffeoyl quinic acid and its alkyl esters. The antifungal activities of 5-O-caffeoyl quinic acid (5-CQA) and of methyl, butyl, octyl, and dodecyl esters or 5-CQA, were tested on five toxigenic moulds from the Aspergillus genus (Aspergillus flavus, Aspergillus nomius, Aspergillus ochraceus, Aspergillus parasiticus, Aspergillus westerdijkiae). These mycotoxin producers' moulds may contaminate many types of food crops throughout the food chain posing serious health hazard to animals and humans. The use of chemical methods to decrease mycotoxin producer moulds contamination on food crops in the field, during storage, and/or during processing, has been proved to be efficient. In this work, the antifungal effect of 5-CQA and a homologous series of 5-CQA esters (methyl, butyl, octyl, dodecyl), was investigated using the microdilution method and the minimum inhibitory concentrations (MIC50 and MIC80). All molecules presented antifungal activity, and two esters showed a MIC for all fungi: octyl (MIC50 â‰¤ 0.5-0.75 mg/mL, MIC80 = 1.0-1.5 mg/mL) and dodecyl (MIC50 = 0.75-1.25 mg/mL) chlorogenates. Dodecyl chlorogenate showed a MIC80 (1.5 mg/mL) only for A. parasiticus. The maximum percent of growth inhibition on aspergillii was observed with octyl (78.4-92.7%) and dodecyl (54.5-83.7%) chlorogenates, being octyl chlorogenate the most potent antifungal agent. It was thus concluded that lipophilization improved the antifungal properties of 5-CQA, which increased with the ester alkyl chain length, exhibiting a cut-off effect at 8 carbons. As far as we know, it is the first report demonstrating that lipophilization may improve the antifungal activity of 5-CQA on five toxigenic moulds from the Aspergillus genus. Lipophilization would be a novel way to synthesize a new kind of antifungal agents with a good therapeutic value or a potential use as preservative in food or cosmetics. 23904460 Correlation between overall survival and growth modulation index in pre-treated sarcoma patients: a study from the French Sarcoma Group. Growth modulation index (GMI), the ratio of two times to progression measured in patients receiving two successive treatments (GMI = TTP2/TTP1), has been proposed as a criterion of phase II clinical trials. Nevertheless, its use has been limited until now. We carried out a retrospective multicentre study in soft tissue sarcoma patients receiving a second-line treatment after doxorubicin-based regimens to evaluate the link between overall survival and GMI. Second-line treatments were classified as 'active' according to the EORTC-STBSG criteria (3-month progression-free rate >40% or 6-month PFR >14%). Comparisons used chi-squared and log-rank tests. The population consisted in 106 men and 121 women, 110 patients (48%) received 'active drugs'. Median OS from the second-line start was 317 days. Sixty-nine patients experienced GMI >1.33 (30.4%). Treatments with 'active drug' were not associated with OS improvement: 490 versus 407 days (P = 0.524). Median OS was highly correlated with GMI: 324, 302 and 710 days with GMI <1, GMI = [1.00-1.33], and GMI >1.33, respectively (P < 0.0001). In logistic regression analysis, the sole predictive factor was the number of doxorubicin-based chemotherapy cycles. GMI seems to be an interesting end point that provides additional information compared with classical criteria. GMI >1.33 is associated with significant OS improvement. 23967012 The mysterious case of the C. elegans gut granule: death fluorescence, anthranilic acid and the kynurenine pathway. Gut granules are lysosome-like organelles with acidic interiors that are found in large numbers within the intestine of the nematode Caenorhabditis elegans. They are particularly prominent when viewed under ultraviolet light, which causes them to emit intense blue fluorescence. Yet the function of these large and abundant organelles in this heavily-studied model organism remains unclear. One possibility is that they serve as storage organelles, for example of zinc. A new clue to gut granule function is the identification of the blue fluorescent material that they contain as a glycosylated form of anthranilic acid, which is derived from tryptophan by action of the kynurenine pathway. This compound can also serve a surprising role as a natural, endogenous marker of organismal death. 23515584 Efficacy of D-penicillamine, a sequestering acetaldehyde agent, in the prevention of alcohol relapse-like drinking in rats. RATIONALE: Nowadays, very few approved anti-relapse treatments for alcoholism exist, and their overall efficacy can be considered moderate. An exciting rationale drug development opportunity for the treatment of chronic alcoholism is the use of acetaldehyde sequestering agents. Although these compounds are able to attenuate or prevent most of the behavioral and neurochemical effects of ethanol, the efficacy of acetaldehyde sequestration, by using agents such as D-penicillamine (DP), in relapse prevention has not been studied yet. OBJECTIVES: The aim of this study was to analyze the effects of DP treatment on the alcohol deprivation effect (ADE) in long-term ethanol-experienced rats as a model of relapse behavior and measure drug plasma and brain levels during treatment. METHODS: Rats were subcutaneously implanted with mini-osmotic pumps delivering 0, 0.25, or 1 mg/h of DP during 1 week. The efficacy to prevent ADE was determined. DP plasma and brain levels achieved during its subcutaneous administration were measured. In a second experiment, animals received bilateral infusions of 0 or 1.5 μg/h of DP directly into pVTA, and the appearance of ADE was evaluated. RESULTS: One milligram per hour, but not 0.25 mg/h, DP infusion prevented ADE and reduced the total ethanol preference in animals. DP plasma concentrations associated with ADE suppression were around 3-4 μg/ml, and brain DP levels in these conditions were about 2-3 % of those found in plasma. Intra-pVTA DP administration also suppressed ADE. CONCLUSION: DP is able to prevent alcohol-relapse-like drinking in rats suggesting that this drug may be a useful new tool in the management of relapse in alcohol-dependent patients. 23715169 A tissue-engineered gastric cancer model for mechanistic study of anti-tumor drugs. The use of the traditional xenograft subcutaneous tumor model has been contested because of its limitations, such as a slow tumorigenesis, inconsistent chemotherapeutic results, etc. In light of these challenges, we aim to revamp the traditional model by employing an electrospun scaffold composed of polydioxanone, gelatin and elastin to boost the tumorigenesis. The scaffold featured a highly porous microstructure and successfully supported the growth of tumor cells in vitro without provoking apoptosis. In vivo studies showed that in the scaffold model the tumor volume increased by 43.27% and the weight by 75.58%, respectively, within a 12-week period. In addition, the scaffold model saw an increase of CD24(+) and CD44(+) cells in the tumor mass by 42% and 313%, respectively. The scaffolding materials did not lead to phenotypic changes during the tumorigenesis. Thereafter, in the scaffold model, we found that the chemotherapeutic regimen of docetaxel, cisplatin and fluorouracil unleashed a stronger capability than the regimen comprising cisplatin and fluorouracil to deplete the CD44(+) subpopulation. This discovery sheds mechanistic lights on the role of docetaxel for its future chemotherapeutic applications. This revamped model affords cancer scientists a convenient and reliable platform to mechanistically investigate the chemotherapeutic drugs on gastric cancer stem cells. 22883473 Estimating remission from untreated major depression: a systematic review and meta-analysis. Few studies have examined spontaneous remission from major depression. This study investigated the proportion of prevalent cases of untreated major depression that will remit without treatment in a year, and whether remission rates vary by disorder severity. Method Wait-list controlled trials and observational cohort studies published up to 2010 with data describing remission from untreated depression at ⩽2-year follow-up were identified. Remission was defined as rescinded diagnoses or below threshold scores on standardized symptom measures. Nineteen studies were included in a regression model predicting the probability of 12-month remission from untreated depression, using logit transformed remission proportion as the dependent variable. Covariates included age, gender, study type and diagnostic measure. Wait-listed compared to primary-care samples, studies with longer follow-up duration and older adult compared to adult samples were associated with lower probability of remission. Child and adolescent samples were associated with higher probability of remission. Based on adult samples recruited from primary-care settings, the model estimated that 23% of prevalent cases of untreated depression will remit within 3 months, 32% within 6 months and 53% within 12 months. It is undesirable to expect 100% treatment coverage for depression, given many will remit before access to services is feasible. Data were drawn from consenting wait-list and primary-care samples, which potentially over-represented mild-to-moderate cases of depression. Considering reported rates of spontaneous remission, a short untreated period seems defensible for this subpopulation, where judged appropriate by the clinician. Conclusions may not apply to individuals with more severe depression. 23505206 Sclerostin and bone strength in women in their 10(th) decade of life. Sclerostin is a potent inhibitor of bone formation but has been shown to correlate positively with areal bone mineral density (aBMD). Little is known about its relationship to parameters of bone strength and volumentric BMD (vBMD) as measured by peripheral quantitative computed tomography (pQCT). We measured both serum sclerostin and parameters of tibial bone size and strength by pQCT to characterize this relationship. Our study population consisted of 223 Caucasian and 35 African American women (mean age 87) from the Study of Osteoporotic Fractures (SOF) cohort, who had usable pQCT scans of the tibia at sites 4% (T4%), 33% (T33%), and 66% (T66%) from the ankle. Analysis of covariance was used to test for differences in age-adjusted means of aBMD, pQCT variables, and serum biomarkers across sclerostin quartiles. Black women had significantly lower median sclerostin (34.3 pmol/L) than white women (48.5 pmol/L) (p = 0.05). Women in the highest sclerostin quartile had 7-14.5% higher hip aBMD and pQCT parameters of vBMD and bone size than those in the lowest quartile in multivariate models adjusting for age, race, weight, height and diabetes. The association of sclerostin with parameters of bone strength differed dramatically between T33% and T66% sites. At T66%, women in the highest sclerostin quartile had pQCT strength parameters 9.4-15.3% greater than the lowest quartile, whereas no trend was found for the T33% site. Our results suggest paradoxical associations between circulating sclerostin and bone size, density and strength. © 2013 American Society for Bone and Mineral Research. 23955695 EnerCage: A Smart Experimental Arena with Scalable Architecture for Behavioral Experiments. Wireless power, when coupled with miniaturized implantable electronics, has the potential to provide a solution to several challenges facing neuroscientists during basic and preclinical studies with freely behaving animals. The EnerCage system is one such solution as it allows for uninterrupted electrophysiology experiments over extended periods of time and vast experimental arenas, while eliminating the need for bulky battery payloads or tethering. It has a scalable array of overlapping planar spiral coils (PSCs) and 3-axis magnetic sensors for focused wireless power transmission to devices on freely moving subjects. In this paper, we present the first fully-functional EnerCage system, in which the number of PSC drivers and magnetic sensors was reduced to 1/3rd of the number used in our previous design via multi-coil coupling. The power transfer efficiency (PTE) has been improved to 5.6% at a 120 mm coupling distance and a 48.5 mm lateral misalignment (worst-case) between the transmitter (Tx) array and receiver (Rx) coils. The new EnerCage system is equipped with an Ethernet backbone, further supporting its modular/scalable architecture, which in turn allows experimental arenas with arbitrary shapes and dimensions. A set of experiments on a freely behaving rat were conducted by continuously delivering 20 mW to the electronics in the animal headstage for more than one hour in a powered 3538 cm2 experimental area. 23391363 Preparation of novel porous starch microsphere foam for loading and release of poorly water soluble drug. Abstract Background: Organic porous material is a promising carrier for enhancing the dissolution of poorly water soluble drug. The aim of the present study was to enhance dissolution and oral bioavailability of lovastatin (LV) by preparing a porous starch microsphere foam (PSM) using a novel method, meanwhile, looking into the mechanism of improving dissolution of LV. Methods: PSM was prepared by the W/O emulsion - freeze thawing method. The porous structure of PSM was characterized by scanning electron microscopy (SEM) and nitrogen adsorption/desorption analysis. The adsorption role of nanopores on the drug dissolution and physical state of LV was systematically studied by instrumental analysis, and in vitro and in vivo drug dissolution studies. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate carrier cytotoxicity. Results: The SEM images of PSM showed nanometer-sized pores. Physical state characterization indicated that porous structure effectively limited the degree of crystallinity of LV. The results of in vitro and in vivo tests testified that PSM accelerated the release of LV and enhanced its oral bioavailability in comparison with crude LV and commercial capsules. The loaded PSM powder indicated a good physical stability under storage for 12 months. MTT assay shows PSM has no toxicity for Caco-2 cell. Conclusion: The preparation was a promising method to produce small and uniform PSM with markedly enhanced dissolution rate and oral bioavailability due to the spatial confinement effect of porous structure. The present work demonstrates the significant potential for the use of PSM as a novel delivery system for poorly water soluble drugs. 23515406 New strategies in the treatment of multiple myeloma. Multiple myeloma is the second most common hematologic malignancy affecting terminally differentiated plasma cells. Although high-dose chemotherapy and autologous stem cell transplantation have improved survival in younger patients, the natural history of multiple myeloma has been changed with the availability of six new agents approved in the past 10 years (thalidomide, bortezomib, lenalidomide, liposomal doxorubicin, carfilzomib, and pomalidomide). Despite this significant improvement in the overall outcome, multiple myeloma remains incurable in the majority of patients, prompting a continued search for additional therapeutic options. Extensive molecular and genomic characterization of multiple myeloma cells in their bone marrow milieu, which affects myeloma cell growth and survival, has provided a number of novel drugable targets and pathways. Perturbation of protein catabolism at multiple levels has become an important target in multiple myeloma. Similarly, improvements in monoclonal antibody generation and vaccine development, along with identification of a number of cell surface and cellular targets, have led to the development of various strategies, including antibodies and antibody-drug conjugates that are under investigation preclinically and in early clinical studies. We propose that eventually, molecularly informed multiagent combination therapies will be required to eliminate the multiple myeloma cell clone for long-term disease control. 23797667 Pulmonary Expression of Oncostatin M (OSM) Promotes Inducible BALT Formation Independently of IL-6, Despite a Role for IL-6 in OSM-Driven Pulmonary Inflammation. Inducible BALT (iBALT) is associated with immune responses to respiratory infections as well as with local pathology derived from chronic inflammatory lung diseases. In this study, we assessed the role of oncostatin M (OSM) in B cell activation and iBALT formation in mouse lungs. We found that C57BL/6 mice responded to an endotracheally administered adenovirus vector expressing mouse OSM, with marked iBALT formation, increased cytokine (IL-4, IL-5, IL-6, IL-10, TNF-α, and IL-12), and chemokine (CXCL13, CCL20, CCL21, eotaxin-2, KC, and MCP-1) production as well as inflammatory cell accumulation in the airways. B cells, T cells, and dendritic cells were also recruited to the lung, where many displayed an activated phenotype. Mice treated with control adenovirus vector (Addl70) were not affected. Interestingly, IL-6 was required for inflammatory responses in the airways and for the expression of most cytokines and chemokines. However, iBALT formation and lymphocyte recruitment to the lung tissue occurred independently of IL-6 and STAT6 as assessed in gene-deficient mice. Collectively, these results support the ability of OSM to induce B cell activation and iBALT formation independently of IL-6 and highlight a role for IL-6 downstream of OSM in the induction of pulmonary inflammation. 23955102 Hemifield or hemispace: what accounts for the ipsilateral advantages in visually guided aiming? Aiming movements to targets presented on the same side as the reaching limb are faster and more accurate than movements made across the body. These advantages are typically attributed to within-hemisphere sensorimotor control. However, contrary to the within- versus between-hemisphere model, we have shown that some of these advantages tend to go with the side of the movement, rather than the side of the target (Carey et al. Exp Brain Res 112:496-504, 1996; Carey and Otto-de Haart Neuropsychologia 39:894, 2001). Barthélémy and Boulinghez (Exp Brain Res 147:305-312, 2002) acknowledge that our biomechanical account fits data for post-onset movement parameters such as peak velocity and duration, yet they report evidence for some within- versus between-hemisphere contributions to reaction time (RT) advantages. To examine a possible difference between early and late movement kinematics fitting these alternative models, we have dissociated field and space in a different way, which required arm movements with differential inertial consequences, as well as unpredictability of target location in terms of visual field. The data suggest that visual field may contribute some of the variance to hemispatial effects, but only for the right hand. In a second experiment, we used an antipointing task to examine hemispatial versus visual field effects on RTs and to revisit the possible hand difference identified in experiment 1. We found that hemispace accounted for all of the ipsilateral advantages, including RT, for both right and left hands. Results are discussed in terms of the computational requirements of eye-hand coordination in relative unconstrained conditions. 23845910 Optimal variable flip angle schemes for dynamic acquisition of exchanging hyperpolarized substrates. In metabolic MRI with hyperpolarized contrast agents, the signal levels vary over time due to T1 decay, T2 decay following RF excitations, and metabolic conversion. Efficient usage of the nonrenewable hyperpolarized magnetization requires specialized RF pulse schemes. In this work, we introduce two novel variable flip angle schemes for dynamic hyperpolarized MRI in which the flip angle is varied between excitations and between metabolites. These were optimized to distribute the magnetization relatively evenly throughout the acquisition by accounting for T1 decay, prior RF excitations, and metabolic conversion. Simulation results are presented to confirm the flip angle designs and evaluate the variability of signal dynamics across typical ranges of T1 and metabolic conversion. They were implemented using multiband spectral-spatial RF pulses to independently modulate the flip angle at various chemical shift frequencies. With these schemes we observed increased SNR of [1-(13)C]lactate generated from [1-(13)C]pyruvate, particularly at later time points. This will allow for improved characterization of tissue perfusion and metabolic profiles in dynamic hyperpolarized MRI. 23941965 Canine visceral leishmaniasis: Incidence and risk factors for infection in a cohort study in Brazil. Zoonotic visceral leishmaniasis in Brazil is caused by Leishmania infantum parasites and is transmitted by sand flies of the Phlebotominae family. Dogs are the main urban reservoirs and represent the major source of contagion for the vectors. Studies have shown that most infected dogs are polymerase chain reaction-positive months before seroconversion. Herein, we describe a cohort study designed to identify the incidence of and risk factors for L. infantum infection as detected by polymerase chain reaction-restriction fragment length polymorphism. To determine the risk factors for infection, we conducted a baseline canine survey (n=1443) from which dogs were selected for the cohort study (n=282) involving three evaluations over the course of a 26-month follow-up period. Serology, molecular tests, and a structured questionnaire were used. The risk factors for infection were identified by means of the Cox regression model. The overall infection incidence was 5.8 per 100 dog-months (95% confidence interval 5.1-6.5). Increased risk of infection was associated with the presence of previous cases of canine visceral leishmaniasis in the domiciles (hazard ratio [HR] 1.4; 95% confidence interval [CI] 1.1-1.8) and unplastered house walls (HR 3.6; 95% CI 1.6-8.1). These risk factors suggest that insecticide spraying in cracks and crevices in unplastered walls can reduce biting rates within and around homes. Furthermore, our results demonstrate that the Visceral Leishmaniasis Control and Surveillance Program should adopt environmental management measures in homes with previous cases of canine visceral leishmaniasis, because these homes are more likely to maintain the transmission cycle. 23567492 Morphology of the male reproductive system and sperm ultrastructure of the egg parasitoid Gryon pennsylvanicum (Ashmead) (Hymenoptera, Platygastridae). Gryon pennsylvanicum is a platygastrid hymenopteran that has lately received increasing attention in Europe due to its possible use in biological control of the conifer seed bug pest Leptoglossus occidentalis. Here the male reproductive system and the spermatogenesis of this species, along with those of Gryon muscaeformis, are examined ultrastructurally for the first time. The male genital system is formed by a pair of testes, each containing only one follicle, a pair of accessory glands and deferent ducts connected to a single ejaculatory duct. All the stages of spermatogenesis are described in detail. Characteristic features of the Gryon spp. sperm, which are 100 μm long, are the presence of a polygonal nucleus, only one mitochondrial derivative, the occurrence of the centriole adjunct and a typical insect 9 + 9 + 2 flagellar axoneme. The single derivative, however, results from a process in which one of the two mitochondria is lost during spermiogenesis. Unlike in other insects, two centrioles occur in spermatids as a consequence of the ameiotic parthenogenesis. These characteristics stand as a valuable tool for phylogenetic inferences. Furthermore this study suggests a useful strategy for laboratory mass rearing. 23411325 A traceability study on the Moscato wine chain. To address the growing interest of consumers for information on the provenance of foodstuffs, the production chain of world renowned Moscato d'Asti white wine has been studied using the distribution of lanthanides as chemical markers. From soil to must, upon every stage of the chain, samples have been taken and analysed with ICP-MS in order to verify whether the original fingerprint of soil is maintained or not along the chain. Results of this traceability study show clearly that lanthanides fingerprint is kept unaltered in the passage soil-grapes-must, while fractionation occurs upon wine clarifying with bentonites. The second part of the work involves a study on 102 samples of Moscato d'Asti musts in order to verify how they reflect the features of the different geographical zones where they come from, and to build a basis to be able to identify possible adulterations performed by addition of foreign musts. 23864596 Sexual selection accelerates signal evolution during speciation in birds. Sexual selection is proposed to be an important driver of diversification in animal systems, yet previous tests of this hypothesis have produced mixed results and the mechanisms involved remain unclear. Here, we use a novel phylogenetic approach to assess the influence of sexual selection on patterns of evolutionary change during 84 recent speciation events across 23 passerine bird families. We show that elevated levels of sexual selection are associated with more rapid phenotypic divergence between related lineages, and that this effect is restricted to male plumage traits proposed to function in mate choice and species recognition. Conversely, we found no evidence that sexual selection promoted divergence in female plumage traits, or in male traits related to foraging and locomotion. These results provide strong evidence that female choice and male-male competition are dominant mechanisms driving divergence during speciation in birds, potentially linking sexual selection to the accelerated evolution of pre-mating reproductive isolation. 23386248 Refining the UGT1A haplotype associated with irinotecan-induced hematological toxicity in metastatic colorectal cancer patients treated with 5-fluorouracil/irinotecan-based regimens. Despite the importance of UDP-glucuronosyltransferase (UGT) 1A1*28 in irinotecan pharmacogenetics, our capability to predict drug-induced severe toxicity remains limited. We aimed at identifying novel genetic markers that would improve prediction of irinotecan toxicity and response in advanced colorectal cancer patients treated with folic acid (leucovorin), fluorouracil (5-FU), and irinotecan (camptosar)-based regimens. The relationships between UGT1A candidate markers across the gene (n = 21) and toxicity were prospectively evaluated in 167 patients. We included variants in the 3'untranscribed region (3'UTR) of the UGT1A locus, not studied in this context yet. These genetic markers were further investigated in 250 Italian FOLFIRI-treated patients. Several functional UGT1A variants, including UGT1A1*28, significantly influenced risk of severe hematologic toxicity. As previously reported in the Italian cohort, a 5-marker risk haplotype [haplotype II (HII); UGTs 1A9/1A7/1A1] was associated with severe neutropenia in our cohort [odds ratio (OR) = 2.43; P = 0.004]. The inclusion of a 3'UTR single-nucleotide polymorphism (SNP) permitted refinement of the previously defined HI, in which HIa was associated with the absence of severe neutropenia in combined cohorts (OR = 0.55; P = 0.038). Among all tested UGT1A variations and upon multivariate analyses, no UGT1A1 SNPs remained significant, whereas three SNPs located in the central region of UGT1A were linked to neutropenia grade 3-4. Haplotype analyses of these markers with the 3'UTR SNP allowed the identification of a protective HI (OR = 0.50; P = 0.048) and two risk haplotypes, HII and HIII, characterized by 2 and 3 unfavorable alleles, respectively, revealing a dosage effect (ORs of 2.15 and 5.28; P ≤ 0.030). Our results suggest that specific SNPs in UGT1A, other than UGT1A1*28, may influence irinotecan toxicity and should be considered to refine pharmacogenetic testing. 23726951 Biochemical and molecular characterization of Pseudomonas aeruginosa CTM50182 organic solvent-stable elastase. An extracellular alkaline elastase was produced from Pseudomonas aeruginosa CTM50182. It was chromatographically purified using HPLC and Mono Q Sepharose column. Matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF/MS) analysis revealed that the purified enzyme (called AMPP) was a monomer with a molecular mass of 33,015.18Da. The N-terminal 29 amino acid sequence of AMPP showed high homology with those of Pseudomonas elastases. It showed optimal activity at pH 12 and 80°C and was stable at a pH range of 9-12 after 120h of incubation. Its thermoactivity and thermostability were upgraded in the presence of 5mM Co(2+). Its half-life times at 70 and 80°C were 16 and 10h, respectively. It was completely inhibited by ethylene glycol-bis (β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), and 1,10-phenanthroline, suggesting that it belongs to the metalloprotease family. AMPP also exhibited high catalytic efficiency, organic solvent-tolerance, and hydrolysis. The lasB gene encoding AMPP was cloned, sequenced, and expressed in Escherichia coli. The biochemical properties of the extracellular purified recombinant enzyme (rAMPP) were similar to those of native AMPP. This organic solvent-stable protease could be considered a potential candidate for application as a biocatalyst in the synthesis of enzymatic peptides. 23932856 Scaling-up the medical workforce in Timor-Leste: Challenges of a great leap forward. The health services system of Timor-Leste (T-L) will, by 2015, add 800 physicians, most of them trained in Cuba, to the 233 employed by the national health system in 2010-2011. The need for more physicians is not in discussion: poor health indicators, low coverage and utilization of services, and poor quality of services are well documented in T-L. However, the choice of this scaling-up, with a relatively narrow focus on the medical workforce, needs to be assessed for its relevance to the health profile of the country, for its comprehensiveness in terms of other complementary measures needed to make it effective. This article discusses the potential effects of the rapid scaling-up of the medical workforce, and the organizational capacity needed to monitor the process and eventually mitigate any deleterious consequences. The analysis is based on a review of documentation collected on site (T-L) and on interviews with key-informants conducted in 2011. We stress that any workforce scaling-up is not simply a matter of increasing numbers of professionals, but should combine improved training, distribution, working conditions, management and motivation, as a means towards better performing health services' systems. This is a major challenge in a context of limited organizational and managerial capacity, underdeveloped information systems, limited training and research capacity, and dependency on foreign aid and technical assistance. Potential risks are associated with funding the additional costs of recruiting more personnel, associated expenditures on infrastructure, equipment and consumables, the impact on current staff mix, and the expected increased demand for services. We conclude that failing to manage effectively the forthcoming "great leap forward" will have long term effects: formal policies and plans for the balanced development of the health workforce, as well as strengthened institutions are urgently needed. 23684826 Epidemiology of invasive pneumococcal disease in the pre-conjugate vaccine era: South Africa, 2003-2008. Dynamics of pneumococcal disease incidence and serotype distribution prior to introduction of pneumococcal conjugate vaccines (PCV) will assist in understanding effects of the vaccine over time and will be important in choosing the optimal PCV formulation. We conducted active, laboratory-based, national surveillance for invasive pneumococcal disease (IPD) through the Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA) from 2003 through 2008. Over 130 laboratories report to this system. Pneumococci were serotyped using Quellung and isolates screened for resistance by disk diffusion; minimum inhibitory concentrations were determined on potentially resistant isolates. We used univariate and multivariable multinomial regression models to assess differences between serotypes. GERMS-SA identified 8674 cases among children <5 years. Overall, 58% (3849/6668), 65% (4314/6668), and 85% (5669/6668) of cases and 61% (455/751), 64% (482/751), 82% (616/751) of deaths were due to serotypes included in 7-valent PCV, 10-valent PCV and 13-valent PCV, respectively. Serotypes 6A and 19A accounted for 16% (527/3252) of penicillin non-susceptible disease. In 2008, reported incidence of IPD was 6-fold higher in children <1 compared to children 1-4 years of age: 87 per 100,000 population and 14/100,000, respectively. The relative risk of IPD was 21-fold (95% CI, 19-24) and 34-fold (29-41) greater in HIV-infected compared to HIV-uninfected children in the <1 year and 1-4-year-old age groups respectively. On multivariable analysis serotypes 6B (relative risk ratio (RRR) 0.7; confidence interval (CI) 0.5-0.9), 18C (RRR 0.3; CI 0.1-0.5), 1 (RRR 0.2; CI 0.1-0.4) and 8 (RRR 0.2; CI 0.1-0.4) were significantly less common in HIV-infected individuals than serotype 14. All vaccine formulations have the potential to prevent most cases and deaths from IPD in children in South Africa. Vaccines with protection against 19A would be advantageous in South Africa. 23890499 A historical perspective on the essex-lopresti injury. An Essex-Lopresti injury is a fracture of the radial head with concomitant dislocation of the distal radioulnar joint and rupture of the interosseous membrane. Poor outcomes have been associated with this rare injury if the dislocation of the distal radioulnar joint is missed in the acute setting. This injury is named after the British orthopedic surgeon Peter Essex-Lopresti, who made a number of important observations about this injury in 1951. Peter Essex-Lopresti was a promising young surgeon, and his untimely death at the age of 35 brought an early end to a remarkable career. This article investigates the evolution of treatment for this injury and sheds light on the life of the surgeon for whom the injury is named. 23819973 Degradation mechanism of monosaccharides and xylan under pyrolytic conditions with theoretic modeling on the energy profiles. Xylan and three monosaccharides (mannose, galactose, and arabinose) were selected as model compounds to investigate the mechanism of hemicellulose pyrolysis. The evolution of several typical pyrolysis products were observed by thermogravimetric analysis coupled to Fourier transform infrared spectroscopy. Monosaccharides underwent similar pyrolysis routes involving ring opening and secondary decomposition. Breakage of the O-acetyl groups and 4-O-methylglucuronic acid units in xylan branches resulted in its different pyrolysis behavior for the formation of acetic acid, CO2, and CO. The detailed reaction pathways of the monosaccharides were studied using density functional theory calculations. Furfural formation was more favorable than the formation of 1-hydroxy-2-propanone and 4-hydroxydihydrofuran-2(3H)-one during xylose degradation. However, in the pyrolysis of mannose and galactose, formation of 5-hydroxymethyl-2-furaldehyde was preferred because of the high energy barrier of the dissociation of the hydroxymethyl group. Meanwhile, the breakage of O-acetyl groups leading to acetic acid formation easily occurred because of its lower energy barrier. 23872723 Anti-Inflammatory Effect of Auraptene Extracted from Trifoliate Orange (Poncirus Trifoliate) on LPS-Stimulated RAW 264.7 Cells. Poncirus trifoliate is a traditional Chinese medicinal plant used for treating inflammation-related diseases for a long time and trifoliate orange contains abundant auraptene. The present study was to evaluate auraptene as a potential anti-inflammatory agent and investigate the mechanism of auraptene against prostaglandins E2 (PGE2) and cyclooxygenase-2 (COX-2) on lipopolysaccharide (LPS)-stimulated RAW 264.7 cells by comparing it with aspirin as a positive control group. The methods of enzyme-linked immunosorbent assay, reverse transcriptive polymerase chain reaction, real-time PCR, and western-blotting were used in the study. The results showed that auraptene exhibited better biocompatibility and lower cytotoxicity. At the same time, it significantly inhibited the production of PGE2 on LPS-stimulated macrophage cells. The auraptene-treated group had a higher COX-2 mRNA expression but relatively lower COX-2 protein level which implied that auraptene suppressed the post-transcriptional expression of COX-2 protein but not the transcriptional process. Compared with aspirin, the lower cytotoxicity of auraptene can make it a potential source for medicine that can benefit patients who are suffering from chronic inflammatory diseases and need long-term medication. 23664767 Evaluation of lung function and deposition of aerosolized bronchodilators carried by heliox associated with positive expiratory pressure in stable asthmatics: A randomized clinical trial. While administration of medical aerosols with heliox and positive airway pressure are both used clinically to improve aerosol delivery, few studies have differentiated their separate roles in treatment of asthmatics. The aim of this randomized, double blinded study is to differentiate the effect of heliox and oxygen with and without positive expiratory pressure (PEP), on delivery of radiotagged inhaled bronchodilators on pulmonary function and deposition in asthmatics. 32 patients between 18 and 65 years of age diagnosed with stable moderate to severe asthma were randomly assigned into four groups: (1) Heliox + PEP (n = 6), (2) Oxygen + PEP (n = 6), (3) Heliox (n = 11) and (4) Oxygen without PEP (n = 9). Each group received 1 mg of fenoterol and 2 mg of ipratropium bromide combined with 25 mCi (955 Mbq) of Technetium-99m and 0.9% saline to a total dose volume of 3 mL placed in a Venticis(®) II nebulizer attached to a closed, valved mask with PEP of 0 or 10 cm H2O. Both gas type and PEP level were blinded to the investigators. Images were acquired with a single-head scintillation camera with the longitudinal and transverse division of the right lung as regions of interest (ROIs). While all groups responded to bronchodilators, only group 1 showed increase in FEV1%predicted and IC compared to the other groups (p < 0.04). When evaluating the ROI in the vertical gradient we observed higher deposition in the middle and lower third in groups 1 (p = 0.02) and 2 (p = 0.01) compared to group 3. In the horizontal gradient, a higher deposition in the central region in groups 1 (p = 0.03) and 2 (p = 0.02) compared to group 3 and intermediate region of group 2 compared to group 3. We conclude that aerosol deposition was higher in groups with PEP independent of gas used, while bronchodilator response with Heliox + PEP improved FEV1 % and IC compared to administration with Oxygen, Oxygen with PEP and Heliox alone. Trial registration NCT01268462. 23394107 Polymer-coated echogenic lipid nanoparticles with dual release triggers. Although lipid nanoparticles are promising drug delivery vehicles, passive release of encapsulated contents at the target site is often slow. Herein, we report contents release from targeted, polymer-coated, echogenic lipid nanoparticles in the cell cytoplasm by redox trigger and simultaneously enhanced by diagnostic frequency ultrasound. The lipid nanoparticles were polymerized on the external leaflet using a disulfide cross-linker. In the presence of cytosolic concentrations of glutathione, the lipid nanoparticles released 76% of encapsulated contents. Plasma concentrations of glutathione failed to release the encapsulated contents. Application of 3 MHz ultrasound for 2 min simultaneously with the reducing agent enhanced the release to 96%. Folic acid conjugated, doxorubicin-loaded nanoparticles showed enhanced uptake and higher cytotoxicity in cancer cells overexpressing the folate receptor (compared to the control). With further developments, these lipid nanoparticles have the potential to be used as multimodal nanocarriers for simultaneous targeted drug delivery and ultrasound imaging. 23939617 Metal ion as both a cofactor and a probe of metal-binding sites in a uranyl-specific DNAzyme: a uranyl photocleavage study. DNAzymes are known to bind metal ions specifically to carry out catalytic functions. Despite many studies since DNAzymes were discovered nearly two decades ago, the metal-binding sites in DNAzymes are not fully understood. Herein, we adopt uranyl photocleavage to probe specific uranyl-binding sites in the 39E DNAzyme with catalytically relevant concentrations of uranyl. The results indicate that uranyl binds between T23 and C25 in the bulge loop, G11 and T12 in the stem loop of the enzyme strand, as well as between T2.4 and G3 close to the cleavage site in the substrate strand. Control experiments using two 39E DNAzyme mutants revealed a different cleavage pattern of the mutated region. Another DNAzyme, the 8-17 DNAzyme, which has a similar secondary structure but shows no activity in the presence of uranyl, indicated a different uranyl-dependent photocleavage as well. In addition, a close correlation between the concentration-dependent photocleavage and enzymatic activities is also demonstrated. Together, these experiments suggest that uranyl photocleavage has been successfully used to probe catalytically relevant uranyl-binding sites in the 39E DNAzyme. As uranyl is the cofactor of the 39E DNAzyme as well as the probe, specific uranyl binding has now been identified without disruption of the structure. 23848251 Platelet CMK-5 as an Excellent Mesoporous Carbon to Enhance the Pseudocapacitance of Polyaniline. A high-performance supercapacitor electrode consisting of platelet ordered mesoporous carbon CMK-5 and polyaniline (PANi) was prepared by chemical oxidative polymerization of aniline in the presence of CMK-5. The PANi with uniform size of 2-5 nm was primarily confined in the mesochannels of CMK-5 at low PANi loadings (40 and 51 wt %), whereas at a high loading of 64 wt %, additional PANi thin films with thicknesses of 5-10 nm were coated on the surface of the CMK-5 particles. Such CMK-5-PANi composites afforded a high electrochemical active surface area for surface Faradic redox reactions, leading to a more than 50% utilization efficiency when considering the theoretical capacitance of PANi of about 2000 F/g. As a result, a specific capacitance of 803 F/g and an energy density of 27.4 Wh/kg were achieved for CMK-5-PANi composite electrode with 64 wt % PANi, showing substantial improvement as compared with symmetric capacitors configured with CMK-5 electrodes (10.1 Wh/kg) or pure PANi electrodes (16.4 Wh/kg). Moreover, an excellent rate capability and a substantially enhanced electrochemical stability with 81% capacitance retention as compared with 68% of pure PANi were also observed over 1000 charge-discharge cycles at a constant current density of 4.0 A/g. 23658342 Effect of corn bran and steep inclusion in finishing diets on diet digestibility, cattle performance, and nutrient mass balance. One metabolism trial and 2 finishing trials were conducted to evaluate the effects of adding corn bran and steep liquor (steep) in replacement of dry-rolled corn (DRC) on diet digestibility, cattle performance, and nutrient mass balance in open feedlot pens. The metabolism trial (Exp. 1) used 8 ruminally cannulated heifers in a 4 × 4 Latin square design and the 2 finishing trials used 128 steer calves fed for 167 d (Exp. 2) and 256 yearling steers fed for 126 d (Exp. 3). Dietary treatments for all trials included a DRC-based control (CON), 30% corn bran (30/0), 30% corn bran plus 15% steep (30/15), and 45% corn bran plus 15% steep (45/15), in which by-products replaced DRC and molasses in the diet (DM basis). Diets were not isonitrogenous or isoenergetic. In the metabolism trial, feeding the by-product diets produced greater rumen pH (5.95) than CON (5.76; P < 0.01). Total tract DM and OM digestibility were greater for heifers fed CON than the by-product diets (P < 0.01). Dry matter and NDF ruminal disappearance (%/h) of corn bran were numerically less for cattle fed the CON diet than the by-product diets (2.36 vs. 2.84 and 0.72 vs. 1.66, respectively). In the performance trials, steers fed the by-product diets consumed more DM (P = 0.06) and G:F was either similar for all diets in Exp. 2 (P = 0.56) or less for cattle fed 30/0 than the other diets in Exp. 3 (P = 0.05). Percent N loss was reduced in Exp. 2 by including corn bran in diets compared with CON (P < 0.01). However, in Exp. 3, no differences in percent N loss were detected among treatments (P = 0.16), but more N was removed in the manure from pens where steers were fed by-products (P = 0.01). Although steep did not improve diet digestibility, it was beneficial in maintaining cattle performance in the feedlot studies. Feeding corn bran in combination with steep increased manure N removed and N in compost, but decreased percent N lost during the winter months only. 23070934 Mindfulness-based stress reduction for family caregivers: a randomized controlled trial. Caring for a family member with dementia is associated with chronic stress, which can have significant deleterious effects on caregivers. The purpose of the Balance Study was to compare a mindfulness-based stress reduction (MBSR) intervention to a community caregiver education and support (CCES) intervention for family caregivers of people with dementia. We randomly assigned 78 family caregivers to an MBSR or a CCES intervention, matched for time and attention. Study participants attended 8 weekly intervention sessions and participated in home-based practice. Surveys were completed at baseline, postintervention, and at 6 months. Participants were 32- to 82-year-old predominately non-Hispanic White women caring for a parent with dementia. MBSR was more effective at improving overall mental health, reducing stress, and decreasing depression than CCES. Both interventions improved caregiver mental health and were similarly effective at improving anxiety, social support, and burden. MBSR could reduce stress and improve mental health in caregivers of family members with dementia residing in the community. 23649003 Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clinical features characteristic of small-cell prostate carcinoma (SCPC), "anaplastic," often emerge during the progression of prostate cancer. We sought to determine the efficacy of platinum-based chemotherapy in patients meeting at least one of seven prospectively defined "anaplastic" clinical criteria, including exclusive visceral or predominantly lytic bone metastases, bulky tumor masses, low prostate-specific antigen levels relative to tumor burden, or short response to androgen deprivation therapy. A 120-patient phase II trial of first-line carboplatin and docetaxel (CD) and second-line etoposide and cisplatin (EP) was designed to provide reliable clinical response estimates under a Bayesian probability model with early stopping rules in place for futility and toxicity. Seventy-four of 113 (65.4%) and 24 of 71 (33.8%) were progression free after four cycles of CD and EP, respectively. Median overall survival (OS) was 16 months [95% confidence interval (CI), 13.6-19.0 months]. Of the seven "anaplastic" criteria, bulky tumor mass was significantly associated with poor outcome. Lactic acid dehydrogenase strongly predicted for OS and rapid progression. Serum carcinoembryonic antigen (CEA) concentration strongly predicted OS but not rapid progression. Neuroendocrine markers did not predict outcome or response to therapy. Our findings support the hypothesis that patients with "anaplastic" prostate cancer are a recognizable subset characterized by a high response rate of short duration to platinum-containing chemotherapies, similar to SCPC. Our results suggest that CEA is useful for selecting therapy in men with castration-resistant prostate cancer and consolidative therapies to bulky high-grade tumor masses should be considered in this patient population. 23386609 The Sec7 Guanine Nucleotide Exchange Factor GBF1 Regulates Membrane Recruitment of BIG1 and BIG2 Guanine Nucleotide Exchange Factors to the Trans-Golgi Network (TGN). Three Sec7 guanine nucleotide exchange factors (GEFs) activate ADP-ribosylation factors (ARFs) to facilitate coating of transport vesicles within the secretory and endosomal pathways. GBF1 recruits COPI to pre-Golgi and Golgi compartments, whereas BIG1 and BIG2 recruit AP1 and GGA clathrin adaptors to the trans-Golgi network (TGN) and endosomes. Here, we report a functional cascade between these GEFs by showing that GBF1-activated ARFs (ARF4 and ARF5, but not ARF3) facilitate BIG1 and BIG2 recruitment to the TGN. We localize GBF1 ultrastructurally to the pre-Golgi, the Golgi, and also the TGN. Our findings suggest a model in which GBF1 localized within pre-Golgi and Golgi compartments mediates ARF activation to facilitate recruitment of COPI to membranes, whereas GBF1 localized at the TGN mediates ARF activation that leads to the recruitment of BIG1 and BIG2 to the TGN. Membrane-associated BIG1/2 then activates ARFs that recruit clathrin adaptors. In this cascade, an early acting GEF (GBF1) activates ARFs that mediate recruitment of late acting GEFs (BIG1/2) to coordinate coating events within the pre-Golgi/Golgi/TGN continuum. Such coordination may optimize the efficiency and/or selectivity of cargo trafficking through the compartments of the secretory pathway. 23939881 Enantioselective Toxic Effects and Degradation of Myclobutanil Enantiomers in Scenedesmus obliquus. Research on the enantioselective environmental behavior of chiral pesticides has been a hot spot of environmental chemistry recently. In this study, the acute toxicity of myclobutanil enantiomers was investigated with the aquatic algae Scendesmus obliquus. After exposure for 96 h, the EC50 values for (-)-myclobutanil, rac-myclobutanil and (+)-myclobutanil were 3.951, 2.760, and 2.128 mg/L, respectively. The photosynthetic pigment (chlorophyll a, chlorophyll b, and carotenoids) and antioxidant enzyme activities catalase (CAT) were determined to evaluate the different toxic effects when S. obliquus were exposed to 1.5, 5 and 15 mg/L of rac-myclobutanil, (-)-myclobutanil, and (+)-myclobutanil for 96 h, respectively. In addition, the degradation of myclobutanil enantiomers in S. obliquus was also studied. Myclobutanil in the medium inoculated with algae degraded faster than in the uninoculated medium. The degradation of (-)-myclobutanil was faster than that of (+)-myclobutanil at a concentration of 3 mg/L. On the basis of these data, the acute toxicity and toxic effects of myclobutanil against S. obliquus were concluded to be enantioselective, and such enantiomeric differences should be taken into consideration in pesticide risk assessment. Chirality 00:000-000, 2013. © 2013 Wiley Periodicals, Inc. 23726923 Nanocrystalline forsterite for biomedical applications: synthesis, microstructure and mechanical properties. Forsterite (Mg2SiO4) because of its exceptionally high fracture toughness which is close to that of cortical bones has been nominated as a possible successor to calcium phosphate bioceramics. Recent in vitro studies also suggest that forsterite possesses good bioactivity and promotes osteoblast proliferation as well as adhesion. However studies on preparation and sinterability of nanocrystalline forsterite remain scarce. In this work, we use a solid-state reaction with magnesium oxide (MgO) and talc (Mg3Si4(OH)2) as the starting precursors to synthesize forsterite. A systematic investigation was carried out to elucidate the effect of preparatory procedures including heat treatment, mixing methods and sintering temperature on development of microstructures as well as the mechanical properties of the sintered forsterite body. 23806382 Stent grafts for central venous occlusive disease in patients with ipsilateral hemodialysis access. To assess long-term outcomes of stent grafts in patients with symptomatic central venous stenoses and occlusions ipsilateral to hemodialysis grafts or fistulas. The study included 52 of 55 consecutive patients with symptomatic stenoses of the central veins draining upper limb dialysis access grafts or fistulas treated with stent grafts. Indications for stent grafts were poor angioplasty results, rapid recurrence, or total occlusion. Endpoints were lesion patency and access patency following intervention. Mean follow-up was 25 months with a median of 24 months and 1.25 additional procedures per patient year. Patency rates were calculated using Kaplan-Meier analysis. All stent grafts were successfully deployed. The lesion patency rates at 6, 12, 24, and 36 months after intervention were 60%, 40%, 28%, and 28%. The access patency rates at 6, 12, 24, and 36 months after intervention were 96%, 94%, 85%, and 72%. There was one major complication and no minor complications. In 40 patients (77%), the internal jugular vein confluence was covered by the stent graft. In five patients, the dialysis circuits became occluded, with no clinical sequelae in four; one patient was lost to follow-up. The contralateral brachiocephalic vein was covered in three patients (6%), preventing contralateral access construction in one patient. Central vein stent graft placement in patients with hemodialysis access is associated with prolonged access patency. Coverage of major vein confluences, which occurred in 83% of the patients in this series, can compromise future access and should be avoided whenever possible by careful technique. 23962524 Social Position and Frailty. ABSTRACT This study sought to determine (1) if measures of social position are associated with frailty; (2) if any observed association between social position and frailty is a threshold or gradient effect; and (3) if any observed association is independent of possible confounders. Data were drawn from a sample of 1,751 community-dwelling adults, aged 65 and older, living in the Canadian province of Manitoba in 1991. Education, self-reported income adequacy, and self-reported income satisfaction were used as measures of social position. Frailty was graded based on functional loss, cognition, and urinary incontinence. Multivariate regression analyses revealed, after adjusting for possible confounding factors, that all measures of social position were strongly associated with frailty in a gradient, rather than a threshold, manner. We conclude that social gradients for frailty are present in older adults, although a causal mechanism is not yet clear. 23144004 Enhancing the photocatalytic activity of anatase TiO2 by improving the specific facet-induced spontaneous separation of photogenerated electrons and holes. Recently, it has been proven that directional flow of photogenerated charge carriers occurs on specific facets of TiO(2) nanocrystals. Herein, we demonstrate that the photocatalytic activity of anatase TiO(2) nanocrystals in both photoreduction and photooxidation processes can be enhanced by selectively depositing Pt nanoparticles on the {101} facets, which strengthens spontaneously surface-induced separation between photogenerated electrons and holes in the photocatalysis process. An optimal ratio of the oxidative {001} facets to the reductive {101} facets exists with regard to the photocatalysis of the faceted TiO(2) nanocrystals, and this is crucial for balancing the recombination and redox reaction rates of photogenerated electrons and holes. The present work might help us gain deeper insight into the relation between the specific surface of semiconductor photocatalysts and their photocatalytic activities and provides us with a new route to design photocatalysts with high photocatalytic activity. 23727431 Brachytherapy: current status and future strategies - can high dose rate replace low dose rate and external beam radiotherapy? Brachytherapy delivers the most conformal high dose radiotherapy possible to the prostate, using either a low dose rate (LDR) or high dose rate (HDR) technique. It may be used either alone as monotherapy or in combination with external beam radiotherapy (EBRT) as a local boost. Comparative efficacy studies, including one randomised controlled trial, consistently show higher cancer control rates when brachytherapy is used compared with EBRT alone, with even some evidence of improvement in survival. There are now extensive mature data supporting the use of LDR as monotherapy for patients with low-risk and selected intermediate-risk disease, with most series reporting long-term disease control rates of over 90% after high-quality implants. HDR is most commonly combined with EBRT to treat intermediate- and high-risk disease, with disease control rates of over 90% reported. The low alpha/beta ratio of prostate cancer combined and the ability to optimally sculpt dose distribution provides the biological and dosimetric rationale for HDR. HDR enables more consistent implant quality than LDR, with evidence of lower acute and late toxicity. Many dose and fractionation schedules of HDR in combination with EBRT have been investigated, but a single fraction of 10-15 Gy is commonly combined with EBRT to a dose of 40-50 Gy to treat intermediate- and high-risk disease. High disease control rates are also reported with HDR as monotherapy, particularly in patients with low- and intermediate-risk disease. Although older series have delivered four to six fractions of HDR, there is growing evidence to support the delivery of HDR in three or even two fractions. Single-fraction HDR monotherapy is now being investigated and if early data are confirmed with longer follow-up, may well become the treatment of choice for many men with localised prostate cancer. 23321625 Meta-analysis of telomere length in 19 713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect. Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19 713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64-0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother-offspring (r=0.42; P-value=3.60 × 10(-61)) than father-offspring correlation (r=0.33; P-value=7.01 × 10(-5)), and a significant positive association with paternal age at offspring birth (β=0.005; P-value=7.01 × 10(-5)). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 × 10(-30)) was seen, which appeared stronger in older spouse pairs (mean age ≥55 years; r=0.31; P-value=4.27 × 10(-23)) than in younger pairs (mean age<55 years; r=0.20; P-value=3.24 × 10(-10)). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.European Journal of Human Genetics advance online publication, 16 January 2013; doi:10.1038/ejhg.2012.303. 23541506 Effect of different arginine methylations on the thermodynamics of Tat peptide binding to HIV-1 TAR RNA. RNA-binding proteins are an important class of mediators that regulate cell function and differentiation. Methylation of arginine, a post-translational modification (PTM) found in these proteins, can modulate their function. Arginine can be monomethylated or dimethylated, depending on the type of methyl transferases involved. This paper describes a comparative study of the thermodynamics of unmodified and modified Tat peptide interaction with TAR RNA, where the peptide is methylated at epsilon (ɛ) and eta (η) nitrogen atoms of guanidinium group of arginine side chain at position 52 or 53. The results indicate that monomethylation of arginine at epsilon (ɛ) nitrogen atom enhances binding affinity, owing to a more favourable enthalpy component which overrides the less favourable entropy change. In contrast, monomethylation of arginine residue at η nitrogen results in reduced binding affinity originating exclusively from a less favourable enthalpy change leaving entropic component unaffected. However, in case of simultaneous methylation at ɛ and η positions, the binding parameters remain almost unaffected, when compared to the unmodified peptide. In case of symmetric dimethylation at η position the observed enthalpy change of the binding was found to be smaller than the values obtained for the unmodified peptide. Asymmetric dimethylation at η position showed the most reduced binding affinities owing to less favourable enthalpy changes. These results provide insights that enable elucidation of the biological outcome of arginine methylation as PTMs that regulate protein function, and will contribute to our understanding of how these PTMs are established in vitro and in vivo. 23269396 The usefulness of preoperative computed tomography and intraoperative neuromonitoring identification of the nonrecurrent inferior laryngeal nerve. The objective of this study was to avoid the nonrecurrent inferior laryngeal nerve (NRLN) injury during surgery, we performed preoperative CT examinations to determine the variation in abnormal course of the right subclavian artery as an indictor of the presence of the NRLN and used intraoperative neuromonitoring (IONM) to identify nerve. Preoperative thyroid CT examinations were performed in 783 thyroid surgery patients. The imaging characteristics that suggested the presence of the NRLN were the following: (1) the arteria lusoria arising from the dorsal side of the aortic arch and passing through the trachea and esophagus posteriorly, and the CT image showing the characteristic "hook-like" morphology; (2) that the arteria lusoria imaging could be observed posteriorly to the trachea and esophagus; and (3) that the arteria lusoria traveled transversely from the rear of the right common carotid artery to the right subaxillary region. IONM has been applied to localize and identify NRLN. The brachiocephalic trunk was shown in 779 cases and not in the remaining four cases (0.5 %, 4/783), and these four were assumed to have the arteria lusoria. The separation point and path of the NRLNs were localized and identified precisely with IONM. The NRLN was observed during all surgeries. These four cases did not exhibit hoarseness after surgery. In conclusion, understanding of the course variations of the right subclavian artery using a preoperative CT examination provides an indicator of the presence of a NRLN. Combining these evaluation methods with IONM can avoid NRLN injury. 23873477 Confidence intervals after multiple imputation: combining profile likelihood information from logistic regressions. In the logistic regression analysis of a small-sized, case-control study on Alzheimer's disease, some of the risk factors exhibited missing values, motivating the use of multiple imputation. Usually, Rubin's rules (RR) for combining point estimates and variances would then be used to estimate (symmetric) confidence intervals (CIs), on the assumption that the regression coefficients were distributed normally. Yet, rarely is this assumption tested, with or without transformation. In analyses of small, sparse, or nearly separated data sets, such symmetric CI may not be reliable. Thus, RR alternatives have been considered, for example, Bayesian sampling methods, but not yet those that combine profile likelihoods, particularly penalized profile likelihoods, which can remove first order biases and guarantee convergence of parameter estimation. To fill the gap, we consider the combination of penalized likelihood profiles (CLIP) by expressing them as posterior cumulative distribution functions (CDFs) obtained via a chi-squared approximation to the penalized likelihood ratio statistic. CDFs from multiple imputations can then easily be averaged into a combined CDF c , allowing confidence limits for a parameter β  at level 1 - α to be identified as those β* and β** that satisfy CDF c (β*) = α ∕ 2 and CDF c (β**) = 1 - α ∕ 2. We demonstrate that the CLIP method outperforms RR in analyzing both simulated data and data from our motivating example. CLIP can also be useful as a confirmatory tool, should it show that the simpler RR are adequate for extended analysis. We also compare the performance of CLIP to Bayesian sampling methods using Markov chain Monte Carlo. CLIP is available in the R package logistf. Copyright © 2013 John Wiley & Sons, Ltd. 23838728 Teacher and Child Predictors of Achieving IEP Goals of Children with Autism. It is encouraging that children with autism show a strong response to early intervention, yet more research is needed for understanding the variability in responsiveness to specialized programs. Treatment predictor variables from 47 teachers and children who were randomized to receive the COMPASS intervention (Ruble et al. in The collaborative model for promoting competence and success for students with ASD. Springer, New York, 2012a) were analyzed. Predictors evaluated against child IEP goal attainment included child, teacher, intervention practice, and implementation practice variables based on an implementation science framework (Dunst and Trivette in J Soc Sci 8:143-148, 2012). Findings revealed one child (engagement), one teacher (exhaustion), two intervention quality (IEP quality for targeted and not targeted elements), and no implementation quality variables accounted for variance in child outcomes when analyzed separately. When the four significant variables were compared against each other in a single regression analysis, IEP quality accounted for one quarter of the variance in child outcomes. 23692664 Successful systemic high-dose ribavirin treatment of respiratory syncytial virus-induced infections occurring pre-engraftment in allogeneic hematopoietic stem cell transplant recipients. Respiratory syncytial virus (RSV) is a frequent cause of respiratory tract infectious disease (RTID) in allogeneic hematopoietic stem cell transplant (HSCT) recipients associated with a high mortality once infection has progressed from upper RTID (URTID) to lower RTID (URTID). Aerosolized ribavirin (RBV) is considered a cornerstone of treatment, but is expensive and has toxic side effects on patients and staff. In this study, RSV infection was detected by polymerase chain reaction (PCR) from routinely collected throat swabs in HSCT patients. Infected individuals were treated according to an institutional protocol using intravenous (IV) RBV for patients with LRTID and oral ribavirin for URTID. RSV infection was diagnosed in 10 patients (median age 60 years) a median of 15 days after allogeneic HSCT for high-risk acute myeloid leukemia. Five patients with LRTID received IV RBV within 7 days after HSCT, and 5 with URTID were treated with oral RBV 12-40 days after HSCT. One patient died of septic shock associated with Pseudomonas aeruginosa-induced pneumonia 28 days after HSCT in prolonged neutropenia. All patients became RSV PCR negative on throat swabs within a median of 22 days from start of RBV. Despite severe lymphopenia, no patient treated for URTID progressed to LRTID. Neutrophil recovery was delayed in 3 patients. We show that IV and oral RBV were efficacious in preventing progression and reducing mortality of RSV infection in this small series of allogeneic HSCT recipients. Randomized studies are not to be expected for this condition and therefore reporting case series could help in determining optimal RSV treatment. 23934444 A regulatory variant in CYP2E1 affects the risk of lung squamous cell carcinoma. Cytochrome P450 2E1 (CYP2E1), an ethanol-inducible enzyme, has been shown to metabolically activate various carcinogens, which is critical for the development of cancers. It has been demonstrated that CYP2E1 polymorphisms alter the transcriptional activity. However, studies on the association between CYP2E1 -1239G>C polymorphism and non-small cell lung cancer have reported conflicting results. Thus, the gain of the present study was to investigate whether CYP2E1 -1239G>C polymorphism is associated with the development of non-small cell lung cancer in Chinese population. A case-control study was conducted in which CYP2E1 -1239G>C polymorphism was analyzed in 526 Chinese patients with non-small cell lung cancer and 526 age-matched healthy controls by polymerase chain reaction-restriction fragment length polymorphism. Odds ratios were estimated by multivariate logistic regression. A meta-analysis was conducted to evaluate the association of CYP2E1 -1239G>C polymorphism with the risk of lung cancer in Chinese population by calculating pooled odds ratio (OR). For CYP2E1 -1239G>C polymorphism, -1239C allele carriers (OR = 0.67; 95 % confidence interval (CI) = 0.51-0.87; P = 0.002) were associated with a decreased risk of non-small cell lung cancer when compared with -1239GG homozygotes. In the group analyses by pathological types, for lung squamous cell carcinoma and other types, the ORs of the C allele carriers were 0.60 (95 % CI = 0.41-0.88; P = 0.009) and 0.54 (95 % CI = 0.30-0.99; P = 0.045). In the group analysis of smoking status, the OR for the -1239C allele-containing genotype was higher than that for -1239GG genotype (OR = 0.57; 95 % CI = 0.40-0.81; P = 0.002) among smokers, but not among nonsmokers. Moreover, when the risk associated with CYP2E1 polymorphism was further evaluated within strata of <25 and ≥25 pack-years smoked, this effect between susceptible genotypes and smoking was mostly evident among light smokers (<25 pack-years) with OR of 0.42 (95 % CI 0.23-0.79), but not among heavy smokers with OR of 0.87 (95 % CI 0.53-1.43). In the group analyses by TNM stage, there was no significant difference between CYP2E1 -1239G>C polymorphism and the risk of non-small cell lung cancer. Meta-analysis data also showed that the carriers of CYP2E1 -1239C allele had a protect effect on the risk of lung cancer in Chinese with overall OR of 0.77 (95 % CI 0.66-0.90). CYP2E1 -1239G>C polymorphism was associated with a decreased risk of development of non-small cell lung cancer in Chinese patients. The association displays a manner of gene-environment interaction between this polymorphism and smoking status. 23818066 Probing alloy composition gradient and nanometer-scale carrier localization in single AlGaN nanowires by nanocathodoluminescence. The optical properties of single AlGaN nanowires grown by plasma-assisted molecular beam epitaxy have been studied by nanocathodoluminescence. Optical emission was found to be position-dependent and to occur in a wide wavelength range, a feature which has been assigned to a composition gradient along the nanowire growth axis, superimposed on local composition fluctuations at the nanometer scale. This behavior is associated with the growth mode of such AlGaN nanowires, which is governed by kinetics, leading to the successive formation of (i) a zone with strong local composition fluctuations followed by (ii) a zone with a marked composition gradient and, eventually, (iii) a zone corresponding to a steady state regime and the formation of a homogeneous alloy. 23673146 The time-course of hindbrain neuronal activity varies according to location during either intraperitoneal or subcutaneous tumor growth in rats: single Fos and dual Fos/dopamine β-hydroxylase immunohistochemistry. Neuronal activity in the nucleus of the solitary tract, ventrolateral medulla, area postrema, and parabrachial nucleus was studied in rats with intraperitoneal or subcutaneous tumors on the 7th, 14th, 21st, and 28th day after injection of fibrosarcoma tumor cells. We found that the number of Fos and dopamine β-hydroxylase immunopositive neurons differs between animals with intraperitoneal and subcutaneous tumors and also between tumor-bearing rats at different times following injection. Our data indicate that responses of the brainstem structures to peripheral tumor growth depend on the localization as well as the stage of the tumor growth. 23889403 Pump-controlled directional light emission from random lasers. The angular emission pattern of a random laser is typically very irregular and difficult to tune. Here we show by detailed numerical calculations that one can overcome the lack of control over this emission pattern by actively shaping the spatial pump distribution. We demonstrate, in particular, how to obtain customized pump profiles to achieve highly directional emission. Going beyond the regime of strongly scattering media where localized modes with a given directionality can simply be selected by the pump, we present an optimization-based approach which shapes extended lasing modes in the weakly scattering regime according to any predetermined emission pattern. 23825115 Minimizing the risk of cancer: tissue architecture and cellular replication limits. Normal somatic cells are capable of only a limited number of divisions, which prevents unlimited cell proliferation and the onset of tumours. Cancer cells find ways to circumvent this obstacle, typically by expressing the enzyme telomerase and less often by alternative recombination strategies. Given this fundamental link between cellular replication limits and cancer, it is important to understand how a tissue's architecture affects the replicative capacity of a cell population. We define this as the average number of remaining divisions at equilibrium. The lower the replication capacity, the lower the chances to escape the replication limit during abnormal growth when a tumour develops. In this paper, we examine how the replication capacity is influenced by defining characteristics of cell lineages, such as the number of intermediate cell compartments, self-renewal capability of cells and division rates. We describe an optimal tissue architecture that minimizes the replication capacity of dividing cells and thus the risk of cancer. Interestingly, some of the features that define an optimal tissue architecture have been documented in a variety of tissues, suggesting that they may have evolved as a cancer-protecting strategy in multicellular organisms. 23892167 The use of proteomic analysis for exploring the phytoremediation mechanism of Scirpus triqueter to pyrene. Scirpus triqueter has been reported to be an effective phytoremediation plant for pyrene dissipation. The study of S. triqueter in response to pyrene is crucial to understand the mechanism of phytoremediation. To gain a certain extent understanding of S. triqueter in response to pyrene, S. triqueter seedlings were exposed to 50mgkg(-1) pyrene and a comparative proteomic analysis of total proteins was performed. 37 and 55 proteins were significantly differentially expressed in the shoot and root of S. triqueter upon exposure, respectively. 24 proteins (17 proteins in shoot and 7 proteins in root) were identified on the basis of the homology of their peptide profiles with existing protein sequences using mass spectrometry analysis. Analysis of protein expression patterns revealed that proteins in shoot associated with photosynthesis, defense, energy and matter metabolism, coenzyme metabolism and protein metabolism. Moreover, the proteins related photosynthesis accounted for more than 70% of the identified proteins. The proteins in root associated with stress, defense, energy metabolism, protein modification and carbohydrate metabolism. Pyrene appears to have an important deleterious effect on primary carbon metabolism, the synthesis of proteins and signal transduction. The present study demonstrates the use of proteomic approach to help us understand the phytoremediation mechanism of S. triqueter. 23298976 Microstructural tissue damage in normal appearing brain tissue accumulates with Framingham Stroke Risk Profile Score: Magnetization transfer imaging results of the Austrian Stroke Prevention Study. Magnetization transfer imaging detects cerebral microstructural tissue alterations. We examined the association between the Framingham Stroke Risk Profile (FSRP) score and magnetization transfer imaging (MTI) measures in pathological and normal appearing brain tissue in clinically normal elderly subjects to determine if stroke risk leads to brain tissue destruction beyond what is visible in conventional MRI scans. The study cohort is from the Austrian Stroke Prevention Study (ASPS). A total of 316 subjects underwent MTI and had a complete risk factor assessment sufficient to calculate the FSRP score. There were 205 women and 111 men with a mean age of 70.2 years ranging from 54 to 82 years. Subjects were grouped into four categories of stroke risk probability ranging from 3% to 88% for men and 1% to 84% for women. A higher FSRP score was significantly and independently associated with a MTR peak position shift indicating global microstructural alterations in brain tissue (BT) and in normal appearing brain tissue (NABT). The mean MTR in white matter hyperintensities (WMH) correlated inversely with increasing stroke risk. Age explained most of the variance in MTR peak position, all other risk factors of the FSRP score contributed significantly but explained an additional 2% of the variance of this MRI measure, only. Increasing risk for stroke leads to microstructural brain changes invisible by standard MRI. The validity, the underlying pathogenic mechanisms and the clinical importance of these abnormalities needs to be further determined. 23959102 Physico-chemical characterization-based safety evaluation of nanocalcium. Nano- and microcalcium provided from the KFDA were compared in terms of physico-chemical properties. Calcium samples were tested using EF-TEM and X-ray diffractometry to check for size/morphology and crystal formation, respectively. Two samples of nano- and microcalcium were selected for further evaluation by FE-SEM, DLS (nano-size, 200-500nm; agglomerate, >5μm; micro-size, 1.5-30μm), and electron spin resonance. Both samples were heterogeneous in size, existed as single crystal and aggregated form, and did not generate reactive oxygen species. The specific surface area of nano- and microcalcium measured by N2 Brunauere Emmette Teller method was 12.90±0.27m(2)/g and 1.12±0.19m(2)/g, respectively. Inductively coupled plasma optical emission spectrometry analysis revealed the release of 2-3 times more calcium ion from nano- compared to microcalcium at pH 5 and 7. Genotoxicity and acute single-dose and repeated-dose 14-day oral toxicity testing in SD rats performed to evaluate the safety of nanocalcium did not reveal toxicity. However, long-term monitoring will be required for an unequivocal conclusion. A nanocalcium dose of 1g/kg is recommended as the maximum dose for repeated dose 13-week oral toxicity. Further studies could provide details of toxicity of nanocalcium on the repeated dose 13-week oral toxicity test. 23641825 Nonsurgical treatment of chronic subdural hematoma with tranexamic acid. Object Chronic subdural hematoma (CSDH) is a common condition after head trauma. It can often be successfully treated surgically by inserting a bur hole and draining the liquefied hematoma. However, to the best of the authors' knowledge, for nonemergency cases not requiring surgery, no reports have indicated the best approach for preventing hematoma enlargement or resolving it completely. The authors hypothesized that hyperfibrinolysis plays a major role in liquefaction of the hematoma. Therefore, they evaluated the ability of an antifibrinolytic drug, tranexamic acid, to completely resolve CSDH compared with bur hole surgery alone. Methods From 2007 to 2011, a total of 21 patients with CSDH seen consecutively at Kuki General Hospital, Japan, were given 750 mg of tranexamic acid orally every day. Patients were identified by a retrospective records review, which collected data on the volume of the hematoma (based on radiographic measurements) and any complications. Follow-up for each patient consisted of CT or MRI every 21 days from diagnosis to resolution of the CSDH. Results Of the 21 patients, 3 with early stages of CSDH were treated by bur hole surgery before receiving medical therapy. The median duration of clinical and radiographic follow-up was 58 days (range 28-137 days). Before tranexamic acid therapy was initiated, the median hematoma volume for the 21 patients was 58.5 ml (range 7.5-223.2 ml); for the 18 patients who had not undergone surgery, the median hematoma volume was 55.6 ml (range 7.5-140.5 ml). After therapy, the median volume for all 21 patients was 3.7 ml (range 0-22.1 ml). No hematomas recurred or progressed. Conclusions Chronic subdural hematoma can be treated with tranexamic acid without concomitant surgery. Tranexamic acid might simultaneously inhibit the fibrinolytic and inflammatory (kinin-kallikrein) systems, which might consequently resolve CSDH. This medical therapy could prevent the early stages of CSDH that can occur after head trauma and the recurrence of CSDH after surgery. 23842715 Synergy between polymorphism, pressure, spin-crossover and temperature in [Fe(PM-BiA)2(NCS)2]: a neutron powder diffraction investigation. The pressure dependencies of the lattice parameters of the spin transition compound [Fe(PM-BiA)2(NCS)2] have been derived from neutron powder diffraction measurements at low temperature. The study of the compound [Fe(PM-BiA)2(NCS)2]-pI has first confirmed the atypical spin crossover behaviour under pressure of this compound that shows a pressure induced structural transition inducing the transformation into a different polymorph, [Fe(PM-BiA)2(NCS)2]-pII. This phenomenon avoids a first-order spin transition in favour of continuous transition around 0.75 GPa at ambient temperature. Low temperature measurements under pressure up to 1.07 GPa allowed us not only to describe the spin-crossover for both polymorphs but also to reach phase-diagram regions where both polymorphs co-exist in different spin-states. Finally, the reversibility of the structural variations has been demonstrated. 23778095 Tabulation of irreducible representations of the crystallographic space groups and their superspace extensions. New tables of irreducible representations (IRs) are introduced for the 230 crystallographic space groups (SGs) in three-dimensional space, at both special and non-special k vectors, and for their extensions to (3 + d)-dimensional superspace (`superspace-extended SGs' or SSESGs). Neither a tabulation of SG IR matrices for non-special k vectors nor a tabulation of SSESG IR matrices for d > 1 have been previously published. These tabulations are made possible by a new form in which the IR matrices of SGs are separated as a product of a translation part T and a point-operation part P, and where the IR matrices of SSESGs are separated as a product of a phase-shift part Q and a point-operation part P(s). Both T and Q have a simple prescribed form that does not need to be tabulated. Also, the new IR matrices are in a convenient block form which allows one to see by inspection which parts of the matrices and the associated order parameters belong to which arm of the star of k. In addition to complex IR matrices, real physically irreducible representation (PIR) matrices are tabulated. The new IR and PIR tables are available on the ISO-IR website (http://stokes.byu.edu/iso/irtables.php) in both convenient human-readable and computer-readable forms. 23904064 ARSH 2: Reproductive and Sexual Health Knowledge, Attitude and Practices: Comparison Among Boys and Girls (10-24 y). To compare the knowledge, attitude and practice of boys and girls on reproductive sexual health and their perspective on the needs of adolescents on this aspect. This comparative study was conducted among boys and girls between 10 and 24 y in three districts of Kerala; through a cross sectional community survey using a pretested structured schedule with additional sexuality related questions for 15-24 y age group. Higher percentage of boys knew about condoms (95.1 %, p 0.001) whereas higher percentage of girls (56.5 %, p 0.001) knew about copper-T. Girls had a better knowledge on legal age of marriage (91 %, p 0.001), that both the partners are equally responsible for the problem of infertility (89.7 %, p 0.009) and that the gender of the baby is determined by male sperm (60.4 %, p 0.001). Above 90 % of boys and girls demanded adolescent care services and facilities for counseling. This comparative study on knowledge, attitude and practice of boys and girls between 10 and 24 y has shown that greater proportion of girls had correct knowledge on the legal age of marriage, ideal age of pregnancy, preferred an arranged marriage and felt the need for premarital counseling. 23177254 Chemotherapy of leishmaniasis part X: synthesis and bioevaluation of novel terpenyl heterocycles. Some novel α and β ionone based chalcones and their dihydropyrazolidines/pyrazolidines have been synthesized and evaluated for their in vitro and in vivo antileishmanial activities against Leishmania donovani. Amongest all, one compound (4d) exhibited significant in vitro activity against intracellular amastigotes of Leishmania donovani with IC(50) values of 7.49 μM and was found promising as compared to reference drug, miltefosine. On the basis of good Selectivity Index (S.I.), the compound was further tested for its in vivo response against Leishmania donovani/hamster model and has shown significant inhibition of parasite multiplication (81%). The present study has helped us in identifying a new lead that could be exploited as a potential antileishmanial agent. 23841493 Nationwide Emergency Department Visits for Priapism in the United States. The epidemiology of priapism is not well characterized. A small number of studies based on inpatient data or small population samples have estimated the incidence to range from 0.34 to 1.5 cases per 100,000 males. To estimate the current epidemiology and impact on resource utilization of priapism in the United States (US). Rate of emergency department encounters for priapism in the US. Emergency department (ED) visits for priapism were analyzed using discharge data from the Nationwide Emergency Department Sample (NEDS), Healthcare Cost and Utilization Project (HCUP). Priapism encounters were identified by ICD9 code. Priapism encounters were analyzed for patient and hospital characteristics, associated diagnoses, and hospital charge. Established weighting in the sample was used to calculate nationwide estimates. A total of 8,738 ED encounters for priapism were identified between 2006 and 2009 in the NEDS. This translated to an estimated 39,964 encounters out of a total of 496,195,793 ED visits, or 8.05 per 100,000 ED visits (95% confidence interval [CI] 7.59-8.51). 21.1% of patients had a concurrent diagnosis of sickle cell disease (SCD). 72.1% of all patients were discharged home from the ED, while only 49.6% of patients with SCD were discharged home. A concurrent diagnosis of SCD was associated with an odds ratio (OR) of 3.84 (95% CI 3.65-4.05) for admission to the hospital when controlling for age, region, hospital and payer type. The mean hospital charge was $1,778 per encounter if discharged home and $41,909 per encounter if admitted. The estimated mean total annual charge for priapism was $123,860,432 with 86.8% of charges attributed to inpatient admissions. Our estimate of the rate of ED visits for priapism was significantly higher than prior estimates with a SCD concurrence rate lower than previously estimated. Stein DM, Flum AS, Cashy J, Zhao LC, and McVary KT. Nationwide emergency department visits for priapism in the United States. J Sex Med **;**:**-**. 23688668 Quantitative evaluation of the ease of rupture of industrially promising microalgae by high pressure homogenization. The susceptibility to rupture of the microalgae Nannochloropsis sp., Chlorella sp. and Tetraselmis suecica by high pressure homogenization was compared quantitatively to the yeast Saccharomyces cerevisiae. Methods for quantifying cell rupture were investigated including cell counting, turbidity, metabolite release and particle sizing. Cell counting was the only reliable method for quantitative comparisons of all microalgae, with turbidity complicated by agglomeration of cell debris for T. suecica, and measurement of metabolite release affected by degradation occurring for all microalgae after significant rupture. The rupture of all microalgae followed exponential decay as a function of number of passes. The pressure required to achieve rupture of 50% of the cells per pass was determined to be 170, 1070, 1380, and ca. 2000 bar for Tetraselmis sp., Chlorella sp., S. cerevisiae, and Nannochloropsis sp., respectively. These results extend the criteria for selecting microalgae for industrial applications beyond consideration of growth and compositional attributes. 23434419 Improved guanide compounds which bind the CXCR4 co-receptor and inhibit HIV-1 infection. The G-protein coupled receptor CXCR4 is a co-receptor for HIV-1 infection and is involved in signaling cell migration and proliferation. In a previous study of non-peptide, guanide-based CXCR4-binding compounds, spermine and spermidine phenylguanides inhibited HIV-1 entry at low micromolar concentrations. Subsequently, crystal structures of CXCR4 were used to dock a series of naphthylguanide derivatives of the polyamines spermidine and spermine. Synthesis and evaluation of the naphthylguanide compounds identified our best compound, spermine tris-1-naphthylguanide, which bound CXCR4 with an IC(50) of 40 nM and inhibited the infection of TZM-bl cells with X4, but not R5, strains of HIV-1 with an IC(50) of 50-100 nM. 23959910 Patient-specific modelling of head-up tilt. Short-term cardiovascular responses to head-up tilt (HUT) involve complex cardiovascular regulation in order to maintain blood pressure at homoeostatic levels. This manuscript presents a patient-specific model that uses heart rate as an input to fit the dynamic changes in arterial blood pressure data during HUT. The model contains five compartments representing arteries and veins in the upper and lower body of the systemic circulation, as well as the left ventricle facilitating pumping of the heart. A physiologically based submodel describes gravitational pooling of the blood into the lower extremities during HUT, and a cardiovascular regulation model adjusts cardiac contractility and vascular resistance to the blood pressure changes. Nominal parameter values are computed from patient-specific data and literature estimates. The model is rendered patient specific via the use of parameter estimation techniques. This process involves sensitivity analysis, prediction of a subset of identifiable parameters, and non-linear optimization. The approach proposed here was applied to the analysis of aortic and carotid HUT data from five healthy young subjects. Results showed that it is possible to identify a subset of model parameters that can be estimated allowing the model to fit changes in arterial blood pressure observed at the level of the carotid bifurcation. Moreover, the model estimates physiologically reasonable values for arterial and venous blood pressures, blood volumes and cardiac output for which data are not available. 23627998 Determinants of clinical right ventricular failure after congenital heart surgery in adults. Right ventricular (RV) failure after cardiac surgery is a clinical entity with high morbidity and mortality. Patients with congenital heart disease (CHD) often undergo right-sided cardiac surgery. The authors aimed to identify determinants of RV failure after cardiac surgery to differentiate patients with increased risk. A retrospective chart review. University hospital. Adults with CHD operated on between January 2001 and January 2011. Clinical characteristics, laboratory tests, surgical data, and intensive care unit outcome were obtained from medical records. The diagnosis of clinical RV failure was made by careful review of the medical records by 2 independent physicians. Patients only were identified as having RV failure if (1) they had elevated jugular venous pressure, (2) they had impaired postoperative RV function on transthoracic echocardiography, and (3) a diagnosis of RV failure was documented clearly in the medical charts by the treating physician. Data of 412 consecutive patients (median age 36 [range 18-74] years, 56% male) were studied. Eighteen patients had clinical RV failure (4.4%) postoperatively, of whom 6 patients died. Patients undergoing left- and both-sided surgery had an equal risk of developing clinical RV failure as compared with patients undergoing right-sided surgery. In multivariate logistic regression analysis, preoperative impaired RV function, supraventricular tachycardia, and cardiopulmonary bypass time >150 minutes were the strongest determinants of clinical RV failure (p<0.05, for all). RV failure after cardiac surgery is a serious complication, and occurs regardless of the side of surgery. A tailored approach in patients with CHD at highest risk of RV failure should be considered. 23730736 Analysis of Fe(III) Heme Binding to Cysteine-Containing Heme-Regulatory Motifs in Proteins. Regulatory heme binds to specific motifs in proteins and controls a variety of biochemical processes. Several of these proteins were recently shown to form complexes with ferric and/or ferrous heme via a cysteine residue as axial ligand. The objective of this study was to examine the heme-binding properties of a series of cysteine-containing peptides with focus on CP motif sequences. The peptides displayed different binding behavior upon Fe(III) heme application with characteristic wavelength shifts of the Soret band to 370 nm or 420-430 nm and in some cases to both wavelengths. Whereas for most of the peptides containing a cysteine only a shift to 420-430 nm was observed, CP-containing peptides exhibited a preference for a shift to 370 nm. Detailed structural investigation using Raman and NMR spectroscopy on selected representatives revealed different binding modes with respect to iron ion coordination, which reflected the results of the UV-vis studies. A predicted short sequence stretch derived from dipeptidyl peptidase 8 was additionally examined with respect to CP motif binding to heme on the peptide as well as on the protein level. The heme association was confirmed with the first solution structure of a CP-peptide-heme complex and, moreover, an inhibitory effect of Fe(III) heme on the enzyme's activity. The relevance of both the use of model compounds to elucidate the molecular mechanism underlying regulatory heme binding and its potential for the investigation of regulatory heme control is discussed. 23733891 Genetic Selection for Constitutively Trimerized Human HSF1 Mutants Identifies a Role for Coiled-Coil Motifs in DNA Binding. Human heat shock transcription factor 1 (HSF1) promotes the expression of stress-responsive genes and is a critical factor for the cellular protective response to proteotoxic and other stresses. In response to stress, HSF1 undergoes a transition from a repressed cytoplasmic monomer to a homotrimer, accumulates in the nucleus, binds DNA, and activates target gene transcription. Although these steps occur as sequential and highly regulated events, our understanding of the full details of the HSF1 activation pathway remains incomplete. Here we describe a genetic screen in humanized yeast that identifies constitutively trimerized HSF1 mutants. Surprisingly, constitutively trimerized HSF1 mutants do not bind to DNA in vivo in the absence of stress and only become DNA binding competent upon stress exposure, suggesting that an additional level of regulation beyond trimerization and nuclear localization may be required for HSF1 DNA binding. Furthermore, we identified a constitutively trimerized and nuclear-localized HSF1 mutant, HSF1 L189P, located in LZ3 of the HSF1 trimerization domain, which in response to proteotoxic stress is strongly compromised for DNA binding at the Hsp70 and Hsp25 promoters but readily binds to the interleukin-6 promoter, suggesting that HSF1 DNA binding is in part regulated in a locus-dependent manner, perhaps via promoter-specific differences in chromatin architecture. Furthermore, these results implicate the LZ3 region of the HSF1 trimerization domain in a function beyond its canonical role in HSF1 trimerization. 23761561 Nutrition management of infants with surgical short bowel syndrome and intestinal failure. Appropriate nutrition recommendations are important for the successful management of the infant with an injured gastrointestinal tract postsurgery who is at risk for intestinal failure. Management strategies that can be used to augment successful adaptation and prevent liver disease are summarized in this review. These include appropriate postoperative fluid and electrolyte management, modification of parenteral nutrition to minimize intestinal failure-associated liver disease, early and aggressive enteral feeding advancement, the use of hormonal and trophic agents, prevention of central line-associated bloodstream infections using ethanol lock, appropriate treatment, and prevention of pathologic small bowel bacterial overgrowth. 23950689 Ancyronyx Erichson, 1847 (Coleoptera, Elmidae) from Mindoro, Philippines, with description of the larvae and two new species using DNA sequences for the assignment of the developmental stages. Ancyronyx buhid sp. n. and Ancyronyx tamaraw sp. n. are described based on adults and larvae, matched using their cox1 or cob DNA sequence data. Additional records of Ancyronyx schillhammeri Jäch, 1994 and Ancyronyx minerva Freitag & Jäch, 2007 from Mindoro are listed. The previously unknown larva of Ancyronyx schillhammeri is also described here, aided by cox1 data. The new species and larval stages are described in detail and illustrated by SEM and stacked microscopic images. Keys to the adult and larval Ancyronyx species of Mindoro and an updated checklist of Philippine Ancyronyx species are provided. The usefulness as bioindicators, the phylogenetic relationships and biogeographic aspects affecting the distribution patterns are briefly discussed. 23386714 Active mitral ring for post-surgical remote correction of residual mitral regurgitation on the beating heart. Residual mitral regurgitation after valve repair worsens patients' clinical outcome. Postimplant adjustable mitral rings potentially address this issue, allowing the reshaping of the annulus on the beating heart under echocardiography control. We developed an original mitral ring allowing valve geometry remodelling after the implantation and designed an animal study to assess device effectiveness in correcting residual mitral regurgitation. The device consists of two concentric rings: one internal and flexible, sutured to the mitral annulus and a second external and rigid. A third conic element slides between the two rings, modifying the shape of the flexible ring. This sliding element is remotely activated with a rotating tool. Animal model: in adult swine, under cardio pulmonary bypass and cardiac arrest, we shortened the primary chordae of P2 segment to reproduce Type III regurgitation and implanted the active ring. We used intracardiac ultrasound to assess mitral regurgitation and the efficacy of the active ring to correct it. Severe mitral regurgitation (3+ and 4+) was induced in eight animals, 54 ± 6 kg in weight. Vena contracta width decreased from 0.8 ± 0.2 to 0.1 cm; proximal isovelocity surface area radius decreased from 0.8 ± 0.2 to 0.1 cm and effective regurgitant orifice area decreased from 0.50 ± 0.1 to 0.1 ± 0.1 cm(2). Six animals had a reversal of systolic pulmonary flow that normalized following the activation of the device. All corrections were reversible. Postimplant adjustable mitral ring corrects severe mitral regurgitation through the reversible modification of the annulus geometry on the beating heart. It addresses the frequent and morbid issue of recurrent mitral valve regurgitation. 23274894 G6PC2: A Negative Regulator of Basal Glucose-Stimulated Insulin Secretion. Elevated fasting blood glucose (FBG) is associated with increased risk for the development of type 2 diabetes and cardiovascular-associated mortality. Genome-wide association studies (GWAS) have linked polymorphisms in G6PC2 with variations in FBG and body fat, although not insulin sensitivity or glucose tolerance. G6PC2 encodes an islet-specific, endoplasmic reticulum-resident glucose-6-phosphatase catalytic subunit. A combination of in situ perfused pancreas, in vitro isolated islet, and in vivo analyses were used to explore the function of G6pc2 in mice. G6pc2 deletion had little effect on insulin sensitivity and glucose tolerance, whereas body fat was reduced in female G6pc2 knockout (KO) mice on both a chow and high-fat diet, observations that are all consistent with human GWAS data. G6pc2 deletion resulted in a leftward shift in the dose-response curve for glucose-stimulated insulin secretion (GSIS). As a consequence, under fasting conditions in which plasma insulin levels were identical, blood glucose levels were reduced in G6pc2 KO mice, again consistent with human GWAS data. Glucose-6-phosphatase activity was reduced, whereas basal cytoplasmic calcium levels were elevated in islets isolated from G6pc2 KO mice. These data suggest that G6pc2 represents a novel, negative regulator of basal GSIS that acts by hydrolyzing glucose-6-phosphate, thereby reducing glycolytic flux. 23274086 AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. AMPK is a metabolic sensor that helps maintain cellular energy homeostasis. Despite evidence linking AMPK with tumor suppressor functions, the role of AMPK in tumorigenesis and tumor metabolism is unknown. Here we show that AMPK negatively regulates aerobic glycolysis (the Warburg effect) in cancer cells and suppresses tumor growth in vivo. Genetic ablation of the α1 catalytic subunit of AMPK accelerates Myc-induced lymphomagenesis. Inactivation of AMPKα in both transformed and nontransformed cells promotes a metabolic shift to aerobic glycolysis, increased allocation of glucose carbon into lipids, and biomass accumulation. These metabolic effects require normoxic stabilization of the hypoxia-inducible factor-1α (HIF-1α), as silencing HIF-1α reverses the shift to aerobic glycolysis and the biosynthetic and proliferative advantages conferred by reduced AMPKα signaling. Together our findings suggest that AMPK activity opposes tumor development and that its loss fosters tumor progression in part by regulating cellular metabolic pathways that support cell growth and proliferation. 23400899 Acute exposure to DE-71 causes alterations in visual behavior in zebrafish larvae. Polybrominated diphenyl ethers (PBDEs) cause neurobehavioral toxicity, but their effects on visual behavior remain unknown. In the present study, the impact of PBDEs on visual behavior was examined using optokinetic responses and phototaxis in zebrafish larvae. Zebrafish embryos were exposed to pentabrominated diphenyl ethers mixture (DE-71) at concentrations of 0, 0.32, 3.58, and 31.0 µg/L until 15 d postfertilization. The authors then assessed photoreceptor opsin expression, retinal histology, and visual behavior of the larvae. The results showed that the transcriptions of the opsin genes, zfrho and zfgr1, were significantly upregulated. Western blotting further demonstrated a significant increase in rhodopsin protein expression after exposure of the larvae to DE-71. Histological examination revealed the following morphological alterations in the retina: increased area of inner nuclear layer, decreased area of inner plexiform layer, and decreased density of ganglion cells. Tests of optokinetic and phototactic behavior showed hyperactive responses on exposure to DE-71, including increased saccadic eye movements and phototactic response. The present study is the first to demonstrate that the acute exposure of zebrafish larvae to DE-71 causes biochemical and structural changes in the eye that lead to behavioral alterations. Analysis of these visual behavioral paradigms may be useful in predicting the adverse effects of toxicants on visual function in fish. Environ Toxicol Chem 2013;32:1370-1375. © 2013 SETAC. 23916990 Hybrid-SPRITE MRI. In a FID based frequency encoding MRI experiment the central part of k-space is not generally accessible due to the probe dead time. This portion of k-space is however crucial for image reconstruction. SPRITE (Single Point Ramped Imaging with T1 Enhancement), SPI with a linearly ramped phase encode gradient, has been employed to image short relaxation time systems for many years with great success. It is a robust imaging method in significant measure because it provides acquisition of high quality k-space origin data. We propose a new sampling scheme, termed hybrid-SPRITE, combining phase and frequency encoding to ensure high quality images with reduced acquisition times, reduced gradient duty cycle and increased sensitivity. In hybrid-SPRITE, numerous time domain points are collected to assist image reconstruction. An Inverse Non-uniform Discrete Fourier Transform (INDFT) is employed in 1D applications. A pseudo-polar grid is exploited in 2D hybrid-SPRITE for rapid and accurate image reconstruction. 23879417 Laparoscopic management of giant splenic true cyst with partial splenectomy: A case report. Non-parasitic splenic cysts are relatively rare, and the optimal surgical treatment for them remains controversial. Laparoscopic unroofing is a relatively safe and easy technique, but a significant number of recurrences has been reported. Thus, complete cystectomy with partial splenectomy is recommended by several surgeons. However, patients sometimes suffer from intraoperative bleeding. Here, we report a patient with a giant non-parasitic splenic cyst who underwent subtotal cystectomy with partial splenectomy. After the dissection of the vessels circulating the upper pole at the splenic hilum, the resection line of the splenic parenchyma was on the ischemic side of the cyanotic demarcation line. A vessel sealing system and laparoscopic coagulation shears were used for the resection. We intentionally left about 10% of the cyst wall to avoid bleeding from the non-ischemic splenic parenchyma and remaining vessels. No recurrence has been detected after 6 months of observation. We believe this method could be a useful alternative procedure for the treatment of non-parasitic splenic cysts and preservation of the splenic parenchyma. 23826643 Buccal Bone Formation After Flapless Extraction: A Randomized Controlled Clinical Trial Comparing Recombinant Human Bone Morphogenetic Protein-2/Absorbable Collagen Carrier and Collagen Sponge Alone. Background: Flapless extraction of teeth allows for undisturbed preservation of the nearby periosteum and source of osteoprogenitor cells. Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been used for different bone augmentation purposes with great osteoinductive capacity. The aim of this study was to compare the bone regenerative ability of rhBMP-2 on an absorbable collagen sponge (ACS) carrier to a collagen sponge (CS) alone in extraction sites with >50% buccal dehiscence. Methods: Thirty-nine patients requiring extraction of a hopeless tooth with >50% buccal dehiscence were enrolled. Following flapless extraction and randomization, either rhBMP-2/ACS carrier or the CS alone was placed in the extraction site. A baseline cone beam computed tomography (CBCT) scan was obtained of the site after extraction and a similar scan was obtained 5 months post-operatively. Medical imaging and DICOM viewing software were used to compare the baseline and five month post-operative images of the study site and assess ridge width measurements, vertical height changes, and buccal plate regeneration. Results: Radiographically, CBCT analysis showed that with 50% or more of buccal bone destruction, the rhBMP-2/ACS was able to regenerate a portion of the lost buccal plate, maintain theoretical ridge dimensions, and allow for implant placement 5 months following extraction. The test group performed significantly (p<0.05) better in regards to clinical buccal plate regeneration (4.75mm vs. 1.85mm), clinical ridge width at 5 months (6.0mm vs. 4.62mm), and the radiographic ridge width at 3mm from the alveolar crest (6.17mm vs. 4.48mm) following molar exclusion. There was also significantly (p<0.05) less remaining buccal dehiscence, both clinically (6.81mm vs. 10.0mm) and radiographically (3.42mm vs. 5.16mm), at 5 months in the test group. Significantly (p<0.05) more implants were placed in the test group without the need for additional augmentation. The mean loss in vertical ridge height on the lingual/palatal was less in the test sites but was not significantly (p=0.514) different between the test and control group (0.39mm vs. 0.64mm). Conclusions: RhBMP-2/ACS compared to a CS alone used in flapless extraction sites with a buccal dehiscence was able to regenerate lost buccal plate, maintain theoretical ridge dimensions and allow for implant placement 5 months later. 23940103 Intercostal and pectoral nerve transfers to re-innervate the biceps muscle in obstetric brachial plexus lesions. In obstetric brachial plexus lesions with avulsion injury, nerve grafting for biceps muscle re-innervation may not be possible owing to the unavailability of a proximal stump. In such cases, the intercostal nerves or medial pectoral nerve can serve as donor nerves in an end-to-end transfer to the musculocutaneous nerve. The present study reports the results of both techniques from a single institution in a consecutive series of 42 patients between 1995 and 2008. From 1995 to 2000 we always used the intercostal nerve transfer, and from 2001 to 2008 both techniques were used. Biceps muscle force ≥Medical Research Council Grade 3 was achieved in 37 of 42 patients after a mean follow-up of 44 months. There was no statistical difference in the results in the medial pectoral nerve transfer group (n = 25) and the intercostal nerve transfer group (n = 17). 23707257 Anti-neuroinflammatory diarylheptanoids from the rhizomes of Dioscorea nipponica. In a continuing search for bioactive constituents from Dioscoreaceae medicinal plants, two new cyclic diarylheptanoids, diosniponol A (1) and B (2), together with 10 known compounds (3-12) were isolated from the rhizomes of Dioscorea nipponica. The structures of these new compounds were determined by spectroscopic analyses, including extensive two-dimensional nuclear magnetic resonance, high-resolution mass spectrometry, and optical rotation. All isolated compounds 1-12 were evaluated for their effects on nitric oxide (NO) production in murine microglia cell line BV-2. Compounds 8 and 11 showed potent inhibitory activities on NO production (IC50 13.36 and 14.36 μM, respectively) without cell toxicity in lipopolysaccharide-activated BV-2 cells. 23905639 Von Willebrand factor and thrombosis: risk factor, actor and pharmacological target. Thrombosis is the pathological face of the hemostatic process, and is still the major cause of death in the Western society. Many different components have been identified that contribute to the thrombotic occlusion of the vasculature and several therapeutic approaches have been developed to treat this severe clinical complication. In the last several years, a number of new agents have been under (pre)clinical investigation that are targeting von Willebrand factor (VWF), a protein that nicely exemplifies the thin line between the normal hemostatic process and an overly active system that gives rise to thrombotic events. Indeed, several epidemiological studies have found that increased plasma levels of VWF are associated with an increased risk for cardiovascular complications. VWF is a multimeric protein that is pertinent to the recruitment of platelets to the growing thrombus. VWF and platelets circulate together without interacting under normal conditions, and should combine into a thrombus selectively when necessary. This delicate process is highly regulated by various endothelial- and plasma proteins as well as by changes in shear stress. In the present review, an update is provided about our current knowledge on VWF as a risk factor, mediator and pharmacological target in association with thrombosis. 23845067 Molecular Mechanisms of the Crosstalk Between Mitochondria and NADPH Oxidase Through Reactive Oxygen Species-Studies in White Blood Cells and in Animal Models. Abstract Aims: Oxidative stress is involved in the development of cardiovascular disease. There is a growing body of evidence for a crosstalk between different enzymatic sources of oxidative stress. With the present study, we sought to determine the underlying crosstalk mechanisms, the role of the mitochondrial permeability transition pore (mPTP), and its link to endothelial dysfunction. Results: NADPH oxidase (Nox) activation (oxidative burst and translocation of cytosolic Nox subunits) was observed in response to mitochondrial reactive oxygen species (mtROS) formation in human leukocytes. In vitro, mtROS-induced Nox activation was prevented by inhibitors of the mPTP, protein kinase C, tyrosine kinase cSrc, Nox itself, or an intracellular calcium chelator and was absent in leukocytes with p47phox deficiency (regulates Nox2) or with cyclophilin D deficiency (regulates mPTP). In contrast, the crosstalk in leukocytes was amplified by mitochondrial superoxide dismutase (type 2) (MnSOD(+/-)) deficiency. In vivo, increases in blood pressure, degree of endothelial dysfunction, endothelial nitric oxide synthase (eNOS) dysregulation/uncoupling (e.g., eNOS S-glutathionylation) or Nox activity, p47phox phosphorylation in response to angiotensin-II (AT-II) in vivo treatment, or the aging process were more pronounced in MnSOD(+/-) mice as compared with untreated controls and improved by mPTP inhibition by cyclophilin D deficiency or sanglifehrin A therapy. Innovation: These results provide new mechanistic insights into what extent mtROS trigger Nox activation in phagocytes and cardiovascular tissue, leading to endothelial dysfunction. Conclusions: Our data show that mtROS trigger the activation of phagocytic and cardiovascular NADPH oxidases, which may have fundamental implications for immune cell activation and development of AT-II-induced hypertension. Antioxid. Redox Signal. 00, 000-000. 23891718 Mechanisms of talin-dependent integrin signaling and crosstalk. Cells undergo dynamic remodeling of the cytoskeleton during adhesion and migration on various extracellular matrix (ECM) substrates in response to physiological and pathological cues. The major mediators of such cellular responses are the heterodimeric adhesion receptors, the integrins. Extracellular or intracellular signals emanating from different signaling cascades cause inside-out signaling of integrins via talin, a cystokeletal protein that links integrins to the actin cytoskeleton. Various integrin subfamilies communicate with each other and growth factor receptors under diverse cellular contexts to facilitate or inhibit various integrin-mediated functions. Since talin is an essential mediator of integrin activation, much of the integrin crosstalk would therefore be influenced by talin. However, despite the existence of an extensive body of knowledge on the role of talin in integrin activation and as a stabilizer of ECM-actin linkage, information on its role in regulating inter-integrin communication is limited. This review will focus on the structure of talin, its regulation of integrin activation and discuss its potential role in integrin crosstalk. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. 23894627 Reading and visual search: a developmental study in normal children. Studies dealing with developmental aspects of binocular eye movement behaviour during reading are scarce. In this study we have explored binocular strategies during reading and during visual search tasks in a large population of normal young readers. Binocular eye movements were recorded using an infrared video-oculography system in sixty-nine children (aged 6 to 15) and in a group of 10 adults (aged 24 to 39). The main findings are (i) in both tasks the number of progressive saccades (to the right) and regressive saccades (to the left) decreases with age; (ii) the amplitude of progressive saccades increases with age in the reading task only; (iii) in both tasks, the duration of fixations as well as the total duration of the task decreases with age; (iv) in both tasks, the amplitude of disconjugacy recorded during and after the saccades decreases with age; (v) children are significantly more accurate in reading than in visual search after 10 years of age. Data reported here confirms and expands previous studies on children's reading. The new finding is that younger children show poorer coordination than adults, both while reading and while performing a visual search task. Both reading skills and binocular saccades coordination improve with age and children reach a similar level to adults after the age of 10. This finding is most likely related to the fact that learning mechanisms responsible for saccade yoking develop during childhood until adolescence. 23122117 Comparison of different methods to quantify fat classes in bakery products. The definition of fat differs in different countries; thus whether fat is listed on food labels depends on the country. Some countries list crude fat content in the 'Fat' section on the food label, whereas other countries list total fat. In this study, three methods were used for determining fat classes and content in bakery products: the Folch method, the automated Soxhlet method, and the AOAC 996.06 method. The results using these methods were compared. Fat (crude) extracted by the Folch and Soxhlet methods was gravimetrically determined and assessed by fat class using capillary gas chromatography (GC). In most samples, fat (total) content determined by the AOAC 996.06 method was lower than the fat (crude) content determined by the Folch or automated Soxhlet methods. Furthermore, monounsaturated fat or saturated fat content determined by the AOAC 996.06 method was lowest. Almost no difference was observed between fat (crude) content determined by the Folch method and that determined by the automated Soxhlet method for nearly all samples. In three samples (wheat biscuits, butter cookies-1, and chocolate chip cookies), monounsaturated fat, saturated fat, and trans fat content obtained by the automated Soxhlet method was higher than that obtained by the Folch method. The polyunsaturated fat content obtained by the automated Soxhlet method was not higher than that obtained by the Folch method in any sample. 23529822 Identification of developmentally appropriate screening items for disruptive behavior problems in preschoolers. Screening preschool-aged children for disruptive behavior disorders is a key step in early intervention. The study goal was to identify screening items with excellent measurement properties at sub-clinical to clinical levels of disruptive behavior problems within the developmental context of preschool-aged children. Parents/caregivers of preschool-aged children (N = 900) were recruited from four pediatric primary care settings. Participants (mean age = 31, SD = 8) were predominantly female (87 %), either white (55 %) or African-American (42 %), and biological parents (88 %) of the target children. In this cross-sectional survey, participants completed a sociodemographic questionnaire and two parent-report behavioral rating scales: the PSC-17 and the BPI. Item response theory analyses provided item parameter estimates and information functions for 18 externalizing subscale items, revealing their quality of measurement along the continuum of disruptive behaviors in preschool-aged children. Of 18 investigated items, 5 items measured only low levels of disruptive behaviors among preschool-aged children. The remaining 13 items measured sub-clinical to clinical levels of disruptive behavior problems (i.e., >1.5 SD); however, 5 of these items offered less information, suggesting unreliable measurement. The remaining 8 items had high discrimination and difficulty parameters, offering considerable measurement information at sub-clinical to clinical levels of disruptive behavior problems. Behaviors measured by the 8 selected parent-report items were consistent with those identified in recent efforts to distinguish developmentally typical misbehaviors from clinically concerning behaviors among preschool-aged children. These items may have clinical utility in screening young children for disruptive behavior disorders. 23894294 Beyond the levant: first evidence of a pre-pottery neolithic incursion into the nefud desert, saudi arabia. Pre-Pottery Neolithic assemblages are best known from the fertile areas of the Mediterranean Levant. The archaeological site of Jebel Qattar 101 (JQ-101), at Jubbah in the southern part of the Nefud Desert of northern Saudi Arabia, contains a large collection of stone tools, adjacent to an Early Holocene palaeolake. The stone tool assemblage contains lithic types, including El-Khiam and Helwan projectile points, which are similar to those recorded in Pre-Pottery Neolithic A and Pre-Pottery Neolithic B assemblages in the Fertile Crescent. Jebel Qattar lies ∼500 kilometres outside the previously identified geographic range of Pre-Pottery Neolithic cultures. Technological analysis of the typologically diagnostic Jebel Qattar 101 projectile points indicates a unique strategy to manufacture the final forms, thereby raising the possibility of either direct migration of Levantine groups or the acculturation of mobile communities in Arabia. The discovery of the Early Holocene site of Jebel Qattar suggests that our view of the geographic distribution and character of Pre-Pottery Neolithic cultures may be in need of revision. 23810930 Examining the relationships between attention deficit/hyperactivity disorder and developmental coordination disorder symptoms, and writing performance in Japanese second grade students. The purpose of this study was to explore the relationships between attention deficit/hyperactivity disorder and developmental coordination disorder symptoms and writing performance in Japanese second grade students from regular classrooms. The second grade students (N=873) in Japanese public elementary schools participated in this study. We examined a variety of writing tasks, such as tracing, copying, handwriting (Hiragana and Katakana), and spelling (Hiragana, Katakana, and Kanji). We employed the Japanese version of the home form ADHD-rating scale (ADHD-RS) and the Japanese version of the Developmental Coordination Disorder Questionnaire (DCDQ-J) to assess the developmental characteristics of the participating children. Seven writing performance scores were submitted to a principal component analysis with a promax rotation, which yielded three composite scores (Spelling Accuracy, Tracing and Copying Accuracy, and Handwriting Fluency). A multiple regression analysis found that inattention predicted Spelling Accuracy and Handwriting Fluency and that hyperactive-impulsive predicted Handwriting Fluency. In addition, fine motor ability predicted Tracing and Copying Accuracy. The current study offered empirical evidence suggesting that developmental characteristics such as inattention and fine motor skill are related to writing difficulties in Japanese typical developing children. 23438859 Painting by numbers: increasing the parts list for chromatin domains. In this issue of Molecular Cell, van Bemmel and colleagues (2013) report the genome-wide mapping of 42 novel chromatin factors, systematically identifying new components of the various chromatin domains present in fly cells. 23880962 Synthesis and first complexes of C(4/5) P-bifunctional imidazole-2-thiones. A synthetic route to C(4/5)-bis(phosphinoyl)imidazole-2-thiones (7d,e) (d: R(1) = (n)Bu, R(2) = Me; e: R(1) = n-dodecyl, R(2) = Me) and C(4/5)-bis(thio/selenophosphinoyl)imidazole-2-thiones (8b,c), (9a,b,e) and 10a (a: R(1) = R(2) = Me; b: R(1) = R(2) = Ph, c: R(1) = (i)Pr, R(2) = Me) is presented that employs initial C(5) lithiation of mono-phosphinoyl/thiophosphinoyl substituted imidazole-2-thiones (3c-e)/(4a-c,e) followed by reaction with chlorodiphenylphosphane, leading to mixed phosphinoyl and phosphanyl substituted imidazole-2-thiones (5c-e) or mixed thiophosphinoyl and phosphanyl substituted imidazole-2-thiones (6a-c,e). Subsequent oxidation of mixed phosphinoyl and phosphanyl substituted imidazole-2-thione (5d,e) with H2O2-urea gives the bis(phosphinoyl) substituted imidazole-2-thiones (7d,e), and the oxidation of mixed thiophosphinoyl and phosphanyl substituted imidazole-2-thione (6a-c,e) using H2O2-urea, elemental sulfur or elemental selenium gives a set of mixed P(v)-chalcogenide substituted imidazole-2-thiones (8b,c), (9a,b,e) and 10a, respectively. P(v,v) substituted imidazole-2-thiones 7d and 9a reacted with tellurium tetrachloride, titanium tetrachloride or palladium dichloride to give complexes 11d, (12d and 12d') and 14a, respectively, having a bidentate chelate (11d and 14a) or a monodentate bonding motif (12d,d'). The titanium complexes 12d,d' slowly and selectively converted into the mono-ethoxy substituted product 13 possessing a seven membered chelate motif being unprecedented in the titanium chemistry of phosphine oxide donor ligands. The compounds were characterized by elemental analyses, spectroscopic and spectrometric methods and, in addition, X-ray diffraction studies in the case of 5c, 7d, 8b, 9a and 13. 23930975 Trans-Sialidase Inhibition Assay Detects Trypanosoma cruzi Infection in Different Wild Mammal Species. Abstract The detection of Trypanosoma cruzi infection in mammals is crucial for understanding the eco-epidemiological role of the different species involved in parasite transmission cycles. Xenodiagnosis (XD) and hemoculture (HC) are routinely used to detect T. cruzi in wild mammals. Serological methods are much more limited because they require the use of specific antibodies to immunoglobulins of each mammalian species susceptible to T. cruzi. In this study we detected T. cruzi infection by trans-sialidase (TS) inhibition assay (TIA). TIA is based on the antibody neutralization of a recombinant TS that avoids the use of anti-immunoglobulins. TS activity is not detected in the co-endemic protozoan parasites Leishmania spp and T. rangeli. In the current study, serum samples from 158 individuals of nine wild mammalian species, previously tested by XD, were evaluated by TIA. They were collected from two endemic areas in northern Argentina. The overall TIA versus XD co-reactivity was 98.7% (156/158). All 18 samples from XD-positive mammals were TIA-positive (co-positivity, 100%) and co-negativity was 98.5% (138/140). Two XD-negative samples from a marsupial (Didelphis albiventris) and an edentate (Dasypus novemcinctus) were detected by TIA. TIA could be used as a novel tool for serological detection of Trypanosoma cruzi in a wide variety of sylvatic reservoir hosts. 23759860 Biofunctionalized nanoparticles with pH-responsive and cell penetrating blocks for gene delivery. Bridging the gap between nanoparticulate delivery systems and translational gene therapy is a long sought after requirement in nanomedicine-based applications. However, recent developments regarding nanoparticle functionalization have brought forward the ability to synthesize materials with biofunctional moieties that mimic the evolved features of viral particles. Herein we report the versatile conjugation of both cell penetrating arginine and pH-responsive histidine moieties into the chitosan polymeric backbone, to improve the physicochemical characteristics of the native material. Amino acid coupling was confirmed by 2D TOCSY NMR and Fourier transform infrared spectroscopy. The synthesized chitosan-histidine-arginine (CH-H-R) polymer complexed plasmid DNA biopharmaceuticals, and spontaneously assembled into stable 105 nm nanoparticles with spherical morphology and positive surface charge. The functionalized delivery systems were efficiently internalized into the intracellular compartment, and exhibited remarkably higher transfection efficiency than unmodified chitosan without causing any cytotoxic effect. Additional findings regarding intracellular trafficking events reveal their preferential escape from degradative lysosomal pathways and nuclear localization. Overall, this assembly of nanocarriers with bioinspired moieties provides the foundations for the design of efficient and customizable materials for cancer gene therapy. 23896832 Implementing Delirium Screening in the ICU: Secrets to Success. To review delirium screening tools available for use in the adult ICU and PICU, to review evidence-based delirium screening implementation, and to discuss common pitfalls encountered during delirium screening in the ICU. Review of delirium screening literature and expert opinion. Over the past decade, tools specifically designed for use in critically ill adults and children have been developed and validated. Delirium screening has been effectively implemented across many ICU settings. Keys to effective implementation include addressing barriers to routine screening, multifaceted training such as lectures, case-based scenarios, one-on-one teaching, and real-time feedback of delirium screening, and interdisciplinary communication through discussion of a patient's delirium status during bedside rounds and through documentation systems. If delirium is present, clinicians should search for reversible or treatable causes because it is often multifactorial. Implementation of effective delirium screening is feasible but requires attention to implementation methods, including a change in the current ICU culture that believes delirium is inevitable or a normal part of a critical illness, to a future culture that views delirium as a dangerous syndrome which portends poor clinical outcomes and which is potentially modifiable depending on the individual patients circumstances. 23928995 Breast tumor kinase (Brk/PTK6) is a mediator of hypoxia-associated breast cancer progression. Basal-type triple-negative breast cancers (TNBC) are aggressive and difficult to treat compared to luminal-type breast cancers. TNBC often express abundant Met receptors and are enriched for transcriptional targets regulated by hypoxia inducible factor 1-alpha (HIF-1α), which independently predicts cancer relapse and increased metastatic risk. Brk/PTK6 kinase is a critical downstream effector of Met signaling and required for HGF-induced cell migration. Herein, we examined Brk regulation by HIFs in TNBC in vitro and in vivo. Brk mRNA and protein levels are upregulated strongly in vitro by hypoxia, low glucose and reactive oxygen species. In HIF-silenced cells, Brk expression relied upon HIF-1α and HIF-2α, which we found to regulate BRK transcription directly. HIF-1α/2α silencing in MDA-MB-231 cells diminished xenograft growth and Brk re-expression reversed this effect. These findings were pursued in vivo by crossing wap-Brk and METmut transgenic mice. In this setting, Brk expression augmented METmut-induced mammary tumor formation and metastasis. Unexpectedly, tumors arising in either METmut or wap-Brk;METmut mice expressed abundant levels of Sik, the mouse homolog of Brk, which conferred increased tumor formation and decreased survival. Taken together, our results identify HIF-1α/2α as novel regulators of Brk expression and suggest that Brk is a key mediator of hypoxia-induced breast cancer progression. Targeting Brk expression or activity may provide an effective means to block the progression of aggressive breast cancers. 23928681 Effects of surfactants on electrochemically prepared Ag nanostructures. The morphology and corrosion behavior of electrochemically prepared Ag nanostructures (NSs) have been examined in the absence and presence of potassium citrate, polyvinylpyrrolidone (PVP) and polyoxyethylene(20) sorbitan monolaurate (Tween-20). These additives give rise to morphologically distinct Ag NSs. The presence of citrate increases the dissolution of Ag and creates finer nanostructured Ag surfaces with more cavities, while Tween-20 protects the Ag surface against corrosion in alkaline solution and generates spherical non-packed nanofeatured Ag surfaces. 23713609 Environmental implications of jatropha biofuel from a silvi-pastoral production system in central-west Brazil. We present a life cycle assessment of synthetic paraffinic kerosene produced from Jatropha curcas. The feedstock is grown in an intercropping arrangement with pasture grasses so that Jatropha is coproduced with cattle. Additional innovations are introduced including hybrid seeds, detoxification of jatropha seedcake, and cogeneration. Two fuel pathways are examined including a newly developed catalytic decarboxylation process. Sensitivities are examined including higher planting density at the expense of cattle production as well as 50% lower yields. Intercropping with pasture and detoxifying seedcake yield coproducts that are expected to relieve pressure on Brazil's forests and indirectly reduce environmental impacts of biofuel production. Other innovations also reduce impacts. Results of the baseline assessment indicate that innovations would reduce impacts relative to the fossil fuel reference scenario in most categories including 62-75% reduction in greenhouse gas emissions, 64-82% reduction in release of ozone depleting chemicals, 33-52% reduction in smog-forming pollutants, 6-25% reduction in acidification, and 60-72% reduction in use of nonrenewable energy. System expansion, which explicitly accounts for avoided deforestation, results in larger improvements. Results are robust across allocation methodologies, improve with higher planting density, and persist if yield is reduced by half. 23811827 Genotoxicity Profile of Azidothymidine In Vitro. Azidothymidine (Zidovudine, AZT) is part of the standard care of treatment for acquired immunodeficiency syndrome since many years. A great number of studies on the genotoxic potential of AZT have been published, but no comprehensive hypothesis yet explains all observations. We investigated a multitude of genotoxic endpoints, both in vitro and in vivo, with the goal to complete the picture. The mutagenic potential of AZT in bacteria was found to be restricted to strains with an "ochre" target sequence and could be abrogated both by thymidine supplementation and rat liver S9 mix. Single-strand breaks in mammalian cells were detected in the comet assay after short-term treatment (3h) with AZT, which did not induce micronuclei. The latter were mainly seen after prolonged exposure (24 and 48h) and are probably not directly related to AZT incorporation into DNA. Our data demonstrate that short-term exposure to low AZT concentrations does not induce biologically relevant micronucleation. Only treatment with high concentrations of AZT for prolonged time periods manifests in substantial micronucleus induction. Furthermore, we found that high concentrations of thymidine have no effect in the comet assay but increase micronucleus frequency in a manner very similar to AZT. These results lead us to the following hypothesis: AZT is triphosphorylated and then incorporated into DNA strands, leading to mutations and cytotoxicity. Cellular attempts to repair these DNA lesions as well as stalled replication forks due to chain termination are detectable with the comet assay. Increased micronucleus frequency is likely related to nucleotide pool imbalance. 23523667 Observations of mealtimes in hospital aged care rehabilitation wards. Malnutrition is common in long-stay elderly hospitalized patients and their dietary intakes are often poor, despite the provision of adequate quantities of food to meet patient needs. The aim of this study was to identify environmental factors that were associated with achieving adequate food consumption in a hospital context. This study observed the daily routines of 30 elderly patients over 2days in rehabilitation wards in three Australian hospitals. All activities associated with mealtimes were recorded, from the commencement of breakfast to the conclusion of supper at the end of the day. Four key themes emerged: the eating location; assistance given at meals; negative and positive interruptions. The time taken to eat meals averaged 22min, ranging from 3 to 55min. Food intakes appeared to be better when meals were consumed communally in a dining room. There were many occasions when patients needed more assistance to eat than was available. The most common factors negatively affecting meal consumption were medication rounds, inappropriate placement of trays, packaging being hard to open, and patient showering. The presence of visitors, dietitians and nutrition assistants appeared to improve dietary intakes. Trials of protected mealtimes in Australian hospitals are certainly important and timely. 23872841 Reactivity landscape of pyruvate under simulated hydrothermal vent conditions. Pyruvate is an important "hub" metabolite that is a precursor for amino acids, sugars, cofactors, and lipids in extant metabolic networks. Pyruvate has been produced under simulated hydrothermal vent conditions from alkyl thiols and carbon monoxide in the presence of transition metal sulfides at 250 °C [Cody GD et al. (2000) Science 289(5483):1337-1340], so it is plausible that pyruvate was formed in hydrothermal systems on the early earth. We report here that pyruvate reacts readily in the presence of transition metal sulfide minerals under simulated hydrothermal vent fluids at more moderate temperatures (25-110 °C) that are more conducive to survival of biogenic molecules. We found that pyruvate partitions among five reaction pathways at rates that depend upon the nature of the mineral present; the concentrations of H2S, H2, and NH4Cl; and the temperature. In most cases, high yields of one or two primary products are found due to preferential acceleration of certain pathways. Reactions observed include reduction of ketones to alcohols and aldol condensation, both reactions that are common in extant metabolic networks. We also observed reductive amination to form alanine and reduction to form propionic acid. Amino acids and fatty acids formed by analogous processes may have been important components of a protometabolic network that allowed the emergence of life. 23891728 From preclinical to clinical development: The example of a novel treatment for obesity. Clinical development of drugs for CNS disorders can be a challenging and risky endeavor. In this article we look at the steps required to move a preclinical candidate compound into clinical development. We use the case study of ALB-127158(a), an MCH1 antagonist for the treatment of obesity via a central mechanism to highlight the steps needed to move into early clinical development. Preclinical studies demonstrated that the compound produced significant weight loss in rodents. Based on the observation that the weight loss was caused by a reduction in food intake it was possible to build measures of ingestive behavior into the early clinical development plan. Single and multiple ascending dose studies were conducted in normal and overweight volunteers. The compound was safe and well tolerated with good PK characteristics. ALB-127158(a) was shown to have some effects on measures of 'hunger' and 'desire to eat', unfortunately these effects only occurred at doses higher than those predicted from the preclinical studies. A subsequent study looking at compound levels in the cerebrospinal fluid (CSF) suggested lower brain exposure than seen in the preclinical models. Based on this data and the limited efficacy observed it was possible to terminate further progression of this compound for obesity before costly long-term weight loss studies were initiated. However, recent reports have demonstrated that MCH acting via MCH1 receptors located on intestinal epithelial cells may be a critical mediator of inflammatory responses within the gastrointestinal (GI) tract. MCH1 receptor antagonists may therefore have a beneficial effect in disorders such as inflammatory bowel disease (IBD). Based on this evidence a peripherally selective MCH1 receptor antagonist such as ALB-127158(a) may be a potential treatment for IBD. This example demonstrates how using data from the preclinical studies is possible to build decision points into an early clinical development plan that will allow early assessment of potential efficacy and allow timely go/no go decisions. 23680656 Control of the human osteopontin promoter by ERRα in colorectal cancer. Colorectal cancer is the second leading cause of death from cancer. Osteopontin (OPN) is a component of tumor extracellular matrix identified as a key marker of cancer progression. The estrogen-related receptor α (ERRα) has been implicated in endocrine-related cancer development and progression, possibly through modulation of cellular energy metabolism. Previous reports that ERRα regulates OPN expression in bone prompted us to investigate whether ERRα controls OPN expression in human colorectal cancer. Using a tissue microarray containing 83 tumor-normal tissue pairs of colorectal cancer samples, we found that tumor epithelial cells displayed higher staining for ERRα than normal mucosa, in correlation with elevated OPN expression. In addition, knocking down endogenous ERRα led to reduced OPN expression in HT29 colon cancer cells. Promoter analysis, inhibition of ERRα activity, and expression and mutation of potential ERRα response elements in the proximal promoter of human OPN showed that ERRα and its obligate co-activator, peroxisome proliferator-activated receptor γ co-activator-1 α, positively control human OPN promoter activity. Furthermore, chromatin immunoprecipitation experiments confirmed in vivo occupancy of the OPN promoter by ERRα in HT29 cells, suggesting that OPN is a direct target of ERRα in colorectal cancer. These findings suggest an additional mechanism by which ERRα participates in the development and progression of colorectal cancer, further supporting the relevance of targeting ERRα with antagonists as anticancer agents. 23557591 Effects of prediabetes and diabetes on left ventricular and coronary microvascular functions. BACKGROUND: Coronary flow reserve (CFR) provides independent prognostic information in diabetic patients with known or suspected coronary artery disease. However, there have been no substantial data to evaluate CFR in prediabetics. Accordingly, we aimed to evaluate CFR in subjects with prediabetes using second harmonic transthoracic Doppler echocardiography. METHODS AND RESULTS: We measured CFR of 65 subjects with prediabetes, 45 patients with overt type 2 diabetes, and 43 sex and age matched normoglycemic healthy subjects with normal glucose tolerance. Ages, gender, existence of hypertension or hypercholesterolemia, smoking status were similar among the groups. CFR was significantly lower in diabetics (2.15±0.39) than in prediabetics (2.39±0.45) and controls (2.75±0.35); in addition, it was significantly lower in prediabetics than controls. Only 2 (5%) of control subjects had abnormal CFR (<2) but 11 (17%) prediabetic subjects and 19 (42%) diabetic patients had abnormal CFR. We found that only age (β=-0.31, P<0.01) and presence of the diabetes (β=-0.57, P<0.01) were significant predictors of lower CFR in a multivariable model that adjusted for other variables. CFR was significantly and inversely correlated with age (r=-0.15, P=0.04), fasting glucose level (r=-0.27, P=0.001), postprandial glucose level (r=0.43, P<0.001), hemoglobin A1C level (r=-0.34, P<0.001), LDL cholesterol level (r=0.22, P=0.009), mitral A velocity (r=-0.27, P=0.001) and Tei index (r=-0.19, P=0.02), whereas mitral E/A ratio, mitral Em (r=0.18, P=0.02), mitral Em/Am ratio (r=0.23, P=0.004) were significantly and positively correlated with CFR. CONCLUSION: CFR is impaired in subjects with prediabetics, but this impairment is not as severe as that in diabetics. 23822826 Modern Pharmacotheraphy of Lung Disease: Anti-Leukotriene Agents for the Treatment of Lung Disease. Leukotrienes (LTs) C4, D4, and E4, collectively termed cysteinyl LTs (cysLTs), are lipid mediators formed by the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism. Originally recognized for their potent bronchoconstrictor actions, they were subsequently determined to also promote inflammation, microvascular permeability, and mucus secretion. These actions that are so central to asthma pathophysiology are mediated to a significant extent by ligation of the cysLT receptor 1 (CysLT1). Antagonism of CysLT1 and inhibition of 5-LO have both been shown to have clinical utility in the management of asthma, but substantial inter-individual heterogeneity is observed in the response to these agents. In this article, we review the biologic actions of LTs, their biosynthetic pathways and cognate receptors, the pharmacology of available anti-LT agents, and the clinical evidence for the use of anti-LT agents as mono-therapy and combination therapy in asthma. We also consider heterogeneity of response, the possible roles of cysLT receptors other than CysLT1, the role of another class of LT, LTB4, and the potential role of LTs in lung diseases other than asthma. 22075688 On the benefit of magnetic magnesium nanocarrier in cardiovascular toxicity of aluminum phosphide. The present study was designed to determine the effect of a new (25)Mg(2+)-carrying nanoparticle ((25)MgPMC16) on energy depletion, oxidative stress, and electrocardiographic (ECG) parameters on heart tissue of the rats poisoned by aluminum phosphide (AlP). (25)MgPMC16 at doses of 0.025, 0.05, and 0.1 median lethal dose (LD50 = 896 mg/kg) was administered intravenously (iv) 30 min after a single intragastric administration of AlP (0.25 LD50). Sodium bicarbonate (Bicarb; 2 mEq/kg, iv) was used as the standard therapy. After anesthesia, the animals were rapidly connected to an electronic cardiovascular monitoring device for monitoring of ECG, blood pressure (BP), and heart rate (HR). Later lipid peroxidation, antioxidant power, ATP/ADP ratio, and Mg concentration in the heart were evaluated. Results indicated that after AlP administration, BP and HR decreased while R-R duration increased. (25)MgPMC16 significantly increased the BP and HR at all doses used. We found a considerable increase in antioxidant power, Mg level in the plasma and the heart and a reduction in lipid peroxidation and ADP/ATP ratio at various doses of (25)MgPMC16, but (25)MgPMC16-0.025 + Bicarb was the most effective combination therapy. The results of this study support that (25)MgPMC16 can increase heart energy by active transport of Mg inside the cardiac cells.(25)MgPMC16 seems ameliorating AlP-induced toxicity and cardiac failure necessitating further studies. 23887941 Na+/K+-ATPase β2-subunit (AMOG) expression abrogates invasion of glioblastoma-derived brain tumor-initiating cells. BackgroundMechanisms of glioma invasion remain to be fully elucidated. Glioma cells within glioblastoma multiforme (GBM) range from well-differentiated tumor cells to less-differentiated brain tumor-initiating cells (BTICs). The β2-subunit of Na(+)/K(+)-ATPase, called the adhesion molecule on glia (AMOG), is highly expressed in normal glia but is thought to be universally downregulated in GBM. To test our hypothesis that expression of AMOG is heterogeneous in GBM and confers a less invasive phenotype, we compared it between BTICs and differentiated cells from patient-matched GBM and then tested GBM invasion in vitro after AMOG overexpression.MethodsImmunohistochemistry, immunoblotting, and real-time PCR were used to characterize AMOG protein and mRNA expression in tumor samples, BTICs, and differentiated cells. Matrigel invasion assay, scratch assay, and direct cell counting were used for testing in vitro invasion, migration, and proliferation, respectively.ResultsWhile AMOG expression is heterogeneous in astrocytomas of grades II-IV, it is lost in most GBM. BTICs express higher levels of AMOG mRNA and protein compared with patient-matched differentiated tumor cells. Overexpression of AMOG decreased GBM cell and BTIC invasion without affecting migration or proliferation. Knockdown of AMOG expression in normal human astrocytes increased invasion.ConclusionsAMOG expression inhibits GBM invasion. Its downregulation increases invasion in glial cells and may also represent an important step in BTIC differentiation. These data provide compelling evidence implicating the role of AMOG in glioma invasion and provide impetus for further investigation. 23376781 Catechins are not major components responsible for the beneficial effect of Camellia sinensis on the ovarian δ-ALA-D activity inhibited by cadmium. Cadmium has been associated with a wide spectrum of deleterious effects on the reproductive tissues, including ovary. This investigation evaluated the protective role of Camellia sinensis (green, white and red teas) in the cadmium-induced inhibition of ovarian δ-aminolevulinate dehydratase (δ-ALA-D) activity in vitro and ex vivo. This study demonstrated that green and white teas restored the cow ovary δ-ALA-D activity inhibited by cadmium whereas red tea had no effect in vitro. In addition, green tea was able to restore enzyme activity inhibited after acute cadmium exposure in mice ovary. Teas infusions composition was assessed by HPLC in a quantitative assay for catechins, purine alkaloids and gallic acid as well as total polyphenol content. The greatest effect of green tea observed in vitro as well as the protective role presented in the ex vivo study could be attributed to the major content of phenols, but not catechins. In fact, catechins were not able to restore enzyme activity inhibited by cadmium, demonstrating that these compounds are not major components responsible for the beneficial effect of green tea observed in this study. This study demonstrated the helpful effect of green tea infusion in ameliorating a marker protein of cadmium intoxication in ovarian tissue. 23845895 Modelling hemodynamic response function in epilepsy. Electroencephalography and functional magnetic resonance imaging (fMRI) can be combined to noninvasively map abnormal brain activation elicited by epileptic processes. A major aim was to investigate the impact of a subject-specific hemodynamic response function (HRF) to describe the differences across patients versus the use of a standard model. We developed and applied on simulated and real data a method designed to choose optimum HRF model for identifying fMRI activation maps. In simulation, the ability of five models to reproduce data was assessed: four standard and an individual-based HRF model (ibHRF). In clinical data, drug-resistant epileptic patients underwent fMRI to investigate hemodynamic responses evoked by interictal activity. When data are simulated with models different from the standard ones, the results obtained with ibHRF are superior to those obtained with the standard HRFs. Results on real data indicate an increase in extent and degree of activation with the ibHRF in comparison of the results obtainable using standard HRFs. The use of the same HRF in all patients is inappropriate and resolves in biased extension of the activation maps. The new method could represent an useful diagnostic tool for other clinical studies that may be biased because of misspecification of HRF. 23060412 Hormesis: its impact on medicine and health. This article offers a broad assessment of the hormetic dose response and its relevance to biomedical researchers, physicians, the pharmaceutical industry, and public health scientists. This article contains a series of 61 questions followed by relatively brief but referenced responses that provides support for the conclusion that hormesis is a reproducible phenomenon, commonly observed, with a frequency far greater than other dose-response models such as the threshold and linear nonthreshold dose-response models. The article provides a detailed background information on the historical foundations of hormesis, its quantitative features, mechanistic foundations, as well as how hormesis is currently being used within medicine and identifying how this concept could be further applied in the development of new therapeutic advances and in improved public health practices. 23558924 Forearm blood flow response to acute exercise in obese and non-obese males. Chronic exercise is thought to improve endothelium-dependent vasodilation; however, few studies have evaluated the effects of acute exercise on microvascular vasodilatory capacity (MVC). Moreover, no studies have compared MVC responses in obese and non-obese individuals following acute exercise. To evaluate MVC, utilizing forearm blood flow (FBF) and excess blood flow (EBF) before and up to 48 h after a single exercise bout to elicit peak oxygen consumption (VO2peak) in obese and non-obese males. Twelve obese (37.0 ± 1.1 kg/m(2)) and 12 non-obese (21.9 ± 0.3 kg/m(2)) males volunteered to participate. FBF measures, before and during reactive hyperemia (RH), were obtained prior to (PRE-E), immediately after (POST-E), and at 1 (POST-1), 2 (POST-2), 24 (POST-24), and 48 (POST-48) hours after exercise. EBF, was calculated as the difference between FBF, before and during RH. Blood samples were obtained to evaluate the response of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), which are potential modifiers of MVC. FBF before and during RH were significantly (P < 0.05) increased in both groups POST-E. The EBF magnitude of change from PRE-E was significantly (P < 0.05) elevated in non-obese when compared with obese males. Although not related to MVC, concentrations of IL-6 significantly decreased between POST-2 and POST-24 in both groups. An acute bout of exercise designed to elicit VO2peak significantly increased forearm MVC in non-obese and obese males, although the magnitude of change in EBF from PRE-E to POST-E was greater in non-obese males. 22626061 Effect of air polishing with glycine powder on titanium abutment surfaces. The aim of the present study was to evaluate morphological changes induced by glycine powder air polishing on titanium surfaces and its effect on bacteria recolonization in comparison with sodium bicarbonate powder. 5 mm wide and 1 mm thick titanium grade II disks were divided into three groups of treatments: (i) no treatment; (ii) air polishing with glycine powder; (iii) air polishing with sodium bicarbonate powder. Specimens were characterized by laser profilometry, scanning electron microscopy (SEM) and then installed onto removable appliances worn for 24 h by healthy volunteers. Surface contamination was evaluated using SEM and counting the number of colony forming units (CFU). SEM observation revealed an increased roughness with the formation of craters on samples treated with sodium bicarbonate powder, while not in glycine ones. Statistical analysis failed to show significant differences of both Ra and Rmax parameters in treated groups. SEM observation of specimens surfaces, after 24 h of permanence in the oral cavity, showed a higher contamination of the disks treated with sodium bicarbonate compared with those not treated (P < 0.05). Conversely, the group treated with glycine showed the lower contamination if compared with bicarbonate-treated group (P < 0.05). Air polishing with glycine powder may be considered as a better method to remove plaque from dental implant because glycine is less aggressive than sodium bicarbonate powder. Moreover, the use of glycine powder seems to have an active role on the inhibition of bacterial recolonization of implants in a short test period (24 h). Further studies are needed to demonstrate the bacteriostatic properties of glycine, envisaged on the basis of reduced contamination of the disks polished with glycine compared with those not treated. 23932502 Bioimaging and pulmonary applications of self-assembled Flt1 peptide-hyaluronic acid conjugate nanoparticles. Despite wide exploitation of corticosteroid drugs for the treatment of asthma, the poor therapeutic effect on a neutrophilic subtype of asthma prohibits the full recovery of asthma patients. In this work, dexamethasone (Dexa) was loaded in Flt1 peptide-hyaluronic acid (HA) conjugate nanoparticles to overcome the limitation of corticosteroid resistance for the treatment of neutrophilic pulmonary inflammation. Flt1 peptide-HA conjugates are self-assembled to nanoparticles because of hydrophobic Flt1 peptide conjugated to HA by benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) chemistry. In vitro bioimaging showed efficient internalization of Flt1 peptide-HA conjugate nanoparticles into lung epithelial cells by HA-receptor mediated endocytosis. Also, ex vivo imaging for the biodistribution in ICR mice revealed long-term retention of Flt1 peptide-HA conjugate nanoparticles in deep lung tissues possibly due to mucoadhesive property of HA. On the basis of bioimaging results for pulmonary drug delivery applications, we prepared Dexa-loaded Flt1 peptide-HA conjugate nanoparticles. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) confirmed the formation of nanoparticles, which reduced cytokine levels of lipopolysaccharide (LPS)-stimulated cells more efficiently than free Dexa. Furthermore, according to the bronchoalveolar lavage (BAL) cellularity and histological analysis, Dexa loaded Flt1 peptide-HA conjugate nanoparticles showed remarkable therapeutic effects in both eosinophilic and neutrophilic asthma model mice. 23909322 Preparation of entangled and antiferromagnetic States by dissipative Rydberg pumping. We propose and analyze an approach for preparation of high fidelity entanglement and antiferromagnetic states using Rydberg mediated interactions with dissipation. Using asymmetric Rydberg interactions the two-atom Bell singlet is a dark state of the Rydberg pumping process. Master equation simulations demonstrate Bell singlet preparation fidelity F=0.998. Antiferromagnetic states are generated on a four-spin plaquette in agreement with results found from diagonalization of the transverse field Ising Hamiltonian. 23052744 Long-term results of surgery for papillary thyroid carcinoma with local recurrence. Surgical treatment of local recurrent papillary thyroid carcinoma is still controversial because of the increased morbidity in comparison to primary surgery, and the unclear efficacy. This study analyzed the efficacy and safety of surgery for recurrent disease. A retrospective cohort analysis of 86 patients who underwent surgery for local recurrent papillary thyroid carcinoma at a single institution during the period 1979-2009. The cause-specific survival rates of all patients at 5, 10, and 20 years were 86 % (95 % CI 77-95 %), 74 % (95 % CI 62-87 %), and 36 % (95 % CI 18-54 %), respectively. A univariate analysis found that gender, age >45 years at reoperation and macroscopic non-curative surgery for recurrence affected the cause-specific survival rates. The latter two features remained significant in a multivariate analysis. Permanent recurrent nerve paralysis and hypoparathyroidism developed in 4 (4.7 %) and 5 (5.8 %) patients, respectively. Surgery for local recurrent papillary thyroid carcinoma could be effective when macroscopic curative dissection was possible, and that the procedure was safe and was associated with minimal morbidity. Therefore, repeat surgery for local recurrent papillary thyroid carcinoma is worthwhile. 23940565 Subtracted diversity array identifies novel molecular markers including retrotransposons for fingerprinting echinacea species. Echinacea, native to the Canadian prairies and the prairie states of the United States, has a long tradition as a folk medicine for the Native Americans. Currently, Echinacea are among the top 10 selling herbal medicines in the U.S. and Europe, due to increasing popularity for the treatment of common cold and ability to stimulate the immune system. However, the genetic relationship within the species of this genus is unclear, making the authentication of the species used for the medicinal industry more difficult. We report the construction of a novel Subtracted Diversity Array (SDA) for Echinacea species and demonstrate the potential of this array for isolating highly polymorphic sequences. In order to selectively isolate Echinacea-specific sequences, a Suppression Subtractive Hybridization (SSH) was performed between a pool of twenty-four Echinacea genotypes and a pool of other angiosperms and non-angiosperms. A total of 283 subtracted genomic DNA (gDNA) fragments were amplified and arrayed. Twenty-seven Echinacea genotypes including four that were not used in the array construction could be successfully discriminated. Interestingly, unknown samples of E. paradoxa and E. purpurea could be unambiguously identified from the cluster analysis. Furthermore, this Echinacea-specific SDA was also able to isolate highly polymorphic retrotransposon sequences. Five out of the eleven most discriminatory features matched to known retrotransposons. This is the first time retrotransposon sequences have been used to fingerprint Echinacea, highlighting the potential of retrotransposons as based molecular markers useful for fingerprinting and studying diversity patterns in Echinacea. 23606057 Time-dependent regulation of neuregulin-1β/ErbB/ERK pathways in cardiac differentiation of mouse embryonic stem cells. Neuregulin-1β (NRG-1β)/ErbB signaling plays crucial roles in the cardiac differentiation of mouse embryonic stem cells (ESCs), but its roles and the underlying mechanisms in cardiac differentiation are incompletely understood. This study showed that NRG-1β significantly increased the percentage of beating embryoid bodies (EBs) and up-regulated the gene expressions of Nkx2.5, GATA4, α-actin, MLC-2v, and ANF in a time-dependent manner, with no effect on the gene expressions of HCN4 and Tbx3. Inhibition of ErbB receptors with AG1478 significantly decreased the percentage of beating EBs; down-regulated the gene expressions of Nkx2.5, GATA4, MLC-2v, ANF, and α-actin; and concomitantly up-regulated the gene expressions of HCN4 and Tbx3 in a time-dependent manner. Moreover, the up-regulation of transcripts for Nkx2.5 and GATA4 by NRG-1β was blocked by the extracellular signal-related kinases (ERK) 1/2 inhibitor, U0126. However, U0126 could not inhibit the transcript up-regulations of MLC-2v and ANF by NRG-1β. The protein quantitation results were consistent with those of gene quantitation. Our results suggest that NRG-1β/ErbB signaling plays critical roles in the cardiac differentiation of mouse ESCs and in the subtype specification of cardiomyocytes in a time-dependent manner. The ERK1/2 pathway may be involved in the early cardiogenesis, but not in the subtype specification of cardiomyocytes. 23583511 Design considerations for PAMAM dendrimer therapeutics. We have previously shown that methotrexate (MTX) conjugated to a cancer-specific poly amido amine (PAMAM) dendrimer has a higher therapeutic index than MTX alone. Unfortunately, these therapeutics have been difficult to advance because of the complicated syntheses and an incomplete understanding of the dendrimer properties. We wished to address these obstacles by using copper-free click chemistry to functionalize the dendrimer scaffolds and to exploring the effects of two dendrimer properties (the targeting ligand and drug linkage) on cytotoxicity. We conjugated either ester or amide-linker modified MTX to dendrimer scaffolds with or without folic acid (FA). Because of multivalency, the FA and MTX functionalized dendrimers had similar capacities to target the folate receptor on cancer cells. Additionally, we found that the ester- and amide-linker modified MTX compounds had similar cytotoxicity but the dendrimer-ester MTX conjugates were much more cytotoxic than the dendrimer-amide MTX conjugates. These results clarify the impact of these properties on therapeutic efficacy and will allow us to design more effective polymer therapeutics. 23017402 Phytochemical profile of Rosmarinus officinalis and Salvia officinalis extracts and correlation to their antioxidant and anti-proliferative activity. The goal of this study was to monitor the anti-proliferative activity of Rosmarinus officinalis and Salvia officinalis extracts against cancer cells and to correlate this activity with their phytochemical profiles using liquid chromatography/diode array detection/electrospray ion trap tandem mass spectrometry (LC/DAD/ESI-MS(n)). For the quantitative estimation of triterpenic acids in the crude extracts an NMR based methodology was used and compared with the HPLC measurements, both applied for the first time, for the case of betulinic acid. Both extracts exerted cytotoxic activity through dose-dependent impairment of viability and mitochondrial activity of rat insulinoma m5F (RINm5F) cells. Decrease of RINm5F viability was mediated by nitric oxide (NO)-induced apoptosis. Importantly, these extracts potentiated NO and TNF-α release from macrophages therefore enhancing their cytocidal action. The rosemary extract developed more pronounced antioxidant, cytotoxic and immunomodifying activities, probably due to the presence of betulinic acid and a higher concentration of carnosic acid in its phytochemical profile. 23410589 DNA damage and oxidative stress in human B lymphoblastoid cells after combined exposure to hexavalent chromium and nickel compounds. In the present study, human B lymphoblastoid cells were exposed to potassium dichromate and/or nickel chloride for 24h or 48h. The cell viability and DNA damage induced by these compounds was measured with the CCK-8 assay and Comet assay, respectively. In addition, the generation of reactive oxygen species (ROS) and the levels of malondialdehyde (MDA) were measured using commercially available kits. Our results indicated that potassium dichromate could decrease cell viability and induce DNA damage in human B lymphoblastoid cells in a time - and concentration - dependent manner, but the toxicity of nickel chloride was not so obvious at concentrations used in our study. The results of ROS showed that both two compounds could only induce weak elevation of ROS level, but MDA levels were significantly enhanced. Antagonistic effects of cytotoxicity were mainly found between Cr (VI) and Ni (II), and synergistic effects of DNA damage and oxidative stress were partially found between these two compounds. Moreover, there were good correlations between the results of comet assay and the results of oxidative stress assays. It is suggested that synergistic DNA damage induced by simultaneously exposure of hexavalent chromium and nickel compounds is possibly related to oxidative stress. 23942680 QRS duration, bundle-branch block morphology, and outcomes among older patients with heart failure receiving cardiac resynchronization therapy. The benefits of cardiac resynchronization therapy (CRT) in clinical trials were greater among patients with left bundle-branch block (LBBB) or longer QRS duration. To measure associations between QRS duration and morphology and outcomes among patients receiving a CRT defibrillator (CRT-D) in clinical practice. Retrospective cohort study of Medicare beneficiaries in the National Cardiovascular Data Registry's ICD Registry between 2006 and 2009 who underwent CRT-D implantation. Patients were stratified according to whether they were admitted for CRT-D implantation or for another reason, then categorized as having either LBBB or no LBBB and QRS duration of either 150 ms or greater or 120 to 149 ms. All-cause mortality; all-cause, cardiovascular, and heart failure readmission; and complications. Patients underwent follow-up for up to 3 years, with follow-up through December 2011. Among 24 169 patients admitted for CRT-D implantation, 1-year and 3-year mortality rates were 9.2% and 25.9%, respectively. All-cause readmission rates were 10.2% at 30 days and 43.3% at 1 year. Both the unadjusted rate and adjusted risk of 3-year mortality were lowest among patients with LBBB and QRS duration of 150 ms or greater (20.9%), compared with LBBB and QRS duration of 120 to 149 ms (26.5%; adjusted hazard ratio [HR], 1.30 [99% CI, 1.18-1.42]), no LBBB and QRS duration of 150 ms or greater (30.7%; HR, 1.34 [99% CI, 1.20-1.49]), and no LBBB and QRS duration of 120 to 149 ms (32.3%; HR, 1.52 [99% CI, 1.38-1.67]). The unadjusted rate and adjusted risk of 1-year all-cause readmission were also lowest among patients with LBBB and QRS duration of 150 ms or greater (38.6%), compared with LBBB and QRS duration of 120 to 149 ms (44.8%; adjusted HR, 1.18 [99% CI, 1.10-1.26]), no LBBB and QRS duration of 150 ms or greater (45.7%; HR, 1.16 [99% CI, 1.08-1.26]), and no LBBB and QRS duration of 120 to 149 ms (49.6%; HR, 1.31 [99% CI, 1.23-1.40]). There were no observed associations with complications. Among fee-for-service Medicare beneficiaries undergoing CRT-D implantation in clinical practice, LBBB and QRS duration of 150 ms or greater, compared with LBBB and QRS duration less than 150 ms or no LBBB regardless of QRS duration, was associated with lower risk of all-cause mortality and of all-cause, cardiovascular, and heart failure readmissions. 23289770 Stereoselective Rh2(S-IBAZ)4-catalyzed cyclopropanation of alkenes, alkynes, and allenes: asymmetric synthesis of diacceptor cyclopropylphosphonates and alkylidenecyclopropanes. A mild and highly stereoselective rhodium(II)-catalyzed cyclopropanation of alkenes, alkynes, and allenes with diacceptor diazo compounds is reported. Using the phosphonate moiety as an efficient trans-directing group, the first catalytic asymmetric route to diacceptor cycloprop(en)ylphosphonates was developed by employing an α-cyano diazophosphonate and Rh(2)(S-IBAZ)(4) as chiral catalyst. The isosteric character of phosphonic and carboxylic acid derivatives allowed the alternative use of an α-cyano diazo ester in the process, leading to α-cyano cycloprop(en)ylcarboxylates in high yields and stereoselectivities. Taking advantage of the particular reactivity of the cyanocarbene intermediates involved in this system, the scope of compatible substrates could be extended to substituted allenes, leading to the development of the first catalytic enantioselective method for the synthesis of diacceptor alkylidenecyclopropanes. 23871029 Phytochemical profile of a Japanese black-purple rice. Black-purple rice is becoming popular with health conscious food consumers. In the present study, the secondary metabolites in dehulled black-purple rice cv. Asamurasaki were analysed using HPLC-PDA-MS(2). The seeds contained a high concentration of seven anthocyanins (1400μg/g fresh weight) with cyanidin-3-O-glucoside and peonidin-3-O-glucoside predominating. Five flavonol glycosides, principally quercetin-3-O-glucoside and quercetin-3-O-rutinoside, and flavones were detected at a total concentration of 189μg/g. The seeds also contained 3.9μg/g of carotenoids consisting of lutein, zeaxanthin, lycopene and β-carotene. γ-Oryzanol (279μg/g) was also present as a mixture of 24-methylenecycloartenol ferulate, campesterol ferulate, cycloartenol ferulate and β-sitosterol ferulate. No procyanidins were detected in this variety of black-purple rice. The results demonstrate that the black-purple rice in the dehulled form in which it is consumed by humans contains a rich heterogeneous mixture of phytochemicals which may provide a basis for the potential health benefits, and highlights the possible use of the rice as functional food. 23870885 Sacha inchi (Plukenetia volubilis): A seed source of polyunsaturated fatty acids, tocopherols, phytosterols, phenolic compounds and antioxidant capacity. Fatty acids (FA), phytosterols, tocopherols, phenolic compounds, total carotenoids and hydrophilic and lipophilic ORAC antioxidant capacities were evaluated in 16 cultivars of Sacha inchi (SI) seeds with the aim to valorise them and offer more information on the functional properties of SI seeds. A high α linolenic (α-Ln) fatty acid content was found in all cultivars (ω3, 12.8-16.0g/100g seed), followed by linoleic (L) fatty acid (ω6, 12.4-14.1g/100g seed). The ratio ω6/ω3 was within the 0.83-1.09 range. γ- and δ-tocopherols were the most important tocopherols, whereas the most representative phytosterols were β-sitosterol and stigmasterol. Contents of total phenolics, total carotenoids and hydrophilic and lipophilic antioxidant capacities ranged from 64.6 to 80mg of gallic acid equivalent/100g seed; from 0.07 to 0.09mg of β-carotene equivalent/100g of seed; from 4.3 to 7.3 and, from 1.0 to 2.8μmol of Trolox equivalent/g of seed, respectively, among the evaluated SI cultivars. Results showed significant differences (p<0.05) among the evaluated SI cultivars in the contents of ω3, ω6, antioxidant capacities and other evaluated phytochemicals. SI seeds should be considered as an important dietary source of health promoting phytochemicals. 23411221 Investigation of isotope dilution mass spectrometric (ID-MS) method to determine niacin in infant formula, breakfast cereals and multivitamins. An isotope dilution LC/mass spectrometric (ID-LC/MS) method was developed as a candidate reference method for the accurate determination of niacin in infant formula, breakfast cereals and multivitamin. After spiking nicotinamide-d(4) as an internal standard, infant formula and breakfast cereal samples were hydrolysed under alkaline condition. Samples were then analysed in SRM mode to detect nicotinic acid and nicotinic acid-d(4) at m/z 124→80 and 127→84, respectively. In the case of multivitamin sample that contains mainly free nicotinamide, LC/MS monitored nicotinamide and nicotinamide-d(4) at their SRM channels of m/z 123→80 and m/z 127→84, respectively, after simple extraction. The repeatability and reproducibility were tested for the validation of the developed ID/LC-MS method. Additionally, the developed analytical method was applied to determine total niacin contents in homogenised infant formula, homogenised multivitamin, and commercially available products including different types of infant formula, breakfast cereals, and multivitamin tablets. 23943900 Childhood Cancer Survivors' Familiarity With and Opinions of the Patient Protection and Affordable Care Act. The Patient Protection and Affordable Care Act (ACA) offers avenues to increase insurance options and access to care; however, it is unknown whether populations with pre-existing conditions, such as cancer survivors, will benefit from the expanded coverage options. We explored childhood cancer survivors' familiarity with and opinion of the ACA to understand how survivors' insurance coverage may be affected. From April to July 2012 we conducted in-depth, semistructured telephone interviews with 53 adult survivors recruited from the Utah Cancer SEER Registry. Participants were randomly selected from sex, age, and rural/urban strata and were younger than 21 years at time of diagnosis. Interviews were recorded, transcribed, and analyzed with NVivo 9 by two coders (kappa = 0.94). We report on the 49 participants who had heard of the ACA. Most survivors were unaware of ACA provisions beyond the insurance mandate. Few knew about coverage for children up to age 26 or pre-existing insurance options. Although one third believed the ACA could potentially benefit them via expanded insurance coverage, many were concerned that the ACA would lead to rising health care costs and decreasing quality of care. Survivors had concerns specific to their cancer history, including fears of future health care rationing if they developed subsequent health problems. Childhood cancer survivors have a low level of familiarity with the ACA and are unaware of how it may affect them given their cancer history. These survivors require targeted education to increase knowledge about the ACA. 23940535 Autonomic substrates of the response to pups in male prairie voles. Caregiving by nonparents (alloparenting) and fathers is a defining aspect of human social behavior, yet this phenomenon is rare among mammals. Male prairie voles (Microtus ochrogaster) spontaneously exhibit high levels of alloparental care, even in the absence of reproductive experience. In previous studies, exposure to a pup was selectively associated with increased activity in oxytocin and vasopressin neurons along with decreased plasma corticosterone. In the present study, physiological, pharmacological and neuroanatomical methods were used to explore the autonomic and behavioral consequences of exposing male prairie voles to a pup. Reproductively naïve, adult male prairie voles were implanted with radiotransmitters used for recording ECG, temperature and activity. Males responded with a sustained increase in heart-rate during pup exposure. This prolonged increase in heart rate was not explained by novelty, locomotion or thermoregulation. Although heart rate was elevated during pup exposure, respiratory sinus arrhythmia (RSA) did not differ between these males and males exposed to control stimuli indicating that vagal inhibition of the heart was maintained. Blockade of beta-adrenergic receptors with atenolol abolished the pup-induced heart rate increase, implicating sympathetic activity in the pup-induced increase in heart rate. Blockade of vagal input to the heart delayed the males' approach to the pup. Increased activity in brainstem autonomic regulatory nuclei was also observed in males exposed to pups. Together, these findings suggest that exposure to a pup activates both vagal and sympathetic systems. This unique physiological state (i.e. increased sympathetic excitation of the heart, while maintaining some vagal cardiac tone) associated with male caregiving behavior may allow males to both nurture and protect infants. 23935179 Relations of arterial stiffness and endothelial function to brain aging in the community. To determine the association of arterial stiffness and pressure pulsatility, which can damage small vessels in the brain, with vascular and Alzheimer-type brain aging. Stroke- and dementia-free Framingham Offspring Study participants (n = 1,587, 61 ± 9 years, 45% male) underwent study of tonometric arterial stiffness and endothelial function (1998-2001) and brain MRI and cognition (1999-2002). We related carotid-femoral pulse wave velocity (CFPWV), mean arterial and central pulse pressure, and endothelial function to vascular brain aging by MRI (total cerebral brain volume [TCBV], white matter hyperintensity volume, silent cerebral infarcts) and vascular and Alzheimer-type cognitive aging (Trails B minus Trails A and logical memory-delayed recall, respectively). Higher CFPWV was associated with lower TCBV, greater white matter hyperintensity volume, and greater prevalence of silent cerebral infarcts (all p < 0.05). Each SD greater CFPWV was associated with lower TCBV equivalent to 1.2 years of brain aging. Mean arterial and central pulse pressure were associated with greater white matter hyperintensity volume (p = 0.005) and lower TCBV (p = 0.02), respectively, and worse verbal memory (both p < 0.05). Associations of tonometry variables with TCBV and white matter hyperintensity volume were stronger among those aged 65 years and older vs those younger than 65 years (p < 0.10 for interaction). Brachial artery endothelial function was unrelated to MRI measures (all p > 0.05). Greater arterial stiffness and pressure pulsatility are associated with brain aging, MRI vascular insults, and memory deficits typically seen in Alzheimer dementia. Future investigations are warranted to evaluate the potential impact of prevention and treatment of unfavorable arterial hemodynamics on neurocognitive outcomes. 23410179 Sex differences in stroke case fatality: a meta-analysis. In recent years, there were great controversies about gender disparities in stroke outcome. The study was aimed to investigate sex differences in stroke case fatality on all published studies based in a comprehensive meta-analysis. A systematic search of Pubmed, EMBASE, SCOPUS, ISI Web of Science, and Cochrane Library was conducted for the included papers between 1992 and 2009. For the pooled group and subgroup analysis, fixed effects or random effects model were used to find sex differences in case fatality of stroke with a Mantel-Haenszel method. Meta-regression analysis was performed to study methodological heterogeneity. Thirty-six population-based studies, together with three randomized clinical trials (RCTs), were included in the present study. For the pooled group, there was an overall hazard risk of 1.13 for women compared with men. A hazard risk of 1.27 was observed for women in RCTs subgroup and 1.12 for women in population-based subgroup. The regression analysis found no significant correlation between methodological variables and heterogeneity. Due to the limited data about sex differences in stroke case fatality, the findings should be treated cautiously as preliminary. More large multicenter clinical trials should be performed to verify the reliability of the results. 23632324 Tendon graft revitalization using adult anterior cruciate ligament (ACL)-derived CD34+ cell sheets for ACL reconstruction. As a new strategy for enhancing recovery after anterior cruciate ligament (ACL) reconstruction, we developed a cell sheet wrapped graft using ACL-derived CD34+ cells. Our results from an ex vivo cell migration assay demonstrated gradual cell migration into the graft from the cell sheet, and an enzyme-linked immunosorbent assay indicated that the cell sheet cultures secreted a significantly greater amount of VEGF than typical monolayer cultures. In the in vivo study, the rats received one of three possible ACL reconstruction treatments; 1) a tendon graft wrapped in an ACL-derived CD34+ cell sheet, 2) a tendon graft and ACL-derived CD34+ cell injection, or 3) the control group that received just the tendon graft. The in vivo studies revealed that the ACL-derived CD34+ cell sheet wrapped grafts demonstrated a greater number of the cells derived from the cell sheets incorporated within the bone tunnel site and grafted tendon. We believe the incorporated CD34+ cells enhanced the healing of both the bone-tendon junction and the grafted tendon in the reconstructed rat ACLs by increasing proprioceptive recovery, graft maturation, and biomechanical strength. ACL-derived CD34+ cell sheet wrapped grafts could become a promising strategy to revitalize tendon autografts and recovery after ACL reconstruction resulting in superior and quicker recovery in patients requiring ACL reconstruction. 23874761 GPR56 Functions Together with α3β1 Integrin in Regulating Cerebral Cortical Development. Loss of function mutations in GPR56, which encodes a G protein-coupled receptor, cause a specific human brain malformation called bilateral frontoparietal polymicrogyria (BFPP). Studies from BFPP postmortem brain tissue and Gpr56 knockout mice have previously showed that GPR56 deletion leads to breaches in the pial basement membrane (BM) and neuronal ectopias during cerebral cortical development. Since α3β1 integrin also plays a role in pial BM assembly and maintenance, we evaluated whether it functions together with GPR56 in regulating the same developmental process. We reveal that loss of α3 integrin enhances the cortical phenotype associated with Gpr56 deletion, and that neuronal overmigration through a breached pial BM occurs earlier in double knockout than in Gpr56 single knockout mice. These observations provide compelling evidence of the synergism of GPR56 and α3β1 integrin in regulating the development of cerebral cortex. 23574424 Biological effects of functionalizing copolymer scaffolds with nanodiamond particles. Significant evidence has indicated that poly(L-lactide)-co-(ɛ-caprolactone) [(poly(LLA-co-CL)] scaffolds could be one of the suitable candidates for bone tissue engineering. Oxygen-terminated nanodiamond particles (n-DP) were combined with poly(LLA-co-CL) and revealed to be positive for cell growth. In this study, we evaluated the influence of poly(LLA-co-CL) scaffolds modified by n-DP on attachment, proliferation, differentiation of bone marrow stromal cells (BMSCs) in vitro, and on bone formation using a sheep calvarial defect model. BMSCs were seeded on either poly(LLA-co-CL)- or n-DP-coated scaffolds and incubated for 1 h. Scanning electron microscopy (SEM) and fluorescence microscopy were used in addition to protein and DNA measurements to evaluate cellular attachment on the scaffolds. To determine the effect of n-DP on proliferation of BMSCs, cell/scaffold constructs were harvested after 3 days and evaluated by Bicinchoninic Acid (BCA) protein assay and SEM. In addition, the osteogenic differentiation of cells grown for 2 weeks on the various scaffolds and in a dynamic culture condition was evaluated by real-time RT-PCR. Unmodified and modified scaffolds were implanted into the calvaria of six-year-old sheep. The expression of collagen type I (COL I) and bone morphogenetic protein-2 (BMP-2) after 4 weeks as well as the formation of new bone after 12 and 24 weeks were analyzed by immunohistochemistry and histology. Scaffolds modified with n-DP supported increased cell attachment and the mRNA expression of osteopontin (OPN), bone sialoprotein (BSP), and BMP-2 were significantly increased after 2 weeks of culture. The BMSCs had spread well on the various scaffolds investigated after 3 days in the study with no significant difference in cell proliferation. Furthermore, the in vivo data revealed more positive staining of COL I and BMP-2 in relation to the n-DP-coated scaffolds after 4 weeks and presented more bone formation after 12 and 24 weeks. n-DP modification significantly increased cell attachment and differentiation of BMSCs on poly(LLA-co-CL) scaffolds in vitro and enhanced bone formation in vivo. 23674493 PI3K pathway dependencies in endometrioid endometrial cancer cell lines. Endometrioid endometrial cancers (EEC) frequently harbor coexisting mutations in phosphoinositide 3-kinase (PI3K) pathway genes, including PTEN, PIK3CA, PIK3R1, and KRAS. We sought to define the genetic determinants of PI3K pathway inhibitor response in EEC cells, and whether PTEN-mutant EEC cell lines rely on p110β signaling for survival. Twenty-four human EEC cell lines were characterized for their mutation profile and activation state of PI3K and mitogen-activated protein kinase (MAPK) signaling pathway proteins. Cells were treated with pan-class I PI3K, p110α, and p110β isoform-specific, allosteric mTOR, mTOR kinase, dual PI3K/mTOR, mitogen-activated protein/extracellular signal-regulated kinase (MEK), and RAF inhibitors. RNA interference (RNAi) was used to assess effects of KRAS silencing in EEC cells. EEC cell lines harboring PIK3CA and PTEN mutations were selectively sensitive to the pan-class I PI3K inhibitor GDC-0941 and allosteric mTOR inhibitor temsirolimus, respectively. Subsets of EEC cells with concurrent PIK3CA and/or PTEN and KRAS mutations were sensitive to PI3K pathway inhibition, and only 2 of 6 KRAS-mutant cell lines showed response to MEK inhibition. KRAS RNAi silencing did not induce apoptosis in KRAS-mutant EEC cells. PTEN-mutant EEC cell lines were resistant to the p110β inhibitors GSK2636771 and AZD6482, and only in combination with the p110α selective inhibitor A66 was a decrease in cell viability observed. Targeted pan-PI3K and mTOR inhibition in EEC cells may be most effective in PIK3CA- and PTEN-mutant tumors, respectively, even in a subset of EECs concurrently harboring KRAS mutations. Inhibition of p110β alone may not be sufficient to sensitize PTEN-mutant EEC cells and combination with other targeted agents may be required. 23416882 Analyzing lead absorption by the sycamore tree species in the industrial park of Rasht, Iran. In this study, the subject of heavy metal concentration in soil, rock, sediment, surface water and groundwater, which can be caused by natural or man-posed pollution, was analyzed in the industrial park of Rasht. These concentrations were compared with the standard range of environmental data. Heavy metals are important environmental pollutants that can cause health hazards to humans, plants and microorganisms by entering food chain. This study aimed to investigate the absorption of lead by the leaves of sycamore tree species in the industrial park of Rasht. For this purpose, a sample of 32 sycamore tree species were randomly selected at a specified time, and the concentration of lead were measured using an atomic absorption device. Results showed that the amount of lead absorption by sycamore leaves is remarkable. The highest amount of lead absorption by sycamore leaves was detected at station 1 (Khazar Steel) and the lowest amount at station 2 (control station). 23868954 Management of Boerhaave's syndrome with an over-the-scope clip. Boerhaave's syndrome is a spontaneous barotraumatic disruption of the distal oesophagus secondary to an abrupt increase in intraoesophageal pressure during vomiting. Management ranges from a conservative approach to an oesophagectomy. The over-the-scope-clip (OTSC, Ovesco Endoscopy GmbH, Tuebingen, Germany) system is a newly designed clipping method for tissue mechanical compression in the gastrointestinal tract. We report the case of a patient referred with a delayed diagnosis of Boerhaave's syndrome and successfully treated by OTSC application followed by lung decortication. 23908493 Undisclosed antiretroviral drug use in a multi-national clinical trial (HPTN 052). The HIV Prevention Trials Network (HPTN) 052 enrolled serodiscordant couples. HIV-infected index participants reported no prior antiretroviral (ARV) treatment at enrollment. ARV drug testing was performed retrospectively using enrollment samples from a subset of index participants. ARV drugs were detected in 45/96 (46.9%) participants with undetectable viral load (VL), 2/48 (4.2%) participants with low VL, and 1/65 (1.5%) participants with high VL (P<0.0001). ARV drugs were also detected in follow-up samples from participants who were not on study-administered treatment. ARV drug testing may be useful in addition to self-report of ARV drug use in some clinical trial settings. 23868019 Development, validation and clinical evaluation of a dried urine spot method for determination of hippuric acid and creatinine. The purpose of this study was to develop and validate a HPLC-DAD method for determination of creatinine and hippuric acid in dried urine spots (DUS), evaluating its clinical applicability. Sample preparation was based on a simple one step extraction with water. Analysis was performed in a reversed phase column Hypersil Gold® C18 (150×4.6mm, 3μm) with isocratic elution. Mobile phase was a mixture of triethylammonium phosphate buffer 5mM, pH3.3 and acetonitrile (90:10, v/v). Total analytical run time was 6min. Precision assays presented CV% lower than 11.8%. Accuracy was 96.0-103%. The lower limit of quantitation was 50mgL(-1). Mean extraction yields were 99% for CR and 79.3% for HA. Analytes were stable in DUS up to 11days at 40°C. The method was tested in 49 paired DUS and urine samples, with acceptable agreement. HA-CR concentration ratios in DUS were in the range of 0.06 to 2.74, being in average 100.7% from those values found in urine. DUS samples are a useful alternative for biological monitoring of toluene occupational exposure, especially in Developing Countries where sample logistics could be an important concern. 23871508 Does chronic warfarin cause increased blood loss and transfusion during lumbar spinal surgery? The use of oral anticoagulation therapy such as warfarin is projected to increase significantly as the population ages and the prevalence of cardiovascular disease increases. Current recommendations state that warfarin be discontinued before surgery and the international normalized ratio (INR) normalized. To determine if stopping warfarin 7 days before surgery and correcting INR had any effect on intraoperative blood loss or the requirements for blood product transfusion. This was a retrospective cohort study in a high-volume tertiary care center. Sample comprised 263 consecutive patients who underwent elective lumbar spinal surgery. The outcome measures were intraoperative blood loss, intraoperative blood transfusion, postoperative blood transfusion, and the number of blood products transfused. The records of patients undergoing elective spinal surgery were analyzed for patient demographic data, comorbidities, coagulation panel laboratory findings, operative characteristics, blood loss, and blood transfusion requirements. These included patients undergoing full laminectomies with or without posterolateral fusion and instrumentation. Patients on warfarin were analyzed for the mean dosage of warfarin and underlying pathology that required anticoagulation. All patients on warfarin had their anticoagulation therapy stopped 7 days before surgery and their INR checked preoperatively to confirm normalization. Both univariate and multiple linear regression analyses were performed. The patients on warfarin had a mean intraoperative blood loss of 839 mL compared with 441 mL for patients not on warfarin (p<.01). Multiple regression analysis determined that warfarin and number of spinal levels decompressed/fused/instrumented were predictors for increased blood loss (R(2)=0.37). Patients on warfarin also had increased postoperative blood transfusions (23.1% compared with 7.4%, p=.04). There was no significant difference between groups in terms of intraoperative blood transfusion or number of units transfused. Patients on chronic anticoagulation therapy with warfarin who have their therapy stopped 7 days before surgery and have their INR normalized still demonstrated increased intraoperative blood loss and requirement for postoperative transfusion. Surgeons should be aware of the increased propensity of these patients to bleed despite adherence to protocols and should attempt to mitigate this risk. 23847482 Flying fruit flies correct for visual sideslip depending on relative speed of forward optic flow. As a fly flies through its environment, static objects produce moving images on its retina, and this optic flow is essential for steering and course corrections. Different types of rotation and translation produce unique flow fields, which fly brains are wired to identify. However, a feature of optic flow unique to translational motion is that adjacent images may move across the retina at different speeds, depending on their distance from the observer. Many insects take advantage of this depth cue, called motion parallax, to determine the distance to objects. We wanted to know if differential object speeds affect the corrective responses of fruit flies when they experience unplanned course deviations. We presented tethered flying flies with optic flow and measured their corrective responses to sideways perturbations of images with different relative forward speeds. We found that flying flies attend to the relative speed of dots during forward motion, and adjust their corrective responses to sideslip deviations depending on this cue. With no other distinguishing features (such as brightness or size), flies mounted a greater response to sideways deviations that were signaled by faster moving dots in the forward flow field, those that appeared radially closer by their speeds. This is consistent with the interpretation that fruit flies attend to seemingly nearer objects, and correct more strongly when they indicate a perturbation. 23918206 Topical secretoneurin gene therapy accelerates diabetic wound healing by interaction between heparan-sulfate proteoglycans and basic FGF. Diabetic foot ulcers represent a therapeutic problem of high clinical relevance. Reduced vascular supply, neuropathy and diminished expression of growth factors strongly contribute to wound healing impairment in diabetes. Secretoneurin, an angiogenic neuropeptide, has been shown to improve tissue perfusion in different animal models by increasing the amount of vessels in affected areas. Therefore, topical secretoneurin gene therapy was tested in a full thickness wound healing model in diabetic db/db mice. Secretoneurin significantly accelerated wound closure in these mice and immunohistochemistry revealed higher capillary and arteriole density in the wounded area compared to control mice. In-vitro, the mechanism of action of secretoneurin on human dermal microvascular endothelial cells was evaluated in normal and diabetic cells. Secretoneurin shows positive effects on in vitro angiogenesis, proliferation and apoptosis of these cells in a basic fibroblast growth factor dependent manner. A small molecular weight inhibitor revealed fibroblast growth factor receptor 3 as the main receptor for secretoneurin mediated effects. Additionally, we could identify heparan-sulfates as important co-factor of secretoneurin induced binding of basic fibroblast growth factor to human dermal endothelial cells. We suggest topical secretoneurin plasmid therapy as new tool for delayed wound healing in patients suffering from diabetes. 23697546 Forecasting the future of stroke in the United States: a policy statement from the american heart association and american stroke association. Stroke is a leading cause of disability, cognitive impairment, and death in the United States and accounts for 1.7% of national health expenditures. Because the population is aging and the risk of stroke more than doubles for each successive decade after the age of 55 years, these costs are anticipated to rise dramatically. The objective of this report was to project future annual costs of care for stroke from 2012 to 2030 and discuss potential cost reduction strategies. The American Heart Association/American Stroke Association developed methodology to project the future costs of stroke-related care. Estimates excluded costs associated with other cardiovascular diseases (hypertension, coronary heart disease, and congestive heart failure). By 2030, 3.88% of the US population >18 years of age is projected to have had a stroke. Between 2012 and 2030, real (2010$) total direct annual stroke-related medical costs are expected to increase from $71.55 billion to $183.13 billion. Real indirect annual costs (attributable to lost productivity) are projected to rise from $33.65 billion to $56.54 billion over the same period. Overall, total annual costs of stroke are projected to increase to $240.67 billion by 2030, an increase of 129%. These projections suggest that the annual costs of stroke will increase substantially over the next 2 decades. Greater emphasis on implementing effective preventive, acute care, and rehabilitative services will have both medical and societal benefits. (Stroke. 2013;44:2361-2375.). 23897173 The current state of pancreas transplantation. For many patients with type 1 diabetes mellitus and selected patients with type 2 diabetes mellitus, a successful pancreas transplant is the only definitive long-term treatment that both restores euglycaemia without the risk of severe hypoglycaemia and prevents, halts or reverses secondary complications. These benefits come at the cost of major surgery and lifelong immunosuppression. Nevertheless, pancreas transplants are safe and effective, with patient survival rates currently >95% at 1 year and >88% at 5 years; graft survival rates are almost 85% at 1 year and >60% at 5 years. The estimated half-life of a pancreas graft is now 7-14 years. The improvements in graft survival are attributable to considerable reductions in technical failures and in immunologic graft losses. Pancreas recipients have reduced mortality compared with waiting candidates or patients with diabetes mellitus who undergo a kidney transplant alone. Pancreas transplants should be more frequently offered to nonuraemic patients with brittle diabetes mellitus to prevent the development of secondary diabetic complications and to avoid the need for a kidney transplant. Although the results of islet transplantation have also improved, islet recipients rarely maintain long-term insulin independence despite the use of multiple organ donor pancreases. Pancreas transplants and islet transplants should be considered complementary, not mutually exclusive, procedures that are chosen on the basis of the individual patient's surgical risk. 23968852 Brain-targeting delivery for RNAi neuroprotection against cerebral ischemia reperfusion injury. Nanoparticles (NPs) with modification of brain-targeting molecules have been extensively exploited for therapeutic gene delivery across the blood-brain barrier (BBB). As one of the effective RNA interference (RNAi) approaches, short hairpin RNA (shRNA) has been proved to be promising in the field of gene therapy. Apoptosis signal-regulating kinase 1 (Ask1) has been reported to be an important target for gene therapy against cerebral ischemia reperfusion injury. In this study, dendrigraft poly-l-lysine (DGL) was decorated by dermorphin (a μ-opiate receptor agonist) through PEG for efficient brain-targeting, then complexed with anti-Ask1 shRNA plasmid DNA, yielding the DGL-PEG-dermorphin/shRNA NPs. The DGL-PEG-dermorphin/shRNA NPs were characterized and estimated the brain-targeting ability. In vitro, increased cellular uptake and transfection efficiency were explored; in vivo, preferable accumulation and gene transfection in brain were showed in images. The DGL-PEG-dermorphin/shRNA NPs also revealed high efficiency of neuroprotection. As a result of RNAi, corresponding mRNA was distinctly degraded, expression of Ask1 protein was obviously suppressed, apoptotic cell death was apparently decreased and cerebral infarct area was significantly reduced. Above all, DGL-PEG-dermorphin/shRNA NPs were proved to be efficient and safe for brain-targeting RNAi neuroprotection against cerebral ischemia reperfusion injury. 23660681 Motor and perceptual sequence learning: different time course of parallel processes. The aim was to determine the extent and time course of motor and perceptual learning in a procedural learning task, and the relation of these two processes. Because environmental constraints modulate the relative impact of different learning mechanisms, we chose a simple learning task similar to real-life exercise. Thirty-four healthy individuals performed a visuomotor serial reaction time task. Learning blocks with high stimulus-response compatibility were practiced repeatedly; in between these, participants performed test blocks with the same or a different (mirror-inverted, or new) stimulus sequence and/or with the same or a different (mirror-inverted) stimulus-response allocation. This design allowed us to measure the progress of motor learning and perceptual learning independently. Results showed that in the learning blocks, a steady reduction of the reaction times indicated that - as expected - participants improved their skills continuously. Analysis of the test blocks indicated that both motor learning and perceptual learning were significant. The two mechanisms were correlated (r=0.62, P<0.001). However, their time course was different: the impact of motor learning increased strongly from earlier to later intervals, whereas the progress of perceptual learning was more stable but slower. In conclusion, in a simple visuomotor learning task, participants can learn the motor sequence and the stimulus sequence in parallel. The positive correlation of motor and perceptual learning suggests that the two mechanisms act in synergy and are not alternative opposing strategies. The impact of these two learning mechanisms changes over time: motor learning sets in later and becomes relevant only in the course of training. 22886720 Fibroblast growth factor 23 inhibits extrarenal synthesis of 1,25-dihydroxyvitamin D in human monocytes. Vitamin D is a potent stimulator of monocyte innate immunity, and this effect is mediated via intracrine conversion of 25-hydroxyvitamin D (25OHD) to 1,25-dihydroxyvitamin D (1,25(OH)(2) D). In the kidney, synthesis of 1,25(OH)(2) D is suppressed by fibroblast growth factor 23 (FGF23), via transcriptional suppression of the vitamin D-activating enzyme 1α-hydroxylase (CYP27B1). We hypothesized that FGF23 also suppresses CYP27B1 in monocytes, with concomitant effects on intracrine responses to 1,25(OH)(2) D. Healthy donor peripheral blood mononuclear cell monocytes (PBMCm) and peritoneal dialysate monocyte (PDm) effluent from kidney disease patients were assessed at baseline to confirm the presence of mRNA for FGF23 receptors (FGFRs), with Klotho and FGFR1 being more strongly expressed than FGFR2/3/4 in both cell types. Immunohistochemistry showed coexpression of Klotho and FGFR1 in PBMCm and PDm, with this effect being enhanced following treatment with FGF23 in PBMCm but not PDm. Treatment with FGF23 activated mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) pathways in PBMCm, demonstrating functional FGFR signaling in these cells. FGF23 treatment of PBMCm and PDm decreased expression of mRNA for CYP27B1. In PBMCm this was associated with downregulation of 25OHD to 1,25(OH)(2) D metabolism, and concomitant suppression of intracrine induced 24-hydroxylase (CYP24A1) and antibacterial cathelicidin (LL37). FGF23 suppression of CYP27B1 was particularly pronounced in PBMCm treated with interleukin-15 to stimulate synthesis of 1,25(OH)(2) D. These data indicate that FGF23 can inhibit extra-renal expression of CYP27B1 and subsequent intracrine responses to 1,25(OH)(2) D in two different human monocyte models. Elevated expression of FGF23 may therefore play a crucial role in defining immune responses to vitamin D and this, in turn, may be a key determinant of infection in patients with chronic kidney disease (CKD). 23460363 Buffer-Stable Chitosan-Polyglutamic Acid Hybrid Nanoparticles for Biomedical Applications. In spite of their attractive features, widespread biomedical applications of CS nanoparticles are yet to be realized due to their poor stability in physiological conditions, such as in buffer system at pH 7.4. Buffer-stable chitosan-based hybrid NPs (HNPs) are reported and characterized. Buffer stability is achieved by introducing polyglutamic acid to chitosan. The effect of PGA to CS molar ratio and crosslinking on HNP integrity, buffer stability, and biodegradability are studied. Preliminary in vitro studies are carried out to evaluate targeted uptake efficiency of folate conjugated HNPs. Successful demonstration of buffer stability and cancer cell targeting by HNPs achieves important milestones for chitosan-based nanoparticle technology. 23930806 Blood flow vectoring control in aortic arch using full and partial clamps. Early diagnosis and treatment of aneurysm plays an important role in reducing the mortality risk of rupture. The aneurysm is a complex phenomenon and caused by different reasons, such as arteriosclerosis and heredity. In addition, pressure and Wall Shear Stress are two known factors influencing the establishment of an aneurysm. The aim of this study is to investigate the effect of using a full or partial clamp to control the blood flow streamlines and hence the location of stress concentration in a clean configuration of aorta. The main question is how to control the stresses distribution in order to reduce the possibility of aneurysm growth with less negative effects on the other sides. A simple form of aortic arch with three branches is considered to simulate the effect of changing blood flow streamlines directions. A parameter study has been performed on the main characteristics of clamp, i.e. size, location, and the percentage of coverage. The Shear Stress Transport model is employed to simulate steady-state Newtonian blood flow when the Reynolds number is about 6500. Simulations are conducted using the commercial CFD solver ANSYS Fluent. The obtained results show that the location of clamp is more effective than the size. It is also found that increasing the depth of clamp has a negative impact on mean velocity field and hence on stress concentration. The present results demonstrate that the Blood Flow Vectoring Control (BFVC) can change the main form of flow streamlines and consequently the distributions of pressure and Wall Shear Stress. A partial clamp leads to better results. 23406264 Combining whole-brain voxel-wise analysis with in vivo tractography of diffusion behavior after sports-related concussion in adolescents: a preliminary report. Abstract We have previously shown that sports-related concussion in adolescents is associated with changes in whole-brain properties of white-matter pathways. Here, we assess local changes within these pathways. Twelve adolescents with a clinical diagnosis of subacute concussion and 10 healthy adolescents matched for age, gender, and physical activity completed magnetic resonance imaging scanning. Voxel-wise tract-based spatial statistics and tractography were performed to assess local changes in diffusion-based measures of microstructural properties of white-matter pathways (fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity) between the two groups. Fractional anisotropy values were higher for the concussed group in multiple cluster regions using tract-based spatial statistics, primarily in frontal white-matter regions, including the anterior corona radiata bilaterally. Using these regions of altered diffusion characteristics to seed fiber tractography, significantly reduced axial diffusivity in tracts passing through these areas were detected in the concussed group (p=0.04). A trend toward reduced mean and radial diffusivity in the concussed group was also observed within the same reconstructed tracts. Diffusion behavior within these tracts was significantly correlated with an assessment of concussion status (Sports Concussion Assessment Tool 2). Fractional anisotropy within the reconstructed tracts was not significantly different between the two groups. These results suggest that subacute concussion in adolescents is associated with altered diffusion properties within regional white-matter tissue and along reconstructed fiber pathways. Combining voxel-wise analysis with fiber tractography provides an alternative objective approach to evaluate and identify subtle changes in white-matter fiber integrity after concussion. 23714175 Oral Angiotensin-(1-7) prevented obesity and hepatic inflammation by inhibition of resistin/TLR4/MAPK/NF-κB in rats fed with high-fat diet. Obesity is characterized by a pro-inflammatory state commonly associated with type 2 diabetes and fat-liver disease. In the last few years, different studies pointed out the role of Angiotensin (Ang)-(1-7) in the metabolic regulation. The aim of the present study was to evaluate the effect of oral-administration of Ang-(1-7) in metabolism and inflammatory state of high-fat feed rats. Twenty-four male Sprague Dawley rats were randomized into three groups: High Fat Diet (HFD); Standard Diet (ST); High Fat Diet+Angiotensin-(1-7) [HFD+Ang-(1-7)]. Glycemic profile was evaluated by glucose tolerance and insulin sensitivity tests, plasmatic glucose and insulin. Cholesterol, HDL and triglycerides analyses presented lipidic profile. RT-PCR evaluated mRNA expression to ACE, ACE2, resistin, TLR4, IL-6, TNF-α and NF-κB genes. The main results showed that oral Ang-(1-7) decreased body weight and abdominal fat-mass. In addition, HFD+Ang-(1-7) treated rats presented enhanced glucose tolerance, insulin-sensitivity and decreased plasma-insulin levels, as well as a significant decrease in circulating lipid levels. These alterations were accompanied by a marked decreased expression of resistin, TLR4, ACE and increased ACE2 expression in liver. Furthermore, Ang-(1-7) decreases phosphorylation of MAPK and increases NF-κB expression. These alterations diminished expression of interleukin-6 and TNF-α, ameliorate inflammatory state in liver. In summary, the present study showed that oral-treatment with Ang-(1-7) in high-fat feed rats improved metabolism down-regulating resistin/TLR4/NF-κB-pathway. 23931585 Occult hepatitis B infections among blood donors in Lao PDR. In Lao People's Democratic Republic, hepatitis B virus is highly endemic. However, blood donations are only screened for HBsAg, leaving a risk of transmission by HBsAg-negative occult infected donors. Here, we characterized first-time blood donors to assess prevalence of hepatitis B virus infections and occult infected donors. Sera were screened for HBsAg, HBeAg and anti-HBs, anti-HBc and anti-HBe antibodies. Occult HBV infections (OBIs) were assessed in HBsAg-negative sera by PCR, and sera of HBsAg positive and occult infected donors were phylogenetically characterized. 9·6% of the donors were HBsAg positive, and 45.5% were positive for at least one of the hepatitis B virus serum markers. More than 40% HBsAg carriers were HBeAg positive, with HBeAg seroconversion occurring around 30 years of age. Furthermore, 10·9% of HBsAg-negative, anti-HBc and/or anti-HBs-positive donors were occult infected with hepatitis B virus. Thus, at least 3·9% of blood donations would potentially be unsafe, but hepatitis B virus DNA copy numbers greatly varied between donors. In Lao People's Democratic Republic, a sizable proportion of HBsAg-negative and anti-HBc antibody-positive blood donations are potentially DNA positive and infective for hepatitis B. 23618717 A French cohort of childhood leukemia survivors: impact of hematopoietic stem cell transplantation on health status and quality of life. The late effects and quality of life (QoL) in childhood acute leukemia survivors were compared between hematopoietic stem cell transplantation (HSCT) recipients and patients who underwent conventional therapy. The study included 943 patients, 256 of whom underwent HSCT (27.1%). Medical visits were conducted to detect the occurrence of physical late effects. Based on patient age, different questionnaires were used to assess QoL. To evaluate the association between HSCT and each type of late effect or QoL dimension, the appropriate multivariate regressions were performed. QoL mean scores were compared with those obtained for age- and sex-matched French control subjects. Of all the survivors, 674 (71.5%) had at least 1 late effect, with the risk being 5.0 CI95 (3.0-8.6) times higher for transplantation survivors. For child survivors, scoring of QoL showed no significant differences between the treatment groups. The adult HSCT survivors reported lower physical dimension QoL scores than chemotherapy survivors. Compared with French norms, the survivor group reported a significantly lower mental composite score; however, the physical composite score showed no significant difference. Thus, transplanted survivors have a high risk of developing late effects, resulting in a decreased physical well-being in adulthood. However, long after treatment completion, childhood leukemia survivors report that effects on psychological well-being are more important than they are in physical QoL dimensions. 23903294 Exercise-induced exaggerated blood pressure response in men with the metabolic syndrome: the role of the autonomous nervous system. Abnormalities in the autonomic nervous system in the presence of insulin resistance may be involved in the pathophysiology of obesity-associated hypertension. We evaluated the association between exercise-induced exaggerated blood pressure (BP) response [exercise-induced hypertension (EIH)] and heart rate variability (HRV) and insulin resistance in men with metabolic syndrome (MetS). Ninety-eight resting normotensive men with MetS underwent a maximal symptom-limited treadmill test. BP was measured after a 5-min rest (anticipatory BP) every 3 min during exercise and during the recovery period. EIH was defined as maximum systolic BP of 220 mmHg or higher and/or maximum diastolic BP of 100 mmHg or higher. Insulin resistance was estimated using HOMA-IR. Each participant underwent a 3-h oral glucose tolerance test (OGTT). HRV was derived from a 24-h Holter. About half of the participants (52%) presented EIH. Resting BPs at baseline were 125±10/83±7 mmHg in participants with EIH and 120±9/80±6 mmHg (P=0.01) in the group with normal BP response to exercise. OGTT glucose levels were higher in the group with EIH (all P<0.04) as well as HOMA-IR compared with participants with normal BP response to exercise (P=0.03). In terms of HRV, 24-h standard deviation of the RR intervals (SDNN) was lower in participants with EIH (P=0.04) as well as 24-h daytime and night-time high frequency and low frequency (P<0.05). Normotensive men with MetS but with EIH have greater insulin resistance as well as lower HRV parasympathetic and sympathetic indices. These features may be involved in the pathophysiology of EIH. 23792134 Different adaptation of the motor activity rhythm to chronic phase shifts between adolescent and adult rats. Chronic phase shifts is a common feature in modern societies, which may induce sleep alterations and other health problems. The effects of phase shift on the circadian rhythms have been described to be more pronounced in old than in young animals. However, few works address the effects of chronic phase shifts during adolescence. Here we tested the development of the motor activity circadian rhythm of young rats under chronic phase shifts, which consisted on 6-h advances (A), 6h delays (D) or 6h advances and delays alternated every 5 days (AD) during the first 60 days after weaning. Moreover, the rhythmic pattern was compared to that of adult rats under the same lighting conditions. Results indicate that adolescent rats, independently on the lighting environment, developed a clear circadian rhythm, whose amplitude increased the first 50 days after weaning and showed a more stable circadian rhythm than adults under the same lighting conditions. In the case of A and AD groups, circadian disruption was observed only in adult rats. In all groups, the offset of activity correlated with light pattern better than the onset, and this correlation was always higher in the case of the rhythm of the pubertal rats. When AD groups were transferred to constant darkness, the group submitted to this condition during adolescence showed shorter period than that submitted in their adulthood. In conclusion, differently from adult rats, adolescent rats submitted to chronic phase shifts did not show circadian disruption and developed a single circadian rhythm, suggesting permanent changes in the circadian system. 23825226 An obesogenic diet during mouse pregnancy modifies maternal nutrient partitioning and the fetal growth trajectory. In developed societies, high-sugar and high-fat (HSHF) diets are now the norm and are increasing the rates of maternal obesity during pregnancy. In pregnant rodents, these diets lead to cardiovascular and metabolic dysfunction in their adult offspring, but the intrauterine mechanisms involved remain unknown. This study shows that, relative to standard chow, HSHF feeding throughout mouse pregnancy increases maternal adiposity (+30%, P<0.05) and reduces fetoplacental growth at d 16 (-10%, P<0.001). At d 19, however, HSHF diet group pup weight had normalized, despite the HSHF diet group placenta remaining small and morphologically compromised. This altered fetal growth trajectory was associated with enhanced placental glucose and amino acid transfer (+35%, P<0.001) and expression of their transporters (+40%, P<0.024). HSHF feeding also up-regulated placental expression of fatty acid transporter protein, metabolic signaling pathways (phosphoinositol 3-kinase and mitogen-activated protein kinase), and several growth regulatory imprinted genes (Igf2, Dlk1, Snrpn, Grb10, and H19) independently of changes in DNA methylation. Obesogenic diets during pregnancy, therefore, alter maternal nutrient partitioning, partly through changes in the placental phenotype, which helps to meet fetal nutrient demands for growth near term. However, by altering provision of specific nutrients, dietary-induced placental adaptations have important roles in programming development with health implications for the offspring in later life.-Sferruzzi-Perri, A. N., Vaughan, O. R., Haro, M., Cooper, W. N., Musial, B., Charalambous, M., Pestana, D., Ayyar, S., Ferguson-Smith, A. C., Burton, G. J., Constancia, M., Fowden, A. L. An obesogenic diet during mouse pregnancy modifies maternal nutrient partitioning and the fetal growth trajectory. 23376022 Influence of GluN2 subunit identity on NMDA receptor function. N-methyl-d-aspartate receptors (NMDARs) are ligand-gated ion channels ('ionotropic' receptors) activated by the major excitatory neurotransmitter, l-glutamate. While the term 'the NMDAR' is often used it obscures the fact that this class of receptor contains within it members whose properties are as different as they are similar. This heterogeneity was evident from early electrophysiological, pharmacological and biochemical assessments of the functional properties of NMDARs and while the molecular basis of this heterogeneity has taken many years to elucidate, it indicated from the outset that the diversity of NMDAR phenotypes could allow this receptor family to subserve a variety of functions in the mammalian central nervous system. In this review we highlight some recent studies that have identified structural elements within GluN2 subunits that contribute to the heterogeneous biophysical properties of NMDARs, consider why some recently described novel pharmacological tools may permit better identification of native NMDAR subtypes, examine the evidence that NMDAR subtypes differentially contribute to the induction of long-term potentiation and long-term depression and discuss how through the use of chimeric proteins additional insights have been obtained that account for NMDAR subtype-dependency of physiological and pathophysiological signalling. This article is part of a Special Issue entitled 'GluR-dep synaptic plasticity'. 23890832 Prevalence of Modifiable Surgical Site Infection Risk Factors in Hip and Knee Joint Arthroplasty Patients at an Urban Academic Hospital. Surgical site infections after hip and knee arthroplasty can be devastating if they lead to periprosthetic joint infection. We examined the prevalence of the modifiable risk factors for surgical site infection described by the American Academy of Orthopaedic Surgery Patient Safety Committee. Our study of 300 cases revealed that only 20% of all cases and 7% of revision cases for infection had no modifiable risk factors. The most common risk factors were obesity (46%), anemia (29%), malnutrition (26%), and diabetes (20%). Cases with obesity or diabetes were associated with all histories of remote orthopedic infection, 89% of urinary tract infections, and 72% of anemia cases. The high prevalence of several modifiable risk factors demonstrates that there are multiple opportunities for perioperative optimization of such comorbidities. 23549282 Isolation and Structure Elucidation of Three New Dolastanes from the Brown Alga Dilophus spiralis. Three new dolastane diterpenes (1-3) and five previously reported perhydroazulenes were isolated from the organic extracts of the brown alga Dilophus spiralis. The structure elucidation and the assignment of the relative configurations of the isolated natural products were based on extensive analyses of their spectroscopic data, whereas the absolute configuration of metabolite 2 was determined through its chemical conversion to a previously isolated compound of known configuration. 23820981 The Consequences of Long-Term Glycogen Synthase Kinase-3 Inhibition on Normal and Insulin Resistant Rat Hearts. Glycogen synthase kinase-3 (GSK-3) is a serine-threonine protein kinase, discovered as a regulator of glycogen synthase. GSK-3 may regulate the expression of SERCA-2a potentially affecting myocardial contractility. It is known to phosphorylate and inhibit IRS-1, thus disrupting insulin signalling. This study aimed to determine whether myocardial GSK-3 protein and its substrate proteins are dysregulated in obesity and insulin resistance, and whether chronic GSK-3 inhibition can prevent or reverse this. Weight matched male Wistar rats were rendered obese by hyperphagia using a special diet (DIO) for 16 weeks and compared to chow fed controls. Half of each group was treated with the GSK-3 inhibitor CHIR118637 (30 mg/kg/day) from week 12 to16 of the diet period. Biometric and biochemical parameters were measured and protein expression determined by Western blotting and specific antibodies. Ca(2+)ATPase activity was determined spectrophotometrically. Cardiomyocytes were prepared by collagenase perfusion and insulin stimulated 2-deoxy-glucose uptake determined. DIO rats were significantly heavier than controls, associated with increased intra-peritoneal fat and insulin resistance. GSK-3 inhibition did not affect weight but improved insulin resistance, also on cellular level. It had no effect on GSK-3 expression but elevated its phospho/total ratio and elevated IRS-2 expression. Obesity lowered SERCA-2a expression and activity while GSK-3 inhibition alleviated this. The phospho/total ratio of phospholamban underscored inhibition of SERCA-2a in obesity. In addition, signs of myocardial hypertrophy were observed in treated control rats. GSK-3 inhibition could not reverse all the detrimental effects of obesity but may be harmful in normal rat hearts. It regulates IRS-2, SERCA-2a and phospholamban expression but not IRS-1. 23164673 The glycogen synthase kinase-3β/nuclear factor-kappa B pathway is involved in cinobufagin-induced apoptosis in cultured osteosarcoma cells. Cinobufagin, a major component of cinobufacini (huachansu), is an important cardenolidal steroid. Several studies have suggested that cinobufagin has potent anti-cancer effects. The present study examines the apoptosis-inducing activity and the underlying mechanism of action of cinobufagin in osteosarcoma (OS) cells. Our results showed that cinobufagin potently inhibited the proliferation of U2OS, MG63 and SaOS-2 cells. Significant increases in G2/M cell-cycle arrest and apoptosis in OS cells were also observed. The expression levels of several apoptotic proteins were assessed after cinobufagin treatment in U2OS cells. Among them, xIAP, cIAP-1, survivin and Bcl-2 levels decreased remarkably, while the levels of Bax and cleaved-PARP increased. Furthermore, we validated the inhibition of GSK-3β/NF-κB signaling following cinobufagin treatment. Western blots showed a decrease in nuclear p65 protein expression after exposure to different concentrations of cinobufagin, while the phosphorylation of GSK-3β was simultaneously increased. Transduction with constitutively active forms of GSK-3β could protect against the downregulation of p65 and upregulation of cleaved-PARP that are induced by cinobufagin treatment. However, combined treatment with cinobufagin and SB216367 resulted in a significant reduction in p65 and an increase in cleaved-PARP in U2OS cells. Altogether, these results show that cinobufagin is a promising agent for the treatment of OS. These studies are the first to reveal the involvement of the GSK-3β/NF-κB pathway in cinobufagin-induced apoptosis. 23683508 Comparative analysis of the chloroplast proteomes of a wheat (Triticum aestivum L.) single seed descent line and its parents. To understand the photosynthetic basis in a single seed descent line 10 (SSDL10) of wheat contained high ATP in leaves, the chloroplast proteome was compared to SSDL10 and its parents using a combination of 2-DE and MALDI-TOF MS and MS/MS. More than 300 protein spots could be reproducibly detected in the 2D gel. 18 spots were differentially expressed between SSDL10 and the parents, 16 of which were identified by MS with the localization in chloroplasts. These proteins are grouped into diverse functional categories, including Calvin cycle and electron transport in photosynthesis, redox homeostasis, metabolism, and regulation. In addition to Rubisco large subunit, the content of photosynthetic electron transfers such as chlorophyll a-b binding protein, ATP synthase δ subunit, ferredoxin-NADP(+) oxidoreductase (FNR) was higher in SSDL10 than in its parents. Furthermore, cyclic electron transfer around photosystem I (CET) was faster in SSDL10 than in the parents. Analysis of NADPH-NBT oxidoreductase activity combined with immuno-detection further revealed that, the activity of two high molecular mass protein complexes containing FNR probably involved, the CET appeared higher in SSDL10 than in the parents. The possible mechanism for the regulative role of CET in photosynthesis in SSDL10 is discussed. 23958468 From antibody to clinical phenotype, the black box of the antiphospholipid syndrome: Pathogenic mechanisms of the antiphospholipid syndrome. The antiphospholipid syndrome (APS) is diagnosed by the combination of vascular thrombosis and/or pregnancy morbidity and the detection of antiphospholipid antibodies (aPLs) in plasma. In the last few years, a great effort has been made to unravel the mechanism by which aPLs cause thrombosis and a vast amount of mechanisms have been proposed. aPLs were proposed to induce a prothrombotic state by influencing the cellular blood compartment, the plasma compartment, the vascular wall and even metabolic pathways beyond the hemostatic system. However, due to the diversity in the mechanisms and the differences in the methodology, the focus of the mechanistical studies in this field seems to be largely diffused. It is hard to imagine that aPLs can exert such a diversity of effects, resulting in either thrombosis and/or pregnancy morbidity and the relationship between aPLs and the clinical manifestations remains to be a mysterious "black box". In an attempt to get insight in what takes place inside the black box, we have analyzed 126 mechanistical studies on aPLs and discussed differences in the type of antibodies that were used, the involvement of beta2-glycoprotein I (β2GPI), and the criteria used to diagnose APS patients. 23763963 Longitudinal predictors of stopping smoking in young adulthood. This study aims to describe the longitudinal individual and environmental predictors of stopping smoking among a group of young adult smokers. From a longitudinal population-based cohort of Midwestern youth, we analyzed semi-annual surveys when study participants were between the ages of 18 and 21 years. Using data from 2001-2008, we restricted analyses to individuals who, at age 18 years, reported smoking between 1 and 30 days in the previous month (n = 1,022). We used generalized linear mixed modeling to analyze demographic, attitudinal, and social-environmental predictors of stopping smoking over time. After adjusting for smoking frequency at baseline, demographic and attitudinal factors that were associated with stopping smoking over time included increased age and attending college; male gender, smoking frequency and agreeing that cigarettes are calming were significantly associated with continued smoking. Social-environmental factors associated with stopping smoking over time included a household ban on smoking and living in a state with a clean indoor air policy; factors associated with continued smoking included living with a smoker and having close friends who smoke. Both individual and social-environmental factors can serve as risk and protective factors for stopping smoking between ages 18 and 21 years. These factors should be used to refine more effective smoking cessation and prevention interventions in young adults. 23845523 Does Age Affect Analgesia Provision at Discharge among Children with Long Bone Fractures Requiring Emergency Care? Inadequate treatment of painful conditions in children is a significant and complex problem. The wide range of cognitive abilities associated with a child's age is a particular challenge for providers treating children with painful conditions. To examine the effect of patient age on the provision of analgesic medicines at discharge in children treated emergently for a long bone fracture. A retrospective review was performed of all patients during a 1-year period with a long bone fracture treated in two urban pediatric Emergency Departments (EDs). Eight hundred seventy-eight patients were identified who met our inclusion criteria. Nearly 60% of patients received a prescription for an opioid-containing medicine and 19% received a prescription for an over-the-counter analgesic medicine at ED discharge. Patients younger than 4 years old had lower pain scores, less severe fractures, and overall were significantly less likely to receive an opioid-containing prescription compared to children 4 years old or greater. In children with more severe fractures requiring reduction in the ED, no significant age-related differences were noted in opioid prescription rates. No age-related significant differences were noted for over-the-counter prescription analgesic medicines provided at discharge. Young patient age is associated with different analgesic prescription patterns in children treated in the ED for a long bone fracture. 22818387 Efficacy and Limitations of Multimodal Endovascular Revascularization Other Than Clot Retrieval for Acute Stroke Caused by Large-vessel Occlusion. The purpose of this study was to evaluate the efficacy of multimodal endovascular treatment (EVT) other than clot retrieval for acute large-vessel occlusion (LVO). Fifty-six consecutive patients with a median National Institutes of Health Stroke Scale (NIHSS) score of 15 were included this study. In all cases, intravenous administration of recombinant tissue plasminogen activator had failed (n = 23) or was contraindicated (n = 33). The modes of EVT performed included intra-arterial thrombolysis, mechanical clot disruption including balloon angioplasty, and stent placement. We retrospectively analyzed the treatment efficacy of these techniques and patient outcome. Successful reperfusion (Thrombolysis in Cerebral Infarction grade 2B or 3) was achieved in 40 of 56 patients (71.4%), and 26 of 56 patients (46.4%) had a favorable clinical outcome (modified Rankin Scale [mRS] score 0 to 2 at 90 days). Successful reperfusion (odds ratio [OR] 163; P = .003), age (OR 0.83; P = .007), and baseline NIHSS score (OR 0.71; P = .009) were independently associated with favorable clinical outcome by multivariate analysis. Successful reperfusion rates of internal carotid terminus or M1 proximal occlusions were significantly lower than those of other vessel occlusion (47.6% v 85.7%; P = .005). Clinically significant procedure-related complications occurred in 1.8% (1/56), and symptomatic intracerebral hemorrhage (sICH) within 48 hours after EVT was observed in 5.4% (3/56) of patients. Multimodal EVT for acute LVO yields a high reperfusion rate with a minimal risk of sICH and contributes to favorable patient outcomes. These techniques should be considered when clot retrieval is unsuitable or ineffective. 23846936 Novel agents and future prospects in the treatment of pancreatic adenocarcinoma. Pancreatic adenocarcinoma is one of the most aggressive malignancies and the fourth leading cause of cancer-related mortality in the United States. The majority of patients are diagnosed at advanced stage with inoperable locally advanced tumors or metastatic disease, and palliative chemotherapy remains the best therapeutic option for these patients. Despite intensive clinical and pre-clinical research over the last few years, the combination of the anti-metabolite drug gemcitabine with the targeted agent erlotinib, is considered standard of care in the treatment of these patients, with only minimal or modest efficacy. Therefore, novel therapeutic approaches are currently under clinical investigation in an attempt to produce more definite results for this fatal disease. In this paper we summarize five most interesting research abstracts as presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting. In two studies, nimotuzumab, a monoclonal antibody against epidermal growth factor receptor (EGFR) (Abstract #4009) and bavituximab, a monoclonal antibody against phosphatidylserine (Abstract #4054) are tested in combination with gemcitabine in patients with advanced pancreatic cancer. Abstract #4012 is a study of gemcitabine with vismodegib, a novel hedgehog pathway inhibitor, whereas in Abstract #4035, toxicity and efficacy results of sunitinib in combination with gemcitabine in patients with pancreatic adenocarcinoma are presented. Lastly, safety results of pimasertib, a novel mitogen-activated protein kinase kinase (MEK) inhibitor, combined with the standard gemcitabine are presented in Abstract #4041. 23810166 Comparison between ImmunoCard STAT!(®) and real-time PCR as screening tools for both O157:H7 and non-O157 Shiga toxin-producing Escherichia coli in Southern Alberta, Canada. An increasing number of non-O157 Shiga toxin-producing Escherichia coli (STEC) infections and outbreaks have been reported. In this study, we evaluated the performance of ImmunoCard STAT!(®) (Meridian Bioscience, Inc., Cincinnati, OH, USA) as a method to screen stool specimens for STEC (O157 and non-O157). An in-house real-time PCR method was used as the "gold standard". We also evaluated the prevalence and clinical characteristics of STEC infections in the Alberta South West Zone. From July to November 2011, 819 stool specimens submitted for routine stool culture were tested. With our in-house real-time PCR, 7 O157:H7 and 10 non-O157 STEC isolates were identified for a total of 17 STECs. In comparison, ImmunoCard STAT!(®) identified a total of 6, resulting in a sensitivity and specificity of 35% and 99%, respectively (P < 0.05). Because of the low sensitivity, ImmunoCard STAT!(®) cannot be recommended as a routine screening test for STEC from enriched stool specimens. The rate of STEC positivity as detected by PCR was 2.08%, of which 0.86% was O157:H7 and 1.22% non-O157 STEC. Five of the 7 cases of STEC O157 infection experienced bloody diarrhea, and 1 developed hemolytic uremic syndrome. 23745972 Groundwater protection and unconventional gas extraction: the critical need for field-based hydrogeological research. Unconventional natural gas extraction from tight sandstones, shales, and some coal-beds is typically accomplished by horizontal drilling and hydraulic fracturing that is necessary for economic development of these new hydrocarbon resources. Concerns have been raised regarding the potential for contamination of shallow groundwater by stray gases, formation waters, and fracturing chemicals associated with unconventional gas exploration. A lack of sound scientific hydrogeological field observations and a scarcity of published peer-reviewed articles on the effects of both conventional and unconventional oil and gas activities on shallow groundwater make it difficult to address these issues. Here, we discuss several case studies related to both conventional and unconventional oil and gas activities illustrating how under some circumstances stray or fugitive gas from deep gas-rich formations has migrated from the subsurface into shallow aquifers and how it has affected groundwater quality. Examples include impacts of uncemented well annuli in areas of historic drilling operations, effects related to poor cement bonding in both new and old hydrocarbon wells, and ineffective cementing practices. We also summarize studies describing how structural features influence the role of natural and induced fractures as contaminant fluid migration pathways. On the basis of these studies, we identify two areas where field-focused research is urgently needed to fill current science gaps related to unconventional gas extraction: (1) baseline geochemical mapping (with time series sampling from a sufficient network of groundwater monitoring wells) and (2) field testing of potential mechanisms and pathways by which hydrocarbon gases, reservoir fluids, and fracturing chemicals might potentially invade and contaminate useable groundwater. 22930740 Work-related factors and early retirement intention: a study of the Danish eldercare sector. Western countries are experiencing an ageing and shrinking workforce in the eldercare sector. This study investigated whether 12 different work-related factors are associated with early retirement intentions of employees in the Danish eldercare sector. We tested whether three hypotheses explained the increase of early retirement intention: (i) high job demands (four factors) and low resources (four factors); (ii) low job attitude (three factors); and (iii) high physical strain (one factor). We included 2444 employees (aged 45-57 years) from two waves (T1 and T2) from a prospective study. Multinomial logistic regression models showed whether 12 work-related factors (T1) were associated with early retirement intention (T2); very early retirement intention and early retirement intention vs. normal retirement intention. Only 14% of the participants wished to retire at the normal retirement age (65 years or older). High physical strain [hypothesis (iii)] and low and normal affective organizational commitment [hypothesis (ii)] were associated with very early retirement intention. None of the other work-related factors associated with early retirement intention. Future interventions should focus on reducing physical strain and increase or maintain affective organizational commitment among employees in the eldercare sector to postpone retirement. 23770152 Porcine hemagglutinating encephalomyelitis virus induces apoptosis in a porcine kidney cell line via caspase-dependent pathways. Porcine hemagglutinating encephalomyelitis is an acute, highly contagious disease in piglets that is caused by the porcine hemagglutinating encephalomyelitis virus (PHEV). However, the pathogenesis of PHEV and the relationship between PHEV and the host cells are not fully understood. In this study, we investigated whether the PHEV-induced cytopathic effect (CPE) was caused by apoptosis. Replication of PHEV in a porcine kidney-derived cell line (PK-15 cells) caused an extensive CPE, leading to the destruction of the entire monolayer and the death of the infected cells. Staining with Hoechst 33,342 revealed morphological changes in the nuclei and chromatin fragmentation. In addition, PHEV caused DNA fragmentation detectable by agarose gel electrophoresis 48h post-infection, increasing with the incubation time. The percentage of apoptotic cells increased with the incubation time and reached a maximum at 96h post-infection, as determined using flow cytometry and fluorescence microscopy of cells that were stained with annexin V-FITC and propidium iodide (PI). Moreover, as is commonly observed for coronavirus infections of other animals, the activities of the effecter caspase, caspase-3, and the initiator caspases, caspase-8 and caspase-9, which are representative factors in the death receptor-mediated apoptotic pathway and the mitochondrial apoptotic pathway, respectively, were increased in PHEV-infected PK-15 cells. Moreover, the tripeptide pan-ICE (caspase) inhibitor Z-VAD-FMK blocked PHEV-induced apoptosis but did not have an effect on virus production by 96h post-infection. These results suggested that PHEV induces apoptosis in PK-15 cells via a caspase-dependent pathway. Apoptotic death of infected cells is detrimental to animals because it causes cell and tissue destruction. Although the pathological characteristics of PHEV are largely unknown, apoptosis may be the pathological basis of the lesions resulting from PHEV infection. 23170799 Stem cell-mediated gene delivering for the treatment of cerebral ischemia: progress and prospectives. Ischemic stroke is one of the leading causes of death and disability worldwide. There is no effective treatment for ischemic stroke apart from thrombolytic therapy, which has a narrow therapeutic time window. Gene therapy has proven to be effective in experimental stroke, but it suffers from disadvantages that limit its clinical application, such as difficulty in intracranial delivering of therapeutic genes, low efficacy in transfecting host cells and long-term expression of exogenous genes. Delivering therapeutic genes to the ischemic brain via stem cells is an alternative strategy of combined gene and stem cell therapy. There are advantages for stem cell-mediated gene delivery as opposed to direct gene transfer. In recent years, studies used stem cells that over-express different neurotrophic factors, such as BDNF, GDNT, or NT3, and found that the delivery of these genetically-modified stem cells to animal models of ischemic stroke is safe and effective, thus suggesting that stem cell-based gene therapy may be a promising treatment for stroke. This review summarizes the advantages and recent progress of stem cell-based gene therapy for ischemic stroke. We also discuss the relevant strategy for optimizing stem cell-based gene therapy and discuss the potential strategies for its future application. 23769304 Chain length mismatch and packing effects on the thermotropic phase behavior of salt-free catanionic surfactants. Thermotropic liquid crystal formation by salt-free catanionic surfactants (alkyltrimethylammonium alkylsulfonates, herein designated as TAmSon) has been investigated as a function of chain length mismatch (asymmetry). Previous studies on these compounds have revealed an unusual and rich asymmetry-dependent lyotropic phase behavior. Herein, phase transition temperatures and transition enthalpies/entropies were determined by differential scanning calorimetry, while mesophases were assigned by polarized light microscopy. Three series of compounds were investigated, namely: the TA16Son series, where n=6-10; the TAmSo8 series, where m=12-16; and a constant m+n series, TAmSon where m+n=22. Typically, several solid phases and two smectic mesophases are found prior to isotropization to the liquid phase. As asymmetry decreases, two somewhat counterintuitive tendencies emerge: a general decrease in enthalpy/entropy for solid-solid and solid-first mesophase transitions, and an increase in solid-first mesophase transition temperatures. Yet, solid phases are seen to be more stable for the most asymmetric compounds, while the second mesophase is more stable for the least asymmetric ones, in what appears to be a more complex behavior than expected. The results are globally interpreted in terms of subtle differences in chain interdigitation and packing, and odd-even chain effects. 23885665 Purification and characterization of recombinant envelope protein GP5 of porcine reproductive and respiratory syndrome virus from E. coli. The major envelope protein, GP5, in porcine reproductive and respiratory syndrome virus (PRRSV) plays critical roles in the assembly, invasion and immune response of PRRSV particle, and is one of the mostly studied candidates in the development of recombinant vaccines. In this research, a purification process including immobilized metal affinity chromatography (IMAC) and hydrophobic interaction chromatography (HIC) was developed to prepare recombinant envelope protein GP5 with His-tag from an E. coli strain transformed with pGEM-ORF5. The result of cell culture indicated that His-tagged GP5 protein was expressed mainly in soluble form. After cell disruption, His-tagged GP5 protein was successfully purified by Ni(2+)-chelating Sepharose Fast Flow with a yield and purity of 80.5% and 48%, respectively. Recombinant GP5 protein was further purified by HIC to achieve a purity of 95%. Moreover, the purified rGP5 is shown in monomeric form contrasting the dimeric or tetrameric form when purified by a CEX-HIC process directly from PRRSV virions as reported in a previous study. 23850682 Safety of ranibizumab in routine clinical practice: 1-year retrospective pooled analysis of four European neovascular AMD registries within the LUMINOUS programme. Evaluation of 1-year safety profile of intravitreal ranibizumab 0.5 mg in neovascular age-related macular degeneration (NV-AMD) within routine clinical practice. The LUMINOUS programme comprises a prospective observational study assessing ranibizumab 'real-world' safety and clinical effectiveness across licensed indications worldwide and an annual retrospective pooled safety analysis from completed NV-AMD ranibizumab registries. 1-year data from four European registries are available. This retrospective pooled safety analysis assessed 1-year incidence rates for safety events of particular interest (key ocular or systemic events possibly related to the injection procedure or vascular endothelial growth factor inhibition) together with treatment exposure. Patients were treated according to local protocols within the ranibizumab licence. Data of 4444 patients from registries in Germany (n=3470), the Netherlands (n=243), Belgium (n=260) and Sweden (n=471) were retrospectively pooled. Between 70.4% and 84.4% of enrolled patients completed 1 year of follow-up. Most frequent overall ocular events of particular interest were retinal pigment epithelial tears (27 patients; <1%) and intraocular pressure-related events (12 patients; <0.3%). Most frequent non-ocular event of particular interest was stroke (19 patients; 0.4%); annual incidence of stroke was low across all registries (0.0-0.5%). Ranibizumab demonstrated favourable 1-year safety profile for NV-AMD in this routine clinical practice sample, consistent with previous reported trial data. Additional data from a larger patient population are needed to better describe the long-term safety profile of ranibizumab in routine clinical practice and further evaluate risk for infrequent but serious events in 'real-life' settings. The 5-year LUMINOUS prospective observational study will address this need. 23640173 Association of personality, neighbourhood, and civic participation with the level of perceived social support: The HUNT study, a cross-sectional survey. Aim: The aim of the current study was to examine the association of personality, neighbourhood, and civic participation with the level of perceived social support if needed. Methods: The sample consists of a total of 35,797 men (16,035) and women (19,762) drawn from the Nord-Trøndelag Health Study 3 (HUNT3), aged 20-89, with a fully completed short version of the Eysenck Personality Questionnaire (EPQ) including a complete response to questions regarding perceived social support. A multinomial logistic regression model was used to investigate the association between the three-category outcomes (high, medium, and low) of perceived social support. Results: The Chi-square test detected a significant (p < 0.001) association between personality, sense of community, civic participation, self-rated health, living arrangement, age groups, gender, and perceived social support, except between perceived social support and loss of social network, in which no significance was found. The crude and adjusted multinomial logistic regression models show a relation between medium and low scores on perceived social support, personality, and sources of social support. Interactions were observed between gender and self-rated health. Conclusions: There is an association between the level of perceived social support and personality, sense of community in the neighbourhood, and civic participation. Even if the interaction between men and self-reported health decreases the odds for low and medium social support, health professionals should be aware of men with poor health and their lack of social support. 23080286 Localized reentrant tachycardia in the aorta contiguity region mimicking perimitral atrial flutter in the context of atrial fibrillation ablation. We describe a case with a focal atrial tachycardia (AT) masquerading as perimitral atrial flutter revealed after circumferential pulmonary vein antral isolation for atrial fibrillation. It was successfully terminated and became noninducible by a point ablation on the left atrial anterior wall (LAAW) near the mitral annulus in contact with the aortic root and on the left superior pulmonary vein-left atrial appendage ridge, without any linear ablation, using electroanatomical mapping and conventional precise mapping with a maximum amplified gain within the low-voltage area. The AT revealed in our case was an LAAW-aorta contiguity area-related AT. 23904353 Exercise training undertaken by people within 12 months of lung resection for non-small cell lung cancer. Decreased exercise capacity and impairments in health-related quality of life (HRQoL) are common in people following lung resection for non-small cell lung cancer (NSCLC). Exercise training has been demonstrated to confer gains in exercise capacity and HRQoL for people with a range of chronic conditions, including chronic obstructive pulmonary disease and heart failure, as well as in people with cancers such as prostate and breast cancer. A programme of exercise training for people following lung resection for NSCLC may confer important gains in these outcomes. To date, evidence of its efficacy in this population is unclear. The primary aim of this study was to determine the effects of exercise training on exercise capacity in people following lung resection (with or without chemotherapy) for NSCLC. The secondary aims were to determine the effects on other outcomes such as HRQoL, lung function (forced expiratory volume in one second (FEV1)), peripheral muscle force, dyspnoea and fatigue as well as feelings of anxiety and depression. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 2 of 12), MEDLINE (via PubMed) (1966 to February 2013), EMBASE (via Ovid) (1974 to February 2013), SciELO (The Scientific Electronic Library Online) (1978 to February 2013) as well as PEDro (Physiotherapy Evidence Database) (1980 to February 2013). We included randomised controlled trials (RCTs) in which study participants with NSCLC, who had recently undergone lung resection, were allocated to receive either exercise training or no exercise training. Two review authors screened the studies and identified those for inclusion. Meta-analyses were performed using post-intervention data for those studies in which no differences were reported between the exercise and control group either: (i) prior to lung resection, or (ii) following lung resection but prior to the commencement of the intervention period. Although two studies reported measures of quadriceps force on completion of the intervention period, meta-analysis was not performed on this outcome as one of the two studies demonstrated significant differences between the exercise and control group at baseline (following lung resection). We identified three RCTs involving 178 participants. Three out of the seven domains included in the Cochrane Collaboration's 'seven evidence-based domains' table were identical in their assessment across the three studies (random sequence generation, allocation concealment and blinding of participants and personnel). The domain which had the greatest variation was 'blinding of outcome assessment' where one study was rated at low risk of bias, one at unclear risk of bias and the remaining one at high risk of bias. On completion of the intervention period, exercise capacity as measured by the six-minute walk distance was statistically greater in the intervention group compared to the control group (mean difference (MD) 50.4 m; 95% confidence interval (CI) 15.4 to 85.2 m). No between-group differences were observed in HRQoL (standardised mean difference (SMD) 0.17; 95% CI -0.16 to 0.49) or FEV1 (MD -0.13 L; 95% CI -0.36 to 0.11 L). Differences in quadriceps force were not demonstrated on completion of the intervention period. The evidence summarised in our review suggests that exercise training may potentially increase the exercise capacity of people following lung resection for NSCLC. The findings of our systematic review should be interpreted with caution due to disparities between the studies, methodological limitations, some significant risks of bias and small sample sizes. This systematic review emphasises the need for larger RCTs. 23932637 Normal breast tissue stiffness measured by a new ultrasound technique: Virtual touch tissue imaging quantification (VTIQ). To evaluate normal breast tissue stiffness with virtual touch tissue imaging quantification (VTIQ) using prospectively collected data. B-mode ultrasound and VTIQ were performed in 132 breasts in 97 women. Mean values of VTIQ for parenchyma and fatty tissue were compared between those measured in healthy breasts and in the surrounding of histologically proven benign and malignant breast lesions. Moreover we reviewed VTIQ values according to breast density measured by the American College of Radiology (ACR) categories. In addition we analyzed re-test reliability of VTIQ. In 132 breasts the mean VTIQ values in parenchyma were significantly higher than in fatty tissue (3.23m/s±0.74 versus 2.5m/s±0.61; p<0.0001). In healthy breasts as well as in the surrounding of a benign or malignant lesions the VTIQ values of parenchyma were similar (p=0.12). In fatty tissue, small differences between mean VTIQ values of 2.25m/s±0.51, 2.52m/s±0.48 and 2.65m/s±0.71 (p=0.01) in the respective groups were observed. The comparison of mean VTIQ values of parenchyma and fatty tissue in more and less dense breasts (ACR 1+2 versus ACR 3+4 breasts) also yielded no statistically significant difference. The re-test reliability of VTIQ assessed with three independent measurements was moderate (interclass-correlation of 0.52 (p<0.0001)). VTIQ is a reliable method for measuring the stiffness of breast tissue. We propose standard values for healthy parenchyma and fatty tissues independent of the surrounding tissue or the ACR category. 23561144 Proportions of A1, A2, B and C β-casein protein variants in retail milk in the UK. The A1 variant protein of the β-casein family has been implicated in various disease states although much evidence is weak or contradictory. The primary objective was to measure, for the first time, the proportions of the key β-casein variant proteins in UK retail milk over the course of one year. In total, 55 samples of semi-skimmed milk were purchased from five supermarkets over the course of a year and the proportions of the A1, A2, B and C casein variant proteins were measured, using high resolution HPLC-MS. The results showed that β-casein in UK retail milk comprises approximately 0.58, 0.31, 0.07 and 0.03 A2, A1, B and C protein variants, respectively. The proportion of A2 is higher than some early studies would predict although the reasons for this and any implications for health are unclear. 23863218 How often do our liver core biopsies reach current definitions of adequacy? Needle core biopsy is a key tool in diagnosis and assessment of many medical liver diseases, but there is evidence that the combination of small size of the specimen obtained and the patchy nature of many of these diseases can result in misdiagnosis or incorrect staging. The Royal College of Pathologists has therefore published guidelines for assessment of adequacy. To assess whether these guidelines were being observed, we reviewed cases reported in our department over a 15-year period. Results showed that only 19.8% of cores would be considered adequate, 56.4% were suboptimal and 23.8% were inadequate. We discuss the issues around recommendations on the minimum size of liver biopsies, potential factors limiting biopsy size and whether further refinement of the guidelines for adequacy is required. 23822552 Health care payments in the Asia Pacific: validation of five survey measures of economic burden. Many low and middle-income countries rely on out-of-pocket payments to help finance health care. These payments can pose financial hardships for households; valid measurement of this type of economic burden is therefore critical. This study examines the validity of five survey measures of economic burden caused by health care payments. We analyzed 2002/03 World Health Survey household-level data from four Asia Pacific countries to assess the construct validity of five measures of economic burden due to health care payments: any health expenditure, health expenditure amount, catastrophic health expenditure, indebtedness, and impoverishment. We used generalized linear models to assess the correlations between these measures and other constructs with which they have expected associations, such as health care need, wealth, and risk protection. Measures of impoverishment and indebtedness most often correlated with health care need, wealth, and risk protection as expected. Having any health expenditure, a large health expenditure, or even a catastrophic health expenditure did not consistently predict degree of economic burden. Studies that examine economic burden attributable to health care payments should include measures of impoverishment and indebtedness. 23895033 Multivessel coronary artery disease: quantifying how recent trials should influence clinical practice. The majority (70%) of coronary revascularizations concern patients with multivessel disease (MVD). Treatment options include medical therapy, percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). CABG surgery has been shown to improve survival compared with medical therapy. PCI relieves angina compared with medical therapy and is equivalent to CABG in low complex MVD. Other benefits are currently being evaluated in ongoing trials. In complex MVD, CABG results in lower rates of long-term mortality, myocardial infarction and repeat revascularization compared with PCI. These results are more pronounced in diabetics and in patients with lesions that are anatomically more complex. The application of the results of clinical trials may be limited due to restrictive eligibility criteria. Comparative effectiveness studies are, therefore, needed to complement the results of trials, but also have inherent limitations. Inappropriateness criteria provide an important tool to measure how evidence from trials, large registries and guidelines is integrated in clinical practice. Checklists and decision aids may also lead to better application of the latest evidence and lower rates of inappropriate use. Decision-making is centered around heart team discussions and risk scores. Economic considerations will increasingly be included in decision-making, since the economic impact of ischemic heart disease is high and the growth of healthcare expenditure is unsustainable. In this context, CABG is associated with higher upfront costs, but is economically attractive at long-term follow-up. 23839275 A comparative study on the possible zinc binding sites of the human ZnT3 zinc transporter protein. The brain specific zinc transporter protein ZnT3 can be related to the amyloid neuropathology of Alzheimer's disease. In order to analyze the metal binding ability of human ZnT3 protein, here we report a potentiometric and solution structural (UV-Vis, CD, EPR, NMR) study of nickel(ii), copper(ii) and zinc(ii) complexes of three peptides mimicking the possible metal binding sequences of this protein. The peptide (Ac-RHQAGPPHSHR-NH2) is a minimalist, the cyclic peptide (cyclo(Ac-CKLHQAGPPHSHGSRGAEYAPLEEGPEEKC-NH2) is a more complete model of the intracellular His-rich loop, which is widely accepted as a putative metal binding site. The peptide (Ac-PFHHCHRD-NH2) is the model of the conserved cytoplasmic N-terminal -HHCH- sequence. In the physiological pH-range, the Zn, ZnH3 and Zn complexes are the major species in the corresponding binary systems, with {3Nim}, {3Nim,2/3Oamide} and {3Nim,S(-)} coordination environments, respectively. The species Zn has 3-4 orders of magnitude higher stability than the other two complexes, indicating the presence of a high-affinity zinc-binding site at the N-terminal tail of the human ZnT3 transporter. Moreover, shows preferred zinc binding as compared to nickel (log β(Zn) - log β(Ni) = 2.3), probably due to the higher preference of zinc(ii) for tetrahedral geometry. These facts suggest that zinc binding to the N-terminal -HHCH- sequence of human ZnT3 may be involved in the biological activity of this zinc transporter protein in zinc sensing, binding or translocation processes. 23886985 Normalization of similarity-based individual brain networks from gray matter MRI and its association with neurodevelopment in infants with intrauterine growth restriction. Obtaining individual biomarkers for the prediction of altered neurological outcome is a challenge of modern medicine and neuroscience. Connectomics based on magnetic resonance imaging (MRI) stands as a good candidate to exhaustively extract information from MRI by integrating the information obtained in a few network features that can be used as individual biomarkers of neurological outcome. However, this approach typically requires the use of diffusion and/or functional MRI to extract individual brain networks, which require high acquisition times and present an extreme sensitivity to motion artifacts, critical problems when scanning fetuses and infants. Extraction of individual networks based on morphological similarity from gray matter is a new approach that benefits from the power of graph theory analysis to describe gray matter morphology as a large-scale morphological network from a typical clinical anatomic acquisition such as T1-weighted MRI. In the present paper we propose a methodology to normalize these large-scale morphological networks to a brain network with standardized size based on a parcellation scheme. The proposed methodology was applied to reconstruct individual brain networks of 63 one-year-old infants, 41 infants with intrauterine growth restriction (IUGR) and 22 controls, showing altered network features in the IUGR group, and their association with neurodevelopmental outcome at two years of age by means of ordinal regression analysis of the network features obtained with Bayley Scale for Infant and Toddler Development, third edition. Although it must be more widely assessed, this methodology stands as a good candidate for the development of biomarkers for altered neurodevelopment in the pediatric population. 23927955 Early cardiac catheterization is associated with improved survival in comatose survivors of cardiac arrest without STEMI. To determine if early cardiac catheterization (CC) is associated with improved survival in comatose patients who are resuscitated after cardiac arrest when electrocardiographic evidence of ST-elevation myocardial infarction (STEMI) is absent. We conducted a retrospective observational study of a prospective cohort of 754 consecutive comatose patients treated with therapeutic hypothermia (TH) following cardiac arrest. A total of 269 (35.7%) patients had cardiac arrest due to a ventricular arrhythmia without STEMI and were treated with TH. Of these, 122 (45.4%) received CC while comatose (early CC). Acute coronary occlusion was discovered in 26.6% of patients treated with early CC compared to 29.3% of patients treated with late CC (p=0.381). Patients treated with early CC were more likely to survive to hospital discharge compared to those not treated with CC (65.6% vs. 48.6%; p=0.017). In a multivariate regression model that included study site, age, bystander CPR, shock on admission, comorbid medical conditions, witnessed arrest, and time to return of spontaneous circulation, early CC was independently associated with a significant reduction in the risk of death (OR 0.35, 95% CI 0.18-0.70, p=0.003). In comatose survivors of cardiac arrest without STEMI who are treated with TH, early CC is associated with significantly decreased mortality. The incidence of acute coronary occlusion is high, even when STEMI is not present on the postresuscitation electrocardiogram. 23951022 Comparison of IHC, FISH and RT-PCR Methods for Detection of ALK Rearrangements in 312 Non-Small Cell Lung Cancer Patients in Taiwan. Recently Echinoderm microtubule-associated protein-like 4- anaplastic lymphoma kinase (EML4-ALK) fusion gene has become an important biomarker for ALK tyrosine kinase inhibitor (crizotinib) treatment in NSCLC. However, the best detection method and the significance of EML4-ALK variant types remain uncertain. Reverse transcriptase-polymerase chain reaction (RT-PCR), fluorescence in Situ hybridization (FISH) and Immunohistochemical (IHC) stain were performed on tumor tissues of 312 NSCLC patients for detection of ALK rearrangements. Mutation analyses for EGFR and KRAS genes were also performed. Thirteen of the 312 patients (4.17%) had ALK rearrangements detected by RT-PCR. If RT-PCR data was used as the gold standard, FISH tests had a low sensitivity (58.33%), but very good specificity (99.32%). IHC stain had better sensitivity (91.67%) than FISH, but lower specificity (79.52%), when the cut off was IHC2+. All of the 8 patients with high abundance of EML4-ALK positive cells in tumor tissues (assessed by the signal intensities of the RT-PCR product), were also have high expression of ALK protein (IHC3+), and positive for FISH, except one failed in FISH. Variants 3a+3b (4/5, 80%) of EML4-ALK fusion gene were more common to have high abundance of EML4-ALK positive cells in tumor tissues than variant 1 (1/3, 33.3%). Meta-analysis of the published data of 2273 NSCLC patients revealed that variant 3 (23/44, 52.3%) was the most common type in Chinese population, while variant 1 (28/37, 75.7%) was most common in Caucasian. Among the three detection methods, RT-PCR could detect not only the presence of EML4-ALK fusion gene and their variant types, but also the abundance of EML4-ALK positive cells in NSCLC tumor tissues. The latter two factors might affect the treatment response to anti-ALK inhibitor. Including RT-PCR as a diagnostic test for ALK inhibitor treatment in the prospective clinical trials is recommended. 23599353 Home-based versus in-hospital cardiac rehabilitation after cardiac surgery: a nonrandomized controlled study. Exercise rehabilitation after cardiac surgery has beneficial effects, especially on a long-term basis. Rehabilitative programs with telemedicine plus appropriate technology might satisfy the needs of performing rehabilitation at home. The purpose of this study was to compare exercise capacity after home-based cardiac rehabilitation (HBCR) or in-hospital rehabilitation in patients at low to medium risk for early mortality (EuroSCORE 0-5) following cardiac surgery. A quasi-experimental study was conducted. At hospital discharge, patients were given the option to decide whether to enroll in the HBCR program. Clinical examinations (electrocardiography, cardiac echo color Doppler, chest radiography, blood samples) of patients in the HBCR group were collected during 4 weeks of rehabilitation, and exercise capacity (assessed using the Six-Minute Walk Test [6MWT]) was assessed before and after rehabilitation. A group of patients admitted to the in-hospital rehabilitation program was used as a comparison group. Patients in the HBCR group were supervised at home by a medical doctor and telemonitored daily by a nurse and physical therapist by video conference. Periodic home visits by health staff also were performed. One hundred patients were recruited into the HBCR group. An equal number of patients was selected for the comparison group. At the end of the 4-week study, the 2 groups showed improvement from their respective baseline values only in the 6MWT. No difference was found in time × group interaction. Because patients self-selected to enroll in the HBCR program and because they were enrolled from a single clinical center, the results of the study cannot be generalized. In patients who self-selected HBCR, the program was found to be effective and comparable to the standard in-hospital rehabilitative approach, indicating that rehabilitation following cardiac surgery can be implemented effectively at home when coadministered with an integrated telemedicine service. 23917291 History of kidney stones and the risk of coronary heart disease. Kidney stone disease is common and may be associated with an increased risk of coronary heart disease (CHD). Previous studies of the association between kidney stones and CHD have often not controlled for important risk factors, and the results have been inconsistent. To examine the association between a history of kidney stones and the risk of CHD in 3 large prospective cohorts. A prospective study of 45,748 men and 196,357 women in the United States without a history of CHD at baseline who were participants in the Health Professionals Follow-up Study (HPFS) (45,748 men aged 40-75 years; follow-up from 1986 to 2010), Nurses' Health Study I (NHS I) (90,235 women aged 30-55 years; follow-up from 1992 to 2010), and Nurses' Health Study II (NHS II) (106,122 women aged 25-42 years; follow-up from 1991 to 2009). The diagnoses of kidney stones and CHD were updated biennially during follow-up. Coronary heart disease was defined as fatal or nonfatal myocardial infarction (MI) or coronary revascularization. The outcome was identified by biennial questionnaires and confirmed through review of medical records. RESULTS Of a total of 242,105 participants, 19,678 reported a history of kidney stones. After up to 24 years of follow-up in men and 18 years in women, 16,838 incident cases of CHD occurred. After adjusting for potential confounders, among women, those with a reported history of kidney stones had an increased risk of CHD than those without a history of kidney stones in NHS I (incidence rate [IR], 754 vs 514 per 100,000 person-years; multivariable hazard ratio [HR], 1.18 [95% CI, 1.08-1.28]) and NHS II (IR, 144 vs 55 per 100,000 person-years; multivariable HR, 1.48 [95% CI, 1.23-1.78]). There was no significant association in men (IR, 1355 vs 1022 per 100,000 person-years; multivariable HR, 1.06 [95% CI, 0.99-1.13]). Similar results were found when analyzing the individual end points (fatal and nonfatal MI and revascularization). Among the 2 cohorts of women, a history of kidney stones was associated with a modest but statistically significantly increased risk of CHD; there was no significant association in a separate cohort of men. Further research is needed to determine whether the association is sex-specific. 23778429 An artificial restriction DNA cutter for site-selective gene insertion in human cells. With the use of a chemistry-based artificial restriction DNA cutter (combination of Ce(IV)-EDTA and a pair of pcPNA), both an antibiotic-resistance gene and a fluorescent reporter protein gene were incorporated into the targeted site through homologous recombination in human cells. 23859918 Enhancing HIV/AIDS, Viral Hepatitis, Sexually Transmitted Disease, and Tuberculosis Prevention in the United States Through Program Collaboration and Service Integration: The Case for Broader Implementation. HIV infection, viral hepatitis, sexually transmitted diseases, and tuberculosis in the United States remain major public health concerns. The current disease-specific prevention approach oftentimes has led to narrow success and missed opportunities for increasing program capacity, leveraging resources, addressing social and structural determinants, and accelerating health impact-suggesting a need for greater innovation to prevent related diseases. The National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention's Program Collaboration and Service Integration (PCSI) strategic priority aims to strengthen collaborative engagement across these disease areas and to integrate services at the client level. In this review, we articulate the 5 principles of PCSI-appropriateness, effectiveness, flexibility, accountability, and acceptability. Drawing upon these principles and published literature, we discuss the case for change that underlies PCSI, summarize advances in the field since 2007, and articulate key next steps. Although formal evaluation is needed to fully assess the health impact of PCSI, available evidence suggests that this approach is a promising tool to advance prevention goals. 23837182 Prenatal alcohol exposure and educational achievement in children aged 8-9 years. This study examines the relationships between the dose, pattern, and timing of prenatal alcohol exposure and achievement in reading, writing, spelling, and numeracy in children aged 8 to 9 years. Data from a randomly selected, population-based birth cohort of infants born to non-Indigenous women in Western Australia between 1995 and 1997 (n = 4714) (Randomly Ascertained Sample of Children born in Australia's Largest State Study cohort) were linked to the Western Australian Midwives' Notification System and the Western Australian Literacy and Numeracy Assessment statewide education testing program. The records for 86% (n = 4056) of the cohort were successfully linked with education records when the children were aged 8 to 9 years. The associations between prenatal alcohol exposure and achievement of national benchmarks in school numeracy, reading, spelling, and writing tests and nonattendance for the tests was examined. Logistic regression was used to generate adjusted odds ratios (aOR) and 95% confidence intervals (CI), adjusting for potential confounding factors. The referent group included children of mothers who previously drank alcohol but who abstained during pregnancy. Children were twice as likely not to achieve the benchmark for reading after heavy prenatal alcohol exposure during the first trimester (aOR 2.26; 95% CI 1.10-4.65) and for writing when exposed to occasional binge drinking in late pregnancy (aOR 2.35; 95% CI 1.04-5.43). Low-moderate prenatal alcohol exposure was not associated with academic underachievement. The type of learning problems expressed depends on the dose, pattern, and timing of prenatal alcohol exposure. 23851729 Development of a PCR technique specific for Demodex injai in biological specimens. The identification of Demodex injai as a second Demodex species of dog opened new questions and challenges in the understanding on the Demodex-host relationships. In this paper, we describe the development of a conventional PCR technique based on published genome sequences of D. injai from GenBank that specifically detects DNA from D. injai. This technique amplifies a 238-bp fragment corresponding to a region of the mitochondrial 16S rDNA of D. injai. The PCR was positive in DNA samples obtained from mites identified morphologically as D. injai, which served as positive controls, as well as in samples from three cases of demodicosis associated with proliferation of mites identified as D. injai. Furthermore, the PCR was positive in 2 out of 19 healthy dogs. Samples of Demodex canis and Demodex folliculorum were consistently negative. Skin samples from seven dogs with generalized demodicosis caused by D. canis were all negative in the D. injai-specific PCR, demonstrating that in generalized canine demodicosis, mite proliferation is species-specific. This technique can be a useful tool in the diagnosis and in epidemiologic and pathogenic studies. 23947923 Dual effects of molybdenum on mouse oocyte quality and ovarian oxidative stress. A sub-acute toxicity test was performed to investigate the effects of molybdenum (Mo) on ovarian function. ICR adult female mice were exposed to Mo by free access to distilled water containing the Mo at 5, 10, 20, and 40 mg/L for 14 days. Compared to the control group, M II oocyte morphology, ovary index, and ovulation improved within the 5 mg/L Mo group, but were negatively affected by Mo at 40 mg/L. Morphologically abnormal ovarian mitochondria were observed at ≥ 20 mg/L. These alterations accompanied the changes in superoxide dismutase (SOD), glutathione peroxidise (GPx), and malondialdehyde (MDA) levels in ovaries. In conclusion, Mo affects oocyte quality possibly through regulating ovarian oxidative stress in a dose-dependent manner. It appears that Mo may improve ovarian function at a suitable concentration, which might be a candidate for the treatment of female infertility. 23872030 Consequences of Interstitial Cystitis/Bladder Pain Symptoms on Women's Work Participation and Income: Results from a National Household Sample. To describe differences in work participation and income by bladder symptom impact and comorbidities among women with interstitial cystitis/bladder pain syndrome (IC/BPS). Cross-sectional data from 2767 respondents under age 65 identified with IC/BPS symptoms analyzed. The data are from the RAND Interstitial Cystitis Epidemiology (RICE) survey and include retrospective self-reports of IC/BPS impact, severity, years since onset, and related comorbidities (depressive symptomology, number of conditions), work participation and income, and personal characteristics. Multiple regressions predicted five current work outcomes: works now, kept from working by pain, missed work days, days worked when bothered by symptoms, and real income change since symptom onset. Controlling for work status at symptom onset and personal characteristics, greater bladder symptom impact predicted greater likelihood of not now working, kept more days from working by pain, missed more work days, and working more days with symptoms. More depressive symptomology and greater number of co-morbidities predicted reduced work participation. Women experienced no growth in real income since symptom onset. Measures of symptom severity were not associated with any of the economic outcomes. Greater IC/BPS symptom impact, depressive symptomology, and count of comorbidities (but not symptom severity) were each associated with less work participation and leveling of women's long-term earnings. Management of bladder symptom impact on non-work-related activities and depressive symptomology may improve women's work outcomes. 23872114 The Kunitz-protease inhibitor domain in amyloid precursor protein reduces cellular mitochondrial enzymes expression and function. Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) and this can be contributed by aberrant metabolic enzyme function. But, the mechanism causing this enzymatic impairment is unclear. Amyloid precursor protein (APP) is known to be alternatively spliced to produce three major isoforms in the brain (APP695, APP751, APP770). Both APP770 and APP751 contain the Kunitz Protease Inhibitory (KPI) domain, but the former also contain an extra OX-2 domain. APP695 on the other hand, lacks both domains. In AD, up-regulation of the KPI-containing APP isoforms has been reported. But the functional contribution of this elevation is unclear. In the present study, we have expressed and compared the effect of the non-KPI containing APP695 and the KPI-containing APP751 on mitochondrial function. We found that the KPI-containing APP751 significantly decreased the expression of three major mitochondrial metabolic enzymes; citrate synthase, succinate dehydrogenase and cytochrome c oxidase (COX IV). This reduction lowers the NAD(+)/NADH ratio, COX IV activity and mitochondrial membrane potential. Overall, this study demonstrated that up-regulation of the KPI-containing APP isoforms is likely to contribute to the impairment of metabolic enzymes and mitochondrial function in AD. 23967936 Optimizing stepwise rotation of dodecahedron sound source to improve the accuracy of room acoustic measures. Dodecahedron sound sources are widely used for acoustical measurement purposes as they produce a good approximation of omnidirectional radiation. Evidence shows that such an assumption is acceptable only in the low-frequency range (namely below 1 kHz), while at higher frequencies sound radiation is far from being uniform. In order to improve the accuracy of acoustical measurements obtained from dodecahedron sources, international standard ISO 3382 suggests an averaging of results after a source rotation. This paper investigates the effects of such rotations, both in terms of variations in acoustical parameters and spatial distribution of sound reflections. Taking advantage of a spherical microphone array, the different reflection patterns were mapped as a function of source rotation, showing that some reflections may be considerably attenuated for different aiming directions. This paper investigates the concept of averaging results while changing rotation angles and the minimum number of rotations required to improve the accuracy of the average value. Results show that averages of three measurements carried out at 30° angular steps are closer to actual values and show much less fluctuation. In addition, an averaging of the directional intensity components of the selected responses stabilizes the spatial distribution of the reflections. 23936386 Why herd size matters - mitigating the effects of livestock crashes. Analysing the effect of pastoral risk management strategies provides insights into a system of subsistence that have persevered in marginal areas for hundreds to thousands of years and may shed light into the future of around 200 million households in the face of climate change. This study investigated the efficiency of herd accumulation as a buffer strategy by analysing changes in livestock holdings during an environmental crisis in the Saami reindeer husbandry in Norway. We found a positive relationship between: (1) pre- and post-collapse herd size; and (2) pre-collapse herd size and the number of animals lost during the collapse, indicating that herd accumulation is an effective but costly strategy. Policies that fail to incorporate the risk-beneficial aspect of herd accumulation will have a limited effect and may indeed fail entirely. In the context of climate change, official policies that incorporate pastoral risk management strategies may be the only solution for ensuring their continued existence. 23747557 Metal cycling during sediment early diagenesis in a water reservoir affected by acid mine drainage. The discharge of acid mine drainage (AMD) into a reservoir may seriously affect the water quality. To investigate the metal transfer between the water and the sediment, three cores were collected from the Sancho Reservoir (Iberian Pyrite Belt, SW Spain) during different seasons: turnover event; oxic, stratified period; anoxic and under shallow perennially oxic conditions. The cores were sliced in an oxygen-free atmosphere, after which pore water was extracted by centrifugation and analyzed. A sequential extraction was then applied to the sediments to extract the water-soluble, monosulfide, low crystallinity Fe(III)-oxyhydroxide, crystalline Fe(III)-oxide, organic, pyrite and residual phases. The results showed that, despite the acidic chemistry of the water column (pH<4), the reservoir accumulated a high amount of autochthonous organic matter (up to 12wt.%). Oxygen was consumed in 1mm of sediment due to organic matter and sulfide oxidation. Below the oxic layer, Fe(III) and sulfate reduction peaks developed concomitantly and the resulting Fe(II) and S(II) were removed as sulfides and probably as S linked to organic matter. During the oxic season, schwertmannite precipitated in the water column and was redissolved in the organic-rich sediment, after which iron and arsenic diffused upwards again to the water column. The flux of precipitates was found to be two orders of magnitude higher than the aqueous one, and therefore the sediment acted as a sink for As and Fe. Trace metals (Cu, Zn, Cd, Pb, Ni, Co) and Al always diffused from the reservoir water and were incorporated into the sediments as sulfides and oxyhydroxides, respectively. In spite of the fact that the benthic fluxes estimated for trace metal and Al were much higher than those reported for lake and marine sediments, they only accounted for less than 10% of their total inventory dissolved in the column water. 23884078 Dynamics of a vertical cavity quantum cascade phonon laser structure. Driven primarily by scientific curiosity, but also by the potential applications of intense sources of coherent sound, researchers have targeted the phonon laser (saser) since the invention of the optical laser over 50 years ago. Here we fabricate a vertical cavity structure designed to operate as a saser oscillator device at a frequency of 325 GHz. It is based on a semiconductor superlattice gain medium, inside a multimode cavity between two acoustic Bragg reflectors. We measure the acoustic output of the device as a function of time after applying electrical pumping. The emission builds in intensity reaching a steady state on a timescale of order 0.1 μs. We show that the results are consistent with a model of the dynamics of a saser cavity exactly analogous to the models used for describing laser dynamics. We also obtain estimates for the gain coefficient, steady-state acoustic power output and efficiency of the device. 23765753 Total Testosterone and Sex Hormone-binding Globulin are Significantly Associated with Metabolic Syndrome in Middle-aged and Elderly Men. Testosterone and sex hormone-binding globulin (SHBG) have been shown to be associated with metabolic syndrome (MS) in men. This study aimed at validating these relationships in a group of middle-aged and elderly men and assessing their strength of association to MS. A cross-sectional study of 332 Malaysian men aged 40 years and above was conducted. The blood of subject was collected under fasting condition for determination of testosterone, SHBG, glucose and lipid levels. Their medical history, smoking and alcohol consumption status, waist circumference (WC), body mass index (BMI) and blood pressure (BP) were recorded. All testosterone and SHBG levels were significantly reduced in MS subjects compared to non-MS subjects (p<0.05). Testosterone and SHBG were correlated significantly with most of the MS indicators without adjustments. In multiple regression analysis, the triglyceride level was the only MS indicator that was significantly, inversely and independently associated with all testosterone measurements and SHBG (p<0.05). Waist circumference was significantly and negatively associated with SHBG level (p<0.05) though not independent of BMI. Total testosterone and SHBG were significantly and inversely associated with the presence of MS. Testosterone and SHBG are potential intervention targets for the prevention of MS in men. 23949940 Magnetic resonance imaging in brachial plexus injury. Brachial plexus injury represents the most severe nerve injury of the extremities. While obstetric brachial plexus injury has showed a reduction in the number of cases due to the improvements in obstetric care, brachial plexus injury in the adult is an increasingly common clinical problem. The therapeutic measures depend on the pathologic condition and the location of the injury: Preganglionic avulsions are usually not amenable to surgical repair; function of some denervated muscles can be restored with nerve transfers from intercostals or accessory nerves and contralateral C7 transfer. Postganglionic avulsions are repaired with excision of the damaged segment and nerve autograft between nerve ends or followed up conservatively. Magnetic resonance imaging is the modality of choice for depicting the anatomy and pathology of the brachial plexus: It demonstrates the location of the nerve damage (crucial for optimal treatment planning), depicts the nerve continuity (with or without neuroma formation), or may show a completely disrupted/avulsed nerve, thereby aiding in nerve-injury grading for preoperative planning. Computed tomography myelography has the advantage of a higher spatial resolution in demonstration of nerve roots compared with MR myelography; however, it is invasive and shows some difficulties in the depiction of some pseudomeningoceles with little or no communication with the dural sac. 23882155 Incidence of and risk factors for hungry bone syndrome in 84 patients with secondary hyperparathyroidism. Secondary hyperparathyroidism develops in nearly all patients with end-stage renal disease. Parathyroidectomy is often performed when medical therapy fails. The most common postoperative complication, hungry bone syndrome (HBS), requires early recognition and treatment. A total of 84 patients who underwent parathyroidectomy because of secondary hyperparathyroidism were investigated. Detailed analysis of laboratory parameters (calcium, phosphate, parathyroid hormone, hemoglobin, and urea levels) and baseline characteristics (age at time of surgery, duration of renal replacement therapy, and medication) was performed to detect preoperative predictors for the development of HBS. Average overall follow-up of the cohort was 4.7 years. Within this time frame, 13 of 84 patients had to undergo a second surgery because of recurrent disease, and HBS occurred in 51.2%. Only decreased preoperative calcium levels and younger age at time of surgery were significant predictors of HBS. Minimal levels of calcium were detected 3 weeks after surgery. Preoperative vitamin D therapy could not prevent HBS and could not shorten the duration of intravenous calcium supplementation. HBS is a very common complication after parathyroidectomy. Younger patients and patients with low preoperative calcium levels were at higher risk for the development of HBS. Remarkably, preoperative vitamin D therapy could not prevent HBS and had no impact on the length of intravenous calcium supplementation. Intensive monitoring of calcium levels must be performed for at least 3 weeks after surgery. 23905654 Zn(2+) and Pyrophosphate Sensing: Selective Detection in Physiological Conditions and Application in DNA-Based Estimation of Bacterial Cell Numbers. A diformyl-quinoline based receptor (L1) exhibits selective colorimetric and fluorometric sensing of Zn(2+) in aqueous medium at pH 7.4 based on the intraligand charge transfer (ICT) process. The in situ formed phenoxo-bridged complex, L1·2Zn can selectively and specifically sense PPi among all the other biologically important anions including ATP through reversible binding. The detection limit for Zn(2+) and PPi were found to be approximately 56 and 2 ppb, respectively. The unique selectivity of the PPi by the L1-Zn ensemble could be used as an analytical tool to probe PPi generation in a prototype polymerase chain reaction (PCR) setup and track DNA amplification with higher sensitivity as compared to conventional agarose gel electrophoresis. Interestingly, the principle of PPi estimation in PCR rendered rapid estimation of bacterial cell numbers with a limit of detection of 10 CFU of Escherichia coli MTCC 433 in as early as 10 PCR cycles. The proposed method of PPi sensing offers interesting application potential in PCR-based rapid diagnostics for pathogenic agents and microbiological quality control. 23386200 Dose finding by concentration-response versus dose-response: a simulation-based comparison. AIM: The investigations reported here aimed to evaluate the incremental benefit for dose finding by concentration-response analysis versus dose-response analysis. METHODS: Trials were simulated using an Emax model for a range of scenarios of drug properties, trial design options and target response levels. The simulated data were analysed by concentration-response and dose-response modelling; a dose was then chosen to target a specific response level in a confirmatory trial. The two approaches were compared in terms of the quality of model parameter estimation and the success rate for the confirmatory trial. RESULTS: While the accuracy for ED50 estimation was comparably good with both approaches, the precision was up to 90 % higher with concentration-response approach. The difference was most notable when clearance was highly variable between subjects and the top dose was relatively low. The higher precision by the concentration-response analysis lead to better dose selection and up to 20 % higher success rate for the subsequent confirmatory trial. The relatively small difference in success rate translated into a remarkable difference in sample size requirement. CONCLUSION: By customising these parameters, the approach and the findings can be applied to assessing the value of pharmacokinetic sampling in particular trial situations. 23958947 Optimization via specific fluorescence brightness of a receptor-targeted probe for optical imaging and positron emission tomography of sentinel lymph nodes. ABSTRACT. The optical properties of a receptor-targeted probe designed for dual-modality mapping of the sentinel lymph node (SLN) was optimized. Specific fluorescence brightness was used as the design criterion, which was defined as the fluorescence brightness per mole of the contrast agent. Adjusting the molar ratio of the coupling reactants, IRDye 800CW-NHS-ester and tilmanocept, enabled us to control the number of fluorescent molecules attached to each tilmanocept, which was quantified by H1 nuclear magnetic resonance spectroscopy. Quantum yields and molar absorptivities were measured for unconjugated IRDye 800CW and IRDye 800CW-tilmanocept (800CW-tilmanocept) preparations at 0.7, 1.5, 2.3, 2.9, and 3.8 dyes per tilmanocept. Specific fluorescence brightness was calculated by multiplication of the quantum yield by the molar absorptivity and the number of dyes per tilmanocept. It predicted that the preparation with 2.3 dyes per tilmanocept would exhibit the brightest signal, which was confirmed by fluorescence intensity measurements using three optical imaging systems. When radiolabeled with Ga68 and injected into the footpads of mice, the probe identified SLNs by both fluorescence and positron emission tomography (PET) while maintaining high percent extraction by the SLN. These studies demonstrated the feasibility of 800CW-tilmanocept for multimodal SLN mapping via fluorescence and PET-computed tomography imaging. 23831544 Perfluoroalkyl acids in the Canadian environment: Multi-media assessment of current status and trends. In Canada, perfluoroalkyl acids (PFAAs) have been the focus of several monitoring programs and research and surveillance studies. Here, we integrate recent data and perform a multi-media assessment to examine the current status and ongoing trends of PFAAs in Canada. Concentrations of perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), and other long-chain perfluorocarboxylates (PFCAs) in air, water, sediment, fish, and birds across Canada are generally related to urbanization, with elevated concentrations observed around cities, especially in southern Ontario. PFOS levels in water, fish tissue, and bird eggs were below their respective Draft Federal Environmental Quality Guidelines, suggesting there is low potential for adverse effects to the environment/organisms examined. However, PFOS in fish and bird eggs tended to exceed guidelines for the protection of mammalian and avian consumers, suggesting a potential risk to their wildlife predators, although wildlife population health assessments are needed to determine whether negative impacts are actually occurring. Long-term temporal trends of PFOS in suspended sediment, sediment cores, Lake Trout (Salvelinus namaycush), and Herring Gull (Larus argentatus) eggs collected from Lake Ontario increased consistently from the start of data collection until the 1990s. However, after this time, the trends varied by media, with concentrations stabilizing in Lake Trout and Herring Gull eggs, and decreasing and increasing in suspended sediment and the sediment cores, respectively. For PFCAs, concentrations in suspended sediment, sediment cores, and Herring Gulls generally increased from the start of data collection until present and concentrations in Lake Trout increased until the late 1990s and subsequently stabilized. A multimedia comparison of PFAA profiles provided evidence that unexpected patterns in biota of some of the lakes were due to unique source patterns rather than internal lake processes. High concentrations of PFAAs in the leachate and air of landfill sites, in the wastewater influent/effluent, biosolids, and air at wastewater treatment plants, and in indoor air and dust highlight the waste sector and current-use products (used primarily indoors) as ongoing sources of PFAAs to the Canadian environment. The results of this study demonstrate the utility of integrating data from different media. Simultaneous evaluation of spatial and temporal trends in multiple media allows inferences that would be impossible with data on only one medium. As such, more co-ordination among monitoring sites for different media is suggested for future sampling, especially at the northern sites. We emphasize the importance of continued monitoring of multiple-media for determining future responses of environmental PFAA concentrations to voluntary and regulatory actions. 23778852 Storable palladacycles for selective functionalization of alkyne-containing proteins. We report the facile preparation of palladacycles as storable arylpalladium(II) reagents from acetanilides via cyclopalladation. The palladacycles exhibit good stability in PBS buffer and are capable of functionalizing a metabolically encoded HPG-containing protein, thus providing a new type of biocompatible organometallic reagent for selectively functionalizing the alkyne-encoded proteins. 23571417 fMRI in the awake marmoset: somatosensory-evoked responses, functional connectivity, and comparison with propofol anesthesia. Functional neuroimaging in animal models is essential for understanding the principles of neurovascular coupling and the physiological basis of fMRI signals that are widely used to study sensory and cognitive processing in the human brain. While hemodynamic responses to sensory stimuli have been characterized in humans, animal studies are able to combine very high resolution imaging with invasive measurements and pharmacological manipulation. To date, most high-resolution studies of neurovascular coupling in small animals have been carried out in anesthetized rodents. Here we report fMRI experiments in conscious, awake common marmosets (Callithrix jacchus), and compare responses to animals anesthetized with propofol. In conscious marmosets, robust BOLD fMRI responses to somatosensory stimulation of the forearm were found in contralateral and ipsilateral regions of the thalamus, primary (SI) and secondary (SII) somatosensory cortex, and the caudate nucleus. These responses were markedly stronger than those in anesthetized marmosets and showed a monotonic increase in the amplitude of the BOLD response with stimulus frequency. On the other hand, anesthesia significantly attenuated responses in thalamus, SI and SII, and abolished responses in caudate and ipsilateral SI. Moreover, anesthesia influenced several other aspects of the fMRI responses, including the shape of the hemodynamic response function and the interareal (SI-SII) spontaneous functional connectivity. Together, these findings demonstrate the value of the conscious, awake marmoset model for studying physiological responses in the somatosensory pathway, in the absence of anesthesia, so that the data can be compared most directly to fMRI in conscious humans. 23719627 Chemical equilibria in the UO2(2+)-H2O2-F-/OH- systems and possible solution precursors for the formation of [Na6(OH2)8]@[UO2(O2)F]24(18-) and [Na6(OH2)8]@[UO2(O2)OH]24(18-) clusters. The focus of this study is on the relationship between uranyl(VI) poly-peroxo clusters in the solid state and their possible precursors in solution. For this purpose, the complex formation in the ternary U(VI)-H2O2-F(-) system has been studied by potentiometric titrations, measuring p[H(+)] and p[F(-)], revealing that significant amounts of ternary uranyl(VI)-peroxide-fluoride complexes are formed. Based on the analysis of these data we find that there are two models consistent with structure data and previous speciation in the uranyl(VI)-peroxide-carbonate system (Dalton. Trans., 2012, 41, 11635-11641). One model contains ternary complexes (UO2)4(O2)4F(-) and (UO2)4(O2)4F2(2-) and the other (UO2)4(O2)4F(-) and (UO2)5(O2)5F3(3-); we have chosen the second model as the one most consistent with available information. We suggest that (UO2)4(O2)4F(-) is a building block in the U-24 cluster, [Na6(OH2)8]@[UO2(O2)F]24(18-) identified in a single-crystal X-ray diffraction study of the solid phase that slowly precipitates from the slightly acidic test solutions. At p[H(+)] ≈ 9.5, a new solid phase is formed that contains the cluster [Na6(OH2)8]@[UO2(O2)OH]24(18-), also identified from an X-ray structure. Both structures contain η(2)-η(2) bridging peroxide and η(2) bridging fluoride or hydroxide ions, respectively. As fluoride bridges are unknown in solution coordination chemistry, it is unlikely that the U-24 fluoride cluster is formed in solution. We suggest that both the solid state fluoride and hydroxide clusters are formed in the crystallization from smaller precursors identified in solution. The study illustrates the importance of accurate control of the solution chemistry when preparing poly-peroxo-metallate clusters and also that the mechanism of their formation is still an open field of research. 23916069 HLA-B27 and antigen presentation: At the crossroads between immune defense and autoimmunity. The HLA-B27 is historically studied as a susceptibility factor in spondyloarthropathies and, primarily, in ankylosing spondylitis (AS). Over the recent years however, it has been rediscovered as protective factor against some severe viral infections. This is due to the high capacity of virus-specific, HLA-B27-restricted CD8+ T cells for both intrinsic (i.e. polyfunctionality, high avidity, low sensitivity to Treg cell-mediated suppression) and extrinsic (i.e. rapid and efficient antigen processing and presentation) factors. It is tempting to speculate that these two aspects are not independent and that the association of B27 molecules to autoimmunity is the downside of this superior functional efficacy which, in given genetic backgrounds and environmental conditions, can support a chronic inflammation leading to spondyloarthropathies. Still, the pathogenic role of HLA-B27 molecules in AS is elusive. Here, we focus on the biology of HLA-B27 from the genetics to the biochemistry and to the structural/dynamical properties of B27:peptide complexes as obtained from atomistic molecular dynamics simulation. Overall, the results point at the antigen presentation as the key event in the disease pathogenesis. In particular, an extensive comparison of HLA-B*2705 and B*2709 molecules, that differ in a single amino acid (Asp116 to His116) and are differentially associated with AS, indicates that position 116 is crucial for shaping the entire peptide-presenting groove. 23416002 Amino acid derived quinazolines as Rock/PKA inhibitors. SAR and lead optimization studies for Rock inhibitors based on amino acid-derived quinazolines are described. Studies demonstrated that these amino acid derived quinazolinones were mainly pan-Rock (I & II) inhibitors. While selectivity against other kinases could be achieved, selectivity for most of these compounds against PKA was not achieved. This is distinct from Rock inhibitors based on non-amino acid derived quinazolinones, where high selectivity against PKA could be obtained.(22) The inhibitors presented here in some cases possessed sub-nanomolar inhibition of Rock, nanomolar potency in ppMLC cell based assays, low to fair cytochrome P-450 inhibition, and good human microsomal stability. 23661021 MMP-2 -1306C > T polymorphism in breast cancer: a case-control study in a South European population. This case control study aims to investigate the role of MMP-2 -1306C > T polymorphism as a potential risk factor and possible prognostic marker for breast cancer in a South European population. 113 consecutive incident cases of histologically confirmed ductal breast cancer and 124 healthy controls were recruited. MMP-2 -1306C > T polymorphism was genotyped; multivariate logistic regression as well as Cox regression analysis were performed. MMP-2 -1306C > T status was not associated with breast cancer risk either at the total sample or at the subanalyses on premenopausal and postmenopausal women. At the survival analysis, a trend towards a favorable association between MMP-2 -1306C > T allele and disease-free survival as well as overall survival was observed. Regarding subanalyses on ER-negative and ER-positive cases, the favorable association implicating MMP-2 -1306C > T allele was particularly evident among ER-positive cases; no significant associations emerged among ER-negative cases. MMP-2 -1306C > T polymorphism does not seem to be a risk factor for breast cancer in South European population; however, a trend towards a favorable association with survival has been observed. 23900217 Notch-induced transcription factors are predictive of survival and 5-fluorouracil response in colorectal cancer patients. Background:The purpose of this study was to evaluate the expression of Notch-induced transcription factors (NTFs) HEY1, HES1 and SOX9 in colorectal cancer (CRC) patients to determine their clinicopathologic and prognostic significance.Methods:Levels of HEY1, HES1 and SOX9 protein were measured by immunohistochemistry in a nonmalignant and malignant tissue microarray of 441 CRC patients, and the findings correlated with pathologic, molecular and clinical variables.Results:The NTFs HEY1, HES1 and SOX9 were overexpressed in tumours relative to colonic mucosa (OR=3.44, P<0.0001; OR=7.40, P<0.0001; OR=4.08 P<0.0001, respectively). HEY1 overexpression was a negative prognostic factor for all CRC patients (HR=1.29, P=0.023) and strongly correlated with perineural and vascular invasion and lymph node (LN) metastasis. In 5-fluorouracil (5-FU)-treated patients, the tumour overexpression of SOX9 correlated with markedly poorer survival (HR=8.72, P=0.034), but had no predictive effect in untreated patients (HR=0.70, P=0.29). When HEY1, HES1 and SOX9 expression were combined to predict survival with chemotherapy, in treated patients there was an additive increase in the risk of death with each NTF overexpressed (HR=2.09, P=0.01), but no prognostic import in the untreated patient group (HR=0.74, P=0.19).Conclusion:The present study is the first to discover that HEY1 overexpression correlates with poorer outcome in CRC, and NTF expression is predictive of CRC patient survival with 5-FU chemotherapy. If confirmed in future studies, testing of NTF expression has the potential to enter routine pathological practice for the selection of patients to undergo chemotherapy alone or in combination with Notch inhibitors. 23968540 Antigenic and Molecular Characterization of Avian Influenza A(H9N2) Viruses, Bangladesh. Human infection with avian influenza A(H9N2) virus was identified in Bangladesh in 2011. Surveillance for influenza viruses in apparently healthy poultry in live-bird markets in Bangladesh during 2008-2011 showed that subtype H9N2 viruses are isolated year-round, whereas highly pathogenic subtype H5N1 viruses are co-isolated with subtype H9N2 primarily during the winter months. Phylogenetic analysis of the subtype H9N2 viruses showed that they are reassortants possessing 3 gene segments related to subtype H7N3; the remaining gene segments were from the subtype H9N2 G1 clade. We detected no reassortment with subtype H5N1 viruses. Serologic analyses of subtype H9N2 viruses from chickens revealed antigenic conservation, whereas analyses of viruses from quail showed antigenic drift. Molecular analysis showed that multiple mammalian-specific mutations have become fixed in the subtype H9N2 viruses, including changes in the hemagglutinin, matrix, and polymerase proteins. Our results indicate that these viruses could mutate to be transmissible from birds to mammals, including humans. 23822809 Nitric Oxide Deficiency and Endothelial Dysfunction in Pulmonary Arterial Hypertension. Nitric oxide (NO) signaling plays a major role in modulating vascular tone and remodeling in the pulmonary circulation, but its role in the pathogenesis of pulmonary vascular diseases is still not completely understood. Numerous abnormalities of NO synthesis and signaling have been identified in animal models of pulmonary vascular disease and in humans with pulmonary hypertension. Many of these abnormalities have become targets of new therapies for the treatment of pulmonary hypertension. However, it is unclear to what extent alterations in NO signaling contribute to pulmonary hypertensive responses or merely reflect abnormalities induced by the underlying disease. This perspective examines the current understanding of altered NO signaling in pulmonary hypertensive diseases and discusses how these alterations may contribute to the pathogenesis of pulmonary hypertension. The efficacy and limitations of presently available therapies for pulmonary hypertension that target NO signaling are reviewed along with an update on investigational therapies that also utilize this pathway to reverse pulmonary hypertensive changes. 23904312 Synovial sarcoma of the larynx treated by supraglottic laryngectomy: Case report and literature review. We describe a case of synovial sarcoma of the larynx, and we discuss the use of fluorescence in situ hybridization (FISH) in confirming the diagnosis. The patient was a 21-year-old woman who presented with a recurrence of a previously resected supraglottic tumor of the aryepiglottic folds. A horizontal supraglottic laryngectomy was performed, and the 0.5-cm tumor was resected. Histopathologic study suggested that it was a biphasic malignant tumor compatible with a synovial sarcoma. The diagnosis of synovial sarcoma was confirmed by FISH immunohistochemistry with the use of an SYT break-apart probe. The patient recovered satisfactorily, but at follow-up 5 years and 4 months later, tumoral activity was evident in the left side of the neck. A biopsy found that 5 lymph nodes contained a metastasis of the synovial sarcoma. Again, a bilateral neck dissection was performed, and it revealed that 16 of 16 right-side nodes and 36 of 36 left-side nodes were negative. Two months later, the patient received 46 Gy of radiotherapy in 23 sessions. She remained free of disease during 2 more years of follow-up. Synovial sarcoma of the larynx is a rare entity. Organ preservation seems to be indicated in these cases. The histologic diagnosis may be difficult. In this case, the identification of a genetic mutation corroborated the diagnosis. 23239649 Efficacy of the African weaver ant Oecophylla longinoda (Hymenoptera: Formicidae) in the control of Helopeltis spp. (Hemiptera: Miridae) and Pseudotheraptus wayi (Hemiptera: Coreidae) in cashew crop in Tanzania. Cashew, Anacardium occidentale, is an economically important cash crop for more than 300 000 rural households in Tanzania. Its production is, however, severely constrained by infestation by sap-sucking insects such as Helopeltis anacardii, H. schoutedeni and Pseudotheraptus wayi. The African weaver ant, Oecophylla longinoda, is an effective biocontrol agent of hemipteran pests in coconuts in Tanzania, but its efficacy in the control of Helopeltis spp. and P. wayi in Tanzanian cashew has not been investigated so far. The aim of this study was therefore to evaluate the efficacy of O. longinoda in the management of these insect pests in the cashew crop at different sites of the Coast region of Tanzania. Colonisation levels of O. longinoda, expressed as weaver ant trails, varied from 57.1 to 60.6% and from 58.3 to 67.5% in 2010 and 2011 respectively. The mean number of leaf nests per tree varied from five to eight nests in 2010 and from five to nine nests in 2011. There was a negative correlation between numbers of nests and pest damage. Oecophylla longinoda-colonised cashew trees had the lowest shoot damage by Helopeltis spp. of 4.8 and 7.5% in 2010 and 2011, respectively, as opposed to uncolonised cashew trees with 36 and 30% in 2010 and 2011 respectively. Similarly, nut damage by P. wayi was lowest in O. longinoda-colonised trees, with only 2.4 and 6.2% in 2010 and 2011 as opposed to uncolonised trees with 26 and 21%. Oecophylla longinoda is an effective biocontrol agent of the sap-sucking pests of cashew in the Coast region of Tanzania and should be considered as an important component of IPM. © 2012 Society of Chemical Industry. 23894584 Associations between a Polymorphism in the Pleiotropic GCKR and Age-Related Phenotypes: The HALCyon Programme. The glucokinase regulatory protein encoded by GCKR plays an important role in glucose metabolism and a single nucleotide polymorphism (SNP) rs1260326 (P446L) in the gene has been associated with several age-related biomarkers, including triglycerides, glucose, insulin and apolipoproteins. However, associations between SNPs in the gene and other ageing phenotypes such as cognitive and physical capability have not been reported. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women from five UK cohorts aged between 44 and 90+ years were genotyped for rs1260326. Meta-analysis was used to pool within-study genotypic associations between the SNP and several age-related phenotypes, including body mass index (BMI), blood lipid levels, lung function, and cognitive and physical capability. We confirm the associations between the minor allele of the SNP and higher triglycerides and lower glucose levels. We also observed a triglyceride-independent association between the minor allele and lower BMI (pooled beta on z-score = -0.04, p-value = 0.0001, n = 16,251). Furthermore, there was some evidence for gene-environment interactions, including physical activity attenuating the effects on triglycerides. However, no associations were observed with measures of cognitive and physical capability. Findings from middle-aged to older adults confirm associations between rs1260326 GCKR and triglycerides and glucose, suggest possible gene-environment interactions, but do not provide evidence that its relevance extends to cognitive and physical capability. 23936765 A Rising Cancer Prevention Target of RSK2 in Human Skin Cancer. RSK2 is a p90 ribosomal S6 kinase family (p90(RSK)) member regulating cell proliferation and transformation induced by tumor promoters such as epithelial growth factor (EGF) and 12-O-tetradecanoylphorbol-13-acetate. This family of p90(RSK) has classified as a serine/threonine kinase that respond to many growth factors, peptide hormones, neurotransmitters, and environmental stresses such as ultraviolet (UV) light. Our recent study demonstrates that RSK2 plays a key role in human skin cancer development. Activation of RSK2 by EGF and UV through extracellular-activated protein kinases signaling pathway induces cell cycle progression, cell proliferation, and anchorage-independent cell transformation. Moreover, knockdown of RSK2 by si-RNA or sh-RNA abrogates cell proliferation and cell transformation of non-malignant human skin keratinocyte, and colony growth of malignant melanoma (MM) cells in soft agar. Importantly, activated and total RSK2 protein levels are highly detected in human skin cancer tissues including squamous cell carcinoma, basal-cell carcinoma, and MM. Kaempferol and eriodictyol are natural substances to inhibit kinase activity of the RSK2 N-terminal kinase domain, which is a critical kinase domain to transduce their activation signals to the substrates by phosphorylation. In this review, we discuss the role of RSK2 in skin cancer, particularly in activation of signaling pathways and potent natural substances to target RSK2 as chemopreventive and therapeutic agents. 23928217 Co-expression pattern of dopamine beta-hydroxylase (DβH) and neuropeptide Y (NPY) within sympathetic innervation of ovary and umbilical cord of the European bison (Bison bonasus L.). Co-expression of dopamine β-hydroxylase (DβH) and neuropeptide Y (NPY) has never been examined in ovary (OV) and umbilical cord (UC) of the European bison (Eb), the endangered wild species. The OV and UC samples were harvested from seasonally eliminated Eb females (45-120 days post coitum). Frozen histological sections were examined by double fluorescent immunohistochemistry (dF-IHC), using the primary mouse anti-DβH monoclonals and rabbit anti-NPY polyclonals and then the immunocomplexes were visualized with FITC and CY3 fluorophores, respectively. Numerous DβH immunoreactive nerve fibers (DβH-IRs) and a little less frequent NPY-IRs were found in the bundle-like structures, innervating mainly perivascular regions of the OV. The NPY-IRs constantly co-expressed DβH, while some DβH-IRs did not express NPY. This specific pattern of innervation was observed both in the stromal and cortical regions of the OV. The simultaneous co-expression of DβH and NPY were also detected in the UC, in which specific single or bundle-like structures ran along the smooth muscles of blood vessels. The spatial-specific co-expression of DβH and NPY in OV and UC, may suggest that these markers are involved in the control of vascularization that regulates nourishing blood circulation required for proper pregnancy maintenance and efficient embryo/fetus development in the Eb. 23946405 Therapeutic Margins in a Novel Preclinical Model of Retinitis Pigmentosa. The third-most common cause of autosomal recessive retinitis pigmentosa (RP) is due to defective cGMP phosphodiesterase-6 (PDE6). Previous work using viral gene therapy on PDE6-mutant mouse models demonstrated photoreceptors can be rescued if administered before degeneration. However, whether visual function can be rescued after degeneration onset has not been addressed. This is a clinically important question, as newly diagnosed patients exhibit considerable loss of rods and cones in their peripheral retinas. We have generated and characterized a tamoxifen inducible Cre-loxP rescue allele, Pde6b(Stop), which allows us to temporally correct PDE6-deficiency. Whereas untreated mutants exhibit degeneration, activation of Cre-loxP recombination in early embryogenesis produced stable long-term rescue. Reversal at later time-points showed partial long-term or short-lived rescue. Our results suggest stable restoration of retinal function by gene therapy can be achieved if a sufficient number of rods are treated. Because patients are generally diagnosed after extensive loss of rods, the success of clinical trials may depend on identifying patients as early as possible to maximize the number of treatable rods. 23915286 MicroRNA-433 negatively regulates the expression of thymidylate synthase (TYMS) responsible for 5-fluorouracil sensitivity in HeLa cells. Thymidylate synthase (TYMS) is an important folate-dependent enzyme in DNA synthesis and an important target for cancer chemotherapy. High TYMS expression levels in tumors are generally associated with resistance to 5-fluorouracil (5-FU). The cause of the variability in TYMS expression is still not fully understood, however, only a small proportion of the TYMS expression can be explained by TYMS genetic polymorphisms. The purpose of this study is to identify novel microRNAs (miRNAs) which regulate the expression of TYMS and to determine whether miRNAs binding to the 3[prime]-untranslated region (UTR) of TYMS mRNA affect the proliferation of HeLa cells treated with 5-FU. An in silico search was performed to find potential binding sites of miRNAs in TYMS mRNA. The efficacy of predicted miRNAs at the 3[prime]-UTR of TYMS mRNA was evaluated using a dual-luciferase reporter assay. TYMS mRNA and protein expression in HeLa cells was quantified with real-time RT-PCR and Western blotting, respectively. The effects of miR-433 on cell proliferative activity were determined by WST-8 assay. The overexpression of miR-433 was associated with significantly decreased reporter activity in the plasmid containing the 3[prime]-UTR of TYMS mRNA (P < 0.01). The levels of TYMS mRNA and protein in HeLa cells were significantly decreased by the overexpression of miR-433 (P < 0.05). Furthermore, miR-433 increased inhibition of cell proliferation in HeLa cells treated with 5-FU at over 2.0 muM. The results indicate that miR-433 post-transcriptionally regulates the expression of TYMS mRNA and protein, and increases sensitivity to 5-FU in HeLa cells. This is the first report showing that a miRNA regulating TYMS expression has a significant impact on sensitivity to 5-FU treatment. 23941815 Modelling the lattice dynamics in SixGe1-x alloys. The development of simplified models for the simulation of thermodynamic and thermal transport properties in random alloys is of great importance. In this paper we show how a simple second nearest neighbour model can reliably capture the lattice dynamics of SixGe1-x alloys. The model parameters are extracted from DFT-calculated force constant matrices for pure Si, pure Ge and the Si0.5Ge0.5 ordered alloy. We extract the nearest neighbour contributions directly from density functional theory, whereas effective interactions are obtained for the second nearest neighbour contributions. We demonstrate how the thermal properties, including the expansion coefficient, can be reliably reproduced and that the model is transferable to random SixGe1-x alloys. 23360366 Amyloid fiber formation by synthetic peptides derived from the sequence of the protein CsgA of Escherichia coli. We characterized the formation of amyloid fibers by two peptides derived from the CsgA sequence: R5 (133- 151) corresponding to the whole repeating unit R5 and a truncated form of this peptide called R5T (134-143). In the presence of either of the two peptides: an increase in the fluorescence intensity of Thioflavin T was observed; a shift of the absorbance of Congo red was measured; spontaneous formation of amyloid fibers was observed by polarized light as well asatomic force microscopy imaging. Large-size aggregates were observed with R5 while R5T formed fagots of individualized fibers. The infrared spectroscopy analysis revealed the presence of a greater number of intermolecular bonds for R5. In conclusion, a 10 aminoacids peptide derived from the R5 sequence was sufficient for the spontaneous formation of amyloid fibrils but not to form large-size aggregates of fibers. 23728508 A novel flexible nanogenerator made of ZnO nanoparticles and multiwall carbon nanotube. In this paper, a novel flexible nanogenerator (FNG) made of zinc-oxide (ZnO) nanoparticles (NPs) and multiwall-carbon nanotubes (MW-CNTs) is presented. In this structure, ZnO NPs and MW-CNTs are mixed with polydimethylsiloxane (PDMS) uniformly to form an entire flexible nanogenerator. Serial tests illustrate that the output voltage and power density are as high as 7.5 V and 18.75 μW per cycle, respectively. Furthermore, by foot stamp on the FNG, a peak voltage as high as 30 V can be generated. Comparing to the control samples, it is also proved that adding MW-CNTs into the matrix could significantly enhance the output voltage from 0.8 to 7.5 V. In summary, our work indicates that the realization of flexible nanogenerators made of ZnO NPs and MW-CNTs is technologically feasible, which may bring out some important and interesting applications in energy harvesting. 23932383 Therapeutic and prognostic implications of subarachnoid hemorrhage in patients who suffered cardiopulmonary arrest and underwent cardiopulmonary resuscitation during an emergency room stay. Aneurysmal subarachnoid hemorrhage (SAH) is a well-known cause of sudden cardio-pulmonary arrest (CPA). Even after successful cardio-pulmonary resuscitation (CPR), the prognosis of patients following an aneurysmal SAH presenting with CPA remains dismal. However, there have been anecdotal reports of good outcomes with appropriate interventions. Pseudo-SAH resulting from marked elevation of intracranial pressure (ICP) after CPR, can mimic SAH in head computed tomographic (CT) scan. Such manifestations hamper resuscitation or delay appropriate neurosurgical management. This study assessed incidence and clinical characteristics of SAH-CPR or pseudo-SAH-CPR patients among non-traumatic CPA-CPR patients, and investigated their therapeutic and prognostic implication. During the 5-year observation period, 63 non-traumatic coma patients with CT evidence of high attenuation areas in the basal cistern who suffered arrest and underwent CPR during initial resuscitation in the emergency room, were reviewed retrospectively. They were divided into two groups according to the imaging pattern: true-SAH vs. pseudo-SAH, and then true-SAH group were further divided into two groups according to the CT acquisition time: brain CT before arrest vs. brain CT after arrest. Demographic, clinical, and CT data were assessed, and the primary outcome was measured using the 30-day Glasgow Outcome Scale (GOS) score, and the final outcome was evaluated at the end of 3 months post-ictus. When compared with pseudo-SAH (n=28) patients, true-SAH (n=35) patients showed a higher Hounsfield unit values in the affected area, earlier CT acquisition time before CPR, more survivors beyond 3 months (all p<0.05); however, the 30-day survival rate was not significantly different. Of the true-SAH patients, ruptured intracranial aneurysms were found in eight patients, and definite intervention was administered in four patients. When SAH patients were categorized according to the temporal relationship with CPR, the group of 24 patients undergoing CT scan before CPR showed a lower frequency of intraventricular hemorrhage, but showed a higher chance of surgical treatment and survival at 30 days and 3 months compared to the group undergoing CT scan after CPR. The overall survival between true-SAH and pseudo-SAH group was different significantly. Administering definite treatment for a ruptured aneurysm in instances of true SAH could save patients, albeit infrequently. A Prompt CT scan could guarantee recognition of high-density area, blood in the ventricle, and subsequent identification of the ruptured aneurysm, altogether preventing re-bleeding and warranting further systemic resuscitation. 23951108 Comparison enhances size sensitivity: neural correlates of outcome magnitude processing. Magnitude is a critical feature of outcomes. In the present study, two event-related potential (ERP) experiments were implemented to explore the neural substrates of outcome magnitude processing. In Experiment 1, we used an adapted gambling paradigm where physical area symbols were set to represent potential relative outcome magnitudes in order to exclude the possibility that the participants would be ignorant of the magnitudes. The context was manipulated as total monetary amount: ¥4 and ¥40. In these two contexts, the relative outcome magnitudes were ¥1 versus ¥3, and ¥10 versus ¥30, respectively. Experiment 2, which provided two area symbols with similar outcome magnitudes, was conducted to exclude the possible interpretation of physical area symbol for magnitude effect of feedback-related negativity (FRN) in Experiment 1. Our results showed that FRN responded to the relative outcome magnitude but not to the context or area symbol, with larger amplitudes for relatively small outcomes. A larger FRN effect (the difference between losses and wins) was found for relatively large outcomes than relatively small outcomes. Relatively large outcomes evoked greater positive ERP waves (P300) than relatively small outcomes. Furthermore, relatively large outcomes in a high amount context elicited a larger P300 than those in a low amount context. The current study indicated that FRN is sensitive to variations in magnitude. Moreover, relative magnitude was integrated in both the early and late stages of feedback processing, while the monetary amount context was processed only in the late stage of feedback processing. 23828186 Efficacy of strengthening or aerobic exercise on pain relief in people with knee osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. Objective:We performed a systematic review and meta-analysis of randomized controlled trials to investigate the differences in the efficacies between strengthening and aerobic exercises for pain relief in people with knee osteoarthritis.Data sources:This search was applied to Medline, Cochrane Central Register of Controlled Trials, the Physiotherapy Evidence Database, and the Cumulative Index to Nursing and Allied Health Literature. All literature published from each source's earliest date to March 2013 was included.Review methods:Trials comparing the effects of exercise intervention with those of either non-intervention or psycho-educational intervention were collected. Meta-analysis was performed for trials in which therapeutic exercise was carried out with more than three sessions per week up to eight weeks, for pain in people with knee osteoarthritis. All trials were categorised into three subgroups (non-weight-bearing strengthening exercise, weight-bearing strengthening exercise, and aerobic exercise). Subgroup analyses were also performed.Results:Data from eight studies were integrated. Overall effect of exercise was significant with a large effect size (standardised mean difference (SMD): -0.94; 95% confidence interval -1.31 to -0.57). Subgroup analyses showed a larger SMD for non-weight-bearing strengthening exercise (-1.42 [-2.09 to -0.75]) compared with weight-bearing strengthening exercise (-0.70 [-1.05 to -0.35]), and aerobic exercise (-0.45 [-0.77 to -0.13]).Conclusion:Muscle strengthening exercises with or without weight-bearing and aerobic exercises are effective for pain relief in people with knee osteoarthritis. In particular, for pain relief by short-term exercise intervention, the most effective exercise among the three types is non-weight-bearing strengthening exercise. 23933399 Angiotensin II promotes cardiac differentiation of embryonic stem cells via angiotensin type 1 receptor. As embryonic stem cells (ESCs) represent an attractive candidate cell source for obtaining cardiomyocytes to be used in cell replacement therapy, it is thus of considerable importance to understand the mechanism by which cardiac differentiation is regulated. In previous studies, we have shown that angiotensin type 1 receptor (AT1R) expressed in cardiomyocytes derived from mouse embryonic stem cells. However, little is known about the role of AT1R in cardiac differentiation, which plays a key role in cardiac physiology and pharmacology. In the present study, we demonstrated that AT1R agonist significantly enhanced cardiac differentiation as determined by increased percentage of beating embryoid bodies and a higher expression level of cardiac markers. On the contrary, AT1R agonist stimulated differentiation was reversed in the presence of AT1R antagonist. In addition, by administering selective inhibitors we found that the effect of AT1R was driven via extracellular-signal regulated kinase, c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase pathways. These findings suggest that AT1R signaling plays a key role in cardiac differentiation of ESCs. 23926254 Goofy coordinates the acuity of olfactory signaling. The basic scheme of odor perception and signaling from olfactory cilia to the brain is well understood. However, factors that affect olfactory acuity of an animal, the threshold sensitivity to odorants, are less well studied. Using signal sequence trap screening of a mouse olfactory epithelium cDNA library, we identified a novel molecule, Goofy, that is essential for olfactory acuity in mice. Goofy encodes an integral membrane protein with specific expression in the olfactory and vomeronasal sensory neurons and predominant localization to the Golgi compartment. Goofy-deficient mice display aberrant olfactory phenotypes, including the impaired trafficking of adenylyl cyclase III, stunted olfactory cilia, and a higher threshold for physiological and behavioral responses to odorants. In addition, the expression of dominant-negative form of cAMP-dependent protein kinase results in shortening of olfactory cilia, implying a possible mechanistic link between cAMP and ciliogenesis in the olfactory sensory neurons. These results demonstrate that Goofy plays an important role in establishing the acuity of olfactory sensory signaling. 23873442 Improved hidden Markov model for nosocomial infections. We propose a novel hidden Markov model (HMM) for parameter estimation in hospital transmission models, and show that commonly made simplifying assumptions can lead to severe model misspecification and poor parameter estimates. A standard HMM that embodies two commonly made simplifying assumptions, namely a fixed patient count and binomially distributed detections is compared with a new alternative HMM that does not require these simplifying assumptions. Using simulated data, we demonstrate how each of the simplifying assumptions used by the standard model leads to model misspecification, whereas the alternative model results in accurate parameter estimates. 23816945 Is 18F-FDG PET/CT Useful for Distinguishing Between Primary Thyroid Lymphoma and Chronic Thyroiditis? This study aims to investigate the usefulness of F-FDG PET/CT for distinguishing between primary thyroid lymphoma (PTL) and chronic thyroiditis. We retrospectively reviewed the data of 196 patients with diffuse F-FDG uptake of the thyroid gland and enrolled patients who were diagnosed as having PTL or chronic thyroiditis based on the medical records, pathological findings, and laboratory data. The enrolled patients comprised 10 PTL patients (M/F = 4:6) and 51 chronic thyroiditis patients (M/F = 8:43). Images had been acquired on a PET/CT scanner at 100 minutes after intravenous injection of F-FDG. The PTL group consisted of 7 patients with diffuse large B-cell lymphoma (DLBCL) and 3 with mucosa-associated lymphoid tissue (MALT) lymphoma. The maximum standardized uptake value (SUVmax) was significantly higher in the PTL group than that in the chronic thyroiditis group (25.3 ± 8.0 and 7.4 ± 3.2, P < 0.001). On the other hand, the CT density (Hounsfield unit: HU) was significantly lower in the PTL group than that in the chronic thyroiditis group (46.1 ± 7.0 HU and 62.1 ± 6.9 HU, P < 0.001). Within the PTL group, the SUVmax was significantly higher in the cases of DLBCL than in those of MALT lymphoma (29.0 ± 6.4 and 16.7 ± 2.3, P = 0.017). The SUVmax was significantly higher and the CT density was significantly lower in PTL as compared with those in chronic thyroiditis. Thus, F-FDG PET/CT may be useful for distinguishing between PTL and chronic thyroiditis. 23728071 A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features. The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT)/mammalian target of rapamycin (mTOR) pathway is upregulated in a number of human cancers, including non-small cell lung cancer (NSCLC). Its potential role in NSCLC progression provides an attractive target for anticancer therapy. The expression of phosphorylated mTOR (p-mTOR), phosphorylated AKT (p-AKT), p85α and p110γ subunits of PI3K, phosphorylated p70S6K (p-p70S6K), phosphatase and tensin homolog (PTEN) and phosphorylated 4E-BP1 (p‑4E‑BP1) was examined by immunohistochemistry in 102 NSCLC specimens. The results were correlated with clinicopathological features. We also examined 61 of our cases for the presence of PIK3CA, AKT1, PTEN and K-RAS mutations. A common PIK3CA mutation was detected at exon 9 in 2 samples (p.E545K), whereas another sample displayed a rare mutation (p.D1018N). Furthermore, 10 out of 54 cases (18.5%) had a K-RAS mutation at codon 12, 5 had a PTEN mutation (exons 7 and 8) and 1 case had an AKT1 mutation (p.E17K). PTEN mutations were associated with nodal metastases. The expression of p-mTOR positively correlated with that of p-AKT and p-p70S6K and was higher in adenocarcinomas along with nuclear p110γPI3K expression, whereas p-4E-BP1 expression was higher in squamous cell carcinomas. We also established a positive association between p85αPI3K or p110γPI3K and cytoplasmic p-AKT and its downstream effectors. An inverse correlation was noted between p-4E-BP1 immunoexpression and tumour status and nuclear p-AKT expression as regards tumour stage. Univariate survival analysis demonstrated that p-4E-BP1 expression, either alone or in combination with cytoplasmic p-AKT expression had an adverse prognostic significance in adenocarcinomas. The combination of p-4E‑BP1 and cytoplasmic p-AKT expression remained significant in the multivariate analysis as a function of their interaction with histological type. Our data demonstrate the significance of p‑4E‑BP1 immunoexpression as a molecular marker of prognostic value in adenocarcinomas, particularly when combined with p-AKT. 23945202 Treatment Approach and Outcomes of Vaginal Melanoma. To describe the characteristics of primary vaginal melanoma patients in the Surveillance, Epidemiology, and End Result database and to determine the outcome from the treatment approaches. From the Surveillance, Epidemiology, and End Result registry, 201 patients with vaginal melanoma were identified. Patients' characteristics and prognostic factors including age, race, extent of surgery, and use of radiation therapy were obtained. The median age was 68 years (range, 28-100 years). The population was 73% white, 11% black, and 16% Asian/American Indian. International Federation of Gynecology and Obstetrics staging results were stage I (46%), stage II (18%), stage III (3%), stage IVA (3%), stage IVB (12%), and unknown (18%). Treatment approach included surgical resection of the primary site in 70%, whereas 35% of the patients underwent lymph node resection. Approximately 40% of the patients received radiotherapy, which was primarily used in the adjuvant setting. Overall survival at 2 and 5 years was 24% and 15%, respectively. Presence of lymph nodes at diagnosis was associated with worse overall survival (hazard ratio, 1.98; P = 0.02). Adjuvant radiation did not offer a statistically significant overall survival advantage compared to surgery alone. Vaginal melanoma is a rare diagnosis primarily affecting the elderly. Overall survival is low even for patients presenting with disease limited to the vagina. Lymph node involvement at diagnosis is strongly predictive of worse overall survival. Most patients are treated with surgical resection with varying use of adjuvant radiotherapy. Further research is needed to identify the etiology and improve the outcome of this aggressive disease. 23927123 Viscous effects in a static physical model of the uniform glottis. The classic work on laryngeal flow resistance by van den Berg et al. [J. Acoust. Soc. Am. 29, 626-631 (1957)] is revisited. These authors used a formula to summarize their measurements, and thus they separated the effects of entrance loss and pressure recovery from those of viscosity within the glottis. Analysis of intraglottal pressure distributions obtained from the physical model M5 [R. Scherer et al., J. Acoust. Soc. Am. 109, 1616-1630 (2001)] reveals substantial regions within the glottis where the pressure gradient is almost constant for glottal diameters from 0.005 to 0.16 cm, as expected when viscous effects dominate the flow resistance of a narrow channel. For this set of glottal diameters, the part of the pressure gradient that has a linear dependence on the glottal volume velocity is isolated. The inverse cube diameter of the Poiseuille expression for glottal flows is examined with the data set provided by the M5 intraglottal pressure distributions. The Poiseuille effect is found to give a reasonable account of viscous effects in the diameter interval from 0.0075 to 0.02 cm, but an inverse 2.59 power law gives a closer fit across all diameters. 23583855 Lower CSF interleukin-6 predicts future depression in a population-based sample of older women followed for 17 years. The literature regarding cerebrospinal fluid (CSF) cytokines in geriatric depression is sparse. The aim of this study was to examine associations between CSF interleukin-6 (IL-6) and related proinflammatory cytokines and current and future depression in a population-based sample of older women who were followed for 17 years. 83 non-demented women aged 70-84 years who participated in the Prospective Population Study of Women in Gothenburg, Sweden took part in a lumbar puncture in 1992-3. CSF- IL-6, interleukin-1β (IL-1β), interleukin- 8 (IL-8) and tumor necrosis factor-α (TNF-α) were measured. Psychiatric symptoms were rated with the Comprehensive Psychopathological Rating Scale at baseline and at three subsequent face-to-face examinations. Depression (major or minor) was diagnosed in accordance with DSM-IV/DSM-IV research criteria. At baseline, women with ongoing depression had lower levels of IL-6 (p<0.04), IL-8 (p<0.05) and TNF-α (p<0.05) compared with those without depression. In women without depression at baseline, lower CSF IL-6 levels predicted depression at one or more follow-up examination (p<0.03). Results from the generalized linear mixed logistic model using all baseline and follow-up data on depression status and Mini Mental State Examination score showed a significant relationship between IL-6 and depression (p=0.005 OR 0.370 CI [0.184-0.744]). Lower levels of CSF IL-6 were associated with current depression and with future depression during a follow-up of almost two decades. Our findings suggest that lower levels of CSF IL-6 may be related to depression vulnerability in later life. 23930658 Evaluation of a stretching program to increase worker flexibility. This article describes the evaluation of a stretching program intended to increase worker flexibility. 23756751 The SRS-Schwab Adult Spinal Deformity Classification: Assessment and Clinical Correlations Based on a Prospective Operative and Nonoperative Cohort. The Schwab-SRS classification of adult spinal deformity (ASD) is a validated system that provides a common language for the complex pathology of ASD. Classification reliability has been reported; however, correlation with treatment has not been assessed. To assess the clinical relevance of the SRS-Schwab classification based on correlations with health-related quality of life (HRQOL) measures and the decision to pursue operative versus non-operative treatment. Prospective analysis of consecutive ASD patients (age≥18yrs) collected through a multi-center group. The SRS-Schwab classification includes a curve type descriptor and three sagittal spinopelvic modifiers (sagittal vertical axis, pelvic tilt, pelvic incidence/lumbar lordosis mismatch). Differences in demographics, HRQOL (ODI, SRS-22, SF-36), and classification between operative and non-operative patients were evaluated. 527 patients (mean age 52.9 years, range: 18.4-85.1) met inclusion criteria. Significant differences in HRQOL were identified based on SRS-Schwab curve type, with thoracolumbar and primary sagittal deformities associated with greater disability and poorer health status than thoracic or double curve deformities. Operative patients had significantly poorer grades for each of the sagittal spinopelvic modifiers, and progressively higher grades were associated with significantly poorer HRQOL (p<0.05). Patients with worse sagittal spinopelvic modifier grades were significantly more likely to require major osteotomies, iliac fixation, and decompression (p≤0.009). The SRS-Schwab classification provides a validated language to describe and categorize ASD. The present study demonstrates that the SRS-Schwab classification reflects severity of disease state based on multiple measures of HRQOL, and significantly correlates with the important decision of whether to pursue operative versus non-operative treatment. 23942571 Why PEO as a binder or polymer coating increases capacity in the Li-S system. PEO, used either as a binder or a polymer coating, and PEGDME, used as an electrolyte additive, are shown to increase the reversible capacity of Li-S cells. The effect, in all three cases, is the same: an improved solvent system for the electrochemistry of sulfur species and suppression of cathode passivation on discharge. This constitutes a novel interpretation of the mechanistic behaviour of polyethers in the Li-S system, and sheds new light upon several previous studies. 23731616 Personal medication preparedness among veteran and nonveteran men and women in the california population. Introduction The health of people with chronic medical conditions is particularly vulnerable to the disruptions caused by public health disasters, especially when there is massive damage to the medical infrastructure. Government agencies and national organizations recommend that people with chronic illness prepare for disasters by stockpiling extra supplies of medications. Problem A wide range of chronic illnesses has long been documented among veterans of the US armed forces. Veterans with chronic illness could be at great risk of complications due to disaster-related medication disruptions; however, the prevalence of personal medication preparedness among chronically ill veterans is not currently known. Data was used from the 2009 California Health Interview Survey on 28,167 respondents who reported taking daily medications. After adjusting for differences in age, health status, and other characteristics, calculations were made of the percentage of respondents who had a two-week supply of emergency medications and, among respondents without a supply, the percentage who said they could obtain one. Veteran men, veteran women, nonveteran men, and nonveteran women were compared. Medication supplies among veteran men (81.9%) were higher than among nonveteran women (74.8%; P < .0001) and veteran women (81.1%; P = 0.014). Among respondents without medication supplies, 67.2% of nonveteran men said that they could obtain a two-week supply, compared with 60.1% of nonveteran women (P = .012). Discussion Among adults in California with chronic illness, veteran men are more likely to have personal emergency medication supplies than are veteran and nonveteran women. Veteran men may be more likely to be prepared because of their training to work in combat zones and other emergency situations, which perhaps engenders in them a culture of preparedness or self-reliance. It is also possible that people who choose to enlist in the military are different from the general population in ways that make them more likely to be better prepared for emergencies. Veterans in California have a relatively high level of emergency medication preparedness. Given the health complications that can result from disaster-related medication disruptions, this is a promising finding. Disasters are a national concern, however, and the personal preparedness of veterans in all parts of the nation should be assessed; these findings could serve as a useful reference point for such work in the future. Heslin K , Gin J , Afable M , Ricci K , Dobalian A . Personal medication preparedness among veteran and nonveteran men and women in the California population. Prehosp Disaster Med. 2013; 28(4):1-8 . 23477504 Steroids Glycosylated with Both d- and l-Arabinoses from the South China Sea Gorgonian Dichotella gemmacea. Three new 19-hydroxy steroidal glycosides, namely, junceellosides E-G (2-4), were isolated together with the known analogue junceelloside C (1) from the South China Sea gorgonian Dichotella gemmacea. The structures of these compounds were elucidated by a combination of detailed spectroscopic analyses, chemical methods, and comparison with reported data. These glycosides are found to have sugar moieties of both β-l- and β-d-arabinopyranoses by HPLC analysis of their thiocarbamoyl-thiazolidine derivatives and those of authentic d- and l-arabinoses, leading to the structure revision of junceelloside C (1). This is the first report of steroidal glycosides from the gorgonian D. gemmacea and the first report of glycosides with β-l-arabinopyranose from marine sources. 23729195 Solvent-polarity-tuned morphology and inversion of supramolecular chirality in a self-assembled pyridylpyrazole-linked glutamide derivative: nanofibers, nanotwists, nanotubes, and microtubes. The self-assembly of a low-molecular-weight organogelator into various hierarchical structures has been achieved for a pyridylpyrazole linked L-glutamide amphiphile in different solvents. Upon gel formation, supramolecular chirality was observed, which exhibited an obvious dependence on the polarity of the solvent. Positive supramolecular chirality was obtained in nonpolar solvents, whereas it was inverted into negative supramolecular chirality in polar solvents. Moreover, the gelator molecules self-assembled into a diverse array of nanostructures over a wide scale range, from nanofibers to nanotubes and microtubes, depending on the solvent polarity. Such morphological changes could even occur for the xerogels in the solvent vapors. We found that the interactions between the pyridylpyrazole headgroups and the solvents could subtly change the stacking of the molecules and, hence, their self-assembled nanostructures. This work exemplifies that organic solvents can significantly involve the gelation, as well as tune the structure and properties, of a gel. 23895583 Effects of uric acid on endothelial dysfunction in early chronic kidney disease and its mechanisms. An increase in serum uric acid (UA) occurs during the early and middle stages of chronic kidney disease (CKD) and aggravates the deterioration of kidney function. This study aims to explore the relation between UA and endothelial dysfunction in early CKD and its mechanisms in a murine model. The experimental animals were randomly divided into three groups (n = 10): sham-operation group (control group), right nephrectomy only group (CKD group) and right nephrectomy with oxonic potassium group (CKD with hyperuricemia group). Furthermore, we analyzed the relation between UA and endothelial dysfunction indices in early CKD as well as its mechanisms. Linear regression analysis showed that the level of serum UA had a significant positive correlation with serum endothelin-1 and the percentage of collagen I positive area, but a negative correlation with serum nitric oxide (NO) and NO/endothelin-1 ratio. In addition, the level of serum UA had significant positive correlations with serum malonaldehyde, serum C-reactive protein, serum oxidatively-modified low-density lipoprotein and serum low-density lipoprotein, but a negative correlation with serum superoxide dismutase. Endothelial dysfunction in the CKD group was significant and had a positive correlation with the level of serum UA. Endothelial dysfunction in early CKD with hyperuricemia is perhaps related to oxidative stress, micro-inflammation and lipid oxidation. 23531416 Using whole mount in situ hybridization to examine thyroid hormone deiodinase expression in embryonic and larval zebrafish: A tool for examining OH-BDE toxicity to early life stages. Polybrominated diphenyl ethers (PBDEs) and their oxidative metabolites (hydroxylated PBDEs; OH-BDEs) are known endocrine disrupting contaminants that have been shown to disrupt thyroid hormone regulation both in mammals and in fish. The purpose of this study was to determine the precise organ and tissue locations that express genes critical to thyroid hormone regulation in developing zebrafish (Danio rerio), and to determine the effects of an OH-BDE on their expression. While RT-PCR can provide quantitative data on gene expression, it lacks spatial sensitivity to examine localized gene expression; and, isolation of organs from zebrafish embryos is technically difficult, if not impossible. For this reason, the present study used whole mount in situ hybridization to simultaneously localize and quantify gene expression in vivo. While PBDEs and OH-BDEs have been shown to inhibit the activity and expression of deiodionases, a family of enzymes that regulate thyroid hormone concentrations intracellularly, it is unclear whether or not they can affect regional expression of the different isoforms during early development. In this study we investigated deiodinase 1 (Dio1), deiodinase 2 (Dio2), and deiodinase 3 (Dio3) mRNA expression at the following life stages (2, 8, and 1k-cells; 50%-epiboly, 6 and 18-somites, 22, 24, 48, 72 hpf and/or 10 dpf) in zebrafish and found life stage specific expression of these genes that were highly localized. To demonstrate the use of this technique for investigating potential endocrine disrupting effects, zebrafish embryos were exposed to 1, 10 and 100nM 6-OH-BDE-47. Significant increases in mean intensity of Dio1 and Dio3 expression in the periventricular zone of brain and pronephric duct, respectively (quantified by measuring intensity of coloration using ImageJ analysis software) were observed, suggesting localized response at the HPT axis with the possibility of impacting neurodevelopment. Our results demonstrate effects of OH-BDEs on thyroid regulating gene expression and provide more insight into potential sites of injury during early life stages. 23855724 HIV Testing in the Nation's Opioid Treatment Programs, 2005-2011: The Role of State Regulations. To identify the extent to which clients in a national sample of opioid treatment programs (OTPs) received HIV testing in 2005 and 2011; to examine relationships between state laws for informed consent and pretest counseling and rates of HIV testing among OTP clients. Data were collected from a nationally representative sample of OTPs in 2005 (n = 171) and 2011 (n = 200). Random-effects logit and interval regression analyses were used to examine changes in HIV testing rates and the relationship of state laws to HIV testing among OTPs. Data on OTP provision of HIV testing were collected in phone surveys from OTP managers; data also were collected on state laws for HIV testing. The percentage of OTPs offering HIV testing decreased significantly from 93 percent in 2005 to 64 percent in 2011. Similarly, the percentage of clients tested decreased from an average of 41 percent in 2005 to 17 percent in 2011. OTPs located in states whose laws do not require pretest counseling and that use opt-out consent were more likely to provide HIV testing and to test higher percentages of clients. The results show the need to increase HIV testing among OTP clients; the results also underscore the beneficial possibilities of dropping pretest counseling as a requirement for HIV testing and of using the opt-out approach to informed consent for testing. 23949006 Non-Linear Relationships between Aflatoxin B1 Levels and the Biological Response of Monkey Kidney Vero Cells. Aflatoxin-producing fungi contaminate food and feed during pre-harvest, storage and processing periods. Once consumed, aflatoxins (AFs) accumulate in tissues, causing illnesses in animals and humans. Most human exposure to AF seems to be a result of consumption of contaminated plant and animal products. The policy of blending and dilution of grain containing higher levels of aflatoxins with uncontaminated grains for use in animal feed implicitly assumes that the deleterious effects of low levels of the toxins are linearly correlated to concentration. This assumption may not be justified, since it involves extrapolation of these nontoxic levels in feed, which are not of further concern. To develop a better understanding of the significance of low dose effects, in the present study, we developed quantitative methods for the detection of biologically active aflatoxin B1 (AFB1) in Vero cells by two independent assays: the green fluorescent protein (GFP) assay, as a measure of protein synthesis by the cells, and the microculture tetrazolium (MTT) assay, as a measure of cell viability. The results demonstrate a non-linear dose-response relationship at the cellular level. AFB1 at low concentrations has an opposite biological effect to higher doses that inhibit protein synthesis. Additional studies showed that heat does not affect the stability of AFB1 in milk and that the Vero cell model can be used to determine the presence of bioactive AFB1 in spiked beef, lamb and turkey meat. The implication of the results for the cumulative effects of low amounts of AFB1 in numerous foods is discussed. 23751900 No association between MspI allele of the ADRA2A polymorphism and ADHD: meta-analysis of family-based studies. There is evidence for a genetic contribution to attention-deficit hyperactivity disorder (ADHD), although no candidate genes have attained genome-wide significance to date. Given that the noradrenergic system has been implicated in ADHD, the gene for the α2-adrenergic receptor (ADRA2A) has been hypothesized to contribute to the pathogenesis of ADHD. The present investigation reports results from a meta-analysis of family-based studies that did not find a significant association between the MspI polymorphism of the ADRA2A gene and ADHD. 23546335 Children's Exposure to Mercury-Contaminated Soils: Exposure Assessment and Risk Characterization. Exposure to mercury (Hg)-contaminated soils may pose a health risk to children by way of oral, dermal, and inhalatory pathways. However, risk characterization studies, including contaminant bioaccessibility with child-specific exposure parameters and scenarios, are lacking. The objectives of this study were (1) to assess children's Hg exposure using characterization and oral bioaccessibility data from Hg-contaminated soils characterized in previous studies (n = 8); and (2) to characterize probabilistic risk in terms of hazard index (HI) considering ingestion, dermal, and inhalation pathways. Total Hg concentrations in soils ranged from 2.61 to 1.15 Ã— 10(4) mg kg(-1). For moderately contaminated soils (S1-S5: Hg â‰¤ 12.15 mg kg(-1)), low oral bioaccessibility values (1.5-7.5 %) lead to HI < 1 in all scenarios. However, exposure to highly contaminated soils (S6-S8) may pose serious risks to children under normal exposure (HI 0.89-66.5) and soil-pica behaviour scenarios (HI up to 131). All three pathways significantly contributed to the risk. Using total Hg concentrations in calculations (assuming 100 % bioavailability) instead of considering Hg bioavailability leads to risk overestimation. Further research on oral, inhalatory, and dermal bioavailability of Hg, as well as child play behaviour, is recommended to obtain more accurate risk estimates. 23719542 The role of NADPH oxidase in taurine attenuation of Streptococcus uberis-induced mastitis in rats. In order to evaluate the role of taurine on the oxidative stress mediated by NADPH oxidase in Streptococcus uberis-induced (S. uberis) mastitis, rats were administered daily (per os) 100mg/kg of taurine (group TS) or an equal volume of physiological saline (group CS) from gestation day 14 until parturition. Seventy-two hours after parturition, approximately 100cfu of S. uberis was infused into each of 2 mammary glands. Pretreatment with taurine significantly decreased mRNA and protein expression of p47phox and p22phox in mammary tissues. The total anti-oxidation capability (T-AOC) levels and superoxide dismutase (SOD) activities decreased, while malondialdehyde (MDA) levels increased both in mammary tissues and serum of rats with intramammary S. uberis infusion. Gavage administration of taurine moderated this change. Concentrations of interleukin-1β (IL-1β) and IL-6 in mammary glands decreased as a result of taurine administration. Significant differences (P<0.05) were present at 48 and 72 h post S. uberis-infusion (PI) for IL-1β and 72 h PI for IL-6. Our data indicate that, in S. uberis-induced mastitis, taurine has the ability of regulating redox conditions which leads to the suppression of oxidative stress and secretion of proinflammatory cytokines. This phenomenon may be ascribed to taurines's ability to inhibit the expression of NADPH oxidase. 23549764 Intraocular pressure variation during colorectal laparoscopic surgery: standard pneumoperitoneum leads to reversible elevation in intraocular pressure. The potential effects of laparoscopic surgery on intra- and postoperative intraocular pressure (IOP) are not completely understood. Although prior studies have reported that pneumoperitoneum may increase IOP, it is not clear whether this increase is related to the effects of pneumoperitoneum or to the patient's position, such as the Trendelenburg position. This study aimed to evaluate the potential fluctuations of IOP during colorectal laparoscopic surgery in two groups of patients: those with and those without Trendelenburg positioning. For this prospective study 45- to 85-year-old patients undergoing laparoscopic colorectal surgery were enrolled after a thorough ophthalmologic assessment. The study protocol included measurement of IOP at eight different time points (before, during, and after surgery) using a contact tonometer in both eyes. The study enrolled 29 patients: 17 (58.6 %) with Trendelenburg position placement during surgery and 12 (41.4 %) without Trendelenburg positioning. The two groups did not differ in terms of gender, age, body mass index (BMI), American Society of Anesthesiology (ASA) class, or operative time. In all the patients, pneumoperitoneum induction led to a mild rise in IOP, averaging 4.1 mmHg. The patients with Trendelenburg positioning showed a greater increase than the patients without it (5.05 vs 4.23 mmHg at 45 min; p = 0.179), but IOP evaluation 48 h after surgery showed no substantial differences between the two groups. Among the 29 patients, 17 (58.6 %) showed an increase in IOP of 5 mmHg or more during surgery. A greater percentage of the patients who underwent Trendelenburg positioning showed an IOP increase of 5 mmHg or more (76.5 vs 33.3 %; p = 0.020). At the multivariate analysis, no potential predictors of increased IOP during surgery was identified. Standard pneumoperitoneum (≤14 mmHg) led to mild and reversible IOP increases. A trend was observed toward a greater IOP increase in patients with Trendelenburg positioning. Thus, the patient's position during surgery may represent a stronger risk factor for IOP increase than pneumoperitoneum-related intraabdominal pressure. 23773729 Transcatheter aortic valve replacement: does kidney function affect outcome? Chronic kidney disease is a significant risk factor for mortality as well as acute kidney injury in cardiac surgery. The impact of contrast agent application on outcome is not well described in patients undergoing transcatheter aortic valve implantation. We analyzed data of 270 patients who underwent transcatheter aortic valve implantation (TAVI) between September 2008 and March 2012. Acute kidney injury was defined according to modified risk, injury, failure, loss and end-stage renal failure criteria. Patients on chronic hemodialysis were analyzed separately (n = 15). In 129 (47.8%) patients chronic kidney disease was apparent preoperatively. On average, 83.7 (± 32.4) mL of contrast agent were used per patient. Postoperatively, 41 patients (15.2%) developed acute kidney injury. In 19 patients (7.1%) transient renal replacement therapy was necessary; no chronic hemodialysis was required. Thirty-day-mortality did not differ between patients with or without chronic kidney disease (7.0% vs 7.1%, p = 0.97). Additionally, chronic kidney disease had no influence on the incidence of postoperative acute kidney injury (12.8% vs 20.2%, p = 0.07) or postoperative hemodialysis (5.0% vs 10.5%, p = 0.08). No correlation between the amount of contrast agent applied and the incidence of acute kidney injury could be verified (p = 0.57). Preoperative chronic kidney disease does not increase the risk of mortality and acute kidney injury after transcatheter aortic valve implantation. Acute kidney injury after TAVI is associated with an elevated risk of mortality. The amount of contrast agent applied intra-procedurally does not affect the risk of acute kidney injury. 22960624 Centrally acting oximes in reactivation of tabun-phosphoramidated AChE. Organophosphates (OP) inhibit acetylcholinesterase (AChE, EC 3.1.1.7), both in peripheral tissues and central nervous system (CNS), causing adverse and sometimes fatal effects due to the accumulation of neurotransmitter acetylcholine (ACh). The currently used therapy, focusing on the reactivation of inhibited AChE, is limited to peripheral tissues because commonly used quaternary pyridinium oxime reactivators do not cross the blood brain barrier (BBB) at therapeutically relevant levels. A directed library of thirty uncharged oximes that contain tertiary amine or imidazole protonable functional groups that should cross the BBB as unionized species was tested as tabun-hAChE conjugate reactivators along with three reference oximes: DAM (diacetylmonoxime), MINA (monoisonitrosoacetone), and 2-PAM. The oxime RS150D [N-((1-(3-(2-((hydroxyimino)methyl)-1H-imidazol-1-yl)propyl)-1H-1,2,3-triazol-4-yl)methyl)benzamide] was highlighted as the most promising reactivator of the tabun-hAChE conjugate. We also observed that oximes RS194B [N-(2-(azepan-1-yl)ethyl)-2-(hydroxyimino)acetamide] and RS41A [2-(hydroxyimino)-N-(2-(pyrrolidin-1-yl)ethyl)acetamide], which emerged as lead uncharged reactivators of phosphylated hAChE with other OPs (sarin, cyclosarin and VX), exhibited only moderate reactivation potency for tabun inhibited hAChE. This implies that geometry of oxime access to the phosphorus atom conjugated to the active serine is an important criterion for efficient reactivation, along with the chemical nature of the conjugated moiety: phosphorate, phosphonate, or phosphoramidate. Moreover, modification of the active center through mutagenesis enhances the rates of reactivation. The phosphoramidated-hAChE choline-binding site mutant Y337A showed three-times enhanced reactivation capacity with non-triazole imidazole containing aldoximes (RS113B, RS113A and RS115A) and acetamide derivative (RS194B) than with 2PAM. 23464929 Oversampling to Overcome Overfitting: Exploring the Relationship between Data Set Composition, Molecular Descriptors, and Predictive Modeling Methods. The traditional biological assay is very time-consuming, and thus the ability to quickly screen large numbers of compounds against a specific biological target is appealing. To speed up the biological evaluation of compounds, high-throughput screening is widely used in the fields of biomedical, biological information, and drug discovery. The research presented in this study focuses on the use of support vector machines, a machine learning method, various classes of molecular descriptors, and different sampling techniques to overcome overfitting to classify compounds for cytotoxicity with respect to the Jurkat cell line. The cell cytotoxicity data set is imbalanced (a few active compounds and very many inactive compounds), and the ability of the predictive modeling methods is adversely affected in these situations. Commonly imbalanced data sets are overfit with respect to the dominant classified end point; in this study the models routinely overfit toward inactive (noncytotoxic) compounds when the imbalance was substantial. Support vector machine (SVM) models were used to probe the proficiency of different classes of molecular descriptors and oversampling ratios. The SVM models were constructed from 4D-FPs, MOE (1D, 2D, and 21/2D), noNP+MOE, and CATS2D trial descriptors pools and compared to the predictive abilities of CATS2D-based random forest models. Compared to previous results in the literature, the SVM models built from oversampled data sets exhibited better predictive abilities for the training and external test sets. 23842529 Rapid Cl-/HCO3- exchange kinetics of AE1 in HEK293 cells and hereditary stomatocytosis red blood cells. Anion Exchanger 1 or Band 3 is a membrane protein responsible for the rapid exchange of chloride for bicarbonate across the red blood cell membrane. Nine mutations leading to single amino-acid substitutions in the transmembrane domain of AE1 are associated with dominant hereditary stomatocytosis, monovalent cation leaks and reduced anion exchange activity. We set up a stopped-flow spectrofluorometry assay coupled with flow cytometry to investigate the anion transport and membrane expression characteristics of wild-type recombinant AE1 in HEK293 cells, using an inducible expression system. Likewise, study of three stomatocytosis associated mutations (R730C, E758K and G796R), allowed the validation of our method. Measurement of the rapid and specific chloride/bicarbonate exchange by surface expressed AE1 showed that E758K mutant was fully active compared to WT AE1, whereas R730C and G796R mutants were inactive, reinforcing previously reported data on other experimental models. Stopped-flow analysis of AE1 transport activity in red blood cell ghost preparations revealed a 50% reduction of G796R compared to WT AE1 corresponding to a loss of function of the G796R mutated protein, in accordance with the heterozygous status of the AE1 variant patients. In conclusion, stopped-flow led to measurement of rapid transport kinetics using the natural substrate for AE1, and conjugated with flow cytometry, allowed a reliable correlation of chloride/bicarbonate exchange to surface expression of AE1, both in recombinant cells and ghosts and therefore a fine comparison of function between different stomatocytosis samples. This technical approach thus provides significant improvements in anion exchange analysis in red blood cells. 23389051 Process engineering with planetary ball mills. Planetary ball mills are well known and used for particle size reduction on laboratory and pilot scales for decades while during the last few years the application of planetary ball mills has extended to mechanochemical approaches. Processes inside planetary ball mills are complex and strongly depend on the processed material and synthesis and, thus, the optimum milling conditions have to be assessed for each individual system. The present review focuses on the insight into several parameters like properties of grinding balls, the filling ratio or revolution speed. It gives examples of the aspects of grinding and illustrates some general guidelines to follow for modelling processes in planetary ball mills in terms of refinement, synthesis' yield and contamination from wear. The amount of energy transferred from the milling tools to the powder is significant and hardly measurable for processes in planetary ball mills. Thus numerical simulations based on a discrete-element-method are used to describe the energy transfer to give an adequate description of the process by correlation with experiments. The simulations illustrate the effect of the geometry of planetary ball mills on the energy entry. In addition the imaging of motion patterns inside a planetary ball mill from simulations and video recordings is shown. 23292436 7 Tesla compatible in-bore display for functional magnetic resonance imaging. A liquid crystal display was modified for use inside a 7 T MR magnet. SNR measurements were performed using different imaging sequences with the monitor absent, present, or activated. fMRI with a volunteer was conducted using a visual stimulus. SNR was reduced by 3.7 %/7.9 % in echo planar/fast-spin echo images when the monitor was on which can be explained by the limited shielding of the coated front window (40 dB). In the fMRI experiments, activated regions in the visual cortex were clearly visible. The monitor provided excellent resolution at minor SNR reduction in EPI images, and is thus suitable for fMRI at ultra-high field. 23220742 The selective SYK inhibitor P505-15 (PRT062607) inhibits B cell signaling and function in vitro and in vivo and augments the activity of fludarabine in chronic lymphocytic leukemia. B-cell receptor (BCR) associated kinases including spleen tyrosine kinase (SYK) contribute to the pathogenesis of B-cell malignancies. SYK is persistently phosphorylated in a subset of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), and SYK inhibition results in abrogation of downstream kinase activity and apoptosis. P505-15 (also known as PRT062607) is a novel, highly selective, and orally bioavailable small molecule SYK inhibitor (SYK IC(50) = 1 nM) with anti-SYK activity that is at least 80-fold greater than its affinity for other kinases. We evaluated the preclinical characteristics of P505-15 in models of NHL and CLL. P505-15 successfully inhibited SYK-mediated B-cell receptor signaling and decreased cell viability in NHL and CLL. Oral dosing in mice prevented BCR-mediated splenomegaly and significantly inhibited NHL tumor growth in a xenograft model. In addition, combination treatment of primary CLL cells with P505-15 plus fludarabine produced synergistic enhancement of activity at nanomolar concentrations. Our findings support the ongoing development of P505-15 as a therapeutic agent for B-cell malignancies. A dose finding study in healthy volunteers has been completed. 23472949 Ontogeny of the ovary in polycystic ovary syndrome. Activation of primordial follicles into the growing pool, selection of the dominant follicle, and its eventual ovulation require complex endocrine and metabolic interactions as well as intraovarian paracrine signals to coordinate granulosa cell proliferation, theca cell differentiation, and oocyte maturation. Early preantral follicle development relies mostly upon mesenchymal-epithelial cell interactions, intraovarian paracrine signals, and oocyte-secreted factors, whereas development of the antral follicle depends on circulating gonadotropins as well as locally derived regulators. In women with polycystic ovary syndrome (PCOS), ovarian hyperandrogenism, hyperinsulinemia from insulin resistance, and altered intrafollicular paracrine signaling perturb the activation, survival, growth, and selection of follicles, causing accumulation of small antral follicles within the periphery of the ovary, giving it a polycystic morphology. Altered adipocyte-ovarian interactions further compound these adverse events on follicle development and also can harm the oocyte, particularly in the presence of increased adiposity. Finally, endocrine antecedents of PCOS occur in female infants born to mothers with PCOS, which suggests that interactions between genes and the maternal-fetal hormonal environment may program ovarian function after birth. 23773412 Measuring functional impact of cognitive impairment: Validation of the Parkinson's Disease Cognitive Functional Rating Scale. Little is known on the impact of cognitive impairment on instrumental activities of daily living (IADL) in pre-dementia stages of Parkinson's disease (PD). To investigate the clinimetric properties, applicability and responsiveness of a brief questionnaire (twelve-item; maximum score = 24) for rating functional abnormalities associated to cognitive impairment in non-demented PD patients (ND-PD). Two studies were carried-out: (1) a clinimetric study validated the Parkinson's Disease-Cognitive Functional Rating Scale (PD-CFRS) against the Older Americans Resource Survey (OARS-IADL) in 53 ND-PD patients and 53 matched controls; (2) A prospective multicenter 6-month responsiveness study involving 120 ND-PD patients explored sensitivity to change. In the clinimetric study the PD-CFRS showed intermediate concurrent validity (ICC = 0.50), high test-retest (ICC = 0.82), inter-rater reliability (ICC = 0.80) and internal consistency (Cronbach's α = 0.79), and higher coefficient of variation to detect dysfunction in ND-PD patients (PD-CFRS 86.6% vs. OARS-IADL 8.1%). There was a strong relationship between the PD-CFRS and the global cognitive status determined with the PD-Cognitive Rating Scale (r = -0.72, p < 0.0001). The responsiveness study recruited 63 patients with normal cognition and 57 with mild cognitive impairment (MCI); an increase of 2 points in the PD-CFRS after 6 months was associated with a clinically significant worsening of the cognitive functional status. According to a discriminant analysis a PD-CFRS cut-off score of ≥3 was found to be optimal for detecting functional impairment in PD-MCI patients. Cognitive impairment exerts measurable impact on IADL in ND-PD patients that can be reliable measured with the PD-CFRS, a PD-validated instrument that can be useful in clinical and research settings. 23863831 Vector decoys trick the immune response. Humoral immunity to adeno-associated viral vectors can be overcome by using empty capsid mutant "decoys" for preexisting antibodies (Mingozzi et al., this issue). 23936530 Laulimalide Induces Dose-Dependent Modulation of Microtubule Behaviour in the C. elegans Embryo. Laulimalide is a microtubule-binding drug that was originally isolated from marine sponges. High concentrations of laulimalide stabilize microtubules and inhibit cell division similarly to paclitaxel; however, there are important differences with respect to the nature of the specific cellular defects between these two drugs and their binding sites on the microtubule. In this study, we used Caenorhabditis elegans embryos to investigate the acute effects of laulimalide on microtubules in vivo, with a direct comparison to paclitaxel. We observed surprising dose-dependent effects for laulimalide, whereby microtubules were stabilized at concentrations above 100 nM, but destabilized at concentrations between 50 and 100 nM. Despite this behaviour at low concentrations, laulimalide acted synergistically with paclitaxel to stabilize microtubules when both drugs were used at sub-effective concentrations, consistent with observations of synergistic interactions between these two drugs in other systems. Our results indicate that laulimalide induces a concentration-dependent, biphasic change in microtubule polymer dynamics in the C. elegans embryo. 23862923 The application of the thermodynamic perturbation theory to study the hydrophobic hydration. The thermodynamic perturbation theory was tested against newly obtained Monte Carlo computer simulations to describe the major features of the hydrophobic effect in a simple 3D-Mercedes-Benz water model: the temperature and hydrophobe size dependence on entropy, enthalpy, and free energy of transfer of a simple hydrophobic solute into water. An excellent agreement was obtained between the theoretical and simulation results. Further, the thermodynamic perturbation theory qualitatively correctly (with respect to the experimental data) describes the solvation thermodynamics under conditions where the simulation results are difficult to obtain with good enough accuracy, e.g., at high pressures. 23937063 An Evaluation of Interactive Web-Based Curricula for Teaching Code Status Discussions. Abstract Background: Teaching resuscitation discussions to medical students and residents is time intensive and should be taught by teachers with competence in this area of clinical practice. There are plenty of data that these discussions are often inadequate, and that communication skills training, while time and faculty intensive, improves these conversations. The role of online instruction in teaching communication skills, such as resuscitation discussions, is not established. Objective: The study objective was to evaluate the effectiveness of an interactive online curriculum in teaching code status discussions to third-year medical students at one medical school. Design: In this study we block randomized third-year medical students to one of two web-based curricula versus a similar written curriculum and used standardized patient scores on a communication exercise to measure differences in performance. We used student surveys to measure student satisfaction with the curricula. Setting/subjects: Of 121 students participating in the study between April 2007 and March 2008, 88 were randomized to one of two website formats and 33 to the written curriculum. Measurements: We compared average scores on content and communication checklists between groups. Results: There were no differences between the three groups in the primary outcome of student performance. We could not analyze data on satisfaction with or completion rates for the three curricula due to poor response rates to the student surveys. Conclusions: This block randomized study of web-based curricula versus a written curriculum did not show differences in student performance in code status discussions. The optimal use of online communication training remains unclear and requires further investigation. 23922679 Circulating endothelial cells and procoagulant microparticles in patients with glioblastoma: prognostic value. Circulating endothelial cells and microparticles are prognostic factors in cancer. However, their prognostic and predictive value in patients with glioblastoma is unclear. The objective of this study was to investigate the potential prognostic value of circulating endothelial cells and microparticles in patients with newly diagnosed glioblastoma treated with standard radiotherapy and concomitant temozolomide. In addition, we have analyzed the methylation status of the MGMT promoter. Peripheral blood samples were obtained before and at the end of the concomitant treatment. Blood samples from healthy volunteers were also obtained as controls. Endothelial cells were measured by an immunomagnetic technique and immunofluorescence microscopy. Microparticles were quantified by flow cytometry. Microparticle-mediated procoagulant activity was measured by endogen thrombin generation and by phospholipid-dependent clotting time. Methylation status of MGMT promoter was determined by multiplex ligation-dependent probe amplification. Pretreatment levels of circulating endothelial cells and microparticles were higher in patients than in controls (p<0.001). After treatment, levels of microparticles and thrombin generation decreased, and phospholipid-dependent clotting time increased significantly. A high pretreatment endothelial cell count, corresponding to the 99(th) percentile in controls, was associated with poor overall survival. MGMT promoter methylation was present in 27% of tumor samples and was associated to a higher overall survival (66 weeks vs 30 weeks, p<0.004). Levels of circulating endothelial cells may have prognostic value in patients with glioblastoma. 23738528 PEG-phosphorylcholine hydrogels as tunable and versatile platforms for mechanobiology. We report here the synthesis of a new class of hydrogels with an extremely wide range of mechanical properties suitable for cell studies. Mechanobiology has emerged as an important field in bioengineering, in part due to the development of synthetic polymer gels and fibrous protein biomaterials to control and quantify how cells sense and respond to mechanical forces in their microenvironment. To address the problem of limited availability of biomaterials, in terms of both mechanical range and optical clarity, we have prepared hydrogels that combine poly(ethylene glycol) (PEG) and phosphorylcholine (PC) zwitterions. Our goal was to create a hydrogel platform that exceeds the range of Young's moduli reported for similar hydrogels, while being simple to synthesize and manipulate. The Young's modulus of these "PEG-PC" hydrogels can be tuned over 4 orders of magnitude, much greater than commonly used hydrogels such as PEG-diacrylate, PEG-dimethacrylate, and polyacrylamide, with smaller average mesh sizes and optical clarity. We prepared PEG-PC hydrogels to study how substrate mechanical properties influence cell morphology, focal adhesion structure, and proliferation across multiple mammalian cell lines, as a proof of concept. These novel PEG-PC biomaterials represent a new and useful class of mechanically tunable hydrogels for mechanobiology. 23959773 Phylogenetic position of Indian termites (Isoptera: Termitidae) with their respective genera inferred from DNA sequence analysis of the mitochondrial cytochrome oxidase gene subunit I compared to subunit II. The present work was aimed to investigate the phylogenetic analysis of different species of Indian termites belonging to the family termitidae based on mitochondrial genes COI and COII. The sequences so obtained from public database revealed grouping of termites according to their ecological distribution. The sequences of the species under investigation were characterized on the basis of frequencies of nucleotide bases and in most of the species, a significantly high percentage of A+T base composition was observed. Phylogenetic tree revealed positioning of species according to the analysis of their cytochrome oxidase subunits. 23480425 Adaptive aggregation of Peptide model systems. Jet-cooled infrared spectra of acetylated glycine, alanine, and dialanine esters and their dimers are reported in the amide A and amide I-III regions. They serve as particularly simple peptide aggregation models and are found to prefer a single backbone conformation in the dimer that is different from the most stable monomer backbone conformation. In the case of alanine, evidence for topology-changing chirality discrimination upon dimer formation is found. The jet spectroscopic results are compared to gas phase spectra and quantum chemical calculations. They provide reliable benchmarks for the evaluation of the latter in the field of peptide interactions. 23656482 Environmental assessment of management options for nutrient flows in the food chain in China. The nitrogen (N) and phosphorus (P) costs of food production have increased greatly in China during the last 30 years, leading to eutrophication of surface waters, nitrate leaching to groundwater, and greenhouse gas emissions. Here, we present the results of scenario analyses in which possible changes in food production-consumption in China for the year 2030 were explored. Changes in food chain structure, improvements in technology and management, and combinations of these on food supply and environmental quality were analyzed with the NUFER model. In the business as usual scenario, N and P fertilizer consumption in 2030 will be driven by population growth and diet changes and will both increase by 25%. N and P losses will increase by 44 and 73%, respectively, relative to the reference year 2005. Scenarios with increased imports of animal products and feed instead of domestic production, and with changes in the human diet, indicate reductions in fertilizer consumption and N and P losses relative to the business as usual scenario. Implementation of a package of integrated nutrient management measures may roughly nullify the increases in losses in the business as usual scenario and may greatly increase the efficiency of N and P throughout the whole food chain. 23108801 Large-area fabrication of periodic sub-15 nm-width single-layer graphene nanorings. A periodically aligned array of graphene nanorings (GRNRs) with a sub-15 nm linewidth at a pitch of 450 nm is fabricated with a large area, 9 cm(2) , through conventional nanoimprint lithography coupled with sophisticated metal deposition and plasma-etching processes. The existence of the single-layer GRNRs is verified by various techniques. 23964657 Lean body mass and muscle function in head and neck cancer patients and healthy individuals - results from the DAHANCA 25 study. Introduction. Loss of lean body mass is common following radiotherapy in patients with head and neck squamous cell carcinoma (HNSCC) and may reduce maximal muscle strength and functional performance. However, the associations between lean body mass, muscle strength and functional performance are unclear and no studies in HNSCC patients have compared the levels of these variables to the levels seen in healthy individuals. Purpose. The purpose of the present study was to investigate the associations between lean body mass, maximal muscle strength and functional performance in HNSCC patients and to compare the levels of these variables after radiotherapy and after progressive resistance training with the levels in healthy individuals. Material and methods. Lean body mass (dual energy X-ray absorptiometry), maximal muscle strength (isokinetic dynamometry) and functional performance (10 m max gait speed, 30 s chair rise, 30 s arm curl, stair climb) from HNSCC patients from the DAHANCA 25 trials and data from 24 healthy individuals were included. Results. Lean body mass and maximal muscle strength were significantly associated according to the gender and age-adjusted linear regression model (p < 0.0001). In addition, maximal muscle strength were associated with 30 s arm curl performance, 10 m max gait speed and 30 s chair rise (p < 0.0001). Multiple regression analyses showed that HNSCC patients expressed significant lower levels of the investigated variables after radiotherapy than healthy individuals (p < 0.0001), and that all differences were evened out after training. Conclusions. Significant associations were found between lean body mass, maximal muscle strength and functional performance in HNSCC patients. Patients expressed lower levels of these variables compared with healthy individuals, suggesting that lean body mass is a clinically relevant health factor in HNSCC patients. 23923031 BAFF Controls Neural Cell Survival through BAFF Receptor. Various neuroprotective factors have been shown to help prevention of neuronal cell death, which is responsible for the progression of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, most of these therapeutic potentials have been tested by administration of recombinant proteins, transgenic expression or virus vector-mediated gene transfer. Therefore, it remains to be clarified whether any endogenous factors has advantage for neuroprotection in a pathological nervous system. Here we show the role of BAFF-R signaling pathway in the control of neural cell survival. Both B cell-activating factor (BAFF) and its receptor (BAFF-R) are expressed in mouse neurons and BAFF-R deficiency reduces the survival of primary cultured neurons. Although many studies have so far addressed the functional role of BAFF-R on the differentiation of B cells, impaired BAFF-R signaling resulted in accelerated disease progression in an animal model of inherited ALS. We further demonstrate that BAFF-R deficient bone marrow cells or genetic depletion of B cells does not affect the disease progression, indicating that BAFF-mediated signals on neurons, not on B cells, support neural cell survival. These findings suggest opportunities to improve therapeutic outcome for patients with neurodegenerative diseases by synthesized BAFF treatment. 23911857 Do poison frogs recognize chemical cues of the other sex or do they react to cues of stressed conspecifics? Although anuran communication primarily takes place acoustically, chemical cues are also often used for intra- and intersexual communication in frogs. In the present study we analyzed the behavior of the poison frog Ranitomeya variabilis when presented chemical cues of same-sex or opposite-sex conspecifics. Chemical cues were obtained by keeping a single frog on a moist paper towel for about 47h. Afterwards two paper towels were offered to a test animal, one containing the chemical cues, the other containing rainwater only. We ran trials presenting female cues to males, males cues to males as well as male cues to females. The results of the trials were not significant in terms of intersexual communication. The overall response revealed a clear avoidance strategy which leads us to the assumption that disturbance cues unintentionally occurred during the experiment. The rather small size of the containers used to obtain chemical cues prior to the trials probably lead to confinement stress which consequently caused increased urination containing stress hormones that were detected by the test animals. This is the first proof of disturbance cues and their effects in adult anurans. The results of this study do not allow conclusions about inter- or intrasexual chemical communication of R. variabilis, but they allow implications and revisions for future experiments on this topic. 23566598 Preservation of human ovarian follicles within tissue frozen by vitrification in a xeno-free closed system using only ethylene glycol as a permeating cryoprotectant. To study the preservation of follicles within ovarian tissue vitrified using only one or a combination of three permeating cryoprotectants. Experimental study. University hospital. Ovarian tissue was donated by consenting women undergoing elective cesarean section. Ovarian tissue was vitrified in closed sealed vials using either a combination of dimethyl sulfoxide, 1,2-propanediol, and ethylene glycol (EG), or only EG as permeating cryoprotectants. Ovarian tissue was vitrified with the use of two vitrification methods. Tissue from the same donor was used for comparison of two different solutions. The morphology of the follicles was evaluated after vitrification, warming, and culture by light microscopy and transmission electron microscopy. Apoptosis was assessed by immunohistochemistry for active caspase-3 in fresh and vitrified tissue. Light and electron microscopic analysis showed equally well preserved morphology of oocytes, granulosa cells, and ovarian stroma when either of the vitrification solutions was used. No apoptosis was observed in primordial and primary follicles. Using only EG as a permeating cryoprotectant in a closed tube gives as good ultrastructural preservation of ovarian follicles as a more complicated system using several cryoprotectants. 23229420 An inelastic retropubic suburethral sling in women with intrinsic sphincter deficiency. We evaluated outcomes of an inelastic retropubic sling in patients with intrinsic sphincteric deficiency (ISD). This is a retrospective review of women diagnosed with ISD according to urodynamic parameters who underwent a retropubic suburethral sling surgery using a tape with minimal elasticity. All patients in the study where followed up at 2, 6, and 24 weeks and yearly. Outcome measures included self-assessed satisfaction, daily incontinence episodes and pad usage, standardized stress test, postvoid residual volume, and surgical complications. Two hundred and forty-seven patients were involved in this study, with a median follow-up of 43 [interquartile range (IQR) 22-77] weeks and a minimum of 12 weeks. Two patients (0.008 %) had a positive stress test postoperatively. There was a decrease in daily incontinence events (median 1.5-0) (p < 0.001) and pad usage per day (median 1.5-0) (p < 0.001). Two hundred and sixteen (87.4 %) patients reported subjective improvement in symptoms. Urinary retention was found in 18 (7.2 %) patients, and 19 (7.7 %) patients required reintervention, mostly with bulking agent injections for persistent incontinence. No tape-related mesh exposures were reported. Retropubic suburethral inelastic slings represent a good option for treating patients with ISD, with satisfactory continent rates and low postoperative complications. 22849312 Influence of whole-body vibration on biodistribution of the radiopharmaceutical [(99m)Tc]methylene diphosphonate in Wistar rats. Abstract Purpose: The radionuclide bone scan is the basis of skeletal nuclear medicine imaging. Bone scintigraphy is a highly sensitive method for indicating disease in bone. Mechanical stimulation in the manner of whole-body vibration (WBV) appears beneficial to the maintenance and/or enhancement of skeletal mass in individuals. The aim of this work was to evaluate the effect of WBV on the biodistribution of the radiopharmaceutical [(99m)Tc]methylene diphosphonate ((99m)Tc-MDP ) in Wistar rats. Materials and methods: In the biodistribution analysis, animals were anesthetized with sodium thiopental, the radiopharmaceutical (99m)Tc-MDP was administered via ocular plexus and after 10 min the animals were submitted to vibration of 20 Hz (1 min) in an oscillatory platform. Following, the animals were sacrificed, the organs were isolated, the radioactivity determined in a well counter, and the percentages of radioactivity per gram (%ATI/g) in the organs were calculated. An unpaired t-test following Welch test (p < 0.05) was done for statistical analysis of the results. Results: The biodistribution was significantly (p < 0.05) decreased in kidney, bone, lung, stomach, prostate and bowel. Conclusion: The analysis of the results indicates that the vibration could produce metabolic alterations with influence in the uptake of the radiopharmaceutical (99m)Tc-MDP in bone, stomach, bowel, prostate, kidney and bladder. 23722934 Influence of pressurized cyclic stretch and endothelial cell presence on multipotent stem cell osteogenic commitment. Applied mechanical stretch and blood vessel invasion are key stimuli to which progenitor cells are exposed in post-natal endochondral bone formation. Understanding the combined effects of cyclic stretch and endothelial cell (EC) presence on multipotent stem cell (MSC) osteogenesis therefore has the potential to lead to improved MSC-based bone regeneration strategies. Toward this goal, 10T1/2 mouse MSCs were encapsulated in tubular poly(ethylene glycol) diacrylate [PEGDA] hydrogels with moduli within the "osteogenic" range in order to induce osteogenesis. Half of the constructs were fabricated with a luminal EC layer. All of the EC(+) (EC(+)/dyn(+)) and half of the EC(-) constructs (EC(-)/dyn(+)) were subjected to pressurized cyclic stretch in the absence of osteogenic media supplements, with remaining EC(-) constructs (EC(-)/dyn(-)) serving as static controls. At day 10 of culture, expression of the bone extracellular matrix protein osteopontin was over 3.3- and 1.9-fold higher in the EC(+)/dyn(+) and EC(-)/dyn(+) constructs, respectively, relative to day 0. At day 22 of culture, osteopontin levels could not be statistically distinguished from day 0 in the EC(+)/dyn(+) constructs and were one-third less than day 0 in the EC(-)/dyn(+) constructs. In contrast, at day 22 levels of an osteogenic marker alkaline phosphatase (AP) were over 2.4- and 1.4-fold higher in the EC(+)/dyn(+) and EC(-)/dyn(+) constructs, respectively, relative to day 0. Furthermore, at day 22 matrix mineralization in both dynamic groups was increased over 2.5-fold and over 9-fold relative to the EC(-)/dyn(-) and day 0 groups, respectively. Cumulatively, these results suggest that pressurized cyclic stretch alone significantly increases the rate/degree of osteogenesis relative to static culture. However, EC presence combined with pressured cyclic stretch appears to further enhance the rate/degree of MSC osteogenesis and/or to support a distinct osteogenic "fingerprint" compared to that promoted by cyclic stretch alone. 23685434 Human TREX component Thoc5 affects alternative polyadenylation site choice by recruiting mammalian cleavage factor I. The transcription-export complex (TREX) couples mRNA transcription, processing and nuclear export. We found that CFIm68, a large subunit of a heterotetrameric protein complex mammalian cleavage factor I (CFIm), which is implicated in alternative polyadenylation site choice, co-purified with Thoc5, a component of human TREX. Immunoprecipitation using antibodies against different components of TREX indicated that most likely both complexes interact via an interaction between Thoc5 and CFIm68. Microarray analysis using human HeLa cells revealed that a subset of genes was differentially expressed on Thoc5 knockdown. Notably, the depletion of Thoc5 selectively attenuated the expression of mRNAs polyadenylated at distal, but not proximal, polyadenylation sites, which phenocopied the depletion of CFIm68. Chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-Seq) indicated that CFIm68 preferentially associated with the 5' regions of genes; strikingly, the 5' peak of CFIm68 was significantly and globally reduced on Thoc5 knockdown. We suggest a model in which human Thoc5 controls polyadenylation site choice through the co-transcriptional loading of CFIm68 onto target genes. 23847156 Multilevel Hierarchically Ordered Artificial Biomineral. Living organisms are known for creating complex organic-inorganic hybrid materials such as bone, teeth, and shells, which possess outstanding functions as compared to their simple mineral forms. This has inspired many attempts to mimic such structures, but has yielded few practical advances. In this study, a multilevel hierarchically ordered artificial biomineral (a composite of hydroxyapatite and gelatine) with favorable nanomechanical properties is reported. A typical optimized HAp/gelatin hybrid material in the perpendicular direction of the HAp c-axis has a modulus of 25.91 + 1.78 GPa and hardness of 0.90 + 0.10 GPa, which well matches that of human cortical bone (modulus 24.3 + 1.4 GPa, hardness 0.69 + 0.05 GPa). The bottom-up crystal constructions (from nano- to micro- to macroscale) of this material are achieved through a hard template approach by the phase transformation from DCP to HAp. The structural biomimetic material shows another way to mimic the complex hierarchical designs of sclerous tissues which have potential value for application in hard tissue engineering. 23054424 The role of narrative and metaphor in the cancer life story: a theoretical analysis. Being diagnosed with cancer can be one of those critical incidents that negatively affect the self. Identity is threatened when physical, psychological, and social consequences of chronic illness begin to erode one's sense of self and challenge an individual's ability to continue to present the self he or she prefers to present to others. Based on the notion of illness trajectory and adopting a Ricoeurian narrative perspective, this theoretical paper shall explore the impact of cancer disease on identity and establish the crucial importance of metaphor in the narratives of life with cancer. Findings indicate that in cancer narratives the illness experience supplies the narrative structure with temporal and spatial meeting points that make the narrative comprehensible and meaningful. Cancer forces identity changes not only from having to endure the long-term physical and psychosocial effects of the disease, but also from inevitable existential questions about life's meaning. Improved medical knowledge today means improved ethnomedical practices. Metaphor can bridge the gap between the cancer experience and the world of technology and treatment, helping patients to symbolically control their illness. 23877310 Update on Anesthetic Complications of Robotic Thoracic Surgery. In the last decade, there has been increase use of the da Vinci® robot surgical system to perform minimally invasive thoracic surgery. The robotic technology can be applied for surgery of the lungs, mediastinum, and esophagus. A number of case reports have been shown steep learning curve, and promising surgical outcome with this new technology. However, anesthesia management of the robotic thoracic surgery can be complex and requires further education. For example, most of the cases require sufficient lung collapse in order to provide adequate surgical field. In addition, a unique operative setting, such as patient positioning and capnothorax can make anesthesia management further challenging. Hence, anesthesiologists should have better awareness of adverse events or complications related to the robotic surgery to accomplish successful anesthesia management. This review will focus on the potential complications of robotic thoracic surgery involving the lungs, mediastinum and esophagus. 23783807 Switching the regioselectivity via indium(III) and gold(I) catalysis: a post-Ugi intramolecular hydroarylation to azepino- and azocino-[c,d]indolones. A post-Ugi indium(III)- and gold(I)-mediated regioselective intramolecular hydroarylation for the synthesis of azepino- and azocino-[c,d]indolones is described. 23707411 Stand dynamics and tree coexistence in an analytical structured model: The role of recruitment. Understanding the mechanisms of coexistence and niche partitioning in plant communities is a central question in ecology. Current theories of forest dynamics range between the so-called neutral theories which assume functional equivalence among coexisting species to forest simulators that explain species assemblages as the result of tradeoffs in species individual strategies at several ontogenetic stages. Progress in these questions has been hindered by the inherent difficulties of developing analytical size-structured models of stand dynamics. This precludes examination of the relative importance of each mechanism on tree coexistence. In previous simulation and analytical studies emphasis has been given to interspecific differences at the sapling stage, and less so to interspecific variation in seedling recruitment. In this study we develop a partial differential equation model of stand dynamics in which competition takes place at the recruitment stage. Species differ in their size-dependent growth rates and constant mortality rates. Recruitment is described as proportional to the basal area of conspecifics, to account for fecundity and seed supply per unit of basal area, and is corrected with a decreasing function of species specific basal area to account for competition. We first analyze conditions for population persistence in monospecific stands and second we investigate conditions of coexistence for two species. In the monospecific case we found a stationary stand structure based on an inequality between mortality rate and seed supply. In turn, intra-specific competition does not play any role on the asymptotic extinction or population persistence. In the two-species case we found that coexistence can be attained when the reciprocal negative effect on recruitment follows a given relation with respect to intraspecific competition. Specifically a tradeoff between recruitment potential (i.e. shade tolerance or predation avoidance) and fecundity or growth rate. This is to our knowledge the first study that describes coexistence mechanisms in an analytical size-structured model in terms of competitive differences at the regeneration state. 23963191 A Joint-Constraint Model-Based System for Reconstructing Total Knee Motion. Comprehending knee motion is an essential requirement for studying the causes of knee disorders. In this paper we propose a new 2D-3D registration system based on joint-constraint model for reconstructing total knee motion. The proposed model that contains bone geometries and an articulated joint mechanism is first constructed from multi-postural magnetic resonance (MR) volumetric images. Then, the bone segments of the model are hierarchically registered to each frame of the given single-plane fluoroscopic video that records the knee activity. The bone posture is iteratively optimized using a modified chamfer matching algorithm to yield the simulated radiograph (SR) which is the best fit to the underlying fluoroscopic image. Unlike conventional registration methods computing posture parameters for each bone independently, the proposed femorotibial and patellofemoral joint models properly maintain the articulations between femur, tibia and patella during the registration processes. As a result, we can obtain a sequence of registered knee postures showing smooth and reasonable physiologic patterns of motion. The proposed system also provides joint-space interpolation to densely generate intermediate postures for motion animation. The effectiveness of the proposed method was validated by computer simulation, animal cadaver and in-vivo knee testing. The mean target registration errors (mTREs) for femur, tibia and patella were less than 1.5 mm. In particular, small out-of-plane registration errors (less than 1 mm (translation) and 2 degree (rotation)) were achieved in animal cadaver assessments. 23947565 Comparative analysis of non-coding RNAs in the antibiotic-producing Streptomyces bacteria. Non-coding RNAs (ncRNAs) are key regulatory elements that control a wide range of cellular processes in all bacteria in which they have been studied. Taking advantage of recent technological innovations, we set out to fully explore the ncRNA potential of the multicellular, antibiotic-producing Streptomyces bacteria. Using a comparative RNA sequencing analysis of three divergent model streptomycetes (S. coelicolor, S. avermitilis and S. venezuelae), we discovered hundreds of novel cis-antisense RNAs and intergenic small RNAs (sRNAs). We identified a ubiquitous antisense RNA species that arose from the overlapping transcription of convergently-oriented genes; we termed these RNA species 'cutoRNAs', for convergent untranslated overlapping RNAs. Conservation between different classes of ncRNAs varied greatly, with sRNAs being more conserved than antisense RNAs. Many species-specific ncRNAs, including many distinct cutoRNA pairs, were located within antibiotic biosynthetic clusters, including the actinorhodin, undecylprodigiosin, and coelimycin clusters of S. coelicolor, the chloramphenicol cluster of S. venezuelae, and the avermectin cluster of S. avermitilis. These findings indicate that ncRNAs, including a novel class of antisense RNA, may exert a previously unrecognized level of regulatory control over antibiotic production in these bacteria. Collectively, this work has dramatically expanded the ncRNA repertoire of three Streptomyces species and has established a critical foundation from which to investigate ncRNA function in this medically and industrially important bacterial genus. 23947656 Training emergency services' dispatchers to recognise stroke: an interrupted time-series analysis. Stroke is a time-dependent medical emergency in which early presentation to specialist care reduces death and dependency. Up to 70% of all stroke patients obtain first medical contact from the Emergency Medical Services (EMS). Identifying 'true stroke' from an EMS call is challenging, with over 50% of strokes being misclassified. The aim of this study was to evaluate the impact of the training package on the recognition of stroke by Emergency Medical Dispatchers (EMDs). This study took place in an ambulance service and a hospital in England using an interrupted time-series design. Suspected stroke patients were identified in one week blocks, every three weeks over an 18 month period, during which time the training was implemented. Patients were included if they had a diagnosis of stroke (EMS or hospital). The effect of the intervention on the accuracy of dispatch diagnosis was investigated using binomial (grouped) logistic regression. In the Pre-implementation period EMDs correctly identified 63% of stroke patients; this increased to 80% Post-implementation. This change was significant (p=0.003), reflecting an improvement in identifying stroke patients relative to the Pre-implementation period both the During-implementation (OR=4.10 [95% CI 1.58 to 10.66]) and Post-implementation (OR=2.30 [95% CI 1.07 to 4.92]) periods. For patients with a final diagnosis of stroke who had been dispatched as stroke there was a marginally non-significant 2.8 minutes (95% CI -0.2 to 5.9 minutes, p=0.068) reduction between Pre- and Post-implementation periods from call to arrival of the ambulance at scene. This is the first study to develop, implement and evaluate the impact of a training package for EMDs with the aim of improving the recognition of stroke. Training led to a significant increase in the proportion of stroke patients dispatched as such by EMDs; a small reduction in time from call to arrival at scene by the ambulance also appeared likely. The training package has been endorsed by the UK Stroke Forum Education and Training, and is free to access on-line. 23455590 Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders. Severe psychiatric disorders such as schizophrenia are related to cognitive and negative symptoms, which often are resistant to current treatment approaches. The glutamatergic system has been implicated in the pathophysiology of schizophrenia and affective disorders. A key component is the dysfunction of the glutamatergic N-methyl-D-aspartate (NMDA) receptor. Substances regulating activation/inhibition of the NMDA receptor have been investigated in schizophrenia and major depression and are promising in therapeutic approaches of negative symptoms, cognition, and mood. In schizophrenia, add-on treatments with glycine, D-serine, D-alanine, D-cycloserine, D-amino acid oxidase inhibitors, glycine transporter-1 (GlyT-1) inhibitors (e.g., sarcosine, bitopertin) and agonists (e.g., LY2140023) or positive allosteric modulator (e.g., ADX71149) of group II metabotropic glutamate receptors (mGluRs) have been studied. In major depression, the NMDA receptor antagonists (e.g., ketamine, AZD6765), GluN2B subtype antagonists (e.g., traxoprodil, MK-0657), and partial agonists (e.g., D-cycloserine, GLYX-13) at the glycine site of the NMDA receptor have been proven to be effective in animal studies and first clinical trials. In addition, clinical studies of mGluR2/3 antagonist BCI-838 (a prodrug of BCI-632 (MGS0039)), mGluR2/3-negative allosteric modulators (NMAs) (e.g., RO499819, RO4432717), and mGluR5 NAMs (e.g., AZD2066, RO4917523) are in progress. Future investigations should include effects on brain structure and activation to elucidate neural mechanisms underlying efficacy of these drugs. 23416144 Cysteamine: an old drug with new potential. Cysteamine is an amino thiol with the chemical formula HSCH2CH2NH2. Endogenously, cysteamine is derived from coenzyme A degradation, although its plasma concentrations are low. Most experience with cysteamine as a drug originates from the field of the orphan disease cystinosis, in which cysteamine is prescribed to decrease intralysosomal cystine accumulation. However, over the years, the drug has been used for several other applications both in vitro and in vivo. In this article, we review the different applications of cysteamine, ending with an overview of ongoing clinical trials for new indications, such as neurodegenerative disorders and nonalcoholic fatty liver disease (NAFLD). The recent development of an enteric-coated cysteamine formulation makes cysteamine more patient friendly and will extend its applicability for both old and new indications. 23118479 SpliceAid-F: a database of human splicing factors and their RNA-binding sites. A comprehensive knowledge of all the factors involved in splicing, both proteins and RNAs, and of their interaction network is crucial for reaching a better understanding of this process and its functions. A large part of relevant information is buried in the literature or collected in various different databases. By hand-curated screenings of literature and databases, we retrieved experimentally validated data on 71 human RNA-binding splicing regulatory proteins and organized them into a database called 'SpliceAid-F' (http://www.caspur.it/SpliceAidF/). For each splicing factor (SF), the database reports its functional domains, its protein and chemical interactors and its expression data. Furthermore, we collected experimentally validated RNA-SF interactions, including relevant information on the RNA-binding sites, such as the genes where these sites lie, their genomic coordinates, the splicing effects, the experimental procedures used, as well as the corresponding bibliographic references. We also collected information from experiments showing no RNA-SF binding, at least in the assayed conditions. In total, SpliceAid-F contains 4227 interactions, 2590 RNA-binding sites and 1141 'no-binding' sites, including information on cellular contexts and conditions where binding was tested. The data collected in SpliceAid-F can provide significant information to explain an observed splicing pattern as well as the effect of mutations in functional regulatory elements. 23746735 An ant colony optimization based algorithm for identifying gene regulatory elements. It is one of the most important tasks in bioinformatics to identify the regulatory elements in gene sequences. Most of the existing algorithms for identifying regulatory elements are inclined to converge into a local optimum, and have high time complexity. Ant Colony Optimization (ACO) is a meta-heuristic method based on swarm intelligence and is derived from a model inspired by the collective foraging behavior of real ants. Taking advantage of the ACO in traits such as self-organization and robustness, this paper designs and implements an ACO based algorithm named ACRI (ant-colony-regulatory-identification) for identifying all possible binding sites of transcription factor from the upstream of co-expressed genes. To accelerate the ants' searching process, a strategy of local optimization is presented to adjust the ants' start positions on the searched sequences. By exploiting the powerful optimization ability of ACO, the algorithm ACRI can not only improve precision of the results, but also achieve a very high speed. Experimental results on real world datasets show that ACRI can outperform other traditional algorithms in the respects of speed and quality of solutions. 23916824 Effect of type and ratio of solubilising polymer on characteristics of hot-melt extruded orodispersible films. In formulating an orodispersible film (ODF), it is important for polymer choice to strike a balance between mechanical properties and release rates. Studies have been done to study polymer combinations. However, there is a lack of a systematic study to determine key factors affecting these properties. We studied the effect of varying the ratios of a solubilising polymer (Kollidon(®) VA 64 or Soluplus(®)) to a film forming polymer, hydroxypropyl cellulose (HPC), on mechanical properties and release rates of hot-melt extruded ODFs using a 2(3) factorial design. The two drugs evaluated were chlorpheniramine and indomethacin. The main effects impacting mechanical properties were the drug and two-way interaction between drug and solubilising polymer. For dissolution, the main effects were the solubilising polymer; the drug; and the two-way interaction between solubilising polymer and ratio of solubilising to film forming polymer. Both drugs exhibited plasticising effects on the polymer matrix and had higher film ductility and lower film stiffness. Kollidon(®) VA 64-containing films performed better in terms of drug release whereas Soluplus(®)-containing films had better mechanical properties. The dissolution rate can be improved by decreasing film thickness. The findings of our study will be crucial to forming a robust ODF formulation. 22902323 High levels of arachidonic acid and peroxisome proliferator-activated receptor-alpha in breast cancer tissues are associated with promoting cancer cell proliferation. Fatty acids are endogenous ligands of peroxisome proliferator-activated receptor-alpha (PPARα), which is linked to the regulation of fatty acid uptake, lipid metabolism and breast cancer cell growth. This study was designed to screen candidate fatty acids from breast cancer tissue and to investigate the effects of these candidate fatty acids on PPARα expression, cell growth and cell cycle progression in breast cancer cell lines. One breast cancer tissue and one reference tissue were each taken from 30 individual breasts to examine for fatty acid composition and PPARα expression. The cancer cell lines MDA-MB-231 (ER-), MCF-7 (ER++++) and BT-474 (ER++) were used to explore the mechanisms regulating cell proliferation. We found that arachidonic acid (AA) and PPARα were highly expressed in the breast cancer tissues. AA stimulated the growth of all three breast cancer cells in a time- and dose-dependent manner. The growth stimulatory effect of AA was associated with PPARα activation, and the most potent effect was found in MCF-7 cells. The stimulation of cell proliferation by AA was accompanied by the increased expression of cyclin E, a reduced population of G1 phase cells, and a faster G1/S phase transition. In contrast, AA had no effects on the levels of CDK2, CDK4, cyclin D1, p27, Bcl-2 and Bax. Our results demonstrate that high levels of AA and PPARα expression in human breast cancer tissues are associated with ER-overexpressed breast cancer cell proliferation, which is involved in activating PPARα, stimulating cyclin E expression, and promoting faster G1/S transition. 23915073 Oral chemoprevention with acetyl salicylic Acid, vitamin d and calcium reduces the risk of tobacco carcinogen-induced bladder tumors in mice. Bladder cancer is a common urological malignancy with high recurrence rate, which may be reduced by chemoprevention. The aim was to evaluate chemoprevention in a mouse model of tobacco carcinogen-induced bladder tumors. A total of 60 A/J mice were randomized to normal diet, diet with low calcium, and diet with chemoprevention (acetyl salicylic acid, 1-alpha 25(0H)2-vitamin D3 and calcium). There were significantly fewer tumors (0 (0-0) vs. 0 (0-2), p = .045) and fewer animals with tumors (0/20 vs. 5/20, p = .045) in the chemoprevention group compared with controls. Thus, chemoprevention diet effectively reduced the tumor promoting effect of tobacco carcinogens in the mouse bladder. 23851121 Loss of mitochondrial peptidase Clpp leads to infertility, hearing loss plus growth retardation via accumulation of CLPX, mtDNA and inflammatory factors. The caseinolytic peptidase P (CLPP) is conserved from bacteria to humans. In the mitochondrial matrix, it multimerizes and forms a macromolecular proteasome-like cylinder together with the chaperone CLPX. In spite of a known relevance for the mitochondrial unfolded protein response, its substrates and tissue-specific roles are unclear in mammals. Recessive CLPP mutations were recently observed in the human Perrault variant of ovarian failure and sensorineural hearing loss. Here, a first characterization of CLPP null mice demonstrated complete female and male infertility and auditory deficits. Disrupted spermatogenesis already at the spermatid stage and ovarian follicular differentiation failure were evident. Reduced pre-/post-natal survival and marked ubiquitous growth retardation contrasted with only light impairment of movement and respiratory activities. Interestingly, the mice showed resistance to ulcerative dermatitis. Systematic expression studies detected up-regulation of other mitochondrial chaperones, accumulation of CLPX and mtDNA as well as inflammatory factors throughout tissues. T-lymphocytes in the spleen were activated. Thus, murine Clpp deletion represents a faithful Perrault model. The disease mechanism probably involves deficient clearance of mitochondrial components and inflammatory tissue destruction. 23880433 A review of nitrous oxide mitigation by farm nitrogen management in temperate grassland-based agriculture. Nitrous oxide (N2O) emission from grassland-based agriculture is an important source of atmospheric N2O. It is hence crucial to explore various solutions including farm nitrogen (N) management to mitigate N2O emissions without sacrificing farm profitability and food supply. This paper reviews major N management practices to lower N2O emission from grassland-based agriculture. Restricted grazing by reducing grazing time is an effective way to decrease N2O emissions from excreta patches. Balancing the protein-to-energy ratios in the diets of ruminants can also decrease N2O emissions from excreta patches. Among the managements of synthetic fertilizer N application, only adjusting fertilizer N rate and slow-released fertilizers are proven to be effective in lowering N2O emissions. Use of bedding materials may increase N2O emissions from animal houses. Manure storage as slurry, manipulating slurry pH to values lower than 6 and storage as solid manure under anaerobic conditions help to reduce N2O emissions during manure storage stage. For manure land application, N2O emissions can be mitigated by reducing manure N inputs to levels that satisfy grass needs. Use of nitrification inhibitors can substantially lower N2O emissions associated with applications of fertilizers and manures and from urine patches. N2O emissions from legume based grasslands are generally lower than fertilizer-based systems. In conclusion, effective measures should be taken at each step during N flow or combined options should be used in order to mitigate N2O emission at the farm level. 23796442 Insertion of beta-alanine in model peptides for copper binding to His96 and His111 of the human prion protein. The prion protein coordinates copper with high affinity in the regions encompassing residues 92-99 (GGGTHSQW) and 106-115 (KTNMKHMAGA). Cu(II) binding to these sites involves the coordination of the His96/His111 imidazole ring and backbone deprotonated amides that precede the His residue. Such a coordination arrangement involves the formation of hexa- and penta-membered cycles that provide further stabilization of the metal-peptide complex. The purpose of the present study is to introduce a methylene group in the peptide backbone, to evaluate the impact of increasing the size of these cycles in Cu(II) binding. Thus, a β-alanine residue was inserted at different positions preceding the His residue in these prion fragments, and their Cu(II) coordination properties were assessed by UV-Visible absorption, circular dichroism, and electron paramagnetic resonance. Spectroscopic data show that the insertion of a methylene group leads to a completely different Cu(II) coordination that involves the His96/His111 imidazole ring and nitrogen or oxygen atoms provided by the peptide backbone towards the C-terminal. This study clearly shows that two main factors determine the nature of Cu(II)-peptide complexes involving an anchoring His residue and deprotonated amides from the backbone chain: i) the stabilization of Cu(II)-peptide complexes due to the formation of cyclic structures (i.e. chelate effect) and ii) the nature of the residues associated to the deprotonated amide groups that participate in metal ion coordination. 23917168 Out of balance-systemic iron homeostasis in iron-related disorders. Iron is an essential element in our daily diet. Most iron is required for the de novo synthesis of red blood cells, where it plays a critical role in oxygen binding to hemoglobin. Thus, iron deficiency causes anemia, a major public health burden worldwide. On the other extreme, iron accumulation in critical organs such as liver, heart, and pancreas causes organ dysfunction due to the generation of oxidative stress. Therefore, systemic iron levels must be tightly balanced. Here we focus on the regulatory role of the hepcidin/ferroportin circuitry as the major regulator of systemic iron homeostasis. We discuss how regulatory cues (e.g., iron, inflammation, or hypoxia) affect the hepcidin response and how impairment of the hepcidin/ferroportin regulatory system causes disorders of iron metabolism. 23116145 A cyclometallated iridium(III) complex as a c-myc G-quadruplex stabilizer and down-regulator of c-myc oncogene expression. A new cyclometallated iridium(III) complex with the 2,2'-biquinoline N-donor ligand has been synthesized and characterized. The interaction and affinity of the complex towards c-myc G-quadruplex and duplex DNA have been investigated using UV/Vis spectroscopy and gel mobility shift assay. These studies revealed that complex 1 binds to c-myc G-quadruplexes (Pu22 and Pu27) with high affinity but does not interact with duplex DNA either by intercalation or groove binding. The ability of 1 to stabilize c-myc G-quadruplex DNA in vitro has also been examined through a PCR stop assay and a cell-based luciferase reporter assay. Complex 1 displays promising cytotoxic activity against the HeLa cell line with sub-micromolar potency. 23880828 Longitudinal patterns of psychological distress in adult survivors of childhood cancer. Background:This study investigated longitudinal patterns of psychological distress in adult survivors of childhood cancer.Methods:Participants included 4569 adult survivors in the Childhood Cancer Survivor Study Cohort (CCSS) who completed the Brief Symptom Inventory-18 on three occasions between 1994 and 2010. Longitudinal latent class analysis was used to identify discrete classes of psychological distress. Predictors of class membership were examined through logistic regression modelling with odds ratios (ORs) and 95% confidence intervals (CIs) reported.Results:Survivors were a median of 39 years of age and 30 years from diagnosis at the most recent follow-up. Most survivors reported few or no symptoms of distress over time, although subsets of survivors reported persistently elevated (depression: 8.9%; anxiety: 4.8%; somatisation: 7.2%) or significant increases in distress symptoms over the follow-up period (depression: 10.2%; anxiety: 11.8%; somatisation: 13.0%). Increasing distress symptoms were predicted by survivor perception of worsening physical health over time (depression: OR=3.3; 95% CI=2.4-4.5; anxiety: OR=3.0; 95% CI=2.2-4.0; somatisation: OR=5.3; 95% CI=3.9-7.4). Persistent distress symptoms were also predicted by survivor perception of worsening physical health over time, as well as by worsening pain and ending analgesic use.Conclusion:Subgroups of adult survivors are at-risk for chronic distress or significant increases in distress decades following their original cancer diagnosis. Routine screening of psychological distress in adult survivors of childhood cancer is warranted, especially for survivors who experience physical health morbidities.British Journal of Cancer advance online publication 23 July 2013; doi:10.1038/bjc.2013.428 www.bjcancer.com. 23561145 RP-HPLC and chemometrics for wheat flour protein characterisation in an industrial bread-making process monitoring context. In the baking industry, a difficult task is to keep the quality perceived by the consumer as constant as possible, given the inner variability of flour, e.g. due to different wheat mixtures, harvesting time, etc. Here, we evaluated the influence of flour batches properties on bread quality, considering an industrial bread making process. In particular, flour composition in terms of protein fractions (gliadins, glutenins) has been determined by means of RP-HPLC, to assess the inter- and intra-batch variability of flour mixtures deliveries at a baking plant. Multivariate data analysis allowed evaluation of correlation between flour protein composition and technological properties. A great variability within different deliveries of a same flour batch emerged, as well as a considerable seasonal variability. Correlation models among protein sub-fractions, technological properties and bread quality are difficult to establish; however, the role of the protein profile on flour behaviour in bread making could be highlighted. 23889760 The microbiological profile of lacrimal abscess: two decades of experience from a tertiary eye care center. The aim of this study is to exclusively report the microbiological spectrum of lacrimal abscess and the antibiotic sensitivity patterns of the organisms. Retrospective interventional study on 112 eyes of 112 patients who presented to the ophthalmic plastic clinic of a tertiary eye care center over a period of 23 years from January 1990 to February 2013 with lacrimal abscess were reviewed for demographic and microbiological profile. The culture results, organisms isolated, and their antibiotic sensitivity were studied. The mean age at presentation was 37 years. The female to male ratio was 2:1. There was no significant difference in the laterality between the right and left eyes. Gram-positive organisms were the most commonly isolated accounting for 56.3% (63/112), and the commonest species isolated was Staphylococcus aureus in 25% (28/112) of the patients. Hemophilus influenzae was the commonest gram-negative isolate accounting for 30.2% of all the gram-negative isolates. Of the patients, 10.7% (12/112) showed no organisms on smear as well as sterile cultures. Gram-positive organisms were commonly sensitive to penicillins and vancomycin whereas gram-negative organisms were sensitive to quinolones and aminoglycosides. Gram-positive organisms are quite common as compared to gram-negative ones in cases of lacrimal abscess. The results of this study have significant bearing on the treatment of patients with lacrimal abscess. 23444774 Simultaneous high-performance liquid chromatographic determination of a rhein-diclofenac prodrug and its active compounds. In order to study the hydrolytic characterization of an anti-inflammatory prodrug (RD-1) in vitro, a simple, specific, precise and accurate method for the simultaneous determination of prodrug and its two hydrolytic active compounds was development using reverse phase high-performance liquid chromatography (RP-HPLC). The chromatographic separation was performed on an ODS-2 C18 column (250 mm x 4.6 mm, 5.0 microm particle size) with a simple elution programme. The mobile phase was methanol-0.1%phosphoric acid solution (adjusted pH to 2.3) (80:20, v/v); wavelength of 257nm and mobile phase flow rate of 1.0 mL/min was utilized for the quantitative analysis. Excellent linear behaviors over the investigated concentration ranges were observed with the values of R2 higher than 0.999 for all the analytes. The validated method was successfully applied to the simultaneous determination of prodrug and its active components. 23197392 Reliability and validity of a person-centered care staff survey in veterans health administration community living centers. The objective of this study was to test and revise a staff assessment of person-centered care (PCC) within the Veterans Health Administration (VA) Community Living Center (CLC) setting. Starting with measures of PCC initially developed through the Better Jobs Better Care (BJBC) study, we conducted cognitive interviews with CLC staff to assess applicability to the VA setting. We then (a) modified the questionnaire based on respondent feedback, (b) administered the revised survey via Internet to 265 staff at 8 VA CLCs, and (c) examined the psychometric properties of the revised 50-item BJBC PCC instrument using multitrait analysis. Scale reliabilities met the criterion for group comparisons (alpha levels ranged from 0.84 to 0.91). The pattern of item correlations and intra- and interscale correlations indicating convergent and discriminant validity, respectively, were both 100%. Our results support the broader use of the BJBC survey within VA. In addition, given the high levels of internal consistency reliability of the current scales, it is likely that a psychometrically sound short form of the instrument could be created. Further research on construct and convergent validity are warranted to support the broader application of the instrument. 23856757 High-throughput deterministic single cell encapsulation and droplet pairing, fusion and shrinkage in a single microfluidic device. In this article, we present a microfluidic device capable of successive high-yield single cell encapsulation in droplets, with additional droplet pairing, fusion and shrinkage. Deterministic single cell encapsulation is realized using Dean-coupled inertial ordering of cells in a Yin-Yang shaped curved microchannel using a double T-junction, with a frequency over 2000 Hz, followed by controlled droplet pairing with a 100% success rate. Subsequently, droplet fusion is realized using electrical actuation resulting in electrocoalescence of two droplets, each containing a single HL60 cell, with 95% efficiency. Finally, volume reduction of the fused droplet up to 75% is achieved by a triple pitchfork structure. This droplet volume reduction is necessary to obtain close cell-cell membrane contact necessary for final cell-electrofusion, leading to hybridoma formation, which is the ultimate aim of this research. This article is protected by copyright. All rights reserved. 23949189 Broncholithiasis with Recurrent Lithoptysis: A Case Report. Objective: To report a case of broncholithiasis with different types of calculi in the tracheobronchial tree. Clinical Presentation and Intervention: A 50-year-old male who suffered from hemoptysis presented with recurrent broncholith expectoration due to past tuberculous middle lobe syndrome. Bronchoscopic examination revealed loose and embedded broncholiths located at two different bronchi. A surgical resection was suggested, but he refused. Conclusion: The diagnosis of broncholithiasis should be kept in mind in patients who had hemoptysis and calcified mediastinal lymph nodes on thorax computerized tomography, and diagnostic bronchoscopy should be done to prove the relationship of the tracheobronchial tree with a broncholith. © 2013 S. Karger AG, Basel. 23872240 Involuntary attention enhances identification accuracy for unmasked low contrast letters using non-predictive peripheral cues. There is controversy regarding whether or not involuntary attention improves response accuracy at a cued location when the cue is non-predictive and if these cueing effects are dependent on backward masking. Various perceptual and decisional mechanisms of performance enhancement have been proposed, such as signal enhancement, noise reduction, spatial uncertainty reduction, and decisional processes. Herein we review a recent report of mask-dependent accuracy improvements with low contrast stimuli and demonstrate that the experiments contained stimulus artifacts whereby the cue impaired perception of low contrast stimuli, leading to an absence of improved response accuracy with unmasked stimuli. Our experiments corrected these artifacts by implementing an isoluminant cue and increasing its distance relative to the targets. The results demonstrate that cueing effects are robust for unmasked stimuli presented in the periphery, resolving some of the controversy concerning cueing enhancement effects from involuntary attention and mask dependency. Unmasked low contrast and/or short duration stimuli as implemented in these experiments may have a short enough iconic decay that the visual system functions similarly as if a mask were present leading to improved accuracy with a valid cue. 23944231 Problem-based learning (PBL) and speech-language pathology: A tutorial. Abstract The aim of this tutorial is to provide an introduction to problem-based learning (PBL), particularly as applied to speech-language pathology (SLP) programs. The tutorial is aimed at the reader who is less familiar with this learning approach. Additionally, it serves as a framework for the articles that follow in this special issue on PBL programs in SLP and other clinical education programs. A brief history of PBL is provided and the rationale and context for this approach are identified. PBL is defined and differentiated from related educational approaches. Different models and variations of PBL are outlined. The key components of PBL are further illustrated using the tutorial cycle. Finally, we present one specific case of a PBL-based SLP program in detail. This tutorial will provide a deeper understanding of PBL for many higher educators in SLP. The strengths of this approach are outlined and the challenges are identified, particularly for those contemplating converting an existing "traditional" course or curriculum. 23813602 Schistosomiasis chemotherapy. After malaria, schistosomiasis (or bilharzia) is the second most prevalent disease in Africa, and is occurring in over 70 countries in tropical and subtropical regions. It is estimated that 600 million people are at risk of infection, 200 million people are infected, and at least 200 000 deaths per year are associated with the disease. All schistosome species are transmitted through contact with fresh water that is infested with free-swimming forms of the parasite, which is known as cercariae and produced by snails. When located in the blood vessels of the host, larval and adult schistosomes digest red cells to acquire amino acids for growth and development. Vaccine candidates have been unsuccessful up to now. Against such devastating parasitic disease, the antischistosomal arsenal is currently limited to a single drug, praziquantel, which has been used for more than 35 years. Because the question of the reduction of the activity of praziquantel was raised recently, it is thus urgent to create new and safe antischistosomal drugs that should be combined with praziquantel to develop efficient bitherapies. 23953134 Hodgkin lymphoma in Africa: Present and future. Hodgkin lymphoma (HL) was described for the first time in 1832 by Sir Thomas Hodgkin, who is considered the father of the disease. This lymphoma occupies a special place among childhood malignancies, due to its high rate of cure. HL is described as one of the most common haematological malignancies in African children. Despite high rates of survival achieved in resource rich countries, the outcome in Africa is not as rewarding as many challenges are encountered. This paper reviews published African studies on childhood HL in order to delineate the amplitude of this health problem and its African specifics, in the quest for effective ways to improve the outcome of the children diagnosed with this disease. 23809328 Metabolism of c9,t11-conjugated linoleic acid (CLA) in humans. The c9,t11 isomer of conjugated linoleic acid (CLA) is the most abundant CLA form present in the human diet, and is particularly prevalent in milk and dairy products, and is known to exert several health benefits in experimental animal models. A possible mechanism of action of c9,t11CLA relies on its metabolism via desaturases and elongases and partial beta oxidation in peroxisomes. In this study, we aimed to establish plasma incorporation of c9,t11CLA and its downstream metabolites in healthy volunteers after daily dietary intakes of 0.8g, 1.6g or 3.2g of c9,t11CLA in capsule form for two months. Following supplementation, the plasma concentrations of c9,t11CLA and its metabolites conjugated dienes (CD) 18:3 and the beta oxidation product CD 16:2 were incorporated in a linear fashion, while on the other hand CD 20:3 reached a plateau following intakes of 1.6g/d of dietary intake, and was not further increased following higher CLA intakes. We may conclude that supplementation of c9,t11 CLA levels result in linear responses of CLA and its main metabolites in plasma. In addition, only the highest concentration of CLA intake tested (3.2g/d) yielded plasma concentrations of CLA and metabolites close to the range found sufficient to exert nutritional effects in experimental animal models. 23254551 Formation and infrared absorption of protonated naphthalenes (1-C10H9+ and 2-C10H9+) and their neutral counterparts in solid para-hydrogen. Protonated naphthalene (C(10)H(9)(+)) and its neutral counterparts (hydronaphthyl radicals, C(10)H(9)) are important intermediates in the reactions of aromatic compounds and in understanding the unidentified infrared (IR) emissions from interstellar media. We report the IR spectra of 1-C(10)H(9)(+), 2-C(10)H(9)(+), 1-C(10)H(9), and 2-C(10)H(9) trapped in solid para-hydrogen (p-H(2)); the latter three are new. These species were produced upon electron bombardment of a mixture of naphthalene (C(10)H(8)) and p-H(2) during matrix deposition. The intensities of IR features of 1-C(10)H(9)(+) decreased after the matrix was maintained in darkness for 19 h, whereas those of 1-C(10)H(9) and 2-C(10)H(9) increased. Irradiation of this matrix sample with light at 365 nm diminished lines of 1-C(10)H(9)(+) and 2-C(10)H(9) and enhanced lines of 1-C(10)H(9) and 2-C(10)H(9)(+); the latter species was unstable and converted to 1-C(10)H(9)(+) in less than 30 min and 2-C(10)H(9) was converted to 1-C(10)H(9) at 365 nm. Observed wavenumbers and relative intensities of these species agree satisfactorily with the anharmonic vibrational wavenumbers and IR intensities predicted with the B3PW91/6-311++G(2d,2p) method. Compared with spectra recorded previously with IR photodissociation of Ar-tagged C(10)H(9)(+) or IR multiphoton dissociation of C(10)H(9)(+), our method has the advantages of producing high-resolution IR spectra with a wide spectral coverage, true IR intensity and excellent ratio of signal to noise; both protonated species and their neutral counterparts are produced with little interference from other fragments. With these advantages, the IR spectra of 1-C(10)H(9)(+), 2-C(10)H(9)(+), 1-C(10)H(9), and 2-C(10)H(9) are here clearly characterized. 23951076 Enamel Matrix Derivative Inhibits Adipocyte Differentiation of 3T3-L1 Cells via Activation of TGF-βRI Kinase Activity. Enamel matrix derivative (EMD), an extract of fetal porcine enamel, and TGF-β can both suppress adipogenic differentiation. However, there have been no studies that functionally link the role of EMD and TGF-β in vitro. Herein, we examined whether TGF-β signaling contributes to EMD-induced suppression of adipogenic differentiation. Adipogenesis was studied with 3T3-L1 preadipocytes in the presence of SB431542, an inhibitor of TGF-βRI kinase activity. SB431542 reversed the inhibitory effect of EMD on adipogenic differentiation, based on Oil Red O staining and mRNA expression of lipid regulated genes. SB431542 also reduced EMD-stimulated expression of connective tissue growth factor (CTGF), an autocrine inhibitor of adipogenic differentiation. Moreover, short interfering (si)RNAs for CTGF partially reversed the EMD-induced suppression of lipid regulated genes. We conclude that the TGF-βRI - CTGF axis is involved in the anti-adipogenic effects of EMD in vitro. 23944794 Child mortality drops with cash incentives for immunisations. A government programme in Brazil that gives cash to poor people on condition they vaccinate their children and make use of health services has contributed to a large reduction in the country's child mortality rate. 23866293 Detection of transient regional myocardial ischemia using body surface Delta map in patients referred for myocardial perfusion imaging-A pilot study. The diagnosis of transient regional myocardial ischemia (TRMI) in patients presenting with stable chest pain is a challenge. Exercise Tolerance Test (ETT) is no longer recommended in most cases due to its flaws. Alternative tests are more expensive and less readily available. The BSM Delta map is an intuitive color display of digitally subtracted ST-segment shift derived from two 80-electrode BSM recordings at baseline and at peak stress, and has shown promise as a tool for detection of TRMI. The purpose of this pilot study was to assess the feasibility of BSM Delta map as a tool to detect TRMI using dobutamine stress ECG gated single-photon emission computed tomography myocardial perfusion imaging (MPI) as a reference. Forty consecutive patients were recruited who were referred for MPI with a history of angina-like symptoms. The BSM Delta map was derived from two 80-electrode body surface mapping system recordings carried out simultaneously with MPI at (a) baseline and (b) peak dobutamine stress. Standard 12-lead ECGs were also recorded at the same time points. The mean patient age was 68±7.1years, and 52% (21/40) were female. Using MPI as the reference the sensitivity of BSM Delta map was 82% (9/11) and specificity was 86% (25/29) (95% CI 0.688-0.992), positive likelihood ratio 5.93 (95% CI 2.29-15), negative likelihood ratio 0.21 (95% CI 0.06-0.75). The sensitive of the 12-lead ECG was 36% (4/11) and specificity was 76% (22/29) (95% CI 0.356-0.767), positive likelihood ratio 1.51 (95% CI 0.55-4.15), negative likelihood ratio 0.84 (95% CI 0.51-1.37). BSM Delta map is more sensitive and specific (McNemar's chi-square test p=0.03 (95% CI, 0.448-0.924). The PPV and NPV for BSM Delta map were 69% (9/13) and 93% (25/27) respectively, compared with 36% (4/11) and 76% (22/29) for 12-lead ECG. This pilot study confirms the feasibility of using Delta map in this context and suggests that it has promising diagnostic accuracy and is superior to the 12-lead ECG. It could potentially represent a clinically suitable screening tool for TRMI in patients presenting with stable chest pain, since it is near patient and requires little specialist training for acquisition and interpretation. A larger clinical study is now required. 23774782 Preparation and characterization of 5-sulphosalicylic acid doped tetraethoxysilane composite ion-exchange material by sol-gel method. In this manuscript, we report the preparation and characterization of sulphosalicylic doped tetraethoxysilane (SATEOS), composite material by sol-gel method as a new ion exchanger for the removal of Ni(II) from aqueous solution. The fine granular material was prepared by acid catalyzed condensation polymerization through sol-gel mechanism in the presence of cationic surfactant. The material has an ion exchange capacity of 0.64mequiv./g(dry) for sodium ions, 0.60mequiv./g(dry) for potassium ions, 1.84mequiv./g(dry) for magnesium ions, 1.08mequiv./g(dry) for calcium ions and 1.36mequiv./g(dry) for strontium ions. Its X-ray diffraction studies suggest that it is crystalline in nature. The material has been characterized by SEM, IR, TGA and DTG so as to identify the various functional groups and ion exchange sites present in this material. Quantum chemical computations at DFT/B3LYP/6-311G (d,p) level on model systems were performed to substantiate the structural conclusions based ion instrumental techniques. Investigations into the elution behaviour, ion exchange reversibility and distribution capacities of this material towards certain environmentally hazardous metal ions are also performed. The material shows good chemical stability towards acidic conditions and exhibits fast elution of exchangeable H(+) ions under neutral conditions. This material shows remarkable selectivity for Ni(II) and on the basis of its Kd value (4×10(2) in 0.01M HClO4) some binary separations of Ni(II) from other metal ions are performed. 23807471 Torsional resonance mode atomic force microscopy in liquid with Lorentz force actuation. In this work, we present a design based on Lorentz force induction to excite pure torsional resonances of different types of cantilevers in air as well as in water. To demonstrate the atomic force microscopy imaging capability, the phase-modulation torsional resonance mode is employed to resolve fine features of purple membranes in a buffer solution. Most importantly, force-versus-distance curves using a relatively stiff cantilever can clearly detect the characteristic oscillatory profiles of hydration layers at a water-mica interface, indicating the high force sensitivity of the torsional mode. The high resonance frequencies and high quality-factors for the torsional mode may be of great potential for high-speed and high-sensitivity imaging in aqueous environment. 23711695 Evaluation of the redesigned conformable GORE TAG thoracic endoprosthesis for traumatic aortic transection. To evaluate the safety and effectiveness of the conformable GORE TAG thoracic endoprosthesis (CTAG) device (W. L. Gore and Associates, Flagstaff, Ariz) for the endovascular repair of traumatic aortic transections. A prospective, nonrandomized, multicenter trial was conducted at 21 sites. Primary safety end points included 30-day all-cause mortality. The effectiveness end point was freedom from a major device event requiring reintervention through 1-month follow-up. Fifty-one subjects were enrolled between December 2009 and January 2011 with polytraumatic injuries and a mean Injury Severity Score of 32 ± 14. The proximal mean intimal aortic diameter measured 24 mm, while the mean distal intimal diameter was 22 mm. A total of 57 CTAG devices were implanted (mean, 1.1/subject; range, 1-2) with a mean patient age of 44 years (range, 21-87) and a male-to-female ratio of 2:1. Technical success was 100% with an operative mortality of 0%. Femoral access was utilized in 96% of patients. The mean procedure time and blood loss was 105 minutes and 148 mL, respectively. All subjects required admission to an intensive care unit with a mean hospital stay of 14.6 days. Adjuvant techniques (ie, lumbar drains and induced hypertension) to prevent paraplegia were used in only 7.8% of patients. No patient developed paraplegia despite 63% having complete or partial left subclavian artery coverage and only 9% of those receiving left subclavian artery revascularization. In addition, there were no device compressions or major device events reported. Overall mortality at 30 days was 7.8%, and all were adjudicated by the clinical events committee as not being device or procedure related. Serious adverse events occurred in 39.2% of patients through 30 days. To date, there have been no conversions to open repair. Two site-reported endoleaks were detected during the mean follow-up of 4.2 months, which did not require reintervention. The CTAG device was demonstrated to be a safe and effective treatment for traumatic aortic transection based on 30-day outcomes. There were no device-related serious adverse events. 23915346 Alkylimidazolium Based Ionic Liquids: Impact of Cation Symmetry on their Nanoscale Structural Organization. Aiming at evaluating the impact of the cation symmetry on the nanostructuration of ionic liquids (ILs), in this work, the densities and viscosities as a function of temperature, and Small-Wide Angle X-ray Scattering (SWAXS) patterns at ambient conditions were determined and analyzed for 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (asymmetric) and 1,3-dialkylimidazolium bis(trifluoromethylsulfonyl)imide (symmetric) series of ionic liquids. The symmetric IL series, [CN/2CN/2im][NTf2], presents lower viscosities than the asymmetric [CN-1C1im][NTf2] counterparts. For ionic liquids from [C1C1im][NTf2] until [C6C6im][NTf2], an odd-even effect in the viscosity along the cation alkyl side chain length was observed, in contrast with a linear increase found for the ones ranging between [C6C6im][NTf2] and [C10C10im][NTf2]. The analysis of the viscosity data along the alkyl side chain length reveals a trend shift that occurs at [C6C1im][NTf2] for the asymmetric and at [C6C6im][NTf2] for the symmetric series. These results are further supported by SWAXS measurements at ambient conditions. The gathered data indicate that both asymmetric and symmetric members are characterized by the occurrence of a distinct degree of mesoscopic structural organization above a given threshold in the side alkyl chain length, regardless the cation symmetry. The data also highlight a difference in the alkyl chain dependence of the mesoscopic clusters sizes for symmetric and asymmetric cations, reflecting a different degree of interdigitation of the aliphatic tails in the two families. The trend shift found in this work is related with the structural segregation in the liquid after a critical alkyl length size (CALS) is attained and has particular relevance in the cation structural isomerism with higher symmetry. 23700151 Melatonin-receptor-1-deficiency affects neurogenic differentiation factor immunoreaction in pancreatic islets and enteroendocrine cells of mice. Neurogenic differentiation factor (NeuroD) is a transcription factor involved in the differentiation of neurons and in the control of energy balance and metabolism. It plays a key role in type 1 and type 2 diabetes. Melatonin is an important rhythmic endocrine signal within the circadian system of mammals and modulates insulin secretion and glucose metabolism. In the mouse pars tuberalis, NeuroD mRNA levels show day/night variation, which is independent of the molecular clock gene mPER1 but depends on the functional melatonin receptor 1 (MT1). So far, little is known about the effect of melatonin on NeuroD synthesis in the gastrointestinal tract. Thus, NeuroD protein levels and cellular localization were analyzed by immunohistochemistry in pancreatic islets and duodenal enteroendocrine cells of MT1- and mPER1-deficienct mice. In addition, the localization of NeuroD-positive cells was analyzed by double-immunofluorescence and confocal laser microscopy. In duodenal enteroendocrine cells and pancreatic islets of WT and PER1-deficient mice, NeuroD immunoreaction showed a peak during the early subjective night. In contrast, this peak was absent in MT1-deficent mice. These data suggest that melatonin, by acting on MT1 receptors, affects NeuroD expression in the gastrointestinal tract and thus might contribute to circadian regulation in metabolic functions. 23545193 Pressure-assisted sample preparation for proteomic analysis. Pressure-assisted digestion of proteins, also known as pressure cycling technology (PCT), using a Barocycler NEP 2320 was compared with the conventional method using atmospheric pressure. Our objective was to demonstrate that PCT provides more controlled enzymatic digestion of proteins than prolonged digestion at atmospheric pressure ranging from 18 to 24 h. More controlled digestion would be beneficial for studies of highly posttranslationally modified protein such as histones. For the comparison of these two techniques, recombinant and native histone H4 were used as model proteins. PCT was optimized for pressure and time, and it was found to be most effective at 15 kpsi for 120 min of incubation. In conclusion, the PCT method was found to be much faster than using atmospheric pressure. PCT was also found to allow for unambiguous control of digestion parameters and to provide a high yield of sequence coverage compared with atmospheric pressure. 23628211 Changes of hippocampal beta-alanine and citrulline levels are paralleling early and late phase of retrieval in the Morris Water Maze. Although a series of amino acids (AA) have been associated with spatial memory formation, there is limited information on concentrations of beta-alanine and citrulline in rodent brains. Given the importance of AA metabolism in cognitive functions it was the aim of the study to determine hippocampal levels of beta-alanine and citrulline in rats during two different phases of memory retrieval in a spatial memory paradigm. Ten rats were used per group and the first group was trained and sacrificed five min, the second six hours following retrieval in the Morris Water Maze (MWM) and the third and fourth group were untrained, yoked controls. Hippocampi were taken and free AA were determined using a well-established HPLC protocol. Beta-alanine and citrulline levels were higher in trained rat hippocampi, during both, early and late phase of memory retrieval. Taurine, methionine, cysteine, lysine and ornithine levels were higher in yoked rats at the late phase while tyrosine was higher in yoked rats during the early phase. There were no significant correlations between time spent in the target quadrant and any of the AA levels. Herein, an AA pattern, different between yoked and trained animals at early and late phase of memory retrieval is shown, indicating probable involvement of different AA pathways in animals trained and untrained in the MWM. The results may be useful for the interpretation of previous studies and the design of future experiments to identify amino acids as possible targets for modulating spatial memory. 23869398 The yield and cost of colonoscopy in patients with metastatic cancer of unknown primary. Although gastroenterologists are asked to perform colonoscopy in patients with metastatic cancer of unknown primary (MCUP), studies evaluating this practice are lacking. To determine the yield and cost of colonoscopy in patients referred for colonoscopy with an indication of MCUP. We prospectively and retrospectively assessed colonoscopies performed from 2000 to 2011 at a county, a university, and a Veterans Administration medical centre to identify patients referred for colonoscopy for the indication of MCUP. Exclusion criteria included overt or occult bleeding, iron-deficiency anaemia, familial-colon-cancer syndrome, prior colon cancer, imaging suggesting colorectal lesion, and palpable rectal mass. Outcomes were the number of primary colon cancers and costs based on 2012 Medicare reimbursements. Two (1%) of the 160 patients meeting enrollment criteria had a primary colon cancer identified, and both died within 1 month after diagnosis without receiving therapy targeted at colon cancer. One patient without colon cancer had a perforation because of colonoscopy, which required surgery and colostomy. The cost of a strategy of routinely performing colonoscopy in patients referred with MCUP was $84 736 per colon primary identified. Primary colon cancer was rarely identified at colonoscopy in patients with MCUP and no standard indications for diagnostic colonoscopy. Furthermore, the cost to diagnose one additional colon primary was very high. Those with colon cancer had advanced disease and were unable to benefit from targeted therapy. Routine colonoscopy for MCUP cannot be recommended at present. 23495066 uCyt+/ImmunoCyt and cytology in the detection of urothelial carcinoma: An update on 7422 analyses. The aim of the current study was to report the results of 7422 uCyt+/ImmunoCyt and cytology analyses that were performed over the course of 9 years at the study institution for the evaluation and follow-up of patients with urothelial carcinoma. Between January 2002 and March 2011, 2217 patients with a mean age of 69.5 years (range, 15 years-99 years) were enrolled in the current study. All patients seen for the follow-up of bladder and/or upper tract urothelial cancer as well as those with a history that was suspicious for bladder cancer were recruited. In all patients, a voided urinary cytology and uCyt+/ImmunoCyt test was performed. Patients underwent routine cystoscopy as well as cystoscopy when cytology and/or the uCyt+/ImmunoCyt test yielded positive results. Lesions that were detected cystoscopically were biopsied and removed transurethrally. A total of 7422 uCyt+/ImmunoCyt and cytology analyses were performed. Of the 7422 uCyt+/ImmunoCyt tests and cytologies that were performed, 7075 (95.3%) were considered adequate. A total of 578 patients (with 1156 analyses) underwent biopsy and 728 (63%) samples had a histologically proven urothelial carcinoma. Overall sensitivity was 34.5% for cytology, 68.1% for uCyt+/ImmunoCyt, and 72.8% for the 2 tests combined. Overall specificity was 97.9% for cytology, 72.3% for uCyt+/ImmunoCyt, and 71.9% for the 2 tests combined. Cytology and the uCyt+/ImmunoCyt test together had an overall sensitivity of 72.8%, with 59% for grade 1, 77% for grade 2, and 90% for grade 3 tumors (according to the 1973 World Health Organization grading classification system). On the basis of their 9-year experience, the authors confirm the value of uCyt+/ImmunoCyt and cytology analyses in the follow-up of patients with non-muscle-invasive urothelial cancer. This could potentially reduce the number and cost of routine cystoscopic examinations in patients who are followed for bladder carcinoma. Cancer (Cancer Cytopathol) 2013;121:392-397. © 2013 American Cancer Society. 23800626 Alfalfa dodder (Cuscuta campestris) toxicity in horses: clinical, haematological and serum biochemical findings. The objective of this observational study is to describe clinical, haematological and serum biochemical findings of horses affected with alfalfa dodder (Cuscuta campestris) toxicity. Twenty horses naturally exposed to alfalfa dodder toxicity were examined and information was collected on history and clinical signs. Physical examination was done on horses in the premises (n=20), and venous blood samples of 12 horses were submitted for haematology and serum biochemical examination for each horse. Abnormal clinical signs started around 36 hours after horses were fed the contaminated alfalfa. Abnormal signs were seen in 11 horses and those included diarrhoea (n=8), decreased appetite (n=7), neurological signs (n=4) and abdominal pain (n=1). Some horses had multiple clinical signs of the above. The results of complete blood cell count revealed leukocytopenia, neutropenia and thrombocytopenia. Serum biochemical analysis revealed decreased ALP, AST and CPK levels and increased direct bilirubin level. The used alfalfa was stopped immediately and a different alfalfa from a new container that did not contain any weeds was fed. Horses on the premises were observed closely, and the abnormal clinical signs resolved within three days. No treatment was implemented. Knowledge about toxicity of horses by Cuscuta species is scarce in the English veterinary literature and very limited. 23897635 Palivizumab Prophylaxis during Nosocomial Outbreaks of Respiratory Syncytial Virus in a Neonatal Intensive Care Unit: Predicting Effectiveness with an Artificial Neural Network Model. To identify subgroups of premature infants who may benefit from palivizumab prophylaxis during nosocomial outbreaks of respiratory syncytial virus (RSV) infection. Retrospective analysis using an artificial intelligence model. Level IIIB, 35-bed, neonatal intensive care unit (NICU) at a tertiary care hospital in the United Arab Emirates. One hundred seventy six premature infants, born at a gestational age of 22-34 weeks, and hospitalized during four RSV outbreaks that occurred between April 2005 and July 2007. We collected demographic and clinical data for each patient by using a standardized form. Input data consisted of seven categoric and continuous variables each. We trained, tested, and validated artificial neural networks for three outcomes of interest: mortality, days of supplemental oxygen, and length of NICU stay after the index case was identified. We compared variable impacts and performed reassignments with live predictions to evaluate the effect of palivizumab. Of the 176 infants, 31 (17.6%) received palivizumab during the outbreaks. All neural network configurations converged within 4 seconds in less than 400 training cycles. Infants who received palivizumab required supplemental oxygen for a shorter duration compared with controls (105.2 ± 7.2 days vs 113.2 ± 10.4 days, p=0.003). This benefit was statistically significant in male infants whose birth weight was less than 0.7 kg and who had hemodynamically significant congenital heart disease. Length of NICU stay after identification of the index case and mortality were independent of palivizumab use. Palivizumab may be an effective intervention during nosocomial outbreaks of RSV in a subgroup of extremely low-birth-weight male infants with hemodynamically significant congenital heart disease. 23925926 The effect of a Rapid Access Prostate Cancer Clinic on prostate cancer patient and disease characteristics, primary treatment and surgical workload. In 2009, Rapid Access Prostate Cancer Clinics (RAPC) were introduced to St. James's Hospital to improve the access and organisation of patients to prostate cancer investigations and treatment. To observe the effects of the RAPC on prostate cancer diagnosis, primary treatment and overall workload. Using a prospectively designed patient database, the records of all prostate cancer patients between 2007 and 2011 were retrieved and analysed. Data were obtained for age, PSA, biopsy Gleason score and primary treatment modality and charted for the observation and comparison of trends. Seven hundred and eighty-nine patients had a new diagnosis of prostate cancer between 2007 and 2011. The median PSA prior to the RAPC was 9.7-13.1 ng/ml, which decreased to 7.79-9 ng/ml after the RAPC. Prior to the RAPC, 77-81 biopsies were performed annually versus 149-271 in the post-RAPC era. Annual requirements for radical prostatectomy also increased from 12 to 27 in the post-RAPC era. Conversely, an initially increasing percentage of patients for radiotherapy was reversed in the post-RAPC period. An increasing trend for higher grade PCa (Gleason score 4 + 4 and higher) was also reversed. The introduction of a RAPC improves the overall pathological characteristics of patients with prostate cancer. However, RAPCs are also associated with a considerable increase in surgical workload. These are important considerations for units considering the incorporation of a similar facility in their institutions. 23342998 Detecting Allosteric Sites of HIV-1 Reverse Transcriptase by X-ray Crystallographic Fragment Screening. HIV-1 reverse transcriptase (RT) undergoes a series of conformational changes during viral replication and is a central target for antiretroviral therapy. The intrinsic flexibility of RT can provide novel allosteric sites for inhibition. Crystals of RT that diffract X-rays to better than 2 Å resolution facilitated the probing of RT for new druggable sites using fragment screening by X-ray crystallography. A total of 775 fragments were grouped into 143 cocktails, which were soaked into crystals of RT in complex with the non-nucleoside drug rilpivirine (TMC278). Seven new sites were discovered, including the Incoming Nucleotide Binding, Knuckles, NNRTI Adjacent, and 399 sites, located in the polymerase region of RT, and the 428, RNase H Primer Grip Adjacent, and 507 sites, located in the RNase H region. Three of these sites (Knuckles, NNRTI Adjacent, and Incoming Nucleotide Binding) are inhibitory and provide opportunities for discovery of new anti-AIDS drugs. 23677999 Evolutionary Changes in Chlorophyllide a Oxygenase (CAO) Structure Contribute to the Acquisition of a New Light-harvesting Complex in Micromonas. Chlorophyll b is found in photosynthetic prokaryotes and primary and secondary endosymbionts, although their light-harvesting systems are quite different. Chlorophyll b is synthesized from chlorophyll a by chlorophyllide a oxygenase (CAO), which is a Rieske-mononuclear iron oxygenase. Comparison of the amino acid sequences of CAO among photosynthetic organisms elucidated changes in the domain structures of CAO during evolution. However, the evolutionary relationship between the light-harvesting system and the domain structure of CAO remains unclear. To elucidate this relationship, we investigated the CAO structure and the pigment composition of chlorophyll-protein complexes in the prasinophyte Micromonas. The Micromonas CAO is composed of two genes, MpCAO1 and MpCAO2, that possess Rieske and mononuclear iron-binding motifs, respectively. Only when both genes were introduced into the chlorophyll b-less Arabidopsis mutant (ch1-1) was chlorophyll b accumulated, indicating that cooperation between the two subunits is required to synthesize chlorophyll b. Although Micromonas has a characteristic light-harvesting system in which chlorophyll b is incorporated into the core antennas of reaction centers, chlorophyll b was also incorporated into the core antennas of reaction centers of the Arabidopsis transformants that contained the two Micromonas CAO proteins. Based on these results, we discuss the evolutionary relationship between the structures of CAO and light-harvesting systems. 23844795 Neutral pH and copper ions promote eumelanogenesis after the dopachrome stage. The diversity of pigmentation in the skin, hair, and eyes of humans has been largely attributed to the diversity of pH in melanosomes with acidic pH being proposed to suppress melanin production. Tyrosinase has an optimum pH of 7.4 and its activity is suppressed greatly at lower pH values. The first step of eumelanogenesis is the oxidation of tyrosine to dopachrome (DC) via dopaquinone. However, how eumelanogenesis is controlled by pH beyond this stage is not known. In this study, we examined the effects of pH (5.3-7.3) on the conversion of DC to 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) and the subsequent oxidation of DHI and DHICA to form eumelanin. The effects of Cu(2+) ions on those reactions were also compared. The results indicate that an acidic pH greatly suppresses the late stages of eumelanogenesis and that Cu(2+) ions accelerate the conversion of DC to DHICA and its subsequent oxidation. 23051874 Health-related quality of life and associated factors in Chinese women with cervical cancer: a 9-month follow-up. There is a lack of health-related quality of life (HRQOL) studies in Chinese women with cervical cancer. The objectives of this study were to investigate the HRQOL trajectory in women with cervical cancer in Mainland China in the 9 months following diagnosis and to identify factors that influence HRQOL. Initially, 187 patients with cervical cancer were included in the study, but at each follow-up, the number declined to 128, 112, and 106, respectively. The Functional Assessment of Cancer Therapy-Cervix (FACT-Cx) was used to collect data sequentially at the time of diagnosis (T1) and at 3 (T2), 6 (T3), and 9 months after diagnosis (T4). Medical characteristics, sense of coherence, and social support were included as factors likely to contribute to HRQOL. Functional Assessment of Cancer Therapy-Cervix ranged in mean from 120.30 at T1 to 126.22 at T4 (P = .001), whereas social/family well-being ranged from 23.56 at T1 to 20.23 at T4 (P = .025). In the stepwise regression with FACT-Cx as the independent variable, sense of coherence entered the equation with the highest standardized coefficients (0.554) at T1 and stage II at T2 and T3 (-0.53 and -0.26, respectively). Satisfaction with family relationships had the second highest standardized coefficient (-0.21) at T3. Overall HRQOL improved, although social/family well-being deteriorated. Sense of coherence contributed to HRQOL initially, whereas disease stage and family support did so later on. The study highlights the importance of identifying those with a low sense of coherence at the time of diagnosis. Family members should be included in caring process as a vital source of social support. 23949653 Paradiscogaster flindersi and P. oxleyi n. sp. (Digenea: Faustulidae): overlapping host and geographical distributions in corallivore chaetodontid fishes in the tropical Indo-west Pacific. A total of 2,868 individuals of 47 species of chaetodontids were examined for faustulids at seven major localities in the Tropical Indo-West Pacific (TIWP). Combined morphological and molecular analyses allowed us to describe Paradiscogaster oxleyi n. sp. from three localities in the TIWP and in three host species, Chaetodon lunulatus Quoy & Gaimard (type-host), C. ornatissimus Cuvier and C. meyeri Bloch & Schneider. Molecular analysis of the ITS2 region of rDNA from two host species and three localities supports the morphology-based conclusion that P. oxleyi n. sp. is the same species at the three localities. Paradiscogaster flindersi Bray, Cribb & Barker, 1994 is reported from three new localities in the TIWP and is now known from 13 chaetodontid species. Sequences from samples consistent with P. flindersi differed from those from P. oxleyi n. sp. in 11-12 base pairs. The host ranges of the two species overlap broadly. Neither species was found in French Polynesia but both were found at Swain Reefs on the Great Barrier Reef. Only one of the two species was found at each of the five other sites. Both species occur almost exclusively in specialist corallivores allowing the inference that the metacercariae occur in corals. Finally, a key to the species of Paradiscogaster is provided. 23682813 Hydrogen Sulfide Attenuates Opioid Dependence by Suppression of Adenylate Cyclase/cAMP Pathway. Abstract Aims: The best-established mechanism of opioid dependence is the up-regulation of adenylate cyclase (AC)/cAMP pathway, which was reported to be negatively regulated by hydrogen sulfide (H2S), a novel endogenous neuromodulator. The present study was, therefore, designed to determine whether H2S is able to attenuate the development of opioid dependence via down-regulating AC/cAMP pathway. Results: We demonstrated that application of sodium hydrosulphide (NaHS) and GYY4137, two donors of H2S, significantly alleviated naloxone-induced robust withdrawal jumping (the most sensitive and reliable index of opioid physical dependence) in morphine-treated mice. Repeated treatment with NaHS inhibited the up-regulated protein expression of AC in the striatum of morphine-dependent mice. Furthermore, NaHS also attenuated morphine/naloxone-elevated mRNA levels of AC isoform 1 and 8, production of cAMP, and phosphorylation of cAMP response element-binding protein (CREB) in mice striatum. These effects were mimicked by the application of exogenous H2S or over-expression of cystathione-β-synthase, an H2S -producing enzyme, in SH-SY5Y neuronal cells on treatment with [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-Enkephalin, a selective μ-opioid receptor agonist. Blockade of extracellular-regulated protein kinase 1/2 (ERK1/2) with its specific inhibitor attenuated naloxone-induced CREB phosphorylation. Pretreatment with NaHS or stimulation of endogenous H2S production also significantly suppressed opioid withdrawal-induced ERK1/2 activation in mice striatum or SH-SY5Y cells. Innovation: H2S treatment is important in prevention of the development of opioid dependence via suppression of cAMP pathway in both animal and cellular models. Conclusion: Our data suggest a potential role of H2S in attenuating the development of opioid dependence, and the underlying mechanism is closely related to the inhibition of AC/cAMP pathway. Antioxid. Redox Signal. 00, 000-000. 23877265 Minimally invasive approaches for thoracic decompression from discectomy to corpectomy. Surgical approaches to the thoracic spine have evolved in recent decades with the development of advanced instrumentation techniques and an increased emphasis on reducing surgical morbidity. Multiple methods to access this area have been described, from a conventional open to a more minimally invasive approach, such as anterior-based, via supra- or transmanubrium, via thoracoscopy, lateral-based approach, extreme lateral mini-thoracotomy, and dorsolateral approaches, transpedicular, costotransversectomy and the lateral extracavitary access. The technique used is often determined by the affected spinal level, pathological process, and surgeon preference. Each of these approaches requires expertise in the specific technique, and has its own complication profile. Over time, these techniques have undergone improvement to limit approach-related morbidity and minimize soft tissue dissection, resulting in better patient outcomes. These different approaches present distinct advantages and disadvantages for which a thorough understanding of the regional anatomy is required to avoid approach-related complications. For these reasons, surgeon experience and confidence in the various techniques are major factors in the decision-making process and patient outcomes. 23729653 Key amino Acid residues involved in the transitions of L- to R-type protofilaments of the salmonella flagellar filament. The flagellar filament enables bacteria to swim by functioning as a helical propeller. The filament is a supercoiled assembly of a single protein, flagellin, and is formed by 11 protofilaments arranged in a circle. Bacterial swimming and tumbling correlate with changes of the various helical structures, called polymorphic transformation, that are determined by the ratios of two distinct forms of protofilaments, the L and R types. The polymorphic transformation is caused by transition of the protofilament between L and R types. Elucidation of this transition mechanism has been addressed by comparing the atomic structures of L- and R-type straight filaments or using massive molecular dynamic simulation. Here, we found amino acid residues required for the transition of the protofilament using fliC-intragenic suppressor analysis. We isolated a number of revertants producing supercoiled filaments from mutants with straight filaments and identified the second-site mutations in all of the revertants. The results suggest that Asp107, Gly426, and Ser448 and Ser106, Ala416, Ala427, and Arg431 are the key residues involved in inducing supercoiled filaments from the R- and the L-type straight filaments, respectively. Considering the structures of the R- and L-type protofilaments and the relationship between the rotation of the flagellar motor and the polymorphic transformation, we propose that Gly426, Ala427, and Arg431 contribute to the first stage of the transition and that Ser106, Asp107, and Ala416 play a role in propagating the transitions along the flagellar filament. 23581996 Self-Sorting Click Reactions That Generate Spatially Controlled Chemical Functionality on Surfaces. This Article describes the generation of a patterned surface that can be postpolymerization modified to incorporate fragile macromolecules or delicate biomolecules without the need for special equipment. Two monomers that undergo different click reactions, pentafluorophenyl acrylate (PFPA) and 4-(trimethylsilyl) ethynylstyrene (TMSES), were sequentially polymerized from a silicon surface in the presence of a shadowmask with UV light, generating 12.5 and 62 μm pitch patterns. Two different dyes, 1-aminomethylpyrene (AMP) and 5-azidofluorescein (AF), were covalently attached to the polymer brushes through aminolysis and dual desilylation/copper(I)-catalyzed alkyne/azide cycloaddition (CuAAC) in one pot. Unlike most CuAAC reactions, the terminal alkyne of TMSES was not deprotected prior to functionalization. Although a 2 nm thickness increase was observed for poly(PFPA) brushes after polymerization of TMSES, cross-contamination was not visible through fluorescence microscopy after functionalization. 23090647 Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. Linaclotide, a potent guanylate cyclase C agonist, is a therapeutic peptide approved in the United States for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. We present for the first time the metabolism, degradation, and disposition of linaclotide in animals and humans. We examined the metabolic stability of linaclotide in conditions that mimic the gastrointestinal tract and characterized the metabolite MM-419447 (CCEYCCNPACTGC), which contributes to the pharmacologic effects of linaclotide. Systemic exposure to these active peptides is low in rats and humans, and the low systemic and portal vein concentrations of linaclotide and MM-419447 observed in the rat confirmed both peptides are minimally absorbed after oral administration. Linaclotide is stable in the acidic environment of the stomach and is converted to MM-419447 in the small intestine. The disulfide bonds of both peptides are reduced in the small intestine, where they are subsequently proteolyzed and degraded. After oral administration of linaclotide, <1% of the dose was excreted as active peptide in rat feces and a mean of 3-5% in human feces; in both cases MM-419447 was the predominant peptide recovered. MM-419447 exhibits high-affinity binding in vitro to T84 cells, resulting in a significant, concentration-dependent accumulation of intracellular cyclic guanosine-3',5'-monophosphate (cGMP). In rat models of gastrointestinal function, orally dosed MM-419447 significantly increased fluid secretion into small intestinal loops, increased intraluminal cGMP, and caused a dose-dependent acceleration in gastrointestinal transit. These results demonstrate the importance of the active metabolite in contributing to linaclotide's pharmacology. 23745668 Dual-index evaluation of character changes in Panax ginseng C. A. Mey stored in different conditions. Panax ginseng C. A. Mey has been used as a traditional medicine and functional food in Asia for thousands of years for its improvement of human immunity and metabolism and its antitumor and antifatigue activities. This study reports the impact of storage conditions and storage period on the quality of P. ginseng. The contents of four major ginsenosides in P. ginseng and phosphorylation activities of Akt of ginseng extracts were affected by both storage conditions and storage period. In contrast, the ATP generation capacity of ginseng extracts was affected by storage conditions, but not by storage period. The results showed that the quality of P. ginseng could be well maintained at a relative humidity between 70% and 90%, and dry conditions might decrease the quality of P. ginseng. Through dual-index evaluation, the present study extended our knowledge on the changes of ginsenosides and bioactivities in P. ginseng with respect to different storage conditions and storage periods. 23867025 Prostate-Specific Antigen Testing: Men's Responses to 2012 Recommendation Against Screening. The U.S. Preventive Services Task Force (USPSTF) released a draft recommendation advising against prostate-specific antigen (PSA) testing in October 2011, a major shift from previous years of recommending neither for or against PSA testing due to insufficient evidence. The purpose of this study was to assess men's awareness of the new recommendation, and their responses to it. This study comprised a web survey of men aged 40-74 years that was conducted through GfK Custom Research, LLC's Knowledge Panel(®) from November 22 to December 2, 2011. Chi-square tests and logistic regression analyses were conducted to identify factors associated with disagreement with and intention to follow the recommendation. Data were analyzed in March 2012. The survey sample included 1089 men without a history of prostate cancer. After reviewing the recommendation, 62% agreed with the recommendation. Age and worry about getting prostate cancer were significantly related to disagreement with the recommendation. Only 13% of respondents were intenders (they planned to follow the U.S. Preventive Services Task Force recommendation and not get a prostate-specific antigen test in the future); 54% were non-intenders (they planned to not follow the U.S. Preventive Services Task Force recommendation and get a prostate-specific antigen test in the future; and 33% were undecided. Black race, higher income, having a PSA test in the past 2 years, and being somewhat/very worried about getting prostate cancer were all positively associated with being a non-intender. Study findings suggest that consumers are favorably disposed to PSA testing, despite new evidence suggesting that the harms outweigh the benefits. The new USPSTF recommendation against PSA testing in all men may be met with resistance. 23841511 Zn(II) Ions Substantially Perturb Cu(II) Ion Coordination in Amyloid-β at Physiological pH. The interaction of Cu(II) and Zn(II) ions with amyloid-β (Aβ) plays an important role in the etiology of Alzheimer's disease. We describe the use of electron spin resonance (ESR) to measure metal-binding competition between Cu(II) and Zn(II) in amyloid-β at physiological pH. Continuous wave ESR measurements show that the affinity of Cu(II) toward Aβ(1-16) is significantly higher than that of Zn(II) at physiological pH. Importantly, of the two known Cu(II) coordination modes in Aβ, component I and component II, Zn(II) displaces Cu(II) only from component I. Our results indicate that at excess amounts of Zn(II) component II becomes the most dominant coordination mode. This observation is important as Aβ aggregates in the brain contain a high Zn(II) ion concentration. In order to determine details of the metal ion competition, electron spin echo envelope modulation experiments were carried out on Aβ variants that were systematically (15)N labeled. In the presence of Zn(II), most peptides use His 14 as an equatorial ligand to bind Cu(II) ions. Interestingly, Zn(II) ions completely substitute Cu(II) ions that are simultaneously coordinated to His 6 and His 13. Furthermore, in the presence of Zn(II), the proportion of Cu(II) ions that are simultaneously coordinated to His 13 and His 14 is increased. On the basis of our results we suggest that His 13 plays a critical role in modulating the morphology of Aβ aggregates. 23902912 Elevated oxidative damage is correlated with reduced fitness in interpopulation hybrids of a marine copepod. Aerobic energy production occurs via the oxidative phosphorylation pathway (OXPHOS), which is critically dependent on interactions between the 13 mitochondrial DNA (mtDNA)-encoded and approximately 70 nuclear-encoded protein subunits. Disruptive mutations in any component of OXPHOS can result in impaired ATP production and exacerbated oxidative stress; in mammalian systems, such mutations are associated with ageing as well as numerous diseases. Recent studies have suggested that oxidative stress plays a role in fitness trade-offs in life-history evolution and functional ecology. Here, we show that outcrossing between populations with divergent mtDNA can exacerbate cellular oxidative stress in hybrid offspring. In the copepod Tigriopus californicus, we found that hybrids that showed evidence of fitness breakdown (low fecundity) also exhibited elevated levels of oxidative damage to DNA, whereas those with no clear breakdown did not show significantly elevated damage. The extent of oxidative stress in hybrids appears to be dependent on the degree of genetic divergence between their respective parental populations, but this pattern requires further testing using multiple crosses at different levels of divergence. Given previous evidence in T. californicus that hybridization disrupts nuclear/mitochondrial interactions and reduces hybrid fitness, our results suggest that such negative intergenomic epistasis may also increase the production of damaging cellular oxidants; consequently, mtDNA evolution may play a significant role in generating postzygotic isolating barriers among diverging populations. 23955266 Gene Expression Profiling as a Tool to Investigate the Molecular Machinery Activated during Hippocampal Neurodegeneration Induced by Trimethyltin (TMT) Administration. Trimethyltin (TMT) is an organotin compound exhibiting neurotoxicant effects selectively localized in the limbic system and especially marked in the hippocampus, in both experimental animal models and accidentally exposed humans. TMT administration causes selective neuronal death involving either the granular neurons of the dentate gyrus or the pyramidal cells of the Cornu Ammonis, with a different pattern of localization depending on the different species studied or the dosage schedule. TMT is broadly used to realize experimental models of hippocampal neurodegeneration associated with cognitive impairment and temporal lobe epilepsy, though the molecular mechanisms underlying the associated selective neuronal death are still not conclusively clarified. Experimental evidence indicates that TMT-induced neurodegeneration is a complex event involving different pathogenetic mechanisms, probably acting differently in animal and cell models, which include neuroinflammation, intracellular calcium overload, and oxidative stress. Microarray-based, genome-wide expression analysis has been used to investigate the molecular scenario occurring in the TMT-injured brain in different in vivo and in vitro models, producing an overwhelming amount of data. The aim of this review is to discuss and rationalize the state-of-the-art on TMT-associated genome wide expression profiles in order to identify comparable and reproducible data that may allow focusing on significantly involved pathways. 23456695 Rhythm of carbon and nitrogen fixation in unicellular cyanobacteria under turbulent and highly aerobic conditions. Nitrogen fixing cyanobacteria are being increasingly explored for nitrogenase-dependent hydrogen production. Commercial success however will depend on the ability to grow these cultures at high cell densities. Photo-limitation at high cell densities leads to hindered photoautotrophic growth while turbulent conditions, which simulate flashing light effect, can lead to oxygen toxicity to the nitrogenase enzyme. Cyanothece sp. strain ATCC 51142, a known hydrogen producer, is reported to grow and fix nitrogen under moderately oxic conditions in shake flasks. In this study, we explore the growth and nitrogen fixing potential of this organism under turbulent conditions with volumetric oxygen mass transfer coefficient (KL a) values that are up to 20-times greater than in shake flasks. In a stirred vessel, the organism grows well in turbulent regime possibly due to a simulated flashing light effect with optimal growth at Reynolds number of approximately 35,000. A respiratory burst lasting for about 4 h creates anoxic conditions intracellularly with near saturating levels of dissolved oxygen in the extracellular medium. This is concomitant with complete exhaustion of intracellular glycogen storage and upregulation of nifH and nifX, the genes encoding proteins of the nitrogenase complex. Further, the rhythmic oscillations in exhaust gas CO2 and O2 profiles synchronize faithfully with those in biochemical parameters and gene expression thereby serving as an effective online monitoring tool. These results will have important implications in potential commercial success of nitrogenase-dependent hydrogen production by cyanobacteria. Biotechnol. Bioeng. 2013; 110:2371-2379. © 2013 Wiley Periodicals, Inc. 23927833 Role of cervical vestibular evoked myogenic potential response in identifying vestibular dysfunction. Objectives: To analyse cervical vestibular evoked myogenic potential response parameters in normal volunteers and vertiginous patients. Subjects and methods: A prospective study of 50 normal subjects and 50 patients with vertigo was conducted at Chiang Mai University Hospital, Thailand. Cervical vestibular evoked myogenic potential responses were measured using air-conducted, 500-Hz, tone-burst stimuli with subjects in a sitting position with their head turned toward the contralateral shoulder. Results: The mean ± standard deviation age and male:female ratio in the normal (44.0 ± 9.3 years; 12:38) and vertigo groups (44.7 ± 9.8 years; 17:33) were not significantly different. The prevalence of absent responses in the normal (14 per cent) and vertigo ears (46 per cent) differed significantly (p < 0.0001). Other cervical vestibular evoked myogenic potential parameters (i.e. response threshold, P1 and N1 latency, P1-N1 interlatency and interamplitude, inter-ear difference in P1 threshold, and asymmetry ratio) showed no inter-group differences. Conclusion: The absence of a cervical vestibular evoked myogenic potential response is useful in the identification of vestibular dysfunction. However, patients should undergo a comprehensive battery of other vestibular tests to supplement their cervical vestibular evoked myogenic potential response findings. 23944906 Antibiotic Susceptibility of Staphylococci Isolates from Patients with Chronic Conjunctivitis: Including Associated Factors and Clinical Evaluation. Abstract Purpose: To determine species of staphylococci in chronic conjunctivitis, their antibiotic susceptibility pattern, patient treatments, clinical course, and clinical conditions. Methods: In this prospective study, 243 conjunctival cultures were taken from 191 patients with chronic conjunctivitis, we obtained staphylococci susceptibility patterns with E-test, and they were analyzed in coagulase-positive and negative. The minimum inhibitory concentration for 90% of isolates (MIC90) was determined for Staphylococcus aureus and Staphylococcus epidermidis. Additionally, clinical follow-up and associated factors of all patients were analyzed depending on methicillin resistance (MR) or susceptibility (MS) bacterial state. Results: One hundred and eight (44%) cultures were positive; 81 positive cultures were Gram-positive of which, 77 were staphylococci, 29 coagulase-positive with S. aureus as the most prevalent, 89% MS, and 11% MR. And 48 were coagulase-negative with S. epidermidis as the most isolated with 36% of MS and 64% of MR. Poor susceptibility was found in the staphylococcus coagulase-negative/MR group. Moxifloxacin and vancomycin show the best in vitro activity for all isolates. The MIC90 of moxifloxacin and vancomycin were 0.064/1.5, 0.64/3.0, and 1/3.0 for S. aureus-MS, S. epidermidis-MS, and S. epidermidis-MR, respectively. The most frequently associated factors found in patients with positive culture for staphylococcus were exposure to the health care system 23 (29.87%) of 77 patients and dry eye 23 (29.87%) of 77 patients. Both with a proportion of 3 in 10. Conclusion: Coagulase-negative staphylococci were the most frequently isolated from the conjunctiva with 58.33% of MR; even though multiresistance was detected, their susceptibility to a fourth-generation fluoroquinolone, commonly used, such as moxifloxacin, was preserved. 23583488 Development and evaluation of multiplex RT-LAMP assays for rapid and sensitive detection of foot-and-mouth disease virus. This paper describes the evaluation of four novel real-time multiplex reverse transcription loop-mediated isothermal amplification (RT-LAMP) assays for rapid and sensitive diagnosis of foot-and-mouth disease (FMD). In order to overcome the genetic diversity of FMD viruses (FMDV), these multiplex RT-LAMP assay pairs were established by combining four newly designed primer sets with two primer sets that had been previously published. Using a real-time turbidimeter to detect amplification products and a panel of 300 samples collected throughout the world over a 78-year period, the performance of the multiplex RT-LAMP assays was compared with a FMDV-specific real-time RT-PCR assay. The most successful of the four multiplex RT-LAMP assays achieved a diagnostic sensitivity and specificity of 98.0% and 98.1%, and did not falsely detect FMDV in known negatives or samples containing swine vesicular disease virus, vesicular stomatitis virus or vesicular exanthema of swine virus. Furthermore, the analytical sensitivity of this multiplex RT-LAMP assay was at least as good as the individual component RT-LAMP tests. This is the first report of the development of a multiplex RT-LAMP to accommodate the high sequence variability encountered in RNA virus genomes and these results support the use of RT-LAMP as a cost-effective tool for simple diagnosis of FMD. 23860718 Intestinal Bacteria Modify Lymphoma Incidence and Latency by Affecting Systemic Inflammatory State, Oxidative Stress, and Leukocyte Genotoxicity. Ataxia-telangiectasia is a genetic disorder associated with high incidence of B-cell lymphoma. Using an ataxia-telangiectasia mouse model, we compared lymphoma incidence in several isogenic mouse colonies harboring different bacterial communities, finding that intestinal microbiota are a major contributor to disease penetrance and latency, lifespan, molecular oxidative stress, and systemic leukocyte genotoxicity. High-throughput sequence analysis of rRNA genes identified mucosa-associated bacterial phylotypes that were colony-specific. Lactobacillus johnsonii, which was deficient in the more cancer-prone mouse colony, was causally tested for its capacity to confer reduced genotoxicity when restored by short-term oral transfer. This intervention decreased systemic genotoxicity, a response associated with reduced basal leukocytes and the cytokine-mediated inflammatory state, and mechanistically linked to the host cell biology of systemic genotoxicity. Our results suggest that intestinal microbiota are a potentially modifiable trait for translational intervention in individuals at risk for B-cell lymphoma, or for other diseases that are driven by genotoxicity or the molecular response to oxidative stress. Cancer Res; 73(14); 4222-32. ©2013 AACR. 23875500 The IRS and "your health care". At most times, the IRS is one of America's least loved institutions, but this past month has been a particularly bad period for the agency. 23809916 Exserohilum infections associated with contaminated steroid injections: a clinicopathologic review of 40 cases. September 2012 marked the beginning of the largest reported outbreak of infections associated with epidural and intra-articular injections. Contamination of methylprednisolone acetate with the black mold, Exserohilum rostratum, was the primary cause of the outbreak, with >13,000 persons exposed to the potentially contaminated drug, 741 confirmed drug-related infections, and 55 deaths. Fatal meningitis and localized epidural, paraspinal, and peripheral joint infections occurred. Tissues from 40 laboratory-confirmed cases representing these various clinical entities were evaluated by histopathological analysis, special stains, and IHC to characterize the pathological features and investigate the pathogenesis of infection, and to evaluate methods for detection of Exserohilum in formalin-fixed, paraffin-embedded (FFPE) tissues. Fatal cases had necrosuppurative to granulomatous meningitis and vasculitis, with thrombi and abundant angioinvasive fungi, with extensive involvement of the basilar arterial circulation of the brain. IHC was a highly sensitive method for detection of fungus in FFPE tissues, demonstrating both hyphal forms and granular fungal antigens, and PCR identified Exserohilum in FFPE and fresh tissues. Our findings suggest a pathogenesis for meningitis involving fungal penetration into the cerebrospinal fluid at the injection site, with transport through cerebrospinal fluid to the basal cisterns and subsequent invasion of the basilar arteries. Further studies are needed to characterize Exserohilum and investigate the potential effects of underlying host factors and steroid administration on the pathogenesis of infection. 23899458 Molecular sensitized GdF3:Eu(3+) for color tuning and highly enhanced luminescent properties. In this work, we report on the preparation of [2,3-f]pyrazino[1,10]phenanthroline-2,3-dicarboxylic anions (PPDB(2-)) modified GdF3:Eu(3+) nanocrystals by a versatile ligand exchange approach for highly enhanced luminescent properties. The samples were carefully characterized by X-ray powder diffraction, transmission electron microscopy, infrared spectra and photoluminescence. It is found that all GdF3:Eu(3+) nanoparticles were entirely composed of homogeneous nano-spheres with an average diameter of about 30-35nm. After PPDB(2-) capping, GdF3:Eu(3+) nanocrystals exhibited higher color purity and shorter lifetime time, which can be well recognized as a consequence of surface structure modification and local symmetry alteration near Eu(3+) ions. High color purity and short lifetime of PPDB(2-) modified GdF3:Eu(3+) nanocrystals predict highly enhanced red luminescence, which showed the quantum efficiency of ∼34%. The highly enhanced luminescent property enables its potential application as chemosensor for detection of heavy metal ions. 23537503 Nanocarrier systems for oral drug delivery: Do we really need them? In particular since the last two decades there is constantly increasing interest in nanocarrier systems. They are utilized in order to overcome the major challenges being associated with this route of administration - namely poor solubility (I), poor permeability (II) and poor GI-stability (III). In order to improve drug solubility nanonization of the API, the use of solid lipid nanoparticles and porous adsorbent particles have shown great potential. Nanocrystals and selfnanoemulsifying drug delivery systems (SNEDDS) resulted already in numerous marketed drug products. Moreover, proof-of-principle studies for nanocarrier systems providing enhanced oral drug uptake are available. By providing a comparatively more intimate contact with the absorption membrane, a prolonged GI-residence time and/or exhibiting permeation enhancing properties, oral absorption can be strongly improved. Likely because of safety considerations and because of insufficiently high bioavailability improvements (<5-fold), however, a commercial interest in these systems is limited. Poor GI-stability can be overcome by incorporating the drug in nanocarrier systems providing a protective effect towards an enzymatic attack in the GI-tract. Furthermore, as nanocarrier systems can at least to some extent diffuse into the mucus gel layer releasing their payload there, a presystemic metabolism of the drug on the way between the delivery system and the absorption membrane can be excluded. Future trends are mainly focusing on carrier systems capable of not just improving solubility but providing also controlled drug release as well as on nanocarrier systems capable of efficiently permeating the mucus gel layer without destroying it. 23968325 Residents provide feedback to their clinical teachers: Reflection through dialogue. Background: Physicians play a crucial role in teaching residents in clinical practice. Feedback on their teaching performance to support this role needs to be provided in a carefully designed and constructive way. Aims: We investigated an evaluation system for evaluating supervisors and providing formative feedback. Method: In a design based research approach, the 'Evaluation and Feedback For Effective Clinical Teaching System' (EFFECT-S) was examined by conducting semi-structured interviews with residents and supervisors of five departments in five different hospitals about feedback conditions, acceptance and its effects. Interviews were analysed by three researchers, using qualitative research software (ATLAS-Ti). Results: Principles and characteristics of the design are supported by evaluating EFFECT-S. All steps of EFFECT-S appear necessary. A new step, team evaluation, was added. Supervisors perceived the feedback as instructive; residents felt capable of providing feedback. Creating safety and honesty require different actions for residents and supervisors. Outcomes include awareness of clinical teaching, residents learning feedback skills, reduced hierarchy and an improved learning climate. Conclusions: EFFECT-S appeared useful for evaluating supervisors. Key mechanism was creating a safe environment for residents to provide honest and constructive feedback. Residents learned providing feedback, being part of the CanMEDS and ACGME competencies of medical education programmes. 23508744 Two new tirucallane triterpenoids from the leaves of Aquilaria sinensis. Two new tirucallane triterpenoids, aquilacallanes A-B (1-2), together with 15 known compounds (3-17) were isolated from the leaves of Aquilaria sinensis. The structures of these new compounds were elucidated on the basis of extensive spectroscopic analyses. All compounds were evaluated for their cytotoxic activity against five human cancer cell lines. The known compounds, ursolic acid (7) and 5,7,4'-trimethoxyflavone (14), exhibited weak cytotoxic activity against some cells. 23948856 Using Quantum Principles to Develop Independent Continuing Nursing Education Programs. Innovations in health care call for fresh approaches to continuing nursing education that support lateral relationships, teamwork, and collaboration. To foster this transformation, we devised the following education principles: Everyone teaches, everyone learns; embrace probability; information is dynamic; and trust professionals to practice professionally. These principles guided the development of seven independent, practice-specific, evidence-based continuing nursing education programs totaling 21.5 contact hours for casual-status nurses who practiced as childbirth educators. The programs were popular, promoted teamwork, and increased communication about evidence-based practice. 23298258 All-trans retinoic acid protects hepatocellular carcinoma cells against serum-starvation-induced cell death by upregulating collagen 8A2. As a therapeutic or chemopreventative agent for various cancers, all-trans retinoic acid (atRA) has been reported to inhibit growth, induce apoptosis or cause differentiation. It was found that atRA could protect hepatocellular carcinoma (HCC) cells against cell death induced by serum starvation. Furthermore, it was found that atRA could enhance cell adhesion, but had no effect on the cell cycle and apoptosis. Using an Illumina Human HT-12 v4 expression microarray, 207 upregulated and 173 downregulated genes were identified in HepG2 cells treated with atRA. The most upregulated genes are cytochrome P450 family 26 subfamily A polypeptide 1 (CYP26A1), histidine triad nucleotide binding protein 3 (HINT3), miR-1282 and cytochrome P450 family 26 subfamily B polypeptide 1 (CYP26B1), which showed more than fivefold greater expression. Using Gene Ontology analysis, the greatest significance was found in extracellular-matrix-related molecular functions and the cellular component in upregulated genes. The upregulation of collagen 8A2 (COL8A2) was further confirmed using quantitative RT-PCR and western blotting. Knockdown of COL8A2 blocked enhancement in the early stage of cell adhesion by atRA treatment. Re-expression of COL8A2 in COL8A2-knocked-down HCC cells reversed the effect of small interfering RNA-COL8A2. In addition, COL8A2 could increase HCC cell migration and invasion. Thus, COL8A2 was identified as the key protein involved in the enhancement of cell adhesion of atRA under serum-free conditions. In conclusion, atRA protects HCC cells against serum-starvation-induced cell death by enhancing cell adhesion, and COL8A2 plays an important role in HCC cell migration and invasion. 23864619 The HEX1 Gene of Fusarium graminearum Is Required for Fungal Asexual Reproduction and Pathogenesis and for Efficient Viral RNA Accumulation of Fusarium graminearum Virus 1. The accumulation of viral RNA depends on many host cellular factors. The hexagonal peroxisome (Hex1) protein is a fungal protein that is highly expressed when the DK21 strain of Fusarium graminearum virus 1 (FgV1) infects its host, and Hex1 affects the accumulation of FgV1 RNA. The Hex1 protein is the major constituent of the Woronin body (WB), which is a peroxisome-derived electron-dense core organelle that seals the septal pore in response to hyphal wounding. To clarify the role of Hex1 and the WB in the relationship between FgV1 and Fusarium graminearum, we generated targeted gene deletion and overexpression mutants. Although neither HEX1 gene deletion nor overexpression substantially affected vegetative growth, both changes reduced the production of asexual spores and reduced virulence on wheat spikelets in the absence of FgV1 infection. However, the vegetative growth of deletion and overexpression mutants was increased and decreased, respectively, upon FgV1 infection compared to that of an FgV1-infected wild-type isolate. Viral RNA accumulation was significantly decreased in deletion mutants but was significantly increased in overexpression mutants compared to the viral RNA accumulation in the virus-infected wild-type control. Overall, these data indicate that the HEX1 gene plays a direct role in the asexual reproduction and virulence of F. graminearum and facilitates viral RNA accumulation in the FgV1-infected host fungus. 23781981 Interface control of semicrystalline biopolymer films through thermal reflow. The recent increase in the development of polymer-based technological devices has necessitated a surge in associated fabrication strategies. An adequate understanding of the interfacial properties in such systems is required to meet the challenges inherent to these applications, ranging from electronics to biomedicine. In this work, we utilize thermal reflow to investigate the interfacial properties of multilayer silk fibroin film constructs. We demonstrate that reflow can be utilized to control the water content, glass transition, and β sheet crystallinity of such constructs, leading to control of the mechanical properties at the interface. Such analysis may lend insight into the interfacial properties of similar semicrystalline biopolymers, increasing the number of fabrication options for the development of devices at the biological-technological nexus. 23907422 Effects of cyclosporine and phenytoin on biomarker expressions in gingival fibroblasts of children and adults: an in vitro study. Abstract Background: Both phenytoin (PhT) and cyclosporine (CsA) have been related to gingival overgrowth, but the presence and incidence of cytokines in gingival tissues are associated with different mechanisms. On the basis of a few epidemiologic data, children are more prone to have gingival overgrowth than adults and there is no obvious plausibility to justify this difference. The aim of this study was to investigate the effect of PhT and CsA on the some biological marker expression and compare it among adults and children. Methods: Gingival fibroblasts that had been harvested from adults and children with normal gingiva were incubated with CsA and PhT and then cultured for 48 h. Matrix metalloproteinases (MMP-1 and MMP-2), tissue inhibitor of metalloproteinases (TIMP), collagen (CoL), elastin (Eln), lysyl oxidase (Lysyl), cathepsin (Cat) L and B, and mRNA levels in culture were determined by reverse transcription polymerase chain reaction. The amounts of transforming growth factor-β (TGF-β) and epidermal growth factor (EGF) were assessed by enzyme-linked immunosorbent assay. Results: CsA and PhT stimulated TGF-β and Cat B production and inhibited expression of MMP-1 by fibroblasts. CsA suppressed TIMP in children, but PhT stimulated its expression. In adults, both CSA and PHT increased TGF-β, Lysyl, and EGF levels. CsA reduced Eln level, whereas PhT increased it. Conclusions: The results suggest that CsA and PhT have different effects on biogene marker expression in adults and children, or drug-induced gingival overgrowth is affected by different cellular pathways in children in contrast to that in adults. It seems that in children the MMP-1/TIMP system, and in adults the Lysyl/Eln pathway, plays an important role in impaired CoL metabolism. 23552878 Cytotoxic and Antibacterial Cembranoids from a South China Sea Soft Coral, Lobophytum sp. Chemical examination of a South China Sea soft coral Lobophytum sp. led to the isolation of three new α-methylene-γ-lactone-containing cembranoids, (1R*,3R*, 4R*,14R*,7E,11E)-3,4-epoxycembra-7,11,15(17)-trien-16,14-olide (1), (1R*,7S*,14S*,3E, 11E)-7-hydroperoxycembra-3,8(19),11,15(17)-tetraen-16,14-olide (2), and (1R*,7S*,14S*, 3E,11E)-18-acetoxy-7-hydroperoxycembra-3,8(19),11,15(17)-tetraen-16,14-olide (3), along with eleven known analogues 4-14. The structures of the new compounds were elucidated through extensive spectroscopic analysis, including 1D and 2D NMR data. Compounds 1-3 exhibited moderate cytotoxic activity against the selected tumor cell lines. Moreover, 2 and 3 were found to be moderate inhibitors against the bacteria S. aureus and S. pneumoniae. 23589396 Comparison of nutrient profiling schemes for restricting the marketing of food and drink to children. Many companies have signed voluntary agreements to restrict the marketing of foods high in fat, sugar and salt directly to children. Several nutrient profiling schemes have been proposed for defining products which can be advertised to children. Provides evidence that industry-led nutrient profiling schemes are less effective in restricting the advertising of energy-dense foods compared to government-led models. Provides evidence that industry-led nutrient profiling schemes particularly favour the continued advertising of foods high in sugar. The food and beverage industry have made voluntary pledges to reduce children's exposure to the marketing of energy-dense foods and beverages, and in 2012 announced the replacement of company-specific nutrient profiling schemes with uniform sets of criteria from 2013 (in the USA) and 2014 (in the European Union [EU]). To compare the proposed USA and EU nutrient profiling schemes and three government-led schemes, paying particular attention to the differences in sugar criteria. Food and beverage products permitted to be advertised in the USA under pre-2013 criteria were examined using five nutrient profiling schemes: the forthcoming USA and EU schemes and three government-approved schemes: the US Interagency Working Group (IWG) proposals, the United Kingdom Office of Communications (OfCom) regulations and the Danish Forum co-regulatory Code. Under the new USA and EU nutrient profiling schemes, 88 (49%) and 73 (41%) of a total of 178 products would be permitted to be advertised, respectively. The US IWG permitted 25 (14%) products; the Ofcom regulations permitted 65 (37%) and the Danish Code permitted 13 (7%). Government-led schemes are significantly more restrictive than industry-led schemes, primarily due to their tougher sugar criteria. The Danish Forum (93%) and USA IWG scheme (86%) are the most restrictive of the five examined. Further harmonization of nutrient profiling schemes is needed to reduce children's exposure to the promotion of energy-dense foods. 23784992 The differences in binding 12-carbon aliphatic ligands by bovine β-lactoglobulin isoform A and B studied by isothermal titration calorimetry and X-ray crystallography. Isoforms A (LGB-A) and B (LGB-B) of bovine lactoglobulin, the milk protein, differ in positions 64 (D↔G) and 118 (V↔A). Interactions of LGB-A and LGB-B with sodium dodecyl sulfate (SDS), dodecyltrimethylammonium chloride (DTAC) and lauric acid (LA), 12-carbon ligands possessing differently charged polar groups, were investigated using isothermal titration calorimetry and X-ray crystallography, to study the proton linkage phenomenon and to distinguish between effects related to different isoforms and different ligand properties. The determined values of ΔS and ΔH revealed that for all ligands, binding is entropically driven. The contribution from enthalpy change is lower and shows strong dependence on type of buffer that indicates proton release from the protein varying with protein isoform and ligand type and involvement of LA and Asp64 (in isoform A) in this process. The ligand affinities for both isoforms were arranged in the same order, DTAC < LA < SDS, and were systematically lower for variant B. The entropy change of the complexation process was always higher for isoform A, but these values were compensated by changes in enthalpy, resulting in almost identical ΔG for complexes of both isoforms. The determined crystal structures showed that substitution in positions 64 and 118 did not influence the overall structure of LGB complexes. The chemical character of the ligand polar group did not affect the position of its aliphatic chain in protein β-barrel, indicating a major role of hydrophobic interactions in ligand binding that prevailed even with the repulsion between positively charged DTAC and lysine residues located at binding site entrance. 23723245 The pneumococcal MgaSpn virulence transcriptional regulator generates multimeric complexes on linear double-stranded DNA. The MgaSpn transcriptional regulator contributes to the virulence of Streptococcus pneumoniae. It is thought to be a member of the Mga/AtxA family of global regulators. MgaSpn was shown to activate in vivo the P1623B promoter, which is divergent from the promoter (Pmga) of its own gene. This activation required a 70-bp region (PB activation region) located between both promoters. In this work, we purified an untagged form of the MgaSpn protein, which formed dimers in solution. By gel retardation and footprinting assays, we analysed the binding of MgaSpn to linear double-stranded DNAs. MgaSpn interacted with the PB activation region when it was placed at internal position on the DNA. However, when it was positioned at one DNA end, MgaSpn recognized preferentially the Pmga promoter placed at internal position. In both cases, and on binding to the primary site, MgaSpn spread along the adjacent DNA regions generating multimeric protein-DNA complexes. When both MgaSpn-binding sites were located at internal positions on longer DNAs, electron microscopy experiments demonstrated that the PB activation region was the preferred target. DNA molecules totally or partially covered by MgaSpn were also visualized. Our results suggest that MgaSpn might recognize particular DNA conformations to achieve DNA-binding specificity. 23918240 Deletion of 14.7 Mb 2q32.3q33.3 with a marfanoid phenotype and hypothyroidism. Interstitial 2q deletions are very rare chromosome abnormalities. The 2q32q33 deletion was proposed as a distinct entity with characteristic phenotype. Most patients have feeding problems, growth restriction, moderate to severe developmental delay, speech delay or lack of speech, high, prominent forehead, thin sparse hair, teeth abnormalities and a high or cleft palate. We report on another rare case of interstitial 2q33 deletion found during routine karyotyping and further characterized by the use of a genomic SNP array. The patient presented here has a "Marfanoid" phenotype, hypothyroidism, and a marked tactile hypersensitivity. We concluded that hypothyroidism might be caused by the deletion of the CD28 and/or CTLA4 genes; also cardiological monitoring of patients with the deletion including BMPR2 may be considered in order to prevent the possible medical complications associated with pulmonary hypertension. © 2013 Wiley Periodicals, Inc. 23573972 JNK inhibitors as anti-inflammatory and neuroprotective agents. JNK is involved in a broad range of physiological processes. Several inflammatory and neurodegenerative diseases, such as multiple sclerosis, Alzheimer's and Parkinson's disease have been linked with the dysregulated JNK pathway. Research on disease models using the relevant knockout mice has highlighted the importance of specific JNK isoformsin-particular disorders and has stimulated further efforts in the drug-discovery area. However, most of the experimental evidence for the efficacy of JNK inhibition in animal models is from studies using JNK inhibitors, which are not isoform selective. Some of the more recent compounds exhibit good oral bioavailability, CNS penetration and selectivity against the rest of the kinome. Efforts to design isoform-selective inhibitors have produced a number of examples with various selectivity profiles. This article presents recent progress in this area and comment on the role of isoform selectivity for efficacy. 23939014 Suppression of radiation-induced DNA double-strand break repair by MyD88 is accompanied by apoptosis and crypt loss in mouse colon. Intestinal microbes promote the injurious effects of radiation on those tissues. However, the molecular factors mediating this effect are largely unknown. In this work, we explored the effects of orally administered antibiotics and MyD88, a key adapter molecule in toll-like receptor signaling, on molecular and cellular responses of mouse colon to radiation. Results show that oral antibiotics lowered radiation-induced colonic damage by protecting epithelial cells against radiation-induced apoptosis, leading to increased survival of crypts. MyD88 deficiency partially phenocopied the effects of oral antibiotics on apoptosis and crypt survival, suggesting that colonic microbes exert their injurious effects in part via that molecule. Analysis of DNA double-strand breaks, the primary genotoxic lesions induced by radiation, showed that their early induction in mouse colon was unaffected by MyD88. However, MyD88 deficiency resulted in the later disappearance of DNA double-strand breaks. Loss of DNA double-strand breaks was accompanied by the evidence of increased activation of both the non-homologous end-joining and homologous recombination pathways of DNA repair in MyD88-deficient mice. These results show that colonic microbes and MyD88 regulate DNA double-strand break repair in irradiated mouse colon, effects which exert significant control over radiation-induced apoptosis and crypt survival. 23897215 First principles computational study on the electrochemical stability of Pt-Co nanocatalysts. Using density functional theory (DFT) calculations, we identify the thermodynamically stable configurations of Pt-Co alloy nanoparticles of varying Co compositions and particle sizes. Our results indicate that the most thermodynamically stable structure is a shell-by-shell configuration where the Pt atom only shell and the Co only shell alternately stack and the outermost shell consists of a Pt skin layer. DFT calculations show that the structure has substantially higher dissolution potential of the outermost Pt shell compared with pure Pt nanoparticles of approximately the same size. Furthermore, our DFT calculations also propose that the shell-by-shell structure shows much better oxygen reduction reaction (ORR) activity than conventional bulk or nanoparticles of pure Pt. These novel catalyst properties can be changed when the surfaces are adsorbed with oxygen atoms via selective segregation followed by the electrochemical dissolution of the alloyed Co atoms. However, these phenomena are thermodynamically not plausible if the chemical potentials of oxygen are controlled below a certain level. Therefore, we propose that the shell-by-shell structures are promising candidates for highly functional catalysts in fuel cell applications. 23316748 New prospects for vinblastine analogues as anticancer agents. Boger et al. synthesized a series of C20' urea derivatives of vinblastine that matched or exceeded the potency of vinblastine in cell growth inhibition assays. The studies demonstrated the importance of the H-bond donor on the C20' position and revealed the presence of a space surrounding the C20' substituent that tolerates a wide variety of substituents, remarkably enhancing potency of vinblastine analogues. 23946396 Robust encoding of stimulus identity and concentration in the accessory olfactory system. Sensory systems represent stimulus identity and intensity, but in the neural periphery these two variables are typically intertwined. Moreover, stable detection may be complicated by environmental uncertainty; stimulus properties can differ over time and circumstance in ways that are not necessarily biologically relevant. We explored these issues in the context of the mouse accessory olfactory system, which specializes in detection of chemical social cues and infers myriad aspects of the identity and physiological state of conspecifics from complex mixtures, such as urine. Using mixtures of sulfated steroids, key constituents of urine, we found that spiking responses of individual vomeronasal sensory neurons encode both individual compounds and mixtures in a manner consistent with a simple model of receptor-ligand interactions. Although typical neurons did not accurately encode concentration over a large dynamic range, from population activity it was possible to reliably estimate the log-concentration of pure compounds over several orders of magnitude. For binary mixtures, simple models failed to accurately segment the individual components, largely because of the prevalence of neurons responsive to both components. By accounting for such overlaps during model tuning, we show that, from neuronal firing, one can accurately estimate log-concentration of both components, even when tested across widely varying concentrations. With this foundation, the difference of logarithms, \[\mathrm{log}\hbox{ \hspace{0.17em} }A-\mathrm{log}\hbox{ \hspace{0.17em} }B=\mathrm{log}\frac{A}{B} \], provides a natural mechanism to accurately estimate concentration ratios. Thus, we show that a biophysically plausible circuit model can reconstruct concentration ratios from observed neuronal firing, representing a powerful mechanism to separate stimulus identity from absolute concentration. 23436264 Comparison of subcutaneous and intravenous administration of trastuzumab: a phase I/Ib trial in healthy male volunteers and patients with HER2-positive breast cancer. Trastuzumab is a key component of treatment for human epidermal growth factor receptor 2 (HER2)-positive breast cancer in both the early and metastatic settings. It is administered intravenously, with between 17 and 52 infusions in standard regimens over 1 year. Intravenous administration of trastuzumab requires substantial time commitments for patients and health care professionals and can result in patient discomfort. A subcutaneous formulation of trastuzumab, containing recombinant human hyaluronidase to overcome subcutaneous absorption barriers, would reduce the administration duration and remove the need to establish intravenous access, thus improving the overall convenience of trastuzumab administration. This open-label, 2-part, phase I/Ib study (NCT00800436) was undertaken in healthy male volunteers and female patients with HER2-positive early breast cancer to identify the dose of subcutaneous trastuzumab that resulted in exposure comparable with the approved intravenous trastuzumab dose. A subcutaneous trastuzumab dose of 8 mg/kg was found to result in exposure comparable with the intravenous trastuzumab dose of 6 mg/kg. The subcutaneous formulation was well tolerated, with a trend toward fewer adverse events versus intravenous administration; most adverse events were mild in intensity. These results support an ongoing phase III efficacy and safety study comparing a fixed subcutaneous trastuzumab dose with intravenous trastuzumab administration. 23949253 Generation of 4-((trifluoromethyl)thio)-2H-benzo[e][1,2]thiazine 1,1-dioxides via a reaction of trifluoromethanesulfanylamide with 2-(2-alkynyl)benzenesulfonamide. The incorporation of the (trifluoromethyl)thio group into the benzo[e][1,2]thiazine 1,1-dioxide scaffold via a reaction of trifluoromethanesulfanylamide with 2-(2-alkynyl)benzenesulfonamide is reported. The transformation proceeds under mild conditions to afford the 4-((trifluoromethyl)thio)-2H-benzo[e][1,2]thiazine 1,1-dioxides in moderate to good yields. 23623354 Volumetric-modulated arc therapy in postprostatectomy radiotherapy patients: A planning comparison study. The purpose of this study was to compare postprostatectomy planning for volumetric-modulated arc therapy (VMAT) with both single arc (SA) and double arcs (DA) against dynamic sliding window intensity-modulated radiotherapy (IMRT). Ten cases were planned with IMRT, SA VMAT, and DA VMAT. All cases were planned to achieve a minimum dose of 68Gy to 95% of the planning target volume (PTV) and goals to limit rectal volume >40Gy to 35% and >65Gy to 17%, and bladder volumes >40Gy to 50% and >65Gy to 25%. Plans were averaged across the 10 patients and compared for mean dose, conformity, homogeneity, rectal and bladder doses, and monitor units. The mean dose to the clinical target volume and PTV was significantly higher (p<0.05) for SA compared with DA or IMRT. The homogeneity index was not significantly different: SA = 0.09; DA = 0.08; and IMRT = 0.07. The rectal V40 was lowest for the DA plan. The rectal V20 was significantly lower (p<0.05) for both the VMAT plans compared with IMRT. There were no significant differences for bladder V40 or rectal and bladder V65. The IMRT plans required 1400MU compared with 745 for DA and 708 for SA. This study shows that for equivalent dose coverage, SA and DA VMAT plans result in higher mean doses to the clinical target volume and PTV. This greater dose heterogeneity is balanced by improved low-range rectal doses and halving of the monitor units. 23692748 Antithrombotic activity of 12 table grape varieties. Relationship with polyphenolic profile. The synthesis of tissue factor (TF) by monocytes/macrophages activated by inflammatory agents is of utmost importance in the pathogenesis of thrombotic diseases and substances inhibiting TF synthesis represent novel and promising antithrombotics. We investigated the effect of 12 table grape varieties (white, red and black) on TF synthesis and the possible relation with the phenolic profile. The ability of grape skin extracts (GSEs) to inhibit TF was evaluated in whole blood and isolated mononuclear cells challenged with endotoxin. TF expression was assayed by functional and immunological assays. All GSEs inhibited TF synthesis but with a different efficiency, red grapes being the most active. By correlation analysis, the compounds showing the strongest association with TF-inhibiting activity were quercetin and cyanidin. However, no single polyphenol was able to inhibit TF synthesis as efficiently as the crude grape extracts, unless it was combined with at least another compound, suggesting a synergism. 23334508 One, two, three, four, or is there something more? Numerical discrimination in day-old domestic chicks. Human adults master sophisticated, abstract numerical calculations that are mostly based on symbolic language and thus inimitably human. Humans may nonetheless share a subset of non-verbal numerical skills, available soon after birth and considered the evolutionary foundation of more complex numerical reasoning, with other animals. These skills are thought to be based on the two systems: the object file system which processes small values (<3) and the analogue magnitude system which processes large magnitudes (>4). Infants' ability to discriminate 1 vs. 2, 1 vs. 3, 2 vs. 3, but not 1 vs. 4, seems to indicate that the two systems are independent, implying that the conception of a continuous number processing system is based on precursors that appear to be interrupted at or about the number four. The findings from the study being presented here indicating that chicks are able to make a series of discriminations regarding that borderline number (1 vs. 4, 1 vs. 5, 2 vs. 4) support the hypothesis that there is continuity in the number system which processes both small and large numerousness. 22304229 Selective separation of patchouli alcohol from the essential oil of Cablin potchouli by inclusion crystalline method. In this article, we have focused on the application of non-traditional separation approach, the host-guest inclusion method, into the separation of the active component patchouli alcohol from the essential oil of Cablin potchouli Herb. The host molecule 1,1,6,6-tetraphenylhexa-2,4-diyne-1,6-diol (A) was used to selectively recognise the guest molecule patchouli alcohol (B) in the essential oil of Pogostemon cablin (Blanco) Benth through two strong hydrogen bonding. The inclusion compound was structurally determined by the single crystal X-ray diffraction. The separation effect was examined by gas chromatography for the whole essential oil and the inclusion compound, showing that the inclusion crystalline method is simple, rapid and effective for the separation of patchouli alcohol from the essential oil of C. potchouli Herb. 23788638 Solution NMR Analyses of the C-type Carbohydrate Recognition Domain of DC-SIGNR Protein Reveal Different Binding Modes for HIV-derived Oligosaccharides and Smaller Glycan Fragments. The C-type lectin DC-SIGNR (dendritic cell-specific ICAM-3-grabbing non-integrin-related; also known as L-SIGN or CD299) is a promising drug target due to its ability to promote infection and/or within-host survival of several dangerous pathogens (e.g. HIV and severe acute respiratory syndrome coronavirus (SARS)) via interactions with their surface glycans. Crystallography has provided excellent insight into the mechanism by which DC-SIGNR interacts with small glycans, such as (GlcNAc)2Man3; however, direct observation of complexes with larger, physiological oligosaccharides, such as Man9GlcNAc2, remains elusive. We have utilized solution-state nuclear magnetic resonance spectroscopy to investigate DC-SIGNR binding and herein report the first backbone assignment of its active, calcium-bound carbohydrate recognition domain. Direct interactions with the small sugar fragments Man3, Man5, and (GlcNAc)2Man3 were investigated alongside Man9GlcNAc derived from recombinant gp120 (present on the HIV viral envelope), providing the first structural data for DC-SIGNR in complex with a virus-associated ligand, and unique binding modes were observed for each glycan. In particular, our data show that DC-SIGNR has a different binding mode for glycans on the HIV viral envelope compared with the smaller glycans previously observed in the crystalline state. This suggests that using the binding mode of Man9GlcNAc, instead of those of small glycans, may provide a platform for the design of DC-SIGNR inhibitors selective for high mannose glycans (like those on HIV). (15)N relaxation measurements provided the first information on the dynamics of the carbohydrate recognition domain, demonstrating that it is a highly flexible domain that undergoes ligand-induced conformational and dynamic changes that may explain the ability of DC-SIGNR to accommodate a range of glycans on viral surfaces. 23018585 Approach to a successful selection of antihypertensive drugs for the patient with atherosclerosis. Coronary heart disease has become a medical and public health issue associated with multiple risk factors such as age, diet, and sedentary life style. Associations between hypertension and atherosclerosis have been extensively studied, and several trials have demonstrated antiatherosclerotic properties in some of the most widely used antihypertensive agents. Hence, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers have been the target for a number of controlled randomized trials studying its effect on atherosclerosis progression. Carotid intima-media thickness measurement by ultrasound is used as surrogate of atherosclerosis in most of these controlled trials. This review of the literature aims to summarize the most significant controlled trials involving antihypertensive therapy and atherosclerosis regression based on the carotid intima-media thickness measurement. 23678914 Influence of friends on children's physical activity: a review. We examined evidence for friendship influences on children's physical activity (PA) through systematic searches of online databases in May 2012. We identified 106 studies (25 qualitative) published in English since 2000 that analyzed indicators of friendship influences (e.g., communication about PA, friends' PA, and PA with friends) among persons younger than 19 years. Children's PA was positively associated with encouragement from friends (43 of 55 studies indicating a positive relationship), friends' own PA (30/35), and engagement with friends in PA (9/10). These findings are consistent with friends influencing PA, but most studies did not isolate influence from other factors that could explain similarity. Understanding friendship influences in childhood can facilitate the promotion of lifelong healthy habits. PA with friends should be considered in health promotion programs. 22788665 Natural anthocyanins from phytoresources and their chemical researches. Anthocyanins are a class of naturally occurring polyphenols which have been most widely studied in recent decades for the rapid development of relative techniques. This article first reviews the various anthocyanin resources including fruits, flowers, vegetables and beverages. Besides the direct extraction from natural resources, anthocyanins can also be obtained by semi- or total synthesis. After the introduction of new representative anthocyanins found in the past few years and the major relationships between structures and stability, modern separation and analysis technologies in related studies were summarised, which play an important role in chemical researches of anthocyanins. 23747341 Detection and quantification of endoplasmic reticulum stress in living cells using the fluorescent compound, Thioflavin T. The endoplasmic reticulum (ER) plays a central role in the co- and post-translational modification of many proteins. Disruption of these processes can lead to the accumulation of misfolded proteins in the endoplasmic reticulum - a condition known as endoplasmic reticulum stress. In recent years, the association of endoplasmic reticulum stress with a number of disease pathologies has increased interest in the study of this condition. Current methods to detect endoplasmic reticulum stress are indirect and retrospective. Here we describe a new method to detect and quantify endoplasmic reticulum stress in live cells using Thioflavin T (ThT), a small molecule that exhibits enhanced fluorescence when it binds to protein aggregates. We show that enhanced ThT-fluorescence correlates directly with established indicators of unfolded protein response activation. Furthermore, enhanced ThT-fluorescence can be detected in living cells within 20min of application of an endoplasmic reticulum stress-inducing agent. ThT is capable of detecting endoplasmic reticulum stress induced by distinctly different conditions and compounds, in different cultured cell types as well as in mouse tissue samples. Pre-treatment with a potent endoplasmic reticulum stress-reducing agent, 4-phenylbutyric acid, mitigates the enhanced ThT signal. This new tool will be useful in future research investigating the role of protein misfolding in the development and/or progression of human diseases. 23529449 Health literacy among the Amish: measuring a complex concept among a unique population. The Amish have cultural practices that include formal education through the 8th grade. This study's purpose was to compare the health literacy among Amish to non-Amish adults living in Ohio Appalachia to understand its potential contribution to poorer health behaviors (e.g. lower cancer screening rates). Amish (n = 143) and non-Amish (n = 154) adults completed interviews as part of a lifestyle study. The rapid estimate of adult literacy in medicine (REALM) instrument (score range 0-66) was used and mean REALM scores were compared (t test) and correct pronunciation of each word was compared (Chi square test). Significance was considered at p < 0.001 because of multiple comparisons. Mean REALM scores among Amish males (53.3 ± 13.1) and females (56.2 ± 8.6) were significantly (p < 0.001) lower compared to non-Amish males (61.2 ± 9.8) and females (63.0 ± 6.2). Twelve percent of Amish participants read at or lower than a 6th grade level compared to 2.6 % of non-Amish participants. This study provides a glimpse into how culture may influence health literacy. Many Amish participants had limited or marginal health literacy. Innovative strategies that address inadequate health literacy and specific cultural characteristics are needed to improve health-related behaviors and outcomes among the Amish. 23856187 The role of oxytocin in social bonding, stress regulation and mental health: An update on the moderating effects of context and interindividual differences. In this review we summarize the results and conclusions of five studies as presented in a symposium at the 42nd annual meeting of the International Society for Psychoneuroendocrinology, in New York in September 2012. Oxytocin administration has received increasing attention for its role in promoting positive social behavior and stress regulation, and its potential as a therapeutic intervention for addressing various aspects of psychiatric disorders. However, it has been noted that the observed effects are not uniformly beneficial. In this paper we present five new studies each concluding that contextual and interindividual factors moderate the effects of oxytocin, as well as peripheral oxytocin levels. These findings are in accordance with the recent idea that oxytocin administration may increase sensitivity to social salience cues and that the interpretation of these cues may be influenced by contextual (i.e. presence of a stranger versus friend) or interindividual factors (i.e. sex, attachment style, or the presence of psychiatric symptoms). When social cues in the environment are interpreted as "safe" oxytocin may promote prosociality but when the social cues are interpreted as "unsafe" oxytocin may promote more defensive and, in effect, "anti-social" emotions and behaviors. Likewise, oxytocin appears to promote such agonistic tendencies in individuals who are chronically pre-disposed to view the social milieu in uncertain and/or in negative terms (e.g., those with borderline personality disorder, severe attachment anxiety and/or childhood maltreatment). In all, these studies in pre-clinical animal, healthy humans and patients samples further reinforce the importance of considering both contextual and interindividual factors when trying to understand the role of oxytocin as a biological substrate underlying social bonding and stress regulatory processes and when studying the effects of oxytocin administration in particular in patients with (increased risk for) psychiatric disorders. 23580372 Graphene sheets: gram-scale synthesis of graphene sheets by a catalytic arc-discharge method (small 8/2013). Gram-scale amounts of high-quality graphene sheets are synthesized on page 1330 through an arc-discharge method. An arc, which is generated between two graphite rods when a high voltage is applied by Y. Liu and co-workers, can cause the graphite layers to separate into graphene sheets via a high-temperature exfoliation, or even broken into small clusters/atoms, which then form graphene sheets by catalytic growth, demonstrating that two mechanisms exist in an arc discharge process simultaneously. 22335791 Cyclo-(His,Leu): a new microbial diketopiperazine from a terrestrial Bacillus subtilis strain B38. In continuation of our search for bioactive secondary metabolites from terrestrial Bacillus spp., a new microbial diketopiperazine, cis-cyclo-(His,Leu) (1) was isolated from the ethyl acetate extract of a strain B. subtilis B38, together with cis-cyclo-(Phe,Phe) (2), tryptophane (3), cis-cyclo-(Leu,Tyr) (4), cis-cyclo-(Trp,Tyr) (5) and macrolactin A (6). The chemical structures of the isolated compounds were identified by comparison of their 1D, 2D NMR and HRESIMS data with authentic spectra and literatures. To the best of our knowledge, this is the first time that cyclo-(His,Leu) has been isolated from natural products. 23970215 FITC-quencher based caspase 3-activatable nanoprobes for effectively sensing caspase 3 in vitro and in cells. By employing fluorescence resonance energy transfer (FRET) quenching, we rationally designed two new FITC-quencher based nanoprobes for effectively sensing caspase 3 (Casp3) in vitro and in cells. Our nanoprobes hold promise for assessing the chemotherapeutic effect of cancer treatment. 23214434 Interparticle dispersion, membrane curvature, and penetration induced by single-walled carbon nanotubes wrapped with lipids and PEGylated lipids. Single-walled carbon nanotubes (SWNTs) wrapped with different types of lipids and polyethylene glycol (PEG)-grafted lipids were simulated with lipid bilayers. Simulations were carried out with the previously parametrized coarse-grained (CG) SWNT and PEG force fields that had captured the experimentally observed conformations of self-assembled SWNT-lipid complexes and phase behavior of PEG-grafted lipids. Simulations of multiple copies of the SWNT in water show that all pure SWNTs aggregate, lipid-wrapped SWNTs partially aggregate, but those wrapped with lipids grafted to PEG (M(w) = 550) completely disperse, indicating the effect of short PEG chains on interparticle aggregation, in agreement with experiment. Starting with initial SWNT orientation parallel to the bilayer surface, SWNTs wrapped with lysophospholipids and PEG (M(w) = 550)-grafted lipids insert into the hydrophobic region of the bilayer, while SWNTs wrapped with phospholipids and longer PEG (M(w) = 2000)-grafted lipids do not. These indicate that SWNTs insert because of the hydrophobic interaction with the bilayer tails, but the tight wrapping of charged lipid headgroups and long hydrophilic PEG chains can weaken the hydrophobic interaction and inhibit SWNT insertion. The inserted SWNTs contact the entire tails of neighboring lipids in one leaflet of the bilayer, which disorders the lipid bilayer and induces positive curvature. Our findings indicate that interparticle aggregation, SWNT penetration, and membrane curvature can be modulated by the SWNT-lipid structure and the PEG length. 23957370 Morphologic Characteristics of Blastic Plasmacytoid Dendritic Cell Neoplasm: A Case Report. Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive lymphoma derived from plasmacytoid dendritic cells or precursor dendritic cells. Despite some 240 reported cases, its morphology and especially ultrastructure has not been satisfactorily studied. A case is reported of a 13 year old boy, who, despite chemotherapy, died within a 12-month period. The electron microscopy findings - microvillous processes, nuclei with slight irregularities, a moderate amount of heterochromatin, and rough endoplasmic reticulum in the form of long, narrow profiles, often in parallel arrangements - taken together, serve to distinguish BPDCN from other neoplastic cells, such as monocytes, plasma cells and the cells of chronic lymphocyte leukemia. 23238275 Bisphenol A interferes with thyroid specific gene expression. Bisphenol A (BPA) is an endocrine-disrupting chemical that leads to low-dose human exposure due to its ability to leach from chemically derived products, as polycarbonate plastics and epoxy resin. In addition to its known xeno-endocrine action, BPA exerts a wide range of metabolic effects. Despite the documented BPA exposure outcomes on synthesis of thyroid hormones, there are not any data available on its actions on the thyroid follicular cells, site of synthesis of the thyroid hormones. Recently, it has been shown that several environmental pollutants, as BPA, can exert a thyroid disrupting activity. In this study, we employed in vitro and in vivo (zebrafish) models to examine the effects of BPA in regulating the expression of genes involved in the thyroid hormone synthesis and of their transcriptional regulators at BPA doses as low as 10(-9)M, a dose that is environmentally pertinent and far below the one detected in infants plasma. In both systems we could detect an altered expression of the genes involved in thyroid hormones synthesis and of thyroid specific transcriptional factors in BPA dose and time dependent manner. Our results suggest that BPA exerts a direct effect on thyroid follicular cell. We show that these cells can "sense" very low amount of BPA. Thus they, potentially, represent an ideal in vitro system to develop assays to detect BPA and other pollutants with thyroid disrupting activity at level far below the ones considered to be environmental relevant. Moreover, this report may provide new insight into the mode of BPA-induced deregulation of physiological processes as well as on the extensively debated molecular pathways underlying its biological activities. 23809021 Comparison of ProSeal LMA with Supreme LMA in paediatric patients. Supreme laryngeal mask airway (S-LMA) has been improved in recent years, but comparative studies with a sizeable number of paediatric patients are limited in number. In this study, oropharyngeal leak pressures (OLPs) were compared between S-LMA and ProSeal laryngeal mask airway (P-LMA) in paediatric patients. After obtaining approval from the ethics committee and written informed consent from the relatives of the patients, 60 patients, from 9 months to 5 years of age and 10-20 kg in weight, who were recommended for elective surgery were included in this prospective and randomised study. The patients were assigned to the S-LMA and P-LMA groups. OLP, insertion times, success rates, ease of airway device placement, fibre optical assessment, success rates and insertion times of an orogastric tube (OGT) were compared. P-LMA was placed successfully in all the patients. One patient was intubated in the S-LMA group. The outcomes of a total of 59 patients were analysed. The insertion times of the airway devices were shorter in the S-LMA group than in the P-LMA group (S-LMA; 12.2 ± 2.9, P-LMA; 15.4 ± 3.7 s) (P = 0.001). The first insertion attempts of airway device placement were similar. The OLPs were similar (P-LMA; 17.2 ± 2.3, S-LMA; 16.4 ± 1.7 cm H2 O). The fibre-optically determined anatomic position was better in the P-LMA group (P = 0.02). The insertion time of the OGT was shorter with S-LMA than with P-LMA (P = 0.01). Our findings suggest that S-LMA has OLPs similar to those of P-LMA in paediatric patients and that S-LMA provides successful positive pressure ventilation. 23906587 A multilevel analysis of the role of the family and the state in self-rated health of elderly Chinese. This study examines the geographical variations of self-rated health of the elderly based on the 2008 Chinese Longitudinal Healthy Longevity Survey. Multilevel logistic models are employed to estimate how individual, family, and institutional factors affect the health of the elderly at both individual and province levels. Results show that while individual characteristics help to explain self-rated health, the family remains an important determinant. Those with nobody to care for them, those in poverty and those who have to rely on medical insurance report the worst health. The role of the state is relatively limited in contributing to the health of the elderly. There are substantial between province differences. 23436305 Construction of robust enzyme nanocapsules for effective organophosphate decontamination, detoxification, and protection. Nanocapsules of organophosphorous hydrolase with enhanced enzyme activity and stability are prepared via in situ polymerization, providing a novel class of nanoparticles for the decontamination and detoxification of organophosphates such as chemical warfare agents and pesticides. Using the nanocapsules as building blocks, bioactive nanocomposites are also fabricated, enabling their use for organophosphate protection. 22753282 Transventricular balloon dilation and stenting of the RVOT in small infants with tetralogy of fallot with pulmonary atresia. The management of small infants with tetralogy of Fallot (TOF) with pulmonary atresia (PA) and hypoplastic pulmonary arteries can be very challenging. In three small infants (weight range 2,200-3,600 g, pulmonary trunk 2.0-3.2 mm), initial palliation consisted of sternotomy, transventricular puncture of the right ventricular outflow tract and atretic pulmonary valve, followed by balloon dilation (n = 1) or stent deployment (n = 2) from the right ventricle into the pulmonary trunk (stent diameter 5-6 mm, length 16 mm). The procedure resulted in adequate palliation with good anterograde flow to the pulmonary arteries and near normal saturations in all three patients (>92%); there was no associated morbidity. Additional transvenous stenting was required in all patients because of progressive muscular infundibular stenosis after a median of 3 months. Two patients evolved to full repair at the age of 5 months and one patient with multiple hilar stenoses requires additional percutaneous procedures through the stented RV outflow tract. Transventricular balloon dilation and stenting of the RVOT through medial sternotomy as initial palliation strategy appears a safe and well tolerated alternative treatment in small infants with TOF with PA and a hypoplastic pulmonary trunk. © 2013 Wiley Periodicals, Inc. 23752744 Application of heterogeneous catalysts prepared by mechanochemical synthesis. Mechanochemical synthesis has the potential to provide more sustainable preparative routes to catalysts than the current multistep solvent-based routes. In this review, the mechanochemical synthesis of catalysts is discussed, with emphasis placed on catalysts for environmental, energy and chemical synthesis applications. This includes the formation of mixed-metal oxides as well as the process of dispersing metals onto solid supports. In most cases the process involves no solvent. Encouragingly, there are several examples where the process is advantageous compared with the more normal solvent-based methods. This can be because of process cost or simplicity, or, notably, where it provides more active/selective catalysts than those made by conventional wet chemical methods. The need for greater, and more systematic, exploration of this currently unconventional approach to catalyst synthesis is highlighted. 23881129 Direct electrochemistry of hemoglobin immobilized on a functionalized multi-walled carbon nanotubes and gold nanoparticles nanocomplex-modified glassy carbon electrode. Direct electron transfer of hemoglobin (Hb) was realized by immobilizing Hb on a carboxyl functionalized multi-walled carbon nanotubes (FMWCNTs) and gold nanoparticles (AuNPs) nanocomplex-modified glassy carbon electrode. The ultraviolet-visible absorption spectrometry (UV-Vis), transmission electron microscopy (TEM) and Fourier transform infrared (FTIR) methods were utilized for additional characterization of the AuNPs and FMWCNTs. The cyclic voltammogram of the modified electrode has a pair of well-defined quasi-reversible redox peaks with a formal potential of -0.270 ± 0.002 V (vs. Ag/AgCl) at a scan rate of 0.05 V/s. The heterogeneous electron transfer constant (ks) was evaluated to be 4.0 ± 0.2 s-1. The average surface concentration of electro-active Hb on the surface of the modified glassy carbon electrode was calculated to be 6.8 ± 0.3 × 10-10 mol cm-2. The cathodic peak current of the modified electrode increased linearly with increasing concentration of hydrogen peroxide (from 0.05 nM to 1 nM) with a detection limit of 0.05 ± 0.01 nM. The apparent Michaelis-Menten constant (Kmapp) was calculated to be 0.85 ± 0.1 nM. Thus, the modified electrode could be applied as a third generation biosensor with high sensitivity, long-term stability and low detection limit. 23847652 Principal component analysis reveals the 1000 Genomes Project does not sufficiently cover the human genetic diversity in Asia. The 1000 Genomes Project (1KG) aims to provide a comprehensive resource on human genetic variations. With an effort of sequencing 2,500 individuals, 1KG is expected to cover the majority of the human genetic diversities worldwide. In this study, using analysis of population structure based on genome-wide single nucleotide polymorphisms (SNPs) data, we examined and evaluated the coverage of genetic diversity of 1KG samples with the available genome-wide SNP data of 3,831 individuals representing 140 population samples worldwide. We developed a method to quantitatively measure and evaluate the genetic diversity revealed by population structure analysis. Our results showed that the 1KG does not have sufficient coverage of the human genetic diversity in Asia, especially in Southeast Asia. We suggested a good coverage of Southeast Asian populations be considered in 1KG or a regional effort be initialized to provide a more comprehensive characterization of the human genetic diversity in Asia, which is important for both evolutionary and medical studies in the future. 23942249 Association between low bone mineral density and increased α-defensin in salivary fluid among postmenopausal women. This study aims to evaluate the concentration of α-defensin human neutrophil peptide-1 (HNP-1; a peptide released by neutrophils) in salivary fluid among postmenopausal women and to compare bone mineral density among postmenopausal women with different concentrations of this peptide. We consecutively enrolled 61 postmenopausal women. Bone density was measured by dual-energy x-ray absorptiometry, and α-defensin HNP-1 was identified by proteomic analysis of salivary fluid specimen. We found a significant difference in bone mineral density among postmenopausal women with different concentrations of α-defensin HNP-1 in salivary fluid. In particular, women with higher α-defensin concentrations had the lowest bone density in comparison with those with a lower concentration of defensin (P = 0.03 between groups). Univariate and multivariate linear regression analyses showed a significative inverse relationship between bone mineral density and age (r = -0.58, β = -0.56) and peak of α-defensin (r = -0.26, β = -0.21). Low bone mineral density is found in postmenopausal women with high α-defensin HNP-1 concentrations. Therefore, α-defensin HNP-1 could be a novel biomarker for osteoporosis. 23963211 Reinventing bioinnovation. The landscape for bioinnovation is undergoing a seismic shift as drug developers, regulators, academic institutions, and government research organizations adapt to the formidable challenge of bringing new medicines to market. The inability to translate current advances in the scientific understanding of disease into new therapeutics is forcing all sectors to replace traditional drug development paradigms with newer and more efficient models. This issue of Clinical Pharmacology & Therapeutics explores these changes to the bioinnovation ecosystem. 23866962 Does use of a virtual environment change reaching while standing in patients with traumatic brain injury? Although numerous virtual reality applications have been developed for sensorimotor retraining in neurologically impaired individuals, it is unclear whether the virtual environment (VE) changes motor performance, especially in patients with brain injuries. To address this question, the movement characteristics of forward arm reaches during standing were compared in physical and virtual environments, presented at different viewing angles. Fifteen patients with traumatic brain injuries (TBI) and 15 sex- and age-matched healthy individuals performed virtual reaches in a computer-generated courtyard with a flower-topped hedge. The hedge was projected on a flat screen and viewed in 3D format in 1 of 3 angles: 10° above horizon (resembling a real-world viewing angle), 50° above horizon, or 90° above horizon (directly overhead). Participants were instructed to reach with their dominant hand avatar and to touch the farthest flower possible without losing their balance or stepping. Virtual reaches were compared with reaches-to-point to a target in an equivalent physical environment. A set of kinematic parameters was used. Reaches by patients with TBI were characterized by shorter distances, lower peak velocities, and smaller postural displacements than reaches by control individuals. All participants reached ~9% farther in the VE presented at a 50° angle than they did in the physical environment. Arm displacement in the more natural 10° angle VE was reduced by the same 9-10% compared to physical reaches. Virtual reaches had smaller velocity peaks and took longer than physical reaches. The results suggest that visual perception in the VE differs from real-world perception and the performance of functional tasks (e.g., reaching while standing) can be changed in TBI patients, depending on the viewing angle. Accordingly, the viewing angle is a critical parameter that should be adjusted carefully to achieve maximal therapeutic effect during practice in the VE. 23809191 A conduction block in sciatic nerves can be detected by magnetic motor root stimulation. Useful diagnostic techniques for the acute phase of sciatic nerve palsy, an entrapment neuropathy, are not well established. The aim of this paper is to demonstrate the diagnostic utility of magnetic sacral motor root stimulation for sciatic nerve palsy. We analyzed the peripheral nerves innervating the abductor hallucis muscle using both electrical stimulations at the ankle and knee and magnetic stimulations at the neuro-foramina and conus medullaris levels in a patient with sciatic nerve palsy at the level of the piriformis muscle due to gluteal compression related to alcohol consumption. On the fourth day after onset, magnetic sacral motor root stimulation using a MATS coil (the MATS coil stimulation method) clearly revealed a conduction block between the knee and the sacral neuro-foramina. Two weeks after onset, needle electromyography supported the existence of the focal lesion. The MATS coil stimulation method clearly revealed a conduction block in the sciatic nerve and is therefore a useful diagnostic tool for the abnormal neurophysiological findings associated with sciatic nerve palsy even at the acute phase. 23727539 Synthesis and antimosquito properties of 2,6-substituted benzo[d]thiazole and 2,4-substituted benzo[d]thiazole analogues against Anopheles arabiensis. A novel and efficient one pot synthesis was developed for 2,6-substituted-benzo[d]thiazole analogues 4a-k and 2,4-substituted-benzo[d]thiazole analogues 4l-pvia three component condensation reaction of substituted arylaldehyde, 2-amino-6-halo/4-methyl-benzo[d]thiazole and 2-naphthol or 6-hydroxyquinoline in presence of 10% w/v NaCl in water by microwave method. This method enabled for short reaction times, easy work-up and significant high yields. The title compound 4b was used for single crystal X-ray studies in order to understand its conformation and packing features. The title compounds 4a-p were screened for antimosquito properties such as repellency, insecticidal and larvicidal activity against Anopheles arabiensis by mosquito feeding-probing assay, cone bio-assay and standard WHO larvicidal assay, respectively. Among these analogous 4b, 4d and 4p exhibit the highest repellent activity comparable to the positive control DEET, and 4a and 4k knockdown most mosquitoes on repellent assays. 23708137 Expression of the Rhizobium leguminosarum bv. trifolii pssA Gene, Involved in Exopolysaccharide Synthesis, Is Regulated by RosR, Phosphate, and the Carbon Source. Rhizobium leguminosarum bv. trifolii pssA encodes a glucosyl-isoprenylphosphate (IP)-transferase involved in the first step of exopolysaccharide (EPS) synthesis. It was found that the pssA gene is an important target for regulation of this biosynthetic pathway. The data of this study indicate that pssA transcription is a very complex and mainly positively regulated process. A detailed analysis of a 767-bp-long pssA upstream region revealed the presence of several sequence motifs recognized by regulatory proteins that are associated with phosphate-, carbon-, and iron-dependent regulation. In addition, numerous inverted repeats of different lengths have been identified in this region. pssA transcription is directed from two distal P1 and proximal P3 promoters whose sequences demonstrate a significant identity to promoters recognized by RNA polymerase sigma factor σ(70). Among rhizobial proteins, RosR seems to be a primary regulator that positively affects pssA expression. This protein binds to RosR box 1 located downstream of the P1 promoter. In addition, phosphate and the carbon source strongly affect pssA transcription. A significantly lower level of pssA expression was observed in both the wild-type strain growing under phosphate-rich conditions and the phoB mutant. In this regulation, the PhoB protein and Pho box 2 located upstream of the P3 promoter were engaged. pssA transcription is also significantly affected by glucose. Transcriptional analysis of a set of pssA-lacZ fusions expressed in Escherichia coli wild-type and cyaA and crp mutants confirmed that cyclic AMP (cAMP) receptor protein (CRP) and two cAMP-CRP boxes located upstream of the P1 are required for this upregulation. Moreover, the production of EPS was totally abolished in R. leguminosarum bv. trifolii mutant strains 4440 and 1012 containing a Tn5 insertion downstream of the P3 promoter and downstream of the P3 -35 hexamer, respectively. 23942840 Integration of genomic and functional approaches reveals enhancers at LMX1A and LMX1B. LMX1A and LMX1B encode two closely related members of the LIM homeobox family of transcription factors. These genes play significant, and frequently overlapping, roles in the development of many structures in the nervous system, including the cerebellum, hindbrain, spinal cord roof plate, sensory systems and dopaminergic midbrain neurons. Little is known about the cis-acting regulatory elements (REs) that dictate their temporal and spatial expression or about the regulatory landscape surrounding them. The availability of comparative sequence data and the advent of genomic technologies such as ChIP-seq have revolutionized our capacity to identify regulatory sequences like enhancers. Despite this wealth of data, the vast majority of loci lack any significant in vivo functional exploration of their non-coding regions. We have completed a significant functional screen of conserved non-coding sequences (putative REs) scattered across these critical human loci, assaying the temporal and spatial control using zebrafish transgenesis. We first identify and describe the LMX1A paralogs lmx1a and lmx1a-like, comparing their expression during embryogenesis with that in mammals, along with lmx1ba and lmx1bb genes. Consistent with their prominent neuronal expression, 47/71 sequences selected within and flanking LMX1A and LMX1B exert spatial control of reporter expression in the central nervous system (CNS) of mosaic zebrafish embryos. Upon germline transmission, we identify CNS reporter expression in multiple independent founders for 22 constructs (LMX1A, n = 17; LMX1B, n = 5). The identified enhancers display significant overlap in their spatial control and represent only a fraction of the conserved non-coding sequences at these critical genes. Our data reveal the abundance of regulatory instruction located near these developmentally important genes. 23764825 The association between premature plantarflexor muscle activity, muscle strength, and equinus gait in patients with various pathologies. This study provides an overview on the association between premature plantarflexor muscle activity (PPF), muscle strength, and equinus gait in patients with various pathologies. The purpose was to evaluate whether muscular weakness and biomechanical alterations are aetiological factors for PPF during walking, independent of the underlying pathology. In a retrospective design, 716 patients from our clinical database with 46 different pathologies (orthopaedic and neurologic) were evaluated. Gait analysis data of the patients included kinematics, kinetics, electromyographic activity (EMG) data, and manual muscle strength testing. All patients were clustered three times. First, patients were grouped according to their primary pathology. Second, all patients were again clustered, this time according to their impaired joints. Third, groups of patients with normal EMG or PPF, and equinus or normal foot contact were formed to evaluate the association between PPF and equinus gait. The patient groups derived by the first two cluster methods were further subdivided into patients with normal or reduced muscle strength. Additionally, the phi correlation coefficient was calculated between PPF and equinus gait. Independent of the clustering, PPF was present in all patient groups. Weak patients revealed PPF more frequently. The correlations of PPF and equinus gait were lower than expected, due to patients with normal EMG during loading response and equinus. These patients, however, showed higher gastrocnemius activity prior to foot strike together with lower peak tibialis anterior muscle activity in loading response. Patients with PPF and a normal foot contact possibly apply the plantarflexion-knee extension couple during loading response. While increased gastrocnemius activity around foot strike seems essential for equinus gait, premature gastrocnemius activity does not necessarily produce an equinus gait. We conclude that premature gastrocnemius activity is strongly associated with muscle weakness. It helps to control the knee joint under load independent from the underlying disease, and it is therefore a secondary deviation. If treated as primary target, caution should be exercised. 23732987 Viral delivery of antioxidant genes as a therapeutic strategy in experimental models of amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with no effective treatment to date. Despite its multi-factorial aetiology, oxidative stress is hypothesized to be one of the key pathogenic mechanisms. It is thus proposed that manipulation of the expression of antioxidant genes that are downregulated in the presence of mutant SOD1 may serve as a therapeutic strategy for motor neuronal protection. Lentiviral vectors expressing either PRDX3 or NRF2 genes were tested in the motor neuronal-like NSC34 cell line, and in the ALS tissue culture model, NSC34 cells expressing the human SOD1(G93A) mutation. The NSC34 SOD1(G93A) cells overexpressing either PRDX3 or NRF2 showed a significant decrease in endogenous oxidation stress levels by 40 and 50% respectively compared with controls, whereas cell survival was increased by 30% in both cases. The neuroprotective potential of those two genes was further investigated in vivo in the SOD1(G93A) ALS mouse model, by administering intramuscular injections of adenoassociated virus serotype 6 (AAV6) expressing either of the target genes at a presymptomatic stage. Despite the absence of a significant effect in survival, disease onset or progression, which can be explained by the inefficient viral delivery, the promising in vitro data suggest that a more widespread CNS delivery is needed. 23545452 Antigenic peptide trimming by ER aminopeptidases--insights from structural studies. Generation and destruction of antigenic peptides by ER resident aminopeptidases ERAP1 and ERAP2 have been shown in the last few years to be important for the correct functioning and regulation of the adaptive immune response. These two highly homologous aminopeptidases appear to have evolved complex mechanisms well suited for their biological role in antigen presentation. Furthermore, polymorphic variability in these enzymes appears to affect their function and predispose individuals to disease. This review discusses our current understanding of the molecular mechanisms behind ERAP1/2 function as suggested by several recently determined crystallographic structures of these enzymes. 23199679 Cerebral blood volume combined with amplitude-integrated EEG can be a suitable guide to control hypoxic/ischemic insult in a piglet model. The purposes of this study are to compare two hypoxic/ischemic (H/I) insults using amplitude-integrated EEG (aEEG), alone or combined with cerebral blood volume (CBV), as a guide to control hypoxia and to determine which protocol most effectively produces a consistent degree of survivable neuropathological damage in a newborn piglet model of perinatal asphyxia. Eighteen piglets were subjected to H/I insult of 20-min low aEEG (LAEEG). After the 20-min, the aEEG group was maintained with low mean arterial blood pressure for 10min. The procedure for the aEEG plus CBV group was stopped if CBV became the rated value after 20min of LAEEG. We measured changes in CBV using a near-infrared time-resolved spectroscopy (TRS) and cerebral electrocortical activity using aEEG until 6h post-insult. At 5days post insult, the piglets' brains were perfusion-fixed and stained with hematoxylin/eosin. Piglets were grouped as undamaged or damaged; piglets that did not survive to 5days were grouped separately as dead. Among surviving piglets, CBV combined with aEEG resulted in significantly greater percentage of damaged piglets than aEEG alone. We conclude that combining CBV with aEEG may be a more effective guide to control H/I insult in a newborn piglet model than aEEG alone. 23954691 AAGL Practice Report: Practice Guidelines for Laparoscopic Subtotal/Supracervical Hysterectomy (LSH). The purpose of this guideline is to provide clinicians with evidence-based information about the techniques and outcomes for LSH. 23906122 Drug use among sex workers in Hungary. Drug use and sex work are both controversial issues with multiple interesting connections. This article presents findings from the first-ever survey on drug use and sex work in Hungary. The study aimed to chart the prevalence, function, and problems of drug use among various groups of sex workers. Survey forms were collected from 510 participants (average age 29.5 years, 91% female) in and near Budapest over a period of six months. The results show that sex workers have manifold higher lifetime prevalence, 84.3%, of illicit drug use compared with the prevalence of the Hungarian general young adult population, 20.9%. In our sample, it was very rare to perform sex work for alcohol or drugs (5%) or for money to purchase alcohol or drugs (20%). Findings also indicate notable relationships between location-based sex work types and the drugs used. One-third of the street sex workers reported regular amphetamine use, but none reported regular cocaine use. On the contrary, no escorts reported regular amphetamine use, but 38% admitted to regular cocaine use. The location of sex work may pose an additional occupational health risk factor for substance use. Regular use of alcohol was twice as typical (64%) for sex workers who were employed in bars, in salons/parlors, or alone in rented apartments than it was for those working in other indoor locations (33-34%). Furthermore, 74% of street sex workers smoked tobacco compared with 17% of escorts. Problem drug use was roughly estimated by asking the participants about the main problem domains (medical, legal, social, etc.) from the Addiction Severity Index instrument. The most problematic drug was amphetamine, and the most frequent problem was prolonged or excessive drug use. These main findings may contribute to more focused planning of health intervention services, harm reduction measures, outreach programs, and specific treatments. 23526300 Determination of the variations in levels of phenolic compounds in soybean (Glycine max Merr.) sprouts infected by anthracnose (Colletotrichum gloeosporioides). Soybean sprouts (Kongnamool) are one of the most popular and nutritive traditional vegetables in East Asia. Anthracnose caused by Colletotrichum gloeosporioides is one of the most serious diseases of soybean sprouts. In order to obtain basic information for breeding and/or selecting soybean genotypes with increased natural defense against anthracnose, phenolic compounds were profiled for healthy and infected soybean (Glycine max Merr.) sprouts by using high-performance liquid chromatography coupled with tandem mass spectrometry. Tryptophan and eight phenolic compounds (daidzin, genistin, malonyldaidzin, malonylgenistin, daidzein, glycitein, genistein and coumestrol) were determined from healthy and inoculated sprouts. Total identified phenolic content was 40.02 ± 0.03 mg kg(-1) , 99.4% of which was isoflavones. The monitoring suggested that de novo induced glycitein appeared to act as a phytoalexin in the defence mechanism of the soybean sprouts against C. gloeosporioides, and constitutively formed seven phenolic components that functioned as phytoanticipins in the diseased soybean sprouts. © 2013 Society of Chemical Industry. 23900213 Risk of ischemic cerebrovascular and coronary events in adult users of anticonvulsant medications in routine care settings. Older-generation anticonvulsants that highly induce cytochrome P450 enzyme system activity produce metabolic abnormalities that may increase cardiovascular risk. The objective of this study was to evaluate the risk of ischemic cerebrovascular and coronary events in adult new users of anticonvulsants that highly induce cytochrome P450 activity compared with other anticonvulsant agents, as observed in a routine care setting. This was a cohort study of patients 40 to 64 years old from the HealthCore Integrated Research Database who had initiated an anticonvulsant medication between 2001 and 2006 and had no recorded major coronary or cerebrovascular condition in the 6 months before treatment initiation. Propensity score (PS) matching was used to evaluate ischemic cerebrovascular and coronary risk among anticonvulsant new users. High-dimensional propensity score (hdPS)-matched analyses were used to confirm adjusted findings. The study identified 913 events in 166 031 unmatched new treatment episodes with anticonvulsant drugs. In a PS-matched population of 22 864 treatment episodes, the rate ratio (RR) for ischemic coronary or cerebrovascular events associated with highly inducing agents versus other agents was 1.22 (95% CI, 0.90-1.65). The RR moved to 0.99 (95% CI, 0.73-1.33) with adjustment for hdPS matching (RR, 1.47; 95% CI, 0.95-2.28 for cerebrovascular events; RR, 0.70; 95% CI, 0.47-1.05 for coronary events). In this exploratory analysis, there was no evidence of a consistent and statistically significant effect of initiating anticonvulsants that highly induce cytochrome P450 activity on ischemic coronary or cerebrovascular outcomes compared with other agents, given routine care utilization patterns. 23821066 The Role of Normal Versus Twisted Intramolecular Charge Transfer Fluorescence in Predicting the Forms of Inclusion Complexes of Ethyl-4-dialkylaminobenzoate with α-Cyclodextrin in Aqueous Solution. An evidence is introduced through the b- and the twisted intramolecular charge transfer (TICT) fluorescence of ethyl-4-(N,N-dimethylamino)benzoate (EDMAB) and ethyl-4-(N,N-diethylamino)benzoate (EDEAB), confirming the role of donor size on the formation and emission of various inclusion complexes formed between these probes and α-CD in aqueous solution. A large variation in the b-fluorescence band of EDEAB as compared to that of EDMAB and a large variation in the TICT-fluorescence band of EDMAB as compared to that EDEAB, as the concentration of α-CD is increased in their aqueous solutions are observed. These variations are supported by time resolved fluorescence (TRF) spectra, fluorescence decay lifetimes and red edge effect (REE) results. 23733011 Subacute toxicity of copper and glyphosate and their interaction to earthworm (Eisenia fetida). Glyphosate (GPS) and copper (Cu) are common pollutants in soils, and commonly co-exist. Due to the chemical structure of GPS, it can form complexes of heavy metals and interface their bioavailability in soil environment. In order to explore the interactions between GPS and Cu, subacute toxicity tests of Cu and GPS on soil invertebrate earthworms (Eisenia fetida) were conducted. The relative weight loss and whole-worm metal burdens increased significantly with the increasing exposure concentration of Cu, while the toxicity of GPS was insignificant. The joint toxicity data showed that the relative weight loss and the uptake of Cu, as well as the superoxide dismutase, catalase and malondialdehyde activities, were significantly alleviated in the present of GPS, which indicated that GPS could reduce the toxicity and bioavailability of Cu in the soil because of its strong chelating effects. 23313339 Zinc protection against aluminium induced altered lipid profile and membrane integrity. The aim of the present study was to investigate the effects of Zinc (Zn) supplementation on lipid profile and fluidity of cerebrum and cerebellum membranes of rats treated with aluminium (Al). Sprague dawley male rats were divided into four different treatment groups viz: Control, aluminium treated, zinc treated and aluminium+zinc treated. Aluminium (AlCl3) was administered orally at a dose of 100mg/kgb.wt./day (dissolved in drinking water). Zinc as zinc sulphate was supplemented to rats at a dose of 227mg/l in drinking water. A significant decrease in the levels of total lipids, glycolipids, phospholipids, cholesterol and gangliosides contents were observed in both the cerebrum and cerebellum following Al exposure, which were found to be significantly increased following Zn supplementation. On the contrary, Al treatment caused a significant increase in the formation of conjugated dienes, which were observed to be reduced on Zn co-treatment. Further, Al treatment significantly elevated the fluorescence polarization, anisotropy and order parameter, which however were normalized upon Zn co-administration. Hence, the present study depicts the potential of Zn in moderating the changes caused by Al on membrane composition and fluidity in rat brain. 23943597 Perinatal grief following a termination of pregnancy for fetal abnormality: the impact of coping strategies. Pregnancy termination for fetal abnormality (TFA) can have significant psychological repercussions, but little is known about the coping strategies involved in dealing with TFA. This study examined the relationships between women's coping strategies and perinatal grief. 166 women completed a survey online. Coping and perinatal grief were measured using the Brief COPE and Short Perinatal Grief scales. Data were analysed through multiple regression analyses. Despite using mostly adaptive coping strategies, women's levels of grief were high and varied according to obstetric and termination variables. Grief was predicted by: behavioural disengagement, venting, planning, religion, self-blame, being recently bereaved, being childless at the time of TFA, not having had children/being pregnant since TFA, and uncertainty about the decision to terminate the pregnancy. Acceptance and positive reframing negatively predicted grief. Identifying women vulnerable to poor psychological adjustment and promoting coping strategies associated with lower levels of grief may be beneficial. This could be addressed through information provision and interventions such as Cognitive Behavioural Therapy or Acceptance and Commitment Therapy. This article is protected by copyright. All rights reserved. 23827323 In situ SERS probing of nano-silver coated individual yeast cells. For understanding cells functionalities and their communications, there is a need for highly sensitive cell analysis platforms capable of assessing non-specific chemicals on the surface and in the vicinity of cells. We report a microfluidic system integrating dielectrophoresis and surface enhanced Raman scattering (SERS) for the trapping and real time monitoring of cell functions in isolated and grouped cell clusters. Yeast cells are coated with silver nanoparticles to enable highly sensitive SERS analysis. The SERS responses of cells are examined under various conditions: live vs. dead and isolated vs. grouped. This work illustrates the feasibility of the system for in situ cell monitoring and analysis of secreted chemicals during their growth, metabolism, proliferation and apoptosis. 23746878 Therapeutic impact of CT-guided percutaneous catheter drainage in treatment of deep tissue abscesses. Combination therapy of CT-guided percutaneous drainage and antibiotics is the first-line treatment for abscesses. Its effectiveness has been demonstrated. However, the therapeutic impact of this procedure for infection treatment has never been reported. We retrospectively analyzed all 47 patients who received CT-guided percutaneous drainage for infection treatment. Patients' characteristics, pathogens isolated, antibiotics administered, technical and clinical outcomes, complications related to this procedure and therapeutic impacts were investigated. Patients were 26 males and 21 females. The mean age was 63.5 years (±18.7). The diseases targeted were 19 retroperitoneal abscesses, 18 intra-abdominal abscesses, three pelvic abscesses, and seven others. As for technical outcomes, all of the 54 procedures (100%) were successful. As for clinical outcomes, 44 (93.6%) were cured and three patients (6.4%) died. No complications related to this procedure were found in this study. A total of 42 patients (88%) had a change in the management of their infection as a result of CT-guided percutaneous drainage, such as selection and discontinuation of antibiotics. In conclusion, CT-guided percutaneous drainage is a safe and favorable procedure in the treatment of deep tissue abscesses. Therapeutic impact of these procedures helped physicians make a rational decision for antibiotics selection. 23856248 PTK6 Activation at the Membrane Regulates Epithelial-Mesenchymal Transition in Prostate Cancer. The intracellular tyrosine kinase protein tyrosine kinase 6 (PTK6) lacks a membrane-targeting SH4 domain and localizes to the nuclei of normal prostate epithelial cells. However, PTK6 translocates from the nucleus to the cytoplasm in human prostate tumor cells. Here, we show that while PTK6 is located primarily within the cytoplasm, the pool of active PTK6 in prostate cancer cells localizes to membranes. Ectopic expression of membrane-targeted active PTK6 promoted epithelial-mesenchymal transition in part by enhancing activation of AKT, thereby stimulating cancer cell migration and metastases in xenograft models of prostate cancer. Conversely, siRNA-mediated silencing of endogenous PTK6 promoted an epithelial phenotype and impaired tumor xenograft growth. In mice, PTEN deficiency caused endogenous active PTK6 to localize at membranes in association with decreased E-cadherin expression. Active PTK6 was detected at membranes in some high-grade human prostate tumors, and PTK6 and E-cadherin expression levels were inversely correlated in human prostate cancers. In addition, high levels of PTK6 expression predicted poor prognosis in patients with prostate cancer. Our findings reveal novel functions for PTK6 in the pathophysiology of prostate cancer, and they define this kinase as a candidate therapeutic target. Cancer Res; 73(17); 1-12. ©2013 AACR. 23264062 Urban stormwater harvesting and reuse: a probe into the chemical, toxicology and microbiological contaminants in water quality. Stormwater is one of the last major untapped urban water resources that can be exploited as an alternative water source in Australia. The information in the current Australian Guidelines for Water Recycling relating to stormwater harvesting and reuse only emphasises on a limited number of stormwater quality parameters. In order to supply stormwater as a source for higher value end-uses, a more comprehensive assessment on the potential public health risks has to be undertaken. Owing to the stochastic variations in rainfall, catchment hydrology and also the types of non-point pollution sources that can provide contaminants relating to different anthropogenic activities and catchment land uses, the characterisation of public health risks in stormwater is complex, tedious and not always possible through the conventional detection and analytical methods. In this study, a holistic approach was undertaken to assess the potential public health risks in urban stormwater samples from a medium-density residential catchment. A combined chemical-toxicological assessment was used to characterise the potential health risks arising from chemical contaminants, while a combination of standard culture methods and quantitative polymerase chain reaction (qPCR) methods was used for detection and quantification of faecal indicator bacteria (FIB) and pathogens in urban stormwater. Results showed that the concentration of chemical contaminants and associated toxicity were relatively low when benchmarked against other alternative water sources such as recycled wastewater. However, the concentrations of heavy metals particularly cadmium and lead have exceeded the Australian guideline values, indicating potential public health risks. Also, high numbers of FIB were detected in urban stormwater samples obtained from wet weather events. In addition, qPCR detection of human-related pathogens suggested there are frequent sewage ingressions into the urban stormwater runoff during wet weather events. Further water quality monitoring study will be conducted at different contrasting urban catchments in order to undertake a more comprehensive public health risk assessment for urban stormwater. 23913423 A Novel Tripartite Aromatic Acids Transporter Is Essential for Terephthalate Uptake in Comamonas sp. Strain E6. A novel type of aromatic acids transporter, which is similar to the tripartite tricarboxylate transporter (TTT), has been suggested to be involved in terephthalate (TPA) uptake by Comamonas sp. strain E6. This suggestion was based on the presence of the putative TPA-binding protein gene, tphC, in the TPA catabolic operon. The tphC gene is essential for growth on TPA, and similar to the genes encoding TTT-like substrate-binding proteins. Here we identified the two sets of E6 genes as tctBA and tpiBA, which encode TTT-like cytoplasmic transmembrane proteins. Disruption of tctA showed no influence on TPA uptake, but resulted in a complete loss of the uptake of citrate. This loss suggests that tctA is involved in citrate uptake. On the other hand, disruption of tpiA or tpiB demonstrated that both genes are essential for TPA uptake. Only when both tphC and tpiBA were introduced with the TPA catabolic genes into cells of a non-TPA degrading Pseudomonas strain, the resting cells of the transformant acquired the ability to convert TPA. From all these results, it was concluded that the TPA uptake system consists of the TpiA-TpiB membrane components and TPA-binding TphC. Interestingly, not only was the tpiA mutant of E6 unable to grow on TPA, or isophthalate, it also showed significant growth delays on o-phthalate and protocatechuate. These results suggested that the TpiA-TpiB membrane components are able to interact with multiple substrate-binding proteins. The tpiBA genes were constitutively transcribed as a single operon in E6 cells, whereas the transcription of tphC was positively regulated by TphR. TPA uptake by E6 cells was completely inhibited by a protonophore, carbonyl cyanide m-chlorophenyl hydrazone, indicating that the TPA uptake system requires a proton motive force. 22574752 Chemical composition of essential oil from Calligonum polygonoides Linn. The essential oil from air dried buds and roots of Calligonum polygonoides Linn., has been extracted from dry steam distillation and analysed for chemical composition by gas chromatography-mass spectrometry. In total, 27 and 10 compounds were analysed qualitatively and quantitatively, accounting for 68.42% and 82.12% total contents of the essential oils of buds and roots, respectively. It contains a complex mixture of terpenoids, hydrocarbons, phenolic compounds, acid derivatives and ketones. The main component of essential oil was ethyl homovanillate (11.79%) in buds and drimenol (29.42%) in roots. 23923071 Histometric analyses of cancellous and cortical interface in autogenous bone grafting. Surgical procedures involving the rehabilitation of the maxillofacial region frequently require bone grafts; the aim of this research was to evaluate the interface between recipient and graft with cortical or cancellous contact. 6 adult beagle dogs with 15 kg weight were included in the study. Under general anesthesia, an 8 mm diameter block was obtained from parietal bone of each animal and was put on the frontal bone with a 12 mm 1.5 screws. Was used the lag screw technique from better contact between the recipient and graft. 3-week and 6-week euthanized period were chosen for histometric evaluation. Hematoxylin-eosin was used in a histologic routine technique and histomorphometry was realized with IMAGEJ software. T test was used for data analyses with p<0.05 for statistical significance. The result show some differences in descriptive histology but non statistical differences in the interface between cortical or cancellous bone at 3 or 6 week; as natural, after 6 week of surgery, bone integration was better and statistically superior to 3-week analyses. We conclude that integration of cortical or cancellous bone can be usefully without differences. 23813599 Multiscale geometric modeling of macromolecules II: Lagrangian representation. Geometric modeling of biomolecules plays an essential role in the conceptualization of biolmolecular structure, function, dynamics, and transport. Qualitatively, geometric modeling offers a basis for molecular visualization, which is crucial for the understanding of molecular structure and interactions. Quantitatively, geometric modeling bridges the gap between molecular information, such as that from X-ray, NMR, and cryo-electron microscopy, and theoretical/mathematical models, such as molecular dynamics, the Poisson-Boltzmann equation, and the Nernst-Planck equation. In this work, we present a family of variational multiscale geometric models for macromolecular systems. Our models are able to combine multiresolution geometric modeling with multiscale electrostatic modeling in a unified variational framework. We discuss a suite of techniques for molecular surface generation, molecular surface meshing, molecular volumetric meshing, and the estimation of Hadwiger's functionals. Emphasis is given to the multiresolution representations of biomolecules and the associated multiscale electrostatic analyses as well as multiresolution curvature characterizations. The resulting fine resolution representations of a biomolecular system enable the detailed analysis of solvent-solute interaction, and ion channel dynamics, whereas our coarse resolution representations highlight the compatibility of protein-ligand bindings and possibility of protein-protein interactions. © 2013 Wiley Periodicals, Inc. 23846809 NSE, a Potential Biomarker, Is Closely Connected to Diabetic Peripheral Neuropathy. OBJECTIVETo explore the relationship between serum neuron-specific enolase (NSE) levels and diabetic neuropathy.RESEARCH DESIGN AND METHODSType 1 or 2 diabetic and healthy control subjects (n = 568) were randomly enrolled in a cross-sectional study. Diabetic neuropathy status was documented by the presence of clinical symptoms or signs, electromyography, quantitative sensory tests, and cardiac autonomic neuropathy tests. The severity of the neuropathy was staged by composite scores. Serum NSE was measured using electrochemiluminescence immunoassay. The demographic and clinical variables were obtained through an interviewer questionnaire.RESULTSSerum NSE levels increased slightly in diabetic subjects compared with normal subjects (9.1 [1.5] vs. 8.7 [1.7], P = 0.037), and the levels increased greatly in diabetic subjects with neuropathy compared with those without (10.8 [2.8] vs. 9.1 [1.5], P = 0.000). The association of NSE with diabetic neuropathy was independent of the hyperglycemic state (fasting blood glucose, HbA1c, duration, and the type of diabetes) and other potential confounders affecting NSE levels (e.g., age, sex, and renal status) (odds ratio 1.48 [1.13-1.74], P = 0.001). In addition, NSE levels increased with and were closely correlated to the stages of neuropathy (r = 0.63 [0.52-0.74], P = 0.000). The optimal cutoff point for serum NSE levels to distinguish patients with diabetic neuropathy from those without was 10.10 μg/L, with a sensitivity of 66.3% and a specificity of 72.5%.CONCLUSIONSSerum NSE levels are closely associated with peripheral neuropathy in patients with diabetes. Future studies are warranted to clarify the relationship. 23847101 Widespread evidence of cooperative DNA binding by transcription factors in Drosophila development. Regulation of eukaryotic gene transcription is often combinatorial in nature, with multiple transcription factors (TFs) regulating common target genes, often through direct or indirect mutual interactions. Many individual examples of cooperative binding by directly interacting TFs have been identified, but it remains unclear how pervasive this mechanism is during animal development. Cooperative TF binding should be manifest in genomic sequences as biased arrangements of TF-binding sites. Here, we explore the extent and diversity of such arrangements related to gene regulation during Drosophila embryogenesis. We used the DNA-binding specificities of 322 TFs along with chromatin accessibility information to identify enriched spacing and orientation patterns of TF-binding site pairs. We developed a new statistical approach for this task, specifically designed to accurately assess inter-site spacing biases while accounting for the phenomenon of homotypic site clustering commonly observed in developmental regulatory regions. We observed a large number of short-range distance preferences between TF-binding site pairs, including examples where the preference depends on the relative orientation of the binding sites. To test whether these binding site patterns reflect physical interactions between the corresponding TFs, we analyzed 27 TF pairs whose binding sites exhibited short distance preferences. In vitro protein-protein binding experiments revealed that >65% of these TF pairs can directly interact with each other. For five pairs, we further demonstrate that they bind cooperatively to DNA if both sites are present with the preferred spacing. This study demonstrates how DNA-binding motifs can be used to produce a comprehensive map of sequence signatures for different mechanisms of combinatorial TF action. 23665617 Hexachlorocyclohexanes (HCHs) in placenta and umbilical cord blood and dietary intake for women in Beijing, China. Placenta and umbilical cord blood are important media for investigating maternal-fetal exposure to environmental pollutants. Historically hexachlorocyclohexanes (HCHs) were once widely-used in China. In this study, residues of HCHs were measured in placenta and umbilical cord blood samples for 40 women from Beijing. The measured median values of HCHs were 62.0 and 68.8 ng/g fat in placenta and umbilical cord blood, respectively. Concentrations of HCHs in placenta and umbilical cord blood of urban cohort were higher than those of rural group due to enhanced consumption of fish, meat, and milk. Residues of HCHs in placenta were significantly correlated with total food consumption, dietary intake, and maternal age, and could be predicted using the parameters dependent upon ingestion of meat and milk. The transplacental exposure of fetuses to HCHs was revealed by a close association between the residual levels in the paired placenta and the paired umbilical cord blood samples. 23922547 Expressional analysis of the astrocytic Kir4.1 channel in a pilocarpine-induced temporal lobe epilepsy model. The inwardly rectifying potassium (Kir) channel Kir4.1 in brain astrocytes mediates spatial K(+) buffering and regulates neural activities. Recent studies have shown that loss-of-function mutations in the human gene KCNJ10 encoding Kir4.1 cause epileptic seizures, suggesting a close relationship between the Kir4.1 channel function and epileptogenesis. Here, we performed expressional analysis of Kir4.1 in a pilocarpine-induced rat model of temporal lobe epilepsy (TLE) to explore the role of Kir4.1 channels in modifying TLE epileptogenesis. Treatment of rats with pilocarpine (350 mg/kg, i.p.) induced acute status epilepticus, which subsequently caused spontaneous seizures 7-8 weeks after the pilocarpine treatment. Western blot analysis revealed that TLE rats (interictal condition) showed significantly higher levels of Kir4.1 than the control animals in the cerebral cortex, striatum, and hypothalamus. However, the expression of other Kir subunits, Kir5.1 and Kir2.1, remained unaltered. Immunohistochemical analysis illustrated that Kir4.1-immunoreactivity-positive astrocytes in the pilocarpine-induced TLE model were markedly increased in most of the brain regions examined, concomitant with an increase in the number of glial fibrillary acidic protein (GFAP)-positive astrocytes. In addition, Kir4.1 expression ratios relative to the number of astrocytes (Kir4.1-positive cells/GFAP-positive cells) were region-specifically elevated in the amygdala (i.e., medial and cortical amygdaloid nuclei) and sensory cortex. The present study demonstrated for the first time that the expression of astrocytic Kir4.1 channels was elevated in a pilocarpine-induced TLE model, especially in the amygdala, suggesting that astrocytic Kir4.1 channels play a role in modifying TLE epileptogenesis, possibly by acting as an inhibitory compensatory mechanism. 23489240 Relationship between fixation stability measured with MP-1 and reading performance. People with visual impairment have reduced reading performance, which is thought to be related to unstable or eccentric fixation. New microperimeters such as the MP-1 offer straightforward analysis of fixation stability. The aim of this study was to investigate the relationship between fixation stability and reading speed in a large cohort of people with diverse causes of visual impairment and to verify the correlation between reading speed and different methods for the quantification of fixation. The better eye of one hundred and twenty subjects was assessed. Fixation values were obtained from the MP-1 microperimeter. Reading speed was evaluated using newspaper text with magnifiers if required. The poorest fixation stability and reading performance was found in people with age-related macular degeneration while the best fixation was in retinitis pigmentosa subjects. A linear relationship was found between reading speed and the proportion of fixations within 2° (r² = 0.51, p < 0.001) and 4° (r² = 0.36, p < 0.001). A negative correlation was found between reading speed and all three bivariate contour ellipse areas (BCEA; for log transformation of 1-S.D., 2-S.D. and 3-S.D.: r² = 0.39, p < 0.001). In a multiple regression model, proportion of points falling within 2° and 4° circle was significantly related to reading speed (r² = 0.55, p < 0.01; r² = 0.43 p < 0.01); also BCEAs values were strongly related to reading ability only in patients with central vision loss (r² = 0.62, p < 0.01 for LogBCEA 68.2%; r² = 0.61, p < 0.01 for LogBCEA 95.4% and 99.6%) and peripheral defect (r² = 0.52, p < 0.01 for LogBCEA 68.2%; r² = 0.50, p < 0.01 for LogBCEA 95.4%; r² = 0.49, p < 0.01 for LogBCEA 99.6%) but not in combined defect subjects. The study confirms that in people with visual impairment the reduced reading performance is correlated with fixation instability. Moreover, there is a strong relationship between reading speed and both the proportion of fixations falling within 2° and 4° and bivariate contour ellipse area values. 23607488 Genetic diversity and structure in Asian native goat analyzed by newly developed SNP markers. In the current study, a total of 65 single nucleotide polymorphisms (SNPs) within the intron region were developed in goat (Capra hircus) by utilizing genomic information of cattle and sheep due to poor available genomic information on goat. Using these markers, we carried out genetic diversity and structure analyses for 10 Asian goat populations. The phylogenetic tree and principal components analysis showed good correspondence between clustered populations and their geographic locations. The STRUCTURE software analysis illustrated six divergent genetic structures among 10 populations. Myanmar and Cambodia populations showed high admixture patterns with different ancestry, suggesting genetic introgression into native goat populations. We also investigated the correlation between genetic diversity and geographic distance from a domestication center. This result showed a decreasing trend of genetic diversity according to the distance (P = 0.014). This result supported common consensus that western Asia is one of the centers of origin for modern Asian domestic goat. 23918548 Male-Produced Sex Pheromone of the Carrion Beetles, Oxelytrum discicolle and its Attraction to Food Sources. Carrion beetles are part of the great diversity of insects collected on cadavers. In Brazil, beetles of the genus Oxelytrum have great forensic importance in post mortem interval (PMI) estimation. We investigated the system of chemical communication in the attraction of these necrophagous beetles. Gas chromatographic analysis (GC) of female and male aeration extracts revealed the presence of two male-specific compounds, produced in a ratio of 94:6. Bioassays showed that the combination of male produced volatiles and the odor of a food source (carcass volatiles) were attractive to females. Mass and infrared spectral analyses of the male-specific compounds suggested that they were both unsaturated hydrocarbons. Several micro-derivatizations were carried out with the natural products, and the target structures were identified as (Z)-1,8-heptadecadiene (major) and 1-heptadecene (minor). The structure of the minor component was assigned by co-injection with a commercial standard. A seven-step synthesis was developed to synthesize (Z)-1,8-heptadiene, which co-eluted with the major natural product on three different GC stationary phases. Y-tube olfactometer assays showed that the mixture of synthetic standards in the naturally occurring proportion was slightly attractive to females. The results contribute both to the understanding of the chemical ecology of O. discicolle and to its potential to improve the accuracy of PMI estimation. 23839500 Toll-like receptor 4 antagonist attenuates intracerebral hemorrhage-induced brain injury. Accumulating evidence indicates that inflammatory responses cause secondary injury after intracerebral hemorrhage (ICH). We recently demonstrated the involvement of toll-like receptor 4 (TLR4) signaling in these processes. The purpose of the current study was to investigate the protective effect and mechanism of TAK-242 (Ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1 -carboxylate, Takeda), a TLR4 antagonist, in an ICH mouse model. TAK-242 was intraperitoneally injected 6 hours after ICH once daily for 5 successive days. We assessed neurological deficit scores; changes in brain water content; and levels of inflammatory factors, DNA damage, and neuronal degeneration in perihematomal region 1, 3, and 5 days after ICH. Peripheral inflammatory cell infiltration was determined using flow cytometry; and the expression of TLR4 downstream signaling molecules was assessed by Western blot. TAK-242 significantly reduced brain water content, neurological deficit scores, and levels of inflammatory factors. The levels of DNA damage and neuronal degeneration were also significantly decreased, as was peripheral inflammatory cell infiltration. The expression of TLR4 downstream signaling molecules, including myeloid differentiation primary response gene 88, toll/IR-1(TIR)-domain-containing adaptor protein inducing interferon-beta IκBα, nuclear factor-κBp65, and phosphorylated nuclear factor-κBp65, was significantly downregulated. The results suggest that TLR4 antagonist reduced inflammatory injury and neurological deficits in a mouse model of ICH. The mechanism may involve decreased expression of signaling molecules downstream of TLR4. 23929677 Caffeine stimulates hepatic lipid metabolism via autophagy-lysosomal pathway. Caffeine is one of the world's most consumed drugs. Recently, several studies showed that its consumption is associated with lower risk for non-alcoholic fatty liver disease (NAFLD), an obesity-related condition that recently has become the major cause of liver disease worldwide. Although caffeine is known to stimulate hepatic fat oxidation, its mechanism of action on lipid metabolism is still not clear. Here, we show that caffeine surprisingly is a potent stimulator of hepatic autophagic flux. Using genetic, pharmacological, and metabolomic approaches, we demonstrate that caffeine reduces intra-hepatic lipid content and stimulates β-oxidation in hepatic cells and liver via an autophagy-lysosomal pathway. Furthermore, caffeine induced autophagy involved down-regulation of mTOR signaling and alteration in hepatic amino acids and sphingolipid levels. In mice fed a high fat diet, caffeine markedly reduces hepatosteatosis and concomitantly increases autophagy and lipid uptake in lysosomes. Conclusion: Taken together, these results provide novel insight into caffeine's lipolytic actions through autophagy in mammalian liver and its potential beneficial effects in NAFLD. (Hepatology 2013;). 23210775 New chemotherapeutic strategies against malaria, leishmaniasis and trypanosomiases. Due to the persistent lack of suitable vaccines, chemotherapy remains the only option for the treatment of patients infected by protozoan parasites. However, most available antiparasitic drugs have serious disadvantages, ranging from high cost and poor compliance to high toxicity and rapid induction of resistance. In recent decades basic research laboratories identified a considerable number of promising new molecules, but their development has not been pursued in depth by pharmaceutical firms because of poor prospects of economic return. The establishment of adequately funded public-private partnerships is currently reversing the trend. This review deals with new drugs against Plasmodium, Leishmania and Trypanosoma parasites, focusing on the molecules that are in the most advanced stage of development. The purpose of this article is to provide the reader with a panoramic view of the updated literature on the challenges and strategies of contemporary antiprotozoal drug research, paying the due attention to the already published reviews. 22107354 Physical and psychological stressors linked with stress fractures in recruit training. This study aimed to measure ambulation in infantry army basic training, and to evaluate if covering more distance can explain stress fractures in a stressor-stress model. Forty-four male combat recruits (18.7 ± 0.7 years) participated in a 6-month rigorous high intensity combat training program. Baseline data included anthropometric measurements, VO2 max, and psychological questionnaires. Actual distance covered was measured using a pedometer over an 11-week training period. Psychological questionnaires were repeated after 2 months. Sixteen recruits were diagnosed with stress fractures by imaging (SFi = 36.4%). Statistical analysis included comparing measured variables between SFi and those without stress fractures (NSF). The recruits covered 796 ± 157 km, twofold the distance planned of 378 km (P < 0.001). The SFi group covered a distance 16.4% greater than that of the NSF group (866 ± 136 and 744 ± 161 km, respectively, P < 0.01), and also demonstrated greater psychological stress. These data reveal the importance of adherence to or enforcement of military training programs. In the light of these data, the Israeli Defense Forces program needs reappraisal. A stressor-stress response might explain the susceptibility of certain recruits for injury. Using advanced technology, monitoring ambulation may prevent stress fracture development by limiting subjects exceeding a certain level. Psychological profile may also play a role in predicting stress fracture development. 23643854 Hepcidin-25: Measurement by LC-MS/MS in serum and urine, reference ranges and urinary fractional excretion. A liquid chromatography tandem-mass spectrometry (LC-MS/MS) method was developed for reliably quantifying hepcidin-25 in human urine and serum. A 95% reference range was established for serum hepcidin-25 levels by standardizing the sampling time between 8:00am and 11:00am in 90 apparently healthy volunteers. The association between hepcidin-25 concentration and other biological parameters was studied using multivariable analysis and the coefficient of renal excretion of hepcidin-25 was calculated. Preanalytical variables were also investigated. The LC-MS/MS method was validated using a recent validation strategy based on accuracy profiles. Good results were obtained in terms of trueness, precision, and linearity in the following dosing ranges: from 0.77 to 200nmol/L for urine and from 0.48 to 100nmol/L for serum. The 95% reference range of serum hepcidin-25 concentration established after excluding known conditions that affect hepcidin-25 expression was 1.5 to 15.2nmol/L. A difference between genders was demonstrated with a median concentration of 5.5 versus 7.2nmol/L for women and men, respectively. Serum hepcidin-25 concentrations were strongly correlated with ferritin and, to a lesser extent, with iron levels. The coefficient of renal excretion ranged from 0.1 to 16.4%. Higher values of hepcidin-25 concentrations were observed on ethylene diamine tetraacetate tubes compared to serum or lithium-heparin devices. 23884856 Quality by design: scale-up of freeze-drying cycles in pharmaceutical industry. This paper shows the application of mathematical modeling to scale-up a cycle developed with lab-scale equipment on two different production units. The above method is based on a simplified model of the process parameterized with experimentally determined heat and mass transfer coefficients. In this study, the overall heat transfer coefficient between product and shelf was determined by using the gravimetric procedure, while the dried product resistance to vapor flow was determined through the pressure rise test technique. Once model parameters were determined, the freeze-drying cycle of a parenteral product was developed via dynamic design space for a lab-scale unit. Then, mathematical modeling was used to scale-up the above cycle in the production equipment. In this way, appropriate values were determined for processing conditions, which allow the replication, in the industrial unit, of the product dynamics observed in the small scale freeze-dryer. This study also showed how inter-vial variability, as well as model parameter uncertainty, can be taken into account during scale-up calculations. 23861444 A versatile microsatellite instability reporter system in human cells. Here, we report the investigation of microsatellite instability (MSI) in human cells with a newly developed reporter system based on fluorescence. We composed a vector into which microsatellites of different lengths and nucleotide composition can be introduced between a functional copy of the fluorescent protein mCherry and an out-of-frame copy of EGFP; in vivo frameshifting will lead to EGFP expression, which can be quantified by fluorescence activated cell sorting (FACS). Via targeted recombineering, single copy reporters were introduced in HEK293 and MCF-7 cells. We found predominantly -1 and +1 base pair frameshifts, the levels of which are kept in tune by mismatch repair. We show that tract length and composition greatly influences MSI. In contrast, a tracts' potential to form a G-quadruplex structure, its strand orientation or its transcriptional status is not affecting MSI. We further validated the functionality of the reporter system for screening microsatellite mutagenicity of compounds and for identifying modifiers of MSI: using a retroviral miRNA expression library, we identified miR-21, which targets MSH2, as a miRNA that induces MSI when overexpressed. Our data also provide proof of principle for the strategy of combining fluorescent reporters with next-generation sequencing technology to identify genetic factors in specific pathways. 23866783 Le Fort II Fractures Are Associated With Death: A Comparison of Simple and Complex Midface Fractures. To investigate whether complex midface fractures have a greater association with death and intracranial injury than simple midface fractures. A retrospective chart review was performed for patients with blunt-mechanism midface fractures who had presented to an urban trauma center from 1998 to 2010. The survival and intracranial injury status was evaluated for patients with simple and complex midface fractures, including Le Fort, naso-orbitoethmoid, and/or zygomaticomaxillary fractures. Intracranial injury included hemorrhage and brainstem injury. Patients with upper face fractures were excluded to minimize confounding. Adjusted relative risk estimates were obtained using multivariate regression analysis. Of 3,291 patients with midface fractures, 213 (6.3%) died and 693 (21.3%) had an intracranial injury. The cumulative mortality reached 11.6% in patients with complex midface fractures and 5.1% in those with simple midface fractures (P < .001). Patients with complex midface fractures were 57% more likely to die (relative risk = 1.57; P < .005). Specifically, Le Fort II fractures independently conferred a 94% increased risk of death (relative risk = 1.94; P < .01), but Le Fort I and III fractures were not significantly associated with death. Among patients presenting without neurologic impairment, those with Le Fort II and III fractures remained 2.88-fold (P < .01) and 2.54-fold (P < .001) more likely to have an underlying intracranial injury, respectively. Le Fort II fractures are associated with increased mortality. Furthermore, Le Fort II and III fractures are associated with serious intracranial injury, even in the absence of alterations in consciousness. These patients should be monitored with heightened vigilance and followed up closely during hospitalization, regardless of the presenting clinical findings. 23948490 Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain. Because the treatment and management of neuropathic pain are extremely complicated, the characterization of novel analgesics and neuroprotectors with safe toxicological profiles is a crucial need to develop efficient therapies. Several investigations revealed that the natural neurosteroid allopregnanolone (AP) exerts analgesic, neuroprotective, antidepressant and anxiolytic effects. These effects result from AP ability to modulate GABAA, glycine, L- and T-type calcium channels. It has been shown that AP treatment induced beneficial actions in humans and animal models with no toxic side effects. In particular, a multi-parametric analysis revealed that AP efficiently counteracted chemotherapy-evoked neuropathic pain in rats. It has also been demonstrated that the modulation of AP-producing enzyme, 3α-hydroxysteroid oxido-reductase (3α-HSOR), in the spinal cord regulates thermal and mechanical pain thresholds of peripheral nerve injured neuropathic rats. The painful symptoms were exacerbated by intrathecal injections of provera (pharmacological inhibitor of 3α-HSOR) which decreased AP production in the spinal cord. By contrast, the enhancement of AP concentration in the intrathecal space induced analgesia and suppression of neuropathic symptoms. Moreover, in vivo siRNA-knockdown of 3α-HSOR expression in healthy rat dorsal root ganglia increased thermal and mechanical pain perceptions while AP evoked a potent antinociceptive action. In humans, blood levels of AP were inversely associated with low back and chest pain. Furthermore, oral administration of AP analogs induced antinociception. Altogether, these data indicate that AP, which possesses a high therapeutic potential and a good toxicological profile, may be used to develop effective and safe strategies against chronic neuropathic pain. 23462385 The 'double hitch' manoeuvre in laparoscopic pyeloplasty - early experience. Intra-corporeal anastomosis in laparoscopic pyeloplasty is laborious, time consuming and challenging. 14 children underwent laparoscopic dismembered pyeloplasty using a three port, transperitoneal approach over a one year period in whom a novel approach ("double hitch" manoeuvre) (Group-2, n = 9) was used and operating times compared with the conventional "single hitch" (Group-1, n = 5). The mean operating time in Group 1 (172.4 min) and in Group 2 (129.5 min) was significantly different. Mean follow up in Group-1 and Group-2 was 14 and 6 months respectively. Utilisation of the "double hitch" manoeuvre in laparoscopic pyeloplasty reduces the operating time and probably makes it less laborious. 23948764 Optimization of protein purification and characterization using Thermofluor screens. The efficient large scale production of recombinant proteins depends on the careful conditioning of the protein as it is isolated and purified to homogeneity. Low protein stability leads to low purification yields as a result of protein degradation, precipitation and folding instability. It is often necessary to go through several iterations of trial-and-error to optimize the homogeneity, stability and solubility of the protein sample. We have set up Thermofluor assays to identify customized protocols for the preparation and characterization of individual protein constructs. We apply a two-step approach: we first screen for global parameters, followed by a search for protein-specific additives. The first screen has been designed in such a way, that it is possible to discern global stability trends according to pH, salt concentration, buffer type and concentration. The second screen contains small molecules that can affect the folding, aggregation state and solubility of the protein construct and also includes small molecules that specifically bind and stabilize proteins. The screens are designed to evaluate purification and storage protocols, and aim to provide hints to optimize these protocols. The home-made screens have been tested on more than 200 different protein constructs at the Sample Preparation and Characterization (SPC) facility at EMBL Hamburg. We describe which RT-PCR machines can be adapted to perform Thermofluor assays, what are the necessary experimental conditions to set up a screen, some leads on how to interpret the data and we give several examples of Thermofluor applications beyond stability screens. 23856622 Structures of Intermediates along the Catalytic Cycle of Terminal Deoxynucleotidyltransferase: Dynamical Aspects of the Two-Metal Ion Mechanism. Terminal deoxynucleotidyltransferase (Tdt) is a non-templated eukaryotic DNA polymerase of the polX family that is responsible for the random addition of nucleotides at the V(D)J junctions of immunoglobulins and T-cell receptors. Here we describe a series of high-resolution X-ray structures that mimic the pre-catalytic state, the post-catalytic state and a competent state that can be transformed into the two other ones in crystallo via the addition of dAMPcPP and Zn(2+), respectively. We examined the effect of Mn(2+), Co(2+) and Zn(2+) because they all have a marked influence on the kinetics of the reaction. We demonstrate a dynamic role of divalent transition metal ions bound to site A: (i) Zn(2+) (or Co(2+)) in Metal A site changes coordination from octahedral to tetrahedral after the chemical step, which explains the known higher affinity of Tdt for the primer strand when these ions are present, and (ii) metal A has to leave to allow the translocation of the primer strand and to clear the active site, a typical feature for a ratchet-like mechanism. Except for Zn(2+), the sugar puckering of the primer strand 3' terminus changes from C2'-endo to C3'-endo during catalysis. In addition, our data are compatible with a scheme where metal A is the last component that binds to the active site to complete its productive assembly, as already inferred in human pol beta. The new structures have potential implications for modeling pol mu, a closely related polX implicated in the repair of DNA double-strand breaks, in a complex with a DNA synapsis. 23761632 B Cell-intrinsic TLR7 signaling is required for optimal B cell responses during chronic viral infection. The importance for activation of innate immunity by pattern recognition receptors in forming an effective adaptive immune response is well known. TLRs were demonstrated to be critical for Ab responses to a variety of immunizations. In particular, recent evidence suggests that B cell-intrinsic TLR signaling is required for optimal responses to virus-like Ags, but the mechanisms by which TLR signaling impacts Ab responses during infection in vivo is unclear. In the current study, we demonstrate that deficiency of TLR7 in B cells alone is sufficient to significantly impact Ab responses in mice during chronic viral infection. This effect was independent of T follicular helper cells and resulted in a loss of plasma cells generated later, but not early, in the response. The defect in plasma cell formation appeared to be secondary to a qualitative effect of TLR signaling on the germinal center (GC) B cell response. GC B cells in TLR7-deficient mice proliferated to a lesser extent and had a greater proportion of cells with phenotypic characteristics of light zone, relative to dark zone, GC B cells. These results suggest that B cell-intrinsic TLR signaling in vivo likely affects plasma cell output by altered selection of Ag-specific B cells in the GC. 23915977 MiR-125b, miR-100 and miR-99a co-regulate vincristine resistance in childhood acute lymphoblastic leukemia. MicroRNA-125b (miR-125b), miR-99a and miR-100 are overexpressed in vincristine-resistant acute lymphoblastic leukemia (ALL). Cellular viability of ETV6-RUNX1-positive Reh cells significantly increased in presence of 9ng/mL vincristine upon co-expression of miR-125b/miR-99a (91±4%), miR-125b/miR-100 (93±5%) or miR-125b/miR-99a/miR-100 (82±17%) compared with miR-125b-transduced cells (38±13%, P<0.05). Co-expression of these miRNAs resulted in downregulation of DNTT, NUCKS1, MALAT1, SNRPE, PNO1, SET, KIF5B, PRPS2, RPS11, RPL38 and RPL23A (fold-change 1.3-1.9, p<0.05). Similarly, 7 out of these genes are lower expressed in vincristine-resistant ALL cells of children (p<0.05). The concerted function of miR-125b in combination with miR-99a and/or miR-100 illustrates the complexity of vincristine-resistant pediatric ALL. 23182176 Cognitive impairment and optic nerve axonal loss in patients with clinically isolated syndrome. To investigate cognitive impairment, to assess optical nerve axonal loss, and to determinate whether there is correlation between optical nerve axonal loss and cognition impairment in Clinically Isolated Syndrome (CIS). Fifteen CIS patients and 15 controls were submitted to Wechsler memory scale, Rey Auditory Verbal Learning, Rey Complex Figure, Paced Auditory Serial Addition, Digit Span, verbal fluency, stroop color, D2, and Digit Symbol tests. CIS patients were evaluated by optical coherence tomography (OCT) (23 eyes). CIS patients had worse performance in Paced Auditory Serial Addition Test (PASAT) 2 seconds (P=0.009) and fluency tests (P=0.0038). Optical nerve axonal loss was found more frequently in eyes with previous optic neuritis (ON) (85.7%) than in those without previous ON (21.7%) (P=0.0146). There were no significant correlations between optical nerve axonal loss and cognitive findings. CIS patients had worse cognitive performance than controls. OCT can detect axonal loss resulting from optical neuritis and subclinical axonal loss in eyes without previous optical neuritis. Optical nerve axonal loss was not correlated with cognition. 23965337 A Receptor-Specific Function for Notch2 in Mediating Vascular Smooth Muscle Cell Growth Arrest Through p27kip1. Rationale: Deregulated vascular smooth muscle cell (VSMC) proliferation contributes to multiple vascular pathologies, and Notch signaling regulates VSMC phenotype. Objective: Previous work focused on Notch1 and Notch3 in VSMC during vascular disease; however, the role of Notch2 is unknown. Because injured murine carotid arteries display increased Notch2 in VSMC as compared to uninjured arteries, we sought to understand the impact of Notch2 signaling in VSMC. Methods and Results: In human primary VSMC, Jagged-1 (Jag-1) significantly reduced proliferation through specific activation of Notch2. Increased levels of p27(kip1) were observed downstream of Jag-1/Notch2 signaling, and required for cell cycle exit. Jag-1 activation of Notch resulted in increased phosphorylation on serine 10, decreased ubiquitination and prolonged half-life of p27(kip1). Jag-1/Notch2 signaling robustly decreased S-phase kinase associated protein (Skp2), an F-box protein that degrades p27(kip1) during G1. Over expression of Skp2 prior to Notch activation by Jag-1 suppressed the induction of p27(kip1). Additionally, increased Notch2 andp27(kip1) expression was co-localized to the non-proliferative zone of injured arteries as indicated by co-staining with proliferating cell nuclear antigen (PCNA), whereas Notch3 was expressed throughout normal and injured arteries, suggesting Notch2 may negatively regulate lesion formation. Conclusions: We propose a receptor specific function for Notch2 in regulating Jag-1-induced p27(kip1) expression and growth arrest in VSMC. During vascular remodeling, co-localization of Notch2 and p27(kip1)to the non-proliferating region supports a model where Notch2 activation may negatively regulate VSMC proliferation to lessen the severity of the lesion. Thus Notch2 is a potential target for control of VSMC hyperplasia. 23842782 Negligible water surface charge determined using Kelvin probe and total reflection X-ray fluorescence techniques. The water surface charge has been extensively debated in recent decades. Electrophoretic mobilities of air bubbles in water and disjoining pressures between the surfaces of aqueous films suggest that the surface of water exhibits a significant negative charge. This is commonly attributed to a strong adsorption of hydroxide ions at the interface, though spectroscopic measurements and simulation studies suggest surface depletion of hydroxide ions. Alternatively, the negative surface charge could arise from surface contamination with trace charged surfactants. We have probed the variation in the surface charge of water with pH by measuring surface potentials using the Kelvin probe technique. Independently, the abundance in the interfacial layer of "reporter ions" (Rb(+) and Br(-)), which must be affected by a charged surface, has been monitored using the total reflection X-ray fluorescence (TRXF) technique. Special care was taken to prove the high sensitivity of this technique as well as to avoid surface contaminants. The magnitude of the surface charge was found to be below 1 e per 500 nm(2) (TRXF). No evidence of variations in the surface potential between pH 2-3 and pH 9-12 was detected within the accuracies of the methods (5 mV for Kelvin probe and 2 mV for TRXF). Hence, our findings suggest that the clean water surface exhibits negligible charge in a wide pH range. 23856115 Co-operative inhibitory effects of hydrogen peroxide and iodine against bacterial and yeast species. Hydrogen peroxide and iodine are powerful antimicrobials widely used as antiseptics and disinfectants. Their antimicrobial properties are known to be enhanced by combining them with other compounds. We studied co-operative inhibitory activities (synergism, additive effects and modes of growth inhibition) of hydrogen peroxide and iodine used concurrently against 3 bacterial and 16 yeast species. Synergistic or additive inhibitory effects were shown for hydrogen peroxide and iodine mixtures against all 19 species used in the study. Both biocides were mostly cidal individually and in mixtures against Pseudomonas aeruginosa and Staphylococcus aureus. Both compounds manifested static inhibitory effects individually, but their mixtures were synergistically cidal for Saccharomyces cerevisiae and Escherihia coli. Cells of S. cerevisiae treated with hydrogen peroxide and iodine-hydrogen peroxide mixture produced increased numbers of respiratory deficient mutants indicating genotoxic effects. Iodine and hydrogen peroxide used concurrently interact synergistically or additively against a range of prokaryotic and eukaryotic microorganisms. The study provides an insight as to how these traditional antimicrobials could be used more effectively for disinfection and antisepsis. In addition, a simple approach is proposed for scoring genotoxicity of different biocides by using the budding yeast system. 23954678 Protective effect of serofendic acid, administered intravenously, on cerebral ischemia-reperfusion injury in rats. Serofendic acid is a low-molecular-weight compound extracted from fetal calf serum. We previously reported that intracerebroventricular administration of serofendic acid prevents cerebral ischemia-reperfusion injury. However, the effect of peripheral administration of serofendic acid on cerebral ischemia-reperfusion injury has not been examined. In the present study, we investigated the effect of intravenous administration of serofendic acid against cerebral ischemia-reperfusion injury using transient middle cerebral artery occlusion model rats. Serofendic acid (10mg/kg) administrated three times, including 30min before the onset of ischemia, just after the onset of ischemia and just before reperfusion reduced the infarct volume and improved the neurological dysfunction induced by ischemia-reperfusion without affecting regional cerebral blood flow or physiological parameters. However, there were no protective effects when serofendic acid (30mg/kg) was only administered once at 30min before the onset of ischemia, just after the onset of ischemia, or just before reperfusion. Our results reveal the importance of maintaining the blood concentration of serofendic acid for preventing cerebral ischemia-reperfusion injury. 23661792 Vaccine Poliovirus Shedding and Immune Response to Oral Polio Vaccine in HIV-Infected and -Uninfected Zimbabwean Infants. Background. With prolonged replication, attenuated polioviruses used in oral polio vaccine (OPV) can mutate into vaccine-derived poliovirus (VDPV) and cause poliomyelitis outbreaks. Individuals with primary humoral immunodeficiencies can become chronically infected with vaccine poliovirus, allowing it to mutate into immunodeficiency-associated VDPV (iVDPV). It is unclear if children perinatally infected with the human immunodeficiency virus (HIV), who have humoral as well as cellular immunodeficiencies, might be sources of iVDPV. Methods. We conducted a prospective study collecting stool and blood samples at multiple time points from Zimbabwean infants receiving OPV according to the national schedule. Nucleic acid extracted from stool was analyzed by real-time polymerase chain reaction for OPV serotypes. Results. We analyzed 825 stool samples: 285 samples from 92 HIV-infected children and 540 from 251 HIV-uninfected children. Poliovirus shedding was similar after 0-2 OPV doses but significantly higher in the HIV-infected versus uninfected children after ≥3 OPV doses, particularly within 42 days of an OPV dose, independent of seroconversion status. HIV infection was not associated with prolonged or persistent poliovirus shedding. HIV infection was associated with significantly lower polio seroconversion rates. Conclusions. HIV infection is associated with decreased mucosal and humoral immune responses to OPV but not the prolonged viral shedding required to form iVDPV. 23811038 Decarboxylase gene expression and cadaverine and putrescine production by Serratia proteamaculans in vitro and in beef. Studies of the molecular basis of microbial metabolic activities that are important for the changes in food quality are valuable in order to help in understanding the behavior of spoiling bacteria in food. The growth of a psychrotrophic Serratia proteamaculans strain was monitored in vitro and in artificially inoculated raw beef. Two growth temperatures (25°C and 4°C) were tested in vitro, while growth at 15°C and 4°C was monitored in beef. During growth, the expression of inducible lysine and ornithine-decarboxylase genes was evaluated by quantitative reverse transcription-PCR (qRT-PCR), while the presence of cadaverine and putrescine was quantified by LC-ESI-MS/MS. The expression of the decarboxylase genes, and the consequent production of cadaverine and putrescine were shown to be influenced by the temperature, as well as by the complexity of the growth medium. Generally, the maximum gene expression and amine production took place during the exponential and early stationary phase, respectively. In addition, lower temperatures caused slower growth and gene downregulation. Higher amounts of cadaverine compared to putrescine were found during growth in beef with the highest concentrations corresponding to microbial loads of ca. 9CFU/g. The differences found in gene expression evaluated in vitro and in beef suggested that such activities are more reliably investigated in situ in specific food matrices. 23239534 Threshold collision-induced dissociation of hydrated magnesium: experimental and theoretical investigation of the binding energies for Mg(2+)(H2O)x complexes (x=2-10). The sequential bond energies of Mg(2+)(H2O)x complexes, in which x=2-10, are measured by threshold collision-induced dissociation in a guided ion beam tandem mass spectrometer. From an electrospray ionization source that produces an initial distribution of Mg(2+)(H2O)x complexes in which x=7-10, complexes down to x=3 are formed by using an in-source fragmentation technique. Complexes smaller than Mg(2+)(H2O)3 cannot be formed in this source because charge separation into MgOH(+)(H2O) and H3O(+) is a lower-energy pathway than simple water loss from Mg(2+)(H2O)3. The kinetic energy dependent cross sections for dissociation of Mg(2+)(H2O)x complexes, in which x=3-10, are examined over a wide energy range to monitor all dissociation products and are modeled to obtain 0 and 298 K binding energies. Analysis of both primary and secondary water molecule losses from each sized complex provides thermochemistry for the sequential hydration energies of Mg(2+) for x=2-10 and the first experimental values for x=2-4. Additionally, the thermodynamic onsets leading to the charge-separation products from Mg(2+)(H2O)3 and Mg(2+)(H2O)4 are determined for the first time. Our experimental results for x=3-7 agree well with quantum chemical calculations performed here and previously calculated binding enthalpies, as well as previous measurements for x=6. The present values for x=7-10 are slightly lower than previous experimental results and theory, but within experimental uncertainties. 23108927 Flexible and stretchable polymers with embedded magnetic nanostructures. A novel pathway is presented to transfer and embed functional patterned magnetic nanostructures into flexible and stretchable polymeric membranes. The geometrical and magnetic properties are maintained through the process, realized even directly inside a microfluidic channel. These results pave the way to the realization of smart biomedical systems and devices based on the integration of magnetic nanostructures into new classes of substrates. 22419622 Recall, relevance and application of an in-school sexual and reproductive health intervention 7-9 years later: perspectives of rural Tanzanian young people. Many adolescent sexual and reproductive health (ASRH) interventions have improved knowledge and reduced reported sexual risk behaviours, but found no impact on HIV. We explored potential reasons for this in 23 in-depth interviews, conducted 7-9 years after exposure to ASRH intervention. We discussed participants' memories and views of the relevance of the in-school intervention, and their subsequent ability to apply what they had learned. While most participants had favourable memories of the intervention, few recalled specific details. Most reported that the intervention had been relevant, although few reported being able to apply the teachings. Men found it easier to apply lessons about condoms than women. Inability to apply the intervention teachings was often linked to cultural norms around fertility and/or gender power relations. ASRH interventions should address structural factors such as the quality of parenting and explicitly link interventions to young peoples' future aspiration. 23899638 Estimated Dopamine D2 Receptor Occupancy and Remission in Schizophrenia: Analysis of the CATIE Data. In treating schizophrenia, 65% to 80% occupancy of dopamine D2 receptors optimizes therapeutic efficacy while minimizing risks of extrapyramidal symptoms and cognitive impairments. However, it is unclear as to whether it is necessary to keep D2 receptor occupancy within this therapeutic window to maintain clinical response. The data set from phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial was reappraised. Thirty patients receiving risperidone (12 patients), olanzapine (12 patients), or ziprasidone (6 patients) fulfilled the following definition of remission and were included: a score of 3 or less on the 8 specific items in the Positive and Negative Syndrome Scale (ie, P1, P2, P3, N1, N4, N6, G5, and G9; adopted from Andreasen et al, 2005) at the initial assessment and months 1, 2, and 6. Peak and trough D2 receptor occupancy levels at month 6 were estimated from plasma antipsychotic concentrations using population pharmacokinetic analysis and our D2 prediction model. Estimated mean ± SD peak and trough D2 receptor occupancy levels at month 6 were 70.3% ± 9.8% and 60.5% ± 20.2%, respectively; among these individuals, 46.7% (14 patients) did not achieve continuous blockade of 65% or greater (ie, trough D2 occupancy of <65%). In conclusion, approximately half of patients with remission did not achieve continuous blockade of estimated D2 receptor occupancy 5% or greater. These results extend our previous findings and suggest that sustained D2 receptor occupancy greater than 65% may not always be necessary for the maintenance treatment of schizophrenia. 23936184 How about Lunch? Consequences of the Meal Context on Cognition and Emotion. Although research addresses the effects of a meal's context on food preference, the psychological consequences of meal situations are largely unexplored. We compared the cognitive and emotional effects of a restaurant meal eaten in the company of others to a solitary meal consumed in a plain office using pre- and post-tests analysis and controlling for the kind and amount of food consumed. Three tasks were conducted, measuring: (1) semantic memory (2) cognitive control and error monitoring, and (3) processing of emotional facial expressions. Covert processes in these tasks were assessed with event-related brain potentials. A mood rating questionnaire indicated a relaxation effect of the restaurant as compared to the plain meal situation. The restaurant meal increased sensitivity to threatening facial expressions and diminished cognitive control and error monitoring. No effects were observed for semantic memory. These findings provide the first experimental evidence that a restaurant meal with a social component may be more relaxing than a meal eaten alone in a plain setting and may reduce cognitive control. 23422867 Effect of isoflavone soy protein supplementation on endometrial thickness, hyperplasia, and endometrial cancer risk in postmenopausal women: a randomized controlled trial. This study aims to determine whether long-term isoflavone soy protein (ISP) supplementation affects endometrial thickness and rates of endometrial hyperplasia and cancer in postmenopausal women. In this randomized, double-blind, placebo-controlled trial, 350 postmenopausal women aged 45 to 92 years were randomized to a total daily dose of 154 mg of ISP or a milk protein-matched placebo for a 3-year period. Women with a surgically absent uterus were excluded from the analysis (final study population, N = 224). The main outcome measures were as follows: mean change in endometrial thickness on transvaginal ultrasound from baseline until up to 36 months of follow-up and the incidence of endometrial sampling, endometrial hyperplasia, and endometrial cancer. A total of 666 visits among 224 participants were evaluated. Treatment groups did not significantly differ on the mean baseline or on-trial changes in endometrial thickness. Of the 103 placebo-treated participants, 7 (6.8%) underwent endometrial biopsy; 6 (85.7%) of these biopsies were benign. One woman in the placebo group was diagnosed with complex endometrial hyperplasia with atypia and underwent hysterectomy. The pathology result from this surgical operation was stage IB endometrial cancer. Of the 121 participants in the soy group, 9 (7.4%) underwent endometrial biopsy. The results were benign in all nine cases (100%). Although the rate of hyperplasia/malignancy was higher in the placebo group (14.3% vs 0%), the difference was not statistically significant. Three-year ISP supplementation has no effect on endometrial thickness or on the rates of endometrial hyperplasia and cancer in postmenopausal women. 23444198 Cellular control of connective tissue matrix tension. The biomechanical behavior of connective tissue in response to stretching is generally attributed to the molecular composition and organization of its extracellular matrix. It also is becoming apparent that fibroblasts play an active role in regulating connective tissue tension. In response to static stretching of the tissue, fibroblasts expand within minutes by actively remodeling their cytoskeleton. This dynamic change in fibroblast shape contributes to the drop in tissue tension that occurs during viscoelastic relaxation. We propose that this response of fibroblasts plays a role in regulating extracellular fluid flow into the tissue, and protects against swelling when the matrix is stretched. This article reviews the evidence supporting possible mechanisms underlying this response including autocrine purinergic signaling. We also discuss fibroblast regulation of connective tissue tension with respect to lymphatic flow, immune function, and cancer. 23859905 Urethral lymphogranuloma venereum infections in men with anorectal lymphogranuloma venereum and their partners: the missing link in the current epidemic? Urethral lymphogranuloma venereum (LGV) is not screened routinely. We found that in 341 men having sex with men with anorectal LGV, 7 (2.1%) had concurrent urethral LGV. Among 59 partners, 4 (6.8%) had urethral LGV infections. Urethral LGV is common, probably key in transmission, and missed in current routine LGV screening algorithms. 22944093 An open randomized controlled trial of median sternotomy versus anterolateral left thoracotomy on morbidity and health care resource use in patients having off-pump coronary artery bypass surgery: The Sternotomy Versus Thoracotomy (STET) trial. Our objective was to compare off-pump coronary artery bypass surgery carried out via a left anterolateral thoracotomy (ThoraCAB) or via a conventional median sternotomy (OPCAB). Recent advances in minimally invasive cardiac surgery have extended the technique to allow complete surgical revascularization on the beating heart via thoracotomy. Patients undergoing nonemergency primary surgery were enrolled between February 2007 and September 2009 at 2 centers. The primary outcome was the time from surgery to fitness for hospital discharge as defined by objective criteria. A total of 93 patients were randomized to off-pump coronary artery bypass surgery via a median sternotomy (OPCAB) and 91 to off-pump coronary artery bypass surgery via a left anterolateral thoracotomy (ThoraCAB). The surgery was longer for patients in the ThoraCAB group (median, 4.1 vs 3.3 hours) and there were fewer with more than 3 grafts (2% vs 17%). The median time from surgery to fitness for discharge was 6 days (interquartile range, 4-7) in the ThoraCAB group versus 5 days (interquartile range, 4-7) in the OPCAB group (P = .53). The intubation time was shorter, by on average 65 minutes, in the ThoraCAB group (P = .017), although the time in intensive care was similar (P = .91). Pain scores were similar (P = .97), but more analgesia was required in the ThoraCAB group (median duration, 38.8 vs 35.5 hours, P < .001; tramadol use, 66% vs 49%, P = .024). ThoraCAB was associated with significantly worse lung function at discharge (average difference, -0.25 L, P = .01) but quality of life scores at 3 and 12 months were similar (P = .52). The average total cost was 10% higher with ThoraCAB (P = .007). ThoraCAB resulted in no overall clinical benefit relative to OPCAB. 23894194 Proteasome Inhibition by Bortezomib Increases IL-8 Expression in Androgen-Independent Prostate Cancer Cells: The Role of IKKα. Expression of the proinflammatory and proangiogenic chemokine IL-8, which is regulated at the transcriptional level by NF-κB, is constitutively increased in androgen-independent metastatic prostate cancer and correlates with poor prognosis. Inhibition of NF-κB-dependent transcription was used as an anticancer strategy for the development of the first clinically approved 26S proteasome inhibitor, bortezomib (BZ). Even though BZ has shown remarkable antitumor activity in hematological malignancies, it has been less effective in prostate cancer and other solid tumors; however, the mechanisms have not been fully understood. In this article, we report that proteasome inhibition by BZ unexpectedly increases IL-8 expression in androgen-independent prostate cancer PC3 and DU145 cells, whereas expression of other NF-κB-regulated genes is inhibited or unchanged. The BZ-increased IL-8 expression is associated with increased in vitro p65 NF-κB DNA binding activity and p65 recruitment to the endogenous IL-8 promoter. In addition, proteasome inhibition induces a nuclear accumulation of IκB kinase (IKK)α, and inhibition of IKKα enzymatic activity significantly attenuates the BZ-induced p65 recruitment to IL-8 promoter and IL-8 expression, demonstrating that the induced IL-8 expression is mediated, at least partly, by IKKα. Together, these data provide the first evidence, to our knowledge, for the gene-specific increase of IL-8 expression by proteasome inhibition in prostate cancer cells and suggest that targeting both IKKα and the proteasome may increase BZ effectiveness in treatment of androgen-independent prostate cancer. 23890083 APOBEC3 inhibits DEAD-END function to regulate microRNA activity. The RNA binding protein DEAD-END (DND1) is one of the few proteins known to regulate microRNA (miRNA) activity at the level of miRNA-mRNA interaction. DND1 blocks miRNA interaction with the 3'-untranslated region (3'-UTR) of specific mRNAs and restores protein expression. Previously, we showed that the DNA cytosine deaminase, APOBEC3 (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide like 3), interacts with DND1. APOBEC3 has been primarily studied for its role in restricting and inactivating retroviruses and retroelements. In this report, we examine the significance of DND1-APOBEC3 interaction. We found that while human DND1 inhibits miRNA-mediated inhibition of P27, human APOBEC3G is able to counteract this repression and restore miRNA activity. APOBEC3G, by itself, does not affect the 3'-UTR of P27. We found that APOBEC3G also blocks DND1 function to restore miR-372 and miR-206 inhibition through the 3'-UTRs of LATS2 and CX43, respectively. In corollary experiments, we tested whether DND1 affects the viral restriction function or mutator activity of APOBEC3. We found that DND1 does not affect APOBEC3 inhibition of infectivity of exogenous retrovirus HIV (ΔVif) or retrotransposition of MusD. In addition, examination of Ter/Ter;Apobec3-/- mice, lead us to conclude that DND1 does not regulate the mutator activity of APOBEC3 in germ cells. In summary, our results show that APOBEC3 is able to modulate DND1 function to regulate miRNA mediated translational regulation in cells but DND1 does not affect known APOBEC3 function. 23836525 Lateral entorhinal cortex is necessary for associative but not nonassociative recognition memory. The lateral entorhinal cortex (LEC) provides one of the two major input pathways to the hippocampus and has been suggested to process the nonspatial contextual details of episodic memory. Combined with spatial information from the medial entorhinal cortex it is hypothesised that this contextual information is used to form an integrated spatially selective, context-specific response in the hippocampus that underlies episodic memory. Recently, we reported that the LEC is required for recognition of objects that have been experienced in a specific context (Wilson et al. (2013) Hippocampus 23:352-366). Here, we sought to extend this work to assess the role of the LEC in recognition of all associative combinations of objects, places and contexts within an episode. Unlike controls, rats with excitotoxic lesions of the LEC showed no evidence of recognizing familiar combinations of object in place, place in context, or object in place and context. However, LEC lesioned rats showed normal recognition of objects and places independently from each other (nonassociative recognition). Together with our previous findings, these data suggest that the LEC is critical for associative recognition memory and may bind together information relating to objects, places, and contexts needed for episodic memory formation. © 2013 Wiley Periodicals, Inc. 22813462 Deep understanding of the interaction between thienorphine and UDP-glucuronosyltransferase (UGT) isoforms. Thienorphine has been demonstrated to be a potent, long-acting partial opioid agonist. It is being developed as a good candidate to treat opioid dependence. The thienorphine's glucuronide was detected after thienorphine was incubated with human liver microsomes (HLMs). Recombinant UGT isoforms screening experiment and enzyme kinetic study showed that UGT1A1 completely contributed to the glucuronidation of thienorphine. Among the tested UGT isoforms, UGT1A3 and UGT2B7 were inhibited by thienorphine, with other UGT isoforms negligibly influenced. The inhibition type is competitive, and inhibition kinetic parameters (K(i)) were 1.65 and 5.27 μM for UGT1A3 and UGT2B7, respectively. However, due to low plasma concentration of thienorphine, in vivo drug-drug interaction might not occur. 23904289 Candida albicans is not always the preferential yeast colonising humans: a study amongst Wayampi Amerindians. In industrialized countries Candida albicans is considered as the predominant commensal yeast of the human intestine with∼40% prevalence in healthy adults. We discovered a highly original colonization pattern that challenges this current perception by studying in a four year interval a cohort of 151 Amerindians living in a remote community (French Guiana), and animals from their environment. C. albicans prevalence was persistently low (3% and 7% of yeast carriers). By contrast Candida krusei and Saccharomyces cerevisiae were detected in over 30% of carriers. We showed that C. krusei and S. cerevisiae carriage was of food or environmental origin whereas C. albicans carriage was associated with specific risk factors (being female and living in a crowded household). We also showed using whole-genome sequence comparison that C. albicans strains can persist in the intestinal tract of a healthy individual over a 4 year period. 23570511 Oral supplementation of medium-chain fatty acids during the dry period supports the neutrophil viability of peripartum dairy cows. A randomised clinical trial was conducted to explore the effect of orally supplemented medium-chain fatty acids (MCFA) to heifers and cows starting 6-8 weeks prior to expected calving date on blood and milk polymorphonuclear neutrophilic leucocyte (PMNL) apoptosis between 1 and 3 d in milk (DIM). The effects of MCFA-supplementation on the likelihood of intramammary infections (IMI) in early lactation, and test-day somatic cell count (SCC) and average daily milk yield (MY) during the first 4 months of lactation were evaluated as well. Twenty-two animals were included of which half were orally supplemented with MCFA starting 6-8 weeks prior to calving and half served as non-supplemented controls. The PMNL viability in both blood and milk was quantified using dual-colour flow cytometry with fluorescein-labelled annexin and propidium iodide. In non-supplemented animals, % blood PMNL apoptosis significantly increased between start of supplementation and early lactation, reflecting a potential reduction in innate immune capacity, whereas this was not true in the MCFA-supplemented animals. Similar results were seen in milk PMNL apoptosis. Overall, the % apoptotic milk PMNL between 1 and 3 DIM was significantly lower in the MCFA-supplemented group compared with the non-supplemented group. There was no substantial effect of oral MCFA-supplementation on the likelihood of quarter IMI nor on the composite test-day milk SCC or average daily MY. In conclusion, oral MCFA-supplementation starting 6-8 weeks before expected calving date supported the blood and milk neutrophil viability in early lactating dairy cows. Still, this was not reflected in an improvement of udder health nor MY in early and later lactation. The results should trigger research to further unravel the mechanisms behind the observed immunomodulating effect, and the potential relevance for the cows' performances throughout lactation. 23711363 Short- and Long-term Outcomes of Surgery for Severe Tricuspid Regurgitation. There is little data available for Spain on the outcomes of surgical treatment for severe tricuspid regurgitation. The aim of this study was to analyze clinical and echocardiographic outcomes in a series of patients who received surgical treatment for severe tricuspid regurgitation and to compare outcomes according to the operative approach to valve repair or replacement. Retrospective study in 119 consecutive patients with severe tricuspid regurgitation undergoing valve surgery between April 1996 and February 2010. A total of 61 ringless and 23 ring annuloplasties were performed and 11 bioprostheses and 24 mechanical prostheses were implanted. Perioperative mortality was 18.5% and was associated with age and cardiopulmonary bypass time. During clinical follow-up (median, 41 [interquartile range, 24-89] months), 2 reoperations were required in the ring annuloplasty and mechanical prosthesis groups; prosthetic thrombosis was diagnosed in 4 patients in the latter group. Total mortality after follow-up was 29.9% and was associated with age>70 years and extracorporeal circulation time. The emergence of new severe tricuspid regurgitation was associated with age and ringless annuloplasty (P=.04). Ringless repair was significantly associated with recurrence of severe tricuspid regurgitation. The use of mechanical prostheses was associated with a high rate of thrombosis. No significant differences in perioperative or total mortality were found between the different methods used for repair or valve replacement. Full English text available from:www.revespcardiol.org/en. 23906709 Genomic characterization of six novel Bacillus pumilus bacteriophages. Twenty-eight bacteriophages infecting the local host Bacillus pumilus BL-8 were isolated, purified, and characterized. Nine genomes were sequenced, of which six were annotated and are the first of this host submitted to the public record. The 28 phages were divided into two groups by sequence and morphological similarity, yielding 27 cluster BpA phages and 1 cluster BpB phage, which is a BL-8 prophage. Most of the BpA phages have a host range restricted to distantly related strains, B. pumilus and B. simplex, reflecting the complexities of Bacillus taxonomy. Despite isolation over wide geographic and temporal space, the six cluster BpA phages share most of their 23 functionally annotated protein features and show a high degree of sequence similarity, which is unique among phages of the Bacillus genera. This is the first report of B. pumilus phages since 1981. 23730938 Modelling stomatal conductance in response to environmental factors. Stomata are an attractive system for modellers for many reasons, and the literature contains a large number of papers describing models that predict stomatal conductance as a function of environmental factors. The approaches and goals of these models vary considerably. This review summarizes these different approaches and discusses their strengths and weaknesses with a focus on mechanistically based models. The critical unresolved questions are highlighted and placed in the context of current research on stomatal physiology. Finally, directions for future research are considered. 23772445 Facile synthesis of benzofurans via copper-catalyzed aerobic oxidative cyclization of phenols and alkynes. Regioselective synthesis of polysubstituted benzofurans using a copper catalyst and molecular oxygen from phenols and alkynes in a one-pot procedure has been reported. The transformation consists of a sequential nucleophilic addition of phenols to alkynes and oxidative cyclization. A wide variety of phenols and alkynes can be used in the same manner. 23460349 Closure of patent ductus arteriosus in children, small infants, and premature babies with Amplatzer duct occluder II additional sizes: Multicenter study. To evaluate safety and efficacy of closure of patent ductus arteriosus (PDA) with Amplatzer duct occluder II Additional Sizes (ADO II AS) and to report early and midterm results of the device in children and very young symptomatic infants. Retrospective analysis of angiographic data of 60 children from four pediatric cardiology centers. The median patient age and weight were 6.5 (0.5-168) months and 6.8 (1.19-57) kg, respectively. In the study, 26 children had a body weight of ≤6 kg. Of these 26 children, 9 had a body weight of ≤3 kg. The median narrowest diameter of PDA was 2 (1.2-4) mm. Ductal anatomy was Type A in 29, Type B in 2, Type C in 11, Type D in 1, and Type E in 16 patients, and a residual PDA after surgery in 1 patient. Closure with ADO II AS was achieved in 58 (96.6%) of 60 attempted cases. In two infants, the device was not released because of significant residual shunt. ADO II was used in one, and the other was sent to surgery. Complete closure was observed in all ADO II AS deployed children by the next day on echocardiography. Median follow-up was 12 (1-18) months. Neither death nor any major complications occurred. Our study shows that closure of medium and small sized PDA by using ADO II AS device is effective and safe in children. The use of the device will expand the field of application of PDA closure in small infants. © 2013 Wiley Periodicals, Inc. 23823021 Involvement of exercise-induced MIF in the prevention of fatty liver disease. AbstractPhysical inactivity can lead to obesity and fat accumulation in various tissues. Critical complications of obesity include type II diabetes and nonalcoholic fatty liver disease (NAFLD). Exercise has been reported to have ameliorating effects on obesity and NAFLD. However, the underlying mechanism is not fully understood. We showed that liver expression of macrophage migration inhibitory factor (MIF) was increased after 4 weeks of treadmill exercise. Phosphorylation of AMP-activated protein kinase and acetyl-CoA carboxylase in human hepatocyte cell lines was enhanced after MIF treatment. These responses were accompanied by increases in lipid oxidation. Moreover, inhibition of either AMPK or CD74 resulted in inhibition of MIF-induced lipid oxidation. Furthermore, the administration of MIF to a human hepatocyte cell line and mice liver reduced liver X receptor (LXR) agonist-induced lipid accumulation. Taken together, these results indicate that MIF is highly expressed in the liver during physical exercise and may prevent hepatic steatosis by activating the AMPK pathway. 23835258 Apamin induces early afterdepolarizations and torsades de pointes ventricular arrhythmia from failing rabbit ventricles exhibiting secondary rises in intracellular calcium. A secondary rise of intracellular Ca(2+) (Cai) and an upregulation of apamin-sensitive K(+) current (IKAS) are characteristic findings of failing ventricular myocytes. We hypothesize that apamin, a specific IKAS blocker, may induce torsades de pointes (TdP) ventricular arrhythmia from failing ventricles exhibiting secondary rises of Cai. To test the hypothesis that small conductance Ca(2+) activated IKAS maintains repolarization reserve and prevents ventricular arrhythmia in a rabbit model of heart failure (HF). We performed Langendorff perfusion and optical mapping studies in 7 hearts with pacing-induced HF and in 5 normal control rabbit hearts. Atrioventricular block was created by cryoablation to allow pacing at slow rates. The left ventricular ejection fraction reduced from 69.1% [95% confidence interval 62.3%-76.0%] before pacing to 30.4% [26.8%-34.0%] (N = 7; P < .001) after pacing. The corrected QT interval in failing ventricles was 337 [313-360] ms at baseline and 410 [381-439] ms after applying 100 nmol/L of apamin (P = .01). Apamin induced early afterdepolarizations (EADs) in 6 ventricles, premature ventricular beats (PVBs) in 7 ventricles, and polymorphic ventricular tachycardia consistent with TdP in 4 ventricles. The earliest activation site of EADs and PVBs always occurred at the site with long action potential duration and large amplitude of the secondary rises of Cai. Apamin induced secondary rises of Cai in 1 nonfailing ventricle, but no EAD or TdP were observed. In HF ventricles, apamin induces EADs, PVBs, and TdP from areas with secondary rises of Cai. IKAS is important in maintaining repolarization reserve and preventing TdP in HF ventricles. 23897007 Ki 67 is an Independent Predictive Biomarker of Cancer Specific and Local Recurrence-Free Survival After Lung Tumor Ablation. The objective of this work was to evaluate the feasibility of histopathological analysis of tissue extracted on multitined electrodes and assess whether tissue characteristics can be used as biomarkers of oncologic outcomes after lung tumor radiofrequency (RF) ablation. Treatment-related data regarding RF ablation of lung malignancies at our institution was collected using a Health Insurance Portability and Accountability Act-compliant ablation database. Institutional review board waiver was obtained for this study. Immunohistochemical analysis of tissue extracted from the electrodes after lung tumor RF ablation was performed for proliferation (Ki-67) and apoptosis (caspase-3). Patient, tumor demographics, and ablation parameters were recorded. Local tumor progression-free survival (LPFS), disease-specific survival (DSS), and overall survival (OS) were assessed using Kaplan-Meier methodology. Multivariate analysis determined factors affecting these oncological outcomes. A total of 47 lung tumors in 42 patients were ablated; 30 specimens were classified as coagulation necrosis (CN) and 17 as Ki-67-positive (+) tumor cells (viable). Tumor sizes were similar in the CN and Ki-67+ groups (P = 0.32). Median LPFS was 10 versus 16 months for Ki-67+ and CN groups, and 1-year LPFS was 34 and 75 %, respectively (P = 0.003). Median OS was 20 and 46 months (P = 0.12), and median DSS was 20 and 68 months (P = 0.01) for the Ki-67 + and CN groups, respectively. Identification of Ki-67+ tumor cells more than tripled the risk of death from cancer [hazard ratio (HR) = 3.65; 95 % confidence interval (95 % CI), 1.34-9.95; P = 0.01] and tripled the risk of local tumor progression (LTP) (HR = 3.01; 95 % CI, 1.39-6.49; P = 0.005). Ki-67+ tumor cells on the electrode after pulmonary tumor RF ablation is an independent predictor of LTP, shorter LPFS, and DSS. 23916411 Spatial variability in selenium and mercury interactions in a key recreational fish species: Implications for human health and environmental monitoring. Selenium's (Se) protective effects against mercury (Hg) toxicity have been demonstrated; however, this is seldom considered in health assessments, where dietary exposure is still evaluated by Hg concentration alone. Se:Hg ratios and selenium health benefit values (Se HBVs) offer a more comprehensive seafood safety model. Here we describe total mercury (THg), methylmercury (MeHg) and Se concentrations in fish from a Hg-polluted estuary. Spatial variation in THg, MeHg and Se was evident, though all regions maintained Se:Hg ratio values >1. Se HBV varied between regions and in one region mean negative values (-5.17) were evident. This study provides the first evidence that quoting a single all-encompassing Se HBV is not appropriate when species demonstrate strong site fidelity. It highlights the need for research into Se-Hg relationships in environments with established Hg pollution and reinforces the assertion that Se concentration be considered in assessments of human health risk to Hg exposure. 23922422 Depressive symptoms in tourette syndrome and affective disorders: a controlled study. Tourette syndrome (TS) is a neuropsychiatric condition characterised by multiple motor and vocal tics, as well as a spectrum of behavioural problems. Previous research found that 76% of patients with TS experience depressive symptoms, with 13% fulfilling diagnostic criteria for depression. We set out to assess the severity of affective symptoms in patients with TS, in comparison to patients with primary affective disorders (recurrent major depressive disorder, rMDD; bipolar affective disorder types I/II, BPD-I/II), and healthy controls. Both patients with affective disorders and controls completed the Beck Depression Inventory (BDI)-IA, whilst patients with TS completed the BDI-II. Total BDI-II scores were transformed using an equipercentile equating method for converting raw total BDI-II to BDI-IA scores. Data from 14/21 items had corresponding anchor points between the two versions and were therefore suitable for analysis. This cross-sectional study included N=3,066 participants: TS (N=65), rMDD (N=696), BPD-I (N=1515), BPD-II (N=497), and controls (N=293). Depressive symptoms did not show any association with ethnicity or age. Patients with TS scored significantly higher than healthy controls (P=<.001) for all relevant items. When comparing depression ratings between patients with TS and patients with primary affective disorders, total BDI scores in TS were not significantly different from BPD-I or BPD-II, but significantly lower than rMDD (P=.030). Specifically, patients with rMDD scored higher on the self-criticalness, libido, suicidality and anergia items (P=.003 - >< .001). The TS group also showed statistically significant differences in BDI scores across gender, with female patients reporting higher scores (P=.013), particularly in the guilt, suicidality, crying, irritability and libido items (P=.047 - .002). > Depression appears to be a prominent feature in TS and seems to have a different phenotype to that in rMDD. Female patients with TS present a particularly high risk to develop severe depressive symptoms. This has relevant clinical implications in terms of screening, management and prognosis of this patient population. 23147420 Implications of global climate change for the assessment and management of human health risks of chemicals in the natural environment. Global climate change (GCC) is likely to alter the degree of human exposure to pollutants and the response of human populations to these exposures, meaning that risks of pollutants could change in the future. The present study, therefore, explores how GCC might affect the different steps in the pathway from a chemical source in the environment through to impacts on human health and evaluates the implications for existing risk-assessment and management practices. In certain parts of the world, GCC is predicted to increase the level of exposure of many environmental pollutants due to direct and indirect effects on the use patterns and transport and fate of chemicals. Changes in human behavior will also affect how humans come into contact with contaminated air, water, and food. Dietary changes, psychosocial stress, and coexposure to stressors such as high temperatures are likely to increase the vulnerability of humans to chemicals. These changes are likely to have significant implications for current practices for chemical assessment. Assumptions used in current exposure-assessment models may no longer apply, and existing monitoring methods may not be robust enough to detect adverse episodic changes in exposures. Organizations responsible for the assessment and management of health risks of chemicals therefore need to be more proactive and consider the implications of GCC for their procedures and processes. 23775372 The sisters of mindfulness. This article introduces the issue of Journal of Clinical Psychology: In Session entitled "Beyond Meditation: Mindfulness-Related Clinical Practices." In the article, I describe how the "sisters of mindfulness"-forgiveness, gratitude, loving-kindness, compassion, acceptance, and best-self visualization-are each interconnected and important forms of mindfulness as well as tenets of Buddhist psychology. Each of these practices reflect mental strengths that are being integrated into the brain's neuroplastic development as a function of modern day psychotherapy. 23610058 Suppression of Epithelial to Mesenchymal Transitioning (EMT) Enhances Ex Vivo Reprogramming of Human Exocrine Pancreatic Tissue towards Functional Insulin Producing β-Like Cells. Due to the lack of tissue available for islet transplantation, new sources of β-cells have been sought for the treatment of type 1 diabetes. The aim of this study was to determine whether the human exocrid fraction from the islet isolation procedure could be reprogrammed to provide additional islet tissue for transplantation. The exocrine enriched cells rapidly dedifferentiated in culture and grew as a mesenchymal monolayer. Genetic lineage tracing confirmed that these mesenchymal cells arose in part through a process of epithelial to mesenchymal transitioning (EMT). A protocol was developed whereby transduction of these mesenchymal cells with adenoviruses containing Pdx1, Ngn3, MafA and Pax4 generated a population of cells that were enriched in glucagon-secreting α-like cells. Transdifferentiation or reprogramming towards insulin secreting β-cells was enhanced, however, when using unpassaged cells in combination with inhibition of EMT by inclusion of ROCK and TGF-β1 inhibitors. Resultant cells were able to secrete insulin in response to glucose and on transplantation, to normalise blood glucose levels in streptozotocin diabetic NOD/Scid mice. In conclusion, reprogramming of human exocrine enriched tissue can best be achieved using fresh material under conditions whereby EMT is inhibited. .rather than allowing the culture to expand as a mesenchymal monolayer. 23377117 Isolation of a flavonoid, apigenin 7-O-glucoside, from Mentha longifolia (L.) Hudson subspecies longifolia and its genotoxic potency. Mentha is a medicinal and aromatic plant belonging to the Lamiaceae family, which is widely used in food, flavor, cosmetic and pharmaceutical industries. Recently, it has been found that the use of Mentha as a pharmaceutical source is based on its phytochemical constituents that have far been identified as tannins, saponins, phenolic acids and flavonoids. This study was designed to evaluate the mutagenic and antimutagenic activities of apigenin 7-O-glucoside (A7G), a flavonoid isolated from Mentha longifolia (L.) Hudson subspecies longifolia (ML). The possible antimutagenic potential of A7G was examined against mutagens ethyl methanesulfonate and acridine in an eukaryotic cell system Saccharomyces cerevisiae and sodium azide in Salmonella typhimurium TA1535 and 9-aminoacridine in S. typhimurium TA1537. According to our findings, any concentrations of the A7G used did not show mutagenic activity but exerted strong antimutagenic activities at tested concentrations. The inhibition rates for the Ames test ranged from 27.2% (S. typhimurium TA1535: 0.4 μM/plate) to 91.1% (S. typhimurium TA1537: 0.2 μM/plate) and for the yeast deletion assay from 4% to 57.7%. This genotoxicological study suggests that a flavonoid from ML owing to antimutagenic properties is of great pharmacological importance and might be beneficial to industries producing food additives, cosmetics and pharmaceuticals products. 23578740 Medical error, disclosure and patient safety: A global view of quality care. Medical errors are a prominent issue in health care. Numerous studies point at the high prevalence of adverse events, many of which are preventable. Although there is a range of severity in errors, they all cause harm, to the patient, to the system, or both. While errors have many causes, including human interactions and system inadequacies, the focus on individuals rather than the system has led to an unsuitable culture for improving patient safety. Important areas of focus are diagnostic procedures and clinical laboratories because their results play a major role in guiding clinical decisions in patient management. Proper disclosure of medical errors and adverse events is also a key area for improvement. Globally, system improvements are beginning to take place, however, in Canada, policies on disclosure, error reporting and protection for physicians remain non-uniform. Achieving a national standard with mandatory reporting, in addition to a non-punitive system is recommended to move forward. 23137047 Reversible and cyclical transformations between solid and hollow nanostructures in confined reactions of manganese oxide and silica within nanosized spheres. Annealing of MnO@SiO(2) nanospheres in a reducing gas environment resulted in the transformation of the core-shell structure into a hollow structure as a result of outward diffusion of MnO species into the thermodynamically more stable silicate phase. When the hollow silicate nanospheres were oxidized, the interior cavities were refilled with a Mn(3)O(4) phase segregated from the silicate phase, and the hollow structure reverted to the initial core-shell structure. More interestingly, when catalytically active Pt nanocrystals were introduced into the manganese oxide/silica system, the Mn(3)O(4) was readily reduced to the chemically reactive MnO, even at low temperature, which enabled reconversion of the solid nanospheres with a Mn(3)O(4) core to hollow nanostructures during reductive annealing. Therefore, when MnO@SiO(2)/Pt(II) nanospheres were subjected to an oxidation/reduction cycle by repeatedly switching the flowing gas between air and hydrogen, the nanospheres underwent a reversible change between solid and hollow structures, depending on the gas environment. The solid-to-hollow-to-solid transformation was successfully cycled many times simply by repeatedly switching the flowing gas during annealing. 23713571 Greenhouse gas emissions and the interrelation of urban and forest sectors in reclaiming one hectare of land in the Pacific Northwest. The interrelation between urban areas and land use options for greenhouse gas mitigation was evaluated by assessing the utility of urban residuals for soil reclamation. Long-term impacts on soil C storage for mine lands restored with urban organic residuals were quantified by sampling historic sites reclaimed both conventionally and with residuals-based amendments. Use of amendments resulted in greater C storage compared to conventional practices for all sites sampled, with increases ranging from 14.2 Mg C ha(-1) in a coalmine in WA to 38.4 Mg C ha(-1) for a copper mine in British Columbia. Expressed as Mg C per Mg amendment, effective C increases ranged from 0.03 to 0.31 Mg C per Mg amendment. Results were applied to three alternative land-use scenarios to model the net GHG balance for a site restored to forest or low-density development. The model included construction of 3.9 243 m(2)-homes, typical of urban sprawl. Emissions for home and road construction and use over a 30-year period resulted in net emissions of 1269 Mg CO2. In contrast, conventional reclamation to forestland or reclamation with 100 Mg of residuals resulted in net GHG reductions of -293 and -475 Mg CO2. Construction of an equivalent number of smaller homes in an urban core coupled with restoration of 1 ha with amendments was close to carbon neutral. These results indicate that targeted use of urban residuals for forest reclamation, coupled with high-density development, can increase GHG mitigation across both sectors. 23585307 Fine Tuning of the Structure of Pt-Cu Alloy Nanocrystals by Glycine-Mediated Sequential Reduction Kinetics. Uniform Pt-Cu alloy nanocrystals in the shape of dendrite,, yolk-cage, and box structures are prepared via a facile wet-chemical reduction route in which glycine is demonstrated to alter the reduction kinetics of metal cations, critical to the morphology of the obtained product. These alloy nanocrystals exhibit superior specific activity and stability in the electro-oxidation of methanol. 23672990 Relation of elevated serum uric Acid levels to incidence of atrial fibrillation in patients with type 2 diabetes mellitus. The association between serum uric acid (SUA) levels and atrial fibrillation (AF) is currently poorly known. We examined the association between SUA levels and risk of incident AF in patients with type 2 diabetes mellitus. We followed for 10 years a random sample of 400 type 2 diabetic outpatients, who were free from AF at baseline. A standard 12-lead electrocardiography was undertaken annually and a diagnosis of incident AF was confirmed in affected participants by a single cardiologist. Over 10 years, there were 42 incident AF cases (cumulative incidence of 10.5%). Elevated SUA level was associated with an increased risk of incident AF (odds ratio 2.43, 95% confidence interval 1.8 to 3.4, p <0.0001 for each 1-SD increase in SUA level). Adjustments for age, gender, body mass index, hypertension, chronic kidney disease, electrocardiographic features (left ventricular hypertrophy and PR interval), and use of diuretics and allopurinol did not attenuate the association between SUA and incident AF (adjusted odds ratio 2.44, 95% confidence interval 1.6 to 3.9, p <0.0001). Further adjustment for variables that were included in the 10-year Framingham Heart Study-derived AF risk score did not appreciably weaken this association. Results remained unchanged even when SUA was modeled as a categorical variable (stratifying by either SUA median or hyperuricemia), and when patients with previous coronary heart disease or heart failure were excluded from analysis. In conclusion, our findings suggest that elevated SUA levels are strongly associated with an increased incidence of AF in patients with type 2 diabetes mellitus even after adjustment for multiple clinical risk factors for AF. 22370636 Conditional activation of Pik3ca(H1047R) in a knock-in mouse model promotes mammary tumorigenesis and emergence of mutations. Oncogenic mutations in PIK3CA, which encodes the phosphoinositide-3-kinase (PI3K) catalytic subunit p110α, occur in ∼25% of human breast cancers. In this study, we report the development of a knock-in mouse model for breast cancer where the endogenous Pik3ca allele was modified to allow tissue-specific conditional expression of a frequently found Pik3ca(H1047R) (Pik3ca(e20H1047R)) mutant allele. We found that activation of the latent Pik3ca(H1047R) allele resulted in breast tumors with multiple histological types. Whole-exome analysis of the Pik3ca(H1047R)-driven mammary tumors identified multiple mutations, including Trp53 mutations that appeared spontaneously during the development of adenocarinoma and spindle cell tumors. Further, we used this model to test the efficacy of GDC-0941, a PI3K inhibitor, in clinical development, and showed that the tumors respond to PI3K inhibition. 23706401 Visible-light-mediated Sr-Bi2O3 photocatalysis of tetracycline: Kinetics, mechanisms and toxicity assessment. Photodegradation of tetracycline (TC) was investigated in aqueous solution by visible-light-driven photocatalyst Sr-doped β-Bi2O3 (Sr-Bi2O3) prepared via solvothermal synthesis. The decomposition of TC by Sr-Bi2O3 under visible light (λ>420nm) irradiation followed pseudo-first-order kinetics, and the removal ratio reached 91.2% after 120min of irradiation. Sr-Bi2O3 photocatalysis is able to break the naphthol ring of TC which decomposes to m-cresol via dislodging hydroxyl group step by step by photogenerated electron. This mechanism was verified by electron spin resonance measurement, the addition of radical scavengers and the intermediate product analysis, indicating that the photogenerated electron acts as a reductant and can be the key to the degradation process. In contrast, in TiO2 photocatalysis the naphthol ring is broken via oxidation by hydroxyl radical, while in direct photolysis the ring remains intact. In addition, the toxicity of photodegradation products was analyzed by bioluminescence inhibition. After 120min of irradiation by Sr-Bi2O3, the toxicity decreases by 90.6%, which is more substantial than direct photolysis (70%) and TiO2 photocatalysis (80%), indicating that the Sr-Bi2O3 photocatalysis is more eco-friendly than the other two methods. 22144114 Cytologic findings of a clear cell parathyroid lesion. On fine-needle aspiration (FNA) biopsy, clear cell parathyroid lesions can be misdiagnosed as thyroid neoplasms, salivary gland neoplasms, paraganglioma, or even metastatic renal cell carcinoma. We report the clinicopathological, cytologic, and histologic findings of a clear cell parathyroid tumor in a 64-year-old HIV-positive patient. A computed tomography (CT) scan with contrast showed a heterogeneous and enhancing mass at the inferolateral aspect of the left thyroid lobe. FNA showed a cellular smear with many single and loosely clustered tumor cells with finely granular and vacuolated light-purple cytoplasm and central nuclei. Occasional microfollicular structures were noted. No colloid was seen. This FNA was misdiagnosed as a follicular neoplasm of the thyroid. Sections of the excised mass showed large polyhedral cells with well-defined cell membranes and clear cytoplasm with a small amount of eosinophilic granular material. These clear cells were positive for pancytokeratin and PTH immunohistochemical stains. These results favored a diagnosis of parathyroid Water Clear Cell Adenoma. This brief report highlights the cytologic findings of clear cell parathyroid lesions and their potential diagnostic pitfalls. Diagn. Cytopathol. 2013;41:725-728. © 2013 Wiley Periodicals, Inc. 23967952 The effects of working memory capacity and semantic cues on the intelligibility of speech in noise. This study examined how semantically related information facilitates the intelligibility of spoken sentences in the presence of masking sound, and how this facilitation is influenced by masker type and by individual differences in cognitive functioning. Dutch sentences were masked by stationary noise, fluctuating noise, or an interfering talker. Each sentence was preceded by a text cue; cues were either three words that were semantically related to the sentence or three unpronounceable nonwords. Speech reception thresholds were adaptively measured. Additional measures included working memory capacity (reading span and size comparison span), linguistic closure ability (text reception threshold), and delayed sentence recognition. Word cues facilitated speech perception in noise similarly for all masker types. Cue benefit was related to reading span performance when the masker was interfering speech, but not when other maskers were used, and it did not correlate with text reception threshold or size comparison span. Better reading span performance was furthermore associated with enhanced delayed recognition of sentences preceded by word relative to nonword cues, across masker types. The results suggest that working memory capacity is associated with release from informational masking by semantically related information, and additionally with the encoding, storage, or retrieval of speech content in memory. 23899091 The interplay between drug resistance and fitness in malaria parasites. Controlling the spread of antimalarial drug resistance, especially resistance of Plasmodium falciparum to artemisinin-based combination therapies, is a high priority. Available data indicate that, as with other microorganisms, the spread of drug-resistant malaria parasites is limited by fitness costs that frequently accompany resistance. Resistance-mediating polymorphisms in malaria parasites have been identified in putative drug transporters and in target enzymes. The impacts of these polymorphisms on parasite fitness have been characterized in vitro and in animal models. Additional insights have come from analyses of samples from clinical studies, both evaluating parasites under different selective pressures and determining the clinical consequences of infection with different parasites. With some exceptions, resistance-mediating polymorphisms lead to malaria parasites that, compared with wild type, grow less well in culture and in animals, and are replaced by wild type when drug pressure diminishes in the clinical setting. In some cases, the fitness costs of resistance may be offset by compensatory mutations that increase virulence or changes that enhance malaria transmission. However, not enough is known about effects of resistance mediators on parasite fitness. A better appreciation of the costs of fitness-mediating mutations will facilitate the development of optimal guidelines for the treatment and prevention of malaria. 23736685 The Greater Metropolitan Medical Alumni Council (GMMAC): The Realization of a Need. The greater New York metropolitan area includes 8 medical schools. Their alumni association (AA) presidents formed a council 6 years ago, meeting 3 times a year to share ideas and identify best practices to solve mutual problems challenging students and alumni. A survey of the 8 medical AAs was conducted; all responded, and the results constitute the data in this report. Mean AA membership was 2509 or 33% of mean alumni populations (7489). Two AAs conferred membership at graduation; hence, 100% of alumni were AA members. Omitting these 2 AAs reduced mean participation to 1722 or 23%. Alumni association support staff averaged 3.8 persons (range, 1-7 persons). The 2 most frequently cited AA challenges were membership and fund-raising. All AAs had annual or biennial reunions and considered the reunion to be a major commitment of resources. Despite this commitment, mean reunion attendance was only 242 alumni (range, 40-500 alumni) or 7.3% of alumni in anniversary years (5-year intervals). The mean number of alumni who contributed annually to their alma mater through its AA was 1936 alumni (range, 500-3500 alumni), or 26% (range, 5%-47%). Medical AAs reported mean assets of $2,755,000 (range, $6475-$11,000,000). The mean AA budget was $298,750, of which 65% (range, 13%-100%) was devoted to "medical student support". The most frequently cited student activities were "career night" (100%), "white coat ceremonies" (63%), medical equipment (stethoscopes, etc, 50%), and alumni host programs (38%). Eleven additional medical student activities received financial support from the 8 AAs in varying proportions. Each AA in the Greater Metropolitan Medical Alumni Council has derived significant benefit from the application of best practices to its individual problem set. In particular, a nascent AA developed significant momentum in its formation and development by its participation in the Greater Metropolitan Medical Alumni Council. Additionally, these data provide a foundation for the development of best practices within medical school AA for optimizing support of student programs and alumni participation. Stronger AAs will translate into enhanced support of educational programs for medical students. We urge formation of similar medical AA organizations in other metropolitan areas. 23618358 Transcriptional regulation of the alpha-1 type II collagen gene by nuclear factor κB/p65 and Sox9 in the chondrocytic phenotype of uterine carcinosarcomas. Uterine carcinosarcomas (U-CSs) are considered monoclonal in origin, but little is known about the mechanisms for establishment of heterologous sarcomatous components. Here, we examine the functional roles of nuclear factor κB (NF-κB)/p65 and Sox9 in the transcriptional regulation of alpha-1 type II collagen (COL2A1), a hallmark of chondrogenesis, during morphologic change in the direction of the chondrocytic phenotype. In 32 cases of U-CS, both phosphorylated p65 and Sox9 expression were colocalized in Col2A1-positive sarcomatous components, particularly in cartilaginous elements, with strongly positive correlation (ρ = 0.72, P = .005). A positive association of Col2A1 expression between protein (immunohistochemistry) and messenger RNA (in situ hybridization) assays was evident in sarcomatous components, whereas 9 cases also showed distinct positive signals for the messenger RNA without protein expression in carcinomatous elements, probably through a posttranscriptional and/or posttranslational modulation mechanism. In the Ishikawa endometrial cancer line, overexpression of p65 could activate transcription of COL2A1 promoter-intron reporters through binding to specific NF-κB sites in the first intron, along with up-regulation of Sox9. Exogenous induction of Sox9 also caused an increase in transcription of COL2A1, in contrast to a repression of the p65-mediated COL2A1 transcription, suggesting the existence of a negative feedback loop. These data, therefore, suggest that NF-κB/p65 signaling, as well as Sox9, may contribute to changes in the morphology of U-CS cells toward the chondrocytic phenotype through modulation of COL2A1 transcription. 23898862 A Modified Database Search Strategy Leads to Improved Identification of in Vitro Brominated Peptides Spiked into a Complex Proteomic Sample. Inflammation leads to activation of immune cells, resulting in production of hypobromous acid. Few investigations have been performed on protein bromination on a proteomic scale, even though bromination is a relatively abundant protein modification in endogenously brominated proteomes. Such studies have been hampered by the lack of an optimized database search strategy. In order to address this issue, we performed nano-LC-MS/MS analysis of an in vitro generated, trypsin-digested brominated human serum albumin standard, spiked into a complex trypsin-digested proteomic background, in an LTQ-Orbitrap instrument. We found that brominated peptides spiked in at a 1-10% ratio (mass:mass) were easily identified by manual inspection when higher-energy collisional dissociation (HCD) and collision induced dissociation (CID) were employed as the dissociation mode; however, confident assignment of brominated peptides from protein database searches required a novel approach. By addition of a custom modification, corresponding to the substitution of a single bromine with (81)Br rather than (79)Br for dibromotyrosine ((79)Br(81)BrY), the number of validated assignments for peptides containing dibromotyrosine increased significantly when analyzing both high resolution and low resolution MS/MS data. This new approach will facilitate the identification of proteins derived from endogenously brominated proteomes, providing further knowledge about the role of protein bromination in various pathological states. 23644566 Seasonal synchronicity of algal assemblages in three Midwestern agricultural streams having varying concentrations of atrazine, nutrients, and sediment. Numerous studies characterizing the potential effects of atrazine on algal assemblages have been conducted using micro- or mesocosms; however, few evaluations focused on in situ lotic algal communities, potentially confounding risk assessment conclusions. This exploratory study, conducted at several sites in the midwestern United States where atrazine is commonly used, presents in situ observations of native algal communities relative to atrazine exposure and other parameters. Planktonic and periphytic algae from three streams in three Midwestern states, having historically differing atrazine levels, were sampled over a 16-week period in 2011 encompassing atrazine applications and the summer algal growth period at each site. Changes in abundance, diversity, and composition of algal communities were placed in the context of hydrological, climatic, and water quality parameters (including components sometimes present in agricultural runoff) also collected during the study. Diatoms dominated communities at each of the three sites and periphyton was much more abundant than phytoplankton. As expected, significant variations in algal community and environmental parameters were observed between sites. However, correspondence analysis plots revealed that patterns of temporal variation in algal communities at each site and in periphyton or phytoplankton were dominated by seasonal environmental gradients. Significant concordance in these seasonal patterns was detected among sites and between phytoplankton and periphyton communities (via procrustes Protest analysis), suggesting synchronicity of algal communities across a regional scale. While atrazine concentrations generally exhibited seasonal trends at the study watersheds; no effects on algal abundance, diversity or assemblage structure were observed as a result of atrazine pulses. This lack of response may be due to exposure events of insufficient concentration or duration (consistent with previously reported results) or the composition of the algal assemblages present. This was in contrast to the effects of elevated flow events, which were associated with significant changes in periphyton abundance, diversity and assemblage. 23945217 Stability properties of PrP(Sc) from cattle with experimental transmissible spongiform encephalopathies: use of a rapid whole homogenate, protease-free assay. Transmissible Spongiform Encephalopathies (TSEs), including scrapie in sheep, chronic wasting disease (CWD) in cervids, transmissible mink encephalopathy (TME), and bovine spongiform encephalopathy (BSE), are fatal diseases of the nervous system associated with accumulation of misfolded prion protein (PrP(Sc)). Different strains of TSEs exist, associated with different PrP(Sc) conformations that can be probed by the stability assay, in which PrP(Sc) is treated with increasing concentrations of the denaturant guanidine hydrochloride (GdnHCl). Here, we provide the first comprehensive application of a rapid, protease-free version of the GdnHCl stability assay to brain tissue from cattle experimentally infected with various TSE isolates. Consistent with previous findings from a single Japanese isolate, the L-type isolates of BSE are not distinguishable from classical BSE in this assay. In contrast, H-type isolates of BSE, including our unique isolate of E211K BSE, exhibit higher stability than classical BSE, suggesting that its increased protection against protease digestion at the BSE N-terminus is associated with a higher stability in GdnHCl. While the difference in stability in our version of the assay is likely not large enough for effective use in a diagnostic laboratory setting, the use of alternative experimental conditions may enhance this effect. TSEs from other natural host species that have been passaged in cattle, including CWD and TME, were not distinguishable from classical BSE, while isolates of cattle passaged scrapie exhibited a slight increase in stability as compared to classical BSE. These results suggest that the core of PrP(Sc), as probed in this assay, has similar stability properties among cattle-passaged TSE isolates and that the conformational differences that lead to changes in the proteinase K cleavage site do not cause large changes in the stability of PrP(Sc) from TSE-affected cattle. However, the stability differences observed here will provide a basis of comparison for new isolates of atypical BSE observed in the future and in other geographic locations, especially in the case of H-type BSE. 23850948 Evaluation of Luminex xTAG Gastrointestinal Pathogen Analyte-Specific Reagents for High-Throughput, Simultaneous Detection of Bacteria, Viruses, and Parasites of Clinical and Public Health Importance. Acute diarrheal disease (ADD) can be caused by a range of pathogens, including bacteria, viruses, and parasites. Conventional diagnostic methods, such as culture, microscopy, biochemical assays, and enzyme-linked immunosorbent assays (ELISA), are laborious and time-consuming and lack sensitivity. Combined, the array of tests performed on a single specimen can increase the turnaround time (TAT) significantly. We validated a 19plex laboratory-developed gastrointestinal pathogen panel (GPP) using Luminex xTAG analyte-specific reagents (ASRs) to simultaneously screen directly in fecal specimens for diarrhea-causing pathogens, including bacteria (Campylobacter jejuni, Salmonella spp., Shigella spp., enterotoxigenic Escherichia coli [ETEC], Shiga toxin-producing E. coli [STEC], E. coli O157:H7, Vibrio cholerae, Yersinia enterocolitica, and toxigenic Clostridium difficile), parasites (Giardia lamblia, Cryptosporidium spp., and Entamoeba histolytica), and viruses (norovirus GI and GII, adenovirus 40/41, and rotavirus A). Performance characteristics of GPP ASRs were determined using 48 reference isolates and 254 clinical specimens. Stool specimens from individuals with diarrhea were tested for pathogens using conventional and molecular methods. Using the predictive methods as standards, the sensitivities of the GPP ASRs were 100% for adenovirus 40/41, norovirus, rotavirus A, Vibrio cholerae, Yersinia enterocolitica, Entamoeba histolytica, Cryptosporidium spp., and E. coli O157:H7; 95% for Giardia lamblia; 94% for ETEC and STEC; 93% for Shigella spp.; 92% for Salmonella spp.; 91% for C. difficile A/B toxins; and 90% for Campylobacter jejuni. The overall comparative performance of the GPP ASRs with conventional methods in clinical samples was 94.5% (range, 90% to 97%), with 99% (99.0% to 99.9%) specificity. Implementation of the GPP ASRs enables our public health laboratory to offer highly sensitive and specific screening and identification of the major ADD-causing pathogens. 23648794 Temperature sensitivity of cellulase adsorption on lignin and its impact on enzymatic hydrolysis of lignocellulosic biomass. Unproductive enzyme adsorption is an important factor in addition to steric hindrance of lignin that limits the enzymatic hydrolysis of lignocellulosic biomass. While both are important factors, enzymatic hydrolysis of pretreated biomass is most likely conducted in the presence of certain amount of lignin residues that may not necessarily present accessibility hindrance, but can competitively absorb the enzyme. This paper presents a study with purified lignin samples to elucidate the role of unproductive enzyme adsorption. It appeared that lignin adsorbed cellulase quickly at 4 °C with adsorption equilibrium reached within 1h, similar to that observed for crystalline cellulose. Increasing temperature to 50 °C (typical hydrolytic reaction condition) facilitated the rate of cellulase adsorption on cellulose with a peak of adsorption reached at 0.25 h; however, adsorption on lignin was surprisingly slower and took over 12h to reach equilibrium, which was accompanied with a 10-fold increase in adsorption capacity. Despite the high adsorption capacity of lignin (which is comparable to that of cellulose) at 50 °C, the presence of added lignin imposed only minimal impact on the enzyme apparent activity, most likely due to the slow adsorption kinetics of lignin. 23599311 Using ultradeep pyrosequencing to study HIV-1 coreceptor usage in primary and dual infection. HIV-1 dual infection (DI) and CXCR4 (X4) coreceptor usage are associated with accelerated disease progression but frequency and dynamics of coreceptor usage during DI is unknown. Ultradeep sequencing was used to interrogate for DI and infer coreceptor usage in longitudinal blood samples of 102 subjects. At baseline, X4 usage was high (23 subjects harbored X4 variants) and was not associated with infection duration or DI. Coreceptor usage changed over time in 12 of 47 participants, and X4 usage emerged in 4 of 41 monoinfections vs 2 of 5 superinfections (P = .12), suggesting a weak statistical trend toward occurrence of superinfection and acquiring X4 usage. 23934057 GIS as a Community Engagement Tool: Developing a Plan to Reduce Infant Mortality Risk Factors. This article describes how a community coalition focusing on maternal and child health engages community participation through the use of geographic information systems (GIS) mapping, developing strategies that culminate in the implementation of a service delivery plan to improve birth outcomes. Vital statistics data from 2007 to 2009 was analyzed by zip code in Pinellas County Florida to produce choropleth thematic maps using ArcGIS for 3 year rolling average infant deaths and single year percentages for prematurity. The maps were presented at the organization's annual coalition meeting to discuss risk areas, changes over time in the selected indicators and solicit community feedback on how to best target issues addressing infant mortality and prematurity. The maps identified new zip codes of concern for prematurity in addition to known high risk zip codes for both infant mortality and prematurity. The community identified changes in demographic composition and changes in housing patterns, such as new mobile home areas, in the high risk areas. In response, the community assisted the Coalition in developing a holistic plan addressing risk factors affecting birth outcomes by expanding current services, hiring a nutritionist, and contracting a health navigator. When compared to tables and charts, a visual depiction of a neighborhood by recognizable zip codes is a useful tool to help community decision makers better visualize public health concerns and interpret trends based on local knowledge. Public health professionals should use this community knowledge to interpret research results and implement strategies to improve birth outcomes. 22964353 Single surgical procedure combining epicardial pacemaker implantation and subsequent extraction of the infected pacing system for pacemaker-dependent patients. Management of pacemaker infection in pacing-dependent patients is often challenging. Typically, temporary pacing is used while antibiotic therapy is given for a number of days before reimplantation of a new endocardial system. This results in a prolonged hospital stay and complications associated with temporary pacing. In this study, we examine the feasibility of performing a single combined procedure of epicardial pacemaker implantation followed by system extraction. One hundred consecutive infected pacemaker-dependent patients underwent implantation of 2 epicardial ventricular leads and were converted to a ventricular demand pacing system. The infected pacing system was then extracted during the same procedure. Patients were followed up for 12 months. Significant pericardial bleeding developed during the procedure in 3 patients. The presence of the pericardial drain positioned during the implantation of the epicardial pacing system meant that cardiac tamponade did not occur, allowing surgical repair with sternotomy to be carried out under stable hemodynamic conditions. Two of these 100 patients died in the 30-day postoperative period; 1 death was due to septic shock and 1 to pulmonary distress. Median 1-year epicardial pacing thresholds were stable and excellent (1.4 ± 0.9 volts). However, 1 of the 2 leads developed increased thresholds in 6 patients, which led to the exclusive use of other ventricular lead. A single combined procedure of surgical epicardial pacemaker implantation and pacemaker system extraction appears to be a safe and effective method for managing pacemaker-dependent patients with infected pacemakers. 23966304 The outcome of patients with renal involvement in pediatric-onset systemic lupus erythematosus - a 20-year experience in Asia. Systemic lupus erythematosus (SLE) predominantly affects women of childbearing age, but 15-20% of cases are diagnosed during childhood. It is important for physicians to understand the epidemiology and clinical presentation for early detection and diagnosis of this disease in difference races. The aim of this retrospective review was to provide a 20-year experience for initial clinical and laboratory manifestations and outcomes in pediatric-onset SLE (pSLE) in a medical center in Asia. We reviewed medical records between April 1990 and June 2012 of patients with a diagnosis of International Classification of Diseases, Ninth Revision (ICD-9) code 710.0 (SLE), who admitted or received follow-up in the Department of Pediatrics at Chang Chung Memorial Hospital. Patients with a diagnosis of SLE prior to their 18th birthday and followed up at our hospital were eligible for inclusion in this study. Medical records regarding age, gender, date of birth and diagnosis, clinical manifestations at diagnosis, laboratory results, image studies and the classification criteria were reviewed. Patients received regular outpatient department follow-up and laboratory survey every 1-6 months. The study cohort consisted of 189 patients; 164 females (86.87%) and 25 males (13.23%). The overall mean age at pSLE diagnosis was 12.62 ± 2.77 years. The most common clinical symptom was malar rash, followed by arthritis and oral ulcers. There was no significant difference in clinical and laboratory manifestations between females and males. More than half of the patients presented with renal involvement initially. The most common histological finding was Class IV lupus nephritis (LN), especially in males (p = 0.034) and young age. Even with severe LN, the rate of end-stage renal disease (ESRD) was low if adequate treatment was initiated. The 5, 10 and 15-year ESRD-free survival rates were 95.4%, 94.0% and 89.9% in patients with biopsy-proven LN. However, infection was the leading cause of mortality. Therefore, aggressive treatment for major organ involvement is important, but physicians must also be aware of fatal infection. The overall survival rates were 5 years: 93.4% and 10-20 years: 89.6%. 23774003 2-[(18)F]Fluoroethanol and 3-[(18)F]fluoropropanol: facile preparation, biodistribution in mice, and their application as nucleophiles in the synthesis of [(18)F]fluoroalkyl aryl ester and ether PET tracers. 2-[(18)F]Fluoroethoxy and 3-[(18)F]fluoropropoxy groups are common moieties in the structures of radiotracers used with positron emission tomography. The objectives of this study were (1) to develop an efficient one-step method for the preparation of 2-[(18)F]fluoroethanol (2-[(18)F]FEtOH) and 3-[(18)F]fluoropropanol (3-[(18)F]FPrOH); (2) to demonstrate the feasibility of using 2-[(18)F]FEtOH as a nucleophile for the synthesis of 2-[(18)F]fluoroethyl aryl esters and ethers; and (3) to determine the biodistribution profiles of 2-[(18)F]FEtOH and 3-[(18)F]FPrOH in mice. 2-[(18)F]FEtOH and 3-[(18)F]FPrOH were prepared by reacting n-Bu4N[(18)F]F with ethylene carbonate and 1,3-dioxan-2-one, respectively, in diethylene glycol at 165°C and purified by distillation. 2-[(18)F]fluoroethyl 4-fluorobenzoate and 1-(2-[(18)F]fluoroethoxy)-4-nitrobenzene were prepared by coupling 2-[(18)F]FEtOH with 4-fluorobenzoyl chloride and 1-fluoro-4-nitrobenzene, respectively. Biodistribution and PET/CT imaging studies of 2-[(18)F]FEtOH and 3-[(18)F]FPrOH were performed in normal female Balb/C mice. The preparation of 2-[(18)F]FEtOH and 3-[(18)F]FPrOH took 60min, and their decay-corrected yields were 88.6±2.0% (n=9) and 65.6±10.2% (n=5), respectively. The decay-corrected yields for the preparation of 2-[(18)F]fluoroethyl 4-fluorobenzoate and 1-(2-[(18)F]fluoroethoxy)-4-nitrobenzene were 36.1±5.4% (n=3) and 27.7±10.7% (n=3), respectively. Imaging/biodistribution studies in mice using 2-[(18)F]FEtOH showed high initial radioactivity accumulation in all major organs followed by very slow clearance. On the contrary, by using 3-[(18)F]FPrOH, radioactivity accumulated in all major organs was cleared rapidly, but massive in vivo defluorination (31.3±9.57%ID/g in bone at 1h post-injection) was observed. Using 2-[(18)F]FEtOH/3-[(18)F]FPrOH as a nucleophile is a competitive new strategy for the synthesis of 2-[(18)F]fluoroethyl/3-[(18)F]fluoropropyl aryl esters and ethers. Our biodistribution data emphasize the importance of in vivo stability of PET tracers containing a 2-[(18)F]fluoroethyl or 3-[(18)F]fluoropropyl group due to high background and high bone uptake resulting from 2-[(18)F]FEtOH and 3-[(18)F]FPrOH, respectively. This is especially important for their aryl ester derivatives which are prone to in vivo hydrolysis. 23376440 Sodium arsenite induces cyclooxygenase-2 expression in human uroepithelial cells through MAPK pathway activation and reactive oxygen species induction. Arsenic can induce reactive oxygen species (ROS) leading to oxidative stress and carcinogenesis. Bladder is one of the major target organs of arsenic, and cyclooxygenase-2 (COX-2) may play an important role in arsenic-induced bladder cancer. However, the mechanism by which arsenic induces COX-2 in bladder cells remains unclear. This study aimed at investigating arsenic-mediated intracellular redox status and signaling cascades leading to COX-2 induction in human uroepithelial cells (SV-HUC-1). SV-HUC-1 cells were exposed to sodium arsenite and COX-2 expression, mitogen-activated protein kinase (MAPK) phosphorylation, glutathione (GSH) levels, ROS induction and Nrf2 expression were quantified. Our results demonstrate that arsenite (1-10 μM) elevates COX-2 expression, GSH levels, ROS and Nrf2 expression. Arsenite treatment for 24h stimulates phosphorylation of ERK and p38, but not JNK in SV-HUC-1 cells. Induction of Cox-2 mRNA levels by arsenite was attenuated by inhibitors of ERK, p38 and JNK. Arsenite-induced ROS generation and COX-2 expression were significantly attenuated by treatment with melatonin (a ROS scavenger), but enhanced by DL-buthionine-(S, R)-sulfoximine (BSO, an inhibitor of gamma-glutamylcysteine synthetase (γ-GCS) resulting in lower GSH and increased ROS levels). These data indicate that arsenite promotes an induction of ROS, which results in an induction of COX-2 expression through activation of the MAPK pathway. 22614096 Adiposity to muscle ratio predicts incident physical limitation in a cohort of 3,153 older adults-an alternative measurement of sarcopenia and sarcopenic obesity. Conventionally, sarcopenia is defined by muscle mass and physical performance. We hypothesized that the disability caused by sarcopenia and sarcopenic obesity was related to the amount of adiposity or body weight bearing on a unit of muscle mass, or the adiposity to muscle ratio. We therefore examined whether this ratio could predict physical limitation by secondary analysis of the data in our previous study. We recruited 3,153 community-dwelling adults aged >65 years and their body composition was measured by dual-energy X-ray absorptiometry. Assessment of physical limitation was undertaken 4 years later. The relationship between baseline adiposity to muscle ratio and incident physical limitation was examined by logistic regression. In men, the adiposity to muscle ratios, namely total body fat to lower-limb muscle mass, total body fat to fat-free mass (FFM), and body weight to FFM, were predictive of physical limitation before and after adjustment for the covariates: age, Mini-mental Status Examination score, Geriatric Depression Scale score >8, and the diagnosis of chronic obstructive pulmonary disease, diabetes mellitus, hypertension, heart disease, and stroke (all p values < 0.001), when the total body fat to lower-limb muscle mass ratio was greater than or equal to 0.75. In women, throughout the entire range of that ratio, all three adiposity to muscle ratios were associated with physical limitation 4 years later both before and after adjustment for the same set of covariates (all p values < 0.05). Sarcopenia and sarcopenic obesity as measured by the body weight or adiposity bearing on a unit of muscle mass (the adiposity to muscle ratio) could predict incident or worsening physical limitation in older women across the entire range of the total body fat to lower-limb muscle mass ratio; and in older men when this ratio was equal to or greater than 0.75. 23886027 A randomized double blind placebo controlled clinical trial of N-Acetylcysteine added to risperidone for treating autistic disorders. This study examined the efficacy and safety of N-acetylcysteine (NAC) augmentation for treating irritability in children and adolescents with autism spectrum disorders (ASD). Forty children and adolescents met diagnostic criteria for ASD according to DSM-IV. They were randomly allocated into one of the two groups of NAC (1200 mg/day)+risperidone or placebo+risperidone. NAC and placebo were administered in the form of effervescent and in two divided doses for 8 weeks. Irritability subscale score of Aberrant Behavior Checklist (ABC) was considered as the main outcome measure. Adverse effects were also checked. The mean score of irritability in the NAC+risperidone and placebo+risperidone groups at baseline was 13.2(5.3) and 16.7(7.8), respectively. The scores after 8 weeks were 9.7(4.1) and 15.1(7.8), respectively. Repeated measures of ANOVA showed that there was a significant difference between the two groups after 8 weeks. The most common adverse effects in the NAC+risperidone group were constipation (16.1%), increased appetite (16.1%), fatigue (12.9%), nervousness (12.9%), and daytime drowsiness (12.9%). There was no fatal adverse effect. Risperidone plus NAC more than risperidone plus placebo decreased irritability in children and adolescents with ASD. Meanwhile, it did not change the core symptoms of autism. Adverse effects were not common and NAC was generally tolerated well. This trial was registered at http://www.irct.ir. The registration number of this trial was IRCT201106103930N6. 23790088 Baseline neurocognitive scores in athletes with attention deficit-spectrum disorders and/or learning disability. Object Up to 16% of children in the US between the ages of 3 and 17 years have either attention deficit-spectrum disorder or a learning disability (LD). Sports-related concussions among youth athletes represent a significant public health concern, and neurocognitive testing is a method to evaluate the severity of cognitive impairment and recovery after a sports-related concussion. The goal of this study was to assess baseline neurocognitive differences between athletes with attention deficit hyperactivity disorder (ADHD) and/or LD versus those with neither disorder and to establish normative data for these special populations. Methods Between August 2007 and March 2012, 6636 young athletes underwent baseline neurocognitive testing performed using the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) battery. Of these participants, 90 had self-reported LD only, 262 had self-reported ADHD only, and 55 reported both. Those with ADHD and/or LD were matched with 407 participants with no history of ADHD or LD by age, sex, and number of prior concussions. The mean scores and SDs were calculated for each group to obtain normative values. A pairwise comparison between each diagnostic group was done to assess whether LD and/or ADHD diagnostic status predicted participants' baseline neurocognitive scores. Results Participants with ADHD had significantly lower verbal memory, visual memory, and visual motor processing speed scores, along with significantly higher reaction time, impulse control, and symptom scores compared with those without LD or ADHD. Participants with LD had similar results, with significantly lower verbal memory, visual memory, and visual motor processing speed scores, higher reaction time and symptom score, but did not differ in their impulse control score compared with those without LD or ADHD. Participants with both LD and ADHD had a significantly lower visual motor speed score and a significantly higher reaction time and symptom score than those without LD or ADHD, but did not differ with regard to the other composite scores. Conclusions Athletes with ADHD and/or LD have lower baseline ImPACT neurocognitive scores compared with athletes without ADHD and LD. Preliminary normative neurocognitive data for these special populations are provided. 23841713 The role of adipocytes in the modulation of iron metabolism in obesity. A tight relationship between iron deficiency and obesity is known to exist. The chronic low-grade inflammation that characterizes obesity enhances hepcidin production, the principal regulator of iron availability. Adipose tissue is known to secret interleukin-6 and leptin that triggers hepcidin production. It was found that adipose tissue also expresses hepcidin and hemojuvelin, a regulator of hepcidin production. These recent findings suggest that adipose tissue may have an important role in erythropoiesis particularly on obesity that is still poorly clarified. This paper discusses these findings and how they can modulate erythropoiesis. 23100128 Automatically extracting sentences from Medline citations to support clinicians' information needs. Online health knowledge resources contain answers to most of the information needs raised by clinicians in the course of care. However, significant barriers limit the use of these resources for decision-making, especially clinicians' lack of time. In this study we assessed the feasibility of automatically generating knowledge summaries for a particular clinical topic composed of relevant sentences extracted from Medline citations. The proposed approach combines information retrieval and semantic information extraction techniques to identify relevant sentences from Medline abstracts. We assessed this approach in two case studies on the treatment alternatives for depression and Alzheimer's disease. A total of 515 of 564 (91.3%) sentences retrieved in the two case studies were relevant to the topic of interest. About one-third of the relevant sentences described factual knowledge or a study conclusion that can be used for supporting information needs at the point of care. The high rate of relevant sentences is desirable, given that clinicians' lack of time is one of the main barriers to using knowledge resources at the point of care. Sentence rank was not significantly associated with relevancy, possibly due to most sentences being highly relevant. Sentences located closer to the end of the abstract and sentences with treatment and comparative predications were likely to be conclusive sentences. Our proposed technical approach to helping clinicians meet their information needs is promising. The approach can be extended for other knowledge resources and information need types. 23523547 Towards the bioequivalence of pressurised metered dose inhalers 1: Design and characterisation of aerodynamically equivalent beclomethasone dipropionate inhalers with and without glycerol as a non-volatile excipient. A series of semi-empirical equations were utilised to design two solution based pressurised metered dose inhaler (pMDI) formulations, with equivalent aerosol performance but different physicochemical properties. Both inhaler formulations contained the drug, beclomethasone dipropionate (BDP), a volatile mixture of ethanol co-solvent and propellant (hydrofluoroalkane-HFA). However, one formulation was designed such that the emitted aerosol particles contained BDP and glycerol, a common inhalation particle modifying excipient, in a 1:1 mass ratio. By modifying the formulation parameters, including actuator orifice, HFA and metering volumes, it was possible to produce two formulations (glycerol-free and glycerol-containing) which had identical mass median aerodynamic diameters (2.4μm±0.1 and 2.5μm±0.2), fine particle dose (⩽5μm; 66μg±6 and 68μg±2) and fine particle fractions (28%±2% and 30%±1%), respectively. These observations demonstrate that it is possible to engineer formulations that generate aerosol particles with very different compositions to have similar emitted dose and in vitro deposition profiles, thus making them equivalent in terms of aerosol performance. Analysis of the physicochemical properties of each formulation identified significant differences in terms of morphology, thermal properties and drug dissolution of emitted particles. The particles produced from both formulations were amorphous; however, the formulation containing glycerol generated particles with a porous structure, while the glycerol-free formulation generated particles with a primarily spherical morphology. Furthermore, the glycerol-containing particles had a significantly lower dissolution rate (7.8%±2.1%, over 180min) compared to the glycerol-free particles (58.0%±2.9%, over 60min) when measured using a Franz diffusion cell. It is hypothesised that the presence of glycerol in the emitted aerosol particles altered solubility and drug transport, which may have implications for BDP pharmacokinetics after deposition in the respiratory tract. 23944253 Regulation of ATP-Gated P2X Channels: From Redox Signaling to Interactions with Other Proteins. Significance: The family of purinergic P2X receptors (P2XR) is part of ligand-gated superfamily of channels activated by extracellular ATP. P2XRs are present in virtually all mammalian tissues as well as in tissues of other vertebrate and nonvertebrate species and mediate a large variety of functions, including fast transmission at central synapses, contraction of smooth muscle cells, platelet aggregation, and macrophage activation to proliferation and cell death. Recent advances: The recent solving of crystal structure of the zebrafish P2X4.1R is a major advance in understanding of structural correlates of channel activation and regulation. Combined with growing information obtained in the post-structure era and the reinterpretation of previous work within the context of the tridimensional structure, these data provide a better understanding of how the channel operates at the molecular levels. Critical Issues: This review focuses on the relationship between redox signaling and P2XR function. We also discuss other allosteric modulation of P2XR gating in the physiological/pathophysiological context. This includes the summary of extracellular actions of trace metals, which can be released to the synaptic cleft, pH decrease that happens during ischemia and inflammation, and calcium, an extracellular and intracellular messenger. Future directions: Our evolving understanding of activation and regulation of P2XRs is helpful in clarifying the mechanism by which these channels trigger and modulate cellular functions. Further research is required to identify the signaling pathways contributing to the regulation of the receptor activity and to develop novel and receptor-specific allosteric modulators, which could be used in in vivo with therapeutic potential. 23943852 Gene expression signatures but not cell cycle checkpoint functions distinguish AT carriers from normal individuals. Ataxia telangiectasia (AT) is a rare autosomal recessive disease caused by mutations in the ataxia telangiectasia-mutated gene (ATM). AT carriers with one mutant ATM allele are usually not severely affected although they carry increased risk of cancer. There has not been an easy and reliable diagnostic method to identify AT carriers. Cell cycle checkpoint functions upon ionizing radiation (IR)-induced DNA damage and gene expression signatures were analyzed in the current study to test for differential responses in human lymphoblastoid cell lines with different ATM genotypes. While both dose- and time-dependent G1 and G2 checkpoint functions were highly attenuated in ATM-/- cell lines, these functions were preserved in ATM+/- cell lines equivalent to ATM+/+ cell lines. However, gene expression signatures at both baseline (consisting of 203 probes) and post-IR treatment (consisting of 126 probes) were able to distinguish ATM+/- cell lines from ATM+/+ and ATM-/- cell lines. Gene ontology (GO) and pathway analysis of the genes in the baseline signature indicated that ATM function-related categories, DNA metabolism, cell cycle, cell death control and the p53 signaling pathway, were over-represented. The same analyses of the genes in the IR-responsive signature revealed that biological categories including response to DNA damage stimulus, p53 signaling and cell cycle pathways were over-represented, which again confirmed involvement of ATM functions. The results indicate that AT carriers who have unaffected G1 and G2 checkpoint functions can be distinguished from normal individuals and AT patients by expression signatures of genes related to ATM functions. 23899383 Impact of injection solvents on supercritical fluid chromatography. Even though there has been a rapid development in instrumentation and applications of supercritical fluid chromatography (SFC), relatively little is known about retention mechanisms compared to high-performance liquid chromatography (HPLC). Much effort has been made to characterize the influence of injection solvents on chromatographic efficiency in HPLC, however has been left rather uninvestigated in the domain of SFC. In this study properties of different injection solvents have been studied and correlated with properties of seven various analytes on three different columns, a C18, a 2-ethylpyridine and a bare-silica column. Aided by calculations of correlation coefficients and principal component analysis (PCA), the physical properties of injection solvents and the interactions between injection solvent, solute and stationary phase were investigated. The findings of this work shows that interactions capable of masking accessible silanol groups on a C18 column are of importance in order to maximize the plate number. While solvents with dipolar and hydrogen bond interaction properties are associated negatively with chromatographic efficiency using polar columns. Properties such as molar density, vapor pressure and boiling point were related to sharper peaks, mostly likely because of solubility issues of the injection solvent into the methanol-modified carbon dioxide. However, no additional solubility due to hydrogen interactions between the injection solvent and the carbon dioxide in SFC was observed. Surface tension and viscosity was not particularly associated with a decrease in plate numbers. By increasing the injection volume a stronger correlation between solubility related properties and plate numbers were obtained. Additional experiments showed that the resistance in solubility became an issue when performing partial-loop injection where additional washing solvent entered the system, thus providing broadened peaks. 23665383 Molecular mechanisms of reactive oxygen species-related pulmonary inflammation and asthma. Asthma is a highly relevant disorder that can be induced by many environmental factors such as allergens and pollutants. One of the most critical pathological symptoms of asthma is airway inflammation. In order to identify a cause of respiratory inflammation, we thoroughly examine the unique role of reactive oxygen species (ROS). Evidence supports that the inhalation of aggravating compounds such as allergens can promote the increased generation of ROS. Accordingly, ROS have a proven role in the cellular signaling cascades of many respiratory diseases that cause respiratory inflammation, including asthma. Although there is no known cure for asthma, current treatments effectively lessen the inflammation symptom. Based on the investigations of asthma pathogenesis and the mechanism of ROS formation, we have identified several novel anti-inflammatory therapeutic treatments, shedding light on a fundamental understanding for the cure of this disorder. In this review, we will outline the pathogenesis of asthma and its relationship to ROS, oxidative stress, and pulmonary inflammation. 23344461 Photosensitizing agents and the risk of non-melanoma skin cancer: a population-based case-control study. It is well-known that UV light exposure and a sun-sensitive phenotype are risk factors for the development of non-melanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). In this New Hampshire population-based case-control study, we collected data from 5,072 individuals, including histologically confirmed cases of BCC and SCC, and controls via a personal interview to investigate possible associations between photosensitizing medication use and NMSC. After adjustment for potentially confounding factors (e.g., lifetime number of painful sunburns), we found a modest increase in risk of SCC (odds ratio (OR)=1.2, 95% confidence interval (CI)=1.0-1.4) and BCC (OR=1.2, 95% CI=0.9-1.5), in particular early-onset BCC, (50 years of age) (OR=1.5, 95% CI=1.1-2.1) associated with photosensitizing medication use. For SCC the association was strongest among those with tendency to sunburn rather than tan. We also specifically found associations with BCC, and especially early-onset BCC, and photosensitizing antimicrobials. In conclusion, certain commonly prescribed photosensitizing medications may enhance the risk of developing SCC, especially in individuals with a sun-sensitive phenotype, and may increase the risk of developing BCC and incidence of BCC at a younger age. 23673418 Understanding the relationship of performance with nanofiller content in the biomimetic layered nanocomposites. Montmorillonite/poly(vinyl alcohol) (MMT/PVA) nanocomposites spanning the complete range of MMT content (0-100 wt%) are prepared by simple evaporation-induced assembly. Effects of MMT content on the structure and mechanical properties of nanocomposites are systematically investigated and exhibit two important transitions at MMT contents of 30 wt% and 70 wt%. In the range of 0-30 wt%, the nanocomposites show a random structure. With the content of PVA increasing, the mechanical properties of the resultant nanocomposites were dramatically enhanced and were higher than that by prediction according to the conventional composite model. In the range of 30-70 wt%, the nanocomposites show a nacre-like layered structure with alternating MMT platelets and PVA layers, and all PVA is completely restricted by MMT platelets. The mechanical properties of nanocomposites were further improved by increasing the content of MMT, and reached the maximum value at the MMT content of 70 wt%. The 70 wt% MMT/PVA nanocomposite has a tensile strength of 219 ± 19 MPa, which is 5.5 times higher than that of a pure PVA film and surpasses nacre and reported biomimetic layered clay/PVA composites. When the MMT content is higher than 70 wt%, the layered structure is transformed to tactoids, which deteriorate mechanical properties. These results offer comprehensive understanding for developing high-performance biomimetic layered nanocomposite materials with high nanofiller loading. 23519949 Personal, professional, and work factors associated with Australian clinical medical practitioners' experiences of workplace aggression. This study examined the extent to which a range of personal, professional, and work factors are associated with workplace aggression experienced by medical practitioners in Australian clinical practice settings. An exploratory, descriptive study of cross-sectional, self-report survey design was undertaken in the third wave of the Medicine in Australia: Balancing Employment and Life survey during 2010-2011. Of 16 327 medical practitioners sampled, 9951 (60.9%) responded and 9449 (57.9%) worked in clinical practice. Logistic regression was undertaken to detect statistically significant associations between a suite of personal, professional, and work variables and eight binary outcome variables measuring exposure to verbal or written and physical aggression from patients, patients' relatives or carers, co-workers and others external to the workplace during the previous year. Age was consistently negatively associated and external control orientation was consistently positively associated with workplace aggression exposure from each source. Key variables related to work conditions (total hours worked, unpredictable work hours, a poor support network of other doctors, patients with unrealistic expectations, patients with complex health and social problems) and the presence of workplace aggression prevention and minimization strategies (alerts to high risk of aggression, restricting or withdrawing access for aggressive persons and optimized patient waiting) were also associated with aggression exposure. A broader implementation of strategies to prevent and minimize the likelihood and consequences of workplace aggression is required and needs to take account of both the individual and sub-group profiles of medical practitioners. Strategies need to mitigate the more challenging aspects of medical work, including excessive work hours, inadequate access to professional support networks, and larger caseloads of patients with complex conditions. 23967195 Drug content effects on the dispersion performance of adhesive mixtures for inhalation. The drug content in adhesive mixtures for inhalation is known to influence their dispersion performance, but the direction and magnitude of this influence depends on other variables. In the past decades several mechanisms have been postulated to explain this finding and a number of possible interacting variables have been identified. Still, the role of drug content in the formulation of adhesive mixtures for inhalation, which includes its significance as an interacting variable to other parameters, is poorly understood. Therefore, the results from a series of drug detachment experiments are presented in which the effect of drug content and its dependence on flow rate, the mixing time and the type of drug is studied. Furthermore, it is investigated whether the effect depends on the range within which the drug content is changed. Quantitative and qualitative multiple order interactions are observed between these variables, which may be explained by a shifting balance between three different mechanisms. The results therefore demonstrate that accounting for (multiple order) interactions between variables has to be part of quality by design activities and the rational design of future experiments. 22780871 Resampling versus Repair in Evolution Strategies Applied to a Constrained Linear Problem. We study the behaviour of multi-recombination evolution strategies for the problem of maximising a linear function with a single linear constraint. Two variants of the algorithm are considered: a strategy that resamples infeasible candidate solutions and one that applies a simple repair mechanism. Integral expressions that describe the strategies' one-generation behaviour are derived and used in a simple zeroth order model for the steady state attained when operating with constant step size. Applied to the analysis of cumulative step size adaptation, the approach provides an intuitive explanation for the qualitative difference in the algorithm variants' behaviour. The findings have implications for the design of constraint handling techniques to be used in connection with cumulative step size adaptation. 23835818 Pairing physician education with patient activation to improve shared decisions in prostate cancer screening: a cluster randomized controlled trial. BACKGROUND Most expert groups recommend shared decision making for prostate cancer screening. Most primary care physicians, however, routinely order a prostate-specific antigen (PSA) test with little or no discussion about whether they believe the potential benefits justify the risk of harm. We sought to assess whether educating primary care physicians and activating their patients to ask about prostate cancer screening had a synergistic effect on shared decision making, rates and types of discussions about prostate cancer screening, and the physician's final recommendations. METHODS Our study was a cluster randomized controlled trial among primary care physicians and their patients, comparing usual education (control), with physician education alone (MD-Ed), and with physician education and patient activation (MD-Ed+A). Participants included 120 physicians in 5 group practices, and 712 male patients aged 50 to 75 years. The interventions comprised a Web-based educational program for all intervention physicians and MD-Ed+A patients compared with usual education (brochures from the Centers for Disease Control and Prevention). The primary outcome measure was patients' reported postvisit shared decision making regarding prostate cancer screening; secondary measures included unannounced standardized patients' reported shared decision making and the physician's recommendation for prostate cancer screening. RESULTS Patients' ratings of shared decision making were moderate and did not differ between groups. MD-Ed+A patients reported that physicians had higher prostate cancer screening discussion rates (MD-Ed+A = 65%, MD-Ed = 41%, control=38%; P <.01). Standardized patients reported that physicians seeing MD-Ed+A patients were more neutral during prostate cancer screening recommendations (MD-Ed+A=50%, MD-Ed=33%, control=15%; P <.05). Of the male patients, 80% had had previous PSA tests. CONCLUSIONS Although activating physicians and patients did not lead to significant changes in all aspects of physician attitudes and behaviors that we studied, interventions that involved physicians did have a large effect on their attitudes toward screening and in the discussions they had with patients, including their being more likely than control physicians to engage in prostate cancer screening discussions and more likely to be neutral in their final recommendations. 23910481 Effect of the Duration of Emergency Department Observation on Computed Tomography Use in Children With Minor Blunt Head Trauma. We determine the effect of the duration of emergency department (ED) observation on computed tomography (CT) rate for children with minor blunt head trauma. We performed a prospective cohort study of children with blunt head trauma and a Glasgow Coma Scale score greater than 14. We defined time from injury as the time from head injury to initial physician (emergency attending physician or fellow) assessment. For children who were observed in the ED before CT decisionmaking, we defined ED observation time as time from initial physician assessment to the decision whether to obtain a CT. After adjusting for time from injury, patient age, sex, physician type, and study month, we measured the effect of ED observation time on CT rate in each of the 3 Pediatric Emergency Care Applied Research Network Traumatic Brain Injury risk groups. Of the 1,605 eligible patients, we enrolled 1,381 (86%). Of the enrolled patients, 676 (49%) were observed in the ED and 272 (20%) had a CT performed. After adjustment, every hour of ED observation time was associated with a decrease in CT rate for children in all 3 traumatic brain injury risk groups: high risk (adjusted odds ratio [OR] 0.11; 95% confidence interval [CI] 0.05 to 0.24), intermediate risk (adjusted OR 0.28; 95% CI 0.21 to 0.36), and low risk (adjusted OR 0.47; 95% CI 0.31 to 0.73). All 8 children with a significant traumatic brain injury had an immediate CT. For children with minor blunt head trauma, ED observation time was associated with a time-dependent reduction in cranial CT rate, with no delay in the diagnosis of a significant traumatic brain injury. 23945138 Engineering online and in-person social networks to sustain physical activity: application of a conceptual model. High rates of physical inactivity compromise the health status of populations globally. Social networks have been shown to influence physical activity (PA), but little is known about how best to engineer social networks to sustain PA. To improve procedures for building networks that shape PA as a normative behavior, there is a need for more specific hypotheses about how social variables influence PA. There is also a need to integrate concepts from network science with ecological concepts that often guide the design of in-person and electronically-mediated interventions. Therefore, this paper: (1) proposes a conceptual model that integrates principles from network science and ecology across in-person and electronically-mediated intervention modes; and (2) illustrates the application of this model to the design and evaluation of a social network intervention for PA.Methods/design: A conceptual model for engineering social networks was developed based on a scoping literature review of modifiable social influences on PA. The model guided the design of a cluster randomized controlled trial in which 308 sedentary adults were randomly assigned to three groups: WalkLink+: prompted and provided feedback on participants' online and in-person social-network interactions to expand networks for PA, plus provided evidence-based online walking program and weekly walking tips; WalkLink: evidence-based online walking program and weekly tips only; Minimal Treatment Control: weekly tips only. The effects of these treatment conditions were assessed at baseline, post-program, and 6-month follow-up. The primary outcome was accelerometer-measured PA. Secondary outcomes included objectively-measured aerobic fitness, body mass index, waist circumference, blood pressure, and neighborhood walkability; and self-reported measures of the physical environment, social network environment, and social network interactions. The differential effects of the three treatment conditions on primary and secondary outcomes will be analyzed using general linear modeling (GLM), or generalized linear modeling if the assumptions for GLM cannot be met. Results will contribute to greater understanding of how to conceptualize and implement social networks to support long-term PA. Establishing social networks for PA across multiple life settings could contribute to cultural norms that sustain active living.Trial registration: ClinicalTrials.gov NCT01142804. 23470776 Environmental stress, oxytocin receptor gene (OXTR) polymorphism, and mental health following collective stress. We examined whether the oxytocin receptor gene (OXTR) single nucleotide polymorphism (SNP) rs53576 genotype buffers the combined impact of negative social environments (e.g., interpersonal conflict/constraint) and economic stress on post-traumatic stress (PTS) symptoms and impaired daily functioning following collective stress (September 11th terrorist attacks). Saliva was collected by mail and used to genotype 704 respondents. Participants completed Web-based assessments of pre-9/11 mental health, acute stress 9-23days after 9/11, the quality of social environments 1year post-9/11, economic stress 18months post-9/11, and PTS symptoms and impaired functioning 2 and 3years post-9/11. Interactions between negative social environments and economic stress were examined separately based on OXTR rs53576 genotype (GG vs. any A allele). For individuals with an A allele, a negative social environment significantly increased PTS symptoms without regard to the level of economic stress experienced. However, for respondents with a GG genotype, negative social environments predicted elevated PTS symptoms only for those also experiencing high economic stress. Gender moderated associations between negative social environments, economic stress, and impaired functioning. The functioning of females was most affected by negative social environments regardless of genotype and economic stress, whereas the functioning of males was differentially susceptible to economic stress depending on OXTR genotype and negative social environments. These findings suggest that it is important to consider the combined impact of gender and ongoing stress in different domains as moderators of genetic vulnerability following collective stress. 23612434 Peripubertal Diazepam Administration Prevents the Emergence of Dopamine System Hyperresponsivity in the MAM Developmental Disruption Model of Schizophrenia. Schizophrenia is believed to arise from an interaction of genetic predisposition and adverse environmental factors, with stress being a primary variable. We propose that alleviating anxiety produced in response to stress during a sensitive developmental period may circumvent the dopamine (DA) system alterations that may correspond to psychosis in adults. This was tested in a developmental rat model of schizophrenia based on prenatal administration of the mitotoxin methyl azoxymethanol acetate (MAM). MAM administration leads to a hyperdopaminergic state consisting of an increase in the number of DA neurons firing spontaneously, which correlates with an increased behavioral response to amphetamine. MAM-treated rats exhibited a heightened level of anxiety during adolescence. Peripubertal administration of the antianxiety agent diazepam was found to prevent the increase in DA neuron activity and blunt the behavioral hyperresponsivity to amphetamine in these rats. These data suggest that the pathophysiological factors leading to the onset of psychosis in early adulthood may be circumvented by controlling the response to stress during the peripubertal period. 23305624 Validating a faster method for reconstitution of Crotalidae Polyvalent Immune Fab (ovine). BACKGROUND: Reconstitution of CroFab(®) (Crotalidae Polyvalent Immune Fab [ovine]) lyophilized drug product was previously performed using 10 mL sterile water for injection followed by up to 36 min of gentle swirling of the vial. CroFab has been clinically demonstrated to be most effective when administered within 6 h of snake envenomation, and improved clinical outcomes are correlated with quicker timing of administration. An alternate reconstitution method was devised, using 18 mL 0.9% saline with manual inversion, with the goal of shortening reconstitution time while maintaining a high quality, efficacious product. METHODS: An analytical study was designed to compare the physicochemical properties of 3 separate batches of CroFab when reconstituted using the standard procedure (10 mL WFI with gentle swirling) and a modified rapid procedure using 18 mL 0.9% saline and manual inversion. The physical and chemical characteristics of the same 3 batches were assessed using various analytic methodologies associated with routine quality control release testing. In addition further analytical methodologies were applied in order to elucidate possible structural changes that may be induced by the changed reconstitution procedure. RESULTS: Batches A, B, and C required mean reconstitution times of 25 min 51 s using the label method and 3 min 07 s (a 88.0% mean decrease) using the modified method. Physicochemical characteristics (color and clarity, pH, purity, protein content, potency) were found to be highly comparable. Characterization assays (dynamic light scattering, analytical ultracentrifugation, LC-MS, SDS-PAGE and circular dichroism spectroscopy were also all found to be comparable between methods. DISCUSSION: When comparing CroFab batches that were reconstituted using the labeled and modified methods, the physicochemical and biological (potency) characteristics of CroFab were not significantly changed when challenged by the various standard analytical methodologies applied in routine quality control analysis. Additionally, no changes in the CroFab molecule regarding degradation, aggregation, purity, structure, or mass were observed. CONCLUSION: The analyses performed validated the use of the more rapid reconstitution method using 18 mL 0.9% saline in order to allow a significantly reduced time to administration of CroFab to patients in need. 23836168 Fidaxomicin versus Conventional Antimicrobial Therapy in 59 Recipients of Solid Organ and Hematopoietic Stem Cell Transplantation with Clostridium difficile-Associated Diarrhea. The feasibility of fidaxomicin versus vancomycin and metronidazole (conventional therapy) was assessed in 59 transplant recipients with 61 episodes of Clostridium difficile-associated diarrhea (CDAD). Overall clinical cure was achieved in 86% of episodes, and in 7% of episodes, infection recurred. Fidaxomicin was well tolerated. Clinical cures were not significantly different compared with conventional therapy (67% versus 89%, respectively; P = 0.06). Univariate analysis of predictors for lack of clinical cure included continued use of broad-spectrum systemic antibiotics (P = 0.026) and prior diagnosis of CDAD (95% confidence interval, 1.113 to 19.569; odds ratio, 4.667; P = 0.041). New-onset vancomycin-resistant Enterococcus (VRE) colonization was not noted after fidaxomicin therapy alone. However, this occurred in 10 of 28 patients (36%) following conventional therapy, and 2 of 3 patients with subsequent bacteremia died. 23829499 Wax ester profiling of seed oil by nano-electrospray ionization tandem mass spectrometry. Wax esters are highly hydrophobic neutral lipids that are major constituents of the cutin and suberin layer. Moreover they have favorable properties as a commodity for industrial applications. Through transgenic expression of wax ester biosynthetic genes in oilseed crops, it is possible to achieve high level accumulation of defined wax ester compositions within the seed oil to provide a sustainable source for such high value lipids. The fatty alcohol moiety of the wax esters is formed from plant-endogenous acyl-CoAs by the action of fatty acyl reductases (FAR). In a second step the fatty alcohol is condensed with acyl-CoA by a wax synthase (WS) to form a wax ester. In order to evaluate the specificity of wax ester biosynthesis, analytical methods are needed that provide detailed wax ester profiles from complex lipid extracts. We present a direct infusion ESI-tandem MS method that allows the semi-quantitative determination of wax ester compositions from complex lipid mixtures covering 784 even chain molecular species. The definition of calibration prototype groups that combine wax esters according to their fragmentation behavior enables fast quantitative analysis by applying multiple reaction monitoring. This provides a tool to analyze wax layer composition or determine whether seeds accumulate a desired wax ester profile. Besides the profiling method, we provide general information on wax ester analysis by the systematic definition of wax ester prototypes according to their collision-induced dissociation spectra. We applied the developed method for wax ester profiling of the well characterized jojoba seed oil and compared the profile with wax ester-accumulating Arabidopsis thaliana expressing the wax ester biosynthetic genes MaFAR and ScWS. We developed a fast profiling method for wax ester analysis on the molecular species level. This method is suitable to screen large numbers of transgenic plants as well as other wax ester samples like cuticular lipid extracts to gain an overview on the molecular species composition. We confirm previous results from APCI-MS and GC-MS analysis, which showed that fragmentation patterns are highly dependent on the double bond distribution between the fatty alcohol and the fatty acid part of the wax ester. 23567941 Photocrosslinkable biodegradable elastomers based on cinnamate-functionalized polyesters. Synthetic biodegradable elastomers are an emerging class of materials that play a critical role in supporting innovations in bioabsorbable medical implants. This paper describes the synthesis and characterization of poly(glycerol-co-sebacate)-cinnamate (PGS-CinA), a biodegradable elastomer based on hyperbranched polyesters derivatized with pendant cinnamate groups. PGS-CinA can be prepared via photodimerization in the absence of photoinitiators using monomers that are found in common foods. The resulting network exhibits a Young's modulus of 50.5-152.1kPa and a projected in vitro degradation half-life time between 90 and 140days. PGS-CinA elastomers are intrinsically cell-adherent and support rapid proliferation of fibroblasts. Spreading and proliferation of fibroblasts are loosely governed by the substrate stiffness within the range of Young's moduli in PGS-CinA networks that were prepared. The thermo-mechanical properties, biodegradability and intrinsic support of cell attachment and proliferation suggest that PGS-CinA networks are broadly applicable for use in next generation bioabsorable materials including temporary medical devices and scaffolds for soft tissue engineering. 23748088 Redox mediator enhanced simultaneous decolorization of azo dye and bioelectricity generation in air-cathode microbial fuel cell. Enhanced simultaneous decolorization of Congo red and bioelectricity generation with anthraquinone-2,6-disulphonic disodium salt (AQDS), riboflavin (RF) and humic acid (HA) as mediators in air-cathode microbial fuel cell (MFC) was demonstrated. Compared with mediator-free MFC, the MFC with added 0.005mM AQDS, 0.005mM RF or 1g/L HA showed 36%, 26% and 15% increase in maximum power density along with 394%, 450%, and 258% increases in decolorization rates of Congo red, respectively. Addition of mediators at higher concentration further increased power and Congo red decolorization but the increases were not proportional to the rise in mediator concentration. Based on decreases of anode charge transfer resistance and increases of Congo red decolorization, the mediators kinetically promote the extracellular electron transfer between bacteria, anode and Congo red. Microbial analysis showed that addition of mediators changed the composition of anodic microbial community and stimulated the growth of species belonging to Chlorobi, Endomicrobia and Firmicutes. 23902675 Subsequent intra-abdominal fibromatosis mimicking recurrent gastrointestinal stromal tumor. Intra-abdominal fibromatosis (IAF) commonly develops in patients who had abdominal surgery. In rare instances, it occurs subsequent to gastrointestinal stromal tumor (GIST). This special situation has clinical significance in imatinib era. About 1000 patients with GIST in our institution from 1993 to 2010 were re-evaluated based on their clinical and pathological data, the treatment strategies and the follow-up information. We identified 2 patients who developed IAF after GIST resection. Patient 1 was a 54 year-old male and had 5 cm × 4.5 cm × 3.5 cm jejunal GIST excised on February 22, 1994. Three years later, an abdominal mass with 7 cm × 6 cm × 3 cm was identified. He was diagnosed as recurrent GIST from clinical point of view. After excision, the second tumor was confirmed to be IAF. Patient 2 was a 45-year-old male and had 6 cm × 4 cm × 3 cm duodenal GIST excised on August 19, 2008. One year later, a 4 cm mass was found at the original surgical site. The patient refused to take imatinib until the tumor increased to 8 cm six months later. The tumor continued to increase after 6 months' imatinib therapy, decision of surgical resection was made by multidisciplinary team. The second tumor was confirmed to be IAF with size of 17 cm × 13 cm × 11 cm. Although IAF subsequent to GIST is very rare, it is of clinical significance in imatinib era as an influencing factor for making clinical decision. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1076715989961803. 23583698 Isolation, purification, culture and characterisation of myoepithelial cells from normal and neoplastic canine mammary glands using a magnetic-activated cell sorting separation system. Mammary gland tumours, the most common malignant neoplasm in bitches, often display myoepithelial (ME) cell proliferation. The aim of this study was to isolate, purify, culture and characterise ME cells from normal and neoplastic canine mammary glands. Monodispersed cells from three normal canine mammary glands and five canine mammary tumours were incubated with an anti-Thy1 antibody and isolated by magnetic-activated cell sorting (MACS). Cells isolated from two normal glands (cell lines CmME-N1 and CmME-N2) and four tumours (cell lines CmME-K1 from a complex carcinoma, CmME-K2 from a simple tubulopapillary carcinoma, and CmME-K3 and CmME-K4 from two carcinomas within benign tumours) were cultured in supplemented DMEM/F12 media for 40days. Cell purity was >90%. Tumour-derived ME cell lines exhibited heterogeneous morphology, growth patterns and immunocytochemical expression of cytokeratins, whereas cell lines from normal glands retained their morphology and levels of cytokeratin expression during culture. Cell lines from normal glands and carcinomas within benign tumours grew more slowly than those from simple and complex carcinomas. This methodology has the potential to be used for in vitro analysis of the role of ME cells in the growth and progression of canine mammary tumours. 23869618 A novel androgen signalling pathway uses dihydrotestosterone, but not testosterone, to activate the epidermal growth factor receptor signalling cascade in prostate stromal cells. Human prostate growth and function are tightly controlled by androgens which are generally thought to exert their effects by regulating gene transcription. However, a rapid, non-genomic steroid action, often involving an elevation of intracellular calcium ([Ca(2+) ]i ), has also been described in a number of cell types. In this study we investigate whether androgens acutely regulate [Ca(2+) ]i in stromal cells derived from the human prostate. Human prostatic stromal cells (HCPSC) were loaded with the calcium-sensitive fluorophore, FURA2-AM (10 μM). Changes in [Ca(2+) ]i in response to the androgens, dihydrotestosterone (DHT) and testosterone, as well as epidermal growth factor (EGF) were measured by fluorescence microscopy. DHT, but not testosterone (0.03-300 nM) elicited concentration-independent elevations of [Ca(2+) ]i within one minute of addition. These responses were blocked by the androgen receptor antagonist, flutamide (10 μM), the sarcoplasmic reticulum ATPase pump inhibitor, thapsigargin (1 μM), the inositol triphosphate receptor inhibitor, 2-aminoethyldiphenyl borate (50 μM) and the phospholipase C inhibitor, U-73122 (1 μM). Responses were also blocked by the L-type calcium channel blocker, nifedipine (1 μM) and by removal of extracellular calcium. A similar transient elevation of [Ca(2+) ]i was elicited by EGF (100 ng mL(-1) ). The EGF receptor inhibitor, AG 1478 (30 nM), and the matrix metalloproteinase inhibitor, marimastat (100 nM) blocked the DHT-induced elevation of [Ca(2+) ]i . These studies show that DHT elicits an androgen receptor-dependent acute elevation of [Ca(2+) ]i in HCPSC, most likely by activating EGF receptor signalling. 23475431 Characteristics and determinants of adult patients with acute poisoning attending the accident and emergency department of a teaching hospital in Qatar. Data about etiologic and demographic characteristics of acute poisoning in adults in Qatar are lacking. This prospective observational study was undertaken to analyze characteristics and possible determinants of acute poisoning in adults in Qatar. During 2010, 18,073 patients attended the emergency department of Hamad General Hospital, a teaching hospital in Qatar. Out of them, 599 (3.3%) patients were diagnosed as "poisoning case" with either chemical or pharmaceutical substances. The prevalence rate of poisoning incidence was 35.3/100,000 population. Seven patients died, corresponding with a case-fatality rate of 0.39/1000. The majority were male (65%) and the mean age was 34 years. The poisons involved were mainly chemicals (61.6%) and pharmaceuticals (38.4%). Female, mainly single, suffered more intentional poisoning compared to male. Of the patients aged 60 years and above (7.2%), the majority (95.3%) suffered unintentional poisoning with pharmaceuticals; 56% with warfarin, 12% with digoxin and 7% with insulin. Multivariate analysis shows that female gender, single status, younger than 35 years of age, being poisoned by pharmaceutical products, and the need for hospitalization are significant determinants for acute intentional poisoning after adjusting all other possible covariates. The findings of this study can be used to establish awareness and prophylactic campaigns in Qatar. 23751302 Determinants of participation in leisure activities among adolescents with cerebral palsy. Studies have identified restrictions in engagement in leisure activities for adolescents with disabilities. Participation is a complex construct and likely influenced by a variety of factors. These potential determinants have not yet been sufficiently explored in the population of adolescents with cerebral palsy (CP). The objective of this study is to estimate the potential influence of adolescent characteristics and environmental factors as determinants of participation in leisure activities for adolescents with CP. A cross-sectional design was used. Participants were adolescents (12-19 years old) with cerebral palsy. Participants were assessed with the Vineland Adaptive Behavior Scale - II, Gross Motor Function Measure, Gross Motor Function Classification System, Manual Ability Classification System and completed the Self-Perception Profile for Adolescents, Dimensions of Mastery Questionnaire, Strengths and Difficulties Questionnaire, Family Environment Scale, the European Child Environment Questionnaire and the Preferences for Activities of Children. The main outcome measure was the Children's Assessment of Participation and Enjoyment. 187 adolescents (age M=15.4; SD=2.2) completed the study. Multivariate models of participation in leisure revealed associations with factors related to the adolescents' functional characteristics and attitudes, the family environment, socioeconomic status, and contextual factors such as school type, and collectively explained from 28% (diversity of skill-based activities) up to 48% (intensity and diversity of self-improvement activities) of the variance in intensity and diversity in five leisure participation domains (diversity: r(2)=.33 recreational; r(2)=.39 active-physical; r(2)=.33 social activities). Adolescent's mastery motivation, self-perception and behavior were individually associated with participation in different activity domains, but did not strongly predict participation within multivariate models, while preferences for activities were strong predictors of participation in all domains, except for skill-based activities. Engagement in different types of leisure activities is important for adolescents' development and well-being. Health care professionals should consider adolescents' and families' characteristics to promote participation in leisure activities. 23888906 FEZ1 expression in reactive astrocytes in a rat model of Parkinson's disease. Fasciculation and elongation protein zeta-1 (FEZ1) is a critical regulator of dopaminergic neuron differentiation and dopamine release. However, to date, few studies evaluating the expression patterns of FEZ1 in Parkinson's disease (PD) have been reported. The aim of this study was to investigate the expression and cellular localisation of FEZ1 in a rat model of PD and to explore the role of FEZ1 in PD pathogenesis. Male Sprague-Dawley rats were randomly divided into two groups: a PD group and a sham group. A model of PD was established by injecting 6-Hydroxydopamine Hydrobromide (6-OHDA) into the right medial forebrain bundle of rats. Sham-lesioned rats were infused with equivalent amounts of saline and served as controls. The expression levels of FEZ1 mRNA and protein in striatum and substantia nigra were examined by real-time PCR and by Western blot analysis, respectively. Immunohistochemistry was performed to identify the cellular localisation of FEZ1 in sham-lesioned and PD rats. Western blot and real-time PCR analyses demonstrated that FEZ1 was present in normal rat brain striatum and substantia nigra. After the 6-OHDA injection, FEZ1 expression gradually increased, peaked and then decreased. Immunohistochemical detection showed a shift of FEZ1 expression from tyrosine hydroxylase positive neurons in sham-lesioned rats to astrocytes in PD rats. Our results indicate that FEZ1 plays a role in the astrocytic protection of dopamine neurons and in the regulation of the neuronal microenvironment during the progression of PD. 23868835 Honeybees can learn the relationship between the solar ephemeris and a newly-experienced landscape: a confirmation. Honeybees learn the spatial relationship between the sun's pattern of movement and the landscape immediately surrounding their nest, which allows bees to locate the sun under overcast skies by reference to the landscape alone. Surprisingly, when bees have been transplanted from their natal landscape to a rotated twin landscape - such as from one treeline to a similar but differently oriented treeline - the bees have failed to learn the relationship between the sun and the second landscape. This raises the question of whether bees can ever learn the relationship between the sun's pattern of movement and a landscape other than their natal one. Here we confirm, with new and necessary controls, that bees can indeed learn the relationship between the sun's pattern of movement and a second (that is, non-natal) landscape, if the second landscape is panoramically different from the bees' natal site. We transplanted bees from their natal site to a panoramically different second site and, three days later, tested the bees' knowledge of the relationship between the sun and the second landscape. The test involved observing the bees' communicative dances under overcast skies at a third site that was rotated twin of the second. These bees oriented their dances using a memory of the sun's course in relation to the second landscape, indicating that they had learned this relationship. Meanwhile, control bees transplanted directly from the natal site to the third site, skipping the second, danced differently, confirming the importance of the experimental bees' experience at the second site. 23770366 A mental retardation gene, motopsin/prss12, modulates cell morphology by interaction with seizure-related gene 6. A serine protease, motopsin (prss12), plays a significant role in cognitive function and the development of the brain, since the loss of motopsin function causes severe mental retardation in humans and enhances social behavior in mice. Motopsin is activity-dependently secreted from neuronal cells, is captured around the synaptic cleft, and cleaves a proteoglycan, agrin. The multi-domain structure of motopsin, consisting of a signal peptide, a proline-rich domain, a kringle domain, three scavenger receptor cysteine-rich domains, and a protease domain at the C-terminal, suggests the interaction with other molecules through these domains. To identify a protein interacting with motopsin, we performed yeast two-hybrid screening and found that seizure-related gene 6 (sez-6), a transmembrane protein on the plasma membrane of neuronal cells, bound to the proline-rich/kringle domain of motopsin. Pull-down and immunoprecipitation analyses indicated the interaction between these proteins. Immunocytochemical and immunohistochemical analyses suggested the co-localization of motopsin and sez-6 at neuronal cells in the developmental mouse brain and at motor neurons in the anterior horn of human spinal cords. Transient expression of motopsin in neuro2a cells increased the number and length of neurites as well as the level of neurite branching. Interestingly, co-expression of sez-6 with motopsin restored the effect of motopsin at the basal level, while sez-6 expression alone showed no effects on cell morphology. Our results suggest that the interaction of motopsin and sez-6 modulates the neuronal cell morphology. 23852583 THE adaptive responses of TRPC1 and TRPC3 during skeletal muscle atrophy and regrowth. Introduction: We assessed the time-dependent changes of transient receptor potential channel 1 (TRPC1) and TRPC3 expression and localization associated with muscle atrophy and regrowth in vivo. Methods: Mice were subjected to hindlimb unloading for 7 or 14 days (7U, 14U), followed by 3, 7, or 14 days of reloading (3R, 7R, 14R). Results: Soleus muscle mass and tetanic force were reduced significantly at 7U and 14U and recovered by 14R. Recovery of muscle fiber cross-sectional area was observed by 28R. TRPC1 mRNA was unaltered during the unloading-reloading period. However, protein expression remained depressed through 14R. Decreased localization of TRPC1 to the sarcolemma was observed. TRPC3 mRNA and protein expression levels were decreased significantly during the early phase of reloading. Discussion: Given the known role of these channels in muscle development, changes observed in TRPC1 and TRPC3 may relate closely to the muscle atrophy and remodeling processes. © 2013 Wiley Periodicals, Inc. 23936565 Dengue and other common causes of acute febrile illness in Asia: an active surveillance study in children. Common causes of acute febrile illness in tropical countries have similar symptoms, which often mimic those of dengue. Accurate clinical diagnosis can be difficult without laboratory confirmation and disease burden is generally under-reported. Accurate, population-based, laboratory-confirmed incidence data on dengue and other causes of acute fever in dengue-endemic Asian countries are needed. This prospective, multicenter, active fever surveillance, cohort study was conducted in selected centers in Indonesia, Malaysia, Philippines, Thailand and Vietnam to determine the incidence density of acute febrile episodes (≥38°C for ≥2 days) in 1,500 healthy children aged 2-14 years, followed for a mean 237 days. Causes of fever were assessed by testing acute and convalescent sera from febrile participants for dengue, chikungunya, hepatitis A, influenza A, leptospirosis, rickettsia, and Salmonella Typhi. Overall, 289 participants had acute fever, an incidence density of 33.6 per 100 person-years (95% CI: 30.0; 37.8); 57% were IgM-positive for at least one of these diseases. The most common causes of fever by IgM ELISA were chikungunya (in 35.0% of in febrile participants) and S. Typhi (in 29.4%). The overall incidence density of dengue per 100 person-years was 3.4 by nonstructural protein 1 (NS1) antigen positivity (95% CI: 2.4; 4.8) and 7.3 (95% CI: 5.7; 9.2) by serology. Dengue was diagnosed in 11.4% (95% CI: 8.0; 15.7) and 23.9% (95% CI: 19.1; 29.2) of febrile participants by NS1 positivity and serology, respectively. Of the febrile episodes not clinically diagnosed as dengue, 5.3% were dengue-positive by NS1 antigen testing and 16.0% were dengue-positive by serology. During the study period, the most common identified causes of pediatric acute febrile illness among the seven tested for were chikungunya, S. Typhi and dengue. Not all dengue cases were clinically diagnosed; laboratory confirmation is essential to refine disease burden estimates. 23945461 Viewpoints about collaboration between primary care and public health in Canada. Although there is a global movement toward health system integration and collaboration, little is known about values, beliefs, and attitudes towards collaboration between stakeholders in public health (i.e. promotion, protection, and prevention with vulnerable groups and/or at the population level) and primary care (i.e., family practices, nurse-led clinics). The purpose of this study was to explore viewpoints of key stakeholders regarding primary care (PC) and public health (PH) collaboration in Canada. We used Q-methodology to identify common viewpoints held by participants who attended a national meeting in Canada in 2010 to discuss PC and PH collaboration. The study was conducted in two phases. In Phase 1 a Q-sample, a Q-sort table, and a short demographic questionnaire were developed which were used in Phase 2 for data collection. The Q-sorts then were analysed to identify the salient factors and consensus statements. In total, 25 multidisciplinary individuals including researchers, policy-makers, directors, managers, and practitioners (e.g., nurses, family physicians, dietitians) participated. Using a by-person factor analysis, three factors (salient viewpoints) emerged. Factors were named based on their distinguishing statements as follows: a) System Driven Collaborators, b) Cautious Collaborators, and c) Competent Isolationists. System Driven Collaborators strongly believed that a clear mandate from the top is needed to enable PH, PC and the rest of the health system to effectively work together and that people in different branches in the Ministry/ Ministries have to strongly believe in collaboration, actively support it, and develop directed policies to foster organizations work together. Cautious Collaborators strongly supported the idea of having better consciousness-raising about what collaborations might be possible and beneficial, and also reflecting on the collaborations already in place. The Competent Isolationists strongly believed that it is necessary for PC and PH sectors to spend time to ensure that both parties clearly understand the differences between their roles. They believe that physicians, nurses, and social workers will not see the value in collaboration because they lack inter-professional educational programs. Different viewpoints are held by stakeholders around PC and PH collaboration which have the potential to influence the success of collaborations. Understanding and managing these differences is important to assist change management processes required to build and maintain strong PC and PH collaborations. 23053704 A micro-computed tomography study of canal configuration of multiple-canalled mesiobuccal root of maxillary first molar. Detailed information of complex anatomical configuration of mesiobuccal (MB) root is essential for successful endodontic treatment in maxillary first molars. The aims of this study were to investigate the configuration types present in multiple-canalled MB roots of maxillary first molars using micro-computed tomography (μCT) and to evaluate whether further modification to current configuration classifications are needed for in-depth morphology study of MB root canal system. One hundred and fifty-four extracted human maxillary first molar MB roots were scanned by μCT (Skyscan) and their canals were reconstructed by 3D modeling software. Root canal configurations were categorized according to the classifications proposed by Weine and Vertucci. Canal configurations that did not fit into both classifications were categorized as non-classifiable. One hundred and thirteen (73.4 %) MB roots had multiple canals. The most predominant canal configuration was Weine type III (two orifices and two foramens). Thirty-three (29.2 %) and 20 (17.7 %) MB roots had non-classifiable configuration types that could not be classified by the Weine and Vertucci classification, respectively. Three configurations (types 1-3, 2-3-2-3-2, and 2-3-4-3-2) were first reported in maxillary first molar MB roots. The present μCT study provided an in-depth analysis of canal configurations of the MB roots of maxillary first molar and suggests that additional modification of current configuration classifications may be needed to more accurately reflect the morphology configurations of MB roots. Clinicians should consider the complex canal configurations of the maxillary first molar MB roots during surgical or nonsurgical endodontic procedures. 23905810 Evaluation of microbial contamination of tomatoes and peppers at retail markets in monterrey, Mexico. The source of a large outbreak of foodborne disease related to Salmonella-contaminated jalapeño peppers has been traced to Nuevo Leon, Mexico. The objective of this work was to evaluate the microbiological quality of tomatoes and jalapeño peppers from markets and supermarkets from the metropolitan area of Monterrey, Nuevo León, Mexico. One hundred sixty samples (40 bola tomatoes, 40 saladette [Roma] tomatoes, 40 serrano peppers, and 40 jalapeño peppers) were purchased. Stems from peppers were removed and analyzed separately. Samples were analyzed for indicator organisms and Salmonella, following the Mexican Official Methods. The results showed that the presence of indicator organisms varied among samples and origins, and levels were relatively high in peppers (average 4.4 to 4.7 log CFU/g for total mesophilic, 3.25 to 3.73 log CFU/g for total coliforms, and 1.69 log CFU/g for fecal coliforms). Saladette tomatoes and serrano peppers showed the greatest microorganism levels (∼1 log CFU/g higher) in comparison with the other varieties. Pepper stems typically had indicator microbial levels ∼1 to 2 log CFU/g higher than levels in smooth flesh. Only one tomato and one jalapeño sample were positive for Salmonella. However, in the case of the pepper, the contamination was found in the stem. Although the microbiological quality of tomatoes and peppers sampled was similar to that found in markets from developed countries, the presence of pathogens causes a risk of infection for consumers. 23472655 Global iodine nutrition: where do we stand in 2013? Background: Dietary iodine intake is required for the production of thyroid hormone. Consequences of iodine deficiency include goiter, intellectual impairments, growth retardation, neonatal hypothyroidism, and increased pregnancy loss and infant mortality. Summary: In 1990, the United Nations World Summit for Children established the goal of eliminating iodine deficiency worldwide. Considerable progress has since been achieved, largely through programs of universal salt iodization. Approximately 70% of all households worldwide currently have access to adequately iodized salt. In 2013, as defined by a national or subnational median urinary iodine concentration of 100-299 μg/L in school-aged children, 111 countries have sufficient iodine intake. Thirty countries remain iodine-deficient; 9 are moderately deficient, 21 are mildly deficient, and none are currently considered severely iodine-deficient. Ten countries have excessive iodine intake. In North America, both the United States and Canada are generally iodine-sufficient, although recent data suggest pregnant U.S. women are mildly iodine-deficient. Emerging issues include discrepancies between urinary iodine status in pregnant women compared to school-aged children in some populations, the problem of re-emerging iodine deficiency in parts of the developed world, the importance of food industry use of iodized salt, regions of iodine excess, and the potential effects of initiatives to lower population sodium consumption on iodine intake. Conclusions: Although substantial progress has been made over the last several decades, iodine deficiency remains a significant health problem worldwide and affects both industrialized and developing nations. The ongoing monitoring of population iodine status remains crucially important, and particular attention may need to be paid to monitoring the status of vulnerable populations, such as pregnant women and infants. There is also need for ongoing monitoring of iodized salt and other dietary iodine sources in order to prevent excess as well as insufficient iodine nutrition. Finally, it will be essential to coordinate interventions designed to reduce population sodium intake with salt iodization programs in order to maintain adequate levels of iodine nutrition as salt intake declines. 23948766 Light propagation in structural anisotropic media in the steady-state and time domains. The determination of the reduced scattering and absorption coefficients of structural anisotropic turbid semi-infinite media and slabs was investigated in the steady-state and time domains. Forward calculations were performed with a Monte Carlo model that considered both cylindrical scatterers aligned in different directions as well as scatterers that were described by a rotationally symmetric scattering function. Analytical solutions of the isotropic and anisotropic diffusion equations were applied to retrieve the optical properties. It was found in the steady-state and time domains that the solutions of the anisotropic diffusion equation have systematic errors compared to the Monte Carlo simulations not only for small distances from the source. However, it is shown that in the time domain it is possible to retrieve useful values for the optical properties using the isotropic and the anisotropic diffusion equations. 23754703 A Charge-Stabilizing, Multimodular, Ferrocene-Bis(triphenylamine)-Zinc-porphyrin-Fullerene Polyad. A novel multimodular donor-acceptor polyad featuring zinc porphyrin, fullerene, ferrocene, and triphenylamine entities was designed, synthesized, and studied as a charge-stabilizing, photosynthetic-antenna/reaction-center mimic. The ferrocene and fullerene entities, covalently linked to the porphyrin ring, were distantly separated to accomplish the charge-separation/hole-migration events leading to the creation of a long-lived charge-separated state. The geometry and electronic structures of the newly synthesized compound was deduced by B3LYP/3-21G(*) optimization, while the energy levels for different photochemical events was established using data from the optical absorption and emission, and electrochemical studies. Excitation of the triphenylamine entities revealed singlet-singlet energy transfer to the appended zinc porphyrin. As predicted from the energy levels, photoinduced electron transfer from both the singlet and triplet excited states of the zinc porphyrin to fullerene followed by subsequent hole migration involving ferrocene was witnessed from the transient absorption studies. The charge-separated state persisted for about 8.5 μs and was governed by the distance between the final charge-transfer product, that is, a species involving a ferrocenium cation and a fullerene radical anion, with additional influence from the charge-stabilizing triphenylamine entities located on the zinc-porphyrin macrocycle. 23571068 DNA repair activity in fish and interest in ecotoxicology: A review. The knowledge of DNA repair in a target species is of first importance as it is the primary line of defense against genotoxicants, and a better knowledge of DNA repair capacity in fish could help to interpret genotoxicity data and/or assist in the choice of target species, developmental stage and tissues to focus on, both for environmental biomonitoring studies and DNA repair testing. This review focuses in a first part on what is presently known on a mechanistic basis, about the various DNA repair systems in fish, in vivo and in established cell lines. Data on base excision repair (BER), direct reversal with O(6)-alkylguanine transferase and double strand breaks repair, although rather scarce, are being reviewed, as well as nucleotide excision repair (NER) and photoreactivation repair (PER), which are by far the most studied repair mechanisms in fish. Most of these repair mechanisms seem to be strongly species and tissue dependent; they also depend on the developmental stage of the organisms. BER is efficient in vivo, although no data has been found on in vitro models. NER activity is quite low or even inexistent depending on the studies; however this lack is partly compensated by a strong PER activity, especially in early developmental stage. In a second part, a survey of the ecotoxicological studies integrating DNA repair as a parameter responding to single or mixture of contaminant is realized. Three main approaches are being used: the measurement of DNA repair gene expression after exposure, although it has not yet been clearly established whether gene expression is indicative of repair capacity; the monitoring of DNA damage removal by following DNA repair kinetics; and the modulation of DNA repair activity following exposure in situ, in order to assess the impact of exposure history on DNA repair capacity. Since all DNA repair processes are possible targets for environmental pollutants, we can also wonder at which extent such a modulation of repair capacities in fish could be the base for the development of new biomarkers of genotoxicity. Knowing the importance of the germ cell DNA integrity in the reproductive success of aquatic organisms, the DNA repair capacity of such cells deserve to be more studied, as well as DNA repair capacities of established fish cell lines. The limited amount of available data, which shows low/slow DNA repair capacities of fish cell lines compared with mammalian cell lines, concerned mainly the NER system; thus this point merits to be explored more deeply. Additionally, since some of the DNA repair systems appear more efficient in embryo larval stages, it would be of interest to consider embryonic cell lineages more closely. 23754298 Ophiobolin A, a sesterterpenoid fungal phytotoxin, displays higher in vitro growth-inhibitory effects in mammalian than in plant cells and displays in vivo antitumor activity. Ophiobolin A, a sesterterpenoid produced by plant pathogenic fungi, was purified from the culture extract of Drechslera gigantea and tested for its growth-inhibitory activity in both plant and mammalian cells. Ophiobolin A induced cell death in Nicotiana tabacum L. cv. Bright Yellow 2 (TBY-2) cells at concentrations ≥10 µM, with the TBY-2 cells showing typical features of apoptosis-like cell death. At a concentration of 5 µM, ophiobolin A did not affect plant cell viability but prevented cell proliferation. When tested on eight cancer cell lines, concentrations <1 µM of ophiobolin A inhibited growth by 50% after 3 days of culture irrespective of their multidrug resistance (MDR) phenotypes and their resistance levels to pro-apoptotic stimuli. It is, thus, unlikely that ophiobolin A exerts these in vitro growth-inhibitory effects in cancer cells by activating pro-apoptotic processes. Highly proliferative human keratinocytes appeared more sensitive to the growth-inhibitory effects of ophiobolin A than slowly proliferating ones. Ophiobolin A also displayed significant antitumor activity at the level of mouse survival when assayed at 10 mg/kg in the B16F10 mouse melanoma model with lung pseudometastases. Ophiobolin A could, thus, represent a novel scaffold to combat cancer types that display various levels of resistance to pro-apoptotic stimuli and/or various MDR phenotypes. 23962067 Surface reengineering of RPA70N enables co-crystallization with an inhibitor of the RPA interaction motif of ATRIP. Replication Protein A (RPA) is the primary single stranded DNA (ssDNA) binding protein in eukaryotes. The N-terminal domain of the RPA70 subunit (RPA70N) interacts via a basic cleft with a wide range of DNA processing proteins, including several that regulate DNA damage response and repair. Small molecule inhibitors that disrupt these protein-protein interactions are therefore of interest as chemical probes of these critical DNA processing pathways and as inhibitors to counter the up-regulation of DNA damage response and repair associated with treatment of cancer patients with radiation or DNA damaging agents. Determination of three-dimensional structures of protein-ligand complexes is an important step for elaboration of small molecule inhibitors. However, although crystal structures of free RPA70N and an RPA70N-peptide fusion construct have been reported, RPA70N-inhibitor complexes have been recalcitrant to crystallization. Analysis of the P61 lattice of RPA70N crystals led us to hypothesize that the ligand-binding surface was occluded. Surface reengineering to alter key crystal lattice contacts lead to the design of RPA70N E7R, E100R and E7R, E100R mutants. These mutants crystallized in a P212121 lattice that clearly had significant solvent channels open to the critical basic cleft. Analysis of X-ray crystal structures, target peptide binding affinities, and (15)N-(1)H HSQC NMR spectra showed that the mutations do not result in perturbations of the RPA70N ligand-binding surface. The success of the design was demonstrated by determining the structure of RPA70N E7R soaked with a ligand discovered in a previously reported molecular fragment screen. A fluorescence anisotropy competition binding assay revealed this compound can inhibit the interaction of RPA70N with the peptide binding motif from the DNA damage response protein ATRIP. The implications of the results are discussed in the context of ongoing efforts to design RPA70N inhibitors. 23893543 Rapid degradation of solid-phase bound peptides by the 20S proteasome. Proteasomes are cellular proteases involved in the degradation of numerous cellular proteins. The 20S proteasome is a cylindrical 28-mer protein complex composed of two outer heptameric α-rings forming the entrance for the protein substrate and two inner heptameric β-rings carrying the catalytic sites. Numerous in vitro studies have provided evidence that the 20S proteasome may degrade peptides of various lengths and even unfolded full-length polypeptide chains. However, a direct demonstration that the 20S proteasome may also cleave surface-attached immobilized peptides is lacking so far. To this end, we used a model system by coupling peptides from different source proteins covalently to the surface of glass beads and applied nanoLC/MS analysis to monitor the generation of proteolytic fragments in the presence of the 20S proteasome. Detectable amounts of cleavage products occurred within a few minutes indicating a much higher cleavage rate than observed with the same substrates in solution. Our finding lends support to the idea that proteasomes may directly degrade segments of membrane-bound proteins protruding into the aqueous phase. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd. 23908480 Association of the outer membrane protein Omp33with fitness and virulence of Acinetobacter baumannii. Outer membrane protein 33 (Omp33) is an outer membrane porin of Acinetobacterbaumannii associated with carbapenem resistance. However, the role of Omp33 in the fitness and virulence of A. baumannii remains unknown. In the present study, we investigated the role of Omp33 in fitness and virulence of A. baumannii by using an isogenic knockoutstrain deficient in the omp33 gene (JPAB02), derived from the ATCC 17978wt.Bothin vitro andin vivo defect in the growth rate was found in the JPAB02 strain in competition with theATCC 17978wthighlighting the effect of Omp33 on the metabolic fitness. A significantreduction was observed bothin adherence and invasionofhuman lung epithelial cells and in cytotoxicity of these cells and macrophages withJPAB02. In a murine peritoneal sepsis model, JPAB02 strain exhibited lower lethal dose 0 (LD0), LD50, and LD100, and dissemination in mice, withreduced bacterial concentration in spleen and lungs. From these data, we concluded thatOmp33play animportant role for fitnessand virulence of A. baumannii. 23824763 Cannabinoids Inhibit T-cells via Cannabinoid Receptor 2 in an In Vitro Assay for Graft Rejection, the Mixed Lymphocyte Reaction. Cannabinoids are known to have anti-inflammatory and immunomodulatory properties. Cannabinoid receptor 2 (CB2) is expressed mainly on leukocytes and is the receptor implicated in mediating many of the effects of cannabinoids on immune processes. This study tested the capacity of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) and of two CB2-selective agonists to inhibit the murine Mixed Lymphocyte Reaction (MLR), an in vitro correlate of graft rejection following skin and organ transplantation. Both CB2-selective agonists and Δ(9)-THC significantly suppressed the MLR in a dose dependent fashion. The inhibition was via CB2, as suppression could be blocked by pretreatment with a CB2-selective antagonist, but not by a CB1 antagonist, and none of the compounds suppressed the MLR when splenocytes from CB2 deficient mice were used. The CB2 agonists were shown to act directly on T-cells, as exposure of CD3(+) cells to these compounds completely inhibited their action in a reconstituted MLR. Further, the CB2-selective agonists completely inhibited proliferation of purified T-cells activated by anti-CD3 and anti-CD28 antibodies. T-cell function was decreased by the CB2 agonists, as an ELISA of MLR culture supernatants revealed IL-2 release was significantly decreased in the cannabinoid treated cells. Together, these data support the potential of this class of compounds as useful therapies to prolong graft survival in transplant patients. 22580630 The Relationships Among Satisfaction With Social Support, Quality of Life, and Survival 5 to 10 Years After Heart Transplantation. Despite the fact that social support has been found to be important to cardiovascular health, there is a paucity of information regarding the relationship between social support and outcomes long-term after heart transplantation (HT). Therefore, the purposes of our retrospective analyses of a prospective, longitudinal study were to examine (1) the relationship between satisfaction with social support and post-HT health-related quality of life (HRQOL) and survival and (2) whether 2 types of social support (emotional and tangible) were predictors of survival and HRQOL. Data were collected from 555 HT patients over a 5-year period (78% male, 88% white; mean age, 53.8 years at time of transplantation) at 4 US medical centers using the following instruments: Social Support Index, Quality of Life Index, Heart Transplant Stressor Scale, Jalowiec Coping Scale, and medical records review. Statistical analyses included t tests, correlations, Kaplan-Meier survival actuarials, and linear and multivariable regression. Patients were very satisfied with overall social support from 5 to 10 years after HT (0 = very satisfied, 1 = very dissatisfied), which was stable across time (P = .74). Satisfaction with emotional social support (P = .53) and tangible social support (P = .61) also remained stable over time. When stratified into low, medium, and high levels of satisfaction, satisfaction with social support was not related to survival (P = .24). At 5 years, overall satisfaction with social support was a predictor of HRQOL (r = 0.59, P < .0001), and satisfaction with emotional social support was a predictor of HRQOL at 10 years after HT (r = 0.66, P < .0001). Patients were very satisfied over time with emotional and tangible social support. While social support explained quality of life outcomes, it did not predict survival. Knowledge of relationships among social support, stress, and outcomes may assist clinicians to address social support needs and resources long-term after HT. 23892429 Suppression of inflammatory gene expression in T cells by Porphyromonas gingivalis is mediated by targeting MAPK signaling. There is increasing awareness of the effects of Porphyromonas gingivalis on host immune responses. Degradation of cytokines and chemokines by cysteine proteinases has previously been reported. However, the precise mechanisms by which P. gingivalis is able to alter intracellular signaling, and thus proliferation and inflammation, have not been described. We have previously reported suppression of activator protein-1 (AP-1) and degradation of IL-2 by proteinases from P. gingivalis. In the present study, we have analyzed the effects of P. gingivalis on Jurkat T-cell signal transduction and subsequent IL-2 and CXCL8 expression. We found that CXCL8, but not IL-2, gene expression levels were significantly suppressed by viable P. gingivalis. Analysis of intracellular signaling revealed an inhibitory effect of P. gingivalis on c-Jun and c-Fos, but not NFκB (p50 and p65), NFAT or STAT5 expression. This inhibitory effect was not due to suppression of mitogen-activated protein kinase (MAPK) (p38, erk and JNK) gene expression, but was rather due to prevention of protein kinase C (PKC) and p38 phosphorylation, as demonstrated by western blot analysis. Furthermore, SOCS1 and SOCS3 expression levels decreased following treatment of Jurkat T cells with viable P. gingivalis. The results indicate that P. gingivalis is able to suppress inflammatory gene expression by targeting the activity of MAPK pathways in T cells, which was confirmed by using specific inhibitors of NF-κB, PKC, ERK, p38 and JNK.Cellular & Molecular Immunology advance online publication, 29 July 2013; doi:10.1038/cmi.2013.23. 23563577 Is discontinuation of clopidogrel necessary for intracapsular hip fracture surgery? Analysis of 102 hemiarthroplasties. An increasing number of elderly patients are managed with long-term antiplatelet therapy. Such patients often present with hip fracture requiring surgical intervention and may be at increased risk of perioperative bleeding and complications. The aim of this study was to ascertain whether it is necessary to stop clopidogrel preoperatively to avoid postoperative complications following hip hemiarthroplasty surgery in patients with intracapsular hip fracture. A retrospective review of 102 patients with intracapsular hip fracture with either perioperative clopidogrel therapy [clopidogrel group (CG)] or no previous clopidogrel exposure [no clopidogrel group (NCG)] who underwent hip hemiarthroplasty surgery was undertaken. Statistical comparison on pre- and postoperative haemoglobin, American Society of Anesthesiologists (ASA) grade, comorbidities, operative time, transfusion requirements, hospital length of stay (LOS), wound infection, haematoma and reoperation rate between the two groups was undertaken. Regression analysis was undertaken to ascertain the risk ratios (RR) of complications and transfusion associated with clopidogrel. There was no difference with respect to ASA grade, comorbidities (except cardiac comorbidities), pre- and postoperative haemoglobin levels, operation time, age or gender between the two groups. Four and two patients, respectively, required transfusion postoperatively in the CG and NCG (p = 0.37). There was no difference with respect to LOS, wound infection, haematoma or reoperation rate between the two groups postoperatively. The covariate-adjusted RR for complications and transfusion while being on clopidogrel were 0.43 [95 % confidence interval (CI) 0.07-2.60] and 3.96 (95 % CI 0.40-39.68), respectively. Continuing clopidogrel therapy throughout the perioperative period in patients with intracapsular hip fracture is not associated with an increased risk of complications following hip hemiarthroplasty surgery. 23939376 AN UROKINASE RECEPTOR-DERIVED PEPTIDE INHIBITING VEGF-DEPENDENT DIRECTIONAL MIGRATION AND VASCULAR SPROUTING. The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration and uPAR88-92 is the minimal sequence required to induce cell motility. We previously shown that soluble forms of uPAR elicit angiogenic responses through their uPAR88-92 chemotactic sequence and that the synthetic peptide SRSRY exerts similar effects. By a drug-design approach, based on the conformational analysis of the uPAR88-92 sequence, we developed peptides (pERERY, RERY and RERF), which potently inhibit signaling triggered by uPAR88-92. In this study, we present evidence that these peptides are endowed also with a clear-cut anti-angiogenic activity, although to different extents. The most active RERF prevents tube formation by human endothelial cells exposed to SRSRY. RERF also inhibits VEGF-triggered endothelial cell migration and cord-like formation in a dose-dependent manner, starting in the femtomolar range. RERF prevents F-actin polymerization, recruitment of αvβ3 integrin at focal adhesions and αvβ3/VEGFR2 complex formation in endothelial cells exposed to VEGF. At molecular level, inhibitory effect of RERF on VEGF signaling is shown by the decreased amount of phospho-FAK and phospho-Akt in VEGF-treated cells. In vivo, RERF prevents VEGF-dependent capillary sprouts originating from the host vessels that invaded angioreactors implanted in mice and neovascularization induced by sub-corneal implantation of pellets containing VEGF in rabbits. Consistently, RERF reduced the growth and vascularization rate of tumors formed by HT1080 cells injected subcutaneously in the flanks of nude mice, indicating that RERF is a promising therapeutic agent for the control of diseases fuelled by excessive angiogenesis, such as cancer. 23880943 Tattooing complicated by multivalvular bacterial endocarditis. Tattooing is becoming a popular practice and more commonly done. Although modern tattooing is considered a more hygienic and technological version of ancient methods, previously reported cases point out the risk of infection after tattooing due to use of nonsterile equipment or suboptimal infection-control practices. Infective endocarditis (IE) after tattooing has been reported only in 1 patient with bicuspid aortic valvular disease. Herein, we report a case of multivalvular IE secondary to tattooing in a patient without known prior valvular heart disease. 22702954 Abundant immunoglobulin E-positive cells in skin lesions support an allergic etiology of atopic dermatitis in the elderly. Background/Objectives  Atopic dermatitis (AD) in the elderly is gradually increasing in industrialized countries in association with the aging of society. We report herein four cases of elderly AD {three extrinsic [immunoglobulin (Ig)E-mediated allergy]; one intrinsic (non-IgE-allergy)} in which we investigated the presence of IgE+ cells in lesional skin. Methods/Results  Single immunohistochemical and double immunofluorescence stainings were performed for skin biopsy specimens from AD patients and non-atopic control subjects with chronic eczema. In the lesional lichenified skin of patients with extrinsic elderly AD, numerous IgE+ cells were found among inflammatory cells infiltrates in the upper dermis. Comparative analysis of single immunohistochemistry results using serial paraffin and/or frozen sections found that many IgE+ cells showed identical distributions to tryptase+ mast cells. IgE+ cells coincident with CD1a+ Langerhans cells in the epidermis were found in small numbers only in frozen sections. Double immunofluorescence staining for IgE and CD11c revealed cells coexpressing IgE and CD11c with a dendritic morphology in the papillary and upper dermis. These IgE+ mast cells and IgE+ CD11c+ cells were also found in cured normal-looking skin from a patient with extrinsic elderly AD after successful treatment. Although only a few weakly positive IgE+ cells were detected, no IgE+CD11c+ cells were found in specimens from patients with intrinsic elderly AD or non-atopic chronic eczema. Conclusion  IgE-mediated allergic inflammation may play an important role in the pathobiology of elderly AD, similar to other age groups of AD. 23836640 Geminin deploys multiple mechanisms to regulate Cdt1 before cell division thus ensuring the proper execution of DNA replication. Cdc10-dependent transcript 1 (Cdt1) is an essential DNA replication protein whose accumulation at the end of the cell cycle promotes the formation of pre-replicative complexes and replication in the next cell cycle. Geminin is thought to be involved in licensing replication by promoting the accumulation of Cdt1 in mitosis, because decreasing the Geminin levels prevents Cdt1 accumulation and impairs DNA replication. Geminin is known to inhibit Cdt1 function; its depletion during G2 leads to DNA rereplication and checkpoint activation. Here we show that, despite rapid Cdt1 protein turnover in G2 phase, Geminin promotes Cdt1 accumulation by increasing its RNA and protein levels in the unperturbed cell cycle. Therefore, Geminin is a master regulator of cell-cycle progression that ensures the timely onset of DNA replication and prevents its rereplication. 23914889 Dermatologic surgery and cosmetic procedures during pregnancy and the post-partum period. Dermatologic surgery is changed in the pregnant and postpartum patient. The physiologic changes associated with pregnancy require attention to the timing of surgery as well as the positioning and technique to maximize the outcome for the patient. The surgeon must also remember the risks to the fetus or nursing newborn in planning any surgical procedure. This is the one time when there is more than one patient in every procedure. This article will review the timing of surgery, tumors of pregnancy, surgical positioning, local anesthetics, surgical technique, and cosmetic procedures. This information should help provide a safe surgical procedure for the mother and the child. 23700130 Bias and sensitivity of proprioception of a passively felt hand path with and without a secondary task. Previously, we observed changes in the scale, rotation, and location of drawn shapes when subjects simultaneously performed a secondary task, but not in the shape or proportion of the drawing. We suggested the secondary task impacted motor planning and execution or proprioception of the primary task. To isolate for proprioceptive effects, here we used the same secondary task during passive shape perception. A robotic manipulandum moved the subject's hand around the perimeter of a template shape and then a test shape differing in size, proportion, or location. Subjects also performed the same primary task while simultaneously performing a secondary task of reporting the orientation of right or left tilted arrows. We compared the performance between single and dual task, and different workspaces. In single-task conditions, subjects perceived scale, location, and proportion very close to the actual (all biases under 1 cm). A secondary task only increased the uncertainty range for judgment of scale, with no other effect. Subjects judged shapes in the centered workspace to be smaller and closer relative to the template compared with those in the peripheral workspace, although in that workspace, it was more difficult to discern changes in the proportion of the shape. The result for scale in the current passive paradigm is not different from our active study in which efference copy was available. This suggests that the scale parameters of the shape, whether actively or passively encountered, are disrupted by task interference at the level of proprioception or sensory integration rather than motor planning and execution. 23489244 Optical coherence tomography for measuring the tear film meniscus: correlation with schirmer test and tear-film breakup time. To compare tear meniscus height (TMH) and area (TMA) values obtained by optical coherence tomography (OCT) with the Schirmer test and tear-film break-up time (TBUT) values. In this prospective cross-sectional study, the right eyes of 300 consecutive patients were studied. All patients underwent routine ophthalmologic examination. Schirmer and TBUT measurements were taken, and tear-film OCT images were obtained. Using OCT, the TMH (i.e. the line connecting the intersection of the meniscus with the cornea and eyelid) and cross-sectional TMA were calculated. Patients were divided into Groups 1 (Schirmer values ≤5 mm) and 2 (Schirmer values >5 mm). Data were analyzed using SPSS 13.0 software. The Mann-Whitney U-test was used for the comparison of groups. Correlations between tear parameters were analyzed. There were no significant differences in age, logMAR, or IOP values (p = 0.480, 0.077 and 0.146, respectively) between the two groups. Mean TBUTs were 5.1 ± 2.9 and 9.5 ± 4.2 s for Groups 1 and 2, respectively (p < 0.001). Mean TMHs were 237.9 ± 108.9 and 324.3 ± 158.9 μm for Groups 1 and 2, respectively (p < 0.001). Mean TMAs were significantly lower in Group 1 compared to Group 2 (p < 0.001; 0.027 ± 0.028 versus 0.055 ± 0.059 mm(2), respectively). Correlations between Schirmer values and TMH, and between Schirmer values and TMA, were significant (p = 0.001 and <0.001, respectively). OCT values were significantly lower in patients with Schirmer values of <5 mm. Tear meniscus measurements obtained by OCT are reliable for establishing a diagnosis of dry eye. 23897819 Myocilin Mediates Myelination in the Peripheral Nervous System through ErbB2/3 Signaling. The glaucoma-associated gene, myocilin, is expressed in ocular and non-ocular tissues including the peripheral nervous system, but its functions in these tissues remain poorly understood. We demonstrate that in sciatic nerve, myocilin is expressed in Schwann cells with high concentrations at the nodes of Ranvier. There, myocilin interacts with gliomedin, neurofascin, and NrCAM, which are essential for node formation and function. Treatment of isolated dorsal root ganglion cultures with myocilin stimulates clustering of the nodal proteins neurofascin and sodium channel NaV1.2. Sciatic nerves of myocilin null mice express reduced levels of several myelin-associated and basal membrane proteins compared with those of wild-type littermates. They also demonstrate reduced myelin sheath thickness and partial disorganization of the nodes. Myocilin signaling through ErbB2/3 receptors may contribute to these observed effects. Myocilin binds to ErbB2/ErbB3, activates these receptors and affects the downstream PI3K-AKT signaling pathway. These data implicate a role for myocilin in the development and/or maintenance of myelination and nodes of Ranvier in sciatic nerve. 22504946 The financial crisis and global health: the International Monetary Fund's (IMF) policy response. In this article, we interrogate the policy response of the International Monetary Fund (IMF) to the global financial crisis, and discuss the likely global health implications, especially in low-income countries. In doing so, we ask if the IMF has meaningfully loosened its fiscal deficit targets in light of the economic challenges posed by the financial crisis and adjusted its macro-economic policy advice to this new reality; or has the rhetoric of counter-cyclical spending failed to translate into additional fiscal space for IMF loan-recipient countries, with negative health consequences? To answer these questions, we assess several post-crisis IMF lending agreements with countries requiring financial assistance, and draw upon recent academic studies and civil society reports examining policy conditionalities still being prescribed by the IMF. We also reference recent studies examining the health impacts of these conditionalities. We demonstrate that while the IMF has been somewhat more flexible in its crisis response than in previous episodes of financial upheaval, there has been no meaningful rethinking in the application of dominant neoliberal macro-economic policies. After showing some flexibility in the initial crisis response, the IMF is pushing for excessive contraction in most low and middle-income countries. We conclude that there remains a wide gap between the rhetoric and the reality of the IMF's policy and programming advice, with negative implications for global health. 23583673 Ionic profile of honey as a potential indicator of botanical origin and global environmental pollution. Aim of this study was to determine by Ion Chromatography ions (Na(+), Ca(++), Mg(++), NH4(+), Cl(-), Br(-), SO4(2-), NO3(-), PO4(3-)) in honeys (honeydew and floral nectar honeys) from different Italian Regions and from countries of the Western Balkan area. The compositional data were processed by multivariate analysis (PCA and HCA). Arboreal honeydew honeys from the Western Balkans had higher concentrations (from two to three times) of some environmental pollutants (Br(-), SO4(2-) and PO4(3-) contents), due to industrial and agricultural activities, than those from Italian regions. The cationic profiles were very similar in both groups. Multivariate analysis indicated a clear difference between nectar honeys and arboreal/honeydew honeys (recognition of the botanical origin). These findings point to the potential of ionic constituents of honey as indicators of environmental pollution, botanical origin and authenticity. 22743048 Social vs. environmental stress models of depression from a behavioural and neurochemical approach. Major depression is a mental disorder often preceded by exposure to chronic stress or stressful life events. Recently, animal models based on social conflict such as chronic social defeat stress (CSDS) are proposed to be more relevant to stress-induced human psychopathology compared to environmental models like the chronic mild stress (CMS). However, while CMS reproduces specifically core depressive symptoms such as anhedonia and helplessness, CSDS studies rely on the analysis of stress-induced social avoidance, addressing different neuropsychiatric disorders. Here, we study comparatively the two models from a behavioural and neurochemical approach and their possible relevance to human depression. Mice (C57BL/6) were exposed to CMS or CSDS for six weeks and ten days. Anhedonia was periodically evaluated. A battery of test applied during the fourth week after the stress procedure included motor activity, memory, anxiety, social interaction and helplessness. Subsequently, we examined glutamate, GABA, 5-HT and dopamine levels in the prefrontal cortex, hippocampus and brainstem. CMS induced a clear depressive-like profile including anhedonia, helplessness and memory impairment. CSDS induced anhedonia, hyperactivity, anxiety and social avoidance, signs also common to anxiety and posttraumatic stress disorders. While both models disrupted the excitatory inhibitory balance in the prefrontal cortex, CMS altered importantly this balance in the brainstem. Moreover, CSDS decreased dopamine in the prefrontal cortex and brainstem. We suggests that while depressive-like behaviours might be associated to altered aminoacid neurotransmission in cortical and brain stem areas, CSDS induced anxiety behaviours might be linked to specific alteration of dopaminergic pathways involved in rewarding processes. 23911783 Behavior of MCPA in four intensive cropping soils amended with fresh, composted, and aged olive mill waste. An evaluation was made of the impact of olive mill waste and its organic matter transformation on the sorption, desorption, leaching, and degradation of the herbicide MCPA when the waste was applied to four Mediterranean soils. The soils were amended in the laboratory with fresh, composted, and field-aged olive mill waste (OW, COW, and AOW treatments, respectively). It was found that the greater the amount of OW applied to the soils, but especially the greater its organic matter maturity, the greater the adsorption of MCPA. Compared with unamended soils, at the 5% rate of application the adsorption capacity increased by between 9.8% and 40%, 148% and 224%, and by 258% for the OW, COW, and AOW amended soils, respectively. The hysteresis coefficients were significantly lower in the OW-amended soils than in AOW or COW-amended soils, indicating that the adsorbed MCPA could be easily desorbed in OW-amended soils if the amendment is not aged or composted. While the OW addition greatly extended the persistence of MCPA, the application of COW enhanced MCPA degradation in all the soils, as corresponded to the increased soil microbial activity indicated by the higher levels of soil dehydrogenase activity. Fresh OW amendment significantly increased the amount of MCPA leached (from 13.7% in the most alkaline soil to 36.7% in the most acidic, at the 5% rate of application), favored by the higher levels of water soluble organic carbon content. However, leaching losses of the herbicide were reduced by up to 39.9% and 55.3% in the COW- and AOW-amended soils at the 5% loading rate, respectively. The use of OW with a high degree of organic matter maturity may be regarded as a potentially useful management practice to reduce MCPA leaching in soils with low organic matter content. The application of fresh OW, however, could well increase the risk of groundwater contamination by this herbicide, especially in acidic soils. 23305921 Synthesis and dual biological effects of hydroxycinnamoyl phenylalanyl/prolyl hydroxamic acid derivatives as tyrosinase inhibitor and antioxidant. We previously reported that caffeoyl-amino acidyl-hydroxamic acid (CA-Xaa-NHOH) acted as both a good antioxidant and tyrosinase inhibitor, in particular when caffeic acid was conjugated with proline or amino acids having aromatic ring like phenylalanine. Here, various hydroxycinnamic acid (HCA) derivatives were further conjugated with phenylalanyl hydroxamic acid and prolyl hydroxamic acid (HCA-Phe-NHOH and HCA-Pro-NHOH) to study the structure and activity relationship as both antioxidants and tyrosinase inhibitors. When their biological activities were evaluated, all HCA-Phe-NHOH and HCA-Pro-NHOH exhibited enhanced antioxidant activity compared to HCA alone. Moreover, derivatives of caffeic acid, ferulic acid, and sinapic acid inhibited lipid peroxidation more efficiently than vitamin E analogue (Trolox). In addition, derivatives of caffeic acid and sinapic acid efficiently inhibited tyrosinase activity and reduced melanin content in melanocytes Mel-Ab cell. 23643587 Partial deletion of β9 loop in pancreatic lipase-related protein 2 reduces enzyme activity with a larger effect on long acyl chain substrates. Structural studies on pancreatic lipase have revealed a complex architecture of surface loops surrounding the enzyme active site and potentially involved in interactions with lipids. Two of them, the lid and β9 loop, expose a large hydrophobic surface and are considered as acyl chain binding sites based on their interaction with an alkyl phosphonate inhibitor. While the role of the lid in substrate recognition and selectivity has been extensively studied, the implication of β9 loop in acyl chain stabilization remained hypothetical. The characterization of an enzyme with a natural deletion of the lid, guinea pig pancreatic lipase-related protein 2 (GPLRP2), suggests however an essential contribution of the β9 loop in the stabilization of the acyl enzyme intermediate formed during the lipolysis reaction. A GPLRP2 mutant with a seven-residue deletion of β9 loop (GPLRP2-Δβ9) was produced and its enzyme activity was measured using various substrates (triglycerides, monoglycerides, galactolipids, phospholipids, vinyl esters) with short, medium and long acyl chains. Whatever the substrate tested, GPLRP2-Δβ9 activity is drastically reduced compared to that of wild-type GPLRP2 and this effect is more pronounced as the length of substrate acyl chain increases. Changes in relative substrate selectivity and stereoselectivity remained however weak. The deletion within β9 loop has also a negative effect on the rate of enzyme inhibition by alkyl phosphonates. All these findings indicate that the reduced enzyme turnover observed with GPLRP2-Δβ9 results from a weaker stabilization of the acyl enzyme intermediate due to a loss of hydrophobic interactions. 23104969 Differential influences of ethanol on early exposure to racemic methylphenidate compared with dexmethylphenidate in humans. Enantioselective hydrolysis of oral racemic methylphenidate (dl-MPH) by carboxylesterase 1 (CES1) limits the absolute bioavailability of the pharmacologically active d-MPH isomer to approximately 30% and that of the inactive l-MPH to only 1-2%. Coadministration of dl-MPH with ethanol results in elevated d-MPH plasma concentrations accompanied by CES1-mediated enantioselective transesterification of l-MPH to l-ethylphenidate (EPH). The present study tested the hypothesis that administration of the pure isomer dexmethylphenidate (d-MPH) will overcome the influence of ethanol on d-MPH absorption by eliminating competitive CES1-mediated presystemic metabolism of l-MPH to l-EPH. Twenty-four healthy volunteers received dl-MPH (0.3 mg/kg) or d-MPH (0.15 mg/kg), with or without ethanol (0.6 g/kg). During the absorption phase of dl-MPH, concomitant ethanol significantly elevated d-MPH plasma concentrations (44-99%; P < 0.005). Furthermore, immediately following the ethanol drink the subjective effects of "high," "good," "like," "stimulated," and overall "effect" were significantly potentiated (P ≤ 0.01). Plasma l-EPH concentrations exceeded those of l-MPH. Ethanol combined with pure d-MPH did not elevate plasma d-MPH concentrations during the absorption phase, and the ethanol-induced potentiation of subjective effects was delayed relative to dl-MPH-ethanol. These findings are consistent with l-MPH competitively inhibiting presystemic CES1 metabolism of d-MPH. Ethanol increased the d-MPH area under the curve (AUC)(0-inf) by 21% following dl-MPH (P < 0.001) and 14% for d-MPH (P = 0.001). In men receiving d-MPH-ethanol, the d-MPH absorption partial AUC(0.5-2 hours) was 2.1 times greater and the time to maximum concentration (T(max)) occurred 1.1 hours earlier than in women, consistent with an increased rate of d-MPH absorption reducing hepatic extraction. More rapid absorption of d-MPH carries implications for increased abuse liability. 23868258 Ultrasensitive fluorescent proteins for imaging neuronal activity. Fluorescent calcium sensors are widely used to image neural activity. Using structure-based mutagenesis and neuron-based screening, we developed a family of ultrasensitive protein calcium sensors (GCaMP6) that outperformed other sensors in cultured neurons and in zebrafish, flies and mice in vivo. In layer 2/3 pyramidal neurons of the mouse visual cortex, GCaMP6 reliably detected single action potentials in neuronal somata and orientation-tuned synaptic calcium transients in individual dendritic spines. The orientation tuning of structurally persistent spines was largely stable over timescales of weeks. Orientation tuning averaged across spine populations predicted the tuning of their parent cell. Although the somata of GABAergic neurons showed little orientation tuning, their dendrites included highly tuned dendritic segments (5-40-µm long). GCaMP6 sensors thus provide new windows into the organization and dynamics of neural circuits over multiple spatial and temporal scales. 23669646 The associations of body image, anxiety, and smoking among mexican-origin youth. Among Mexican-origin teenagers, anxiety is associated with cigarette experimentation, while among girls and young women from other ethnic groups the desire to be thin is associated with smoking. However, little is known about the associations of body image concerns with smoking in Mexican-origin youth, particularly when accounting for anxiety. In 2005-2006, 1,328 Mexican-origin adolescents aged 11 to 13 years enrolled in a cohort study to examine nongenetic and genetic factors associated with cigarette experimentation. In 2008-2009, 1,154 participants completed a follow-up when they reported their smoking status, anxiety, and body image. Height and weight were measured. In 2010-2011, 1,001 participants completed another follow-up when they reported their smoking status. Multivariate multinomial regression models were computed to examine associations between smoking behavior assessed in 2010-2011 and body image score, anxiety, and body mass index assessed in 2008-2009, controlling for gender, country of birth, age, and parental education. Of the 892 participants with complete data, 48% were boys, 74% were U.S.-born and in 2008-2009, were 14.29 years (SD = 1) old. Having smoked less than a whole cigarette was associated with being male (OR = 1.53), older age (OR = 1.42), a body mass index <85th percentile (OR = 1.93), and poor body image (OR = 1.12). Having smoked more than one cigarette was associated with being male (OR = 3.54), older age (OR = 1.86), anxiety (OR = 1.04), and poor body image (OR = 1.11). Poor body image and anxiety were independently associated with cigarette experimentation among Mexican-origin youth. Implications for the design of culturally appropriate smoking prevention messages are discussed. 23835777 Long Noncoding RNA: a New Player of Heart Failure? One the most important discoveries of the post-genomic era is that a large fraction of the genome transcribes a heterogeneous population of noncoding RNAs (ncRNA). ncRNAs shorter than 200 nucleotides are usually identified as short/small ncRNAs-examples include PIWI-interacting RNAs, small interfering RNAs, and microRNAs (miRNAs)-whereas those longer than 200 nucleotides are classified as long ncRNAs (lncRNAs). These molecules are emerging as important regulators of cellular process, such as development, differentiation, and metabolism. Not surprisingly, ncRNAs are involved also in human diseases, such as cancer and metabolic and neuronal disorders. Although the role of miRNAs is being largely investigated in cardiovascular biology, little is known about other classes of ncRNA in this field. However, recent reports have started to reveal the importance of lncRNA in heart development and suggest also an involvement in heart failure. Here, we will discuss these reports and the therapeutic potential of lncRNA for heart failure. 23097178 Factors associated with serum/plasma concentrations of vitamins A, C, E and carotenoids in older people throughout Europe: the EUREYE study. To report on plasma/serum levels of antioxidant vitamin and carotenoids in older adults resident in multiple countries in Europe and examine relationships with potential modifiers. Population-based cross-sectional European Eye Study in 7 centres from northern to southern Europe. In total, 4,133 participants aged 65 years or over, collected by random sampling, were recruited. Questionnaires relating to diet, lifestyle and medical history were administered. Non-fasting blood samples were analysed in a single laboratory for vitamins A, C and E and a panel of carotenoids. Associations were analysed by bootstrapped multivariable regression analysis. Centre and season influenced the serum and plasma concentrations of all antioxidant vitamins and carotenoids. Gender, BMI, smoking, age, education, alcohol consumption and supplement use were also significantly associated with some, but not all, of the antioxidant vitamins and carotenoids examined. The proportion of variance explained ranged from 4.8 % for retinol to 25.2 % for zeaxanthin. In older people, antioxidant vitamin and carotenoid status varies by centre and season, but is also associated with other behavioural and lifestyle variables. Studies aiming to demonstrate an association between antioxidant vitamins and carotenoid status and chronic disease risk should consider these potential confounders. 23405013 ERK-mediated phosphorylation of fibroblast growth factor receptor 1 on Ser777 inhibits signaling. Fibroblast growth factor 1 (FGF1) controls cellular activities through the activation of specific cell-surface FGF receptors (FGFRs). Transphosphorylation of tyrosine residues in the kinase domain of FGFRs leads to activation of intracellular signaling cascades, including those mediated by mitogen-activated protein kinases (MAPKs). FGFRs also contain a serine-rich C-terminal tail. We identified a regulatory mechanism of FGFR signaling involving phosphorylation of Ser(777) in the C-terminal region of FGFR1 by the MAPKs extracellular signal-regulated kinase 1 (ERK1) and ERK2. Prevention of the phosphorylation of Ser(777) in FGFR1 or mutation of Ser(777) to alanine enhanced FGF-stimulated receptor tyrosine phosphorylation and increased cell proliferation, cell migration, and axonal growth. A form of FGFR1 with a phosphomimetic mutation at Ser(777) exhibited reduced signaling. Activation of MAPKs by other receptor tyrosine kinases also resulted in phosphorylation of Ser(777) in FGFR1, thereby enabling crosstalk regulation of FGFR activity by other signaling pathways. Our data reveal a negative feedback mechanism that controls FGF signaling and thereby protects the cell from excessive activation of FGFR. 23643735 Ion-pair strategy for enabling amifostine oral absorption: Rat in situ and in vivo experiments. This study shows the effect of ion pair formation on intestinal absorption and oral bioavailability of amifostine. Amifostine is a prodrug used as a highly potent and selective radiotherapy and chemotherapy protectant but due to its low lipophilicity and charge at physiological pH range, its trans epithelial transport and its potential for oral drug delivery is very low. Ion pair formation with negatively charged counter ions was evaluated by in situ rat perfusion studies as a possible strategy to enhance intestinal absorption of amifostine. Succinic acid, phthalic acid and benzoic acid were used as counter ions. Rat intestinal perfusion studies confirmed a statistically significant increase in amifostine permeability in the presence of the counter ions in the order of succinic>phthalic>benzoic. Rat pharmacokinetic studies in vivo were performed to calculate oral absolute bioavailability of amifostine alone and with ion pairs in order to confirm the in situ perfusion results and the applicability of the ion pair approach. Intravenous and intraduodenal administrations were done in rats using a permanent jugular vein cannulation technique and a duodenal cannulation method to avoid drug degradation in stomach. In vivo oral bioavailability studies demonstrated a 20-30-fold increase in amifostine bioavailability with succinic acid depending on counter ion ratio and 10-fold increase with phthalic acid as ion pair. In summary ion pair strategy with succinic acid could enable amifostine oral administration on enteric coated formulations. 23641676 Pharmacogenetic considerations for late life depression therapy. Introduction: Geriatric depression is a heterogeneous disorder with a complex genetic background. Current first-line treatment of depression is associated with a lower therapeutic outcome in aged depressed patients, when compared to younger subjects. Research which has explored this inadequate response has highlighted several factors which have come into play with the pharmacogenetics of antidepressants in the elderly being a particular area of interest. Areas covered: The authors perform a critical review of the English language articles from PubMed using search terms such as late-life/geriatric depression, antidepressants, pharmacogenetics, pharmacogenomics, pharmacokinetic, genetic, genotype, remission, therapy, treatment and polymorphism. Expert opinion: The emerging clinical and pharmacogenetic data are slowly unveiling the importance of the genome - age interaction in antidepressant response. This data introduces a critical new parameter in personalized medicine. A profound analysis of the age factor in the pharmacogenetics of antidepressant response is imperative, in order to elucidate the clinical significance of these findings and thereby improve patient treatment in the elderly. 23897671 Serial computed tomographic and positron emission tomographic properties of injection material used for vocal fold augmentation. This study aimed to demonstrate the radiological properties of hyaluronic acid (HA) and calcium hydroxylapatite (CAHA) on serial computed tomography (CT) and positron emission tomography (PET) scan. Retrospective Case Series. Retrospective chart and imaging analysis of patients who underwent HA or CAHA injection laryngoplasty. Total of 243 patients who underwent more than one CT of PET after last injection laryngoplasty were included. Sixty-eight patients received HA injection and 175 patients received CAHA injection. In all cases HA showed hypo-density in CT and no abnormal uptake on PET. CAHA showed bright calcific density on CT scan and high uptake on PET but had disappeared with time in 18 months if injected less than 0.85 mL in amount. These findings support previous clinical studies on CAHA longevity and provide proper radiological interpretation on injection materials in the vocal folds. IV (Case series) Laryngoscope, 2013. 23792425 Ultra-deep profiling of alternatively spliced Drosophila Dscam isoforms by circularization-assisted multi-segment sequencing. The Drosophila melanogaster gene Dscam (Down syndrome cell adhesion molecule) can generate thousands of different ectodomains via mutual exclusive splicing of three large exon clusters. The isoform diversity plays a profound role in both neuronal wiring and pathogen recognition. However, the isoform expression pattern at the global level remained unexplored. Here, we developed a novel method that allows for direct quantification of the alternatively spliced exon combinations from over hundreds of millions of Dscam transcripts in one sequencing run. With unprecedented sequencing depth, we detected a total of 18 496 isoforms, out of 19 008 theoretically possible combinations. Importantly, we demonstrated that alternative splicing between different clusters is independent. Moreover, the isoforms were expressed across a broad dynamic range, with significant bias in cell/tissue and developmental stage-specific patterns. Hitherto underappreciated, such bias can dramatically reduce the ability of neurons to display unique surface receptor codes. Therefore, the seemingly excessive diversity encoded in the Dscam locus might nevertheless be essential for a robust self and non-self discrimination in neurons. 23736671 Hyperbaric nursing. The varied clinical applications for hyperbaric oxygen therapy have led to the development of a unique, highly skilled nursing specialty of hyperbaric nursing. The ever-increasing availability of hyperbaric medicine and the broadening scope of clinical indications have fueled the need for highly skilled hyperbaric nurses. 23193182 Islet α-, β-, and δ-cell development is controlled by the Ldb1 coregulator, acting primarily with the islet-1 transcription factor. Ldb1 and Ldb2 are coregulators that mediate Lin11-Isl1-Mec3 (LIM)-homeodomain (HD) and LIM-only transcription factor-driven gene regulation. Although both Ldb1 and Ldb2 mRNA were produced in the developing and adult pancreas, immunohistochemical analysis illustrated a broad Ldb1 protein expression pattern during early pancreatogenesis, which subsequently became enriched in islet and ductal cells perinatally. The islet-enriched pattern of Ldb1 was similar to pan-endocrine cell-expressed Islet-1 (Isl1), which was demonstrated in this study to be the primary LIM-HD transcription factor in developing and adult islet cells. Endocrine cell-specific removal of Ldb1 during mouse development resulted in a severe reduction of hormone⁺ cell numbers (i.e., α, β, and δ) and overt postnatal hyperglycemia, reminiscent of the phenotype described for the Isl1 conditional mutant. In contrast, neither endocrine cell development nor function was affected in the pancreas of Ldb2(-/-) mice. Gene expression and chromatin immunoprecipitation (ChIP) analyses demonstrated that many important Isl1-activated genes were coregulated by Ldb1, including MafA, Arx, insulin, and Glp1r. However, some genes (i.e., Hb9 and Glut2) only appeared to be impacted by Ldb1 during development. These findings establish Ldb1 as a critical transcriptional coregulator during islet α-, β-, and δ-cell development through Isl1-dependent and potentially Isl1-independent control. 23900231 Surgical Management of Parapharyngeal Ganglioneuroma: Case Report and Review of the Literature. Parapharyngeal ganglioneuroma is a rare benign tumor, with fewer than 40 cases having been reported in the literature. We report a case of parapharyngeal ganglioneuroma in a child, including the presentation, diagnostic testing, treatment, outcome and a review of the literature. The patient presented with a large cervical mass arising from the cervical sympathetic chain. Complete excision of the ganglioneuroma was possible via a transcervical dissection approach without mandibulotomy. Clinical follow-up was conducted, and no recurrence has been observed to date. © 2013 S. Karger AG, Basel. 23554136 Yerba mate tea and mate saponins prevented azoxymethane-induced inflammation of rat colon through suppression of NF-κB p65ser(311) signaling via IκB-α and GSK-3β reduced phosphorylation. Yerba mate tea (YMT) has a chemopreventive role in a variety of inflammatory diseases. The objective was to determine the capability of YMT and mate saponins to prevent azoxymethane (AOM)-induced colonic inflammation in rats. YMT (2% dry leaves, w/v, as a source of drinking fluid) (n = 15) and mate saponins (0.01% in the diet, at a concentration present in one cup of YMT) (n = 15) were given ad libitum to rats 2 weeks prior to AOM-injection until the end of the study; while control rats (n = 15) received a basal diet and drinking water. After 8-weeks of study, total colonic mucosa was scraped (n = 3 rats/group) and the remaining colons (n =12 rats/group) were cut into three equal sections and aberrant crypt foci (ACF) were analyzed. YMT reduced ACF formation from 113 (control group) to 89 (P < 0.05). YMT and mate saponins reduced the expression of proinflammatory molecules COX-2 and iNOS with concomitant reduction in p-p65 (P < 0.05). Immunohistochemical analysis of the formalin-fixed middle colons showed that YMT and mate saponins reduced the expression of p-p65(ser311) by 45.7% and 43.1%, respectively, in comparison to the control (P < 0.05). In addition, the expression of molecules upstream of NF-κB such as p-IκB-α and p-GSK-3β(Y216) was downregulated by YMT 24.7% and 24.4%, respectively (P < 0.05). Results suggest the mechanism involved in the chemopreventive effect of YMT and mate saponin consumption in AOM induced-colonic inflammation in rats is through inhibition of NF-κB. © 2013 BioFactors, 39(4):430-440, 2013. 23809932 From the "bell-bottom" to a migrated "running stent" and then a successful conversion to hypogastric branched endograft. Preservation of one or both internal iliac arteries (IIA) during endovascular repair of an abdominal aortic aneurysm (AAA) reduces the risk of buttock claudication, sexual dysfunction, and pelvic ischemia. Various techniques have been reported for this purpose. We report a case involving the proximal migration of a bell-bottom limb of a previous endovascular aneurysm repair (EVAR), leading to a type I distal endoleak. On reconstruction, the stent graft resembled a person running and was subsequently named a "running stent"; this had no particular clinical relevance. The patient was successfully treated endovascularly using a branched iliac device. To our knowledge, this is the first reported case of the use of an iliac branched device to treat a type 1b endoleak. 23530995 Repeatability of autofluorescence lifetime imaging at the human fundus in healthy volunteers. We aim to evaluate the repeatability of a new fluorescence lifetime imaging (FLIM) technique which measures time-resolved autofluorescence to assess metabolism of the retina. We performed FLIM with two spectral channels (channel 1: 490-560 nm and channel 2: 560-700 nm) on 10 healthy volunteers, with 10 replicates per volunteer. From the 30° fundus FLIM images, we selected three regions: the fovea, the optic disc and the papillo-macular bundle. For each channel in these regions, we determined an average multi-exponential approximation with three components, and the six resulting parameters, α1-α3 (amplitudes) and τ1-τ3 (fluorescence lifetimes), were analyzed in terms of the coefficient of variation (CV). Repeatability was highest in the papillo-macular bundle, followed by the fovea and the optic disc. Repeatability was higher in channel 1 (mean CV of 7.9%) than in channel 2 (mean CV of 17.7%). The average CV for the diagnostically most relevant channel 1 and the most relevant parameters was as follows: τ1 (5.5%) and τ2 (4.7%) in the papillo-macular bundle, and τ1 (6.8%) and τ2 (6.9%) in the fovea. We demonstrated repeatability of FLIM measurement results within acceptable ranges of variation. Based on the detailed coefficients of variation, we derived recommendations for parameter ranges suitable for diagnostic applications. 23834560 Lower socioeconomic status is associated with worse outcomes after both listing and transplanting children with heart failure. The relationship between SES and outcomes surrounding pediatric cardiac transplantation is complex and influenced by recipient race. Broad-based studies of SES have not been performed. A retrospective review of all 5125 primary pediatric heart transplants performed in the United States between 2000 and 2011. Patients were stratified by SES based on zip code of residence and U.S. census data (low SES: 1637; mid-SES: 2253; high SES: 1235). Survival following listing and transplantation was compared across strata. Risk-adjusted long-term mortality on the waitlist was higher among low SES patients (hazard 1.32, CI 1.07-1.63). The relationship between SES and outcomes varied by race. Early risk-adjusted post-transplant outcomes were worst among high SES patients (10.8% vs. low SES: 8.9%, p < 0.05). The incidence of non-compliance was higher among low SES patients (p < 0.0001). Long-term risk-adjusted patient survival was poorer among low (hazard 1.41, CI 1.10-1.80) and mid-SES (1.29, 1.04-1.59) groups. Low SES is associated with worse outcomes on both the waitlist and late following transplantation. Higher SES patients had more complex transplants with higher early mortality. Further research should be directed at identifying and addressing underlying causal factors for these disparities. 23465756 Reengineering viruses and virus-like particles through chemical functionalization strategies. Increasing demands from nanotechnology require increasingly more rigorous methods to control nanoparticle traits such as assembly, size, morphology, monodispersity, stability, and reactivity. Viruses are a compelling starting point for engineering nanoparticles, as eons of natural biological evolution have instilled diverse and desirable traits. The next step is to reengineer these viruses into something functional and useful. These reengineered particles, or virus-based nanoparticles (VNPs), are the foundation for many promising new technologies in drug delivery, targeted delivery, vaccines, imaging, and biocatalysis. To achieve these end goals, VNPs must often be manipulated genetically and post-translationally. We review prevailing strategies of genetic and noncovalent functionalization and focus on the covalent modifications using natural and unnatural amino acid residues. 23506298 Disturbance regimes, gap-demanding trees and seed mass related to tree height in warm temperate rain forests worldwide. For tropical lowland rain forests, Denslow (1987) hypothesized that in areas with large-scale disturbances tree species with a high demand for light make up a larger proportion of the flora; results of tests have been inconsistent. There has been no test for warm temperate rain forests (WTRFs), but they offer a promising testing ground because they differ widely in the extent of disturbance. WTRF is dominated by microphylls sensu Raunkiaer and has a simpler structure and range of physiognomy than tropical or subtropical rain forests. It occurs in six parts of the world: eastern Asia, New Zealand, Chile, South Africa, SE Australia and the Azores. On the Azores it has been mostly destroyed, so we studied instead the subtropical montane rain forest (STMRF) on the Canary Islands which also represents a relict of the kind of WTRF that once stretched across southern Eurasia. We sought to find whether in these six regions the proportion of tree species needing canopy gaps for establishment reflects the frequency and/or extent of canopy disturbance by wind, landslide, volcanic eruptions (lava flow and ash fall), flood or fire. We used standard floras and ecological accounts to draw up lists of core tree species commonly reaching 5 m height. We excluded species which are very rare, very localized in distribution, or confined to special habitats, e.g. coastal forests or rocky sites. We used published accounts and our own experience to classify species into three groups: (1) needing canopy gaps for establishment; (2) needing either light shade throughout or a canopy gap relatively soon (a few months or years) after establishment; and (3) variously more shade-tolerant. Group 1 species were divided according the kind of canopy opening needed: tree-fall gap, landslide, lava flow, flood or fire. Only some of the significant differences in proportion of Group 1 species were consistent with differences in the extent of disturbance; even in some of those cases other factors seem likely to have had a major determining influence during evolution. We also sought to determine whether the species that are at least 'short-term persistent' in the soil seed bank (lasting 2-4 years) are all species needing canopy gaps for establishment. The answer was negative; large numbers of seeds of some shade-tolerants accumulate in the soil, and these species are able to benefit from soil disturbance in deep shade. We found a significant and strong positive relationship in Japan between mean seed mass and mature tree height, a weak positive relationship in New Zealand and no relationship in any of the other four regions. When comparing the seed mass values of Group 1 and Group 3 species we obtained different answers depending on whether or not we confined ourselves to taxonomically controlled contrasts. In only two of the four regions with an appreciable number of species in Group 1 is the mean seed mass of such species significantly lower than that of Group 3 species when taxonomic relatedness is ignored. 23450729 Assessment of work-related exposure to polycyclic aromatic hydrocarbons in Italy. Polycyclic aromatic hydrocarbons (PAHs) are generally present in the workplace environment as complex mixtures and often difficult to identify a priori. The aim of this study is to evaluate the level and coverage of occupational exposure to PAHs in Italy. Data were collected from exposure registries of companies with mandatory reporting to the National Workers' Compensation Authority. Statistical analyses were carried out on the retrieved information and the number of workers potentially exposed was estimated for some industrial sectors. Overall 12,849 measurements of exposure levels to individual PAHs were selected from the database of registries in the period 1996-2010. Most exposures occurred in the manufacture of chemicals (N = 5,383, 51%), and the occupational group most frequently measured was chemical-processing-plant operator (N = 3,930, 31%). Measurements were associated to various PAHs, including benzo[a]pyrene, benzo[a]anthracene, benzo[b]fluoranthene, benzo[k]fluoranthene, dibenz[a,h]anthracene, and benzo[j]fluoranthene. Overall, 39,230 workers were estimated as potentially at risk of exposure to PAHs in the selected industrial sectors. This study summarized data recorded in the Italian occupational exposure database and identified specific exposure patterns to PAHs. The systematic recording of occupational exposures is a source of data that allows the recognition, control, and prevention of high-risk situations for workers' health. Am. J. Ind. Med. 56:897-906, 2013. © 2013 Wiley Periodicals, Inc. 23881846 Benefit of Warfarin Compared with Aspirin in Heart Failure Patients in Sinus Rhythm: A Subgroup Analysis of WARCEF, a Randomized Controlled Trial. -The Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found no difference in the primary outcome between warfarin and aspirin in 2305 patients with reduced left ventricular ejection fraction in sinus rhythm. However, it is unknown if any subgroups benefit from warfarin or aspirin. -We used a Cox model stepwise selection procedure to identify subgroups that may benefit from warfarin or aspirin on the WARCEF primary outcome. A secondary analysis added major hemorrhage to the outcome. The primary efficacy outcome was time to the first to occur of ischemic stroke, intracerebral hemorrhage, or death. Only age group was a significant treatment effect modifier (p for interaction 0.003). Younger patients benefitted from warfarin over aspirin on the primary outcome (4.81 vs. 6.76 events per 100 patient-years: HR 0.63, 95% CI 0.48-0.84, p=0.001). In older patients, therapies did not differ (9.91 vs. 9.01 events per 100 patient-years: HR 1.09, 95% CI 0.88-1.35, p=0.44). With major hemorrhage added, in younger patients the event rate remained lower for warfarin than aspirin (5.41 vs. 7.25 per 100 patient-years: HR 0.68, 95% CI 0.52-0.89, p=0.005), but in older patients it became significantly higher for warfarin (11.80 vs. 9.35 per 100 patient-years: HR 1.25, 95% CI 1.02-1.53, p=0.03). -In patients under 60 years, warfarin improved outcomes over aspirin with or without inclusion of major hemorrhage. In patients 60 years and older, there was no treatment difference, but the aspirin group had significantly better outcomes when major hemorrhage was included. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00041938. 23893082 Therapeutic Evaluation of Ex Vivo-Generated Versus Natural Regulatory T-cells in a Mouse Model of Chronic Gut Inflammation. : The objectives of this study were to (a) evaluate and compare the ability of ex vivo-generated induced regulatory T cells (iTregs) and freshly isolated natural Tregs (nTregs) to reverse/attenuate preexisting intestinal inflammation in a mouse model of chronic colitis and (b) quantify the Treg-targeted gene expression profiles of these two Treg populations. We found that ex vivo-generated iTregs were significantly more potent than nTregs at attenuating preexisting colitis. This superior therapeutic activity was associated with increased accumulation of iTregs within the mesenteric lymph nodes and large and significant reductions in interleukin (IL)-6 and IL-17A expression in the colons of iTreg- versus nTreg-treated mice. The enhanced immunosuppressive activity of iTregs was not because of increased expression or stability of Foxp3 as iTregs and nTregs obtained from the mesenteric lymph nodes, and colons of reconstituted mice expressed similar levels of this important transcription factor. In addition, we observed a total of 27 genes that were either upregulated or downregulated in iTregs when compared with nTregs. Although iTregs were found to be superior at reversing established disease, their message levels of IL-10 and IL-35 and surface expression of the gut-homing molecules CCR9 and α4β7 were significantly reduced when compared with nTregs. Taken together, our data demonstrate that ex vivo-generated iTregs are significantly more potent than nTregs at attenuating preexisting gut inflammation despite reduced expression of classical regulatory cytokines and gut-homing molecules. Our data suggest that the immunosuppressive activity of iTregs may be because of their ability to directly or indirectly decrease expression of IL-6 and IL-17A within the inflamed bowel. 23813498 Self-Assembled π-Extended Condensed Benzothiophene Nanoribbons for Field-Effect Transistors. Nanostructures: A new air-stable π-extended condensed benzothiophene was prepared by starting from 4,8-dioctyl-oxybenzo[1,2-b:4,5-b']dithiophene in about 54 % overall yield. Highly ordered 1D organic nanoribbons of the resultant compound were formed by molecular self-assembly. An individual nanoribbon-based organic field-effect transistor exhibited an average mobility of 0.05 cm(2)  V(-1)  s(-1) . 23763272 Practical selective hydrogenation of α-fluorinated esters with bifunctional pincer-type ruthenium(II) catalysts leading to fluorinated alcohols or fluoral hemiacetals. Selective hydrogenation of fluorinated esters with pincer-type bifunctional catalysts RuHCl(CO)(dpa) 1a, trans-RuH2(CO)(dpa) 1b, and trans-RuCl2(CO)(dpa) 1c under mild conditions proceeds rapidly to give the corresponding fluorinated alcohols or hemiacetals in good to excellent yields. Under the optimized conditions, the hydrogenation of chiral (R)-2-fluoropropionate proceeds smoothly to give the corresponding chiral alcohol without any serious decrease of the ee value. 23597449 Açai (Euterpe oleracea Mart.) feeding attenuates dimethylhydrazine-induced rat colon carcinogenesis. This study investigated the protective effect of spray-dried açaí powder (AP) intake on colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH) in male Wistar rats. After 4weeks of DMH administrations, the groups were fed with standard diet, a diet containing 2.5% or 5.0% AP or a diet containing 0.2% N-acetylcysteine (NAC) for 10weeks, using aberrant crypt foci (ACF) as the endpoint. Additionally, two groups were fed with standard diet or a diet containing 5.0% AP for 20weeks, using colon tumors as the endpoint. In ACF assay, a reduction in the number of aberrant crypts (ACs) and ACF (1-3 AC) were observed in the groups fed with 5.0% AP (37% AC and 47% ACF inhibition, p=0.036) and 0.2% NAC (39% AC and 41% ACF inhibition, p=0.042). In tumor assay, a reduction in the number of invasive tumors (p<0.005) and tumor multiplicity (p=0.001) was observed in the group fed with 5.0% AP. Also, a reduction in tumor Ki-67 cell proliferation (p=0.003) and net growth index (p=0.001) was observed in the group fed with 5.0% AP. Therefore the findings of this study indicate that AP feeding may reduce the development of chemically-induced rat colon carcinogenesis. 23876835 Epigallocatechin-3-gallate attenuates head and neck cancer stem cell traits through suppression of Notch pathway. Most solid cancers including head and neck squamous carcinoma (HNSC) are believed to be initiated from and maintained by cancer stem cells (CSCs) that are responsible for treatment resistance, resulting in tumour relapse. Epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in green tea, can potently inhibit cancer growth and induce apoptosis in various cancers, including HNSC. However, its effect on HNSC CSCs is not well elucidated. In this study, we examined the anti-tumour effect of EGCG on HNSC CSCs. We demonstrated that EGCG inhibits the self-renewal capacity of HNSC CSCs by suppressing their sphere forming capacity, and attenuates the expression of stem cell markers, such as Oct4, Sox2, Nanog and CD44. EGCG treatment augmented cisplatin-mediated chemosensitivity by suppressing ABCC2 and ABCG2 transporter genes, which are putative molecules of treatment resistance of CSC. In addition, the combination treatment of EGCG and cisplatin inhibited tumour formation and induced apoptosis in a xenograft model. As one of mechanisms of suppression of HNSC CSC traits, EGCG decreased the transcriptional level of Notch, resulting in the inhibition of Notch signalling. Collectively, our data suggest that EGCG in combination with cisplatin can be used for the management of HNSC CSCs. 23673072 Spinal cord ischemia after thoracic stent-grafting: causes apart from intercostal artery coverage. Examination of a large collective combined with individual case analyses may give new insights into mechanisms and prevention of spinal cord ischemia (SCI) after thoracic endovascular repair. In an 11-year period, stent-grafts were implanted in 406 patients for various aortic pathologic conditions. The mean age was 63 years (15-91 years) and 300 (74%) patients were men; 58 patients underwent staged thoracic stent-graft procedures. The length of aorta covered was between 75 and 584 mm (mean, 204 mm). Thoracoabdominal branched or fenestrated stent-grafts were implanted in 11 patients. The left subclavian artery was occluded in 161 patients (39%); this occurred in half of them (n = 78) after protective revascularization. Prophylactic cerebrospinal fluid (CSF) drainage was used selectively in 4 cases; no neuromonitoring was used. The incidence of SCI was 2.7% (n = 11); 6 patients (1.5%) had major permanent deficits. Conditions that had a potential influence on SCI were analyzed. Statistical correlation was found for previous conventional or endovascular abdominal aortic aneurysm repair (odds ratio [OR], 4.8), coverage of the entire descending thoracic aorta (OR, 3.6), and implantation of thoracoabdominal branched and fenestrated stent-grafts (OR, 9.5). Individual analyses revealed other conditions that might have played a role, such as embolization into the segmental arteries, severe visceral ischemia, profound hemorrhagic shock, and heparin-induced thrombocytopenia. The incidence of SCI is unexpectedly low despite extensive sacrifice of intercostal arteries. Extended coverage of the thoracic and thoracoabdominal aorta seems to have a higher risk, but other factors may contribute to the individual disaster. 23745730 Accurate method for the determination of intramolecular (13)c isotope composition of ethanol from aqueous solutions. A new method, combining headspace solid phase microextraction (HS-SPME) with an online pyrolysis system coupled with isotope ratio mass spectrometry (IRMS), is developed for the determination of the intramolecular (13)C isotope composition of ethanol in aqueous solutions. The δ(13)C values of the pyrolytic fragments (CO, CH4, C2H4) are shown to be highly reproducible (sd <0.4‰). Furthermore, using 14 ethanol samples of known intramolecular isotope distribution, the CO and CH4 fragments are shown to arise solely from the methylene (CH2OH) and methyl (CH3) carbon atom positions of the original ethanol, respectively. Although the different steps (extraction and pyrolysis) fractionate between (12)C and (13)C, the isotopic fractionation is reproducible (sd <0.4‰), allowing correcting factors to be applied in order to back-calculate the original δ(13)CCH2OH and δ(13)CCH3 values of ethanol. The method thus allows the determination of the isotope composition of ethanol at the intramolecular and molecular levels, within a single run and a short experimental time (30 min), and with a very easy sample preparation. The method is then applied to alcoholic beverages to show its potential for authentication purposes. 23554409 Interaction between abscisic acid and nitric oxide in PB90-induced catharanthine biosynthesis of catharanthus roseus cell suspension cultures. Elicitations are considered to be an important strategy to improve production of secondary metabolites of plant cell cultures. However, mechanisms responsible for the elicitor-induced production of secondary metabolites of plant cells have not yet been fully elucidated. Here, we report that treatment of Catharanthus roseus cell suspension cultures with PB90, a protein elicitor from Phytophthora boehmeriae, induced rapid increases of abscisic acid (ABA) and nitric oxide (NO), subsequently followed by the enhancement of catharanthine production and up-regulation of Str and Tdc, two important genes in catharanthine biosynthesis. PB90-induced catharanthine production and the gene expression were suppressed by the ABA inhibitor and NO scavenger respectively, showing that ABA and NO are essential for the elicitor-induced catharanthine biosynthesis. The relationship between ABA and NO in mediating catharanthine biosynthesis was further investigated. Treatment of the cells with ABA triggered NO accumulation and induced catharanthine production and up-regulation of Str and Tdc. ABA-induced catharanthine production and gene expressions were suppressed by the NO scavenger. Conversely, exogenous application of NO did not stimulate ABA generation and treatment with ABA inhibitor did not suppress NO-induced catharanthine production and gene expressions. Together, the results showed that both NO and ABA were involved in PB90-induced catharanthine biosynthesis of C. roseus cells. Furthermore, our data demonstrated that ABA acted upstream of NO in the signaling cascade leading to PB90-induced catharanthine biosynthesis of C. roseus cells. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 29:994-1001, 2013. 23892051 Glutamate induces H2O2 synthesis in nonsynaptic brain mitochondria. Mitochondrial reactive oxygen species regulate many important biological processes. We studied H2O2 formation by nonsynaptic brain mitochondria in response to the addition of low concentrations of glutamate, an excitatory neurotransmitter. We demonstrated that glutamate at concentrations from 10 to 50μM stimulated the H2O2 generation in mitochondria up to 4-fold, in a dose-dependent manner. The effect of glutamate was observed only in the presence of Ca(2+) (20μM) in the incubation medium, and the rate of calcium uptake by the brain mitochondria was increased by up to 50% by glutamate. Glutamate-dependent effects were sensitive to the NMDA receptor inhibitors MK-801 (10μM) and D-AP5 (20μM) and the inhibitory neurotransmitter glycine (5mM). We have shown that the H2O2 formation caused by glutamate is associated with complex II and is dependent on the mitochondrial potential. We have found that nonsynaptic brain mitochondria are a target of direct glutamate signaling, which can specifically activate H2O2 formation through mitochondrial respiratory chain complex II. The H2O2 formation induced by glutamate can be blocked by glycine, an inhibitory neurotransmitter that prevents the deleterious effects of glutamate in brain mitochondria. 23792573 Detection of DSS-induced gastrointestinal mucositis in mice by non-invasive optical near-infrared (NIR) imaging of cathepsin activity. Approximately 1.4 million people of the US population suffer from Inflammatory Bowel Disease (IBD) of which the most common conditions are ulcerative colitis (UC) and Crohn disease (CD). Colonoscopy and small bowel follow through are considered the current gold standard in diagnosing IBD. However, improved imaging and increased diagnostic sensitivity could be beneficial. Optical molecular imaging has the potential to become a powerful and practical tool for early detection, image-guided biopsy, and surgery in diagnosing and treating patients with IBD. Here we used a well characterized chemical model to initiate experimental IBD in mice by feeding with dextran sulfate sodium (DSS) containing drinking water in an attempt to investigate the utility of non-invasive infrared (NIR) optical imaging in the detection gastrointestinal (GI) injury. We employed a "smart probe" (ProSense680) cleaved and fluorescently activated in the NIR-spectrum by various forms of secreted cathepsins. This probe has previously been shown to serve as a biomarker for the homing of inflammatory cells to injury. Our investigation suggests that NIR optical imaging can detect cathepsin-dependent probe cleavage non-invasively in animals with DSS-induced IBD. Increased tissue probe-retention and fluorescence was associated with increased infiltration of inflammatory cells, epithelial atrophy and sterilization of the mucosa. Furthermore, using NIR-imaging ex vivo we were able to document regional "hot spots" of inflammatory damage to the large intestine suggesting this method potentially could be coupled with colonoscopy investigation to aid in the sampling and the diagnostics of IBD. 23896475 Chromosome 5 monosomy of Candida albicans controls susceptibility to various toxic agents including major antifungals. Candida albicans is a prevailing fungal pathogen with a diploid genome that can adapt to environmental stresses by losing or gaining an entire chromosome or a large portion of a chromosome. We have previously found that the loss of one copy of chromosome 5 (Ch5) allows for adaptation to the toxic sugar L-sorbose. The latter is similar to caspofungin and other antifungals from the echinocandins class in that it represses synthesis of cell wall glucan in fungi. Here, we extended the study of the phenotypes controlled by Ch5 copy number. We examined 57 strains, either disomic or monosomic for Ch5 representing five different genetic backgrounds, and found that the monosomy of Ch5 causes elevated levels of chitin and repressed levels of 1,3-β-glucan components of the cell wall, as well as diminished cellular ergosterol. Increased deposition of chitin in the cell wall could be explained, at least partially, by a twofold down regulation of CHT2 on the monosomic Ch5 that encodes chitinase and a 1.5-fold up regulation of CHS7 on Ch1 that encodes the protein required for wild-type chitin synthase III activity. Other important outcomes of Ch5 monosomy consist of susceptibility changes to agents representing four major classes of antifungals. Susceptibility to caspofungin increased or decreased, susceptibility to 5-fluorocytosine decreased, whereas susceptibility to fluconazole and amphotericin B increased. Our results suggest that Ch5 monosomy represents an unrecognized C. albicans regulatory strategy that impinges on multiple stress response pathways. 23080424 Endogenous CSE/H2 S system mediates TNF-α-induced insulin resistance in 3T3-L1 adipocytes. Tumour necrosis factor-α (TNF- α)is a major contributor to the pathogenesis of insulin resistance associated with obesity and type 2 diabetes. It has been found that endogenous hydrogen sulfide (H2 S) contributes to the pathogenesis of diabetes. We have hypothesized that TNF-α-induced insulin resistance is involved in endogenous H2 S generation. The aim of the present study is to investigate the role of endogenous H2 S in TNF-α-induced insulin resistance by studying 3T3-L1 adipocytes. We found that treatment of 3T3-L1 adipocytes with TNF-α leads to deficiency in insulin-stimulated glucose consumption and uptake and increase in endogenous H2 S generation. We show that cystathionine γ-lyase (CSE) is catalysed in 3T3-L1 adipocytes to generate H2 S and that CSE expression and activity are upregulated by TNF-α treatment. Inhibited CSE by its potent inhibitors significantly attenuates TNF-α-induced insulin resistance in 3T3-L1 adipocytes, whereas H2 S treatment of 3T3-L1 adipocytes impairs insulin-stimulated glucose consumption and uptake. These data indicate that endogenous CSE/H2 S system contributes to TNF-α-caused insulin resistance in 3T3-L1 adipocytes. Our findings suggest that modulation of CSE/H2 S system is a potential therapeutic avenue for insulin resistance. Copyright © 2012 John Wiley & Sons, Ltd. 23861202 Leaving a legacy neutralizes negative effects of death anxiety on creativity. Mortality salience (MS) can lead to a paralyzing terror, and to cope with this, people strive for literal or symbolic immortality. As MS leads to conformity and narrow-mindedness, we predicted that MS would lead to lower creativity, unless creativity itself could lead to leaving a legacy and thus symbolic immortality. We show that this pattern holds (Experiment 1), but only when creativity is socially valued (Experiment 2). Finally, especially individualistic people are more creative under MS when they can leave a legacy than when they cannot, and high originality predicts subsequent accessibility of death thoughts (Experiment 3). Implications are discussed. 23789682 In vivo quantification of T1ρ in lumbar spine disk spaces at 3 T using parallel transmission MRI. T1ρ MRI is an emerging, quantitative imaging modality that has been shown to correlate with proteoglycan content of disk material in vitro at 1.5 T. The purpose of this study is to quantify T1ρ values at all lumbar spine disk space levels at 3 T with parallel-transmission MRI in healthy adult volunteers. Thirty-four subjects (15 men, ages 21-60 years [mean age, 38.4 years]; and 19 women, ages 20-56 years [mean age, 36.5 years]) with no history of back pain or surgery underwent T1ρ MRI of the lumbar spine at 3 T with parallel transmission and sagittal T2-weighted imaging. Mean T1ρ values of all lumbar spine disk space levels were quantified. Linear regression analysis and Spearman rank correlation were performed on age, sex, degenerative grade (Pfirrmann scores), and T1ρ with significance set at p < 0.05 and correlations considered strong for r > 0.7 and moderate for r = 0.5-0.7. There was a statistically significant moderate negative correlation between T1ρ and subject age at disk space levels L1-2 through L4-5 (inclusive) (p < 0.001) and L5-S1 (p < 0.01). There was a statistically significant difference in T1ρ between all age groups sampled (p < 0.01) and a significant difference between T1ρ and Pfirrmann grades 1-3 (p < 0.01). T1ρ MRI in the lumbar spine with parallel transmission shows signifi-cant negative correlations with age at all disk space levels, which lends support to a potential role for T1ρ as a quantitative, in vivo biomarker of disk degeneration. 23434647 The Interaction of Adrenomedullin and Macrophages Induces Ovarian Cancer Cell Migration via Activation of RhoA Signaling Pathway. Tumor-associated macrophages (TAMs) are correlated with poor prognosis in many human cancers; however, the mechanism by which TAMs facilitate ovarian cancer cell migration and invasion remains unknown. This study was aimed to examine the function of adrenomedullin (ADM) in macrophage polarization and their further effects on the migration of ovarian cancer cells. Exogenous ADM antagonist and small interfering RNA (siRNA) specific for ADM expression were treated to macrophages and EOC cell line HO8910, respectively. Then macrophages were cocultured with HO8910 cells without direct contact. Flow cytometry, Western blot and real-time PCR were used to detect macrophage phenotype and cytokine production. The migration ability and cytoskeleton rearrangement of ovarian cancer cells were determined by Transwell migration assay and phalloidin staining. Western blot was performed to evaluate the activity status of signaling molecules in the process of ovarian cancer cell migration. The results showed that ADM induced macrophage phenotype and cytokine production similar to TAMs. Macrophages polarized by ADM promoted the migration and cytoskeleton rearrangement of HO8910 cells. The expression of RhoA and its downstream effector, cofilin, were upregulated in macrophage-induced migration of HO8910 cells. In conclusion, ADM could polarize macrophages similar to TAMs, and then polarized macrophages promote the migration of ovarian cancer cells via activation of RhoA signaling pathway in vitro. 23831769 Magnetically responsive dry fluids. Ferrofluids and dry magnetic particles are two separate classes of magnetic materials with specific niche applications, mainly due to their distinct viscosity and interparticle distances. For practical applications, the stability of these two properties is highly desirable but hard to achieve. Conceptually, a possible solution to this problem would be encapsulating the magnetic particles but keeping them free to rotate inside a capsule with constant interparticle distances and thus shielded from changes in the viscosity of the surrounding media. Here we present an example of such materials by the encapsulation of magnetic ferrofluids into highly hydrophobic silica, leading to the formation of dry ferrofluids, i.e., a material behaving macroscopically as a dry powder but locally as a ferrofluid where magnetic nanoparticles are free to rotate in the liquid. 23177257 Design, synthesis and inhibitory activities of naringenin derivatives on human colon cancer cells. Based on the previous result, several naringenin derivatives modified at position 7 with bulky substituents were designed and synthesized, and their inhibitory effects on HCT116 human colon cancer cells were tested using a clonogenic assay. The half maximal inhibitory concentrations (IC(50)) of five naringenin derivatives ranged between 1.20 μM and 20.01 μM which are much better than naringenin used as a control. In addition, new structural modification at C-4 of flavanone results in improving both the anti-cancer effect and anti-oxidative effect. In vitro cyclin dependent kinase 2 (CDK2) binding assay was carried out based on the previous results. To elucidate the possible interaction between naringenin derivatives and CDK2, in silico docking study was performed. This result demonstrates the rationale for the different inhibitory activities of the naringenin derivatives. These findings could be used for designing cancer therapeutic or preventive flavanone-derived agents. 23909502 Indications for intestinal transplantation: recognizing the scope and limits of total parenteral nutrition. Total parenteral nutrition (TPN) is currently the treatment of choice for patients with intestinal failure. Intestinal failure in adults is mostly due to short bowel syndrome, which is most often caused by ischemia and Crohn's disease. However, TPN fails in a substantial number of cases. For patients with TPN failure, intestinal transplantation (ITx) may be offered as a treatment. TPN failure is considered to be present either if nutrition itself is not possible or if complications of TPN occur. These complications can, for example, originate from recurrent line infections or thrombosis. As TPN is usually a lifelong therapy and is associated with substantial impairment of the quality of life, the tolerance of each patient to this procedure is another important consideration in the decision making about whether to perform transplantation. The survival rates of intestinal transplant recipients have now reached the same level as that of recipients of other solid organ transplants. A five-yr survival of up to 80% has been reported in specialized centers, whereas registry data show rates of <80%. Although in about one-third of patients, isolated ITx is sufficient, patients with concurrent liver disease (mostly due to TPN) benefit from combined intestinal and liver transplantation. In some cases, multivisceral transplantation is necessary. Here, we review the current indications for ITx with a special focus on TPN. 23952217 Mechanism and Selectivity in Nickel-Catalyzed Cross- Electrophile Coupling of Aryl Halides with Alkyl Halides. The direct cross-coupling of two different electro- philes, such as an aryl halide with an alkyl halide, offers many ad- vantages over conventional cross-coupling methods that require a carbon nucleophile. Despite its promise as a versatile synthetic strategy, a limited understanding of the mechanism and origin of cross selectivity has hindered progress towards reaction develop- ment and design. Herein, we shed light on the mechanism for the nickel-catalyzed cross-electrophile coupling of aryl halides with alkyl halides and demonstrate that the selectivity arises from an unusual catalytic cycle that combines both polar and radical steps to form the new C-C bond. 23377859 Sediment-associated pesticides in an urban stream in guangzhou, china: implication of a shift in pesticide use patterns. Pesticide use patterns in China have changed in recent years; however, the study of the environmental fate of current-use pesticides (CUPs) and their ecotoxicological significance in aquatic ecosystems is limited. In the present study, sediments were collected from an urban stream in the Chinese city of Guangzhou. Sediment-associated legacy organochlorine pesticides and CUPs-including organophosphates, pyrethroids, fipronil, and abamectin-were analyzed. Additionally, the relative toxicity of the sediments was evaluated with 10-d bioassays using Chironomus dilutus. Fifteen of 16 sediments collected from the stream were acutely toxic to C. dilutus, with 81% of the samples causing 100% mortality. Abamectin, fipronil, and pyrethroids (mainly cypermethrin) were identified as the principal contributors to the noted toxicity in the midges, with median predicted toxic units of 1.63, 1.63, and 1.03, respectively. Sediments taken from downstream sites, where residential and industrial regions were located, had elevated CUP concentrations and sediment toxicity compared with upstream sites. The present study is the first of its kind to link sediment CUPs, fipronil, and abamectin concentrations with toxicity in urban streams in China with a focus on shifting pesticide usage patterns. Environ. Toxicol. Chem. 2013;32:1040-1047. © 2013 SETAC. 23816259 Accelerators/decelerators of achieving universal access to sexual and reproductive health services: a case study of Iranian health system. At the 1994 International Conference on Population and Development (ICPD), held in Cairo, the global community agreed to the goal of achieving universal access to sexual and reproductive health (SRH) and rights by 2015. This research explores the accelerators and decelerators of achieving universal access to the sexual and reproductive health targets and accordingly makes some suggestions. We have critically reviewed the latest national reports and extracted the background data on each SRH indicator. The key stakeholders, both national and international, were visited and interviewed at two sites. A total of 55 in-depth interviews were conducted with religious leaders, policy-makers, senior managers, senior academics, and health care managers. Six focus-group discussions were also held among health care providers. The study was qualitative in nature. Obstacles on the road to achieving universal access to SRH can be viewed from two perspectives. One gap exists between current achievements and the targets. The other gap arises due to age, marital status, and residency status. The most recently observed trends in the indicators of the universal access to SRH shows that the achievements in the "unmet need for family planning" have been poor. Unmet need for family planning could directly be translated to unwanted pregnancies and unwanted childbirths; the former calls for sexual education to underserved people, including adolescents; and the latter calls for access to safe abortion. Local religious leaders have not actively attended international goal-setting programs. Therefore, they usually do not presume a positive attitude towards these goals. Such negative attitudes seem to be the most important factors hindering the progress towards universal access to SRH. Lack of international donors to fund for SRH programs is also another barrier. In national levels both state and the society are interactively playing their roles. We have used a cascade model for presenting the barriers at the state levels from the strategic planning to implementation. Social factors are to be considered as a background for other factors at all stages. Accelerating universal access to SRH requires adequate funding, firm political commitment, creative programming, and the involvement of diverse actors, including faith-based, civil society, and private sector partners. 23486562 Accuracy of four-dimensional phase-contrast velocity mapping for blood flow visualizations: a phantom study. Time-resolved three-dimensional, three-directional phase-contrast magnetic resonance velocity mapping (4D PC-MRI) is a powerful technique to depict dynamic blood flow patterns in the human body. However, the impact of phase background effects on flow visualizations has not been thoroughly studied previously, and it has not yet been experimentally demonstrated to what degree phase offsets affect flow visualizations and create errors such as inaccurate particle traces. To quantify background phase offsets and their subsequent impact on particle trace visualizations in a 4D PC-MRI sequence. Additionally, we sought to investigate to what degree visualization errors are reduced by background phase correction. A rotating phantom with a known velocity field was used to quantify background phase of 4D PC-MRI sequences accelerated with SENSE as well as different k-t BLAST speed-up factors. The deviation in end positions between particle traces in the measured velocity fields were compared before and after the application of two different phase correction methods. Phantom measurements revealed background velocity offsets up to 7 cm/s (7% of velocity encoding sensitivity) in the central slice, increasing with distance from the center. Background offsets remained constant with increasing k-t BLAST speed-up factors. End deviations of up to 5.3 mm (1.8 voxels) in the direction perpendicular to the rotating disc were found between particle traces and the seeding plane of the traces. Phase correction by subtraction of the data from the stationary phantom reduced the average deviation by up to 56%, while correcting the data-set with a first-order polynomial fit to stationary regions decreased average deviation up to 78%. Pathline visualizations can be significantly affected by background phase errors, highlighting the importance of dedicated and robust phase correction methods. Our results show that pathline deviation can be substantial if adequate phase background errors are not minimized. 23957917 Bile duct carcinoma involving the common channel associated with pancreaticobiliary maljunction shows an extension pattern similar to ductal carcinoma of the pancreas. Biliary tract cancer occurs frequently in patients with pancreaticobiliary maljunction (PBM), although no details of its clinicopathological characteristics have been reported. Here we describe a case of bile duct (BD) cancer that developed in association with PBM. This BD cancer involved the common channel, extended to the main pancreatic duct (MPD) via the common channel, and invaded the pancreatic parenchyma, where its growth and spread, and features of its recurrence, were similar to those of ductal carcinoma of the pancreas. We assumed that MPD extension of BD cancer via the common channel was the reason for its deep spread to the pancreas, since BD cancer usually spreads along the BD and rarely reaches the common channel of the ampulla of Vater. During the follow-up of patients with PBM, attention should be paid to involvement of the common channel by BD cancer and also to cancer developing silently in the pancreas after extrahepatic BD resection. 23662830 Ophthalmological outcome after resection of tumors based on the pineal gland. Object Descriptions of visual dysfunction in pineal gland tumors tend to focus on upward gaze palsy alone. The authors aimed to characterize the nature, incidence, and functional significance of ophthalmological dysfunction after resection of tumors based on the pineal gland. Methods Review of a retrospective case series was performed and included consecutive patients who underwent surgery performed by a consultant neurosurgeon between 2002 and 2011. Only tumors specifically based on the pineal gland were included; tumors encroaching on the pineal gland from other regions were excluded. All patients with visual signs and/or symptoms were reviewed by a specialist consultant neuroophthalmologist to accurately characterize the nature of their deficits. Visual disturbance was defined as visual symptoms caused by a disturbance of ocular motility. Results A total of 20 patients underwent resection of pineal gland tumors. Complete resection was obtained in 85%, and there were no perioperative deaths. Visual disturbance was present in 35% at presentation; of those who had normal ocular motility preoperatively 82% had normal motility postoperatively. In total, 55% of patients had residual visual disturbance postoperatively. Although upward gaze tended to improve, significant functional deficits remained, particularly with regard to complex convergence and accommodation dysfunction. Prisms were used in 25% but were only ever partially effective. Visual outcome was only related to preoperative visual status and tumor volume (multivariate analysis). Conclusions Long-term visual morbidity after pineal gland tumor resection is common and leads to significant functional impairment. Improvement in deficits rarely occurs spontaneously, and prisms only have limited effectiveness, probably due to the dynamic nature of supranuclear ocular movement coordination. 23850547 Transgene and immune gene expression following intramuscular injection of Atlantic salmon (Salmo salar L.) with DNA-releasing PLGA nano- and microparticles. The use of poly-(D,L-lactic-co-glycolic) acid (PLGA) particles as carriers for DNA delivery has received considerable attention in mammalian studies. DNA vaccination of fish has been shown to elicit durable transgene expression, but no reports exist on intramuscular administration of PLGA-encapsulated plasmid DNA (pDNA). We injected Atlantic salmon (Salmo salar L.) intramuscularly with a plasmid vector containing a luciferase (Photinus pyralis) reporter gene as a) naked pDNA, b) encapsulated into PLGA nano- (∼320 nm) (NP) or microparticles (∼4 Î¼m) (MP), c) in an oil-based formulation, or with empty particles of both sizes. The ability of the different pDNA-treatments to induce transgene expression was analyzed through a 70-day experimental period. Anatomical distribution patterns and depot effects were determined by tracking isotope labeled pDNA. Muscle, head kidney and spleen from all treatment groups were analyzed for proinflammatory cytokines (TNF-α, IL-1β), antiviral genes (IFN-α, Mx) and cytotoxic T-cell markers (CD8, Eomes) at mRNA transcription levels at days 1, 2, 4 and 7. Histopathological examinations were performed on injection site samples from days 2, 7 and 30. Injection of either naked pDNA or the oil-formulation was superior to particle treatments for inducing transgene expression at early time-points. Empty particles of both sizes were able to induce proinflammatory immune responses as well as degenerative and inflammatory pathology at the injection site. Microparticles demonstrated injection site depots and an inflammatory pathology comparable to the oil-based formulation. In comparison, the distribution of NP-encapsulated pDNA resembled that of naked pDNA, although encapsulation into NPs significantly elevated the expression of antiviral genes in all tissues. Together the results indicate that while naked pDNA is most efficient for inducing transgene expression, the encapsulation of pDNA into NPs up-regulates antiviral responses that could be of benefit to DNA vaccination. 23893315 Remission of Type 2 Diabetes Mellitus Should Not Be the Foremost Goal after Bariatric Surgery. Remission of type 2 diabetes (T2D) is a desired outcome after bariatric surgery (BS). Even if this goal is not achieved, individuals who do not strictly fulfill remission criteria experience an overall improvement. The aim of this study was to evaluate the metabolic control status in patients considered as diabetes "non-remitters." A retrospective study of 125 patients (59.2 % women) with preoperative diagnosis of T2D who underwent BS in a single center (2006-2011) was conducted. We collected anthropometric and metabolic parameters before surgery and at 1-year follow-up. T2D remission was defined according to the 2009 consensus statement: glycosylated hemoglobin (HbA1c) <6 %, fasting glucose (FG) <100 mg/dLs, and absence of pharmacologic treatment. We evaluated metabolic status of non-remitters, according to the American Diabetes Association's (ADA) target recommendations: HbA1c <7 %, LDL-c <100 mg/dL, triglycerides <150 mg/dL, and HDL-c >40 (male) or >50 mg/dL (female). Statistics: analysis of variance. Baseline characteristics (mean ± SD): age 53.5 ±â€‰9.7 years, BMI 43.5 ±â€‰5.6 kg/m(2), time since diagnosis of T2D 7.7 ±â€‰7.9 years, FG 162.0 ±â€‰56.3 mg/dL, HbA1c 7.7 ±â€‰1.6 %. ADA's target recommendations were present in 12 patients (9.6 %) preoperatively, and in 45 (36.0 %) at 1-year follow-up (p <0.001). Sixty-two (49.6 %) patients did not achieve diabetes remission; 26 (41.9 %) had now diet treatment, 30 (48.4 %) oral medications, and 6 (9.7 %) required insulin. Of the non-remitters, 57 (91.9 %) had HbA1c <7 % and 18 (40.0 %) achieved ADA's target recommendations. There were no differences between remitters and non-remitters in the number of individuals reaching ADA's combined metabolic control. Although almost 50 % of the patients may not be classified as diabetes remitters, their significant improvement in metabolic control should be regarded as a success, according to most scientific societies' target recommendations. 23733564 An antibody-free strategy for screening putative HDM2 inhibitors using crude bacterial lysates expressing GST-HDM2 recombinant protein. Targeting the interaction of p53 with its natural inhibitor MDM2 by the use of small synthetic molecules has emerged as a promising pharmacological approach to restore p53 oncosuppressor function in cancers retaining wild-type p53. The first critical step in the experimental validation of newly synthesized small molecules developed to inhibit MDM2-p53 interaction is represented by the evaluation of their efficacy in preventing the formation of the MDM2-p53 complex. This can be achieved using the in vitro reconstructed recombinant MDM2-p53 complex in cell-free assays. A number of possible approaches have been proposed, which are however not suitable for screening large chemical libraries, due to the high costs of reagents and instrumentations, or the need of large amounts of highly pure recombinant proteins. Here we describe a rapid and cheap method for high-throughput screening of putative inhibitors of MDM2-p53 complex formation - based on the use of GST-recombinant proteins - that does not require antibodies and recombinant protein purification steps from bacterial cell lysates. Copyright © 2013 John Wiley & Sons, Ltd. 23412171 Is platelet-rich plasma able to enhance the results of arthroscopic microfracture in early osteoarthritis and cartilage lesion over 40 years of age? Most studies suggested that arthroscopic microfracture is effective method at only less than 40 years of age. Thus, the authors thought that "how can this indication regarding age be extended?," and tried to find a way to use this technique effectively over 40 years of age. The aim of this study was the first to report the results regarding the PRP as an adjunct for arthroscopic microfracture in the early osteoarthritic (OA) knee with cartilage lesion over 40 years of age. 49 patients who underwent arthroscopic microfracture for cartilage lesion sized less than 4 cm(2) with early OA, aged 40-50 years, were enrolled and randomly divided into 2 groups: a control group with only arthroscopic microfracture (25 patients) and a study group with arthroscopic microfracture and PRP (24 patients). The patients were prospectively evaluated with VAS, IKDC score at preoperative and postoperative 1, 6, 12, and 24 months. And we perform second arthroscopies in 10 patients of each group to identify the extent of cartilage restoration at 4-6 months postoperatively. There were significant improvements in clinical results between preoperative evaluation and postoperative 2 years in both groups (p = 0.017). In the postoperative 2 years, clinical results showed significantly better in the study group than in the control group (p = 0.012). In post-arthroscopic finding, hardness and elasticity degree was better in the study group. The PRP injection with arthroscopic microfracture would be improved the results in early osteoarthritic knee with cartilage lesion in 40-50 years old, and the indication of this technique could be extended to 50 years. 23871914 Calcein release behavior from liposomal bilayer; influence of physicochemical/mechanical/structural properties of lipids. The design of the drug delivery depends upon different parameters. One of the most noticeable factors in design of the drug delivery is drug-release profile which determines the site of action, the concentration of the drug at the time of administration, the period of time that the drug must remain at a therapeutic concentration. To get a better understanding of drug release, large unilamellar liposomes containing calcein were prepared using 1,2-dioleoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and 1,2-palmitoyl-sn-glycero-3-phosphocholine, and a mixture of them; calcein was chosen as a model of hydrophilic drug. The calcein permeability across liposomal membrane (with different compositions) was evaluated on the basis of the first-order kinetic by spectrofluorometer. Also, the effects of liposome composition/fluidity as well as the incubation temperature/pH were investigated. Furthermore, we simulated the digestion condition in the gastrointestinal tract in humans, to mimic human gastro-duodenal digestion to monitor calcein release during the course of the digestion process. In vitro digestion model ''pH stat'' was used to systematically examine the influence of pH/enzyme on phospholipid liposomes digestion under simulated gastro-duodenal digestion. The results revealed that calcein permeates across liposomal membrane without membrane disruption. The release rate of calcein from the liposomes depends on the number and fluidity of bilayers and its mechanical/physical properties such as permeability, bending elasticity. Chemo-structural properties of drugs like as partition coefficient (Log P), H-bonding, polar surface area (PSA) are also determinative parameter in release behavior. Finally, stimulated emission depletion (STED) microscopy was used to study calcein translocation through liposomal bilayers. 23945741 Application of visible and near infrared spectroscopy for rapid analysis of chrysin and galangin in chinese propolis. A novel method for the rapid determination of chrysin and galangin in Chinese propolis of poplar origin by means of visible and near infrared spectroscopy (Vis-NIR) was developed. Spectral data of 114 Chinese propolis samples were acquired in the 325 to 1,075 nm wavelength range using a Vis-NIR spectroradiometer. The reference values of chrysin and galangin of the samples were determined by high performance liquid chromatography (HPLC). Partial least squares (PLS) models were established using the spectra analyzed by different preprocessing methods. The effective wavelengths were selected by successive projections algorithm (SPA) and employed as the inputs of PLS, back propagation-artificial neural networks (BP-ANN), multiple linear regression (MLR) and least square-support vector machine (LS-SVM) models. The best results were achieved by SPA-BP-ANN models established with the Savitzky-Golay smoothing (SG) preprocessed spectra, where the r and RMSEP were 0.9823 and 1.5239 for galangin determination and 0.9668 and 2.4841 for chrysin determination, respectively. The results show that Vis-NIR demosntrates powerful capability for the rapid determination of chrysin and galangin contents in Chinese propolis. 23858452 Characterization of the nitric oxide reductase from Thermus thermophilus. Nitrous oxide (N2O) is a powerful greenhouse gas implicated in climate change. The dominant source of atmospheric N2O is incomplete biological dentrification, and the enzymes responsible for the release of N2O are NO reductases. It was recently reported that ambient emissions of N2O from the Great Boiling Spring in the United States Great Basin are high, and attributed to incomplete denitrification by Thermus thermophilus and related bacterial species [Hedlund BP, et al. (2011) Geobiology 9(6)471-480]. In the present work, we have isolated and characterized the NO reductase (NOR) from T. thermophilus. The enzyme is a member of the cNOR family of enzymes and belongs to a phylogenetic clade that is distinct from previously examined cNORs. Like other characterized cNORs, the T. thermophilus cNOR consists of two subunits, NorB and NorC, and contains a one heme c, one Ca(2+), a low-spin heme b, and an active site consisting of a high-spin heme b and FeB. The roles of conserved residues within the cNOR family were investigated by site-directed mutagenesis. The most important and unexpected result is that the glutamic acid ligand to FeB is not essential for function. The E211A mutant retains 68% of wild-type activity. Mutagenesis data and the pattern of conserved residues suggest that there is probably not a single pathway for proton delivery from the periplasm to the active site that is shared by all cNORs, and that there may be multiple pathways within the T. thermophilus cNOR. 23929657 All-Metal Clusters that Mimic the Chemistry of Halogens. Owing to their s(2) p(5) electronic configuration, halogen atoms are highly electronegative and constitute the anionic components of salts. Whereas clusters that contain no halogen atoms, such as AlH4 , mimic the chemistry of halogens and readily form salts (e.g., Na(+) (AlH4 )(-) ), clusters that are solely composed of metal atoms and yet behave in the same manner as a halogen are rare. Because coinage-metal atoms (Cu, Ag, and Au) only have one valence electron in their outermost electronic shell, as in H, we examined the possibility that, on interacting with Al, in particular as AlX4 (X=Cu, Ag, Au), these metal atoms may exhibit halogen-like properties. By using density functional theory, we show that AlAu4 not only mimics the chemistry of halogens, but also, with a vertical detachment energy (VDE) of 3.98 eV in its anionic form, is a superhalogen. Similarly, analogous to XHX superhalogens (X=F, Cl, Br), XAuX species with VDEs of 4.65, 4.50, and 4.34 eV in their anionic form, respectively, also form superhalogens. In addition, Au can also form hyperhalogens, a recently discovered species that show electron affinities (EAs) that are even higher than those of their corresponding superhalogen building blocks. For example, the VDEs of M(AlAu4 )2 (-) (M=Na and K) and anionic (FAuF)Au(FAuF) range from 4.06 to 5.70 eV. Au-based superhalogen anions, such as AlAu4 (-) and AuF2 (-) , have the additional advantage that they exhibit wider optical absorption ranges than their H-based analogues, AlH4 (-) and HF2 (-) . Because of the catalytic properties and the biocompatibility of Au, Au-based superhalogens may be multifunctional. However, similar studies that were carried out for Cu and Ag atoms have shown that, unlike AlAu4 , AlX4 (X=Cu, Ag) clusters are not superhalogens, a property that can be attributed to the large EA of the Au atom. 23929826 A Designed 5-Fluorouracil-Based Bridged Silsesquioxane as an Autonomous Acid-Triggered Drug-Delivery System. Two new prodrugs, bearing two and three 5-fluorouracil (5-FU) units, respectively, have been synthesized and were shown to efficiently treat human breast cancer cells. In addition to 5-FU, they were intended to form complexes through H-bonds to an organo-bridged silane prior to hydrolysis-condensation through sol-gel processes to construct acid-responsive bridged silsesquioxanes (BS). Whereas 5-FU itself and the prodrug bearing two 5-FU units completely leached out from the corresponding materials, the prodrug bearing three 5-FU units was successfully maintained in the resulting BS. Solid-state NMR ((29) Si and (13) C) spectroscopy show that the organic fragments of the organo-bridged silane are retained in the hybrid through covalent bonding and the (1) H NMR spectroscopic analysis provides evidence for the hydrogen-bonding interactions between the prodrug bearing three 5-FU units and the triazine-based hybrid matrix. The complex in the BS is not affected under neutral medium and operates under acidic conditions even under pH as high as 5 to deliver the drug as demonstrated by HPLC analysis and confirmed by FTIR and (13) C NMR spectroscopic studies. Such functional BS are promising materials as carriers to avoid the side effects of the anticancer drug 5-FU thanks to a controlled and targeted drug delivery. 23813970 Medulloblastoma in a patient with the PTPN11 p.Thr468Met mutation. Medulloblastoma is the commonest brain tumor in childhood and in a minority of patients is associated with an underlying genetic disorder such as Gorlin syndrome or familial adenomatous polyposis. Increased susceptibility to certain tumors, including neuroblastoma and some hematological malignancies, is recognized in disorders caused by mutations in genes encoding components of the RAS signaling pathway which include Noonan syndrome, Noonan syndrome with multiple lentigines (NSML; formerly called LEOPARD syndrome), Costello syndrome, Cardiofaciocutaneous syndrome, Legius syndrome, and Neurofibromatosis type 1 (NF1), collectively termed RASopathies. Although an association between medulloblastoma and NF1 has been reported, this tumor has not previously been reported in other RASopathies. We present a patient with NSML caused by the recurrent PTPN11 mutation c.1403C > T (p.Thr468Met) in whom medulloblastoma was diagnosed at age 10 years. Medulloblastoma could therefore be part of the tumor spectrum associated with this disorder. © 2013 Wiley Periodicals, Inc. 23968652 Influence of electron dose rate on electron counting images recorded with the K2 camera. A recent technological breakthrough in electron cryomicroscopy (cryoEM) is the development of direct electron detection cameras for data acquisition. By bypassing the traditional phosphor scintillator and fiber optic coupling, these cameras have greatly enhanced sensitivity and detective quantum efficiency (DQE). Of the three currently available commercial cameras, the Gatan K2 Summit was designed specifically for counting individual electron events. Counting further enhances the DQE, allows for practical doubling of detector resolution and eliminates noise arising from the variable deposition of energy by each primary electron. While counting has many advantages, undercounting of electrons happens when more than one electron strikes the same area of the detector within the analog readout period (coincidence loss), which influences image quality. In this work, we characterized the K2 Summit in electron counting mode, and studied the relationship of dose rate and coincidence loss and its influence on the quality of counted images. We found that coincidence loss reduces low frequency amplitudes but not the signal-to-noise ratio of the recorded image. It also has little influence on high frequency signals. Images of frozen hydrated archaeal 20S proteasome (∼700kDa, D7 symmetry) recorded at the optimal dose rate retained both high-resolution signal and low-resolution contrast and enabled calculating a 3.6Å three-dimensional reconstruction from only 10,000 particles. 23873446 Desorption electrospray ionization mass spectrometry (DESI-MS) applied to the speciation of arsenic compounds from fern leaves. The different chemical forms of arsenic compounds, including inorganic and organic species, present distinct environmental impacts and toxicities. Desorption electrospray ionization mass spectrometry (DESI-MS) is an excellent technique for in situ analysis, as it operates under atmospheric pressure and room temperature and is conducted with no/minimal sample pretreatment. Aimed at expanding its scope, DESI-MS is applied herein for the quick and reliable detection of inorganic (arsenate-As(V): AsO4 (3-) and arsenite-As(III): AsO2 (-)) and organic (dimethylarsinic acid-DMA: (CH3)2AsO(OH) and disodium methyl arsonate hexahydrate: CH3AsO3·2Na·6H2O) arsenic compounds in fern leaves. Operational conditions of DESI-MS were optimized with DMA standard deposited on paper surfaces to improve ionization efficiency and detection limits. Mass spectra data for all arsenic species were acquired in both the positive and negative ion modes. The positive ion mode was shown to be useful in detecting both the organic and inorganic arsenic compounds. The negative ion mode was shown only to be useful in detecting As(V) species. Moreover, MS/MS spectra were recorded to confirm the identity of each arsenic compound by the characteristic fragmentation profiles. Optimized conditions of DESI-MS were applied to the analysis of fern leaves. LC-ICP-MS was employed to confirm the results obtained by DESI-MS and to quantify the arsenic species in fern leaves. The results confirmed the applicability of DESI-MS in detecting arsenic compounds in complex matrices. 23948222 Sensory symptoms in restless legs syndrome: the enigma of pain. Restless legs syndrome (RLS) is a common sensorimotor condition characterized by an urge to move the legs, worsening of symptoms at rest and during the evening/night, and improvement of symptoms with movement. Our review explores the role and impact of sensory symptoms in RLS. The phenomenology of RLS is discussed, highlighting the difficulty patients have in describing their sensations and in differentiating between sensory and motor symptoms. Sensory symptoms have a significant impact on quality of life but remain much less well understood than motor symptoms and sleep disturbances in RLS. Although RLS symptoms usually are not described as painful, sensory manifestations in RLS do share some similarities with chronic pain sensations, and RLS frequently occurs in chronic pain and neuropathic conditions. Peripheral neuropathies may account for some of the sensory disturbances in secondary RLS, while alterations in central somatosensory processing may be a more viable explanation for the sensory disturbances in primary RLS. The effectiveness of analgesics in treating RLS supports the concept of abnormal sensory modulation in RLS and suggests an overlap between pain modulatory pathways and sensory disturbances. Future studies are needed to better understand the experiential and biologic aspects of altered sensory experiences in RLS. 23597791 1,1-Difluoroethyl-substituted triazolothienopyrimidines as inhibitors of a human urea transport protein (UT-B): New analogs and binding model. The kidney urea transport protein UT-B is an attractive target for the development of small-molecule inhibitors with a novel diuretic ('urearetic') action. Previously, two compounds in the triazolothienopyrimidine scaffold (1a and 1c) were reported as UT-B inhibitors. Compound 1c incorporates a 1,1-difluoroethyl group, which affords improved microsomal stability when compared to the corresponding ethyl-substituted compound 1a. Here, a small focused library (4a-4f) was developed around lead inhibitor 1c to investigate the requirement of an amidine-linked thiophene in the inhibitor scaffold. Two compounds (4a and 4b) with nanomolar inhibitory potency (IC50≈40nM) were synthesized. Computational docking of lead structure 1c and 4a-4f into a homology model of the UT-B cytoplasmic surface suggested binding with the core heterocycle buried deep into the hydrophobic pore region of the protein. 23934001 Nativity disparities in late-stage diagnosis and cause-specific survival among Hispanic women with invasive cervical cancer: an analysis of Surveillance, Epidemiology, and End Results data. While cervical cancer screening and risk behaviors have been found to vary among US- and foreign-born Hispanic women, many cancer epidemiology studies have conceptualized Hispanics as a homogenous group. Here, we examine differences in cervical cancer stage at diagnosis and survival among Hispanic women by nativity. We use data from the Surveillance, Epidemiology, and End Results program, 1998-2008. Nativity was based on place of birth and was categorized as US versus foreign born. Distant and regional tumors were classified as late stage, while local tumors were classified as early stage. Forty-seven percent of cases of invasive cervical cancer among Hispanics were diagnosed at a late stage, and over half of invasive cervical cancer cases were among foreign-born women. Foreign-born Hispanic women were significantly more likely than US-born Hispanics to have late-stage diagnosis, after adjusting for age at diagnosis and tumor histology (adjusted odds ration = 1.09, p value = 0.003). There was heterogeneity in the association between nativity and survival by stage at diagnosis. Among cases with early-stage diagnosis, survival was poorer among foreign-born versus US-born Hispanics after adjusting for age at diagnosis, histology, and cancer-directed therapy [adjusted hazard ratios (HR) = 1.31, p value = 0.030]. However, among cases with late-stage diagnosis, survival was better among foreign-born Hispanics (adjusted HR = 0.81, p value < 0.001). We hypothesize that nativity differences in survival may be indicative of diverse risk, screening, and treatment profiles. Given such differences, it may be inappropriate to aggregate Hispanics as a single group for cervical cancer research. 23743348 Fatty acid transport proteins chronically relocate to the transverse-tubules in muscle from obese Zucker rats but are resistant to further insulin-induced translocation. Recently, we have demonstrated that FA transport proteins are located within the t-tubule fraction of rodent muscle, and that insulin stimulation causes their translocation to this membrane fraction. Chronic relocation of the FA transport protein FAT/CD36 to the sarcolemma is observed in obese rodents and humans, and correlates with intramuscular lipid accumulation and insulin resistance. It is not known whether in an obese, insulin resistant state FA transporters also chronically relocate to the t-tubules. Furthermore, it is not known whether the insulin-stimulated translocation of the various FA transport proteins to the t-tubules is impaired in insulin resistance. Sarcolemmal and t-tubule membrane fractions were isolated via differential centrifugation from muscles of lean and obese female Zucker rats during basal or insulin stimulated conditions. FA transport proteins were measured via western blot on both membrane fractions. Our results demonstrate that in muscle from insulin resistant Zucker rats, FAT/CD36, FABPpm and FATP1 are all increased on the t-tubules in the basal state (+72%, +120%, and +69%, respectively), potentially contributing to the accumulation of intramuscular lipids. Insulin failed to increase the content of the FA transport proteins on either the t-tubule or sarcolemma above the elevated basal levels, analogous to the well characterized impairment of insulin-stimulated GLUT4 translocation to both membrane domains in obesity. FA transport proteins chronically relocate to the t-tubule domain in insulin resistant muscle, potentially contributing to lipid accumulation. Further translocation of the FA transport proteins to this domain during insulin stimulation, however, is impaired. 23849085 Extension of the right internal thoracic artery with the radial artery in extensive re-do coronary artery bypass grafting. Patients with extensive coronary artery disease often require re-do coronary artery bypass grafting. However, autologous bypass material is sometimes sparse. Since long term patency of arterial graft material is superior to venous bypass grafting, we developed a technique to perform re-do total arterial coronary artery bypass grafting extending the right internal thoracic artery (RITA) with the radial artery (RA) in an end to end fashion to gain the needed length in patients with and without an open left thoracic artery (LITA). We performed this approach in 27 consecutive patients (age: 67.93 +/- 7.51 years). Data was analyzed retrospectively. 19 operations were first re-op, 6 were second re-op and two were third re-op procedures. Cardiopulmonary bypass time was 115.42 minutes (+/-31.92 minutes) with one OPCAB procedure, and clamp time was 55.09 minutes (+/-22.41 minutes) excluding 10 procedures performed on beating heart. Bypass grafting included the RCA, Cx and LAD. An average of 1.96 anastomoses were performed in each patient. Complication rate was low with one intra-operative apoplexy and one prolonged wound healing after harvest of the radial artery. One patient needed long term pulmonary assist. There was no intra-operative or early postoperative death. The operational technique of elongation of the internal thoracic artery with the radial artery proved to be safe and feasible with acceptable operation times for a re-do procedure. We recommend this as an additional option to existing methods to perform a complete arterial revascularization mainly in patients with open left internal thoracic artery to LAD bypass. 23681079 LC3 and p62 as diagnostic markers of drug-induced autophagic vacuolar cardiomyopathy: a study of 3 cases. Autophagic vacuolar cardiomyopathy is an underrecognized, but potentially fatal, complication of treatment with chloroquine (CQ) and its derivative hydroxychloroquine (HCQ), which are used as therapy for malaria and common connective tissue disorders. Currently, the diagnosis of autophagic vacuolar cardiomyopathy is established through an endomyocardial biopsy and requires electron microscopy, which is not widely available and has a significant potential for sampling error. Recently, we have reported that immunohistochemistry for autophagic markers LC3 and p62 can replace electron microscopy in the diagnosis of HCQ-induced and colchicine-induced autophagic vacuolar skeletal myopathies. In the current study, we use 3 cases of CQ-induced or HCQ-induced cardiomyopathy and 1 HCQ-treated control case to show that the same two markers can be used to diagnose autophagic vacuolar cardiomyopathies by light microscopy. CQ-induced or HCQ-induced autophagic vacuolar cardiomyopathy is not universally fatal, but successful treatment requires early detection. By lowering the barriers to diagnosis, the application of these immunohistochemical markers will decrease the number of misdiagnosed patients, thus increasing the likelihood of favorable clinical outcomes. 23542121 Evaluation of three-dimensional polymer gel dosimetry using X-ray CT and R2 MRI. It is difficult to obtain images of thin slices from measurement of spin-spin relaxation (R2) with magnetic resonance imaging (MRI) using the traditional dose reading method of polymer gel dosimetry. In this study, the dose reading method was performed using X-ray computed tomography (CT) for proton beam measurements in order to enable collection of thin slices. In addition, three-dimensional (3D) images of polymer gels were constructed using volume rendering. As a result of acquisition of thin slices, more detailed 3D data consisting of smaller voxel sizes compared to R2 were acquired. However, it was found that with thin slice thicknesses and small voxels, the signal-to-noise ratio around the voxels deteriorated. In addition, the coefficient of variation of non-irradiated gels with CT was smaller than that with R2 MRI. 23946407 Plastic modification of anti-saccades: adaptation of saccadic eye movements aimed at a virtual target. Saccades allow us to visually explore our environment. Like other goal-directed movements, their accuracy is permanently controlled by adaptation mechanisms that, in the laboratory, can be induced by systematic displacement of the "real" visual target during the saccade. However, in an anti-saccade (AS) task, the target is "virtual" because gaze has to be shifted away from the "real" visual target toward its mentally defined mirror position. Here, we investigated whether the brain can adapt movements aimed at a virtual target by trying, for the first time, to adapt AS. Healthy human volunteers produced leftward AS during three different exposure phases in which a visual target provided feedback after the AS. In the adaptation condition, the feedback target appeared after completion of the AS response at a location shifted outward from final eye position (immediate non-veridical feedback). In the two control conditions, adaptation was prevented by delaying (800 ms) the shifted feedback target (delayed-shift) or by providing an immediate but veridical feedback at the mirror position of the visual target (no-shift). Results revealed a significant increase of AS gain only in the adaptation condition. Moreover, testing pro-saccades (PS) before and after exposure revealed a significant increase of leftward PS gain in the adaptation condition. This transfer of adaptation supports the hypotheses of a motor level of AS adaptation and of a visual level of AS vector inversion. Together with data from the literature, these results also provide new insights into adaptation and planning mechanisms for AS and for other subtypes of voluntary saccades. 23857344 CEACAM6 induces epithelial-mesenchymal transition and mediates invasion and metastasis in pancreatic cancer. Pancreatic cancer is a disease with an extremely poor prognosis. The acquisition of invasion properties in pancreatic cancer is accompanied by the process of epithelial-mesenchymal transition (EMT). Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is emerging as an important determinant of the malignant phenotype in a range of cancers, including pancreatic cancer. Therefore, the aim of this study was to evaluate the potential involvement of CEACAM6 in the invasion and metastasis of pancreatic cancer cells via EMT regulation. The results of our study showed a positive association between CEACAM6 expression and poor prognosis of pancreatic cancer, differentiation and lymph node metastasis. Elevated levels of CEACAM6 in pancreatic cancer cells promoted EMT, migration and invasion in vitro and metastasis in animal models, whereas shRNA-mediated CEACAM6 knockdown had the opposite effect. Furthermore, we demonstrated that miR-29a/b/c specific for CEACAM6 could regulate its expression at the post-transcriptional level. Collectively, our findings identified CEACAM6, which is regulated by miR-29a/b/c, as an important positive regulator of EMT in pancreatic cancer offering an explanation for how elevated levels of CEACAM6 are likely to contribute to the highly metastatic phenotype of pancreatic cancer. 23477594 The effect of dietary supplementation of nitric oxide donor and inhibitor on nNOS expression in and motility of the small intestine of broilers. We investigated the effect of dietary supplementation of sodium nitroprusside (SNP), a nitric oxide (NO) donor, and N-nitro-L-arginine methyl ester (L-NAME), a NO inhibitor, on neuronal nitric oxide synthase (nNOS) expression in and motility of small intestinum in broilers. A total of 560, one-day-old Ross 308 hybrid mixed sex broiler chicks were divided randomly into one control and seven treatment groups for a 42 day feeding trial including starter phase (0-21 days) and grower phase (22-42 days). The control group was fed a basal diet and the experimental groups were the fed basal diet supplemented with 25, 50, 100 and 200 mg/kg SNP and 25, 50 or 100 mg/kg L-NAME. Ten chickens from each group were sacrificed to collect samples on days 21 and 42. The expression patterns of nNOS immunoreactivity in nerve fibers were determined by immunohistochemistry. In the contractility studies, longitudinal isolated strips of duodenum, jejunum and ileum were treated with 10(-5) M L-arginine and 10(-4) M SNP. Immunohistochemistry revealed that nNOS expression was not detectable in the duodenum or ileum of either the control or experimental groups. On the other hand, nNOS immunoreactivity in the jejunum control group showed a strong reaction on day 21, but the reaction was weak on day 42. nNOS expression clearly was suppressed on day 21 by the diet supplemented with L-NAME, while the diet supplemented with SNP stimulated nNOS expression on day 21. Contractility experiments revealed that spontaneous contractility of isolated strips of duodenum, jejunum and ileum showed no significant difference among groups. Spontaneous contractions of all strips were inhibited by L-arginine and SNP in all groups. The percentage inhibition rate of spontaneous contractions of jejunum application on days 21 and 42 after L-arginine decreased in the group supplemented with 100 mg/kg L-NAME. The percentage inhibition rate on day 21 after SNP application decreased in both groups that received 50 and 100 mg/kg L-NAME. We demonstrated the expression pattern of nNOS in nerve fibers in jejunum of broiler chickens. Contractility studies revealed that the NOS-NO pathway may play a role in smooth muscle contraction of small intestine of chickens. Feeding strategies that supplement NO donor and NO inhibitor can be of physiological importance to small intestine motility owing to alteration of nNOS expression in the jejunum. 23643415 Kinetic sonication effects in aqueous acetonitrile solutions. Reaction rate levelling by ultrasound. The kinetics of the pH-independent hydrolysis of 4-methoxyphenyl dichloroacetate were investigated with and without ultrasonic irradiation in acetonitrile-water binary mixtures containing 0.008 to 35 wt.% of acetonitrile and the kinetic sonication effects (kson/knon) were calculated. Molecular dynamics (MD) simulations of the structure of the solutions were performed with ethyl acetate as the model ester. The ester is preferentially solvated by acetonitrile. The excess of acetonitrile over water in the solvation shell grows fast with an increase in the co-solvent content in the bulk solution. In parallel, the formation of a second solvation shell rich in acetonitrile takes place. Significant kinetic sonication effects for the hydrolysis were explained with facile destruction of the diffuse second solvation shell followed by a rearrangement of the remaining solvent layer under sonication. The rate levelling effect of ultrasound was discussed. In an aqueous-organic binary solvent, independent of the solvent composition, the ultrasonic irradiation evokes changes in the reaction medium which result in an almost identical solvation state of the reagent thus leading to the reaction rate levelling. 23397419 Lipid Efflux Mediated by Alkylphospholipids in HepG2 Cells. Antitumoural alkylphospholipid (APL) analogues alter cholesterol homoeostasis in HepG2 cells by interfering with cholesterol transport from the plasma membrane to the endoplasmic reticulum (ER) and at the same time stimulating the release of considerable quantities of membrane cholesterol. The capacity of APLs to stimulate cholesterol efflux is suppressed when cells are incubated simultaneously with APLs and serum whilst the inhibition of cholesterol transport to the ER (measured in terms of the synthesis of esterified cholesterol) persists, indicating that both effects are independent of each other. Interestingly, our results suggest that both raft and non-raft membrane domains contribute to the cholesterol released to APLs. In addition, a marked efflux of choline-bearing phospholipids (phosphatidylcholine (PC) and sphingomyelins (SM)) was found to be related to this release of cholesterol. Finally, we observed that APL micelles composed of cholesterol might act as donor/acceptor cholesterol systems. Thus, the findings of this study clearly demonstrate that antitumoural APLs act as extracellular acceptors, stimulating cholesterol and phospholipid efflux, although they may also play a role as cholesterol donors. 23661790 Incidence of serious bacterial infections in febrile children with sickle cell disease. To determine the incidence of serious bacterial infections in febrile children with sickle cell disease and to describe the outcomes of children discharged from the pediatric emergency department. We conducted a retrospective chart review of 188 febrile patients with sickle cell disease presenting to our pediatric emergency department over a 10-year period. Serious bacterial infection was defined as bacteremia, meningitis, urinary tract infection, osteomyelitis, or pneumonia. Our overall incidence rate for serious bacterial infections was 16.0% (95% confidence interval [CI] = 10.8% to 21.2%). Pneumonia had the highest incidence rate of 13.8% (95% CI = 8.8% to 18.8%). This was followed by bacteremia and urinary tract infections, both with incidence rates of 1.1% (95% CI = 0.0% to 2.5%). We had no cases of meningitis or osteomyelitis in our study group. We had an incidence of 16.0% for serious bacterial infections in febrile children with sickle cell disease, with the majority of patients diagnosed with pneumonia. 23829560 Structural Evidence: A Single Charged Residue Affects Substrate Binding in Cytochrome P450 BM-3. Cytochrome P450 BM-3 is a bacterial enzyme with sequence similarity to mammalian P450s that catalyzes the hydroxylation of fatty acids with high efficiency. Enzyme-substrate binding and dynamics has been an important topic of study in cytochromes P450, since most of the crystal structures published show the substrate in an inactive state. We have determined a new crystal structure of cytochrome P450 BM-3 in complex with N-palmitoylglycine (NPG), which unexpectedly showed a direct bidentate ion-pair between NPG and arginine 47 (R47). We further explored the role of R47, the only charged residue in the binding pocket in cytochrome P450 BM-3, through mutagenesis and crystallographic studies. The mutations of R47 to glutamine (R47Q), glutamic acid (R47E), and lysine (R47K) were designed to investigate the role of this residue's charge in binding and catalysis. The oppositely charged R47E mutation had the greatest effect on activity and binding. The crystal structure of R47E BMP shows that the glutamic acid side chain is blocking the entrance to the binding pocket, accounting for NPG's low binding affinity and charge repulsion. For R47Q and R47K BM-3, the mutations caused only a slight change in kcat and a large change in Km and Kd, which suggests that R47 mostly is involved in binding and that our crystal structure represents an initial binding step in the P450 cycle. 23937233 Examination of Frontal and Parietal Tectocortical Attention Pathways in Spina Bifida Meningomyelocele using Probabilistic Diffusion Tractography. Abnormalities of the midbrain tectum are common but variable malformations in spina bifida meningomyelocele (SBM) and have been linked to neuropsychological deficits in attention orienting. The degree to which variations in tectum structure influence white matter (WM) connectivity to cortical regions is unknown. To assess relations of tectal structure and connectivity to frontal and parietal cortical regions, probabilistic diffusion tractography was performed on 106 individuals (80 SBM, 26 typically developing (TD)) to isolate anterior versus posterior tectocortical WM pathways. Results showed that those with SBM exhibited significantly reduced tectal volume, along with decreased fractional anisotropy (FA) in posterior but not anterior tectocortical WM pathways when compared to TD individuals. The group with SBM also showed greater within-subject discrepancies between frontal and parietal WM integrity compared to the TD group. Of those with SBM, qualitative classification of tectal beaking based on radiological review was associated with increased axial diffusivity across both anterior and posterior tectocortical pathways, relative to individuals with SBM and a normal appearing tectum. These results support previous volumetric findings of greater impairment to posterior versus anterior brain regions in SBM, and quantifiably relate tectal volume, tectocortical WM integrity, and tectal malformations in this population. 23530710 Mental health differences between frequent cannabis users with and without dependence and the general population. To compare the prevalence of mental disorders between frequent cannabis users with and without dependence and the general population. Cross-sectional comparison of interview data. Enriched community sample of frequent cannabis users and a representative sample of non-users and non-frequent users from the general population. A total of 521 young adult (aged 18-30 years) frequent cannabis users, 252 of whom were with DSM-IV cannabis dependence (D+) and 269 without DSM-IV cannabis dependence (D-), and 1072 young adults from the general population. Multinomial logistic regression was used to compare groups regarding the presence of DSM-IV mental disorders. Detailed measures of cannabis use, childhood adversity and other substance use were considered confounders. Compared with the general population, externalizing disorders were more prevalent in D- [odds ratio (OR) = 8.91, P < 0.001] and most prevalent in D+ (OR = 17.75, P < 0.001), but internalizing disorders were associated only with D+ (mood OR = 4.15, P < 0.001; anxiety OR = 2.20, P = 0.002). Associations were attenuated (and often became non-significant) after correction for childhood adversity and substance use other than cannabis. However, the prevalence of mental disorders remained higher in D+ compared with D- (OR = 2.40, P < 0.001), although cannabis use patterns were remarkably similar. Cannabis use patterns, childhood adversity and the use of other substances are similar in dependent and non-dependent frequent cannabis users. With the exception of more externalizing disorders, the mental health condition of non-dependent frequent cannabis users is similar to that of the general population, whereas it is worse in dependent frequent cannabis users. 23876978 Targeted conformational search with map-restrained self-guided Langevin dynamics: Application to flexible fitting into electron microscopic density maps. We present a map-restrained self-guided Langevin dynamics (MapSGLD) simulation method for efficient targeted conformational search. The targeted conformational search represents simulations under restraints defined by experimental observations and/or by user specified structural requirements. Through map-restraints, this method provides an efficient way to maintain substructures and to set structure targets during conformational searching. With an enhanced conformational searching ability of self-guided Langevin dynamics, this approach is suitable for simulating large-scale conformational changes, such as the formation of macromolecular assemblies and transitions between different conformational states. Using several examples, we illustrate the application of this method in flexible fitting of atomic structures into density maps derived from cryo-electron microscopy. 23685977 Metabolic energy sensors (AMPK and SIRT1), protein carbonylation and cardiac failure as biomarkers of thermal stress in an intertidal limpet: linking energetic allocation with environmental temperature during aerial emersion. The effects of heat stress on organisms are manifested at the levels of organ function, metabolic activity, protein stability and gene expression. Here, we examined effects of high temperature on the intertidal limpet Cellana toreuma to determine how the temperatures at which (1) organ failure (cardiac function), (2) irreversible protein damage (carbonylation) and (3) expression of genes encoding proteins involved in molecular chaperoning (hsp70 and hsp90) and metabolic regulation (ampk and sirt1) occur compare with field temperatures, which commonly exceed 30°C and can reach 46°C. Heart failure, indexed by the Arrhenius break temperature, occurred at 34.3°C. Protein carbonylation rose significantly at 38°C. Genes for heat shock proteins HSP70 (hsp70) and HSP90 (hsp90), for two subunits of AMP-activated protein kinase (AMPK) (ampkα and ampkβ) and for histone/protein deacetylase SIRT1 (sirt1) all showed increased expression at 30°C. Temperatures of maximal expression differed among genes, as did temperatures at which upregulation ceased. Expression patterns for ampk and sirt1 indicate that heat stress influenced cellular energy homeostasis; above ~30°C, upregulation of ATP-generating pathways is suggested by elevated expression of genes for ampk; an altered balance between reliance on carbohydrate and lipid fuels is indicated by changes in expression of sirt1. These results show that C. toreuma commonly experiences temperatures that induce expression of genes associated with the stress response (hsp70 and hsp90) and regulation of energy metabolism (ampk and sirt1). At high temperatures, there is likely to be a shift away from anabolic processes such as growth to catabolic processes, to provide energy for coping with stress-induced damage, notably to proteins. 23943104 Diagnosis and management of benign liver tumors. The widespread use of imaging modalities and the continuous improvement in their sensitivity have lead to an increasing number of incidental findings of focal liver masses, either solitary or multiple. Most of these so-called incidentalomas are benign and are discovered in healthy, asymptomatic patients. The main issue is to ensure the proper diagnosis, so that clear management recommendations can be provided. Surgery is rarely indicated in these circumstances. Infrequently, benign liver tumors are diagnosed because of symptoms or complications, and require urgent management including surgery as a major role in the cure. Due to better understanding of the clinical and pathological features of benign liver tumors, the increased accuracy of imaging tools, and improvement in surgical techniques (including laparoscopy), the management of these lesions has evolved. Here the clinical and biological features of the most common solid and cystic benign liver tumors are reviewed, and the key points of management focusing on the role of surgery, preventive or diagnostic, are addressed. 23763983 Automated interventions for multiple health behaviors using conversational agents. An automated health counselor agent was designed to promote both physical activity and fruit and vegetable consumption through a series of simulated conversations with users on their home computers. The agent was evaluated in a 4-arm randomized trial of a two-month daily contact intervention comparing: (a) physical activity; (b) fruit and vegetable consumption; (c) both interventions; and (d) a non-intervention control. Physical activity was assessed using daily pedometer steps. Daily servings of fruit and vegetables were assessed using the NIH/NCI self-report Fruit and Vegetable Scan. Participants in the physical activity intervention increased their walking on average compared to the control group, while those in the fruit and vegetable intervention and combined intervention decreased walking. Participants in the fruit and vegetable intervention group consumed significantly more servings per day compared to those in the control group, and those in the combined intervention reported consuming more compared to those in the control group. Automated health intervention software designed for efficient re-use is effective at changing health behavior. Automated health behavior change interventions can be designed to facilitate translation and adaptation across multiple behaviors. 23335435 Internalization Pathways of Anisotropic Disc-Shaped Zeolite L Nanocrystals with Different Surface Properties in HeLa Cancer Cells. Information about the mechanisms underlying the interactions of nanoparticles with living cells is crucial for their medical application and also provides indications of the putative toxicity of such materials. Here the uptake and intracellular delivery of disc-shaped zeolite L nanocrystals as porous aminosilicates with well-defined crystal structure, uncoated as well as with COOH-, NH(2) -, polyethyleneglycol (PEG)- and polyallylamine hydrochloride (PAH) surface coatings are reported. HeLa cells are used as a model system to demonstrate the relation between these particles and cancer cells. Interactions are studied in terms of their fates under diverse in vitro cell culture conditions. Differently charged coatings demonstrated dissimilar behavior in terms of agglomeration in media, serum protein adsorption, nanoparticle cytotoxicity and cell internalization. It is also found that functionalized disc-shaped zeolite L particles enter the cancer cells via different, partly not yet characterized, pathways. These in vitro results provide additional insight about low-aspect ratio anisotropic nanoparticle interactions with cancer cells and demonstrate the possibility to manipulate the interactions of nanoparticles and cells by surface coating for the use of nanoparticles in medical applications. 23864675 Choosing the rules: distinct and overlapping frontoparietal representations of task rules for perceptual decisions. Behavior is governed by rules that associate stimuli with responses and outcomes. Human and monkey studies have shown that rule-specific information is widely represented in the frontoparietal cortex. However, it is not known how establishing a rule under different contexts affects its neural representation. Here, we use event-related functional MRI (fMRI) and multivoxel pattern classification methods to investigate the human brain's mechanisms of establishing and maintaining rules for multiple perceptual decision tasks. Rules were either chosen by participants or specifically instructed to them, and the fMRI activation patterns representing rule-specific information were compared between these contexts. We show that frontoparietal regions differ in the properties of their rule representations during active maintenance before execution. First, rule-specific information maintained in the dorsolateral and medial frontal cortex depends on the context in which it was established (chosen vs specified). Second, rule representations maintained in the ventrolateral frontal and parietal cortex are independent of the context in which they were established. Furthermore, we found that the rule-specific coding maintained in anticipation of stimuli may change with execution of the rule: representations in context-independent regions remain invariant from maintenance to execution stages, whereas rule representations in context-dependent regions do not generalize to execution stage. The identification of distinct frontoparietal systems with context-independent and context-dependent task rule representations, and the distinction between anticipatory and executive rule representations, provide new insights into the functional architecture of goal-directed behavior. 23940584 Sparstolonin B inhibits pro-angiogenic functions and blocks cell cycle progression in endothelial cells. Sparstolonin B (SsnB) is a novel bioactive compound isolated from Sparganium stoloniferum, an herb historically used in Traditional Chinese Medicine as an anti-tumor agent. Angiogenesis, the process of new capillary formation from existing blood vessels, is dysregulated in many pathological disorders, including diabetic retinopathy, tumor growth, and atherosclerosis. In functional assays, SsnB inhibited endothelial cell tube formation (Matrigel method) and cell migration (Transwell method) in a dose-dependent manner. Microarray experiments with human umbilical vein endothelial cells (HUVECs) and human coronary artery endothelial cells (HCAECs) demonstrated differential expression of several hundred genes in response to SsnB exposure (916 and 356 genes, respectively, with fold change ≥2, p<0.05, unpaired t-test). Microarray data from both cell types showed significant overlap, including genes associated with cell proliferation and cell cycle. Flow cytometric cell cycle analysis of HUVECs treated with SsnB showed an increase of cells in the G1 phase and a decrease of cells in the S phase. Cyclin E2 (CCNE2) and Cell division cycle 6 (CDC6) are regulatory proteins that control cell cycle progression through the G1/S checkpoint. Both CCNE2 and CDC6 were downregulated in the microarray data. Real Time quantitative PCR confirmed that gene expression of CCNE2 and CDC6 in HUVECs was downregulated after SsnB exposure, to 64% and 35% of controls, respectively. The data suggest that SsnB may exert its anti-angiogenic properties in part by downregulating CCNE2 and CDC6, halting progression through the G1/S checkpoint. In the chick chorioallantoic membrane (CAM) assay, SsnB caused significant reduction in capillary length and branching number relative to the vehicle control group. Overall, SsnB caused a significant reduction in angiogenesis (ANOVA, p<0.05), demonstrating its ex vivo efficacy. 23813750 Repair of avascular meniscal injuries using juvenile meniscal fragments: An in vitro organ culture study. We investigated whether the implantation of juvenile allograft and minced meniscal fragments could improve the healing of avascular meniscal injuries, which cannot heal spontaneously. Concentric cylindrical explants were excised from the inner two-thirds of swine medial menisci. The inner cylinder consisted of a "sandwich" structure, with minced juvenile meniscal fragments, juvenile meniscal columns, minced mature meniscal fragments, or mature meniscal columns implanted in the middle. The explants were cultured in vitro for 2, 4, or 6 weeks. Interfacial meniscal repair was assessed by histology, immunohistochemistry, biomechanical testing, and confocal laser scanning microscopy. Histology and confocal microscopy results revealed that tissue repair and cell accumulation at the interface were best at all time points in the juvenile meniscal fragments group, followed by the juvenile columns, minced mature fragments, and mature columns groups, respectively. At 6 weeks, the implantation of juvenile allograft and minced meniscal fragments increased the shear strength, peak force, and energy to failure in the peripheral interface. Picosirius red/polarized light microscopy and immunohistochemistry results showed concurrent expression of type I and II collagen in the interfacial repair tissue. In conclusion, implantation of juvenile allograft and minced meniscal fragments could increase the healing of avascular meniscal injury in vitro. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1514-1519, 2013. 23811082 Effect of substrate competition in kinetic models of metabolic networks. Substrate competition can be found in many types of biological processes, ranging from gene expression to signal transduction and metabolic pathways. Although several experimental and in silico studies have shown the impact of substrate competition on these processes, it is still often neglected, especially in modelling approaches. Using toy models that exemplify different metabolic pathway scenarios, we show that substrate competition can influence the dynamics and the steady state concentrations of a metabolic pathway. We have additionally derived rate laws for substrate competition in reversible reactions and summarise existing rate laws for substrate competition in irreversible reactions. 23745742 Effects of surface charge and hydrophobicity on anodic biofilm formation, community composition, and current generation in bioelectrochemical systems. The focus of this study was to investigate the effects of surface charge and surface hydrophobicity on anodic biofilm formation, biofilm community composition, and current generation in bioelectrochemical systems (BESs). Glassy carbon surfaces were modified with -OH, -CH3, -SO3(-), or -N(+)(CH3)3 functional groups by electrochemical reduction of aryl diazonium salts and then used as anodes with poised potential of -0.2 V (vs Ag/AgCl). The average startup times and final current densities for the -N(+)(CH3)3, -OH, -SO3(-), and -CH3, electrodes were (23 d, 0.204 mA/cm(2)), (25.4 d, 0.149 mA/cm(2)), (25.9 d, 0.114 mA/cm(2)), and (37.2 d, 0.048 mA/cm(2)), respectively. Biofilms on different surfaces were analyzed by nonturnover cyclic voltammetry (CV), fluorescence in situ hybridization (FISH), and 16S rRNA gene amplicon pyrosequencing. The results demonstrated that 1) differences in the maximum current output between surface modifications was correlated with biomass quantity, and 2) all biofilms were dominated by Geobacter populations, but the composition of -CH3-associated biofilms differed from those formed on surfaces with different chemical modification. This study shows that anode surface charge and hydrophobicity influences biofilm development and can lead to significant differences in BESs performance. Positively charged and hydrophilic surfaces were more selective to electroactive microbes (e.g. Geobacter) and more conducive for electroactive biofilm formation. 23740215 Contributions of cardiomyocyte-cardiac fibroblast-immune cell interactions in heart failure development. The heart contains various types of cells, including cardiomyocytes, cardiac fibroblasts, many kinds of immune cells and vascular cells. Initial studies mainly focused on cardiomyocytes, which directly reflect the contractile function of the heart. Recently, pivotal functions of cardiac fibroblasts have been revealed in the maintenance of cardiac function, physiological cardiac remodeling after heart stress and pathological remodeling using genetically engineered mouse models, like the fibroblast-specific gene knockout mouse, bone marrow transplantation and immune cell-specific gene knockout. Moreover, chronic inflammation is considered to be a basic pathological mechanism that underlies various diseases, including heart failure. In the development of heart failure, the contributions of immune cells like T lymphocytes and monocyte/macrophage lineage cells have been also reported. Immune cells have diverse and multiple functions in regulating both pro-inflammatory effects and the resolution of heart failure. On the one hand, immune cells have protective effects to compensate for and overcome heart stresses. On the other hand, they also contribute to sustained inflammation and result in the development of heart failure. These observations prompted a shift in the heart-related studies to include the complex communications between cardiomyocytes and other kinds of cardiac cells, including inflammatory cells residing in or recruited to the heart. This review will summarize the current knowledge regarding cell-cell interactions during cardiac remodeling and the development of heart failure. We will especially focus on the interactions among cardiomyocytes, cardiac fibroblasts and immune cells. 23585326 Heat stress does not augment ventilatory responses to presyncopal limited lower body negative pressure. Simulated haemorrhage, e.g. lower body negative pressure (LBNP), reduces central blood volume and mean arterial pressure, while ventilation increases. Passive whole-body heat stress likewise increases ventilation. The objective of this project was to test the hypothesis that ventilatory responses to reductions in central blood volume and arterial pressure during simulated haemorrhage are enhanced when individuals are heat stressed rather than normothermic. Eight healthy men (34 ± 9 years old, 176 ± 6 cm tall and 80.2 ± 4.2 kg body weight) underwent a simulated haemorrhagic challenge via LBNP until presyncope on two separate occasions, namely normothermic control and whole-body heat-stress trials. Baseline ventilation and core and mean skin temperatures were not different between trials (all P > 0.05). Prior to LBNP, heat stress increased core (from 36.8 ± 0.2 to 38.2 ± 0.2°C, P < 0.05) and mean skin temperatures (from 33.9 ± 0.5 to 38.1 ± 0.6°C, P < 0.05), as well as minute ventilation (from 8.01 ± 2.63 to 13.68 ± 6.68 l min(-1), P < 0.01). At presyncope, mean arterial pressure and middle cerebral artery blood velocity decreased in both trials (P < 0.05). At presyncope, ventilation increased to 23.22 ± 6.78 (P < 0.01) and 25.88 ± 10.16 l min(-1) (P < 0.01) in the normothermic and hyperthermic trials, respectively; however, neither the increase in ventilation from the pre-LBNP period nor the absolute ventilation was different between normothermic and hyperthermic trials (P > 0.05). These data suggest that the increase in ventilation during simulated haemorrhage induced via LBNP is not altered in heat-stressed humans. 23902472 Prelithiation of Silicon-Carbon Nanotube Anodes for Lithium Ion Batteries by Stabilized Lithium Metal Powder (SLMP). Stabilized lithium metal powder (SLMP) has been applied during battery assembly to effectively prelithiate high capacity (1500-2500 mAh/g) silicon-carbon nanotube (Si-CNT) anodes, eliminating the 20-40% first cycle irreversible capacity loss. Pressure-activation of SLMP is shown to enhance prelithiation and enable capacity matching between Si-CNT anodes and lithium nickel cobalt aluminum oxide (NCA) cathodes in full batteries with minimal added mass. The prelithiation approach enables high energy density NCA/Si-CNT batteries achieving >1000 cycles at 20% depth-of-discharge. 23727138 Patients' transition in the intensive care units: concept analysis. Adequate preparation of critically ill patients throughout their transition experience within and following discharge from the Intensive Care Unit is an important element of the nursing care process during critical illness. However, little is known about nurses' perspectives of, and engagement in, caring for critically ill patients during their transition experiences. This paper aims to review the literature about the concept of transition within the context of critically ill patients in the Intensive Care Unit, focusing on Intensive Care Unit nurses. CINAHL, MEDLINE, OVID, Science Direct, SAGE eReference and SAGE Journal Online data bases were searched for relevant literature published since 1970. The critically ill patients' transitions in Intensive Care Units are generally described as a period of transfer or change of situation, or the experience of inner change or role during and after the illness. The critically ill patients' transition experience per se is not directly described, nor is nurses' understanding of it. Nurses' understanding of critically ill patients' transition may significantly impact the patients' care in the Intensive Care Unit. Thus, research is needed that focuses more on evaluating nurses' understanding of patients' transition and its consequences. 23660182 Temporal trends in the incidence, treatment, and outcomes of hip fracture in older patients initiating dialysis in the United States. Patients with ESRD experience a fivefold higher incidence of hip fracture than the age- and sex-matched general population. Despite multiple changes in the treatment of CKD mineral bone disorder, little is known about long-term trends in hip fracture incidence, treatment patterns, and outcomes in patients on dialysis. Fourteen annual cohorts (1996-2009) of older patients (≥67 years) initiating dialysis in the United States were studied. Eligible patients had Medicare fee-for-service coverage for ≥2 years before dialysis initiation and were followed for ≤3 years for a first hip fracture. Type of treatment (internal fixation or partial or total hip replacement) was ascertained along with 30-day mortality. Cox and modified Poisson regressions were used to describe trends in study outcomes. This study followed 409,040 patients over 607,059 person-years, during which time 17,887 hip fracture events were recorded (29.3 events/1000 person-years). Compared with patients incident for ESRD in 1996, adjusted hip fracture rates increased until the 2004 cohort (+41%) and declined thereafter. Surgical treatment included internal fixation in 56%, partial hip replacement in 29%, and total hip replacement in 2%, which remained essentially unchanged over time; 30-day mortality after hip fracture declined from 20% (1996) to 16% (2009). Hip fracture incidence rates remain higher today than in patients reaching ESRD in 1996, despite multiple purported improvements in the management of CKD mineral bone disorder. Although recent declines in incidence and steady declines in associated short-term mortality are encouraging, hip fractures remain among the most common and consequential noncardiovascular complications of ESRD. 23788467 Organocatalytic synthesis of highly functionalized pyridines at room temperature. Amines by all means: A unique aza-Rauhut-Currier/cyclization/desulfonation cascade reaction between allenoates and N-sulfonyl-1-aza-1,3-dienes, catalyzed by the readily available diamine TMEDA, has been developed. This strategy provides facile access to a broad range of valuable highly functionalized pyridines in good yields under very mild reaction conditions. 23913308 Cone beam CT guidance provides superior accuracy for complex needle paths compared with CT guidance. Objective: To determine the accuracy of cone beam CT (CBCT) guidance and CT guidance in reaching small targets in relation to needle path complexity in a phantom. Methods: CBCT guidance combines three-dimensional CBCT imaging with fluoroscopy overlay and needle planning software to provide real-time needle guidance. The accuracy of needle positioning, quantified as deviation from a target, was assessed for inplane, angulated and double angulated needle paths. Four interventional radiologists reached four targets along the three paths using CBCT and CT guidance. Accuracies were compared between CBCT and CT for each needle path and between the three approaches within both modalities. The effect of user experience in CBCT guidance was also assessed. Results: Accuracies for CBCT were significantly better than CT for the double angulated needle path (2.2 vs 6.7 mm, p<0.001) for all radiologists. CBCT guidance showed no significant differences between the three approaches. For CT, deviations increased with increasing needle path complexity from 3.3 mm for the inplane placements to 4.4 mm (p=0.007) and 6.7 mm (p<0.001) for the angulated and double angulated CT-guided needle placements, respectively. For double angulated needle paths, experienced CBCT users showed consistently higher accuracies than trained users [1.8 mm (range 1.2-2.2) vs 3.3 mm (range 2.1-7.2) deviation from target, respectively; p=0.003]. Conclusion: In terms of accuracy, CBCT is the preferred modality, irrespective of the level of user experience, for more difficult guidance procedures requiring double angulated needle paths as in oncological interventions. Advances in knowledge: Accuracy of CBCT guidance has not been discussed before. CBCT guidance allows accurate needle placement irrespective of needle path complexity. For angulated and double-angulated needle paths, CBCT is more accurate than CT guidance. 23720795 Minimum core genome sequence typing of bacterial pathogens: a unified approach for clinical and public health microbiology. Bacterial pathogens impose a heavy health burden worldwide. In the new era of high-throughput sequencing and online bioinformatics, real-time genome typing of infecting agents, and in particular those with potential severe clinical outcomes, holds promise for guiding clinical care to limit the detrimental effects of infections and to prevent potential local or global outbreaks. Here, we sequenced and compared 85 isolates of Streptococcus suis, a zoonotic human and swine pathogen, wherein we analyzed 32 recognized serotypes and 75 sequence types representing the diversity of the species and the human clinical isolates with high public health significance. We found that 1,077 of the 2,469 genes are shared by all isolates. Excluding 201 common but mobile genes, 876 genes were defined as the minimum core genome (MCG) of the species. Of 190,894 single-nucleotide polymorphisms (SNPs) identified, 58,501 were located in the MCG genes and were referred to as MCG SNPs. A population structure analysis of these MCG SNPs classified the 85 isolates into seven MCG groups, of which MCG group 1 includes all isolates from human infections and outbreaks. Our MCG typing system for S. suis provided a clear separation of groups containing human-associated isolates from those containing animal-associated isolates. It also separated the group containing outbreak isolates, including those causing life-threatening streptococcal toxic shock-like syndrome, from sporadic or less severe meningitis or bacteremia-only isolates. The typing system facilitates the application of genome data to the fields of clinical medicine and epidemiology and to the surveillance of S. suis. The MCG groups may also be used as the taxonomical units of S. suis to define bacterial subpopulations with the potential to cause severe clinical infections and large-scale outbreaks. 23340121 Systems biology approaches to evaluate arsenic toxicity and carcinogenicity: An overview. Long term exposure to arsenic, either through groundwater, food stuff or occupational sources, results in a plethora of dermatological and non-dermatological health effects including multi-organ cancer and early mortality. Several epidemiological studies, across the globe have reported arsenic-induced health effects and cancerous outcomes; but the prevalence of such diseases varies depending on environmental factors (geographical location, exposure level), and genetic makeup (and variants thereof); which is further modulated by several other factors like ethnicity, age-sex, smoking status, diet, etc. It is also interesting to note that, chronic arsenic exposure to a similar extent, even among the same family members, result in wide inter-individual variations. To understand the adverse effect of this toxic metabolite on biological system (cellular targets), and to unravel the underlying molecular basis (at the level of transcript, proteome, or metabolite), a holistic, systems biology approach was taken. Due to the paradoxical nature and unavailability of any suitable animal model system; the literature review is primarily based on cell line and population based studies. Thus, here we present a comprehensive review on the systems biology approaches to explore the underlying mechanism of arsenic-induced carcinogenicity, along with our own observations and an overview of mitigation strategies and their effectiveness till date. 23857426 Determination of free amino acids in African gourd seed milks by capillary electrophoresis with light-emitting diode induced fluorescence and laser-induced fluorescence detection. A CE technique coupled to LIF detection (488 nm) or LED-induced fluorescence detection (470 nm) has been evaluated to acquire a cheap way to analyze amino acids (AAs) whilst maintaining the best sensitivity. To quantitate AAs in milk of Cucurbitaceae of Sub-Saharan Africa, they were labeled with FITC. We used an optimized separation buffer composed of 30 mM boric acid buffer adjusted to pH 9.3 with NaOH (1 M) containing 12 mM SDS and 5% ethylene glycol v/v; prior to the injections, the derivatized samples are diluted 100 times. The LOQs in the sample are Arg: 1.1 μM, Ala: 3.5 μM, and Glu 8.9 μM. Cucumeropsis mannii (CM) Naudin and Citrullus lanatus (CL) are vegetable sources rich in proteins and AAs of high quality. Our analyses have led to the identification of 11 AAs in CL and CM milks. Phe, Trp, and Ala are predominant in the two types of lyophilized milks, while Asp and Val demonstrate very low contents. Six essential AAs (Phe, Thr, Val, Trp, Ile, and Leu) are present in both types of extracts, but lysine was not detected, indicating that this AA is missing in gourd milk. These results should be useful in efforts to complement or replace very expensive cow milk or the less-appreciated soya milk with milk from available local agroressources. 23494510 Safety and long-term results of endoscopic transanal resection in treating rectal adenomas: 15 years' experience. Endoscopic transanal resection (ETAR) is a scarcely used technique to treat large or sessile rectal adenomas not amenable to polypectomy. The purpose of this study was to evaluate safety and long-term results of ETAR in treating rectal adenomas in three hospitals over 15 years. Patients who underwent ETAR during 1996-2010 were retrospectively analyzed with respect to patient, adenoma, and operative characteristics, earlier operations, complications, follow-up time, recurrence rates, recurrence treatment, and cancer incidence. Ninety-two patients underwent a total 111 ETARs to treat rectal adenoma. The mean age of patients was 71 years, and the median ASA class 3. Twenty-eight patients previously had received other treatments for rectal adenoma. Incidental carcinoma was found in eight patients. Sixty-seven adenomas were treated with only one ETAR and 17 with two or three ETARs. Sixty-seven patients did not have a recurrence, whereas 14 patients had an adenoma recurrence and 3 patients developed invasive carcinoma during a mean follow-up of 30 months. Complications occurred in 14 patients; all were minor, except for one explorative laparotomy without findings. No mortalities or conversions to open surgery occurred. ETAR is a minimally invasive and safe technique with inexpensive instrumentation to treat rectal adenomas that are not amenable to polypectomy. Adenoma recurrence rate was 15 % and cancer incidence 3 % in follow-up. 23838308 Reactive Oxygen Species in Chronic Rhinosinusitis and Secondhand Smoke Exposure. ObjectiveReactive oxygen species (ROS) can potentiate cellular injury and inflammation. This study aimed to (1) assess the presence of reactive oxygen species in the sinus tissue of patients with chronic rhinosinusitis (CRS) and (2) assess the impact of secondhand smoke (SHS) exposure on reactive oxygen species (ROS) production.Study DesignRetrospective cohort study.SettingAcademic medical center.Subjects and MethodsSinus tissue samples from patients undergoing sinus surgery were analyzed using diaminobenzidine (DAB) staining to assess for ROS. Stained specimens were photographed at random by a blinded photographer and then quantified by 3 blinded graders. The patient's SHS exposure was determined by hair nicotine levels. Results were compared between non-smoke exposed cohorts and those exposed to secondhand smoke and by diagnosis.ResultsSixty-nine adults undergoing sinus surgery were included in the study. For the non-SHS-exposed cohorts, chronic rhinosinusitis with nasal polyps (CRSwNP) had the highest number of DAB+ cells/high-powered field (hpf) followed by chronic rhinosinusitis without nasal polyps (CRSsNP) and controls. When comparing the control patients to their SHS-exposed counterparts, SHS exposure yielded statistically significantly higher levels of DAB-positive cells/hpf. SHS exposure did not affect DAB staining in CRSsNP or CRSwNP patients.ConclusionROS are differentially expressed in various subtypes of CRS. SHS exposure increases ROS in sinus tissue of control patients, but the clinical significance of this is unclear. 23922728 Association of major depressive episode with negative outcomes of tuberculosis treatment. Pulmonary tuberculosis (TB) persists an important contributor to the burden of diseases in developing countries. TB control success is based on the patient's compliance to the treatment. Depressive disorders have been negatively associated with compliance of therapeutic schemes for chronic diseases. This study aimed to estimate the significance and magnitude of major depressive episode as a hazard factor for negative outcomes (NO), including abandon or death in patients receiving TB treatment. A longitudinal study was conducted to evaluate the association of major depressive episode (MDE), as measured by a 5-item version of the Center for Epidemiological Studies Depression Scale (CES-D) with NO to TB treatment. Patients with confirmed TB were enrolled before the start of TB treatment. Baseline measurements included socio-demographic variables as well as the CES-D, which was also applied every month until the end of the treatment. Death and treatment default were assessed monthly. Survivor function (SF) for NO according to MDE status (CES-D≥6) at baseline (MDEb) was estimated. Cox's Regression was performed for bivariate analyses as well as for the multivariate model. A total of 325 patients accepted to participate in the study, of which 34 where excluded for diagnosis of MDR-TB. NO was observed in 24 patients (8.2%); 109 (37%) presented MDEb. Statistically significant difference was found on the SF of patients with and without MDEb (0.85 vs. 0.96, p-value = 0.002). The hazard ratio for NO, controlled for age, sex, marital status and instruction level was 3.54 (95%CI 1.43-8.75; p-value = 0.006). The presence of MDE at baseline is associated to NO of TB treatment. Targeting detection and treatment of MDE may improve TB treatment outcomes. 23898011 Video Event Detection: From Subvolume Localization To Spatio-Temporal Path Search. Although sliding window-based approaches have been quite successful in detecting objects in images, it is not a trivial problem to extend them to detecting events in videos. We propose to search for spatio-temporal paths for video event detection. This new formulation can accurately detect and locate video events in cluttered and crowded scenes, and is robust to camera motions. It can also well handle the scale, shape, and intra-class variations of the event. Compared to event detection using spatio-temporal sliding windows, the spatio-temporal paths correspond to the event trajectories in the video space, thus can better handle events composed by moving objects. We prove that the proposed search algorithm can achieve the global optimal solution with the lowest complexity. Experiments are conducted on realistic video datasets with different event detection tasks, such as anomaly event detection, walking person detection, and running detection. Our proposed method is compatible to different types of video features or object detectors and robust to false and missed local detections. It significantly improves the overall detection and localization accuracy over the state-of-the-art methods. 23551575 Asymmetric dimethylarginine levels in children with sickle cell disease and its correlation to tricuspid regurgitant jet velocity. Pulmonary hypertension (PH) is an increasingly recognized life-threatening complication in sickle cell disease (SCD), with associated high mortality in adults. The prevalence of PH in children with SCD is still unknown. The etiology and pathophysiologic mechanisms are still not well understood. To assess the plasma levels of asymmetric dimethylarginine (ADMA) in children with SCD and its correlation with elevated tricuspid regurgitant jet velocity and other hemolytic markers. This study was carried out on a cohort of patients (30) with SCD and 30 healthy children as a control group. Certain investigations were carried out for all subjects: CBC, lactate dehydrogenase (LDH), ferritin, reticulocytic count, bilirubin, AST, ALT, and plasma levels of ADMA. Doppler echocardiography was carried out for all subjects. The prevalence of high tricuspid regurgitant velocity (TRV) was 30% in SCD patients. ADMA mean plasma level was significantly higher in patients than in controls (0.79 ± 0.15 Î¼mol/L and 0.46 ± 0.11 Î¼mol/L, respectively, P < 0.001). ADMA was significantly higher in patients with high TRV than those with normal TRV (1.10 ± 0.11 Î¼mol/L, 0.80 ± 0.06 Î¼mol/L, respectively, P < 0.001). There was a significant positive correlation between ADMA plasma levels and TRV ≥2.5 m/s (r = 0.475). High plasma ADMA levels may be implicated in the pathogenesis of increased tricuspid regurgitant jet velocity in children with SCD. 23844909 Unraveling the binding mechanism of asiatic acid with human serum albumin and its biological implications. Asiatic acid (AsA), a naturally occurring pentacyclictriterpenoid found in Centella asiatica, plays a major role in neuroprotection, anticancer, antioxidant, and hepatoprotective activities. Human serum albumin (HSA), a blood plasma protein, participates in the regulation of plasma osmotic pressure and transports endogenous and exogenous substances. The study undertaken to analyze the drug-binding mechanisms of HSA is crucial in understanding the bioavailability of drugs. In this study, we analyzed the cytotoxic activity of AsA on HepG2 (human hepatocellular carcinoma) cell lines and its binding, conformational, docking, molecular simulation studies with HSA under physiological pH 7.2. These studies revealed a clear decrease in the viability of HepG2 cells upon exposure to AsA in a dose-dependent manner with an IC50 of 45 μM. Further studies showed the quenching of intrinsic fluorescence of HSA by AsA with a binding constant of K AsA = 3.86 ± 0.01 × 10(4) M(-1), which corresponds to the free energy of (ΔG) -6.3 kcal M(-1) at 25 °C. Circular dichroism (CD) studies revealed that there is a clear decrease in the α-helical content from 57.50 ± 2.4 to 50% ± 2.3 and an increase in the β-turns from 25 ± 0.65 to 29% ± 0.91 and random coils from 17.5% ± 0.95 to 21% ± 1.2, suggesting partial unfolding of HSA. Autodock studies revealed that the AsA is bound to the subdomain IIA with hydrophobic and hydrophilic interactions. From molecular dynamics, simulation data (RMSD, Rg and RMSF) emphasized the local conformational changes and rigidity of the residues of both HSA and HSA-AsA complexes. 23615401 Induction of heme oxygenase-1 and inhibition of TPA-induced matrix metalloproteinase-9 expression by andrographolide in MCF-7 human breast cancer cells. Matrix metalloproteinase-9 (MMP-9) plays a critical role in cancer metastasis. Andrographolide (AP) is a diterpene lactone in the leaves and stem of Andrographis paniculata (Burm. f) Ness that has been reported to possess anticancer activity. In this study, we investigated the effect of AP on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMP-9 expression and invasion in MCF-7 breast cancer cells and the possible mechanisms involved. The results showed that AP dose-dependently inhibited TPA-induced MMP-9 protein expression, enzyme activity, migration and invasion. In addition, AP significantly induced heme oxygenase-1 (HO-1) messenger RNA (mRNA) and protein expression. Transfection with HO-1 small interfering RNA knocked down the HO-1 expression and reversed the inhibition of MMP-9 expression by AP. HO-1 end products, such as carbon monoxide, free iron and bilirubin, suppressed the TPA-induced MMP-9 mRNA and protein expression, enzyme activity, migration and invasion in MCF-7 cells. Furthermore, TPA-induced extracellular signal-regulated kinase (ERK) 1/2 and Akt phosphorylation and the DNA binding activity of activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB) were attenuated by pretreatment with AP and HO-1 end products. In conclusion, these results suggest that AP inhibits TPA-induced cell migration and invasion by reducing MMP-9 activation, which is mediated mainly by inhibition of the ERK1/2 and phosphatidylinositol 3-kinase/Akt signaling pathways and subsequent AP-1 and NF-κB transactivation. Additionally, induction of HO-1 expression is at least partially involved in the inhibition of TPA-induced MMP-9 activation and cell migration in MCF-7 cells by AP. 23852672 Global optimization of parameters in the reactive force field ReaxFF for SiOH. We have used unbiased global optimization to fit a reactive force field to a given set of reference data. Specifically, we have employed genetic algorithms (GA) to fit ReaxFF to SiOH data, using an in-house GA code that is parallelized across reference data items via the message-passing interface (MPI). Details of GA tuning turn-ed out to be far less important for global optimization efficiency than using suitable ranges within which the parameters are varied. To establish these ranges, either prior knowledge can be used or successive stages of GA optimizations, each building upon the best parameter vectors and ranges found in the previous stage. We have finally arrive-ed at optimized force fields with smaller error measures than those published previously. Hence, this optimization approach will contribute to converting force-field fitting from a specialist task to an everyday commodity, even for the more difficult case of reactive force fields. © 2013 Wiley Periodicals, Inc. 23826917 Protein Serine/Threonine Phosphotase-2A is Differentially Expressed and Regulates Eye Development in Vertebrates. Protein serine/threonine phosphatase-2A (PP-2A) is one of the key enzymes responsible for dephosphorylation in vertebrates. PP-2A-mediated dephosphorylation participates in many different biological processes including cell proliferation, differentiation, transformation, apoptosis, autophage and senescence. However, whether PP-2A directly controls animal development remains to be explored. Here, we present direct evidence to show that PP-2A displays important functions in regulating eye development of vertebrates. Using goldfish as a model system, we have demonstrated the following novel information. First, inhibition of PP-2A activity leads to significant death of the treated embryos, which is derived from blastomere apoptosis associated with enhanced phosphorylation of Bcl-XL at Ser-62, and the survived embryos displayed severe phenotype in the eye. Second, knockdown of PP-2A with morpholino oligomers leads to significant death of the injected embryos. The survived embryos from PP-2A knockdown displayed clear retardation in lens differentiation. Finally, overexpression of each catalytic subunit of PP-2A also causes death of majority of the injected embryos and leads to absence of goldfish eye lens or severely disturbed differentiation. Together, our results provide direct evidence that protein phosphatase-2A is important for normal eye development in goldfish. 23865419 Deep brain stimulation modulates nonsense-mediated RNA decay in Parkinson's patients leukocytes. Nonsense-Mediated decay (NMD) selectively degrades mRNA transcripts that carry premature stop codons. NMD is often triggered by alternative splicing (AS) modifications introducing such codons. NMD plays an important regulatory role in brain neurons, but the in vivo dynamics of AS and NMD changes in neurological diseases and under treatment were scarcely explored. Here, we report exon arrays analysis of leukocyte mRNA AS events prior to and following Deep Brain Stimulation (DBS) neurosurgery, which efficiently improves the motor symptoms of Parkinson's disease (PD), the leading movement disorder, and is increasingly applied to treat other diseases. We also analyzed publicly available exon array dataset of whole blood cells from mixed early and advanced PD patients. Our in-house exon array dataset of leukocyte transcripts was derived from advanced PD patients' pre- and post-DBS stimulation and matched healthy control volunteers. The mixed cohort exhibited 146 AS changes in 136 transcripts compared to controls, including 9 NMD protein-level assessed events. In comparison, PD patients from our advanced cohort differed from healthy controls by 319 AS events in 280 transcripts, assessed as inducing 27 protein-level NMD events. DBS stimulation induced 254 AS events in 229 genes as compared to the pre-DBS state including 44 NMD inductions. A short, one hour electrical stimulus cessation caused 234 AS changes in 125 genes compared to ON-stimulus state, 22 of these were assessed for NMD. Functional analysis highlighted disease-induced DNA damage and inflammatory control and its reversal under ON and OFF stimulus as well as alternative splicing in all the tested states. The study findings indicate a potential role for NMD both in PD and following electrical brain stimulation. Furthermore, our current observations entail future implications for developing therapies for PD, and for interfering with the impaired molecular mechanisms that underlie PD and other neurodegenerative and neurological disorders, as well as DBS-treatable conditions in general. 23839752 Racial differences in the association of serum 25-hydroxyvitamin D concentration with coronary heart disease events. Low circulating concentrations of 25-hydroxyvitamin D (25[OH]D) have been consistently associated with an increased risk of coronary heart disease (CHD) in white populations. This association has not been rigorously evaluated in other races or ethnicities, in which the distributions of 25(OH)D concentration and possibly other aspects of 25(OH)D metabolism differ. To examine the association of serum 25(OH)D concentration with risk of CHD in a multiethnic population. We studied 6436 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), recruited from July 2000 through September 2002, who were free of known cardiovascular disease at baseline. We measured baseline serum 25(OH)D concentrations using a mass spectrometry assay calibrated to established standards. We tested associations of 25(OH)D with adjudicated CHD events assessed through May 2012. Primary outcome measure was time to first adjudicated CHD event, defined as myocardial infarction, angina, cardiac arrest, or CHD death. During a median follow-up of 8.5 years, 361 participants had an incident CHD event (7.38 events per 1000 person-years). Associations of 25(OH)D with CHD differed by race/ethnicity (P for interaction < .05). After adjustment, lower 25(OH)D concentration was associated with a greater risk of incident CHD among participants who were white (n = 167 events; hazard ratio [HR], 1.26 [95% CI, 1.06-1.49] for each 10-ng/mL decrement in 25(OH)D) or Chinese (HR, 1.67 [95% CI, 1.07-2.61]; n = 27). In contrast, 25(OH)D was not associated with risk of CHD in participants who were black (HR, 0.93 [95% CI, 0.73-1.20]; n = 94) or Hispanic (HR, 1.01 [95% CI, 0.77-1.33]; n = 73). Lower serum 25(OH)D concentration was associated with an increased risk of incident CHD events among participants who were white or Chinese but not black or Hispanic. Results evaluating 25(OH)D in ethnically homogeneous populations may not be broadly generalizable to other racial or ethnic groups. 23752310 Kinetics and Epigenetics of Retroviral Silencing in Mouse Embryonic Stem Cells Defined by Deletion of the D4Z4 Element. Retroviral vectors are silenced in embryonic stem (ES) cells by epigenetic mechanisms whose kinetics are poorly understood. We show here that a 3'D4Z4 insulator directs retroviral expression with persistent but variable expression for up to 5 months. Combining an internal 3'D4Z4 with HS4 insulators in the long terminal repeats (LTRs) shows that these elements cooperate, and defines the first retroviral vector that fully escapes long-term silencing. Using FLP recombinase to induce deletion of 3'D4Z4 from the provirus in ES cell clones, we established retroviral silencing at many but not all integration sites. This finding shows that 3'D4Z4 does not target retrovirus integration into favorable epigenomic domains but rather protects the transgene from silencing. Chromatin analyses demonstrate that 3'D4Z4 blocks the spread of heterochromatin marks including DNA methylation and repressive histone modifications such as H3K9 methylation. In addition, our deletion system reveals three distinct kinetic classes of silencing (rapid, gradual or not silenced), in which multiple epigenetic pathways participate in silencing at different integration sites. We conclude that vectors with both 3'D4Z4 and HS4 insulator elements fully block silencing, and may have unprecedented utility for gene transfer applications that require long-term gene expression in pluripotent stem (PS) cells. 23963517 Origin of the chemical and kinetic stability of graphene oxide. At moderate temperatures (≤ 70°C), thermal reduction of graphene oxide is inefficient and after its synthesis the material enters in a metastable state. Here, first-principles and statistical calculations are used to investigate both the low-temperature processes leading to decomposition of graphene oxide and the role of ageing on the structure and stability of this material. Our study shows that the key factor underlying the stability of graphene oxide is the tendency of the oxygen functionalities to agglomerate and form highly oxidized domains surrounded by areas of pristine graphene. Within the agglomerates of functional groups, the primary decomposition reactions are hindered by both geometrical and energetic factors. The number of reacting sites is reduced by the occurrence of local order in the oxidized domains, and due to the close packing of the oxygen functionalities, the decomposition reactions become - on average - endothermic by more than 0.6 eV. 23291046 Substituted phenyl groups improve the pharmacokinetic profile and anti-inflammatory effect of urea-based soluble epoxide hydrolase inhibitors in murine models. Soluble epoxide hydrolase inhibitors (sEHIs) are anti-inflammatory, analgesic, anti-hypertensive, cardio- and renal-protective in multiple animal models. However, the earlier adamantyl-containing urea-based inhibitors are rapidly metabolized. Therefore, new potent inhibitors with the adamantyl group replaced by a substituted phenyl group were synthesized to presumptively offer better pharmacokinetic (PK) properties. Here we describe the improved PK profile of these inhibitors and the anti-inflammatory effect of the most promising one in a murine model. The PK profiles of inhibitors were determined following p.o. administration and serial bleeding in mice. The anti-inflammatory effect of 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), the most promising inhibitor among the five sEHIs tested, was investigated in a lipopolysaccharide (LPS)-challenged murine model. The earlier broadly-used adamantyl-containing sEHI, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), was used for comparison. Compared with the earlier adamantyl-containing urea-based inhibitors, substituted phenyl-containing urea-based inhibitors afford more favorable PK properties, such as higher Cmaxs, larger AUCs and longer t1/2s, which, as expected, show more stable metabolic stability. Moreover, oral administration of TPPU dramatically reversed the shifts caused by LPS-challenge in plasma levels of inflammatory cytokines, epoxides and corresponding diols, which is more potent than t-AUCB. The substituted phenyl-containing sEHIs are more metabolically stable than those with adamantyl group, resulting in more potent efficacy in vivo. This indicates a new strategy for development of sEHIs for further study toward clinical trials. 23924244 Navigating Ambivalence: How Heterosexual Young Adults Make Sense of Desire Differences. The miscommunication hypothesis is the assumption that many incidents of acquaintance rape and coercive sex follow from miscommunication between men and women. This hypothesis is entrenched in popular, academic, and judicial understandings of sexual relationships. Recently some evidence has suggested that there is little miscommunication between sexual partners and that the hypothesis does not explain acquaintance rape or other forms of sexual violence. The present study used qualitative methodology in which men and women were asked to imagine themselves in a particular heterosexual dating situation and write what they think happened between the beginning (when sex was refused by one partner) and the end (when sex happened). Thematic analysis of the data found no evidence for miscommunication between partners under conditions of differences in desire. Instead, ambivalence about sexual activity was commonly described by women and men and was most often resolved to both parties' satisfaction. Coercion by men was present in a minority of narratives under conditions of clear understanding of women's refusals. The study thus provides a rich, experience-based representation of heterosexual sexual activity, with considerable potential for the development of effective education campaigns. 21790906 Ethanol inhibits excitatory neurotransmission in the nucleus accumbens of adolescent mice through GABAA and GABAB receptors. Age-related differences in various acute physiological and behavioral effects of alcohol have been demonstrated in humans and in other species. Adolescents are more sensitive to positive reinforcing properties of alcohol than adults, but the cellular mechanisms that underlie such a difference are not clearly established. We, therefore, assessed age differences in the ability of ethanol to modulate glutamatergic synaptic transmission in the mouse nucleus accumbens (NAc), a brain region importantly involved in reward mechanisms. We measured field excitatory postsynaptic potentials/population spikes (fEPSP/PS) in NAc slices from adolescent (22-30 days old) and adult (5-8 months old) male mice. We found that 50mM ethanol applied in the perfusion solution inhibits glutamatergic neurotransmission in the NAc of adolescent, but not adult, mice. This effect is blocked by the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline and by the GABAB receptor antagonist CGP 55845. Furthermore, bicuculline applied alone produces a stronger increase in the fEPSP/PS amplitude in adult mice than in adolescent mice. Activation of GABAA receptors with muscimol produces a stronger and longer lasting depression of neurotransmission in adolescent mice as compared with adult mice. Activation of GABAB receptors with SKF 97541 also depresses neurotransmission more strongly in adolescent than in adult mice. These results demonstrate that an increased GABA receptor function associated with a reduced inhibitory tone underlies the depressant action of ethanol on glutamatergic neurotransmission in the NAc of adolescent mice. 23583760 Gingko biloba extracts protect auditory hair cells from cisplatin-induced ototoxicity by inhibiting perturbation of gap junctional intercellular communication. Gap junctional intercellular communication (GJIC) may play an important role in the hearing process. Cisplatin is an anticancer drug that causes hearing loss and Gingko biloba extracts (EGb 761) have been used as an antioxidant and enhancer for GJIC. The purpose of this study was to examine the efficiency of EGb 761 in protecting against cisplatin-induced apoptosis and disturbance of GJIC. House Ear Institute-Organ of Corti 1 auditory cells were cultured and treated with cisplatin (50 μM) and EGb (300 μg/ml) for 24h, and then analyzed by immunocytochemistry (Annexin V/propidium iodide) and Western blots. GJIC was evaluated by scrape-loading dye transfer (SLDT). Basal turn organ of Corti (oC) explants from neonatal (p3) rats were exposed to cisplatin (1-10 μM) and EGb (50-400 μg/ml). The number of intact hair cells was counted by co-labeling with phalloidin and MyoVIIa. EGb prevented cisplatin-induced apoptosis in immunostaining and decreased caspase 3 and poly-ADP-ribose polymerase bands, which were increased in cisplatin-treated cells in Western blots. EGb prevented abnormal intracellular locations of connexin (Cx) 26, 30, 31, and 43 in cells treated with cisplatin and increased quantities of Cx bands. EGb also prevented cisplatin-induced disturbance of GJIC in SLDT. In oC explants, EGb significantly prevented hair cell damage induced by cisplatin. In animal studies, EGb significantly prevented cisplatin-induced hearing loss across 16 and 32 kHz. These results show that cisplatin induces ototoxicity including hearing loss as well as down-regulation of GJIC and inhibition of Cxs in auditory cells. EGb prevents hearing loss in cisplatin-treated rats by inhibiting down-regulation of Cx expression and GJIC. The disturbance of GJIC or Cx expression may be one of the important mechanisms of cisplatin-induced ototoxicity. 23949388 Surgical Treatment and Prevention of Recurrence of Urethral Calculi Associated with Hairballs after Urethroplasty. Objectives: To evaluate technical aspects and outcome of preventing urethrocutaneous fistula and calculi recurrence in surgical treatment of urethral calculi associated with hairballs after urethroplasty. Patients and Methods: Sixteen patients who had urethral calculi associated with hairballs after urethroplasty underwent urethrolithotomy and trimming and epilation of the neourethra. While operating, we made a staggered incision of the skin and urethra, carefully su-tured the urethral incision, and covered it by well-vascularized tissue. A tube-in-tube stent method was performed on the latter 12 patients for better drainage of the exudates that accumulated in the urethra. Results: All calculi were successfully removed. Surgical site infection occurred in the last one of the former 4 patients and resulted in an urethrocutaneous fistula. There were no other complications. All patients were followed up for 2-7 years; no urethral stenosis or recurrence of calculi was observed, and remarkable reduction of urethral hair was obtained. Conclusions: Urethrolithotomy and trimming and epilation of the neourethra seem to be appropriate treatments for urethral calculi associated with hairballs after urethroplasty. Full attention should be paid to fistula prevention. © 2013 S. Karger AG, Basel. 23354695 Environmental concentrations and bioaccumulations of cadmium and zinc in coastal watersheds along the Chinese Northern Bohai and Yellow Seas. Cadmium (Cd) and zinc (Zn) in surface water, sediment, carp, and crab samples collected from upstream and downstream regions of coastal watersheds along the Chinese Northern Bohai and Yellow Seas were analyzed to provide a comprehensive understanding and assessment of their environmental concentrations and bioaccumulations. The results showed that downstream waters contaminated with Zn would have adverse effects on aquatic organisms. Although nearly all sediments were contaminated with Cd due to human activities, little potential existed for Cd toxicity in sediment-dwelling fauna. Concentrations of Cd and Zn in most water, sediment, carp, and crab were less than published values. The downstream carp and crabs had higher mean bioaccumulation factors and biota-sediment accumulation factors for Cd but lower mean biota-sediment accumulation factors for Zn than the upstream carp and crabs. Based on the relationships among Cd and Zn concentrations in water, sediment, and biota, the authors conclude that Cd and Zn in crabs primarily derived from sediment exposure. Although Cd and Zn in water and sediment originated from some of the same sources, the sources of Cd or Zn in water were likely different from those in sediment. 23377754 Using statistical power analysis as a tool when designing a monitoring program: experience from a large-scale Swedish landscape monitoring program. The National Inventory of Landscapes in Sweden (NILS) is a large-scale, sample-based monitoring program that combines aerial photointerpretation with field inventory to follow landscape-scale biophysical conditions and changes. A statistical power analysis was conducted before the NILS program began in 2003 with the aim to determine an appropriate sampling effort and compare some design alternatives. The chosen sampling effort was then evaluated in a second power analysis conducted just before the first 5-year re-inventory rotation started. The latter power analysis revealed which magnitude of actual change might be detected within the future for different central monitoring variables. This article reports results from these power analyses and discusses our experiences in using power analysis as a tool for designing large-scale monitoring programs. The results showed that even quite small changes in the more common variables, such as land cover types and more common plant species, can be detected on the national scale. However, on the regional scale, or for less common variables, changes will be more difficult to detect. The power analyses have revealed the size level of changes that will be possible to detect. The results have also generated incentives for further improvements of NILS, e.g., input to the modification and revision of the variable content, flow and hierarchy, and incentives for launching other complementary monitoring programs connected to NILS. They have also created a basis for a better and more user-oriented communication of results from NILS to different stakeholders. 23463325 MTHFR C677T polymorphism was an ethnicity-dependent risk factor for cervical cancer development: evidence based on a meta-analysis. Many studies have studied the associations between 5, 10-methylene tetrahydrofolate reductase (MTHFR) polymorphisms and susceptibilities of cervical cancer and cervical intraepithelial neoplasia (CIN); however, the results were inconsistent. The aim of this study was to further assess the relationships by the method of meta-analysis. Two investigators independently searched the PubMed, Embase, Wang Fang (Chinese database) and CNKI (China National Knowledge Infrastructure), with latest update to July 1st, 2011. The pooled odds ratio (OR) and 95 % confidence interval (95 % CI) were used to assess the strength of the associations by using fixed- or random-effect model. Ten case-control studies were included in this meta-analysis including a total of 1,803 cervical cancer or CIN cases and 2,363 controls. Pooled analyses showed that T allele of MTHFR C677T was significantly associated with increased CIN risk [OR (95 % CI): 1.28 (1.03-1.50) for CT vs. CC], especially for low-grade CIN risk. In addition, MTHFR C677T rather than A1298C polymorphism was associated with risk of cervical cancer. Stratifying analyses for ethnicity indicated that T allele of MTHFR C677T was associated with increased cervical cancer risk for Asian [OR (95 % CI): 1.56 (1.17-2.08) for TT vs. CC; 1.53 (1.19-1.96) for TT vs. C carriers] while decreased risk for Caucasian [OR (95 % CI): 0.63 (0.45-0.89) for TT vs. CC; 0.66 (0.56-0.79) for T carriers vs. CC]. This meta-analysis suggested that there was no association between MTHFR A1298C polymorphism and cervical cancer risk. However, MTHFR C677T was an ethnicity-dependent risk factor for cervical cancer occurrence. In addition, T allele of C677T was significantly associated with risk of low grade of CIN incidence. Because of modest limitations of our study, well-designed studies with large sample size were needed to confirm our findings in the future. 23220561 Effects of the natural endocrine disruptor equol on the pituitary function in adult male rats. Equol (EQ), a potent biologically active metabolite of the soy isoflavone daidzein, interacts with estrogen receptors (ERs), however, as suggested recently, EQ may also exert anti-androgenic actions in androgen regulated tissues like prostate and seminal vesicles in adult male rats. However, data regarding a putative anti-androgenic activity of EQ on pituitary function in male individuals are still lacking. Therefore, we investigated the effects of EQ on androgen- and estrogen-regulated gene expressions in the pituitary and circulating luteinizing hormone (LH) and prolactin (PRL) levels in adult male rats. 3-Month-old male Sprague-Dawley rats (n=12 per group) were treated by gavage for 5 days with either EQ (100 and 250 mg/kg BW/day) or vehicle olive oil (1 ml/rat/day). As reference compound, the pure anti-androgenic drug flutamide (FLUT) was employed at a dose of 100 mg/kg BW/day. At day 5, animals were sacrificed. Levels of pituitary hormones and gene expression were measured by radioimmunoassays and quantitative TaqMan(®) real-time reverse transcription polymerase chain reaction, respectively. The present findings revealed that the pituitary mechanisms involved in the effects of EQ and FLUT were different due to the opposite changes in the mRNA expression levels of estrogen receptor subtype alpha (ERα)-, truncated estrogen receptor product-1 (TERP-1)- and -2 (TERP-2)-, gonadotropin releasing hormone receptor (GnRH receptor)-, beta-subunit of LH (LHβ)-, and gonadotropin alpha subunit (α-subunit) genes. EQ displayed typical ER-agonistic actions as shown by the significant increases in ERα-, TERP-1/-2 mRNA expressions and serum PRL levels along with the significant reduction in serum LH levels, whereas FLUT exerted opposite effects on gonadotropin secretion and expression. Taken together, our findings are the first in vivo data that upon sub-acute oral exposure of EQ show an estrogenic effect on reproductive endocrine activity of the pituitary in adult male rats. However, EQ did not exert anti-androgenic effects on male rat pituitary function as observed at the levels of mRNA expression of androgen- and estrogen-regulated genes and circulating pituitary hormones. 23861228 Calcium-Mediated Secondary Cross-Linking of Bisphosphonated Oligo(poly(ethylene glycol) Fumarate) Hydrogels. This study demonstrates, for the first time, that synthetic PEG-based hydrogels can be cross-linked reversibly by calcium upon functionalization of the polymer backbone with bisphosphonate groups (BPs) that allow for the formation of strong coordination bonds with divalent metal ions such as Mg(2+) and Ca(2+) . More specifically, it is shown that BP-functionalized hydrogels can be shaped by providing calcium ions as reversible physical cross-linkers. 23866950 Three-dimensional plotting and printing of an implant drilling guide: simplifying guided implant surgery. To present an efficient workflow for the production of implant drilling guides using virtual planning tools. For this purpose, laser surface scanning, cone beam computed tomography, computer-aided design and manufacturing, and 3-dimensional (3D) printing were combined. Intraoral optical impressions (iTero, Align Technologies, Santa Clara, CA) and digital 3D radiographs (cone beam computed tomography) were performed at the first consultation of 1 exemplary patient. With image processing techniques, the intraoral surface data, acquired using an intraoral scanner, and radiologic 3D data were fused. The virtual implant planning process (using virtual library teeth) and the in-office production of the implant drilling guide was performed after only 1 clinical consultation of the patient. Implant surgery with a computer-aided design and manufacturing produced implant drilling guide was performed during the second consultation. The production of a scan prosthesis and multiple preoperative consultations of the patient were unnecessary. The presented procedure offers another step in facilitating the production of drilling guides in dental implantology. Four main advantages are realized with this procedure. First, no additional scan prosthesis is needed. Second, data acquisition can be performed during the first consultation. Third, the virtual planning is directly transferred to the drilling guide without a loss of accuracy. Finally, the treatment cost and time required are reduced with this facilitated production process. 23962402 Cooking up a culinary identity for Belgium. Gastrolinguistics in two Belgian cookbooks (19(th) century). The notion of cookbooks as socio-historic markers in a society is generally accepted within food studies. As both representations and prescriptions of food practices, perceived habits and attitudes towards food, they represent a certain identity for their readers. This paper investigates the nature of the identity that Belgian cookbooks constructed through their rhetoric. An important part of this study is to explore how and to what extent explicit reference to Belgium was made. To this end recipe titles/labels and recipe comments used in two leading bourgeois cookbooks from nineteenth-century Belgium were subjected to a quantitative and qualitative content analysis. The analysis showed that clear attention was paid to national culinary preferences. In terms of a domestic culinary corpus, it became apparent that both the Dutch and French editions of these cookbooks promoted dishes that were ascribed a Belgian origin. Internationality, however, was also an important building block of Belgian culinary identity. It was part of the desire of Belgian bourgeoisie to connect with an international elite. It fit into the 'search for sophistication', which was also expressed through the high representation of the more costly meats and sweet dishes. In addition, other references associated with bourgeois norms and values, such as family, convenience and frugality, were additional building blocks of Belgian culinary identity. Other issues such as tradition, innovation and health, were also matters of concerns to these Belgian cookbooks. 23194562 The application of Near-Infrared Reflectance Spectroscopy (NIRS) to detect melamine adulteration of soya bean meal. Soya bean products are used widely in the animal feed industry as a protein based feed ingredient and have been found to be adulterated with melamine. This was highlighted in the Chinese scandal of 2008. Dehulled soya (GM and non-GM), soya hulls and toasted soya were contaminated with melamine and spectra were generated using Near Infrared Reflectance Spectroscopy (NIRS). By applying chemometrics to the spectral data, excellent calibration models and prediction statistics were obtained. The coefficients of determination (R(2)) were found to be 0.89-0.99 depending on the mathematical algorithm used, the data pre-processing applied and the sample type used. The corresponding values for the root mean square error of calibration and prediction were found to be 0.081-0.276% and 0.134-0.368%, respectively, again depending on the chemometric treatment applied to the data and sample type. In addition, adopting a qualitative approach with the spectral data and applying PCA, it was possible to discriminate between the four samples types and also, by generation of Cooman's plots, possible to distinguish between adulterated and non-adulterated samples. 23615400 Proteomic analysis reveals that pardaxin triggers apoptotic signaling pathways in human cervical carcinoma HeLa cells: cross talk among the UPR, c-Jun and ROS. Pardaxin, an antimicrobial peptide secreted by the Red Sea flatfish Pardachirus marmoratus, inhibits proliferation and induces apoptosis of human cancer cell lines. However, the underlying molecular mechanisms are only partially understood at present. In this study, we used proteomic approaches and network reconstruction to clarify the mechanism of pardaxin-induced apoptosis in human cervical carcinoma HeLa cells. We identified that pardaxin-regulated proteins predominantly function in the unfolded protein response, oxidative stress and cytoskeletal distribution. Molecular examination of signal transduction and cellular localization demonstrated that the activator protein-1 transcription factor was activated, which eventually caused apoptosis via both caspase- and apoptosis-inducing factor-dependent pathways. Scavenging of reactive oxygen species (ROS) alleviated c-Jun activation, and small interfering RNA knockdown of c-Jun abrogated pardaxin-induced caspase activation and cell death, thereby implicating ROS and c-Jun in pardaxin-induced apoptosis signaling. In summary, this study provides the first protein-interacting network maps and novel insights into the biological responses and potential toxicity of pardaxin. 23886231 Chemotactic responses of peripheral blood eosinophils to prostaglandin D2 in atopic keratoconjunctivitis. Eosinophils appear to be key cells in the pathogenesis of conjunctival inflammation in atopic keratoconjunctivitis (AKC). Chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) mediates prostaglandin D2 (PGD2)-dependent migration of eosinophils. However, it is unclear whether CRTH2/PGD2-dependent eosinophil migration is upregulated in allergic diseases. To compare the chemotactic responses of peripheral blood eosinophils to prostaglandin D2 in patients with severe AKC and healthy individuals. We used an enzyme immunoassay system to measure PGD2 levels in tears and blood samples from healthy individuals and patients with AKC. CRTH2 expression on peripheral blood eosinophils was determined using reverse-transcriptase polymerase chain reaction (RT-PCR), flow cytometry, and an oligonucleotide array system. Chemotaxis experiments were performed using a modified Boyden chamber technique and an optical assay system. The PGD2 concentrations were higher in tears from patients with severe AKC compared with healthy individuals. RT-PCR (severe and mild cases), flow cytometry (mild cases), and GeneChip analyses revealed a significantly higher expression of CRTH2 on peripheral blood eosinophils in patients with AKC than in healthy individuals. PGD2 and its stable metabolite 13,14-dihydro-15-keto-PGD2, a CRTH2 agonist, induced chemotaxis of eosinophils from patients with AKC; chemotaxis was significantly enhanced in eosinophils from patients with severe AKC compared with those from healthy individuals. CRTH2 is more abundantly expressed on eosinophils from patients with AKC and promoted PGD2-dependent migration to a greater extent than in healthy individuals. 23959699 Base-Stabilized Boryl and Cationic Haloborylene Complexes of Iron. The synthesis of base-stabilized boryl and borylene complexes is reported. An N-heterocyclic carbene (NHC)-stabilized iron-dihydroboryl complex was prepared by two different routes including methane liberation and salt elimination. A range of base-stabilized iron-dichloroboryl complexes was prepared by addition of Lewis bases to boryl complexes. Base-stabilized, cationic monochloroborylene complexes were synthesized from these boryl complexes by halide abstraction by using weakly coordinating anions. 23894315 Difluorinated-Curcumin (CDF) Restores PTEN Expression in Colon Cancer Cells by Down-Regulating miR-21. Despite recent advancement in medicine, nearly 50% of patients with colorectal cancer show recurrence of the disease. Although the reasons for the high relapse are not fully understood, the presence of chemo- and radiotherapy-resistant cancer stem/stem-like cells, where many oncomirs like microRNA-21 (miR-21) are upregulated, could be one of the underlying causes. miR-21 regulates the processes of invasion and metastasis by downregulating multiple tumor/metastatic suppressor genes including PTEN (phosphatase and tensin homolog). Tumor suppressor protein PTEN controls self-renewal of stem cells. Indeed, our current data demonstrate a marked downregulation of PTEN in SCID mice xenografts of miR-21 over-expressing colon cancer HCT116 cells. Colonospheres that are highly enriched in cancer stem/stem like cells reveal increased miR-21 expression and decreased PTEN. Difluorinated curcumin (CDF), a novel analog of the dietary ingredient curcumin, which has been shown to inhibit the growth of 5-Flurouracil + Oxaliplatin resistant colon cancer cells, downregulated miR-21 in chemo-resistant colon cancer HCT116 and HT-29 cells and restored PTEN levels with subsequent reduction in Akt phosphorylation. Similar results were also observed in metastatic colon cancer SW620 cells. Since PTEN-Akt confers drug resistance to different malignancies including colorectal cancer, our observation of normalization of miR-21-PTEN-Akt pathway by CDF suggests that the compound could be a potential therapeutic agent for chemotherapy-resistant colorectal cancer. 23825334 Microclimatic conditions and their effects on sheep behavior during a live export shipment from Australia to the Middle East. The microclimate can potentially impact the health and welfare of livestock exported by ship. Within-pen microclimatic conditions were recorded and the effects of ammonia on sheep behavior investigated on a voyage from Australia to the Middle East. Ammonia, carbon dioxide, and hydrogen sulfide as well as wet-bulb, dry-bulb, and dew-point temperature and air speed were mapped in 20 open-deck focal pens, with the focus on the behavior and location of a marked sheep in each pen. Air speed was highly variable in most pens, with pockets of high but transient concentrations of ammonia (30.7 to 44.2 mg/m(3)) in 20% of pens that had no or minimal air flow. Carbon dioxide concentrations varied in some pens, but overall concentrations of carbon dioxide and hydrogen sulfide were low. Sheep in pens previously identified to have high ammonia concentrations, high wet-bulb temperatures, and low wind speed stood longer (P = 0.003) and spent less time feeding (P = 0.01) and ruminating (P = 0.004) than those in pens previously identified with low ammonia, low wet-bulb temperature, and high wind speed. Moreover, sheep exposed to increased ammonia concentrations held their head higher (P = 0.004) to avoid the greater ammonia concentrations at lower heights, and these sheep had more conjunctivitis (P < 0.001). Sheep movement around the pen was limited. Increased time spent lying down (P = 0.04) and more rhythmical behavior in the second half of the voyage indicated that the sheep adjusted to shipboard conditions over time. It is concluded that high, transient concentrations of ammonia existed in some pens, which adversely affected the behavior of sheep. 23692284 Pre-synaptic kainate receptor-mediated facilitation of glutamate release involves PKA and Ca(2+) -calmodulin at thalamocortical synapses. We have investigated the mechanisms underlying the facilitatory modulation mediated by kainate receptor (KAR) activation in the cortex, using isolated nerve terminals (synaptosomes) and slice preparations. In cortical nerve terminals, kainate (KA, 100 Î¼M) produced an increase in 4-aminopyridine (4-AP)-evoked glutamate release. In thalamocortical slices, KA (1 Î¼M) produced an increase in the amplitude of evoked excitatory post-synaptic currents (eEPSCs) at synapses established between thalamic axon terminals from the ventrobasal nucleus onto stellate neurons of L4 of the somatosensory cortex. In both, synaptosomes and slices, the effect of KA was antagonized by 6-cyano-7-nitroquinoxaline-2,3-dione, and persisted after pre-treatment with a cocktail of antagonists of other receptors whose activation could potentially have produced facilitation of release indirectly. Mechanistically, the observed effects of KA appear to be congruent in synaptosomal and slice preparations. Thus, the facilitation by KA of synaptosomal glutamate release and thalamocortical synaptic transmission were suppressed by the inhibition of protein kinase A and occluded by the stimulation of adenylyl cyclase. Dissecting this G-protein-independent regulation further in thalamocortical slices, the KAR-mediated facilitation of synaptic transmission was found to be sensitive to the block of Ca(2+) permeant KARs by philanthotoxin. Intriguingly, the synaptic facilitation was abrogated by depletion of intracellular Ca(2+) stores by thapsigargin, or inhibition of Ca(2+) -induced Ca(2+) -release by ryanodine. Thus, the KA-mediated modulation was contingent on both Ca(2+) entry through Ca(2+) -permeable KARs and liberation of intracellular Ca(2+) stores. Finally, sensitivity to W-7 indicated that the increased cytosolic [Ca(2+) ] underpinning KAR-mediated regulation of synaptic transmission at thalamocortical synapses, requires downstream activation of calmodulin. We conclude that neocortical pre-synaptic KARs mediate the facilitation of glutamate release and synaptic transmission by a Ca(2+) -calmodulin dependent activation of an adenylyl cyclase/cAMP/protein kinase A signalling cascade, independent of G-protein involvement. Ca(2+) /calmodulin involvement in pre-synaptic kainate receptors facilitation of glutamate release at thalamocortical synapses. We determined the mechanism by which kainate receptors (KARs) mediate a facilitation of glutamate release at thalamo-L4 cortical cell synapses. We find that an increase in cytosolic Ca(2+) concentration, contingent on extra- and intra-cellular sources, in the pre-synaptic thalamic neuron, operates through the formation of Ca(2+) -calmodulin complexes to activate an AC/cAMP/PKA signalling pathway. This action of KARs may support learning and memory processes. 23893663 Segmentation and quantification of bone erosions in high-resolution peripheral quantitative computed tomography datasets of the metacarpophalangeal joints of patients with rheumatoid arthritis. Objective. To develop a precise three-dimensional (3D) segmentation technique for bone erosions in high-resolution peripheral quantitative CT (HR-pQCT) datasets to measure their volume, surface area and shape parameters. Assessment of bone erosions in patients with RA is important for diagnosis and evaluation of treatment efficacy. HR-pQCT allows quantifying periarticular bone loss in arthritis.Methods. HR-pQCT scans with a spatial resolution of about 120 µm of the second to fourth metacarpophalangeal joints were acquired in patients with RA. Erosions were identified by placing a seed point in each of them. After applying 3D segmentation, the volume, surface area and sphericity of erosions were calculated. Results were compared with an approximation method using manual measurements. Intra- and interoperator precision analysis was performed for both the 3D segmentation and the manual technique.Results. Forty-three erosions were assessed in 18 datasets. Intra- and interoperator precisions (RMSCV/RMSSD) for erosion volume were 5.66%/0.49 mm(3) and 7.76%/0.76 mm(3), respectively. The correlation between manual measurements and their simulation using segmentation volumes was r = 0.87. Precision errors for the manual method were 15.39% and 0.36 mm(3), respectively.Conclusion. We developed a new precise 3D segmentation technique for quantification of bone erosions in HR-pQCT datasets that correlates to the volume, shape and surface area of the erosion. The technique allows fast and effective measurement of the erosion size and could therefore be helpful for rapid and quantitative assessment of erosion size. 23869704 Antagonism of endogenous nociceptin/orphanin FQ inhibits infarction associated ventricular arrhythmias via PKC dependent mechanism in rats. Evidence indicates nociceptin/orphanin FQ (N/OFQ) may participate in the pathology of cardiac arrhythmias associated with myocardial infarction. But the role of N/OFQ in the arrhythmogenesis in acute myocardial infarction is unclear. The aim of this study was to investigate the effects of endogenous N/OFQ on infarction associated arrhythmias. The expression of N/OFQ, PKC activity and ventricular arrhythmias in presence and absence of UFP-101, a specific antagonist of N/OFQ receptor, were examined following permanent coronary artery occlusion in anaesthetized rats. The effect of N/OFQ on action potential duration was examined in isolated rat cardiomyocytes. It was observed that N/OFQ was increased by 41% in the myocardium after coronary artery occlusion (P < 0.01, versus control). Pretreatment with UFP-101 (10(-7) mol Kg(-1) , i.v.) reduced the incidence of ventricular ectopic beats by 70% and ventricular tachycardia by 51% respectively (all P < 0.05 versus control). Meanwhile, PKC activity was elevated in the rats treated with UFP-101 (by 35%, P < 0.05, versus control). A selective PKC inhibitor, Calphostin C, completely abolished the anti-arrhythmic effects of UFP-101 (P < 0.01). N/OFQ (at 10(-11) mol/L, 10(-9) mol/L and 1×10(-7) mol/L) shortened the action potential duration, by 3% (P > 0.05), 10% (P < 0.05) and 22% (P < 0.01) respectively, via N/OFQ receptor. Antagonism of endogenous N/OFQ produces anti-arrhythmic effects on ventricular arrhythmias in acute myocardial infarction, possibly via modulating PKC activity and action potential of myocytes. 23397585 Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Iodothyronine deiodinase types I, II, and III (D1, D2, and D3, respectively), which constitute a family of selenoenzymes, activate and inactivate thyroid hormones through the removal of specific iodine moieties from thyroxine and its derivatives. These enzymes are important in the biological effects mediated by thyroid hormones. The expression of activating and inactivating deiodinases plays a critical role in a number of cell systems, including the neuronal system, during development as well as in adult vertebrates. To investigate deiodinase-disrupting chemicals based on transcriptomic responses, we examined differences in gene expression profiles between T3-treated and deiodinase-knockdown SH-SY5Y cells using microarray analysis and quantitative real-time RT-PCR. A total of 1,558 genes, consisting of 755 upregulated and 803 downregulated genes, were differentially expressed between the T3-treated and deiodinase-knockdown cells. The expression levels of 10 of these genes (ID2, ID3, CCL2, TBX3, TGOLN2, C1orf71, ZNF676, GULP1, KLF9, and ITGB5) were altered by deiodinase-disrupting chemicals (2,3,7,8-tetrachlorodibenzo-p-dioxin, polychlorinated biphenyls, propylthiouracil, iodoacetic acid, methylmercury, β-estradiol, methimazole, 3-methylcholanthrene, aminotriazole, amiodarone, cadmium chloride, dimethoate, fenvalerate, octylmethoxycinnamate, iopanoic acid, methoxychlor, and 4-methylbenzylidene-camphor). These genes are potential biomarkers for detecting deiodinase deficiency and predicting their effects on thyroid hormone production. 23892840 Impact of pulmonary arterial hypertension and its therapy on indices of heart rate variability. Aim To compare heart rate variability (HRV) indices between pulmonary arterial hypertension (PAH) patients and controls, and to investigate whether therapy improves heart rhythm. Methods Thirty-eight patients and 20 controls underwent Holter monitoring. HRV was analyzed before and after PAH therapy. Various time, and frequency domain indices of HRV analysis including standard deviation of all normal-to-normal intervals, standard deviation of mean values for all normal-to-normal intervals over 5 min, and square root of the mean square differences of successive RR intervals were recorded and analyzed before and after 1 year of PAH therapy. Results Significant differences with regard to diminished physical capacity, impared cardiac output, increased BNP in PAH cohort; HRV indices were diminished compared to controls and no differences between before and after PAH therapy with respect to analysis of HRV. Patients exhibited depressed HRV and therapy failed to improve HRV indices suggesting urgent unmet need for better therapeutic options. Conclusion Patients with PAH exhibit severely depressed HRV. Surprisingly, PAH specific therapy for 1 year with phosphodiesterase- 5 inhibitor, prostacyclin analogue, endhotelin receptor antagonist, or their combination failed to improve HRV indices suggesting urgent unmet need for better therapeutic options. 23633030 Hospital Variation in Patient-Reported Outcomes at the Level of EQ-5D Dimensions: Evidence from England. The English Department of Health has introduced routine collection of patient-reported outcome data for selected surgical procedures to facilitate patient choice and increase hospital accountability. However, using aggregate health outcome scores, such as EQ-5D utilities, for performance assessment purposes causes information loss and raises statistical and normative concerns. . For hip replacement surgery, we explore a) the change in patient-reported outcomes between baseline and follow-up on 5 health dimensions (EQ-5D), b) the extent to which treatment impact varies across hospitals, and c) the extent to which hospital performance on EQ-5D dimensions is correlated with performance on the EQ-5D utility index. . We combine information on pre- and postoperative EQ-5D outcomes with routine inpatient data for the financial year 2009-2010. The sample consists of 21,000 patients in 153 hospitals. We employ hierarchical ordered probit risk-adjustment models that recognize the multilevel nature of the data and the response distributions. The treatment impact is modeled as a random coefficient that varies at the hospital level. We obtain hospital-specific empirical Bayes (EB) estimates of this coefficient. We estimate separate models for each EQ-5D dimension and the EQ-5D utility index and analyze correlations of EB estimates across these. . Hospital treatment is associated with improvements in all EQ-5D dimensions. Variability in treatment impact is most pronounced on the mobility and usual activities dimensions. Conversely, only pain/discomfort and anxiety/depression correlate well with performance measures based on utilities. This leads to different assessments of hospital performance across metrics. . Our results indicate which hospitals are better than others in improving health across particular EQ-5D dimensions. We demonstrate the importance of evaluating dimensions of the EQ-5D separately for the purposes of hospital performance assessment. 23916755 Downregulation of CFTR promotes epithelial-to-mesenchymal transition and is associated with poor prognosis of breast cancer. The epithelial-to-mesenchymal transition (EMT), a process involving the breakdown of cell-cell junctions and loss of epithelial polarity, is closely related to cancer development and metastatic progression. While the cystic fibrosis transmembrane conductance regulator (CFTR), a Cl(-) and HCO3(-) conducting anion channel expressed in a wide variety of epithelial cells, has been implicated in the regulation of epithelial polarity, the exact role of CFTR in the pathogenesis of cancer and its possible involvement in EMT process have not been elucidated. Here we report that interfering with CFTR function either by its specific inhibitor or lentiviral miRNA-mediated knockdown mimics TGF-β1-induced EMT and enhances cell migration and invasion in MCF-7. Ectopic overexpression of CFTR in a highly metastatic MDA-231 breast cancer cell line downregulates EMT markers and suppresses cell invasion and migration in vitro, as well as metastasis in vivo. The EMT-suppressing effect of CFTR is found to be associated with its ability to inhibit NFκB targeting urokinase-type plasminogen activator (uPA), known to be involved in the regulation of EMT. More importantly, CFTR expression is found significantly downregulated in primary human breast cancer samples, and is closely associated with poor prognosis in different cohorts of breast cancer patients. Taken together, the present study has demonstrated a previously undefined role of CFTR as an EMT suppressor and its potential as a prognostic indicator in breast cancer. 23121683 Effect of Bone Marrow Mesenchymal Stem Cell Transplant on Synovial Proliferation in Rats With Type II Collagen-Induced Arthritis. To investigate the influence and mechanism of bone marrow mesenchymal stem cell transplant in the synovial proliferation of type II collagen-induced arthritis. From the bone marrow of Sprague-Dawley rats, mesenchymal stem cells were isolated and expanded. Forty rats were randomly divided into 5 groups: normal control, early mesenchymal stem cell treatment, late mesenchymal stem cell treatment, early collagen-induced arthritis control, and late collagen-induced arthritis control. The mesenchymal stem cells and normal saline were injected through the tail vein, and the following parameters were observed: arthritis index, articular pathology changes, serum vascular endothelial growth factor level, tumor necrosis factor-?, and interluekin-17 levels as detected through stable enzyme-linked immunosorbent assay. The arthritis index and articular pathologic scores of the early and late treatment groups were lower compared with those of the control groups (P < .05). The arthritis index and articular pathologic scores of the late treatment group were lower than those of the early treatment group (P < .05). The levels of vascular endothelial growth factor, tumor necrosis factor-α, and interluekin-17 of the early and late treatment groups were significantly decreased compared with the collagen-induced arthritis control groups (P < .05), and these levels were positively correlated with the arthritis index and articular pathologic scores (P < .05). The transplant of mesenchymal stem cells in rats with collagen-induced arthritis can inhibit the proliferation of synovium, which may be attributed to the reduced expression of vascular endothelial growth factor, tumor necrosis factor-?, and interluekin-17. 23857389 Chronic hepatitis B prognostic markers other than pre-treatment viral load predicted composite treatment outcome. Chronic hepatitis B (CHB) is a globally common infectious disease. Its clinical course is complicated. In Southeast Asia, nucleos(t)ide analogues (NA) are commonly used drugs for CHB treatment. Composite treatment outcome has often been used in CHB clinical practice, but rarely predicted epidemiologically. This study aimed to compare the composite treatment outcome between CHB patients with low and high treatment-naïve viral load, and to identify its predictors This retrospective cohort study followed up 95 CHB patients on NA treatment for a year. Composite treatment outcome was defined as undetectable HBV DNA level, ALT normalization and, HBeAg clearance in the case of HBeAg-positive patients. Multinomial logistic regression analysis was applied to analyze the significant treatment response predictors. Complete composite treatment outcome was achieved by 52% of CHB patients with an initial viral load < 6.5 log 10 copies /ml, but 31% of those had an initial viral load ≥ log 6.5 log 10 copies /ml. Outcome was predicted by HBeAg negativity (adjusted relative risk ratio, aRRR = 11.1, 95 % confidence interval, CI 3-41.3) and ALT normalization within the sixth month of therapy (aRRR = 6.7, CI 1.8-24.9). An elevation of ALT to more than 1.5 times the normal value (40 IU/ml) can lead to an incomplete response on NA therapy (aRRR = 6.2, CI 1.5-26.6.) Routine clinical markers other than pre-treatment viral load predicted composite CHB outcome on NA Therapy. 23562497 Discovering and targeting the basic mechanism of neurodegeneration: The role of peptides from the C-terminus of acetylcholinesterase: Non-hydrolytic effects of ache: The actions of peptides derived from the C-terminal and their relevance to neurodegeneration. Acetylcholinesterase (AChE) is now well-established widely as a signalling molecule with non-hydrolytic functions including trophic activity in a diverse variety of situations in both neural and non-neural tissues. We have focussed on the observation that AChE, operating as a trophic agent independent of its enzymatic action, does indeed trigger calcium entry into neurons. It is possible that AChE has a dual non-classical action that ranges along a trophic-toxic axis, depending on amount, duration of availability and, most significantly, age. The neurodegenerative diseases could therefore be viewed as aberrant activation of developmental mechanisms with 'non-cholinergic' AChE as a, perhaps the, pivotal molecule. We have identified two peptides that could be cleaved from the C-terminus of T-AChE, one (T14), within the other (T30), and which have a strong sequence homology to the comparable region of beta-amyloid whilst the inert residue within the T30 sequence ('T15') acts as a control, and is without effect. We have subsequently been able to ascribe the trophic-toxic actions of the both T14 and T30 peptides to the modulation of calcium influx via an allosteric site on the alpha-7 nicotinic acetylcholine receptor (α7-nAChR). If the scenario described here is indeed the primary mechanism of neurodegeneration, then interception of the actions of the 'non-cholinergic' AChE-peptides T14 and T30 at the α7-nAChR, would be a promising novel therapy for arresting and stabilising cell loss in Alzheimer's disease, whereas detection of the peptides ideally in the blood, could provide a sensitive surrogate marker. If the marker was sensitive enough to be detected pre-symptomatically in a routine blood test, then the medication for arresting further cell loss could be initiated at that time, and the symptoms would never appear. This dual approach of identifying the marker and then intercepting its further action, could thus amount to an effective treatment for Alzheimer's and other neurodegenerative diseases. 23870250 The mechanism of detergent solubilization of lipid bilayers. Multiple data are available on the self-assembly of mixtures of bilayer-forming amphiphiles, particularly phospholipids and micelle-forming amphiphiles, commonly denoted detergents. The structure of such mixed assemblies has been thoroughly investigated, described in phase diagrams, and theoretically rationalized in terms of the balance between the large spontaneous curvature of the curvophilic detergent and the curvophobic phospholipids. In this critical review, we discuss the mechanism of this process and try to explain the actual mechanism involved in solubilization. Interestingly, membrane solubilization by some detergents is relatively slow and the common attribute of these detergents is that their trans-bilayer movement, commonly denoted flip-flop, is very slow. Only detergents that can flip into the inner monolayer cause relatively rapid solubilization of detergent-saturated bilayers. This occurs via the following sequence of events: 1), relatively rapid penetration of detergent monomers into the outer monolayer; 2), trans-membrane equilibration of detergent monomers between the two monolayers; 3), saturation of the bilayer by detergents and consequent permeabilization of the membrane; and 4), transition of the whole bilayer to thread-like mixed micelles. When the detergent cannot flip to the inner monolayer, the outer monolayer becomes unstable due to mass imbalance between the monolayers and inclusion of the curvophilic detergent molecules in a flat surface. Consequently, the outer monolayer forms mixed micellar structures within the outer monolayer. Shedding of these micelles into the aqueous solution results in partial solubilization. The consequent leakage of detergent into the liposome results in trans-membrane equilibration of detergent and subsequent micellization through the rapid bilayer-saturation mechanism. 23860417 Physical Activity, Sedentary Behavior and C-Reactive Protein in Pregnancy. Elevated C-reactive protein (CRP) is associated with adverse pregnancy outcomes. In non-pregnant populations, physical activity has been inversely associated with CRP, but this association has not been evaluated during pregnancy. The purpose of this study was to evaluate the association between objectively measured physical activity, sedentary behavior, and CRP by pregnancy trimester. We evaluated this association among 294 pregnant participants in the National Health and Nutrition Examination Survey (2003-2004 and 2005-2006). Physical activity (min/day) was assessed via accelerometer using established cutpoints. CRP (mg/L) was measured using a high sensitivity assay. Multivariable linear regression was used to determine the relationship between physical activity, sedentary behavior, and CRP by trimester of pregnancy. Among women in the second trimester, after adjusting for age, BMI, smoking status, and history of adverse pregnancy outcomes, light intensity physical activity was associated with lower CRP (β= -0.002, p=0.05). In unadjusted models, sedentary time and proportion of wear time spent sedentary were positively associated with CRP (β = 0.048, p=0.02; β = 2.36, p=0.03; respectively), however, the relationship was no longer statistically significant in multivariable models (β = 0.33, p=0.2; β = 1.96, p=0.08; respectively). Neither physical activity nor sedentary behavior was associated with CRP among women in the first or third trimester. Objectively measured LPA had a protective effect on CRP among women in the second trimester of pregnancy. Findings highlight the need for longitudinal studies of pregnancy physical activity and CRP with careful control for clinical characteristics of the current pregnancy. 23723069 Leucine-rich Repeat and Immunoglobulin Domain-containing Protein-1 (Lrig1) Negative Regulatory Action toward ErbB Receptor Tyrosine Kinases Is Opposed by Leucine-rich Repeat and Immunoglobulin Domain-containing Protein 3 (Lrig3). Lrig1 is the founding member of the Lrig family of transmembrane leucine-rich repeat proteins, which also includes Lrig2 and Lrig3. Lrig1 is a negative regulator of oncogenic receptor tyrosine kinases, including ErbB and Met receptors, and promotes receptor degradation. Lrig1 has recently emerged as both a tumor suppressor and a key regulator of epidermal and epithelial stem cell quiescence. Despite this, little is known of the mechanisms by which Lrig1 is regulated. Lrig3 was recently reported to increase ErbB receptor expression suggesting that it may function in a manner opposite to Lrig1. In this study, we explore the interaction between Lrig1 and Lrig3 and demonstrate that Lrig1 and Lrig3 functionally oppose one another. Lrig3 opposes Lrig1 negative regulatory activity and stabilizes ErbB receptors. Conversely, Lrig1 destabilizes Lrig3, limiting Lrig3's positive effects on receptors and identifying Lrig3 as a new target of Lrig1. These studies provide new insight into the regulation of Lrig1 and uncover a complex cross-talk between Lrig1 and Lrig3. 23350706 Molecular reorganization in organic field-effect transistors and its effect on two-dimensional charge transport pathways. Charge transport in organic thin film transistors takes place in the first few molecular layers in contact with the gate dielectric. Here we demonstrate that the charge transport pathways in these devices are extremely sensitive to the orientational defects of the first monolayers, which arise from specific growth conditions. Although these defects partially heal during the growth, they cause depletion of charge carriers in the first monolayer, and drive the current to flow in the monolayers above the first one. Moreover, the residual defects induce lower crystalline order and charge mobility. These results, which are not intuitively explained by electrostatics arguments, have been obtained by combining in situ real time structural and electrical characterization together with ex situ AFM measurements, on thin films of a relevant n-type organic semiconductor, N,N'-bis(n-octyl)-dicyanoperylene-3,4:9,10-bis dicarboximide grown by sublimation in a quasi-layer-by-layer mode at different substrate temperatures. 23549733 Mechanisms of metal-catalyzed dehydrocoupling reactions. This review summarizes selected mechanistic insight garnered from reactions that form bonds between main group elements with liberation of hydrogen, dehydrocoupling or dehydropolymerization reactions. Focus has been made where mechanistic study has been done or provides unique insight as compared to previous work. Thus, a limited number of catalysts and substrates will be discussed, but a broad range of mechanistic features will be noted. A comparative approach considering dehydrocoupling reactions that appear to proceed by certain mechanistic steps is taken here, beginning with steps that are well established and general then moving to those that are newer, at least to this application. 23603616 New anticancer active and selective phenylene-bisbenzothiazoles: Synthesis, antiproliferative evaluation and DNA binding. Novel amidino-derivatives of phenylene-bisbenzothiazoles were synthesized and tested for their antiproliferative activity against several human cancer cell lines, as well as DNA-binding properties. The synthetic approach used for preparation of isomeric amidino substituted-phenylene-bis-benzothyazoles 3a-3f was achieved by condensation reaction of isophthaloyl dichloride 1a and terephthaloyl dichloride 1b or with phthalic acid 1c with 5-amidinium-2-aminobenzothiolate 2a and 5-(imidazolinium-2-yl)-2-aminobenzothiolate 2b in good yields. The targeted compounds were converted in the desired water soluble dihydrochloride salts by reaction of appropriate free base with concd HCl in ethanol or acetic acid. All tested compounds (3a-3f) showed antiproliferative effects on tumour cells in a concentration-dependant manner. The strongest activity and cytotoxicity was observed for diimidazolinyl substituted phenylene-bisbenzothiazole compound 3b. These effects were shown to be related to DNA-binding properties, topoisomerase I and II poisoning effects and apoptosis induction. The highest tested selectivity towards tumour cells was observed for the imidazolyl substituted phenylene-benzothiazole 3d that showed no cytotoxic effects on normal fibroblasts making it an excellent candidate for further chemical optimization and preclinical evaluation. 23900212 Synthesis, structural and magnetic characterisation of iron(ii/iii), cobalt(ii) and copper(ii) cluster complexes of the polytopic ligand: N-(2-pyridyl)-3-carboxypropanamide. Herein we describe the synthesis, structural and magnetic characterisation of three transition metal cluster complexes that feature the polytopic ligand N-(2-pyridyl)-3-carboxypropanamide (): [Fe3(III)Fe2(II)(HL)6(O)(H2O)3][ClO4]5·3MeCN·4H2O, , [Co8(HL)8(O)(OH)4(MeOH)3(H2O)]-[ClO4]3·5MeOH·2H2O, , and [Cu6(Lox)4(MeOH)(H2O)3]·MeOH, . Complex is a mixed valence penta-nuclear iron cluster containing the archetypal {Fe3(III)O} triangular basic carboxylate cluster at its core, with two Fe(ii) ions above and below the core coordinated to three bidentate pyridyl-amide groups. The structure of the octanuclear Co(ii) complex, , is based upon a central Co4 square with the remaining four Co(ii) centres at the 'wing-tips' of the complex. The cluster core is replete with bridging oxide, hydroxide and carboxylate groups. Cluster contains an oxidised derivative of the ligand, , generated in situ through hydroxylation of an α-carbon atom. This hexanuclear cluster has a 'barrel-like' core and contains Cu(ii) ions in both square planar and square-based pyramidal geometries. Bridging between Cu(ii) centres is furnished by alkoxide and carboxylate groups. Magnetic studies on reveals dominant antiferro-magnetic interactions for and , leading to small non-zero spin ground states, while shows ferro-magnetic exchange between the Cu(ii) centres to give an S = 3 spin ground state. 23739651 Effects of recombinant adenovirus hepatocyte growth factor gene on myocardial remodeling in spontaneously hypertensive rats. Background and Myocardial hypertrophy and fibrosis are important determinants of congestive heart failure. Previous work has shown that hepatocyte growth factor (HGF) can reduce acute myocardial injury and tissue fibrosis. This study was designed to examine the effects of HGF on myocardial remodeling following sustained hypertension. Methods and There were 4 experimental groups (n = 6) that included spontaneously hypertensive rats (SHRs) injected with 0.1 mL of adenovirus (Ad)-null into the left ventricular (LV) free wall, SHR injected with 0.1 mL of Ad-HGF gene (5 × 10(9) pfu/mL), and SHR injected with 0.1 mL of normal saline, and Wistar Kyoto rats injected with 0.1 mL of Ad-null served as control. At 4 weeks after injection, rats were sacrificed, and HGF expression, myocardial fibrosis, and LV function were determined. We observed that HGF protein expression was reduced in the hearts of SHR (P < .05 vs normal control) and it was markedly increased in SHR injected with Ad-HGF (P < .01 vs SHR injected with Ad-null). Myocardial fibrosis, collagen I, LV mass index (LVMI), and LV end-diastolic pressure (LVEDP) were increased and -dP/dtmax was decreased in SHR injected with Ad-null or normal saline (P < .01 vs normal control). Upregulation of myocardial HGF expression in SHR significantly suppressed myocardial fibrosis, collagen I content, LVMI, LVEDP, and increased -dP/dtmax (all P < .05 vs SHR-Ad-null, n = 6). These findings indicate that HGF expression is attenuated in hypertrophic and fibrotic myocardium of SHR. The forced increase in HGF exerts a salutary effect on myocardial fibrosis, collagen I expression, and hemodynamic parameters. 23319110 Detection of breast cancer with a computer-aided detection applied to full-field digital mammography. A study was conducted to evaluate the sensitivity of computer-aided detection (CAD) with full-field digital mammography in detection of breast cancer, based on mammographic appearance and histopathology. Retrospectively, CAD sensitivity was assessed in total group of 152 cases for subgroups based on breast density, mammographic presentation, lesion size, and results of histopathological examination. The overall sensitivity of CAD was 91 % (139 of 152 cases). CAD detected 100 % (47/47) of cancers manifested as microcalcifications; 98 % (62/63) of those manifested as non-calcified masses; 100 % (15/15) of those manifested as mixed masses and microcalcifications; 75 % (12/16) of those manifested as architectural distortions, and 69 % (18/26) of those manifested as focal asymmetry. CAD sensitivity was 83 % (10/12) for cancers measuring 1-10 mm, 92 % (37/40) for those measuring 11-20 mm, and 92 % (92/100) for those measuring >20 mm. There was no significant difference in CAD detection efficiency between cancers in dense breasts (88 %; 69/78) and those in non-dense breasts (95 %; 70/74). CAD showed a high sensitivity of 91 % (139/152) for the mammographic appearance of cancer and 100 % sensitivity for identifying cancers manifested as microcalcifications. Sensitivity was not influenced by breast density or lesion size. CAD should be effective for helping radiologists detect breast cancer at an earlier stage. 23950832 Correction: Pixels as ROIs (PAR): A Less-Biased and Statistically Powerful Approach for Gleaning Functional Information from Image Stacks. [This corrects the article on p. e69047 in vol. 8.]. 23931094 Advances in personalized therapy for lung cancer. Introduction: Personalized medicine based on tumor characteristics is transforming the management of lung cancer. This review provides an overview of clinically approved strategies to personalize treatment for lung cancer as well as evolving strategies in various stages of clinical development. Areas covered: Selecting therapy based on various tumor characteristics such as histology and presence of specific molecular alterations will be covered. This review will not only discuss the role of targeted agents in personalizing care for lung cancer but also the strategies to personalize traditional chemotherapeutic agents. Expert opinion: Advances in genomic medicine to identify key genetic alterations with subsequent development of matching targeted agents are rapidly changing the management of lung cancer. Being able to target key driver molecular aberrations is certainly exciting and clinically meaningful, but only for a limited period of time. Intra- and intertumoral heterogeneity is a major contributor to therapy resistance, a substantial roadblock to durable response. Better understanding of resistance mechanism is at least as important as identifying new targetable genetic changes to effectively advance personalized therapy for lung cancer. Finally, optimization of biopsy specimens and rigorous validation steps to ensure reliability of diagnostic methods would be critical in moving forward. 23964997 Habit reversal training in trichotillomania: guide for the clinician. Trichotillomania (hair-pulling disorder) involves repetitive hair pulling that can cause significant distress and impairment in functioning. Both children and adults suffer from the disorder. Habit reversal training (HRT) is the trichotillomania treatment with the most empirical support. HRT begins with developing an in-depth understanding of the client's unique pulling behaviors. The major components of HRT can then be carried out in a way that targets the client's specific needs. These include awareness training and self-monitoring, stimulus control and competing response procedures. Within each of these components the client learns to recognize his or her pulling urges, avoid situations in which pulling is more likely and adopt behaviors that can be used instead of pulling. Future work will involve evaluating the efficacy of adding therapy models such as mindfulness meditation in order to further enhance the effectiveness of HRT, and studying the long-term efficacy of HRT for children and adults. 23899170 The Role of α-Synuclein in Neurodegenerative Diseases: From Molecular Pathways in Disease to Therapeutic Approaches. Parkinson disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer's disease (AD). The formation of the cytoplasmic inclusions named "Lewy bodies" in the brain, considered to be a marker for neuronal degeneration in PD and dementia with Lewy bodies. However, Lewy bodies (LBs) are also observed in approximately 60 percent of both sporadic and familial cases with AD. LBs consist of fibrils mainly formed by post-translational modified α-synuclein (α-syn) protein. The modifications can be truncation, phosphorylation, nitration and mono-, di-, or tri-ubiquitination. Development of disease seems to be linked to events that increase the concentration of α-syn or cause its chemical modification, either of which can accelerate α-syn aggregation. Examples of such events include increased copy number of genes, decreased rate of degradation via the proteasome or other proteases, or modified forms of α-syn. As the aggregation of α-syn in the brain has been strongly implicated as a critical step in the development of several neurodegenerative diseases, the current search for disease-modifying drugs is focused on modification of the process of α-syn deposition in the brain. Recently researchers have screened and designed various molecules that are selectively focused on inhibiting or preventing α-syn aggregation and toxicity. Another strategy that has emerged is to target α-syn expression as a potential therapy for neurodegenerative diseases associated with LBs. 23943776 Cost-effectiveness of HCV case-finding for people who inject drugs via dried blood spot testing in specialist addiction services and prisons. People who inject drugs (PWID) are at high risk for acquiring hepatitis C virus (HCV), but many are unaware of their infection. HCV dried blood spot (DBS) testing increases case-finding in addiction services and prisons. We determine the cost-effectiveness of increasing HCV case-finding among PWID by offering DBS testing in specialist addiction services or prisons as compared to using venepuncture. Cost-utility analysis using a dynamic HCV transmission model among PWID, including: disease progression, diagnosis, treatment, injecting status, incarceration and addition services contact. DBS testing in specialist addiction services or prisons. Intervention impact was determined by a meta-analysis of primary data. Costs (in UK £, £1=US$1.60) and utilities (quality-adjusted life years, QALYs) were attached to each state and the incremental cost effectiveness ratio (ICER) determined. Multivariate uncertainty and one-way sensitivity analyses were performed. For a £20 000 per QALY gained willingness-to-pay threshold, DBS testing in addiction services is cost-effective (ICER of £14 600 per QALY gained). Under the base-case assumption of no continuity of treatment/care when exiting/entering prison, DBS testing in prisons is not cost-effective (ICER of £59 400 per QALY gained). Results are robust to changes in HCV prevalence; increasing PWID treatment rates to those for ex-PWID considerably reduces ICER (£4500 and £30 000 per QALY gained for addiction services and prison, respectively). If continuity of care is >40%, the prison DBS ICER falls below £20 000 per QALY gained. Despite low PWID treatment rates, increasing case-finding can be cost-effective in specialist addiction services, and in prisons if continuity of treatment/care is ensured. 23863120 Magnesium lithospermate B reduces myocardial ischemia/reperfusion injury in rats via regulating the inflammation response. Abstract Context: Magnesium lithospermate B (MLB), an active polyphenol acid of Danshen [Radix Salviae miltiorrhizae (Labiatae)], showed renoprotective, neuroprotective and myocardial salvage effects. Previous studies demonstrated that MLB could effectively suppress the production of cytokines and their associated signaling pathways in activated human T cells. Objective: The purpose of this study was to examine the beneficial effects of MLB on myocardial ischemia/reperfusion (MI/R) injury and to explore its potential mechanisms related to anti-inflammation. Materials and methods: Sprague-Dawley rats were grouped as sham group, model group and MLB-treated (15, 30 and 60 mg/kg) groups. Animals were subjected to MI/R injury by the occlusion of left anterior descending artery for 30 min followed by reperfusion for 3 h. At the end of reperfusion, blood samples were collected to determine the serum levels of cardiac troponin (cTnI), creatine kinase-MB (CK-MB), tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6). Hearts were harvested to assess infarct size, histopathological changes and the activity of myeloperoxidase (MPO). The expression of phosphor-IkB-α and phosphor-nuclear factor kappa B (NF-κB) were assayed by western blot. Results: MLB administration significantly (p < 0.05) reduced: (1) ST-segment elevation (0.23 mv), (2) the infarct size (22.5%), (3) histological scores of myocardial injury (1.67 score), (4) myocardial injury marker enzymes: cTnI (5.64 ng/ml) and CK-MB (49.57 ng/ml) levels, (5) pro-inflammatory cytokines: TNF-α (97.36 pg/ml), IL-1β (93.35 pg/ml) and IL-6 (96.84 pg/ml) levels, (6) MPO activity (1.82 U/mg), (7) phosphor-NF-κB (0.87) and phosphor-IkB-α (0.96) expression. Discussion and conclusion: Our study provided evidence that MLB ameliorated the inflammatory process associated with MI/R injury via NF-κB inactivation. 23884252 Isolated Port-Site Metastasis After Robotic Hysterectomy for Stage IA Endometrial Adenocarcinoma. Port-site metastasis is a known complication of laparoscopic surgery, although it has been described less in robotic surgery. There are limited reports of such occurrences in current literature. Two patients underwent robotic-assisted total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection for stage IA endometrial cancer. One patient's surgery was complicated by uterine perforation but the other surgery was uncomplicated. Both patients had development of isolated port-site metastasis and required resection followed by chemotherapy and radiation. Port-site metastasis is a surgical complication with an unclear etiology. There are no clear data to suggest a lower incidence with robotic surgery. Patients at low risk for recurrence still may experience development of port-site metastasis. 23910759 Consistency errors in p-values reported in Spanish psychology journals. Background: Recent reviews have drawn attention to frequent consistency errors when reporting statistical results. Method: We have reviewed the statistical results reported in 186 articles published in four Spanish psychology journals. Of these articles, 102 contained at least one of the statistics selected for our study: Fisher- F , Student- t and Pearson-c 2 . Results: Out of the 1,212 complete statistics reviewed, 12.2% presented a consistency error, meaning that the reported p-value did not correspond to the reported value of the statistic and its degrees of freedom. In 2.3% of the cases, the correct calculation would have led to a different conclusion than the reported one. In terms of articles, 48% included at least one consistency error, and 17.6% would have to change at least one conclusion. In meta-analytical terms, with a focus on effect size, consistency errors can be considered substantial in 9.5% of the cases. Conclusion: These results imply a need to improve the quality and precision with which statistical results are reported in Spanish psychology journals. 23835157 Redirecting catalysis from proteolysis to perhydrolysis in subtilisin Carlsberg. Enzyme promiscuity describes the ability of biocatalysts to catalyze conversions beyond their natural reactions. Enzyme engineering to promote side reactions is attractive for synthetic and industrial applications. For instance, a subtilisin Carlsberg protease variant (T58A/L216W) catalyzes in addition to its proteolytic activity the generation of peroxycarboxylic acids from corresponding esters in the presence of hydrogen peroxide. In the current study we used a semi-rational design approach to shift the specificity of subtilisin Carlsberg towards production of peroxycarboxylic acid. Among other identified amino acid substitutions, position Gly165 in the S1 binding pocket provided insights in subtilisin Carlsberg's promiscuity by promoting ester perhydrolysis. Catalytic constants of subtilisin Carlsberg for perhydrolysis of methyl-propionate, methyl-butyrate and methyl-pentanoate were increased up to 3.5-, 5.4- and 5.5-fold, respectively, while proteolysis was decreased up to 100-fold for N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide substrate (suc-AAPF-pNA). 23940599 Study on different molecular weights of chitosan as an immobilization matrix for a glucose biosensor. Two chitosan samples (medium molecular weight (MMCHI) and low molecular weight (LMCHI)) were investigated as an enzyme immobilization matrix for the fabrication of a glucose biosensor. Chitosan membranes prepared from acetic acid were flexible, transparent, smooth and quick-drying. The FTIR spectra showed the existence of intermolecular interactions between chitosan and glucose oxidase (GOD). Higher catalytic activities were observed on for GOD-MMCHI than GOD-LMCHI and for those crosslinked with glutaraldehyde than using the adsorption technique. Enzyme loading greater than 0.6 mg decreased the activity. Under optimum conditions (pH 6.0, 35°C and applied potential of 0.6 V) response times of 85 s and 65 s were observed for medium molecular weight chitosan glucose biosensor (GOD-MMCHI/PT) and low molecular weight chitosan glucose biosensor (GOD-LMCHI/PT), respectively. The apparent Michaelis-Menten constant ([Formula: see text]) was found to be 12.737 mM for GOD-MMCHI/PT and 17.692 mM for GOD-LMCHI/PT. This indicated that GOD-MMCHI/PT had greater affinity for the enzyme. Moreover, GOD-MMCHI/PT showed higher sensitivity (52.3666 nA/mM glucose) when compared with GOD-LMCHI/PT (9.8579 nA/mM glucose) at S/N>3. Better repeatability and reproducibility were achieved with GOD-MMCHI/PT than GOD-LMCHI/PT regarding glucose measurement. GOD-MMCHI/PT was found to give the highest enzymatic activity among the electrodes under investigation. The extent of interference encountered by GOD-MMCHI/PT and GOD-LMCHI/PT was not significantly different. Although the Nafion coated biosensor significantly reduced the signal due to the interferents under study, it also significantly reduced the response to glucose. The performance of the biosensors in the determination of glucose in rat serum was evaluated. Comparatively better accuracy and recovery results were obtained for GOD-MMCHI/PT. Hence, GOD-MMCHI/PT showed a better performance when compared with GOD-LMCHI/PT. In conclusion, chitosan membranes shave the potential to be a suitable matrix for the development of glucose biosensors. 23821655 Diagnosing and Understanding the Maxillary Lip-tie (Superior Labial, the Maxillary Labial Frenum) as it Relates to Breastfeeding. Successful breastfeeding is dependent upon an infant's ability to correctly latch onto a mother's breast. If an infant is born with oral soft tissue abnormalities such as tongue-tie or lip-tie, breastfeeding may become challenging or impossible. During the oral evaluation of an infant presenting with breastfeeding problems, one area that is often overlooked and undiagnosed and, thus, untreated is the attachment of the upper lip to the maxillary gingival tissue. Historically, this tissue has been described as the superior labial frenum, median labial frenum, or maxillary labial frenum. These terms all refer to a segment of the mucous membrane in the midline of the upper lip containing loose connective tissue that inserts into the maxillary arch's loose, unattached gingival or tight, attached gingival tissue. There is no muscle contained within this tissue. In severe instances, this tissue may extend into the area behind the upper central incisors and incisive papilla. The author has defined and identified the restrictions of mobility of this tissue as a lip-tie, which reflects the clinical attachment of the upper lip to the maxillary arch. This article discusses the diagnosis and classifications of the lip-tie, as it affects an infant's latch onto the mother's breast. As more and more women choose to breastfeed, lip-ties must be considered as an impediment to breastfeeding, recognizing that they can affect a successful, painless latch and milk transfer. 23821319 Ill Health or Illness: A Reply to Hofmann. In this article I respond to Björn Hofmann's criticism of some elements in my theory of health. Hofmann's main objective is to question "Nordenfelt's basic premise that you can be ill without having negative first-person experiences, and to investigate the consequences of abandoning the premise." One of Hofmann's critical points is that my theory of health does not lend voice to the individual. My response is essentially conducted in four steps: (1) I question the aim of conceptual analysis that Hofmann proposes for the analysis of the notion of health. (2) I maintain that my analysis, in spite of Hofmann's contention, lends voice to the individual. It does so via my notion of subjective illness but also via my notion of vital goal. (3) I argue that conditions, such as coma, paralysis and mania are salient instances of ill health and that these may become neglected if the use of the terms "ill" and "illness" is restricted to instances where negative subjective experiences are present. (4) I rehearse my main arguments for selecting disability as the core element of ill health and respond to Hofmann's contention that persons who are in great pain can sometimes nevertheless perform perfectly. 23834062 Photochemistry of "End-Only" Oligo-p-phenylene Ethynylenes: Complexation with Sodium Dodecyl Sulfate Reduces Solvent Accessibility. Cationic oligo-p-phenylene ethynylenes are very effective light-activated biocides and biosensors but degrade upon exposure to light. In this study, we explore the photochemistry of a class of "end-only" compounds from this series, which have cationic moieties on the ends of the backbone. Product characterization by mass spectrometry reveals that the photoreactivity of these molecules is higher than that of a previously studied oligomer and that the primary products of photolysis result from the addition of water or oxygen across the triple bond. In addition, a product suggesting the addition of peroxide or other reactive oxygen species across the triple bond was observed. To explore avenues by which the photodegradation of these compounds can be mitigated, the effects of complexation with sodium dodecyl sulfate micelles on their photochemistry was explored. Classical molecular dynamics simulations revealed that compounds that were protected from photolysis by SDS buried their phenylene ethynylene backbones into the interior of the micelle, protecting it from contact with water. This work has revealed a molecular basis for the protection of a novel class of light-activated biocides from irradiation that is consistent with the proposed photochemistry of these compounds. This information can be useful for developing photodegradation-resistant biocidal materials and applications for current compounds and leads to new molecular design. 23850280 The molecular basis of sugar sensing in Drosophila larvae. Evaluation of food chemicals is essential to make appropriate feeding decisions. The molecular genetic analysis of Gustatory receptor (Gr) genes and the characterization of the neural circuits that they engage has led to a broad understanding of taste perception in adult Drosophila [1, 2]. For example, eight relatively highly conserved members of the Gr gene family (Gr5a, Gr61a, and Gr64a-f), referred to as sugar Gr genes, are thought to be involved in sugar taste in adult flies [3-8], while the majority of the remaining Gr genes are likely to encode bitter taste receptors [9-11], albeit some function as pheromone [12-14] and carbon dioxide [15, 16] receptors. In contrast to the adult fly, relatively little is known about the cellular and molecular basis of taste perception in larvae. Here, we identify Gr43a, which was recently shown to function as a hemolymph fructose sensor in adult flies [17], as the major larval sugar receptor. We show that it is expressed in taste neurons, proventricular neurons, as well as sensory neurons of the brain. Larvae lacking Gr43a fail to sense sugars, while larvae mutant for all eight sugar Gr genes exhibit no obvious defect. Finally, we show that brain neurons are necessary and sufficient for sensing all main dietary sugars, which probably involves a postingestive mechanism of converting carbohydrates into fructose. 23870160 Preoperative steroid treatment does not improve markers of inflammation after cardiac surgery in neonates: Results from a randomized trial. Neonatal cardiac surgery requiring cardiopulmonary bypass results in a heightened inflammatory response. Perioperative glucocorticoid administration is commonly used in an attempt to reduce the inflammatory cascade, although characterization of the cytokine response to steroids in neonatal cardiac surgery remains elusive because of highly variable approaches in administration. This randomized trial was designed to prospectively evaluate the effect of specific glucocorticoid dosing protocols on inflammatory markers in neonatal cardiac surgery requiring cardiopulmonary bypass. Neonates scheduled for cardiac surgery were randomly assigned to receive either 2-dose (8 hours preoperatively and operatively, n = 36) or single-dose (operatively, n = 32) methylprednisolone at 30 mg/kg per dose in a prospective double-blind trial. The primary outcome was the effect of these steroid regimens on markers of inflammation. Secondary analyses evaluated the association of specific cytokine profiles with postoperative clinical outcomes. Patient demographics, perioperative variables, and preoperative indices of inflammation were similar between the single- and 2-dose groups. Preoperative cytokine response after the 2-dose methylprednisolone protocol was consistent with an anti-inflammatory effect, although this did not persist into the postoperative period. Premedication baseline levels of interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor α were predictive of postoperative intensive care unit and hospital length of stay. Only interleukin-8 demonstrated a postoperative response associated with duration of intensive care unit and hospital stay. The addition of a preoperative dose of methylprednisolone to a standard intraoperative methylprednisolone dose does not improve markers of inflammation after neonatal cardiac surgery. The routine administration of preoperative glucocorticoids in neonatal cardiac surgery should be reconsidered. 23759295 Biliary obstruction: Not always simple! Exploration of biliary obstruction may involve many imaging methods and a large number of people. Radiologists, hepato-gastro-enterologists and surgeons may examine using ultrasound, CT, MRI, endoscopic ultrasonography, and percutaneous, intraoperative or endoscopic retrograde cholangiography. Interpreting radiological examinations and choosing an optimal strategy can be difficult. The aim of this paper is therefore: to explain how to explore a clinical and laboratory picture of biliary obstruction using imaging, by presenting its main causes, the methods of exploring them and their radiological signs; to suggest suitable exploration strategies; and to illustrate some of the traps that can make it difficult to diagnose the cause of the obstruction. 23838767 Evidence for widespread structural brain changes in glaucoma: a preliminary voxel-based MRI study. Purpose: To investigate structural brain changes in patients with glaucoma. Methods: High resolution T1-weighted anatomical brain MRI images were collected in 15 patients with glaucoma of varying severity and 15 age-, race- and gender-matched controls. Exclusion criteria included neurological disease, another disorder which could affect the visual field, and score of less than 25 on the mini-mental status exam. The scans were analyzed with an automatic volumetric MRI technique to measure the volumes of 93 structures in each brain. Analyses of covariance with age as a covariate were carried out to identify structures that differed significantly between the two groups (i.e., glaucoma versus normal control). The volumes of all brain structures in the group of 15 glaucoma patients were also correlated with clinical measures of disease severity. Linear multivariate regression analyses were conducted to determine the significance of these relationships. Results: 5 structures differed significantly between the two groups (p<0.05). These included the right and left inferior occipital gyri, as well as the right middle occipital gyrus, right inferior temporal gyrus, and the right occipital lobe white matter. Interestingly, all of these structures were larger in the glaucoma group than in the control group. Within the group of glaucoma patients, 38% of all brain structures had independent associations between decreasing volume and more severe disease in multivariate regression analysis. Conclusion: These results suggest that patients with glaucoma undergo widespread and complex changes in cortical brain structure and that the extent of these changes correlates with disease severity. 23360369 Synthesis and Structure-Activity Relationships of N-Methyl-5,6,7-trimethoxylindoles as Novel Antimitotic and Vascular Disrupting Agents. Several new series of 5,6,7-trimethoxyindole derivatives were synthesized and their structure-activity relationships (SARs) were studied. Some of these compounds exhibited strong antiproliferative activities in the submicromolar range. N-Methyl-5,6,7-trimethoxylindoles 21 and 31 displayed the highest antiproliferative activities, with IC(50) values ranging from 22 to 125 nM in four human cancer cell lines and activated human umbilical vein endothelial cells (HUVECs). In addition to vascular disrupting activity verified by in vitro assays, compounds 21 and 31 displayed much higher selectivity for activated HUVECs versus quiescent HUVECs than those of colchicine and combretastatinA-4. The polymerization of cancer cell tubulin was inhibited and the cell cycle was arrested in the G2/M phase after treatment with 21 and 31. It was showed that 21 disrupted tumor vasculature by use of in vivo assay. Our results suggest that these two new compounds we synthesized may become the promising leads for the development of vascular disrupting agents. 23685642 Reflective plasmonic color filters based on lithographically patterned silver nanorod arrays. We demonstrate reflection-mode plasmonic color filters based on lithographically patterned silver nanorods with ultrasmall inter-rod gaps. Fine and effective tuning of the plasmon resonance is shown by varying array periodicities. We determine the dependence of reflected intensity on diameter/periodicity ratio and then develop reflective plasmonic color filters using dense nanorod arrays. Experimental results agree well with theoretical calculations. Our approach is potentially useful for plasmon-assisted sensing, imaging and displays. 23747207 Outcomes of intrastromal corneal ring segments for treatment of keratoconus: Five-year follow-up analysis. To report the long-term refractive and optical quality outcomes of patients with intrastromal corneal ring segments (ICRS) to treat keratoconus and to analyze the results according to the patients' age. Vissum Instituto Oftalmologico de Alicante, Alicante, Spain. Case series. The uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), manifest refraction, corneal topography, and aberrometry were evaluated before and after ICRS implantation in eyes with keratoconus. The follow-up was 5 years in all cases. The study comprised 51 eyes (35 patients; age range 15 to 56 years). After 6 months, the improvement in the UDVA, CDVA, spherical equivalent, and mean keratometry (K) value was statistically significant (P<.05). Five years postoperatively, these parameters remained unchanged (P=.31). Slight regression (0.97 diopter [D]) was observed in the mean K between 6 months and 5 years; the regression was not statistically significant (P=.39). Anterior corneal aberrometric values decreased; however, the changes were not statistically significant (P≥.10). Linear regression analysis showed no correlation between the age of the patients and the changes observed in the mean K throughout the follow-up (P>.05, r(2) = 0.001). Intrastromal corneal ring segment implantation in keratoconus patients provided long-term improvement of the refractive and topographic status. There was no correlation between the amount of individual changes in the mean K reading and patient age. No author has a financial or proprietary interest in any material or method mentioned. 23647456 TRIM13 (RFP2) downregulation decreases tumour cell growth in multiple myeloma through inhibition of NF Kappa B pathway and proteasome activity. Multiple myeloma (MM) is an incurable neoplasm caused by proliferation of malignant plasma cells in the bone marrow (BM). MM is characterized frequently by a complete or partial deletion of chromosome 13q14, seen in more than 50% of patients at diagnosis. Within this deleted region the tripartite motif containing 13 (TRIM13, also termed RFP2) gene product has been proposed to be a tumour suppressor gene (TSG). Here, we show that low expression levels of TRIM13 in MM are associated with chromosome 13q deletion and poor clinical outcome. We present a functional analysis of TRIM13 using a loss-of-function approach, and demonstrate that TRIM13 downregulation decreases tumour cell survival as well as cell cycle progression and proliferation of MM cells. In addition, we provide evidence for the involvement of TRIM13 downregulation in inhibiting the NF kappa B pathway and the activity of the 20S proteasome. Although this data does not support a role of TRIM13 as a TSG, it substantiates important roles of TRIM13 in MM tumour survival and proliferation, underscoring its potential role as a novel target for therapeutic intervention. 23870093 Prenatal and early childhood bisphenol A concentrations and behavior in school-aged children. Early life exposure to bisphenol A (BPA), an endocrine disrupting chemical used in some food and beverage containers, receipts, and dental sealants, has been associated with anxiety and hyperactivity in animal studies. A few human studies also show prenatal and childhood BPA exposure to be associated with behavior problems in children. We measured BPA in urine from mothers during pregnancy and children at 5 years of age (N=292). Child behavior was assessed by mother and teacher report at age 7 years and direct assessment at age 9 years. Prenatal urinary BPA concentrations were associated with increased internalizing problems in boys, including anxiety and depression, at age 7. No associations were seen with prenatal BPA concentrations and behaviors in girls. Childhood urinary BPA concentrations were associated with increased externalizing behaviors, including conduct problems, in girls at age 7 and increased internalizing behaviors and inattention and hyperactivity behaviors in boys and girls at age 7. This study adds to the existing literature showing associations of early life BPA exposure with behavior problems, including anxiety, depression, and hyperactivity in children. Additional information about timing of exposure and sex differences in effect is still needed. 23912164 Preventing Posttraumatic Stress Following Pediatric Injury: A Randomized Controlled Trial of a Web-Based Psycho-Educational Intervention for Parents. The study objective is to evaluate the feasibility and efficacy of a web-based intervention for parents (AfterTheInjury.org [ATI]) in promoting emotional recovery following pediatric injury. 100 children with injuries requiring medical attention and their parents were randomly assigned to the intervention or usual care. Efficacy outcomes included parent knowledge and child and parent posttraumatic stress symptoms (PTSS). All parents in the intervention group completed the intervention (directed use of ATI) in the hospital. 56% reported using ATI online post-discharge, and 100% of these parents found it helpful. Parent knowledge increased immediately post-intervention, but there was no significant intervention impact on parent knowledge or PTSS at a 6-week follow-up. Relationships between knowledge and PTSS were identified. Brief web-based interventions introduced during child hospitalization are a feasible strategy to reach many parents following pediatric injury. Preventing psychological symptoms may require more than parental education alone. 23917419 Animated Pose Templates for Modelling and Detecting Human Actions. This paper presents Animated Pose Templates for detecting short-term, long-term and contextual actions from cluttered scenes in videos. Each pose template consists of two components: i) a shape template whose appearances represented by the Histogram of Oriented Gradient features; and ii) a motion template using the Histogram of Optical Flow features. While this pose template is suitable for detecting short-term action snippets, we extend it in two ways: i) for long-term actions, we animate the pose templates by adding temporal constraints in a Hidden Markov Model; and ii) for contextual actions, we treat contextual objects as additional parts of the pose templates. To train the model, we manually annotate part locations on some key frames, then introduce a Semi-Supervised Structural SVM algorithm that iterates between: i) learning model parameters from labeled data by solving a structural SVM optimization; and 2) imputing latent variables on unannotated frames and progressively accepting high score ones as newly labelled examples. The inference algorithm has two steps: i) Detecting top candidates for the pose templates; and ii) Computing the sequence of pose templates. Both are done by dynamic programming. In experiments, we test our method on both public and our own datasets. The results show that our model achieves comparable or better performance than state-of-the-art. 23902454 Role of Conformational Entropy in the Activity and Regulation of the catalytic subunit of Protein Kinase A. Protein kinase A (PKA) is the archetypical phosphokinase, sharing a catalytic core with the entire protein kinase superfamily. In eukaryotes, the ubiquitous location of PKA makes it one of the most important cellular signaling molecules, involved in a myriad of events. The catalytic-subunit of PKA (PKA-C) is one of the most studied enzymes and was the first kinase to be crystallized; however, the effects of ligand binding, post-translational modifications, and mutations on the activity of the kinase have been difficult to understand with only structural data. Here, we review our latest NMR studies on PKA-C, the results of which underscore the role of fast and slow conformational dynamics in the activation and inhibition of the kinase. This article is protected by copyright. All rights reserved. 23769318 Erlotinib-induced autophagy in epidermal growth factor receptor mutated non-small cell lung cancer. Erlotinib is a commonly used tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC). Autophagy is a catabolic process in response to stress and deprivation of nutrients. This study aims to investigate whether autophagy confers acquired resistance to erlotinib treatment in NSCLC. Four NSCLC cell lines (HCC827, HCC4006, H358 and H1975) with different epidermal growth factor receptor (EGFR) mutation status (exon 19 deletion, exon 19 deletion, wild-type and L858R/T790M respectively) were selected. MTT assay, crystal violet staining and Annexin-V assay were performed to determine cell viability and apoptosis. Autophagic proteins were detected by Western blot. Acidic vesicular organelle (AVO) formation was determined by acridine orange staining. Autophagy inhibitor (chloroquine) and RNA interference were used to demonstrate the biological effect of erlotinib-induced autophagy. In line with EGFR mutation status, it was shown that both HCC827 and HCC4006 cells were sensitive to erlotinib, while H358 and H1975 cell lines were resistant. Erlotinib treatment at clinically relevant concentrations induced autophagy (increased LC3II expression, Atg-5/Atg12 conjugation, formation of AVO and p62 degradation) in sensitive NSCLC cell lines, via p53 nuclear translocation, AMPK activation and mTOR suppression. Addition of chloroquine, as an autophagy inhibitor, enhanced erlotinib sensitivity in sensitive cells. Similarly, silencing of Atg5 or Beclin-1 significantly increased sensitivity to erlotinib in both sensitive cell lines. In contrast, there was no induction of autophagy in resistant H358 and H1975 cell lines upon erlotinib exposure. Erlotinib can induce both apoptosis and autophagy in sensitive NSCLC cell lines with activating EGFR mutation (exon 19 del). Inhibition of autophagy can further enhance sensitivity to erlotinib in EGFR-mutated NSCLC, suggesting that autophagy may serve as a protective mechanism. 23692762 Evaluation of thermal treatment markers in wheat flour-derived products cooked in conventional and in low-emissivity ovens. Different markers for the assessment of thermal treatment entity of food products were investigated on a model bread prepared from wheat flour. Samples were submitted to different cooking procedures by combining three different times and temperatures, and employing two different ovens: a low-emissivity oven and a conventional one. The cook value index was calculated for each sample to evaluate the entity of the thermal treatment. Furosine, maltose:maltulose ratio, colour indexes (L, a, b) have been evaluated in all samples. Furosine has been quantified by capillary electrophoresis-mass spectrometry, maltose:maltulose ratio was determined by HPAEC-PAD, colour indexes were measured by spectrophotometer method. Values for weight loss during cooking and surface temperature have also been monitored. A statistical analysis showed good correlation between the cook value index and all the parameters evaluated. Low emissivity oven shown higher performances and lower energy consumption than conventional oven. 23815083 iPad-presented social stories for young children with autism. Abstract Objective: This study investigated the effectiveness of iPad-presented social stories in increasing the on-task behaviour of three young children with autism. Method: A single-subject with multiple baseline across participants design was employed with three 4-year-old children to assess intervention effectiveness during structured table top activities. Observational data were digitally recorded, scored, graphed, and interpreted using 10-second interval measures over 5-min periods across baseline, intervention, and withdrawal phases. Results: The combination of the social story together with the iPad proved to be an effective intervention for one of the three child participants. These findings confirm that the intervention may be effective with some children, but not others. Conclusion: Overall, this study builds on existing research that supports social stories as a promising practice. Further research into the use of iPad-presented social stories, particularly for children of varying ages, abilities, and learning styles is recommended. 23263687 Immunoanalysis of dehydrins in Araucaria angustifolia embryos. The aim of this study was to describe the dehydrin content of mature Araucaria angustifolia embryos, a species of endangered and economically important conifers, native to southern Brazil, northeastern Argentina, and eastern Paraguay. The A. angustifolia seeds have been categorized as recalcitrant. Dehydrins were studied by western blot analysis and in situ immunolocalization microscopy using antibodies raised against the K segment, a highly conserved lysine-rich 15-amino acid sequence extensively used to recognize proteins immunologically related to the dehydrin family. Western blot analysis of the heat-stable protein fraction, as estimated by 15 % SDS-PAGE, revealed three main bands of approximately 20-, 26-, and 29-kDa; when 17.5 % SDS-PAGE was used, each band resolved into two other bands. Two thermosensitive dehydrin bands of around 16 and 35 kDa were common to the axis and cotyledons, and another thermosensitive band, with molecular mass of approximately 10 kDa, was present in the cotyledons only. Following alkaline phosphatase (AP) treatment, a gel mobility shift was detected for each one of the four main bands that can be due to phosphorylation. Dehydrins were detected in all axis and cotyledon tissues using in situ immunolocalization microscopy. At the subcellular level, dehydrins were immunolocalized in the nuclei, protein bodies, and microbodies. In the nucleus, dehydrins were found to be associated with chromatin. We concluded that the gel mobility shift for the four main bands (probably due to phosphorylation), the presence of thermosensitive bands, and the specific localizations in nuclei and protein bodies provide key starting points to understand the function of dehydrins in the embryo cells of this species. 23658373 Incidence and risk of treatment-related mortality in cancer patients treated with the mammalian target of rapamycin inhibitors. Inhibition of the mammalian target of rapamycin (mTOR) is an established treatment for multiple malignancies. We carried out an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in cancer patients treated with mTOR inhibitors. PubMed, conferences and clinicaltrials.gov databases were searched for articles reported from January 1966 to June 2012. Eligible studies were limited to approved mTOR inhibitors (everolimus and temsirolimus) and reported on patients with cancer, randomized design and adequate safety profiles. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. In all, 3193 patients from eight randomized, controlled trials (RCTs) were included, 2236 from everolimus trials and 957 from temsirolimus trials. The relative risk (RR) of FAEs related to mTOR inhibitors use was 2.20 (95% CI, 1.25-3.90; P = 0.006) compared with control patients. On subgroup analysis, no difference in the rate of FAEs was found between everolimus and temsirolimus or between tumor types [renal cell carcinoma (RCC) versus non-RCC]. No evidence of publication bias was observed. The use of mTOR inhibitors is associated with a small but higher risk of FAEs compared to control patients. In the appropriate clinical scenario, the use of these drugs remains justified in their approved indications. 23817497 A versatile electrochemical cell for the preparation and characterisation of model electrocatalytic systems. An electrochemical cell for the controllable modification and comprehensive electrochemical characterisation of model electro-catalytic surfaces has been developed. In-depth electrochemical characterisation of stationary electrodes as well as rotating disc electrode (RDE) measurements in hanging meniscus configuration becomes possible. Additionally, the temperature of the electrodes in contact with electrolytes can be accurately controlled between room temperature and 70-80 °C. It is of particular importance for model electro-catalytic studies that in one experimental set-up (i) electrochemical metal and non-metal deposition to adjust the amount of the foreign atoms at the surface, (ii) controllable thermal treatment to vary the position of these atoms at the surface and subsurface regions, and (iii) state-of-the-art techniques common in electrocatalysis to characterise the resulting samples are possible. The deposition and annealing procedures under various atmospheres allow accurate control over the position of the foreign atoms at the electrode surface as overlayers, surface alloys and sub-surface (or near-surface) alloys, where the solute element is preferentially located in the second atomic layer of the host metal. The cell enables us to perform all operations without exposing the samples to the laboratory atmosphere at any of the experimental stages. To demonstrate the performance and advantages of the developed cell, we use model experiments with Pt(111) single crystal electrodes and Pt(111) surfaces modified with (sub)monolayer amounts of copper. 23325368 The 5-HT1D/1B receptor agonist sumatriptan enhances fear of simulated speaking and reduces plasma levels of prolactin. This study measured the effects of the preferential 5-HT1D/1B receptor agonist sumatriptan in healthy volunteers who performed the Simulated Public Speaking Test (SPST), which recruits the neural network involved in panic disorder and social anxiety disorder. In a double-blind, randomised experiment, 36 males received placebo (12), 50 mg (12) or 100 mg (12) of sumatriptan 2 h before the SPST. Subjective, physiological and hormonal measures were taken before, during and after the test. The dose of 100 mg of sumatriptan increased speech-induced fear more than either a 50mg dose of the drug or placebo. The largest dose of sumatriptan also enhanced vigilance more than placebo, without any change in blood pressure, heart rate or electrical skin conductance. Sumatriptan decreased plasma levels of prolactin. A significant but moderate increase in plasma cortisol after SPST occurred, independent of treatment. Because sumatriptan decreases 5-HT release into the extracellular space, the potentiation of SPST-induced fear caused by the drug supports the hypothesis that 5-HT attenuates this emotional state. As acute administration of antidepressants has also been shown to enhance speaking fear and increase plasma prolactin, in contrast to sumatriptan, the 5-HT regulation of stress-hormone release is likely to be different from that of emotion. 23844716 Helix stabilized, thermostable, and protease-resistant self-assembled Peptide nanostructures as potential inhibitors of protein-protein interactions. Self-assembled peptide nanostructures with actively folded secondary structures have potential to mimic the function of proteins. We here show that α-helix-stabilized self-assembled peptide nanostructures (αSSPNs), whose sizes are comparable to those of proteins, have potential to be developed as protein-protein interaction (PPI) inhibitors along with several unprecedented properties. Using p53-MDM2 PPI as a model system, the molecular recognition and modulation of PPIs by αSSPN grafted with a p53 α-helix (p53 αSSPN) were investigated. The competition assay showed that the p53 αSSPN can inhibit the p53-MDM2 interaction. Interestingly, the p53 αSSPN was far more resistant to degradation by the protease chymotrypsin than the monomeric p53 peptide and had high thermal stability. These results suggest that the αSSPN scaffold holds great potential to be developed as a novel class of PPI inhibitors. 23587277 Cardiovascular risk profile and lifestyle habits in a cohort of Italian cardiologists (from the SOCRATES Survey). Cardiologists' cardiovascular profile and lifestyle habits are poorly known worldwide. To offer a snapshot of the personal health habits of Italian cardiologists, the Survey on Cardiac Risk Profile and Lifestyle Habits in a Cohort of Italian Cardiologists (SOCRATES) was undertaken. A Web-based electronic self-reported survey, accessible through a dedicated Web site, was used for data entry, and data were transferred through the Web to a central database. The survey was divided into 4 sections: baseline characteristics, medical illnesses and traditional cardiovascular risk factors, lifestyle habits, and selected medication use. The e-mail databases of 3 national scientific societies were used to survey a large and representative sample of Italian cardiologists. During the 3-month period of the survey, 1,770 of the 5,240 cardiologists contacted (33.7%) completed and returned ≥1 sections of the questionnaire. More than 49% of the participants had 1 of the 5 classic risk factors (hypertension, hypercholesterolemia, active smoking, diabetes, and previous vascular events). More than 28% of respondents had 2 to 5 risk factors, and only 22.1% had none and therefore, according to age and gender, could be considered at low to intermediate risk. Despite the reported risk factors, >90% of cardiologists had a self-reported risk perception quantified as mild, such as low or intermediate. Furthermore, overweight and obesity, physical inactivity, and stress at work or at home were commonly reported, as well as limited use of cardiovascular drugs, such as statins or aspirin. In conclusion, the average cardiovascular profile of Italian cardiologist is unlikely to be considered ideal or even favorable according to recent statements and guidelines regarding cardiovascular risk. 23841525 Application of the International Diabetes Federation and American Diabetes Association criteria in the assessment of metabolic control after bariatric surgery. The International Diabetes Federation (IDF) and the American Diabetes Association (ADA) have introduced specific criteria to define the 'optimization' of the metabolic state and glycaemic 'remission' of type 2 diabetes mellitus (T2DM) after bariatric surgery, respectively. Our objective was to assess the percentage of patients achieving these criteria. Data were collected for body mass index, glycaemic markers, lipids, blood pressure, hypoglycaemia and medication usage from 396 morbidly obese T2DM patients who underwent bariatric surgery in two centres and followed up for 2 years. At year 1, 14% of patients achieved the IDF criteria and 38% the ADA criteria, whereas at 2 years 8 and 9% satisfied these criteria, respectively. A relatively low proportion of patients achieved optimization of the metabolic state and T2DM remission. These patients may potentially benefit from the combination of bariatric surgery and adjuvant medical therapy to achieve optimal metabolic outcomes. 23877318 IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma. Isocitrate dehydrogenase (IDH) enzymes have recently become a focal point for research aimed at understanding the biology of glioma. IDH1 and IDH2 are mutated in 50%-80% of astrocytomas, oligodendrogliomas, oligoastrocytomas, and secondary glioblastomas but are seldom mutated in primary glioblastomas. Gliomas with IDH1/2 mutations always harbor other molecular aberrations, such as TP53 mutation or 1p/19q loss. IDH1 and IDH2 mutations may serve as prognostic factors because patients with an IDH-mutated glioma survive significantly longer than those with an IDH-wild-type tumor. However, the molecular pathogenic role of IDH1/2 mutations in the development of gliomas is unclear. The production of 2-hydroxyglutarate and enhanced NADP+ levels in tumor cells with mutant IDH1/2 suggest mechanisms through which these mutations contribute to tumorigenesis. Elucidating the pathogenesis of IDH mutations will improve understanding of the molecular mechanisms of gliomagenesis and may lead to development of a new molecular classification system and novel therapies. 23894666 The cell wall-associated mycolactone polyketide synthases are necessary but not sufficient for mycolactone biosynthesis. Mycolactones are polyketide-derived lipid virulence factors made by the slow-growing human pathogen, Mycobacterium ulcerans. Three unusually large and homologous plasmid-borne genes (mlsA1: 51 kb, mlsB: 42 kb and mlsA2: 7 kb) encode the mycolactone type I polyketide synthases (PKS). The extreme size and low sequence diversity of these genes has posed significant barriers for exploration of the genetic and biochemical basis of mycolactone synthesis. Here, we have developed a truncated, more tractable 3-module version of the 18-module mycolactone PKS and we show that this engineered PKS functions as expected in the natural host M. ulcerans to produce an additional polyketide; a triketide lactone (TKL). Cell fractionation experiments indicated that this 3-module PKS and the putative accessory enzymes encoded by mup045 and mup038 associated with the mycobacterial cell wall, a finding supported by confocal microscopy. We then assessed the capacity of the faster growing, Mycobacterium marinum to harbor and express the 3-module Mls PKS and accessory enzymes encoded by mup045 and mup038. RT-PCR, immunoblotting, and cell fractionation experiments confirmed that the truncated Mls PKS multienzymes were expressed and also partitioned with the cell wall material in M. marinum. However, this heterologous host failed to produce TKL. The systematic deconstruction of the mycolactone PKS presented here suggests that the Mls multienzymes are necessary but not sufficient for mycolactone synthesis and that synthesis is likely to occur (at least in part) within the mycobacterial cell wall. This research is also the first proof-of-principle demonstration of the potential of this enzyme complex to produce tailored small molecules through genetically engineered rearrangements of the Mls modules. 23763248 Measuring communicative participation using the FOCUS©: Focus on the Outcomes of Communication Under Six. The FOCUS© is a new outcome tool for use by both parents and clinicians that measures changes in the communicative participation skills of preschool children. Changes in communicative participation skills as measured by the FOCUS were compared across three groups of children: those with speech impairments only (SI), those with language impairments only (LI) and those with both speech and language impairments (S/LI). Participating families (n = 112, 75 male children) were recruited through 13 Canadian organizations. Children ranged from 10 months to 6 years 0 months (mean = 2.11 years; SD = 1.18 years) and attended speech-language intervention. Parents completed the FOCUS at the start and end of treatment. There were 23 children in the SI group, 62 children in the LI group and 27 children in the S/LI group. The average amount of the children's therapy varied from 7 to 10 h. The FOCUS captures changes in communicative participation for children with a range of communication disorder types and severities. All three groups of children made clinically important improvements according to their FOCUS scores (MCID ≥ 16 points). The FOCUS captured improvements in intelligibility, independent communication, play and socialization. The FOCUS measured positive changes in communicative participation skills for all three groups of children after 7-10 h of speech-language therapy. An outcome measure that targets only specific speech and language skills would miss many of the important social function changes associated with speech-language treatment. 23925719 Autonomic dysfunction in adult-onset alexander disease : A case report and review of the literature. Alexander disease (AxD) is an astrogliopathy, resulting from a mutation in the glial fibrillary astrocytic protein gene. Different clinical subtypes have been described, including infantile, juvenile, and adult onset, based upon the age at which symptoms begin. Patients with the adult-onset form, develop a progressive, spastic paraparesis, palatal myoclonus, ataxia, and bulbar weakness. Autonomic nervous system (ANS) dysfunction has been reported as a potential manifestation of adult-onset AxD, but has not been well characterized. We report a case of adult-onset AxD with symptomatic orthostatic hypotension (OH) and heat intolerance that underwent formal autonomic testing. In addition, a comprehensive literature search was conducted to review the frequency and pattern of autonomic dysfunction in this patient population. A 51-year-old patient was diagnosed with AxD at the age of 47, following an 8-year history of vertigo, intermittent diplopia, and sleep disturbance. The patient developed symptoms of OH, erectile dysfunction, and heat intolerance soon after his diagnosis. Autonomic testing demonstrated OH on tilt-table testing (47 mmHg decrease in BP with 18 BPM heart rate increment) with absent late phase II and IV responses during the Valsalva maneuver, severe cardiovagal impairment, and preserved postganglionic sympathetic sudomotor function. These findings were interpreted as being consistent with central autonomic failure. The most common autonomic symptoms reported in other AxD cases include constipation, urinary incontinence, and sphincter dysfunction. To our knowledge, this is the first report of formal autonomic testing in AxD. Signs and symptoms of ANS impairment can occur in patients with AxD, and can include orthostatic hypotension and bowel/bladder dysfunction. Autonomic testing in our patient suggests impairment in central autonomic pathways. 23508559 Transcription activator-like effector nucleases (TALENs): a highly efficient and versatile tool for genome editing. Transcription activator-like effector (TALE) nucleases (TALENs) have recently emerged as a revolutionary genome editing tool in many different organisms and cell types. The site-specific chromosomal double-strand breaks introduced by TALENs significantly increase the efficiency of genomic modification. The modular nature of the TALE central repeat domains enables researchers to tailor DNA recognition specificity with ease and target essentially any desired DNA sequence. Here, we comprehensively review the development of TALEN technology in terms of scaffold optimization, DNA recognition, and repeat array assembly. In addition, we provide some perspectives on the future development of this technology. 23921557 Behavioral correlates of extra-pair copulation in Indri indri. Active pursuit of extra-pair mating has been reported for Indri indri, the socially monogamous largest living lemur. This study, conducted in a mountain rainforest in eastern Madagascar, presents the first evidence for extra-pair mating of indri and discusses the alternative mating strategy and alteration of the social, territorial, spatial, and vocal behavior of the adult female of a group of wild indris. Further studies may investigate whether extra-pair copulation is an attempt to breed with a partner of superior quality and thus lead to extra-pair paternity. If so, it could potentially play a role in maintaining genetic variability within a population. 23312472 Highly selective 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase. We report the SAR around a series of 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase. 2-Aminophenethyl analogs demonstrate excellent potency but moderate kinase selectivity, while 2-aminobenzyl analogs that fill the Ala571 subpocket exhibit good inhibition activity and excellent kinase selectivity. 23936452 D-cycloserine in Prelimbic Cortex Reverses Scopolamine-Induced Deficits in Olfactory Memory in Rats. A significant interaction between N-methyl-D-aspartate (NMDA) and muscarinic receptors has been suggested in the modulation of learning and memory processes. The present study further investigates this issue and explores whether d-cycloserine (DCS), a partial agonist at the glycine binding site of the NMDA receptors that has been regarded as a cognitive enhancer, would reverse scopolamine (SCOP)-induced amnesia in two olfactory learning tasks when administered into the prelimbic cortex (PLC). Thus, in experiment 1, DCS (10 µg/site) was infused prior to acquisition of odor discrimination (ODT) and social transmission of food preference (STFP), which have been previously characterized as paradigms sensitive to PLC muscarinic blockade. Immediately after learning such tasks, SCOP was injected (20 µg/site) and the effects of both drugs (alone and combined) were tested in 24-h retention tests. To assess whether DCS effects may depend on the difficulty of the task, in the STFP the rats expressed their food preference either in a standard two-choice test (experiment 1) or a more challenging three-choice test (experiment 2). The results showed that bilateral intra-PLC infusions of SCOP markedly disrupted the ODT and STFP memory tests. Additionally, infusions of DCS alone into the PLC enhanced ODT but not STFP retention. However, the DCS treatment reversed SCOP-induced memory deficits in both tasks, and this effect seemed more apparent in ODT and 3-choice STFP. Such results support the interaction between the glutamatergic and the cholinergic systems in the PLC in such a way that positive modulation of the NMDA receptor/channel, through activation of the glycine binding site, may compensate dysfunction of muscarinic neurotransmission involved in stimulus-reward and relational learning tasks. 23405965 Indolizine derivatives as HIV-1 VIF-ElonginC interaction inhibitors. Compound 1 (VEC-5) was identified as a potent small molecular HIV-1 VIF inhibitor that targets the VIF-ElonginC interaction. A structure-activity relationship study was carried out to develop compounds with improved efficacy against HIV-1 and 49 indolizine derivatives of three categories were designed and synthesized. We found that 5 compounds exhibited promising anti-HIV-1 activity and the most active compound 2g had an IC(50) value of 11.0 μM. These results provide new information to develop highly potent small-molecule HIV-1 VIF inhibitors. © 2013 John Wiley & Sons A/S. 23969153 Potential role of advanced MRI techniques for the peritumoural region in differentiating glioblastoma multiforme and solitary metastatic lesions. Differentiation between solitary metastatic lesions and glioblastomas, two of the most common malignant brain neoplasms, is often a diagnostic challenge. The purpose of this review is to emphasize the potential roles of advanced magnetic resonance imaging (MRI) techniques, including diffusion-based techniques, such as diffusion-weighted imaging (DWI), exponential DWI, and diffusion tensor imaging, MR perfusion, and MR spectroscopy, as well as conventional MRI, in making a distinction between glioblastomas and solitary metastases in peritumoural regions. Integration of advanced MRI features with conventional MRI, may provide valuable information for differentiating glioblastoma from solitary metastatic lesions. 23845805 Strategies for active TNF-α vaccination in rheumatoid arthritis treatment. Local overexpression of tumor necrosis factors alpha (TNF-α) is critically involved in the inflammatory response and tissue destruction of rheumatoid arthritis (RA). Currently, the blockade of TNF-α by passive immunotherapy is indeed efficacious in the treatment of RA, but it still present some disadvantages. Induction of high level of anti-TNF-α neutralizing autoantibodies by TNF-α autovaccine has been developed to avoid these shortcomings. This review is to briefly introduce several vaccination approaches that have been used to induce a B cell response, including coupled TNF-α (entire/peptide) with a carrier protein, modified TNF-α with foreign Th cell epitopes, and engineered DNA vaccine. These methods showed remarkable therapeutic efficiency in experimental animals which indicated that active TNF-α immunization would be a promising and cost-effective new treatment option for RA. 23722917 Evaluation of medical journal web sites. In the past 10 years, most medical journals have developed Web sites that not only deliver the electronic version of their publication but also provide a multimedia collection of resources, articles, educational tools, and external links to meet the needs and interests of the 21st century clinician. This article presents an evaluation tool with 5 criteria to assess the quality and scope of a medical journal's Web site and provides readers with an assessment and detailed tour through the Web sites of 5 major medical journals. 23677638 Performance of density functional theory in computing nonresonant vibrational (hyper)polarizabilities. A set of exchange-correlation functionals, including BLYP, PBE0, B3LYP, BHandHLYP, CAM-B3LYP, LC-BLYP, and HSE, has been used to determine static and dynamic nonresonant (nuclear relaxation) vibrational (hyper)polarizabilities for a series of all-trans polymethineimine (PMI) oligomers containing up to eight monomer units. These functionals are assessed against reference values obtained using the Møller-Plesset second-order perturbation theory (MP2) and CCSD methods. For the smallest oligomer, CCSD(T) calculations confirm the choice of MP2 and CCSD as appropriate for assessing the density functionals. By and large, CAM-B3LYP is the most successful, because it is best for the nuclear relaxation contribution to the static linear polarizability, intensity-dependent refractive index second hyperpolarizability, static second hyperpolarizability, and is close to the best for the electro-optical Pockels effect first hyperpolarizability. However, none of the functionals perform satisfactorily for all the vibrational (hyper)polarizabilities studied. In fact, in the case of electric field-induced second harmonic generation all of them, as well as the Hartree-Fock approximation, yield the wrong sign. We have also found that the Pople 6-31+G(d) basis set is unreliable for computing nuclear relaxation (hyper)polarizabilities of PMI oligomers due to the spurious prediction of a nonplanar equilibrium geometry. 23606448 A Generic Micropatterning Platform to Direct Human Mesenchymal Stem Cells from Different Origins Towards Myogenic Differentiation. Human mesenchymal stem cells (MSCs) derived from various origins show varied differentiation capability. Recent work shows that cell shape manipulation via micropatterning can modulate the differentiation of bone-marrow-derived MSCs. Herein, the effect of micropatterning on the myogenesis of MSCs isolated from three different sources (bone marrow, fetal tissue, and adipose) is reported. All the well-aligned cells, regardless of source, predominantly commit to myogenic lineage, as shown by the significant upregulation of myogenic gene markers and positive myosin heavy chain staining. It is demonstrated that our novel micropattern can be used as a generic platform for inducing myogenesis of MSCs from different sources and may also have the potential to be extended to induce other lineage commitment. 23954759 Prospective biomarker evaluation in patients with osteonecrosis of the jaw who received bisphosphonates. Bone biomarkers have been suggested for the risk assessment for osteonecrosis of the jaw, a serious complication associated with bisphosphonate (BP) use; however, no consensus has been reached. This study investigated the possible associations between bone biomarkers and the development of bisphosphonates-related osteonecrosis of the jaw (BRONJ). This is a case-control study of 37 patients with BRONJ (age, 73.6±11.2years) who had at least 1 sample available at diagnosis, out of which, 35 were taking BPs for osteoporosis and 2 patients for bone metastasis. Age- and gender-matched 37 patients who had been exposed to BPs for >24months and had no evidence of BRONJ after dentoalveolar surgery served as control group. The association between biomarkers (osteocalcin [OC], deoxypyridinoline [DPD], C-terminal telopeptide of collagen I [CTX], N-terminal telopeptides [NTX], bone-specific alkaline phosphatase [BAP], and parathyroid hormone [PTH]) and BRONJ development, the effects of BP discontinuation on biomarkers, and the performance of biomarkers for risk assessment was investigated. In our study, the PTH levels were found to be significantly higher in BRONJ patients compared to controls (P<0.05). But the OC, DPD, CTX, NTX, and BAP levels were not significantly different between the 2 groups (P>0.05). The CTX level in reference to a 150pg/mL cutoff was also not significant for BRONJ development (P>0.05). Among BRONJ patients who discontinued BP, in a linear mixed model, only CTX showed a significant increase over time (β=0.002, P=0.007). The cutoff PTH level was >41.52pg/mL (AUC=0.719, P=0.009), and that of CTX was ≤0.094ng/mL (AUC=0.619, P=0.069). In conclusion, there is insufficient evidence for the risk prediction for BRONJ of current bone biomarkers; additional research is necessary. 23793149 Crystallographic data processing for free-electron laser sources. A processing pipeline for diffraction data acquired using the `serial crystallography' methodology with a free-electron laser source is described with reference to the crystallographic analysis suite CrystFEL and the pre-processing program Cheetah. A detailed analysis of the nature and impact of indexing ambiguities is presented. Simulations of the Monte Carlo integration scheme, which accounts for the partially recorded nature of the diffraction intensities, are presented and show that the integration of partial reflections could be made to converge more quickly if the bandwidth of the X-rays were to be increased by a small amount or if a slight convergence angle were introduced into the incident beam. 23822608 Report of the second joint meeting of ESOT and AST: current pipelines in biotech and pharma. Following the first joint meeting organized by the European (ESOT) and American (AST) Societies of Transplantation in 2010, a second joint meeting was held in Nice, France, on October 12-14, 2012 at the Palais de la Mediterannee. Co-chairs of the scientific advisory committee were Dr. Flavio Vincenti (AST) and Dr. Teun Van Gelder (ESOT). The goal was to discuss the key unmet needs in solid organ transplantation with the opportunity to interrelate current basic research efforts with clinical translation. Thus, the topic of this second meeting "Transformational therapies and diagnostics in transplantation" was devised and a summary of this meeting follows. 23944198 Characterization of Dopant Diffusion within Semiconducting Polymer and Small Molecule Films using Infrared Active Vibrational Modes and Attenuated Total Reflectance IR Spectroscopy. ABSTRACT. Understanding dopant diffusion with in organic and polymeric semiconductors is of great importance towards the development of organic photovoltaic and electronic devices, many of which require layered structures with controlled doping profiles (ex. p-n and p-i-n structures). The current paper demonstrates a new method to determine diffusion and permeability coefficients for dopant diffusion within polymeric and small molecule organic semiconductors using attenuated total reflectance infrared spectroscopy (ATR-IR) and taking advantage of the intense infrared active vibrational bands created when dopants such as iodine accept charge from semiconducting polymer to generate polaronic species. The diffusion and permeability coefficients for I2 within P3HT are determined to be 2.5x10-11 ± 1.2 x10-11 cm2/s and 2.4 x10-8 ± 1.2 x 10-8 cm2/s-atm respectively. The approach is applied to P3HT/PCBM (1:1 mass ratio) films, and diffusion and permeability coefficients through these composite film are determined to be 7.8x10-11 ± 2.8x10-11 cm2/s and 4.8 x 10-8 ± 1.3x10-8 cm2/s-atm. Finally, the approach is extended to determining iodine diffusion within the polycrystalline semiconductor tetraphenylporphyrin (TPP) in a bilayer film with P3HT, and the diffusion coefficient of iodine through TPP is determined to be 7.1 x 10-14 ± 1.1 x 10-14 cm2/s. Although the current paper determines diffusion and permeability for the dopant iodine, this approach should be applicable to a wide array of dopants and polymeric and small molecule semiconductors of interest in photovoltaic and electronic applications. 23892769 Unmet HIV Service Needs Among Black Men Who Have Sex with Men in the United States. The National HIV/AIDS Strategy (NHAS) clearly emphasized the need to provide services to black men who have sex with men (MSM). However, there are no estimates of the unmet HIV-related service delivery needs among black MSM. We estimate that of 195,313 black MSM living with HIV in the US, 50,196 were not yet diagnosed, and 145,118 were aware of their seropositivity (of whom 67,625 were not linked to care and 77,493 were linked to care). Also, of those already diagnosed, ~43,390 had undetectable viral load and 101,728 had detectable viral load. Approximately 19,545 of diagnosed black MSM engage in unprotected risk behavior in serostatus-discordant partnerships. The cost of delivering services needed to meet the NHAS goals is ~$2.475 billion in 2011 U.S. dollars. Mathematical modeling suggests that provisions of these services would avert 6213 HIV infections at an economically favorable cost of $20,032 per quality-adjusted life year saved. 23966460 Difficulty in the intravesical morcellation procedure for leiomyoma of the prostate enucleated by HoLEP. Leiomyoma of prostate are rare benign neoplasms that are usually diagnosed incidentally through postoperative pathological examination. A 70-year-old man is presented with severe symptoms of lower urinary tract obstruction. Although a digital rectal examination and the prostate-specific antigen level did not suggest malignancy, transrectal ultrasonography showed an unusual homogenous echoic mass measuring 45×37 mm in size in the prostate. A needle biopsy was performed and pathological diagnosis was prostatic leiomyoma. Holmium laser enucleation of prostate (HoLEP) was chosen and performed to resect the tumour. Although the enucleation step presented no problems, the morcellation procedure using a conventional transurethral mechanical morcellator was very difficult owing to the firmness of the tissue. By using a bipolar erectrosurgical loop, fragmentation and removal of tissue was accomplished. This is the first case reported of these rare neoplasms in which HoLEP was offered as a less invasive surgical approach. We emphasise the firmness of the leiomyomatous tissue, which would lead to morcellation failure. 23811481 Enzyme-free and ultrasensitive electrochemical detection of nucleic acids by target catalyzed hairpin assembly followed with hybridization chain reaction. An isothermal, enzyme-free and ultrasensitive protocol for electrochemical detection of DNA is proposed based on the ingenious combination of target catalyzed hairpin assembly and hybridization chain reaction (HCR) strategies for two-step signal amplification. The DNA hairpin assembly on the electrode is triggered by target DNA, accompanied by the release of target DNA for the successive hybridization and assembly process. The newly emerging DNA fragment on the electrode after hairpin assembly is further used to propagate the HCR between methylene blue-labeled signal probe and auxiliary probe, inducing a remarkably amplified electrochemical signal. The current dual signal amplification strategy is relatively simple and inexpensive owing to avoid the use of any kind of enzyme or sophisticated equipment. It can achieve a sensitivity of 0.1fM with a wide linear dynamic range from 1×10(-15) to 1×10(-10)M and discriminate mismatched DNA from perfect matched target DNA with a high selectivity. The high sensitivity and selectivity make this method a great potential for early diagnosis in gene-related diseases. 23616215 Coordination structures of Mg(2+) and Ca(2+) in three types of tobacco calmodulins in solution: Fourier-transform infrared spectroscopic studies of side-chain COO(-) groups. Calmodulin (CaM) is a Ca(2+) -binding protein that regulates a number of fundamental cellular activities. Nicotiana tabacum CaM (NtCaM) comprises 13 genes classified into three types, among which gene expression and target enzyme activation differ. We performed Fourier-transform infrared spectroscopy to compare the secondary and coordination structures of Mg(2+) and Ca(2+) among NtCaM1, NtCaM3, and NtCaM13 as representatives of the three types of NtCaMs. Data suggested that NtCaM13 has a different secondary structure due to the weak β-strand bands and the weak 1661 cm(-1) band. Coordination structures of Mg(2+) of NtCaM3 and NtCaM13 were similar but different from that of NtCaM1, while the Ca(2+) -binding manner was similar among the three CaMs. The amplitude differences of the band at 1554-1550 cm(-1) obtained by second-derivative spectra indicated that the intensity change of the band of NtCaM13 was smaller in response to [Ca(2+) ] increases under low [Ca(2+) ] conditions than were those of NtCaM1 and NtCaM3, while the intensity reached the same level under high [Ca(2+) ]. Therefore, NtCaM13 has a characteristic secondary structure and specific Mg(2+) -binding manner and needs higher [Ca(2+) ] for bidentate Ca(2+) coordination of 12th Glu in EF-hand motifs. The Ca(2+) -binding mechanisms of the EF-hand motifs of the three CaMs are similar; however, the cation-dependent conformational change in NtCaM13 is unique among the three NtCaMs. © 2013 Wiley Periodicals, Inc. Biopolymers 99: 472-483, 2013. 23836368 Changes of concentrations of elements in deciduous teeth with age. The aim of this study was to describe the issue of changes in the concentration of some elements (Mn, Fe, Mg, Cu, K, Cr, Pb, Cd, and Ca) in the mineral composition of deciduous teeth and to answer the question whether there was a tendency to change the metal concentration, depending on children's age. Physiological replacement of deciduous teeth is preceded with the remodeling process occurring in the mineral structure. The elemental composition of deciduous teeth tissue during their natural loss is the result of these transformations. The subject of the study was deciduous teeth taken from the children (n = 45, aged 5-14 years), residing in southern Poland, obtained as a result of noninvasive physiological replacement. The concentration of metals in samples was determined over the atomic absorption spectroscopy method. The results of the research showed a statistically significant decrease in the concentration of the analyzed elements in deciduous teeth of older children compared to younger children. The total concentration of all metals studied against the Ca content, expressed as the value of the constant cationic equilibrium, did not change in a statistically significant manner, depending on the age of the children (p > 0.05). 23948054 The consumption and recycling collection system of PET bottles: A case study of Beijing, China. After studying the recycling collection system of polyethylene terephthalate (PET) bottles worldwide, the authors conducted an intercept survey in Beijing. Two separate questionnaires were issued, one questionnaire to PET bottle consumers and one to PET bottle recyclers. In this study, consumers are defined as people that consume PET-bottled beverages in their daily life. Recyclers were defined as those involved in the collection and recycling of PET bottles. These include scavengers, itinerant waste buyers, small community waste-buying depots, medium/large redemption depots, and recycling companies. In total, 580 surveys were completed, including 461 by consumers and 119 by recyclers. The authors found that consumption of PET bottles in Beijing was nearly 100,000 tonnes in 2012. Age, occupation, gender, and education were identified as significant factors linked to PET-bottled beverage consumption, while income was not a significant factor. 90% Of post-consumed PET bottles were collected by informal collectors (i.e., scavengers and itinerant waste buyers). The survey also found that nearly all PET bottles were reprocessed by small factories that were not designed with pollution control equipment, which allows them to offer higher prices for waste recyclable bottles. As Beijing is trying to build a formal recycling collection system for recyclables, subsidies should be given to the formal recycling sector rather than being charged land use fees, and attention should also be given to informal recyclers that make their living from the collection of recyclables. Informal and formal sectors may work together by employing the scavengers and itinerant waste buyers for the formal sectors. In addition to the recycling of PET bottles, concern should also be allocated to reduce consumption, especially among young people, as they, compared to other groups, have a stronger demand for PET-bottled beverages and will be the main body of society. 23856913 Application of capillary electrophoretic chips in protein profiling of plant extracts for identification of genetic modifications of maize. In this study, the chip gel electrophoresis with LIF detection was applied in protein profiling of fractionated and total extracts of maize standards. The sensitivity of such determinations can be enhanced by lyophilization of extracts or employing filtering and preconcentration with cutoff filters. Combinatorial peptide ligand library applied for sample processing prior to the electrophoretic analysis was, especially, an effective pretreatment step in the determination of low-abundance proteins. Several repeatable differences were observed for protein profiles between maize standards not containing the genetically modified organisms (GMOs) and those containing GMO, which can be potentially employed for identification of GMO in maize samples and foods of maize origin. 23690484 The Ubiquitin-CXCR4 Axis Plays an Important Role in Acute Lung Infection-Enhanced Lung Tumor Metastasis. Our goals were to test the effect of acute lung infection on tumor metastasis and to investigate the underlying mechanisms.EXPERIMENTAL DESIGN: We combined bacteria-induced and lipopolysaccharide (LPS)-induced acute lung injury/inflammation (ALI) mouse models with mouse metastatic models to study the effect of acute inflammation on lung metastasis in mice. The mechanisms were investigated in ex vivo, in vitro, and in vivo studies.RESULTS: Both bacteria- and LPS-induced ALI significantly enhanced lung metastasis of four tail vein-injected mouse tumor cell lines. Bacteria also enhanced lung metastasis when 4T1 cells were orthotopically injected. The bronchoalveolar lavage fluid (BALF) from LPS- or bacteria-injected mice stimulated migration of tumor cells. In vivo tracking of metastatic RM-9 cells showed that bacterial injection enhanced early dissemination of tumor cells to the lung. The majority of the BALF migratory activity could be blocked by AMD3100, a chemokine receptor 4 (CXCR4) inhibitor. All tested cell lines expressed CXCR4. The levels of extracellular ubiquitin, but not stromal cell-derived factor-1, in BALF were significantly increased by LPS. Ubiquitin was able to induce AMD3100-sensitive migration of tumor cells. Finally, the antibacterial agent amoxicillin and the CXCR4 inhibitor AMD3100 blocked the enhancement effect of bacterial infection on tumor metastasis.CONCLUSIONS: Acute lung infection dramatically increased cancer cell homing to the lung and lung metastasis. This change may be due to an alteration of the lung microenvironment and preparation of a favorable metastatic "niche." This effect was seen in multiple cancer types and thus may have broad applications for cancer patients in prevention and/or treatment of metastasis. Clin Cancer Res; 19(17); 1-11. ©2013 AACR. 23244461 Effects of repeated sterilization cycles on primary stability of orthodontic mini-screws. To determine if repeated sterilization has deleterious effects on the clinical stability of mini-screws. Thirty each of the following mini-screws were tested: Aarhus (American Orthodontics, Sheboygan, Wisc), VectorTAS (Ormco Corporation, Orange, Calif), Dual-Top (RMO, Denver, Colo), and Ortho Anchor (KLS Martin, Jacksonville, Fla). Controls were sterilized once using a steam autoclave (Statim 5000, SciCan USA, Canonsburg, Pa). Each group of mini-screws was divided into three groups: the control (n = 10) and two test groups (n  =10, each). Test groups were cycled five and 10 times respectively. All screws were inserted into custom-designed synthetic blocks that simulated mandibular bone. Maximum insertion torque and lateral displacement force data were recorded and subjected to statistical testing. Two-way analysis of variance (ANOVA) and three-way mixed ANOVA were used for statistical analyses for maximum insertion torque data and lateral displacement force data, respectively. Level of significance was established at P < .05. Insertion torque values displayed significant differences between both of the groups and sterilization cycles (P < .05). Significant differences were observed between American Aarhus mini-screws and both RMO and KLS Martin mini-screws. Ormco Vector mini-screws also differed significantly from the KLS Martin mini-screws in this comparison (P < .05). For lateral displacement, there was a significant main effect of groups, F(1,36) = 14.5 (P < .05). Significant differences were observed between American Aarhus mini-screws and all three of the other groups (P < .05). The examined groups displayed statistical differences of variable quality that may not affect their clinical stability. 23841890 Centrally Mediated Erectile Dysfunction in Rats with Type 1 Diabetes: Role of Angiotensin II and Superoxide. Erectile dysfunction is a serious complication of diabetes mellitus. Apart from the peripheral actions, central mechanisms are also responsible for penile erection. This study aims to determine the contribution of angiotensin (ANG) II in the dysfunction of central N-methyl-D-aspartic acid (NMDA)- and nitric oxide (NO)-induced erectile responses in streptozotocin-induced type 1 diabetic (T1D) rats. Three weeks after streptozotocin injections, rats were randomly treated with the angiotensin-converting enzyme inhibitor-enalapril, or the ANG II type 1 receptor blocker, losartan, or the superoxide dismutase mimetic, tempol, or vehicle via chronic intracerebroventricular infusion by osmotic mini-pump for 2 weeks. Central NMDA receptor stimulation or the administration of the NO donor, sodium nitroprusside (SNP)-induced penile erectile responses and concurrent behavioral responses were monitored in conscious rats. Two weeks of enalapril, losartan, or tempol treatment significantly improved the erectile responses to central microinjection of both NMDA and SNP in the paraventricular nucleus (PVN) of conscious T1D rats (NMDA responses-T1D+enalapril: 1.7 ± 0.6, T1D+losartan: 2.0 ± 0.3, T1D+tempol: 2.0 ± 0.6 vs. T1D+vehicle: 0.6 ± 0.3 penile erections/rat in the first 20 minutes, P < 0.05; SNP responses-T1D+enalapril: 0.9 ± 0.3, T1D+losartan: 1.3 ± 0.3, T1D+tempol: 1.4 ± 0.4 vs. T1D+vehicle: 0.4 ± 0.2 penile erections/rat in the first 20 minutes, P < 0.05). Concurrent behavioral responses including yawning and stretching, induced by central NMDA and SNP microinjections, were also significantly increased in T1D rats after enalapril, losartan, or tempol treatments. Neuronal NO synthase expression within the PVN was also significantly increased, and superoxide production was reduced in T1D rats after these treatments. These data strongly support the contention that enhanced ANG II mechanism/s within the PVN of T1D rats contributes to the dysfunction of central NMDA-induced erectile responses in T1D rats via stimulation of superoxide. Zheng H, Liu X, and Patel KP. Centrally mediated erectile dysfunction in rats with type 1 diabetes: Role of angiotensin II and superoxide. J Sex Med **;**:**-**. 23543012 In vitro characterisation of the anti-intravasative properties of the marine product heteronemin. Metastases destroy the function of infested organs and are the main reason of cancer-related mortality. Heteronemin, a natural product derived from a marine sponge, was tested in vitro regarding its properties to prevent tumour cell intravasation through the lymph-endothelial barrier. In three-dimensional (3D) cell cultures consisting of MCF-7 breast cancer cell spheroids that were placed on lymph-endothelial cell (LEC) monolayers, tumour cell spheroids induce "circular chemorepellent-induced defects" (CCIDs) in the LEC monolayer; 12(S)-Hydroxyeicosatetraenoic acid (12(S)-HETE) and NF-κB activity are major factors inducing CCIDs, which are entry gates for tumour emboli intravasating the vasculature. This 3D co-culture is a validated model for the investigation of intravasation mechanisms and of drugs preventing CCID formation and hence lymph node metastasis. Furthermore, Western blot analyses, NF-κB reporter, EROD, SELE, 12(S)-HETE, and adhesion assays were performed to investigate the properties of heteronemin. Five micromolar heteronemin inhibited the directional movement of LECs and, therefore, the formation of CCIDs, which were induced by MCF-7 spheroids. Furthermore, heteronemin reduced the adhesion of MCF-7 cells to LECs and suppressed 12(S)-HETE-induced expression of the EMT marker paxillin, which is a regulator of directional cell migration. The activity of CYP1A1, which contributed to CCID formation, was also inhibited by heteronemin. Hence, heteronemin inhibits important mechanisms contributing to tumour intravasation in vitro and should be tested in vivo. 23547963 Mesenchymal stem cells: promising for myocardial regeneration? The pandemic of cardiovascular disease is continuously expanding as the result of changing life styles and diets throughout the Old and New World. Immediate intervention therapy saves the lives of many patients after acute myocardial infarction (MI). However, for many this comes at the price of adverse cardiac remodeling and heart failure. Currently, no conventional therapy can prevent the negative aftermath of MI and alternative treatments are warranted. Therefore, cardiac stem cell therapy has been put forward over the past decade, albeit with modest successes. Mesenchymal Stem Cells (MSC) are promising because these are genuine cellular factories of a host of secreted therapeutic factors. MSC are obtained from bone marrow or adipose tissue (ADSC). However, the heart itself also contains mesenchymal- like stem cells, though more difficult to acquire than ADSC. Interestingly, mesenchymal cells such as fibroblasts can be directly or indirectly reprogrammed to all myocardial cell types that require replacement after MI. To date, the paracrine and juxtacrine mechanisms of ADSC and other MSC on vessel formation are best understood. The preconditioning of, otherwise naive, stem cells is gaining more interest: previously presumed deleterious stimuli such as hypoxia and inflammation, i.e. causes of myocardial damage, have the opposite effect on mesenchymal stem cells. MSC gain a higher therapeutic capacity under hypoxia and inflammatory conditions. In this review, mesenchymal stem cells and their working mechanisms are put into the perspective of clinical cardiac stem cell therapy. 23517190 Role and interpretation of fluorodeoxyglucose-positron emission tomography/computed tomography in HIV-infected patients with fever of unknown origin: a prospective study. The aim of the study was to evaluate prospectively the usefulness of fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in investigation of fever of unknown origin (FUO) in HIV-positive patients and to determine whether HIV viraemia impacts on FDG-PET/CT performance. The FDG-PET/CT results of 20 HIV-infected patients with FUO were analysed and compared with the FDG-PET/CT results of 10 HIV-infected viraemic patients without FUO. The performance of FDG-PET/CT for identifying the aetiology of FUO was assessed. Final diagnosis for FUO was based on histopathology, microbiological assays, or clinical and imaging follow-up. FDG-PET/CT contributed to the diagnosis or exclusion of a focal aetiology of the febrile state in 80% of patients with FUO. The presence of increased FDG uptake in the central lymph node has 100% specificity for focal aetiology of fever, even in viraemic patients. The absence of hypermetabolic central lymph nodes in FUO patients has 100% negative predictive value for focal disease. Lymph node biopsy in central hypermetabolic areas allowed, in 100% of cases, identification of underlying disease in patients with FUO. Biopsy of peripheral lymph nodes should be performed in lymph nodes with maximum standardized uptake value (SUVmax) ≥ 6-8 (sensitivity 62.5%; specificity 75%) and avoided in lymph nodes with SUVmax = 0-4 (specificity 0%). High HIV viraemia does not prevent correct interpretation of FDG-PET/CT. As in HIV-negative patients, we confirm the usefulness of FDG-PET/CT in investigation of FUO in HIV-positive patients even if they are viraemic. 23436395 Maturation of peptide-positive synaptic arbors in the medicinal leech requires rhythmic target activity. The formation and refinement of synaptic connections are dependent on the activity that emerges from nascent synaptic connections. Such activity has the effect of regulating the production and release of specific neurotransmitters. To determine the role of activity in regulating the production of peptide-positive synapses, we used antibodies against Phe-Met-Arg-Phe-NH₂ and acetylated α-tubulin as well as intracellular injections of Neurobiotin to examine varicosities belonging to heart excitor (HE) neurons on the heart tubes of medicinal leeches, Hirudo spp. We found that the production of peptide-positive varicosities increased considerably during the last week of embryogenesis, which coincided with the emergence of rhythmic activity of the heart tube. When we compromised central input to HE neurons with bicuculline or by surgical ablation of the central pattern generator during early embryogenesis, we found that activity in the heart tubes and its rhythmicity were greatly diminished. Furthermore, the activity of HE neurons had also lost its rhythmicity and appeared tonic, and production of peptide-positive varicosities was substantially reduced as well. Partial surgical ablations that preserved rhythmic activity in the heart tube while disrupting heart tube innervation by some HE neurons still resulted in peptide-positive varicosity production. Taken together, our results suggest that postsynaptic rhythmic activity of the heart tube is necessary and sufficient for the development and maturation of peptide-positive synapses. 23872285 Neural correlates of audiovisual speech processing in a second language. Neuroimaging studies of audiovisual speech processing have exclusively addressed listeners' native language (L1). Yet, several behavioural studies now show that AV processing plays an important role in non-native (L2) speech perception. The current fMRI study measured brain activity during auditory, visual, audiovisual congruent and audiovisual incongruent utterances in L1 and L2. BOLD responses to congruent AV speech in the pSTS were stronger than in either unimodal condition in both L1 and L2. Yet no differences in AV processing were expressed according to the language background in this area. Instead, the regions in the bilateral occipital lobe had a stronger congruency effect on the BOLD response (congruent higher than incongruent) in L2 as compared to L1. According to these results, language background differences are predominantly expressed in these unimodal regions, whereas the pSTS is similarly involved in AV integration regardless of language dominance. 23760623 Potential protective effects of oral administration of allicin on acrylamide-induced toxicity in male mice. Acrylamide (AA) forms during the heating of starchy foods at high temperature, and is regarded as a potential genotoxic carcinogen. However, with the worldwide concern about the carcinogenicity of AA, how to reduce the toxicity of AA has become a hot research topic. In this study, we further discussed the effects of oral administration of allicin on AA-induced toxicity by determining the hematological, biochemical and immunological parameters in the serum, kidney, liver, and brain of male mice. Our data showed that the orally administered allicin of 5, 10, and 20 mg kg(-1) bw d(-1) could significantly decrease thiobarbituric reactive substances (TBARS) and myeloperoxidase (MPO) levels, and simultaneously remarkably increased the superoxide dismutase (SOD) activity, glutathione S-transferase (GST) and glutathione (GSH) levels in the kidney, liver, and brain of the AA-treated mice. Furthermore, oral administration of allicin not only significantly decreased aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), tumor necrosis factor α (TNF-α), interleukin (IL)-1β, interleukin (IL)-6, reactive oxygen species (ROS), and 8-hydroxy-desoxyguanosine (8-OHdG), but also increased interleukin (IL)-10 in the serum of AA-treated mice. Therefore, it was concluded that oral administration of allicin had a significant in vivo protective effect against the AA induced toxicity. 23747754 An illusory distortion of moving form driven by motion deblurring. Many visual processes integrate information over protracted periods, a process known as temporal integration. One consequence of this is that objects that cast images that move across the retinal surfaces can generate blurred form signals, similar to the motion blur that can be captured in photographs taken with slow shutter speeds. Subjectively, retinal motion blur signals are suppressed from awareness, such that moving objects seem sharply defined. One suggestion has been that this subjective impression is due to humans not being able to distinguish between focussed and blurred moving objects. Contrary to this suggestion, here we report a novel illusion, and consequent experiments, that implicate a suppressive mechanism. We find that the apparent shape of circular moving objects can be distorted when their rear edges lag leading edges by ∼60ms. Moreover, we find that sensitivity for detecting blur, and for discriminating between blur intensities, is uniformly worse for physical blurs added behind moving objects, as opposed to in-front. Also, it was easier to differentiate between slight and slightly greater physical blurs than it was to differentiate between slight blur and the absence of blur, both behind and in-front of moving edges. These 'dipper' functions suggest that blur signals must reach a threshold intensity before they can be detected, and that the relevant threshold is effectively elevated for blur signals trailing behind moving contours. In combination, these data suggest moving objects look sharply defined, at least in part, because of a functional adaptation that actively suppresses motion blur signals from awareness. 23282278 Multicolor fluorescent semiconducting polymer dots with narrow emissions and high brightness. Fluorescent semiconducting polymer dots (Pdots) have attracted great interest because of their superior characteristics as fluorescent probes, such as high fluorescence brightness, fast radiative rates, and excellent photostability. However, currently available Pdots generally exhibit broad emission spectra, which significantly limit their usefulness in many biological applications involving multiplex detections. Here, we describe the design and development of multicolor narrow emissive Pdots based on different boron dipyrromethene (BODIPY) units. BODIPY-containing semiconducting polymers emitting at multiple wavelengths were synthesized and used as precursors for preparing the Pdots, where intraparticle energy transfer led to highly bright, narrow emissions. The emission full width at half-maximum of the resulting Pdots varies from 40 to 55 nm, which is 1.5-2 times narrower than those of conventional semiconducting polymer dots. BODIPY 520 Pdots were about an order of magnitude brighter than commercial Qdot 525 under identical laser excitation conditions. Fluorescence imaging and flow cytometry experiments indicate that the narrow emissions from these bright Pdots are promising for multiplexed biological detections. 23859073 Dissociation-Based Screening of Nanoparticle-Protein Interaction via Flow Field-Flow Fractionation. A protein corona will be formed on nanoparticles (NPs) entering a biological matrix, which can influence particles' subsequent behaviors inside the biological systems. For proteins bound stably to the NPs, they can exhibit different association/dissociation rates. The binding kinetics could affect interaction of the NPs with cell surface receptors and possibly contribute to the outcomes of NPs uptake. In the present study, a method to differentiate the corona proteins based on their relative dissociation rates from the NPs was developed, employing flow field-flow fraction (F4) in combination with centrifugation. The proteins bound to the superparamagnetic iron oxide NPs (SPION) present in an IgG/albumin depleted serum were isolated via collection of the SPIONs by either F4 or centrifugation. They were subsequently analyzed by LC-MS/MS and identified. Because the SPION-protein complexes injected to F4 dissociated continuously under the nonequilibrium separation condition, only the proteins with slow enough dissociation rates would be collected with the NPs in the eluent of F4. However, in centrifugation, proteins with good affinity to the SPIONs were collected regardless of the dissociation rates of the complexes. In both cases, the nonbinding ones were washed off. Capillary electrophoresis and circular dichroism were employed to verify the binding situations of a few SPION-protein interactions, confirming the effectiveness of our method. Our results support that our method can screen for proteins binding to NPs with fast on-and-off rates, which should be the ones quickly exchanging with the free matrix proteins when the NPs are exposed to a new biological media. Thus, our method will be useful for investigation of the temporal profile of protein corona and its evolution in biological matrices as well as for high-throughput analysis of the dynamic feature of protein corona related to particle properties. 23321863 Indoor and outdoor measurements of particle number concentration in near-highway homes. Exposure to high levels of traffic-generated particles may pose risks to human health; however, limited measurement has been conducted at homes near highways. The purpose of this study was to characterize differences between indoor and outdoor particle number concentration (PNC) in homes near to and distant from a highway and to identify factors that may affect infiltration. We monitored indoor and outdoor PNC (6-3000 nm) for 1-3 weeks at 18 homes located <1500 m from Interstate-93 (I-93) in Somerville, MA (USA). Median hourly indoor and outdoor PNC pooled over all homes were 5.2 × 10(3) and 5.9 × 10(3) particles/cm(3), respectively; the median ratio of indoor-to-outdoor PNC was 0.95 (5(th)/95th percentile: 0.42/1.75). Homes <100 m from I-93 (n=4) had higher indoor and outdoor PNC compared with homes >1000 m away (n=3). In regression models, a 10% increase in outdoor PNC was associated with an approximately equal (10.8%) increase in indoor PNC. Wind speed and direction, temperature, time of day and weekday were also associated with indoor PNC. Average mean indoor PNC was lower for homes with air conditioners compared with homes without air conditioning. These results may have significance for estimating indoor, personal exposures to traffic-related air pollution. 23817595 Dyslipidemia and hyperinsulinemia in children and adolescents with chronic liver disease: relation to disease severity. Abstract Background: Lipid metabolism is profoundly disturbed in chronic liver diseases (CLD). Moreover, patients with cirrhosis displayed chronically elevated serum insulin (SI) concentrations. Objectives: The aim of this work was to assess fasting lipid profile (FLP) and SI levels among Egyptian patients with CLD and their relation to severity of liver disease. Methods: A total of 40 Egyptian children with CLD were compared with 30 age-, sex-, and pubertal stage-matched controls. All subjects were subjected to history and auxological assessment; their FLP, fasting blood glucose (FBG) and SI were measured; and their fasting glucose/insulin (G/I) ratios were calculated. Results: Total cholesterol (TC, p=0.006), triglycerides (TG, p=0.03), low density lipoproteins (LDL, p=0.034), and SI (p<0.001) were significantly higher while high density lipoproteins (HDL, p<0.001) and G/I ratio (p<0.001) were significantly lower as serum albumin decreased; these were also lower among cases with a progressive decrease going from child A to C. Of the 40 studied cases, eight (20%) had hypercholesterolemia, 13 (32.5%) had hypertriglyceridemia, 17 (42.5%) had low HDL and 9 (22.5%) had high LDL, 32 (80%) had hyperinsulinemia (HI), and 11 (27.5%) had insulin resistance (IR). Conclusions: Dyslipidemia and HI were frequent findings in patients with CLD, which worsened with increased severity of CLD. 23632054 A comparison of ultrasound-guided and landmark-based approaches to saphenous nerve blockade: a prospective, controlled, blinded, crossover trial. Blockade of the saphenous nerve is often used for surgeries below the knee. Depending on the approach, success rates vary widely ranging from 33% to 88%. In this prospective volunteer study, we compared 2 ultrasound-guided techniques, the modified vastus medialis and perifemoral saphenous nerve block with a below the knee field block. Twenty volunteer adults, in a single-blinded, crossover, prospective trial underwent 3 different saphenous nerve blocks. The primary end point of block success was loss of sensation in the distal two-thirds distribution of the saphenous nerve. Secondary variables included time to perform the block, time to sensory loss, pain during block, and motor weakness. Compared with the below the knee field block success rate (30%), both the modified vastus medialis and perifemoral techniques had significantly higher success rates (80%, difference 50% with confidence interval [CI], 23%-77%, P = 0.009, and 100%, difference 70% with CI, 41%-91%, P < 0.001, respectively). However, the difference when comparing the perifemoral ultrasound technique against the modified vastus medialis ultrasound technique did not show significance (difference 20% with CI, -7% to 49%, P = 0.125). Also, no statistical differences were found with the other variables measured, except the perifemoral technique showed faster block performance times than below the knee field block (P = 0.007). In our prospective study, we have demonstrated that ultrasound-guided above the knee saphenous nerve blocks have higher success rates than a below the knee field block and are easily performed in a short amount of time. 23621152 SPL8 and miR156-targeted SPL genes redundantly regulate Arabidopsis gynoecium differential patterning. SPL8 and miR156-targeted SPL genes are known to play an essential role in Arabidopsis anther development. Here we show that these SPL genes are also expressed within the developing gynoecium, where they redundantly control development of the female reproductive tract. Whereas the gynoecium morphology in the spl8 single mutant is largely normal, additional down-regulation of miR156-targeted SPL genes results in a shortened style and an apically swollen ovary narrowing onto an elongated gynophore. In particular, the septum does not form properly and lacks a transmitting tract. Loss of SPL8 function enhances the mutant phenotypes of ett, crc and spt, indicating a functional overlap between SPL8 and these genes in regulating gynoecium development. Furthermore, gynoecium development of 35S:MIR156b spl8-1 double mutants shows enhanced sensitivity to a polar auxin transport inhibitor, and the expression pattern of the auxin biosynthesis gene YUCCA4 is altered compared to wild-type. Our observations imply that SPL8 and miR156-targeted SPL genes control gynoecium patterning through interference with auxin homeostasis and signalling. 23378173 Different Metabolic Responses during Incremental Exercise Assessed by Localized 31P MRS in Sprint and Endurance Athletes and Untrained Individuals. Until recently, assessment of muscle metabolism was only possible by invasive sampling. 31P magnetic resonance spectroscopy (31P MRS) offers a way to study muscle metabolism non-invasively. The aim of the present study was to use spatially-resolved 31P MRS to assess the metabolism of the quadriceps muscle in sprint-trained, endurance-trained and untrained individuals during exercise and recovery. 5 sprint-trained (STA), 5 endurance-trained (ETA) and 7 untrained individuals (UTI) completed one unlocalized 31P MRS session to measure phosphocreatine (PCr) recovery, and a second session in which spatially-resolved 31P MR spectra were obtained. PCr recovery time constant (τ) was significantly longer in STA (50±17 s) and UTI (41±9 s) than in ETA (30±4 s), (P<0.05). PCr changes during exercise differed between the groups, but were uniform across the different components of the quadriceps within each group. pH during recovery was higher for the ETA than for the UTI (P<0.05) and also higher than for the STA (P<0.01). Muscle volume was greater in STA than in UTI (P<0.05) but not different from ETA. Dynamic 31P MRS revealed considerable differences among endurance and sprint athletes and untrained people. This non-invasive method offers a way to quantify differences between individual muscles and muscle components in athletes compared to untrained individuals. 23742867 Identification and expression analysis on bactericidal permeability-increasing protein (BPI)/lipopolysaccharide-binding protein (LBP) of ark shell, Scapharca broughtonii. Bactericidal permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (LBP) are the numbers of the lipid transfer protein/lipopolysaccharide-binding protein family and play crucial roles in the innate immune response to Gram-negative bacteria. A novel Sb-BPI/LBP1 from ark shell Scapharca broughtonii was isolated by expressed sequence tag (EST) and RACE techniques. The Sb-BPI/LBP1 cDNA encoded a polypeptide of 484 amino acids with a putative signal peptide of 21 amino acid residues and a mature protein of 463 amino acids. The deduced amino acid sequence of Sb-BPI/LBP1 contained an N-terminal BPI/LBP/CETP domain BPI1 with three functional regions that display LPS-binding activity, and a C-terminal BPI/LBP/CETP domain BPI2. In structure and sequence, Sb-BPI/LBP1 showed highly similar to those of the BPI/LBPs from invertebrate and non-mammalian vertebrate, the LBPs and BPIs from mammal. By quantitative real-time RT-PCR, Sb-BPI/LBP1 transcripts could be detected in all normal tested tissues, including hepatopancreas, adductor muscle, mantle margin, heart, gonad, gill and hemocytes, and was universally up-regulatable at 24 h post LPS challenge. The mRNA expression of Sb-BPI/LBP1 in hemocytes was the most sensitive to LPS challenge, significantly up-regulated at 12 h post LPS challenge and peaked at 24 h (16.76-fold, P < 0.05). These results suggested that Sb-BPI/LBP1 was a constitutive and inducible acute-phase protein contributing to the host immune defense against Gram-negative bacterial infection in ark shell S. broughtonii. 23933050 In vitro and in vivo correlation of disintegration and bitter taste masking using orally disintegrating tablet containing ion exchange resin-drug complex. Although the taste-masking of bitter drug using ion exchange resin has been recognized, in vitro testing using an electronic tongue (e-Tongue) and in vivo bitterness test by human panel test was not fully understood. In case of orally disintegrating tablet (ODT) containing bitter medicine, in vitro and in vivo disintegration is also importance for dosage performance. Donepezil hydrochloride was chosen as a model drug due to its bitterness and requires rapid disintegration for the preparation of ODT. In this study, ion exchange resin drug complex (IRDC) at three different ratios (1:2, 1:1, 2:1) was prepared using a spray-drying method and then IRDC-loaded ODT containing superdisintegrants (crospovidone, croscarmellose sodium, and sodium starch glycolate) were prepared by the direct compression method. The physical properties and morphologies were then characterized by scanning electron microscopy (SEM), X-ray powder diffraction (PXRD) and electrophoretic laser scattering (ELS), respectively. The in vitro taste-masking efficiency was measured with an electronic tongue (e-Tongue). In vivo bitterness scale was also evaluated by human volunteers and then we defined new term, "bitterness index (BI)" to link in vitro e-Tongue. There was a good correlation of IRDC between in vitro e-Tongue values and in vivo BI. Furthermore, IRDC-loaded ODT showed good in vitro/in vivo correlation in the disintegration time. The optimal IRDC-loaded ODTs displayed similar drug release profiles to the reference tablet (Aricept(®) ODT) in release media of pH 1.2, pH 4.0, pH 6.8 and distilled water but had significantly better palatability in vivo taste-masking evaluation. The current IRDC-loaded ODT according to the in vitro and in vivo correlation of disintegration and bitter taste masking could provide platforms in ODT dosage formulations of donepezil hydrochloride for improved patient compliances. 23837838 Serum levels of N-terminal proB-type natriuretic peptide in mechanically ventilated critically ill patients--relation to tidal volume size and development of acute respiratory distress syndrome. Serum levels of N-terminal proB-type natriuretic peptide (NT-proBNP) are elevated in patients acute respiratory distress syndrome (ARDS). Recent studies showed a lower incidence of acute cor pulmonale in ARDS patients ventilated with lower tidal volumes. Consequently, serum levels of NT-proBNP may be lower in these patients. We investigated the relation between serum levels of NT-proBNP and tidal volumes in critically ill patients without ARDS at the onset of mechanical ventilation. Secondary analysis of a randomized controlled trial of lower versus conventional tidal volumes in patients without ARDS. NT-pro BNP were measured in stored serum samples. Serial serum levels of NT-pro BNP were analyzed controlling for acute kidney injury, cumulative fluid balance and presence of brain injury. The primary outcome was the effect of tidal volume size on serum levels of NT-proBNP. Secondary outcome was the association with development of ARDS. Samples from 150 patients were analyzed. No relation was found between serum levels of NT-pro BNP and tidal volume size. However, NT-proBNP levels were increasing in patients who developed ARDS. In addition, higher levels were observed in patients with acute kidney injury, and in patients with a more positive cumulative fluid balance. Serum levels of NT-proBNP are independent of tidal volume size, but are increasing in patients who develop ARDS. 23073475 Testing the cancer stem cell hypothesis in melanoma: The clinics will tell. Whether tumorigenic cancer stem cells (CSCs) exist in melanoma has been the focus of much controversy in recent years. A number of studies have pointed to the existence of melanoma cell sub-populations that act as CSCs and can be distinguished from other tumor cells based on specific surface marker expression or specific properties such as the capacity for extensive self-renewal. Other studies failed to identify melanoma stem cells and proposed that the potential to initiate tumors is a wide spread feature in melanoma inherent to most if not all cells of the tumor mass. As with normal stem cells, the term CSC is based on an operational definition, indicating not just a tumor-initiating cell, but also a cell with the capacity to sustain long-term tumor propagation. Therefore, the experimental set-up chosen to identify putative CSCs in melanoma is crucial: Both the method of tumor cell preparation and the procedure used to assess CSC properties in vivo influence the experimental outcome and hence its interpretation. In this review, we summarize our current knowledge on CSCs and the role of stem cell properties in melanoma and discuss recent findings with respect to their clinical relevance. 23253145 Statistical optimization and fabrication of a press coated pulsatile dosage form to treat nocturnal Acid breakthrough. Objective: Present work focuses on the use of mimosa seed gum to develop a drug delivery system making combined use of floating and pulsatile principles, for the chrono-prevention of nocturnal acid breakthrough. Methodology: The desired aim was achieved by fabricating a floating delivery system bearing time - lagged coating of Mimosa pudica seed polymer for the programmed release of Famotidine. Response Surface Methodology was the statistical tool that was employed for experiment designing, mathematical model generation and optimization study. A 3(2) full factorial design was used in designing the experiment.% weight ratio of mimosa gum to hydroxy propyl methyl cellulose in the coating combination and the coating weight were the independent variables, whereas the lag time and the cumulative % drug release in 360 minutes were the observed responses. Key findings: Results revealed that both the coating composition and the coating weight significantly affected the release of drug from the dosage form. Conclusion: The optimized formulation prepared according to the computer generated software, Design-Expert(®) deciphered response which were in close proximity with the experimental responses, thus confirming the robustness as well as accuracy of the predicted model for the utilization of natural polymer like mimosa seed gum for the chronotherapeutic treatment of nocturnal acid breakthrough. 23751782 New case of mitochondrial HMG-CoA synthase deficiency. Functional analysis of eight mutations. Mitochondrial HMG-CoA synthase deficiency is a rare inherited metabolic disorder that affects ketone-body synthesis. Acute episodes include vomiting, lethargy, hepatomegaly, hypoglycaemia, dicarboxylic aciduria, and in severe cases, coma. This deficiency may have been under-diagnosed owing to the absence of specific clinical and biochemical markers, limitations in liver biopsy and the lack of an effective method of expression and enzyme assay for verifying the mutations found. To date, eight patients have been reported with nine allelic variants of the HMGCS2 gene. We present a new method of enzyme expression and a modification of the activity assay that allows, for first time, the functional study of missense mutations found in patients with this deficiency. Four of the missense mutations (p.V54M, p.R188H, p.G212R and p.G388R) did not produce proteins that could have been detected in soluble form by western blot; three produced a total loss of activity (p.Y167C, p.M307T and p.R500H) and one, variant p.F174L, gave an enzyme with a catalytic efficiency of 11.5%. This indicates that the deficiency may occur with partial loss of activity of enzyme. In addition, we describe a new patient with this deficiency, in which we detected the missense allelic variant, c.1162G>A (p.G388R) and the nonsense variant c.1270C>T (p.R424X). 23896123 Enhancement of protective immune response to recombinant Toxoplasma gondii ROP18 antigen by ginsenoside Re. Toxoplasma gondii, the etiological agent of toxoplasmosis, is an obligate intracellular protozoan parasite that infects a variety of mammals including humans. In an attempt to find new antigen-adjuvant combinations that enhance the immunogenicity of antigen candidates for toxoplasma vaccines, we analyzed the potent protection in mice immunized with recombinant protein ROP18 when co-administered with ginsenoside Re, a most important component isolated from Panax ginseng. All immunized mice produced specific anti-rROP18 immunoglobulins, with high levels of IgG antibody and a mixed IgG1/IgG2a response, with predominance of IgG1 production. The cellular and humoral immune responses were associated with the production of IFN-γ and IL-4 cytokines respectively. Vaccinated mice displayed a significantly increased survival time compared with control mice which died within 6days of challenge with RH strain. Our data demonstrate that by addition of ginsenoside Re, the rROP18 triggered a stronger humoral and cellular response against T. gondii, and that Re is a promising vaccine adjuvant against toxoplasmosis, deserves further evaluation and development. 23831287 Tandem-repeat proteins: regularity plus modularity equals design-ability. Researchers in the field of rational protein design face a significant challenge, which arises from the two defining and inter-related features of typical globular protein structures, namely topological complexity and cooperativity. In striking contrast to globular proteins, tandem repeat proteins, such as ankyrin, tetratricopeptide and leucine-rich repeats, have regular, modular, linearly arrayed structures which makes it especially straightforward to dissect and redesign their properties. Here we review what we have learnt about the biophysics of natural repeat proteins and recent progress in applying that knowledge to engineer the thermodynamics, folding pathways and molecular recognition properties of tandem repeat proteins, and we discuss the wealth of possibilities presented for the extension of this modular construction process to build new molecules for use in medicine and biotechnology. 23889520 Toxic Effects Induced By Curcumin In Human Astrocytoma Cell Lines. Abstract OBJECTS: The objective of this study was to describe the toxicity induced by curcumin in human astrocytoma cell lines. The effects induced by curcumin, at 100 µM for 24h, were evaluated in four astrocytoma cell lines using crystal violet assay and through the evaluation of morphological and ultrastructural changes by electron microscopy. Also, the results of vital staining with acridine orange and propidium iodide for acidic vesicles and apoptotic bodies were analyzed and the expression of the Beclin1 gene was assessed by RT-PCR. The cells treated with curcumin at 100 µM induced an inhibitory concentration50 of viability with morphological changes characterized by a progressive increase in large, non-acidic vesicles devoid of cytoplasmic components and organelles, but that conserved the cell nuclei. No DNA breakage was observed. The astrocytoma cells showed no apoptosis, necrosis or autophagy. Expression of BECLIN1 was not induced (p < 0.05) by curcumin in the astrocytoma cells. Curcumin at 100 µm induced a new type of death cell in astrocytoma cell lines. 23863350 Comparison of soft-tissue and bone surgeries in the treatment of developmental dysplasia of the hip in 18-24-month-old patients. The aim of this study was to compare soft-tissue and bone surgeries in 18-24-month-old patients with developmental dysplasia of the hip (DDH). A total of 77 hips of 53 patients were analyzed. Soft-tissue surgery was performed in 31 hips of 25 patients. In the final examination, 23 hips, excluding hips of eight patients who underwent secondary bone surgery, were evaluated (group I). Bone surgery was performed on 46 hips of 28 patients (group II). In group I, the acetabular index was 41° preoperatively and was 20.4° in the final examinations. In group II, the acetabular index was 42° preoperatively and was 15° in the final examinations. To avoid unnecessary surgeries and complications, soft-tissue surgery should be preferred for DDH in 18-24-month-old patients. 23799953 Cortical speech sound differentiation in the neonatal intensive care unit predicts cognitive and language development in the first 2 years of life. Neurodevelopmental delay in childhood is common in infants born preterm, but is difficult to predict before infants leave the neonatal intensive care unit (NICU). We hypothesized that event-related potential (ERP) methodology characterizing the cortical differentiation of speech sounds in hospitalized infants would predict cognitive and language outcomes during early childhood. We conducted a prospective study of 57 infants in NICU (34 male, gestational age at birth 24-40wks), quantifying the amplitude of ERP responses to speech sounds before discharge (median gestational age 37.1wks), followed by standardized neurodevelopmental assessments at 12 months and 24 months. Analyses were performed using ordinary least squares linear regression. Overall validity of constructs using all ERP variables, as well as sex, maternal education, gestational age, and age at ERP, was good and allowed significant prediction of cognitive and communication outcomes at 12 months and 24 months (R(2) =22-42%; p<0.05). Quantitative models incorporating specific ERPs, gestational age, and age at ERP explained a large proportion of the variance in cognition and receptive language on the Bayley Scales of Infant Development at 24 months (R(2) >50%; p<0.05). This study establishes ERP methodology as a valuable research tool to quantitatively assess cortical function in the NICU and to predict meaningful outcomes in early childhood. 23559332 Comparison between daily supplementation doses of 200 versus 400 IU of vitamin D in infants. The daily supplementation of vitamin D is mandatory for infants. However, there are still conflicting opinions about the exact daily dose. Thus, we aimed to evaluate a daily supplementation dose of 200 IU is sufficient and compared the supplementation doses of 200 and 400 IU per day. One hundred and sixty-nine infants were randomly assigned to two groups (group1, 200 IU/day; group 2, 400 IU/day) and there were 75 infants in group 1 and 64 were in group 2 with a total number of 139. The median levels of 25-hydroxyvitamin D3 were significantly increased in group 2 at the age of 4 months (group 1, 39.60 mcg/L; group 2, 56.55 mcg/L; p < 0.0001). We clearly demonstrated that at the age of 4 months, none of the infants on the group 2 had a serum level of 25-hydroxyvitamin D3 less than 30 mcg/L. However, 21.3 % of the infants in group 1 had a level below 30 mcg/L. Thus, in order to avoid vitamin D deficiency and rickets, we recommend supplementation dose of vitamin D at 400 IU/day as a safe and effective dose. 23392239 Safety and feasibility of interventional pulmonologists performing bedside percutaneous endoscopic gastrostomy tube placement. Prior to the 1980s, permanent feeding tube placement was limited to an open surgical procedure until Gauderer and colleagues described the safe placement of percutaneous endoscopic gastrostomy (PEG) tubes. This procedure has since expanded beyond the realm of surgeons to include gastroenterologists, thoracic surgeons, and interventional radiologists. In some academic centers, interventional pulmonologists (IPs) also perform this procedure. We describe the safety and feasibility of PEG tube placement by IPs in a critically ill population. Prospectively collected data of patients in a medical ICU undergoing PEG tube placement from 2003 to 2007 at a tertiary-care center were reviewed. Inclusion criteria included all PEG tube insertions performed or attempted by the IP team. Data were collected on mortality, PEG tube removal rate, total number of days with PEG tube, and complication rates. Follow-up included hospital length of stay and phone contact after discharge. Procedural and long-term PEG-related complications were recorded. Seventy-two patients were studied. PEG tube insertion was completed successfully in 70 (97.2%), with follow-up data in 69 of these 70. Thirty-day mortality was 11.7%. No deaths or immediate complications were attributed to PEG tube placement. PEG tube removal occurred in 27 patients, with a median time to removal of 76 days. Bedside PEG tube placement can be performed safely and effectively by trained IPs. Because percutaneous tracheostomy is currently performed by IPs, the ability to place both PEG and tracheostomy tubes at the same time has the potential for decreased costs, anesthesia exposure, procedural times, ventilator times, and ICU days. 23859129 The Effect of Ligand Lipophilicity on the Nanoparticle Encapsulation of Pt(IV) Prodrugs. In an effort to expand the therapeutic range of platinum anticancer agents, several new approaches to platinum-based therapy, including nanodelivery, are under active investigation. To better understand the effect of ligand lipophilicity on the encapsulation of Pt(IV) prodrugs within polymer nanoparticles, the series of compounds cis,cis,trans-[Pt(NH3)2Cl2L2] was prepared, where L = acetate, propanoate, butanoate, pentanoate, hexanoate, heptanoate, octanoate, nonanoate, and decanoate. The lipophilicities of these compounds, assessed by reversed-phase HPLC, correlate with the octanol/water partition coefficients of their respective free carboxylic acid ligands, which in turn affect the degree of encapsulation of the Pt(IV) complex within the hydrophobic core of poly(lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-PEG-COOH) nanoparticles. The most lipophilic compound investigated, cis,cis,trans-[Pt(NH3)2Cl2(O2C(CH2)8CH3)2], displayed the best encapsulation. This compound was therefore selected to evaluate the effect of increased platinum concentration on encapsulation. As the platinum concentration was increased, there was an initial increase in encapsulation followed by a decrease due to macroscopic precipitation. Maximal loading occurred when the platinum complex was present at a 40% w/w ratio with respect to polymer during the nanoprecipitation step. Particles formed under these optimal conditions had diameters of approximately 50 nm, as determined by transmission electron microscopy. 23651123 Clinical features, anger management and anxiety: a possible correlation in migraine children. Psychological factors can increase severity and intensity of headaches. While great attention has been placed on the presence of anxiety and/or depression as a correlate to a high frequency of migraine attacks, very few studies have analyzed the management of frustration in children with headache. Aim of this study was to analyze the possible correlation between pediatric migraine severity (frequency and intensity of attacks) and the psychological profile, with particular attention to the anger management style. We studied 62 migraineurs (mean age 11.2 ± 2.1 years; 29 M and 33 F). Patients were divided into four groups according to the attack frequency (low, intermediate, high frequency, and chronic migraine). Pain intensity was rated on a 3-levels graduate scale (mild, moderate and severe pain). Psychological profile was assessed by Picture Frustration Study test for anger management and SAFA-A scale for anxiety. We found a relationship between IA/OD index (tendency to inhibit anger expression) and both attack frequency (r = 0.328, p = 0.041) and intensity (r = 0.413, p = 0.010). When we analyzed the relationship between anxiety and the headache features, a negative and significant correlation emerged between separation anxiety (SAFA-A Se) and the frequency of attacks (r = -0.409, p = 0.006). In our patients, the tendency to express and emphasize the presence of the frustrating obstacle (EA/OD index) showed a positive correlation with anxiety level (“Total anxiety” scale: r = 0.345; p = 0.033). Our results suggest that children suffering from severe migraine tend to inhibit their angry feelings. On the contrary, children with low migraine attack frequency express their anger and suffer from separation anxiety. 23857662 Immunoserological parameters in SLE: high-avidity anti-dsDNA detected by ELISA are the most closely associated with the disease activity. We assessed the relationship between the serum levels of antibodies against double-stranded DNA (dsDNA), C1q, nucleosomes, histones, C3 and C4 complement components with one another, with organ involvement and overall disease activity in patients with systemic lupus erythematosus (SLE). One hundred seventy-five sera from 99 patients with SLE, 31 sera of patients with other connective tissue diseases, and 20 sera from healthy blood donors were tested. SLE disease activity was assessed by modified SLEDAI-2K (M-SLEDAI-2K), not including complement and anti-dsDNA descriptors. Anti-dsDNA antibodies were measured by indirect immunofluorescence on Crithidia luciliae (CLIFT), standard enzyme-linked immunosorbent assay (ELISA) and ELISA for high-avidity antibodies. The most significant risk factor for renal involvement were anti-C1q antibodies (OR = 3.88, p < 0.05), high-avidity anti-dsDNA antibodies for polyserositis (OR = 7.99, p < 0.01), anti-histone antibodies for joint involvement (OR = 2.75, p < 0.05), and low C3 for cytopenia (OR = 11.96, p < 0.001) and mucocutaneous lesions (OR = 3.32, p < 0.01). Multiple linear regression analysis showed that disease activity in SLE could be predicted by the levels of antibodies against dsDNA determined by standard (p < 0.05) and high-avidity (p < 0.001) ELISA, and inversely associated with concentration of C3 (p < 0.001). Using stepwise method, high-avidity anti-dsDNA antibodies were found to be in the closest association to M-SLEDAI-2K. Moreover, positive test for high-avidity anti-dsDNA antibodies appeared as an independent risk factor for moderately to severely active disease (M-SLEDAI-2K>5) (OR = 5.5, p < 0.01). The presence of high-avidity anti-dsDNA antibodies represented a risk for renal, joint, and most importantly for serosal involvement. Our results suggest that simple and reliable ELISA for high-avidity anti-dsDNA antibodies is the test of good clinical utility for the assessment of global SLE activity. 23647844 Nanomechanical analysis of pigmented human melanoma cells. Based on hitherto measurements of elasticity of various cells in vitro and ex vivo, cancer cells are generally believed to be much softer than their normal counterparts. In spite of significant research efforts on the elasticity of cancer cells, only few studies were undertaken with melanoma cells. However, there are no reports concerning pigmented melanoma cells. Here, we report for the first time on the elasticity of pigmented human melanoma cells. The obtained data show that melanin significantly increases the stiffness of pigmented melanoma cells and that the effect depends on the amount of melanin inside the cells. The dramatic impact of melanin on the nanomechanical properties of cells puts into question widely accepted paradigm about all cancer cells being softer than their normal counterparts. Our findings reveal significant limitations of the nanodiagnosis approach for melanoma and contribute to better understanding of cell elasticity. 23729020 The effect of young age on outcomes in head and neck cancer. Many head and neck surgeons believe that young patients with head and neck cancer (HNCA) have poorer outcomes than older patients, whereas the evidence in the literature is mixed. We sought to review our HNCA population to evaluate for survival differences between young and older patients. Matched pair retrospective cohort study. A matched pair retrospective cohort study was completed of mucosal HNCA patients at our academic center (2003-2008). Patients aged 45 or less when diagnosed were identified as cases and matched one-to-one to controls by site of tumor, stage of disease, and gender. Risk factors, disease and treatment variables, and survival outcomes were compared between groups. In addition, a subset survival analysis was completed with oropharyngeal cancer patients and nonoropharyngeal cancer patients. There were 87 cases matched to 87 controls. Despite no difference in T and N stage between groups, cases more frequently underwent neck dissection. On Kaplan-Meier and multivariate analysis, overall survival was marginally better for all young patients, whereas disease-free survival was significantly better. Within the subgroup analysis, the statistically significant disease-free survival advantage was lost for young patients with oropharyngeal cancer but maintained for all other sites. In this cohort, young HNCA patients had mildly improved overall survival but statistically greater disease-free survival. There was no statistically significant survival difference between young and older patients with oropharyngeal cancer, potentially secondary to a human papillomavirus effect. 2b. Laryngoscope, 123:1896-1902, 2013. 23915389 Fabrication and Characterization of Nanotemplated Carbon Monolithic Material. A novel hierarchical nanotemplated carbon monolithic rod (NTCM) was prepared using a novel facile nanotemplating approach. The NTCM was obtained using C60-fullerene modified silica gels as hard templates, which were embedded in a phenolic resin containing a metal catalyst for localized graphitization, followed by bulk carbonization, and template and catalyst removal. TEM, SEM, and BET measurements revealed that NTCM possessed an integrated open hierarchical porous structure, with a trimodal pore distribution. This porous material also possessed a high mesopore volume and narrow mesopore size distribution. During the course of carbonization, the C60 conjugated to aminated silica was partly decomposed, leading to the formation of micropores. The Raman signature of NTCM was very similar to that of multiwalled carbon nanotubes as exemplified by three major peaks as commonly observed for other carbon materials, i.e., the sp(3) and sp(2) carbon phases coexisted in the sample. Surface area measurements were obtained using both nitrogen adsorption/desorption isotherms (BET) and with a methylene blue binding assay, with BET results showing the NTCM material possessed an average specific surface area of 435 m(2) g(-1), compared to an area of 372 m(2) g(-1) obtained using the methylene blue assay. Electrochemical studies using NTCM modified glassy carbon or boron doped diamond (BDD) electrodes displayed quasi-reversible oxidation/reduction with ferricyanide. In addition, the BDD electrode modified with NTCM was able to detect hydrogen peroxide with a detection limit of below 300 nM, whereas the pristine BDD electrode was not responsive to this target compound. 23937713 Isolation of midgut escape mutants of two American genotype dengue 2 viruses from Aedes aegypti. Several studies have shown that American genotype dengue 2 viruses (DENV2) have reduced viral fitness in the mosquito vector, Aedes aegypti, compared to other DENV2 genotypes. Diminished replication efficiency or inability to efficiently traverse membrane barriers encompassing organs such as the midgut or salivary glands are considered major factors negatively impacting viral fitness in the mosquito. We analyzed the vector competence of Ae. aegypti for two American DENV2 strains, QR94 and PR159 originating from Mexico and Puerto-Rico, respectively. Both strains infected mosquito midguts following acquisition of infectious bloodmeals. However, DENV2-QR94 and DENV2-PR159 poorly disseminated from the midgut at 7 or 14 days post-bloodmeal (pbm). We detected one virus isolate, EM33, among 31 DENV2-QR94 infected mosquitoes, and one isolate, EM41, among 121 DENV2-PR159 infected mosquitoes, generating high virus titers in mosquito carcasses at 7 days pbm. In oral challenge experiments, EM33 and EM41 showed midgut dissemination rates of 40-50%. Replication efficiency of EM41 in secondary mosquito tissue was similar to that of a dissemination-competent control strain, whereas the replication efficiency of EM33 was significantly lower than that of the control virus. The genome sequence of DENV2-QR94 encoded seven unique amino acids (aa), which were not found in 100 of the most closely related DENV2 strains. EM33 had one additional aa change, E202K, in the E protein. DENV2-PR159 encoded four unique aa residues, one of them E202K, whereas EM41 had two additional aa substitutions, Q77E in the E protein and E93D in NS3. Our results indicate that the midgut of Ae. aegypti acts as a selective sieve for DENV2 in which genetically distinct, dissemination-competent virus variants are rapidly selected from the viral quasispecies to be transmitted to vertebrates. 23851367 Reconstruction of the Achilles Tendon and Overlying Skin Defect: 3 Case Reports. Although various reconstruction surgery techniques are available to repair the posterior heel defects, the compound defects reconstruction is an ongoing surgical challenge. Complex, free tissue flaps are often clinically used in this repair operation but the techniques have some disadvantages, including intraoperative tedious dissections, vascular anastomosis, and postoperative thrombogenesis. Here, we present a single-stage procedure for Achilles tendon and its overlying skin defects repair with a complex posterior tibial artery perforator-based tissue flap on 3 patients. This method can repair the Achilles tendon and the soft tissue defects simultaneously in a relatively short operative time. The prognosis of the 3 operative patients described here was great for participating in exercise and daily work unassisted 18 to 26 months after operation. Clinical results indicate that our operative method can be effective in repair of Achilles tendon and its overlying skin defects without major complications. 23356883 Revealing the excited-state dynamics of the fluorescent protein Dendra2. Green-to-red photoconversion is a reaction that occurs in a limited number of fluorescent proteins and that is currently mechanistically debated. In this contribution, we report on our investigation of the photoconvertible fluorescent protein Dendra2 by employing a combination of pump-probe, up-conversion and single photon timing spectroscopic techniques. Our findings indicate that upon excitation of the neutral green state an excited state proton transfer proceeds with a time constant of 3.4 ps between the neutral green and the anionic green states. In concentrated solution we detected resonance energy transfer (25 ps time constant) between green and red monomers. The time-resolved emission spectra suggest also the formation of a super-red species, first observed for DsRed (a red fluorescent protein from the corallimorph species Discosoma) and consistent with peculiar structural details present in both proteins. 23504875 Exposure-Exposure Relationship of Tocilizumab, an Anti-IL-6 Receptor Monoclonal Antibody, in a Large Population of Patients With Rheumatoid Arthritis. Relationships between tocilizumab exposure and response were evaluated using data from 4 phase III studies. Increased tocilizumab exposure was associated with improvements in Disease Activity Score using 28 joints (DAS28) and American College of Rheumatology (ACR) criteria and with a decrease in inflammation markers. A population pharmacokinetic/pharmacodynamic (PKPD) model was developed to describe data from 2 studies. An indirect-response model with a sigmoid Emax (maximal drug effect) inhibitory drug effect on DAS28 "production" rate adequately described the relationship between tocilizumab concentration and DAS28. Mean minimum serum tocilizumab concentration at steady state was greater than the EC50 (concentration at which 50% of Emax on DAS28 is reached) with the 8-mg/kg dose but not with the 4-mg/kgdose. Simulations within a large rheumatoid arthritis (RA) population showed that DAS remission rates were 38% for 8 mg/kg and 24% for 4 mg/kg. Tocilizumab was more potent in RA patients with higher baseline interleukin-6 levels, but this effect was not clinically significant. Other covariates (eg, presence of neutralizing antitocilizumab antibodies) did not demonstrate a clinically meaningful effect on tocilizumab DAS28 dose-response relationships. These data support clinical observations that tocilizumab 8 mg/kg is more effective than 4 mg/kg in reducing disease activity. 23211698 Deep-intronic ATM mutation detected by genomic resequencing and corrected in vitro by antisense morpholino oligonucleotide (AMO). Recent development of next-generation DNA sequencing (NGS) techniques is changing the approach to search for mutations in human genetic diseases. We applied NGS to study an A-T patient in which one of the two expected mutations was not found after DHPLC, cDNA sequencing and MLPA screening. The 160-kb ATM genomic region was divided into 31 partially overlapping fragments of 4-6 kb and amplified by long-range PCR in the patient and mother, who carried the same mutation by segregation. We identified six intronic variants that were shared by the two genomes and not reported in the dbSNP(132) database. Among these, c.1236-405C>T located in IVS11 was predicted to be pathogenic because it affected splicing. This mutation creates a cryptic novel donor (5') splice site (score 1.00) 405 bp upstream of the exon 12 acceptor (3') splice site. cDNA analysis showed the inclusion of a 212-bp non-coding 'pseudoexon' with a premature stop codon. We validated the functional effect of the splicing mutation using a minigene assay. Using antisense morpholino oligonucleotides, designed to mask the cryptic donor splice-site created by the c.1236-405C>T mutation, we abrogated the aberrant splicing product to a wild-type ATM transcript, and in vitro reverted the functional ATM kinase impairment of the patients' lymphoblasts. Resequencing is an effective strategy for identifying rare splicing mutations in patients for whom other mutation analyses have failed (DHPLC, MLPA, or cDNA sequencing). This is especially important because many of these patients will carry rare splicing variants that are amenable to antisense-based correction. 23386252 Prognostic study of sevoflurane-based general anesthesia on cognitive function in children. It is unclear whether volatile general anesthetics have sustained adverse effects on the immature brains of children. We performed a self-controlled study to evaluate the effects of strabismus surgery under sevoflurane-based general anesthesia on the cognitive function of pediatric patients. The study included 100 children of ages 4 to 7 years old scheduled to undergo strabismus correction under sevoflurane-based general anesthesia. Cognitive function was tested 1 day before the operation (T1), 1 month after the operation (T2), and 6 months after the operation by the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) (Third Edition) method, which consists of 150 items. The scores at T1 were compared with scores at T2 and T3. Seventy-two children completed the three tests. At T1, they were 66.1 ± 7.7 months old and had a mean body weight of 21.6 ± 4.0 kg. The mean anesthesia time was 67.3 ± 9.8 min. The mean interval between T1 and T2 was 25.4 ± 6.8 days, and that between T1 and T3 was 182.1 ± 27.7 days. No statistically significant decrease in WPPSI scores was observed between T1 and T2, or between T1 and T3. These findings from our self-controlled study show that sevoflurane-based general anesthesia does not have significantly adverse effects on the cognitive function of 4- to 7-year-old children at 1 month and 6 months after strabismus surgery. Additional studies with a larger sample size are needed. 23580378 Age differences in treatment response to a collaborative care intervention for anxiety disorders. Some data suggest that older adults with anxiety disorders do not respond as well to treatment as do younger adults. We examined age differences in outcomes from the Coordinated Anxiety Learning and Management (CALM) study, an effectiveness trial comparing usual care to a computer-assisted collaborative care intervention for primary care patients with panic disorder, generalised anxiety disorder, post-traumatic stress disorder (PTSD), and/or social anxiety disorder. This is the first study to examine the efficacy of a collaborative care intervention in a sample that included both younger and older adults with anxiety disorders. We hypothesised that older adults would show a poorer response to the intervention than younger adults. We examined findings for the overall sample, as well as within each diagnostic category (clinicaltrials.gov identifier: NCT00347269). The CALM intervention was more effective than usual care among younger adults overall and for those with generalised anxiety disorder, panic disorder and social anxiety disorder. Among older adults, the intervention was effective overall and for those with social anxiety disorder and PTSD but not for those with panic disorder or generalised anxiety disorder. The effects of the intervention also appeared to erode by the 18-month follow-up, and there were no significant effects on remission among the older adults. These results are consistent with the findings of other investigators suggesting that medications and psychotherapy for anxiety disorders may not be as effective for older individuals as they are for younger people. 23837519 Nebulized oil-in-water nanoemulsion mists for pulmonary delivery: development, physico-chemical characterization and in vitro evaluation. Abstract Context: This study presents novel nanostructured oil-in-water (o/w) mists based on self-nanoemulsifying (SNE) mixtures capable of delivering poorly water-soluble drugs into the lungs. Objective: Formulation development of an o/w nanoemulsion (NE) capable of being nebulized for pulmonary delivery of poorly water-soluble drugs. Materials and methods: SNE mixtures were prepared and evaluated using Tween 80 and Cremophor RH 40 as surfactants; Transcutol P, Capryol 90 and PEG 400 as cosurfactants; and Labrafac Lipophile Wl 1349 (a medium-chain triglyceride) as an oil. Liquid NEs were analyzed by light scattering, zeta potential, transmission electron microscopy (TEM) and in vitro drug release studies. The aqueous NE was nebulized and assessed by light scattering and TEM. The formulation was aseptically filtered and the sterility validated. In vitro cytotoxicity of the formulations was tested in NIH 3T3 cells. The capability of the formulation to deliver a poorly water-soluble drug was determined using ibuprofen. Results: Ibuprofen was found to be stable in the NEs. The formulations were neutrally charged with a droplet size of about 20 nm. TEM images displayed 100 nm oil droplets. The aseptic filtration method produced sterile NE. The nebulized mist revealed properties ideal for pulmonary delivery. The biocompatible aerosol has a nanostructure consisting of several oil nanodroplets enclosed within each water drop. Solubility and in vitro drug release studies showed successful incorporation and release of ibuprofen. Conclusion: The developed formulation could be used as an inhalation for delivering material possessing poor water solubility into the lungs. 23912424 Assessing the value of species: a case study on the willingness to pay for species protection in Chile. We conduct a valuation of species protection in central Chile's Campana National Park (CNP) using the choice experiment (CE) method. The CNP has been recognized as having global relevance for the conservation of biological diversity. Specifically, the aim is to estimate the willingness to pay (WTP) of park visitors for protection of different protected species in the area: popular species of flora and fauna that are known by visitors of the park, inconspicuous species (phytofagous, fungus) that are unknown to visitors, and species with conservation problems of which visitors are unaware. We also investigate the WTP for different levels of species biodiversity protection within the sample as the WTP for biodiversity protection is sensitive to the way in which biodiversity is presented to respondents. The levels of species biodiversity protection are represented using "icon" inconspicuous species and numbers of inconspicuous species protected in La Campana National Park. This methodology allowed us to obtain information on the sensitivity of the participants to the scope of the information provided. Overall, visitors attach positive and significant values to the local conservation of species. These values are derived not only from the desire to preserve popular species in the area but also from the preservation or assured existence of inconspicuous species that are protected in the park. Visitors behave as consumers who are sensitive to changes in the price of park admission as a result of the implementation of specific strategies for wildlife conservation management in the park. Furthermore, the study also elucidates the observations that the public is able to perceive biodiversity conservation in broader terms than a single species and that greater benefits are attached to the conservation of multiple species than single ones. Results also provide insights into methodological considerations regarding the conceptual framework used to assess the valuation of biodiversity changes in developing countries, including the level of biological diversity and the scale of the change. 23935978 Contrasting fish behavior in artificial seascapes with implications for resources conservation. Artificial reefs are used by many fisheries managers as a tool to mitigate the impact of fisheries on coastal fish communities by providing new habitat for many exploited fish species. However, the comparison between the behavior of wild fish inhabiting either natural or artificial habitats has received less attention. Thus the spatio-temporal patterns of fish that establish their home range in one habitat or the other and their consequences of intra-population differentiation on life-history remain largely unexplored. We hypothesize that individuals with a preferred habitat (i.e. natural vs. artificial) can behave differently in terms of habitat use, with important consequences on population dynamics (e.g. life-history, mortality, and reproductive success). Therefore, using biotelemetry, 98 white seabream (Diplodus sargus) inhabiting either artificial or natural habitats were tagged and their behavior was monitored for up to eight months. Most white seabreams were highly resident either on natural or artificial reefs, with a preference for the shallow artificial reef subsets. Connectivity between artificial and natural reefs was limited for resident individuals due to great inter-habitat distances. The temporal behavioral patterns of white seabreams differed between artificial and natural reefs. Artificial-reef resident fish had a predominantly nocturnal diel pattern, whereas natural-reef resident fish showed a diurnal diel pattern. Differences in diel behavioral patterns of white seabream inhabiting artificial and natural reefs could be the expression of realized individual specialization resulting from differences in habitat configuration and resource availability between these two habitats. Artificial reefs have the potential to modify not only seascape connectivity but also the individual behavioral patterns of fishes. Future management plans of coastal areas and fisheries resources, including artificial reef implementation, should therefore consider the potential effect of habitat modification on fish behavior, which could have key implications on fish dynamics. 23817821 Thematic analysis of cardiac care patients' explanations for declining contribution to a genomic research-based biobank. Health care delivery systems increasingly ask patients to contribute biological samples for future genomic-based health research during critical care admissions, as the result of genome-based research requirements of unprecedented large sample sizes. Few reports describe patients' perceptions and responses to actual biobanking approaches in clinical settings. A qualitative study was conducted to explore 568 cardiac care patients' explanations of why they declined to contribute their samples to a future genomic research biobank. To (1) identify themes emerging from explanations for declining contribution to the research biobanking initiative and (2) determine how the content informs the stewardship conceptual framework that addresses evidence-based clinical ethics practices in genomic and genetic research biobanking. This qualitative study used an analytic method that combines inductive and deductive approaches to identify themes in patients' explanations for declining to contribute to a research biobank initiative. The hybrid design has relevance to health services research that seeks to develop taxonomy, themes, and theory. Inductive approaches showed that themes of intrusion and autonomy dominated explanations. Deductive approaches affirmed previously proposed elements of a stewardship conceptual framework that addresses ethics in biobanking. Research in understanding patients' perceptions can guide nursing and biobank practices in developing best practices. 23419388 Danshen mediates through estrogen receptors to activate Akt and inhibit apoptosis effect of Leu27IGF-II-induced IGF-II receptor signaling activation in cardiomyoblasts. Post-menopausal women show dramatically increased cardiovascular disease morbidity (CVD). Danshen is used widely in China for the treatment of cardiovascular disorders, including coronary heart disease. Danshen possesses lipid-soluble biologically active components with a structure similar to 17β-estrodiol (E2). This study assesses whether the cardio-protection exerted by Danshen is mediated through the ERs within H9c2 cardiomyoblast cells. Cardiomyoblast cells pretreated with Fulvestrant (ICI 182,780), an estrogen receptor antagonist was applied to investigate the estrogenic activity of Danshen. The Danshen extract preventive effects on Leu27IGF-II-induced IGF-IIR signaling activator and H9c2 cell apoptosis were identified using TUNEL assay, JC-1 staining and Western blot assay. We found that Danshen extract treatments significantly enhanced phosphorylated Akt through estrogen receptor activation to inhibit Leu27IGF-II-induced calcineurin activation and block H9c2 cell apoptosis. Danshen extracts suppressed the IGF-IIR signaling proteins, pro-apoptotic proteins and reversed the mitochondrial membrane instability induced by Leu27IGF-II. However, the cardioprotective properties of Danshen to inhibit Leu27IGF-II-induced cell apoptosis and promote cell survival were attenuated by applying ICI, which suggests that the Danshen cardioprotective effect is mediated through estrogen receptors. All our data indicated that Danshen exerts strong estrogenic activity which can be considered a novel selective estrogen receptor modulator (SERM) against IGF2R signaling that blocks cardiac apoptosis. 23932766 Characterization of the dynamics of fat cell turnover in different bovine adipose tissue depots. In many but not all high producing cows, the energy requirements for milk yield and maintenance exceed energy intake by voluntary feed intake during early lactation. Prioritizing milk secretion, body reserves mainly from adipose tissue are mobilized and imply an increased risk for metabolic diseases. Reducing the energy output via milk by decreasing the milk fat content through feed supplements containing conjugated linoleic acids (CLAs) may attenuate the negative energy balance during this period. In two separate trials, variables characterizing fat cell turnover were investigated in different subcutaneous and visceral fat depots from primiparous heifers (n=25) during early lactation, and subcutaneous fat from non-lactating, over-conditioned heifers (n=12) by immunohistochemistry. The portion of apoptotic adipocytes was consistently greater than that of proliferating cells and preadipocytes; the sporadically observed effects of CLA were limited to visceral fat. Lactating heifers had more apoptosis and less preadipocytes than non-lactating heifers. 23839808 Warfarin initiation nomograms for venous thromboembolism. Venous thromboembolism (VTE) is a common condition in hospital patients. Considerable controversy is ongoing regarding optimal initial warfarin dosing for patients with acute deep venous thrombosis (DVT) and pulmonary embolism (PE). Achieving a therapeutic international normalized ratio (INR) with warfarin as soon as possible is important because this minimizes the duration of parenteral medication necessary to attain immediate anticoagulation, and it potentially decreases the cost and inconvenience of treatment. Although a 5-mg loading-dose nomogram tends to prevent excessive anticoagulation, a 10-mg loading-dose nomogram may achieve a therapeutic INR more quickly. To evaluate the efficacy of a 10-mg warfarin nomogram compared with a 5-mg warfarin nomogram among patients with VTE. The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched January 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 12). The review authors searched PubMed (last searched 10 April 2013) and LILACS (last searched 28 February 2013). In addition, the review authors contacted pharmaceutical companies. Randomized controlled studies comparing warfarin initiation nomograms of 10 and 5 mg in patients with VTE. Two review authors independently assessed trial quality and extracted data. The review authors contacted study authors for additional information. Four trials involving 494 participants were included. Three studies involving 383 participants provided data on the proportion of participants who had achieved a therapeutic INR by day five. Significant benefit of a 10-mg warfarin nomogram was observed (risk ratio [RR] 1.27, 95% confidence interval [CI] 1.05 to 1.54), although with substantial heterogeneity (I(2) = 90%). The review authors analyzed each study separately because it was not possible to perform a subgroup analysis. One study showed significant benefit of a 10-mg warfarin nomogram for the proportion of outpatients with VTE who had achieved a therapeutic INR by day five (RR 1.78, 95% CI 1.41 to 2.25), with the number needed to treat for an additional beneficial outcome (NNTB = 3, 95% CI 2 to 4); another study showed significant benefit of a 5-mg warfarin nomogram in outpatients with VTE (RR 0.58, 95% CI 0.36 to 0.93) with NNTB = 5 (95% CI 3 to 28); a third study showed no difference (RR 1.08, 95% CI 0.65 to 1.80). No difference was observed in recurrent venous thromboembolism (RVTE) at 90 days when the warfarin nomogram of 10 mg was compared with the warfarin nomogram of 5 mg (RR 1.48, 95% CI 0.39 to 5.56); no difference was observed in major bleeding at 14 days (RR 1.69, 95% CI 0.22 to 13.04) and at 90 days (RR 0.62, 95% CI 0.10 to 3.78). No difference was observed in minor bleeding at 14 to 90 days (RR 0.32, 95% CI 0.15 to 1.83) or in length of hospital stay (mean difference [MD] -2.30 days, 95% CI -7.96 to 3.36). In patients with acute thromboembolism (DVT or PE) aged 18 years or older, considerable uncertainty surrounds the use of a 10-mg or a 5-mg loading dose for initiation of warfarin to achieve an INR of 2.0 to 3.0 on the fifth day of therapy. Heterogeneity among analyzed studies limits certainty surrounding optimal warfarin initiation nomograms. 22733434 Long-term arsenic exposure induces histone H3 Lys9 dimethylation without altering DNA methylation in the promoter region of p16(INK4a) and down-regulates its expression in the liver of mice. Long-term exposure of humans to high concentrations of arsenic is associated with an increased risk of cancer. Previous studies have suggested that arsenic exposure promotes tumorigenesis by inducing changes in the expression of tumor-related genes by dysregulating DNA methylation at tumor-related gene loci. However, the causal relationships between epigenetic changes and both arsenic exposure and tumorigenesis are still unclear. In the present study, we investigated whether arsenic can change the expression of tumor-related genes by inducing epigenetic modifications before tumorigenesis. We did so by investigating the effects of long-term arsenic exposure on representative epigenetic modifications, DNA methylation and histone modifications, in the tumor-free normal liver of C57Bl/6 mice. We focused on the tumor-related genes, p16(INK4a) , RASSF1A, Ha-ras and ER-α as target genes, because their expression and promoter methylation status in mice have been reported to be affected by long-term arsenic exposure. The results showed that long-term arsenic exposure induced a significant decrease in expression of p16(INK4a) associated with an increase in level of dimethylated histone H3 lysine 9 (H3K9), a transcription-suppressive histone modification, in the promoter region, but that DNA methylation of the promoter region was unaffected. The results also showed a significant increase in recruitment of H3K9 histone methyltransferase G9a to the promoter after arsenic exposure. These findings suggest that long-term arsenic exposure may induce down-regulation of p16(INK4a) by targeting recruitment of G9a and H3K9 dimethylation without altering DNA methylation before tumorigenesis in the liver. Copyright © 2012 John Wiley & Sons, Ltd. 22878862 Modeling the structure and proton transfer pathways of the mutant His-107-Tyr of human carbonic anhydrase II. We present molecular modeling of the structure and possible proton transfer pathways from the surface of the protein to the zinc-bound water molecule in the active site of the mutant His-107-Tyr of human carbonic anhydrase II (HCAII). No high-resolution structure or crystal structure is available till now for this particular mutant due to its lack of stability at physiological temperature. Our analysis utilizes as starting point a series of structures derived from high-resolution crystal structure of the wild type protein. While many of the structures investigated do not reveal a complete path between the zinc bound water and His-64, several others do indicate the presence of a transient connection even when His-64 is present in its outward conformation. Mutation at the residue 107 also reveals the formation of a new path into the active site. Competing contributions from His-64 sidechain rotation from its outward conformation are also evaluated in terms of optimal path analysis. No indication of a lower catalytic efficiency of the mutant is evident from our results under the condition of thermal stability of the mutant. 23855632 The contribution of dominance and inbreeding depression in estimating variance components for litter size in Pannon White rabbits. In a synthetic closed population of Pannon White rabbits, additive (VA ), dominance (VD ) and permanent environmental (VPe ) variance components as well as doe (bF d ) and litter (bF l ) inbreeding depression were estimated for the number of kits born alive (NBA), number of kits born dead (NBD) and total number of kits born (TNB). The data set consisted of 18,398 kindling records of 3883 does collected from 1992 to 2009. Six models were used to estimate dominance and inbreeding effects. The most complete model estimated VA and VD to contribute 5.5 ± 1.1% and 4.8 ± 2.4%, respectively, to total phenotypic variance (VP ) for NBA; the corresponding values for NBD were 1.9 ± 0.6% and 5.3 ± 2.4%, for TNB, 6.2 ± 1.0% and 8.1 ± 3.2% respectively. These results indicate the presence of considerable VD . Including dominance in the model generally reduced VA and VPe estimates, and had only a very small effect on inbreeding depression estimates. Including inbreeding covariates did not affect estimates of any variance component. A 10% increase in doe inbreeding significantly increased NBD (bF d  = 0.18 ± 0.07), while a 10% increase in litter inbreeding significantly reduced NBA (bF l  = -0.41 ± 0.11) and TNB (bF l  = -0.34 ± 0.10). These findings argue for including dominance effects in models of litter size traits in populations that exhibit significant dominance relationships. 23829469 Induction of ankylosis in the incisor for orthodontic tooth movement in rats. The present research evaluated the induction of ankylosis and the eruption rate in rat incisors, with the aim of achieving stable anchorage for orthodontic tooth movement (OTM) of the molars. Fifteen male Wistar rats were used. In the Experimental group, the right superior incisor of each animal was extracted, denuded of the PDL and the dental papilla, and reimplanted. The Control group was the left superior incisors. The eruption rate was measured at 7, 10, 12, 14, and 16 days after replantation. NiTi closed springs with a 50cN release force were installed for additional 9 days, and the eruption rate was determined. Then, the rats were sacrificed, and ankylosis was examined by microscopic analysis. Differences with P < 0.01 were defined as statistically significant. The eruption rates were 0 and 0.39 mm day(-1) in the Experimental group and Control group, respectively. All incisors of the Experimental group showed ankylosis according to histological analysis. The methodology used to induce ankylosis in this study was effective for anchoring the incisors during the OTM of rat molars, eliminating the undesirable effects consequent to continuous eruption. 23835261 Thermogravimetric-mass spectrometric analysis on combustion of lignocellulosic biomass. Combustion characteristics of biomass main components and three lignocellulosic biomass (fir wood, eucalyptus wood and pine bark) were investigated by thermogravimetric analysis coupled with mass spectrometry. The combustion of biomass was divided into two main steps, devolatilization and char oxidation stage. Heating rate effect was also studied. Generally, the higher the heating rate, the higher the decomposition temperature. Furthermore, the weight loss rate decreased due to particle temperature gradients. Combustion kinetics were studied. Models based on reaction order (Oi), nucleation (Ni) and diffusion (Di) achieved the best fitting to the experimental data. Cellulose oxidation presented the highest activation energies. CO, CO2 and H2O were the main components evolved from combustion. Additionally, light hydrocarbons (CH4 and C2H5) were also present. Finally, nitrogen compounds were in a higher proportion than sulfur compounds being released as primary amines and NOx. 23942346 The effect of statistical learning on internal stimulus representations: Predictable items are enhanced even when not predicted. Statistical learning is the automatic and unconscious learning of environmental regularities and is a basic mechanism of learning in a variety of human perceptual and cognitive domains. Previous studies have mainly focused on the associative mechanisms of statistical learning. However, an unexplored question is whether the internal representations of individual stimuli are altered as their associations are learned. Using a temporal statistical learning paradigm, we examine this question across three experiments and find clear evidence that the internal representations of individual stimuli are differentially altered according to their degree of temporal predictability. These findings complement previous accounts of statistical learning and reveal an enriched mechanism of human learning, such that learning to associate items also enhances the representations of certain items relative to others. 23559039 Analysis of sequence diversity of human metapneumovirus collected from young children with acute respiratory tract infections in South India. Human metapneumovirus (hMPV), which has a global distribution, is an important cause of acute respiratory tract infections, especially in children and immunocompromised patients. We investigated the genetic variability of partial nucleoprotein (N) gene sequences of hMPV strains identified among young children in South India. The sequences of the N gene were compared with previously reported sequences available in the GenBank repository. The results showed that strains are localized in a geographically circumscribed area (topotype). The results also demonstrates that viruses from the same genetic lineage can circulate concurrently within a given location during a given season. The close clustering of the majority of our hMPV isolates indicates that the N gene sequences in the virus population are relatively homogeneous, and suggests temporal rather than geographic variations in the evolutionary pattern. In our study, the majority of the strains belonged to genetic lineage B2 (71.1 %), followed by A2b (18.4 %), A2a (7.9 %), and B1 (2.6 %), demonstrating the presence of 4 of the 5 known genotypes of hMPV. Global alignment of the nucleotide sequences showed that the strains are closely related to sequences from Canada, The Netherlands, and Australasia. Differences at the nucleotide level and the amino acid level were identified. The results provide evidence for the diversity of the N gene of hMPV in samples collected from South India compared with global strains. When investigated for selective pressure, the sequences showed 1 positively selected site and 19 negatively selected sites. These data should prove useful in further investigations of the evolutionary dynamics of hMPV infection. 23647073 Effect of planning for connectivity on linear reserve networks. Although the concept of connectivity is decades old, it remains poorly understood and defined, and some argue that habitat quality and area should take precedence in conservation planning instead. However, fragmented landscapes are often characterized by linear features that are inherently connected, such as streams and hedgerows. For these, both representation and connectivity targets may be met with little effect on the cost, area, or quality of the reserve network. We assessed how connectivity approaches affect planning outcomes for linear habitat networks by using the stock-route network of Australia as a case study. With the objective of representing vegetation communities across the network at a minimal cost, we ran scenarios with a range of representation targets (10%, 30%, 50%, and 70%) and used 3 approaches to account for connectivity (boundary length modifier, Euclidean distance, and landscape-value [LV]). We found that decisions regarding the target and connectivity approach used affected the spatial allocation of reserve systems. At targets ≥50%, networks designed with the Euclidean distance and LV approaches consisted of a greater number of small reserves. Hence, by maximizing both representation and connectivity, these networks compromised on larger contiguous areas. However, targets this high are rarely used in real-world conservation planning. Approaches for incorporating connectivity into the planning of linear reserve networks that account for both the spatial arrangement of reserves and the characteristics of the intervening matrix highlight important sections that link the landscape and that may otherwise be overlooked. El Efecto de la Planeación para la Conectividad en Redes de Reservas Lineales. 22936359 Successful surgical resection of leiomyoma obstructing the trachea. We report a case of 51-year-old woman with a severely airway-obstructing leiomyoma who underwent successful tracheal resection. A preoperative tumor biopsy was avoided not to cause any risk of suffocation. At surgery, an endotracheal intubation distal to the tumor was achieved with a bronchoscopic guidance. A segmental resection of the trachea with a primary end-to-end anastomosis was performed via a half-splitting median sternotomy. Negative surgical margins for tumor were confirmed intraoperatively. Final pathological diagnosis was a primary tracheal leiomyoma. Definitive surgical resection is a treatment of choice for such airway-obstructing, wide-based leiomyoma. Although a bronchoscopic removal of the tumor is an alternative choice, the risks of suffocation, positive surgical margins, and perforation of the trachea need to be carefully discussed if it is considered. 23727675 Comparative study between derivative spectrophotometry and multivariate calibration as analytical tools applied for the simultaneous quantitation of Amlodipine, Valsartan and Hydrochlorothiazide. Four simple, accurate and specific methods were developed and validated for the simultaneous estimation of Amlodipine (AML), Valsartan (VAL) and Hydrochlorothiazide (HCT) in commercial tablets. The derivative spectrophotometric methods include Derivative Ratio Zero Crossing (DRZC) and Double Divisor Ratio Spectra-Derivative Spectrophotometry (DDRS-DS) methods, while the multivariate calibrations used are Principal Component Regression (PCR) and Partial Least Squares (PLSs). The proposed methods were applied successfully in the determination of the drugs in laboratory-prepared mixtures and in commercial pharmaceutical preparations. The validity of the proposed methods was assessed using the standard addition technique. The linearity of the proposed methods is investigated in the range of 2-32, 4-44 and 2-20μg/mL for AML, VAL and HCT, respectively. 23836734 Understanding why patients of low socioeconomic status prefer hospitals over ambulatory care. Patients with low socioeconomic status (SES) use more acute hospital care and less primary care than patients with high socioeconomic status. This low-value pattern of care use is harmful to these patients' health and costly to the health care system. Many current policy initiatives, such as the creation of accountable care organizations, aim to improve both health outcomes and the cost-effectiveness of health services. Achieving those goals requires understanding what drives low-value health care use. We conducted qualitative interviews with forty urban low-SES patients to explore why they prefer to use hospital care. They perceive it as less expensive, more accessible, and of higher quality than ambulatory care. Efforts that focus solely on improving the quality of hospital care to reduce readmissions could, paradoxically, increase hospital use. Two different profile types emerged from our research. Patients in Profile A (five or more acute care episodes in six months) reported social dysfunction and disability. Those in Profile B (fewer than five acute care episodes in six months) reported social stability but found accessing ambulatory care to be difficult. Interventions to improve outcomes and values need to take these differences into account. 23846745 SICOP: identifying significant co-interaction patterns. Interactions between various types of molecules that regulate crucial cellular processes are extensively investigated by high-throughput experiments and require dedicated computational methods for the analysis of the resulting data. In many cases, these data can be represented as a bipartite graph because it describes interactions between elements of two different types such as the influence of different experimental conditions on cellular variables or the direct interaction between receptors and their activators/inhibitors. One of the major challenges in the analysis of such noisy datasets is the statistical evaluation of the relationship between any two elements of the same type. Here, we present SICOP (significant co-interaction patterns), an implementation of a method that provides such an evaluation based on the number of their common interaction partners, their so-called co-interaction. This general network analytic method, proved successful in diverse fields, provides a framework for assessing the significance of this relationship by comparison with the expected co-interaction in a suitable null model of the same bipartite graph. SICOP takes into consideration up to two distinct types of interactions such as up- or downregulation. The tool is written in Java and accepts several common input formats and supports different output formats, facilitating further analysis and visualization. Its key features include a user-friendly interface, easy installation and platform independence. The software is open source and available at cna.cs.uni-kl.de/SICOP under the terms of the GNU General Public Licence (version 3 or later). agnes.horvat@iwr.uni-heidelberg.de or zweig@cs.uni-kl.de. 23864549 In-silico modeling of atrial repolarization in normal and atrial fibrillation remodeled state. Atrial fibrillation (AF) is the most common cardiac arrhythmia, and the total number of AF patients is constantly increasing. The mechanisms leading to and sustaining AF are not completely understood yet. Heterogeneities in atrial electrophysiology seem to play an important role in this context. Although some heterogeneities have been used in in-silico human atrial modeling studies, they have not been thoroughly investigated. In this study, the original electrophysiological (EP) models of Courtemanche et al., Nygren et al. and Maleckar et al. were adjusted to reproduce action potentials in 13 atrial regions. The parameter sets were validated against experimental action potential duration data and ECG data from patients with AV block. The use of the heterogeneous EP model led to a more synchronized repolarization sequence in a variety of 3D atrial anatomical models. Combination of the heterogeneous EP model with a model of persistent AF-remodeled electrophysiology led to a drastic change in cell electrophysiology. Simulated Ta-waves were significantly shorter under the remodeling. The heterogeneities in cell electrophysiology explain the previously observed Ta-wave effects. The results mark an important step toward the reliable simulation of the atrial repolarization sequence, give a deeper understanding of the mechanism of atrial repolarization and enable further clinical investigations. 23924413 Indirect adaptive control of nonlinear systems based on bilinear neuro-fuzzy approximation. In this paper, we investigate the indirect adaptive regulation problem of unknown affine in the control nonlinear systems. The proposed approach consists of choosing an appropriate system approximation model and a proper control law, which will regulate the system under the certainty equivalence principle. The main difference from other relevant works of the literature lies in the proposal of a potent approximation model that is bilinear with respect to the tunable parameters. To deploy the bilinear model, the components of the nonlinear plant are initially approximated by Fuzzy subsystems. Then, using appropriately defined fuzzy rule indicator functions, the initial dynamical fuzzy system is translated to a dynamical neuro-fuzzy model, where the indicator functions are replaced by High Order Neural Networks (HONNS), trained by sampled system data. The fuzzy output partitions of the initial fuzzy components are also estimated based on sampled data. This way, the parameters to be estimated are the weights of the HONNs and the centers of the output partitions, both arranged in matrices of appropriate dimensions and leading to a matrix to matrix bilinear parametric model. Based on the bilinear parametric model and the design of appropriate control law we use a Lyapunov stability analysis to obtain parameter adaptation laws and to regulate the states of the system. The weight updating laws guarantee that both the identification error and the system states reach zero exponentially fast, while keeping all signals in the closed loop bounded. Moreover, introducing a method of "concurrent" parameter hopping, the updating laws are modified so that the existence of the control signal is always assured. The main characteristic of the proposed approach is that the a priori experts information required by the identification scheme is extremely low, limited to the knowledge of the signs of the centers of the fuzzy output partitions. Therefore, the proposed scheme is not vulnerable to initial design assumptions. Simulations on selected examples of well-known benchmarks illustrate the potency of the method. 23047022 Characterisation of acetylcholinesterase release from neuronal cells. Although acetylcholinesterase (AChE) is primarily a hydrolytic enzyme, metabolising the neurotransmitter acetylcholine in cholinergic synapses, it also has some non-catalytic functions in the brain which are far less well characterised. AChE was shown to be secreted or shed from the neuronal cell surface like several other membrane proteins, such as the amyloid precursor protein (APP). Since AChE does not possess a transmembrane domain, its anchorage in the membrane is established via the Proline Rich Membrane Anchor (PRiMA), a transmembrane protein. Both the subunit oligomerisation and membrane anchor of AChE are shared by a related enzyme, butyrylcholinesterase (BChE), the physiological function of which in the brain is unclear. In this work, we have assayed the relative activities of AChE and BChE in membrane fractions and culture medium of three different neuronal cell lines, namely the neuroblastoma cell lines SH-SY5Y and NB7 and the mouse basal forebrain cell line SN56. In an effort to understand the shedding process of AChE, we have used several pharmacological treatments, which showed that it is likely to be mediated in part by an EDTA- and batimastat-sensitive, but GM6001-insensitive metalloprotease, with the possible additional involvement of a thiol isomerase. Cellular release of AChE by SH-SY5Y is significantly enhanced by the muscarinic acetylcholine receptor (mAChR) agonists carbachol or muscarine, with the effect of carbachol blocked by the mAChR antagonist atropine. AChE has been implicated in the pathogenesis of Alzheimer's disease and it has been shown that it accelerates formation and increases toxicity of amyloid fibrils, which have been closely linked to the pathology of AD. In light of this, greater understanding of AChE and BChE physiology may also benefit AD research. 23903597 Improved production of laccase by Daedalea flavida: consideration of evolutionary process optimization and batch-fed culture. The genetic algorithm was used effectively to find the optimal values of eight process variables for the maximum laccase production by Daedalea flavida in a stationary culture. The algorithm was modified suitably to improve laccase production with 18 parallel experiments in 4 generations. A high enzyme titer of 65 % was achieved after the optimization and compared to the titer obtained before optimization. To study the effect of the surface immobilized growth on the enzyme production, the fungus was grown on three solid carriers. When cultured on polymer composite fibers, polyurethane foam, or steel wool, at least 2.5 times more biomass was produced, compared to the biomass produced in support-free growth. On the contrary, the mycelia grown on solid support produced much less laccase than non-adhering mycelia. Four parallel runs of batch-fed cultures were done, using the cell mass of D. flavida to evaluate the influence of four different volumes of medium exchanged on laccase production. For sustainable production of the enzyme, complete exchange of medium was favorable, where the laccase activity increased continuously in six consecutive cycles, though, 50 % exchange of medium produced the maximum laccase in terms of mean enzyme activity obtained in six cycles. 23528290 Hong Kong: embracing a fast aging society with limited welfare. With a noninterventionist government and an ideology emphasizing family self-reliance, yet one of the oldest populations around the world, Hong Kong faces many unresolved policy issues in aging, including public financial support, long-term care, and the lack of health or mental health care policies for older people. Despite funding limitations, research is vibrant and population aging is drawing more researchers into the field. Following a review of some of the major research activities, we conclude with some observations on a few key issues for the field of gerontology to move forward with in Hong Kong. 23861803 Neuroprotective activity of peripherally administered liver growth factor in a rat model of Parkinson's disease. Liver growth factor (LGF) is a hepatic mitogen purified some years ago that promotes proliferation of different cell types and the regeneration of damaged tissues, including brain tissue. Considering the possibility that LGF could be used as a therapeutic agent in Parkinson's disease, we analyzed its potential neuroregenerative and/or neuroprotective activity when peripherally administered to unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. For these studies, rats subjected to nigrostriatal lesions were treated intraperitoneally twice a week with LGF (5 microg/rat) for 3 weeks. Animals were sacrificed 4 weeks after the last LGF treatment. The results show that LGF stimulates sprouting of tyrosine hydroxylase-positive terminals and increases tyrosine hydroxylase and dopamine transporter expression, as well as dopamine levels in the denervated striatum of 6-OHDA-lesioned rats. In this structure, LGF activates microglia and raises tumor necrosis factor-alpha protein levels, which have been reported to have a role in neuroregeneration and neuroprotection. Besides, LGF stimulates the phosphorylation of MAPK/ERK1/2 and CREB, and regulates the expression of proteins which are critical for cell survival such as Bcl2 and Akt. Because LGF partially protects dopamine neurons from 6-OHDA neurotoxicity in the substantia nigra, and reduces motor deficits in these animals, we propose LGF as a novel factor that may be useful in the treatment of Parkinson's disease. 23919158 An ecological genetic delineation of local seed-source provenance for ecological restoration. An increasingly important practical application of the analysis of spatial genetic structure within plant species is to help define the extent of local provenance seed collection zones that minimize negative impacts in ecological restoration programs. Here, we derive seed sourcing guidelines from a novel range-wide assessment of spatial genetic structure of 24 populations of Banksia menziesii (Proteaceae), a widely distributed Western Australian tree of significance in local ecological restoration programs. An analysis of molecular variance (AMOVA) of 100 amplified fragment length polymorphism (AFLP) markers revealed significant genetic differentiation among populations (ΦPT = 0.18). Pairwise population genetic dissimilarity was correlated with geographic distance, but not environmental distance derived from 15 climate variables, suggesting overall neutrality of these markers with regard to these climate variables. Nevertheless, Bayesian outlier analysis identified four markers potentially under selection, although these were not correlated with the climate variables. We calculated a global R-statistic using analysis of similarities (ANOSIM) to test the statistical significance of population differentiation and to infer a threshold seed collection zone distance of ∼60 km (all markers) and 100 km (outlier markers) when genetic distance was regressed against geographic distance. Population pairs separated by >60 km were, on average, twice as likely to be significantly genetically differentiated than population pairs separated by <60 km, suggesting that habitat-matched sites within a 30-km radius around a restoration site genetically defines a local provenance seed collection zone for B. menziesii. Our approach is a novel probability-based practical solution for the delineation of a local seed collection zone to minimize negative genetic impacts in ecological restoration. 23955341 CREB and NF-κB Mediate the Tamoxifen-induced Upregulation of GLT-1 in Rat Astrocytes. Tamoxifen (TX), a selective estrogen receptor modulator, exerts antagonistic effects on breast tissue and is used to treat breast cancer. Recent evidence also suggests it may act as an agonist in brain tissue. Previously, we reported that TX enhanced the expression and function of glutamate transporter (GLT-1) in rat astrocytes, an effect that was mediated by transforming growth factor-α (TGF-α). In order to gain further insight into the mechanisms that mediate TX-induced upregulation of GLT-1 (EAAT2 in humans), we investigated its effect on GLT-1 at the transcriptional level. TX phosphorylated the cAMP response element binding protein (CREB) and recruited CREB to the GLT-1 promoter consensus site. TX effect on astrocytic GLT-1 was attenuated by the inhibition of protein kinase A (PKA), the upstream activator of the CREB pathway. In addition, TX effect on GLT-1 promoter activity was abolished by the inhibition of the NF-kB pathway. Furthermore, TX recruited the NF-kB subunits p65 and p50 to the NF-kB binding domain of the GLT-1 promoter. Mutation of NF-kB (triple, -583/-282/-251) or CRE (-308) sites on the GLT-1 promoter led to significant repression of the promoter activity, but neither mutant completely abolished the TX-induced GLT-1 promoter activity. Mutation of both the NF-kB (-583/-282/-251) and CRE (-308) sites led to a complete abrogation of TX effect on GLT-1 promoter activity. Taken together, our findings establish that TX regulates GLT-1 via CREB and NF-kB pathways. 23453262 Inhibition of proteolysis in histiotrophic nutrition pathways alters DNA methylation and one-carbon metabolism in the organogenesis-stage rat conceptus. Epigenetic modifications, including DNA methylation, contribute to the transcriptional regulation of developmental genes that control growth and differentiation during embryogenesis. The methyl donor, S-adenosylmethionine (SAM), is biosynthesized from methionine and adenosine triphosphate by methionine adenosyltransferase 2a (Mat2a) in the one-carbon (C1) metabolism pathway. SAM biosynthesis requires a steady supply of nutrients, vitamins and cofactors obtained by the developing conceptus through histiotrophic nutrition pathways (HNPs). The visceral yolk sac (VYS) captures proteins and their substrate cargos by receptor-mediated endocytosis and degrades them using lysosomal proteases. We hypothesize that leupeptin, a protease inhibitor, reduces the availability of methionine and C1 substrates, restricting SAM biosynthesis and altering patterns of DNA methylation. Rat conceptuses were exposed to 50 and 100 μM leupeptin in whole embryo culture for periods of 26 h from gestational day (GD) 10 or 6 h on GD11. After 6 h on GD11, the 100-μM leupeptin treatment significantly decreased methionine in embryo (EMB) and VYS, reduced Mat2a protein levels and inhibited Mat2a specific activity, all of which produced a significant 52% reduction of SAM in the VYS. The 50- and 100-μM leupeptin treatments significantly decreased global methylation levels by 6%-9% in EMB and by 11%-15% in VYS following both 6- and 26-h exposure periods. This study demonstrates that HNP disruption alters C1 activity and significantly reduces global DNA methylation during organogenesis. Because epigenetic reprogramming is crucial for normal differentiation and growth, these findings suggest a possible mechanism through which nutrients and environmental factors may alter early developmental regulation. 23929271 Alleviation of exogenous 6-benzyladenine on two genotypes of eggplant (Solanum melongena Mill.) growth under salt stress. Cytokinins were recently shown to control plant adaptation to environmental stresses. To characterize the roles of cytokinins in the tolerance of eggplant (Solanum melongena Mill.) to salt stress, the protective effects of 6-benzyladenine (6-BA) on the growth, photosynthesis, and antioxidant capacity in the leaves of two eggplant cultivars Huqie12 (salt-sensitive) and Huqie4 (salt-tolerant) were investigated. Under 90 mM NaCl stress, Huqie4 showed higher biomass accumulation and less oxidative damage compared to the Huqie12. Application of exogenous 10 Î¼M 6-BA significantly alleviated the growth suppression caused by salt stress in two eggplant genotypes. In parallel with the growth, 6-BA application in salt-stressed plants resulted in enhanced chlorophyll contents, as well as photosynthetic parameters such as net CO2 assimilation rate (P n), stomatal conductance (g s), transpiration rate (E), and intercellular CO2 concentration (C i). Furthermore, exogenous 6-BA also significantly reduced the O2 (-) production rate and malondialdehyde content and markedly increased the antioxidant enzymes superoxide dismutase and peroxidase, the antioxidant metabolites ascorbate and reduced glutathione (GSH), and proline in both genotypes under salt stress. The results indicate that exogenous 6-BA is useful to improve the salt resistance of eggplant, which is most likely related to the increase in photosynthesis and antioxidant capacity. 22918713 Regional variations in early intervention utilization for children with developmental delay. We tested whether state-level variations in early intervention program (EI) participation were consistent with rates of key risk factors for early developmental delay. Based on the results of prior studies, we focused on child poverty and low birth weight as risk factors, included state threshold for EI eligibility by category (classified as broad/moderate or narrow), and aggregated the states into regions. Bivariate analyses were done in SPSS 15.0. All data were for 2009. Results were tested against data for prior years to ascertain whether findings for 2009 were anomalous. Nationally, 2.67 % of the age-eligible population was served in EI (range among states, 1.24-6.51 %). Variation in EI participation was significant at the regional level. Early intervention participation was lowest in the south and highest in the northeast (p < 0.01). Regional variations in low birth weight (p < 0.01) and child poverty (p < 0.01) were also significant. Both were highest in the south. While EI participation varied significantly by state eligibility standards, this factor did not entirely explain variance in utilization. Results for 2009 were representative of multi-year trend data. National EI utilization rates consistently lagged behind need as identified in epidemiologic studies from multiple sources. The results strongly suggest that there is a significant population of infants and toddlers who need but do not receive EI services, especially in the south. 23937570 Measuring the Orientation of Taurine in the Active Site of the Non-Heme Fe(II)/α-Ketoglutarate Dependent Taurine Hydroxylase (TauD) using Electron Spin Echo Envelope Modulation (ESEEM) Spectroscopy. The position and orientation of taurine near the non-heme Fe(II) center of the α-ketoglutarate (α-KG) dependent taurine hydroxylase (TauD) was measured using Electron Spin Echo Envelope Modulation (ESEEM) spectroscopy. TauD solutions containing Fe(II), α-KG, and natural abundance taurine or specifically deuterated taurine were prepared anaerobically and treated with nitric oxide (NO) to make an S=3/2 {FeNO}7 complex that is suitable for robust analysis with EPR spectroscopy. Using ratios of ESEEM spectra collected for TauD samples having natural abundance taurine or deuterated taurine, 1H and 14N modulations were filtered out of the spectra and interactions with specific deuterons on taurine could be studied separately. The Hamiltonian parameters used to calculate the amplitudes and line shapes of frequency spectra containing isolated deuterium ESEEM were obtained with global optimization algorithms. Additional statistical analysis was performed to validate the interpretation of the optimized parameters. The strongest 2H hyperfine coupling was to a deuteron on the C1 position of taurine and was characterized by an effective dipolar distance of 3.90 ± 0.25 Å from the {FeNO}7 paramagnetic center. The principal axes of this C1-2H hyperfine coupling and nuclear quadrupole interaction tensors were found to make angles of 26 ± 5º and 52 ± 17º, respectively, with the principal axis of the {FeNO}7 zero-field splitting tensor. These results are discussed within the context of the orientation of substrate taurine prior to the initiation of hydrogen abstraction. 23912324 Fatty Acid profile of the initial oral biofilm (pellicle): an in-situ study. The first step of bioadhesion on dental surfaces is the formation of the acquired pellicle. This mainly acellular layer is formed instantaneously on all solid surfaces exposed to oral fluids. It is composed of proteins, glycoproteins and lipids. However, information on the lipid composition is sparse. The aim of the present study was to evaluate the fatty acid (FA) profile of the in-situ pellicle for the first time. Furthermore, the impact of rinses with safflower oil on the pellicle's FA composition was investigated. Pellicles were formed in situ on bovine enamel slabs mounted on individual upper jaw splints. The splints were carried by ten subjects over durations of 3-240 min. After comprehensive sample preparation, gas chromatography coupled with electron impact ionization mass spectrometry (GC-EI/MS) was used in order to characterize qualitatively and quantitatively a wide range of FA (C12-C24). The relative FA profiles of the pellicle samples gained from different subjects were remarkably similar, whereas the amount of FA showed significant interindividual variability. An increase in FA in the pellicle was observed over time. The application of rinses with safflower oil resulted in an accumulation of its specific FA in the pellicle. Pellicle formation is a highly selective process that does not correlate directly with salivary composition, as shown for FA. 23467980 Adult-to-adult right-lobe living donor liver transplantation in high model for end-stage liver disease score recipients with hepatitis B virus-related benign liver diseases. We evaluated the safety and efficacy of adult-to-adult right-lobe living donor liver transplantation (ARL-LDLT) in HBV-related benign liver disease recipients with high model for end-stage liver disease (MELD) scores. The subjects of this study were 70 adult patients who underwent ARL-LDLT and 191 who underwent DDLT, for HBV-related end-stage liver diseases, between May 2002 and December 2009. Short-term outcomes were assessed by 30-day mortality and graft loss, parameters indicating graft dysfunction, length of hospital stay, and postoperative complications within 3 months. Long-term transplant outcomes were measured by graft- and patient survival and HBV recurrence rates at 1, 3, and 5 years. There were no differences in donor outcomes or recipient short-term outcomes between the groups, although recipients with a high MELD score (Group H) had a higher incidence of pneumonia. High MELD score versus low MELD score recipients had similar 1-, 3-, and 5-year patient survival rates and post-transplant HBV recurrence rates. In the matched DDLT cases, a similar tendency was observed between group H and group L. ARL-LDLT can be performed safely and effectively in high-MELD score patients with HBV-related benign liver disease; thus, a high MELD score may not contraindicate ARL-LDLT. 23564007 Phylogenetically Diverse Denitrifying and Ammonia-Oxidizing Bacteria in Corals Alcyonium gracillimum and Tubastraea coccinea. To date, the association of coral-bacteria and the ecological roles of bacterial symbionts in corals remain largely unknown. In particular, little is known about the community components of bacterial symbionts of corals involved in the process of denitrification and ammonia oxidation. In this study, the nitrite reductase (nirS and nirK) and ammonia monooxygenase subunit A (amoA) genes were used as functional markers. Diverse bacteria with the potential to be active as denitrifiers and ammonia-oxidizing bacteria (AOB) were found in two East China Sea corals: stony coral Alcyonium gracillimum and soft coral Tubastraea coccinea. The 16S rRNA gene library analysis demonstrated different communities of bacterial symbionts in these two corals of the same location. Nitrite reductase nirK gene was found only in T. coccinea, while both nirK and nirS genes were detected in A. gracillimum, which might be the result of the presence of different bacterial symbionts in these two corals. AOB rather than ammonia-oxidizing archaea were detected in both corals, suggesting that AOB might play an important role in the ammonia oxidation process of the corals. This study indicates that the coral bacterial symbionts with the potential for nitrite reduction and ammonia oxidation might have multiple ecological roles in the coral holobiont, which promotes our understanding of bacteria-mediated nitrogen cycling in corals. To our knowledge, this study is the first assessment of the community structure and phylogenetic diversity of denitrifying bacteria and AOB in corals based on nirK, nirS, and amoA gene library analysis. 23506561 Evaluation of Constituents of Piper retrofractum Fruits on Neurotrophic Activity. Three new compounds, 1-3, together with 22 known compounds, were isolated from the fruits of Piper retrofractum. The structures of the new compounds were elucidated on the basis of spectroscopic data analysis and comparison with literature values. Compound 1 was found to enhance the neurite outgrowth of NGF-mediated PC12 cells at concentrations ranging from 0.1 to 10 μM. 23845108 Genomics analysis of potassium channel genes in songbirds reveals molecular specializations of brain circuits for the maintenance and production of learned vocalizations. A fundamental question in molecular neurobiology is how genes that determine basic neuronal properties shape the functional organization of brain circuits underlying complex learned behaviors. Given the growing availability of complete vertebrate genomes, comparative genomics represents a promising approach to address this question. Here we used genomics and molecular approaches to study how ion channel genes influence the properties of the brain circuitry that regulates birdsong, a learned vocal behavior with important similarities to human speech acquisition. We focused on potassium (K-)Channels, which are major determinants of neuronal cell excitability.Starting with the human gene set of K-Channels, we used cross-species mRNA/protein alignments, and syntenic analysis to define the full complement of orthologs, paralogs, allelic variants, as well as novel loci not previously predicted in the genome of zebra finch (Taeniopygia guttata). We also compared protein coding domains in chicken and zebra finch orthologs to identify genes under positive selective pressure, and those that contained lineage-specific insertions/deletions in functional domains. Finally, we conducted comprehensive in situ hybridizations to determine the extent of brain expression, and identify K-Channel gene enrichments in nuclei of the avian song system. We identified 107 K-Channel finch genes, including 6 novel genes common to non-mammalian vertebrate lineages. Twenty human genes are absent in songbirds, birds, or sauropsids, or unique to mammals, suggesting K-Channel properties may be lineage-specific. We also identified specific family members with insertions/deletions and/or high dN/dS ratios compared to chicken, a non-vocal learner. In situ hybridization revealed that while most K-Channel genes are broadly expressed in the brain, a subset is selectively expressed in song nuclei, representing molecular specializations of the vocal circuitry. Together, these findings shed new light on genes that may regulate biophysical and excitable properties of the song circuitry, identify potential targets for the manipulation of the song system, and reveal genomic specializations that may relate to the emergence of vocal learning and associated brain areas in birds. 22035039 Factors related to quality of life and satisfaction with nasal appearance in patients treated for unilateral cleft lip and palate. Objective : To identify factors related to quality of life (QoL) and satisfaction with nasal appearance among patients treated for unilateral cleft lip and palate (UCLP). Design : Cross-sectional population study with long-term follow-up. Patients/Settings : All patients with UCLP born between 1960 and 1987, treated at Uppsala University Hospital, were invited (n  =  109); 86 (79%) participated. Mean follow-up time was 35 years. Main Outcome Measures : Quality of life was measured with Short Form-36 (SF-36) and analyzed using mental and physical cluster scores (MCS and PCS). Nasal appearance was self-assessed with the "Satisfaction With Appearance" questionnaire and by panel judgment. Multivariate regression analyses explored endogenous factors (age, gender, infancy cleft width, nasal function, nasolabial appearance) and exogenous factors (marital status, number of children, education level, operation method, number of rhinoplasties performed). Results : A larger cleft width in infancy was associated with less satisfaction with nasal appearance as adults. A lower mental health QoL was associated with less satisfaction with nasal appearance. Despite female gender being linked to less satisfaction with nasal appearance, it was associated with higher mental health QoL. Higher resistance during nasal breathing was associated with lower physical health QoL. Conclusions : Gender and infant cleft width may affect QoL and satisfaction with nasal appearance among adults. They are potential predictive factors for satisfaction with nasal appearance and QoL during adulthood. The correlation of nasal function impairment and decreased physical health QoL underlines the importance of treatment of nasal symptoms in these patients. 23294333 A safety study on single intravenous dose of tetrachloro-diphenyl glycoluril [iodogen] dissolved in dimethyl sulphoxide (DMSO). Abstract 1. Iodogen (tetrachloro-diphenyl glycoluril) dissolved in DMSO (dimethyl sulphoxide) appears indispensable in radioiodination of hypericin for a new anticancer strategy. We studied the safety of intravenously administered iodogen/DMSO in mice (n = 132). 2. Median lethal dose (LD(50)) of iodogen/DMSO was determined with doses of 40.0, 50.0, 55.0, 60.0, 65.0 and 70.0 mg/kg. Next, toxicity of iodogen/DMSO at 30.0 mg/kg was evaluated using saline and DMSO as controls. Changes in behaviour, body weight and serum biochemistry were evaluated. Histopathology of lungs, heart, liver and kidney was performed. 3. LD(50) values of iodogen/DMSO were 59.5 mg/kg (95% confidence limits (CI): 54.1-65.4 mg/kg) and 61.0 mg/kg (95%CI: 56.2-66.2 mg/kg) for female and male mice, respectively. Similar to that of control groups, no animal deaths were encountered after iodogen/DMSO administration at 30.0 mg/kg. Body weights over 24 h were not altered in all groups, but significantly higher in iodogen/DMSO and DMSO groups (p < 0.05) 14 d post-injection. Blood urea nitrogen and alkaline phosphatase increased (p < 0.05) in iodogen/DMSO group without clinical symptoms. No pathologies were found by gross and microscopic inspection. 4. A single dose of iodogen/DMSO up to 30.0 mg/kg, over 3000 times the dose in potential human applications, appears safe, with an LD(50) doubling that dose in mice. 23883443 Encapsulation of Clay within Polymer Particles in a High-Solids Content Aqueous Dispersion. By using a two-step polymerization process, it was possible to encapsulate clay platelets within polymer particles dispersed in water. First, seed polymer particles with chemically bonded clay were obtained by batch miniemulsion polymerization. Then, the clay was buried within the particles by the addition of neat monomer in a second step. The final stable dispersions can have a solids content of up to 50 wt %. Transmission electron microscopy images clearly show the presence of clay platelets inside the polymer colloids, although they are not totally exfoliated. The obtained nanocomposites showed an increase in both the storage modulus in the rubbery state and the water resistance as the clay content increases. The approach presented here might be useful for encapsulating other high-aspect ratio nanofillers. 22451347 The anxiolytic potential and psychotropic side effects of an echinacea preparation in laboratory animals and healthy volunteers. We investigated the toxicity, psychotropic side effects and anxiolytic potential of an Echinacea angustifolia extract that produced promising effects in laboratory tests performed earlier. Rats were studied in the elevated plus-maze, conditioned fear, open-field, object recognition and conditioned place preference tests. Toxicity was studied in rats after intragastric administration. The preparation decreased anxiety in the elevated plus-maze and ameliorated contextual conditioned fear. No lethality or behavioural signs of discomfort were noticed in rats treated with 1000 and 3000 mg/kg Echinacea angustifolia. The extract was without effect in tests of locomotion (open-field), memory (object recognition) and rewarding potential (conditioned place preference) within a wide dose range. A pharmacological formulation based on the same E. angustifolia extract was tested in human subjects. One or two tablets per day were administered for 1 week to healthy volunteers scoring high on the State-Trait Anxiety Inventory (STAI). The tablets contained 20 mg of the plant extract. Data were collected using a structured self-assessment diary technique. The high dose (2 tablets per day) decreased STAI scores within 3 days in human subjects, an effect that remained stable for the duration of the treatment (7 days) and for the 2 weeks that followed treatment. The lower dose (1 tablet per day) did not affect anxiety significantly. 23852905 The effect of pulsed electromagnetic radiation from mobile phone on the levels of monoamine neurotransmitters in four different areas of rat brain. The use of mobile phones is rapidly increasing all over the world. Few studies deal with the effect of electromagnetic radiation (EMR) on monoamine neurotransmitters in the different brain areas of adult rat. The aim of the present study was to investigate the effect of EMR on the concentrations of dopamine (DA), norepinephrine (NE) and serotonin (5-HT) in the hippocampus, hypothalamus, midbrain and medulla oblongata of adult rats. Adult rats were exposed daily to EMR (frequency 1800 MHz, specific absorption rate 0.843 W/kg, power density 0.02 mW/cm2, modulated at 217 Hz) and sacrificed after 1, 2 and 4 months of daily EMR exposure as well as after stopping EMR for 1 month (after 4 months of daily EMR exposure). Monoamines were determined by high performance liquid chromatography coupled with fluorescence detection (HPLC-FD) using their native properties. The exposure to EMR resulted in significant changes in DA, NE and 5-HT in the four selected areas of adult rat brain. The exposure of adult rats to EMR may cause disturbances in monoamine neurotransmitters and this may underlie many of the adverse effects reported after EMR including memory, learning, and stress. 23896305 Mortality among clients seeking treatment for buprenorphine abuse in Finland. It is unclear whether buprenorphine abuse is associated with a similar risk of death to other substance abuse. This study examined all-cause mortality rates and causes of deaths among clients seeking treatment for buprenorphine abuse. Structured clinical interviews were conducted with 4685 clients between January 1998 and August 2008. Records of deaths that occurred among these clients were extracted from the Official Causes of Death Register in Finland. Standardized mortality ratios (SMRs) with 95% confidence intervals (CI) were computed using national mortality rates over a 13-year follow-up to examine excess mortality. Kaplan-Meier survival analysis was used to compare survival between buprenorphine and other clients. Sixty-one of 780 (7.8%) clients who sought treatment for buprenorphine abuse and 408 of 3905 (10.4%) other clients died during the 13-year follow-up period. The most common cause of death was drug-related in buprenorphine (n=25, 41.0%) and other clients (n=142, 34.8%). Survival rates were similar among buprenorphine and other clients (log-rank χ[df=1](2)=0.215, p=0.643). The SMR was 3.0 (95% CI 2.3-3.8) and 3.1 (95% CI 2.8-3.4) for buprenorphine and other clients, respectively. Excess mortality was highest among women aged 20-29 years, and more pronounced in buprenorphine clients (SMR 27.9 [95% CI 12.6-49.0]) compared to other clients (SMR 14.0 [95% CI 9.3-19.6]). Clients seeking treatment for buprenorphine abuse had a three times higher mortality rate than the national average, with the excess risk highest among female clients. Overall mortality rates were similar among clients seeking treatment for buprenorphine and other substance abuse. 23246355 Dual action spirobicycloimidazolidine-2,4-diones: antidiabetic agents and inhibitors of aldose reductase-an enzyme involved in diabetic complications. The desired 3-(arylsulfonyl)spiroimidazolidine-2,4-diones were synthesized by reacting spiroiminoimidazolidine-2,4-dione with arylsulfonyl chlorides. Spiroimidazolidine-2,4-dione was in turn synthesized from norcamphor. Structures of the synthesized molecules were established by modern spectroscopic techniques. The synthesized compounds were screened for in vivo antidiabetic activity and aldose reductase inhibition. Compounds 2a, 2b and 2g exhibited excellent dual activity, compound 2a being most prominent. These results reveal that the synthesized compounds may serve as the molecule of choice to treat diabetes and diabetic complications using a single medication. 23969353 Primary Care, the ROAD Less Traveled: What First-Year Medical Students Want in a Specialty. Medical students are increasingly choosing non-primary-care specialties. Students consider lifestyle in selecting their specialty, but how entering medical students perceive lifestyle is unknown. This study investigates how first-year students value or rate lifestyle domains and specialty-selection characteristics and whether their ratings vary by interest in primary care (PC). During the 2012-2013 academic year, the authors conducted a cross-sectional survey of first-year medical students from 11 MD-granting medical schools. Using a five-point Likert-type scale (1 = not important at all; 5 = extremely important), respondents rated the importance of 5 domains of good lifestyle and 21 characteristics related to specialty selection. The authors classified students into five groups by PC interest and assessed differences by PC interest using one-way analysis of variance. Of 1,704 participants, 1,020 responded (60%). The option "type of work I am doing" was the highest-rated lifestyle domain (mean 4.8, standard deviation [SD] 0.6). "Being satisfied with the job" was the highest-rated specialty-selection characteristic (mean 4.7, SD 0.5). "Availability of practice locations in rural areas" was rated lowest (mean 2.0, SD 1.1). As PC interest decreased, the importance of "opportunities to work with underserved populations" also decreased, but importance of "average salary earned" increased (effect sizes of 0.98 and 0.94, respectively). First-year students valued enjoying work. The importance of financial compensation was inversely associated with interest in PC. Examining the determinants of enjoyable work may inform interventions to help students attain professional fulfillment in PC. 23073818 Methods to diagnose acute anterior cruciate ligament rupture: a meta-analysis of instrumented knee laxity tests. The aims of this meta-analysis were to determine the sensitivity and specificity of the KT 1000 Arthrometer, Stryker Knee Laxity Tester and Genucom Knee Analysis System for ACL rupture. It was hypothesized that the KT 1000 test is the most sensitive and specific. Secondly, it was hypothesized that the sensitivity and specificity of the KT 1000 arthrometer increase when the amount of Newton force is increased. An electronic database search was performed using MEDLINE and EMBASE. All cross-sectional and cohort studies comparing one or more instrumented examination tests for diagnosing acute complete ACL rupture in living human subjects to an accepted reference standard such as arthroscopy, arthrotomy and MRI were included. The sensitivity of the KT 1000 Arthrometer with 69 N was 0.54. With 89 N, the sensitivity was 0.78 and the specificity 0.92, and with maximum manual force, the sensitivity was 0.93 and the specificity 0.93. For the Stryker Knee Laxity Tester, the sensitivity was 0.82 and the specificity 0.90. And for the Genucom Knee Analysis System, the sensitivity was 0.74 and the specificity 0.82. The KT Arthrometer performed with maximum manual force has the highest sensitivity, specificity, accuracy and positive predictive value for diagnosing ACL rupture. Meta-analysis, Level I. 23954266 Linking phospholipase C isoforms with differentiation function in human vascular smooth muscle cells. The phosphoinositol-phospholipase C (PLC) family of enzymes consists of a number of isoforms, each of which has different cellular functions. PLCγ1 is primarily linked to tyrosine kinase transduction pathways, whereas PLCδ1 has been associated with a number of regulatory proteins, including those controlling the cell cycle. Recent studies have shown a central role of PLC in cell organisation and in regulating a wide array of cellular responses. It is of importance to define the precise role of each isoform, and how this changes the functional outcome of the cell. Here we investigated differences in PLC isoform levels and activity in relation to differentiation of human and rat vascular smooth muscle cells. Using Western blotting and PLC activity assay, we show that PLCδ1 and PLCγ1 are the predominant isoforms in randomly cycling human vascular smooth muscle cells (HVSMCs). Growth arrest of HVSMCs for seven days of serum deprivation was consistently associated with increases in PLCδ1 and SM α-actin, whereas there were no changes in PLCγ1 immuno-reactivity. Organ culture of rat mesenteric arteries in serum free media (SFM), a model of de-differentiation, led to a loss of contractility as well as a loss of contractile proteins (SM α-actin and calponin) and PLCδ1, and no change in PLCγ1 immuno-reactivity. Taken together, these data indicate that PLCδ1 is the predominant PLC isoform in vascular smooth muscle, and confirm that PLCδ1 expression is affected by conditions that affect the cell cycle, differentiation status and contractile function. 22709946 Enhanced mGlu5-receptor dependent long-term depression at the Schaffer collateral-CA1 synapse of congenitally learned helpless rats. Alterations of the glutamatergic system have been implicated in the pathophysiology and treatment of major depression. In order to investigate the expression and function of mGlu5 receptors in an animal model for treatment-resistant depression we used rats bred for congenital learned helplessness (cLH) and the control strain, bred for resistance against inescapable stress, congenitally. not learned helpless rats (cNLH). Western blot analysis showed an increased expression of mGlu5 (but not mGlu1a) receptors in the hippocampus of cLH rats, as compared with control cNLH rats. We also examined mGlu1/5 receptor signaling by in vivo measurement of DHPG-stimulated polyphosphoinositides hydrolysis. Stimulation of (3)H-inositolmonophosphate formation induced by i.c.v. injection of DHPG was enhanced by about 50% in the hippocampus of cLH rats. Correspondingly, DHPG-induced long-term depression (LTD) at Schaffer collateral/CA1 pyramidal cell synapses was amplified in hippocampal slices of cLH rats, whereas LTD induced by low frequency stimulation of the Schaffer collaterals did not change. Moreover, these effects were associated with decreased basal dendritic spine density of CA1 pyramidal cell in cLH rats. These data raise the attractive possibility that changes in the expression and function of mGlu5 receptors in the hippocampus might underlie the changes in synaptic plasticity associated with the depressive-like phenotype of cLH rats. However, chronic treatment of cLH rats with MPEP did not reverse learned helplessness, indicating that the enhanced mGlu5 receptor function is not the only player in the behavioral phenotype of this genetic model of depression. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23518276 Tricyclic thiazoles are a new class of angiogenesis inhibitors. Tricyclic thiazoleamine derivatives that were identified as hits in a screen against human umbilical vein endothelial cell proliferation were subjected to a structure-activity relationship study. Two structurally superimposable scaffolds-4H-thiochromeno[4,3-d]thiazol-2-amine and 5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-d]thiazol-2-amine derivatives-yielded low-micromolar inhibitors, and two among them 37 and 43 also exhibited antiangiogenic activity in an endothelial tube formation assay. Thus, 37 and 43 can serve as leads to develop a novel class of antiangiogenic agents. 23948053 Investigation on characteristics of leachate and concentrated leachate in three landfill leachate treatment plants. Concentrated leachate from membrane treatment processes is a potential pollution source for the surroundings. In this study, with comparison of the landfill leachate, chemical and microbial characteristics of concentrated leachate including biodegradability, amount of nitrogenous compounds and heavy metals, dissolved organic matter composition, and microbial community were investigated in three landfill leachate treatment plants. The results showed that hydrophilic (HyI) fraction was the major dissolved organic carbon in the landfill leachates, accounting for 54.6-60.7%, while humic substances including humic acid (HA) and fulvic acid (FA) were relatively higher in the concentrated leachates, ranging from 61.7% to 69.2%. Conjugated nitrogen existed mainly in FA and HyI in the concentrated leachates. The analysis of excitation emission matrix fluorescence spectroscopy, specific ultraviolet absorbance at 254nm (SUVA254) and GC/MS showed that aromatic compounds, long-chain hydrocarbons and halohydrocarbons were abundant in the concentrated leachates. During landfill leachate treatment processes, Cl(-), SO4(2-) and heavy metals were commonly accumulated in the concentrated leachates. NO3(-)N and/or NH4(+)N were the major nitrogenous compounds in the concentrated leachates. All the leachates from three landfill sites contained toluene in the range of 44.5-728.4μgL(-1). Ethylbenzene, chlorobenzene, and the phthalic acid esters including dibutyl phthalate, dimethyl phthalate and di-n-octyl phthalate were also detected in the concentrated leachates. Higher microbial diversity was observed in the concentrated leachate in comparison with landfill leachate. 23873694 Nuclear genes with sex bias in Ruditapes philippinarum (Bivalvia, veneridae): Mitochondrial inheritance and sex determination in DUI species. Mitochondria are inherited maternally in most metazoans, but in bivalves with Doubly Uniparental Inheritance (DUI) a mitochondrial lineage is transmitted through eggs (F-type), and another through sperm (M-type). In DUI species, a sex-ratio distortion of the progeny was observed: some females produce a female-biased offspring (female-biased family), others a male-biased progeny (male-biased family), and others a 50:50 sex-ratio. A peculiar segregation pattern of M-type mitochondria in DUI organisms appears to be correlated with the sex bias of these families. According to a proposed model for the inheritance of M-type mitochondria in DUI, the transmission of sperm mitochondria is controlled by three nuclear genes, named W, X, and Z. An additional S gene with different dosage effect would be involved in sex determination. In this study, we analyzed structure and localization of three transcripts (psa, birc, and anubl1) with specific sex and family biases in the Manila clam Ruditapes philippinarum. In situ hybridization confirmed the localization of these transcripts in gametogenic cells. In other animals, homologs of these genes are involved in reproduction and ubiquitination. We hypothesized that these genes may have a role in sex determination and could also be responsible for the maintenance/degradation of spermatozoon mitochondria during embryo development of the DUI species R. philippinarum, so that we propose them as candidate factors of the W/X/Z/S system. J. Exp. Zool. (Mol. Dev. Evol.) 9999B: 1-13, 2013. © 2013 Wiley Periodicals, Inc. 23449203 Particle condition change in emulsion admixture evaluated by in situ flow particle imaging analysis. We evaluated the particle state change in emulsion admixtures using in situ flow particle imaging analysis (FPIA). Ropion® intravenous (flurbiprofen axetil: Ropion®) served as the model emulsion formulation. A binary mixture of Ropion® and normal saline (NS), and a ternary admixture of Ropion®, NS, and Gaster® injection (famotidine: Gaster®) or Primperan® injection (metoclopramide hydrochloride: Primperan®) were prepared and the change in emulsion particle state was analyzed using FPIA under in situ condition. The effect of storage on pH change and the chemical stability of flurbiprofen axetil were also investigated. In Ropion®, various particle images (mean diameter: 2.4 µm) were obtained. From our analysis of changes in scattergrams and particle images, changing behaviors of emulsion particles as a function of storage time depended on the systems of admixture samples. In Ropion®/NS and Ropion®/Gaster®/NS systems, mean particle size and particle number increased with lengthening storage time; however, these values were dramatically increased beyond 6 h in the Ropion®/Primperan®/NS system, corresponding to a decrease in measured pH. The decomposition of flurbiprofen axetil due to incompatibility was not observed in all systems. Detailed information on the change in emulsion particle state was obtained using FPIA, indicating that this method is useful to evaluate state changes in emulsion admixtures under in situ condition. 23203004 BRAF (V600E) associates with cytoplasmatic localization of p27kip1 and higher cytokeratin 19 expression in papillary thyroid carcinoma. The genetic alterations are responsible for the altered protein expression in tumors. The knowledge of the link between the altered protein expression and genetic alterations may provide potentially important biological and clinical information. In this study, the expression of some protein markers (Gal-3, p21Kip1, CK19) known to be associated to the papillary thyroid carcinoma (PTC) was assessed in a series of surgical samples by immunohistochemistry, and the association between expression of these markers and the BRAF (V600E) mutation was investigated. Gal-3 positive staining was evident in 26 % of benign nodules. The BRAF (V600E) mutation and Gal-3 expression, were found in 55.5 and 87 % of PTC respectively, and were unlinked. The expression of CK19 in benign nodules was weak and limited to scattered follicular cells. Diffuse cytoplasmatic expression of CK19 was present in malignant tumors in a variable percentage of cells. A higher percentage of CK19 expressing cells was associated with BRAF (V600E) (P â‰¤ 0.001). All benign nodules displayed nuclear p27kip1 in more than 15 % of the cells. Twenty-nine PTC showed a cytoplasmatic staining with negative nuclei. PTC with cytoplasmatic or 0-5 % of cells with nuclear staining, 6-15 % or >15 % of cells with nuclear staining were 72 (66.7 %), 24 (22.2 %), and 12 (11.1 %) respectively. In BRAF (V600E) positive tumors, the cytoplasmatic localization of p27kip1 was significantly more frequent (P = 0.024). In conclusion, we provide evidences that BRAF (V600E) is non-associated with Gal-3 expression, whereas it is associated with cytoplasmatic localization of p27kip1 and higher CK19 expression in PTC. 23567033 Identification of active compounds from Caesalpinia sappan L. extracts suppressing IL-6 production in RAW 264.7 cells by PLS. ETHNOPHARMACOLOGICAL RELEVANCE: Caesalpinia sappan L. is distributed in Southeast Asia and also used as herbal medicine for the treatment of various diseases such as burning sensations, leprosy, dysentery, osteoarthritis and rheumatoid arthritis (RA). The overproduction of IL-6 plays an important role in the prognosis of RA, but the active compounds from the extracts of Caesalpinia sappan L. suppressing IL-6 production remain unknown. AIMS OF THE STUDY: Identifying the main active compounds of Caesalpinia sappan L. extracts inhibiting the IL-6 production in LPS-stimulated RAW 264.7 cells by partial least squares (PLS). MATERIALS AND METHODS: Sixty-four samples with different proportions of compounds were prepared from Caesalpinia sappan L. by supercritical CO2 fluid extraction (SCFE) and refluxing. Each of 64 samples was applied to RAW 264.7 cells with LPS to evaluate whether IL-6 production by LPS is affected by addition of each sample. The IL-6 production in medium was determined by ELISA and the inhibitory activity of each sample was analyzed. In addition, the fingerprints of these 64 samples were also established by ultra-performance liquid chromatography electrospray ionization tandem mass spectrometry (UPLC-MS). We used the PLS, a simplified method, to evaluate the results from IL-6 production and fingerprints. RESULTS: Each of 64 samples markedly suppressed LPS-induced IL-6 production in RAW cells. The fingerprints by UPLC-MS clearly revealed variations among 64 samples produced in different extract conditions. The PLS analysis with IL-6 production and fingerprints by UPLC-MS suggested that the peaks 71, 93, 150, 157, 168 have more influence on the inhibitory activity of Caesalpinia sappan L. extracts. The peaks 71, 93, 150 are likely representing sappanone A, protosappanin E and neoprotosappanin, respectively. The peaks 157 and 168 are still at large. CONCLUSION: This is the first report that sappanone A, protosappanin E, neoprotosappanin and two unidentified compounds can be considered as possible active compounds that might inhibit IL-6 production. Further studies are needed to confirm the effectiveness of these five compounds on IL-6 production and possible mechanism. 23844156 Smokers' decision making: more than mere risk taking. The fact that smoking is bad for people's health has become common knowledge, yet a substantial amount of people still smoke. Previous studies that sought to better understand this phenomenon have found that smoking is associated with the tendency to take risk in other areas of life as well. The current paper explores factors that may underlie this tendency. An experimental analysis shows that smokers are more easily tempted by immediate high rewards compared to nonsmokers. Thus the salience of risky alternatives that produce large rewards most of the time can direct smokers to make bad choices even in an abstract situation such as the Iowa Gambling Task. These findings suggest that the risk taking behavior associated with smoking is not related to the mere pursuit of rewards but rather reflects a tendency to yield to immediate temptation. 23471964 Tumor-suppressive Maspin Functions as a Reactive Oxygen Species Scavenger: IMPORTANCE OF CYSTEINE RESIDUES. Maspin is a member of the serine protease inhibitor (serpin) superfamily and displays tumor-suppressing activity by controlling cell migration, proliferation, apoptosis, and adhesion. Here, we provide evidence that maspin acts as a reactive oxygen species (ROS) scavenger through oxidation of three structurally exposed cysteine thiols to sulfenic acid. Ablation of these cysteine residues in maspin resulted in a significant increase in total ROS production in mouse mammary TM40D cells. Also, cells containing a triple-cysteine mutant of maspin showed elevated ERK1/2 activity, a downstream target of ROS, and enhanced proliferation and colony formation. These findings establish a novel mechanism by which maspin utilizes its cysteine thiols to inhibit oxidative stress and cell growth. 23746460 Toward a cross-species understanding of empathy. Although signs of empathy have now been well documented in non-human primates, only during the past few years have systematic observations suggested that a primal form of empathy exists in rodents. Thus, the study of empathy in animals has started in earnest. Here we review recent studies indicating that rodents are able to share states of fear, and highlight how affective neuroscience approaches to the study of primary-process emotional systems can help to delineate how primal empathy is constituted in mammalian brains. Cross-species evolutionary approaches to understanding the neural circuitry of emotional 'contagion' or 'resonance' between nearby animals, together with the underlying neurochemistries, may help to clarify the origins of human empathy. 23754554 Dietary zinc intake is inversely associated to metabolic syndrome in male but not in female urban adolescents. To evaluate the relationship of copper and zinc dietary intakes with metabolic syndrome (MetS) in adolescents. The sample consisted of 1,311 adolescents aged 11-16 years, and MetS definition by de Ferranti et al. was used. Nutritional intakes, anthropometrical and biochemical markers were measured. In males, highest quartile of zinc intake was inversely associated with MetS without and with adjustment by covariables. Without adjustment, highest quartile of copper intake was inversely associated (marginal significance) with MetS, but with adjustment, the relationship was not maintained. Likewise in male gender, elevated waist circumference was the only MetS component inversely associated with highest quartiles of zinc (without and with adjustment) and copper (significant in crude analysis and marginal significant in adjustment by covariables) intakes. In the girls, only waist circumference was significant and inversely associated with highest quartiles of zinc and copper intakes but the association did not remain significant after adjustments. In the adolescents of this study, zinc intake could be more associated to a clustering of anthropometric, vascular, and metabolic alterations than to these alterations separately, and also it is inversely related to this clustering (MetS). However, studies in other populations are necessary to confirm and explain the finding of exclusive association zinc intake-MetS in male gender adolescents. Further research is required to explore biomarkers of physiological processes (antioxidant function, blood flow regulation, and epigenetic modulation dependent of zinc) in relation to zinc intake and MetS in pediatric and adult populations. 23351005 Copper(I)-catalyzed borylative exo-cyclization of alkenyl halides containing unactivated double bond. A borylative exo-cyclization of alkenyl halides has been reported. The reaction includes the regioselective addition of a borylcopper(I) intermediate to unactivated terminal alkenes, followed by the intramolecular substitution of the resulting alkylcopper(I) moiety for the halide leaving groups. Experimental and theoretical investigations of the reaction mechanism have also been described. This reaction provides a new method for the synthesis of alkylboronates containing strained cycloalkyl structures from simple starting materials. 23714094 Haplotypes associated with resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum in two malaria endemic locations in Colombia. Colombia has four main malaria transmission zones. In vivo efficacy studies carried out in these areas showed big differences in the response of Plasmodium falciparum to treatment with sulphadoxine-pyrimethamine. In addition, there is still insufficient information about the genetics of P. falciparum populations. The objective of this study was to determine the haplotypes in dhfr and dhps genes of P. falciparum circulating in two distinct endemic zones. Samples from patients with non-complicated P. falciparum malaria were collected: 135 from Tumaco and 206 from Tierralta. Alleles 108 and 51 of the dhfr gene, and 437 and 540 of the dhps gene were analyzed by PCR/enzymatic restriction, while alleles 59 and 164 (dhfr), and 581(dhps) by PCR/dot blot/hybridization. Five different haplotypes were found, of which the triple mutant 51I/C59/108N/I164/437G/K540/A581 was the most frequent (54.6%). In Tumaco, the parasites with wild haplotype predominated, while mutant parasites predominated in Tierralta. Another interesting finding is the presence of the C59R mutation in the dhfr gene in two samples, a mutation rarely found in South America. These data provide information about parasite population genetics and highlight the importance of starting a long term molecular surveillance program. 23856008 Sagittal abdominal diameter shows better correlation with cardiovascular risk factors than waist circumference and BMI. Obesity (abdominal adiposity) is a risk factor for cardiovascular diseases and the most used methods to measure the adiposity are body mass index (BMI), waist circumference (WC), and sagittal abdominal diameter (SAD). To correlate BMI, WC, and SAD with biochemical parameters and blood pressure in adults. A non-experimental exploratory/descriptive and cross sectional study was developed and it was assessed 133 subjects (59 men and 74 women) aging between 18 and 87 years. It was registered the patients' weight (kg), height (m), BMI (kg/m2), WC (cm) and SAD (cm), and these parameters were correlated with glycemia, triglycerides, total cholesterol, HDL-c, LDL-c and blood pressure. After adjustment for gender and age, it was observed a positive correlation between SAD and systolic arterial blood pressure (r = 0.20), glycemia (r = 0.20), triglycerides (r = 0.32), LDL (r = 0.26), total cholesterol (TC) (r = 0.33), and a negative correlation with HDL-c (r = -0.21) (p < 0.05). It was observed a positive correlation between WC and systolic arterial blood pressure (r = 0.14), triglycerides (r = 0.31), total cholesterol (r = 0.21), and a negative correlation with HDL-c (r = -0.24) (p < 0.05). BMI showed a positive correlation with systolic arterial blood pressure (r = 0.22), total cholesterol (r = 0.20), and triglycerides (r = 0.23) (p < 0.05). SAD correlated with almost all the cardiovascular risk factors analyzed and it might be considered the best predictor of abdominal fat and cardiovascular risk. 23500116 Analysis of the enhanced oral bioavailability of fenofibrate lipid formulations in fasted humans using an in vitro-in silico-in vivo approach. Lipid-based formulations have established a significant role in the formulation of poorly soluble drugs for oral administration. In order to better understand their potential advantages over solid oral dosage forms, we studied the solubility and dissolution/precipitation characteristics of three self-microemulsifying drug delivery system (SMEDDS) formulations and one suspension of micronized fenofibrate in lipid excipients, for which pharmacokinetic studies had already been reported in the open literature. The in vitro dispersion/dissolution studies were carried out in biorelevant media using USP II apparatus. These were followed up by in silico simulations using STELLA® software, in which not only dispersion/dissolution, but also the precipitation and re-dissolution of fenofibrate was taken into account. While unformulated drug exhibited poor solubility (0.22μg/mL in FaSSGF and 4.31μg/mL in FaSSIF-V2(PO4)) and dissolved less than 2% in dissolution tests, the solubility of fenofibrate in the presence of the lipid excipients increased dramatically (e.g., to 65.44μg/mL in the presence of the Myritol 318/TPGS/Tween 80 SMEDDS) and there was an attendant increase in the dissolution (over 80% from capsules containing the Myritol 318/TPGS/Tween 80 SMEDDS and about 20% from the dispersion of fenofibrate in lipid excipients). For the four lipid-based fenofibrate formulations studied, combining in vitro data in biorelevant media with in silico simulation resulted in accurate prediction of the in vivo human plasma profiles. The point estimates of Cmax and AUC ratio calculated from the in silico and in vivo plasma profiles fell within the 0.8-1.25 range for the SMEDDS solution and capsule formulations, suggesting an accurate simulation of the in vivo profiles. This similarity was confirmed by calculation of the respective f2 factors. Sensitivity analysis of the simulation profiles revealed that the SMEDDS formulations had virtually removed any dependency of absorption on the dissolution rate in the small intestine, whereas for the dispersion in lipid excipients, this barrier remained. Such results pave the way to optimizing the performance of oral lipid-based formulations via an in vitro-in silico-in vivo approach. 23935571 Essentials of psychoanalytic process and change: how can we investigate the neural effects of psychodynamic psychotherapy in individualized neuro-imaging? The paper focuses on the essentials of psychoanalytic process and change and the question of how the neural correlates and mechanisms of psychodynamic psychotherapy can be investigated. The psychoanalytic approach aims at enabling the patient to "remember, repeat, and work through" concerning explicit memory. Moreover, the relationship between analyst and patient establishes a new affective configuration which enables a reconstruction of the implicit memory. If psychic change can be achieved it corresponds to neuronal transformation. Individualized neuro-imaging requires controlling and measuring of variables that must be defined. Two main methodological problems can be distinguished: the design problem addresses the issue of how to account for functionally related variables in an experimentally independent way. The translation problem raises the question of how to bridge the gaps between different levels of the concepts presupposed in individualized neuro-imaging (e.g., the personal level of the therapist and the client, the neural level of the brain). An overview of individualized paradigms, which have been used until now is given, including Operationalized Psychodynamic Diagnosis (OPD-2) and the Maladaptive Interpersonal Patterns Q-Start (MIPQS). The development of a new paradigm that will be used in fMRI experiments, the "Interpersonal Relationship Picture Set" (IRPS), is described. Further perspectives and limitations of this new approach concerning the design and the translation problem are discussed. 23330972 Interaction between group IIb divalent transition-metal cations and 3-mercaptopropionic acid: a computational and topological perspective. Density functional theory was applied to study the interaction of group IIb transition-metal cations (Zn(2+), Cd(2+), and Hg(2+)) with one and two fully or partially deprotonated 3-mercaptopropionic acid ligands. In this investigation, we determined the geometries of all possible complexes resulting from the coordination of the metal ions with the ligands at different binding sites selected on each ligand. The relative energies of the complexes, metal-ion affinities, free energies, and entropies were also determined. The natures of the bonds were critically analyzed by natural bond orbital (NBO) analysis and clarified further using the atoms-in-molecules (AIM) approach. The substantial influence of the solvent (water) polarization on the energetics, geometries, and bonding of the molecular complexes was also investigated by the conductor-like screening solvation model (COSMO). In an attempt to simulate the complexes in an aqueous environment, water molecules were added explicitly to complete the coordination sphere of the metal cations, and the corresponding metal-ion affinities were calculated to study the effect of microhydration. 23179744 Reliability and safety of functional capacity evaluation in patients with whiplash associated disorders. Introduction Whiplash-associated disorders (WAD) are a burden for both individuals and society. It is recommended to evaluate patients with WAD at risk of chronification to enhance rehabilitation and promote an early return to work. In patients with low back pain (LBP), functional capacity evaluation (FCE) contributes to clinical decisions regarding fitness-for-work. FCE should have demonstrated sufficient clinimetric properties. Reliability and safety of FCE for patients with WAD is unknown. Methods Thirty-two participants (11 females and 21 males; mean age 39.6 years) with WAD (Grade I or II) were included. The FCE consisted of 12 tests, including material handling, hand grip strength, repetitive arm movements, static arm activities, walking speed, and a 3 min step test. Overall the FCE duration was 60 min. The test-retest interval was 7 days. Interclass correlations (model 1) (ICCs) and limits of agreement (LoA) were calculated. Safety was assessed by a Pain Response Questionnaire, observation criteria and heart rate monitoring. Results ICCs ranged between 0.57 (3 min step test) and 0.96 (short two-handed carry). LoA relative to mean performance ranged between 15 % (50 m walking test) and 57 % (lifting waist to overhead). Pain reactions after WAD FCE decreased within days. Observations and heart rate measurements fell within the safety criteria. Conclusions The reliability of the WAD FCE was moderate in two tests, good in five tests and excellent in five tests. Safety-criteria were fulfilled. Interpretation at the patient level should be performed with care because LoA were substantial. 23913931 Change in Fast Walking Speed Preceding Death: Results From a Prospective Longitudinal Cohort Study. Walking speed (WS) predicts mortality. However, it is unclear if decline in WS increases prior to death. We examined whether (a) WS declined faster in persons who died during the follow-up compared with those who remained alive and (b) adding change in WS to a model including age, sex, and baseline WS improved prediction of mortality. Data are from 4,016 participants of the Dijon center of the Three-City study (France), aged 65-85 years. Fast WS (FWS) was measured up to five times over a 12-year period. Mortality was ascertained until 2012. Linear mixed models using a backward time scale showed that FWS declined faster in 908 participants who died during the follow-up (annual change = -0.031 m/s) than in those who survived (-0.021 m/s), corresponding to a difference of -0.009 (95% confidence interval = -0.013 to -0.005) m/s. Compared with "normal" change in FWS (annual change ≥-0.04 m/s), "substantial" decline (<-0.08 m/s) was associated with a 1.4-fold greater risk of mortality (hazards ratio = 1.40, confidence interval = 1.02-1.92) and small decline (-0.08 to -0.04 m/s) with a 1.2-fold greater risk (hazards ratio = 1.18, confidence interval = 0.89-1.57). The net reclassification index when adding these categories of change in FWS to the model adjusted for age, sex, and baseline FWS was 19.0% (0.6, 36.8%). Participants who died during the follow-up had a steeper decline in FWS than the others. Both baseline FWS and FWS decline predict mortality. 23179201 Postprandial glucose, insulin and gastrointestinal hormones in healthy and diabetic subjects fed a fructose-free and resistant starch type IV-enriched enteral formula. Reducing the dietary glycaemic response has been proposed as a means of reducing the risk of diabetes. To evaluate the effects of a new diabetes-specific formula (DSF) enriched with resistant starch type IV and fructose-free on postprandial glycaemia, insulinaemia and gastrointestinal hormones in healthy volunteers and in outpatient type 2 diabetics. (1) Twenty-four healthy volunteers were divided into two groups: Group 1 ( n = 10) was provided 50 g of the carbohydrate (CHO) constituent of the new product and 50 g of glucose separated by 1 week; Group 2 ( n = 14) was provided 400 ml of the new DSF (T-Diet Plus(®) Diabet NP) and 400 ml of a control product separated by 1 week. (2) Ten type 2 diabetic patients received 400 ml of the new DSF and two other commercially available DSF (Glucerna(®) SR and Novasource(®) Diabet) on three occasions separated by 1 week. Venous blood samples were drawn at time 0 and at different times until 120 min. Glucose, insulin and gastrointestinal hormones were determined. Glycaemic and insulinaemic indices and glycaemic load were calculated. The CHO constituent and the new DSF showed low glycaemic index and glycaemic load. In healthy subjects, insulin and C-peptide release were lower after administration of the CHO constituent as well as after the new DSF (P < 0.001). Ghrelin, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) production were lower after intake of the CHO constituent (P ranging from <0.001 to 0.019) compared with glucose, and GIP was lower after ingestion of the new DSF (P = 0.002) than after the control product. In type 2 diabetic patients, glucose AUC was lower after the administration of the new DSF (P = 0.037) compared with the others. Our results indicate that this new product could be beneficial for diabetic patients. 23640221 Differential washout of FDG activity in two different inflammatory lesions: implications for delayed imaging. We describe the changes of FDG uptake in different inflammatory lesions on multiple time point FDG PET/CT. FDG uptake in granulomatous lesions was more intense and focal, with higher intensity on delayed images. In contrast, FDG uptake in chronic arthritic joint inflammation was diffuse and mild, without significant change over time, while FDG uptake in nonarthritic joints was at near-background level with decreased activity on delayed images. The retention index was significantly higher in patients with granulomatous lesions than that in other groups. Our finding indicates differential FDG uptake and clearance in active granulomas versus chronic inflammation. 23835411 Enhanced 1,2-dichloroethane degradation in heavy metal co-contaminated wastewater undergoing biostimulation and bioaugmentation. Biostimulation, bioaugmentation and dual-bioaugmentation strategies were investigated in this study for efficient bioremediation of water co-contaminated with 1,2-dichloroethane (1,2-DCA) and heavy metals, in a microcosm set-up. 1,2-DCA concentration was periodically measured in the microcosms by gas chromatographic analysis of the headspace samples, while bacterial population and diversity were determined by standard plate count technique and Polymerase chain reaction and denaturing gradient gel electrophoresis (PCR-DGGE) analysis, respectively. Dual-bioaugmentation, proved to be most effective exhibiting 22.43%, 26.54%, 19.58% and 30.49% increase in 1,2-DCA degradation in microcosms co-contaminated with As(3+), Cd(2+), Hg(2+) and Pb(2+), respectively, followed by bioaugmentation and biostimulation. Dual-bioaugmented microcosms also exhibited the highest increase in the biodegradation rate constant (k1) resulting in 1.76-, 2-, 1.7- and 2.1-fold increase in As(3+), Cd(2+), Hg(2+) and Pb(2+) co-contaminated microcosms respectively, compared to the untreated microcosms. Dominant bacterial strains obtained from the co-contaminated microcosms were found to belong to the genera Burkholderia, Pseudomonas, Bacillus, Enterobacter and Bradyrhizobium, previously reported for 1,2-DCA and other chlorinated compounds degradation. PCR-DGGE analysis revealed variation in microbial diversity over time in the different co-contaminated microcosms. Results obtained in this study have significant implications for developing innovative bioremediation strategies for treating water co-contaminated with chlorinated organics and heavy metals. 23017408 Phenylalanine ammonia lyase (PAL) enzyme activity and antioxidant properties of some cyanobacteria isolates. In the present study, six cyanobacteria isolates were evaluated for the PAL enzyme activity, and their methanol extracts were assessed for the total phenolic amount and other antioxidant parameters. Synechocystis sp. BASO444 and Synechocystis sp. BASO673 isolates with high levels of total phenols (66.0±1.2μg/mg, 78.1±1.8μg/mg, respectively) also showed high levels of PAL activities (20.5±3.1U/mg protein, 17.2±2.3U/mg protein, respectively) and strong antioxidant activities. To understand the effect of l-phenylalanine (l-phe) on the PAL activity, total phenolic amount, and phenolic constituents, isolates were evaluated with 100mg/l l-phe. While PAL activities exhibited no significant change with l-phe addition, total phenolic amount of the isolates significantly increased. HPLC analysis revealed gallic acid, trans-cinnamic acid, p-coumaric acid, and ferulic acid as the main compounds. Results suggested that the two isolate mights be an important source for the l-phe inducible phenolic compounds. 23908655 Expression of recombinant antibodies. Recombinant antibodies are highly specific detection probes in research, diagnostics, and have emerged over the last two decades as the fastest growing class of therapeutic proteins. Antibody generation has been dramatically accelerated by in vitro selection systems, particularly phage display. An increasing variety of recombinant production systems have been developed, ranging from Gram-negative and positive bacteria, yeasts and filamentous fungi, insect cell lines, mammalian cells to transgenic plants and animals. Currently, almost all therapeutic antibodies are still produced in mammalian cell lines in order to reduce the risk of immunogenicity due to altered, non-human glycosylation patterns. However, recent developments of glycosylation-engineered yeast, insect cell lines, and transgenic plants are promising to obtain antibodies with "human-like" post-translational modifications. Furthermore, smaller antibody fragments including bispecific antibodies without any glycosylation are successfully produced in bacteria and have advanced to clinical testing. The first therapeutic antibody products from a non-mammalian source can be expected in coming next years. In this review, we focus on current antibody production systems including their usability for different applications. 23937415 Clinical investigation of receptor and non-receptor tyrosine kinase inhibitors for the treatment of epithelial ovarian cancer. Introduction: Epithelial ovarian cancer (EOC) is the second most common gynecologic malignancy and the leading cause of death from gynecologic cancer in the USA. EOC is an exquisitely chemo-sensitive disease with response rates of over 75% in the upfront setting. Despite this, due to high rates of recurrence and development of chemo-resistance, the overall survival of EOC remains about 25%. Thus, there is a great need for new therapeutic approaches to render more durable responses. Based on preclinical and early phase clinical studies, key targeted pathways include targets that drive angiogenesis and chemo-resistance. Receptor tyrosine kinases and non-receptor tyrosine kinases play important roles in these processes and several small molecule tyrosine kinase inhibitors (TKIs) are in clinical development. Areas covered: This review summarizes clinical rationale, mechanisms of action and clinical data for the TKIs under evaluation in the Phase III setting for EOC. Expert opinion: Despite reasonable preclinical activity, small molecule TKIs are unlikely to improve patient survival as single agent therapies in an unselected EOC population. Incorporation of tissue evaluation during ongoing clinical trials is required to identify molecularly defined groups that respond to single agents and direct rational combination strategies based on mechanisms of resistance to improve outcomes in EOC. 23924785 Mixotrophic haptophytes are key bacterial grazers in oligotrophic coastal waters. Grazing rate estimates indicate that approximately half of the bacterivory in oligotrophic oceans is due to mixotrophic flagellates (MFs). However, most estimations have considered algae as a single group. Here we aimed at opening the black-box of the phytoflagellates (PFs) <20 μm. Haptophytes, chlorophytes, cryptophytes and pigmented dinoflagellates were identified using fluorescent in situ hybridization or by standard 4',6-diamidino-2-phenylindole staining. Their fluctuations in abundance, cell size, biomass and bacterivory rates were measured through an annual cycle in an oligotrophic coastal system. On average, we were able to assign to these groups: 37% of the total pico-PFs and 65% of the nano-PFs composition. Chlorophytes were mostly picoplanktonic and they never ingested fluorescently labeled bacteria. About 50% of the PF <20 μm biomass was represented by mixotrophic algae. Pigmented dinoflagellates were the least abundant group with little impact on bacterioplankton. Cryptophytes were quantitatively important during the coldest periods and explained about 4% of total bacterivory. Haptophytes were the most important mixotrophic group: (i) they were mostly represented by cells 3-5 μm in size present year-round; (ii) cell-specific grazing rates were comparable to those of other bacterivorous non-photosynthetic organisms, regardless of the in situ nutrient availability conditions; (iii) these organisms could acquire a significant portion of their carbon by ingesting bacteria; and (iv) haptophytes explained on average 40% of the bacterivory exerted by MFs and were responsible for 9-27% of total bacterivory at this site. Our results, when considered alongside the widespread distribution of haptophytes in the ocean, indicate that they have a key role as bacterivores in marine ecosystems.The ISME Journal advance online publication, 8 August 2013; doi:10.1038/ismej.2013.132. 23504562 The effects of poor sleep on cognitive, affective, and physiological responses to a laboratory stressor. Recent research suggests that poor sleep may be associated with altered stress regulation. This study aims to examine the associations between prior-night and prior-month sleep measures and affective, cognitive, and physiological responses to a laboratory stressor. Ninety-eight (50 % female) young adults completed measures of sleep quality in the context of a laboratory stress study. Measures included positive (PA) and negative affects (NA) and blood pressure (BP) reactivity, as well as change in pre-sleep arousal. Prior-month poor sleep quality and sleep disturbances predicted dampened BP reactivity. Both prior-night and prior-month sleep quality predicted greater decrease in PA. Sleep-associated monitoring predicted NA reactivity and prolonged cognitive and affective activation. Prior-month sleep continuity predicted greater cognitive pre-sleep arousal change, and prior-month sleep quality, daytime dysfunction, and disturbances predicted prolonged cognitive and affective activation. Findings suggest that inadequate sleep confers vulnerability to poor cognitive, affective, and physiological responses to stress. 23763276 Metabolic phenotypes of Saccharomyces cerevisiae mutants with altered trehalose 6-phosphate dynamics. In Saccharomyces cerevisiae, synthesis of T6P (trehalose 6-phosphate) is essential for growth on most fermentable carbon sources. In the present study, the metabolic response to glucose was analysed in mutants with different capacities to accumulate T6P. A mutant carrying a deletion in the T6P synthase encoding gene, TPS1, which had no measurable T6P, exhibited impaired ethanol production, showed diminished plasma membrane H+-ATPase activation, and became rapidly depleted of nearly all adenine nucleotides which were irreversibly converted into inosine. Deletion of the AMP deaminase encoding gene, AMD1, in the tps1 strain prevented inosine formation, but did not rescue energy balance or growth on glucose. Neither the 90%-reduced T6P content observed in a tps1 mutant expressing the Tps1 protein from Yarrowia lipolytica, nor the hyperaccumulation of T6P in the tps2 mutant had significant effects on fermentation rates, growth on fermentable carbon sources or plasma membrane H+-ATPase activation. However, intracellular metabolite dynamics and pH homoeostasis were strongly affected by changes in T6P concentrations. Hyperaccumulation of T6P in the tps2 mutant caused an increase in cytosolic pH and strongly reduced growth rates on non-fermentable carbon sources, emphasizing the crucial role of the trehalose pathway in the regulation of respiratory and fermentative metabolism. 23959219 Effect of long term organic amendments and vegetation of vineyard soils on the microscale distribution and biogeochemistry of copper. In this study we evaluated the effect of the long term organic management of a vineyard-soil on the biogeochemistry of copper at the micro-aggregate scale. The model vineyard-soil (Mâcon-France) experienced a long-term field-experiment that consisted in amendments and vegetations with various materials and plants. We studied specifically the effect of Straw (S) and Conifer Compost (CC) organic amendments and Clover (Cl) and Fescue (F) vegetation on the fate of copper (fungicide) in the surface layer of this loamy soil, through a comparison with the Non Amended soil (NA). After collection the five soils were immediately physically fractionated in order to obtain 5 granulometric size-fractions. All soils and size-fractions were quantitatively characterized in terms of granulometry, chemical content and copper distribution, speciation and bioavailability to bacteria and plants. The results showed strong increases of soil-constituents aggregation for all treatments (Cl>CC>S>F>NA), in relation with the increased cementation of soil-constituents by organic matter (OM). The distribution patterns of all major elements and organic carbon were found highly variable within the soil sub-fractions and also between the 5 treatments. Due to their specific inorganic and organic composition, soil sub-fractions can thus be considered as a specific microbial habitat. Added OM accumulated preferentially in the 20-2μm and in the >250μm of the 5 soils. The distribution patterns of copper as well as its speciation and bioavailability to bacteria in the soil sub-fractions were shown to be strongly different among the five soils, in relation with OM distribution. Our results also suggest that Cu-bioavailability to plants is controlled by soil-rhizosphere structure. Altogether our results permitted to show that long-term organic management of a vineyard soil induced stable modifications of soil physical and chemical properties at both macro and micro-scales. These modifications affected in turn the micro-scale biogeochemistry of copper, and especially its bioavailability to bacteria and plants. 23488980 The relationship between trough drug concentrations and ductal closure in preterm infants treated with three-dose-oral ibuprofen. Abstract The aim of the present study was to characterize the pharmacokinetic profile of oral ibuprofen on consecutive 3 d by trough serum levels, and if possible to define a cut-off level for ductal closure in preterm infants. The study enrolled 20 preterm infants with gestational age ≤30 weeks, birth weight <1250 g and hemodynamically significant patent ductus arteriosus (hsPDA). Patients received oral ibuprofen at an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 h. Patients were compared for serum ibuprofen levels in addition to their demographic and clinical data in case of their response to the treatment. hsPDA closed in 16 (80%) of the patients. Although mean ibuprofen levels on consecutive 3 d showed a plateau in general, ibuprofen serum levels on the first treatment day were statistically low in patients with unclosed hsPDA (p = 0.003). The optimal cut-off value for serum ibuprofen level on the first treatment day was measured as 5.5 mg/l with 100% sensitivity and 93% specificity. Serum ibuprofen level on the first treatment day seems to be an important factor for a successful ductal closure. Target concentration approach by the evaluation of trough level may be applicable to real-time dosing strategy. 23314959 Short-Term Culture of Ovarian Cortical Strips From Capuchin Monkeys (Sapajus apella): A Morphological, Viability, and Molecular Study of Preantral Follicular Development In Vitro. The aim of this study was to evaluate whether an in vitro culture (IVC) medium containing either or not β-mercaptoethanol (BME), bone morphogenetic protein 4 (BMP4), or pregnant mare serum gonadotrophin (PMSG) could be able to promote the development of capuchin monkeys' preantral follicles enclosed in ovarian cortical strips. Follicular viability after IVC was similar to control (89.32%). Primordial follicle recruitment to primary stage was not reached with IVC, but the rate of secondary follicle formation was increased in the medium supplemented with BME, BMP4, and PMSG (44.86%) when compared to IVC control (9.20%). In the medium supplemented with BME, BMP4, and PMSG, contrary to other media, anti-müllerian hormone-messenger RNA (mRNA) expression in ovarian tissue was upregulated (3.4-fold), while that of growth differentiation factor-9 was maintained. The BMP4-mRNA expression, however, appeared downregulated in all cultured tissues. Our findings show a favorable effect of BME, BMP4, and PMSG on the in vitro development of secondary follicles from capuchin monkeys. 23279133 Growth hormone therapy and craniofacial bones: a comprehensive review. Growth hormone (GH) has significant effects on linear bone growth, bone mass and bone metabolism. The primary role of GH supplementation in children with GH deficiency, those born small for gestational age or with other types of disorders in somatic development is to increase linear growth. However, GH therapy seems to elicit varying responses in the craniofacial region. Whereas the effects of GH administration on somatic development are well documented, comparatively little is known of its effects on the craniofacial region. The purpose of this review was to search the literature and compile results from both animal and human studies related to the impact of GH on craniofacial growth. 23689233 Graphene oxide grafted with Pd17Se15 nano-particles generated from a single source precursor as a recyclable and efficient catalyst for C-O coupling in O-arylation at room temperature. The Pd17Se15 nanoparticles, synthesized for the first time from a single source precursor [Pd(L)Cl2] {L = 1,3-bis(phenylselenyl)propan-2-ol} and grafted onto graphene oxide, show high catalytic activity in C-O coupling between aryl/heteroaryl chlorides/bromides and phenol at room temperature (Pd loading 1 mol%; yield up to 94%). 23884723 Daptomycin underexposure in a young intravenous drug user who was affected by life-threatening Staphylococcus aureus-complicated skin and soft tissue infection associated with bacteraemia. We describe the case of an intravenous drug user affected by life-threatening Staphylococcus aureus-complicated skin and soft tissue infection with associated bacteraemia who, while on replacement therapy with methadone, required 11 mg/kg/day daptomycin to achieve trough (Cmin) and peak (Cmax) plasma levels similar to those observed with the standard dosage of 6 mg/kg in healthy volunteers (mean ± standard deviation: Cmin 12.35 ± 0.80 mg/L, Cmax 63.90 ± 8.71 mg/L). Clinical pharmacological advice based on real time therapeutic drug monitoring may be helpful for optimizing daptomycin exposure in these patients. Physicians should take into account that dosages much higher than the standard ones may be needed, probably as a consequence of augmented drug clearance. 23919137 Getting the biggest birch for the bang: restoring and expanding upland birchwoods in the Scottish Highlands by managing red deer. High deer populations threaten the conservation value of woodlands and grasslands, but predicting the success of deer culling, in terms of allowing vegetation to recover, is difficult. Numerical simulation modeling is one approach to gain insight into the outcomes of management scenarios. We develop a spatially explicit model to predict the responses of Betula spp. to red deer (Cervus elaphus) and land management in the Scottish Highlands. Our model integrates a Bayesian stochastic stage-based matrix model within the framework of a widely used individual-based forest simulation model, using data collected along spatial and temporal gradients in deer browsing. By initializing our model with the historical spatial locations of trees, we find that densities of juvenile trees (<3 m tall) predicted after 9-13 years closely match counts observed in the field. This is among the first tests of the accuracy of a dynamical simulation model for predicting the responses of tree regeneration to herbivores. We then test the relative importance of deer browsing, ground cover vegetation, and seed availability in facilitating landscape-level birch regeneration using simulations in which we varied these three variables. We find that deer primarily control transitions of birch to taller (>3 m) height tiers over 30 years, but regeneration also requires suitable ground cover for seedling establishment. Densities of adult seed sources did not influence regeneration, nor did an active management scenario where we altered the spatial configuration of adults by creating "woodland islets". Our results show that managers interested in maximizing tree regeneration cannot simply reduce deer densities but must also improve ground cover for seedling establishment, and the model we develop now enables managers to quantify explicitly how much both these factors need to be altered. More broadly, our findings emphasize the need for land managers to consider the impacts of large herbivores rather than their densities. 23904068 The 'information spectrum': a qualitative study of how breast cancer surgeons give information and of how their patients experience it. Cancer clinicians are routinely criticised for communicating information poorly to patients, but expert guidance is sometimes contradictory or impractical. We wanted to understand how, and how well, breast cancer surgeons in their normal practice balanced the competing tasks of informing patients while keeping them hopeful. In a post-operative surgical outpatient clinic in a UK breast unit, we recruited 9 surgeons and 20 breast cancer patients with whom they consulted. We audio recorded and interviewed both patients and surgeons about their consultations, then analysed data qualitatively within and across cases taking a constant comparative approach. Every consultation contained biomedical factually explicit information, but the information that was most significant for patients was factually less explicit. Progressively less explicit forms, along a 'spectrum' of information, included: judgments about treatment implications; judgments about prognosis; evaluative comments; and clues about what information signified. Surgeons used the less explicit types of information to communicate hope. Where prognosis was poor, communication was confined to more explicit information. Surgeons' practice was closely aligned with what patients sought. Common criticisms of cancer clinicians for giving 'too little' information belie the complexity of their task in simultaneously managing information needs and hope. The 'information spectrum' could help educators and clinicians to understand this task. Copyright © 2013 John Wiley & Sons, Ltd. 23641028 Structure of the Physical Therapy Benefit in a Typical Blue Cross Blue Shield Preferred Provider Organization Plan Available in the Individual Insurance Market in 2011. The Affordable Care Act of 2010 establishes American Health Benefit Exchanges. The benefit design of insurance plans in state health insurance exchanges will be based on the structure of existing small-employer-sponsored plans. The purpose of this study was to describe the structure of the physical therapy benefit in a typical Blue Cross Blue Shield (BCBS) preferred provider organization (PPO) health insurance plan available in the individual insurance market in 2011. A cross-sectional survey design was used. The physical therapy benefit within 39 BCBS PPO plans in 2011 was studied for a standard consumer with a standard budget. First, whether physical therapy was a benefit in the plan was determined. If so, then the structure of the benefit was described in terms of whether the physical therapy benefit was a stand-alone benefit or part of a combined-discipline benefit and whether a visit or financial limit was placed on the physical therapy benefit. Physical therapy was included in all BCBS plans that were studied. Ninety-three percent of plans combined physical therapy with other disciplines. Two thirds of plans placed a limit on the number of visits covered. The results of the study are limited to 1 standard consumer, 1 association of insurance companies, 1 form of insurance (a PPO), and 1 PPO plan in each of the 39 states that were studied. Physical therapy is a covered benefit in a typical BCBS PPO health insurance plan. Physical therapy most often is combined with other therapy disciplines, and the number of covered visits is limited in two thirds of plans. 23693152 UNC1062, a new and potent Mer inhibitor. Abnormal activation of Mer kinase has been implicated in the oncogenesis of many human cancers including acute lymphoblastic and myeloid leukemia, non-small cell lung cancer, and glioblastoma. We have discovered a new family of small molecule Mer inhibitors, pyrazolopyrimidine sulfonamides, that potently inhibit the kinase activity of Mer. Importantly, these compounds do not demonstrate significant hERG activity in the PatchXpress assay. Through structure-activity relationship studies, 35 (UNC1062) was identified as a potent (IC50 = 1.1 nM) and selective Mer inhibitor. When applied to live tumor cells, UNC1062 inhibited Mer phosphorylation and colony formation in soft agar. Given the potential of Mer as a therapeutic target, UNC1062 is a promising candidate for further drug development. 23796663 Fuel burnup calculation of Ghana MNSR using ORIGEN2 and REBUS3 codes. Ghana Research Reactor-1 core is to be converted from HEU fuel to LEU fuel in the near future and managing the spent nuclear fuel is very important. A fuel depletion analysis of the GHARR-1 core was performed using ORIGEN2 and REBUS3 codes to estimate the isotopic inventory at end-of-cycle in order to help in the design of an appropriate spent fuel cask. The results obtained for both codes were consistent for U-235 burnup weight percent and Pu-239 build up as a result of burnup. 23700188 Available evidence and outcome of off-label use of rituximab in clinical practice. To analyze the therapeutic indications for off-label use of rituximab, the available evidence for its use, the outcomes, and the cost. This was a retrospective analysis of patients treated with rituximab for off-label indications from January 2007 to December 2009 in two tertiary hospitals. Information on patient characteristics, medical conditions, and therapeutic responses was collected from medical records. Available evidence for the efficacy of rituximab in each condition was reviewed, and the cost of treatment was calculated. A total of 101 cases of off-label rituximab use were analyzed. The median age of the patients involved was 53 [interquartile range (IQR) 37.5-68.0] years; 55.4 % were women. The indications for prescribing rituximab were primarily hematological diseases (46 %), systemic connective tissue disorders (27 %), and kidney diseases (20 %). Available evidence supporting rituximab treatment for these indications mainly came from individual cohort studies (53.5 % of cases) and case series (25.7 %). The short-term outcome (median 3 months, IQR 2-4 months) was a complete response in 38 % of cases and partial response in 32.6 %. The highest short-term responses were observed for systemic lupus erythematosus and membranous glomerulonephritis, and the lowest was for neuromyelitis optica, idiopathic thrombocytopenic purpura, and miscellaneous indications. Some response was maintained in long-term follow-up (median 23 months IQR 12-30 months) in 69.2 % of patients showing a short-term response. Median cost per patient was 5,187.5 (IQR 5,187.5-7,781.3). In our study, off-label rituximab was mainly used for the treatment of hematological, kidney, and systemic connective tissue disorders, and the response among our patient cohort was variable depending on the specific disease. The level of evidence supporting the use of rituximab for these indications was low and the cost was very high. We conclude that more clinical trials on the off-label use of rituximab are needed, although these may be difficult to conduct in some rare diseases. Data from observational studies may provide useful information to assist prescribing in clinical practice. 23954630 PEGylation of HPMA-based block copolymers enhances tumor accumulation in vivo: A quantitative study using radiolabeling and positron emission tomography. This paper reports the body distribution of block copolymers (made by controlled radical polymerization) with N-(2-hydroxypropyl)methacrylamide (HPMA) as hydrophilic block and lauryl methacrylate (LMA) as hydrophobic block. They form micellar aggregates in aqueous solution. For this study the hydrophilic/hydrophobic balance was varied by incorporation of differing amounts of poly(ethylene glycol) (PEG) side chains into the hydrophilic block, while keeping the degree of polymerization of both blocks constant. PEGylation reduced the size of the micellar aggregates (Rh=113 to 38nm) and led to a minimum size of 7% PEG side chains. Polymers were labeled with the positron emitter (18)F, which enables to monitor their biodistribution pattern for up to 4h with high spatial resolution. These block copolymers were investigated in Sprague-Dawley rats bearing the Walker 256 mammary carcinoma in vivo. Organ/tumor uptake was quantified by ex vivo biodistribution as well as small animal positron emission tomography (PET). All polymers showed renal clearance with time. Their uptake in liver and spleen decreased with size of the aggregates. This made PEGylated polymers - which form smaller aggregates - attractive as they show a higher blood pool concentration. Within the studied polymers, the block copolymer of 7% PEGylation exhibited the most favorable organ distribution pattern, showing highest blood-circulation level as well as lowest hepatic and splenic uptake. Most remarkably, the in vivo results revealed a continuous increase in tumor accumulation with PEGylation (independent of the blood pool concentration) - starting from lowest tumor uptake for the pure block copolymer to highest enrichment with 11% PEG side chains. These findings emphasize the need for reliable (non-invasive) in vivo techniques revealing overall polymer distribution and helping to identify drug carrier systems for efficient therapy. 23644143 Ionic liquid functionalized graphene/Au nanocomposites and its application for electrochemical immunosensor. In this work, a new nanocomposite, which was composed of ionic liquid functionalized graphene sheet (IL-GS) loaded gold nanoparticles (AuNPs), was prepared. The IL-GS was directly synthesized by the electrochemical exfoliation of graphite in ionic liquid (IL). Due to the modification of the IL, IL-GS can not only be dispersed easily in aqueous solution to form a homogeneous colloidal suspension of individual sheet, but also exhibits an improved conductivity. Meanwhile, the loaded AuNPs on the nanocomposites can increase the specific surface area to capture a large amount of antibodies as well as improve the capability of electron transfer. The IL-GS-Au nanocomposites were successfully employed for the fabrication of a facile and sensitive electrochemical immunosensor. Carcinoembryonic antigen (CEA) was used as a model protein. The proposed immunosensor exhibits a wide linear detection range (LDR) from 1 fg mL⁻¹ to 100 ng mL⁻¹, and an ultralow limit of detection (LOD) of 0.1 fg mL⁻¹ (S/N=3). In addition, for the detection of clinical serum samples, it is well consistent with the data determined by the developed immunoassay and ELISA, indicating that the immunosensor provides a possible application for the detection of CEA in clinical diagnostics. 23964281 How to study deep roots-and why it matters. The drivers underlying the development of deep root systems, whether genetic or environmental, are poorly understood but evidence has accumulated that deep rooting could be a more widespread and important trait among plants than commonly anticipated from their share of root biomass. Even though a distinct classification of "deep roots" is missing to date, deep roots provide important functions for individual plants such as nutrient and water uptake but can also shape plant communities by hydraulic lift (HL). Subterranean fauna and microbial communities are highly influenced by resources provided in the deep rhizosphere and deep roots can influence soil pedogenesis and carbon storage.Despite recent technological advances, the study of deep roots and their rhizosphere remains inherently time-consuming, technically demanding and costly, which explains why deep roots have yet to be given the attention they deserve. While state-of-the-art technologies are promising for laboratory studies involving relatively small soil volumes, they remain of limited use for the in situ observation of deep roots. Thus, basic techniques such as destructive sampling or observations at transparent interfaces with the soil (e.g., root windows) which have been known and used for decades to observe roots near the soil surface, must be adapted to the specific requirements of deep root observation. In this review, we successively address major physical, biogeochemical and ecological functions of deep roots to emphasize the significance of deep roots and to illustrate the yet limited knowledge. In the second part we describe the main methodological options to observe and measure deep roots, providing researchers interested in the field of deep root/rhizosphere studies with a comprehensive overview. Addressed methodologies are: excavations, trenches and soil coring approaches, minirhizotrons (MR), access shafts, caves and mines, and indirect approaches such as tracer-based techniques. 23525945 Diagnosis and treatment planning of acute aortic emergencies using a handheld DICOM viewer. Acute aortic syndromes and traumatic aortic injury are often diagnosed on CT angiography, possibly requiring emergent intervention. Advances in handheld computing have created the possibility of viewing full DICOM datasets from a remote location. We evaluated the ability to diagnose and characterize acute aortic pathologies on CT angiograms of the thorax using an iPhone-based DICOM viewer. This study was performed after Institutional Review Board approval. Fifteen CT angiograms of the thorax in suspected acute aortic syndromes were evaluated by three blinded radiologists on a handheld device using a DICOM viewer. Studies were evaluated for the ability to identify and classify aortic dissection, transection, or intramural hematoma, measure aortic dimensions, and identify mediastinal hematoma, arch variants, and pulmonary pathology. Studies were compared to blinded interpretations on a dedicated PACS workstation. The aortic pathology was correctly identified as aortic transection/pseudoaneurysm (n = 5), type A dissection (n = 2), and type A intramural hematoma (n = 1) by all reviewers, with no false-positive interpretations. This represents a sensitivity and specificity of 100 %. Mediastinal hematoma (n = 6), pneumothorax (five right, three left), and arch vessel involvement (n = 2) were identified in all cases. There was 88.5 % accuracy in identifying arch variants. Measurement of the size of the involved aortic segment was similar on handheld device and PACS workstation; however the adjacent normal aorta was 1.2 ±â€‰1.0 mm larger on the handheld device (p = 0.03). Handheld DICOM viewers may be useful for emergent consultations and triage, and may expedite preprocedure planning to reduce the time interval between diagnostic scan and therapeutic intervention. 23888198 Non-coronary myocardial infarction in myasthenia gravis: Case report and review of the literature. Cardiovascular adverse events in patients with myasthenia gravis (MG) are rare, but the early recognition of such events is crucial. We describe a case of a non-coronary myocardial infarction (MI) during the initial treatment period with pyridostigmine bromide in a female patient with MG. Clinicians should be cautious about the appearance of potential MI in patients with MG. A baseline electrocardiogram is advocated, when the early recognition of the MI clinical signs and the laboratory findings (myocardial markers) are vital to the immediate and appropriate management of this medical emergency, as well as to prevent future cardiovascular events. In this case report possible causes of myocardial adverse events in the context of MG, which may occur during the ongoing treatment and the clinical course of the disease, are discussed. 23754273 Testing visual short-term memory of pigeons (Columba livia) and a rhesus monkey (Macaca mulatta) with a location change detection task. Change detection is commonly used to assess capacity (number of objects) of human visual short-term memory (VSTM). Comparisons with the performance of non-human animals completing similar tasks have shown similarities and differences in object-based VSTM, which is only one aspect ("what") of memory. Another important aspect of memory, which has received less attention, is spatial short-term memory for "where" an object is in space. In this article, we show for the first time that a monkey and pigeons can be accurately trained to identify location changes, much as humans do, in change detection tasks similar to those used to test object capacity of VSTM. The subject's task was to identify (touch/peck) an item that changed location across a brief delay. Both the monkey and pigeons showed transfer to delays longer than the training delay, to greater and smaller distance changes than in training, and to novel colors. These results are the first to demonstrate location-change detection in any non-human species and encourage comparative investigations into the nature of spatial and visual short-term memory. 23844158 Fitness loss and library size determination in saturation mutagenesis. Saturation mutagenesis is a widely used directed evolution technique, in which a large number of protein variants, each having random amino acids in certain predetermined positions, are screened in order to discover high-fitness variants among them. Several metrics for determining the library size (the number of variants screened) have been suggested in the literature, but none of them incorporates the actual fitness of the variants discovered in the experiment. We present the results of an extensive simulation study, which is based on probabilistic models for protein fitness landscape, and which investigates how the result of a saturation mutagenesis experiment - the fitness of the best variant discovered - varies as a function of the library size. In particular, we study the loss of fitness in the experiment: the difference between the fitness of the best variant discovered, and the fitness of the best variant in variant space. Our results are that the existing criteria for determining the library size are conservative, so smaller libraries are often satisfactory. Reducing the library size can save labor, time, and expenses in the laboratory. 23934782 Sparsely populated residue conformations in protein structures: Revisiting "experimental" Ramachandran maps. The Ramachandran map clearly delineates the regions of accessible conformational (φ-ψ) space for amino acid residues in proteins. Experimental distributions of φ, ψ values in high resolution protein structures, reveal sparsely populated zones within fully allowed regions and distinct clusters in apparently disallowed regions. Conformational space has been divided into 14 distinct bins. Residues adopting these relatively rare conformations are presented and amino acid propensities for these regions are estimated. Inspection of specific examples in a completely "arid", fully allowed region in the top left quadrant establishes that side-chain and backbone interactions may provide the energetic compensation necessary for populating this region of φ-ψ space. Asn, Asp and His residues showed the highest propensities in this region. The two distinct clusters in the bottom right quadrant which are formally disallowed on strict steric considerations correspond to the gamma turn (C7 axial) conformation (bin 12) and the i+1 position of type II' β-turns (bin 13). Of the 516 non-Gly residues in bin 13, 384 occupied the i+1 position of type II' β-turns. Further examination of these turn segments revealed a high propensity to occur at the N- terminus of helices and as a tight turn in β-hairpins. The β-strand-helix motif with the type II' β-turn as a connecting element was also found in as many as 57 examples. © Proteins 2013. © 2013 Wiley Periodicals, Inc. 23777416 Genomic regions affecting backfat thickness and cannon bone circumference identified by genome-wide association study in a Duroc pig population. We performed a genome-wide association study using the porcine 60K SNP array to detect QTL regions for nine traits in a three-generational Duroc samples (n = 651), viz. generations 1, 2 and 3 from a population selected over five generations using a closed nucleus breeding scheme. We applied a linear mixed model for association mapping to detect SNP effects, adjusting for fixed effects (sex and season) and random polygenic effects (reflecting genetic relatedness), and derived a likelihood ratio statistic for each SNP using the efficient mixed-model association method. We detected a region on SSC6 for backfat thickness (BFT) and on SSC7 for cannon bone circumference (CANNON), with a genome-wide significance of P < 0.01 after Bonferroni correction. These regions had been detected previously in other pig populations. Six genes are located in the BFT-associated region, while the CANNON-associated region includes 66 genes. In the future, significantly associated SNPs, derived by sequencing the coding regions of the six genes in the BFT region, can be used in marker-assisted selection of BFT, whereas haplotypes constructed from the SSC7 region with strong LD can be used to select for the CANNON trait in our resource family. 23792456 Shape effect on a single-nanoparticle-based plasmonic nanosensor. Plasmonic refractometric nanosensors based on single nanostructures, i.e. spherical, nanorodand bipyramid-shaped gold nanoparticles, are investigated and compared numerically by employing the finite-difference time-domain method. The results show that the plasmonic sensing ability is distributed anisotropically around the nanorod and bipyramid, even for spherical nanoparticles when the illumination light is linearly polarized. To optimize nanosensor performance, some anisotropy in the shape of nanoparticles is required, this latter serving as an intrinsic light polarization filter to suppress the disturbance from localized surface plasmon resonance in other directions. The plasmonic near-field can be engineered by controlling the shape to achieve a concentrated and localized electromagnetic field, in direct relation with the sensing ability. Taking these factors into account, the gold bipyramid nanoconstruct which is easily available in experiment is proposed as an efficient plasmonic sensing platform. The bipyramid presents both highly localized sensitivity and high scattering cross-section, thus avoiding the trade-off during the selection of the widely used nanorod-shaped sensors. The parameters of the bipyramid structure can be optimized by numerical simulation to improve the plasmonic sensing. Our findings permit a deeper understanding of single-nanoparticle-sensor behavior, and the study provides an opportunity to optimize the plasmonic sensor. 23869693 Regional circadian period difference in the suprachiasmatic nucleus of the mammalian circadian center. The suprachiasmatic nucleus (SCN) is the mammalian circadian rhythm center. Individual oscillating neurons have different endogenous circadian periods, but they are usually synchronized by an intercellular coupling mechanism. The differences in the period of each oscillating neuron have been extensively studied; however, the clustering of oscillators with similar periods has not been reported. In the present study, we artificially disrupted the intercellular coupling among oscillating neurons in the SCN and observed regional differences in the periods of the oscillating small-latticed regions of the SCN using a transgenic rat carrying a luciferase reporter gene driven by regulatory elements from a per2 clock gene (Per2::dluc rat). The analysis divided the SCN into two regions - a region with periods shorter than 24 h (short-period region, SPR) and another with periods longer than 24 h (long-period region, LPR). The SPR was located in the smaller medial region of the dorsal SCN, whereas the LPR occupied the remaining larger region. We also found that slices containing the medial region of the SCN generated shorter circadian periods than slices that contained the lateral region of the SCN. Interestingly, the SPR corresponded well with the region where the SCN phase wave is generated. We numerically simulated the relationship between the SPR and a large LPR. A mathematical model of the SCN based on our findings faithfully reproduced the kinetics of the oscillators in the SCN in synchronized conditions, assuming the existence of clustered short-period oscillators. 22996137 Microtubule network is required for insulin-induced signal transduction and actin remodeling. Both microtubule and actin are required for insulin-induced glucose uptake. However, the roles of these two cytoskeletons and their relationship in insulin action still remain unclear. In this work, we examined the morphological change of microtubule/actin and their involvement in insulin signal transduction using rat skeletal muscle cells. Insulin rapidly led to microtubule clustering from ventral to dorsal surface of the cell. Microtubule filaments were rearranged to create space where new actin structures formed. Disruption of microtubule prevented insulin-induced actin remodeling and distal insulin signal transduction, with reduction in surface glucose transporter isoform 4 (GLUT4) and glucose uptake. Though microtubule mediated actin remodeling through PKCζ, reorganization of microtubule depended on tyrosine phosphorylation of insulin receptor, the mechanism is different from insulin-induced actin remodeling, which relied on the activity of PI3-kinase and PKCζ. We propose that microtubule network is required for insulin-induced signal transduction and actin remodeling in skeletal muscle cells. 23665483 Simple and fast PO-CL method for the evaluation of antioxidant capacity of hydrophilic and hydrophobic antioxidants. A simple and fast procedure is described for evaluating the antioxidant activity of hydrophilic and hydrophobic compounds by using the peroxyoxalate-chemiluminescence (PO-CL) reaction of Bis(2,4,6-trichlorophenyl) oxalate (TCPO) with hydrogen peroxide in the presence of di(tert-butyl)2-(tert-butylamino)-5-[(E)-2-phenyl-1-ethenyl]3,4-furandicarboxylate as a highly fluorescent fluorophore. The IC50 values of the well-known antioxidants were calculated and the results were expressed as gallic equivalent antioxidant capacity (GEAC). It was found that the proposed method is free of physical quenching and oxidant interference, for this reason, proposed method is able to determine the accurate scavenging activity of the antioxidants to the free radicals. Finally, the proposed method was applied to the evaluation of antioxidant activity of complex real samples such as soybean oil and sunflower oil (as hydrophobic samples) and honey (as hydrophilic sample). To the best of our knowledge, this is the first time that total antioxidant activity can be determined directly in soybean oil, sunflower oil and honey (not in their extracts) using PO-CL reactions. 23947757 Factors associated with recency of HIV testing amongst men residing in Scotland who have sex with men. Rates of HIV testing are increasing among men who have sex with men (MSM) in Scotland and the UK. However, it remains vital to encourage MSM to test for HIV. The aim of the current study was to determine which factors discriminated among three groups of MSM: those tested for HIV within the previous year, those who had tested over one year previously, and those who had never tested. Cross-sectional data were collected using self-report, anonymous questionnaires from MSM frequenting gay venues in Glasgow, Scotland, during July 2010 (N = 822, response rate 62.6%). Those who identified themselves as HIV positive (n = 38), did not normally reside in Scotland (n = 88), and did not provide information on HIV testing (n = 13), were excluded (139 excluded, leaving N = 683). Around 57% (n = 391) had tested for HIV within the previous year, 23% (n = 155) had tested over one year previously and 20% (n = 137) had never tested. Compared with those tested within the previous year, those tested over one year previously and those never tested had greater fear of a positive-HIV test result, a weaker norm for HIV testing, and were more likely to have had no anal sex partners at all within the previous year. Those tested over one year previously were significantly older than both other groups (who were more likely to be under 25 years of age). Unprotected anal intercourse (UAI) did not discriminate among the HIV testing groups. The results highlight the need to promote HIV testing in Scotland among those under 25 years and over 45 years, those with high fear of testing, and those whose sexual behaviour puts them at risk. Interventions to increase HIV testing should promote positive norms and challenge the fear of a positive result. 23865885 Development of a model to simulate infection dynamics of Mycobacterium bovis in cattle herds in the United States. Objective-To develop a mathematical model to simulate infection dynamics of Mycobacterium bovis in cattle herds in the United States and predict efficacy of the current national control strategy for tuberculosis in cattle. Design-Stochastic simulation model. Sample-Theoretical cattle herds in the United States. Procedures-A model of within-herd M bovis transmission dynamics following introduction of 1 latently infected cow was developed. Frequency- and density-dependent transmission modes and 3 tuberculin test-based culling strategies (no test-based culling, constant [annual] testing with test-based culling, and the current strategy of slaughterhouse detection-based testing and culling) were investigated. Results were evaluated for 3 herd sizes over a 10-year period and validated via simulation of known outbreaks of M bovis infection. Results-On the basis of 1,000 simulations (1,000 herds each) at replacement rates typical for dairy cattle (0.33/y), median time to detection of M bovis infection in medium-sized herds (276 adult cattle) via slaughterhouse surveillance was 27 months after introduction, and 58% of these herds would spontaneously clear the infection prior to that time. Sixty-two percent of medium-sized herds without intervention and 99% of those managed with constant test-based culling were predicted to clear infection < 10 years after introduction. The model predicted observed outbreaks best for frequency-dependent transmission, and probability of clearance was most sensitive to replacement rate. Conclusions and Clinical Relevance-Although modeling indicated the current national control strategy was sufficient for elimination of M bovis infection from dairy herds after detection, slaughterhouse surveillance was not sufficient to detect M bovis infection in all herds and resulted in subjectively delayed detection, compared with the constant testing method. Further research is required to economically optimize this strategy. 23483727 Intratracheal transplantation of bone marrow-derived mesenchymal stem cells reduced airway inflammation and up-regulated CD4(+) CD25(+) regulatory T cells in asthmatic mouse. Mesenchymal stem cells attenuate the severity of lung injury due to their immunomodulatory properties. The effect of bone marrow-derived mesenchymal stem cells on asthma is seldom reported. We have examined the effect of BMSCs on airway inflammation in asthma. Forty female BALB/c mice were equally randomised into PBS group, BMSCs treatment group, BMSCs control group and asthmatic group. Reactivity of the airway to acetylcholine was measured by barometric plethysmography. Cytokine profiles of bronchoalveolar lavage fluid and serum were determined by enzyme-linked immunosorbent assay. Morphometric analysis was done with haematoxylin and periodic-acid Schiff staining. Engraftment of BMSCs in asthmatic mice significantly decreased the number of eosinophils and mononuclear cells in bronchoalveolar lavage fluid and the airway (P < 0.05). Both goblet cell hyperplasia and responsiveness to acetylcholine were significantly reduced in BMSCs treatment groups. Moreover, BMSCs engraftment caused significant increases the ratio of Treg in pulmonary lymph node and interleukin-10 (IL-10) and interleukin-12 levels in BALF and serum. We conclude that BMSCs engraftment ameliorated airway inflammation and improved lung function in asthmatic mouse and the protective effect might be mediated by upregulating Treg and partly involved with increasing IL-10. 23953385 Prasugrel versus clopidogrel for patients with unstable angina or non-ST-segment elevation myocardial infarction with or without angiography: a secondary, prespecified analysis of the TRILOGY ACS trial. Treatment with prasugrel and aspirin improves outcomes compared with clopidogrel and aspirin for patients with acute coronary syndrome who have had angiography and percutaneous coronary intervention; however, no clear benefit has been shown for patients managed first with drugs only. We assessed outcomes from the TRILOGY ACS trial based on whether or not patients had coronary angiography before treatment was chosen. TRILOGY ACS (ClinicalTrials.gov number NCT00699998) was a randomised controlled trial, done at more than 800 sites worldwide. Patients with non-ST-elevation acute coronary syndrome who were selected for management with revascularisation were randomly assigned to clopidogrel or prasugrel. The primary endpoint was cardiovascular death, myocardial infarction, or stroke at 30 months. In the present analysis we assessed differences in the primary endpoint by angiography status and whether the effects of treatment on the primary endpoint differed between patients who had angiography before enrolment and those who had not. 7243 patients younger than 75 years were included in the TRILOGY ACS primary analysis. 3085 (43%) had angiography at baseline, 4158 (57%) had not. Fewer patients who had angiography reached the primary endpoint at 30 months compared with those who did not have angiography, according to Kaplan-Meier analysis (281/3085 [12·8%] vs 480/4158 [16·5%], adjusted hazard ratio [HR] 0·63, 95% CI 0·53-0·75; p<0·0001). The proportion of patients who reached the primary endpoint was lower in the prasugrel group than in the clopidogrel group for those who had angiography (122/1524 [10·7%] vs 159/1561 [14·9%], HR 0·77, 95% CI 0·61-0·98; p=0·032) but did not differ between groups in patients who did not have angiography (242/2096 [16·3%] vs 238/2062 [16·7%], HR 1·01, 0·84-1·20; p=0·94; pinteraction=0·08). Overall, TIMI major bleeding and GUSTO severe bleeding were rare. Bleeding outcomes tended to be higher with prasugrel but did not differ significantly between treatment groups in either angiography cohort. Among patients who had angiography who took prasugrel there were fewer cardiovascular deaths, myocardial infarctions, or strokes than in those who took clopidogrel. This result needs to be corroborated, but it is consistent with previous trials of more versus less intensive antiplatelet treatment. When angiography is done for acute coronary syndrome and anatomic coronary disease confirmed, the benefits and risks of intensive antiplatelet treatment exist whether the patient is treated with drugs or percutaneous coronary intervention. Daiichi Sankyo, Eli Lilly. 23931899 Clinical Benefit From Pemetrexed Before and After Crizotinib Exposure and From Crizotinib Before and After Pemetrexed Exposure in Patients With Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer. Crizotinib produces high response rates and prolonged PFS in ALK+ NSCLC. Retrospective analyses suggest enhanced sensitivity to pemetrexed in crizotinib naive ALK+ NSCLC. Cross-resistance between crizotinib and pemetrexed has not been previously investigated. Patients with stage IV ALK+ NSCLC treated with PEM-CRIZ, or CRIZ-PEM were identified. Overall PFS and PFS excluding central nervous system events (eCNS) were compared. Objective response rates in evaluable patients were 66% (PEM-CRIZ) and 75% (CRIZ-PEM) for pemetrexed and 84% (CRIZ-PEM) and 66% (PEM-CRIZ) for crizotinib. For PEM-CRIZ (n = 29), median PFS and eCNS PFS were both 6 months with pemetrexed, and 10 and 14.5 months, respectively, with crizotinib. For CRIZ-PEM (n = 9), median PFS and eCNS PFS were 4.5 and 3 months, respectively, with pemetrexed, and 8.5 and 7.5 months, respectively, with crizotinib. There was a statistically significant increase in the risk of an overall PFS event with pemetrexed when administered after crizotinib (P = .0277; hazard ratio [HR], 2.5898; 95% confidence interval [CI], 1.1100-6.0424), but differences in the risk of an eCNS PFS event were not significant (P = 0.4913; HR, 1.3521; 95% CI, 0.5727-3.1920). Neither overall nor eCNS PFS for patients while taking crizotinib was associated with a sequence effect relative to pemetrexed. Crizotinib and pemetrexed are active drugs in ALK+ NSCLC. PFS benefit appeared higher with crizotinib than with pemetrexed. PFS benefit from pemetrexed was less after crizotinib compared with before crizotinib, however, this difference was only statistically significant for overall and not eCNS PFS. Pemetrexed exposure did not seem to affect crizotinib outcomes. 23419014 Heterogeneous vapor bubble nucleation on a rough surface. Vapor bubble nucleation on a microrough surface wetted by a volatile, incompressible liquid has been analyzed. The work of formation of a critical nucleus in a surface cavity has been evaluated. Concave sites of a surface with negative curvature can decrease the height of the activation barrier for the formation of a critical nucleus. The average density of the nucleation sites has been evaluated for a surface whose (small) deviation from a plane is specified by a Gaussian random function. 23933028 Felled oil palm trunk as a renewable source for biobutanol production by Clostridium spp. This study aimed to convert felled oil palm trunk to biobutanol by Clostridium spp. For efficient utilization of oil palm trunk, it was separated into sap and trunk fiber. The sap was used directly while the trunk fiber was hydrolyzed to fermentable sugars before use. Among five clostridia strains screened, Clostridium acetobutylicum DSM 1731 was the most suitable strain for butanol production from the sap without any supplementation of nutrients. It produced the highest amount of butanol (14.4g/L) from the sap (sugar concentration of 50g/L) with butanol yield of 0.35g/g. When hydrolysate from the trunk fiber was used as an alternative carbon source (sugar concentration of 30g/L), of the strains tested Clostridium beijerinckii TISTR 1461 produced the highest amount of butanol (10.0g/L) with butanol yield of 0.41g/g. The results presented herein suggest that oil palm trunk is a promising renewable substrate for biobutanol production. 23519207 Aluminium salalen complexes based on 1,2-diaminocyclohexane and their exploitation for the polymerisation of rac-lactide. In this paper nine various salalen ligands have been prepared and characterised. The steric and electronic effects of both the salen and salan fragments have been varied in a systematic fashion to ascertain how this affects the selectivity for the ROP of rac-lactide. These were complexed to AlMe3 to generate pseudo trigonal bypyramidal metal centred complexes. Upon addition of benzyl alcohol the active initiator can be easily prepared. The complexes were screened for the ROP of rac-lactide in solution and melt conditions. PLA with narrow molecular weight distributions (PDIs range from 1.07-1.67) could be isolated with moderate degrees of tacticity. Significantly it was found that chloro groups on the imine fragment increased the degree of heterotactic enchainment in the polymer. The kinetics for one series of salalen-Al complexes was also investigated. 22963410 Scalp hair loss after transsphenoidal adenomectomy in patients with acromegaly. Scalp hair loss is often encountered in clinical practice in Japan after successful surgery for acromegaly. However, this intriguing issue has not been addressed in the literature. The aim of this study was to examine scalp hair loss after surgery for acromegaly. Postoperative scalp hair loss was surveyed using a mail-back questionnaire given to 511 patients undergoing primary surgery for acromegaly, 484 of whom constitute the patient pool in this study. Of the 484 patients, 263 (54%) patients noticed varying degrees of hair loss between 3 and 6 months after surgery [the degree of alopecia was minimal in 50 patients (10%), moderate in 117 patients (24%), and severe in 96 patients (20%)], although postoperative hair loss was noticed only in six (3·6%) of 167 patients with nonfunctioning adenomas. Postoperative hair loss was significantly more common in female patients, cured patients and patients with severe postoperative growth hormone deficiency. Among those 263 patients, full recovery was reported by 85 patients (32%), incomplete recovery by 88 patients (34%), and hardly any recovery by 90 patients (34%). A lack of hair recovery was significantly more common in male patients or in patients with severe hair loss after surgery. This, the first large-scale, single-centre, clinical study to shed light on the issue of postoperative hair loss after surgery for acromegaly, shows that it is important to prospectively inform patients that varying degrees of hair loss occur in a large number of acromegalic patients, especially after successful surgery. 23948433 Identification and functional implication of nuclear localization signals in the N-terminal domain of JMJD5. JMJD5 has recently been reported to participate in circadian rhythm regulation, embryological development, osteoclastogenesis and tumorigenesis. Although JMJD5 has been found mainly localized in the nucleus of cells, how it enters the nucleus remains unclear. Here we report that JMJD5 contains a functional bipartite nuclear localization signal (NLS) and a chromosome region maintenance 1 (CRM1)-dependent nuclear export signal (NES). Importin α/β and transportin-1 were further identified as JMJD5-associated transport proteins, and different binding regions were determined for the two nuclear import receptors. Additionally, we demonstrate that both the active NLS and the JmjC domain of JMJD5 are necessary for cyclin A1 transcription. Chromatin immunoprecipitation (ChIP) analysis confirmed the alterations of di-methylated lysine 36 of histone H3 (H3K36me2) in the coding region of cyclin A1. These results reveal that the N-terminal domain is essential for the nuclear localization of JMJD5 and its normal enzymatic function towards substrates in the nucleus. 23847583 A Tale of Two Maladies? Pathogenesis of Depression with and without the Huntington's Disease Gene Mutation. Huntington's disease (HD) is an autosomal dominant disorder caused by a tandem repeat expansion encoding an expanded tract of glutamines in the huntingtin protein. HD is progressive and manifests as psychiatric symptoms (including depression), cognitive deficits (culminating in dementia), and motor abnormalities (including chorea). Having reached the twentieth anniversary of the discovery of the "genetic stutter" which causes HD, we still lack sophisticated insight into why so many HD patients exhibit affective disorders such as depression at very early stages, prior to overt appearance of motor deficits. In this review, we will focus on depression as the major psychiatric manifestation of HD, discuss potential mechanisms of pathogenesis identified from animal models, and compare depression in HD patients with that of the wider gene-negative population. The discovery of depressive-like behaviors as well as cellular and molecular correlates of depression in transgenic HD mice has added strong support to the hypothesis that the HD mutation adds significantly to the genetic load for depression. A key question is whether HD-associated depression differs from that in the general population. Whilst preclinical studies, clinical data, and treatment responses suggest striking similarities, there are also some apparent differences. We discuss various molecular and cellular mechanisms which may contribute to depression in HD, and whether they may generalize to other depressive disorders. The autosomal dominant nature of HD and the existence of models with excellent construct validity provide a unique opportunity to understand the pathogenesis of depression and associated gene-environment interactions. Thus, understanding the pathogenesis of depression in HD may not only facilitate tailored therapeutic approaches for HD sufferers, but may also translate to the clinical depression which devastates the lives of so many people. 23905952 Transnasal endoscopic approach to the pediatric craniovertebral junction and rostral cervical spine: case series and literature review. The endoscopic transnasal approach to the rostral pediatric spine and craniovertebral junction is a relatively new technique that provides an alternative to the traditional transoral approach to the anterior pediatric spine. In this case series, the authors provide 2 additional examples of patients undergoing endoscopic transnasal odontoidectomies for ventral decompression of the spinal cord. Both patients would have required transection of the palate to undergo an effective transoral operation, which can be a cause of significant morbidity. In one case, transnasal decompression was initially incomplete, and decompression was successfully achieved via a second endoscopic transnasal operation. Both cases resulted in significant neurological recovery and stable long-term spinal alignment. The transnasal approach benefits from entering into the posterior pharynx at an angle that often reduces the length of postoperative intubation and may speed a patient's return to oral intake. Higher reoperation rates are a concern for many endoscopic approaches, but there are insufficient data to conclude if this is the case for this procedure. Further experience with this technique will provide a better understanding of the indications for which it is most effective. Transcervical and transoral endoscopic approaches have also been reported and provide additional options for pediatric anterior cervical spine surgery. 23843539 Response selectivity is correlated to dendritic structure in parvalbumin-expressing inhibitory neurons in visual cortex. Inhibitory neurons have been shown to perform a variety of functions within brain circuits, including shaping response functions in target cells. Still, how the properties of specific inhibitory neuron classes relate to their local circuits remains unclear. To better understand the distribution and origins of orientation selectivity in inhibitory neurons expressing the calcium binding protein parvalbumin (PV) in the mouse primary visual cortex, we labeled PV(+) neurons with red fluorescent protein (RFP) and targeted them for cell-attached electrophysiological recordings. PV(+) neurons could be broadly tuned or sharply tuned for orientation but tended to be more broadly tuned than unlabeled neurons on average. The dendritic morphology of PV(+) cells, revealed by intracellular labeling, was strongly correlated with tuning: highly tuned PV(+) neurons had shorter dendrites that branched nearer to the soma and had smaller dendritic fields overall, whereas broadly tuned PV(+) neurons had longer dendrites that branched farther from the soma, producing larger dendritic fields. High-speed two-photon calcium imaging of visual responses showed that the orientation preferences of highly tuned PV(+) neurons resembled the preferred orientations of neighboring cells. These results suggest that the diversity of the local neighborhood and the nature of dendritic sampling may both contribute to the response selectivity of PV(+) neurons. 23541061 Novel collagen/gelatin scaffold with sustained release of basic fibroblast growth factor: clinical trial for chronic skin ulcers. Chronic skin ulcers such as diabetic ulcers and venous leg ulcers are increasing and are a costly problem in healthcare. We have developed a novel artificial dermis, collagen/gelatin sponge (CGS), which is capable of sustained release of basic fibroblast growth factor (bFGF) for more than 10 days. The objective of this study was to investigate the safety and efficacy of CGS impregnated with bFGF in the treatment of chronic skin ulcers. Patients with chronic skin ulcers that had not healed in at least 4 weeks were treated with CGS impregnated with bFGF at 7 or 14 μg/cm(2) after debridement, and the wound bed improvement was assessed 14 days after application. Wound bed improvement was defined as a granulated and epithelialized area on day 14 with a proportion to the baseline wound area after debridement of 50% or higher. The wound area, the wound area on day 14, and the granulation area on day 14 were independently measured by blinded reviewers in a central review using digital images of wounds taken with a calibrator. Patients were followed up until 28 days after application to observe the adverse reactions related to the application of CGS. From May 2010 to June 2011, 17 patients were enrolled and, in 16 patients, the wound bed improved. Among the randomized patients in step 2, no significant difference was seen between the low-dose group and the high-dose group. No serious adverse reactions were observed. Adverse reactions with a clear causal relationship to the study treatment were mild and patients quickly recovered from them. This study is the first-in-man clinical trial of CGS and showed the safety and efficacy of CGS impregnated with bFGF in the treatment of chronic skin ulcers. This combination therapy could be a promising therapy for chronic skin ulcers. 23850251 Strain echocardiography improves risk prediction of ventricular arrhythmias after myocardial infarction. The aim of this study was to test the hypothesis that strain echocardiography might improve arrhythmic risk stratification in patients after myocardial infarction (MI). Prediction of ventricular arrhythmias after MI is challenging. Left ventricular ejection fraction (LVEF) <35% is the main parameter for selecting patients for implantable cardioverter-defibrillator therapy. In this prospective, multicenter study, 569 patients >40 days after acute MI were included, 268 of whom had ST-segment elevation MIs and 301 non-ST-segment elevation MIs. By echocardiography, global strain was assessed as average peak longitudinal systolic strain from 16 left ventricular segments. Time from the electrocardiographic R-wave to peak negative strain was assessed in each segment. Mechanical dispersion was defined as the standard deviation from these 16 time intervals, reflecting contraction heterogeneity. Ventricular arrhythmias, defined as sustained ventricular tachycardia or sudden death during a median 30 months (interquartile range: 18 months) of follow-up, occurred in 15 patients (3%). LVEFs were reduced (48 ± 17% vs. 55 ± 11%, p < 0.01), global strain was markedly reduced (-14.8 ± 4.7% vs. -18.2 ± 3.7%, p = 0.001), and mechanical dispersion was increased (63 ± 25 ms vs. 42 ± 17 ms, p < 0.001) in patients with arrhythmias compared with those without. Mechanical dispersion was an independent predictor of arrhythmic events (per 10-ms increase, hazard ratio: 1.7; 95% confidence interval: 1.2 to 2.5; p < 0.01). Mechanical dispersion and global strain were markers of arrhythmias in patients with non-ST-segment elevation MIs (p < 0.05 for both) and in those with LVEFs >35% (p < 0.05 for both), whereas LVEF was not (p = 0.33). A combination of mechanical dispersion and global strain showed the best positive predictive value for arrhythmic events (21%; 95% confidence interval: 6% to 46%). Mechanical dispersion by strain echocardiography predicted arrhythmic events independently of LVEF in this prospective, multicenter study of patients after MI. A combination of mechanical dispersion and global strain may improve the selection of patients after MI for implantable cardioverter-defibrillator therapy, particularly in patients with LVEFs >35% who did not fulfill current implantable cardioverter-defibrillator indications. 23911216 The influence of consuming an egg or an egg-yolk buttermilk drink for 12 wk on serum lipids, inflammation, and liver function markers in human volunteers. Dietary cholesterol elevates serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) concentrations modestly. There are indications that the cholesterol-raising effect depends on the food matrix, that is, sphingolipids and lactic acid bacteria are suggested to influence cholesterol metabolism. Traditional buttermilk is rich in both sphingolipids and lactic acid bacteria. Therefore, the aim of this study was to evaluate whether effects on cholesterol metabolism depend on food matrix (e.g., cholesterol provided as egg [yolk] or incorporated into traditionally prepared buttermilk drink). Participants (N = 97) took part in a 12-wk intervention study. The controls (n = 20) continued their regular egg consumption of one to two eggs a week. The other two groups consumed either one extra egg per day (n = 57) or a buttermilk drink containing one egg yolk (n = 20). Blood was sampled at day 1 and at the end of the experimental period (day 90) to analyze serum lipids, lipoproteins, and markers reflecting cholesterol metabolism, low-grade systemic inflammation, endothelial activity, and liver function. Serum TC and LDL-C concentrations increased significantly by respectively 0.63 mmol/L (P < 0.05) and 0.59 mmol/L (P < 0.05) in women consuming one additional egg per day compared with controls. There were no effects on markers for inflammation, endothelial activity, or liver function. The increase in serum TC and LDL-C concentration was no longer significant in women consuming the same egg yolk incorporated in a buttermilk drink (0.33 mmol/L [P = 0.66] and 0.31 mmol/L [P = 0.55], respectively). Daily egg consumption for 12 wk increases serum TC and LDL-C concentrations in women but not markers for inflammation, endothelial activity, and liver function. Interestingly, the rise in serum LDL-C concentrations is less pronounced when egg yolk is incorporated into a buttermilk drink, indeed suggesting that fractions in the buttermilk might influence dietary cholesterol absorption. 23711918 Synthesis and anticancer activity of dichloroplatinum(II) complexes of podophyllotoxin. A series of dichloroplatinum(II) complexes of podophyllotoxin (PPT) were prepared, and their cytotoxicity against sensitive (A-549, HeLa, HCT-8, Hep-G2, K562) and resistant (ADM/K562) cell lines were evaluated. Complex cis-[4α-O-(2″,3″-diaminopropanoyl)-podophyllotoxin] dichloride platinum(II) (12) displayed most potent cytotoxicity with IC50 value in the range 0.071-2.98 μM. Complex 12 induces cell cycle arrest in the G2/M phase, and inhibits the formation of microtubules in HeLa cells. Furthermore, this complex exhibits potent DNA cleavage capabilities. 23921138 Slow Oscillations of KATP Conductance in Mouse Pancreatic Islets Provide Support for Electrical Bursting Driven by Metabolic Oscillations. We used the patch clamp technique in situ to test the hypothesis that slow oscillations in metabolism mediate slow electrical oscillations in mouse pancreatic islets by causing oscillations in KATP channel activity. Total conductance was measured over the course of slow bursting oscillations in surface β-cells of islets exposed to 11.1 mM glucose by either switching from current clamp to voltage clamp at different phases of the bursting cycle or by clamping the cells to -60 mV and running two-second voltage ramps from -120 to -50 mV every 20 seconds. The membrane conductance, calculated from the slopes of the ramp current-voltage curves, oscillated and was larger during the silent phase than during the active phase of the burst. The ramp conductance was sensitive to diazoxide, and the oscillatory component was reduced by sulfonylureas or by lowering extracellular glucose to 2.8 mM, suggesting that the oscillatory total conductance is due to oscillatory KATP channel conductance. We demonstrate that these results are consistent with the Dual Oscillator Model, in which glycolytic oscillations drive slow electrical bursting, but not with other models in which metabolic oscillations are secondary to calcium oscillations. The simulations also confirm that oscillations in membrane conductance can be well estimated from measurements of slope conductance and distinguished from gap junction conductance. The data, combined with insights from mathematical models, support a mechanism of slow (~5 min) bursting driven by oscillations in metabolism, rather than by oscillations in the intracellular free calcium concentration. 23530834 Design, Synthesis, Biological Evaluation, and Docking Studies of (S)-Phenylalanine Derivatives with a 2-Cyanopyrrolidine Moiety as Potent Dipeptidyl Peptidase 4 Inhibitors. A novel series of (S)-phenylalanine derivatives with a 2-cyanopyrrolidine moiety were designed and synthesized through a rational drug design strategy. Biological evaluation revealed that most tested compounds were potent dipeptidyl peptidase 4 (DPP-4) inhibitors, among them, the cyclopropyl-substituted phenylalanine derivative 11h displayed the most potent DPP-4 inhibitory activity with an IC50 value of 0.247 μM. In addition, molecular docking analysis of the representative compounds 11h, 11k, and 15a were performed, which not only revealed the impact of binding modes on DPP-4 inhibitory activity, but also provided additional methodological values for design and optimization. © 2013 John Wiley & Sons A/S. 23875952 Quantification and comparison of psychiatric distress in African patients with albinism and vitiligo: a 5-year prospective study. Vitiligo and Albinism are two disorders of pigmentation that make the affected African highly visible and strikingly different from their peers. Both pose considerable management challenges, attract significant stigma and profound impairment of quality of life. To determine and compare psychiatric distress in vitiligo and albinism using the Hospital Anxiety and Depression Scale (HADS). Participants were 87 albinos and 102 vitiligo adult patients seen at an urban tertiary hospital in Nigeria between 2004 and 2009. Prevalence of psycho morbidity was 59% (60/102) in vitiligo compared with 26% (23/87) in the albinos. The mean anxiety score was estimated to be 2.55 points lower for albino patients (95% CI: 1.47 to 3.64), and the mean depression score 2.76 points lower (95% CI: 1.84 to 3.68), after adjustment for age, sex and marital status. However, significant differences were not observed when comparing the vitiligo patients with the subset of albino patients with skin cancer. Older patients had significantly higher anxiety and depression scores. Females had significantly higher anxiety scores (but not depression scores) compared to males. Genital involvement in vitiligo was significantly associated with anxiety but not depression. We found that the African with vitiligo suffers significantly higher psychiatric distress than the African albino on average. Clinical evaluation of these patients would be incomplete without assessment of their psycho morbidity. There is need for increased focus on cancer prevention strategies in the African albino. 23628391 Incidence and risk factors of anti-HLA immunization after pregnancy. Pregnancy is the only natural source of anti-HLA immunization. The exact frequency of this immunization remains undetermined as prior studies either used methods with a low sensitivity or were performed late after delivery. We present here the first study on women at delivery evaluating anti-HLA immunization by Luminex. We also attempted to isolate factors influencing immunization, such as soluble HLA-G (sHLA-G) levels and genetic polymorphisms. With Luminex, anti-HLA immunization was observed in 54.4% of the women. As expected, immunization frequency increased with the number of children, reaching 74% in women with >2 deliveries. Among immunized women, strong cytotoxic Ab (as detected by Complement Dependent Cytotoxicity) were associated with a lower level of sHLA-G. None of the studied polymorphisms influenced immunization rate in the whole cohort. Among 94 first pregnant women with no history of miscarriage, the -174 IL-6 gene promoter mutation (G/C) appeared more frequently in non immunized women (69% vs. 45% in immunized ones, p=0.02). Lastly, the occurrence of a miscarriage before the first live delivery significantly decreased immunization. These results may help to understand mechanisms of pregnancy induced immunization. They also have an impact in the management of previous pregnant women requiring organ or hematopoietic stem cell transplantation. 23933000 Comparative judgments of symbolic and non-symbolic stimuli yield different patterns of reaction times. Are different magnitudes, such as Arabic numerals, length and area, processed by the same system? Answering this question can shed light on the building blocks of our mathematical abilities. A shared representation theory suggested that discriminability of all magnitudes complies with Weber's law. The current work examined this suggestion. We employed comparative judgment tasks to investigate different types of comparisons - conceptual comparison of numbers, physical comparison of numbers and physical comparison of different shapes. We used 8 different size ratios and plotted reaction time as a function of these ratios. Our findings suggest that the relationship between discriminability and size ratio is not always linear, as previously suggested; rather, it is modulated by the type of comparison and the type of stimuli. Hence, we suggest that the representation of magnitude is not as rigid as previously suggested; it changes as a function of task demands and familiarity with the compared stimuli. 23428307 No increased sensitivity in brain activity of adolescents exposed to mobile phone-like emissions. To examine the potential sensitivity of adolescents to radiofrequency electromagnetic field (RF EMF) exposures, such as those emitted by mobile phones. In a double-blind, randomized, crossover design, 22 adolescents aged 11-13 years (12 males) underwent three experimental sessions in which they were exposed to mobile phone-like RF EMF signals at two different intensities, and a sham session. During exposure cognitive tasks were performed and waking EEG was recorded at three time-points subsequent to exposure (0, 30 and 60 min). No clear significant effects of RF EMF exposure were found on the waking EEG or cognitive performance. Overall, the current study was unable to demonstrate exposure-related effects previously observed on the waking EEG in adults, and also provides further support for a lack of an influence of mobile phone-like exposure on cognitive performance. Adolescents do not appear to be more sensitive than adults to mobile phone RF EMF emissions. 23899407 Big-endothelin 1 (big ET-1) and homocysteine in the serum of dogs with chronic kidney disease. This study was aimed at determining the serum concentration of homocysteine (Hcy) and big endothelin-1 (big ET-1, the precursor of endothelin) in dogs with chronic kidney disease (CKD) with and without hypertension, proteinuria and inflammation, in order to explore their role as biomarkers of hypertension associated with CKD. Hcy and big ET-1 were measured using an enzyme-linked immunosorbent assay and an enzymatic cyclic reaction, respectively, in dogs with CKD staged, as proposed by the International Renal Interest Society (IRIS), using serum creatinine, urinary protein to creatinine (UPC) ratio and systolic blood pressure, and classified as affected or not by inflammation based on the serum concentration of C-reactive protein (CRP). Serum Hcy was significantly higher in dogs of IRIS stages II, III and IV compared with controls and in proteinuric compared with non-proteinuric dogs. No differences relating to the degree of hypertension or to the CRP concentration were found. Serum big ET-1 significantly increased in dogs of IRIS stage IV compared with controls, in proteinuric compared with non-proteinuric dogs, in dogs with severe hypertension compared with those without hypertension, and in dogs with increased CRP compared to those with normal CRP concentrations. Hcy only correlated with serum creatinine but big ET-1 significantly correlated with serum creatinine, UPC ratio, systolic blood pressure, and increased CRP. In conclusion, both Hcy and big ET-1 increase in dogs with CKD. Although further research is needed, big ET-1, but not Hcy, may also be considered as a biomarker of hypertension. 23947381 Poly-L-Lysine Compacts DNA, Kills Bacteria and Improves Proteases Inhibition in Cystic Fibrosis Sputum. Rationale: Neutrophil serine proteases in cystic fibrosis (CF) lung secretions partially resist inhibition by natural and exogenous inhibitors, mostly because DNA impairs their control. Cationic polypeptides display the property of condensing DNA and retain antimicrobial properties. We hypothesized that DNA condensation by cationic polypeptides in CF sputum would result in a better control of CF inflammation and infection. Objectives: We examined whether poly-L-lysine would compact DNA in CF lung secretions and liquefy CF sputum, improve the control of extracellular proteases by exogenous inhibitors and whether it displays antibacterial properties towards CF-associated bacteria. Methods: We used fluorogenic methods to measure proteolytic activities and inhibition by protease inhibitors in whole sputum homogenates from CF patients before and after treatment with poly-L-lysine. Antibacterial properties of poly-L-lysine were measured in bacterial cultures and in whole CF sputum. Poly-L-lysine toxicity was evaluated after aerosolization by histological analysis, flow cytometry and quantification of proinflammatory cytokines. Measurements and main results: Poly-L-lysine compacts CF sputum DNA, generating a liquid phase that improves ciliary beating frequency at the lung epithelium surface, and allows the control of neutrophil elastase and cathepsin G by their natural inhibitors. It retains antimicrobial properties against P. aeruginosa and S. aureus at doses that induce no inflammation in the mouse lung after aerosol administration. Conclusions: Poly-L-lysine may be an alternative to Dornase-alpha to liquefy sputum with added benefits, since it helps natural inhibitors to better control the deleterious effects of extracellularly released neutrophil serine proteases and has the ability to kill bacteria in CF sputum. 23852749 Graphene oxide nanoparticles for enhanced photothermal cancer cell therapy under the irradiation of a femtosecond laser beam. Nano-sized graphene and graphene oxide (GO) are promising for biomedical applications, such as drug delivery and photothermal therapy of cancer. It is observed in this work that the ultrafast reduction of GO nanoparticles (GONs) with a femtosecond laser beam creates extensive microbubbling. To understand the surface chemistry of GONs on the microbubble formation, the GONs were reduced to remove most of the oxygen-containing groups to get reduced GONs (rGONs). Microbubbling was not observed when the rGONs were irradiated by the laser. The instant collapse of the microbubbles may produce microcavitation effect that brings about localized mechanical damage. To understand the potential applications of this phenomenon, cancer cells labeled with GONs or rGONs were irradiated with the laser. Interestingly, the microbubbling effect greatly facilitated the destruction of cancer cells. When microbubbles were produced, the effective laser power was reduced to less than half of what is needed when microbubbling is absent. This finding will contribute to the safe application of femtosecond laser in the medical area by taking advantage of the ultrafast reduction of GONs. It may also find other important applications that need highly localized microcavitation effects. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013. 23883881 Comprehensive abortion care: evidence of improvements in hospital-level indicators in Tigray, Ethiopia. Approximately 18% of maternal deaths in East Africa is attributable to unsafe abortion. Availability of comprehensive abortion care (CAC) services at all levels of the healthcare system, including medical abortion, has the potential to increase access to safe abortion thereby reducing the burden of unsafe abortion. This study sought to assess trends in abortion-related morbidity indicators in referral hospitals. Researchers conducted a secondary data analysis on retrospectively collected data. Data analysed were collected from four hospitals in the Tigray region of Ethiopia that took part in a CAC pilot project. Providers were trained in mid-2009 to provide abortion services using all available technologies. Data records from hospitals were collected in 2012 for the years 2006 through 2012; 2006/2007 data were too sparse to include in the analyses. Trends in abortion-related services show a significant decrease in treatment of incomplete abortion, inverting the relationship between safe terminations and treatment of incompletes as a percentage of total abortions. Medication abortion was nearly non-existent in 2008, but increased steadily, representing 80% of total procedures in 2012. The inclusion of medication abortion and availability of CAC also contributed to a decline in inpatient procedures and prevalence of complications. The trends observed in the data demonstrate how increased availability of CAC services at all levels of the healthcare system, among other factors, can contribute to reductions in the burden of unsafe abortion at referral hospitals. 23301911 Clinical and morphological features of serosal form of eosinophilic gastroenteritis in a retrospective study of 10 children. Eosinophilic gastroenteritis (EG) is an increasingly recognized inflammatory disease characterized by gastrointestinal (GI) symptoms and eosinophilic infiltration of the GI tract. Serosal form is one subtype of EG. The aetiology and pathogenesis of EG are unknown and the diagnosis and treatment properly are difficult for physician. A retrospective study of 10 paediatric patients (mean age 10.8 years) was performed to review records of medical, endoscopic, ultrasonographic findings and histological features. All the cases presented abdominal pain symptom in this study. Supra-umbilical pain was the main location of pain. The pain intensity of cases was from mild to moderate. Vomiting and diarrhoea may also be found. All the cases manifested as peripheral eosinophilia and eosinophilic ascites (EA) detected by ultrasonograph and ascetic fluid white cell differential count were analysed. Erythema was the predominate feature seen on endoscopy. Histologic examination showed patchy eosinophilic infiltration in the GI tract in all patients. Symptom remission within 1 week and ascites absorbed within 2-3 weeks in all the patients treated with steroids. Serosal form of EG affects paediatric patients as well as adults, which can be diagnosed early and correctly through realising the character of the disease. Histopathology is the gold standard for diagnosis. Corticosteroids are the first line therapy. 23615131 Extended treatment with peginterferon α-2a in combination with lamivudine or adefovir for 96 weeks yields high rates of HBeAg and HBsAg seroconversion. The study aimed to investigate the efficacy and safety of peginterferon α-2a (PEG IFNα-2a) in combination with lamivudine or adefovir in the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB). In total, 47 patients with HBeAg-positive CHB received either PEG IFNα-2a (135 μg once weekly) plus lamivudine (100 mg daily) or adefovir (10 mg daily). All patients completed 96 weeks of therapy and were followed up for a further 24 weeks. Baseline characteristics and treatment efficacy of the two groups were similar. All patients achieved hepatitis B virus (HBV) DNA <500 copies/mL at 96 weeks, and none had a virological rebound after stopping the therapy. The rate of HBeAg seroconversion was 46.8% at 48 weeks, increased to 74.5% at 96 weeks, and kept at 72.3% at 120 weeks. Hepatitis B surface antigen (HBsAg) seroconversion rate was 6.4% at 48 weeks, increased to 21.3% at 96 weeks, and kept at 27.7% at 120 weeks. Extended treatment with PEG IFNα-2a with lamivudine or adefovir for 96 weeks is a promising strategy to achieve high rates of sustainable HBeAg and HBsAg seroconversion and HBV DNA suppression in patients with HBeAg-positive CHB. 23892287 Transactivation specificity is conserved among p53 family proteins and depends on a response element sequence code. Structural and biochemical studies have demonstrated that p73, p63 and p53 recognize DNA with identical amino acids and similar binding affinity. Here, measuring transactivation activity for a large number of response elements (REs) in yeast and human cell lines, we show that p53 family proteins also have overlapping transactivation profiles. We identified mutations at conserved amino acids of loops L1 and L3 in the DNA-binding domain that tune the transactivation potential nearly equally in p73, p63 and p53. For example, the mutant S139F in p73 has higher transactivation potential towards selected REs, enhanced DNA-binding cooperativity in vitro and a flexible loop L1 as seen in the crystal structure of the protein-DNA complex. By studying, how variations in the RE sequence affect transactivation specificity, we discovered a RE-transactivation code that predicts enhanced transactivation; this correlation is stronger for promoters of genes associated with apoptosis. 23918669 Treatment of Tracheomalacia with Aortopexy in Children in Glasgow. Objective The aim of this study was to assess outcomes of infants and children undergoing aortopexy and to try and establish which children would derive the greatest benefit from this complex intervention.Materials and Methods This is a retrospective case series in a pediatric tertiary referral hospital between 1993 and 2012. A case sheet review was performed to collect demographic data and identify outcomes for each child. The effects of the subtype of tracheomalacia, weight at surgery, symptoms at presentation, surgical approach, and preoperative ventilation were considered.Results There were 30 children who underwent aortopexy during the study period. Of the 30 children in the study, 21 children (70%) were male. The gestational age at birth ranged between 25 and 41 weeks (9 children [30%] were preterm). Age at surgery was between 2 and 140 weeks (mean; 31.5 weeks, median; 26 weeks). The onset of symptoms was between birth and 18 months (mean; 3.8 months, median; 3.5 months). The presenting symptoms were stridor (n = 9; 30%), failed extubation (n = 4; 13%), death attacks (n = 8; 27%), and cyanosis (n = 9; 30%). The underlying pathology was primary in 10 children (33%) and secondary in 18 children. The diagnosis was made by bronchoscopy in 26 children (93%). Imaging was performed in 25 children (83%). Aortopexy in our institution is performed by general pediatric surgeons (n = 8; 27%) and cardiothoracic surgeons (n = 22; 73%). In the immediately postoperative period, 25 children (83%) were thriving. Of the children that required another procedure; 1 child was reintubated (3%), 2 children had a tracheostomy (6%), 1 child had a stent (3%), and 2 children died (6%). Clinical follow-up of these children was between 1 month and 12 years. Long term, in 22 children (73%) were asymptomatic.Conclusion There were no clinical predictors of outcome identified, but aortopexy is a safe effective procedure for children with severe tracheomalacia. 23885877 Neuron survival: say it with flowers. The Flower protein family is part of a cell-cell communication pathway that regulates cell competition, in which fit cells eliminate less fit neighbors. A new study demonstrates that this pathway can also govern the culling of unwanted neurons during development. 23887128 Oral epithelial stem cells in tissue maintenance and disease: the first steps in a long journey. The identification and characterization of stem cells is a major focus of developmental biology and regenerative medicine. The advent of genetic inducible fate mapping techniques has made it possible to precisely label specific cell populations and to follow their progeny over time. When combined with advanced mathematical and statistical methods, stem cell division dynamics can be studied in new and exciting ways. Despite advances in a number of tissues, relatively little attention has been paid to stem cells in the oral epithelium. This review will focus on current knowledge about adult oral epithelial stem cells, paradigms in other epithelial stem cell systems that could facilitate new discoveries in this area and the potential roles of epithelial stem cells in oral disease.International Journal of Oral Science (2013) 5, doi:10.1038/ijos.2013.46; published online 26 July 2013. 23699069 Pneumocystis jirovecii multilocus genotyping profiles in Northern Ireland. Pneumocystis jirovecii causes pneumonia, a severe opportunistic infection in immunosuppressed patients that has both person-to-person airborne transmission and environmental transmission as important routes of infection. An increasing incidence of P. jirovecii in Northern Ireland prompted a detailed epidemiological and molecular review that included enhanced surveillance on all lower respiratory specimens. Genotyping of these P. jirovecii positive specimens was undertaken using multiple locus sequence typing (MLST) targeting known variable regions of the P. jirovecii genome. Multiple circulating types were found among all patient risk categories. However, a predominance of one MLST type was found in a P. jirovecii outbreak amongst the renal transplant population. Our results demonstrate the diversity of P. jirovecii strains amongst the local immunosuppressed cohort and highlight the importance of genotyping in the investigation of common sources of P. jirovecii amongst immunosuppressed patients. 23934371 Thin and thick target PIXE analyses to assess the mechanism of Cu(2+) removal by Egeria densa. In this work the PIXE technique was used to study the mechanism of metal sorption by dead biomass. Several batch copper-sorption experiments were performed by using Egeria densa biomass. PIXE measurements were performed in solid and liquid samples. Element concentrations in biosorbent samples were determined using the Clara software. Based on the mass balance among the major elements in the liquid and solid phases before and after the Cu-removal experiments, an ion exchange process is suggested as the main mechanism. 22771193 Safety and feasibility of laparoscopic appendicovesicostomy in children. Mitrofanoff appendicovesicostomy is needed for securing a conduit for clean intermittent catheterization in children with myelomeningocele, posterior urethral valves and non-neuropathic neuropathic bladder. An open technique is widely used; herein we report our initial experience with minimally invasive laparoscopic appendicovesicostomy in children. During 2007-2011 we operated on 4 male children with a mean age of 6 years (3-9) suffering from posterior urethral valves (1), myelomeningocele (2), and non-neuropathic neuropathic bladder (1). A posterior Mitrofanoff trough was used in one child while in the remaining children we used the anterior Mitrofanoff trough. The mean operative time was 3.5 h (3-5). The mean hospital stay was 3.7 days (2-5). The mean follow up was 12.5 months (5-30). All are continent; one child was converted to open because of failure to pass the catheter at the end of the procedure. Cosmetic aspect is perfect. No difficulty in catheterization was encountered. Laparoscopic Mitrofanoff is a feasible, safe and effective technique associated with low morbidity. 23732563 RAPID: fast and accurate sequence-based prediction of intrinsic disorder content on proteomic scale. Recent research in the protein intrinsic disorder was stimulated by the availability of accurate computational predictors. However, most of these methods are relatively slow, especially considering proteome-scale applications, and were shown to produce relatively large errors when estimating disorder at the protein- (in contrast to residue-) level, which is defined by the fraction/content of disordered residues. To this end, we propose a novel support vector Regression-based Accurate Predictor of Intrinsic Disorder (RAPID). Key advantages of RAPID are speed (prediction of an average-size eukaryotic proteome takes <1h on a modern desktop computer); sophisticated design (multiple, complementary information sources that are aggregated over an input chain are combined using feature selection); and high-quality and robust predictive performance. Empirical tests on two diverse benchmark datasets reveal that RAPID's predictive performance compares favorably to a comprehensive set of state-of-the-art disorder and disorder content predictors. Drawing on high speed and good predictive quality, RAPID was used to perform large-scale characterization of disorder in 200+ fully sequenced eukaryotic proteomes. Our analysis reveals interesting relations of disorder with structural coverage and chain length, and unusual distribution of fully disordered chains. We also performed a comprehensive (using 56000+ annotated chains, which doubles the scope of previous studies) investigation of cellular functions and localizations that are enriched in the disorder in the human proteome. RAPID, which allows for batch (proteome-wide) predictions, is available as a web server at http://biomine.ece.ualberta.ca/RAPID/. 23883290 Effect of changes in a food frequency questionnaire: comparing data from two national dietary survey instruments among 12-month-old infants. National dietary surveys among Norwegian 12-months olds have been conducted twice: in 1999 and 2007. At both time-points diet were assessed by a semi-quantitative food frequency questionnaire (SFFQ) (the SFFQ-1999 and the SFFQ-2007). Modifications in the SFFQ-2007 compared to the SFFQ-1999 have been made; therefore, the objective of the present study has been to explore the comparability of the data obtained by the two questionnaires. Moreover, reliability of maternal recall of infant feeding practices was assessed. Three hundred Norwegian infants born in April 2007 were invited to participate by completing both the SFFQ-1999 and the SFFQ-2007. An invitation letter and one of two questionnaires were sent by mail to the mother/parents about two weeks before the child turned 12 months of age. The study had a cross-over design where half of the sample received the SFFQ-1999 first and then about 2--3 weeks later they received the SFFQ-2007. The second half received the SFFQ-2007 first, and then 2--3 weeks later they received the SFFQ-1999. Ninety three participants completed both questionnaires (SFFQ-1999 and SFFQ-2007). For nutrients, the largest significant differences between the questionnaires were found for intake of vitamin D and added sugar, where added sugar was reported lower and vitamin D was reported higher with the SFFQ-2007 compared to the SFFQ-1999. For food items, lower intake of yoghurt and higher intake of vegetables and fish were observed with the SFFQ-2007 compared to the SFFQ-1999. In addition, reliable answers with regard to breastfeeding status, age for breastfeeding cessation and age for introducing solid foods were found. There was reasonable comparability between the two questionnaires for most nutrients and foods. The differences between the two questionnaires could mainly be explained by modifications that had occurred over time, where changes in the food composition databases used and especially changes in commercial recipes with regard to baby food products seemed to be of major importance. The differences are important to take into account when interpreting dietary trends among Norwegian 12 month-olds in the period from 1999 to 2007. This study also implies that maternal recall of infant feeding practices is reliable. 23603678 Alga-produced cholera toxin-Pfs25 fusion proteins as oral vaccines. Infectious diseases disproportionately affect indigent regions and are the greatest cause of childhood mortality in developing countries. Practical, low-cost vaccines for use in these countries are paramount to reducing disease burdens and concomitant poverty. Algae are a promising low-cost system for producing vaccines that can be orally delivered, thereby avoiding expensive purification and injectable delivery. We engineered the chloroplast of the eukaryotic alga Chlamydomonas reinhardtii to produce a chimeric protein consisting of the 25-kDa Plasmodium falciparum surface protein (Pfs25) fused to the β subunit of the cholera toxin (CtxB) to investigate an alga-based whole-cell oral vaccine. Pfs25 is a promising malaria transmission-blocking vaccine candidate that has been difficult to produce in traditional recombinant systems due to its structurally complex tandem repeats of epidermal growth factor-like domains. The noncatalytic CtxB domain of the cholera holotoxin assembles into a pentameric structure and acts as a mucosal adjuvant by binding GM1 ganglioside receptors on gut epithelial cells. We demonstrate that CtxB-Pfs25 accumulates as a soluble, properly folded and functional protein within algal chloroplasts, and it is stable in freeze-dried alga cells at ambient temperatures. In mice, oral vaccination using freeze-dried algae that produce CtxB-Pfs25 elicited CtxB-specific serum IgG antibodies and both CtxB- and Pfs25-specific secretory IgA antibodies. These data suggest that algae are a promising system for production and oral delivery of vaccine antigens, but as an orally delivered adjuvant, CtxB is best suited for eliciting secretory IgA antibodies for vaccine antigens against pathogens that invade mucosal surfaces using this strategy. 23219857 Off-target effects of thrombolytic drugs: apolipoprotein A-I proteolysis by alteplase and tenecteplase. The administration of thrombolytic drugs is of proven benefit in a variety of clinical conditions requiring acute revascularization, including acute myocardial infarction (AMI), ischemic stroke, pulmonary embolism, and venous thrombosis. Generated plasmin can degrade non-target proteins, including apolipoprotein A-I (apoA-I), the major protein constituent of high-density lipoproteins (HDL). Aim of the present study was to compare the extent of apoA-I proteolytic degradation in AMI patients treated with two thrombolytic drugs, alteplase and the genetically engineered t-PA variant tenecteplase. ApoA-I degradation was evaluated in sera from 38 AMI patients treated with alteplase or tenecteplase. In vitro, apoA-I degradation was tested by incubating control sera or purified HDL with alteplase or tenecteplase at different concentrations (5-100 μg/ml). Treatment with alteplase and tenecteplase results in apoA-I proteolysis; the extent of apoA-I degradation was more pronounced in alteplase-treated patients than in tenecteplase-treated patients. In vitro, the extent of apoA-I proteolysis was higher in alteplase-treated sera than in tenecteplase-treated sera, in the whole drug concentration range. No direct effect of the two thrombolytic agents on apoA-I degradation was observed. In addition to apoA-I, apoA-IV was also degraded by the two thrombolytic agents and again proteolytic degradation was higher with alteplase than tenecteplase. In conclusion, this study indicates that both alteplase and tenecteplase cause plasmin-mediated proteolysis of apoA-I, with alteplase resulting in a greater apoA-I degradation than tenecteplase, potentially causing a transient impairment of HDL atheroprotective functions. 23681195 Influence of food substrates on the development of the blowflies Calliphora vicina and Calliphora vomitoria (Diptera, Calliphoridae). The blowflies Calliphora vicina and Calliphora vomitoria are among the first colonizers of human remains in Europe. Laboratory development studies with immature stages of these blowflies for postmortem interval (PMI) calculations are generally performed on different media such as processed food substrates or liver of various animals. The question arises whether these media per se influence the development of larvae and thus PMI calculations? In this systematic approach, the effects of an assortment of food substrates on the development of the larvae were analyzed. C. vomitoria showed much better growth on processed substrates such as beef, pork, turkey, and mixed minced meats than on unprocessed substrates such as beef and pork liver and turkey steak. Beef liver even impeded full development of the species and resulted in death of all individuals. C. vomitoria was therefore categorized as a specialist. Even though mixed minced meat yielded low pupariation rates for C. vicina, the species showed, otherwise, comparable growth rates on all substrates tested and was thus considered to be a generalist. These findings emphasize the importance of parameters besides temperature on the development rates of forensically important fly larvae. 23701660 Intercellular communication by related bacterial protein toxins: colicins, contact-dependent inhibitors, and proteins exported by the type VI secretion system. Bacteria are in constant conflict with competing bacterial and eukaryotic cells. To cope with the various challenges, bacteria developed distinct strategies, such as toxins that inhibit the growth or kill rivals of the same ecological niche. In recent years, two toxin systems have been discovered - the type VI secretion system and the contact-dependent growth inhibition (CDI) system. These systems have structural and functional similarities and share features with the long-known gram-negative bacteriocins, such as small immunity proteins that bind to and inactivate the toxins, and target sites on DNA, tRNA, rRNA, murein (peptidoglycan), or the cytoplasmic membrane. Colicins, CdiA proteins, and certain type VI toxins have a modular design with the transport functions localized in the N-terminal region and the activity functions localized in the C-terminal region. Despite these common properties, the sequences of toxins and immunity proteins of colicins, CDI systems, and type VI systems show little similarity. 23939425 Probing the reactivity of o-phthalaldehydic acid/methyl ester: synthesis of N-isoindolinones and 3-arylaminophthalides. A new method for the synthesis of N-substituted isoindolinones and 3-arylaminophthalides was developed through aza-Wittig/cyclisation. The reaction of o-phthalaldehydic acid methyl ester with benzylic, aromatic and aliphatic azides gave N-isoindolinones whereas reaction of o-phthalaldehydic acid with the aromatic azides gave 3-arylaminophthalides. 23928080 Strong genome-wide divergence between sympatric European river and brook lampreys. Lampreys, together with hagfishes, are the only extant representatives of jawless vertebrates and thus of prime interest for the study of vertebrate evolution [1]. Most lamprey genera occur in two forms with divergent life histories: a parasitic, anadromous and a non-parasitic, freshwater resident form [2-8]. The taxonomic status of such 'paired species' is disputed, however. While indistinguishable at larval stages, but clearly distinct as adults, they cannot be differentiated with available genetic data [6,7], which has fuelled speculations that the two forms may in fact represent products of phenotypic plasticity within a single species. Here, we use restriction site-associated DNA sequencing (RADseq) to examine the genetic population structure of sympatric European river (Lampetra fluviatilis L., 1758) and brook (Lampetra planeri Bloch, 1784) lampreys. We find strong genetic differentiation and identify numerous fixed and diagnostic single nucleotide polymorphisms (SNPs) between the two species, 12 of which can be unequivocally assigned to specific genes. 23826828 Combining in silico protein stability calculations with structure-function relationships to explore the effect of polymorphic variation on cytochrome P450 drug metabolism. We carried out an in silico structural analysis of 348 non-synonymous single nucleotide polymorphisms, found across nine of the major human drug metabolising cytochrome P450 isoforms, to determine the effects of mutations on enzyme structure and function. Previous functional studies in our group have delineated regions of the cytochrome P450 structure important for substrate recognition, substrate and product access and egress from the active site and interaction with the cytochrome P450 reductase. Here we combine the information from those studies with new in silico calculations on the effect of mutations on protein stability and we compare our results to experimental data in order to establish the likely causes of altered drug metabolism observed for cytochrome P450 variants in functional assays to date, in the process creating a cytochrome P450 polymorphic variant map. Using the computational tool Site Directed Mutator we predicted destabilising mutations that result in altered enzyme function in vitro with a specificity of 83%. We found that 75% of all cytochrome P450 mutations that show altered activity in vitro are either predicted to be destabilising to protein structure or are found within regions predicted to be important for catalytic activity. Furthermore, we found that 70% of the mutations that showed similar activity to the wild-type enzyme in in vitro studies lie outside of functional regions important for catalytic activity and are predicted to have no effect on protein stability. Our resultant cytochrome P450 polymorphic variant map should therefore find utility in predicting the likely functional effect of uncharacterised variants on drug metabolism. 23864684 Coordinated regulation of hepatic energy stores by leptin and hypothalamic agouti-related protein. Like obesity, prolonged food deprivation induces severe hepatic steatosis; however, the functional significance of this phenomenon is not well understood. In this study, we show that the fall in plasma leptin concentration during fasting is required for the development of hepatic steatosis in mice. Removal of leptin receptors from AGRP neurons diminishes fasting-induced hepatic steatosis. Furthermore, the suppressive effects of leptin on fasting-induced hepatic steatosis are absent in mice lacking the gene encoding agouti-related protein (Agrp), suggesting that this function of leptin is mediated by AGRP. Prolonged fasting leads to suppression of hepatic sympathetic activity, increased expression of acyl CoA:diacylglycerol acyltransferase-2 in the liver, and elevation of hepatic triglyceride content and all of these effects are blunted in the absence of AGRP. AGRP deficiency, despite having no effects on feeding or body adiposity in the free-fed state, impairs triglyceride and ketone body release from the liver during prolonged fasting. Furthermore, reducing CNS Agrp expression in wild-type mice by RNAi protected against the development of hepatic steatosis not only during starvation, but also in response to consumption of a high-fat diet. These findings identify the leptin-AGRP circuit as a critical modulator of hepatic triglyceride stores in starvation and suggest a vital role for this circuit in sustaining the supply of energy from the liver to extrahepatic tissues during periods of prolonged food deprivation. 23872916 Disseminated Encephalomyelitis-Like Central Nervous System Neoplasm in Childhood. A malignant neoplasm in the central nervous system with diffuse white matter changes on magnetic resonance imaging (MRI) is rare in children. It could be misdiagnosed as acute disseminated encephalomyelitis. This report presents our experience based on 4 patients (3 male, 1 female; aged 7-13 years) whose MRI showed diffuse lesions in white matter and who were initially diagnosed with acute disseminated encephalomyelitis. All of the patients received corticosteroid therapy. After brain biopsy, the patients were diagnosed with gliomatosis cerebri, primitive neuroectodermal tumor and central nervous system lymphoma. We also provide literature reviews and discuss the differentiation of central nervous system neoplasm from acute disseminated encephalomyelitis. 23841557 Vasotocin mRNA Expression is Sensitive to Testosterone and Oestradiol in the Bed Nucleus of the Stria Terminalis in Female Japanese Quail. Vasotocin-producing parvocellular neurones in the medial part of the bed nucleus of the stria terminalis (BSTM) of many species of birds and mammals show sexual dimorphism and great plasticity in response to hormonal and environmental stimuli. In the BSTM of Japanese quail, vasotocin-immunoreactive neurones are visible and sensitive to testosterone exclusively in males. In males, gonadectomy decreases and testosterone restores vasotocin-immunoreactive cells and fibres by acting on vasotocin mRNA transcription. The insensitivity of female vasotocin-immunoreactive neurones to the activating effects of testosterone is the result of organisational effects of early exposure to oestradiol. Female quail also show vasotocin mRNA-expressing neurones in the BSTM, although it is not known whether the insensitivity of the vasotocinergic neurones to testosterone originates at the level of vasotocin gene transcription in this sex. Therefore, initially, the present study analysed the effects of acute treatment with testosterone on vasotocin mRNA expression in the BSTM of gonadectomised male and female quail using in situ hybridisation. Gonadectomy decreased (and a single injection of testosterone increased) the number of vasotocin mRNA-expressing neurones and intensity of the vasotocin mRNA hybridisation signal similarly in both sexes. Notably, testosterone increased vasotocin mRNA expression in ovariectomised females over that shown by intact quail. However, this treatment had no effect on vasotocin immunoreactivity. A second experiment analysed the effects of testosterone metabolites, oestradiol and 5α-dihydrotestosterone, on vasotocin mRNA expression in female quail. Oestradiol (but not 5α-dihydrotestosterone) fully mimicked the effects of testosterone on the number of vasotocin mRNA-expressing neurones and the intensity of the vasotocin mRNA hybridisation signal. Taken together, these results show, for the first time, that gonadal steroids strongly activate vasotocin mRNA expression in the BSTM of female quail. 23632251 Soil moisture modulates the effects of the timing and amount of rainfall on faecal moisture and development of Haemonchus contortus and Trichostrongylus colubriformis to infective third stage larvae. Recent experiments on the effects of rainfall and/or soil moisture (SM) on development of sheep gastro-intestinal nematodes to infective L3 stage have used soil of relatively low moisture content in small experimental samples that dry out faster than field soil. To determine whether higher and more sustained SM content modulates the effects of rainfall amount and timing on faecal moisture (FM) and development of H. contortus and T. colubriformis to infective third stage larvae (L3), a climate-controlled chamber experiment was conducted. It was designed to test the effects of rainfall amount (0, 12 and 24mm), rainfall timing (days -1, 0 and 3 relative to faecal deposition) and soil moisture maintained at 10, 20 and 30% on these variables. Total recovery of L3 14 days after faecal deposition was significantly affected by SM, rainfall timing and their interaction (P<0.01), but not by rainfall amount or species or other two-way interactions. Recovery of L3 was maximal (28%) with a SM treatment of 30% and simulated rainfall on day 3. Faecal moisture was significantly affected by collection day, SM treatment, rainfall amount and rainfall timing with significant interaction between many of these effects (P<0.05). A positive linear association between FM and total L3 recovery was strongest on day 4 after faecal deposition (R(2)=0.64, P<0.001) for H. contortus and day 6 (R(2)=0.78, P<0.001) for T. colubriformis. Overall the results show that SM is able to modulate the effects of rainfall timing and amount with increased SM acting to broaden the window of opportunity for the free-living stages to respond to post deposition rainfall to complete development to L3. If SM is maintained in the range 10-30%, the reported benefits of early rainfall (days -1 and 0) of up to 24mm appear to be negated with later rainfall (day 3) proving more beneficial. These results require field confirmation. 23273648 Effect of primary correction of nasal septal deformity in complete unilateral cleft lip and palate on the craniofacial morphology. To assess the long-term effect of primary correction of the nasal septum during lip repair in unilateral complete cleft lip and palate on the craniofacial morphology. The study material consisted of 54 lateral cephalograms made at the ages 7-22, including 28 cephalograms of patients from a study group (aged 7-14 years) after a primary correction of the nasal septum during lip closure and 26 cephalograms of patients from a control group (aged 12-22 years) operated on without septal correction. All cephalograms have been analysed with regard to skeletal, dental and soft-tissue relationships. Data distribution has been checked using Shapiro-Wilk test (α = 0.05). Student t-test was used to compare values of normal distribution and for the latter - Mann-Whitney test. The comparison of all cephalometric values between the study and control groups revealed a statistically significant (α = 0.05) difference only for H (p = 0.0267), 1+: NB angle (p = 0.0175) and 1+: NA (mm) (p = 0.0249). Each of the three cephalometric measurements mentioned were greater in the study than in the control group. No negative effect from the primary nasal septum correction on maxillary development could be found in the study group. 23850012 Does Parental Warmth and Responsiveness Moderate the Associations between Parenting Practices and Children's Health-related Behaviors? To determine whether a higher number of parenting practices, such as those concerning meals, bedtime, and limited screen time, is associated with children's health behaviors. In addition, to determine whether perceived parental warmth and responsiveness toward the child strengthens (moderates) the associations between parenting practices and health behaviors. Cross-sectional study. School-based survey in which children completed questionnaires at school, and parents at home. A total of 805 child-parent dyads were used in analyses. Intake of nutrient-dense and energy-rich foods, meal frequency per day, sleep duration, and screen time. Linear and logistic regression analyses. Moderation was tested by adding the interaction term of parenting practices and parental warmth/responsiveness to the models. When moderation occurred, stratified analyses were conducted. A higher number of parenting practices was associated with more favorable health behaviors. Stronger associations between parenting practices and nutrient-dense food intake and meal frequency were found when children perceived high parental warmth/responsiveness. Stronger associations between parenting practices and energy-rich food intake and screen time were found when children perceived low parental warmth/responsiveness. Parental warmth/responsiveness seems to strengthen the associations between parenting practices and favorable health behaviors. This knowledge could be used in family-focused obesity interventions. 23969550 Sex-Specific Differences in the Development of Acute Alcohol-Induced Liver Steatosis in Mice. Results of several animal studies suggest that similar to humans, female rodents are more susceptible to chronic alcohol-induced liver disease (ALD). The aim of the present study was to determine whether female mice are more susceptible to acute alcohol-induced steatosis than male mice and to investigate possible mechanisms involved. Male and female C57BL/6J mice received one single dose of ethanol (6 g/kg bodyweight) or isocaloric maltose-dextrin solution intragastrically. Plasma alcohol concentration, markers of hepatic steatosis, activation of the TLR-4 signaling cascade and triglyceride export as well as lipid peroxidation and of iron metabolism were measured 12 h after acute alcohol intake. In male and female ethanol-treated mice, plasma alcohol concentrations were still markedly increased 12 h after the alcohol challenge, which was associated with a significant accumulation of lipids in the liver and increase of transaminases in plasma; however, lipid accumulation was ∼3-fold higher in females in comparison with male animals. Expression of MyD88 was only found to be significantly induced in livers of female alcohol-exposed mice, whereas protein levels of ApoB were found to be significantly lower only in livers of female mice exposed to ethanol. Levels of 4-HNE protein adducts and ferritin were induced in livers of male and female ethanol-treated mice. Taken together, these data suggest that female mice are also more susceptible to acute alcohol-induced liver steatosis and that this involves an increased activation of TLR-4-dependent signaling pathways in the liver. 23726784 Mycobacterial growth inhibition in murine splenocytes as a surrogate for protection against Mycobacterium tuberculosis (M. tb). Development of an improved vaccine against tuberculosis (TB) is hindered by the lack of a surrogate of protection. Efficacy of new TB vaccines in humans can only be evaluated by expensive and time consuming efficacy trials within TB endemic areas. It is critical that vaccines with the greatest potential to protect are selected for these trials. Mycobacterial growth inhibition assays (MGIAs) have been developed with the hope that these in-vitro functional assays will correlate with protection, which could aid in the selection of the best vaccine candidates. The present study describes the use of the BACTEC system to perform MGIAs in mice. We demonstrate reproducible mycobacterial growth inhibition in splenocytes from BCG immunised mice compared with unimmunised mice (P < 0.023), which corresponded with in-vivo efficacy against Mycobacterium tuberculosis (M. tb) challenge. Microarray data showed extensive differential gene expression in splenocyte responses to ex-vivo BCG stimulation between unimmunised and BCG-immunised mice. TH1 responses, including IFN-γ, nitric oxide synthase (NOS2) and Interleukin -17 (IL-17) expression were enhanced in BCG immunised mice, indicating a possible mechanism for mycobacterial growth inhibition. Further investigation into whether the BACTEC MGIA can be used as a surrogate of protection in humans and preclinical animal models is now warranted. 23504990 Evaluation of serotonin 5-HT1A receptors in rodent models using [(18) F]mefway PET. Serotonin 5-HT1A receptors have been investigated in various CNS disorders, including epilepsy, mood disorders, and neurodegeneration. [(18) F]Mefway (N-{2-[4-(2'-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(cis/trans-4'-[(18) F]fluoromethylcyclohexane)-carboxamide) has been developed as a suitable positron emission tomography (PET) imaging agent for these receptors. We have now evaluated the suitability of [(18) F]trans-mefway in rat and mouse models using PET and computerized tomography (CT) imaging and corroborated with ex vivo and in vitro autoradiographic studies. Normal Sprague-Dawley rats and Balb/C mice were used for PET/CT imaging using intravenously injected [(18) F]trans-mefway. Brain PET data were coregistered with rat and mouse magnetic resonance imaging template and regional distribution of radioactivity was quantitated. Selected animals were used for ex vivo autoradiographic studies to confirm regional brain distribution and quantitative measures of binding, using brain region to cerebellum ratios. Binding affinity of trans-mefway and WAY-100635 was measured in rat brain homogenates. Distribution of [(18) F]trans-4-fluoromethylcyclohexane carboxylate ([(18) F]FMCHA), a major metabolite of [(18) F] trans-mefway, was assessed in the rat by PET/CT. The inhibition constant, Ki for trans-mefway was 0.84 nM and that for WAY-100635 was 1.07 nM. Rapid brain uptake of [(18) F]trans-mefway was observed in all rat brain regions and clearance from cerebellum was fast and was used as a reference region in all studies. Distribution of [(18) F]trans-mefway in various brain regions was consistent in PET and in vitro studies. The dorsal raphe was visualized and quantified in the rat PET but identification in the mouse was difficult. The rank order of binding to the various brain regions was hippocampus > frontal cortex > anterior cingulate cortex > lateral septal nuclei > dorsal raphe nuclei. [(18) F]trans-Mefway appears to be an effective 5-HT1A receptor imaging agent in rodents for studies of various disease models. Synapse 67:596-608, 2013. © 2013 Wiley Periodicals, Inc. 23890959 Differences between physician and patient in the perception of symptoms and their severity in COPD. Chronic Obstructive Pulmonary Disease (COPD) impairs quality of life and presents symptoms that affect the lives of patients. Our study analysed the degree of concordance between the patients and their pulmonologists in the perception of the severity of symptoms. A cross-sectional, descriptive, multicentre study was conducted in patients with COPD. From a list of 10 symptoms (cough, dry mouth, chest pain, expectoration, wheezing/whistling in the lungs, depression/sadness/discouragement, fatigue/tiredness/general lack of energy, anxiety/nervousness, breathlessness/shortness of breath upon exertion and difficulty sleeping/sleep disorders) each investigator and patient assessed those which, in their opinion, most concerned or affected the patient. A total of 450 patients were included in the study (91.3% males, 66.7 years old (SD = 10.2), FEV1(%) 51.7% (SD = 12.7%)). At an aggregate level, breathlessness/shortness of breath, fatigue/tiredness and coughing were identified by patients and physicians as being the most relevant symptoms. However, according to the concordance analysis conducted with individual pairs (each pulmonologist with his/her patient), only 52.8% coincided when identifying the symptom that most concerned or affected the life of the patient. The concordance analysed by the Kappa index between patients and physicians was poor (<0.42). The degree of physician-patient concordance was greater in patients with more severe COPD. The patients and their pulmonologists identified the same three main symptoms of COPD but showed low concordance when assessing the impact of the symptoms of the illness. 23650146 A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations. 23846109 ACR Appropriateness Criteria® Chronic Dyspnea: Suspected Pulmonary Origin. Dyspnea, described as breathlessness or shortness of breath, is usually caused by cardiopulmonary disease. The role of imaging in chronic dyspnea (>1 mo in duration) with suspected pulmonary origin is reviewed as suggested by the American College of Radiology Appropriateness Criteria Expert Panel on Thoracic Imaging. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. 23281296 Bifunctional nanoparticles constructed using one-pot encapsulation of a fluorescent polymer and magnetic (Fe3O4) nanoparticles in a silica shell. Integration of biocompatible silica with a fluorescent polymer (PDDF) and superparamagnetic iron oxide nanoparticles (Fe3 O4 ) to form uniform core-shell nanostructures has the great potential to form particles for use in multimodal bioimaging applications. Core-shell nanoparticles (PDDF/Fe3 O4 @SiO2 ) exhibit fluorescent and magnetic properties that are favorable for their use in magnetic separation and guiding applications, as well as optical and magnetic resonance (MR) imaging capabilities. With the biological analysis in an in vitro intracellular permeation and cytotoxicity test, chemical conjugation of the surface using folic acid (FA) molecules can provide the nanoparticles with cell-targeting properties, localizing the nanoparticles to folate receptors (FRs) on target KB cells that over-express the FRs. 23859481 Karyotyping of diffuse large B-cell lymphomas: loss of 17p is associated with poor patient outcome. Cytogenetic studies of patients with diffuse large B-cell lymphoma (DLBCL) have revealed a large spectrum of chromosomal abnormalities, some of which may be clinically relevant. We wanted to evaluate possible associations between commonly acquired chromosome aberrations and prognosis in a large cohort of patients. All patients with DLBCL treated at our center during 1999-2010 with an abnormal G-banding karyotype determined on cells short-term cultured from diagnostic biopsies were included. Detailed information on staging, treatment, and outcome was available for all patients. Of the 110 patients available for analysis, there were 48 deaths and 27 relapses after a median follow-up of 4.5 yr. Eleven different chromosomal abnormalities were detected in more than ten percent of patients. Of those, only loss of 17p, including the TP53 tumor suppressor gene, was significantly associated with inferior long-term prognosis. Five year overall and progression-free survival frequencies were 32% and 27% for patients with loss of 17p and 67% and 59% in patients without this abnormality. In a relatively large cohort of patients with DLBCL analyzed by chromosome banding, loss of 17p was the only chromosomal abnormality associated with inferior survival in uni- and multivariate analysis. 23822069 On the Stereochemical Inertness of the Auride Lone Pair: Ab Initio Studies of AAu (A = K, Rb, Cs). The "lone" 6s electron pair often plays a key role in determining the structure and physical properties of compounds containing sixth-row elements in their lower oxidation states: Tl(+), Pb(2+), and Bi(3+) with the [Xe]4f(14)5d(10)6s(2) electronic configuration. The lone pairs on these ions are associated with reduced structural symmetries, including ferroelectric instabilities and other important phenomena. Here we consider the isoelectronic auride Au(-) ion with the [Xe]4f(14)5d(10)6s(2) electronic configuration. Ab initio density functional theory methods are employed to probe the effect of the 6s lone pair in alkali-metal aurides (KAu, RbAu, and CsAu) with the CsCl structure. The dielectric constants, Born effective charges, and structural instabilities suggest that the 6s lone pair on the Au(-) anion is stereochemically inert to minor mechanical and electrical perturbation. Pressures greater than 14 GPa, however, lead to reorganization of the electronic structure of CsAu and activate lone-pair involvement and Au-Au interactions in bonding, resulting in a transformation from the cubic CsCl structure type to an orthorhombic Cmcm structure featuring zigzag Au-Au chains. 23909513 A Case of CD8+ Small/Medium-Sized Pleomorphic T-Cell Lymphoma: Clinical and Histopathological Differential Diagnosis. CD8+ lymphoid proliferation is a rare type of cutaneous T cell lymphomas.(1) Recently CD8+ lymphoid proliferations that usually present with solitary, slow-growing nodules on face or ear displaying a resolutionary course after treatment have raised the possibility of a distinct entity though the prognostic influence of CD8 phenotype is still unclear. Irrespective of histopathological appearence suggesting a high-grade lymphoma in some cases, clinical behavior should be the main point for the determination of treatment.(2, 13) This article is protected by copyright. All rights reserved. 23703283 Chemical proteomics-driven discovery of oleocanthal as an Hsp90 inhibitor. Hsp90, a key target in cancer therapy, has been identified as the main partner of oleocanthal, an olive oil bioactive compound. A combination of chemical and biological assays disclosed its mechanism of action at the molecular level. 22751751 Longitudinal study of perceived negative impact in African American and Caucasian mothers of children with autism spectrum disorder. The purpose of this study was to examine the stability of mothers' perceptions of the negative impact of having a child with ASD in a sample of African American and Caucasian families as their children transitioned to early adolescence. Participants were mothers and children participating in an ongoing longitudinal study of children referred for diagnosis of ASD at age two. Analyses included data from two time points, when child participants were approximately 9 and 14 years old. Linear mixed model analyses were used to examine the relationship between the primary outcome variable, mothers' perceived negative impact across time, and hypothesized predictors. Negative impact increased significantly from late childhood to into adolescence. However, African American mothers with lower education reported significantly lower levels of perceived negative impact at both time points. Findings show that for some families, the transition to adolescence is a period in which mothers experience increased amounts of negative impact and highlight the importance of examining the influence of socioeconomic variables. Furthermore, data suggest that there may be cultural differences mediating the relationship between maternal education, ethnicity, and perceived negative impact. Implications for the importance of including families from varying levels of socioeconomic status in ASD research are discussed. 23939011 Experimental verification of dose calculation using the simplified Monte Carlo method with an improved initial beam model for a beam-wobbling system. A beam delivery system using a single-radius-beam-wobbling method has been used to form a conformal irradiation field for proton radiotherapy in Japan. A proton beam broadened by the beam-wobbling system provides a non-Gaussian distribution of projection angle different in two mutually orthogonal planes with a common beam central axis, at a certain position. However, the conventional initial beam model for dose calculations has been using an approximation of symmetric Gaussian angular distribution with the same variance in both planes (called here a Gaussian model with symmetric variance (GMSV)), instead of the accurate one. We have developed a more accurate initial beam model defined as a non-Gaussian model with asymmetric variance (NonGMAV), and applied it to dose calculations using the simplified Monte Carlo (SMC) method. The initial beam model takes into account the different distances of two beam-wobbling magnets from the iso-center and also the different amplitudes of kick angle given by each magnet. We have confirmed that the calculation using the SMC with NonGMAV reproduced the measured dose distribution formed in air by a mono-energetic proton beam passing through a square aperture collimator better than with the GMSV and with a Gaussian model with asymmetric variance (GMAV) in which different variances of angular distributions are used in the two mutually orthogonal planes. Measured dose distributions in a homogeneous phantom formed by a modulated proton beam passing through a range shifter and an L-shaped range compensator, were consistent with calculations using the SMC with GMAV and NonGMAV, but in disagreement with calculations using the SMC with GMSV. Measured lateral penumbrae in a lateral direction were reproduced better by calculations using the SMC with NonGMAV than by those with GMAV, when an aperture collimator with a smaller opening was used. We found that such a difference can be attributed to the non-Gaussian angular distribution of the initial beam at a lateral position for the beam-wobbling system. Calculations using the SMC with NonGMAV are effective to reproduce dose distributions formed by a beam-wobbling system more accurately than that with GMSV or that with GMAV. 23914177 Sex-specific and strain-dependent effects of early life adversity on behavioral and epigenetic outcomes. Early life adversity can have a significant long-term impact with implications for the emergence of psychopathology. Disruption to mother-infant interactions is a form of early life adversity that may, in particular, have profound programing effects on the developing brain. However, despite converging evidence from human and animal studies, the precise mechanistic pathways underlying adversity-associated neurobehavioral changes have yet to be elucidated. One approach to the study of mechanism is exploration of epigenetic changes associated with early life experience. In the current study, we examined the effects of postnatal maternal separation (MS) in mice and assessed the behavioral, brain gene expression, and epigenetic effects of this manipulation in offspring. Importantly, we included two different mouse strains (C57BL/6J and Balb/cJ) and both male and female offspring to determine strain- and/or sex-associated differential response to MS. We found both strain-specific and sex-dependent effects of MS in early adolescent offspring on measures of open-field exploration, sucrose preference, and social behavior. Analyses of cortical and hippocampal mRNA levels of the glucocorticoid receptor (Nr3c1) and brain-derived neurotrophic factor (Bdnf) genes revealed decreased hippocampal Bdnf expression in maternally separated C57BL/6J females and increased cortical Bdnf expression in maternally separated male and female Balb/cJ offspring. Analyses of Nr3c1and Bdnf (IV and IX) CpG methylation indicated increased hippocampal Nr3c1 methylation in maternally separated C57BL/6J males and increased hippocampal Bdnf IX methylation in male and female maternally separated Balb/c mice. Overall, though effect sizes were modest, these findings suggest a complex interaction between early life adversity, genetic background, and sex in the determination of neurobehavioral and epigenetic outcomes that may account for differential vulnerability to later-life disorder. 23668370 Robust closed-loop control of induction and maintenance of propofol anesthesia in children. During closed-loop control, a drug infusion is continually adjusted according to a measure of clinical effect (e.g., an electroencephalographic depth of hypnosis (DoH) index). Inconsistency in population-derived pediatric pharmacokinetic/pharmacodynamic models and the large interpatient variability observed in children suggest a role for closed-loop control in optimizing the administration of intravenous anesthesia. To clinically evaluate a robustly tuned system for closed-loop control of the induction and maintenance of propofol anesthesia in children undergoing gastrointestinal endoscopy. One hundred and eight children, aged 6-17, ASA I-II, were enrolled. Prior to induction of anesthesia, NeuroSENSEâ„¢ sensors were applied to obtain the WAVCNS DoH index. An intravenous cannula was inserted and lidocaine (0.5 mg·kg(-1) ) administered. Remifentanil was administered as a bolus (0.5 Î¼g·kg(-1) ), followed by continuous infusion (0.03 Î¼g·kg(-1) ·min(-1) ). The propofol infusion was closed-loop controlled throughout induction and maintenance of anesthesia, using WAVCNS as feedback. Anesthesia was closed-loop controlled in 102 cases. The system achieved and maintained an adequate DoH without manual adjustment in 87/102 (85%) cases. Induction of anesthesia (to WAVCNS  â‰¤ 60) was completed in median 3.8 min (interquartile range (IQR) 3.1-5.0), culminating in a propofol effect-site concentration (Ce ) of median 3.5 Î¼g·ml(-1) (IQR 2.7-4.5). During maintenance of anesthesia, WAVCNS was measured within 10 units of the target for median 89% (IQR 79-96) of the time. Spontaneous breathing required no manual intervention in 91/102 (89%) cases. A robust closed-loop system can provide effective propofol administration during induction and maintenance of anesthesia in children. Wide variation in the calculated Ce highlights the limitation of open-loop regimes based on pharmacokinetic/pharmacodynamic models. 23905934 Robotic reconstruction of lower ureteral strictures. Distal ureteral reconstruction is increasingly being performed by minimally-invasive surgical techniques. The robotic surgical platform provides an additional modality for repairing distal ureteral defects with the associated benefits of a minimally-invasive approach. This article reviews and describes the technical aspects of robotic distal ureteral reconstruction. In addition to discussion of the operative technique, factors such as patient selection, preoperative and postoperative evaluation, and published outcomes are addressed. 23637126 Implications of DPP4 modification of proteins that regulate stem/progenitor and more mature cell types. Dipeptidylpeptidase (DPP) 4 has the potential to truncate proteins with a penultimate alanine, proline, or other selective amino acids at the N-terminus. DPP4 truncation of certain chemokines, colony-stimulating factors, and interleukins have recently been linked to regulation of hematopoietic stem/progenitor cells, more mature blood cells, and other cell types. We believe that the potential role of DPP4 in modification of many regulatory proteins, and their subsequent effects on numerous stem/progenitor and other cell-type functions has not been adequately appreciated. This review addresses the potential implications of the modifying effects of DPP4 on a large number of cytokines and other growth-regulating factors with either proven or putative DPP4 truncation sites on hematopoietic cells, and subsequent effects of DPP4-truncated proteins on multiple aspects of steady-state and stressed hematopoiesis, including stem/progenitor cell, and more mature cell, function. 23701236 Diabetes Attitudes, Wishes and Needs second study (DAWN2™): cross-national benchmarking indicators for family members living with people with diabetes. The second Diabetes Attitudes, Wishes and Needs (DAWN2) study examined the experiences of family members of people with diabetes for benchmarking and identifying unmet needs or areas for improvement to assist family members and those with diabetes to effectively self-manage. In total, 2057 family members of people with diabetes participated in an online, telephone or in-person survey designed to assess the impact of diabetes on family life, family support for people with diabetes and educational and community support. Supporting a relative with diabetes was perceived as a burden by 35.3% (range across countries 10.6-61.7%) of respondents. Over half of respondents [51.4% (22.5-76.0%)] rated their quality of life as 'good' or 'very good'. However, distress about the person with diabetes was high, with 61.3% (31.5-86.4%) worried about hypoglycaemia. The impact of diabetes on aspects of life was felt by 51.8% (46.9-58.6%). The greatest negative effect was on emotional well-being [44.6% (31.8-63.0%)], although depression was less common [11.6% (4.2-20.0%)]. Many respondents did not know how to help the person with diabetes [37.1% (17.5-53.0%)] and wanted to be more involved in their care [39.4% (15.5-61.7%)]. Participation in diabetes educational programmes was low [23.1% (9.4-43.3%)], although most of those who participated found them helpful [72.1% (42.1-90.3%)]. Diabetes has a negative impact on family members of people with diabetes. DAWN2 provides benchmarking indicators of family members' psychosocial needs that will help identify the support required for, and from, them to improve the lives of people with diabetes and their families. 23943315 Similarities and Differences in Patient Characteristics Between Heart Failure Registries Versus Clinical Trials. Acute and chronic heart failure results in significant morbidity and mortality to patients and is a major concern for the healthcare systems. Various randomized controlled trials have demonstrated an improvement in morbidity and mortality for patients with heart failure. However, the findings of these trials are often applicable to a limited population. Several large-scale registries are now shedding insight as to the treatment, outcomes, and follow-up of patients in a real-life clinical setting. The objective of this review is to examine some of the heart failure therapies, such as cardiac resynchronization therapy, implantable cardioverter defibrillators and medications, in the context of randomized trials versus clinical registries. This review will also identify how registries are improving patient outcomes and how they are uncovering differences and gaps in treatment in non-randomized trial settings. 23895587 On the assessment of the added value of new predictive biomarkers. The surge in biomarker development calls for research on statistical evaluation methodology to rigorously assess emerging biomarkers and classification models. Recently, several authors reported the puzzling observation that, in assessing the added value of new biomarkers to existing ones in a logistic regression model, statistical significance of new predictor variables does not necessarily translate into a statistically significant increase in the area under the ROC curve (AUC). Vickers et al. concluded that this inconsistency is because AUC "has vastly inferior statistical properties," i.e., it is extremely conservative. This statement is based on simulations that misuse the DeLong et al. method. Our purpose is to provide a fair comparison of the likelihood ratio (LR) test and the Wald test versus diagnostic accuracy (AUC) tests. We present a test to compare ideal AUCs of nested linear discriminant functions via an F test. We compare it with the LR test and the Wald test for the logistic regression model. The null hypotheses of these three tests are equivalent; however, the F test is an exact test whereas the LR test and the Wald test are asymptotic tests. Our simulation shows that the F test has the nominal type I error even with a small sample size. Our results also indicate that the LR test and the Wald test have inflated type I errors when the sample size is small, while the type I error converges to the nominal value asymptotically with increasing sample size as expected. We further show that the DeLong et al. method tests a different hypothesis and has the nominal type I error when it is used within its designed scope. Finally, we summarize the pros and cons of all four methods we consider in this paper. We show that there is nothing inherently less powerful or disagreeable about ROC analysis for showing the usefulness of new biomarkers or characterizing the performance of classification models. Each statistical method for assessing biomarkers and classification models has its own strengths and weaknesses. Investigators need to choose methods based on the assessment purpose, the biomarker development phase at which the assessment is being performed, the available patient data, and the validity of assumptions behind the methodologies. 23970407 Depletion of RNA-binding protein RBM8A (Y14) causes cell cycle deficiency and apoptosis in human cells. RBM8A (Y14) contains an RNA-binding motif and forms a tight heterodimer with Magoh. The heterodimer is known to be a member of the exon junction complex that forms on mRNA before export and it is required for mRNA metabolism processes such as splicing, mRNA export and nonsense-mediated mRNA decay. Recently, deficient cellular proliferation has been observed in RBM8A- or Magoh-depleted cells. These results prompted us to study the role of RBM8A in cell cycle progression of human tumour cells. The depletion of RBM8A in A549 cells resulted in poor cell survival and the accumulation of mitotic cells. After release from G1/S arrest induced by a double thymidine block, the RBM8A-silenced cells could not proceed to the next G1 phase beyond G2/M phase. Finally, the sub-G1 population increased and the apoptosis markers caspases 3/7 were activated. Silenced cells exhibited an increased frequency of multipolar or monopolar centrosomes, which may have caused the observed deficiency in cell cycle progression. Finally, silencing of either RBM8A or Magoh resulted in mutual downregulation of the other protein. These results illustrate that the RBM8A-Magoh mRNA binding complex is required for M phase progression and both proteins may be novel targets for anticancer therapy. 23239592 Three-Dimensional CdS-Titanate Composite Nanomaterials for Enhanced Visible-Light-Driven Hydrogen Evolution. 3D Hierarchical echinus-like titanate spheres (HETSs), serving as the supporting material for CdS nanoparticles, are synthesized via a fast one-step hydrothermal method. The obtained 3D CdS-HETS composite materials show enhanced H2 generation under visible light irradiation. 23887064 Fabrication of computationally designed scaffolds by low temperature 3D printing. The development of artificial bone substitutes that mimic the properties of bone and simultaneously promote the desired tissue regeneration is a current issue in bone tissue engineering research. An approach to create scaffolds with such characteristics is based on the combination of novel design and additive manufacturing processes. The objective of this work is to characterize the microstructural and the mechanical properties of scaffolds developed by coupling both topology optimization and a low temperature 3D printing process. The scaffold design was obtained using a topology optimization approach to maximize the permeability with constraints on the mechanical properties. This procedure was studied to be suitable for the fabrication of a cage prototype for tibial tuberosity advancement application, which is one of the most recent and promising techniques to treat cruciate ligament rupture in dogs. The microstructural and mechanical properties of the scaffolds manufactured by reacting α/β-tricalcium phosphate with diluted phosphoric acid were then assessed experimentally and the scaffolds strength reliability was determined. The results demonstrate that the low temperature 3D printing process is a reliable option to create synthetic scaffolds with tailored properties, and when coupled with topology optimization design it can be a powerful tool for the fabrication of patient-specific bone implants. 23909817 Selectively Bred Crossed High-Alcohol-Preferring Mice Drink to Intoxication and Develop Functional Tolerance, But Not Locomotor Sensitization During Free-Choice Ethanol Access. Crossed high-alcohol-preferring (cHAP) mice were selectively bred from a cross of the HAP1 Ã— HAP2 replicate lines and demonstrate blood ethanol concentrations (BECs) during free-choice drinking reminiscent of those observed in alcohol-dependent humans. In this report, we investigated the relationship between free-choice drinking, intoxication, tolerance, and sensitization in cHAP mice. We hypothesized that initially mice would become ataxic after drinking alcohol, but that increased drinking over days would be accompanied by increasing tolerance to the ataxic effects of ethanol (EtOH). Male and female cHAP mice had free-choice access to 10% EtOH and water (E), while Water mice (W) had access to water alone. In experiment 1, the first drinking experience was monitored during the dark portion of the cycle. Once E mice reached an average intake rate of ≥1.5 g/kg/h, they, along with W mice, were tested for footslips on a balance beam, and BECs were assessed. In experiments 2, 3, and 4, after varying durations of free-choice 10% EtOH access (0, 3, 14, or 21 days), mice were challenged with 20% EtOH and tested for number of footslips on a balance beam or locomotor stimulant response. Blood was sampled for BEC determination. We found that cHAP mice rapidly acquire alcohol intakes that lead to ataxia. Over time, cHAP mice developed behavioral tolerance to the ataxic effects of alcohol, paralleled by escalating alcohol consumption. However, locomotor sensitization did not develop following 14 days of free-choice EtOH access. Overall, we observed increases in free-choice drinking with extended alcohol access paralleled by increases in functional tolerance, but not locomotor sensitization. These data support our hypothesis that escalating free-choice drinking over days in cHAP mice is driven by tolerance to alcohol's behavioral effects. These data are the first to demonstrate that escalating free-choice consumption is accompanied by increasing alcohol tolerance. In addition to buttressing the hypothesized importance of tolerance in drinking, our findings suggest that cHAP mice may be a unique, translational resource for studying tolerance as a contributor to and consequence of chronic, excessive EtOH consumption. 23858458 Crop manuring and intensive land management by Europe's first farmers. The spread of farming from western Asia to Europe had profound long-term social and ecological impacts, but identification of the specific nature of Neolithic land management practices and the dietary contribution of early crops has been problematic. Here, we present previously undescribed stable isotope determinations of charred cereals and pulses from 13 Neolithic sites across Europe (dating ca. 5900-2400 cal B.C.), which show that early farmers used livestock manure and water management to enhance crop yields. Intensive manuring inextricably linked plant cultivation and animal herding and contributed to the remarkable resilience of these combined practices across diverse climatic zones. Critically, our findings suggest that commonly applied paleodietary interpretations of human and herbivore δ(15)N values have systematically underestimated the contribution of crop-derived protein to early farmer diets. 23479220 Post-mortem computed tomography compared to forensic autopsy findings: a French experience. The principal aim of our study was to establish concordance between post-mortem CT (PMCT) and forensic standard autopsy (SA) in detecting lesions according to different anatomical regions. A secondary aim was to determine the efficacy of PMCT in showing lethal lesions. PMCTs were compared with autopsies in 236 cadavers in different contexts of death. PMCT findings were assessed by two independent radiologists. Concordance between PMCT and autopsy was almost perfect in showing skull, basal skull and hyoid bone fractures as well as in detecting facial, vertebral or pelvic fractures. Both examinations were discordant in demonstrating some intracranial injuries, vascular or organ wounds (more findings showed by autopsy), as well in showing free air in anatomical cavities (more findings detected by PMCT). Moreover, PMCT was effective in determining lethal lesions in the context of craniofacial trauma or after a gunshot wound. Concordance between the findings of the two radiologists was almost perfect for each type of lesion. PMCT could be considered as effective as SA in determining the cause of death in certain traumatic events. It was also effective in showing lethal lesions and could be a useful tool in reducing the number of SA. KEY POINTS : • Post-mortem CT is increasingly performed as an alternative/adjunct to formal autopsy. • More modern CT systems provide greater anatomical scope. • PMCT can usually determine the cause of most deaths following trauma. • Prospective studies are still required to establish an algorithm for forensic CT. 23935105 Specialization Among Iron-Sulfur Cluster Helicases to Resolve G-Quadruplex DNA Structures that Threaten Genomic Stability. G-quadruplex (G4) DNA, an alternate structure formed by Hoogsteen hydrogen bonds between guanines in G-rich sequences, threatens genomic stability by perturbing normal DNA transactions including replication, repair, and transcription. A variety of G4 topologies (intra- and inter-molecular) can form in vitro, but the molecular architecture and cellular factors influencing G4 landscape in vivo is not clear. Helicases that unwind structured DNA molecules are emerging as an important class of G4-resolving enzymes. The BRCA1-associated FANCJ helicase is among those helicases able to unwind G4 DNA in vitro, and FANCJ mutations are associated with breast cancer and linked to Fanconi anemia. FANCJ belongs to a conserved Iron-Sulfur (Fe S) cluster family of helicases important for genomic stability including XPD (nucleotide excision repair), DDX11 (sister chromatid cohesion), and RTEL (telomere metabolism), genetically linked to Xeroderma pigmentosum/Cockayne syndrome, Warsaw Breakage syndrome, and Dyskeratosis congenita, respectively. To elucidate the role of FANCJ in genomic stability, its molecular functions in G4 metabolism were examined. FANCJ efficiently unwound in a kinetic and ATPase dependent manner entropically favored uni molecular G4 DNA, whereas other Fe-S helicases tested did not. The G4 specific ligands Phen-DC3 or Phen-DC6 inhibited FANCJ helicase on uni-molecular G4 approximately 1000-fold better than bi- or tetra-molecular G4 DNA. The G4 ligand Telomestatin (TMS) induced DNA damage in human cells depleted of FANCJ but not DDX11 or XPD. These findings suggest FANCJ is a specialized Fe-S cluster helicase that preserves chromosomal stability by unwinding uni-molecular G4 DNA likely to form in transiently unwound single-stranded genomic regions. 23837695 Sleep disorders in myotonic dystrophy type 2: a controlled polysomnographic study and self-reported questionnaires. There is a paucity of data available regarding the occurrence of sleep disorders in myotonic dystrophy type 2 (DM2). In this study the sleep-wake cycle and daytime sleepiness were investigated in DM2 patients and compared with results from healthy subjects and myotonic dystrophy type 1 (DM1) patients. Twelve DM2 outpatients, 12 age- and sex-matched healthy controls and 18 DM1 patients were recruited. Subjective quality of sleep was assessed by means of the Pittsburgh Sleep Quality Index (PSQI). Both the Epworth Sleepiness Scale and the Daytime Sleepiness Scale were performed in order to evaluate excessive daytime sleepiness (EDS). All participants underwent polysomnographic monitoring over 48 h as well as the Multiple Sleep Latency Test. Sleep efficiency was < 90% in 12/12 DM2 patients, and significantly reduced when compared with controls or with DM1. Decreased sleep efficiency was associated with sleep-disordered breathing in seven out of 12 DM2 patients and/or periodic limbs movements of sleep (PLMS) in three out of eight patients. Six DM2 patients showed REM sleep without atonia, whereas none of the controls or DM1 patients showed REM sleep dysregulation. The global PSQI score was higher in DM2 patients than in controls and DM1 patients. Sleep quality in DM2 patients is poorer than in DM1 patients and controls. Sleep apnea is the most common sleep disorder in DM2 patients. Obstructive sleep apnea and sleep fragmentation may represent the main cause of EDS, whereas PLMS is a frequent finding in DM1. 23935094 SLP-76 sterile alpha motif (SAM) and individual H5 alpha helix mediates oligomer formation for microclusters and T-cell activation. Despite the importance of the immune adaptor SLP-76 in T cell immunity, it has been unclear whether SLP-76 directly self-associates to form higher order oligomers for T-cell activation. In this study, we show that SLP-76 self-associates in response to TCR ligation as mediated by the N-terminal sterile alpha motif (SAM) domain. SLP-76 co-precipitated alternately tagged SLP-76 in response to anti-CD3 ligation. Dynamic light scattering (DLS) and fluorescent microscale thermophoresis (MST) of the isolated SAM domain (residues 1-78) revealed evidence of dimers and tetramers. Consistently, deletion of the SAM region eliminated SLP-76 co-precipitation of itself, concurrent with a loss of microcluster formation, NFAT transcription and interleukin 2 production in Jurkat or primary T-cells. Further, the H5 alpha helix within the SAM domain contributed to self-association. Retention of H5 in the absence of H1-4 sufficed to support SLP-76 self-association with smaller microclusters that nevertheless, enhanced anti-CD3 driven AP1/NFAT transcription and IL-2 production. By contrast, deletion of the H5 domain resulted impaired self-association and anti-CD3 induced AP1/NFAT transcription. Our data identifies for the first time a role for the SAM domain in mediating SLP-76 self-association for T-cell function. 23756727 Breast cancer and leptomeningeal disease (LMD): hormone receptor status influences time to development of LMD and survival from LMD diagnosis. Leptomeningeal disease (LMD) occurs in 5 % of breast cancer patients. The aim of this study was to identify risk factors related to survival and time to development of LMD in breast cancer patients. A retrospective analysis of breast cancer patients with LMD, evaluated in MDACC between 1995 and 2011. 103 patients with diagnosis of breast cancer and LMD were identified (one male). The median age at LMD diagnosis was 49.2 years. 78.2 % had invasive ductal carcinoma. Hormone receptors (HRs) were positive in 55.3 % of patients, 47.4 % were human epidermal growth factor receptor 2-positive and 22.8 % were triple negative. 52 % of the patients were treated with WBRT, 19 % with spinal radiation, 36 % with systemic chemotherapy and 55 % with intrathecal chemotherapy. Estimated median overall survival from time of breast cancer diagnosis was 3.66 years. Median survival from time of LMD diagnosis was 4.2 months. Time from breast cancer diagnosis to LMD was 2.48 years. In multivariate analysis, HR status and stage at diagnosis were significantly associated with time to LMD diagnosis (p < 0.05). In triple negative patients, time to LMD was shorter. In patients who were HR positive, time to LMD was longer. Survival from LMD diagnosis was significantly associated with both treatment, as well as positive HR status (multivariate analysis p < 0.05). In conclusion LMD has dismal prognosis in breast cancer patients. HR status contributes to time to LMD diagnosis and survival from LMD diagnosis. The impact of treatment aimed at LMD cannot be ascertained in our retrospective study due to the inherent bias associated with the decision to treat. 23806328 A novel method to value real options in health care: the case of a multicohort human papillomavirus vaccination strategy. A large number of economic evaluations have already confirmed the cost-effectiveness of different human papillomavirus (HPV) vaccination strategies. Standard analyses might not capture the full economic value of novel vaccination programs because the cost-effectiveness paradigm fails to take into account the value of active management. Management decisions can be seen as real options, a term used to refer to the application of option pricing theory to the valuation of investments in nonfinancial assets in which much of the value is attributable to flexibility and learning over time. The aim of this article was to discuss the potential advantages shown by using the payoff method in the valuation of the cost-effectiveness of competing HPV immunization programs. This was the first study, to the best of our knowledge, to use the payoff method to determine the real option values of 4 different HPV vaccination strategies targeting female subjects aged 12, 15, 18, and 25 years. The payoff method derives the real option value from the triangular payoff distribution of the project's net present value, which is treated as a triangular fuzzy number. To inform the real option model, cost-effectiveness data were derived from an empirically calibrated Bayesian model designed to assess the cost-effectiveness of a multicohort HPV vaccination strategy in the context of the current cervical cancer screening program in Italy. A net health benefit approach was used to calculate the expected fuzzy net present value for each of the 4 vaccination strategies evaluated. Costs per quality-adjusted life-year gained seemed to be related to the number of cohorts targeted: a single cohort of girls aged 12 years (€10,955 [95% CI, -1,021 to 28,212]) revealed the lowest cost among the 4 alternative strategies evaluated. The real option valuation challenged the cost-effectiveness dominance of a single cohort of 12-year-old girls. The simultaneous vaccination of 2 cohorts of girls aged 12 and 15 years yielded a real option value (€17,723) equivalent to that attributed to a single cohort of 12-year-old girls (€17,460). The payoff method showed distinctive advantages in the valuation of the cost-effectiveness of competing health care interventions, essentially determined by the replacement of the nonfuzzy numbers that are commonly used in cost-effectiveness analysis models, with fuzzy numbers as an input to inform the real option pricing method. The real option approach to value uncertainty makes policy making in health care an evolutionary process and creates a new "space" for decision-making choices. 23909390 Revising oxygen targeting for very low birth weight infants. Translating new knowledge into practice requires sufficient time, administrative support, and access to current information. A regional level III neonatal intensive care unit was tasked with updating a best practice that challenged the history of its well-recognized success in this field. Using strategies that can be applied in any setting, this interprofessional team drove the successful adoption of the updated best practice using a multidimensional implementation plan to promote patient safety. 23940726 Two variants of the C-reactive protein gene are associated with risk of pre-eclampsia in an american Indian population. The etiology of pre-eclampsia (PE) is unknown; but it is accepted that normal pregnancy represents a distinctive challenge to the maternal immune system. C-reactive protein is a prominent component of the innate immune system; and we previously reported an association between PE and the CRP polymorphism, rs1205. Our aim was to explore the effects of additional CRP variants. The IBC (Cardiochip) genotyping microarray focuses on candidate genes and pathways related to the pathophysiology of cardiovascular disease. This study recruited 140 cases of PE and 270 matched controls, of which 95 cases met criteria as severe PE, from an American Indian community. IBC array genotypes from 10 suitable CRP SNPs were analyzed. A replication sample of 178 cases and 427 controls of European ancestry was also genotyped. A nominally significant difference (p value <0.05) was seen in the distribution of discordant matched pairs for rs3093068; and Bonferroni corrected differences (P<0.005) were seen for rs876538, rs2794521, and rs3091244. Univariate conditional logistic regression odds ratios (OR) were nominally significant for rs3093068 and rs876538 models only. Multivariate logistic models with adjustment for mother's age, nulliparity and BMI attenuated the effect (OR 1.58, P = 0.066, 95% CI 0.97-2.58) for rs876538 and (OR 2.59, P = 0.050, 95% CI 1.00-6.68) for rs3093068. An additive risk score of the above two risk genotypes shows a multivariate adjusted OR of 2.04 (P = 0.013, 95% CI 1.16-3.56). The replication sample also demonstrated significant association between PE and the rs876538 allele (OR = 1.55, P = 0.01, 95% CI 2.16-1.10). We also show putative functionality for the rs876538 and rs3093068 CRP variants. The CRP variants, rs876538 and rs3093068, previously associated with other cardiovascular disease phenotypes, show suggestive association with PE in this American Indian population, further supporting a possible role for CRP in PE. 23690401 Fitness, Stress Resistance, and Extraintestinal Virulence in Escherichia coli. The extraintestinal virulence of Escherichia coli is dependent on numerous virulence genes. However, there is growing evidence for a role of the metabolic properties and stress responses of strains in pathogenesis. We assessed the respective roles of these factors in strain virulence by developing phenotypic assays for measuring in vitro individual and competitive fitness and the general stress response, which we applied to 82 commensal and extraintestinal pathogenic E. coli strains previously tested in a mouse model of sepsis. Individual fitness properties, in terms of maximum growth rates in various media (Luria-Bertani broth with and without iron chelator, minimal medium supplemented with gluconate, and human urine) and competitive fitness properties, estimated as the mean relative growth rate per generation in mixed cultures with a reference fluorescent E. coli strain, were highly diverse between strains. The activity of the main general stress response regulator, RpoS, as determined by iodine staining of the colonies, H2O2 resistance, and rpoS sequencing, was also highly variable. No correlation between strain fitness and stress resistance and virulence in the mouse model was found, except that the maximum growth rate in urine was higher for virulent strains. Multivariate analysis showed that the number of virulence factors was the only independent factor explaining the virulence in mice. At the species level, growth capacity and stress resistance are heterogeneous properties that do not contribute significantly to the intrinsic virulence of the strains. 23794648 Neuropathic pain: a pathway for care developed by the British Pain Society. Neuropathic pain is a common chronic pain condition that can be challenging to treat, particularly for non-specialists. The development of the Map of Medicine care pathway for the management of neuropathic pain was led by the British Pain Society. Focusing on treatment by non-specialists, this pathway is based on new evidence, consensus, and the interests of service users. This paper presents the care pathway and accompanying evidence base, highlighting its salient features, and discussing important treatment points. After initial assessment, the pathway progresses through first-, second-, and third-line drug treatment, includes advice on topical treatment and opioids (in specific circumstances), and describes non-pharmacological approaches. Importantly, timely review of patients and referral to specialist secondary or tertiary care must be considered as vital components of the pathway. Although the emphasis was not on specialist treatment, advice is given on existing interventions, including neural stimulation and multi-disciplinary care. These, and other steps on the pathway, will be subject to further review as more evidence becomes available. In the meantime, the pathway represents a straightforward, valuable and accessible approach for healthcare professionals managing the distress and impact of neuropathic pain. 23909401 In response to oxidative stress and energy restriction AMPK and PKC collaborate to induce the phosphorylation of Serine 413 on PIP5K1B resulting in decreased kinase activity and reduced PtdIns(4,5)P2 synthesis. The spatial and temporal regulation of the second messenger, phosphatidylinositol(4,5)bisphosphate (PtdIns(4,5)P2 ) has been shown to be crucial for regulating numerous processes in the cytoplasm and in the nucleus. Three isoforms of phosphatidylinositol 4-phosphate 5-kinase (PIP5K1 A, B and C) are responsible for the regulation of the major pools of cellular PIP2. PIP5K1B is negatively regulated in response to oxidative stress although it remains unclear which pathways regulate its activity. In this study we have investigated the regulation of PIP5K1B by protein phosphorylation. Using mass spectrometric analysis we identified 12 phosphorylation sites on PIP5K1B. We developed a phospho-specific antibody to S413 and showed that its phosphorylation was increased in response to treatment of cells with phorbol ester, H2O2 or energy restriction. Using inhibitors, we define a stress dependent pathway that requires the activity of the cellular energy sensor AMP-Kinase (AMPK) and Protein Kinase C (PKC) to regulate S413 phosphorylation. Furthermore, we demonstrate that PKC can directly phosphorylate S413 in vitro. Mutation of S413 to aspartate to mimic serine phosphorylation decreased both PIP5K1B activity in vitro and PtdIns(4,5)P2 synthesis in vivo. Our studies show that collaboration between AMPK and PKC dictates the extent of S413 phosphorylation on PIP5K1B and regulates PtdIns(4,5)P2synthesis. 23909863 Lessons Learned from the Development of Health Applications in a Tertiary Hospital. Abstract Background: Adoption of smart devices for hospital use has been increasing with the development of health applications (apps) for patient point-of-care and hospital management. To promote the use of health apps, we describe the lessons learned from developing 12 health apps in the largest tertiary hospital in Korea. Materials and Methods: We reviewed and analyzed 12 routinely used apps in three categories-Smart Clinic, Smart Patient, and Smart Hospital-based on target users and functions. The log data for each app were collected from the date of release up until December 2012. Results: Medical personnel accessed a mobile electronic medical record app classified as Smart Clinic an average of 452 times per day. Smart Hospital apps are actively used to communicate with each other. Patients logged on to a mobile personal health record app categorized as Smart Patient an average of 222 times per day. As the mobile trend, the choice of supporting operating system (OS) is more difficult. By developing these apps, a monitoring system is needed for evaluation. Conclusions: We described the lessons learned regarding OS support, device choice, and developmental strategy. The OS can be chosen according to market share or hospital strategic plan. Smartphones were favored compared with tablets. Alliance with an information technology company can be the best way to develop apps. Health apps designed for smart devices can be used to improve healthcare. However, to develop health apps, hospitals must define their future goals and carefully consider all the aspects. 23968098 Theoretical determination of anisotropic thermal conductivity for crystalline 1,3,5-triamino-2,4,6-trinitrobenzene (TATB). Bond stretching and three-center angle bending potentials have been developed to extend an existing rigid-bond 1,3,5-triamino-2,4,6-trinitrobenzene molecular dynamics force field [D. Bedrov, O. Borodin, G. D. Smith, T. D. Sewell, D. M. Dattelbaum, and L. L. Stevens, J. Chem. Phys. 131, 224703 (2009)] for simulations requiring fully flexible molecules. The potentials were fit to experimental vibrational spectra and electronic structure predictions of vibrational normal modes using a combination of zero kelvin eigenmode analysis for the isolated molecule and power spectra for the isolated molecule and crystal. A reverse non-equilibrium molecular dynamics method [F. Müller-Plathe, J. Chem. Phys. 106, 6082 (1997)] was used to obtain the room temperature, atmospheric pressure thermal conductivity along three directions in a well-defined, non-orthogonal basis. The thermal conductivity was found to be significantly anisotropic with values 1.13 ± 0.07, 1.07 ± 0.07, and 0.65 ± 0.03 W m(-1) K(-1) for directions nominally parallel to the a, b, and c lattice vectors, respectively. 23232305 Surgical Treatment of Atrial Septal Defect in a Patient with Familial Antithrombin-III Deficiency. Purpose: A 41-year-old woman with familial antithrombin-III deficiency was admitted to our hospital for patch closure of an atrial septal defect. Antithrombin-III activity was 43% and its antigen level was 12.2 mg/dl, was diagnosed so type I antithrombin-IIIdeficiency was diagnosed.Methods: A dose of 2500 U of antithrombin-III concentrate was administered at 1 day before surgery, 1 hour before surgery, and 1 day after surgery. Heparinazation was performed at 200 IU/kg and the activated clotting time increased from a baseline of 140s to 622s. After establishing cardiopulmonary bypass and cardioplegic arrest, closure of the septal defect was done with a pericardial patch.Results: The activated clotting time was maintained at more than 400s during cardiopulmonary bypass. There were no intraoperative complications and the postoperative course was uneventful.Conclusion: In patients with familial antithrombin-III deficiency, administration of antithrombin-III concentrate is effective when cardiopulmonary bypass is required. 23440928 Carnosine inhibits Aβ(42) aggregation by perturbing the H-bond network in and around the central hydrophobic cluster. Aggregation of the amyloid-β peptide (Aβ) into fibrillar structures is a hallmark of Alzheimer's disease. Thus, preventing self-assembly of the Aβ peptide is an attractive therapeutic strategy. Here, we used experimental techniques and atomistic simulations to investigate the influence of carnosine, a dipeptide naturally occurring in the brain, on Aβ aggregation. Scanning force microscopy, circular dichroism and thioflavin T fluorescence experiments showed that carnosine does not modify the conformational features of Aβ42 but nonetheless inhibits amyloid growth. Molecular dynamics (MD) simulations indicated that carnosine interacts transiently with monomeric Aβ42 by salt bridges with charged side chains, and van der Waals contacts with residues in and around the central hydrophobic cluster ((17)LVFFA(21)). NMR experiments on the nonaggregative fragment Aβ12-28 did not evidence specific intermolecular interactions between the peptide and carnosine, in agreement with MD simulations. However, a close inspection of the spectra revealed that carnosine interferes with the local propensity of the peptide to form backbone hydrogen bonds close to the central hydrophobic cluster (residues E22, S26 and N27). Finally, MD simulations of aggregation-prone Aβ heptapeptide segments show that carnosine reduces the propensity to form intermolecular backbone hydrogen bonds in the region 18-24. Taken together, the experimental and simulation results (cumulative MD sampling of 0.2 ms) suggest that, despite the inability of carnosine to form stable contacts with Aβ, it might block the pathway toward toxic aggregates by perturbing the hydrogen bond network near residues with key roles in fibrillogenesis. 23911761 Molecular mechanism of Ca(2+)-catalyzed fusion of phospholipid micelles. Although membrane fusion plays key roles in intracellular trafficking, neurotransmitter release, and viral infection, its underlying molecular mechanism and its energy landscape are not well understood. In this study, we employed all-atom molecular dynamics simulations to investigate the fusion mechanism, catalyzed by Ca(2+) ions, of two highly hydrated 1-palmitoyl-2-oleoyl-sn-3-phosphoethanolamine (POPE) micelles. This simulation system mimics the small contact zone between two large vesicles at which the fusion is initiated. Our simulations revealed that Ca(2+) ions are capable of catalyzing the fusion of POPE micelles; in contrast, we did not observe close contact of the two micelles in the presence of only Na(+) or Mg(2+) ions. Determining the free energy landscape of fusion allowed us to characterize the underlying molecular mechanism. The Ca(2+) ions play a key role in catalyzing the micelle fusion in three aspects: creating a more-hydrophobic surface on the micelles, binding two micelles together, and enhancing the formation of the pre-stalk state. In contrast, Na(+) or Mg(2+) ions have relatively limited effects. Effective fusion proceeds through sequential formation of pre-stalk, stalk, hemifused-like, and fused states. The pre-stalk state is the state featuring lipid tails exposed to the inter-micellar space; its formation is the rate-limiting step. The stalk state is the state where a localized hydrophobic core is formed connecting two micelles; its formation occurs in conjunction with water expulsion from the inter-micellar space. This study provides insight into the molecular mechanism of fusion from the points of view of energetics, structure, and dynamics. 23592237 Enantioseparation of aromatic amino acids using CEC monolith with novel chiral selector, N-methacryloyl-L-histidine methyl ester. A new type of polymethacrylate-based monolithic column with chiral stationary phase was prepared for the enantioseparation of aromatic amino acids, namely D,L-phenylalanine, D,L-tyrosine, and D,L-tryptophan by CEC. The monolithic column was prepared by in situ polymerization of butyl methacrylate (BMA), N-methacryloyl-L-histidine methyl ester (MAH), and ethylene dimethacrylate (EDMA) in the presence of porogens. The porogen mixture included DMF and phosphate buffer. MAH was used as a chiral selector. FTIR spectrum of the polymethacrylate-based monolith showed that MAH was incorporated into the polymeric structure via in situ polymerization. Some experimental parameters including pH, concentration of the mobile phase, and MAH concentration with regard to the chiral CEC separation were investigated. Single enantiomers and enantiomer mixtures of the amino acids were separately injected into the monolithic column. It was observed that L-enantiomers of aromatic amino acids migrated before D-enantiomers. The reversal enantiomer migration order for tryptophan was observed upon changing of pH. Using the chiral monolithic column (100 μm id and 375 μm od), the best chiral separation was performed in 35:65% ACN/phosphate buffer (pH 8.0, 10 mM) with an applied voltage of 12 kV in CEC. SEM images showed that the chiral monolithic column has a continuous polymeric skeleton and large through-pore structure. 23934230 Reversible Adaptive Trees. We describe reversible adaptive trees, a class of stochastic algorithms modified from the formerly described adaptive trees. They evolve in time a finite subset of an ambient Euclidean space of any dimension, starting from a seed point and, accreting points to the evolving set, they grow branches towards a target set which can depend on time. In contrast with plain adaptive trees, which were formerly proven to have strong convergence properties to a static target, the points of reversible adaptive trees are removed from the tree when they have not been used recently enough in a path from the root to an accreted point. This, together with a straightening process performed on the branches, permits the tree to follow some moving targets and still remain adapted to it. We then discuss in what way one can see such reversible trees as a model for a qualitative property of resilience, which leads us to discuss qualitative modeling. 23935901 Using complete genome comparisons to identify sequences whose presence accurately predicts clinically important phenotypes. In clinical settings it is often important to know not just the identity of a microorganism, but also the danger posed by that particular strain. For instance, Escherichia coli can range from being a harmless commensal to being a very dangerous enterohemorrhagic (EHEC) strain. Determining pathogenic phenotypes can be both time consuming and expensive. Here we propose a simple, rapid, and inexpensive method of predicting pathogenic phenotypes on the basis of the presence or absence of short homologous DNA segments in an isolate. Our method compares completely sequenced genomes without the necessity of genome alignments in order to identify the presence or absence of the segments to produce an automatic alignment of the binary string that describes each genome. Analysis of the segment alignment allows identification of those segments whose presence strongly predicts a phenotype. Clinical application of the method requires nothing more that PCR amplification of each of the set of predictive segments. Here we apply the method to identifying EHEC strains of E. coli and to distinguishing E. coli from Shigella. We show in silico that with as few as 8 predictive sequences, if even three of those predictive sequences are amplified the probability of being EHEC or Shigella is >0.99. The method is thus very robust to the occasional amplification failure for spurious reasons. Experimentally, we apply the method to screening a set of 98 isolates to distinguishing E. coli from Shigella, and EHEC from non-EHEC E. coli strains and show that all isolates are correctly identified. 23883110 Color Variation Assay of the Anthocyanins from Açai Fruit (Euterpe oleracea): A Potential New Dye for Vitreoretinal Surgery. Abstract Aim: The goals of this study were to determine the potential for use of the natural anthocyanins from the açai fruit (Euterpe oleracea) during vitreoretinal surgery and the ideal physicochemical properties of the dye. Methods: We evaluated the color variations of the dye at different pHs and osmolarities with or without the use of mordants as a potential new tool for internal limiting membrane peeling. The extracts of anthocyanin from the açai fruit were analyzed by spectrophotometry to determine the degree of color variations associated with various pHs and osmolarities. The experiments were conducted in test tubes filled with tryptophan soya media and Petri dishes prepared with agar media. Results: We observed various shades of green, red, and purple in the extracts of the anthocyanin dye at different pHs and osmolarities. The assay to adjust the anthocyanin solution similar to the physiologic retinal environment (osmolarity, 300 mOsm; pH, 7.00) resulted in a shade of purple that may be useful to stain the intraocular microstructures during vitreoretinal surgery. The physicochemical property of the purple anthocyanin solutions from the açai fruit was observed at physiologic pH and osmolarity. Conclusion: Anthocyanins from the açai fruit may be useful to enhance visualization of the intraocular microstructures during vitreoretinal surgery. 23962766 Modality-Specific Occult Intrarenal Pseudoaneurysm in a Renal Allograft and the Legacy of Catheter Angiography. A 69-year-old man with history of end-stage-renal disease (ESRD) underwent successful kidney transplantation from a cadaveric donor in November 2011. However, posttransplant recovery was complicated by delayed graft function and recurrent gross hematuria. Serial Doppler ultrasound (US) of the renal allograft demonstrated a pseudoaneurysm with interval increase in size. However, it could not be visualized with other modalities, including an initial angiogram (postoperative day 49) and a second angiogram (postoperative day 68), followed by surgical exploration (postoperative day 71), which demonstrated complete intra-aneurysmal thrombosis on intraoperative Doppler US. Unfortunately, the patient's hematuria continued and a repeat Doppler US 48 hours later demonstrated a persistent pseudoaneurysm. Therefore, on postoperative day 75, we performed targeted percutaneous intra-aneurysmal thrombin injection under dual image guidance, which showed complete intra-aneurysmal thrombosis on intraprocedural Doppler US. Hematuria recurred the next day. A third angiogram (postoperative day 77) finally illuminated the hidden pseudoaneurysm occult on the first and second angiographic studies (sensitivity [index case] 33%) and surgery. This allowed for successful coil embolization of a subsegmental feeding branch with an excellent outcome. We support a more aggressive management with serial angiography and embolization of the intrarenal symptomatic pseudoaneurysm rather than surgery in renal allograft recipients, with the benefits outweighing the risks. 23927586 Comparison of Bayley-2 and Bayley-3 scores at 18 months in term infants following neonatal encephalopathy and therapeutic hypothermia. Neuroprotection trials for neonatal encephalopathy use moderate or severe disability as an outcome, with the Bayley Scales of Infant Development, Second Edition (Bayley-2) Index scores of <70 as part of the criteria. The Bayley Scales of Infant and Toddler, 3rd Development, Third Edition (Bayley-3) have superseded Bayley-2 and yield higher than expected scores in typically developing and high-risk infants. The aim of this study, therefore, was to compare Bayley-2 scores and Bayley-3 scores in term-born infants surviving neonatal encephalopathy treated with hypothermia. Sixty-one term-born infants (37 males, 24 females; median gestational age at birth 40wks, range 36-42wks; median birthweight 3280g, range 2295-5050) following neonatal encephalopathy and hypothermia had contemporaneous assessment at 18 months using the Bayley-2 and Bayley-3. The median Bayley-3 Cognitive Composite score was 7 points higher than the median Bayley-2 Mental Developmental Index (MDI) score and the median Bayley-3 Motor Composite score was 18 points higher than the median Bayley-2 Psychomotor Developmental Index (PDI) score. Ten children had a Bayley-2 MDI of <70; only three children had Bayley-3 combined Cognitive/Language scores of <70. Eleven children had Bayley-2 PDI scores of <70 and four had modified Bayley-3 Motor Composite scores of <70. Applying regression equations to Bayley-3 scores adjusted rates of severe delay to similar proportions found using Bayley-2 scores. Fewer children were classified with severe delay using the Bayley-3 than the Bayley-2, which prohibits direct comparison of scores. Increased Bayley-3 cut-off thresholds for classifying severe disability are recommended when comparing studies in this clinical group using Bayley-2 scores. 23885139 miR-20b, miR-98, miR-125b-1*, and let-7e* as new potential diagnostic biomarkers in ulcerative colitis. To use microarray-based miRNA profiling of colonic mucosal biopsies from patients with ulcerative colitis (UC), Crohn's disease (CD), and controls in order to identify new potential miRNA biomarkers in inflammatory bowel disease. Colonic mucosal pinch biopsies from the descending part were obtained endoscopically from patients with active UC or CD, quiescent UC or CD, as well as healthy controls. Total RNA was isolated and miRNA expression assessed using the miRNA microarray Geniom Biochip miRNA Homo sapiens (Febit GmbH, Heidelberg, Germany). Data analysis was carried out by principal component analysis and projection to latent structure-discriminant analysis using the SIMCA-P+12 software package (Umetrics, Umea, Sweden). The microarray data were subsequently validated by quantitative real-time polymerase chain reaction (qPCR) performed on colonic tissue samples from active UC patients (n = 20), patients with quiescent UC (n = 19), and healthy controls (n = 20). The qPCR results were analyzed with Mann-Whitney U test. In silico prediction analysis were performed to identify potential miRNA target genes and the predicted miRNA targets were then compared with all UC associated susceptibility genes reported in the literature. The colonic mucosal miRNA transcriptome differs significantly between UC and controls, UC and CD, as well as between UC patients with mucosal inflammation and those without. However, no clear differences in the transcriptome of patients with CD and controls were found. The miRNAs with the strongest differential power were identified (miR-20b, miR-99a, miR-203, miR-26b, and miR-98) and found to be up-regulated more than a 10-fold in active UC as compared to quiescent UC, CD, and controls. Two miRNAs, miR-125b-1* and let-7e*, were up-regulated more than 5-fold in quiescent UC compared to active UC, CD, and controls. Four of the seven miRNAs (miR-20b, miR-98, miR-125b-1*, and let-7e*) were validated by qPCR and found to be specifically upregulated in patients with UC. Using in silico analysis we found several predicted pro-inflammatory target genes involved in various pathways, such as mitogen-activated protein kinase and cytokine signaling, which are both key signaling pathways in UC. The present study provides the first evidence that miR-20b, miR-98, miR-125b-1*, and let-7e* are deregulated in patients with UC. The level of these miRNAs may serve as new potential biomarkers for this chronic disease. 23600433 Causes and circumstances of death in pulmonary arterial hypertension. Rationale: The causes and circumstances surrounding death are understudied in patients with pulmonary arterial hypertension (PAH). Objectives: We sought to determine the specific reasons and characteristics surrounding the death of patients with PAH. Methods: All deaths of patients with pulmonary hypertension (PH) followed in the Cleveland Clinic Pulmonary Vascular Program were prospectively reviewed by the PH team. A total of 84 patients with PAH (age 58 ± 14 yr; 73% females) who died between June 2008 and May 2012 were included. Measurements and Main Results: PH was determined to be the direct cause of death (right heart failure or sudden death) in 37 (44%) patients; PH contributed to but did not directly cause death in 37 (44%) patients; and the death was not related to PH in the remaining cases (n = 7; 8.3%). In three (3.6%) patients the final cause of death could not be adequately assessed. Most patients died in a healthcare environment and most received PH-specific therapies. In our cohort, 50% of all patients with PAH and 75.7% of those who died of right heart failure received parenteral prostanoid therapy. Less than half of patients had advanced healthcare directives. Conclusions: Most patients with PAH in our cohort died of their disease; however, right ventricular failure or sudden death was the sole cause of death in less than half of patients. 23899700 The point prevalence of otitis media with effusion in secondary school children in Pokhara, Nepal: A cross-sectional study. Otitis media with effusion (OME) is a condition of uncertain aetiology seen in paediatric practice. It has important sequelae that can result in significant morbidity. Worldwide documentation of OME prevalence in older children is poor as OME is traditionally seen in children below the age of 6 years. Available research in Nepal reports a prevalence of OME in children between the ages of 3 and 8 years as high as 27%. This study aims to establish a reliable prevalence of OME in children between the ages of 9 and 16 years in order to inform public health policy and target limited resources. This cross-sectional study was undertaken in Pokhara, Nepal. Two different school populations were examined, government and non-government. Children in these schools between 9 and 16 years underwent clinical assessment for OME with otoscopy and tympanometry. Demographic data were also collected to identify potential OME risk factors. For each school population the prevalence of unilateral, bilateral and all case OME was calculated as percentages with 95% confidence intervals. A total of 494 children were recruited in this study (government=187, non-government=307). Fourteen were excluded due to impacted cerumen or other ENT pathology making it very difficult to conduct a clinical assessment. In the combined school populations the point prevalence of OME was 12.9%. The peak prevalence of OME was found in children aged 10 years (23.1%). A higher point prevalence of OME was found in the non-government school population than the government school (government=9.3%, non-government=15.0%). This difference was not statistically significant (χ(2)=3.209, df=1, p=0.073). Age was found to be significant predictor of OME. Contrary to its established natural history OME has been found to be widespread in older children in Nepal. No significant predictors of OME were established and rates did not vary significantly between school types. Studies need to be conducted in a larger population to investigate this further. To fully assess disease burden of OME amongst children in Nepal, prevalence in children not regularly attending schools also needs investigation. 23719266 RRM2 regulates Bcl-2 in head and neck and lung cancers: a potential target for cancer therapy. Ribonucleotide reductase subunit M2 (RRM2) plays an active role in tumor progression. Recently, we reported that depletion of RRM2 by systemic delivery of a nanoparticle carrying RRM2-specific siRNA suppresses head and neck tumor growth. The aim of this study is to clarify the underlying mechanism by which RRM2 depletion inhibits tumor growth. siRNA-mediated gene silencing was carried out to downregulate RRM2. Immunoblotting, reverse-transcriptase PCR, confocal microscopy, tissue fractionation, gene overexpression and knockdown were employed to analyze critical apoptosis signaling. Conventional immunohistochemistry and quantum dot-based immunofluorescence were applied to detect RRM2 and Bcl2 expression and localization in tissue samples from patients and mice. Knockdown of RRM2 led to apoptosis through the intrinsic pathway in head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) cell lines. We showed that Bcl-2 is a key determinant controlling apoptosis, both in vitro and in vivo, and that RRM2 depletion significantly reduces Bcl-2 protein expression. We observed that RRM2 regulates Bcl-2 protein stability, with RRM2 suppression leading to increased Bcl-2 degradation, and identified their colocalization in HNSCC and NSCLC cells. In a total of 50 specimens each from patients with HNSCC and NSCLC, we identified the colocalization of Bcl-2 and RRM2 and found a significant positive correlation between their expression in HNSCC (R = 0.98; P < 0.0001) and NSCLC (R = 0.92; P < 0.0001) tumor tissues. Our novel findings add to the knowledge of RRM2 in regulating expression of the antiapoptotic protein Bcl-2 and reveal a critical link between RRM2 and Bcl-2 in apoptosis signaling. 23924165 Optimal treatment for spinal cord injury associated with cervical canal stenosis (OSCIS): a study protocol for a randomized controlled trial comparing early versus delayed surgery. The optimal management of acute cervical spinal cord injury (SCI) associated with preexisting canal stenosis remains to be established. The objective of this study is to examine whether early surgical decompression (within 24 hours after admission) would result in greater improvement in motor function compared with delayed surgery (later than two weeks) in cervical SCI patients presenting with canal stenosis, but without bony injury. OSCIS is a randomized, controlled, parallel-group, assessor-blinded, multicenter trial. We will recruit 100 cervical SCI patients who are admitted within 48 hours of injury (aged 20 to 79 years; without fractures or dislocations; American Spinal Injury Association (ASIA) grade C; preexisting spinal canal stenosis). Patients will be enrolled from 36 participating hospitals across Japan and randomly allocated in a 1:1 ratio to either early surgical decompression (within 24 hours after admission) or delayed surgery following at least two weeks of conservative treatment. The primary outcomes include: 1) the change from baseline to one year in the ASIA motor score; 2) the total score of the Spinal Cord Independence Measure and 3) the proportion of patients who are able to walk without human assistance. The secondary outcomes are: 1) the health-related quality of life as measured by the Medical Outcomes Study Short Form 36 and the EuroQol 5 Dimension; 2) the Neuropathic Pain Symptom Inventory and 3) the walking status as evaluated with the Walking Index for Spinal Cord Injury II. The analysis will be on an intention-to-treat basis. The primary analysis will be a comparison of the primary and secondary outcomes one year after the injury. The results of this study will provide evidence of the potential benefit of early surgical decompression compared to the current 'watch and wait' strategy. 23921497 Standardized Uptake Value and Resection Margin Involvement Predict Outcomes in pN0 Head and Neck Cancer. ObjectiveThe aim of this study was to evaluate the prognostic factors of patients with pathologically negative lymph node (pN0) head and neck cancer.Study DesignCase series with chart review.SettingCollege medical center.Subjects and MethodsThe medical records of 120 patients were reviewed. Primary tumor sites included 46 larynx, 45 oral cavity, 17 oropharynx, and 12 hypopharynx.ResultsThe recurrence rate was 14% (17/120) over a mean observation period of 33 months. Median (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) maximal standardized uptake value (SUVmax; using 8.5 as a cutoff; P = .001), positive surgical margins (P = .005), and pathologic T stage (P = .012) were found to be associated with recurrence. The 5-year disease-specific survival rate (DSSR) in our cohort was 86%. Patients with an SUVmax value higher than 8.5 and positive surgical margins had significantly decreased 5-year DSSR based on Kaplan-Meier survival curves. Multivariate Cox regression analysis confirmed the significant association between median SUVmax (using 8.5 as a cutoff; hazard ratio [HR], 6.13; 95% confidence interval [CI], 1.79-20.93; P = .004) and margin involvement (HR, 4.98; 95% CI, 1.42-17.47; P = .012).ConclusionA median (18)F-FDG PET/CT SUVmax cutoff values of 8.5 or greater and positive surgical margins were associated with adverse outcomes in patients with pN0 head and neck cancer. 23829768 Rate Rules, Branching Ratios, and Pressure Dependence of the HO2 + Olefin Addition Channels. In this work, we present high-pressure rate rules and branching ratios for the addition of HO2 to olefins through the concerted addition channel to form an alkyl peroxy radical (HO2 + olefin → RO2) and through the radical addition channel to form a β-hydroperoxy alkyl radical (HO2 + olefin → β-QOOH). These rate rules were developed by calculating rate constants for a series of addition reactions involving olefins with varying degrees of branching. The individual rate expressions were determined from electronic structure calculations performed at the CBS-QB3 level of theory combined with TST calculations. The calculated rate constants were found to be in good agreement with those reported in the literature. Next, we calculated apparent pressure- and temperature-dependent rate constants for HO2 addition to the terminal site of 1-butene using an energy-grained master equation (ME) approach and QRRK calculations with a modified strong collision (MSC) approximation. The two methods gave similar results for both reaction classes. We found that, for the radical addition reaction, the high-pressure limit for the stabilization channel is not reached until unusually high pressures (>1000 atm). Instead, this reaction leads to the direct formation of an oxirane + OH. In general, the results for the major channels are in reasonable agreement with prior theoretical and experimental data. Finally, to explicitly examine the effect of pressure, we compared concentration-time profiles for the reactions of HO2 plus butene in air that were obtained using both high-pressure and pressure-dependent mechanisms at 10 and 100 atm. These simulations showed that, contrary to general expectations, the manifestation of pressure falloff effects in kinetic modeling studies might be more prevalent at increasing pressures. This behavior is attributed to the reaction of β-QOOH with O2, the rate of which increases with increasing pressure of air. This bimolecular reaction competes with the unimolecular reactions of β-QOOH under conditions where falloff effects are important for that channel. 23861250 Defective tubulin organization and proplatelet formation in murine megakaryocytes lacking Rac1 and Cdc42. Blood platelets are anuclear cell fragments that are essential for blood clotting. Platelets are produced by bone marrow megakaryocytes (MKs), which extend protrusions, so-called proplatelets, into bone marrow sinusoids. Proplatelet formation requires a profound reorganization of the MK actin and tubulin cytoskeleton. Rho GTPases, such as RhoA, Rac1 and Cdc42, are important regulators of cytoskeletal rearrangements in platelets, however, the specific roles of these proteins during platelet production are not established. Using conditional knockout mice, we show here that Rac1 and Cdc42 possess redundant functions in platelet production and function. In contrast to single deficiency of either protein, double-deficiency of Rac1 and Cdc42 in MKs resulted in macrothrombocytopenia, abnormal platelet morphology and impaired platelet function. Double-deficient bone marrow MKs matured normally in vivo, but displayed highly abnormal morphology and uncontrolled fragmentation. Consistently, lack of Rac1/Cdc42 virtually abrogated proplatelet formation in vitro. Strikingly, this phenotype was associated with severely defective tubulin organization, while actin assembly and structure were barely affected. Together, these results suggest that the combined action of Rac1 and Cdc42 is crucial for platelet production, particularly by regulating microtubule dynamics. 23842817 The double macchiato years; awards for the best basic science and epidemiology papers in 2012. It's increasingly difficult to get published in Thorax so we commend all those who managed it in 2012; and salute all those who tried and failed. We think that comparisons are invidious but our chief editors, with all their schoolboy charm, disagree so here are our awards for the best basic science and epidemiological manuscripts in the year of the London Olympics. 23396530 Arylamine organic dyes for dye-sensitized solar cells. Arylamine organic dyes with donor (D), π-bridge (π) and acceptor (A) moieties for dye-sensitized solar cells (DSCs) have received great attention in the last decade because of their high molar absorption coefficient, low cost and structural variety. In the early stages, the efficiency of DSCs with arylamine organic dyes with D-π-A character was far behind that of DSCs with ruthenium(II) complexes partly due to the lack of information about the relationship between the chemical structures and the photovoltaic performance. However, exciting progress has been recently made, and power conversion efficiencies over 10% were obtained for DSCs with arylamine organic dyes. It is thus that the recent research and development in the field of arylamine organic dyes employing an iodide/triiodide redox couple or polypyridyl cobalt redox shuttles as the electrolytes for either DSCs or solid-state DSCs has been summarized. The cell performance of the arylamine organic dyes are compared, providing a comprehensive overview of arylamine organic dyes, demonstrating the advantages/disadvantages of each class, and pointing out the field that needs to reinforce the research direction in the further application of DSCs. 23810159 Proximal direct endarterectomy combined with simultaneous distal endovascular therapy for chronic full-length occlusion of the superficial femoral artery in elderly patients. The most proximal ostial site of the chronic occlusive superficial femoral artery is not suitable for ballooning or stenting because the deep femoral artery may be occluded by these procedures. Thus, the feasibility of performing an open endarterectomy for the occluded ostium of the superficial femoral arteries combined with an endovascular therapy for the remaining distal site was evaluated. Eleven critically ischemic limbs in 10 elderly patients with poor general health were enrolled. They had full-length occlusion of the superficial femoral artery involving its ostium. The ostial site was managed with an open endarterectomy followed by endovascular therapy for the remaining distal site. All procedures were successfully performed. All patients experienced pain relief, and the wounds healed. During the follow-up observation period (average: 23.9 ± 14.7 months), nine patients died. None of the patients, including those who had lost patency of the superficial femoral artery, received major amputation. Elderly patients, including those who were in terminal stage, were able to withstand the operation, and their postoperative quality of life was not compromised. Although the patency following the surgery was limited, sparing the deep femoral artery could either prevent or delay the recurrence of critical limb ischemia. 23900257 Formation and stability of 3-5 atom gold clusters from gold complexes during the catalytic reaction: dependence on ligands and counteranions. Gold complexes and salts decompose to catalytically active 3-5 atom gold clusters during the one-pot acylation-hydration of propargyl alcohols. Kinetic and spectroscopic studies show that released ligands and counteranions exert a direct effect on the formation and stability of the clusters. 23819793 Recommendations for prophylaxis of pregnancy-related venous thromboembolism in carriers of inherited thrombophilia. Comment on the 2012 ACCP guidelines: a rebuttal. We thank Drs. De Stefano, Grandone, and Martinelli for their comments on our chapter in the 2012 edition of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis [1]. Modification of our guidelines for antepartum prophylaxis in women with prior venous thromboembolism and in those with asymptomatic thrombophilia was based not on new data, but on a careful reappraisal of the available literature and development of recommendations through rigorous use of the GRADE system [2]. A similar process in 2008 led to significant modifications in our guidance for anticoagulant management of pregnant women with mechanical prosthetic heart valves [3]. This article is protected by copyright. All rights reserved. 23866825 Systemic administration of 3-bromopyruvate reveals its interaction with serum proteins in a rat model. 3-bromopyruvate (3-BrPA) is a glycolytic inhibitor that affects cancer cells by targeting energy metabolism. Preclinical reports have established that a 1.75 mM dose of 3-BrPA is effective and sufficient to inhibit tumor growth when administered under a loco-regional approach (intraarterial and intratumoral). This loco-regional therapeutic dose was found to be nontoxic when given systemically as well. Yet, the mechanism underlying this lack of toxicity of 1.75 mM 3-BrPA during systemic delivery is unknown. Here, we investigated the mechanism associated with the lack of organ toxicity when 1.75 mM 3-BrPA was administered systemically using radiolabeled (14C)-3-BrPA in Sprague--Dawley rats. Data obtained from tissue-autoradiography of rats infused with 14C-3-BrPA showed strong 14C-signal in tissue sections of various organs except the brain corroborating that 3-BrPA does not cross the blood--brain barrier. Significantly, Hematoxylin & Eosin staining and apoptosis assay of tissue sections positive for 14C-signal showed no signs of toxicity or apoptosis. Convincingly, the 14C-signal observed in tissue-autoradiography emanates from 3-BrPA that is non-reactive or non-toxic, hence we further investigated whether the lack of toxicity is due to its interaction or alkylation with serum components. Analysis of serum proteins by 1D and 2D-gel electrophoretic autoradiography showed that 14C-BrPA selectively binds to peptides of molecular mass ~50-60 kDa. Mass spectrometry data suggested that 14C-BrPA could interact with alpha1-antitrypsin and a peptide of albuminoid-family. Our data indicate that selective interaction of 3-BrPA with serum proteins could contribute to the apparent lack of tissue-toxicity at the indicated close when the drug is given systematically in Sprague--Dawley rats. 22618298 Age-related changes in joint coordination during balance recovery. Falls represent a significant health risk in the elderly and often result in injuries that require medical attention. Reduced ability to control motion of the whole-body center of mass (COM) has been shown to identify elderly people at risk of falling. To explore effective preventive strategies and interventions, we studied adult age-related differences in multijoint coordination to control the COM during balance recovery. We used the uncontrolled manifold (UCM) analysis, which can decompose movement variability of joints into good movement variability (motor equivalent) and bad movement variability (nonmotor equivalent). The good variability does not affect the COM position, while the bad variability does. Twenty-nine subjects, including 16 healthy young (26.1 ±â€‰4.5 year) and 13 older (74.6 ±â€‰5.6 year) adults without systematic disease, neurological disease, or a severe degenerative condition stood on a flat platform, and received an unexpected backward translation. The older adults had similar amounts of joint movement as the young adults during balance recovery except for the thoracic-lumbar joint. However, the UCM analysis showed that the older adults changed their joint coordination pattern to control the COM and had a lower motor equivalent index with increased nonmotor equivalent variability (bad variability). We conclude that normal aging adults lose the compensatory strategy of flexibly controlling multiple joints when stabilizing the COM after receiving a balance perturbation. 23954528 Radiation therapy dosimetry system. New therapeutic treatments generally aim to increase therapeutic efficacy while minimizing toxicity. Many aspects of radiation dosimetry have been studied and developed particularly in the field of external radiation. The success of radiotherapy relies on monitoring the dose of radiation to which the tumor and the adjacent tissues are exposed. Radiotherapy techniques have evolved through a rapid transition from conventional three-dimensional (3D) conformal radiation therapy to intensity-modulated radiation therapy (IMRT) treatments or radiosurgery and robotic radiation therapy. These advances push the frontiers in our effort to provide better patient care by improving the precision of the absorbed dose delivered. This paper presents state-of-the art radiation therapy dosimetry techniques as well as the value of integral dosimetry (INDOS), which shows promise in the fulfillment of radiation therapy dosimetry requirements. 23910394 Reuse of olive mill effluents from two-phase extraction process by integrated advanced oxidation and reverse osmosis treatment. In this work, complete reclamation of the olive mill effluents coming from a two-phase olive oil extraction process (OME-2) was studied on a pilot scale. The developed depuration procedure integrates an advanced oxidation process based on Fenton's reagent (secondary treatment) coupled with a final reverse osmosis (RO) stage (purification step). The former aims for the removal of the major concentration of refractory organic pollutants present in OME-2, whereas the latter provides efficient purification of the high salinity. Complete physicochemical composition of OME-2 after the secondary treatment was examined, including the particle size distribution, organic matter gradation and bacterial growth, in order to assess the selection of the membrane and its fouling propensity. Hydrodynamics and selectivity of the membrane were accurately modelized. Upon optimization of the hydrodynamic conditions, the RO membrane showed stable performance and fouling problems were satisfactorily overcome. Steady-state permeate flux equal to 21.1Lh(-1)m(-2) and rejection values up to 99.1% and 98.1% of the organic pollutants and electroconductivity were respectively attained. This ensured parametric values below standard limits for reuse of the regenerated effluent, e.g. in the olives washing machines, offering the possibility of closing the loop and thus rending the production process environmentally friendly. 23845160 Remitted Male Schizophrenia Patients with Sexual Dysfunction. Despite the high prevalence of sexual dysfunction among male schizophrenia patients, there is still a paucity of research on this area. The study aims to determine the prevalence of sexual dysfunction and any association between male patients with schizophrenia in remission and the sociodemographic profile, medication, depression, anxiety, psychopathology of illness, body mass index, and waist circumference. A cross-sectional study with nonprobability sampling method was conducted in a psychiatric outpatient clinic in Taiping Hospital (Perak, Malaysia) over a 7-month period. A total of 111 remitted male schizophrenia patients were recruited. The validated Malay version of the International Index of Erectile Function (Mal-IIEF-15) was administered to the patients and assessed over 4-week duration in the domains of erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction. Logistic regression analysis was employed. Prevalence and associated factors for sexual dysfunction in each domain are the main outcome measures. All five domains of sexual functioning in patients showed a high prevalence of dysfunction ranging from 78.4% to 97.1% with orgasmic dysfunction being the least impaired and intercourse satisfaction the worst impaired. Among the domains, only orgasmic dysfunction was significantly associated with race, i.e., Chinese at lower risk for impairment than the Malays (OR = 0.23; 95% CI: 0.07, 0.76; P = 0.018); education, i.e., patients with education higher than primary level were at higher risk for dysfunction (OR = 6.49; 95% CI: 1.32, 32.05; P = 0.022); and Positive and Negative Syndrome Scale (PANSS)-positive subscale, i.e., higher PANSS-positive score was a protective factor for orgasmic dysfunction (OR = 0.54; 95% CI: 0.33, 0.89; P = 0.015). The prevalence of sexual dysfunction was generally high. Malay patients and those with education higher than primary level were at higher risk for orgasmic dysfunction whereas higher PANSS-positive score was protective against the impairment. The high rate of sexual dysfunction in schizophrenia patients warrants a routine inquiry into patients' sexuality and the appropriate problems being addressed. Ong KY, Muhd Ramli ER, and Che Ismail H. Remitted male schizophrenia patients with sexual dysfunction. J Sex Med **;**:**-**. 23963497 Microenterprise Development Interventions for Sexual Risk Reduction: A Systematic Review. Comprehensive interventions that address both individual and structural determinants associated with HIV/STI risk are gaining increasing attention over the past decade. Microenterprise development offers an appealing model for HIV prevention by addressing poverty and gender equality. This study systematically reviewed the effects of microenterprise development interventions on HIV/STI incidence and sexual risk behaviors. Microenterprise development was defined as developing small business capacity among individuals to alleviate poverty. Seven eligible research studies representing five interventions were identified and included in this review. All of the studies targeted women, and three focused on sex workers. None measured biomarker outcomes. All three sex worker studies showed significant reduction in sexual risk behaviors when compared to the control group. Non-sex worker studies showed limited changes in sexual risk behavior. This review indicates the potential utility of microenterprise development in HIV risk reduction programs. More research is needed to determine how microenterprise development can be effectively incorporated in comprehensive HIV control strategies. 23834569 Case-based anatomy teaching: a viable alternative? Background:  Over the last two decades, there has been a decline in the amount of time available for anatomy teaching in the medical undergraduate curriculum, and new methods of anatomy teaching have been adopted for pragmatic reasons, with little evidence base to support their proposed educational benefits. This study seeks to establish the effect of a case-based teaching method on students' confidence in anatomy. Methods:  Forty-three student volunteers in the clinical phase of the Glasgow medical course were given weekly anatomy teaching sessions based on clinical case presentations over 4 weeks. The students were given an anatomy test, and were asked to rate their confidence in their anatomy knowledge before and after the teaching sessions. Results:  There was a two-point increase in students' self-rated confidence, and a 10.9 per cent increase in average test score after the case-based anatomy teaching sessions. Both of these increases were statistically significant (p < 0.001 and p < 0.001, respectively). Discussion:  Case-based anatomy instruction can significantly improve students' confidence and knowledge of anatomy. This method of teaching was also highly rated by students, which may make it a viable option for the teaching of anatomy in the modern medical curriculum. 23836246 Dyssegmental dysplasia, Silverman-Handmaker type: prenatal ultrasound findings and molecular analysis. The objective of this study is to describe the prenatal sonographic features and the results of DNA analysis on three fetuses with dyssegmental dysplasia, Silverman-Handmaker type (DD-SH). A retrospective review of three fetuses with confirmed DD-SH was conducted. The fetal ultrasound findings, the radiological characteristics, and the results of the mutation analysis of the heparan sulphate perlecan gene 2 (HSPG2) were reviewed. There were three cases in two families with DD-SH diagnosed prenatally. The main prenatal ultrasound and the radiological features of DD-SH were severe limb shortening and vertebral segmentation and fusion defects (anisospondyly). The DNA analysis of the HSPG2 gene showed that the two affected fetuses in a nonconsanguineous family had a compound heterozygote for the c.646G > T transversion in exon 7 and a c.5788C > T transition in exon 46. The fetus born to the consanguineous couple had a homozygous mutation c.1356-27_1507 + 59del. DD-SH can be diagnosed prenatally using fetal ultrasound as early as 13 weeks. Xrays and DNA analysis of the HSPG2 gene are important for the confirmation of the diagnosis and for the preimplantation and prenatal diagnosis in pregnancies at risk. © 2013 John Wiley & Sons, Ltd. 23864932 Recent advances in pediatric gastroenterology, hepatology and nutrition. Pediatric gastroenterology, hepatology and nutrition are rapidly evolving, exciting and diverse disciplines. Because the field is so expansive, this commentary highlights important trends, rather than narrowly focusing on specific advances. Examples of advances in the highest impact and rapidly moving areas of pediatric gastroenterology are reviewed, including the intestinal microbiome, biomedical genomics, the biology of unique gastrointestinal cell types, and microRNAs (miRNAs). 23770974 A comparative study of the catalysis of peptide bond formation by oxide surfaces. It is well-known that amino acids deposited on some inorganic oxides undergo peptidic condensation. It is seldom realised however that a large diversity of behaviours can be observed in such systems. Here we use the apparently simple case of glycine-non-porous silica as a reference system, in which glycine (Gly) dimerisation to diketopiperazine (DKP) is easy to evidence, especially when using TG in combination with NMR. We then proceed to compare it with other AA deposited on the same support on the one hand, with Gly deposited on other mineral surfaces on the other hand. In a final section, we provide more detailed mechanistic information on the glycine condensation process on silica, including kinetic data and a (13)C solid-state NMR follow up of the species at various stages of thermal condensation. The best mechanism to rationalise these data involves a crucial step of isomerisation from zwitterion to neutral glycine, and the participation of several distinct types of surface sites probably consisting of silanol ensembles. 23822199 Changes in signaling pathways induced by vandetanib in a human medullary thyroid carcinoma model, as analyzed by Reverse Phase Protein Array. Background: Medullary thyroid carcinoma (MTC) is a rare tumor that is due to activating mutations in the proto-oncogene RET. Vandetanib, a tyrosine-kinase inhibitor, has been recently approved to treat adult patients with metastatic MTC. The aim of this study was to investigate changes in signaling pathways induced by vandetanib treatment in preclinical MTC models, using the reverse-phase protein array method (RPPA). Methods: The human TT cell line was used to assess in vitro and in vivo activity of vandetanib. Protein extracts from TT cells or TT xenografted mice, treated by increasing concentrations of vandetanib for different periods of time, were probed with a set of 12 antibodies representing major signaling pathways, using RPPA. Results were validated using two distinct protein detection methods, western-immunoblotting and immunohistochemistry. Results: Vandetanib displays antiproliferative and antiangiogenic activities and inhibits RET auto-phosphorylation. MAPK and AKT pathways were the two major signaling pathways inhibited by vandetanib. Interestingly, phosphorylated levels of NFκB-p65 were significantly increased by vandetanib. Comparable results were obtained in both the in vitro and in vivo approaches as well as for the protein detection methods, although some discrepancies were observed between RPPA and western-immunoblotting. Conclusions: Results confirmed the reliability and the utility of RPPA for screening global changes induced in signaling pathways by kinase inhibitors. MAPK and AKT were identified as the main pathways involved in vandetanib response in MTC models. Our results also suggest alternative routes for controlling the disease and provide a rationale for the development of therapeutic combinations based on the comprehensive identification of molecular events induced by inhibitors. 23770316 Organophosphorus esters in the oceans and possible relation with ocean gyres. Four organophosphorus esters (OPEs) were detected in aerosol samples collected in the West Pacific, the Indian Ocean and the Southern Ocean from 2009 to 2010, suggesting their circumpolar and global distribution. In general, the highest concentrations were detected near populated regions in China, Australia and New Zealand. OPE concentrations in the Southern Ocean were about two orders of magnitude lower than those near major continents. Additionally, relatively high OPE concentrations were detected at the Antarctic Peninsula, where several scientific survey stations are located. The four OPEs investigated here are significantly correlated with each other, suggesting they may derive from the same source. In the circumpolar transect, OPE concentrations were associated with ocean gyres in the open ocean. Their concentrations were positively related with average vorticity in the sampling area suggesting that a major source of OPEs may be found in ocean gyres where plastic debris is known to accumulate. 23401393 Enhancement of mechanical properties of experimental composite by Fuller's earth nanofibers for cervical restoration. In this research, we studied improvement of mechanical properties of dimethacrylate-silica based dental composites by addition of Fuller's Earth (FE) clay. Three composites were made as base compounds consisting of 68, 58, and 48 wt % resin and 31, 41, and 51 wt % silica, respectively. Afterward, the composites were modified by adding FE. Mechanical properties including flexural strength, flexural modulus, work-of-fracture, fracture toughness, and microhardness were measured. Clay particles and fracture surface of composites consisting of 51 wt % silica (with and without FE) were examined by SEM. Measured results showed that flexural strength, work-of-fracture, flexural modulus, and microhardness of all composites increased by including FE nanofibers. Fracture toughness except for composite including 51 wt % silica had similar variations. It seems that locating FE nanofibers in weak resin region among silica particles leads to strengthening mechanisms, such as bridging and crack deflection, which cause improvement in mechanical properties. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2013. 23799786 Upgrading Light Hydrocarbons via Tandem Catalysis: A Dual Homogeneous Ta/Ir System for Alkane/Alkene Coupling. Light alkanes and alkenes are abundant but are underutilized as energy carriers because of their high volatility and low energy density. A tandem catalytic approach for the coupling of alkanes and alkenes has been developed in order to upgrade these light hydrocarbons into heavier fuel molecules. This process involves alkane dehydrogenation by a pincer-ligated iridium complex and alkene dimerization by a Cp*TaCl2(alkene) catalyst. These two homogeneous catalysts operate with up to 60/30 cooperative turnovers (Ir/Ta) in the dimerization of 1-hexene/n-heptane, giving C13/C14 products in 40% yield. This dual system can also effect the catalytic dimerization of n-heptane (neohexene as the H2 acceptor) with cooperative turnover numbers of 22/3 (Ir/Ta). 23905865 Role of LC-MS/MS in hair testing for the determination of common drugs of abuse and other psychoactive drugs. Hair testing has been used in toxicological investigations for the last two decades, but only recently a remarkable extension of hair analysis to a variety of application fields was observed, besides drug abuse recognition. The dramatic improvements of LC-MS/MS instrumentation make the detection of tiny amounts of almost whatever drug in hair possible, even after single-dose intake. The progresses observed during the last 5 years in the detection of psychoactive substances in hair are reviewed herein. The literature is partitioned according to the target compounds, namely traditional drugs of abuse, new psychoactive substances and pharmaceutical psychoactive substances. The LC-MS/MS methods presented are addressed to determine a single class of drugs, with the primary aim of accurate quantitation, or to perform multiclass analysis, for rapid and effective screening protocols. 23842795 Exploring NMR methods as a tool to select suitable fluorescent nucleotide analogues. Fluorescent analogues provide important tools for biochemical/biophysical research. However, the analogues contain chemical modifications much larger than those known to affect ligand-binding, such as the inversion of a carbon centre or substitution of an atom. We lack experimental tools and protocols to select the most appropriate fluorescent analogue. Herein, we use several NMR spectroscopy methods, including Saturation Transfer Difference (STD), STD competition and transferred nuclear Overhauser effect spectroscopy (Tr-NOESY), as tools to select appropriate fluorescent probes. Annexin A6 (AnxA6) is a ubiquitous protein that forms in vitro GTP-induced ion channels. We used this protein as a model and screened guanosine triphosphate (GTP) and four fluorescent analogues against AnxA6. STD reported that the GTP moiety of all ligands made similar contacts with the protein, despite additional interactions between the fluorescent tags and AnxA6. Competition STD experiments verified that the analogues and GTP bind to the same site. Tr-NOESY indicated that the bound conformation of the base relative to ribose is altered for some analogues compared to GTP. MANT-GTP or the BODIPY thioester of guanosine 5'-O-(3-thiotriphosphate) are the most suitable fluorescent analogues for AnxA6, according to NMR. These results reveal NMR as a useful technique to select and design proper fluorescent tags for biochemical/biophysical assays. 23624435 Concentration-dependent inhibition of Escherichia coli O157:H7 and heterocyclic amines in heated ground beef patties by apple and olive extracts, onion powder and clove bud oil. The effects of plant compounds on Escherichia coli O157:H7 and two major heat-induced heterocyclic amines (HCAs) MeIQx and PhIP in grilled ground beef patties were determined. Ground beef with added apple and olive extracts, onion powder, and clove bud oil was inoculated with E. coli O157:H7 (10⁷ CFU/g) and cooked to reach 45 °C at the geometric center, flipped and then cooked for another 5 min. Cooled samples were taken for microbiological and HCA analyses. Olive extract at 3% reduced E. coli O157:H7 to below detection. Reductions of up to 1 log were achieved with apple extract. Olive and apple extracts reduced MeIQx by up to 49.1 and 50.9% and PhIP by up to 50.6 and 65.2%, respectively. Onion powder reduced MeIQx and PhIP by 47 and 80.7%, respectively. Inactivation of E. coli O157:H7 and suppression of HCAs in grilled meat were achieved by optimized amounts of selected plant compounds. 23836068 The autopsy study of 553 cases of sudden cardiac death in Chinese adults. Despite a recent epidemiological study reporting a lower incidence of sudden cardiac death (SCD) in China as compared with that in Western countries, the exact causes of SCD are still unknown. Using a uniform review protocol and diagnostic criteria, a retrospective autopsy study identified 553 cases of SCD in 14,487 consecutive autopsies from eight regions in China representing different geographic and population features. Their ages ranged from 18 to 80 years (median 43.0 years) with a ratio of 4.3/1.0 for male/female. Out-of-hospital deaths and unwitnessed cases accounted for 74.3 and 22.6 %, respectively. The main causes of death were coronary atherosclerotic disease (CAD 50.3 %), myocarditis (14.8 %), and hypertrophic cardiomyopathy (4.5 %), with unexplained sudden death accounting for 12.1 % of the cases. CAD had a proportion of 10.4 % in victims <35 years, lower as compared with 59.0 and 83.0 % in victims aged 35-54 and in victims ≥55 years. On the other hand, myocarditis and unexplained sudden death were major causes and accounted for 34.7 and 22.5 % in victims <35 years. In order to differentiate the degree of the cause-effect relationship between autopsy findings and sudden death, a grading method was used in this series and characterized 24.3 % of findings as certain, 52.9 % as highly probable, and 22.8 % as uncertain. Our data indicated that there most likely are less CAD but more myocarditis and unexplained sudden death in Chinese youth with SCD than in populations from Western countries. Molecular genetic testing should be conducted in those cases with uncertain findings and unexplained sudden death in routine autopsy. 23911440 Neural correlates of obsessive-compulsive related dysfunctional beliefs. There have been few attempts to integrate neurobiological and cognitive models of obsessive-compulsive disorder (OCD), although this might constitute a key approach to clarify the complex etiology of the disorder. Our study aimed to explore the neural correlates underlying dysfunctional beliefs hypothesized by cognitive models to be involved in the development and maintenance of OCD. We obtained a high-resolution magnetic resonance image from fifty OCD patients and 30 healthy controls, and correlated them, voxel-wise, with the severity of OC-related dysfunctional beliefs assessed by the Obsessive Beliefs Questionnaire-44. In healthy controls, significant negative correlations were observed between anterior temporal lobe (ATL) volume and scores on perfectionism/intolerance of uncertainty and overimportance/need to control thoughts. No significant correlations between OBQ-44 domains and regional gray matter volumes were observed in OCD patients. A post-hoc region-of-interest analysis detected that the ATLs was bilaterally smaller in OCD patients. On splitting subjects into high- and low-belief subgroups, we observed that such brain structural differences between OCD patients and healthy controls were explained by significantly larger ATL volumes among healthy subjects from the low-belief subgroup. Our results suggest a significant correlation between OC-related dysfunctional beliefs and morphometric variability in the anterior temporal lobe, a brain structure related to socio-emotional processing. Future studies should address the interaction of these correlations with environmental factors to fully characterize the bases of OC-related dysfunctional beliefs and to advance in the integration of biological and cognitive models of OCD. 23438319 Placental weight relative to birthweight in pregnancies with maternal diabetes mellitus. To study the association of maternal diabetes mellitus with placental weight, birthweight and placental weight-to-birthweight ratio. Population-based study. Medical Birth Registry of Norway. All singleton births in Norway during 1999-2008 (n = 536,997). We compared the distribution of placental weight z-scores and placental weight-to-birthweight ratio between pregnancies with and without diabetes. The associations of diabetes with placental weight z-scores were also estimated as odds ratios with and without adjustment for birthweight, maternal age, parity, preeclampsia, smoking and cesarean delivery. Placental weight, birthweight and placental weight-to-birthweight ratio. Mean placental weight was 736.6 g in diabetic pregnancies and 672.1 g in non-diabetic pregnancies. The corresponding birthweights were 3682.1 g and 3557.0 g. In diabetic pregnancies, 26.2% of the placentas were in the highest decile of placental weight z-score, as compared with 9.7% in non-diabetic pregnancies (p < 0.001). The corresponding figures for being in the highest decile of placental weight-to-birthweight ratio were 18.2 and 9.9% (p < 0.001). The crude odds ratio for having a placenta in the highest decile of placental weight z-score was 3.29 (95% confidence interval 3.14-3.45) in diabetic pregnancies with non-diabetic pregnancies as the reference. After adjustment for birthweight and other variables, the odds ratio was 2.42 (95% confidence interval 2.29-2.56). In diabetic pregnancies, placental weight as well as placental weight relative to birthweight were higher than in non-diabetic pregnancies. 23869211 Distinct Contributions of TNF Receptor 1 and 2 to TNF-Induced Glomerular Inflammation in Mice. TNF is an important mediator of glomerulonephritis. The two TNF-receptors TNFR1 and TNFR2 contribute differently to glomerular inflammation in vivo, but specific mechanisms of TNFR-mediated inflammatory responses in glomeruli are unknown. We investigated their expression and function in murine kidneys, isolated glomeruli ex vivo, and glomerular cells in vitro. In normal kidney TNFR1 and TNFR2 were preferentially expressed in glomeruli. Expression of both TNFRs and TNF-induced upregulation of TNFR2 mRNA was confirmed in murine glomerular endothelial and mesangial cell lines. In vivo, TNF exposure rapidly induced glomerular accumulation of leukocytes. To examine TNFR-specific inflammatory responses in intrinsic glomerular cells but not infiltrating leukocytes we performed microarray gene expression profiling on intact glomeruli isolated from wildtype and Tnfr-deficient mice following exposure to soluble TNF ex vivo. Most TNF-induced effects were exclusively mediated by TNFR1, including induced glomerular expression of adhesion molecules, chemokines, complement factors and pro-apoptotic molecules. However, TNFR2 contributed to TNFR1-dependent mRNA expression of inflammatory mediators in glomeruli when exposed to low TNF concentrations. Chemokine secretion was absent in TNF-stimulated Tnfr1-deficient glomeruli, but also significantly decreased in glomeruli lacking TNFR2. In vivo, TNF-induced glomerular leukocyte infiltration was abrogated in Tnfr1-deficient mice, whereas Tnfr2-deficiency decreased mononuclear phagocytes infiltrates, but not neutrophils. These data demonstrate that activation of intrinsic glomerular cells by soluble TNF requires TNFR1, whereas TNFR2 is not essential, but augments TNFR1-dependent effects. Previously described TNFR2-dependent glomerular inflammation may therefore require TNFR2 activation by membrane-bound, but not soluble TNF. 23965920 Biphasic myosin II light chain activation during clot retraction. Clot retraction is an essential step during primary haemostasis, thereby promoting thrombus stability and wound healing. Integrin αIIbβ3 plays a critical role in clot retraction, by inducing acto-myosin interactions that allow platelet cytoskeleton reorganisation. However, the signalling pathways that lead to clot retraction are still misunderstood. In this study, we report the first data on the kinetics of myosin II light chain (MLC) phosphorylation during clot retraction. We found an early phosphorylation peak followed by a second peak. By using specific inhibitors of kinases and small G proteins, we showed that MLC kinase (MLCK), RhoA/ROCK, and Rac-1 were involved in clot retraction and in the early MLC phosphorylation peak. Only Rac-1 and actin polymerization, controlled by outside-in signalling, were crucial to the second MLC phosphorylation peak. 23813005 FuncISH: learning a functional representation of neural ISH images. High-spatial resolution imaging datasets of mammalian brains have recently become available in unprecedented amounts. Images now reveal highly complex patterns of gene expression varying on multiple scales. The challenge in analyzing these images is both in extracting the patterns that are most relevant functionally and in providing a meaningful representation that allows neuroscientists to interpret the extracted patterns. Here, we present FuncISH--a method to learn functional representations of neural in situ hybridization (ISH) images. We represent images using a histogram of local descriptors in several scales, and we use this representation to learn detectors of functional (GO) categories for every image. As a result, each image is represented as a point in a low-dimensional space whose axes correspond to meaningful functional annotations. The resulting representations define similarities between ISH images that can be easily explained by functional categories. We applied our method to the genomic set of mouse neural ISH images available at the Allen Brain Atlas, finding that most neural biological processes can be inferred from spatial expression patterns with high accuracy. Using functional representations, we predict several gene interaction properties, such as protein-protein interactions and cell-type specificity, more accurately than competing methods based on global correlations. We used FuncISH to identify similar expression patterns of GABAergic neuronal markers that were not previously identified and to infer new gene function based on image-image similarities. Supplementary data are available at Bioinformatics online. 23857881 Subporphyrins with an axial bc bond. Axial fabrications of subporphyrins have been conveniently accomplished by the reaction of B(methoxo)triphenylsubporphyrin with Grignard reagents such as aryl-, heteroaryl-, ferrocenyl-, β-styryl-, phenylethynyl-, and ethylmagnesium bromides. The axial groups thus introduced are not conjugated with the subporphyrin core. This situation leads to effective fluorescence quenching of subporphyrins when the axial group is strongly electron donating such as 4-dimethylaminophenyl and ferrocenyl groups. 23918940 CCM1-ICAP-1 complex controls β1 integrin-dependent endothelial contractility and fibronectin remodeling. The endothelial CCM complex regulates blood vessel stability and permeability. Loss-of-function mutations in CCM genes are responsible for human cerebral cavernous malformations (CCMs), which are characterized by clusters of hemorrhagic dilated capillaries composed of endothelium lacking mural cells and altered sub-endothelial extracellular matrix (ECM). Association of the CCM1/2 complex with ICAP-1, an inhibitor of β1 integrin, prompted us to investigate whether the CCM complex interferes with integrin signaling. We demonstrate that CCM1/2 loss resulted in ICAP-1 destabilization, which increased β1 integrin activation and led to increased RhoA-dependent contractility. The resulting abnormal distribution of forces led to aberrant ECM remodeling around lesions of CCM1- and CCM2-deficient mice. ICAP-1-deficient vessels displayed similar defects. We demonstrate that a positive feedback loop between the aberrant ECM and internal cellular tension led to decreased endothelial barrier function. Our data support that up-regulation of β1 integrin activation participates in the progression of CCM lesions by destabilizing intercellular junctions through increased cell contractility and aberrant ECM remodeling. 23873125 Surgical treatment of typical peripheral schwannomas: the risk of new postoperative deficits. Although peripheral schwannomas can be resected without postoperative neurological complications, surgeons must anticipate the possibility that new neurological deficits could develop. In order to evaluate the risk of neurological complications in the surgical treatment of these tumours, we performed a retrospective review of cases involving schwannomas in the extremities, as well as an analysis of the related literature. We reviewed a combined series of 72 schwannomas from the extremities presenting for surgical excision. Meticulous analysis of the files was undertaken, searching for pre-operative findings that could be more frequent in patients with surgical complications. The incidence, severity, and transitory nature of post-operative complications in our series was observed and compared against the literature. Eleven patients (15.2 %) developed new neurological deficits after surgery: sensory disturbance in seven cases, motor weakness in three, and a single wound hematoma. Most of these complications were temporary. Statistical analysis demonstrated a positive relationship between the presence of complications and both patient age under 50 years (p = 0.02) and tumours greater than 3 cm in greatest diameter (p = 0.02). Although relatively infrequent, the potential for novel post-operative deficits after the surgical treatment of peripheral schwannomas does exist and should be included during pre-operative counseling. 22796044 Classification of Aurora kinase inhibitors by self-organizing map (SOM) and support vector machine (SVM). The Aurora kinase family (consisting of Aurora-A, -B and -C) is an important group of enzymes that controls several aspects of cell division in mammalian cells. In this study, 512 compounds of Aurora-A and -B inhibitors were collected. They were classified into three classes: dual Aurora-A and Aurora-B inhibitors, selective inhibitors of Aurora-A and selective inhibitors of Aurora-B by Self-Organizing Map (SOM) and Support Vector Machine (SVM). The prediction accuracies of the models (based on the training/test set splitting using SOM method) for the test set were 92.2% for SOM1 and 93.8% for SVM1, respectively. In addition, the extended connectivity fingerprints (ECFP_4) for all the molecules were calculated and structure-activity relationship of Aurora kinase inhibitors was summarized, which may be helpful to find the important structural features of inhibitors relating to the selectivity to Aurora kinases. 23169689 Discovery of Schaeffer's acid analogues as lead structures of mycobacterium tuberculosis type II dehydroquinase using a rational drug design approach. Rational ligand design: Schaeffer's acid analogues were identified as novel inhibitors of M. tuberculosis type II dehydroquinase, a key enzyme of the shikimate pathway. Their likely binding mode was predicted using a combination of ensemble docking and flexible active site residues. Potentially, this scaffold could provide a good starting point for the design of antitubercular agents. 23787300 Fast calibration of SPECT monolithic scintillation detectors using un-collimated sources. Monolithic scintillation detectors for positron emission tomography and single-photon emission computed tomography (SPECT) imaging have many advantages over pixelated detectors. The use of monolithic crystals allows for reducing the scintillator cost per unit volume and increasing the sensitivity along with the energy and timing resolution of the detector. In addition, on thick detectors the depth-of-interaction can be determined without additional hardware. However, costly and complex calibration procedures have been proposed to achieve optimal detector performance for monolithic detectors. This hampers their use in commercial systems. There is thus, a need for simple calibration routines that can be performed on assembled systems. The main goal of this work is to develop a simplified calibration procedure based on acquired training data. In comparison with other methods that use training data acquired with beam sources attached to robotic stages, the proposed method uses a static un-collimated activity source with simple geometry acquiring in a reasonable time. Once the data are acquired, the calibration of the detector is accomplished in three steps: energy calibration based on the k-means clustering method, self-organization based on the self-organizing maps algorithm, and distortion correction based on the Monge-Kantorovich grid adaptation. The proposed calibration method was validated for 2D positioning using a SPECT detector. Similar results were obtained by comparison with an existing calibration method (maximum likelihood estimation). In conclusion, we proposed a novel calibration method for monolithic scintillation detectors that greatly simplifies their use with optimal performance in SPECT systems. 23017397 C-dideoxyhexosyl flavones from the stems and leaves of Passiflora edulis Sims. The stems and leaves of Passiflora edulis Sims, are used as a folk medicine for treating both anxiety and nervousness in American countries. Phytochemical investigation of the n-butanol (n-BuOH) fraction of this plant led to the isolation of four new 2,6-dideoxyhexose-C-glycosyl flavones, including luteolin-8-C-β-digitoxopyranosyl-4'-O-β-d-glucopyranoside (1), apigenin-8-C-β-digitoxopyranoside (2), apigenin-8-C-β-boivinopyranoside (3) and luteolin-8-C-β-boivinopyranoside (4), together with five known compounds (5-9). The structures of these compounds were elucidated by extensive spectroscopic methods. All compounds were evaluated for their neurite outgrowth enhancing activities and the results indicated that luteolin (7) enhanced NGF-induced neurite outgrowth in PC12 cells at 50.0μM. 23850650 Expression of the calcium binding proteins Necab-1,-2 and -3 in the adult mouse hippocampus and dentate gyrus. The family of EF-hand calcium binding proteins is composed of more than 250 members. In search for other neuronal markers, we studied the expression pattern of Necab-1, -2 and -3 in the Ammons horn of adult mice at the gene- and protein levels using in-situ hybridization and immunohistochemistry. The genes for the three Necab's were expressed in specific, non-overlapping areas of the hippocampus. A minority of the Necab-positive interneurons were GABA-ergic, and they virtually never coexpressed one of the classical calcium binding proteins (calretinin, calbindin D-28k and parvalbumin). Necab's are promising new neuronal markers in the brain. 23834352 Nutrient sensing and metabolic stress pathways in innate immunity. Cells monitor nutrient availability through several highly conserved pathways that include the mTOR signalling axis regulated by AKT/PI3K, HIF and AMPK, as well as the GCN2/eIF2α integrated stress response pathway that provides cellular adaptation to amino acid starvation. Recent evidence has identified a critical interplay between these nutrient sensing pathways and innate immunity to bacterial pathogens, viruses and parasites. These observations suggest that, in addition to the well-characterized pro-inflammatory signalling mediated by pattern recognition molecules, a metabolic stress programme contributes to shape the global response to pathogens. 23868110 Oestrogens and overactive bladder. Estrogens are known to have a major role in the function of the lower urinary tract although the role of exogenous estrogen replacement therapy in the management of women with lower urinary tract dysfunction remains controversial. Whilst for many years systemic and vaginal estrogen therapy was felt to be beneficial in the treatment of lower urinary and genital tract symptoms this evidence has recently been challenged by large epidemiological studies investigating the use of systemic hormone replacement therapy. Consequently the role of estrogen in the management of postmenopausal women with Overactive Bladder (OAB) remains uncertain. In addition the evidence base regarding the use of exogenous estrogen therapy has changed significantly over the last decade and has led to a major changes in current clinical practice. The aim of this article is to review the evidence for the role of estrogen therapy in the management of OAB focusing on current knowledge with regard to both systemic and local estrogen therapy as well as investigating the emerging role of combination therapy with antimuscarinic agents. Neurourol. Urodynam. © 2013 Wiley Periodicals, Inc. 23362212 Gold nanotip array for ultrasensitive electrochemical sensing and spectroscopic monitoring. A gold nanotip array platform with a combination of ultrasensitive electrochemical sensing and spectroscopic monitoring capability is reported. Adenosine triphosphate is detected down to 1 pM according to the impedance changes in response to aptamer-specific binding. Furthermore, the local molecular information can be monitored at the individual plasmonic nanotips, and hence provide the capability for a better understanding of complex biological processes. 23542442 Central functional response to the novel peptide cannabinoid, hemopressin. Hemopressin is the first peptide ligand to be described for the CB1 cannabinoid receptor. Hemopressin acts as an inverse agonist in vivo and can cross the blood-brain barrier to both inhibit appetite and induce antinociception. Despite being highly effective, synthetic CB1 inverse agonists are limited therapeutically due to unwanted, over dampening of central reward pathways. However, hemopressin appears to have its effect on appetite by affecting satiety rather than reward, suggesting an alternative mode of action which might avoid adverse side effects. Here, to resolve the neuronal circuitry mediating hemopressin's actions, we have combined blood-oxygen-level-dependent, pharmacological-challenge magnetic resonance imaging with c-Fos functional activity mapping to compare brain regions responsive to systemic administration of hemopressin and the synthetic CB1 inverse agonist, AM251. Using these complementary methods, we demonstrate that hemopressin activates distinct neuronal substrates within the brain, focused mainly on the feeding-related circuits of the mediobasal hypothalamus and in nociceptive regions of the periaqueductal grey (PAG) and dorsal raphe (DR). In contrast to AM251, there is a distinct lack of activation of the brain reward centres, such as the ventral tegmental area, nucleus accumbens and orbitofrontal cortex, which normally form a functional activity signature for the central action of synthetic CB1 receptor inverse agonists. Thus, hemopressin modulates the function of key feeding-related brain nuclei of the mediobasal hypothalamus, and descending pain pathways of the PAG and DR, and not higher limbic structures. Thus, hemopressin may offer behaviourally selective effects on nociception and appetite, without engaging reward pathways. 23934205 Teeth and Tongue Discoloration after Linezolid Treatment in Children. We describe three children who developed teeth and tongue discoloration while receiving intravenous linezolid for 2 to 3 weeks. Linezolid was co-administered with piperacillin-tazobactam or meropenem. Teeth and tongue discoloration was reversible with dental cleaning after discontinuation of linezolid. We review the published pediatric and adult cases regarding teeth and tongue discoloration after linezolid administration. 23666911 Multiphysics computational models for cardiac flow and virtual cardiography. A multiphysics simulation approach is developed for predicting cardiac flows as well as for conducting virtual echocardiography (ECHO) and phonocardiography (PC) of those flows. Intraventricular blood flow in pathological heart conditions is simulated by solving the three-dimensional incompressible Navier-Stokes equations with an immersed boundary method, and using this computational hemodynamic data, echocardiographic and phonocardiographic signals are synthesized by separate simulations that model the physics of ultrasound wave scattering and flow-induced sound, respectively. For virtual ECHO, a Doppler ultrasound image is reproduced through Lagrangian particle tracking of blood cell particles and application of sound wave scattering theory. For virtual PC, the generation and propagation of blood flow-induced sounds ('hemoacoustics') is directly simulated by a computational acoustics model. The virtual ECHO is applied to reproduce a color M-mode Doppler image for the left ventricle as well as continuous Doppler image for the outflow tract of the left ventricle, which can be verified directly against clinically acquired data. The potential of the virtual PC approach for providing new insights between disease and heart sounds is demonstrated by applying it to modeling systolic murmurs caused by hypertrophic cardiomyopathy. Copyright © 2013 John Wiley & Sons, Ltd. 23601001 A prospective randomized single-center study on the risk of asymptomatic cerebral lesions comparing irrigated radiofrequency current ablation with the cryoballoon and the laser balloon. Asymptomatic cerebral lesions (ACL) may occur during atrial fibrillation (AF) ablation. We sought to compare the ACL incidence between 3 contemporary technologies: (1) irrigated radiofrequency current (RFC), (2) the single big cryoballoon (CB), and (3) the endoscopic laser-balloon (LB) in a prospective randomized pilot study. Ninety-nine patients were treated in 3 groups. Diffusion weighted MRI was acquired pre- (n = 20) and 24-48 h postablation (n = 99). After ablation, new ACL were detected in 22% of patients without significant differences between groups (RFC 8/33; CB 6/33; LB 8/33; P = 0.8). The presence of hypertension was identified as the only independent predictor of ACL by univariate regression analysis. During LB ablation, more ablation lesions (140 ± 19 vs 119 ± 18; P = 0.007) were applied during longer procedures (166 ± 36 vs 143 ± 32 min; P = 0.05) in patients with ACL. Univariate analysis revealed that a higher number of ablation lesions predicted ACL (P = 0.02). In this prospective, randomized, single-center pilot study, ablation technology did not influence the occurrence of ACL during AF ablation. 23823233 A model for the interfacial kinetics of phospholipase D activity on long-chain lipids. The membrane-active enzyme phospholipase D (PLD) catalyzes the hydrolysis of the phosphodiester bond in phospholipids and plays a critical role in cell signaling. This catalytic reaction proceeds on lipid-water interfaces and is an example of heterogeneous catalysis in biology. Recently we showed that planar lipid bilayers, a previously unexplored model membrane for these kinetic studies, can be used for monitoring interfacial catalytic reactions under well-defined experimental conditions with chemical and electrical access to both sides of the lipid membrane. Employing an assay that relies on the conductance of the pore-forming peptide gramicidin A to monitor PLD activity, the work presented here reveals the kinetics of hydrolysis of long-chain phosphatidylcholine lipids in situ. We have developed an extension of a basic kinetic model for interfacial catalysis that includes product activation and substrate depletion. This model describes the kinetic behavior very well and reveals two kinetic parameters, the specificity constant and the interfacial quality constant. This approach results in a simple and general model to account for product accumulation in interfacial enzyme kinetics. 23477500 Characteristics of scheduled bleeding manipulation with combined hormonal contraception in university students. There is a lack of information concerning the decision factors and sources of information influencing women who purposefully deviate from the prescribed use of their combined hormone contraceptives to exert elective control of their scheduled bleeding. A self-administered email survey of scheduled bleeding practices and beliefs was distributed to 11,900 female students at the University of Oregon. Assessment of survey participant characteristics, scheduled bleeding manipulation features and attitudes and knowledge toward hormonal contraception was analyzed. Of 1719 respondents to the survey, 1374 (79.9%) reported using combined hormonal contraception currently or recently. Approximately 17% of these women altered their scheduled bleeding pattern by deviating from package instructions. Of these, 50% indicated they delayed or skipped their scheduled bleeding for convenience or personal choice. Within this group, 47% of women indicated they learned to modify their scheduled bleeding from health care professionals, while 30% indicated such knowledge was obtained from family or friends. Characteristics that decreased the likelihood of this practice included being of Asian race, use of hormonal contraceptive for bleeding cycle regulation, following a regular exercise program, and personal preference for a monthly cycle. The majority of university females who choose to modify their scheduled bleeding cycle with combined hormonal contraceptives do so for convenience rather than to avoid menstrual symptoms, and many learn from nonmedical sources. There is some disparity between the preferences of menstruation frequency and actual scheduled bleeding pattern behaviors, suggesting potential for improvement in patient education. 23896262 Pulmonary neuroendocrine tumors with nuclear inclusion. Nuclear inclusion or pseudoinclusion is a peculiar cytological feature, and its recognition in appropriate clinicopathological settings can aid in the diagnosis of several disease entities. To the best of our knowledge, only 1 case of pulmonary neuroendocrine tumor (NET) with nuclear pseudoinclusion has been reported. A review of 227 patients who had undergone surgical resection for pulmonary NETs revealed 2 tumors with different mechanisms of nuclear inclusion. To explore the cause of nuclear inclusion, NET with nuclear inclusion was characterized immunohistochemically and ultrastructurally. Nuclear inclusions were observed in 2 of the 227 (0.9%) patients with pulmonary NETs. The first patient was a 46-year-old woman with small cell carcinoma. Tumor cells with nuclear inclusions were distributed focally. Ultrastructural analysis showed that these inclusions were pseudoinclusions. The second patient was a 62-year-old man with large-cell neuroendocrine carcinoma. Nuclear inclusions were observed in the focal area of the tumor. Immunohistochemical analysis revealed that the intra-nuclear materials consisted of biotin and aberrant cytoplasmic and nuclear accumulation of β-catenin. Mutational analysis revealed a CTNNB1 gene mutation. Although very rare, diagnostic errors may be observed in cases of pulmonary NETs with nuclear inclusions. The mechanisms of nuclear inclusion differed, with one due to herniation of the cytoplasm into the nucleus (pseudoinclusion) and the other due to accumulation of biotin resulting from a CTNNB1 gene mutation. 23194516 Immunomodulatory effect of Ganoderma atrum polysaccharide on CT26 tumor-bearing mice. Ganoderma atrum has attracted great attention for its antitumor activity. However, the mechanism remains unclear. A G. atrum polysaccharide (PSG-1) showed pronounced antitumor activity in this study. PSG-1 did not kill CT26 cells directly, but inhibited the proliferation of CT26 cells via the activation of peritoneal macrophages (MΦ). In vivo, PSG-1 significantly suppressed the tumor growth in CT26 tumor-bearing mice. The treatment caused a significant increase in the immune organ index and the phagocytosis of macrophages. The production of TNF-α, IL-1β and nitric oxide also increased. Furthermore, we found that PSG-1 acted on Toll-like receptor (TLR) 4, signaled through p38 MAPK pathway, then activated NF-κB and stimulated TNF-α production. We further found that PSG-1 increased the expression of TLR4 and NF-κB, the degradation of IκBα and the phosphorylation of p38 MAPK. In summary, we have demonstrated that PSG-1 could activate macrophages via TLR4-dependent signaling pathways, improve immunity and inhibit tumor growth. 23876280 Precursors of cognitive impairments in psychotic disorders: A population-based study. Cognitive deficits have been found to be more prevalent in psychotic than in other disorders. Longitudinal research has shown that these deficits were generally already existent before onset of illness and are therefore not necessarily attributable to neurodegenerative processes. This study investigated whether both low IQ and markers of premorbid cognitive dysfunction independently contribute to an increased risk for psychoses. In a cross-sectional study about 50,000 young Swiss males completed a survey of intellectual problems in childhood/adolescence and other vulnerability factors during military call-up in 2005/2006. Subsequently, military IQ assessments were carried out on the entire sample. Diagnostic assessments were conducted according to International Classification of Diseases-10th edition (ICD-10). Low, especially performance, IQ was highly associated with an increased risk for psychotic disorders after adjusting for preexisting cognitive deficits and covariates, while in other disorders this association was less marked. Furthermore, preexisting intellectual problems emerged as important risk factors for psychoses. Our results confirm the importance of low IQ as characteristic of psychoses. Although premorbid intellectual deficits are common in people who go on to develop psychosis, neurodegenerative disease processes may also precipitate further declines in fluid cognitive functions. Assessment of cognitive functioning should be taken into account in early detection of psychoses. 23832389 Recreational Drugs of Abuse. The use of recreational drugs of abuse continues to expand without limitations to national boundaries, social status, race, or education. Beyond the prevalence of illicit drug use and dependence, their contribution to the global burden of disease and death are large and troubling. All medical providers should be aware of the evolving drugs of abuse and their medical and social consequences. In addition to heroin and stimulants such as cocaine and methamphetamine, new designer stimulants called "bath salts" and cannabinoids called "spice," along with the abuse of prescription drugs and volatile substances, are now widely recognized problems in many societies. The wide variety and continuingly expanding clinical manifestations of toxicity of recreational drugs of abuse is not widely appreciated by clinicians. This edition attempts to summarize six major classes of drugs of abuse and their clinical effects with special emphasis on their immunological and respiratory effects. 23876800 Virulent Shigella flexneri affects the secretion, expression, and glycosylation of gel-forming mucins in mucus-producing cells. Mucin glycoproteins are secreted in large amounts by the intestinal epithelium and constitute an efficient component of innate immune defenses to promote homeostasis and protect against enteric pathogens. In this study, our objective was to investigate how the bacterial enteropathogen Shigella flexneri that causes bacillary dysentery copes with the mucin defense barrier. We report that upon in vitro infection of mucin-producing polarized human intestinal epithelial cells, virulent S. flexneri manipulates the secretion of gel-forming mucins. This phenomenon that is only triggered by the virulent strain results in accumulation of mucins at the cell apical surface, leading to appearance of a gel-like structure that favors access of bacteria to the cell surface and the subsequent invasion process. We identify MUC5AC, a gel-forming mucin, as a component of this structure. Formation of this gel does not depend on modifications of electrolyte concentrations, induction of trefoil factor expression, endoplasmic reticulum stress, or response to unfolded proteins. In addition, transcriptional and biochemical analysis of infected cells reveal modulations of mucin gene expression and modifications of mucin glycosylation patterns, both induced by virulent bacteria in a type three secretion system-dependent manner. Thus, S. flexneri has developed a dedicated strategy to alter the mucus barrier by targeting key elements of the gel-forming capacity of mucins: gene transcription, protein glycosylation, and secretion. 23936223 Identification of a Novel Bacterial Outer Membrane Interleukin-1Β-Binding Protein from Aggregatibacter actinomycetemcomitans. Aggregatibacteractinomycetemcomitans is a gram-negative opportunistic oral pathogen. It is frequently associated with subgingival biofilms of both chronic and aggressive periodontitis, and the diseased sites of the periodontium exhibit increased levels of the proinflammatory mediator interleukin (IL)-1β. Some bacterial species can alter their physiological properties as a result of sensing IL-1β. We have recently shown that this cytokine localizes to the cytoplasm of A. actinomycetemcomitans in co-cultures with organotypic gingival mucosa. However, current knowledge about the mechanism underlying bacterial IL-1β sensing is still limited. In this study, we characterized the interaction of A. actinomycetemcomitans total membrane protein with IL-1β through electrophoretic mobility shift assays. The interacting protein, which we have designated bacterial interleukin receptor I (BilRI), was identified through mass spectrometry and was found to be Pasteurellaceae specific. Based on the results obtained using protein function prediction tools, this protein localizes to the outer membrane and contains a typical lipoprotein signal sequence. All six tested biofilm cultures of clinical A. actinomycetemcomitans strains expressed the protein according to phage display-derived antibody detection. Moreover, proteinase K treatment of whole A. actinomycetemcomitans cells eliminated BilRI forms that were outer membrane specific, as determined through immunoblotting. The protein was overexpressed in Escherichia coli in both the outer membrane-associated form and a soluble cytoplasmic form. When assessed using flow cytometry, the BilRI-overexpressing E. coli cells were observed to bind 2.5 times more biotinylated-IL-1β than the control cells, as detected with avidin-FITC. Overexpression of BilRI did not cause binding of a biotinylated negative control protein. In a microplate assay, soluble BilRI bound to IL-1β, but this binding was not specific, as a control protein for IL-1β also interacted with BilRI. Our findings suggest that A. actinomycetemcomitans expresses an IL-1β-binding surface-exposed lipoprotein that may be part of the bacterial IL-1β-sensing system. 23313557 FXR-dependent and -independent interaction of glucocorticoids with the regulatory pathways involved in the control of bile acid handling by the liver. Treatment with glucocorticoids (GCs) may cause adverse effects, including cholestasis. The ability of dexamethasone, prednisolone and budesonide to affect the liver handling of bile acids (BAs) has been investigated. In rats treated with GCs for 4 days, altered serum and bile BA levels, changed conjugation pattern, and delayed and decreased ability to conjugate/secrete exogenously administered deoxycholate, were found using HPLC-MS/MS. RT-QPCR analyses revealed that GC treatment also induced a down-regulation of liver nuclear receptors (Fxr, Gr and Shp), transporters (Ntcp, Mrp4 and Bcrp) and enzymes (Cyp7a1 and Baat), whereas Bsep, Mrp2 and Cyp27a1 were up-regulated. Human HepG2 and Alexander cell lines were used as in vitro models of liver cells with and without constitutive FXR expression, respectively. In HepG2 cells, GCs induced a decreased expression of FXR and SHP, and inhibited the regulatory effect of GW4064 on FXR-target genes. In Alexander cells, only when they were transfected with FXR+RXR, GW4064 caused up-regulation of SHP and OSTβ, and a down-regulation of CYP27A1. GCs had the opposite effect on these genes, both in the absence and in the presence of FXR expression. Co-transfection of Alexander cells with IR-1-Luc and FXR+RXR revealed that GCs did not inhibit but moderately enhanced FXR activity. Moreover, GCs have a synergistic effect on GW4064-induced FXR activation, whereas chenodeoxycholate and GW4064 have an additive effect. In conclusion, GCs are able to directly or indirectly activate FXR but they also antagonize, through FXR-independent mechanisms, the expression of FXR and FXR target genes involved in the hepatic handling of BAs. 23786407 Regular or covert sex defines two lineages and worldwide superclones within the leaf-curl plum aphid (Brachycaudus helichrysi, Kaltenbach). Asexual reproduction occurs widely in plants and animals, particularly in insects. Aphid species usually reproduce by cyclic parthenogenesis, but many species include obligate asexual lineages. We recently showed that the leaf-curl plum aphid, Brachycaudus helichrysi, actually encompasses two lineages, B. helichrysi H1 and H2. Ecological data suggest that these lineages have different life cycles. We conducted a large population genetics study, based on 14 microsatellite loci, to infer their respective life cycles and investigate their population structure and geographical distribution. Brachycaudus helichrysi H1 displayed the genetic signature of cyclical parthenogenesis, using plum trees as primary hosts for sexual reproduction, as classically described for B. helichrysi. This global survey showed that the Central Asian population of H1 was clearly differentiated from American-European populations. By contrast, B. helichrysi H2 displayed the typical signature of obligate asexual reproduction. H2 encompassed at least eight highly successful genotypes or superclones. This lack of ability to undergo sexual reproduction was confirmed for one of the superclones by sex induction experiments. We found only one B. helichrysi H2 population that underwent sexual reproduction, which was collected from peach trees, in Northern India. Our results confirm that H1 and H2 have different life cycles. Brachycaudus helichrysi H1 is clearly heteroecious using plum trees as primary hosts, while B. helichrysi H2 encompasses several anholocyclic lineages, and some heteroecious populations that until now have only been found associated with peach trees as primary hosts. We discuss implications of these findings for the pest status of B. helichrysi lineages. 23913819 Rhodium-Catalyzed Tandem Cyclopropanation/Cope Rearrangement of 4-Alkenyl-1-sulfonyl-1,2,3-triazoles with Dienes. Take your pick…︁ A practical method for the synthesis of structurally diverse rhodium vinylcarbenes from stable 1-sulfonyl-1,2,3-triazole precursors has been developed. The reaction is general for a broad range of 4-alkenyl triazoles and dienes, enabling the stereoselective synthesis of a variety of polycyclic imines, which are readily converted into amines or aldehydes in a one-pot process. 23842762 Size and structure of Chlorella zofingiensis/FeCl3 flocs in a shear flow. Flocculation is a promising method to overcome the economic hurdle to separation of algae from its growth medium in large scale operations. However, understanding of the floc structure and the effects of shear on the floc structure are crucial to the large scale implementation of this technique. The floc structure is important because it determines, in large part, the density and settling behavior of the algae. Freshwater algae floc size distributions and fractal dimensions are presented as a function of applied shear rate in a Couette cell using ferric chloride as a flocculant. Comparisons are made with measurements made for a polystyrene microparticle model system taken here as well as reported literature results. The algae floc size distributions are found to be self-preserving with respect to shear rate, consistent with literature data for polystyrene. Three fractal dimensions are calculated which quantitatively characterize the complexity of the floc structure. Low shear rates result in large, relatively dense packed flocs which elongate and fracture as the shear rate is increased. The results presented here provide crucial information for economically implementing flocculation as a large scale algae harvesting strategy. Biotechnol. Bioeng. 2013;xxx: xx-xx. © 2013 Wiley Periodicals, Inc. 23783485 Associations between UGT1A1*6/*28 polymorphisms and irinotecan-induced severe toxicity in Chinese gastric or esophageal cancer patients. The aim of this study was to investigate the associations between UDP-glucuronosyltransferase (UGT) 1A1 polymorphisms and irinotecan-induced toxicities in Chinese advanced gastric or esophageal cancer patients. The genotypes of UGT1A1*6 and UGT1A1*28 were analyzed by PCR amplification and Sanger sequencing in 42 gastric and 91 esophageal cancer patients receiving irinotecan-containing chemotherapy. The influences of UGT1A1*6/*28 polymorphisms on severe diarrhea and neutropenia were analyzed. The overall incidence of UGT1A1*6/*28 variants in gastric cancer and esophageal cancer was 38.1 % (GA: 31.0 %; AA: 6.9 %), 28.6 % (TA6/TA7: 26.2 %; TA7/TA7: 2.4 %) and 33.0 % (GA: 28.6 %; AA: 4.4 %), 25.3 % (TA6/TA7: 23.1 %; TA7/TA7: 2.2 %) in our cohort, respectively. A total of 10 patients (gastric cancer: 9.5 %, 4/42; esophageal cancer: 6.6 %, 6/91) had severe diarrhea and 35 patients (gastric cancer: 35.7 %, 15/42; esophageal cancer: 22.0 %, 20/91) had severe neutropenia. Statistic analysis between UGT1A1 genotyping and severe diarrhea was not conducted due to the limited number of patients. For gastric cancer, it seemed that only UGT1A1*6 variant was associated with severe neutropenia (P = 0.042), while among esophageal cancer patients, UGT1A1*6 (P = 0.011) or UGT1A1*28 (P = 0.026) variants were significantly associated with severe neutropenia. UGT1A1*6 variant was closely associated with severe neutropenia both in gastric cancer and in esophageal cancer, but the association between UGT1A1*28 variant and severe neutropenia in gastric and esophageal cancer was not consistent in this study, which would be validated in the future large samples. 23834331 Emerging pressure-release materials for drug delivery. Drug delivery systems for non-specialist uses and application under field conditions are required for medical action in disaster situations and in developing countries. A possible solution for drug delivery under those conditions might be provided by mechanical manipulation of host-guest interactions that could allow drug release control by simple human actions such as hand motion. This editorial article presents recent research developments on control of molecular recognition, capture and release involving macroscopic mechanical motions. In particular, pressure-induced drug release from a cyclodextrin-linked gel has been used to realize controlled release of entrapped drugs upon applying an easy-to-perform mechanical procedure. These easy-action-based drug delivery systems can be applied at will by unskilled staff or patients and are expected to be used to assist medically patients in less-favorable environments anywhere in the world. 23494081 Robot-assisted Posterior Retroperitoneoscopic Adrenalectomy Using Single-port Access: Technical Feasibility and Preliminary Results. Posterior retroperitoneoscopic adrenalectomy (PRA) has several benefits compared with transperitoneal adrenalectomy in that it is safe and has a short learning curve. In addition, it provides direct short access to the target organ, prevents irritation to the intraperitoneal space, and does not require retraction of adjacent organs.1 (-) 3 We have performed several cases of robot-assisted PRA using single-port access for small adrenal tumors. This multimedia article introduces the detailed methods and preliminary results of this procedure. Five patients underwent single-port robot-assisted PRA between March 2010 and June 2011 at our institution. During the procedure, patients were placed in a prone jackknife position with their hip joints bent at a right angle (Fig. 1). A 3 cm transverse skin incision was made just below the lowest tip of the 12th rib (Fig. 2), and the Glove port (Nelis, Kyung-gi, Korea) was placed through the skin incision while maintaining pneumoretroperitoneum (Fig. 3). CO2 was then insufflated to a pressure of 18 mm Hg to create an adequate working space. A 10 mm robotic camera with a 30-degree up view was placed at the center of the incision through the most cephalic portion of the Glove port. A Maryland dissector or Prograsp forceps (Intuitive Surgical, Inc., Sunnyvale, CA) was placed on the medial side of the incision, and Harmonic curved shears (Intuitive Surgical) were placed on the lateral side of the incision (Fig. 4). Using the Maryland dissector and the harmonic curved shears, the Gerota fascia is opened, perinephric fat is dissected, and the kidney upper pole is mobilized to expose the adrenal gland (Fig. 5). Gland dissection starts with lower margin detachment from the upper kidney pole in a lateral to medial direction (Fig. 6). After dissecting the adrenal gland from surrounding adipose tissue and medial isolation of the adrenal central vein, the vessel is ligated with a 5 mm hemolock clip (Fig. 7). Patient clinicopathologic data were analyzed retrospectively. The mean patient age was 56.6 ± 8.7 (range, 47-69) years. Right and left side approaches were used in two and three patients, respectively. All cases were adrenal cortical adenoma. The mean tumor size was 1.48 ± 0.28 (range, 1.0-1.7) cm. The mean surgery duration (skin to skin) was 159.4 ± 57.6 (range, 103-245) minutes, and the mean estimated blood loss was 46.0 ± 56.8 (range, 5-120) ml. The average time to oral intake and postoperative hospital stay were 0.65 ± 0.11 (range, 0.54-0.79) days and 4.0 ± 2.23 (range, 3-8) days, respectively. There were no conversions to open surgery or postoperative compli- cations. Some trials of minimally invasive single-access surgery of the adrenal gland have recently been performed.4 (,) 5 However, these new techniques have several limitations as a result of restrictions on instrumentation movement because of the small access ports used and relatively low-quality images produced. The recent introduction of the da Vinci S surgical robot system (Intuitive Surgical) to endoscopic surgery has improved instrumental dexterity and provided the surgeon with an ergonomically designed operating system. This system is also potentially safer and more meticulous in performing operations than endoscopic procedures as a result of a 3-D, magnified, stable operative view.6 (,) 7 The advantages of the da Vinci S surgical robot system and the numerous benefits of the posterior retroperitoneal approach motivated us to utilize single-port robot-assisted PRA. The primary selection criteria were small tumor size and a minimal amount of periadrenal fatty tissue because robot-assisted PRA using single-port access provides a small operative space, which causes manipulation problems when tumors are large. To ensure the safe application of these new techniques, we recommend that novice surgeons begin using single-port robot-assisted PRA for smaller tumors < 2 cm in patients with a body mass index of < 30 kg/m(2), gradually extending the size and body mass index as they accumulate experience. Although robot-assisted PRA using single-port access could not be compared with the other robotic adrenalectomy techniques in this study, the potential advantages of this approach compared to conventional robot-assisted transperitoneal adrenalectomy include a reduction in postoperative ileus, bacterial contamination, and intestinal complications because the peritoneal cavity is not opened, in addition to a reduction in postoperative pain because of its minimally invasive nature. Our initial experiences with robot-assisted PRA using single-port access assured us of its safety and feasibility for the resection of small adrenal tumors. Although single-port robot-assisted PRA appears to be safe and feasible, further experience and research is required to optimize patient selection criteria and verify its advantages over the traditional three-incision PRA technique. 23893978 Dietary lipid sources and levels for weanling pigs. Collaborative studies comprising growth performance and metabolism experiments were conducted to reevaluate growth performance and nutrient and energy utilization responses of nursery pigs to dietary lipid sources and levels. Two lipid sources (soybean oil or tallow) were included at the rate of 1%, 3%, or 5% at the expense of cornstarch in a 2 × 3 factorial arrangement for 6 diets, and Lys was added to maintain a constant calorie:Lys ratio. A growth performance experiment (d 0 to 7, d 7 to 21, and d 21 to 35 postweaning) involving a total of 822 crossbred pigs was conducted at 9 research stations. Each station contributed 2 to 7 replicate pens with 4 to 6 pigs per pen, resulting in a total of 28 replicate pens per diet. The initial BW ranged from 5.9 to 7.3 kg, and the final BW ranged from 20.9 to 28.9 kg. Diets fed during d 7 to 21 and d 21 to 35 were evaluated with 120 barrows in 2 metabolism experiments with 10 individually fed barrows per diet to determine digestibility and retention of nutrients and energy. Lipid source and the interaction between lipid level and source did not affect growth performance. Lipid did not affect growth performance from d 0 to 7. There was a quadratic decrease (P < 0.05) in ADG with increasing level of added lipid only during d 7 to 21 postweaning. The ADFI was decreased (P < 0.01) both during d 7 to 21 and d 21 to 35 postweaning with increasing level of lipid supplementation. A linear improvement (P < 0.001) in G:F with increasing level of lipid supplementation occurred during both d 21 to 35 and d 0 to 35 postweaning. There was a linear increase in DE, ME, and nitrogen-corrected ME (MEn) of diets fed during d 7 to 21 postweaning with increasing lipid level regardless of lipid source. For diets fed during d 21 to 35 postweaning, there were interactions (P < 0.05) between lipid source and level for digestibility of DM, N, lipid, and energy and for DE, ME, and MEn of diets. The improved feed efficiency was, perhaps, partly attributable to the increase in ME content of the diets with added lipids. There were interactions (P < 0.05) between lipid source and level for efficiency of energy use for BW gain for diets fed during d 21 to 35. The efficiencies of use of DE, ME, and NE for BW gain were not affected in pigs fed diets containing increasing levels of soybean oil; however, there were linear increases in these response criteria for pigs fed diets containing increasing levels of tallow. These results indicate that the energy values of soybean oil from the 2012 NRC study used in formulating these diets were fairly accurate. 23596326 Identification of candidate genes encoding an LDL-C QTL in baboons. Cardiovascular disease (CVD), the leading cause of death in developed countries and dyslipidemia, is a major risk factor for CVD. We previously identified a cluster of quantitative trait loci (QTL) on baboon chromosome 11 for multiple related quantitative traits for serum low-density lipoprotein cholesterol (LDL-C). Here we report differentially regulated hepatic genes that appear to encode an LDL-C QTL that influences LDL-C levels in baboons. We performed hepatic whole genome expression profiling for LDL-C discordant baboons fed a high-cholesterol, high-fat (HCHF) diet for 7 weeks. We detected expression of 117 genes within the QTL 2-LOD-support interval. Three genes were differentially expressed in low LDL-C responders and 8 in high LDL-C responders in response to a HCHF diet. Seven genes (ACVR1B, CALCOCO1, DGKA, ERBB3, KRT73, MYL6B, TENC1) showed discordant expression between low and high LDL-C responders. To prioritize candidate genes, we integrated miRNA and mRNA expression profiles using network tools and found that four candidates (ACVR1B, DGKA, ERBB3, TENC1) were miRNA targets and the miRNAs were inversely expressed to the target genes. Candidate gene expression was validated using QRT-PCR and Westerns. This study reveals candidate genes that influence variation in LDL-C in baboons and potential genetic mechanisms for further investigation. 23475060 Corrosion protection performance of porous strontium hydroxyapatite coating on polypyrrole coated 316L stainless steel. Polypyrrole/strontium hydroxyapatite bilayer coatings were achieved on 316L stainless steel (316L SS) by the electropolymerisation of pyrrole from sodium salicylate solution followed by the electrodeposition of porous strontium hydroxyapatite. The formation and the morphology of the bilayer coatings were characterised by Fourier transform infrared spectroscopy (FT-IR) and high resolution scanning electron microscopy (HRSEM), respectively. The corrosion resistance of the coated 316L SS specimens was investigated in Ringer's solution by electrochemical techniques and the results were substantiated with inductively coupled plasma atomic emission spectrometry (ICP-AES). The passive film underneath the polypyrrole layer is effective in protecting 316L SS against corrosion in Ringer's solution. Moreover, we believe that the top porous strontium hydroxyapatite layer can provide potential bioactivity to the 316L SS. 23664129 Central nervous system vasculitis secondary to systemic sclerosis. Systemic sclerosis (SSc) or scleroderma is a connective tissue disease with a diverse array of clinical manifestations secondary to underlying fibrosis and autoimmunity. Central nervous system (CNS) impairment is uncommon in SSc. Here we report the fourth known patient with CNS vasculitis caused by SSc. In each previous report, the patient was a middle-aged to elderly female. Our patient was 24years old at the time of presentation, significantly younger than the other reported patients. Importantly, our patient's rapidly progressive clinical course and poor response to immunosuppression have not been reported in patients with CNS vasculitis secondary to scleroderma. Although CNS vasculitis is extremely rare in SSc, our report suggests that clinicians should consider this diagnosis in the differential of SSc patients with neurologic impairment. 23843113 Combined solid-phase microextraction and high-performance liquid chromatography with ultroviolet detection for simultaneous analysis of clenbuterol, salbutamol and ractopamine in pig samples. A simple and sensitive method based on the combination of solid-phase microextraction (SPME) and high-performance liquid chromatography with ultroviolet detection was developed for the simultaneous determination of clenbuterol, salbutamol and ractopamine in pig samples. Parameters of the SPME procedure affecting extraction efficiency, such as the type of fiber, extraction time, extraction temperature, ion strength, pH of sample and stirring rate, were optimized. The developed method was validated according to the International Conference on Harmonization guidelines. The calibration curves were linear over a range of 0.5-50 µg/L for clenbuterol and ractopamine, and 0.2-20 µg/L for salbutamol. The limits of detection were 0.1 µg/L for clenbuterol, 0.05 µg/L for salbutamol and 0.1μg/L for ractopamine, respectively. The averages of intra- and inter-day accuracy ranged from 79.8 to 92.4%. The intra-day and inter-day precision were below 9.6% for the three analytes. This method exhibited the advantages of simplicity, rapidity and low solvent consumption, and was suitable for the monitoring of β2 -agonists residue in pig samples. Copyright © 2013 John Wiley & Sons, Ltd. 23958439 From fatty-acid sensing to chylomicron synthesis: Role of intestinal lipid-binding proteins. Today, it is well established that the development of obesity and associated diseases results, in part, from excessive lipid intake associated with a qualitative imbalance. Among the organs involved in lipid homeostasis, the small intestine is the least studied even though it determines lipid bioavailability and largely contributes to the regulation of postprandial hyperlipemia (triacylglycerols (TG) and free fatty acids (FFA)). Several Lipid-Binding Proteins (LBP) are expressed in the small intestine. Their supposed intestinal functions were initially based on what was reported in other tissues, and took no account of the physiological specificity of the small intestine. Progressively, the identification of regulating factors of intestinal LBP and the description of the phenotype of their deletion have provided new insights into cellular and molecular mechanisms involved in fat absorption. This review will discuss the physiological contribution of each LBP in the main steps of intestinal absorption of long-chain fatty acids (LCFA): uptake, trafficking and reassembly into chylomicrons (CM). Moreover, current data indicate that the small intestine is able to adapt its lipid absorption capacity to the fat content of the diet, especially through the coordinated induction of LBP. This adaptation requires the existence of a mechanism of intestinal lipid sensing. Emerging data suggest that the membrane LBP CD36 may operate as a lipid receptor that triggers an intracellular signal leading to the modulation of the expression of LBP involved in CM formation. This event could be the starting point for the optimized synthesis of large CM, which are efficiently degraded in blood. Better understanding of this intestinal lipid sensing might provide new approaches to decrease the prevalence of postprandial hypertriglyceridemia, which is associated with cardiovascular diseases, insulin resistance and obesity. 23874526 Evidence of Multiple Disease Resistance (MDR) and Implication of Meta-Analysis in Marker Assisted Selection. Meta-analysis was performed for three major foliar diseases with the aim to find out the total number of QTL responsible for these diseases and depict some real QTL for molecular breeding and marker assisted selection (MAS) in maize. Furthermore, we confirmed our results with some major known disease resistance genes and most well-known gene family of nucleotide binding site (NBS) encoding genes. Our analysis revealed that disease resistance QTL were randomly distributed in maize genome, but were clustered at different regions of the chromosomes. Totally 389 QTL were observed for these three major diseases in diverse maize germplasm, out of which 63 QTL were controlling more than one disease revealing the presence of multiple disease resistance (MDR). 44 real-QTLs were observed based on 4 QTL as standard in a specific region of genome. We also confirmed the Ht1 and Ht2 genes within the region of real QTL and 14 NBS-encoding genes. On chromosome 8 two NBS genes in one QTL were observed and on chromosome 3, several cluster and maximum MDR QTL were observed indicating that the apparent clustering could be due to genes exhibiting pleiotropic effect. Significant relationship was observed between the number of disease QTL and total genes per chromosome based on the reference genome B73. Therefore, we concluded that disease resistance genes are abundant in maize genome and these results can unleash the phenomenon of MDR. Furthermore, these results could be very handy to focus on hot spot on different chromosome for fine mapping of disease resistance genes and MAS. 23708436 A novel methodology for analysis of enantiomers through determination of their critical micelle concentrations using spectrophotometric method. A novel methodology for analysis of enantiomer composition of chiral compounds based on measuring of their critical micelle concentration by using spectrophotometric technique is introduced. The proposed method does not require any chiral selector and the corresponding process is simple, fast, reproducible, and inexpensive. The procedure was successfully applied for analysis of naproxen. The critical micelle concentration data showed that (R)-naproxen could be determined with an RSD of 1.1% and a relative error of -5.6% when a real sample containing the racemic mixture of naproxen with a total concentration of 0.04 mM was tested. 23933054 Changes in plasma BDNF levels induced by methylphenidate in children with ADHD. It has been suggested that BDNF may play a role in the pathogenesis of ADHD. Our aim is to determine whether methylphenidate can induce changes in plasma BDNF levels of children with ADHD. We assessed levels of plasma BDNF in 28 ADHD patients (age range=3.5-10years) before and after 6weeks treatment with effective dosages of methylphenidate. Then we evaluated the correlation of levels of plasma BDNF with clinical variables, especially ADHD Conner's parents rating scale. According to the paired sample T-test, the mean plasma BDNF level in the baseline was 193.06pg/ml, whereas 271.06pg/ml in the end point, thus showing significantly higher mean plasma BDNF levels in the post-treatment situation than in the pretreatment (t=-3.393, df=27, p=0.002). Pearson's correlation test revealed that there was also significant negative correlation between levels of BDNF in the plasma of ADHD patients before treatment and improvement in hyperactivity symptoms with treatment (Pearson's correlation=-0.395, p=0.037). The mean plasma BDNF levels increased after 6weeks of treatment with methylphenidate. Also, we found an improvement in hyperactivity symptoms with decreasing baseline plasma BDNF levels. We recommend that more studies should be conducted in order to assess the possible roles of plasma BDNF levels in treatment response prediction and prognosis. 23090686 Weismann versus morgan revisited: clashing interpretations on animal regeneration. This paper has three principal aims: first, through a detailed analysis of the hypotheses and assumptions underlying Weismann's and Morgan's disagreement on the nature of animal regeneration, it seeks to readdress the imbalance in coverage of their discussion, providing, at the same time, a fascinating case-study for those interested in general issues related to controversies in science. Second, contrary to Morgan's beliefs according to which Weismann employed a speculative and unempirical method of scientific investigation, the article shows that Weismann performed experiments, made observations and proposed 'undogmatic' theories open to refutation. Third, through the reconstruction of Weismann's and Morgan's disagreement, this study illustrates how biology, during the very late nineteenth and early twentieth centuries, was undergoing important changes. I argue that this controversy clearly and convincingly demonstrates how some important epistemic assumptions became increasingly problematic for some members of the younger generations of biologists. At the end of my discussion I will also argue that Weismann and Morgan both had strong well-grounded arguments supporting their conclusions; for this reason I suggest a few factors ("taken-for-granted" beliefs or assumptions) that could explain why their disagreement was doomed to remain unresolved. In particular, I will analyze their diverse explicative interests, their different theoretical concerns and their distinct use of the available evidence. 23895551 Beneath it all: bedrock geology of the Catskill Mountains and implications of its weathering. The Devonian-age bedrock of the Catskill Mountains has been the focus of many studies. This paper reviews the character and composition of the rocks of the Catskills, and examines weathering (rock decay) processes and their implications in the Catskills. Rocks of the Catskills and closest foothills consist of siliciclastic rocks (sandstones, mudrocks, conglomerates) with minimal, locally dispersed carbonate rocks. The former are dominated by quartz, metamorphic and sedimentary rock fragments, and clay minerals. Other minor sediment components include cements, authigenic and heavy minerals, and fossil organic matter. Physical, chemical, and biological weathering of the Catskill bedrock since uplift of the Appalachian region, combined with glaciation, have dissected a plateau of nearly horizontally layered rocks into a series of ridges, valleys, and peaks. The varied weathering processes, in conjunction with many factors (natural and anthropogenic), fragment the rocks, forming sediment and releasing various elements and compounds. These may have positive, neutral, or negative implications for the region's soils, waters, ecology, and human usage. A new generation of studies and analyses of the Catskill bedrock is needed to help answer a broad set of questions and problems across various fields of interest. 23899480 A phenomenological investigation into the opposing effects of fluid flow on sonochemical activity at different frequency and power settings. 1. Overhead stirring. The effect of flow in an ultrasonic reactor is an important consideration for practical applications and for the scale-up of ultrasonic processing. Previous literature on the influence of flow on sonochemical activity has reported conflicting results. Therefore, this work examined the effect of overhead stirring at four different frequencies, 40, 376, 995 and 1179kHz, in two different reactor configurations. Comparable power settings were utilised to elucidate the underlying mechanisms of interactions between the flow and sonochemical activity. The sonochemical activity was determined by the yield of hydrogen peroxide, measured by iodide dosimetry, and the active region was visualised with sonochemiluminescence imaging. The overhead stirring in the low frequency reactor altered the yield of hydrogen peroxide so it produced the maximum yield out of the four frequencies. The increase in hydrogen peroxide yield was attributed to a reduction in coalescence at 40kHz. However at the higher frequencies, coalescence was not found to be the main reason behind the observed reductions in sonochemical yield. Rather the prevention of wave propagation and the reduction of the standing wave portion of the field were considered. 23915213 Q fever in pregnant goats: humoral and cellular immune responses. Q fever is a zoonosis caused by the intracellular bacterium Coxiella burnetii. Both humoral and cellular immunity are important in the host defence against intracellular bacteria. Little is known about the immune response to C. burnetii infections in domestic ruminants even though these species are the major source of Q fever in humans. To investigate the goat's immune response we inoculated groups of pregnant goats via inhalation with a Dutch outbreak isolate of C. burnetii. All animals were successfully infected. Phase 1 and Phase 2 IgM- and IgG-specific antibodies were measured. Cellular immune responses were investigated by interferon-gamma, enzyme-linked immunosorbent spot test (IFN-γ Elispot), lymphocyte proliferation test (LPT) and systemic cytokines. After two weeks post inoculation (wpi), a strong anti-C. burnetii Phase 2 IgM and IgG antibody response was observed while the increase in IgM anti-Phase 1 antibodies was less pronounced. IgG anti-Phase 1 antibodies started to rise at 6 wpi. Cellular immune responses were observed after parturition. Our results demonstrated humoral and cellular immune responses to C. burnetii infection in pregnant goats. Cell-mediated immune responses did not differ enough to distinguish between Coxiella-infected and non-infected pregnant animals, whereas a strong-phase specific antibody response is detected after 2 wpi. This humoral immune response may be useful in the early detection of C. burnetii-infected pregnant goats. 23909867 Stereodynamic chemosensor with selective circular dichroism and fluorescence readout for in situ determination of absolute configuration, enantiomeric excess, and concentration of chiral compounds. A stereodynamic chemosensor having a parallel arrangement of a substrate-binding salicylaldehyde unit and an adjacent pyridyl N-oxide fluorophore undergoes rapid condensation with chiral amino alcohols and subsequent asymmetric transformation of the first kind toward a single rotamer. Crystallographic analysis shows that the concomitant central-to-axial chirality imprinting is controlled by minimization of steric repulsion and by intramolecular hydrogen bonding between the bound amino alcohol and the proximate N-oxide group. The substrate binding event results in strong CD effects and characteristic fluorescence changes which can be used for instantaneous in situ determination of the absolute configuration, enantiomeric composition and total concentration of a variety of chiral amino alcohols. This chemosensing approach avoids time-consuming workup and purification steps, and it is applicable to minute sample amounts which reduces the use of solvents and limits waste production. 23701845 Stabilities of hemoglobins A and S in dried blood spots stored under controlled conditions. We aimed to measure separately the contributions of heat and humidity to changes in levels of hemoglobins A and S in dried-blood-spot (DBS) samples. We stored paired sets of DBSs at 37°C for predetermined intervals in low-humidity and high-humidity environments. Hemoglobin A and S levels of all samples in each complete set were measured in a single high performance liquid chromatography run. During the one-month storage intervals, both hemoglobin species lost about 35% of initial levels in low-humidity storage and almost all of initial levels in high-humidity storage. Minimizing both humidity and temperature in the transportation and storage environments of DBS samples is essential to maintaining the integrity of the hemoglobin tetramer molecules. 23871783 Interactions between dietary flavonoids apigenin or luteolin and chemotherapeutic drugs to potentiate anti-proliferative effect on human pancreatic cancer cells, in vitro. The objectives were to assess the potential of dietary flavonoids apigenin (Api) and luteolin (Lut) to enhance the anti-proliferative effects of chemotherapeutic drugs on BxPC-3 human pancreatic cancer cells and to investigate the potential molecular mechanism of action. Simultaneous treatment or pretreatment (0, 6, 24 and 42h) of flavonoids and chemotherapeutic drugs at various concentrations (0-50μM) were assessed using the MTS cell proliferation assay. Simultaneous treatment with either flavonoid (13, 25 or 50μM) and chemotherapeutic drugs 5-fluorouracil (5-FU, 50μM) or gemcitabine (Gem, 10μM) for 60h resulted in mostly less-than-additive effects (p<0.05). Pretreatment for 24h with 13μM of either Api or Lut, followed by Gem for 36h was optimal to inhibit cell proliferation. Pretreatment of cells with 11-19μM of either flavonoid for 24h resulted in 59-73% growth inhibition when followed by Gem (10μM, 36h). Lut (15μM, 24h) pretreatment followed by Gem (10μM, 36h), significantly decreased protein expression of nuclear GSK-3β and NF-κB p65 and increased pro-apoptotic cytosolic cytochrome c. Pretreatment of BxPC-3 human pancreatic cancer cells with low concentrations of Api or Lut effectively aid in the anti-proliferative activity of chemotherapeutic drugs. 23886475 How integrins control breast biology. This article explores new ideas about how the ECM-integrin axis controls normal and malignant breast biology. We discuss the role of integrins in mammary stem cells, and how cell-matrix interactions regulate ductal and alveolar development and function. We also examine the contribution of integrins to tissue disorganisation and metastasis, and how an altered stromal and ECM tumour microenvironment affects the cancer cell niche both within primary tumours and at distant sites. Finally, we mention novel strategies for integrin-directed breast cancer treatment. 23877983 Corneal Nerve Loss Detected With Corneal Confocal Microscopy Is Symmetrical and Related to the Severity of Diabetic Polyneuropathy. OBJECTIVETo establish if corneal nerve loss, detected using in vivo corneal confocal microscopy (IVCCM), is symmetrical between right and left eyes and relates to the severity of diabetic neuropathy.RESEARCH DESIGN AND METHODSPatients (n = 111) with type 1 and type 2 diabetes and 47 age-matched healthy control subjects underwent detailed assessment and stratification into no (n = 50), mild (n = 26), moderate (n = 17), and severe (n = 18) neuropathy. IVCCM was performed in both eyes and corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) and the tortuosity coefficient were quantified.RESULTSAll corneal nerve parameters differed significantly between diabetic patients and control subjects and progressively worsened with increasing severity of neuropathy. The reduction in CNFD, CNBD, and CNFL was symmetrical in all groups except in patients with severe neuropathy.CONCLUSIONSIVCCM noninvasively detects corneal nerve loss, which relates to the severity of neuropathy, and is symmetrical, except in those with severe diabetic neuropathy. 23768576 Antitumor activity of Portulaca oleracea L. polysaccharides against cervical carcinoma in vitro and in vivo. Portulaca oleracea L. has been used as folk medicine in different countries to treat different ailments in humans. P. oleracea L. polysaccharide (POL-P), extracted from P. oleracea L., is found to have bioactivities such as hypoglycemic and hypolipidemic activities, antioxidant and antitumor activities. In our study, a water-soluble polysaccharide (POL-P3b) was successfully purified from Galium verum L. by DEAE cellulose and Sephadex G-200 column chromatography. To evaluate the anticancer efficacy and associated mechanisms of POL-P3b on cervical cancer in vitro and in vivo, we showed that treatment of HeLa cell with POL-P3b inhibited cell proliferation. In addition, POL-P3b significantly inhibited tumor growth in U14-bearing mice. Further analysis indicated that POL-P3b possesses the activity of inhibiting cervical cancer cell growth in vitro and in vivo at a concentration- and time-dependent manner, and the mechanisms were associated with Sub-G1 phase cell cycle arrest, triggering DNA damage and inducing apoptosis. 23885788 Tolterodine for the treatment of urge urinary incontinence. Introduction: Overactive bladder (OAB) and its resultant urge urinary incontinence (UUI) are significant problems that medically, psychologically and financially affect people. The constellation of symptoms comprising OAB affects ∼ 16% of the adult population and its prevalence increases with aging. The typical class of medications used to treat OAB is antimuscarinics. Areas covered: OAB medications, with a focus on tolterodine for the treatment of UUI are reviewed. A thorough review of English language literature using EMBASE/Medline and PubMed has been performed. Expert opinion: Tolterodine provides a reasonable starting point when treating patients with OAB and UUI. Efficacy and tolerability are generally comparable between tolterodine and other newer antimuscarinics. Tolterodine is a good option as part of the algorithm in the treatment of OAB and UUI. 23933414 MTHFR C677T and A1298C gene polymorphisms and their relation to homocysteine level in Egyptian children with congenital heart diseases. To investigate the association of combined MTHFR C677T and A1298C gene polymorphisms with congenital heart diseases (CHD) in Egyptian children and their mothers and to determine their effect on homocysteine level in these children. MTHFR C677T and A1298C polymorphisms were genotyped in 160 Egyptian children (80 patients with CHD and 80 healthy controls) and their mothers using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), while, homocysteine (Hcy) level was measured optically by enzymatic method. We found that MTHFR 677TT genotype, T allele, 1298CC genotype, and C allele were associated with 2.61, 2.0, 2.91 and 1.99 fold increased risk of CHD in Egyptian children respectively. Furthermore, the frequencies of MTHFR 1298AC and CC genotypes and C allele significantly increased in mothers with CHD affected children. The homocysteine levels were significantly increased in MTHFR 677TT and 1298CC genotypes in children with CHD. Our study demonstrated an association of MTHFR A1298C polymorphisms with CHD in Egyptian children and their mothers, while, MTHFR C677T polymorphisms were significantly associated with the risk of CHD in the children only. An association between combined MTHFR A1298C and C677T polymorphisms and CHD was recorded in the children and their mothers. Also, homocysteine levels were significantly increased with both MTHFR 677TT and 1298CC genotypes in Egyptian children with CHD. 23910811 Co-existence of renovascular hypertension, polyarteritis nodosa, antiphospholipid syndrome and methylenetetrahydrofolate reductase mutation. We present a hypertensive child with a co-existence of polyarteritis nodosa, anti-phospholipid antibodies (aPL), methylenetetrahydrofolate reductase (MTHFR) mutation and increased lipoprotein a level. Elevated renin, aldosterone and aPL levels, micro-aneurysms, occlusion and thrombosis at left and right renal artery were found. Anti-hypertensive agents, prednisolone and pulse cyclophosphamide therapy were started and a stent was inserted in the left renal artery. Two months later, brain magnetic resonance imaging/magnetic resonance imaging angiography showed acute infarct area of the left parietofrontal lobe and middle cerebral artery stenosis. We found bilateral peripheral neuropathy, persistent aPL and elevated Lp(a) level and heterozygous A1298C/MTHFR mutation. Intravenous immunoglobulin and low-molecular-weight heparin treatment was added. In conclusion, our observation suggests that in patients with systemic vasculitis, such as polyarteritis nodosa, aPL are probably associated with greater thrombotic risks. The investigation of the LP(a) levels and MTHFR mutations as a synergic pro-coagulant effect might also be considered for determining patients with vasculitis at risk for severe thrombotic events. 23921929 Cochlear implant electrode failure secondary to silicone touch-up during device manufacturing. Retrospective case report. Tertiary referral cochlear implant center. A 21-year-old woman was implanted with Advanced Bionics HiFocus Clarion device without complication. Five years later, the patient presented with dizziness, fluctuating implant performance, and facial pain. Surgical exploration revealed a torn electrode silicon casing in conjunction with scar contraction bending the electrode against bony facial nerve canal at the facial recess. Suspension of the electrode such that the damaged portion was not in contact with mastoid cavity led to temporary resolution of symptoms. Explantation and reimplantation procedures were carried out 2 months later. Postexplantation device analysis by the manufacturer demonstrated silicone touch-up at the site of failure. Six years since reimplantation, the patient has remained symptom-free. It is very likely that the touch-up silicon weakened the electrode and, in conjunction with chronic scar contraction, led to the tear on the silicon casing. Isolated cochlear implant electrode failure is a rare but possible long-term complication in older generation devices. The author reports 1 case of implant device failure partly because of silicon touch-up that was applied at the location of electrode failure during its manufacturing process. 23458270 Cortical ependymoma with unusual histologic features. Cortical ependymomas are rare gliomas with classic ependymal features but are unusual in primarily involving the cerebral cortex. Here, we present a 19-year old woman with new-onset seizures who was found to have a large, cortically based non-enhancing lesion with scalloping of the overlying calvarium. Abundant ependymal features were present including classic ependymal cytology, diffuse GFAP and dot-like EMA positivity, and well developed cilia, microvilli, and intercellular junctions on ultrastructural analysis. Additionally, the tumor showed areas of infiltrative growth similar to angiocentric glioma as well as striking mucin-filled microcystic spaces somewhat reminiscent of myxopapillary ependymoma. Thus far, the patient shows no evidence of recurrence following gross total resection. This case demonstrates detailed morphologic, immunohistochemical, and ultrastructural evidence supporting a relationship between cortical ependymoma and angiocentric glioma and suggesting that cortical ependymomas can have myxopapillary as well as classic features. 23911808 Treatment of central type lung cancer by combined cryotherapy: Experiences of 47 patients. Most patients with central type lung cancer (CTLC) are not candidates for surgery; systemic chemotherapy and external beam radiotherapy are the main treatments but have not greatly affected patient outcome. Combined percutaneous and endobronchial cryotherapy has been used successfully to treat CTLC; this study aimed to determine its feasibility and safety. Forty-seven patients with unresectable CTLC (22 endotracheal, 26 tracheal wall and 21 extratracheal tumors) underwent 69 sessions of combined percutaneous cryosurgery, endobronchial cryosurgery and airway stenting. The long diameter of all tumors was <5cm. Biopsy showed non-small cell lung cancer (NSCLC) in 40 patients (medium or well differentiated in 20 cases, poorly differentiated in 20) and small cell lung cancer (SCLC) in seven. Within 3days after treatment, ventilatory capacity and performance status had obviously increased and cough, signs of dyspnea, hemoptysis and atelectasis improved significantly, but symptoms of pneumothorax and pleural effusion emerged. After 2weeks, all complications had disappeared completely, as had cough. Progression-free survival (PFS) for endotracheal tumors (8±4months) was shorter than that for tracheal wall (13±6months, P<0.05) and extratracheal (14±8months, P<0.01) tumors. The PFS of NSCLC (11±5months) was significantly longer than that of SCLC (4±2months, P<0.0001). The PFS of medium or well differentiated CTLC (15±8months) was significantly longer than that of poorly differentiated CTLC (7±3months, P<0.0001). In conclusion, combined cryotherapy is a safe and effective treatment for CTLC, with PFS largely influenced by tumor location and pathologic type. 23842781 Missing Consent Forms in the Preoperative Area: A Single-Center Assessment of the Scope of the Problem and Its Downstream Effects. Missing consent forms at surgery can lead to delays in patient care, provider frustration, and patient anxiety. We sought to assess the scope and magnitude of this problem at our institution. We surveyed key informants to determine the frequency and effect of missing consent forms. We found that 66% of patients were missing signed consent forms at surgery and that this caused a delay for 14% of operative cases. In many instances, the missing consent forms interfered with team rounds and resident educational activities. In addition, residents spent less time obtaining consent and were often uncomfortable obtaining consent for major procedures. Finally, 40% of faculty felt dissatisfied with resident consent forms, and more than two-thirds felt patients were uncomfortable with being asked for consent by residents. At our center, missing consent forms led to delayed cases, burdensome and inadequate consent by residents, and extra work for nursing staff. 23542331 Efficacy and safety of oral chelators in treatment of patients with Wilson disease. Wilson disease is a genetic copper storage disorder that causes hepatic and neurologic symptoms. Chelating agents (D-penicillamine, trientine) are used as first-line therapies for symptomatic patients, but there are few data from large cohorts. We assessed the safety of D-penicillamine and trientine therapy and outcomes of patients with Wilson disease. We performed a retrospective analysis of data on 380 patients with Wilson disease from tertiary care centers in Germany and Austria, and 25 additional patients from the EUROWILSON registry. Chelator-based treatment regimens were analyzed for their effect on neurologic and hepatic symptoms and for adverse events that led to discontinuation of therapy (Kaplan-Meier estimation; data were collected for a mean of 13.3 y after therapy began). Changes in medication were common, resulting in analysis of 471 chelator monotherapies (326 patients receiving D-penicillamine and 141 receiving trientine). Nine of 326 patients treated with D-penicillamine and 3 of 141 patients given trientine underwent liver transplantation. Adverse events leading to discontinuation of treatment were more frequent among those receiving D-penicillamine than trientine (P = .039). Forty-eight months after therapy, hepatic deterioration was reported in only 4 of 333 patients treated initially with a chelating agent. Hepatic improvements were observed in more than 90%, and neurologic improvements were observed in more than 55%, of therapy-naive patients, and values did not differ significantly between treatments. However, neurologic deterioration was observed less frequently in patients given D-penicillamine first (6 of 295) than those given trientine first (4 of 38; P = .018). Chelating agents are effective therapies for most patients with Wilson disease; D-penicillamine and trientine produce comparable outcomes, although D-penicillamine had a higher rate of adverse events. Few patients receiving chelation therapy had neurologic deterioration, which occurred more frequently in patients who received trientine. 23861016 Matching tumor risk with aggressiveness of treatment in men with multiple comorbidities and early-stage prostate cancer. Men with multiple comorbidities are often overtreated for low-risk prostate cancer, but it is unclear whether they are undertreated for high-risk cancer, which has appreciable short-term prostate cancer-specific mortality. This study characterized the impact of comorbidity on treatment and survival in men with differing tumor risks. The researchers sampled 1482 men with nonmetastatic prostate cancer at 2 Veterans Affairs hospitals between 1998 and 2004, using multivariate probit regression to determine probabilities of aggressive treatment among men with differing Charlson comorbidity scores within D'Amico tumor risk strata. Using competing-risks regression, a comparison was made of 8-year cancer-specific mortality for men treated aggressively and nonaggressively among Charlson score-tumor risk pairs. The study sample comprised 516 men (36%) with low-risk, 475 men (33%) with intermediate-risk, and 432 men (30%) with high-risk prostate cancer. Men with high-risk disease tended to have lower probability of aggressive treatment than other risk strata, regardless of comorbidity. Among men with Charlson scores 3+, probabilities of aggressive treatment did not increase with higher tumor risk (0.48, 0.61, 0.49 for low-, intermediate-, and high-risk disease, respectively). In competing-risks analysis, aggressive treatment was not associated with cancer-specific survival benefit in men with multiple comorbidities (Charlson scores of 2 or 3+) and low- and intermediate-risk disease, but there was a strong trend toward survival advantage in such men with high-risk disease. Aggressiveness of treatment is poorly matched with tumor risk in men with significant comorbidity. Men with major comorbidities should consider conservative management for low- and intermediate-risk disease and aggressive treatment for high-risk disease. Cancer 2013. © 2013 American Cancer Society. 23881652 Simple behavioural interventions for nocturnal enuresis in children. Nocturnal enuresis (bedwetting) is a socially disruptive and stressful condition which affects around 15% to 20% of five year olds and up to 2% of adults. Although there is a high rate of spontaneous remission, the social, emotional and psychological costs can be great. Behavioural interventions for treating bedwetting are defined as interventions that require a behaviour or action by the child which promotes night dryness and includes strategies which reward that behaviour. Behavioural interventions are further divided into:(a) simple behavioural interventions - behaviours or actions that can be achieved by the child without great effort; and(b) complex behavioural interventions - multiple behavioural interventions which require greater effort by the child and parents to achieve, including enuresis alarm therapy.This review focuses on simple behavioural interventions.Simple behavioural interventions are often used as a first attempt to improve nocturnal enuresis and include reward systems such as star charts given for dry nights, lifting or waking the children at night to urinate, retention control training to enlarge bladder capacity (bladder training) and fluid restriction. Other treatments such as medications, complementary and miscellaneous interventions such as acupuncture, complex behavioural interventions and enuresis alarm therapy are considered elsewhere. To determine the effects of simple behavioural interventions in children with nocturnal enuresis.The following comparisons were made:1. simple behavioural interventions versus no active treatment;2. any single type of simple behavioural intervention versus another behavioural method (another simple behavioural intervention, enuresis alarm therapy or complex behavioural interventions);3. simple behavioural interventions versus drug treatment alone (including placebo drugs) or drug treatment in combination with other interventions. We searched the Cochrane Incontinence Group Specialised Trials Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE in process, and handsearching of journals and conference proceedings (searched 15 December 2011). The reference lists of relevant articles were also searched. All randomised or quasi-randomised trials of simple behavioural interventions for treating nocturnal enuresis in children up to the age of 16. Studies which included children with daytime urinary incontinence or children with organic conditions were also included in this review if the focus of the study was on nocturnal enuresis. Trials focused solely on daytime wetting and trials of adults with nocturnal enuresis were excluded. Two reviewers independently assessed the quality of the eligible trials and extracted data. Differences between reviewers were settled by discussion with a third reviewer. Sixteen trials met the inclusion criteria, involving 1643 children of whom 865 received a simple behavioural intervention. Within each comparison, outcomes were mostly addressed by single trials, precluding meta-analysis. The only exception was bladder training versus enuresis alarm therapy which included two studies and demonstrated that alarm therapy was superior to bladder training.In single small trials, rewards, lifting and waking and bladder training were each associated with significantly fewer wet nights, higher full response rates and lower relapse rates compared to controls. Simple behavioural interventions appeared to be less effective when compared with other known effective interventions (such as enuresis alarm therapy and drug therapies with imipramine and amitriptyline). However, the effect was not sustained at follow-up after completion of treatment for the drug therapies. Based on one small trial, cognitive therapy also appeared to be more effective than rewards. When one simple behavioural therapy was compared with another, there did not appear to be one therapy that was more effective than another. Simple behavioural methods may be superior to no active treatment but appear to be inferior to enuresis alarm therapy and some drug therapy (such as imipramine and amitriptyline). Simple behavioural therapies could be tried as first line treatment before considering enuresis alarm therapy or drug therapy, which may be more demanding and have adverse effects, although evidence supporting their efficacy is lacking. 23933834 β2-Adrenergic receptor agonist administration promotes counter-regulatory responses and recovery from hypoglycaemia in rats. We have previously reported that local activation of β2-adrenergic receptors (B2ARs) in the ventromedial hypothalamus (VMH) enhances hypoglycaemic counter-regulation. This study examines whether peripheral delivery of a selective B2AR agonist could also promote counter-regulatory responses and thereby has potential therapeutic value to limit hypoglycaemia risk. Conscious male Sprague-Dawley rats received an intra-arterial injection of the B2AR specific agonist, formoterol, or a control solution either before a hyperinsulinaemic-hypoglycaemic clamp study or immediately before recovery from insulin-induced hypoglycaemia. In addition, the capacity of a VMH-targeted microinjection of a B2AR antagonist to limit the anti-insulin effect of the B2AR agonist was assessed. Systemic delivery of B2AR agonist markedly reduced the exogenous glucose infusion rate (GIR) required during the hypoglycaemic clamp study. This effect was mediated by blockade of insulin's inhibitory effect on endogenous glucose production. Local blockade of B2ARs within the VMH using a specific antagonist partially diminished the effect of systemic activation of B2ARs during hypoglycaemia at least in part by diminishing the adrenaline (epinephrine) response to hypoglycaemia. Peripheral B2AR agonist injection also enhanced glucose recovery from insulin-induced hypoglycaemia. Systemic B2AR agonist administration acts to limit insulin-induced hypoglycaemia by offsetting insulin's inhibitory effect on hepatic glucose production. This effect appears to be predominately mediated via a direct effect on liver B2ARs, but a small stimulatory effect on B2ARs within the VMH cannot be excluded. Our data suggest that formoterol may have therapeutic value to limit the risk of hypoglycaemia in patients with diabetes. 23921330 In vitro Biomechanical Study to Quantify Range of Motion, Intradiscal Pressure, and Facet Force of Three-level Dynamic Stabilization Constructs With Decreased Stiffness. Study Design. An in vitro biomechanical study.Objectives. Perform in vitro biomechanical testing on a lumbar spine using a 6 degree of freedom machine. To compare the range of motion, intradiscal pressure, and facet force of different three-level dynamic stabilization constructs to traditional rigid constructs. To determine the effect of decreasing the stiffness of the dynamic construct on the various parameters.Summary of Background Data. Dynamic stabilization systems are a surgical option that may minimize the development of adjacent segment disease.Methods. Seven T12-S1 specimens were tested at ±7.5 Nm in flexion-extension, lateral bending, and axial rotation. The testing sequence was 1) intact, 2) intact with facet sensors (IFS), 3) L3-S1 rigid (3R), 4) L3-L4 dynamic and L4-S1 rigid (1D-2R A), 5) L3-L5 dynamic and L5-S1 rigid (2D-1R A), and 6) L3-S1 dynamic (3D A). Constructs 1D-2R A, 2D-1R A, and 3D A were tested again with the specialized designs of B and C of decreased stiffness. Range of motion, intradiscal pressure, and facet force were measured.Results. In all loading modes there was a trend of increasing motion with decreased stiffness. Significant differences were seen with more dynamic stabilization levels but no significance was seen with only decreasing the stiffness. 3R Facet force at the caudal instrumented level significantly decreased compared to intact and dynamic stabilization constructs during axial rotation.Conclusions. Biomechanical testing resulted in a trend of increased ROM across instrumented levels as the stiffness was decreased. Dynamic stabilization increase the ROM across instrumented levels compared to rigid rods. These results suggest that decreasing the stiffness of the construct may lessen the probability of adjacent level disease. Although the specialized devices are not commercially available, clinical data would be necessary for a clearer understanding of adjacent level effects and to confirm the in vitro biomechanical findings. 23085190 Ts6 and Ts2 from Tityus serrulatus venom induce inflammation by mechanisms dependent on lipid mediators and cytokine production. Inflammatory mediators are thought to be involved in the systemic and local immune response induced by the Tityus serrulatus scorpion envenomation. New functional aspects of lipid mediators have recently been described. Here, we examine the unreported role of lipid mediators in cell recruitment to the peritoneal cavity after an injection with Ts2 or Ts6 toxins isolated from the T. serrulatus scorpion venom. In this report, we demonstrate that following a single intraperitoneal (i.p.) injection of Ts2 or Ts6 (250 μg/kg) in mice, there was an induction of leukocytosis with a predominance of neutrophils observed at 4, 24, 48 and 96 h. Moreover, total protein, leukotriene (LT)B(4), prostaglandin (PG)E(2) and pro-inflammatory cytokine levels were increased. We also observed an increase of regulatory cytokines, including interleukin (IL)-10, after the Ts2 injection. Finally, we observed that Ts2 or Ts6 injection in 5-lipoxygenase (LO) deficient mice and in wild type (WT) 129sv mice pre-treated with LTs and PGs inhibitors (MK-886 and celecoxib, respectively) a reduction the influx of leukocytes occurs in comparison to WT. The recruitment of these cells demonstrated a phenotype characteristic of neutrophils, macrophages, CD4 and CD8 lymphocytes expressing GR1+, F4/80+, CD3+/CD4+ and CD3+/CD8+, respectively. In conclusion, our data demonstrate that Ts2 and Ts6 induce inflammation by mechanisms dependent on lipid mediators and cytokine production. Ts2 may play a regulatory role whereas Ts6 exhibits pro-inflammatory activity exclusively. 23892035 Characteristic mutations found in the ML0411 gene of Mycobacterium leprae isolated in Northeast Asian countries. Genome analysis of Mycobacterium leprae strain Kyoto-2 in this study revealed characteristic nucleotide substitutions in gene ML0411, compared to the reference genome M. leprae strain TN. The ML0411 gene of Kyoto-2 had six SNPs compared to that of TN. All SNPs in ML0411 were non-synonymous mutations that result in amino acid replacements. In addition, a seventh SNP was found 41bp upstream of the start codon in the regulatory region. The seven SNP sites in the ML0411 region were investigated by sequencing in 36 M. leprae isolates from the Leprosy Research Center in Japan. The SNP pattern in 14 of the 36 isolates showed similarity to that of Kyoto-2. Determination of the standard SNP types within the 36 stocked isolates revealed that almost all of the Japanese strains belonged to SNP type III, with nucleotide substitutions at position 14676, 164275, and 2935685 of the M. leprae TN genome. The geographical distribution pattern of east Asian M. leprae isolates by discrimination of ML0411 SNPs was investigated and interestingly turned out to be similar to that of tandem repeat numbers of GACATC in the rpoT gene (3 copies or 4 copies), which has been established as a tool for M. leprae genotyping. All seven Korean M. leprae isolates examined in this study, as well as those derived from Honshu Island of Japan, showed 4 copies of the 6-base tandem repeat plus the ML0411 SNPs observed in M. leprae Kyoto-2. They are termed Northeast Asian (NA) strain of M. leprae. On the other hand, many of isolates derived from the Okinawa Islands of Japan and from the Philippines showed 3 copies of the 6-base tandem repeat in addition to the M. leprae TN ML0411 type of SNPs. These results demonstrate the existence of M. leprae strains in Northeast Asian region having characteristic SNP patterns. 23707312 Motor and parietal cortex stimulation for phantom limb pain and sensations. Limb amputation may lead to chronic painful sensations referred to the absent limb, ie phantom limb pain (PLP), which is likely subtended by maladaptive plasticity. The present study investigated whether transcranial direct current stimulation (tDCS), a noninvasive technique of brain stimulation that can modulate neuroplasticity, can reduce PLP. In 2 double-blind, sham-controlled experiments in subjects with unilateral lower or upper limb amputation, we measured the effects of a single session of tDCS (2 mA, 15 min) of the primary motor cortex (M1) and of the posterior parietal cortex (PPC) on PLP, stump pain, nonpainful phantom limb sensations and telescoping. Anodal tDCS of M1 induced a selective short-lasting decrease of PLP, whereas cathodal tDCS of PPC induced a selective short-lasting decrease of nonpainful phantom sensations; stump pain and telescoping were not affected by parietal or by motor tDCS. These findings demonstrate that painful and nonpainful phantom limb sensations are dissociable phenomena. PLP is associated primarily with cortical excitability shifts in the sensorimotor network; increasing excitability in this system by anodal tDCS has an antalgic effect on PLP. Conversely, nonpainful phantom sensations are associated to a hyperexcitation of PPC that can be normalized by cathodal tDCS. This evidence highlights the relationship between the level of excitability of different cortical areas, which underpins maladaptive plasticity following limb amputation and the phenomenology of phantom limb, and it opens up new opportunities for the use of tDCS in the treatment of PLP. 23935007 The Arabidopsis Floral Repressor BFT Delays Flowering by Competing with FT for FD Binding under High Salinity. Soil salinity is one of the most serious agricultural problems that significantly reduce crop yields in the arid and semi-arid regions. It influences various phases of plant growth and developmental processes, such as seed germination, leaf and stem growth, and reproductive propagation. Salt stress delays the onset of flowering in many plant species. We have previously reported that the Arabidopsis BROTHER OF FT AND TFL1 (BFT) acts as a floral repressor under salt stress. However, the molecular mechanisms underlying the BFT function in the salt regulation of flowering induction is unknown. In this work, we found that BFT delays flowering under high salinity by competing with FLOWERING LOCUS T (FT) for binding to the FD transcription factor. The flowering time of FD-deficient fd-2 mutant was insensitive to high salinity. BFT interacts with FD in the nucleus via the C-terminal domain of FD, which is also required for the interaction of FD with FT, and interferes with the FT-FD interaction. These observations indicate that BFT constitutes a distinct salt stress signaling pathway that modulates the function of the FT-FD module and possibly provides an adaption strategy that fine-tunes photoperiodic flowering under high salinity. 23470300 Resistance to Exercise-Induced Weight Loss: Compensatory Behavioral Adaptations. In many interventions that are based on an exercise program intended to induce weight loss, the mean weight loss observed is modest and sometimes far less than what the individual expected. The individual responses are also widely variable, with some individuals losing a substantial amount of weight, others maintaining weight, and a few actually gaining weight. The media have focused on the subpopulation that loses little weight, contributing to a public perception that exercise has limited utility to cause weight loss. The purpose of the symposium was to present recent, novel data that help explain how compensatory behaviors contribute to a wide discrepancy in exercise-induced weight loss. The presentations provide evidence that some individuals adopt compensatory behaviors, that is, increased energy intake and/or reduced activity, that offset the exercise energy expenditure and limit weight loss. The challenge for both scientists and clinicians is to develop effective tools to identify which individuals are susceptible to such behaviors and to develop strategies to minimize their effect. 23929603 Evaluation of liver disease progression in the German HCV (1b)-contaminated anti-D cohort at 35 years after infection. The natural course of HCV infection remains controversial. The German HCV (1b)-contaminated anti-D cohort provides an ideal population to investigate the natural course of HCV infection in a large and homogenous cohort of young women from the date of HCV inoculation. Our previous follow-up studies at 20 years and 25 years after infection suggested slow fibrosis progression rates in this unique cohort. The aim of our prospective community-based multicenter study was to re-evaluate the liver disease progression in 718 patients of the original anti-D cohort at 35 years after infection. Patients with self-limited HCV infection (n=189) were compared to those who failed to eliminate the virus spontaneously (n=529), comprising patients who were treatment naive (n=197) or achieved a sustained virological response (SVR, n=149) respectively failed to clear the virus (non-SVR, n=183) after antiviral therapy. In the overall cohort, 9.3% of patients showed clinical signs of liver cirrhosis at 35 years after infection. Liver disease progression largely depended on the HCV infection status. The highest proportion of patients with clinical signs of end-stage liver disease was observed in the non-SVR group (15.3%), whereas decreased cirrhosis rates were detected in the SVR group (6%) and in patients with self-limited HCV infection (1.1%, p=6.2x10(-6) ). Overall survival was significantly enhanced following SVR compared to treatment naive patients or non-SVR (p=0.027). Conclusion: The present study provides further evidence for a mild but significant disease progression at 35 years after infection in the German HCV (1b)-contaminated anti-D cohort. Patients with self-limited HCV infection or SVR after antiviral treatment were protected from progressive liver disease and showed the best clinical long-term outcome. (Hepatology 2013; 00:000-000). 23907111 One pot synthesis of poly(3-hexylthiophene)-block-poly(hexadecyloxylallene) by sequential monomer addition. A series of poly(3-hexylthiophene)-b-poly(hexadecyloxylallene) copolymers has been synthesized in one pot via sequential monomer addition by using Ni(dppp)Cl2 as a single catalyst. The copolymerization has been revealed to proceed by a controlled chain extension mechanism and the block copolymer can self-assemble into a well-defined supramolecular structure in solution and exhibit microphase separation in the solid state. 23344927 Regulation of sodium and calcium in Daphnia magna exposed to silver nanoparticles. The toxicity of manufactured silver nanoparticles (AgNPs) has been widely studied, but the influence of AgNPs on the major ions (such as sodium [Na] and calcium [Ca]) regulations are unknown. In the present study, a freshwater cladoceran Daphnia magna was exposed to commercial AgNPs coated with polyvinylpyrrolidone. After 48 h, the Na body content was significantly reduced by AgNO3 exposure, but the Ca body content was significantly increased under AgNO3 and AgNP exposures, respectively. No effect was observed on the body concentrations of Na and Ca at 50 to 500 µg/L AgNPs with 1-µM cysteine addition. Exposure of AgNO3 and AgNPs inhibited the Na influx and elevated the Na efflux. In contrast, their exposure increased the Ca influx, but did not affect the Ca efflux. The results of the present study demonstrated the significant influences of AgNO3 and AgNPs (without cysteine) on Na and Ca regulations. Such effect of AgNPs on Na and Ca regulation disappeared after cysteine addition, indicating that the soluble Ag released from AgNPs played a major role in the ionoregulatory dysfunction. 23755823 Surface modification of several dental substrates by non-thermal, atmospheric plasma brush. The purpose of this study was to reveal the effectiveness of non-thermal atmospheric plasma brush in surface wettability and modification of four dental substrates. Specimens of dental substrates including dentin, enamel, and two composites Filtek Z250, Filtek LS Silorane were prepared (∼2mm thick, ∼10mm diameter). The prepared surfaces were treated for 5-45s with a non-thermal atmospheric plasma brush working at temperatures from 36 to 38°C. The plasma-treatment effects on these surfaces were studied with contact-angle measurement, X-ray photoemission spectroscopy (XPS) and scanning electron microscopy (SEM). The non-thermal atmospheric argon plasma brush was very efficient in improving the surface hydrophilicity of four substrates studied. The results indicated that water contact angle values decreased considerably after only 5s plasma treatment of all these substrates. After 30s treatment, the values were further reduced to <5°, which was close to a value for super hydrophilic surfaces. XPS analysis indicated that the percent of elements associated with mineral in dentin/enamel or fillers in the composites increased. In addition, the percent of carbon (%C) decreased while %O increased for all four substrates. As a result, the O/C ratio increased dramatically, suggesting that new oxygen-containing polar moieties were formed on the surfaces after plasma treatment. SEM surface images indicated that no significant morphology change was induced on these dental substrates after exposure to plasmas. Without affecting the bulk properties, a super-hydrophilic surface could be easily achieved by the plasma brush treatment regardless of original hydrophilicity/hydrophobicity of dental substrates tested. 23327877 Transport by OATP1B1 and OATP1B3 enhances the cytotoxicity of epigallocatechin 3-O-gallate and several quercetin derivatives. Organic anion transporting polypeptides (OATPs) 1B1 and 1B3 are transporters that are expressed selectively in human hepatocytes under normal conditions. OATP1B3 is also expressed in certain cancers. Flavonoids such as green tea catechins and quercetin glycosides have been shown to modulate the function of some OATPs. In the present study, the extent to which six substituted quercetin derivatives (1-6) affected the function of OATP1B1 and OATP1B3 was investigated. Uptake of the radiolabeled model substrates estradiol 17β-glucuronide, estrone 3-sulfate, and dehydroepiandrosterone sulfate (DHEAS) was determined in the absence and presence of compounds 1-6 using Chinese hamster ovary (CHO) cells stably expressing either OATP1B1 or OATP1B3. Several of compounds 1-6 inhibited OATP-mediated uptake of all three model substrates, suggesting that they could also be potential substrates. Compound 6 stimulated OATP1B3-mediated estradiol 17β-glucuronide uptake by increasing the apparent affinity of OATP1B3 for its substrate. Cytotoxicity assays demonstrated that epigallocatechin 3-O-gallate (EGCG) and most of compounds 1-6 killed preferentially OATP-expressing CHO cells. EGCG, 1, and 3 were the most potent cytotoxic compounds, with EGCG and 3 selectively killing OATP1B3-expressing cells. Given that OATP1B3 is expressed in several cancers, EGCG and some of the quercetin derivatives studied might be promising lead compounds for the development of novel anticancer drugs. 23883319 Effects of solar particle event proton radiation on parameters related to ferret emesis. The effectiveness of simulated solar particle event (SPE) proton radiation to induce retching and vomiting was evaluated in the ferret experimental animal model. The endpoints measured in the study included: (1) the fraction of animals that retched or vomited, (2) the number of retches or vomits observed, (3) the latency period before the first retch or vomit and (4) the duration between the first and last retching or vomiting events. The results demonstrated that γ ray and proton irradiation delivered at a high dose rate of 0.5 Gy/min induced dose-dependent changes in the endpoints related to retching and vomiting. The minimum radiation doses required to induce statistically significant changes in retching- and vomiting-related endpoints were 0.75 and 1.0 Gy, respectively, and the relative biological effectiveness (RBE) of proton radiation at the high dose rate did not significantly differ from 1. Similar but less consistent and smaller changes in the retching- and vomiting-related endpoints were observed for groups irradiated with γ rays and protons delivered at a low dose rate of 0.5 Gy/h. Since this low dose rate is similar to a radiation dose rate expected during a SPE, these results suggest that the risk of SPE radiation-induced vomiting is low and may reach statistical significance only when the radiation dose reaches 1 Gy or higher. 23863222 Value and Limitations of Transpulmonary Pressure Calculations During Intra-Abdominal Hypertension. To clarify the effect of progressively increasing intra-abdominal pressure on esophageal pressure, transpulmonary pressure, and functional residual capacity. Controlled application of increased intra-abdominal pressure at two positive end-expiratory pressure levels (1 and 10 cm H2O) in an anesthetized porcine model of controlled ventilation. Large animal laboratory of a university-affiliated hospital. Eleven deeply anesthetized swine (weight 46.2 ± 6.2 kg). Air-regulated intra-abdominal hypertension (0-25 mm Hg). Esophageal pressure, tidal compliance, bladder pressure, and end-expiratory lung aeration by gas dilution. Functional residual capacity was significantly reduced by increasing intra-abdominal pressure at both positive end-expiratory pressure levels (p ≤ 0.0001) without corresponding changes of end-expiratory esophageal pressure. Above intra-abdominal pressure 5 mm Hg, plateau airway pressure increased linearly by ~ 50% of the applied intra-abdominal pressure value, associated with commensurate changes of esophageal pressure. With tidal volume held constant, negligible changes occurred in transpulmonary pressure due to intra-abdominal pressure. Driving pressures calculated from airway pressures alone (plateau airway pressure - positive end-expiratory pressure) did not equate to those computed from transpulmonary pressure (tidal changes in transpulmonary pressure). Increasing positive end-expiratory pressure shifted the predominantly negative end-expiratory transpulmonary pressure at positive end-expiratory pressure 1 cm H2O (mean -3.5 ± 0.4 cm H2O) into the positive range at positive end-expiratory pressure 10 cm H2O (mean 0.58 ± 1.2 cm H2O). Despite its insensitivity to changes in functional residual capacity, measuring transpulmonary pressure may be helpful in explaining how different levels of positive end-expiratory pressure influence recruitment and collapse during tidal ventilation in the presence of increased intra-abdominal pressure and in calculating true transpulmonary driving pressure (tidal changes of transpulmonary pressure). Traditional interpretations of respiratory mechanics based on unmodified airway pressure were misleading regarding lung behavior in this setting. 23855709 Quantification of bone changes in a collagen-induced arthritis mouse model by reconstructed three dimensional micro-CT. Inflammatory arthritis is a chronic disease, resulting in synovitis and subchondral and bone area destruction, which can severely affect a patient's quality of life. The most common form of inflammatory arthritis is rheumatoid arthritis (RA) in which many of the disease mechanisms are not well understood. The collagen-induced arthritis (CIA) mouse model is similar to RA as it exhibits joint space narrowing and bone erosion as well as involves inflammatory factors and cellular players that have been implicate in RA. Quantitative data for disease progression in RA models is difficult to obtain as serum blood markers may not always reflect disease state and physical disease indexes are subjective. Thus, it is important to develop tools to objectively assess disease progression in CIA. Micro-CT (Computed Tomography) is a relatively mature technology that has been used to track a variety of anatomical changes in small animals. In this study, micro-CT scans of several joints of control and CIA mice were acquired at 0, 4, 7, and 9 weeks after the immunization with collagen type II. Each micro-CT scan was analyzed by applying a segmentation algorithm to individual slices in each image set to provide 3-dimensional representations of specific bones including the humerus, femur, and tibia. From these representations, the volume and mean density of these bones were measured and compared. This analysis showed that both the volume and the density of each measured bone of the CIA mice were significantly smaller than those of the controls at week 7. This study demonstrates that micro-CT can be used to quantify bone changes in the CIA mouse model as an alternative to disease index assessments. In conclusion, micro-CT could be useful as a non-invasive method to monitor the efficacy of new treatments for RA tested in small animals. 23756994 Classification and evolutionary analysis of the basic helix-loop-helix gene family in the green anole lizard, Anolis carolinensis. Helix-loop-helix (bHLH) proteins play essential regulatory roles in a variety of biological processes. These highly conserved proteins form a large transcription factor superfamily, and are commonly identified in large numbers within animal, plant, and fungal genomes. The bHLH domain has been well studied in many animal species, but has not yet been characterized in non-avian reptiles. In this study, we identified 102 putative bHLH genes in the genome of the green anole lizard, Anolis carolinensis. Based on phylogenetic analysis, these genes were classified into 43 families, with 43, 24, 16, 3, 10, and 3 members assigned into groups A, B, C, D, E, and F, respectively, and 3 members categorized as "orphans". Within-group evolutionary relationships inferred from the phylogenetic analysis were consistent with highly conserved patterns observed for introns and additional domains. Results from phylogenetic analysis of the H/E(spl) family suggest that genome and tandem gene duplications have contributed to this family's expansion. Our classification and evolutionary analysis has provided insights into the evolutionary diversification of animal bHLH genes, and should aid future studies on bHLH protein regulation of key growth and developmental processes. 23965165 Management of blood pressure in acute stroke. The importance of elevated or low arterial blood pressure (BP) early after stroke, and the need for pharmacological intervention to control BP, remains controversial. Debate surrounds if, when and how to intervene. This debate is informed by conflicting results from observational data and underpowered clinical trials and substantive outcome data are lacking. Accordingly, management decisions have largely been left up to the individual treating physician and guidelines are based on 'good practice' and theory rather than level 1, grade A evidence. Substantial progress has been made in recent years, particularly in the field of hemorrhagic stroke, where recently presented and soon to completed large-scale trials may finally give us a firm evidence base. For ischemic stroke, many important studies have informed our understanding of the basic pathophysiology, epidemiology, treatment and outcomes of BP management in acute stroke and, although not yet constituting a solid 'evidence base', are helping us from the 'cognitive quick-sand' of small studies and personal experiences. 23531815 The effects of hibernation on the contractile and biochemical properties of skeletal muscles in the thirteen-lined ground squirrel, Ictidomys tridecemlineatus. Hibernation is a crucial strategy of winter survival used by many mammals. During hibernation, thirteen-lined ground squirrels, Ictidomys tridecemlineatus, cycle through a series of torpor bouts, each lasting more than a week, during which the animals are largely immobile. Previous hibernation studies have demonstrated that such natural models of skeletal muscle disuse cause limited or no change in either skeletal muscle size or contractile performance. However, work loop analysis of skeletal muscle, which provides a realistic assessment of in vivo power output, has not previously been undertaken in mammals that undergo prolonged torpor during hibernation. In the present study, our aim was to assess the effects of 3 months of hibernation on contractile performance (using the work loop technique) and several biochemical properties that may affect performance. There was no significant difference in soleus muscle power output-cycle frequency curves between winter (torpid) and summer (active) animals. Total antioxidant capacity of gastrocnemius muscle was 156% higher in torpid than in summer animals, suggesting one potential mechanism for maintenance of acute muscle performance. Soleus muscle fatigue resistance was significantly lower in torpid than in summer animals. Gastrocnemius muscle glycogen content was unchanged. However, state 3 and state 4 mitochondrial respiration rates were significantly suppressed, by 59% and 44%, respectively, in mixed hindlimb skeletal muscle from torpid animals compared with summer controls. These findings in hindlimb skeletal muscles suggest that, although maximal contractile power output is maintained in torpor, there is both suppression of ATP production capacity and reduced fatigue resistance. 23827710 The nuclear lamina regulates germline stem cell niche organization via modulation of EGFR signaling. Stem cell niche interactions have been studied extensively with regard to cell polarity and extracellular signaling. Less is known about the way in which signals and polarity cues integrate with intracellular structures to ensure appropriate niche organization and function. Here, we report that nuclear lamins function in the cyst stem cells (CySCs) of Drosophila testes to control the interaction of CySCs with the hub. This interaction is important for regulation of CySC differentiation and organization of the niche that supports the germline stem cells (GSCs). Lamin promotes nuclear retention of phosphorylated ERK in the CySC lineage by regulating the distribution of specific nucleoporins within the nuclear pores. Lamin-regulated nuclear epidermal growth factor (EGF) receptor signaling in the CySC lineage is essential for proliferation and differentiation of the GSCs and the transient amplifying germ cells. Thus, we have uncovered a role for the nuclear lamina in the integration of EGF signaling to regulate stem cell niche function. 23824389 Progression of foot deformity in Charcot neuropathic osteoarthropathy. Charcot neuropathic osteoarthropathy associated foot deformity can result in joint instability, ulceration, and even amputation. The purpose of the present study was to follow patients with and without active Charcot osteoarthropathy for as long as two years to examine the magnitude and timing of foot alignment changes. We studied fifteen subjects with Charcot osteoarthropathy and nineteen subjects with diabetes mellitus and peripheral neuropathy without Charcot osteoarthropathy for one year; eight of the subjects with osteoarthropathy and five of the subjects with diabetes and peripheral neuropathy were followed for two years. Bilateral weight-bearing radiographs of the foot were made at baseline for all subjects, with repeat radiographs being made at six months for the osteoarthropathy group and at one and two years for both groups. Radiographic measurements included the Meary angle, cuboid height, calcaneal pitch, and hindfoot-forefoot angle. The Meary angle, cuboid height, and calcaneal pitch worsened in feet with Charcot osteoarthropathy over one year as compared with the contralateral, uninvolved feet and feet in patients with diabetes and peripheral neuropathy. Cuboid height continued to worsen over the two-year follow-up in the feet with Charcot osteoarthropathy. These feet also had a greater change in the hindfoot-forefoot angle at one year as compared with the feet in patients with diabetes and peripheral neuropathy and at two years as compared with the contralateral, uninvolved feet. In patients with Charcot neuropathic osteoarthropathy, radiographic alignment measurements demonstrate the presence of foot deformity at the time of the initial clinical presentation and evidence of progressive changes over the first and second years. The six-month data suggest worsening of medial column alignment prior to lateral column worsening. This radiographic evidence of worsening foot alignment over time supports the need for aggressive intervention (conservative bracing or surgical fixation) to attempt to prevent limb-threatening complications. 23837415 Patient-centered disease management (PCDM) for heart failure: study protocol for a randomised controlled trial. Chronic heart failure (HF) disease management programs have reported inconsistent results and have not included comorbid depression management or specifically focused on improving patient-reported outcomes. The Patient Centered Disease Management (PCDM) trial was designed to test the effectiveness of collaborative care disease management in improving health status (symptoms, functioning, and quality of life) in patients with HF who reported poor HF-specific health status. Patients with a HF diagnosis at four VA Medical Centers were identified through population-based sampling. Patients with a Kansas City Cardiomyopathy Questionnaire (KCCQ, a measure of HF-specific health status) score of < 60 (heavy symptom burden and impaired quality of life) were invited to enroll in the PCDM trial. Enrolled patients were randomized to receive usual care or the PCDM intervention, which included: (1) collaborative care management by VA clinicians including a nurse, cardiologist, internist, and psychiatrist, who worked with patients and their primary care providers to provide guideline-concordant care management, (2) home telemonitoring and guided patient self-management support, and (3) screening and treatment for comorbid depression. The primary study outcome is change in overall KCCQ score. Secondary outcomes include depression, medication adherence, guideline-based care, hospitalizations, and mortality. The PCDM trial builds on previous studies of HF disease management by prioritizing patient health status, implementing a collaborative care model of health care delivery, and addressing depression, a key barrier to optimal disease management. The study has been designed as an 'effectiveness trial' to support broader implementation in the healthcare system if it is successful. Unique identifier: NCT00461513. 23423726 Transpulmonary thermodilution cardiac output measurement is not affected by severe pulmonary oedema: a newborn animal study. /st> The transpulmonary thermodilution (TPTD) technique is widely used in clinical practice for measuring cardiac output (CO). This study was designed to investigate the influence of various levels of pulmonary oedema on the reliability of CO measurements by the TPTD method. /st> In 11 newborn lambs pulmonary oedema was induced using a surfactant washout technique. Serial CO measurements using TPTD (COTPTD) were performed at various amounts of lung water. Simultaneously, CO was measured by an ultrasound flow probe around the main pulmonary artery (COMPA) and used as the standard reference. CO was divided by the body surface area to calculate cardiac index (CI). Data were analysed using correlational statistics and Bland-Altman analysis. /st> One lamb died prematurely. A total of 56 measurements in 10 lambs were analysed with a median CIMPA of 2.95 (IQR 1.04) litre min(-1) m(-2). Mean percentage increase in extravascular lung water (EVLW) between the start and the end of the study was 126.4% (sd 40.4). Comparison of the two CO methods showed a mean bias CI of -0.16 litre min(-1) m(-2) (limits of agreement ±0.73 litre min(-1) m(-2)) and a percentage error of 23.8%. Intraclass correlation coefficients were 0.91 (95% CI 0.81-0.95) for absolute agreement and 0.92 (95% CI 0.87-0.95) for consistency. Acceptable agreement was confirmed by a tolerability-agreement ratio of 0.39. The within-subject correlation between the amount of EVLWI and the bias between the two methods was not significant (-0.02; P=0.91). /st> CO measurements by the transpulmonary thermodilution technique over a wide range of CI values are not affected by the presence of high EVLWI. The slight underestimation of the CO is independent of the amount of pulmonary oedema. 23566937 Field efficacy of eprinomectin against the sucking louse Haematopinus asini on naturally infested donkeys. A trial was conducted to assess the efficacy of eprinomectin (EPR) against the sucking louse Haematopinus asini on naturally infested donkeys. Parasitological investigations were performed on fifteen animals. On day 0, donkeys received EPR pour-on at the manufacturer's recommended cattle dose. Louse counts were performed on days -1, 7, 14, 21, 28, 35, 42, 49 and 56 at seven predilection sites on the skin of each donkey. EPR was completely effective (100%) from day 7, until the end of the study. Clinically no adverse reactions were observed in any of donkeys treated. EPR was considered to be 100% effective against H. asini. This is the first trial to evaluate the efficacy of EPR against a natural louse infestation in donkeys. 23364468 Swinging heart in acute pancreatitis. : Pleural effusions and ascites are not uncommon in acute pancreatitis; however, pericardial effusions complicated by cardiac tamponade are extremely rare and definite treatment has yet to be established. This case report illustrates the findings in a 57-year-old patient, who was diagnosed of an acute alcoholic pancreatitis. The clinical course was complicated by recurrent episodes of acute pancreatitis, and eventually, the patient developed acute circulatory failure that was caused by cardiac tamponade. The patient was successfully treated by an emergency pericardiocentesis; however, although the patient was treated with intrapericardial triamcinolone and octreotide, pericardial effusion reoccurred. Eventually, a pancreaticopericardial fistula was diagnosed by endoscopic retrograde cholangiopancreaticography, and after successful stent placement in a disrupted pancreatic duct, the clinical recovery was uneventful. To the best of the authors' knowledge, this is the first case of a successful endoscopic treatment of a pancreaticopericardial fistula complicated by cardiac tamponade in a patient with acute pancreatitis. 23925408 Characterization of blubber fatty acid signatures in northern elephant seals (Mirounga angustirostris) over the postweaning fast. Phocids routinely fast for extended periods. During these fasts, energetic requirements are met primarily through the catabolism of blubber lipid. To assess whether fatty acid (FA) composition changes during the postweaning fast in northern elephant seals, blubber biopsies were acquired longitudinally from 43 pups at 2.3 ± 1.5 and 55.2 ± 3.7 days postweaning in 1999 and 2000. At weaning, short-chain monounsaturated FA (SC-MUFA, ≤18 carbons) dominated the blubber while saturated FA (SFA) were found in the next highest proportion. The major FA (all ≥1 % by mass) comprised approximately 91 % of total blubber FA. In both years, 18:1n-9 and 16:0 were the most prevalent FA. Major FA mobilized during the fast consisted of polyunsaturated FA (PUFA), SFA, and SC-MUFA. Long-chain MUFA (>18 carbons) tended to be conserved. The fractional mobilization value of 20:5n-3 was the highest, resulting in significant reductions of this PUFA. Although concentrations of some blubber FA changed significantly during the postweaning fast, the general FA signature of blubber was similar at weaning and near the end of the fast. Changes in some FA differed across years. For example, the concentration of 20:4n-6, a minor PUFA, was significantly reduced in 1999 but not in 2000. FA mobilization patterns in northern elephant seal pups are somewhat similar to those reported previously for other fasting phocids and terrestrial mammals, though there are some notable differences. Differences in FA mobilization patterns across mammalian species may be related to differences in diets, geographical distribution, environmental factors, physiological adaptations, and life history stage. 23605986 Managing Bronchiolitis Obliterans Syndrome (BOS) and Chronic Lung Allograft Dysfunction (CLAD) in Children: What Does the Future Hold? The success of pediatric lung transplantation continues to be limited by long-term graft dysfunction. Historically this has been characterized as an obstructive spirometric defect in the form of the bronchiolitis obliterans syndrome (BOS). It is recognized, however, that this does not reflect many of the other acknowledged etiologies of chronic lung dysfunction-noting it is the sum of the parts that contribute to respiratory morbidity and mortality after transplant. The term chronic lung allograft dysfunction (CLAD) has been coined to reflect these other entities and, in particular, a group of relatively recently described lung disorders called the restrictive allograft syndrome (RAS). RAS is characterized by a restrictive spirometric defect. Although these entities have not yet been studied in a pediatric setting their association with poor compliance, antibody-mediated rejection (AMR), and post-infectious lung damage (particularly viral) warrants attention by pediatric lung transplant teams. Current therapy for the BOS subset of CLAD is otherwise limited to changing immunosuppressants and avoiding excessive infectious risk by avoiding over-immunosuppression. Long-term macrolide therapy in lung transplantation is not of proven efficacy. Reviewing previous BOS studies to explore restrictive spirometric cases and joint projects via groups like the International Pediatric Lung Transplant Collaborative will be the way forward to solve this pressing problem. 23904743 Porphyrin derivatives as inhibitors for acetylcholinesterase from Drosophila melanogaster. The cure for Alzheimer's disease (AD) is still unknown. According to Cholinergic hypothesis, Alzheimer's disease is caused by the reduced synthesis of the neurotransmitter, Acetylcholine. Regional cerebral blood flow can be increased in patients with Alzheimer's disease by Acetylcholinesterase (AChE) inhibitors. In this regard, Tetraphenylporphinesulfonate (TPPS), 5,10,15,20- Tetrakis (4-sulfonatophenyl) porphyrinato Iron(III) Chloride (FeTPPS) and 5,10,15,20-Tetrakis (4-sulfonatophenyl) porphyrinatoIron(III) nitrosyl Chloride (FeNOTPPS) were investigated as candidate compounds for inhibition of Acteylcholinesterase of Drosophila melanogaster (DmAChE) by use of Molecular Docking. The results show that FeNOTPPS forms the most stable complex with DmAChE. 23542138 Three-dimensional mapping and comparative analysis of the distal human corpus cavernosum and the inflatable penile prosthesis. The intricate anatomy of the corpus cavernosum in both the flaccid and tumescent state has not been fully elucidated. We report our experience using a three-dimensional (3D) scanner to reconstruct cadaveric casts and compare them with 3D images of two prototypes of penile prosthesis. Two different models of the Titan Coloplast inflatable penile prosthesis were analyzed using a 3D scanner. The first was the standard model and the second was a newer model with a rounder silicone tip. Two cadaveric phalluses were harvested using Smooth-Cast 300Q polyurethane molding. The molds were excised and scanned along side the penile prosthesis. 3D scans were completed and analyzed using Leios Mesh software, and GOM Inspect software. The 3D scans demonstrated the mean human corporal radii 2 mm from the distal tip to be 36.51 mm (36.01-37.0 mm), which is an obtuse angle. The standard Titan penile prosthesis spherical radius at the same level was 202.52 mm, while the new silicone tip prosthesis had a radius of 139.33 mm. 3D mapping further demonstrated the trajectory of the cavernosa appeared curvilinear and the distal ends appeared blunt. The use of cadaveric cavernosal molds in combination with the 3D scanner allowed us to accurately image the corpus cavernosum for the first time. Our findings suggest that anatomically accurate corporal tips appear to be relatively blunt and that the new Titan silicone tip penile prosthesis more closely resembles the human corporal tip. 23552851 Dioscin-induced autophagy mitigates cell apoptosis through modulation of PI3K/Akt and ERK and JNK signaling pathways in human lung cancer cell lines. Our previous study has revealed that dioscin, a compound with anti-inflammatory, lipid-lowering, anticancer and hepatoprotective effects, may induce autophagy in hepatoma cells. Autophagy is a lysosomal degradation pathway that is essential for cell survival and tissue homeostasis. In this study, the role of autophagy and related signaling pathways during dioscin-induced apoptosis in human lung cancer cells was investigated. Results from 4'-6-diamidino-2-phenylindole and annexin-V/PI double-staining assay showed that caspase-3- and caspase-8-dependent, and dose-dependent apoptoses were detected after a 24-h dioscin treatment. Meanwhile, autophagy was detected as early as 12 h after an exposure to low-dose dioscin, as indicated by an up-regulated expression of LC3-II and beclin-1 proteins. Blockade of autophagy with bafilomycin A1 or 3-methyladenine sensitized the A549 and H1299 cells to apoptosis. Treatment of A549 and H1299 cells with dioscin caused a dose-dependent increase in ERK1/2 and JNK1/2 activity, accompanied with a decreased PI3K expression and decreased phosphorylation of Akt and mTOR. Taken together, this study demonstrated for the first time that autophagy occurred earlier than apoptosis during dioscin-induced human lung cancer cell line apoptosis. Dioscin-induced autophagy via ERK1/2 and JNK1/2 pathways may provide a protective mechanism for cell survival against dioscin-induced apoptosis to act as a cytoprotective reaction. 23941762 Pharmacological Treatment of Dementia: A Scoping Review of Systematic Reviews. Background: Until now, multiple reviews on the pharmacological treatment of dementia have been published. Methods: We performed a scoping review to summarize research findings and to identify gaps in the existing literature. We searched the literature and assessed the risk of bias of the included reviews. A team of clinical experts assessed the fields in which more research is necessary. Fifty-five reviews with a low risk of bias were included, most of them concerning the treatment of cognitive decline (n = 16) and behavioral symptoms (n = 10) in Alzheimer's disease (AD). For cognitive impairment, cholinesterase inhibitors (n = 13) and memantine (n = 7) were described most frequently. Little information was found about the treatment of depression in dementia. Conclusions: For many current treatments, there is sufficient evidence. New research should focus on the symptomatic treatment of the earliest and most salient complaints in AD as well as on disease-modifying interventions acting at the level of the amyloid cascade. © 2013 S. Karger AG, Basel. 23936456 Small Molecule ErbB Inhibitors Decrease Proliferative Signaling and Promote Apoptosis in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. The presence of the Philadelphia chromosome in patients with acute lymphoblastic leukemia (Ph(+)ALL) is a negative prognostic indicator. Tyrosine kinase inhibitors (TKI) that target BCR/ABL, such as imatinib, have improved treatment of Ph(+)ALL and are generally incorporated into induction regimens. This approach has improved clinical responses, but molecular remissions are seen in less than 50% of patients leaving few treatment options in the event of relapse. Thus, identification of additional targets for therapeutic intervention has potential to improve outcomes for Ph+ALL. The human epidermal growth factor receptor 2 (ErbB2) is expressed in ∼30% of B-ALLs, and numerous small molecule inhibitors are available to prevent its activation. We analyzed a cohort of 129 ALL patient samples using reverse phase protein array (RPPA) with ErbB2 and phospho-ErbB2 antibodies and found that activity of ErbB2 was elevated in 56% of Ph(+)ALL as compared to just 4.8% of Ph(-)ALL. In two human Ph+ALL cell lines, inhibition of ErbB kinase activity with canertinib resulted in a dose-dependent decrease in the phosphorylation of an ErbB kinase signaling target p70S6-kinase T389 (by 60% in Z119 and 39% in Z181 cells at 3 µM). Downstream, phosphorylation of S6-kinase was also diminished in both cell lines in a dose-dependent manner (by 91% in both cell lines at 3 µM). Canertinib treatment increased expression of the pro-apoptotic protein Bim by as much as 144% in Z119 cells and 49% in Z181 cells, and further produced caspase-3 activation and consequent apoptotic cell death. Both canertinib and the FDA-approved ErbB1/2-directed TKI lapatinib abrogated proliferation and increased sensitivity to BCR/ABL-directed TKIs at clinically relevant doses. Our results suggest that ErbB signaling is an additional molecular target in Ph(+)ALL and encourage the development of clinical strategies combining ErbB and BCR/ABL kinase inhibitors for this subset of ALL patients. 23271678 Feeding of selenium alone or in combination with glucoraphanin differentially affects intestinal and hepatic antioxidant and phase II enzymes in growing rats. The anti-carcinogenic effects of sulforaphane (SFN) are based on the up-regulation of antioxidant enzymes (AE) and phase II enzymes (PIIE) through the transcription factor Nrf2. Current knowledge on the roles of the SFN precursor glucoraphanin (GRA) on these processes is limited. Anti-carcinogenic effects of Se depending on glutathione peroxidase (GPx) activity have also been reported. We studied effects and possible synergisms of Se and GRA on the expression and activity of a broad spectrum of AE and PIIE in jejunum, colon and the liver of rats fed diets differing in Se and GRA concentration. In all organs, GPx1 mRNA expression was 70 % to 90 % lower in Se deficiency than in Se sufficiency. GPx2 expression increased in jejunum and liver under Se deficiency and decreased in the colon. Se deficiency increased most colonic AE and PIIE compared to Se adequacy. Adequate and in particular supranutritive Se combined with GRA increased colonic AE and PIIE expression up to 3.72-fold. In the liver Se deficiency raised the expression of AE and PIIE up to 4.49-fold. GRA attenuated liver AE and PIIE response in Se deficiency. Expression- and correlation analyses revealed that Keap1 mRNA better reflects AE and PIIE gene expression than Nrf2 mRNA. We conclude that: (1) GPx1 sensitively indicates Se deficiency; (2) the influence of Se and Nrf2/Keap1 on GPx2 expression depends on the organ; (3) GRA combined with supranutritive Se may effectively protect against inflammation and colon cancer; (4) future investigations on AE and PIIE expression should consider the role of Keap1 to a higher extent. 23900156 How to make a specific diagnosis of panniculitis on clinical grounds alone: an integrated pathway of general criteria and specific findings. A clinical approach to the vexing problem of diagnosis of panniculitis is traced in this paper, in order to obtain from the clinical findings, history and laboratory data of the patient useful, detailed and precise information, essential to address dermatologists to a specific clinical diagnosis of panniculitis. This approach is created in the same way as when a dermatologist faces any other dermatological disease, be it inflammatory or neoplastic. A common behavior in case of panniculitis is in fact just to take an adequate biopsy and wait for the pathologist report. This is indeed a limitation both for the dermatologist and above all for the pathologist, who is in tremendous need for detailed clinical information before signing his report. The most common types of panniculitides, taking into account their main clinical diagnostic criteria, will be considered. In particular, Erythema Nodosum, Panniculitides in Sarcoidosis, Pancreatic Panniculitis, Lupus Panniculitis, Erythema Induratum/Nodular Vasculitis and Weber-Christian Panniculitis/Rothman-Makai Pannicultis will be analyzed. Every chapter will consider general criteria (epidemiology, age and gender, distribution of the lesions, laboratory findings) and specific findings (characteristics of the lesions, i.e. redness, pain, tenderness, evolution, ulceration, sites of involvement) as well as comorbidities and systemic signs and sympthoms. Detailed analysis of the general criteria integrated with the specific findings will allow the clinicians to reach a clinical diagnosis with a high degree of confidence. 23592271 Computerized image analysis of iron-stained macrophages. Analysis of iron levels in single cells is critical to understand the consequences of impaired regulation of iron homeostasis. Here we establish a method to analyze intracellular iron deposits by computerized image analysis of Prussian blue-stained alveolar macrophages as a test system. We efficiently detected small differences in macrophage steady-state iron levels in Hfe (-/-) mice as well as inflammation-induced iron sequestration upon lipopolysaccharide instillation. In conclusion, computerized image analysis of single cells is a robust and reproducible tool suitable for iron measurements in small sample sets with limited cell yield. 23228182 Amino acid-based zwitterionic poly(serine methacrylate) as an antifouling material. A serine-based zwitterionic poly(serine methacrylate) (pSerMA) was developed in this work to be used as a potential antifouling material. A surface-initiated photoiniferter-mediated polymerization (SI-PIMP) method was used to graft polymer brushes on gold surfaces. The pSerMA-grafted samples with different polymer film thicknesses were readily prepared by varying the UV-irradiation time. With the optimal film thickness, the adsorptions from bovine serum albumin, human serum, and human plasma onto the pSerMA-grafted surfaces, as evaluated by a surface plasmon resonance (SPR) biosensor, were 1.8, 9.2, and 12.9 ng/cm(2), respectively, comparable to the traditional antifouling material such as poly(ethylene glycol). The pSerMA-grafted surfaces also strongly resisted adhesion from bovine aortic endothelial cells. This is the first work to develop an amino acid-based zwitterionic polymer as an antifouling material, demonstrating that pSerMA is a promising alternative to the traditional ethylene glycol-based antifouling materials. 23758505 Electrochemical enzyme-linked immunosorbent assay featuring proximal reagent generation: detection of human immunodeficiency virus antibodies in clinical samples. We describe a simple electrochemical immunoassay for human immunodeficiency virus (HIV) antibody detection that localizes capture and detection reagents in close proximity to a microelectrode. Antigenic peptides from HIV-1 gp41 or HIV-2 gp36 were covalently attached to a SU-8 substrate that also presented a template for the deposition of three-dimensional microelectrodes. The detection of HIV antibodies was achieved with an electrochemical immunoassay where an alkaline phosphatase conjugated secondary antibody reacts with p-aminophenyl phosphate (pAPP) to produce a redox-active product, p-aminophenol. The current derived from the oxidation of the reporter group increased linearly over a wide antibody concentration range (0.001-1 μg mL(-1)), with a detection limit of 1 ng mL(-1) (6.7 pM) for both HIV-1 and HIV-2. This level of sensitivity is clinically relevant, and the feasibility of this approach for clinical sample testing was also evaluated with HIV clinical patient samples, with excellent performance observed compared against a commercially available gold standard. This approach was used to develop the first electrochemical enzyme-linked immunosorbent assay (ELISA) to detect HIV in clinical samples, and excellent performance relative to a gold standard test was achieved. 23395550 Benefit of a new hearing device utilizing cartilage conduction. Our previous study demonstrated that sound was effectively transmitted by attaching a transducer to the aural cartilage even without fixation pressure. This new method for sound transmission was found by Hosoi in 2004, and was termed cartilage conduction (CC). CC can be utilized even in hearing-impaired patients who cannot use air-conduction hearing aids owing to continuous otorrhea or aural atresia. A prototype hearing aid employing CC was investigated in this study. Four patients with conditions such as continuous otorrhea and acquired aural atresia after surgery participated in this study. The CC hearing aid was fitted, and its benefits were assessed by audiometric tests and interview. Thresholds and speech recognition scores improved in all subjects. However, in subjects with continuous otorrhea, it was difficult to obtain the gains according to the target gains owing to their severe hearing loss and the limitation of the output level. On the other hand, unexpectedly large gains were obtained below 2kHz in the patient with acquired aural atresia. These large gains were probably caused by soft tissue filling the postoperative space. No subjects complained of pain associated with the attachment of the transducer, although such problems are usually observed for a bone-conduction (BC) hearing aid. This feature is considered one of the advantages of the CC hearing aid. The results of the audiometric tests and interview suggest that the CC hearing aid has potential as a useful amplification device for hearing disability. Unfortunately, if the soft tissue pathway is not involved, the current device is insufficient for the patients with severe hearing loss. The improvement of the output level will lead to develop a reliable CC hearing aid as an alternative to BC hearing aids or bone anchored hearing aids. 23949563 Low-Volume Morning-Only Polyethylene Glycol with Specially Designed Test Meals versus Standard-Volume Split-Dose Polyethylene Glycol with Standard Diet for Colonoscopy: A Prospective, Randomized Trial. Background/Aims: Split-dose polyethylene glycol (PEG) is a standard bowel preparation regimen for colonoscopy, but the large volume is burdensome to ingest and the night dose causes sleep disturbance. This study was performed to evaluate the efficacy and tolerability of a bowel preparation protocol using low-volume morning-only PEG with specially designed low-residue test meals (LV-PEG with TM) compared to a standard-volume split-dose PEG bowel preparation with a standard diet (SV-PEG with SD). Methods: This was a single-center, prospective, randomized, investigator-blinded, noninferiority study. The primary end point was bowel preparation quality according to the Ottawa scale. Tolerability, compliance, adverse events, sleep quality and polyp/adenoma detection were also assessed. Results: Among 197 patients analyzed (mean age 54.6 years, 51.3% men), 97 received LV-PEG with TM and 100 received SV-PEG with SD. The Ottawa score for the total colon was 3.76 ± 2.07 in the LV-PEG with TM group and 3.67 ± 1.57 in the SV-PEG with SD group (p = 0.723; difference 0.09, 95% confidence interval -0.60 to 0.42). The compliance was high (more than 95%) in both groups (p = 0.621). PEG was easier to ingest for patients in the LV-PEG with TM group compared to the SV-PEG with SD group [visual analogue scale (VAS) for difficulty: 4.64 ± 2.46 vs. 5.97 ± 2.42, respectively; p < 0.001]. Diet instructions were also easier to comply with for patients in the LV-PEG with TM group compared to the SV-PEG with SD group (VAS for difficulty: 3.11 ± 2.25 vs. 4.00 ± 2.39, respectively; p = 0.008). Patients in the LV-PEG with TM group had a lower incidence of abdominal bloating (p = 0.012) and better sleep quality (p < 0.001). There was no difference between the groups regarding polyp and adenoma detection. Conclusions: LV-PEG with TM and SV-PEG with SD have similar efficacy with regard to bowel preparation for colonoscopy. LV-PEG with TM provided easier PEG intake and diet compliance, less abdominal bloating and better sleep quality than SV-PEG with SD. 23856327 Analysis of 10 years drug lifecycle management (LCM) activities in the Japanese market. We investigated drug lifecycle management (LCM) activities in the Japanese market by examining new and updated approvals by the Pharmaceuticals and Medical Devices Agency (PMDA) between 2001 and 2010. PMDA gave a total of 726 approvals, of which 263 and 463 were new and updated approvals, respectively. Approvals for new indication comprised of more than 60% of updated approvals regardless of chemical or biological entities, therapeutic area and the company nationality. The case study on anti-rheumatoid arthritis biologics showed that the addition of new indications accelerated their sales exponentially. Thus, the development of new indications is an effective LCM approach for creation of new values of existing drugs. 23877570 Kynurenine Increases Matrix Metalloproteinase-1 and -3 expression in Cultured Dermal Fibroblasts and Improves Scarring in vivo. We previously demonstrated that the formation of hypertrophic scarring on the wounds of a rabbit ear fibrotic model was significantly reduced by grafting a bilayer skin substitute expressing indoleamine 2, 3-dioxygenase (IDO). Here, we hypothesize that the improved healing quality is due to ECM modulatory effect of IDO-mediated tryptophan metabolites. To test this hypothesis, a series of in vitro and in vivo experiments were conducted and the findings revealed a significant increase in the expression of MMP-1 in fibroblasts either transduced with human IDO gene or cultured with conditioned media obtained from IDO-expressing cells. Consistent with this finding, Kyn treatment markedly increased the levels of MMP-1 and MMP-3 expression through activation of the MEK-ERK1/2 MAPK signaling pathway. On the other hand, Kyn significantly suppressed the expression of type I collagen in fibroblasts as compared to that of control. To test the anti-fibrogenic effect of Kyn in an in vivo model, rabbit ear fibrotic wounds were topically treated with cream containing 50 μg Kyn /l00 μl of cream per wound. The result showed a marked improvement in scar formation relative to the controls. These findings collectively suggest that Kyn can potentially be used as an anti-fibrogenic agent for treating hypertrophic scarring.Journal of Investigative Dermatology accepted article preview online, 22 July 2013. doi:10.1038/jid.2013.303. 23485033 Cognitive outcome in adolescents and young adults after repeat courses of antenatal corticosteroids. To investigate whether repeat courses of antenatal corticosteroids have long-term effects on cognitive and psychological functioning. In a prospective cohort study, 58 adolescents and young adults (36 males) who had been exposed to 2-9 weekly courses of betamethasone in utero were assessed with neuropsychological tests and behavior self-reports. Unexposed subjects (n = 44, 25 males) matched for age, sex, and gestational age at birth served as a comparison group. In addition, individuals exposed in utero to a single course (n = 25, 14 males) were included for dose-response analysis. Group differences were investigated using multilevel linear modeling. Mean scores obtained in 2 measures of attention and speed were significantly lower in subjects exposed to 2 or more antenatal corticosteroids courses (Symbol Search, P = .009; Digit Span Forward, P = .02), but these were not dose-dependent. Exposure to repeat courses of antenatal corticosteroids was not associated with general deficits in higher cognitive functions, self-reported attention, adaptability, or overall psychological function. Although this study indicates that repeat exposure to antenatal corticosteroids may have an impact on aspects of executive functioning, it does not provide support for the prevailing concern that such fetal exposure will have a major adverse impact on cognitive functions and psychological health later in life. 23347071 Supramolecular hydrogels from in situ host-guest inclusion between chemically modified cellulose nanocrystals and cyclodextrin. When grafted β-cyclodextrin is used as targeting sites, Pluronic polymers have been introduced on the surface of cellulose nanocrystals by means of inclusion interaction between β-cyclodextrin and hydrophobic segment of the polymer. Because of the steric stabilization effect, surface poly(ethylene glycol) chains facilitate the dispersion and compatibility of nanocrystals, which also enhance the loading levels of nanocrystals in the hydrogel system. Meanwhile, uncovered poly(ethylene glycol) segments render the participating inclusion of α-cyclodextrin for the architecture of in situ hydrogels. Surface grafting and inclusion reactions were proved by solid (13)C NMR and FTIR. Grafting efficiency of β-cyclodextrin and inclusion efficiency of Pluronic on the surface of nanocrystals were confirmed by UV spectroscopy and elemental analysis. A significant enhancement of the structural and thermal stability of in situ hydrogels with high loading levels of modified nanocrystals (>5.77 wt %) was observed by rheological analysis. Further study reveals the performance and behavior of hydrogels under a different pH environment. Finally, in situ hydrogels were used as drug carrier for in vitro release of doxorubicin and exhibit the behavior of prolonged drug release with special release kinetics. 23444173 Functional studies of MP62 during male chromatin decondensation in sea urchins. In amphibians, sperm histone transition post-fertilization during male pronucleus formation is commanded by histone chaperone Nucleoplasmin (NPM). Here, we report the first studies to analyze the participation of a Nucleoplasmin-like protein on male chromatin remodeling in sea urchins. In this report, we present the molecular characterization of a nucleoplasmin-like protein that is present in non fertilized eggs and early zygotes in sea urchin specie Tetrapygus niger. This protein, named MP62 can interact with sperm histones in vitro. By male chromatin decondensation assays and immunodepletion experiments in vitro, we have demonstrated that this protein is responsible for sperm nucleosome disorganization. Furthermore, as amphibian nucleoplasmin MP62 is phosphorylated in vivo immediately post-fertilization and this phosphorylation is dependent on CDK-cyclin activities found after fertilization. As we shown, olomoucine and roscovitine inhibits male nucleosome decondensation, sperm histone replacement in vitro and MP62 phosphorylation in vivo. This is the first report of a nucleoplasmin-like activity in sea urchins participating during male pronucleus formation post-fecundation. 23394402 Surface structures of PDMS incorporated with quaternary ammonium salts designed for antibiofouling and fouling release applications. Poly(dimethylsiloxane) (PDMS) materials have been extensively shown to function as excellent fouling-release (FR) coatings in the marine environment. The incorporation of biocide moieties, such as quaternary ammonium salts (QAS), can impart additional antibiofouling properties to PDMS-based FR coating systems. In this study, the molecular surface structures of two different types of QAS-incorporated PDMS systems were investigated in different chemical environments using sum frequency generation vibrational spectroscopy (SFG). Specifically, a series of PDMS coatings containing either a QAS with a single ammonium salt group per molecule or a quaternary ammonium-functionalized polyhedral oligomeric silsesquioxane (Q-POSS) were measured with SFG in air, water, and artificial seawater (ASW) to investigate the relationships between the interfacial surface structures of these materials and their antifouling properties. Although previous studies have shown that the above-mentioned materials are promising contact-active antifouling coatings, slight variations of the QAS structure can lead to substantial differences in the antifouling performance. Indeed, the SFG results presented here indicated that the surface structures of these materials depend on several factors, such as the extent of quaternization, the molecular weight of the PDMS component, and the functional groups of the QAS used for incorporation into the PDMS matrix. It was concluded that in aqueous environments a lower extent of Q-POSS quaternization and the use of ethoxy (instead of methoxy) functional groups for QAS incorporation facilitated the extension of the alkyl chains away from the nitrogen atom of the QAS on the surface. The SFG results correlated well with the antifouling activity studies that indicated that the coatings exhibiting a lower concentration of longer alkyl chains protruding out of the surface can neutralize microorganisms more effectively, ultimately leading to better antifouling performance. Furthermore, the results of this study provide additional evidence that incorporated QAS exert their antimicrobial activity through a two-step interaction. The first step is the adsorption of the bacteria on the surface as a result of the electrostatic attraction between the negatively charged microorganisms and the positively charged QAS nitrogen atoms on the surface. The second step is the disruption of the cell membranes by the penetration of the QAS long, extended alkyl chains. 23558055 Sjögren's syndrome and aromatase inhibitors treatment: is there a link? - 23643917 Conjugation of succinic acid to non-ionogenic amphiphilic polymers modulates their interaction with cell plasma membrane and reduces cytotoxic activity. Pluronic block copolymers L61 and L121 were reacted with succinic anhydride to produce, respectively, their mono- and bisderivatives with succinic acid. The critical micelle concentration of Pluronics decreased after modification. The modification of Pluronic L61 promoted its association with the plasma membrane of human cells and increased membrane damage, while the membranotropic activity of modified Pluronic L121 reduced compared to the initial copolymer. Modified Pluronics interfered with the viability, apoptosis induction and metabolism of A549 cells and skin fibroblasts to a much lesser extent presumably due to the introduction of succinic acid residue inhibited intracellular penetration of copolymers. Modified Pluronic L121 promoted the cellular uptake of doxorubicin and rhodamine 123 in A549 cells attributed to the inhibition of membrane P-glycoprotein. Our study provides an approach to assessing the mechanism of interaction of amphiphilic polymers with living cells and demonstrates that Pluronic-succinic acid conjugates can be used as safe and efficient modulators of intracellular drug delivery. 23608222 Cephalic phase insulin secretion is KATP channel-independent. Glucose-induced insulin secretion from pancreatic ß-cells depends critically on activity of ATP-sensitive K+ channels (KATP channel). We previously generated mice lacking Kir6.2, the pore subunit of the ß-cell KATP channel (Kir6.2-/-), that show almost no insulin secretion in response to glucose in vitro. In the present study, we compared insulin secretion by voluntary feeding (self-motivated, oral nutrient ingestion) and by forced feeding (intra-gastric nutrient injection via gavage) in wild-type (Kir6.2+/+) and Kir6.2-/- mice. Under ad libitum feeding or during voluntary feeding of standard chow, blood glucose levels and plasma insulin levels were similar in Kir6.2+/+ and Kir6.2-/- mice. By voluntary feeding of carbohydrate alone, insulin secretion was induced significantly in Kir6.2-/- mice, but was markedly attenuated compared to that in Kir6.2+/+ mice. On forced feeding of standard chow or carbohydrate alone, the insulin secretory response was markedly impaired or completely absent in Kir6.2-/- mice. Pre-treatment of a muscarine receptor antagonist, atropine methyl nitrate, which does not cross the blood-brain barrier, almost completely blocked insulin secretion induced by voluntary feeding of standard chow or carbohydrate in Kir6.2-/- mice. Substantial glucose-induced insulin secretion was induced in pancreas perfusion study of Kir6.2-/- mice only in the presence of carbamylcholine. These results suggest that a KATP channel-independent mechanism mediated by the vagal nerve plays a critical role in insulin secretion in response to nutrients in vivo. 23809872 Ethanol drinking in withdrawal seizure-prone and -resistant selected mouse lines. Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) mouse lines were bidirectionally selectively bred, respectively, to have severe or mild ethanol withdrawal handling-induced convulsions (HICs) after cessation of 3 days of ethanol vapor inhalation. Murine genotypes with severe withdrawal have been found to show low ethanol consumption, and high consumers show low withdrawal. An early drinking study with WSP and WSR mice showed modest evidence consistent with this genetic correlation, but there were several limitations to that experiment. We therefore conducted a thorough assessment of two bottle ethanol preference drinking in both replicate pairs of WSP/WSR selected lines in mice of both sexes. Greater preference drinking of WSR-2 than WSP-2 female mice confirmed the earlier report. However, in the parallel set of selected lines, the WSP-1 mice drank more than the WSR-1s. Naive mice tested for preference for sucrose, saccharin and quinine did not differ markedly for any tastant. Finally, in a test of binge-like drinking, Drinking in the Dark (DID), WSP mice drank more than WSR mice and attained significantly higher (but still modest) blood ethanol concentrations. Tests of acute withdrawal after DID showed a mild, but significant elevation in handling-induced convulsions in the WSP line. These results provide further evidence that 2-bottle ethanol preference and DID are genetically distinguishable traits. 23915160 Morphology of the claw closer muscle in two estuarine crab species (crustacea, varunidae): an ultrastructural study. We analyzed the ultrastructural features of the claw closer muscles in two estuarine crabs, Cyrtograpsus angulatus and Neohelice granulata, by transmission electron microscopy. Adult male crabs at intermolt stage were collected in the Mar Chiquita Coastal Lagoon (Buenos Aires, Argentina). The muscle fibers of both species showed evident striations, peripheral and intermyofibrillar nuclei, clefts in continuity with T and Z tubules, sarcoplasmic reticulum and T tubules forming dyads and triads usually located between the A and I bands, and mitochondria located mainly beneath the sarcolemma. Glycogen was observed as diffuse, small particles among myofilaments. The claw closer muscle of C. angulatus exhibited two fiber types: one with relatively fast-contracting fibers (shorter sarcomeres, myofilaments with an ordered arrangement, lineal Z discs, a well-developed sarcotubular system) and fatigue-resistant (numerous large mitochondria); and the other type, with slower-contracting fibers (longer sarcomeres, less orderly arranged myofilaments, wavy Z discs, a less developed sarcotubular system) and less resistant to fatigue (lower mitochondrial density). N. granulata showed only the slow, less resistant to fatigue type. The fibers less resistant to fatigue and more slowly contracting would presumably be used primarily for displays and agonistic interactions, whereas fast fibers with abundant mitochondria would be associated with continuous movements during feeding and grooming. 23904995 Genome-wide analysis of 3'-untranslated regions supports the existence of post-transcriptional regulons controlling gene expression in trypanosomes. In eukaryotic cells, a group of messenger ribonucleic acids (mRNAs) encoding functionally interrelated proteins together with the trans-acting factors that coordinately modulate their expression is termed a post-transcriptional regulon, due to their partial analogy to a prokaryotic polycistron. This mRNA clustering is organized by sequence-specific RNA-binding proteins (RBPs) that bind cis-regulatory elements in the noncoding regions of genes, and mediates the synchronized control of their fate. These recognition motifs are often characterized by conserved sequences and/or RNA structures, and it is likely that various classes of cis-elements remain undiscovered. Current evidence suggests that RNA regulons govern gene expression in trypanosomes, unicellular parasites which mainly use post-transcriptional mechanisms to control protein synthesis. In this study, we used motif discovery tools to test whether groups of functionally related trypanosomatid genes contain a common cis-regulatory element. We obtained conserved structured RNA motifs statistically enriched in the noncoding region of 38 out of 53 groups of metabolically related transcripts in comparison with a random control. These motifs have a hairpin loop structure, a preferred sense orientation and are located in close proximity to the open reading frames. We found that 15 out of these 38 groups represent unique motifs in which most 3'-UTR signature elements were group-specific. Two extensively studied Trypanosoma cruzi RBPs, TcUBP1 and TcRBP3 were found associated with a few candidate RNA regulons. Interestingly, 13 motifs showed a strong correlation with clusters of developmentally co-expressed genes and six RNA elements were enriched in gene clusters affected after hyperosmotic stress. Here we report a systematic genome-wide in silico screen to search for novel RNA-binding sites in transcripts, and describe an organized network of several coordinately regulated cohorts of mRNAs in T. cruzi. Moreover, we found that structured RNA elements are also conserved in other human pathogens. These results support a model of regulation of gene expression by multiple post-transcriptional regulons in trypanosomes. 23877893 Halomonas zhaodongensis sp. nov., a slightly halophilic bacterium isolated from saline-alkaline soils in Zhaodong, China. A slightly halophilic bacterium (strain NEAU-ST10-25(T)) was isolated from saline-alkaline soils in Zhaodong City, Heilongjiang Province, China. The strain is a Gram-negative, aerobic motile rod. It accumulates poly-β-hydroxyalkanoate and produces exopolysaccharide. It produces beige-yellow colonies. Growth occurs at NaCl concentrations (w/v) of 0-15 % (optimum 3 %), at temperatures of 4-60 °C (optimum 35 °C) and at pH 6-12 (optimum pH 9). Its G+C content is 53.8 mol%. Phylogenetic analyses based on the separate 16S rRNA gene and concatenation of the 16S rRNA, gyrB and rpoD genes indicate that it belongs to the genus Halomonas in the class Gammaproteobacteria. The most phylogenetically related species is Halomonas alkaliphila DSM 16354(T), with which strain NEAU-ST10-25(T) showed 16S rRNA, gyrB and rpoD gene sequence similarities of 99.2, 82.3 and 88.2 %, respectively. The results of DNA-DNA hybridization assays showed 60.47 ± 0.69 % DNA relatedness between strain NEAU-ST10-25(T) and H. alkaliphila DSM 16354(T), 42.43 ± 0.37 % between strain NEAU-ST10-25(T) and Halomonas venusta DSM 4743(T) and 30.62 ± 0.43 % between strain NEAU-ST10-25(T) and Halomonas hydrothermalis DSM 15725(T). The major fatty acids are C18:1 ω7c (62.3 %), C16:0 (17.6 %), C16:1 ω7c/C16:1 ω6c (7.7 %), C14:0 (2.9 %), C12:0 3-OH (2.8 %), C10:0 (2.1 %) and C18:1 ω9c (1.6 %) and the predominant respiratory quinone is ubiquinone 9 (Q-9). The proposed name is Halomonas zhaodongensis, NEAU-ST10-25(T) (=CGMCC 1.12286(T) = DSM 25869(T)) being the type strain. 23411171 Anti-inflammatory effects of an aqueous extract of Welsh onion green leaves in mice. The anti-inflammatory effects of an aqueous extract of Welsh onion green leaves (WOE) in mice was investigated. Administration of WOE, in the range of 0.25-1g/kg, showed a concentration dependent inhibition on paw edema development after carrageenan treatment in mice. The anti-inflammatory effects of WOE were closely attributed to decreased levels of tissue NO and tumor necrosis factor-α (TNF-α). Further evidence for WOE's protection is shown in the reduction of lipid oxidation and the increase of antioxidant enzyme activities, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPX) in vivo. Further, WOE also decreased the number of acetic acid-induced writhing responses and formalin-induced pain in the late phase in mice. Overall, the results showed that WOE might serve as a natural source of anti-inflammatory compounds. 23842664 Circular dichroism nano-imaging of two-dimensional chiral metal nanostructures. Here we report on a nanoscale circular dichroism (CD) imaging for a two-dimensional chiral pair of nanostructures to elucidate the relationship between nanoscale chirality and CD activity. The chiral pair exhibited local ellipticity as high as 42 degrees in the CD signal at the center, with signals of both handedness coexisting in one nanostructure. 23678020 Discharge properties of abductor hallucis before, during, and after an isometric fatigue task. Abductor hallucis is the largest muscle in the arch of the human foot and comprises few motor units relative to its physiological cross-sectional area. It has been described as a postural muscle, aiding in the stabilization of the longitudinal arch during stance and gait. The purpose of this study was to describe the discharge properties of abductor hallucis motor units during ramp and hold isometric contractions, as well as its discharge characteristics during fatigue. Intramuscular electromyographic recordings from abductor hallucis were made in 5 subjects; from those recordings, 42 single motor units were decomposed. Data were recorded during isometric ramp contractions at 60% maximum voluntary contraction (MVC), performed before and after a submaximal isometric contraction to failure (mean force 41.3 ± 15.3% MVC, mean duration 233 ± 116 s). Motor unit recruitment thresholds ranged from 10.3 to 54.2% MVC. No significant difference was observed between recruitment and derecruitment thresholds or their respective discharge rates for both the initial and postfatigue ramp contractions (all P > 0.25). Recruitment threshold was positively correlated with recruitment discharge rate (r = 0.47, P < 0.03). All motor units attained similar peak discharge rates (14.0 ± 0.25 pulses/s) and were not correlated with recruitment threshold. Thirteen motor units could be followed during the isometric fatigue task, with a decline in discharge rate and increase in discharge rate variability occurring in the final 25% of the task (both P < 0.05). We have shown that abductor hallucis motor units discharge relatively slowly and are considerably resistant to fatigue. These characteristics may be effective for generating and sustaining the substantial level of force that is required to stabilize the longitudinal arch during weight bearing. 23325334 Non-invasive dynamic near-infrared imaging and quantification of vascular leakage in vivo. Preclinical vascular research has been hindered by a lack of methods that can sensitively image and quantify vascular perfusion and leakage in vivo. In this study, we have developed dynamic near-infrared imaging methods to repeatedly visualize and quantify vascular leakage in mouse skin in vivo, and we have applied these methods to transgenic mice with overexpression of vascular endothelial growth factors VEGF-A or -C. Near-infrared dye conjugates were developed to identify a suitable vascular tracer that had a prolonged circulation lifetime and slow leakage into normal tissue after intravenous injection. Dynamic simultaneous imaging of ear skin and a large blood vessel in the leg enabled determination of the intravascular signal (blood volume fraction) from the tissue signal shortly after injection and quantifications of vascular leakage into the extravascular tissue over time. This method allowed for the sensitive detection of increased blood vascularity and leakage rates in K14-VEGF-A transgenic mice and also reliably measured inflammation-induced changes of vascularity and leakage over time in the same mice. Measurements after injection of recombinant VEGF-A surprisingly revealed increased blood vascular leakage and lymphatic clearance in K14-VEGF-C transgenic mice which have an expanded cutaneous lymphatic vessel network, potentially indicating unanticipated effects of lymphatic drainage on vascular leakage. Increased vascular leakage was also detected in subcutaneous tumors, confirming that the method can also be applied to deeper tissues. This new imaging method might facilitate longitudinal investigations of the in vivo effects of drug candidates, including angiogenesis inhibitors, in preclinical disease models. 23847505 Task-specific effect of transcranial direct current stimulation on motor learning. Transcranial direct current stimulation (tDCS) is a relatively new non-invasive brain stimulation technique that modulates neural processes. When applied to the human primary motor cortex (M1), tDCS has beneficial effects on motor skill learning and consolidation in healthy controls and in patients. However, it remains unclear whether tDCS improves motor learning in a general manner or whether these effects depend on which motor task is acquired. Here we compare whether the effect of tDCS differs when the same individual acquires (1) a Sequential Finger Tapping Task (SEQTAP) and (2) a Visual Isometric Pinch Force Task (FORCE). Both tasks have been shown to be sensitive to tDCS applied over M1, however, the underlying processes mediating learning and memory formation might benefit differently from anodal transcranial direct current stimulation (anodal-tDCS). Thirty healthy subjects were randomly assigned to an anodal-tDCS group or sham-group. Using a double-blind, sham-controlled cross-over design, tDCS was applied over M1 while subjects acquired each of the motor tasks over three consecutive days, with the order being randomized across subjects. We found that anodal-tDCS affected each task differently: the SEQTAP task benefited from anodal-tDCS during learning, whereas the FORCE task showed improvements only at retention. These findings suggest that anodal-tDCS applied over M1 appears to have a task-dependent effect on learning and memory formation. 23617769 Caenorhabditis elegans as a model for intracellular pathogen infection. The genetically tractable nematode Caenorhabditis elegans is a convenient host for studies of pathogen infection. With the recent identification of two types of natural intracellular pathogens of C. elegans, this host now provides the opportunity to examine interactions and defence against intracellular pathogens in a whole-animal model for infection. C. elegans is the natural host for a genus of microsporidia, which comprise a phylum of fungal-related pathogens of widespread importance for agriculture and medicine. More recently, C. elegans has been shown to be a natural host for viruses related to the Nodaviridae family. Both microsporidian and viral pathogens infect the C. elegans intestine, which is composed of cells that share striking similarities to human intestinal epithelial cells. Because C. elegans nematodes are transparent, these infections provide a unique opportunity to visualize differentiated intestinal cells in vivo during the course of intracellular infection. Together, these two natural pathogens of C. elegans provide powerful systems in which to study microbial pathogenesis and host responses to intracellular infection. 23720401 Single-Nucleotide Polymorphisms in Nucleotide Excision Repair Genes, Cigarette Smoking, and the Risk of Head and Neck Cancer. Cigarette smoking is associated with increased head and neck cancer (HNC) risk. Tobacco-related carcinogens are known to cause bulky DNA adducts. Nucleotide excision repair (NER) genes encode enzymes that remove adducts and may be independently associated with HNC, as well as modifiers of the association between smoking and HNC. Using population-based case-control data from the Carolina Head and Neck Cancer Epidemiology (CHANCE) Study (1,227 cases and 1,325 controls), race-stratified (White, African American), conventional, and hierarchical logistic regression models were used to estimate ORs with 95% intervals (I) for the independent and joint effects of cigarette smoking and 84 single-nucleotide polymorphisms (SNP) from 15 NER genes on HNC risk. The odds of HNC were elevated among ever cigarette smokers and increased with smoking duration and frequency. Among Whites, rs4150403 on ERCC3 was associated with increased HNC odds (AA+AG vs. GG; OR, 1.28; 95% CI, 1.01-1.61). Among African Americans, rs4253132 on ERCC6 was associated with decreased HNC odds (CC+CT vs. TT; OR, 0.62; 95% CI, 0.45-0.86). Interactions between ever cigarette smoking and three SNPs (rs4253132 on ERCC6, rs2291120 on DDB2, and rs744154 on ERCC4) suggested possible departures from additivity among Whites. We did not find associations between some previously studied NER variants and HNC. We did identify new associations between two SNPs and HNC and three suggestive cigarette-SNP interactions to consider in future studies. We conducted one of the most comprehensive evaluations of NER variants, identifying a few SNPs from biologically plausible candidate genes associated with HNC and possibly interacting with cigarette smoking. Cancer Epidemiol Biomarkers Prev; 22(8); 1428-45. ©2013 AACR. 23325491 Design and synthesis of some new quinazolin-4-(3H)-ones as anticonvulsant and antidepressant agents. A series of 3-[(4-substituted-benzylidene)-amino]-2-phenyl-3H-quinazolin-4-ones (5a-k) were synthesized by reacting 3-amino-2-phenyl-1H-quinazolin-4-one with p-hydroxybenzaldehyde, and then further with various alkyl/benzyl halides or substituted phenacyl bromides. The structures of the compounds were confirmed on the basis of IR, NMR, MS and elemental analysis. Anticonvulsant activities were evaluated using the MES and scPTZ tests. Some of the selected compounds were evaluated for antidepressant activity by forced swim pool test. Compound 3-[(4-butoxy-benzylidene)-amino]-2-phenyl-3H-quinazolin-4-one was emerged as the most promising anticonvulsant agent without any motor impairment effect. The whole brain GABA estimation of brain homogenate indicated that the anticonvulsant activity of above mentioned quinazolinone derivatives might be due to an increased GABA concentration. 23423713 Modulation of cytochrome P450 1 (Cyp1) by vanadium in hepatic tissue and isolated hepatocyte of C57BL/6 mice. The objective of the current study was to investigate the effect of vanadium (V(5+)) on Cyp1 expression and activity in C57BL/6 mice liver and isolated hepatocytes. For this purpose, C57BL6 mice were injected intraperitoneally with V(5+) (5 mg/kg) in the absence and presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (15 μg/kg) for 6 and 24 h. Furthermore, isolated hepatocytes from C57BL6 mice were treated with V(5+) (5, 10, and 20 μM) in the absence and presence of TCDD (1 nM) for 3, 6, 12, and 24 h. In vivo, V(5+) alone did not significantly alter Cyp1a1, Cyp1a2, or Cyp1b1 mRNA, protein, or catalytic activity levels. Upon co-exposure to V(5+) and TCDD, V(5+) significantly potentiated the TCDD-mediated induction of the Cyp1a1, Cyp1a2, and Cyp1b1 mRNA, protein, and catalytic activity levels at 24 h. In vitro, V(5+) decreased the TCDD-mediated induction of Cyp1a1 mRNA, protein, and catalytic activity levels. Furthermore, V(5+) significantly inhibited the TCDD-induced AhR-dependent luciferase activity. V(5+) also increased serum hemoglobin (Hb) levels in animals treated for 24 h. Upon treatment of isolated hepatocytes with Hb alone or in the presence of TCDD, there was an increase in the AhR-dependent luciferase activity. When isolated hepatocytes were treated for 2 h with V(5+) in the presence of TCDD, followed by replacement of the medium with new medium containing Hb, there was further potentiation to the TCDD-mediated effect. The present study demonstrates that there is a differential modulation of Cyp1a1 by V(5+) in C57BL/6 mice livers and isolated hepatocytes and demonstrates Hb as an in vivo specific modulator. 23401142 Relaxin: New Pathophysiological Aspects and Pharmacological Perspectives for an Old Protein. Human relaxin-2 (hereafter simply defined as "relaxin") is a 6-kDa peptidic hormone best known for the physiological role played during pregnancy in the growth and differentiation of the reproductive tract and in the renal and systemic hemodynamic changes. This factor can also be involved in the pathophysiology of arterial hypertension and heart failure, in the molecular pathways of fibrosis and cancer, and in angiogenesis and bone remodeling. It belongs to the relaxin peptide family, whose members comprehensively exert numerous effects through interaction with different types of receptors, classified as relaxin family peptide (RXFP) receptors (RXFP1, RXFP2, RXFP3, RXFP4). Research looks toward the in-depth examination and complete understanding of relaxin in its various pleiotropic actions. The intent is to evaluate the likelihood of employing this substance for therapeutic purposes, for instance in diseases where a deficit could be part of the underlying pathophysiological mechanisms, also avoiding any adverse effect. Relaxin is already being considered as a promising drug, especially in acute heart failure. A careful study of the different RXFPs and their receptors and the comprehension of all biological activities of these hormones will probably provide new drugs with a potential wide range of therapeutic applications in the near future. 23558695 The role of Nrf2 in the attenuation of cardiovascular disease. Oxidative stress is a component of many human diseases, including cardiovascular diseases (CVD). Exercise and various phytochemicals activate nuclear factor (erythroid-derived 2)-like 2 (Nrf2), the master regulator of antioxidant defenses, and attenuate CVD. This review highlights Nrf2 regulation by exercise and phytochemicals and the role of Nrf2 as a therapeutic target in CVD. 23759931 Neuroendocrine carcinoma of the stomach: morphologic and immunohistochemical characteristics and prognosis. Neuroendocrine carcinoma (NEC) of the stomach has been recognized as a highly malignant tumor; however, because of its rarity, limited information is available regarding its clinicopathologic characteristics. Here, we investigated the morphologic and immunohistochemical features and prognosis of 51 cases of gastric NEC. Histologically, 40 lesions were large cell type, and 11 were small cell type. The large majority of the tumors exhibited a solid growth pattern (94%), with subsets of tumors showing trabecular (18%), scirrhous (10%), or tubular growth patterns (6%). Thirty-six cases (71%) had adenocarcinoma components and/or dysplasia. Among them, 26 cases (51%) were associated with intramucosal adenocarcinoma or dysplasia. Immunohistochemically, synaptophysin, chromogranin A, and CD56 were diffusely expressed in 48 (94%), 44 (86%), and 24 cases (47%), respectively. Two recently reported neuroendocrine markers, ASH1 and NKX2.2, were diffusely positive in 12 (24%) and 17 cases (33%), respectively. The diffuse or focal expression of TTF-1 was observed in 19 cases (37%). Among the 41 patients who underwent a curative resection, 16 patients (39%) developed radiologic recurrences, and the liver was the most frequent site of recurrence (11 patients, 27%). The 3- and 5-year overall survival rates were 57.8% and 44.7%, respectively. Regarding patient outcome, none of the histologic subclassifications, including small cell versus large cell types and the presence versus the absence of adenocarcinoma components and/or dysplasia, were significant. In a multivariate analysis, curative surgery was identified as the sole independent prognostic factor (P=0.03). Although gastric NECs exhibit significant morphologic diversity, their histologic subclassification is unlikely to be of immediate clinical relevance. 23206319 A randomized trial of a low-trapping nonselective N-methyl-d-aspartate channel blocker in major depression. The high-affinity N-methyl-D-aspartate (NMDA) antagonist ketamine exerts rapid antidepressant effects but has psychotomimetic properties. AZD6765 is a low-trapping NMDA channel blocker with low rates of associated psychotomimetic effects. This study investigated whether AZD6765 could produce rapid antidepressant effects in subjects with treatment-resistant major depressive disorder (MDD). In this double-blind, randomized, crossover, placebo-controlled study, 22 subjects with DSM-IV treatment-resistant MDD received a single infusion of either AZD6765 (150 mg) or placebo on 2 test days 1 week apart. The primary outcome measure was the Montgomery-Åsberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline and 60, 80, 110, and 230 min postinfusion and on Days 1, 2, 3, and 7 postinfusion. Several secondary outcome measures were also used, including the Hamilton Depression Rating Scale. Within 80 min, Montgomery-Åsberg Depression Rating Scale scores significantly improved in subjects receiving AZD6765 compared with placebo; this improvement remained significant only through 110 min (d = .40). On the Hamilton Depression Rating Scale, a drug difference was found at 80 and 110 min and at Day 2 (d = .49). Overall, 32% of subjects responded to AZD6765, and 15% responded to placebo at some point during the trial. No difference was observed between the groups with regard to psychotomimetic or dissociative adverse effects. In patients with treatment-resistant MDD, a single intravenous dose of the low-trapping NMDA channel blocker AZD6765 was associated with rapid but short-lived antidepressant effects; no psychotomimetic effects were observed. 23750799 Rapid loss of efficacy to the antiseizure drugs lamotrigine and carbamazepine: a novel experimental model of pharmacoresistant epilepsy. Kindling is a well-established model of secondarily generalized partial seizures that is widely employed in the search for novel antiseizure drugs. During the kindling and postkindling acquisition phase, an active process of neuronal remodeling occurs. We tested the hypothesis that exposure to the voltage-gated sodium channel blockers lamotrigine (LTG) and carbamazepine (CBZ) during the period of active remodeling will lead to a diminished therapeutic effect. Two days after the last kindling stimulation, fully kindled rats were randomized to receive either 0.5% methyl cellulose (MC), LTG (30 mg/kg), or CBZ (40 mg/kg). The effect of LTG and CBZ on behavioral seizure severity and electrographic afterdischarge duration (ADD) was recorded. One week after this treatment, rats in both groups were rechallenged with LTG 30 or CBZ 40 mg/kg and their seizure score and ADD recorded. In vitro efficacy of LTG on neuronal action potentials was also evaluated using whole cell current clamp recording in hippocampal brain slices obtained from kindled control rats, LTG-sensitive kindled rats, and LTG-resistant kindled rats. When acutely administered 48 h after the last kindling stimulation, LTG and CBZ blocked the expression of behavioral seizures and reduced the ADD. In contrast, a second challenge dose of LTG or CBZ administered after a 7-day "no drug, no stimulation" period did not result in reduction of either the seizure score or the ADD. Interestingly, the potassium channel opener, ezogabine, also known as retigabine (EZG; 40 mg/kg), blocked the expression of behavioral seizures at both time points evaluated (i.e., 2 days and 9 days after last stimulation). In vivo resistance to LTG was associated with a similar reduction in the ability of LTG to limit action potential firing in CA1 neurons. LTG (50 μm) significantly decreased the number of action potentials generated by a depolarizing current pulse in neurons recorded from slices obtained from kindled control and LTG-sensitive rats, but not in slices obtained from LTG-resistant rats. Collectively, results obtained from both in vivo and in vitro studies demonstrate that even a single exposure to the sodium channel blockers LTG, or CBZ, during the postkindling remodeling phase leads to an altered pharmacologic response to these two ASDs, but not to EZG. The LTG- and CBZ-resistant amygdala kindled rats may serve as a useful model of therapy-resistant epilepsy. 23965272 Characterization of the glutamate-specific endopeptidase from Bacillus licheniformis expressed in Escherichia coli. Glutamate-specific endopeptidase from Bacillus licheniformis (GSE-BL) is widely used in peptide recovery and synthesis because of its unique substrate specificity. However, the mechanism underlying its specificity is still not thoroughly understood. In this study, the roles of the prosegment and key amino acids involved in the proteolytic activity of GSE-BL were investigated. Loss of the GSE-BL prosegment severely restricted enzymatic activity towards Z-Phe-Leu-Glu-pNA. A homologous model of GSE-BL revealed that it contains the catalytic triad "His47, Asp96 and Ser 167", which was further confirmed by site-directed mutagenesis. In vitro mutagenesis further indicated that Val2, Arg89 and His190 are essential for enzymatic activity towards Z-Phe-Leu-Glu-pNA. Moreover, the catalytic efficiency of Phe57Ala GSE-BL towards Z-Phe-Leu-Glu-pNA was 50% higher than that of the native mature GSE-BL. This is the first study to fully elucidate the key amino acids for proteolytic activity of GSE-BL. Mature GSE-BL could be obtained through self-cleavage alone when Lys at -1 position was replaced by Glu, providing a new strategy for the preparation of mature GSE-BL. This study yielded some valuable insights into the substrate specificity of glutamate-specific endopeptidase, establishing a foundation for broadening the applications of GSE-BL. 23928469 ATM is required for the repair of Topotecan-induced replication-associated double-strand breaks. DNA replication is a promising target for anti-cancer therapies. Therefore, the understanding of replication-associated DNA repair mechanisms is of great interest. One key factor of DNA double-strand break (DSB) repair is the PIK kinase Ataxia-Telangiectasia Mutated (ATM) but it is still unclear whether ATM is involved in the repair of replication-associated DSBs. Here, we focused on the involvement of ATM in homology-directed repair (HDR) of indirect DSBs associated with replication. Experiments were performed using ATM-deficient and -proficient human cells. Replication-associated DSBs were induced with Topotecan (TPT) and compared with γ-irradiation (IR). Cell survival was measured by clonogenic assay. Overall DSB repair and HDR were evaluated by detecting residual γH2AX/53BP1 and Rad51 foci, respectively. Cell cycle distribution was analysed by flow cytometry and protein expression by Western blot. ATM-deficiency leads to enhanced numbers of residual DSBs, resulting in a pronounced S/G2-block and decreased survival upon TPT-treatment. In common with IR, persisting Rad51 foci were detected following TPT-treatment. These results demonstrate that ATM is essentially required for the completion of HR-mediated repair of TPT-induced DSBs formed indirectly at replication forks. 23931017 Reconstruction of the bronchus and pulmonary artery. Sleeve lobectomy (SL) (lobectomy associated with resection and reconstruction of the bronchus, the pulmonary artery, or both) has proved to be a suitable choice for the treatment of centrally sited non-small cell lung cancer. SL for lung cancer is indicated when a tumor or an N1 lymph node infiltrates the origin of a lobar bronchus, the origin of the lobar branches of the pulmonary artery, or both but not to the extent that a pneumonectomy is required. SL can be performed safely and effectively, even after induction therapy, without an increased complication rate. 23432059 Transient Receptor Potential (TRP) Cation Channels in Diabetes. Transient Receptor Potential (TRP) proteins constitute a family of cation channels with very diverse permeation and gating properties. Likewise they have a very diverse role in mammalian physiology ranging from sensory nerve endings, the cardiac muscle to immune cells. Increasing evidence has implicated TRP channels in the pathology of diabetes, both on the level of insulin release from the pancreatic ß cells and in secondary conditions such as diabetic neuropathy, nephropathy and vasculopathy. In this review we summarize these recent findings, which all together indicate that TRP channels are interesting drug targets for the treatment of patients suffering from diabetes. 23321687 Caffeine has greater potency and efficacy than theophylline to reverse the motor impairment caused by chronic but not acute interruption of striatal dopaminergic transmission in rats. In order to assess whether caffeine and theophylline have the same potency and efficacy to reverse the impairment of motor function caused by acute or chronic interruption of striatal dopamine transmission, a comparison of their dose-response relationship was made in the acute model of haloperidol-induced catalepsy, and the chronic model of unilateral lesion of the dopamine nigrostriatal pathway with 6-hydroxydopamine. At equimolar doses, both drugs reduced catalepsy intensity and increased its onset latency in a dose-dependent fashion, showing comparable potencies and attaining the maximal effect at similar doses. Catalepsy intensity: caffeine ED50 = 24.1 μmol/kg [95% CI, 18.4-31.5]; theophylline ED50 = 22.0 μmol/kg [95% CI, 17.0-28.4]. Catalepsy latency: caffeine ED50 = 27.0 μmol/kg [95% CI, 21.1-34.6]; theophylline ED50 = 28.8 μmol/kg [95% CI, 22.5-36.7]. In one group of hemiparkinsonian rats (n = 5), caffeine caused a dose-dependent recovery of the contralateral forepaw stepping: ED50 = 2.4 μmol/kg/day [95% CI, 1.9-3.1]), reaching its maximum at the dose of 5.15 μmol/kg/day. When the treatment of these same rats was switched to 5.15 μmol/kg/day of theophylline, the stepping recovery was only 51 ± 12% of that induced by caffeine. Assessing the dose-response relationship of theophylline in another group of hemiparkinsonian rats (n = 7) revealed that it caused stepping recovery in an all-or-none fashion. Thus, the three lower doses had no effect, but at the dose of 5.15 μmol/kg/day theophylline suddenly increased the stepping to 56 ± 5% of the maximal effect observed when the treatment of these same rats was switched to an equimolar dose of caffeine. Increasing the dose of theophylline up to 15.45 μmol/kg/day caused no further stepping improvement since it was only 41 ± 6% of the maximal effect produced by caffeine at the dose of 5.15 μmol/kg/day. Given that theophylline showed less potency and efficacy than caffeine to reverse the motor impairment caused by chronic, but not acute, interruption of striatal dopaminergic transmission in rats, it is suggested that caffeine would provide more benefits than theophylline to improve the motor function in patients with Parkinson's disease. 23813010 Learning subgroup-specific regulatory interactions and regulator independence with PARADIGM. High-dimensional '-omics' profiling provides a detailed molecular view of individual cancers; however, understanding the mechanisms by which tumors evade cellular defenses requires deep knowledge of the underlying cellular pathways within each cancer sample. We extended the PARADIGM algorithm (Vaske et al., 2010, Bioinformatics, 26, i237-i245), a pathway analysis method for combining multiple '-omics' data types, to learn the strength and direction of 9139 gene and protein interactions curated from the literature. Using genomic and mRNA expression data from 1936 samples in The Cancer Genome Atlas (TCGA) cohort, we learned interactions that provided support for and relative strength of 7138 (78%) of the curated links. Gene set enrichment found that genes involved in the strongest interactions were significantly enriched for transcriptional regulation, apoptosis, cell cycle regulation and response to tumor cells. Within the TCGA breast cancer cohort, we assessed different interaction strengths between breast cancer subtypes, and found interactions associated with the MYC pathway and the ER alpha network to be among the most differential between basal and luminal A subtypes. PARADIGM with the Naive Bayesian assumption produced gene activity predictions that, when clustered, found groups of patients with better separation in survival than both the original version of PARADIGM and a version without the assumption. We found that this Naive Bayes assumption was valid for the vast majority of co-regulators, indicating that most co-regulators act independently on their shared target. http://paradigm.five3genomics.com. Supplementary data are available at Bioinformatics online. 23872284 Reaction time variability in ADHD: A meta-analytic review of 319 studies. Individuals with ADHD are characterized as ubiquitously slower and more variable than their unaffected peers, and increased reaction time (RT) variability is considered by many to reflect an etiologically important characteristic of ADHD. The present review critically evaluates these claims through meta-analysis of 319 studies of RT variability in children, adolescents, and adults with ADHD relative to typically developing (TD) groups, clinical control groups, and themselves (subtype comparisons, treatment and motivation effects). Random effects models corrected for measurement unreliability and publication bias revealed that children/adolescents (Hedges' g=0.76) and adults (g=0.46) with ADHD demonstrated greater RT variability relative to TD groups. This increased variability was attenuated by psychostimulant treatment (g=-0.74), but unaffected by non-stimulant medical and psychosocial interventions. Individuals with ADHD did not evince slower processing speed (mean RT) after accounting for RT variability, whereas large magnitude RT variability deficits remained after accounting for mean RT. Adolescents and adults with ADHD were indistinguishable from clinical control groups, and children with ADHD were only minimally more variable than clinical control children (g=0.25). Collectively, results of the meta-analysis indicate that RT variability reflects a stable feature of ADHD and other clinical disorders that is robust to systematic differences across studies. 23316023 Modern subunit vaccines: development, components, and research opportunities. Traditional vaccines, based on the administration of killed or attenuated microorganisms, have proven to be among the most effective methods for disease prevention. Safety issues related to administering these complex mixtures, however, prevent their universal application. Through identification of the microbial components responsible for protective immunity, vaccine formulations can be simplified, enabling molecular-level vaccine characterization, improved safety profiles, prospects to develop new high-priority vaccines (e.g. for HIV, tuberculosis, and malaria), and the opportunity for extensive vaccine component optimization. This subunit approach, however, comes at the expense of decreased immunity, requiring the addition of immunostimulatory agents (adjuvants). As few adjuvants are currently used in licensed vaccines, adjuvant development represents an exciting area for medicinal chemists to play a role in the future of vaccine development. In addition, immune responses can be further customized though optimization of delivery systems, tuning the size of particulate vaccines, targeting specific cells of the immune system (e.g. dendritic cells), and adding components to aid vaccine efficacy in whole immunized populations (e.g. promiscuous T-helper epitopes). Herein we review the current state of the art and future direction in subunit vaccine development, with a focus on the described components and their potential to steer the immune response toward a desired response. 23960100 Caged Naloxone Reveals Opioid Signaling Deactivation Kinetics. The spatiotemporal dynamics of opioid signaling in the brain remain poorly defined. Photoactivatable opioid ligands provide a means to quantitatively measure these dynamics and their underlying mechanisms in brain tissue. Although activation kinetics can be assessed using caged agonists, deactivation kinetics are obscured by slow clearance of agonist in tissue. In order to reveal deactivation kinetics of opioid signaling we developed a caged competitive antagonist that can be quickly photoreleased in sufficient concentrations to render agonist dissociation effectively irreversible. CNV-NLX, a caged analog of the competitive opioid antagonist naloxone (NLX), was readily synthesized from commercially available NLX in good yield and found to be devoid of antagonist activity at heterologously expressed opioid receptors. Photolysis in slices of rat locus coeruleus produced a rapid inhibition of the ionic currents evoked by multiple agonists of the mu opioid receptor (MOR), but not of α-adrenergic receptors, which activate the same pool of ion channels. Using the high-affinity peptide agonist dermorphin (DERM), we established conditions under which light-driven deactivation rates are independent of agonist concentration and thus intrinsic to the agonist-receptor complex. Under these conditions, some MOR agonists yielded deactivation rates that are limited by G-protein signaling, whereas others appeared limited by agonist dissociation. Therefore, the choice of agonist determines which feature of receptor signaling is unmasked by CNV-NLX photolysis. 23847049 Molecular modeling indicates distinct classes of missense variants with mild and severe XLRS phenotypes. X-linked retinoschisis (XLRS) is a vitreo-retinal degeneration caused by mutations in the RS1 gene which encodes the protein retinoschisin (RS1), required for the structural and functional integrity of the retina. Data are presented from a group of 38 XLRS patients from Moorfields Eye Hospital (London, UK) who had one of 18 missense mutations in RS1. Patients were grouped based on mutation severity predicted by molecular modeling: mild (class I), moderate (intermediate) and severe (class II). Most patients had an electronegative scotopic bright flash electroretinogram  (ERG) (reduced b/a-wave ratio) in keeping with predominant inner retinal dysfunction. An association between the type of structural RS1 alterations and the severity of b/a-wave reduction was found in all but the oldest group of patients, significant in patients aged 15-30 years. Severe RS1 missense changes were associated with a lower ERG b/a ratio than were mild changes, suggesting that the extent of inner retinal dysfunction is influenced by the effect of the mutations on protein structure. The majority of class I mutations showed no changes involving cysteine residues. Class II mutations caused severe perturbations due to the removal or insertion of cysteine residues or due to changes in the hydrophobic core. The ERG b/a ratio in intermediate cases was abnormal but showed significant variability, possibly related to the role of proline or arginine residues. We also conducted a second study, using a completely independent cohort, to indicate a genotype-ERG phenotype correlation. 23939296 Corneal Sensation After Small-Incision Lenticule Extraction. To compare effects of small-incision lenticule extraction (SMILE) and femtosecond laser-assisted in situ keratomileusis (F-LASIK) on corneal sensation and dry eye parameters. In this prospective, randomized, contralateral-eye study, 28 patients with myopia or myopic astigmatism in both eyes were enrolled. One eye of each patient was treated by SMILE, and the fellow eye was treated by F-LASIK. Mean outcome measures Cochet-Bonnet esthesiometry, Schirmer test with anesthesia, tear breakup time, and tear film osmolarity were evaluated preoperatively as well as 1 week, 1 month, 3 months, and 6 months after surgery. Corneal sensation was reduced after both SMILE and F-LASIK surgeries 1 week, 1 month, and 3 months after surgery (p < 0.05 in both groups). Corneal sensation was significantly lower after F-LASIK than after SMILE at postoperative 1 week, 1 month, and 3 months (p < 0.01 for all points). Dry eye parameters such as tear breakup time, Schirmer test, and tear film osmolarity did not change significantly in any of the procedures and were not significantly different between the procedures at any follow-up visits. The findings of the study revealed that, although both F-LASIK and SMILE procedures changed the corneal sensation 1 week, 1 month, and 3 months after surgery, they did not affect the dry eye parameters at any point. 23921521 Therapeutic Decisions in Multiple Sclerosis: Moving Beyond Efficacy. Several innovative disease-modifying treatments (DMTs) for relapsing-remitting multiple sclerosis have been licensed recently or are in late-stage development. The molecular targets of several of these DMTs are well defined. All affect at least 1 of 4 properties, namely (1) trafficking, (2) survival, (3) function, or (4) proliferation. In contrast to β-interferons and glatiramer acetate, the first-generation DMTs, several newer therapies are imbued with safety issues, which may be attributed to their structure or metabolism. In addition to efficacy, understanding the relationship between the mechanism of action of the DMTs and their safety profile is pertinent for decision making and patient care. In this article, we focus primarily on the safety of DMTs in the context of understanding their pharmacological characteristics, including molecular targets, mechanism of action, chemical structure, and metabolism. While understanding mechanisms underlying DMT toxicities is incomplete, it is important to further develop this knowledge to minimize risk to patients and to ensure future therapies have the most advantageous benefit-risk profiles. Recognizing the individual classes of DMTs described here may be valuable when considering use of such agents sequentially or possibly in combination. 23883698 Acute kidney injury is a frequent complication in critically ill neonates on extracorporeal membrane oxygenation: a 14-year cohort study. Newborns in need of extracorporeal membrane oxygenation (ECMO) support are at high risk of developing acute kidney injury (AKI). AKI may occur as part of multiple organ failure and can be aggravated by exposure to components of the extracorporeal circuit. AKI necessitates adjustment of dosage of renally eliminated drugs and avoidance of nephrotoxic drugs. We aimed to systematically define the incidence and clinical course of AKI in critically ill neonates receiving ECMO support. This study reviewed prospectively collected clinical data (including age, diagnosis, ECMO course, and serum creatinine [SCr]) of all ECMO-treated neonates within our institution spanning a fourteen-year period. AKI was defined using the Risk, Injury, Failure, Loss of renal function, and End-stage renal disease (RIFLE) classification. SCr data were reviewed per ECMO day and compared to age-specific SCr reference values. Accordingly, patients were assigned to RIFLE categories (Risk, Injury, or Failure as 150%, 200% or 300% of median SCr reference values). Data are presented as median and interquartile range (IQR) or number and percentage (%). 242 patients were included of whom 179 survived (74%). Median age at start ECMO was 39 hours [IQR 26 - 63]; median ECMO duration was 5.8 days [IQR 3.9 - 9.4]. 153 patients (64%) had evidence of AKI, with 72 (30%) qualifying as Risk, 55 (23%) as Injury and 26 (11%) as Failure. At the end of the study period only 71 patients (46%) out of all 153 AKI patients improved at least one RIFLE category. Using regression analysis it was found that nitric oxide ventilation (p=0.04) and younger age at start ECMO (p=0.004) were significant predictors of AKI. Survival until intensive care unit discharge was significantly lower for patients in the Failure category (35%) as compared to the Non-AKI (78%), Risk (82%) and Injury category (76%), with all p<0.001, while there were no significant differences between the three latter RIFLE categories. Two thirds of neonates on ECMO suffered from AKI, with a significantly increased mortality risk for patients in the Failure category. As AKI during childhood may predispose for chronic kidney disease in adulthood, long-term monitoring of kidney function after ECMO is warranted. 23474589 Changes in Insulin Resistance and HbA1c Are Related to Exercise-Mediated Changes in Body Composition in Older Adults With Type 2 Diabetes: Interim outcomes from the GREAT2DO Trial. OBJECTIVETo investigate changes in body composition after 12 months of high-intensity progressive resistance training (PRT) in relation to changes in insulin resistance (IR) or glucose homeostasis in older adults with type 2 diabetes.RESEARCH DESIGN AND METHODSOne-hundred three participants were randomized to receive either PRT or sham exercise 3 days per week for 12 months. Homeostatic model of assessment 2 (HOMA2-IR) and glycosylated hemoglobin (HbA1c) were used as indices of IR and glucose homeostasis. Skeletal muscle mass (SkMM) and total fat mass were assessed using bioelectrical impedance. Visceral adipose tissue, mid-thigh cross-sectional area, and mid-thigh muscle attenuation were quantified using computed tomography.RESULTSWithin the PRT group, changes in HOMA2-IR were associated with changes in SkMM (r = -0.38; P = 0.04) and fat mass (r = 0.42; P = 0.02). Changes in visceral adipose tissue tended to be related to changes in HOMA2-IR (r = 0.35; P = 0.07). Changes in HbA1c were related to changes in mid-thigh muscle attenuation (r = 0.52; P = 0.001). None of these relationships were present in the sham group (P > 0.05). Using ANCOVA models, participants in the PRT group who had increased SkMM had decreased HOMA2-IR (P = 0.05) and HbA1c (P = 0.09) compared with those in the PRT group who lost SkMM. Increases in SkMM in the PRT group decreased HOMA2-IR (P = 0.07) and HbA1c (P < 0.05) compared with those who had increased SkMM in the sham group.CONCLUSIONSImprovements in metabolic health in older adults with type 2 diabetes were mediated through improvements in body composition only if they were achieved through high-intensity PRT. 23440867 Promising new molecular targeted therapies in head and neck cancer. Despite advances in multimodality therapies for the treatment of squamous cell carcinoma of the head and neck (SCCHN), survival rates, functional outcomes and toxicities of therapy remain poor. The recognition of the prognostic value of human papillomavirus (HPV) status, and the advent of biologically targeted therapies with potential for decreased toxicities and increased selectivity, represent significant developments in our understanding of SCCHN. Targeted agents currently approved or under investigation for SCCHN include epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab, panitumumab, zalutumumab, nimotuzumab), EGFR tyrosine kinase inhibitors (gefitinib, erlotinib, lapatinib, afatanib, dacomitinib), vascular endothelial growth factor receptor (VEGFR) inhibitors (bevacizumab, sorafenib, sunitinib, vandetanib) and various inhibitors of other pathways and targets, including phosphatidylinositol 3' kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), MET and insulin-like growth factor receptor (IGF-1R). On-going clinical trials are evaluating these emerging agents and their combinations in the treatment of SCCHN. 23941871 A form of Mitofusin 2 (Mfn2) lacking the transmembrane domains and the C-terminal end stimulates metabolism in muscle and liver cells. Mitofusin 2 (Mfn2), a protein that participates in mitochondrial fusion, is required to maintain normal mitochondrial metabolism in skeletal muscle and in liver. Given that muscle Mfn2 is repressed in obese or type 2 diabetic subjects, this protein may have a potential pathophysiological role in these conditions. In order to evaluate whether the metabolic effects of Mfn2 can be dissociated from its function in mitochondrial dynamics, we have studied a form of Mfn2, lacking the two transmembrane domains and the C-terminal coiled-coil (Mfn2). This form localized in mitochondria but did not alter mitochondrial morphology in cells or in skeletal muscle fibers. The expression of Mfn2 in mouse skeletal muscle stimulated glucose oxidation and enhanced respiratory control ratio, which occurred in the absence of changes in mitochondrial mass. The expression of Mfn2 in mouse liver or in hepatoma cells stimulated gluconeogenesis. In addition, Mfn2 activated basal and maximal respiration both in muscle and liver cells. In all, we show that a form of Mfn2 lacking mitochondrial fusion activity stimulates mitochondrial function, and enhances glucose metabolism in muscle and liver tissues. This study suggests that Mfn2 regulates metabolism independently of changes in mitochondrial morphology. 23928968 Cover picture: eur. J. Immunol. 8'13. This month's colorful cover features mouse bone marrow-derived dendritic cells (DCs) that were treated with H2 O2 for 10 minutes on ice. DNA damage was evaluated by single-cell gel electrophoresis (also known as the comet assay) and stained with SYBR® Green for DNA visualization. The image was taken from Licandro et al., (pp. 2126-2137) in which the authors show that DNA damage is reduced in Nlrp3(-/-) DCs. The authors also demonstrate that Nlrp3(-/-) DCs had lower levels of cell death compared with wildtype DCs in response to danger signals. These findings provide evidence for the involvement of the NLRP3 inflammasome in the DNA damage response induced by cellular stress. The image was digitally-colored using CometScore® software for aesthetic purposes. 23644050 Sensory and consumer evaluation of pork loins from crossbreeds between Danish Landrace, Yorkshire, Duroc, Iberian and Mangalitza. Iberian (I) and Mangalitza (M) boars were crossed with Duroc (D) and Landrace/Yorkshire (LY) sows and compared with the traditional crossbreed DLY. The sensory attributes were analysed, and consumers evaluated the fried loins. Gas chromatography (GC) aroma analysis was performed on the fried meat, and fatty acid composition was determined on the loin and the subcutaneous fat, respectively. No marked differences were found in odour, appearance or flavour/taste between the alternative crossbreeds and DLY; however, the alternative crossbreeds had improved textural properties. Consumer evaluation revealed that the alternative crossbreeds obtained positive associations compared with DLY, and MD was ranked best or second best by almost 60% of the consumers. No pronounced differences were found in the aroma compounds between the different crossbreeds. Correlations were found between the fatty acid composition and sensory attributes. In conclusion, by crossing the alternative breeds Iberian and Mangalitza with traditional Danish pig breeds it is possible to produce pork with attractive sensory attributes. 23893938 Polyurethanes: Versatile Materials and Sustainable Problem Solvers for Today's Challenges. Polyurethanes are the only class of polymers that display thermoplastic, elastomeric, and thermoset behavior depending on their chemical and morphological makeup. In addition to compact polyurethanes, foamed variations in particular are very widespread, and they achieve their targeted properties at very low weights. The simple production of sandwich structures and material composites in a single processing step is a key advantage of polyurethane technology. The requirement of energy and resource efficiency increasingly demands lightweight structures. Polyurethanes can serve this requirement by acting as matrix materials or as flexible adhesives for composites. Polyurethanes are indispensable when it comes to high-quality decorative coatings or maintaining the value of numerous objects. They are extremely adaptable and sustainable problem solvers for today's challenges facing our society, all of which impose special demands on materials. 23877303 Biochemical and thermodynamic characteristics of thermo-alkali-stable xylanase from a novel polyextremophilic Bacillus halodurans TSEV1. The purified extracellular xylanase of polyextremophilic Bacillus halodurans TSEV1 has been visualized as a single band on SDS-PAGE and eluted as single peak by gel filtration, with a molecular mass of 40 kDa. The peptide finger print and cloned xylanase gene sequence analyses indicate that this enzyme belongs to GH family 10. The active site carboxyl residues are mainly involved in catalysis, while tryptophan residues are involved in substrate binding. The enzyme is optimally active at 80 °C and pH 9.0, and stable in the pH range of 7.0-12.0 with T 1/2 of 35 min at 80 °C (pH 9.0). Activation energy for birch wood xylan hydrolysis is 30.51 kJ mol(-1). The K m, V max and k cat (birchwood xylan) are 2.05 mg ml(-1), 333.33 Î¼mol mg(-1 )min(-1) and 3.33 Ã— 10(4) min(-1), respectively. The pKa1 and pKa2 of ionizable groups of the active site that influence V max are 8.51 and 11.0. The analysis of thermodynamic parameters for xylan hydrolysis suggests this as a spontaneous process. The enzyme is resistant to chemical denaturants like urea and guanidinium-HCl. The site-directed mutagenesis of catalytic glutamic acid residues (E196 and E301) resulted in a complete loss of activity. The birch wood xylan hydrolyzate contained xylobiose and xylotriose as the main products without any trace of xylose, and the enzyme hydrolyzes xylotetraose and xylopentaose rapidly to xylobiose. Thermo-alkali-stability, resistance to various chemical denaturants and mode of action make it a useful biocatalyst for generating xylo-oligosaccharides from agro-residues and bleaching of pulp in paper industries. 22860635 No evidence for treating friends' children like kin in canadian androphilic men. Given that same-sex sexual orientation is associated with lower reproductive success, how have genes associated with male androphilia (i.e., male sexual attraction/arousal to adult men) persisted over evolutionary time? The Kin Selection Hypothesis proposes that by directing valuable resources toward kin, androphilic men may enhance their indirect fitness and thereby offset the fitness costs of not reproducing directly. Support for this hypothesis has been garnered from studies conducted in Samoa, but not from studies of "gay" men in industrialized cultures (i.e., Canada, Japan, United Kingdom, and the United States). This cross-cultural difference may be due to relatively greater geographic and familial disconnect experienced by androphilic "gay" men in industrialized cultures. This article reasons that in more industrialized settings, friends' children may serve as non-adaptive proxies for nieces and nephews. Hence, it was predicted that Canadian androphilic men would exhibit elevated altruistic tendencies toward their friends' children compared with gynephilic men and androphilic women. This prediction was not supported. However, in line with previous research, the results indicated that androphilic women are more likely to behave altruistically toward friends' children compared to gynephilic men. Other possible explanations for the existing cross-cultural discrepancy in altruistic tendencies toward nieces and nephews are discussed. 23924184 Assessing Interpersonal Profiles Associated With Varying Levels of Effortful Control. Research has linked individual differences in effortful control (EC) with variations in interpersonal functioning in children and adolescents. Using the Inventory of Interpersonal Problems-Short Circumplex (Hopwood, Pincus, DeMoor, & Koonce, 2008), this study investigated interpersonal problem profiles associated with EC in 763 nonclinical young adults. We found that individuals with low EC reported intrusive interpersonal problems and high levels of interpersonal distress, whereas individuals with high EC reported cold interpersonal problems but low levels of interpersonal distress. Results suggest that EC might play an important role in shaping interpersonal functioning. 23881450 The development of regional functional connectivity in preterm infants into early childhood. Resting state networks are proposed to reflect the neuronal connectivity that underlies cognitive processes. Consequently, abnormal behaviour of these networks due to disease or altered development may predict poor cognitive outcome. To understand how very preterm birth may affect the development of resting state connectivity, we followed a cohort of very preterm-born infants from birth through to 4 years of age using resting state functional MRI. From a larger longitudinal cohort of infants born very preterm (<32 weeks gestational age), 36 at birth, 30 at term, 21 two-year and 22 four-year resting state fMRI datasets were acquired. Using seed-based connectivity analyses with seeds in the anterior cingulate cortex, posterior cingulate cortex, left and right motor-hand regions and left and right temporal lobes, we investigated local and inter-region connectivity as a function of group and age. We found strong local connectivity during the preterm period, which matured into inter-hemispheric and preliminary default-mode network correlations by 4 years of age. This development is comparable to the resting state networks found in term-born infants of equivalent age. The results of this study suggest that differences in developmental trajectory between preterm-born and term-born infants are small and, if present, would require a large sample from both populations to be detected. 23841612 The mitochondrial genome of the pinewood nematode (Bursaphelenchus xylophilus) lineage introduced in Europe. Abstract The pinewood nematode (PWN) Bursaphelenchus xylophilus is the causative agent of pine wilt disease and the greatest biological threat to conifer forests worldwide. Here we describe the near-complete mitochondrial DNA (mtDNA) sequence (12,945 bp) of the PWN lineage recently introduced in Europe. The absence of polymorphisms across the mtDNA of three Portuguese isolates suggests that a single mitochondrial lineage was introduced in southwestern Europe. We also found that Portuguese isolates have an incomplete stop codon (TA) at COX3, while the reference mtDNA from a South Korean isolate has a complete stop codon (TAA). Moreover, two insertion/deletion polymorphisms change the ND4 protein in a stretch of seven amino acids, and a polymorphic mononucleotide repeat alters the predicted structure of the tyrosine tRNA in different geographical isolates. Overall, the new PWN mtDNA sequence provides a basis for studying the European dispersion of this important invasive species. 23587837 Structure-activity relationships of hybrid annonaceous acetogenins: Powerful growth inhibitory effects of their connecting groups between heterocycle and hydrophobic carbon chain bearing THF ring on human cancer cell lines. Five novel hybrid molecules of annonaceous acetogenins and insecticides targeting mitochondrial complex I were synthesized and their growth inhibitory activities against 39 human cancer cell lines were investigated. It was revealed that the connecting group between the N-methylpyrazole part and the hydrophobic alkyl chain bearing the THF ring influenced their biological activities significantly. Amide-connected analog 2, in particular, showed selective and very potent activity (<10 nM) against some cancer cell lines. 23911795 Predicting response to the anti-estrogen fulvestrant in recurrent ovarian cancer. Anti-estrogen therapy appears to have efficacy in a subset of ovarian cancers, as demonstrated in multiple phase II studies. Identifying sensitive patients early in treatment may allow for targeted, low-toxicity primary therapy or prevention of recurrence. We have previously demonstrated that the likelihood of response to letrozole could be improved by patient selection based on estrogen-pathway marker expression. We sought to identify ovarian cancer biomarkers that might indicate sensitivity to fulvestrant, an estrogen receptor antagonist. Tissue samples from the primary tumors of patients enrolled in a phase II study of fulvestrant for the treatment of multiply-recurrent ovarian cancer were embedded randomly in a tissue microarray (TMA). Estrogen receptor alpha (ERα) expression was assessed by both conventional immunohistochemistry (IHC) and quantitative immunofluorescence (IF) (AQUA) while expression of 14 other estrogen-regulated markers was assessed by quantitative IF and correlated with clinical outcomes. Almost half of patients experienced clinical benefit (CR+PR+SD) at 90days despite a median of 5 previous treatment regimens. 24 of 26 patient samples were available and included in the TMA. ERα expression, measured either by conventional IHC or by AQUA analysis, was associated with clinical benefit, while TFF1 and vimentin expression (measured by IF AQUA score) was predictive of progression-free survival. These results confirm our previous observation that clinical ovarian cancer includes a subset of tumors with sensitivity to estrogen pathway blockade. Expression profile of sensitive tumors appears to be detectably different from insensitive tumors, suggesting that further improvements in treatment efficacy can be obtained through appropriate patient selection. 23263897 Factors associated with the effectiveness of plasma exchange for the treatment of NMO-IgG-positive neuromyelitis optica spectrum disorders. To identify factors associated with plasma exchange response in neuromyelitis optica (NMO) spectrum disorders, the clinical and magnetic resonance imaging (MRI) features of 31 NMO-IgG-positive patients receiving plasma exchange for steroid-resistant exacerbations were analyzed. Functional improvement was observed in 65% of the patients. A lower baseline Expanded Disability Status Scale score was associated with favorable response (p = 0.040). Patients without cord atrophy had a higher success rate than patients with atrophy (p = 0.016). Levels of NMO-IgG did not differ between responders and non-responders before and after plasma exchange. In conclusion, a minimal pre-existing disability is the primary determinant of the effectiveness of plasma exchange. 23508665 Pharmacokinetics of colistin in critically ill patients with multidrug-resistant Gram-negative bacilli infection. Colistin, which had not been used widely because of nephrotoxicity and neurotoxicity, has gained clinical importance in recent times due to the resurgence of multidrug-resistant Gram-negative bacilli. Very few studies, especially pharmacokinetic studies, have been performed with intravenous colistimethate sodium, and none in India. The aim of our study was to study the single-dose and steady-state pharmacokinetics of colistin in patients with multidrug-resistant Gram-negative bacilli infections. This was a prospective open-label pharmacokinetic study done in an intensive care unit in a tertiary care hospital on 15 critically ill patients with proven multidrug-resistant Gram-negative bacilli infection. Colistimethate sodium was injected as intermittent intravenous infusions in accordance with the recommendations on the package insert. For patients weighing ≥ 60 kg with a normal renal function or with a creatinine clearance (CLCR) of between 20 and 50 ml/min, the drug was administered at 2 million international units (MIU) every 8 h; for those with a CLCR of 10-20 ml/min, the dose was 2 MIU every 12 h. Those patients who weighed <60 kg were administered 50,000 IU/kg/day in three divided doses at 8-h intervals. Both single-dose and steady-state pharmacokinetics of colistin were determined and correlated with clinical outcomes. A wide inter-individual variation was observed in pharmacokinetic parameters. The median (range) of the maximum plasma drug concentration/minimum inhibitory concentration (Cmax/MIC) ratio for Acinetobacter spp. was 13.4 (1.3-40.3) following the administration of a single dose of colistimethate sodium and 26.3 (0.9-64.9) at steady-state. For Pseudomonas spp., these values were 3.18 (1.6-23.1) following the single dose and 3.82 (2.3-10.9) at steady-state. For those patients whose cultures grew Acinetobacter spp., an optimum value of the Cmax/MIC ratio of >8 was achieved in seven of nine patients after the single dose and in seven of eight patients at steady-state. For those patients whose cultures grew Pseudomonas spp, only one patient after the single dose and one patient at steady-state achieved a Cmax/MIC ratio of >8. A significant association was noted between dose and survival, and a trend was observed with patients weighing ≤ 60 kg (who received 50,000 IU/kg/day instead of 6 MIU/day for those >60 kg) having an increased mortality. The pharmacokinetic parameters of colistin were comparable to those reported in previous studies in critically ill patients. However, the recommended dose may be inadequate to maintain the Cmax/MIC ratio to an optimal level-at least in patients infected with Pseudomonas spp. The dose recommendation should be based only on creatinine clearance and not body weight. 23949962 Domiciliary diurnal variation of fractional exhaled nitric oxide for asthma control. A major goal of asthma management is maintaining optimal control. Current assessment is based on symptoms and lung function.We evaluated whether domiciliary daily home FeNO monitoring could be useful as an index of asthma control.Fifty asthmatic subjects and 15 healthy volunteers with a range of asthma severity underwent asthma control questionnaire (ACQ), spirometry before and after salbutamol and sputum induction. FeNO and peak expiratory flow (PEF) were measured twice daily for 2 weeks. A record of exacerbations was obtained 3 months later.Diurnal FeNO variation in uncontrolled asthmatics was significantly greater than in controlled asthmatics (p<0.01). PEF variation was not different. The daily variation of FeNO levels was also greater in uncontrolled asthmatics compared to controlled asthmatic and healthy subjects (p<0.01). 80% of uncontrolled asthmatics experienced at least one or more exacerbations over the 3 months after the enrolment. The combination of diurnal FeNO variation ≥16.6% and ACQ scores ≥1.8 was best at predicting uncontrolled asthma (AUC; 0.91, 95%CI: 0.86-0.97, p<0.001).Diurnal variation in FeNO can be used as a biomarker of asthma control and as a predictor of the risk of future exacerbation. Prospective studies are warranted. 23332468 Cranial vault growth patterns of plagiocephaly and trigonocephaly patients following fronto-orbital advancement: A long-term anthropometric outcome assessment. Fronto-orbital advancement (FOA) is the most common technique used to correct plagiocephaly and trigonocephaly. The aim of this study was to investigate the cranial vault growth following FOA and to compare the growth pattern to the normal standard. Fifty-two Swiss children (25 with anterior plagiocephaly and 27 with trigonocephaly) between the surgical ages of 8 and 10 months were included in this 5-year follow-up study. A standardised time protocol (before the procedure; 6 weeks and 6 months after the surgery; and then annually until the age of six) for anthropometric skull measurements (head circumference, cranial length, and breadth and cephalic indices) was used to analyse the pre- and post-operative cranial vault growth patterns. Data were converted into the Z-score for standardised inter-centre comparison. For all the patients, a significant improvement in the shape of the cranial vault following FOA was observed. In both the plagiocephaly and trigonocephaly groups, the long-term cranial growth patterns (head circumference and cranial length and breadth) significantly differed following this procedure in comparison to those of the control group. The cephalic indices remained constant; no significant changes were found in either study population. Fronto-orbital advancement in anterior craniosynostotic patients between the ages of 8 and 10 months seems to be ideal, as the procedure promotes solid cranial vault growth, ensuring positive surgical results. 23939686 'Mediterranean' dietary pattern for the primary prevention of cardiovascular disease. The Seven Countries study in the 1960s showed that populations in the Mediterranean region experienced lower cardiovascular disease (CVD) mortality probably as a result of different dietary patterns. Later observational studies have confirmed the benefits of adherence to a Mediterranean dietary pattern on CVD risk factors. Clinical trial evidence is limited, and is mostly in secondary prevention. To determine the effectiveness of a Mediterranean dietary pattern for the primary prevention of CVD. We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 9 of 12, September 2012); MEDLINE (Ovid, 1946 to October week 1 2012); EMBASE (Ovid, 1980 to 2012 week 41); ISI Web of Science (1970 to 16 October 2012); Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database and Health Economics Evaluations Database (Issue 3 of 12, September 2012). We searched trial registers and reference lists of reviews and applied no language restrictions. We selected randomised controlled trials in healthy adults and adults at high risk of CVD. A Mediterranean dietary pattern was defined as comprising at least two of the following components: (1) high monounsaturated/saturated fat ratio, (2) low to moderate red wine consumption, (3) high consumption of legumes, (4) high consumption of grains and cereals, (5) high consumption of fruits and vegetables, (6) low consumption of meat and meat products and increased consumption of fish, and (7) moderate consumption of milk and dairy products. The comparison group received either no intervention or minimal intervention. Outcomes included clinical events and CVD risk factors. Two review authors independently extracted data and contacted chief investigators to request additional relevant information. We included 11 trials (15 papers) (52,044 participants randomised). Trials were heterogeneous in the participants recruited, in the number of dietary components and follow-up periods. Seven trials described the intervention as a Mediterranean diet. Clinical events were reported in only one trial (Women's Health Initiative 48,835 postmenopausal women, intervention not described as a Mediterranean diet but increased fruit and vegetable and cereal intake) where no statistically significant effects of the intervention were seen on fatal and non-fatal endpoints at eight years. Small reductions in total cholesterol (-0.16 mmol/L, 95% confidence interval (CI) -0.26 to -0.06; random-effects model) and low-density lipoprotein (LDL) cholesterol (-0.07 mmol/L, 95% CI -0.13 to -0.01) were seen with the intervention. Subgroup analyses revealed statistically significant greater reductions in total cholesterol in those trials describing the intervention as a Mediterranean diet (-0.23 mmol/L, 95% CI -0.27 to -0.2) compared with control (-0.06 mmol/L, 95% CI -0.13 to 0.01). Heterogeneity precluded meta-analyses for other outcomes. Reductions in blood pressure were seen in three of five trials reporting this outcome. None of the trials reported adverse events. The limited evidence to date suggests some favourable effects on cardiovascular risk factors. More comprehensive interventions describing themselves as the Mediterranean diet may produce more beneficial effects on lipid levels than those interventions with fewer dietary components. More trials are needed to examine the impact of heterogeneity of both participants and the intervention on outcomes. 23864163 Tumor-specific T-cell help is associated with improved survival in melanoma. Despite success with immune checkpoint inhibitors, clinical benefit from cancer vaccines remains elusive. Combined targeting of melanoma-specific CD4(+) and CD8(+) T-lymphocyte epitopes was associated with improved survival compared with targeting either alone, or when a nonspecific helper epitope was used. We discuss the potential role of antigen-specific CD4 help. Clin Cancer Res; 19(15); 4021-3. ©2013 AACR. 23863973 Synthesis of Pt-Ni/graphene via in situ reduction and its enhanced catalyst activity for methanol oxidation. A simple in situ reduction approach was used to obtain Pt3Ni/reduced graphene oxide (rGO) with dominant {111} facets. The catalytic activity of Pt-Ni/rGO toward methanol electro-oxidation was studied by performing cyclic voltammetry. The Pt3Ni/rGO nanocatalysts exhibited improved catalytic activity and durability. 23178986 Enhanced plasmid production in miniaturized high-cell-density cultures of Escherichia coli supported with perfluorinated oxygen carrier. A simple method for plasmid minipreps in closed 1.5 mL microcentrifuge tubes using a cultivation medium with internal substrate delivery (EnBase(®)) in combination with a two-phase perfluorodecalin (PFD) system supplying additional oxygen to the E. coli culture is described. The procedure can simply be performed on a thermoshaker using only 50 Î¼L cultivation volume. Twenty and twenty-five percent higher cell densities and plasmid concentration, respectively, were obtained with the additional oxygen delivery system when compared to cultures without PFD. Compared to standard 2 mL LB cultures ninefold higher cell densities and eightfold higher plasmid concentrations were achieved for the smaller culture volume. The μL-scale cultures can be directly utilized in further plasmid purification without any centrifugation step or the subsequent removal of the supernatant. This simplifies the routine procedure considerably. Furthermore, the new method is very robust considering the time of cultivation. Highest plasmid concentrations were already obtained after only 6 h of cultivation, but the plasmid concentration remained high (87 % of the maximum) even until 8 h of cultivation. Aside from the advantage of this method for the daily routine, we believe that it could also be applied to automated high-throughput processes. 23758290 Cross-functionalities of Bacillus deacetylases involved in bacillithiol biosynthesis and bacillithiol-S-conjugate detoxification pathways. BshB, a key enzyme in bacillithiol biosynthesis, hydrolyses the acetyl group from N-acetylglucosamine malate to generate glucosamine malate. In Bacillus anthracis, BA1557 has been identified as the N-acetylglucosamine malate deacetylase (BshB); however, a high content of bacillithiol (~70%) was still observed in the B. anthracis ∆BA1557 strain. Genomic analysis led to the proposal that another deacetylase could exhibit cross-functionality in bacillithiol biosynthesis. In the present study, BA1557, its paralogue BA3888 and orthologous Bacillus cereus enzymes BC1534 and BC3461 have been characterized for their deacetylase activity towards N-acetylglucosamine malate, thus providing biochemical evidence for this proposal. In addition, the involvement of deacetylase enzymes is also expected in bacillithiol-detoxifying pathways through formation of S-mercapturic adducts. The kinetic analysis of bacillithiol-S-bimane conjugate favours the involvement of BA3888 as the B. anthracis bacillithiol-S-conjugate amidase (Bca). The high degree of specificity of this group of enzymes for its physiological substrate, along with their similar pH-activity profile and Zn2+-dependent catalytic acid-base reaction provides further evidence for their cross-functionalities. 23679915 Medicinal Chemistry of Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors. Nicotinamide phoshophoribosyltransferase (NAMPT) plays a key role in the replenishment of the NAD pool in cells. This in turn makes this enzyme an important player in bioenergetics and in the regulation of NAD-using enzymes, such as PARPs and sirtuins. Furthermore, there is now ample evidence that NAMPT is secreted and has a role as a cytokine. An important role of either the intracellular or extracellular form of NAMPT has been shown in cancer, inflammation, and metabolic diseases. The first NAMPT inhibitors (FK866 and CHS828) have already entered clinical trials, and a surge in interest in the synthesis of novel molecules has occurred. The present review summarizes the recent progress in this field. 23885025 The Public Health Responsibility Deal: how should such a complex public health policy be evaluated? The Public Health Responsibility Deal (RD) in England was launched in 2011 as a public-private partnership which aims to 'tap into the potential for businesses and other influential organisations to make a significant contribution to improving public health by helping us to create this environment'. It has come under criticism from public health advocates and others, who have suggested that it will be ineffective or perhaps even harmful. Like many public health policies, there have also been demands to know whether it 'works'. We conducted a scoping review and used this, supplemented with interviews with stakeholders, to develop a detailed logic model of the RD (presented here) to help understand its likely outcomes and the pathways by which these may be achieved as a basis for planning an evaluation. Evaluations of complex interventions require not just assessment of effects (including outcomes), but also a clear conceptualization of the intervention and its processes. The way the RD and the pledges made by participant organizations has been presented makes it difficult at this stage to evaluate whether the RD 'works' in terms of improving health. Instead, any evaluation needs to put together a jigsaw of evidence about processes, mechanisms and potential future health and non-health impacts, in part using the current scientific evidence. This task is ongoing. 23939015 Mitophagy and neurodegeneration: The zebrafish model system. Autophagy is responsible for the degradation of cytoplasmic components and organelles such as mitochondria. The selective degradation of damaged mitochondria by autophagy is termed mitophagy, and is an important quality control mechanism. Neurons, being highly specialized cells, are particularly susceptible to defects of autophagy. Impairments in mitochondrial function and their dynamics are present in many neurodegenerative diseases, and modulators of both mitochondrial physiology and autophagy present themselves as promising therapeutic targets. Zebrafish are now established as a valuable tool for disease modeling. A wide variety of genetic and molecular techniques can be employed to highlight pathogenic processes and dissect disease pathways. This review will explore the role that zebrafish have so far played in our understanding of mitophagy in neurodegeneration, and will discuss how they might be used to drive the wider mitophagy field forward. 23887906 Complete Genome Sequences of Two Human Respiratory Syncytial Virus Genotype A Strains from India, RSV-A/NIV1114046/11 and RSV-A/NIV1114073/11. Two complete genomes of human respiratory syncytial virus subtype A (HRSV-A), with and without a 72-nucleotide duplication in the C-terminal glycoprotein G gene, were sequenced and analyzed. Characterization of these genomes will improve understanding of the diversity, emergence, virulence, pathogenicity, and transmissibility of a novel RSV-A genotype with a 72-nucleotide G gene duplication. 23857384 Risk factors for bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli in a Turkish hospital. Bloodstream infection caused by extended-spectrum beta-lactamase (ESBL)-producing pathogens has become a serious concern worldwide. The purpose of this study was to identify risk factors for bacteremia due to ESBL-producing Escherichia coli in a Turkish hospital. We retrospectively reviewed the medical records of patients with E. coli bacteremia in a tertiary care centre from January 2007 to October 2011. Data from patients such as demographic features, underlying conditions, and antibiotic exposure were analysed. A total of 113 patients with bacteremia due to E. coli were included and data from patients with ESBL-producing E. coli (case patients) were compared to those with non-ESBL-producing E. coli (control patients). The frequency of ESBL producers was 38.9% (44/113). Exposure to fluoroquinolones and cephalosporins, history of intra-abdominal surgery intervention, and presence of central venous catheteter and urinary catheteter were more frequently detected among case patients (P < 0.05). Independent risk factors for bacteremia due to ESBL-producing E. coli were exposure to fluoroquinolones (OR 13.39, 95% CI 1.28-140.03) and cephalosporins (OR 3.48, 95% CI 1.03-11.74). Previous use of fluoroquinolone and cephalosporin in patients with bacteremia caused by E. coli increased the risk for ESBL-producing strains. 23748442 ZFP36L2 is required for self-renewal of early burst-forming unit erythroid progenitors. Stem cells and progenitors in many lineages undergo self-renewing divisions, but the extracellular and intracellular proteins that regulate this process are largely unknown. Glucocorticoids stimulate red blood cell formation by promoting self-renewal of early burst-forming unit-erythroid (BFU-E) progenitors. Here we show that the RNA-binding protein ZFP36L2 is a transcriptional target of the glucocorticoid receptor (GR) in BFU-Es and is required for BFU-E self-renewal. ZFP36L2 is normally downregulated during erythroid differentiation from the BFU-E stage, but its expression is maintained by all tested GR agonists that stimulate BFU-E self-renewal, and the GR binds to several potential enhancer regions of ZFP36L2. Knockdown of ZFP36L2 in cultured BFU-E cells did not affect the rate of cell division but disrupted glucocorticoid-induced BFU-E self-renewal, and knockdown of ZFP36L2 in transplanted erythroid progenitors prevented expansion of erythroid lineage progenitors normally seen following induction of anaemia by phenylhydrazine treatment. ZFP36L2 preferentially binds to messenger RNAs that are induced or maintained at high expression levels during terminal erythroid differentiation and negatively regulates their expression levels. ZFP36L2 therefore functions as part of a molecular switch promoting BFU-E self-renewal and a subsequent increase in the total numbers of colony-forming unit-erythroid (CFU-E) progenitors and erythroid cells that are generated. 23122150 Authentication of beeswax (Apis mellifera) by high-temperature gas chromatography and chemometric analysis. Chemical characterization and authentication of beeswax of Apis mellifera was performed by high temperature capillary gas chromatography coupled to electron impact mass spectrometry or to flame ionisation detection and chemometric analysis. Many major components (>50) of beeswax, odd and even hydrocarbons, oleofin, palmitate, oleate and hydroxypalmitate monoesters were detected, and for the first time palmitate and oleate monoesters esterified with 1-octadecanol and 1-eicosanol are reported to be present in beeswax. Unsupervised pattern recognition procedures, cluster analysis and principal component analysis, were used to find data patterns and successfully differentiate authentic and paraffin adulterated beeswax based on the chemical profile obtained. Independent assessment of beeswax quality and performance of the unsupervised classification methods were performed using classical analytical parameters. The discrimination power of the chemometric unsupervised methods for detection of paraffin adulterated beeswax was superior to the discriminating power of classical analytical parameters. Using linear discriminant analysis, classification rules for authentic and paraffin adulterated beeswax samples were developed. The model was validated by leave-one-out cross validation and showed good recognition and prediction abilities, 100% and 99%, respectively. 23863956 Ascorbic acid inhibits ferric nitrilotriacetate induction of ornithine decarboxylase, DNA synthesis, oxidative stress, and hepatotoxicity in rats. Ascorbic acid (AA) is a naturally occurring phenolic compound with antioxidant properties used in food, cosmetics, and pharmaceutical products. In this study, the effect of AA on ferric nitrilotriacetate (Fe-NTA)-induced hepatotoxicity in rats has been examined. Fe-NTA alone enhances ornithine decarboxylase activity to 4.5-fold and tritiated thymidine incorporation in DNA to 3.6-fold in livers compared with the corresponding saline-treated controls. The enhanced ornithine decarboxylase activity and DNA synthesis showed a reduction to 3.02- and 1.88-fold, respectively, at a higher dose of 2 mg AA per day per animal, compared with the Fe-NTA-treated groups. Fe-NTA treatment also enhanced the hepatic microsomal lipid peroxidation to 1.7-fold compared to saline-treated controls. These changes were reversed significantly in animals receiving pretreatment of AA. The present data shows that AA can reciprocate the toxic effects of Fe-NTA and can serve as a potent chemopreventive agent to suppress oxidant-induced tissue injury and hepatotoxicity in rats. 23613093 Clinicopathologic and immunohistochemical features of primary ductal adenocarcinoma of lacrimal gland: five new cases and review of literature. A primary ductal adenocarcinoma of the lacrimal gland is a rare epithelial malignant tumor, and its clinicopathological and immunohistochemical features have not been well determined. The purpose of this study was to determine the clinicopathological characteristics of lacrimal duct carcinomas and to determine their long-term prognosis. We performed immunohistochemical studies of biological and proliferative markers of primary ductal adenocarcinomas of the lacrimal gland in five patients, and followed their long term prognosis. We also reviewed nine published cases of primary ductal adenocarcinomas of the lacrimal gland. All specimens were positive for the androgen receptor, and three of five specimens overexpressed the HER-2/neu protein. Nuclear immunostaining for p53 ranged from 10 % to 95 % and that of Ki-67 from 20 % to 70 % in the tumor cells. Four of five patients had distant metastases and three patients died from the disease during the 5-year follow-up. Our findings indicate that primary ductal adenocarcinomas of the lacrimal gland express androgen receptors and a wide range of proliferative markers. Their long-term prognosis is poor. 22497569 Precision-cut intestinal slices as in vitro tool for studies on drug metabolism. The role of the intestine in drug metabolism has long been underestimated as a consequence of the technical difficulty to discern the role of the intestine from that of the liver in in vivo experiments and of the lack of in vitro models that are sufficiently viable and fully representing the physiology and anatomy of the intestine. Recently the precision-cut slice model, which is widely used for liver and kidney, was also adapted for the small and large intestine. In this review the application of precision-cut intestinal slices (PCIS) for research in drug metabolism and transport is discussed. PCIS can be prepared from animal and human tissues from all regions of the intestine allowing investigation of species differences and regional gradients of activities of metabolizing enzymes. They are viable for 8-24 h of incubation and show high activity of drug metabolizing enzymes, representative for the in vivo activity. They have been successfully used to study drug-drug interactions such as induction, inhibition and regulation of drug metabolizing enzymes, transporters and nuclear factors. Moreover they appear to be a suitable model for studies on cold preservation of donor organs for transplantation, and allow exploring inter-organ interactions by co-incubation with precision-cut slices of other organs. Their application as model for drug-induced intestinal toxicity is still in its infancy but appears to be promising. PCIS, prepared from human and animal tissues, represent a powerful translational model for drug metabolism, transport and toxicity studies and as such contributes to the reduction and replacement of animal experiments. 23695650 A biomechanical study of the recovery in spinal stability of flexion/extension and torsion after the resection of different posterior lumbar structures in a sheep model. Posterior lumbar structures are vital for spinal stability, and many researchers thought that laminectomy and facetectomy would lead to severe spinal instability. However, because living organisms have compensatory repair capacities, their long-term condition after injuries may change over time. To study the changes in the lumbar biomechanical stability of flexion/extension and torsion at different time points after the resection of various posterior structures, as well as to assess the capacity for self-healing, sheep that had undergone laminectomy or facetectomy were used as an experimental animal model. The injured sheep models included three groups: laminectomy only, laminectomy plus left total facetectomy, and laminectomy plus bilateral facetectomy. Eight nonoperative sheep were used as the control group. At 0, 6, 12, 24, and 36 weeks after injury, the lumbar specimens were harvested for biomechanical testing using the Instron 8874 servohydraulic biomechanical testing system. The changes in the injured lumbar spine were also analyzed through radiological examination. The lumbar stability in flexion/extension and torsion was severely decreased after the three types of surgery. After 6 weeks, the flexion/extension mechanical parameters recovered substantially; each parameter had returned to normal levels by 12 weeks and exceeded the intact group by 24 and 36 weeks. Torsional stiffness also recovered gradually over time. All injury groups demonstrated decreased intervertebral space and degeneration or even fusion in the small joints of the surgical segment or in adjacent segments. These results indicate that the body has the ability to repair the mechanical instability to a certain extent. 23695028 Association between GSTP1 Ile105Val polymorphism and oxaliplatin-induced neuropathy: a systematic review and meta-analysis. The association between glutathione-S-transferase P1 (GSTP1) Ile105Val polymorphism and oxaliplatin-induced neuropathy has been investigated in a number of published studies. However, most of these studies were based on small sample sizes and the results remained inconsistent. To assess the relationship between GSTP1 gene Ile105Val polymorphism and its susceptibility to oxaliplatin-induced neuropathy, a meta-analysis of previous studies was conducted. Two investigators independently searched studies published up to December 2012 from the databases of PubMed, EMBASE and The Cochrane Library. The pooled effect was calculated as odds ratio (OR) and corresponding 95 % confidence intervals (CIs) using fixed-effect or random-effect model. Twelve prospective trials and two retrospective clinical trials involving 2,191 participants met the inclusion criteria. Combined analyses of these studies showed no significant associations between GSTP1 Ile105Val polymorphism and oxaliplatin-induced neuropathy, yielding OR of 1.08 (95 %CI 0.67-1.74, P = 0.754) in dominant model. Similar results were also obtained in recessive model (OR = 1.67, 95 %CI 0.56-4.93, P = 0.357) and allelic analysis (OR = 1.22, 95 %CI 0.67-2.24, P = 0.513). Since significant heterogeneity across studies, the pooled effects were calculated by random-effect model. No evidence of publication biases was identified in this meta-analysis. This meta-analysis did not support the hypothesis that GSTP1 Ile105Val polymorphism was related to the occurrence of neurotoxicity in oxaliplatin-treated patients. Given the limited number of studies and potential bias, large-scale and well-designed clinical trials should be needed to confirm these hypotheses. 23171498 Thought disorder in the meta-structure of psychopathology. Dimensional models of co-morbidity have the potential to improve the conceptualization of mental disorders in research and clinical work, yet little is known about how relatively uncommon disorders may fit with more common disorders. The present study estimated the meta-structure of psychopathology in the US general population focusing on the placement of five under-studied disorders sharing features of thought disorder: paranoid, schizoid, avoidant and schizotypal personality disorders, and manic episodes as well as bipolar disorder. Method Data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions, a face-to-face interview of 34 653 non-institutionalized adults in the US general population. The meta-structure of 16 DSM-IV Axis I and Axis II psychiatric disorders, as assessed by the Alcohol Use Disorder and Associated Disabilities Interview Schedule DSM-IV version (AUDADIS-IV), was examined using exploratory and confirmatory factor analysis. We document an empirically derived thought disorder factor that is a subdomain of the internalizing dimension, characterized by schizoid, paranoid, schizotypal and avoidant personality disorders as well as manic episodes. Manic episodes exhibit notable associations with both the distress subdomain of the internalizing dimension as well as the thought disorder subdomain. The structure was replicated for bipolar disorder (I or II) in place of manic episodes. As our understanding of psychopathological meta-structure expands, incorporation of disorders characterized by detachment and psychoticism grows increasingly important. Disorders characterized by detachment and psychoticism may be well conceptualized, organized and measured as a subdimension of the internalizing spectrum of disorders. Manic episodes and bipolar disorder exhibit substantial co-morbidity across both distress and thought disorder domains of the internalizing dimension. Clinically, these results underscore the potential utility of conceptualizing patient treatment needs using an approach targeting psychopathological systems underlying meta-structural classification rubrics. 23692887 Abdominal pain and asthenia as common clinical features in hospitalized children for giardiasis. Giardiasis is a disease with worldwide distribution, although its prevalence differs from country to country. In order to investigate the clinical pattern of giardiasis in in-patient children, a case-control study was carried out. In-patient children who had Giardia lamblia infection were compared with non Giardia-infected children, focusing only on 4 clinical manifestations: diarrhoea, abdominal pain, asthenia and vomiting. In multivariable analysis, abdominal pain (odds ratio [OR] 4.71, 95% confidence intervals [CI] 2.66-8.32) and asthenia (OR 3.30, 95% CI 1.16-9.37) had positive and independent associations with Giardia infection. The present study supports the potential role of G. lamblia in abdominal pain in children who attend- and are admitted- to a hospital in Havana City, and highlights the importance to keep abdominal pain and asthenia in mind in hospital admitted children in the event of an association with an evocative epidemiological context. 23910376 Assimilate translocation and expression of sucrose transporter, OsSUT1, contribute to high-performance ripening under heat stress in the heat-tolerant rice cultivar Genkitsukushi. High temperature reduces the grain quality of rice, a situation likely to become more frequent because of global warming. We studied the effects of high-temperature stress on grain quality of heat-tolerant cultivar 'Genkitsukushi' and heat-sensitive cultivar 'Tsukushiroman'. When day/night temperatures were 31/26°C from heading until maturity, the grain quality of 'Genkitsukushi' was rated at the first inspection grade (high quality), whereas 'Tsukushiroman' showed a remarkable increase in the percentage of white immature kernels (low quality). Nonstructural carbohydrate content in the stem of 'Genkitsukushi' the early maturation was significantly higher than in 'Tsukushiroman' and greatly decreased under high temperature. From 14 to 21 days after heading, the expression of the sucrose transporter gene, OsSUT1, was higher in the stem of 'Genkitsukushi' grown under high temperature than in 'Tsukushiroman'. In addition, the expression of OsSUT1 in the grains of 'Genkitsukushi' was significantly higher than in 'Tsukushiroman' during the ripening period. These results indicate that sugar transport functions more effectively in 'Genkitsukushi' than in 'Tsukushiroman', and that the effectiveness of sugar transport contributes to maintaining high grain quality in 'Genkitsukushi' under high-temperature conditions. 23866833 Diet, iron biomarkers and oxidative stress in a representative sample of Mediterranean population. The consumption pattern characterized by high consumption of vegetables, fruit, fish, olive oil and red wine has been associated with improvements in the total antioxidant capacity of individuals and reduced incidence of diseases related to oxidation. Also, high body iron levels may contribute to increase the oxidative stress by the generation of reactive oxygen species. The objective of this study is to analyze the relationship between antioxidant and pro-oxidant factors obtained from the diet and iron biomarkers on lipoprotein oxidation and total antioxidant capacity in a representative sample of the Mediterranean population. Cross-sectional prospective study, carried out with 815 randomly selected subjects (425 women and 390 men). Dietary assessment (3-day food records), iron biomarkers (serum ferritin, serum iron and transferrin saturation), biochemical markers of lipoperoxidation (TBARS), antioxidant capacity (ORAC) and CRP (C-Reactive Protein) were determined. Multiple Linear Regression (MLR) models were applied to analyze the association between diet factors and iron biomarkers on TBARS and ORAC levels. We observed that lipoperoxidation measured by TBARS increased by age but no differences were observed by sex. Antioxidant capacity measured by ORAC is independent of age and sex. In general, increasing age, tobacco, heme iron intake from meat and fish and transferrin saturation were independently and positively associated with TBARS, while non-heme iron was negatively associated. Vegetables, vitamin C intake and serum ferritin were positively associated with ORAC, whereas saturated fatty acids and meat intake were negatively associated. In our general population, we observed that oxidative stress is related to aging, but antioxidant capacity is not. The highest intake of dietary non-heme iron, vegetables and vitamin C intake exerts a protective effect against oxidation while the highest intake of dietary heme iron from meat and fish and saturated fatty acids are associated with increased oxidative stress. High levels of circulating iron measured by transferrin saturation are associated with increased oxidative stress in women however its association with the higher levels of serum ferritin is controversial. 23447551 Expression of sall4 in taste buds of zebrafish. We characterized the expression of sall4, a gene encoding a zinc finger transcription factor involved in the maintenance of embryonic stem cells, in taste buds of zebrafish (Danio rerio). Using an enhancer trap line (ET5), we detected enhanced green fluorescent protein (EGFP) in developing and adult transgenic zebrafish in regions containing taste buds: the lips, branchial arches, and the nasal and maxillary barbels. Localization of EGFP to taste cells of the branchial arches and lips was confirmed by co-immunolabeling with antibodies against calretinin and serotonin, and a zebrafish-derived neuronal marker (zn-12). Transgenic insertion of the ET construct into the zebrafish genome was evaluated and mapped to chromosome 23 in proximity (i.e. 23 kb) to the sall4 gene. In situ hybridization and expression analysis between 24 and 96 h post-fertilization (hpf) demonstrated that transgenic egfp expression in ET5 zebrafish was correlated with the spatial and temporal pattern of expression of sall4 in the wild-type. Expression was first observed in the central nervous system and branchial arches at 24 hpf. At 48 hpf, sall4 and egfp expression was observed in taste bud primordia surrounding the mouth and branchial arches. At 72 and 96 hpf, expression was detected in the upper and lower lips and branchial arches. Double fluorescence in situ hybridization at 3 and 10 dpf confirmed colocalization of sall4 and egfp in the lips and branchial arches. These studies reveal sall4 expression in chemosensory cells and implicate this transcription factor in the development and renewal of taste epithelia in zebrafish. 23726002 Low-dose radiation therapy (2 gy × 2) in the treatment of orbital lymphoma. Low-dose radiation has become increasingly used in the management of indolent non-Hodgkin lymphoma (NHL), but has not been studied specifically for cases of ocular adnexal involvement. The objective of this study is to investigate the effectiveness of low-dose radiation in the treatment of NHL of the ocular adnexa. We reviewed the records of 20 NHL patients with 27 sites of ocular adnexal involvement treated with low-dose radiation consisting of 2 successive fractions of 2 Gy at our institution between 2005 and 2011. The primary endpoint of this study is freedom from local relapse (FFLR). At a median follow-up time of 26 months (range 7-92), the overall response rate for the 27 treated sites was 96%, with a complete response (CR) rate of 85% (n=23) and a partial response rate of 11% (n=3). Among all treated sites with CR, the 2-year FFLR was 100%, with no in-treatment field relapses. The 2-year freedom from regional relapse rate was 96% with 1 case of relapse within the ipsilateral orbit (outside of the treatment field). This patient underwent additional treatment with low-dose radiation of 4 Gy to the area of relapse achieving a CR and no evidence of disease at an additional 42 months of follow-up. Orbital radiation was well tolerated with only mild acute side effects (dry eye, conjunctivitis, transient periorbital edema) in 30% of treated sites without any reports of long-term toxicity. Low-dose radiation with 2 Gy × 2 is effective and well tolerated in the treatment of indolent NHL of the ocular adnexa with high response rates and durable local control with the option of reirradiation in the case of locoregional relapse. 23790688 Imaging features of extrapulmonary small cell carcinoma. Small cell carcinoma accounts for approximately 20% of lung cancers; however, it rarely occurs at other sites. Extrapulmonary small cell carcinoma (EPSCC) is notoriously aggressive with a strong propensity for both regional and distant spread. The majority of the literature on these uncommon tumours is from a clinicopathological viewpoint with a relative paucity of detail regarding the radiological findings. This review will focus on the imaging features of EPSCC in its predominant sites of origin: the gastrointestinal tract, genitourinary tract, head, neck, and breast. We will also discuss the role of positron-emission tomography (PET)/computed tomography (CT) in the staging of EPSCC. 23969981 Olfactory Receptor 51E1 as a Novel Target in Somatostatin Receptor Negative Lung Carcinoids. Somatostatin receptors (SSTRs) may be used in lung carcinoids (LCs) for diagnosis and therapy, although additional targets are clearly warranted. This study aimed to investigate whether olfactory receptor 51E1 (OR51E1) may be a potential target for LCs. OR51E1 coding sequence was analyzed in LC cell lines, NCI-H727 and NCI-H720. OR51E1 transcript expression was investigated in LC cell lines and frozen specimens by quantitative real-time PCR. OR51E1, SSTR2, SSTR3, and SSTR5 expression was evaluated by immunohistochemistry on paraffin-embedded sections of 73 typical carcinoids (TCs), 14 atypical carcinoids (ACs) and 11 regional/distant metastases, and compared to OctreoScan data. Immunohistochemistry results were rendered semiquantitatively on a scale from 0 to 3+, taking into account the cellular compartmentalization (membrane vs. cytoplasm) and the percentage of tumor cells (<50% vs. >50%). Our results showed that wild-type OR51E1 transcript was expressed in both LC cell lines. OR51E1 mRNA was expressed in 9/12 TCs and 7/9 ACs (p=NS). Immunohistochemically, OR51E1, SSTR2, SSTR3 and SSTR5 were detected in 85%, 71%, 25% and 39% of TCs, and in 86%, 79%, 43% and 36% of ACs, respectively. OR51E1 immunohistochemical scores were higher or equal compared to SSTRs in 79% of TCs and 86% of ACs. Furthermore, in the LC cases where all SSTR subtypes were lacking, membrane OR51E1 expression was detected in 10/17 TCs and 1/2 ACs. Moreover, higher OR51E1 immunohistochemical scores were detected in 5/6 OctreoScan-negative LC lesions. Therefore, the high expression of OR51E1 in LCs makes it a potential novel diagnostic target in SSTR-negative tumors. 23827824 Finding meaning in caring for a spouse with dementia. Dementia caregiving can be burdensome with many challenges, especially for spousal caregivers who are elderly and may have limited resources and chronic conditions of their own. However, it can also be an opportunity for growth and transcendence. Thematic qualitative analysis was conducted with 11 caregiver interviews to investigate how spousal caregivers of individuals with dementia found personal meaning in their caregiving experience. Caregivers commonly had altruistic values, and the discipline to live those values. They found meaning by believing in a choice of attitude and perceiving satisfaction in living according to their values in life. They had faith in a higher power, a strong sense of love for their spouses and they derived strength from past challenges. Positive attitudes among caregivers of individuals with dementia may be enhanced by sharing these stories and strategies. Study results also provide an expansion beyond commonly held views of caregiving for nurses. 23821572 Mass spectrometric studies shed light on unusual oxidative transformations of 1,2-dehydro-N-acetyldopa. Lamellarins are a group of over 70 plus bioactive marine natural compounds possessing a 6,7-dihydroxycoumarin moiety. Although they appear to derive from 3,4-dihydroxyphenylalanine (dopa), practically nothing is known about the metabolic fate of these compounds. Biochemical considerations indicate that they could arise from a N-acetyl-1,2-dehydrodopa precursor through oxidative cyclization reaction. To assess the above hypothesis, we synthesized N-acetyl-1,2-dehydrodopa and conducted oxidation studies with commercially available mushroom tyrosinase and evaluated the course of the reaction with reversed-phase liquid chromatography/mass spectrometry (LC/MS). Mushroom tyrosinase readily oxidized N-acetyl-1,2-dehydrodopa - not to the normally expected quinone - but to an unstable quinone methide isomer, which rapidly cyclized to produce the dihydroxycoumarin product, 3-aminoacetyl esculetin. Interestingly, 3-aminoacetyl esculetin was further oxidized to a second quinone methide derivative that exhibited an addition reaction with the parent dihydroxycoumarin generating dimeric and other oligomeric products in the reaction mixture. LC/MS analysis of the N-acetyl-1,2-dehydrodopa oxidation reaction reveals not only a possible novel oxidative cyclization route for the biosynthesis of coumarin-type dehydrodopa compounds in marine organisms, but also unusual oxidative transformations of dehydro dopa derivatives. 23727606 Association of ERCC1-C118T and -C8092A polymorphisms with lung cancer risk and survival of advanced-stage non-small cell lung cancer patients receiving platinum-based chemotherapy: A pooled analysis based on 39 reports. The published data on the predictive role of ERCC1 polymorphisms in lung cancer risk and survival of patients with advanced non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy remains inconsistent. The aim of this meta-analysis was to determine the role of ERCC1 gene polymorphisms (C118T and C8092A) in this clinical situation. Eligible studies were included and assessed for quality using multiple search strategies. Thirty-nine published papers involving 9615 cases (4606 with Stage III/IV disease) and 5542 controls were included in the analysis. Pooled odds ratios (OR) or hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate risk. ERCC1-C118T was associated with lung cancer risk. The OR was 0.90 (95% CI: 0.81-0.99, p=0.043) in an additive genetic model (C allele vs. T allele) and 0.77 (95% CI: 0.63-0.95, p=0.013) in a recessive genetic model (CC/CT vs. TT). The corresponding risk was 0.74 (95% CI: 0.58-0.94, p=0.013) based on a homozygous comparison (CC vs. TT). No significant correlation was found for ERCC1 C8092A and there was no obvious relationship between ERCC1 C118T/C8092A polymorphisms and objective response to platinum-based chemotherapy. Overall survival (OS) of patients with non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy was significantly related to ERCC1 C118T (HR: 1.29, 95% CI: 1.07-1.56, p=0.007, CT/TT vs. CC). There was no relationship between ERCC1 C8092A and survival (HR: 1.32, 95% CI: 0.84-2.10, p=0.23, CA/AA vs. CC). These findings suggest that ERCC1 C118T polymorphisms may serve as a biomarker for lung cancer risk and have prognostic value in patients with advanced non-small cell lung cancer (NSCLC) undergoing platinum-based treatment. Further studies with larger numbers of subjects from a worldwide arena are needed to validate the associations. 23707511 CGRP-alpha application: a potential treatment to improve osseoperception of endosseous dental implants. Dental implants have been used to restore missing teeth for several decades. However, the capacity of implants to feel the mechanical stimuli and transmit neural signals remains lower than that of natural teeth. The poor osseoperception of dental implants is due to the absence of periodontal ligaments and Ruffini-like endings as well as the secondary injury during the implant surgery and then the insufficient regeneration of damaged peripheral nerve fibers around the implants. It is a hot topic to improve the quantity and density of peripheral nerve fibers or mechanoreceptors around endosseous dental implants. Calcitonin gene-related peptide-alpha (αCGRP), a neuropeptide widely distributed throughout the central and peripheral nervous systems, is found to be upregulated in regenerating axons within injury zones and be capable of promoting local Schwann cells proliferation, which is critical for partnering during peripheral nerve regeneration. Moreover, researches show that αCGRP is a potent vasodilator and a physiologic activator of bone formation. Thus, we hypothesize that local application of αCGRP may promote peripheral nerve fibers regeneration during the bone healing progress after dental implant surgery, thus improve the osseoperception of dental implants. 23959837 Reporting of ethical requirements in phase III surgical trials. Disclosure of obtaining informed consent from patients (ICP) and research ethics committee (REC) approval in published reports is sometimes omitted. To date, no disclosure data are available on surgical research. Our aim was to assess whether REC approval and ICP were documented in surgical trials. Overall, 657 randomised trials, published between 2005 and 2010 in 10 international journals, were included. We collected the report rate of REC approval and ICP and contacted the corresponding author when ethical information was lacking. Among the 657 randomised controlled trials (RCT), 576 (87.7%) stated that an REC had approved the research, and 606 (92.2%) stated that ICP had been requested. Furthermore, 28 RCTs (4.3%) reported neither REC nor ICP. The phase III randomised surgical trials that were analysed were shown to have respected fundamental ethical principles in approximately 90% of the cases examines. 23859835 A novel multi-commutated method for the determination of hydroxytyrosol in enriched foods using mercaptopropionic acid-capped CdTe quantum dots. Hydroxytyrosol (HXT) has been reported to have beneficial effects for human health, such as antioxidant and antimicrobial properties and an important contribution to the prevention of cardiovascular disease. Hence, exhaustive research is currently being performed to prepare functional foods, such as tomato juice or milk, with HXT. This paper presents a multi-commutated flow method based on the quenching effect that HXT has on the fluorescence of water-soluble mercaptopropionic acid-capped CdTe quantum dots. Under optimal conditions a linear working range was obtained for concentrations between 10 and 250 ng µl(-1). In order to demonstrate the suitability of the proposed method for the determination of HXT, HXT-enriched samples were prepared. Using a QuEChERS (quick, easy, cheap, effective, rugged and safe) procedure for extraction, HXT was determined in the prepared functional foods (milk, infant formula, tomato juice and tomato soup). Recoveries of 100% ± 8%, relative standard deviations (RSDs) lower than 5% and high sample throughput of 70 samples per h show the potential of the system for the analysis of HXT in food samples. 23950667 The genus Alterosa Blahnik, 2005 (Trichoptera, Philopotamidae, Philopotaminae) in northeastern Brazil, including the description of three new species and an identification key for the genus. Alterosa Blahnik, 2005 contains 35 described species distributed in southern and southeastern Brazil. Three new species of Alterosa from northeastern Brazil are described and illustrated, Alterosa amadoi sp. n., Alterosa castroalvesi sp. n. and Alterosa caymmii sp. n., the first records of the genus from northeastern Brazil. An identification key for all known species of the genus is also presented. 23871337 Genome-wide linkage analysis of carotid artery lumen diameter: The strong heart family study. A significant proportion of the variability in carotid artery lumen diameter is attributable to genetic factors. Carotid ultrasonography and genotyping were performed in the 3300 American Indian participants in the Strong Heart Family Study (SHFS) to identify chromosomal regions harboring novel genes associated with inter-individual variation in carotid artery lumen diameter. Genome-wide linkage analysis was conducted using standard variance component linkage methods, implemented in SOLAR, based on multipoint identity-by-descent matrices. Genome-wide linkage analysis revealed a significant evidence for linkage for a locus for left carotid artery diastolic and systolic lumen diameters in Arizona SHFS participants on chromosome 7 at 120cM (lod=4.85 and 3.77, respectively, after sex and age adjustment, and lod=3.12 and 2.72, respectively, after adjustment for sex, age, height, weight, systolic and diastolic blood pressure, diabetes mellitus and current smoking). Other regions with suggestive evidence of linkage for left carotid artery diastolic and systolic lumen diameter were found on chromosome 12 at 153cM (lod=2.20 and 2.60, respectively, after sex and age adjustment, and lod=2.44 and 2.16, respectively, after full covariate adjustment) in Oklahoma SHFS participants; suggestive linkage for right carotid artery diastolic and systolic lumen diameter was found on chromosome 9 at 154cM (lod=2.72 and 3.19, respectively after sex and age adjustment, and lod=2.36 and 2.21, respectively, after full covariate adjustment) in Oklahoma SHFS participants. We found significant evidence for loci influencing carotid artery lumen diameter on chromosome 7q and suggestive linkage on chromosomes 12q and 9q. 23885021 Oropharyngeal dysphagia in an elderly post-operative hip fracture population. Love et al (2013) claim new findings linking intervention for hip fracture with dysphagia. This commentary reflects on whether this represents novel data or simply reiterates previously recognised patterns, not necessarily specific to surgical hip-repair. Issues are addressed in the context of prevalence of dysphagia in community and care-home living older people; effects of operative procedures on swallowing; methods for screening for dysphagia; and methodological decisions made by Love et al. The role of dysphagia screening policies is briefly considered. 23887342 Less Efficacious Conditioned Pain Modulation and Sensory Hypersensitivity in Chronic Whiplash-associated Disorders in Singapore. Cultural differences in pain perception exist. Although chronic whiplash-associated disorder (WAD) is well investigated in western countries, little is known about its presentation in Singapore. We studied the neck motion and pain sensitivity in people with chronic WAD in Singapore. Thirty chronic WAD participants [>3 mo, Neck Disability Index: 40% (SD 17%)] were age, sex, and ethnicity matched with 30 pain-free controls. All 60 participants underwent the following tests: active neck motion, pain thresholds [pressure, brachial plexus provocation test (BPPT), cold], cold pain tolerance, and conditioned pain modulation (CPM). The test stimulus of contact heat and conditioning stimulus of cold water immersion was used to assess CPM. Data were evaluated to determine differences between WAD and control groups. Active neck motion (F1,29=80.02), pain thresholds of blunt pressure (F1,29=20.84), BPPT (F1,29=54.56), and cold (Z=-4.31) were significantly lower in participants with WAD (P<0.0001). Cold pressor pain tolerance was significantly lower in participants with WAD (Z=-2.89, P=0.02). A less efficacious CPM was also demonstrated in participants with WAD (F1,29=9.20, P=0.03). A combination of BPPT and cold hyperalgesia best predicted the WAD group (sensitivity=96.7%, specificity=96.7%). These findings of sensory hypersensitivity and decreased neck motion in Singaporeans with chronic WAD are consistent with physical impairments reported in western populations. 23749141 Stimuli-responsive polymer films. Stimuli-responsive polymer films undergo interesting structural and property changes upon external stimuli. Their applications have extended from smart coatings to controlled drug release, smart windows, self-repair and other fields. This tutorial review summarizes non-covalent bonding, reversible reactions and responsive molecules that have played important roles in creating stimuli-responsive systems, and presents the recent development of three types of responsive polymer systems: layer-by-layer polymer multilayer films, polymer brushes, and self-repairing polymer films, with a discussion of their response mechanism. Future research efforts include comprehensive understanding of the response mechanism, producing polymer systems with controlled response properties regarding single or multiple external signals, combining polymer film fabrication with nanotechnology, improving the stability of polymer films on substrates, and evaluating the toxicity of the degradation products. 23745667 Selective nucleic acid capture with shielded covalent probes. Nucleic acid probes are used for diverse applications in vitro, in situ, and in vivo. In any setting, their power is limited by imperfect selectivity (binding of undesired targets) and incomplete affinity (binding is reversible, and not all desired targets bound). These difficulties are fundamental, stemming from reliance on base pairing to provide both selectivity and affinity. Shielded covalent (SC) probes eliminate the longstanding trade-off between selectivity and durable target capture, achieving selectivity via programmable base pairing and molecular conformation change, and durable target capture via activatable covalent cross-linking. In pure and mixed samples, SC probes covalently capture complementary DNA or RNA oligo targets and reject two-nucleotide mismatched targets with near-quantitative yields at room temperature, achieving discrimination ratios of 2-3 orders of magnitude. Semiquantitative studies with full-length mRNA targets demonstrate selective covalent capture comparable to that for RNA oligo targets. Single-nucleotide DNA or RNA mismatches, including nearly isoenergetic RNA wobble pairs, can be efficiently rejected with discrimination ratios of 1-2 orders of magnitude. Covalent capture yields appear consistent with the thermodynamics of probe/target hybridization, facilitating rational probe design. If desired, cross-links can be reversed to release the target after capture. In contrast to existing probe chemistries, SC probes achieve the high sequence selectivity of a structured probe, yet durably retain their targets even under denaturing conditions. This previously incompatible combination of properties suggests diverse applications based on selective and stable binding of nucleic acid targets under conditions where base-pairing is disrupted (e.g., by stringent washes in vitro or in situ, or by enzymes in vivo). 23846914 Biomarkers for Pancreatic Cancer: Is it Ready for Primetime? No abstract available. 23589407 Modulation of carbon tetrachloride-induced nephrotoxicity in rats by n-hexane extract of Sonchus asper. Sonchus asper is traditionally used in the treatment of renal dysfunction. In the present study, protective effects of S. asper against carbon tetrachloride (CCl4)-induced nephrotoxicity of rats were determined. In this study, 24 male albino rats (190-200 g) were equally divided into four groups. Group I (control group) was given saline (1 ml/kg body weight (b.w.), 0.85% NaCl) and dimethyl sulfoxide (1 ml/kg b.w.); group II was treated with CCl4 (1 ml/kg b.w. intraperitoneally); groups III and IV were administered with CCl4 and after 48 h with S. asper n-hexane extract (SHE; 100 and 200 mg/kg b.w.). All the treatments were given twice a week for 4 weeks. The results revealed that CCl4-induced oxidative stress as evidenced by the significant depletion of antioxidant enzymes, namely, superoxide dismutase, catalase, peroxidase, glutathione-S-transferase, glutathione peroxidase, glutathione reductase, and glutathione contents, while increased lipid peroxidation (thiobarbituric acid-reactive substances contents). Administration of SHE significantly ameliorated (p < 0.01) the activity of antioxidant enzymes and reduced lipid peroxides. Coadministration revealed that S. asper extract can protect the kidney against CCl4-mediated oxidative damage by restoring the activity of antioxidant enzyme, due to the presence of plant bioactive constituents. 23669495 Pleural mesothelium lubrication after hyaluronidase, neuraminidase or pronase treatment. Coefficient of kinetic friction (μ) of pleural mesothelium has been found to increase markedly after mesothelial blotting and rewetting. This increase disappeared after addition of a solution with hyaluronan or sialomucin, though previous morphological studies showed that only sialomucin occurs in mesothelial glycocalyx. In this research we investigated whether μ of rabbit pleural mesothelium increased after hyaluronidase, neuraminidase or pronase treatment. Hyaluronidase and neuraminidase did not increase μ, though neuraminidase cleaved sialic acid from mesothelial glycocalyx of diaphragm specimens, and removed hystochemical stain of sialic acid from glycocalyx. Sialomucin treated with neuraminidase lowered μ of blotted mesothelium, though less than untreated sialomucin; this feature plus lubrication provided by other molecules could explain why μ did not increase after neuraminidase. Short pronase treatment (in order to affect only glycocalyx proteins) increased μ; this increase was removed by hyaluronan or sialomucin. After pronase treatment μ decreased with increase in sliding velocity, indicating a regime of mixed lubrication, as in blotted mesothelium. 23860116 Histopathologic Evaluation of the Sentinel Lymph Node for Malignant Melanoma: The Unstandardized Process. : Metastasis from malignant melanoma (MM) usually first presents in the draining lymph node basin and thus sentinel lymph node (SLN) biopsy is a staging tool used to predict risk of metastases and death in higher risk tumors and has become the standard of care. Differences in the processing and methods used in the histopathological examination of SLNs can affect the positivity rate for metastatic MM because isolated MM deposits may be small and variably distributed in the SLN. The examination of SLNs is not standardized. The authors surveyed institutions across the United States who process SLNs for MM to better characterize the current methods used and to suggest a standardized approach to improve the reliability of the SLN biopsy. A survey of 142 academic institutions in the United States regarding the methods used in the evaluation of the SLN biopsy for MM was conducted. Thirty-two institutions responded. Eighty-one percent of the institutions (26 of 32) had a protocol that they used for SLN examination. In regards to gross dissection, 28% of the responders (9 of 32) initially bivalve (cut the SLN in half), whereas 59% (19 of 32) use a bread loaf technique, cutting the SLN at even intervals without specifically commenting about orientation to the hilum. The number of levels initially cut from the SLN block varied from 1 to 8 levels per block. Thirty-nine percent of the respondents (12 of 31) routinely order immunohistochemistry before evaluation of the initial hematoxylin- and eosin-stained sections. Eighty percent of the respondents (24 of 30) report the maximum dimension of the metastatic tumor deposit. The response rate was low (22%), and most respondents did not indicate how many SLN accessions were performed at their institution each year. Histologic protocols for processing SLNs for MM vary among institutions. Different methods of handling SLNs result in varying sensitivities for detection of metastases. Data derived from these varied approaches to develop and determine prognostic and staging categories may be inconsistent. A standardized yet practical approach is needed to provide reliable information on which prognosis can be determined and therapeutic guidelines can be based. The hope is for dermatologists and those treating patients with MM to understand the intricacies and inconsistencies involved in performance and interpretation of this key staging tool. 23485366 A meta-analysis of cortical inhibition and excitability using transcranial magnetic stimulation in psychiatric disorders. To evaluate transcranial magnetic stimulation (TMS) measures of inhibition and excitation in obsessive-compulsive disorder (OCD), major depressive disorder (MDD) and schizophrenia (SCZ). Paradigms included: short-interval cortical inhibition (SICI), cortical silent period (CSP), resting motor threshold, intracortical facilitation, and motor evoked potential amplitude. A literature search was performed using PubMed, Ovid Medline, Embase Psychiatry and PsycINFO 1990 through April 2012. A significant Hedge's g was found for decreased SICI (g=0.572, 95% confidence interval [0.179, 0.966], p=0.004), enhanced intracortical facilitation (g=0.446, 95% confidence interval [0.042, 0.849], p=0.030) and decreased CSP (g=-0.466, 95% confidence interval [-0.881, -0.052], p=0.027) within the OCD population. For MDD, significant effect sizes were demonstrated for decreased SICI (g=0.641, 95% confidence interval [0.384, 0.898], p=0.000) and shortened CSP (g=-1.232, 95% confidence interval [-1.530, -0.933], p=0.000). In SCZ, a significant Hedge's g was shown for decreased SICI (g=0.476, 95% confidence interval [0.331, 0.620], p=0.000). Inhibitory deficits are a ubiquitous finding across OCD, MDD, SCZ and enhancement of intracortical facilitation is specific to OCD. Provides a clear platform from which diagnostic procedures can be developed. 23732694 Highly glucose tolerant β-glucosidase from Aspergillus unguis: NII 08123 for enhanced hydrolysis of biomass. Aspergillus unguis NII-08123, a filamentous fungus isolated from soil, was found to produce β-glucosidase (BGL) activity with high glucose tolerance. Cultivation of the fungus in different carbon sources resulted in the secretion of different isoforms of the enzyme. A low molecular weight isoform, which retained ~60 % activity in the presence of 1.5 M glucose, was purified to homogeneity and the purified enzyme exhibited a temperature and pH optima of 60 °C and 6, respectively. The K m and V max of the enzyme were 4.85 mM and 2.95 U/mg, respectively, for 4-nitrophenyl β-D-glucopyranoside. The glucose inhibition constant of the enzyme was 0.8 M, indicating high glucose tolerance, and this is the second-highest glucose tolerance ever reported from the Aspergillus nidulans group. The glucose-tolerant BGL from A. unguis, when supplemented to cellulase preparation from Penicillium, could improve biomass hydrolysis efficiency by 20 % in 12 h compared to the enzyme without additional beta glucosidase supplementation. The beta glucosidase from A. unguis is proposed as a highly potent "blend-in" for biomass saccharifying enzyme preparations. 23813301 Highly efficient factorial designs for cDNA microarray experiments: use of approximate theory together with a step-up step-down procedure. Abstract A general method for obtaining highly efficient factorial designs of relatively small sizes is developed for cDNA microarray experiments. It allows the main effects and interactions to be of possibly unequal importance. First, the approximate theory is employed to get an optimal design measure which is then discretized. It is, however, observed that a naïve discretization may fail to yield an exact design of the stipulated size and, even when it yields such an exact design, there is often scope for improvement in efficiency. To address these issues, we propose a step-up/down procedure which is seen to work very well. The resulting designs turn out to be quite robust to possible dye-color effects and heteroscedasticity. We focus on the baseline and all-to-next parametrizations but our method works equally well also for hybrids of the two and other parametrizations. 23557706 mTOR Regulates Nox4-Mediated Podocyte Depletion in Diabetic Renal Injury. Podocyte apoptosis is a critical mechanism for excessive loss of urinary albumin that eventuates in kidney fibrosis. Pharmacological doses of the mTOR inhibitor rapamycin reduce albuminura in diabetes. We explored the hypothesis that mTOR mediates podocyte injury in diabetes. High glucose (HG) induces apoptosis of podocytes, inhibits AMPK activation, inactivates tuberin and activates mTOR. HG also increases the levels of Nox4 and Nox1 and NADPH oxidase activity. Inhibition of mTOR by low dose rapamycin decreases HG-induced Nox4 and Nox1, NADPH oxidase activity and podocyte apoptosis. Inhibition of mTOR had no effect on AMPK or tuberin phosphorylation indicating that mTOR is downstream of these signaling molecules. In isolated glomeruli of OVE26 mice, there is similar decrease in the activation of AMPK and tuberin and activation of mTOR with increase in Nox4 and NADPH oxidase activity. Inhibition of mTOR by small dose of rapamycin reduces podocyte apoptosis, attenuates glomerular injury and albuminuria. Our data provide evidence for a novel function of mTOR in Nox4-derived ROS generation and podocyte apoptosis that contributes to urinary albumin excretion in type 1 diabetes. Thus mTOR and or NADPH oxidase inhibition may represent a therapeutic modality of diabetic kidney disease. 23266617 How is Anxiety Involved in the Longitudinal Relationship between Brooding Rumination and Depressive Symptoms in Adolescents? A growing body of research supports the application of Response Styles Theory to adolescent populations. Although the essential dynamic, namely that rumination increases the incidence of depressive symptoms, has been demonstrated among adolescents, a number of important empirical questions remain, such as: what are the gender differences and developmental trends for brooding and reflective rumination?; does a reciprocal relationship exist between brooding or reflective rumination, on the one hand, and depressive symptoms and anxiety, on the other hand, over time? and how do additional variables (i.e., anxiety) impact upon the rumination-depressive symptoms relationship? In this study, self-reported levels of rumination (both brooding and reflective), and anxious and depressive symptoms were measured longitudinally across 4 months in a sample of 976 community adolescents (46 % females), aged 11-16 years old. Mean group differences showed that female adolescents reported engaging in more brooding rumination than male adolescents beginning at 13 years of age. A reciprocal brooding rumination to depressive symptoms relationship and a reciprocal brooding rumination to anxiety relationship were found over time, and they did not differ for boys and girls. We tested the possibility that anxious symptoms would function as a third variable, but the obtained model showed that brooding rumination and anxiety both contributed unique variance in predicting changes in depressive symptoms over time. 23515641 The importance of measuring and accounting for potential biases in respondent-driven samples. Respondent-driven sampling (RDS) is often viewed as a superior method for recruiting hard-to-reach populations disproportionately burdened with poor health outcomes. As an analytic approach, it has been praised for its ability to generate unbiased population estimates via post-stratified weights which account for non-random recruitment. However, population estimates generated with RDSAT (RDS Analysis Tool) are sensitive to variations in degree weights. Several assumptions are implicit in the degree weight and are not routinely assessed. Failure to meet these assumptions could result in inaccurate degree measures and consequently result in biased population estimates. We highlight potential biases associated with violating the assumptions implicit in degree weights for the RDSAT estimator and propose strategies to measure and possibly correct for biases in the analysis. 23846731 Trametinib: first global approval. Trametinib is an orally bioavailable mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor with antineoplastic activity. The compound specifically binds to MEK1 and MEK2, resulting in inhibition of growth factor-mediated cell signalling and cellular proliferation in various cancers. Originally developed by Japan Tobacco, GlaxoSmithKline has licensed exclusive worldwide rights to the compound and conducted development in a number of different cancer types. Trametinib, as a monotherapy, has been approved in the US for the treatment of unresectable or metastatic malignant melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. The compound, as a monotherapy, has also been submitted for regulatory review in the EU for BRAF mutation-positive malignant melanoma, and is in phase III development in Europe, Argentina, Canada and Oceania. Phase II development is underway for pancreatic cancer, non-small cell lung cancer and relapsed or refractory leukaemias. GlaxoSmithKline is also developing trametinib for use in combination with dabrafenib in BRAF V600 mutation-positive metastatic cutaneous melanoma; the combination is at the preregistration stage in the EU and a phase III clinical programme is underway worldwide. Phase II development for this combination is also underway in colorectal cancer. Several phase I trials have also been initiated to evaluate trametinib in combination with other drugs for the treatment of various solid tumours and haematological malignancies. A paediatric oral solution formulation has been assessed against the oral tablet formulation in a phase I trial. This article summarizes the milestones in the development of trametinib leading to this first approval for unresectable or metastatic BRAF mutation-positive malignant melanoma. 23807802 Can mechanical balloon dissection be applied to cleave fibrotic submucosal tissues? A pilot study in a porcine model. Background and study aims: Removal of a lesion containing an ulcer scar is one of the most challenging applications of endoscopic submucosal dissection (ESD). The present study examined whether a novel balloon dissector could cleave fibrotic submucosal tissue beneath ulcer scars.Methods: Six pigs were studied. Endoscopic mucosal resection (EMR) with ligation was performed at 7 or 8 sites in the stomach for each animal; 4 weeks later, 23 sites with a visible scar were selected for submucosal dissection. The procedure involved first creating a submucosal fluid cushion (SFC) by injecting either saline mixed with mesna or pure saline. A slender, compliant balloon with a diameter of 8, 13, or 18 mm was inserted into the SFC. The balloon was unfolded and thrust forward to cleave the fibrotic submucosa over approximately 5 cm.Results: Fibrotic submucosa was dissected within 90 seconds in 17 of 23 attempts. Isolating the ulcer scar from the muscularis with the SFC prior to balloon dissection and using a thinner balloon catheter both ensured a better dissection.Conclusions: The fibrotic submucosa underlying post-EMR scars can be dissected with the novel balloon dissector, although the technique is less effective in cases with no sign of lifting. 23789854 Spin State Diagrams of 3d(n) Cations in Tetragonally Distorted Octahedral Sites. The possible existence of an intermediate spin state is now a few decades fascinating solid state chemists and physicists, experimentalists, and theoreticians. In this article, we revise some recent results on the stability diagrams of spin states, low, high, or intermediate, in distorted environments and extend their approach to redraw more realistic diagrams for d(4), d(5), and d(6) ions in a tetragonally distorted 6-fold oxygen environment (D4h, D2d, and C4ν). The model relies on a point charge model and further uses effective parameters to account for the cubic field drift on spin state change and for suitable values for solid state of the expectation values of the 3d-radial wave functions; additionally the model uses rational parameters to characterize the distortion; finally, we also consider the possible existence of states' combinations to propose reliable stability diagrams. Whatever the representation involved in the distortion, the existence domain of the intermediate spin state appears very small and more likely replaced with mixtures of cations in low and high spin states; the opportunity of induced distortive ordering is discussed. 23585460 The Notch signaling pathway as a mediator of tumor survival. The Notch signaling pathway is evolutionarily conserved and responsible for cell fate determination in the developing embryo and mature tissue. At the molecular level, ligand binding activates Notch signaling by liberating the Notch intracellular domain, which then translocates into the nucleus and activates gene transcription. Despite the elegant simplicity of this pathway, which lacks secondary messengers or a signaling cascade, Notch regulates gene expression in a highly context- and cell-type-dependent manner. Notch signaling is frequently dysregulated, most commonly by overactivation, across many cancers and confers a survival advantage on tumors, leading to poorer outcomes for patients. Recent studies demonstrate how Notch signaling increases tumor cell proliferation and provide evidence that active Notch signaling maintains the cancer stem-cell pool, induces epithelial-mesenchymal transition and promotes chemoresistance. These studies imply that pharmacological inhibition of Notch signaling may refine control of cancer therapy and improve patient survival. Gamma secretase inhibitors (GSIs) are drugs that inhibit Notch signaling and may be successful in controlling cancer cell growth in conjunction with standard chemotherapy, but substantial side effects have hampered their widespread use. Recent efforts have been aimed at the development of antibodies against specific Notch receptors and ligands with the hope of limiting side effects while providing the same therapeutic benefit as GSIs. Together, studies characterizing Notch signaling and modulation have offered hope that refined methods targeting Notch may become powerful tools in anticancer therapeutics. 23913834 Data visualization in environmental proteomics. From raw data to gene expression profiles, from single cultures to complex microbial communities, environmental proteomics works with data of different complexity levels that need to be interpreted in detail or in its entirety. Although data visualization is closely connected with data analysis approaches; this work will scope solely on data visualization. Complementing traditional tools such as bar charts or line graphs scientists and visualization professionals have been provided sophisticated visualization tools. Many rules and concerns regarding the display of single but also complex data will be reviewed and discussed. Visual approaches such as micro-charts, heat maps, stream graphs, and tree maps will be brought to the reader's attention and demonstrated by using real data sets. This article is protected by copyright. All rights reserved. 23837934 An eccrine angiomatous hamartoma with histopathological features of a papillary haemangioma in a neonate. Eccrine angiomatous hamartoma (EAH) is a benign hamartomatous tumour characterized by a combination of proliferative eccrine and vascular elements. Papillary haemangioma (PH) is a distinct cutaneous haemangioma with predominantly intravascular capillary proliferation within dilated thin-walled blood vessels. EAHs have been reported in combination with various vascular components. We present the first case in the dermatological literature, to our knowledge, of a patient with congenital EAH with the histopathological features of a PH. 23897706 Germline single nucleotide polymorphisms associated with response of urothelial carcinoma to platinum-based therapy: the role of the host. Variations in urothelial carcinoma (UC) response to platinum chemotherapy are common and frequently attributed to genetic and epigenetic variations of somatic DNA. We hypothesized that variations in germline DNA may contribute to UC chemosensitivity. DNA from 210 UC patients treated with platinum-based chemotherapy was genotyped for 80 single nucleotide polymorphisms (SNPs). Logistic regression was used to examine the association between SNPs and response, and a multivariable predictive model was created. Significant SNPs were combined to form a SNP score predicting response. Eleven UC cell lines were genotyped as validation. Six SNPs were significantly associated with 101 complete or partial responses (48%). Four SNPs retained independence association and were incorporated into a response prediction model. Each additional risk allele was associated with a nearly 50% decrease in odds of response [odds ratio (OR) = 0.51, 95% confidence interval 0.39-0.65, P = 1.05 × 10(-7)). The bootstrap-adjusted area under the curves of this model was greater than clinical prognostic factors alone (0.78 versus 0.64). The SNP score showed a positive trend with chemosensitivity in cell lines (P = 0.115). Genetic variants associated with response of UC to platinum-based therapy were identified in germline DNA. A model using these genetic variants may predict response to chemotherapy better than clinical factors alone. 23962625 A parallel group cohort to determine the measurement properties of an early inflammatory arthritis detection tool. Objectives. To determine the comprehensibility, internal consistency, test-retest reliability and discriminative properties of an early inflammatory arthritis (IA) detection tool.Methods. Four groups were recruited from outpatient clinics at two tertiary care hospitals: early IA, established IA, non-IA musculoskeletal conditions (MSK) and non-MSK. Participants attended a study visit where they completed the 11-item tool with binary yes/no response options. Comprehensibility was assessed for each tool item on a 5-point Likert scale. For test-retest assessment, the tool was mailed to participants following a 2-week recall washout interval. Two items were randomly selected to test internal consistency. Discriminative properties compared tool item responses with blinded rheumatologist clinical assessments. A previously developed rheumatology triage algorithm was externally validated.Results. A total of 170 participants were enrolled in the study. Comprehensibility approached unity for all tool items. The internal consistency Kuder-Richardson Formula 20 was 0.985 (P < 0.0001). The mean test-retest reliability kappa (s.d.) was 0.81 (0.02). The intraclass correlation coefficient (ICC) (95% CI) for summed yes responses between test and retest phases was 0.94 (0.93, 0.95) and for algorithm scores was 0.97 (0.96, 0.98). Patient responses were significantly associated with the corresponding clinical evaluations (P < 0.0001, respectively). The sum of yes responses and rheumatology triage algorithm scores both differentiated early IA from each of the other three groups (P < 0.004, respectively). The scoring algorithm receiver operating characteristic plot area under the curve (s.e.) was 0.829 (0.003).Conclusion. The tool has favourable measurement and discriminative properties. The discriminative properties of the rheumatology triage scoring algorithm were externally validated. 23451932 A survey of tobacco dependence treatment services in 121 countries. To report progress among Parties to the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) in developing tobacco dependence treatment systems in accordance with FCTC Article 14 and the Article 14 guidelines recommendations. Cross-sectional study. Electronic survey from December 2011 to August 2012. One hundred and sixty-three of the 174 Parties to the FCTC at the time of our survey. The 51-item questionnaire contained 21 items specifically on treatment systems. Questions covered the availability of basic treatment infrastructure and national cessation support systems. We received responses from 121 (73%) of the 166 countries surveyed. Fewer than half of the countries had national treatment guidelines (n = 53, 44%), a government official responsible for tobacco dependence treatment (n = 49, 41%), an official national treatment strategy (n = 53, 44%) or provided tobacco cessation support for health workers (n = 55, 46%). More than half encouraged brief advice in existing health care services (n = 68, 56%), while only 44 (36%) had quitlines and only 20 (17%) had a network of treatment support covering the whole country. Low- and middle-income countries had less tobacco dependence treatment provision than high-income countries. Most countries, especially low- and middle-income countries, have not yet implemented the recommendations of FCTC Article 14 or the FCTC Article 14 guidelines. 23665312 Myelophil attenuates brain oxidative damage by modulating the hypothalamus-pituitary-adrenal (HPA) axis in a chronic cold-stress mouse model. Myelophil is composed of Astragali Radix and Salviae Miltiorrhizae Radix, according to the long traditional pharmacological practices, and it has been used for patients with chronic fatigue-associated symptoms including concentration problem or memory loss. This study aimed to evaluate the clinical relevance of Myelophil on brain oxidative damage using a chronic cold stress mice model. Balb/c mice were subjected to cold stress (4°C for 4h) six times per week for 2 weeks with or without oral administration of Myelophil (50, 100, or 200mg/kg), or ascorbic acid (50mg/kg). Chronic cold stress induced histopathological hippocampal apoptosis with drastically increased serum levels of total reactive oxygen species and nitric oxide, as well as brain lipid peroxidation levels, protein carbonyl, and caspase-3/7 activity. These alterations were significantly ameliorated by Myelophil treatment. Myelophil administration significantly recovered the depleted glutathione and its enzymes, superoxide dismutase activity, and catalase protein and gene expression levels. Serum levels of corticosterone, dopamine, and adrenaline were notably altered by chronic cold stress but were significantly ameliorated by Myelophil treatment. Myelophil also normalized alterations in tumor necrosis factor-α, interleukin (IL)-1β, and IL-10 gene expression and protein levels. Chronic cold stress up-regulated gene expression levels of phenylethanolamine N-methyltransferase and monoamine oxidase-B, and glucocorticoid receptors in the hypothalamus and hippocampus, respectively, whereas Myelophil treatment completely normalized these levels. These results suggest that Myelophil has potent pharmaceutical effects against chronic cold-stress-induced brain damage by relieving oxidative stress and inflammation and regulating stress hormones in mice. 23939981 Co-incorporation of the PB2 and PA polymerase subunits from human H3N2 influenza virus is a critical determinant of the replication of reassortant ribonucleoprotein complexes. The influenza virus RNA polymerase, composed of the PB1, PB2, and PA subunits, has a potential role in influencing genetic reassortment. Recent studies on the reassortment of human H3N2 strains suggest that the co-incorporation of PB2 and PA from the same H3N2 strain appears to be important for efficient virus replication; however, the underlying mechanism remains unclear. Here, we reconstituted reassortant ribonucleoprotein (RNP) complexes and demonstrated that the RNP activity was severely impaired when the PA subunit of H3N2 strain A/NT/60/1968 (NT PA) was introduced into H1N1 or H5N1 polymerase. The NT PA did not affect the correct assembly of the polymerase trimeric complex, but it significantly reduced replication-initiation activity when provided with a vRNA promoter and severely impaired the accumulation of RNP, which led to the loss of RNP activity. Mutational analysis demonstrated that PA residues184N and 383N were the major determinants of the inhibitory effect of NT PA and 184N/383N sequences were unique to human H3N2 strains. Significantly, NT PB2 specifically relieved the inhibitory effect of NT PA, and the PB2 residue 627K played a key role. Our results suggest that PB2 from the same H3N2 strain might be required for overcoming the inhibitory effect of H3N2 PA in the genetic reassortment of influenza virus. 23339777 In vitro toxicity of camalexin derivatives in human cancer and non-cancer cells. The aim of the study was to investigate the cytotoxic activity of camalexin and its five synthetic derivatives in cancer and non-cancer cells. In cancer cells the benzocamalexin (BC) displayed the most potent activity with an IC value of 23.3-30.1 μmol/L. On the other hand, minimal toxicity (IC>100.0 μmol/L) in non-cancer cells was observed. Based on these results, BC was selected for further studies. Flow cytometric analysis revealed a BC-induced arrest of the cell cycle in the G2 phase associated with downregulation of α-tubulin, α1-tubulin, β5-tubulin expression. These findings suggest that the inhibitory effect of BC is mediated via inhibition of microtubule formation. Moreover, BC downregulated the expression of microtubule-related protein indicating the effect of this compound on microtubule assembly. After treatment with BC increase of the sub-G DNA content fraction was noted which is considered to be a marker of apoptotic cell death. Apoptosis was also confirmed by DNA fragmentation assay. Moreover, quantitative real-time PCR showed that BC downregulated the expression of antiapoptotic genes Bcl-2 and Bcl-xL and upregulated the expression of proapoptotic Bax. Taken together, our study suggests that the blockade of cell cycle progression and initiation of apoptosis may play an important role in the antiproliferative activity of BC in human cancer cells. 23520265 PHARMACODYNAMIC EFFECTS OF A D-AMINO ACID OXIDASE INHIBITOR INDICATE A SPINAL SITE OF ACTION IN RAT MODELS OF NEUROPATHIC PAIN. Inhibition of D-amino acid oxidase (DAAO) activity is a potential target for the treatment of chronic pain. Here we characterized the effects of systemic administration of the DAAO inhibitor 4H-furo[3,2-b]pyrrole-5-carboxylic acid (SUN) in rat models of neuropathic and inflammatory pain. Oral administration of SUN dose-dependently attenuated tactile allodynia induced by ligation of the L5 spinal nerve (SNL), and similarly reversed thermal hyperalgesia produced by chronic constriction injury (CCI). In addition, SUN was efficacious against Complete Freund's Adjuvant (CFA)-induced thermal hyperalgesia. In these models, maximal reversal of pain-related behaviors corresponded with maximum rates-of-increase in brain and plasma D-serine concentrations, indicative of full inhibition of DAAO activity. To investigate the possible site(s) of action, we recorded spontaneous nerve activity and mechanically-evoked responses of central spinal cord dorsal horn neurons and compared these to spontaneous activity of peripheral dorsal root filaments in anesthetized SNL model animals. Oral SUN reduced spontaneous activity in both central and peripheral recordings at doses and pretreatment times that corresponded to reduced mechanical allodynia in behavioral experiments. Following i.v. administration of SUN, the onset of action for this central effect was rapid (maximal effects within 30 minutes), but was abolished by severing afferent inputs to the dorsal horn. Overall, these results indicate that inhibition of DAAO in peripheral afferent-spinal circuits reduced spontaneous neuronal activity to attenuate pain-related behaviors in rat models of neuropathic and inflammatory pain. 23881955 The association between stroke, depression, and 5-year mortality among very old people. Depression after stroke has been associated with increased mortality, but little is known about this association among very old people. A population-based study among people ≥85 years of age was conducted in northern Sweden and Finland, comprising cross-sectional assessments and subsequent survival data. The 452 individuals who had completed the Geriatric Depression Scale-15 assessment were selected. Depression was defined as a score of ≥5 on the geriatric depression scale. Of those with a history of stroke, 38 of 88 (43.2%) people were depressed, and 11 of the 38 (28.9%) were treated with antidepressants, compared with 91 of 364 (25.0%) depressed (P=0.001) and 17 of 91 (18.7%) treated with antidepressants among those without stroke. Having a history of stroke and ongoing depression was associated with increased 5-year mortality compared with having only stroke (hazard ratio, 1.90; confidence interval, 1.15-3.13), having only depression (hazard ratio, 1.59; confidence interval, 1.03-2.45), and compared with having neither stroke nor depression (hazard ratio, 2.50; confidence interval, 1.69-3.69). Having only stroke without depression did not increase mortality compared with having neither stroke nor depression. A history of stroke was associated with increased mortality among very old people but only among those who were also depressed. Depression seemed to be underdiagnosed and undertreated. 23616232 Screening for occult malignancy with FDG-PET/CT in patients with unprovoked venous thromboembolism. Extensive screening strategies to detect occult cancer in patients with unprovoked venous thromboembolism (VTE) are complex and no benefit in terms of survival has been reported. FDG-PET/CT (2-[F-18] fluoro-2-deoxy-D-glucose positron emission tomography combined with computed tomography), a noninvasive technique for the diagnosis and staging of malignancies, could be useful in this setting. Consecutive patients ≥ 50 years with a first unprovoked VTE episode were prospectively included. Screening with FDG-PET/CT was performed 3-4 weeks after the index event. If positive, appropriate diagnostic work-up was programmed. Clinical follow-up continued for 2 years. Blood samples were collected to assess coagulation biomarkers. FDG-PET/CT was negative in 68/99 patients (68.7%), while suspicious FDG uptake was detected in 31/99 patients (31.3%). Additional diagnostic work-up confirmed a malignancy in 7/31 patients (22.6%), with six of them at early stage. During follow-up, two patients with negative FDG-PET/CT were diagnosed with cancer. Sensitivity (S), positive (PPV) and negative predictive values (NPV) of FDG-PET/CT as single tool for the detection of occult malignancy were 77.8% (95% CI: 0.51-1), 22.6% (95% CI: 0.08-0.37) and 97.1% (95% CI: 0.93-1), respectively. Median tissue factor (TF) activity in patients with occult cancer was 5.38 pM vs. 2.40 pM in those without cancer (p = 0.03). Limitation of FDG-PET/CT screening to patients with TF activity > 2.8 pM would improve the PPV to 37.5% and reduce the costs of a single cancer diagnosis from 20,711€ to 11,670€. FDG-PET/CT is feasible for the screening of occult cancer in patients with unprovoked VTE, showing high S and NPV. The addition of TF activity determination may be useful for patient selection. 23868949 Novel modulating effects of PKC family genes on the relationship between serum vitamin D and relapse in multiple sclerosis. The interplay between genes and environmental factors on multiple sclerosis (MS) clinical course has been little studied. We conducted a prospective cohort study of 141 participants with relapsing-remitting MS (RRMS) and genotype data followed from 2002 to 2005 and examined genes in the vitamin D metabolism and vitamin D receptor (VDR)/retinoid X receptor (RXR) transcription factor formation pathway. Gene-vitamin D interactions and the genetic predictors of relapse were assessed using survival analysis. Genetic predictors of 25-hydroxyvitamin D (25(OH)D) were evaluated by multilevel mixed-effects linear regression. Significance threshold was adjusted by Bonferroni correction for the number of genes evaluated. The relationship between 25(OH)D and hazard of relapse was significantly different for different alleles of two intronic single nucleotide polymorphisms (SNPs) (rs908742 in PRKCZ and rs3783785 in PRKCH) in the protein kinase C (PKC) family genes (pinteraction=0.001, padj=0.021, respectively). Two other intronic SNPs (rs1993116 in CYP2R1and rs7404928 in PRKCB) were significantly associated with lower levels of 25(OH)D (pinteraction=0.001, padj=0.021, respectively). A cumulative effect of multiple 'risk' genotypes on 25(OH)D levels and hazard of relapse was observed for the significant SNPs (ptrend=7.12×10(-6) for 25(OH)D levels, ptrend=8.86×10(-6) for hazard of relapse). Our data support the hypothesis that gene-vitamin D interactions may influence MS clinical course and that the PKC family genes may play a role in the pathogenesis of MS relapse through modulating the association between 25(OH)D and relapse. 23884626 Proteins in amorphous saccharide matrices: Structural and dynamical insights on bioprotection. Bioprotection by sugars, and in particular trehalose peculiarity, is a relevant topic due to the implications in several fields. The underlying mechanisms are not yet clearly elucidated, and remain the focus of current investigations. Here we revisit data obtained at our lab on binary sugar/water and ternary protein/sugar/water systems, in wide ranges of water content and temperature, in the light of the current literature. The data here discussed come from complementary techniques (Infrared Spectroscopy, Molecular Dynamics simulations, Small Angle X-ray Scattering and Calorimetry), which provided a consistent description of the bioprotection by sugars from the atomistic to the macroscopic level. We present a picture, which suggests that protein bioprotection can be explained in terms of a strong coupling of the biomolecule surface to the matrix via extended hydrogen-bond networks, whose properties are defined by all components of the systems, and are strongly dependent on water content. Furthermore, the data show how carbohydrates having similar hydrogen-bonding capabilities exhibit different efficiency in preserving biostructures. 23554574 Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis. Hypothalamic neurons are main regulators of energy homeostasis. Neuronal function essentially depends on plasma membrane-located gangliosides. The present work demonstrates that hypothalamic integration of metabolic signals requires neuronal expression of glucosylceramide synthase (GCS; UDP-glucose:ceramide glucosyltransferase). As a major mechanism of central nervous system (CNS) metabolic control, we demonstrate that GCS-derived gangliosides interacting with leptin receptors (ObR) in the neuronal membrane modulate leptin-stimulated formation of signaling metabolites in hypothalamic neurons. Furthermore, ganglioside-depleted hypothalamic neurons fail to adapt their activity (c-Fos) in response to alterations in peripheral energy signals. Consequently, mice with inducible forebrain neuron-specific deletion of the UDP-glucose:ceramide glucosyltransferase gene (Ugcg) display obesity, hypothermia, and lower sympathetic activity. Recombinant adeno-associated virus (rAAV)-mediated Ugcg delivery to the arcuate nucleus (Arc) significantly ameliorated obesity, specifying gangliosides as seminal components for hypothalamic regulation of body energy homeostasis. 23673519 A prospective study on dinghy sailors' training habits and injury incidence with a comparison between elite sailor and club sailor during a 12-month period. Sailing is an Olympic sport practiced by both men and women of all ages. Despite being a popular sport, we have found no prospective studies investigating the injury incidence and training quantity such as found for other sports. The purpose of this study was to do an inventory over dinghy sailors' training habits, injury incidence and type of injury. In this prospective cohort study, 45 sailors (17 women and 28 men), age 17-31 years, were included. 24 sailors belonged to the SWE Sailing Team and 21 were club sailors. All the participants kept a training diary, and once a month for 12 months they reported their training and injuries through a web-based questionnaire. Each time a sailor reported an injury, they were contacted by the researchers and an injury form was completed. The SWE Sailing Team performed significantly (p=0.006) more physical training than the club sailor. There was no significant difference (p=0.7) in hours of sail training. A total of 144 injuries were reported. The most common injury location was the knee (19%), followed by the lower leg (13%) and shoulder (12%). 30% of the injuries occurred during physical training, 17% during sail training and 12% during sail racing. The most common injury location was the knee. The largest proportion of injuries occurred during physical training and unspecified activities. The least number of injuries occurred during sail racing. The injury location was different between the older more experienced sailor (more upper extremity injuries) compared with the younger sailors (more trunk injuries). 23835158 Directed evolution of a family 26 glycoside hydrolase: Endo-β-1, 4-mannanase from Pantoea agglomerans A021. Pantoea agglomerans endo-β-1, 4-mannanase (Man26P) hydrolyzes hemicellulose by cleaving the internal bonds in the mannan-based chains. In order to obtain improved enzymes and understand the structure-function relationship better, Man26P was engineered using a modified DNA shuffling method and a 96-well plate high-throughput screening technology. Compared to the wild-type enzyme, two mutants Gly267Ser and His134Arg/Phe141Leu with 1.14- and 3.30-fold increased catalytic efficiency (kcat/Km) toward locust bean gum (LBG) were obtained from the mutant library containing 19,700 clones. Combined with site-directed mutagenesis, more substitutions were introduced into the 134 site, among which, His134Arg and His134Lys exhibited 2.81- and 2.75-fold increased catalytic efficiency versus the wild-type enzyme. And with an increase in the pKa values of the side chains of the mutated residues at the 134 site, a decrease was observed in their Km values against LBG. The molecular modeling and the docking analysis of the substrate suggest that the enhancement of polar contacts or positive charges at the 134 site contribute to the interaction of the enzyme with the substrate. Furthermore, the nature of the residue at the 267 site could also significantly affect the enzyme activity by regulating substrate binding affinity and product release. The study provides useful information for the directed evolution of mannanases. 23489415 Patterns of neural connectivity during an attention bias task moderate associations between early childhood temperament and internalizing symptoms in young adulthood. Biased attention to threat is found in both individuals with anxiety symptoms and children with the childhood temperament of behavioral inhibition (BI). Although perturbed fronto-amygdala function is implicated in biased attention among anxious individuals, no work has examined the neural correlates of attention biases in BI. Work in this area might clarify underlying mechanisms for anxiety in a sample at risk for internalizing disorders. We examined the relations among early childhood BI, fronto-amygdala connectivity during an attention bias task in young adulthood, and internalizing symptoms, assessed in young adulthood. Children were assessed for BI at multiple age points from infancy through age seven. On the basis of a composite of observational and maternal report data, we selected 21 young adults classified as having a history of BI and 23 classified as non-BI for this study (n = 44). Participants completed an event-related functional magnetic resonance imaging attention-bias task involving threat (angry faces) and neutral trials. Internalizing symptoms were assessed by self-report and diagnostic interviews. The young adults characterized in childhood with BI exhibited greater strength in threat-related connectivity than non-behaviorally inhibited young adults. Between-group differences manifested in connections between the amygdala and two frontal regions: dorsolateral prefrontal cortex and anterior insula. Amygdala-insula connectivity also interacted with childhood BI to predict young adult internalizing symptoms. Behavioral inhibition during early childhood predicts differences as young adults in threat and attention-related fronto-amygdala connectivity. Connectivity strength, in turn, moderated the relations between early BI and later psychopathology. 23279118 Effects on caregiver burden of education related to home care in patients undergoing hemodialysis. Caring for a patient undergoing hemodialysis is highly stressful and can negatively affect a caregiver's physical and psychological well-being. This study was conducted to examine the effect of educational support concerning caregiver burden and given to the caregivers of hemodialysis patients. This experimental study was performed with 122 caregivers. Patients' data were collected by means of Personal Information Form and Zarit Caregiver Burden Scale (ZCBS). Characteristics of caregivers of hemodialysis patients were analyzed descriptively in terms of frequencies and percentages for categorical data, means, and standard deviations. Mann-Whitney U test, Kruskall-Wallis test, and percentages were used in the data analysis. The mean ZCBS score was 52.1 ± 8.6 (range, 0-88). Among the caregivers, the mean score of the ZCBS was significantly higher in women, single, young, family relatives as "daughter/sister/brother/daughter-in-law and town/district, high educational level (P < 0.05). Moreover, the mean score of the ZCBS was significantly higher in caregivers who have health problems/diseases. In addition, this study explored the educational needs of home-based such as nutrition (35.2%), dialysis (27.8%), fistula care (20.4%), catheter care (18.8%), the information about chronic kidney disease (18.0%), blood pressure (17.2%), weight control (17.2%), hygiene (3.1%), and travel/exercise (6.5%). The post-educational mean scores (55.0 ± 7.6) of caregiver burden were observed to be lower than the pre-educational scores (43.9 ± 5.2), and the difference was found to be statistically significant. The home-based educational program demonstrated a decrease in the burden of hemodialysis caregivers. 23847576 Thirty shades of truth: conspiracy theories as stories of individuation, not of pathological delusion. Recent studies on conspiracy theories employ standardized questionnaires, thus neglecting their narrative qualities by reducing them to mere statements. Recipients are considered as consumers only. Two empirical studies-a conventional survey (n = 63) and a study using the method of narrative construction (n = 30)-which were recently conducted by the authors of this paper-suggest that the truth about conspiracy theories is more complex. Given a set of statements about a dramatic historic event (in our case 9/11) that includes official testimonies, allegations to a conspiracy and extremely conspiratorial statements, the majority of participants created a narrative of 9/11 they deemed plausible that might be considered a conspiracy theory. The resulting 30 idiosyncratic stories imply that no clear distinction between official story and conspiratorial narrative is possible any more when the common approach of questionnaires is abandoned. Based on these findings, we present a new theoretical and methodological approach which acknowledges conspiracy theories as a means of constructing and communicating a set of personal values. While broadening the view upon such theories, we stay compatible with other approaches that have focused on extreme theory types. In our view, accepting conspiracy theories as a common, regulative and possibly benign phenomenon, we will be better able to understand why some people cling to immunized, racist and off-wall stories-and others do not. 23828269 Benthic foraminiferal response to trace element pollution-the case study of the Gulf of Milazzo, NE Sicily (Central Mediterranean Sea). The response of benthic foraminiferal assemblages to trace element pollution in the marine sediments of the Gulf of Milazzo (north-eastern Sicily) was investigated. Since the 1960s, this coastal area has been a preferred site for the development of two small marinas and a commercial harbour as well as for heavy industry. Forty samples collected in the uppermost 3-4 cm of an undisturbed layer of sediment in the littoral environment were used for this benthic foraminiferal analysis. The enrichment factors (EFs) of selected trace elements (As, Co, Cr, Cu, Mn, Ni, Pb and Zn) were also calculated. Changes both in benthic foraminiferal assemblages and in some trace elements concentrations have provided evidence that the gulf's littoral zone can be subdivided into three sectors characterised by environmental changes in the marine ecosystem. In the sector unpolluted, close to the Milazzo Cape, foraminiferal assemblages exhibit high values of species richness and foraminiferal density while trace element concentrations and their EFs are very low. Here, the highest densities of Miliolids and epiphytic species are present. On the contrary, in the sector polluted, from the marinas to the crude oil refinery, foraminiferal density and species diversity are low, and assemblages are dominated, albeit with very low densities, by species that tolerate stressed environmental conditions, such as LOFAs, agglutinants and Ammonia spp. Here, the highest trace elements concentrations of Pb, Zn and Cu and related EFs were detected. Eastwards, in the sector moderately polluted, foraminiferal populations are quite poor. They are characterised by low values of species richness and foraminiferal densities, nevertheless trace element concentrations become lower than in the other sectors and their EFs are often below 1. Deformed foraminifera, with percentages up to 7.14 %, were found in all three of the sectors. Differences in benthic foraminiferal assemblages, coupled with results from statistical analysis, indicate that anthropogenic trace element pollution could be considered as one of the most important causes of the modifications of foraminiferal assemblages in the study area. 23743034 Effects of grape seed extract on the oxidative and microbial stability of restructured mutton slices. The antioxidant and antimicrobial efficacy of grape seed extract (GSE) was studied in restructured mutton slices (RMS) under aerobic and vacuum packaging conditions during refrigerated storage. The RMS treated with grape seed extract (GSE) had significantly (P<0.05) lower thiobarbituric acid reactive substance (TBARS) values and free fatty acids (FFA) % compared to control (C) and butylated hydroxy anisole (BHA) treated RMS during storage at 4±1°C. Addition of GSE significantly (P<0.05) reduced the total psychrophilic and coliform counts in RMS during refrigerated storage. The GSE treated mutton slices recorded significantly (P<0.05) superior scores of color, flavor, juiciness and overall palatability than C and BHA treated RMS. The TBARS values, FFA % and microbial counts increased significantly (P<0.05) during storage. It can be concluded that GSE has excellent antioxidant and antimicrobial properties compared to control and BHA treated RMS during refrigerated storage under aerobic and vacuum conditions. 23845424 Subtle Interplay between Synaptotagmin and Complexin Binding to the SNARE Complex. Ca(2+)-triggered neurotransmitter release depends on the formation of SNARE complexes that bring the synaptic vesicle and plasma membranes together, on the Ca(2+) sensor synaptotagmin-1 and on complexins, which play active and inhibitory roles. Release of the complexin inhibitory activity by binding of synaptotagmin-1 to the SNARE complex, causing complexin displacement, was proposed to trigger exocytosis. However, the validity of this model was questioned based on the observation of simultaneous binding of complexin-I and a fragment containing the synaptotagmin-1 C2 domains (C2AB) to membrane-anchored SNARE complex. Using diverse biophysical techniques, here we show that C2AB and complexin-I do not bind to each other but can indeed bind simultaneously to the SNARE complex in solution. Hence, the SNARE complex contains separate binding sites for both proteins. However, total internal reflection fluorescence microscopy experiments show that C2AB can displace a complexin-I fragment containing its central SNARE-binding helix and an inhibitory helix (Cpx26-83) from membrane-anchored SNARE complex under equilibrium conditions. Interestingly, full-length complexin-I binds more tightly to membrane-anchored SNARE complex than Cpx26-83, and it is not displaced by C2AB. These results show that interactions of N- and/or C-terminal sequences of complexin-I with the SNARE complex and/or phospholipids increase the affinity of complexin-I for the SNARE complex, hindering dissociation induced by C2AB. We propose a model whereby binding of synaptotagmin-1 to the SNARE complex directly or indirectly causes a rearrangement of the complexin-I inhibitory helix without inducing complexin-I dissociation, thus relieving the inhibitory activity and enabling cooperation between synaptotagmin-1 and complexin-I in triggering release. 23820079 Inactivated West Nile Virus (WNV) vaccine, Duvaxyn WNV, protects against a highly neuroinvasive lineage 2 WNV strain in mice. Lineage 2 West Nile Virus (WNV) is endemic to southern Africa and Madagascar, and has recently been associated with encephalitis outbreaks in humans and horses in South Africa, central Europe, Italy and Greece. Commercial vaccines have mostly been evaluated against WNV lineage 1 strains and their efficacy against lineage 2 strains rarely reported. To evaluate protection of Duvaxyn WNV vaccine against lineage 2 strains associated with encephalitis in South Africa, mice were vaccinated twice intramuscularly three weeks apart, and challenged four weeks later with highly neuroinvasive lineage 1 strain NY385/99 or lineage 2 strain SPU93/01. Neutralising antibody titres were measured at the time of challenge and three weeks later. Immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) were conducted on brains of mice that succumbed during the trial, on controls and on vaccinated mice that survived. Serum neutralising antibodies in vaccinated mice were detected but low three weeks after primovaccination. Three weeks post-challenge, vaccinated mice had significantly higher serum neutralising antibody titres against both lineages than unvaccinated controls. After challenge, all vaccinated mice remained healthy but all unvaccinated mice demonstrated severe neurological signs with 75% mortality rate. WNV was not detected in brains of vaccinated mice whereas virus replicated in most unvaccinated mice challenged with either lineage. Gross and microscopic lesions were found only in unvaccinated mice challenged with both lineages. Duvaxyn WNV vaccine provided complete protection against challenge with lineage 2 WNV and stimulated significant cross protective neutralising antibodies in mice against lineage 2. 23659767 Intratympanic manganese administration revealed sound intensity and frequency dependent functional activity in rat auditory pathway. The cochlear plays a vital role in the sense and sensitivity of hearing; however, there is currently a lack of knowledge regarding the relationships between mechanical transduction of sound at different intensities and frequencies in the cochlear and the neurochemical processes that lead to neuronal responses in the central auditory system. In the current study, we introduced manganese-enhanced MRI (MEMRI), a convenient in vivo imaging method, for investigation of how sound, at different intensities and frequencies, is propagated from the cochlear to the central auditory system. Using MEMRI with intratympanic administration, we demonstrated differential manganese signal enhancements according to sound intensity and frequencies in the ascending auditory pathway of the rat after administration ofintratympanicMnCl2.Compared to signal enhancement without explicit sound stimuli, auditory structures in the ascending auditory pathway showed stronger signal enhancement in rats who received sound stimuli of 10 and 40kHz. In addition, signal enhancement with a stimulation frequency of 40kHz was stronger than that with 10kHz. Therefore, the results of this study seem to suggest that, in order to achieve an effective response to high sound intensity or frequency, more firing of auditory neurons, or firing of many auditory neurons together for the pooled neural activity is needed. 23844746 Influence of Discrete and Continuous Culture Conditions on Human Mesenchymal Stem Cell Lineage Choice in RGD Concentration Gradient Hydrogels. Stem cells have shown lineage-specific differentiation when cultured on substrates possessing signaling groups derived from the native tissue. A distinct determinant in this process is the concentration of the signaling motif. While several groups have been working actively to determine the specific factors, concentrations, and mechanisms governing the differentiation process, many have been turning to combinatorial and gradient approaches in attempts to optimize the multiple chemical and physical parameters needed for the next advance. However, there has not been a direct comparison between the cellular behavior and differentiation of human mesenchymal stem cells cultured in gradient and discrete substrates, which quantitates the effect of differences caused by cell-produced, soluble factors due to design differences between the culture systems. In this study, the differentiation of human mesenchymal stem cells in continuous and discrete polyethylene glycol dimethacrylate (PEGDM) hydrogels containing an RGD concentration gradient from 0 to 14 mM were examined to study the effects of the different culture conditions on stem-cell behavior. Culture condition was found to affect every osteogenic (alkaline phosphatase, Runx 2, type 1 collagen, bone sailoprotein, and calcium content) and adipogenic marker (oil red and peroxisome proliferator-activated receptor gamma) examined regardless of RGD concentration. Only in the continuous gradient culture did RGD concentration affect human mesenchymal stem-cell lineage commitment with low RGD concentrations expressing higher osteogenic differentiation than high RGD concentrations. Conversely, high RGD concentrations expressed higher adipogenic differentiation than low RGD concentrations. Cytoskeletal actin organization was only affected by culture condition at low RGD concentrations, indicating that it played a limited role in the differences in lineage commitment observed. Therefore, the role of discrete versus gradient strategies in high-throughput experimentation needs to be considered when designing experiments as we show that the respective strategies alter cellular outcomes even though base scaffolds have similar material and chemical properties. 23325574 Expression of Hsp70 in the mud crab, Scylla paramamosain in response to bacterial, osmotic, and thermal stress. Hsp70 is involved in immune responses against infectious pathogens, thermal, and osmotic stress. To understand the immune defense mechanisms of the mud crab Scylla paramamosain, genomic DNA, transcript level and antimicrobial activities of Hsp70 were analyzed. Genomic DNA sequence analysis revealed one intron in this gene. Furthermore, six SNPs were detected by direct sequencing from 30 samples in this study. Hsp70 mRNA was expressed in almost all tissues examined. By using the quantitative real-time PCR, the expression level of Hsp70 in hemocytes showed a clear time-dependent expression pattern during the 96 h after stimulated by Vibrio alginolyticus. Then, recombinant Hsp70 was obtained by using the bacterial expression system, but no obvious antimicrobial activity has been found for the protein in the antimicrobial tests. After osmotic stress, the expression of Hsp70 in hemocytes showed this gene was induced by the high salinity (30 ‰) for at least 96 h. Hsp70 mRNA expression in hemocytes was analyzed after thermal stress at 6 h, the highest and the lowest expression level of Hsp70 was observed at 36 and 15 °C, respectively. These results indicated that Hsp70 was inducible by bacterial, osmotic, and thermal stress, and therefore plays an important role, different from antibacterial peptide, in innate immune responses of S. paramamosain. 23879439 Sexual chance taking: A qualitative study on sexuality among detained youths. Background Many, although not all, juvenile detainees are known to be sexual risk-takers but little attention has been paid to why they engage in early sexual intercourse, have more partners, often have sex under the influence of drugs or alcohol, and without protection. Objective To understand the rationale behind sexual risk-taking among detained adolescents. Method Qualitative study of interviews with nine girls and 11 boys, aged 15 to 20 years, at detention centres in southern Sweden. Results Two major categories surface in the analysis of the interviews: contradictions and vulnerability. A core category, chance outdoes risk that describes the adolescents' pragmatic view on sexual risk-taking as being a chance of something good rather than a risk of something bad, captures the connection between these categories and the individual. Conclusion Among our interviewees, sexual chance taking appears rewarding. Recognising this rationality is valuable for all professionals promoting sexual health within similar groups of youths. 23754278 The Peptidyl-prolyl Isomerase Pin1 Up-regulation and Proapoptotic Function in Dopaminergic Neurons: RELEVANCE TO THE PATHOGENESIS OF PARKINSON DISEASE. Parkinson disease (PD) is a chronic neurodegenerative disease characterized by a slow and progressive degeneration of dopaminergic neurons in substantia nigra. The pathophysiological mechanisms underlying PD remain unclear. Pin1, a major peptidyl-prolyl isomerase, has recently been associated with certain diseases. Notably, Ryo et al. (Ryo, A., Togo, T., Nakai, T., Hirai, A., Nishi, M., Yamaguchi, A., Suzuki, K., Hirayasu, Y., Kobayashi, H., Perrem, K., Liou, Y. C., and Aoki, I. (2006) J. Biol. Chem. 281, 4117-4125) implicated Pin1 in PD pathology. Therefore, we sought to systematically characterize the role of Pin1 in PD using cell culture and animal models. To our surprise we observed a dramatic up-regulation of Pin1 mRNA and protein levels in dopaminergic MN9D neuronal cells treated with the parkinsonian toxicant 1-methyl-4-phenylpyridinium (MPP(+)) as well as in the substantia nigra of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Notably, a marked expression of Pin1 was also observed in the substantia nigra of human PD brains along with a high co-localization of Pin1 within dopaminergic neurons. In functional studies, siRNA-mediated knockdown of Pin1 almost completely prevented MPP(+)-induced caspase-3 activation and DNA fragmentation, indicating that Pin1 plays a proapoptotic role. Interestingly, multiple pharmacological Pin1 inhibitors, including juglone, attenuated MPP(+)-induced Pin1 up-regulation, α-synuclein aggregation, caspase-3 activation, and cell death. Furthermore, juglone treatment in the MPTP mouse model of PD suppressed Pin1 levels and improved locomotor deficits, dopamine depletion, and nigral dopaminergic neuronal loss. Collectively, our findings demonstrate for the first time that Pin1 is up-regulated in PD and has a pathophysiological role in the nigrostriatal dopaminergic system and suggest that modulation of Pin1 levels may be a useful translational therapeutic strategy in PD. 23454895 pH-sensitive nanocargo based on smart polymer functionalized graphene oxide for site-specific drug delivery. Graphene oxide (GO) was functionalized covalently with pH-sensitive poly(2-(diethylamino) ethyl methacrylate) (PDEA) by surface-initiated in situ atom transfer radical polymerization. The structure of the PDEA-grafted GO (GO-PDEA) were examined by Fourier-transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, X-ray photoelectron spectroscopy, thermogravimetric analysis and atomic force microscopy. The grafted PDEA endowed the GO sheets with good solubility and stability in physiological solutions. Simple physisorption by π-π stacking and hydrophobic interactions on GO-PDEA can be used to load camptothecin (CPT), a widely used water-insoluble cancer drug. The loaded CPT was released only at the lower (acidic) pH normally found in a tumor environment but not in basic and neutral pH. GO-PDEA did not show practical toxicity to N2a cancer cells but the GO-PDEA-CPT complex exhibited high potency in killing N2a cancer cells in vitro. These results suggest that the GO-PDEA nanocargo carrier might be a promising material for site-specific anticancer drug delivery and controlled release. 23621148 Mechanism of Fibrinogen Adsorption at Solid Substrates at lower pH. Adsorption of fibrinogen was theoretically studied using the three dimensional (3D) random sequential adsorption (RSA) model. Fibrinogen molecule shape was approximated by the bead model considering the presence of flexible side arms. Various cases were considered inter alia, the side-on adsorption mechanisms and the 3D side-on/end-on simultaneous adsorption mechanism. The latter mechanisms is pertinent to fibrinogen adsorption at lower pH where the entire molecule is positively charged. Extensive calculations enabled one to determine the jamming surface concentration (coverage) of molecules adsorbed under the side-on and end-on orientations as well as the total coverage. For the 3D model the maximum surface concentration was 7.29x103 μm-2 corresponding to the protein coverage of 4.12 mg m-2 (without considering hydration). Additionally, the surface blocking functions for the side-on and the 3D adsorption regimes were determined and analytically approximated for the entire range of coverage by the interpolating polynomials. Using these blocking functions, fibrinogen adsorption kinetics for diffusion controlled transport conditions was evaluated. Comparison of these theoretical results with experimental data was made. It was demonstrated that the 3D model properly reflects the maximum coverage of fibrinogen adsorbed on latex particles determined via the electrokinetic (electrophoretic mobility) and AFM measurements. Also, streaming potential measurements of fibrinogen adsorption kinetics on mica were successfully interpreted in terms of the 3D adsorption model. The theoretical results derived in this work have implications for basic science providing information on mechanisms of anisotropic protein adsorption. Key words: adsorption of fibrinogen, fibrinogen adsorption at lower pH, irreversible adsorption of fibrinogen, jamming coverage of fibrinogen, kinetics of fibrinogen adsorption, random sequential adsorption modeling of fibrinogen adsorption. 23945048 An experimental clinical evaluation of EIT imaging with ℓ1 data and image norms. Electrical impedance tomography (EIT) produces an image of internal conductivity distributions in a body from current injection and electrical measurements at surface electrodes. Typically, image reconstruction is formulated using regularized schemes in which ℓ2-norms are used for both data misfit and image prior terms. Such a formulation is computationally convenient, but favours smooth conductivity solutions and is sensitive to outliers. Recent studies highlighted the potential of ℓ1-norm and provided the mathematical basis to improve image quality and robustness of the images to data outliers. In this paper, we (i) extended a primal-dual interior point method (PDIPM) algorithm to 2.5D EIT image reconstruction to solve ℓ1 and mixed ℓ1/ℓ2 formulations efficiently, (ii) evaluated the formulation on clinical and experimental data, and (iii) developed a practical strategy to select hyperparameters using the L-curve which requires minimum user-dependence. The PDIPM algorithm was evaluated using clinical and experimental scenarios on human lung and dog breathing with known electrode errors, which requires a rigorous regularization and causes the failure of reconstruction with an ℓ2-norm solution. The results showed that an ℓ1 solution is not only more robust to unavoidable measurement errors in a clinical setting, but it also provides high contrast resolution on organ boundaries. 23810294 Inhibition of C2C12 myotube atrophy by a novel HSP70 inducer, celastrol, via activation of Akt1 and ERK1/2 pathways. Celastrol (CEL) is known as a potent inducer of heat shock protein (HSP) in non-muscle cells and exhibits cytoprotective function and inhibitory effects on proteasome and glucocorticoid receptor activities. To investigate an anti-atrophic effect of CEL on skeletal muscle cells, C2C12 myotubes were treated with 150μM dexamethasone (DEX) for 24h and 1.5μM CEL was added for the last 6h during the 24h DEX treatment. Compared to the control, the myotube diameter was reduced by a factor of 0.30 by DEX, but CEL treatment almost abrogated the DEX-induced atrophy. CEL treatment also increased expression of HSP72 and phosphorylation of heat shock transcription factor 1 (p-HSF1) 11-fold and 3.4-fold, respectively, as well as accumulation of p-HSF1 in the nucleus. Furthermore, CEL treatment elevated activities of Akt1, p70/S6K and ERK1/2 2.0- to 4.4-fold whereas DEX had no effect on these signaling activities. Inhibition of Akt1 and ERK1/2 pathways by specific inhibitors confirmed CEL-induced anti-atrophic effect. Moreover, DEX-mediated downregulation of FoxO3 phosphorylation and upregulation of MuRF1 expression and proteasome activity were abrogated by CEL treatment. These results demonstrate a novel anti-atrophic function of CEL in muscle cells via both activation of protein anabolic signals and suppression of catabolic signaling activities. 23851682 Tumor-infiltrating regulatory T cells inhibit endogenous cytotoxic T cell responses to lung adenocarcinoma. Immune cells comprise a substantial proportion of the tumor mass in human nonsmall cell lung cancers (NSCLC), but the precise composition and significance of this infiltration are unclear. In this study, we examined immune complexity of human NSCLC as well as NSCLC developing in CC10-TAg transgenic mice, and revealed that CD4(+) T lymphocytes represent the dominant population of CD45(+) immune cells, and, relative to normal lung tissue, CD4(+)Foxp3(+) regulatory T cells (Tregs) were significantly increased as a proportion of total CD4(+) cells. To assess the functional significance of increased Tregs, we evaluated CD8(+) T cell-deficient/CC10-TAg mice and revealed that CD8(+) T cells significantly controlled tumor growth with antitumor activity that was partially repressed by Tregs. However, whereas treatment with anti-CD25-depleting mAb as monotherapy preferentially depleted Tregs and improved CD8(+) T cell-mediated control of tumor progression during early tumor development, similar monotherapy was ineffective at later stages. Because mice bearing early NSCLC treated with anti-CD25 mAb exhibited increased tumor cell death associated with infiltration by CD8(+) T cells expressing elevated levels of granzyme A, granzyme B, perforin, and IFN-γ, we therefore evaluated carboplatin combination therapy resulting in a significantly extended survival beyond that observed with chemotherapy alone, indicating that Treg depletion in combination with cytotoxic therapy may be beneficial as a treatment strategy for advanced NSCLC. 23969952 Internal Carotid Artery variations in Velocardiofacial Syndrome patients and it's implications for surgery. Velocardiofacial syndrome (VCFS) is the most common genetic syndrome causing cleft palate and velopharyngeal insufficiency. A pharyngeal flap is considered to be effective procedure, with success rates of 78 to 98 percent. Medially displaced internal carotid arteries in VCFS are well-known and carry a risk during pharyngeal flap surgery. Preoperative imaging evaluation is routinely recommended. This study was designed to evaluate the frequency of medially deviated internal carotid arteries in both VCFS patients and general pediatric population, and assess their minimum distance to the pharyngeal walls in order to define the potential risk of ICA injury during pharyngeal surgery. From July 2003 to July 2012, 23 consecutive patients, who were diagnosed as VCFS and underwent posterior pharyngeal flap operation, were reviewed retrospectively 21 control subjects who did not have VCFS but underwent oropharynx MRI were reviewed. We assessed the medial deviation of internal carotid artery and the minimum distance to the posterior wall at the level of oropharynx. Medial deviation of at least one internal carotid artery (ICA) was documented 10 patients (43.5%) in VCFS patients as compared with 3 patients (14.3%) in control group.(P=0.034) The mean of the minimum distance to the posterior pharyngeal wall was 3.78 ± 1.86 in VCFS patients as compared with 9.17 ± 2.94 in control group.(P= 0.014) Only one patient had significant medial dislocation of ICA and the closest distance from the pharyngeal wall was 0.86mm. The deviated internal carotid artery was located in the submucosal plane and near the level where the distal end of pharyngeal flap was expected. But injury to the internal carotid artery did not occur and there was no excessive intraoperative or postoperative bleeding. In VCFS patients, medial dislocation of internal carotid artery was common and the length of the minimum distance to the pharyngeal wall was short comparing with control group. However, In most of our patients variations, the course of the cervical portion of the ICA is irrelevant to the pharyngeal flap operations. We concluded that preoperative vascular imaging study is not cost-effective in VCFS patients, but intraoperative use of ultrasound imaging is still valuable for the purpose of planning pharyngeal flap. 23681313 Electronic structures and magnetic properties of MoS2 nanostructures: atomic defects, nanoholes, nanodots and antidots. Developing approaches to effectively induce and control the magnetic states is critical to the use of magnetic nanostructures in quantum information devices but is still challenging. Here MoS2-based nanostructures including atomic defects, nanoholes, nanodots and antidots are characterized with spin-polarized density functional theory. The S-vacancy defect is more likely to form than the Mo-vacancy defect due to the form of Mo-Mo metallic bonds. Among different shaped nanoholes and nanodots, triangle ones associated with ferromagnetic characteristic are most energetically favorable, and exhibit unexpected large spin moments that scale linearly with edged length. In particular, S-terminated triangle nanodots show strong spin anisotropy around the Fermi level with a substantial collective characteristic of spin states at edges, enabling it to a desired spin-filtering structure. However, in the antidot, the net spin, coupled order and stability of spin states can be engineered by controlling type and distance of internal nanoholes. Based on the analysis of the spin coupled mechanism, a specific antidot structure, the only S-terminated antidot, was determined to exhibit a large net spin with long-range ferromagnetic coupling above room temperature. Given the recent achievement of graphene- and BN-based nanohole, nanodot and antidot structures, we believe that our calculated results are suitable for experimental verification and implementation opening a new path to explore MoS2-based magnetic nanostructures. 23697662 Impact of pretreatments on morphology and enzymatic saccharification of shedding bark of Melaleuca leucadendron. The effects of subcritical water (SCW) and dilute acid pretreatments on the shedding bark of Melaleuca leucadendron (paper bark tree, PBT) biomass morphology, crystallinity index (CrI) and enzymatic saccharification were studied. The morphology of PBT bark was characterized by X-ray diffraction, scanning electron microscopy and Fourier transform infrared spectroscopy. SCW pretreatment mainly extracted amorphous parts of the biomass hence its CrI increased, partial decrystallization of cellulose and exposing of intact nanofibers of cellulose were observed for SCW pretreatment at 180°C. On the other hand, dilute acid pretreatment at 160°C exhibited a large decrease in CrI, an increase in surface area, a decrease in lignin content and decrystallization of cellulose as well as the peel-off and degradation of some nanofiber bundles. Dilute acid and SCW pretreatments of PBT biomass resulted in about 4.5 fold enhancement in glucose release relative to the untreated one. 23750905 Linking anti-predator behaviour to prey demography reveals limited risk effects of an actively hunting large carnivore. Ecological theory predicts that the diffuse risk cues generated by wide-ranging, active predators should induce prey behavioural responses but not major, population- or community-level consequences. We evaluated the non-consumptive effects (NCEs) of an active predator, the grey wolf (Canis lupus), by simultaneously tracking wolves and the behaviour, body fat, and pregnancy of elk (Cervus elaphus), their primary prey in the Greater Yellowstone Ecosystem. When wolves approached within 1 km, elk increased their rates of movement, displacement and vigilance. Even in high-risk areas, however, these encounters occurred only once every 9 days. Ultimately, despite 20-fold variation in the frequency of encounters between wolves and individual elk, the risk of predation was not associated with elk body fat or pregnancy. Our findings suggest that the ecological consequences of actively hunting large carnivores, such as the wolf, are more likely transmitted by consumptive effects on prey survival than NCEs on prey behaviour. 23683596 Discovery of N-(4'-(indol-2-yl)phenyl)sulfonamides as novel inhibitors of HCV replication. A series of novel 2-phenylindole analogs were synthesized and evaluated for activity in subgenomic HCV replicon inhibition assays. Several compounds containing small alkyl sulfonamides on the phenyl ring exhibiting submicromolar EC50 values against the genotype 1b replicon were identified. Among these, compound 25d potently inhibited the 1b replicon (EC50=0.17 μM) with 147-fold selectivity with respect to cytotoxicity. Compound 25d was stable in the presence of human liver microsomes and had a good pharmacokinetic profile in rats with an IV half-life of 4.3h and oral bioavailability (F) of 58%. 23543463 Effects of a TASER(®) conducted energy weapon on the circulating red-blood-cell population and other factors in Sus scrofa. In previous studies hematocrit has been consistently increased in an anesthetized animal model after exposures to TASER(®) conducted energy weapons (CEWs). In the present study we analyzed changes in blood cell counts and red blood cell membrane proteins following two 30-s applications of a TASER C2 device (which is designed for civilian use). Hematocrit increased significantly from 33.2 ± 2.4 (mean ± SD) to 42.8 ± 4.6 % immediately after CEW exposure of eleven pigs (Sus scrofa). Red blood cell count increased significantly from 6.10 ± 0.55 Ã— 10(12)/L to 7.45 ± 0.94 Ã— 10(12)/L, and mean corpuscular volume increased significantly from 54.5 ± 2.4 fl to 57.8 ± 2.6 fl. Mean corpuscular hemoglobin concentration decreased significantly from 20.5 ± 0.7 to 18.5 ± 0.6 mM. Thirty protein spots (from two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis, selected for detailed comparison) exhibited greater densities 30-min post-exposure compared with pre-exposure values. A greater number of echinocytes were observed following CEW exposure. On the basis of these results it appears that, during the strong muscle contractions produced by TASER CEWs, a specific population of red blood cells (RBCs) may be released from the spleen or other reservoirs within the body. The total time of CEW exposure in the present study was relatively long compared with exposures in common law-enforcement scenarios. Despite statistically significant changes in red blood cell counts (and other measures directly related to RBCs), the alterations were short-lived. The transient nature of the changes would be likely to counteract any potentially detrimental effects. 23090004 The results of the Tokyo Trial of Prevention of Post-ERCP Pancreatitis with Risperidone (Tokyo P3R): a multicenter, randomized, phase II, non-placebo-controlled trial. A previous study suggested that ulinastatin effectively prevented post-ERCP pancreatitis (PEP) and hyperenzymemia (PEH) in patients at average risk. In experimental models, risperidone, a selective serotonin 2A antagonist, ameliorated acute pancreatitis. We assessed the effect of risperidone combined with ulinastatin for the prevention of PEP in high-risk patients. In a multicenter, randomized, controlled, phase II trial, patients undergoing therapeutic ERCP were randomly assigned to receive ulinastatin (150000 U) with or without risperidone (1 mg). A risperidone tablet was taken orally 30-60 min before ERCP and ulinastatin was administered intravenously for 10 min immediately prior to ERCP. The primary end point was the incidence of PEP; secondary end points were PEH severity and enzyme levels (amylase, pancreatic amylase, lipase). A total of 226 patients (113 per group) were included in the study. Six patients in the risperidone + ulinastatin group and ten patients in the ulinastatin group developed pancreatitis (5.3 vs. 8.8 %, p = 0.438). The incidence of moderate/severe PEP was lower in the risperidone + ulinastatin group (1.8 %) than in the ulinastatin group (4.4 %), but this difference was not significant. Although the incidence of PEH did not differ significantly, post-ERCP levels of all pancreatic enzymes were significantly lower in the risperidone + ulinastatin group. Prophylactic oral risperidone administration in combination with ulinastatin did not reduce the incidence and severity of PEP in high-risk patients as compared with ulinastatin alone. However, risperidone showed an additive effect with ulinastatin, reducing serum pancreatic enzyme levels. 23955452 Poorly differentiated colorectal cancers: correlation of microsatellite instability with clinicopathologic features and survival. Objectives: To evaluate the association of microsatellite instability (MSI) with clinicopathologic features and oncologic outcomes in patients with poorly differentiated colorectal cancer (PD). Methods: Study patients were divided into well-differentiated colorectal cancer (WD) and PD, which were compared according to histologic differentiation and MSI status. Results: Among 1,941 patients, PD was more frequent among microsatellite-unstable tumors (23.6%) than among microsatellite-stable (MSS) tumors (4.2%, P < .001). Patients with PD had worse 4-year overall survival rates than patients with WD (78.6% vs 88.2%, P = 0.010). Compared with MSS-PD tumors, MSI-PD tumors were characterized by right-colon predilection, larger size, and infrequent lymph node metastasis (P < .001 to P = .007). Conclusions: The clinicopathologic characteristics of PD were closely associated with those of MSI. The outcomes of MSI-PD tumors were better than those of MSS-PD tumors, but this finding did not reach statistical significance. 23776224 Pyrimidine motif triple helix in the Kluyveromyces lactis telomerase RNA pseudoknot is essential for function in vivo. Telomerase is a ribonucleoprotein complex that extends the 3' ends of linear chromosomes. The specialized telomerase reverse transcriptase requires a multidomain RNA (telomerase RNA, TER), which includes an integral RNA template and functionally important template-adjacent pseudoknot. The structure of the human TER pseudoknot revealed that the loops interact with the stems to form a triple helix shown to be important for activity in vitro. A similar triple helix has been predicted to form in diverse fungi TER pseudoknots. The solution NMR structure of the Kluyveromyces lactis pseudoknot, presented here, reveals that it contains a long pyrimidine motif triple helix with unexpected features that include three individual bulge nucleotides and a C(+)•G-C triple adjacent to a stem 2-loop 2 junction. Despite significant differences in sequence and base triples, the 3D shape of the human and K. lactis TER pseudoknots are remarkably similar. Analysis of the effects of nucleotide substitutions on cell growth and telomere lengths provides evidence that this conserved structure forms in endogenously assembled telomerase and is essential for telomerase function in vivo. 23926442 Influence of immunotherapy with autologous dendritic cells on innate and adaptive immune response in cancer. The objective of this study was to evaluate some of the mechanisms involved in the activation of the immune system in patients with advanced-stage cancer (n = 7) who received an autologous dendritic cell vaccine. We examined the immune response mediated by macrophages (CD14+), natural killer cells (CD56+), and B lymphocytes (CD19+) by flow cytometry and assessed the expression of Th1 (IFN-γ, TNF-α, IL-2, and IL-12), Th2 (IL-4), and Treg (TGF-β) cytokines by flow cytometry and an enzyme-linked immunosorbent assay. The CD14+ TNF-α+ population was significantly increased (P < 0.04) when patients received the vaccine; IL-2 expression in both NK cells and in B lymphocytes was increased after a transient initial increase showed a nearly significant decrease (P < 0.07 and P < 0.06 respectively), whereas the CD19+ and CD56+ populations did not show significant changes. Dendritic cell-based immunotherapy led to increased secretion of IFN-γ and IL-12 and reduced secretion of TGF-β. In conclusion, it is likely that the autologous dendritic cell vaccine stimulated the immune cells from the peripheral blood of patients with cancer and generally increased the production of Th1 cytokines, which are related to immunomodulatory responses against cancer. 23905936 Tips for successful open surgical reconstruction of posterior urethral disruption injuries. This article provides an overview of the open surgical management of posterior urethral disruption injuries. The discussion includes the evaluation of the patient before surgery with a focus on urethral imaging and details of posterior urethroplasty surgical technique. 23570899 Is it possible to estimate the compressive force in the lumbar spine from intradiscal pressure measurements? A finite element evaluation. Knowledge about in vivo spinal compressive forces is a basic requirement for spinal biomechanics. Their direct measurement is not yet possible. Therefore, compressive forces are estimated from in vivo measured intradiscal pressure values. However, it is still not evident how precise these estimations are. A finite element model of the spine was employed to simulate elementary body positions and the compressive force at level L4-5 was calculated. This value was compared with different estimations calculated by multiplying the intradiscal pressure with the disc's cross-sectional area and with a correction factor. A model specific and different previously employed correction factors were used. Separately, in vivo forces were estimated from previously measured pressure values. A model specific correction factor leads for all body positions to a good estimation (error <4%) of the force except for extension (error >27%). Non-model specific correction factors lead to estimation errors of up to 44%. When accounting for these limitations, in vivo forces were estimated e.g. for standing between 430N and 600N. Compressive forces can be estimated for non-extended body positions when the individual correction factor is known. In vivo forces can be estimated from intradiscal pressure values within a certain range. 23814098 The chemokine CXCL6 restricts human trophoblast cell migration and invasion by suppressing MMP-2 activity in the first trimester. Can the chemokine CXCL6 affect trophoblast cell migration and invasion in human first-trimester placenta? Chemokine CXCL6 inhibits trophoblast cell migration and invasion by suppressing matrix metalloproteinase (MMP)-2 activity in human first-trimester placenta. Several chemokines including CXCL8, CXCL12, CXCL14, CXCL16, CX3CL1, CCL14 and CCL4 can promote or inhibit trophoblast cell migration and invasion in human first-trimester placenta. We used the trophoblast cell line HTR8/SVneo cells, primary trophoblast cells and villi explants to investigate the effect of rhCXCL6 on trophoblast cell migration and invasion. First, the CXCL6 RNA transcript level was detected in HTR8/SVneo cells derived from human first-trimester, second-trimester and third-trimester placenta by RT-PCR. Protein expression of CXCL6 and its receptors was tested in first-trimester placenta by immunohistochemistry. Secreted CXCL6 protein was detected in HTR8/SVneo cell supernatants by enzyme-linked immunosorbent assay. Secondly, the effect of rhCXCL6 on HTR8/SVneo cell proliferation was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Thirdly, the effect of rhCXCL6 on cell migration and invasion of HTR8/SVneo cells, primary trophoblast cells and villi explants was tested by transwell migration and invasion assays, respectively. Last, MMP-2 and MMP-9 activity in the supernatants of HTR8/SVneo and primary trophoblast cells treated by rhCXCL6 in the invasion assay was assessed by gelatin zymography. Abundance of the CXCL6 RNA transcript increased with pregnancy development. CXCL6 and its receptor were expressed in several cells at the human maternal-fetal interface. RhCXCL6 inhibited trophoblast cell migration and invasion by suppressing MMP-2 activity. These experiments are only in vitro. According to the literature, CXCL6 could promote tumour cell migration and invasion by accelerating MMP-9 activity. However, CXCL6 inhibited trophoblast cell migration and invasion by suppressing MMP-2 activity in human first-trimester interface. These data suggest that strict regulation of CXCL6 is required for normal migration and invasion of cells, such as those involved at the maternal-fetal interface. This study was supported by grants from the National Natural Science Foundation of China (No. 81070497), The Ministry of Education Doctoral Program Foundation of China (No. 20070025003) and the Beijing Municipal Science & Technology New Star Project of China (No. 2008B66). None of the authors has any conflict of interest to declare. None. 23923972 Pretransplant coronary artery disease associated with worse clinical outcomes in pancreas transplantation. Coronary artery disease (CAD) is common in patients with type I diabetes and may be associated with worse outcomes in patients undergoing pancreas transplantation (PT). This study evaluates PT patients to determine the pre transplant prevalence of CAD and assesses the post-transplant outcomes including complications and survival. This study is a retrospective review of PTs from 2003 to 2011. Diagnosis of CAD required cardiac catheterization. Outcomes included: myocardial infarction (MI), stroke, and survival. There were 405 transplants in 389 patients with median follow-up of 56 months. Pre transplant prevalence of CAD was 19% (n = 74). There was no increased risk of perioperative, 90-d or one-yr mortality for patients with CAD. The CAD group did have increased risk of MI (11% vs. 1%, p < 0.001) and stroke (8% vs. 3%, p = 0.02). Controlling for patient and donor age, and history of CAD, the CAD group had decreased patient survival at five yr (82% vs. 90%, p = 0.09, HR 1.77) by Cox regression. Patients with type I diabetes and CAD have increased risk of MI and stroke post-pancreas transplant, with decreased five-yr survival. Patients without CAD and a negative pre transplant cardiac evaluation carry a low risk of post-transplant MI. 23886709 Identification of nuclear retention domains in the RBM20 protein. RBM20 is a nuclear protein which regulates alternative splicing of expressed genes that have a key role in cardiac function. By cloning the human and mouse RBM20 cDNA, producing expressing vectors for truncated proteins, and comparing their sub-cellular distribution in transfected cells, we have identified the sequences necessary for RBM20 full nuclear retention. The region overlaps an RNA binding motif and a serine-arginine domain. The sequence is conserved in many species but belongs only to RBM20 orthologs. The RMB20 tissue specificity, together with the properties of its nuclear localization determinant, demonstrates a specific evolutionary selection of post-transcriptional regulation factors. 23918618 Biologic Agents in Islet Transplantation. Islet transplantation is today an accepted modality for treating selected patients with frequent hypoglycemic events or severe glycemic lability. Despite tremendous progress in islet isolation, culture, and preservation, clinical use is still restricted to a limited subset, and lifelong immunosuppression is required. Issues surrounding limited islet revascularization and immune destruction remain. One of the major challenges is to prevent alloreactivity and recurrence of autoimmunity against β-cells. These two hurdles can be effectively reduced by immunosuppressive therapy combining induction and maintenance treatments. The introduction of highly potent and selective biologic agents has significantly reduced the frequency of acute rejection and has prolonged graft survival, while minimizing the complications of this therapeutic scheme. This review will address the most important biological agents used in islet transplantation. We provide a historical perspective of their introduction into clinical practice and their role in current clinical protocols, aiming at improved engraftment efficiency, increased long-term survival, and better overall results of clinical islet transplantation. 23796266 Burnout in orthopaedic surgeons: a review. Training and practice of orthopaedic surgery are stressful endeavours, placing orthopaedic surgeons at risk of burnout. Burnout syndrome is associated with negative outcomes for patients, institutions and, especially, the surgeon. The aim of this review is to summarize available literature on burnout among orthopaedic surgeons and provide recommendations for future work in this field. A search of MEDLINE (1946-present) and EMBASE (search terms: 'Burnout, Professional' AND 'Orthopaedics'; 'Stress, Psychological' AND 'Orthopaedic Surgery'; 'Fatigue, Mental' AND 'Orthopaedic Surgery') was performed. The authors focused on articles that assessed burnout among orthopaedic surgeons. All studies used the Maslach Burnout Inventory allowing for cross-study (and cross-country) comparisons. Burnout rates among orthopaedic surgeons are in the range of 50-60%, higher than surgeons in general (range: 30-40% for surgeons in general), with the highest rate (emotional exhaustion and depersonalization scores) among orthopaedic residents, followed by department chairs, followed by faculty members. Both objective factors (caseload, practice setting, etc.) and subjective factors (perception that career was unrewarding, perception of lack of autonomy, etc.) contribute to burnout; however, subjective factors show a stronger correlation. Despite the heavy burnout rates among orthopaedic surgeons, little work has been performed in this field. Factors responsible for burnout among various orthopaedic populations should be determined, and appropriate interventions designed to reduce burnout. 23763964 Impact of social network characteristics on shelter use among street youth in san francisco. We examined the cross-sectional and longitudinal association between social network characteristics and street youths' shelter use, a determinant of health outcomes for homeless youth. We analyzed interview data from 138 street youth recruited through venue-based sampling in San Francisco, to assess the cross-sectional relationship between shelter use in youths' social networks and youths' reported shelter use. We also assessed the relationship between baseline network shelter use and shelter use at 6-month follow-up. Low proportions of street youth reported shelter use at baseline (38%) and follow-up (29.6%). Twenty-nine (26.9%) youth were in networks with shelter users at baseline, compared with 17 youth (15.7%) at follow-up. In cross-sectional analysis, youth in networks with shelter users had 5-fold increased odds of reporting shelter use (OR: 5.86, p = .006). A 1-person increase in the number of network shelter users was associated with 2-fold increased odds of youths' shelter use (OR: 2.16, p = .02). In longitudinal analysis, youth in networks with shelter users at baseline had nearly 5-fold increased odds of shelter use at follow-up (OR: 4.95, p = .01). A 1-person increase in the number of network shelter users at baseline was associated with 3-fold increased odds of shelter use at follow-up (OR: 3.15, p = .004). Shelter users seem to cluster together. Shelter use by extended network members was associated with increased odds of youths' own shelter use. Understanding how network behaviors influence street youths' health-related behaviors, such as shelter use, could inform network-based interventions encouraging service uptake among marginalized and hard-to-reach street youth populations. 23224644 Mobility and ecological risk assessment of trace metals in polluted estuarine sediments using a sequential extraction scheme. The three-stage sequential extraction procedure for the fractionation of Cd, Cr, Cu, Ni, Pb, and Zn, proposed by the Commission of the European Communities Bureau of Reference, was applied to sediment five samples collected from the Sal estuary, Sergipe State, northeast Brazil, in September 2009. The method showed satisfactory recoveries, detection limits, and standard deviations for determinations of trace metals in the sediments. Cd and Pb were the metals most prevalent in the bioavailable fractions (carbonates, Fe and Mn oxides, organic matter, and sulfides), while Ni, Zn, Cu, and Cr showed higher percentages in the inert fraction. The order of mobility of the metals was Cd (66%) > Pb (65%) > Zn (59%) > Ni (57%) = Cr (57%) > Cu (56%). Possible toxicity related to these metals was examined using the risk assessment code, and by comparing the chemical data with sediment quality guideline ERL-ERM values. Results obtained using the two methods were in agreement, and showed low to medium risk for all metals, indicating that adverse effects on aquatic biota should rarely occur. 23733520 The neural interaction between the arterial baroreflex and muscle metaboreflex is preserved in older men. Sympathetic baroreflex sensitivity is increased during selective activation of the skeletal muscle metaboreflex with post-exercise ischemia (PEI) in young adults. However, to date, there are no data demonstrating this neural interaction between the arterial baroreflex and the muscle metaboreflex in healthy older adults. Therefore, the goal of the current study was to examine the influence of healthy aging on the metabolic component of the exercise pressor reflex and its interaction with the arterial baroreflex in the control of sympathetic outflow. PEI following static handgrip performed at 30% maximum voluntary contraction was used to isolate muscle metaboreflex activation in young (n=10; 24±1 yrs; resting blood pressure (BP) 116±3/64±3 mmHg) and older men (n=9; 59±2 yrs; resting BP 120±2/77±2 mmHg). Arterial BP (Finometer) and muscle sympathetic nerve activity (MSNA) were measured continuously. Weighted linear regression analysis between MSNA and diastolic BP was used to estimate arterial baroreflex MSNA gain. There were no age-related differences in the increase in mean BP (14±3 young vs. 15±2 older mmHg; P>0.05) or MSNA burst frequency (11±2 young vs. 9±1 older bursts/min; P>0.05) during PEI. Likewise, the gain of arterial baroreflex control of total MSNA increased to a similar extent in both groups during PEI (young: -4.2±0.9 baseline vs. -6.3±1.1 PEI AU/beat/mmHg; older: -3.7±1.1 baseline vs. -6.7±1.4 PEI AU/beat/mmHg; P<0.05 for both). Collectively, these findings indicate that the neural interaction between the arterial baroreflex and the skeletal muscle metaboreflex in the regulation of MSNA is preserved in healthy aging. 23564313 Vinblastine-induced apoptosis of melanoma cells is mediated by Ras homologous A protein (Rho A) via mitochondrial and non-mitochondrial-dependent mechanisms. Despite the availability of melanoma treatment at the primary site, the recurrence of local melanoma can metastasize to any distant organ. Currently, the available therapies for the treatment of metastatic melanoma are of limited benefit. Thus, the functional analysis of conventional therapies may help to improve their efficiency in the treatment of metastatic melanoma. In the present study, the exposure of melanoma cells to vinblastine was found to trigger apoptosis as evidenced by the loss of mitochondrial membrane potential, the release of both cytochrome c and apoptosis inducing factor, activation of caspase-9 and 3, and cleavage of Poly (ADP-ribose)-Polymerase. Also, vinblastine enhances the phosphorylation of Ras homologous protein A, the accumulation of reactive oxygen species, the release of intracellular Ca(2+), as well as the activation of apoptosis signal-regulating kinase 1, c-jun-N-terminal kinase, p38, inhibitor of kappaBα (IκBα) kinase, and inositol requiring enzyme 1α. In addition, vinblastine induces the DNA-binding activities of the transcription factor NF-κB, HSF1, AP-1, and ATF-2, together with the expression of HSP70 and Bax proteins. Moreover, inhibitory experiments addressed a central role for Rho A in the regulation of vinblastine-induced apoptosis of melanoma cells via mitochondrial and non-mitochondrial-dependent mechanisms. In conclusion, the present study addresses for the first time a central role for Rho A in the modulation of vinblastine-induced apoptosis of melanoma cells and thereby provides an insight into the molecular action of vinblastine in melanoma treatment. 23903808 The Villain Team-Up or how Trichomonas vaginalis and bacterial vaginosis alter innate immunity in concert. Complex interactions of vaginal microorganisms with the genital tract epithelium shape mucosal innate immunity, which holds the key to sexual and reproductive health. Bacterial vaginosis (BV), a microbiome-disturbance syndrome prevalent in reproductive-age women, occurs commonly in concert with trichomoniasis, and both are associated with increased risk of adverse reproductive outcomes and viral infections, largely attributable to inflammation. To investigate the causative relationships among inflammation, BV and trichomoniasis, we established a model of human cervicovaginal epithelial cells colonised by vaginal Lactobacillus isolates, dominant in healthy women, and common BV species (Atopobium vaginae, Gardnerella vaginalis and Prevotella bivia). Colonised epithelia were infected with Trichomonas vaginalis (TV) or exposed to purified TV virulence factors (membrane lipophosphoglycan (LPG), its ceramide-phosphoinositol-glycan core (CPI-GC) or the endosymbiont Trichomonas vaginalis virus (TVV)), followed by assessment of bacterial colony-forming units, the mucosal anti-inflammatory microbicide secretory leucocyte protease inhibitor (SLPI), and chemokines that drive pro-inflammatory, antigen-presenting and T cells. TV reduced colonisation by Lactobacillus but not by BV species, which were found inside epithelial cells. TV increased interleukin (IL)-8 and suppressed SLPI, likely via LPG/CPI-GC, and upregulated IL-8 and RANTES, likely via TVV as suggested by use of purified pathogenic determinants. BV species A vaginae and G vaginalis induced IL-8 and RANTES, and also amplified the pro-inflammatory responses to both LPG/CPI-GC and TVV, whereas P bivia suppressed the TV/TVV-induced chemokines. These molecular host-parasite-endosymbiont-bacteria interactions explain epidemiological associations and suggest a revised paradigm for restoring vaginal immunity and preventing BV/TV-attributable inflammatory sequelae in women. 23629862 Leukotriene B4 type-1 receptor signaling promotes liver repair after hepatic ischemia/reperfusion injury through the enhancement of macrophage recruitment. Recruited macrophages play a critical role in liver repair after acute liver injury. Leukotriene B4 (LTB4) is a potent chemoattractant for macrophages. In this study, we investigated the role of LTB4 receptor type 1 (BLT1) in liver repair during hepatic ischemia/reperfusion (I/R) injury. BLT1-knockout mice (BLT1(-/-)) or their wild-type counterparts (WT) were subjected to partial hepatic I/R. Compared with WT, BLT1(-/-) exhibited delayed liver repair and hepatocyte proliferation accompanied by a 70% reduction in the recruitment of macrophages and a 70-80% attenuation in hepatic expression of epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and VEGF receptor 1 (VEGFR1). Disruption of BLT1 signaling also reduced the expression of EGF by 67% on recruited macrophages expressing VEGFR1 in the injured liver. Treatment of WT mice with an EGF-neutralizing antibody delayed liver repair and reduced macrophage recruitment, compared with control immunoglobulin G (IgG). BLT1 signaling enhanced the expression of VEGF, VEGFR1, and EGF in isolated peritoneal macrophages in vitro. These results indicate that BLT1 signaling plays a role in liver repair after hepatic I/R through enhanced expression of EGF in recruited macrophages and that the development of a specific agonist for BLT1 could be useful for liver recovery from acute liver injury.-Ohkubo, H., Ito, Y., Minamino, T., Mishima, T., Hirata, M., Hosono, K., Shibuya, M., Yokomizo, T., Shimizu, T., Watanabe, M., Majima, M. Leukotriene B4 type-1 receptor signaling promotes liver repair after hepatic ischemia/reperfusion injury through the enhancement of macrophage recruitment. 23865388 Use of continuous renal replacement therapy in acute aluminum phosphide poisoning: a novel therapy. Abstract Aluminum phosphide is most common cause of poisoning in northern India. There is no specific antidote available and management of such cases is mainly supportive with high mortality. We present two cases of severe acute aluminium phosphide poisoning where continuous renal replacement therapy (CRRT) was started early along with other resuscitative measures and both the patients survived. 23122162 Fucoxanthin content and antioxidant properties of Undaria pinnatifida. This study investigated the fucoxanthin content of New Zealand (NZ) Undaria pinnatifida harvested from two locations in the Marlborough Sounds, New Zealand across its growing season. Fucoxanthin content and antioxidant properties of processed New Zealand U. pinnatifida and commercial wakame from Japan and Korea were further compared. Results showed that U. pinnatifida harvested from Port Underwood had higher fucoxanthin content in the blade compared to Pelorus Sound. The sporophyll also contained a significant amount of fucoxanthin throughout the harvest season, although lower than in the blade. Two antioxidant measurement methods, DPPH and CUPRAC, were utilised to measure antioxidant activities. Processed NZ U. pinnatifida had a lower fucoxanthin content and antioxidant activity than freeze-dried Undaria. Fucoxanthin content and antioxidant activities of NZ processed U. pinnatifida were not significantly different from other commercial samples from Japan and Korea. In conclusion, U. pinnatifida in New Zealand has a great potential to be a food and nutraceutical resource. 23736846 Asymmetric construction of fluorinated imidazolidines via Cu(I)-catalyzed exo'-selective 1,3-dipolar cycloaddition of azomethine ylides with fluorinated imines. Expedient access to optically active fluorinated 2,4-trans-imidazolidines was successfully developed via Cu(I)-catalyzed exo'-selective 1,3-DC of azomethine ylides with fluorinated imines. 23924097 News in brief. A roundup of the latest nursing news. 23585525 What is the relevance of Ikaros gene deletions as a prognostic marker in pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia? New prognostic markers are needed for upfront identification of patients with acute lymphocytic leukemia with a high risk of relapse or who are not likely to respond to the most aggressive chemotherapy. We focused our analysis on Ikaros (IKZF1) gene deletions in a homogeneous cohort of 410 pediatric patients with Philadelphia chromosome-negative, B-cell precursor acute lymphoblastic leukemia enrolled in Italy into the AIEOP-BFM ALL2000 study. We confirm their reported poor prognostic value, although the associated event-free survival was relatively high (approximately 70%). The difference in the cumulative incidence of relapse between patients positive or not for IKZF1 deletions was not marked: 24.2% (5.9) versus 13.1% (1.8) overall and 23.9% (6.6) versus 16.5% (2.5) in the intermediate-risk subgroup. In line with this, IKZF1 deletions were not an independent prognostic factor for the hazard of relapse. Most IKZF1-deleted cases stratified in the high-risk group relapsed, suggesting that once identified, patients with these deletions require an alternative treatment. In conclusion, the need of and benefit from introducing IKZF1 deletions as an additional stratification marker for patients with Philadelphia-negative B-cell precursor acute lymphoblastic leukemia remain questionable. 23891331 Divided Eyelid Nevus: A Lid-Sparing, Staged Surgical Approach. To describe a method for staged partial resection of congenital divided eyelid nevus. The rationale, technique, and outcomes for this approach are described. Retrospective chart review of a case series. Clinical records of 12 patients with divided eyelid nevus were reviewed with attention to presenting features, surgical management, histopathology, and follow-up course. Surgical approach involved the use of bipolar and thermal cautery to ablate the eyelid margin component, skin excision for cutaneous lesions, and then repair with advancement flaps or skin grafting. Eight patients with divided nevus were treated with a staged surgical approach: 5 primarily and 3 as revision cases. Average age was 16.3 years at primary presentation (range, 2-36 years), 16.5 years at initial surgery (range 2-36 years), and 36.0 years at presentation for revision (range, 12-72 years). Primary patients required 1 (n = 3) or 2 (n = 2) surgeries. Revision patients required 2 (n = 1) or 3 (n = 2) procedures in addition to those they had already undergone. Anterior lamellar repair was by granulation (n = 2), local skin flaps (n = 3), or skin grafts (n = 3). Average follow-up was 21.6 months (range, 0-98 months). No adverse effects or malignant transformations were seen. Patients with divided eyelid nevi often present for surgical management because of cosmetic and functional concerns. Because small-to-medium congenital nevi have a low risk of malignant transformation, total excision may not be necessary. A staged surgical approach with cautery ablation and contouring of the eyelid margin component and surgical resection of the anterior lamellar portion may be a reasonable treatment strategy for these patients. 23194186 Variation in human β-defensin genes: new insights from a multi-population study. Human β-defensin 2 (hBD-2) and hBD-3, encoded by DEFB4 and DEFB103A, respectively, have shown anti-HIV activity, and both genes exhibit copy number variation (CNV). Although the role of hBD-1, encoded by DEFB1, in HIV-1 infection is less clear, single nucleotide polymorphisms (SNPs) in DEFB1 may influence viral loads and disease progression. We examined the distribution of DEFB1 SNPs and DEFB4/103A CNV, and the relationship between DEFB1 SNPs and DEFB4/103A CNV using samples from two HIV/AIDS cohorts from the United States (n = 150) and five diverse populations from the Coriell Cell Repositories (n = 46). We determined the frequencies of 10 SNPs in DEFB1 using a post-PCR, oligonucleotide ligation detection reaction-fluorescent microsphere assay, and CNV in DEFB4/103A by real-time quantitative PCR. There were noticeable differences in the frequencies of DEFB1 SNP alleles and haplotypes among various racial/ethnic groups. The DEFB4/103A copy numbers varied from 2 to 8 (median, 4), and there was a significant difference between the copy numbers of self-identified whites and blacks in the US cohorts (Mann-Whitney U-test P = 0.04). A significant difference was observed in the distribution of DEFB4/103A CNV among DEFB1 -52G/A and -390T/A genotypes (Kruskal-Wallis P = 0.017 and 0.026, respectively), while not in the distribution of DEFB4/103A CNV among -52G/A_-44C/G_-20G/A diplotypes. These observations provide additional insights for further investigating the complex interplay between β-defensin genetic polymorphisms and susceptibility to, or the progression or severity of, HIV infection/disease. 23790437 Transfection and intracellular trafficking properties of carbon dot-gold nanoparticle molecular assembly conjugated with PEI-pDNA. The work employs carbon dot (CD) which has been emerging as a fluorescent nanomaterial with excellent biocompatibility and perceived as a promising alternative to quantum dot (QD), to monitor the association/dissociation of polymeric carrier/plasmid DNA (pDNA) complex during transfection. To shed light on the underlying post-endosomal events and provide the insight to design rational and efficient gene delivery vector, the adopted strategy exploited the quenching of the fluorescence of CD by Au nanoparticles. The surface of CD and Au was modified with highly cationic polymer, polyethylenimine (PEI) and subsequent treatment with non-labeled pDNA gave rise to quenched delivery complex. High salt concentration triggered the dissociation of the complex with accompanied fluorescence recovery arising due to the increase in distance between CD and Au. The studies revealed the potential of the developed CD-PEI/Au-PEI/pDNA ternary nano-assembly as a highly efficient hybrid transfecting agent with high cell viability under the optimum condition. The changes occurred at the intracellular level during transfection especially post-endosomal step were monitored by fluorescence measurement using fluorescence microscope. This nano-assembly system was found to be very effective at monitoring the carrier/pDNA dissociation in a non-labeled manner, thus provides efficient strategy to study the mechanistic aspect of polymer-mediated pDNA delivery. 23656508 Phosphodiesterase-4 inhibitor therapy for lung diseases. Phosphodiesterases (PDEs) are a superfamily of enzymes that catalyze the breakdown of cAMP and/or cyclic guanosine monophosphate (GMP) to their inactive form. PDE4 is the main selective cAMP-metabolizing enzyme in inflammatory and immune cells. Because PDE4 is highly expressed in leukocytes and other inflammatory cells involved in the pathogenesis of inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD), inhibition of PDE4 has been predicted to have an antiinflammatory effect and thus therapeutic efficacy. The limited and inconsistent efficacy and side effects of the early compounds made their further development less desirable in asthma, given the excellent efficacy/tolerability ratio of inhaled steroids. The lack of effective antiinflammatory drug treatment for COPD has thus shifted the interest in development toward COPD. Roflumilast, the only PDE4 inhibitor that has reached the market because of the good efficacy/tolerability ratio, is recommended for patients with COPD with severe airflow limitation, symptoms of chronic bronchitis, and a history of exacerbations, whose disease is not adequately controlled by long-acting bronchodilators. Albeit safe, it maintains significant side effects (diarrhea, nausea, weight loss) that make it intolerable in some patients. Future developments of PDE4 inhibitors include extended indications of roflumilast (1) in patients with COPD, and (2) in other respiratory (e.g., asthma) and nonrespiratory chronic inflammatory/metabolic conditions (e.g., diabetes), as well as (3) the development of new molecules with PDE4 inhibitory properties with an improved efficacy/tolerability profile. 23824235 Community treatment orders: the experiences of Non-Maori and Maori within mainstream and Maori mental health services. Community treatment orders (CTOs) are sometimes used to coerce patients into treatment on the basis that such treatment is in their best interest. The experiences of Maori, New Zealand's indigenous ethnic minority are less well known and this paper compares the views of Maori and non-Maori about CTOs. Patients with experience of CTOs for greater than 6 months participated. Self-report measures were used to identify patients' views of compulsory treatment. Demographic data, heath service characteristics, the experience of coercion, views of compulsory community treatment, satisfaction with care, social functioning, and psychopathology were assessed. There were few differences in demographic or clinical characteristics between Maori and non-Maori. There were no differences in the views of Maori compared to non-Maori patients with respect to compulsory community treatment. There were no differences in the views of Maori cared for by mainstream compared to culturally specialist Maori mental health service. In a well-established system of compulsory treatment, there is no evidence of greater negative impact of CTOs in an indigenous minority population. The opportunity for Maori to self-select between mainstream and specialist Maori mental health services may minimize the negative aspects of compulsory community treatment for Maori. 23937913 Targeting colorectal cancer cells with single-walled carbon nanotubes conjugated to anticancer agent SN-38 and EGFR antibody. In this study, single-walled carbon nanotubes (SWNTs) conjugated with antibody C225 were used to achieve targeted therapy against EGFR over-expressed colorectal cancer cells. In addition, the control release of the chemotherapeutic drug, 7-Ethyl-10-hydroxy-camptothecin (SN38), was studied. We used three different colorectal cancer cell lines, HCT116, HT29, and SW620, listed in the order of decreasing expression levels of EGFR. Our results showed that SWNT could use C225 to specifically bind to EGFR-expressed cells. The cellular uptakes of SWNT of EGFR over-expressed cells (HCT116 and HT29) were much higher than that of the negative control (SW620). We, next, demonstrated that receptor-mediated endocytosis was the primary cell entry route for SWNT. As a consequence, abundant amount of SN38 was released and EGFR over-expressed cells were killed. The drug control release process was studied by utilizing human carboxylesterase enzyme (hCE) that would break the bond linking SN38 and SWNT-carrier in cytoplasm. The intracellular SN38 release observed by confocal microscopy showed that SN38 actually dissociated from the SWNT-carrier first. SN38's entry to nucleus was then followed while the SWNT-carrier still remained in the cytoplasm. Overall, all these data suggested that SWNT could be a good carrier for targeting controlled release therapy. 23401387 Wear mechanism and tribological characteristics of porous NiTi shape memory alloy for bone scaffold. The abraded debris might cause osteocytic osteolysis on the interface between implants and bone tissues, thus inducing the subsequent mobilization of implants gradually and finally resulting in the failure of bone implants, which imposes restrictions on the applications of porous NiTi shape memory alloys (SMAs) scaffolds for bone tissue engineering. In this work, the effects of the annealing temperature, applied load, and porosity on the tribological behavior and wear resistance of three-dimensional porous NiTi SMA are investigated systematically. The porous structure and phase transformation during the exothermic process affect the tribological properties and wear mechanism significantly. In general, a larger porosity leads to better tribological resistance but sometimes, SMAs with small porosity possess better wear resistance than ones with higher porosity during the initial sliding stage. It can be ascribed to the better superelasticity of the former at the test temperature. The porous NiTi phase during the exothermic reaction also plays an important role in the wear resistance. Generally, porous NiTi has smaller friction coefficients under high loads due to stress-induced superelasticity. The wear mechanism is discussed based on plastic deformation and microcrack propagation. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 101A: 2586-2601, 2013. 23949782 Effects of vitamin C on characteristics retaining of in vitro-cultured mouse adipose-derived stem cells. Adipose-derived stem cells (ADSCs), a subset of mesenchymal stem cells, have promising potential for regenerative medicine applications. However, the efficient culture of mouse adipose-derived stem cells (mADSCs) is complicated or impracticable and many properties of mADSCs are still unknown. Here, we report that vitamin C (Vc) is available for the long-term culture of mADSCs in vitro. Compared with that cultured without Vc, mADSCs growing in Vc-added media proliferate faster. The occurrence of replicative senescence and transformation of Vc-treated mADSCs is also postponed. Vc also enhanced the secretory activity of collagen and adipogenic differentiation ability of mADSCs. Moreover, the expression of CD44, Sca-1, and CD105 is higher in Vc-treated mADSCs than nontreated ones. We also found that genes related to proliferation, secretion, and pluripotency are all promoted in Vc-treated mADSCs. However, the adipogenesis ability and expression of CD44, Sca-1, and CD105 decreased when passage increased from very low passages, in parallel to the downregulation of closed-related gene expression. Our results indicate that Vc is essential for the maintenance of original properties of mADSCs in vitro; additional insights into the function of Vc on mADSCs are provided. Furthermore, as the passage increased in six passages, the characteristics of mADSCs with Vc addition were also revealed. 23812668 A Novel Aldehyde Dehydrogenase-3 Activator (Alda-89) Protects Submandibular Gland Function from Irradiation without Accelerating Tumor Growth. To determine the effect of Alda-89 (an ALDH3 activitor) on (i) the function of irradiated (radiotherapy) submandibular gland (SMG) in mice, (ii) its toxicity profile, and (iii) its effect on the growth of head and neck cancer (HNC) in vitro and in vivo. Adult mice were infused with Alda-89 or vehicle before, during, and after radiotherapy. Saliva secretion was monitored weekly. Hematology, metabolic profile, and postmortem evaluation for toxicity were examined at the time of sacrifice. Alda-89 or vehicle was applied to HNC cell lines in vitro, and severe combined immunodeficient (SCID) mice transplanted with HNC in vivo with or without radiation; HNC growth was monitored. The ALDH3A1 and ALDH3A2 protein expression was evaluated in 89 patients with HNC and correlated to freedom from relapse (FFR) and overall survival (OS). Alda-89 infusion significantly resulted in more whole saliva production and a higher percentage of preserved acini after radiotherapy compared with vehicle control. There was no difference in the complete blood count, metabolic profile, and major organ morphology between the Alda-89 and vehicle groups. Compared with vehicle control, Alda-89 treatment neither accelerated HNC cell proliferation in vitro, nor did it affect tumor growth in vivo with or without radiotherapy. Higher expression of ALDH3A1 or ALDH3A2 was not significantly associated with worse FFR or OS in either human papillomavirus (HPV)-positive or HPV-negative group. Alda-89 preserves salivary function after radiotherapy without affecting HNC growth or causing measurable toxicity in mice. It is a promising candidate to mitigate radiotherapy-related xerostomia. Clin Cancer Res; 19(16); 4455-64. ©2013 AACR. 22804334 Engineering challenges in biodiesel production from microalgae. In recent years, the not too distant exhaustion of fossil fuels is becoming apparent. Apart from this, the combustion of fossil fuels leads to environmental concerns, the emission of greenhouse gases and issues with global warming and health problems. Production of biodiesel from microalgae may represent an attractive solution to the above mentioned problems, and can offer a renewable source of fuel with fewer pollutants. This review presents a compilation of engineering challenges related to microalgae as a source of biodiesel. Advantages and current limitations for biodiesel production are discussed; some aspects of algae cells biology, with emphasis on cell wall composition, as it represents a barrier for fatty acid extraction and lipid droplets are also presented. In addition, recent advances in the different stages of the manufacturing process are included, starting from the strain selection and finishing in the processing of fatty acids into biodiesel. 23410154 Emerging Role of Colloidal Drug Delivery Systems (CDDS) in NSAID Topical Administration. NSAIDs are the most commonly prescribed category of drugs for the treatment of musculoskeletal pain and inflammation associated with many conditions. Topical administration of these drugs is always the best choice since adverse effects occur commonly with systemic NSAID therapy. Colloidal drug delivery systems (CDDS) are interesting systems, which are able to improve the duration of drug residence in the skin and to allow an achievable drug sustained and controlled release compared to conventional topical formulations.This review focuses on micro and nanoemulsions, vesicular carriers and nanoparticles as novel high efficiency delivery systems of NSAIDs in topical applications. 23929263 Diffusion-Weighted MR Imaging of Benign and Malignant Breast Lesions Before and After Contrast Enhancement. Purpose: Many publications describe the use of diffusion-weighted imaging (DWI) in breast MRI. This article addresses the question of when to apply the DWI sequence in the course of the scan protocol. The effect of T1-shortening contrast media (CM) on the ADC values of breast lesions is investigated.Materials and Methods: Data were acquired on a 1.5 T scanner. 60 patients with 79 lesions (20 benign, 59 malignant) were included. The DWI sequence (4 mm slice thickness, b-values: 50, 400, 800) was applied before and after CM administration. Before calculating the ADC map, the b50, b400 and b800 series were analyzed concerning lesion displacement. ADC values before and after CM application were compared.Results: The mean lesion size was 1.5 ± 0.8 cm. On the basis of the b50 and b400 measurements, the mean ADC value of benign lesions was 1.89 ± 0.30 × 10-3 mm2/s before and 1.85 ± 0.28 ×10-3 mm2/s after CM administration. The consecutive values for two pure mucinous carcinomas were 1.88 × 10-3 mm2/s and 1.81 × 103 mm2/s and for the remaining malignant lesions 1.00 ± 0.18 × 10-3 mm2/s and 0.88 ± 0.21 × 10-3 mm2. On the basis of the b50, b400 and b800 measurements, the mean ADC value of benign lesions was 1.99 ± 0.37 × 10-3 mm2/s before and 1.97 ± 0.30 × 10-3 mm2/s after CM application, whereas the mean ADC value of the malignant lesions was 0.90 ± 0.14 × 10-3 mm2/s before and 0.80 ± 0.14 × 10-3 mm2/s after CM application. While there was no significant change for benign lesions, the ADC value decrease in post-contrast malignant lesions was highly significant.Conclusion: DWI after CM is possible and even leads to slightly better lesion discrimination between benign and malignant. However, further studies need to be performed to verify this.Citation Format: 23826984 Endothelial dysfunction in hyperandrogenic polycystic ovary syndrome is not explained by either obesity or ectopic fat deposition. Polycystic ovary syndrome (PCOS) is associated with insulin resistance, increased visceral fat and non-alcoholic fatty liver disease (NAFLD) all of which may contribute to endothelial dysfunction, an early marker of cardiovascular disease risk. Our objective was to examine the relationships between endothelial dysfunction in PCOS, the volume of adipose tissue compartments and the size of intracellular triglyceride pools in liver and skeletal muscle. Thirty-five women with PCOS (mean±SD; 26±6y, 36±5kg/m2) and 16 control women (31±8y, 30±6kg/m2) were recruited. Endothelial function was assessed in the brachial artery using flow-mediated dilation (FMD). Visceral (VAT) and abdominal subcutaneous adipose tissue (SAT) volume were determined by whole body magnetic resonance imaging, and liver and skeletal muscle triglyceride by 1H magnetic resonance spectroscopy. Cardiorespiratory fitness and insulin resistance (HOMA-IR) were also determined. Differences between groups were analysed using independent t-tests and analysis of covariance. FMD was impaired in PCOS by 4.6% (95% CI=3.0-7.7, P<0.001), and this difference decreased only slightly to 4.2% (95% CI=2.4-6.1, P<0.001) when FMD was adjusted for individual differences in visceral and subcutaneous adipose tissue and HOMA-IR. This magnitude of impairment was also similar in lean and obese PCOS women. The results suggest that endothelial dysfunction in PCOS is not explained by body fat distribution or volume. FMD might be a useful independent prognostic tool to assess CVD risk in this population. 23812776 Effect of pressure sensitive adhesive and vehicles on permeation of terbinafine across porcine hoof membrane. The purpose of this study was to investigate characteristics of transungual drug delivery and the feasibility of developing a drug-in-adhesive formulation of terbinafine. The permeation of terbinafine from a PSA matrix across porcine hoof membrane was determined using a plate containing poloxamer gel. The permeation rate of terbinafine across hairless mouse skin was evaluated using a flow-through diffusion cell system. The permeation of terbinafine across the hoof membranes was the highest from the silicone adhesive matrix, followed by PIB, and most of the acrylic adhesives, SIS, and SBS. The rank order of permeation rate across mice skin was different from the rank order across porcine hooves. The amount of terbinafine permeated across the porcine hoof membranes poorly correlated with the amount of terbinafine remaining inside the hooves after 20 days, however, the ratio between rate of terbinafine partitioning into the hoof membrane and its rate of diffusion across the membrane was relatively constant within the same type of PSA. For influence of various vehicles in enhancing permeation of terbinafine across the hoof membrane, all vehicles except Labrasol(®) showed tendency to improve permeation rate. However, the enhancement ratio of a given vehicle differed from one adhesive to another with a moderate correlation between them. The infrared spectrum of the hoof treated with NMP, PPG 400 or PEG 200 indicated that the conformation of keratin changed from a non-helical to a helical structure. 23877095 Make caffeine visible: a fluorescent caffeine "traffic light" detector. Caffeine has attracted abundant attention due to its extensive existence in beverages and medicines. However, to detect it sensitively and conveniently remains a challenge, especially in resource-limited regions. Here we report a novel aqueous phase fluorescent caffeine sensor named Caffeine Orange which exhibits 250-fold fluorescence enhancement upon caffeine activation and high selectivity. Nuclear magnetic resonance spectroscopy and Fourier transform infrared spectroscopy indicate that π-stacking and hydrogen-bonding contribute to their interactions while dynamic light scattering and transmission electron microscopy experiments demonstrate the change of Caffeine Orange ambient environment induces its fluorescence emission. To utilize this probe in real life, we developed a non-toxic caffeine detection kit and tested it for caffeine quantification in various beverages. Naked-eye sensing of various caffeine concentrations was possible based on color changes upon irradiation with a laser pointer. Lastly, we performed the whole system on a microfluidic device to make caffeine detection quick, sensitive and automated. 23728712 Stem-directed growth of highly fluorescent silver nanoclusters for versatile logic devices. This work described for the first time the stem-directed growth of silver nanoclusters (AgNCs) with high brightness using the well-chosen hairpin DNA structure. In comparison with the corresponding double-stranded (ds) DNA capped AgNCs, the fluorescence emission of hairpin DNA structure templated AgNCs were lighted up with 12.5-fold enhancement fluorescent intensity by sequence modification with T-loop. It provided a new prospect for precise placement of nanoscale optical elements onto DNA scaffolds. And these DNA protected AgNCs exhibited the base sequence, strand length and microenvironment-dependent fluorescent properties. Benefiting from these properties, versatile logic gates (or, not, inhibit, XNOR, implication) were constructed using different ions as inputs with AgNCs as signal transducer. 23579178 Mechanisms of Glucose Lowering of Dipeptidyl Peptidase-4 Inhibitor Sitagliptin When Used Alone or With Metformin in Type 2 Diabetes: A double-tracer study. OBJECTIVETo assess glucose-lowering mechanisms of sitagliptin (S), metformin (M), and the two combined (M+S).RESEARCH DESIGN AND METHODSWe randomized 16 patients with type 2 diabetes mellitus (T2DM) to four 6-week treatments with placebo (P), M, S, and M+S. After each period, subjects received a 6-h meal tolerance test (MTT) with [(14)C]glucose to calculate glucose kinetics. Fasting plasma glucose (FPG), fasting plasma insulin, C-peptide (insulin secretory rate [ISR]), fasting plasma glucagon, and bioactive glucagon-like peptide (GLP-1) and gastrointestinal insulinotropic peptide (GIP) was measured.RESULTSFPG decreased from P, 160 ± 4 to M, 150 ± 4; S, 154 ± 4; and M+S, 125 ± 3 mg/dL. Mean post-MTT PG decreased from P, 207 ± 5 to M, 191 ± 4; S, 195 ± 4; and M+S, 161 ± 3 mg/dL (P < 0.01]. The increase in mean post-MTT plasma insulin and in ISR was similar in P, M, and S and slightly greater in M+S. Fasting plasma glucagon was equal (∼65-75 pg/mL) with all treatments, but there was a significant drop during the initial 120 min with S 24% and M+S 34% (both P < 0.05) vs. P 17% and M 16%. Fasting and mean post-MTT plasma bioactive GLP-1 were higher (P < 0.01) after S and M+S vs. M and P. Basal endogenous glucose production (EGP) fell from P 2.0 ± 0.1 to S 1.8 ± 0.1 mg/kg ⋅ min, M 1.8 ± 0.2 mg/kg ⋅ min [both P < 0.05 vs. P), and M+S 1.5 ± 0.1 mg/kg ⋅ min (P < 0.01 vs. P). Although the EGP slope of decline was faster in M and M+S vs. S, all had comparable greater post-MTT EGP inhibition vs. P (P < 0.05).CONCLUSIONSM+S combined produce additive effects to 1) reduce FPG and postmeal PG, 2) augment GLP-1 secretion and β-cell function, 3) decrease plasma glucagon, and 4) inhibit fasting and postmeal EGP compared with M or S monotherapy. 23441904 Molecular interactions between lecithin and bile salts/acids in oils and their effects on reverse micellization. It has been known that the addition of bile salts to lecithin organosols induces the formation of reverse wormlike micelles and that the worms are similar to long polymer chains that entangle each other to form viscoelastic solutions. In this study, we further investigated the effects of different bile salts and bile acids on the growth of lecithin reverse worms in cyclohexane and n-decane. We utilized rheological and small-angle scattering techniques to analyze the properties and structures of the reverse micelles. All of the bile salts can transform the originally spherical lecithin reverse micelles into wormlike micelles and their rheological behaviors can be described by the single-relaxation-time Maxwell model. However, their efficiencies to induce the worms are different. In contrast, before phase separation, bile acids can induce only short cylindrical micelles that are not long enough to impart viscoelasticity. We used Fourier transform infrared spectroscopy to investigate the interactions between lecithin and bile salts/acids and found that different bile salts/acids employ different functional groups to form hydrogen bonds with lecithin. Such effects determine the relative positions of the bile salts/acids in the headgroups of lecithin, thus resulting in varying efficiencies to alter the effective critical packing parameter for the formation of wormlike micelles. This work highlights the importance of intermolecular interactions in molecular self-assembly. 23871865 Sublingual microcirculation is impaired in post-cardiac arrest patients. We hypothesized that microcirculatory dysfunction, similar to that seen in sepsis, occurs in post-cardiac arrest patients and that better microcirculatory flow will be associated with improved outcome. We also assessed the association between microcirculatory dysfunction and inflammatory markers in the post-cardiac arrest state. We prospectively evaluated the sublingual microcirculation in post-cardiac arrest patients, severe sepsis/septic shock patients, and healthy control patients using Sidestream Darkfield microscopy. Microcirculatory flow was assessed using the microcirculation flow index (MFI) at 6 and 24h in the cardiac arrest patients, and within 6h of emergency department admission in the sepsis and control patients. We evaluated 30 post-cardiac arrest patients, 16 severe sepsis/septic shock patients, and 9 healthy control patients. Sublingual microcirculatory blood flow was significantly impaired in post-cardiac arrest patients at 6h (MFI 2.6 [IQR: 2-2.9]) and 24h (2.7 [IQR: 2.3-2.9]) compared to controls (3.0 [IQR: 2.9-3.0]; p<0.01 and 0.02, respectively). After adjustment for initial APACHE II score, post-cardiac arrest patients had significantly lower MFI at 6-h compared to sepsis patients (p<0.03). In the post-cardiac arrest group, patients with good neurologic outcome had better microcirculatory blood flow as compared to patients with poor neurologic outcome (2.9 [IQR: 2.4-3.0] vs. 2.6 [IQR: 1.9-2.8]; p<0.03). There was a trend toward higher median MFI at 24h in survivors vs. non-survivors (2.8 [IQR: 2.4-3.0] vs. 2.6 [IQR: 2.1-2.8] respectively; p<0.09). We found a negative correlation between MFI-6 and vascular endothelial growth factor (VEGF) (r=-0.49, p=0.038). However, after Bonferroni adjustment for multiple comparisons, this correlation was statistically non-significant. Microcirculatory dysfunction occurs early in post-cardiac arrest patients. Better microcirculatory function at 24h may be associated with good neurologic outcome. 23857772 Kinesin-1-syntaphilin coupling mediates activity-dependent regulation of axonal mitochondrial transport. Axonal mitochondria are recruited to synaptic terminals in response to neuronal activity, but the mechanisms underlying activity-dependent regulation of mitochondrial transport are largely unknown. In this paper, using genetic mouse model combined with live imaging, we demonstrate that syntaphilin (SNPH) mediates the activity-dependent immobilization of axonal mitochondria through binding to KIF5. In vitro analysis showed that the KIF5-SNPH coupling inhibited the motor adenosine triphosphatase. Neuronal activity further recruited SNPH to axonal mitochondria. This motor-docking interplay was induced by Ca(2+) and synaptic activity and was necessary to establish an appropriate balance between motile and stationary axonal mitochondria. Deleting snph abolished the activity-dependent immobilization of axonal mitochondria. We propose an "Engine-Switch and Brake" model, in which SNPH acts both as an engine off switch by sensing mitochondrial Rho guanosine triphosphatase-Ca(2+) and as a brake by anchoring mitochondria to the microtubule track. Altogether, our study provides new mechanistic insight into the molecular interplay between motor and docking proteins, which arrests axonal mitochondrial transport in response to changes in neuronal activity. 23808963 Hand eczema among healthcare professionals in the Netherlands: prevalence, absenteeism, and presenteeism. Healthcare professionals have a high risk of developing hand eczema. Hand eczema can interfere with their work. To investigate the prevalence of self-reported hand eczema among healthcare professionals in the Netherlands, and to investigate absenteeism and presenteeism resulting from hand eczema. A questionnaire-based observational study was performed. Participants were recruited from hospitals and nursing homes in the Netherlands. The study population consisted of 1232 healthcare professionals. We used the NOSQ-2002 to measure hand eczema and the PRODISQ for absenteeism and presenteeism. The 1-year prevalence of hand eczema among healthcare professionals was 12%. Among all participants, 47% reported symptoms related to hand eczema. Sick leave resulting from hand eczema was reported by 0.3% of healthcare professionals in general, and by 1.7% of healthcare professionals with hand eczema. In the group with hand eczema, 3.1% reported a large effect on presenteeism. The 1-year prevalence of hand eczema among healthcare professionals in the Netherlands is low, but the prevalence of symptoms related to hand eczema is quite high. Hand eczema seems to have little impact on work in terms of absenteeism and presenteeism. 23776240 Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Synaptic loss is the cardinal feature linking neuropathology to cognitive decline in Alzheimer's disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here, using FRET-based glutamate sensor imaging, we show that amyloid-β peptide (Aβ) engages α7 nicotinic acetylcholine receptors to induce release of astrocytic glutamate, which in turn activates extrasynaptic NMDA receptors (eNMDARs) on neurons. In hippocampal autapses, this eNMDAR activity is followed by reduction in evoked and miniature excitatory postsynaptic currents (mEPSCs). Decreased mEPSC frequency may reflect early synaptic injury because of concurrent eNMDAR-mediated NO production, tau phosphorylation, and caspase-3 activation, each of which is implicated in spine loss. In hippocampal slices, oligomeric Aβ induces eNMDAR-mediated synaptic depression. In AD-transgenic mice compared with wild type, whole-cell recordings revealed excessive tonic eNMDAR activity accompanied by eNMDAR-sensitive loss of mEPSCs. Importantly, the improved NMDAR antagonist NitroMemantine, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from Aβ-induced damage both in vitro and in vivo. 23782454 The bile acid membrane receptor TGR5: a novel pharmacological target in metabolic, inflammatory and neoplastic disorders. Abstract TGR5 is the G-protein-coupled bile acid-activated receptor, found in many human and animal tissues. Considering different endocrine and paracrine functions of bile acids, the current review focuses on the role of TGR5 as a novel pharmacological target in the metabolic syndrome and related disorders, such as diabetes, obesity, atherosclerosis, liver diseases and cancer. TGR5 ligands improve insulin sensitivity and glucose homeostasis through the secretion of incretins. The bile acid/TGR5/cAMP signaling pathway increases energy expenditure in brown adipose tissue and skeletal muscle. Activation of TGR5 in macrophages inhibits production of proinflammatory cytokines and attenuates the development of atherosclerosis. This receptor has been detected in many cell types of the liver where it has anti-inflammatory effects, thus reducing liver steatosis and damage. TGR5 also modulates hepatic microcirculation and fluid secretion in the biliary tree. In cell culture models TGR5 has been linked to signaling pathways involved in metabolism, cell survival, proliferation and apoptosis, which suggest a possible role of TGR5 in cancer development. Despite the fact that TGR5 ligands may represent novel drugs for prevention and treatment of different aspects of the metabolic syndrome, clinical studies are awaited with the perspective that they will complete TGR5 biology and identify efficient and safe TGR5 agonists. 23833207 Spiral countercurrent chromatography. For many years, high-speed countercurrent chromatography conducted in open tubing coils has been widely used for the separation of natural and synthetic compounds. In this method, the retention of the stationary phase is solely provided by the Archimedean screw effect by rotating the coiled column in the centrifugal force field. However, the system fails to retain enough of the stationary phase for polar solvent systems such as the aqueous-aqueous polymer phase systems. To address this problem, the geometry of the coiled channel was modified to a spiral configuration so that the system could utilize the radially acting centrifugal force. This successfully improved the retention of the stationary phase. Two different types of spiral columns were fabricated: the spiral disk assembly, made by stacking multiple plastic disks with single or four interwoven spiral channels connected in series, and the spiral tube assembly, made by inserting the tetrafluoroethylene tubing into a spiral frame (spiral tube support). The capabilities of these column assemblies were successfully demonstrated by separations of peptides and proteins with polar two-phase solvent systems whose stationary phases had not been well retained in the earlier multilayer coil separation column for high-speed countercurrent chromatography. 23846853 Synthesis and Biological Evaluation of 2-Arylamino-5-(3'-Indolyl)-1,3,4-Oxadiazoles as Potent Cytotoxic Agents. Rationally simple: Coupling of two key scaffolds in medicinal chemistry, the indole and 1,3,4-oxadiazole ring systems, gave rise to 2-arylamino-5-(3'-indolyl)-1,3,4-oxadiazoles with IC50 values in the nanomolar range against a panel of tumor cell lines. Preliminary structure-activity relationship studies indicate potential for improved selectivity through further manipulation of the oxadiazole C-2 and C-5 positions. 23816038 The Cholesterol, Hypertension, And Glucose Education (CHANGE) study: results from a randomized controlled trial in African Americans with diabetes. Cardiovascular disease (CVD) and diabetes account for one-third of the mortality difference between African American and white patients. We evaluated the effect of a CVD risk reduction intervention in African Americans with diabetes. We randomized 359 African Americans with type 2 diabetes to receive usual care or a nurse telephone intervention. The 12-month intervention provided monthly self-management support and quarterly medication management facilitation. Coprimary outcomes were changes in systolic blood pressure (SBP), hemoglobin A1c (HbA1c), and low-density lipoprotein cholesterol (LDL-C) over 12 months. We estimated between-intervention group differences over time using linear mixed-effects models. The secondary outcome was self-reported medication adherence. The sample was 72% female; 49% had low health literacy, and 37% had annual income <$10,000. Model-based estimates for mean baseline SBP, HbA1c, and LDL-C were 136.8 mm Hg (95% CI 135.0-138.6), 8.0% (95% CI 7.8-8.2), and 99.1 mg/dL (95% CI 94.7-103.5), respectively. Intervention patients received 9.9 (SD 3.0) intervention calls on average. Primary providers replied to 76% of nurse medication management facilitation contacts, 18% of these resulted in medication changes. There were no between-group differences over time for SBP (P = .11), HbA1c (P = .66), or LDL-C (P = .79). Intervention patients were more likely than those receiving usual care to report improved medication adherence (odds ratio 4.4, 95% CI 1.8-10.6, P = .0008), but adherent patients did not exhibit relative improvement in primary outcomes. This intervention improved self-reported medication adherence but not CVD risk factor control among African Americans with diabetes. Further research is needed to determine how to maximally impact CVD risk factors in African American patients. 22532125 A qualitative analysis of influences on recovery following a first episode of psychosis. Understanding perceived influences on recovery following a first episode of psychosis could help improve services. Thematic analysis was used to examine important influences on early recovery identified by 30 individuals receiving services in an early intervention programme. Social support, medication, meaningful activities and lifestyle modification were identified as helpful, and stigma, substance abuse and medication side effects as harmful. Perceptions of benefits of social support and the negative effects of stigma were particularly prominent. suggest the importance of assistance with engagement in valued activities and relationships, and provision of messages of worth and hope for recovery. 23423569 Munc18b is a major mediator of insulin exocytosis in rat pancreatic β-cells. Sec1/Munc18 proteins facilitate the formation of trans-SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complexes that mediate fusion of secretory granule (SG) with plasma membrane (PM). The capacity of pancreatic β-cells to exocytose insulin becomes compromised in diabetes. β-Cells express three Munc18 isoforms of which the role of Munc18b is unknown. We found that Munc18b depletion in rat islets disabled SNARE complex formation formed by syntaxin (Syn)-2 and Syn-3. Two-photon imaging analysis revealed in Munc18b-depleted β-cells a 40% reduction in primary exocytosis (SG-PM fusion) and abrogation of almost all sequential SG-SG fusion, together accounting for a 50% reduction in glucose-stimulated insulin secretion (GSIS). In contrast, gain-of-function expression of Munc18b wild-type and, more so, dominant-positive K314L/R315L mutant promoted the assembly of cognate SNARE complexes, which caused potentiation of biphasic GSIS. We found that this was attributed to a more than threefold enhancement of both primary exocytosis and sequential SG-SG fusion, including long-chain fusion (6-8 SGs) not normally (2-3 SG fusion) observed. Thus, Munc18b-mediated exocytosis may be deployed to increase secretory efficiency of SGs in deeper cytosolic layers of β-cells as well as additional primary exocytosis, which may open new avenues of therapy development for diabetes. 23847529 A positive feedback cell signaling nucleation model of astrocyte dynamics. We constructed a model of calcium signaling in astrocyte neural glial cells that incorporates a positive feedback nucleation mechanism, whereby small microdomain increases in local calcium can stochastically produce global cellular and intercellular network scale dynamics. The model is able to simultaneously capture dynamic spatial and temporal heterogeneities associated with intracellular calcium transients in individual cells and intercellular calcium waves (ICW) in spatially realistic networks of astrocytes, i.e., networks where the positions of cells were taken from real in vitro experimental data of spontaneously forming sparse networks, as opposed to artificially constructed grid networks or other non-realistic geometries. This is the first work we are aware of where an intracellular model of calcium signaling that reproduces intracellular dynamics inherently accounts for intercellular network dynamics. These results suggest that a nucleation type mechanism should be further investigated experimentally in order to test its contribution to calcium signaling in astrocytes and in other cells more broadly. It may also be of interest in engineered neuromimetic network systems that attempt to emulate biological signaling and information processing properties in synthetic hardwired neuromorphometric circuits or coded algorithms. 23893928 Gas chromatography/trace analysis of derivatized azelaic acid as a stability marker. Azelaic acid, a naturally occurring saturated dicarboxylic acid, is found in many topical formulations for its various medical benefits or as a byproduct of the oxidative decomposition of unsaturated fatty acids. The poor volatility of azelaic acid hinders its applicability in GC analysis. Therefore, azelaic acid was derivatized by methylation and silylation procedures to enhance its volatility for GC analysis. Accordingly, dimethyl azelate (DMA) and di(trimethylsilyl) azelate were synthesized and characterized by GC-MS. Subsequently, a GC with flame ionization detection method was developed and validated to analyze trace amounts of azelaic acid in some marketed skin creams. Unlike DMA, di(trimethylsilyl) azelate was chemically unstable and degraded within few hours. Nonane was used as a stable internal standard. Variability due to derivatization and extraction was controlled by a standard addition procedure. DMA analysis was linear in a wide concentration range (100 ng/mL to 100 mg/mL). Moreover, the method was accurate (96.4-103.4%) and precise with inter- and intraday variability <2.0% and LOQ and LOD of 100 and 10 ng/mL, respectively. 23954698 Effects of praziquantel and sanguinarine on expression of immune genes and susceptibility to Aeromonas hydrophila in goldfish (Carassius auratus) infected with Dactylogyrus intermedius. Praziquantel and sanguinarine have been demonstrated positive therapeutic effects on monogenean Dactylogyrus intermedius; however, few studies have considered the post impacts of these antiparasitic chemicals on host after repelling the parasites. The changes of expression of selected immune genes (CCL-1, CXCL-8, IL-1β-1, IL-1β-2, TNFα-1, TNFα-2 and TGF-β) in gill, kidney and spleen and bacterial loads of Aeromonas hydrophila in gill, kidney, spleen and liver following bath administration of these antiparasitic chemicals were evaluated. The results showed that praziquantel and sanguinarine up-regulated to varying degrees of CXCL-8, IL-1β-1, IL-1β-2, TNFα-1 and TNFα-2 in gill, kidney and spleen. They both decreased the CCL-1 expression in gill while increased it in kidney and spleen. However, in all the tested tissues, the expression of TGF-β decreased in praziquantel treated goldfish whereas that increased in sanguinarine treated goldfish. The A. hydrophila challenge test showed that the praziquantel treatment enhanced the susceptibility to A. hydrophila while sanguinarine treatment decreased the susceptibility, as compared with the non-treated group. Overall, the results indicate that bath administration of praziquantel and sanguinarine modulates the immune related genes in goldfish and these may, to some extent, affect their ability to resist bacterial pathogens. 23847176 A Review of the Neurological and Neurosurgical Implications of Tuberculosis in Children. Tuberculous involvement of the central nervous system (CNS) and vertebral column is the most lethal and disabling form of tuberculosis (TB). Several factors contribute to poor outcome, including cerebrovascular involvement with ischemia, hydrocephalus, direct parenchymal injury and formation of abscess and inflammation in the brain and spinal cord, hyponatremia, seizures, and delayed diagnosis. Spinal spondylitis from TB and associated spinal deformity is the leading cause of paraplegia in developing countries. The evidence for supportive treatment of TB infection of the CNS is limited, leading to substantial differences in management protocols. Many of the treatment approaches used in TB infection of the CNS have been extrapolated from treatment of other acute neurological disorders such as bacterial meningitis and traumatic brain injury. We review data from the available literature and highlight questions relating to the neurological and neurosurgical care of children with TB infection of the CNS and vertebral column. 23928955 Combined spinal and general anesthesia vs general anesthesia for robotic sacrocervicopexy: a randomized controlled trial. Gynecologic laparoscopic surgery is frequently accompanied by early postoperative pain. This study assessed the effect of combined general and spinal anesthesia on postoperative pain score, analgesic use, and patient satisfaction following robotic surgeries. This was a randomized controlled trial. Thirty-eight consecutive women who underwent robotic surgeries for pelvic organ prolapse (sacrocolpopexy with or without subtotal hysterectomy) were randomly assigned to receive general anesthesia (control group, n = 20) or combined general with spinal anesthesia (study group, n = 18). Pain scores were assessed at rest and while coughing using a visual analog scale (VAS) 0-10. Dosage of analgesic medication consumption was retrieved from patients' charts. There were no statistically significant differences between the two groups with respect to demographic data and intraoperative hemodynamic parameters. In the postanesthesia care unit (PACU) mean total IV morphine and meperidine dosages were significantly lower for the study than the control group (0.33 vs 7.59 mg, 1.39 vs 27.89 mg, respectively, P < 0.003, <0.001, respectively). In addition, a significantly lower percentage of patients belonging to the study group demanded analgesic medications while in the PACU (33 vs 53 %, P = 0.042). Pain scores in the PACU and during postoperative day 1 were significantly lower in the study group than in the control group (delta VAS 1.9 vs 3.0, P = 0.04). Satisfaction with pain treatment among both patients and nurses was significantly higher in the study group. Reported levels of pain and analgesic use during the first 24 h following robotic gynecologic surgery were significantly lower following general and spinal anesthesia compared to general anesthesia alone. 23911773 A Non-invasive Modality: The US Virtual Touch Tissue Quantification (VTTQ) for Evaluation of Breast Cancer. We evaluated the biologic features of breast tissues using a newly developed non-invasive diagnostic system, named virtual touch tissue quantification. A total of 180 patients including 115 invasive ductal carcinoma, 30 ductal carcinoma in situ, 4 mucinous carcinoma, 7 invasive lobular carcinoma, 8 fibroadenoma, 12 fibrocystic change and 4 intraductal papilloma were studied at Nahanishi Clinic, Okinawa. We first compared the results of virtual touch tissue quantification according to each histologic subtype and determined the optimal cutoff values for virtual touch tissue quantification to distinguish benign from malignant tissues, using the receiver operating characteristic method. In addition, we also examined the correlation between virtual touch tissue quantification velocities and Ki-67, estrogen receptor, progesterone receptor or human epidermal growth factor receptor 2 in cases of invasive ductal carcinoma using linear regression analyses and Student's t-test. Virtual touch tissue quantification velocities were statistically higher in malignant cases than in benign cases (P < 0.05, respectively) and the best cutoff value for the virtual touch tissue quantification velocity which could differentiate benign from malignant cases was 2.89 m/s. There were statistically significant correlations between the virtual touch tissue quantification velocity and the Ki-67 labeling index (r = 0.338, r(2) = 0.114 and P < 0.001) and significant inverse correlations between virtual touch tissue quantification and the estrogen receptor (r = -0.311, r(2) = 0.097 and P < 0.001) or progesterone receptor (r = -0.361, r(2) = 0.131 and P < 0.001) status of invasive ductal carcinoma. There were also significant differences of the average velocities between human epidermal growth factor receptor 2-positive (6.39 ± 1.44 m/s) and -negative (4.43 ± 1.41 m/s) cases (P < 0.001). Virtual touch tissue quantification could be a valuable clinical tool for estimating breast cancer pathology in a non-invasive fashion. 23578970 Electrochemical impedance spectrum frequency optimization of bitter taste cell-based sensors. Electrochemical impedance spectrum frequency optimization to bitter taste receptor cell-based sensors is discussed in this paper. The bitter taste receptor cells (the enteroendocrine STC-1 cells and the ICR mouse isolated taste bud cells) are cultured on carbon screen printed electrodes and used as sensing elements. The HEK-293 cells and dead isolated ICR mouse taste bud cells, without bitter taste receptor expression, are used in negative control experiments. The electrochemical impedance spectrum data is recorded and processed by bistable stochastic resonance for signal-to-noise ratio analysis. The bitter taste receptor cell-based sensor selectively responds to bitter tastants. The tastants species and concentrations can be decided by signal-to-noise ratio parameters. The signal-to-noise ratio eigen peak changes with the shift of electrochemical impedance spectrum frequencies. ICR mouse isolated taste bud cell-based sensor presents bitter tastants perception abilities. 9kHz is the optimal frequency for STC-1 cell-based sensor measurement. For isolated ICR mouse taste bud cells, 1.2kHz is the optimal frequency. Negative control experiments results indicate that cells with no taste receptor expression have no discriminating ability for tastant even if they are modulated by different frequencies. The taste cell-based sensor is of great practical value. 23665374 Alternative TLRs are stimulated by bacterial ligand to induce TLR2-unresponsive colon cell response. Although pathogenic bacteria penetrate colonic cells causing infection, the role of its surface molecules serving as key Toll-like receptor (TLR) ligands and triggering response remains unexplored. We show that TLR2-ligand porin up-regulated TLR4 on HT-29 cells, which the TLR4-ligand LPS could not. TLR1 that co-express with TLR2 got stimulated with TLR4. Besides the two TLRs, MD-2 was expressed revealing that the TLR4 co-receptor is not exclusive for LPS signaling. SARM-1 that mostly down-regulates TLR-signaling, demonstrated central role in signaling by engaging IRF-3 and NF-κB for cell activity. Porin induced type 1 chemokines particularly MCP-3, while porin-stimulated HT-29 culture supernatant displayed PBMC migration, collectively suggesting that the chemokines influence colon and immune cell cross-talk. In TLR2 down-regulated HT-29 cells, we found TLR1 and TLR4 as substitute TLRs to identify porin and orchestrate signaling. Thus, TLR replacement for PAMP recognition demonstrates specificity of ligand·TLR association can compromise and is a necessary alternative for successful execution of immune responses. 23887045 Time Trends in Biological Fertility in Western Europe. We investigated trends in biological fertility in a comprehensive analysis of 5 major European data sets with data on time to pregnancy (TTP) and proportion of contraceptive failures. In particular, we distinguished a period effect from a birth cohort effect (lifelong tendency) in both sexes. Attempts at conception not resulting in birth were excluded. We analyzed data on pregnancies occurring in 9,247 couples between 1953 and 1993 and performed sensitivity analyses to check the robustness of findings. Separate analyses of each time effect showed an increasing fertility trend. Mutually adjusted analyses demonstrated that this rise was visible as a male cohort effect for both TTP and contraceptive failure. On the other hand, the female birth cohort effect showed a slight fall in the first half of the study period for both TTP and contraceptive failure. As a period effect, fertility remained generally stable, the slight trends in TTP and contraceptive failure being in opposite directions, likely indicating an artifact. The rising trend accords with most previous evidence. The increasing trend in male fertility does not contradict the previously reported semen quality deterioration, the effects of which are calculated to be small. The declining female fertility accords with a falling dizygotic twinning rate during the same period. 23893609 The effects of methamphetamine self-administration on cortical monoaminergic deficits induced by subsequent high-dose methamphetamine administrations. Preclinical models suggest that repeated high-dose methamphetamine (METH) exposures, administered in a "binge-like" pattern, acutely decrease norepinephrine (NE), and acutely and persistently decrease serotonin (5-hydroxytryptamine; 5HT) content in the frontal cortex. However, the impact of METH self-administration on this region is unknown. Because of the importance of the monoaminergic neurons in the frontal cortex to a variety of cognitive and addictive processes, effects of METH self-administration on cortical NE and 5HT content were assessed. Results revealed several novel findings. First, METH self-administration decreased cortical NE content as assessed 24 h after last exposure. Consistent with previous preclinical reports after a binge METH regimen, this decrease was reversed 8 days after the final METH exposure. Second, and in contrast to our previous reports involving the hippocampus or striatum, METH self-administration caused persistent decreases in 5HT content as assessed 8 days after the final METH exposure. Of note, the magnitude of this decrease (∼20%) was less than that observed typically after a binge METH treatment. Third, prior METH self-administration attenuated METH-induced serotonergic deficits as assessed 7 days, but not 1 h, following a neurotoxic METH regimen. No protection was observed when the binge exposure occurred 15 days after the last self-administration session. Taken together, these data demonstrate important and selective alterations in cortical serotonergic neuronal function subsequent to METH self-administration. These data provide a foundation to investigate complex questions involving "resistance" to the persistent deficits caused by neurotoxic METH exposure and frontal cortical function. Synapse, 2013. © 2013 Wiley Periodicals, Inc. 23861906 The Dynamics of Connexin Expression, Degradation and Localisation Are Regulated by Gonadotropins during the Early Stages of In Vitro Maturation of Swine Oocytes. Gap junctional communication (GJC) plays a primordial role in oocyte maturation and meiotic resumption in mammals by directing the transfer of numerous molecules between cumulus cells and the oocyte. Gap junctions are made of connexins (Cx), proteins that regulate GJC in numerous ways. Understanding the dynamic regulation of connexin arrangements during in vitro maturation (IVM) could provide a powerful tool for controlling meiotic resumption and consequently in vitro development of fully competent oocytes. However, physiological events happening during the early hours of IVM may still be elucidated. The present study reports the dynamic regulation of connexin expression, degradation and localization during this stage. Cx43, Cx45 and Cx60 were identified as the main connexins expressed in swine COC. Cx43 and Cx45 transcripts were judged too static to be a regulator of GJC, while Cx43 protein expression was highly responsive to gonadotropins, suggesting that it might be the principal regulator of GJC. In addition, the degradation of Cx43 expressed after 4.5 h of IVM in response to equine chorionic gonadotropin appeared to involve the proteasomal complex. Cx43 localisation appeared to be associated with GJC. Taken together, these results show for the first time that gonadotropins regulate Cx43 protein expression, degradation and localisation in porcine COC during the first several hours of IVM. Regulation of Cx43 may in turn, via GJC, participate in the development of fully competent oocytes. 23870476 Relationship between CYP1A1 polymorphisms and invasion and metastasis of breast cancer. To investigate the relationship between CYP1A1 genetic polymorphisms and the invasion and metastasis of breast cancer. The CYP1A1 gene polymorphism (an T-C transversion at nucleotide position 3801) was detected by the polymerase chain reaction and restriction fragment length polymorphism in 80 cases with breast cancer and 60 samples of normal breast tissue. The difference in genotypic distribution frequency between the groups, the correlation between the genotypes and the factors related to prognosis were analyzed. The incidence of homozygous and variant genotypes had no difference between the breast cancer group and controls group (P=0.746). The proportion of variant genotype increased as clinical stage (P=0.006) advanced, as well as with increased numbers of lymph node metastases (P=0.010). In patients with breast cancer there is a correlation between the CYP1A1 CC allele and some factors indicating poor prognosis, including more lymph node metastases as well as a more advanced clinical stage. 23830782 Cutaneous toxicities of BRAF inhibitors: Clinical and pathological challenges and call to action. Somatic mutations in the BRAF gene have been identified as the most frequent and relevant to develop targeted molecular therapies in melanoma. Recently, seminal clinical trials have provided indisputable evidence that BRAF inhibitors improve response rate, progression free and overall survival in BRAFV600 mutated metastatic melanoma patients, thus representing the novel standard of care. Dermatological "off target" effects of these so-called 'targeted therapies' have to be considered, however, and among them the most intriguing are cutaneous adverse reactions. Skin toxicity is of relevance for at least three reasons: (1) it worsens the patient's quality of life and may be difficult to manage, (2) its heterogeneous clinical presentation differs from the clinico-pathological pictures observed in patients who do not receive BRAF inhibitors, and; (3) onset of skin cancer represents a model of carcinogenesis which may help to better understand the potential visceral tumorigenesis induced by BRAF inhibitors. This manuscript summarizes and critically reviews the state of the art of skin toxicity associated with BRAF inhibitors. Special attention will be paid to clinical presentation and histopathological findings, as well as related challenges for clinicians, pathologists, and basic scientists. 23930973 Serological Evidence for Exposure of Dogs to Rickettsia conorii, Rickettsia typhi, and Orientia tsutsugamushi in Sri Lanka. Abstract Vector-borne rickettsial infection is a major cause of febrile illnesses throughout the world. Although vertebrates hosting the vectors play a vital role in the natural cycle of rickettsiae, studies have not been conducted on them in Sri Lanka. Therefore, the present study was designed to determine the exposure of dog population in Rajawatta, Thambavita, and areas of the Western Slopes and Unawatuna of Sri Lanka to rickettsial pathogens. A total of 123 dog blood samples were collected from those areas. Samples were tested for antibodies against Rickettsia conorii (RC) of the spotted fever group (SFG), Rickettsia typhi (RT) of the typhus group (TG), and Orientia tsutsugamushi (OT) of the scrub typhus group (ST) of rickettsiae by indirect immunofluorescence antibody test (IFA). Samples with titers ≥1:64 were considered as positive in this study. Collectively, 49% dogs were found to have antibodies against the rickettsial agents. Of the dogs, 42%, 24%, and 2% had antibodies against RC, OT, and RT, respectively. The seropositive rate of 100% was observed in areas of the Western Slopes, whereas the lowest rate of 20% was in Unawatuna. Among the positive samples, antibody titers against RC and OT ranged from 1/64 to 1/8192. In contrast, the few dogs that tested positive for RT showed very low titers of 1/64 and 1/128. Results of this study show the extent of exposure to the pathogen and its dispersion in the natural ecology. We suggest that dogs could be acting as reservoirs in the rickettsial transmission cycle or could be effective tracer animals that can be used to detect areas with potential for future outbreaks. 23768116 Proteomic Analysis of Early Reprogramming Events in Murine Somatic Cells Incubated with Xenopus laevis Oocyte Extracts Demonstrates Network Associations with Induced Pluripotency Markers. Abstract The reprogramming of somatic cells into a pluripotent/embryonic-like state holds great potential for regenerative medicine, bypassing ethical issues associated with embryonic stem cells (ESCs). Numerous methods, including somatic cell nuclear transfer (SCNT), fusion to pluripotent cells, the use of cell extracts, and expression of transcription factors, have been used to reprogram cells into ES-like cells [termed induced pluripotent stem cells (iPSCs)]. This study investigated early events in the nuclei of permeabilized murine somatic cells incubated in cytoplasmic extract prepared from Xenopus laevis germinal vesicle-stage oocytes by identifying proteins that showed significant quantitative changes using proteomic techniques. A total of 69 protein spots from two-dimensional electrophoresis were identified as being significantly altered in expression after treatment, and 38 proteins were identified by tandem mass spectrometry. Network analysis was used to highlight pathway connections and interactions between these identified proteins, which were found to be involved in many functions-primarily nuclear structure and dynamics, transcription, and translation. The pluripotency markers Klf4, c-Myc, Nanog, and POU5F1 were highlighted by the interaction network analysis, as well as other compounds/proteins known to be repressed in pluripotent cells [e.g., protein kinase C (PRKC)] or enhanced during differentiation of ESCs (e.g., retinoic acid). The network analysis also indicated additional proteins and pathways potentially involved in early reprogramming events. 23827234 Synthesis and biological activity of benzo-fused 7-deazaadenosine analogues. 5- and 6-substituted 4-amino- or 4-alkylpyrimido[4,5-b]indole ribonucleosides. Two series of new 4-aminopyrimido[4,5-b]indole ribonucleosides bearing phenyl or hetaryl group at position 5 or 6 have been prepared by Suzuki or Stille cross-coupling reactions employing X-Phos ligand with (het)arylboronic acids or stannanes. A series of 4-substituted nucleosides has been also prepared by Pd-catalyzed cross-couplings or nucleophilic substitution. Some of these compounds displayed moderate antiviral activities against HCV and dengue viruses. 23624580 Prospective assessment of the impact of endometriomas and their removal on ovarian reserve and determinants of the rate of decline in ovarian reserve. Do the presence of endometriomas and their laparoscopic excision lead to a decrease in ovarian reserve as assessed by serum anti-Müllerian hormone (AMH) levels? Both the presence and excision of endometriomas cause a significant decrease in serum AMH levels, which is sustained 6 months after surgery. No previous comparison of serum AMH levels between women with and without endometrioma has been reported. However, studies have suggested a decline in serum AMH levels 1-3 months after endometrioma excision but long-term data are needed. A prospective cohort study including 30 women with endometrioma >2 cm were age matched with 30 healthy women without ovarian cysts. Women with endometrioma underwent laparoscopic excision with the stripping technique. Serum AMH level and antral follicle count (AFC) were determined preoperatively, 1 and 6 months after surgery. Correlation analyses were undertaken in order to identify determinants of surgery-related change in ovarian reserve. Compared with controls at baseline, women with endometrioma had lower AMH levels (4.2 ± 2.3 versus 2.8 ± 2.2 ng/ml, respectively, P = 0.02) and AFC (14.7 ± 4.1 versus 9.7 ± 4.8, respectively, P < 0.01). Serum AMH levels were further decreased 6 months after surgery (2.8 ± 2.2 versus 1.8 ± 1.3 ng/ml, P = 0.02), while AFC remained unchanged (9.7 ± 4.8 versus 10.4 ± 4.2, P = 0.63). The rate of decline in AMH was not correlated with age, laterality of endometrioma, cyst diameter or the number of primordial follicles on the surgical specimens. The preoperative serum AMH level was positively correlated with the rate of decline in serum AMH after surgery (r = 0.47, P = 0.02). The absence of a non-treated group of women with endometriomas as a further control prevents comment on the presence of a progressive decline in ovarian reserve related to endometrioma per se. The sample size may be too small for detection of factors correlated with the extent of ovarian damage. While the findings are mostly in agreement with previous studies, the present study is the first to show that the presence of endometrioma per se is associated with a decrease in ovarian reserve. The extent of surgery-related decline in ovarian reserve is not predictable using preoperative or perioperative factors. It may be prudent to measure AMH levels preoperatively and delay/avoid surgical excision as far as is possible if subsequent fertility is a concern. Additional studies are required to further investigate whether the endometrioma-related decline in ovarian reserve per se is progressive in nature and whether it exceeds the surgery-related decline. This study was funded by the Research Fund of the Uludag University School of Medicine. The authors have no conflict of interest associated with this study. 23969988 An association study between the norepinephrine transporter gene and depression. A potential approach for identification of candidate genes for depression is characterization of chromosomal rearrangements. Through analysis of a chromosome translocation in an individual with recurrent depression, we identified a potential candidate gene: the norepinephrine transporter (NET; SLC6A2 for solute carrier 6 family member 2). The gene is responsible for the reuptake of norepinephrine and dopamine into presynaptic nerve terminals and the norepinephrine system appears to play an important role in depression. We therefore analyzed genetic variants within SLC6A2 for association with depression in 408 affected and 559 control individuals from Denmark. After quality control of the genotypes, 31 of 45 single nucleotide polymorphisms (SNPs) were left for analyses. One SNP showed a nominal association with depression but did not survive correction for multiple testing. The results from our study do not suggest SLC6A2 as a susceptibility gene for depression in the Danish population. 23902186 Fracture risk following menopause is reduced by combining medications. Osteoporosis medications increase bone-mineral density (BMD) and lower the risk of fracture. 23891236 Is preeclampsia associated with restless legs syndrome? Restless legs syndrome (RLS) is a common neurologic disorder. Secondary RLS includes pregnancy and iron deficiency. Prevalence of RLS in pregnancy ranges from 11% to 27%. We aimed to assess the frequency and characteristics of RLS in pregnancy in a Peruvian population and to evaluate the possible pregnancy or delivery complications due to RLS. We assessed 218 consecutive expectant mothers at the inpatient clinic of the Hospital San Bartolome in Lima, Peru. Assessment was performed by using the standard diagnostic criteria for RLS and by using a clinical and diagnostic interview. Questionnaires for RLS severity, idiopathic RLS (IRLS), and excessive daytime sleepiness (EDS) according to the Epworth sleepiness scale (ESS) were used. Blood examination was performed for hemoglobin and hematocrit. For comparison, RLS patients were matched for age and body mass index (BMI) with pregnant women without RLS. Out of 218 patients, 40 (18.4%) fulfilled diagnostic criteria for RLS. In RLS patients, prophylactic iron supplementation therapy during pregnancy was less frequently taken (P=.02). Pregnant women with RLS had a higher ESS score than pregnant controls (10.6 +/- 3.1 vs 7.6. +/- 3.6; P<.001). Preeclampsia was more frequent in RLS (7/40 vs 1/39; P=.03). In our study, RLS was frequent in pregnant Peruvian women, especially in those without prophylactic iron supplementation. RLS patients described more EDS. Preeclampsia was more common in RLS. Our study is the first study to indicate a possible association between RLS and preeclampsia. 23934258 Synthesis and Biological Evaluation of 1,2,4-Triazole and 1,3,4-Thiadiazole Derivatives as Potential Cytotoxic Agents. A series of new 3-amino-5-sulfanyl-1,2,4-triazole and 2-amino-5-sulfanyl-1,3,4- thiadiazole derivatives have been synthesized and their cytotoxicities were evaluated on a panel of human cancer cell lines (BxPC-3, H1975, SKOV-3, A875, HCT116, etc.). The best one (compound 5m) exhibited activities with IC50 values ranging from 0.04 to 23.6 µM against nine human cancer cell lines. Further biological evaluation indicated that DNA replication was blocked by treatment with compound 5m in HCT116 cells. 23292201 The assessment of particulate matter emitted from stone-crushing industry by correlating rock textures with particles generated after comminution and dispersed in air environment. The generation and emission of particulate matter from abrasion industry are subjects of the pollution monitoring by multidisciplinary study involving earth sciences and engineering disciplines. This work investigates the correlation between textural properties of in situ rock with class size distribution and morphology of particles generated after rock comminution and particles emitted in the air. A special comminution-dust sampling architecture was realised. The combined use of scanning electron microscopy and particle size analyser was considered in performing digital image analysis on both crushed products and airborne particles collected onto membrane filters. The results show that the size and morphology of crushed particles are linked to the petrographic rock properties. In particular, particles with fibrous morphology are prominent in rocks showing foliated textures where elongated minerals occurred, with implication for asbestos-bearing rocks. For what concerns the airborne particles, the results show that their aerodynamic diameters are independent of the crusher operating conditions. External parameters probably intervene in the distribution of the airborne particles emission, including the dynamic air fluxes, or environmental conditions. By applying mathematical models, the morphology and size range of airborne particles following the comminution processes can be predicted, and results has implication for pollutants contamination due to particulate matters emitted by crush stone industry. 23715534 An inorganic-organic double network hydrogel of graphene and polymer. An inorganic-organic double network (DN) hydrogel of graphene and poly(acrylic acid) (PAA) has been prepared by a two step synthesis. At first, reduced graphene oxide hydrogel (rGO) was prepared by a reduction-induced in situ self-assembly, and then acrylic acid monomer was adsorbed into the first network and was polymerized therein to form a second PAA network. The as-prepared rGO-PAA DN hydrogel shows both elasticity and electrical conductivity, and has potential application as a flexible conductive material for the next generation of electric devices. 23794470 Amination of Heteroaryl Chlorides: Palladium Catalysis or SN Ar in Green Solvents? The reaction of heteroaryl chlorides in the pyrimidine, pyrazine and quinazoline series with amines in water in the presence of KF results in a facile SN Ar reaction and N-arylation. The reaction is less satisfactory with pyridines unless an additional electron-withdrawing group is present. The results showed that the transition-metal-free SN Ar reaction not only compares favourably to palladium-catalysed coupling reactions but also operates under environmentally acceptable ("green") conditions in terms of the base and solvent. 23658341 Effect of ramp configuration on easiness of handling, heart rate, and behavior of near-market weight pigs at unloading. Three experiments, each using 280 pigs, were conducted in a simulated compartment to test the effect of angle of entrance (AOE) to the ramp (90°, 60°, 30°, or 0°), ramp slope (0°, 16°, 21°, or 26°), and an initial 20-cm step associated with 16° or 21° ramp slopes on the ease of handling, heart rate (HR), and behavior of near market-weight pigs during unloading. Heart rate (pigs and handler), unloading time, interventions of the handler, and reactions of the pigs were monitored. The results of the first experiment show that using a 90° AOE had detrimental effects on ease of handling (P < 0.05), HR of the pig (P < 0.05), and behavior (P < 0.05). The 0° and 30° AOE appeared to improve the ease of unloading, whereas the 60° AOE had an intermediate effect. The 30° AOE appeared to be preferable, because pigs moved at this angle balked less frequently (P < 0.01) and required less manipulation (P < 0.05) than pigs moved with a 0° AOE. The results of the second experiment show that the use of a flat ramp led to the easiest unloading, as demonstrated by the lower number of balks (P < 0.001) when pigs were moved to the ramp and less frequent use of paddle (P = 0.001) or voice (P < 0.001) on the ramp, compared with the other treatments. However, the flat ramp did not differ from the 21° ramp in many of the variables reflecting ease of handling, which may be explained by the difference in configuration between the ramps. The results also show that the use of the steepest ramp slope had the most detrimental effect on balking and backing up behavior of pigs (P < 0.001), and handling (touches, slaps, and pushes; P < 0.05 for all) when moved to the ramp and on unloading time (P < 0.01). No differences in pig HR (P < 0.05) and ease of handling on the ramp (P < 0.05) were found between a 26° and 16° ramp slope, suggesting that the length of the ramp may be one of the factors that make unloading more difficult. The results of the last experiment show that an initial step made unloading physically more demanding for the handler (P < 0.001) and pigs on the ramp (P < 0.05) as demonstrated by their greater HR. The greater difficulty of handling (P < 0.01) and reluctance to move (P < 0.05) of pigs moved toward the 16° ramp with a step suggest that pigs perceived this ramp as more psychologically challenging. Making a few changes in terms of the design of the ramp could improve the efficiency of handling and reduce stress in pigs. 23909351 Anomalous ground state of the electrons in nanoconfined water. Water confined on the scale of 20 Ã…, is known to have different transport and thermodynamic properties from that of bulk water, and the proton momentum distribution has recently been shown to have qualitatively different properties from that exhibited in bulk water. The electronic ground state of nanoconfined water must be responsible for these anomalies but has so far not been investigated. We show here for the first time, using x-ray Compton scattering and a computational model, that the ground state configuration of the valence electrons in a particular nanoconfined water system, Nafion, is so different from that of bulk water that the weakly electrostatically interacting molecule model of water is clearly inapplicable. We argue that this is a generic property of nanoconfinement. The present results demonstrate that the electrons, and hence the protons as well, of nanoconfined water are in a distinctly different quantum state from that of bulk water. Biological cell function must make use of the properties of this state and cannot be expected to be described correctly by empirical models based on the weakly interacting molecules model. 23678027 Ca2+-pumping impairment during repetitive fatiguing contractions in single myofibers: role of cross-bridge cycling. The energy cost of contractions in skeletal muscle involves activation of both actomyosin and sarcoplasmic reticulum (SR) Ca(2+)-pump (SERCA) ATPases, which together determine the overall ATP demand. During repetitive contractions leading to fatigue, the relaxation rate and Ca(2+) pumping become slowed, possibly because of intracellular metabolite accumulation. The role of the energy cost of cross-bridge cycling during contractile activity on Ca(2+)-pumping properties has not been investigated. Therefore, we inhibited cross-bridge cycling by incubating isolated Xenopus single fibers with N-benzyl-p-toluene sulfonamide (BTS) to study the mechanisms by which SR Ca(2+) pumping is impaired during fatiguing contractions. Fibers were stimulated in the absence (control) and presence of BTS and cytosolic calcium ([Ca(2+)]c) transients or intracellular pH (pHi) changes were measured. BTS treatment allowed normal [Ca(2+)]c transients during stimulation without cross-bridge activation. At the time point that tension was reduced to 50% in the control condition, the fall in the peak [Ca(2+)]c and the increase in basal [Ca(2+)]c did not occur with BTS incubation. The progressively slower Ca(2+) pumping rate and the fall in pHi during repetitive contractions were reduced during BTS conditions. However, when mitochondrial ATP supply was blocked during contractions with BTS present (BTS + cyanide), there was no further slowing in SR Ca(2+) pumping during contractions compared with the BTS-alone condition. Furthermore, the fall in pHi was significantly less during the BTS + cyanide condition than in the control conditions. These results demonstrate that factors related to the energetic cost of cross-bridge cycling, possibly the accumulation of metabolites, inhibit the Ca(2+) pumping rate during fatiguing contractions. 23844034 Comparison of Systemic and Mucosal Immunization with Helper-Dependent Adenoviruses for Vaccination against Mucosal Challenge with SHIV. Most HIV-1 infections are thought to occur at mucosal surfaces during sexual contact. It has been hypothesized that vaccines delivered at mucosal surfaces may mediate better protection against HIV-1 than vaccines that are delivered systemically. To test this, rhesus macaques were vaccinated by intramuscular (i.m.) or intravaginal (ivag.) routes with helper-dependent adenoviral (HD-Ad) vectors expressing HIV-1 envelope. Macaques were first immunized intranasally with species C Ad serotype 5 (Ad5) prior to serotype-switching with species C HD-Ad6, Ad1, Ad5, and Ad2 vectors expressing env followed by rectal challenge with CCR5-tropic SHIV-SF162P3. Vaccination by the systemic route generated stronger systemic CD8 T cell responses in PBMC, but weaker mucosal responses. Conversely, mucosal immunization generated stronger CD4 T cell central memory (Tcm) responses in the colon. Intramuscular immunization generated higher levels of env-binding antibodies, but neither produced neutralizing or cytotoxic antibodies. After mucosal SHIV challenge, both groups controlled SHIV better than control animals. However, more animals in the ivag. group had lower viral set points than in in the i.m. group. These data suggest mucosal vaccination may have improve protection against sexually-transmitted HIV. These data also demonstrate that helper-dependent Ad vaccines can mediate robust vaccine responses in the face of prior immunity to Ad5 and during four rounds of adenovirus vaccination. 23768598 Hyaluronan scaffolds via diglycidyl ether crosslinking: toward improvements in composition and performance. A novel approach for hyaluronic acid (HA) crosslinking via diglycidyl ether (DGE) was investigated for scaffolds fabrication. In particular, HA sponges were obtained by lyophilization and then reacted with 1,4-butandiol diglycidyl ether (BDDGE) in heterogeneous conditions. Insoluble matrices with 4-20% of the reactive sites of HA modified were produced. The hydrogels showed high swelling capability depending on external stimuli; when equilibrated in physiological solution, pore ranged from 70 to 130 μm and G' values were in the range 2-10 kPa. The matrices proved highly stable in cell culture conditions and to enzymatic degradation. A biological evaluation revealed good cellular viability within the scaffolds in two weeks experiments. The main achievement consists in that the novel conditions (BDDGE and heterogeneous reaction) permitted to obtain insoluble, directly structured and potentially applicable scaffolds with the lower content of crosslinker reported to date. The in vitro characterization outcomes propose the hydrogels as promising substrates for soft tissues regeneration. 23832266 Long-term follow-up after native tissue repair for pelvic organ prolapse. There are large variations in reported frequency of recurrence and subsequent treatment after pelvic organ prolapse (POP) surgery. We hypothesized that native tissue repair entails high subjective satisfaction and good objective results, with low POP reoperation rates and few complications. The 1-year results of 699 women having had native tissue repair for POP at our urogynecological unit from 2002 to 2005 were evaluated using an internal quality control database. A short-form physician check list for patient subjective and objective outcomes has been routinely used for 1-year controls since 2002, and results are registered longitudinally in the database. Patients' medical records up to 2012 were reviewed for information on recurrent POP symptoms. A telephone interview was performed to assess POP recurrences potentially treated elsewhere. The cumulative incidence for reoperation was calculated comparing partial with complete (surgical treatment of all three compartments) native tissue repairs. Subjective satisfaction was stated by 94 % of patients at the 1-year control, and 84 % had stage 0-I in any compartment using the POP Quantification (POP-Q) system. The 5-year reoperation rate was significantly lower in the complete vs. the partial (2.6 % vs. 8.9 %) repair group. Cumulative incidence of reoperation showed a slight but constant increase over the years. POP surgery using native tissue repair entails low reoperation rates with excellent subjective and objective results and should be the first choice in treating primary POP, providing use of adequate surgical technique. 23857008 Reaction of trisubstituted alkenes with iron porphyrin carbenes: facile synthesis of tetrasubstituted dienes and cyclopentadienes. The unprecedented reaction of trisubstituted alkenes with iron porphyrin carbenes has been successfully developed. Both multiply substituted 1,3-butadiene and cyclopentadiene products are readily accessible with high efficiency and selectivity in good yields. 23487551 Increased protein intake decreases postnatal growth faltering in ELBW babies. To determine whether purposely designed nutritional guidelines for extremely low birthweight (ELBW; birth weight <1000 g) babies result in protein intakes that meet international consensus recommendations, and whether this results in improved growth from birth to discharge. A prospective cohort study of nutritional intakes and growth in ELBW babies. A tertiary neonatal intensive care unit in New Zealand. 100 ELBW babies who survived for the first month of life, 50 before the introduction of the guideline (Lo Pro) and 50 after (Hi Pro). Introduction of a nutritional guideline aimed at increasing protein intakes to meet international consensus recommendations. Weekly protein intakes over the first month of life and growth until discharge. Hi Pro babies had significantly higher protein intakes in the first month of life than Lo Pro babies (mean (SD), 3.8 (0.3) vs 3.3 (0.4) g/kg.day, p<0.0001) and a significantly greater growth velocity (GV) over the first 30 days after regaining birth weight (19.5 (5.0) vs 16.2 (5.4) g/kg.day, p<0.002). Hi Pro babies had a significantly lesser Z-score change between birth and discharge than Lo Pro babies for weight (0.0 (1.2) vs -0.9 (1.1), p=0.001), length (-0.8 (0.8) vs -1.2 (1.1), p=0.02) and head circumference (-0.2 (1.1) vs -1.1 (1.6), p<0.001). Simple, standardised nutritional guidelines can result in recommended protein intakes for ELBW babies being achieved and result in increased GV. Downward crossing of centiles between birth and discharge, common in ELBW babies, is significantly reduced for weight, length and head circumference. 23699054 Differences in spectral profiles between rostral and caudal premotor cortex when hand-eye actions are decoupled. The aim of this research was to understand how the brain controls voluntary movement when not directly interacting with the object of interest. In the present study, we examined the role of premotor cortex in this behavior. The goal of this study was to characterize the oscillatory activity within the caudal and rostral subdivisions of dorsal premotor cortex (PMdc and PMdr) with a change from the most basic reaching movement to one that involves a simple dissociation between the actions of the eyes and hand. We were specifically interested in how PMdr and PMdc respond when the eyes and hand are decoupled by moving along different spatial planes. We recorded single-unit activity and local field potentials within PMdr and PMdc from two rhesus macaques during performance of two types of visually guided reaches. During the standard condition, a visually guided reach was performed whereby the visual stimulus guiding the movement was the target of the reach itself. During the nonstandard condition, the visual stimulus provided information about the direction of the required movement but was not the target of the motor output. We observed distinct task-related and topographical differences between PMdr and PMdc. Our results support functional differences between PMdr and PMdc during visually guided reaching. PMdr activity appears more involved in integrating the rule-based aspects of a visually guided reach, whereas PMdc is more involved in the online updating of the decoupled reach. More broadly, our results highlight the necessity of accounting for the nonstandard nature of a motor task when interpreting movement control research data. 23481635 9G DNAChip Technology: Self-Assembled Monolayer (SAM) of ssDNA for Ultra-Sensitive Detection of Biomarkers. A 9G DNAChip obtained by allowing the formation of a self-assembled monolayer (SAM) of oligonucleotides appended with nine consecutive guanines on the chip surface has been applied in the detection of biomarkers. Using a 9G DNAChip, biomarker in the concentration range of 4 pg/mL to 40 fg/mL can be easily differentiated in the buffer matrix. Moreover, it is the first time that a biomarker with a concentration of 40 fg/mL has been detected in a mixture of proteins without use of any signal amplification technique. 23411329 Purification, properties and cDNA cloning of glutamate decarboxylase in germinated faba bean (Vicia faba L.). Gamma-aminobutyric acid (GABA) is a non-protein amino acid with bioactive functions in humans. In this work, glutamate decarboxylase (EC 4.1.1.15, GAD) which is key in the GABA bioformation was purified from 5-day germinated faba beans and characterized. A single band was observed at 58 kDa using sodium dodecyl sulphate gel electrophoresis. GAD optimal activity was at pH 6.0 at 40°C with a K(m) value for glutamic acid (Glu) of 2.63 mM. The enzyme was inhibited significantly by Cu(2+), Fe(3+), Mg(2+), Ba(2+), aminoxyacetate, EGTA, Na(2)EDTA, l-cysteine and beta-mercaptoethanol; and activated at low Ca(2+) 0.2mM. Using RT-PCR, the GAD cDNA was sequenced which indicated 1787 bp long, containing a 1527 bp open reading frame (ORF) that encoded 509 amino-acid peptides with a calculated molecular weight of 57.74 kDa and a pI of 5.41 (GenBank accession number: JX444699). 23958289 Does regional compared to local anaesthesia influence outcome after arteriovenous fistula creation? An arteriovenous fistula is the optimal form of vascular access in patients with end-stage renal failure requiring haemodialysis. Unfortunately, approximately one-third of fistulae fail at an early stage. Different anaesthetic techniques can influence factors associated with fistula success, such as intraoperative blood flow and venous diameter. A regional anaesthetic brachial plexus block results in vasodilatation and improved short- and long-term fistula flow compared to the infiltration of local anaesthetic alone. This, however, has not yet been shown in a large trial to influence long-term fistula patency, the ultimate clinical measure of success.The aim of this study is to compare whether a regional anaesthetic block, compared to local anaesthetic infiltration, can improve long-term fistula patency. This study is an observer-blinded, randomised controlled trial. Patients scheduled to undergo creation of either brachial or radial arteriovenous fistulae will receive a study information sheet, and consent will be obtained in keeping with the Declaration of Helsinki. Patients will be randomised to receive either: (i) an ultrasound guided brachial plexus block using lignocaine with adrenaline and levobupivicaine, or (ii) local anaesthetic infiltration with lignocaine and levobupivicaine.A total of 126 patients will be recruited. The primary outcome is fistula primary patency at three months. Secondary outcomes include primary patency at 1 and 12 months, secondary patency and fistula flow at 1, 3 and 12 months, flow on first haemodialysis, procedural pain, patient satisfaction, change in cephalic vein diameter pre- and post-anaesthetic, change in radial or brachial artery flow pre- and post-anaesthetic, alteration of the surgical plan after anaesthesia as guided by vascular mapping with ultrasound, and fistula infection requiring antibiotics. No large randomised controlled trial has examined the influence of brachial plexus block compared with local anaesthetic infiltration on the long-term patency of arteriovenous fistulae. If the performance of brachial plexus block increases fistulae patency, this will have significant clinical and financial benefits as the number of patients able to commence haemodialysis when planned should increase, and the number of "redo" or revision procedures should be reduced. This study has been approved by the West of Scotland Research Ethics Committee 5 (reference no. 12/WS/0199) and is registered with the ClinicalTrials.gov database (reference no. NCT01706354). 23830872 Integrin α7 Binds Tissue Inhibitor of Metalloproteinase 3 to Suppress Growth of Prostate Cancer Cells. Integrin α7 (ITGA7) is a tumor-suppressor gene that is critical for suppressing the growth of malignant tumors; however, the mechanisms allowing ITGA7 to suppress the growth of cancer cells remain unclear. Herein, we show that ITGA7 binds to tissue inhibitor of metalloproteinase 3 (TIMP3) in prostate cancer cells. The ITGA7-TIMP3 binding led to a decreased protein level of tumor necrosis factor α, cytoplasmic translocation of NF-κB, and down-regulation of cyclin D1. These changes led to an accumulation of cells in G0/G1 and a dramatic suppression of cell growth. Knocking down TIMP3 or ITGA7/TIMP3 binding interference largely abrogated the signaling changes induced by ITGA7, whereas a mutant ITGA7 lacking TIMP3 binding activity had no tumor-suppressor activity. Interestingly, knocking down ITGA7 ligand laminin β1 enhanced ITGA7-TIMP3 signaling and the downstream tumor-suppressor activity, suggesting the existence of a counterbalancing role between extracellular matrix and integrin signaling. As a result, this report demonstrates a novel and critical signaling mechanism of ITGA7, through the TIMP3/NF-κB/cyclin D1 pathway. 23933173 mTOR activation in immature cells of primary nasopharyngeal carcinoma and anti-tumor effect of rapamycin in vitro and in vivo. The mammalian target of rapamycin (mTOR) signaling is a key pathway in the progression of different cancers and in the homeostasis of stem cells. Here, we investigated the link between mTOR signaling and cancer stem cells (CSCs) in nasopharyngeal carcinoma (NPC). We found that human primary NPC expressed embryonic stem cell (ESC) markers: CD133, SOX2 and OCT4 as well as pmTOR and pS6. Primary ESC-positive NPC cells could form secondary NPC in BALB/c nude mice. Rapamycin, an mTOR inhibitor, significantly suppressed ESC-positive NPC cell growth in vitro and tumor formation in vivo. Our findings suggest that mTOR signaling is activated in CSC-like cells and plays an important role in NPC growth. 23950879 The Contribution of Emotional Partners to Sexual Risk Taking and Violence among Female Sex Workers in Mombasa, Kenya: A Cohort Study. To assess sexual risk-taking of female sex workers (FSWs) with emotional partners (boyfriends and husbands), compared to regular and casual clients. Experiences of violence and the degree of relationship control that FSWs have with emotional partners are also described. Cohort study with quarterly follow-up visit over 12-months. Four hundred HIV-uninfected FSWs older than 16 years were recruited from their homes and guesthouses in Mombasa, Kenya. A structured questionnaire assessed participant characteristics and study outcomes at each visit, and women received risk-reduction counselling, male and female condoms, and HIV testing. Four or more unprotected sex acts in the past week were reported by 21.3% of women during sex with emotional partners, compared to 5.8% with regular and 4.8% with casual clients (P<0.001). Total number of unprotected sex acts per week was 5-6-fold higher with emotional partners (603 acts with 259 partners) than with regular or casual clients (125 acts with 456, and 98 acts with 632 clients, respectively; P<0.001). Mostly, perceptions of "trust" underscored unprotected sex with emotional partners. Low control over these relationships, common to many women (36.9%), was linked with higher partner numbers, inconsistent condom use, and being physically forced to have sex by their emotional partners. Half experienced sexual or physical violence in the past year, similarly associated with partner numbers and inconsistent condom use. High-risk sexual behaviour, low control and frequent violence in relationships with emotional partners heighten FSWs' vulnerability and high HIV risk, requiring targeted interventions that also encompass emotional partners. 23873772 Decreased survival in normal karyotype aml with single nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5'-nucleotidase. Purpose: De novo acute myeloid leukemia with normal karyotype (NK-AML) comprises a large group of patients with no common cytogenetic alterations and with a large variation in treatment response. Single nucleotide polymorphisms (SNPs) in genes related to the metabolism of the nucleoside analogue AraC, the backbone in AML treatment, might affect drug sensitivity and treatment outcome. Therefore, SNPs may serve as prognostic biomarkers aiding clinicians in individualized treatment decisions, with the aim of improving patient outcomes. Experimental design: We analyzed polymorphisms in genes encoding cytidine deaminase (CDA 79A>C rs2072671 and -451C>T rs532545), 5'-nucleotidase (cN-II 7A>G rs10883841), and deoxycytidine kinase (DCK 3'UTR 948T>C rs4643786) in 205 de novo NK-AML patients. Results: In FLT3-ITD-positive patients, the CDA 79C/C and -451T/T genotypes were associated with shorter overall survival compared to other genotypes (5 vs. 24 months, p <0.001, and 5 vs. 23 months, p = 0.015, respectively) and this was most pronounced in FLT3-ITD-positive/NPM1-positive patients. We observed altered in vitro sensitivity to topoisomerase inhibitory drugs, but not to nucleoside analogues, and a decrease in global DNA methylation in cells carrying both CDA variant alleles. A shorter survival was also observed for the cN-II variant allele, but only in FLT3-ITD-negative patients (25 vs. 31 months, p = 0.075). Conclusion: Our results indicate that polymorphisms in genes related to nucleoside analog drug metabolism may serve as prognostic markers in de novo NK-AML. 23907606 The Oxford Unicompartmental Knee Fails at a High Rate in a High-volume Knee Practice. The Oxford knee is a unicompartmental implant featuring a mobile-bearing polyethylene component with excellent long-term survivorship results reported by the implant developers and early adopters. By contrast, other studies have reported higher revision rates in large academic practices and in national registries. Registry data have shown increased failure with this implant especially by lower-volume surgeons and institutions. In the setting of a high-volume knee arthroplasty practice, we sought to determine (1) the failure rate of the Oxford unicompartmental knee implant using a failure definition for aseptic loosening that combined clinical features, plain radiographs, and scintigraphy, and (2) whether increased experience with this implant would decrease failure rate, if there is a learning curve effect. Eighty-three Oxford knee prostheses were implanted between September 2005 and July 2008 by the principal investigator. Radiographic and clinical data were available for review for all cases. A failed knee was defined as having recurrent pain after an earlier period of recovery from surgery, progressive radiolucent lines compared with initial postoperative radiographs, and a bone scan showing an isolated area of uptake limited to the area of the replaced compartment. Eleven knees in this series failed (13%); Kaplan-Meier survivorship was 86.5% (95% CI, 78.0%-95.0%) at 5 years. Failure occurrences were distributed evenly over the course of the study period. No learning curve effect was identified. Based on these findings, including a high failure rate of the Oxford knee implant and the absence of any discernible learning curve effect, the principal investigator no longer uses this implant. Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. 23860122 MLK3 promotes metabolic dysfunction induced by saturated fatty acid-enriched diet. Saturated fatty acids activate the c-Jun NH2-terminal kinase (JNK) pathway, resulting in chronic low-grade inflammation and the development of insulin resistance. Mixed-lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that mediates JNK activation in response to saturated fatty acids in vitro; however, the exact mechanism for diet-induced JNK activation in vivo is not known. Here, we have used MLK3-deficient mice to examine the role of MLK3 in a saturated-fat diet model of obesity. MLK3-KO mice fed a high-fat diet enriched in medium-chain saturated fatty acids for 16 wk had decreased body fat compared with wild-type (WT) mice due to increased energy expenditure independently of food consumption and physical activity. Moreover, MLK3 deficiency attenuated palmitate-induced JNK activation and M1 polarization in bone marrow-derived macrophages in vitro, and obesity induced JNK activation, macrophage infiltration into adipose tissue, and expression of proinflammatory cytokines in vivo. In addition, loss of MLK3 improved insulin resistance and decreased hepatic steatosis. Together, these data demonstrate that MLK3 promotes saturated fatty acid-induced JNK activation in vivo and diet-induced metabolic dysfunction. 23355074 Non-syndromic sensorineural prelingual deafness: the importance of genetic counseling in demystifying parents' beliefs about the cause of their children's deafness. Recent advances in molecular genetics have allowed the determination of the genetic cause of some childhood non-syndromic deafness. In Portugal only a small proportion of families are referred to a clinical genetics service in order to clarify the etiology of the deafness and to provide genetic counseling. Consequently, there are no published studies of the prior beliefs of parents about the causes of hereditary deafness of their children and their genetic knowledge after receipt of genetic counseling. In order to evaluate the impact of genetic counseling, 44 parents of 24 children with the diagnosis of non-syndromic sensorineural prelingual deafness due to mutations in the GJB2 (connexin 26), completed surveys before and after genetic counseling. Before counseling 13.6 % of the parents knew the cause of deafness; at a post-counseling setting this percentage was significantly higher, with 84.1 % of the parents accurately identifying the etiology. No significant differences were found between the answers of mothers and fathers either before or after genetic counseling. Parents' level of education was a significant factor in pre-test knowledge. After genetic counseling 95.5 % of the parents stated that the consultation had met their expectations, 70.5 % remembered correctly the inheritance pattern, and 93.2 % correctly recalled the chance of risk of deafness. These results underline the importance of genetic counseling in demystifying parents' beliefs about the etiology of their children's deafness. 23127146 Is polycystic ovary syndrome, a state of relative estrogen excess, a real risk factor for estrogen-dependant malignancies? Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting women of fertile age. It is associated with several risk factors and long-term health consequences. Chronic anovulation combined with relative estrogen excess and consequent prolonged stimulatory effect on the endometrium can lead to the pathogenesis of hormonal dependant carcinoma. PCOS is thus traditionally reported to be associated with increased risk of endometrial, as well as breast and ovarian cancers. This article provides a critical literature review of the relationship between PCOS and the incidence of estrogen-dependant gynecological tumours, and it then discusses whether the commonly cited risk factor association can be substantiated by high quality studies which comply with the requirements of "evidence-based medicine." 23881171 Lack of Association of Homocysteine Concentrations with Oxidative Stress, Alterations in Carotid Intima Media Thickness and Endothelial Reactivity in Prepubertal Children. Background and Aims: Our purpose was to assess the presence of risk factors for cardiovascular diseases (alterations in the lipid profile, fasting glycaemia, high arterial pressure values, oxidative stress, increased intima media thickness and impaired endothelium-dependent vasodilation) in prepubertal children with elevated homocysteine (Hcy) levels. Methods: In a cross-sectional study, 35 children with Hcy levels ≥7.3 μmol/l were matched by gender and age with 29 children with Hcy levels ≤4.1 μmol/l. Our collected data included weight, height, waist circumference, systemic arterial pressure, lipid profile, fasting glycaemia and oxidative stress markers. A Doppler ultrasound was performed to measure the carotid intima media thickness and the endothelium-dependent vasodilation of the brachial artery. Results: There were no statistically significant differences between the groups regarding the lipid profile and fasting glycaemia, blood pressure or oxidative stress. Overweight and obesity (body mass index z-score > +1) were more frequent in the group with Hcy ≥7.3 μmol/l when compared to the group with Hcy ≤4.1 μmol/l [13/35 (37.1%) vs. 4/29 (13.8%); p = 0.035]. After adjusting for nutritional status, there were no differences in the intima media thickness and endothelium-dependent vasodilation between children with high and low Hcy levels. Conclusions: Among the cardiovascular risk factors investigated in the present study, which was based on prepubertal children, only overweight and obesity were associated with increased Hcy concentrations (≥7.3 μmol/l). 23933067 Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study. A new betacoronavirus-Middle East respiratory syndrome coronavirus (MERS-CoV)-has been identified in patients with severe acute respiratory infection. Although related viruses infect bats, molecular clock analyses have been unable to identify direct ancestors of MERS-CoV. Anecdotal exposure histories suggest that patients had been in contact with dromedary camels or goats. We investigated possible animal reservoirs of MERS-CoV by assessing specific serum antibodies in livestock. We took sera from animals in the Middle East (Oman) and from elsewhere (Spain, Netherlands, Chile). Cattle (n=80), sheep (n=40), goats (n=40), dromedary camels (n=155), and various other camelid species (n=34) were tested for specific serum IgG by protein microarray using the receptor-binding S1 subunits of spike proteins of MERS-CoV, severe acute respiratory syndrome coronavirus, and human coronavirus OC43. Results were confirmed by virus neutralisation tests for MERS-CoV and bovine coronavirus. 50 of 50 (100%) sera from Omani camels and 15 of 105 (14%) from Spanish camels had protein-specific antibodies against MERS-CoV spike. Sera from European sheep, goats, cattle, and other camelids had no such antibodies. MERS-CoV neutralising antibody titres varied between 1/320 and 1/2560 for the Omani camel sera and between 1/20 and 1/320 for the Spanish camel sera. There was no evidence for cross-neutralisation by bovine coronavirus antibodies. MERS-CoV or a related virus has infected camel populations. Both titres and seroprevalences in sera from different locations in Oman suggest widespread infection. European Union, European Centre For Disease Prevention and Control, Deutsche Forschungsgemeinschaft. 23929434 The highly prevalent BRCA2 mutation c.2808_2811del (3036delACAA) is located in a mutational hotspot and has multiple origins. BRCA2-c.2808_2811del (3036delACAA) is one of the most reported germline mutations in non-Ashkenazi breast cancer patients. We investigated its genetic origin in 51 Spanish carrier families that were genotyped with eleven 13q polymorphic markers. Three independent associated haplotypes were clearly distinguished accounting for 23 (WCL), 20 (ECL) and 6 families (SoS). Mutation age was estimated with the DMLE software in a range of 45-68 and 45-71 generations for WCL and ECL haplotypes, respectively. The most prevalent variants, c.2808_2811del and c.2803G>A, were located in a double-hairpin loop structure (c.2794-c.2825) predicted by Quikfold that was proposed as a mutational hotspot. To check this hypothesis, random mutagenesis was performed over a 923-bp fragment of BRCA2 and 86 DNA variants were characterized. Interestingly, three mutations reported in the mutation databases (c.2680G>A, c.2944del and c.2957dup) were replicated and 20 affected the same position with different nucleotide changes. Moreover, five variants were placed in the same hairpin-loop of c.2808_2811del, and one affected the same position (c.2808A>G). In conclusion, our results support that at least three different mutational events occurred to generate c.2808_2811del. Other highly prevalent DNA variants, such as BRCA1-c.68_69delAG and BRCA2-c.5946delT and c.8537delAG, are concentrated in hairpin-loops suggesting that these structures may represent mutational hotspots. 23856076 Face perception is category-specific: Evidence from normal body perception in acquired prosopagnosia. Does the human visual system contain perceptual mechanisms specialized for particular object categories such as faces? This question lies at the heart of a long-running debate in face perception. The face-specific hypothesis posits that face perception relies on mechanisms dedicated to faces, while the expertise hypothesis proposes that faces are processed by more generic mechanisms that operate on objects we have extended experience with. Previous studies that have addressed this question using acquired prosopagnosia are inconclusive because the non-face categories tested (e.g., cars) were not well-matched to faces in terms of visual exposure and perceptual experience. Here we compare perception of faces and bodies in four acquired prosopagnosics. Critically, we used face and body tasks that generate comparable inversion effects in controls, which indicates that our tasks engage orientation-specific perceptual mechanisms for faces and bodies to a similar extent. Three prosopagnosics were able to discriminate bodies normally despite their impairment in face perception. Moreover, they exhibited normal inversion effects for bodies, suggesting their body perception was carried out by the same mechanisms used by controls. Our findings indicate that the human visual system contains processes specialized for faces. 23912999 Molecular Characterization of Mutant Mouse Strains Generated from the EUCOMM/KOMP-CSD ES Cell Resource. The Sanger Mouse Genetics Project generates knockout mice strains using the EUCOMM/KOMP-CSD embryonic stem (ES) cell collection and characterizes the consequences of the mutations using a high-throughput primary phenotyping screen. Upon achieving germline transmission, new strains are subject to a panel of quality control (QC) PCR- and qPCR-based assays to confirm the correct targeting, cassette structure, and the presence of the 3' LoxP site (required for the potential conditionality of the allele). We report that over 86 % of the 731 strains studied showed the correct targeting and cassette structure, of which 97 % retained the 3' LoxP site. We discuss the characteristics of the lines that failed QC and postulate that the majority of these may be due to mixed ES cell populations which were not detectable with the original screening techniques employed when creating the ES cell resource. 22899597 Interrogating scarcity: how to think about 'resource-scarce settings'. The idea of resource scarcity permeates health ethics and health policy analysis in various contexts. However, health ethics inquiry seldom asks-as it should-why some settings are 'resource-scarce' and others not. In this article I describe interrogating scarcity as a strategy for inquiry into questions of resource allocation within a single political jurisdiction and, in particular, as an approach to the issue of global health justice in an interconnected world. I demonstrate its relevance to the situation of low- and middle-income countries (LMICs) with brief descriptions of four elements of contemporary globalization: trade agreements; the worldwide financial marketplace and capital flight; structural adjustment; imperial geopolitics and foreign policy. This demonstration involves not only health care, but also social determinants of health. Finally, I argue that interrogating scarcity provides the basis for a new, critical approach to health policy at the interface of ethics and the social sciences, with specific reference to market fundamentalism as the value system underlying contemporary globalization. 23939709 Exposing Laboratory-Reared Fleas to Soil and Wild Flea Feces Increases Transmission of Yersinia pestis. Laboratory-reared Oropyslla montana were exposed to soil and wild-caught Oropsylla montana feces for 1 week. Fleas from these two treatments and a control group of laboratory-reared fleas were infected with Yersinia pestis, the etiological agent of plague. Fleas exposed to soil-transmitted Y. pestis to mice at a significantly greater rate (50.0% of mice were infected) than control fleas (23.3% of mice were infected). Although the concentration of Y. pestis in fleas did not differ among treatments, the minimum transmission efficiency of fleas from the soil and wild flea feces treatments (6.9% and 7.6%, respectively) were more than three times higher than in control fleas (2.2%). Our results suggest that exposing laboratory-reared fleas to diverse microbes alters transmission of Y. pestis. 23917791 Quantitative DNA methylation analysis improves epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome. Beckwith-Wiedemann syndrome (BWS) is a rare disorder characterized by overgrowth and predisposition to embryonal tumors. BWS is caused by various epigenetic and/or genetic alterations that dysregulate the imprinted genes on chromosome region 11p15.5. Molecular analysis is required to reinforce the clinical diagnosis of BWS and to identify BWS patients with cancer susceptibility. This is particularly crucial prenatally because most signs of BWS cannot be recognized in utero. We established a reliable molecular assay by pyrosequencing to quantitatively evaluate the methylation profiles of ICR1 and ICR2. We explored epigenotype-phenotype correlations in 19 patients that fulfilled the clinical diagnostic criteria for BWS, 22 patients with suspected BWS, and three fetuses with omphalocele. Abnormal methylation was observed in one prenatal case and 19 postnatal cases, including seven suspected BWS. Seven cases showed ICR1 hypermethylation, five cases showed ICR2 hypomethylation, and eight cases showed abnormal methylation of ICR1 and ICR2 indicating paternal uniparental disomy (UPD). More cases of ICR1 alterations and UPD were found than expected. This is likely due to the sensitivity of this approach, which can detect slight deviations in methylation from normal levels. There was a significant correlation (p < 0.001) between the percentage of ICR1 methylation and BWS features: severe hypermethylation (range: 75-86%) was associated with macroglossia, macrosomia, and visceromegaly, whereas mild hypermethylation (range: 55-59%) was associated with umbilical hernia and diastasis recti. Evaluation of ICR1 and ICR2 methylation by pyrosequencing in BWS can improve epigenotype-phenotype correlations, detection of methylation alterations in suspected cases, and identification of UPD. 23939782 Harnessing Reversible Oxidative Addition: Application of Diiodinated Aromatic Compounds in the Carboiodination Process. An I for an I: Conditions for the intramolecular carboiodination and the simultaneous convergent intramolecular carboiodination/intermolecular Heck reaction of various diiodoarenes were developed. The ability of the Pd(0) /QPhos catalyst/ligand combination to undergo reversible oxidative addition allows these reactions to proceed well, thus increasing both the appeal and utility of this class of substrates in site-selective cross-coupling reactions. 23879553 Necropsy Findings in Dogs that Died During Grooming or other Pet Service Procedures. Procedures involved in grooming, bathing, and other pet services can often lead animals to death. Of the necropsies of 1391 animals carried out at a private diagnostic laboratory in Sao Paulo, Brazil from 2004 to 2009, 94 were dogs that died during the above-mentioned procedures. Young male dogs and small breeds like Poodle Miniature, Yorkshire Terrier, and Lhasa Apso were most frequently observed. Blunt-force trauma was responsible for the deaths of 31% of the animals, with a higher incidence of trauma to the head, characterized chiefly by fractures and nervous tissue lesions. In the other 69% of cases, the animals showed signs of stress, and died due to pulmonary edema and hemorrhage. As we cannot rule out the intentional character in some situations, this article provides veterinary forensic support for veterinarians and pet owners, especially in lawsuits, helping in finding the cause of animal's death in such pet services. 23561078 In vivo and in vitro antioxidant activity and α-glucosidase, α-amylase inhibitory effects of flavonoids from Cichorium glandulosum seeds. The aim of this study was to investigate the antioxidant, anti-glucosidase and anti-amylase activities of total flavonoids (TFs) from Cichorium glandulosum seeds, and to analyse its chemical composition by HPLC-ESI/MS. In vitro study, radical scavenging IC50 values of TFs were 7.33±0.093, 9.24±0.100, 154.33±11.38 and 256.7±4.86μg/ml for DPPH, ABTS, hydroxyl radicals, and superoxide anion, respectively. In the 8-64mg/ml range, α-glucosidase and α-amylase were inhibited by TFs to a certain extent. In vivo, the treatment groups with TFs (100, 200, 400mg/kg) showed a significant decrease in the malondialdehyde level, the superoxide dismutase and glutathione levels were restored to almost normal levels, and the catalase and glutathione peroxidase levels significantly increased compared to the CCl4-intoxicated group in rats. The present study suggests that C. glandulosum seeds should be given special attention because of their antioxidant and anti-glucosidase, anti-amylase activity. 23600657 Development and in vitro evaluation of a nanoemulsion for transcutaneous delivery. Abstract Objective: The purpose of this study is to develop a nanoemulsion formulation for its use as a transcutaneous vaccine delivery system. Materials and methods: With bovine albumin-fluorescein isothiocyanate conjugate (FITC-BSA) as a vaccine model, formulations were selected with the construction of pseudo-ternary phase diagrams and a short-term stability study. The size of the emulsion droplets was furthered optimized with high-pressure homogenization. The optimized formulation was evaluated for its skin permeation efficiency. In vitro skin permeation studies were conducted with shaved BALB/c mice skin samples with a Franz diffusion cell system. Different drug concentrations were compared, and the effect of the nanoemulsion excipients on the permeation of the FITC-BSA was also studied. Results: The optimum homogenization regime was determined to be five passes at 20 000 psi, with no evidence of protein degradation during processing. With these conditions, the particle diameter was 85.2 nm ± 15.5 nm with a polydispersity index of 0.186 ± 0.026 and viscosity of 14.6 cP ± 1.2 cP. The optimized formulation proved stable for 1 year at 4 °C. In vitro skin diffusion studies show that the optimized formulation improves the permeation of FITC-BSA through skin with an enhancement ratio of 4.2 compared to a neat control solution. Finally, a comparison of the skin permeation of the nanoemulsion versus only the surfactant excipients resulted in a steady state flux of 23.44 μg/cm(2)/h for the nanoemulsion as opposed to 6.10 μg/cm(2)/h for the emulsifiers. Conclusion: A novel nanoemulsion with optimized physical characteristics and superior skin permeation compared to control solution was manufactured. The formulation proposed in this study has the flexibility for the incorporation of a variety of active ingredients and warrants further development as a transcutaneous vaccine delivery vehicle. 23766510 Crucial Role for Phylogenetically Conserved Cytoplasmic Loop 3 in ABCC4 Protein Expression. The ABC transporter ABCC4 is recognized as an ATP-dependent exporter of endogenous substances as well as an increasing variety of anionic chemotherapeutics. A loss-of-function variant of zebrafish Abcc4 was identified with a single amino acid substitution in the cytoplasmic loop T804M. Because this substituted amino acid is highly conserved among ABCC4 orthologs and is located in cytoplasmic loop 3 (CL3), we investigated the impact of this mutation on human and zebrafish Abcc4 expression. We demonstrate that zebrafish Abcc4 T804M or human ABCC4 T796M exhibit substantially reduced expression, coupled with impaired plasma membrane localization. To understand the molecular basis for the localization defect, we developed a homology model of zebrafish Abcc4. The homology model suggested that the bulky methionine substitution disrupted side-chain contacts. Molecular dynamic simulations of a fragment of human or zebrafish CL3 containing a methionine substitution indicated altered helicity coupled with reduced thermal stability. Trifluoroethanol challenge coupled with circular dichroism revealed that the methionine substitution disrupted the ability of this fragment of CL3 to readily form an α-helix. Furthermore, expression and plasma membrane localization of these mutant ABCC4/Abcc4 proteins are mostly rescued by growing cells at subphysiological temperatures. Because the cystic fibrosis transmembrane conductance regulator (ABCC7) is closely related to ABCC4, we extended this by engineering certain pathogenic CFTR-CL3 mutations, and we showed they destabilized human and zebrafish ABCC4. Altogether, our studies provide the first evidence for a conserved domain in CL3 of ABCC4 that is crucial in ensuring its proper plasma membrane localization. 23892045 Can a road safety measure be both effective and ineffective at the same time? A game-theoretic model of the effects of daytime running lights. Studies that have evaluated the effects on accidents of daytime running lights for cars have consistently found that cars using daytime running lights are involved in fewer multi-party accidents in daylight than cars not using daytime running lights. However, studies evaluating the effects of mandatory use of daytime running lights have not always found an accident reduction. Although findings are mixed, there is a tendency for the aggregate effects of daytime running lights (i.e. the effects of an increasing share of traffic using daytime running lights) to be smaller than the intrinsic effects (i.e. the difference in accident involvement between cars using and not using daytime running lights). This paper presents a game-theoretic model to explain these apparently inconsistent findings. The game-theoretic model is based on so called Schelling-diagrams, originally introduced by Nobel laureate in economics Schelling. The effects of daytime running lights are modelled by means of Schelling-diagrams. It is shown that it is by no means impossible for cars using daytime running lights to always be safer than cars not using daytime running lights, while the total number of accidents remains constant even if the percentage of cars using daytime running lights increases from, say, 10% to 90%. 23391859 Image-guided percutaneous ablation therapies for local recurrences of thyroid tumors. The incidence of thyroid carcinoma has increased steadily over the last few decades. Most differentiated thyroid carcinomas (DTC) are cured thanks to the initial treatment with surgery and radioiodine therapy. Nevertheless, neck lymph node metastases are found in a few of these patients during their long-term clinical and ultrasound follow-up. In some of these cases radioiodine treatment may not be effective in eradicating nodal metastases due to scant 131-I uptake. Additionally, a few of these patients undergo repeated neck explorations and/or resections. Based on these considerations and on the frequently indolent course of DTC neck metastases, a non-surgical therapeutic approach should be considered to control small local foci of DTC. There is increasing interest in mini-invasive image-guided procedures that can be performed under local anesthesia which do not affect the performance status of the patient. Image-guided minimally invasive ablative therapies delivered by using needle-like applicators include both thermal and non-thermal source techniques. Over the past 25 years, these therapies have gained widespread attention and, in many cases, broad clinical acceptance as methods for treating focal malignancies. In an attempt to overcome the limitations of treating certain unresectable tumor types not amenable to a further surgical treatment, a few investigators have reported successfully combining percutaneous therapies with other oncologic treatment strategies (combined treatments). In this review, we reported mini-invasive techniques more commonly employed in selected cases to ameliorate local compressive symptoms, control hormonal production, and reduce the volume of neoplastic tissue prior to traditional palliative treatment. 23777919 The in vivo performance of ferrocenyl tamoxifen lipid nanocapsules in xenografted triple negative breast cancer. Triple-negative breast cancers (TNBC) represent the most aggressive form of breast cancers and their treatment are challenging due to the tumor heterogeneity. The high death rate and the limited systemic treatment options for TNBC necessitate the search for alternative chemotherapeutics. We previously found that FcOHTAM, an organometallic derivative of hydroxytamoxifen, showed in vitro a strong antiproliferative effect on various breast cancer cell lines, including MDA-MB-231 cells, the archetype of TNBC. In this study, we developed stealth FcOHTAM loaded lipid nanocapsules (LNCs) to further evaluate this novel drug on a TNBC xenografted model. Cell cycle analysis of MDA-MB-231 cells confirmed the preservation of the drug activity through LNCs causing a cycle arrest in phase S after 48 h exposure at the IC50 concentration (2 μm). Two intraperitoneal injections of FcOHTAM loaded LNCs (20 mg/kg) administered to luciferase-transfected MDA-MB-231 tumors bearing mice led to a marked delay in tumor growth. As a consequence, a significantly lower tumor volume was obtained at the end of the experiment with a difference of 36% at day 38 compared to the untreated group. These results represent the first evidence of an in vivo effect of FcOHTAM and ferrocenyl derivatives in general on xenografted breast tumors. 23316979 Enhancement of angiogenesis by a 27 kDa lectin from perivitelline fluid of horseshoe crab embryos through upregulation of VEGF and its receptor. Angiogenesis, the expansion of a capillary network, is implicated in several pathological conditions. Drug-based inhibition of angiogenesis is being explored as therapy. Conversely, therapeutic angiogenesis contributes to control conditions such as ischemia. Here we report pro-angiogenic activity of perivitelline fluid (PVF) from Indian horseshoe crab embryos and one of its purified fractions, a 27 kDa lectin, using the chick embryonic chorioallantoic membrane assay. Enhancement in number and diameter of blood vessels after treatment with PVF and lectin suggested their pro-angiogenic effect. Quantitative RT-PCR showed that this effect is mediated through modulation of expression of VEGF and VEGFR-2/kinase domain receptor genes. 23967348 Evaluation of genetic polymorphisms in patients with multiple chemical sensitivity. Multiple chemical sensitivity (MCS) is a chronic medical condition characterized by symptoms that the affect an individual's response to low-level chemical exposure. In this study, we identified a chemical sensitive population (CSP) and investigated the effect of genetic polymorphisms on their risk of chemical sensitivity. A quick environment exposure sensitivity (QEESI) questionnaire was used to survey 324 Japanese male workers whose DNA samples had been collected and stored. The following genes, which encode enzymes affecting the metabolic activation of a large number of xenobiotic compounds, were selected and analyzed in order to determine their influence on genetic predisposition to CSP: cytochrome P450 (CYP) 2E1, N-acetyl transferase (NAT) 2, glutathione S-transferase (GST) M1, GSTT1, GSTP1, low Km aldehyde dehydrogenase (ALDH2), and superoxide dismutase (SOD) 2. Significant case-control distributed differences were observed in SOD2 polymorphisms and allele frequency distribution in high chemical sensitive subjects. Both the significant adjusted OR of 4.30 (95% CI, 1.23-15.03) and 4.53 (95% CI, 1.52-13.51) were observed in SOD2 Ala/Ala and Val/Ala compared to Val/Val and in SOD2 Ala/Ala compared to Val/Ala compared to Val/Val genetic analysis in the high chemical sensitivity case-control study. We observed that high chemical sensitive individuals diagnosed by using Japanese criteria as MCS patients were more significantly associated with SOD2 polymorphisms. 23963221 Impacts of Mariculture on the Diversity of Bacterial Communities within Intertidal Sediments in the Northeast of China. Mariculture is one of the major seafood supplies worldwide and has caused serious environmental concerns on the coastal zone. Its rapid development has been shown to disrupt the sediment ecosystems and thus influence the benthic bacterial communities. Bacterial diversity and community structure within both adjacent farms and non-cultured zones intertidal sediments along the coasts of Qinhuangdao and Dalian, China, were investigated using full-length 16S rRNA gene-based T-RFLP analyses and clone library construction. Richness and Shannon-Wiener index were significantly increased at sites adjacent the mariculture farm with mean values of 29 and 2.97 from peak profiles of T-RFLP result. Clustering analyses suggested that impacts of mariculture on bacterial diversity of sediment were significantly larger than those resulted from temporal and spatial scales. Upon comparisons of RFLP patterns from 602 clones from libraries of the selected five samples, 137 OTUs were retrieved. Members of γ- and δ-Proteobacteria, Bacilli, Flavobacteria, and Actinobacteria were recorded in all libraries. In addition, γ-Proteobacteria were dominant in all samples (21.7~45.0 %). Redundancy analysis revealed that the distribution of bacterial composition seemed to be determined by the variables of salinity, PO4 (3-)-P, NH4 (+)-N, and Chlorophyll a content. The phyla of γ-Proteobacteria, Clostridia, Flavobacteria, Bacilli, and Planctomycetes were principal components to contribute to the bacterial differences of clone libraries. Our finding demonstrated that these phyla could display variations of bacterial composition linked to environmental disturbance resulted from mariculture. 23023451 Feasibility of 3D Ultrasound to Evaluate Upper Extremity Nerves. Purpose: This study investigates the performance of a 3 D Ultrasound (US) system in imaging elbow and wrist nerves. Materials and Methods: Twenty healthy volunteers with asymptomatic median, ulnar and radial nerves were prospectively investigated. Bilateral 3DUS scans of the elbows and wrists were acquired by using a commercially available US scanner (18 MHz, AplioXG, Toshiba) and stored as a 3 D volume by a dedicated software (CURE, Robarts Research Institute). Retrospectively, qualitative (image quality, atypical nerve location, findings potentially associated with compression neuropathy) and quantitative (cross-sectional area measurements) evaluations were performed. Results: In all 200 nerves 3DUS was feasible (100 %). Image quality was insufficient in 13.5 % (25 ulnar nerve elbow, 2 radial nerve) and sonomorphology was not assessable in those nerves. Measurement of cross sectional areas was feasible in all nerves (100 %). Median cross-sectional area (range) were: median nerve elbow 7 mm2 (6 - 9), radial nerve 3 mm2 (1 - 4), ulnar nerve elbow 8 mm2 (5 - 11), median nerve wrist 8 mm2 (5 - 10), and ulnar nerve wrist 4 mm2 (2 - 6). No significant changes in nerve cross-sectional area along each nerve was found. Ulnar nerve subluxation was found in 2 nerves (6.7 %). No anconeus epitrochlearis muscle or osteophytes were found. Conclusion: 3DUS is a feasible method for assessing nerves of the upper extremity and has been shown to provide a good overview of the median, ulnar and radial nerve at the elbow and wrist, but is limited for evaluation of the ulnar nerve in the cubital tunnel. This technique enables reliable measurements at different locations along the nerve. 23845013 Adhoc electromagnetic compatibility testing of non-implantable medical devices and radio frequency identification. The use of radiofrequency identification (RFID) in healthcare is increasing and concerns for electromagnetic compatibility (EMC) pose one of the biggest obstacles for widespread adoption. Numerous studies have documented that RFID can interfere with medical devices. The majority of past studies have concentrated on implantable medical devices such as implantable pacemakers and implantable cardioverter defibrillators (ICDs). This study examined EMC between RFID systems and non-implantable medical devices. Medical devices were exposed to 19 different RFID readers and one RFID active tag. The RFID systems used covered 5 different frequency bands: 125--134 kHz (low frequency (LF)); 13.56 MHz (high frequency (HF)); 433 MHz; 915 MHz (ultra high frequency (UHF])) and 2.4 GHz. We tested three syringe pumps, three infusion pumps, four automatic external defibrillators (AEDs), and one ventilator. The testing procedure is modified from American National Standards Institute (ANSI) C63.18, Recommended Practice for an On-Site, Ad Hoc Test Method for Estimating Radiated Electromagnetic Immunity of Medical Devices to Specific Radio-Frequency Transmitters. For syringe pumps, we observed electromagnetic interference (EMI) during 13 of 60 experiments (22%) at a maximum distance of 59 cm. For infusion pumps, we observed EMI during 10 of 60 experiments (17%) at a maximum distance of 136 cm. For AEDs, we observed EMI during 18 of 75 experiments (24%) at a maximum distance of 51 cm. The majority of the EMI observed was classified as probably clinically significant or left the device inoperable. No EMI was observed for all medical devices tested during exposure to 433 MHz (two readers, one active tag) or 2.4 GHz RFID (two readers). Testing confirms that RFID has the ability to interfere with critical medical equipment. Hospital staff should be aware of the potential for medical device EMI caused by RFID systems and should be encouraged to perform on-site RF immunity tests prior to RFID system deployment or prior to placing new medical devices in an RFID environment. The methods presented in this paper are time-consuming and burdensome and suggest the need for standard test methods for assessing the immunity of medical devices to RFID systems. 23863077 Counselling clients to follow 'the rules' of safe sex and ARV treatment. Ideas of 'responsible sexuality' are located at the centre of counselling in current antiretroviral treatment (ART) programmes. This paper analyses counselling practices in three HIV/AIDS clinics in Uganda on the basis of participant observation of counselling sessions and interviews with counsellors. The paper illustrates how counsellors concentrate on giving general behavioural instructions, while clients tend to demonstrate their compliance to these 'rules' rather than sharing their more intimate thoughts. This is especially the case in the contested terrain of sexual and reproductive behaviour. To explore this phenomenon, the paper analyses a number of dynamics characterising HIV counselling in Uganda, including the pressures of the global bio-political project to 'save lives' with ART, the counsellors' working conditions in resource-constrained clinics, the professional authority of counsellors and the clients' challenges to following the rules. 23952790 Mammography Utilization: Patient Characteristics and Breast Cancer Stage at Diagnosis. OBJECTIVE. Missed mammograms represent missed opportunities for earlier breast cancer diagnosis. The purposes of this study were to identify patient characteristics associated with missed mammograms and to examine the association between missed mammograms and breast cancer stage at diagnosis. MATERIALS AND METHODS. Mammography frequency and cancer stage were retrospectively examined in 1368 cases of primary breast cancer diagnosed at our clinic from 2002 to 2008. RESULTS. Regardless of age (median, 62.7 years), 1428 women who underwent mammography were more likely to have early-stage (stage 0-II) breast cancer at diagnosis than were those who did not undergo mammography (p < 0.001). Similarly, the number of mammographic examinations in the 5 years before diagnosis was inversely related to stage: 57.3% (94/164) of late-stage cancers were diagnosed in women missing their last five annual mammograms. In a multivariate analysis, family history of breast cancer was most predictive of undergoing mammography (odds ratio, 3.492; 95% CI, 2.616-4.662; p < 0.0001) followed by number of medical encounters (odds ratio, 1.022; 95% CI, 1.017-1.027; p < 0.0001). Time to travel to the nearest mammography center was also predictive of missing mammograms: Each additional minute of travel time decreased the odds of undergoing at least one mammographic examination in the 5 years before cancer diagnosis (odds ratio, 0.990; 95% CI, 0.986-0.993; p < 0.0001). CONCLUSION. Missing a mammogram, even in the year before a breast cancer diagnosis, increases the chance of a cancer diagnosis at a later stage. Interventions to encourage use of mammography may be of particular benefit to women most likely to miss mammograms, including those with no family history of breast cancer, fewer encounters with the health care system, and greater travel distance to the mammography center. 23849240 Physical and emotional well-being and the balance of needed and received emotional support: Age differences in a daily diary study. Whether received social support matches the actual needs of the recipient is a largely overlooked aspect in research on associations of support and well-being. In particular, studies that investigate the match of needed and received support from a within-person perspective are rare. Therefore, we investigated the daily within-person relationship of well-being and the balance of needed and received social support in a German Sample of 79 younger (23-34 years) and 88 older adults (68-83 years). Health complaints and negative affect were predicted with linear effects of received and needed emotional support and quadratic effects of the balance (i.e., difference) of these two aspects using multilevel modeling of self-reports over 20 days. The predicted beneficial association between a match of needed and received support (i.e., a support balance) and well-being was observed among younger adults. Needed support was associated with more health complaints and negative affect on the same day. The match of needed and received support is important for well-being, particularly in younger adults. Future research should account for support needed in research on received support and shed more light into the processes underlying these short-term within-person relationships of social support and well-being. 23899861 Regulation of Helicoverpa armigera ecdysone receptor by miR-14 and its potential link to baculovirus infection. Baculoviruses are well known for their ability to suppress the host development by altering its physiological and morphological changes. During its pathogenesis, the virus targets the host immune system, steroid hormones or apoptotic genes to evade anti-viral responses. Recent evidence indicate that viruses may use their own or host-encoded microRNAs (miRNA) to achieve this. In this study, utilizing microarray analysis, we found that the miRNA profile of Helicoverpa armigera larvae alters upon H. armigera single nucleopolyhedrovirus (HaSNPV) infection. Northern blot analyses revealed down-regulation of four miRNAs including the well-conserved and abundantly expressed miR-14. It was established that miR-14 positively regulates the H. armigera ecdysone receptor (Ha-EcR). Consistent with decreased levels of miR-14 following HaSNPV infection, the transcript levels of its target gene Ha-EcR declined around 72h post-infection. In vivo and in vitro studies revealed that in the presence of the synthetic miR-14 mimic the transcript levels of Ha-EcR significantly increased. The miRNA-target interaction was further confirmed by a GFP reporter assay. Further, application of the miRNA mimic led to reduced replication of the virus. These results suggest that, by down-regulating miR-14, HaSNPV may reduce the Ha-EcR transcript levels providing another classic example of virus-mediated manipulation of host physiology. 23855419 Attenuation of histamine-induced airway effects by intranasal application of levocetirizine in mice. Abstract The present study was performed to investigate the histamine-induced airway effect of levocetirizine, an active enantiomer of cetirizine, by intranasal application using ddY mice. Nasal rubbing and sneezing after histamine application into the nasal cavity were used as an index of histamine-induced airway effect in mice. Intranasal application of levocetirizine inhibited both nasal rubbing and sneezing concentration-dependently, and the ED50 values were 0.62 (0.51-0.77) and 0.70 (0.51-1.02) %/site for nasal rubbing and sneezing, respectively. ED50 values of cetirizine were 1.24 (1.02-1.59) and 1.35 (1.02-2.08) %/site for nasal rubbing and sneezing, respectively. Levocetirizine also inhibited nasal rubbing and sneezing when administered orally. These results clearly indicate that levocetirizine was about two times more potent than cetirizine by intranasal application, similar to the findings of the former's affinity for human histamine H1 receptors. In addition, the present findings raise the expectation of the development of levocetirizine nasal drops. 23298334 Smart mesoporous SiO2 nanoparticles for the DNAzyme-induced multiplexed release of substrates. The fluorescent dyes methylene blue, MB(+), and thionine, Th(+), can be trapped in the pores of mesoporous silica, MP-SiO(2), by means of functional nanostructures consisting of the Mg(2+)- or Zn(2+)-dependent DNAzyme sequences. In the presence of Mg(2+) or Zn(2+) ions the respective DNAzymes are activated, leading to the specific cleavage of the respective caps, and the selective release of MB(+) or Th(+). The enlargement of the conserved loop domains of the Mg(2+)- or Zn(2+)-dependent DNAzyme sequences with foreign nucleotides prohibits the formation of active DNAzymes and eliminates the release of the respective dyes. This is due to the flexibility of the loops that lacks affinity for the association of the ions. The insertion of aptamer sequences (e.g., the adenosine-5'-triphosphate (ATP) aptamer) or ion-binding sequences (e.g., T-rich Hg(2+) ion-binding domains) as foreign components to the loop regions allows the formation of active Mg(2+)- or Zn(2+)-dependent DNAzyme structures through the cooperative formation of aptamer-ATP complexes or T-Hg(2+)-T bridges. These aptamer-substrate complexes or T-Hg(2+)-T bridges allosterically stabilize and activate the DNAzymes, thus allowing the selective release of the fluorescent substrates MB(+) or Th(+). The metal ion-driven DNAzyme release of substrates from the pores of MP-SiO(2), and particularly the allosteric activation of the DNAzymes through cooperative aptamer-substrate complexes or metal-ion bridges, has important future nanomedical implications for targeted release of drugs. This is demonstrated with the triggered release of the anticancer drug, doxorubicin, by the Mg(2+)-DNAzyme-locked pores or by the aptamer-ATP complex-triggered activation of the Mg(2+)-dependent DNAzyme. 23939141 Autophagy induction promotes aristolochic acid-I-induced renal injury in vivo and in vitro. Studies have found that ingestion of aristolochic acid (AA) causes nephropathy first by inducing renal tubular cell apoptosis acutely. It is currently unknown whether crosstalk between autophagy and apoptosis orchestrates the fate of tubular cells in acute AA nephropathy. We tested this hypothesis by acute administration of AA in vivo and in vitro. Autophagy was first induced in vivo through enhancing Atg5 and LC3-II expressions in kidneys of AA-I-treated rats. Punctuate LC3-GFP dots and autophagosomes were detected in this acute AA-I nephropathy rat model. We subsequently utilized normal rat renal proximal tubular epithelial cells (NRK52E) to study the autophagy mechanisms involved in acute AA-I nephropathy, with 100μM AA-I (median lethal dose 50) given in vitro. Cleavage of poly (ADP-ribose) polymerase (PARP), nuclear condensation, and fragmentation were demonstrated in the AA-I-treated NRK52E cells. Furthermore, AA-I induced Atg5 and LC3-II expressions and punctuated LC3-GFP dots. Autophagy flux by using lysosome inhibitor E64 induced the accumulation of LC3-II, which further promoted apoptosis through enhancing PARP cleavage. Inhibition of autophagy by 3-methyl adenine also led to the attenuation of AA-I-induced apoptosis, manifesting as decreased PARP cleavage, nuclei condensation, and decreased the number of cells negative for acridine orange/ethidium bromide staining. In addition, knockdown of Atg5 by short hairpin RNA attenuated LC3-II expression and PARP cleavage in NRK52E cells. Taken together, these findings suggested that the acute phase of AA-I-induced nephropathy is associated with induction of Atg5-dependent autophagy, which promotes renal tubular cell apoptosis. 23939982 Analysis of Soybean mosaic virus genetic diversity in Iran allows the characterization of a new mutation resulting in overcoming Rsv4-resistance. The genetic variation and population structure of Soybean mosaic virus (SMV) in Iran was analyzed through the characterization of a set of isolates collected in the soybean-growing provinces of Iran. The partial nucleotide sequence of these isolates showed a single, undifferentiated population with low genetic diversity, highly differentiated from other SMV world populations. These traits are compatible with a population bottleneck associated with the recent introduction of SMV in Iran. Phylogenetic analyses suggest that SMV was introduced into Iran from East Asia, with at least three introduction events. The limited genetic diversification of SMV in Iran may be explained by strong negative selection in most viral genes eliminating most mutations, together with recombination purging deleterious mutations. The pathogenicity of Iranian SMV isolates was typified on a set of soybean differential lines either susceptible or carrying different resistance genes or alleles to SMV. Two pathotypes were distinguished according to the ability to overcome Rsv4 resistance in line V94-5152. Amino acid sequence comparisons of isolates virulent and avirulent on V94-5152 (Rsv4), plus site-directed mutagenesis in a biologically active cDNA clone, identified mutation S1053N in the P3 protein as the determinant for virulence on V94-5152. Codon 1053 was shown to be under positive selection, and S1053N-determined Rsv4-virulence occurred in isolates with different genealogies. The V94-5152 (Rsv4) -virulence determinant in Iranian isolates maps into a different amino acid position in the P3 protein than those previously reported, indicating different evolutionary pathways towards resistance-breaking that might be conditioned by sequence context. 23869946 The Mycobacterium tuberculosis DNA gyrase possesses two functional GyrA-boxes. In contrast to most bacteria which possess two type II topoisomerases (Topo IV and DNA gyrase), Mycobacterium tuberculosis possesses only one, DNA gyrase, which is functionally a hybrid enzyme. Functional differences between the two type IIA topoisomerases are thought to be specified by a C-terminal DNA binding domain (CTD) which controls DNA recognition. To explore the molecular mechanism responsible for the hybrid functions of the M. tuberculosis DNA gyrase, we conducted a series of sequence analyses and structural and biochemical experiments with the isolated GyrA CTD and the holoenzyme. While the CTD displayed a global structure similar to that of bona fide GyrA and ParC paralogs, it harbors a second key motif similar in all respects to that of the conserved GyrA-box sequence motif. Biochemical assays showed that the GyrA-box is responsible for DNA supercoiling, whereas the second GyrA-box-like motif (GyrA-box-l) is responsible for the enhanced decatenation activity suggesting that the mechanistic originality of M. tuberculosis DNA gyrase depends largely on the particular DNA path around the CTD allowed for by the presence of GyrA-box-l. Our results provide also, through phylogenetic exploration of the entire Corynebacterineae suborder, new and broader insight into the functional diversity of bacterial type IIA topoisomerases. 23813629 Emotion-Focused Therapy for the Treatment of Social Anxiety: An Overview of the Model and a Case Description. Emotion-focused therapy (EFT) is an integrative and experiential treatment approach that views emotions as fundamentally adaptive and privileges attention to, and exploration of, emotional experiences. EFT has been demonstrated to be efficacious with depression, interpersonal trauma and marital discord, but application to anxiety disorders is in its initial stages. The purpose of this paper is to present the main principles of using EFT with socially anxious patients and to make the case that EFT is particularly well suited for working with this patient group. The primary change processes in EFT for social anxiety include improving emotion awareness, reducing experiential avoidance and the activation and transformation of shame that underlies the symptomatic anxiety. Such processes lead to less self-criticism, to more self-compassion and self-soothing and to a more favourable perception of the self. A case example is used to illustrate how these principles were applied with a socially anxious patient. Copyright © 2013 John Wiley & Sons, Ltd. Although cognitive-behavioral therapies (CBT) are effective for social anxiety disorder (SAD), a substantial number of patients do not respond to CBT or remain considerably symptomatic at the end of treatment. Therefore, more treatment options for SAD are necessary in order to improve patient care.Emotion-focused therapy (EFT), which is an efficacious treatment for depression, complex trauma, and couples' distress may also be efficacious for SAD.EFT offers an emotion-based case formulation of SAD, in which social anxiety is conceptualized as secondary to primary maladaptive shame. A primary goal in EFT for SAD is to access and evoke shame in order to transform it. 23689727 Epidemiology of isoniazid resistance mutations and their effect on tuberculosis treatment outcomes. Isoniazid resistance is highly prevalent in Vietnam. We investigated the molecular and epidemiological characteristics and the association with first-line treatment outcomes of the main isoniazid resistance mutations in Mycobacterium tuberculosis in codon 315 of the katG and in the promoter region of the inhA gene. Mycobacterium tuberculosis strains with phenotypic resistance to isoniazid from consecutively diagnosed smear-positive tuberculosis patients in rural Vietnam were subjected to Genotype MTBDRplus testing to identify katG and inhA mutations. Treatment failure and relapse were determined by sputum culture. In total, 227 of 251 isoniazid-resistant strains (90.4%) had detectable mutations: 75.3% in katG codon 315 (katG315) and 28.2% in the inhA promoter region. katG315 mutations were significantly associated with pretreatment resistance to streptomycin, rifampin, and ethambutol but not with the Beijing genotype and predicted both unfavorable treatment outcome (treatment failure or death) and relapse; inhA promoter region mutations were only associated with resistance to streptomycin and relapse. In tuberculosis patients, M. tuberculosis katG315 mutations but not inhA mutations are associated with unfavorable treatment outcome. inhA mutations do, however, increase the risk of relapse, at least with treatment regimens that contain only isoniazid and ethambutol in the continuation phase. 23918804 Tetrahymena Telomerase Holoenzyme Assembly, Activation, and Inhibition by Domains of the p50 Central Hub. The eukaryotic reverse transcriptase, telomerase, adds tandem telomeric repeats to chromosome ends to promote genome stability. The fully assembled telomerase holoenzyme contains a ribonucleoprotein (RNP) catalytic core and additional proteins that modulate the ability of the RNP catalytic core to elongate telomeres. Electron microscopy (EM) structures of Tetrahymena telomerase holoenzyme revealed a central location of the relatively uncharacterized p50 subunit. Here we have investigated the biochemical and structural basis for p50 function. We show that the p50-bound RNP catalytic core has a relatively slow rate of tandem repeat synthesis but high processivity of repeat addition, indicative of high stability of enzyme-product interaction. The rate of tandem repeat synthesis is enhanced by p50-dependent recruitment of the holoenzyme single-stranded DNA binding subunit, Teb1. An N-terminal p50 domain is sufficient to stimulate tandem repeat synthesis and bridge the RNP catalytic core, Teb1, and the p75 subunit of the holoenzyme subcomplex p75/p19/p45. In cells, the N-terminal p50 domain assembles a complete holoenzyme that is functional for telomere maintenance, albeit at shortened telomere lengths. Also, in EM structures of holoenzymes only the N-terminal domain of p50 is visible. Our findings provide new insights about subunit and domain interactions and functions within the Tetrahymena telomerase holoenzyme. 23676306 Imaging in epilepsy. This is a review of the use of neuroimaging in epilepsy outlining the imaging strategy for new onset seizures and also those with intractable focal seizures being investigated as potential epilepsy surgery candidates. The review describes the radiological features of conditions which may be encountered in each clinical context, together with advice on the optimum imaging protocols to detect epileptogenic lesions. The review also presents the role of imaging in presurgical planning, the demonstration of eloquent function, grid placement and postoperative assessment. 23478437 Global Gene Expression Profiling Reveals Functional Importance of Sirt2 in Endothelial Cells under Oxidative Stress. The NAD+-dependent deacetylases Sirt1 and Sirt2 mediate cellular stress responses and are highly expressed in vascular endothelial cells. In contrast to the well-documented protective actions of Sirt1, the role of endothelial Sirt2 remains unknown. Using cDNA microarray and PCR validation, we examined global gene expression changes in response to Sirt2 knock down in primary human umbilical vein endothelial cells under oxidative stress. We found that Sirt2 knock down changed expression of 340 genes, which are mainly involved in cellular processes including actin binding, cellular amino acid metabolic process, transmembrane receptor protein serine/threonine kinase signaling, ferrous iron transport, protein transport and localization, cell morphogenesis, and functions associated with endosome membrane and the trans-Golgi network. These genes and associated functions were largely non-overlapping with those altered by Sirt1 knock down. Moreover, we showed that pharmacological inhibition of Sirt2 attenuated oxidant-induced cell toxicity in endothelial cells. These suggest that Sirt2 is functionally important in endothelial cells under oxidative stress, and may have a primarily distinct role as compared to Sirt1. Our results may provide a basis for future studies aiming to dissect the specific signaling pathway(s) that mediates specific Sirt2 functions in endothelial cells. 23474318 Synergistic effects between pesticide stress and predator cues: Conflicting results from life history and physiology in the damselfly Enallagma cyathigerum. There is increasing awareness that the negative effects of anthropogenic stressors may be magnified in the presence of natural stressors. Very few of these studies have included physiology, yet including physiological studies may help learning about the mechanistic base of such synergisms at the life history level and identify synergistic interactions not translated in life history traits. We studied in Enallagma cyathigerum damselfly larvae potential synergistic effects between exposure to the pesticide glyphosate and predator cues on a key life history trait, growth rate, its associated behavioural trait, food intake, and three types of physiological traits known to be affected by both stressors in isolation: the stress protein Hsp70, energy storage and variables related to oxidative stress and damage. The pesticide and predator cues reduced growth rate in an additive way. Food intake increased under pesticide exposure and was not affected by the predator cues, indicating physiological mediation of the growth reduction. One potential physiological mechanism was that both stressors additively increased Hsp70 levels, this may also have contributed to the reduced levels of total carbohydrates when exposed to predator cues. Chronic exposure to predator cues reduced oxygen consumption, possibly to avoid too high costs of an increased metabolic rate. This reduction did not occur in the presence of the pesticide, reflecting the need for energetically expensive defence mechanisms (such as Hsp70 upregulation). When both stressors were combined, there was a reduction of the antioxidant enzyme superoxide dismutase activity (SOD) and an associated increase of oxidative damage in lipids. While synergistic interactions were not present for growth rate and food intake, they were identified for antioxidant defence and oxidative damage. This novel type of "hidden" synergistic interaction may have profound fitness implications, and when ignored will lead to underestimations of the impact of pollutants in natural populations where predators are omnipresent. 23546824 Inhibition of avian leukosis virus subgroup J replication by miRNA targeted against env. No effective vaccine has been developed against the subgroup J avian leukosis virus (ALV-J). The genetic diversity of ALV-J might be related to the env gene, therefore, we selected conserved sequences of the env gene and designed interference sequence. In this study, microRNAs (miRNAs) were designed and synthesized, corresponding to conserved regions of the env gene. These miRNAs were cloned into the linearized eukaryotic expression vector. The recombinant plasmids were transfected into DF-1 cells. After transfection, the cells were inoculated with ALV-J. In reporter assays, the transfection efficiency is 80 % by indirect immunofluorescence (IFA). Expression of the virus envelope glycoprotein was measured by IFA and western blotting assays. The relative expression of env gene was determined using quantitative PCR. Our results show that the mi-env 231 and mi-env 1384 could effectively suppress the replication of ALV-J with an efficiency of 68.7-75.2 %. These data suggest that the miRNAs targeting the env can inhibit replication of ALV-J efficiently. This finding provides evidence that miRNAs could be used as a potential tool against ALV infection. 23903749 Feeding andesitic eruptions with a high-speed connection from the mantle. Convergent margin volcanism is ultimately fed by magmas generated in the mantle, but the connection between the mantle and the eruption at the surface is typically obscured by cooling, crystallization and magma mixing within the crust. Geophysical techniques are also not very effective in the lower and middle crust, where seismic events are rare and resolution is generally poor. It has thus been unclear how fast mantle-derived magmas transit the crust and recharge crustal magma chambers. Here we use diffusion modelling of nickel zonation profiles in primitive olivines from diverse primary melts to show how mantle recharge may occur on timescales as short as eruptions themselves. In Irazú volcano in Costa Rica, magmas apparently ascend from their source region in the mantle through crust about 35 kilometres thick in just months to years, recharging hybrid basaltic andesites over the course of the eruption. These results show that large stratovolcanoes with shallow magma chambers may still preserve the deep record of their mantle origin in olivine crystals. This approach--documenting magma ascent timescales from the mantle beneath a convergent margin stratovolcano--can be applied to other eruptions that record magma mixing with recharge melts. Signs of volcanic unrest are typically monitored at the surface or upper crust; new efforts should look deeper, tracking magma movement from the base of the crust to the surface in the months to years before eruptions. 23838867 Perioperative statin therapy is not associated with reduced risk of anastomotic leakage after colorectal resection. Anastomotic leakage is a serious complication of colorectal surgery. Several studies have demonstrated the beneficial pleiotropic effects of statins, and preliminary studies have suggested that perioperative statin treatment may be associated with reduced risk of anastomotic leakage. We aimed to investigate whether perioperative statin therapy was associated with a reduced anastomotic leakage rate after colorectal resections with primary anastomosis. The study was based on prospectively collected data from the Danish Colorectal Cancer Group and electronically registered medical records holding information on perioperative statin therapy. Data were collected from the 6 major surgical centers responsible for all elective colorectal cancer surgery in the eastern part of Denmark. We collected data on 2766 patients with electronically registered medical records who underwent resection of the colon or rectum with primary anastomosis from 2006 to 2009. The primary outcome measured was anastomotic leakage requiring surgical intervention. Five hundred eighteen patients (19%) were treated with statins perioperatively. Four hundred ninety-six patients received statins both before and after surgery. Fifty-two patients (10.5%) received high-dose statin therapy. Possible risk factors for anastomotic leakage were identified via univariate regression analyses. In subsequent multivariate analysis, perioperative statin therapy was not associated with reduced anastomotic leakage rate (OR (95% CI) 1.31 (0.84-2.05), p = 0.23). We identified intraoperative blood transfusion, rectal resection (versus colonic), male sex, and tobacco usage as risk factors for anastomotic leakage in the multivariate analysis. This study is limited by its observational design and missing data on comorbidities and BMI. Perioperative statin therapy was not significantly associated with reduced anastomotic leakage rate after colorectal resection with primary anastomosis. 23436135 Assessment of oxidative, inflammatory, and fibrinolytic biomarkers and DNA strand breakage in hypercholesterolemia. The aim of this study was to assess the levels of oxidative, inflammatory, and fibrinolytic biomarkers as well as DNA strand breakage in hypercholesterolemic subjects. Fasting glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, uric acid, total protein, albumin, apolipoprotein (Apo) A, Apo B, advanced oxidation protein products (AOPP), increased ischemia-modified albumin (IMA), -SH, NOx, IL-6, and D-dimer levels were assessed, and DNA strand breakage was evaluated using comet assay in 38 patients with hypercholesterolemia and 20 healthy controls. Total cholesterol, triglycerides, LDL cholesterol, Apo A, Apo B, AOPP, IMA, IL-6, and D-dimer concentrations were significantly higher in subjects with hypercholesterolemia. However, NOx and plasma -SH group concentrations were lower in hypercholesterolemic subjects, while no significant differences were observed with respect to DNA strand breakage between the two groups. Hypercholesterolemia is related to oxidative stress and inflammation. Accordingly, AOPP concentration was higher in subjects with hypercholesterolemia, and we speculate that AOPP can reflect the enhancement of protein oxidation and inflammation. 23902592 Emerging role of cancer stem cells in the biology and treatment of ovarian cancer: basic knowledge and therapeutic possibilities for an innovative approach. In 2013 there will be an estimated 22,240 new diagnoses and 14,030 deaths from ovarian cancer in the United States. Despite the improved surgical approach and the novel active drugs that are available today in clinical practice, about 80% of women presenting with late-stage disease have a 5-year survival rate of only 30%. In the last years a growing scientific knowledge about the molecular pathways involved in ovarian carcinogenesis has led to the discovery and evaluation of several novel molecular targeted agents, with the aim to test alternative models of treatment in order to overcome the clinical problem of resistance. Cancer stem cells tend to be more resistant to chemotherapeutic agents and radiation than more differentiated cellular subtypes from the same tissue. In this context the study of ovarian cancer stem cells is taking on an increasingly important strategic role, mostly for the potential therapeutic application in the next future. In our review, we focused our attention on the molecular characteristics of epithelial ovarian cancer stem cells, in particular on possible targets to hit with targeted therapies. 23463480 Cytokine response to acute running in recreationally-active and endurance-trained men. To compare the cytokine response to exhaustive running in recreationally-active (RA) and endurance-trained (ET) men. Eleven RA men (VO2max 55 ± 7 mL·min(-1)·kg(-1)) and 10 ET men (VO₂max 68 ± 7 mL·min(-1)·kg(-1)) followed a controlled diet and refrained from volitional exercise for 8 days. On the fourth day, participants completed 60 min of treadmill running (65 % VO₂max), followed by intermittent running to exhaustion (70 % VO₂max). Fasting blood was obtained at baseline, after 20, 40 and 60 min of exercise, at the end of intermittent exercise, during 2 h of recovery and on four follow-up days (FU1-FU4). Tumour necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1ra) and creatine kinase (CK) were measured. Exercise increased the concentrations of all cytokines and CK, but there were no significant differences between groups. IL-1β increased (2.2-2.5-fold, P < 0.001) during exercise, while TNF-α was increased (1.6-2.0-fold, P < 0.001) during exercise and for 2 h post-exercise. IL-6 (71-84-fold, P < 0.001) and IL-1ra (52-64-fold, P < 0.001) were increased throughout exercise and up to FU1, peaking immediately after exercise and at 1.5-2 h post-exercise, respectively. CK concentrations were increased (P < 0.001) throughout exercise and up to FU4, peaking at FU1, but were not associated with changes in any cytokines. Exhaustive running resulted in modest and transient increases in TNF-α and IL-1β, and more marked and prolonged increases in IL-6 and IL-1ra, but improved training status did not affect this response. Increased CK might indicate either exercise-induced muscle cell disruption or increased cell permeability, although neither appears to have contributed to the increased cytokine concentrations. 23416798 Dexamethasone antagonizes the in vivo myotoxic and inflammatory effects of Bothrops venoms. In the present work we investigated the toxic activities of two Bothrops snake venoms using in vivo and in vitro experimental protocols in mice and tested the protective effect of dexamethasone (DEXA) in different conditions, comparing it with the polyvalent antivenom. We also expanded the investigations on the antiophidic effect of the Eclipta prostrata (EP) crude extract. The administration of Bothrops jararaca and Bothrops jararacussu snake venoms induced muscle damage demonstrated in vivo by the elevation on plasma creatine kinase (CK) activity in mice and by the decrease in CK content in the extensor digitorum longus (EDL) muscle of these animals, and in vitro by the increase in the rate of CK release from the isolated EDL muscle. We also observed inflammatory response following perimuscular injection of B. jararacussu venom (1.0 mg/kg). Treatment with DEXA (1.0 mg/kg) preserved over 50% of the EDL muscle CK content in vivo when evaluated 24 and 72 h after the injection of B. jararacussu venom in mice, and likewise reduced about 20% of the edema induced by this venom. DEXA reduced in 50% the presence of inflammatory cells and their activity in EDL muscle. The EP extract (50 mg/kg) showed similar ability in preventing the induction of edema and the decrease in muscle CK content, and its association with DEXA showed additive effect. EP reduced over 77% of the plasma CK activity induced by the B. jararacussu venom. In the in vitro experiments, DEXA was not able to change the rate of CK release from EDL muscles exposed to 25 μg/mL of B. jararacussu venom, neither to prevent the fall in the amplitude of the indirectly evoked twitch at the phrenic-diaphragm preparation. EP extract showed otherwise a protective effect on these protocols, reaching up to 100% of protection when concentrations of 50.0 and 100.0 μg/mL were used. Altogether our results show that inflammation is at least in part responsible for the tissue damage induced by Bothrops snake venoms, once the steroidal anti-inflammatory drug dexamethasone was able to decrease the myotoxic effects of these venoms, by reducing the inflammatory response to the venom injection. 23822556 Synthesis and Biological Evaluation of a New Series of Highly Functionalized 7'-homo-Anhydrovinblastine Derivatives. Sixteen new 7'-homo-anhydrovinblastine derivatives were prepared in one or two steps from vinorelbine by means of an original and regiospecific rearrangement and subsequent diastereoselective reduction. This strategy has allowed fast access to a family of vinca alkaloid derivatives with an enlarged and functionalized ring C'. Their synthesis and biological evaluation are reported. One compound (compound 35) is 1.7 times more active than vinorelbine as a tubulin assembly inhibitor. Moreover, some of these compounds are highly cytotoxic, and two of them are more potent than vinorelbine on HCT116 and K562 cell lines. Molecular modeling studies, carried out with two of the new vinca derivatives, provide useful hints about how a given functionalization introduced at positions 7' and 8' of the C' ring results in improved binding interactions between one of the new derivatives and the interdimer interface when compared to the parent compound vinblastine. 23347877 5-Iodo-2-aminoindan (5-IAI): chemistry, pharmacology, and toxicology of a research chemical producing MDMA-like effects. In 2010, an internet snapshot of EMCDDA anticipated the presence of 5-iodo-2-aminoindan (5-IAI) within the recreational drug market. In 2011, this compound, a psychoactive derivative of 2-aminoindane, was identified in recreational products sold in the United Kingdom. 5-IAI is a rigid analogue of p-iodoamphetamine producing MDMA-like effects. The aim of this paper is to summarize the clinical, pharmacological, and toxicological information about this new potential drug of abuse. 23702165 Serial study of lymph node cell subsets using fine needle aspiration in pigtail macaques. Lymphoid tissues are of intense interest for studies of the pathogenesis of human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques but are relatively difficult to sample non-invasively. Fine needle aspiration (FNA) cytology, conventionally a diagnostic procedure for lymphadenopathy, can be used for longitudinal study of tissue cell subsets during HIV/SIV infection. In this study, we serially sampled lymph node (LN) FNA from pigtail macaques and studied cell subsets in the aspect of absolute count, frequency, and functionality by flow cytometry. The median recovered lymphocyte count from FNA samples was 2.01×10(5) (3.0×10(3) to 2.25×10(6), n=38) and median CD4+ T cell subset recovered was 5.94×10(4) (277 to 6.17×10(5), n=38). Although we observed a relatively large variation in the frequencies of cell subsets of FNA samples taken from different time points, the cell subset composition of FNA samples, in particular T cell and CD4+ T cell frequencies, was broadly comparable to whole excised LNs (n=6) and distinct from peripheral blood. A subset of CD4+ T cells that is located almost exclusively in secondary lymphoid tissues, T follicular helper (TFH) cells, was readily identifiable in LN FNAs and the TFH cell frequencies were strongly correlated with B cell frequencies. In vitro functionality of FNA lymphocytes was demonstrated using polyclonal SEB stimulation, resulting in a median 6% of responding CD4+ T cells, comparable to circulating CD4+ T lymphocytes. We conclude that serial sampling of macaque LNs using FNA is a potentially useful method to study the immunopathogenesis of SIV infection and may be extended to HIV infection. 23466502 Altered neuroendocrine status at the onset of CNS lupus-like disease. Neuropsychiatric (NP) manifestations and brain atrophy are common, etiologically unexplained complications of the systemic autoimmune disease lupus erythematosus (SLE). Similar to patients with NP SLE, behavioral deficits and neurodegeneration occur in aged, lupus-prone MRL/lpr mice. In order to gain a better understanding of the time course and nature of CNS involvement, we compare the neuro-immuno-endocrine profiles of two lupus-prone MRL/lpr stocks, which differ in disease onset and severity. Mice from stock 485 (characterized by early lupus-like manifestations) display blunted responsiveness to palatable solutions and impaired nocturnal activity as early as 7 weeks of age. They also have increased IgG in cerebrospinal fluid (CSF) before high serum autoantibody levels and splenomegaly are detected. Moreover, when compared to age-matched 6825 controls, 485 mice exhibit elevated serum corticosterone, enlarged left adrenal gland, and enhanced haematoxylin/eosin staining in the hypothalamic paraventricular nucleus. Swimming speed and novel object exploration become impaired only when more severe peripheral manifestations are documented in 17 week-old 485 mice. The obtained results suggest that performance deficits during the prodromal phase of NP SLE-like disease are associated with autoantibodies in CSF and asymmetric activation of the hypothalamus-pituitary-adrenal axis. Subsequent deterioration in behavioral performance evolves alongside systemic autoimmunity and inflammation. Although a leaky blood-CSF barrier is a possible explanation, one may hypothesize that, similar to neonatal lupus, maternal antibodies to brain antigens cross blood-placental barrier during embryogenesis and induce early endocrine and behavioral deficits in offspring. 23578341 Asymmetric dimethylarginine predicts decline of glucose tolerance in men with stable coronary artery disease: a 4.5-year follow-up study. BACKGROUND: Endothelial dysfunction, largely dependent on impaired nitric oxide bioavailability, has been reportedly associated with incident type 2 diabetes. Our aim was to test the hypothesis that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide formation, might be linked to future deterioration in glucose tolerance in stable coronary artery disease (CAD). METHODS: We studied 80 non-diabetic men (mean age 55 +/- 11 years) with stable angina who underwent successful elective complex coronary angioplasty and were receiving a standard medical according to practice guidelines. Plasma ADMA and its structural isomer symmetric dimethylarginine (SDMA) were measured prior to coronary angiography. An estimate of insulin resistance by homeostasis model assessment (HOMA-IR index) was calculated from fasting insulin and glucose. Deterioration in glucose tolerance was defined as development of type 2 diabetes or progression from a normal glucose tolerance to impaired fasting glucose. RESULTS: Over a median follow-up of 55 months 11 subjects developed type 2 diabetes and 13 progressed to impaired fasting glucose. Incident deterioration of glucose tolerance was associated with ADMA (hazard ratio [HR] per 1-SD increment 1.64 [95% CI: 1.14--2.35]; P = 0.007), log (HOMA-IR index) (HR = 1.60 [1.16--2.20]; P = 0.004) and body-mass index (HR = 1.44 [0.95--2.17]; P = 0.08) by univariate Cox regression. ADMA (HR = 1.65 [1.14--2.38]; p = 0.008) and log (HOMA-IR index) (HR = 1.55 [1.10--2.17]; P = 0.01) were multivariate predictors of a decline in glucose tolerance. ADMA and SDMA were unrelated to body-mass index, HOMA-IR index, insulin or glucose. CONCLUSIONS: ADMA predicts future deterioration of glucose tolerance independently of baseline insulin resistance in men with stable CAD. Whether this association reflects a contribution of endothelial dysfunction to accelerated decline of insulin sensitivity, or represents only an epiphenomenon accompanying pre-diabetes, remains to be elucidated. The observed relationship might contribute to the well-recognized ability of ADMA to predict cardiovascular outcome. 23876723 Human hair in the identification of cocaine abuse with cantilever-enhanced photoacoustic spectroscopy and principal component analysis. In this study, a novel approach combining different techniques, including Fourier transform infrared (FT-IR) spectroscopy, photoacoustic spectroscopy (PAS) with an interferometric cantilever microphone, and principal component analysis (PCA) along with a proper data preprocessing procedure, have been used in the investigation of hair samples for cocaine abuse. Hair fibers from cocaine-overdose patients have been measured using a simple procedure involving cantilever-enhanced photoacoustic Fourier transform infrared spectroscopy. In addition, a reference group of hair samples from subjects with no cocaine abuse has been measured. We present a first approach to discriminate the cocaine users from the reference group with the photoacoustic method and PCA. With proper data preprocessing methods, the two groups were successfully separated according to their spectra. The results were confirmed with two different classification methods independent of the principal component data analysis. 23315275 Relationship between oxidative stress and chronic daily headache in children. The aim of this study was to investigate the relationship between oxidative stress and chronic daily headache (CDH) in children. Although there are reports that oxidative injury may play a role in the pathophysiology of some neurologic disorders, such as migraine and epilepsy, by disrupting or destroying cell membranes through the formation of free radical and reactive oxygen species, the pathophysiology of headache is not clearly established. A total of 38 children (16 boys and 22 girls) with CDH, aged between 7 and 15 years, were enrolled in the study. The control group consisted of 39 healthy children (17 boys and 22 girls), aged between 7 and 14 years. The mean age was 10.9 ± 2.2 years for both the groups. Activities of erythrocyte superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) as well as malondialdehyde (MDA) levels in all the children of both the groups were measured. Mean activities of erythrocyte SOD, CAT, and GPx as well as MDA levels were significantly higher in the study group than in the control group (p < 0.001). The findings of this study suggest that oxidative stress may play a causal or consequential role in children with CDH. 23108167 Methotrexate-conjugated and hyperbranched polyglycerol-grafted Fe₃O₄ magnetic nanoparticles for targeted anticancer effects. Superparamagnetic nanoparticles grafted with hyperbranched polyglycerol (HPG) and conjugated with methotrexate (MTX) (MNP-g-HPG-MTX) were synthesized via a sol-gel reaction followed by thiol-ene click chemistry and esterification reaction. The successful grafting of MTX and HPG onto the nanoparticles was confirmed by X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FT-IR) spectroscopy, and UV-visible spectroscopy. The HPG-graft layer confers the magnetic nanoparticles with good dispersibility and stability in aqueous medium and macrophage-evasive property while the MTX acts as a chemotherapeutic drug as well as a tumor targeting ligand. The dose-dependent targeting and anticancer effect of the MNP-g-HPG-MTX nanoparticles were evaluated, and the results showed that depending on the amount of conjugated MTX and the concentration of the incubated nanoparticles, the uptake of MNP-g-HPG-MTX nanoparticles by human head and neck cancer (KB) cells can be eight times or more higher than those by 3T3 fibroblasts and RAW macrophages. As a result, the MNP-g-HPG-MTX nanoparticles are capable of killing ∼50% of the KB cells while at the same time exhibiting low cytotoxicity towards 3T3 fibroblasts and RAW macrophages. Thus, such nanoparticles can potentially be used as active targeting anticancer agents. 23875963 Influence of Full-Contour Zirconia Surface Roughness on Wear of Glass-Ceramics. The purpose of this study was to evaluate the influence of full-contour (Y-TZP) zirconia surface roughness (glazed vs. as-machined) on the wear behavior of glass-ceramics. Thirty-two full contour Y-TZP (Diazir®) specimens (hereafter referred to as zirconia sliders) (ϕ = 2 mm, 1.5 mm in height) were fabricated using CAD/CAM and sintered according to the manufacturer's instructions. Zirconia sliders were embedded in brass holders using acrylic resin and then randomly assigned (n = 16) according to the surface treatment received, that is, as-machined or glazed. Glass-ceramic antagonists, Empress/EMP and e.max/EX, were cut into tabs (13 × 13 × 2 mm(3) ), wet-finished, and similarly embedded in brass holders. Two-body pin-on-disk wear testing was performed at 1.2 Hz for 25,000 cycles under a 3 kg load. Noncontact profilometry was used to measure antagonist height (μm) and volume loss (mm(3) ). Qualitative data of the zirconia testing surfaces and wear tracks were obtained using SEM. Statistics were performed using ANOVA with a significance level of 0.05. As-machined yielded significantly higher mean roughness values (Ra = 0.83 μm, Rq = 1.09 μm) than glazed zirconia (Ra = 0.53 μm, Rq = 0.78 μm). Regarding glass-ceramic antagonist loss, as-machined zirconia caused significantly less mean height and volume loss (68.4 μm, 7.6 mm(3) ) for EMP than the glazed group (84.9 μm, 9.9 mm(3) ), while no significant differences were found for EX. Moreover, EMP showed significantly lower mean height and volume loss than EX (p < 0.0001). SEM revealed differences on wear characteristics between the glass-ceramics tested. e.max wear was not affected by zirconia surface roughness; however, Empress wear was greater when opposing glazed zirconia. Overall, surface glazing on full-contour zirconia did not minimize glass-ceramic wear when compared with as-machined zirconia. 23785179 Correlates and cross-linguistic comparisons of informativeness and efficiency on nicholas and brookshire discourse stimuli in spanish/english bilingual adults. The purpose of this study was to determine (a) correlates of informativeness and efficiency in discourse and (b) potential cross-linguistic and stimulus type (picture vs. nonpicture) differences in measures of informativeness and efficiency in Spanish/English bilingual adults in the United States. Eighty-eight Spanish/English young bilingual adults who self-reported being functional in both languages completed the discourse tasks from Nicholas and Brookshire (1993). Responses were analyzed with an adapted version of the scoring system that is based on correct information units (CIUs), the variable corresponding to informative words. Regression analyses showed that among participant-provided data, self-ratings of proficiency accounted for most of the variance in informativeness over time (CIUs/min), although usage was also important in Spanish. When naming accuracy was added as a variable, verb-naming accuracy superseded all variables as accounting for the most variance in CIUs/min across languages. Overall, participants provided more information more efficiently in English as compared to Spanish. The results provide preliminary evidence that Nicholas and Brookshire stimuli and scoring procedures may be appropriate for Spanish/English bilinguals and suggest that self-ratings and usage information collected from participants, as well as naming accuracies, may be predictive of informativeness and efficiency in discourse. 23934203 Detection of EGFR gene mutations in non-small cell lung cancer: Lessons from a single-institution routine analysis of 1,403 tumor samples. Activating mutations of the epidermal growth factor receptor (EGFR) in lung tumors are associated with a dramatic response to tyrosine kinase inhibitors. Therefore, routine analysis of pathological specimens is mandatory in clinical practice. We have prospectively tested tumors from Caucasian lung tumor patients between January 2010 and June 2012. DNA was extracted from formalin-fixed paraffin-embedded tissues following macrodissection. The p.L858R substitution was assessed by allele-specific PCR and exon 19 deletions by PCR and DNA fragment analysis. Using a robust process from patient sampling to screening methods, we analyzed samples from 1,403 patients. The EGFR status could be successfully determined for 1,322 patients. EGFR mutations were detected in 179 (13.5%) patients, with female and adenocarcinoma histology predominance. Mutated patients were significantly older than non‑mutated patients. Similar mutation rates were obtained with primary tumors and metastases, and with surgical resection, bronchial biopsies, CT-guided needle biopsies and transbronchial needle aspiration. The sensitivity of our assays allowed us to detect EGFR mutations in samples poor (<10%) in tumor cells. Finally, the mutation rate was much higher in tumors expressing the TTF-1 antigen (145/820; 17.7%) than in TTF-1 negative tumors (3/218; 1.4%). The results obtained through routine analysis of more than 1,300 samples indicated that all types of specimen can be analyzed without any significant bias. TTF-1 immunostaining may be used to predict negative EGFR mutation status. 23892007 Active decorrelation in the basal ganglia. The cytoarchitecturally-homogeneous appearance of the globus pallidus, subthalamic nucleus and substantia nigra has long been said to imply a high degree of afferent convergence and sharing of inputs by nearby neurons. Moreover, axon collaterals of neurons in the external segment of the globus pallidus and the substantia nigra pars reticulata arborize locally and make inhibitory synapses on other cells of the same type. These features suggest that the connectivity of the basal ganglia may impose spike-time correlations among the cells, and it has been puzzling that experimental studies have failed to demonstrate such correlations. One possible solution arises from studies of firing patterns in basal ganglia cells, which reveal that they are nearly all pacemaker cells. Their high rate of firing does not depend on synaptic excitation, but they fire irregularly because a dense barrage of synaptic inputs normally perturbs the timing of their autonomous activity. Theoretical and computational studies show that the responses of repetitively-firing neurons to shared input or mutual synaptic coupling often defy classical intuitions about temporal synaptic integration. The patterns of spike-timing among such neurons depend on the ionic mechanism of pacemaking, the level of background uncorrelated cellular and synaptic noise, and the firing rates of the neurons, as well as the properties of their synaptic connections. Application of these concepts to the basal ganglia circuitry suggests that the connectivity and physiology of these nuclei may be configured to prevent the establishment of permanent spike-timing relationships between neurons. The development of highly synchronous oscillatory patterns of activity in Parkinson's disease may result from the loss of pacemaking by some basal ganglia neurons, and accompanying breakdown of the mechanisms responsible for active decorrelation. 23765117 Ontogenetic profile of innate immune related genes and their tissue-specific expression in brown trout, Salmo trutta (Linnaeus, 1758). The innate immune system is a fundamental defense weapon of fish, especially during early stages of development when acquired immunity is still far from being completely developed. The present study aims at looking into ontogeny of innate immune system in the brown trout, Salmo trutta, using RT-PCR based approach. Total RNA extracted from unfertilized and fertilized eggs and hatchlings at 0, 1 h and 1, 2, 3, 4, 5, 6, 7 weeks post-fertilization was subjected to RT-PCR using self-designed primers to amplify some innate immune relevant genes (TNF-α, IL-1β, TGF-β and lysozyme c-type). The constitutive expression of β-actin was detected in all developmental stages. IL-1β and TNF-α transcripts were detected from 4 week post-fertilization onwards, whereas TGF-β transcript was detected only from 7 week post-fertilization onwards. Lysozyme c-type transcript was detected early from unfertilized egg stage onwards. Similarly, tissues such as muscle, ovary, heart, brain, gill, testis, liver, intestine, spleen, skin, posterior kidney, anterior kidney and blood collected from adult brown trout were subjected to detection of all selected genes by RT-PCR. TNF-α and lysozyme c-type transcripts were expressed in all tissues. IL-1β and TGF-β transcripts were expressed in all tissues except for the brain and liver, respectively. Taken together, our results show a spatial-temporal expression of some key innate immune-related genes, improving the basic knowledge of the function of innate immune system at early stage of brown trout. 23908387 Stimulants as specific inducers of dopamine-independent sigma agonist self-administration in rats. A previous study showed that cocaine self-administration induced dopamine-independent reinforcing effects of selective agonists mediated by their actions at sigma1 receptors (σ1Rs), which are intracellularly-mobile chaperone proteins implicated in abuse-related effects of stimulants. The present study assessed whether the induction was specific to self-administration of cocaine. Rats were trained to self-administer the dopamine releaser, d-methamphetamine (0.01-0.32 mg/kg/injection), the mu-opioid receptor agonist, heroin (0.001-0.032 mg/kg/injection), and the non-competitive N-methyl-D-aspartate (NMDA) receptor/channel antagonist ketamine (0.032-1.0 mg/kg/injection). As with cocaine, self-administration of d-methamphetamine induced the reinforcing effects of the selective σ1R agonists, PRE-084 and (+)-pentazocine (0.032-1.0 mg/kg/injection, each). In contrast, neither self-administration of heroin nor ketamine induced PRE-084 or (+)-pentazocine (0.032-10 mg/kg/injection, each) self-administration. Though the σ1R agonists did not maintain responding in subjects with histories of heroin or ketamine self-administration, substitution for those drugs was obtained with appropriate agonists (e.g. remifentanil, 0.1-3.2 µg/kg/injection, for heroin and (+)-MK 801, 0.32-10.0 µg/kg/injection, for ketamine). The σR antagonist BD 1008 (1.0-10 mg/kg) dose-dependently blocked PRE-084 self-administration but was inactive against d-methamphetamine, heroin, and ketamine. In contrast, PRE-084 self-administration was not affected by the dopamine receptor antagonist, (+)-butaclamol (10-100 μg/kg), nor the opioid antagonist, (-)-naltrexone (1.0-10 mg/kg), whereas these antagonists were active against d-methamphetamine and heroin self-administration, respectively. The results indicate that experience specifically with indirect-acting dopamine agonists induce reinforcing effects of previously inactive σ1R agonists. It is further suggested that induced σ1R reinforcing mechanisms may play an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for its treatment. 22981993 Peptide reactivity assay using spectrophotometric method for high-throughput screening of skin sensitization potential of chemical haptens. Haptens must react with cellular proteins to be recognized by antigen presenting cells. Therefore, monitoring reactivity of chemicals with peptide/protein has been considered an in vitro skin sensitization testing method. The reactivity of peptides with chemicals (peptide reactivity) has usually been monitored by chromatographic methods like HPLC or LC/MS, which are robust tools for monitoring common chemical reactions but are rather expensive and time consuming. Here, we examined the possibility of using spectrophotometric methods to monitor peptide reactivity. Two synthetic peptides, Ac-RWAACAA and Ac-RWAAKAA, were reacted with 48 chemicals (34 sensitizers and 14 non-sensitizers). Peptide reactivity was measured by monitoring unreacted peptides with UV-Vis spectrophotometer using 5,5'-dithiobis-2-nitrobenzoic acid as a detection reagent for the free thiol group of cysteine-containing peptide or fluorometer using fluorescamine™ as a detection reagent for the free amine group of lysine-containing peptide. Chemicals were categorized as sensitizers when they induced more than 10% depletion of cysteine-containing peptide or 20% depletion of lysine-containing peptide. The sensitivity, specificity, and accuracy of this method were 82.4%, 85.7%, and 83.3%, respectively. These results demonstrate that spectrophotometric methods can be easy, fast, and high-throughput screening tools for the prediction of the skin sensitization potential of chemical haptens. 23965079 Extend nurse training. Bleeding is an accepted risk of surgery. It is one of the things that nurses look for post-operatively and one of the reasons why vital signs are recorded. 23924311 Co3O4/Carbon Aerogel Hybrids as Anode Materials for Lithium-Ion Batteries with Enhanced Electrochemical Properties. A facile hydrothermal and sol-gel polymerization route was developed for large-scale fabrication of well-designed Co3O4 nanoparticles anchored carbon aerogel (CA) architecture hybrids as anode materials for lithium-ion batteries with improved electrochemical properties. The three-dimensional (3D) mesoporous Co3O4/CA hierarchical hybrids display an improved lithium storage performance and cycling stability, because of the intimate integration and strong synergistic effects between the Co3O4 nanoparticles and CA matrices. Such an interconnected Co3O4/CA hierarchical hybrid can effectively utilize the good conductivity, large surface area, 3D interconnected mesoporous structure, mechanical flexibility, chemical stability, and the short length of Li-ion transport of the CA matrix. The incorporation of Co3O4 nanoparticles into the interconnected CA matrix effectively reduces the number of active sites of Co3O4/CA hybrids, thus greatly increasing the reversible specific capacity and the initial Coulombic efficiency of the hybrids. The Co3O4/CA hybrid material displays the best lithium storage performance and good cycling stability as the Co3O4 loading content is up to 25 wt %, retains a Coulombic efficiency of 99.5% and a specific discharge capacity of 779 mAh g(-1) after 50 cycles, 10.1 and 1.6 times larger than the specific discharge capacity of 73 mAh g(-1) and 478 mAh g(-1) for Co3O4 and CA samples, respectively. The hierarchical hybrid nanostructures with enhanced electrochemical activities using a CA matrix framework can find potential applications in the related conversion reaction electrodes. 23826960 Dietary supplementation with omega-3 polyunsaturated fatty acids ameliorates acute pneumonia induced by Klebsiella pneumoniae in BALB/c mice. The immune benefits associated with the optimal intake of dietary fatty acids are widely known. The objective of the present investigation was to elucidate the role of omega-3 polyunsaturated fatty acids (n-3 PUFA) food source on acute pneumonia induced by Klebsiella pneumoniae. Three different n-3 PUFA preparations (cod liver oil, Maxigard, and flaxseed oil) were orally supplemented and infection was induced in different groups of experimental mice. Mice fed olive oil and normal saline served as oil and saline controls, respectively. After 2 weeks of fatty acid feeding, no effect on the establishment of infection was observed when acute pneumonia was induced in animals. On the other hand, 6 weeks of n-3 PUFA administration was found to improve resistance in mice, as reduced lung bacterial load coupled with significant improvement in pathology was seen in infected mice. Alveolar macrophages collected from all 3 groups of mice fed n-3 PUFA exhibited a significant decrease in the level of apoptosis following infection with K. pneumoniae and an enhanced in vitro phagocytic potential for the pathogen. Lower lung levels of nitric oxide, malondialdehyde, and lactate dehydrogenase were associated with a decrease in the severity of tissue damage. There was a significant increase in the lung levels of pro-inflammatory cytokines (tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β)). No significant change was observed in the levels of interleukin-10 (IL-10). This study highlights that dietary n-3 PUFA supplementation exerts an overall beneficial effect against acute experimental pneumonia. This mechanism is operative through upregulation of nonspecific and specific immune defenses of the host. 23624791 Distinct responses of protein turnover regulatory pathways in hypoxia- and semistarvation-induced muscle atrophy. The balance of muscle protein synthesis and degradation determines skeletal muscle mass. We hypothesized that hypoxia-induced muscle atrophy and alterations in the regulation of muscle protein turnover include a hypoxia-specific component, in addition to the observed effects of reduction in food intake in response to hypoxia. Mice were subjected to normoxic, hypoxic (8% oxygen), or pair-fed conditions for 2, 4, and 21 days. Cell-autonomous effects of hypoxia on skeletal muscle were also assessed in differentiated C2C12 myotubes. Hypoxia induced an initial rapid loss of body and muscle weight, which remained decreased during chronic hypoxia and could only in part be explained by the hypoxia-induced reduction of food intake (semistarvation). Regulatory steps of protein synthesis (unfolded protein response and mammal target of rapamycin signaling) remained active in response to acute and sustained hypoxia but not to semistarvation. Activation of regulatory signals for protein degradation, including increased expression of Murf1, Atrogin-1, Bnip3, and Map1lc3b mRNAs, was observed in response to acute hypoxia and to a lesser extent following semistarvation. Conversely, the sustained elevation of Atrogin-1, Bnip3, and Map1lc3b mRNAs and the increased activity of their upstream transcriptional regulator Forkhead box O1 were specific to chronic hypoxia because they were not observed in response to reduced food intake. In conclusion, altered regulation of protein turnover during hypoxia-induced muscle atrophy resulted from an interaction of semistarvation and a hypoxia-specific component. The finding that food restriction but not hypoxia-induced semistarvation inhibited regulatory steps in protein synthesis suggests a hypoxia-specific impairment of the coordination between protein-synthesis signaling and protein-degradation signaling in skeletal muscle. 23880753 Multiple Endocrine Neoplasia: The Enigma of MEN. Multiple endocrine neoplasia (MEN) is an array of tumors found in various endocrine glands throughout the human body. A wide spectrum of clinical manifestations accompanies this syndrome. The complexities of the glandular function and subtle development of symptoms can cause the diagnosis to be missed, and individuals with MEN can be an enigma to the care team. Appropriate differential diagnosis and assessment are critical for these individuals to receive optimal care. An interprofessional team of health care providers, including an endocrinologist and an advanced practice endocrine nurse, must work in concert to orchestrate a plan of care across the continuum. Those specialized nurses who encounter individuals with MEN in a critical care setting are positioned to support the patient, the family, and the care team through this maze of multiple endocrinopathies and tumors. 23907485 Epigenetic Regulation of Pancreatic Islets. Epigenetic mechanisms, including DNA methylation, histone modifications, and noncoding RNA expression, contribute to regulate islet cell development and function. Indeed, epigenetic mechanisms were recently shown to be involved in the control of endocrine cell fate decision, islet differentiation, β-cell identity, proliferation, and mature function. Epigenetic mechanisms can also contribute to the pathogenesis of complex diseases. Emerging knowledge regarding epigenetic mechanisms suggest that they may be involved in β-cell dysfunction and pathogenesis of diabetes. Epigenetic mechanisms could predispose to the diabetic phenotype such as decline of β-cell proliferation ability and β-cell failure, and account for complications associated with diabetes. Better understanding of epigenetic landscapes of islet differentiation and function may be useful to improve β-cell differentiation protocols and discover novel therapeutic targets for prevention and treatment of diabetes. 23937162 Prodrug/Enzyme Based Acceleration of Absorption of Hydrophobic Drugs: An in Vitro Study. Poor water solubility of APIs is a key challenge in drug discovery and development as it results in low drug bioavailability upon local or systemic administration. The prodrug approach is commonly utilized to enhance solubility of hydrophobic drugs. However, for accelerated drug absorption, supersaturated solutions need to be employed. In this work, a novel prodrug/enzyme based system was developed wherein prodrug and enzyme are coadministered at the point of absorption (e.g., nasal cavity) to form in situ supersaturated drug solutions for enhanced bioavailability. A combination of fosphenytoin/alkaline phosphatase was used as a model system. Prodrug conversion kinetics were evaluated with various prodrug/enzyme ratios at pH 7.4 and 32 °C. Phenytoin permeation rates were determined at various degrees of supersaturation (S = 0.8-6.1), across confluent Madin Darby canine kidney II-wild type monolayers (a nasal epithelium model), with prodrug and enzyme spiked into the apical chamber. Membrane intactness was confirmed by measuring transepithelial electrical resistance and inulin permeability. Fosphenytoin and phenytoin concentrations were analyzed using HPLC. Results indicated that a supersaturated solution could be formed using such prodrug/enzyme systems. Drug absorption increased proportionately with increasing degrees of supersaturation; this flux was 1.5-6 fold greater than that for the saturated phenytoin solution. The experimental data fitted reasonably well to a two compartment pharmacokinetic (PK) model with first order conversion of prodrug to drug. This prodrug/enzyme system markedly enhances drug transport across the model membrane. Applied in vivo, this strategy could be used to facilitate drug absorption through mucosal membranes when absorption is limited by solubility. 23182954 Effects of ozone and fine particulate matter (PM(2.5)) on rat system inflammation and cardiac function. In order to understand the toxic mechanisms of cardiovascular system injuries induced by ambient PM(2.5) and/or ozone, a subacute toxicological animal experiment was designed with exposure twice a week for 3 continuous weeks. Wistar rats were randomly categorized into 8 groups (n=6): 1 control group, 3 groups exposed to fine particulate matters (PM(2.5)) alone at 3 doses (0.2, 0.8, or 3.2 mg/rat), 1 group to ozone (0.81 ppm) alone and 3 groups to ozone plus PM(2.5) at 3 doses (0.2, 0.8, or 3.2 mg/rat). Heart rate (HR) and electrocardiogram (ECG) was monitored at approximately 24-h both after the 3rd exposure and the last (6th) exposure, and systolic blood pressure (SBP) was monitored at approximately 24-h after the 6th exposure. Biomarkers of systemic inflammation and injuries (CRP, IL-6, LDH, CK), heart oxidative stress (MDA, SOD) and endothelial function (ET-1, VEGF) were analyzed after the 6th exposure. Additionally, myocardial ultrastructural alterations were observed under transmission electron microscopy (TEM) for histopathological analyses. Results showed that PM(2.5) alone exposure could trigger the significant increase of CRP, MDA, CK, ET-1 and SBP and decrease of heart rate variability (HRV), a marker of cardiac autonomic nervous system (ANS) function. Ozone alone exposure in rats did not show significant alterations in any indicators. Ozone plus PM(2.5) exposure, however, induced CRP, IL-6, CK, LDH and MDA increase, SOD and HRV decrease significantly in a dose-response way. Meanwhile, abnormal ECG types were monitored in rats exposed to PM(2.5) with and without ozone and obvious myocardial ultrastructural changes were observed by TEM. In conclusion, PM(2.5) alone exposure could cause inflammation, endothelial function and ANS injuries, and ozone potentiated these effects induced by PM(2.5). 23902188 Prevalence of mental disorders in offspring is not increased by IVF and ICSI techniques. Researchers assessed the mental health of children born after fertility treatment in Denmark, comparing their risk of mental disorders with that of spontaneously conceived children. 23696477 Randomized clinical trial on enhanced recovery versus standard care following open liver resection. Enhanced recovery programmes (ERPs) have been shown to reduce length of hospital stay (LOS) and complications in colorectal surgery. Whether ERPs have the same benefits in open liver resection surgery is unclear, and randomized clinical trials are lacking. Consecutive patients scheduled for open liver resection were randomized to an ERP group or standard care. Primary endpoints were time until medically fit for discharge (MFD) and LOS. Secondary endpoints were postoperative morbidity, pain scores, readmission rate, mortality, quality of life (QoL) and patient satisfaction. ERP elements included greater preoperative education, preoperative oral carbohydrate loading, postoperative goal-directed fluid therapy, early mobilization and physiotherapy. Both groups received standardized anaesthesia with epidural analgesia. The analysis included 46 patients in the ERP group and 45 in the standard care group. Median MFD time was reduced in the ERP group (3 days versus 6 days with standard care; P < 0·001), as was LOS (4 days versus 7 days; P < 0·001). The ERP significantly reduced the rate of medical complications (7 versus 27 per cent; P = 0·020), but not surgical complications (15 versus 11 per cent; P = 0·612), readmissions (4 versus 0 per cent; P = 0·153) or mortality (both 2 per cent; P = 0·987). QoL over 28 days was significantly better in the ERP group (P = 0·002). There was no difference in patient satisfaction. ERPs for open liver resection surgery are safe and effective. Patients treated in the ERP recovered faster, were discharged sooner, and had fewer medical-related complications and improved QoL. ISRCTN03274575 (http://www.controlled-trials.com). 23528877 The short course in toxinology: Training the trainers. Clinical toxinology is the medical discipline dealing with the diagnosis, treatment and prevention of toxin diseases caused by exposure to venomous animals and poisonous animals, plants and mushrooms. Currently there is no national or international organisation accrediting or training doctors in this discipline. A few courses covering some aspects of clinical toxinology exist, either with limited curricula, or with only a minor clinical focus, or with a very regional, non-global focus. The only comprehensive clinical toxinology course is the one provided in Adelaide, Australia, running regularly since 1997. Hundreds of doctors from many nations have attended the course since 1997. This course covers venomous animals, poisonous animals, plants and mushrooms, from a full global perspective, with an international faculty and an exit exam. Though lasting only one week, extensive pre-reading material is mandated. The current Course Handbook is about 500 pages. Emphasis is on clinically relevant information and is focused on the needs of doctors treating cases. While it is expected that attendees will have, or acquire, direct experience managing cases of toxin disease and will use the knowledge and skills gained in the course in direct patient care, they may also act as resource people in their home region/nation to promote increased skills in clinical toxinology amongst the wider medical workforce. This course may form the nucleus from which IST can develop a global accredited training scheme in clinical toxinology. Such a scheme will require input from diverse global regions and will be far more comprehensive and over a much longer time than the current Short Course, though likely will incorporate the Short Course in some way, or a derivative of it. 23266005 Nano-crystalline diamond-coated titanium dental implants - A histomorphometric study in adult domestic pigs. Promising biomaterial characteristics of diamond-coatings in biomedicine have been described in the literature. However, there is a lack of knowledge about implant osseointegration of this surface modification compared to the currently used sandblasted acid-etched Ti-Al6-V4 implants. The aim of this study was to investigate the osseointegration of microwave plasma-chemical-vapour deposition (MWP-CVD) diamond-coated Ti-Al6-V4 dental implants after healing periods of 2 and 5 months. Twenty-four MWP-CVD diamond-coated and 24 un-coated dental titanium-alloy implants (Ankylos(®)) were placed in the frontal skull of eight adult domestic pigs. To evaluate the effects of the nano-structured surfaces on bone formation, a histomorphometric analysis was performed after 2 and 5 months of implant healing. Histomorphometry analysed the bone-to-implant contact (BIC). No significant difference in BIC for the diamond-coated implants in comparison to reference implants could be observed for both healing periods. Scanning electron microscopy revealed an adequate interface between the bone and the diamond surface. No delamination or particle-dissociation due to shearing forces could be detected. In this study, diamond-coated dental titanium-alloy implants and sandblasted acid-etched implants showed a comparable degree of osseointegration. 23817215 Adeno-associated Virus 9 Mediated FKRP Gene Therapy Restores Functional Glycosylation of α-dystroglycan and Improves Muscle Functions. Mutations in the FKRP gene are associated with a wide range of muscular dystrophies from mild limb-girdle muscular dystrophy (LGMD) 2I to severe Walker-Warburg syndrome and muscle-eye-brain disease. The characteristic biochemical feature of these diseases is the hypoglycosylation of α-dystroglycan (α-DG). Currently there is no effective treatment available. In this study, we examined the adeno-associated virus serotype 9 vector (AAV9)-mediated gene therapy in the FKRP mutant mouse model with a proline to leucine missense mutation (P448L). Our results showed that intraperitoneal administration of AAV9-FKRP resulted in systemic FKRP expression in all striated muscles examined with the highest levels in cardiac muscle. Consistent with our previous observations, FKRP protein is localized in the Golgi apparatus in myofibers. Expression of FKRP consequently restored functional glycosylation of α-DG in the skeletal and cardiac muscles. Significant improvement in dystrophic pathology, serum creatine kinase levels and muscle function was observed. Only limited FKRP transgene expression was detected in kidney and liver with no detectable toxicity. Our results provided evidence for the utility of AAV-mediated gene replacement therapy for FKRP-related muscular dystrophies.Molecular Therapy (2013); doi:10.1038/mt.2013.156. 23718987 Epidermal adrenergic signaling contributes to inflammation and pain sensitization in a rat model of complex regional pain syndrome. In many patients, the sympathetic nervous system supports pain and other features of complex regional pain syndrome (CRPS). Accumulating evidence suggests that interleukin (IL)-6 also plays a role in CRPS, and that catecholamines stimulate production of IL-6 in several tissues. We hypothesized that norepinephrine acting through specific adrenergic receptors expressed on keratinocytes stimulates the production of IL-6 and leads to nociceptive sensitization in a rat tibial fracture/cast model of CRPS. Our approach involved catecholamine depletion using 6-hydroxydopamine or, alternatively, guanethidine, to explore sympathetic contributions. Both agents substantially reduced nociceptive sensitization and selectively reduced the production of IL-6 in skin. Antagonism of IL-6 signaling using TB-2-081 also reduced sensitization in this model. Experiments using a rat keratinocyte cell line demonstrated relatively high levels of β2-adrenergic receptor (β2-AR) expression. Stimulation of this receptor greatly enhanced IL-6 expression when compared to the expression of IL-1β, tumor necrosis factor (TNF)-α, or nerve growth factor. Stimulation of the cells also promoted phosphorylation of the mitogen-activated protein kinases P38, extracellular signal-regulated kinase, and c-Jun amino-terminal kinase. Based on these in vitro results, we returned to animal testing and observed that the selective β2-AR antagonist butoxamine reduced nociceptive sensitization in the CRPS model, and that local injection of the selective β2-AR agonist terbutaline resulted in mechanical allodynia and the production of IL-6 in the cells of the skin. No increases in IL-1β, TNF-α, or nerve growth factor levels were seen, however. These data suggest that in CRPS, norepinephrine released from sympathetic nerve terminals stimulates β2-ARs expressed on epidermal keratinocytes, resulting in local IL-6 production, and ultimately, pain sensitization. 22904292 Low injury rate strongly correlates with team success in Qatari professional football. Although the incidence of football injuries should relate to team success there is little empirical evidence. We investigated the relationship between injury incidence and team success in Qatar first-division football clubs. Using a prospective cohort study design, we captured exposure and injuries in Qatar male elite football for a season. Club performance was measured by total league points, ranking, goal scored, goals conceded and number of matches won, drawn or lost. Lower injury incidence was strongly correlated with team ranking position (r=0.929, p=0.003), more games won (r=0.883, p=0.008), more goals scored (r=0.893, p=0.007), greater goal difference (r=0.821, p=0.003) and total points (r=0.929, p=0.003). Lower incidence rate was strongly correlated with team success. Prevention of injuries may contribute to team success. 23635999 Effect of angiotensin converting enzyme gene I/D polymorphism and its expression on clinical outcome in acute respiratory distress syndrome. Background: The role of the D allele of the angiotensin-converting enzyme (ACE) gene I/D polymorphism in the clinical outcomes of patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS) remains controversial. Our aim was to assess simultaneously the effect of the ACE I/D polymorphisms as well as the serum and BALF ACE levels on prognosis of patients with ARDS. Methods: Sixty-nine mechanically ventilated patients with ALI/ARDS were recruited. ACE activity levels both in serum and BALF were assessed by chemical methods. Patients were genotyped for ACE I/D polymorphisms. Time-to-event analysis evaluated the variables associated with the 28-day and 90-day mortality. Finally, we performed a meta-analysis of studies examining the association between ACE I/D polymorphisms and mortality of ALI/ARDS patients. Results: In the multivariable model, age, lung compliance, serum lactate and serum ACE levels were significantly associated with both 28- and 90-day mortality. No significant correlation was found between serum and BALF ACE levels (Spearman's rho=0.054; P=0.66). Serum ACE concentrations were significantly higher (P=0.046) in patients with D/D genotype versus the two other groups combined (I/D and I/I genotypes). The meta-analysis of 6 studies (including ours) provided evidence that D allele is significantly associated with increased mortality in ALI/ARDS patients, yielding a per-allele odds ratio of 1.76 (95% CI: 1.19, 2.59). Conclusion: Serum ACE levels appear to be affected by the I/D polymorphism and are correlated with prognosis in patients with ALI/ARDS indicating that further investigation of the clinical significance of the ACE in ARDS might be of value. 23550989 Natural killer cell receptor repertoire is comparable amongst newly diagnosed acute myeloid leukemia of different French-American-British subtypes, risk categories and chemosensitivities. We studied the natural killer (NK) receptor repertoire by flow cytometry for 78 patients with newly diagnosed acute myeloid leukemia (AML) and correlated the expression with their biological and clinical characteristics. CD3-CD56+ NK cells constituted a median of 11.68% of the lymphocyte subset. The NK receptors including the killer immunoglobulin-like receptors, natural cytotoxicity receptors and C-type lectin receptors were comparable amongst the various French-American-British (FAB) subtypes and amongst patients in the better, intermediate and poor risk categories. Neither was there any difference in NK receptor repertoire between patients who achieved a remission with induction chemotherapy and those who were chemorefractory, indicating the absence of a prognostic impact of NK receptor repertoire at the time of diagnosis of AML. Compared with NK cells from 16 healthy donors, most of the NK receptors were expressed at a significantly lower level, suggesting a defective NK cell population as a cause or result of AML. 23870306 Intestinal irony: how probiotic bacteria outcompete bad bugs. In this issue of Cell Host & Microbe, Deriu et al. present a mechanistic explanation underlying the benefits of certain probiotic bacteria. Intestinal bacteria compete for the essential nutrient iron, leading to replacement of pathogenic Salmonella by the probiotic Escherichia coli Nissle, which is better equipped with iron acquisition systems, and resolution of infectious colitis. 23918571 Outcomes of Gleason Score ≤8 among High Risk Prostate Cancer Treated with 125I Low Dose Rate Brachytherapy Based Multimodal Therapy. Purpose: To investigate the role of low dose rate (LDR) brachytherapy-based multimodal therapy in high-risk prostate cancer (PCa) and analyze its optimal indications. Materials and Methods: We reviewed the records of 50 high-risk PCa patients [clinical stage ≥T2c, prostate-specific antigen (PSA) >20 ng/mL, or biopsy Gleason score ≥8] who had undergone 125I LDR brachytherapy since April 2007. We excluded those with a follow-up period <3 years. Biochemical recurrence (BCR) followed the Phoenix definition. BCR-free survival rates were compared between the patients with Gleason score ≥9 and Gleason score ≤8. Results: The mean initial PSA was 22.1 ng/mL, and mean D90 was 244.3 Gy. During a median follow- up of 39.2 months, biochemical control was obtained in 72% (36/50) of the total patients; The estimated 3-year BCR-free survival was 92% for the patients with biopsy Gleason scores ≤8, and 40% for those with Gleason scores ≥9 (p<0.001). In Cox multivariate analysis, only Gleason score ≥9 was observed to be significantly associated with BCR (p=0.021). Acute and late grade ≥3 toxicities were observed in 20% (10/50) and 36% (18/50) patients, respectively. Conclusion: Our results showed that 125I LDR brachytherapy-based multimodal therapy in high-risk PCa produced encouraging relatively long-term results among the Asian population, especially in patients with Gleason score ≤8. Despite small number of subjects, biopsy Gleason score ≥9 was a significant predictor of BCR among high risk PCa patients after brachytherapy. 23796125 Highly Hydrophilic Polyvinylidene Fluoride (PVDF) Ultrafiltration Membranes via Postfabrication Grafting of Surface-Tailored Silica Nanoparticles. Polyvinylidene fluoride (PVDF) has drawn much attention as a predominant ultrafiltration (UF) membrane material due to its outstanding mechanical and physicochemical properties. However, current applications suffer from the low fouling resistance of the PVDF membrane due to the intrinsic hydrophobic property of the membrane. The present study demonstrates a novel approach for the fabrication of a highly hydrophilic PVDF UF membrane via postfabrication tethering of superhydrophilic silica nanoparticles (NPs) to the membrane surface. The pristine PVDF membrane was grafted with poly(methacrylic acid) (PMAA) by plasma induced graft copolymerization, providing sufficient carboxyl groups as anchor sites for the binding of silica NPs, which were surface-tailored with amine-terminated cationic ligands. The NP binding was achieved through a remarkably simple and effective dip-coating technique in the presence or absence of the N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC)/N-hydroxysuccinimide (NHS) cross-linking process. The properties of the membrane prepared from the modification without EDC/NHS cross-linking were comparable to those for the membrane prepared with the EDC/NHS cross-linking. Both modifications almost doubled the surface energy of the functionalized membranes, which significantly improved the wettability of the membrane and converted the membrane surface from hydrophobic to highly hydrophilic. The irreversibly bound layer of superhydrophilic silica NPs endowed the membranes with strong antifouling performance as demonstrated by three sequential fouling filtration runs using bovine serum albumin (BSA) as a model organic foulant. The results suggest promising applications of the postfabrication surface modification technique in various membrane separation areas. 23873895 Sample size requirements for training high-dimensional risk predictors. A common objective of biomarker studies is to develop a predictor of patient survival outcome. Determining the number of samples required to train a predictor from survival data is important for designing such studies. Existing sample size methods for training studies use parametric models for the high-dimensional data and cannot handle a right-censored dependent variable. We present a new training sample size method that is non-parametric with respect to the high-dimensional vectors, and is developed for a right-censored response. The method can be applied to any prediction algorithm that satisfies a set of conditions. The sample size is chosen so that the expected performance of the predictor is within a user-defined tolerance of optimal. The central method is based on a pilot dataset. To quantify uncertainty, a method to construct a confidence interval for the tolerance is developed. Adequacy of the size of the pilot dataset is discussed. An alternative model-based version of our method for estimating the tolerance when no adequate pilot dataset is available is presented. The model-based method requires a covariance matrix be specified, but we show that the identity covariance matrix provides adequate sample size when the user specifies three key quantities. Application of the sample size method to two microarray datasets is discussed. 23199103 Pandemic H1N1 influenza surveillance in Haiti, July-December 2009. Please cite this paper as: Fitter et al. (2012) Pandemic H1N1 influenza surveillance in Haiti, July-December 2009. Influenza and Other Respiratory Viruses DOI: 10.1111/irv.12060. From June 2009 through December 2009, Haiti conducted sentinel surveillance for influenza. 499 samples were collected and tested using real-time RT-PCR. 197 (39.5%) were positive for influenza, including 95 (48%) pandemic (H1N1) 2009, 57 (29%) seasonal influenza A and 45 (23%) influenza B. The median age of pandemic (H1N1) 2009 cases was 21.7; two-thirds of pandemic (H1N1) 2009 cases were in patients aged 6 years - 35 years. Pandemic activity peaked in September and co-circulated with other influenza subtypes. The age distribution and seasonality of pandemic (H1N1) 2009 in Haiti were similar to other countries in the Caribbean region. 23889776 Precision of a novel computed tomographic method for quantification of femoral varus in dogs and an assessment of the effect of femoral malpositioning. To assess the precision of a novel protocol for determination of femoral varus angle (FVA) using computed tomography (CT) in dogs, and to quantify the effect of femoral rotational and sagittal plane malpositioning on measured FVA. Cross-sectional study. Femora (n = 66) from dogs that had pelvic limb CT examination for patellar instability (26) or other reasons (10). Three observers measured FVA of each of 66 femora on three separate occasions. Standardized orientation of a volume rendered image was achieved by superimposition of the caudal and distal aspects of the femoral condyles on a lateral projection, definition of a sagittal plane axis, and finally rotation through 90° to yield a cranial projection. Intra- and inter-observer variability were estimated using the intra-class correlation coefficient. The effect of variation in rotational and sagittal plane orientation on measured FVA was subsequently quantified using 6 femora with FVAs between -0.4° and 19°. Intra-class correlation coefficients for the 3 observers, indicating intra-observer variation, were 0.982, 0.937, and 0.974. The intra-class correlation coefficient of the means of the results from each observer, indicating inter-observer variation, was 0.976. Consistent linear variations in measured FVA occurred as a result of rotational malpositioning in all 6 tested femora, and as a result of sagittal plane malpositioning in femora with FVAs ≥ 7.9°. The reported protocol for the measurement of FVA in dogs is repeatable and reproducible. Small variations in femoral orientation, as might be expected with conventional radiography, lead to clinically significant alterations in measured FVA. 23867627 Structural insights into substrate recognition in proton-dependent oligopeptide transporters. Short-chain peptides are transported across membranes through promiscuous proton-dependent oligopeptide transporters (POTs)-a subfamily of the major facilitator superfamily (MFS). The human POTs, PEPT1 and PEPT2, are also involved in the absorption of various drugs in the gut as well as transport to target cells. Here, we present a structure of an oligomeric POT transporter from Shewanella oneidensis (PepTSo2), which was crystallized in the inward open conformation in complex with the peptidomimetic alafosfalin. All ligand-binding residues are highly conserved and the structural insights presented here are therefore likely to also apply to human POTs. 23748052 The synthetic food colouring agent Allura Red AC (E129) is not genotoxic in a flow cytometry-based micronucleus assay in vivo. The safety of several azo colouring agents, used as food additives, has during the years been questioned. Allura Red AC (E129) has in some publications been classified as genotoxic. In fact, in the European Union, Allura Red is permitted as a food additive in human food, but, surprisingly, it was not acceptable as an additive for use in animal feed. In this study we have evaluated whether Allura Red is genotoxic using a flow cytometer-based micronucleus assay in peripheral blood of mice. Male FVB mice were given a single intra-peritoneal injection of various doses of Allura Red and sacrificed at 46h after treatment. The tested doses were 0, 100, 200, 400, 600, 800, 1000, 1500, and 2000mg/kg body weight (b.w.). Each dose group constituted three mice, except for in the dose group of 1000mg/kgb.w., which constituted four mice. Blood samples were collected and the frequency of micronucleated polychromatic erythrocytes (fMNPCE) and the cell proliferation (%PCE) was determined. The analyses did not show any significant difference in the %PCE or in the fMNPCE. Consequently, under the testing circumstances one can conclude that Allura Red is not genotoxic. 23958421 Effects of direct infusion of bone marrow-derived progenitor cells and indirect mobilization of hematopoietic progenitor cells on atherosclerotic plaque and inflammatory process in atherosclerosis. We sought to investigate the effects of lin-/sca+ cells, endothelial progenitor cells (EPCs) and granulocyte colony-stimulating factor (G-CSF) administration on atherosclerotic plaque progression. Apolipoprotein E-deficient (apoE(-/-)) mice were splenectomized and treated with high-cholesterol diet for 6weeks in order to induce atherosclerotic plaque development. Bone marrow-derived Lin-/sca-1+ cells were isolated and further cultured to early growth endothelial progenitor cells (EPCs). Mice were divided in four groups (n=10/group) and received two intravenous injections of 5×10(5) cells (lin-/sca-1+ or EPCs), or granulocyte colony-stimulating factor (G-CSF 100μg/kg/day) for 7days or normal saline. The same interventions were administered to animals, which had undergone unilateral hind-limb ischemia. Effects on inflammatory parameters, lesion severity, and atherosclerotic plaque area size were assessed. The administration of both G-CSF and progenitor cells significantly decreased the levels of IL-6, 6weeks after the initiation of treatment. Atherosclerotic lesion area was reduced by G-CSF (atherosclerotic plaque area percentage 22.94%±3.68, p=0.001), by lin-/sca-1+ (23.27%±5.98, p=0.002) and cultured EPCs (23.16±4.86%, p=0.002) compared to control (32.75%±7.05). In the atherosclerotic mice that underwent limb ischemia, the atherosclerotic plaque area, was not significantly different between the treatment groups cultured EPCs-treated mice and the control group (p=NS, for all). Direct infusion of progenitor cells and indirect mobilization of hematopoietic progenitor cells decreased plaque progression and levels of inflammatory molecules in a murine model of atherosclerosis. Treatment with G-CSF, lin-/sca-1+, or EPCs may exert beneficial effects on vascular inflammation and atherosclerotic plaque progression. However, the effects are diminished in an ischemic setting. 23933176 Genomics and epigenomics of clear cell renal cell carcinoma: Recent developments and potential applications. Majority of clear cell renal cell carcinomas (ccRCCs) are diagnosed in the advanced metastatic stage resulting in dramatic decrease of patient survival. Thereby, early detection and monitoring of the disease may improve prognosis and treatment results. Recent technological advances enable the identification of genetic events associated with ccRCC and reveal significant molecular heterogeneity of ccRCC tumors. This review summarizes recent findings in ccRCC genomics and epigenomics derived from chromosomal aberrations, DNA sequencing and methylation, mRNA, miRNA expression profiling experiments. We provide a molecular insight into ccRCC pathology and recapitulate possible clinical applications of genomic alterations as predictive and prognostic biomarkers. 23103298 Possible ways of fagopyrin biosynthesis and production in buckwheat plants. The present work extends knowledge about possible biosynthesis of fagopyrin in buckwheat plants by providing possible candidate genes for its biosynthesis and the role of type III polyketide synthases (PKSs). Moreover, new information is presented about the possible connection between naphthodianthrones and phenolic biosynthesis. Possible regulation of fagopyrin biosynthesis and production under different growth conditions is also discussed. 23265519 Production of the α-glycosidase inhibitor 1-deoxynojirimycin from Bacillus species. 1-Deoxynojirimycin (DNJ), a potent α-glycosidase inhibitor, has therapeutic applications in treatments of HIV, Gaucher's disease, and diabetes. DNJ has been extracted from natural sources (mulberry leaves) for therapeutic purposes; however, DNJ ingredients are in limited supply and are costly to obtain on a large scale. Since certain strains of Bacillus and Streptomyces species reportedly produce DNJ, they may serve as potential sources for high-yield DNJ production. In this study, we obtained evidence for a DNJ production in Bacillus subtilis DSM704 by hydrophilic interaction chromatography-tandem mass spectrometry. In addition, from a screen of 750 microorganisms, we identified additional Bacillus strains (Bacillus amyloliquefaciens AS385 and Bacillus subtilis B4) that produce DNJ in large quantities. Investigation of the effect of various culture conditions, using Bacillus subtilis DSM704 and the DNJ high-production Bacillus strains, provided evidence for the importance of sorbitol supplementation on the yield of the DNJ precursor, 2-amino-2-deoxy-D-mannitol, thereby increasing DNJ production. The role of sorbitol in increased DNJ production was supported by an observed increase in mRNA expression of the biosynthetic gene, gabT1. When Bacillus amyloliquefaciens AS385 was cultured in medium supplemented with sorbitol, extracellular DNJ concentration reached a maximum of 460 mg/l of medium (equivalent to 9.20mg/g of freeze-dried medium), indicating that this strain can serve as a source for food- and drug-grade products. These findings not only lead to a further understanding of the DNJ biosynthetic pathway, but also suggest a method for microbial mass production of DNJ for therapeutic applications. 23970460 Apathy in Elderly Nondemented Patients With Parkinson's Disease: Clinical Determinants and Relationship to Quality of Life. Objectives:To describe the prevalence and clinical determinants of apathy in elderly nondemented patients with Parkinson's disease (PD) and their relationship to quality of life (QoL).Methods:A total of 106 nondemented elderly patients with PD were examined using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Starkstein Apathy Scale, Hospital Anxiety and Depression Scale, Beck Depression Inventory-II, and 39-item Parkinson's disease quality of life questionnaire.Results:Apathy was present in 54% of the studied population. Factors associated with apathy were higher depression scores and a lower daily levodopa equivalent dose. Longer disease duration, higher motor MDS-UPDRS subscore, and higher depression and anxiety scores, but not apathy, were found to be associated with worse QoL.Conclusions:Although apathy does not seem to be an independent predictor of worse QoL specifically in elderly patients with PD, it remains very relevant, as its presence increases caregiver burden. Both depression and potential dopaminergic treatment underdosing can be properly managed, thus potentially reducing the prevalence and severity of apathy in a proportion of the apathetic patients with PD. 23942243 Relationships between dietary macronutrients and adult neurogenesis in the regulation of energy metabolism - CORRIGENDUM. Of the environmental factors which have an impact on body weight, nutrients are most influential. Within normal limits, hypothalamic and related neuronal populations correct perturbations in energy metabolism, to return the body to its nutritional set-point, either through direct response to nutrients or indirectly via peripheral appetite signals. Excessive intake of certain macronutrients, such as simple carbohydrates and SFA, can lead to obesity and attendant metabolic dysfunction, also reflected in alterations in structural plasticity, and, intriguingly, neurogenesis, in some of these brain regions. Neurogenesis, previously thought to occur only in the embryo, is now known to take place in the adult brain, dependent on numerous stimulating and inhibiting factors, including dietary components. Because of classic associations between neurogenesis and the hippocampus, in learning and cognition, this brain region has also been the focus of attention in the study of links between diet and neurogenesis. Recently, however, a more complete picture of this relationship has been building: not only has the hypothalamus been shown to satisfy the criteria for a neurogenic niche, but appetite-related mediators, including circulating hormones, such as leptin and ghrelin, pro-inflammatory cytokines and the endocannabinoid intracellular messengers, are also being examined for their potential role in mediating neurogenic responses to macronutrients. The present review draws together these observations and investigates whether n-3 PUFA may exert their attenuating effects on body weight through the stimulation of adult neurogenesis. Exploration of the effects of nutraceuticals on neurogenic brain regions may encourage the development of new rational therapies in the fight against obesity. 23968065 Communication: Autodetachment versus internal conversion from the S1 state of the isolated GFP chromophore anion. The anionic form of p-hydroxybenzylidene-2,3-dimethylimidazolinone (HBDI) has been extensively employed as a model of the chromophore of the green fluorescence protein. The bright S1 excited state HBDI(-) has a measured lifetime of 1.4 ps in the gas-phase and is dominated by two non-radiative decay mechanisms: internal conversion and autodetachment into the neutral continuum. Here, time-resolved photoelectron spectroscopy has been used to determine the yields of these two channels from which the lifetime for autodetachment was found to be ∼30 ps. 23890776 Peer Sexual Harassment and Deliberate Self-Injury: Longitudinal Cross-Lag Investigations in Canada and Sweden. Although the receipt of peer sexual harassment in schools has been linked to deliberate self-injury, the direction of association over time has not been tested. Two longitudinal studies examined whether receipt of peer sexual harassment within schools predicts engagement in deliberate self-injury or vice versa. Differences between boys and girls were also tested. Surveys were conducted in two countries, Canada and Sweden. Measures of sexual harassment and deliberate self-injury were administered yearly in classrooms. Two waves of data were collected in the Canadian study (N = 161, 59.6% girls, mean age = 13.82 years); three waves of data were collected in Sweden (N = 513, 47% girls, mean age = 13.23 years). In the Canadian study, deliberate self-injury predicted subsequent peer sexual harassment; the converse relationship was not significant. No significant gender differences were found. Across the three waves of the Swedish study, peer sexual harassment predicted self-injury from T1 to T2, and self-injury predicted peer sexual harassment from T2 to T3. However, self-injury did not mediate peer sexual harassment at T1 and T3. Tests of gender differences revealed self-injury predicted sexual harassment from T2 to T3 among Swedish girls but not boys. Adolescents who deliberately self-injure may be vulnerable to sexual harassment by peers at school. Cultural norms may have a role in whether this process applies primarily to girls or to both genders. Sexual harassment by peers may also increase self-injury, but this is not subsequently linked to increases in receipt of sexual harassment. 22827775 Antidepressant-like effect of bis-eugenol in the mice forced swimming test: evidence for the involvement of the monoaminergic system. Dehydrodieugenol, known as bis-eugenol, is a eugenol ortho dimer, and both compounds were able to exhibit anti-inflammatory and antioxidant activities in previous studies. Furthermore, eugenol showed antidepressant-like effect; however, the biological actions of bis-eugenol on experimental models for screening antidepressant activity are still unknown. The present study investigated a possible antidepressant-like activity of bis-eugenol in the forced swimming test (FST) and tail suspension test (TST) in mice and the involvement in the monoaminergic system in this effect. In addition, a neurochemical analysis on brain monoamines of mice acutely treated with bis-eugenol was also conducted. Bis-eugenol decreased the immobility time in the FST and TST without accompanying changes in ambulation in the open field test at 10 mg/kg, i.p.. Nevertheless, it induced ambulation at 25 and 50 mg/kg doses. The anti-immobility effect of bis-eugenol (10 and 50 mg/kg, i.p.) was prevented by pretreatment of mice with p-chlorophenylalanine (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis, for four consecutive days), yohimbine (1 mg/kg, i.p., an α2-adrenoceptor antagonist), SCH23390 (15 Î¼g/kg, s.c., a dopamine D1 receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist). Monoamines analysis using high-performance liquid chromatograph revealed significant increase in the 5-HT, NE and DA levels in brain striatum. The present study indicates that bis-eugenol possesses antidepressant-like activity in FST and TST by altering dopaminergic, serotonergic and noradrenergic systems function. 23773695 An optimized fluorogenic ADAMTS13 assay with increased sensitivity for the investigation of patients with thrombotic thrombocytopenic purpura. Most ADAMTS13 assays use non-physiological conditions (low ionic strength, low pH, barium chloride), are subject to interference from plasma proteins, hemoglobin and bilirubin, and have limited sensitivity, especially for inhibitors. We addressed these constraints by designing a substrate that can be used in undiluted plasma. A polypeptide was expressed in E. coli that corresponds to von Willebrand factor Gln(1599) -Arg(1668) , with mutations N1610C and K1617R and an N-terminal Gly. Substrate FRETS-rVWF71 was prepared by modifying Cys(1610) with DyLight 633 (abs 638 nm, em 658 nm) and the N-terminus with IRDye QC-1 (abs 500-800 nm). Assays were performed at pH 7.4 in 150 mm NaCl, 10 mm CaCl2 . Serum and plasma anticoagulated with citrate or heparin had equivalent ADAMTS13 activity with FRETS-rVWF71. Neither bilirubin (≤ 20 mg dL(-1) ) nor hemoglobin (≤ 20 g L(-1) ) interfered with product detection. Assays with FRETS-rVWF71 and FRETS-VWF73 gave similar results (R(2 ) = 0.95) for plasma from 80 subjects with thrombotic microangiopathy, 22 subjects with other causes of thrombocytopenia, and 20 healthy controls. The limit of detection with FRETS-rVWF71 for ADAMTS13 activity was ≤ 0.3%. Inhibitor assays with FRETS-rVWF71 gave titers ~2.5-fold higher than with FRETS-VWF73 and clearly distinguished patients with and without inhibitors. FRETS-rVWF71 is suitable for ADAMTS13 assays in minimally diluted plasma or serum without interference from proteins, bilirubin or free hemoglobin in plasma. Optimized detection of ADAMTS13 inhibitors will facilitate the monitoring of antibody responses during the treatment of thrombotic thrombocytopenic purpura. 23848988 Comorbidity of Migraine and Psychiatric Disorders Among Substance-Dependent Inpatients. Limited and conflicting data exist regarding the prevalence of psychiatric disorders, particularly substance use disorders (SUDs), among migraineurs in inpatient clinical settings. As part of a larger cross-sectional study, 181 substance-dependent inpatients completed a structured psychiatric interview and measures of psychiatric symptoms and migraine. Standardized mean differences were used to quantify differences between inpatients with and without migraine across 4 domains of predictors (demographic variables, non-SUD psychiatric diagnoses, specific SUDs, and self-reported psychiatric symptoms). The predictors within each domain that best discriminated between the migraine and no-migraine groups were identified using a classification tree approach with Bonferroni corrections. These candidate predictors were subsequently entered into a multivariate logistic regression to predict migraine status, which was then replicated using bootstrapping of 500 samples. Associations between migraine status and SUD treatment dropout were also examined. Forty-four of the 181 (24.3%) participants met criteria for migraine. Migraineurs were more likely to be female (34.8% vs 18.3%) and reported higher levels of current anxiety symptoms (mean [standard deviation]: 19.7 [11.0] vs 11.3 [10.3]). Having a lifetime diagnosis of generalized anxiety disorder (56.8% vs 27%, odds ratio 3.47, 95% confidence interval [CI] 1.39-10.58) or a current diagnosis of alcohol dependence (45.5% vs 24.1%, odds ratio 3.79, 95% CI 1.63-13.62) was associated with more than a 3-fold risk of migraine. These 4 variables in combination were forced into the final multivariate model, which differentiated well between those with and without migraine (area under the receiver operating characteristic curve = 0.81; 95% CI 0.73-0.88). Migraine was not differentially associated with increased risk for SUD treatment dropout (13.6% vs 16.1% dropout among those without migraine). A history of generalized anxiety disorder, high levels of current anxiety symptoms, and current alcohol dependence are the strongest psychiatric predictors of migraine status among substance-dependent inpatients. However, migraine status is not associated with SUD treatment dropout. 23859917 The legal aspects of expedited partner therapy practice: do state laws and policies really matter? Expedited partner therapy (EPT) is a potential partner treatment strategy. Significant efforts have been devoted to policies intended to facilitate its practice. However, few studies have attempted to evaluate these policies. We used data on interviewed gonorrhea cases from 12 sites in the STD Surveillance Network in 2010 (n = 3404). Patients reported whether they had received EPT. We coded state laws relevant to EPT for gonorrhea using Westlaw legal research database and the general legal status of EPT in STD Surveillance Network sites from Centers for Disease Control and Prevention's Web site in 2010. We also coded policy statements by medical and other boards. We used χ tests to compare receipt of EPT by legal/policy variables, patient characteristics, and provider type. Variables significant at P < 0.10 in bivariate analyses were included in a logistic regression model. Overall, 9.5% of 2564 interviewed patients with gonorrhea reported receiving EPT for their partners. Receipt of EPT was significantly higher where laws and policies authorizing EPT existed. Where EPT laws for gonorrhea existed and EPT was permissible, 13.3% of patients reported receiving EPT as compared with 5.4% where there were no EPT laws and EPT was permissible, and 1.0% where there were no EPT laws and EPT was potentially allowable (P < 0.01). Expedited partner therapy was higher where professional boards had policy statements supporting EPT (P < 0.01). Receipt of EPT did not differ by most patient characteristics or provider type. Policy-related findings were similar in adjusted analyses. Expedited partner therapy laws and policies were associated with higher reports of receipt of EPT among interviewed gonorrhea cases. 23416130 Dexamethasone alters epithelium proliferation and survival and suppresses Wnt/β-catenin signaling in developing cleft palate. Dexamethasone (Dex) contributes to a cleft palate, but the cellular and molecular mechanisms responsible for the deleterious effect on the developing palate are unclear. Wnt signaling is a causal mechanism of Dex-induced osteoporosis, so this study was conducted to determine whether Dex-induced cleft palate may result from altered Wnt signaling. Administration of Dex to mice completely inhibited canonical Wnt/β-catenin signaling and altered cell proliferation and apoptosis of the craniofacial epithelium in developing embryos. Thus, downregulated Wnt/β-catenin signaling was associated with Dex-induced cleft palate. Moreover, altered cell fate by Dex responsible for small palates, delaying shelf elevation and unfused palates was a crucial mechanism in cleft palate. Our findings help in elucidating the mechanisms of Dex-induced cleft palate. 23371493 Abstinence from repeated amphetamine treatment induces depressive-like behaviors and oxidative damage in rat brain. RATIONALE: Amphetamine has a significant potential for abuse and addiction. Among prolonged abusers, amphetamine withdrawal-induced depressive symptoms are common; however, their pathophysiological mechanism is not fully understood. Previously, we found that repeated treatment with amphetamine for 2 weeks induced oxidative stress in rat brain. OBJECTIVES: The purpose of the current study is to analyze whether abstinence from repeated amphetamine treatment in rats induces depressive-like behaviors and if oxidative damage in the brain continues during abstinence. METHODS: Rats were given repeated treatment with amphetamine once daily at 1, 2, or 4 mg/kg for 14 days. From 10 to 14 days after final amphetamine treatment, behavioral changes were monitored using open field test, novel object recognition test, and forced swim test. Oxidative damage in the medial frontal cortex and hippocampus was analyzed by immunohistochemistry. RESULTS: We found that drug abstinence after repeated amphetamine stimulation decreased locomotor activity and exploratory behavior in the open field test, increased immobility in the forced swim test, and had no significant effect on the recognition index in the novel object recognition test. We also found that amphetamine abstinence increased levels of 4-hydroxynonenal-protein adducts and 8-hydroxyguanosine in rat medial frontal cortex and in CA3 and dentate gyrus regions of the hippocampus. CONCLUSIONS: These results suggest that amphetamine abstinence displays depressive-like behaviors in rats and induces oxidative damage to lipids and RNA in rat brain. Our findings indicate that the process of oxidative stress may play a role in pathophysiological changes during drug abstinence from repeated amphetamine stimulation. 23931992 The need for research maps to navigate published work and inform experiment planning. The increasing volume, complexity, and interconnectedness of published studies in neuroscience make it difficult to determine what is known, what is uncertain, and how to contribute effectively to one's field. There is a pressing need to develop automated strategies to help researchers navigate the vastness of the published record. Simplified, interactive, and unbiased representations of previous findings (i.e., research maps) would be invaluable in preparing research surveys, in guiding experiment planning, and in evaluating research plans and contributions. Principles normally used in weighing research findings, including reproducibility and convergence, could be automated and incorporated into research maps. Here, we discuss a series of recent advances that are bringing us closer than ever to being able to derive systematic, comprehensive, but also interactive and user-friendly research maps. These maps could revolutionize the way we review the literature, plan experiments, and fund and publish science. 23543629 Pharmacokinetic characterization of CK2 inhibitor CX-4945. Over-expression of protein kinase CK2 is highly linked to the survival of cancer cells and the poor prognosis of patients with cancers. CX-4945, a potent and selective orally bioavailable ATP-competitive inhibitor of CK2, inhibits the oncogenic cellular events such as proliferation and angiogenesis, and the increase of tumor growth in mouse xenograft model. In this study, the pharmacokinetic information about CX-4945 was provided; at 10 μM, CX-4945 with high stability in human and rat liver microsome exhibited low percentage of inhibition (<10 %) in CYP450 isoforms (1A2, 2C19, 3A4), but considerable inhibition (~70 %) in CYP450 2C9 and 2D6. In hERG potassium channel inhibition assay, CX-4945 exhibited relatively low inhibition rate. Additionally, CX-4945 showed high MDCK cell permeability (>10 × 10(-6) cm/s) and above 98 % of plasma protein binding in the rat. After intravenous administration, Vss (1.39 l/kg) and extremely low CL (0.08 l/kg/h) were observed. Moreover, orally administrated CX-4945 showed high bioavailability (>70 %) and these data might be related to the MDCK cell permeability results. 23676527 Assessment of the Risk of Ischemic Heart Disease and its Relevant Factors among Japanese Police Officers. Objectives: Compared to other public employees, police officers have higher absence rates due to heart diseases, and ischemic heart disease (IHD) is one of the most frequent causes of death in their occupational life. The aim of this study was to investigate the prevalence of the risk factors for IHD among police officers and to examine its association with working conditions and lifestyles. Methods: First, 58 male police officers who developed IHD from 1996 to 2011 and 116 age- and rank-matched controls who were free from cerebro- and cardiovascular diseases were compared with respect to the prevalence of traditional risk factors five years before the onset of IHD. Then, the prevalence of IHD risk factors, and the frequency of metabolic syndrome (MetS) by age group, working condition and lifestyle were investigated in a cross-sectional survey of data of 1,539 male police officers and 153 male office workers in a prefectural police force. Results: In the case control study, the IHD cases had significantly higher prevalences of hypertension (p<0.001), hyper-LDL-cholesterolemia (p<0.05), glucose intolerance (p<0.05), and hyperuricemia (p<0.05) before the onset of IHD. Multiple logistic regression analysis revealed that hypertension (odds ratio [95% confidence interval] : 3.96 [1.82-8.59]), glucose intolerance (3.28 [1.34-8.03]), hypo-HDL-cholesterolemia (2.26 [1.03-4.97]), and hyper-LDL-cholesterolemia (2.18 [1.03-4.61]) were independently associated with the development of IHD (model chi-square, p<0.001; correct classification rate, 77.0%). In the cross sectional analyses, among the police officers, abdominal obesity (waist circumference of ≥85 cm) was significantly more frequent (57.3% vs. 35.3%, p<0.001) and the prevalence of dyslipidemia and glucose intolerance increased with age more remarkably than in the general office workers. In the age-group of 45-59 years, the clustering number of risk factors in individuals (1.8 vs. 1.4, p<0.01) and the frequency of MetS (25.0 vs. 15.5, p<0.1) were greater in the police officers than the office workers. Among the police officers, subjects with MetS had significantly higher rates of shift work (33.6% vs. 25.4%, p<0.01), lack of sound sleep (42.5% vs. 33.7%, p<0.01), and heavy drinking (12.8 vs. 6.3%, p<0.01) than those without MetS. Conclusions: In this study, the development of IHD in police officers was significantly associated with traditional risk factors, especially with hypertension, dyslipidemia and glucose intolerance. The increase with age of the prevalence of IHD risk factors and the frequency of MetS were greater in police officers than office workers. Irregular working conditions, such as shift work, long working time, and unfavorable lifestyles, e.g. alcohol drinking and poor sleeping conditions, may influence the higher prevalence of risk factors for IHD in police officers. 23224831 Molecular cloning of vasa gene and the effects of LHRH-A on its expression in blue tilapia Oreochromis aureus. The full length of vasa cDNA in blue tilapia Oreochromis aureus was cloned and sequenced using reverse transcription-polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE). Nucleotide sequence analysis revealed that the cDNA contained 2,143 bp and was consisted of a 48-bp 5' untranslated terminal region (5'-UTR), a 157-bp 3' untranslated terminal region (3'-UTR) and a 1,938-bp open reading frame (ORF) which encoded 645 amino acids. Homological protein analysis showed that vasa in O. aureus was highly conserved with Nile tilapia Oreochromis niloticus. Tissue distribution expression analysis indicated that vasa was specifically expressed in the gonads. Using in situ hybridization, we found that vasa was expressed in spermatogonia and spermatocytes rather than spermatids and sperm. In order to examine the influence of luteinizing hormone releasing hormone analog (LHRH-A) on vasa, the in vivo injections were performed different concentrations of LHRH-A. Our results showed that LHRH-A induced meiosis and down-regulated vasa mRNA expression. In summary, our results showed that vasa was specifically expressed in gonads and LHRH-A inhibited vasa expression in the testis. Our results also suggested that LHRH-A could regulate vasa gene expression in O. aureus testis. 23676419 Prevalence and risk factors of extrapancreatic malignancies in a large cohort of patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas. The objectives of this study are to estimate prevalence and incidence of extrapancreatic malignancies (EPMs) among intraductal papillary mucinous neoplasms (IPMNs) of the pancreas, and to identify risk factors for their occurrence. We conducted multicentric cohort study in Italy from January 2010 to January 2011 including 390 IPMN cases. EPMs were grouped as previous, synchronous (both prevalent) and metachronous (incident). We calculated the observed/expected (O/E) ratio of prevalent EPMs, and compared the distribution of demographic, medical history and lifestyle habits. Ninety-seven EPMs were diagnosed in 92 patients (23.6%), among them 78 (80.4%) were previous, 14 (14.4%) were synchronous and 5 (5.2%) were metachronous. O/E ratios for prevalent EPMs were significantly increased for colorectal carcinoma (2.26; CI 95% 1.17-3.96), renal cell carcinoma (6.00; CI 95% 2.74-11.39) and thyroid carcinoma (5.56; CI 95% 1.80-12.96). Increased age, heavy cigarette smoking, alcohol consumption and first-degree family history of gastric cancer are significant risk factors for EPMs, while first-degree family history of colorectal carcinoma was borderline. We report an increased prevalence of EPMs in Italian patients with IPMN, especially for colorectal carcinoma, renal cell and thyroid cancers. A systematic surveillance of IPMN cases for such cancer types would be advised. 23670974 Interleukin-18 Activates Skeletal Muscle AMPK and Reduces Weight Gain and Insulin Resistance in Mice. Circulating interleukin (IL)-18 is elevated in obesity, but paradoxically causes hypophagia. We hypothesized that IL-18 may attenuate high-fat diet (HFD)-induced insulin resistance by activating AMP-activated protein kinase (AMPK). We studied mice with a global deletion of the α-isoform of the IL-18 receptor (IL-18R(-/-)) fed a standard chow or HFD. We next performed gain-of-function experiments in skeletal muscle, in vitro, ex vivo, and in vivo. We show that IL-18 is implicated in metabolic homeostasis, inflammation, and insulin resistance via mechanisms involving the activation of AMPK in skeletal muscle. IL-18R(-/-) mice display increased weight gain, ectopic lipid deposition, inflammation, and reduced AMPK signaling in skeletal muscle. Treating myotubes or skeletal muscle strips with IL-18 activated AMPK and increased fat oxidation. Moreover, in vivo electroporation of IL-18 into skeletal muscle activated AMPK and concomitantly inhibited HFD-induced weight gain. In summary, IL-18 enhances AMPK signaling and lipid oxidation in skeletal muscle implicating IL-18 in metabolic homeostasis. 23373754 How the quantum efficiency of a highly emissive binuclear copper complex is enhanced by changing the processing solvent. Polymorphism is often linked to the choice of processing solvents. Packing effects or the preference of one certain conformer as possible causes of this phenomenon are strongly dependent on solvents and especially on their polarity. Even in amorphous solids, the microstructure can be controlled by the choice of solvents. Polymorphs or amorphous solids featuring different packing densities can exhibit different properties in terms of stability or optical effects. The influence of these effects on a binuclear, strongly luminescent copper(I) complex was investigated. Many possible applications for luminescent, amorphous coordination compounds, such as organic light-emitting diodes, sensors, and organic lasers, rely on photophysical properties like quantum efficiency to be repeatable. The effect of processing solvents in this context is often underestimated, but very relevant for utilization in device manufacturing and should therefore be understood more deeply. In this work, theoretical derivations, DFT calculations, X-ray-diffraction, photoluminescence spectroscopy, and the time-dependent single-photon-counting-technique (TDSPC) were used to understand this phenomenon more deeply. The influence of five different solvents on Cu2I2(MePyrPHOS)3 was probed. This resulted in a modulation of the photoluminescence quantum yield ϕ between 0.5 and 0.9 in amorphous solid state. A new polymorph of the material with slightly reduced values for ϕ has been identified. The reduced efficiency could be correlated with a higher porosity and a reduced packing density. Dense packing reduces nonradiative decay by geometrical fixation and thus increases the quantum efficiency. The existence of similar effects on aluminum and iridium compounds has been confirmed by application of different processing solvents on Alq3 and Ir(ppy)3. These results show that a tuning of the efficiency of a emissive metal complexes by choosing a proper processing solvent is possible. If highly efficient materials for practical applications are desired, an evaluation of multiple solvents has to be considered. 23335627 Hypoxia stress test reveals exaggerated cardiovascular effects in hypertensive rats after exposure to the air pollutant acrolein. Exposure to air pollution increases the risk of cardiovascular morbidity and mortality, especially in susceptible populations. Despite increased risk, adverse responses are often delayed and require additional stress tests to reveal latent effects of exposure. The goal of this study was to use an episode of "transient hypoxia" as an extrinsic stressor to uncover latent susceptibility to environmental pollutants in a rodent model of hypertension. We hypothesized that exposure to acrolein, an unsaturated aldehyde and mucosal irritant found in cigarette smoke, diesel exhaust, and power plant emissions, would increase cardiopulmonary sensitivity to hypoxia, particularly in hypertensive rats. Spontaneously hypertensive and Wistar Kyoto (normotensive) rats, implanted with radiotelemeters, were exposed once for 3h to 3 ppm acrolein gas or filtered air in whole-body plethysmograph chambers and challenged with a 10% oxygen atmosphere (10min) 24h later. Acrolein exposure increased heart rate, blood pressure, breathing frequency, and minute volume in hypertensive rats and also increased the heart rate variability parameter LF, suggesting a potential role for increased sympathetic tone. Normotensive rats only had increased blood pressure during acrolein exposure. The hypoxia stress test after acrolein exposure revealed increased diastolic blood pressure only in hypertensive rats and increased minute volume and expiratory time only in normotensive rats. These results suggest that hypertension confers exaggerated sensitivity to air pollution and that the hypoxia stress test is a novel tool to reveal the potential latent effects of air pollution exposure. 23925897 Dipyridyl immobilized ionic liquid-type hybrid-silica monolith for hydrophilic interaction electrochromatography. A pyridinium-based immobilized ionic liquid-type multifunctional hybrid-silica monolith was prepared by the in-situ polymerization of 3-chloropropyl-silica matrix and 4, 4'-dipyridyl for hydrophilic interaction capillary electrochromatography (HI-CEC). The obtained hybrid monolith possessed of high stable skeletal microstructures with obviously hydrophilic retention mechanism under acetonitrile content more than 50% in the mobile phase. Strong and stable anodic electroosmotic flow (EOF) could be observed under a broad pH range from pH 3.0 to 9.0. Due to the immobilized dipyridyl groups bonded to the silica matrix surface, the resulting hydrophilic hybrid monolith possessed multiple separation interactions including hydrogen bond, π-π and anion-exchange. Excellent separations of various polar analytes including electro-neutral phenols, charged acid nucleotides and basic analytes were successfully achieved. The highest column efficiencies up to 120 000, 164 000 and 106 000 plates/m were obtained for nucleotides, nucleic acid bases and nucleosides and nicotines, respectively. These results demonstrated that the dipyridyl immobilized ionic liquid functionalized hybrid monolith possessed highly mechanical stability and good chromatographic performance for hydrophilic interaction electrochromatography. This article is protected by copyright. All rights reserved. 23584544 Antibacterial oxazolidinone analogues having a N-hydroxyacetyl-substituted seven-membered [1,2,5]triazepane or [1,2,5]oxadiazepane C-ring unit. We synthesized a series of oxazolidinone analogues bearing a N-hydroxyacetyl-substituted [1,2,5]triazepane or [1,2,5]oxadiazepane C-ring unit as homologues of an earlier drug candidate, eperezolid. Several of these compounds exhibited potent in vitro antibacterial activities towards not only Gram-positive, but also Gram-negative and linezolid-resistant pathogens. Compounds 21a and 21b, bearing a thiocarbamate side chain, showed high in vivo activity against methicillin-resistant Staphylococcus aureus SR3637, together with a promising safety profile in terms of weak inhibition of monoamine oxidase and cytochrome P450 isozymes. 23827987 Tobacco smoke exposure and endothelial dysfunction in patients with advanced coronary artery disease. INTRODUCTION Exposure to tobacco smoke is associated with a higher cardiovascular risk, especially in patients with coronary artery disease (CAD).  OBJECTIVES The aim of the study was to evaluate whether active or passive tobacco smoking might affect endothelial dysfunction markers in advanced atherosclerosis. PATIENTS AND METHODS We studied 181 consecutive patients with advanced CAD (53 women and 128 men) aged 60±8 years, including 102 (56.3%) active self-declared smokers. Plasma asymmetric dimethylarginine (ADMA), thrombomodulin (TM) and plasminogen activator inhibitor-1 (PAI-1), combined with serum cotinine concentrations, a marker of tobacco smoking were determined. RESULTS Plasma ADMA was higher in active smokers compared to nonsmokers (0.60 ±0.09 vs 0.49±0.08 μmol/l , p<0.001). There were similar intergroup differences in TM (4.60±2.11 vs 3.0±1.7 ng/ml, p<0.0001) and PAI-1 (30.3±12.4 vs 23.6±11.3 ng/ml, p<0.0001). Positive correlations between cotinine and ADMA (r= 0.71, p<0.0001), TM (r=0.53, p<0.0001) and PAI-1 (r=0.58, p<0.0001) were observed. In 21 (26.6%) patients who declared to be nonsmokers cotinine (mean 6.30±22.5 ng/ml) significantly correlated with ADMA, TM and PAI-1 (all p<0.001). Multivariate regression analysis showed that cotinine is the independent predictor of ADMA, TM and PAI-1 in the whole patient group. CONCLUSION Despite long-lasting endothelial injury in advanced CAD, continued cigarette smoking is still able to enhance endothelial damage via elevated ADMA associated increased inhibition of fibrinolysis. 23702091 Airway and parenchymal manifestations of pulmonary aspergillosis. Pulmonary aspergillosis encompasses a heterogeneous group of mycoses that result from either colonisation or pathogenic damage of lung tissue by Aspergillus fungi. These clinical entities range from relatively benign saprophytic hypersensitivity associated with fungal inhabitation to life threatening invasive disease. The diagnosis of pulmonary disorders related to Aspergillus is on the increase and it is more important than ever those both general and respiratory physicians have a good understanding of these disorders. This paper reviews the contemporary understanding of the clinical, radiographic and histopathological aspects of pulmonary aspergillosis. 23950205 A qualitative study comparing experiences of the surgical safety checklist in hospitals in high-income and low-income countries. Bold claims have been made for the ability of the WHO surgical checklist to reduce surgical morbidity and mortality and improve patient safety regardless of the setting. Little is known about how far the challenges faced by low-income countries are the same as those in high-income countries or different. We aimed to identify and compare the influences on checklist implementation and compliance in the UK and Africa. Ethnographic study involving observations, interviews and collection of documents. Thematic analysis of the data. Operating theatres in one African university hospital and two UK university hospitals. 112 h of observations were undertaken. Interviews with 39 theatre and administrative staff were conducted. Many staff saw value in the checklist in the UK and African hospitals. Some resentment was present in all settings, linked to conflicts between the philosophy behind the checklist and the realities of local cultural, social and economic contexts. Compliance-involving use, completeness and fidelity-was considerably higher, though not perfect, in the UK settings. In these hospitals, compliance was supported by established structures and systems, and was not significantly undermined by major resource constraints; the same was not true of the low-income context. Hierarchical relationships were a major barrier to implementation in all settings, but were more marked in the low-income setting. Introducing a checklist in a professional environment characterised by a lack of accountability and transparency could make the staff feel jeopardised legally, professionally, and personally, and it encouraged them to make misleading records of what had actually been done. Surgical checklist implementation is likely to be optimised, regardless of the setting, when used as a tool in multifaceted cultural and organisational programmes to strengthen patient safety. It cannot be assumed that the introduction of a checklist will automatically lead to improved communication and clinical processes. 23389819 Soy isoflavone intake and breast cancer risk in Japan: from the Takayama study. The effects of soy or isoflavone intake on breast cancer need to be examined further in epidemiologic studies. We assessed the associations of soy and isoflavone intake with breast cancer incidence in a population-based prospective cohort study in Japan. Participants were members from the Takayama study, aged 35 years or older in 1992. The follow-up was conducted from the time of the baseline study (September 1, 1992) to the end of March 2008. Cancer incidence was mainly confirmed through regional population-based cancer registries. Breast cancer was defined as code C50 according to ICD-10. Soy and isoflavone intakes were assessed with a validated food frequency questionnaire. Using the Cox proportional hazard models, the association of soy and isoflavone intake with breast cancer was assessed after adjustments for age, body mass index, physical activity, smoking, alcohol consumption, education, age at menarche, age at first delivery, menopausal status, number of children and history of hormone replacement therapy. Among the 15,607 women analyzed, 172 had developed breast cancer. The relative risks of postmenopausal breast cancer were lower among women with higher intakes of soy (trend p = 0.023) and isoflavone (trend p = 0.046), although the relative risks of premenopausal breast cancer were not associated with intakes of soy and isoflavone. Decreased risks of breast cancer were found even among women with a moderate intake of soy and isoflavone. These results suggested that soy and isoflavone intakes have a protective effect on postmenopausal breast cancer. 23876388 Perception of conversations: The importance of semantics and intonation in children's development. In conversations, adults readily detect and anticipate the end of a speaker's turn. However, little is known about the development of this ability. We addressed two important aspects involved in the perception of conversational turn taking: semantic content and intonational form. The influence of semantics was investigated by testing prelinguistic and linguistic children. The influence of intonation was tested by presenting participants with videos of two dyadic conversations: one with normal intonation and one with flattened (removed) intonation. Children of four different age groups-two prelinguistic groups (6- and 12-month-olds) and two linguistic groups (24- and 36-month-olds)-and an adult group participated. Their eye movements were recorded, and the frequency of anticipated turns was analyzed. Our results show that (a) the anticipation of turns was reliable only in 3-year-olds and adults, with younger children shifting their gaze between speakers regardless of the turn taking, and (b) only 3-year-olds anticipated turns better if intonation was normal. These results indicate that children anticipate turns in conversations in a manner comparable (but not identical) to adults only after they have developed a sophisticated understanding of language. In contrast to adults, 3-year-olds rely more strongly on prosodic information during the perception of conversational turn taking. 23265477 Biochemical characterisation of Alaska pollock, Pacific whiting, and threadfin bream surimi as affected by comminution conditions. Salt-soluble protein, surface reactive sulfhydryl content, and surface hydrophobicity of Alaska pollock, Pacific whiting, and threadfin bream surimi were characterised, as affected by various comminution conditions. Chopping time/temperatures were explored in consideration of their habitat temperatures. Salt-soluble protein (SSP) significantly decreased when chopping time was extended. Corresponding to our follow-up study, no relationship between SSP and gel texture was found. Surface hydrophobicity was inversely proportional to SSP concentration, indicating the unfolding of protein upon comminution. Alaska pollock surimi demonstrated aggregation during chopping at 10 and 20 °C, based on the surface hydrophobicity. Surface reactive sulfhydryl (SRSH) contents of the three fish species behaved differently. The SH groups were oxidized to disulphide bonds when higher chopping temperature was applied. As a result, increased SRSH content was not observed in Alaska pollock (10 and 20 °C chopping) and threadfin bream paste (25 and 30 °C chopping). 23664294 Impact of age on long-term outcome after primary angioplasty with bare-metal or drug-eluting stent (from the DESERT cooperation). Despite mechanical reperfusion, elderly patients with ST-segment elevation myocardial infarction (STEMI) still experience unsatisfactory outcomes. Drug-eluting stents (DES) have significantly reduced target-vessel revascularization (TVR), but concerns have emerged about the higher risk of late stent thrombosis, which may be more pronounced in elderly patients. Therefore, the aim of this study was to evaluate the impact of age on outcome in patients with STEMI who underwent primary angioplasty with bare-metal stents (BMS) or DES. Our population comprised 6,298 patients who underwent primary angioplasty and stent implantation included in the Drug-Eluting Stent in Primary Angioplasty (DESERT) Cooperation database. Age was significantly associated with female gender (p <0.001), diabetes (p <0.001), hypertension (p <0.001), previous myocardial infarction (MI; p <0.001), ischemia time (p <0.001), and anterior MI (p <0.001) but inversely related to smoking (p <0.001). Elderly patients most often had infarct-related artery located in the descending artery (p = 0.014) and impaired postprocedural thrombolysis in myocardial infarction flow (p <0.001). Elderly patients were less often on clopidogrel at follow-up. At long-term follow-up, age was associated with a higher rate of death (hazard ratio [95% confidence interval] = 2.17 [1.97 to 2.39], p <0.0001), whereas no impact was observed on reinfarction (p = 0.36), stent thrombosis (p = 0.84), and TVR (p = 0.54). These results were confirmed in patients receiving both BMS and DES. The impact of age on mortality was confirmed after correction for baseline confounding factors (gender, diabetes hypertension, hypercholesterolemia, smoking, ischemia time, anterior MI, infarct-related artery location, and postprocedural thrombolysis in myocardial infarction 3 flow; adjusted hazard ratio [95% confidence interval] = 2.13 [1.78 to 2.56], p <0.001). In conclusion, this study shows that in patients with STEMI who underwent primary angioplasty, age is independently associated with higher mortality, observed with both BMS and DES, whereas no impact was observed on the rate of reinfarction, stent thrombosis, and TVR. 23883936 Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease. Late-onset Alzheimer's disease (LOAD) risk is strongly influenced by genetic factors such as the presence of the apolipoprotein E ε4 allele (referred to here as APOE4), as well as non-genetic determinants including ageing. To pursue mechanisms by which these affect human brain physiology and modify LOAD risk, we initially analysed whole-transcriptome cerebral cortex gene expression data in unaffected APOE4 carriers and LOAD patients. APOE4 carrier status was associated with a consistent transcriptomic shift that broadly resembled the LOAD profile. Differential co-expression correlation network analysis of the APOE4 and LOAD transcriptomic changes identified a set of candidate core regulatory mediators. Several of these--including APBA2, FYN, RNF219 and SV2A--encode known or novel modulators of LOAD associated amyloid beta A4 precursor protein (APP) endocytosis and metabolism. Furthermore, a genetic variant within RNF219 was found to affect amyloid deposition in human brain and LOAD age-of-onset. These data implicate an APOE4 associated molecular pathway that promotes LOAD. 23815613 Glucosamine-Induced Reduction of Integrin β4 and Plectin Complex Stimulates Migration and Proliferation in Mouse Embryonic Stem Cells. We investigated the role of glucosamine (GlcN) on the integrin β4/plectin complex and its role in the regulation of mouse embryonic stem cell (mESC) migration and proliferation. GlcN significantly decreased integrin β4 mRNA/protein expression, whereas plectin protein expression did not change. Also, decrease of integrin β4 expression caused reduction of integrin β4/plectin complex formation, and then increased cell migration. GlcN increased intracellular calcium influx and protein kinase C (PKC) phosphorylation followed by integrin β4 serine phosphorylation and reduction of the integrin β4/plectin complex. GlcN entered into the cell through glucose transporter 1 and then increased O-GlcNAc transferase (OGT) and the level of glycosylation (CTD110.6). Inhibition of OGT (OGT inhibitor; ST045849) increased integrin β4/plectin complex opposite with decreased cell migration. Moreover, GlcN increased O-GlcNAc-specificity protein 1 (Sp1) and nuclear translocated p-Sp1 stimulated calmodulin (CaM) expression, which combined with plectin. In addition, GlcN increased Akt glycosylation and glycogen synthase kinase-3β (GSK-3β) phosphorylation, and then Snail1 glycosylation. Snail small interfering ribonucleic acid (siRNA) reversed the reduction of integrin β4/plectin complex and dissociation of cell junctions (tight and adherent junction). GlcN increased cell migration, cell cycle regulatory proteins [cyclinD1, cyclin-dependent kinase 4 (CDK4), cyclinE, and CDK2], and the percentage of S phase cells, which were inhibited by a PKC inhibitor, CaM siRNA, or Snail1 siRNA. Additionally, GlcN maintained the undifferentiation status of ESCs. In conclusion, GlcN contributed to migration and proliferation of mESCs through integrin β4/plectin complex reduction via Ca(2+)/PKC, as well as the Sp1/CaM and Akt/GSK-3β/Snail1 signaling pathway. 23010566 Iodinated nano-emulsions as contrast agents for preclinical X-ray imaging: Impact of the free surfactants on the pharmacokinetics. This study presents new important aspects in the design of contrast agents for X-ray preclinical imaging. The first one is a new simple formulation of long circulating contrast agents, formulated from a commercial iodinated oil, and resulting in CT contrast agents containing more than twice the iodine concentration commercial contrast agents. The second point is a methodological aspect, utilizing tangential filtration for reducing the residual surfactants in the bulk phase and serving as well for concentrating droplets (and iodine) in the suspension. The last point is a more general aspect regarding the influence of the free surfactant on the pharmacokinetics and biodistribution of the nano-emulsion droplets on mice. We showed that cross-flow filtration is efficient for concentrating the droplets and reducing the concentration of free surfactant from 10wt.% to 1wt.%, without any changes in the nano-emulsion droplet morphologies or surface properties. We also showed that the presence of free surfactant has a significant impact on the elimination way of the nano-emulsion droplets, shared between liver and kidneys. The purified nano-emulsions are preferentially eliminated by the kidneys in contrast to raw nano-emulsions, predominantly eliminated by the liver. In practice, for two similar suspensions, half-life decreases from 4.1±1.10h to 2.5±0.77h before and after purification. Since the design and development of long circulating systems are critical in numerous domains, and not for preclinical CT imaging, this study presents important results in that field, taken under a formulation and technical point of view. 23859634 Direct Arylation of Oligonaphthalenes Using PIFA/BF3·Et2O: From Double Arylation to Larger Oligoarene Products. Direct dehydrogenative coupling between the linear ter- and quaternaphthalenes and substituted benzenes was achieved under the Kita conditions using the hypervalent PIFA/BF3 reagent. Products resulting from either the double arylation of the naphthalenic substrate or the formal dimerizative arylation have been prepared. For example, in the latter mode, ternaphthalene was converted into a series of linear octiarenes (counting the capping Ar). The process represents an alternative to the cross-coupling methodologies employed in related syntheses and proceeds via a selective functionalization of six relatively inert aromatic CH bonds. 23795643 Serving the new masters - dendritic cells as hosts for stealth intracellular bacteria. Dendritic cells (DCs) serve as the primers of adaptive immunity, which is indispensable for the control of the majority of infections. Interestingly, some pathogenic intracellular bacteria can subvert DC function and gain the advantage of an ineffective host immune reaction. This scenario appears to be the case particularly with so-called stealth pathogens, which are the causative agents of several under-diagnosed chronic diseases. However, there is no consensus how less explored stealth bacteria like Coxiella, Brucella and Francisella cross-talk with DCs. Therefore, the aim of this review was to explore the issue and to summarize the current knowledge regarding the interaction of above mentioned pathogens with DCs as crucial hosts from an infection strategy view. Evidence indicates that infected DCs are not sufficiently activated, do not undergo maturation and do not produce expected proinflammatory cytokines. In some cases, the infected DCs even display immunosuppressive behaviour that may be directly linked to the induction of tolerogenicity favouring pathogen survival and persistence. 23619605 Nasal dosimetry of inspired naphthalene vapor in the male and female B6C3F1 mouse. Naphthalene vapor is a nasal cytotoxicant in the rat and mouse but is a nasal carcinogen in only the rat. Inhalation dosimetry is a critical aspect of the inhalation toxicology of inspired vapors and may contribute to the species differences in the nasal response. To define the nasal dosimetry of naphthalene in the B6C3F1 male and female mouse, uptake of naphthalene vapor was measured in the surgically isolated upper respiratory tract (URT) at inspiratory flow rates of 25 or 50ml/min. Uptake was measured at multiple concentrations (0.5, 3, 10, 30ppm) in controls and mice treated with the cytochrome P450 inhibitor 5-phenyl-1-pentyne. In both sexes, URT uptake efficiency was strongly concentration dependent averaging 90% at 0.5ppm compared to 50% at 30ppm (25ml/min flow rate), indicating saturable processes were involved. Both uptake efficiency and the concentration dependence of uptake were significantly diminished by 5-phenyl-1-pentyne indicating inspired naphthalene vapor is extensively metabolized in the mouse nose with saturation of metabolism occurring at the higher concentrations. A hybrid computational fluid dynamic physiologically based pharmacokinetic model was developed for nasal dosimetry. This model accurately predicted the observed URT uptake efficiencies. Overall, the high URT uptake efficiency of naphthalene in the mouse nose indicates the absence of a tumorigenic response is not attributable to low delivered dose rates in this species. 23959593 Allele frequency distribution of 1691G>A F5 (which confers Factor V Leiden) across Europe, including Slavic populations. The allele 1691A F5, conferring Factor V Leiden, is a common risk factor in venous thromboembolism. The frequency distribution for this allele in Western Europe has been well documented; but here data from Central, Eastern and South-Eastern Europe has been included. In order to assess the significance of the collated data, a chi-squared test was applied, and Tukey tests and z-tests with Bonferroni correction were compared. Results: A distribution with a North-Southeast band of high frequency of the 1691A F5 allele was discovered with a pocket including some Southern Slavic populations with low frequency. European countries/regions can be arbitrarily delimited into low (group 1, <2.8 %, mean 1.9 % 1691A F5 allele) or high (group 2, ≥2.8 %, mean 4.0 %) frequency groups, with many significant differences between groups, but only one intra-group difference (the Tukey test is suggested to be superior to the z-tests). Conclusion: In Europe a North-Southeast band of 1691A F5 high frequency has been found, clarified by inclusion of data from Central, Eastern and South-Eastern Europe, which surrounds a pocket of low frequency in the Balkans which could possibly be explained by Slavic migration. There seem to be no indications of variation in environmental selection due to geographical location. 23396042 Molecular dissection of botulinum neurotoxin reveals interdomain chaperone function. Clostridium botulinum neurotoxin (BoNT) is a multi-domain protein made up of the approximately 100 kDa heavy chain (HC) and the approximately 50 kDa light chain (LC). The HC can be further subdivided into two halves: the N-terminal translocation domain (TD) and the C-terminal Receptor Binding Domain (RBD). We have investigated the minimal requirements for channel activity and LC translocation. We utilize a cellular protection assay and a single channel/single molecule LC translocation assay to characterize in real time the channel and chaperone activities of BoNT/A truncation constructs in Neuro 2A cells. The unstructured, elongated belt region of the TD is demonstrated to be dispensable for channel activity, although may be required for productive LC translocation. We show that the RBD is not necessary for channel activity or LC translocation, however it dictates the pH threshold of channel insertion into the membrane. These findings indicate that each domain functions as a chaperone for the others in addition to their individual functions, working in concert to achieve productive intoxication. 23922723 Land suitability assessment on a watershed of loess plateau using the analytic hierarchy process. In order to reduce soil erosion and desertification, the Sloping Land Conversion Program has been conducted in China for more than 15 years, and large areas of farmland have been converted to forest and grassland. However, this large-scale vegetation-restoration project has faced some key problems (e.g. soil drying) that have limited the successful development of the current ecological-recovery policy. Therefore, it is necessary to know about the land use, vegetation, and soil, and their inter-relationships in order to identify the suitability of vegetation restoration. This study was conducted at the watershed level in the ecologically vulnerable region of the Loess Plateau, to evaluate the land suitability using the analytic hierarchy process (AHP). The results showed that (1) the area unsuitable for crops accounted for 73.3% of the watershed, and the main factors restricting cropland development were soil physical properties and soil nutrients; (2) the area suitable for grassland was about 86.7% of the watershed, with the remaining 13.3% being unsuitable; (3) an area of 3.95 km(2), accounting for 66.7% of the watershed, was unsuitable for forest. Overall, the grassland was found to be the most suitable land-use to support the aims of the Sloping Land Conversion Program in the Liudaogou watershed. Under the constraints of soil water shortage and nutrient deficits, crops and forests were considered to be inappropriate land uses in the study area, especially on sloping land. When selecting species for re-vegetation, non-native grass species with high water requirements should be avoided so as to guarantee the sustainable development of grassland and effective ecological functioning. Our study provides local land managers and farmers with valuable information about the inappropriateness of growing trees in the study area along with some information on species selection for planting in the semi-arid area of the Loess Plateau. 23695504 Cell Wall Pectic Arabinans Influence the Mechanical Properties of Arabidopsis thaliana Inflorescence Stems and Their Response to Mechanical Stress. Little is known of the dynamics of plant cell wall matrix polysaccharides in response to the impact of mechanical stress on plant organs. The capacity of the imposition of a mechanical stress (periodic brushing) to reduce the height of the inflorescence stem of Arabidopsis thaliana seedlings has been used to study the role of pectic arabinans in the mechanical properties and stress responsiveness of a plant organ. The arabinan-deficient-1 (arad1) mutation that affects arabinan structures in epidermal cell walls of inflorescence stems is demonstrated to reduce the impact on inflorescence stem heights caused by mechanical stress. The arabinan-deficient-2 (arad2) mutation, that does not have detectable impact on arabinan structures, is also shown to reduce the impact on stem heights caused by mechanical stress. The LM13 linear arabinan epitope is specifically detected in epidermal cell walls of the younger, flexible regions of inflorescence stems and increases in abundance at the base of inflorescence stems in response to an imposed mechanical stress. The strain (percentage deformation) of stem epidermal cells in the double mutant arad1 × arad2 is lower in unbrushed plants than in wild-type plants, but rises to wild-type levels in response to brushing. The study demonstrates the complexity of arabinan structures within plant cell walls and also that their contribution to cell wall mechanical properties is a factor influencing responsiveness to mechanical stress. 23916752 Assessment of rhythmic entrainment at multiple timescales in dyslexia: Evidence for disruption to syllable timing. Developmental dyslexia is associated with rhythmic difficulties, including impaired perception of beat patterns in music and prosodic stress patterns in speech. Spoken prosodic rhythm is cued by slow (<10 Hz) fluctuations in speech signal amplitude. Impaired neural oscillatory tracking of these slow amplitude modulation (AM) patterns is one plausible source of impaired rhythm tracking in dyslexia. Here, we characterise the temporal profile of the dyslexic rhythm deficit by examining rhythmic entrainment at multiple speech timescales. Adult dyslexic participants completed two experiments aimed at testing the perception and production of speech rhythm. In the perception task, participants tapped along to the beat of 4 metrically-regular nursery rhyme sentences. In the production task, participants produced the same 4 sentences in time to a metronome beat. Rhythmic entrainment was assessed using both traditional rhythmic indices and a novel AM-based measure, which utilised 3 dominant AM timescales in the speech signal each associated with a different phonological grain-sized unit (0.9-2.5 Hz, prosodic stress; 2.5-12 Hz, syllables; 12-40 Hz, phonemes). The AM-based measure revealed atypical rhythmic entrainment by dyslexic participants to syllable patterns in speech, in perception and production. In the perception task, both groups showed equally strong phase-locking to Syllable AM patterns, but dyslexic responses were entrained to a significantly earlier oscillatory phase angle than controls. In the production task, dyslexic utterances showed shorter syllable intervals, and differences in Syllable:Phoneme AM cross-frequency synchronisation. Our data support the view that rhythmic entrainment at slow (∼5 Hz, Syllable) rates is atypical in dyslexia, suggesting that neural mechanisms for syllable perception and production may also be atypical. These syllable timing deficits could contribute to the atypical development of phonological representations for spoken words, the central cognitive characteristic of developmental dyslexia across languages. This article is part of a Special Issue entitled . 23809874 Six minute walk test in type III spinal muscular atrophy: A 12month longitudinal study. The aim of our longitudinal multicentric study was to establish the changes on the 6min walk test (6MWT) in ambulant SMA type III children and adults over a 12month period. Thirty-eight ambulant type III patients performed the 6MWT at baseline and 12months after baseline. The distance covered in 6min ranged between 75 and 510m (mean 294.91, SD 127) at baseline and between 50 and 611m (mean 293.41m, SD 141) at 12months. The mean change in distance between baseline and 12months was -1.46 (SD 50.1; range: -183 to 131.8m). The changes were not correlated with age or baseline values (p>.05) even though younger patients reaching puberty, had a relatively higher risk of showing deterioration of more than 30m compared to older patients. Our findings provide the first longitudinal data using the 6MWT in ambulant SMA patients. 23416039 Effects of lurasidone in behavioral models of depression. Role of the 5-HT7 receptor subtype. Major depression is a common psychiatric disorder associated with high symptomatic and functional burdens. Pharmacological treatment is often effective, but there remain substantial unmet needs in the form of non-responders, delayed onset of clinical effect, and side effects. Recent studies have positioned the serotonin 5-HT7 receptor as a new target for the treatment of depression. Preclinical studies have shown that antagonists induce an antidepressant-like response, a phenotype that can also be observed in mice lacking the receptor. Lurasidone is a new atypical antipsychotic agent with very high affinity for the 5-HT7 receptor. Patients in clinical trials have reported improved scores in depression ratings. We have tested lurasidone in both acute and chronic mouse models of depression. In the tail suspension and forced swim tests lurasidone decreased immobility, an antidepressant-like response. The effect required functional 5-HT7 receptors as it was absent in mice lacking the receptor. In the repeated open-space swim test lurasidone was able to reverse the despair induced by repeated swims in a manner similar to the commonly used antidepressant citalopram. The results provide evidence that lurasidone can act as a 5-HT7 receptor antagonist and provide a possible explanation for the antidepressant effect data currently emerging from lurasidone clinical trials. Additionally, the results give further support for targeting the 5-HT7 receptor in the treatment of depression. It will be of interest to clinically evaluate lurasidone as an antidepressant either as monotherapy or as an adjunctive therapy to available drugs. 23886875 Brain perfusion and upper limb motor function: A pilot study on the correlation between evolution of asymmetry in cerebral blood flow and improvement in Fugl-Meyer Assessment score after rTMS in chronic post-stroke patients. Few studies have explored the refinement of asymmetry in regional cerebral blood flow in relation to behavioral improvement after treatment. The purpose of this retrospective pilot study was to identify cerebral cortical regions with improved perfusion that correlated with improvement of upper limb motor function after repetitive transcranial magnetic stimulation (rTMS). The study subjects were 33 post-stroke patients with upper limb hemiparesis who underwent rTMS combined with intensive occupational therapy (mean±SD age: 64.9±11.2years; time since onset of stroke: 57.3±45.9months). Fugl-Meyer Assessment (FMA) and the Wolf Motor Function Test (WMFT) were applied before and after treatment to evaluate motor function in the affected upper limb. Regional brain perfusion was measured by single-photon emission computed tomography, and the percentages of asymmetry values (asymmetry index [AI]) for 52 bilateral regions of interest were calculated. The change in AI was calculated as the post-intervention minus pre-intervention values. Changes in AI in the superior and middle frontal areas correlated significantly and negatively with changes in FMA score (superior: r=-0.406, P=0.03, R(2)=0.251; middle: r=-0.437, P<0.001, R(2)=0.306), but not with changes in WMFT log performance time. Changes in AI less than zero reflect improved perfusion, suggesting that upper limb motor function improvement in post-stroke patients reflects evolution of brain perfusion in the superior and middle frontal areas. 23832517 Gastrointestinal mucus proteome reveals Muc2 and Muc5ac accompanied by a set of core proteins - 2. Studies of mucus in mouse stomach, small intestine, and colon. The mucus that protects the surface of the gastrointestinal tract is rich in specialized O-glycoproteins called mucins, but little is known about other mucus proteins or their variability along the GI tract. To ensure that only mucus was analyzed, we combined collection from explant tissues mounted in perfusion chambers, liquid sample preparation, single-shot mass spectrometry, and specific bioinformatics tools, to characterize the proteome of the murine mucus from stomach to distal colon. With our approach, we identified ~1,300 proteins in the mucus. We found no differences in the protein composition or abundance between genders, but there were clear differences in mucus along the tract. Noticeably, mucus from duodenum showed similarities to the stomach, probably reflecting the normal distal transport. Qualitatively, there were however fewer differences than might had been anticipated, suggesting a relatively stable core proteome (~80% of the total identified). Quantitatively, we found significant differences (~40% of the proteins) that could reflect mucus specialization throughout the gastrointestinal tract. Hierarchical clustering pinpointed a number of such proteins that correlated with Muc2 (e.g. Clca1, Zg16, Klk1). This study provides a deeper knowledge of the gastrointestinal mucus proteome that will be important in further understanding this poorly studied mucosal protection system. 23141876 Non-alcoholic fatty liver disease and cardiovascular risk. The term "Non-alcoholic fatty liver disease" (NAFLD) covers a series of liver lesions similar to those induced by alcohol, but not caused by alcohol use. The importance of NAFLD lies in the high prevalence in Western societies and, from the point of view of the liver, in its progression from steatosis to cirrhosis and liver cancer. More recently, NAFLD has been found to be associated with lipid metabolism disorders, the deposition of fat outside of the adipocytes, insulin resistance and Metabolic Syndrome. Also attributed to NAFLD is a heightened systemic pro-inflammatory state, which accelerates arteriosclerosis, thereby increasing cardiovascular risk and associated cardiovascular events. Here we provide an update to the etiopathogenesis of NAFLD, its influence on cardiovascular disease, and the treatment options. 22651799 Purification and characterization of OXA-23 from Acinetobacter baumannii. Although the existence of blaOXA-23 is reported in various parts of the world, the product of blaOXA-23 gene, OXA-23, has not been purified and its kinetic properties are not known. In this study, OXA-23 of Acinetobacter baumannii isolated from Kocaeli University intensive care unit was characterized after purification using recombinant methods. Preliminary results showed that conventional protein purification methods were not effective for purification of OXA-23. Therefore, OXA-23 was fused to maltose-binding protein of Escherichia coli, the fused protein was expressed and purified to homogeneity. Kinetic properties of the pure protein were then studied with substrates e.g., imipenem, meropenem, cefepime, ceftazidime, ampicilline, piperacillin, penicillin G, and nitrocefin. Also clavulanic acid, tazobactam, and sulbactam concentrations that inhibit 50% of OXA-23 enzyme activity were calculated. Modelling of OXA-23 revealed its ionic surface structure, conformation in the fused form and its topology allowing us to make predictions for OXA-23 substrate specificity. 23873030 Mutations that disrupt PHOXB interaction with the neuronal calcium sensor HPCAL1 impede cellular differentiation in neuroblastoma. Heterozygous germline mutations in PHOX2B, a transcriptional regulator of sympathetic neuronal differentiation, predispose to diseases of the sympathetic nervous system, including neuroblastoma and congenital central hypoventilation syndrome (CCHS). Although the PHOX2B variants in CCHS largely involve expansions of the second polyalanine repeat within the C-terminus of the protein, those associated with neuroblastic tumors are nearly always frameshift and truncation mutations. To test the hypothesis that the neuroblastoma-associated variants exert their effects through loss or gain of protein-protein interactions, we performed a large-scale yeast two-hybrid screen using both wild-type (WT) and six different mutant PHOX2B proteins against over 10 000 human genes. The neuronal calcium sensor protein HPCAL1 (VILIP-3) exhibited strong binding to WT PHOX2B and a CCHS-associated polyalanine expansion mutant but only weakly or not at all to neuroblastoma-associated frameshift and truncation variants. We demonstrate that both WT PHOX2B and the neuroblastoma-associated R100L missense and the CCHS-associated alanine expansion variants induce nuclear translocation of HPCAL1 in a Ca(2+)-independent manner, while the neuroblastoma-associated 676delG frameshift and K155X truncation mutants impair subcellular localization of HPCAL1, causing it to remain in the cytoplasm. HPCAL1 did not appreciably influence the ability of WT PHOX2B to transactivate the DBH promoter, nor did it alter the decreased transactivation potential of PHOX2B variants in 293T cells. Abrogation of the PHOX2B-HPCAL1 interaction by shRNA knockdown of HPCAL1 in neuroblastoma cells expressing PHOX2B led to impaired neurite outgrowth with transcriptional profiles indicative of inhibited sympathetic neuronal differentiation. Our results suggest that certain PHOX2B variants associated with neuroblastoma pathogenesis, because of their inability to bind to key interacting proteins such as HPCAL1, may predispose to this malignancy by impeding the differentiation of immature sympathetic neurons.Oncogene advance online publication, 22 July 2013; doi:10.1038/onc.2013.290. 23597075 Polyelectrolyte Multilayers Promote Stent-Mediated Delivery of DNA to Vascular Tissue. We report an approach to deliver DNA to vascular tissue in vivo using intravascular stents coated with degradable, DNA-containing polyelectrolyte multilayers (PEMs). Ionically cross-linked multilayers ∼120 nm thick were fabricated layer-by-layer on the surfaces of balloon-mounted stainless steel stents using plasmid DNA and a hydrolytically degradable poly(β-amino ester) (polymer 1). Characterization of stents coated using a fluorescently end-labeled analog of polymer 1 revealed film erosion to be uniform across the surfaces of the stents; differential stresses experienced upon balloon expansion did not lead to faster film erosion or dose dumping of DNA in areas near stent joints when stents were incubated in physiologically relevant media. The ability of film-coated stents to transfer DNA and transfect arterial tissue in vivo was then investigated in pigs and rabbits. Stents coated with films fabricated using fluorescently labeled DNA resulted in uniform transfer of DNA to sub-endothelial tissue in the arteries of pigs in patterns corresponding to the locations and geometries of stent struts. Stents coated with films fabricated using polymer 1 and plasmid DNA encoding EGFP resulted in expression of EGFP in the medial layers of stented tissue in both pigs and rabbits two days after implantation. The results of this study, combined with the modular and versatile nature of layer-by-layer assembly, provide a polymer-based platform that is well suited for fundamental studies of stent-mediated gene transfer. With further development, this approach could also prove useful for the design of nonviral, gene-based approaches for prevention of complications that arise from the implantation of stents and other implantable interventional devices. 23899542 Effects of Retinoids in Mouse Models of Colitis: Benefit or Danger to the Gastrointestinal Tract? In vitro and in vivo data have shown that retinoid treatment promotes an anti-inflammatory milieu with few adverse effects toward the gastrointestinal tract. The in vivo studies reported here further evaluate retinoid effects in 2 mouse models of inflammatory bowel disease. Chronic dextran sulfate sodium colitis was induced in age- and weight-matched C57Bl/6 mice by 4 cycles of dextran sulfate sodium administration (6-8 animals/group). At cycle 4, animals were administered 13-cis-retinoic acid (isotretinoin, 30 mg/kg) or vehicle (oral gavage) or 4-oxo-13-cis-retinoic acid (15 mg/kg, intraperitoneal) daily. T-cell transfer colitis was induced in CB17 SCID mice by transfer of naive CD4CD62L T cells and treated by transfer of regulatory CD4CD25 T cells (4-6 animals/group); isolated from BALB/c mice after treatment with isotretinoin or vehicle, as above, for 2 weeks. Assessments included endoscopic and histological scores, myeloperoxidase activity, serum cytokines, and plasma isotretinoin levels. Retinoid-treated animals with colitis showed comparable changes in myeloperoxidase activity, and endoscopic and histological scores, versus untreated animals with colitis. Modest and comparable changes were seen in body weight and colon length in animals injected with naive T cells from isotretinoin-treated donors versus those injected with T cells from vehicle-treated donors. Retinoid treatment was consistently associated with lower interleukin-12 levels, which, after the transfer of naive T cells from isotretinoin-treated donors, supported isotretinoin-mediated predisposition of naive T cells toward reduced proinflammatory cytokine expression. Colitis had no effect on isotretinoin exposure. Retinoids attenuate the proinflammatory cytokine response in vivo, with only modest effects on body weight and parameters of gastrointestinal morphology. 23666767 The critical flux method for reduced filter membrane fouling when monitoring high-solids digesters. Membrane fouling currently makes filtration of high-solids anaerobic sludges difficult and this is discouraging online monitoring of volatile fatty acids and control of high-solids digesters. The present study tests the critical flux approach to reduce membrane fouling. Filtration tests are performed on two sludges, filtered via a side-stream off two full-scale digesters. Sub-critical flux operating conditions (for minimal cake layer formation) are identified for each of the sludges and the filtration units are operated at these conditions to assess longer term performance. Results for one of the sludges (co-digested primary and secondary sludge) is found to be encouraging, showing that sufficient flux rates (up to 40 L m(-2) h(-1) ) can be readily sustained to allow longer term digester monitoring and control. Filtration performance for this sludge did not deteriorate significantly over the test period. Results for the other test sludge (digested thermally hydrolyzed waste activated sludge) were not as favorable and indicated that application may be limited for very high solids digesters (>5% total solids concentration). Differences in filtration behavior for the two test sludges were ascribed to the presence of complex soluble organics, the concentration of sludge solids and their particle size. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 29:1059-1063, 2013. 23892049 Inhibitory avoidance in CD1 mice: Sex matters, as does the supplier. The purpose of the present work was to study possible differences in the learning of inhibitory avoidance (also called passive avoidance) in male and female CD1 mice acquired from three different suppliers, for which a one-trial step-through version of the paradigm was employed. Ninety-six mice from Charles River (France), Janvier (France) and Harlan (The Netherlands) laboratories were divided by sex and assigned to group C, J or H, respectively (n=16). The animals were tested in the training phase (foot-shock: 0.3mA, 5s) and again for avoidance (no foot-shock delivered) one week later. Inhibitory avoidance learning (test latencies significantly higher than training latencies) was observed in every one of the six groups of animals. The variable Supplier was statistically significant, showing better to worse avoidance in C, J and H mice (in that order). A post hoc analysis showed differences between groups C and H. Females tended to exhibit avoidance learning to a greater extent than males. Our results suggest that inhibitory avoidance learning in CD1 mice varies depending on the breeding facilities from which they originate, and that females should be included in inhibitory avoidance studies. 23838121 Purification and characterization of a GH43 β-xylosidase from Enterobacter sp. identified and cloned from forest soil bacteria. The use of lignocellulosic biomass for second generation biofuels requires optimization of enzymatic breakdown of plant cell walls. In this work, cellulolytic bacteria were isolated from a native and two cultivated forest soil samples. Amplification of glycosyl hydrolases was attempted by using a low stringency-degenerate primer PCR strategy, using total soil DNA and bulk DNA pooled from positive colonies as template. A set of primers was designed based on Acidothermus cellulolyticus genome, by search of conserved domains of glycosyl hydrolases (GH) families of interest. Using this approach, a fragment containing an open reading frame (ORF) with 98% identity to a putative GH43 beta-xylosidase coding gene from Enterobacter cloacae was amplified and cloned. The full protein was expressed in Escherichia coli as N-terminal or C-terminal His-tagged fusions and purified under native conditions. Only N-terminal fusion protein, His-Xyl43, presented beta-xylosidase activity. On pNPX, optimal activity was achieved at pH 6 and 40°C and Km and Kcat values were 2.92mM and 1.32seg(-1), respectively. Activity was also demonstrated on xylobiose (X2), with Km 17.8mM and Kcat 380s(-1). These results demonstrated that Xyl43 is a functional beta-xylosidase and it is the first evidence of this activity for Enterobacter sp. 23861351 Potential-Dependent Surface-Enhanced Resonance Raman Spectroscopy at Nanostructured TiO2 : A Case Study on Cytochrome b5. Nanostructured titanium dioxide (TiO2 ) electrodes, prepared by anodization of titanium, are employed to probe the electron-transfer process of cytochrome b5 (cyt b5 ) by surface-enhanced resonance Raman (SERR) spectroscopy. Concomitant with the increased nanoscopic surface roughness of TiO2 , achieved by raising the anodization voltage from 10 to 20 V, the enhancement factor increases from 2.4 to 8.6, which is rationalized by calculations of the electric field enhancement. Cyt b5 is immobilized on TiO2 under preservation of its native structure but it displays a non-ideal redox behavior due to the limited conductivity of the electrode material. The electron-transfer efficiency which depends on the crystalline phase of TiO2 has to be improved by appropriate doping for applications in bioelectrochemistry. 23961259 Epidermal growth factor receptor mutation in lung adenocarcinoma in India: A single center study. Adenocarcinoma, a subgroup of non-small cell lung cancer, is the most frequent form occurring in the non-smokers. Mutation in tyrosine kinase domain of epidermal growth factor receptor (EGFR) has been a common feature observed in lung adenocarcinoma. The study was carried out to detect the prevalence of EGFR mutation in lung adenocarcinoma. EGFR mutation status in 166 lung adenocarcinoma patients was obtained retrospectively. Mutation tests were performed on paraffin embedded tissue blocks as a routine diagnostic procedure by polymerase chain reaction followed by direct nucleotide sequencing. Patient's demographics and other clinical details were obtained from the medical records. EGFR mutation was detected in 43/166 (25.9%) patients. Gender wise mutation was observed as 18/55 (32.7%) in females and 25/111 (22.5%) in males. Overall, EGFR mutation was correlated with never smokers and distant metastasis (P < 0.05), but not associated with the gender, disease stage and pleural effusion. Exon 19 deletions were significantly correlated with females, never smokers, pleural effusion and distant metastasis (P < 0.05). However, point mutation on exon 21 did not show any statistical association with the above variables. Median overall survival was 22 months (95% confidence interval, 15.4-28.6). Female sex, EGFR mutation and absence of metastasis are associated with good prognosis. EGFR mutation in lung adenocarcinoma was higher in never smokers, females and patients with distant metastasis. However, it was not linked with tobacco smoking. The prevalence of EGFR mutation observed is in range with the previously published reports from the Asian countries. 23948371 Tuberal hypothalamic expression of the glial intermediate filaments, glial fibrillary acidic protein and vimentin across the turkey hen (Meleagris gallopavo) reproductive cycle: Further evidence for a role of glial structural plasticity in seasonal reproduction. Glia regulate the hypothalamic-pituitary-gonadal (HPG) axis in birds and mammals. This is accomplished mechanically by ensheathing gonadotrophin-releasing hormone I (GnRH) nerve terminals thereby blocking access to the pituitary blood supply, or chemically in a paracrine manner. Such regulation requires appropriate spatial associations between glia and nerve terminals. Female turkeys (Meleagris gallavapo) use day length as a primary breeding cue. Long days activate the HPG-axis until the hen enters a photorefractory state when previously stimulatory day lengths no longer support HPG-axis activity. Hens must then be exposed to short days before reactivation of the reproductive axis occurs. As adult hens have discrete inactive reproductive states in addition to a fertile state, they are useful for examining the glial contribution to reproductive function. We immunostained tuberal hypothalami from short and long-day photosensitive hens, plus long-day photorefractory hens to examine expression of two intermediate filaments that affect glial morphology: glial fibrillary acidic protein (GFAP) and vimentin. GFAP expression was drastically reduced in the central median eminence of long day photosensitive hens, especially within the internal zone. Vimentin expression was similar among groups. However, vimentin-immunoreactive fibers abutting the portal vasculature were significantly negatively correlated with GFAP expression in the median eminence, which is consistent with our hypothesis for a reciprocal relationship between GFAP and vimentin expression. It appears that up-regulation of GFAP expression in the central median eminence of turkey hens is associated with periods of reproductive quiescence and that photofractoriness is associated with the lack of a glial cytoskeletal response to long days. 23852355 Warning signals of regime shifts as intrinsic properties of endogenous dynamics *. Abstract Ecosystem dynamics can exhibit large, nonlinear changes after small changes in an environmental parameter that passes a critical threshold. These regime shifts are often associated with loss of biodiversity and ecosystem services. Because critical thresholds for regime shifts are hard to determine with precision, some recent studies have focused on deriving signals from dynamics leading up to the thresholds. Models in these studies depend on using noise terms independent of system parameters and variables to add stochasticity. However, demographic stochasticity, an important source of random variability, arises directly from system dynamics. In this study, a framework is developed for modeling demographic stochasticity in a mechanistic way, incorporating system variables and parameters. This framework is applied to a deterministic, dynamic model of a coral reef benthos. The resulting stochastic model indicates that increasing variance-but not skewness-is consistently found in system dynamics approaching a critical threshold of grazing pressure. Even if the threshold is breached, attraction of transient dynamics by a saddle point provides an opportunity for regime shift reversal by management intervention. These results suggest that early warning signals of regime shifts can arise intrinsically in endogenous dynamics and can be detected without reliance on random environmental forcings. 22795390 Shoulder pain: differential diagnosis with mechanical diagnosis and therapy extremity assessment - a case report. Mechanical Diagnosis and Therapy (MDT) is now probably the only non-specific classification system that can be used with both spinal and non-spinal patients. Derangement syndrome, which presents with rapid changes in symptoms or mechanical response with the use of repeated movements, appears to be common in both spinal and extremity cases. Shoulder problems can be attributed to specific shoulder problems, but may also be referred from the neck. The case report describes a patient presenting with shoulder pain and limitations to shoulder function, and who tested positive to functional shoulder tests. However, repeated neck movements demonstrated the ability to worsen and improve the shoulder pain and limitations. MDT was an effective tool at making the differential diagnosis between 'genuine' and referred shoulder pain. 23080480 The impact of intrapersonal, interpersonal, and community factors on the identity formation of young adults with cancer: a qualitative study. The purpose of this study was to examine how young adult cancer patients make sense of their experiences with cancer. Semi-structured interviews were conducted with patients at an urban tertiary care center The sample for this study included 15 young adult cancer survivors. The ages of the participants ranged from 18 to 30 years. The sample was 67% female (n = 10) and 33% male (n = 5). The sample was 87% Caucasian (n = 13) and 13% Hispanic (n = 2). Fifty-three percent of the participants were between ages 18 and 23 years (n = 8), and 47% of the participants were between ages 24 and 30 years (n = 7). Three themes emerged from the data: intrapersonal change, interpersonal interactions, and role and identity in the hospital and the community. As they inevitably lose control in their lives, young adult patients seek to return to a familiar lifestyle that they consider as 'normal'. The formation of a revised identity and redefined set of norms allows the patients to regain control and express their individualism. This study contributes to our knowledge of the experiences of young adult cancer patients and survivors. The findings serve to inform young adults, caregivers, and health professionals on coping with illness and its aftermath. Copyright © 2012 John Wiley & Sons, Ltd. 23822563 Evaluation of a multisite educational intervention to improve mobilization of older patients in hospital: protocol for mobilization of vulnerable elders in Ontario (MOVE ON). Functional decline is a common adverse outcome of hospitalization in older people. Often, this decline is not related to the illness that precipitated admission, but to the process of care delivered in hospital. The association between immobility and adverse consequences is well established, yet older inpatients spend significant amounts of time supine in bed. We aim to implement and evaluate the impact of an evidence-based strategy to promote early mobilization and prevent functional decline in older patients admitted to university-affiliated acute care hospitals in Ontario, Canada. We will implement a multi-component educational intervention to support a change in practice to enhance mobilization of older patients.Methods/design: Implementation of our early mobilization strategy is guided by the Knowledge to Action Cycle. Through focus groups with frontline staff, we will identify barriers and facilitators to early mobilization. We will tailor the intervention at each site to the identified barriers and facilitators, focusing on the following key messages: to complete a mobility assessment and care plan within 24 hours of the decision to admit patients aged 65 years and older; to achieve mobilization at least 3 times per day; and, to ensure that mobilization is scaled and progressive. The primary outcome, number of patients observed out of bed, will be documented three times per day (in the morning, at lunch and in the afternoon), two days each week. This data collection will occur over 3 phases: pre-implementation (10 weeks), implementation (8 weeks), and post-implementation (20 weeks). This is the first large, multisite study to evaluate the impact of a multi-component knowledge translation strategy on rates of mobilization of older patients in hospital. Our implementation is framed by the Knowledge to Action Cycle, and the intervention is being adapted to the local context. These unique features render our intervention approach more generalizable to multiple practice settings. Contextualization of the intervention has also facilitated engagement of participants from multiple hospitals. Upon completion of this study, we will better understand the barriers and facilitators to implementing an early mobilization strategy across a spectrum of hospitals, as well as the impact of a mobilization strategy. 23834059 Material resources, energy, and nutrient recovery from waste: are waste refineries the solution for the future? Waste refineries focusing on multiple outputs of material resources, energy carriers, and nutrients may potentially provide more sustainable utilization of waste resources than traditional waste technologies. This consequential life cycle assessment (LCA) evaluated the environmental performance of a Danish waste refinery solution against state-of-the-art waste technology alternatives (incineration, mechanical-biological treatment (MBT), and landfilling). In total, 252 scenarios were evaluated, including effects from source-segregation, waste composition, and energy conversion pathway efficiencies. Overall, the waste refinery provided global warming (GW) savings comparable with efficient incineration, MBT, and bioreactor landfilling technologies. The main environmental benefits from waste refining were a potential for improved phosphorus recovery (about 85%) and increased electricity production (by 15-40% compared with incineration), albeit at the potential expense of additional toxic emissions to soil. Society's need for the outputs from waste, i.e., energy products (electricity vs transport fuels) and resources (e.g., phosphorus), and the available waste composition were found decisive for the selection of future technologies. On the basis of the results, it is recommended that a narrow focus on GW aspects should be avoided as most waste technologies may allow comparable performance. Rather, other environmental aspects such as resource recovery and toxic emissions should receive attention in the future. 23859477 F + (H2O)2 Reaction: The Second Water Removes the Barrier. In light of controversy concerning the classical barrier for the F + H2O → HF + OH reaction, higher level theoretical methods are applied. Both aug-cc-pV5Z CCSD(T) and cc-pVQZ full CCSDT methods predict a low classical barrier of about 2 kcal/mol. For the analogous water dimer reaction, the presence of the second water molecule erases this barrier entirely. An entrance complex F···(H2O)2 is found lying 7.3 kcal/mol below separated F + (H2O)2. A barrier follows this complex on the reaction coordinate, but lying 3.1 kcal/mol below the reactants. There is also an exit complex HF···H2O3 lying 11.0 kcal/mol below the separated products HF + H2O3. Thus the reactions of atomic fluorine with the water monomer and dimer are qualitatively different. 23948787 Open-Label Treatment With Escitalopram in Patients With Social Anxiety Disorder and Fear of Blushing. Fear of blushing (FB) is a form of social anxiety disorder (SAD) characterized by an intense and obsessive threat of blushing in front of other people. No data are available on the specific efficacy of antidepressants on FB. This open-label pilot study investigated whether the selective serotonin reuptake inhibitor escitalopram specifically improves symptoms of FB in SAD patients.Thirty-nine patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for SAD and presenting a significant FB according to the Salpêtrière Erythrophobia Questionnaire (SEQ) were administered open-label escitalopram (10-30 mg/d) for 12 weeks. A systematic assessment, at baseline and at week 12, included the SEQ, the Liebowitz Social Anxiety Scale, and the Hospital Anxiety and Depression scale.From the 39 patients included, 31 attended the week 4 visit, and 28 the week 12 visit. Significant reductions of FB were observed after 4 weeks of treatment and were more pronounced at the end of the 12-week treatment since patients experienced a 60% decrease in their FB symptoms (P < 0.001). Nineteen subjects (67.8%) reported a 50% decrease or more of their SEQ score, and 14 (50%) met criteria for remission of FB (SEQ score <7). The effect sizes of changes on SEQ, Liebowitz Social Anxiety Scale, and Hospital Anxiety and Depression scale scores were high, with η ranging between 0.53 and 0.86.Results of this open-label study suggest that escitalopram can be a useful treatment for FB associated with SAD, even if large controlled trials are now needed to further evaluate this result. 23941710 Simultaneous saccharification and fermentation of Agave tequilana fructans by Kluyveromyces marxianus yeasts for bioethanol and tequila production. Agave tequilana fructans (ATF) constitute a substrate for bioethanol and tequila industries. As Kluyveromyces marxianus produces specific fructanases for ATF hydrolysis, as well as ethanol, it can perform simultaneous saccharification and fermentation. In this work, fifteen K. marxianus yeasts were evaluated to develop inoculums with fructanase activity on ATF. These inoculums were added to an ATF medium for simultaneous saccharification and fermentation. All the yeasts, showed exo-fructanhydrolase activity with different substrate specificities. The yeast with highest fructanase activity in the inoculums showed the lowest ethanol production level (20g/l). Five K. marxianus strains were the most suitable for the simultaneous saccharification and fermentation of ATF. The volatile compounds composition was evaluated at the end of fermentation, and a high diversity was observed between yeasts, nevertheless all of them produced high levels of isobutyl alcohol. The simultaneous saccharification and fermentation of ATF with K. marxianus strains has potential for industrial application. 23735704 Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer: Subgroup analysis from the BOLERO-2 study. Everolimus (EVE; an inhibitor of mammalian target of rapamycin [mTOR]) enhances treatment options for postmenopausal women with hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer (ABC) who progress on a non-steroidal aromatase inhibitor (NSAI). This is especially true for patients with visceral disease, which is associated with poor prognosis. The BOLERO-2 (Breast cancer trial of OraLEveROlimus-2) trial showed that combination treatment with EVE and exemestane (EXE) versus placebo (PBO)+EXE prolonged progression-free survival (PFS) by both investigator (7.8 versus 3.2months, respectively) and independent (11.0 versus 4.1months, respectively) central assessment in postmenopausal women with HR(+), HER2(-) ABC recurring/progressing during/after NSAI therapy. The BOLERO-2 trial included a substantial proportion of patients with visceral metastases (56%). Prespecified exploratory subgroup analysis conducted to evaluate the efficacy and safety of EVE+EXE versus PBO+EXE in a prospectively defined subgroup of patients with visceral metastases. At a median follow-up of 18months, EVE+EXE significantly prolonged median PFS compared with PBO+EXE both in patients with visceral metastases (N=406; 6.8 versus 2.8months) and in those without visceral metastases (N=318; 9.9 versus 4.2months). Improvements in PFS with EVE+EXE versus PBO+EXE were also observed in patients with visceral metastases regardless of Eastern Cooperative Oncology Group performance status (ECOG PS). Patients with visceral metastases and ECOG PS 0 had a median PFS of 6.8months with EVE+EXE versus 2.8months with PBO+EXE. Among patients with visceral metastases and ECOG PS ⩾1, EVE+EXE treatment more than tripled median PFS compared with PBO+EXE (6.8 versus 1.5months). Adding EVE to EXE markedly extended PFS by ⩾4months among patients with HR(+) HER2(-) ABC regardless of the presence of visceral metastases. Novartis. 23817023 Liver receptor homolog-1 is essential for pregnancy. Successful pregnancy requires coordination of an array of signals and factors from multiple tissues. One such element, liver receptor homolog-1 (Lrh-1), is an orphan nuclear receptor that regulates metabolism and hormone synthesis. It is strongly expressed in granulosa cells of ovarian follicles and in the corpus luteum of rodents and humans. Germline ablation of Nr5a2 (also called Lrh-1), the gene coding for Lrh-1, in mice is embryonically lethal at gastrulation. Depletion of Lrh-1 in the ovarian follicle shows that it regulates genes required for both steroid synthesis and ovulation. To study the effects of Lrh-1 on mouse gestation, we genetically disrupted its expression in the corpus luteum, resulting in luteal insufficiency. Hormone replacement permitted embryo implantation but was followed by gestational failure with impaired endometrial decidualization, compromised placental formation, fetal growth retardation and fetal death. Lrh-1 is also expressed in the mouse and human endometrium, and in a primary culture of human endometrial stromal cells, reduction of NR5A2 transcript abundance by RNA interference abrogated decidualization. These findings show that Lrh-1 is necessary for maintenance of the corpus luteum, for promotion of decidualization and for formation of the placenta. It therefore has multiple, indispensible roles in establishing and sustaining pregnancy. 23876883 Left ventricular 12 segmental strain imaging predicts response to cardiac resynchronization therapy. The number of non-responders to cardiac resynchronization therapy (CRT) exposes the need for better patient selection criteria for CRT. This study aimed to identify echocardiographic parameters that would predict the response to CRT. Forty-five consecutive patients receiving CRT-D implantation for heart failure (HF) were included in this prospective study. New York Heart Association (NYHA) class, 6-minute walk distance, electrograph character, and multi echocardiographic parameters, especially in strain patterns, were measured and compared before and six months after CRT in the responder and non-responder groups. Response to CRT was defined as a decrease in left ventricular endsystolic volume (LVESV) of 15% or more at 6-month follow up. Twenty-two (48.9%) patients demonstrated a response to CRT at 6-month follow-up. Significant improvement in NYHA class (P < 0.01), left ventricular end-diastolic volume (LVEDV) (P < 0.01), and 6-minute walk distance (P < 0.01) was shown in this group. Although there was an interventricular mechanical delay determined by the difference between left and right ventricular pre-ejection intervals ((42.87 ± 19.64) ms vs. (29.43 ± 18.19) ms, P = 0.02), the standard deviation of time to peak myocardial strain among 12 basal, mid and apical segments (Tε-SD) ((119.97 ± 43.32) ms vs. (86.62 ± 36.86) ms, P = 0.01) and the non-ischemic etiology (P = 0.03) were significantly higher in responders than non-responders, only the Tε-SD (OR = 1.02, 95% CI = 1.01 - 1.04, P = 0.02) proved to be a favorable predictor of CRT response after multivariate Logistic regression analysis. The left ventricular 12 segmental strain imaging is a promising echocardiographic parameter for predicting CRT response. 23726182 Correlation between back shape and spinal loads. The purpose of this study was to determine the correlation between the back shape of the lumbar region and the spinal loads during activities performed in the sagittal plane. Measurements were performed in four subjects who had suffered from a compression fracture of a lumbar vertebral body which was treated with a telemeterized vertebral body replacement that is able to measure six load components in vivo. An Epionics SPINE measurement system was used to determine the lumbar lordosis angle. The relationship between the lordosis angle and the corresponding loads was quantified with the Spearman's rank correlation coefficient method. Measurements were performed during thirteen exercises in lying, standing or sitting. During upper body flexion, the force increased on average by approximately 285N and the lordosis angle decreased by 15°. The change of the force for elevating 30N in one hand was on average approximately 190N and for the lordosis angle 2°. Correlation coefficients greater than 0.6 were found for exercises that involved both large back shape and load changes, such as upper body flexion. A strong increase in spinal load can be associated with an increase or a decrease of the lordosis angle. Only for considerable changes of the lordosis angle in an upright body position was a strong correlation between lordosis angle and implant force found. 23619616 Risk factors for vertical incomplete resection in endoscopic submucosal dissection as total excisional biopsy for submucosal invasive colorectal carcinoma. Endoscopic submucosal dissection (ESD) for colorectal tumor is a minimally invasive treatment. Histologic information obtained from the entire ESD specimen is important for therapy selection in submucosal invasive colorectal carcinoma (SMca). This study aimed to identify risk factors for vertical incomplete resection (vertical margin-positive [VM+]) when ESD was performed as total excisional biopsy for SMca. From June 2003 through December 2011, 78 SMca cases were resected by ESD at Hiroshima University Hospital. Patient and tumor characteristics, intraoperative variables, and histopathology were compared between the VM+ group and the vertical complete resection (vertical margin-negative) group. The ability of magnifying endoscopy (ME) and endoscopic ultrasonography (EUS) to predict VM+ was assessed. ESD resulted in VM+ in eight cases (10.3 %), with a greater percentage invading to a depth of ≥2,000 vs. <2,000 Î¼m (P = 0.047). Severe submucosal fibrosis was found in five of the eight cases (62.5 %, P = 0.017). Poor differentiation was seen at the deepest invasive portion in six cases (75.0 %), and two of six cases had an invasion depth <2,000 Î¼m. Of 39 EUS cases, 36 not showing deep invasion close to the muscularis propria were completely resected by ESD. Submucosal fibrosis and poor differentiation at the deepest invasive portion may be risk factors for VM+ in colorectal ESD for tumors with submucosal deep invasion. ME plus EUS is more likely to help determine whether ESD is indicated as complete total excisional biopsy for SMca. 23239216 Enemy release promotes range expansion in a host plant. Climate is considered to be the predominant driver shaping species distributions at macroecological scales, yet the importance of incorporating biotic interactions in predicting future range margins under climate change scenarios is increasingly being recognised. We used translocation studies to investigate how survival and growth patterns of an understory shrub planted at latitudes within its range, at its range limit and beyond its polewards boundary (in areas it may colonise as a result of shifting climate envelopes) are affected by the presence of a primary herbivore. Specifically, we tested the null hypotheses that: (1) biotic interactions do not exert a significant role in limiting survival and growth rates across the limits of a host plant's latitudinal range, and (2) at smaller spatial scales biotic interactions do not exert a significant role in determining survival and growth rates at edge versus interior position within a forest fragment. We found that the understory shrub Macropiper excelsum is able to survive polewards of its current latitudinal limit within the first year after transplant; in fact, growth is higher outside the plant's current natural range than within its present-day distribution. This trend is particularly pronounced in forest core environments and corresponds closely to patterns of reduced herbivory outside the plant's range. The absence of the primary herbivore, Cleora scriptaria, and concomitant reduction in the suppressive effects of herbivory outside of the plant's range appear to be supporting enhanced growth and survival. If host plants are able to successfully track their climatic niche and disperse into novel areas prior to the arrival of their natural predators, it is possible that 'enemy release' may facilitate the establishment of plant species. These findings highlight the importance of considering biotic interactions alongside abiotic variables when predicting future species' ranges under climate change. 23561218 Polyphasic approach to the identification of Aspergillus section Flavi isolated from Brazil nuts. The aim of this study was to use a polyphasic approach to identify Aspergillus section Flavi isolated from Brazil nuts collected in the Amazon forest: investigation of macro- and microscopic morphology, production of extrolites, heat-resistance fungi, and sequencing of DNA regions. The following Aspergillus section Flavi species were identified: Aspergillus flavus (75.5%), Aspergillus nomius (22.3%), and Aspergillus parasiticus (2.2%). All A. nomius and A. parasiticus isolates produced aflatoxins B and G, but not cyclopiazonic acid (CPA). A. flavus isolates were more diversified and a high frequency of mycotoxigenic strains was observed. The polyphasic approach permitted the reliable identification of section Flavi species. The rate of mycotoxigenic strains was high (92.7%) and mainly included A. flavus strains producing elevated levels of aflatoxins and CPA. These results highlight the possibility of co-occurrence of both toxins, increasing their potential toxic effect in this commodity. 23852931 Witnessed sleep-related seizure and sudden unexpected death in infancy: a case report. Witnessed reports of sudden death are rare, but critical to deciphering its mechanism(s). We report such a death in a seemingly healthy 8-month-old boy in whom seizures and respiratory distress in the prone position were witnessed upon discovery during a sleep period. Following cardiopulmonary resuscitation, anoxic encephalopathy resulted in "brain death" and withdrawal of life support after 2 days. The autopsy did not reveal a primary anatomic cause of death. Metabolic evaluation failed to uncover an inborn error of ammonia, amino, organic, or fatty acid metabolism. Seizures in this case may have been secondary to cerebral hypoxia-ischemia complicating cardiorespiratory arrest of unknown etiology. Yet, they may represent the first manifestation of idiopathic epilepsy, triggering cardiopulmonary arrest, analogous to the terminal events postulated in sudden and unexplained death in epilepsy. This report alerts the forensic community to the possibility that sudden and unexplained death in infants may be due to seizures. 23831080 Potent anti-cervical cancer activity: Synergistic effects of Thai medicinal plants in recipe N040 selected from the MANOSROI III database. One of the prestigious Thai/Lanna folklore wisdoms is the medicinal plant recipes. Thai/Lanna medicinal plant recipe database MANOSROI III has been developed by Prof. Dr. Jiradej Manosroi. It consists of over 200,000 recipes covering all diseases including cancer. To investigate the in vitro and in vivo anti-cervical cancer activity and the active constituents of the Thai medicinal plant recipe N040 selected from the MANOSROI III database. The extracts of recipe N040 and single medicinal plants in the recipe were prepared by hot water and methanol extraction, respectively. The n-hexane, ethyl acetate (EtOAc), n-butanol (n-BuOH) and water fractions of Caesalpinia sappan, the plant which showed the highest anti-proliferative activity were prepared by liquid-liquid partition extraction. The fraction which showed the highest anti-proliferative activity was further isolated for active constituents. Anti-proliferative activity of recipe N040, methanolic extracts, fractions of Caesalpinia sappan and brazilin, an active constituent on HeLa cell were investigated using sulforhodamine B (SRB) assay. Anti-oxidative activities including free radical scavenging and metal ion-chelating activities, as well as the phenolic and flavonoid contents of these fractions were also determined. The in vivo anti-cancer activity of recipe N040 on HeLa cell xenograft and the subchronic toxicity were performed in nude mice and rats, respectively. N040 showed the potent in vitro anti-proliferative activity on HeLa cell with the IC50 value of 0.11µg/ml. Phytochemicals detected in the plants were steroids/triterpenoids, tannins, flavonoids, saponins and alkaloids. For the single plant, methanolic extract of Caesalpinia sappan gave the highest anti-proliferative activity with the IC50 of 33.46µg/ml. EtOAc fraction of Caesalpinia sappan showed the highest anti-proliferative and free radical scavenging activities with the IC50 and SC50 of 17.81 and 21.95µg/ml which were 1.88 and 0.83 folds of its methanolic extract and ascorbic acid, respectively. Poor metal chelating activity (MC50>500µg/ml) was observed in methanolic extract and all fractions. The highest phenolic and flavonoid contents were observed in the methanolic extract. Brazilin, the known compound isolated from the EtOAc fraction exhibited potent anti-proliferative activity with the IC50 of 0.28µg/ml which was higher than its methanolic extract and EtOAc fraction of 119.50 and 63.61 folds, respectively, but only 0.39 fold of the recipe extract N040. The tumor size of the HeLa cell xenograft nude mice treated with the recipe N040 at the dose of 44.50mg/kg body weight per day was significantly smaller (p<0.05) than that of the control with the relative tumor weight inhibition of 57.23% which was 0.65 fold of cisplatin. In the subchronic toxicity study, N040 given orally at the dose of 1000mg/kg body weight per day for 90 days showed no alteration in body weight gain, hematology [except the increase mean corpuscular hemoglobin (MCH) in the treated male rats] and clinical blood chemistry (except the increase blood glucose in the treated male rats) both in female and male rats. Only minor lesions of the organs including lung, liver, kidney and small intestine were observed in both sexes. This study has demonstrated the synergistic effect of the plants composed in the recipe which resulted in the potent anti-cancer activity and confirmed the traditionally use of the recipe N040. In addition, this study has also suggested the compound brazilin isolated from Caesalpinia sappan for its high potential to be further investigated as a novel anti-cervical cancer drug. 23798571 Novel, Gel-free Proteomics Approach Identifies RNF5 and JAMP as Modulators of GPCR Stability. The maturation and folding of G protein-coupled receptors are governed by mechanisms that remain poorly understood. In an effort to characterize these biological events, we optimized a novel, gel-free proteomic approach to identify partners of the β2-adrenergic receptor (β2AR). In addition to a number of known interacting proteins such as heterotrimeric G protein subunits, this allowed us to identify proteins involved in endoplasmic reticulum (ER) QC of the receptor. Among β2AR-associated proteins is Ring finger protein 5 (RNF5), an E3 ubiquitin ligase anchored to the outer membrane of the ER. Coimmunoprecipitation assays confirmed, in a cellular context, the interaction between RNF5 and the β2AR as well as the prostaglandin D2 receptor (DP). Confocal microscopy revealed that DP colocalized with RNF5 at the ER. Coexpression of RNF5 with either receptor increased levels of their expression, whereas small interfering RNA-mediated knockdown of endogenous RNF5 promoted the opposite. RNF5 did not modulate the ubiquitination state of β2AR or DP. Instead, RNF5 ubiquitinated JNK-associated membrane protein (JAMP), a protein that recruits the proteasome to the ER membrane and that is negatively regulated by RNF5-mediated ubiquitination. JAMP coimmunoprecipitated with both β2AR and DP and decreased total receptor protein levels through proteasomal degradation. Expression of DP, a receptor largely retained in the ER, promoted proteasome recruitment by JAMP. Degradation of both receptors via JAMP was increased when RNF5 was depleted. Our data suggest that RNF5 regulates the turnover of specific G protein-coupled receptors by ubiquitinating JAMP and preventing proteasome recruitment. 23847135 Biliary Tree Stem Cells, Precursors to Pancreatic Committed Progenitors: Evidence for Possible Life-Long Pancreatic Organogenesis. Peribiliary glands (PBGs) in bile duct walls, and pancreatic duct glands (PDGs) associated with pancreatic ducts, in humans of all ages, contain a continuous, ramifying network of cells in overlapping maturational lineages. We show that proximal (PBGs)-to-distal (PDGs) maturational lineages start near the duodenum with cells expressing markers of pluripotency (NANOG,OCT4,SOX2), proliferation (Ki67), self-replication (SALL4), and early hepato-pancreatic commitment (SOX9,SOX17,PDX1,LGR5), transitioning to PDG cells with no expression of pluripotency or self-replication markers, maintenance of pancreatic genes (PDX1), and expression of markers of pancreatic endocrine maturation (NGN3,MUC6,insulin). Radial-axis lineages start in PBGs near the ducts' fibromuscular layers with stem cells and end at the ducts' lumens with cells devoid of stem cell traits and positive for pancreatic endocrine genes. Biliary tree-derived cells behaved as stem cells in culture under expansion conditions, culture plastic and serum-free Kubota's Medium, proliferating for months as undifferentiated cells, whereas pancreas-derived cells underwent only ∼8-10 divisions, then partially differentiated towards an islet fate. Biliary tree-derived cells proved precursors of pancreas' committed progenitors. Both could be driven by 3-dimensional conditions, islet-derived matrix components and a serum-free, hormonally defined medium for an islet fate (HDM-P), to form spheroids with ultrastructural, electrophysiological and functional characteristics of neoislets, including glucose regulatability. Implantation of these neoislets into epididymal fat pads of immuno-compromised mice, chemically rendered diabetic, resulted in secretion of human C-peptide, regulatable by glucose, and able to alleviate hyperglycemia in hosts. The biliary tree-derived stem cells and their connections to pancreatic committed progenitors constitute a biological framework for life-long pancreatic organogenesis. 23924959 First Identification of 5,11-Dideoxytetrodotoxin in Marine Animals, and Characterization of Major Fragment Ions of Tetrodotoxin and Its Analogs by High Resolution ESI-MS/MS. Even though tetrodotoxin (TTX) is a widespread toxin in marine and terrestrial organisms, very little is known about the biosynthetic pathway used to produce it. By describing chemical structures of natural analogs of TTX, we can start to identify some of the precursors that might be important for TTX biosynthesis. In the present study, an analog of TTX, 5,11-dideoxyTTX, was identified for the first time in natural sources, the ovary of the pufferfish and the pharynx of a flatworm (planocerid sp. 1), by comparison with totally synthesized (-)-5,11-dideoxyTTX, using high resolution ESI-LC-MS. Based on the presence of 5,11-dideoxyTTX together with a series of known deoxy analogs, 5,6, 11-trideoxyTTX, 6,11-dideoxyTTX, 11-deoxyTTX, and 5-deoxyTTX, in these animals, we predicted two routes of stepwise oxidation pathways in the late stages of biosynthesis of TTX. Furthermore, high resolution masses of the major fragment ions of TTX, 6,11-dideoxyTTX, and 5,6,11-trideoxyTTX were also measured, and their molecular formulas and structures were predicted to compare them with each other. Although both TTX and 5,6,11-trideoxyTTX give major fragment ions that are very close, m/z 162.0660 and 162.1020, respectively, they are distinguishable and predicted to be different molecular formulas. These data will be useful for identification of TTXs using high resolution LC-MS/MS. 23516330 Parathyroid Hormone (PTH) and PTH-Related Peptide Domains Contributing to Activation of Different PTH Receptor-Mediated Signaling Pathways. Parathyroid hormone (PTH) and parathyroid hormone related peptide (PTHrP), acting through the osteoblast PTH1R, play important roles in bone remodeling. Intermittent administration of PTH(1-34) (teriparatide) leads to bone formation while continuous administration paradoxically leads to bone resorption. Activation of PTH1R promotes regulation of multiple signaling pathways, including Gs/cAMP/PKA, Gq/calcium/PKC, β-arrestin recruitment and ERK1/2 phosphorylation as well as receptor internalization but their role in promoting anabolic and catabolic actions of PTH(1-34) are unclear. In the present investigation, a collection of PTH(1-34) and PTHrP(1-34) peptide analogs were evaluated in orthogonal hPTH1R functional assays capturing Gs- and Gq-signaling, β-arrestin recruitment, ERK1/2 phosphorylation and receptor internalization to further define patterns of of PTH1R signaling they stimulate and to further establish peptide domains contributing to agonist activity. Results indicate that both N- and C-terminal domains are critical for activation of signaling pathways. However, modifications of both regions leads to more substantial decreases in agonist potency and efficacy to stimulate Gq-signaling, β-arrestin recruitment, ERK1/2 phosphorylation and receptor internalization than to stimulate Gs. The substantial contribution of the peptide C-terminal domain in activation of hPTH1R-signaling suggests a role in positioning of the peptide N-terminal region into the receptor J-domain. Several PTH and PTHrP peptide analogs evaluated in this study promote different patterns of biased agonist signaling and may serve as useful tools to further elucidate therapeutically relevant PTH1R signaling in osteoblasts. With a better understanding of therapeutically relevant signaling, novel biased peptides with desired signaling could be designed for safer and more effective treatment of osteoporosis. 23818595 MST1 functions as a key modulator of neurodegeneration in a mouse model of ALS. Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by loss of motor neurons. Dominant mutations in the gene for superoxide dismutase 1 (SOD1) give rise to familial ALS by an unknown mechanism. Here we show that genetic deficiency of mammalian sterile 20-like kinase 1 (MST1) delays disease onset and extends survival in mice expressing the ALS-associated G93A mutant of human SOD1. SOD1(G93A) induces dissociation of MST1 from a redox protein thioredoxin-1 and promotes MST1 activation in spinal cord neurons in a reactive oxygen species-dependent manner. Moreover, MST1 was found to mediate SOD1(G93A)-induced activation of p38 mitogen-activated protein kinase and caspases as well as impairment of autophagy in spinal cord motoneurons of SOD1(G93A) mice. Our findings implicate MST1 as a key determinant of neurodegeneration in ALS. 23697346 PA21, a New Iron-Based Noncalcium Phosphate Binder, Prevents Vascular Calcification in Chronic Renal Failure Rats. Chronic renal failure (CRF) is associated with the development of secondary hyperparathyroidism and vascular calcifications. We evaluated the efficacy of PA21, a new iron-based noncalcium phosphate binder, in controlling phosphocalcic disorders and preventing vascular calcifications in uremic rats. Rats with adenine-diet-induced CRF were randomized to receive either PA21 0.5, 1.5, or 5% or CaCO3 3% in the diet for 4 weeks, and were compared with uremic and nonuremic control groups. After 4 weeks of phosphate binder treatment, serum calcium, creatinine, and body weight were similar between all CRF groups. Serum phosphorus was reduced with CaCO3 3% (2.06 mM; P ≤ 0.001), PA21 1.5% (2.29 mM; P < 0.05), and PA21 5% (2.21 mM; P ≤ 0.001) versus CRF controls (2.91 mM). Intact parathyroid hormone was strongly reduced in the PA21 5% and CaCO3 3% CRF groups to a similar extent (1138 and 1299 pg/ml, respectively) versus CRF controls (3261 pg/ml; both P ≤ 0.001). A lower serum fibroblast growth factor 23 concentration was observed in the PA21 5%, compared with CaCO3 3% and CRF, control groups. PA21 5% CRF rats had a lower vascular calcification score compared with CaCO3 3% CRF rats and CRF controls. In conclusion, PA21 was as effective as CaCO3 at controlling phosphocalcic disorders but superior in preventing the development of vascular calcifications in uremic rats. Thus, PA21 represents a possible alternative to calcium-based phosphate binders in CRF patients. 23915116 Interactions between Solid Surfaces Mediated by Polyethylene Oxide Polymers: Effect of Polymer Concentration. Using total internal reflection microscopy (TIRM), we have systematically measured the interactions between a microsphere and a flat hydrophilic surface in the presence of polyethylene oxide (PEO) polymer solution. Our results reveal that PEO significantly mediates the interaction forces between the two surfaces. At low polymer concentration, the interactions between two surfaces in the presence of PEO are mainly dominated by repulsive forces, originating from diffuse layer overlap. At intermediate polymer concentration, a long-range and weak attraction sets in. This force is likely attributed to the depletion attraction due to the presence of free PEO chains in bulk solution; however, a simple hard-sphere AO model fails to precisely describe the attraction. At high polymer concentration where PEO chains overlap, the attraction disappears, and levitation of the microsphere probe is detected. We argue that at this overlapping region, the correlation length of PEO chains is much smaller than the size of single PEO molecule, leading to weakening and disappearing of the depletion attraction. Finally, at very high concentration, oscillatory structural force is obviously found, indicating the significant structural ordering of the PEO chains under confinement. 23703872 Novel CLCNKB Mutations Causing Bartter Syndrome Affect Channel Surface Expression. Mutations in the CLCNKB gene encoding the ClC-Kb Cl(-) channel cause Bartter syndrome, which is a salt-losing renal tubulopathy. Here, we investigate the functional consequences of seven mutations. When expressed in Xenopus laevis oocytes, four mutants carried no current (c.736G>C, p.Gly246Arg; c.1271G>A, p.Gly424Glu; c.1313G>A, p.Arg438His; c.1316T>C, p.Leu439Pro), whereas others displayed a 30%-60% reduction in conductance as compared with wild-type ClC-Kb (c.242T>C, p.Leu81Pro; c.274C>T, p.Arg92Trp; c.1052G>C, p.Arg351Pro). Anion selectivity and sensitivity to external Ca(2+) and H(+) , typical of the ClC-Kb channel, were not modified in the partially active mutants. In oocytes, we found that all the mutations reduced surface expression with a profile similar to that observed for currents. In HEK293 cells, the currents in the mutants had similar profiles to those obtained in oocytes, except for p.Leu81Pro, which produced no current. Furthermore, p.Arg92Trp and p.Arg351Pro mutations did not modify the unit-conductance of closely related ClC-K1. Western blot analysis in HEK293 cells showed that ClC-Kb protein abundance was lower for the nonconducting mutants but similar to wild-type for other mutants. Overall, two classes of mutants can be distinguished: nonconducting mutants associated with low total protein expression, and partially conducting mutants with unaltered channel properties and ClC-Kb protein abundance. 23694729 Estimation of main greenhouse gases emission from household energy consumption in the West Bank, Palestine. The main GHGs (CO₂, NO(x), and SO₂) have been quantified based on national energy and population statistics. The results show that the contribution of households' energy consumption in the West Bank to global CO₂ emission is about 0.016%, while contribution of total energy consumption by all sectors is about 0.041%. The results show that wood is the most polluting energy source in terms of CO₂ and NO(x) emission, while electricity is the most polluting source in terms of SO₂. Other sources like diesel, kerosene, and LPG that contribute to the GHGs emission are also quantified. The total amounts of CO₂, NO(x), and SO₂ by households in the West Bank are 4.7 million tonne per year, 3.02 thousand tonne per year, and 2.23 thousand tonne per year respectively. This study presents a set of measures that might help in reducing the level of GHGs emission and protect the environment. 23830860 Association of marital status with the incidence of suicide: A population-based Cohort Study in Japan (Miyagi cohort study). Marital status is one of the most frequently replicated predictors of suicide. The purpose of this study was to examine the effect of marital status on the risk of suicide by gender, using a large population-based cohort in Japan. The Miyagi cohort study was a population-based, prospective cohort study of Japanese adults aged between 40 and 64 years. Between June and August 1990, 47,604 participants residing in 14 municipalities of Miyagi Prefecture, Japan, completed a questionnaire on various health-related lifestyles, including marital status. During 18 years of follow-up, 146 of the participants committed suicide. We used the Cox proportional hazards regression model to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for suicide mortality according to marital status with adjustment for potential confounders. A total of 106 and 40 deaths from suicide were recorded during 344,813 and 365,524 person-years of follow-up among 20,671 men and 21,076 women, respectively. We found that marital status was significantly associated with the risk of completing suicide only in men. Among men, after multivariate adjustment, HRs in reference to married were as follows: widowed or divorced, 2.84 (95% CI: 1.37-5.90); unmarried, 1.56 (95% CI: 0.67-3.64). A significantly increased risk of suicidal death was observed among widowed or divorced men, whereas no such trend was evident for women. Our results suggest that men who are widowed or divorced, or unmarried, are at increased risk of suicide, whereas no such risk is evident for women. 23891041 Infrared digital thermography of scrotum in early selection of progressive varicocele. Varicocele is frequent but correctable cause of male infertility. Varicocelectomy is the most commonly performed operative procedure for varicocele. Majority of varicocele patients do not have fertility problem, therefore surgical correction is not recommended in all prevalent cases. On the other hand, varicocele is a progressive condition in some cases and individual with varicocele is at risk for developing impairment which can ultimately lead to semen deterioration and consequent infertility. Selection of patients with varicocele that will progress and cause infertility is beyond our current diagnostic capabilities. Diagnostic assessment of varicocele depends on physical examination and scrotal ultrasound/doppler. Infrared digital thermography of scrotum is a non-invasive and objective diagnostic method for early varicocele detection by means of temperature measurement on the scrotal skin surface. The criteria for diagnostic use of scrotal thermography were recently presented. We hypothesize that the infrared digital thermography of scrotum could be the cornerstone in detection of varicoceles that tend to progress with impairment of semen quality and will require surgical correction, among all prevalent varicocele cases. 23963447 Microfibril-associated glycoprotein 2 (MAGP2) loss-of-function has pleiotropic effects in vivo. Microfibril-associated glycoprotein-1 and -2 are evolutionarily related but structurally divergent proteins that are components of microfibrils of the extracellular matrix (ECM). Using mice with a targeted inactivation of Mfap5, the gene for MAGP2 protein, we demonstrate that MAGPs have shared as well as unique functions in vivo. Mfap5-/- mice appear grossly normal, are fertile, and have no reduction in life span. Cardiopulmonary development is typical. The animals are normotensive and have vascular compliance comparable to age-matched wild-type mice, which is indicative of normal, functional elastic fibers. Loss of MAGP2 alone does not significantly alter bone mass or architecture and loss of MAGP2 in tandem with loss of MAGP1 does not exacerbate MAGP1-dependent osteopenia. MAGP2-deficient mice are neutropenic, which contrasts with monocytopenia described in MAGP1-deficient animals. This suggests MAGP1 and MAGP2 have discrete functions in hematopoiesis. In the cardiovascular system, MAGP1; MAGP2 double knockout mice (Mfap2-/-; Mfap5-/-) show age-dependent aortic dilation. These findings indicate that MAGPs have shared primary functions in maintaining large vessel integrity. In solid phase binding assays, MAGP2 binds active TGFβ1, TGFβ2, and BMP2. Together, these data demonstrate that loss of MAGP2 expression in vivo has pleiotropic effects potentially related to MAGP2's ability to regulate growth factors or participate in cell signaling. 23644538 Predictive factors of outcome and hemorrhage after acute ischemic stroke treated by mechanical thrombectomy with a stent-retriever. The study attempts to identify notable factors predicting poor outcome, death, and intracranial hemorrhage in patients with acute ischemic stroke undergoing mechanical thrombectomy with stent retriever. These data could be useful to improve the selection of patients for thrombectomy. Patients with acute ischemic stroke treated with the Solitaire FR device were retrospectively analyzed from a prospectively collected database. We assessed the effect of selected demographic characteristics, clinical and imaging factors on poor outcome at 3 months (modified Rankin score 3-6), mortality at 3 months, and hemorrhage at day 1 (symptomatic and asymptomatic). From May 2010 to April 2012, 59 consecutive patients with an acute ischemic stroke underwent mechanical thrombectomy. At 3 months, 57.6 % of the patients were functionally independent (modified Rankin Scale 0-2) and mortality was 20.4 %. Multivariate analyses revealed that a thrombus length > 14 mm (p = 0.02; OR 7.55; 95 % CI 1.35-42.31) and longer endovascular procedure duration (p = 0.01; OR 1.04; 95 % CI 1.01-1.07) were independently associated with poor outcome. A higher baseline Alberta Stroke Program Early CT (ASPECT) score (p = 0.04; OR 0.79 per point; 95 % CI 0.63-0.99) and successful recanalization (p = 0.02; OR 0.07; 95 % CI 0.01-0.72) were independent predictors of good functional outcome. Baseline ASPECT score (p < 0.01; OR 0.65; 95 % CI 0.54-0.78) independently predicted symptomatic intracranial hemorrhage at day 1. Absolute baseline ASPECT score reflects early symptomatic hemorrhage risk and functional outcome at 3 months. Thrombus length measured on MRI play an important role on functional outcome at 3 months after thrombectomy. Further analyses are needed to determine its importance in the selection of patients for mechanical thrombectomy. 23397218 The surgeon's real dose exposure during balloon kyphoplasty procedure and evaluation of the cement delivery system: a prospective study. Balloon kyphoplasty is currently widely used for the treatment of vertebral compression fractures (VCFs). Procedure safety is directly linked to precise radiological imaging generated by various X-ray systems (C-arm, O-arm(®), angiography table, etc.). This minimally invasive spinal surgery is, by definition, associated with significant radiation exposure for both patient and surgeon. Real dose exposure received by the surgeon is usually difficult to precisely record. In our center, all Balloon Kyphoplasty Procedures (BKP) are now performed using an O-arm(®) image guidance system to control cement augmentation in VCF. Our preliminary experience described reduced dose exposure compared to C-arm guided procedures. We present here an additional way to considerably reduce the amount of radiation received by the surgeon during BKP using a new injection system. We prospectively evaluated O-arm(®) guided BKP in 20 consecutive patients alternatively allocated to either classic O-arm(®) BKP with direct bone filler injection or BKP using a new Cement Delivery System (CDS). Eye, wrist, finger and leg measurements were taken bilaterally and compared between the two groups. The radiation dose received by the surgeon's finger, wrist and leg was reduced by greater than 80 % when using the CDS. It allows the surgeon to work way below the most severe annual limit of dose exposure, which may not be the case when using a classical bone filler direct injection mechanism. We believe that when using this new intraoperative injection system, the surgeon's overall anatomic exposure is significantly reduced without compromising the critical procedure steps. 23921147 Chemokine receptor expression on integrin-mediated stellate projections of prostate cancer cells in 3D culture. The chemokine receptor CXCR7 has emerged as a regulator of prostate tumor growth and invasion, along with the well-established role of its closely related receptor, CXCR4, and their shared ligand, SDF-1α. Consequently, inhibition of the CXCR7/CXCR4/SDF-1α axis may assist in controlling prostate tumor growth and progression. To facilitate the development of potential therapeutics, further clarification of CXCR7 function is required, specifically in relation to CXCR4. In this study, we report that CXCR7 and CXCR4 were co-expressed in LNCaP, DU145 and PC3 cell lines in 2D culture. When cultured in 3D using Matrigel, a marked up-regulation of both receptors was observed in PC3 cells. Interestingly, both CXCR7 and CXCR4 co-localized within radiating cellular structures, termed stellate projections, which protruded outward into the matrix. The stellate projections were rich in the expression of pro-invasive integrin β1, β-laminin and MMP-11 proteins. The development of the stellate projections was mediated by integrin β1-mediated interactions with the ECM, which also regulated the expression of CXCR7 and CXCR4. Taken together, these results demonstrate that integrin-mediated cell-ECM interactions can modulate tumor cell morphology, and regulate the expression of chemokine receptors which are associated with the invasive phenotype and progression of PCa. 23079670 Tandem inverse-electron-demand hetero-/retro-Diels-Alder reactions for aromatic nitrogen heterocycle synthesis. The merged inverse-electron-demand hetero-Diels-Alder (ihDA)/retro-Diels-Alder (rDA) reaction sequence can be used to rapidly synthesise highly functionalised nitrogen heteroaromatics. The reaction offers many advantages: high atom economy, high levels of regioselectivity, it rarely requires a catalyst and, in some cases, can be performed in the absence of solvent. In this tutorial review we discuss the range of commonly used dienophiles and aza-dienes for this process whilst highlighting the reactivity trends, and illustrating their applications. 23748991 Perceived knowledge and self-confidence of pediatric nurses as patient educators. Patient education is an integral component of nursing care. Patient education has been associated with favorable patient outcomes but may be difficult if resources are unavailable, "teachable moments" are unrecognized, or if self-confidence of the nurses providing the education is low. Using the theoretical model developed by the authors and focusing on the delivery of patient/family education, we examined pediatric nurses' perceptions about patient/family education in the hospital setting. A 20-item questionnaire that explored factors affecting teaching behaviors of 54 pediatric nurses in an acute care hospital setting was completed. Results from this study suggest that pediatric nurses' confidence was disorder-specific. Nurses were confident providing education about common disorders (asthma, pneumonia, and bronchiolitis) and less confident providing education about less common disorders (oncology, cardiac). The barrier to providing education identified most often was lack of written materials. Findings from this study can be used to develop teaching resources for nurses and to plan educational programs specific to less common pediatric problems. 23970368 The Role of Radionuclide Imaging in Epilepsy, Part 1: Sporadic Temporal and Extratemporal Lobe Epilepsy. Epilepsy is one of the most common yet diverse neurologic disorders, affecting almost 1%-2% of the population. Presently, radionuclide imaging such as PET and SPECT is not used in the primary diagnosis or evaluation of recent-onset epilepsy. However, it can play a unique and important role in certain specific situations, such as in noninvasive presurgical localization of epileptogenic brain regions in intractable-seizure patients being considered for epilepsy surgery. Radionuclide imaging can be particularly useful if MR imaging is either negative for lesions or shows several lesions of which only 1 or 2 are suspected to be epileptogenic and if electroencephalogram changes are equivocal or discordant with the structural imaging. Similarly, PET and SPECT can also be useful for evaluating the functional integrity of the rest of the brain and may provide useful information on the possible pathogenesis of the neurocognitive and behavioral abnormalities frequently observed in these patients. 23100158 Apoptosis initiation of β-ionone in SGC-7901 gastric carcinoma cancer cells via a PI3K-AKT pathway. β-ionone has been shown to hold potent anti-proliferative and apoptosis induction properties in vitro and in vivo. To investigate the effects of β-ionone on apoptosis initiation and its possible mechanisms of action, we qualified cell apoptosis, proteins related to apoptosis and a phosphatidylinositol 3-kinase (PI3K)-AKT pathway in human gastric adenocarcinoma cancer SGC-7901 cells. The results demonstrated that β-ionone-induced apoptosis in a dose-dependent manner in SGC-7901 cells treated with β-ionone (25, 50, 100 and 200 μmol/L) for 24 h. β-ionone was also shown to induce the expression of cleaved-caspase-3 and inhibit bcl-2 expression in SGC-7901 cells in a dose-dependent manner. The significantly decreased levels of p-PI3K and p-AKT expression were observed in SGC-7901 cells after β-ionone treatments in a time- and dose-dependent manner (P < 0.01). Thus, the apoptosis induction in SGC-7901 cells by β-ionone may be regulated through a PI3K-AKT pathway. These results demonstrate a potential mechanism by which β-ionone to induce apoptosis initiation in SGC-7901 cells. 23294255 Development of new cyclic plasmin inhibitors with excellent potency and selectivity. The trypsin-like serine protease plasmin is a target for the development of antifibrinolytic drugs for use in cardiac surgery with cardiopulmonary bypass or organ transplantations to reduce excessive blood loss. The optimization of our recently described substrate-analogue plasmin inhibitors, which were cyclized between their P3 and P2 side chains, provided a new series with improved efficacy and excellent selectivity. The most potent inhibitor 8 binds to plasmin with an inhibition constant of 0.2 nM, whereas K(i) values >1 μM were determined for nearly all other tested trypsin-like serine proteases, with the exception of trypsin, which is also inhibited in the nanomolar range. Docking studies revealed a potential binding mode in the widely open active site of plasmin that explains the strong potency and selectivity profile of these inhibitors. The dialkylated piperazine-linker segment contributes to an excellent solubility of all analogues. Based on their overall profile the presented inhibitors are well suited for further development as injectable antifibrinolytic drugs. 22996307 Selective regulation of nicotine and polyamines biosynthesis in tobacco cells by enantiomers of ornithine. L- and D-amino acids have diverse functions and effects on the metabolism, growth, and development of plants. Ornithine (Orn) plays a main role in the biosynthesis of many amino acids, nicotinic alkaloids, and polyamines in tobacco. This investigation describes the impact of Orn enantiomers on the production and distribution of free, conjugated, and bound polyamines, as well as nicotine in tobacco cells. It was recognized that the biosynthesis of metabolites was differently upregulated by each enantiomer. Putrescine was abundantly produced by exogenous L-ornithine (L-Orn), and both spermidine and spermine were significantly accumulated in D-ornithine (D-Orn)-supplied tobacco cells. Furthermore, nicotine production was highly upregulated by L-Orn, while the addition of D-Orn had no effect on the nicotine content of tobacco cells. It was observed that transcript expression of S-adenosylmethionine decarboxylase, as the key enzyme of spermidine/spermine biosynthesis, is coincident with their metabolic levels and is highly upregulated by D-Orn, as opposed to L-Orn. These results indicate that both enantiomers of Orn can trigger selected biosynthetic pathways in the cells, at the transcript level. Regarding these observations, it is proposed that L- and D-Orn function differently in the same biological pathways in which the latter, D-Orn specifically regulates important polyamines in the plant cells. 23920025 Using developmental trajectories to examine verbal and visuospatial short-term memory development in children and adolescents with Williams and Down syndromes. Williams (WS) and Down (DS) syndromes have been associated with specifically compromised short-term memory (STM) subsystems. Individuals with WS have shown impairments in visuospatial STM, while individuals with DS have often shown problems with the recall of verbal material. However, studies have not usually compared the development of STM skills in these domains, in these populations. The present study employed a cross-sectional developmental trajectories approach, plotting verbal and visuospatial STM performance against more general cognitive and chronological development, to investigate how the domain-specific skills of individuals with WS and DS may change as development progresses, as well as whether the difference between STM skill domains increases, in either group, as development progresses. Typically developing children, of broadly similar cognitive ability to the clinical groups, were also included. Planned between- and within-group comparisons were carried out. Individuals with WS and DS both showed the domain-specific STM weaknesses in overall performance that were expected based on the respective cognitive profiles. However, skills in both groups developed, according to general cognitive development, at similar rates to those of the TD group. In addition, no significant developmental divergence between STM domains was observed in either clinical group according to mental age or chronological age, although the general pattern of findings indicated that the influence of the latter variable across STM domains, particularly in WS, might merit further investigation. 23358945 Closed-loop control of renal perfusion pressure in physiological experiments. This paper presents the design, experimental modeling, and control of a pump-driven renal perfusion pressure (RPP)-regulatory system to implement precise and relatively fast RPP regulation in rats. The mechatronic system is a simple, low-cost, and reliable device to automate the RPP regulation process based on flow-mediated occlusion. Hence, the regulated signal is the RPP measured in the left femoral artery of the rat, and the manipulated variable is the voltage applied to a dc motor that controls the occlusion of the aorta. The control system is implemented in a PC through the LabView software, and a data acquisition board NI USB-6210. A simple first-order linear system is proposed to approximate the dynamics in the experiment. The parameters of the model are chosen to minimize the error between the predicted and experimental output averaged from eight input/output datasets at different RPP operating conditions. A closed-loop servocontrol system based on a pole-placement PD controller plus dead-zone compensation was proposed for this purpose. First, the feedback structure was validated in simulation by considering parameter uncertainty, and constant and time-varying references. Several experimental tests were also conducted to validate in real time the closed-loop performance for stepwise and fast switching references, and the results show the effectiveness of the proposed automatic system to regulate the RPP in the rat, in a precise, accurate (mean error less than 2 mmHg) and relatively fast mode (10-15 s of response time). 23685029 Evaluation of bacteriophage therapy to control Clostridium difficile and toxin production in an in vitro human colon model system. Clostridium difficile is a leading cause of hospital-acquired diarrhoea and represents a major challenge for healthcare providers. Due to the decreasing efficacy and associated problems of antibiotic therapy there is a need for synergistic and alternative treatments. In this study we investigated the use of a specific bacteriophage, ΦCD27, in a human colon model of C. difficile infection. Our findings demonstrate a significant reduction in the burden of C. difficile cells and toxin production with phage treatment relative to an untreated control, with no detrimental effect on commensal bacterial populations. The results demonstrate the potential of phage therapy, and highlight the limitations of using phages that have lysogenic capacity. 23410729 Cluster of Urrets-Zavalia syndrome: a sequel of toxic anterior segment syndrome. To report the largest cluster of Urrets-Zavalia Syndrome (UZS), which occurred as a sequel of toxic anterior segment syndrome (TASS) after uneventful cataract surgery, and to evaluate the possible causes and risk factors to prevent additional cases. Department of Ophthalmology, Liaquat University of Medical & Health Sciences, Hyderabad, Pakistan. Prospective Case Series. 15 consecutive TASS cases following uneventful cataract surgery were evaluated for potential causes and risk factors. Main outcome measures included visual acuity, anterior segment reaction, corneal oedema, intraocular pressure, pupillary reaction and response to topical and/or systemic steroid therapy at first day, first week and first month postoperatively. The TASS incidence in this study was 0.08%. All cases presented with corneal oedema, anterior chamber reaction and fixed dilated pupils on first postoperative day. One month postoperatively, the anterior segment inflammation improved considerably in all patients. There was a statistically significant difference between the mean Best-corrected visual acuity (BCVA) at first postoperative day (2.32±0.93 LogMAR) and mean BCVA at 1 month (0.49±0.12 LogMAR) (p=0.0001). The rate of UZS in this study was 93%. Ringer lactate solution was found to be the offending agent of TASS, and replacing it brought a halt to this cluster. Timely diagnosis, steroid therapy and close monitoring are the main keys for properly managing TASS. To our knowledge, we report, for the first time, the largest cluster of UZS occurring as a sequel of TASS. 23872305 NUP214-ABL1 mediated cell proliferation in T-cell acute lymphoblastic leukemia is dependent on the LCK kinase and various interacting proteins. The NUP214-ABL1 fusion protein is a constitutively active protein tyrosine kinase that is found in 6% of patients with T-cell acute lymphoblastic leukemia and that promotes proliferation and survival of T-lymphoblasts. Although NUP214-ABL1 is sensitive to ABL1 kinase inhibitors, development of resistance to these compounds is a major clinical problem, underlining the need for additional drug targets in the sparsely studied NUP214-ABL1 signaling network. In this work, we identify and validate the SRC family kinase LCK as a protein whose activity is absolutely required for the proliferation and survival of T-cell acute lymphoblastic leukemia cells that depend on NUP214-ABL1 activity. These findings underscore the potential of SRC kinase inhibitors and of the dual ABL/SRC kinase inhibitors dasatinib and bosutinib for treating of NUP214-ABL1 positive T-cell acute lymphoblastic leukemia. In addition, we used mass spectrometry to identify protein interaction partners of NUP214-ABL1. Our results strongly support that the signaling network of NUP214-ABL1 is distinct from that previously reported for BCR-ABL1. Moreover, we identify three NUP214-ABL1 interacting proteins, MAD2L1, NUP155, and SMC4, as strictly required for the proliferation and survival of NUP214-ABL1 positive T-cell acute lymphoblastic leukemia cells. In conclusion, this work identifies LCK, MAD2L1, NUP155 and SMC4 as four new potential drug targets in NUP214-ABL1 positive T-cell acute lymphoblastic leukemia. 23788145 Chronic pain following abdominal free flap breast reconstruction: a prospective pilot analysis. Chronic pain after breast reconstruction is an ill-defined process which can generate significant patient morbidity and disability. The purpose of this study was to examine chronic, persistent pain in a prospective study of free flap breast reconstruction patients, in an effort to identify possible points of intervention and counseling. We performed a prospective study evaluating function, quality of life, and satisfaction in patients undergoing abdominally based autologous reconstruction between 2006 and 2010. Using the short form 36, we examined the presence of chronic body pain (>4 months) as well as overall mental and physical health. Patients with debilitating pain were compared to those without in a post hoc analysis. Overall, 399 women underwent reconstruction during the study period, with 149 enrolling and having long-term follow-up in this portion of the prospective study. Twenty-six (17%) of 149 patients experienced chronic body pain that was moderately debilitating after autologous reconstruction, making it one of the most common complications experienced in this cohort. No differences were noted in demographics, medical history, procedure type, history of axillary surgery, radiation treatment, surgical outcomes, or follow-up time between the cohorts. However, patients with chronic pain were found to have higher preoperative pain scores (P < 0.0001) and lower physical, mental, and overall health scores across time points. All scores significantly worsened with time in comparison to the cohort without pain, who, in contrast showed score improvement across all areas. Although pain issues trended toward being noted in postoperative visits more frequently in the chronic pain cohort (37% vs 19%, P = 0.051), only 1 (4.2%) patient was referred for pain service consultation. Additionally, satisfaction with reconstruction was significantly lower in patients who demonstrated chronic pain (P = 0.03). Factors contributing to chronic pain continue to be elusive and understudied. Our data demonstrate the importance of screening for chronic pain, as we determined that preoperative pain is linked to increased, moderately debilitating postoperative chronic pain. Persistent chronic pain, in turn, is associated with significant morbidity, disability, and dissatisfaction. Such patients with pain issues may benefit from additional preoperative counseling and early involvement of the pain service. 22974071 The pragmatic language abilities of children with ADHD following a play-based intervention involving peer-to-peer interactions. Abstract Children with Attention Deficit Hyperactivity Disorder (ADHD) commonly experience significant pragmatic language deficits which put them at risk of developing emotional and social difficulties. This study aimed to examine the pragmatic language exhibited in a peer-to-peer interaction between the children with ADHD and their playmates following a pilot play-based intervention. Participants were children (aged 5-11 years) diagnosed as having ADHD (n = 14) and their self-selected typically-developing playmate. Pragmatic language was measured using the Pragmatic Protocol (PP) and the Structured Multidimensional Assessment Profiles (S-MAPs). Children's structural language was also screened and compared against their pragmatic language skills pre-post play-based intervention. The pragmatic language of children with ADHD improved significantly from pre-post intervention as measured by both the PP and S-MAPs. Both children with and without structural language difficulties improved significantly from pre- to post-intervention using S-MAPs; only children with structural language difficulties improved significantly using PP. The findings support the notion that pragmatic skills may improve following a play-based intervention that is characterized by didactic social interaction. As pragmatic language is a complex construct, it is proposed that clinicians and researchers reconsider the working definition of pragmatic language and the operationalization thereof in assessments. 23628338 Understanding sources of sea lice for salmon farms in Chile. The decline of fisheries over recent decades and a growing human population has coincided with an increase in aquaculture production. As farmed fish densities increase, so have their rates of infectious diseases, as predicted by the theory of density-dependent disease transmission. One of the pathogen that has increased with the growth of salmon farming is sea lice. Effective management of this pathogen requires an understanding of the spatial scale of transmission. We used a two-part multi-scale model to account for the zero-inflated data observed in weekly sea lice abundance levels on rainbow trout and Atlantic salmon farms in Chile, and to assess internal (farm) and external (regional) sources of sea lice infection. We observed that the level of juvenile sea lice was higher on farms that were closer to processing plants with fish holding facilities. Further, evidence for sea lice exposure from the surrounding area was supported by a strong positive correlation between the level of juvenile sea lice on a farm and the number of gravid females on neighboring farms within 30 km two weeks prior. The relationship between external sources of sea lice from neighboring farms and juvenile sea lice on a farm was one of the strongest detected in our multivariable model. Our findings suggest that the management of sea lice should be coordinated between farms and should include all farms and processing plants with holding facilities within a relatively large geographic area. Understanding the contribution of pathogens on a farm from different sources is an important step in developing effective control strategies. 23634807 Pepino mosaic virus triple gene block protein 1 (TGBp1) interacts with and increases tomato catalase 1 activity to enhance virus accumulation. Various plant factors are co-opted by virus elements (RNA, proteins) and have been shown to act in pathways affecting virus accumulation and plant defence. Here, an interaction between Pepino mosaic virus (PepMV) triple gene block protein 1 (TGBp1; p26) and tomato catalase 1 (CAT1), a crucial enzyme in the decomposition of toxic hydrogen peroxide (H₂O₂), was identified using the yeast two-hybrid assay, and confirmed via an in vitro pull-down assay and bimolecular fluorescent complementation (BiFC) in planta. Each protein was independently localized within loci in the cytoplasm and nuclei, sites at which their interaction had been visualized by BiFC. Following PepMV inoculation, CAT mRNA and protein levels in leaves were unaltered at 0, 3 and 6 days (locally) and 8 days (systemically) post-inoculation; however, leaf extracts from the last two time points contained increased CAT activity and lower H₂O₂ evels. Overexpression of PepMV p26 in vitro and in planta conferred the same effect, suggesting an additional involvement of TGBp1 in potexvirus pathogenesis. The accumulation of PepMV genomic and subgenomic RNAs and the expression of viral coat protein in noninoculated (systemic) leaves were reduced significantly in CAT-silenced plants. It is postulated that, during PepMV infection, a p26-CAT1 interaction increases H₂O₂ cavenging, thus acting as a negative regulator of plant defence mechanisms to promote PepMV infections. 23836837 Participation in cardiac rehabilitation and survival after coronary artery bypass graft surgery: a community-based study. Cardiac rehabilitation (CR) is recommended for all patients after coronary artery bypass surgery, yet little is known about the long-term mortality effects of CR in this population. We performed a community-based analysis on residents of Olmsted County, Minnesota, who underwent coronary artery bypass surgery between 1996 and 2007. We assessed the association between subsequent outpatient CR attendance and long-term survival. Propensity analysis was performed. Cox proportional hazards regression was then used to assess the association between CR attendance and all-cause mortality adjusted for the propensity to attend CR. We identified 846 eligible patients (age 66±11 years, 76% men, and 96% non-Hispanic whites) who survived at least 6 months after surgery, of whom 582 (69%) attended CR. During a mean (±SD) follow-up of 9.0±3.7 years, the 10-year all-cause Kaplan-Meier mortality rate was 28% (193 deaths). Adjusted for the propensity to attend CR, participation in CR was associated with a 10-year relative risk reduction in all-cause mortality of 46% (hazard ratio, 0.54; 95% confidence interval, 0.40-0.74; P<0.001) and a 10-year absolute risk reduction of 12.7% (number needed to treat=8). There was no evidence of a differential effect of CR on mortality with respect to age (≥65 versus <65 years), sex, diabetes, or prior myocardial infarction. CR attendance is associated with a significant reduction in 10-year all-cause mortality after coronary artery bypass surgery. Our results strongly support national standards that recommend CR for this patient group. 23937753 Outcomes of Functional Weight-bearing Rehabilitation of Achilles Tendon Ruptures. The introduction of functional rehabilitation for patients with Achilles tendon rupture has dramatically changed treatment programs for this condition. The authors introduced a functional weight-bearing protocol for patients with an acute Achilles tendon rupture treated operatively and nonoperatively in 2002. They hypothesized that no significant differences would exist in the rerupture rates and functional outcomes between the groups. Between 2002 and 2008, the authors collected data on 80 consecutive patients treated with a weight-bearing functional orthosis for complete Achilles tendon rupture. Following evidence-based counseling, 51 patients chose nonoperative treatment and 29 chose operative treatment. Outcome measures included rerupture rates, other complications, and functional scoring. The nonoperative group was a decade older (median age, 47 years [range, 27-80 years]) than the operative group (median age, 37 years [range, 24-55 years]). Rerupture was noted in 2 (4%) patients in the nonoperative treatment group and 1 (3%) patient in the operative group. Two (7%) patients in the operative group developed superficial wound infections and reported no nerve injuries. Median Achilles Tendon Total Rupture Score was 82 points in the nonoperative group and 94 in the operative group. Median Victorian Institute of Sports Assessment-Achilles tendinopathy questionnaire scores were 60 and 91 for the nonoperative and operative groups, respectively. Both groups had low rerupture rates. Functional scores, using the newly validated Achilles Tendon Total Rupture Score, were lower in the nonoperative group. 23896214 Does low serum 25 OH vitamin D interact with very strenuous physical activity, facilitating development of rhabdomyolysis? Vitamin D plays an important and increasingly understood role in muscle health and performance. Vitamin D exhibits a nuclear receptor for transcription interaction and a transmembrane receptor, giving it genomic and non-genomic interactions. Vitamin D receptors have been described that affect muscle function. Vitamin D has also been correlated with muscle performance. Beyond its role in normal muscle function, vitamin D deficiency can interact with statins to produce myalgia-myositis, which can be reversed by normalizing serum vitamin D [7,13]. Exertional rhabdomyolysis may occur in diverse settings including marathons, ice skating, bicycling and swimming. Our hypothesis is that subjects with pre-existing low serum 25OHD are selected out for exertional rhabdomyolysis during strenuous activities. We review exercise induced severe rhabdomyolysis in association with heat stroke with subsequent disseminated intravascular coagulation in a thin, athletic, dark skinned, conditioned young man, occurring in the setting of a 5K race, subsequently found to have severe 25 OH vitamin D deficiency (6ng/ml, laboratory lower normal limit >30ng/ml). We suggest that when very low vitamin D is documented, it be normalized before major prolonged exertion. We hypothesize that normalization of vitamin D before heavy exertion could perhaps prevent the severe muscle damage events and sequelae as was the case for this patient. 23768836 Co-occurring insomnia and obstructive sleep apnea. Prior research investigating co-occurring insomnia/obstructive sleep apnea (CIO) has mainly focused on comparing comorbid patients, obstructive sleep apnea (OSA), and insomnia (INS) to those with OSA alone. This approach is informative but omits the potentially interesting comparison of comorbid patients to those with INS alone. Our study used an incomplete factorial design, crossing OSA (present or absent) with INS (present or absent) to more clearly focus on the question, is comorbid INS an epiphenomenon of OSA or an independent disorder? Our study was an archival analysis from the database of a sleep center comparing consecutively diagnosed patients characterized as OSA or INS. A third group, CIO, was derived from the OSA group. Our study was conducted at an American Academy of Sleep Medicine-accredited sleep disorders center. We studied 299 patients, including 94 OSA, 97 INS, and 108 CIO. Patients ranged from ages 15 to 86years. Groups were compared on polysomnography (PSG), sleep pattern, sleep stages, sleep pathology, self-reported sleep concerns, and self-reported daytime functioning. From a consecutive group of OSA patients, we estimate the prevalence of CIO at 67.4%. Based mainly on multivariate analysis of covariance (MANCOVA) controlling for demographic differences between groups, we found few if any significant differences between CIO and INS alone or between CIO and OSA alone. The clinical presentation of CIO is indistinguishable from INS alone, both with respect to PSG findings and to self-reported sleep onset and sleep maintenance disturbance. We observed a weak relation between OSA severity and co-occurring INS. These data are consistent with the view that INS with co-occurring OSA is an independent, self-sustaining disorder. We hypothesized that in some unknown proportion of cases, OSA initially instigated the INS, but the INS was then perpetuated and reshaped by sleep concerns and self-defeating compensatory behaviors. 23032726 Imaging in the cardiovascular and metabolic disease area. There is a widely held belief that the use of non-invasive imaging can reduce the gap between basic science and clinical proof-of-concept, ultimately improving decision-making and therefore the efficiency of the drug development process. Imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) are routinely used in oncology and neuroscience drug development. However, less attention has been paid to the systematic use of imaging in the cardiovascular and metabolic disease area. Here, with an emphasis on 'early clinical' development, we discuss the application of imaging in those areas, highlighting opportunities and challenges. 23968147 Transglutaminse 2 and EGGL, the protein cross-link formed by Transglutaminse 2, as therapeutic targets for disabilities of old age. Ageing of the extracellular matrix (ECM), the protein matrix that surrounds and penetrates the tissues and binds the body together, contributes significantly to functional aging of tissues. ECM proteins become increasingly cross-linked with age, and this cross-linking is probably important in the decline of the ECM's function. In this paper I review the role of EGGL, a cross-link formed by transglutaminase enzymes, and particularly the widely expressed isozyme TG2, in the aging ECM. There is little direct data on EGGL accumulation with age, and no direct evidence of a role of EGGL in the aging of the ECM outwith pathology. However, several lines of circumstantial evidence suggest that EGGL accumulates with age, and its association with pathology suggests that this might reflect degradation of ECM function. TG activity increases with age in many circumstances, ECM protein turnover is such that some EGGL made by TG is likely to remain in place for years if not decades in healthy tissue, and both EGGL and TG levels are enhanced by age-related diseases. If further research shows EGGL does accumulate with age, removing it could be of therapeutic benefit. I review blockade of TG and active removal of EGGL as therapeutic strategies, and conclude that both have promise. EGGL removal may have benefit for acute fibrotic diseases such as tendinopathy, and for treating generalized decline in ECM function with old age. Extracellular TG2 and EGGL are therefore therapeutic targets both for specific and more generalized diseases of aging. 23964961 Potent Histone Deacetylase Inhibitors Derived from 4-(Aminomethyl)-N-hydroxybenzamide with High Selectivity for the HDAC6 Isoform. A screen for HDAC6 inhibitors identified acyl derivatives of 4-(aminomethyl)-N-hydroxybenzamide as potent leads with unexpected selectivity over the other sub-types. We designed and synthesized constrained heterocyclic analogs such as tetrahydroisoquinolines that show further enhanced HDAC6 selectivity and inhibitory activity in cellular assays. Selectivity may be attributed to the benzylic spacer more effectively accessing the wider channel of HDAC6 compared to other HDAC sub-types as well as hydrophobic capping groups interacting with the protein surface near the rim of the active site. 23957376 Trough colistin plasma level is an independent risk factor for nephrotoxicity: a prospective observational cohort study. Data regarding the most efficacious and least toxic schedules for the use of colistin are scarce. The aim of this study was to determine the incidence and the potential risk factors of colistin-associated nephrotoxicity including colistin plasma levels. A prospective observational cohort study was conducted for over one year in patients receiving intravenous colistin methanesulfonate sodium (CMS). Blood samples for colistin plasma levels were collected immediately before (Cmin) and 30 minutes after CMS infusion (Cmax). Renal function was assessed at baseline, on day 7 and at the end of treatment (EOT). Severity of acute kidney injury (AKI) was defined by the RIFLE (risk, injury, failure, loss, and end-stage kidney disease) criteria. One hundred and two patients met the inclusion criteria. AKI related to CMS treatment on day 7 and at the end of treatment (EOT) was observed in 26 (25.5%) and 50 (49.0%) patients, respectively. At day 7, Cmin (OR, 4.63 [2.33-9.20]; P < 0.001) was the only independent predictor of AKI. At EOT, the Charlson score (OR 1.26 [1.01-1.57]; P = 0.036), Cmin (OR 2.14 [1.33-3.42]; P = 0.002), and concomitant treatment with >= 2 nephrotoxic drugs (OR 2.61 [1.0-6.8]; P = 0.049) were independent risk factors for AKI. When Cmin was evaluated as a categorical variable, the breakpoints that better predicted AKI were 3.33 mg/L (P < 0.001) on day 7 and 2.42 mg/L (P < 0.001) at EOT. When using the RIFLE criteria, colistin-related nephrotoxicity is observed in a high percentage of patients. Cmin levels are predictive of AKI. Patients who receive intravenous colistin should be closely monitored and Cmin might be a new useful tool to predict AKI. 23846167 Mechanistic insights into iron catalyzed dehydrogenation of formic acid: β-hydride elimination vs. direct hydride transfer. Density functional theory calculations reveal a complete reaction mechanism with detailed energy profiles and transition state structures for the dehydrogenation of formic acid catalyzed by an iron complex, [P(CH2CH2PPh2)3FeH](+). In the cationic reaction pathway, a β-hydride elimination process is confirmed to be the rate-determining step in this catalytic reaction. A potential reaction pathway starting with a direct hydride transfer from HCOO(-) to Fe is found to be possible, but slightly less favorable than the catalytic cycle with a β-hydride elimination step. 23890256 Detection and molecular typing of Leishmania tropica from Phlebotomus sergenti and lesions of cutaneous leishmaniasis in an emerging focus of Morocco. Cutaneous leishmaniasis is an infectious disease caused by flagellate protozoa of the genus Leishmania. In Morocco, anthroponotic cutaneous leishmaniasis due to Leishmania tropica is considered as a public health problem, but its epidemiology has not been fully elucidated. The main objective of this study was to detect Leishmania infection in the vector, Phlebotomus sergenti and in human skin samples, in the El Hanchane locality, an emerging focus of cutaneous leishmaniasis in central Morocco. A total of 643 sand flies were collected using CDC miniature light traps and identified morphologically. Leishmania species were characterized by ITS1 PCR-RFLP and ITS1-5.8S rRNA gene nested-PCR of samples from 123 females of Phlebotomus sergenti and 7 cutaneous leishmaniasis patients. The sand flies collected consisted of 9 species, 7 of which belonged to the genus Phlebotomus and two to the genus Sergentomyia. Phlebotomus sergenti was the most predominant (76.67%).By ITS1 PCR-RFLP Leishmania tropica was found in three Phlebotomus sergenti females and four patients (4/7). Using nested PCR Leishmania tropica was identified in the same three Phlebotomus sergenti females and all the 7 patients. The sequencing of the nested PCR products recognized 7 haplotypes, of which 6 have never been described. This is the first molecular detection and identification of Leishmania tropica in human skin samples and Phlebotomus sergenti in support of its vector status in El Hanchane. The finding of seven Leishmania tropica haplotypes underscores heterogeneity of this species at a high level in Morocco. 23871080 In vivo digestion of bovine milk fat globules: Effect of processing and interfacial structural changes. II. Upper digestive tract digestion. The aim of this research was to study the effect of milk processing on the in vivo upper digestive tract digestion of milk fat globules. Fasted rats were serially gavaged over a 5h period with cream from raw, pasteurised, or pasteurised and homogenised milk. Only a few intact dietary proteins and peptides were present in the small intestinal digesta. Significantly (P<0.05) more longer chain (C⩾10) fatty acids were present in the digesta of rats gavaged with raw (448mgg(-1) digesta dry matter (DDM)) and homogenised creams (528mgg(-1) DDM), as compared to pasteurised and homogenised cream (249mgg(-1) DDM). Microscopy techniques were used to investigate the structural changes during digestion. Liquid-crystalline lamellar phases surrounding the fat globules, fatty acid soap crystals and lipid-mucin interactions were evident in all small intestinal digesta. Overall, the pasteurised and homogenised cream appeared to be digested to a greater extent. 23570697 In situ electron backscatter diffraction investigation of recrystallization in a copper wire. The microstructural evolution of a cold drawn copper wire (reduction area of 38%) during primary recrystallization and grain growth was observed in situ by electron backscatter diffraction. Two thermal treatments were performed, and successive scans were acquired on samples undergoing heating from ambient temperature to a steady state of 200°C or 215°C. During a third in situ annealing, the temperature was continuously increased up to 600°C. Nuclei were observed to grow at the expense of the deformed microstructure. This growth was enhanced by the high stored energy difference between the nuclei and their neighbors (driving energy in recrystallization) and by the presence of high-angle grain boundaries of high mobility. In the early stages of growth, the nuclei twin and the newly created orientations continue to grow to the detriment of the strained copper. At high temperatures, the disappearance of some twins was evidenced by the migration of the incoherent twin boundaries. Thermal grooving of grain boundaries is observed at these high temperatures and affects the high mobile boundaries but tends to preserve the twin boundaries of lower energy. Thus, grooving may contribute to the twin vanishing. 23082771 ALK-positive anaplastic large cell lymphoma presenting as intradural spinal mass: First reported case and review of literature. Anaplastic large cell lymphoma (ALCL) is characterized by large anaplastic cells of T-cell or null-cell phenotype expressing CD30 (Ki-1 antigen). In most cases this neoplasm expresses the anaplastic lymphoma kinase (ALK), a chimeric protein resulting from the t(2;5)(p23;q35) translocation. ALK-positive anaplastic large cell lymphoma is most frequent in the first three decades of life and shows a male predominance, involving both nodal and extranodal sites, but rarely the CNS. We report a 21-year-old patient with a previous history of nodal ALK-positive ALCL, lymphohistiocytic subtype, who was admitted for recent occurrence of left-sided anesthesia with pain and progressive motor weakness of both legs. An MRI of the spine documented an intradural extramedullary mass dislocating the thoracic cord, suggesting a meningioma and the patient underwent surgical decompression. Histological examination revealed a lymphoproliferative neoplasm with morphology and immunophenotype of ALK-positive anaplastic large cell lymphoma. After surgery, all preoperative symptoms disappeared. To our knowledge, no cases of ALCL presenting as secondary localization with an intradural extramedullary spinal mass have been reported in the literature. 23755924 Results of a 5-week schedule of modern total skin electron beam radiation therapy. To report the outcomes of a 5-week schedule of total skin electron beam radiation therapy (TSEB) for mycosis fungoides (MF). Over 5 years, 41 patients with confirmed MF were treated with a modern TSEB technique delivering 30 Gy in 20 fractions over 5 weeks to the whole skin surface. Data were collected prospectively and entered into the skin tumor unit research database. Skin modified skin weighted assessment tool score data were collected to determine response, duration of response, survival, and toxicity. The outcomes were analyzed according to the patient's stage before TSEB, prognostic factors, and adjuvant treatments. Seventeen patients were stage 1B, 19 were stage IIB, 3 were stage III, and 2 were stage IV. The overall response rate was 95%, with a complete response rate of 51%. Seventy-six percent of patients had relapsed at median follow-up of 18 months. The median time to relapse was 12 months, to systemic therapy was 15 months, and to modified skin weighted assessment tool progression above baseline was 44 months. The complete response rate was 59% in stage IB and 47% in stage IIB patients. The median time to skin relapse was longer in stage IB compared with stage IIB, 18 months versus 9 months. The median time to systemic therapy was longer in stage IB compared with stage IIB, >56 months versus 8 months. The median overall survival was 35 months: >56 months for stage IB, 25 months for stage IIB, 46 months for stage III, and 23.5 months for stage IV. Fifteen patients received adjuvant psoralen + ultraviolet A treatment with no difference seen in the time to relapse. This 5-week schedule of TSEB for MF has a high response rate with comparable duration of response to other regimens. Future studies are needed to find adjuvant and combination treatments to improve the duration of response. 23876714 A new method to analyze postural stability during a transition task from double-leg stance to single-leg stance. Time to stabilization (TTS) has been introduced as a method to analyze dynamic postural stability during jump and landing tasks, but has also been applied during the transition task from double-leg stance (DLS) to single-leg stance (SLS). However, the application of the originally described TTS technique during the latter task has some important limitations. The first goal of this study was to present an adapted version of the TTS technique to provide an effective alternative method to better analyze postural stability during the transition from DLS to SLS. The second goal was to study the influence of pathology and different speeds on postural stability outcomes. Fifteen healthy control subjects and 15 subjects with chronic ankle instability (CAI) performed the transition task on their preferred speed and as fast as possible, with eyes open and with eyes closed. Subjects with CAI performed the transition significantly slower when moving at their preferred speed with eyes closed. The time subjects needed to reach a new stability point was not discriminative between groups and largely dependent on movement speed. However, the amount of sway after this new stability point was significantly increased in the CAI group and when eyes were closed. The results of this study suggest that subjects with CAI have a decreased ability to overcome the postural perturbation created by the voluntary movement from DLS to SLS. Focusing only on TTS during the transition from DLS to SLS may lead at least in some cases to misinterpretations when assessing postural stability. 23953935 Patient information ahead of thyroid surgery. Guidelines of the French Society of Oto-Rhino-Laryngology and Head and Neck Surgery (SFORL). The authors present the guidelines of the French Society of Oto-Rhino-Laryngology and Head and Neck Surgery (SFORL) on patient information ahead of thyroid surgery. A multidisciplinary medical team was tasked with a scientific literature review on this topic. The texts retrieved were analyzed by an independent committee. A joint meeting drew up the final guidelines. The strength of the recommendations (grade A, B or C) was based on levels of evidence. It is recommended that the results of preoperative exploration and the indications for surgery should be explained to the patient. Patients should be informed as to the type of surgery, surgical objectives, risks and consequences. It is mandatory to obtain the patient's written consent before surgery. Appropriate medical information is a critical step in patient management. 23845221 Development of 3D-QSAR CoMSIA models for 5-(biphenyl-2-yl)-1H-tetrazole derivatives as angiotensin II receptor type 1 (AT1) antagonists. As a development strategy for backups of Fimasartan (1), a comparative molecular similarity indices analysis (CoMSIA) of a set of sixty-five 5-(biphenyl-2-yl)-1H-tetrazole derivatives has been performed to find out the pharmacophore elements for angiotensin II receptor type 1 (AT1) blockade. The most potent compound containing pyrimidin-4(3H)-one ring, Fimasartan (1) was used to align the molecules. As a result, we obtained 3D-QSAR model which provided good predictivity for both the training set (q(2)=0.846, r(2)=0.975) and the external test set (rpred(2)=0.980). This model would guide the design of backups for Fimasartan (1), a launched oral antihypertensive agent. 23932629 A safer way of suturing in Foker's technique. Foker's technique allows esophageal lengthening facilitating end to end anastomosis in long gap esophageal atresia. The problem faced with this technique is that the traction sutures cut through the tissues leading to re-operations. Our aim was to find a technique of suturing that will prevent the sutures from cutting through the esophagus. After dissection of the upper and lower esophageal pouches, purse string sutures were placed, two each on both pouches. Clips were applied at the ends of both the pouches. Sutures were brought out on the posterior chest wall and traction applied. This was tried in a total of three cases. Case 1 was a newborn with pure esophageal atresia, Case 2 was an eighteen month old child with cervical esophagostomy and gastrostomy, and Case 3 had esophageal atresia with distal fistula. Two cases were done thoracoscopically and the third one by thoracotomy. In all three cases sutures held and lengthening could be obtained. In the first case it took twelve days, in the second case six days, and in third case eight days for the ends to come together. This modification of traction sutures is simple and reduces the risk of suture disruption. 23580782 Comparison of regulatory T cells in hemodialysis patients and healthy controls: implications for cell therapy in transplantation. Cell-based therapy with natural (CD4(+)CD25(hi)CD127(lo)) regulatory T cells to induce transplant tolerance is now technically feasible. However, regulatory T cells from hemodialysis patients awaiting transplantation may be functionally/numerically defective. Human regulatory T cells are also heterogeneous, and some are able to convert to proinflammatory Th17 cells. This study addresses the suitability of regulatory T cells from hemodialysis patients for cell-based therapy in preparation for the first clinical trials in renal transplant recipients (the ONE Study). Healthy controls and age- and sex-matched hemodialysis patients without recent illness/autoimmune disease on established, complication-free hemodialysis for a minimum of 6 months were recruited. Circulating regulatory T cells were studied by flow cytometry to compare the regulatory T cell subpopulations. Regulatory T cells from members of each group were compared for suppressive function and plasticity (IL-17-producing capacity) before and after in vitro expansion with and without Rapamycin, using standard assays. Both groups had similar total regulatory T cells and subpopulations I and III. In each subpopulation, regulatory T cells expressed similar levels of the function-associated markers CD27, CD39, HLA-DR, and FOXP3. Hemodialysis regulatory T cells were less suppressive, expanded poorly compared with healthy control regulatory T cells, and produced IL-17 in the absence of Rapamycin. However, Rapamycin efficiently expanded hemodialysis regulatory T cells to a functional and stable cell product. Rapamycin-based expansion protocols should enable clinical trials of cell-based immunotherapy for the induction of tolerance to renal allografts using hemodialysis regulatory T cells. 23519376 Gold nanoparticle-enhanced luminescence of silicon quantum dots co-encapsulated in polymer nanoparticles. The preparation of two-component polymer composite nanoparticles encapsulating both Si quantum dots (SiQDs) and Au nanoparticles (AuNPs) by a single step miniemulsion polymerization of divinylbenzene is described. This simple and robust method affords well-defined polymer composite nanoparticles with mean diameters in a range of 100-200 nm and with narrow polydispersity indices as determined by dynamic light scattering and transmission electron microscopy. The successful encapsulation of AuNPs within poly(divinylbenzene) was confirmed by UV-visible spectroscopy and from TEM images. Plasmon-enhanced fluorescence of the luminescence of the SiQDs by AuNPs encapsulated within the polymer composite nanoparticles was evaluated by confocal microspectroscopy, and luminescence enhancements of up to 15 times were observed. These observations indicate that the luminescence of the SiQDs is enhanced by the proximity of the AuNPs. The polymer composite nanoparticles were successfully ink-jet printed onto a glass substrate, which demonstrates that these composites are processable in printing applications. 23127602 Distribution, fate and histopathological effects of ethion insecticide on selected organs of the crayfish, Procambarus clarkii. This study aims to investigate the fate and histopathological effects of ethion on selected organs of the crayfish, Procamabrus clarkii. Crayfish were exposed to 1 mg l(-1) (14)C-ethion and the concentrations of ethion and its possible degradation products were measured in water and different organs of the crayfish over both the exposure and recovery periods. Chromatographic analysis revealed that ethion was degraded into ethion monooxon, ethion dioxon, O,O-diethyl phosphorothioate, O-ethyl phosphorothioate and one unknown compound. At the end of exposure period, ethion was accumulated in different organs of the crayfish especially in the hepatopancreas and gills. Following the transfer of crayfish to clean water for seven days, the concentration of insecticide residues were decreased in both the hepatopancreas and gills suggesting that these organs play an important role in elimination of ethion. On the other hand, the exposure of the crayfish to ¼ 96 h-LC(50) (0.36 mg l(-1)) of ethion caused extensive ultrastructural alterations to both hepatopancreas and gill epithelial cells. In the hepatopancreas, the most notable pathological features included vacuolation, degradation and distinct cell lysis. In the gill epithelium, the histopathological alterations included infiltration of hemocytes, cytoplasmic vacuolation and a decrease in the number of basal plasma membrane infoldings. 23899867 Validation of the Arabic Version of the Early Inflammatory Arthritis Detection Tool. Objective: To evaluate the reliability and validity of the Arabic version of the Early Inflammatory Arthritis Questionnaire (EIAQ-A), a detection tool for screening for early inflammatory arthritis (EIA) in Arabic-speaking populations. Subjects and Methods: A cross-sectional study was conducted among 30 consecutive participants (21 female and 9 male) attending the Internal Medicine Outpatient Clinic at Mubarak Al-Kabeer Hospital. They completed the self-administered EIAQ-A twice within a 2-week period. Their disease activity was evaluated during the visits based on clinical and laboratory variables. Cross-cultural adaptation was performed using forward and backward translations of the original questionnaire. Test-retest reliability of the EIAQ-A was evaluated using the measure of agreement, kappa (κ), between the response of participants in the two interviews. Internal consistency of the EIAQ-A was measured using the Kudar-Richardson-20 coefficient (KR-20), a binary response equivalent to Cronbach's α. External construct validity was assessed by Spearman's rank correlation coefficient (rs) between the score of EIAQ-A and both clinical and laboratory variables of disease activity. Results: The test-retest reliability for EIAQ-A was good (κ = 0.558) for the overall score and between 0.841 and 0.368 for the subscale scores. Internal consistency had an acceptable value of KR-20 = 0.869. The construct validity for EIAQ-A was high for all disease activity variables tested, rs was between 0.727 (swollen joint count) and 0.896 (visual analog scale pain score). Conclusion: The EIAQ-A was a reliable and valid tool for population screening for EIA. Its use may accelerate the early detection of EIA in Arabic-speaking communities. 23835032 Real-time cell analysis - A new method for dynamic, quantitative measurement of infectious viruses and antiserum neutralizing activity. A newly developed electronic cell sensor array - the xCELLigence real-time cell analysis (RTCA) system is tested currently for dynamic monitoring of cell attachment, proliferation, damage, and death. In this study, human enterovirus (HEV71) infection of human rhabdomyosarcoma (RD) was used as an in vitro model to validate the application of this novel system as a straightforward and efficient assay for quantitative measurement of infectious viruses based on virus-induced cytopathic effect (CPE). Several experimental tests were performed including the determination of optimal seeding density of the RD cells in 96-well E-plates, RTCA real-time monitoring of the virus induced CPE and virus titer calculation, and viral neutralization test to determine HEV71 antibody titer. Traditional 50% tissue culture infective dose (TCID50) assay was also conducted for methodology comparison and validation, which indicated a consistent result between the two assays. These findings indicate that the xCELLigence RTCA system can be a valuable addition to current viral assays for quantitative measurement of infectious viruses and quantitation of neutralization antibody titer in real-time, warranting for future research and exploration of applications to many other animal and human viruses. 23939913 Mapping Functional Interaction Sites of Human Prune C-Terminal Domain by NMR Spectroscopy in Human Cell Lysates. Get well prune: The C-terminal third domain of h-prune is largely unfolded and involved in relevant protein-protein interactions, particularly with Nm23-H1, GSK-3β and gelsolin. This study shows that protein functions mediated by protein-protein interactions can be accurately followed in cell lysates by using NMR spectroscopy fast experiments, which could be easily used for a very efficient NMR drug discovery strategy. 22574728 A new phenylethanoid glucoside from Plantago depressa Willd. Chemical research of Plantago depressa Willd. led to one new phenylethanoid glucoside with α-L-rhamnosyl (1 → 2)-β-D-glucose structure, together with four known compounds. These five compounds (1-5) were isolated from the family Plantaginaceae for the first time; the chemotaxonomic significance of cerebrosides was also discussed. 23893040 Enhanced second harmonic generation from Au nanoparticle arrays by femtosecond laser irradiation. Ultrafast laser irradiation of planar Au nanoparticle arrays is shown to double the particle plasmon quality factor and to enhance second harmonic generation 40-fold. It is found that the irradiation induces a morphological change of nano-cylinders into asymmetric droplet-like shapes with reduced surface roughness without altering their lithographically defined locations. These findings can be used to improve the performance of linear and nonlinear plasmonic devices. 23970150 Aging-Related Genes in Mesenchymal Stem Cells: A Mini-Review. Adult stem cells in mammalian organs play pivotal roles in the maintenance and repair of these organs throughout the life of the adult and maintain the proper homeostasis of a tissue or organ. Among the adult stem cells described to date, mesenchymal stem cells (MSCs) are highlighted for clinical applications because MSCs have many advantages for cell therapy, including multilineage differentiation, homing, immune modulation and wound-healing effects. However, as the aging of MSCs leads to an age-associated decline in their number and function, it is important to clarify the age-associated factors and regulatory mechanism associated with the MSC aging process. In this review, we amass and discuss the recent data related to age-associated genes in MSCs. In particular, the activities of epigenetic regulatory factors, including histone acetylase and DNA methyltransferase, modulate gene expression and crosstalk with each other during the MSC senescence process. p16(INK4A) and high-mobility group A2 play important age-associated roles in the regulation of MSC stemness, and lamin A- and prelamin A-dependent nuclear abnormalities have significant biological relevance in MSC aging. Taken together, the information described here, including the epigenetic regulatory factors, transcription factors and cell signaling, could be used toward the development of treatments for MSC aging and related defects. 23350855 Actinobaculum schaalii, a commensal of the urogenital area. WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Actinobaculum schaalii is considered to be a part of the normai flora in the genital and urinary tract area. It has been associated to urinary tract infection (UTI), sepsis, osteomyelitis, endocarditis and Foumier's gangrene. So far it has mainly been isolated from urine, blood and pus, and predominantly in elderly patients. This study examined the habitat of A. schaalii by collecting samples from skin and urine in patients with kidney or ureter stones before and after treatment with Extracorporeal Shock Wave Lithotripsy (ESWL). Additionally faeces and vaginal swabs from routine specimen in patients not undergoing ESWL and without known urinary calculi were also analysed. The study does not find A. schaalii in faeces but shows it to be presents on skin and mucosa in the genital area. A. schaalii is also shown a possible pathogen in the stone-patient group undergoing ESWL. To study the habitat of Actinobaculum schaalii by examing groin swabs, faeces samples and vaginal swabs, and to determine whether it is a common uropathogen in patients with kidney or ureter stones. A quantitative real-time PCR assay was used to analyse all samples, which were collected between 2010 and 2011. A total of 38 patients (24 men and 14 women), with kidney or ureter stones and undergoing extracorporeal shock wave lithotripsy (ESWL), provided urine samples and had groin swabs taken. In addition, 30 faecal samples and 19 vaginal swabs that had been sent for routine microbiological examinations from patients outside the ESWL group were analysed. A chi-squared test was used to analyse the differences between patient groups, studying samples from urine, faeces samples, groin swabs and vaginal swabs. Actinobaculum schaalii was found in the urine samples from 14 (37%) patients undergoing ESWL, and in both urine and groin swabs from seven (18%) patients. Actinobaculum schaalii was not found in faeces samples but it was found in six (32%) of the vaginal swabs, predominantly in patients >50 years (P = 0.06). The study indicates that A. schaalii is a commensal found on skin, urine and vaginal mucosa in the human urogenital area and supports other investigations in its finding that the elderly are at greatest risk of being colonized with A. schaalii. 23529686 Role of endometrial power Doppler ultrasound using the international endometrial tumor analysis group classification in predicting intrauterine pathology. To assess the contribution of the terms and definitions recently described by international endometrial tumor analysis (IETA) group when evaluating endometrial lesions on power Doppler imaging. Patients requiring endometrial sampling were examined prospectively by transvaginal B-mode and power Doppler sonography (PDS) the day before scheduled diagnostic procedure. Sonographic features were classified using IETA group classification. These were compared with the final histopathological diagnosis. Ninety-seven patients were included in the study. The histopathological diagnoses were as follows: endometrial polyp: 39 cases (40.2 %), endometrial hyperplasia: 9 cases (9.3 %), submucous myoma: 10 cases (10.3 %), endometrium cancer: 7 cases (7.2 %), non-specific findings: 32 cases (33 %). The sensitivity, specificity and positive and negative predictive values for single dominant or branching single dominant vessel pattern in diagnosing endometrial polyps were 66.67, 98.28, 96.3 and 81.43 %; for multiple vessels with focal origin pattern in diagnosing endometrial cancer, they were 42.86, 91.11, 27.27 and 95.35 %; for multifocal origin at the myometrial-endometrial junction in diagnosing other non-specific endometria, they were 81.25, 89.23, 78.79 and 90.62 %; for scattered vessel pattern in diagnosing endometrial hyperplasia, they were 88.89, 88.64, 44.4 and 98.73 % and for circular flow pattern in diagnosing submucosal fibroids, they were 80, 100, 100 and 97.75 %, respectively. The color score of the endometrium was not statistically different among different endometrial pathologies (P value >0.05). The nomenclature described by IETA group for power Doppler assessment of the endometrium is clinically valuable and reasonable. Using this terminology, it will be easier to compare results of different studies on endometrial Doppler sonography in the future. 23928208 Microalgae for high-value compounds and biofuels production: A review with focus on cultivation under stress conditions. Microalgal biomass as feedstock for biofuel production is an attracting alternative to terrestrial plant utilization for biofuels production. However, today the microalgal cultivation systems for energy production purposes seem not yet to be economically feasible. Microalgae, though cultivated under stress conditions, such as nutrient starvation, high salinity, high temperature etc. accumulate considerable amounts (up to 60-65% of dry weight) of lipids or carbohydrates along with several secondary metabolites. Especially some of the latter are valuable compounds with an enormous range of industrial applications. The simultaneous production of lipids or carbohydrates for biofuel production and of secondary metabolites in a biorefinery concept might allow the microalgal production to be economically feasible. This paper aims to provide a review on the available literature about the cultivation of microalgae for the accumulation of high-value compounds along with lipids or carbohydrates focusing on stress cultivation conditions. 23125180 Cross-species transcriptomic analysis of mouse and rat lung exposed to chloroprene. β-Chloroprene (2-chloro-1,3-butadiene), a monomer used in the production of neoprene elastomers, is of regulatory interest due to the production of multiorgan tumors in mouse and rat cancer bioassays. A significant increase in female mouse lung tumors was observed at the lowest exposure concentration of 12.8 ppm, whereas a small, but not statistically significant increase was observed in female rats only at the highest exposure concentration of 80 ppm. The metabolism of chloroprene results in the generation of reactive epoxides, and the rate of overall chloroprene metabolism is highly species dependent. To identify potential key events in the mode of action of chloroprene lung tumorigenesis, dose-response and time-course gene expression microarray measurements were made in the lungs of female mice and female rats. The gene expression changes were analyzed using both a traditional ANOVA approach followed by pathway enrichment analysis and a pathway-based benchmark dose (BMD) analysis approach. Pathways related to glutathione biosynthesis and metabolism were the primary pathways consistent with cross-species differences in tumor incidence. Transcriptional BMD values for the pathway were more similar to differences in tumor response than were estimated target tissue dose surrogates based on the total amount of chloroprene metabolized per unit mass of lung tissue per day. The closer correspondence of the transcriptional changes with the tumor response is likely due to their reflection of the overall balance between metabolic activation and detoxication reactions, whereas the current tissue dose surrogate reflects only oxidative metabolism. 23778778 Phytoremediation Potential of Solanum nigrum L. Under Different Cultivation Protocols. In this study, Solanum nigrum L. was used as a hyperaccumulator for remediation of cadmium contaminated soil, and 3 different cultivation protocols were investigated. The results showed that a double cropping treatment enhanced the phytoremediation efficiency significantly, since it increased the amount of Cd extracted in one growing season by a factor of 1.62 compared to single cropping. However, the labor cost for double cropping was twice that of single cropping. If the time consumed is considered as a cost of phytoremediation, the double cropping treatment might be considered as an effective and economic cultivation protocol by reducing the overall time required to reach the targeted soil quality. 23906670 Follow-up care for alcohol misuse among OEF/OIF veterans with and without AUD and PTSD. Little is known about follow-up care for alcohol misuse in the Veterans Affairs (VA) health care system among Operations Enduring and Iraqi Freedom (OEF/OIF) veterans with and without alcohol use disorders (AUD) and/or posttraumatic stress disorder (PTSD). Using data from 4725 OEF/OIF VA outpatients with alcohol screening (2006-2010), we compared the prevalence of follow-up for alcohol misuse-brief intervention (BI) or referral to treatment-among patients with and without AUD and/or PTSD. Among 933 (19.7%) patients with alcohol misuse (AUDIT-C ≥5), 77.0% had AUD and/or PTSD. Rates of BI or referral for alcohol misuse were higher among patients with AUD (76.9%) and both AUD and PTSD (70.1%) compared to those with PTSD only (53.1%) and neither AUD nor PTSD (52.3%). Among OEF/OIF VA outpatients with alcohol misuse, those with AUD had higher rates of follow-up for alcohol misuse than those without, but PTSD was not associated with differential follow-up. 23948903 Animal Models of the Sporadic Form of Alzheimer's Disease: Focus on the Disease and Not Just the Lesions. Alzheimer's disease is multifactorial and involves several different mechanisms. The sporadic form of the disease accounts for over 99% of the cases. As of yet, there is no practical and widely available animal model of the sporadic form of the disease. In the Alzheimer's disease brain, the lysosomal enzyme asparaginyl endopeptidase is activated and translocated from the neuronal lysosomes to the cytoplasm, probably due to brain acidosis caused by ischemic changes associated with age-associated microinfarcts. The activated asparaginyl endopeptidase cleaves inhibitor-2 of protein phosphatase-2A, I2PP2A, into I2NTF and I2CTF which translocate to the neuronal cytoplasm and inhibit the protein phosphatase activity and consequently the abnormal hyperphosphorylation of tau. Employing adeno-associated virus serotype 1 (AAV1) vector containing I2NTF-CTF and transduction of the brains of newborn rat pups with this virus, an animal model has been generated. The AAV1-I2NTF-CTF rats show neurodegeneration and cognitive impairment at 4 months and abnormal hyperphosphorylation and aggregation of tau and intraneuronal accumulation of amyloid-β at 13 months. The AAV1-I2NTF-CTF rats not only offer a disease-relevant model of the sporadic form of Alzheimer's disease but also represent a practical and widely available animal model. This short perspective on the need to focus on and develop the disease-relevant models of the sporadic form of Alzheimer's disease very much reflects the thinking of Inge Grundke-Iqbal who passed away on September 22, 2012 and to whom this article is dedicated. 23821466 The Therapeutic Potential of miRNAs in Cardiac Fibrosis: Where Do We Stand? Recent developments in basic and clinical science have turned the spotlight to miRNAs for their potential therapeutic efficacy. Since their discovery in 1993, it has become clear that miRNAs act as posttranscriptional regulators of protein expression. Their clinical potential was further highlighted by the results of miRNA-based interventions in small laboratory animals. More importantly, their therapeutic effectiveness has been shown recently in phase 2a clinical studies in patients with hepatitis C virus infection, where inhibition of miRNA-122 showed prolonged and dose-dependent viral suppression. A recent study surprisingly revealed the presence of plant-derived miRNAs in the blood of healthy humans. This finding opens up the possibility to explore miRNA-mediated therapeutics derived from (genetically modified) food. Having arrived at this point in our understanding of miRNAs, we provide an overview of current evidence and future potential of miRNA-based therapeutics, focusing on their application in cardiac fibrosis. 23921208 Synthesis, characterization and evaluation of release retardant modified starches of Lagenaria siceraria seeds. Starch isolated from under-utilized seeds of five different cultivars of Lagenaria siceraria (Mol.) standley (Cucurbitaceae) was carboxymethylated. The influence of the degree of substitution (DS) on physicochemical properties and drug release properties of starches was studied. The physicochemical profiles of the derivatives were assessed by means of FT-IR, XRD, SEM, elemental analysis, reaction efficiency, water binding capacity, swelling power, powder characteristics and visual estimation. The highest values of the DS obtained when the carboxymethylation was performed at 45°C for 4h. Scanning electron microscopy (SEM) showed that after carboxymethylation, the granular appearance of the native starch was distorted. The new bands at 1576.87cm(-1) and 1423.81cm(-1) in Fourier transform infrared (FT-IR) indicated that the starch granules were substituted. Wide-angle X-ray diffractometry revealed that crystallinity was reduced significantly after carboxymethylation. Powder studies revealed that these starches possess potential for pharmaceutical applications. The matrix tablets were found to release the drug by Korsmeyer and Peppas kinetics. The carboxymethylated starches with high DS can be used as a drug release retardant in sustained release formulations, as the drug dissolution rate of native starches was significantly lower than the modified starches. 23335063 Animal model for mammary tumor growth in the bone microenvironment. Advanced breast cancer commonly spreads to the bones, lungs, liver or brain, and bone is the most common site of breast cancer metastasis. Nearly all patients with advanced breast cancer develop bone metastasis and suffer from serious bone metastasis-associated complications, including chronic pain, fracture, spinal cord compression and hypercalcemia. Metastasis formation in the bone is a complex process that requires cooperative reciprocal interactions between tumor cells and the cellular environment of the bone, which includes osteoclasts and osteoblasts. We have developed a murine bone invasion model of breast cancer, which required a simple surgical technique and mimics the biology of the disease. Osteolytic and/or osteoblastic lesions induced in the tumor-bone interface allowed us to explore cellular and molecular interactions between malignant cells and skeletal tissue in a syngeneic setting. In this review, we will discuss a different animal model that provides a consistent and reproducible platform for investigating the molecular mechanisms underlying tumor-bone interaction and breast cancer-induced osteolytic changes. 23850417 Variable definitions of the influenza season and their impact on vaccine effectiveness estimates. Vaccine effectiveness (VE) studies are often made for a "season" which may refer to different analysis periods in different systems. We examined whether the use of four different definitions of season would materially affect estimates of influenza VE using data from the Victorian general practice sentinel surveillance network for 2007-2012. In general, the choice of analysis period had little effect on VE estimates (≤five percentage points) when there was a statistically significant protective effect of vaccination (2007, 2010 and 2012). In contrast, for years when the analysis period varied widely depending on the method used and when VE estimates were imprecise, the change in VE estimate was as much as 43 percentage points (2008). Studies of influenza VE should clearly define the analysis period used and, where possible, provide sensitivity analyses to align this definition with other VE studies. 23567630 High throughput capture of circulating tumor cells using an integrated microfluidic system. In this work, we introduced an integrated microfluidic system for fast and efficient circulating tumor cell (CTC) isolation and capture. In this microfluidic platform, a combination of microfluidic deterministic lateral displacement array and affinity-based cell capture architecture, allows for the high efficiency cancer cell enrichment and continuous high throughput and purity cancer cell capture. Using this device to isolate breast cancer cells from spiked blood samples, we achieved an enrichment factor of 1500×, and a high processing throughput of 9.6mL/min with 90% capture yield and more than 50% capture purity at cell concentration 10(2)cells/mL. This integrated platform offers a promising approach for CTC capture with high recovery rates, purity and stability, and exhibits potential capability in cancer cell culture and drug screening. 23808570 Early stage alopecia areata is associated with inflammation in the upper dermis and damage to the hair follicle infundibulum. Alopecia areata (AA) is a non-scarring inflammatory hair loss disease. We investigated the early pathological changes of AA to identify possible factors participating in its pathogenesis. Clinical, laboratory and pathological features of 87 AA patients were investigated. Anti-nuclear antibody was found in 11 of 85 patients tested (13%), with a higher percentage in women (21%) than men (5%) (P = 0.026). In early AA lesions, inflammatory infiltration in the upper dermis and epithelial cell damage of the hair follicle infundibulum, just above the sebaceous gland, was observed. Liquefaction and disarrangement of peripheral infundibular epithelial cells coexisted with T-lymphocytic invasion and regression of the lower follicle. The latter findings positively correlated with the presence of eosinophils and perivascular mononuclear cell infiltration in the upper dermis. Eosinophilic infiltration was found in 35 patients (40%) and was positively correlated to elevated serum IgE levels (r = 0.21, P = 0.044), a more severe perivascular lymphocytic inflammation in the upper dermis (r = 0.24, P = 0.026), as well as a prominent swarm of bees-like peri-follicular infiltration (r = 0.41, P < 0.001). Mast cells were abundant in the upper dermis, especially around blood vessels, and positively correlated with eosinophil presence (r = 0.30, P = 0.027). Damage to the hair follicle infundibulum in the upper dermis might be an important component of early changes in AA lesions, possibly caused by lymphocyte cell infiltration in the same area. AA may involve damage of the upper hair follicle as well as the bulb, possibly involving hypersensitivity and autoimmunity. 23917335 Preoperative oral rehydration therapy with 2.5 % carbohydrate beverage alleviates insulin action in volunteers. Preoperative carbohydrate loading enhances insulin action by approximately 50 %. In some Japanese hospitals, preoperative oral rehydration therapy is performed for preventing dehydration during surgery. We hypothesized that preoperative oral rehydration therapy with a 2.5 % carbohydrate beverage that is widely used in Japan can enhance insulin action. Therefore, we investigated the effect of this 2.5 % carbohydrate beverage on insulin action in volunteers. Six healthy volunteers participated in this crossover randomized study. The participants were segregated into 2 groups: an oral rehydration therapy with 2.5 % carbohydrate beverage group (group A) and a control group (group B). Subjects in group B were allowed to drink only water from 9 pm the day before the test; conversely, group A fasted from 9 pm onward and drank 500 ml of the beverage containing 2.5 % carbohydrate (OS-1; Otsuka Pharmaceutical Factory, Tokushima, Japan) between 9 and 12 pm and again at 6.30 am. At 8.30 am, a hyperinsulinemic normoglycemic clamp was initiated using an artificial pancreas STG-22 (Nikkiso, Tokyo, Japan). Insulin action was evaluated in both groups using the glucose infusion rate. Blood glucose levels at the initiation of the clamp procedure were similar. However, the glucose infusion rate for group A was significantly higher than that of group B (8.6 ± 1.5 vs. 6.8 ± 2.0 mg/kg/min, p = 0.009). In conclusion, the hyperinsulinemic normoglycemic clamp using an artificial pancreas showed that the administration of a 2.5 % carbohydrate oral rehydration solution for preoperative oral rehydration therapy improves insulin action in volunteers. 23850842 Molecular characterization of a trisegmented chrysovirus isolated from the radish Raphanus sativus. Radish (Raphanus sativus L.) is cultivated worldwide and is of agronomic importance. dsRNAs associated with partitiviruses were previously found in many R. sativus varieties. In this study, three large dsRNAs from radish were cloned using a modified single primer amplification technique. These three dsRNAs-of lengths 3638, 3517 and 3299 bp-shared conserved untranslated terminal regions, and each contained a major open reading frame putatively encoding the chrysoviral replicase, capsid protein and protease respectively. Isometric virus-like particles (VLP), approximately 45nm in diameter, were isolated from the infected radish plants. Northern blotting indicated that these dsRNAs were encapsidated in the VLP. The virus containing these dsRNA genome segments was named Raphanus sativus chrysovirus 1 (RasCV1). Phylogenetic analysis revealed that RasCV1 is a new species of the Chrysoviridae family and forms a plant taxon with another putative plant chrysovirus, Anthurium mosaic-associated virus (AmaCV). Furthermore, no fungal mycelia were observed in radish leaf tissues stained with trypan blue. These results indicated that RasCV1 is most likely a plant chrysovirus rather than a chrysovirus in symbiotic fungi. An exhaustive BLAST analysis of RasCV1 and AmaCV revealed that chrysovirus-like viruses might widely exist in eudicot and monocot plants and that endogenization of chrysovirus segments into plant genome might have ever happened. 23644027 Two novel and functional DNA sequence variants within an upstream enhancer of the human NKX2-5 gene in ventricular septal defects. Mortality in patients with congenital heart disease (CHD) is significantly increased even with successful surgeries. The main causes are late cardiac complications, such as heart failure and arrhythmia, probably due to genetic defects. To date, genetic causes for CHD remain largely unknown. NKX2-5 gene encodes a highly conserved homeobox transcription factor, which is essential to the heart development in embryos and cardiac function in adults. Mutations in NKX2-5 gene have been implicated in diverse types of CHD, including ventricular septal defect (VSD). As NKX2-5 is a dosage-sensitive regulator, we have speculated that changed NKX2-5 levels may mediate CHD development by influencing cardiac gene regulatory network. In previous studies, we have analyzed the NKX2-5 gene promoter and a proximal enhancer in VSD patients. In the present study, we further genetically and functionally analyzed an upstream enhancer of the NKX2-5 gene in large cohorts of VSD patients (n=340) and controls (n=347). Two novel heterozygous DNA sequence variants (DSVs), g.17483576C>G and g.17483564C>T, were identified in three VSD patients, but none in controls. Functionally, these two DSVs significantly decreased the activity of the enhancer (P<0.01). Another novel heterozygous DSV, g.17483557Ins, was found in both VSD patients and controls with similar frequencies (P>0.05). Taken together, our data suggested that the DSVs within the upstream enhancer of the NKX2-5 gene may contribute to a small number of VSD. Therefore, genetic studies of CHD may provide insight into designing novel therapies for adult CHD patients. 23179119 Is the acetabulum retroverted in slipped capital femoral epiphysis? Recent biplanar radiographic studies have demonstrated acetabular retroversion and increased superolateral femoral head coverage in hips with slipped capital femoral epiphysis (SCFE), seemingly divergent from earlier CT-based studies suggesting normal acetabular version. We therefore asked: Are there differences in (1) acetabular version at the superior ¼ of the acetabular dome (AV(sup)), (2) acetabular version at the center of the femoral head (AV(cen)), and (3) superolateral femoral head coverage (lateral center-edge angle [LCEA]) among affected SCFE hips, unaffected hips, and normal controls? We identified 32 patients with SCFE who underwent CT between 2007 and 2012. Twenty-three met our inclusion criteria. Seventy-six age- and sex-matched normal patients comprised the control group. Pelvic rotation, tilt, and inclination were corrected on each CT. AV(sup), AV(cen), and LCEA were measured. The mean AV(sup) of the affected hips (-1.71°) demonstrated retroversion compared to the unaffected hips and the control group; the mean AV(sup) of the unaffected hips was similar to that of the normal controls. Mean AVcen was similar among the three groups. The LCEA was higher in affected and unaffected SCFE hips than in the control group (34.3° versus 34.5° versus 28.9°, respectively), but we found no difference between affected and unaffected hips. Our data suggest an association of superior acetabular retroversion and increased superolateral femoral head coverage in SCFE. Whether this represents a primary abnormal morphology or a secondary pathologic response remains unclear. Further studies investigating the role of acetabular morphology in SCFE and its implications for development of symptomatic femoroacetabular impingement are warranted. 23877284 Wave modes of collective vortex gyration in dipolar-coupled-dot-array magnonic crystals. Lattice vibration modes are collective excitations in periodic arrays of atoms or molecules. These modes determine novel transport properties in solid crystals. Analogously, in periodical arrangements of magnetic vortex-state disks, collective vortex motions have been predicted. Here, we experimentally observe wave modes of collective vortex gyration in one-dimensional (1D) periodic arrays of magnetic disks using time-resolved scanning transmission x-ray microscopy. The observed modes are interpreted based on micromagnetic simulation and numerical calculation of coupled Thiele equations. Dispersion of the modes is found to be strongly affected by both vortex polarization and chirality ordering, as revealed by the explicit analytical form of 1D infinite arrays. A thorough understanding thereof is fundamental both for lattice vibrations and vortex dynamics, which we demonstrate for 1D magnonic crystals. Such magnetic disk arrays with vortex-state ordering, referred to as magnetic metastructure, offer potential implementation into information processing devices. 23933801 Exploring novel targets of basal-like breast carcinoma by comparative gene profiling and mechanism analysis. The heterogeneity of breast cancer makes its diagnosis and treatment far from being optimal. Analysis of traditional pathological and prognostic markers based on immunohistochemistry (IHC) is inadequate in elucidating the inherent heterogeneity of breast cancer, especially basal-like breast carcinoma (BLBC) which displays complex and unique epidemiological, phenotypic, and molecular features with distinctive relapse patterns and poor clinical outcomes. Gene expression profiling opened an avenue in research as independent predictors by classifying breast cancers into discrete groups with prognostic references, but it is not cost-effective in clinical application. It is necessary to develop an effective predictive gene list from gene profiling to optimize the treatment with traditional markers. In this report, we analyzed the correlation between IHC and gene profiling of breast cancer with an emphasis on the BLBC, highlighting the potential discovery of diagnostic markers and cellular mechanisms that may guide the development of BLBC-targeted therapy. Random forest-based classification and PAM50 gene-sets were used in the comparison analysis of traditional prognostic markers including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and microarray profiles. An intrinsic 40-gene set was developed to classify breast cancer subtypes, and genes expression differentiations were used to explore the different mechanisms between the BLBC and non-BLBC subtypes based on the comparison of clinicopathological markers and microarray profiling. Pathways and DNA repairs were analyzed to evaluate the biological mechanisms in BLBC and other breast cancer subtypes. It is reasonable to define BLBC as those tumors that are negative for ER, PR, and HER2 by IHC for their accordance with gene expression profiles. Focal adhesion kinase, ERBB, and their signaling pathways may play crucial role in BLBC. The intrinsic 40-gene set can be used to classify breast cancer and help to optimize therapeutic management of BLBC. 23677786 Proposals for the classification of human rhinovirus species A, B and C into genotypically assigned types. Human rhinoviruses (HRVs) frequently cause mild upper respiratory tract infections and more severe disease manifestations such as bronchiolitis and asthma exacerbations. HRV is classified into three species within the genus Enterovirus of the family Picornaviridae. HRV species A and B contain 75 and 25 serotypes identified by cross-neutralization assays, although the use of such assays for routine HRV typing is hampered by the large number of serotypes, replacement of virus isolation by molecular methods in HRV diagnosis and the poor or absent replication of HRV species C in cell culture. To address these problems, we propose an alternative, genotypic classification of HRV-based genetic relatedness analogous to that used for enteroviruses. Nucleotide distances between 384 complete VP1 sequences of currently assigned HRV (sero)types identified divergence thresholds of 13, 12 and 13 % for species A, B and C, respectively, that divided inter- and intra-type comparisons. These were paralleled by 10, 9.5 and 10 % thresholds in the larger dataset of >3800 VP4 region sequences. Assignments based on VP1 sequences led to minor revisions of existing type designations (such as the reclassification of serotype pairs, e.g. A8/A95 and A29/A44, as single serotypes) and the designation of new HRV types A101-106, B101-103 and C34-C51. A protocol for assignment and numbering of new HRV types using VP1 sequences and the restriction of VP4 sequence comparisons to type identification and provisional type assignments is proposed. Genotypic assignment and identification of HRV types will be of considerable value in the future investigation of type-associated differences in disease outcomes, transmission and epidemiology. 23793147 Better models by discarding data? In macromolecular X-ray crystallography, typical data sets have substantial multiplicity. This can be used to calculate the consistency of repeated measurements and thereby assess data quality. Recently, the properties of a correlation coefficient, CC1/2, that can be used for this purpose were characterized and it was shown that CC1/2 has superior properties compared with `merging' R values. A derived quantity, CC*, links data and model quality. Using experimental data sets, the behaviour of CC1/2 and the more conventional indicators were compared in two situations of practical importance: merging data sets from different crystals and selectively rejecting weak observations or (merged) unique reflections from a data set. In these situations controlled `paired-refinement' tests show that even though discarding the weaker data leads to improvements in the merging R values, the refined models based on these data are of lower quality. These results show the folly of such data-filtering practices aimed at improving the merging R values. Interestingly, in all of these tests CC1/2 is the one data-quality indicator for which the behaviour accurately reflects which of the alternative data-handling strategies results in the best-quality refined model. Its properties in the presence of systematic error are documented and discussed. 23844703 The binding sites of monoclonal antibodies to the nonreducing end of Francisella tularensis O-antigen accommodate mainly the terminal saccharide. We have previously described two types of protective B cell epitopes in the O-antigen (OAg) of the Gram negative bacterium Francisella tularensis: repeating internal epitopes targeted by the vast majority of anti-OAg monoclonal antibodies (mAbs), and a non-overlapping epitope at the nonreducing end targeted by the previously unique IgG2a mAb FB11. We now generated and characterized three mAbs specific for the nonreducing end of F. tularensis OAg, partially encoded by the same variable region germline genes, indicating that they target the same epitope. Like FB11, the new mAbs, Ab63 (IgG3), N213 (IgG3), and N62 (IgG2b), had higher antigen-binding bivalent avidity than internal-binding anti-OAg mAbs, and an oligosaccharide containing a single OAg repeat was sufficient for optimal inhibition of their antigen-binding. The X-ray crystal structure of N62 Fab showed that the antigen-binding site is lined mainly by aromatic amino acids that form a small cavity, which can accommodate no more than one and a third sugar residues, indicating that N62 binds mainly to the terminal Qui4NFm residue at the nonreducing end of OAg. In efficacy studies with mice infected intranasally with the highly virulent F. tularensis strain SchuS4, N62, N213 and Ab63 prolonged survival and reduced blood bacterial burden. These results yield insights into how antibodies to nonreducing ends of microbial polysaccharides can contribute to immune protection despite the smaller size of their target epitopes compared with antibodies to internal polysaccharide regions. This article is protected by copyright. All rights reserved. 23161544 Next generation sequencing in predicting gene function in podophyllotoxin biosynthesis. Podophyllum species are sources of (-)-podophyllotoxin, an aryltetralin lignan used for semi-synthesis of various powerful and extensively employed cancer-treating drugs. Its biosynthetic pathway, however, remains largely unknown, with the last unequivocally demonstrated intermediate being (-)-matairesinol. Herein, massively parallel sequencing of Podophyllum hexandrum and Podophyllum peltatum transcriptomes and subsequent bioinformatics analyses of the corresponding assemblies were carried out. Validation of the assembly process was first achieved through confirmation of assembled sequences with those of various genes previously established as involved in podophyllotoxin biosynthesis as well as other candidate biosynthetic pathway genes. This contribution describes characterization of two of the latter, namely the cytochrome P450s, CYP719A23 from P. hexandrum and CYP719A24 from P. peltatum. Both enzymes were capable of converting (-)-matairesinol into (-)-pluviatolide by catalyzing methylenedioxy bridge formation and did not act on other possible substrates tested. Interestingly, the enzymes described herein were highly similar to methylenedioxy bridge-forming enzymes from alkaloid biosynthesis, whereas candidates more similar to lignan biosynthetic enzymes were catalytically inactive with the substrates employed. This overall strategy has thus enabled facile further identification of enzymes putatively involved in (-)-podophyllotoxin biosynthesis and underscores the deductive power of next generation sequencing and bioinformatics to probe and deduce medicinal plant biosynthetic pathways. 23970915 Outside the Black Box: Re-assessing Pediatric Antidepressant Prescription. The purpose of this review is to assess whether evidence supports a favorable risk/benefit profile for pediatric antidepressant use and reconsideration of the black box. The review examines studies post-black box purporting to show declines in pediatric antidepressant use and rising youth suicide, summarizes evidence for efficacy and safety of pediatric antidepressants, and discusses irregularities in recent meta-analyses of fluoxetine for youth. Pediatric antidepressant prescription did not significantly decline post-black box and youth suicide has risen only in recent years. Recent meta-analyses fail to undermine evidence that antidepressants are associated with increased risk of suicidality in youth. First line prescription of antidepressants for youth is not advisable. The black box and international warnings on pediatric use of antidepressants are warranted. Wider availability of psychosocial options for depressed youth is recommended. Abstract available from the publisher. 23927235 Time course of a perceptual enhancement effect for noise-masked speech in reverberant environments. Speech intelligibility has been shown to improve with prior exposure to a reverberant room environment [Brandewie and Zahorik (2010). J. Acoust. Soc. Am. 128, 291-299] with a spatially separated noise masker. Here, this speech enhancement effect was examined in multiple room environments using carrier phrases of varying lengths in order to control the amount of exposure. Speech intelligibility enhancement of between 5% and 18% was observed with as little as 850 ms of exposure, although the effect's time course varied considerably with reverberation and signal-to-noise ratio. In agreement with previous work, greater speech enhancement was found for reverberant environments compared to anechoic space. 23839399 132 Cortical-spinal neural prosthesis for restoring volitional limb movement in a paralyzed primate avatar. Motor paralysis is among the most disabling aspects of injury to the central nervous system. Here, we devised a novel cortical-spinal neural prosthetic "bypass" that uses cortically recorded neural activity to control the limb of functionally paralyzed primates. In order to first create functionally paralyzed primates, we developed a unique dual-monkey paralysis model in which neural activity in the premotor cortex of 1 monkey controlled the movement of another sedated primate avatar. We then devised a novel recording-elicitation approach that approximated the activity of pre-motor neurons encoding the controlling monkey's motor intent with unconstrained planar limb movements induced by distal spinal cord and muscle stimulation in the avatar. To do this, we first estimated intended movement directions in primates based on the activities of proximally recorded premotor neurons using 2 separate methods based either on the innate direction tuning of premotor cortical neurons or their adaptive sensorimotor plasticity. We then empirically 'matched' this information, in real-time, with the closest direction of unconstrained planar limb movements elicited by spinal cord and/or muscle stimulations. We find that functionally paralyzed primates were capable of both directing and adapting to motor approximations in order to reach circular targets variably displayed on a screen using stimulation elicited limb movements. We also find that basic volitional control of movement could be largely achieved irrespective of how the animal's motor intent was inferred; using either the innate tuning activities of premotor neurons or their adaptive sensorimotor responses. Simultaneously recorded neurons that were not assigned to control movement, in contrast, did not concomitantly modulate their firing activities with the intended targets. This study describes a novel cortical-spinal neural prosthesis and demonstrates restoration of basic volitional movement in paralyzed primates. 23928112 Heat stroke activates a stress-induced cytokine response in skeletal muscle. Heat stroke (HS) induces a rapid elevation in a number of circulating cytokines. This is often attributed to the stimulatory effects of endotoxin, released from damaged intestine, on immune cells. However, parenchymal cells also produce cytokines, and skeletal muscle, comprising a large proportion of body mass, is thought to participate. We tested the hypothesis that skeletal muscle exhibits a cytokine response to HS that parallels the systemic response in conscious mice heated to a core temperature of 42.4°C (TCMax). Diaphragm and hindlimb muscles showed a rapid rise in interleukin-6 (IL-6) and interleuin-10 (IL-10) mRNA and transient inhibition of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) throughout early recovery, a pattern that parallels changes in circulating cytokines. IL-6 protein was transiently elevated in both muscles at ≈32 min after reaching TCMax. Other responses observed included an upregulation of toll-like receptor-4, (TLR-4) and heat shock protein-72 (HSP-72) mRNA, but no change in TLR-2 or HSP25 mRNA. Furthermore, the mRNA c-jun and c-fos, increased. Together, c-jun/c-fos form the activator protein-1 (AP-1) transcription factor, critical for stress-induced regulation of IL-6. Interestingly, a second "late-phase" (24 h) cytokine response, with increases in IL-6, IL-10, IL-1β, and TNF-α protein were observed in hindlimb, but not diaphragm muscle. These results demonstrate that skeletal muscle responds to HS with a distinct "stress-induced immune response," characterized by an early upregulation of IL-6, IL-10 and TLR-4 and suppression of IL-1β and TNF-α mRNA, a pattern discrete from classic innate immune cytokine responses. 23613106 Noninvasive positron emission tomography imaging of cell death using a novel small-molecule probe, (18)F labeled bis(zinc(II)-dipicolylamine) complex. The synthetic bis(zinc(II)-dipicolylamine) (DPAZn2) coordination complexes are known to have a high specific and selective affinity to target the exposed phosphatidylserine (PS) on the surface of dead and dying cells. An (18)F-labeled DPAZn2 complex (4-(18)F-Fluoro-benzoyl-bis(zinc(II)-dipicolylamine), (18)F-FB-DPAZn2) as positron emission tomography (PET) tracer was developed and evaluated for in vivo imaging of tumor treated with a chemical agent. The in vitro cell stain studies revealed that fluorescent DPAZn2 complexes (Dansyl-DPAZn2) stained the same cells (apoptotic and necrotic cells) as fluorescein isothiocyanate (FITC) labeled Annexin V (FITC-Annexin V). The radiosynthesis of (18)F-FB-DPAZn2 was achieved through the amidation the precursor bis(2,2'-dipicolylamine) derivative (DPA2) with the prosthetic group N-succinimidyl-4-[(18)F]-fluorobenzoate ((18)F-SFB) and chelation with zinc nitrate. In the biodistribution study, the fast clearance of (18)F-FB-DPAZn2 from blood and kidney was observed and high uptake in liver and intestine within 90 min postinjection was also found. For the PET imaging, significantly higher tumor uptake of (18)F-FB-DPAZn2 was observed in the adriamycin (ADM)-treated Hepa1-6 hepatocellular carcinoma-bearing mice than that in the untreated tumor-model mice, while a slightly decreased tumor uptake of (18)F-FDG was found in the ADM-treated tumor-bearing mice. The results indicate that (18)F-FB-DPAZn2 has the similar capability of apoptosis detection as FITC-Annexin V and seems to be a potential PET tracer for noninvasive evaluation and monitoring of anti-tumor chemotherapy. The high uptake of (18)F-FB-DPAZn2 in the abdomen needs to optimize the structure for improving its pharmacokinetics characteristics in the future work. 23767984 Increase in β-Ionone, a Carotenoid-Derived Volatile in Zeaxanthin-Biofortified Sweet Corn. Carotenoids are responsible for the yellow color of sweet corn (Zea mays var. saccharata), but are also potentially the source of flavor compounds from the cleavage of carotenoid molecules. The carotenoid-derived volatile, β-ionone, was identified in both standard yellow sweet corn ('Hybrix5') and a zeaxanthin-enhanced experimental variety ('HZ') designed for sufferers of macular degeneration. As β-ionone is highly perceivable at extremely low concentration by humans, it was important to confirm if alterations in carotenoid profile may also affect flavor volatiles. The concentration of β-ionone was most strongly correlated (R(2) > 0.94) with the β-arm carotenoids, β-carotene, β-cryptoxanthin, and zeaxanthin, and to a lesser degree (R(2) = 0.90) with the α-arm carotenoid, zeinoxanthin. No correlation existed with either lutein (R(2) = 0.06) or antheraxanthin (R(2) = 0.10). Delaying harvest of cobs resulted in a significant increase of both carotenoid and β-ionone concentrations, producing a 6-fold increase of β-ionone in 'HZ' and a 2-fold increase in 'Hybrix5', reaching a maximum of 62 μg/kg FW and 24 μg/kg FW, respectively. 23844698 Basic mechanics of DNA methylation and the unique landscape of the DNA methylome in metal-induced carcinogenesis. Abstract DNA methylation plays an intricate role in the regulation of gene expression and events that compromise the integrity of the methylome may potentially contribute to disease development. DNA methylation is a reversible and regulatory modification that elicits a cascade of events leading to chromatin condensation and gene silencing. In general, normal cells are characterized by gene-specific hypomethylation and global hypermethylation, while cancer cells portray a reverse profile to this norm. The unique methylome displayed in cancer cells is induced after exposure to carcinogenic metals such as nickel, arsenic, cadmium, and chromium (VI). These metals alter the DNA methylation profile by provoking both hyper- and hypo-methylation events. The metal-stimulated deviations to the methylome are possible mechanisms for metal-induced carcinogenesis and may provide potential biomarkers for cancer detection. Development of therapies based on the cancer methylome requires further research including human studies that supply results with larger impact and higher human relevance. 23943257 Vomer flap for hard palate repair is related to favorable maxillary growth in unilateral cleft lip and palate. Vomer flap repair is assumed to improve maxillary growth because of reduced scarring in growth-sensitive areas of the palate. Our aim was to evaluate whether facial growth in patients with unilateral cleft lip and palate was significantly affected by the technique of hard palate repair (vomer flap versus two-flap). For this retrospective longitudinal study, we analyzed 334 cephalometric radiographs from 95 patients with nonsyndromic complete unilateral cleft lip and palate who underwent hard palate repair by two different techniques (vomer flap versus two-flap). Clinical notes were reviewed to record treatment histories. Cephalometry was used to determine facial morphology and growth rate. The associations among facial morphology at age 20, facial growth rate, and technique of hard palate repair were assessed using generalized estimating equation analysis. The hard palate repair technique significantly influenced protrusion of the maxilla (SNA: β = -3.5°, 95 % CI = -5.2-1.7; p = 0.001) and the anteroposterior jaw relation (ANB: β = -4.2°, 95 % CI = -6.4-1.9; p = 0.001; Wits: β = -5.7 mm, 95 % CI = -9.6-1.2; p = 0.01) at age 20, and their growth rates (SNA p = 0.001, ANB p < 0.01, and Wits p = 0.02). The results suggest that in patients with unilateral cleft lip and palate, vomer flap repair has a smaller adverse effect than two-flap on growth of the maxilla. This effect on maxillary growth is on the anteroposterior development of the alveolar maxilla and is progressive with age. We now perform hard palate closure with vomer flap followed by soft palate closure using Furlow palatoplasty. These findings may improve treatment outcome by modifying the treatment protocol for patients with unilateral cleft lip and palate. 23298754 Choline status and neurodevelopmental outcomes at 5 years of age in the Seychelles Child Development Nutrition Study. Choline is an essential nutrient that is found in many food sources and plays a critical role in the development of the central nervous system. Animal studies have shown that choline status pre- and postnatally can have long-lasting effects on attention and memory; however, effects in human subjects have not been well studied. The aim of the present study was to examine the association between plasma concentrations of free choline and its related metabolites in children and their neurodevelopment in the Seychelles Child Development Nutrition Study, an ongoing longitudinal study assessing the development of children born to mothers with high fish consumption during pregnancy. Plasma concentrations of free choline, betaine, dimethylglycine (DMG), methionine and homocysteine and specific measures of neurodevelopment were measured in 210 children aged 5 years. The children's plasma free choline concentration (9·17 (sd 2·09) μmol/l) was moderately, but significantly, correlated with betaine (r 0·24; P= 0·0006), DMG (r 0·15; P= 0·03), methionine (r 0·24; P= 0·0005) and homocysteine (r 0·19; P= 0·006) concentrations. Adjusted multiple linear regression revealed that betaine concentrations were positively associated with Preschool Language Scale – total language scores (β = 0·066; P= 0·04), but no other associations were evident. We found no indication that free choline concentration or its metabolites, within the normal physiological range, are associated with neurodevelopmental outcomes in children at 5 years of age. As there is considerable animal evidence suggesting that choline status during development is associated with cognitive outcome, the issue deserves further study in other cohorts. 23791116 Mitral Annular Displacement by Doppler Tissue Imaging May Identify Coronary Occlusion and Predict Mortality in Patients with Non-ST-Elevation Myocardial Infarction. Mitral annular displacement (MAD) is a simple marker of left ventricular (LV) systolic function. The aim of this study was to test the hypothesis that MAD can distinguish patients with non-ST-segment elevation myocardial infarctions (NSTEMIs) from those with significant coronary artery disease without infarctions, identify coronary occlusion, and predict mortality in patients with NSTEMIs. MAD was compared with established indices of LV function. In this retrospective study, 167 patients with confirmed NSTEMIs were included at two Scandinavian centers. Forty patients with significant coronary artery disease but without myocardial infarctions were included as controls. Doppler tissue imaging was performed at the mitral level of the left ventricle in the three apical planes, and velocities were integrated over time to acquire MAD. LV ejection fraction, global longitudinal strain (GLS), and wall motion score index were assessed according to guidelines. MAD and GLS could accurately distinguish patients with NSTEMIs from controls. During 48.6 ± 12.1 months of follow-up, 22 of 167 died (13%). MAD, LV ejection fraction, and GLS were reduced and wall motion score index was increased among those who died compared with those who survived (P < .001, P < .001, P < .001, and P = .02, respectively). Multivariate Cox proportional-hazards analyses revealed that MAD was an independent predictor of death (hazard ratio, 1.36; 95% confidence interval, 1.07-1.73; P = .01). MAD and GLS were reduced and wall motion score index was increased in patients with coronary artery occlusion compared with those without occlusion (P = .006, P = .001, and P = .02), while LV ejection fraction did not differ (P = .20). MAD accurately identified patients with NSTEMIs, predicted mortality, and identified coronary occlusion in patients with NSTEMIs. 23924115 Safe staffing. It is not that nurses don't care - it's just that they have too many people to care for. 23943764 The Activity and Specificity of the Outer Membrane Protein Chaperone SurA Are Modulated by a Proline Isomerase Domain. ABSTRACT SurA is a component of the periplasmic chaperone network that plays a central role in biogenesis of integral outer membrane β-barrel proteins (OMPs) in Escherichia coli. Although SurA contains two well-conserved proline isomerase (PPIase) domains, the contribution of these domains to SurA function is unclear. In the present work, we show that defects in OMP assembly caused by mutation of the β-barrel assembly factors BamA or BamB can be corrected by gain-of-function mutations in SurA that map to the first PPIase domain. These mutations apparently bypass the requirement for a stable interaction between SurA and the Bam complex and enhance SurA chaperone activity in vivo despite destabilization of the protein in vitro. Our findings suggest an autoinhibitory mechanism for regulation of SurA chaperone activity through interdomain interactions involving a PPIase domain. We propose a model in which SurA activity is modulated by an interaction between SurA and the Bam complex that alters the substrate specificity of the chaperone. IMPORTANCE The dominant surA mutations described here alter amino acid residues that are highly conserved in eukaryotic homologs of SurA, including Pin1, the human proline isomerase (PPIase) implicated in Alzheimer's disease and certain cancers. Consequently, a mechanistic description of SurA function may enhance our understanding of clinically important PPIases and their role(s) in disease. In addition, the virulence of Gram-negative bacterial pathogens, such as Salmonella, Shigella, and Escherichia coli O157:H7, is largely dependent on SurA, making this PPIase/chaperone an attractive antibiotic target. Investigating the function of SurA in outer membrane (OM) biogenesis will be useful in the development of novel therapeutic strategies for the disruption of the OM or the processes that are essential for its assembly. 23800534 Drug exposure: inclusion of dispensed drugs before pregnancy may lead to underestimation of risk associations. To assess the impact of exposure misclassification on risk associations when using prescription databases as the source for drug exposure in pregnancy by applying results from a validation analysis of exposure classification. Linkage of data on 27,656 participants in the Norwegian Mother and Child Cohort Study (MoBa) with the Norwegian Prescription Database (NorPD). Exposure to selective serotonin reuptake inhibitors (SSRIs) was defined by dispensed drugs during pregnancy including different time windows before pregnancy. The validity of NorPD data was estimated using self-reported use in MoBa as the reference standard. We applied the results from the validation analysis on data from a Nordic study on SSRI use in pregnancy and risk of persistent pulmonary hypertension in the newborn. Sensitivity increased and specificity decreased when the time window in NorPD was expanded before pregnancy. Using the same time window as in the Nordic study (+90 days before pregnancy), for use in early pregnancy, the odds ratio (OR) corrected for misclassification was 2.6 compared with the OR of 1.6 in the Nordic study. Expansion of the time window to include intervals before pregnancy can lead to lower specificity and underestimation of risk associations. 23518639 Autoimmunity-related neutrophilic dermatosis: a newly described entity that is not exclusive of systemic lupus erythematosus. : Neutrophilic dermatoses have long been known to be associated with autoinmune systemic diseases. Recently, a small number of cases of a disorder distinct from Sweet syndrome or bullous lupus erythematosus (LE) have been described as specifically related to systemic LE under diverse terms, including nonbullous neutrophilic dermatosis, nonbullous neutrophilic LE, and Sweet-like neutrophilic dermatosis. We describe 7 patients that developed urticarial lesions in the context of a known or concurrently diagnosed autoimmune connective tissue disease. Of a total of 7 patients, 6 were afflicted by systemic LE and 1 by rheumatoid arthritis and secondary Sjögren syndrome. Histological findings in all patients included an interstitial and perivascular neutrophilic infiltrate with leukocytoclasia, vacuolar alteration along the dermal-edidermal junction, and no vasculitis. Most patients had active systemic disease at the time of the cutaneous eruption. Skin lesions resolved rapidly after the administration of immunomodulating agents. In conclusion, we provide additional evidence of the existence of a recently defined nonbullous neutrophilic dermatosis in the context of autoimmune connective tissue diseases and propose the term autoimmunity-related neutrophilic dermatosis as an appropriate designation. Furthermore, we believe that this entity should prompt physicians to screen the presence of an active systemic disorder in afflicted patients. 23963360 Combining Erlotinib and Cetuximab is Associated with Activity in Patients with Non Small Cell Lung Cancer (including Squamous Cell Carcinomas) and Wild-Type EGFR or Resistant Mutations. Preclinical data suggest that combined epidermal growth factor receptor (EGFR) targeting with an EGFR tyrosine kinase inhibitor and an anti-EGFR monoclonal antibody may be superior over single-agent targeting. Therefore, as part of a phase I study, we analyzed the outcome of 20 patients with non-small cell lung cancer treated with the combination of erlotinib and cetuximab. EGFR mutation status was ascertained in a CLIA-approved lab. There were 10 men; median number of prior therapies, 5. Overall, 2 of 20 patients (10%) achieved partial response (PR), one of whom had a TKI-resistant EGFR insertion in exon 20, time to treatment failure (TTF) = 24+ months; and, the other patient had squamous cell histology (EGFR wild-type), TTF=7.4 months. In addition, 3 of 20 patients (15%) achieved stable disease (SD) ≥6 months (one of whom had wild-type EGFR and squamous cell histology, and two patients had an EGFR TKI-sensitive mutation, one of whom had failed prior erlotinib therapy). Combination therapy with ertotinib plus cetuximab was well tolerated. The most common toxicities were rash, diarrhea, and hypomagnesemia. The recommended phase II dose was erlotinib 150 mg oral daily and cetuximab 250 mg/m2 IV weekly. In summary, erlotinib and cetuximab treatment was associated with SD ≥6 months/PR in 5 of 20 patients with non-small cell lung cancer (25%), including individuals with squamous histology, TKI-resistant EGFR mutations, and wild-type EGFR, and those who had progressed on prior erlotinib after an initial response. This combination warrants further study in select populations of non-small cell lung cancer. 23920031 Aggressive Hydration with Lactated Ringer's Solution Reduces Pancreatitis Following Endoscopic Retrograde Cholangiopancreatography. Pancreatitis is the most common serious complication of endoscopic retrograde cholangiopancreatography (ERCP). We performed a pilot study to determine whether aggressive peri-procedural hydration with lactated Ringer's solution reduces the incidence of pancreatitis following ERCP. Patients who underwent first-time ERCP were randomly assigned to groups (2:1) that received aggressive hydration with lactated Ringer's solution (3 cc/kg/hr during the procedure, a 20 cc/kg bolus after the procedure, and 3cc/kg/hr for 8 hours following the procedure, n=39) or standard hydration with the same solution (1.5 cc/kg/hr during and for 8 hrs after procedure, n=23). Serum levels of amylase, visual analog pain scores (scale of 0-10), and volume overload were assessed at baseline and 2, 8, and 24 hrs after ERCP. The primary endpoint, post-ERCP pancreatitis was defined as hyperamylasemia (level of amylase > 3 times the upper limit of normal) and increased epigastric pain (≥3 points on visual analog scale) persisting for ≥24 hrs after the procedure. Secondary endpoints included hyper-amylasemia, increased pain, and volume overload. None of the patients who received aggressive hydration developed post-ERCP pancreatitis, compared with 17% of patients who received standard hydration (P=.016). Hyperamylasemia developed in 23% of patients who received aggressive hydration vs 39% of those who received standard hydration (P=.116, non-significant); increased epigastric pain developed in 8% of patients who received aggressive hydration vs 22% of those who received standard hydration (P=.146, non-significant). No patients had evidence of volume overload. Based on a pilot study, aggressive intravenous hydration with lactated Ringer's solution appears to reduce the development of post-ERCP pancreatitis and is not associated with volume overload. ClinicalTrials.gov number, NCT 01758549. 23640072 A randomized, double-blind, placebo-controlled crossover study of α4β 2* nicotinic acetylcholine receptor agonist AZD1446 (TC-6683) in adults with attention-deficit/hyperactivity disorder. RATIONALE: Stimulation of nicotinic cholinergic systems has been shown to alleviate ADHD symptoms and to improve cognitive performance. AZD1446 is a selective α4β2* nicotinic acetylcholine receptor agonist with potential effect on the symptoms of ADHD. OBJECTIVES: The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics of AZD1446 in adults with ADHD treated for 2 weeks. METHOD: This was a randomized, double-blind, placebo-controlled crossover trial. Participants were 79 adults with ADHD, grouped according to their use of nicotine-containing products. Nicotine non-users received placebo and two of three AZD1446 treatment regimens (80 mg tid, 80 mg qd, 10 mg tid). Nicotine users received placebo, AZD1446 80 mg tid and 80 mg qd. Efficacy measures included the Conners' Adult ADHD Rating Scale and cognitive measures of immediate and delayed verbal episodic memory, learning, attention, working memory, executive functioning, and spatial problem solving (CogState computerized test battery). RESULTS: There was no significant effect of AZD1446 on any of the clinical scores irrespective of dose, schedule, or concomitant use of nicotine products. A statistically significant improvement was seen on the Groton Maze Learning Task, a measure of executive functioning, in nicotine non-users after treatment with AZD1446 80 mg qd. CONCLUSIONS: AZD1446 was well tolerated, but did not significantly improve ADHD symptoms after 2 weeks of treatment compared to placebo. While the present study does not support the therapeutic utility of AZD1446 in ADHD, its potential pro-cognitive effects remain to be explored in other neuropsychiatric disorders. 23623199 Assessment of angiogenic markers and female sex hormone receptors in pregnancy tumor of the gingiva. Oral pregnancy tumors (OPTs) arise on the inflamed gingiva of women after the first trimester of pregnancy. The expression of angiogenic markers and female hormone receptors was assessed. Immunohistochemistry was used to analyze the expression of estrogen and progesterone receptors and the expression of angiogenic factors, such as vascular endothelial growth factor (VEGF) and its receptor, fibroblast growth factor (FGF), and hypoxia inducible factors 1α and 3α (HIF1α and HIF3α). Experimental groups included 9 OPTs, 10 oral pyogenic granulomas from nonpregnant women of the same age, and 9 oral pyogenic granulomas from postmenopausal women. VEGF expression in stromal histiocytes and endothelial cells of small vessels was positively correlated in the OPT group (P < .05 by χ(2) test). VEGF receptor also was overexpressed in stromal histiocytes and endothelial cells of OPTs compared with oral pyogenic granulomas from nonpregnant and postmenopausal women (P < .005 by χ(2) test). No correlation was detected among estrogen and progesterone receptors, FGF and HIF1α and HIF3α (ER and PgR respectively) in the 3 experimental groups. VEGF-associated angiogenesis is most likely involved in the pathogenesis of the lesion. These results imply that local inhibition of VEGF activity could be an adjuvant therapeutic approach for OPTs to control hemorrhage, which can be massive at the surgical excision of such lesions during pregnancy. 23583023 Disrupted small-world brain network in children with Down Syndrome. To explore how the global organization or topology of the functional brain connectivity (FBC) is affected in Down Syndrome (DS). As the brain is a highly complex network including numerous nonlinearly interacted neuronal areas, the FBCs of typically developing (TD) children and DS patients were computed using a nonlinear synchronization method. Then the differences in global organization of the obtained FBCs of the two groups were analyzed, in all electroencephalogram (EEG) frequency bands, in the framework of Small-Worldness Network (a network with optimum balance between segregation and integration of information). The topology of the functional connectivity of DS patients is disrupted in the whole brain in alpha and theta bands, and especially in the left intra-hemispheric brain networks in upper alpha band. The global organization of the DS brain does not resemble a Small-World network, but it works as a random network. It is the first study on global organization of the FBC in DS. 23666752 IVF culture medium affects human intrauterine growth as early as the second trimester of pregnancy. When does a difference in human intrauterine growth of singletons conceived after IVF and embryo culture in two different culture media appear? Differences in fetal development after culture of embryos in one of two IVF media were apparent as early as the second trimester of pregnancy. Abnormal fetal growth patterns are a major risk factor for the development of chronic diseases in adult life. Previously, we have shown that the medium used for culturing embryos during the first few days after fertilization significantly affects the birthweight of the resulting human singletons. The exact onset of this growth difference was unknown. In this retrospective cohort study, all 294 singleton live births after fresh embryo transfer in the period July 2003 to December 2006 were included. These embryos originated from IVF treatments that were part of a previously described clinical trial. Embryos were allocated to culture in either Vitrolife or Cook commercially available sequential culture media. We analysed ultrasound examinations at 8 (n = 290), 12 (n = 83) and 20 weeks' (n = 206) gestation and used first-trimester serum markers [pregnancy-associated plasma protein-A (PAPP-A) and free β-hCG]. Differences between study groups were tested by the Student's t-test, χ(2) test or Fisher's exact test, and linear multivariable regression analysis to adjust for possible confounders (for example, parity, gestational age at the time of ultrasound and fetal gender). A total of 294 singleton pregnancies (Vitrolife group nVL = 168, Cook group: nC = 126) from 294 couples were included. At 8 weeks' gestation, there was no difference between crown-rump length-based and ovum retrieval-based gestational age (ΔGA) (nVL = 163, nC = 122, adjusted mean difference, -0.04 days, P = 0.84). A total of 83 women underwent first-trimester screening at 12 weeks' gestation (nVL = 45, nC = 38). ΔGA, nuchal translucency (multiples of median, MoM) and PAPP-A (MoM) did not differ between the study groups. Free β-hCG (MoM) ± SEM differed significantly (1.55 ± 0.19 in Vitrolife versus 1.06 ± 0.10 in Cook; P = 0.031, Student's t-test). At 20 weeks' gestation, a more advanced GA, reflecting an increased fetal growth, was seen at ultrasound examination in the Vitrolife group (n = 115) when compared with the Cook group (n = 91). After adjustment for confounding factors, both the difference between GA based on three biparietal diameter dating formulas minus the actual (ovum retrieval based) GA (adjusted mean difference + 1.14 days (P = 0.04), +1.14 days (P = 0.04) and +1.36 days (P = 0.048)), as well as head circumference (HC) and trans-cerebellar diameter (TCD) were significantly higher in the Vitrolife group (HCvl 177.3 mm, HCc 175.9 mm, adjusted mean difference 1.8, P = 0.03; TCDvl 20.5 mm, TCDc 20.2 mm, adjusted mean difference 0.4, P = 0.008). A first trimester (12 weeks) fetal screening was not yet offered routinely during the study period, therefore only 28% of women in our study participated in this elective screening programme. Although all sonographers were experienced and specially trained to perform these ultrasound examinations and were unaware of the randomization procedure, we cannot totally rule out possible intra- and inter-observer variability. Despite being indispensable in daily practice, sonographic weight formulas have a limited accuracy. According to the fetal origins hypothesis, many adult diseases originate in utero owing to adaptations made by the fetus to the environment it encounters. This study indicates that the embryonic environment is already important for fetal development. Therefore, our study emphasizes the need to investigate fetal growth patterns after assisted reproduction technologies and long-term health outcomes of IVF children, especially in relation to the culture medium used during the first few days of preimplantation development. Not applicable. 23926331 Test-retest reliability of eye tracking in the visual world paradigm for the study of real-time spoken word recognition. Researchers have begun to use eye tracking in the visual world paradigm (VWP) to study clinical differences in language processing, but the reliability of such laboratory tests has rarely been assessed. In this article, the authors assess test-retest reliability of the VWP for spoken word recognition. Methods Participants performed an auditory VWP task in repeated sessions and a visual-only VWP task in a third session. The authors performed correlation and regression analyses on several parameters to determine which reflect reliable behavior and which are predictive of behavior in later sessions. Results showed that the fixation parameters most closely related to timing and degree of fixations were moderately-to-strongly correlated across days, whereas the parameters related to rate of increase or decrease of fixations to particular items were less strongly correlated. Moreover, when including factors derived from the visual-only task, the performance of the regression model was at least moderately correlated with Day 2 performance on all parameters ( R > .30). The VWP is stable enough (with some caveats) to serve as an individual measure. These findings suggest guidelines for future use of the paradigm and for areas of improvement in both methodology and analysis. 23791736 Statistical analysis of the effects of polyethylene glycol concentration and molecular weight on the sedimentation and resuspendability behavior of model aqueous dispersions. This work investigates the flocculation effect of polyethylene glycol (PEG) on typical aqueous dispersions, such as O/W emulsions and solid/liquid suspensions. Hereby, sunflower oil and flubendazole were selected as model ingredients, whereas microfluidization at variable driving air pressure was used to enable particle size distribution variations for both systems. The molecular weight of PEG varied from 2000 to 12,000g/mol while its concentration ranged from 50 to 100mg/ml. Statistical analysis revealed that both PEG concentration and molecular weight showed a flocculation enhancing effect. Hereby the inhibiting effect of particle size toward the formation of voluminous and easily resuspendable sediment could at least partially be overcome by selecting appropriate PEG characteristics. 23910001 Pullout Strength of Bone-Patellar Tendon-Bone Allograft Bone Plugs: A Comparison of Cadaver Tibia and Rigid Polyurethane Foam. To compare the load-to-failure pullout strength of bone-patellar tendon-bone (BPTB) allografts in human cadaver tibias and rigid polyurethane foam blocks. Twenty BPTB allografts were trimmed creating 25 mm Ã— 10 mm Ã— 10 mm tibial plugs. Ten-millimeter tunnels were drilled in 10 human cadaver tibias and 10 rigid polyurethane foam blocks. The BPTB anterior cruciate ligament allografts were inserted into these tunnels and secured with metal interference screws, with placement of 10 of each type in each material. After preloading (10 N), cyclic loading (500 cycles, 10 to 150 N at 200 mm/min) and load-to-failure testing (200 mm/min) were performed. The endpoints were ultimate failure load, cyclic loading elongation, and failure mode. No difference in ultimate failure load existed between grafts inserted into rigid polyurethane foam blocks (705 N) and those in cadaver tibias (669 N) (P = .69). The mean rigid polyurethane foam block elongation (0.211 mm) was less than that in tibial bone (0.470 mm) (P = .038), with a smaller standard deviation (0.07 mm for foam) than tibial bone (0.34 mm). All BPTB grafts successfully completed 500 cycles. The rigid polyurethane foam block showed less variation in test results than human cadaver tibias. Rigid polyurethane foam blocks provide an acceptable substitute for human cadaver bone tibia for biomechanical testing of BPTB allografts and offer near-equivalent results. 23877107 Genetic variations in UDP-glucuronosyltransferase 2B15 in a Korean population. UDP-glucuronosyltransferase 2B15 (UGT2B15) is involved in the glucoronidation of steroid hormones as well as many drugs. Genetic variations in UGT2B15 have been shown to affect enzyme function and suggested to have a role in human diseases, such as breast and prostate cancers. In the present study, we sequenced genomic DNA from 50 normal Korean subjects to identify single nucleotide polymorphisms (SNPs) in UGT2B15. A total of thirteen genetic variations were found: two in exons, two in introns, seven in the 5'-untranslated region (UTR), and two in the 3'-UTR. The order and frequency distribution of UGT2B15 variations was: -1139T>C (rs9994887), -508G>A (rs1120265), -506T>A (rs1580083), 253T>G (rs1902023) (42%), 23687A>T (rs4148271) (31%), 2635A>T (rs2045100) (28%), -497 C>T (14%), -378C>T (14%), 23669C>T (12%), and 23476A>C (rs4148269) (11%), as well as other minor alleles with a frequency of <10%. Thirteen variations were used to characterize linkage disequilibrium structures at the UGT2B15 locus. Five tag SNPs were identified, and the observed allelic frequencies were compared to those of other ethnic populations. This information describing genetic polymorphisms in UGT2B15 could serve as an important resource for studying individual variations in drug and hormone metabolism in Korean as well as other ethnic populations. 23821456 MCM3 Protein Expression in Follicular and Classical Variants of Papillary Thyroid Carcinoma. Minichromosome maintenance (MCM) proteins are needed as licensors in the DNA replication of eukaryotic cells and transcriptional control of MCM genes has critical role in the regulation of MCM functions. Different MCM protein family members are proposed as diagnostic or prognostic markers in various cancers due to their increased proliferative potential. Among MCM family members, minichromosome maintenance protein 3 (MCM3) expressions in both mRNA and protein levels were shown to be associated with papillary thyroid carcinoma (PTC). But, the usability of MCM3 in some histological variants of PTC might be controversial due to tissue specific molecular heterogeneities. In follicular variant of papillary thyroid carcinoma (FVPTC), a number of genes including MCM3 were shown to be differentially expressed which were specific to this kind of variant. Using immunohistochemistry method, MCM3 protein expression levels were compared in FVPTC, classic variant of papillary thyroid carcinoma (CVPTC), and multi-nodular goiter (MNG) tissues in a group of 32 cases. There was meaningful differences between MNG vs. FVPTC (p = 0.016) and MNG vs. CVPTC (p = 0.019) while there was no significant difference in the comparison FVPTC vs. CVPTC (p = 0.15). Four of the 5 CVPTC cases having surrounding tissue invasion had high expression values. For FVPTC and CVPTC, MCM3 protein expression results were parallel to our previous mRNA expression study while there was downregulation in protein expression despite the increased expression of MCM3 mRNA in MNG suggesting tissue-specific post-transcriptional events in benign thyroid neoplasms of which should be focused on. Moreover, the relatively lower MCM3 protein expression in FVPTC comparing to CVPTC could be due to a different tumorigenic pathway favored in this type of tissue. 23806064 Catalyst-controlled divergent C-h functionalization of unsymmetrical 2-aryl cyclic 1,3-dicarbonyl compounds with alkynes and alkenes. Achieving site-selective, switchable C-H functionalizations of substrates that contain several different types of reactive C-H bonds is an attractive objective to enable the generation of different products from the same starting materials. Herein, we demonstrate the divergent C-H functionalization of unsymmetrical 2-aryl cyclic 1,3-dicarbonyl compounds that contain two distinct, nonadjacent sites for initial C-H functionalization, where product selectivity is achieved through catalyst control. By use of a palladium-N-heterocyclic carbene complex as the precatalyst, these substrates undergo oxidative annulation with alkynes to provide spiroindenes exclusively. In contrast, a ruthenium-based catalyst system gives benzopyrans as the major products. Examples of divergent, oxidative C-H alkenylations of the same substrates are also provided. 23945695 Rates of dinosaur limb evolution provide evidence for exceptional radiation in Mesozoic birds. Birds are the most diverse living tetrapod group and are a model of large-scale adaptive radiation. Neontological studies suggest a radiation within the avian crown group, long after the origin of flight. However, deep time patterns of bird evolution remain obscure because only limited fossil data have been considered. We analyse cladogenesis and limb evolution on the entire tree of Mesozoic theropods, documenting the dinosaur-bird transition and immediate origins of powered flight. Mesozoic birds inherited constraints on forelimb evolution from non-flying ancestors, and species diversification rates did not accelerate in the earliest flying taxa. However, Early Cretaceous short-tailed birds exhibit both phenotypic release of the hindlimb and increased diversification rates, unparalleled in magnitude at any other time in the first 155 Myr of theropod evolution. Thus, a Cretaceous adaptive radiation of stem-group birds was enabled by restructuring of the terrestrial locomotor module, which represents a key innovation. Our results suggest two phases of radiation in Avialae: with the Cretaceous diversification overwritten by extinctions of stem-group birds at the Cretaceous-Palaeogene boundary, and subsequent diversification of the crown group. Our findings illustrate the importance of fossil data for understanding the macroevolutionary processes generating modern biodiversity. 22608895 Percutaneous device closure of atrial septal defect results in very early and sustained changes of right and left heart function. To investigate the echocardiographic effects of percutaneous closure of secundum atrial septal defect (ASD) in adults and assess which pre-closure parameters predict good response to closure. ASD is a common congenital heart disease often undiscovered until adulthood. ASD closure has been revolutionized by the use of percutaneous devices. The effects of these procedures on echocardiographic parameters are not well characterized. Patients undergoing percutaneous device closure of ASD between June 2007 and June 2009 had 3 sequential echocardiograms reviewed: pre-procedure, immediate post-procedure (24hours) and 6-8weeks post-procedure. Significant changes from baseline were investigated using paired t-test/1-way ANOVA. Pearson correlation (2-tailed) tests were used to categorize patients as 'good responders' to closure in terms of selected parameters. 129 echocardiograms in 43 consecutive patients were included. Remodeling of both ventricles occurred immediately following ASD closure and was sustained. Right ventricular (RV) diameter in diastole decreased by 13.5% and 19.3% compared to baseline at 24hours and 6-8weeks post-closure, respectively (p<0.05); Left ventricular (LV) diameter in diastole increased by 8.5% and 15.6%, respectively (p<0.05). Functional parameters of the RV also demonstrated early and sustained decreases (TAPSE decreased by 8.3% and 17% compared to baseline at 24hours and 6-8weeks post-closure, respectively (p<0.05)). Smaller RV baseline diameter appeared to predict good response to closure. Percutaneous ASD closure has immediate, sustained benefits on multiple echocardiographic parameters. Good responders have smaller RV at baseline, suggesting early closure is preferable. 23746358 Transmission and Persistence of Methicillin-Resistant Staphylococcus aureus in Milk, Environment, and Workers in Dairy Cattle Farms. Abstract The aim of this study was to determine the presence and persistence of methicillin-resistant Staphylococcus aureus (MRSA) in milk, farm environment, and farmers on 22 dairy cattle farms in Korea during 2008-2009. Genetic relatedness among the MRSA isolates was also investigated. Of 1146 samples examined, 35 of 559 (6.3%) quarter milk samples from 371 cows, four of 86 (4.7%) hand and nose samples from 43 farmers, and 6 of 501 (1.2%) farm environment samples were MRSA positive. Except for three isolates, all MRSA were classified into ST72-spa t324-SCCmec IV with PVL negative, the most predominant clonal type among community-associated MRSA in South Korea. All 35 MRSA-positive milk samples from 19 cows were obtained from a single farm (Farm G) out of 22 (4.5%) farms tested. The farm G was revisited 1 year later and milk samples were collected for examination of MRSA again. Two of six previous MRSA-positive cattle that had been kept on the farm still harbored MRSA genetically identical to MRSA strains, which were isolated from the same farm a year ago. The results of this study provide the evidence of transmission of MRSA among cattle, farm environment, and farmers and also long-term persistence of MRSA in animals. 23665129 Potentiometric sensing of nuclease activities and oxidative damage of single-stranded DNA using a polycation-sensitive membrane electrode. A simple, general and label-free potentiometric method to measure nuclease activities and oxidative DNA damage in a homogeneous solution using a polycation-sensitive membrane electrode is reported. Protamine, a linear polyionic species, is used as an indicator to report the cleavage of DNA by nucleases such as restriction and nonspecific nucleases, and the damage of DNA induced by hydroxyl radicals. Measurements can be done with a titration mode or a direct detection mode. For the potentiometric titration mode, the enzymatic cleavage dramatically affects the electrostatical interaction between DNA and protamine and thus shifts the response curve for the potentiometric titration of the DNA with protamine. Under the optimized conditions, the enzyme activities can be sensed potentiometrically with detection limits of 2.7×10(-4)U/µL for S1 nuclease, and of 3.9×10(-4)U/µL for DNase I. For the direct detection mode, a biocomplex between protamine and DNA is used as a substrate. The nuclease of interest cleaves the DNA from the protamine/DNA complex into smaller fragments, so that free protamine is generated and can be detected potentiometrically via the polycation-sensitive membrane electrode. Using a direct measurement, the nuclease activities could be rapidly detected with detection limits of 3.2×10(-4)U/µL for S1 nuclease, and of 4.5×10(-4)U/µL for DNase I. Moreover, the proposed potentiometric assays demonstrate the potential applications in the detection of hydroxyl radicals. It is anticipated that the present potentiometric strategy will provide a promising platform for high-throughput screening of nucleases, reactive oxygen species and the drugs with potential inhibition abilities. 23890973 Molecular snapshot of Mycobacterium tuberculosis population structure and drug-resistance in Kyrgyzstan. Kyrgyzstan is a post-Soviet country in Central Asia marked with high incidence and mortality rates of tuberculosis (TB). The present study provided first assessment of Mycobacterium tuberculosis population structure and drug-resistance in civilian population here. The collection included 103 M. tuberculosis DNA samples subjected to the analysis of rifampin and isoniazid resistance mutations and spoligotyping. The major spoligotype-defined families were Beijing (n = 62), T (n = 14), LAM (n = 9), Ural-2 (n = 6) and Ural-1 (n = 3). Genotypically, 20 isolates were RIF-resistant, 28 were INH-resistant, 17 were multidrug-resistant. Drug resistant isolates were more prevalent among Beijing than non-Beijing groups (P = 0.03). The predominance of the mainly "Russian" spoligotypes among the non-Beijing strains (LAM-RUS and Ural-1) in this study along with previously demonstrated prevalence of the Russia-specific subtype of the Beijing family in Kyrgyz prison (Mokrousov et al., 2009) suggest that the current population structure of M. tuberculosis in Kyrgyzstan has been mainly formed within the course of the 20th century when the country was a part of the Russian Empire and Soviet Union. On the other hand, a prevalence of the Asia-specific Ural-2 type in the oldest age group (68-85 years old; P < 0.0001) may present a heritage of the more distant historical events. In summary, we suggest: (i) a clear shift of the local M. tuberculosis population structure during the last 100 years and (ii) a critical impact of the Beijing genotype on the current situation with drug resistant TB in Kyrgyzstan. 23703299 Mechanism and capacities of reducing ecological cost through rice-duck cultivation. Rice-duck cultivation is the essence of Chinese traditional agriculture. A scientific assessment of the mechanism and its capacity is of theoretical significance and practical value in improving modern agricultural technology. The duck's secretions, excreta and their treading, pecking and predation decrease the occurrence of plant diseases, pests and weeds, enrich species diversity and improve the field environment. The rice-duck intergrowth system effectively prevents rice planthoppers and rice leafhoppers. The control effects can be up to 98.47% and 100% respectively; it also has effects on the control of Chilo suppressalis, Tryporyza incertulas and the rice leafrollers. Notable control results are found on sheath blight, while the effects on other diseases are about 50%. Harm from weeds is placed under primary control; prevention of weeds is sequenced by broadleaf weeds > sedge weeds > Gramineae weeds. Contents of soil organic matter, N, P and K are improved by the system; nutrient utilization is accelerated, resulting in decreased fertilizer application. Greenhouse gas emissions are reduced by 1-2% and duck fodder is saved in this system. There is also an obvious economic benefit. Compared to conventional rice cultivation, rice-duck cultivation shows great benefits to ecologic cost and economic income. © 2013 The Authors. Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. 23452148 Effect of remote ischaemic preconditioning on renal protection in patients undergoing laparoscopic partial nephrectomy: a 'blinded' randomised controlled trial. To evaluate whether remote ischaemic preconditioning (RIPC) reduces renal injury in patients undergoing laparoscopic partial nephrectomy (LPN). In all, 82 patients undergoing LPN were randomly assigned to either the RIPC or control group, with 40 and 38 patients, respectively completing 6-months follow-up. RIPC was conducted after induction of anaesthesia, which consisted of three 5-min cycles of right lower limb ischaemia and 5 min of reperfusion during each cycle. The primary outcome was the absolute change in glomerular filtration rate (GFR) of the affected kidney by renal scintigraphy from baseline to 6 months. The secondary outcomes included urinary retinol-binding protein (RBP) levels measured at 24 and 48 h, serum creatinine, and estimated GFR (eGFR) at 1 and 6 months, and changes in GFR by renal scintigraphy. There were no differences in the change of GFR of the affected kidney at 6 months, while it was significantly decreased by 15.0% in the control group vs 8.8% in the RIPC group at 1 month (P = 0.034). The urinary RBP levels increased 8.4-fold at 24 h in the control group compared with a lower increase of 3.9-fold in the RIPC group (P < 0.001). There were no differences in the serum creatinine level or eGFR at 1 and 6 months between the two groups. In patients undergoing LPN, RIPC using transient lower limb ischaemia may reduce renal impairment in the short term, but failed in the longer term despite a non-significant trend in favour of RIPC. These novel data support the need for a larger study of RIPC during LPN surgery. 23846505 Bracing improves clinical outcomes but does not affect the medial knee joint space in osteoarthritic patients during gait. Osteoarthritis (OA) of the knee is commonly treated through the use of medial compartment unloading braces which have been shown to improve clinical symptoms. The objective of this study was to assess the effects of a medial compartment unloading brace on biomechanical measurements and clinical outcomes. We hypothesized that brace usage would lead to increased medial joint space and improved clinical outcomes. Ten patients with medial compartment OA were prescribed a medial compartment unloading brace and underwent dynamic biplane radiograph imaging while walking with and without the brace. The Western Ontario and McMaster University Osteoarthritis (WOMAC) Index was used to assess pain before brace wear and at the time of testing. The 3D position and orientation of the femur and tibia were determined using a model-based tracking technique. Patients saw an average improvement of 33 % in their WOMAC scores (p = 0.01). This study failed to detect any statistically significant changes in the functional joint space, knee kinematics, or contact centre location between the braced and unbraced condition (n.s.). The data from this study, using a highly accurate (±0.6 mm and ±0.6°) 3D radiograph analysis of dynamic tibiofemoral motion, suggest that the brace is ineffective at increasing joint space. However, it was shown to be effective in improving clinical outcome and therefore should continue to be prescribed to patients even though the mechanism of its effectiveness remains unknown. LEVEL OF EVIDENCE: IV. 23958280 A comparative study of Toxoplasma gondii seroprevalence in three healthy Chinese populations detected using native and recombinant antigens. Toxoplasmosis is one of the most common parasitic zoonoses. The seroprevalence of Toxoplasma gondii infection in humans varies widely worldwide. Detection of Toxoplasma-specific antibodies has been a gold standard method for both epidemiological investigation and clinical diagnosis. Genetic investigation indicated that there is a wide distribution of different genome types or variants of the parasite prevalent in different areas. Thus the reliability of using antigens from parasites of a single genome type for diagnosis and epidemiology purposes needs to be extensively evaluated. In this study, the prevalence of T. gondii infection among 880 clinically healthy individuals in China was systematically tested using crude soluble native antigens and purified recombinant antigens of type I and II T. gondii. The T. gondii-specific IgG and IgM in the sera was further confirmed using commercial Toxoplasmosis Diagnosis Kits and Western blot assays. The sero-prevalence of T. gondii-specific IgG detected with crude native Type I and type II antigens was 12.2% and 11.3% respectively. Whereas the overall prevalence was more than 20% when combined with the results obtained with recombinant tachyzoite and bradyzoite antigens. There was an obvious variation in immune-recognition of parasite antigens among the individuals studied. The general prevalence of anti-T. gondii IgG in the study population was likely much higher than previously reported. The data also suggested that there is more genetic diversity among the T. gondii isolates in China. Further, combination of recombinant antigens with clear immuno-recognition will be able to generate more sensitive diagnostic results than those obtained with crude antigens of T. gondii tachyzoites. 23881639 Examining duration of binge eating episodes in binge eating disorder. The primary goal of this article is to examine and clarify characteristics of binge eating in individuals with binge eating disorder (BED), particularly the duration of binge eating episodes, as well as potential differences between individuals with shorter compared to longer binge eating episodes. Two studies exploring binge eating characteristics in BED were conducted. Study 1 examined differences in clinical variables among individuals (N = 139) with BED who reported a short (<2 h) versus long (≥2 h) average binge duration. Study 2 utilized an ecological momentary assessment design to examine the duration and temporal pattern of binge eating episodes in the natural environment in a separate sample of nine women with BED. Participants in Study 1 who were classified as having long duration binge eating episodes displayed greater symptoms of depression and lower self-esteem, but did not differ on other measures of eating disorder symptoms, compared to those with short duration binge eating episodes. In Study 2, the average binge episode duration was approximately 42 min, and binge eating episodes were most common during the early afternoon and evening hours, as well as more common on weekdays versus weekends. Past research on binge episode characteristics, particularly duration, has been limited to studies of binge eating episodes in bulimia nervosa. This study contributes to the existing literature on characteristics of binge eating in BED. © 2013 Wiley Periodicals, Inc. (Int J Eat Disord 2013). 23937672 Exploiting the Higher Specificity of Silver Amalgamation: Selective Detection of Mercury(II) by Forming Ag/Hg Amalgam. Heavy metal ion pollution poses severe risks in human health and the environment. Driven by the need to detect trace amounts of mercury, this article demonstrates, for the first time, that silver/mercury amalgamation, combining with DNA-protected silver nanoparticles (AgNPs), can be used for rapid, easy and reliable screening of Hg(2+) ions with high sensitivity and selectivity over competing analytes. In our proposed approach, Hg(2+) detection is achieved by reducing the mercury species to elemental mercury, silver atoms were chosen as the mercury atoms' acceptors by forming Ag/Hg amalgam. To signal fluorescently this silver amalgamation event, a FAM-labeled ssDNA was employed as the signal reporter. AgNPs were grown on the DNA strand that resulted in greatly quenching the FAM fluorescence. Formation of Ag/Hg amalgam suppresses AgNPs growth on the DNA, leading to fluorescence signal increase relative to the fluorescence without Hg(2+) ions, as well as marked by fluorescence quenching. This FAM fluorescence enhancement can be used for detection of Hg(2+) at the a few nanomolar level. Moreover, due to excellent specificity of silver amalgamation with mercury, the sensing system is highly selective for Hg(2+) and does not respond to other metal ions with up to millimolar concentration levels. This sensor is successfully applied to determination of Hg(2+) in tap water, spring water and river water samples. The results shown herein have important implications in the development of new fluorescent sensors for the fast, easy, and selective detection and quantification of Hg(2+) in environmental and biological samples. 22980918 Sex differences in language asymmetry are age-dependent and small: a large-scale, consonant-vowel dichotic listening study with behavioral and fMRI data. Men are often believed to have a functionally more asymmetrical brain organization than women, but the empirical evidence for sex differences in lateralization is unclear to date. Over the years we have collected data from a vast number of participants using the same consonant-vowel dichotic listening task, a reliable marker for language lateralization. One dataset comprised behavioral data from 1782 participants (885 females, 125 non-right-handers), who were divided in four age groups (children <10 yrs, adolescents = 10-15 yrs, younger adults = 16-49 yrs, and older adults >50 yrs). In addition, we had behavioral and functional imaging (fMRI) data from another 104 younger adults (49 females, aged 18-45 yrs), who completed the same dichotic listening task in a 3T scanner. This database allowed us to comprehensively test whether there is a sex difference in functional language lateralization. Across all participants and in both datasets a right ear advantage (REA) emerged, reflecting left-hemispheric language lateralization. Accordingly, the fMRI data revealed a leftward asymmetry in superior temporal lobe language processing areas. In the N = 1782 dataset no main effect of sex but a significant sex by age interaction emerged: the REA increased with age in both sexes but as a result of an earlier onset in females the REA was stronger in female than male adolescents. In turn, male younger adults showed greater asymmetry than female younger adults (accounting for <1% of variance). There were no sex differences in children and older adults. The males in the fMRI dataset (N = 104) also had a greater REA than females (accounting for 4% of variance), but no sex difference emerged in the neuroimaging data. Handedness did not affect these findings. Taken together, our findings suggest that sex differences in language lateralization as assessed with dichotic listening exist, but they are (a) not necessarily reflected in fMRI data, (b) age-dependent and (c) relatively small. 23628500 Synergistic effect of exercise and statins on femoral strength in rats. It is now widely recognized that in order to optimize bone health in the later years, bone healthy behaviors should begin at a young age and continue throughout life. Prescribed orally to lower lipid levels in adults of all ages, statins have also been shown to stimulate bone formation in vitro by promoting bone morphogenic protein-2 (BMP-2) activity and to stimulate bone formation in vivo. Weight bearing exercise is well known to stimulate bone formation through a mechanism whereby mechanical loading is 'sensed' by the mechano-sensors leading to a cascade of events involving the activation of osteoblasts. For individuals with high cholesterol levels, both of these interventions are recommended throughout adult life. Since statins and exercise stimulate bone formation via different mechanisms, we hypothesized that exercise in combination with oral simvastatin synergistically increases bone mineral density and strength. Mature adult female, Sprague Dawley rats were divided into 4 groups: control (n=9), statin only (n=8), exercise only (n=11), and statin plus exercise (n=11). Simvastatin was given to the two groups at a dose of 10mg/kg/day in standard rat chow for the entire 5week period. All rats ate the same mass of food. The two exercise groups ran on a treadmill with progressively greater speeds and time, ending on week 5 at 30m/min for 60min. After 5weeks, rats were euthanized, and excised femurs were scanned for areal bone mineral density (BMD) and tested by three point bending to obtain the following performance measures: maximum force (strength), stiffness, and work-to-fracture. Only the group treated with statins and exercise showed a positive effect on the biomechanical performance of the femurs. Compared to controls, this group had increased maximum force, stiffness, moment of inertia, and BMD. Linear regression analysis revealed that the increased performance was related to increased BMD. We conclude that the combination of oral statins and appropriate exercise increases bone strength better than either individual treatment and may provide optimal protection against osteoporosis. 23734638 Synovial deposition of wild-type transthyretin-derived amyloid in knee joint osteoarthritis patients. Abstract Objective: To investigate histological features of deposited amyloid in the synovial tissue and its clinical significance in knee joint osteoarthritis (OA) patients. Methods: We prospectively enrolled 232 consecutive patients who underwent arthroplasty or total replacement of the knee joint for treatment of OA. Congo red staining and immunohistochemistry were performed in the synovial tissue obtained at surgery. When transthyretin (TTR)-derived amyloid was positive, we analyzed all 4 exons of the TTR gene using the direct DNA sequencing method in order to detect mutations. Results: We analyzed 322 specimens in this study. Twenty-six specimens (8.1%) obtained from 21 patients (5 men and 16 women; mean, 79.0 ± 4.6 years) showed deposition of amyloid, which was positively stained with the anti-TTR antibody. Eighteen patients showed inhomogeneous accumulations of amyloid in the loose connective tissue under the synovial epithelia sometimes with nodule formation, while in the remaining three, small vessels in the adipose tissue were involved. Medical records of these patients revealed nothing remarkable in the clinical course, laboratory data or macroscopic intraarticular findings at surgery. No mutations were detectable in the TTR gene analysis. Conclusion: Wild-type TTR-derived amyloid may affect the synovial tissue as a result of long-term mechanical stress or as a part of senile systemic amyloidosis in approximately 8% of knee joint OA patients. No obvious clinical significance was found in synovial deposition of amyloid. 23200002 Geographical provenance of palm oil by fatty acid and volatile compound fingerprinting techniques. Analytical methods are required in addition to administrative controls to verify the geographical origin of vegetable oils such as palm oil in an objective manner. In this study the application of fatty acid and volatile organic compound fingerprinting in combination with chemometrics have been applied to verify the geographical origin of crude palm oil (continental scale). For this purpose 94 crude palm oil samples were collected from South East Asia (55), South America (11) and Africa (28). Partial least squares discriminant analysis (PLS-DA) was used to develop a hierarchical classification model by combining two consecutive binary PLS-DA models. First, a PLS-DA model was built to distinguish South East Asian from non-South East Asian palm oil samples. Then a second model was developed, only for the non-Asian samples, to discriminate African from South American crude palm oil. Models were externally validated by using them to predict the identity of new authentic samples. The fatty acid fingerprinting model revealed three misclassified samples. The volatile compound fingerprinting models showed an 88%, 100% and 100% accuracy for the South East Asian, African and American class, respectively. The verification of the geographical origin of crude palm oil is feasible by fatty acid and volatile compound fingerprinting. Further research is required to further validate the approach and to increase its spatial specificity to country/province scale. 23932736 The bipolar disorder prodrome revisited: Is there a symptomatic pattern? To assess the phenomenology and course of pre-(hypo)manic and pre-depressed prodromal symptoms, including mood swings, as precursors of bipolar disorder (BD) in a German multi-center study. Semi-structured interviews [Bipolar Prodrome Symptom Scale-Retrospective (BPSS-R); Semi-structured Interview for Mood Swings] were administered to patients within 8 years of BD (BD I, BD II) onset. Forty two outpatients were included (40.5% male, mean age 35.1±10.0 years, illness onset at 30.5±9.5 years). Feeling extremely energetic (85.7%), racing thoughts (78.6%), physical agitation (76.2%), overtalkativeness (71.4%), and low sleep requirement (71.4%) occurred most frequently prior to the first (hypo)manic episode, whereas depressed mood (83.0%), reduced vitality (81.0%), physical exhaustion (78.6%), tiredness (76.2%), and insomnia (66.7%) preceded pre-depressively. Mood lability (p=.006), odd ideas (p=.003) and the psychosis index score (p=.003) differed significantly in prevalence depending on the episodes' mood. Extremely energetic (p=.046), overtalkativeness (p<.001), and racing thoughts (p=.013) lasted significantly longer prior to depression. Neither severity nor frequency of prodromal symptoms differed significantly. Most of the symptoms emerged during the proximal prodromal phase. Links between mood swings and subsequent BD were found. Symptoms were evaluated retrospectively with self-reporting tools in bipolar patients from academic treatment settings without comparison to clinical controls. Not only specific depressive or manic but also general symptoms occurred prior to both affective episodes. The pre-depressive prodrome lasted longer than the pre-manic one, but severity and frequency did not differ significantly. Mood swings and disturbed diurnal rhythm occurred prior to both episodes as early signs of BD. 23770450 Synthesis of N-substituted acyclic β-amino acids and their investigation as GABA uptake inhibitors. In this publication, we describe the synthesis of new inhibitors for the GABA transporter subtypes GAT1 and especially GAT3. We started with 3-aminopropanoic acid possessing a distinct preference for GAT3 in comparison to GAT1 and furthermore its homolog 3-aminobutanoic acid. A series of respective N-substituted amino acids was synthesized by selective N-monoalkylation of these parent structures with 6 different arylalkyl alcohols via a Mitsunobu-type reaction. The resulting compounds were investigated for their inhibitory potency GABA transporter subtypes. Among all tested compounds the 4,4-diphenylbut-3-enyl substituted 3-aminobutanoic acid (rac)-6b showed highest potency with a pIC50 value of 5.34 at GAT1. Unfortunately, the expected GAT3 potency for 2-[tris(4-methoxyphenyl)methoxy]ethyl substituted derivatives was not as high as observed for the respective nipecotic acid derivatives. 23583933 Genetic deletion of the adenosine A2A receptor prevents nicotine-induced upregulation of α7, but not α4β2* nicotinic acetylcholine receptor binding in the brain. Considerable evidence indicates that adenosine A2A receptors (A2ARs) modulate cholinergic neurotransmission, nicotinic acetylcholine receptor (nAChR) function, and nicotine-induced behavioural effects. To explore the interaction between A2A and nAChRs, we examined if the complete genetic deletion of adenosine A2ARs in mice induces compensatory alterations in the binding of different nAChR subtypes, and whether the long-term effects of nicotine on nAChR regulation are altered in the absence of the A2AR gene. Quantitative autoradiography was used to measure cytisine-sensitive [(125)I]epibatidine and [(125)I]α-bungarotoxin binding to α4β2* and α7 nAChRs, respectively, in brain sections of drug-naïve (n = 6) or nicotine treated (n = 5-7), wild-type and adenosine A2AR knockout mice. Saline or nicotine (7.8 mg/kg/day; free-base weight) were administered to male CD1 mice via subcutaneous osmotic minipumps for a period of 14 days. Blood plasma levels of nicotine and cotinine were measured at the end of treatment. There were no compensatory developmental alterations in nAChR subtype distribution or density in drug-naïve A2AR knockout mice. In nicotine treated wild-type mice, both α4β2* and α7 nAChR binding sites were increased compared with saline treated controls. The genetic ablation of adenosine A2ARs prevented nicotine-induced upregulation of α7 nAChRs, without affecting α4β2* receptor upregulation. This selective effect was observed at plasma levels of nicotine that were within the range reported for smokers (10-50 ng ml(-1)). Our data highlight the involvement of adenosine A2ARs in the mechanisms of nicotine-induced α7 nAChR upregulation, and identify A2ARs as novel pharmacological targets for modulating the long-term effects of nicotine on α7 receptors. 23597508 Connexin channel modulators and their mechanisms of action. Gap junction channels and hemichannels formed by the connexin family of proteins play important roles in many aspects of tissue homeostasis in the brain and in other organs. In addition, connexin channels have been proposed as pharmacological targets in the treatment of a number of human disorders. In this review, we describe the connexin-subtype selectivity and specificity of pharmacological agents that are commonly used to modulate connexin channels. We also highlight recent progress made towardtoward identifying new agents for connexin channels that act in a selective and specific manner. Finally, we discuss developing insights into possible mechanisms by which these agents modulate connexin channel function. This article is part of a Special Issue entitled 'Connexin based channels'. 22734442 Mobilised bone marrow-derived cells accelerate wound healing. Massive skin defects caused by severe burn and trauma are a clinical challenge to surgeons. Timely and effective wound closure is often hindered by the lack of skin donor site. Bone marrow-derived cells (BMDCs) have been shown to 'differentiate' into multiple tissue cells. In this study we focused on the direct manipulation of endogenous BMDCs, avoiding the immunocompatibility issues and complicated cell isolation, purification, identification and amplification procedures in vitro on wound repair. We found that mobilisation of the BMDCs into the circulation significantly increased the amount of BMDCs at the injury site which in turn accelerated healing of large open wound. We used a chimeric green fluorescent protein (GFP) mouse model to track BMDCs and to investigate their role in full-thickness skin excisional wounds. We have shown that bone marrow mobilisation by granulocyte colony stimulating factor (G-CSF) exerted multiple beneficial effects on skin repair, both by increasing the engraftment of BMDCs into the skin to differentiate into multiple skin cell types and by upregulating essential cytokine mRNAs critical to wound repair. The potential trophic effects of G-CSF on bone marrow stem cells to accelerate wound healing could have a significant clinical impact. 23638711 Effects of exclusive breastfeeding intervention on child growth and body composition: the MINIMat trial, Bangladesh. Exclusive breastfeeding (EBF) for 6 months is recommended for optimal infant health, but the evidence for longer-term impacts is weak. We examined whether randomization to receive EBF counselling (BFC) in rural Bangladeshi women had an impact on childhood growth trajectories and body composition. In the Maternal and Infant Nutrition Interventions in Matlab trial, 4436 pregnant women were randomized to six equally sized, food and micronutrient groups. Of these, 3214 were randomized during the last trimester of pregnancy to receive either BFC or the usual/standard health message (UHM). Their infants were extensively followed up, with anthropometric measurements between 0 and 54 months and assessment of body composition at 54 months. The mean duration of EBF in the BFC group was 111 days compared to 76 days in the UHM group (mean difference: 35.0 days, 95% CI 30.6-39.5, p < 0.001). There was no difference in growth trajectories between the BFC and UHM groups and no difference in body composition at 54 months. Children exposed to prenatal multiple micronutrients (vs 60 mg iron and folate) combined with BFC (vs UHM), however, had slower linear growth (mean difference -0.17 SD score, p < 0.01). Exclusive breastfeeding counselling resulted in neither differential growth trajectories in infancy and childhood, nor body composition differences at 54 months. The combination of prenatal multiple micronutrient supplementation (MMS) and BFC was unfavourable for linear growth during 0-54 months, which raises questions about possible negative effects of MMS. 21761275 Role of religious attendance and identity conflict in psychological well-being. A sample of individuals who identified as gay or lesbian were administered measures of church attendance, their religious organization's view of homosexuality, perceived conflict between religious faith identity and sexual orientation identity, social support, depression, and generalized anxiety. Among participants who rated their church as rejecting of homosexuality, greater frequency of attendance was related to a higher incidence of GAD symptoms, but not depression. No correlation was found for those attending accepting faith communities. Those who attend rejecting faith communities attended services less often, experienced greater identity conflict, and reported significantly less social support than those of the Accepted group. Regression analyses indicated that identity conflict and social support did not fully account for the relationship between attendance and GAD symptoms. Overall, findings from the current study support previous suggestions that participation in conservative or rejecting religious communities may adversely affect the emotional well-being of GL individuals. 23601203 Design, Synthesis and biological evaluation of catecholamine vehicle for studying dopaminergic system. Catecholamine mimetic EDTA-bis(tyramide) was synthesized and characterized by various spectroscopic techniques (NMR, Mass spectroscopy) and λem 310 nm for the excitation at 270 nm. Molecular docking studies were performed with Human Serum Albumin (HSA: PDB 1E78), showing binding pattern with amino acid residues Arg218, Arg222 and Lys444, identifies the ligand-HSA interaction for the transportation affinity of the ligand at the specific site of the target. Subsequently binding study with HSA at λex =350 nm found to be 5.847x10(4) M(-1) shows effective quenching effect. Additionally to go more insight AChE binding affinity was investigated, which shows 90% binding affinity for the 10 mM concentration. IC50 value was was found 18.60 μM for MAO-B inhibition. Finally, EDTA-bis(tyramide) labeled with (99m) Tc to investigate its in-vivo radiopharmaceutical efficiency, having 97% binding affinity with 98% radiochemical purity. In-vivo studies were carried out for (99m) Tc- EDTA-bis(tyramide) included blood kinetics showed a quick wash out from the circulation via renal route and biodistribution revealed that maximum%ID/g was found in kidney at 1h and its scintigraphy image shows 3.96% brain uptake with respect to whole body. This article is protected by copyright. All rights reserved. 23625906 Studying the effect of antioxidants on cytogenetic manifestations of solvent exposure in paint industry. OBJECTIVE: To investigate the antioxidant role in reversing cytogenetic changes caused by solvent exposure in paint industry.Subjects and METHODS: A prospective controlled clinical trial was performed on 39 workers exposed to solvents and 39 workers not exposed to solvents by supplying a mixture of antioxidant vitamins (A, C, E and selenium) and the after effects of such regimen were analyzed. Environmental monitoring was carried out for air concentrations of different solvents at workplace. Exposed group was cytogenetically tested before and after giving the mixture of antioxidant vitamins for 1 month duration. RESULTS: Frequency of chromosomal aberrations (CAs) and the mean of sister chromatid exchanges (SCEs) were statistically significantly higher among exposed workers than among controls. After the supplementation of antioxidants, there was a statistically significant decrease in the frequency of CAs, and 88% abnormal levels of SCEs were back to normal levels. CONCLUSION: Antioxidant supplementation decreases the frequency of CAs and SCEs among exposed workers. 23714736 The transcription factor Foxk1 is expressed in developing and adult mouse neuroretina. The forkhead transcription factor Foxk1 is an important regulator of myogenic progenitor cells. Since our previous data from mouse retina revealed that Foxk1 is upregulated in Ptf1a-deficient mice we investigated the spatial and temporal expression of Foxk1 during development of mouse retina. Expression of Foxk1 was analyzed on both mRNA and protein level. To identify Foxk1 transcripts, retina and cerebrum (positive control) of adult animals (postnatal day 90 (P90)) was subjected to reverse transcription polymerase chain reaction (RT-PCR) and sequencing of the amplified cDNA. The Foxk1 protein was analyzed in adult retina by Western blotting and in developing eyes at embryonic day (E) 13, 15, E17, P0, P4, P7, P10 and P90 by immunohistochemistry. Localization of Foxk1 expression was determined using cell-specific markers by double labelling. Foxk1 transcripts were detected in adult retina by RT-PCR and confirmed by sequencing. Western blot analysis confirmed the expression of Foxk1 protein in the adult retina. Immunohistochemical examination of developing eyes localized the protein to bipolar, amacrine and ganglion cells with an onset of Foxk1 expression from E15 onwards. The expression pattern during development suggests that Foxk1 may have an important role in retinal cells. 23412178 Combined medial open-wedge high tibial osteotomy and modified Maquet procedure for medial compartmental osteoarthritis and patellofemoral arthritis of the knee. Patellofemoral arthritis comes frequently with medial compartmental osteoarthritis. The combination of closed wedge high tibial osteotomy with tibial tuberosity anteriorization osteotomy has been introduced in several reports, but this technique is a technically demanding procedure and the outcomes of this technique show variable results. This article describes a novel osteotomy technique that combines medial open-wedge high tibial osteotomy (HTO) and tibial tuberosity anteriorization osteotomy (TTAO) for medial compartmental osteoarthritis and patellofemoral arthritis of the knee. Twelve knees in 10 patients who were diagnosed with combined medial compartmental osteoarthritis with patellofemoral compartmental arthritis were treated with the combination of medial open-wedge HTO and TTAO and were followed up for more than 1 year. We evaluated the patients with the Lysholm functional questionnaires, the hospital for special surgery score (HSS), and the international knee documentation committee (IKDC) criteria (mean follow-up, 14.8 months). Union was achieved in all cases within 12 weeks. The mean Lysholm score increased from 42 preoperatively to 82.5 postoperatively (p < 0.001), the HSS increased from 57.5 preoperatively to 83 postoperatively (p < 0.001), and the IKDC score increased from 51 preoperatively to 82 postoperatively (p < 0.001). There were no other complications, such as iatrogenic fractures, nonunion, wound problem, collapse or loss of correction, and so on. The combination of medial open-wedge HTO and modified Maquet procedure (TTAO) is considered to be an effective treatment modality for medial and patellofemoral compartmental osteoarthritis. This technique could, therefore, constantly provide a minimally invasive, precise correction of the deformity and a firm fixation that is enough to allow early rehabilitation. 23921925 Recurrent contralateral hearing loss after 2 craniotomies for vestibular schwannoma: etiologic implications. To describe recurrent sudden sensorineural hearing loss after contralateral vestibular schwannoma resection and re-resection. Clinical capsule report. Tertiary academic referral hospital. A patient who underwent 2 craniotomies for vestibular schwannoma. In 2003, a patient experienced contralateral low-frequency sensorineural hearing loss after undergoing translabyrinthine resection of a vestibular schwannoma. This resolved after a course of oral steroids. Seven years later, in 2010, the patient developed tumor recurrence. After retrosigmoid resection, the patient experienced a similar episode of transient, contralateral, low-frequency predominant sensorineural hearing loss. The recurrence of contralateral hearing loss after craniotomies years apart suggests that patient specific anatomic risk factors predispose an individual to hearing loss after contralateral cerebellopontine angle surgery. Patients with previous history of contralateral hearing loss should be counseled that they may be at increased risk for recurrent loss in the setting of re-resection. 23817642 Effect of aging on formation of reactive oxygen species by mitochondria of rat heart. Mitochondrial electron transport chain is thought to be a major source of reactive oxygen species (ROS) during aging. However, this view is supported mainly by accumulation of mitochondrial oxidative damage with age and the exact sites of ROS formation remains unknown. In the present study, we measured rate of ROS formation using 2',7'-dichlorofluorescein (DCF) probe in cardiac mitochondria from adult (6-month-old), old (15-month-old) and senescent (26-month-old) rats. In mitochondria oxidizing complex II substrate, succinate, the rate of ROS formation progressively increased with age. In the presence of complex I inhibitor rotenone or complex III inhibitor antimycin A, the rate ROS formation significantly decreased, but even the combination of inhibitors could not fully prevent generation of ROS. Age-dependent increase of ROS formation was accompanied by a loss of thiol groups, tryptophan degradation and increased lipid peroxidation. These data suggest that in addition to complex I and complex II other mitochondrial sites can contribute to accelerated ROS generation and oxidative damage during aging. 23819847 Factors associated with patient, and diagnostic delays in Chinese TB patients: a systematic review and meta-analysis. Delay in seeking care is a major impediment to effective management of tuberculosis (TB) in China. To elucidate factors that underpin patient and diagnostic delays in TB management, we conducted a systematic review and meta-analysis of factors that are associated with delays in TB care-seeking and diagnosis in the country. This review was prepared following standard procedures of the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and checklist. Relevant studies published up to November 2012 were identified from three major international and Chinese literature databases: Medline/PubMed, EMBASE and CNKI (China National Knowledge Infrastructure). We included 29 studies involving 38,947 patients from 17 provinces in China. Qualitative analysis showed that key individual level determinants of delays included socio-demographic and economic factors, mostly poverty, rural residence, lack of health insurance, lower educational attainment, stigma and poor knowledge of TB. Health facility determinants included limited availability of resources to perform prompt diagnosis, lack of qualified health workers and geographical barriers.Quantitative meta-analysis indicated that living in rural areas was a risk factor for patient delays (pooled odds ratio (OR) (95% confidence interval (CI)): 1.79 (1.62, 1.98)) and diagnostic delays (pooled OR (95% CI): 1.40 (1.23, 1.59)). Female patients had higher risk of patient delay (pooled OR (95% CI): 1.94 (1.13, 3.33)). Low educational attainment (primary school and below) was also a risk factor for patient delay (pooled OR (95% CI): 2.14 (1.03, 4.47)). The practice of seeking care first from Traditional Chinese Medicine (TMC) providers was also identified as a risk factor for diagnostic delay (pooled OR (95% CI): 5.75 (3.03, 10.94)). Patient and diagnostic delays in TB care are mediated by individual and health facility factors. Population-based interventions that seek to reduce TB stigma and raise awareness about the benefits of early diagnosis and prompt treatment are needed. Policies that remove patients' financial barriers in access to TB care, and integration of the informal care sector into TB control in urban and rural settings are central factors in TB control. 23820255 Hormonal risk factors and invasive epithelial ovarian cancer risk by parity. Background:Recent studies have suggested that several ovarian cancer risk factors differ by parity status, but these findings have not been confirmed. We evaluated whether known risk factors of ovarian cancer differ between nulliparous and parous women using data from two large prospective cohorts.Methods:Data from the National Institutes of Health-AARP Diet and Health Study and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial were combined for this analysis. Cox regression models were used to estimate associations with ovarian cancer risk. Risk heterogeneity by parity status was assessed using likelihood-ratio tests.Results:Among the 125 437 women included in the analysis, there were 16 589 (13%) nulliparous women and 108 848 (87%) parous women. Of the 623 women diagnosed with invasive epithelial ovarian cancer, 102 (16%) were nulliparous and 521 (84%) were parous. While parity reduced ovarian cancer risk, no differences were found for other risk factors by parity. Among ever users of hormone therapy, body mass index suggestively increased the risk of ovarian cancer by 1.5-fold in nulliparous but not parous women (P-heterogeneity=0.08).Conclusion:While nulliparous women have higher ovarian cancer risk than parous women, our findings suggest that the relative effects of most other risk factors do not differ by parity. 23723310 Risk factors, clinical presentation, and neuroimaging findings of neonatal perforator stroke. To date, studies on neonatal stroke have mainly focused on cortical stroke. We have focused on perforator strokes, noncortical strokes in the arterial vascular perforator area. We sought to identify risk factors and evaluate clinical presentation and neuroimaging findings for neonatal perforator stroke, which seems to be under-recognized. All infants admitted to our tertiary intensive care unit in ≈12 years, whose perforator stroke was diagnosed with postnatal brain imaging, were enrolled in this study. Demographic, perinatal, and postnatal data were evaluated. Seventy-nine perforator strokes were detected in 55 patients (28 boys), with a median gestational age of 37 1/7 weeks (range 24 1/7 to 42 1/7 weeks, 25 preterm). Perforator stroke was asymptomatic in most patients (58%). Initial diagnosis was predominantly made with cranial ultrasound (80%) in the first week of life (60%). Risk factors for stroke were present in all cases: maternal, fetal, and perinatal. Likely pathogenic mechanisms were prolonged birth asphyxia (16%), hypoxia or hypotension (15%), embolism (15%), infection (15%), acute blood loss (9%), and birth trauma (9%). Previously described risk factors for developing neonatal main artery stroke are probably also associated with neonatal perforator stroke. Perforator stroke is often asymptomatic, but cranial ultrasound is a reliable diagnostic tool in diagnosing perforator stroke. 23801412 Layer-by-layer aqueous rapid synthesis of ZIF-8 films on a reactive surface. The synthesis of zeolitic imidazolate framework-8 (ZIF-8) films in an aqueous system was achieved. ZIF-8 films with controllable thickness were successfully grown on a modified substrate at room temperature. The 3-(2-imidazolin-1-yl)propyltriethoxysilane (IPTES) was used to first form a pseudo-surface of ZIF-8 on a glass substrate, followed by layer-by-layer growth. The film thickness of ZIF-8 was controlled within the range from 220 to 640 nm per growth cycle by changing the reactivity of the zinc source. Notably, the use of a preorganized zinc source led to drastic changes in the formation rate of ZIF-8. The use of a low-reactivity growth solution containing zinc acetate thus allowed the preparation of dense ZIF-8 films. 23518229 Structural elucidation of possible lutein oxidation products mediated through peroxyl radical inducer 2,2'-Azobis (2-methylpropionamidine) dihydrochloride: Antioxidant and cytotoxic influence of oxidized lutein in HeLa cells. Aim of this study was to elucidate lutein oxidation products mediated through peroxyl radical inducer 2,2'-Azobis (2-methylpropionamidine) dihydrochloride (AAPH) and to study antioxidant and cytotoxic effects of oxidized lutein using liposome and HeLa cells. Lutein (20μmol) with AAPH (5mM) in liposome's was incubated at 37°C in dark for 3h, oxidized lutein products were characterized by LC-MS (APCI(+)) and studied for their free radical scavenging activity and cytotoxic effects in terms of cell viability, cellular glutathione, and malondialdehyde levels. AAPH mediated lutein fragmented ions were identified as 551 (M(+)+H(+)-H2O), 391 (M(+)+H(+)+O2-C22H32O) and 276 (M(+)+H(+)+O2-C12H20O) and its isomers as 13-Z lutein, 13-Z zeaxanthin, 13'-Z zeaxanthin and all-E zeaxanthin. Free radical scavenging activity of oxidized lutein was higher by 32.7% (IC50, 2.64μg) than lutein (IC50, 5.28μg). Oxidized lutein lowered the lipid peroxidation (21%), HeLa cells viability (22%) and glutathione levels (32%) than lutein. To conclude, the oxidized lutein may be highly reactive, since oxidation by AAPH results in peroxyl radical ions, which can react with conjugated polyene chain of lutein that could lead to higher antioxidant and cytotoxic effects on HeLa cells. 23438096 Analysis of intracellular human immunodeficiency virus (HIV)-1 drug resistance mutations in multi-failed HIV-1-infected patients treated with a salvage regimen: 72-week follow-up. The human immunodeficiency virus (HIV) mutational archive of proviral DNA was monitored during a 72-week follow-up in 20 multidrug-experienced HIV-1-infected patients treated with a darunavir/ritonavir-based salvage therapy. At the beginning of the study, all patients harboured a number of intracellular drug resistance-associated mutations (RAMs) in peripheral blood mononuclear cells. In some patients, a significant fluctuation in the number of RAMs was observed during the observation period. However, all patients, notwithstanding the presence or the fluctuation of intracellular RAMs, showed a persistently undetectable viraemia. The data suggest that the archived resistant viral variants change during suppressive therapy, but that the variants are unable to re-emerge and to affect virological response. 23651635 A survivin-associated adaptive response in radiation therapy. Adaptive responses can be induced in cells by very low doses of ionizing radiation resulting in an enhanced resistance to much larger exposures. The inhibitor of apoptosis protein, survivin, has been implicated in many adaptive responses to cellular stress. Computerized axial tomography used in image-guided radiotherapy to position and monitor tumor response uses very low radiation doses ranging from 0.5 to 100 mGy. We investigated the ability of these very low radiation doses administered along with two 2 Gy doses separated by 24 hours, a standard conventional radiotherapy dosing schedule, to initiate adaptive responses resulting in the elevation of radiation resistance in exposed cells. Human colon carcinoma (RKO36), mouse sarcoma (SA-NH), along with transformed mouse embryo fibroblasts, wild type or cells lacking functional tumor necrosis factor receptors 1 and 2 were used to assess their relative ability to express an adaptive response when grown either to confluence in vitro or as tumors in the flank of C57BL/6 mice. The survival of each of these cells was elevated from 5% to 20% (P ≤ 0.05) as compared to cells not receiving a 100 mGy or lesser dose. In addition, the cells exposed to 100 mGy exhibited elevations in survivin levels, reductions in apoptosis frequencies, and loss of an adaptive response if transfected with survivin siRNA. This survivin-mediated adaptive response has the potential for affecting outcomes if regularly induced throughout a course of image guided radiation therapy. Cancer Res; 73(14); 4418-28. ©2013 AACR. 23608469 Equilibrium and kinetic aspects of sodium cromoglycate adsorption on chitosan: mass uptake and surface charging considerations. Chitosan has more and more been suggested as a material for use as adsorbent in the treatment of effluents as well as in the synthesis of drug-loaded nanoparticles for controlled release. In both cases, a good understanding of the process of adsorption, both kinetically and in terms of equilibrium, has an importance of its own. In this manuscript we study the interaction between sodium cromoglycate, a drug used in asthma treatment, and chitosan. Equilibrium experiments showed that Sips (or Freundlich-Langmuir) isotherm described well the resultant data and adsorption possibly occurred as in multilayers. A model based on ordinary reaction-rate theory, compounded of two processes, each one with a correlated velocity constant, described the kinetics of sorption. Kinetic and equilibrium data suggested the possibility of surface rearrangement, favored by the increase of temperature. 23800472 Being an adolescent with a cochlear implant in the world of hearing people: coping in school, in society and with self identity. The cochlear implant has revolutionized functioning with severe-to-profound sensori-neural loss. A deaf child implanted at an early age with good habilitation may have good language abilities and function well in daily life. As the implanted child grows up, managing in the world of hearing people may become more complex. During adolescence, the teenager copes with many issues, including identity, socialization with the peer group, and managing in the school setting. These issues may be even more challenging for the adolescents using a cochlear implant. This study was designed to shed light on how adolescents with cochlear implants experience coping with the issues mentioned. Twelve teenagers (14-18 years old), fairly similar to the entire adolescent implanted population at the center at which the study was conducted, participated in the study. They had been unilaterally or bilaterally implanted at differing ages. The participants filled out a questionnaire dealing with their functioning in the educational setting, their social preferences and functioning, and their identity as hearing or deaf. The results were analyzed using the principles of thematic analysis. At school, some reported better achievements than others but they all expressed some difficulty functioning in class mainly in situations involving several speakers. From a social point of view, some reported a preference for association with normal hearing peers, whereas others favored hard-of-hearing friends, and one had no preference. Of those who touched on the topic of self-identity, one referred to herself as deaf, eight defined themselves as hard-of-hearing, and two consider themselves hearing. From the responses of these teenagers, it is clear that adolescents with cochlear implants are a heterogeneous group. Parents and teachers should be aware that adolescents with implants, even when successful academically, may experience difficulties in the classroom setting. Most of the participants in this study learning in a mainstream setting, preferred social relationships with hearing peers (to hard of hearing/deaf). The responses of these adolescents with cochlear implants support the conjecture that they have both a hearing identity and a deaf identity, which may be expressed at varying intensities depending on the situation at the time. 23403085 Neuroprotective effects of mercaptoethylleonurine and mercaptoethylguanidine analogs on hydrogen peroxide-induced apoptosis in human neuronal SH-SY5Y cells. A series of mercaptoethylleonurine and mercaptoethylguanidine derivatives were designed and synthesized. Their neuroprotective effects toward H2O2-induced apoptosis were investigated in human SH-SY5Y cells. The results from these studies identified several potent compounds, with compound 8k emerging as the most effective. Further investigation demonstrated that 8k reduced H2O2-induced activation of mitochondrial apoptosis by inhibiting the expression of Bax and elevating the expression of Bcl-2. Moreover, the molecular mechanism underlying the observed neuroprotective effects of 8k was exerted via the Akt and JNK pathways. Compound 8k can be a lead compound for further discovery of neuroprotective medicine. 23919303 Novel 1H-Pyrrolo[2,3-b]pyridine Derivative Nortopsentin Analogues: Synthesis and Antitumor Activity in Peritoneal Mesothelioma Experimental Models. In this study, we describe the synthesis of new nortopsentin analogues, 1H-pyrrolo[2,3-b]pyridine derivatives and their biological effects in experimental models of diffuse malignant peritoneal mesothelioma (DMPM), a rare and rapidly fatal disease, poorly responsive to conventional therapies. The three most active compounds, 1f (3-[2-(5-fluoro-1-methyl-1H-indol-3-yl)-1,3-thiazol-4-yl]-1H-pyrrolo[2,3-b]pyridine), 3f (3-[2-(1H-indol-3-yl)-1,3-thiazol-4-yl]-1-methyl-1H-pyrrolo[2,3-b]pyridine), and 1l (3-[2-(5-fluoro-1-methyl-1H-indol-3-yl)-1,3-thiazol-4-yl]-1-methyl-1H-pyrrolo[2,3-b] pyridine), which were shown to act as cyclin-dependent kinase 1 inhibitors, consistently reduced DMPM cell proliferation and induced a caspase-dependent apoptotic response, with a concomitant reduction of the expression of the active Thr(34)-phosphorylated form of the antiapoptotic protein survivin. Moreover, the combined treatment of DMPM cells with 3f derivative and paclitaxel produced a synergistic cytotoxic effect, which was paralleled by an enhanced apoptotic response. In the mouse model, i.p. administration of 1f, 3f, and 1l derivatives was effective, resulting in a significant tumor volume inhibition of DMPM xenografts (range, 58-75%) at well-tolerated doses, and two complete responses were observed in each treatment group. 22936531 Obesity among kuwaitis aged 50 years or older: prevalence, correlates, and comorbidities. Objectives: Obesity is a serious global health problem. Our objectives are to assess the prevalence of overweight and obesity among elderly Kuwaitis aged 50 or older, examine their sociodemographic correlates, and analyze the association between obesity and its comorbidities. Methods: A cross-sectional face-to-face interview survey using a structured questionnaire was conducted among 2,443 Kuwaiti men and women aged 50 or older. Height and weight were measured and body mass index (BMI) was calculated. About 81% respondents were overweight of whom 46% were obese. Mean BMI was 30.0 (31.2 for women and 28.1 for men). Multinomial logistic regression analysis revealed that relatively young elderly Kuwaitis (50-59) were 1.7 and 2.2 times more likely to be overweight and obese, respectively, compared with those aged 70 or older. Married individuals had 2.3 times higher risk to be overweight or obese than non-married individuals. Women were 3.6 times more likely to suffer from obesity than men. Overweight and obesity were found to be independent risk factors for hypertension (OR = 1.3 and 1.9, respectively), diabetes (OR = 1.4), and osteoarthritis (OR = 1.8 and 1.6, respectively). Conclusions: Prevalence of overweight and obesity is alarmingly high among elderly Kuwaitis. The associated disease burden is substantial. Stakeholders should address the problem and launch national extensive health-promoting campaigns targeting perceptible lifestyle changes. 23953642 Prevalence of cerebrospinal fluid oligoclonal IgG bands in Greek patients with clinically isolated syndrome and multiple sclerosis. Lower prevalence of cerebrospinal fluid oligoclonal IgG bands (IgG-OCBs) has been reported in multiple sclerosis (MS) patients from Southern Europe compared to other western countries. We aimed to determine the prevalence of CSF OCBs in Greek MS patients and to examine their relation with some selected clinical and demographical features. Included patients fulfilled the 2005 McDonald criteria for definite MS (CDMS) or clinically isolated syndrome (CIS) and had a spinal tap performed between 2006 and 2010. Paired CSF and plasma samples were analyzed using isoelectric focusing followed by IgG-specific immunofixation. A pattern of two or more bands present only in the CSF was defined as positive. OCB status was correlated with age at disease onset, initial symptomatology, relapse rate, disease subtype, disease duration, medication, EDSS score and MSSS. Of the 231 included patients (53.2% with CDMS and 48.6% with CIS) 67.5% had OCBs. The prevalence of positive patterns did not differ between CIS and CDMS patients (67.6% vs. 67.5%, respectively). OCB-positive patients were younger than OCB-negative patients (35.2±10.3 vs. 38.7±11.8 years respectively, p=0.022) and had more frequently cervical spinal cord lesions (x(2)=7.08, p=0.008). No difference was observed between the two subgroups in the other studied disease parameters. Despite the lower frequency of positive IgG-OCB patterns in our patients, both subgroups were mostly similar with regard to their clinical and demographic characteristics suggesting that the OCB status lacks prognostic significance in MS. 23613615 Thalamic Atrophy Is Associated with Development of Clinically Definite Multiple Sclerosis. Purpose: To investigate the association between the development of thalamic and cortical atrophy and the conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndrome (CIS). Materials and Methods: This prospective study was approved by the institutional review board. Informed consent was given by 216 CIS patients, and patients were treated with 30 µg of intramuscular interferon β1a once a week. They were assessed with a magnetic resonance (MR) imaging examination at baseline, 6 months, 1 year, and 2 years. Patients were evaluated within 4 months of an initial demyelinating event, had two or more brain lesions on MR images, and had two or more oligoclonal bands in cerebrospinal fluid. MR imaging measures of progression included cumulative number and volume of contrast agent-enhanced (CE) new and enlarged T2 lesions, and changes in whole-brain, tissue-specific global, and regional gray matter volumes. Regression and mixed-effect model analyses were used. Results: Over 2 years, 92 of 216 patients (42.6%) converted to CDMS; 122 (56.5%) CIS patients fulfilled McDonald 2005 criteria and 153 (70.8%) fulfilled McDonald 2010 criteria for MR imaging dissemination in time and space. The mean time to first relapse was 3.1 months, and mean annual relapse rate was 0.46. In mixed-effect model analysis, the lateral ventricle volume (P = .005), accumulation of CE (P = .007), new total T2 (P = .009) and new enlarging T2 lesions (P = .01) increase, and thalamic (P = .009) and whole-brain (P = .019) volume decrease were associated with development of CDMS. In multivariate regression analysis, decrease in thalamic volumes and increase in lateral ventricle volumes (P = .009) were MR imaging variables associated with the development of CDMS. Conclusion: Measurement of thalamic atrophy and increase in ventricular size in CIS is associated with CDMS development and should be used in addition to the assessment of new T2 and CE lesions. © RSNA, 2013 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122424/-/DC1. 23926166 Multiple Broad-Spectrum Beta-Lactamase Targets for Comprehensive Surveillance. Real-time PCR testing for blaKPC, blaNDM, blaVIM, blaIMP, and blaCTX-M was performed on rectal swabs obtained from residents of two long-term acute care facilities. While blaKPC was detected in 69/102 (67.6%), testing for four other targets increased the positivity rate for a broad-spectrum β-lactamase to 73.5% (McNemar p=0.03). 23660520 Ecosystem services in Mediterranean river basin: climate change impact on water provisioning and erosion control. The Mediterranean basin is considered one of the most vulnerable regions of the world to climate change and such changes impact the capacity of ecosystems to provide goods and services to human society. The predicted future scenarios for this region present an increased frequency of floods and extended droughts, especially at the Iberian Peninsula. This paper evaluates the impacts of climate change on the water provisioning and erosion control services in the densely populated Mediterranean Llobregat river basin of. The assessment of ecosystem services and their mapping at the basin scale identify the current pressures on the river basin including the source area in the Pyrenees Mountains. Drinking water provisioning is expected to decrease between 3 and 49%, while total hydropower production will decrease between 5 and 43%. Erosion control will be reduced by up to 23%, indicating that costs for dredging the reservoirs as well as for treating drinking water will also increase. Based on these data, the concept for an appropriate quantification and related spatial visualization of ecosystem service is elaborated and discussed. 22359397 Neural substrates of the self-memory system: new insights from a meta-analysis. The self has been the topic of philosophical inquiry for centuries. Neuropsychological data suggest that the declarative self can be fractionated into three functionally independent systems processing personal information at several levels of abstraction, including episodic memories of one's own life (episodic autobiographical memory, EAM), semantic knowledge of facts about one's own life (semantic autobiographical memory, SAM), and semantic summary representations of one's personal identity (conceptual self, CS). Our proposal here was to present a comprehensive description of the neural networks underpinning self-representations. To this aim, we performed three meta-analyses, one each for EAM, SAM, and CS, using the activation likelihood estimation (ALE) method. We expected a shift from posterior to anterior structures associated with the incrementally increasing level of abstraction of self-representations. The key finding was that EAM predominantly activates posterior and limbic regions including hippocampus. SAM is associated with anterior activations and also posterior and limbic activations in a lesser degree than EAM. CS mainly recruits medial prefrontal structures. Interestingly, medial prefrontal cortex is activated irrespective of the level of abstraction, but a more caudal part is recruited during CS, while SAM and EAM activate more rostral portions. To conclude, in line with the previous proposals, our results corroborate the idea that the declarative self is not monolithic but a multidimensional construct comprising distinct representations at different levels of abstraction. 23507868 Inhibitory effects of in vivo oxidized high-density lipoproteins on platelet aggregation: evidence from patients with abetalipoproteinemia. There is evidence that high-density lipoproteins (HDLs) may regulate platelet function, but disparate results exist regarding the effects of oxidized HDLs on platelets. The objective of our study was to determine the role of in vivo oxidized HDLs on platelet aggregation. Platelet aggregation and redox status were investigated in 5 patients with abetalipoproteinemia (ABLP) or homozygous hypobetalipoproteinemia, two rare metabolic diseases characterized by the absence of apolipoprotein B-containing lipoproteins, compared to 5 control subjects. Platelets isolated from plasma of patients with ABLP aggregated 4 to 10 times more than control platelets, depending on the agonist. By contrast, no differences in the extent of platelet aggregation were observed between ABLP platelet-rich plasma (PRP) and control PRP, suggesting the presence of a protective factor in ABLP plasma. ABLP HDLs inhibited agonist-induced platelet aggregation by binding to SR-BI, while control HDLs had no effect. On the other hand, lipoprotein-deficient plasma from patients with ABLP did not inhibit platelet aggregation. Severe oxidative stress was evidenced in patients with ABLP. Compared to control HDLs, ABLP HDLs showed a 40% decrease of α-tocopherol and an 11-fold increased malondialdehyde concentration. These results demonstrate that in vivo oxidized HDLs do not lose their antiaggregatory properties despite oxidation.-Calzada, C., Véricel, E., Colas, R., Guillot, N., El Khoury, G., Drai, J., Sassolas, A., Peretti, N., Ponsin, G., Lagarde, M., Moulin, P. Inhibitory effects of in vivo oxidized high-density lipoproteins on platelet aggregation: evidence from patients with abetalipoproteinemia. 23337607 Prenatal exposure to bisphenol A impacts midbrain dopamine neurons and hippocampal spine synapses in non-human primates. Prevalent use of bisphenol-A (BPA) in the manufacture of resins, plastics and paper products has led to frequent exposure of most people to this endocrine disruptor. Some rodent studies have suggested that BPA can exert detrimental effects on brain development. However as rodent models cannot be relied on to predict consequences of human exposure to BPA during development, it is important to investigate the effects of BPA on non-human primate brain development. Previous research suggests that BPA preferentially targets dopamine neurons in ventral mesencephalon and glutamatergic neurons in hippocampus, so the present work examined the susceptibility of these systems to low dose BPA exposure at the fetal and juvenile stages of development in non-human primates. Exposure of pregnant rhesus monkeys to relatively low levels of BPA during the final 2 months of gestation, induced abnormalities in fetal ventral mesencephalon and hippocampus. Specifically, light microscopy revealed a decrease in tyrosine hydroxylase-expressing (dopamine) neurons in the midbrain of BPA-exposed fetuses and electron microscopy identified a reduction in spine synapses in the CA1 region of hippocampus. In contrast, administration of BPA to juvenile vervet monkeys (14-18 months of age) was without effect on these indices, or on dopamine and serotonin concentrations in striatum and prefrontal cortex, or on performance of a cognitive task that tests working memory capacity. These data indicate that BPA exerts an age-dependent detrimental impact on primate brain development, at blood levels within the range measured in humans having only environmental contact with BPA. 23860102 Healthy Characters? An Investigation of Marketing Practices in Children's Food Advertising. To determine the nutritional quality of foods advertised with familiar children's characters and health-related messages. Children's programming aired on the most popular broadcast and cable channels during 2011 was sampled to form a composite weekday and weekend day. All food advertisements (ads) included in this programming were content analyzed. Five hundred seventy-seven food ads. Familiar characters promoting products were either trade or licensed characters. A product's nutritional quality was determined using the United States Department of Health and Human Services' categorizations, based on the frequency foods should be consumed. Health cues were present when a food was claimed to be healthy, physical activity was depicted, or the product was associated with fruit. Frequencies and chi square analyses were conducted; P < .05. Nearly three quarters (73%) of food ads targeting children use a familiar character. The majority of these ads (72%) promote foods of low nutritional quality, yet 53% employ a health-related message. Familiar characters proliferate in food advertising to children, yet marketers do not adhere to recommendations that characters promote strictly healthy foods. Future research is needed to investigate effects and inform policy decisions in this realm. 23859726 Structural bias in the sentencing of felony defendants. As incarceration rates have risen in the US, so has the overrepresentation of African Americans and Latinos among prison inmates. Whether and to what degree these disparities are due to bias in the criminal courts remains a contentious issue. This article pursues two lines of argument toward a structural account of bias in the criminal law, focusing on (1) cumulative disadvantages that may accrue over successive stages of the criminal justice process, and (2) the contexts of racial disadvantage in which courts are embedded. These arguments are tested using case-level data on male defendants charged with felony crimes in urban US counties in 2000. Multilevel binary and ordinal logit models are used to estimate contextual effects on pretrial detention, guilty pleas, and sentence severity, and cumulative effects are estimated as conditional probabilities that are allowed to vary by race across all three outcomes. Results yield strong, but qualified, evidence of cumulative disadvantage accruing to black and Latino defendants, but do not support the contextual hypotheses. When the cumulative effects of bias are taken into account, the estimated probability of the average African American or Latino felon going to prison is 26% higher than that of the average Anglo. 23404692 Current-use pesticides in stream water and suspended particles following runoff: Exposure, effects, and mitigation requirements. The European Union's directive for sustainable use of pesticides requires implementing risk mitigation measures at streams threatened by pesticide entries. The need for mitigation measures was investigated at 10 stream sites within an intensively used arable region in central Germany by characterizing pesticide exposure following edge-of-field runoff and effects on the aquatic macroinvertebrates. Moreover, the influence of riparian buffer strip width (as a mitigation measure) at the sampling sites was considered. Generally, invertebrate fauna was dominated by pesticide-tolerant species, suggesting a high pesticide exposure at almost all sites. This result is also reflected by the elevated levels of suspended particle contamination in terms of toxic units (logTUMax  > -2), corresponding to one-hundredth of the median lethal concentration (LC50) to Daphnia magna. At two sites that received high aqueous-phase entries of the pyrethroid lambda-cyhalothrin (logTUMax  > -0.6), the abundance and number of sensitive species in terms of the species at risk index decreased during the pesticide application period. In contrast, no acute significant negative effects on macroinvertebrates were observed at sites characterised by low water-phase toxicity (logTUMax  < -3.5). An influence of riparian buffer strip width on pesticide exposure was not observed, supposedly because of the presence of erosion rills and ephemeral ditches. In conclusion, results show that mitigation measures (such as the improvement of currently present riparian buffer strips) are needed in the study area. Environ Toxicol Chem 2013;32:1254-1263. © 2013 SETAC. 23932182 Maternal and neonatal outcomes following additional doses of vaginal prostaglandin E2 for induction of labour: a retrospective cohort study. To assess maternal and neonatal outcomes following the use of additional doses of vaginal prostaglandins (PGE2) above the recommended dose for induction of labour in post-dates pregnancies. Retrospective cohort study set in Aberdeen Maternity Hospital, Aberdeen, UK. A total of 3514 nulliparous women with labour induced with vaginal PGE2 (3mg tablet or 2mg gel) for a post-dates singleton pregnancy from January 1994 to December 2009 were included. Women receiving≤2 doses of PGE2 were compared with those receiving>2 doses (maximum 5 doses). Binary logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI). Primary outcomes included mode of delivery, terbutaline use, indication for CS, postpartum haemorrhage, neonatal unit admission, and Apgar score<7. A further analysis was conducted which stratified for number of doses of PGE2 given. Of the 3514 women who met inclusion criteria, 605 (17%) received PGE2 that exceeded the licensed dose. They were more likely to deliver by caesarean section (53.4% vs. 31.8%, OR 2.2, 95% CI 1.8-2.6), have a caesarean section for 'failed' induction of labour (11.4% vs. 1.9%, OR 4.1, 95% CI 1.3-13.2) or lack of progress in labour (37% vs. 17%, OR 2.8, 95% CI 2.3-3.4), but not for fetal concerns (8.2% vs. 8.8% OR 0.9, 95% CI 0.7-1.3). Terbutaline use and postpartum haemorrhage was no more likely (0.7% vs. 0.9% OR 0.6 95% CI 0.3-1.5 and 19.8% vs. 18.9% OR1.01, 95% CI 0.97-1.06 respectively). Apgar score<7 (1.1% vs. 1.3% OR 0.9 95% CI 0.8-1.1) and neonatal unit admission (13.7% vs. 10.7% OR 1.2 95% CI 0.8-1.6) were similar in both groups. The use of additional doses of vaginal PGE2 above the recommended dose for induction of labour was not associated with increased maternal or neonatal morbidity and almost half of these women achieved a vaginal delivery. 23731659 Clinical and genetic evaluation of a Chinese family with isolated oligodontia. Oligodontia is defined as the congenital absence of 6 or more permanent teeth excluding the third molar. Tooth agenesis may be classified as syndromic/non-syndromic and as familial/sporadic. To date, more than 300 genes have been found to be involved in tooth development, but only a few of these genes, such as MSX1, PAX9 and AXIN2, are related to the condition of non-syndromic oligodontia. The objective of the present work was to investigate the disease-causing gene of non-syndromic oligodontia in a Han Chinese family and analyse the pathogenesis of mutations that result in oligodontia. We examined all individuals of the oligodontia family by clinical and radiographic examinations. Based on the clinical manifestations, the candidate genes MSX, PAX9 and AXIN2 were selected to analyse and screen for mutations. The clinical evaluation suggested that the family might show non-syndromic oligodontia. DNA sequencing of the MSX1 gene revealed two mutations in the two patients with oligodontia: a heterozygotic silent mutation, c.348C>T (P.Gly116=), in exon 1 and a homozygotic deletion of 11 nucleotides (c.469+56delins GCCGGGTGGGG) in the intron. However, the silent mutation and the deletion mutation were thought to be known polymorphisms (rs34165410 and rs34341187) by bioinformatics analysis. We did not detect any mutations in the PAX9 and AXIN2 genes of oligodontia patients. Our finding suggests that identified polymorphisms (c.348C>T and c.469+56delins GCCGGGTGGGG) may be responsible for the oligodontia phenotype in this Chinese family, but the association requires further study. 23863995 Short, terminally modified 2'-OMe RNAs as inhibitors of microRNA. We applied 14-mer 2'-OMe RNAs as inhibitors of selected micro RNAs. To improve their properties, we introduced a trimethoxystilbene residue at the 5'-terminus and three 2'-fluoro-2'-deoxynucleotides at the 3'-terminus to obtain potent inhibitors, whose mismatch discrimination is substantially better than that of typically applied >18-mers. 23420562 The protein corona mediates the impact of nanomaterials and slows amyloid beta fibrillation. Put your coat on: It is well recognized that the surfaces of nanomaterials in biological media are covered by various biomolecules (e.g., proteins). A) The protein corona creates a shell over different nanomaterials, regardless of their physicochemical properties (e.g., composition and shape), resulting in reduced levels of amyloid beta fibril formation. B) Pristine nanomaterials might have acceleratory effects on the fibrillation of amyloid beta. 23892367 RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions of cIAP1/2 depletion or TAK1 kinase inhibition. Receptor-interacting protein kinase (RIPK) 1 and RIPK3 have emerged as essential kinases mediating a regulated form of necrosis, known as necroptosis, that can be induced by tumor necrosis factor (TNF) signaling. As a consequence, inhibiting RIPK1 kinase activity and repressing RIPK3 expression levels have become commonly used approaches to estimate the contribution of necroptosis to specific phenotypes. Here, we report that RIPK1 kinase activity and RIPK3 also contribute to TNF-induced apoptosis in conditions of cellular inhibitor of apoptosis 1 and 2 (cIAP1/2) depletion or TGF-β-activated kinase 1 (TAK1) kinase inhibition, implying that inhibition of RIPK1 kinase activity or depletion of RIPK3 under cell death conditions is not always a prerequisite to conclude on the involvement of necroptosis. Moreover, we found that, contrary to cIAP1/2 depletion, TAK1 kinase inhibition induces assembly of the cytosolic RIPK1/Fas-associated protein with death domain/caspase-8 apoptotic TNF receptor 1 (TNFR1) complex IIb without affecting the RIPK1 ubiquitylation status at the level of TNFR1 complex I. These results indicate that the recruitment of TAK1 to the ubiquitin (Ub) chains, and not the Ub chains per se, regulates the contribution of RIPK1 to the apoptotic death trigger. In line with this, we found that cylindromatosis repression only provided protection to TNF-mediated RIPK1-dependent apoptosis in condition of reduced RIPK1 ubiquitylation obtained by cIAP1/2 depletion but not upon TAK1 kinase inhibition, again arguing for a role of TAK1 in preventing RIPK1-dependent apoptosis downstream of RIPK1 ubiquitylation. Importantly, we found that this function of TAK1 was independent of its known role in canonical nuclear factor-κB (NF-κB) activation. Our study therefore reports a new function of TAK1 in regulating an early NF-κB-independent cell death checkpoint in the TNFR1 apoptotic pathway. In both TNF-induced RIPK1 kinase-dependent apoptotic models, we found that RIPK3 contributes to full caspase-8 activation independently of its kinase activity or intact RHIM domain. In contrast, RIPK3 participates in caspase-8 activation by acting downstream of the cytosolic death complex assembly, possibly via reactive oxygen species generation.Cell Death and Differentiation advance online publication, 26 July 2013; doi:10.1038/cdd.2013.94. 22678081 Theoretical study of the pH-dependent antioxidant properties of vitamin C. Molecules acting as antioxidants capable of scavenging reactive oxygen species (ROS) are of utmost importance in the living cell. Vitamin C is known to be one of these molecules. In this study we have analyzed the reactivity of vitamin C toward the [Formula: see text] and [Formula: see text] ROS species, in all acidic, neutral and basic media. In order to do so, density functional theory (DFT) have been used. More concretely, the meta-GGA functional MPW1B95 have been used. Two reaction types have been studied in each case: addition to the ring atoms, and hydrogen/proton abstraction. Our results show that [Formula: see text] is the most reactive species, while [Formula: see text] displays low reactivity. In all three media, vitamin C reactions with two hydroxyl radicals show a wide variety of possible products. 23880365 Tetraspanin-3 regulates protective immunity against Eimeria tenella infection following immunization with dendritic cell-derived exosomes. The effects of immunization with dendritic cell (DC) exosomes, which had been incubated with a tetraspanin-3 (Tspan-3) blocking antibody (Ab) or with an isotype-matched non-immune IgG, were studied using an experimental model of Eimeria tenella avian coccidiosis. Purified exosomes from cecal tonsil and splenic DCs expressed Tspan-3 protein. Chickens injected with exosomes incubated with the control IgG and derived from cecal tonsil DCs preloaded in vitro with E. tenella Ag had Ag-immunostaining cells in the ceca, but not the spleen. Conversely, Ag-containing cells were found only in the spleen, but not the ceca, of chickens given IgG treated splenic DC exosomes. Interestingly, chickens that received exosomes incubated with Tspan-3 Ab had Ag-containing cells observed in both lymphoid organs following administration of exosomes from either DC population. After injection of exosomes non-incubated with Tspan-3 Ab, greater numbers of cells secreting interleukin-2 (IL-2), IL-16, interferon-γ, and E. tenella-reactive Abs were observed in the cecal tonsils of chickens immunized with cecal DC exosomes compared with the spleen. By contrast, more cytokine-and Ab-producing cells were present in the spleen of chickens given splenic DC exosomes compared with the ceca. Incubation with Tspan-3 Ab gave similar numbers of cytokine- and Ab-producing cells in the cecal tonsils and spleen regardless of the source of exosomes. Immunization with E. tenella Ag-loaded cecal tonsil DC exosomes increased in vivo resistance against subsequent E. tenella infection. Increased protection against infection following cecal DC exosome immunization was partially blocked by incubation of exosomes with Tspan-3 Ab. These results suggest that Tspan-3 is involved in the tissue distribution, as well as cytokine and Ab production, following DC exosome administration, and that Tspan-3 contributes to in vivo protection against experimental E. tenella challenge infection following exosomal immunization. 23360381 The complete mitochondrial genome of Liobagrus kingi (Teleostei, Siluriformes: Amblycipitidae). Liobagrus kingi is endemic to southwest China and listed as endangered species (IUCN 2012). Genetic diversity is necessary for conservation issue. In studying this, the complete mitochondrial genome sequence of L. kingi has been obtained with PCR, which contains 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes, and a non-coding control region with the total length of 16,483 bp. The gene arrangement and composition are similar to that of other vertebrates. Most of the genes are encoded on heavy strand, except for eight tRNA and ND6 genes. Just like most other vertebrates, the against bias of G has a universality in different statistical results. The complete mitochondrial genome sequence of L. kingi would contribute to better understand population genetics and protect its genetic diversity. 23888424 Gabapentin add-on for drug-resistant partial epilepsy. The majority of people with epilepsy have a good prognosis and their seizures are well controlled by a single antiepileptic drug, but up to 30% develop drug-resistant epilepsy, especially those with partial seizures. In this review we summarise the current evidence regarding the antiepileptic drug gabapentin, when used as an add-on treatment for drug-resistant partial epilepsy. To evaluate the efficacy and tolerability of gabapentin when used as an add-on treatment for people with drug-resistant partial epilepsy. This is an updated version of the original Cochrane review published in The Cochrane Library 2009, Issue 4. We searched the Cochrane Epilepsy Group's Specialised Register (14 May 2013), the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 4, The Cochrane Library) (April 2013) and MEDLINE (1946 to 14 May 2013). We imposed no language restrictions. Randomised, placebo-controlled, double-blind, add-on trials of gabapentin in people with drug-resistant partial epilepsy. Trials using an active drug control group or which compared doses of gabapentin were also included in the review. Two review authors independently selected trials for inclusion and extracted the relevant data. We assessed the following outcomes: (a) seizure frequency and seizure freedom; (b) treatment withdrawal (any reason); (c) adverse effects. Primary analyses were intention-to-treat. We also undertook sensitivity best and worst-case analyses. We estimated summary risk ratios for each outcome and evaluated dose-response in regression models. Eleven trials were included representing 2125 randomised participants. We combined data from six trials in meta-analyses of 1206 randomised participants. The overall risk ratio (RR) for 50% or greater reduction in seizure frequency compared to placebo was 1.89 (95% confidence interval (CI) 1.40 to 2.55). Dose regression analysis (for trials in adults) shows increasing efficacy with increasing dose, with 25.3% (19.3 to 32.3) of people responding to 1800 mg of gabapentin compared to 9.7% on placebo, a 15.5% increase in response rate (8.5 to 22.5). The RR for treatment withdrawal compared to placebo was 1.05 (95% CI 0.74 to 1.49). Adverse effects were significantly associated with gabapentin compared to placebo. Risk ratios were as follows: ataxia 2.01 (99% CI 0.98 to 4.11), dizziness 2.43 (99% CI 1.44 to 4.12), fatigue 1.95 (99% CI 0.99 to 3.82) and somnolence 1.93 (99% CI 1.22 to 3.06). No significant differences were found for the adverse effects of headache (RR 0.79, 99% CI 0.46 to 1.35) or nausea (RR 0.95, 99% CI 0.52 to 1.73). Overall the studies together are rated as low/unclear risk of bias due to information on each risk of bias domain not being available. Gabapentin has efficacy as an add-on treatment in people with drug-resistant partial epilepsy. However, the trials reviewed were of relatively short duration and provide no evidence for the long-term efficacy of gabapentin beyond a three-month period. The results cannot be extrapolated to monotherapy or to people with other epilepsy types. 23750935 Tangeretin sensitizes SGS1-deficient cells by inducing DNA damage. Tangeretin, a polymethoxyflavone found in citrus peel, has been shown to have antiatherogenic, anti-inflammatory, and anticarcinogenic properties. However, the underlying target pathways are not fully characterized. We investigated the tangeretin sensitivity of yeast (Saccharomyces cerevisiae) mutants for DNA damage response or repair pathways. We found that tangeretin treatment significantly reduced (p < 0.05) survival rate, induced preferential G1 phase accumulation, and elevated the DNA double-strand break (DSB) signal γH2A in DNA repair-defective sgs1Δ cells, but had no obvious effects on wild-type cells or mutants of the DNA damage checkpoint (including tel1Δ, sml1Δ mec1Δ, sml1Δ mec1Δ tel1Δ, and rad9Δ mutants). Additionally, microarray data indicated that tangeretin treatment up-regulates genes involved in nutritional processing and down-regulates genes related to RNA processing in sgs1Δ mutants. These results suggest tangeretin may sensitize SGS1-deficient cells by increasing a marker of DNA damage and by inducing G1 arrest and possibly metabolic stress. Thus, tangeretin may be suitable for chemosensitization of cancer cells lacking DSB-repair ability. 23883915 Transfusion strategies and development of acute respiratory distress syndrome in combat casualty care. Damage-control resuscitation (DCR) has been advocated to reduce mortality in military and civilian settings. However, DCR and excessive crystalloid resuscitation may be associated with a higher incidence of acute respiratory distress syndrome (ARDS). We sought to examine the impact of resuscitation strategies on ARDS development in combat casualty care. A retrospective review of Joint Theater Trauma Registry data on US combat casualties who received at least 1 U of blood product within the first 24 hours of care was performed, cross-referenced with the cohort receiving mechanical ventilation (n = 1,475). Massive transfusion (MT, ≥10 red blood cells [RBCs] and/or whole blood in 24 hours) and volume/ratios of plasma/RBC, platelet/RBC, and crystalloid/RBC (C/RBC, crystalloid liters/RBC units) were examined using bivariate/multivariate logistic regression and local regression analyses as ARDS risk factors, controlling for age, injury severity, admission systolic blood pressure, and Glasgow Coma Scale (GCS) score. ARDS was identified in 95 cases (6.4%). MT was required in 550 (37.3%) of the analysis cohort. ARDS was more common in MT (46 of 550, 8.4%) versus no-MT cohort (49 of 925, 5.3%), but mortality was not different (17.4% MT vs. 16.3% no-MT). ARDS patients received significantly increased crystalloid of blood product volumes. Increased crystalloid resuscitation (C/RBC ratio > 1.5) occurred in 479 (32.7%) of 1,464 patients. Unadjusted mortality was significantly increased in the cohort with C/RBC ratio of 1.5 or less compared with those with greater than 1.5 (19.1% vs. 6.3%, p < 0.0001), but no difference in ARDS (6.5% vs. 6.6%) was identified. Platelet/RBC ratio did not impact on ARDS. Increasing plasma (odds ratio, 1.07; p = 0.0062) and crystalloid (odds ratio, 1.04; p = 0.041) volumes were confirmed as independent ARDS risk factors. In modern combat casualty care, increased plasma and crystalloid infusion were identified as independent risk factors for ARDS. These findings support a practice of decreased plasma/crystalloid transfusion in trauma resuscitation once hemorrhage control is established to achieve the mortality benefit of DCR and ARDS prevention. Epidemiologic and prognostic study, level IV. 23852649 Comparison of Oxidative Aromatic Coupling and the Scholl Reaction. Does the dehydrogenative coupling of aromatic compounds mediated by AlCl3 at high temperatures and also by FeCl3 , MoCl5 , PIFA, or K3 [Fe(CN)6 ] at room temperature proceed by the same mechanism in all cases? With the growing importance of the synthesis of aromatic compounds by double CH activation to give various biaryl structures, this question becomes pressing. Since some of these reactions proceed only in the presence of non-oxidizing Lewis acids and some only in the presence of certain oxidants, the authors venture the hypothesis that, depending on the electronic structure of the substrates and the nature of the "catalyst", two different mechanisms can operate. One involves the intermediacy of a radical cation and the other the formation of a sigma complex between the acid and the substrate. The goal of this Review is to encourage further mechanistic studies hopefully leading to an in-depth understanding of this phenomenon. 23631663 Associations between sports participation, levels of moderate to vigorous physical activity and cardiorespiratory fitness in childrenand adolescents. Abstract The purpose of this study was to analyse the associations between sports participation, levels of moderate to vigorous physical activity (MVPA) and cardiorespiratory fitness (CRF). The study comprised 310 participants (183 girls and 127 boys) aged 11-18 years. Sports participation was assessed by questionnaire and habitual physical activity (PA) was measured objectively with accelerometers. The 20-m shuttle-run test was used to estimate CRF. Logistic regression analyses were carried out with CRF as the outcome. The odds ratio (OR) for being fit was greater for those who comply with 60 min · day(-1) in MVPA (OR = 2.612; 95%confidence interval [CI] = 1.614-4.225) in comparison with those who do not. Participation in competitive sports at club levels increased the chances of being fit (OR = 13.483; 95%CI = 4.560-39.864), independently of MVPA levels. There were positive and significant trends in CRF and objectively measured PA across the levels of engagement in competitive sports (P < 0.05). Concluding, participation in competitive sports at club level is more effective than other organised or non-organised sports to reach healthier levels of CRF and recommend levels of MVPA. 23930783 Maternal birthweight is associated with subsequent risk of vitamin d deficiency in early pregnancy. Maternal low birthweight and vitamin D deficiency in pregnancy are associated with a similar spectrum of adverse pregnancy outcomes including pre-eclampsia and gestational diabetes. However, the relationship between maternal birthweight and subsequent vitamin D concentrations in early pregnancy is largely unknown. We assessed whether self-reported maternal birthweight was associated with risk of early pregnancy vitamin D deficiency (≤20 ng/mL) among a pregnancy cohort (n = 658). Serum 25-hydroxyvitamin D [25(OH)D] was measured using liquid chromatography-tandem mass spectroscopy. Adjusting for maternal characteristics and month of blood draw, a 100-g higher maternal birthweight was associated with a 5.7% decreased risk of early pregnancy 25(OH)D deficiency [odds ratio (OR) = 0.94; 95% confidence interval (CI) 0.90, 0.99]. Low-birthweight (<2500 g) women were 3.7 times as likely to have early pregnancy 25(OH)D deficiency compared with normal-birthweight women [OR = 3.69; 95% CI 1.63, 8.34]. These relationships were not modified by either pre-pregnancy overweight status [body mass index (BMI) ≥25 kg/m(2) ] or adulthood weight trajectory (BMI change ≥2 kg/m(2) from age 18 to pre-pregnancy). Further research on shared developmental mechanisms that determine birthweight and vitamin D homeostasis may help identify targets and related preventative measures for adverse pregnancy and birth outcomes. 23780226 Determination of chlorobenzenes in water samples based on fully automated microextraction by packed sorbent coupled with programmed temperature vaporization-gas chromatography-mass spectrometry. A fully automated method consisting of microextraction by packed sorbent (MEPS) coupled directly to programmed temperature vaporizer-gas chromatography-mass spectrometry (PTV-GC-MS) has been developed to determine the 12 chlorobenzene congeners (chlorobenzene; 1,2-, 1,3-, and 1,4-dichlorobenzene; 1,2,3-, 1,2,4-, and 1,3,5-trichlorobenzene; 1,2,3,4-, 1,2,3,5-, and 1,2,4,5-tetrachlorobenzene; pentachlorobenzene; and hexachlorobenzene) in water samples. The effects of the variables on MEPS extraction, using a C18 sorbent, and the instrumental PTV conditions were studied. The internal standard 1,4-dichlorobenzene d4 was used as a surrogate. The proposed method afforded good reproducibility, with relative standard deviations (RSD %) lower than 12 %. The limits of detection varied between 0.0003 Î¼g L(-1) for 1,2,3,4-tetrachlorobenzene and 0.07 Î¼g L(-1) for 1,3- and 1,4-dichlorobenzene, while those of quantification varied between 0.001 Î¼g L(-1) and 0.2 Î¼g L(-1) for the same compounds. Accuracy of the proposed method was confirmed by applying it to the determination of chlorobenzenes in different spiked water samples, including river, reservoir, and effluent wastewater. 23902563 Copolymer-mediated synthesis of hydroxyapatite nanoparticles in an organic solvent. The objective of this research is to develop a nanoparticle synthesis scheme that controls nanoparticle shape and surface chemistry concomitantly. Specifically, a method to synthesize hydroxyapatite nanoparticles using a dispersed block copolymer template is explored, which produces spherical and needle-shaped nanoparticles, and at the end of the synthesis, the block copolymer is retained as a surface coating on the nanoparticles. This strategy has been used previously with double-hydrophilic block copolymers (DHBCs) as the dispersed template; however, in this work, an alternative block copolymer chemistry is explored in an effort to extend this method to synthesis in organic solvents, producing nanoparticles that are organophilic instead of hydrophilic. The hydroxyapatite nanoparticles were synthesized using poly(methyl methacrylate)-b-poly(methacrylic acid) (PMMA-b-PMAA) as the dispersed template and tetrahydrofuran as the solvent. The synthesis proceeds following the ionization of the PMAA block of the copolymer and association between this ionized group and the calcium precursor ions. To investigate the degree of shape control available, the concentration of block copolymer solution and the amount of precursor were systematically varied, and the synthesized HAp nanoparticles were characterized. SEM images showed that needle and spherical HAp nanoparticles could be synthesized by changing the block copolymer concentration. TGA, FT-IR, and XRD results indicated that the block copolymer used for synthesis remained on the HAp particle surface. Overall, these results indicate that the shape of the nanoparticles produced by this method was related to the Ca(2+)/COO(-) mole ratio used during synthesis, similar to results obtained with DHBC template synthesis. The qualitative agreement between the shape control mechanisms in the two synthesis schemes suggests that this relationship could be general to the overall synthesis scheme and provide a mechanism for controlling nanoparticle shape with many block copolymer chemistries. 23867017 The ER luminal binding protein (BiP) alleviates Cd(2+)-induced programmed cell death through endoplasmic reticulum stress-cell death signaling pathway in tobacco cells. Cadmium (Cd) is very toxic to plant cells and Cd(2+) stress induces programmed cell death (PCD) in Nicotiana tabacum L. cv. bright yellow-2 (BY-2) cells. In plants, PCD can be regulated through the endoplasmic reticulum (ER) stress-cell death signaling pathway. However, the mechanism of Cd(2+)-induced PCD remains unclear. In this study, we found that Cd(2+) treatment induced ER stress in tobacco BY-2 cells. The expression of two ER stress markers NtBLP4 and NtPDI and an unfolded protein response related transcription factor NtbZIP60 were upregulated with Cd(2+) stress. Meanwhile, the PCD triggered by prolonged Cd(2+) stress could be relieved by two ER chemical chaperones, 4-phenylbutyric acid and tauroursodeoxycholic acid. These results demonstrate that the ER stress-cell death signaling pathway participates in the mediation of Cd(2+)-induced PCD. Furthermore, the ER chaperone AtBiP2 protein alleviated Cd(2+)-induced ER stress and PCD in BY-2 cells based on the fact that heterologous expression of AtBiP2 in tobacco BY-2 cells reduced the expression of NtBLP4 and a PCD-related gene NtHsr203J under Cd(2+) stress conditions. In summary, these results suggest that the ER stress-cell death signaling pathway regulates Cd(2+)-induced PCD in tobacco BY-2 cells, and that the AtBiP2 protein act as a negative regulator in this process. 23301766 Improved self-healing of polyethylene/carbon black nanocomposites by their shape memory effect. In this work, the improved self-healing of cross-linked polyethylene (PE) (cPE)/carbon black (CB) nanocomposites by their shape memory effect (SME) is investigated. CB nanoparticles are found to be homogeneously dispersed in the PE matrix and significantly increase the strength of the materials. Compared with the breaking of linear PE (lPE) at the melting temperature (T(m)), the cPE and cPE/CB nanocomposites still have high strength above T(m) due to the formation of networks. The cPE and cPE/CB nanocomposites show both high strain fixity ratio (R(f)) and high strain recovery ratio (R(r)). Crystallization-induced elongation is observed for all the prepared shape memory polymer (SMP) materials and the effect becomes less remarkable with increasing volume fraction of CB nanoparticles (v(CB)). The scratch self-healing tests show that the cross-linking of PE matrix, the addition of CB nanoparticles, and the previous stretching in the direction perpendicular to the scratch favor the closure of the scratch and its complete healing. This SME-aided self-healing could have potential applications in diverse fields such as coating and structure materials. 23898396 Using a web-based game to prevent posttraumatic stress in children following medical events: design of a randomized controlled trial. Medical events including acute illness and injury are among the most common potentially traumatic experiences for children. Despite the scope of the problem, only limited resources are available for prevention of posttraumatic stress symptoms (PTSS) after pediatric medical events. Web-based programs provide a low-cost, accessible means to reach a wide range of families and show promise in related areas of child mental health. To describe the design of a randomized controlled trial that will evaluate feasibility and estimate preliminary efficacy of Coping Coach, a web-based preventive intervention to prevent or reduce PTSS after acute pediatric medical events. Seventy children and their parents will be randomly assigned to either an intervention or a waitlist control condition. Inclusion criteria require that children are aged 8-12 years, have experienced a medical event, have access to Internet and telephone, and have sufficient competency in the English language to complete measures and understand the intervention. Participants will complete baseline measures and will then be randomized to the intervention or waitlist control condition. Children in the intervention condition will complete module 1 (Feelings Identification) in the hospital and will be instructed on how to complete modules 2 (Appraisals) and 3 (Avoidance) online. Follow-up assessments will be conducted via telephone at 6, 12, and 18 weeks after the baseline assessment. Following the 12-week assessment, children in the waitlist control condition will receive instructions for completing the intervention. Primary study outcomes include data on intervention feasibility and outcomes (child appraisals, coping, PTSS and health-related quality of life). Results will provide data on the feasibility of the implementation of the Coping Coach intervention and study procedures as well as estimations of efficacy to determine sample size for a larger study. Potential strengths and limitations of this design are discussed. 23401283 Nonribosomal assembly of natural lipocyclocarbamate lipoprotein-associated phospholipase inhibitors. EXPANDING OUR KNOWLEDGE: Natural lipocyclocarbamate natural products have provided the inspiration for the first-in-class synthetic phospholipase inhibitor darapladib, currently in phase III clinical trials for the treatment of atherosclerosis. Here, we discuss their biosynthesis by a nonribosomal peptide synthetase. 23257267 Genipin stimulates glucose transport in C2C12 myotubes via an IRS-1 and calcium-dependent mechanism. Genipin, a compound derived from Gardenia jasminoides Ellis fruits, has been used over the years in traditional Chinese medicine to treat symptoms of type 2 diabetes. However, the molecular basis for its antidiabetic effect has not been fully revealed. In this study, we investigated the effects of genipin on glucose uptake and signaling pathways in C(2)C(12) myotubes. Our study demonstrates that genipin stimulated glucose uptake in a time- and dose-dependent manner. The maximal effect was achieved at 2 h with a concentration of 10 μM. In myotubes, genipin promoted glucose transporter 4 (GLUT4) translocation to the cell surface, which was observed by analyzing their distribution in subcellular membrane fraction, and increased the phosphorylation of insulin receptor substrate-1 (IRS-1), AKT, and GSK3β. Meanwhile, genipin increased ATP levels, closed K(ATP) channels, and then increased the concentration of calcium in the cytoplasm in C(2)C(12) myotubes. Genipin-stimulated glucose uptake could be blocked by both the PI3-K inhibitor wortmannin and calcium chelator EGTA. Moreover, genipin increases the level of reactive oxygen species and ATP in C(2)C(12) myotubes. These results suggest that genipin activates IRS-1, PI3-K, and downstream signaling pathway and increases concentrations of calcium, resulting in GLUT4 translocation and glucose uptake increase in C(2)C(12) myotubes. 23665536 Structural and biochemical characterization of the broad substrate specificity of Bacteroides thetaiotaomicron commensal sialidase. Sialidases release the terminal sialic acid residue from a wide range of sialic acid-containing polysaccharides. Bacteroides thetaiotaomicron, a symbiotic commensal microbe, resides in and dominates the human intestinal tract. We characterized the recombinant sialidase from B. thetaiotaomicron (BTSA) and demonstrated that it has broad substrate specificity with a relative activity of 97, 100 and 64 for 2,3-, 2,6- and 2,8-linked sialic substrates, respectively. The hydrolysis activity of BTSA was inhibited by a transition state analogue, 2-deoxy-2,3-dehydro-N-acetyl neuraminic acid, by competitive inhibition with a Ki value of 35μM. The structure of BSTA was determined at a resolution of 2.3Å. This structure exhibited a unique carbohydrate-binding domain (CBM) at its N-terminus (a.a. 23-190) that is adjacent to the catalytic domain (a.a. 191-535). The catalytic domain has a conserved arginine triad with a wide-open entrance for the substrate that exposes the catalytic residue to the surface. Unlike other pathogenic sialidases, the polysaccharide-binding site in the CBM is near the active site and possibly holds and positions the polysaccharide substrate directly at the active site. The structural feature of a wide substrate-binding groove and closer proximity of the polysaccharide-binding site to the active site could be a unique signature of the commensal sialidase BTSA and provide a molecular basis for its pharmaceutical application. 23827095 Bone regeneration in rat calvarial defects implanted with fibrous scaffolds composed of a mixture of silicate and borate bioactive glasses. Previous studies have evaluated the capacity of porous scaffolds composed of a single bioactive glass to regenerate bone. In the present study, scaffolds composed of a mixture of two different bioactive glasses (silicate 13-93 and borate 13-93B3) were created and evaluated for their response to osteogenic MLO-A5 cells in vitro and their capacity to regenerate bone in rat calvarial defects in vivo. The scaffolds, which have similar microstructures (porosity=58-67%) and contain 0, 25, 50 and 100wt.% 13-93B3 glass, were fabricated by thermally bonding randomly oriented short fibers. The silicate 13-93 scaffolds showed a better capacity to support cell proliferation and alkaline phosphatase activity than the scaffolds containing borate 13-93B3 fibers. The amount of new bone formed in the defects implanted with the 13-93 scaffolds at 12weeks was 31%, compared to values of 25, 17 and 20%, respectively, for the scaffolds containing 25, 50 and 100% 13-93B3 glass. The amount of new bone formed in the 13-93 scaffolds was significantly higher than in the scaffolds containing 50 and 100% 13-93B3 glass. While the 13-93 fibers were only partially converted to hydroxyapatite at 12weeks, the 13-93B3 fibers were fully converted and formed a tubular morphology. Scaffolds composed of an optimized mixture of silicate and borate bioactive glasses could provide the requisite architecture to guide bone regeneration combined with a controllable degradation rate that could be beneficial for bone and tissue healing. 23837939 Evaluation of cyclophosphamide pulse therapy as an adjuvant to oral corticosteroid in the management of pemphigus vulgaris. Corticosteroids are the mainstay of treatment for pemphigus. However, despite the introduction of adjuvant therapy for PV, the mortality rate has remained static over the past 2 decades, and consequently, a new adjuvant therapy that is both safe and effective is needed. Intravenous pulse cyclophosphamide has shown encouraging results in few studies, with a better safety profile than the oral formulation, and with better treatment compliance. We undertook a randomized, prospective, non-blinded trial to assess the efficacy of cyclophosphamide pulse therapy (CPT) as an adjuvant to oral corticosteroid in pemphigus vulgaris (PV). We enrolled 60 patients with mild to moderate active disease to receive either daily oral prednisolone or intravenous CPT prednisolone for 1 year, and they were then followed up for another year. At the end of the study period, the time taken to initiate response was similar in both groups, but in the group who received pulse cyclophosphamide, there was a reduced time to remission, a greater proportion of cases who achieved remission, a lower number of patients who relapsed while on treatment or after stopping treatment, and a lower cumulative dose of corticosteroid. Hence, the overall trend was in favour of CPT, although this was not significant. CPT also had a good safety profile. Based on the results of this trial, CPT may be a useful adjuvant in PV in terms of reducing time to remission, relapse rates and cumulative dose of steroid, and it has a good safety profile. 23684932 Numerical modelling and experimental investigation of drug release from layered silicone matrix systems. Medical devices and polymeric matrix systems that release drugs or other bioactive compounds are of interest for a variety of applications. The release of the drug can be dependent on a number of factors such as the solubility, diffusivity, dissolution rate and distribution of the solid drug in the matrix. Achieving the goal of an optimal release profile can be challenging when relying solely on traditional experimental work. Accurate modelling complementing experimentation is therefore desirable. Numerical modelling is increasingly becoming an integral part of research and development due to the significant advances in computer simulation technology. This work focuses on numerical modelling and investigation of multi-layered silicone matrix systems. A numerical model that can be used to model multi-layered systems was constructed and validated by comparison with experimental data. The model could account for the limited dissolution rate and effect of the drug distribution on the release profiles. Parametric study showed how different factors affect the characteristics of drug release. Multi-layered medical silicone matrices were prepared in special moulds, where the quantity of drug in each layer could be varied, and release was investigated with Franz-diffusion cell setup. Data for long-term release was fitted to the model and the full depletion of the system predicted. The numerical model constructed for this study, whose input parameters are the diffusion, effective dissolution rate and dimensional solubility coefficients, does not require any type of steady-state approximation. These results indicate that numerical model can be used as a design tool for development of controlled release systems such as drug-loaded medical devices. 23436198 An ultra scale-down characterization of low shear stress primary recovery stages to enhance selectivity of fusion protein recovery from its molecular variants. Fusion proteins offer the prospect of new therapeutic products with multiple functions. The primary recovery is investigated of a fusion protein consisting of modified E2 protein from hepatitis C virus fused to human IgG1 Fc and expressed in a Chinese hamster ovary (CHO) cell line. Fusion protein products inevitably pose increased challenge in preparation and purification. Of particular concerns are: (i) the impact of shear stress on product integrity and (ii) the presence of product-related contaminants which could prove challenging to remove during the high resolution purification steps. This paper addresses the use of microwell-based ultra scale-down (USD) methods to develop a bioprocess strategy focused on the integration of cell culture and cell removal operations and where the focus is on the use of operations which impart low shear stress levels even when applied at eventual manufacturing scale. An USD shear device was used to demonstrate that cells exposed to high process stresses such as those that occur in the feed zone of a continuous non-hermetic centrifuge resulted in the reduction of the fusion protein and also the release of glycosylated intracellular variants. In addition, extended cell culture resulted in release of such variants. USD mimics of low shear stress, hydrohermetic feed zone centrifugation and of depth filtration were used to demonstrate little to no release during recovery of these variants with both results verified at pilot scale. Furthermore, the USD studies were used to predict removal of contaminants such as lipids, nucleic acids, and cell debris with, for example, depth filtration delivering greater removal than for centrifugation but a small (~10%) decrease in yield of the fusion protein. These USD observations of product recovery and carryover of contaminants were also confirmed at pilot scale as was also the capacity or throughput achievable for continuous centrifugation or for depth filtration. The advantages are discussed of operating a lower yield cell culture and a low shear stress recovery process in return for a considerably less challenging purification demand. 23927228 The development of a modified spectral ripple test. Poor spectral resolution can be a limiting factor for hearing impaired listeners, particularly for complex listening tasks such as speech understanding in noise. Spectral ripple tests are commonly used to measure spectral resolution, but these tests contain a number of potential confounds that can make interpretation of the results difficult. To measure spectral resolution while avoiding those confounds, a modified spectral ripple test with dynamically changing ripples was created, referred to as the spectral-temporally modulated ripple test (SMRT). This paper describes the SMRT and provides evidence that it is sensitive to changes in spectral resolution. 23818059 ChenPhos: Highly Modular P-Stereogenic C1 -Symmetric Diphosphine Ligands for the Efficient Asymmetric Hydrogenation of α-Substituted Cinnamic Acids. These cats are purrfectionists: The ChenPhos ligands showed dramatically higher catalytic activity in the title reaction than their C2 -symmetric predecessor with two dimethylaminoethyl-substituted ferrocenyl(phenyl)phosphanyl groups. The ready accessibility, extreme air stability, and high enantioselectivity, activity, and productivity of these ligands make them very promising for a wide range of practical applications. 23954792 Adenosine prevents isoprenaline-induced cardiac contractile and electrophysiological dysfunction. Excessive levels of catecholamines are believed to contribute to cardiac dysfunction in a variety of disease states, including myocardial infarction and heart failure, and are particularly implicated in stress-induced cardiomyopathy, an increasingly recognized cardiomyopathy associated with significant morbidity and mortality. We have previously shown that a high dose of isoprenaline induces reversible regional dysfunction of the left ventricle in mice. We now hypothesize that adenosine can prevent cardiac dysfunction in this mouse model of stress-induced cardiomyopathy. Hundred male C57BL/6 mice were injected with 400mg/kg isoprenaline and then randomized to either 400mg/kg adenosine or saline. Cardiac function was evaluated by echocardiography at baseline and 2, 24, 48, 72, 96 and 120min post isoprenaline. Myocardial fibrosis was quantified after 10 days. Intracellular lipid accumulation was quantified after 2 and 24h. Electrophysiological parameters and degree of lipid accumulation were evaluated in cultured HL1 cardiomyocytes. Two hours post isoprenaline treatment, echocardiographic parameters of global and posterior wall regional function were significantly better in adenosine-treated mice (P<0.05). This difference persisted at 24h, but saline-treated mice gradually recovered over the next 96h. Intracellular lipid accumulation was also significantly lower in adenosine mice. We found no sign of fibrosis in the adenosine mice, whereas the extent of fibrosis in isoprenaline mice was 1.3% (P<0.05). Furthermore, adenosine-treated HL1 cells showed preserved electrophysiological function and displayed less severe intracellular lipid accumulation in response to isoprenaline. In conclusion, adenosine attenuates isoprenaline-induced cardiac dysfunction in mice and cells. 23400845 Environmental fate of three novel brominated flame retardants in aquatic mesocosms. Currently, little is known about the environmental fate and persistence of novel brominated flame retardants (NBFRs). The recent detection of NBFRs in sediment cores and air samples provides insight into their persistence and potential for transport. Limited numbers of laboratory studies have examined the fate and behavior of these compounds, but field-based fate studies have been especially lacking. The authors conducted an aquatic mesocosm experiment to assess the behavior of three NBFRs: bis(tribromophenoxy)ethane (BTBPE), tetrabromobisphenol A bis(2,3-dibromopropyl ether; TBBPA-DBPE), and Firemaster BZ-54, a commercial mixture containing bis(2-ethylhexyl)tetrabromophthalate (BEHTBP) and 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EHTeBB) in a ratio of 1:4. Analysis by gas chromatography-mass spectrometry, operated in the electron capture negative ionization mode, revealed partitioning between the particulate and sediment phases, with BTBPE, TBBPA-DBPE, and BEHTBP identified as being environmentally persistent in both the particulate and the sediment compartments. The median dissipation times (DT50) differed in each compartment, with more rapid disappearance in the particulate (9-30 d) compared with the sediment compartment (>100 d) for each compound. The degradation products were more concentrated in the particulate compartment and corresponded to known photodegradation products. The ratio of EHTeBB to BEHTBP differed in the mesocosm compartments compared with the technical product used for treatment, indicating increased degradation of EHTeBB relative to BETHBP. Environ. Toxicol. Chem. 2013;32:1060-1068. © 2013 SETAC. 23537499 Real-time evaluation of milk quality as reflected by clotting parameters of individual cow's milk during the milking session, between day-to-day and during lactation. Real-time analysis of milk coagulation properties as performed by the AfiLab™ milk spectrometer introduces new opportunities for the dairy industry. The study evaluated the performance of the AfiLab™ in a milking parlor of a commercial farm to provide real-time analysis of milk-clotting parameters -Afi-CF for cheese manufacture and determine its repeatability in time for individual cows. The AfiLab™ in a parlor, equipped with two parallel milk lines, enables to divert the milk on-line into two bulk milk tanks (A and B). Three commercial dairy herds of 220 to 320 Israeli Holstein cows producing ∼11 500 l during 305 days were selected for the study. The Afi-CF repeatability during time was found significant (P < 0.001) for cows. The statistic model succeeded in explaining 83.5% of the variance between Afi-CF and cows, and no significant variance was found between the mean weekly repeated recordings. Days in milk and log somatic cell count (SCC) had no significant effect. Fat, protein and lactose significantly affected Afi-CF and the empirical van Slyke equation. Real-time simulations were performed for different cutoff levels of coagulation properties where the milk of high Afi-CF cutoff value was channeled to tank A and the lower into tank B. The simulations showed that milk coagulation properties of an individual cow are not uniform, as most cows contributed milk to both tanks. Proportions of the individual cow's milk in each tank depended on the selected Afi-CF cutoff. The assessment of the major causative factors of a cow producing low-quality milk for cheese production was evaluated for the group that produced the low 10% quality milk. The largest number of cows in those groups at the three farms was found to be cows with post-intramammary infection with Escherichia coli and subclinical infections with streptococci or coagulase-negative staphylococci (∼30%), although the SCC of these cows was not significantly different. Early time in lactation together with high milk yield >50 l/day, and late in lactation together with low milk yield<15 l/day and estrous (0 to 5 days) were also important influencing factors for low-quality milk. However, ∼50% of the tested variables did not explain any of the factors responsible for the cow producing milk in the low - 10% Afi-CF. 23928462 Attenuation and immunogenicity of host-range extended modified vaccinia virus Ankara recombinants. Modified vaccinia virus Ankara (MVA) is being widely investigated as a safe smallpox vaccine and as an expression vector to produce vaccines against other infectious diseases and cancer. MVA was isolated following more than 500 passages in chick embryo fibroblasts and suffered several major deletions and numerous small mutations resulting in replication defects in human and most other mammalian cells as well as severe attenuation of pathogenicity. Due to the host range restriction, primary chick embryo fibroblasts are routinely used for production of MVA-based vaccines. While a replication defect undoubtedly contributes to safety of MVA, it is worth considering whether host range and attenuation are partially separable properties. Marker rescue transfection experiments resulted in the creation of recombinant MVAs with extended mammalian cell host range. Here, we characterize two host-range extended rMVAs and show that they (i) have acquired the ability to stably replicate in Vero cells, which are frequently used as a cell substrate for vaccine manufacture, (ii) are severely attenuated in immunocompetent and immunodeficient mouse strains following intranasal infection, (iii) are more pathogenic than MVA but less pathogenic than the ACAM2000 vaccine strain at high intracranial doses, (iv) do not form lesions upon tail scratch in mice in contrast to ACAM2000 and (v) induce protective humoral and cell-mediated immune responses similar to MVA. The extended host range of rMVAs may be useful for vaccine production. 23957746 Fate of a Giant {Mo72Fe30}-Type Polyoxometalate Cluster in an Aqueous Solution at Higher Temperature: Understanding Related Keplerate Chemistry, from Molecule to Material. When the giant icosahedral {Mo72Fe30} cluster containing compound [Mo72Fe30O252(CH3COO)12{Mo2O7(H2O)}2{H2Mo2O8(H2O)}(H2O)91]·150H2O (1) is refluxed in water for 36 h, it results in the formation of nanoiron molybdate, Fe2(MoO4)3, in the form of a yellow precipitate; this simple approach not only generates nanoferric molybdate at a moderate temperature but also helps to understand the stability of {Mo72Fe30} in terms of the linker-pentagon complementary relationship. 23852643 The molecular basis for ethnic variation and histological subtype differences in prostate cancer. Prostate cancer is a common malignancy among men in Western countries. Recently the morbidity and mortality of prostate cancer increase dramatically in several oriental countries including China. Rapidly evolving technology in molecular biology such as high-throughput sequencing and integrative analysis of genomic and transcriptomic landscapes have enabled the identification of key oncogenic events for prostate cancer initiation, progression and resistance to hormonal therapy. These surging data of prostate cancer genome also provide insights on ethnic variation and the differences in histological subtype of this disease. In this review, differences in the incidence of prostate cancer and the prevalence of main genetic alterations between Asian and Western populations are discussed. We also review the recent findings on the mechanisms underlying neuroendocrine differentiation of prostate cancer and the development of small cell neuroendocrine carcinoma after androgen deprivation therapy. 23967264 Metabolic Flux Analysis during the Exponential Growth Phase of Saccharomyces cerevisiae in Wine Fermentations. As a consequence of the increase in global average temperature, grapes with the adequate phenolic and aromatic maturity tend to be overripe by the time of harvest, resulting in increased sugar concentrations and imbalanced C/N ratios in fermenting musts. This fact sets obvious additional hurdles in the challenge of obtaining wines with reduced alcohols levels, a new trend in consumer demands. It would therefore be interesting to understand Saccharomyces cerevisiae physiology during the fermentation of must with these altered characteristics. The present study aims to determine the distribution of metabolic fluxes during the yeast exponential growth phase, when both carbon and nitrogen sources are in excess, using continuous cultures. Two different sugar concentrations were studied under two different winemaking temperature conditions. Although consumption and production rates for key metabolites were severely affected by the different experimental conditions studied, the general distribution of fluxes in central carbon metabolism was basically conserved in all cases. It was also observed that temperature and sugar concentration exerted a higher effect on the pentose phosphate pathway and glycerol formation than on glycolysis and ethanol production. Additionally, nitrogen uptake, both quantitatively and qualitatively, was strongly influenced by environmental conditions. This work provides the most complete stoichiometric model used for Metabolic Flux Analysis of S. cerevisiae in wine fermentations employed so far, including the synthesis and release of relevant aroma compounds and could be used in the design of optimal nitrogen supplementation of wine fermentations. 23793514 Platelet-rich plasma for the treatment of patellar tendinopathy: clinical and imaging findings at medium-term follow-up. The purpose of this study was to evaluate the efficacy of multiple platelet-rich plasma (PRP) injections on the healing of chronic refractory patellar tendinopathy, and report the quality and duration of the clinical improvement up to a medium-term follow-up. Forty-three patients (mean age, 30.6 years; mean BMI, 24.7; 42 men, one woman) affected by chronic patellar proximal tendinopathy were enrolled in this trial. Eleven patients were affected by bilateral tendinopathy. They underwent three ultrasound guided intra-tendinous injections of five millilitres PRP, two weeks apart from each other. Patients were prospectively evaluated initially, then after two, six, and up to mean 48.6 ±â€‰8.1 months of follow-up (minimum evaluation at 36 months). The following evaluation tools were used: Blanzina, VISA-P, EQ-VAS for general health, and Tegner scores. Patients' overall satisfaction and time to return to sport were also reported. Good and stable results were documented over time, with the VISA-P score increasing from 44.1 ±â€‰15.6 at baseline to 61.4 ±â€‰22.2 at two months, 76.6 ±â€‰25.4 at six months, and 84.3 ±â€‰21.6 at four years' follow-up. The same trend was confirmed by the other scores used, and 80 % of the patients were satisfied and returned to previous sports activities. Significantly poorer results were obtained in patients with a longer history of symptoms, and poor results were also observed in bilateral lesions. No correlation between ultrasonographic and clinical findings could be found. Multiple injections of PRP provided a good clinical outcome for the treatment of chronic recalcitrant patellar tendinopathy with stable results up to medium-term follow-up. Patients affected by bilateral pathology and presenting a long history of pain obtained significantly poorer results. 23684701 Preventing congenital neonatal heart block in offspring of mothers with anti-SSA/Ro and SSB/La antibodies: A review of published literature and registered clinical trials. Offspring of women with anti-SSA/Ro-SSB/La antibodies are believed to be at risk for congenital heart block (CHB). Whether this risk can be reduced, and what constitutes standard of care treatment is, however, unclear. The objective of this review therefore was to determine whether currently proposed standard of care treatments to avoid CHB in offspring of mothers at risk are evidence-based. To do so, we conducted a review of the literature under appropriate keywords and phrases in Medline/PubMed and Google Scholar for the years 2000-2013. Reference lists were further reviewed, and relevant manuscripts were pulled. We also reviewed www.clinicaltrials.gov for registered studies. In the absence of randomized prospective clinical trials, a meta-analysis was not feasible. We, therefore, reviewed lower evidence level studies individually. Risk of CHB actually appears more closely associated with general autoimmunity than, specifically, with SSA/Ro-SSB/La antibodies. This and other observations raise questions whether CHB is caused by passively transferred maternal autoimmunity, as is currently widely believed. Observational studies suggest the possible effectiveness of intravenous gamma globulin (IV-Ig) and hydroxychloroquine (Plaquenil) in reducing CHB-risk. Evidence for both is, however, inconclusive, and studies are biased in favor of hydroxychloroquine and against IV-Ig. Based on the review of the literature, current evidence of effectiveness for any treatment has to be judged as insufficient. Among the available treatment options, some considerations favor IV-Ig over hydroxychloroquine or, alternatively, suggest treatment with IV-Ig periconceptionally and into early gestation, with hydroxychloroquine added or replacing IV-Ig at approximately 10weeks gestational age. Benefits for the utilization of steroid drugs are unclear. Since no treatment can be considered as established, prevention of CHB in offspring should be considered experimental, and performed under appropriate study conditions. 23744688 Analysis of Morphologic and Hemodynamic Parameters for Unruptured Posterior Communicating Artery Aneurysms with Oculomotor Nerve Palsy. BACKGROUND AND PURPOSE:Posterior communicating artery aneurysms with oculomotor nerve palsy may imply sudden enlargement of the aneurysm sac and have a high risk of rupture. Our aim was to identify the morphologic and hemodynamic parameters in this special period of aneurysm progression and to assess related rupture risk indices.MATERIALS AND METHODS:We analyzed the morphologic and hemodynamic parameters of 9 unruptured posterior communicating artery aneurysms with oculomotor nerve palsy and 9 ruptured ones. The morphologic parameters were measured and calculated from patient-specific 3D rotational angiographic images, and pulsatile computational fluid dynamic simulation was then performed for hemodynamic parameters.RESULTS:There was no significant statistical difference between the 2 groups in size, aspect ratio, size ratio, aneurysm angle, or vessel angle; analysis only demonstrated a significantly lower wall shear stress of the aneurysm wall in the symptomatic unruptured group in hemodynamics (P = .024), whereas there were no differences in wall shear stress of the parent artery, low wall shear stress area, and oscillatory shear index.CONCLUSIONS:From morphologic and hemodynamic perspectives, we demonstrated that posterior communicating artery aneurysms with oculomotor nerve palsy had characteristics similar to those of ruptured ones, except for lower wall shear stress on the aneurysm wall, which might indicate an important role in aneurysm rupture. 22225709 Pacing transmural scar tissue reduces left ventricle reverse remodeling after cardiac resynchronization therapy. In patients with ischemic heart failure undergoing cardiac resynchronization therapy (CRT) the underlying myocardial substrate at the left ventricle (LV) pacing site may affect CRT response. However, the effect of delivering the pacing stimulus remote, adjacent to or over LV transmural scar tissue (TST) identified by echocardiography is still unknown. First, 35 patients with healed myocardial infarction (57 ± 11 years) were prospectically studied to demonstrate the capability of echocardiographic end-diastolic wall thickness (EDWT) to identify LV-TST as defined by delayed enhancement magnetic resonance imaging (DE-MRI). Subsequently, in 136 patients (65 ± 10 years) who underwent CRT, EDWT was retrospectively evaluated at baseline. The LV catheter placement was defined over, adjacent to and remote from TST if pacing was delivered at a scarred segment, at a site 1 segment adjacent to or remote from scarred segments. CRT response was defined as LV end-systolic volume (ESV) decrease by at least 10% after 6 months. A EDWT ≤ 5mm identified TST at DE-MRI with 92% sensitivity and 96% specificity. In the 76 CRT responders, less overall and posterolateral TST segments and more segments paced remote from TST areas were found. At the multivariate regression analysis, the number of TST segments and scar/pacing relationship showed a significant association with CRT response. In addition to LV global scar burden, CRT response relates also to the myocardial substrate underlying pacing site as evaluated by standard echocardiography. This information may expand the role of echocardiography to guide pacing site avoiding pacing at TST areas. 23707249 Anomalies in ovary following oral exposure to oxytocin: Mechanistic studies. Ovarian anomalies following oral oxytocin (OT) (1 and 10ng/100μl) exposure of female Wistar rat pups (10-day old) for 25 days was undertaken as OT injections are illegally used for milk let down in cattle thereby causing oral exposure to human population from early age. OT exposure resulted in increased ovarian weight, γ globulin, total number of follicles, and number of corpus luteum (CLs); indicating higher ovulation. The mechanism may involve over-expression of pEGFR followed by downstream pERK1/2 and subsequently increased ovarian PGE-2 along with enhanced COX-2, HAS-2 & TSG-6 (matrix deposition proteins) and GDF-9 (oocyte factor) proteins, suggesting that oral exposure of OT may affect the physiology and function of the ovary. Further, in vitro studies showed increased internalization of OT in IEC-6 cells which further supports that orally administered OT may cause altered manifestations as shown above following internalization in mucosal membrane. 23792790 Post-axial polydactyly type A2, overgrowth and autistic traits associated with a chromosome 13q31.3 microduplication encompassing miR-17-92 and GPC5. Genomic rearrangements at chromosome 13q31.3q32.1 have been associated with digital anomalies, dysmorphic features, and variable degree of mental disability. Microdeletions leading to haploinsufficiency of miR17∼92, a cluster of micro RNA genes closely linked to GPC5 in both mouse and human genomes, has recently been associated with digital anomalies in the Feingold like syndrome. Here, we report on a boy with familial dominant post-axial polydactyly (PAP) type A, overgrowth, significant facial dysmorphisms and autistic traits who carries the smallest germline microduplication known so far in that region. The microduplication encompasses the whole miR17∼92 cluster and the first 5 exons of GPC5. This report supports the newly recognized role of miR17∼92 gene dosage in digital developmental anomalies, and suggests a possible role of GPC5 in growth regulation and in cognitive development. 23220611 New mycotoxins from marine-derived fungus Aspergillus sp. SCSGAF0093. Nine mycotoxins including six aspergillic acid group toxins, aluminiumneoaspergillin (1), zirconiumneoaspergillin (2), aspergilliamide (3), ferrineoaspergillin (5), flavacol (6), neoaspergillic acid (7), and three ochratoxins, ochratoxin A n-butyl ester (4), ochratoxin A (8), ochratoxin A methyl ester (9), were isolated from the fermentation broth of marine gorgonian derived fungus Aspergillus sp. SCSGAF0093. Four of them (1-4) were new mycotoxins, and their structures were elucidated on the basis of spectroscopic analysis and chemical evidence. The bio-toxicity of compounds 1-9 were determined by brine shrimp lethality bioassay with median lethal concentration (LC(50)) values of 2.59-205.67 μM. This was the first report about zirconium complex obtained from nature and ochratoxins isolated from marine environment. 22155887 Evaluation of total oxidative status and total antioxidant capacity in patients with endemic fluorosis. The objective of the present study was to determine the plasma total oxidative status (TOS) and total antioxidant capacity (TAC) in patients with endemic fluorosis. A total of 79 (35 males and 44 females; mean age 44.0 ± 11.9 years) patients with endemic fluorosis and 55 (23 males and 32 females; mean age 48.3 ± 8.5 years) age-, sex- and body mass index-matched healthy controls were included in this study. The urine fluoride levels and plasma TOS and TAC levels were measured. The urine fluoride levels of fluorosis patients were significantly higher than control subjects as expected (1.91 ± 0.15 vs. 0.49 ± 0.13 mg/L, respectively; p < 0.001). TOS was significantly higher in fluorosis group than in control group (17.55 ± 3.82 vs. 15.06 ± 4.31 μmol H(2)O(2) Eq/L, respectively; p = 0.001). TAC was significantly lower in fluorosis group than in control group (1.60 ± 0.36 vs. 1.82 ± 0.51 mmol Trolox Eq/L, respectively; p = 0.004). Oxidative stress index (OSI) was significantly higher in fluorosis group than in control group (11.5 ± 3.8 vs. 8.8 ± 3.7, respectively; p < 0.001). Correlation analysis in all the groups indicated that TAC was negatively correlated with urine fluoride (r = -0.25, p = 0.003), TOS was positively correlated with urine fluoride (r = 0.34, p < 0.001) and OSI was positively correlated with urine fluoride (r = 0.36, p < 0.001). The results of our study demonstrate that oxidative stress plays an important role in the pathogenesis of the endemic fluorosis. 23832422 A longitudinal examination of adolescent response inhibition: neural differences before and after the initiation of heavy drinking. Response inhibition abnormalities contribute to several maladaptive behaviors commonly observed during adolescence, including heavy drinking. The present study aimed to determine whether abnormalities in brain response during response inhibition predate or follow adolescents' transition into heavy drinking, which is pivotal in identifying the neural antecedents and consequences of adolescent alcohol use. Longitudinal functional magnetic resonance imaging (fMRI) acquired during a response inhibition task was collected on adolescents before the onset of heavy drinking and then again on the same scanner approximately 3 years later. Adolescents who transitioned into heavy drinking (n = 20) were matched to continuously nondrinking adolescents (n = 20) on baseline and follow-up demographic and developmental variables. During no-go relative to go trials, participants showed responses common to inhibitory circuitry: frontal (e.g., pre-supplementary motor area), temporal, and parietal regions. A repeated measures analysis of covariance revealed that adolescents who later transitioned into heavy drinking showed less fMRI response contrast at baseline than continuous nondrinkers in frontal, parietal, subcortical, and cerebellar regions (p < 0.01, clusters >756 Î¼l), then increased activation after the onset of heavy drinking in frontal, parietal, and cerebellar areas. Future heavy drinkers showed less activation of inhibitory circuitry before the onset of heavy drinking. After transitioning into heavy drinking, they showed more activation during response inhibition than nondrinking controls. These results contribute to the growing literature suggesting that neural vulnerabilities exist prior to the onset of substance use, and the initiation of heavy drinking may lead to additional alterations in brain functioning. 23266269 Protective effect of ganodermanondiol isolated from the Lingzhi mushroom against tert-butyl hydroperoxide-induced hepatotoxicity through Nrf2-mediated antioxidant enzymes. Ganodermanondiol, a biologically active compound, was isolated from the Lingzhi mushroom (Ganoderma lucidum). The present study examined the protective effects of ganodermanondiol against tert-butyl hydroperoxide (t-BHP)-induced hepatotoxicity. Ganodermanondiol protected human liver-derived HepG2 cells through nuclear factor-E2-related factor 2 (Nrf2) pathway-dependent heme oxygenase-1 expressions. Moreover, ganodermanondiol increased cellular glutathione levels and the expression of the glutamine-cysteine ligase gene in a dose-dependent manner. Furthermore, ganodermanondiol exposure enhanced the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and its upstream kinase activators, LKB1 and Ca(2+)/calmodulin-dependent protein kinase-II (CaMKII). This study indicates that ganodermanondiol exhibits potent cytoprotective effects on t-BHP-induced hepatotoxicity in human liver-derived HepG2 cells, presumably through Nrf2-mediated antioxidant enzymes and AMPK. 23139074 C3'/C4'-Stereochemical Effects of Digitoxigenin α-L-/α-D-Glycoside in Cancer Cytotoxicity. Sweet'n low in stereo: A Wharton reaction was employed along with a diastereoselective palladium-catalyzed glycosylation and other post-glycosylation transformations to synthesize digitoxin analogues. Cytotoxic evaluation against a panel of cancer cell lines uncovered the stereochemical and substitutional limits of the C3'/C4'-hydroxy functionality in digitoxin monosaccharide. 23770888 Assistive technology for promoting choice behaviors in three children with cerebral palsy and severe communication impairments. A technology-based program to promote independent choice behaviors by three children with cerebral palsy and multiple disabilities was assessed. The program was based on learning principles and assistive technology (i.e., customized input devices/sensors, personal computers, screening of preferred stimuli according to a binomial criterion). The first purpose of the present study was to provide the participants with a new set-up of assistive technology and to allow them to choose among three categories (i.e., food, beverage and leisure), and to request a specific item out of four in each category, adopting a procedure that minimized (according to a conditional probability criterion) unintentional choices. The second aim of the study was to carry out the effects of the program on detectable mood signs (i.e., happiness index). The study was conducted according to an ABAB sequence with a subsequent post intervention check for each participant. The results showed an increase of engagement and of the happiness index during intervention phases. Psychological as well as educational implications were discussed. 23920043 Mitochondrial DNA methylation as a next-generation biomarker and diagnostic tool. Recent expansion of our knowledge on epigenetic changes strongly suggests that not only nuclear DNA (nDNA), but also mitochondrial DNA (mtDNA) may be subjected to epigenetic modifications related to disease development, environmental exposure, drug treatment and aging. Thus, mtDNA methylation is attracting increasing attention as a potential biomarker for the detection and diagnosis of diseases and the understanding of cellular behavior in particular conditions. In this paper we review the current advances in mtDNA methylation studies with particular attention to the evidences of mtDNA methylation changes in diseases and physiological conditions so far investigated. Technological advances for the analysis of epigenetic variations are promising tools to provide insights into methylation of mtDNA with similar resolution levels as those reached for nDNA. However, many aspects related to mtDNA methylation are still unclear. More studies are needed to understand whether and how changes in mtDNA methylation patterns, global and gene specific, are associated to diseases or risk factors. 23383712 Menopause, estrogens and frailty. Abstract The controversy surrounding the results from the Women's Health Initiative (WHI) trials published a decade ago caused a significant decline in the use of menopausal hormone replacement therapy. However, these results have been vehemently contested and several lines of evidence suggest that in perimenopausal and non-obese women, estrogen therapy may indeed be of benefit. There is ample proof that menopause causes a loss of musculoskeletal tissue mass and quality, thereby causing a loss of health and quality of life. There is also solid evidence that hormone replacement therapy in itself prevents most of these effects in connective tissue in it self. Besides the independent, direct effects on the musculoskeletal tissues, estrogen deficiency also reduces the ability to adequately respond and adapt to external mechanical and metabolic stressors, e.g. exercise, which are otherwise the main stimuli that should maintain musculoskeletal integrity and metabolic function. Thus, normophysiological estrogen levels appear to exert a permissive effect on musculoskeletal adaptations to loading, thereby likely improving the outcome of rehabilitation following critical illness, musculoskeletal trauma or orthopedic surgical therapy. These effects add to the evidence supporting the use of estrogen therapy, particularly accelerated gain of functional capacity and independence following musculoskeletal disuse. 23852003 Quantitative ultrasonic computed tomography using phase-insensitive pyroelectric detectors. The principle of using ultrasonic computed tomography (UCT) clinically for mapping tissue acoustic properties was suggested almost 40 years ago. Despite strong research activity, UCT been unable to rival its x-ray counterpart in terms of the ability to distinguish tissue pathologies. Conventional piezoelectric detectors deployed in UCT are termed phase-sensitive (PS) and it is well established that this property can lead to artefacts related to refraction and phase-cancellation that mask true tissue structure, particularly for reconstructions involving attenuation. Equally, it has long been known that phase-insensitive (PI) detectors are more immune to this effect, although sufficiently sensitive devices for clinical use have not been available. This paper explores the application of novel PI detectors to UCT. Their operating principle is based on exploiting the pyroelectric properties of the piezoelectric polymer polyvinylidene difluoride. An important detector performance characteristic which makes it particularly suited to UCT, is the lack of directionality of the PI response, relative to the PS detector mode of operation. The performance of the detectors is compared to conventional PS detection methods, for quantitatively assessing the attenuation distribution within various test objects, including a two-phase polyurethane phantom. UCT images are presented for a range of single detector apertures; tomographic reconstruction images being compared with the known structure of phantoms containing inserts as small as 3 mm, which were readily imaged. For larger diameter inserts (>10 mm), the transmitter-detector combination was able to establish the attenuation coefficient of the insert to within ±10% of values determined separately from plane-wave measurements on representative material plaques. The research has demonstrated that the new PI detectors are significantly less susceptible to refraction and phase-cancellation artefacts, generating realistic images in situations where conventionally-employed through-transmission PS detection techniques were unable to do so. The implications of the study to the potential screening of breast disease are discussed. 23945634 Facile synthesis of nitrogen doped reduced graphene oxide as a superior metal-free catalyst for oxidation. Nitrogen (5.61 at%) doped reduced graphene oxide synthesized via a facile method was demonstrated as a superior metal-free catalyst for activation of peroxymonosulfate. Codoping with boron would further enhance the catalytic activity and the stability, providing a promising green material for environmental remediation. 23147668 Biological network inference for drug discovery. A better understanding of the pathophysiology should help deliver drugs whose targets are involved in the causative processes underlying a disease. Biological network inference uses computational methods for deducing from high-throughput experimental data, the topology and the causal structure of the interactions among the drugs and their targets. Therefore, biological network inference can support and contribute to the experimental identification of both gene and protein networks causing a disease as well as the biochemical networks of drugs metabolism and mechanisms of action. The resulting high-level networks serve as a foundational basis for more detailed mechanistic models and are increasingly used in drug discovery by pharmaceutical and biotechnology companies. We review and compare recent computational technologies for network inference applied to drug discovery. 23932157 Quality of life among prostate cancer patients: A prospective longitudinal population-based study. To investigate the course of quality of life (QoL) among prostate cancer patients treated with external beam radiotherapy and to compare the results with QoL of a normal age-matched reference population. The study population was composed of 227 prostate cancer patients, treated with radiotherapy. The EORTC QLQ-C30 was used to assess QoL before radiotherapy and six months, one year, two years and three years after completion of radiotherapy. Mixed model analyses were used to investigate longitudinal changes in QoL. QoL of prostate cancer patients was compared to that of a normative cohort using a multivariate analysis of covariance. A significant decline in QoL was observed after radiotherapy (p<0.001). The addition of hormonal therapy to radiotherapy was associated with a lower level of role functioning. Patients with coronary heart disease and or chronic obstructive pulmonary disease or asthma had a significantly worse course in QoL. Although statistically significant, all differences were classified as small or trivial. Prostate cancer patients experience a small worsening of QoL as compared with baseline and as compared with a normal reference population. As co-morbidity modulates patients' post-treatment QoL, a proper assessment of co-morbidity should be included in future longitudinal analyses on QoL. 23803603 Plasma Membrane Calcium ATPase Activity Is Regulated by Actin Oligomers through Direct Interaction. As recently described by our group, plasma membrane calcium ATPase (PMCA) activity can be regulated by the actin cytoskeleton. In this study, we characterize the interaction of purified G-actin with isolated PMCA and examine the effect of G-actin during the first polymerization steps. As measured by surface plasmon resonance, G-actin directly interacts with PMCA with an apparent 1:1 stoichiometry in the presence of Ca(2+) with an apparent affinity in the micromolar range. As assessed by the photoactivatable probe 1-O-hexadecanoyl-2-O-[9-[[[2-[(125)I]iodo-4-(trifluoromethyl-3H-diazirin-3-yl)benzyl]oxy]carbonyl]nonanoyl]-sn-glycero-3-phosphocholine, the association of PMCA to actin produced a shift in the distribution of the conformers of the pump toward a calmodulin-activated conformation. G-actin stimulates Ca(2+)-ATPase activity of the enzyme when incubated under polymerizing conditions, displaying a cooperative behavior. The increase in the Ca(2+)-ATPase activity was related to an increase in the apparent affinity for Ca(2+) and an increase in the phosphoenzyme levels at steady state. Although surface plasmon resonance experiments revealed only one binding site for G-actin, results clearly indicate that more than one molecule of G-actin was needed for a regulatory effect on the pump. Polymerization studies showed that the experimental conditions are compatible with the presence of actin in the first stages of assembly. Altogether, these observations suggest that the stimulatory effect is exerted by short oligomers of actin. The functional interaction between actin oligomers and PMCA represents a novel regulatory pathway by which the cortical actin cytoskeleton participates in the regulation of cytosolic Ca(2+) homeostasis. 23777243 Using the polymeric ouzo effect for the preparation of polysaccharide-based nanoparticles. The polymeric ouzo effect, a nanoprecipitation process, is used for the preparation of polysaccharide-based nanoparticles. Dextran, pullulan, and starch were esterified with hydrophobic carboxylic acid anhydrides to obtain hydrophobic polysaccharides, which are insoluble in water. The additional introduction of methacroyl residues offers the possibility to cross-link the generated nanostructures, which become insoluble in organic solvents. To make use of the ouzo effect for the formation of nanoparticles, the polymer has to be soluble in an organic solvent, which is miscible with water. Here, acetone and THF were used. Immediately after the organic polymer solution is added to water, nanoparticles are generated. The size of the nanoparticles can be adjusted between 50 and 200 nm by changing the concentration of the initial polysaccharide solution. The degree of hydrophobic substitution was shown to have a very minor effect on the particle size. Dispersions with solids contents of up to 2% were obtained. Furthermore, the mechanical properties of the nanoparticles were investigated with force microscopy, and it was shown by fluorescence correlation spectroscopy that a fluorescent dye could be encapsulated in the nanoparticles by the applied nanoprecipitation procedure. 23865813 Application of Fordisc 3.0 to Explore Differences Among Crania of North American and South African Blacks and Whites(.) Using discriminant function analysis, classification accuracies for ancestry and sex in white and black South Africans were compared using North American (FDB), African groups in Howells (HDB), and South African (SADB) databases in FORDISC 3.0. (FD3). Twenty-four standard linear measures were collected from a total of 86 black and 101 white crania obtained from the Pretoria Bone Collection. White and black South Africans classified 73% correctly in FDB, 55% correctly in HDB, and 71% correctly in SADB. The percentage of atypical cases was higher with FDB than SADB. In all three databases, misclassification occurred more with sex than ancestry revealing differences in sexual dimorphism between population groups. Broad ancestral differences may explain low misclassification rates for ancestry. FD3, with a modern South African reference sample, can assist South African anthropologists to standardize methodology and to justify procedures for estimating ancestry. 23904062 Hepatitis A in Children- Clinical Course, Complications and Laboratory Profile. To study the course and complications of hepatitis A in children. Seventy eight children diagnosed as acute viral hepatitis A by IgM antiHAV were prospectively studied for involvement of other systems and complications. The mean age of children was 7.85 ±â€‰3.4 y. Jaundice was present in all the patients as this was the inclusion criteria. Fever was present in 82.1 %, hepatomegaly in 98.7 % and splenomegaly in 39.7 %. More than 5 fold rise in Aspartate transaminase (AST) and Alaninetransaminase (ALT), were seen in 62 cases (79.5 %) and 55 cases (70.5 %) respectively. Coagulopathy (Prothrombin time INR > 1.5) was observed in 12 cases (15.4 %) and abnormal APTT in 10 cases (12.8 %). Thrombocytopenia was observed in 5.1 % of children and 8.9 % had more than 2 hematological abnormalities. Ascites was noted in 35 cases (44.9 %), gallbladder wall thickening in 32 cases (41 %) and pleural effusion in 11 cases (14.1 %). Acute renal failure, acute glomerulonephritis and acute pancreatitis were present in 1 case (1.3 %) each. Raised CK-MB values more than 3 times the normal was noted in 5 cases (6.4 %). On follow up, most of the children recovered completely by 2 mo and prolonged cholestasis was observed in 2 of them. In the present study mortality was 1.3 % and it was attributable to fulminant hepatic failure. Eventhough hepatitis A infection is a self-limiting disease, extrahepatic manifestations and mortality are not uncommon. All cases should be followed up till complete recovery and only a strong index of suspicion will enable us to recognize the complications. 23311530 Cardiovascular magnetic resonance as an alternate method for serial evaluation of proximal aorta: comparison with echocardiography. Thoracic aortic disease is a known cause of aortic dilatation and poses significant risk of aortic dissection and rupture. Serial assessment of aortic root dimensions is traditionally performed using echocardiography, which is limited with older age and following surgery, due to poor acoustic windows. Although diastolic measurements are utilized as standard practice in decision making of adult aortopathy, systolic diameters are utilized in pediatric practice. Three-dimensional steady-state free precision (3D-SSFP) has shown promise as an alternate method for providing accurate and reproducible aortic measurements. The agreement between proximal aorta measurements by diastolic 3D-SSFP and echocardiography (both systole and diastole) was examined in 40 subjects. The maximum inner diameters at aortic annulus, root and sinotubular junction demonstrated excellent agreement between 3D-SSFP and echocardiography for all the 3 levels. The best agreement was observed for diastolic root dimensions with a mean difference of +0.01 cm, limits of agreement being -0.26 to +0.28 cm. Three D-SSFP can be used interchangeably with echocardiography in the serial assessment of the aortic root size. Careful attention to obtain an imaging plane utilizing 3D multiplanar reformatting is critical to maximize the agreement between the two imaging modalities. 23852571 Colon cleansing for colonoscopy 2013: current status. Colonoscopy requires adequate bowel cleansing to be safe and effective. There are a variety of options available. This review will focus on highlighting new products, administration techniques emphasizing the value of split-dose and same-day regimens, safety, and options for inadequate cleansing. 23521797 Discovery of oxysterol-derived pharmacological chaperones for NPC1: implication for the existence of second sterol-binding site. Niemann-Pick type C1 (NPC1) is a polytopic endosomal membrane protein required for efflux of LDL-derived cholesterol from endosomes, and mutations of this protein are associated with Niemann-Pick disease type C, a fatal neurodegenerative disease. At least one prevalent mutation (I1061T) has been shown to cause a folding defect, which results in failure of endosomal localization, leading to a loss-of-function phenotype. Here, we show that several oxysterols and their derivatives act as pharmacological chaperones; binding of these compounds to I1061T NPC1 corrects the localization/maturation defect of the mutant protein. Further, these compounds alleviate intracellular cholesterol accumulation in patient-derived fibroblasts, suggesting that they may have therapeutic potential. These oxysterol derivatives bind to a domain of NPC1 that is different from the known N-terminal sterol-binding domain; i.e., there is an additional sterol-binding site on NPC1. 23678899 Factors explaining racial/ethnic disparities in rates of physician recommendation for colorectal cancer screening. Physician recommendation plays a crucial role in receiving endoscopic screening for colorectal cancer (CRC). This study explored factors associated with racial/ethnic differences in rates of screening recommendation. Data on 5900 adults eligible for endoscopic screening were obtained from the National Health Interview Survey. Odds ratios of receiving an endoscopy recommendation were calculated for selected variables. Planned, sequenced logistic regressions were conducted to examine the extent to which socioeconomic and health care variables account for racial/ethnic disparities in recommendation rates. Differential rates were observed for CRC screening and screening recommendations among racial/ethnic groups. Compared with Whites, Hispanics were 34% less likely (P < .01) and Blacks were 26% less likely (P < .05) to receive this recommendation. The main predictors that emerged in sequenced analysis were education for Hispanics and Blacks and income for Blacks. After accounting for the effects of usual source of care, insurance coverage, and education, the disparity reduced and became statistically insignificant. Socioeconomic status and access to health care may explain major racial/ethnic disparities in CRC screening recommendation rates. 23721831 Low dielectric, nanoporous fluorinated polyimide films prepared from PCL-PI-PCL triblock copolymer using retro-Diels-Alder reaction. The triblock copolymers with the majority phase comprising fluorinated polyimide and the minor phase consisting of poly (ε-caprolactone) (PCL) were synthesized through Diels-Alder reaction between PI-Maleimide and PCL-Furfuryl Amine. The chemical composition and structure of the copolymers were characterized by nuclear magnetic resonance (NMR), gel permeation chromatography (GPC), and differential scanning calorimetry (DSC). Films of the copolymers were spined and microphase-separation of the thin film was achieved by solvent annealing in N,N-dimethylformamide (DMF) vapor. The microphase-separation morphology was investigated by atomic force microscopy (AFM). Based on the microphase-separation structures, nanoporous fluorinated polyimide films were obtained after removal of the PCL block can removed via a retro-DA (Diels-Alder) reaction using a simple heating and immersing procedure. The nanoporous thin film was characterized by Transmission electron microscopy (TEM). The dielectric property of the nanoporous fluorinated polyimide films was investigated. It was found that the nanopores introduction could effectively reduce the dielectric constant from 2.82 of PI dense films to 2.10 of nanoporous PI films. 23484493 Optimization of Chloronitrobenzamides (CNBs) as Therapeutic Leads for Human African Trypanosomiasis (HAT). We previously reported the discovery of the activity of chloronitrobenzamides (CNBs) against bloodstream forms of Trypanosoma brucei . Herein we disclose extensive structure-activity relationship and structure-property relationship studies aimed at identification of tractable early leads for clinical development. These studies revealed a promising lead compound, 17b, that exhibited nanomolar potency against T. brucei (EC50 = 27 nM for T. b. brucei , 7 nM for T. b. rhodesiense , and 2 nM for T. b. gambiense ) with excellent selectivity for parasite cells relative to mammalian cell lines (EC50 > 25 μM). In addition compound 17b displayed suitable physiochemical characteristics and microsomal stability (t1/2 > 4 h for human and mouse) to justify pursuing in vivo studies. 23553493 Odour-active compounds in guava (Psidium guajava L. cv. Red Suprema). Solid phase microextraction and simultaneous distillation-extraction combined with GC-FID, GC/MS, aroma extract dilution analysis and odour activity values were used to analyse volatile compounds from guava (Psidium guajava L. cv. Red Suprema) and to estimate the most odour-active compounds. The analysis led to the detection of 141 compounds, 121 of which were positively identified. The composition of guava fruit volatiles included 43 esters, 37 terpenes, 18 aldehydes, 16 alcohols, ten acids, six ketones, four furans and seven miscellaneous compounds. Seventeen odorants were considered as odour-active compounds, with (E)-β-ionone, ethyl hexanoate, ethyl butanoate, hexanal, (Z)-3-hexenal, hexyl acetate, (E)-2-hexenal and limonene contributing most to the typical guava aroma of this cultivar. © 2013 Society of Chemical Industry. 23788251 Arylation with unsymmetrical diaryliodonium salts: a chemoselectivity study. Phenols, anilines, and malonates have been arylated under metal-free conditions with twelve aryl(phenyl)iodonium salts in a systematic chemoselectivity study. A new "anti-ortho effect" has been identified in the arylation of malonates. Several "dummy groups" have been found that give complete chemoselectivity in the transfer of the phenyl moiety, irrespective of the nucleophile. An aryl exchange in the diaryliodonium salts has been observed under certain arylation conditions. DFT calculations have been performed to investigate the reaction mechanism and to elucidate the origins of the observed selectivities. These results are expected to facilitate the design of chiral diaryliodonium salts and the development of catalytic arylation reactions that are based on these sustainable and metal-free reagents. 23332923 Expression of mammaglobin and gross cystic disease fluid protein-15 in breast carcinomas. Immunohistochemical analysis of gross cystic disease fluid protein-15 (GCDFP-15) and mammaglobin (MGB) is frequently used in routine practice for assessment of metastases or regional recurrences of breast origin. Breast cancer is highly heterogeneous. Expression of these 2 markers in various breast cancer subtypes has not been well studied. In addition, the usefulness of these two markers in combination in detecting breast origin has not been explored. In this study, a large cohort of breast cancers was evaluated for GCDFP-15 and MGB expression, both individually and combined. Their expression was correlated with cancer subtypes, other biomarkers and clinicopathologic parameters. A higher sensitivity for MGB (42.3%) than GCDFP-15 (31.6%) in detecting cancers of breast origin was observed. Combining both increased the sensitivity further, both for primary tumor (53.0%) and for nodal metastases (69.0%). GCDFP-15 was associated significantly with a breast cancer profile of good prognosis tumors, including lower grade (P < .001), pN (P = .029) and Ki-67 (P < .001) as well as negative basal markers expression (P = .043, .009, and .049 for c-Kit, CK5/6 and epidermal growth factor receptor, respectively) and, thus, may not be sensitive for detection of poor prognosis tumors. MGB has the highest expression in HER2-overexpressing cancers (56.6%), and may be a potentially useful marker for this subtype. Nonetheless, both markers showed low expression in the basal like (BLBC) subtype (11.9% and 21.4% for GCDFP-15 and MGB respectively), therefore, the detection of BLBC remains problematic. Negative results need to be interpreted with caution, and correlation with other clinical findings may be required to exclude the possibility of metastatic BLBC. 23912460 Hyperactivation of EGFR and downstream effector phospholipase D1 by oncogenic FAM83B. Despite the progress made in targeted anticancer therapies in recent years, challenges remain. The identification of new potential targets will ensure that the arsenal of cancer therapies continues to expand. FAM83B was recently discovered in a forward genetic screen for novel oncogenes that drive human mammary epithelial cell (HMEC) transformation. We report here that elevated FAM83B expression increases Phospholipase D (PLD) activity, and that suppression of PLD1 activity prevents FAM83B-mediated transformation. The increased PLD activity is engaged by hyperactivation of epidermal growth factor receptor (EGFR), which is regulated by an interaction involving FAM83B and EGFR. Preventing the FAM83B/EGFR interaction by site-directed mutation of lysine 230 of FAM83B suppressed PLD activity and MAPK signaling. Furthermore, ablation of FAM83B expression from breast cancer cells inhibited EGFR phosphorylation and suppressed cell proliferation. We propose that understanding the mechanism of FAM83B-mediated transformation will provide a foundation for future therapies aimed at targeting its function as an intermediary in EGFR, MAPK and mTOR activation.Oncogene advance online publication, 5 August 2013; doi:10.1038/onc.2013.293. 23906583 Persistent low hCG levels beyond pregnancy: report of two cases and review of the literature. Unexpected finding or persistence of low human chorionic gonadotropin (hCG) levels is not a rare situation. It requires a clinico-biological approach in order to avoid misunderstandings that could lead to inappropriate diagnostic or therapeutic attitudes. Beyond pregnancy, persistent low levels of hCG may be associated with various benign and malignant conditions, i.e. quiescent gestational trophoblastic disease (QTD), raised pituitary hCG or false positive elevation caused by circulating heterophile antibodies. We report the cases of two non-pregnant patients with low serum hCG. In the first case, hCG levels raised during several years following a spontaneous abortion. The likelihood of heterophilic antibodies interference was ruled out and extensive clinical investigation excluded the presence of a tumour. The diagnosis was QTD. In the second case, elevated hCG came to light as an incidental finding in a women with chronic renal failure and led the clinicians to question the laboratory. The cause was probably an increase in pituitary hCG consecutive to terminal renal failure. These cases illustrate the importance of understanding the biology of the hCG and the causes of its persistent low elevation, which are reviewed in this article. It is essential to demonstrate clinically the presence of a tumour in order to avoid unnecessary and ineffective chemotherapy and/or hysterectomy. 23966982 Glutamate and GABA in Appetite Regulation. Appetite is regulated by a coordinated interplay between gut, adipose tissue, and brain. A primary site for the regulation of appetite is the hypothalamus where interaction between orexigenic neurons, expressing Neuropeptide Y/Agouti-related protein, and anorexigenic neurons, expressing Pro-opiomelanocortin cocaine/Amphetamine-related transcript, controls energy homeostasis. Within the hypothalamus, several peripheral signals have been shown to modulate the activity of these neurons, including the orexigenic peptide ghrelin and the anorexigenic hormones insulin and leptin. In addition to the accumulated knowledge on neuropeptide signaling, presence and function of amino acid neurotransmitters in key hypothalamic neurons brought a new light into appetite regulation. Therefore, the principal aim of this review will be to describe the current knowledge of the role of amino acid neurotransmitters in the mechanism of neuronal activation during appetite regulation and the associated neuronal-astrocytic metabolic coupling mechanisms. Glutamate and GABA dominate synaptic transmission in the hypothalamus and administration of their receptors agonists into hypothalamic nuclei stimulates feeding. By using (13)C High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance spectroscopy based analysis, the Cerdán group has shown that increased neuronal firing in mice hypothalamus, as triggered by appetite during the feeding-fasting paradigm, may stimulate the use of lactate as neuronal fuel leading to increased astrocytic glucose consumption and glycolysis. Moreover, fasted mice showed increased hypothalamic [2-(13)C]GABA content, which may be explained by the existence of GABAergic neurons in key appetite regulation hypothalamic nuclei. Interestingly, increased [2-(13)C]GABA concentration in the hypothalamus of fasted animals appears to result mainly from reduction in GABA metabolizing pathways, rather than increased GABA synthesis by augmented activity of the glutamate-glutamine-GABA cycle. 23846832 Apoptotic effects of tamoxifen on leukocytes from horse peripheral blood and bronchoalveolar lavage fluid. A reduction in inflammatory cell apoptosis is an important concept in the maintenance of inflammation and a potential target for the resolution of inflammation in many inflammatory diseases. Dysregulation of apoptosis has been implicated in a range of diseases, including tumors, neurodegenerative disorders and autoimmunity, and may also be implicated in allergic asthma. In horses, recurrent airway obstruction (RAO) is an asthma-like condition that is characterized increased survival neutrophil bronchial. Tamoxifen is a synthetic, non-steroidal, anti-estrogen agent that is widely used for treating all stages of breast cancer and has been approved for the prevention of breast cancer in high-risk women. The observed efficacy of tamoxifen has been attributed to both growth arrest and the induction of apoptosis. Therefore, the aim of our study was to evaluate the ability of tamoxifen to induce apoptosis in vitro in granulocytic cells from peripheral blood and in mononuclear cells from bronchoalveolar lavage fluid (BALF) in horses. Flow cytometry using commercial AnnexinV-FITC and propidium iodide was used to quantify early and late apoptotic leukocytes, respectively. The results showed a significant increase in early apoptosis in peripheral blood and bronchial granulocytic cells treated with tamoxifen. The rate of early apoptosis of mononuclear cells from blood and BALF when incubated with tamoxifen was significantly lower compared with granulocytic cells. We did not observe a direct effect of tamoxifen on late apoptosis in any of the in vitro assays in the cell types used here. These results indicate that the apoptotic mechanisms under these experimental conditions would affect only blood and BALF granulocytic cells, particularly in early apoptosis. Finally, further in vitro and in vivo studies are needed to better understand apoptotic mechanisms because tamoxifen could be used to treat chronic, inflammatory pathologies associated with granulocytes and allergic diseases, such as asthma or equine RAO. 23918651 Inhibition of mitotic clonal expansion mediates fisetin-exerted prevention of adipocyte differentiation in 3T3-L1 cells. Adipocytes are the key player in adipose tissue inflammation and subsequent systemic insulin resistance and its development involves complex process of proliferation and differentiation of preadipocytes. Fistein, a polyphenol flavonoid, is known to exert anti-inflammatory, anti-carcinogenic and anti-diabetic effects. In this study, we aimed to investigate the effect of fisetin on adipocyte proliferation and differentiation in 3T3-L1 preadipocyte cell line and its mechanism of action. We found that fisetin inhibits adipocyte differentiation in a concentration dependent manner, which were evidenced by Oil Red O staining and the protein expression of mature adipocyte marker genes fatty acid synthase and peroxisome proliferator-activated receptor γ. Moreover, the proliferation of preadipocytes was also markedly suppressed by treatment of fisetin for 24 and 48 h in the differentiation medium. We also found that fisetin inhibition of adipocyte differentiation was largely due to the effect on mitotic clonal expansion. Fisetin suppression of preadipocyte proliferation at early stage of differentiation was accompanied by the changes of expression of a series of cell cycle regulatory proteins. Altogether, our results suggest that the inhibition of adipocyte differentiation by fisetin may be at least in part mediated by cell cycle arrest during adipogenesis. 23306951 The colon carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is actively secreted in the distal colon of the rat: an integrated view on the role of PhIP transport and metabolism in PhIP-induced colon carcinogenesis. Epidemiological studies show that a positive correlation exists between the consumption of strongly heated meat and fish and the development of colorectal tumours. In this context, it has been postulated that the uptake of toxic substances formed during meat and fish processing such as heterocyclic aromatic amines (HCAs) may be causally related to colon carcinogenesis. In a previous study, we have shown that 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundantly formed HCA in the above-mentioned food items, is mainly absorbed in the small intestine (i.e. proximal jejunum) of the rat. In the present study, we analysed whether PhIP can actively be secreted by enterocytes in the rat proximal jejunum and distal colon. Unidirectional PhIP flux rates from the mucosal-to-the serosal compartment (J ms ) and in the opposite direction (J sm ) were examined in Ussing chambers with (14)C-PhIP as radiotracer and in the absence of electrochemical gradients. Under these experimental conditions, significant negative net flux rates (J net  = J ms  - J sm ) can only be explained by an active secretion of PhIP into the luminal compartment, and such an effect was observed in the rat distal colon, but not in the proximal jejunum. Moreover, the data obtained suggest that the breast cancer resistance protein, the multidrug resistance protein 4 and P-glycoprotein are not involved in the active secretion of PhIP in the rat distal colon. The potential role of PhIP transport in colon carcinogenesis is discussed. 23949273 Unplanned Pregnancy in Adolescents: Association with Family Structure, Employed Mother, and Female Friends with Health-Risk Habits and Behaviors. Previous publications have suggested that living in a nonintact family household and socializing with girlfriends who smoke or who consume alcoholic beverages favor the development of health-risk habits and customs in adolescents. However, their relationship with unplanned pregnancy in adolescents has not been determined. We investigated the association between family structure, employed mother, and female friends with health-risk habits and behaviors with unplanned pregnancy in adolescents (n = 3,130). After adjusting for low maternal educational level and low family income, logistic regression analyses showed that having an employed mother and socializing with girlfriends who have health-risk habits or behaviors, rather than living in a nonintact family household, appear to be the most important health-risk factors for unplanned pregnancy in adolescents. It is important for health-care programs for adolescents to be revised and for their strategies be strengthened in order to reach the objectives for which they were created. 23574786 κ-Opioid receptor in the nucleus is a novel prognostic factor of esophageal squamous cell carcinoma. Opioid receptors, members of the G-protein-coupled receptor superfamily, appear to be involved in cancer progression. However, the expression and significance of opioid receptors in esophageal squamous cell carcinoma (ESCC) remain unclear. In this study, we demonstrated by flow cytometry that μ, δ, and κ-opioid receptors (MOR, DOR, and KOR) are expressed to various degrees in ESCC cell lines. The KOR protein was further examined by several methods in ESCC cell lines and tissues. Immunocytochemical staining localized KOR to the cell membrane in KYSE180 cells and the nucleus in EC109 cells, whereas no signal or weak staining of the cytoplasm was observed in KYSE150 cells. The expression of KOR was confirmed in ESCC cells by Western blotting. Furthermore, immunohistochemistry staining showed that KOR was up-regulated in ESCC tissues compared with nontumorous esophageal epithelium (P = .004, χ(2) test). Moreover, high nuclear KOR expression was significantly correlated with lymph node metastasis in 256 ESCC cases (R = 0.144; P = .030, Kendall τB test). Patients with high nuclear KOR expression in ESCC had a significantly poorer prognosis (P = .001, log-rank test). Multivariate Cox analysis revealed that KOR in the nucleus was an independent prognostic factor (hazard ratio, 1.789; 95% confidence interval, 1.177-2.720; P = .006). Our results suggest that KOR is involved in the carcinogenesis or progression of ESCC and that nuclear KOR may be indicative of prognosis. 23727353 Role of caveolin-1 and caveolae signaling in endotoxemia and sepsis. Caveolae, plasma membrane invaginations of 60-80nm in diameter, are a subset of lipid rafts enriched in cholesterol and sphingolipids. Caveolae are expressed in various tissues and cell types, such as endothelial cells, macrophages, neutrophils and adipocytes. The functions of caveolae are diverse and include endocytosis, transcytosis, potocytosis, calcium signaling, and regulation of various signaling events. Although growing evidence has increased our understanding of caveolae function, the role of caveolae in sepsis is still a controversial issue. In this review, we present a number of studies addressing caveolae and sepsis and describe the signaling pathways involved, including the LPS-eNOS-TLR4-NFκB, MKK3/p38 MAPK, cPLA2/p38 MAPK, STAT3/NFκB and IL-1β-IL-1R1 pathways. Different studies using endotoxemia and bacteremia animal models have provided distinct conclusions about the function of caveolae, and we discuss these inconsistencies. Taken together, the current data suggest that the function of caveolae in sepsis, which involves a number of signaling pathways, is complex and warrants further studies. 23949542 Report on the 2nd Annual Infinium HumanMethylation450 Array Workshop 15 April 2013 QMUL, London, UK. The Illumina's Infinium HumanMethylation450 platform for DNA methylome analysis has become a popular choice for large-scale studies as an extension of the previous hugely popular HumanMethylation27 BeadChip. After the success of last year's meeting ( 1) discussing the initial analysis of this then new platform, this year's meeting (held at Queen Mary, University of London) included the presentation of now established pipelines and normalization methods for data analysis and included some exciting tools for down-stream analysis. The importance of defining cell composition was a new topic mentioned by most speakers. The epigenome varies between cell types and insuring that methylation differences are related to sample treatment and not a differing cell population is essential. The meeting was attended by 215 computational and bench scientists from 18 countries. There were 11 speakers, a small poster session, and a discussion session. Talks were recorded and are now freely available at http://www.illumina.com/applications/epigenetics/array-based_methylation_analysis/methylation-array-analysis-education.ilmn. 23374349 Conformational coupling across the plasma membrane in activation of the EGF receptor. How the epidermal growth factor receptor (EGFR) activates is incompletely understood. The intracellular portion of the receptor is intrinsically active in solution, and to study its regulation, we measured autophosphorylation as a function of EGFR surface density in cells. Without EGF, intact EGFR escapes inhibition only at high surface densities. Although the transmembrane helix and the intracellular module together suffice for constitutive activity even at low densities, the intracellular module is inactivated when tethered on its own to the plasma membrane, and fluorescence cross-correlation shows that it fails to dimerize. NMR and functional data indicate that activation requires an N-terminal interaction between the transmembrane helices, which promotes an antiparallel interaction between juxtamembrane segments and release of inhibition by the membrane. We conclude that EGF binding removes steric constraints in the extracellular module, promoting activation through N-terminal association of the transmembrane helices. 23736382 Distribution of mRNA transcripts and translation activity in skeletal myofibers. We examine the distribution of gene products in skeletal myofibers, which are highly differentiated multinucleated cells exhibiting a specific cellular architecture. In situ hybridization studies of adult rat myofibers with a single nucleus infected with influenza virus suggested that the viral mRNA products were distributed beneath the sarcolemma around the nucleus of origin. In situ hybridization studies with a poly-T oligonucleotide probe to detect endogenous mRNAs indicated their concentration around the nuclei and distribution beneath the sarcolemma in a cross-striated fashion at the A-I junctions (costamers). Labeling with bromouridine resulted in a similar distribution pattern. The ribosomal distribution pattern indicated concentration around the myonuclei but an intracellular component was also seen. Localization of the translating ribosomes by puromycylation revealed prominent spots perinuclearly and in the core regions of the myofibers. These spots flanked Golgi elements. Our results thus suggest that the total mRNA pool is heavily concentrated within the perinuclear and subsarcolemmal regions. However, the ribosomes and the translational activity did not follow this distribution pattern, so the mRNA transcripts were not restricted to a region beneath the sarcolemma. Furthermore, experiments utilizing green fluorescent protein showed the rapid movement of proteins within the endomembrane system, which thus facilitated proteins to reach their site of function irrespective of the site of synthesis. 23775078 Foxm1 expression in prostate epithelial cells is essential for prostate carcinogenesis. The treatment of advanced prostate cancer (PCa) remains a challenge. Identification of new molecular mechanisms that regulate PCa initiation and progression would provide targets for the development of new cancer treatments. The Foxm1 transcription factor is highly up-regulated in tumor cells, inflammatory cells, and cells of tumor microenvironment. However, its functions in different cell populations of PCa lesions are unknown. To determine the role of Foxm1 in tumor cells during PCa development, we generated two novel transgenic mouse models, one exhibiting Foxm1 gain-of-function and one exhibiting Foxm1 loss-of-function under control of the prostate epithelial-specific Probasin promoter. In the transgenic adenocarcinoma mouse prostate (TRAMP) model of PCa that uses SV40 large T antigen to induce PCa, loss of Foxm1 decreased tumor growth and metastasis. Decreased prostate tumorigenesis was associated with a decrease in tumor cell proliferation and the down-regulation of genes critical for cell proliferation and tumor metastasis, including Cdc25b, Cyclin B1, Plk-1, Lox, and Versican. In addition, tumor-associated angiogenesis was decreased, coinciding with reduced Vegf-A expression. The mRNA and protein levels of 11β-Hsd2, an enzyme playing an important role in tumor cell proliferation, were down-regulated in Foxm1-deficient PCa tumors in vivo and in Foxm1-depleted TRAMP C2 cells in vitro. Foxm1 bound to, and increased transcriptional activity of, the mouse 11β-Hsd2 promoter through the -892/-879 region, indicating that 11β-Hsd2 was a direct transcriptional target of Foxm1. Without TRAMP, overexpression of Foxm1 either alone or in combination with inhibition of a p19(ARF) tumor suppressor caused a robust epithelial hyperplasia, but was insufficient to induce progression from hyperplasia to PCa. Foxm1 expression in prostate epithelial cells is critical for prostate carcinogenesis, suggesting that inhibition of Foxm1 is a promising therapeutic approach for prostate cancer chemotherapy. 23403272 Paeoniflorin protects human EA.hy926 endothelial cells against gamma-radiation induced oxidative injury by activating the NF-E2-related factor 2/heme oxygenase-1 pathway. Pulmonary endothelial cells have been demonstrated to have a critical role in the pathogenesis of radiation-induced lung injury. Our preliminary experiments indicated that Paeoniflorin protected human EA.hy926 endothelial cells from radiation-induced oxidative injury. This study was designed to confirm the protective effect of Paeoniflorin against radiation-induced endothelial cellular damage and to elucidate the underlying mechanisms. Preincubation of EA.hy926 cells with Paeoniflorin before γ-radiation resulted in significant inhibition of apoptosis, a decrease in mitochondrial membrane potential and enhanced cell viability. In particular, we showed that Paeoniflorin significantly reduced the formation of intracellular reactive oxygen species (ROS), the level of malondialdehyde (MDA) and lactate dehydrogenase (LDH) leakage, and enhanced production of the endogenous antioxidants, glutathione (GSH) and superoxide dismutase (SOD) in EA.hy926 cells. Treatment of these cells with Paeoniflorin significantly induced HO-1 expression. Moreover, Paeoniflorin promoted the nuclear translocation of nuclear factor erythroid 2 related factor-2 (Nrf-2). The Paeoniflorin-induced HO-1 expression was abrogated by Nrf2 siRNA. Furthermore, inhibition of HO-1 with zinc protoporphyrin IX (ZNPP) significantly reversed the protective effect of Paeoniflorin against radiation-induced damage in EA.hy926 cells. Our findings confirmed that Paeoniflorin protected EA.hy926 cells against radiation-induced injury through the Nrf2/HO-1 pathway. 23927891 Absorption of resveratrol by vascular endothelial cells through passive diffusion and an SGLT1-mediated pathway. Resveratrol is a natural polyphenol that exerts potent effects to suppress atherosclerosis. However, its low concentration in plasma has placed this role in doubt. Thus, resveratrol effects might be dependent on its transport into vascular endothelium, a question not previously addressed in spite of its obvious and fundamental importance. Via high-performance liquid chromatography and liquid chromatography/mass spectrometry, we found that resveratrol was absorbed by human umbilical vein endothelial cells in a temperature-, concentration- and time-dependent manner, suggesting the involvement of passive diffusion and active transport. As determined by confocal laser scanning microscopy, resveratrol primarily distributed throughout the cytoplasm. Furthermore, resveratrol absorption was modulated by serum proteins and sodium-dependent glucose transporter 1 (SGLT1) yet inhibited by glucose (an SGLT1 substrate) and phlorizin (an SGLT1 selective inhibitor), as well as SGLT1 siRNA transfection. Additionally, Sprague-Dawley rats were intragastrically administrated with 100mg/kg of resveratrol and the concentration of resveratrol in blood vessels declined more slowly up to 24h compared to that in the blood. Our results suggested that resveratrol uptake by vascular endothelial cells involved both passive diffusion and an SGLT1-mediated process, at least partially. Moreover, the intracellular resveratrol pool may be more important than the serum level in vivo. These provide new insights into the cardiovascular benefits of resveratrol. 22445329 Fetal and infant origins of diabetes and ill health: evidence from Puerto Rico's 1928 and 1932 hurricanes. A natural experiment is employed to analyze the relationship between living standards, diabetes, and cardiovascular disease. Results show that shocks generated by two powerful tropical storms striking Puerto Rico during the late 1920s and early 1930s had long-term consequences consistent with the fetal origins hypothesis. Individuals in the womb or early infancy in the aftermath of the storms are more likely to report a diagnosis of hypertension, high cholesterol, diabetes, and are considerably more likely to have no formal schooling. 23608596 Systems-wide Analysis of K-Ras, Cdc42, and PAK4 Signaling by Quantitative Phosphoproteomics. Although K-Ras, Cdc42, and PAK4 signaling are commonly deregulated in cancer, only a few studies have sought to comprehensively examine the spectrum of phosphorylation-mediated signaling downstream of each of these key signaling nodes. In this study, we completed a label-free quantitative analysis of oncogenic K-Ras, activated Cdc42, and PAK4-mediated phosphorylation signaling, and report relative quantitation of 2152 phosphorylated peptides on 1062 proteins. We define the overlap in phosphopeptides regulated by K-Ras, Cdc42, and PAK4, and find that perturbation of these signaling components affects phosphoproteins associated with microtubule depolymerization, cytoskeletal organization, and the cell cycle. These findings provide a resource for future studies to characterize novel targets of oncogenic K-Ras signaling and validate biomarkers of PAK4 inhibition. 23902248 Inhaled gene therapy in lung cancer: proof-of-concept for nano-oncology and nanobiotechnology in the management of lung cancer. Lung cancer still remains one of the leading causes of death among cancer patients. Although novel targeted therapies have been established in everyday treatment practice, and conventional platinum-based doublets have demonstrated effective results regarding overall and progression-free survival, we have still failed to achieve long-term survival. Therefore, several strategies of applying locoregional therapy are under investigation. Aerosol chemotherapy is already under investigation and, taking this a step further, aerosol gene therapies with multiple delivery systems are being developed. Several efforts have demonstrated its efficiency and effectiveness, but there are still multiple factors that have to be considered and combined to achieve an overall more effective multifunctional treatment. In the current review, we present data regarding aerosol delivery systems, transporters, carriers, vectors, genes, toxicity, efficiency, specificity, lung microenvironment and delivery gene therapy systems. Finally, we present current studies and future perspectives. 23919242 Glycosylation: impact, control and improvement during therapeutic protein production. Abstract The emergence of the biopharmaceutical industry represented a major revolution for modern medicine, through the development of recombinant therapeutic proteins that brought new hope for many patients with previously untreatable diseases. There is a ever-growing demand for these therapeutics that forces a constant technological evolution to increase product yields while simultaneously reducing costs. However, the process changes made for this purpose may also affect the quality of the product, a factor that was initially overlooked but which is now a major focus of concern. Of the many properties determining product quality, glycosylation is regarded as one of the most important, influencing, for example, the biological activity, serum half-life and immunogenicity of the protein. Consequently, monitoring and control of glycosylation is now critical in biopharmaceutical manufacturing and a requirement of regulatory agencies. A rapid evolution is being observed in this context, concerning the influence of glycosylation in the efficacy of different therapeutic proteins, the impact on glycosylation of a diversity of parameters/processes involved in therapeutic protein production, the analytical methodologies employed for glycosylation monitoring and control, as well as strategies that are being explored to use this property to improve therapeutic protein efficacy (glycoengineering). This work reviews the main findings on these subjects, providing an up-to-date source of information to support further studies. 23910516 Periodontal Disease and Recurrent Vascular Events in Stroke/Transient Ischemic Attack Patients. Periodontal disease (PD) has been shown to be associated with incident stroke. We investigated whether PD is independently associated with recurrent vascular events and certain inflammatory markers in stroke/transient ischemic attack (TIA) patients. In this prospective, longitudinal, hospital-based cohort study, PD was assessed in stroke/TIA patients. High periodontal disease (HPD) was defined as the highest tertile of extent (% of sites) with an attachment loss of 5 mm or more. Serum interleukin-6 (IL-6), high-sensitivity C-reactive protein, and soluble intracellular adhesion molecule 1 (s-ICAM) were measured. The patients were followed for recurrent vascular events-stroke, TIA, myocardial infarction, and vascular death. In the 106 patients who were evaluated, 40 (38%) showed HPD and 27 (26%) had recurrent vascular events over a median of 24 months (range, 12-24 months). HPD patients had higher levels of IL-6 (P = .01) and s-ICAM (P = .03). HPD was associated with recurrent vascular events before (log-rank P = .01; hazard ratio [HR], 2.6; 95% confidence interval [CI], 1.2-5.7) and after adjustment for significant confounders-age and stroke status (HR, 2.5; 95% CI, 1.1-5.5; P = .03); adjustment for possible confounders-age, male, years of education, and cardioembolic strokes (HR, 2.8; 95% CI, 1.2-6.5; P = .02); and adjustment for propensity score that accounted for all potential measured confounders (HR, 2.8; 95% CI, 1.2-6.5; P = .02). There is an independent association between HPD and recurrent vascular events in stroke/TIA patients. HPD is also associated with higher serum levels of IL-6 and s-ICAM. 23666681 Safety and tolerability of intensified, N-terminal pro brain natriuretic peptide-guided compared with standard medical therapy in elderly patients with congestive heart failure: results from TIME-CHF. NT-proBNP-guided therapy results in intensification of medical heart failure (HF) therapy and is suggested to improve outcome. However, it is feared that an intensified, NT-proBNP-guided therapy carries a risk of adverse effects. Therefore, the safety and tolerability of NT-proBNP-guided therapy in the Trial of Intensified vs standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) was assessed. A total of 495 chronic HF patients, aged ≥60, with an LVEF ≤45%, NYHA class ≥II, randomized to NT-proBNP-guided or symptom-guided therapy and ≥1 month follow-up were included in the present safety analysis. All adverse events (AEs) were recorded during the 18-month trial period. A total of 5212 AEs were noted, 433 of them serious. NT-proBNP-guided therapy led to a higher up-titration of HF medication and was well tolerated, with a dropout rate (12% vs. 11%, P = 1.0) and AE profile [number of AEs/patient-year 4.7 (2.8-9.4) vs. 5.4 (2.7-11.4), P = 0.69; number of severe AEs/patient-year 0.7 (0-2.7) vs. 1.3 (0-3.9), P = 0.21] similar to that of symptom-guided therapy, although most subjects in both treatment groups (96% vs. 95%, P = 0.55) experienced at least one AE. Age and number of co-morbidities were associated with AEs and interacted with the safety profile of NT-proBNP-guided therapy: positive effects were more frequent in younger and less co-morbid patients whereas potential negative effects-although small and related to non-severe AEs only-were only seen in the older and more co-morbid patients. NT-proBNP-guided therapy is safe in elderly and highly co-morbid HF patients. Trial registration ISRCTN43596477. 23649348 Degradation of polyvinyl alcohol under mechanothermal stretching. Mechanical and thermal properties of polyvinyl alcohol (PVA) are characterized and analyzed using in situ X-ray photoelectron spectroscopy (XPS) and quantum chemistry calculations. It is found that the carbon peaks-commonly used as the reference for spectroscopic analysis-shift under mechanical and thermal stretching. Results also indicate that, at different temperatures and among the various functional groups present in PVA, the carbon in the C-O group is the most stable. Computational calculations showed that Hartree-Fock/10-31G (d) reproduces the binding energy of core carbon electrons with an accuracy of 95 %, which is enough to characterize bonds, allowing the results of the spectroscopic analysis to be corroborated. 23932451 Synthesis and biological evaluation of berberine-thiophenyl hybrids as multi-functional agents: Inhibition of acetylcholinesterase, butyrylcholinesterase, and Aβ aggregation and antioxidant activity. A series of berberine-thiophenyl hybrids were designed, synthesised, and evaluated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and β-amyloid (Aβ) aggregation and as antioxidants. Among these hybrids, compounds 4f and 4i, berberine linked with o-methylthiophenyl and o-chlorothiophenyl by a 2-carbon spacer, were observed to be potent inhibitors of AChE, with IC50 values of 0.077 and 0.042μM, respectively. Of the tested compounds, 4i was also the most potent inhibitor of BuChE, with an IC50 value of 0.662μM. Kinetic studies and molecular modelling simulations of the AChE-inhibitor complex indicated that a mixed-competitive binding mode existed for these berberine derivatives. The biological studies also demonstrated that these hybrids displayed interesting activities, including Aβ aggregation inhibition and antioxidant properties. 23848460 Cell length growth in fission yeast: an analysis of its bilinear character and the nature of its rate change transition. During their mitotic cycle, cylindrical fission yeast cells grow exclusively at their tips. Length growth starts at birth and halts at mitotic onset when the cells begin to prepare for division. While the growth pattern was initially considered to be exponential, during the last three decades an increasing amount of evidence indicated that it is rather a bilinear function [two linear segments separated by a rate change point (RCP)]. The main focus of this work was to clarify this and to elucidate the further question of whether the rate change occurs abruptly at the RCP or more smoothly during a transition period around it. We have analyzed the individual growth patterns obtained by time-lapse microscopy of 60 wild-type cells separately as well as that of the 'average' cell generated from their superposition. Linear, exponential, and bilinear functions were fitted to the data, and their suitability was compared using objective model selection criteria. This analysis found the overwhelming majority of the cells (70%) to have a bilinear growth pattern with close to half of them showing a smooth and not an abrupt transition. The growth pattern of the average cell was also found to be bilinear with a smooth transition. 23623320 Development and assessment of healthy properties of meat and meat products designed as functional foods. This review deals with the two major aspects to be considered in the context of meat-based functional foods and human health. One involves the different strategies used to improve (increase or reduce) the presence of bioactive (healthy and unhealthy) compounds in meat and meat products in order to develop potential meat-based functional foods; these strategies are basically concerned with animal production practices, meat processing and storage, distribution and consumption conditions. Since the link between the consumption of those foods and their potentially beneficial effects (improving health and/or reducing the risk of several chronic diseases) needs to be demonstrated scientifically, the second aspect considered is related to intervention studies to examine the functional capacity of meat-based potentially functional foods in humans, discussing how the functionality of a food can be assessed in terms of its effects on health in relation to both target body functions and risk factors. 23708531 Colorimetric detection of ractopamine and salbutamol using gold nanoparticles functionalized with melamine as a probe. A highly selective and sensitive method is developed for colorimetric detection of ractopamine and salbutamol using gold nanoparticles (AuNPs) functionalized with melamine (MA), respectively. The presence of these β-agonists induces the aggregation of gold nanoparticles through hydrogen-bonding interaction that was accompanied by a distinct change in color and optical properties, which could be monitored by a UV-vis spectrophotometer or even naked eyes. This process caused a significant decrease in the absorbance ratio (A670 nm/A520 nm) of melamine-gold nanoparticles (MA-AuNPs), and the color changed from wine red to blue. The systems exhibited a wide liner range, from 1×10(-10)M to 5×10(-7)mol/L with a correlation coefficient of 0.995 for ractopamine, and 1×10(-10)M to 1×10(-5)mol/L with a correlation coefficient of 0.996 for salbutamol, with measuring the absorbance ratio (A670 nm/A520 nm). The detection limit of these β-agonists is as low as 1×10(-11)mol/L. Particularly, the developed method has been applied to the analysis of real swine feed samples and has achieved satisfactory results. 23518194 Novel filtration markers as predictors of all-cause and cardiovascular mortality in US adults. New filtration markers, including β-trace protein (BTP) and β₂-microglobulin (B2M), may, similar to cystatin C, enable a stronger prediction of mortality compared to serum creatinine-based estimated glomerular filtration rate (eGFRcr). We sought to evaluate these mortality associations in a representative sample of US adults. Prospective cohort study. 6,445 adults 20 years or older from the Third National Health and Nutrition Examination Survey (1988-1994) with mortality linkage through December 31, 2006. Serum cystatin C, BTP, and B2M levels and eGFRcr categorized into quintiles, with the highest quintile (lowest for eGFRcr) split into tertiles (subquintiles Q5a-Q5c). All-cause, cardiovascular disease, and coronary heart disease mortality. Demographic- and multivariable-adjusted Cox proportional hazard models. During follow-up, 2,392 deaths (cardiovascular, 1,079; coronary heart disease, 605) occurred. Levels of all 4 filtration markers were associated with mortality risk after adjusting for demographics (P trend<0.02). Adjusted for mortality risk factors, compared to the middle quintile, the highest subquintiles for cystatin C (Q5c: HR, 1.94; 95% CI, 1.43-2.62), BTP (Q5c: HR, 2.14; 95% CI, 1.56-2.94), and B2M (Q5c: HR, 2.58; 95% CI, 1.96-3.41) were associated with increased all-cause mortality risk, whereas the association was weaker for eGFRcr (Q5c: HR, 1.31; 95% CI, 0.84-2.04). Associations persisted for the novel markers and not for eGFRcr at eGFRcr ≥60 mL/min/1.73 m². Trends were similar for cardiovascular disease and coronary heart disease mortality. Single measurements of markers from long-term stored samples. The strong association of cystatin C level with mortality compared with serum creatinine estimates is shared by BTP and B2M. This supports the utility of alternative filtration markers beyond creatinine when improved risk prediction related to decreased GFR is needed. 23814019 Integrated phosphoproteomic and metabolomic profiling reveals NPM-ALK-mediated phosphorylation of PKM2 and metabolic reprogramming in anaplastic large cell lymphoma. The mechanisms underlying the pathogenesis of the constitutively active tyrosine kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expressing anaplastic large cell lymphoma are not completely understood. Here we show using an integrated phosphoproteomic and metabolomic strategy that NPM-ALK induces a metabolic shift toward aerobic glycolysis, increased lactate production, and biomass production. The metabolic shift is mediated through the anaplastic lymphoma kinase (ALK) phosphorylation of the tumor-specific isoform of pyruvate kinase (PKM2) at Y105, resulting in decreased enzymatic activity. Small molecule activation of PKM2 or expression of Y105F PKM2 mutant leads to reversal of the metabolic switch with increased oxidative phosphorylation and reduced lactate production coincident with increased cell death, decreased colony formation, and reduced tumor growth in an in vivo xenograft model. This study provides comprehensive profiling of the phosphoproteomic and metabolomic consequences of NPM-ALK expression and reveals a novel role of ALK in the regulation of multiple components of cellular metabolism. Our studies show that PKM2 is a novel substrate of ALK and plays a critical role in mediating the metabolic shift toward biomass production and tumorigenesis. 23619409 Genetically and environmentally mediated divergence in lateral line morphology in the Trinidadian guppy (Poecilia reticulata). Fish and other aquatic vertebrates use their mechanosensory lateral line to detect objects and motion in their immediate environment. Differences in lateral line morphology have been extensively characterized among species; however, intraspecific variation remains largely unexplored. In addition, little is known about how environmental factors modify development of lateral line morphology. Predation is one environmental factor that can act both as a selective pressure causing genetic differences between populations, and as a cue during development to induce plastic changes. Here, we test whether variation in the risk of predation within and among populations of Trinidadian guppies (Poecilia reticulata) influences lateral line morphology. We compared neuromast arrangement in wild-caught guppies from distinct high- and low-predation population pairs to examine patterns associated with differences in predation pressure. To distinguish genetic and environmental influences, we compared neuromast arrangement in guppies from different source populations reared with and without exposure to predator chemical cues. We found that the distribution of neuromasts across the body varies between populations based on both genetic and environmental factors. To the best of our knowledge, this study is the first to demonstrate variation in lateral line morphology based on environmental exposure to an ecologically relevant stimulus. 23199762 Aberrant resting-state connectivity in non-psychotic individuals with auditory hallucinations. Although auditory verbal hallucinations (AVH) are a core symptom of schizophrenia, they also occur in non-psychotic individuals, in the absence of other psychotic, affective, cognitive and negative symptoms. AVH have been hypothesized to result from deviant integration of inferior frontal, parahippocampal and superior temporal brain areas. However, a direct link between dysfunctional connectivity and AVH has not yet been established. To determine whether hallucinations are indeed related to aberrant connectivity, AVH should be studied in isolation, for example in non-psychotic individuals with AVH. Method Resting-state connectivity was investigated in 25 non-psychotic subjects with AVH and 25 matched control subjects using seed regression analysis with the (1) left and (2) right inferior frontal, (3) left and (4) right superior temporal and (5) left parahippocampal areas as the seed regions. To correct for cardiorespiratory (CR) pulsatility rhythms in the functional magnetic resonance imaging (fMRI) data, heartbeat and respiration were monitored during scanning and the fMRI data were corrected for these rhythms using the image-based method for retrospective correction of physiological motion effects RETROICOR. In comparison with the control group, non-psychotic individuals with AVH showed increased connectivity between the left and the right superior temporal regions and also between the left parahippocampal region and the left inferior frontal gyrus. Moreover, this group did not show a negative correlation between the left superior temporal region and the right inferior frontal region, as was observed in the healthy control group. Aberrant connectivity of frontal, parahippocampal and superior temporal brain areas can be specifically related to the predisposition to hallucinate in the auditory domain. 23865685 Targeted expression of SbMATE in the root distal transition zone is responsible for sorghum aluminum resistance. Aluminum (Al) toxicity is one of the major limiting factors for crop production on acid soils that comprise significant portions of the world's lands. Aluminum resistance in the cereal crop Sorghum bicolor is mainly achieved by Al-activated root apical citrate exudation, which is mediated by the plasma membrane localized citrate efflux transporter encoded by SbMATE. Here we precisely localize tissue- and cell-specific Al toxicity responses as well as SbMATE gene and protein expression in root tips of an Al-resistant near-isogenic line (NIL). We found that Al induced the greatest cell damage and generation of reactive oxygen species specifically in the root distal transition zone (DTZ), a region 1-3 mm behind the root tip where transition from cell division to cell elongation occurs. These findings indicate that the root DTZ is the primary region of root Al stress. Furthermore, Al-induced SbMATE gene and protein expression were specifically localized to the epidermal and outer cortical cell layers of the DTZ in the Al-resistant NIL, and the process was precisely coincident with the time course of Al induction of SbMATE expression and the onset of the recovery of roots from Al-induced damage. These findings show that SbMATE gene and protein expression are induced when and where the root cells experience the greatest Al stress. Hence, Al-resistant sorghum plants have evolved an effective strategy to precisely localize root citrate exudation to the specific site of greatest Al-induced root damage, which minimizes plant carbon loss while maximizing protection of the root cells most susceptible to Al damage. 23926887 Decreased Enteric Fatty Acid Amide Hydrolase Activity is Associated with Colonic Inertia in Slow Transit Constipation. Constipation is one of the most common chronic digestive complaints. Gastrointestinal transit studies have divided it into three patterns: normal transit, slow-transit constipation (STC) and outlet obstruction. It has been demonstrated that STC patients respond poorly to standard therapies, and the etiology of STC remains poorly understood. Animal studies have also shown that fatty acid amide hydrolase(FAAH) controls intestinal motility through its putative receptors or nonreceptor-mediated pathways. However, the role of FAAH in STC has not been elaborated. A case series was carried out on thirty-two STC patients fulfilling the Rome II criteria and on twenty-four controls. All of the subjects underwent a laparotomy in Shengjing Hospital. Colonic specimens were obtained and used for FAAH expression analysis, enzyme activity assay and cannabinoids detection. FAAH immunoreactivity occurred in the enteric neurons and in the surface epithelial and glands. The expression level and enzyme activity of FAAH in the STC group were both significantly lower than those in the control group (P<0.05). The amounts of anandamide, 2-AG, and PEA, which are negatively correlated with enzyme activity, were significantly higher in the constipation group than that in the control group. In the STC group, CB1 immunoreactivity occurred predominantly in the submucosal and myenteric fibers which were obviously strong and wave-like in their appearance. Enteric ganglions decreased or disappeared. The tone of the enteric cannabinoids system is disturbed in STC, and the decreased enteric FAAH activity contributes to colonic inertia in slow transit constipation. 23193284 PTMcode: a database of known and predicted functional associations between post-translational modifications in proteins. Post-translational modifications (PTMs) are involved in the regulation and structural stabilization of eukaryotic proteins. The combination of individual PTM states is a key to modulate cellular functions as became evident in a few well-studied proteins. This combinatorial setting, dubbed the PTM code, has been proposed to be extended to whole proteomes in eukaryotes. Although we are still far from deciphering such a complex language, thousands of protein PTM sites are being mapped by high-throughput technologies, thus providing sufficient data for comparative analysis. PTMcode (http://ptmcode.embl.de) aims to compile known and predicted PTM associations to provide a framework that would enable hypothesis-driven experimental or computational analysis of various scales. In its first release, PTMcode provides PTM functional associations of 13 different PTM types within proteins in 8 eukaryotes. They are based on five evidence channels: a literature survey, residue co-evolution, structural proximity, PTMs at the same residue and location within PTM highly enriched protein regions (hotspots). PTMcode is presented as a protein-based searchable database with an interactive web interface providing the context of the co-regulation of nearly 75 000 residues in >10 000 proteins. 22956307 Role of TNF-α in renal damage in mice showing hepatic steatosis induced by high fat diet. The present study was designed to investigate the role of TNF-α in renal damage observed in mice with hepatic steatosis. We induced hepatic steatosis in mice using high fat diet and treated mice with ectanercept at the dose sufficient to block TNF-α receptors or vehicle for 1 month. Plasma TNF-α, total cholesterol (TC), triglyceride (TG), LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C) were determined at the end of this treatment. Renal damage was identified by histologic observation and the higher of serum blood urea nitrogen (BUN) and creatinine. Also, changes of PPAR-δ in kidney and renal mesangial cell (RMC) were analyzed using Western blot. Plasma TNF-α was markedly raised in mice showing hepatic steatosis. However, the levels of blood lipids (TC, TG, HDL-C, and LDL-C) and TNF-α were not modified by the treatment of etanercept although the hepatic steatosis has been improved. Etanercept shows renal protection from histological identification and recovery of serum BUN and creatinine levels. Moreover, restoration of PPAR-δ expression by etanercept was observed in mice kidney. Direct effect of TNF-α on PPAR-δ expression was also characterized in RMC cell. We suggest that renal damage in mice with hepatic steatosis is mainly induced by increase of TNF-α through the decrease of renal PPAR-δ. Etanercept could block TNF-α receptors to restore PPAR-δ and improve renal function in mice with hepatic steatosis. 23649969 Aging of sensorimotor processes: a systematic study in Fitts' task. Though age-related decrease in information-processing capacities is hypothesized to be a prominent cause of behavioral slowing, it has been scarcely systematically studied in goal-directed motor tasks. The present study investigated how the decrease in information processing affects the sensorimotor processes underlying the control of a discrete Fitts' task. The index of difficulty (ID) of the task was manipulated using changes in either target distance (D) or target width (W). In each manipulation, movement (MTs), acceleration (ATs) and deceleration times (DTs) of young and older participants were compared across eight ID levels. They were analyzed with efficiency functions, state traces and Brinley plots. Our results showed that older participants were always slower. However, in both age groups, MTs were longer in D manipulation, which resulted from a slowing of both ATs and DTs, while W manipulation affected mainly DTs. In D manipulation, equivalent age-related slowing ratios were observed for AT and DT (1.3). In W manipulation, ATs of older participants were additively slower than those of young participants. Conversely, DTs presented a multiplicative slowing ratio of 1.3. These findings showed that ID manipulations differentially loaded information processing in the nervous system and that age-related slowing of multisensory control processes was independent of the manipulated dimension. Nevertheless, ID manipulations revealed different age-related adaptations to task constraints, suggesting that D and W manipulations are complementary means to assess age-related slowing of the processes involved in target-directed rapid-aiming tasks, with D scaling being more specific to capture the slowing of force-impulse control. 23827228 Chronic ketamine produces altered distribution of parvalbumin-positive cells in the hippocampus of adult rats. The underlying mechanisms of schizophrenia pathogenesis are not well understood. Increasing evidence supports the glutamatergic hypothesis that posits a hypofunction of the N-methyl d-aspartate (NMDA) receptor on specific gamma amino-butyric acid (GABA)-ergic neurons may be responsible for the disorder. Alterations in the GABAergic system have been observed in schizophrenia, most notably a change in the expression of parvalbumin (PV) in the cortex and hippocampus. Several reports also suggest abnormal neuronal migration may play a role in the etiology of schizophrenia. The current study examined the positioning and distribution of PV-positive cells in the hippocampus following chronic treatment with the NMDA receptor antagonist ketamine. A robust increase was found in the number of PV-positive interneurons located outside the stratum oriens (SO), the layer where most of these cells are normally localized, as well as an overall numerical increase in CA3 PV cells. These results suggest ketamine leads to an abnormal distribution of PV-positive cells, which may be indicative of aberrant migratory activity and possibly related to the Morris water maze deficits observed. These findings may also be relevant to alterations observed in schizophrenia populations. 22889206 Biotransformation of serotonin derivatives by the larvae of common cutworm (Spodoptera litura). Seven serotonin derivatives (1-7) were biotransformed using larvae of Spodoptera litura. N-p-methoxy cinnamoyl serotonin (3) was converted into its O-demethylated compound, N-p-coumaroyl serotonin (2). Furthermore, N-feruloyl serotonin (5) and N-isoferuloyl serotonin (6) were converted into, two new compounds, N-feruloyl serotonin-4'-O-β-D-glucopyranoside (8) and N-isoferuloyl serotonin-3'-O-β-D-glucopyranoside (9), respectively. These structures were established by IR, 1D-NMR and 2D-NMR spectral studies. 23468116 A cost-effective solution for the reliable determination of cell numbers of microorganisms in liquid culture. The concentration of microorganisms in growth medium is an important parameter in microbiological research. One of the approaches to determine this parameter is based on the physical interaction of small particles with light that results in light scattering. Table-top spectrophotometers can be used to determine the scattering properties of a sample as a change in light transmission. However, a portable, reliable, and maintenance-free instrument that can be built from inexpensive parts could provide new research opportunities. In this report, we show how to build such an instrument. This instrument consists of a low power monochromatic light-emitting diode, a monolithic photodiode, and a microcontroller. We demonstrate that this instrument facilitates the precise determination of cell concentrations for the bacteria Escherichia coli and Pseudomonas aeruginosa as well as the cyanobacterium Synechocystis sp. PCC 6803 and the green alga Chlamydomonas reinhardtii. 23930940 Negatively Charged Metal Oxide Nanoparticles Interact with the 20S Proteasome and Differentially Modulate Its Biologic Functional Effects. The multicatalytic ubiquitin-proteasome system (UPS) carries out proteolysis in a highly orchestrated way and regulates a large number of cellular processes. Deregulation of the UPS in many disorders has been documented. In some cases, such as carcinogenesis, elevated proteasome activity has been implicated in disease development, while the etiology of other diseases, such as neurodegeneration, includes decreased UPS activity. Therefore, agents that alter proteasome activity could suppress as well as enhance a multitude of diseases. Metal oxide nanoparticles, often developed as diagnostic tools, have not previously been tested as modulators of proteasome activity. Here, several types of metal oxide nanoparticles were found to adsorb to the proteasome and show variable preferential binding for particular proteasome subunits with several peptide binding "hotspots" possible. These interactions depend on the size, charge, and concentration of the nanoparticles and affect proteasome activity in a time-dependent manner. Should metal oxide nanoparticles increase proteasome activity in cells, as they do in vitro, unintended effects related to changes in proteasome function can be expected. 23597419 SNP in TXNRD2 associated with radiation-induced fibrosis: a study of genetic variation in reactive oxygen species metabolism and signaling. The aim of the study was to identify noninvasive markers of treatment-induced side effects. Reactive oxygen species (ROS) are generated after irradiation, and genetic variation in genes related to ROS metabolism might influence the level of radiation-induced adverse effects (AEs). 92 breast cancer (BC) survivors previously treated with hypofractionated radiation therapy were assessed for the AEs subcutaneous atrophy and fibrosis, costal fractures, lung fibrosis, pleural thickening, and telangiectasias (median follow-up time 17.1 years). Single-nucleotide polymorphisms (SNPs) in 203 genes were analyzed for association to AE grade. SNPs associated with subcutaneous fibrosis were validated in an independent BC survivor material (n=283). The influence of the studied genetic variation on messenger ribonucleic acid (mRNA) expression level of 18 genes previously associated with fibrosis was assessed in fibroblast cell lines from BC patients. Subcutaneous fibrosis and atrophy had the highest correlation (r=0.76) of all assessed AEs. The nonsynonymous SNP rs1139793 in TXNRD2 was associated with grade of subcutaneous fibrosis, the reference T-allele being more prevalent in the group experiencing severe levels of fibrosis. This was confirmed in another sample cohort of 283 BC survivors, and rs1139793 was found significantly associated with mRNA expression level of TXNRD2 in blood. Genetic variation in 24 ROS-related genes, including EGFR, CENPE, APEX1, and GSTP1, was associated with mRNA expression of 14 genes previously linked to fibrosis (P≤.005). Development of subcutaneous fibrosis can be associated with genetic variation in the mitochondrial enzyme TXNRD2, critically involved in removal of ROS, and maintenance of the intracellular redox balance. 23883297 Predictors of reading fluency in Italian orthography: Evidence from a cross-sectional study of primary school students. This study investigates the role of linguistic and visuospatial attentional processes in predicting reading fluency in typical Italian readers attending primary school. Tasks were administered to 651 children with reading fluency z scores > -1.5 standard deviation to evaluate their phonological awareness, rapid automatized naming (RAN), verbal short-term memory, vocabulary, visual search skills, verbal-visual recall, and visual-spatial attention. Hybrid models combining confirmatory factor analysis and path analysis were used to evaluate the data obtained from younger (first and second grade) and older (third-fifth grade) children, respectively. The results showed that phonological awareness and RAN played a significant role among younger children, while also vocabulary, verbal short-term memory, and visuospatial attention were significant factors among older children. 22802575 Abstract encoding of auditory objects in cortical activity patterns. The human brain is thought to process auditory objects along a hierarchical temporal "what" stream that progressively abstracts object information from the low-level structure (e.g., loudness) as processing proceeds along the middle-to-anterior direction. Empirical demonstrations of abstract object encoding, independent of low-level structure, have relied on speech stimuli, and non-speech studies of object-category encoding (e.g., human vocalizations) often lack a systematic assessment of low-level information (e.g., vocalizations are highly harmonic). It is currently unknown whether abstract encoding constitutes a general functional principle that operates for auditory objects other than speech. We combined multivariate analyses of functional imaging data with an accurate analysis of the low-level acoustical information to examine the abstract encoding of non-speech categories. We observed abstract encoding of the living and human-action sound categories in the fine-grained spatial distribution of activity in the middle-to-posterior temporal cortex (e.g., planum temporale). Abstract encoding of auditory objects appears to extend to non-speech biological sounds and to operate in regions other than the anterior temporal lobe. Neural processes for the abstract encoding of auditory objects might have facilitated the emergence of speech categories in our ancestors. 23808367 The past, present and future of minimally invasive therapy in urology: A review and speculative outlook. Abstract Introduction: Twenty-five years of SMIT represents an important date. In this article we want to elaborate the development of minimally invasive surgery in urology during the last three decades and try to look 25 years ahead. Material and methods: As classical scenarios to demonstrate the changes which have revolutionized surgical treatment in urology, we have selected the management of urolithiasis, renal tumour, and localized prostate cancer. This was based on personal experience and a review of the recent literature on MIS in Urology on a MEDLINE/PUBMED research. For the outlook to the future, we have taken the expertise of two senior urologists, middle-aged experts, and upcoming junior fellows, respectively. Results: Management of urolithiasis has been revolutionized with the introduction of non-invasive extracorporeal shock wave lithotripsy (ESWL) and minimally invasive endourology in the mid-eighties of the last century obviating open surgery. This trend has been continued with perfection and miniaturization of endourologic armamentarium rather than significantly improving ESWL. The main goal is now to get rid of the stone in one session rather in multiple non-invasive treatment sessions. Stone treatment 25 years from today will be individualized by genetic screening of stone formers, using improved ESWL-devices for small stones and transuretereal or percutaneous stone retrieval for larger and multiple stones. Management of renal tumours has also changed significantly over the last 25 years. In 1988, open radical nephrectomy was the only therapeutic option for renal masses. Nowadays, tumour size determines the choice of treatment. Tumours >4 cm are usually treated by laparoscopic nephrectomy, smaller tumours, however, can be treated either by open, laparoscopic or robot-assisted partial nephrectomy. For patients with high co-morbidity focal tumour ablation or even active surveillance represents a viable option. In 25 years, imaging of tumours will further support early diagnosis, but will also be able to determine the pathohistological pattern of the tumour to decide whether the patient requires removal, ablation or active surveillance. Management of localized prostate cancer underwent significant changes as well. 25 years ago open retropubic nerve-sparing radical prostatectomy was introduced as the optimal option for effective treatment of the cancer providing minimal side-effects. Basically, the same operation is performed today, but with robot-assisted laparoscopic techniques providing 7-DOF instruments, 3D-vision and tenfold magnification and enabling the surgeon to work in a sitting position at the console. In 25 years, prostate cancer may be managed in most cases by focal therapy and/or genetically targeting therapy. Only a few patients may still require robot-assisted removal of the entire gland. Discussion: There has been a dramatic change in the management of the most frequent urologic diseases almost completely replacing open surgery by minimally invasive techniques. This was promoted by technical realisation of physical principles (shock waves, optical resolution, master-slave system) used outside of medicine. The future of medicine may lie in translational approaches individualizing the management based on genetic information and focalizing the treatment by further improvement of imaging technology. 23872488 A new era: endoscopic tissue transplantation. To describe basic principles of tissue engineering with emphasis on the potential role of gastrointestinal endoscopy in regenerative medicine. Stricturing associated with endoscopic submucosal resection and circumferential endoscopic mucosal resection can be prevented through transplantation of autologous epidermal cell sheets or seeded decellularized biological scaffolds. Lower esophageal sphincter augmentation through injection of muscle-derived cells is a novel potential treatment for gastroesophageal reflux disease. Stem cell derived tissue has been used to repair injured colon in a mouse model of colitis. A bioengineered internal anal sphincter has been successfully implanted in mice and showed preserved functionality. The immediate foreseeable application of tissue engineering in gastrointestinal endoscopy is in the field of mucosal repair after acute injury. Tissue regeneration can be achieved through expansion of autologous somatic cells or by induction of multipotent or pluripotent stem cells. Advances in cellular scaffolding have made bioengineering of complex tissues a reality. Tissue engineering in endoscopy is also being pioneered by studies looking at enteral sphincter augmentation and regeneration. The availability of engineered tissue for endoscopic application will increase with advances in cell-culturing techniques. 23566331 Rapid magnetic removal of aqueous heavy metals and their relevant mechanisms using nanoscale zero valent iron (nZVI) particles. Much work is devoted to heavy metal sorption, reduction and relevant mechanisms by nanoscale zero valent iron (nZVI) particle, but fewer studies utilize its magnetic properties in aqueous metal removals. Here, we have investigated the use of nZVI particles both electrosprayed (E-nZVI) and non-electrosprayed (NE-nZVI) with different concentration levels (0.186-1.86 mg/mL) in removing aqueous Cd(II), Cr(IV), and Pb(II) through the magnetic separation means. The effects of the reaction time (5-20 min) and magnetic treatment time (1-30 min) on relevant magnetic removal efficiencies were studied. Metal ion concentration was analyzed using inductively coupled plasma (ICP), and the magnetically obtained metal-nZVI mixtures were further analyzed using X-ray photoelectron spectroscopy (XPS). Results showed that the magnetic removal efficiencies of heavy metals varied with the metal species, nZVI loading, reaction and magnetic separation time. In most cases, use of 1.5 mg/mL E-nZVI or NE-nZVI resulted in removal efficiencies of more than 80% for Pb(II), Cd(II), and Cr(IV). Increasing the magnetic treatment time from 1 to 20 min was shown to lead to ≈ 20% increase in Pb(II) removal efficiency, but no improvements for Cd(II) and Cr(IV). In contrast, increasing the reaction time decreased the Pb(II) removal efficiency, yet no effects observed for Cd(II) and Cr(IV). In general, 1 min reaction and 5 min magnetic treatment were found sufficient to achieve considerable heavy metal removals. For comparable efficiencies, use of magnetic method could significantly reduce nZVI loading. XPS analysis results indicated that atomic percentages of O 1s, Fe 2p, Cd 3d, Pb 4f and Cr 2p varied with metal exposures. Different from Cd(II) and Cr(IV), aqueous iron ions might be possibly present when treating Pb(II). This study demonstrated a rapid heavy metal removal method using the magnetic property of nZVI particles, while contributing to understanding of the relevant removal mechanisms. 23117006 Acetylcholinesterase and agrin: Different functions, similar expression patterns, multiple roles. Acetylcholinesterase (AChE) and agrin play unique functional roles in the neuromuscular junction (NMJ). AChE is a cholinergic and agrin a synaptogenetic component. In spite of their different functions, they share several common features: their targeting is determined by alternative splicing; unlike most other NMJ components they are expressed in both, muscle and motor neuron and both reside on the synaptic basal lamina of the NMJ. Also, both were reported to play various nonjunctional roles. However, while the origin of basal lamina bound agrin is undoubtedly neural, the neural origin of AChE, which is anchored to the basal lamina with collagenic tail ColQ, is elusive. Hypothesizing that motor neuron proteins targeted to the NMJ basal lamina share common temporal pattern of expression, which is coordinated with the formation of basal lamina, we compared expression of agrin isoforms with the expression of AChE-T and ColQ in the developing rat spinal cord at the stages before and after the formation of NMJ basal lamina. Cellular origin of AChE-T and agrin was determined by in situ hybridization and their quantitative levels by RT PCR. We found parallel increase in expression of the synaptogenetic (agrin 8) isoform of agrin and ColQ after the formation of basal lamina supporting the view that ColQ bound AChE and agrin 8 isoform are destined to the basal lamina. Catalytic AChE-T subunit and agrin isoforms 19 and 0 followed different expression patterns. In accordance with the reports of other authors, our investigations also revealed various alternative functions for AChE and agrin. We have already demonstrated participation of AChE in myoblast apoptosis; here we present the evidence that agrin promotes the maturation of heavy myosin chains and the excitation-contraction coupling. These results show that common features of AChE and agrin extend to their capacity to play multiple roles in muscle development. 23731275 MicroRNA-503 suppresses proliferation and cell-cycle progression of endometrioid endometrial cancer by negatively regulating cyclin D1. MicroRNAs (miRNAs) are post-transcriptional inhibitor regulators of gene expression that act by directly binding complementary mRNA and are key determinants of cancer initiation and progression. In this study, we revealed a role for the tumor-suppressor miRNA miR-503 in endometrioid endometrial cancer (EEC) cells. The miR-503 expression level gradually decreases across normal endometrial tissues, endometrial tissues with complex atypical hyperplasia, and EEC tissues. A relatively high level of miR-503 in EEC tissues indicates a longer survival time in EEC patients. The expression of a cell cycle-associated oncogene encoding cyclin D1 (CCND1) was inversely correlated with miR-503 expression in EEC tissues and cell lines. CCND1 has a binding sequence of miR-503 within its 3' untranslated region, and was confirmed to be a direct target of miR-503 by the fluorescent reporter assays. Increasing the miR-503 level in EEC cells suppressed cell viability, colon formation activity and cell-cycle progression, and the inhibited oncogenic phenotypes induced by miR-503 were alleviated by ectopic expression of CCND1 without the untranslated region sequence. Furthermore, in vivo studies also suggested a suppressive effect of miR-503 on EEC cell-derived xenografts. miR-503 increased in cell cycle-arrested EEC cells, and was restored to a normal level in EEC cells after cell cycle re-entry, while CCND1 displayed the opposite expression pattern. Collectively, this study suggested that miR-503 plays a tumor-suppressor role by targeting CCND1. Abnormal suppression of miR-503 leads to an increase in the CCND1 level, which may promote carcinogenesis and progression of EEC. 23294220 Attenuating Staphylococcus aureus Virulence Gene Regulation: A Medicinal Chemistry Perspective. Virulence gene expression in Staphylococcus aureus is tightly regulated by intricate networks of transcriptional regulators and two-component signal transduction systems. There is now an emerging body of evidence to suggest that the blockade of S. aureus virulence gene expression significantly attenuates infection in experimental models. In this Perspective, we will provide insights into medicinal chemistry strategies for the development of chemical reagents that have the capacity to inhibit staphylococcal virulence expression. These reagents can be broadly grouped into four categories: (1) competitive inhibitors of the accessory gene regulator (agr) quorum sensing system, (2) inhibitors of AgrA-DNA interactions, (3) RNAIII transcription inhibitors, and (4) inhibitors of the SarA family of transcriptional regulators. We discuss the potential of specific examples of antivirulence agents for the management and treatment of staphylococcal infections. 23914844 8β-hydroxy-3-oxopimar-15-ene exerts anti-inflammatory effects by inhibiting ROS-mediated activation of the TRAF6-ASK1-p38 signaling pathway. Abstract The flying squirrel's droppings (Pteropus pselaphon) have been used for improving the blood circulation, arresting bleeding to treat hematological disorders, and reducing pain. Here, 8β-hydroxy-3-oxopimar-15-ene (OXO), one of main constituents of P. pselaphon, was examined for its anti-inflammatory activity in murine macrophages. We found that OXO significantly suppressed LPS-induced nitric oxide (NO) without exerting cytotoxic effects on RAW 264.7 cells. OXO inhibited the expression of LPS-induced iNOS and COX-2 protein and their mRNA in a dose-dependent manner. Also, TNF-α, IL-6, and PGE2 secretion was decreased by OXO in LPS-stimulated macrophages. These inflammatory biomarkers were attributed to the suppression of LPS-induced activation of p38 MAPK and subsequent activation of two components of AP-1 (c-Jun and c-Fos), but not of ERK, JNK, NF-κB. Moreover, OXO inhibited LPS-induced intracellular reactive oxygen species (ROS) production and co-incubation of OXO and hydrogen peroxide (H2O2) suppressed the phosphorylation of p38 in a concentration-dependent manner. In addition, OXO completely disrupted the formation of TRAF6-ASK complex in the cells. Therefore, we demonstrate here that OXO can potentially inhibit several biomarkers related to inflammation through inhibition of ROS-mediated activation of TRAF6-ASK1-p38 pathway. 23829186 Solid state manipulation of lornoxicam for cocrystals - physicochemical characterization. Abstract Context: Lornoxicam is an analgesic and anti-inflammatory drug of choice and belongs to Class II (low solubility) of BCS (Biopharmaceutical Classification System). Thus bioavailabilities problems are predominant. Objective: Through crystal engineering approach, a method was developed for obtaining multi-component cocrystals of lornoxicam using pharmaceutically acceptable compounds as guests. Materials and methods: Lornoxicam guest-free form was obtained from solution crystallization. Supramolecular synthon approach indicated that lornoxicam was in orthorhombic form. Further presence of intermolecular hydrogen bonding with layered structures was identified. Solvent drop grinding method permitted the formation of cocrystals of lornoxicam with catechol, resorcinol, benzoic acid, hydroxyquinone and 2,4 dihydroxy benzoic acid, all are capable of forming hydrogen bonding. Results and discussion: Lornoxicam cocrystals exhibited the difference in melting points and decomposition characteristics. The analysis of infrared (IR) indicated the shifting of characteristic bands of lornoxicam. The XPRD (X-Ray Powder Diffraction) pattern indicated the crystallinity of cocrystals and significant difference in 2θ value of intense peaks. Differential scanning calorimetry spectra of cocrystals denoted the changes in fusion endotherms, which are in agreements with melting points. The pH solubility profile of lornoxicam showed sigmoidal curve, which substantiated the pKa-dependent solubility. Lornoxicam cocrystals also exhibited a similar pH-solubility profile. Thus pairing of lornoxicam and coformers in the solution at high pH media was assumed. The in vitro dissolution studies of cocrystals were conducted at pH 4.0. The rapid rate of dissolution of cocrystals was observed in initial 10 min. The extent of dissolution was enhanced by 20% on account of cocrystallization. Conclusion: The lornoxicam cocrystals were obtained with improved physicochemical characteristics. 23911015 Effects of high somatic cell counts in milk on reproductive hormones and oestrus behaviour in dairy cows with special reference to those with concurrent lameness. The present investigation aims to establish the reason(s) why dairy cows with high somatic cell counts (SCCs; >100,000 cells/ml) are less fertile than cows with low SCCs alone. The objective of Study One was to determine whether differences in steroid hormone profiles could explain the low incidence of ovulation in cows with combined High SCC and lameness. Between 30 and 80 days post-partum, animals were scored for SCC and lameness and three groups were formed: Healthy (n=22), High SCC alone (n=12) or High SCC + Lame (n=9). The ovarian follicular phases of all cows were synchronised by administering gonadotrophin releasing hormone (GnRH) followed seven days later by prostaglandin F2alpha (PG). Milk samples were collected daily throughout the entire study period; twice daily during the follicular phase, blood samples were taken and the ovaries were monitored using ultrasonography. Progesterone concentrations were similar in all three groups during each of five specific time periods, i.e. throughout the five days before PG injection, the peri-ovulatory period, on Day 5 and on Day 7, and during the mid luteal phase 12-17 days after ovulation (P>0.13). Mean plasma oestradiol concentrations monitored every 12h during the 36h period before ovulation were similar in all groups (Healthy, 2.80±0.30pg/ml; High SCC alone, 3.82±0.48pg/ml; High SCC+Lame 2.94±0.51pg/ml; P=0.175). The objective of Study Two was to establish whether cows with High SCC (scored and synchronised as above) display different behaviours, especially the intensity and timing of oestrus. Intervals from PG to the onset of oestrus or to the first stand-to-be-mounted (STBM) were longer for the High SCC cows than the Low SCC animals (n=8 and 20; P=0.011 and 0.002, respectively). Also, cows with High SCC tended to have a less intense oestrus and a lower maximum oestrus score per 30-min period than Low SCC cows (P=0.063 and 0.066, respectively). In conclusion, High SCC±lameness did not affect progesterone or twice daily oestradiol profiles but the onset of oestrus was delayed and oestrus tended to be less intense in cows with High SCC. These factors could explain low fertility associated with High SCC. 23969703 X-ray fluorescence measurements of arsenic micro-distribution in human nail clippings using synchrotron radiation. Arsenic (As) distribution in nail clippings from three healthy human subjects was investigated using the microbeam experimental setup of the hard x-ray micro-analysis (HXMA) beamline from the Canadian Light Source (CLS) synchrotron. A pair of toenail and fingernail clippings was collected from each of three subjects (one contributed two fingernail clippings). The fingernail and toenail clippings were embedded in polyester resin and cut in cross-sectional slices with an average thickness of 270 µm. Nine nail clipping cross sections were analyzed from the three subjects. The same method was used to produce five cross sections of nail phantom clippings with concentrations of As ranging from 0 to 20 µg g(-1), in increments of 5 µg g(-1). These samples were used to produce a calibration line for the As Kα peak. The energy of the x-ray beam was set at 13 keV for optimal excitation of As and the beam size was 28 Ã— 10 µm(2). Each sample was analyzed using a point-by-point scanning technique in a 45° beam-sample and 90° beam-detector geometry. The dwelling time was set at 30 s for the human nail clippings and 20 s for the nail phantom clippings, using a step size of 50 µm in both the horizontal and vertical directions for all samples. As concentration for each point was calculated based on the calibration line parameters and the fitted amplitude of the observed As Kα peak. As concentration maps were produced for each nail clipping cross section. The maps show that small regions (<0.1 mm(2)) with higher As concentrations (>1 µg g(-1)) are located predominantly in the ventral and dorsal layers of the nail. The results are in agreement with findings reported in a recent study and can be linked to nail histology and keratin structure. 23798702 Oxygen-coupled Redox Regulation of the Skeletal Muscle Ryanodine Receptor/Ca2+ Release Channel (RyR1): SITES AND NATURE OF OXIDATIVE MODIFICATION. In mammalian skeletal muscle, Ca(2+) release from the sarcoplasmic reticulum (SR) through the ryanodine receptor/Ca(2+)-release channel RyR1 can be enhanced by S-oxidation or S-nitrosylation of separate Cys residues, which are allosterically linked. S-Oxidation of RyR1 is coupled to muscle oxygen tension (pO2) through O2-dependent production of hydrogen peroxide by SR-resident NADPH oxidase 4. In isolated SR (SR vesicles), an average of six to eight Cys thiols/RyR1 monomer are reversibly oxidized at high (21% O2) versus low pO2 (1% O2), but their identity among the 100 Cys residues/RyR1 monomer is unknown. Here we use isotope-coded affinity tag labeling and mass spectrometry (yielding 93% coverage of RyR1 Cys residues) to identify 13 Cys residues subject to pO2-coupled S-oxidation in SR vesicles. Eight additional Cys residues are oxidized at high versus low pO2 only when NADPH levels are supplemented to enhance NADPH oxidase 4 activity. pO2-sensitive Cys residues were largely non-overlapping with those identified previously as hyperreactive by administration of exogenous reagents (three of 21) or as S-nitrosylated. Cys residues subject to pO2-coupled oxidation are distributed widely within the cytoplasmic domain of RyR1 in multiple functional domains implicated in RyR1 activity-regulating interactions with the L-type Ca(2+) channel (dihydropyridine receptor) and FK506-binding protein 12 as well as in "hot spot" regions containing sites of mutation implicated in malignant hyperthermia and central core disease. pO2-coupled disulfide formation was identified, whereas neither S-glutathionylated nor sulfenamide-modified Cys residues were observed. Thus, physiological redox regulation of RyR1 by endogenously generated hydrogen peroxide is exerted through dynamic disulfide formation involving multiple Cys residues. 23837665 First-Principles Characterization of the Energy Landscape and Optical Spectra of Green Fluorescent Protein along the A→I→B Proton Transfer Route. Structures and optical spectra of the green fluorescent protein (GFP) forms along the proton transfer route A→I→B are characterized by first-principles calculations. We show that in the ground electronic state the structure representing the wild-type (wt) GFP with the neutral chromophore (A-form) is lowest in energy, whereas the systems with the anionic chromophore (B- and I-forms) are about 1 kcal/mol higher. In the S65T mutant, the structures with the anionic chromophore are significantly lower in energy than the systems with the neutral chromophore. The role of the nearby amino acid residues in the chromophore-containing pocket is re-examined. Calculations reveal that the structural differences between the I- and B-forms (the former has a slightly red-shifted absorption relative to the latter) are based not on the Thr203 orientation, but on the Glu222 position. In the case of wt-GFP, the hydrogen bond between the chromophore and the His148 residue stabilizes the structures with the deprotonated phenolic ring in the I- and B-forms. In the S65T mutant, concerted contributions from the His148 and Thr203 residues are responsible for a considerable energy gap between the lowest energy structure of the B type with the anionic chromophore from other structures. 23588205 Zebrafish keratocyte explant cultures as a wound healing model system: differential gene expression & morphological changes support epithelial-mesenchymal transition. The control of collective cell migration of zebrafish keratocyte sheets in explant culture is of interest for cell migration and epithelial wound healing and depends on the gene expression profile. In a zebrafish genome array, ∼17.5% of the probe sets were differentially expressed greater than two-fold (p≤0.003) between 1 and 7 days of explant culture. Among the differentially expressed genes were a variety of wound healing-related genes and many of the biomarkers for epithelial-mesenchymal transition (EMT), including a switch from keratin and E-cadherin to vimentin and N-cadherin expression and several EMT-related transcription factors were found to be differentially expressed. Supporting evidence for EMT is seen in both morphological change and rearrangement of the actin cytoskeleton and in expression of cadherins during explant culture with a visible disassembly of the cell sheet. TGFβ1 and TNFα expression were analyzed by qPCR at various time points and peak differential expression of both cytokines occurred at 3 days, indicating that the EMT process is ongoing under conditions routinely used in the study of fish keratocyte motility. These data establish that an EMT process is occurring during zebrafish keratocyte explant culture and support the use of this system as a wound healing model. 23340896 Television Viewing and Low Leisure-Time Physical Activity in Adolescence Independently Predict the Metabolic Syndrome in Mid-Adulthood. OBJECTIVEWe investigated whether television (TV) viewing and low leisure-time physical activity in adolescence predict the metabolic syndrome in mid-adulthood.RESEARCH DESIGN AND METHODSTV viewing habits and participation in leisure-time physical activity at age 16 years were assessed by self-administered questionnaires in a population-based cohort in Northern Sweden. The presence of the metabolic syndrome at age 43 years was ascertained in 888 participants (82% of the baseline sample) using the International Diabetes Federation criteria. Odds ratios (ORs) and CIs were calculated using logistic regression.RESULTSThe overall prevalence of the metabolic syndrome at age 43 years was 26.9%. Adjusted OR for the metabolic syndrome at age 43 years was 2.14 (95% CI 1.24-3.71) for those who reported "watching several shows a day" versus "one show/week" or less and 2.31 (1.13-4.69) for leisure-time physical activity "several times/month" or less compared with "daily" leisure-time physical activity at age 16 years. TV viewing at age 16 years was associated with central obesity, low HDL cholesterol, and hypertension at age 43 years, whereas low leisure-time physical activity at age 16 years was associated with central obesity and triglycerides at age 43 years.CONCLUSIONSBoth TV viewing and low leisure-time physical activity in adolescence independently predicted the metabolic syndrome and several of the metabolic syndrome components in mid-adulthood. These findings suggest that reduced TV viewing in adolescence, in addition to regular physical activity, may contribute to cardiometabolic health later in life. 23778002 Intrusive images and voluntary memory for affective pictures: Contextualization and dual-task interference. The present study addressed the role of context information and dual-task interference during the encoding of negative pictures on intrusion development and voluntary recall. Healthy participants were shown negative pictures with or without context information. Pictures were either viewed alone or concurrently with a visuospatial or verbal task. Participants reported their intrusive images of the pictures in a diary. At follow-up, perceptual and contextual memory was tested. Participants in the context group reported more intrusive images and perceptual voluntary memory than participants in the no context group. No effects of the concurrent tasks were found on intrusive image frequency, but perceptual and contextual memory was affected according to the cognitive load of the task. The analogue method cannot be generalized to real-life trauma and the secondary tasks may differ in cognitive load. The findings challenge a dual memory model of PTSD but support an account in which retrieval strategy, rather than encoding processes, accounts for the experience of involuntary versus voluntary recall. 23777953 Mucosal application of cationic poly(d,l-lactide-co-glycolide) microparticles as carriers of DNA vaccine and adjuvants to protect chickens against infectious bursal disease. Infectious bursal disease virus (IBDV) is an immunosuppressive virus of chickens. The virus protein (VP) 2 induces neutralizing antibodies, which protect chickens against the disease. The aim of this study was to develop a cationic poly(d,l-lactide-co-glycolide) (PLGA) microparticle (MP) based IBDV-VP2 DNA vaccine (MP-IBDV-DNA) for chickens to be delivered orally and by eye drop route. The tested IBDV-VP2 DNA vaccines were immunogenic for specific-pathogen-free chickens and induced an antibody response after intramuscular application. Co-inoculation with a plasmid encoding chicken IL-2 (chIL-2) or CpG-ODN did not significantly improve protection against IBDV challenge. However, the application of a MP-IBDV-DNA vaccine alone or in combination with a delayed oral and eye drop application of cationic MP loaded with CpG-ODN or chIL-2 improved protection against challenge. The MP-IBDV-DNA-vaccinated chickens showed less pathological and histopathological bursal lesions, a reduced IBDV antigen load as well as T-cell influx into the bursa of Fabricius (BF) compared to the other groups (p<0.05). The addition of chIL-2 loaded MP improved challenge virus clearance from the BF as demonstrated by lower neutralizing antibody titers and reduced IL-4 and IFN-α mRNA expression in the bursa at 7 days postchallenge compared to the other challenged groups. Overall, the efficacy of the IBDV-DNA vaccine was improved by adsorption of the DNA vaccine onto cationic PLGA-MP, which also allowed mucosal application of the DNA vaccine. 23808421 Molecular markers of biomass burning in arctic aerosols. Biomass burning is one of the most important sources of organic matter in the atmosphere as it affects the absorption and scattering of solar radiation, creates cloud condensation nuclei and possibly influences ice and snow albedo. Here we created and validated an analytical method using HPLC/(-)-ESI-MS/MS to determine phenolic compounds (PCLCs): vanillic acid, isovanillic acid, homovanillic acid, syringic acid, syringaldehyde, ferulic acid, p-coumaric acid, and coniferyl aldehyde at trace levels in particulate matter. We analyzed eighteen high-volume air samples from Ny Ålesund (Svalbard) collected during the boreal spring and summer of 2010. Biomass burning molecules including PCLCs (<0.49 μm, mean atmospheric concentration 6 pg m(-3)), levoglucosan (0.004 to 0.682 ng m(-3)) and acrylamide (32 fg m(-3) to 166 fg m(-3)) were present in the sampled aerosols. Levoglucosan concentrations, an unambiguous cellulose combustion tracer, derived from 2010 Russian fires. PCLCs levels in the Ny Alesund atmosphere in different size fractions reflected both long-range transport linked to biomass burning and a terrigenous local source. 23881311 A novel 'pipeline' system for downstream preparation of therapeutic monoclonal antibodies. A novel 'pipeline' system for the preparation of therapeutic monoclonal antibodies (mAb) in a non-GMP compliant environment has been developed. We used sterile silica-gel pipes to connect individual process units, in order to form a fully-enclosed and seamlessly connected system. This 'pipeline' system was used to implement downstream preparation processes for a humanized anti-CD146 mAb, huAA98, which is a therapeutic mAb generated to inhibit cancer-related angiogenesis. The quality assessment of the huAA98 end-product indicated that endotoxin levels were 0.016 EU/ml, protein A levels were 1.08 ng/ml and host cell protein (HCP) was undetectable. Thus, all measures were below the clinical criteria set by the Chinese Pharmacopoeia (Edition 2010). Having passed our proof-of-concept test, this 'pipeline' system can be used as a universal platform for the preparation of mAbs suitable for pre-clinical studies, in a non-GMP compliant laboratory environment. 23906884 Gden: An indicator for European noise maps comparison and to support action plans. Ten years after the approval of the Environmental Noise Directive 2002/49/EC (END) a large experience have been acquired to develop noise maps and action plans: the Noise Observation and Information Service for Europe maintained by the European Environment Agency (EEA) on behalf of the European Commission contains all data delivered in accordance with the END by Members States within the first round of implementation of the END. This large database should be useful to evaluate the pollution of Europe and to guide policy makers to establish best practices. However, local procedures and national methods do not permit a direct comparison of data reported. A comparison within agglomerations in EU is here carried out in order to find suitable indicators to identify most polluted cities despite different methods used. Critical and quiet areas have been assessed in action plans, but national laws and requirements are various, as different indicators used for their identification. The analysis was performed on noise exposure classes distribution, grouping them together using Gden and Gnight indicators to offer a new tool for presenting noise maps of the cities to the public permitting their comparison and for drawing detailed action plans. Strong relationship between these indicators and highly annoyed and highly sleep-disturbed people percentages are obtained. Furthermore, a comparison between Gden and Qcity Noise Scoring for local hot spot identification is carried out for the agglomeration of Pisa, where different transportation noise sources are present. The final goal is to define faster methods for suitable indicators calculation in hot spot identifications. 23900120 Outcome of children with Japanese encephalitis and predictors of outcome in southwestern China. We aimed to investigate the outcome of children with Japanese encephalitis (JE) and to examine the predictors of the outcome. We reviewed the medical records of children with laboratory-confirmed Japanese encephalitis hospitalized in Children's Hospital of Chongqing Medical University in 2010. At least six months after discharging from hospital, the outcome of patients was assessed with the Liverpool Outcome Score. We also examined the predictors of the outcome by using multiple logistic regression analysis. Of the 108 children with JE, 87 patients with full available information were included. Eight (9%) died in hospital or before follow-up. Six (7%) had severe sequelae greatly impairing their functions and likely to make them dependent. Nine (10%) had moderate sequelae mildly affecting their functions and probably compatible with independent living. Sixteen (18%) had minor sequelae with mild effects on function, personality change or on medication. Forty-eight (55%) demonstrated full recovery. A combination of ≧2 witnessed convulsions and abnormal breathing pattern predicted a poor outcome with 78% sensitivity and 98% specificity. Death and severe disability are common in children with JE. Seizures and abnormal breathing pattern may predict a poor outcome. 23946098 An angiographic atlas of intracranial arterial diameters associated with cerebral aneurysms. The successful treatment of intracranial aneurysms is dependent on a full understanding of the anatomic relationship of a given aneurysm to its parent artery(s) and nearby branches. Furthermore, new endovascular technologies are often limited by size constraints. Currently, there is no complete atlas describing diameters for each major intracranial arterial segment. We sought to obtain these data by performing a systematic analysis of selected cerebral angiography images from the International Study of Unruptured Intracranial Aneurysms (ISUIA). Four hundred and forty-five patients with unruptured intracranial aneurysms from the ISUIA database were reviewed. Using previously described techniques, artery diameters were measured for all arteries involved in the aneurysm neck for each patient. Measurements were obtained from 695 different aneurysm-associated arterial segments among 445 patient angiograms (mean 1.6 measurements per aneurysm). Artery diameters, mean, median, SEM and IQRs based upon the different arterial segments are presented. This angiographic almanac of aneurysm-associated intracranial arterial diameters may be of benefit in establishing standard norms through which devices, protocols and research aims may be developed. 23706343 Experts and beginners benefit from three-dimensional echocardiography: a multicenter study on the assessment of mitral valve prolapse. Three-dimensional (3D) transesophageal echocardiography (TEE) has been claimed to provide more information than two-dimensional (2D) TEE in the localization of mitral valve prolapse (MVP). However, most studies have been performed by experts in echocardiography, without accounting for differences in training or expertise. This multicenter study was designed to assess the differences between experts and inexperienced echocardiographers in localizing MVP and ruptured chordae tendineae using 2D and real-time 3D TEE. Thirty-six observers from 10 institutions in Germany and Switzerland interpreted 2D and 3D transesophageal echocardiographic images from six patients selected to represent a large spectrum of MVP diversity. Surgical findings served as a reference. Individual performance in the prediction of pathology was scored. Differences between 15 experts and 21 beginners in TEE were assessed, and the benefits conferred by 3D TEE were compared. Both study groups scored significantly higher when interpreting 3D transesophageal echocardiographic images (P ≤ .001). The experts were superior in 2D MVP localization (14.8%; P ≤ .001), a difference that diminished with 3D TEE (1.4%; P = .41). The benefit of access to 3D information for MVP localization was greater for inexperienced echocardiographers compared with experts (P < .001). The reported diagnostic advantage of 3D TEE over 2D TEE in MVP assessment for expert echocardiographers can be transferred to inexperienced echocardiographers. Inexperienced echocardiographers benefit from the technology to a greater extent than their expert colleagues. 23936219 Protein Phosphatase 1ß Limits Ring Canal Constriction during Drosophila Germline Cyst Formation. Germline cyst formation is essential for the propagation of many organisms including humans and flies. The cytoplasm of germline cyst cells communicate with each other directly via large intercellular bridges called ring canals. Ring canals are often derived from arrested contractile rings during incomplete cytokinesis. However how ring canal formation, maintenance and growth are regulated remains unclear. To better understand this process, we carried out an unbiased genetic screen in Drosophila melanogaster germ cells and identified multiple alleles of flapwing (flw), a conserved serine/threonine-specific protein phosphatase. Flw had previously been reported to be unnecessary for early D. melanogaster oogenesis using a hypomorphic allele. We found that loss of Flw leads to over-constricted nascent ring canals and subsequently tiny mature ring canals, through which cytoplasmic transfer from nurse cells to the oocyte is impaired, resulting in small, non-functional eggs. Flw is expressed in germ cells undergoing incomplete cytokinesis, completely colocalized with the Drosophila myosin binding subunit of myosin phosphatase (DMYPT). This colocalization, together with genetic interaction studies, suggests that Flw functions together with DMYPT to negatively regulate myosin activity during ring canal formation. The identification of two subunits of the tripartite myosin phosphatase as the first two main players required for ring canal constriction indicates that tight regulation of myosin activity is essential for germline cyst formation and reproduction in D. melanogaster and probably other species as well. 23921803 Cloning and Mutagenesis of Catechol 2,3-Dioxygenase Gene from the Gram-Positive Planococcus sp. Strain S5. In this study, the catechol 2,3-dioxygenase gene that encodes a 307- amino-acid protein was cloned from Planococcus sp. S5. The protein was identified to be a member of the superfamily I, subfamily 2A of extradiol dioxygenases. In order to study residues and regions affecting the enzyme's catalytic parameters, the c23o gene was randomly mutated by error-prone PCR. The wild-type enzyme and mutants containing substitutions within either the C-terminal or both domains were functionally produced in Escherichia coli and their activity towards catechol was characterized. The C23OB65 mutant with R296Q substitution showed significant tolerance to acidic pH with an optimum at pH 5.0. In addition, it showed activity more than 1.5 as high as that of the wild type enzyme and its Km was 2.5 times lower. It also showed altered sensitivity to substrate inhibition. The results indicate that residue at position 296 plays a role in determining pH dependence of the enzyme and its activity. Lower activity toward catechol was shown for mutants C23OB58 and C23OB81. Despite lower activity, these mutants showed higher affinity to catechol and were more sensitive to substrate concentration than nonmutated enzyme. 23508652 Clinically silent PML and prolonged immune reconstitution inflammatory syndrome in a patient with multiple sclerosis treated with natalizumab. We report the case of a woman with natalizumab-treated multiple sclerosis (MS) and clinically silent progressive multifocal leukoencephalopathy (PML) with an unusually long preclinical phase, followed by acute symptoms due to development of immune reconstitution inflammatory syndrome (IRIS). Furthermore, the course of the IRIS was prolonged and continued to progress even five months after natalizumab treatment was ceased. This case shows that PML and IRIS can have a considerably variable course in natalizumab-treated MS patients and underlines the need for PML screening in JC virus antibody-positive patients in order to detect clinically silent cases. 23945983 Higher-order repeat structure in alpha satellite DNA is an attribute of hominoids rather than hominids. Alpha satellite DNA (AS), a major DNA component of primate centromeres, is composed of a tandem array of repeat units of approximately 170 bp. The AS of hominids (family Hominidae; humans and great apes) includes sequences organized into higher-order repeat (HOR) structures, with a periodic appearance of multiple copies of the basic repeat units. Here, we identified an HOR in AS of the siamang, a small ape phylogenetically distinct from hominids but included in hominoids (superfamily Hominoidea). We sequenced long stretches of genomic DNA, and found a repetition of blocks consisting of six and four basic repeat units. Thus, AS organization into HOR is an attribute of hominoids, rather than, as currently postulated, hominids. In addition to centromeres, siamangs carry AS in terminal heterochromatin blocks, and it cannot be determined at present whether these HOR-containing AS sequences originate from the centromere or from the terminal heterochromatin. Even if the latter is the case, these sequences might affect the composition of centromeric AS by being transferred to the centromere.Journal of Human Genetics advance online publication, 15 August 2013; doi:10.1038/jhg.2013.87. 23529015 Antinociceptive effect and gastroprotective mechanisms of 3,5-diprenyl-4-hydroxyacetophenone from Ageratina pichinchensis. The present study aimed to evaluate the antinociceptive activity (in inflammatory and neuropathic pain models) and gastroprotective effect of the 3,5-diprenyl-4-hydroxyacetophenone (HYDP), isolated from Ageratina pichinchensis. The gastroprotective activity of this plant was previously reported by our workgroup, finding encesanescin to be one active compound. The present results show that HYDP reduced nociception in a dose-dependent manner in carrageenan and L5/L6 spinal nerve ligation, with efficacies of 72.6 and 57.1%, respectively, at doses of 100 and 562mg/kg. HYDP also showed gastroprotective activity in the model of ethanol-induced gastric lesion, with a 75.59% maximum inhibition of ulcers at a dose of 100mg/kg. This gastroprotective effect was attenuated by N(G)-nitro-l-arginine methyl ester, indomethacin and N-ethylmaleimide, indicating that NO, prostaglandins and sulfhydryl groups are involved in the mechanisms of action. This is the first evidence, to our knowledge, of the antinociceptive and gastroprotective activities of HYDP. 23296404 Ebullition rates and mercury concentrations in St. Lawrence river sediments and a benthic invertebrate. Ebullition, the release of gas from anaerobic decomposition in sediments, was recorded in a mercury-contaminated depositional zone (Zone 1) of the St. Lawrence River Area of Concern in Cornwall, Ontario, Canada. The aim of the present study was to test if this disturbance affected the bioavailability of total mercury (THg) and methylmercury (MeHg) in surficial sediments to a benthic invertebrate (Echinogammarus ischnus). Ebullition rates ranged from <1 to 2,800 ml/m(2) daily, with methane gas comprising 29 to 84% of the total. No direct effects of ebullition were found on either abiotic (sediment or pore water THg or MeHg concentrations) or biotic (amphipod THg or MeHg concentrations) variables measured. Instead, amphipod MeHg concentrations were best predicted by pore water THg and MeHg concentrations, organic matter of surficial sediments, and water depth and location. Trend surface analyses demonstrated that a shallow, southwestern part of Zone 1 was most contaminated with pore water mercury, which decreased in a gradient toward the northeast. Further study is needed to determine if the amount of sediment resuspended by ebullition affects the spatial distribution of mercury. 23771130 Hierarchical wreath-like Au-Co(OH)2 microclusters for water oxidation at neutral pH. Hierarchical Au-Co(OH)2 microclusters have been synthesized by a facile ethanol-assisted hydrothermal method on FTO glass substrates. The as-fabricated Au-Co(OH)2 forms a typical wreath-shaped structure on a nanosheet with an urchin-like Au-Co(OH)2 structure located in the centre surrounded by densely grown Co(OH)2 nanoarrays. Morphological evolution of the Au-Co(OH)2 microclusters through intermediate steps could be identified by varying the reaction time. The incorporated electronegative Au may be responsible for the decrease of binding energy of Au-Co(OH)2 compared to Co(OH)2. The Au-Co(OH)2 electrode was found to be a promising catalyst for the oxygen evolution reaction (OER) in neutral pH solutions, with a larger roughness factor, lower OER onset and much higher current density than a Co(OH)2 electrode. The improvement of the OER activity of Au-Co(OH)2 microclusters may be due to their large surface area provided by the 3D network of microclusters, and the incorporation of Au as an electron sink to facilitate the oxidation of Co(ii) and Co(iii) to Co(iv). 23949306 Behavioral and life-history evidence for interspecific competition in the larvae of two heliconian butterflies. Interspecific competition in herbivorous insects remains a controversial issue. To date, many studied systems have not met assumptions of the traditional competition theory, and a new paradigm has been emerging. We examined the behavioral and life-history consequences of common host plant use of Heliconius erato and Dryas iulia (Nymphalidae) in relation to Passiflora suberosa (Passifloraceae). Larvae of the former use the apical portion of this host; the latter is presumably able to explore all plant parts. We assessed host use pattern in relation to leaf age, when reared either alone (D. iulia) or together (D. iulia and H. erato). Larval feeding choice tests with respect to leaf age were performed, and performance was recorded. Observations were made to assess antagonistic behavior of H. erato and D. iulia towards each other, if any. Similarly to H. erato, D. iulia fed on the young leaves significantly more than the mature ones; larvae were not induced to prefer mature leaves. First instars of H. erato used only the apical parts of P. suberosa and displayed aggressive behavior towards D. iulia, which moved to the lower shoot portions. Larval mortality and development time of both species significantly increased when reared together; such performance costs were more pronounced in D. iulia than H. erato. Our study gathers evidences that use of P. suberosa by these heliconian butterflies represent a case of competitive exclusion resulting in niche differentiation, where costs are higher for D. iulia than H. erato. 23608535 MAPKAPK2/3 Regulate SERCA2a Expression and Fiber Type Composition to Modulate Skeletal Muscle and Cardiomyocyte Function. The MAPK-activated protein kinases 2 and 3 (MAPKAPK2/3, MK2/3) represent protein kinases downstream of the p38 mitogen-activated protein kinase (MAPK). Using MK2/3 double knockout mice (MK2/3(-/-)), we analyzed the role of MK2/3 in cross-striated muscle by transcriptome and proteome analyses, and by histology. We demonstrated enhanced expression of the slow oxidative skeletal muscle myofiber gene program, including the PPARγ coactivator 1α (PGC-1α). Using reporter gene and electrophoretic gel mobility shift assays we demonstrated that MK2 catalytic activity directly regulated the promoters of the fast fiber-specific myosin heavy chain IId/x and the slow fiber-specific sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) 2 gene. Elevated SERCA2a gene expression caused by a decreased transcription factor Egr-1 to Sp1 ratio was associated with accelerated relaxation and enhanced contractility in MK2/3(-/-) cardiomyocytes, concomitant with improved force parameters in MK2/3(-/-) soleus muscle. These results link MK2/3 to the regulation of calcium dynamics and identify enzymatic activity of MK2/3 as a critical factor for modulating cross-striated muscle function by generating a unique muscle phenotype exhibiting both, reduced fatigability and enhanced force in MK2/3(-/-) mice. Hence, the p38-MK2/3 axis may represent a novel target for the design of therapeutic strategies for diseases related to fiber type changes or impaired SERCA2 function. 23962024 Evaluation of seven DNA barcodes for differentiating closely related medicinal Gentiana species and their adulterants. Species identification of living organisms by standard DNA sequences has been well-accepted. Consortium for the Barcode of Life (CBOL) recommends chloroplast regions rbcL and matK as the DNA barcodes for the land plants. This study aims to evaluate the feasibility and limitations of rbcL, matK, and 5 other commonly used regions as the DNA barcodes for the medicinal Gentiana and their adulterants, Gentiana. rhodantha and Podophyllum hexandrum. The species differentiation power of rbcL, matK, nuclear internal transcribed spacer (ITS) and 5S rRNA intergenic spacer, and chloroplast trnH-psbA, trnL-F and rpl36-rps8 intergenic spacers were tested in different medicinal Gentiana, including Gentiana scabra, Gentiana triflora, Gentiana manshurica and Gentiana rigescens, from common adulterants such as Gentiana rhodantha and Podophyllum hexandrum (a toxic herb producing podophyllotoxin). All seven tested loci could be used to differentiate medicinal Gentiana species from their adulterants, and to distinguish Guanlongdan from Jianlongdan. In terms of general differentiation powers, rbcL and matK had no significant advantages over the other five loci. Only the 5S rRNA and trnL-F intergenic spacers were able to discriminate the closely related species G. triflora, G. scabra and G. manshurica. The DNA barcodes rbcL and matK are useful in differentiation of closely related medicinal species of Gentiana, but had no significant advantages over the other five tested loci. 23898020 Development of a sirolimus-eluting poly (l-lactide)/poly(4-hydroxybutyrate) absorbable stent for peripheral vascular intervention. Abstract Fully absorbable drug-eluting stent platforms are currently entering the clinical arena for the interventional treatment of coronary artery disease. This new technology also holds potential for application in peripheral vascular settings. Our study reports on the development of a sirolimus- (SIR) eluting absorbable polymer stent made from a blend of poly(l-lactide) and poly(4-hydroxybutyrate) (PLLA/P4HB) for peripheral vascular intervention. Stent prototypes were laser-cut from PLLA/P4HB tubes (I.D.=2.2 mm, t=250 µm), spray-coated with different PLLA/P4HB/SIR solutions, and bench-tested to determine expansion properties, fatigue, trackability and in vitro drug release kinetics. The stent prototypes were expanded with a 5.0×20 mm balloon catheter, and exhibited a recoil of 3.6% upon balloon deflation. Stent collapse pressure of 0.4 bar (300 mm Hg) was measured under external pressure load. Sustained scaffolding properties were observed in vitro over 14 weeks of radial fatigue loading (50±25 mm Hg at 1.2 Hz). Trackability was demonstrated in bench tests with an 8 French contralateral introducer sheath. SIR release kinetics were adjusted over a broad range by varying the PLLA/P4HB ratio of the coating matrix. The newly developed absorbable SIR-eluting PLLA/P4HB stent successfully fulfilled the requirements for peripheral vascular intervention under in vitro conditions. 23959253 Copper changes the yield and cadmium/zinc accumulation and cellular distribution in the cadmium/zinc hyperaccumulator Sedum plumbizincicola. Non-accumulated metals in mixed metal contaminated soils may affect hyperaccumulator growth and metal accumulation and thus remediation efficiency. Two hydroponics experiments were conducted to investigate the effects of copper (Cu) on cadmium (Cd) and zinc (Zn) accumulation by the Cd/Zn hyperaccumulator Sedum plumbizincicola, Cu toxicity and plant detoxification using chemical sequential extraction of metals, sub-cellular separation, micro synchrotron radiation based X-ray fluorescence, and transmission electron microscopy. Compared with the control (0.31μM Cu), 5-50μM Cu had no significant effect on Cd/Zn accumulation, but Cu at 200μM induced root cell plasmolysis and disordered chloroplast structure. The plants held Cu in the roots and cell walls and complexed Cu in insoluble forms as their main detoxification mechanisms. Exposure to 200μM Cu for 4 days inhibited plant Cd uptake and translocation but did not affect Zn concentrations in roots and stems. Moreover, unloading of Cd and Zn from stem to leaf was restrained compared to control plants, perhaps due to Cu accumulation in leaf veins. Copper may thus interfere with root Cd uptake and restrain Cd/Zn unloading to the leaves. Further investigation of how Cu affects plant metal uptake may help elucidate the Cd/Zn hyper-accumulating mechanisms of S. plumbizincicola. 23731387 Cytomegalovirus infection post-pancreas-kidney transplantation - results of antiviral prophylaxis in high-risk patients. Cytomegalovirus (CMV) is a major pathogen affecting solid organ transplant (SOT) recipients. Prophylactic strategies have decreased the rate of CMV infection/disease among SOT. However, data on the effect of current prophylactic strategies for simultaneous pancreas-kidney (SPK) or pancreas after kidney (PAK) transplant remain limited. We report our experience of CMV prophylaxis in SPK/PAK recipients. A total of 130 post-SPK/PAK patients were analyzed retrospectively for the rate of CMV and the risk factors associated with the acquisition of CMV. All patients received antiviral prophylaxis. The follow-up period was one yr post-transplant or until death. The rate of CMV post-SPK/PAK transplant was 24%, 44%, and 8.2% among the whole cohort, the D+/R- and the R+ groups, respectively. Median time of prophylaxis was 49 (0-254) d. In the whole cohort, risk factors for CMV infection/diseases were D+/R- CMV status (odds ratio [OR] = 16.075), preceding non-CMV (infection caused by bacteria or fungi and other viruses) infection (OR = 6.362) and the duration of prophylaxis (OR = 0.984). Among the CMV D+/R- group, non-CMV infection was the only risk factor for CMV disease (OR = 10.7). Forty-four per cent (25/57) of the D+/R- recipients developed CMV infection/disease despite CMV prophylaxis. Current CMV prophylaxis failed to prevent CMV infection/disease in this group of patients. 23907139 Prenatal diagnosis and postnatal outcome of fetal intracranial hemorrhage. The aim of this study was to present our experience with six cases of fetal intracranial hemorrhage (ICH) in terms of prenatal diagnostic features, and postnatal outcome. The database of prenatal diagnosis unit was searched for antenatally diagnosed ICH cases. Maternal characteristics, ultrasound (US), and magnetic resonance imaging (MRI) findings, clinical course, and postnatal outcome were noted. We evaluated six consecutive cases of fetal ICH. One case was terminated at 24 weeks, and remaining five cases were delivered between 34 and 38 weeks. Five cases (5/6) had intraventricular, and one (1/6) had intraparenchymal hemorrhage. Hemorrhages were right sided in five cases (5/6), left sided in one case (1/6). Dilated and echogenic ventricular wall were the common US findings. No predisposing factor was detected in four of the cases, and intrauterine growth restriction was an underlying factor in two fetuses. Intrauterine progression of the hydrocephaly, and parenchymal thinning was seen in four cases (4/6). In three of four cases (3/4) with progressive grade 3-4 hemorrhage and hydrocephaly, postnatal outcome were dismal, and one case had mild neurological impairment at three months. In one case which had non-progressive mild ventriculomegaly, the lesion regressed after 4 weeks, and had normal short-term outcome CONCLUSION: Fetal ICH can be accurately identified and categorized by antenatal sonography, and fetal MRI. Although intrauterine regression or normal short-term postnatal outcome is possible, the outcome is usually poor for fetuses with high grade and/or progressive lesions. Therefore, further studies assessing long-term postnatal outcome are needed. 23903937 A framework for improving access and customer service times in health care: application and analysis at the UCLA medical center. There has been an increasing emphasis on health care efficiency and costs and on improving quality in health care settings such as hospitals or clinics. However, there has not been sufficient work on methods of improving access and customer service times in health care settings. The study develops a framework for improving access and customer service time for health care settings. In the framework, the operational concept of the bottleneck is synthesized with queuing theory to improve access and reduce customer service times without reduction in clinical quality. The framework is applied at the Ronald Reagan UCLA Medical Center to determine the drivers for access and customer service times and then provides guidelines on how to improve these drivers. Validation using simulation techniques shows significant potential for reducing customer service times and increasing access at this institution. Finally, the study provides several practice implications that could be used to improve access and customer service times without reduction in clinical quality across a range of health care settings from large hospitals to small community clinics. 23601185 Midterm oncological outcomes of laparoscopic vs open radical prostatectomy (RP). To compare the midterm risks of biochemical recurrence (BCR) and salvage radiation therapy (SRT) after laparoscopic (LRP) and open retropubic radical prostatectomy (RRP). Strong evidence that these techniques are comparable to the 'gold standard' of open RRP is lacking, as most comparative studies are limited by short follow-up or rely on historical controls. We studied 1000 consecutive patients concurrently treated by either LRP or RRP between 2001 and 2005. LRPs were performed by a single surgeon and RRP by four surgeons. Primary outcomes were BCR and SRT. Survival analysis included relevant clinical and pathological variables. Of 844 included patients, 244 underwent LRP and 600 RRP. Clinical and pathological characteristics were similar in both groups. Most patients had Gleason 6 tumours (68%) and pT2 disease (86%). The median follow-up was 6.1 years and median time to recurrence 3.4 years. Overall, BCR occurred in 14% of patients: 13.1% after LRP and 14.7% after RRP. SRT was performed in 10.7% of patients both after LRP and RRP. In uni- and multivariate Cox regression models, surgical technique was not a significant predictor of BCR or SRT. Our results suggest that in high-volume centres, LRP provides equivalent oncological control to RRP. 23104136 N-Arachidonyl glycine does not activate G protein-coupled receptor 18 signaling via canonical pathways. Recent studies propose that N-arachidonyl glycine (NAGly), a carboxylic analogue of anandamide, is an endogenous ligand of the Gα(i/o) protein-coupled receptor 18 (GPR18). However, a high-throughput β-arrestin-based screen failed to detect activation of GPR18 by NAGly (Yin et al., 2009; JBC, 18:12328). To address this inconsistency, this study investigated GPR18 coupling in a native neuronal system with endogenous signaling pathways and effectors. GPR18 was heterologously expressed in rat sympathetic neurons, and the modulation of N-type (Ca(v)2.2) calcium channels was examined. Proper expression and trafficking of receptor were confirmed by the "rim-like" fluorescence of fluorescently tagged receptor and the positive staining of external hemagglutinin-tagged GPR18-expressing cells. Application of NAGly on GPR18-expressing neurons did not inhibit calcium currents but instead potentiated currents in a voltage-dependent manner, similar to what has previously been reported (Guo et al., 2008; J Neurophysiol, 100:1147). Other proposed agonists of GPR18, including anandamide and abnormal cannabidiol, also failed to induce inhibition of calcium currents. Mutants of GPR18, designed to constitutively activate receptors, did not tonically inhibit calcium currents, indicating a lack of GPR18 activation or coupling to endogenous G proteins. Other downstream effectors of Gα(i/o)-coupled receptors, G protein-coupled inwardly rectifying potassium channels and adenylate cyclase, were not modulated by GPR18 signaling. Furthermore, GPR18 did not couple to other G proteins tested: Gα(s), Gα(z), and Gα(15). These results suggest NAGly is not an agonist for GPR18 or that GPR18 signaling involves noncanonical pathways not examined in these studies. 23681455 Sleep Disorders in US Military Personnel: A High Rate of Comorbid Insomnia and Obstructive Sleep Apnea. Sleep disturbances are among the most common symptoms of military personnel who return from deployment. The objective of our study was to determine the presence of sleep disorders in US military personnel referred for evaluation of sleep disturbances after deployment and examine associations between sleep disorders and service-related diagnoses of depression, mild traumatic brain injury, pain, and posttraumatic stress disorder (PTSD). This was a cross-sectional study of military personnel with sleep disturbances who returned from combat within 18 months of deployment. Sleep disorders were assessed by clinical evaluation and polysomnogram with validated instruments to diagnose service-related illnesses. Of 110 military personnel included in our analysis, 97.3% were men (mean age, 33.6 ± 8.0 years; mean BMI, 30.0 ± 4.3 kg/m2), and 70.9% returned from combat within 12 months. Nearly one-half (47.3%) met diagnostic criteria for two or more service-related diagnoses. Sleep disorders were diagnosed in 88.2% of subjects; 11.8% had a normal sleep evaluation and served as control subjects. Overall, 62.7% met diagnostic criteria for obstructive sleep apnea (OSA) and 63.6% for insomnia. The exclusive diagnoses of insomnia and OSA were present in 25.5% and 24.5% of subjects, respectively; 38.2% had comorbid insomnia and OSA. Military personnel with comorbid insomnia and OSA were significantly more likely to meet criteria for depression (P < .01) and PTSD (P < .01) compared with control subjects and those with OSA only. Comorbid insomnia and OSA is a frequent diagnosis in military personnel referred for evaluation of sleep disturbances after deployment. This diagnosis, which is difficult to treat, may explain the refractory nature of many service-related diagnoses. 23873297 Epigenetics meets radiation biology as a new approach in cancer treatment. Cancer is a disease that results from both genetic and epigenetic changes. In recent decades, a number of people have investigated the disparities in gene expression resulting from variable DNA methylation alteration and chromatin structure modification in response to the environment. Especially, colon cancer is a great model system for investigating the epigenetic mechanism for aberrant gene expression alteration. Ionizing radiation (IR) could affect a variety of processes within exposed cells and, in particular, cause changes in gene expression, disruption of cell cycle arrest, and apoptotic cell death. Even though there is growing evidence on the importance of epigenetics and biological processes induced by radiation exposure in various cancer types including colon cancer, specific epigenetic alterations induced by radiation at the molecular level are incompletely defined. This review focuses on discussing possible IR-mediated changes of DNA methylation and histone modification in cancer. 23178985 Using fluorochemical as oxygen carrier to enhance the growth of marine microalga Nannochloropsis oculata. The commercial value of marine Nannochloropsis oculata has been recognized due to its high content of eicosapentaenoic acid (>50 % w/w). To make it as a profitable bioresource, one of the most desirable goals is to develop a quality-controlled, cost-effective, and large-scale photobioreactor for N. oculata growth. Generally, closed culture system can offer many advantages over open system such as small space requirement, controllable process and low risk of contamination. However, oxygen accumulation is often a detrimental factor for enclosed microalgal culture that has seriously hampered the development of microalga-related industries. In this study, we proposed to use fluorochemical as oxygen carrier to overcome the challenge where four liquid fluorochemicals namely perfluorooctyl bromide, perfluorodecalin, methoxynonafluorobutane, and ethoxynonafluorobutane were investigated separately. Our results showed that the microalgal proliferation with different fluorinated liquids was similar and comparable to the culture without a fluorochemical. When cultured in the photobioreactor with 60 % oxygen atmosphere, the N. oculata can grow up in all the fluorochemical photobioreactors, but completely inhibited in the chamber without a fluorochemical. Moreover, the perfluorooctyl bromide system exhibited the most robust efficacy of oxygen removal in the culture media (perfluorooctyl bromide > perfluorodecalin > methoxynonafluorobutane > ethoxynonafluorobutane), and yielded a >3-fold increase of biomass production after 5 days. In summary, the developed fluorochemical photobioreactors offer a feasible means for N. oculata growth in closed and large-scale setting without effect of oxygen inhibition. 23500477 Myelin basic protein immunosensor for multiple sclerosis detection based upon label-free electrochemical impedance spectroscopy. A novel highly sensitive impedimetric Myelin Basic Protein (MBP) immunosensor for the determination of a Multiple Sclerosis (MS) autoantibody, Anti-Myelin Basic Protein (Anti-MBP) was developed by immobilization of MBP on Gelatin and Gelatin-Titanium Dioxide (TiO₂) modified platinium electrode. Cyclic voltammetric (CV) and Electrochemical Impedance Spectroscopic (EIS) methods were employed in determination of the electrode responses and applicability. Gelatin-MBP and gelatin-TiO₂-MBP electrodes were prepared by chemical immobilization of the substrates onto the platinium electrodes. The formal potentials of MBP confined on gelatin-MBP and gelatin-TiO₂-MBP surfaces are estimated to be 195 and 205 mV, respectively. Thus, a little more reversible electron transfer reaction occurs on the gelatin-TiO₂-MBP immunosensor surface. The peak separations of MBP (150 mV and 110 mV s(-1) at 100 mV s(-1)) and the asymmetric anodic and cathodic peak currents indicate that the electron transfer between Anti-MBP and gelatin-MBP/gelatin-TiO₂-MBP immunosensor is quasireversible. Control samples containing a nonspecific human immunoglobulin G (hIgG) antibody were also studied, and calibration curves were obtained by subtraction of the responses for specific and nonspecific antibody-based sensors. Gelatin-MBP and gelatin-TiO₂-MBP immunosensors have detection limit of 0.1528 ng ml(-1) and 0.1495 ng ml(-1) respectively. This immunosensor exhibits high sensitivity and low response times (58 s for gelatin-MBP and 46 s for gelatin-TiO₂-MBP immunosensor). The developed label-free impedimetric immunosensors also provide a simple and sensitive detection method for the specific determination of Anti-MBP in human cerebrospinal fluid (CSF) and serum samples. 23122158 Simultaneous separation and purification of total polyphenols, chlorogenic acid and phlorizin from thinned young apples. An efficient preparative separation of polyphenols from thinned young apples (TYA) has been developed in the present study. X-5 resin was verified to offer the best adsorption capacity and desorption ratio for total polyphenols among the eight macroporous resins investigated. Influential factors, such as pH value and concentration of feeding solution, strippant, and adsorption isotherm to the separation of total polyphenols, were successively investigated on X-5 resin. After one run treatment, the phenolic content was increased 2.12-fold from 35.17% to 74.64%, with a recovery yield of 89.35%. Chlorogenic acid and phlorizin were selectively purified using X-5 and polyamide resins. The contents of chlorogenic acid and phlorizin were 15.20% and 97.52% with recovery yields of 89.16% and 64.95%, respectively. The method developed will provide a potential approach for its wide industrial and pharmaceutical use. 23444775 Rapid identification of sibutramine in dietary supplements using a stepwise approach. Adulteration of botanical food supplements with undeclared synthetic drugs is a common problem. One of the most affected product groups are the slimming agents. There are no analytical protocols for the detection of synthetic adulterants from these products. The present study aimed at the development of a multistep analytical method for the quick and reliable determination of sibutramine, one of the most common adulterants among botanical food supplements. The extract of a sibutramine-containing slimming formula was analysed by colour tests, TLC, HPLC-DAD, MS and NMR. The multistep method proposed by the authors allows the quick identification of sibutramine in counterfeit samples in laboratories with different instrumentation. 23888854 Wing shape variation associated with mimicry in butterflies. Mimetic resemblance in unpalatable butterflies has been studied by evolutionary biologists for over a century, but has largely focused on the convergence in wing color patterns. In Heliconius numata, discrete color-pattern morphs closely resemble comimics in the distantly related genus Melinaea. We examine the possibility that the shape of the butterfly wing also shows adaptive convergence. First, simple measures of forewing dimensions were taken of individuals in a cross between H. numata morphs, and showed quantitative differences between two of the segregating morphs, f. elegans and f. silvana. Second, landmark-based geometric morphometric and elliptical Fourier outline analyses were used to more fully characterize these shape differences. Extension of these techniques to specimens from natural populations suggested that, although many of the coexisting morphs could not be discriminated by shape, the differences we identified between f. elegans and f. silvana hold in the wild. Interestingly, despite extensive overlap, the shape variation between these two morphs is paralleled in their respective Melinaea comimics. Our study therefore suggests that wing-shape variation is associated with mimetic resemblance, and raises the intriguing possibility that the supergene responsible for controlling the major switch in color pattern between morphs also contributes to wing shape differences in H. numata. 23928956 Good quality sleep is associated with better academic performance among university students in Ethiopia. This study assessed the association of sleep quality with academic performance among university students in Ethiopia. This cross-sectional study of 2,173 college students (471 female and 1,672 male) was conducted in two universities in Ethiopia. Students were selected into the study using a multistage sampling procedure, and data were collected through a self-administered questionnaire. Sleep quality was assessed using Pittsburgh Sleep Quality Index, and academic performance was based on self-reported cumulative grade point average. The Student's "t" test, analysis of variance, and multiple linear regression were used to evaluate associations. We found that students with better sleep quality score achieved better on their academic performance (P value = 0.001), while sleep duration was not associated with academic performance in the final model. Our study underscores the importance of sleep quality on better academic performance. Future studies need to identify the possible factors which influence sleep quality other than the academic environment repeatedly reported by other literature. It is imperative to design and implement appropriate interventions to improve sleep quality in light of the current body of evidence to enhance academic success in the study setting. 23426398 New insight into the enhanced visible-light photocatalytic activities of B-, C- and B/C-doped anatase TiO2 by first-principles. The geometry structures, formation energies and electronic properties of the B-, C- and B/C-doped anatase TiO2 were investigated by the density functional theory (DFT) calculations of first-principles. The results indicated that the visible-light absorption and photocatalytic activities of the B-, C- and B/C-doped anatase TiO2 were not only influenced by the energy gaps (Eg) and the distributions of impurity states, but also affected by the locations of Fermi levels (EF) and the energies of the edges of band gaps (Ev for the top of valence bands and Ec for the bottom of conduction bands). However, the above four factors changed with the doped models of TiO2. The impurity states in the band gaps reduced the maximum energy gaps in the band gaps, which is responsible for the absorption of visible light. The Fermi levels at the bottom of conduction bands indicated the existence of Ti(3+) ions, which enhanced the separation rates of photogenerated electrons and holes. Further, the energies of the edges of band gaps, determining the dominant types of oxidants (O2(-), hole, ˙OH) in the photocatalytic degradation, were discussed. Moreover, the stability of the doped TiO2 depended on its growth conditions (O-rich or Ti-rich environment). The O-rich growth condition is beneficial to the substitutional B and C atoms to Ti atoms, while the Ti-rich growth condition is favorable to the other doped TiO2 including the most stable co-doped TiO2 with the interstitial B atom and the substitutional C atom to O atom. In addition, our results also showed that the B/C-doped TiO2 inherited the partial electronic properties of single-doped TiO2, but also exhibited many new electronic properties, implying that the electronic properties of co-doped systems are not a mechanical mixture of those of both single-doped systems. 23749967 Heterozygosity for the f508del mutation in the cystic fibrosis transmembrane conductance regulator anion channel attenuates influenza severity. Background. Seasonal and pandemic influenza are significant public health concerns. Influenza stimulates respiratory epithelial Cl(-) secretion via the cystic fibrosis transmembrane conductance regulator (CFTR). The purpose of this study was to determine the contribution of this effect to influenza pathogenesis in mice with reduced CFTR activity. Methods. C57BL/6-congenic mice heterozygous for the F508del CFTR mutation (HET) and wild-type (WT) controls were infected intranasally with 10 000 focus-forming units of influenza A/WSN/33 (H1N1) per mouse. Body weight, arterial O2 saturation, and heart rate were monitored daily. Pulmonary edema and lung function parameters were derived from ratios of wet weight to dry weight and the forced-oscillation technique, respectively. Levels of cytokines and chemokines in bronchoalveolar lavage fluid were measured by enzyme-linked immunosorbent assay. Results. Relative to WT mice, influenza virus-infected HET mice showed significantly delayed mortality, which was accompanied by attenuated hypoxemia, cardiopulmonary dysfunction, and pulmonary edema. However, viral replication and weight loss did not differ. The protective HET phenotype was correlated with exaggerated alveolar macrophage and interleukin 6 responses to infection and was abrogated by alveolar macrophage depletion, using clodronate liposomes. Conclusions. Reduced CFTR expression modulates the innate immune response to influenza and alters disease pathogenesis. CFTR-mediated Cl(-) secretion is therefore an important host determinant of disease, and CFTR inhibition may be of therapeutic benefit in influenza. 23887141 Glucose-conditioned flavor preference learning requires co-activation of NMDA and dopamine D1-like receptors within the amygdala. The role of amygdala (AMY) NMDA receptor signaling and its interaction with dopamine D1-like receptor signaling in glucose-mediated flavor preference learning was investigated. In Experiment 1, rats were trained with a flavor (CS+) paired with intragastric (IG) 8% glucose infusions and a different flavor (CS-) paired with IG water infusions. In the two-bottle tests (Expression), bilateral intra-AMY injections of the NMDA receptor antagonist, AP5 (0, 5 and 10nmol/brain), did not block the CS+ preference. In Experiment 2, new rats received intra-AMY injections of either vehicle or AP5 (10nmol), prior to training sessions with CS+/IG glucose and CS-/IG water. In the two-bottle tests without drug treatment, AP5 rats failed to prefer the CS+ flavor (50%). In Experiments 3, new rats were trained as in Experiment 2 except that, during training, half the rats received AP5 injections (5nmol) in one side of the AMY and SCH23390 (D1-like receptor antagonist, 6nmol), in the contralateral AMY (Drug/Drug group). The remaining rats received vehicle injections in one side of the AMY and either AP5 (5nmol) or SCH23390 (6nmol) in the contralateral AMY (Drug/Vehicle group). The two-bottle choice tests without drug treatment revealed that, unlike the Drug/Vehicle group (85%), the Drug/Drug group failed to prefer the CS+ flavor (50%). These results reveal an essential role for AMY NMDA receptor activation in the acquisition of flavor preference learning induced by the post-oral reinforcing properties of glucose and demonstrate that such learning is based on co-activation of NMDA and DA D1 receptors within this forebrain structure. 23934537 CXCR4(+) and FLK-1(+) Identify Circulating Cells Associated with Improved Cardiac Function in Patients Following Myocardial Infarction. The biomarkers CXCR4/FLK-1 select cardiac progenitors from a stem cell pool in experimental models. However, the translational value of these cells in human ischemic heart disease is unknown. Here, flow-cytometry identified CD45(-)/CXCR4(+)/FLK-1(+) cells in 30 individuals without ischemic heart disease and 33 first-time acute myocardial infarction (AMI) patients. AMI patients had higher CD45(-)/CXCR4(+)/FLK-1(+) cell-load at 48-h and 3- and 6-months post-AMI (p = 0.003,0.04,0.04, respectively) than controls. Cardiovascular risk factors and left ventricular (LV) ejection fraction were not associated with cell-load. 2D-speckle-tracking strain echocardiography assessment of LV systolic function showed improvement in longitudinal strain and dyssynchrony during follow-up associated with longitudinal increases in and higher 48-h post-AMI CD45(-)/CXCR4(+)/FLK-1(+) cell-load (r = -0.525, p = 0.025; r = -0.457, p = 0.029, respectively). In conclusion, CD45(-)/CXCR4(+)/FLK-1(+) cells are present in adult human circulation, increased in AMI and associated with improved LV systolic function. Thus, CD45(-)/CXCR4(+)/FLK-1(+) cells may provide a diagnostic tool to follow cardiac regenerative capacity and potentially serve as a prognostic marker in AMI. 23885201 New molecular evidence supports the species status of Kaempfer's Woodpecker (Aves, Picidae). Kaempfer's Woodpecker (Celeus obrieni) is the only species of the genus Celeus endemic to Brazil. The description of this taxon as a subspecies of the Rufous-headed Woodpecker (Celeus spectabilis) was based on a single specimen. While C. obrieni and C. spectabilis are now considered separate species based on morphological and limited molecular evidence, no study has critically tested the reciprocal monophyly and degree of evolutionary independence between these taxa with several specimens. Herein, fragments of the mitochondrial and nuclear DNA of three recently-collected specimens of C. obrieni were analyzed to evaluate the degree of evolutionary differentiation of this taxon with respect to C. spectabilis. The results confirm the reciprocal monophyly between the specimens of C. obrieni and C. spectabilis. The genetic divergence values for the two taxa also support their classification as independent species, given that they are greater than the values recorded among other closely-related but separate species of the same genus. Estimates of the divergence time between C. obrieni and C. spectabilis indicate that cladogenesis occurred in the mid-Pleistocene, during a period of major climatic fluctuations and landscape change, consistent with the hypothesis of a corridor of open bamboo dominated forests and woodland stretching. 23937719 Two types of exercise-induced neuroplasticity in congenital hemiparesis: a transcranial magnetic stimulation, functional MRI, and magnetoencephalography study. Early unilateral brain lesions can lead to a persistence of ipsilateral corticospinal projections from the contralesional hemisphere, which can enable the contralesional hemisphere to exert motor control over the paretic hand. In contrast to the primary motor representation (M1), the primary somatosensory representation (S1) of the paretic hand always remains in the lesioned hemisphere. Here, we report on differences in exercise-induced neuroplasticity between individuals with such ipsilateral motor projections (ipsi) and individuals with early unilateral lesions but 'healthy' contralateral motor projections (contra). Sixteen children and young adults with congenital hemiparesis participated in the study (contralateral [Contra] group: n=7, four females, three males; age range 10-30y, median age 16y; ipsilateral [Ipsi] group: n=9, four females, five males; age range 11-31y, median age 12y; Manual Ability Classification System levels I to II in all individuals in both groups). The participants underwent a 12-day intervention of constraint-induced movement therapy (CIMT), consisting of individual training (2h/d) and group training (8h/d). Before and after CIMT, hand function was tested using the Wolf Motor Function Test (WMFT) and diverging neuroplastic effects were observed by transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG). Statistical analysis of TMS data was performed using the non-parametric Wilcoxon signed-rank test for pair-wise comparison; for fMRI standard statistical parametric and non-parametric mapping (SPM5, SnPM3) procedures (first level/second level) were carried out. Statistical analyses of MEG data involved analyses of variance (ANOVA) and t-tests. While MEG demonstrated a significant increase in S1 activation in both groups (p=0.012), TMS showed a decrease in M1 excitability in the Ipsi group (p=0.036), but an increase in M1 excitability in the Contra group (p=0.043). Similarly, fMRI showed a decrease in M1 activation in the Ipsi group, but an increase in activation in the M1-S1 region in the Contra group (for both groups p<0.001 [SnPM3] within the search volume). Different patterns of sensorimotor (re)organization in individuals with early unilateral lesions show, on a cortical level, different patterns of exercise-induced neuroplasticity. The findings help to improve the understanding of the general principles of sensorimotor learning and will help to develop more specific therapies for different pathologies in congenital hemiparesis. 23770547 Contribution of the aquitard to the regional groundwater hydrochemistry of the underlying confined aquifer in the Pearl River Delta, China. Aquitards are capable of generating and preserving large amounts of chemicals. The release of the chemicals from the aquitards poses a potential contamination risk to groundwater that may be used as a drinking water source. This work aimed to identify the contribution of hydrogeochemical processes in the aquitards to groundwater hydrochemistry in the underlying confined basal aquifer by studying the coastal Quaternary aquifer-aquitard system of the Pearl River Delta, China. The system was submerged by paleo-seawater in the early Holocene and mainly receives infiltration of precipitation at present, as indicated by investigations on stable isotopes (δ(2)H, δ(18)O), water chemistry (SO4(2-) and Cl(-)) and salinity. Significant correlations between total dissolved solids in the basal aquifer and the thickness of the overlying aquitard further suggested the contribution of the aquitard to the groundwater hydrochemistry in the aquifer. Significant correlations between the chloride concentrations in aquitard porewater and that in groundwater in the aquifer, and between the thickness of the aquitard and the chloride concentrations in groundwater indicated the strong influence of the aquitard on the chloride in the aquifer. This is probably because the low-permeability aquitard is capable of preserving the paleo-seawater in the aquifer and releasing the salinity from the aquitard down to the aquifer via downward flow or diffusion. Isotopic and geochemical studies revealed that the aquitard is also responsible for generating and preserving large amounts of naturally occurring ammonium. Analysis between the concentrations of ammonium in groundwater in the basal aquifer and the total available ammonium in aquitard sediments suggested that the former is significantly controlled by the latter. 23573999 UP780, a Chromone-Enriched Aloe Composition Improves Insulin Sensitivity. Abstract Background: Diabetic individuals experience elevated fasting glucose, glycosylated hemoglobin (HbA1c), and plasma insulin and impaired glucose tolerance. Adiponectin is a hormone inversely correlated with insulin resistance. Here we describe the activity of aloesin, an aloe chromone that increases adiponectin production and, when formulated with an aloe polysaccharide composition, improves the insulin sensitivity in db/db and diet-induced obese-diabetic mice. Methods: Two aloe chromones, aloesin and aloesinol, were tested in vitro for adiponectin production. Following confirmation of glucose-lowering activity in a high-fat diet (HFD)-induced mouse model, aloesin was formulated with an Aloe vera inner leaf gel powder polysaccharide preparation to yield a composition designated UP780. Efficacy of UP780 was evaluated in HDF-induced and db/db mouse models. GW1929, a synthetic peroxisome proliferator-activated receptor-γ (PPARγ) agonist, was used as a positive control. Results: After 3 weeks of treatment of HDF-induced mice, plasma insulin levels were decreased 37.9% and 46.7% by aloesin and aloesinol, respectively. In db/db mice, the chromone- (2% chromone:98% aloe polysaccharide) enriched UP780 aloe composition showed a 33.7% and 46.0% decrease in fasting triglyceride and plasma glucose levels after 10 weeks of oral treatment, respectively. Diabetic mice gavaged with 200 mg/kg of UP780 for 10 weeks showed a 30.3% decrease in fasting blood glucose levels and a 32.2% reduction in plasma insulin. In both animal models, UP780 showed a statistically significant improvement in blood glucose clearance. Conclusion: These findings indicate that UP780, a chromone-standardized, aloe-based composition, could potentially be used as a natural product option to facilitate the maintenance of healthy blood glucose levels. 23937107 Strategies for delivering local anesthetics to the skin: focus on liposomes, solid lipid nanoparticles, hydrogels and patches. Introduction: Dermal and transdermal drug delivery systems offer the possibility to control the release of the drug for an extended period of time. In particular, skin-delivery of local anesthetics (LA) is one of the most important strategies to increase the local drug concentration and to reduce systemic adverse reactions. Areas covered: During the development phase of new formulations for skin-delivery of LA one should consider a set of desirable features such providing suitable adhesion, easy application/removal and also to be biocompatible, biodegradable and non-toxic. This review emphasizes the main strategies for skin-delivery of LA considering those features in relation to the composition of the delivery systems described. The topics highlight the relationships between physico-chemical studies and pharmaceutical applications for liposomes and solid lipid nanoparticles as well as the formulation and clinical applications for hydrogels and patches. Expert opinion: The development of LA skin-delivery systems using hydrogels and different permeation enhancers, liposomes or lipid nanoparticles (as isolated carrier systems or as their dispersion in a gel-base) and patches have been explored as alternatives to commercial formulations, modifying the release rate of LA, increasing bioadhesive properties and reducing toxicity, resulting in an improved therapeutic efficacy. This review should provide to the reader a special emphasis on four delivery-systems, comprising the group of liposomes and lipid nanoparticles, hydrogels and patches technologies looking forward their application for skin anesthesia. 23835484 Ratiometric highly sensitive luminescent nanothermometers working in the room temperature range. Applications to heat propagation in nanofluids. There is an increasing demand for accurate, non-invasive and self-reference temperature measurements as technology progresses into the nanoscale. This is particularly so in micro- and nanofluidics where the comprehension of heat transfer and thermal conductivity mechanisms can play a crucial role in areas as diverse as energy transfer and cell physiology. Here we present two luminescent ratiometric nanothermometers based on a magnetic core coated with an organosilica shell co-doped with Eu(3+) and Tb(3+) chelates. The design of the hybrid host and chelate ligands permits the working of the nanothermometers in a nanofluid at 293-320 K with an emission quantum yield of 0.38 ± 0.04, a maximum relative sensitivity of 1.5% K(-1) at 293 K and a spatio-temporal resolution (constrained by the experimental setup) of 64 × 10(-6) m/150 × 10(-3) s (to move out of 0.4 K - the temperature uncertainty). The heat propagation velocity in the nanofluid, (2.2 ± 0.1) × 10(-3) m s(-1), was determined at 294 K using the nanothermometers' Eu(3+)/Tb(3+) steady-state spectra. There is no precedent of such an experimental measurement in a thermographic nanofluid, where the propagation velocity is measured from the same nanoparticles used to measure the temperature. 23920214 SCINTIGRAPHIC ASSESSMENT OF RADIOAEROSOL PULMONARY DEPOSITION THROUGH ACAPELLA DEVICE WITH DIFFERENT NEBULISER CONFIGURATIONS. Acapella® 27 produces high frequency oscillations and positive expiratory pressure (HFOPEP) for use in bronchial hygiene. However, its performance in aerosol delivery has not been described. The aim of this study was to evaluate the effect of nebulizer configuration in relation to the HFOPEP device on deposition of radiotagged aerosols with healthy subjects. 10 healthy male subjects (mean age of 24.4±2.2 years) participated in a crossover study that compared pulmonary delivery of 4 mL of Tc99m- DTPA(25mCi) and 0.9% saline solution via jet nebulizer with the following configurations: A-nebulizer attached to the distal end of equipment (distal); B -nebulizer placed between the mouthpiece and the device (proximal); and C -inhalation with the nebulizer alone (control). Scintigraphy was performed to count radioaerosol particles deposited in the regions of interest (ROI) in both lungs in vertical (upper, middle, lower) and horizontal (central, intermediate, peripheral) gradients. Deposition between the right and left lungs was similar, with no significant differences between device configurations. Lung deposition was less with A compared to B (p=.001, for both lungs), and C (p=.003 and p=.001, right and left lungs, respectively). No differences were found between configurations B and C. Vertical gradient demonstrated lower deposition with A in comparison to B (upper, p<.0001; middle, p=.001 and lower regions, p=.003) and configuration C (both upper and middle, p=.001; lower regions, p=.002) with up to a 3 fold difference in the middle lower regions. Horizontal gradient also showed a lower deposition in configuration A when compared to B (central,p<.0001 and peripheral,p=.0002) and C (central and peripheral, p=0.002) differences of 3-4 fold were observed in the central and peripheral regions. Placement of jet nebulizer distal to the HFOPEP devise is recommended by the manufacturer decreased intrapulmonary deposition compared placement of the nebulizer between device and the patient airway or the nebulizer alone. 23834333 Anthryl-Substituted 3-Silylene-2-silaaziridine Obtained by Isomerization of Disilacyclopropanimine: An Exocyclic Silene Showing a Distinct Intramolecular Charge Transfer Transition. An anthryl-substituted exocyclic silene, 3-silylene-2-silaaziridine, was synthesized by isomerization of the corresponding disilacyclopropanimine. The UV-vis spectrum of the silene shows a distinct intramolecular charge transfer (ICT) transition from the π orbital of the Si═C double bond to the π* orbital of the anthryl moiety. The relatively high-lying π(Si═C) orbital of the 3-silylene-2-silaaziridine moiety and the low-lying π* orbital of the anthryl group would be responsible for the distinct ICT band. 23561393 Investigation of an angular spectrum approach for pulsed ultrasound fields. An Angular Spectrum Approach (ASA) is formulated and employed to simulate linear pulsed ultrasound fields for high bandwidth signals. A geometrically focused piston transducer is used as the acoustic source. Signals are cross-correlated to find the true sound speed during the measurement to make the simulated and measured pulses in phase for comparisons. The calculated sound speed in the measurement is varied between 1487.45 m/s and 1487.75 m/s by using different initial values in the ASA simulation. Results from the pulsed ASA simulations using both Field II simulated and hydrophone measured acoustic sources are compared to the Field II simulated and hydrophone measured pulses, respectively. The total relative root mean square (RMS) errors of the pulsed ASA are investigated by using different time-point, zero-padding factors, spatial sampling interval and temporal sampling frequency in the simulation. Optimal parameters for the ASA are found in the simulation. The RMS error of the ASA simulation is reduced from 10.9% to 2.4% for the optimal parameters when comparing to Field II simulations. The comparison between the ASA calculated and measured pulses are illustrated and the corresponding RMS error is 25.4%. 23822979 Differentiation of Human Induced Pluripotent Stem Cells into Functional Enterocyte-Like Cells Using a Simple Method. Human induced pluripotent stem (iPS) cells were differentiated into the endoderm using activin A and were then treated with fibroblast growth factor 2 (FGF2) for differentiation into intestinal stem cell-like cells. These immature cells were then differentiated into enterocyte-like cells using epidermal growth factor (EGF) in 2% fetal bovine serum (FBS). At the early stage of differentiation, mRNA expression of caudal type homeobox 2 (CDX2), a major transcription factor related to intestinal development and differentiation, and leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), an intestinal stem cell marker, was markedly increased by treatment with FGF2. When cells were cultured in medium containing EGF and a low concentration of FBS, mRNAs of specific markers of intestinal epithelial cells, including sucrase-isomaltase, the intestinal oligopeptide transporter SLC15A1/peptide transporter 1 (PEPT1), and the major metabolizing enzyme CYP3A4, were expressed. In addition, sucrase-isomaltase protein expression and uptake of β-Ala-(L)-Lys-N-7-amino-4-methylcoumarin-3-acetic acid (β-Ala-Lys-AMCA), a fluorescence-labeled substrate of the oligopeptide transporter, were detected. These results demonstrate a simple and direct method for differentiating human iPS cells into functional enterocyte-like cells. 22373865 A novel group therapy for children with ADHD and severe mood dysregulation. Objective: No psychosocial treatments have been developed for children with ADHD and severe mood dysregulation (SMD) despite the significant prevalence and morbidity of this combination. Therefore, the authors developed a novel treatment program for children with ADHD and SMD. Method: The novel therapy program integrates components of cognitive-behavioral therapies for affect regulation with a parent-training intervention for managing recurrent defiant behaviors. It consists of nine 105-min child and parent groups run in unison. A pilot trial was conducted with seven participants with ADHD and SMD ages 7 to 12 who were on a stable stimulant regimen. Results: Six of the seven (86%) families completed the program. Participants showed large improvements in depressive symptoms, mood lability, and global functioning. Milder improvements in externalizing behaviors were observed. Conclusion: Results suggest the feasibility and potential efficacy of the therapy program for children with ADHD and SMD and warrant a larger controlled trial. 23545415 PRIMA-1 induces autophagy in cancer cells carrying mutant or wild type p53. PRIMA-1 is a chemical compound identified as a growth suppressor of tumor cells expressing mutant p53. We previously found that in the MDA-MB-231 cell line expressing high level of the mutant p53-R280K protein, PRIMA-1 induced p53 ubiquitination and degradation associated to cell death. In this study, we investigated the ability of PRIMA-1 to induce autophagy in cancer cells. In MDA-MB-231 and HCT116 cells, expressing mutant or wild type p53, respectively, autophagy occurred following exposure to PRIMA-1, as shown by acridine orange staining, anti-LC3 immunofluorescence and immunoblots, as well as by electron microscopy. Autophagy was triggered also in the derivative cell lines knocked-down for p53, although to a different extent than in the parental cells expressing mutant or wild type p53. In particular, while wild type p53 limited PRIMA-1 induced autophagy, mutant p53 conversely promoted autophagy, thus sustaining cell viability following PRIMA-1 treatment. Therefore, the autophagic potential of PRIMA-1, besides being cell context dependent, could be modulated in a different way by the presence of wild type or mutant p53. Furthermore, since both cell lines lacking p53 were more sensitive to the cytotoxic effect of PRIMA-1 than the parental ones, our findings suggest that a deregulated autophagy may favor cell death induced by this drug. 23798496 Altered Ca2+ concentration, permeability and buffering in the myofiber Ca2+ store of a mouse model of malignant hyperthermia. Malignant hyperthermia (MH) is linked to mutations in the type 1 ryanodine receptor, RyR1, the Ca(2+) channel of the sarcoplasmic reticulum (SR) of skeletal muscle. The Y522S MH mutation was studied for its complex presentation, which includes structurally and functionally altered cell "cores". Imaging cytosolic and intra-SR [Ca(2+)] in muscle cells of heterozygous YS mice we determined Ca(2+) release flux activated by clamp depolarization, permeability of the SR membrane- P, ratio of flux and [Ca(2+)] gradient- and SR Ca(2+) buffering power-B. In YS cells resting [Ca(2+)]SR was 45% of the value in normal littermates (WT). P was more than doubled, so that initial flux was normal. Measuring [Ca(2+)]SR(t) revealed dynamic changes in B(t). The alterations were similar to those caused by cytosolic BAPTA, which promotes release by hampering Ca(2+)-dependent inactivation (CDI). The [Ca(2+)] transients showed abnormal "breaks", decaying phases after an initial rise, traced to a collapse in flux and P. Similar breaks occurred in WT myofibers with calsequestrin reduced by siRNA; calsequestrin content, however, was normal in YS muscle. Thus, the Y522S mutation causes greater openness of the RyR1, lowers resting [Ca(2+)]SR and alters SR Ca(2+) buffering in a way that copies the functional instability observed upon reduction of calsequestrin content. The similarities with the effects of BAPTA suggest that the mutation, occurring near the cytosolic vestibule of the channel, reduces CDI as one of its primary effects. The unstable SR buffering, mimicked by silencing of calsequestrin, may help precipitate the loss of Ca(2+) control that defines a fulminant MH event. 23139348 The peri-islet basement membrane, a barrier to infiltrating leukocytes in type 1 diabetes in mouse and human. We provide the first comprehensive analysis of the extracellular matrix (ECM) composition of peri-islet capsules, composed of the peri-islet basement membrane (BM) and subjacent interstitial matrix (IM), in development of type 1 diabetes in NOD mice and in human type 1 diabetes. Our data demonstrate global loss of peri-islet BM and IM components only at sites of leukocyte infiltration into the islet. Stereological analyses reveal a correlation between incidence of insulitis and the number of islets showing loss of peri-islet BM versus islets with intact BMs, suggesting that leukocyte penetration of the peri-islet BM is a critical step. Protease- and protease inhibitor-specific microarray analyses (CLIP-CHIP) of laser-dissected leukocyte infiltrated and noninfiltrated pancreatic islets and confirmatory quantitative real time PCR and protein analyses identified cathepsin S, W, and C activity at sites of leukocyte penetration of the peri-islet BM in association with a macrophage subpopulation in NOD mice and human type 1 diabetic samples and, hence, potentially a novel therapeutic target specifically acting at the islet penetration stage. Interestingly, the peri-islet BM and underlying IM are reconstituted once inflammation subsides, indicating that the peri-islet BM-producing cells are not lost due to the inflammation, which has important ramifications to islet transplantation studies. 23592504 Transcriptomic Analysis of Peripheral Blood Mononuclear Cells in Rapid Progressors in Early HIV Infection Identifies a Signature Closely Correlated with Disease Progression. A substantial percentage (10%-15%) of HIV-infected individuals experience a sharp decline in CD4(+) T-cell counts and progress to AIDS quickly after primary infection. Identification of biomarkers distinguishing rapid progressors (RPs) vs chronic progressors (CPs) is critical for early clinical intervention and could provide novel strategies to facilitate vaccine design and immune therapy. mRNA and microRNA (miRNA) expression profiles in the peripheral blood mononuclear cells (PBMCs) of RPs and CPs were investigated at 111 (22) days [mean (SD)] of HIV infection. The association of mRNA and miRNA expression with disease progression was examined by ROC analysis and Kaplan-Meier survival analysis. Pathway enrichment analysis showed that genes with deregulated expression in RPs were primarily involved in apoptosis pathways. Furthermore, we found that 5 miRNAs (miR-31, -200c, -526a, -99a, and -503) in RPs were significantly decreased compared to those in CPs (P < 0.05). The decreased expression of these miRNAs was associated with a rapid disease of progression of HIV infection with a 94% predictive value as measured by the area under the curve. The upregulated predicted targets from the 5 signature miRNAs and all upregulated genes identified from mRNA microarray analysis converged to the apoptosis pathway. Moreover, overexpression of miR-31 in primary human T cells promoted their survival. Our results have identified a distinct transcriptomic signature in PBMCs of RPs and provided novel insights to the pathogenesis of HIV infection. 23918929 The vitamin K oxidoreductase is a multimer that efficiently reduces vitamin K epoxide to hydroquinone to allow vitamin K-dependent protein carboxylation. The vitamin K oxidoreductase (VKORC1) recycles vitamin K to support the activation of vitamin K-dependent (VKD) proteins, which have diverse functions that include hemostasis and calcification. VKD proteins are activated by Glu carboxylation that depends upon the oxygenation of vitamin K hydroquinone (KH2). The vitamin K epoxide (KO) product is recycled by two reactions, i.e. KO reduction to vitamin K quinone (K) and then to KH2, and recent studies have called into question whether VKORC1 reduces K to KH2. Analysis in insect cells lacking endogenous carboxylation components showed that r-VKORC1 reduces KO to efficiently drive carboxylation, indicating KH2 production. Direct detection of the vitamin K reaction products is confounded by KH2 oxidation, and we therefore developed a new assay that stabilized KH2 and allowed quantitation. Purified VKORC1 analyzed in this assay showed efficient KO to KH2 reduction. Studies in 293 cells expressing tagged r-VKORC1 revealed that VKORC1 is a multimer, most likely a dimer. A monomer can only perform one reaction, and a dimer is therefore interesting in explaining how VKORC1 accomplishes both reactions. An inactive mutant (VKORC1(CC132/135AA)) was dominant negative in heterodimers with wild type VKORC1, resulting in decreased KO reduction in cells and carboxylation in vitro. The results are significant regarding human VKORC1 mutations, as warfarin resistant patients have mutant and wild type VKORC1 alleles. A VKORC1 dimer indicates a mixed population of homodimers and heterodimers that may have different functional properties, and VKORC1 reduction may therefore be more complex in these patients than previously appreciated. 23562407 Postoperative analgesic effects of dexketoprofen, buprenorphine and tramadol in dogs undergoing ovariohysterectomy. The objective of this study was to compare the postoperative analgesic effects of dexketoprofen, tramadol, and buprenorphine in dogs undergoing ovariohysterectomy. Seventy-five adult female dogs were randomly assigned to receive an intravenous injection (IV) of 1mg/kg of dexketoprofen (D), 0.02 mg/kg of buprenorphine (B) or 2mg/kg of tramadol (T). Pain assessment was performed during 48 h after ovariohysterectomy using a dynamic interactive visual analogue scale (DIVAS) and Glasgow composite measure pain scale (CMPS-SF). Rescue analgesia was required in 43%, 21%, and 5% of dogs in the B, T, and D groups, respectively, with significant differences between B and D (p=0.010) groups. The DIVAS and CMPS-SF values of the B group were significantly higher than those of the T and D groups. The most common undesirable effect was dysphoria in dexketoprofen group. Tramadol and dexketoprofen provide superior postoperative analgesia compared with buprenorphine in dogs undergoing ovariohysterectomy. 23772883 Synthesis of stachybotrin C and all of its stereoisomers: structure revision. We disclose the first total synthesis of stachybotrin C, a potent neuroprotective natural compound. All of the four stereoisomers have been prepared and fully characterized with the aim to attribute the absolute configuration of the two adjacent stereocenters of the stachybotrin C. 23940825 New twist to nuclear import: When two travel together. Ribosomes are the nanomachines that synthesize all cellular proteins from mRNA templates. In eukaryotes, ribosomes, which are composed of ribosomal proteins and rRNA, are mainly assembled in the nucleus. Thus, ribosomal proteins require a nuclear transport step from their place of synthesis in the cytoplasm to their site of assembly in the nucleus. Recognition of import substrates is mediated by different types of nuclear localization signals, which are either directly recognized by import receptors or recruited to these via adaptor proteins. The novel transport adaptor Syo1 (Symportin), which is dedicated to the synchronous import of two functionally related ribosomal proteins, has recently been described. In this review, we highlight and discuss these findings in the context of our current knowledge of ribosome assembly and nucleocytoplasmic transport. We propose that nuclear co-import of functionally and topologically linked cargo could be a widespread strategy to streamline assembly of macromolecular complexes in the nucleus. 23969479 The possible use of combined electrical impedance and ultrasound velocity measurements for the non-invasive measurement of temperature during mild hyperthermia. This paper explores the possibility of using combined measurements of electrical impedance and changes in ultrasound time of flight for determining deep body temperature during mild hyperthermia. Simultaneous electrical impedance spectra (1 kHz-1024 kHz) and ultrasound time-of-flight measurements were made on layered sheep liver and fat tissue samples as the temperature was increased from 30-50 °C. The change in propagation velocity for 100% fat and 100% liver samples was found to vary linearly with temperature and the temperature coefficient of the time-of-flight was shown to vary linearly with the % fat in the sample (0.009% °C(-1)%(-1)). Tetrapolar impedance measurements normalized to 8 kHz were shown to have a small sensitivity to temperature for both liver (0.001% °C(-1) â‰¤ 45 °C) and fat (0.002% °C(-1) â‰¤ 512 kHz) and the best linear correlation between the normalized impedance and the % fat in the sample was found at 256 kHz (gradient 0.026%(-1), r(2) = 0.65). A bootstrap analysis on 15 layered tissue samples evaluated using the normalized impedance at 256 kHz to determine the % fat in the sample and the temperature coefficient of the time of flight to determine the temperature. The results showed differences (including some large differences) between the predicted and measured temperatures and an error evaluation identified the possible origins of these. 23816847 A new type of glucose biosensor based on surface acoustic wave resonator using Mn-doped ZnO multilayer structure. This work reports a high-performance Mn-doped ZnO multilayer structure Love mode surface acoustic wave (SAW) biosensor for the detection of blood sugar. The biosensor was functionalized via immobilizing glucose oxidase onto a pH-sensitive polymer which was attached on Mn-doped ZnO biosensor. The fabricated SAW glucose biosensor is highly sensitive, accurate and fast with good anti-interference. The sensitivity of the SAW glucose biosensor is 7.184MHz/mM and the accuracy is 6.96×10(-3)mM, which is sensitive and accurate enough for glucose monitoring. A good degree of reversibility and stability of the glucose sensor is also demonstrated, which keeps a constant differential frequency shift up to 32 days. Concerning the time response to human serum, the glucose sensor shows a value of 4.6±0.4min when increasing glucose concentrations and 7.1±0.6min when decreasing, which is less than 10min and reach the fast response requirement for medical applications. The Mn-doped ZnO Love mode SAW biosensor can be fully integrated with CMOS Si chips and developed as a portable, passive and wireless real time detection system for blood sugar monitoring in human serum. 23643255 Migraine, triptans, and the risk of developing rosacea: A population-based study within the United Kingdom. Rosacea is a common skin disease, involving neurogenic inflammation and neurovascular dysregulation. Migraine has been associated with vascular changes and sterile inflammation. The 2 diseases have been associated over decades, but evidence is scarce. Triptans have vasoconstricting and antiinflammatory properties, but a potential impact of this drug class on rosacea remains uninvestigated. We sought to analyze the association between migraine or triptan exposure and the risk of developing rosacea within the United Kingdom. We conducted a case-control study using the United Kingdom-based General Practice Research Database. We identified patients with incident rosacea between 1995 and 2009 (cases), and matched 1 rosacea-free control subject to each case. We compared the prevalence of diagnosed migraine and exposure to triptans before the first-time rosacea diagnosis between cases and controls using multivariate conditional logistic regression. Among 53,927 cases and 53,927 controls, we observed a small overall association between rosacea and migraine in women (adjusted odds ratio 1.22, 95% confidence interval 1.16-1.29), but not in men. This effect was somewhat more distinct in female migraineurs aged 50 to 59 years (odds ratio 1.36, 95% confidence interval 1.21-1.53). Female triptan users also revealed slightly increasing risk estimates with increasing age, with the highest odds ratio of 1.66 (95% confidence interval 1.30-2.10) in women aged 60 years or older. This is a retrospective case-control study, for which a certain degree of bias and confounding cannot be ruled out. We observed a slightly increased risk for female migraineurs to develop rosacea, particularly in women with severe migraine aged 50 years or older. 23872690 Response of right ventricular size to treatment with cardiac resynchronization therapy and the risk of ventricular tachyarrhythmias in MADIT-CRT. Cardiac resynchronization therapy (CRT) is increasingly recognized for its ability to reduce ventricular tachyarrhythmias, possibly associated with left ventricular reverse remodeling, but the role of the right ventricle (RV) in this process has not been examined. The purpose of this study was to investigate the relationship between ventricular tachyarrhythmias and change in RV dimensions in patients receiving CRT with a defibrillator (CRT-D). Multivariate Cox proportional hazards regression modeling was used to assess the risk for fast (≥180 bpm) ventricular tachycardia/ventricular fibrillation (VT/VF) or death by baseline and follow-up RV size (defined as right ventricular end-diastolic area [RVEDA]) among 1495 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT). Multivariate analysis showed that treatment with CRT-D was independently associated with a 27% (P = .003) reduction in the risk of VT/VF or death among patients with larger RVs (>first quartile RVEDA ≥13 mm(2)/m(2)) compared with implantable cardioverter-defibrillator (ICD)-only therapy, whereas in patients with smaller RVs there was no significant difference in the risk of VT/VF between the 2 treatment arms (hazard ratio = 1.00, P = .99). At 1-year follow-up, CRT-D patients displayed significantly greater reductions in RVEDA compared to ICD-only patients (P <.001), associated with a corresponding reduction in the risk of subsequent VT/VF or death (>first quartile reduction in RVEDA with CRT-D vs ICD-only: hazard ratio = 0.55, P <.001) independent of changes in left ventricular dimensions. Our findings suggest that the RV may have an important role in determining the antiarrhythmic effect of CRT independent of the effect of the device on the left ventricle. 23888331 Effect of mechanical and metabolic factors on motor function and fatigue in obese men and women: a cross-sectional study. Background - Mechanical overload and poor quality of contractile elements related to metabolic abnormalities concur to motor disability of obesity. The independent contribution of these factors to motor dysfunction in obese individuals is scarcely defined. Aim - Goal of the study is to test the hypothesis that metabolic factors may independently affect motor function in obesity. Methods - Leg maximum power output per unit body mass (W Mb), per unit fat-free mas (W FFM) and fatigue in daily functioning were assessed in 635 obese (BMI≥35 kg/m2) individuals (286 men, 349 women) aged 19-78 yr. The independent effects of age, BMI, insulin resistance and the five components of the metabolic syndrome on W Mb, W FFM and fatigue were evaluated by multivariate analysis. Results - A multiple regression analysis revealed that in both genders W Mb (denoting the individual's performance capability during anaerobic tasks) was independently reduced by age (p<0.001), BMI (p<0.05-0.001) and abnormalities of glucose metabolism (p<0.06- 0.01), while W FFM (representing the muscle intrinsic anaerobic capability) was affected only by age (p<0.001) and glucose metabolism impairment (p<0.06-0.01). In both genders fatigue was increased by age (p<0.001) and BMI (p<0.05-0.01), but augmented by low levels of HDL-cholesterol in men only (p<0.05). Conclusions - Beside the dependence from mechanical overload and age, low muscle power output in obese individuals was independently associated also with metabolic abnormalities related to impaired glucose homeostasis. Fatigue and performance, although similarly influenced by age and body mass excess, are affected by different metabolic factors. 23821192 Serine Protease Inhibitor A3K Protects Rabbit Corneal Endothelium From Barrier Function Disruption Induced by TNF-α. To determine if a serine protease inhibitor A3K (SA3K) reduces TNF-α-induced declines in rabbit corneal endothelial junctional barrier integrity. New Zealand rabbit corneas were incubated ex vivo for 24 hours in Dulbecco's modified Eagle's medium (DMEM) containing 10% FBS with or without TNF-α, in the presence or absence of SA3K at different concentrations. Corneal endothelial barrier function permeability was determined based on measurements of FITC-dextran tissue accumulation. Apical junctional complex (AJC) integrity was evaluated of zonula occludens-1 (ZO-1), vascular endothelial (VE)-cadherin, and filamentous actin (F-actin) and associated microtubules, as well as myosin light chain (MLC) by immunofluorescent staining, Western blot analysis, and/or RT-PCR. TNF-α (20 ng/mL) increased corneal endothelial FITC-dextran permeability by 1.8-fold compared with the untreated control. SA3K (100-200 nM) dose dependently suppressed TNF-α-induced increases in permeability. SA3K nearly completely reversed TNF-α-induced disruptions of tight junctional ZO-1 and subjacent adherens junctions VE-cadherin integrity. Interestingly, SA3K reversed TNF-α-induced disruption of AJC linkage to the cytoskeletal F-actin array by restoring F-actin double-band structures. SA3K also attenuated TNF-α-induced microtubule disassembly. Furthermore, SA3K blocked increases in MLC phosphorylation status elicited by TNF-α. SA3K exposure markedly reduced TNF-α-induced disruption of barrier structure and function in the rabbit corneal endothelium by maintaining AJC integrity. These protective effects are due to suppression of MLC activation. SA3K may have, in vivo, a therapeutic potential to offset TNF-α-induced declines in endothelial barrier structural integrity and function. 23601895 Detection and distribution of Tris(2-chloroethyl) phosphate on the East Antarctic ice sheet. Use of PBDEs (Polybrominated Diphenyl Ethers) has been restricted in Europe and North America in recent years. As substitute products with similar properties, OPEs (Organophosphate Esters) are now used as alternatives to PBDEs. Recent research has revealed that, similar to PBDEs, OPEs are also environmentally hazardous like PBDEs. Thus knowledge of their distribution and transport is needed to understand the extent of risk. However, studies on environmental OPEs mainly focus on Europe and North America. Knowledge in the southern hemisphere is very limited. In this study, we analyzed fresh snow samples collected along the transect from Zhongshan Station to Kunlun Station, East Antarctica. Several OPEs were detected in this transect, among which Tris(2-chloroethyl) phosphate (TCEP) had the highest frequency of quantification. It was quantified in most samples from the coastal half of the transect and was detected but not quantified in most samples in the inland half. We show that TCEP at this transect probably originated from the ocean around Antarctica. This study is the first to report the presence of TCEP on the Antarctica ice sheet, providing evidence of its long range transport from the source regions. This work also indicate that TCEP can transport hundreds of kilometers in the Antarctica. 23931769 Clinical utility of immunohistochemistry for the detection of the BRAF v600e mutation in papillary thyroid carcinoma. BRAF V600E mutation is the most common genetic alteration in papillary thyroid cancer (PTC). We used a mutation-specific antibody for immunohistochemical (IHC) detection of the BRAF V600E mutation and correlated expression with clinicopathologic features. The study was designed to validate the accuracy and determine the clinical importance of IHC detection of the BRAF V600E mutation in PTC. Direct sequencing and IHC for BRAF V600E mutation was performed in 37 consecutive patients with PTCs. IHC was scored on an intensity proportion scale. IHC positive tumors were stratified into intensity categories. The categories were assessed for clinicopathologic variables, including age, extrathyroidal extension, lymphovascular invasion, and lymph node metastases. A total of 25 PTCs were BRAF V600E-positive and 12 were BRAF mutation-negative on IHC. The BRAF V600E mutation-specific antibody had a sensitivity of 89% and specificity of 100% for detecting the mutation. Tumors with high-intensity staining were more likely to have extrathyroidal extension. IHC is an accurate method for the detection of the BRAF V600E mutation in PTC, and its ability to quantify the mutation expression may serve as a better predictor of tumor behavior than molecular sequencing. It provides a potentially rapid, easily applicable, and economic alternative to current techniques. 23830111 Carotid blood flow measurement accelerated by compressed sensing: Validation in healthy volunteers. Measurement of blood flow by cine phase-contrast MRI is a valuable technique in the study of arterial disease but is time consuming, especially for multi-slice (4D) studies. Compressed sensing is a modern signal processing technique that exploits sparse signal representations to enable sampling at lower than the conventional Nyquist rate. It is emerging as a powerful technique for the acceleration of MRI acquisition. In this study we evaluated the accuracy of phase-contrast carotid blood flow measurement in healthy volunteers using threefold undersampling of kt-space and compressed sensing reconstruction. Sixteen healthy volunteers were scanned at 1.5T with a retrospectively gated 2D cine phase-contrast sequence. Both fully sampled and three-fold accelerated scans were carried out to measure blood flow velocities in the common carotid arteries. The accelerated scans used a k-t variable density randomised sampling scheme and standard compressed sensing reconstruction. Flow rates were determined by integration of velocities within the manually segmented arteries. Undersampled measurements were compared with fully sampled results. Bland-Altman analysis found that peak velocities and flow rates determined from the compressed sensing scans were underestimated by 5% compared with fully sampled scanning. The corresponding figure for time-averaged flow was 3%. These acceptably small errors with a threefold reduction in scan time will facilitate future extension to 4D flow studies in clinical research and practice. 23857291 On-line capillary electrophoresis derivatization method for high sensitivity analysis of ubiquitin in filtered cerebrospinal fluid. Electrophoretically mediated microanalysis was implemented for on-line fluorescence derivatization of ubiquitin (UBI), a potential biomarker of Alzheimer disease. Ubiquitin was labeled on its amino groups by the Fluoprobes® 488 N-hydroxysuccinimide. The pH of the BGE, the applied electric field, and the washing process of the capillary were optimized. The best derivatization yield was obtained at pH 9.5 under an electric field of ∼210 V/cm. The concentration and volume of the fluorescent dye as well as the sample medium and volume of injected UBI were also optimized. In order to improve further the LOD of UBI, electrophoretically mediated microanalysis was performed in a wider (100 μm id) and longer (110 cm) capillary. As expected, these capillary dimensions improved the analytical sensitivity of UBI when compared to the 50 μm id capillary. Under the optimized conditions, this analytical methodology allowed the analysis of free UBI in standard solution with a LOD of ∼15 nM. Finally, the on-line fluorescent derivatization of UBI was applied to the detection and the quantification of UBI in cerebrospinal fluid (CSF) samples. Due to the high salt concentration of biological samples, desalting of CSF was required prior to the CE analysis. Quantification of UBI in CSF either by a direct evaluation of peak areas or using the standard addition method was achieved. 23872009 Electrogenerated chemiluminescence of novel TiO2/CdS nanocomposites for sensitive assays of cancer cells. A novel TiO2/CdS nanocomposite was prepared and used to fabricate an electrochemiluminescence (ECL) biosensor for the detection of cancer cells for the first time. The nanocomposite exhibited a strong cathodic ECL signal. Folic acid for targeting cell membranes was bound to a TiO2/CdS/3-aminopropyltriethoxysilane film, and specific recognition of folic acid to targeting cells was achieved, leading to a significant decrease in ECL intensity. The decrease in ECL signal was logarithmically related to the cell concentration in the range of 150-9600cellsml(-1). The ECL biosensor could provide a sensitive, selective, and convenient approach for early and accurate detection of cancer cells. 23726821 Prospective study of alcohol consumption and the risk of colorectal cancer before and after folic acid fortification in the United States. To evaluate the influence of alcohol consumption on the risk of colorectal cancer according to folic acid fortification period in the United States. We evaluated the association between alcohol consumption and colorectal cancer by fortification period (before 1998 vs. after 1998) in 2 prospective cohort studies, the Nurses' Health Study (NHS) of women and the Health Professionals Follow-up Study (HPFS) of men, in which 2793 cases of invasive colorectal cancer were documented. Alcohol consumption was associated with an increased risk of colorectal cancer. Among nonusers of multivitamins and/or folic acid supplements, the pooled multivariate relative risk for ≥30 g/d drinkers versus nondrinkers was 1.36 (95% confidence interval [95% CI], 1.09-1.70; P for trend, 0.02). The effect of alcohol consumption was slightly stronger in the prefolic acid fortification period (1980 NHS/1986 HPFS-1998) than in the postfortification period (1998-2008); the pooled multivariate relative risks for ≥30 g/d drinkers versus nondrinkers were 1.31 (95% CI, 1.00-1.71; P for trend, 0.10) in the prefortification period and 1.07 (95% CI, 0.69-1.65; P for trend, 0.67) in the postfortification period. Folic acid fortification may attenuate the adverse effect of high alcohol consumption on the risk of colorectal cancer. 22892197 The long leg radiograph is a reliable method of assessing alignment when compared to computer-assisted navigation and computer tomography. The mechanical alignment of the knee is an important factor in planning for, and subsequently assessing the success of a knee replacement. It is most commonly measured using a long-leg anteroposterior radiograph (LLR) encompassing the hip, knee and ankle. Other modalities of measuring alignment include computer tomography (CT) and intra-operative computer navigation (Cas). Recent studies comparing LLRs to Cas in measuring alignment have shown significant differences between the two and have hypothesized that Cas is a more accurate modality. This study aims to investigate the accuracy of the above mentioned modalities. A prospective study was undertaken comparing alignment as measured by long-leg radiographs and computer tomography to intra-operative navigation measurements in 40 patients undergoing a primary total knee replacement to test this hypothesis. Alignment was measured three times by three observers. Intra- and inter-observer correlation was sought between modalities. Intra-observer correlation was excellent in all cases (>0.98) with a coefficient of repeatability <1.1°. Inter-observer correlation was also excellent measuring >0.960 using LLRs and >0.970 using CT with coefficient of repeatability <2.8°. Inter-modality correlation proved to be higher when comparing LLRs and CT (>0.893), than when comparing either of these modalities with Cas (>0.643 and >0.671 respectively). Pre-operative values had the greatest variability. Given its availability and reduced radiation dose when compared to CT, LLRs should remain the mainstay of measuring the mechanical alignment of the lower limb, especially post-operatively. II. 23255285 Cell-material interactions on biphasic polyurethane matrix. Cell-matrix interaction is a key regulator for controlling stem cell fate in regenerative tissue engineering. These interactions are induced and controlled by the nanoscale features of extracellular matrix and are mimicked on synthetic matrices to control cell structure and functions. Recent studies have shown that nanostructured matrices can modulate stem cell behavior and exert specific role in tissue regeneration. In this study, we have demonstrated that nanostructured phase morphology of synthetic matrix can control adhesion, proliferation, organization and migration of human mesenchymal stem cells (MSCs). Nanostructured biodegradable polyurethanes (PU) with segmental composition exhibit biphasic morphology at nanoscale dimensions and can control cellular features of MSCs. Biodegradable PU with polyester soft segment and hard segment composed of aliphatic diisocyanates and dipeptide chain extender were designed to examine the effect polyurethane phase morphology. By altering the polyurethane composition, morphological architecture of PU was modulated and its effect was examined on MSC. Results show that MSCs can sense the nanoscale morphology of biphasic polyurethane matrix to exhibit distinct cellular features and, thus, signifies the relevance of matrix phase morphology. The role of nanostructured phases of a synthetic matrix in controlling cell-matrix interaction provides important insights for regulation of cell behavior on synthetic matrix and, therefore, is an important tool for engineering tissue regeneration. 23924320 Minimally invasive percutaneous nephrolithotomy for simple and complex renal calyceal stones: a comparative analysis of over 10000 cases. Objective: To determine whether minimally invasive PCNL (MPCNL) is as safe and effective in the treatment of complex renal calyceal stones as it is for simple renal stones. Methods: We retrospectively reviewed 5761(41.2%) simple calyceal stones (isolated renal pelvis and/or isolated calyx) and 8223(58.8%) complex calyceal stones (renal pelvis accompanying two calyces at least) that were treated by MPCNL between the years of 1992-2011. The safety, efficacy, and outcome were compared and analyzed. Results: Stone burden was larger in complex calyceal stones (1763.0 vs. 1018.6 mm2, p<0.05). Patients with simple stones had significantly shorter operative time, less frequency of multiple percutaneous accesses, less hemoglobin drop. They also had higher initial stone free rate (SFR) (77.6% vs. 66.4%) after single session of MPCNL (p<0.05). The differences diminished in the final SFR (86.7% vs. 86.1%) after re-look and/or auxiliary procedures (p>0.05). The complication rate (17.9% vs. 19.0%) and blood transfusion rate (grade II) (2.2% vs. 3.2%) were similar in both group (p>0.05). Both groups had low rate of high Clavien grade complications. However, renal vascular embolization (grade III) were significantly higher in patients with complex calyceal stones (p<0.05). Conclusions: MPCNL is a safe and effective treatment option for complex calyceal stones except a slightly higher frequency embolization rate. There was higher initial stone free rate in simple stones, but this difference diminished with secondary procedures. 23895493 Systematic and Controllable Negative, Zero, and Positive Thermal Expansion in Cubic Zr1-xSnxMo2O8. We describe the synthesis and characterization of a family of materials, Zr1-xSnxMo2O8 (0 < x < 1), whose isotropic thermal expansion coefficient can be systematically varied from negative to zero to positive values. These materials allow tunable expansion in a single phase as opposed to using a composite system. Linear thermal expansion coefficients, αl, ranging from -7.9(2) × 10(-6) to +5.9(2) × 10(-6) K(-1) (12-500 K) can be achieved across the series; contraction and expansion limits are of the same order of magnitude as the expansion of typical ceramics. We also report the various structures and thermal expansion of "cubic" SnMo2O8, and we use time- and temperature-dependent diffraction studies to describe a series of phase transitions between different ordered and disordered states of this material. 23834604 Withholding recess from elementary school students: policies matter. Recess is a key aspect of a healthy elementary school environment and helps to keep students physically active during the school day. Although national organizations recommend that students not be withheld from recess, this practice occurs in schools. This study examined whether district policies were associated with school practices regarding the withholding of recess for behavior management or academic reasons, as well as the use of physical activity (eg, running laps) for behavior management. Data were gathered from administrators at US public elementary schools by mail-back surveys conducted during the spring of the 2008-2009, 2009-2010, and 2010-2011 school years. Corresponding school district policies were gathered and coded. Each year's sample was nationally representative and data were analyzed as a stacked cross-sectional sample. A total of 1,919 surveys were received (61.2% response rate). Averaged over the 3 years, students were not withheld from recess for poor behavior or academic reasons at 28.3% and 26.7% of elementary schools, respectively. Strong district policy was associated with an increased odds of not withholding students from recess for poor behavior (adjusted odds ratio [OR] = 2.27, p < .001) or completing schoolwork (adjusted OR = 1.99, p < .001). Withholding recess was less common in the South versus the West, Midwest, and Northeast. Use of physical activity for behavior management was rare and not associated with district policy. Strengthening district policies may be an effective strategy for changing school practices pertaining to withholding of recess, and to ensure that all students have opportunities to be physically active during the school day. 23931679 Chronic traffic pollution exposure is associated with eosinophilic, but not neutrophilic inflammation in older adult asthmatics. Abstract Objective: Airway inflammatory patterns in older asthmatics are poorly understood despite high asthma-related morbidity and mortality. In this study, we sought to define the relationship between exposure to traffic pollutants, biomarkers in induced sputum, and asthma control in older adults. Methods: Induced sputum was collected from 35 non-smoking adults ≥ 65 years with a physician's diagnosis of asthma and reversibility with a bronchodilator or a positive methacholine challenge. Patients completed the Asthma Control Questionnaire (ACQ), and Elemental Carbon Attributable to Traffic (ECAT), a surrogate for chronic diesel particulate exposure, was determined. Equal numbers of subjects with high (≥0.39 µg/m(3)) versus low (<0.39 µg/m(3)) ECAT were included. Differential cell counts were performed on induced sputum, and myeloperoxidase (MPO) and eosinophil peroxidase (EPO) were measured in supernatants. Regression analyses were used to evaluate the relationship between sputum findings, ACQ scores, and ECAT. Results: After adjustment for potential confounders, subjects with poorly controlled asthma based on ACQ ≥1.5 (n=7) had significantly higher sputum eosinophils (median=4.4%) than those with ACQ <1.5 (n=28; eosinophils=2.6%; β=10.1 [95% CI=0.1-21.0]; p=0.05). Subjects with ACQ ≥1.5 also had significantly higher sputum neutrophils (84.2% versus 65.2%; β=7.1 [0.2-14.6]; p=0.05). Poorly controlled asthma was associated with higher sputum EPO (β= 2.4 [0.2-4.5], p=0.04), but not MPO (p=0.9). High ECAT was associated with higher eosinophils (β= 10.1 [1.8-18.4], p=0.02) but not higher neutrophils (p=0.6). Conclusions: Poorly controlled asthma in older adults is associated with eosinophilic and neutrophilic inflammation. Chronic residential traffic pollution exposure may be associated with eosinophilic, but not neutrophilic inflammation in older asthmatics. 23887079 Embryonic Transcription Factors CDX2 and Oct4 Are Overexpressed in Neuroendocrine Tumors of the Ileum: A Pilot Study. Background: Neuroendocrine tumors (NETs) of the ileum are rare submucosal tumors that are often diagnosed at advanced stages with metastatic spread to the liver causing a carcinoid syndrome. They present as solitary or multiple tumors. In NETs, loss of sequences on chromosomes 11, 16, 18 and 22 or gain of sequences on chromosomes 17 and 19 has been described. In this study we explored the expression of two novel candidate genes, CDX2 and Oct4, in NETs of the ileum and analyzed whether the molecular expression pattern correlates with the clinical phenotype (solitary/multiple tumors). Methods: Data from all patients who underwent surgery for a NET of the ileum between 2000 and 2010 were retrieved from a prospective database. For each patient, frozen normal and tumor tissue was used for the comparison of gene expression levels of two putative cancer stem cell markers, CDX2 and Oct4, using real-time PCR (rtPCR). Serial slides from paraffin blocks were used for immunohistochemistry. Gene expression was compared between normal and tumor tissue as well as between solitary and multiple tumors. Results: 78 patients were identified. In rtPCR, a statistically significant higher expression of CDX2 in tumor tissue (p < 0.001) compared to normal tissue was found. The expression of Oct4 was elevated in the tumors, but did not reach the level of significance (p = 0.155). The expression of both candidate genes was confirmed immunohistochemically and showed a nuclear expression pattern. There was no difference in expression between solitary and multiple tumors or between tumors that had already spread to the liver. Conclusion: CDX2 is overexpressed in ileum NETs, thus playing a role in the tumorigenesis of these rare tumors. Since expression does not correlate with clinical stage or phenotype, it might be an early event in tumor development. © 2013 S. Karger AG, Basel. 23765697 Alternative RNA splicing and cancer. Alternative splicing of pre-messenger RNA (mRNA) is a fundamental mechanism by which a gene can give rise to multiple distinct mRNA transcripts, yielding protein isoforms with different, even opposing, functions. With the recognition that alternative splicing occurs in nearly all human genes, its relationship with cancer-associated pathways has emerged as a rapidly growing field. In this review, we summarize recent findings that have implicated the critical role of alternative splicing in cancer and discuss current understandings of the mechanisms underlying dysregulated alternative splicing in cancer cells. WIREs RNA 2013, 4:547-566. doi: 10.1002/wrna.1178 Conflict of interest: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website. 23943472 Presence of diadenosine polyphosphates in microdialysis samples from rat cerebellum in vivo: effect of mild hyperammonemia on their receptors. Diadenosine triphosphate (Ap3A), diadenosine tetraphosphate (Ap4A), and diadenosine pentaphosphate (Ap5A) have been identified in microdialysis samples from the cerebellum of conscious freely moving rats, under basal conditions, by means of a high-performance liquid chromatography method. The occurrence of Ap3A in the cerebellar microdyalisates is noteworthy, as the presence of this compound in the interstitial medium in neural tissues has not been previously described. The concentrations measured for the diadenosine polyphosphates in the cerebellar dialysate were (in nanomolar) 10.5 ± 2.9, 5.4 ± 1.2, and 5.8 ± 1.3 for Ap3A, Ap4A, and Ap5A, respectively. These concentrations are in the range that allows the activation of the presynaptic dinucleotide receptor in nerve terminals. However, a possible interaction of these dinucleotides with other purinergic receptors cannot be ruled out, as rat cerebellum expresses a variety of P2X or P2Y receptors susceptible to be activated by diadenosine polyphosphates, such as the P2X1-4, P2Y1, P2Y2, P2Y4, and P2Y12 receptors, as demonstrated by quantitative real-time PCR. Also, the ecto-nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP3, able to hydrolyze the diadenosine polyphosphates and terminate their extracellular actions, are expressed in the rat cerebellum. All these evidences contribute to reinforce the role of diadenosine polyphosphates as signaling molecules in the central nervous system. Finally, we have analyzed the possible differences in the concentration of diadenosine polyphosphates in the cerebellar extracellular medium and changes in the expression levels of their receptors and hydrolyzing enzymes in an animal model of moderate hyperammonemia. 23901302 Cognitive behavior therapy for psychological distress in patients with recurrent miscarriage. To examine the reduction of psychiatric symptoms using individual cognitive behavior therapy (CBT) for women who suffer from recurrent miscarriage (RM) and depression and/or anxiety. Patients with RM and a score of five or higher for K6, a self-report screening scale for depression/anxiety, were interviewed to find information about stressful situations, thoughts, and consequent behaviors that are common and potential causes of psychological distress among RM patients. We then performed individual CBT on 14 patients with RM and depression/anxiety, referring to a list from the interviews, and examined the effects of CBT by a paired t-test. Fourteen women received CBT. The mean number of intervention times was 8.9 sessions (standard deviation [SD], 4.6 sessions). The average Beck Depression Inventory-Second Edition and State-Trait Anxiety Inventory-state anxiety scores, self-report screening scales for depression/anxiety, decreased from 13.6 (SD, 8.2) and 49.0 (SD, 7.1) at baseline to 5.2 (SD, 4.4) and 38.0 (SD, 10.2) posttherapy, respectively. These changes were statistically significant. The current preliminary open study confirmed that individual CBT was potentially useful for women with RM and depression and/or anxiety. This finding is the first step towards creating a comprehensive psychological support system for women with RM. 23220107 Nanogel vaccines targeting dendritic cells: contributions of the surface decoration and vaccine cargo on cell targeting and activation. Dendritic cells (DCs) play crucial roles in initiating and promoting immune defences, providing a pivotal target for vaccines. Although nanoparticle/nanogel-based delivery vehicles are showing potential for delivering vaccines to the immune system, there is little information on their characteristics of interaction with DCs. While particle uptake by DCs has been shown, the mechanism of cell targeting has not been studied. Moreover, it is still unclear how particle surface decoration influences the handling of such vaccines by DCs. Accordingly, chitosan nanogels carrying a model antigen, ovalbumin (ova), were analysed for interaction with and processing by DCs. Nanogel surfaces decorated with alginate (alg) or mannosylated alginate (alg-man), were used for targeting particular DC receptors. DC uptake of particles was observed, being dependent on endosomal-based processes. Inhibiting PI3-kinase or lipid raft activities impaired the uptake, which was only reduced, indicating the involvement of more than one endocytic pathway; notably, this was observed with both nanogel-delivered or free ova. Importantly, surface decoration of particles was less influential on particle uptake, contrasting with the ova cargo which played the major role. Such influence of the vaccine cargo has to date been largely ignored. When receptors interacting directly with ova were blocked, this altered the uptake of alg-nanogels and alg-man-nanogels carrying ova. The nanogels did have an influential role, in that modulation of DC functional activity owed more to the nanogel structure. Using an in vitro restimulation assay with ova-specific lymphocytes, nanogel-delivered and free ova were similarly effective at inducing specific antibody. Nanogel-delivered ova with mannose surface decoration was superior to free ova for inducing interferon-γ production by T-lymphocytes. Together, the data demonstrates that particle-based vaccine delivery should consider the influences of both the surface decoration and the vaccine cargo; each can influence different aspects of the interaction with DCs. Such combined influences are likely to impinge on the characteristics of the immune response induced. 23433942 MMP-1, MMP-9, and TIMP-1 levels in oral lichen planus patients with gingivitis or periodontitis. Oral lichen planus (OLP) is a chronic inflammatory disease of unknown aetiology. The aim of this study was to investigate matrix metalloproteinase (MMP)-1, MMP-9, and MMP inhibitor-1 (TIMP-1) levels in gingival crevicular fluid (GCF) by enzyme-linked immunosorbent assay and to investigate MMP-1, MMP-9, and TIMP-1 levels in gingival tissue by immunohistochemical staining of samples from patients with and without OLP. Twenty-seven patients with OLP (gingivitis, OLPG; chronic periodontitis, OLPP) and thirty healthy non-OLP patients (gingivitis, HG; chronic periodontitis, HP) were included in this study. The MMP-1, MMP-9, and TIMP-1 levels in GCF were determined by enzyme-linked immunosorbent assay. The MMP-1, MMP-9, and TIMP-1 levels in gingival tissue were determined by immunohistochemical staining. The mean levels of MMP-1 and MMP-9 in the GCF of OLPP patients were significantly higher and TIMP-1 was significantly lower than in HP patients; similarly, the mean levels of MMP-1 and MMP-9 were higher and TIMP-1 was significantly lower in OLPG patients than in HG patients. Our findings illustrate that tissue MMP-9 levels were statistically higher and TIMP-1 level were significantly lower in the OLPP group in comparison to the HP group, and the OLPG group in comparison to the HG group. The tissue MMP-1 level in the non-OLP group was found to be lower when compared with the OLP groups. But not statistically significant. Increased levels of MMP-1 and MMP-9 with decreased levels of TIMP-1 in GCF and increased MMP-1, MMP-9 levels and decreased TIMP-1 levels in the gingival tissue of OLP patients in combination with poor oral hygiene may cause increased tissue breakdown. The results of our study provide information about the effects of the periodontal status on the enzyme profiles in GCF and gingival tissue of OLP and non-OLP patients. 23928352 Regional behaviour among late Neanderthal groups in Western Europe: A comparative assessment of late Middle Palaeolithic bifacial tool variability. Population dynamics between and within Pleistocene groups are vital to understanding wider behavioural processes like social transmission and cultural variation. The late Middle Palaeolithic (MIS 5d-3, ca. 115,000-35,000 BP [years before present]) permits a novel, data-driven assessment of these concepts through a unique record: bifacial tools made by classic Neanderthals. Previously, studies of late Middle Palaeolithic bifacial tools were hampered by a convoluted plethora of competing terms, types and regional entities. This paper presents a large-scale intercomparison of this tool type, and bridges typo-technological and spatio-temporal data from across Western Europe (Britain, Belgium, the Netherlands, France and Germany). Results indicate a high level of variation among individual bifacial tools and assemblages. Each bifacial tool concept is correlated with various methods of production, resulting in large degrees of morphological variation. Despite such variation, a distinct three-fold, macro-regional pattern was identified: the Mousterian of Acheulean Tradition (MTA) in the southwest dominated by handaxes, the Keilmessergruppen (KMG) in the northeast typified by backed and leaf-shaped bifacial tools, and, finally a new unit, the Mousterian with Bifacial Tools (MBT), geographically situated between these two major entities, and characterised by a wider variety of bifacial tools. Differing local conditions, such as raw material or function, are not sufficient to explain this observed macro-regional tripartite. Instead, the MTA and KMG can be viewed as two distinct cultural traditions, where the production of a specific bifacial tool concept was passed on over generations. Conversely, the MBT is interpreted as a border zone where highly mobile groups of Neanderthals from both the east (KMG) and west (MTA) interacted. Principally, this study presents an archaeological contribution to behavioural concepts such as regionality, culture, social transmission and population dynamics. It illustrates the interpretive potential of large-scale lithic studies, and more specifically the presence of regionalised cultural behaviour amongst late Neanderthal groups in Western Europe. 23925998 Clinical biomarkers of response in advanced renal cell carcinoma. There are now a range of effective targeted agents available for the first- and second-line treatment of advanced renal cell carcinoma (RCC). However, patients with advanced RCC have varied responses to therapy; some experience long-term responses while others may not respond, or even progress rapidly. Characteristics or markers that could be used to determine which patients will benefit most from which agent may enable us to select the optimal treatment of each individual patient, thereby improving efficacy and avoiding unnecessary toxic effects. These characteristics may be at the cellular or genetic level. Alternatively, the occurrence of adverse events may act as surrogate markers of a drug's on treatment activity, enabling prediction of outcomes during treatment. Recently, it has been suggested that during some targeted therapy for advanced RCC, the occurrence of specific adverse events, such as hypertension, hypothyroidism, hand-foot syndrome or fatigue/asthenia, may be associated with improved efficacy. This article reviews the evidence supporting clinical biomarkers in patients with advanced RCC receiving targeted agents. We also consider how these clinical biomarkers may affect the future management of patients with advanced RCC. 23819644 Activity of neutrophil elastase reflects the progression of acute pancreatitis. Objective. Neutrophil elastase (NE) concentration is associated with progression of acute pancreatitis (AP), but measuring total NE concentration includes biologically inactive NE. This study aims to investigate the relationship between NE activity and the aetiology and severity of AP and associated organ failure. Methods. Seventy-five patients admitted to our surgery department with a first episode of AP during 2004-2005 were age- and sex-matched to 20 healthy volunteers (controls). NE activity was assessed using venous blood samples obtained on patient admission and after 1, 2 and 14 days. One sample was also taken from each control. ANOVA was used for statistical comparison between groups. Results. Baseline NE activity (geometric mean; 95% confidence intervals) differed between patients (58.6 nM of substrate 7-amino-4-methylcoumarin [AMC]/hour; 48.52-70.72) and controls (31.5 nM AMC/hour; 25.5-39.0) (p = 0.0003), and did not correlate with time between symptom onset and admission. Patients with alcohol-induced AP demonstrated higher mean activity (59.1 nM AMC/h; 44.7-78.2) than those with gallstone-induced AP (41.7 nM AMC/h; 33.9-51.4) (p = 0.0496). NE activity was higher overall in patients with predicted severe AP (60.9 nM AMC/h; 48.0-77.2) than in those with predicted mild AP (42.1 nM AMC/h; 34.9-50.8) (p = 0.027). Patients with respiratory failure had higher NE activity (82.5 nM AMC/h; 57.5-118.4) than those without (43.9 nM AMC/h; 37.6-51.3) (p = 0.0024). Conclusions. NE activity was associated with predicted severity of AP and AP-associated respiratory failure. Specific NE inhibitors may have therapeutic potential in acute pancreatitis. 23360072 Case study of the Swiss flora for prior phytochemical and biological investigations. Estimates in the literature as to what extent the world's higher plant species have been studied chemically or for bioactivity are contradictory and range from 0.5% to >12%. In this survey, a model to make credible estimates of the extent of their study is proposed and is exemplified by applying it in a case study of plants native to Switzerland. Using a widely available database (SciFinder Scholar), 454 535 literature references for the 2677 native Swiss plant species were retrieved. It was determined that 55% of these species have been investigated phytochemically and 28% for biological activity. The influence of factors such as commonness, growth form, habitat, medicinal use, and reported toxicity on the extent to which different plant groups have been studied is analyzed. The predictive value of random sampling of subsets of plants is compared to the study of the entire Swiss flora, to show that a credible estimate of the extent of prior studies can be achieved with just 5% of these species. 23894460 Role for the epidermal growth factor receptor in chemotherapy-induced alopecia. Treatment of cancer patients with chemotherapeutics like cyclophosphamide often causes alopecia as a result of premature and aberrant catagen. Because the epidermal growth factor receptor (EGFR) signals anagen hair follicles to enter catagen, we hypothesized that EGFR signaling may be involved in cyclophosphamide-induced alopecia. To test this hypothesis, skin-targeted Egfr mutant mice were generated by crossing floxed Egfr and Keratin 14 promoter-driven Cre recombinase mice. Cyclophosphamide treatment of control mice resulted in alopecia while Egfr mutant skin was resistant to cyclophosphamide-induced alopecia. Egfr mutant skin entered catagen normally, as indicated by dermal papilla condensation and decreased follicular proliferation, but did not progress to telogen as did Egfr wild type follicles. Egfr mutant follicles responded with less proliferation, apoptosis, and fewer p53-positive cells after cyclophosphamide. Treatment of control mice with the EGFR inhibitors erlotinib or gefitinib similarly suppressed alopecia and catagen progression by cyclophosphamide. Secondary analysis of clinical trials utilizing EGFR-targeted therapies and alopecia-inducing chemotherapy also revealed evidence for involvement of EGFR in chemotherapy-induced alopecia. Taken together, our results demonstrated the involvement of EGFR signaling in chemotherapy-induced alopecia, which will help in the design of novel therapeutic regimens to minimize chemotherapy-induced alopecia. 23279839 Self-trimerization of ExsD limits inhibition of the Pseudomonas aeruginosa transcriptional activator ExsA in vitro. The opportunistic pathogen Pseudomonas aeruginosa ranks among the leading causes of nosocomial infection. The type III secretion system (T3SS) aids acute Pseudomonas aeruginosa infection by injecting potent cytotoxins into host cells to suppress the host's innate immune response. Expression of all T3SS-related genes is strictly dependent on the transcription factor ExsA. Consequently, ExsA and the biological processes that regulate ExsA function are of great biomedical interest. The present study focused on the ExsA-ExsC-ExsD-ExsE signaling cascade, which ties host cell contact to the upregulation of T3SS gene expression. Prior to T3SS induction, the antiactivator protein ExsD binds to ExsA and blocks ExsA-dependent transcription by interfering with ExsA dimerization and promoter interactions. Upon host cell contact, ExsD is sequestered by the T3SS chaperone ExsC, resulting in the release of ExsA and upregulation of the T3SS. Previous studies have shown that the ExsD-ExsA interactions are not freely reversible. Because independently folded ExsD and ExsA were not found to interact, it has been hypothesized that folding intermediates of the two proteins form the complex. Here, we demonstrate, for the first time, that ExsD alone is sufficient to inhibit ExsA-dependent transcription in vitro and that no other cellular factors are required. More significantly, we show that independently folded ExsD and ExsA are capable of interacting, but only at 37 °C and not at 30 °C. Guided by the crystal structure of ExsD, we designed a monomeric variant of the protein, and demonstrated that ExsD trimerization prevents ExsD from inhibiting ExsA-dependent transcription at 30 °C. We propose that this unique mechanism plays an important role in T3SS regulation. 23957211 Synthesis and Growth Mechanism of Thin-Film TiO2 Nanotube Arrays on FIB Micropatterned 3D Isolated Regions of Titanium on Silicon. In this paper, fabrication and growth mechanism of net-shape micro-patterned self-organized thin-film TiO2 nanotube (TFTN) arrays on silicon substrate is reported. Electrochemical anodization is used to grow the nanotubes from thin-film titanium sputtered on silicon substrate with average diameter of ~30 nm and length of ~1.5 µm using aqueous and organic-based types of electrolytes. Fabrication and growth mechanism of TFTN arrays from micro-patterned three-dimensional (3D) isolated islands of sputtered Ti on silicon substrate is demonstrated for the first time using focused ion beam (FIB) technique. This work demonstrates the use of the FIB technique as a simple, high resolution and mask-less method for high aspect ratio etching for creation of isolated islands and shows great promise toward the use of the proposed approach for the development of metal-oxide nanostructured devices and their integration with micro- and nano-systems within Si-based integrated-circuit devices. 23829356 Anti-D alloimmunization after D-incompatible platelet transfusions: a 14-year single-institution retrospective review. A small, but immunogenic dose of red blood cells (RBCs) may be contained in apheresis platelets (PLTs). Attempts are made to provide D- recipients with D- PLTs to prevent anti-D alloimmunization and the potential for hemolytic disease of the fetus and newborn. Beth Israel Deaconess Medical Center has a policy that when necessary to transfuse D+ PLTs to D- patients, we recommend that RhIG be given when the patient is a woman of child-bearing age or a potential liver transplant patient. We sought to retrospectively determine the rate of anti-D formation after D-incompatible apheresis PLT transfusions in those patients not receiving RhIG and not receiving D+ RBCs over a 14-year period at our institution. All D- patients (626) who received D+ prestorage leukoreduced apheresis PLTs between January 1, 1997, and December 31, 2011, were identified. Those patients who received RhIG (45), D+ RBC transfusions (50), or stem cell transplantation from a D+ donor (16); had prior anti-D (23); or had unresolved Rh at admission (8) were not eligible for analysis. Only those patients who had an antibody screen performed at least 4 weeks after the incipient PLT transfusion were evaluated (130). Of 130 eligible D- patients, 48% women and 57% immunocompetent, who received a total of 565 apheresis PLTs, none formed anti-D. These findings support the use of D+ apheresis PLTs without RhIG irrespective of D status in all recipients. 23968254 Laparoscopic Transhiatal Esophagectomy and Gastric Pull-Up in Long-Gap Esophageal Atresia: Description of the Technique in Our First 10 Cases. Abstract The definition accepted for the largely controversial and multiple criteria condition known as long-gap esophageal atresia (LGEA) is "inability to achieve primary end-to-end anastomosis," particularly in the presence of a tracheo-esophageal fistula. In this article we report our technique of laparoscopic transhiatal esophagectomy and gastric pull-up (TEGPUL) in LGEA, based on the open approach of Spitz. Differences between TEGPUL and the original technique are the absence of a pyloromyotomy, the peel-away technique, the gastric pull-up through the distal esophagus, and its extracorporeal section. We performed the technique in 10 patients: 6 girls and 4 boys. Six had esophageal atresia type III (60%), three had esophageal atresia type I (30%) and one had esophageal atresia type II (10%). Mean time in surgery was 4.43 hours (range, 3.3-7 hours). Average stay in the pediatric intensive care unit was 5.9 days (range, 3-25 days). Average time under mechanical ventilation was 4.6 days (range, 2-8 days). Average total hospital stay was 19.4 days (range, 11-40 days). Oral feeding began at 15.6 days (range, 5-30 days). We believe these steps and the early realization of the technique will reduce the morbidity and mortality among these patients and decrease the number of contraindications to gastric pull-up. Nevertheless, a valid conclusion will require more studies with a larger number of patients and longer follow-up. 23864367 Biomaterials for spinal cord repair. Spinal cord injury (SCI) results in permanent loss of function leading to often devastating personal, economic and social problems. A contributing factor to the permanence of SCI is that damaged axons do not regenerate, which prevents the re-establishment of axonal circuits involved in function. Many groups are working to develop treatments that address the lack of axon regeneration after SCI. The emergence of biomaterials for regeneration and increased collaboration between engineers, basic and translational scientists, and clinicians hold promise for the development of effective therapies for SCI. A plethora of biomaterials is available and has been tested in various models of SCI. Considering the clinical relevance of contusion injuries, we primarily focus on polymers that meet the specific criteria for addressing this type of injury. Biomaterials may provide structural support and/or serve as a delivery vehicle for factors to arrest growth inhibition and promote axonal growth. Designing materials to address the specific needs of the damaged central nervous system is crucial and possible with current technology. Here, we review the most prominent materials, their optimal characteristics, and their potential roles in repairing and regenerating damaged axons following SCi. 23870876 Comparison of chitosan-gelatin composite and bilayer coating and film effect on the quality of refrigerated rainbow trout. The effect of chitosan-gelatin coating and film on the rancidity development in rainbow trout (Oncorhynchus mykiss) fillets during refrigerated storage (4±1°C) was examined over a period of 16days. Composite and bilayer coated and film wrapped fish samples were analysed periodically for microbiological (total viable count, psychrotrophic count) and chemical (TVB-N, POV, TBARS, FFA) characteristics. The results indicated that chitosan-gelatin coating and film retained their good quality characteristics and extend the shelf life of fish samples during refrigerated storage .The coating was better than the film in reducing lipid oxidation of fillets, but there was no significant difference between them in control of bacterial contamination. 23806560 Differential expression of estrogen receptor beta isoforms in prostate cancer through interplay between transcriptional and translational regulation. Estrogen receptor β (ERβ) and its isoforms have different putative functions and expression patterns in prostate cancer. Current studies on 5'-most exons, 0K and 0N, show that their respective promoters are actively involved in transcription. These data, however, do not explain why ERβ isoforms are differentially expressed in normal and cancerous tissues, since 0K and 0N transcripts are detectable in clinical specimens. Various combinations of 5' untranslated exons, termed exon 0Xs, associate with promoter 0K only and exon 0Xs accommodate upstream open reading frames (uORFs) reducing protein expression. Moreover, ERβ1, 2, and 5 are transcriptionally linked to promoter 0K; exon 0Xs are spliced only into ERβ2 and ERβ5 transcripts, suggesting that their expressions are regulated post-transcriptionally by exon 0Xs. This study reveals that expression of ERβ1 is regulated primarily at the transcriptional level, whereas that of ERβ2 and ERβ5 is controlled by the interplay between transcriptional and post-transcriptional regulation. 23910375 Periodic minimal surface organizations of the lipid bilayer at the lung surface and in cubic cytomembrane assemblies. The existence of infinite periodic lipid bilayer structures in biological systems was first demonstrated in cell membrane assemblies. Such periodicity is only possible in symmetric bilayers, and their occurrence is discussed here in relation to the asymmetry of cell membranes in vivo. A periodic membrane conformation in the prolamellar body of plants corresponds to a dormant state without photosynthesis. A similar reversible formation of a dormant state has also been observed in the mitochondria of the amoeba Chaos. In these cases the energy production has become insufficient to maintain the membrane asymmetry. Formation of membranes that are symmetric over the bilayer is proposed to be a principal mechanism behind formation of cubic membrane systems. Another type of bicontinuous minimal surface structure is considered to form the alveolar lining of mammals at normal breathing conditions. The CLP surface corresponds to such a tetragonal surface phase. It is also a symmetric bilayer and in a state of zero energy expenditure. Structural alternatives of the bilayer conformation in this latter system are also discussed here. 23001138 The risky cocktail: what combination effects can we expect between ecstasy and other amphetamines? The recreational and illicit use of amphetaminic designer compounds, specially 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy), is of concern worldwide. Such psychostimulating drugs are frequently present as complex mixtures in 'rave' pills, making concomitant polysubstance use a common trend. However, the understanding of possible combination effects with these substances is still scarce. The present study was aimed at predicting the cytotoxic effects of mixtures of four amphetaminic derivatives: MDMA, methamphetamine, 4-methylthioamphetamine and d-amphetamine in a human hepatoma cell line. Concentration-response curves for all single-mixture components were recorded by the MTT assay. Data obtained for individual agents were then used to compute the additivity expectations for mixtures of definite composition, using the pharmacological models of concentration addition (CA) and independent action. By comparing the predicted calculations with the experimentally observed effects, we concluded that CA accurately predicts the combination of amphetamines, which act together to generate additive effects over a large range of concentrations. Notably, we observed substantial mixture effects even when each drug was present at low concentrations, which individually produced unnoticeable effects. Nonetheless, for all tested mixtures, a small deviation from additivity was observed towards higher concentrations, particularly at high effect levels. A possible metabolic interaction, which could explain such deviation, was investigated, and it was observed that at higher mixture concentrations increased MDMA metabolism could be contributing to divergences from additivity. In conclusion, the present work clearly demonstrates that potentially harmful interactions among amphetaminic drugs are expected when these drugs are taken concomitantly. 23664476 A coupled biological and photocatalysis pretreatment system for the removal of crystal violet from wastewater. The efficiency of a coupled photocatalytic-biological system for removing crystal violet (CV) from an aqueous solution was assessed. Initial experiments demonstrated that the optimal operating parameters for the photoreactor were a 1.5-h reaction time, pH 7.0, and a 2.0-min retention time. Under these conditions, the photocatalytic reaction reduced the toxicity of the CV solution by 94%. Subsequent evaluation of the performance and characteristics of the coupled photocatalytic-biological system in terms of CV removal revealed that the coupled system successfully removed and efficiently mineralized CV in a semi-continuous mode when the CV concentration was <150mgL(-1). Based on our analysis of the degradation products, CV degradation in this coupled system involved stepwise demethylation and aromatic ring opening. Phylogenetic analysis of the bioreactor effluent showed that the predominant phyla were Proteobacteria, followed by Bacteroidetes and Actinobacteria, suggesting that this coupled system is conducive for such processes as demethylation, aromatic ring opening, carbon oxidation, and nitrification. These results were verified in a GC-MS analysis. To our knowledge, this is the first report on CV removal using a coupled system. 22694056 Recurrent gene deletions and the evolution of adaptive cyanogenesis polymorphisms in white clover (Trifolium repens L.). Understanding the molecular evolution of genes that underlie intraspecific polymorphisms can provide insights into the process of adaptive evolution. For adaptive polymorphisms characterized by gene presence/absence (P/A) variation, underlying loci commonly show signatures of long-term balancing selection, with gene-presence and gene-absence alleles maintained as two divergent lineages. We examined the molecular evolution of two unlinked P/A polymorphisms that underlie a well-documented adaptive polymorphism for cyanogenesis (hydrogen cyanide release with tissue damage) in white clover. Both cyanogenic and acyanogenic plants occur in this species, and the ecological forces that maintain this chemical defence polymorphism have been studied for several decades. Using a sample of 65 plants, we investigated the molecular evolution of sequences flanking the two underlying cyanogenesis genes: Ac/ac (controlling the presence/absence of cyanogenic glucosides) and Li/li (controlling the presence/absence of their hydrolysing enzyme, linamarase). A combination of genome walking, PCR assays, DNA sequence analysis and Southern blotting was used to test whether these adaptive P/A polymorphisms show evidence of long-term balancing selection, or whether gene-absence alleles have evolved repeatedly through independent deletion events. For both loci, we detect no signatures of balancing selection in the closest flanking genomic sequences. Instead, we find evidence for variation in the size of the deletions characterizing gene-absence alleles. These observations strongly suggest that both of these polymorphisms have been evolving through recurrent gene deletions over time. We discuss the genetic mechanisms that could account for this surprising pattern and the implications of these findings for mechanisms of rapid adaptive evolution in white clover. 23921855 Effect of child marriage on use of maternal health care services in pakistan. To assess the association between child marriage (before 18 years of age) and maternal health care services use in Pakistan. We limited the data from Pakistan Demographic and Health Survey, 2006-2007, to ever-married females aged 15-24 years with at least one childbirth (n=1,404) to identify differences in prenatal care provision (skilled or unskilled medical care provider), antenatal care (antenatal visits; care at home or a hospital), care at delivery (assistance by unskilled medical care provider), and place of birth by early (younger than 18 years) compared with adult (18 years or older) age at marriage. Associations between child marriage and health care services use were assessed by calculating adjusted odds ratios (OR) using logistic regression models after controlling for demographics, social equity indicators (education, wealth index, rural residence), employment status, and partners' education. Overall, 66.1% of ever-married respondents aged 15-24 years in Pakistan with at least one childbirth were married before the age of 18 years. More than half (61.9%) of females married as children had no formal education, and the majority (71.0%) resided in rural areas. Child marriage was significantly associated with decreased likelihood of any prenatal care (adjusted OR 0.73, 95% confidence interval [CI] 0.534-0.993) and prenatal care by skilled medical care providers (adjusted OR 0.64, 95% CI 0.476-0.871) and increased likelihood of delivery assistance by unskilled medical providers (adjusted OR 1.90, 95% CI 1.435-2.518) and delivery at home (adjusted OR 2.17, 95% CI 1.617-2.915). Efforts to increase the age of marriage and delay childbearing may have population-level effects on reducing disparities between females married as children and adults and improving maternal and child health in Pakistan. : II. 23884264 Rupture of an unscarred uterus in a woman with long-term steroid treatment for systemic lupus erythematosus. Unscarred uterine rupture in association with systemic lupus erythematosus (SLE) and long-term steroid treatment is rare. A 36-year-old primigravid woman conceived a twin gestation after in vitro fertilization therapy. At 23 weeks of gestation, she was found to have a spontaneous rupture of the uterus. Her medical history was significant for SLE for a duration of 19 years, and her condition had been maintained with prednisolone. She had no history of uterine scarring or other known risk factors for uterine rupture. The uterine fundus was the main location of the rupture and a subtotal hysterectomy was performed. Long-term treatment with systemic steroids and SLE may increase the risk of spontaneous rupture of an unscarred uterus. 23404651 Phylogenetic analysis of burkholderia species by multilocus sequence analysis. Burkholderia comprises more than 60 species of environmental, clinical, and agro-biotechnological relevance. Previous phylogenetic analyses of 16S rRNA, recA, gyrB, rpoB, and acdS gene sequences as well as genome sequence comparisons of different Burkholderia species have revealed two major species clusters. In this study, we undertook a multilocus sequence analysis of 77 type and reference strains of Burkholderia using atpD, gltB, lepA, and recA genes in combination with the 16S rRNA gene sequence and employed maximum likelihood and neighbor-joining criteria to test this further. The phylogenetic analysis revealed, with high supporting values, distinct lineages within the genus Burkholderia. The two large groups were named A and B, whereas the B. rhizoxinica/B. endofungorum, and B. andropogonis groups consisted of two and one species, respectively. The group A encompasses several plant-associated and saprophytic bacterial species. The group B comprises the B. cepacia complex (opportunistic human pathogens), the B. pseudomallei subgroup, which includes both human and animal pathogens, and an assemblage of plant pathogenic species. The distinct lineages present in Burkholderia suggest that each group might represent a different genus. However, it will be necessary to analyze the full set of Burkholderia species and explore whether enough phenotypic features exist among the different clusters to propose that these groups should be considered separate genera. 23836788 Long-term monitoring at multiple trophic levels suggests heterogeneity in responses to climate change in the Canadian Arctic tundra. Arctic wildlife is often presented as being highly at risk in the face of current climate warming. We use the long-term (up to 24 years) monitoring records available on Bylot Island in the Canadian Arctic to examine temporal trends in population attributes of several terrestrial vertebrates and in primary production. Despite a warming trend (e.g. cumulative annual thawing degree-days increased by 37% and snow-melt date advanced by 4-7 days over a 23-year period), we found little evidence for changes in the phenology, abundance or productivity of several vertebrate species (snow goose, foxes, lemmings, avian predators and one passerine). Only primary production showed a response to warming (annual above-ground biomass of wetland graminoids increased by 123% during this period). We nonetheless found evidence for potential mismatches between herbivores and their food plants in response to warming as snow geese adjusted their laying date by only 3.8 days on average for a change in snow-melt of 10 days, half of the corresponding adjustment shown by the timing of plant growth (7.1 days). We discuss several reasons (duration of time series, large annual variability, amplitude of observed climate change, nonlinear dynamic or constraints imposed by various rate of warming with latitude in migrants) to explain the lack of response by herbivores and predators to climate warming at our study site. We also show how length and intensity of monitoring could affect our ability to detect temporal trends and provide recommendations for future monitoring. 23628348 Long-term treatment with deferiprone enhances left ventricular ejection function when compared to deferoxamine in patients with thalassemia major. Transfusion and iron chelation treatment have significantly reduced morbidity and improved survival of patients with thalassemia major. However, cardiac disease continues to be the most common cause of death. We report the left-ventricular ejection fraction, determined by echocardiography, in one hundred sixty-eight patients with thalassemia major followed for at least 5years who received continuous monotherapy with deferoxamine (N=108) or deferiprone (N=60). The statistical analysis, using the generalized estimating equations model, indicated that the group treated with deferiprone had a significantly better left-ventricular ejection fraction than did those treated with deferoxamine (coefficient 0.97; 95% CI 0.37; 1.6, p=0.002). The heart may be particularly sensitive to iron-induced mitochondrial damage because of the large number of mitochondria and its low level of antioxidants. Deferiprone, because of its lower molecular weight, might cross into heart mitochondria more efficiently, improving their activity and, thereby, myocardial cell function. Our findings indicate that the long-term administration of deferiprone significantly enhances left-ventricular function over time in comparison with deferoxamine treatment. However, because of limitations related to the design of this study, these findings should be confirmed in a prospective, randomized clinical trial. 23711811 Long-term outcomes of drug-eluting stent implantation versus coronary artery bypass grafting for patients with coronary artery disease and chronic left ventricular systolic dysfunction. Limited data are available on comparing the clinical outcomes of coronary artery bypass grafting (CABG) and drug-eluting stent (DES) implantation in patients with reduced left ventricular systolic function in the DES era. From January 2003 to December 2010, 953 patients with reduced left ventricular systolic function, defined as a left ventricular ejection fraction <50%, who had undergone percutaneous coronary intervention with DESs (n = 402) or CABG (n = 551) were enrolled in a retrospective, observational registry. Patients with acute myocardial infarction were excluded. Propensity score-matching analysis was also performed in 141 patient pairs. The primary outcome was all-cause death. The median follow-up duration was 32 months (interquartile range 15 to 61). All-cause death occurred in 81 patients (20.1%) in the DES group and 98 patient (17.8%) in the CABG group (p = 0.524). After propensity score matching, the long-term cumulative rate of death was not significantly different between the 2 groups (DES vs CABG 21.3% vs 19.1%; adjusted hazard ratio 1.23, 95% confidence interval 0.57 to 2.66, p = 0.603). However, the rate of major adverse cardiac and cerebrovascular events (35.5% vs 24.1%, adjusted hazard ratio 1.69, 95% confidence interval 1.04 to 2.77, p = 0.036) was higher in the DES group than the CABG group. This was driven by the higher incidence of repeat revascularization in the DES group (11.3% vs 4.3%, adjusted hazard ratio 3.65, 95% confidence interval 1.01 to 10.37, p = 0.018). In conclusion, DES implantation provides comparable long-term clinical outcomes, except for repeat revascularization, to CABG in patients with coronary artery disease and chronic left ventricular systolic dysfunction. 23926135 Non-Uniform, Age-Related Decrements in Regional Sweating and Skin Blood Flow. Aging is associated with attenuated thermoregulatory function which varies regionally over the body. Decrements in vasodilation and sweating are well documented with age yet limited data are available concerning the regional relation between these responses. We aimed to examine age-related alterations in the relation between regional sweating (RSR) and skin blood flow (SkBF) to thermal and pharmacological stimuli. Four microdialysis fibers were inserted in the ventral forearm, abdomen, thigh, and lower back of eight healthy aged subjects (64±7 years) and nine young (23±3 years) during 1) acetylcholine dose response (ACh 1x10(-7) - 0.1 M, mean skin temperature 34°C) and 2) passive whole body heating to Δ1°C rise in oral temperature (Tor). RSR and SkBF were measured over each microdialysis membrane using ventilated capsules and laser-Doppler flowmetry. Maximal SkBF was measured at the end of both protocols (50mM SNP). Regional sweating thresholds and RSR were attenuated in aged versus young at all sites (p<0.0001) during whole body heating. Vasodilation thresholds were similar between groups (p>0.05). Attenuated SkBF were observed at the arm and back in the aged, representing 56% and 82% of those in the young at these sites, respectively (0.5 ΔTor). During ACh perfusion SkBF (p=0.137) and RSR were similar between groups (p= 0.326). Together these findings suggest regional age-related decrements in heat-activated sweat gland function but not cholinergic sensitivity. Functional consequences of such thermoregulatory impairment include the compromised ability of older individuals to defend core temperature during heat exposure, and a subsequently greater susceptibility to heat-related illness and injury. 23636513 Should an Involved but Functioning Recurrent Laryngeal Nerve be Shaved or Resected in a Locally Advanced Papillary Thyroid Carcinoma? The issue of whether an involved but functioning recurrent laryngeal nerve (RLN) should be shaved or resected in locally advanced papillary thyroid carcinoma (PTC) remains controversial. Our study aimed to compare the early and late outcomes between those who underwent shaving and those who underwent resection and also to identify independent prognostic factors in this subset of patients. Of the 77 patients with 1 RLN involved by PTC, 39 (50.6 %) underwent RLN preservation (group I) while 38 (49.4 %) underwent RLN resection (group II). Early and late vocal cord function (as assessed by flexible laryngoscopy) and disease status were compared between the 2 groups. A multivariate Cox proportional hazards model was carried out to identify independent factors. Baseline characteristics were comparable between the 2 groups. Although temporary vocal cord palsy rate was similar between the 2 groups (p = 0.532), 5 patients in group II (13.2 %) suffered temporary bilateral vocal cord palsies with 1 requiring a tracheostomy lasting for 1 month. After a median follow-up of 113.8 months, 1 patient from each group developed new onset vocal cord palsy. Presence of distant metastases (hazard ratio [HR] = 5.892, 95 % CI = 1.971-17.604, p = 0.001) and incomplete surgical resection in non-RLN concomitant sites (HR = 2.491, 95 % CI = 1.181-5.476, p = 0.024) were the 2 independent predictors for a poor cancer-specific survival. Our data suggested that shaving could preserve the normal functionality in most of the involved RLNs (>90 %) in the short to medium term. In the presence of distant metastases or incomplete resection in other non-RLN concomitant sites, the argument for shaving over resection appears even stronger. 23870299 Reproducibility of Graft Preparations in Descemet's Membrane Endothelial Keratoplasty. To assess the reproducibility of manual graft preparation and evaluate the incidence rate and nature of structural anomalies of Descemet's membrane (DM) preventing successful graft preparation in DM endothelial keratoplasty (DMEK). Prospective, single-center, nonrandomized, consecutive case series. We analyzed 350 corneoscleral buttons from donors aged 18-95 years stored in Optisol-GS or Dulbecco's modified Eagle's medium and used for DMEK surgery in 343 consecutive patients with Fuchs' endothelial dystrophy or pseudophakic bullous keratopathy. Residual endothelial cell-DM complexes obtained after successful DM stripping for DMEK and whole donor corneas obtained after unsuccessful DM stripping were examined by transmission electron microscopy and immunohistochemistry. Accuracy of the cleavage plane between DM and corneal stroma and structural abnormalities of the DM-stroma interface. Uneventful manual separation without any disruption of DM was achieved in 335 of 350 donor corneas (95.7%) by use of a previously established bimanual submerged preparation technique. Correspondingly, the peeled DM specimens revealed a regular and smooth cleavage plane exposing the amorphous interfacial matrix on their anterior surface. Although 8 of 350 donor corneas (2.3%) showed focal adhesions of DM to the corneal stroma and developed isolated tears during stripping, preparation of the graft could be successfully completed. However, 7 of the 350 donor corneas (2.0%) showed extremely strong adhesion and multiple tears of DM, preventing successful preparation of the graft. These specimens revealed either ultrastructural (peg-like interlockings) or biochemical abnormalities (increased staining intensities for adhesive glycoproteins) along the DM-stroma interface. Using an appropriate technique, manual preparation of grafts for DMEK with reproducible tissue qualities is possible in the vast majority (98%) of donor corneas. Although a relatively rare phenomenon, interindividual variations in DM structure and composition may be responsible for failure of graft preparation in about 2% of donor corneas. The authors have no proprietary or commercial interest in any of the materials discussed in this article. 23821291 Characterization of a D-Stereoselective Aminopeptidase (DamA) Exhibiting Aminolytic Activity and Halophilicity from Aspergillus oryzae. β-Aminopeptidases exhibit both hydrolytic and aminolytic (peptide bond formation) activities and have only been reported in bacteria. We identified a gene encoding the β-aminopeptidase homolog from a genome database of the filamentous fungus Aspergillus oryzae. The gene was overexpressed in A. oryzae, and the resulting recombinant enzyme was purified. Apart from bacterial homologs [β-Ala-para-nitroanilide (pNA)], the enzyme preferred D-Leu-pNA and D-Phe-pNA as substrates. Therefore, we designated this gene as d-stereoselective aminopeptidase A (damA). The purified recombinant DamA was estimated to be a hexamer and was composed of two subunits with molecular masses of 29.5 and 11.5 kDa, respectively. Optimal hydrolytic activity of DamA toward D-Leu-pNA was observed at 50 °C and pH 8.0. The enzyme was stable up to 60 °C and from pH 4.0-11.0. DamA also exhibited aminolytic activity, producing D-Leu-D-Leu-NH2 from D-Leu-NH2 as a substrate. In the presence of 3.0 M NaCl, the amount of pNA liberated from D-Leu-pNA by DamA was 3.1-fold higher than that in the absence of NaCl. Thus, DamA is a halophilic enzyme. The enzyme was utilized to synthesize several hetero-dipeptides containing a D-amino acid at the N-terminus as well as physiologically active peptides. 22554168 Modulation of affective symptoms and resting state activity by brain stimulation in a treatment-resistant case of obsessive-compulsive disorder. The effect of transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) on psychopathological symptoms and resting state brain activity was assessed in a patient with obsessive-compulsive disorder (OCD). tDCS and rTMS had no effect on OC symptoms. tDCS, however, improved depression and anxiety. Functional magnetic resonance imaging at baseline showed an interhemispheric asymmetry with hyperactivation of the left and hypoactivation of the right anterior neural circuits. A reduction of interhemispheric imbalance was detected after tDCS but not after rTMS. tDCS seems to be more effective than rTMS in restoring interhemispheric imbalance and improving anxiety and depression in OCD. 23847541 Macrophages and chemokines as mediators of angiogenesis. Accumulating evidence attests to the important roles of both macrophages and chemokines in angiogenesis. Tumor-associated macrophages or TAMS constitute the major fraction of tumor-infiltrating leukocytes and are recruited by a number of chemoattractants chemoattractants that are produced by the tumor and tumor-associated stroma. This heterogeneous cell population is activated by a variety of stimuli and becomes polarized to result in functionally different phenotypes regarding tumor progression. As opposed to classically activated or M1 macrophages that exhibit anti-tumor functions, most TAMS are considered to be of the alternatively activated or M2 phenotype, and express multiple cytokines, proteases, and chemokines that promote tumor angiogenesis. Chemokines also have disparate effects on angiogenesis regulation, as several members of the CXC and CC chemokine families are potent inducers of angiogenesis, while a subset of CXC chemokines are angiostatic. This review summarizes the current literature regarding the roles and modes of action of macrophage-derived chemokines as mediators of angiogenesis. 23222085 The HIF1A Gene Pro582Ser Polymorphism in Russian Strength Athletes. Gabbasov, RT, Arkhipova, AA, Borisova, AV, Hakimullina, AM, Kuznetsova, AV, Williams, AG, Day, SH, and Ahmetov, II. The HIF1A gene Pro582Ser polymorphism in Russian strength athletes. J Strength Cond Res 27(8): 2055-2058, 2013-Hypoxia-inducible factor-1α (encoded by HIF1A gene) controls a number of genes that are implicated in various cellular functions including glycolysis and cell proliferation and differentiation. The rs11549465 C > T polymorphism in the HIF1A gene, which produces the amino acid substitution Pro582Ser, increases protein stability and transcriptional activity and, therefore, improves glucose metabolism. The aim of our study was to investigate the association between the HIF1A Pro582Ser polymorphism and elite strength athlete status. A total of 208 Russian strength athletes (122 weightlifters and 86 wrestlers) of regional or national competitive standard and 1,413 controls were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. We found that the frequency of the HIF1A 582Ser variant was significantly higher in weightlifters (13.1%, p = 0.0031) and wrestlers (15.7%, p = 0.0002) compared with the controls (7.5%). Additionally, the highest (21.1%, p = 0.0052) frequency of the 582Ser variant was found in a group of elite strength athletes. Thus, our study provides evidence for an association between the HIF1A gene Pro582Ser polymorphism and elite strength athlete status. Although more replication studies are needed, the preliminary data suggest an opportunity to use the analysis of HIF1A polymorphism along with other gene variations and standard phenotypic assessment in sports selection. 23936177 A Comparative Study of Clinicopathological Features between Chronic Cholecystitis Patients with and without Helicobacter pylori Infection in Gallbladder Mucosa. Helicobacter pylori has been isolated from 10%-20% of human chronic cholecystitis specimens but the characteristics of "Helicobacter pylori positive cholecystitis" remains unclear. This study aims to compare the clinicopathological features between chronic cholecystitis patients with and without Helicobacter pylori infection in gallbladder mucosa. Three hundred and twenty-six chronic cholecystitis patients were divided into two groups according to whether Helicobacter pylori could be detected by culture, staining or PCR for Helicobacter 16s rRNA gene in gallbladder mucosa. Positive samples were sequenced for Helicobacter pylori-specific identification. Clinical parameters as well as pathological characteristics including some premalignant lesions and the expression levels of iNOS and ROS in gallbladder were compared between the two groups. Helicobacter pylori infection in gallbladder mucosa was detected in 20.55% of cholecystitis patients. These patients had a higher prevalence of acid regurgitation symptoms (p = 0.001), more histories of chronic gastritis (p = 0.005), gastric ulcer (p = 0.042), duodenal ulcer (p = 0.026) and higher presence of Helicobacter pylori in the stomach as compared to patients without Helicobacter pylori infection in the gallbladder mucosa. Helicobacter pylori 16s rRNA in gallbladder and gastric-duodenal mucosa from the same individual patient had identical sequences. Also, higher incidences of adenomyomatosis (p = 0.012), metaplasia (p = 0.022) and higher enhanced expressions of iNOS and ROS were detected in Helicobacter pylori infected gallbladder mucosa (p<0.05). Helicobacter pylori infection in gallbladder mucosa is strongly associated with Helicobacter pylori existed in stomach. Helicobacter pylori is also correlated with gallbladder premalignant lesions including metaplasia and adenomyomatosis. The potential mechanism might be related with higher ROS/RNS production but needs further investigation. 23912497 Rough Sets for Bias Field Correction in MR Images Using Contraharmonic Mean and Quantitative Index. One of the challenging tasks for magnetic resonance (MR) image analysis is to remove the intensity inhomogeneity artifact present in MR images, which often degrades the performance of an automatic image analysis technique. In this regard, the paper presents a novel approach for bias field correction in MR images. It judiciously integrates the merits of rough sets and contraharmonic mean.While the contraharmonic mean is used in low-pass averaging filter to estimate the bias field in multiplicative model, the concept of lower approximation and boundary region of rough sets deals with vagueness and incompleteness in filter structure definition. A theoretical analysis is presented to justify the use of both rough sets and contraharmonic mean for bias field estimation. The integration enables the algorithm to estimate optimum or near optimum bias field. Some new quantitative indices are introduced to measure intensity inhomogeneity artifact present in a MR image. The performance of the proposed approach, along with a comparison with other approaches, is demonstrated on both simulated and realMR images for different bias fields and noise levels. 23937794 Expression of TRAIL-splice variants in gastric carcinomas: identification of TRAIL-γ as a prognostic marker. TNF-related apoptosis inducing ligand (TRAIL) belongs to the TNF-superfamily that induces apoptotic cell death in a wide range of neoplastic cells in vivo as well as in vitro. We identified two alternative TRAIL-splice variants, i.e. TRAIL-β and TRAIL-γ that are characterized by the loss of their proapoptotic properties. Herein, we investigated the expression and the prognostic values of the TRAIL-splice variants in gastric carcinomas. Real time PCR for amplification of the TRAIL-splice variants was performed in tumour tissue specimens and corresponding normal tissues of 41 consecutive patients with gastric carcinoma. Differences on mRNA-expression levels of the TRAIL-isoforms were compared to histo-pathological variables and correlated with survival data. All three TRAIL-splice variants could be detected in both non-malignant and malignant tissues, irrespective of their histological staging, grading or tumour types. However, TRAIL-β exhibited a higher expression in normal gastric tissue. The proapoptotic TRAIL-α expression was increased in gastric carcinomas when compared to TRAIL-β and TRAIL-γ. In addition, overexpression of TRAIL-γ was associated with a significant higher survival rate. This is the first study that investigated the expression of TRAIL-splice variants in gastric carcinoma tissue samples. Thus, we provide first data that indicate a prognostic value for TRAIL-γ overexpression in this tumour entity. 23936362 How lateral connections and spiking dynamics may separate multiple objects moving together. Over successive stages, the ventral visual system of the primate brain develops neurons that respond selectively to particular objects or faces with translation, size and view invariance. The powerful neural representations found in Inferotemporal cortex form a remarkably rapid and robust basis for object recognition which belies the difficulties faced by the system when learning in natural visual environments. A central issue in understanding the process of biological object recognition is how these neurons learn to form separate representations of objects from complex visual scenes composed of multiple objects. We show how a one-layer competitive network comprised of 'spiking' neurons is able to learn separate transformation-invariant representations (exemplified by one-dimensional translations) of visual objects that are always seen together moving in lock-step, but separated in space. This is achieved by combining 'Mexican hat' functional lateral connectivity with cell firing-rate adaptation to temporally segment input representations of competing stimuli through anti-phase oscillations (perceptual cycles). These spiking dynamics are quickly and reliably generated, enabling selective modification of the feed-forward connections to neurons in the next layer through Spike-Time-Dependent Plasticity (STDP), resulting in separate translation-invariant representations of each stimulus. Variations in key properties of the model are investigated with respect to the network's ability to develop appropriate input representations and subsequently output representations through STDP. Contrary to earlier rate-coded models of this learning process, this work shows how spiking neural networks may learn about more than one stimulus together without suffering from the 'superposition catastrophe'. We take these results to suggest that spiking dynamics are key to understanding biological visual object recognition. 23794403 Energetic N-trinitroethyl-substituted mono-, di-, and triaminotetrazoles. A series of dense energetic N-trinitroethyl-substituted mono-, bis-, and tri-5-aminotetrazoles were obtained by reacting primary amines with in situ generated cyanogen azide, followed by the trinitroethyl functionalization that involves a condensation of a hydroxymethyl intermediate (prepared by a reaction with formaldehyde) with trinitromethane. These compounds were fully characterized by using multinuclear NMR spectroscopy, IR, elemental analysis, differential scanning calorimetry (DSC), and, in one case with 9, with single-crystal XRD analysis. The heats of formation for all compounds were calculated with Gaussian 03 and then combined with experimental densities to determine the detonation pressures (P) and velocities (Dv ) of the energetic materials. Interestingly, most of them exhibited high density, good thermal stability, acceptable oxygen balance, positive heat of formation, low impact sensitivity, and excellent detonation properties, which highlighted their practical application potentials as a fascinating class of highly energetic materials. 23859988 Removal of chromium and lead by a sulfate-reducing consortium using peat moss as carbon source. The effect of pre-treated peat moss on the ability of a sulfate-reducing microbial consortium to remove chromium and lead in solution was evaluated. The most active bacterial community (235.7mmol H2S/g VSS) was selected from among eight consortia. The peat moss was pre-treated with different HCl concentrations and contact times. The best combination of treatments was 20% HCl for 10min. The constant substrate affinity Ks was 740mg COD/L and the ratio COD/SO4(2-) was 0.71. At pH 5, higher production of biogenic sulfide was observed. The up-flowpacked bed bioreactor operated at a flow of 8.3mL/min for 180h to obtain removal efficiency (by sulfate-reducing activity) of 90% lead and 65% chromium. It is important to consider that peat moss is a natural adsorbent that further influences the removal efficiency of metal ions. 23826753 Effects of a 12-month multicomponent exercise program on the body composition of postmenopausal women - the 'Shape up during menopause' program. ABSTRACT Objective: The aim of this study was to identify the effects of a 12-month exercise program on the body composition of postmenopausal women and examine the interaction of menopause characteristics (nature and time of menopause, hormone therapy) with exercise. Methods: A total of 158 postmenopausal Caucasian women were analyzed in this study (70 in the control and 88 in the exercise group). This subset is part of the ''Shape up during Menopause" which is a program that aims to develop exercise and health promotion in postmenopausal women. Exercise and control groups were tested before and at the end of the program. Data related to menopause was obtained through medical history. Measurements of fat mass, visceral fat area, skeletal muscle mass, fat-free mass, soft lean mass, and basal metabolic rate were assessed by octopolar bioimpedance. Results: Alongside basal metabolic rate, all the anthropometric and body composition variables were influenced by the exercise program. The major differences between groups were found in skeletal muscle mass, soft lean mass total, fat-free mass, and skeletal muscle mass index (effect sizes ranged from 0.89 to 6.64). There were no interactive effects found between exercise and menopause characteristics. Conclusions: There were positive changes in all measured variables and no significant interactive effects with menopause characteristics; therefore, our data suggest that exercise alone promoted improvements in postmenopausal women's body composition. 23834385 Separation of intact intestinal epithelium from mesenchyme. Current protocols for separating adult intestinal epithelial cells from the underlying muscular and mesenchymal tissues typically involve extended incubations, harsh mechanical treatment, and exposure to either proteases or chelating agents. The drawbacks of these approaches include fragmentation, contamination with other cell types, reduced viability, and under-representation of crypt cells. Here we describe a gentle procedure that allows harvesting of pure, fully viable sheets of murine intestinal epithelium, with intact crypts and villi, without enzymes or EDTA. The mesenchyme retains intact villus core projections, is virtually free from epithelial cells, and can be cultured in vitro. 23950710 acr-23 Encodes a Monepantel-Sensitive Channel in Caenorhabditis elegans. Monepantel is a member of the recently identified class of anthelmintics known as the amino-acetonitrile derivatives (AADs). Monepantel controls all major gastro-intestinal nematodes in sheep including those that are resistant to the classical anthelmintics. Previous studies have shown that the Caenorhabditis elegans acr-23 and the Haemonchus contortus Hco-mptl-1 genes may be prominent targets of monepantel. With this discovery it became possible to investigate the mode of action of monepantel in nematodes at the molecular level. In the present study, we show that a C. elegans mutant acr-23 strain is fully rescued by expressing the wild-type acr-23 gene. Moreover, we present a new mutant allele, and characterize acr-23 alleles genetically. We also show that acr-23 is expressed in body wall muscle cells, and provide therefore a possible explanation for the paralysis caused by monepantel. Furthermore, genetic evidence suggests that the chaperone RIC-3 is required for expression of full monepantel resistance. Finally, we present reconstitution of the C. elegans ACR-23 receptor in Xenopus laevis oocytes and provide direct evidence of its modulation by monepantel. Conversely, co-injection of the chaperone RIC-3 had no impact for channel reconstitution in X. laevis oocytes. These results reinforce the involvement of the ACR-23 family in the mode of action of monepantel and advance our understanding of this new class of anthelmintics. 23729379 Conformation-Controlled Electron Transport in Single-Molecule Junctions Containing Oligo(phenylene ethynylene) Derivatives. Understanding the relationships between the molecular structure and electronic transport characteristics of single-molecule junctions is of fundamental and technological importance for future molecular electronics. Herein, we report a combined experimental and theoretical study on the single-molecule conductance of a series of oligo(phenylene ethynylene) (OPE) molecular wires, which consist of two phenyl-ethynyl-phenyl π units with different dihedral angles. The molecular conductance was studied by scanning tunneling microscopy (STM)-based break-junction techniques under different conditions, including variable temperature and bias potential, which suggested that a coherent tunneling mechanism takes place in the OPE molecular wires with a length of 2.5 nm. The conductance of OPE molecular junctions are strongly affected by the coupling strength between the two π systems, which can be tuned by controlling their intramolecular conformation. A cos(2)  θ dependence was revealed between the molecular conductance and dihedral angles between the two conjugated units. Theoretical investigations on the basis of density functional theory and nonequilibrium Green's functions (NEGF) gave consistent results with the experimental observations and provided insights into the conformation-dominated molecular conductance. 23135762 Hepatitis C virus kinetics by administration of pegylated interferon-α in human and chimeric mice carrying human hepatocytes with variants of the IL28B gene. Recent studies have demonstrated that genetic polymorphisms near the IL28B gene are associated with the clinical outcome of pegylated interferon α (peg-IFN-α) plus ribavirin therapy for patients with chronic hepatitis C virus (HCV). However, it is unclear whether genetic variations near the IL28B gene influence hepatic interferon (IFN)-stimulated gene (ISG) induction or cellular immune responses, lead to the viral reduction during IFN treatment. Changes in HCV-RNA levels before therapy, at day 1 and weeks 1, 2, 4, 8 and 12 after administering peg-IFN-α plus ribavirin were measured in 54 patients infected with HCV genotype 1. Furthermore, we prepared four lines of chimeric mice having four different lots of human hepatocytes containing various single nucleotide polymorphisms (SNP) around the IL28B gene. HCV infecting chimeric mice were subcutaneously administered with peg-IFN-α for 2 weeks. There were significant differences in the reduction of HCV-RNA levels after peg-IFN-α plus ribavirin therapy based on the IL28B SNP rs8099917 between TT (favourable) and TG/GG (unfavourable) genotypes in patients; the first-phase viral decline slope per day and second-phase slope per week in TT genotype were significantly higher than in TG/GG genotype. On peg-IFN-α administration to chimeric mice, however, no significant difference in the median reduction of HCV-RNA levels and the induction of antiviral ISG was observed between favourable and unfavourable human hepatocyte genotypes. As chimeric mice have the characteristic of immunodeficiency, the response to peg-IFN-α associated with the variation in IL28B alleles in chronic HCV patients would be composed of the intact immune system. 23895374 The good, the bad and the dubious: VHELIBS, a validation helper for ligands and binding sites. Many Protein Data Bank (PDB) users assume that the deposited structural models are of high quality but forget that these models are derived from the interpretation of experimental data. The accuracy of atom coordinates is not homogeneous between models or throughout the same model. To avoid basing a research project on a flawed model, we present a tool for assessing the quality of ligands and binding sites in crystallographic models from the PDB. The Validation HElper for LIgands and Binding Sites (VHELIBS) is software that aims to ease the validation of binding site and ligand coordinates for non-crystallographers (i.e., users with little or no crystallography knowledge). Using a convenient graphical user interface, it allows one to check how ligand and binding site coordinates fit to the electron density map. VHELIBS can use models from either the PDB or the PDB_REDO databank of re-refined and re-built crystallographic models. The user can specify threshold values for a series of properties related to the fit of coordinates to electron density (Real Space R, Real Space Correlation Coefficient and average occupancy are used by default). VHELIBS will automatically classify residues and ligands as Good, Dubious or Bad based on the specified limits. The user is also able to visually check the quality of the fit of residues and ligands to the electron density map and reclassify them if needed. VHELIBS allows inexperienced users to examine the binding site and the ligand coordinates in relation to the experimental data. This is an important step to evaluate models for their fitness for drug discovery purposes such as structure-based pharmacophore development and protein-ligand docking experiments. 23783566 Active site of the solvated thiosulfate ion characterized by hydration structures and dynamics. The reactivity of the terminated sulfur atom within the thiosulfate ion (S2O3(2-)) when it is involved in chemical reactions was investigated through the properties of the molecular hydration shell, obtained from the ab initio quantum mechanical change field molecular dynamics (QMCF MD) simulation. The average geometry indicated the significant effect of explicit water on the reduction of the S-S length, which was reflected in the splitting peaks of the spectrum for the stretching mode of this bond (ν(SS)). A further investigation on a simple model with various theoretical levels exhibited the hydrophobicity of the S-S bond. The evaluation of the molecular coordination number was sensitive to the radii of the atomic hydration spheres, which were obtained from the vague boundaries of the first peak in the atomic radial distribution functions. The number of actual contacts specified 6.8 water molecules interacting with the thiosulfate ion, and 2.4 extra waters located in the molecular hydration shell, forming a H-bonding network with the bulk water. The mean residence times for the water ligands distinguished the asymmetric strength of the hydration shell into a weaker sulfur and three stronger oxygen sites, instigating the terminated sulfur atom as the active site that is involved in chemical reactions. 23824428 Subjective Fatigue in Children with Hearing Loss: Some Preliminary Findings. This study examined the effect of hearing loss on subjective reports of fatigue in school-age children using a standardized measure. As part of a larger ongoing study, subjective ratings of fatigue were obtained using the PedsQL Multidimensional Fatigue Scale. This standardized scale provides a measure of general fatigue, sleep/rest fatigue, cognitive fatigue and an overall composite measure of fatigue. To date, data from 10 children with hearing loss (CHL) and 10 age-matched children with normal hearing (CNH) have been analyzed. These preliminary results show subjective fatigue is increased in school-age children with hearing loss (Cohen's d = .78-1.90). Additionally, the impact of hearing loss on fatigue in school-age children appears pervasive across multiple domains (general, sleep/rest and cognitive fatigue). School-age CHL reported they are significantly more fatigued than CNH. These preliminary data are important given the negative academic and psychosocial consequences associated with fatigue. Further research is needed to determine the underlying mechanisms responsible for this increased fatigue in school-age children with hearing loss, and to identify factors that may modulate (e.g., degree of loss) and mediate (e.g., hearing aid or cochlear implant use) its impact. 23376229 Computational proteomics pitfalls and challenges: HavanaBioinfo 2012 workshop report. The workshop "Bioinformatics for Biotechnology Applications (HavanaBioinfo 2012)", held December 8-11, 2012 in Havana, aimed at exploring new bioinformatics tools and approaches for large-scale proteomics, genomics and chemoinformatics. Major conclusions of the workshop include the following: (i) development of new applications and bioinformatics tools for proteomic repository analysis is crucial; current proteomic repositories contain enough data (spectra/identifications) that can be used to increase the annotations in protein databases and to generate new tools for protein identification; (ii) spectral libraries, de novo sequencing and database search tools should be combined to increase the number of protein identifications; (iii) protein probabilities and FDR are not yet sufficiently mature; (iv) computational proteomics software needs to become more intuitive; and at the same time appropriate education and training should be provided to help in the efficient exchange of knowledge between mass spectrometrists and experimental biologists and bioinformaticians in order to increase their bioinformatics background, especially statistics knowledge. 22634734 The deiodinases and the control of intracellular thyroid hormone signaling during cellular differentiation. Thyroid hormone influences gene expression in virtually all vertebrates. Its action is initiated by the activation of T4 to T3, an outer ring deiodination reaction that is catalyzed by the type 1 or the type 2 iodothyronine selenodeiodinases (D1 or D2). Inactivation of T4 and T3 occurs via inner ring deiodination catalyzed by the type 3 iodothyronine selenodeiodinases (D3). The T4 concentration is generally quite stable in human plasma, with T3 levels also remaining constant. Deiodinase actions are tightly regulated in both pre- and post-natal life when they are required to make local adjustments of intracellular T3 concentrations in a precise spatio- and temporal manner. Although all the signals governing the dynamic expression of deiodinases in specific cell types are not known, many important regulatory factors have been deciphered. This review provides striking examples from the recent literature illustrating how the expression of D2 and D3 is finely tuned during maturation of different organs, and how their action play a critical role in different settings to control intracellular T3 availability. Emerging evidence indicates that in various cell contexts, D2 and D3 are expressed in a dynamic balance, in which the expression of one enzyme is coordinately regulated with that of the other to tightly control intracellular T3 levels commensurate with cell requirements at that time. Deiodinases control TH action in a precise spatio-temporal fashion thereby providing a novel mechanism for the local paracrine and autocrine regulation of TH action. This remarkable tissue-specific regulation of intracellular thyroid status remains hidden due to the maintenance of constant circulating TH concentrations by the hypothalamic-pituitary-thyroid axis. This article is part of a Special Issue entitled Thyroid hormone signalling. 23946514 Antepartum fetal bladder rupture leading to urinary ascitis: attempt to rescue by placement of peritoneo-amniotic shunt. Fetal bladder rupture is a rare complication occurring due to bladder outlet obstruction, mostly posterior urethral valves. A 26-year-old primigravida presented to us at 27 weeks gestation with an ultrasound report showing gross fetal ascitis and mild oligohydramnios. A repeat scan was performed which showed fetal bladder rupture and urinary ascitis. In conjunction with paediatric surgeon, we performed ultrasound-guided placement of double-ended pigtail catheter connecting the fetal peritoneal cavity with the amniotic cavity at 28 weeks gestation. Ultrasound performed 3 days after the placement of the catheter showed its correct placement. Unfortunately, 1 week after the procedure at 29 weeks gestation, the patient had premature rupture of membranes and later went into labour and delivered vaginally. The neonate could not be revived and expired after few hours of birth due to prematurity-related complications. The placement of the shunt could have probably precipitated preterm rupture of membranes. 23870639 The natural history of coronary calcification: A meta-analysis from St Francis and EBEAT trials. Coronary artery calcium score (CACs) is an established quantitative tool for assessing subclinical atherosclerosis. The aim of this study was to assess in a meta-analysis model the natural history and reproducibility of CACs measurements obtained from St Francis and EBEAT trials. We analysed data from 649 individuals: 443 on placebo with 2year follow-up from St Francis trial (Study A) and 209 on 10mg atorvastatin with 1year follow-up of EBEAT trial (Study B). Total CACs and that in the left coronary artery (LCA) branches, left main stem (LMS), left anterior descending (LAD), left circumflex (Cx) and right coronary artery (RCA) were analysed. In view of the wide CACs spectrum, data were logarithmically transformed before the analyses and mixed model analysis was used to evaluate the change of CACs over time. The overall agreement between the two measurements was fairly good, showing a small but significant increase in CAC: 68% of the group as a whole presented an increase in CACs, 23% of the cohort had negligible change in CACs of <10% irrespective of the baseline CACs; and the remaining 10% showed a fall in CACs. Both studies showed similar patterns. The analysis of individual coronary arteries showed significantly higher variability of measurements in the RCA than in the LCA. Males had higher baseline CACs than females, but the rate of progression was not different between genders, irrespectively of age and baseline score. The natural history of CACs was overtime progression in the majority of subjects, irrespective of gender. The higher variability in RCA measurements could be related to the low baseline CACs or exaggerated movement of the right side atrioventricular ring, whereas those for LCA branches are influenced by the branch allocation of the CACs. Large changes to and from zero, might be related to technical limitations. 23392559 Health behavior change among breast cancer patients. Changes in health behavior among women with breast cancer with respect to food intake, exercise and smoking habits are considered. We aimed to analyze (1) significant modifications of these behaviors about a year after breast cancer surgery and (2) the impact of social, medical and behavioral patient characteristics on these changes. Data were derived from a longitudinal study of 229 women (age < 70) in Germany with a first manifestation of breast cancer. Food intake, physical activity and smoking were assessed by means of personal interviews immediately after surgery (T0) and 14 months later (T1). The intake of fruits and vegetables and physical exercise increased significantly over the observation period. Socio-demographic and medical parameters were largely irrelevant for behavioral changes while smoking status turned out as most important for changes in daily fruit consumption. The results demonstrate that breast cancer patients change their lifestyle habits in a significant way even without intervention. Patients who smoke are in particular need of professional support to implement health-promoting behavior, and intervention should especially focus on this group. 23385091 Transdermal delivery of human epidermal growth factor facilitated by a peptide chaperon. Peptide chaperon TD1 was discovered to facilitate several proteins' transdermal delivery via topical co-administration. To design a practical, safe system for advanced transdermal peptide, a novel method was carried out. Human epidermal growth factor (hEGF) was selected as the model biological agent and a fusion protein: TD1-hEGF was designed. Study showed that TD1-hEGF not only had the similar bioactivity with native hEGF, but also possessed considerable higher transdermal ability than hEGF and a co-administration of TD1 and hEGF. These results provided convincing evidence for the advantages of TD1-hEGF in cosmetic and medical applications. Moreover, the fusion pattern between the cargoes and TD1 offered a new approach to facilitate other hydrophilic drugs' transdermal delivery for therapeutic application. 23746335 Herbal medicinal oils in traditional Persian medicine. Abstract Context: In Iran, conventional production methods of herbal oils are widely used by local practitioners. Administration of oils is rooted in traditional knowledge with a history of more than 3000 years. Scientific evaluation of these historical documents can be valuable for finding new potential use in current medicine. Objective: The current study (i) compiled an inventory of herbal oils used in ancient and medieval Persia and (ii) compared the preparation methods and therapeutic applications of ancient times to current findings of medicinal properties in the same plant species. Materials and methods: Information on oils, preparation methods and related clinical administration was obtained from ancient Persian documents and selected manuscripts describing traditional Persian medicine. Moreover, we investigated the efficacy of medicinal plant species used for herbal oils through a search of the PubMed, Scopus and Google Scholar databases. Results: In Iran, the application of medicinal oils date back to ancient times. In medieval Persian documents, 51 medicinal oils produced from 31 plant species, along with specific preparation methods, were identified. Flowers, fruits and leaves were most often used. Herbal oils have been traditionally administered via oral, topical and nasal routes for gastrointestinal, musculoskeletal, and neural diseases, respectively. According to current investigations, most of the cited medicinal plant species were used for their anti-inflammatory and analgesic properties. Conclusions: Medicinal oils are currently available in Iranian medicinal plant markets and are prepared using traditional procedures for desirable clinical outcomes. Other than historical clarification, the present study provides data on clinical applications of the oils that should lead to future opportunities to investigate their potential medicinal use. 23968051 Underwater passive acoustic localization of Pacific walruses in the northeastern Chukchi Sea. This paper develops and applies a linearized Bayesian localization algorithm based on acoustic arrival times of marine mammal vocalizations at spatially-separated receivers which provides three-dimensional (3D) location estimates with rigorous uncertainty analysis. To properly account for uncertainty in receiver parameters (3D hydrophone locations and synchronization times) and environmental parameters (water depth and sound-speed correction), these quantities are treated as unknowns constrained by prior estimates and prior uncertainties. Unknown scaling factors on both the prior and arrival-time uncertainties are estimated by minimizing Akaike's Bayesian information criterion (a maximum entropy condition). Maximum a posteriori estimates for sound source locations and times, receiver parameters, and environmental parameters are calculated simultaneously using measurements of arrival times for direct and interface-reflected acoustic paths. Posterior uncertainties for all unknowns incorporate both arrival time and prior uncertainties. Monte Carlo simulation results demonstrate that, for the cases considered here, linearization errors are small and the lack of an accurate sound-speed profile does not cause significant biases in the estimated locations. A sequence of Pacific walrus vocalizations, recorded in the Chukchi Sea northwest of Alaska, is localized using this technique, yielding a track estimate and uncertainties with an estimated speed comparable to normal walrus swim speeds. 23851982 FTY720 induces apoptosis of chronic myelogenous leukemia cells via dual activation of BIM and BID and overcomes various types of resistance to tyrosine kinase inhibitors. PP2A activator FTY720 has been shown to possess the anti-leukemic activity for chronic myelogenous leukemia (CML), however, the cell killing mechanism underlying its anti-leukemic activity has remained to be verified. We investigated the precise mechanisms underlying the apoptosis induction by FTY720, especially focusing on the roles of BH3-only proteins, and the therapeutic potency of FTY720 for CML. Enforced expression of either BCL2 or the dominant-negative protein of FADD (FADD.DN) partly protected CML cells from apoptosis by FTY720, indicating the involvement of both cell extrinsic and intrinsic apoptosis pathways. FTY720 activates pro-apoptotic BH3-only proteins: BIM, which is essential for apoptosis by BCR-ABL1 tyrosine kinase inhibitors (TKIs), and BID, which accelerates the extrinsic apoptosis pathway. Gene knockdown of either BIM or BID partly protected K562 cells from apoptosis by FTY720, but the extent of cell protection was not as much as that by overexpression of either BCL2 or FADD.DN. Moreover, knockdown of both BIM and BID did not provide additional protection compared with knockdown of only BIM or BID, indicating that BIM and BID complement each other in apoptosis by FTY720, especially when either is functionally impaired. FTY720 can overcome TKI resistance caused by ABL kinase domain mutations, dysfunction of BIM resulting from gene deletion polymorphism, and galectin-3 overexpression. In addition, ABT-263, a BH3-mimetic, significantly augmented cell death induction by FTY720 both in TKI-sensitive and -resistant leukemic cells. These results provide the rationale that FTY720, with its unique effects on BIM and BID, could lead to new therapeutic strategies for CML. 23761637 Exercise prevents Western diet-associated erectile dysfunction and coronary artery endothelial dysfunction: response to acute apocynin and sepiapterin treatment. The aim of this study was to investigate aerobic exercise training as a means to prevent erectile dysfunction (ED) and coronary artery disease (CAD) development associated with inactivity and diet-induced obesity. Male Sprague-Dawley rats were fed a Western diet (WD) or a control diet (CD) for 12 wk. Subgroups within each diet remained sedentary (Sed) or participated in aerobic interval treadmill running throughout the dietary intervention. Erectile function was evaluated under anesthesia by measuring the mean arterial pressure and intracavernosal pressure in response to electrical field stimulation of the cavernosal nerve, in the absence or presence of either apocynin, an NADPH oxidase inhibitor, or sepiapterin, a tetrahydrobiopterin precursor. Coronary artery endothelial function (CAEF) was evaluated ex vivo with cumulative doses of ACh applied to preconstricted segments of the left anterior descending coronary artery. CAEF was assessed in the absence or presence of apocynin or sepiapterin. Erectile function (P < 0.0001) and CAEF (P < 0.001) were attenuated in WD-Sed. Exercise preserved erectile function (P < 0.0001) and CAEF (P < 0.05) within the WD. Erectile function (P < 0.01) and CAEF (P < 0.05) were augmented by apocynin only in WD-Sed, while sepiapterin (P < 0.05) only augmented erectile function in WD-Sed. These data demonstrate that a chronic WD induces impairment in erectile function and CAEF that are commonly partially reversible by apocynin, whereas sepiapterin treatment exerted differential functional effects between the two vascular beds. Furthermore, exercise training may be a practical means of preventing diet-induced ED and CAD development. 23949849 Uterine Artery Suture: A Preventive Approach for Pernicious Placenta Previa. Pernicious placenta previa is an obstetric complication that results in a crisis situation for many patients. Most existing options deal with the problems after delivery leading to unfavorable outcomes. To circumvent this situation, a few preventive simple surgical options have been discussed in this paper. The highlight of the approach is the application of ascending uterine artery suture that drastically reduced the amount of bleeding as compared to that observed in regular surgeries. Combined with the placenta accrete location, wedge resection and 'patch' homeostasis of the serous membrane, the surgical modifications adopted effectively reduced the need for hysterectomy thus preserving the fertility of the patients for the future. Since fetuses were safely removed within 1-2 min, the Apgar scores of the neonates were also largely unaffected. 23726842 Oncogenic B-Raf(V600E) abrogates the AKT/B-Raf/Mps1 interaction in melanoma cells. Activating B-Raf mutations that deregulate the mitogen-activated protein kinase (MAPK) pathway commonly occur in cancer. Although B-Raf(V600E) induces increased Mps1 protein contributing to centrosome amplification and chromosome instability, the regulatory mechanisms of Mps1 in melanoma cells is not fully understood. Here, we report that Mps1/AKT and B-Raf(WT)/ERK signaling form an auto-regulatory negative feedback loop in melanoma cells; notably, oncogenic B-Raf(V600E) abrogates the negative feedback loop, contributing the aberrant Mps1 functions and tumorigenesis. Our findings raise the possibility that targeting the oncogenic B-Raf and Mps1, especially when used in combination could potentially provide great therapeutic opportunities for cancer treatment. 23835327 Reversal of neuropathic pain in diabetes by targeting glycosylation of CaV3.2 T-type calcium channels. It has been established that CaV3.2 T-type voltage-gated calcium channels (T-channels) play a key role in the sensitized (hyperexcitable) state of nociceptive sensory neurons (nociceptors) in response to hyperglycemia associated with diabetes which in turn can be a basis for painful symptoms of peripheral diabetic neuropathy (PDN). Unfortunately, current treatment for painful PDN has been limited by non-specific systemic drugs with significant side effects or potential for abuse.We studied in vitro and in vivo mechanisms of plasticity of CaV3.2 T-channel in a leptin-deficient (ob/ob) mouse model of PDN.We demonstrate that post-translational glycosylation of specific extracellular asparagine residues in CaV3.2 channels accelerates current kinetics, increases current density and augments channel membrane expression. Importantly, de-glycosylation treatment with neuraminidase inhibits native T-currents in nociceptors and in so doing completely and selectively reverses hyperalgesia in diabetic ob/ob mice without altering baseline pain responses in healthy mice.Our study describes a new mechanism for the regulation of CaV3.2 activity and suggests that modulating the glycosylation state of T-channels in nociceptors may provide a way to suppress peripheral sensitization. Understanding the details of this regulatory pathway could facilitate the development of novel specific therapies for the treatment of painful PDN. 23435964 Induction of heme oxygenase-1 protects mouse liver from apoptotic ischemia/reperfusion injury. Ischemia/reperfusion (I/R) injury is the main cause of primary graft dysfunction of liver allografts. Cobalt-protoporphyrin (CoPP)-dependent induction of heme oxygenase (HO)-1 has been shown to protect the liver from I/R injury. This study analyzes the apoptotic mechanisms of HO-1-mediated cytoprotection in mouse liver exposed to I/R injury. HO-1 induction was achieved by the administration of CoPP (1.5 mg/kg body weight i.p.). Mice were studied in in vivo model of hepatic segmental (70 %) ischemia for 60 min and reperfusion injury. Mice were randomly allocated to four main experimental groups (n = 10 each): (1) A control group undergoing sham operation. (2) Similar to group 1 but with the administration of CoPP 72 h before the operation. (3) Mice undergoing in vivo hepatic I/R. (4) Similar to group 3 but with the administration of CoPP 72 h before ischemia induction. When compared with the I/R mice group, in the I/R+CoPP mice group, the increased hepatic expression of HO-1 was associated with a significant reduction in liver enzyme levels, fewer apoptotic hepatocytes cells were identified by morphological criteria and by immunohistochemistry for caspase-3, there was a decreased mean number of proliferating cells (positively stained for Ki67), and a reduced hepatic expression of: C/EBP homologous protein (an index of endoplasmic reticulum stress), the NF-κB's regulated genes (CIAP2, MCP-1 and IL-6), and increased hepatic expression of IκBa (the inhibitory protein of NF-κB). HO-1 over-expression plays a pivotal role in reducing the hepatic apoptotic IR injury. HO-1 may serve as a potential target for therapeutic intervention in hepatic I/R injury during liver transplantation. 23884791 Prospective memory in children and chimpanzees. Prospective memory (PM) involves remembering to do something at a specific time in the future. Here, we investigate the beginnings of this ability in young children (3-year-olds; Homo sapiens) and chimpanzees (Pan troglodytes) using an analogous task. Subjects were given a choice between two toys (children) or two food items (chimpanzees). The selected item was delivered immediately, whereas the unselected item was hidden in an opaque container. After completing an ongoing quantity discrimination task, subjects could request the hidden item by asking for it (children) or by pointing to the container and identifying the item on a symbol board (chimpanzees). Children and chimpanzees showed evidence of prospective-like memory in this task, as evidenced by successful retrieval of the item at the end of the task, sometimes spontaneously with no prompting from the experimenter. These findings contribute to our understanding of PM from an ontogenetic and comparative perspective. 23915331 Performance evaluation of selected n95 respirators and surgical masks when challenged with aerosolized endospores and inert particles. The objective of this study was to assess how the relative efficiency of N95 respirators and surgical masks might vary with different challenge aerosols, utilizing a standardized manikin head form as a surrogate to human participation. A Collision nebulizer aerosolized B. anthracis Sterne strain endospores and polystyrene latex (PSL) particles to evaluate 11 models of N95 respirators and surgical masks. An automated breathing simulator, calibrated to normal tidal volume and active breathing rate, mimicked human respiration. A manikin head form with N95 respirators or surgical masks, and manikin head form without N95 respirators or surgical masks were placed in the bioaerosol chamber. An AGI-30 sampler filled with phosphate buffered water was fitted behind the mouth of each manikin head form to collect endospore bioaerosol samples. PSL aerosols concentrations were quantified by an ARTI Hand Held Particle Counter. Geometric Mean (GM) relative efficiency of N95 respirators and surgical masks challenged with endospore bioaerosol ranged from 34-65%. In PSL aerosol experiments, GM relative efficiency ranged from 35-64% for 1.3 μm particles. GM filtration efficiency of all N95 and surgical N95 respirators filter media evaluated was ≥99% when challenged with particles ≥0.1 μm. GM filtration efficiency of surgical mask filter media ranged from 70-83% with particles ≥0.1 μm and 74-92% with 1.3 μm PSL particles. Relative efficiencies of N95 respirators and surgical masks challenged with aerosolized B. anthracis endospores and PSL were similar. Relative efficiency was similar between N95 respirators and surgical masks on a manikin head form despite clear differences in filtration efficiency. This study further highlights the importance of face seal leakage in the respiratory protection provided by N95 respirators, and demonstrates it on a human surrogate. 23340524 Palladium nanoparticles supported on nitrogen-doped HOPG: a surface science and electrochemical study. We have investigated by photoemission spectroscopy and scanning tunnelling microscopy what are the chemical and structural changes induced by nitrogen ion implantation (500 eV) on highly oriented pyrolytic graphite and how the defects induced by this process modify the growth and thermal stability of palladium nanoparticles, deposited in situ by physical vapour deposition. Since nitrogen derived defects are mostly buried below the surface, they are not accessible for a chemical interaction with metal nanoparticles; however, the amorphization induced by the ion beam in the outermost layers of the substrate beneficially affects the metal morphology, limiting the size of the nanoparticles and improving their thermal stability. The supported nanoparticles have been tested towards the oxygen reduction reaction indicating that the electrochemical activity does not depend significantly on the ion implantation, but mostly on the amount of palladium. 23632438 Small-world networks in neuronal populations: a computational perspective. The analysis of the brain in terms of integrated neural networks may offer insights on the reciprocal relation between structure and information processing. Even with inherent technical limits, many studies acknowledge neuron spatial arrangements and communication modes as key factors. In this perspective, we investigated the functional organization of neuronal networks by explicitly assuming a specific functional topology, the small-world network. We developed two different computational approaches. Firstly, we asked whether neuronal populations actually express small-world properties during a definite task, such as a learning task. For this purpose we developed the Inductive Conceptual Network (ICN), which is a hierarchical bio-inspired spiking network, capable of learning invariant patterns by using variable-order Markov models implemented in its nodes. As a result, we actually observed small-world topologies during learning in the ICN. Speculating that the expression of small-world networks is not solely related to learning tasks, we then built a de facto network assuming that the information processing in the brain may occur through functional small-world topologies. In this de facto network, synchronous spikes reflected functional small-world network dependencies. In order to verify the consistency of the assumption, we tested the null-hypothesis by replacing the small-world networks with random networks. As a result, only small world networks exhibited functional biomimetic characteristics such as timing and rate codes, conventional coding strategies and neuronal avalanches, which are cascades of bursting activities with a power-law distribution. Our results suggest that small-world functional configurations are liable to underpin brain information processing at neuronal level. 23900159 Panniculitis in children. This paper will give a comprehensive view of the most frequent panniculitides seen in childhood, with emphasis on the types exclusively found in infancy, and for all other types of panniculitides also found in adults. Aim of this paper is also to analyze the clinical differences between panniculitis in childhood and in adulthood, and to give reliable histopathologic criteria for a specific diagnosis. A review of the literature is here integrated by authors' personal contribution. Panniculitides in children is a heterogeneous group of diseases, as well as in adult life, characterized by inflammation of the subcutaneous fat. Only very few types of panniculitis are exclusively found in childhood, such as Sclerema neonatorum and subcutaneous fat necrosis of the newborn, while the vast majority of the other types may be found both in paediatric age and in adults. Furthermore, this paper will consider in detail panniculitis according to their frequency, such as Erythema nodosum, Lupus panniculitis, Cold panniculitis, panniculitis in Behçet disease, and poststeroid panniculitis. It will also describe rare forms of panniculitis, such as Eosinophilic panniculitis (a pathological entity debated by many authors), Subcutaneous panniculitis T-cell lymphoma, and the different forms of the so call "Lipophagic panniculitis", encompassing respectively the febrile relapsing panniculitis of Weber-Christian disease and the non-relapsing form of Rothmann-Makai disease. For each type of panniculitis considered concise information will be given about epidemiology, etiology, clinical findings, laboratory data, prognosis and therapy, while histopathologic findings will be described in detail. 23839436 169 Pressure is only part of the story in traumatic brain injured patients; focal cerebral blood flow goes to zero in some patients with adequate cerebral perfusion pressure. The pathophysiology of traumatic brain injury (TBI) is still not clearly understood. Recently, a decompressive craniectomy trial (1) and a trial of intracranial pressure (ICP) treatment with ICP monitoring vs no monitoring (2) failed to support the concept that increases in ICP are exclusively responsible for TBI mortality and morbidity. To analyze the role ICP, cerebral perfusion pressure (CPP = BP-ICP), and cerebral blood flow (CBF) play in head injury, we monitored brain injured patients' ICP, blood pressure (BP), CPP, and focal cerebral blood flow (fCBF), recording the real-time data for computer analysis. 20 patients with severe brain injury were monitored with recordings of ICP, BP, CPP, and fCBF every minute. 17 patients had severe closed TBI, 1 gunshot wound, and 2 intracerebral hemorrhages. 13 patients lived (GCS 3-9, average 5), 7 died (GCS 3-7, average 5). Of the 7 patients who died, 5 had technically adequate recordings before and as death supervened. Graphs were prepared of time vs CPP, ICP and fCBF and reviewed for the time course of fCBF deterioration vs CPP elevation. If CPP obviously and substantially decreased before fCBF decreased, that was termed a pressure death. However, if CPP stayed adequate and fCBF still decreased to zero, that was termed a non-pressure death. Three patients had a pressure death (Fig 1), and 2 patients had a non-pressure death (Fig 2). This may be the first real-time documentation of non-CPP dependent brain death as expressed by fCBF. There are pathological processes in the injured brain that do not directly involve increases in ICP and decreases in CPP. Heretofore clinical treatment efforts in brain injury have focused on ICP: other mechanisms are also extant and should be further investigated so as to more successfully treat brain injury. 23624163 Cardioprotective effect of Aralia elata polysaccharide on myocardial ischemic reperfusion (IR) injury in rats. Based on the previous studies revealing antioxidant activities of a water-soluble polysaccharide (AEP-w1) from the root bark of Aralia elata, the present study was designed to determine if chronic administration of AEP-w1 could reduce ischemic reperfusion (IR) induced myocardial injury. Wistar rats were given three different doses of AEP-w1 (50, 100 and 200mg/kg/day) or vehicle for 30 days, after which myocardial IR injury was induced by the occlusion of left anterior descending (LAD) coronary artery for 45min followed by 60min of reperfusion. Pretreatment with AEP-w1 not only enhanced the serum levels of total antioxidant capacity (T-AOC), superoxide dismutase (SOD) and glutathione (GSH), but also decreased the serum malondialdehyde (MDA) level in rats suffering IR injury. Consistent with this observation, AEP-w1 treatment also restored the myocardial antioxidant status evidenced by increased SOD, catalase (CAT) and glutathione (GSH) and decreased thiobarbituric acid reactive substances (TBARS) as compared to the IR model group. Furthermore, the elevated level of pro-inflammatory cytokines, such as TNF-α and IL-6, and decreased level of anti-inflammatory cytokine IL-10 in vehicle-treated IR rats was reversed by pretreatment with AEP-w1. In addition, AEP-w1 prevented myocardial cell from apoptosis in mice subjected to IR injury. These findings revealed that cardioprotective effect of AEP-w1 was achieved likely through improving endogenous antioxidants, regulating the inflammation response and suppressing myocardial cell apoptosis. 23790124 Cooperation of Endothelial and Smooth Muscle Cells Derived from Human Induced Pluripotent Stem Cells Enhances Neovascularization in Dermal Wounds. Human induced pluripotent stem cells (hiPSCs) are generated through the reprogramming of somatic cells into an embryonic stem cell-like state, such that vascular cells differentiated from hiPSCs might be a suitable autologous cell source for vascular regeneration. The goal of this study was to assess whether cotransplantation of endothelial cells (ECs) and smooth muscle cells (SMCs) differentiated from hiPSCs could promote neovascularization and tissue repair in a murine dermal wound model. hiPSCs were differentiated into ECs and SMCs; the differentiated cells displayed cell-specific surface markers. Compared to primary somatic cells, ECs and SMCs, which were differentiated from hiPSCs, strongly cooperated to enhance in vitro tubular network formation. In vivo gel assays in athymic nude mice showed that the coimplantation of differentiated ECs and SMCs significantly increased vascularization, unlike that observed in the case of implantation of differentiated ECs alone. In a murine full-thickness wound model, when compared with the transplantation of primary somatic cells or phosphate-buffered saline, cotransplantation of differentiated ECs and SMCs markedly enhanced neovascularization in injured tissues and accelerated wound healing. These results demonstrate that cotransplantation of hiPSC-derived ECs and SMCs may be feasible as a new autologous cell therapy for neovascularization and tissue repair. 22514238 Delinquency, androgens, and the family: a test of evolutionary neuroandrogenic theory. There is little doubt that family factors can influence involvement in delinquency, although the full nature and extent of their influences remain unclear. In recent decades, testosterone has been increasingly implicated as a contributor to adolescent offending. The present study sought to determine whether two important types of familial factors-parental socioeconomic status and amicable parent-child relationships-are interacting with testosterone (and possibly other androgens) to affect delinquency. A large sample of North American college students self-reported their involvement in eight categories of delinquency along with self-ratings of various androgen-promoted traits (e.g., muscularity and low-deep voice), parental social status, and the quality of the relationships they had with parents. In both sexes, parent-child relationships and androgens were significantly associated with delinquency but parental social status was not. Factor analysis revealed that the authors' measures of all four categories of variables exhibited strong loadings onto their respective factors. Androgens and amicable parent-child relationships were associated with delinquency but parental social status was not. About one third of the influence of parent-child relationships on delinquency appeared to be attributable to androgens. Findings are discussed from the perspective of the evolutionary neuroandrogenic theory of delinquent and criminal behavior. 23846758 Regulation of STIM1/Orai1-dependent Ca2+ signalling in platelets. Platelet secretion and aggregation as well as thrombus formation of blood platelets critically depend on increase of cytosolic Ca2+ concentration ([Ca2+]i) mainly resulting from intracellular Ca2+ release followed by store operated Ca2+ entry (SOCE) through Ca2+ release activated channels (CRAC). SOCE is in part accomplished by the pore forming unit Orai and its regulator stromal interaction molecule (STIM). Orai1 and STIM1 transcription is stimulated by NF-κB (nuclear factor kappa B). Serum- and glucocorticoid-inducible kinase 1 (SGK1) up-regulates NF-κB-activity in megakaryocytes and thus Orai1-expression and SOCE in platelets. SGK1 is thus a powerful regulator of platelet Ca2+-signalling and thrombus formation and presumably participates in the regulation of platelet activation by a variety of hormones as well as clinical conditions (e.g. type 2 diabetes or metabolic syndrome) associated with platelet hyperaggregability and increased risk of thromboocclusive events. SOCE in platelets is further regulated by scaffolding protein Homer and chaperone protein cyclophilin A (CyPA). Additional potential regulators of Orai1/STIM1 and thus SOCE in platelets include AMP activated kinase (AMPK), protein kinase A (PKA), reactive oxygen species, lipid rafts, pH and mitochondrial Ca2+ buffering. Future studies are required defining the significance of those mechanisms for platelet Orai1 abundance and function, for SOCE into platelets and for platelet function in cardiovascular diseases. 23132170 The potential effects of pomegranate (Punica granatum) juice on carbon tetrachloride-induced nephrotoxicity in rats. The purpose of this study was to evaluate the effect of pomegranate (Punica granatum) in inhibiting and reversing the nephrotoxicity of carbon tetrachloride, a potent oxidative stress inducer which induces cellular kidney damage. Rats were intraperitoneally injected with carbon tetrachloride (2 mL/kg body weight) which produced severe renal tissue damage, as demonstrated by decreased uric acid and dramatic elevation of urea and creatinine. In addition, carbon tetrachloride injection caused oxidative stress in rats, as evidenced by increased lipid peroxidation and nitrite/nitrate (NO x ) concentrations in the renal tissue, along with a remarkable reduction in superoxide dismutase, catalase, glutathione transferase, glutathione reductase, glutathione peroxidase activities and glutathione content. We suggested that pomegranate juice was able to elevate the antioxidant defense system, clean up free radicals, lessen oxidative damages and protect the kidney against carbon tetrachloride-induced toxicity, thus having a potential protective effect. 23942003 The Effects of Surgical Correction of Neuromuscular Scoliosis on Gastric Myoelectrical Activity, Emptying and Upper Gastrointestinal Symptoms - A Prospective Follow-Up Study. Gastrointestinal complications are frequent after surgical correction of neuromuscular scoliosis, but the effects of scoliosis surgery on gastric function and upper gastrointestinal symptoms on long-term are unknown. Thirty-one children (16 spastic, 15 flaccid patients) who underwent surgical correction of neuromuscular scoliosis were included in a prospective follow-up study. Median (range) age at surgery was 14.9 (5-20) years and follow-up time 4.3 (2-8) years. Electrogastrography (n = 28), gastric emptying scintigraphy (n = 17) and structured upper gastrointestinal symptoms questionnaire (n = 26) were evaluated before and after surgery. The results were related to patients' clinical state, type and extent of corrective spinal surgery and gastrointestinal complications. The median main scoliosis curve of 81° (51 - 129°) was corrected to 25° (1.0 - 85°) after surgery. In electrogastrogram, power ratio increased from preoperative 1.4 (0.30 - 11) to postoperative 6.2 (1.2 - 26) in the spastic group (p = 0.008), whereas in the flaccid group power ratio remained unchanged at 2.2 (0.1 - 17). Patients with prolonged postoperative paralytic ileus had the most substantial increase in gastric power ratio (p = 0.038). Correction of sagittal spinal balance correlated with increased postprandial normogastric activity after surgery (R = 0.459; p = 0.004). The gastric emptying results, upper gastrointestinal symptoms and BMI were not significantly altered after scoliosis surgery. Gastric myoelectrical power increased after surgical correction of spastic neuromuscular scoliosis and was associated with prolonged postoperative paralytic ileus. Correction of poor, stooped spinal balance improved gastric myoelectrical activity. The net effect of scoliosis surgery on gastric emptying, upper gastrointestinal symptoms and clinical nutritional state was minimal. 23592767 National Lung Screening Trial: Variability in Nodule Detection Rates in Chest CT Studies. Purpose: To characterize the variability in radiologists' interpretations of computed tomography (CT) studies in the National Lung Screening Trial (NLST) (including assessment of false-positive rates [FPRs] and sensitivity), to examine factors that contribute to variability, and to evaluate trade-offs between FPRs and sensitivity among different groups of radiologists. Materials and Methods: The HIPAA-compliant NLST was approved by the institutional review board at each screening center; all participants provided informed consent. NLST radiologists reported overall screening results, nodule-specific findings, and recommendations for diagnostic follow-up. A noncalcified nodule of 4 mm or larger constituted a positive screening result. The FPR was defined as the rate of positive screening examinations in participants without a cancer diagnosis within 1 year. Descriptive analyses and mixed-effects models were utilized. The average odds ratio (OR) for a false-positive result across all pairs of radiologists was used as a measure of variability. Results: One hundred twelve radiologists at 32 screening centers each interpreted 100 or more NLST CT studies, interpreting 72 160 of 75 126 total NLST CT studies in aggregate. The mean FPR for radiologists was 28.7% ± 13.7 (standard deviation), with a range of 3.8%-69.0%. The model yielded an average OR of 2.49 across all pairs of radiologists and an OR of 1.83 for pairs within the same screening center. Mean FPRs were similar for academic versus nonacademic centers (27.9% and 26.7%, respectively) and for centers inside (25.0%) versus outside (28.7%) the U.S. "histoplasmosis belt." Aggregate sensitivity was 96.5% for radiologists with FPRs higher than the median (27.1%), compared with 91.9% for those with FPRs lower than the median (P = .02). Conclusion: There was substantial variability in radiologists' FPRs. Higher FPRs were associated with modestly higher sensitivity. © RSNA, 2013. 23923018 Do price subsidies on artemisinin combination therapy for malaria increase household use?: evidence from a repeated cross-sectional study in remote regions of Tanzania. The Affordable Medicines Facility-malaria (AMFm) is a pilot program that uses price subsidies to increase access to Artemisinin Combination Therapies (ACTs), currently the most effective malaria treatment. Recent evidence suggests that availability and affordability of ACTs in retail sector drug shops (where many people treat malaria) has increased under the AMFm, but it is unclear whether household level ACT use has increased. HOUSEHOLD SURVEYS WERE CONDUCTED IN TWO REMOTE REGIONS OF TANZANIA (MTWARA AND RUKWA) IN THREE WAVES: March 2011, December 2011 and March 2012, corresponding to 3, 13 and 16 months into the AMFm implementation respectively. Information about suspected malaria episodes including treatment location and medications taken was collected. Respondents were also asked about antimalarial preferences and perceptions about the availability of these medications. Significant increases in ACT use, preference and perceived availability were found between Rounds 1 and 3 though not for all measures between Rounds 1 and 2. ACT use among suspected malaria episodes was 51.1% in March 2011 and increased by 10.9 percentage points by Round 3 (p = .017). The greatest increase was among retail sector patients, where ACT use increased from 31% in Round 1 to 49% in Round 2 (p = .037) and to 61% (p<.0001) by Round 3. The fraction of suspected malaria episodes treated in the retail sector increased from 30.2% in Round 1 to 46.7% in Round 3 (p = .0009), mostly due to a decrease in patients who sought no treatment at all. No significant changes in public sector treatment seeking were found. The AMFm has led to significant increases in ACT use for suspected malaria, especially in the retail sector. No evidence is found supporting the concerns that the AMFm would crowd out public sector treatment or neglect patients in remote areas and from low SES groups. 23166317 Compartmentalization and antiviral effect of efavirenz metabolites in blood plasma, seminal plasma, and cerebrospinal fluid. Efavirenz (EFV) is one of the most commonly prescribed antiretrovirals for use in the treatment of human immunodeficiency virus (HIV) infection. EFV is extensively metabolized by cytochrome P450 to a number of oxygenated products; however, the pharmacologic activity and distribution of these metabolites in anatomic compartments have yet to be explored. The systemic distribution of EFV oxidative metabolites was examined in blood plasma, seminal plasma, and cerebrospinal fluid from subjects on an EFV-based regimen. The 8-hydroxy EFV metabolite was detected in blood plasma, seminal plasma, and cerebrospinal fluid, with median concentrations of 314.5 ng/ml, 358.5 ng/ml, and 3.37 ng/ml, respectively. In contrast, 7-hydroxy and 8,14-hydroxy EFV were only detected in blood plasma and seminal plasma with median concentrations of 8.84 ng/ml and 10.23 ng/ml, and 5.63 ng/ml and 5.43 ng/ml, respectively. Interestingly, protein-free concentrations of metabolites were only detectable in seminal plasma, where a novel dihdyroxylated metabolite of EFV was also detected. This accumulation of protein-free EFV metabolites was demonstrated to be the result of differential protein binding in seminal plasma compared with that of blood plasma. In addition, the oxidative metabolites of EFV did not present with any significant pharmacologic activity toward HIV-1 as measured using an HIV green fluorescent protein single-round infectivity assay. This study is the first to report the physiologic distribution of metabolites of an antiretroviral into biologic compartments that the virus is known to distribute and to examine their anti-HIV activity. These data suggest that the male genital tract may be a novel compartment that should be considered in the evaluation of drug metabolite exposure. 23562368 Melittin peptide kills Trypanosoma cruzi parasites by inducing different cell death pathways. Antimicrobial peptides (AMPs) are components of the innate immune response that represent desirable alternatives to conventional pharmaceuticals, as they have a fast mode of action, a low likelihood of resistance development and can act in conjunction with existing drug regimens. AMPs exhibit strong inhibitory activity against both Gram-positive and Gram-negative bacteria, fungi, viruses, metazoans and other parasites, such as the protozoan Leishmania. Melittin is a naturally occurring AMP, which comprises 40-50% of the dry weight of Apis mellifera venom. Our group has recently shown that crude A. mellifera venom is lethal to Trypanosoma cruzi, the Chagas disease etiologic agent, and generates a variety of cell death phenotypes among treated parasites. Here, we demonstrate that the melittin affected all of T. cruzi developmental forms, including the intracellular amastigotes. The ultrastructural changes induced by melittin suggested the occurrence of different programmed cell death pathways, as was observed in A. mellifera-treated parasites. Autophagic cell death appeared to be the main death mechanism in epimastigotes. In contrast, melittin-treated trypomastigotes appeared to be dying via an apoptotic mechanism. Our findings confirm the great potential of AMPs, including melittin, as a potential source of new drugs for the treatment of neglected diseases, such as Chagas disease. 23858487 Estimating coupling directions in the cardiorespiratory system using recurrence properties. The asymmetry of coupling between complex systems can be studied by conditional probabilities of recurrence, which can be estimated by joint recurrence plots. This approach is applied for the first time on experimental data: time series of the human cardiorespiratory system in order to investigate the couplings between heart rate, mean arterial blood pressure and respiration. We find that the respiratory system couples towards the heart rate, and the heart rate towards the mean arterial blood pressure. However, our analysis could not detect a clear coupling direction between the mean arterial blood pressure and respiration. 23844647 Simulated Visual Fields Produced from Macular RNFLT Data in Patients with Glaucoma. Abstract Purpose: We investigated in detail the correlation between structure and function in the macula, and whether optical coherence tomography (OCT)-measured macular structure could be used to simulate the visual field. Materials and methods: This study comprised 60 eyes of 34 patients with open angle glaucoma (Anderson-Patella classification). To assess macular function, reliable data from the Humphrey field analyzer (HFA, SITA-standard, 10-2 program) for threshold, total deviation (TD), and pattern deviation (PD) were used. To assess macular structure, thickness data for the retinal nerve fiber layer (RNFL), ganglion cell complex (GCC), and ganglion cell layer plus inner plexiform layer (GCL + IPL) from macular OCT maps (3D OCT-2000, Topcon) were analyzed. Spearman's coefficient of correlation analysis was performed to determine the significance of the correlation, as well as the formula for simulation. The formula was used to calculate the simulated threshold, TD, and PD values. The simulation method was validated by comparing results for simulated and actual visual fields in a new data set of 29 eyes from glaucoma patients. Results: In most test points, macular function and the layer-by-layer structure were significantly correlated, however, the distribution of highly-correlated points varied. Simulated grayscale maps of the visual field based on the formula of regression line for RNFLT and thresholds were similar to actual visual fields. There was a significant correlation between simulated visual fields created from RNFLT, GCC and GCL + IPL data and actual average threshold values in all 68 test points (r = 0.63-0.87, p < 0.001) and TD (r = 0.62-0.86, p < 0.001). Conclusion: We found that there was a significant correlation between structure and function in the macular area, and that simulated visual fields from RNFLT data reflected actual visual fields. Such a simulation of macular function from OCT parameters may be useful in assessing glaucoma in patients who have difficulty undergoing actual visual field examinations. 23675687 Educational session as a tool to increase patient satisfaction of switching etanercept from the prefilled syringe to the autoinjection pen. Objective: To assess patients' acceptability of switching etanercept from the prefilled syringe to the autoinjection pen in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis patients. Methods: A two-phase cross-sectional study was designed. First phase: consisted of a 2 h information/education session to present the pen and learning its use. At the end of the session, patients completed a self-administered questionnaire regarding the meeting usefulness. Second phase: eight single-use prefilled Enbrel® Pen Myclic were provided. Results: The number of patients included were 104 (rheumatoid arthritis 58, psoriatic arthritis 31, ankylosing spondylitis 15). Attendees showed a high satisfaction degree with the meeting. A high percentage of patients (74.4 - 95.1%) rated the items of the questionnaire as 'very much'. Patients reported > 95% adherence to etanercept autoinjection pen. The percentage of patients self-administering etanercept increased from 66 to 94% and the percentage of those attending primary care for injection decreased from 23 to 2%. It produced important cost savings, in our study represents > 22.000 euros/year. Pain at the injection site was significantly reduced with the use of autoinjection pen. Ninty seven (93%) patients considered that the use of the autoinjection pen was easier than the syringe and 94.2% chose the pen as their preferred delivery system. Conclusions: The autoinjection pen is an advantageous delivery option for etanercept. This study provides further evidence to support that the education strategy is a valid method for switching anti-TNF-α drugs from syringe to pen in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. 23932758 The Fate of Unplanned Retention of Prosthetic Articulating Spacers for Infected Total Hip and Total Knee Arthroplasty. Eighteen patients with periprosthetic joint infection (11 hips and 7 knees) treated by prosthetic articulating spacers retained their spacers and were followed up at an average of 43.8months(range, 13-78months). Fifteen patients maintained well-functioning spacers for an average of 42.7months, of which 4 patients died with the spacers in situ at an average of 48.7months. The mean Harris Hip Score and Knee Society knee and function scores of survivors were 92, 92, 88, respectively. Spacers were revised in 3 patients because of recurrent infection (n=1) at 24months and mechanical loosening (n=2) at 74 and 50months. Findings of this study suggest that a proportion of patients with unplanned retention of prosthetic spacers appear to function well up to 6years without necessarily requiring further surgical intervention. 23541450 Tuberculosis of the lower cervical spine (C5-C6) in a 24-month-old infant. Tuberculosis (TB) of the cervical spine occurs rarely in younger children whereas the presentation and outcome are different from those of adult cervical spine. Because cervical spinal TB in younger children is rarely reported, the clinical characteristics, the treatments, and the expected outcome of treatments in younger children are still unknown. We present a case of cervical spine TB in a 24-month-old boy that grounds severe vertebral destruction and an extradural abscess. This child presented with neurological deficit in the form of quadraparesis. We performed anterior cervical debridement for this patient; to our best knowledge, the child in this case is the youngest patient reported in the literature as having had cervical TB treated through anterior cervical surgery. The neurological deficits of this patient were recovered soon, and no evidence of recurrence of the tuberculous lesion or of the deformity was revealed by the 6-year follow-up magnetic resonance imaging. Based on our experiences in this case and a review of the literature, we propose that for patients of cervical spine TB in early childhood, anterior excision of diseased bone without grafting should be adequate as a surgical measure. 23344821 Oxidative stress and alteration of biochemical markers in liver and kidney by malathion in rat pups. The present study was undertaken to determine the effects of malathion exposure through maternal milk on oxidative stress, functional an metabolic parameters in kidney and liver of rat pups. We found that lactational exposure to malation (200 mg/kg, body weight (bw)) induced an oxidative stress status assessed by an increase in malondialdhyde (MDA) content, reflecting lipoperoxidation, a decrease in thiol groups' content as well as depletion of enzyme activities as a superoxide dismutase (SOD) and catalase (CAT) on postnatal days (Pnds) 21 and 51. Moreover, the current study showed that malathion induced liver and kidney dysfunctions demonstrated by considerable increase in phosphatase alkaline (PAL), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities as well as total and direct bilirubin, creatinine urea and acid uric contents. We also observed an increase in triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and a decrease in high-density lipoprotein cholesterol (HDL-C) in the plasma of treated rat pups. These findings evidenced that malathion exposure during lactation through maternal milk of rats pups induced kidney and liver oxidative stress as well as functional and metabolic disorders that play a role in the development of others pathologies as cardiovascular diseases and cancers. 23510370 Ectopic Thyroid Tissue in the Adrenal Gland: Report of 2 Cases with Pathogenetic Implications. Background: Ectopic thyroid tissue is usually found anywhere along the embryonic descent pathway of the medial thyroid anlage from the tongue to the trachea (Wölfler area). However, ectopic thyroid tissue in the adrenal gland (ETTAG) is not easy to understand on the basis of thyroid embryology; because it is so rare, the possibility of metastasis should first be considered. Here, we describe 2 cases of ETTAG with pathogenetic implications and review the literature. Patient findings: Two cases of ETTAG presented as incidental cystic adrenal masses in adult females, one having a congenital hernia of Morgagni. The ETTAG was histologically indistinguishable from normal orthotopic thyroid tissue, and its follicular nature was confirmed by immunohistochemical positivity for thyroglobulin, thyroperoxidase, thyroid transcription factor-1 (TTF-1/Titf-1/Nkx2.1), cytokeratin (CK) AE1/AE3, CK 7, pendrin, human sodium iodide symporter (hNIS), paired box gene 8 (PAX8) and FOXE1 (TTF-2), as well as positivity for the messenger RNA of the thyroglobulin gene by in situ hybridization analysis. No C cells (negativity for calcitonin, cromogranin and synaptophysin) were present. Neither BRAF nor KRAS mutations were detected with real-time polymerase chain reaction analysis. Further work-up did not show evidence of thyroid malignancy. Summary: ETTAG is a rare finding, with only 7 cases reported; women are much more frequently affected than men (8:1) and it usually clinically presents in the fifth decade (mean age: 54, range: 38-67) as a cystic adrenal mass incidentally discovered on abdominal ultrasonography and/or in computed tomography images. ETTAG is composed of normal follicular cells without C cells. The expression of some transcription factors (TTF-1, PAX8 and FOXE1) involved in development and/or migration of the medial thyroid anlage is preserved. Coexistence of a congenital hernia of Morgagni in one patient suggests an over-descent of medial thyroid anlage derived cells in its pathogenesis. Conclusion: Although ETTAG pathogenesis remains unknown, the lack of C cells together with the coexistence of a congenital defect of the anterior diaphragm (hernia of Morgagni) in one of our patients could suggest an over-descent of medial thyroid anlagen derived cells in the origin of this heterotopia. 23211697 Refining genome-wide linkage intervals using a meta-analysis of genome-wide association studies identifies loci influencing personality dimensions. Personality traits are complex phenotypes related to psychosomatic health. Individually, various gene finding methods have not achieved much success in finding genetic variants associated with personality traits. We performed a meta-analysis of four genome-wide linkage scans (N=6149 subjects) of five basic personality traits assessed with the NEO Five-Factor Inventory. We compared the significant regions from the meta-analysis of linkage scans with the results of a meta-analysis of genome-wide association studies (GWAS) (N∼17 000). We found significant evidence of linkage of neuroticism to chromosome 3p14 (rs1490265, LOD=4.67) and to chromosome 19q13 (rs628604, LOD=3.55); of extraversion to 14q32 (ATGG002, LOD=3.3); and of agreeableness to 3p25 (rs709160, LOD=3.67) and to two adjacent regions on chromosome 15, including 15q13 (rs970408, LOD=4.07) and 15q14 (rs1055356, LOD=3.52) in the individual scans. In the meta-analysis, we found strong evidence of linkage of extraversion to 4q34, 9q34, 10q24 and 11q22, openness to 2p25, 3q26, 9p21, 11q24, 15q26 and 19q13 and agreeableness to 4q34 and 19p13. Significant evidence of association in the GWAS was detected between openness and rs677035 at 11q24 (P-value=2.6 × 10(-06), KCNJ1). The findings of our linkage meta-analysis and those of the GWAS suggest that 11q24 is a susceptible locus for openness, with KCNJ1 as the possible candidate gene. 23895341 Dovetailing biology and chemistry: integrating the Gene Ontology with the ChEBI chemical ontology. The Gene Ontology (GO) facilitates the description of the action of gene products in a biological context. Many GO terms refer to chemical entities that participate in biological processes. To facilitate accurate and consistent systems-wide biological representation, it is necessary to integrate the chemical view of these entities with the biological view of GO functions and processes. We describe a collaborative effort between the GO and the Chemical Entities of Biological Interest (ChEBI) ontology developers to ensure that the representation of chemicals in the GO is both internally consistent and in alignment with the chemical expertise captured in ChEBI. We have examined and integrated the ChEBI structural hierarchy into the GO resource through computationally-assisted manual curation of both GO and ChEBI. Our work has resulted in the creation of computable definitions of GO terms that contain fully defined semantic relationships to corresponding chemical terms in ChEBI. The set of logical definitions using both the GO and ChEBI has already been used to automate aspects of GO development and has the potential to allow the integration of data across the domains of biology and chemistry. These logical definitions are available as an extended version of the ontology from http://purl.obolibrary.org/obo/go/extensions/go-plus.owl. 23894689 Emergency laparotomy in octogenarians: A 5-year study of morbidity and mortality. To determine the morbidity and mortality associated with emergency laparotomy for a clinically acute abdomen in patients aged ≥ 80 years. In this retrospective audit, octogenarians undergoing emergency laparotomy between 1st January 2005 and 1(st) January 2010 were identified using the Galaxy Theatre System. Patients undergoing abdominal surgery through groin crease incisions or Lanz or Gridiron incisions were excluded. Also simple appendectomies were excluded. All patients were aged 80 years or more at the time of their surgery. Data were obtained using casenote review with a standardised proforma to determine patient age, American Society of Anesthesiologists (ASA) grade, indications for surgery, early (within 30 d) and late (after 30 d) complications, mortality and length of stay. Data were inserted into a Microsoft Excel spreadsheet and analysed. One hundred patients were identified from the database (Galaxy) as having undergone emergency laparotomy. Of those, 55 underwent the procedure for intestinal procedures and 37 for secondary peritonitis. There was a 2:1 female predominance; average age 85 and ASA grade 3. Bowel resection was required in 51 out of the 100 patients and 22 (43%) died. Other procedures included appendicectomy, adhesiolysis, repair of AAA graft leak and colostomies for the pathological process resulting in an acute abdomen. Twelve of 100 patients (12%) suffered intra-operative complications, including splenic and bowel-serosal tears. Seventy patients (70%) had postoperative complications including myocardial infarction, wound infection, haematoma and sepsis. Overall mortality was 45/100 patients (45%). The major causes of death were sepsis (19/45 patients, 42%), underlying cancer (13/45 patients, 29%); with others including bowel obstruction (2/45 patients, 4%), myocardial and intestinal ischaemia and dementia. Emergency laparotomy in octogenarians carries a significant morbidity and mortality. In particular, surgery requiring bowel resection has higher mortality than without resection. 23063413 Establishment of a robust hepatitis C virus replicon cell line over-expressing P-glycoprotein that facilitates analysis of P-gp drug transporter effects on inhibitor antiviral activity. P-glycoprotein (P-gp) is an active efflux pump affecting the pharmacokinetic (PK) profiles of drugs that are P-gp substrates. The Caco-2 bi-directional assay is widely used to identify drug-P-gp interactions in vitro. For molecules exhibiting non-classical drug properties however, ambiguous results limit its use in lead optimization. The goal of this study was to develop a robust cell-based assay system to directly measure the role of P-gp-driven efflux in reducing the potency of hepatitis C virus (HCV) replication inhibitors. Vinblastine (Vin) was employed to select for a Vin-resistant HCV replicon (313-11) from the parental cell line (377-2). The 313-11 cell line was >50-fold resistant to Vin and over-expressed P-gp, as determined by Western immunoblots. Increased expression of P-gp was mediated by up-regulation of the MDR1 transcript. The reduced potency of different classes of HCV replication inhibitors in the 313-11 P-gp cell line was restored in the presence of known P-gp inhibitors. Addition of the P-gp inhibitor, tariquidar, increased the uptake of a radiolabeled HCV replication inhibitor by 14-fold in the 313-11 replicon cell line. Finally, a positive correlation was demonstrated between potency in the 313-11 replicon and the bi-directional Caco-2 efflux ratio for a panel of HCV protease inhibitors. In conclusion, a robust P-gp HCV replicon cell-based assay has been developed to measure the effect of the P-gp efflux pump on the potency of different classes of HCV replication inhibitors. This system establishes a direct correlation between antiviral activity and the effect of P-gp efflux in a single cell line. 23832602 Reactive Oxygen Species-Dependent Down-Regulation of Tumor Suppressor Genes PTEN, USP28, DRAM, TIGAR, and CYLD Under Oxidative Stress. We examined whether steady-state mRNA levels of five tumor suppressor genes are subjected to oxidative stress. Superoxide radical-generating menadione and serum deprivation diminished the steady-state mRNA levels for the genes phosphatase and tensin homolog (PTEN), ubiquitin specific peptidase 28 (USP28), damage-regulated autophagy modulator (DRAM), TP53-induced glycolysis and apoptosis regulator (TIGAR), and cylindromatosis (CYLD). Hydrogen peroxide showed suppression in steady-state mRNA levels for USP28, DRAM, TIGAR, and CYLD but not for PTEN. The steady-state mRNA levels specific for all five genes were enhanced by antioxidants, such as glutathione and N-acetylcysteine. The HepG2 stable transfectants overexpressing the mitochondrial isoform of human glutaredoxin, Grx2a, and containing a relatively low reactive oxygen species (ROS) level were assessed to contain the increased steady-state mRNA levels specific for the five tumor suppressor genes. In brief, the steady-state mRNA levels specific for these genes are negatively regulated by oxidative stress through the mediation of ROS. 23566034 Loss of the Birt-Hogg-Dubé gene product folliculin induces longevity in a hypoxia-inducible factor-dependent manner. Signaling through the hypoxia-inducible factor hif-1 controls longevity, metabolism, and stress resistance in Caenorhabditis elegans. Hypoxia-inducible factor (HIF) protein levels are regulated through an evolutionarily conserved ubiquitin ligase complex. Mutations in the VHL gene, encoding a core component of this complex, cause a multitumor syndrome and renal cell carcinoma in humans. In the nematode, deficiency in vhl-1 promotes longevity mediated through HIF-1 stabilization. However, this longevity assurance pathway is not yet understood. Here, we identify folliculin (FLCN) as a novel interactor of the hif-1/vhl-1 longevity pathway. FLCN mutations cause Birt-Hogg-Dubé syndrome in humans, another tumor syndrome with renal tumorigenesis reminiscent of the VHL disease. Loss of the C. elegans ortholog of FLCN F22D3.2 significantly increased lifespan and enhanced stress resistance in a hif-1-dependent manner. F22D3.2, vhl-1, and hif-1 control longevity by a mechanism distinct from insulin-like signaling. Daf-16 deficiency did not abrogate the increase in lifespan mediated by flcn-1. These findings define FLCN as a player in HIF-dependent longevity signaling and connect organismal aging, stress resistance, and regulation of longevity with the formation of renal cell carcinoma. 23233133 Heterogeneity of gangliosides among T cell subsets. Gangliosides are major components of highly organized membrane microdomains or rafts, yet little is known about the role of gangliosides in raft organization. This is also the case of gangliosides in TCR-mediated activation. Comprehensive structural analysis of gangliosides in the primary thymocytes and CD4(+) T and CD8(+) T cells was not achieved due to technical difficulties. We have found that CD8(+) T cells express very high levels of o-series gangliosides, but on the other hand, CD4(+) T cells preferably express a-series gangliosides. In the TCR-dependent activation, CD4(+) T cells selectively require a-series gangliosides, but CD8(+) T cells do require only o-series gangliosides but not a-series gangliosides. Ganglioside GM3 synthase-deficient mice lacking a-series gangliosides neither exhibited the TCR-dependent activation of CD4(+) T nor developed ovalbumin-induced allergic airway inflammation. These findings imply that the distinct expression pattern of ganglioside species in CD4(+) and CD8(+) T cells define the immune function of each T cell subset. 23824285 Prenatal diagnosis of β-thalassemia in Guangxi Zhuang Autonomous Region, China. The aim of this study was to establish a comprehensive prenatal diagnosis service and to control the birth of thalassemia children in Guangxi Zhuang Automonous Region, China. Prenatal diagnosis was performed in 1,058 couples with 'at risk' β-thalassemia from Guangxi Zhuang Automonous Region. Fetal samplings were collected by chorionic villus sampling in the first trimester, by amniocentesis in the second trimester and by cordocentesis in the third trimester. DNA analysis was carried out using polymerase chain reaction, reverse dot blot assay, multiplex ligation-dependent probe amplification method and DNA sequencing. Automated high-performance liquid chromatography system was used to analyze the fetal hemoglobin in pregnancies in case mutations were unidentified. A total of 12 different β-thalassemia mutations were characterized from 2,116 parents. The most common mutation for β-thalassemia was CD41-42 (-CTTT) followed by CD17 (A→T). Prenatal testing revealed 315 normal fetuses, 500 carriers and 253 β-thalassemia major fetuses. The couples having fetuses with β-thalassemia major were counselled to terminate the pregnancies. Postnatal follow-up confirmed all pregnancies. Our prenatal diagnosis strategy proved to be highly effective in reducing severe thalassemia in pregnant populations. 23774514 Evaluation of a center of excellence program for spine surgery. The Centers for Medicare and Medicaid Services and many private health plans are encouraging patients to seek orthopedic care at hospitals designated as centers of excellence. No evaluations have been conducted to compare patient outcomes and costs at centers of excellence versus other hospitals. The objective of our study was to assess whether hospitals designated as spine surgery centers of excellence by a group of over 25 health plans provided higher quality care. Claims representing approximately 54 million commercially insured individuals were used to identify individuals aged 18-64 years with 1 of 3 types of spine surgery in 2007-2009: 1-level or 2-level cervical fusion (referred to as cervical simple fusion), 1-level or 2-level lumbar fusion (referred to as lumbar simple fusion), or lumbar discectomy and/or decompression without fusion. The primary outcomes were any complication (7 complications were captured) and 30-day readmission. The multivariate models controlled for differences in age, sex, and comorbidities between the 2 sets of hospitals. A total of 29,295 cervical simple fusions, 27,214 lumbar simple fusions, and 28,911 lumbar discectomy/decompressions were identified, of which 42%, 42%, and 47%, respectively, were performed at a hospital designated as a spine surgery center of excellence. Designated hospitals had a larger number of beds and were more likely to be an academic center. Across the 3 types of spine surgery (cervical fusions, lumbar fusions, or lumbar discectomies/decompressions), there was no difference in the composite complication rate [OR 0.90 (95% CI, 0.72-1.12); OR 0.98 (95% CI, 0.85-1.13); OR 0.95 (95% CI, 0.82-1.07), respectively] or readmission rate [OR 1.03 (95% CI, 0.87-1.21); OR 1.01 (95% CI, 0.89-1.13); OR 0.91 (95%, CI 0.79-1.04), respectively] at designated hospitals compared with other hospitals. On average, spine surgery centers of excellence had similar complication rates and readmission rates compared with other hospitals. These results highlight the importance of empirical evaluations of centers of excellence programs. 23937282 Equivalency of tricyclic antidepressants in open-label neuropathic pain study. To compare adverse effects, tolerability and efficacy of the tricyclic antidepressants (TCAs) amitriptyline and nortriptyline in management of neuropathic pain due to peripheral neuropathy (PN). We performed a prospective open-label flexible-dosing comparison of monotherapy or adjuvant therapy using amitriptyline or nortriptyline in PN-associated neuropathic pain. Primary outcomes were quantitative adverse effects and discontinuation rates. Secondary outcomes assessed changes in pain severity, quality of life, disability, sleep efficacy, mood and anxiety, and global improvement. Assessments occurred at 3 and 6 months after initiation. Our hypothesis was that nortriptyline would have better tolerance than amitriptyline. A total of 228 PN patients were enrolled approximately equally for monotherapy and adjuvant therapy. Adverse effects and discontinuation rates were similar between amitriptyline and nortriptyline interventions. Weight gain was more common with amitriptyline, while nortriptyline use was associated with greater prevalence of dry mouth. Secondary outcome measures were similar in both groups, demonstrating improvement from baseline. Amitriptyline and nortriptyline are equivalent for overall adverse effects and discontinuation rates. Either TCA should be equally considered for use in neuropathic pain due to PN. When used as monotherapy or as part of adjuvant therapy, either TCA can be expected to provide approximately 23-26% visual analog scale pain reduction if tolerated. Discontinuations due to inefficacy or adverse effects can be anticipated in 26-37% of patients initiated on either TCA for PN-associated neuropathic pain. 23681359 Erectile dysfunction may be the first clinical sign of insulin resistance and endothelial dysfunction in young men. The purpose of this study is to investigate the possible underlying pathogenesis of erectile dysfunction (ED) without well-known etiology in young men under the age of 40 years. 192 patients and 33 normal controls were enrolled. ED was evaluated by using the International Index of Erectile Function-5 (IIEF-5) questionnaire. Traditional cardiovascular risk factors, hormone levels, and vascular parameters were measured. Insulin resistance (IR) was measured by homeostasis model assessment (HOMA). Patients with ED had significantly higher levels of systolic blood pressure (SBP), high-sensitivity C-reactive protein (Hs-CRP), high Insulin resistance index (HOMA-IR) and carotid intima-media thickness (IMT), compared with controls. The brachial artery endothelium-dependent flow-mediated vasodilation (FMD) values were significantly lower in ED patients. By multivariate logistic regression analysis, FMD, SBP, Hs-CRP and HOMA-IR were significantly associated with ED. In receiver-operating characteristic (ROC) analysis, FMD was a significant predictor of ED (area under the curve (AUC) 0.933, p < 0.001). The cutoff value of FMD <10.4 % had sensitivity of 81.3 % and specificity of 100 %. HOMA-IR was also proven to be predictor of ED (AUC of HOMA-IR 0.759, p < 0.001). ED may be the first clinical sign of endothelial dysfunction and a clinical marker of cardiovascular and metabolic diseases. Subclinical endothelial dysfunction and insulin resistance may be the underlying pathogenesis of ED in young patients without well-known etiology. Measurement of FMD, HOMA-IR can improve our ability to predict and treat ED, as well as subclinical cardiovascular disease early in young men. 23927666 An EGFRvIII-targeted bispecific T-cell engager overcomes limitations of the standard of care for glioblastoma. While advanced surgical techniques, radiation therapy and chemotherapeutic regimens provide a tangible benefit for patients with glioblastoma (GBM), the average survival from the time of diagnosis remains less than 15 months. Current therapy for GBM is limited by the nonspecific nature of treatment, prohibiting therapy that is aggressive and prolonged enough to eliminate all malignant cells. As an alternative, bispecific antibodies can redirect the immune system to eliminate malignant cells with exquisite potency and specificity. We have recently developed an EGF receptor variant III (EGFRvIII)-targeted bispecific antibody that redirects T cells to eliminate EGFRvIII-expressing GBM. The absolute tumor specificity of EGFRvIII and the lack of immunologic crossreactivity with healthy cells allow this therapeutic to overcome limitations associated with the nonspecific nature of the current standard of care for GBM. Evidence indicates that the molecule can exert therapeutically significant effects in the CNS following systemic administration. Additional advantages in terms of ease-of-production and off-the-shelf availability further the clinical utility of this class of therapeutics. 23861820 Dietary Selenium Deficiency Exacerbates DSS-Induced Epithelial Injury and AOM/DSS-Induced Tumorigenesis. Selenium (Se) is an essential micronutrient that exerts its functions via selenoproteins. Little is known about the role of Se in inflammatory bowel disease (IBD). Epidemiological studies have inversely correlated nutritional Se status with IBD severity and colon cancer risk. Moreover, molecular studies have revealed that Se deficiency activates WNT signaling, a pathway essential to intestinal stem cell programs and pivotal to injury recovery processes in IBD that is also activated in inflammatory neoplastic transformation. In order to better understand the role of Se in epithelial injury and tumorigenesis resulting from inflammatory stimuli, we examined colonic phenotypes in Se-deficient or -sufficient mice in response to dextran sodium sulfate (DSS)-induced colitis, and azoxymethane (AOM) followed by cyclical administration of DSS, respectively. In response to DSS alone, Se-deficient mice demonstrated increased morbidity, weight loss, stool scores, and colonic injury with a concomitant increase in DNA damage and increases in inflammation-related cytokines. As there was an increase in DNA damage as well as expression of several EGF and TGF-β pathway genes in response to inflammatory injury, we sought to determine if tumorigenesis was altered in the setting of inflammatory carcinogenesis. Se-deficient mice subjected to AOM/DSS treatment to model colitis-associated cancer (CAC) had increased tumor number, though not size, as well as increased incidence of high grade dysplasia. This increase in tumor initiation was likely due to a general increase in colonic DNA damage, as increased 8-OHdG staining was seen in Se-deficient tumors and adjacent, non-tumor mucosa. Taken together, our results indicate that Se deficiency worsens experimental colitis and promotes tumor development and progression in inflammatory carcinogenesis. 23830452 Characterization of gamma radiation inducible thioredoxin h from Spirogyra varians. In this study, thioredoxin h (Trxh) was isolated and characterized from the fresh water green alga Spirogyra varians, which was one amongst the pool of proteins induced upon gamma radiation treatment. cDNA clones encoding S. varians thioredoxin h were isolated from a pre-constructed S. varians cDNA library. Trxh had a molecular mass of 13.5kDa and contained the canonical WCGPC active site. Recombinant Trxh showed the disulfide reduction activity, and exhibited insulin reduction activity. Also, Trxh had higher 5,5'-dithiobis(2-nitrobenzoic acid) reduction activity with Arabidopsis thioredoxin reductase (TR) than with Escherichia coli TR. Specific expression of the Trxh gene was further analyzed at mRNA and protein levels and was found to increase by gamma irradiation upto the absorbed dose of 3kGy, suggesting that Trxh may have potential functions in protection of biomolecules from gamma irradiation. 23429634 Effect of cataract and its removal on ganglion cell complex thickness and peripapillary retinal nerve fiber layer thickness measurements by fourier-domain optical coherence tomography. To examine the effect of cataract on signal strength index (SSI) and thickness measurements of the ganglion cell complex (GCC) and peripapillary retinal nerve fiber layer (pRNFL) with the RTVue-100 Fourier-domain optical coherence tomography device. GCC and pRNFL measurements were obtained preoperatively in 53 eyes of 53 patients, including 13 glaucoma patients and measurements were repeated postoperatively. Cataract degree was graded by the Lens Opacities Classification System III. Factors associated with segmentation error and with changes in SSI or average thickness of GCC and pRNFL were determined. The prevalence and proportion of segmentation error were higher in GCC measurements compared with pRNFL measurements (prevalence: 28.3% vs. 5.6%, P<0.001; proportion: 5.9% vs. 1.3%, P=0.01). Multivariate analysis showed that segmentation error in GCC measurements was significantly associated with preoperative SSI and the degree of posterior subcapsular opacity. In eyes without segmentation error, postoperative SSI was significantly higher for GCC and pRNFL measurements, whereas postoperative thickness was slightly but significantly higher for all GCC and pRNFL parameters. Multivariate analysis indicated that preoperative SSI was highly correlated with SSI changes and that the presence of glaucoma and preoperative SSI were significantly correlated with average thickness changes of GCC and pRNFL, respectively. In eyes with cataract, segmentation error occurred more frequently in GCC measurements than in pRNFL measurements. After cataract surgery, all thickness parameters in GCC and pRNFL measurements increased slightly. Segmentation errors should be determined, especially in GCC measurements of eyes with cataract and low SSI. 23963262 Exclusive formation of SnO by low temperature single-source AACVD. An easily synthesised Sn(ii) bis(ureide) derivative is shown to be a single-source precursor for the aerosol-assisted CVD of SnO, providing unprecedented levels of oxidation state control at temperatures as low as 250 °C. 23574263 Lorcaserin: a novel serotonin 2C agonist for the treatment of obesity. Obesity has become an epidemic in the United States and its prevalence continues to increase. Adjunctive treatment with pharmacotherapy is often reserved for individuals who fail to achieve their intended weight goals with diet and exercise alone. Current approved therapies for weight loss include phentermine, diethylpropion, orlistat, and phentermine/topiramate. The objective of this paper was to review the place of lorcaserin, a novel serotonin 2C agonist, which was FDA approved in July 2012. Unlike contemporary lipase inhibitors and sympathomimetic amines, lorcaserin is purported to reduce food consumption and increase satiety. A systematic review of the literature for all relevant articles was performed through January 2013 using MEDLINE, Web of Science, and International Pharmaceutical Abstracts using key words related to lorcaserin. Three phase III clinical studies have been published evaluating the efficacy and safety of lorcaserin in various obese populations. A higher proportion of patients receiving lorcaserin (∼47%) lost more than 5% body weight from baseline in comparison with the placebo group (∼25%; p < 0.05 in all studies). Those receiving the recommended dose of lorcaserin 10 mg twice daily lost on average ∼6 kg of body weight from baseline versus ∼3 kg with placebo. Patients with diabetes mellitus also saw significant reductions in their HbA1c with lorcaserin (∼0.9%) versus placebo (∼0.4%; p < 0.001). Lorcaserin is generally well tolerated with the most commonly experienced adverse events being nausea, dizziness, headache, upper respiratory tract infections, and nasopharyngitis. Cardiovascular evaluations showed no appreciable increase in valvulopathy with lorcaserin use versus placebo. For now, pharmacists should continue to recommend the use of lorcaserin as a complement to, not in lieu of, ongoing lifestyle and behavioral modification. 23220590 Inhibition of human alcohol and aldehyde dehydrogenases by cimetidine and assessment of its effects on ethanol metabolism. Previous studies have reported that cimetidine, an H2-receptor antagonist used to treat gastric and duodenal ulcers, can inhibit alcohol dehydrogenases (ADHs) and ethanol metabolism. Human alcohol dehydrogenases and aldehyde dehydrogenases (ALDHs), the principal enzymes responsible for metabolism of ethanol, are complex enzyme families that exhibit functional polymorphisms among ethnic groups and distinct tissue distributions. We investigated the inhibition by cimetidine of alcohol oxidation by recombinant human ADH1A, ADH1B1, ADH1B2, ADH1B3, ADH1C1, ADH1C2, ADH2, and ADH4, and aldehyde oxidation by ALDH1A1 and ALDH2 at pH 7.5 and a cytosolic NAD(+) concentration. Cimetidine acted as competitive or noncompetitive inhibitors for the ADH and ALDH isozymes/allozymes with near mM inhibition constants. The metabolic interactions between cimetidine and ethanol/acetaldehyde were assessed by computer simulation using the inhibition equations and the determined kinetic constants. At therapeutic drug levels (0.015 mM) and physiologically relevant concentrations of ethanol (10 mM) and acetaldehyde (10 μM) in target tissues, cimetidine could weakly inhibit (<5%) the activities of ADH1B2 and ADH1B3 in liver, ADH2 in liver and small intestine, ADH4 in stomach, and ALDH1A1 in the three tissues, but not significantly affect ADH1A, ADH1B1, ADH1C1/2, or ALDH2. At higher drug levels, which may accumulate in cells (0.2 mM), the activities of the weakly-inhibited enzymes may be decreased more significantly. The quantitative effects of cimetidine on metabolism of ethanol and other physiological substrates of ADHs need further investigation. 23847151 MADS Domain Transcription Factors Mediate Short-Range DNA Looping That Is Essential for Target Gene Expression in Arabidopsis. MADS domain transcription factors are key regulators of eukaryotic development. In plants, the homeotic MIKC MADS factors that regulate floral organ identity have been studied in great detail. Based on genetic and protein-protein interaction studies, a floral quartet model was proposed that describes how these MADS domain proteins assemble into higher order complexes to regulate their target genes. However, despite the attractiveness of this model and its general acceptance in the literature, solid in vivo proof has never been provided. To gain deeper insight into the mechanisms of transcriptional regulation by MADS domain factors, we studied how SEEDSTICK (STK) and SEPALLATA3 (SEP3) directly regulate the expression of the reproductive meristem gene family transcription factor-encoding gene VERDANDI (VDD). Our data show that STK-SEP3 dimers can induce loop formation in the VDD promoter by binding to two nearby CC(A/T)6GG (CArG) boxes and that this is essential for promoter activity. Our in vivo data show that the size and position of this loop, determined by the choice of CArG element usage, is essential for correct expression. Our studies provide solid in vivo evidence for the floral quartet model. 23837998 Acute catecholamine cardiomyopathy in patients with phaeochromocytoma or functional paraganglioma. Phaeochromocytomas and paragangliomas (PPGL) can cause acute catecholamine cardiomyopathy (ACC). We assessed the prevalence of ACC and compared the presentation of cases with and without ACC in a large series of PPGL. Single centre retrospective study. Hypertension Unit, University Hospital, Paris. 140 consecutive patients with PPGL, referred from January 2003 to September 2012. Left ventricular ejection fraction (LVEF), perioperative mortality. Fifteen patients (11%) had suffered an ACC, occurring in 14 cases before the diagnosis of PPGL. Precipitating factors were identified in 11 cases. Twelve patients presented with acute pulmonary oedema, including 10 with cardiogenic shock, requiring life support in eight cases. Seven patients (five with pulmonary oedema) presented with acute chest pain and cardiac dysfunction. Electrocardiographic abnormalities were present in 14 cases: ST segment elevation or pathological Q waves, ST segment depression, and/or diffuse T wave inversion. Six patients displayed classical (apical ballooning) or inverted (basal/mid ventricular stunning) takotsubo-like cardiomyopathy. Coronary arteries were always normal on angiography. In patients with ACC, median LVEF rose from 30% (IQR 23-33%) during ACC to 71% (50-72%) before surgery (n=11, p<0.001). Median LVEF before PPGL surgery was 65% (51-72%) and 65% (60-70%) in patients with and without a history of ACC, respectively (not significant). PPGL may present as ACC in 11% of cases, excluding patients dying from undiagnosed tumours. Left ventricular dysfunction is usually reversible before surgery. PPGL should be suspected in patients with acute heart failure without evidence of valvular or coronary artery disease. 23259841 Visualization and virtual screening of the chemical universe database GDB-17. The chemical universe database GDB-17 contains 166.4 billion molecules of up to 17 atoms of C, N, O, S, and halogens obeying rules for chemical stability, synthetic feasibility, and medicinal chemistry. GDB-17 was analyzed using 42 integer value descriptors of molecular structure which we term "Molecular Quantum Numbers" (MQN). Principal component analysis and representation of the (PC1, PC2)-plane provided a graphical overview of the GDB-17 chemical space. Rapid ligand-based virtual screening (LBVS) of GDB-17 using the city-block distance CBD(MQN) as a similarity search measure was enabled by a hashed MQN-fingerprint. LBVS of the entire GDB-17 and of selected subsets identified shape similar, scaffold hopping analogs (ROCS > 1.6 and T(SF) < 0.5) of 15 drugs. Over 97% of these analogs occurred within CBD(MQN) ≤ 12 from each drug, a constraint which might help focus advanced virtual screening. An MQN-searchable 50 million subset of GDB-17 is publicly available at www.gdb.unibe.ch . 23905989 Rab35: GEFs, GAPs and Effectors. Rabs are the largest family of small GTPases and are master regulators of membrane trafficking. Following activation by guanine-nucleotide exchange factors (GEFs), each Rab binds a specific set of effector proteins that mediate the various downstream functions of that Rab. Then, with the help of GTPase-activating proteins, the Rab converts GTP to GDP, terminating its function. There are over 60 Rabs in humans and only a subset has been analyzed in any detail. Recently, Rab35 has emerged as a key regulator of cargo recycling at endosomes, with an additional role in regulation of the actin cytoskeleton. Here, we will focus on the regulation of Rab35 activity by the connecdenn/DENND1 family of GEFs and the TBC1D10/EPI64 family of GTPase-activating proteins. We will describe how analysis of these proteins, as well as a plethora of Rab35 effectors has provided insights into Rab35 function. Finally, we will describe how Rab35 provides a novel link between the Rab and Arf family of GTPases with implications for tumor formation and invasiveness. 23968809 Mapping of cingulate motor function by cortical stimulation. An 8-year-old boy with intractable left mesiofrontal lobe epilepsy underwent placement of stereotactic intracerebral depth electrodes to better localise the epileptogenic zone. Co-registration of preoperative MRI and post-electrode implantation CAT allowed for anatomical localisation of electrode contacts. Electrical stimulation of electrodes over the dorsal and ventral banks of the cingulate cortex on the left produced right foot dorsiflexion and right wrist and elbow flexion, respectively, demonstrating detailed representation of cingulate motor function in humans, somatotopically distributed along the banks of the cingulate sulcus, as seen in the non-human primate. [Published with video sequences]. 23955478 Anastomotic stenosis of the descending colon caused by barium granuloma formation following barium peritonitis: report of a case. Anastomotic stricture reportedly often recurs following barium peritonitis, regardless of whether the anastomotic diameter is initially sufficient. However, the causes of repetitive stricture have not been clarified. We report a case that suggests the pathophysiology of recurrent anastomotic strictures following barium peritonitis. The patient was a 39-year-old Japanese man with idiopathic perforation of the descending colon after undergoing an upper gastrointestinal barium contrast study. After emergency peritoneal lavage and diverting colostomy, created using the perforated region, the patient recovered uneventfully and 3 months later, the colostomy was closed and the perforated colon was resected. However, 7 months after colostomy closure, abdominal distention gradually developed, and colonoscopy revealed an anastomotic stricture. The patient was referred to our hospital where he underwent resection of the anastomotic stricture. The surgical specimen exhibited barium granulomas not only in the subserosa of the entire specimen, but also in the submucosa and lamina propria localized in the anastomotic site. These findings suggest that barium was embedded in the submucosa and lamina propria with manipulation of the stapled anastomosis and that the barium trapped in the anastomotic site caused persistent inflammation, resulting in an anastomotic stricture. 23682586 Management of tuberculosis and latent tuberculosis infection in human immunodeficiency virus-infected persons. The syndemic of human immunodeficiency virus (HIV)/tuberculosis (TB) co-infection has grown as a result of the considerable sociogeographic overlaps between the two epidemics. The situation is particularly worrisome in countries with high or intermediate TB burden against the background of a variable HIV epidemic state. Early diagnosis of TB disease in an HIV-infected person is paramount but suffers from lack of sensitive and specific diagnostic tools. Enhanced symptom screening is currently advocated, and the wide application of affordable molecular diagnostics is urgently needed. Treatment of TB/HIV co-infection involves the concurrent use of standard antiretrovirals and antimycobacterials during which harmful drug interaction may occur. The pharmacokinetic interaction between rifamycin and antiretrovirals is a case in point, requiring dosage adjustment and preferential use of rifabutin, if available. Early initiation of antiretroviral therapy is indicated, preferably at 2 weeks after starting TB treatment for patients with a CD4 of <50 cells/μL. Development of TB-immune reconstitution inflammatory syndrome (TB-IRIS) is however more frequent with early antiretroviral therapy. The diagnosis of TB-IRIS is another clinical challenge, and cautious use of corticosteroids is suggested to improve clinical outcome. As a preventive measure against active TB disease, the screening for latent TB infection should be widely practiced, followed by at least 6-9 months of isoniazid treatment. To date tuberculin skin test remains the only diagnostic tool in high TB burden countries. The role of alternative tests, for example, interferon-γ release assay, would need to be better defined for clinical application. 23583703 Inelastic deformation and microcracking process in human dentin. Dentin is a mineralized collagen tissue with robust mechanical performance. Understanding the mechanical behavior of dentin and its relations to the dentinal structure can provides insight into the design strategies to achieve tooth functions. This study focuses on the inelastic deformation of human dentin and its underlying mechanisms. By combining four-point bending tests with fluorescent staining and laser scanning confocal microscopy, it was found that human dentin, especially root dentin, exhibited significant inelastic deformation and developed extensive microdamage in the form of microcracks prior to fracture. Dense and wavy microcracks spread uniformly across the tensile surface of root dentin, while compressive microcracks formed cross-hatched patterns. The presence of peritubular dentin in coronal dentin dramatically decreased the extent of microcracking, reducing inelasticity. Dentinal tubules were found to be initiation sites of both tensile and compressive microcracks. A unique crack propagation process was observed in root dentin under tension: numerous ring-shaped cracks formed at each dentinal tubule ahead of a growing crack tip. The advance of the tensile microcracks occurred by the merging of those ring-shaped cracks. The current findings on the microcracking process associated with inelastic deformation helps to understand the nature of strength and toughness in dentin, as well as the mechanical significance for structural variations across the whole tooth. 23733266 Expression of miR-206 during the initiation of mammary gland development. MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translational repression or RNA degradation. The aberrant expression of miRNAs might be involved in human diseases, including cancer. The expression of miR-206 in estrogen receptor alpha (ER-α)-positive human breast cancer tissues is well known. However, the expression and regulation of miR-206 in the developing mammary gland has not yet been studied. To understand the effects of miR-206 on mammary gland development, we have profiled gene expression in scramble-transfected and miR-206-overexpressing developing mammary buds. The genes that are potentially regulated by miR-206 in the mammary epithelium and/or mesenchyme, such as Tachykinin1 and Gata3, are known to be breast cancer markers. The expression of Wnt, which is involved in gland positioning, and of the transcription factors Tbx3 and Lef1, which are essential for mammary gland development, changes after miR-206 overexpression. Using a mammary bud in vitro culture system, we have demonstrated that miR-206 acts downstream of ER-α during mammary gland growth. Thus, miR-206 might be a novel candidate for morphogenesis during the initiation of mammary gland formation and the regulation of genes related to mammary gland development and breast cancer. 23893407 IruO is a reductase for heme degradation by IsdI and IsdG in Staphylococcus aureus. Staphylococcus aureus is a common hospital- and community-acquired bacterium that can cause devastating infections and is often multidrug resistant. Iron acquisition is required by S. aureus during an infection and iron acquisition pathways are potential targets for therapies. The gene NWMN2274 in S. aureus strain Newman is annotated as an oxidoreductase of the diverse pyridine nucleotide-disulphide oxidoreductase (PNDO) family. We show that NWMN2274 is an electron donor to IsdG and IsdI catalyzing the degradation of heme and we have renamed this protein IruO. Recombinant IruO is an FAD-containing NADPH-dependent reductase. In the presence of NADPH and IruO, either IsdI or IsdG degraded bound heme 10-fold more rapidly than with the chemical reductant ascorbic acid. Varying IsdI-heme substrate and monitoring loss of the heme Soret band gave a KM of 15 ± 4 μM, a kcat of 5.2 ± 0.7 min(-1), and a kcat/KM of 5.8 × 10(3) M(-1) s(-1). From HPLC and electronic spectra, the major heme degradation products are 5-oxo-δ-bilirubin and 15-oxo-β-bilirubin (staphylobilins), as observed with ascorbic acid. Although heme degradation by IsdI or IsdG can occur in the presence of H2O2, addition of catalase and superoxide dismutase did not disrupt NADPH/IruO heme degradation reactions. The degree of electron coupling between IruO and IsdI or IsdG remains to be determined. Homologs of IruO were identified by sequence similarity in the genomes of Gram-positive bacteria that possess IsdG-family heme oxygenases. A phylogeny of these homologs identifies a distinct clade of PNDOs likely involved in iron uptake systems. IruO is the likely in vivo reductant required for heme degradation by S. aureus. 23883180 A note on protein expression changes in chicken breast muscle in response to time in transit before slaughtering. Aims of the research were to devise a proteome map of the chicken Pectoralis superficialis muscle, as resolved by two-dimensional gel electrophoresis, and to characterize protein expression changes in the soluble protein fraction in commercial conditions due to age and to time in transit before slaughtering. Broilers were reared under commercial conditions until they reached a mean 1.8 kg and 36 d, or 2.6 kg and 46 d of age. Transport to the slaughterhouse took 90 or 220 minutes. Transport-induced stress was assessed from blood metabolites and leukocyte cell counts, revealing significant changes in albumin, glucose and triglyceride concentrations, in heterophils and leukocyte counts for chickens in transit for longer, and in glucose depending mainly on age. The sarcoplasmic protein fractions were extracted from a total of 39 breast muscle samples, collected 15 min post mortem, for analysis by two-dimensional electrophoresis.Image and statistical analyses enabled us to study the qualitative and quantitative differences between the samples. Twelve up- or down-regulated protein spots were detected (P < 0.05): 8 related to the age effect, 2 to time in transit, and 2 to the interaction between the two. Age and time in transit influenced the avian proteome regulating the biological processes linked to the cellular housekeeping functions, related mainly to metabolism, cell division and control of apoptosis. Principal component analysis clustering was used to assess differences between birds. Age difference discriminated between the chickens analyzed better than time in transit, which seemed to have less general impact on the proteome fraction considered here.Isolating and identifying the proteins whose expression changes in response to transport duration and age shed some light on the biological mechanisms underlying growth and stress-related metabolism in chickens. Our results, combined with a further characterization of the chicken proteome associated with commercial chicken slaughtering management, will hopefully inspire alternative strategies and policies, and action to reduce the impact of stress related to time in transit. 23845956 Chelant-assisted phytoextraction and accumulation of Zn by Zea mays. Zea mays plants were exposed to soils with concentrations of Zn ranging from 64 to 1800 mg kg(-1) dw, and the efficiency of three selected chelating agents (trisodium citrate (CI), disodium oxalate (OX) and disodium dihydrogen ethylene-diamine-tetraacetate (EDTA)) in enhancing metal phytoextraction was compared. Zn concentration in plant tissues increased in conjunction with the metal concentration of the soil. EDTA was found to be the most efficient chelating amendment, increasing concentrations of Zn in shoots from 88 mg kg(-1) dw, at 64 mg kg(-1) dw soil, to 8026 mg kg(-1) dw at 1800 mg kg(-1) dw soil. The overall orders of BCFs and TFs which resulted from this study are: EDTA > H2O > OX > CI, and EDTANa2 > OX > CI > H2O, respectively. The more effective uptake of Zn by plants for the control treatment (distilled water only) than for CI and OX was attributed to the neutral or slightly alkaline pH of the two chelant irrigation solutions. Instead, EDTA had a favorable effect on Zn uptake from soil due to its additive chelating and acidifying properties. Among the three chelants, only EDTA significantly increased the Zn phytoextraction potential of Z. mays, while CI and OX induced a low metal uptake from soil by plants. Although Z. mays has a lower Zn accumulation capacity than the hyperaccumulator Thlaspi caerulescens, it could be considered as a potential phytoremediator of soils with elevated Zn concentrations, especially when metal pollution extends to depths greater than 20 cm. 23415228 A genetic program promotes C. elegans longevity at cold temperatures via a thermosensitive TRP channel. Both poikilotherms and homeotherms live longer at lower body temperatures, highlighting a general role of temperature reduction in lifespan extension. However, the underlying mechanisms remain unclear. One prominent model is that cold temperatures reduce the rate of chemical reactions, thereby slowing the rate of aging. This view suggests that cold-dependent lifespan extension is simply a passive thermodynamic process. Here, we challenge this view in C. elegans by showing that genetic programs actively promote longevity at cold temperatures. We find that TRPA-1, a cold-sensitive TRP channel, detects temperature drop in the environment to extend lifespan. This effect requires cold-induced, TRPA-1-mediated calcium influx and a calcium-sensitive PKC that signals to the transcription factor DAF-16/FOXO. Human TRPA1 can functionally substitute for worm TRPA-1 in promoting longevity. Our results reveal a previously unrecognized function for TRP channels, link calcium signaling to longevity, and, importantly, demonstrate that genetic programs contribute to lifespan extension at cold temperatures. 23690229 Calpain inhibition prevents ethanol-induced alterations in spinal motoneurons. Long-term exposure of ethanol (EtOH) alters the structure and function in brain and spinal cord. The present study addresses the mechanisms of EtOH-induced damaging effects on spinal motoneurons in vitro. Altered morphology and biochemical changes of such damage were demonstrated by in situ Wright staining and DNA ladder assay. EtOH at low to moderate (25-50 mM) concentrations induced damaging effects in the motoneuronal scaffold which involved activation of proteases like μ-calpain and caspase-3. Caspase-8 was seen only at higher (100 mM) EtOH concentration. Further, pretreatment with calpeptin, a potent calpain inhibitor, confirmed the involvement of active proteases in EtOH-induced damage to motoneurons. The lysosomal enzyme cathepsin D was also elevated in the motoneurons by EtOH, and this effect was significantly attenuated by inhibitor treatment. Overall, EtOH exposure rendered spinal motoneurons vulnerable to damage, and calpeptin provided protection, suggesting a critical role of calpain activation in EtOH-induced alterations in spinal motoneurons. 23261865 Effects of oxygen and glucose deprivation on synaptic transmission in rat dentate gyrus: role of A(2A) adenosine receptors. The hippocampus is comprised of two distinct subfields that show different responses to hypoxic-ischemic brain injury: the CA1 region is particularly susceptible whereas the dentate gyrus (DG) is quite resistant. Our aim was to determine the synaptic and proliferative response of the DG to severe oxygen and glucose deprivation (OGD) in acute rat hippocampal slices and to investigate the contribution of A(2A) adenosine receptor antagonism to recovery of synaptic activity after OGD. Extracellular recordings of field excitatory post-synaptic potentials (fEPSPs) in granule cells of the DG in brain slices prepared from male Wistar rats were used. A 9-min OGD is needed in the DG to always induce the appearance of anoxic depolarization (AD) and the irreversible block of synaptic activity, as recorded up to 24 h from the end of the insult, whereas only 7-min OGD is required in the CA1 region. Selective antagonism of A(2A) adenosine receptors by ZM241385 significantly prevents or delays the appearance of AD and protects from the irreversible block of neurotransmission induced by 9-min OGD in the DG. The effects of 9-min OGD on proliferation and maturation of cells localized in the subgranular zone of DG in slices prepared from 5-bromo-2'-deoxyuridine (BrdU) treated rats was investigated. Slices were further incubated with an immature neuronal marker, doublecortin (DCX). The number of BrdU(+) cells was significantly decreased 6 h after 9-min OGD and this effect was antagonized by ZM241385. After 24 h from the end of 9-min OGD, the number of BrdU(+) cells returned to that found before OGD and increased arborization of tertiary dendrites of DCX(+) cells was observed. The adenosine A(2A) antagonist ZM241385 protects from synaptic failure and from decreased proliferation of immature neuronal cells at a precocious time after OGD. 23913469 Influence of proband's characteristics on the risk of venous thromboembolism in relatives with factor V Leiden or prothrombin G20210A polymorphisms. In family studies, the risk of venous thromboembolism (VTE) in relatives with factor V Leiden (FVL) or G20210A prothrombin (PT20210A) gene polymorphisms may differ according to genotype and clinical presentation of the proband. To address this hypothesis, a retrospective cohort family study was carried out on 192 kindreds with at least one member with homozygous FVL or PT20210A, for a total of 886 relatives. The proband of the family was heterozygous in 68 and homozygous or with both polymorphisms in 124 kindreds. Twenty-three probands were asymptomatic, 11 had had arterial thrombosis, 7 obstetrical complications, and 151 venous thrombosis (122 VTE and 29 superficial vein thrombosis). The incidence of VTE (per 1000 patient-years) in relatives was higher when the proband had heterozygous than homozygous polymorphism [1.25 (95%CI:0.73-1.91) vs 0.44 (0.19-0.78)], and when the proband had had VTE instead of other or no clinical manifestations [0.95 (0.57-1.42) vs 0.50 (0.19-0.96)]. Compared to relatives belonging to kindreds with homozygous probands without VTE, the adjusted hazard ratio of VTE for relatives selected from kindreds with heterozygous probands with VTE was 4.14 (95%CI:1.17-14.71). The genotype and clinical presentation of the proband influence the risk of VTE in relatives with FVL or PT20210A. 23861251 Abnormal megakaryocyte development and platelet function in Nbeal2-/- mice. Gray platelet syndrome (GPS) is an inherited bleeding disorder associated with macrothrombocytopenia and α-granule-deficient platelets. GPS has been linked to loss of function mutations in NBEAL2 (neurobeachin-like 2), and we describe here a murine GPS model, the Nbeal2(-/-) mouse. As in GPS, Nbeal2(-/-) mice exhibit splenomegaly, macrothrombocytopenia and a deficiency of platelet α-granules and their cargo, including von Willebrand factor (VWF), thrombospondin-1 and platelet factor 4. The platelet α-granule membrane protein P-selectin is expressed at 48% of wild type levels and externalized upon platelet activation. The presence of P-selectin and normal levels of Vps33B and Vps16B in Nbeal2(-/-) platelets suggests that Nbeal2 acts independently of Vps33B/Vps16B at a later stage of α-granule biogenesis. Impaired Nbeal2(-/-) platelet function was shown by flow cytometry, platelet aggregometry, bleeding assays and intravital imaging of laser-induced arterial thrombus formation. Microscopic analysis detected marked abnormalities in Nbeal2(-/-) bone marrow megakaryocytes, which when cultured showed delayed maturation, decreased survival, decreased ploidy and developmental abnormalities, including abnormal extracellular distribution of VWF. Our results confirm that α-granule secretion plays a significant role in platelet function and they also indicate that abnormal α-granule formation in Nbeal2(-/-) mice has deleterious effects on megakaryocyte survival, development and platelet production. 23819837 Effects of the cage unit size and number of cage units as well as bridge unit on the second order nonlinear optical response in multicage electride molecules. Interesting effects of the cage unit size and number of cage units as well as bridge unit on the static first hyperpolarizabilities (β0) for novel multicage electrides are revealed. (1) The small cage unit C8 systems have larger β0 for cage unit size effect. (2) The β0 increases with increasing cage unit number. (3) The effect of the bridge between cage units on β0 is O > NH > CH2. Specially, a novel relationship between the excess electron cloud and β0 is revealed. Assembling the three effects, the constructed multicage electride structure with three small C8 cage units connected by the O-bridge (K···3C8(O)) is a electride salt K(+)[e@3C8(O)](-) and has the considerable β0 value of 7.1 × 10(5) au, which is about 55 times larger than the 13 000 au of the single-cage electride molecule Na3O(+)(e@C20F20)(-). The novel multicage strategy is effective to enhance nonlinear optical (NLO) response. 23917947 Identification of differentially expressed microRNAs across the developing human brain. We present a spatio-temporal assessment of microRNA (miRNA) expression throughout early human brain development. We assessed the prefrontal cortex, hippocampus and cerebellum of 18 normal human donor brains spanning infancy through adolescence by RNA-seq. We discovered differentially expressed miRNAs and broad miRNA patterns across both temporal and spatial dimensions, and between male and female prefrontal cortex. Putative target genes of the differentially expressed miRNAs were identified, which demonstrated functional enrichment for transcription regulation, synaptogenesis and other basic intracellular processes. Sex-biased miRNAs also targeted genes related to Wnt and transforming growth factor-beta pathways. The differentially expressed miRNA targets were highly enriched for gene sets related to autism, schizophrenia, bipolar disorder and depression, but not neurodegenerative diseases, epilepsy or other adult-onset psychiatric diseases. Our results suggest critical roles for the identified miRNAs in transcriptional networks of the developing human brain and neurodevelopmental disorders.Molecular Psychiatry advance online publication, 6 August 2013; doi:10.1038/mp.2013.93. 23902291 An unusual case of reversible acute kidney injury due to chlorine dioxide poisoning. Abstract Chlorine dioxide is a commonly used water disinfectant. Toxicity of chlorine dioxide and its metabolites is rare. In experimental studies, it was shown that acute and chronic toxicity were associated with insignificant hematological changes. Acute kidney injury due to chlorine dioxide was not reported. Two cases of renal toxicity due to its metabolites, chlorate and chlorite were reported. Herein, we report a case of chlorine dioxide poisoning presenting with acute kidney injury. 23829507 Rare causes of closed rupture of the flexor tendon. Abstract Closed injuries to the flexor tendon are relatively rare. We present three rare causes of closed injury to the flexor tendon. Early recognition and adequate treatment by a specialised hand surgeon are crucial for the prognosis of such cases. Delayed diagnosis and treatment often require secondary reconstruction of the flexor tendon, which results in a worse functional outcome. 23907055 The nanostructure of surfactant-DNA complexes with different arrangements. The nanostructure of DNA with different cationic surfactant has been studied in order to elucidate the detailed arrangement concerning the position of DNA and surfactant domains in the complexes. Also, the orientation of the DNA cylinders in the thin films of the complexes was investigated. Attention was directed on the preparation methods of the complexes and to how the different surfactant structure affects the compaction of the DNA. The cationic surfactant-DNA complexes were investigated by X-ray scattering, polarized light microscopy and elemental microanalysis. It was observed that the molecular organization of the complexes between DNA and cationic surfactant corresponds to a hexagonal structure with different packing arrangements. The nanostructure of the complexes depends on the hydrophobic/hydrophilic balance of the cationic surfactant. In particular the use of arginine derived surfactants, with a large polar head group able to interact not only by electrostatics but also by hydrogen bonding, allows for the formation of more compact structures. The results suggest that the smaller the lattice parameter the more compact and stable is the complex implying slower DNA release. 23332439 Integrating buprenorphine maintenance therapy into federally qualified health centers: real-world substance abuse treatment outcomes. Few studies have examined real-world effectiveness of integrated buprenorphine maintenance treatment (BMT) programs in federally qualified health centers (FQHCs). Opioid dependent patients (N=266) inducted on buprenorphine between July 2007 and December 2008 were retrospectively assessed at Connecticut's largest FQHC network. Six-month BMT retention and opioid-free time were collected longitudinally from electronic health records; 136 (51.1%) of patients were followed for at least 12 months. Participants had a mean age of 40.1 years, were primarily male (69.2%) and treated by family practitioners (70.3%). Co-morbidity included HCV infection (59.8%), mood disorders (71.8%) and concomitant cocaine use (59%). Retention on BMT was 56.8% at 6 months and 61.6% at 12 months for the subset observed over 1 year. Not being retained on BMT at 12 months was associated with cocaine use (AOR=2.18; 95% CI=1.35-3.50) while prescription of psychiatric medication (AOR=0.36; 95% CI 0.20-0.62) and receiving on-site substance abuse counseling (AOR=0.34; 95% CI 0.19, 0.59) improved retention. Two thirds of the participants experienced at least one BMT gap of 2 or more weeks with a mean gap length of 116.4 days. Integrating BMT in this large FQHC network resulted in retention rates similarly reported in clinical trials and emphasizes the need for providing substance abuse counseling and screening for and treating psychiatric comorbidity. 23684144 Temporary hemodialysis catheter placement by nephrology fellows: implications for nephrology training. The insertion of temporary hemodialysis catheters is considered to be a core competency of nephrology fellowship training. Little is known about the adequacy of training for this procedure and the extent to which evidence-based techniques to reduce complications have been adopted. We conducted a web-based survey of Canadian nephrology trainees regarding the insertion of temporary hemodialysis catheters. Responses were received from 45 of 68 (66%) eligible trainees. The median number of temporary hemodialysis catheters inserted during the prior 6 months of training was 5 (IQR, 2-11), with 9 (20%) trainees reporting they had inserted none. More than one-third of respondents indicated that they were not adequately trained to competently insert temporary hemodialysis catheters at both the femoral and internal jugular sites. These findings are relevant to a discussion of the current adequacy of procedural skills training during nephrology fellowship. With respect to temporary hemodialysis catheter placement, there is an opportunity for increased use of simulation-based teaching by training programs. Certain infection control techniques and use of real-time ultrasound should be more widely adopted. Consideration should be given to the establishment of minimum procedural training requirements at the level of both individual training programs and nationwide certification authorities. 23293132 Agreement between chest radiography and high-resolution computed tomography in diagnosing dust-related interstitial lung fibrosis. Although it has been suggested that high-resolution computed tomography (HRCT) scans can be obtained when plain radiographs are equivocal for the presence of interstitial lung fibrosis (ILF) caused by inhalation of dust, such as silica, asbestos fibres, etc., the specificity of the findings remains in question. The present study was carried out to compare the relative efficacy of chest radiography by conventional method and HRCT in evaluating ILF which included 22 workers exposed to fibrogenic dust, who were subjected to clinical examination, pulmonary function testing, posteroanterior chest radiography and HRCT. In the six subjects who had findings suggestive of ILF on HRCT, four had normal chest x-ray (CXR) while one each has been diagnosed as having tuberculosis and ILF on CXR. The agreement analysis between HRCT and CXR suggests that there was a poor agreement between HRCT and CXR (kappa = 0.34). 23909282 Increased epicardial fat tissue is a marker of subclinic atherosclerosis in patients with psoriasis. Carotid intima-media thickness (CIMT) is a potential indicator of subclinical atherosclerosis in patients with psoriasis. Epicardial fat thickness (EFT) is proposed as a new cardiometabolic risk factor. We evaluated the association between EFT and CIMT in patients with psoriasis. The present study was cross-sectional and observational, 65 patients with psoriasis and 50 age- and sex- matched control subjects were included the study. Data about echocardiographic EFT, CIMT, anthropometric measurements, and metabolic profile were obtained. The EFT and CIMT were significantly increased (7.3 ± 0.5 mm vs. 6.5 ± 0.5 mm; p<0.01; 0.74 ± 0.11 mm vs. 0.60 ± 0.07 mm; p<0.01, respectively) in patients with psoriasis compared with the controls. EFT significantly correlated with CIMT (r=0.69, p<0.01). In a multiple linear regression model in which EFT was independently associated with psoriasis (β=0.45, p<0.01), age (β=0.33, p=0.01), CIMT (β=0.50, p<0.01), body mass index (β=0.25, p=0.01), high-sensitive C reactive protein (β=0.32, p<0.01), duration of disease (β=0.34, p=0.03). We have demonstrated increased EFT and CIMT in psoriasis patients, and echocardiographic EFT closely correlated with CIMT in patients with psoriasis. The echocardiographic assessment of EFT may have the potential to be a simple marker of subclinical atherosclerosis and increased cardiovascular risk in patients with psoriasis. This article is protected by copyright. All rights reserved. 23816026 Tissue coverage and neointimal hyperplasia in overlap versus nonoverlap segments of drug-eluting stents 9 to 13 months after implantation: in vivo assessment with optical coherence tomography. Histologic experimental studies have reported incomplete neointimal healing in overlapping with respect to nonoverlapping segments in drug-eluting stents (DESs), but these observations have not been confirmed in human coronary arteries hitherto. On the contrary, angiographic and optical coherence tomography studies suggest that DES overlap elicits rather an exaggerated than an incomplete neointimal reaction. Optical coherence tomography studies from 2 randomized trials including sirolimus-eluting, biolimus-eluting, everolimus-eluting, and zotarolimus-eluting stents were analyzed at 9- to 13-month follow-up. Coverage in overlapping segments was compared versus the corresponding nonoverlapping segments of the same stents, using statistical pooled analysis. Forty-two overlaps were found in 31 patients: 11 in sirolimus-eluting stents, 3 in biolimus-eluting stents, 17 in everolimus-eluting stents, and 11 in zotarolimus-eluting stents. The risk ratio of incomplete coverage was 2.35 (95% CI 1.86-2.98) in overlapping versus nonoverlapping segments. Thickness of coverage in overlaps was only 85% (95% CI 81%-90%) of the thickness in nonoverlaps. Significant heterogeneity of the effect was observed, especially pronounced in the comparison of thickness of coverage (I(2) = 90.31). The effect of overlapping DES on neointimal inhibition is markedly heterogeneous: on average, DES overlap is associated with more incomplete and thinner coverage, but in some cases, the overlap elicits an exaggerated neointimal reaction, thicker than in the corresponding nonoverlapping segments. These results might help to understand why overlapping DES is associated with worse clinical outcomes, both in terms of thrombotic phenomena and in terms of restenosis and revascularization. 23894388 Shoe sole tread designs and outcomes of slipping and falling on slippery floor surfaces. A gait experiment was conducted under two shoe sole and three floor conditions. The shoe soles and floors were characterized by the tread and groove designs on the surface. The coefficients of friction (COF) on the floor in the target area were measured. The subjects were required to walk on a walkway and stepping on a target area covered with glycerol. The motions of the feet of the subjects were captured. Gait parameters were calculated based on the motion data. Among the 240 trials, there were 37 no-slips, 81 microslips, 45 slides, and 77 slips. It was found that the condition with shoe sole and floor had both tread grooves perpendicular to the walking direction had the highest COF, the shortest slip distance, and the lowest percentages of slide and slip. The condition with shoe sole and floor had both tread grooves parallel to the walking direction had the lowest COF and the longest slip distance among all experimental conditions. The Pearson's correlation coefficients between slip distance and slip velocity, time to foot flat, foot angle, and compensatory step length were 0.82 (p<0.0001), 0.33 (p<0.0001), -0.54 (p<0.0001), and -0.51 (p<0.0001), respectively. 23715465 Synthesis, structures and magnetic properties of a family of nitrate-bridged octanuclear [Na2Ln6] (Ln = Dy, Tb, Gd, Sm) complexes. A new family of octanuclear lanthanide compounds [Na2Ln6L8(C6H4NH2COO)2(C2H5OH)2(H2O)4(NO3)]·NO3·C2H5OH·nH2O [H2L = 2-{[(2-hydroxy-3-methoxyphenyl)methylidene]amino}benzoic acid; Ln = Dy (1) (n = 15); Tb (2), Gd (3) (n = 14); Sm (4) (n = 16)] have been prepared under hydrothermal conditions. The X-ray crystal structure analysis reveals that complexes 1-4 are isomorphous. The core of the structure is a [4 + 2] combination of an Ln4 cubane and an Ln2 unit. The two units are bridged by a nitrate ion, which is located in the center of the cluster and displays an unusual μ8-η(2):η(2):η(4) tridentate bridging mode. The magnetic studies for complex 1 show that the [Na2Dy6] unit exhibits slow magnetic relaxation behavior. 23656314 Shock hugoniot equations of state for binary ideal (toluene/fluorobenzene) and nonideal (ethanol/water) liquid mixtures. Laser shock Hugoniot data were obtained using ultrafast dynamic ellipsometry (UDE) for both nonideal (ethanol/water solutions with mole percent χethanol = 0%, 3.4%, 5.4%, 7.5%, 9.7%, 11%, 18%, 33%, 56%, 100%) and ideal liquid mixtures (toluene/fluorobenzene solutions with mole percent χtoluene = 0%, 26.0%, 49.1%, 74.9%, 100%). The shock and particle velocities obtained from the UDE data were compared to the universal liquid Hugoniot (ULH) and to literature shock (plate impact) data where available. It was found that the water UDE data fit to a ULH-form equation suggests an intercept of 1.32 km/s, lower than the literature ambient sound speed in water of 1.495 km/s (Mijakovic et al. J. Mol. Liq. 2011, 164, 66-73). Similarly, the ethanol UDE data fit to a ULH-form equation suggests an intercept of 1.45 km/s, which lies above the literature ambient sound speed in ethanol of 1.14 km/s. Both the literature plate impact and UDE Hugoniot data lie below the ULH for water. Likewise, the literature plate impact and UDE Hugoniot data lie above the ULH for ethanol. The UDE Hugoniot data for the mixtures of water and ethanol cross the predictions of the ULH near the same concentration where the sound speed reaches a maximum. In contrast, the UDE data from the ideal liquids and their mixtures are well behaved and agree with ULH predictions across the concentration range. The deviations of the nonideal ethanol/water data from the ULH suggest that complex hydrogen bonding networks in ethanol/water mixtures alter the compressibility of the mixture. 23869657 Behavioral and physiologic adverse effects in adolescent and young adult emergency department patients reporting use of energy drinks and caffeine. Abstract Introduction. This pilot study assessed the prevalence of physiologic and behavioral adverse effects among adolescent (13-17 years) and adult (18-25 years) emergency department patients who reported energy drink and/or caffeinated-only beverage use within the 30 days prior to emergency department presentation. It was hypothesized that energy drink users would report more adverse effects than those who used only traditional caffeinated beverages such as coffee, tea, or soft drinks. Methods. This cross-sectional pilot study was conducted in two urban emergency departments, one adult and one pediatric. Eligible patients were enrolled during a 6-week period between June and August 2010. Participants completed a tablet computer-based, self-administered, anonymous questionnaire about their past 30-day energy drink and/or caffeinated-only beverage use, substance use, and experience of 10 physiologic and 10 behavioral symptoms. Multivariable logistic regression and negative binomial regression models, adjusted for age, gender, and substance use, were created to compare the occurrence of each adverse effect between energy drink and caffeinated-only beverage users. Odds ratios (ORs) and incidence rate ratios (IRRs) were estimated. Results. Of those enrolled, 53.3% reported consuming energy drinks, 39.1% caffeinated-only beverages, and 7.6% no energy drinks or caffeinated-only beverages within the past 30 days. In multivariable logistic regression models, energy drink users were more likely than caffeinated-only beverage users to report having "gotten into trouble at home, school, or work" in the past 30 days (OR: 3.12 [1.24-7.88]). In the negative binomial regression multivariable models, more behavioral effects were reported among drug users (IRR: 1.50 [1.18-1.93]), and more physiologic effects were reported among tobacco users (IRR: 1.42 [1.13-1.80]) and females (IRR: 1.48 [1.21-1.80]), but not among energy drink users. Conclusions. Energy drink users and substance users are more likely to report specific physiologic and behavioral adverse effects. Emergency department clinicians should consider asking patients about energy drink and traditional caffeine usage and substance use when assessing patient symptoms. 23645871 Philadelphia's Lead Court Is Making a Difference. The Philadelphia Lead Court (PLC) was created as an innovative law enforcement strategy to compel property owners to comply with city health codes to remediate their properties of lead hazards, which had led to elevated blood lead levels and lead poisoning in resident children. This study presents a detailed account of and analyzes the opinions of fifteen key informants drawn from the Philadelphia health and law departments and judicial system that staff and run the PLC in response to a fifteen-question structured survey. Main themes reviewed include the effectiveness of the PLC as compared with precourt law enforcement strategies and within the context of a specialized court, the use of fines, the impact of grant funding for remediation work, the major advantages and disadvantages of the PLC, and suggested changes to improve court function, followed by key recommendations. The article concludes that our informants found that the PLC has been very effective and successful. This model could be replicated by other cities with similar health code enforcement challenges. 23968812 Morphologic changes in the aortic wall media after support with a continuous-flow left ventricular assist device. Continuous-flow left ventricular assist devices (LVADs) provide durable, reliable, energy-efficient long-term support. However, the biologic effects of continuous flow are not completely known. Therefore, we examined aortic wall morphology in patients with heart failure before and after prolonged circulatory support with a continuous-flow LVAD. After applying a partial aortic occlusion vascular clamp in the lower half of the ascending aorta, we removed samples of aortic wall tissue and then attached the outflow graft of the pump. Samples were obtained from 11 patients (9 men and 2 women, mean age 65 ± 7 years) with severe heart failure at the time of LVAD implantation. We obtained matched specimens at explantation after heart transplantation (n = 5) or autopsy (n = 6). These specimens were removed from the distal ascending aorta, remote from the aortic anastomotic site. Tissue sections were stained with hematoxylin and eosin, Movat's pentachrome and Masson's trichrome. Smooth muscle actin immunohistochemistry was performed on all sections. To evaluate the morphology of the aortic wall media, we quantitatively graded tissue sections for medial thickness, medial degenerative changes, smooth muscle cell (SMC) disorientation and depletion, elastic fiber fragmentation and depletion, medial fibrosis and atherosclerotic changes. The mean duration of support was 140 ± 136 days (range 87 to 580 days). The histologic evaluation and comparison of specimens obtained before and after LVAD support showed significantly increased foci of medial degeneration, SMC depletion, elastic fiber fragmentation, medial fibrosis and atherosclerotic changes after LVAD support. Mean medial thickness was not significantly different after LVAD support. We observed similar changes between samples obtained at transplantation and those obtained at autopsy. After continuous-flow LVAD support, the morphology of the aortic wall media was altered in all of our patients. The clinical relevance of these findings is unknown. 23507196 Enhanced deposition of cartilage oligomeric matrix protein is a common feature in fibrotic skin pathologies. Skin fibrosis is characterized by activated fibroblasts and an altered architecture of the extracellular matrix. Excessive deposition of extracellular matrix proteins and altered cytokine levels in the dermal collagen matrix are common to several pathological situations such as localized scleroderma and systemic sclerosis, keloids, dermatosclerosis associated with venous ulcers and the fibroproliferative tissue surrounding invasively growing tumors. Which factors contribute to altered organization of dermal collagen matrix in skin fibrosis is not well understood. We recently demonstrated that cartilage oligomeric matrix protein (COMP) functions as organizer of the dermal collagen I network in healthy human skin (Agarwal et al., 2012). Here we show that COMP deposition is enhanced in the dermis in various fibrotic conditions. COMP levels were significantly increased in fibrotic lesions derived from patients with localized scleroderma, in wound tissue and exudates of patients with venous leg ulcers and in the fibrotic stroma of biopsies from patients with basal cell carcinoma. We postulate enhanced deposition of COMP as one of the common factors altering the supramolecular architecture of collagen matrix in fibrotic skin pathologies. Interestingly, COMP remained nearly undetectable in normally healing wounds where myofibroblasts transiently accumulate in the granulation tissue. We conclude that COMP expression is restricted to a fibroblast differentiation state not identical to myofibroblasts which is induced by TGFβ and biomechanical forces. 23962955 Association of decreased prefrontal hemodynamic response during a verbal fluency task with EGR3 gene polymorphism in patients with schizophrenia and in healthy individuals. The early growth response 3 (EGR3) gene is an immediate early gene that is expressed throughout the brain and has been suggested as a potential susceptibility gene for schizophrenia (SZ). EGR3 impairment is associated with various neurodevelopmental dysfunctions, and some animal studies have reported a role for EGR3 function in the prefrontal cortex. Therefore, EGR3 genotype variation may be reflected in prefrontal function. By using multi-channel near-infrared spectroscopy (NIRS) in an imaging genetics approach, we tested for an association between the EGR3 gene polymorphism and prefrontal hemodynamic response during a cognitive task in patients with SZ. We assessed 73 chronic patients with SZ and 73 age-, gender-, and genotype-matched healthy controls (HC) who provided written informed consent. We used NIRS to measure changes in prefrontal oxygenated hemoglobin concentration (oxyHb) during the letter version of a verbal fluency task (VFT). Statistical comparisons were performed among EGR3 genotype subgroups (rs35201266, GG/GA/AA). The AA genotype group showed significantly smaller oxyHb increases in the left dorsolateral prefrontal cortex (DLPFC) during the VFT than the GG and GA genotype groups; this was true for both patients with SZ and HC. Our findings provide in vivo human evidence of a significant influence of EGR3 polymorphisms on prefrontal hemodynamic activation level in healthy adults and in patients with SZ. Genetic variation in EGR3 may affect prefrontal function through neurodevelopment. This study illustrates the usefulness of NIRS in imaging genetics investigations on psychiatric disorders. 23648110 Elicitation of galanthamine biosynthesis by Leucojum aestivum liquid shoot cultures. The effects of methyl jasmonate and jasmonic acid on galanthamine production, phenolic acid content and growth of Leucojum aestivum L. shoot culture, cultivated in submerged conditions were investigated. The best time-point for addition of elicitors was during the exponential phase of the culture growth. The maximal contents of galanthamine and lycorine (226.9 μg/flask and 491.4 μg/flask, 1.36 and 1.67-fold higher compared to the control, respectively) were achieved after elicitation with jasmonic acid, whereas the elicitation with methyl jasmonte resulted in maximal accumulation of phenolic acids. It was demonstrated that the boosting effect of jasmonic acid on Amaryllidacea alkaloid biosynthesis was due to induction of the activity of tyrosine decarboxylase, whereas methyl jasmonate stimulates the biosynthesis of phenolic acids by inducing mainly the activity of phenylalanine ammonia-lyase. 23663039 The Incremental Value of RT Three-Dimensional TEE in the Evaluation of Prosthetic Mitral Valve Ring Thrombosis Complicated with Thromboembolism. Purpose: Although nonobstructive prosthetic valve thrombosis (PVT) does not develop hemodynamic compromise, it carries potential risk for thromboembolism. Real time three-dimensional transesophageal echocardiography (RT-3DTEE), has emerged as a complementary tool in depicting "en face" views of prosthesis compared with two-dimensional transesophageal echocardiography (2DTEE). We aimed to evaluate the utility of RT-3DTEE in assessment of mitral ring-located thrombosis. Method: We present 3 cases of mechanical mitral valve thrombosis complicated by thromboembolism, who were all examined and followed-up by 2D transthoracic echocardiography (TTE), 2DTEE, and RT-3DTEE. Result: The consequencies of thromboembolism in the patients were coronary embolism, transient ischemic attack, and ischemic stroke, respectively. They were all inadequately anticoagulated at the time of admission. 2DTTE and TEE examination was unsatisfactory; RT-3DTEE depicted nonobstructive mitral ring thrombosis in each of the patients. The patients were followed up under effective anticoagulation and antiplatelet therapy. RT-3DTEE was able to demonstrate the evolution of thrombus size in each of the patients. Conclusion: Nonobstructive ring-located PVT which poses risk for thromboembolism, may be diagnosed with certainty and imaged with clarity utilizing RT-3DTEE. 23891961 Lactobacillus plantarum TN8 exhibits protective effects on lipid, hepatic and renal profiles in obese rat. This study aimed to first investigate the immuno-modulatory effects of six newly isolated lactic acid bacteria (LAB) on the peripheral blood mononuclear cells (PBMC) of Wistar rats. Except for Lactobacillus plantarum TN8, all the other strains were noted to induce high levels of pro-inflammatory cytokine IL-12 and low levels of anti-inflammatory cytokine IL-10. The strains also generated low ratios of IL-10/IL-12 cytokine. Strain TN8 was, on the other hand, noted to induce an increase in anti-inflammatory IL-10 cytokine secretion rates and a decrease in pro-inflammatory IL-12, IFN-γ and TNF-α cytokine production. The oral administration of TN8 improved the hepatic and urinary functions of obese rats by inducing decreases (P < 0.05) in alanine amino transferase (ALAT), gamma glutamyl transferase (GGT), plasmatic triglycerides, total cholesterol concentrations, creatinine, urea, and body weight when compared to the control group of animals that underwent an increase in aspartate amino transferase (ASAT) and high density lipoprotein (HDL). Overall, the findings indicate that strain TN8 exhibited a number of attractive properties that might open new promising opportunities for the improvement of various parameters related to animal health performance and the avoidance of antibiotics and drugs as promoting factors. 23842900 A two-step stimulus-response cell-SELEX method to generate a DNA aptamer to recognize inflamed human aortic endothelial cells as a potential in vivo molecular probe for atherosclerosis plaque detection. Aptamers are single-stranded oligonucleotides that are capable of binding wide classes of targets with high affinity and specificity. Their unique three-dimensional structures present numerous possibilities for recognizing virtually any class of target molecules, making them a promising alternative to antibodies used as molecular probes in biomedical analysis and clinical diagnosis. In recent years, cell-systematic evolution of ligands by exponential enrichment (SELEX) has been used extensively to select aptamers for various cell targets. However, aptamers that have evolved from cell-SELEX to distinguish the "stimulus-response cell" have not previously been reported. Moreover, a number of cumbersome and time-consuming steps involved in conventional cell-SELEX reduce the efficiency and efficacy of the aptamer selection. Here, we report a "two-step" methodology of cell-SELEX that successfully selected DNA aptamers specifically against "inflamed" endothelial cells. This has been termed as stimulus-response cell-SELEX (SRC-SELEX). The SRC-SELEX enables the selection of aptamers to distinguish the cells activated by stimulus of healthy cells or cells isolated from diseased tissue. We report a promising aptamer, N55, selected by SRC-SELEX, which can bind specifically to inflamed endothelial cells both in cell culture and atherosclerotic plaque tissue. This aptamer probe was demonstrated as a potential molecular probe for magnetic resonance imaging to target inflamed endothelial cells and atherosclerotic plaque detection. 23892189 UVA-induced ROS generation inhibition by Oenothera paradoxa defatted seeds extract and subsequent cell death in human dermal fibroblasts. UVA radiation stimulates the production of reactive oxygen species (ROS), which react with lipids, proteins and other intracellular molecules leading to oxidative stress, cellular damage and ultimately cell death. There is, therefore, a growing need for substances exhibiting antioxidant activity, which may support repair mechanisms of the skin. This study evaluates the protective effect of the aqueous Oenothera paradoxa Hudziok defatted seeds extract, rich in polyphenolic compounds, against UVA (25 and 50J/cm(2))-induced changes in normal human dermal fibroblasts (NHDFs). The tested extract (0.1-10μg/ml) has decreased, in a concentration-dependent fashion, the UVA-induced release of lactate dehydrogenase (LDH) into the culture medium, the ROS production (with the use of 2',7'-dichlorodihydrofluorescein diacetate) and lipid peroxidation (utilizing redox reactions with ferrous ions) as compared to the control cells (incubated without the extract). Moreover, the extract increased the number of viable (calcein positive) cells decreasing the number of cells in late apoptosis (annexin V-FITC and propidium iodide positive). Thus our results show that O. paradoxa defatted seeds extract may be beneficial for the prevention of UVA skin damage. 23201144 Gestational overgrowth and undergrowth affect neurodevelopment: similarities and differences from behavior to epigenetics. The size of an infant at birth, a measure of gestational growth, has been recognized for many years as a biomarker of future risk of morbidity. Both being born small for gestational age (SGA) and being born large for gestational age (LGA), are associated with increased rates of obesity and metabolic disorder, as well as a number of mental disorders including attention deficit/hyperactivity disorder, autism, anxiety, and depression. The common risks raise the question of what neurobiological mechanisms are altered in SGA and LGA offspring. Here we review recent findings allowing for direct comparison of neurobiological outcomes of SGA and LGA in human and animal models. We also present new data highlighting similarities and differences in behavior and neurobiology in our mouse models of SGA and LGA. Overall, there is significant data to support aberrant epigenetic mechanisms, particularly related to DNA methylation, in the brains of SGA and LGA offspring, leading to disruptions in the cell cycle in development and gene expression in adulthood. 23850067 A review of in vitro cigarette smoke exposure systems. In vitro test methods may be vital in understanding tobacco smoke, the main toxicants responsible for adverse health effects, and elucidating disease mechanisms. There is a variety of 'whole smoke' exposure systems available for the generation, dilution and delivery of tobacco smoke in vitro; these systems can be procured commercially from well-known suppliers or can be bespoke set-ups. These exposure technologies aim to ensure that there are limited changes in the tobacco smoke aerosol from generation to exposure. As the smoke aerosol is freshly generated, interactions in the smoke fractions are captured in any subsequent in vitro analysis. Of the commercially available systems, some have been characterised more than others in terms of published scientific literature and developed biological endpoints. Others are relatively new to the scientific field and are still establishing their presence. In addition, bespoke systems are widely used and offer a more flexible approach to the challenges of tobacco smoke exposure. In this review, the authors present a summary of the major tobacco smoke exposure systems available and critically review their function, set-up and application for in vitro exposure scenarios. All whole smoke exposure systems have benefits and limitations, often making it difficult to make comparisons between set-ups and the data obtained from such diverse systems. This is where exposure and dose measurements can add value and may be able to provide a platform on which comparisons can be made. The measurement of smoke dose, as an emerging field of research, is therefore also discussed and how it may provide valuable and additional data to support existing whole smoke exposure set-ups and aid validation efforts. 23592829 Foodborne Disease Outbreaks Caused by Bacillus cereus, Clostridium perfringens, and Staphylococcus aureus--United States, 1998-2008. From 1998 to 2008, 1229 foodborne outbreaks caused by Bacillus cereus, Clostridium perfringens, and Staphylococcus aureus were reported in the United States; 39% were reported with a confirmed etiology. Vomiting was commonly reported in B. cereus (median, 75% of cases) and S. aureus outbreaks (median, 87%), but rarely in C. perfringens outbreaks (median, 9%). Meat or poultry dishes were commonly implicated in C. perfringens (63%) and S. aureus (55%) outbreaks, and rice dishes were commonly implicated in B. cereus outbreaks (50%). Errors in food processing and preparation were commonly reported (93%), regardless of etiology; contamination by a food worker was only common in S. aureus outbreaks (55%). Public health interventions should focus on these commonly reported errors to reduce the occurrence of outbreaks caused by B. cereus, C. perfringens, and S. aureus in the United States. 23834359 Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. Apoptosis is a form of programmed cell death that is regulated by the Bcl-2 family and caspase family of proteins. The caspase cascade responsible for executing cell death following cytochrome c release is well described; however the distinct roles of caspases-9, -3 and -7 during this process are not completely defined. Here we demonstrate several unique functions for each of these caspases during cell death. Specific inhibition of caspase-9 allows for efficient release of cytochrome c, but blocks changes in mitochondrial morphology and ROS production. We show that caspase-9 can cleave Bid into tBid at amino acid 59 and that this cleavage of Bid is required for ROS production following serum withdrawal. We also demonstrate that caspase-3-deficient MEFs are less sensitive to intrinsic cell death stimulation, yet have higher ROS production. In contrast, caspase-7-deficient MEFs are not resistance to intrinsic cell death, but remain attached to the ECM. Taken together, these data suggest that caspase-9 is required for mitochondrial morphological changes and ROS production by cleaving and activating Bid into tBid. After activation by caspase-9, caspase-3 inhibits ROS production and is required for efficient execution of apoptosis, while effector caspase-7 is required for apoptotic cell detachment. 23942812 Temporary removal of the posterior bony canal wall with reconstruction using microplate osteosynthesis in cholesteatoma surgery: a case series and description of the technique. We describe the surgical technique of temporary removal of the posterior auditory canal wall with reconstruction and report the outcome of using this technique as a treatment method for cholesteatoma in a case series. In 32 cases of cholesteatoma surgery a technique of temporary removal of the posterior bony wall was applied. During primary surgery the posterior auditory canal wall was removed using an oscillating saw. For the purpose of reconstruction, the canal wall was repositioned and fixed using two titanium microplates (n = 26). In case the canal wall could not be reconstructed with osteosynthesis, either glass-ionomeric cement (BioCemâ„¢) was used for fixation (n = 4) or fibrin glue (Tissucolâ„¢) (n = 2) to support the posterior wall. The outcome includes the healing process in the first postoperative month, the absence of residual or recurrent disease and the successful reconstruction of the posterior auditory canal wall as evaluated during second-look surgery. When microplates where used, we saw healing problems of the canal skin in about 4 % of patients. Recurrent cholesteatoma was found in 4 cases (14 %), residual cholesteatoma in 8 ears (25 %). In the osteosynthesis group, successful reconstruction was achieved in 25 patients (96 %). In 3 out of 4 patients of the glass-ionomeric cement group (75 %) excessive granulation tissue developed with extensive bony lysis. Temporary removal of the posterior auditory canal wall offers potential for the control of cholesteatoma. Our first results suggest that osteosynthesis allows for a good anatomical and functional reconstruction. 23562803 Medicinal plants of genus Curculigo: Traditional uses and a phytochemical and ethnopharmacological review. ETHNOPHARMACOLOGICAL RELEVANCE: In the genus Curculigo, Curculigo orchioides Gaertn, Curculigo capitulata (Lour) O. Ktze and Curculigo pilosa (Schumach. & Thonn.) Engl are often used in traditional medicine. Curculigo orchioides is used for the treatment of impotence, limb limpness, arthritis of the lumbar and knee joints, and watery diarrhea in traditional Chinese medicine, and also used as a potent immunomodulator and aphrodisiac in the Ayurvedic medical system. Curculigo capitulata is used for the treatment of consumptive cough, kidney asthenia, impotence and spermatorrhea, hemorrhoids, asthma, jaundice, diarrhea, colic and gonorrhea in traditional Chinese and India medicine, and to treat urinary tract infection, acute renal pelvis and nephritis, nephritis-edema, cystitis, nephrolithiasis, hypertension and rheumatic arthritis in traditional Dai medicine. Curculigo pilosa are applied to treat gastrointestinal and heart diseases in Africa. AIM OF THE REVIEW: This review aims to exhibit up-to-date and comprehensive information about traditional uses, phytochemistry, pharmacology and toxicology of medicinal plants in the genus Curculigo, and has an insight into the opportunities for the future research and development of Curculigo plant. METHODS: A bibliographic investigation was performed by analyzing the information available on Curculigo plant from worldwide accepted scientific databases (Pubmed, Scopus and Web of Science, SciFinder, Google Scholar, Yahoo). Furthermore, information also was obtained from some local and foreign books on ethnobotany and ethnomedicines. RESULTS: Curculigo orchioides, Curculigo capitulata and Curculigo pilosa have been used as traditional medicine to treat kinds of diseases such as impotence, limb limpness, gastrointestinal and heart diseases, etc. Phytochemical investigation of eight species of the genus Curculigo has resulted in identification of more than 110 compounds. The content of curculigoside is used as an indicator to evaluate the quality of rhizome of Curculigo orchioides. The medicinal plants have showed a wide spectrum pharmacological activities, including adaptive, immunostimulatory, taste-modifying and sweet-tasting, antioxidant, mast cell stabilization, antihistaminic and antiasthmatic, hepatoprotective and neuroprotective activity. Toxicological test indicated that Curculigo orchioides at the dose of 120g/kg after administrating rats for 180 days may cause injury of liver and kidney. CONCLUSION: The medicinal plants of genus Curculigo have emerged as a good source of the traditional medicines. Some uses of these plants in the traditional medicines have been validated by pharmacological investigation. However, the mechanism of their actions should be further elucidated; the particular constituent responsible for toxicity should be isolated and identified, and the target tissue and mechanism of toxic ingredients also deserve to be further investigated; more reference substances should be prepared, and sophisticated analytical technologies should be developed to comprehensively assess the quality of Curculigo herbs. These investigations will be helpful for further utilization of the plants of genus Curculigo. 23218732 Substantial impact of illness perceptions on quality of life in patients with Crohn's disease. Crohn's disease (CD) negatively impact patients' health-related quality of life (HRQOL). We used the common sense model to examine the contribution of illness perceptions and coping to HRQOL, in addition to clinical and socio-demographic characteristics. This provides insight into potential targets for psychological interventions aimed at improving HRQOL. Consecutive CD patients undergoing colonoscopy were included. Disease activity was assessed by a clinical and an endoscopic index. Patients completed questionnaires assessing illness perceptions (IPQ-R), coping (Utrecht Coping List), self-perceived health, neuroticism, and HRQOL. Hierarchical multiple regression analyses were performed to assess the contribution of illness perceptions and coping to HRQOL. Illness perceptions were compared to patients with rheumatoid arthritis, myocardial infarction (MI), and head and neck cancer (HNC). Of 82 CD patients, mean age was 42±14years. Clinical and endoscopic active disease was present in 42 (52%) and 49 (60%) patients, respectively. HRQOL was strongly impaired by clinical active disease (r=-0.79), self-perceived health (r=-0.60), and perceived consequences of CD (r=-0.54), but correlated poorly with endoscopic disease activity (r=-0.29). Illness perceptions significantly contributed 3-27% to HRQOL. Coping had no contributory role. CD patients perceived similarly strong consequences of their illness as patients with MI and HNC and had the strongest thoughts about the chronic nature of their illness. CD has a similar impact on patients' daily lives as was observed in patients with MI and HNC. Illness perceptions contribute to HRQOL and should therefore be incorporated in clinical practice, thereby improving HRQOL. 23440015 Mechanism of morphology transformation during annealing of nanostructured gold films on glass. Nanostructured, just-percolated gold films were prepared by evaporation on bare glass. Annealing of the films at temperatures close to or higher than the softening temperature of the glass substrate induces morphological transformation to discrete Au islands and gradual embedding of the formed islands in the glass. The mechanism and kinetics of these processes are studied here using a combination of in situ high-temperature optical spectroscopy; ex situ characterization of the island shape by high-resolution scanning electron microscopy (HRSEM), atomic force microcopy (AFM) and cross-sectional transmission electron microscopy (TEM); and numerical simulations of transmission spectra using the Multiple Multipole Program (MMP) approach. It is shown that the morphological transformation of just-percolated, 10 nm (nominal thickness) Au films evaporated on glass and annealed at 600 °C, i.e., in the vicinity of the substrate glass transition temperature (Tg = 557 °C), proceeds via three processes exhibiting different time scales: (i) fast recrystallization and dewetting, leading to formation of single-crystalline islands (minutes); the initial spectrum characteristic of a continuous Au film is transformed to that of an island film, displaying a surface plasmon (SP) absorption band. (ii) Reshaping and faceting of the single-crystalline islands accompanied by formation of circumferential glass rims around them (first few hours); the overall optical response shows a blue shift of the SP band. (iii) Gradual island embedding in the glass substrate (tens of hours), seen as a characteristic red shift of the SP band. The influence of the annealing atmosphere (air, vacuum) on the embedding process is found to be minor. Numerical modeling of the extinction cross-section corresponding to the morphological transformations during island recrystallization and embedding is in qualitative agreement with the experimental data. 23644136 In silico prediction of the effects of mutations in the human UDP-galactose 4'-epimerase gene: towards a predictive framework for type III galactosemia. The enzyme UDP-galactose 4'-epimerase (GALE) catalyses the reversible epimerisation of both UDP-galactose and UDP-N-acetyl-galactosamine. Deficiency of the human enzyme (hGALE) is associated with type III galactosemia. The majority of known mutations in hGALE are missense and private thus making clinical guidance difficult. In this study a bioinformatics approach was employed to analyse the structural effects due to each mutation using both the UDP-glucose and UDP-N-acetylglucosamine bound structures of the wild-type protein. Changes to the enzyme's overall stability, substrate/cofactor binding and propensity to aggregate were also predicted. These predictions were found to be in good agreement with previous in vitro and in vivo studies when data was available and allowed for the differentiation of those mutants that severely impair the enzyme's activity against UDP-galactose. Next this combination of techniques were applied to another twenty-six reported variants from the NCBI dbSNP database that have yet to be studied to predict their effects. This identified p.I14T, p.R184H and p.G302R as likely severely impairing mutations. Although severely impaired mutants were predicted to decrease the protein's stability, overall predicted stability changes only weakly correlated with residual activity against UDP-galactose. This suggests other protein functions such as changes in cofactor and substrate binding may also contribute to the mechanism of impairment. Finally this investigation shows that this combination of different in silico approaches is useful in predicting the effects of mutations and that it could be the basis of an initial prediction of likely clinical severity when new hGALE mutants are discovered. 23212306 Impairment of novel object recognition in adulthood after neonatal exposure to diazinon. Diazinon is an organophosphate pesticide that is still heavily used in agriculture, home gardening, and indoor pest control in Japan. The present study investigated the effect of neonatal exposure to diazinon on hippocampus-dependent novel object recognition test performance and the expression of the N-methyl-D-aspartate (NMDA) receptor and its signal transduction pathway-related genes in the hippocampi of young adult and adult mice. Male offspring of C3H/HeN mice were subcutaneously treated with 0, 0.5, or 5 mg/kg of diazinon for 4 consecutive days beginning on postnatal day (PND) 8. Beginning on PND 46 or PND 81, a novel object recognition test was performed on 4 consecutive days. The hippocampi were collected on PND 50 or PND 85 after the completion of the novel object recognition test, and the expression levels of neurotrophins and the NMDA receptor and its signal transduction pathway-related genes were examined using real-time RT-PCR. Diazinon-injected mice exhibited a poor ability to discriminate between novel and familiar objects during both the PND 49 and the PND 84 tests. The NMDA receptor subunits NR1 and NR2B and the related protein kinase calcium/calmodulin-dependent protein kinase (CaMK)-IV and the transcription factor cyclic AMP responsive element binding protein (CREB)-1 mRNA levels were reduced in the PND 50 mice. However, no significant changes in the expressions of the NMDA subunits and their signal transduction molecules were observed in the hippocampi of the PND 85 mice. The expression level of nerve growth factor mRNA was significantly reduced in the PND 50 or 85 mice. These results indicate that neonatal diazinon exposure impaired the hippocampus-dependent novel object recognition ability, accompanied by a modulation in the expressions of the NMDA receptor and neurotrophin in young adult and adult mice. 23801313 Evaluation of an endoscopic suturing device for transoral outlet reduction in patients with weight regain following Roux-en-Y gastric bypass. A dilated gastrojejunal anastomosis (GJA) is thought to be associated with weight regain in patients with Roux-en-Y gastric bypass (RYGB). Due to a high rate of perioperative morbidity, surgical revision is not generally performed. The aim of this study was to assess the technical feasibility, safety, and early outcomes of a procedure using a commercially available endoscopic suturing device to reduce the diameter of the GJA. This was a retrospective analysis of 25 consecutive patients who underwent transoral outlet reduction (TORe) for dilated GJA and weight regain. An endoscopic suturing device was used to place sutures at the margin of the GJA in order to reduce its aperture. On chart review, clinical data were available at 3, 6, and 12 months. Patients had regained a mean of 24 kg from their weight loss nadir and had a mean body mass index of 43 kg/m2 at the time of endoscopic revision. Average anastomosis diameter was 26.4 mm. Technical success was achieved in all patients (100 %) with a mean reduction in anastomosis diameter to 6 mm (range 3 - 10 mm), representing a 77.3 % reduction. The mean weight loss in successful cases was 11.5 kg, 11.7 kg, and 10.8 kg at 3, 6, and 12 months, respectively. There were no major complications. This case series demonstrated the technical feasibility, safety, and efficacy of performing gastrojejunostomy reduction using a commercially available endoscopic suturing device. This technique may represent an effective and minimally invasive option for the management of weight regain in patients with RYGB. 23734995 The ORF slr0091 of Synechocystis sp. PCC6803 encodes a high-light induced aldehyde dehydrogenase converting apocarotenals and alkanals. Oxidative cleavage of carotenoids and peroxidation of lipids lead to apocarotenals and aliphatic aldehydes called alkanals, which react with vitally important compounds, promoting cytotoxicity. Although many enzymes have been reported to deactivate alkanals by converting them into fatty acids, little is known about the mechanisms used to detoxify apocarotenals or the enzymes acting on them. Cyanobacteria and other photosynthetic organisms must cope with both classes of aldehydes. Here we report that the Synechocystis enzyme SynAlh1, encoded by the ORF slr0091, is an aldehyde dehydrogenase that mediates oxidation of both apocarotenals and alkanals into the corresponding acids. Using a crude lysate of SynAlh1-expressing Escherichia coli cells, we show that SynAlh1 converts a wide range of apocarotenals and alkanals, with a preference for apocarotenals with defined chain lengths. As suggested by in vitro incubations and using engineered retinal-forming E. coli cells, we found that retinal is not a substrate for SynAlh1, making involvement in Synechocystis retinoid metabolism unlikely. The transcript level of SynAlh1 is induced by high light and cold treatment, indicating a role in the stress response, and the corresponding gene is a constituent of a stress-related operon. The assumptions regarding the function of SynAlh are further supported by the surprisingly high homology to human and plant aldehyde dehydrogenase that have been assigned to aldehyde detoxification. SynAlh1 is the first aldehyde dehydrogenase that has been shown to form both apocarotenoic and fatty acids. This dual function suggests that its eukaryotic homologs may also be involved in apocarotenal metabolism, a function that has not been considered so far. 23969413 Highly hydrophilic and insulating fluorinated reduced graphene oxide. A facile method for the synthesis of highly fluorinated reduced graphene oxide from graphene oxide using BF3-OEt2 solution and alkylthiol/alkylamine on the Gram scale has been described using a detailed mechanism. The maximum fluorination was as high as 38 wt% and the fluorinated reduced graphene oxide produced has great wettability and high insulating properties. 23707772 Bisphenol A down-regulates rate-limiting Cyp11a1 to acutely inhibit steroidogenesis in cultured mouse antral follicles. Bisphenol A (BPA) is the backbone of polycarbonate plastic products and the epoxy resin lining of aluminum cans. Previous studies have shown that exposure to BPA decreases sex steroid hormone production in mouse antral follicles. The current study tests the hypothesis that BPA first decreases the expression levels of the steroidogenic enzyme cytochrome P450 side-chain cleavage (Cyp11a1) and steroidogenic acute regulatory protein (StAR) in mouse antral follicles, leading to a decrease in sex steroid hormone production in vitro. Further, the current study tests the hypothesis that these effects are acute and reversible after removal of BPA. Exposure to BPA (10μg/mL and 100μg/mL) significantly decreased expression of Cyp11a1 and StAR beginning at 18h and 72h, respectively, compared to controls. Exposure to BPA (10μg/mL and 100μg/mL) significantly decreased progesterone levels beginning at 24h and decreased androstenedione, testosterone, and estradiol levels at 72h and 96h compared to controls. Further, after removing BPA from the culture media at 20h, expression of Cyp11a1 and progesterone levels were restored to control levels by 48h and 72h, respectively. Additionally, expression of StAR and levels of androstenedione, testosterone, and estradiol never decreased compared to controls. These data suggest that BPA acutely decreases expression of Cyp11a1 as early as 18h and this reduction in Cyp11a1 may lead to a decrease in progesterone production by 24h, followed by a decrease in androstenedione, testosterone, and estradiol production and expression of StAR at 72h. Therefore, BPA exposure likely targets Cyp11a1 and steroidogenesis, but these effects are reversible with removal of BPA exposure. 23510005 Treatment-resistant depression and risk of suicide. We evaluated whether treatment-resistant depression (TRD) as measured by the Massachusetts General Hospital (MGH) staging method was associated with suicide in a large U.S. health system. Data from the Veterans Health Administration and the National Death Index were used to conduct a case-control study of patients newly diagnosed with depression who received antidepressant treatment between 2003 and 2006. Suicide cases (N = 499) were matched with nonsuicide controls (N = 1994). Conditional logistic regression was used to assess whether MGH stage at time of suicide (or matched date) was associated with case status, adjusting for patient demographic characteristics, comorbidity, and service use. Results indicated 11.6% of suicide cases had MGH stage 3 or greater (indicating at least two antidepressant trials) compared to 6.4% of controls (p < .001). In adjusted analyses, suicide was not significantly more likely among patients with stage 3 or greater (OR 1.52; 95% CI: 0.98, 2.37) or stages 1.5-2.5 (OR 1.19; 95% CI: 0.91, 1.55) compared to patients with stage 1 or less (<10 weeks of antidepressant medication). Staging TRD using MGH criteria is unlikely to substantially improve suicide risk assessment of depressed patients beyond existing measures contained in health system records. 23649926 Preparation of homogeneous samples of double-labelled protein suitable for single-molecule FRET measurements. Preparation of pure and homogenous site specifically single- and double-labelled biopolymers suitable for spectroscopic determination of structural characteristics is a major current challenge in biopolymers chemistry. In particular, proper analysis of single-molecule Förster resonance energy transfer measurements is based on the spectral characteristics of the probes. Heterogeneity of any of the probes may introduce errors in the analysis, and hence, care must be taken to avoid preparation of inhomogeneous labelled biopolymer samples. When we prepared samples of Escherichia coli adenylate kinase (AK) mutants labelled with either Atto 488 or Atto 647N, the products were spectrally inhomogeneous and the composition of the mixture changed gradually over time. We show here that the inhomogeneity was not a result of variation in the dye interaction with neighbouring side chains. Rather, the slow drift of the spectral characteristics of the probes was a characteristic of an irreversible chemical transformation probably due to the hydrolysis of the succinimide ring of the attached dye into its succinamic acid form. Overnight incubation of the labelled protein in mild basic solution accelerated the interconversion, yielding homogeneous labelled samples. Using this procedure, we obtained stable homogenous AK mutant labelled at residues 142 and 188. 23237980 The contributions of viral hepatitis and alcohol to liver-related deaths in opioid-dependent people. Mortality rates are elevated among heroin-dependent populations compared to the general population. Liver disease is emerging as an important contributor to mortality as the heroin-dependent population ages. Two major risk factors for liver disease are hepatitis C virus infection and chronic heavy alcohol use. Both of these are highly prevalent among heroin dependent people, but their relative contribution to liver-related mortality is poorly understood. Data recording all prescriptions of opioid substitution treatment in New South Wales, Australia, 1997-2005, were linked to the National Death Index. Crude and standardised mortality rates and standardised mortality ratios were calculated for liver-related and other major causes of death. Frequency counts were obtained for viral hepatitis and alcohol mentions in underlying liver deaths. There were 208 underlying liver deaths for a CMR of 72.4 per 100,000py (95% CI 62.9, 82.9), and liver deaths occurred at 9.8 times the general population rate (95% CI 8.5, 11.2). There were increases in liver-related mortality over time. Viral hepatitis was mentioned in three-quarters (n=156, 76%), and alcohol in 43% (n=90) of underlying liver deaths. Liver-related deaths were shown to be increasing in this heroin-dependent population, and the majority of these deaths involved chronic viral hepatitis infection. Increased uptake of treatment for hepatitis C virus infection is crucial to reducing the burden of liver-related mortality in this population. Hepatitis B vaccination, and screening of OST patients for alcohol use disorders and delivery of brief interventions as clinically indicated may also be of benefit. 23848339 Beneficial effects of Brassica juncea on cognitive functions in rats. Abstract Context. Brassica juncea (BJ; Linnaeus) Czern & Coss (Brassicaceae), commonly known as Indian mustard, are enriched in redox-active polyphenols with antidiabetic activities. Diverse other health benefits of this edible plant have been described in classical Ayurvedic texts. Objective: The reported experiments were designed to assess therapeutic potential of a methanol extract of BJ leaves for treatment of cognitive disorders associated with diabetes or caused by central cholinergic dysfunctions. Materials and methods: Elevated plus-maze and active- and passive-avoidance tests were used to assess anti-amnesic potentials of BJ (100, 200 and 400 mg/kg/day, p.o., for 10 days) in alloxan diabetic or scopolamine-challenged rats. Treatment effects on brain acetylcholinesterase (AChE), superoxide dismutase (SOD) and catalase (CAT) activities were quantified in behavioral tested animals. Results: Anti-amnesic efficacy of all three tested BJ doses against scopolamine-induced amnesia was almost equal in all behavioral tests. Such efficacy of the extract in diabetic rats was increased always with its increasing doses. All treatments of BJ dose dependently decreased the elevated level of AChE, and significantly increased the SOD and CAT levels in brain homogenates of scopolamine-challenged and diabetic rats. Minimal effective oral daily doses of BJ in all tests were 100 mg/kg/day for 10 consecutive days. Discussion and conclusion: Our observation indicates that BJ could be a therapeutic option for treatment of cognitive disorders associated with diabetes, or caused by cholinergic deficit and brain oxidative status. They also indicate that the bioactive constituents or mode of actions involved in observed effects of the extract in scopolamine-challenged or diabetic rats are most probably not the same. 23628345 NMDA receptors and memory encoding. It is humbling to think that 30 years have passed since the paper by Collingridge, Kehl and McLennan showing that one of Jeff Watkins most interesting compounds, R-2-amino-5-phosphonopentanoate (d-AP5), blocked the induction of long-term potentiation in vitro at synapses from area CA3 of the hippocampus to CA1 without apparent effect on baseline synaptic transmission (Collingridge et al., 1983). This dissociation was one of the key triggers for an explosion of interest in glutamate receptors, and much has been discovered since that collectively contributes to our contemporary understanding of glutamatergic synapses - their biophysics and subunit composition, of the agonists and antagonists acting on them, and their diverse functions in different networks of the brain and spinal cord. It can be fairly said that Collingridge et al.'s (1983) observation was the stimulus that has led, on the one hand, to structural biological work at the atomic scale describing the key features of NMDA receptors that enables their coincidence function to happen; and, on the other, to work with whole animals investigating the contributions that calcium signalling via this receptor can have on rhythmical activities controlled by spinal circuits, memory encoding in the hippocampus (the topic of this article), visual cortical plasticity, sensitization in pain, and other functions. In this article, I lay out how my then interest in long-term potentiation (LTP) as a model of memory enabled me to recognise the importance of Collingridge et al.'s discovery - and how I and my colleagues endeavoured to take things forward in the area of learning and memory. This is in some respects a personal story, and I tell it as such. The idea that NMDA receptor activation is essential for memory encoding, though not for storage, took time to develop and to be accepted. Along the way, there have been confusions, challenges, and surprises surrounding the idea that activation of NMDA receptors can trigger memory. Some of these are described and how they have been addressed and resolved. Last, I touch on some new directions of interest with respect to the functional role of the NMDA receptor in cognition. This article is part of a Special Issue entitled 'GluR-dep synaptic plasticity'. 23837816 New Insights into the HIFU-Triggered Release from Polymeric Micelles. Continuous wave (CW), low frequency, high intensity focused ultrasound (HIFU) is a promising modality to trigger release of active compounds from polymeric micelles. The aim of the present study was to investigate whether high frequency CW as well as pulsed wave (PW) HIFU can induce the release of a hydrophobic agent from non-cross-linked (NCL) and core cross-linked (CCL) poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-lactate] (mPEG-b-p(HPMAm-Lacn)) micelles. It was shown that high frequency CW as well as PW HIFU was able to trigger the release (up to 85%) of a hydrophobic compound (i.e., nile red, NR) from NCL and CCL micelles. No changes in size distribution of the micelles after CW and PW HIFU exposure were observed and no degradation of polymer chain had occurred. We therefore hypothesize that the polymeric micelles are temporally destabilized upon HIFU exposure due to radiation force induced shear forces, leading to NR release on demand. 23387414 Removal of molecular adsorbates on gold nanoparticles using sodium borohydride in water. The mechanism of sodium borohydride removal of organothiols from gold nanoparticles (AuNPs) was studied using an experimental investigation and computational modeling. Organothiols and other AuNP surface adsorbates such as thiophene, adenine, rhodamine, small anions (Br(-) and I(-)), and a polymer (PVP, poly(N-vinylpyrrolidone)) can all be rapidly and completely removed from the AuNP surfaces. A computational study showed that hydride derived from sodium borohydride has a higher binding affinity to AuNPs than organothiols. Thus, it can displace organothiols and all the other adsorbates tested from AuNPs. Sodium borohydride may be used as a hazard-free, general-purpose detergent that should find utility in a variety of AuNP applications including catalysis, biosensing, surface enhanced Raman spectroscopy, and AuNP recycle and reuse. 22991447 Targeted disruption of inducible nitric oxide synthase protects against aging, S-nitrosation, and insulin resistance in muscle of male mice. Accumulating evidence has demonstrated that S-nitrosation of proteins plays a critical role in several human diseases. Here, we explored the role of inducible nitric oxide synthase (iNOS) in the S-nitrosation of proteins involved in the early steps of the insulin-signaling pathway and insulin resistance in the skeletal muscle of aged mice. Aging increased iNOS expression and S-nitrosation of major proteins involved in insulin signaling, thereby reducing insulin sensitivity in skeletal muscle. Conversely, aged iNOS-null mice were protected from S-nitrosation-induced insulin resistance. Moreover, pharmacological treatment with an iNOS inhibitor and acute exercise reduced iNOS-induced S-nitrosation and increased insulin sensitivity in the muscle of aged animals. These findings indicate that the insulin resistance observed in aged mice is mainly mediated through the S-nitrosation of the insulin-signaling pathway. 23845311 Glossina fuscipes populations provide insights for human African trypanosomiasis transmission in Uganda. Uganda has both forms of human African trypanosomiasis (HAT): the chronic gambiense disease in the northwest and the acute rhodesiense disease in the south. The recent spread of rhodesiense into central Uganda has raised concerns given the different control strategies the two diseases require. We present knowledge on the population genetics of the major vector species Glossina fuscipes fuscipes in Uganda with a focus on population structure, measures of gene flow between populations, and the occurrence of polyandry. The microbiome composition and diversity is discussed, focusing on their potential role on trypanosome infection outcomes. We discuss the implications of these findings for large-scale tsetse control programs, including suppression or eradication, being undertaken in Uganda, and potential future genetic applications. 23292321 Theoretical investigation into optical and electronic properties of 1,8-naphthalimide derivatives. A series of 1,8-naphthalimide derivatives has been designed to explore their optical, electronic, and charge transport properties as charge transport and/or luminescent materials for organic light-emitting diodes (OLEDs). The frontier molecular orbitals (FMOs) analysis have shown that the vertical electronic transitions of absorption and emission are characterized as intramolecular charge transfer (ICT) for electron-donating and aromatic groups substituted derivatives. However, the ICT character of the electron-withdrawing substituted derivatives is not significant. The calculated results show that their optical and electronic properties are affected by the substituent groups in 4-position of 1,8-naphthalimide. Our results suggest that 1,8-naphthalimide derivatives with electron-donating -OCH3 and -N(CH3)2 (1 and 2), electron-withdrawing -CN and-COCH3 (3 and 4), 2-(thiophen-2-yl)thiophene (5), 2,3-dihydrothieno[3,4-b][1, 4]dioxine (6), 2-phenyl-1,3,4-oxadiazole (7), and benzo[c][1,2,5]thiadiazole (8) fragments are expected to be promising candidates for luminescent materials for OLEDs, particularly for 5 and 7. In addition, 3 and 7 can be used as promising hole transport materials for OLEDs. This study should be helpful in further theoretical investigations on such kind of systems and also to the experimental study for charge transport and/or luminescent materials for OLEDs. 23644202 Nitroimidazolyl hydrazones are better amoebicides than their cyclized 1,3,4-oxadiazoline analogues: In vitro studies and Lipophilic efficiency analysis. Two series of compounds with hydrazone derivatives (HZ1-HZl2, series 1) and oxadiazoline derivatives (OZ1-OZ12, series 2) of the 2-methyl-5-nitro-1H-imidazole scaffold were designed and synthesized. Physicochemical properties and Lipophilic efficiency (LipE) analysis predicted higher intrinsic quality of the acylhydrazone derivatives (series 1) than their corresponding oxadiazoline analogues (series 2). In vitro antiamoebic results supported the above findings and validated that the acylhydrazone derivatives (HZ1-HZl2) show better activity than the oxadiazoline derivatives (OZ1-OZ12). MTT assay, using HepG2 cell line, revealed noncytotoxic nature of the compounds. The most promising results were observed for compounds HZ5 (IC50 = 0.96 μM) and HZ9 (IC50 = 0.81 μM) both in silico and in vitro. Analysis of the Lipophilic efficiency (LipE) of the compounds provided new insight for the design of potent and selective amoebicides. 23603856 Large networks of vertical multi-layer graphenes with morphology-tunable magnetoresistance. We report on the comparative study of magnetotransport properties of large-area vertical few-layer graphene networks with different morphologies, measured in a strong (up to 10 T) magnetic field over a wide temperature range. The petal-like and tree-like graphene networks grown by a plasma enhanced CVD process on a thin (500 nm) silicon oxide layer supported by a silicon wafer demonstrate a significant difference in the resistance-magnetic field dependencies at temperatures ranging from 2 to 200 K. This behaviour is explained in terms of the effect of electron scattering at ultra-long reactive edges and ultra-dense boundaries of the graphene nanowalls. Our results pave a way towards three-dimensional vertical graphene-based magnetoelectronic nanodevices with morphology-tuneable anisotropic magnetic properties. 23410162 Human disease and drug pharmacology, complex as real life. In the past decades drug discovery practice has escaped from the complexity of the formerly used phenotypic screening in animals to focus on assessing drug effects on isolated protein targets in the search for drugs that exclusively and potently hit one selected target, thought to be critical for a given disease, while not affecting at all any other target to avoid the occurrence of side-effects. However, reality does not conform to these expectations, and, conversely, this approach has been concurrent with increased attrition figures in late-stage clinical trials, precisely due to lack of efficacy and safety. In this context, a network biology perspective of human disease and treatment has burst into the drug discovery scenario to bring it back to the consideration of the complexity of living organisms and particularly of the (patho)physiological environment where protein targets are (mal)functioning and where drugs have to exert their restoring action. Under this perspective, it has been found that usually there is not one but several disease-causing genes and, therefore, not one but several relevant protein targets to be hit, which do not work on isolation but in a highly interconnected manner, and that most known drugs are inherently promiscuous. In this light, the rationale behind the currently prevailing single-target-based drug discovery approach might even seem a Utopia, while, conversely, the notion that the complexity of human disease must be tackled with complex polypharmacological therapeutic interventions constitutes a difficult-torefuse argument that is spurring the development of multitarget therapies. 23166105 Emotion coupling and regulation in anorexia nervosa. The present study sought to investigate emotion regulation strategies in people with anorexia nervosa (AN) and whether the theoretical concept of 'emotion coupling' between anger and disgust could help to explain some of the specific eating disorder symptomatology in people with AN. This 'emotion coupling' hypothesis was tested using a mood induction procedure within laboratory conditions, where individuals with AN (n = 22) were matched with control participants (n = 19). Participants completed a bank of different measures prior to the study, and these included measures of eating pathology, core beliefs about the self and others, and emotion regulation strategies. Within the experimental part of this study, anger, disgust and body size estimation were measured prior to and after an anger induction procedure (i.e., a repeated measures design). People with AN demonstrated a significantly more internal-dysfunctional way to regulate their emotional states, when compared with matched controls. Within the 'emotional coupling' part of the study, participants showed a significant increase in levels of disgust and body size estimation following an anger induction when compared with matched controls. The significance of these results was considered in the light of the new Schematic, Propositional, Analogical and Associative Representation Systems in eating disorders model. Copyright © 2012 John Wiley & Sons, Ltd. Emotions and emotion processing are problematic for people with anorexia nervosa.Overestimation in body size for people with anorexia nervosa may be due to the coupling of anger and disgust.Clinicians need to consider the importance of automatic cognitive routes of emotion elicitation that may maintain certain eating disorder symptoms, such as poor body image. 23852912 Association of the polymorphism of MMP2 with the risk and severity of lumbar disc degeneration in the Chinese Han population. The present study aimed to determine whether the -735 C/T polymorphism of the Matrix Metalloproteinase 2 (MMP2) gene is associated with the risk and severity of lumbar disc degeneration (LDD) in the Chinese Han population. A total of 1008 patients with LDD and 906 healthy controls were enrolled in this study. The grade of disc degeneration was determined according to Schneiderman's classification for Magnetic Resonance Imaging (MRI). The -735 C/T polymorphism of MMP2 was genotyped using polymerase chain reaction and the restriction fragment length polymorphism method. The genotype frequency of the -735 C/T polymorphism was in agreement with the Hardy-Weinberg equilibrium (p = 0.087). The frequencies of the -735CT and TT genotypes were significantly lower among LDD patients compared with normal controls (p < 0.001); CT and TT genotype were significantly associated with a decreased risk of LDD compared with the CC genotype (for TT genotype, p = 0.031; OR 0.413; 95% CI 0.184-0.924; for CT genotype, p < 0.001, OR 0.645, 95% CI 0.506-0.822). Patients with LDD showed significantly higher frequencies of the C allele than normal controls (p < 0.001), T allele was significantly associated with a decreased risk of LDD compared with the C allele (p < 0.001; OR 0.631; 95% CI 0.508-0.783). In addition, the -735TT and CT genotypes, as well as the T allele were associated with lower degenerative grades of LDD compared with CC genotype and the C allele, respectively (both p < 0.001). The -735 C/T polymorphism of MMP2 may be associated with the risk and severity of LDD in the Chinese Han population. 23799774 scAAV9 Intracisternal Delivery Results in Efficient Gene Transfer to the Central Nervous System of a Feline Model of Motor Neuron Disease. Abstract On the basis of previous studies suggesting that vascular endothelial growth factor (VEGF) could protect motor neurons from degeneration, adeno-associated virus vectors (serotypes 1 and 9) encoding VEGF (AAV.vegf) were administered in a limb-expression 1 (LIX1)-deficient cat-a large animal model of lower motor neuron disease-using three different delivery routes to the central nervous system. AAV.vegf vectors were injected into the motor cortex via intracerebral administration, into the cisterna magna, or intravenously in young adult cats. Intracerebral injections resulted in detectable transgene DNA and transcripts throughout the spinal cord, confirming anterograde transport of AAV via the corticospinal pathway. However, such strategy led to low levels of VEGF expression in the spinal cord. Similar AAV doses injected intravenously resulted also in poor spinal cord transduction. In contrast, intracisternal delivery of AAV exhibited long-term transduction and high levels of VEGF expression in the entire spinal cord, yet with no detectable therapeutic clinical benefit in LIX1-deficient animals. Altogether, we demonstrate (i) that intracisternal delivery is an effective AAV delivery route resulting in high transduction of the entire spinal cord, associated with little to no off-target gene expression, and (ii) that in a LIX1-deficient cat model, however, VEGF expressed at high levels in the spinal cord has no beneficial impact on the disease course. 23313547 Knock-down of the oxysterol receptor LXRα impairs cholesterol efflux in human primary macrophages: lack of compensation by LXRβ activation. Liver X Receptors (LXRs) α and β are oxysterol-activated nuclear receptors involved in the control of lipid metabolism and inflammation. Pharmacological activation of LXR is promising in the treatment of atherosclerosis since it can promote cholesterol efflux from macrophages and prevent foam cell formation. However, the development of LXR agonists has been limited by undesirable side-effects such as hepatic steatosis mediated by LXRα activation. Therefore, it has been proposed that targeting LXRα activators to extrahepatic tissues or using LXRβ-specific activators could be used as alternative strategies. It is not clear whether these molecules will retain the full atheroprotective potential of non-selective agonists. Our aim was therefore to determine the contribution of LXRα and LXRβ to the control of cholesterol efflux in human macrophages. LXRα and/or LXRβ expression was suppressed by small interfering RNAs in human primary macrophages treated or not with synthetic LXRα/β dual agonists T0901317 and GW3965. We observed that LXRβ silencing had no detectable impact on the expression of LXR-target genes such as ABCA1 and ABCG1. Moreover it did not affect cholesterol efflux. In contrast, LXRα silencing reduced the response of these LXR-target genes to LXR agonist and inhibited cholesterol efflux to ApoA-I, HDL2 or to endogenous ApoE. Importantly, no differences were observed between LXRα and LXRα/β knockdown conditions. Altogether, our data demonstrate that LXRβ activation is unable to maintain maximal cholesterol efflux capacities in human primary macrophages when LXRα expression is impaired. In contrast to earlier mouse studies, LXRα levels appear as a limiting factor for macrophage cholesterol efflux in humans. 23936026 microRNA-124 Inhibits Migration and Invasion by Down-Regulating ROCK1 in Glioma. The extraordinary invasive capability is a major cause of treatment failure and tumor recurrence in glioma, however, the molecular and cellular mechanisms governing glioma invasion remain poorly understood. Evidence in other cell systems has implicated the regulatory role of microRNA in cell motility and invasion, which promotes us to investigate the biological functions of miR-124 in glioma in this regard. We have found that miR-124 is dramatically downregulated in clinical specimen of glioma and is negatively correlated with the tumor pathological grading in the current study. The cells transfected by miR-124 expression vector have demonstrated retarded cell mobility. Using a bioinformatics analysis approach, rho-associated coiled-coil containing protein kinase 1 (ROCK1), a well-known cell mobility-related gene, has been identified as the target of miR-124. A dual-luciferase reporter assay was used to confirm that miR-124 targeted directly the 3'UTR of ROCK1 gene and repressed the ROCK1 expression in U87MG human glioma cell line. Furthermore, experiments have shown that the decreased cell mobility was due to the actin cytoskeleton rearrangements and the reduced cell surface ruffle in U87MG glioma cells. These results are similar to the cellular responses of U87MG glioma cells to the treatment of Y-27632, an inhibitor of ROCK protein. Moreover, a constitutively active ROCK1 in miR-124 over-expressed glioma cells reversed the effects of miR-124. Our results revealed a novel mechanism that miR-124 inhibits glioma cells migration and invasion via ROCK1 downregulation. These results suggest that miR-124 may function as anti-migration and anti-invasion influence in glioma and provides a potential approach for developing miR-124-based therapeutic strategies for malignant glioma therapy. 23602547 How effective is an ethical international recruitment policy? Reflections on a decade of experience in England. Using evidence from a 2006 postal survey of NHS organisations, plus eight case studies and source country interviews (India; Philippines; Zimbabwe; Poland; Spain) in 2007-2008, the paper explores the impacts of England's 'ethical' recruitment policy as it developed from the late 1990s onwards. It shows that a Code of Practice and bilateral agreements did positively influence the behaviour of NHS organisations and commercial agencies at the height of England's international recruitment drive from 2001 to 2006. However, such policies could only go so far; and other actions are needed to mitigate the downside effects of migration on source countries. One key step is an attitude change that sees countries like England receiving internationally mobile health professionals for the 'value added' that they bring--rather than regarding them primarily as a numerical addition or substitute for the domestically-trained workforce. Another is to plan and manage the domestic workforce in order to deliver on self-sufficiency ambitions. Finally, 'ethical' stances mean placing health professional recruitment/migration into wider development agendas--as a platform for training and skills development for the developing world. Overall, it was the winding down of England's active recruitment policy from 2006 together with subsequent general immigration and professional registration rule changes that had most influence on migration numbers. 23933990 Stable transformation of ferns using spores as targets: Pteris vittata (Chinese brake fern) and Ceratopteris thalictroides (C-fern 'Express'). Ferns (Pteridophyta) are very important members of the plant kingdom that lag behind other taxa with regards to our understanding of their genetics, genomics, and molecular biology. We report here the first instance of stable transformation of fern with recovery of transgenic sporophytes. Spores of the arsenic hyperaccumulating fern Pteris vittata (Chinese brake fern) and tetraploid Ceratopteris thalictroides (C-fern 'Express') were stably transformed by Agrobacterium tumefaciens with constructs containing the P. vittata actin promoter driving a GUSPlus reporter gene. Reporter gene expression assays were performed on multiple tissues and growth stages of gametophytes and sporophytes. Southern blot analysis confirmed stable transgene integration in recovered sporophytes and also confirmed that no plasmid from Agrobacterium was present in the sporophyte tissues. We recovered seven independent transformants of P. vittata and four independent C. thalictroides transgenics. Inheritance analyses using GUS histochemical staining revealed that the GUS transgene was stably expressed in second (T2) generation C. thalictroides sporophytic tissues. In an independent experiment, the gusA gene that was driven by the 2x CaMV 35S promoter was bombarded into P. vittata spores using biolistics in which putatively stable transgenic gametophytes were recovered. Transformation procedures required no tissue culture or selectable marker genes. However, we did attempt to use hygromycin selection, which was ineffective to recover transgenic ferns. This simple stable transformation method should help facilitate functional genomics studies in ferns. 23931635 2,2'-Bipyridine Compounds of Group 14 Elements: A Density Functional Theory Study. The molecular and electronic structures of the 2,2'-bipyridine containing series of group 14 compounds (a) [MF4(bpy)](0); (b) [MCl2(bpy)2](2+/0) (c) [MCl2(bpy)](0); (d) [M(bpy)2](2+/0); (e) [Si(bpy)3](1+,0,1-,2-); and (f) [M(bpy)3](0) (M = C, Si, Ge, Sn, Pb) have been calculated using density functional theory (DFT). Where possible, geometry optimized structures are compared with their experimentally determined structures. In general, good to excellent agreement is observed. It is shown that the three successive one-electron reductions within the experimentally known series [Si(bpy)3](1+,0,1-,2-) are ligand-based and the Si center has a +IV oxidation state throughout. Hence, these species have the electronic structures [Si(IV)(bpy(•))3](+) (S = 1/2), [Si(IV)(bpy(•))2(bpy(2-))](0) (S = 0), [Si(IV)(bpy(•))(bpy(2-))2](-) (S = 1/2), and [Si(IV)(bpy(2-))3](2-) (S = 0). Similarly, it is shown that the crystallographically characterized compound [Si(bpy)2](0) (S = 0) possesses the electronic structure [Si(IV)(bpy(2-))2](0), which contains a tetravalent Si ion and two (bpy(2-))(2-) dianions. It should not be described as [Si(0)(bpy(0))2](0). For the heavier Ge, Sn, and Pb congeners the divalent state, characterized by a stereochemically active electron pair, becomes increasingly significant and dominates in 4-coordinate Sn and Pb species. 22959617 Ficolins in complement activation. Ficolins are a group of multimeric lectins made up of single subunits each of which is composed of a collagen-like domain and a fibrinogen-like domain. Most of the ficolins identified to date bind to acetylated compounds such as N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc). Ficolins in serum are complexed with MBL-associated serine proteases (MASPs) and their truncated proteins. These lectins play an important role in innate immunity. Binding of the ficolin-MASP complex to carbohydrates present on the surface of microbes initiates complement activation via the lectin pathway. 23672194 Intraspecific variation of a desert shrub species in phenotypic plasticity in response to sand burial. Shoot elongation is one of the main plastic responses of plants to burial, a ubiquitous stress factor in dry ecosystems. Yet, intraspecific variation in this response to burial and the extent to which this variation is functionally coordinated with variation in other trait responses are largely unknown. We subjected seedlings of the shrub Caragana intermedia from 18 maternal parents (i.e. different half-sib families) to repeated partial burial to investigate how burial affects shoot growth, stem mechanical traits and associated plasticity. Burial increased both stem elongation and diameter growth of plants, but decreased biomass production. Half-sib families had different rates of shoot elongation, and differed in their response to burial with respect to biomechanical stem properties. Across half-sib families, the magnitude of these responses in mechanical traits was positively correlated with the magnitude of the stem elongation response. These results indicate that plasticity in different stem traits in response to sand burial and intraspecific variation therein are functionally coordinated with respect to mechanical stability. The results emphasize the importance of considering functionally coordinated traits when analyzing phenotypic plasticity in plants. 23612420 Wogonoside displays anti-inflammatory effects through modulating inflammatory mediator expression using RAW264.7 cells. ETHNOPHARMACOLOGICAL RELEVANCE: The root of Scutellaria baicalensis Georgi, also called Huangqin in China, is an herbal-based nutraceutical which is usually used in Chinese medicated diet (CMD). As an abundant ingredient in Huangqin, wogonoside is a flavonoid glycoside. The present work investigated the anti-inflammatory activities of wogonoside in lipopolysaccharides (LPS)-induced RAW264.7 cells. MATERIALS AND METHODS: RAW264.7 cells were used. The inhibition of wogonoside against nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in LPS-induced RAW264.7 cells were measured. Additionally, the effects of wogonoside on mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), TNF-α and IL-6 were also investigated. RESULTS AND DISCUSSION: Wogonoside not only dose-dependently decreased the production of inflammatory mediators including NO and PGE2 but also inhibited the release of pro-inflammatory cytokines including TNF-α and IL-6 in LPS-induced RAW264.7 cells. Furthermore, wogonoside possessed significantly in vitro inhibitory effects on the gene expression of iNOS, COX2, TNF-α and IL-6. CONCLUSION: These results suggest that wogonoside may be used as a functional food component for prevention and treatment of inflammation. 23838633 Insulin versus glucagon crosstalk: central plus peripheral mechanisms. Plasma glucose level depends on the peripheral intra-islet crosstalk between A cells (glucagon) + B-cells (insulin) and D-cells (somatostatin). Gastrointestinal hormones (secretin, CCK-PZ, gastrin, and serotonin) modulate the glucose- and amino acids-induced secretions of insulin and glucagon, respectively. Serotonin (5-HT) arose from the enterochromaffin cells during postprandial periods excites basal but inhibits excited B-cells. Serotonin excites adrenal glands that release adrenaline (Ad) + dopamine (DA). The former is positively correlated with hyperglycemia, whereas DA antagonizes this effect. Noradrenaline (NA) released from both sympathetic nerves and adrenal glands modulates the Ad release from this latter and excites A-cells. Thus, NA attenuates the hyperglycemic effects triggered by Ad. Dopamine released from both sources, adrenal glands and peripheral sympathetic nerves, antagonizes Ad-induced hyperglycemia plus the NA-triggered glucagon secretion. Both plasma insulin and glucagon cross the blood-brain barrier and excite A5(NA) and C1(Ad) neurons, respectively. C1 (Ad) neurons send excitatory drives to both islet A-cells and adrenal glands. Both central nervous system A5(NA) and C1(Ad) nuclei interchange inhibitory axons. Predominance of the former redounds in hyperinsulinism plus hypoglycemia, whereas the latter axis is responsible for hyperglucagonemia + hyperglycemia. In addition, the dorsal raphe serotonergic and the median raphe serotonergic nuclei interchange excitatory axons with the C1 (Ad) and the A5(NA) neurons, respectively. Hence, the former binomial axis (responsible for uncoping stress) is positively correlated with the hyperglycemic syndrome, whereas the A5(NA) + median raphe serotonergic binomial is correlated with hypoglycemia. Hence, the insulin resistance disorder should be underlain by the overactivity of both axes simultaneously. The above pathophysiological mechanisms are consistent with the successful neuropharmacological manipulations addressed to treat these neuroendocrine syndromes. Finally, one of the showiest findings derived from our research work arises from the unbalance between the DA versus 5-HT circulating parameters demonstrating that absolute predominance of the former is always paralleled by hypoglycemia (endogenous depression syndrome), whereas the opposite profile is registered in mammals affected by hyperglycemia (dysthymic depression and uncoping stress syndromes). 23386034 A follow-up linkage study of Finnish pre-eclampsia families identifies a new fetal susceptibility locus on chromosome 18. Pre-eclampsia is a common vascular disorder of pregnancy. It originates in the placenta and targets the maternal endothelium. According to epidemiological research, >50% of the liability to this disorder can be accounted for by genetic factors. Both maternal and fetal genes contribute to the risk, but especially the fetal genetic risk profile is still poorly understood. We have previously detected linkage signals in multiplex Finnish families on chromosomes 2p25, 4q32, and 9p13 using maternal phenotypes. We performed a linkage analysis using updated maternal phenotypes and an unprecedented linkage analysis using fetal phenotypes. Markers genotyped were available from 237 individuals in 15 Finnish families, including 72 affected mothers and 49 affected fetuses. The MERLIN software was used for sample and marker quality control and linkage analysis. The results were compared against the original ones obtained by using the GENEHUNTER 2.1 software. The previous identification of the maternal susceptibility locus to a genetic location at 21.70 cM near marker D2S168 on chromosome 2 was confirmed by using both maternal and fetal phenotypes (maternal non-parametric linkage (NPL) score 3.79, P=0.00008, LOD (logarithm (base 10) of odds)=2.20 and fetal NPL score 2.95, P=0.002, LOD=1.71). As a novel finding, we present a suggestive linkage to chromosome 18 at 86.80 cM near marker D18S64 (NPL score 2.51, P=0.006, LOD=1.20) using the fetal phenotype. We propose that chromosome 18 may harbor a new fetal susceptibility locus for pre-eclampsia. 23926285 Translational Activation of Developmental Messenger RNAs During Neonatal Mouse Testis Development. The basic tenets of germ cell development are conserved among metazoans. Following lineage commitment in the embryo, germ cells proliferate, transition into meiosis, and then differentiate into gametes capable of fertilization. In lower organisms such as Drosophila and C. elegans, germline stem cells (GSCs) make the decision to proliferate or enter meiosis based in large part on the regulated expression of genes by translational control. This study undertakes a direct characterization of mRNAs that experience translational control and their involvement in similar decisions in the mammalian testis. We previously showed that translation of mRNA encoding the germ cell-specific gene Rhox13 was suppressed in the fetal and neonatal testis. By investigating changes in message utilization during neonatal testis development, we found that a large number of mRNAs encoding both housekeeping and germ cell-specific proteins experience enhanced translational efficiency, rather than increase in abundance, in the testis as quiescent gonocytes transition to mitotic spermatogonia. Our results indicate that translational control is a significant regulator of the germ cell proteome during neonatal testis development. 23928141 Use of FLAIR Imaging to Identify Onset Time of Cerebral Ischemia in a Canine Model. BACKGROUND AND PURPOSE:Stroke is a leading cause of death and disability, and many studies have focused on the evolution of FLAIR imaging in the acute and chronic time window. The purpose of this study was to evaluate the potential efficacy of FLAIR-related techniques in identifying the onset time of cerebral ischemia in a canine embolic stroke model.MATERIALS AND METHODS:An embolic ischemic model was generated through the use of an autologous clot in 20 beagle dogs. Both FLAIR and DWI were performed at 3 hours, 4 hours, 5 hours, 6 hours, and 24 hours after embolization, respectively. Visual "DWI-FLAIR mismatch" was defined as hyperintense signal detected on DWI but not on FLAIR. The relative signal intensity of FLAIR-positive lesions and the degree of DWI-FLAIR mismatch was calculated as relative FLAIR = relative signal intensity of FLAIR positive lesions, mismatch degree = (100-VFLAIR/VDWI) × 100%.RESULTS:The ischemic model was successfully established in all animals. FLAIR-positive lesions were seen in 3, 11, 16, 19, and 20 beagle dogs at 5 time points after embolization, respectively. There was significant correlation between the relative FLAIR, degree of DWI-FLAIR mismatch, and the onset time (relative FLAIR: r = +0.42; 95% CI, 0.20-0.60; mismatch degree: r = -0.85; 95% CI, 0.89-0.78). Receiver operating characteristic curves showed that the degree of DWI-FLAIR mismatch could identify the hyperacute ischemic lesions with a sensitivity range from 1.00-0.76; visual DWI-FLAIR mismatch sensitivity ranged from 0.85-0.39, whereas specificity was 0.83-0.95 versus 0.85-1.00.CONCLUSIONS:The relative FLAIR and DWI-FLAIR mismatch values were useful in predicting the onset time in our canine embolic stroke model. The degree of DWI-FLAIR mismatch proposed in our study could be a good indicator with high sensitivity for identifying the hyperacute ischemic stroke. 23482984 Chirality sensing using stereodynamic probes with distinct electronic circular dichroism output. Circular dichroism (CD) spectroscopy is one of the most useful techniques for the stereochemical analysis of chiral biopolymers and fine chemicals. It has become invaluable for the assignment of the absolute configuration, the study of conformational isomers, and the determination of racemization kinetics of CD active chiral compounds. Molecular interactions between a nonracemic chiral substrate and a chromophoric, CD-silent probe that is achiral or exists as a racemic mixture of rapidly interconverting enantiomeric conformations or configurations can induce a strong, characteristic chiroptical readout. A covalent or noncovalent binding event that coincides with a well-defined asymmetric induction process can effectively imprint the chiral information of the substrate on the stereodynamic sensor and thus generate intense Cotton effects in the UV region of the latter. The probe can thus function as a stereochemical reporter unit and analysis of the CD spectrum often provides accurate information about the absolute configuration and enantiomeric composition of the substrate used. In this review, recent developments in circular dichroism analysis of chiral compounds with stereodynamic probes are described and particular emphasis is given to sensor design, chiral induction processes and applications scope. 23929636 Cervical pregnancy with massive bleeding after treatment with methotrexate. This report describes a catastrophic bleeding following methotrexate treatment of cervical pregnancy and dramatic response to Bakri surgical obstetric silicone (SOS) balloon tamponade in controlling massive bleeding. A 42-year-old woman was diagnosed for cervical pregnancy with a viable fetus at 12 weeks by transvaginal ultrasound. Conservative treatment with intrafetal potassium chloride injection and systemic methotrexate were instituted. On the sixth day of therapy, catastrophic bleeding lead to hypovolemic shock. After resuscitation and blood transfusion, we attempt to control the bleeding with evacuation and curettage but was unsuccessful. Bakri SOS balloon tamponade was applied with immediate and effective response. Nevertheless, total abdominal hysterectomy was performed. In conclusion, conservative treatment of cervical pregnancy with systemic methotrexate could be catastrophic in some patients. Control of active bleeding with Bakri SOS balloon tamponade may possibly be helpful in case of uncontrolled bleeding in selected cases. 23861782 Prostate Health Index (Phi) and Prostate Cancer Antigen 3 (PCA3) Significantly Improve Prostate Cancer Detection at Initial Biopsy in a Total PSA Range of 2-10 ng/ml. Many efforts to reduce prostate specific antigen (PSA) overdiagnosis and overtreatment have been made. To this aim, Prostate Health Index (Phi) and Prostate Cancer Antigen 3 (PCA3) have been proposed as new more specific biomarkers. We evaluated the ability of phi and PCA3 to identify prostate cancer (PCa) at initial prostate biopsy in men with total PSA range of 2-10 ng/ml. The performance of phi and PCA3 were evaluated in 300 patients undergoing first prostate biopsy. ROC curve analyses tested the accuracy (AUC) of phi and PCA3 in predicting PCa. Decision curve analyses (DCA) were used to compare the clinical benefit of the two biomarkers. We found that the AUC value of phi (0.77) was comparable to those of %p2PSA (0.76) and PCA3 (0.73) with no significant differences in pairwise comparison (%p2PSA vs phi p = 0.673, %p2PSA vs. PCA3 p = 0.417 and phi vs. PCA3 p = 0.247). These three biomarkers significantly outperformed fPSA (AUC = 0.60), % fPSA (AUC = 0.62) and p2PSA (AUC = 0.63). At DCA, phi and PCA3 exhibited a very close net benefit profile until the threshold probability of 25%, then phi index showed higher net benefit than PCA3. Multivariable analysis showed that the addition of phi and PCA3 to the base multivariable model (age, PSA, %fPSA, DRE, prostate volume) increased predictive accuracy, whereas no model improved single biomarker performance. Finally we showed that subjects with active surveillance (AS) compatible cancer had significantly lower phi and PCA3 values (p<0.001 and p = 0.01, respectively). In conclusion, both phi and PCA3 comparably increase the accuracy in predicting the presence of PCa in total PSA range 2-10 ng/ml at initial biopsy, outperforming currently used %fPSA. 23958902 Non-vascular drug eluting stents as localized controlled drug delivery platform: Preclinical and clinical experience. Stents occupy an important place in the medical field for their widespread application. They have been used in vascular as well as in non-vascular organs for various reasons. Among vascular stents, development of coronary drug eluting stents (DESs) has completely revolutionised the percutaneous coronary intervention. Similarly, attempts have been made to make use of this modality in non-vascular organs. This paper focuses on the preclinical and clinical experience with drug-eluting non-vascular stents with emphasis on drug delivery systems and regulatory requirements for their development. 23933241 Synthesis and characterization of novel fluorogenic substrates of coagulation factor XIII-A. Further development of our recently published Glu(pNA)-containing peptides (Anal. Biochem. 428 (2012) 73-80) provided new fluorogenic substrates for the activated blood coagulation factor XIII. A first series was designed by incorporation of Glu(AMC) at the penultimate position from the N-terminus. For the best derivative H-Tyr-Glu(AMC)-Val-Lys-Val-Ile-NH2 a moderate kcat/Km value of 34 s(-1)M(-1) was determined, which is more than 100-fold reduced compared to the previously reported Glu(pNA) substrates. Furthermore, two FRET substrates were prepared by incorporation of an N-methyl-anthraniloyl fluorophore and a 2,4-dinitrophenyl quencher. Both substrates were excellently cleaved by FXIII-A2∗, which is generated from its zymogen by activation of thrombin in presence of calcium ions. In absence and presence of H-Gly-ethyl ester kcat/Km values of 8010 and 8660 s(-1)M(-1) were found for the conversion of H-Lys(N(Me)Abz)-Glu(NH-(CH2)4-NH-Dnp)-Val-Lys-Val-Ile-NH2 (substrate 8), respectively. These values are more than 200-fold improved compared to the Glu(AMC) substrates. Substrate 8 is suitable for the measurement of FXIII-A2∗ activities in plasma samples as well as for in vitro measurements. Furthermore, it was used for the determination of the inhibitory potency of a newly synthesized chloromethyl ketone derivative Cbz-Phe-Glu(CMK)-Val-Lys-Val-Ile-Gly-NH2, which was found to be a potent irreversible inhibitor of FXIII-A2∗. 21805615 Differential 1-year clinical outcomes for ST-segment elevation myocardial infarction related to stent thrombosis or saphenous vein graft thrombosis. Aim: Thrombosis of stents and of saphenous vein grafts (SVG) remains a severe complication of either revascularization techniques that often are present as ST elevation myocardial infarction (STEMI). The aim of this longitudinal cohort study was to compare the 1-year clinical outcomes among STEMI patients requiring primary PCI due to stent thrombosis and graft occlusion presenting with STEMI. Methods and Results: We prospectively collected data on all patients undergoing primary PCI at the Montreal Heart Institute between April 1, 2007 and March 30, 2008. Study patients were grouped according to the etiology of the STEMI: stent thrombosis, graft thrombosis, or atherosclerosis-related STEMIs (control group). The primary combined end-point, major adverse cardiac events (MACE), was defined as death, myocardial infarction, and target vessel revascularization within 12 months as primary end point. Of the 489 STEMI patients included in the study, 23 were due to stent thrombosis, 22 to graft thrombosis, and 444 in the control group. Stent and graft thromboses were associated with a higher MACE rates, 26.1 and 22.7%, respectively, compared to the control group, 9.3% (P = 0.004). Moreover, only stent thrombosis was associated with an increased risk of MACE (HR 2.57, confidence interval 95% 1.08-6.08. Conclusion: Patients with stent thrombosis present with higher rate of reinfarction while graft thrombosis is associated with an increase in 1-year cardiac mortality. Using multivariate analysis, higher MACE rates were associated with stent thrombosis as compared to graft thrombosis. © 2013 Wiley Periodicals, Inc. 23857328 Potential role of oxidative stress on the prescription of rehabilitation interventions in spinal cord injury. Study design:Review article.Objectives:To provide an overview of free radical biology, particularly with respect to muscle physiology, as well as the potential effects of muscle morphological changes, physical capacity and nutritional status on oxidative stress in people with chronic spinal cord injury (SCI). The potential implications of these factors for determining the optimal dosage of rehabilitation training interventions in people with chronic SCI will also be presented.Setting:Vancouver, BC, Canada.Methods:Literature review.Results:Not applicable.Conclusion:There has been a great deal of focus on rehabilitation exercise interventions providing intensive practice of movements to enhance functional recovery and physical capacity following SCI. However, there is still much to be understood about the appropriate dosage of training parameters (e.g. frequency, duration). It has been known for several decades that exercise increases free radical production, leading to oxidative stress. To date, there has been little consideration of the potential interaction of oxidative stress with training parameters on functional outcomes in chronic SCI. Furthermore, individuals with chronic SCI face many secondary consequences of their injury, such as muscle atrophy, change in muscle fiber type, general deconditioning and nutritional status, that are known to influence free radical production and antioxidant capacity. Better understanding of the potential confounding effects of oxidative stress associated with exercise will improve our ability to determine the optimal 'dose' of rehabilitation training to maximize functional recovery following SCI.Spinal Cord advance online publication, 16 July 2013; doi:10.1038/sc.2013.71. 23817982 Insulinoma-released exosomes activate autoreactive marginal zone-like B cells that expand endogenously in prediabetic NOD mice. Exosomes (EXOs) are nano-sized secreted microvesicles that can function as potent endogenous carriers of adjuvant and antigens. To examine a possible role in autoimmunity for EXOs, we studied EXO-induced immune responses in nonobese diabetic (NOD) mice, an autoimmune-prone strain with tissue-specific targeting at insulin-secreting beta cells. EXOs released by insulinoma cells can activate various antigen-presenting cells to secrete several proinflammatory cytokines and chemokines. A subset of B cells responded to EXO stimulation in culture by proliferation, and expressed surface markers representing marginal zone B cells, which was independent of T helper cells. Importantly, splenic B cells from prediabetic NOD mice, but not diabetic-resistant mice, exhibited increased reactivity to EXOs, which was correlated with a high level of serum EXOs. We found that MyD88-mediated innate TLR signals were essential for the B-cell response; transgenic B cells expressing surface immunoglobulin specific for insulin reacted to EXO stimulation, and addition of a calcineurin inhibitor FK506 abrogated the EXO-induced B-cell response, suggesting that both innate and antigen-specific signals may be involved. Thus, EXOs may contribute to the development of autoimmunity and type 1 diabetes in NOD mice, partially via activating autoreactive marginal zone-like B cells. 23950755 Administration of neuropsychological tests using interactive voice response technology in the elderly: validation and limitations. Interactive voice response (IVR) systems are computer programs, which interact with people to provide a number of services from business to health care. We examined the ability of an IVR system to administer and score a verbal fluency task (fruits) and the digit span forward and backward in 158 community dwelling people aged between 65 and 92 years of age (full scale IQ of 68-134). Only six participants could not complete all tasks mostly due to early technical problems in the study. Participants were also administered the Wechsler Intelligence Scale fourth edition (WAIS-IV) and Wechsler Memory Scale fourth edition subtests. The IVR system correctly recognized 90% of the fruits in the verbal fluency task and 93-95% of the number sequences in the digit span. The IVR system typically underestimated the performance of participants because of voice recognition errors. In the digit span, these errors led to the erroneous discontinuation of the test: however the correlation between IVR scoring and clinical scoring was still high (93-95%). The correlation between the IVR verbal fluency and the WAIS-IV Similarities subtest was 0.31. The correlation between the IVR digit span forward and backward and the in-person administration was 0.46. We discuss how valid and useful IVR systems are for neuropsychological testing in the elderly. 23210853 Metabolomics analysis for biomarker discovery: advances and challenges. Over the last decades there has been a change in biomedical research with the search for single genes, transcripts, proteins, or metabolites being substituted by the coverage of the entire genome, transcriptome, proteome, and metabolome with the "omics" approaches. The emergence of metabolomics, defined as the comprehensive analysis of all metabolites in a system, is still recent compared to other "omics" fields, but its particular features and the improvement of both analytical techniques and pattern recognition methods has contributed greatly to its increasingly use. The feasibility of metabolomics for biomarker discovery is supported by the assumption that metabolites are important players in biological systems and that diseases cause disruption of biochemical pathways, which are not new concepts. In fact, metabolomics, meaning the parallel assessment of multiple metabolites, has been shown to have benefits in various clinical areas. Compared to classical diagnostic approaches and conventional clinical biomarkers, metabolomics offers potential advantages in sensitivity and specificity. Despite its potential, metabolomics still retains several intrinsic limitations which have a great impact on its widespread implementation - these limitations in biological and experimental measurements. This review will provide an insight to the characteristics, strengths, limitations, and recent advances in metabolomics, always keeping in mind its potential application in clinical/ health areas as a biomarker discovery tool. 23713061 Disruption of the L-arabitol dehydrogenase encoding gene in Aspergillus tubingensis results in increased xylanase production. Fungal xylanases are of major importance to many industrial sectors, such as food and feed, paper and pulp, and biofuels. Improving their production is therefore highly relevant. We determined the molecular basis of an improved xylanase-producing strain of Aspergillus tubingensis that was generated by UV mutagenesis in an industrial strain improvement program. Using enzyme assays, gene expression, sequencing of the ladA locus in the parent and mutant, and complementation of the mutation, we were able to show that improved xylanase production was mainly caused by a chromosomal translocation that occurred between a subtilisin-like protease pepD gene and the L-arabitol dehydrogenase encoding gene (ladA), which is part of the L-arabinose catabolic pathway. This genomic rearrangement resulted in disruption of both genes and, as a consequence, the inability of the mutant to use L-arabinose as a carbon source, while growth on D-xylose was unaffected. Complementation with constitutively expressed ladA confirmed that the xylanase overproducing phenotype was mainly caused by loss of ladA function, while a knockout of xlnR in the UV mutant demonstrated that improved xylanase production was mediated by XlnR. This study demonstrates the potential of metabolic manipulation for increased production of fungal enzymes. 23689543 Design and validation of a multi-electrode bioimpedance system for enhancing spatial resolution of cellular impedance studies. This paper reports the design and evaluation of a multi-electrode design that improves upon the statistical significance and spatial resolution of cellular impedance data measured using commercial electric cell-substrate impedance sensing (ECIS) systems. By evaluating cellular impedance using eight independent sensing electrodes, position-dependent impedance measurements can be recorded across the device and compare commonly used equivalent circuit and mathematical models for extraction of cell parameters. Data from the 8-electrode device was compared to data taken from commercial electric cell-substrate impedance sensing (ECIS) system by deriving a relationship between equivalent circuit and mathematically modelled parameters. The impedance systems were evaluated and compared by investigating the effects of arsenic trioxide (As2O3), a well-established chemotherapeutic agent, on ovarian cancer cells. Impedance spectroscopy, a non-destructive, label-free technique, was used to continuously measure the frequency-dependent cellular properties, without adversely affecting the cells. The importance of multiple measurements within a cell culture was demonstrated; and the data illustrated that the non-uniform response of cells within a culture required redundant measurements in order to obtain statistically significant data, especially for drug discovery applications. Also, a correlation between equivalent circuit modelling and mathematically modelled parameters was derived, allowing data to be compared across different modelling techniques. 23892222 Transferable self-welding silver nanowire network as high performance transparent flexible electrode. High performance transparent electrodes (TEs) with figures-of-merit as high as 471 were assembled using ultralong silver nanowires (Ag NWs). A room-temperature plasma was employed to enhance the conductivity of the Ag NW TEs by simultaneously removing the insulating PVP layer coating on the NWs and welding the junctions tightly. Furthermore, we developed a general way to fabricate TEs regardless of substrate limitations by transferring the as-fabricated Ag NW network onto various substrates directly, and the transmittance can remain as high as 91% with a sheet resistivity of 13 Î©/sq. The highly robust and stable flexible TEs will have broad applications in flexible optoelectronic and electronic devices. 23911406 Fish lily type lectin-1 contains β-prism architecture: Immunological characterization. In this study we report a full-length lily type lectin-1 (CsLTL-1) identified from striped murrel, Channa striatus. CsLTL-1 was identified from the established C. striatus cDNA library using GS-FLX™ genome sequencing technology and was found to contain 354 nucleotide base pairs and its open reading frame (ORF) encodes a 118 amino acid residue. CsLTL-1 mRNA is predominately expressed in the gills and is up-regulated upon infection with fungus (Aphanomyces invadans) and bacteria (Aeromonas hydrophila). Hemagglutination studies with recombinant CsLTL-1 show that, at 4μg/ml agglutinates occurs in a calcium independent manner and is inhibited in the presence of d-mannose (50mM) and d-glucose (100mM). The CsLTL-1 sequence was completely characterized using various bioinformatics tools. CsLTL-1 peptide contains a mannose binding site at 30-99 along with its specific motif of β-prism architecture. The phylogenetic analysis showed that CsLTL-1 clustered together with LTL-1 from Oplegnathus fasciatus. CsLTL-1 protein 3D structure was predicted by I-Tasser program and the model was evaluated using Ramachanran plot analysis. The secondary structure analysis of CsLTL-1 reveals that the protein contains 23% β-sheets and 77% coils. The overall results showed that CsLTL-1 is an important immune gene involved in the recognition and elimination of pathogens in murrels. 23927401 Analysis of the transcriptome of the Indonesian coelacanth Latimeria menadoensis. Latimeria menadoensis is a coelacanth species first identified in 1997 in Indonesia, at 10,000 Km of distance from its African congener. To date, only six specimens have been caught and just a very limited molecular data is available. In the present work we describe the de novo transcriptome assembly obtained from liver and testis samples collected from the fifth specimen ever caught of this species. The deep RNA sequencing performed with Illumina technologies generated 145,435,156 paired-end reads, accounting for ~14 GB of sequence data, which were de novo assembled using a Trinity/CLC combined strategy. The assembly output was processed and filtered producing a set of 66,308 contigs, whose quality was thoroughly assessed. The comparison with the recently sequenced genome of the African congener Latimeria chalumnae and with the available genomic resources of other vertebrates revealed a good reconstruction of full length transcripts and a high coverage of the predicted full coelacanth transcriptome.The RNA-seq analysis revealed remarkable differences in the expression profiles between the two tissues, allowing the identification of liver- and testis-specific transcripts which may play a fundamental role in important biological processes carried out by these two organs. Given the high genomic affinity between the two coelacanth species, the here described de novo transcriptome assembly can be considered a valuable support tool for the improvement of gene prediction within the genome of L. chalumnae and a valuable resource for investigation of many aspects of tetrapod evolution. 23603466 Genoprotective effects of lignin isolated from oil palm black liquor waste. Black liquor waste (BLW), a major by-product of palm oil extraction process contains lignin as one of the constituents. Lignin isolated from BLW was evaluated for antioxidant and genoprotective properties and was compared with the commercial lignin for overall efficacy. Antioxidant compounds (phenolics and tannins) and antioxidant activities (phosphomolybdenum assay, ABTS(+) and FRAP assays) of lignin isolated from BLW were compared with commercial lignin. Bone marrow micronucleus (MN) test was employed for evaluating the dose-yield protective effect against cyclophosphamide (CP, 50mg/kg b.w.) induced genotoxicity in mouse. Results revealed isolated lignin to exhibit rich antioxidant activities. A decrease in MN frequency and recovery of P/N ratio (P: polychromatic erythrocytes, N: normochromatic erhythocytes) indicated protective effects of lignin against cyclophosphamide induced genotoxicity and cytotoxicity. The efficacy of BLW-derived lignin as an antioxidant and genoprotective agent was comparable to commercial lignin. Results on lignin isolated from BLW are envisaged to find potential applications in food and/or pharmaceutical industries. 23835068 The distribution and stratification of persistent organic pollutants and fatty acids in bottlenose dolphin (Tursiops truncatus) blubber. Blubber has been used for decades to monitor exposure of marine mammals to persistent organic pollutants (POPs). However, little is known about POP variability as a function of blubber depth and across the body of the animal. Remote blubber biopsy sampling (e.g, projectile biopsy) is the most common technique used to acquire samples from free-swimming animals, yet such techniques may result in variable sampling. It is important to understand whether blubber stratification or body location affects POP concentration or the concentration of other important blubber constituents such as fatty acids (FA). To investigate the influence of sampling depth and location on POP concentration, full depth blubber samples were taken from one stranded bottlenose dolphin (Tursiops truncatus) at six different body sites to assess variation in FA distribution and contaminant storage with body location. Three of the samples from different body locations were separated into histologically distinct layers to examine the effect of blubber depth and body location on POPs and FAs. In this individual, both POPs and FAs were heterogeneous with blubber depth and body location. POP concentrations were significantly greater in ventral (average ΣPBDEs 1350ng/g lipid) and anterior (average ΣPCBs 28700ng/g lipid) body locations and greater in the superficial blubber layer (average ΣPCBs 35500ng/g lipid) when compared to the deep (8390ng/g lipid) and middle (23,700ng/g lipid) layers. Proportionally more dietary FAs were found in dorsal blubber and in middle and deep layers relative to other locations while the reverse was true for biosynthesized FAs. Stratification was further examined in blubber from the same body location in five additional stranded bottlenose dolphins. Although FAs were stratified with blubber depth, lipid-normalized POPs were not significantly different with depth, indicating that POP concentrations can vary in an individual with blubber depth though the direction of POP stratification is not consistent among individuals. 23403332 Comparison of short- and mid-term follow-up between standard and fenestrated endografts. This study compared early and mid-term results of endovascular treatment for abdominal aortic aneurysms (AAAs) and pararenal aneurysms (PRAs). Using data from a prospective database, patients treated with endografts for AAA and PRA between January 2007 and December 2009 were analyzed. In both groups, mortality, endoleak rates, evolution of renal function, reintervention rate at 30 days and at mid-term follow-up, and aneurysmal sac evolution at 1 year were compared. In total, 379 patients were included: 264 treated for AAA and 115 for PRA. Median follow-up was 24 months (range 12-46 months) in both groups. Risk factors and medical history were comparable in both groups, except for chronic renal failure (higher in the PRA group; P = 0.003). The mortality rates at 30 days were 1% and 3% in the AAA and APR groups, respectively (P = 0.10). During follow-up, the mortality rates were 11.1% and 12.8% in the AAA and PRA groups, respectively (P = 0.72). The reoperation rates at 30 days were 8% and 10% in the AAA and PRA groups, respectively (P = 0.72). During follow-up, the reoperation rates were 9.2% and 9.9% in the AAA and PRA groups, respectively (P = 0.85). At 1 year, retraction of the aneurysmal sac was diagnosed in 48% of the patients in the AAA group and in 56% of the patients in the PRA group (P = 0.41). The incidence rates of new postoperative cases of renal insufficiency were 19.3% and 8.1% in the AAA and PRA groups, respectively (P = 0.008). At 30 days, the endoleak rates were 27.5% and 12.7% in the AAA and PRA groups, respectively (P = 0.001). At 1 year, the endoleak rates were 19.4% and 7.3% in the AAA and PRA groups, respectively (P = 0.007). When type II endoleaks were excluded, the endoleak rates were comparable in both groups (P = 0.5). At 1 year, in both groups, a retraction of the aneurysmal sac was significantly correlated to the absence of endoleak (P = 0.001). Early and mid-term results of AAA treatment with standard endografts and PRA treatment with fenestrated endografts are comparable. 23500774 Anti-fibrotic effects of puerarin on CCl4-induced hepatic fibrosis in rats possibly through the regulation of PPAR-γ expression and inhibition of PI3K/Akt pathway. Hepatic fibrosis (HF) is a chronic disease, which primarily leads to liver unregulated metabolism. In this study, we aimed to investigate the therapeutic effects of puerarin (PR), an active ingredient from kudzu root, on CCl4-induced HF rats. PR effectively ameliorated the liver metabolic function, resulting in reduced serum enzymatic activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total-bilirubin (T-bilirubin), extracellular matrix (ECM) contents and increased levels of albumin, total-protein (T-protein) in HF rats. Similarly, pathological examination showed that the CCl4-lesioned liver was mitigated by PR treatments. Meanwhile, we also detected significantly reduced levels of hydroxyproline (Hyp), type III precollagen (PCIII) and collagen I (Col I) in the liver tissue of HF rats, whereas the peroxisome proliferator-activated receptor-gamma (PPAR-γ) expression was effectively increased. Moreover, the expression of tissue inhibitor of metal protease-1 (TIMP-1) was decreased, while the expression of matrix metalloproteinase-2 (MMP-2) was increased. In addition, the expression of p-PI3K and p-Akt was significantly down-regulated by PR treatments. Taken together, PR could attenuate the CCl4-induced toxicity in the hepatocytes of HF rats. It played a protective role in the liver tissue probably through regulating the PPAR-γ expression and blocking the PI3K/Akt pathway to inhibit the excessive deposition of collagen. 23828756 Role of the postnatal radial glial scaffold for the development of the dentate gyrus as revealed by reelin signaling mutant mice. During dentate gyrus development, the early embryonic radial glial scaffold is replaced by a secondary glial scaffold around birth. In contrast to neocortical and early dentate gyrus radial glial cells, these postnatal glial cells are severely altered with regard to position and morphology in reeler mice lacking the secreted protein Reelin. In this study, we focus on the functional impact of these defects. Most radial glial cells throughout the nervous system serve as scaffolds for migrating neurons and precursor cells for both neurogenesis and gliogenesis. Precursor cell function has been demonstrated for secondary radial glial cells but the exact function of these late glial cells in granule cell migration and positioning is not clear. No data exist concerning the interplay between granule neurons and late radial glial cells during dentate gyrus development. Herein, we show that despite the severe morphological defects in the reeler dentate gyrus, the precursor function of secondary radial glial cells is not impaired during development in reeler mice. In addition, selective ablation of Disabled-1, an intracellular adaptor protein essential for Reelin signaling, in neurons but not in glial cells allowed us to distinguish effects of Reelin signaling on radial glial cells from possible secondary effects based on defective granule cells positioning. GLIA 2013;61:1347-1363. 23742884 Guidelines for the Diagnosis and Treatment of Idiopathic Pulmonary Fibrosis. Idiopathic pulmonary fibrosis is defined as a chronic fibrosing interstitial pneumonia limited to the lung, of unknown cause, with poor prognosis and few treatment options. In recent years there has been an increase in their prevalence, probably due to the optimization of diagnostic methods and increased life expectancy. The ATS/ERS Consensus (2000) established the diagnostic criteria and recommendations for the assessment of the disease course and treatment. Later studies have helped to redefine diagnostic criteria and treatment options. In 2011, an international consensus was published, establishing diagnostic criteria and new treatment strategies. These guidelines have been updated with the newest aspects of diagnosis and treatment of idiopathic pulmonary fibrosis. A level of evidence has been identified for the most relevant questions, particularly with regard to treatment options. 23832056 Effect of particle size of drinking-water treatment residuals on the sorption of arsenic in the presence of competing ions. Arsenite [As(III)] and arsenate [As(V)] sorption by Fe- and Al-based drinking-water treatment residuals (WTR) was studied as a function of particle size at different pHs, and in the presence of competing ligands, namely, phosphate, citrate, and oxalate. Both WTRs showed high affinity for As oxyanions. However, Al-WTR showed higher As(III) and As(V) sorption capacity than Fe-WTR because of their greater surface area. The effect of particle size on As sorption was pronounced on Fe-WTR, where the smaller fraction sorbed more As(III) and As(V) than the larger fractions, whereas relatively minor effects of particle size on As sorption was observed for Al-WTR. Arsenite sorption on both WTRs increased with increasing pH up to circum-neutral pHs and then decreased at higher pHs, whereas As(V) sorption decreased steadily with increasing pH. The capacity of competing ligands to inhibit sorption was greater for As(III) than As(V) on both WTRs (particularly on Al-WTR) following the sequence: oxalate3 previous episodes (n=1697) or ≤3 previous episodes (n=3930), and additionally for no previous episodes (n=1381) or at least one previous episode (n=4246). Analyses were conducted by study arm for each clinical trial, and results were then pooled. There was no significant difference between treatment response and number of previous depressive episodes. This unexpected finding suggests that treatments to reduce symptoms of depression during acute illness do not lose efficacy for patients with a longer history of illness. 23876235 Global characterization of signalling networks associated with tamoxifen resistance in breast cancer. Acquired resistance to the anti-estrogen tamoxifen remains a significant challenge in breast cancer management. In this study, we used an integrative approach to characterize global protein expression and tyrosine phosphorylation events in tamoxifen-resistant MCF7 breast cancer cells (TamR) compared with parental controls. Quantitative mass spectrometry and computational approaches were combined to identify perturbed signalling networks, and candidate regulatory proteins were functionally interrogated by siRNA-mediated knockdown. Network analysis revealed that cellular metabolism was perturbed in TamR cells, together with pathways enriched for proteins associated with growth factor, cell-cell and cell matrix-initiated signalling. Consistent with known roles for Ras/MAPK and PI3-kinase signalling in tamoxifen resistance, tyrosine-phosphorylated MAPK1, SHC1 and PIK3R2 were elevated in TamR cells. Phosphorylation of the tyrosine kinase Yes and expression of the actin-binding protein myristoylated alanine-rich C-kinase substrate (MARCKS) were increased two- and eightfold in TamR cells respectively, and these proteins were selected for further analysis. Knockdown of either protein in TamR cells had no effect on anti-estrogen sensitivity, but significantly decreased cell motility. MARCKS expression was significantly higher in breast cancer cell lines than normal mammary epithelial cells and in ER-negative versus ER-positive breast cancer cell lines. In primary breast cancers, cytoplasmic MARCKS staining was significantly higher in basal-like and HER2 cancers than in luminal cancers, and was independently predictive of poor survival in multivariate analyses of the whole cohort (P < 0.0001) and in ER-positive patients (P = 0.0005). These findings provide network-level insights into the molecular alterations associated with the tamoxifen-resistant phenotype, and identify MARCKS as a potential biomarker of therapeutic responsiveness that may assist in stratification of patients for optimal therapy. 23937980 Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility. Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants. 23908567 Comparison of Pain-relieving Effects of Fentanyl versus Ketorolac after Eye Amputation Surgery. To investigate the analgesic effect and incidence of postoperative nausea and vomiting (PONV) between the opioid fentanyl and the non-steroidal anti-inflammatory drug ketorolac in patients who underwent eye amputation surgery. Retrospective observational case series. Eighty-two patients underwent evisceration or enucleation surgery by one surgeon over a 2-year period. Fentanyl by intravenous patient-controlled analgesia (IV-PCA) at 20 µg/kg with 12 mg/kg ondansetron or intravenous ketorolac at 2 mg/kg/day was administered to patients at postoperative days 0, 1, and 2. The pain score was measured using an 11-point visual analog scale (VAS). The incidence of severe nausea requiring anti-emetics and the incidence of vomiting were reviewed. The mean postoperative VAS in the fentanyl group was significantly lower than that in the ketorolac group on the day of operation for both types of surgery (p = 0.001 and p = 0.004, respectively). At postoperative days 1 and 2, the mean VAS was not different between the two groups for either surgical type (p > 0.05 for both days). The mean VAS was significantly higher in eviscerated patients than in enucleated patients at postoperative days 0 and 1 in the fentanyl group (p = 0.023 and p = 0.016, respectively). However, this was not observed in the ketorolac group. The incidence of PONV was higher in the fentanyl group than in the ketorolac group, although this was not statistically significant for either surgical type (p > 0.05 for both groups). Fentanyl was more effective as an analgesic than was ketorolac on the day of operation for both surgical types. There was no difference between the two analgesics on postoperative day 1. The analgesic effect of fentanyl in enucleated patients was significantly higher than in eviscerated patients at postoperative days 0 and 1. The use of fentanyl by IV-PCA was associated with greater PONV despite co-administration with anti-emetics, although this finding was not significant. 23933964 Lung perfusion and ventilation during implantation of left ventricular assist device as a strategy to avoid postoperative pulmonary complications and right ventricular failure. Right ventricular failure is a major contributor to increased morbidity and mortality in patients undergoing left ventricular assist device implantation. Cardiopulmonary bypass is associated with increased pulmonary ischaemia and pulmonary vascular resistance. Continuous pulmonary perfusion and ventilation represents an emerging strategy for pulmonary protection during cardiac surgery. We hypothesize that this technique may have a pivotal role in reducing postoperative right ventricular dysfunction in high-risk patients undergoing LVAD placement. 23868212 Phytal: A Candidate Sex Pheromone Component of the Moroccan Locust Dociostaurus maroccanus. Outbreaks of locusts cause enormous economic losses to agriculture in many countries. To develop environmentally friendly strategies for their control, much research has been focused on the factors that influence locust biology, particularly infochemical-mediated interactions. We present herein the identification and synthesis of both Z and E isomers of phytal (3,7,11,15-tetramethylhexadec-2-enal, 1), which are involved in chemical communication and behaviour of the Moroccan locust, Dociostaurus maroccanus, a serious agricultural pest. The compound was identified by comparison of its chromatographic and spectrometric features and microchemical reactions with those of a synthetic sample. The natural compound was shown to have the R,R configuration by chiral HPLC analysis, and its structure is unique as an insect pheromone component. Both isomers of phytal are produced by sexually mature adult males and elicit electroantennographic responses in antennae of both sexes. In two-choice olfactometer bioassays, males and females significantly preferred the stream enriched with racemic phytal to the control. In contrast, hydrogenated phytal was behaviourally inert. Both isomers of phytal are specific to D. maroccanus as they are absent in the closely related, habitat-sharing species Dociostaurus jagoi and Calliptamus wattenwylianus. Legs and wings are the main release sites of the compound: approximately 90 % of that emitted by living individuals. In biosynthetic studies, phytal appears to proceed from oxidation of phytol (2) after injection of deuterated phytol into the abdomen of the insect or after administration in the diet. Our results demonstrate that phytal is a candidate sex pheromone component of the Moroccan locust; it is produced by mature males, and might be eavesdropped upon by conspecific males. 22975713 Usefulness of the RISK-PCI score to predict stent thrombosis in patients treated with primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: a substudy of the RISK-PCI trial. Stent thrombosis (ST) is an important cause of death after primary percutaneous coronary intervention (pPCI). This substudy aimed at evaluating the usefulness of the RISK-PCI score, originally developed for the prediction of 30-day major adverse cardiovascular events, to predict the occurrence of ST after pPCI. We analyzed 1972 consecutive patients who underwent pPCI with stent implantation between February 2007 and December 2009. Early ST (EST), late ST (LST), and cumulative 1-year ST (CST) were the predefined end points. Definite, probable, and possible ST were included. Models discrimination and calibration to predict ST was tested using receiver-operating characteristics curves and the goodness-of-fit (GoF) test. Sensitivity analyses and 1000-resample bootstrapping were used to evaluate the model's performance. The rates of EST, LST, and CST were 4.6, 1.4, and 6.0 %, respectively. Compared with controls, the cumulative ST group was associated with much higher rates of adverse clinical outcomes at 30-day follow-up (adjusted odds ratio (OR) for death 6.45, adjusted OR for major bleeding 4.41) and at 12-month follow-up (adjusted OR for death 7.35, adjusted OR for major bleeding 4.56). Internal validation confirmed a reasonably good discrimination and calibration of the RISK-PCI score for the prediction of EST (area under the curve (AUC) 0.71, GoF 0.42), LST (AUC 0.69, GoF 0.36), and CST (AUC 0.70, GoF 0.22) after pPCI. ST after pPCI is associated with adverse 30-day and 1-year clinical outcomes. We conclude that the risk of ST could be accurately assessed using the RISK-PCI score, which might help in deciding upon measures aimed at preventing adverse prognosis. 23710587 The safety of postoperative hormone replacement therapy in epithelial ovarian cancer patients in China. Objective This study sought to determine whether postoperative hormone replacement therapy (HRT) has a negative influence on the progression-free and overall survival of epithelial ovarian carcinoma patients. Methods A retrospective chart review identified 77 patients with invasive epithelial ovarian cancer who had received HRT after primary surgical treatment from January 1995 to December 2010 at Peking Union Medical College Hospital. A 1 : 1 cohort of patients with the same diagnosis who did not receive HRT were matched by age and stage. An analysis of both progression-free survival and overall survival was performed using Cox proportional hazards models. Results According to the univariate analysis, HRT did not significantly influence progression-free or overall survival. Similarly, different types of HRT (estrogen alone, tibolone alone or an estrogen-tibolone combination) had no significant effect on the prognosis of epithelial ovarian cancer patients. The FIGO stage, differentiation, histological type and resection status were significantly correlated with progression-free survival and, except for histological type, these factors also significantly influenced overall survival. Finally, the multivariate analysis demonstrated that the strongest independent variable in predicting both progression-free survival and overall survival was the FIGO stage of the disease. Conclusion This study supports the hypothesis that postoperative HRT does not have a negative effect on the progression-free and overall survival of epithelial ovarian cancer patients. However, a multicenter study is needed to support and extend our findings. 23722429 Feasibility of remote magnetic navigation for epicardial ablation. Percutaneous epicardial mapping and ablation is an emerging method to treat ventricular tachycardias (VT), premature ventricular complexes (PVC), and accessory pathways. The use of a remote magnetic navigation system (MNS) could enhance precision and maintain safety. This multiple case history demonstrates the feasibility and safety of the MNS-guided epicardial approach in mapping and ablation of ischaemic VT, outflow tract PVCs, and a left-sided accessory pathway. All patients had previously undergone endocardial mapping for the same arrhythmia. MNS could present an advantage from more precise navigation for mapping and maintaining catheter stability during energy application. 23860507 Three frameworks to predict physical activity behavior in middle school inclusive physical education: a multilevel analysis. The purpose of this study was to examine three frameworks, (a) process-product, (b) student mediation, and (c) classroom ecology, to understand physical activity (PA) behavior of adolescents with and without disabilities in middle school inclusive physical education (PE). A total of 13 physical educators teaching inclusive PE and their 503 students, including 22 students with different disabilities, participated in this study. A series of multilevel regression analyses indicated that physical educators' teaching behavior and students' implementation intentions play important roles in promoting the students' PA in middle school inclusive PE settings when gender, disability, lesson content, instructional model, and class location are considered simultaneously. The findings suggest that the ecological framework should be considered to effectively promote PA of adolescents with and without disabilities in middle school PE classes. 23930676 Genetic variation in the PPARA gene is associated with simvastatin-mediated cholesterol reduction in the Rotterdam Study. Aim: Recently, minor alleles of two strongly linked polymorphisms in the PPARA gene, rs4253728 G>A and rs4823613 A>G, were related to decreased CYP3A4 expression and activity. We studied whether they were associated with the cholesterol-lowering effect of simvastatin. Materials & methods: We identified 123 incident users with cholesterol measurements before and after starting statin therapy in a prospective population-based cohort study. Associations between PPARA polymorphisms and change in total and low-density lipoprotein (LDL)-cholesterol levels were analyzed using linear regression. Results: The minor G allele of the rs4823613 A>G polymorphism was associated with a 0.258 mmol/l (95% CI: -0.470 to -0.046) and a 0.294 mmol/l (95% CI: -0.495 to -0.093) larger reduction in total and LDL-cholesterol, respectively, after starting simvastatin therapy. Results were similar for the rs4253728 G>A polymorphism. Conclusion: The minor alleles of the PPARA rs4253728 and rs4823613 polymorphisms are associated with a better total and LDL-cholesterol-lowering response to simvastatin, possibly through influence on CYP3A4. Original submitted 13 February 2013; Revision submitted 8 May 2013. 23746391 Effects of antagonists of glutamate receptors on pro-inflammatory cytokines in the brain cortex of rats subjected to experimental autoimmune encephalomyelitis. Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Inflammatory cytokines and glutamate neurotoxicity have been proposed as major determinants accompanying the demyelination and axonal degeneration observed during the course of MS. The present study using the animal model of MS known as experimental autoimmune encephalomyelitis (EAE) demonstrates that pharmacological inhibition of ionotropic NMDA glutamate receptors by their antagonists (amantadine and memantine) suppresses neurological symptoms of disease in EAE rats and reduces expression of pro-inflammatory cytokines in the brain. Conversely, antagonists of group I metabotropic glutamate receptors, mGluRs (LY 367385 and MPEP), do not affect the inflammatory process and the neurological condition of EAE rats. 23899421 Open-Circuit Voltage Enhancement on the Basis of Polymer Gel Electrolyte for a Highly Stable Dye-Sensitized Solar Cell. Dye-sensitized solar cells (DSSC) have received considerable attention owing to their low preparation cost and easy fabrication process. However, one of the drawbacks that limits the further application of DSSC is their poor stability, arising from the leakage and volatilization of the liquid organic solvent in the electrolyte. Therefore, to improve the long-term stability of DSSC, polymer gel electrolyte was studied to replace the conventional liquid electrolyte in this work. The results show that compared to liquid electrolyte, DSSC with polymer gel electrolyte has a smaller short-circuit current (Jsc), which decreases with the increase of the polymer gelator. Nevertheless, with the employment of the polymer gel electrolyte, there is a significant enhancement of open-circuit voltage (Voc), and it increases with the increase of the polymer gelator content. The highest Voc, up to 0.873 V, can be obtained for DSSC with a 30% polymer gelator content. The impact of the polymer gel electrolyte on the photovoltaic performance of DSSC, especially on Voc, was studied by analyzing the charge-transfer kinetics in the polymer gel electrolyte. Furthermore, the influence of the polymer gel electrolyte on the long-term stability of DSSC was also investigated. 23932035 Assessment of the implementation of the model of integrated and humanised midwifery health services in Santiago, Chile. during 2007 the Chilean Ministry of Public Health introduced the Model of Integrated and Humanized Health Services, in addition to the Clinical Guide for Humanized Care during Delivery. Three years after its implementation, a study was conducted (i) to describe selected clinical outcomes of women who received care within this model, (ii) to identify the degree of maternal-newborn well-being and (iii) to explore the perception of this humanised attention during labour and delivery by both the professional staff (obstetricians and midwives) and consumers. a cross-sectional, descriptive study using both quantitative and qualitative methods was conducted with 508 women who delivered in two major hospitals within the National Health System in the metropolitan area of Santiago, Chile, from September 2010 until June 2011. The quantitative methods included a validated survey of maternal well-being and an adapted version of the American College of Nurse-Midwives (ACNM) standardised antepartum and intrapartum data set. The qualitative methods included six focus groups discussions (FGDs), with midwives, obstetricians and consumers. Additionally, two in depth interviews were carried out with the directors of the maternity units. the quantitative findings showed poor implementation of the guidelines: 92.7% of the women had medically induced labours (artificial rupture of the membranes and received oxytocin and epidural anaesthesia), and almost one-third of the women reported discontent with the care they received. The qualitative findings showed that the main complaint perceived by the midwives was that the health system was highly hierarchical and medicalised and that the obstetricians were not engaged in this modality of assistance. The women (consumers) highlighted that professionals (midwives and obstetricians) were highly technically skilled, and they felt confident in their assistance. However, women complained about receiving inadequate personal treatment from these professionals. The obstetricians showed no self-critique, stating that they always expressed concern for their patients and that they provided humanised professional assistance. by illuminating the main strengths and weakness with regard to the application of the model, these findings can help to inform strategies and actions to improve its implementation. 23928897 Safety of off-label erythropoiesis stimulating agents in critically ill patients: a meta-analysis. Erythropoiesis stimulating agents (ESAs) are used to treat anemia in critically ill patients. This indication is off-label, because it is not licensed by regulatory authorities. Recently ESAs were suspected to harm critically ill patients. Our objective was to assess the safety of ESAs in off-label indications in critically ill patients. Eleven databases were searched up to April 2012. We considered randomized controlled trials (RCTs) and controlled observational studies in any language that compared off-label ESAs treatment with other effective interventions, placebo or no treatment in critically ill patients. Two authors independently screened and evaluated retrieved records, extracted data and assessed risk of bias and quality of reporting. We used frequentist and Bayesian models to combine studies, and performed sensitivity and subgroup analyses. From 12,888 citations, we included 48 studies (34 RCTs; 14 observational), involving 944,856 participants. Harm reporting was of medium to low quality. There was no statistically significant increased risk of adverse events in general, serious adverse events, the most frequently reported adverse events, and death in critically ill patients treated with ESAs. These results were robust against risk of bias and analysis methods. There is evidence that ESAs increase the risk of clinically relevant thrombotic vascular events, and there is some less certain evidence that ESAs might increase the risk for venous thromboembolism. In critically ill patients, administration of ESAs is associated with a significant increase in clinically relevant thrombotic vascular events but not with other frequently reported adverse events and death. 23851932 GABA Protects Human Islet Cells Against the Deleterious Effects of Immunosuppressive Drugs and Exerts Immunoinhibitory Effects Alone. We recently found that γ-aminobutyric acid (GABA) protects mouse islet β cells. It prevented autoimmune type 1 diabetes in mice, induced islet β-cell regeneration, and exerted immunoinhibitory effects. However, it is not known whether GABA would be equally active on human islet and immune cells. In vitro culture of human islets and immune cells with or without GABA and immunosuppressive drugs. In vitro analysis of apoptosis, proliferation, nuclear factor (NF)-κB activation, calcium signaling, and insulin secretion. GABA reduced human islet cell apoptosis in culture, such that the yield of live cells was approximately tripled after 1 week, and it stimulated insulin secretion. It protected against the deleterious effects of rapamycin, tacrolimus, and mycophenolate mofetil. In human immune cells, GABA had inhibitory effects similar to mouse cells, such as suppressed anti-CD3-stimulated T-cell proliferation, in a GABA type A receptor-dependent fashion. The immunosuppressive mechanisms have been unclear, but we found that GABA blocked calcium influx, which is a key activation signal. GABA also suppressed NF-κB activation in both human islet cells and immune cells. We found that it could be combined with rapamycin to increase its suppressive effects. GABA improved human islet cell survival and had suppressive effects on human immune cells. It inhibited canonical NF-κB activation in both islet and immune cells. This is important because activation of this pathway is detrimental to islet cells and likely promotes damaging autoimmunity and alloreactivity against transplanted islets. These findings suggest that GABA might find applications in clinical islet transplantation. 23528640 Social network analysis used to assess the relationship between the spread of avian influenza and movement patterns of backyard chickens in Ratchaburi, Thailand. In this study, we describe the movement and trading patterns of the backyard chicken in Ratchaburi, Thailand by using social network analysis with egocentric approach. From questionnaire results, we found that there is a close relationship between chicken owners' houses and fresh markets, and we concluded that this relationship needs attention from authorities to prevent future outbreaks of avian flu. Control measures should be applied over pathways to prevent and control highly pathogenic avian influenza subtype H5N1 in the backyard farming system. Results of our study may be useful to relevant authorities and researchers seeking to understand how H5N1 spreads in Ratchaburi. This may reflect on the spread of H5N1 throughout Thailand. 23895675 Theoretical calculation of reorganization energy for electron self-exchange reaction by constrained density functional theory and constrained equilibrium thermodynamics. Within the framework of constrained density functional theory (CDFT), the diabatic or charge localized states of electron transfer (ET) have been constructed. Based on the diabatic states, inner reorganization energy λin has been directly calculated. For solvent reorganization energy λs, a novel and reasonable nonequilibrium solvation model is established by introducing a constrained equilibrium manipulation, and a new expression of λs has been formulated. It is found that λs is actually the cost of maintaining the residual polarization, which equilibrates with the extra electric field. On the basis of diabatic states constructed by CDFT, a numerical algorithm using the new formulations with the dielectric polarizable continuum model (D-PCM) has been implemented. As typical test cases, self-exchange ET reactions between tetracyanoethylene (TCNE) and tetrathiafulvalene (TTF) and their corresponding ionic radicals in acetonitrile are investigated. The calculated reorganization energies λ are 7293 cm(-1) for TCNE/TCNE(-) and 5939 cm(-1) for TTF/TTF(+) reactions, agreeing well with available experimental results of 7250 cm(-1) and 5810 cm(-1), respectively. 23831805 Out-of-hospital cardiac arrest due to drowning among children and adults from the Utstein Osaka Project. Children have better outcomes after out-of-hospital cardiac arrest (OHCA) than adults. However, little is known about the difference in outcomes between children and adults after OHCA due to drowning. The aim of this study is to assess the outcome after OHCA due to drowning between children and adults. Our hypothesis is that outcomes after OHCA due to drowning would be in better among children (<18 years old) compared with adults (≥18 years old). This prospective population-based, observational study included all emergency medical service-treated OHCA due to drowning in Osaka, Japan, between 1999 and 2010 (excluding 2004). Outcomes were evaluated between younger children (0-4 years old), older children (5-17 years old), and adults (≥18 years old). Major outcome measures were one-month survival and neurologically favorable one-month survival defined as cerebral performance category 1 or 2. Multivariate logistic regression analyses were used to account for potential confounders. During the study period, 66,716 OHCAs were documented, and resuscitation was attempted for 62,048 patients (1300 children [2%] and 60,748 adults [98%]). Among these OHCAs, 1737 (3% of OHCAs) were due to drowning (36 younger children [2%], 32 older children [2%], and 1669 adults [96%]). The odds of one-month survival were significantly higher for younger children (28% [10/36]; adjusted odds ratio [AOR], 20.20 [95% confidence interval {CI} 7.45-54.78]) and older children (9% [3/32]; AOR, 4.47 [95% CI 1.04-19.27]) when compared with adults (2% [28/1669]). However, younger children (6% [2/36]; AOR, 5.23 [95% CI 0.52-51.73]) and older children (3% [1/32]; AOR, 2.53 [95% CI 0.19-34.07]) did not have a higher odds of neurologically favorable outcome than adults (1% [11/1669]). In this large OHCA registry, children had better one-month survival rates after OHCA due to drowning compared with adults. Most survivors in all groups had unfavorable neurological outcomes. 23946539 Mechanisms by which a Lack of Germinal Vesicle (GV) Material Causes Oocyte Meiotic Defects: A Study Using Oocytes Manipulated to Replace GV with Primary Spermatocyte Nuclei. Oocytes with germinal vesicles (GV) replaced with somatic nuclei exhibit meiotic abnormalities. Although this suggests an exclusive role for GV material in meiosis, mechanisms by which a lack of GV material causes meiotic defects are unknown. Knowledge on these mechanisms will help us to understand meiotic control, nuclear-cytoplasmic interactions and cellular reprogramming. This study showed that whereas oocytes with pro-metaphase I chromosomes replaced with primary spermatocyte nuclei (PSN) did not, oocytes with GV replaced with PSN (PSG oocytes) displayed meiotic defects. Among the defects, insufficient chromosome condensation with chromosome bridges was associated with spindle abnormalities. Abnormal spindle migration, cortical non-polarization and the aberrant spindle caused randomly positioning of cleavage furrows, leading to large first polar bodies (PB1) and unequal allocation of chromosomes and MAPK between oocyte and PB1. Spindle assembly checkpoint (SAC) was activated but did not stop the mal-division. The unequal MAPK allocation resulted in differences in pronuclear formation and PB1 degeneration; oocytes receiving more MAPK were more capable of forming pronuclear rudiments while PB1 receiving more MAPK degenerated sooner than those that received less. Because none of the PSG oocytes or the enucleated GV oocytes injected with sperm heads showed cortical polarization in spite of chromosome localization close to the oolemma and because the PSG oocytes receiving more MAPK could form only pronuclear rudiments but not normal pronuclei, we suggest that the GV material plays essential roles in polarization and pronuclear formation on top of those played by chromosomes or MAPK. In conclusion, using PSG oocytes as models, this study has revealed the primary pathways by which a lack of GV material cause meiotic defects, laying a foundation for future research on the role of GV material in oocyte meiotic control. 23956045 Total Synthesis of Stemaphylline N-Oxide and Related C9a-Epimeric Analogues. Winning the relay: The first total synthesis of stemaphylline N-oxide has been completed utilizing a bistandem relay ring-closing-metathesis (RRCM) strategy, necessitated by the conformation of the requisite tetraene. This effort also gave unnatural 9a-epi-stemaphylline and 9a-epi-stemaphylline N-oxide. 23877508 The Incidental Suggestive Meningioma Presenting as High 18F FP-CIT Uptake on PET/CT Study. A 76-year-old woman with about a 13-month history of bradykinesia, gait disturbance and resting tremor of right upper extremity was referred to Nuclear Medicine Department. A PET-CT with 229 MBq of F FP-CIT was performed to diagnose suspected early Parkinson's disease (PD). The PET-CT showed a mass lesion with highly intense focal dopamine transporter uptake in the right frontal lobe. A subsequent brain magnetic resonance image also showed a mass in the right frontal lobe demonstrating homogeneous enhancement and extensive surrounding edema, highly suggestive of a brain tumor. 23456551 TR-644 a novel potent tubulin binding agent induces impairment of endothelial cells function and inhibits angiogenesis. TR-644 is a novel combretastatin A-4 (CA-4) analogue endowed with potent microtubule depolymerizing activity superior to that of the lead compound and it also has high affinity to colchicines binding site of tubulin. We tested TR-644 anti-angiogenic effects in human umbilical endothelial cells (HUVEC). It showed no significant effects on the growth of HUVEC cells at concentrations below 1,000 nM, but at much lower concentrations (10-100 nM) it induced inhibition of capillary tube formation, inhibition of endothelial cell migration and affected endothelial cell morphology as demonstrated by the disruption of the microtubule network. TR-644 also increased permeability of HUVEC cells in a time dependent manner. The molecular mechanism for the anti-vascular activity of TR-644 was investigated in detail. TR-644 caused G2/M arrest in endothelial cells and this effect correlated with downregulation of the expression of Cdc25C and Cdc2(Tyr15). Moreover TR-644 inhibited VEGF-induced phosphorylation of VE-cadherin but did not prevent the VEGF-induced phosphorylation of FAK. In chick chorioallantoic membrane in vivo assay, TR-644 (0.1-1.0 pmol/egg) efficiently counteracted the strong angiogenic response induced by FGF. Also CA-4, used as reference compound, caused an antagonistic effect, but in contrast, it induced per se, a remarkable angiogenic response probably due to an inflammatory reaction in the site of treatment. In a mice allogenic tumor model, immunohistochemical staining of tumors with anti-CD31 antibody showed that TR-644 significantly reduced the number of vessel, after 24 h from the administration of a single dose (30 mg/Kg). 23425504 Clinical and MRI predictors of response to interferon-beta and glatiramer acetate in relapsing-remitting multiple sclerosis patients. It is still unclear which patients benefit more from available disease-modifying treatments (DMTs) in multiple sclerosis (MS). Our objective is to identify the baseline clinical and magnetic resonance imaging (MRI) predictors of response to first-line DMTs in a cohort of relapsing-remitting (RR) MS patients in a real-world clinical setting. Consecutive naïve RRMS patients treated with interferon-beta or glatiramer acetate have been included and followed for 2 years. Patients were grouped into responders (R) in case of absence of clinical and MRI activity, and non-responders (NR) if the on-treatment annualized relapse rate (ARR) reduction was < 50% of the ARR in the 2 years before treatment or in the presence of MRI activity (≥ 2 active lesions at 1-year MRI or ≥ 4 active lesions at 1 + 2-year MRI). At 2-year follow-up, 272 patients were R (34.6%) and 322 NR (40.9%), and multivariate analysis revealed that a later age at onset of the disease (P < 0.0001), a lower disability (P < 0.0001) and a lower number of gadolinium-enhancing lesions at baseline MRI (P = 0.002) were predictors of efficacy of DMTs. Moreover, the first year response had a good predictive power on the second year, as 73.7% of 1-year R had no evidence of clinical and MRI activity within the ensuing year. A lower baseline MRI and clinical activity have been identified as predictors of DMT efficacy in patients with RRMS in routine clinical practice. Evaluation of clinical and MRI activity at 1 year is recommended to monitor patients over time. 23858408 Epidemiology of stroke and its subtypes in Chinese vs white populations: A systematic review. We aimed to systematically assess the evidence for differences in the incidence of stroke and distribution of its subtypes in Chinese compared with white populations. We comprehensively sought studies conducted since 1990 in Chinese populations of 1) first-ever stroke incidence (community-based studies only), and 2) pathologic types/subtypes of stroke (hospital- or community-based studies of first-ever or recurrent strokes). We identified community-based studies in white populations from a recent systematic review. For each study, we calculated age-standardized stroke incidence and the proportions of each pathologic type and ischemic subtype, using random-effects meta-analysis to pool proportions of stroke types/subtypes in Chinese and in white populations. Age-standardized annual first-ever stroke incidence in community-based studies was higher among Chinese than white populations (for ages 45-74 years, range 205-584 vs 170-335 per 100,000, respectively). Intracerebral hemorrhage accounted for a larger, more variable proportion of strokes in China than Taiwan (range 27%-51% vs 17%-28%), in Chinese community-based than hospital-based studies (27%-51% vs 17%-30%), and in community-based Chinese than white studies (pooled proportion 33% vs 12%). Although the overall proportion of lacunar ischemic stroke appeared higher in Chinese than white populations, variable study methodologies precluded reliable comparisons. There is good evidence for a slightly higher overall stroke incidence and higher proportion of intracerebral hemorrhage in Chinese vs white populations, but no clear evidence for different distributions of ischemic stroke subtypes. Studies using comparable, population-based case ascertainment and similar classification methods are needed to address this. 23663047 Mycobacterium tuberculosis PE_PGRS17 Promotes the Death of Host Cell and Cytokines Secretion via Erk Kinase Accompanying with Enhanced Survival of Recombinant Mycobacterium smegmatis. Tuberculosis (TB) remains a serious threat to global public health, largely due to the successful manipulation of the host immunity by its etiological agent Mycobacterium tuberculosis. The PE_PGRS protein family of M. tuberculosis might be a contributing factor. To investigate the roles of PE_PGRS17, the gene of PE_PGRS 17 was expressed in nonpathogenic fast growing Mycobacterium smegmatis. We found that the recombinant strain survives better than the control in macrophage cultures, accompanied by more host cell death and a marked higher secretion of tumor necrosis factor-alpha by a recombinant strain compared with control. Blocking the action of Erk kinase by an inhibitor can abolish the above effects. In brief, our data showed that PE_PGRS 17 might facilitate pathogen survival and disserve the host cell via remodeling the macrophages immune niche largely consisting of inflammatory cytokines. This furnishes a novel insight into the immune role of this mycobacterium unique gene family. 23591548 Early Experience with the Incisionless Operating Platform™ (IOP) for the Treatment of Obesity : The Primary Obesity Surgery Endolumenal (POSE) Procedure. We report our initial experience and 6-month outcomes in a single center using the per-oral Incisionless Operating Platform™ (IOP) (USGI Medical) to place transmural plications in the gastric fundus and distal body using specialized suture anchors (the Primary Obesity Surgery Endolumenal [POSE] procedure). A prospective observational study was undertaken with institutional Ethics Board approval in a private hospital in Barcelona, Spain. Indicated patients were WHO obesity class I-II, or III, where patients refused a surgical approach. Between February 28, 2011 and March 23, 2012, the POSE procedure was successfully performed in 45 patients: 75.6 % female; mean age 43.4 ±â€‰9.2 SD (range 21.0-64.0). At baseline: mean absolute weight (AW, kg), 100.8 ±â€‰12.9 (75.5-132.5); body mass index (BMI, kg/m(2)), 36.7 ±â€‰3.8 (28.1-46.6). A mean 8.2 suture-anchor plications were placed in the fundus, 3.0 along the distal body wall. Mean operative time, 69.2 ±â€‰26.6 min (32.0-126.0); patients were discharged in <24 h. Six-month mean AW was 87.0 ±â€‰10.3 (68.0-111.5); BMI decreased 5.8 to 31.3 ±â€‰3.3 (25.1-38.6) (p < 0.001); EWL was 49.4 %; TBWL, 15.5 %. No mortality or operative morbidity. Minor postoperative side effects resolved with treatment by discharge. Patients reported less hunger and earlier satiety post procedure. Liquid intake began 12 h post procedure with full solids by 6 weeks. At 6-month follow-up of a prospective case series, the POSE procedure appeared to provide safe and effective weight loss without the scarring, pain, and recovery issues of open and laparoscopic bariatric surgery. Long-term follow-up and further study are required. 23861594 Cryptogenic transient ischemic attack after nose blowing: association of huge atrial septal aneurysm with patent foramen ovale as potential cause. Association of atrial septal aneurysm (ASA) with patent foramen ovale (PFO) is considered an important risk factor for cardioembolism frequently forwarding paradoxical embolism in patients with cryptogenic or unexplained cerebral ischemic events. We herein describe the case of a 69-year-old male patient reporting uncontrolled movements of the right arm due to a muscle weakness, slurred speech, and paresthesia in the oral region some seconds after he had blown his nose. These neurological symptoms had improved dramatically within a few minutes and were completely regressive at admission to our hospital about two hours later. On transesophageal echocardiography (TEE) a huge ASA associated with PFO was detected. Diagnosis of the large-sized ASA was also confirmed by cardiac magnetic resonance imaging. Due to the early complete recovery from his neurological symptoms, the patient was diagnosed with a transient ischemic attack (TIA). After nine days he was discharged in a good clinical condition under the treatment with oral anticoagulation. It is concluded that in cryptogenic or unexplained stroke or TIA TEE should always be performed to rule out ASA and PFO as potential sources for paradoxical embolism in those inconclusive clinical situations. 23921949 Heterogeneity of Response to Biologic Treatment: Perspective for Psoriasis. Psoriasis treatment responses are affected by patient characteristics. However, the literature does not contain reviews of factors that affect the response to biologic therapies. We therefore performed a comprehensive literature search to identify papers describing demographic, lifestyle, and clinical factors associated with response to biologic drug therapy in psoriatic patients. We found that age, gender, ethnicity, alcohol consumption, smoking, geographic location, age at diagnosis, duration and severity of psoriasis, and baseline C-reactive protein levels did not consistently affect response to biologic psoriasis therapy. However, increased body mass index (BMI) appears to adversely affect responses. It might therefore be valuable to include BMI as a stratification variable in future studies of psoriasis therapies and to consider a patient's weight or BMI when selecting a systemic psoriasis treatment.Journal of Investigative Dermatology accepted article preview online, 6 August 2013. doi:10.1038/jid.2013.326. 23866691 Bee venom effects on ubiquitin proteasome system in hSOD1G85R-expressing NSC34 motor neuron cells. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results from a progressive loss of motor neurons. Familial ALS (fALS) is caused by missense mutations in Cu, Zn-superoxide dismutase 1 (SOD1) that frequently result in the accumulation of mutant-protein aggregates that are associated with impairments in the ubiquitin-proteasome system (UPS). UPS impairment has been implicated in many neurological disorders. Bee venom (BV) extracted from honey bees has been used as a traditional medicine for treating inflammatory diseases and has been shown to attenuate the neuroinflammatory events that occur in a symptomatic ALS animal model. NSC34 cells were transiently transfected with a WT or G85R hSOD1-GFP construct for 24 hrs and then stimulated with 2.5 mug/ml BV for 24 hrs. To determine whether a SOD1 mutation affects UPS function in NSC34 cells, we examined proteasome activity and performed western blotting and immunofluorescence using specific antibodies, such as anti-misfolded SOD1, anti-ubiquitin, anti-GRP78, anti-LC3, and anti-ISG15 antibodies. We found that GFP-hSOD1G85R overexpression induced SOD1 inclusions and reduced proteasome activity compared with the overexpression of GFP alone in NSC34 motor neuronal cells. In addition, we also observed that BV treatment restored proteasome activity and reduced the accumulation of ubiquitinated and misfolded SOD1 in GFP-hSOD1G85R-overexpressing NSC34 motor neuronal cells. However, BV treatment did not activate the autophagic pathway in these cells. Our findings suggest that BV may rescue the impairment of the UPS in ALS models. 23474171 The role of DNA methylation and histone acetylation in the regulation of progesterone receptor isoforms expression in human astrocytoma cell lines. Many progesterone (P4) effects are mediated by its intracellular receptor (PR), which has two isoforms, PR-A and PR-B, each of them with different function and regulation. Differential PR expression in cancer cells has been associated to a PR isoform-specific promoter methylation. In astrocytomas, the most frequent and aggressive brain tumors, PR isoforms expression is directly correlated to the tumor's evolution grade. However, there is no evidence of the role of epigenetic regulation of PR expression in astrocytomas. We evaluated the effect of the demethylating agent 5-aza-2'-deoxycytidine (5AzadC) and the histone deacetylase inhibitor trichostatin A (TSA) on PR expression in human astrocytoma cell lines U373 (grade III) and D54 (grade IV) by RT-PCR and Western blot. Total PR expression increased with 5μM 5AzadC treatment, whereas PR-B expression increased with 5 and 10μM 5AzadC treatment in U373 cells, but not in D54 cells. In U373 cells, PR-A protein content augmented with 10μM 5AzadC treatment, while PR-B content increased with 5 and 10μM 5AzadC. PR-B expression was not modified by the TSA concentrations that were used, and the combination with 5AzadC did not change the effects of the latter. The study of 5AzadC effects on the number of astrocytoma cells showed that P4 treatment increased the number of U373 cells, whereas 5AzadC and the combined treatment with P4 reduced it. Our results suggest that PR-B expression is regulated by methylation and not by histone acetylation in U373 cells, and that DNA demethylation reduced the number of U373 cells. 23775478 Buprenorphine use in pregnant opioid users: a critical review. Pregnancy in opioid users poses a number of problems to treating physicians. Most guidelines recommend maintenance treatment to manage opioid addiction in pregnancy, with methadone being the gold standard. More recently, buprenorphine has been discussed as an alternate medication. The use and efficacy of buprenorphine in pregnancy is still controversial. This article reviews the current database on the basis of a detailed and critical literature search performed in MEDLINE (206 counts). Most of the relevant studies (randomised clinical trials and one national cohort sample) were published in the last 2 years and mainly compared buprenorphine with methadone. Some studies are related to maternal outcomes, others to foetal, neonatal or older child outcomes. With respect to maternal outcomes, most studies suggest that buprenorphine has similar effects to methadone. Very few data from small studies discuss an effect of buprenorphine on neurodevelopment of the foetus. Neonatal abstinence syndrome is common in infants of both buprenorphine- and methadone-maintained mothers. As regards neonatal outcomes, buprenorphine has the same clinical outcome as methadone, although some newer studies suggest that it causes fewer withdrawal symptoms. Since hardly any studies have investigated the combination of buprenorphine with naloxone (which has been suggested to possibly have teratogenic effects) in pregnant women, a switch to buprenorphine monotherapy is recommended in women who become pregnant while receiving the combination product. These novel findings indicate that buprenorphine is emerging as a first-line treatment for pregnant opioid users. 23906705 Cystitis glandularis in a cat. An 8-year-old intact male Persian cat was presented for investigation of chronic haematuria. The cat had episodes of haematuria on several occasions that were non-responsive to antimicrobial therapy. Abdominal ultrasound examination revealed dilation of the renal pelvis and ureters of both kidneys. The urinary bladder wall was thickened, a mass of heterogeneous echogenicity filled the lumen of the bladder, and two parallel thin hyperechoic lines were identified within the lumen, which suggested a urethral catheter. Differential diagnoses for the urinary bladder mass included cystitis and neoplasia. The mass was surgically removed from the urinary bladder, and a urethral catheter was found embedded in the mass. Histopathological findings were consistent with cystitis glandularis of a typical type. Periodic bladder ultrasonographic studies were performed; after 2 years recurrence has not been detected. 23841829 Effects of smoking on visual acuity of central serous chorioretinopathy patients. Abstract Background: The aim of this study was to evaluate the differences, in terms of visual outcome and treatment needs, between smokers and non-smokers central serous chorioretinopathy (CSCR) patients. Methods: The files of 252 patients diagnosed with CSCR who had presented to the Retina Unit of the Ophthalmology Clinic at Dicle University Medical School in Turkey were retrospectively evaluated. Eighty-four smokers, with a known history of smoking of at least one pack-year, and 133 non-smokers were included, whereas 35 patients with additional pathologies were excluded from the study. Results: Of the patients, 192 (88.5%) were male and 25 (11.5%) were female. The mean patient age was 38.8 ± 8.1 years (range: 20-68 years). Visual acuity (VA) of the smoker and non-smoker groups was measured as 0.45 ± 0.35 and 0.24 ± 0.28 logarithm of the minimum angle of resolution (logMar), respectively, at the first visit; 0.19 ± 0.29 and 0.06 ± 0.14 logMar at the sixth month; and 0.07 ± 0.14 and 0.02 ± 0.05 logMar at the ninth month. VA measurements at presentation and during all examinations (1th, 6th and 9th month) were significantly different for the two groups. VA was lower in the smoker group. In 27 patients (12.4%), an additional treatment modality was needed. Of the 27 patients, only 8 (6%) were non-smokers, whereas 19 (22.6%) were smokers. There was no difference between groups in the recurrence rate during follow-up (p = 0.907); 14 (16.7%) smokers and 8 (19.0%) non-smokers experienced a recurrence. Conclusion: This study has shown that patients selected and who are current smokers have poorer vision and need longer treatment. 23846180 Synthesis, characterization, and DNA binding, photocleavage, cytotoxicity, cellular uptake, apoptosis, and on-off light switching studies of Ru(II) mixed-ligand complexes containing 7-fluorodipyrido[3,2-a:2',3'-c]phenazine. Four new ruthenium(II) polypyridyl complexes-[Ru(phen)2(7-F-dppz)](2+) (7-F-dppz is 7-fluorodipyrido[3,2-a:2',3'-c]phenazine, phen is 1,10-phenanthroline), [Ru(bpy)2(7-F-dppz)](2+)(2) (bpy is 2,2'-bipyridine), [Ru(dmb)2(7-F-dppz)](2+) (dmb is 4,4'-dimethyl-2,2'-bipyridine), and [Ru(hdpa)2(7-F-dppz)](2+) (hdpa is 2,2'-dipyridylamine)-have been synthesized and characterized. Their DNA binding behavior has been explored by various spectroscopic titrations and viscosity measurements, which indicated that all the complexes bind to calf thymus DNA by means of intercalation with different binding strengths. The light switching properties of these complexes have been evaluated, and their antimicrobial activities have been investigated. Photoinduced DNA cleavage studies have been performed. All the complexes exhibited efficient photocleavage of pBR322 DNA on irradiation. The cytotoxicity of these complexes has been evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay with various tumor cell lines. Cellular uptake was studied by flow cytometry and confocal microscopy. Flow cytometry experiments showed that these complexes induced apoptosis of HeLa cell lines. 23814235 The cost analysis of cemented versus cementless total hip replacement operations on the NHS. In a time of limited resources, the debate continues over which types of hip prosthesis are clinically superior and more cost-effective. Orthopaedic surgeons increasingly need robust economic evidence to understand the full value of the operation, and to aid decision making on the 'package' of procedures that are available and to justify their practice beyond traditional clinical preference. In this paper we explore the current economic debate about the merits of cemented and cementless total hip replacement, an issue that continues to divide the orthopaedic community. 23595521 Occupational exposure to arsenic and risk of nonmelanoma skin cancer in a multinational European study. Occupational studies show a high risk of lung cancer related to arsenic exposure by inhalation; however, only a few studies, and with conflicting results, previously examined a potential link between arsenic exposure at work and skin cancer. The aim of this study is to assess airborne arsenic exposures at the workplace and to quantify associations with nonmelanoma skin cancer (NMSC). The study sample consists of 618 incident cases of NMSC and 527 hospital-based controls aged 30-79 years from Hungary, Romania and Slovakia. Exposures were evaluated by local experts using occupational histories. Information on host factors and other exposures was collected and used to adjust the associations of interest using multivariable logistic regression. The lifetime prevalence of exposure to work-related arsenic is 23.9% for cases and 15.5% for controls. No significant association between arsenic exposure in the workplace and NMSC was detected, although an increased adjusted odd ratio was observed for participants with higher cumulative lifetime workplace exposure to arsenic in dust and fumes compared to referents [odds ratios (OR) = 1.94, 95% confidence interval (CI) = 0.76-4.95]. There is evidence for modification of the workplace arsenic-NMSC association by work-related sunlight exposure in women, with a markedly increased adjusted OR in the presence of workplace sunlight exposure (OR = 10.22, 95% CI = 2.48-42.07). Workplace coexposure to arsenic and sunlight may thus pose an increased risk of NMSC. 23837438 Interleukin-33 Potentiates Bleomycin-induced Lung Injury. The mechanisms of interstitial lung disease (ILD) remain incompletely understood, though recent observations have suggested an important contribution by interleukin (IL)-33. Substantial elevation in IL-33 expression was found in the lungs of patients with idiopathic pulmonary fibrosis and scleroderma lung disease as well as in the bleomycin injury mouse model. Most of the observed IL-33 expression was intracellular and intranuclear, suggesting involvement of the full-length (fl) protein but not the proteolytically processed mature IL-33 cytokine. The effects of flIL-33 on mouse lungs were assessed independently and in combination with bleomycin injury using recombinant adenovirus-mediated gene delivery. Bleomycin-induced changes were not affected by gene deficiency of the IL-33 receptor T1/ST2. Combined flIL-33 expression and bleomycin injury had a synergistic effect on pulmonary lymphocyte and collagen accumulation, which could be explained by synergistic regulation of the cytokines TGF-β, IL-6, MCP-1, MIP-1α, and TNF-α. By contrast, there was no increase in the levels of the Th2 cytokines IL-4, IL-5, or IL-13. Also, flIL-33 was found to significantly increase expression of several heat shock proteins, particularly HSP70, which is known to be associated with ILD. Thus, full-length IL-33 is a synergistic proinflammatory and profibrotic regulator that acts by stimulating expression of several non-Th2 cytokines and activates expression of HSP70. 23910859 Analyses of odontometric sexual dimorphism and sex assessment accuracy on a large sample. Correct sex assessment of skeletonized human remains allows investigators to undertake a more focused search of missing persons' files to establish identity. Univariate and multivariate odontometric sex assessment has been explored in recent years on small sample sizes and have not used a test sample. Consequently, inconsistent results have been produced in terms of accuracy of sex allocation. This paper has derived data from a large sample of males and females, and applied logistic regression formulae on a test sample. Using a digital caliper, buccolingual and mesiodistal dimensions of all permanent teeth (except third molars) were measured on 600 dental casts (306 females, 294 males) of young adults (18-32 years), and the data subjected to univariate (independent samples' t-test) and multivariate statistics (stepwise logistic regression analysis, or LRA). The analyses revealed that canines were the most sexually dimorphic teeth followed by molars. All tooth variables were larger in males, with 51/56 (91.1%) being statistically larger (p < 0.05). When the stepwise LRA formulae were applied to a test sample of 69 subjects (40 females, 29 males) of the same age range, allocation accuracy of 68.1% for the maxillary teeth, 73.9% for the mandibular teeth, and 71% for teeth of both jaws combined, were obtained. The high univariate sexual dimorphism observed herein contrasts with some reports of low, and sometimes reverse, sexual dimorphism (the phenomenon of female tooth dimensions being larger than males'); the LRA results, too, are in contradiction to a previous report of virtually 100% sex allocation for a small heterogeneous sample. These reflect the importance of using a large sample to quantify sexual dimorphism in tooth dimensions and the application of the derived formulae on a test dataset to ascertain accuracy which, at best, is moderate in nature. 23838281 Automated approximation of center of mass position in X-ray sequences of animal locomotion. A crucial aspect of comparative biomechanical research is the center of mass (CoM) estimation in animal locomotion scenarios. Important applications include the parameter estimation of locomotion models, the discrimination of gaits, or the calculation of mechanical work during locomotion. Several methods exist to approximate the CoM position, e.g. force-plate-based approaches, kinematic approaches, or the reaction board method. However, they all share the drawback of not being suitable for large scale studies, as detailed initial conditions from kinematics are required (force-plates), manual interaction is necessary (kinematic approach), or only static settings can be analyzed (reaction board). For the increasingly popular case of X-ray-based animal locomotion analysis, we present an alternative approach for CoM estimation which overcomes these shortcomings. The main idea is to only use the recorded X-ray images, and to map each pixel to the mass of matter it represents. As a consequence, our approach is surgically noninvasive, independent of animal species and locomotion characteristics, and neither requires prior knowledge nor any kind of user interaction. To assess the quality of our approach, we conducted a comparison to highly accurate reaction board experiments for lapwing and rat cadavers, and achieved an average accuracy of 2.6mm (less than 2% of the animal body length). We additionally verified the practical applicability of the algorithm by comparison to a previously published CoM study which is based on the kinematic method, yielding comparable results. 23934110 Interactome map uncovers phosphatidylserine transport by oxysterol-binding proteins. The internal organization of eukaryotic cells into functionally specialized, membrane-delimited organelles of unique composition implies a need for active, regulated lipid transport. Phosphatidylserine (PS), for example, is synthesized in the endoplasmic reticulum and then preferentially associates-through mechanisms not fully elucidated-with the inner leaflet of the plasma membrane. Lipids can travel via transport vesicles. Alternatively, several protein families known as lipid-transfer proteins (LTPs) can extract a variety of specific lipids from biological membranes and transport them, within a hydrophobic pocket, through aqueous phases. Here we report the development of an integrated approach that combines protein fractionation and lipidomics to characterize the LTP-lipid complexes formed in vivo. We applied the procedure to 13 LTPs in the yeast Saccharomyces cerevisiae: the six Sec14 homology (Sfh) proteins and the seven oxysterol-binding homology (Osh) proteins. We found that Osh6 and Osh7 have an unexpected specificity for PS. In vivo, they participate in PS homeostasis and the transport of this lipid to the plasma membrane. The structure of Osh6 bound to PS reveals unique features that are conserved among other metazoan oxysterol-binding proteins (OSBPs) and are required for PS recognition. Our findings represent the first direct evidence, to our knowledge, for the non-vesicular transfer of PS from its site of biosynthesis (the endoplasmic reticulum) to its site of biological activity (the plasma membrane). We describe a new subfamily of OSBPs, including human ORP5 and ORP10, that transfer PS and propose new mechanisms of action for a protein family that is involved in several human pathologies such as cancer, dyslipidaemia and metabolic syndrome. 23452860 Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Targeted gene regulation on a genome-wide scale is a powerful strategy for interrogating, perturbing, and engineering cellular systems. Here, we develop a method for controlling gene expression based on Cas9, an RNA-guided DNA endonuclease from a type II CRISPR system. We show that a catalytically dead Cas9 lacking endonuclease activity, when coexpressed with a guide RNA, generates a DNA recognition complex that can specifically interfere with transcriptional elongation, RNA polymerase binding, or transcription factor binding. This system, which we call CRISPR interference (CRISPRi), can efficiently repress expression of targeted genes in Escherichia coli, with no detectable off-target effects. CRISPRi can be used to repress multiple target genes simultaneously, and its effects are reversible. We also show evidence that the system can be adapted for gene repression in mammalian cells. This RNA-guided DNA recognition platform provides a simple approach for selectively perturbing gene expression on a genome-wide scale. 23810498 Controlling persister cells of Pseudomonas aeruginosa PDO300 by (Z)-4-bromo-5-(bromomethylene)-3-methylfuran-2(5H)-one. Pseudomonas aeruginosa is a major pathogen causing chronic pulmonary infections; for example, 80% of cystic fibrosis patients get infected by this bacterium as the disease progresses. Such chronic infections are challenging because P. aeruginosa exhibits high-level tolerance to antibiotics by forming biofilms (multicellular structures attached to surfaces), by entering dormancy and forming antibiotic tolerant persister cells, and by conversion to the mucoid phenotype. Recently, we reported that a synthetic quorum sensing inhibitor, (Z)-4-bromo-5-(bromomethylene)-3-methylfuran-2(5H)-one (BF8), can sensitize both planktonic and biofilm-associated persister cells of P. aeruginosa PAO1 to antibiotics at the concentrations non-inhibitory to its growth. In this study, we further characterized the effects of this compound on the mucoid strain P. aeruginosa PDO300. BF8 was found to reduce persistence during the growth of PDO300 and effectively kill the persister cells isolated from PDO300 cultures. In addition to planktonic cells, BF8 was also found to inhibit biofilm formation of PDO300 and reduce associated persistence. These findings broaden the activities of this class of compounds and indicate that BF8 also has other targets in P. aeruginosa in addition to quorum sensing. 23660192 Effects of IV iron isomaltoside-1000 treatment on regional brain iron status in an iron-deficient animal. Iron deficiency has been documented to affect human cognitive function and conditions with brain iron compromise such as the restless legs syndrome (RLS). Intravenous (IV) iron treatment is used to reduce iron deficiency but its effects on brain iron are not known. It is not known if IV iron is effective in correcting regional brain iron deficiencies nor if it poses a risk of producing iron overload in some brain regions. Preclinical study of IV iron in the iron-deficient (ID) murine model is needed to evaluate and develop IV iron treatments for brain iron deficiency. Response to tail vein injections of iron (iron isomaltoside-1000, dose equivalent to 1000 mg for 75 kg adult) or vehicle were evaluated for ID mice by microdialysis assessing non-transferrin bound (NTB) iron in the ventral midbrain (VMB) and autopsy at 3 and 10 days post-injection assessing iron content in critical brain regions. The ID mice showed marked circadian variation in NTB extracellular iron. After iron injection, NTB iron was rapidly increased in the VMB and then decreased over 12h to the levels observed for vehicle. Regional brain iron content at 3 and 10 days post-injection in the iron- compared to vehicle-treated group showed significantly more iron for the VMB and nucleus accumbens but not for the other regions (i.e. prefrontal cortex, caudate-putamen, cerebellum, and pons), which also did not show decreased iron content with the ID diet. Iron isomaltoside-1000 given IV corrects the regional brain iron deficiency in these ID mice without producing iron overload in any of the brain regions studied. This is the first demonstration of effects of IV iron in the brain and it provides a useful preclinical model for this assessment, particularly relevant for developing iron treatments for conditions with problematic iron deficiency, e.g. RLS. 23869889 Metabolic disturbances and defects in insulin secretion in rats with streptozotocin-nicotinamide-induced diabetes. Rats with diabetes induced by streptozotocin (STZ) and nicotinamide (NA) are often used in animal studies concerning various aspects of diabetes. In this experimental model, the severity of diabetes is different depending on doses of STZ and NA. Moreover, diabetic changes in rats with STZ-NA-induced diabetes are not fully characterized. In our present study, metabolic changes and insulin secretion were investigated in rats with diabetes induced by administration of 60 mg of STZ and 90 mg of NA per kg body weight. Four to six weeks after diabetes induction, insulin, glucagon and some metabolic parameters were determined to evaluate the severity of diabetes. Moreover, insulin secretory capacity of pancreatic islets isolated from control and diabetic rats was compared. It was demonstrated that administration of 60 mg of STZ and 90 mg of NA per kg body weight induced relatively mild diabetes, since insulin, glucagon and other analyzed parameters were only slightly affected in diabetic rats compared with control animals. In vitro studies revealed that insulin secretory response was preserved in pancreatic islets of diabetic rats, however, was lower than in islets of control animals. This effect was observed in the presence of different stimuli. Insulin secretion induced by 6.7 and 16.7 mmol/l glucose was moderately reduced in islets of diabetic rats compared with control islets. In the presence of leucine with glutamine, insulin secretion appeared to be also decreased in islets of rats with STZ-NA-induced diabetes. Insulinotropic action of 6.7 mmol/l glucose with forskolin was also deteriorated in diabetic islets. Moreover, it was demonstrated that at a non-stimulatory glucose, pharmacological depolarisation of plasma membrane with a concomitant activation of protein kinase C evoked significant rise in insulin release in islets of control and diabetic rats. However, in diabetic islets, this effect was attenuated. These results indicate that impairment in insulin secretion in pancreatic islets of rats with mild diabetes induced by STZ and NA results from both metabolic and nonmetabolic disturbances in these islets. 23407288 Evaluation of the 3-dimensional endoscope in transsphenoidal surgery. Three-dimensional (3-D) endoscopy is a recent addition to augment the transsphenoidal surgical approach for anterior skull-base and parasellar lesions. We describe our experience implementing this technology into regular surgical practice. Retrospective review of clinical factors and outcomes. All patients were analyzed who had endoscopic endonasal parasellar operations since the introduction of the 3-D endoscope to our practice. Over an 18-month period, 160 operations were performed using solely endoscopic techniques. Sixty-five of these were with the Visionsense VSII 3-D endoscope and 95 utilized 2-dimensional (2-D) high-definition (HD) Storz endoscopes. Intraoperative and postoperative findings were analyzed in a retrospective fashion. Comparing both groups, there was no significant difference in total or surgical operating room times comparing the 2-D HD and 3-D endoscopes (239 minutes vs 229 minutes, P = .47). Within disease-specific comparison, pituitary adenoma resection was significantly shorter utilizing the 3-D endoscope (surgical time 174 minutes vs 147 minutes, P = .03). These findings were independent of resident or fellow experience. There was no significant difference in the rate of complication, reoperation, tumor resection, or intraoperative cerebrospinal fluid leaks. Subjectively, the 3-D endoscope offered increased agility with 3-D techniques such as exposing the sphenoid rostrum, drilling sphenoidal septations, and identifying bony landmarks and suprasellar structures. The 3-D endoscope is a useful alternative to the 2-D HD endoscope for transnasal anterior skull-base surgery. Preliminary results suggest it is more efficient surgically and has a shorter learning curve. As 3-D technology and resolution improve, it should serve to be an invaluable tool for neuroendoscopy. HD, high definition. 23846795 Endovascular Catheter for Magnetic Navigation under MR Imaging Guidance: Evaluation of Safety in Vivo at 1.5T. BACKGROUND AND PURPOSE:Endovascular navigation under MR imaging guidance can be facilitated by a catheter with steerable microcoils on the tip. Not only do microcoils create visible artifacts allowing catheter tracking, but also they create a small magnetic moment permitting remote-controlled catheter tip deflection. A side product of catheter tip electrical currents, however, is the heat that might damage blood vessels. We sought to determine the upper boundary of electrical currents safely usable at 1.5T in a coil-tipped microcatheter system.MATERIALS AND METHODS:Alumina tubes with solenoid copper coils were attached to neurovascular microcatheters with heat shrink-wrap. Catheters were tested in carotid arteries of 8 pigs. The catheters were advanced under x-ray fluoroscopy and MR imaging. Currents from 0 mA to 700 mA were applied to test heating and potential vascular damage. Postmortem histologic analysis was the primary endpoint.RESULTS:Several heat-mitigation strategies demonstrated negligible vascular damage compared with control arteries. Coil currents ≤300 mA resulted in no damage (0/58 samples) compared with 9 (25%) of 36 samples for > 300-mA activations (P = .0001). Tip coil activation ≤1 minute and a proximal carotid guide catheter saline drip > 2 mL/minute also had a nonsignificantly lower likelihood of vascular damage. For catheter tip coil activations ≤300 mA for ≤1 minute in normal carotid flow, 0 of 43 samples had tissue damage.CONCLUSIONS:Activations of copper coils at the tip of microcatheters at low currents in 1.5T MR scanners can be achieved without significant damage to blood vessel walls in a controlled experimental setting. Further optimization of catheter design and procedure protocols is necessary for safe remote control magnetic catheter guidance. 23665693 Biodiesel production from waste chicken fat with low free fatty acids by an integrated catalytic process of composite membrane and sodium methoxide. An integrated process of catalytic composite membranes (CCMs) and sodium methoxide was developed to produce biodiesel from waste chicken fat. The free fatty acids (FFAs) in the chicken oil were converted to methyl esters by esterification with methanol using a novel sulfonated polyethersulfone (SPES)/PES/non-woven fabric (NWF) CCMs in a flow-through catalytic membrane reactor. The CCM is that the NWF fibers were fully embedded in SPES/PES with a homogeneous and microporous structure. The oil obtained after esterification was carried out by transesterification of sodium methoxide. The results showed that the FFAs conversion obtained by CCMs with the acid capacity of 25.28 mmol (H(+)) was 92.8% at the residence time 258s. The CCMs present a good stability during the continuous running of 500 h. The conversion of transesterification was 98.1% under the optimum conditions. The quality of the biodiesel met the international standards. 23438794 Terminal deletion 2q37.3 in a patient with klippel-trenaunay-weber syndrome. Klippel-Trenaunay-Weber syndrome (KTWS) is a rare congenital disorder, characterized by capillary, venous and lymphatic vascular malformations in association with bone and soft tissue hypertrophy. We report a KTWS patient with extensive hemangiomatosis of the right lower limb, trunk and upper limbs; bone and soft tissue hypertrophy of upper limbs, scapular girdle and right lower limb; and muscle atrophy on left lower limb with marked body asymmetry, scoliosis and toe malformations. These pathological features are associated with moderate mental retardation, mild renal and hepatic abnormalities. We identified by array CGH (Comparative Genomic Hybridization) a submicroscopic deletion 2q37.3 that could be related to impaired cognitive function. To our knowledge this is the first reported 2q37.3 microdeletion in a patient with KTWS. 23422337 Ethnobotanical study on traditional use of medicinal plants in South-Western Serbia, Zlatibor district. Ethnopharmacological relevance: This paper provides significant ethnobotanical information on medicinal plant uses in the Zlatibor district, South-Western Serbia. Materials and methods: A survey was performed using questionnaires with 220 informants (mean age 47, 79% female, 21% male). In addition, the use value and the relative importance of species were determined and the informant consensus factor was calculated for the medicinal plants included in the study. Intended plants usage was compared with previous ethnobotanical literature, with reference to the neighboring areas of Zlatibor district. Results: The informants provided data for 69 medicinal plants belonging to 36 families. Rosaceae, Lamiaceae and Asteraceae were the predominant locally used families. The species with the highest use value were Mentha piperita, Matricaria chamomilla, Hypericum perforatum and Achillea millefolium. The most frequently reported medicinal uses were ones for treating gastrointestinal ailments, respiratory problems and skin diseases. Usually, the administration was primarily oral followed by topical applications. All different plant parts were utilized, however leaves were the most exploited parts of the plants. Conclusions: Folk medicine in South-Western Serbia, Zlatibor district is intended mainly as a mode of primary health care in healing of minor illnesses. The results indicate a slight reduction in the ethnobotanical and medical knowledge in this area, when compared with neighboring regions. 23820456 Vemurafenib and ipilimumab: new agents for metastatic melanoma. The development and place in therapy of vemurafenib and ipilimumab for the treatment of metastatic melanoma are reviewed. Vemurafenib is an adenosine triphosphate-competitive, reversible, and highly selective BRAF kinase inhibitor targeted at BRAF-V600E and is a first-line option for patients with BRAF-mutation-positive disease. Vemurafenib has clinically significant antitumor activity in metastatic melanoma, and response rates and overall and progression-free survival rates are improved when compared with dacarbazine. Responses also occur quickly, often within days to weeks of starting treatment. Disadvantages of vemurafenib include the short duration of response; significant skin toxicities, including skin cancers and severe photosensitivity; the need for long-term daily administration; and the potential for drug interactions. Ipilimumab is a fully human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 to enhance and prolong T-cell responses to elicit antitumor activity. Clinical trials have demonstrated the superiority of ipilimumab in terms of overall survival when compared with an immune stimulator and placebo. While the rate of response to ipilimumab is low, responses tended to be more durable than those achieved with vemurafenib. A disadvantage of ipilimumab is that a response may require months, making ipilimumab inappropriate as monotherapy for patients with symptomatic disease. Additional disadvantages are the adverse-effect profile and the requirement of enrollment in the risk evaluation and mitigation strategy program. Vemurafenib and ipilimumab are important advances in the treatment of metastatic melanoma. Benefit is typically short lived for vemurafenib and uncommon for ipilimumab. Neither agent is curative, and clinical trials remain an alternative first-line treatment option. 23739871 Understanding super-resolution nanoscopy and its biological applications in cell imaging. Optical microscopy has been an ideal tool for studying phenomena in live cells because visible light at reasonable intensity does not perturb much of the normal biological functions. However, optical resolution using visible light is significantly limited by the wavelength. Overcoming this diffraction-limit barrier will reveal biological mechanisms, cellular structures, and physiological processes at a nanometer scale, orders of magnitude lower than current optical microscopy. Although this appears to be a daunting task, recently developed photoswitchable probes enable reconstruction of individual images into a super-resolution image, thus the emergence of nanoscopy. Harnessing the resolution power of nanoscopy, we report here nano-resolution fluorescence imaging of microtubules and their network structures in biological cells. The super-resolution nanoscopy successfully resolved nanostructures of a microtubule network-a daunting task that cannot be completed using conventional wide-field microscopy. 23944953 Two new C-methyl flavanones from the rhizomes and frond bases of Matteuccia struthiopteris. Two new C-methyl flavanones, (2S)-5,7-dihydroxy-6,8-dimethyl-4'-methoxydihydroflavone-7-O-(6″-O-acetyl)-β-d-glucopyranoside (1) and (2S)-5,7-dihydroxy-6,8-dimethyldihydroflavone-7-O-(6″-O-acetyl)-β-d-glucopyranoside (2), together with five known compounds, demethoxymatteucinol-7-O-β-d-glucopyranoside (3), matteucinol-7-O-β-d-glucopyranoside (4), 5,7-dihydroxy-6-methyl-4'-methoxydihydroflavone (5), methoxymatteucin (6), and thunberginol C (7), were first isolated from the EtOH extract of the rhizomes and frond bases of Matteuccia struthiopteris. The structures were established by spectral analyses, mainly HR-ESI-MS and 1D and 2D NMR experiments (COSY, HSQC, and HMBC). 23647866 Prevalence of high-risk human papilloma virus among women with hepatitis C virus before liver transplantation. We sought to assess the prevalence and risk factors for high-risk human papillomavirus (HPV) infection among female liver transplant (LT) candidates. Traditional health screening before LT listing has included Pap smear and is typically carried out by the patient's local provider. The prevalence of high-risk HPV in this population has not been studied. With Institutional Review Board approval, 62 LT candidates received a liquid-based Pap smear with high-risk HPV testing as part of their pre-transplant evaluation by a single provider. Clinical variables included age, ethnicity, insurance status, prior Pap smear, and HPV results, HPV risk factors including age of first intercourse, number of lifetime partners, last sexual activity, smoking, birth control pill use, history of sexually transmitted infections, human immunodeficiency virus status, immunosuppressive medication, medical diagnoses, prescribed medications, and history of hepatitis A, B, C, or D. The 62 women had a median age of 56 years, and 39% had high-risk behavior known to be associated with HPV. Ten of 62 patients (16.1%) had high-risk HPV at baseline screening, 5 of whom had atypical cytology. All of the patients who were positive for high-risk HPV had an etiology of hepatitis C virus (HCV) as the underlying cause of liver disease, with the majority (90%) having no history of high-risk behavior for HPV. In contrast, all patients with high-risk behavior who were HCV negative were HPV negative. Fisher's exact test demonstrated a statistically significant relationship between HPV and HCV; odds ratio = 24.4, 95% confidence interval, 1.4, 438.7, P-value = 0.0013. None of the other potential risk factors were associated with HPV in this cohort. In this study, we provide evidence of a strong association between HCV and HPV in LT candidates, which has not been previously reported. HPV positivity was observed in non-sexually active women, suggesting a reactivation of dormant HPV. An association between hepatitis C and high-risk HPV could involve impairment of T-cell function by hepatitis C. These data support close surveillance in women's health screening for LT candidates. Further studies to characterize immune responses in these patients will be in order. 23242478 Primary hepatocyte cultures for pharmaco-toxicological studies: at the busy crossroad of various anti-dedifferentiation strategies. Continuously increasing understanding of the molecular triggers responsible for the onset of diseases, paralleled by an equally dynamic evolution of chemical synthesis and screening methods, offers an abundance of pharmacological agents with a potential to become new successful drugs. However, before patients can benefit of newly developed pharmaceuticals, stringent safety filters need to be applied to weed out unfavourable drug candidates. Cost effectiveness and the need to identify compound liabilities, without exposing humans to unnecessary risks, has stimulated the shift of the safety studies to the earliest stages of drug discovery and development. In this regard, in vivo relevant organotypic in vitro models have high potential to revolutionize the preclinical safety testing. They can enable automation of the process, to match the requirements of high-throughput screening approaches, while satisfying ethical considerations. Cultures of primary hepatocytes became already an inherent part of the preclinical pharmaco-toxicological testing battery, yet their routine use, particularly for long-term assays, is limited by the progressive deterioration of liver-specific features. The availability of suitable hepatic and other organ-specific in vitro models is, however, of paramount importance in the light of changing European legal regulations in the field of chemical compounds of different origin, which gradually restrict the use of animal studies for safety assessment, as currently witnessed in cosmetic industry. Fortunately, research groups worldwide spare no effort to establish hepatic in vitro systems. In the present review, both classical and innovative methodologies to stabilize the in vivo-like hepatocyte phenotype in culture of primary hepatocytes are presented and discussed. 23370971 Time to positivity of blood culture can predict different Candida species instead of pathogen concentration in candidemia. The aim of this study was to systematically evaluate the predictive value of time to positivity (TTP) in candidemia. All first episodes of candidemic patients admitted to our hospital between January 2008 and July 2012 were recorded retrospectively. We analyzed the relationship between TTP, identification of Candida species, antifungal agent susceptibility, and patients' clinical characteristics (30-day mortality, underlying diseases, and associated risk factors). TTP of simulated blood culture with equal inoculum amounts of different Candida species was determined. We included 87 patients during the study period, with a mean TTP of 43.47 ± 19.51 h. TTP of C. glabrata was significantly longer (p < 0.001) and TTP of C. tropicalis was significantly shorter (p < 0.001) than that of other Candida species. Receiver operating characteristic (ROC) curve analysis showed that TTP can predict C. glabrata (with the cut-off value of >45.17 h) and C. tropicalis (with the cut-off value of ≤33.17 h) in candidemia with good sensitivity and specificity. No statistically significant relationship was found between TTP, antifungal agent susceptibility, and patients' clinical characteristics (p > 0.05). TTP was not a risk factor associated with mortality (p > 0.05). The TTP result in simulated blood culture was in accordance with that of the included patients. TTP has been demonstrated to be helpful to differentiate C. glabrata and C. tropicalis from other Candida species in candidemia, and it is not associated with antifungal agent susceptibility and patients' clinical characteristics. TTP cannot predict pathogen concentration in the blood of candidemic patients. 23789973 Does what you hear predict what you will do and say? I evaluate the bottlenecks involved in the simulation mechanism underpinning superior predictive abilities for upcoming actions. This perceptual-motor state is characterized by a complex interrelationship designed to make predictions using a highly fine-tuned and constrained motor operation. The extension of such mechanisms to language may occur only in sensorimotor circuits devoted to the action domain. 23465408 Evidence that Aerobic Fitness Is More Salient than Weight Status in Predicting Standardized Math and Reading Outcomes in Fourth- through Eighth-Grade Students. To determine whether aerobic fitness is more salient than weight status in predicting performance on standardized math and reading tests in fourth- to eighth-grade students. A cross-sectional study of data abstracted from 11 743 students in 47 public schools. Aerobic fitness was defined by entering the healthy fitness zone of Fitnessgram's Progressive Aerobic Cardiovascular Endurance Run, which has been shown to correlate highly with maximum oxygen consumption. Mixed-effects logistic regression analyses were conducted to model the student-level effect of aerobic fitness status on passing the Nebraska State Accountability (NeSA) math and reading tests after adjusting for body mass index (BMI) percentile, free/reduced lunch status, sex, race, grade level, and school type. After adjustment, aerobically fit students had greater odds of passing the NeSA math and reading tests compared with aerobically unfit students regardless of whether the students received free/reduced lunch; however, the effect of being aerobically fit on the standardized test scores was significantly greater for students not receiving free/reduced lunch. Weight status, as measured by BMI percentile, was not a significant predictor of passing the NeSA math or reading test after including free/reduced lunch status in the model. Aerobic fitness was a significant predictor of academic performance; weight status was not. Although decreasing BMI for an overweight or obese child undoubtedly improves overall health, results indicated all students benefit academically from being aerobically fit regardless of weight or free/reduced lunch status. Therefore, to improve academic performance, school systems should focus on the aerobic fitness of every student. 23933230 MicroRNAs as diagnostic markers for pancreatic ductal adenocarcinoma and its precursor, pancreatic intraepithelial neoplasm. Since the discovery of small non-coding RNAs, the analysis of microRNA (miRNA) expression patterns in human cancer have provided new insights into cancer biology. Evidence suggests that deregulated miRNA expression is associated with pancreatic cancer development. In this study, we analyzed the expression of several miRNAs in different types of pancreatic disease to determine if miRNA expression could aid in the diagnosis of pancreatic ductal adenocarcinoma (PDAC) and its precursor, pancreatic intraepithelial neoplasm (PanIN). Pancreatic resection specimens were selected, which included PDAC (n = 16), benign pancreatic parenchyma from corresponding carcinoma cases (n = 16), chronic pancreatitis (n = 4), normal pancreatic parenchyma (n = 5), and PanIN (n = 5). The expression levels of five miRNA (miR-148a, miR-217, miR-21, miR-196a, and miR-10b) were assessed by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) assays. Our data demonstrate that compared to the normal pancreatic parenchyma, miR-148a and miR-217 expression levels were down-regulated in PanIN, particularly in PanIN II-III and PDAC, whereas the level of miR-196 was significantly up-regulated in PDAC and its precursor, PanIN II-III. In addition, we observed that miR-21 was significantly overexpressed in PDAC, and miR-10b was highly expressed in PanIN II-III. Our study demonstrates that certain miRNAs, especially miR-148a, miR-217, and miR-196a, are significantly deregulated in PDAC, including in the early stage of PDAC. These markers can potentially be used as diagnostic markers to distinguish PDAC and its precursor from benign lesions. 23941831 Chronic ulcerative colitis and colorectal cancer. One of the most important consequences of chronically active ulcerative colitis (UC) or Crohn's disease (CD) - the two major forms of inflammatory bowel disease (IBD) - is the development of colorectal cancer (CRC). An increased risk for the occurrence of CRC in up to 30% of affected patients after 35years of UC has been reported. Recent evidence from population based studies indicates a lower risk. Nevertheless the incidence is still significantly increased as compared to individuals without chronic colitis. Colitis-associated CRC (CAC) does not display the adenoma-carcinoma sequence which is typical for sporadic CRC and the pathophysiology appears to be different. Chronic inflammation and the increased turnover of epithelial cells contribute to the development of low- and high-grade dysplasia which may further transform into CAC. Reactive oxygen species (ROS) generated by the inflammatory infiltrate are thought to contribute to the generation of dysplastic lesions. In sporadic CRC the sequence of mutations that finally lead to malignancy involves early activation of Wnt/β-catenin pathway (in 90% of cases) including mutations in adenomatous polyposis coli (APC) tumor suppressor gene, its regulating kinase GSK3β and β-catenin itself. β-catenin mutations are rarer in CAC and mutations in APC occur rather late during the disease progression, whereas there are earlier mutations in p53 and K-ras. Recent data indicate that the intestinal microbiome and its interaction with a functionally impaired mucosal barrier may also play a role in CAC development. CACs frequently show aggressive growth and early metastases. The treatment of CAC in patients with colitis always includes proctocolectomy with ileoanal anastomosis as meta- or synchronic lesions are frequent. 23876573 The effect of complementary and alternative medicine on the quality of life of cancer survivors: A systematic review and meta-analyses. To assess whether quality of life (QOL) improved in cancer survivors who had undertaken a complementary and alternative medicine (CAM) intervention, compared to cancer survivors who had not. A systematic review of randomised controlled trials (RCTs) was undertaken. Electronic databases including MEDLINE, Cochrane CENTRAL, CINAHL, PSYCHINFO, EMBASE, and ClinicalTrials.gov were searched from 1990 to 2012. Search terms incorporating the concepts of cancer survivors, QOL and various types of CAM were used. From 1767 records retrieved and screened 13 full text articles were included in the review. Nine studies were deemed to have a high risk, one a low risk, and three an unclear risk of bias. CAM interventions used incorporated yoga, meditation or mindfulness, energy healing, medical qigong, homoeopathy, or mistletoe therapy. Ten of the studies used breast cancer survivors, whilst the remaining three included other cancer types. The studies had mixed results either showing a significantly greater improvement in QOL in the intervention group compared to the control group, or no significant difference between groups. However, twelve studies were of low to moderate quality, limiting the robustness of findings. This review has identified significant gaps in the evidence base for the effectiveness of CAM on QOL in cancer survivors. Further work in this field needs to adopt more rigorous methodology to help support cancer survivors to actively embrace self-management and effective CAMs, without recommending inappropriate interventions which are of no proven benefit. 23864508 A high-salt diet further impairs age-associated declines in cognitive, behavioral, and cardiovascular functions in male Fischer brown norway rats. Aging-associated declines in cognitive, emotional, and cardiovascular function are well known. Environmental stress triggers critical changes in the brain, further compromising cardiovascular and behavioral health during aging. Excessive dietary salt intake is one such stressor. Here, we tested the effect of high salt (HS) on anxiety, learning-memory function, and blood pressure (BP) in male Fischer brown Norway (FBN) rats. Adult (A; 2 mo) and old (O; 20 mo) male rats were fed normal-salt (NS; 0.4% NaCl) or HS (8% NaCl) diets for 4 wk after being implanted with telemeter probes for conscious BP measurement. Thereafter, tests to assess anxiety-like behavior and learning-memory were conducted. The rats were then killed, and samples of plasma, urine, and brain tissue were collected. We found that systolic BP was higher in O-NS (117 ± 1.2 mm Hg) than in A-NS (105 ± 0.8 mm Hg) rats (P < 0.05). Furthermore, BP was higher in O-HS (124 ± 1.4 mm Hg) than in O-NS (117 ± 1.2 mm Hg) rats (P < 0.05). Moreover, anxiety-like behavior (light-dark and open-field tests) was not different between A-NS and O-NS rats but was greater in O-HS rats than in A-NS, O-NS, or A-HS rats (P < 0.05). Short-term memory (radial arm water maze test) was similar in A-NS and O-NS rats but was significantly impaired in O-HS rats compared with A-NS, O-NS, or A-HS rats (P < 0.05). Furthermore, oxidative stress variables (in plasma, urine, and brain) as well as corticosterone (plasma) were greater in O-HS rats when compared with A-NS, O-NS, or A-HS rats (P < 0.05). The antioxidant enzyme glyoxalase-1 expression was selectively reduced in the hippocampus and amygdala of O-HS rats compared with A-NS, O-NS, or A-HS rats (P < 0.05), whereas other antioxidant enzymes, glutathione reductase 1, manganese superoxide dismutase (SOD), and Cu/Zn SOD remained unchanged. We suggest that salt-sensitive hypertension and behavioral derangement are associated with a redox imbalance in the brain of aged FBN rats. 23370687 ISSLS Prize Winner: Effect of Link Protein Peptide on Human Intervertebral Disc Cells. An in vitro study using human intervertebral disc cells. To evaluate the effect of link protein peptide (LPP) on the expression of disc extracellular matrix macromolecules sulfated glycosaminoglycan, aggrecan, and collagen II. To determine the effect of LPP on catabolic regulators and to compare LPP with both BMP2 and BMP7 in terms of osteoinductivity. Previous studies have shown that N-terminal link-protein peptide (LPP) can induce synthesis of proteoglycans and collagen II in cartilaginous cell types. However, the effect of LPP on human disc cells remains to be investigated. Moreover, the effects of LPP on the catabolic regulators and the osteoinductive potential of LPP are unknown. Human intervertebral disc cells were cultured in alginate beads and treated with LPP, truncated LPPs, and the reverse sequence of LPP (LPR). The levels of aggrecan and collagen II mRNAs were measured by real-time polymerase chain reaction. Sulfated glycosaminoglycan content was assayed using the dimethylmethylene blue method. The protein levels of collagen II and catabolic regulators were determined by enzyme-linked immunosorbent assays and Western blots. The relative osteoinductive potential of LPP was evaluated by comparing the effect of LPP, BMP2, and BMP7 on in vitro markers of osteoinductivity. LPP upregulates expression of aggrecan and collagen II at both mRNA and protein levels. The full length of LPP is required for this upregulation. Neither the reverse sequences of LPP nor the truncated LPPs were as effective as the full-length LPP. LPP selectively inhibits expression of the catabolic regulators interleukin (IL)-1β and MMP1 and has no effect on expression of the other catabolic regulators tumor necrosis factor α, ADAMTS1, ADAMTS4, ADAMTS5, MMP3, and MMP9. LPP has relatively little osteoinductive effect compared with BMP2 and BMP7. LPP could have value in stimulating the growth and regeneration of degenerated discs with less concern of creating unwanted bone.Level of Evidence: N/A. 23941274 VirD: A Virion Display Array for Profiling Functional Membrane Proteins. To facilitate high-throughput biochemical analyses of membrane proteins, we have developed a novel display technology in a microarray format. Both single-pass (cluster of differentiation 4, CD4) and multiple-pass (G protein-coupled receptor 77, GPR77) human transmembrane proteins were engineered to be displayed in the membrane envelop of herpes simplex virions. These viruses produce large spherical virions displaying multiple copies of envelop proteins. Our aim was to engineer this virus to express these human proteins during the virus productive cycle and incorporate the human proteins into the virion during the assembly process. Another strategy presented includes engineering a fusion of glycoprotein C (gC), a major constituent of herpes simplex virus type 1 (HSV-1) virions, by hijacking the cis-acting signals to direct incorporation of the chimeric protein into the virion. The expression of the human proteins in infected cells, at the cell surface and in purified virions, is in the correct transmembrane orientation, and the proteins are biochemically functional. Purified virions printed on glass slides form a high-density Virion Display (VirD) Array, and the displayed proteins were demonstrated to retain their native conformations and interactions on the VirD Array judging by similar assays, such as antibody staining, as well as lectin and ligand binding. This method can be readily scaled or tailored for different modalities including a high-content, high-throughput platform for screening ligands and drugs of human membrane proteins. 23931327 The Delicate Bistability of CaMKII. Calcium/calmodulin-dependent protein kinase II (CaMKII) is a synaptic, autophosphorylating kinase that is essential for learning and memory. Previous models have suggested that CaMKII functions as a bistable switch that could be the molecular correlate of long-term memory, but experiments have failed to validate these predictions. These models involved significant approximations to overcome the combinatorial complexity inherent in a multisubunit, multistate system. Here, we develop a stochastic particle-based model of CaMKII activation and dynamics that overcomes combinatorial complexity without significant approximations. We report four major findings. First, the CaMKII model system is never bistable at resting calcium concentrations, which suggests that CaMKII activity does not function as the biochemical switch underlying long-term memory. Second, the steady-state activation curves are either laserlike or steplike. Both are characterized by a well-defined threshold for activation, which suggests that thresholding is a robust feature of this system. Third, transiently activated CaMKII can maintain its activity over the time course of many experiments, and such slow deactivation may account for the few reports of bistability in the literature. And fourth, under in vivo conditions, increases in phosphatase activity can increase CaMKII activity. This is a surprising and counterintuitive effect, as dephosphorylation is generally associated with CaMKII deactivation. 23963528 Supercritically exfoliated ultrathin vanadium pentoxide nanosheets with high rate capability for lithium batteries. Ultrathin V2O5 nanosheets were successfully prepared through supercritical solvothermal reaction followed by annealing treatment. The formation of ultrathin nanosheets is owing to Ostwald ripening and the effect of supercritical fluids. As cathode material for lithium batteries, the ultrathin V2O5 nanosheets exhibit a capacity of 108 mA h g(-1) at a high rate of up to 10 C at 2.4-4 V and excellent cyclability with little capacity loss after 200 cycles. The enhanced rate performance is attributed to the shortened diffusion distance and the increased electrode-electrolyte contact area of the ultrathin nanosheet structure. It is also demonstrated that the supercritical solvothermal method is effective and facile to scalably synthesize ultrathin nanomaterials for lithium batteries. 23347275 Structure of polyelectrolyte brushes subject to normal electric fields. Molecular dynamic simulations of salt-free polyelectrolyte brushes subject to external fields applied normal to the grafting substrate reveal the three-dimensional monomer and counterion distributions. It is found that below a critical electric field, local electroneutrality holds for densely grafted brushes and the brush height remains independent of field intensity. Above this critical field (which scales as 1/3 with grafting density) brush height increases smoothly, and the fraction of condensed counterions decreases. The brush bifurcates into two subpopulations of stretched and collapsed chains when the grafting density is not low. At intermediate grafting densities, the majority of chains are stretched and the minority are nonstretched. At high grafting densities bifurcation and brush height growth occur consecutively. The majority of the chains are nonstretched at high grafting densities. Although not observed prior to overstretching of the chain model, it is predicted that the two subpopulations will re-merge to a single highly stretched phase when field intensity reaches a third critical value. The ability to control subpopulations of chains suggests that utilizing electric fields normal to polyelectrolyte brushes holds potential as controllable gates in microfluidic devices. 23749994 Antimalarial Activity of Cupredoxins: THE INTERACTION OF PLASMODIUM MEROZOITE SURFACE PROTEIN 119 (MSP119) AND RUSTICYANIN. The discovery of effective new antimalarial agents is urgently needed. One of the most frequently studied molecules anchored to the parasite surface is the merozoite surface protein-1 (MSP1). At red blood cell invasion MSP1 is proteolytically processed, and the 19-kDa C-terminal fragment (MSP119) remains on the surface and is taken into the red blood cell, where it is transferred to the food vacuole and persists until the end of the intracellular cycle. Because a number of specific antibodies inhibit erythrocyte invasion and parasite growth, MSP119 is therefore a promising target against malaria. Given the structural homology of cupredoxins with the Fab domain of monoclonal antibodies, an approach combining NMR and isothermal titration calorimetry (ITC) measurements with docking calculations based on BiGGER is employed on MSP119-cupredoxin complexes. Among the cupredoxins tested, rusticyanin forms a well defined complex with MSP119 at a site that overlaps with the surface recognized by the inhibitory antibodies. The addition of holo-rusticyanin to infected cells results in parasitemia inhibition, but negligible effects on parasite growth can be observed for apo-rusticyanin and other proteins of the cupredoxin family. These findings point to rusticyanin as an excellent therapeutic tool for malaria treatment and provide valuable information for drug design. 23517732 Discovery of 3,3'-diindolylmethanes as potent antileishmanial agents. An efficient protocol for synthesis of 3,3'-diindolylmethanes using recyclable Fe-pillared interlayered clay (Fe-PILC) catalyst under aqueous medium has been developed. All synthesized 3,3'-diindolylmethanes showed promising antileishmanial activity against Leishmania donovani promastigotes as well as axenic amastigotes. Structure-activity relationship analysis revealed that nitroaryl substituted diindolylmethanes showed potent antileishmanial activity. The 4-nitrophenyl linked 3,3'-diindolylmethane 8g was found to be the most potent antileishmanial analog showing IC50 values of 7.88 and 8.37 μM against both L. donovani promastigotes and amastigotes, respectively. Further, a pharmacophore based QSAR model was established to understand the crucial molecular features of 3,3'-diindolylmethanes essential for potent antileishmanial activity. These compounds also exhibited promising antifungal activity against Cryptococcus neoformans, wherein fluorophenyl substituted 3,3'-diindolylmethanes were found to be most potent antifungal agents. Developed synthetic protocol will be useful for economical and eco-friendly synthesis of potent antileishmanial and antifungal 3,3'-diindolylmethane class of compounds. 23683790 Prospective associations between brain activation to cocaine and no-go cues and cocaine relapse. The ability to predict potential for relapse to substance use following treatment could be very useful in targeting aftercare strategies. Recently, a number of investigators have focused on using neural activity measured by fMRI to predict relapse propensity. The purpose of the present study was to use fMRI to investigate prospective associations between brain reactivity to cocaine and response inhibition cues and relapse to cocaine use. Thirty cocaine-dependent participants with clean cocaine urine drug screens (UDS) completed a baseline fMRI scan, including a cocaine-cue reactivity task and a go no-go response inhibition task. After participating in a brief clinical trial of d-cycloserine for the facilitation of cocaine-cue extinction, they returned for a one-week follow-up UDS. Associations between baseline activation to cocaine and inhibition cues and relapse to cocaine use were explored. Positive cocaine UDS was significantly associated with cocaine-cue activation in the right putamen and insula, as well as bilateral occipital regions. Associations between positive cocaine UDS and activation to no-go cues were concentrated in the postcentral gyri, a region involved in response execution. Although preliminary, these results suggest that brain imaging may be a useful tool for predicting risk for relapse in cocaine-dependent individuals. Further, larger-scale naturalistic studies are needed to corroborate and extend these findings. 23374337 Gene copy-number alterations: a cost-benefit analysis. Changes in DNA copy number, whether confined to specific genes or affecting whole chromosomes, have been identified as causes of diseases and developmental abnormalities and as sources of adaptive potential. Here, we discuss the costs and benefits of DNA copy-number alterations. Changes in DNA copy number are largely detrimental. Amplifications or deletions of specific genes can elicit discrete defects. Large-scale changes in DNA copy number can also cause detrimental phenotypes that are due to the cumulative effects of copy-number alterations of many genes simultaneously. On the other hand, studies in microorganisms show that DNA copy-number alterations can be beneficial, increasing survival under selective pressure. As DNA copy-number alterations underlie many human diseases, we will end with a discussion of gene copy-number changes as therapeutic targets. 23921331 The Effect of Facet Joint Injection Versus Systemic Steroids in Low Back Pain: A Randomized Controlled Trial. Study Design. Randomized clinical trialObjective. to compare the effectiveness of facet joint injection versus systemic steroid in patient with diagnosis of facet joint syndrome.Summary of Background Data. The term facet joint syndrome has been used to define back pain originating from the facet joints. Treatment is mainly conservative, although interventions, including intraarticular injections and medial branch nerve blocks are used to manage facet-mediated pain. Several studies have evaluated the effectiveness of these interventions. Results of facet joint injection, however, are conflicting.Methods. Sixty subjects with diagnosis of facet joint syndrome were enrolled in the study. They were randomized into experimental and control groups. The experimental group was submitted to intraarticular injection of six lumbar facet joints with triamcinolone hexacetonide; the control group was submitted to triamcinolone acetonide intramuscular injection of six lumbar paravertebral points. Visits were taken at baseline and at 1, 4, 12 and 24 weeks after interventions. Outcome measures were used: pain visual analogical scale, pain visual analogical scale during extension of the spine, Likert scale, improvement percentage scale, Rolland-Morris, short health survey (SF36), accountability of medications taken.Homogeneity was tested using Student's T, Pearson's Chi- Square and Mann-Whitney tests. ANOVA was used to analyze differences in the groups over time and the Student's t-test to analyze differences between groups at each time evaluation.Results. The groups were similar at baseline. Comparisons between the groups showed, in ANOVA analysis, an improvement in the experimental group regarding diclofenac intake and quality of life, in the "role physical" profile, assessed by SF-36.In the analysis at each time point, an improvement in the experimental group was also found in Rolland Morris, in the improvement percentage scale and in the response to treatment, assessed by the Likert scale.Conclusion. Both treatments were effective, with a slightly superiority of the intraarticular injection of steroids over intramuscular injection. 23844221 Effects of heterogeneous competitor distribution and ramet aggregation on the growth and size structure of a clonal plant. Spatially heterogeneous distribution of interspecific competitors and intraspecific aggregation of offspring ramets may affect the growth and size structure of clonal plant populations, but these have been rarely studied. We conducted a greenhouse experiment in which we grew a population of eight offspring ramets (plants) of the stoloniferous clonal plant Hydrocotyle vulgaris aggregately or segregately in two homogeneous treatments with or without a competing grass Festuca elata and a heterogeneous treatment with a patchy distribution of the grass. In patchy grass treatments, H. vulgaris produced markedly more biomass, ramets and stolons in open patches (without grasses) than in grass patches, but displayed lower size variations as measured by coefficient of variation of biomass, ramets and stolons among the eight plants. In open areas, H. vulgaris produced statistically the same amounts of biomass and even more stolons and showed higher size variations in patchy grass treatments than in open (no grass) treatments. In grass areas, H. vulgaris grew much worse and displayed higher size variations in patchy grass treatments than in full grass treatments. Ramet aggregation decreased the growth of H. vulgaris in open treatments and in both open and grass patches in patchy grass treatments, but had little effect in full grass treatments. Ramet aggregation had little effect on size variations. Therefore, heterogeneous distribution of competitors can affect the growth and size structure of clonal plant populations, and ramet aggregation may decrease population growth when they grow in open environments or heterogeneous environments with a patchy distribution of interspecific competitors. 23872308 Circulating clonotypic B-cells in multiple myeloma and monoclonal gammopathy of undetermined significance. The B-cell compartment where the multiple myeloma stem cell resides, remains unclear. We investigated the potential presence of mature surface-membrane immunoglobulin-positive B lymphocytes clonally-related to the tumoral bone marrow plasma cells among different subsets of peripheral blood B-cells from 10 patients (7 multiple myeloma and 3 monoclonal gammopathies of undetermined significance). Presence of clonotypic immunoglobulin heavy chain gene rearrangements was determined in multiple highly-purified fractions of PB B-lymphocytes including surface membrane IgM+ CD27- naive B-lymphocytes, plus surface membrane IgG+, IgA+ and IgM+ memory CD27+ B-cells, and normal circulating plasma cells, in addition to (mono)clonal plasma cells, by a highly-specific and sensitive allele-specific oligonucleotide polymerase chain reaction directed to the CDR3 sequence of the rearranged IGH gene of tumor plasma cells from individual patients. Our results showed systematic absence of clonotypic rearrangements in all different B-cell subsets analyzed, including, M-component isotype-matched memory B-lymphocytes, at frequencies <0.03 cells/mL (range: 0.0003-0.03 cells/mL); the only exception were the myeloma plasma cells detected and purified from the peripheral blood of 4/7 myeloma patients. These results indicate that circulating B-cells from patients with multiple myeloma and monoclonal gammopaties of undetermined significance are usually devoided of clonotypic B-cells while the presence of immunophenotypically aberrant myeloma plasma cells in peripheral blood of myeloma patients is a relatively frequent finding. 22450748 P21-activated kinase 4 (PAK4) is required for metaphase spindle positioning and anchoring. The oncogenic kinase PAK4 was recently found to be involved in the regulation of the G1 phase and the G2/M transition of the cell cycle. We have also identified that PAK4 regulates Ran GTPase activity during mitosis. Here, we show that after entering mitosis, PAK4-depleted cells maintain a prolonged metaphase-like state. In these cells, chromosome congression to the metaphase plate occurs with normal kinetics but is followed by an extended period during which membrane blebbing and spindle rotation are observed. These bipolar PAK4-depleted metaphase-like spindles have a defective astral microtubule (MT) network and are not centered in the cell but are in close contact with the cell cortex. As the metaphase-like state persists, centrosome fragmentation occurs, chromosomes scatter from the metaphase plate and move toward the spindle poles with an active spindle assembly checkpoint, a phenotype that is reminiscent of cohesion fatigue. PAK4 also regulates the acto-myosin cytoskeleton and we report that PAK4 depletion results in the induction of cortical membrane blebbing during prometaphase arrest. However, we show that membrane blebs, which are strongly enriched in phospho-cofilin, are not responsible for the poor anchoring of the spindle. As PAK4 depletion interferes with the localization of components of the dynein/dynactin complexes at the kinetochores and on the astral MTs, we propose that loss of PAK4 could induce a change in the activities of motor proteins. 23835724 Increased MerTK expression in circulating innate immune cells of patients with septic shock. A new pathway of three protein tyrosine kinase receptors, namely, the TAM receptor family [Tyro-3, Axl and Mer tyrosine kinase (MerTK)], has recently been described to negatively control immune responses. The objective of this prospective, observational, clinical study was to investigate the expression patterns of TAM receptors in circulating white blood cells collected from patients with septic shock. The expression of TAM receptors was measured by flow cytometry in circulating leukocytes from patients with septic shock sampled on days (D) 1-2 (n = 47) and D3-4 (n = 37) after the onset of shock, severe trauma patients at D1-2 after trauma (n = 51) and healthy individuals (n = 23). On D1-2 after injury, MerTK was overexpressed in monocytes and neutrophils collected from patients with septic shock in comparison with those collected from healthy volunteers and trauma patients. This phenomenon was also observed for mRNA. Conversely, the expression of Tyro-3 and Axl was higher in monocytes from trauma patients versus healthy volunteers or those in septic shock. MerTK expression between D1-2 and D3-4 remained elevated in patients suffering from septic shock who died or developed an intensive care unit-acquired infection, whereas it decreased in patients who recovered uneventfully. This in vivo observed expression pattern was reproduced ex vivo after the incubation of healthy volunteer cells with plasma from septic shock or trauma patients. MerTK expression in circulating innate immune cells is increased in patients with septic shock in comparison with healthy volunteers and trauma patients. Persistent MerTK overexpression after septic shock is associated with adverse outcome. The role of this family of receptors in the pathophysiology of injury-induced immune dysfunctions deserves to be specifically investigated. 23241060 Lysozyme hydration in concentrated aqueous solutions. Effect of an equilibrium cluster phase. Water close to proteins plays a key role in determining their structural and functional properties. Despite being a subject of considerable interest, the characterization of hydration water, as far as its total amount is concerned, is still controversial and its influence on protein structure and folding is not yet fully understood. In this work, we have investigated the dielectric properties of lysozyme aqueous solutions over the frequency range where the orientational polarization relaxation of the aqueous phase occurs (from 500 MHz to 50 GHz). Measurements extend over a wide concentration range, up to 300 mg/mL, corresponding to a volume fraction of the order of 0.4. The analysis of the dielectric spectra, based on the decrease of the dielectric increment of the γ-dispersion as a function of protein concentration, allows us to estimate the total amount of hydration water (both bound water and loosely bound water) present in the system investigated. We observe a decrease of the hydration number as a function of the protein concentration. This behavior is well accounted for by considering the formation of small equilibrium clusters with aggregation number of some units, as recently reported by Stradner et al. (1) on the basis of small-angle X-ray and neutron scattering measurements. 23856999 Ischemia-reperfusion injury accelerates human antibody-mediated transplant vasculopathy. The pathogenesis of transplant vasculopathy (TV) is a multifactorial process. We hypothesized that ischemia-reperfusion injury and antibody-mediated damage contribute to the development of TV. Human vessels were procured from nine separate donors undergoing cardiac surgery and stored in saline solution on ice until transplantation. BALB/c Rag2IL-2Rγ mice were transplanted with a human vessel graft on day 0. Purified anti-human leukocyte antigen class I antibody (W6/32), isotype control antibody, or saline was injected into recipient mice weekly until day 42, at which point the degree of intimal expansion (IE) of vessels was assessed by histologic analysis. We found that a prolonged cold ischemia time (6-12 hr) alone did not induce IE. In mice that received antibody where vessels were transplanted within 6 hr of procurement, no IE was observed. By contrast, in vessels exposed to more than 6 hr cold ischemia, both W6/32 antibody (30.4%±6.9%) and isotype control antibody (39.5%±6.0%) promoted significant IE (P<0.05 vs. saline [12.4%±1.7%]). Importantly, the isotype control antibody did not cross-react with human tissue. Interestingly, the number of mouse Fc-receptor-positive cells was significantly increased in human vessels exposed to more than 6 hr cold ischemia but only in the presence of antibody (P<0.05). Antibody, regardless of its specificity, may promote IE in human vessels that are injured through cold ischemia via interaction with Fc-receptor-positive cells. This highlights the importance of controlling the degree of cold ischemia in clinical transplantation in an effort to reduce the risk of TV development. 23566057 Zhizhu decoction promotes gastric emptying and protects the gastric mucosa. Abstract The aim of this study was to evaluate the effects of the Zhizhu decoction on gastric emptying and gastric mucosal protection. The Zhizhu decoction is composed of Aurantii fructus and Atractylodes macrocephala Rhizoma. Results showed that oral administration of the Zhizhu decoction accelerated gastric emptying in mouse and protected gastric mucosa from ethanol-induced ulcers in rat. Our investigations demonstrated that the Zhizhu decoction accelerated gastric emptying, at least in part, by activating the muscarinic and 5-HT3 receptors. The gastroprotective effect is involved in its antioxidant effects and increased vascular endothelial growth factor expression. 23887127 Finite element analysis of multi-piece post-crown restoration using different types of adhesives. The multi-piece post-crown technique is more effective in restoring residual root than other restoration techniques. Various types of adhesives have different material properties that affect restoration. Therefore, the choice of adhesive is particularly important for patients. However, the effect of different kinds of adhesives was not too precise by experimental methods when concerning about individual differences of teeth. One tooth root can only be restored with one type of adhesive in experiment. After the mechanical test, this tooth root cannot be restored with other adhesives. With the help of medical imaging technology, reverse engineering and finite element analysis, a molar model can be reconstructed precisely and restored using different types of adhesives. The same occlusal and chewing loads were exerted on the same restored residual root models with different types of adhesives separately. Results of von Mises stress analysis showed that the adhesives with low Young's modulus can protect the root canal effectively. However, a root canal concentration is apparently produced around the root canal orifice when chewing. Adhesives with large Young's modulus can buffer the stress concentration of the root canal orifice. However, the root canal tissue may be destroyed because the adhesive is too hard to buffer the load.International Journal of Oral Science (2013) 5, doi:10.1038/ijos.2013.50; published online 26 July 2013. 23899402 Gene expression under chronic heat stress in populations of the mustard hill coral (Porites astreoides) from different thermal environments. Recent evidence suggests that corals can acclimatize or adapt to local stress factors through differential regulation of their gene expression. Profiling gene expression in corals from diverse environments can elucidate the physiological processes that may be responsible for maximizing coral fitness in their natural habitat and lead to a better understanding of the coral's capacity to survive the effects of global climate change. In an accompanying paper, we show that Porites astreoides from thermally different reef habitats exhibit distinct physiological responses when exposed to 6 weeks of chronic temperature stress in a common garden experiment. Here, we describe expression profiles obtained from the same corals for a panel of 9 previously reported and 10 novel candidate stress response genes identified in a pilot RNA-Seq experiment. The strongest expression change was observed in a novel candidate gene potentially involved in calcification, SLC26, a member of the solute carrier family 26 anion exchangers, which was down-regulated by 92-fold in bleached corals relative to controls. The most notable signature of divergence between coral populations was constitutive up-regulation of metabolic genes in corals from the warmer inshore location, including the gluconeogenesis enzymes pyruvate carboxylase and phosphoenolpyruvate carboxykinase and the lipid beta-oxidation enzyme acyl-CoA dehydrogenase. Our observations highlight several molecular pathways that were not previously implicated in the coral stress response and suggest that host management of energy budgets might play an adaptive role in holobiont thermotolerance. 23432683 Interlayer breathing and shear modes in few-trilayer MoS2 and WSe2. Two-dimensional (2D) layered transition metal dichalcogenides (TMDs) have recently attracted tremendous interest as potential valleytronic and nanoelectronic materials, in addition to being well-known as excellent lubricants in the bulk. The interlayer van der Waals (vdW) coupling and low-frequency phonon modes and how they evolve with the number of layers are important for both the mechanical and the electrical properties of 2D TMDs. Here we uncover the ultralow frequency interlayer breathing and shear modes in few-layer MoS2 and WSe2, prototypical layered TMDs, using both Raman spectroscopy and first principles calculations. Remarkably, the frequencies of these modes can be perfectly described using a simple linear chain model with only nearest-neighbor interactions. We show that the derived in-plane (shear) and out-of-plane (breathing) force constants from experiment remain the same from two-layer 2D crystals to the bulk materials, suggesting that the nanoscale interlayer frictional characteristics of these excellent lubricants should be independent of the number of layers. 23940125 A diagnosis not to be missed: Non-classic steroid 11β-hydroxylase deficiency presenting with premature adrenarche and hirsutism. Context:Steroid 11β-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia (CAH). Milder non-classic forms are rare and at risk to be missed.Objective:To demonstrate the challenges in diagnosing non-classic 11OHD.Patients and Methods:Patient 1, a 10 year-old boy presented with high-normal blood pressure and previously unexplained exaggerated adrenarche from age 4. Previous tests at the age of eight years showed normal 17-hydroxyprogesterone concentrations with increased androgens. Patient 2, a 14-year old female presented with facial hirsutism, primary amenorrhea, and high-normal blood pressure. Novel CYP11B1 mutations were functionally analyzed in transiently-transfected COS7 cells measuring the conversion of 11-deoxycortisol to cortisol by liquid chromatography/tandem mass spectrometry.Results:Biochemical findings including urinary steroid metabolite analysis by gas chromatography/mass spectrometry were suggestive of 11OHD in all patients. CYP11B1 mutation analysis revealed compound heterozygosity in patient 1 (g.235T>A, p.F79I/ g.2608C>T, p.R138C) and a homozygous mutation in patient 2 and two siblings (g.2623C>T, p.R143W). Functional in vitro analysis demonstrated partially impaired CYP11B1 activity compared to wild-type (p.F79I: 8.8±0.8 (SEM)%; p.R138C 9.8±0.8%; p.R143W 10.6±1.2%).Conclusion:In addition to non-classic 21-hydroxylase deficiency and steroid-secreting tumors, non-classic 11OHD should be to be considered as a important differential diagnosis in patients with unexplained hyperandrogenism without 46,XX disorder of sex development. Non-classic 11OHD is likely to be missed when relying on measuring "standard" steroid hormone panels. This diagnosis needs to be established early in life to avoid long-term health problems such as short stature, hyperandrogenism-related metabolic complications, potentially severe arterial hypertension and cardiovascular consequences. 23735111 Endomicroscopy and endocytoscopy in IBD. Two types of endomicroscopy systems exist. One is integrated into a standard, high-resolution endoscope and one is probe-based, capable of passage through the working channel of a standard endoscope. Endocytoscopy allows visualization of the superficial mucosal layer. Endoscope-integrated and probe-based devices allow magnification of the mucosa up to 1400-fold. Endomicroscopy can differentiate histologic changes of Crohn disease and ulcerative colitis in vivo in real time. Endocytoscopy can discriminate mucosal inflammatory cells, allowing determination of histopathologic activity of ulcerative colitis. Molecular imaging with fluorescence-labeled probes against disease-specific receptors will enable individualized management of inflammatory bowel diseases. 23913689 Characterisation of a serine hydrolase targeted by acyl protein thioesterase inhibitors in Toxoplasma gondii. In eukaryotic organisms, cysteine palmitoylation is an important reversible modification impacting on protein targeting, folding, stability and interactions with partners. Evidence suggests that protein palmitoylation contributes to key biological processes in Apicomplexa with the recent palmitome of the malaria parasite, Plasmodium falciparum, reporting over 400 substrates that are modified with palmitate by a broad range of Palmitoyl Acyl Transferases (PATs). Dynamic palmitoylation cycles require the action of an Acyl Protein Thioesterase (APT) that cleaves palmitate from substrates and conveys reversibility to this post-translational modification. In this work, we identified candidates for APT activity in Toxoplasma gondii. Treatment of parasites with low micromolar concentrations of beta-lactone or triazole urea-based inhibitors that target human APT1 show varied detrimental effects at multiple steps of the parasite lytic cycle. The use of an activity-based probe in combination with these inhibitors revealed the existence of several serine hydrolases that are targeted by APT1 inhibitors. The active serine hydrolase, TgASH1, was identified as the closest homologue to human APT1 and APT2 and characterized further. Biochemical analysis of TgASH1 indicated that this enzyme cleaves substrates with a similar specificity to APTs and homology modelling points toward an APT-like enzyme. TgASH1 is dispensable for parasite survival, which indicates that the severe effects observed with the beta-lactone inhibitors are caused by the inhibition of non-TgASH1 targets. Other ASH candidates for APT activity were functionally characterized and one of them was found resistant to gene disruption due either to an experimental failure or to the essential nature of the protein. 23746413 Social connectedness and predictors of successful ageing. As populations age it is important to minimize the time people live in a less than successful state of ageing. Our aim was to identify predictors of successful ageing. At baseline (1990-1994), demographic, anthropometric, health, social connectedness and behavioural data were collected for 41,514 men and women participating in the Melbourne Collaborative Cohort Study. Only those born in Australia, New Zealand and UK were included in this analysis. At follow-up in 2003-2007 data on health conditions, physical disability and psychological stress were collected and used to define successful ageing. A total of 5512 eligible participants with full data who were aged 70 and over, were included in this longitudinal analysis. Successful ageing at follow-up was defined as aged 70 years or over and absence of diabetes, heart attack, coronary artery bypass graft surgery, angioplasty, stroke, cancer; impairment, perceived major difficulty with physical functioning; and low risk of psychological distress. A body mass index in the healthy range, low waist/hip ratio, not smoking, being physically active, and not having arthritis, asthma, hypertension, or gallstones were associated prospectively with successful ageing. There was no evidence for an association of social connectedness with successful ageing. A healthy lifestyle and maintenance of healthy weight, but not social connectedness, may improve the chances of ageing successfully by our definition. Social connectedness may be related to a perception of ageing well, but it does not appear to help avoid the usual conditions associated with ageing. 23616467 Implementing and sustaining school-located influenza vaccination programs: perspectives from five diverse school districts. Local health departments have typically led school-located influenza vaccination (SLIV) programs, assuming resource-intensive roles in design, coordination, and vaccination. This level of involvement is often not financially sustainable over time. Five diverse school districts in Los Angeles County designed, implemented, refined, and institutionalized their own SLIV programs over 3 years by identifying and maximizing their existing resources. School district nurses and other staff served as project leaders, designing their own vaccination administration process, parental consent, and clinic promotional models. Two districts expanded their existing school immunization clinics and three developed their vaccination capacity with community partnerships. Each district tailored its program in creative resource-minimum ways, sometimes abandoning or adopting new methods/technologies based on the effectiveness in previous seasons. The shared experiences and strategies between district nurses and the local health department described in this article illustrate a district's ability to develop a tailor-made SLIV program, often in less than ideal conditions. 23692931 Risk factors associated with venous thromboembolism in 49,028 mastectomy patients. Venous thromboembolism (VTE) is a potentially preventable disease that carries significant morbidity and mortality. Although malignancy is associated with increased risk for VTE, it varies according to cancer type. Despite the fact that breast cancer is the most common form of cancer in women, the incidence and risk factors associated with VTE in patients undergoing mastectomy have not been well characterized. To address this we utilized the ACS-NSQIP database to identify and characterize independent risk factors for VTE in 49,028 mastectomy patients. We identified 116 cases of VTE in the 49,028 cases analyzed (0.23%). Obesity (BMI > 30, OR = 1.91, p < 0.001), inpatient status (OR = 3.75, p < 0.001), venous catheterization (OR = 2.67, p = 0.012), prolonged operative time >3 h (OR = 4.36, p < 0.001), and immediate reconstruction (OR = 3.23, p < 0.001) were found to be independent risk factors for VTE. While the incidence of VTE is rare in mastectomy patients, the heightened awareness and increased VTE prophylaxis should be considered in high risk groups. 22614763 A Skew-t space-varying regression model for the spectral analysis of resting state brain activity. It is known that in many neurological disorders such as Down syndrome, main brain rhythms shift their frequencies slightly, and characterizing the spatial distribution of these shifts is of interest. This article reports on the development of a Skew-t mixed model for the spatial analysis of resting state brain activity in healthy controls and individuals with Down syndrome. Time series of oscillatory brain activity are recorded using magnetoencephalography, and spectral summaries are examined at multiple sensor locations across the scalp. We focus on the mean frequency of the power spectral density, and use space-varying regression to examine associations with age, gender and Down syndrome across several scalp regions. Spatial smoothing priors are incorporated based on a multivariate Markov random field, and the markedly non-Gaussian nature of the spectral response variable is accommodated by the use of a Skew-t distribution. A range of models representing different assumptions on the association structure and response distribution are examined, and we conduct model selection using the deviance information criterion. (1) Our analysis suggests region-specific differences between healthy controls and individuals with Down syndrome, particularly in the left and right temporal regions, and produces smoothed maps indicating the scalp topography of the estimated differences. 23868481 Clinical costs of colorectal cancer screening in 5 federally funded demonstration programs. The Centers for Disease Control and Prevention initiated the Colorectal Cancer Screening Demonstration Program (CRCSDP) to explore the feasibility of establishing a large-scale colorectal cancer (CRC) screening program for underserved populations in the United States. The authors of this report assessed the clinical costs incurred at each of the 5 participating sites during the demonstration period. By using data on payments to providers by each of the 5 CRCSDP sites, the authors estimated costs for specific clinical services and overall clinical costs for each of the 2 CRC screening methods used by the sites: colonoscopy and fecal occult blood test (FOBT). Among CRCSDP clients who were at average risk for CRC and for whom complete cost data were available, 2131 were screened by FOBT, and 1888 were screened by colonoscopy. The total average clinical cost per individual screened by FOBT (including costs for screening, diagnosis, initial surveillance, office visits, and associated clinical services averaged across all individuals who received screening FOBT) ranged from $48 in Nebraska to $149 in Greater Seattle. This compared with an average clinical cost per individual for all services related to the colonoscopy screening ranging from $654 in St. Louis to $1600 in Baltimore City. Variations in how sites contracted with providers and in the services provided through CRCSDP affected the cost of clinical services and the complexity of collecting cost data. Health officials may find these data useful in program planning and budgeting. Cancer 2013;119(15 suppl):2863-9. © 2013 American Cancer Society. 23756138 Chronic testosterone propionate supplement could activated the Nrf2-ARE pathway in the brain and ameliorated the behaviors of aged rats. Aging is usually associated with a progressive disruption of the redox balance leading to recurrent damage resulting from oxidative stress. Oxidative stress resulting from excessive free-radical release is likely implicated in the initiation and progression of motor behavior disorders. Therefore, antioxidant therapies have received considerable attention in motor behavior defects treatment. The nuclear factor erythroid 2-related factor 2 (Nrf2) binds to antioxidant response element (ARE) to induce antioxidant and phase II detoxification enzymes under conditions of oxidative stress, which reduces oxidative stress and accumulation of toxic metabolites. Testosterone has many physiological and behavioral effects throughout the lifespan and shown to affect motor behavior in adult male rats and gonadectomized rats. However, whether Nrf2-ARE pathway is activated after testosterone administration has not been studied in aged rats. The tilting-plane test and the horizontal-wire test as well as the oxidative stress parameters, the expression of Nrf2, heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO1) and the number of tyrosine hydroxylase immunoreactive (TH-ir) cells in brain were examined in aged rats following chronic subcutaneous injections of testosterone propionate (TP). Our study showed that chronic TP supplement significantly ameliorated the decline of balancing reactions and muscular strength associated with aging. Oxidative stress parameters were ameliorate, the expression of Nrf2, HO-1 and NQO1 at protein or gene levels and the number of TH-ir cells significantly increased in substantia nigra or caudate putamen after TP treatment in aged rats. Our findings demonstrated that chronic TP treatment activated Nrf2-ARE pathway may influence the maintenance of the balancing reactions and muscular strength and reduce TH-ir cells death in aged rats. Therefore, TP supplement have shown for therapeutic strategies in the treatment and modification of motor behavior disorders. 23558678 Annexin A2 regulates β1 integrin internalization and intestinal epithelial cell migration. The gastrointestinal epithelium functions as an important barrier that separates luminal contents from the underlying tissue compartment and is vital in maintaining mucosal homeostasis. Mucosal wounds in inflammatory disorders compromise the critical epithelial barrier. In response to injury, intestinal epithelial cells (IECs) rapidly migrate to reseal wounds. We have previously observed that a membrane associated, Actin binding protein, Annexin A2 (AnxA2), is up-regulated in migrating IECs and plays an important role in promoting wound closure. To identify the mechanisms by which AnxA2 promotes IEC movement and wound closure we used a loss of function approach. AnxA2 specific shRNA was utilized to generate IECs with stable down-regulation of AnxA2. Loss of AnxA2 inhibited IEC migration while promoting enhanced cell-matrix adhesion. These functional effects were associated with increased levels of β1 integrin protein, which is reported to play an important role in mediating the cell-matrix adhesive properties of epithelial cells. Since cell migration requires dynamic turnover of integrin based adhesions, we tested if AnxA2 modulates internalization of cell surface β1 integrin required for forward cell movement. Indeed, pulse-chase biotinylation experiments in IECs lacking AnxA2 demonstrated a significant increase in cell surface β1 integrin that was accompanied by decreased β1 integrin internalization and degradation. These findings support an important role of AnxA2 in controlling dynamics of β1 integrin at the cell surface that in turn is required for the active turnover of cell-matrix associations, cell migration and wound closure. 23253895 Neurocognitive function and state cognitive stress appraisal predict cortisol reactivity to an acute psychosocial stressor in adolescents. Stress and associated alterations in hypothalamic-pituitary-adrenal (HPA) function have deleterious influence on the development of multiple mental and physical health problems. Prior research has aimed to identify individuals most at risk for the development of these stress-related maladies by examining factors that may contribute to inter-individual differences in HPA responses to acute stress. The objectives of this study were to investigate, in adolescents, (1) whether differences in neurocognitive abilities influenced cortisol reactivity to an acute stressor, (2) whether internalizing psychiatric disorders influenced this relationship, and (3) whether acute cognitive stress-appraisal mechanisms mediated an association between neurocognitive function and cortisol reactivity. Subjects were 70 adolescents from a community sample who underwent standardized neurocognitive assessments of IQ, achievement, and declarative memory measures at mean age 14 and whose physiological and behavioral responses to a standardized psychosocial stress paradigm (Trier Social Stress Test, TSST) were assessed at mean age 18. Results showed that, among all adolescents, lower nonverbal memory performance predicted lower cortisol reactivity. In addition, internalizing disorders interacted with verbal memory such that the association with cortisol reactivity was strongest for adolescents with internalizing disorders. Finally, lower secondary cognitive appraisal of coping in anticipation of the TSST independently predicted lower cortisol reactivity but did not mediate the neurocognitive-cortisol relationship. Findings suggest that declarative memory may contribute to inter-individual differences in acute cortisol reactivity in adolescents, internalizing disorders may influence this relationship, and cognitive stress appraisal also predicts cortisol reactivity. Developmental, research, and clinical implications are discussed. 23719088 Methicillin-resistant Staphylococcus aureus carrying SCCmec type II was more frequent than the Brazilian endemic clone as a cause of nosocomial bacteremia. Fifty consecutive MRSA blood isolates were evaluated: 30(60%) carried SCCmec type II (single PFGE clone; sequence type 5 or ST105); 12 (26%), IV; 5 (10%), III; 3 (6%), I. Brazilian endemic clone, carrying SCCmec type III, has been the main nosocomial clone in Brazil; however, this study showed that a clone carrying type II predominated. 23848995 Activation of SNAT1/SLC38A1 in human breast cancer: correlation with p-Akt overexpression. SNAT1 is a subtype of the amino acid transport system A that has been implicated to play a potential role in cancer development and progression, yet its role in breast cancer remains unclear. In present study, we detected SNAT1 expression in breast cancers and explored its underlying mechanism in promoting breast carcinogenesis. RT-PCR and Western blotting were performed to analyze the transcription and protein levels of SNAT1 in breast cancer cell lines and fresh tissues. Tissue microarray blocks containing breast cancer specimens obtained from 210 patients were constructed. Expression of SNAT1 in these specimens was analyzed using immunohistochemical studies. SNAT1 was down-regulated by SNAT1-shRNA in breast cancer cells and the functional significance was measured. SNAT1 was up-regulated in breast cancer cell lines and breast cancer tissues. Overexpression of SNAT1 was observed in 127 cases (60.5%). Expression of SNAT1 was significantly associated with tumor size, nodal metastasis, advanced disease stage, Ki-67, and ER status. Suppression of endogenous SNAT1 leads to cell growth inhibition, cell cycle arrest, and apoptosis of 4T1 cells and lowered the phosphorylation level of Akt. SNAT1 expression correlated significantly with p-Akt expression in human breast cancer samples. The cross-talk between Akt signaling and SNAT1 might play a critical role in the development and progression of breast cancer, providing an important molecular basis for novel diagnostic markers and new attractive targets in the treatment of breast cancer patients. 23733916 Evaluation of the role of endomyocardial biopsy in 851 patients with unexplained heart failure from 2000-2009. Background- Endomyocardial biopsy (EMB) is often considered when the pathogenesis of heart failure cannot be determined by noninvasive testing. Uncertainty remains about the diagnostic and clinical use of EMB in various clinical scenarios. Methods and Results- We examined the characteristics of a cohort of patients with unexplained heart failure who underwent EMB at a tertiary care medical center. We categorized each patient into a clinical scenario as outlined by the 2007 AHA/ACC/ESC guidelines and determined the number of times EMB provided a diagnosis or altered the clinical course. A total of 851 patients underwent EMB from 2000-2009. Overall, 25.5% of EMBs provided a diagnosis and 22.7% of EMBs changed clinical course. Heart failure associated with unexplained restrictive cardiomyopathy was the most common clinical scenario, comprising 33.6% (286/851) of EMBs, and 84 (29.4%) of these EMBs were diagnostic. EMB for unexplained heart failure of <2 weeks duration had a diagnostic yield at 35% (39/109). There were 4 uncommon scenarios where EMB had a high diagnostic and clinical yield. There were 16 complications for an overall rate of 1.9%. Conclusions- We confirm that EMB is useful in acute onset unexplained cardiomyopathy. We demonstrate a role for EMB in suspected infiltrative disease and in the management of rare clinical scenarios, such as suspected hypersensitivity myocarditis, anthracycline cardiomyopathy, cardiac tumors, and arrhythmogenic right ventricular dysplasia/cardiomyopathy. Our results suggest low use of EMB in chronic heart failure that responds to usual care. 23941808 Designer thermal switches: the effect of the contact material on instantaneous thermoelectric transport through a strongly interacting quantum dot. We investigate the effect of contact material on the instantaneous thermoelectric response of a quantum dot pushed suddenly into the Kondo regime via a gate voltage using time dependent non-crossing approximation and linear response Onsager relations. We utilize graphene and metal contacts for this purpose. Instantaneous thermopower displays sinusoidal oscillations whose frequency is proportional to the energy separation between the van Hove singularity in the contact density of states and the Fermi level for both cases, regardless of the asymmetry factor at the onset of the Kondo timescale. The amplitude of the oscillations increases with decreasing temperature, saturating around the Kondo temperature. We also calculate the instantaneous figure of merit and show that the oscillations taking place at temperatures above the Kondo temperature are enhanced more than the ones occurring at lower temperatures due to the violation of the Wiedemann-Franz law. Graphene emerges as a more promising electrode candidate than ordinary metals in single electron devices since it can minimize these oscillations. 23883415 Palladium(II)-Catalyzed Enantioselective Synthesis of α-(Trifluoromethyl)arylmethylamines. Trifluoromethylacetaldimines, generated in situ from the corresponding N,O-acetals, undergo 1,2-addition of arylboroxines under palladium(II) catalysis to generate a variety of α-(trifluoromethyl)arylmethylamines with good to high enantioselectivity (up to 97% ee). The pyridine-oxazolidine (PyOX) class of ligands was found to be particularly suitable for this transformation, which proceeds without exclusion of ambient air and moisture. 23948593 Glutathione controls the redox state of the mitochondrial carnitine/acylcarnitine carrier Cys residues by glutathionylation. The mitochondrial carnitine/acylcarnitine carrier (CAC) is essential for cell metabolism since it catalyzes the transport of acylcarnitines into mitochondria allowing the β-oxidation of fatty acids. CAC functional and structural properties have been characterized. Cys residues which could form disulfides suggest the involvement of CAC in redox switches. The effect of GSH and GSSG on the [(3)H]-carnitine/carnitine antiport catalyzed by the CAC in proteoliposomes has been studied. The Cys residues involved in the redox switch have been identified by site-directed mutagenesis. Glutathionylated CAC has been assessed by glutathionyl-protein specific antibody. GSH led to increase of transport activity of the CAC extracted from liver mitochondria. A similar effect was observed on the recombinant CAC. The presence of glutaredoxin-1 (Grx1) accelerated the GSH activation of the recombinant CAC. The effect was more evident at 37°C. GSSG led to transport inhibition which was reversed by dithioerythritol (DTE). The effects of GSH and GSSG were studied on CAC Cys-mutants. CAC lacking C136 and C155 was insensitive to both reagents. Mutants containing these two Cys responded as the wild-type. Anti-glutathionyl antibody revealed the formation of glutathionylated CAC. CAC is redox-sensitive and it is regulated by the GSH/GSSG couple. C136 and C155 are responsible for the regulation which occurs through glutathionylation. CAC is sensitive to the redox state of the cell switching between oxidized and reduced forms in response to variation of GSSG and GSH concentrations. 23877223 Characterization of a multidrug-resistant chronic myeloid leukemia cell line presenting multiple resistance mechanisms. The multidrug-resistant (MDR) phenotype is multifactorial, and cell lines presenting multiple resistance mechanisms might be good models to understand the importance of the various pathways involved. The present work characterized a MDR chronic myeloid leukemia cell line, derived from K562 through a selective process using daunorubicin. This MDR cell line was shown to be resistant to vincristine, daunorubicin, and partially resistant to imatinib. It showed a slower duplication rate. Overexpression of ABCB1 and ABCC1 was observed at the protein and functional levels and the expression of CD95, a molecule related to cell death, was reduced in the MDR cell line. Conversely, no differences were observed related to the anti-apoptotic molecule Bcl-2 or p53 expression. The activation antigen CD69 was reduced in the MDR cell line and treatment with imatinib further decreased the expressed levels. Furthermore, secretion of IL-8 was diminished in the MDR cell line. When daunorubicin-selected cells were compared to another MDR cell line, Lucena 1, derived from the same parental line K562, and selected with vincristine, a different profile was observed in relation to most aspects studied. When both cell lines were silenced for ABCB1, differences in CD69 and CD95 were maintained, despite resistance reversal. These results reinforce the idea that cell lines selected in vitro may display multiple resistance strategies that may vary with the selective agent used as well as during different steps of the selection process. 23773679 Strategies for defining traits when calculating economic values for livestock breeding: a review. The objective of the present review was (i) to survey different approaches for choosing the complex of traits for which economic values (EVs) are calculated, (ii) to call attention to the proper definition of traits and (iii) to discuss the manner and extent to which relationships among traits have been considered in the calculation of EVs. For this purpose, papers dealing with the estimation of EVs of traits in livestock were reviewed. The most important reasons for incompatibility of EVs for similar traits estimated in different countries and by different authors were found to be inconsistencies in trait definitions and in assumptions being made about relationships among traits. An important problem identified was how to choose the most appropriate criterion to characterise production or functional ability for a particular class of animals. Accordingly, the review covered the following three topics: (i) which trait(s) would best characterise the growth ability of an animal; (ii) how to define traits expressed repeatedly in subsequent reproductive cycles of breeding females and (iii) how to deal with traits that differ in average value between sexes or among animal groups. Various approaches that have been used to solve these problems were discussed. Furthermore, the manner in which diverse authors chose one or more traits from a group of alternatives for describing a specific biological potential were reviewed and commented on. The consequences of including or excluding relationships among economically important traits when estimating the EV for a specific trait were also examined. An important conclusion of the review is that, for a better comparability and interpretability of estimated EVs in the literature, it is desirable that clear and unique definitions of the traits, complete information on assumptions used in analytical models and details on inter-relationships between traits are documented. Furthermore, the method and the model used for the genetic evaluation of specific traits in a certain breeding organisation are important for the exact definition of traits, for which the economic values will be calculated, and for the inclusion or exclusion of relationships among traits in the calculation of the EVs in livestock breeding. 23263854 Consequences of manganese administration for striatal dopamine and motor behavior in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-exposed C57BL/6 mice. Environmental compounds may be important contributors to Parkinson's disease etiology. Epidemiological and experimental evidence for the facilitation of parkinsonism by manganese is equivocal. This work addressed methodological concerns in the few studies of manganese modulation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity in C57BL/6 mice. Male, retired breeder mice received 0 or 100 mg/kg of manganese chloride (MnCl₂; subcutaneously on days 1, 4 and 7) and 0 or 20 mg/kg of MPTP (intraperitoneally on day 8) and survived up to day 15 or 22. On the day of sacrificing, horizontal (grid crossing) and vertical (rearing) open field movement, swimming, grip strength and grip fatigue were examined. Striata were analyzed for dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) using high-performance liquid chromatography. MPTP produced a main effect decrease in striatal dopamine (48.8%) and DOPAC (38.1%), but there was no main effect of MnCl₂ or MnCl₂ x MPTP interaction. However, modulatory interactions were observed between the effects of MnCl₂ and MPTP for grid crossing, rearing and grip strength. Interestingly, these interactions reduced the severity of behavioral deficits attributable to either of these compounds alone. For rearing and grip strength, the MnCl₂ x MPTP interaction was dependent upon survival time. The mechanistic nature of the MnCl₂ x MPTP interaction upon these behaviors, in the absence of such an interaction for striatal dopamine and DOPAC, remains to be clarified. 23795872 Mania precipitated by opioid withdrawal: a retrospective study. Little evidence is available on the occurrence of mania following opioid withdrawal. This is the first report on clinical and demographic characteristics of mania precipitated by opioid withdrawal in a relatively large sample. In this study, we assessed the files of the patients admitted to a large referral psychiatric hospital during a 3-year period with a presentation of manic episode shortly after opioid withdrawal. Forty-five relevant cases (one woman) were found, including 28 patients with their first manic episode, and 17 patients with a previous history of bipolar disorder. Most of the identified cases had a long history (mean = 11.8 years) of opium dependence (24 cases used only opium and 16 cases opium and other opioids) and had recently experienced an intense withdrawal (25 cases). These associations were present in both first-episode patients and those with recurrent episodes. Emergence of mania following opioid withdrawal could be partly explained by mood stabilizing effects of opioids. Other than the type of opioid, it seems that the duration of use and withdrawal method might play a role. Caution should be used while detoxifying patients with a long history of opioid use. 23444342 Obesity and insulin resistance in pediatric acute lymphoblastic leukemia worsens during maintenance therapy. Pediatric acute lymphoblastic leukemia (ALL) survivors are at increased risk for the metabolic syndrome (MS). To establish the trajectory of development during active treatment, we followed patients longitudinally over the first year of maintenance therapy. In a prospective cohort of 34 pediatric ALL patients, followed over the first 12 months of ALL maintenance, we evaluated changes in body mass index (BMI), blood pressure, fasting insulin and glucose, lipids, Homeostatic Metabolic Assessment (HOMA), leptin, and adiponectin. Over the study time period, the median BMI z-score increased from 0.29 to 0.66 (P = 0.001), median fasting insulin levels increased from 2.9 to 3.1 µU/ml (P = 0.023), and the proportion of patients with insulin resistance by HOMA (>3.15) increased from 3% to 24% (P = 0.016). Median leptin increased from 2.5 to 3.5 ng/ml (P = 0.001), with levels correlated with BMI z-score. Median adiponectin level decreased from 18.0 to 14.0 µg/ml (P = 0.009), with levels inversely correlated to BMI z-score. No change in median total cholesterol and LDL levels was observed. Median triglycerides decreased (P < 0.001) and there was a trend to increase in HDL (P = 0.058). Blood pressure did not significantly change, although overall prevalence of systolic and diastolic hypertension was high (23.5% and 26.4%, respectively). Following patients over the first year of ALL maintenance therapy demonstrated that components of the MS significantly worsen over time. Preventive interventions limiting increases in BMI and insulin resistance during maintenance therapy should be targeted during this time period to avoid long-term morbidity associated with the MS in long-term survivors. 23354179 Contrasting patterns of community assembly in the stratified water column of great salt lake, utah. Phylogenetic examinations of communities sampled along geochemical gradients provide a framework for inferring the relative importance of niche-based ecological interactions (competition, environmental filtering) and neutral-based evolutionary interactions in structuring biodiversity. Great Salt Lake (GSL) in Utah exhibits strong spatial gradients due to both seasonal variation in freshwater input into the watershed and restricted fluid flow within North America's largest saline terminal lake ecosystem. Here, we examine the phylogenetic structure and composition of archaeal, bacterial, and eukaryal small subunit (SSU) rRNA genes sampled along a stratified water column (DWR3) in the south arm of GSL in order to infer the underlying mechanism of community assembly. Communities sampled from the DWR3 epilimnion were phylogenetically clustered (i.e., coexistence of close relatives due to environmental filtering) whereas those sampled from the DWR3 hypolimnion were phylogenetically overdispersed (i.e., coexistence of distant relatives due to competitive interactions), with minimal evidence for a role for neutral processes in structuring any assemblage. The shift from phylogenetically clustered to overdispersed assemblages was associated with an increase in salinity and a decrease in dissolved O2 (DO) concentration. Likewise, the phylogenetic diversity and phylogenetic similarity of assemblages was strongly associated with salinity or DO gradients. Thus, salinity and/or DO appeared to influence the mechanism of community assembly as well as the phylogenetic diversity and composition of communities. It is proposed that the observed patterns in the phylogenetic composition and structure of DWR3 assemblages are attributable to the meromictic nature of GSL, which prevents significant mixing between the epilimnion and the hypolimnion. This leads to strong physicochemical gradients at the halocline, which are capable of supporting a greater diversity. However, concomitant shifts in nutrient availability (e.g., DO) at and below the halocline drive competitive interactions leading to hypolimnion assemblages with minimal niche overlap. 23371817 Inadequate levothyroxine replacement for primary hypothyroidism is associated with poor health-related quality of life-a Brazilian multicentre study. This study aimed to verify the impact of levothyroxine replacement on health-related quality of life (HRQoL) in a Brazilian sample of primary hypothyroidism patients. A cross-sectional study was performed with 2,057 consecutive primary hypothyroidism patients on levothyroxine (LT4) replacement at four referral centers in Brazil (median age = 53; 25th percentile = 43; 75th percentile = 61 years). Patient biochemical data were acquired from medical records, and patients completed a questionnaire on socioeconomic issues and clinical signs and symptoms of hypothyroidism. HRQoL was assessed using the SF-36v2. Patients were divided into three groups according to TSH levels: overtreated (OvT; TSH < 0.4 mU/L), appropriately treated (AT; TSH between 0.4 and 4.0 mU/L), and undertreated (UnT; TSH > 4.0 mU/L). Patients were also analyzed by TSH and FT4 serum levels: overt hyperthyroidism (OHyper; TSH < 0.4 mU/L and FT4 > 1.9 ng/dL), subclinical hyperthyroidism (SHyper; TSH < 0.4 mU/L and FT4 0.8-1.9 ng/dL), subclinical hypothyroidism (SHypo; TSH > 4.0 mU/L and FT4 0.8-1.9 ng/dL), and overt hypothyroidism (OHypo; TSH > 4.0 mU/L and FT4 < 0.8 ng/dL). A total of 14.4 % of patients were OvT, with 13.0 % SHyper and 1.4 % OHyper. The prevalence of UnT was 25.9 %, with 21.5 % SHypo and 4.4 % OHypo. Overtreatment was not associated with HRQoL impairment. UnT patients had worse HRQoL than AT patients, especially for physical and emotional aspects, independent of SHypo or OHypo status. Hypothyroidism undertreatment is associated with poor patient HRQoL. Therefore, adequate LT4 therapy should be given to maintain serum TSH within the reference range. 23925995 The risk of cardiovascular disease in patients with osteoarthritis: A prospective longitudinal study. Objective: Our objective was to determine the risk of cardiovascular disease (CVD) among osteoarthritis (OA) patients using population-based administrative data from British Columbia, Canada. Methods: The medical history of a random sample of 600,000 individuals from years 1991 to 2009 were analyzed. 12,745 OA cases and up to 3 non-OA individuals matched by age, sex, and year of diagnosis were followed for CVD events. Cox proportional hazards and Poisson regression models were used to estimate the relative risks (RR) of CVD, myocardial infarction (MI), ischemic heart disease (IHD), congestive heart failure (CHF), and stroke after adjusting for available socio-demographic and medical factors. Results: OA was an independent predictor of CVD. The adjusted RRs (95% CI) were 1.15 (1.04-1.27), 1.26 (1.13- 1.42), and 1.17 (1.07-1.26) among older men, younger women, and older women, respectively. Analyses were stratified by age and sex due to statistically significant interactions between OA and age and sex. RRs (95% CI) among older men, younger women, and older women, respectively, were 1.33 (1.11-1.62), 1.66 (1.37-2.01), and 1.45 (1.22-1.72) for IHD, and 1.25 (1.02-1.54), 1.29 (1.00-1.68), and 1.20 (1.03-1.39) for CHF. Compared to no-OA individuals, OA cases underwent total joint replacements had a 26% increased risk of CVD. Conclusion: This prospective longitudinal study suggests that OA is associated with the increased risk of CVD. Older men and adult women with OA had a higher risk of CVD, particularly IHD and CHF. Further studies are needed to confirm these results and to elucidate the potential biological mechanisms. © 2013 American College of Rheumatology. 23897423 Primary Hypertension in Childhood. There is growing concern about elevated blood pressure in children and adolescents, because of its association with the obesity epidemic. Moreover, cardiovascular function and blood pressure level are determined in childhood and track into adulthood. Primary hypertension in childhood is defined by persistent blood pressure values ≥ the 95th percentile and without a secondary cause. Preventable risk factors for elevated blood pressure in childhood are overweight, dietary habits, salt intake, sedentary lifestyle, poor sleep quality and passive smoking, whereas non-preventable risk factors include race, gender, genetic background, low birth weight, prematurity, and socioeconomic inequalities. Several different pathways are implicated in the development of primary hypertension, including obesity, insulin resistance, activation of the sympathetic nervous system, alterations in sodium homeostasis, renin-angiotensin system and altered vascular function. Prevention of adult cardiovascular disease should begin in childhood by regularly screening for high blood pressure, counseling for healthy lifestyle and avoiding preventable risk factors. 23680817 Antidepressant medication augmented with cognitive-behavioral therapy for generalized anxiety disorder in older adults. OBJECTIVE Generalized anxiety disorder is common among older adults and leads to diminished health and cognitive functioning. Although antidepressant medications are efficacious, many elderly individuals require augmentation treatment. Furthermore, little is known about maintenance strategies for older people. The authors examined whether sequenced treatment combining pharmacotherapy and cognitive-behavioral therapy (CBT) boosts response and prevents relapse in older adults with generalized anxiety disorder. METHOD Participants were individuals at least 60 years of age with generalized anxiety disorder (N=73) who were recruited from outpatient clinics at three sites. Participants received 12 weeks of open-label escitalopram and were then randomly assigned to one of four conditions: 16 weeks of escitalopram (10-20 mg/day) plus modular CBT, followed by 28 weeks of maintenance escitalopram; escitalopram alone, followed by maintenance escitalopram; escitalopram plus CBT, followed by pill placebo; and escitalopram alone, followed by placebo. RESULTS Escitalopram augmented with CBT increased response rates on the Penn State Worry Questionnaire but not on the Hamilton Anxiety Rating Scale compared with escitalopram alone. Both escitalopram and CBT prevented relapse compared with placebo. CONCLUSIONS This study demonstrates effective strategies for treatment of generalized anxiety disorder in older adults. The sequence of antidepressant medication augmented with CBT leads to worry reduction in the short-term. Continued medication prevents relapse, but for many individuals, CBT would allow sustained remission without requiring long-term pharmacotherapy. 23702040 Antidepressant-like effect of ethanol extract from Zuojin Pill, containing two herbal drugs of Rhizoma Coptidis and Fructus Evodiae, is explained by modulating the monoaminergic neurotransmitter system in mice. Zuojin Pill (ZJP), a traditional Chinese medicinal decoction, contains two herbal drugs: Coptis chinensis Franch. and Evodia rutaecarpa (Juss.) Benth. in the ratio of 6:1 (w/w). Previous pharmacological studies have shown that two herbs in ZJP have the antagonistic effects on catecholamine secretion in bovine adrenal medullary cells. Furthermore, the alkaloids from the two herbs in ZJP may provide a protective effect for depression in individuals with a low expressing 5-HTT allele by increasing receptor concentration in serotonergic neurons. However, antidepressant effect has not been reported before and has not been fully clarified. The present study aimed to investigate the antidepressant potential of ethanol extract from ZJP and its monoaminergic mechanism in mice. Seven alkaloids were determined from the ethanol extract of ZJP using High Performance Liquid Chromatography (HPLC) with the gradient mobile phase. The ethanol extract from ZJP was used to evaluate the antidepressant potential in mice. Mouse models of depression including the tail suspension test (TST) and the forced swim test (FST) were used to evaluate the effects of the ethanol extract from ZJP. A possible mechanism was explored in the tests of antagonism of reserpine-induced ptosis and hypothermia, and 5-HTP induced head twitch response in mice. The contents of monoamine neurotransmitters including norepinephrine (NE), serotonin (5-hydroxytryptamine or 5-HT) in hippocampus of mice and NE, 5-HT, dopamine (DA) in striatum of mice were determined by HPLC system with Electrochemical Detector (ECD). The results showed that intragastric administration of the ethanol extract from ZJP (5, 10, 20mg/kg) or fluoxetine (7.5mg/kg) significantly reduced the duration of immobility in TST and FST. However, the effect was not dose-dependent. Ethanol extract from ZJP (5, 10, 20mg/kg) also increased the accumulative number of the 5-HTP-induced head twitch response in mice. The mice were treated with the ethanol extract from ZJP (5, 10, 20mg/kg) or fluoxetine (7.5mg/kg), which could antagonize reserpine-induced ptosis and hypothermia, moreover, both of them could elevate the contents of NE, 5-HT in hippocampus as well as NE, 5-HT, DA in striatum significantly. These results indicate that the ethanol extract from ZJP produced antidepressant-like effect and the possible mechanism, at least in part, is via the central monoaminergic neurotransmitter system and 5-HT plays a major role. 23970797 The noninflammatory role of high mobility group box 1/toll-like receptor 2 axis in the self-renewal of mammary cancer stem cells. Cancer stem cells (CSCs) are responsible for tumor progression, metastases, resistance to therapy, and tumor recurrence. Therefore, the identification of molecules involved in CSC self-renewal is a necessary step toward more effective therapies. To this aim, through the transcription profiling of the murine ErbB2(+) tumor cell line TUBO vs. derived CSC-enriched mammospheres, Toll-like receptor 2 (TLR2) was identified as 2-fold overexpressed in CSCs, as confirmed by qPCR and cytofluorimetric analysis. TLR2 signaling inhibition impaired in vitro mammosphere generation in murine TUBO (60%) and 4T1 (30%) and human MDA-MB-231 (50%), HCC1806 (60%), and MCF7 (50%) cells. In CSC, TLR2 was activated by endogenous high-mobility-group box 1 (HMGB1), inducing IκBα phosphorylation, IL-6 and TGFβ secretion, and, consequently, STAT3 and Smad3 activation. In vivo TLR2 inhibition blocked TUBO tumor takes in 9/14 mice and induced a 2-fold reduction in lung metastases development by decreasing cell proliferation and vascularization and increasing apoptosis. Collectively, these results demonstrate that murine and human mammary CSCs express TLR2 and its ligand HMGB1; this autocrine loop plays a pivotal role in CSC self-renewal, tumorigenesis, and metastatic ability. These findings, while providing evidence against the controversial use of TLR2 agonists in antitumor therapy, lay out new paths toward the design of anticancer treatments.-Conti, L., Lanzardo, S., Arigoni, M., Antonazzo, R., Radaelli, E., Cantarella, D., Calogero, R. A., Cavallo, F. The noninflammatory role of high mobility group box 1/toll-like receptor 2 axis in the self-renewal of mammary cancer stem cells. 23773911 Targeting epigenetics for cancer prevention by dietary cancer preventive compounds--the case of miRNA. In cancer, genetic mutations have long been considered to be the only driver of neoplasia. However, there is increasing evidence that epigenetic alterations could also play a major role in carcinogenesis and cancer. A number of experimental and epidemiologic studies have shown that many classes of dietary phytochemicals possess cancer-preventive and epigenetic-modifying properties. The report by Derry and colleagues in this issue of the journal shows that grape seed extract (GSE) prevents azoxymethane (AOM)-induced colon colitis via epigenetic microRNA (miRNA) regulation. Although the precise mechanism underlying the control of miRNA expression is not well understood currently, epigenetic changes could play a major role. This report, along with increasing evidence showing the impact of dietary phytochemicals on epigenetic activities, offers new perspectives on miRNA and epigenetic regulation in cancer prevention. 23967353 Microtubule-Associated Type II Protein Kinase A Is Important for Neurite Elongation. Neuritogenesis is a process through which neurons generate their widespread axon and dendrites. The microtubule cytoskeleton plays crucial roles throughout neuritogenesis. Our previous study indicated that the amount of type II protein kinase A (PKA) on microtubules significantly increased upon neuronal differentiation and neuritogenesis. While the overall pool of PKA has been shown to participate in various neuronal processes, the function of microtubule-associated PKA during neuritogenesis remains largely unknown. First, we showed that PKA localized to microtubule-based region in different neurons. Since PKA is essential for various cellular functions, globally inhibiting PKA activity will causes a wide variety of phenotypes in neurons. To examine the function of microtubule-associated PKA without changing the total PKA level, we utilized the neuron-specific PKA anchoring protein MAP2. Overexpressing the dominant negative MAP2 construct that binds to type II PKA but cannot bind to the microtubule cytoskeleton in dissociated hippocampal neurons removed PKA from microtubules and resulted in compromised neurite elongation. In addition, we demonstrated that the association of PKA with microtubules can also enhance cell protrusion using the non-neuronal P19 cells. Overexpressing a MAP2 deletion construct which does not target PKA to the microtubule cytoskeleton caused non-neuronal cells to generate shorter cell protrusions than control cells overexpressing wild-type MAP2 that anchors PKA to microtubules. Finally, we demonstrated that the ability of microtubule-associated PKA to promote protrusion elongation was independent of MAP2 phosphorylation. This suggests other proteins in close proximity to the microtubule cytoskeleton are involved in this process. 23161347 Perception-production asymmetries in homophone spelling: the unique influence of aging. Objectives. This research investigated three potential asymmetries in the production and perception of homophone spelling errors: aging, homophone dominance, and priming. A homophone spelling error occurs when a contextually appropriate word (beet) is replaced with its homophone (e.g., beat glaze). Two experiments investigated young and older adults' written production and detection of these errors. Method. Participants wrote sentences (Experiment 1) or detected errors in sentences (Experiment 2) containing a dominant homophone (beat) or subordinate homophone (beet). Homophones were preceded by a prime (neat) that shared orthography with the contextually inappropriate homophone (beat) or by an unrelated control word (fun). Results revealed an aging asymmetry in production and detection as a function of dominance. Older adults made more errors than young adults when producing dominant homophones but fewer errors in producing subordinate homophones. In contrast, older adults consistently made fewer errors than young adults when detecting homophone errors. Independent of aging, dominance had similar effects on production and detection, with more errors on subordinate homophones. Priming had asymmetric effects different from aging by increasing errors in production but not detection. Discussion. These results suggest aging uniquely dissociates perception and production of homophone spelling and demonstrate circumstances under which aging benefits language processing. 23453700 What factors influence midwives' decision to perform or avoid episiotomies? A focus group study. to explore midwives' reasons for performing or avoiding episiotomies and motivation to change episiotomy practice in a large tertiary maternity hospital. using purposive sampling, three focus groups were conducted to achieve theme saturation. Open-ended questions elicited personal reasons for performing or avoiding episiotomy, information sources, and opinions about past and future practice trends. Sessions were audiotaped, and transcripts independently examined by three researchers who coded for themes. An iterative process was used to achieve consensus. Grounded theory was used to interpret data and to derive a theoretical framework for understanding the reasoning that influences episiotomy practice. a high volume delivery unit in Singapore. 20 of 79 licensed midwives, aged 28-70, who performed independent deliveries at the delivery unit. participants recognised maternal, fetal and other factors affecting their own decision to perform episiotomies. Patient request, better healing, midwife's reputation and job satisfaction were cited as main reasons to avoid episiotomy. Key sources informing practice were past training, delivery experience, anecdotal learning and lack of a protocol. There was no consensus on current trends in episiotomy practice. There was an absence of recognition of individual roles in reducing episiotomy rates. Clinicians were perceived as having both positive and negative influence. midwives' reasons for performing episiotomies were attributed to midwifery training, fear of doing harm and perceived clinician expectation, and were not consistent with current international practice guidelines. Reasons for avoiding episiotomies were associated with patient-centeredness and job satisfaction. Midwives agreed on the need to reduce episiotomy rates. with reduction in episiotomy rates as a goal, a combination of guideline education, feedback, peer coaching and collaborative care with doctors may be needed to achieve desired outcomes. Views and experiences of midwives should also be incorporated into strategies to change episiotomy practice. 23965973 Effects of reduced prolamin on seed storage protein composition and the nutritional quality of rice. Rice seed storage proteins accumulate in two types of protein body (PB-I and PB-II) that are nutrient sources for animals. PB-I is indigestible and negatively affects rice protein quality. To improve the nutritional value of rice seeds we are aiming to engineer the composition and accumulation of endogenous seed storage proteins. In this study we generated transgenic rice plants in which 13 kD prolamin genes were suppressed by RNA interference (13 kD pro-RNAi). Analysis based on qRT-PCR confirmed that the targeted 13 kD prolamins were markedly suppressed, and were compensated for by an increase in other storage proteins including 10 kD prolamin, glutelins, and chaperone proteins. The storage protein profiles further revealed that the levels of 13 kD prolamins were significantly reduced, while that of the glutelin precursor was slightly increased and the remaining storage proteins did not change. Amino acid analysis showed that the reduction of 13 kD prolamins resulted in a 28% increase in the lysine content relative to the wild type, indicating that the 13 kD pro-RNAi rice seeds are more nutritious. Furthermore, a reduction in the levels of 13 kD prolamins resulted in abnormal formation of PB-I, which was small and had no lamellar structure. These results suggest that alteration of prolamins can contribute to improving the nutritional quality of rice. 23914939 Interface Chemistry Guided Long-Cycle-Life Li-S Battery. To date, most of the research on electrodes for energy storage has been focused on the active material itself. It is clear that investigating isolated active materials is no longer sufficient to solve all kinds of technological challenges for the development of modern battery infrastructure. From the interface chemistry point of view, a system-level strategy of designing polydopamine coated reduced graphene oxide/sulfur composite cathodes aimed at enhancing cyclic performance was reported in this work. As a soft buffer layer, the polydopamine shell was used to accommodate the volume expansion of S and avoid the leakage of polysulfide during cycling. A cross-link reaction between polydopamine buffer and poly(acrylic acid) binder was further designed to improve the strength of the entire electrode. As a result, the electrode demonstrated excellent cyclic performance with a discharge capacity of 728 mAh/g after 500 cycles at the current density of 0.5 A/g (a very small capacity loss of 0.41 mAh/g per cycle). Most importantly, 530 mAh/g was obtained even at a higher current density of 1 A/g after 800 cycles. Our results indicate the importance of chemically designing interfaces in the whole electrode system on achieving improved performance of electrodes of rechargeable lithium ion batteries. 22941875 Variables associated with time of recovery after hemodialysis. Background: The aim of this study was to evaluate the relationship among time of recovery after hemodialysis (TIRD) and the demographic, social, clinical and laboratory characteristics of hemodialysis patients of a Mediterranean country. Methods: One hundred hemodialysis patients were invited to answer the following question: "How long does it take you to recover from a dialysis session?" Demographic, clinical (Charlson Comorbidity Index [CCI], Mini-Mental State Examination [MMSE] and Geriatric Depression Scale [GDS]) and laboratory variables were recorded, and fatigue qualities (FQs) were assessed through 5 questions: Do you feel tired much of the time? (general); Do you feel that life is empty? (emotional); Do you have trouble concentrating? (cognitive); Do you have difficulty sleeping? (sleepiness); Do you have muscle weakness? (weakness); and Do you feel full of energy? (lack of energy). Results: The means ± SD of TIRD was 205.5 ± 198.6 minutes: 79 patients reported a TIRD <=4 hours, and 21 <=2 hours. TIRD did not differ between males and females (p = 0.382), patients with and without diabetes (p = 0.581), patients with and without coronary disease (p = 0.095), and patients with and without cerebrovascular disease (p = 0.941). CCI, the number of FQs, and GDS and MMSE scores were significantly correlated with the TIRD at univariate analysis. At multiple regression analysis, the number of FQs was related to the TIRD (coefficient 46.99; SE = 17.04; p = 0.008). Excluding the variable FQ, the GDS was independently associated with TIRD (coefficient 3.21; SE = 9.26; p = 0.729). Conclusion: TIRD was independently associated with the number of FQs. When that variable was excluded from the analysis, TIRD was independently associated with the GDS. 23327600 Dynamic Domains in Polymersomes: Mixtures of Polyanionic and Neutral Diblocks Respond More Rapidly to Changes in Calcium than to pH. Chemical triggering of membrane domain dynamics is of broad relevance to cell signaling through lipid bilayers and might also be exploited in application of phase-separated vesicles. Here we describe the morphodynamics and remixing kinetics of spotted polymersomes made with mixtures of polyanionic and neutral amphiphiles plus calcium. Addition of the calcium chelator EDTA to vesicle dispersions produced a decrease in domain size within minutes, whereas increasing the pH with NaOH led to the viscous fingering of domains and decreased domain size over hours. Although the latter suggests that the charge of the polyanion contributes to domain formation, the remixing of more negative chains at high pH is surprising. Domain roughening at high pH is also accelerated by EDTA, which highlights the dominance of cross-bridging. Importantly, even though vesicles were perturbed only externally, the inner and outer leaflets remain coupled throughout, consistent with molecular dynamics simulations and suggestive of an order-disorder transition that underlies the remixing kinetics. 23786249 Do Interleukin-10 and Superoxide Ions Predict Outcomes of Cardiac Extracorporeal Membrane Oxygenation Patients? Abstract Extracorporeal membrane oxygenation (ECMO) is used for cardiogenic shock rescue. It is hard to predict the outcome from this treatment by clinical observation in days soon after installation. We analyzed the plasma levels of interleukin (IL)-6, IL-8, IL-10, reactive oxygen species, and 8-OHdG, and the glutathione peroxidase activities from 23 cases at the time of ECMO installation before resuscitation. Generalized additive models (GAM) were performed to identify the death ranges of every variable, and the variables were further discretized. The impaired release of IL-10 on shock led to death. IL-10 levels at >16.58 pg/ml differentiated death from survival for acute myocardial infarction (AMI) patients, and levels at >143.17 pg/ml did the same for dilated cardiomyopathy (DCMP) patients. The prediction power of discretized IL-10 alone was measured as area under the curve (AUC) 0.913. The generalized linear model was then performed to predict the best composition from both the original and discretized variables and resulted in AUC 0.97 for the combined discretized IL-10 and superoxide ions. Two missed myocarditis cases from IL-10 prediction were resolved by superoxide ion levels. Our observations lead to the hypothesis that a proper response to cardiogenic shock by releasing the appropriate amount of IL-10 is required for survival in the cases of AMI and DCMP. For myocarditis, proper responses in IL-10 and superoxide ions are needed. 23847546 Cough expired volume and airflow rates during sequential induced cough. Cough effectiveness is determined by a combination of volume of air expired and maximum expiratory airflow rate. Studies of cough sensitivity identify cough thresholds based on at least 2 or 5-cough re-accelerations to a stimulus, however, to date no study has examined the interplay between the distribution of cough expired air and cough airflow rates for these induced sequential coughs. The goal of this study was to investigate the relationship between reflex cough re-accelerations, cough airflow and cough inspired and expired volume. Twenty adults (18-40 years, four men) volunteered for study participation, and were outfitted with a facemask in-line with a pneumotachograph and a one-way valve for capsaicin delivery on inspiration. Cough inspired and expired volume (Liters of air) as well as airflow parameters (peak expiratory flow rates L/s) were measured for each cough response. Results demonstrate significant linear relationships between cough expired volume, flow rates, and the total number of coughs produced. Thus, as the number of coughs in an epoch increase, the mechanical effectiveness of coughs within the epoch may decrease according to peak expiratory flow rates and cough expired volume, particularly for coughs comprised of more than 3 re-accelerations. 23602980 Hierarchical use of cues in the missing object recognition task by rats (Rattus norvegicus). This study investigated rats' preferences for using non-spatial and spatial cues in a missing-object recognition task. Rats were trained to find a sunflower seed under any one of four previously missing adjacent objects, the test array of a trial, after having found seeds under three of them in the 'study' array of that trial. On some trials the study and test arrays consisted of a different object at each baited food site and on other trials, of identical objects. A previously missing object's position and orientation within its array and its global position within the large foraging chamber varied over trials but not within trials. Following training, rats received interspersed non- or partially rewarded probe trials with transformed test arrays of dissociated non-spatial (object-specific) and spatial cues on test array feeders. Results from these probe trials revealed that rats preferred to search for a missing object based first on its specific non-spatial features before searching for it based on its local spatial features; that is, its local position followed by its orientation, and finally based on its global position. This hierarchical sequence for using spatial cues was preserved under the identical-objects cueing condition. Rats reversed their preferences between object-specific and local position cues, however, when novel objects replaced the same four different objects in a supplementary experiment. We discussed the implications of these findings in terms of the influence of ecological- and context-dependent factors on information use or retrieval from animals' visuo-spatial working memory. 23951249 Differential impact of statin on new-onset diabetes in different age groups: a population-based case-control study in women from an asian country. Statins reduce cardiovascular risks but increase the risk of new-onset diabetes (NOD). The aim of this study is to determine what effect, if any, statins have on the risk of NOD events in a population-based case-control study. An evaluation of the relationship between age and statin-exposure on NOD risks was further examined in a female Asian population. In a nationwide case-controlled study, the authors assessed 1065 female NOD patients and 10650 controls with matching ages, genders and physician visit dates. The impact of statin-exposure on NOD was examined through multiple logistic regression models. Subgroup analysis for exploring the risk of NOD and statin-exposure in different age groups was performed. Statin-exposure was statistically significantly associated with increased new-onset diabetes risks using multivariate analysis. Interaction effect between age and statin-exposure on NOD risk was noted. For atorvastatin, the risk of cDDDs>60 was highest among the 55-64 year-olds (adjusted odds ratio [OR], 8.0; 95% confidence interval [CI], 2.57-24.90). For rosuvastatin, the risk of cDDDs>60 was highest among the 40-54 year-olds (adjusted OR, 14.8; 95% CI, 2.27-96.15). For simvastatin, the risk of cDDDs>60 was highest among the 55-64 year-olds (adjusted OR, 15.8; 95% CI, 5.77-43.26). For pravastatin, the risk of cDDDs>60 was highest among the 55-64 year-olds (adjusted OR, 14.0; 95% CI, 1.56-125.18). This population-based study found that statin use is associated with an increased risk of NOD in women. The risk of statin-related NOD was more evident for women aged 40-64 years compared to women aged 65 or more, and was cumulative-dose dependent. The use of statins should always be determined by weighing the clinical benefits and potential risks for NOD, and the patients should be continuously monitored for adverse effects. 23884203 Maltose-forming α-amylase from the hyperthermophilic archaeon Pyrococcus sp. ST04. The deduced amino acid sequence from a gene of the hyperthermophilic archaeon Pyrococcus sp. ST04 (Py04_0872) contained a conserved glycoside hydrolase family 57 (GH57) motif, but showed <13 % sequence identity with other known Pyrococcus GH57 enzymes, such as 4-α-glucanotransferase (EC 2.4.1.25), amylopullulanase (EC 3.2.1.41), and branching enzyme (EC 2.4.1.18). This gene was cloned and expressed in Escherichia coli, and the recombinant product (P yrococcus sp. ST04 maltose-forming α-amylase, PSMA) was a novel 70-kDa maltose-forming α-amylase. PSMA only recognized maltose (G2) units with α-1,4 and α-1,6 linkages in polysaccharides (e.g., starch, amylopectin, and glycogen) and hydrolyzed pullulan very poorly. G2 was the primary end product of hydrolysis. Branched cyclodextrin (CD) was only hydrolyzed along its branched maltooligosaccharides. 6-O-glucosyl-β-cyclodextrin (G1-β-CD) and β-cyclodextrin (β-CD) were resistant to PSMA suggesting that PSMA is an exo-type glucan hydrolase with α-1,4- and α-1,6-glucan hydrolytic activities. The half-saturation value (K m) for the α-1,4 linkage of maltotriose (G3) was 8.4 mM while that of the α-1,6 linkage of 6-O-maltosyl-β-cyclodextrin (G2-β-CD) was 0.3 mM. The k cat values were 381.0 min(-1) for G3 and 1,545.0 min(-1) for G2-β-CD. The enzyme was inhibited competitively by the reaction product G2, and the K i constant was 0.7 mM. PSMA bridges the gap between amylases that hydrolyze larger maltodextrins and α-glucosidase that feeds G2 into glycolysis by hydrolyzing smaller glucans into G2 units. 23902479 Evaluation of the potential of the phytocannabinoids, cannabidivarin (CBDV) and Δ(9) -tetrahydrocannabivarin (THCV), to produce CB1 receptor inverse agonism symptoms of nausea in rats. The cannabinoid 1(CB1 ) receptor inverse agonists/antagonists, rimonabant (SR141716, SR) and AM251, produce nausea and potentiate toxin-induced nausea by inverse agonism (rather than antagonism) of the CB1 receptor. Here, we evaluated two phytocannabinoids, cannabidivarin (CBDV) and Δ(9) -tetrahydrocannabivarin (THCV) for their ability to produce these behavioural effects characteristic of CB1 receptor inverse agonism in rats. In Experiment 1, we investigated the potential of THCV and CBDV to produce conditioned gaping (measure of nausea-induced behaviour), in the same manner as SR and AM251. In Experiment 2, we investigated the potential of THCV and CBDV to enhance conditioned gaping produced by a toxin, in the same manner as CB1 receptor inverse agonists. SR (10 and 20 mg kg(-1) ) and AM251 (10 mg kg(-1) ) produced conditioned gaping; however, THCV (10 or 20 mg kg(-1) ) and CBDV (10 or 200 mg kg(-1) ) did not. At a subthreshold dose for producing nausea, SR (2.5 mg kg(-1) ) enhanced LiCl-induced conditioned gaping, whereas Δ(9) -tetrahydrocannabinol (THC, 2.5 and 10 mg kg(-1) ), THCV (2.5 or 10 mg kg(-1) ) and CBDV (2.5 or 200 mg kg(-1) ) did not; in fact, THC (2.5 and 10 mg kg(-1) ), THCV (10 mg kg(-1) ) and CBDV (200 mg kg(-1) ) suppressed LiCl-induced conditioned gaping, suggesting anti-nausea potential. The pattern of findings indicates that neither THCV nor CBDV produced a behavioural profile characteristic of CB1 receptor inverse agonists. As well, these compounds may have therapeutic potential in reducing nausea. 23932839 The taxonicity of schizotypy: Does the same taxonic class structure emerge from analyses of different attributes of schizotypy and from fundamentally different statistical methods? Findings on the population distribution of schizotypy consistently point toward an underlying class structure. However, past research is methodologically homogeneous, chiefly involving analysis of attribute-specific indicators and coherent cut kinetic methods such as maximum covariance (MAXCOV) analysis. Two questions are examined. Are different or overlapping classes identified from different attributes of the schizophrenia phenotype? Do fundamentally different approaches to analysis yield consistent results? Participants (n=1074) completed the Schizotypal Personality Questionnaire (SPQ). Following item screening, MAXCOV analyses were conducted iteratively on attribute-specific item sets (cognitive-perceptual, interpersonal, and disorganized) and a general item set. Latent variable modeling (factor analysis, latent class analysis, and factor-mixture modeling) was used to examine the consistency of the MAXCOV results using items retained in the general set following MAXCOV analysis. Attribute-specific and general item sets gave taxonic MAXCOV curves and base rates of 8.4-10.4% and 3.6%, respectively. Classes were not independent. No latent variable model emerged as uniquely superior but five models distinguished a small high-scoring class populated by members of the MAXCOV general class. Different attributes distinguished overlapping yet nonredundant taxa, and a general schizotypy taxon identified with MAXCOV was also identified in latent variable modeling. 23940062 Double heterozygosity in the BRCA1 and BRCA2 genes in Italian family. Abstract Background: Double heterozygosity (DH) is an extremely rare event in which both BRCA1 and BRCA2 are mutated simultaneously in a family. To date, few cases of DH have been reported, especially in Ashkenazi populations. In Italy some cases of DH have been reported. In this study, we have described an Italian family with double heterozygosity in the BRCA genes. Methods: The proband is a 43-year-old woman with bilateral breast cancer. She presented two pathogenic mutations in both BRCA genes, IVS8+2T>A (c.547+2T>A;p.Gln148Aspfsx51) in BRCA1, K944X (c.2830A>T;p.Lys944X) in BRCA2 and a novel variant IVS4-57A>G (c.426-57A>G) in BRCA2, not previously described. Both mutations were inherited from the paternal lineage in the proband's family. We investigated all available members of this family and we identified other two family members with DH. Results and conclusions: Our observations support the hypothesis of a non-specific severe phenotype in DH carriers in terms of age of disease onset, cumulative lifetime risk and multiple primary tumours. Furthermore, our findings confirm that in order to identify all cases of DH, it is important not to limit the identification of mutations in a single gene, but extend the analysis to BRCA1 and BRCA2 and other breast cancer susceptibility genes. 23937289 Cervical perforation by the strings of a levonorgestrel releasing-intrauterine system: A case report. A very rare case of perforation of the uterine cervix by the strings of a levonorgestrel releasing-intrauterine system (LNG-IUS) in a 47-year-old woman is presented. The method to retrieve the strings back into the cervical canal, leaving the LNG-IUS in situ, is described. We suggest that the threads of an intrauterine contraceptive occasionally may penetrate tissue like setons do, when used for treatment of fistulae. 23353004 Models of drug-induced liver injury for evaluation of phytotherapeutics and other natural products. Extracts from medicinal plants, many of which have been used for centuries, are increasingly tested in models of hepatotoxicity. One of the most popular models to evaluate the hepatoprotective potential of natural products is acetaminophen (APAP)-induced liver injury, although other hepatotoxicity models such as carbon tetrachloride, thioacetamide, ethanol and endotoxin are occasionally used. APAP overdose is a clinically relevant model of drug-induced liver injury. Critical mechanisms and signaling pathways, which trigger necrotic cell death and sterile inflammation, are discussed. Although there is increasing understanding of the pathophysiology of APAP-induced liver injury, the mechanism is complex and prone to misinterpretation, especially when unknown chemicals such as plant extracts are tested. This review discusses the fundamental aspects that need to be considered when using this model, such as selection of the animal species or in vitro system, timing and dose-responses of signaling events, metabolic activation and protein adduct formation, the role of lipid peroxidation and apoptotic versus necrotic cell death, and the impact of the ensuing sterile inflammatory response. The goal is to enable researchers to select the appropriate model and experimental conditions for testing of natural products that will yield clinically relevant results and allow valid interpretations of the pharmacological mechanisms. 23901349 p300 Influences Butyrate-Mediated WNT Hyperactivation In Colorectal Cancer Cells. Deregulated WNT/catenin pathway, usually resulting from mutations in the adenomatous polyposis coli and beta-catenin genes, drives colorectal tumorigenesis. Dietary fiber has been shown to have a protective role against colorectal cancer (CRC). We have previously demonstrated that the histone deacetylase inhibitor (HDACi) butyrate, a fermentation product of dietary fiber, induces WNT/catenin hyperactivation, which promotes CRC cell apoptosis. Therefore, the ability of butyrate to induce WNT hyperactivation and thus promote CRC cell apoptosis may in part explain the preventive function of fiber against CRC. The association between beta-catenin and the transcriptional coactivator p300 may influence WNT/catenin signaling and, therefore, colonic cell physiology. p300 functions as a histone acetylase (HAT); therefore, the modulation of WNT/catenin activity by p300 may influence the ability of the HDACi butyrate to hyperinduce WNT signaling and apoptosis in CRC cells. Our findings indicate that p300 affects the hyperinduction of WNT activity by butyrate. Knockdown of p300 levels represses butyrate-mediated WNT/catenin activity; but still allows for butyrate-mediated apoptosis. Overexpression of p300 stimulates basal and butyrate-induced WNT signaling in some, but not all, CRC cell lines. We also evaluate the role of p300 in therapeutic approaches that target CBP. The small molecule ICG-001, in clinical trial, is a specific inhibitor of CBP-mediated WNT signaling, and previous studies have suggested that p300 is required for the activity of ICG-001. However, we report that ICG-001 maintains full activity against CBP-mediated WNT signaling in p300-deficient cell lines, including the butyrate-resistance line HCT-R. In addition, our findings evaluating combinatorial treatment of ICG-001 and butyrate in HCT-R cells may have important therapeutic implications for the treatment of butyrate-resistant CRCs. 23892408 Incidence and risk of lung cancer in HIV-infected patients. Lung cancer is one of the most common non-AIDS-defining malignancies among HIV-infected patients. The incidence of lung cancer has significantly increased in the HIV-positive population in recent years. The purpose of this study was to summarize the incidence and risk of lung cancer in published population-based studies of people with HIV/AIDS. Published literature from PubMed, Embase, the Web of Science, and Google Scholar was retrieved. Sixty-five publications were selected and assessed for the following parameters: research coverage and location; continent; study period; duration of follow-up; lung cancer cases; HIV cases; incidence rate; and overall SIR or adjusted IRR. In addition, the risk of lung cancer was compared based on age, gender, HIV exposure category, CD4 count, and periods with highly active antiretroviral therapy (HAART). Lung cancer risk was greater among HIV-infected individuals compared with the general population. SIRs or adjusted IRRs were 1.5-3.4 in Europe, 0.7-6.9 in the USA, and 5.0 in Africa. Most, but not all studies did not observe a significant change in the incidence and risk of lung cancer between the pre-HAART and HAART eras. In most studies, the risk of lung cancer was higher among women, younger individuals, and injection drug users (IDUs), but the incidence of lung cancer was higher among men and the elderly. No significant trend in lung cancer risk across CD4 cell count categories was reported among the selected articles. Our study suggests an increase in the incidence and risk of lung cancer in HIV/AIDS population is worldwide. The effect of HAART on the incidence and risk of lung cancer is in dispute. The risk of lung cancer based on gender differences, especially among females, as well as IDUs, requires further investigation. 23928729 Individual Intake of Free-Choice Mineral Mix by Grazing Beef Cows May Be Less Than Typical Formulation Assumptions and Form of Selenium in Mineral Mix Affects Blood Se Concentrations of Cows and Their Suckling Calves. The objectives of this study were to determine (1) the individual ad libitum intake of mineral mix by beef cows managed under a year-long, fall-calving, forage-based production regimen and (2) if Se form in the mineral mix affected the blood Se concentrations of cows and suckling calves. Twenty-four late-gestation (6 to 8 months) Angus-cross cows (2.7 ±â€‰0.8 years; body weight [BW] = 585 ±â€‰58 kg) were blocked by BW and randomly assigned (n = 8) to a mineral supplement treatment (TRT) containing 35 ppm Se as either inorganic (ISe; sodium selenite), organic (OSe; Sel-Plex®), or a 1:1 combination of ISe/OSe (MIX). Cows commonly grazed a 10.1-ha predominately tall fescue pasture and had individual ad libitum access to TRT using in-pasture Calan gates. Cows calved from August to November and calves had common ad libitum access to creep feed and a mineral supplement that lacked Se. Cow jugular blood was taken at 28-day intervals (13 periods) and calf blood was taken with cows from birth through weaning. Individual cow mineral mix (mean = 54.0 ±â€‰7.0 g/day, range = 97.3 to 27.9 ±â€‰7.4 g/day) and Se (mean = 1.82 ±â€‰0.25 mg/day, range = 3.31 to 0.95 ±â€‰0.25 mg/day) intakes were affected by period (P < 0.0001), but not by cow Se TRT (P > 0.30). Cow blood Se (0.109 to 0.229 ±â€‰0.01 Î¼g/mL) was affected (P < 0.002) by period, Se form, and their interaction, with ISe < MIX for periods 8 and 11, ISe < OSe for all periods except period 1, and MIX < OSe for periods 2 to 4, 7, 8, 10, and 12. Calf blood Se (in micrograms Se per milliliter) was correlated with cow blood Se and affected (P < 0.0001) by cow Se TRT, with ISe (0.07 to 0.11) < MIX (0.10 to 0.15) = OSe (0.16 to 0.19). These data reveal that (1) mean supplemental ad libitum cow mineral intake was 36 % less than the typical formulation intake expectations (85 g/day) and, correspondingly, mean supplemental Se intake was 33 % less than that allowed by the FDA and (2) cow Se TRT differentially affected both cow and calf blood Se concentrations, resulting in adequate concentrations for all cows but inadequate concentrations for ISe calves. 22705074 Dissolved gas and ultrasonic cavitation--a review. The physics and chemistry of nonlinearly oscillating acoustic cavitation bubbles are strongly influenced by the dissolved gas in the surrounding liquid. Changing the gas alters among others the luminescence spectrum, and the radical production of the collapsing bubbles. An overview of experiments with various gas types and concentration described in literature is given and is compared to mechanisms that lead to the observed changes in luminescence spectra and radical production. The dissolved gas type changes the bubble adiabatic ratio, thermal conductivity, and the liquid surface tension, and consequently the hot spot temperature. The gas can also participate in chemical reactions, which can enhance radical production or luminescence of a cavitation bubble. With this knowledge, the gas content in cavitation can be tailored to obtain the desired output. 23363530 Neurotoxic potential and cellular uptake of T-2 toxin in human astrocytes in primary culture. The trichothecene mycotoxin T-2 toxin, which is produced by fungi of the Fusarium species, is a worldwide occurring contaminant of cereal based food and feed. The cytotoxic properties of T-2 toxin are already well described with apoptosis being a major mechanism of action in various cell lines as well as in primary cells of different origin. However, only few data on neurotoxic properties of T-2 toxin are reported so far, but in vivo studies showed different effects of T-2 toxin on behavior as well as on levels of brain amines in animals. To further investigate the cytotoxic properties of T-2 toxin on cells derived from brain tissue, normal human astrocytes in primary culture (NHA) were used in this study. Besides studies of cytotoxicity, apoptosis (caspase-3-activation, Annexin V) and necrosis (LDH-release), the cellular uptake and metabolism of T-2 toxin in NHA was analyzed and compared to the uptake in an established human cell line (HT-29). The results show that human astrocytes were highly sensitive to the cytotoxic properties of T-2 toxin, and apoptosis, induced at low concentrations, was identified for the first time as the mechanism of toxic action in NHA. Furthermore, a strong accumulation of T-2 toxin in NHA and HT-29 cells was detected, and T-2 toxin was subjected to metabolism leading to HT-2 toxin, a commonly found metabolite after T-2 toxin incubation in both cell types. This formation seems to occur within the cells since incubations of T-2 toxin with cell depleted culture medium did not lead to any degradation of the parent toxin. The results of this study emphasize the neurotoxic potential of T-2 toxin in human astrocytes at low concentrations after short incubation times. 23896580 Evaluation of immunogen delivery by DNA immunization using non-invasive bioluminescence imaging. The efficacy of DNA vaccines is highly dependent on the methods used for their delivery and the choice of delivery sites/targets for gene injection, pointing at the necessity of a strict control over the gene delivery process. Here, we have investigated the effect of the injection site on gene expression and immunogenicity in BALB/c mice, using as a model a weak gene immunogen, DNA encoding firefly luciferase (Luc) delivered by superficial or deep injection with subsequent electroporation (EP). Immunization was assessed by monitoring the in vivo expression of luciferase by 2D- and 3D-bioluminescence imaging (BLI) and by the end-point immunoassays. Anti-Luc antibodies were assessed by ELISA, and T-cell response by IFN-γ and IL-2 FluoroSpot in which mouse splenocytes were stimulated with Luc or a peptide representing its immunodominant CD8+ T-cell epitope GFQSMYTFV. Monitoring of immunization by BLI identified EP parameters supporting the highest Luc gene uptake and expression. Superficial injection of Luc DNA followed by optimal EP led to a low level Luc expression in the mouse skin, and triggered a CD8+ T-cell response characterized by the peptide-specific secretion of IFN-γ and IL-2, but no specific antibodies. Intramuscular gene delivery resulted in a several-fold higher Luc expression and anti-Luc antibody, but induced low IL-2 and virtually no specific IFN-γ. Photon flux from the sites of Luc gene injection was inversely proportional to the immune response against GFQSMYTFV (p < 0.05). Thus, BLI permitted to control the accuracy of gene delivery and transfection with respect to the injection site as well as the parameters of electroporation. Further, it confirmed the critical role of the site of DNA administration for the type and magnitude of the vaccine-specific immune response. This argues for the use of luminescent reporters in the preclinical gene vaccine tests to monitor both gene delivery and the immune response development in live animals. 22945599 The evaluation of metastatic lymph node ratio staging system in gastric cancer. To evaluate the prognostic value and staging accuracy of the metastatic lymph node ratio (rN) staging system for gastric cancer. A total of 1,075 patients with gastric cancer who underwent curative surgery between 2000 and 2009 at our institute were analyzed. Lymph node status was assigned according to the American Joint Committee on Cancer (AJCC) pN system and rN system. Patients with >15 (group 1, n = 691) and ≤15 lymph nodes (group 2, n = 384) retrieved were analyzed separately. The rN staging system was generated using 0.2 and 0.5 as the cutoff values of lymph node ratio and then compared with AJCC pN stages. A linear regression model revealed that the number of retrieved lymph nodes was related to the number of metastatic lymph nodes, but not with rN. After a median follow-up of 47.66 months, the 5-year survival rates of N0, N1, N2, and N3 patients of group 1 were significantly better than group 2, whereas the differences were not obvious in the rN classification. The rN category is a better prognostic tool than the AJCC pN category for gastric cancer patients after curative surgery regardless of the number of lymph node examined. 23834393 Counteranion and solvent assistance in ruthenium-mediated alkyne to vinylidene isomerizations. The complex [Cp*RuCl((i)Pr2PNHPy)] (1) reacts with 1-alkynes HC≡CR (R = COOMe, C6H4CF3) in dichloromethane furnishing the corresponding vinylidene complexes [Cp*Ru═C═CHR((i)Pr2PNHPy)]Cl (R = COOMe (2a-Cl), C6H4CF3 (2b-Cl)), whereas reaction of 1 with NaBPh4 in MeOH followed by addition of HC≡CR (R = COOMe, C6H4CF3) yields the metastable π-alkyne complexes [Cp*Ru(η(2)-HC≡CR)((i)Pr2PNHPy)][BPh4] (R = COOMe (3a-BPh4), C6H4CF3 (3b-BPh4)). The transformation of 3a-BPh4/3b-BPh4 into their respective vinylidene isomers in dichloromethane is very slow and requires hours to its completion. However, this process is accelerated by addition of LiCl in methanol solution. Reaction of 1 with HC≡CR (R = COOMe, C6H4CF3) in MeOH goes through the intermediacy of the π-alkyne complexes [Cp*Ru(η(2)-HC≡CR)((i)Pr2PNHPy)]Cl (R = COOMe (3a-Cl), C6H4CF3 (3b-Cl)), which rearrange to vinylidenes in minutes, i.e., much faster than their counterparts containing the [BPh4](-) anion. The kinetics of these isomerizations has been studied in solution by NMR. With the help of DFT studies, these observations have been interpreted in terms of chloride- and methanol-assisted hydrogen migrations. Calculations suggest participation of a hydrido-alkynyl intermediate in the process, in which the hydrogen atom can be transferred from the metal to the β-carbon by means of species with weak basic character acting as proton shuttles. 23623991 Chitosan microparticles for delivery of proteins to the retina. Chitosan microparticles (CMPs) have previously been developed for topical applications to the eye, but their safety and efficacy in delivering proteins to the retina have not been adequately evaluated. This study examines the release kinetics of CMPs in vitro, and assesses their biocompatibility and cytotoxicity on retinal cells in vitro and in vivo. Two proteins were used in the encapsulation and release studies: BSA (bovine serum albumin) and tat-EGFP (enhanced green fluorescent protein fused to the transactivator of transcription peptide). Not surprisingly, the in vitro release kinetics were dependent on the protein encapsulated, with BSA showing higher release than tat-EGFP. CMPs containing encapsulated tat-EGFP were tested for cellular toxicity in photoreceptor-derived 661W cells. They showed no signs of in vitro cell toxicity at a low concentration (up to 1mgml(-1)), but at a higher concentration of 10mgml(-1) they were associated with cytotoxic effects. In vivo, CMPs injected into the subretinal space were found beneath the photoreceptor layer of the retina, and persisted for at least 8weeks. Similar to the in vitro studies, the lower concentration of CMPs was generally well tolerated, but the higher concentration resulted in cytotoxic effects and in reduced retinal function, as assessed by electroretinogram amplitudes. Overall, this study suggests that CMPs are effective long-term delivery agents to the retina, but the concentration of chitosan may affect cytotoxicity. 23036451 Prenatal exposure to polychlorinated biphenyls and dioxins from the maternal diet may be associated with immunosuppressive effects that persist into early childhood. We investigated whether prenatal exposure from the maternal diet to the toxicants polychlorinated biphenyls (PCBs) and dioxins is associated with the development of immune-related diseases in childhood. Children participating in BraMat, a sub-cohort of the Norwegian Mother and Child Cohort Study (MoBa), were followed in the three first years of life using annual questionnaires (0-3years; n=162, 2-3years; n=180), and blood parameters were examined at three years of age (n=114). The maternal intake of the toxicants was calculated using a validated food frequency questionnaire from MoBa. Maternal exposure to PCBs and dioxins was found to be associated with an increased risk of wheeze and more frequent upper respiratory tract infections. Furthermore, maternal exposure to PCBs and dioxins was found to be associated with reduced antibody response to a measles vaccine. No associations were found between prenatal exposure and immunophenotype data, allergic sensitization and vaccine-induced antibody responses other than measles. Our results suggest that prenatal dietary exposure to PCBs and dioxins may increase the risk of wheeze and the susceptibility to infectious diseases in early childhood. 23908555 Gamma-tocopherol-N,N-dimethylglycine ester as a potent post-irradiation mitigator against whole body X-irradiation-induced bone marrow death in mice. We examined the radioprotective and mitigative effects of gamma-tocopherol-N,N-dimethylglycine ester (GTDMG), a novel water-soluble gamma-tocopherol derivative, against X-irradiation-induced bone marrow death in mice. Mice (C3H, 10 weeks, male) were injected intraperitoneally with GTDMG suspended in a 0.5% methyl cellulose solution before or after receiving of 7.5-Gy whole body X-irradiation. GTDMG significantly enhanced the 30-day survival rate when given 30 min before or immediately after the irradiation. Its mitigative activity (administered after exposure) was examined further in detail. The optimal concentration of GTDMG given immediately after irradiation was around 100 mg/kg body weight (bw) and the 30-day survival rate was 97.6 ± 2.4%. When GTDMG was administered 1, 10 and 24 h post-irradiation, the survival rate was 85.7 ± 7.6, 75.0 ± 9.7 and 36.7 ± 8.8%, respectively, showing significant mitigation even at 24 h after irradiation (P < 0.05). The value of the dose reduction factor (100 mg/kg bw, given intraperitoneally (i.p.) immediately after irradiation) was 1.25. GTDMG enhanced the recovery of red blood cell-, white blood cell-, and platelet-counts after irradiation and significantly increased the number of endogenous spleen colonies (P < 0.05). Subcutaneous (s.c.) administration also had mitigative effects. In conclusion, GTDMG is a potent radiation mitigator. 23549331 A Distal Enhancer Controls Cytokine-dependent Human cPLA2α Gene Expression. Specific control of group IVA cytosolic phospholipase A2 (cPLA2α or PLA2G4A) expression modulates arachidonic acid production, thus tightly regulating the downstream effects of pro- and anti-inflammatory eicosanoids. The significance of this pathway in human disease is apparent in a range of pathologies from inflammation to tumorigenesis. While much of the regulation of cPLA2α has focused on post-translational phosphorylation of the protein, studies on transcriptional regulation of this gene have focused only on proximal promoter regions. We have identified a DNase I hypersensitive site encompassing a 5' distal enhancer element containing a highly conserved consensus AP-1 site involved in transcriptional activation of cPLA2α by IL-1β. ChIP, knockdown, knockout and overexpression analyses have shown that c-Jun acts both in a negative and positive regulatory role. Transcriptional activation of cPLA2α occurs through the phosphorylation of c-Jun in conjunction with increased association of C/EBPβ with the distal novel enhancer. The association of C/EBPβ with the transcriptional activation complex does not require an obvious DNA binding site. These data provide new and important contributions to the understanding of cPLA2α regulation at the transcriptional level with implications to eicosanoid metabolism, cellular signaling and disease pathogenesis. 23562909 Helper-dependent adenoviral liver gene therapy protects against induced attacks and corrects protein folding stress in acute intermittent porphyria mice. Acute intermittent porphyria (AIP) is a hepatic metabolic disease that results from haplo-insufficient activity of porphobilinogen deaminase (PBGD). The dominant clinical feature is acute intermittent attacks when hepatic heme synthesis is activated by endocrine or exogenous factors. Gene therapy vectors over-expressing PBGD protein in the liver offers potential as a cure for AIP. Here, we developed a helper-dependent adenovirus (HDA) encoding human PBGD (hPBGD) and assessed its therapeutic efficacy in a murine model of AIP. Intravenous or intrahepatic administration of HDA-hPBGD to AIP mice resulted in a sustained hepatic hPBGD expression in a dose-dependent manner. Intrahepatic administration conveyed full protection against induced porphyria attacks at a significantly lower viral dose than intravenous injection. Transgenic hPBGD accumulated only in the cytosol of hepatocytes as the endogenous protein. Characterization of PBGD-deficient mouse strains revealed that a strong PBGD deficiency causes the chronic disturbance of cytosolic and endoplasmic reticulum folding machineries. This disturbance was completely restored over time by the over-expression of hPBGD. HDA-hPBGD is a promising vector that protects against porphyria attacks and resolves the chronic folding stress associated with low levels of PBGD activity. 23229134 Metals loads into the Mediterranean Sea: estimate of Sarno River inputs and ecological risk. The metals pollution in the Sarno River and its environmental impact on the Gulf of Naples (Tyrrhenian Sea, Central Mediterranean Sea) were estimated. Eight selected metals (As, Hg, Cd, Cr, Cu, Ni, Pb and Zn) were determined in the water dissolved phase (DP), suspended particulate matter (SPM) and sediment samples. Selected metals concentrations ranged from 0.32 to 1,680.39 μg l(-1) in water DP, from 103.6 to 7,734.6 μg l(-1) in SPM and from 90.7 to 2,470.3 mg kg(-1) in sediment samples. Contaminant discharges of selected metals into the sea were calculated in about 13,977.6 kg year(-1) showing that this river should account as one of the main contribution sources of metals to the Tyrrhenian Sea. 23295712 Specific surface area of titanium dioxide (TiO2) particles influences cyto- and photo-toxicity. The aim of this study is to examine how different specific surface areas of similar-sized titanium dioxide (TiO(2)) particles could influence both cytotoxicity and phototoxicity. TiO(2) particles of different specific surface areas were compared for their toxic effects on RAW264.7 cells in the absence and presence of UV light. From the results, TiO(2) particles with larger specific surface area were found to induce higher cyto- (UV absent) and photo-toxicity (UV activated) to cells after 24h incubation. The observed cytotoxicity from TiO(2) particles with larger surface area could be explained from their interactions with biomolecules. Upon photoactivation, a larger number of hydroxyl radicals were detected from TiO(2) particles with larger surface area, again suggesting a surface area dependent phototoxic effect. On the other hand, pre-adsorbing TiO(2) particles with extracellular proteins were found to decrease toxicity effects. 23806514 Protective and dysregulated T cell immunity in RSV infection. Respiratory syncytial virus (RSV) is the most important cause of infantile bronchiolitis and a major pathogen in elderly and immunosuppressed persons. Although RSV shows limited antigenic diversity, repeated infections occur throughout life. Vaccine development has been delayed by poor immunogenicity, production issues and the fear of causing enhanced disease. T cells assist in viral clearance, but immune regulation serves to limit these responses and to prevent the exaggerated inflammatory response to RSV infection seen in children with bronchiolitis. Severe RSV disease can therefore be regarded as a dysregulated response to an otherwise trivial infection. Further insights into the role of T cells (including Th17) are needed to enable the rational design of safe, effective vaccines and novel treatments. 23302593 Two new triterpenoid saponins from the root of Platycodon grandiflorum. Two new triterpenoid saponins, named platycodon A (3-O-β-D-glucopyranosyl-16-O-β-D-glucopyranosyl-2β,3β,16β,21β-tetrahydroxyolean-12-en-28-oic acid) and platycodon B (3-O-β-D-glucopyranosyl-16-O-β-D-xylopyranosyl-2β,3β,16β,21β-tetrahydroxyolean-12-en-28-oic acid) were isolated from the roots of Platycodon grandiflorum. The structures of these compounds were elucidated by means of various spectroscopic analyses. Compounds 1 and 2 were tested in HepG-2, A549 and DU145 human cancer cell lines and showed remarkable cytotoxic activities against HepG-2 and A549 cancer cell lines with IC(50) values ranging from 4.9 to 9.4 µM, but they displayed weak cytotoxic activities against DU145 cancer cell line with IC(50) values greater than 10 µM. 23508938 Proximal tubule specific knockout of the Na(+)/H (+) exchanger NHE3: effects on bicarbonate absorption and ammonium excretion. The existing NHE3 knockout mouse has significant intestinal electrolyte absorption defects, making this model unsuitable for the examination of the role of proximal tubule NHE3 in pathophysiologic states in vivo. To overcome this problem, we generated proximal convoluted tubule-specific KO mice (NHE3-PT KO) by generating and crossing NHE3 floxed mice with the sodium-glucose transporter 2 Cre transgenic mice. The NHE3-PT KO mice have >80 % ablation of NHE3 as determined by immunofluorescence microscopy, western blot, and northern analyses, and show mild metabolic acidosis (serum bicarbonate of 21.2 mEq/l in KO vs. 23.7 mEq/l in WT, p < 0.05). In vitro microperfusion studies in the isolated proximal convoluted tubules demonstrated a ∼36 % reduction in bicarbonate reabsorption (J HCO3 = 53.52 ±â€‰4.61 pmol/min/mm in KO vs. 83.09 ±â€‰9.73 in WT) and a ∼27 % reduction in volume reabsorption (J v  = 0.67 ±â€‰0.07 nl/min/mm in KO vs. 0.92 ±â€‰0.06 nl/min/mm in WT) in mutant mice. The NHE3-PT KO mice tolerated NH4Cl acid load well (added to the drinking water) and showed NH4 excretion rates comparable to WT mice at 2 and 5 days after NH4Cl loading without disproportionate metabolic acidosis after 5 days of acid load. Our results suggest that the Na(+)/H(+) exchanger NHE3 plays an important role in fluid and bicarbonate reabsorption in the proximal convoluted tubule but does not play an important role in NH4 excretion. 23950947 Varietal tracing of virgin olive oils based on plastid DNA variation profiling. Olive oil traceability remains a challenge nowadays. DNA analysis is the preferred approach to an effective varietal identification, without any environmental influence. Specifically, olive organelle genomics is the most promising approach for setting up a suitable set of markers as they would not interfere with the pollinator variety DNA traces. Unfortunately, plastid DNA (cpDNA) variation of the cultivated olive has been reported to be low. This feature could be a limitation for the use of cpDNA polymorphisms in forensic analyses or oil traceability, but rare cpDNA haplotypes may be useful as they can help to efficiently discriminate some varieties. Recently, the sequencing of olive plastid genomes has allowed the generation of novel markers. In this study, the performance of cpDNA markers on olive oil matrices, and their applicability on commercial Protected Designation of Origin (PDO) oils were assessed. By using a combination of nine plastid loci (including multi-state microsatellites and short indels), it is possible to fingerprint six haplotypes (in 17 Spanish olive varieties), which can discriminate high-value commercialized cultivars with PDO. In particular, a rare haplotype was detected in genotypes used to produce a regional high-value commercial oil. We conclude that plastid haplotypes can help oil traceability in commercial PDO oils and set up an experimental methodology suitable for organelle polymorphism detection in the complex olive oil matrices. 23876574 The role of mindfulness based interventions in the treatment of obesity and eating disorders: An integrative review. More than one-third of U.S. adults over the age of 20 years are classified as obese and nearly two-thirds are overweight or obese. The prevalence of obesity among U.S. children and adolescents has almost tripled since 1980, with 17% of all youth and children now considered obese. Nine million children aged 6-19 years are overweight, making obesity the largest health care threat facing today's children. Historically, the arsenal against obesity has been primarily focused on interventions that increase physical activity and decrease caloric intake. American weight loss strategies that incorporate dietary modifications and exercise have proven effective in achieving weight loss, but most of the weight is regained over time. Mindfulness based interventions, combined with other traditional weight loss strategies, have the potential to offer a long-term, holistic approach to wellness. However, research reports examining the complementary addition of mindfulness based approaches in the treatment obesity and eating disorders are relatively scarce in the empirical literature. This paper describes what is currently known about the role of mindfulness based interventions when used alone, or in combination with, other traditional approaches in the treatment of obesity and eating disorders. 23927108 On the in situ impedance measurement with pu-probes-Simulation of the measurement setup. High-quality numerical simulations in room acoustics require a detailed knowledge of the acoustic reflection characteristics of the materials in the room, in order to realistically model the interferences between multiple sound reflections at the room boundaries. While different standardized measurement methods exist for the determination of the absorption coefficient and reflection factor these methods can generally not be applied in situ. Thus time-consuming laboratory measurements and the supply of material samples are required. Driven by the obvious demand for a reliable in situ measurement technique, a pu-probe based method has emerged during the last years, which derives the reflection factor based on the simultaneous measurement of sound pressure and velocity. However, previous investigations of the setup and publications by other authors have shown that the measurement results are affected by various uncertainty factors. The present study aims at the identification, separation, and quantitative assessment of the uncertainty factors related to reflection and diffraction effects at the loudspeaker, sensor, and the absorber geometry. Therefore, a purely simulative approach will be used that replicates the actual measurement situation in every detail, including the geometries of sensor, loudspeaker, and absorber. The simulation setup is validated by measurements and is used to systematically separate the different uncertainty factors. 22560941 Effects of telmisartan on proteinuria or albuminuria: A meta-analysis of randomized trials. Although telmisartan is suggested to improve proteinuria/albuminuria (or prevents progression of proteinuria/albuminuria), conclusive evidence is still lacking. We perform the first meta-analysis of randomized controlled trials of telmisartan therapy on proteinuria/albuminuria. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched through February 2012. Eligible studies were prospective randomized controlled trials of telmisartan therapy versus other angiotensin receptor blocker (ARB), angiotensin converting enzyme inhibitor (ACEI), other anti-hypertensive drug therapy, placebo, or no medication and reporting urinary protein/albumin excretion (UPE/UAE) or urinary protein/albumin to creatinine ratio (UPCR/UACR) levels as an outcome. For each study, data regarding percent changes from baseline to final UPE/UAE/UPCR/UACR levels in both the telmisartan and control groups were used to generate mean differences (MDs) and 95% confidence intervals (CIs). Of 49 potentially relevant articles screened initially, 20 reports of randomized trials enrolling a total of 25,425 patients were included. Pooled analysis suggested a significant reduction in percent changes of UPE/UAE/UPCR/UACR in the 7 ARB-control (MD, -19.99%; 95% CI, -28.68% to -11.30%; p<0.00001), 7 ACEI-control (MD, -14.08%; 95% CI, -25.36% to -2.80%; p=0.01), 6 non-ARB/ACEI-control (MD, -39.82%; 95% CI, -55.96% to -23.69%; p<0.00001), and all the 20 trials (MD, -24.36%; 95% CI, -32.85% to -15.87%; p<0.00001). We found that, based on a meta-analysis of 20 randomized controlled trials including >25,000 patients, telmisartan therapy is likely effective in the improvement of proteinuria/albuminuria or in the prevention of progression in proteinuria/albuminuria. 23446772 HSD11B2 CA-repeat and sodium balance. Type 2 11β-hydroxysteroid dehydrogenase encoded by the HSD11B2 gene converts cortisol to inactive cortisone and thus protects the mineralocorticoid receptor from cortisol exposure. Impaired activity of this enzyme leads to mineralocorticoid excess, suggesting HSD11B2 as a candidate locus for patients at risk of developing low renin or salt-sensitive essential hypertension. In the present study, we searched for frequent polymorphisms in 155 Japanese subjects but detected none in the proximal promoter or coding regions of HSD11B2. Following this result, we genotyped a highly polymorphic CA-repeat polymorphism within the first intron in 848 normotensive and 430 hypertensive Japanese patients, and we then analyzed its association with disease and clinical parameters. We confirmed 12 alleles (12, 15-25 CA repeats) in the population and found no significant difference in the distribution of the allele length between normotensive and hypertensive patients. In 174 normal subjects without medication, urinary cortisol excretion was higher in subjects with more CA repeats in the shorter allele, but the ratio of urinary cortisone to cortisol, a reliable marker of renal HSD11B2 activity, did not differ. However, longer CA-repeat length was positively correlated with 24-h urinary sodium excretion, fractional sodium excretion and potassium clearance, and this observation was confirmed when the longer CA-repeat length was dichotomized. Thus, HSD11B2 CA-repeat genotype is not associated with hypertension itself, but with renal sodium excretion, probably through salt intake/appetite. 23834907 The role of interleukin 17 in Crohn's disease-associated intestinal fibrosis. Interleukin (IL)-17A and IL-17E (also known as IL-25) have been implicated in fibrosis in various tissues. However, the role of these cytokines in the development of intestinal strictures in Crohn's disease (CD) has not been explored. We investigated the levels of IL-17A and IL-17E and their receptors in CD strictured and non-strictured gut, and the effects of IL-17A and IL-17E on CD myofibroblasts. IL-17A was significantly overexpressed in strictured compared with non-strictured CD tissues, whereas no significant difference was found in the expression of IL-17E or IL-17A and IL-17E receptors (IL-17RC and IL-17RB, respectively) in strictured and non-strictured CD areas. Strictured CD explants released significantly higher amounts of IL-17A than non-strictured explants, whereas no difference was found as for IL-17E, IL-6, or tumor necrosis factor-α production. IL-17A, but not IL-17E, significantly inhibited myofibroblast migration, and also significantly upregulated matrix metalloproteinase (MMP)-3, MMP-12, tissue inhibitor of metalloproteinase-1 and collagen production by myofibroblasts from strictured CD tissues. Our results suggest that IL-17A, but not IL-17E, is pro-fibrotic in CD. Further studies are needed to clarify whether the therapeutic blockade of IL-17A through the anti-IL-17A monoclonal antibody secukinumab is able to counteract the fibrogenic process in CD. 23316792 Rheological study of mutarotation of fructose in anhydrous state. Rheological measurement was employed to study the mutarotation of D-fructose in anhydrous state. By monitoring the evolution of shear viscosity with time, rate constants for mutarotation were estimated, and two different stages of this reaction were identified. One of the mutarotation stages is rapid and has a low activation energy, whereas the other is much slower and has a much higher activation energy. Possible conversions corresponding to these two phases are discussed. This work demonstrates that, in addition to the routine techniques such polarimetry and gas-liquid chromatography, rheological measurement can be used as an alternative method to continuously monitor the mutarotation of sugars. 23877136 PNU-282987 Improves the Hemodynamic Parameters by Alleviating Vasopermeability and Tissue Edema in Dogs Subjected to a Lethal Burns Shock. Excessive inflammation and high vasopermeability can lead to blood volume loss and tissue edema, which can affect the resuscitation and prognosis for serious burn patients. In this experiment, we investigated the effect of PNU-282987, an α7 nicotine cholinergic receptor agonist on the hemodynamic parameters and survival rate by inhibiting vasopermeability and tissue edema during the fluid resuscitation for lethal burn shock. Forty Beagle dogs with intubation of the carotid artery and jugular vein 24 hours before the injury were subjected to 50% TBSA full-thickness burns, and were randomly divided into following four groups: no resuscitation group (group NR), venous fluid resuscitation group (group R), PNU-282987 treatment group (group P), and fluid resuscitation group plus PNU-282987 group (group RP), with 10 dogs in each group. Hemodynamic variables and biochemical parameters were determined with animals in a conscious and cooperative state. The plasma volume and the vasopermeability were determined by indocyanine green and fluorescein isothiocyanate-dextran, respectively. The level of tumor necrosis factor-α and interleukin-1β in plasma, and the water content of different organs were also determined. The mean arterial pressure, cardiac output, and plasma volume of all dogs decreased significantly, and the lung extravascular water index and pulmonary vascular permeability index increased remarkably after burn. The hemodynamic parameters deteriorated continually in group N dogs, and then anuria, hyperlactacidemia, and multiple organ dysfunctions developed. The mean arterial pressure and cardiac output of dogs in group R and group RP returned to preinjury levels at 48 hours postburn. The lung extravascular water index and pulmonary vascular permeability in group R were higher than those before preinjury. The dogs in group RP were found to have a significant increase in plasma volume and urine output, and a remarkable decrease in the levels of tumor necrosis factor-α, interleukin-1α, lactic acid, and organ functions compared with those of group R (P < .05). The survival rate of RP group (100%; 10/10) was significantly higher than that of group N (0; 0/10), group P (20%; 2/10), and group R (60%; 6/10). PNU-282987 combined with intravenous fluid resuscitation significantly improved hemodynamics and the survival rate in the early period after this lethal burn shock. The mechanism may be attributable to the lowering of the level of proinflammatory mediators, amelioration of vasopermeability-induced visceral edema, less of blood volume loss, and protection of vital organs through activation of cholinergic anti-inflammatory pathway. 22888825 Parental persuasive strategies in the face of daily problems in adolescent type 1 diabetes management. The study examined (1) whether daily diabetes problems that adolescents experience were associated with parental persuasive strategies (e.g., persuading the adolescent to do more to manage diabetes), (2) whether this association was mediated through greater parental worry and lower confidence in adolescents' abilities, and (3) how parental persuasive strategies may provide corrections for subsequent blood glucose control but reduce adolescent confidence for adolescents high in self-efficacy. Adolescents with Type 1 diabetes (N = 180, ages 10.50-15.58 years) and their mothers (N = 176) and fathers (N = 139) completed diaries for 14 days reporting on problems experienced with diabetes, maternal and paternal use of persuasive strategies, and confidence in adolescents' ability to manage diabetes. Parents reported their daily worry about diabetes, adolescents reported their general self-efficacy for diabetes management, and blood glucose was downloaded from glucometers. Across reporters, multilevel modeling revealed that parents used more persuasive strategies on days when more diabetes problems were experienced. This association was mediated through parents' greater worry and lower confidence in adolescents' ability to manage diabetes. Lagged analyses revealed that adolescents' perceptions of maternal persuasive strategies were associated with improvements in next-day blood glucose, but also with reductions in adolescents' daily confidence for those high in self-efficacy. CONCLUSIONs: Parental persuasive strategies appear responsive to daily problems that adolescents experience in diabetes management. Mothers' persuasive strategies may have the dual effects of correcting blood glucose levels but reducing the more self-efficacious adolescents' confidence in their own ability to manage diabetes. 23287313 Effect of pigeon pea (Cajanus cajan L.) on high-fat diet-induced hypercholesterolemia in hamsters. Obesity is associated with increased systemic and airway oxidative stress, which may result from a combination of adipokine imbalance and antioxidant defenses reduction. Obesity-mediated oxidative stress plays an important role in the pathogenesis of dyslipidemia, vascular disease, and nonalcoholic hepatic steatosis. The antidyslipidemic activity of pigeon pea were evaluated by high-fat diet (HFD) hamsters model, in which the level of high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), total cholesterol (TC), and total triglyceride (TG) were examined. We found that pigeon pea administration promoted cholesterol converting to bile acid in HFD-induced hamsters, thereby exerting hypolipidemic activity. In the statistical results, pigeon pea significantly increased hepatic carnitine palmitoyltransferase-1 (CPT-1), LDL receptor, and cholesterol 7α-hydroxylase (also known as cytochrome P450 7A1, CYP7A1) expression to attenuate dyslipidemia in HFD-fed hamsters; and markedly elevated antioxidant enzymes in the liver of HFD-induced hamsters, further alleviating lipid peroxidation. These effects may attribute to pigeon pea contained large of unsaturated fatty acids (UFA; C18:2) and phytosterol (β-sitosterol, campesterol, and stigmasterol). Moreover, the effects of pigeon pea on dyslipidemia were greater than β-sitosterol administration (4%), suggesting that phytosterone in pigeon pea could prevent metabolic syndrome. 23590809 Chondromyxoid fibroma of the calcaneus: two case reports and literature review. Chondromyxoid fibroma occurs primarily in the long tubular bones of the lower extremity, with the foot representing the second most frequent location after the knee. This benign cartilaginous tumor of bone is currently the rarest reported neoplasm of cartilaginous origin. This mass can mimic other benign and malignant bone tumors owing to its variable histologic features. We report 2 cases of chondromyxoid fibroma of the calcaneus with varying presentations. Initially, advanced imaging studies pointed to a diagnosis of a unicameral bone cyst. Pathologic examination is difficult but can be used to differentiate this lesion from more serious conditions. A quick and accurate diagnosis of chondromyxoid fibroma can prevent unnecessary treatment that could be harmful to the patient. 23903545 Identification and subtyping of clinically relevant human and ruminant mycoplasmas using matrix-assisted laser desorption ionization-time of flight mass spectrometry. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has recently emerged as a new technology for the identification of bacteria. In this study, we aimed to evaluate its applicability to human and ruminant mycoplasma identification, which can be demanding and time-consuming using phenotypic or molecular methods. In addition, MALDI-TOF MS was tested as a subtyping tool for certain species. A total of 29 main spectra (MSP) from 10 human and 13 ruminant mycoplasma (sub)species were included in a mycoplasma MSP database to complete the Bruker MALDI Biotyper database. After broth culture and protein extraction, MALDI-TOF MS was applied for identification purposes to 119 human and 143 ruminant clinical isolates previously identified by antigenic or molecular methods and to subcultures of 73 ruminant clinical specimens known to potentially contain several mycoplasma species. MALDI-TOF MS resulted in accurate (sub)species identification, with a score ≥ 1.700 for 96% (251/262) of the isolates. The phylogenetically closest (sub)species were unequivocally distinguished. Although mixtures of strains were reliably detected up to a certain cellular ratio, only the predominant species was identified from the cultures of polymicrobial clinical specimens. For typing purposes, MALDI-TOF MS proved to be able to cluster M. bovis and M. agalactiae isolates as a function of their year of isolation and their genome profile, respectively, and M. pneumoniae isolates as a function of their P1-adhesin type. In conclusion, MALDI-TOF MS is a rapid, reliable and cost-effective method for the routine identification of high-density growing mycoplasmas and shows promising prospects for strain typing. 23627887 Photophysics of delocalized excitons in carbazole dendrimers. The photophysical properties in solution of three generations of carbazole-based dendrons and dendrimers with fluorenyl surface groups were studied using steady-state, time-resolved femtosecond transient absorption and anisotropy, and coherent two-dimensional ultraviolet spectroscopy. It was found that increasing the generation caused a switch in the nature of the emissive state between the first-generation compounds and the second- and third-generation dendrimers. Time-resolved anisotropy measurements revealed low initial anisotropies that decreased with increasing dendrimer generation consistent with increasing intradendrimer interchromophore coupling. Two-dimensional UV spectroscopy showed that the signal from the second- and third-generation dendrimers is the product of multiple chromophores interacting. The maximum number of interacting chromophores is reached by the second generation. 23561126 Fundamental studies on the structural functionality of whey protein isolate in the presence of small polyhydroxyl compounds as co-solute. The present work deals with the changing network morphology of whey protein isolate (15%, w/w) in the presence of glucose syrup (co-solute) with concentrations ranging from 0% to 65%(w/w) in 10mM CaCl2 solution, thus producing formulations with a total level of solids of up to 80%(w/w). Denaturation behaviour and aggregation of whey protein systems were investigated using small deformation dynamic oscillation on shear, micro and modulated differential scanning calorimetry, and confocal laser scanning microscopy. A progression in the mechanical strength of protein aggregates was observed resulting from enhanced protein-protein interactions in the presence of glucose syrup. Addition of the co-solute resulted in better thermal stability of protein molecules by shifting the process of denaturation to higher temperature, as observed by calorimetry. Observations are supported by micrographs showing coherent networks with reduced size of whey protein aggregates in the presence of high levels of glucose syrup, as opposed to thick and random clusters for systems of whey protein by itself. Glass transition phenomenon was observed for condensed protein/co-solute systems, which were treated with theoretical concepts adapted from synthetic polymer research to pinpoint the mechanical glass transition temperature. 23869694 Enantioselective Direct α-Amination of Aldehydes via a Photoredox Mechanism: A Strategy for Asymmetric Amine Fragment Coupling. The direct, asymmetric α-amination of aldehydes has been accomplished via a combination of photoredox and organocatalysis. Photon-generated N-centered radicals undergo enantioselective α-addition to catalytically formed chiral enamines to directly produce stable α-amino aldehyde adducts bearing synthetically useful amine substitution patterns. Incorporation of a photolabile group on the amine precursor obviates the need to employ a photoredox catalyst in this transformation. Importantly, this photoinduced transformation allows direct and enantioselective access to α-amino aldehyde products that do not require postreaction manipulation. 23797954 High-Dosage Ascorbic Acid Treatment in Charcot-Marie-Tooth Disease Type 1A: Results of a Randomized, Double-Masked, Controlled Trial. IMPORTANCE No current medications improve neuropathy in subjects with Charcot-Marie-Tooth disease type 1A (CMT1A). Ascorbic acid (AA) treatment improved the neuropathy of a transgenic mouse model of CMT1A and is a potential therapy. A lower dosage (1.5 g/d) did not cause improvement in humans. It is unknown whether a higher dosage would prove more effective. OBJECTIVE To determine whether 4-g/d AA improves the neuropathy of subjects with CMT1A. DESIGN A futility design to determine whether AA was unable to reduce worsening on the CMT Neuropathy Score (CMTNS) by at least 50% over a 2-year period relative to a natural history control group. SETTING Three referral centers with peripheral nerve clinics (Wayne State University, Johns Hopkins University, and University of Rochester). PARTICIPANTS One hundred seventy-four subjects with CMT1A were assessed for eligibility; 48 did not meet eligibility criteria and 16 declined to participate. The remaining 110 subjects, aged 13 to 70 years, were randomly assigned in a double-masked fashion with 4:1 allocation to oral AA (87 subjects) or matching placebo (23 subjects). Sixty-nine subjects from the treatment group and 16 from the placebo group completed the study. Two subjects from the treatment group and 1 from the placebo group withdrew because of adverse effects. INTERVENTIONS Oral AA (4 g/d) or matching placebo. MAIN OUTCOMES AND MEASURES Change from baseline to year 2 in the CMTNS, a validated composite impairment score for CMT. RESULTS The mean 2-year change in the CMTNS was -0.21 for the AA group and -0.92 for the placebo group, both better than natural history (+1.33). This was well below 50% reduction of CMTNS worsening from natural history, so futility could not be declared (P > .99). CONCLUSIONS AND RELEVANCE Both treated patients and those receiving placebo performed better than natural history. It seems unlikely that our results support undertaking a larger trial of 4-g/d AA treatment in subjects with CMT1A. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00484510. 23836314 Liquid biopsy: monitoring cancer-genetics in the blood. Cancer is associated with mutated genes, and analysis of tumour-linked genetic alterations is increasingly used for diagnostic, prognostic and treatment purposes. The genetic profile of solid tumours is currently obtained from surgical or biopsy specimens; however, the latter procedure cannot always be performed routinely owing to its invasive nature. Information acquired from a single biopsy provides a spatially and temporally limited snap-shot of a tumour and might fail to reflect its heterogeneity. Tumour cells release circulating free DNA (cfDNA) into the blood, but the majority of circulating DNA is often not of cancerous origin, and detection of cancer-associated alleles in the blood has long been impossible to achieve. Technological advances have overcome these restrictions, making it possible to identify both genetic and epigenetic aberrations. A liquid biopsy, or blood sample, can provide the genetic landscape of all cancerous lesions (primary and metastases) as well as offering the opportunity to systematically track genomic evolution. This Review will explore how tumour-associated mutations detectable in the blood can be used in the clinic after diagnosis, including the assessment of prognosis, early detection of disease recurrence, and as surrogates for traditional biopsies with the purpose of predicting response to treatments and the development of acquired resistance. 23897057 Percutaneous Kyphoplasty in the Treatment of Osteoblastic-Related Spinal Metastases. A retrospective study. To evaluate the feasibility, efficacy, and safety of percutaneous kyphoplasty (PKP) for the treatment of painful osteoblastic-related spinal metastases unresponsive to conservative treatments. Percutaneous kyphoplasty (PKP) represents a powerful tool in the management of oncology patients who suffer from painful osteolytic spinal lesions. However, to our knowledge, there have been no reports on the role of PKP in the treatment of osteoblastic metastatic spinal lesions. In this study, we evaluate the potential efficacy of kyphoplasty for the treatment of painful osteoblastic spinal metastases unresponsive to conservative treatments. A retrospective study was performed on 13 patients managed with PKP for painful osteoblastic-related spinal metastases. Visual analog scale pain score and Oswestry disability index questionnaire were used to assess back pain and functional status, respectively. The average visual analog scale pain score before the treatment was 8.5±0.5 compared with 2.0±0.8 three days after the procedure (P<0.001), and remained largely unchanged from 1.6±0.5 at 1 month, 1.5±0.5 at 3 months to 2.2±0.7 at the last follow-up. The Oswestry disability index scores decreased from 77.2±8.2 before the surgery to 34.6±7.4 three days after the operation (P<0.001), 32.2±6.1 at 1 month, 30.2±5.9 at 3 months and 34.5±6.7 at the last follow-up. No symptomatic cement leakage and PKP-related complications were found after operation. PKP is an effective, safe and minimally invasive procedure to treat painful osteoblastic spinal metastases, leading to a significant reduction of pain and improvement of functional status. 23841715 Cytomegalovirus (CMV) genotype in allogeneic hematopoietic stem cell transplantation. Based on sequence variation in the UL55 gene that encodes glycoprotein B (gB), human cytomegalovirus (CMV) can be classified into four gB genotypes. Previous studies have suggested an association between CMV gB genotype and clinical outcome in patients who underwent an allogeneic hematopoietic stem cell transplant (HSCT). The goals of this study were identify patients with active infection caused by CMV in recipients of HSCT; determine the prevalence of CMV genotypes in the study group; correlate genotype with CMV disease, acute GVHD and overall survival. The diagnosis of active CMV infection after allogeneic HSCT was detected by antigenemia (AGM) and/or nested-PCR (N-PCR). Positive samples from patients with active CMV infection were submitted to genotyping using N-PCR to amplify a region of UL55, followed by restriction analysis based on HinfI and RsaI digestion. Real-time PCR (qPCR) was used to determine the viral load during active CMV infection and antiviral treatment. Sixty-three allogeneic HSCT recipients were prospectively evaluated; 49/63 (78%) patients were infected with CMV genotypes - gB1 19/49 (39%), gB2 17/49 (35%), gB3 3/49 (6%), gB4 7/49 (14%) - and 3 (6%) had mixed CMV genotypes (gB1 + gB3, gB1 + gB4 and gB2 + gB4). Characterized by gastrointestinal disease, CMV disease occurred in 3/49 (6.1%) patients, who had CMV gB3 genotype. These gB3 genotype patients presented an increasing AGM number, mean 125 (± 250) (P = 0.70), and qPCR copies/ml, mean 37938 (SD ± 50542) (P = 0.03), during antiviral treatment, when compared with other CMV genotypes. According to CMV genotypes, stratified overall survival was 55% for gB1, 43% for gB2; 0% for gB3 and 57% for gB4 (P = 0.03). One of the restrictions of the presented study was the low number of CMV gB sub-cohorts). However, we demonstrated that the frequency of active CMV infection in this HSCT population was high, and the most prevalent genotype in these patients with active CMV infection was gB1 and gB2 genotype (74%). In Brazil, HSCT recipients seem to carry mainly gB1 and gB2 CMV genotype. 23701594 Intrinsic Structural Heterogeneity and Long-Term Maturation of Amyloid β Peptide Fibrils. Amyloid β peptides form fibrils that are commonly assumed to have a dry, homogeneous, and static internal structure. To examine these assumptions, fibrils under various conditions and different ages have been examined with multidimensional infrared spectroscopy. Each peptide in the fibril had a (13)C═(18)O label in the backbone of one residue to disinguish the amide I' absorption due to that residue from the amide I' absorption of other residues. Fibrils examined soon after they formed, and reexamined after 1 year in the dry state, exhibited spectral changes confirming that structurally significant water molecules were present in the freshly formed fibrils. Results from fibrils incubated in solution for 4 years indicate that water molecules remained trapped within fibrils and mobile over the 4 year time span. These water molecules are structurally significant because they perturb the parallel β-sheet hydrogen bonding pattern at frequent intervals and at multiple points within individual fibrils, creating structural heterogeneity along the length of a fibril. These results show that the interface between β-sheets in an amyloid fibril is not a "dry zipper", and that the internal structure of a fibril evolves while it remains in a fibrillar state. These features, water trapping, structural heterogeneity, and structural evolution within a fibril over time, must be accommodated in models of amyloid fibril structure and formation. 23904381 Silencing endothelin-3 expression attenuates the malignant behaviors of human melanoma cells by regulating SPARC levels. Endothelin-3 (ET-3) is aberrantly expressed in both metastatic melanoma tissues and cultured melanoma cells. Our previous work showed that ET-3 could promote survival of metastatic melanoma cells via its altered expression. In this study, we investigated the mechanisms responsible for these gene-induced phenotypes in melanoma cells. An ET-3 gene sequence-specific shRNA vector pLVTHM-ET3-RNAi was constructed and transfected into human malignant melanoma cells A375 and MMRU, and the resultant molecular events and cellular changes were examined. As compared with the empty-vector group, cell proliferation was slowed down, and the growth inhibition rates were 38.9% in A375 cells and 38.4% in MMRU cells after transfection. In addition, cell invasion capability was also inhibited, with a reduction of 62.2% in A375 cells and 54.3% in MMRU cells. The percentage of apoptotic cells was found to increase. Meanwhile, in both cell lines, secreted protein acidic and rich in cysteine (SPARC) levels were down-regulated together with inhibition of its upstream signaling molecule, NF-κB. Thus, the current results suggested that down-regulated expression of ET3 attenuates the malignant behaviors of human melanoma cells partially by decreasing the expression of SPARC and NF-κB. 23470011 A new sesquiterpene lactone from Salvia plebeia. A new eudesmanolide, 1α-acetoxy-8α,9β-dihydroxy-2-oxo-eudesman-3,7(11)-dien-8,12-olide (2), together with a known eudesmanolide, 1α-acetoxy-8α-hydroxy-2-oxo-eudesman-3,7(11)-dien-8,12-olide (1), and a known flavone, 4',5,7-trihydroxy-6-methoxyflavone (3), was isolated from the plant of Salvia plebeia. Three compounds were structurally elucidated by spectroscopic and chemical methods. 23348877 Investigating the suspension culture on aggregation and function of mouse pancreatic β-cells. The integrity and hierarchical structure of islet influence β-cells physiology dramatically. A culture substrate which can maintain or improve β-cells aggregation shall benefit cell therapy for diabetics. In this study, nontreated, type IV collagen, Lipidure, and ultralow attachment dishes were used to culture a murine β-cell line, MIN-6. The formation and biological performances of pseudoislets were investigated. Results showed that β-cells formed loose and irregular aggregates on nontreated dishes. Oppositely, pseudoislets formed on other three substrates. Most pseudoislets on Lipidure and type IV collagen dishes had a diameter between 100-150 μm with high survival rate, while large pseudoislets (>250 μm) with seriously central necrosis were found on ultralow attachment dishes. Western blot analysis revealed that pseudoislets had relatively higher connexin 36 protein productions relative to single cells. The glucose-stimulated insulin secretion test showed pseudoislets on type IV collagen have high stimulation index. Monolayers from TCPS dishes and pseudoislets from type IV collagen or Lipidure dishes were further transplanted into diabetic mice. Animals received both single cells and pseudoislets had decreasing blood glucose level and regained body weight. Histologic examination revealed that all implants successfully engrafted with positive insulin staining. Interestingly, the area under curve for the intraperitoneal glucose tolerance test showed pseudoislets had superior glucose disappearance rate. This study reveals that isolated islets or insulin-producing cells can be cultured on type IV collagen or Lipidure dishes to improve/maintain integrity prior to transplantation. 22705075 Towards an understanding and control of cavitation activity in 1 MHz ultrasound fields. Various industrial processes such as sonochemical processing and ultrasonic cleaning strongly rely on the phenomenon of acoustic cavitation. As the occurrence of acoustic cavitation is incorporating a multitude of interdependent effects, the amount of cavitation activity in a vessel is strongly depending on the ultrasonic process conditions. It is therefore crucial to quantify cavitation activity as a function of the process parameters. At 1 MHz, the active cavitation bubbles are so small that it is becoming difficult to observe them in a direct way. Hence, another metrology based on secondary effects of acoustic cavitation is more suitable to study cavitation activity. In this paper we present a detailed analysis of acoustic cavitation phenomena at 1 MHz ultrasound by means of time-resolved measurements of sonoluminescence, cavitation noise, and synchronized high-speed stroboscopic Schlieren imaging. It is shown that a correlation exists between sonoluminescence, and the ultraharmonic and broadband signals extracted from the cavitation noise spectra. The signals can be utilized to characterize different regimes of cavitation activity at different acoustic power densities. When cavitation activity sets on, the aforementioned signals correlate to fluctuations in the Schlieren contrast as well as the number of nucleated bubbles extracted from the Schlieren Images. This additionally proves that signals extracted from cavitation noise spectra truly represent a measure for cavitation activity. The cyclic behavior of cavitation activity is investigated and related to the evolution of the bubble populations in the ultrasonic tank. It is shown that cavitation activity is strongly linked to the occurrence of fast-moving bubbles. The origin of this "bubble streamers" is investigated and their role in the initialization and propagation of cavitation activity throughout the sonicated liquid is discussed. Finally, it is shown that bubble activity can be stabilized and enhanced by the use of pulsed ultrasound by conserving and recycling active bubbles between subsequent pulsing cycles. 23891850 Chloroquine: Modes of action of an undervalued drug. For more than two decades, chloroquine (CQ) was largely and deliberately used as first choice drug for malaria treatment. However, worldwide increasing cases of resistant strains of Plasmodium have hampered its use. Nevertheless, CQ has recently been tested as adjunct therapy in several inflammatory situations, such as rheumatoid arthritis and transplantation procedures, presenting intriguing and promising results. In this review, we discuss recent findings and CQ mechanisms of action vis-à-vis its use as a broad adjunct therapy. 23673074 Sleeve pneumonectomy for central non-small cell lung cancer: indications, complications, and survival. Sleeve pneumonectomy is a challenging therapeutic strategy for patients with non-small cell lung cancer (NSCLC) invading the carina. The aim of this study was to illustrate common indications and individual concepts for surgery and to investigate oncologic outcomes and complications. Sixty-four consecutive sleeve pneumonectomies were performed between September 2000 and November 2011. All patients had histologically proven central NSCLC. Data were retrospectively reviewed for indications, complications, and factors influencing long-term survival. Sixty-four patients underwent sleeve pneumonectomy for curative (n = 50, 78%) or palliative therapy (n = 14, 22%). Complete resection was achieved in 83%. Pathologic N2 disease was found in 41%. Complications occurred in 41%, with severe anastomotic problems in 8% of cases. Thirty-day mortality was 3% (n = 2). Outcome was significantly influenced by pathologic nodal status with 5-year survival rates of 70%, 35%, and 9% for N0, N1, and N2 subgroups, respectively. Patients with multilevel N2 disease and contraindications for chemotherapy or radiotherapy had a mean survival of 13 months after palliative surgery. Sleeve pneumonectomy for central NSCLC invading the carina or proximal main bronchus can be performed with tolerable risk and encouraging survival rates in selected cases. Palliative sleeve pneumonectomy displays an option in the absence of alternative therapeutic strategies. 23842626 Oceanic navigation in Cory's shearwaters: evidence for a crucial role of olfactory cues for homing after displacement. Pelagic birds, which wander in the open sea most of the year and often nest on small remote oceanic islands, are able to pinpoint their breeding colony even within an apparently featureless environment, such as the open ocean. The mechanisms underlying their surprising navigational performance are still unknown. In order to investigate the nature of the cues exploited for oceanic navigation, Cory's shearwaters, Calonectris borealis, nesting in the Azores were displaced and released in open ocean at about 800 km from their colony, after being subjected to sensory manipulation. While magnetically disturbed shearwaters showed unaltered navigational performance and behaved similarly to unmanipulated control birds, the shearwaters deprived of their sense of smell were dramatically impaired in orientation and homing. Our data show that seabirds use olfactory cues not only to find their food but also to navigate over vast distances in the ocean. 23336434 Right atrial indexed volume in healthy adult population: reference values for two-dimensional and three-dimensional echocardiographic measurements. Current guidelines do not recommend routine assessment of right atrial volume due to the lack of standardized data. Three-dimensional wall-motion tracking (3D-WMT) is a new technology that allows us to calculate volumes without any geometric assumptions. The aim of this study was to define the indexed reference values for two-dimensional echocardiography (2D-echo) and 3D-WMT in adult healthy population and to assess the intermethod, intra- and interobserver agreement. Prospective study. Nonselected healthy subjects were enrolled. Every patient underwent a 2D-echo and a 3D-WMT examination. 2D-echo right atrial volume was obtained by using the area-length method (A-L) from four- and two-chamber view. 3D-echo volumes were assessed by 3D-WMT. Values were indexed by the patient's body surface area. Sixty consecutive healthy subjects were enrolled. Mean age was 57 ± 12-years old and 27 patients (45%) were male. Average indexed right atrial volume obtained by 2D-echo and 3D-echo was 16.76 ± 8.15 mL/m(2) and 19.05 ± 6.87 mL/m(2) , respectively. Univariate linear regression analysis between 2D-echo and 3D-echo right atrial volumes shows a weak correlation between right atrial volume obtained with 2D-echo compared with 3D-WMT (r = 0.29, CI 95% 0.029-0.66, P = 0.033). The agreement analysis shows a similar result (intraclass correlation coefficient [ICC] = 0.28). The intra- and interobserver agreement analysis showed a better agreement when using 3D-WMT. This is the first study that reports the reference indexed right atrial volume values by means of 2D-echo and 3D-echo in healthy population. 3D-WMT is a feasible and reproducible method to determine right atrial volume. 23871965 The complex fluctuations of probabilistic Boolean networks. Probabilistic Boolean networks (PBNs) are extensions of Boolean networks (BNs), and both have been widely used to model biological systems. In this paper, we study the long-range correlations of PBNs based on their corresponding Markov chains. PBN states are quantified by the deviation of their steady-state distributions. The results demonstrate that, compared with BNs, PBNs can exhibit these dynamics over a wider and higher noise range. In addition, the constituent BNs significantly impact the generation of 1/f dynamics of PBNs, and PBNs with homogeneous steady-state distributions tend to sustain the 1/f dynamics over a wider noise range. 23159887 Expression of cAMP-responsive element binding proteins (CREBs) in fast- and slow-twitch muscles: A signaling pathway to account for the synaptic expression of collagen-tailed subunit (ColQ) of acetylcholinesterase at the rat neuromuscular junction. The gene encoding the collagen-tailed subunit (ColQ) of acetylcholinesterase (AChE) contains two distinct promoters that drive the production of two ColQ mRNAs, ColQ-1 and ColQ-1a, in slow- and fast-twitch muscles, respectively. ColQ-1a is expressed at the neuromuscular junction (NMJ) in fast-twitch muscle, and this expression depends on trophic factors supplied by motor neurons signaling via a cAMP-dependent pathway in muscle. To further elucidate the molecular basis of ColQ-1a's synaptic expression, here we investigated the expression and localization of cAMP-responsive element binding protein (CREB) at the synaptic and extra-synaptic regions of fast- and slow-twitch muscles from adult rats. The total amount of active, phosphorylated CREB (P-CREB) present in slow-twitch soleus muscle was higher than that in fast-twitch tibialis muscle, but P-CREB was predominantly expressed in the fast-twitch muscle at NMJs. In contrast, P-CREB was detected in both synaptic and extra-synaptic regions of slow-twitch muscle. These results reveal, for the first time, the differential distribution of P-CREB in fast- and slow-twitch muscles, which might support the crucial role of cAMP-dependent signaling in controlling the synapse-specific expression of ColQ-1a in fast-twitch muscles. 23861059 Cell and tissue dynamics during Tribolium embryogenesis revealed by versatile fluorescence labeling approaches. Studies on new arthropod models such as the beetle Tribolium castaneum are shifting our knowledge of embryonic patterning and morphogenesis beyond the Drosophila paradigm. In contrast to Drosophila, Tribolium embryos exhibit the short-germ type of development and become enveloped by extensive extra-embryonic membranes, the amnion and serosa. The genetic basis of these processes has been the focus of active research. Here, we complement genetic approaches with live fluorescence imaging of Tribolium embryos to make the link between gene function and morphogenetic cell behaviors during blastoderm formation and differentiation, germband condensation and elongation, and extra-embryonic development. We first show that transient labeling methods result in strong, homogeneous and persistent expression of fluorescent markers in Tribolium embryos, labeling the chromatin, membrane, cytoskeleton or combinations thereof. We then use co-injection of fluorescent markers with dsRNA for live imaging of embryos with disrupted caudal gene function caused by RNA interference. Using these approaches, we describe and compare cell and tissue dynamics in Tribolium embryos with wild-type and altered fate maps. We find that Tribolium germband condensation is effected by cell contraction and intercalation, with the latter being dependent on the anterior-posterior patterning system. We propose that germband condensation drives initiation of amnion folding, whereas expansion of the amniotic fold and closure of the amniotic cavity are likely driven by contraction of an actomyosin cable at the boundary between the amnion and serosa. Our methodology provides a comprehensive framework for testing quantitative models of patterning, growth and morphogenetic mechanisms in Tribolium and other arthropod species. 23948119 Evidence for a regulatory loop between cholecystokinin (CCK) and tryptic enzyme activity in Atlantic cod larvae (Gadus morhua). In order to maximize protein digestion, the release of enzymes into the gut lumen is closely controlled by a regulatory loop. Cholecystokinin (CCK) is among the enteric hormones that play a key role in the control of digestive enzyme secretion, but its role in first feeding larvae is still unclear and may differ between species. However, in all marine fish larvae that have not developed a stomach by first feeding, trypsin is the most important proteolytic enzyme. In order to examine the regulation and feedback mechanisms in the gut of larval cod, we therefore studied the interactions between cholecystokinin and tryptic enzyme activity following the administration of solutions containing test substances directly into the gut. We tube-fed a single dose of physiological saline solution containing either CCK, CCK antagonist, trypsin inhibitor, phytohemagglutinin (PHA; a possible trigger for the digestive response) or physiological saline alone, while a further control group was left untreated. We then followed the response in CCK and tryptic enzyme activity for 0.5-8h after the administration. We performed the experiment on larvae at 26day post first-feeding, which is before the stomach has evolved and the size of the larvae allows easier handling. Individual larvae were analyzed for CCK and tryptic enzyme activity using radioimmunoassay and fluorimetric techniques respectively. Both factors varied over time in the untreated control group, possibly due to an endogenous daily rhythm. The higher CCK levels at 4h and 8h in the saline-injected group may be caused by reflexes initiated by distension of the gut. An increase in tryptic enzyme activity after injection of CCK supports the hypothesis that this hormone plays a part in the release of pancreatic enzymes in larval cod at this developmental stage. However, administration of a CCK antagonist and a trypsin inhibitor did not reveal conclusive results, probably due to the relatively low concentrations used. The response in tryptic activity in the PHA group was similar to the administration of CCK, pointing towards a stimulatory effect of PHA on the proteolytic enzyme capacity of cod larvae. 23936592 Neuronal apoptosis in morphine addiction and its molecular mechanism. This study aimed to investigate neuronal apoptosis and expression of apoptosis related proteins (Fas, Caspase-3 and Bcl-2) in the brain of rates with morphine addiction. A total of 48 adult male Sprague-Dawley rats weighing 190-210 g were randomly divided into 3 groups (n=16 per group): morphine addiction group, morphine abstinence group and control group. Rats in the addiction group and the abstinence group were intraperitoneally treated with morphine for 13 days to induce morphine addiction. In abstinence group, rats were then intraperitoneally treated with naloxone at 5 mg/kg to induce abstinence for 30 min. Rats in the control group were injected with normal saline. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was employed to detect apoptotic cells. Immunohistochemistry and Western blot assay were performed to determine the expressions of Fas, Bcl-2 and Caspase-3 in the hippocampus. When compared with the control group, the proportion of apoptotic neurons increased significantly in the addiction group and the abstinence group (P<0.01), accompanied by significantly increased expressions of Fas and Caspase-3 (P<0.01) and markedly decreased Bcl-2 expression (P<0.01) in the hippocampuse. However, no significant differences were observed between the addiction and the abstinence group (P>0.05). Long term use of morphine can induce neuronal apoptosis in the brain by increasing the expressions of pro-apoptotic Fas and Caspase-3 and decreasing the anti-apoptotic Bcl-2 expression, which might be one of mechanisms underlying the opiate-induced neuronal damage. 23769626 Understanding platinum-induced ototoxicity. Childhood cancer survival rates are now nearly 80% in more developed European countries because of improved therapies and better supportive care. Platinum chemotherapy drugs, such as cisplatin and carboplatin, are the cornerstone of many effective therapeutic protocols for childhood cancer. However, the antitumor efficacy of cisplatin and carboplatin comes at the cost of ototoxicity, which affects at least 60% of pediatric patients. Although ototoxicity is not life threatening, it can have debilitating effects on patients' quality of life. Recently, many initiatives have been launched with the ultimate goal of reducing cisplatin and high-dose carboplatin ototoxicity without compromising antitumor efficacy. This review addresses the incidence of platinum ototoxicity and its clinical presentation, time course, and early diagnostic evaluation. Genetic and non-genetic risk factors for platinum-associated ototoxicity, and their predictive value, are discussed. Recent developments in the prevention of platinum ototoxicity are also summarized. 23536198 Effects of single and combined cell treatments based on low pH and high concentrations of ethanol on the growth and fermentation of Dekkera bruxellensis and Saccharomyces cerevisiae. The alcoholic fermentation in Brazil displays some peculiarities because the yeast used is recycled in a non-aseptic process. After centrifugation, the cells are treated with acid to control the bacterial growth. However, it is difficult to manage the indigenous yeasts without affecting the main culture of Saccharomyces cerevisiae. This work evaluated how the cell treatment could be modified to combat contaminant yeasts based on the differential sensitivities to low pH and high concentrations of ethanol displayed by an industrial strain of S. cerevisiae and three strains of Dekkera bruxellensis, which are common contaminant yeasts in Brazilian fermentation processes. The tests were initially performed in rich medium with a low pH or a high concentration of ethanol to analyse the yeast growth profile. Then, the single and combined effects of low pH and ethanol concentration on the yeast cell viability were evaluated under non-proliferative conditions. The effects on the fermentation parameters were also verified. S. cerevisiae grew best when not subjected to the stresses, but this yeast and D. bruxellensis had similar growth kinetics when exposed to a low pH or increased ethanol concentrations. However, the combined treatments of low pH (2.0) and ethanol (11 or 13 %) resulted in a decrease of D. bruxellensis cell viability almost three times higher than of S. cerevisiae, which was only slightly affected by all cell treatments. The initial viability of the treated cells was restored within 8 h of growth in sugar cane juice, with the exception of the combined treatment for D. bruxellensis. The ethanol-based cell treatment, in despite of slowing the fermentation, could decrease and maintain D. bruxellensis population under control while S. cerevisiae was taking over the fermentation along six fermentative cycles. These results indicate that it may be possible to control the growth of D. bruxellensis without major effects on S. cerevisiae. The cells could be treated between the fermentation cycles by the parcelled addition of 13 % ethanol to the tanks in which the yeast cream is treated with sulphuric acid at pH 2.0. 23685462 Alteration of photochemistry and protein degradation of photosystem II from Chlamydomonas reinhardtii under high salt grown cells. In this study, we evaluated the inhibitory effect of NaCl on cell growth, photochemistry and protein profile of photosystem (PS) II in Chlamydomonas reinhardtii. To study the effect of NaCl on the photosynthetic apparatus, the C. reinhardtii cells were grown at different concentrations (0, 50, 100 and 150 mM). NaCl induced flagellar resorption due to which the cells lost their motility, formation of palmelloids, reduced cell size and slower cell division. Chlorophyll fluorescence transients at different NaCl concentrations had decreased intensities of all peaks (OJIP) indicating the apparent inactivation energies of both donor and acceptor side of PSII. Consequently, inhibition of electron transport occurred particularly at PSII. Further, low temperature emission spectra showed that the rate of damage to the PSII was more when compared to PSI. Also, we have carried out the visible circular dichroism spectra from thylakoids where the major peaks contributed to chlorophyll a and b are equally reduced in different salt grown cells, which may explain the changes at the level of inter pigment-pigment interactions. Furthermore protein profile analysis of PSII revealed that the major subunit of light harvesting complex (LHC)II is more prone to salt stress than core proteins of PSII indicating the light harvesting funnel from LHCII to PSII core is impaired. 23936300 Modeling reconsolidation in kernel associative memory. Memory reconsolidation is a central process enabling adaptive memory and the perception of a constantly changing reality. It causes memories to be strengthened, weakened or changed following their recall. A computational model of memory reconsolidation is presented. Unlike Hopfield-type memory models, our model introduces an unbounded number of attractors that are updatable and can process real-valued, large, realistic stimuli. Our model replicates three characteristic effects of the reconsolidation process on human memory: increased association, extinction of fear memories, and the ability to track and follow gradually changing objects. In addition to this behavioral validation, a continuous time version of the reconsolidation model is introduced. This version extends average rate dynamic models of brain circuits exhibiting persistent activity to include adaptivity and an unbounded number of attractors. 23402744 Sexually dimorphic behavior after developmental exposure to characterize endocrine-mediated effects of different non-dioxin-like PCBs in rats. Many chemicals are known to exhibit endocrine activity and affect reproductive functions in vertebrates and invertebrates. Endocrine effects include influences on sexual differentiation of the brain during development and reproductive and non-reproductive behavior in adult offspring. We previously demonstrated that developmental exposure to a mixture of polychlorinated biphenyls (PCBs) which was reconstituted according to the congener pattern found in human breast milk caused feminization of sweet preference as a sexually dimorphic behavior in adult male rats, following decreases in aromatase activity in the brain of newborn male pups. This result may be due to dioxin-like or non-dioxin-like (NDL) PCBs and their respective effects on steroid hormones. The aim of the present experiments was to determine if exposure to highly purified NDL-PCBs (to remove Ah receptor active contaminants) also results in alteration of sweet preference. Pregnant rats were orally exposed to PCB52 (6 dose groups, total dose of 0-3000mg/kg body weight) or PCB180 (6 dose groups, total dose of 0-1000mg/kg body weight). In a further experiment rat dams were treated with equimolar doses of PCB74 or PCB95 (total dose, 760μmol/kg body weight, corresponding to 229mg/kg or 248mg/kg body weight of PCB74 and PCB95, respectively). Adult male and female offspring were given a choice between a bottle of saccharin solution (0.25%) and a bottle of tap water on five consecutive days. Control females consumed approximately twice as much sweetened solution compared with control males, thus, demonstrating sexual dimorphism of this behavior. Only non-significant reduction of sweet preference was found at the top dose level in female offspring after exposure to PCB52. Female offspring exposed to PCB180 exhibited signs of supernormal behavior as illustrated by increased saccharin consumption at intermediate dose levels. Decreased sweet preference was observed in females after developmental PCB74, whereas males were unaffected. Only PCB95 increased saccharin consumption in exposed males, leading to decreased sexual dimorphism of this behavior and behavioral feminization. The results demonstrate that different NDL-PCBs exhibit differential effects on sexually dimorphic behavior and that feminization occurs after removal of Ah receptor active contaminants. Comparison with data from the literature reveals little evidence for a relation to anti-androgenic activity of the studied NDL-PCBs. 23908012 Miniports versus standard ports for laparoscopic cholecystectomy. In conventional (standard) port laparoscopic cholecystectomy, four abdominal ports (two of 10 mm diameter and two of 5 mm diameter) are used. Recently, use of smaller ports, miniports, have been reported. To assess the benefits and harms of miniport (defined as ports smaller than the standard ports) laparoscopic cholecystectomy versus standard port laparoscopic cholecystectomy. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until February 2013 to identify randomised clinical trials of relevance to this review. Only randomised clinical trials (irrespective of language, blinding, or publication status) comparing miniport versus standard port laparoscopic cholecystectomy were considered for the review. Two review authors collected the data independently. We analysed the data with both fixed-effect and random-effects models using RevMan analysis. For each outcome we calculated the risk ratio (RR), mean difference (MD), or standardised mean difference (SMD) with 95% confidence intervals (CI). We included 12 trials with 734 patients randomised to miniport laparoscopic cholecystectomy (380 patients) versus standard laparoscopic cholecystectomy (351 patients). Only one trial which included 70 patients was of low risk of bias. Miniport laparoscopic cholecystectomy could be completed successfully in more than 80% of patients in most trials. The remaining patients were mostly converted to standard port laparoscopic cholecystectomy but some were also converted to open cholecystectomy. These patients were included for the outcome conversion to open cholecystectomy but excluded from other outcomes. Accordingly, the results of the other outcomes are on 343 patients in the miniport laparoscopic cholecystectomy group and 351 patients in the standard port laparoscopic cholecystectomy group, and therefore the results have to be interpreted with extreme caution.There was no mortality in the seven trials that reported mortality (0/194 patients in miniport laparoscopic cholecystectomy versus 0/203 patients in standard port laparoscopic cholecystectomy). There were no significant differences between miniport laparoscopic cholecystectomy and standard laparoscopic cholecystectomy in the proportion of patients who developed serious adverse events (eight trials; 460 patients; RR 0.33; 95% CI 0.04 to 3.08) (miniport laparoscopic cholecystectomy: 1/226 (adjusted proportion 0.4%) versus standard laparoscopic cholecystectomy: 3/234 (1.3%); quality of life at 10 days after surgery (one trial; 70 patients; SMD -0.20; 95% CI -0.68 to 0.27); or in whom the laparoscopic operation had to be converted to open cholecystectomy (11 trials; 670 patients; RR 1.23; 95% CI 0.44 to 3.45) (miniport laparoscopic cholecystectomy: 8/351 (adjusted proportion 2.3%) versus standard laparoscopic cholecystectomy 6/319 (1.9%)). Miniport laparoscopic cholecystectomy took five minutes longer to complete than standard laparoscopic cholecystectomy (12 trials; 695 patients; MD 4.91 minutes; 95% CI 2.38 to 7.44). There were no significant differences between miniport laparoscopic cholecystectomy and standard laparoscopic cholecystectomy in the length of hospital stay (six trials; 351 patients; MD -0.00 days; 95% CI -0.12 to 0.11); the time taken to return to activity (one trial; 52 patients; MD 0.00 days; 95% CI -0.31 to 0.31); or in the time taken for the patient to return to work (two trials; 187 patients; MD 0.28 days; 95% CI -0.44 to 0.99) between the groups. There was no significant difference in the cosmesis scores at six months to 12 months after surgery between the two groups (two trials; 152 patients; SMD 0.13; 95% CI -0.19 to 0.46). Miniport laparoscopic cholecystectomy can be completed successfully in more than 80% of patients. There appears to be no advantage of miniport laparoscopic cholecystectomy in terms of decreasing mortality, morbidity, hospital stay, return to activity, return to work, or improving cosmesis. On the other hand, there is a modest increase in operating time after miniport laparoscopic cholecystectomy compared with standard port laparoscopic cholecystectomy and the safety of miniport laparoscopic cholecystectomy is yet to be established. Miniport laparoscopic cholecystectomy cannot be recommended routinely outside well-designed randomised clinical trials. Further trials of low risks of bias and low risks of random errors are necessary. 23939653 How is radiating leg pain defined in randomized controlled trials of conservative treatments in primary care? A systematic review. Many terms exist to describe radiating leg pain or symptoms associated with back pain (e.g., sciatica or radiculopathy) and it appears that these terms are used inconsistently. We examined the terms used to describe, and the eligibility criteria used to define, radiating leg pain in randomized controlled trials of conservative treatments, and evaluated how the eligibility criteria compared to an international pain taxonomy. Eligible studies were identified from two systematic reviews and an updated search of their search strategy. Studies were included if they recruited adults with radiating leg pain associated with back pain. Two independent reviewers screened the studies and extracted data. Studies were grouped according to the terms used to describe radiating leg pain. Thirty-one of the seventy-seven included studies used multiple terms to describe radiating leg pain; the most commonly used terms were sciatica (60 studies) and disc herniation (19 studies). Most studies that used the term sciatica included pain distribution in the eligibility criteria, but studies were inconsistent in including signs (e.g., neurological deficits) and imaging findings. Similarly, studies that used other terms to describe radiating leg pain used inconsistent eligibility criteria between studies and to the pain taxonomy, except that positive imaging findings were required for almost all studies that used disc herniation to describe radiating leg pain. In view of the varying terms to describe, and eligibility criteria to define, radiating leg pain, consensus needs to be reached for each of communication and comparison between studies. 23886440 Background levels of Persistent Organic Pollutants in humans from Taiwan: Perfluorooctane sulfonate and perfluorooctanoic acid. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) have recently received attention due to their widespread contamination of the environment. PFOS and PFOA are stable in the environment and resistant to metabolism, hydrolysis, photolysis and biodegradation. PFOS and PFOA have been found in human blood and tissue samples from both occupationally exposed workers and the general worldwide population. This study aimed to determine the background levels of PFOS and PFOA in the Taiwanese population, investigate related factors, and compare exposure in Taiwan to that in other countries. The concentration of PFOS in the 59 serum samples collected from the general population in Taiwan ranged from 3.45 to 25.65ngmL(-1) (median: 8.52), and the concentration of PFOA ranged from 1.55 to 7.69ngmL(-1) (median: 3.22). There was a significant positive correlation (r=0.51; p<0.0001) between PFOS and PFOA concentrations. Males had higher concentrations of PFOA and PFOS than females. PFOS levels in serum increased with age. This study is the first investigation to reveal the PFOS and PFOA levels of serum samples in the general population of Taiwan. The levels of PFOS and PFOA in Taiwanese serum samples were comparable with those from other countries (PFOS: 5.0-35ngmL(-1), PFOA: 1.5-10ngmL(-1)). 23659384 High levels of CD20 expression predict good prognosis in chronic lymphocytic leukemia. Heterogeneity of CD20 expression exists in chronic lymphocytic leukemia (CLL), therefore, we explored the prognostic significance of CD20 expression in Chinese patients with CLL. Multiparameter flow cytometry was used to detect the expression of CD20 in CD5(+) CD19(+) cells. In 172 CLL patients, the median expression percent of CD20 was 97.82% (range, 0-100), and the median mean fluorescence intensity (MFI) of CD20 in CLL cells was 731.45 (range, 0.00-9071.90). The percentage of CD20(+) cells in the patient group with mutated variable region of immunoglobulin genes (IGHV) was higher than in the non-mutant IGHV group (mean, 92.1% vs 80.4%, P < 0.001). There were no differences in the MFI of CD20(+) cells in all prognostic factor groups. Representation of the data using a receiver operating characteristic plot reflected separation between the two IGHV groups, with an area under the curve of 0.661 (95% confidence interval, 0.569-0.753). At the cut-off value of 60.3% for percentage of CD20, the sensitivity and specificity were 90.00% and 38.46%, respectively. Patients whose percentage of CD20 antigen was above 60.3% had longer treatment-free survival (hazard ratio, 0.452; 95% confidence interval, 0.232-0.884, P = 0.020). Percentage and MFI of CD20 were the variables not associated with treatment-free survival by multivariate Cox regression analysis (P < 0.05). High level of CD20 expression in de novo CLL appears to be associated with a good prognosis. 23763269 Egr-1 is a critical regulator of EGF-receptor-mediated expansion of subventricular zone neural stem cells and progenitors during recovery from hypoxia-hypoglycemia. We recently established that the EGF-R (epidermal growth factor receptor) (EGF-R) is an essential regulator of the reactive expansion of SVZ (subventricular zone) NPs (neural precursors) that occurs during recovery from hypoxic-ischemic brain injury. The purpose of the current studies was to identify the conditions and the transcription factor (s) responsible for inducing the EGF-R. Here, we show that the increase in EGF-R expression and the more rapid division of the NPs can be recapitulated in in vitro by exposing SVZ NPs to hypoxia and hypoglycemia simultaneously, but not separately. The EGF-R promoter has binding sites for multiple transcription factors that includes the zinc finger transcription factor, Egr-1. We show that Egr-1 expression increases in NPs, but not astrocytes, following hypoxia and hypoglycemia where it accumulates in the nucleus. To determine whether Egr-1 is necessary for EGF-R expression, we used SiRNAs (small interfering RNA) specific for Egr-1 to decrease Egr-1 expression. Knocking-down Egr-1 decreased basal levels of EGF-R and it abolished the stress-induced increase in EGF-R expression. By contrast, HIF-1 accumulation did not contribute to EGF-R expression and FGF-2 only modestly induced EGF-R. These studies establish a new role for Egr-1 in regulating the expression of the mitogenic EGF-R. They also provide new information into mechanisms that promote NP expansion and provide insights into strategies for amplifying the numbers of stem cells for CNS (central nervous system) regeneration. 23850380 T Cell-Derived Protein S Engages TAM Receptor Signaling in Dendritic Cells to Control the Magnitude of the Immune Response. Dendritic cell (DC) activation is essential for the induction of immune defense against pathogens, yet needs to be tightly controlled to avoid chronic inflammation and exaggerated immune responses. Here, we identify a mechanism of immune homeostasis by which adaptive immunity, once triggered, tempers DC activation and prevents overreactive immune responses. T cells, once activated, produced Protein S (Pros1) that signaled through TAM receptor tyrosine kinases in DCs to limit the magnitude of DC activation. Genetic ablation of Pros1 in mouse T cells led to increased expression of costimulatory molecules and cytokines in DCs and enhanced immune responses to T cell-dependent antigens, as well as increased colitis. Additionally, PROS1 was expressed in activated human T cells, and its ability to regulate DC activation was conserved. Our results identify a heretofore unrecognized, homeostatic negative feedback mechanism at the interface of adaptive and innate immunity that maintains the physiological magnitude of the immune response. 22150026 Chemical constituents and allelopathic and antioxidant activities of Alchorneopsis floribunda Müll. Arg. (Euphorbiaceae). Chemical investigation of extracts from the stems and leaves of Alchorneopsis floribunda Müll. Arg., collected in the Amazon region, was performed. The main isolated compounds were triterpenes (α-amyrin, β-amyrin, lupeol, betulin, betulinic acid, uvaol, erythrodiol and oleanolic acid) and phenolic acid derivatives from 4-hydroxybenzoic acid (gallic and protocatechuic acids and isocorilagin). In the germination assays, high inhibitory allelopathic effects of the extracts and isocorilagin were observed and 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity of isocorilagin was higher than those of the standards used (Trolox and butylated hydroxyanisole). This is the first chemical study of the genus Alchorneopsis (Euphorbiaceae). 23438015 A natural topological insulator. The earth's crust and outer space are rich sources of technologically relevant materials which have found application in a wide range of fields. Well-established examples are diamond, one of the hardest known materials, or graphite as a suitable precursor of graphene. The ongoing drive to discover novel materials useful for (opto)electronic applications has recently drawn strong attention to topological insulators. Here, we report that Kawazulite, a mineral with the approximate composition Bi2(Te,Se)2(Se,S), represents a naturally occurring topological insulator whose electronic properties compete well with those of its synthetic counterparts. Kawazulite flakes with a thickness of a few tens of nanometers were prepared by mechanical exfoliation. They exhibit a low intrinsic bulk doping level and correspondingly a sizable mobility of surface state carriers of more than 1000 cm(2)/(V s) at low temperature. Based on these findings, further minerals which due to their minimized defect densities display even better electronic characteristics may be identified in the future. 19996980 Continuous positive airway pressure treatment in addition to optimal medical therapy for ventricular ectopy in a patient with heart failure and sleep-related breathing disorder. In this report we describe the case of a 56-year-old man with a medical history of onset of asthenia, palpitations and dyspnoea for mild efforts. After a negative ergometric test for myocardial ischaemia and 24-h Holter monitoring showing frequent ventricular premature beats, but an echocardiogram with significant dilation and dysfunction of the left ventricle, coronary angiography was performed and did not show haemodynamically significant stenosis. Regarding the anamnesis of snoring, daytime sleepiness and the relationship between sleep-related breathing disorder and cardiovascular disease, we performed a cardiorespiratory sleep study that indicated a diagnosis of sleep-related breathing disorder with prevalent obstructive apnoea. In addition to optimal medical therapy for cardiovascular disease, the patient began therapy with continuous positive airway pressure during the night. This showed a considerable decrease in ventricular premature beats (VPBs) during the night, a better control of ventricular ectopy during the day and a better compliance with medical therapy. 23765429 Single-step microwave-mediated synthesis of oxazoles and thiazoles from 3-oxetanone: a synthetic and computational study. The direct microwave-mediated condensation between 3-oxetanone and primary amides and thioamides has delivered moderate to good yields of (hydroxymethyl)oxazoles and (hydroxymethyl)thiazoles. The reactions use a sustainable solvent and only require short reaction times. These are highly competitive methods for the construction of two classes of valuable heteroarenes, which bear a useful locus for further elaboration. Electronic structure calculations have shown that the order of events involves chalcogen atom attack at sp(3) carbon and alkyl-oxygen cleavage. The critical role of acid catalysis was shown clearly, and the importance of acid strength was demonstrated. The calculated barriers were also fully consistent with the observed order of thioamide and amide reactivity. Spontaneous ring opening involves a modest degree of CO cleavage, moderating the extent of strain relief. On the acid-catalysed pathway, CO cleavage is less extensive still, but proton transfer to the nucleofuge is well advanced with the carboxylic acid catalysts, and essentially complete with methanesulfonic acid. 23921848 Leaching behaviour of chlorpyriphos and cypermethrin in sandy loam soil. The mobility of chlorpyriphos and cypermethrin in sandy loam soil was studied in soil columns under laboratory conditions at two application rates, 25 and 50 Î¼g, with simulated rainfall of 300 mm. Residues of chlorpyriphos and cypermethrin in soil and leachate were estimated by gas-liquid chromatography and confirmed by gas chromatography-mass spectrometry. Though maximum concentration of both the insecticides was found in the top 10-cm layer, chlorpyriphos was found distributed in the soil up to a depth of 35 cm and cypermethrin remained up to 15 cm. Results indicated the low mobility of both the insecticides under saturated moisture condition and hence may not contaminate ground water. No residues of any insecticide were detected in the leachate fractions. 23892328 The impact of morphological and immunohistological changes in minor salivary glands on the health of the oral cavity in HSCT patients. The objective of this study was to test the relationship between histological changes in minor salivary glands (MSG) and chronic GVHD (cGVHD) severity and OS of hematopoietic SCT (HSCT) patients, and to discriminate the participation of events preceding HSCT that damage MSG, from those linked to cGVHD. The MSG of 57 HSCT patients who were divided into two groups-oral cGVHD (36 cases) and non-cGVHD (21 cases)-were compared with the MSG of a control group of 19 non-HSCT individuals. cGVHD changes were assessed according to National Institutes of Health (NIH) consensus and the systems of Horn et al. Acinar areas and mononuclear cell subsets were set through morphometry. Horn's 'periductal lymphocytic infiltrate' correlated with an extensive form of cGVHD and NIH 'periductal lymphocytes with exocytosis into duct' correlated with global survival. Measurements of the acinar area differed between the three groups, being the lowest in cGVHD patients, but also reduced in non-cGVHD patients. Significant differences among CD45, CD45RO, CD4 and CD8 immunomarked cells/mm(2) were found by comparing the two groups of HSCT patients. In brief, periductal lymphocytic infiltrate and exocytosis implies inflammatory activity and, consequently, might reflect the cGVHD status and influence survival. Acini loss in non-cGVHD patients may be due to pre-transplant events, but massive lymphocyte infiltrate is part of the cGVHD process.Bone Marrow Transplantation advance online publication, 29 July 2013; doi:10.1038/bmt.2013.105. 23266567 DHA supplementation: current implications in pregnancy and childhood. Dietary supplementation with ω-3 long chain fatty acids including docosahexaenoic acid (DHA) has increased in popularity in recent years and adequate DHA supplementation during pregnancy and early childhood is of clinical importance. Some evidence has been built for the neuro-cognitive benefits of supplementation with long chain polyunsaturated fatty acids (LCPUFA) such as DHA during pregnancy; however, recent data indicate that the anti-inflammatory properties may be of at least equal significance. Adequate DHA availability in the fetus/infant optimizes brain and retinal maturation in part by influencing neurotransmitter pathways. The anti-inflammatory properties of LCPUFA are largely mediated through modulation of signaling either directly through binding to receptors or through changes in lipid raft formation and receptor presentation. Our goal is to review the current findings on DHA supplementation, specifically in pregnancy and infant neurodevelopment, as a pharmacologic agent with both preventative and therapeutic value. Given the overall benefits of DHA, maternal and infant supplementation may improve neurological outcomes especially in vulernable populations. However, optimal composition of the supplement and dosing and treatment strategies still need to be determined to lend support for routine supplementation. 23768674 Effects of interpretation training on hostile attribution bias and reactivity to interpersonal insult. Research suggests that individuals high in anger have a bias for attributing hostile intentions to ambiguous situations. The current study tested whether this interpretation bias can be altered to influence anger reactivity to an interpersonal insult using a single-session cognitive bias modification program. One hundred thirty-five undergraduate students were randomized to receive positive training, negative training, or a control condition. Anger reactivity to insult was then assessed. Positive training led to significantly greater increases in positive interpretation bias relative to the negative group, though these increases were only marginally greater than the control group. Negative training led to increased negative interpretation bias relative to other groups. During the insult, participants in the positive condition reported less anger than those in the control condition. Observers rated participants in the positive condition as less irritated than those in the negative condition and more amused than the other two conditions. Though mediation of effects via bias modification was not demonstrated, among the positive condition posttraining interpretation bias was correlated with self-reported anger, suggesting that positive training reduced anger reactivity by influencing interpretation biases. Findings suggest that positive interpretation training may be a promising treatment for reducing anger. However, the current study was conducted with a non-treatment-seeking student sample; further research with a treatment-seeking sample with problematic anger is necessary. 23943730 Serial blood serotonin levels in a randomized controlled trial comparing the efficacy of low-dose amitriptyline, amitriptyline with pindolol and surrogate placebo in patients with chronic tension-type facial pain. Patients often present with chronic facial pain despite normal nasal endoscopy and sinus computerized tomography. Such pain has increasingly been recognized as being of neurological origin with one of the commonest underlying causes being mid-facial segmental tension-type pain (MFP) which is a version of tension headache in the face. Descending serotonergic neuronal projections are known to modulate pain and intra-platelet serotonin levels are an accepted model reflecting central intra-neuronal serotonin. 1.To determine whether low-dose amitriptyline significantly changes whole blood serotonin compared to a surrogate placebo in patients with chronic MFP 2. To determine whether the addition of pindolol, a beta blocker with serotonin receptor blocking properties further alters blood serotonin. Sixty-two patients were randomized to three treatment groups a) amitriptyline , b) amitriptyline with pindolol, and c) loratadine as surrogate placebo. Whole blood serotonin was taken before and after 8 weeks of treatment. Serotonin was also measured in 40 age-matched healthy controls. There was a significant reduction in blood serotonin levels in the amitriptyline with pindolol group. A non-significant reduction was seen in the amitriptyline group, with no change in serotonin levels in the surrogate placebo group. A comparison of change in serotonin with change in pain frequency and intensity scores is presented. Women in the control group had significantly higher serotonin levels than men. Women with tension-type facial pain who failed to respond to treatment had significantly lower blood serotonin than women in the control group. When linked to the clinical response this study provides evidence that the serotonergic system is involved in the modulation of chronic MFP. Serotonin levels are sex-dependent and related to treatment response. 23706642 Preoperative hemoglobin level as a predictor of mortality after aortic valve replacement. The predictive value of preoperative hemoglobin (HB) level on the outcome of patients undergoing valve surgery is not well established. This study evaluated the predictive value of preoperative HB level on survival after aortic valve replacement (AVR). This was a retrospective analysis of prospectively collected data. A single-center study performed in an educational hospital. All consecutive patients (n = 1,808) who underwent AVR between January 1998 and December 2010. Patients were classified into 4 groups according to the preoperative HB level: very low (HB of <12g/dL in men and <11g/dL in women), low (HB of 12-13g/dL in men and 11-12g/dL in women), normal (HB of 13-14.5g/dL in men and 12-13.5g/dL in women), and high normal (HB of ≥14.5g/dL in men and ≥13.5g/dL in women). The mean follow-up duration was 5.58±3.5 years, and the median follow-up duration was 5.38 years. The mean preoperative HB was 14±1.6g/dL for men and 13.0±2.1g/dL for women. Early mortality (≤30 days) was 6.1% in the very-low-HB group, 5.4% in the low-HB group, 3.2% in the normal HB group, and 2.3% in the high-normal-HB group (p = 0.37). Late mortality (>30 days) was 26.1% in the very-low-HB group, 23.7% in the low-HB group, 17.1% in the normal-HB group, and 12.6% in the high-normal-HB group (p<0.0001). The multivariate logistic regression model did not identify low HB as an independent predictor for early mortality. Cox regression multivariate analysis revealed both HB level, as a continuous variable, (p = 0.006), and very-low-HB level (p<0.0001), as independent predictors of late mortality. Cox regression analyses, corrected for confounders, demonstrated that low-HB level is an independent predictor for higher overall mortality (hazard ratio = 2.00, CI 1.41-2.85, p≤0.0001). In patients undergoing AVR, preoperative low-HB level is an independent risk factor for late mortality, but not for early mortality. 23966206 Fluidic-Directed Assembly of Aligned Oligopeptides with π-Conjugated Cores. A microfluidic-based directed assembly strategy is employed to form highly aligned supramolecular structures. Formation of aligned synthetic oligopeptide nanostructures is accomplished using planar extensional flow, which induces alignment of underlying material suprastructures. Fluidic-directed assembly of supramolecular structures allows for unprecedented manipulation at the nano- and mesoscales, which has the potential to provide rapid and efficient control of functional materials properties. 23908265 Designing the Magic Bullet? The Advancement of Immuno-PET into Clinical Use. The development of noninvasive imaging techniques using monoclonal antibodies (mAbs) is a quickly evolving field. Immuno-PET uses positron-emitting isotopes to track the localization of mAbs with excellent image quality. Procedures for labeling mAbs with (89)Zr or (124)I using good manufacturing procedures have been established, and therefore these radiopharmaceuticals are being investigated for clinical use. This short review will focus on immuno-PET with full mAbs using long-lived positron-emitting isotopes ((89)Zr and (124)I) over the past 5 y and discuss their progress into clinical use. 23892166 Pretreatment of 2,4-dinitroanisole (DNAN) producing wastewater using a combined zero-valent iron (ZVI) reduction and Fenton oxidation process. A combined zero-valent iron (ZVI) reduction and Fenton oxidation process was tested for the pretreatment of 2,4-dinitroanisole (DNAN) producing wastewater. Operating conditions were optimized and overall performance of the combined process was evaluated. For ZVI process, almost complete reduction of nitroaromatic compounds was observed at empty bed contact time (EBCT) of 8h. For Fenton process, the optimal pH, H2O2 to Fe(II) molar ratio, H2O2 dosage and hydraulic retention time (HRT) were found to be 3.0, 15, 0.216mol/L and 5h, respectively. After pretreatment by the combined ZVI-Fenton process under the optimal conditions, aromatic organic compound removal was as high as 77.2%, while the majority of COD remained to be further treated by sequent biological process. The combined anaerobic-aerobic process consisted of an anaerobic baffled reactor (ABR) and a moving-bed biofilm reactor (MBBR) was operated for 3 months, fed with ZVI-Fenton effluent. The results revealed that the coupled ZVI-Fenton-ABR-MBBR system was significantly efficient in terms of correcting the effluent's main parameters of relevance, mainly aromatic compounds concentration, COD concentration, color and acute toxicity. These results indicate that the combined ZVI-Fenton process offers bright prospects for the pretreatment of wastewater containing nitroaromatic compounds. 23742937 Recognition of intermolecular G-quadruplexes by full length nucleophosmin. Effect of a leukaemia-associated mutation. Nucleophosmin (NPM) is a nucleolar protein involved in ribosome biogenesis. NPM1 gene is frequently mutated in acute myeloid leukaemia (AML), correlating with aberrant cytoplasmic localization of the protein. NPM attachment to the nucleolus in physiological conditions probably depends on binding to nucleic acids, and this recognition could be altered in AML. NPM associates to guanine-rich DNA sequences, able to fold as "G-quadruplexes". We have analyzed the interaction of pentameric, full length NPM with G-rich oligonucleotides, finding that the protein binds preferentially high-order G-quadruplexes. AML-associated mutation significantly hampers DNA binding, pointing to a possible mechanism contributing to pathological mislocalization of NPM. 23917321 The Antimicrobial Peptide GL13K is Effective in Reducing Biofilm of Pseudomonas aeruginosa. Human Parotid Secretory Protein (PSP; Bpif2a) is predicted to be structurally similar to Bactericidal/Permeability-Increasing protein and Lipopolysaccharide-Binding Protein. Based on the location of known antimicrobial peptides in the latter two proteins potential active peptides were identified in the PSP sequence. One such peptide, GL13NH2 (PSP 141-153) was shown previously to interfere with LPS binding and agglutinate bacteria without bactericidal activity. By introducing three additional positive charged lysine residues the peptide was converted to the novel bactericidal cationic peptide GL13K (MIC 8 μg/ml, 5.6 μM, Pseudomonas aeruginosa). We investigated the antibiofilm activity of GL13K against static, monospecies biofilms of P. aeruginosa PAO1. Two hour exposure of a 24 h biofilm to 64 μg/ml (44.8 μM) GL13K reduced biofilm bacteria by 10(2) and 100 μg/ml (70 μM) GL13K reduced bacteria by 10(3). Similar results could be achieved on 48h old biofilms. Lower concentrations of GL13K (32 μg/ml, 22.4 μM) were successful in reducing biofilm cell numbers in combination with tobramycin. This combination treatment also achieved total eradication of the biofilm in a majority (67.5%) of tested samples. An alanine scan of GL13K revealed the importance of the leucine residue in position six of the peptide sequence where replacement led to a loss of antibiofilm activity, whereas the impact of replacing charged residues was less pronounced. Bacterial metalloproteases were found to partially inactivate GL13K but not a D-amino acid version of the peptide. 23902405 Impact of Suspended Inorganic Particles on Phosphorus Cycling in the Yellow River (China). Phosphorus (P) in water and sediment in the Yellow River was measured for 21 stations from the source to the Bohai Sea in 2006-2007. The average total particulate matter (TPM) increased from 40 mg/L (upper reaches) to 520 mg/L (middle reaches) and 950 mg/L in the lower reaches of the river. The average dissolved PO4 concentration (0.43 μmol/L) was significantly higher than that in 1980's but lower than the world average level despite high nutrient input to the system. Much of the P input was removed by adsorption, which was due to the high TPM rather than the surface activity of the particles since they had low labile Fe and low affinity for P. The sediment was a sink for P in the middle to lower reaches but not in the upper to middle reaches. TPM has been reduced by more than an order of magnitude due to artificial dams operating over recent decades. Modeling revealed that TPM of 0.2-1 g/L was a critical threshold for the Yellow River, below which most of the phosphate input cannot be removed by the particles and may cause eutrophication. These findings are important for river management and land-ocean modeling of global biogeochemical P cycling. 23904034 Supported gold catalysts: new properties offered by nanometer and sub-nanometer structures. Nano-sized gold particles on solid supports offer unexpected catalytic properties, with new discoveries emerging rapidly for oxidation, hydrogenation, coupling, and other reactions. Oxidation of H2 to give H2O2 catalyzed by metal oxide-supported gold nanoclusters (reported in Chem. Commun. in 2002 by the group of Hutchings) offers promise for large-scale application. Catalysis by gold has become a vibrant, expanding field marked by continuing surprises, but fundamental understanding of how these catalysts work is emerging only slowly. 23748027 Silencing the ecdysone synthesis and signaling pathway genes disrupts nymphal development in the whitefly. Sap-sucking insects are important pests in agriculture and good models to study insect biology. The role of ecdysone pathway genes in the life history of this group of insects is largely unknown likely due to a lack of efficient gene silencing methods allowing functional genetic analyses. Here, we developed a new and high throughput method to silence whitefly genes using a leaf-mediated dsRNA feeding method. We have applied this method to explore the roles of genes within the molting hormone-ecdysone synthesis and signaling pathway for the survival, reproduction and development of whiteflies. Silencing of genes in the ecdysone pathway had a limited effect on the survival and fecundity of adult whiteflies. However, gene silencing reduced survival and delayed development of the whitefly during nymphal stages. These data suggest that the silencing method developed here provides a useful tool for functional gene discovery studies of sap-sucking insects, and further indicate the potential of regulating the ecdysone pathway in whitefly control. 23806852 Low tolerance for complications. Assisted reproductive techniques can lead to medical complications such as multiple pregnancy and ovarian hyperstimulation syndrome. A critical appraisal and strategies to reduce the occurrence of these complications are discussed in this manuscript. 23680694 Sex-dependent changes in brain CB1R expression and functionality and immune CB2R expression as a consequence of maternal deprivation and adolescent cocaine exposure. Early life stress has been associated with several psychiatric disorders, including drug addiction. Actually, maternal deprivation (MD) alters the endocannabinoid system, which participates in motivation and reward for drugs, including cocaine. At youth, the rate of cocaine abuse is alarmingly increasing. Herein, we have investigated the consequences of MD and/or adolescent cocaine exposure in brain CB1Rs and CB2Rs in immune tissues. Control and maternally deprived (24h on postnatal day, pnd, 9) male and female Wistar rats were administered cocaine (8mg/kg/day) or saline during adolescence (pnd 28-42). At adulthood, [(3)H]-CP-55,940 autoradiographic binding was employed for the analysis of CB1R density and CP-55,940-stimulated [(35)S]-GTPgammaS binding for CB1R functionality; CB2R expression was analyzed by Western blotting. Sex differences in CB1R expression and functionality were found, and MD induced important and enduring sex-dependent changes. In addition, the plastic changes induced by adolescent cocaine administration in brain CB1Rs were differentially influenced by early life events. MD increased spleen CB2R expression while adolescent cocaine administration attenuated this effect; cocaine exposure also diminished CB2R expression in bone marrow. Present findings provide evidence for changes in brain CB1R expression and functionality and immune CB2R expression as a consequence of early life stress and adolescent cocaine exposure, and indicate functional interactions between both treatments, which in many regions differ between males and females. 23685751 (68)Ga-DOTA (0)-Tyr (3)-octreotide positron emission tomography in head and neck squamous cell carcinoma. (68)Ga-labelled DOTA(0)-Tyr(3)-octreotide positron emission tomography (PET)/CT ((68)Ga-DOTATOC PET/CT) is a routinely used imaging modality for neuroendocrine tumours expressing somatostatin receptors (SSTRs). Recent studies have shown that SSTRs are also expressed in head and neck squamous cell carcinoma (HNSCC). This is the first prospective clinical trial investigating SSTR expression in patients with HNSCC using (68)Ga-DOTATOC. Patients with previously untreated HNSCC underwent (68)Ga-DOTATOC PET/CT (120 MBq, range 81-150 MBq). Tumour tracer uptake was scored, the maximum standardized uptake value (SUVmax) was measured and the tumour to background uptake ratio was calculated. For each patient, PET/CT findings were correlated with immunohistochemical SSTR expression in tumour specimens. Fifteen HNSCC patients were included in the study from May 2011 to May 2012. Tumour-specific (68)Ga-DOTATOC uptake was detected in all patients with an median SUVmax of 4.0 (range 2.2-6.5). Uptake was weak in seven (47 %), moderate in five (33 %) and strong in three (20 %) patients. All tumour specimens were SSTR positive on immunohistochemistry. Of the 15 patients, 14 were positive for SSTR subtype 2, characterized by the highest affinity to octreotide. SSTR expression in HNSCC can be visualized clinically using (68)Ga-DOTATOC PET/CT. SSTR expression in HNSCC could provide a potential target for SSTR-based therapy in patients not amenable to standard treatment modalities, but this cannot be predicted by SSTR immunohistochemistry. 23890700 Metabolic regulation of the cell cycle. There is a growing appreciation that metabolic signals are integrated and coupled to cell cycle progression. However, the molecular wiring that connects nutrient availability, biosynthetic intermediates and energetic balance to the core cell cycle machinery remains incompletely understood. In this review, we explore the recent progress in this area with particular emphasis on how nutrient and energetic status is sensed within the cell to ultimately regulate cell growth and division. The role these pathways play in normal cell function including stem cell biology is also discussed. Furthermore, we describe the growing appreciation that dysregulation of these pathways might contribute to a variety of pathological conditions including metabolic diseases and tumor formation. 23523207 Obese patients undergoing total knee arthroplasty have distinct preoperative characteristics: an institutional study of 4718 patients. Obesity affects a disproportionate proportion of total knee arthroplasty (TKA) patients. Our study explores pre-operative characteristics between obese and non-obese patients undergoing TKA surgery. A cohort of 4718 osteoarthritic patients, undergoing primary TKA, was studied. Patients were stratified according to BMI classes. Each class was compared in terms of age, race, gender, level of education, insurance status, pre-operative WOMAC, SF-36, and Elixhauser comorbidities. There was a positive relationship between BMI and female gender, non-white race, Medicaid, private insurance, and self-pay. A negative relationship was observed between BMI and age, Medicare, WOMAC and SF-36. Obese TKA candidates differ from their non-obese counterparts in a number of demographic, socioeconomic, and clinical characteristics. 23445301 Incidence trends of cannabis and cocaine use from periodic Spanish general population surveys: effect of standardizing results by age structure. This study estimates life-time incidence trends of cannabis and cocaine use over 38 years from general population surveys of drug use (GPSDU) in Spain, taking into account changes of population age structure. Periodic cross-sectional studies. Eight biennial GPSDU from 1995 to 2009 in Spain. Interviewees aged 15-64 years who reported age of first ever cannabis and/or cocaine use between 10 and 64 years between 1971 and 2008. Estimates of raw and standardized incidences were calculated as a weighted mean of the incidences from all surveys. Standardization was conducted to take into account changes of population age structure. Incidence trends were extracted applying weighted cubic smoothing splines to incidence estimates. For both substances, estimated raw incidence trends increased up until 2000 (rates of 11.5 ± 0.7 and 3.6 ± 0.5 per 1000, respectively, for cannabis and cocaine), and then decreased significantly (in 2008, 9.6 ± 1.2 and 2.7 ± 0.6, respectively). In contrast, standardized rates exhibit a steadily increasing trend up to 2000 (9.0 ± 0.6 and 2.8 ± 0.4), followed by a statistically non-significant increasing trend afterwards (in 2008, 9.5 ± 1.2 and 2.8 ± 0.6). The largest increases of incidence were observed in both male and female subjects aged 15-19 years. Using data from Spanish general population surveys of drug use, an apparently decreasing trend of raw incidence rates in both cannabis and cocaine use from 2000 became non-decreasing trends when these rates were standardized. First experiences of cannabis and cocaine use in Spain occur mainly in younger ages (15-19 years). 23872079 Long-Term Disability and Survival in Traumatic Brain Injury: Results From the Nidrr Model Systems. To document long-term survival in one-year survivors of traumatic brain injury (TBI); to compare the use of the Disability Rating Scale (DRS) and Functional Independence Measure (FIM) as factors in the estimation of survival probabilities; and to investigate the effect of time since injury and secular trends in mortality. Cohort study of one-year survivors of TBI; followed up to 20 years post-injury. Statistical methods include standardized mortality ratios (SMRs), Kaplan-Meier survival curve, proportional hazard regression, and "person-year" logistic regression. Post-discharge from National Institute on Disability and Rehabilitation Research-funded TBI Model Systems rehabilitation units. Population-based sample of 7,228 persons who were admitted to a TBI Model Systems facility and survived at least 1 year post-injury. These persons contributed 32,505 person-years, with 537 deaths, over the 1989 to 2011 study period. Not Applicable. Survival. Survival was poorer than that of the general population (SMR=2.1; 95% CI 1.9-2.3). Age, sex, and functional disability were significant risk factors for mortality (p < 0.0001). FIM- and DRS-based proportional hazard survival models had comparable predictive performance (C-index 0.80 vs. 0.80, AIC 11,005 vs 11,015). Time since injury and current calendar year were not significant predictors of long-term survival (both p > 0.05). Long-term survival prognosis in TBI depends on age, sex, and disability. FIM and DRS are useful prognostic measures with comparable statistical performance. Age- and disability-specific mortality rates in TBI have not declined over the last 20 years. A survival prognosis calculator is available at http://www.LifeExpectancy.org/tbims.shtml. 23928225 Optimization of fixed-permeabilized cell monolayers for high throughput micro-neutralizing antibody assays: Application to the zebrafish/viral hemorrhagic septicemia virus (vhsv) model. A new high throughput centrifugation-free method to estimate viral neutralizing antibody levels in low volumes and large numbers of plasma blood samples is described. Cell monolayers were, (i) plated on poly-d-Lys coated 96-wells, (ii) infected with viruses previously incubated with fish plasma containing antibodies, (iii) fixed with formaldehyde to increase cell recovery and avoid centrifugation steps, (iv) permeabilized with Saponin, (v) immunostained in the presence of Saponin by using a monoclonal antibody (MAb) to viral protein, (vi) digested with trypsin to detach cells from the monolayer, in the absence of Saponin to reduce damage of intracellular MAb-antigen complexes, and (vii) gated by flow cytometry using automatic 96-well batch analysis. The method was applied to the determination of plasma neutralizing antibodies from zebrafish (Danio rerio) surviving infections with viral hemorrhagic septicemia virus (VHSV) (an important rhabdovirus of salmonids). This semi-automatic, rapid and practical assay detected anti-VHSV neutralizing antibodies in the plasma (∼3μl per fish) of 95.1% of the zebrafish surviving VHSV infections. The fixed-permeabilized monolayer (FIXPERM) micro-neutralization method might help to analyze sera/plasma from small fish under standarized high throughput conditions. 23375190 Anterior segment characteristics of keratoconus eyes in a sample of Asian population. To assess changes in anterior segment parameters of keratoconus eyes at different stages of the disease in a sample of the Asian population. Files of 32 patients (48 eyes) diagnosed as clinical keratoconus were assessed and the following parameters noted: central corneal thickness (CCT), thinnest corneal thickness (TCT), location of thinnest pachymetry, anterior chamber depth (ACD) at the centre from posterior corneal surface, ACD at 1, 2 and 3mm inferior-paracentral, ACD at thinnest pachymetry, anterior chamber volume (ACV) and anterior chamber angle (ACA). For analysis, keratoconus eyes were classified into 3 subgroups according to mean keratometry readings (mild: K≤47.0D, moderate: 47.0 1.0 mm, and 7 electrodes had errors < 0.2 mm. 99 electrodes (98%) were placed with 1 pass. Average surgical time for bilateral cases was 3 hours 4 minutes and for unilateral cases was 2 hours 23 minutes. 46 of 60 patients now have >6 months clinical followup (range 6-25 months), and no electrodes have required repositioning due to lack of clinical response or stimulation induced adverse effects. The ClearPoint platform demonstrates application accuracy of 0.6 mm. This is a significant improvement over the first generation iMRI technique using the NexFrame (1.2 mm). Errors are consistently in the submillimetric range, with the overwhelming majority of electrodes placed with 1 pass. No patients to date have required electrode repositioning using this anatomically targeted, real-time image guided technique. 23769816 The cost of poor blood specimen quality and errors in preanalytical processes. The increase in the prevalence of medical errors represents a disturbing trend; hospital-based errors are the eighth leading cause of death in the United States. For the clinical laboratory, errors that occur in the preanalytical phase of testing may account for up to 75% of total laboratory errors; 26% of these may have detrimental effects on patient care, which contribute to unnecessary investigations or inappropriate treatment, increase in lengths of hospital stay, as well as dissatisfaction with healthcare services. This review focuses on these errors, particularly those observed in the preanalytical phase, and how they may affect clinical and financial outcomes. Financial ramifications are also demonstrated through a model that estimates the costs of preanalytical errors for the hospital and laboratory as well as patient care. 23663074 Dual-stimulus luminescent lanthanide molecular switch based on an unsymmetrical diarylperfluorocyclopentene. A [2]pseudorotaxane formed from an unsymmetrical diarylperfluorocyclopentene (1) and a Eu(3+) complex of terpyridinyldibenzo-24-crown-8 (2) revealed excellent reversible lanthanide luminescence switching behavior dual-modulated by host-guest and optical stimuli. 23933315 Bitter plants used as substitute of Cinchona spp. (quina) in Brazilian traditional medicine. Bitter tasting plant species are used as tonics and have been previously used to treat intermittent fevers in Brazil, the principal symptom of malaria. Many of these species were named quina and were used as substitutes of Cinchona spp., the source of quinine. To present data on these bitter species named quina and to discuss their potential as sources of bioactive substances. Data about the plants were obtained from a survey of the literature and documents written by early naturalists and clinical doctors living in the 18th and 19th centuries in Brazil. Correlated pharmacological studies were obtained from different scientific databases. A total of 29 species were recorded. The largest number of species belonged to the Rubiaceae family (14), being Remijia ferruginea (A. St.-Hil) DC. the most representative. Strychnos pseudoquina A. St.-Hil. (Loganiaceae), Hortia brasiliana Vand. ex DC. (Rutaceae) and Solanum pseudoquina A. St.-Hil. (Solanaceae) were also frequently mentioned in the historical bibliography. Pharmacological studies have shown the presence of bitter bioactive substances useful to treat digestive disorders and/or with antimalarial activities, in all of the recorded botanic families. This study shows that several bitter species named quina were used in the past as substitute of Cinchona spp. and studying these plants can lead to the development of new products. 23826640 Sweet and sour after renal transplantation: A qualitative study about the positive and negative consequences of renal transplantation. This qualitative study investigated the renal patients' experience of positive and negative consequences of transplantation, as well as the strategies they use to adapt to the transplantation. A qualitative design (30 participants in total), using individual interviews (18 participants) and two focus groups (12 participants in total), was used. The results showed that patients experienced a wide range of positive and negative emotions, in particular, guilt, gratefulness, and fear, partly as a result of their normative persuasions. Normative persuasions may transform inherent positive emotions into negative emotions and subsequent maladaptive behaviour. Not only physical limitations but also physical improvements were found to be related to the experience of negative emotions. Finally, the results indicated that patients mainly used adaptive coping strategies to adjust to life after transplantation, such as looking for opportunities, setting different priorities, making own choices, trying to maintain control, taking good care of oneself, and appreciating other things in life. This study offers several new insights regarding the range of experiences of renal patients after transplantation. Health professionals are invited to pay more attention to the full range of positive and negative experiences following transplantation, including the existence of normative persuasions. Health professionals may assist renal patients by helping them to recognize and acknowledge both positive and negative emotions and to encourage the use of more beneficial coping strategies. What is already known on this subject? The quality of life (QoL) of renal patients significantly improves after transplantation but the post-transplant QoL is lower compared with the QoL in healthy populations. Patients on dialysis and those who have received a donor kidney tend to use mainly emotion-focused coping strategies. What does this study add? This study offers several new insights regarding experiences of renal patients after transplantation: Patients experience a range of positive and negative emotions like guilt, gratefulness, and fear. Emotions are partly a result of normative persuasions. Persuasions may transform positive emotions into negative emotions and maladaptive behaviour. Physical limitations and improvements can due to the persuasions lead to negative emotions. Patients mainly use adaptive coping strategies. 23419389 Approach to distribution and accumulation of dibutyl phthalate in rats by immunoassay. Dibutyl phthalate (DBP) is mainly taken up by the general population from food intake. To estimate intake of phthalates, determining distribution and accumulation of DBP in biological materials was a critical need. In this work, we set up two novel approaches with a monoclonal antibody specific to DBP to determine the distribution and accumulation of DBP in vivo. The contents of DBP in liver, kidney, stomach and testes were detected by immunofluorescence assays and indirect competitive ELISA. This data give directly evidence that indicates the distribution and accumulation of DBP in vivo. Double-label immunofluorescence assay provides with a visual approach to determination of the distribution and accumulation of DBP. It indicated that DBP accumulated in subcutaneous tissue such as sweat gland, hair follicle. Both of immunofluorescence assay and ELISA can be used to detect the content of DBP in biological materials. Our assays showed that DBP accumulated in viscera being rich in fat, such as liver, kidney and could overcome physiological barriers to penetrate testes. The date suggested that the accumulations of DBP exposed through dermal route were less than that of oral route and most of DBP was metabolized in 2 or 3days. 23632636 Early growth response protein-1 mediates lipotoxicity-associated placental inflammation: role in maternal obesity. Obesity is associated with low-grade chronic inflammation, which contributes to cellular dysfunction promoting metabolic disease. Obesity during pregnancy leads to a proinflammatory milieu in the placenta; however, the underlying causes for obesity-induced placental inflammation remain unclear. Here, we examine the mechanisms by which saturated fatty acids and inflammatory cytokines induce inflammation in placental trophoblasts. We conducted global transcriptomic profiling in BeWo cells following palmitate and/or TNFα treatment and gene/protein expression analyses of MAPK pathways and characterized downstream transcription factors directly regulating inflammatory cytokines. Microarray analysis revealed increased expression of genes regulating inflammation, stress response, and immediate early response in cytotrophoblasts in response to palmitic acid (PA), TNFα, or a combination of both (PA + TNFα). Both gene ontology and gene set enrichment analysis revealed MAPK and EGR-1 signaling to be upregulated in BeWo cells, which was confirmed via immunoblotting. Importantly, activation of JNK signaling was necessary for increased proinflammatory cytokine (IL-6, TNFα, and IL-8) and EGR1 mRNA. Consistent with the requirement of JNK signaling, ChIP analysis confirmed the recruitment of c-Jun and other MAPK-responsive immediate early factors on the EGR1 promoter. Moreover, recruitment of EGR-1 on cytokine promoters (IL-6, TNFα, and IL-8) and an impaired proinflammatory response following knockdown of EGR-1 suggested it as a central component of the mechanism facilitating inflammatory gene expression. Finally, akin to in vitro findings, term placenta from obese women also had both increased JNK and p38 signaling and greater EGR-1 protein relative to lean women. Our results demonstrate that lipotoxic insults induce inflammation in placental cells via activation of JNK/EGR-1 signaling. 23852371 Intracellular ASIC1a regulates mitochondrial permeability transition-dependent neuronal death. Acid-sensing ion channel 1a (ASIC1a) is the key proton receptor in nervous systems, mediating acidosis-induced neuronal injury in many neurological disorders, such as ischemic stroke. Up to now, functional ASIC1a has been found exclusively on the plasma membrane. Here, we show that ASIC1a proteins are also present in mitochondria of mouse cortical neurons where they are physically associated with adenine nucleotide translocase. Moreover, purified mitochondria from ASIC1a(-/-) mice exhibit significantly enhanced Ca(2+) retention capacity and accelerated Ca(2+) uptake rate. When challenged with hydrogen peroxide (H2O2), ASIC1a(-/-) neurons are resistant to cytochrome c release and inner mitochondrial membrane depolarization, suggesting an impairment of mitochondrial permeability transition (MPT) due to ASIC1a deletion. Consistently, H2O2-induced neuronal death, which is MPT dependent, is reduced in ASIC1a(-/-) neurons. Additionally, significant increases in mitochondrial size and oxidative stress levels are detected in ASIC1a(-/-) mouse brain, which also displays marked changes (>2-fold) in the expression of mitochondrial proteins closely related to reactive oxygen species signal pathways, as revealed by two-dimensional difference gel electrophoresis followed by mass spectrometry analysis. Our data suggest that mitochondrial ASIC1a may serve as an important regulator of MPT pores, which contributes to oxidative neuronal cell death.Cell Death and Differentiation advance online publication, 12 July 2013; doi:10.1038/cdd.2013.90. 22458250 Trypanosoma cruzi Antioxidant Enzymes As Virulence Factors in Chagas Disease. Abstract Significance: Chagas disease (CD) affects several million people in Latin America and is spreading beyond its classical boundaries due to the migration of infected host and insect vectors, HIV co-infection, and blood transfusion. The current therapy is not adequate for treatment of the chronic phase of CD, and new drugs are warranted. Recent Advances: Trypanosoma cruzi is equipped with a specialized and complex network of antioxidant enzymes that are located at different subcellular compartments which defend the parasite against host oxidative assaults. Recently, strong evidence has emerged which indicates that enzyme components of the T. cruzi antioxidant network (cytosolic and mitochondrial peroxiredoxins and trypanothione synthetase) in naturally occurring strains act as a virulence factor for CD. This precept is recapitulated with the observed increased resistance of T. cruzi peroxirredoxins overexpressers to in vivo or in vitro nitroxidative stress conditions. In addition, the modulation of mitochondrial superoxide radical levels by iron superoxide dismutase (FeSODA) influences parasite programmed cell death, underscoring the role of this enzyme in parasite survival. Critical Issues: The unraveling of the biological significance of FeSODs in T. cruzi programmed cell death in the context of chronic infection in CD is still under examination. Future Directions: The role of the antioxidant enzymes in the pathogenesis of CD, including parasite virulence and persistence, and their feasibility as pharmacological targets justifies further investigation. Antioxid. Redox Signal. 19, 723-734. 23907403 Inhibition of Hippocampal β-Adrenergic Receptors Impairs Retrieval But Not Reconsolidation of Cocaine-Associated Memory and Prevents Subsequent Reinstatement. Retrieval of drug-associated memories is critical for maintaining addictive behaviors, as presentation of drug-associated cues can elicit drug seeking and relapse. Recently, we and others have demonstrated that β-adrenergic receptor (β-AR) activation is necessary for retrieval using both rat and human memory models. Importantly, blocking retrieval with β-AR antagonists persistently impairs retrieval and provides protection against subsequent reinstatement. However, the neural locus at which β-ARs are required for maintaining retrieval and subsequent reinstatement is unclear. Here, we investigated the necessity of dorsal hippocampus (dHipp) β-ARs for drug-associated memory retrieval. Using a cocaine conditioned place preference (CPP) model, we demonstrate that local dHipp β-AR blockade before a CPP test prevents CPP expression shortly and long after treatment, indicating that dHipp β-AR blockade induces a memory retrieval disruption. Furthermore, this retrieval disruption provides long-lasting protection against cocaine-induced reinstatement. The effects of β-AR blockade were dependent on memory reactivation and were not attributable to reconsolidation disruption as blockade of β-ARs immediately after a CPP test had little effect on subsequent CPP expression. Thus, cocaine-associated memory retrieval is mediated by β-AR activity within the dHipp, and disruption of this activity could prevent cue-induced drug seeking and relapse long after treatment.Neuropsychopharmacology advance online publication, 28 August 2013; doi:10.1038/npp.2013.187. 23733736 Axis-oriented, continuous anatase titania films with exposed reactive {100} facets. Homogeneous TiO2 single crystals with high exposure of {100} reactive facets were constructed as a seed monolayer on transparent conductive substrates with the desired orientation of reactive facets. A secondary growth process was subsequently carried out on the monolayer seed film to form an axis-oriented continuous reactive film. Performing secondary growth with different precursors led to optimized conditions for high-performance photoelectrochemical activity of anatase TiO2 films. Experimental techniques such as UV/Vis absorption spectroscopy, X-ray diffraction, high-resolution SEM, and photoelectrochemistry were used to characterize the structural, optical, and photoelectrochemical properties of the as-synthesized films. As a photoanode in a photoelectrochemical cell, the axis-oriented reactive film shows a maximum photocurrent density of 0.3 mA cm(-2), as opposed to 0.075 mA cm(-2) for non-axis-oriented (randomly oriented) TiO2 film. 23229891 PET/CT-guided interventions: personnel radiation dose. To quantify radiation exposure to the primary operator and staff during PET/CT-guided interventional procedures. In this prospective study, 12 patients underwent PET/CT-guided interventions over a 6 month period. Radiation exposure was measured for the primary operator, the radiology technologist, and the nurse anesthetist by means of optically stimulated luminescence dosimeters. Radiation exposure was correlated with the procedure time and the use of in-room image guidance (CT fluoroscopy or ultrasound). The median effective dose was 0.02 (range 0-0.13) mSv for the primary operator, 0.01 (range 0-0.05) mSv for the nurse anesthetist, and 0.02 (range 0-0.05) mSv for the radiology technologist. The median extremity dose equivalent for the operator was 0.05 (range 0-0.62) mSv. Radiation exposure correlated with procedure duration and with the use of in-room image guidance. The median operator effective dose for the procedure was 0.015 mSv when conventional biopsy mode CT was used, compared to 0.06 mSv for in-room image guidance, although this did not achieve statistical significance as a result of the small sample size (p = 0.06). The operator dose from PET/CT-guided procedures is not significantly different than typical doses from fluoroscopically guided procedures. The major determinant of radiation exposure to the operator from PET/CT-guided interventional procedures is time spent in close proximity to the patient. 23901993 Structure and properties of sodium aluminosilicate glasses from molecular dynamics simulations. Addition of alumina to sodium silicate glasses considerably improves the mechanical properties and chemical durability and changes other properties such as ionic conductivity and melt viscosity. As a result, aluminosilicate glasses find wide industrial and technological applications including the recent Corning(®) Gorilla(®) Glass. In this paper, the structures of sodium aluminosilicate glasses with a wide range of Al∕Na ratios (from 1.5 to 0.6) have been studied using classical molecular dynamics simulations in a system containing around 3000 atoms, with the aim to understand the structural role of aluminum as a function of chemical composition in these glasses. The short- and medium-range structures such as aluminum coordination, bond angle distribution around cations, Q(n) distribution (n bridging oxygen per network forming tetrahedron), and ring size distribution have been systematically studied. In addition, the mechanical properties including bulk, shear, and Young's moduli have been calculated and compared with experimental data. It is found that aluminum ions are mainly four-fold coordinated in peralkaline compositions (Al∕Na < 1) and form an integral part of the rigid silicon-oxygen glass network. In peraluminous compositions (Al∕Na > 1), small amounts of five-fold coordinated aluminum ions are present while the concentration of six-fold coordinated aluminum is negligible. Oxygen triclusters are also found to be present in peraluminous compositions, and their concentration increases with increasing Al∕Na ratio. The calculated bulk, shear, and Young's moduli were found to increase with increasing Al∕Na ratio, in good agreement with experimental data. 23775222 The Role of Therapeutic Alliance in Mindfulness Interventions: Therapeutic alliance in Mindfulness Training for Smokers. Mindfulness-based interventions have enjoyed a marked increase in support within biomedical and psychological research and practice in the past two decades. Despite the widespread application of these treatments for a range of psychological and medical conditions, there remains a lack of consensus regarding mechanisms through which these interventions effect change. One plausible yet underexplored mechanism is the therapeutic alliance between participants and mindfulness instructors. In this report, data are presented on therapeutic alliance from the mindfulness arm (n = 37) of a randomized controlled trial of a mindfulness-based smoking cessation treatment. Results suggest that client-reported therapeutic alliance measured midtreatment did not significantly predict primary smoking outcomes. Alliance did predict improvement in posttreatment scores on several outcome variables linked to mindfulness practice, including emotion regulation (β = -.24, p = .042), mindfulness (β = .33, p = .007), negative affect (β = -.33, p = .040), as well as treatment compliance (β = .39, p = .011). Implications of these relationships and the possible role of therapeutic alliance in mindfulness treatments are explored. 23385959 Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by Trolox. While manganese (Mn) is essential for proper central nervous system (CNS) development, excessive Mn exposure may lead to neurotoxicity. Mn preferentially accumulates in the basal ganglia, and in adults it may cause Parkinson's disease-like disorder. Compared to adults, younger individuals accumulate greater Mn levels in the CNS and are more vulnerable to its toxicity. Moreover, the mechanisms mediating developmental Mn-induced neurotoxicity are not completely understood. The present study investigated the developmental neurotoxicity elicited by Mn exposure (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 to PN27 in rats. Neurochemical analyses were carried out on PN29, with a particular focus on striatal alterations in intracellular signaling pathways (MAPKs, Akt and DARPP-32), oxidative stress generation and cell death. Motor alterations were evaluated later in life at 3, 4 or 5 weeks of age. Mn exposure (20 mg/kg) increased p38(MAPK) and Akt phosphorylation, but decreased DARPP-32-Thr-34 phosphorylation. Mn (10 and 20 mg/kg) increased caspase activity and F(2)-isoprostane production (a biological marker of lipid peroxidation). Paralleling the changes in striatal biochemical parameters, Mn (20 mg/kg) also caused motor impairment, evidenced by increased falling latency in the rotarod test, decreased distance traveled and motor speed in the open-field test. Notably, the antioxidant Trolox™ reversed the Mn (20 mg/kg)-dependent augmentation in p38(MAPK) phosphorylation and reduced the Mn (20 mg/kg)-induced caspase activity and F(2)-isoprostane production. Trolox™ also reversed the Mn-induced motor coordination deficits. These findings are the first to show that long-term exposure to Mn during a critical period of neurodevelopment causes motor coordination dysfunction with parallel increment in oxidative stress markers, p38(MAPK) phosphorylation and caspase activity in the striatum. Moreover, we establish Trolox™ as a potential neuroprotective agent given its efficacy in reversing the Mn-induced neurodevelopmental effects. 23790466 Inhibition of polo-like kinase 1 in glioblastoma multiforme induces mitotic catastrophe and enhances radiosensitisation. Glioblastoma multiforme (GBM) is the most common primary brain tumour in the United States of America (USA) with a median survival of approximately 14months. Low survival rates are attributable to the aggressiveness of GBM and a lack of understanding of the molecular mechanisms underlying GBM. The disruption of signalling pathways regulated either directly or indirectly by protein kinases is frequently observed in cancer cells and thus the development of inhibitors of specific kinases has become a major focus of drug discovery in oncology. To identify protein kinases required for the survival of GBM we performed a siRNA-based RNAi screen focused on the human kinome in GBM. Inhibition of the polo-like kinase 1 (PLK1) induced a reduction in the viability in two different GBM cell lines. To assess the potential of inhibiting PLK1 as a treatment strategy for GBM we examined the effects of a small molecule inhibitor of PLK1, GSK461364A, on the growth of GBM cells. PLK1 inhibition arrested cells in the mitotic phase of the cell cycle and induced cell kill by mitotic catastrophe. GBM engrafts treated with GSK461364A showed statistically significant inhibition of tumour growth. Further, exposure of different GBM cells to RNAi or GSK461364A prior to radiation resulted in an increase in their radiosensitivity with dose enhancement factor ranging from 1.40 to 1.53 with no effect on normal cells. As a measure of DNA double strand breaks, γH2AX levels were significantly higher in the combined modality as compared to the individual treatments. This study suggests that PLK1 is an important therapeutic target for GBM and can enhance radiosensitivity in GBM. 23850019 Cancer vaccines: Harnessing the potential of anti-tumor immunity. Although the presence of cancer suggests failure of the immune system to protect against development of tumors, the possibility that immunity can be redirected and focused to generate an anti-tumor response offers great translational possibility. The key to this is identifying antigens likely to be present in any given tumor and functionally critical to tumor survival and growth. Such tumor-associated antigens (TAAs) are varied and optimally should be absent from normal tissue. Of particular interest are TAAs associated with the tumor stroma, as immunity directed against the stroma may restrict the ability of the tumor to grow and metastasize. Important to directing the immune system toward an effect anti-tumor response is the understanding of how TAAs are processed and how the tumor is able to evade immune elimination. The process of immunoediting happens in response to the selective pressure that the immune system places upon tumor cell populations and allows for emergence of tumor cells capable of escaping immune destruction. Efforts to harness the immune system for clinical application has been aided by vaccines based on purified recombinant protein or nucleic acid TAAs. For example, a vaccine for canine melanoma has been developed and approved based on immunization with DNA components of tyrosinase, a glycoprotein essential to melanin synthesis. The performance of cancer vaccines has been aided in some cases when supplemented with immunostimulatory molecules such as interleukin 2 or a novel extracellular matrix vaccine adjuvant. Vaccines with the broadest menu of antigenic targets may be those most likely to succeed against cancer. For this reason, tissue vaccines produced from harvested tumor material may offer significant benefit. With several cancer vaccines on the veterinary and human markets, efforts to understand basic tumor immunology are soon to yield great dividends. 23352378 Attenuated adiposopathy in perivascular adipose tissue compared with subcutaneous human adipose tissue. We hypothesized that human perivascular and subcutaneous adipose tissues hold distinct phenotypic signatures. We also evaluated the impact of clinical parameters on the adipose phenotype. Our overall goal is to understand the determinants of adipose biology so that this tissue can be manipulated therapeutically to lessen peripheral vascular disease. Perivascular and subcutaneous adipose tissues were collected from patients undergoing lower-extremity amputation (n = 27) and protein assayed for proinflammatory mediators (ie, interleukin 6, interleukin 8, leptin, tumor necrosis factor α, monocyte chemoattractant protein-1, and resistin), atheroprotective adiponectin, and the fibrinolysis inhibitor plasminogen activator inhibitor-1. Leptin (2.7-fold, P = .015), TNF-α (2.2-fold, P = .013), MCP-1 (1.5-fold, P = .047), and adiponectin (1.8-fold, P = .004) were more abundant in subcutaneous vs perivascular adipose tissue. Age positively correlated with perivascular adipose tissue PAI-1 expression (β = .64, P = .042), and hyperlipidemia negatively correlated with perivascular adiponectin (β = -1.18, P = .039). Human perivascular and subcutaneous adipose tissues hold distinct phenotypic signatures. In amputation patients, the subcutaneous adipose tissue proinflammatory phenotype was relatively attenuated in perivascular adipose tissue. 23763540 Assembly of Protein-Based Hollow Spheres Encapsulating a Therapeutic Factor. Neurotrophins, as important regulators of neural development, function, and survival, have a therapeutic potential to repair damaged neurons. However, a controlled delivery of therapeutic molecules to injured tissue remains one of the greatest challenges facing the translation of novel drug therapeutics field. This study presents the development of an innovative protein-protein delivery technology of nerve growth factor (NGF) by an electrostatically assembled protein-based (collagen) reservoir system that can be directly injected into the injury site and provide long-term release of the therapeutic. A protein-based biomimetic hollow reservoir system was fabricated using a template method. The capability of neurotrophins to localize in these reservoir systems was confirmed by confocal images of fluorescently labeled collagen and NGF. In addition, high loading efficiency of the reservoir system was proven using ELISA. By comparing release profile from microspheres with varying cross-linking, highly cross-linked collagen spheres were chosen as they have the slowest release rate. Finally, biological activity of released NGF was assessed using rat pheochromocytoma (PC12) cell line and primary rat dorsal root ganglion (DRG) cell bioassay where cell treatment with NGF-loaded reservoirs induced significant neuronal outgrowth, similar to that seen in NGF treated controls. Data presented here highlights the potential of a high capacity reservoir-growth factor technology as a promising therapeutic treatment for neuroregenerative applications and other neurodegenerative diseases. 23399949 The critical effect of polarization on the dynamical structure of guanine quadruplex DNA. Guanine quadruplex DNA (G-DNA), found in eukaryotic telomeres and recently in non-telomeric genomic DNA, plays important biological roles and their structures are being explored as potential targets for therapeutic intervention. Since the quadruplex structure of G-DNA is stabilized by cations, electrostatic interaction is expected to play important roles in the dynamical structure of G-DNA. In current work, MD simulation was carried out to study the dynamical structure of a special G-DNA (with sequence d(G(4)T(4)G(4))) complexed with five K(+) ions. In order to properly include polarization in MD simulation, a new set of polarized nucleic acid specific charge based on fragment quantum chemistry calculation was developed for G-DNA. Our study showed that polarization of the nucleobases by K(+) enhanced electrostatic attraction between the base and ions. This increased attractive interaction is critical to stabilizing the stem-loop junction ions in G-DNA. Without this polarization effect, as in MD simulation using a standard (nonpolarizable) force field, the top and bottom cations escaped into the solvent within just a few nanoseconds. Furthermore, an incorrect bifurcated bonding geometry of G-DNA, found in previous MD simulation study under a standard force field but not observed in experiments, disappeared in the present stimulation using the new polarized force field. The current study bridged an important gap between the simulation study and experimental observation on the dynamical structure of G-DNA. 23063001 Physiological effects of waterborne lead exposure in spiny dogfish (Squalus acanthias). To broaden our knowledge about the toxicity of metals in marine elasmobranchs, cannulated spiny dogfish (Squalus acanthias) were exposed to 20 μM and 100 μM lead (Pb). Since we wanted to focus on sub lethal ion-osmoregulatory and respiratory disturbances, arterial blood samples were analysed for pH(a), PaO(2), haematocrit and total CO(2) values at several time points. Plasma was used to determine urea, TMAO, lactate and ion concentrations. After 96 h, Pb concentrations were determined in a number of tissues, such as gill, rectal gland, skin and liver. To further investigate ion and osmoregulation, Na(+)/K(+)-ATPase activities in gill and rectal gland were analysed as well as rates of ammonia and urea excretion. Additionally, we studied the energy reserves in muscle and liver. Pb strongly accumulated in gills and especially in skin. Lower accumulation rates occurred in gut, kidney and rectal gland. A clear disturbance in acid-base status was observed after one day of exposure indicating a transient period of hyperventilation. The increase in pH(a) was temporary at 20 μM, but persisted at 100 μM. After 2 days, plasma Na and Cl concentrations were reduced compared to controls at 100 μM Pb and urea excretion rates were elevated. Pb caused impaired Na(+)/K(+)-ATPase activity in gills, but not in rectal gland. We conclude that spiny dogfish experienced relatively low ion-osmoregulatory and respiratory distress when exposed to lead, particularly when compared to effects of other metals such as silver. These elasmobranchs appear to be able to minimize the disturbance and maintain physiological homeostasis during an acute Pb exposure. 23954566 Cow's milk allergy: From allergens to new forms of diagnosis, therapy and prevention. The first adverse reactions to cow's milk were already described 2000years ago. However, it was only 50years ago that several groups started with the analysis of cow's milk allergens. Meanwhile the spectrum of allergy eliciting proteins within cow's milk is identified and several cow's milk allergens have been characterized regarding their biochemical properties, folding and IgE binding epitopes. The diagnosis of cow's milk allergy is diverse ranging from fast and cheap in vitro assays to elaborate in vivo assays. Considerable effort was spent to improve the diagnosis from an extract-based into a component resolved concept. There is still no suitable therapy available against cow's milk allergy except avoidance. Therefore research needs to focus on the development of suitable and safe immunotherapies that do not elicit severe side effect. 23748030 Distinct post-transcriptional regulation of Igfbp1 gene by hypoxia in lowland mouse and Qinghai-Tibet plateau root vole Microtus oeconomus. Our previous study revealed the particular expression patterns of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 1 (IGFBP1) in the Qinghai-Tibet plateau root vole (Microtus oeconomus) under hypoxic challenge. Here we report the molecular mechanisms of Igf gene regulation associated with adaptation to hypoxia. M. oeconomus IGF1 and IGFBP1 were shown to be highly conserved. Hypoxia (8.0% O2, 6h) did not change the liver-derived Igf1 expression in either M. oeconomus or mouse. Hypoxia significantly upregulated hepatic Igfbp1 gene expression and IGFBP1 levels in the liver and plasma of the mouse, but not in M. oeconomus. A functional U-rich element in the 3' untranslated region was found in mouse Igfbp1 mRNA, which was associated with Igfbp1 mRNA stabilization and upregulation under hypoxia, and this U-rich element was eliminated in the M. oeconomus Igfbp1, resulting in blunted Igfbp1 mRNA upregulation, which might be understood as a sequence variation modified during molecular evolution under hypoxia. 23252515 Cooperative effects of drug-resistance mutations in the flap region of HIV-1 protease. Understanding the interdependence of multiple mutations in conferring drug resistance is crucial to the development of novel and robust inhibitors. As HIV-1 protease continues to adapt and evade inhibitors while still maintaining the ability to specifically recognize and efficiently cleave its substrates, the problem of drug resistance has become more complicated. Under the selective pressure of therapy, correlated mutations accumulate throughout the enzyme to compromise inhibitor binding, but characterizing their energetic interdependency is not straightforward. A particular drug resistant variant (L10I/G48V/I54V/V82A) displays extreme entropy-enthalpy compensation relative to wild-type enzyme but a similar variant (L10I/G48V/I54A/V82A) does not. Individual mutations of sites in the flaps (residues 48 and 54) of the enzyme reveal that the thermodynamic effects are not additive. Rather, the thermodynamic profile of the variants is interdependent on the cooperative effects exerted by a particular combination of mutations simultaneously present. 23955068 Molecular characterization of human parainfluenza virus type 1 in infants attending Mbagathi District Hospital, Nairobi, Kenya: a retrospective study. Human parainfluenza virus type 1 (HPIV-1), a paramyxovirus, is a leading cause of pediatric respiratory hospitalizations globally. Currently, there is no clinically successful vaccine against HPIV-1. Hence, there is a need to characterize circulating strains of this virus to establish the feasibility of developing a vaccine against the virus. The variable HPIV-1 hemagglutin-neuraminidase (HN) protein is found in the envelope of HPIV-1, where it initiates the infection process by binding to cellular receptors. HN is also the major antigen against which the human immune response is directed against. The present study focused on identifying mutations in the HN gene that would be useful in understanding the evolution of HPIV-1. 21 HPIV-1 isolates were obtained after screening nasopharyngeal samples from patients with influenza-like illness. The samples were collected from Mbagathi District Hospital Nairobi from the period July 2007 to December 2010. RT-PCR was carried out on the isolates using HN-specific primers to amplify a 360 nt in the most polymorphic region and the amplicons sequenced. Genomic data were analysed using a suite of bioinformatic software. Forty eight polymorphic sites with a total of 55 mutations were identified at the nucleotide level and 47 mutations at 23 positions at the amino acid level. There was more radical nonsynonymous amino acid changes (seven positions) observed than conservative nonsynonymous changes (one position) on the HN gene fragment. No positively selected sites were found in the HN protein. The result from the analysis of 21 HPIV-1 Mbagathi isolates demonstrated that the HN gene which is the major antigenic target was under purifying (negative) selection displaying evolutionary stasis. 23897466 Structures of human sirtuin 3 complexes with ADP-ribose and with carba-NAD(+) and SRT1720: binding details and inhibition mechanism. Sirtuins are NAD(+)-dependent protein deacetylases that regulate metabolism and aging processes and are considered to be attractive therapeutic targets. Most available sirtuin modulators are little understood mechanistically, hindering their improvement. SRT1720 was initially described as an activator of human Sirt1, but it also potently inhibits human Sirt3. Here, the molecular mechanism of the inhibition of Sirt3 by SRT1720 is described. A crystal structure of Sirt3 in complex with SRT1720 and an NAD(+) analogue reveals that the compound partially occupies the acetyl-Lys binding site, thus explaining the reported competition with the peptide substrate. The compound packs against a hydrophobic protein patch and binds with its opposite surface to the NAD(+)  nicotinamide, resulting in an exceptionally tight sandwich-like interaction. The observed arrangement rationalizes the uncompetitive inhibition with NAD(+), and binding measurements confirm that the nicotinamide moiety of NAD(+) supports inhibitor binding. Consistently, no inhibitor is bound in a second crystal structure of Sirt3 that was solved complexed with ADP-ribose and crystallized in the presence of SRT1720. These results reveal a novel sirtuin inhibitor binding site and mechanism, and provide a structural basis for compound improvement. 23899971 On leadership from the bedside to the boardroom. E leanor Roosevelt is someone we both greatly admire; many of her quotes, including the one above (Roosevelt, 1960, p. 29) are truly inspiring. She was a respected public figure. Her claim to fame included being the longest-serving First Lady of the United States (1933-1945) and her continued political activism afterward by serving as an American delegate to the newly formed United Nations (UN). She was one of the drafters of the UN Universal Declaration of Human Rights and she chaired the Human Rights Commission. Although she led a privileged life, she was a champion for social justice. Her accomplishments are remarkable and serve as a study in leadership. 23404093 Management of chemotherapy-induced nausea and vomiting : focus on newer agents and new uses for older agents. Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. The use of a combination of a serotonin 5-HT3 receptor antagonist, dexamethasone and a neurokinin 1 (NK1) receptor antagonist has significantly improved the control of acute and delayed emesis in single-day chemotherapy. Palonosetron, a second-generation 5-HT3 receptor antagonist with a different half-life, a different binding capacity and a different mechanism of action than the first-generation 5-HT3 receptor antagonists appears to be the most effective agent in its class. Aprepitant, the first and only agent clinically available in the NK1 receptor antagonist drug class has been used effectively as an additive agent to the 5-HT3 receptor antagonists and dexamethasone to control CINV. Rolapitant and netupitant are other NK1 receptor antagonists that are currently in phase III clinical trials. Despite the control of emesis, nausea has not been well controlled by current agents. Olanzapine, a US-FDA approved antipsychotic, has emerged in recent trials as an effective preventative agent for CINV, as well as a very effective agent for the treatment of breakthrough emesis and nausea. Clinical trials using gabapentin, cannabinoids and ginger have not been definitive regarding their efficacy in the prevention of CINV. Additional studies are necessary for the control of nausea and for the control of CINV in the clinical settings of multiple-day chemotherapy and bone marrow transplantation. 23912526 Electrochemical and chemical tuning of the surface wettability of tetrathiafulvalene self-assembled monolayers. The tuning of the surface wettability of self-assembled monolayers of two novel tetrathiafulvalenes has been achieved by electrochemical and chemical means. 23539208 Determination of pharmaceuticals, personal care products, and pesticides in surface and treated waters: method development and survey. Water is fundamental to the existence of life since it is essential to a series of activities, such as agriculture, power generation, and public and industrial supplies. The residual water generated by these activities is released into the environment, reaches the water systems, and becomes a potential risk to nontarget organisms. This paper reports the development and validation of a quantitative method, based on solid-phase extraction and liquid chromatography tandem mass spectrometry, for the simultaneous analysis of 18 pharmaceuticals and personal care products (PPCPs) and 33 pesticides in surface and drinking waters. The accuracy of the method was determined by calculating the recoveries, which ranged from 70 to 120 % for most pesticides and PPCPs, whereas limits of quantification ranged from 0.8 to 40 ng/L. After the validation step, the method was applied to drinking and surface waters. Pesticides and PPCPs were found in concentrations lower than 135.5 ng/L. The evaluation of different water sources with regard to contamination by pesticides and PPCPs has been quite poor in southern Brazil. 23274777 Chemical constituents from the fibrous root of Ophiopogon japonicus, and their effect on tube formation in human myocardial microvascular endothelial cells. In an effort to identify novel active constituents on the cardiovascular system, a systematic study on macroporous resin adsorption of extracts from the fibrous root of Ophiopogon japonicus was performed in a human myocardial microvascular endothelial cell line (HMMEC) based assay. One novel spirostan, named ophiogenin (1), together with six known spirostans (4-8, 10), and one new sesquiterpene glycoside, named ophioside A (2), together with one known monoterpene glycoside (9) were isolated from the active fractions, and the aglycone of compound 2 that was a new natural compound was obtained from the acid hydrolysis of 2, named ophiopogonol (3). Their structures were determined by spectral and chemical analyses. Furthermore, their effect on HMMEC tube formation was also determined. Our results indicated that compounds 4 and 8 could significantly improve the tube formation and 2 showed moderate increasing effect, while compound 5 exhibited potent inhibitory effect. 23897244 An Examination of the Representativeness Assumption for Twin Studies of Eating Pathology and Internalizing Symptoms. Little research has investigated whether the twin representativeness assumption (that results from twin research generalize to singletons) holds for eating pathology and internalizing symptoms. This study compared disordered eating, depression, and anxiety among young adult female twins versus singletons. Participants included 292 twins and 997 singletons in three samples. Questionnaires included the Minnesota Eating Behavior Survey, Eating Disorder Examination Questionnaire, Beck Depression Inventory, and State-Trait Anxiety Inventory. We examined mean differences between twins' and singletons' scores, after adjusting for age, body mass index, and ethnicity. We found statistically significant mean differences on psychopathology, with twins reporting less disordered eating and internalizing symptoms compared with singletons. Effect sizes of these mean differences were small to moderate. Our results suggest that twins report less disordered eating and internalizing symptoms than singletons, which, combined with the generally small effect sizes, indicate that results from twin samples generalize to singletons. 23661049 Differential Adherence and Expression of Virulence Traits by Candida albicans and Candida parapsilosis in Mono- and Dual-Species Cultures in Artificial Saliva. To evaluate specific virulence factors of Candida albicans and Candida parapsilosis clinical oral isolates in mono- and dual-species culture in the presence of artificial saliva. Two of the strains used in this study were isolated from co-infection (C. albicans AM and C. parapsilosis AM2), and the other two were isolated from single infection (C. albicans AC and C. parapsilosis AD). The number of adhered yeast cells was measured and their enzymatic activity was determined simultaneously. In mono-species culture, C. parapsilosis strains adhered to a higher extent to the surface in comparison with the C. albicans strains. In dual-species culture, the C. parapsilosis strains adhered more in the presence of C. albicans AM. Interestingly, C. albicans AM and C. parapsilosis AD adhered to a higher extent when compared with all other co-cultures. In dual-species culture, the enzymatic activity of C. parapsilosis strains in the presence of C. albicans AC was higher than in the presence of C. albicans AM. The virulence factors of C. albicans and C. parapsilosis differ from strain to strain and are influenced by the presence of other species in culture. To understand the expression of virulence factors in Candida dual-species systems. 23749720 Just-in-time rescue plerixafor in combination with chemotherapy and granulocyte-colony stimulating factor for peripheral blood progenitor cell mobilization. Plerixafor, a recently approved peripheral blood progenitor cell mobilizing agent, is often added to granulocyte-colony stimulating factor (G-CSF) to mobilize peripheral blood progenitor cells in patients with lymphoma or myeloma who cannot mobilize enough CD34+ cells with G-CSF alone to undergo autologous stem cell transplantation. However, data are lacking regarding the feasibility and efficacy of just-in-time plerixafor in combination with chemotherapy and G-CSF. We reviewed the peripheral blood stem cell collection data of 38 consecutive patients with lymphoma (Hodgkin's and non-Hodgkin's) and multiple myeloma who underwent chemomobilization and high-dose G-CSF and just-in-time plerixafor to evaluate the efficacy of this treatment combination. All patients with multiple myeloma and all but one patient with lymphoma collected the minimum required number of CD34+ cells to proceed with autologous stem cell transplantation (>2 × 10(6) /kg of body weight). The median CD34+ cell dose collected in patients with non-Hodgkin lymphoma was 4.93 × 10(6) /kg of body weight. The median CD34+ cell dose collected for patients with multiple myeloma was 8.81 × 10(6) /kg of body weight. Plerixafor was well tolerated; no grade 2 or higher non-hematologic toxic effects were observed. Am. J. Hematol. 88:754-757, 2013. © 2013 Wiley Periodicals, Inc. 23915243 Barbituric Acid-Based Magnetic N-Halamine Nanoparticles as Recyclable Antibacterial Agents. Novel recyclable bactericidal materials, barbituric acid-based magnetic N-halamine nanoparticles (BAMNH NPs), were fabricated by coating of magnetic silica nanoparticles (MS NPs) with barbituric acid-based N-halamine by the aid of the radical polymerization. The sterilizing effect on the bacterial strain is investigated by incubating Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis). The as-prepared BAMNH NPs exhibit higher biocidal activity than the bulk powder barbituric acid-based N-halamine due to the high activated surface area. The structural effect of N-halamine on antimicrobial performance was fully clarified through the comparison between BAMNH NPs and hydantoin-based magnetic N-halamine nanoparticles (HMNH NPs). BAMNH NPs exhibited promising stability toward repeated washing and long-term storage. BAMNH NPs with different chlorine content were comparatively chosen to investigate the influence of chlorine content on the antimicrobial activity. An antibacterial recycle experiment revealed that no significant change occurred in the structure and antibacterial efficiency of BAMNH NPs after five recycle experiments. The combination of barbituric acid-based N-halamine with magnetic component results in an obvious synergistic effect and facilitates the repeated antibacterial applications, providing potential and ideal candidates for sterilization or even for the control of disease. 22735157 Contributions of low and high spatial frequency processing to impaired object recognition circuitry in schizophrenia. Patients with schizophrenia exhibit cognitive and sensory impairment, and object recognition deficits have been linked to sensory deficits. The "frame and fill" model of object recognition posits that low spatial frequency (LSF) information rapidly reaches the prefrontal cortex (PFC) and creates a general shape of an object that feeds back to the ventral temporal cortex to assist object recognition. Visual dysfunction findings in schizophrenia suggest a preferential loss of LSF information. This study used functional magnetic resonance imaging (fMRI) and resting state functional connectivity (RSFC) to investigate the contribution of visual deficits to impaired object "framing" circuitry in schizophrenia. Participants were shown object stimuli that were intact or contained only LSF or high spatial frequency (HSF) information. For controls, fMRI revealed preferential activation to LSF information in precuneus, superior temporal, and medial and dorsolateral PFC areas, whereas patients showed a preference for HSF information or no preference. RSFC revealed a lack of connectivity between early visual areas and PFC for patients. These results demonstrate impaired processing of LSF information during object recognition in schizophrenia, with patients instead displaying increased processing of HSF information. This is consistent with findings of a preference for local over global visual information in schizophrenia. 23572011 Hormonal contraceptive use and discontinuation among HIV-infected women in Uganda and Zimbabwe. Hormonal contraception (HC) use by HIV-infected women has been identified by the World Health Organization as an important strategy for reducing vertical HIV transmission. Little is known about the factors associated with HC discontinuation among HIV-infected women. We analyzed data from a prospective study of HC use among 231 HIV-infected users with oral contraceptive (OC) or injectable depot medroxyprogesterone acetate (DMPA) in Uganda and Zimbabwe. We used Kaplan-Meier survival curves to estimate the median duration of OC and DMPA use and use of any highly effective contraceptive method. Cox proportional hazards models were used to investigate factors associated with HC discontinuation. Median duration was 36 months [95% confidence interval (CI): 14 to 61] for OC use and 19 months (95% CI: 14 to 24) for DMPA use. Median duration of any highly effective method was 36 months (95% CI: 26 to N/A) for OC users and 22 months (95% CI: 14 to 38) for DMPA users. In multivariable analyses, living in Zimbabwe [hazard ratio (HR): 0.39; 95% CI: 0.18 to 0.83], no partner (HR: 7.18; 95% CI: 3.05 to 16.88), and cervical infection (HR: 1.99; 95% CI: 0.90 to 4.41) were associated with OC discontinuation. No partner (HR: 2.00; 95% CI: 1.12 to 3.58), nausea (HR: 1.84; 95% CI: 1.02 to 3.34), and excessive night sweats (HR: 1.80; 95% CI: 0.95 to 3.40) were associated with DMPA discontinuation. Long-term use of HC methods is acceptable to HIV-infected women. Women discontinue for a variety of reasons, primarily unrelated to HIV. Alternative methods and ongoing contraceptive counseling is essential to reduce unplanned pregnancies and vertical HIV transmission. 23319364 Country of origin, age at migration and risk of cutaneous melanoma: a migrant cohort study of 1,100,000 Israeli men. Cutaneous melanoma (CM) is a common cancer with increasing incidence in many parts of the world where light-skinned populations live. We conducted a large-scale nationally representative migrant cohort study to assess country of origin and age at migration as predictors of CM, controlling for possible confounders. Data on 1,086,569 Israeli Jewish males, who underwent a general health examination before compulsory military service at ages 16-19 between the years 1967-2005, were linked to Israel National Cancer Registry to obtain incident CM up to 2006. Cox proportional hazards was used to model time to event. Overall, 1562 incident cases were detected during 19.3 million person-years of follow-up. Origin was a strong independent predictor of CM. Incidence was higher for European (hazard ratio [HR] = 4.08, 95% confidence interval [CI]: 3.55-4.67) and Israeli origin (HR = 2.92, 95% CI: 2.25-3.79) compared to N. African/Asian origin, adjusted for year of birth, years of education, residential socio-economic position, rural residence and body surface area (or height). Among those of European origin, the adjusted risk was significantly lower for those who immigrated after the age of 10 years (HR = 0.58, 95% CI: 0.45-0.73) but not for younger ages (HR = 1.02, 95% CI 0.84-1.23) compared to Israeli born. The high rates of CM among men of European origin and the almost twofold lower risk among those immigrating after age 10 provide solid support for the deleterious role of childhood sun exposure as a risk factor for melanoma. These findings will serve in directing public health and research efforts. 23788444 Palladium-catalyzed skeletal rearrangement of spirotricyclic olefins: a facile one-pot strategy for the synthesis of a novel motif with cyclopentene fused to benzofuran and pyrazolidine. Complex molecule synthesis: An efficient one-pot strategy for the synthesis of a novel framework of benzofuran-pyrazolidine-fused cyclopentenes by a palladium-catalyzed tandem reaction of cyclopropane-bearing spirotricyclic olefins with 2-iodophenols is reported. 23294832 Reconstruction of gluteal defects using free flaps. The TRAM flap, DIEP flap, and gluteal free flaps are routinely used for breast reconstruction. However, these have seldom been described for reconstruction of buttock deformities. We present three cases of free flaps used to restore significant buttock contour deformities. They introduce vascularised bulky tissue and provide adequate cushioning for future sitting, as well as correction of the aesthetic defect. 23868838 Activity of intestinal carbohydrases responds to multiple dietary signals in nestling House sparrows. "Adaptive modulation hypothesis" predicts that activity of digestive enzymes should match the amount of their substrates in diet. Interestingly, many passerine birds do not adjust the activity of intestinal carbohydrases to dietary carbohydrate content. It is difficult to assess the generality of this rule, because in some studies passerines fed on low-carbohydrate and high-lipid diet showed reduced activity of intestinal carbohydrases. However, as carbohydrase activity may be inhibited by high dietary lipid content, it is unclear if observed effects reflected lack of induction by the low carbohydrate levels or suppression by the high lipid. Here, we isolated the specific effects of dietary carbohydrate and lipid on carbohydrases. We hand-fed House sparrow nestlings on diets with 25% of starch and 8% lipid (diet HS), no starch and 20% lipid (HL), or 25% starch and 20% lipid (HSL). Our results show that activity of intestinal carbohydrases is simultaneously induced by dietary carbohydrates and decreased by dietary lipid, although the latter effect seems stronger. Activities of maltase and sucrase summed over the total intestine decreased in order HS>HSL>HL. We observed a complex interaction between diet composition and intestinal position for mass-specific activity of these enzymes, suggesting site-specific responses to changes in digesta composition along the intestines caused by digestion and absorption. We re-interpret results of earlier studies and conclude that there is no unequivocal example of adaptive modulation of intestinal carbohydrases by dietary carbohydrate in adult passerine birds whereas the present experiment confirms that nestlings of at least some species possess such capacity. 23350847 Pyrrolopyrazines as Selective Spleen Tyrosine Kinase Inhibitors. We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series. 23813014 A high-throughput framework to detect synapses in electron microscopy images. Synaptic connections underlie learning and memory in the brain and are dynamically formed and eliminated during development and in response to stimuli. Quantifying changes in overall density and strength of synapses is an important pre-requisite for studying connectivity and plasticity in these cases or in diseased conditions. Unfortunately, most techniques to detect such changes are either low-throughput (e.g. electrophysiology), prone to error and difficult to automate (e.g. standard electron microscopy) or too coarse (e.g. magnetic resonance imaging) to provide accurate and large-scale measurements. To facilitate high-throughput analyses, we used a 50-year-old experimental technique to selectively stain for synapses in electron microscopy images, and we developed a machine-learning framework to automatically detect synapses in these images. To validate our method, we experimentally imaged brain tissue of the somatosensory cortex in six mice. We detected thousands of synapses in these images and demonstrate the accuracy of our approach using cross-validation with manually labeled data and by comparing against existing algorithms and against tools that process standard electron microscopy images. We also used a semi-supervised algorithm that leverages unlabeled data to overcome sample heterogeneity and improve performance. Our algorithms are highly efficient and scalable and are freely available for others to use. Code is available at http://www.cs.cmu.edu/∼saketn/detect_synapses/ 23943258 Measurement equivalence using a mixed-mode approach to administer health-related quality of life instruments. To evaluate the effects of mode, order of administration, and the interaction of mode and order on health-related quality of life scales when self-administered by mixed mode (paper-mode and web-mode) for measurement equivalence. Health-related quality of life data was analyzed from the Cancer of the Prostate Strategic Urologic Research Endeavor using the Medical Outcomes Study (MOS) Short Form-36 (SF-36) and the University of California Los Angeles Prostate Cancer Index (UCLA-PCI). A randomized crossover design assigned participants to two groups with a preferred 2-5-day washout period. Cognitive debriefing evaluated participants' mode preference. Of the 245 men enrolled, 85 % completed both modes. The majority were White (97 %), college educated (66 %), reported an annual income >$75,000 (46 %), and a median age of 69 years. Intraclass correlation coefficients were high for each item on both instruments (r = .54-.97). Exact percentage agreement for yes/no items was high (≥.88). For the SF-36, significant differences were observed for order of administration (physical component and physical function scores) and for the interaction between mode and order (mental component, role emotional, social function, vitality, and mental health scores). For the UCLA-PCI, the largest difference was 12.8 points lower for sexual bother for order of administration by web-mode first (p = .03). Seventy percent preferred the web-mode, 21 % had no preference, and 9 % preferred the paper-mode. Web-mode and paper-mode administrations of the SF-36 and UCLA-PCI are equivalent in men with prostate cancer, implying that mixed-mode survey administration is warranted. 23966189 A Practical Data Recovery Technique for Long-Term Strain Monitoring of Mega Columns during Construction. A practical data recovery method is proposed for the strain data lost during the safety monitoring of mega columns. The analytical relations among the measured strains are derived to recover the data lost due to unexpected errors in long-term measurement during construction. The proposed technique is applied to recovery of axial strain data of a mega column in an irregular building structure during construction. The axial strain monitoring using the wireless strain sensing system was carried out for one year and five months between 23 July 2010 and 22 February 2012. During the long-term strain sensing, three different types of measurement errors occurred. Using the recovery technique, the strain data that could not be measured at different intervals in the measurement were successfully recovered. It is confirmed that the problems that may occur during long-term wireless strain sensing of mega columns during construction could be resolved through the proposed recovery method. 23685785 Fad7 gene identification and fatty acids phenotypic variation in an olive collection by EcoTILLING and sequencing approaches. The ω-3 fatty acid desaturases (FADs) are enzymes responsible for catalyzing the conversion of linoleic acid to α-linolenic acid localized in the plastid or in the endoplasmic reticulum. In this research we report the genotypic and phenotypic variation of Italian Olea europaea L. germoplasm for the fatty acid composition. The phenotypic oil characterization was followed by the molecular analysis of the plastidial-type ω-3 FAD gene (fad7) (EC 1.14.19), whose full-length sequence has been here identified in cultivar Leccino. The gene consisted of 2635 bp with 8 exons and 5'- and 3'-UTRs of 336 and 282 bp respectively, and showed a high level of heterozygousity (1/110 bp). The natural allelic variation was investigated both by a LiCOR EcoTILLING assay and the PCR product direct sequencing. Only three haplotypes were identified among the 96 analysed cultivars, highlighting the strong degree of conservation of this gene. 23859342 Animal and cellular models of Friedreich ataxia. The development and use of animal and cellular models of Friedreich ataxia (FRDA) are essential requirements for the understanding of FRDA disease mechanisms and the investigation of potential FRDA therapeutic strategies. Although animal and cellular models of lower organisms have provided valuable information on certain aspects of FRDA disease and therapy, it is intuitive that the most useful models are those of mammals and mammalian cells, which are the closest in physiological terms to FRDA patients. To date, there have been considerable efforts put into the development of several different FRDA mouse models and relevant FRDA mouse and human cell line systems. We summarize the principal mammalian FRDA models, discuss the pros and cons of each system, and describe the ways in which such models have been used to address two of the fundamental, as yet unanswered, questions regarding FRDA. Namely, what is the exact pathophysiology of FRDA and what is the detailed genetic and epigenetic basis of FRDA? 23900861 Formation, regeneration, and transformation of protoplasts of Streptomyces diastatochromogenes 1628. Toyocamycin exhibits effective biological activities for use against plant pathogenic fungi thanks to its structural similarity to nucleoside. It has been recognized as a promising agricultural antibiotic utilized in controlling the occurrence of plant diseases. In our previous study, a strain that was isolated was identified and designated as Streptomyces diastatochromogenes whose major secondary metabolite was toyocamycin, but the production was largely limited. Protoplast transformation is a useful technique in the improvement of streptomycete. In this study, we optimized some key factors necessary for protoplast formation, regeneration, and transformation of S. diastatochromogenes. When mycelium was cultivated in CP medium with 1 % glycine, harvested at 48 h old, and then treated with 3 mg lysozyme/mL in P buffer for 1 h, the greatest regeneration frequency (42.5 %) of protoplasts was obtained. By using 1 × 10(9)/mL protoplasts with polyethylene glycol 1000 at a concentration of 30 % (w/v), the best performance of protoplast transformation efficiency was 4.8 × 10(3)/μg DNA transformants. 23664186 Biofilm-forming ability of Staphylococcus aureus strains isolated from human skin. Staphylococcus aureus produces various toxins and enzymes, and its presence can exacerbate skin conditions. Previous studies have shown that S. aureus is involved in skin deterioration, even in normal tissue. Biofilm strains show much greater resistance to antimicrobial agents and therefore require a much higher concentration of biocide than planktonic counterparts. As such, alternative strategies and more effective therapeutic agents against biofilm-producing S. aureus in skin are of great interest. Therefore, we turned our attention to differences in 50 clinical biofilm strains isolated from human facial skin. Based on S. aureus density on facial skin, we divided donors into two groups: relatively low density (LSG) and high density (HSG). In general, strong biofilm-forming strains were detected in the HSG donors. Two strains from each of the groups were submitted to gene microarray analysis to investigate expression differences and confirmed by RT-PCR. In total, 111 of 7775 genes were differentially expressed between low (SA2 and SA7) vs. high (SA10 and SA33) biofilm-forming clinical strains. These genes include already well-known as biofilm formation related genes like icaABCD and lrgAB, and newly identified genes (sdrC, sspBCP) by RT-PCR. Comparison of gene expression differences between the two groups available at NCBI Gene Expression Omnibus accession number GSE44268. Our results suggest that S. aureus density in the skin is closely related to biofilm-forming ability, and we have identified several potential target genes that may be involved in regulating biofilm formation in situ. 23651513 Retinol palmitate prevents ischemia-induced cell changes in hippocampal neurons through the Notch1 signaling pathway in mice. Retinol palmitate, an analog of vitamin A, plays multiple roles in the nervous system, including neural differentiation, axon outgrowth, and neural patterning, and is also an antioxidative agent and thereby potential neuroprotectant for brain ischemia. The present study aimed at investigating the protective effects of retinol palmitate against ischemia-induced brain injury in a bilateral common carotid artery occlusion (BCCAO) model in mice. Ischemia induced by 20-min BCCAO resulted in significant neuronal morphological changes and reactive astrocyte proliferation in the hippocampus, particularly in the CA1 region, and these changes were accompanied by increased Notch1 expression. Intraperitoneal retinol palmitate administration before ischemia reduced ischemic neurons with Notch1 expression; the differences were statistically significant in both the 1.2mg/kg group and 12mg/kg group. These results show that retinol palmitate prevents brain ischemia-induced neuronal injury with Notch1 expression and that Notch1 signaling could be involved in the neuroprotective mechanism. Retinol palmitate could be a treatment option for human brain infarction. 23718908 Characterization of Rotating Gantry Micro-CT Configuration for the In Vivo Evaluation of Murine Trabecular Bone. The objective of this study is to determine the optimal physical parameters of a rotating gantry micro-CT system to assess in vivo changes to the trabecular bone of mice. Magnification, binning, peak kilovoltage, beam filtration, and tissue thickness are examined on a commercially available micro-CT system. The X-ray source and detector geometry provides 1.3×, 1.8×, or 3.3× magnification. Binning is examined from no binning to 2 to 4. Energy is varied from 40 to 80 kVp in 10 kVp increments and filter thickness is increased from no filtration to 1.5 mmAl in 0.5 mmAl increments. Mice are imaged at different magnifications and binning combinations to evaluate changes to image quality and microstructure estimation. Increasing magnification from 1.3× to 3.3× and lowering binning from 4 to 1 varies the spatial resolution from 2.5 to 11.8 lp/mm. Increasing the beam energy or filtration thickness decreases Hounsfield unit (HU) estimation, with a maximum rate of change being -286 HU/kVp for 80 kVp. Images for murine trabecular bone are blurred at effective pixel sizes above 60 μm. By comparing resolution, signal-to-noise ratio, and radiation dose, we find that a 3.3× magnification, binning of 2.80 kVp beam with a 0.5 mmAl filter comprises the optimal parameters to evaluate murine trabecular bone for this rotating gantry micro-CT. 23852324 Recruitment of ipsilateral and contralateral upper limb muscles following stimulation of the cortical motor areas in the monkey. It is well established that cortical motor stimulation results in contralateral upper limb (UL) activity. Motor responses are also elicited in the ipsilateral UL, though controversy surrounds the significance of these effects. Evidence suggests that ipsilateral muscle activity is more common following the stimulation of the supplementary motor area (SMA) and dorsal premotor area (PMd), compared to the primary motor cortex (M1), but none of these studies compared effects from all three areas in the same subjects. This has limited our understanding of how these three cortical motor areas influence ipsilateral UL muscle activity. The purpose of this study was to determine the contribution of each of three cortical areas to the production of ipsilateral and contralateral UL. To maximize sensitivity and allow comparison of the effects across cortical areas, we applied the same stimulation parameters (36 pulse stimulus train at 330 Hz) to M1, SMA, and PMd in three adult M. fascicularis and recorded electromyographic (EMG) activity from muscles in the trunk and both ULs. Of all muscle responses identified, 24 % were ipsilateral to the stimulation, mostly in proximal muscles. The highest percentage of ipsilateral responses occurred following SMA stimulation. We also observed that PMd stimulation elicited more suppression responses compared with stimulation of M1 and SMA. The results indicate that ipsilateral motor areas provide a significant contribution to cortical activation of the trunk and proximal UL muscles. These understudied pathways may represent a functional substrate for future strategies to shape UL recovery following injury or stroke. 23567883 Dissociable roles of ventromedial prefrontal cortex (vmPFC) and rostral anterior cingulate cortex (rACC) in value representation and optimistic bias. Optimistic bias (OB) is seen when individuals underestimate their probability of experiencing negative life events and overestimate their probability of experiencing positive life events. A reduced OB has been linked with increased depression symptoms. However, given the relevance of this information to mood and anxiety disorders, little is currently known regarding the neurobiology of OB. In the current study, we examine the neural basis of OB in healthy individuals (n=33) during probability estimation of future positive and negative events occurring to themselves relative to other, comparable individuals. In line with previous work, subjects showed significant OB; they considered themselves significantly more likely to experience future positive and significantly less likely to experience future negative events relative to comparable others. Positive, relative to negative events, un-modulated by subjects' probability estimates, were associated with significantly greater activity within the ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC). Moreover, responses within both regions to positive events negatively related to the healthy subjects' self reports of depression symptoms. However, there was no significant modulation of activity in either region by the subject's OB, objectified as the level to which they thought the event was more likely [positive events] or less likely [negative events] to occur to them relative to comparable others. In contrast, activity within the rostral anterior cingulate cortex (rACC) was positively modulated by OB for positive events and activity within the anterior insula and dorsomedial prefrontal cortex (dmPFC) was negatively modulated by OB for negative events. However, there was no significant relationship between responsiveness within these regions and self reports of depression symptoms. The data are discussed with reference to current models of vmPFC, rACC and anterior insula functioning. 23708884 A novel trifluoromethyl benzopyran induces G1 cell cycle arrest and apoptosis in HeLa human cervical carcinoma cells. In the present study, a biologically active 4-(trifluoromethyl)phenyl piperazin moiety was linked to a 2,2- dimethyl -2H-benzopyran template to generate (3R,4S)-2,2-dimethyl-6-nitro-4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl) chroman -3-ol (C110g), and the cellular and molecular mechanisms by which C110g exerts cytotoxic effects on the HeLa human cervical cancer cell line were further investigated. C110g suppressed the viability of HeLa cells in both concentration- and time-dependent manner (IC50 of 17 µM) by inducing DNA damage and G1 cell cycle arrest. Characteristic changes in nuclear morphology and Annexin V/PI staining pointed to apoptosis as the mode of cell death. The levels of p53 and p21 were increased in the C110g-treated cells, with a corresponding increase in Bax/Bcl-2 protein ratio. Subsequently, C110g induced the cytoplasmic release of cytochrome c from the mitochondria accompanied by a decreased mitochondrial membrane potential and activation of caspase-3 and -9. These results confirmed that the C110g transduced the apoptotic signal via the mitochondrial pathway. Caspase-8, typically associated with the initiation of the death receptor pathway, was activated, suggesting the extrinsic pathway might also be involved. However, C110g did not result in reactive oxygen species (ROS) generation. Taken together, these findings indicate that the DNA damage-dependent p53-regulated mitochondrial pathway as well as the extrinsic pathway play a crucial role in C110g-induced apoptosis, which provide a better understanding of the molecular mechanisms of trifluoromethyl benzopyrans in cervical cancer. 23931931 Lack of association of SLC1A1 variants with schizophrenia in Chinese Han population. In this study, we analyzed four single nucleotide polymorphisms (SNPs) (rs10491734, rs2228622, rs301430 and rs301443) of the solute carrier family 1 gene (SLC1A1) in a set of 616 schizophrenia patients and 638 matched healthy controls of Han Chinese descent. No significant differences of genotype or allele distribution were identified between the patients and controls. Our data suggest that SLC1A1 is unlikely to be a major susceptibility gene for schizophrenia in Han Chinese. 23292249 The physico-chemical "anatomy" of the tautomerization through the DPT of the biologically important pairs of hypoxanthine with DNA bases: QM and QTAIM perspectives. The biologically important tautomerization of the Hyp·Cyt, Hyp*·Thy and Hyp·Hyp base pairs to the Hyp*·Cyt*, Hyp·Thy* and Hyp*·Hyp* base pairs, respectively, by the double proton transfer (DPT) was comprehensively studied in vacuo and in the continuum with a low dielectric constant (ε = 4) corresponding to hydrophobic interfaces of protein-nucleic acid interactions by combining theoretical investigations at the B3LYP/6-311++G(d,p) level of QM theory with QTAIM topological analysis. Based on the sweeps of the energetic, electron-topological, geometric and polar parameters, which describe the course of the tautomerization along the intrinsic reaction coordinate (IRC), it was proved that the tautomerization through the DPT is concerted and asynchronous process for the Hyp·Cyt and Hyp*·Thy base pairs, while concerted and synchronous for the Hyp·Hyp homodimer. The continuum with ε = 4 does not affect qualitatively the course of the tautomerization reaction for all studied complexes. The nine key points along the IRC of the Hyp·Cyt↔Hyp*·Cyt* and Hyp*·Thy↔Hyp·Thy* tautomerizations and the six key points of the Hyp·Hyp↔Hyp*·Hyp* tautomerization have been identified and fully characterized. These key points could be considered as electron-topological "fingerprints" of concerted asynchronous (for Hyp·Cyt and Hyp*·Thy) or synchronous (for Hyp·Hyp) tautomerization process via the DPT. It was found, that in the Hyp*·Cyt*, Hyp·Thy*, Hyp·Hyp and Hyp*·Hyp* base pairs all H-bonds are significantly cooperative and mutually reinforce each other, while the C2H…O2 H-bond in the Hyp·Cyt base pair and the O6H…O4 H-bond in the Hyp*·Thy base pair behave anti-cooperatively, i.e., they become weakened, while two others become strengthened. 23933852 The effect of radiotherapy beam energy on modern cardiac devices: an in vitro study. Radiotherapy (RT) for malignancies can harm pacemakers (PMs) and implantable cardioverter-defibrillators (ICDs). There is some evidence that, besides cumulative dose, the damaging radiation effects increase with beam energy. The aim of this study was to determine whether modern PMs and ICDs are more sensitive to high-energy than to low-energy photon beams.METHODS AND RESULTS: Two groups of unused PMs and explanted ICDs (five PMs and one ICD in each) were subjected to irradiations in a phantom with 6 and 18 megavolt (MV) photons, respectively. The devices were exposed to radiation at doses of 2 gray (Gy) daily to simulate two clinical scenarios with the PM/ICD in the RT field. A cumulative dose of 150 Gy was given to each device, corresponding to approximately twice the therapeutic dose. In the 6 MV group, one episode of PM malfunction was detected after reaching 150 Gy. In the 18 MV group, a total of 14 episodes of malfunction were detected starting at 30 Gy in all five PMs. No episodes appeared in the ICD, at the respective treatment groups. This corresponded to a hazard ratio of 9.11 [∼95% confidence interval (CI): 1.04-79.69] by Cox regression analysis between the two groups. In a repeated measures logistic regression model comparing the incidence rate of malfunctions, the odds ratio was 18.29 (∼95% CI: 1.52-219.41).CONCLUSION: Photon beam energy plays a considerable role in inducing implantable cardiac device malfunctions. Low-energy RT may be safer in PM/ICD patients despite relatively high radiation dose to the device. 23933472 How damaged brains repeat words: A computational approach. Two routes have been proposed for auditory repetition: a lexical route which activates a lexical item and retrieves its phonology, and a nonlexical route which maps input phonology directly onto output phonology. But when is the nonlexical route recruited? In a sample of 103 aphasic patients, we use computational models to select patients who do and do not recruit the nonlexical route, and compare them in light of three hypotheses: 1 - Lexical-phonological hypothesis: when the lexical route is weak, the nonlexical route is recruited. 2 - Nonlexical hypothesis: when the nonlexical route is weak, it is abandoned. 3 - Semantic-access hypothesis: when access to meaning fails, the nonlexical route is recruited. In neurocognitive terms, hypotheses 1 and 2 identify different aspects of the intactness of the dorsal stream, while the third hypothesis focuses on the ventral stream. Our findings (and a subsequent meta-analysis of four studies) support hypotheses 2 and 3. Ultimately, we claim that the choice about whether to recruit the nonlexical route is guided, not by assessment of production abilities that support repetition, but instead by relying on accessible cues, namely whether the speaker understands the word, or can remember its sequence of phonemes. 23852985 The Trade-off Between Costs and Quality of Care in the Treatment of Psychosomatic Patients with Somatoform Pain Disorder. The introduction of efficiency-oriented provider payment systems in inpatient mental healthcare in various Western countries may lead to the use of less healthcare resources in the treatment of patients. To avoid unintended effects on quality of care that may result from reductions in resource utilization, it is essential for decision and policy makers to know whether there is a trade-off between costs and quality of care. The aim of this study was to investigate and quantify the relationship between costs and outcomes in psychosomatic inpatients with somatoform pain disorder. The inclusion criteria for patient selection (n = 101) were (i) a main diagnosis of somatoform pain disorder according to International Classification of Diseases-10 (ICD-10) [F45.4, F45.40, F45.41]; (ii) complete data on the mental component summary reflecting overall functioning of mental health (MCS-8) measured with the Short Form-8 Health Survey (SF-8) within 3 days of the admission and discharge dates; and (iii) treatment at Charité Universitaetsmedizin (Berlin, Germany) during the period January 2006-June 2010. The change in the MCS-8 score incurred over the treatment period was used as an indicator of quality of care. Treatment costs were calculated from the provider's perspective, mainly using bottom-up micro-costing. The year of valuation for cost calculation was 2008 (with no inflation adjustment); for costs provided by the accounting department for services consumed by the patient, the valuation year was based on the year of service provision. We hypothesized that the outcome 'change in MCS-8 score' was a function of the independent variable costs, patient characteristics, socio-demographic variables, pain-related variables, co-morbidities and subjective illness attribution, i.e. whether patients attributed the origin of pain mainly to a somatic cause or not. An interaction term between costs and illness attribution was included to control for the hypothesized differing effects of resource input or costs on the outcome variable conditional on patients' illness attribution. Hausman tests indicated that endogeneity was not present, thus, ordinary least squares regression (OLS) was conducted. We assessed whether the change in the MCS-8 score was clinically meaningful and perceptible by the patient, using the minimal clinical important difference (MCID). For Short Form Health Surveys, the MCID for changes in the mental component summary is typically around 3 points. We found a trade-off between costs and outcome for patients without or with only minor somatic illness attribution (77 % of the sample). This patient group improved 0.4 points in outcome after every 100  increase in total costs per case (F 1,77 = 13.836, t(77) = 3.72, p = 0.0004). For patients with mainly somatic illness beliefs (23 % of the sample), we did not find a trade-off between costs and outcome. For the majority of patients, we found a trade-off between costs and health outcome, thus, it seems advisable to carefully monitor outcome parameters when applying cost containment measures. 23756257 Dispersive liquid-liquid microextraction of thiram followed by microvolume UV-vis spectrophotometric determination. A novel and simple method for the sensitive determination of trace amounts of fungicide thiram is developed by combination of dispersive liquid-liquid microextraction (DLLME) and microvolume UV-vis spectrophotometry. The method is based on the conversion of thiram to a yellow product in the presence of ethanolic potassium hydroxide and copper sulfate, and its extraction into CCL4 using DLLME technique. In this method the ethanol existing in ethanolic KOH plays as disperser solvent and a cloudy solution is formed by injection of only CCl4 as extractant solvent into sample solution. Under the optimum conditions, the calibration graph was linear over the range of 25-1000ngmL(-1) of thiram with limit of detection of 11.5ngmL(-1). The relative standard deviation (RSD) for 100 and 500ngmL(-1) of thiram was 2.7 and 1.1% (n=8), respectively. The proposed method was successfully applied to determination of thiram in water and plant seed samples. 23939876 Abstracts. A novel design for a rapid clean-up method was developed for the analysis of pesticide residues in fruit and vegetables followed by LC-ESI-MS/MS. The acetonitrile-based sample extraction technique was used to obtain the extracts, and further clean-up was carried out by applying the streamlined procedure on a multiplug filtration clean-up column coupled with a syringe. The sorbent used for clean-up in this research is multiwalled carbon nanotubes, which was mixed with anhydrous magnesium sulfate to remove water from the extracts. This method was validated on 40 representative pesticides and apple, cabbage, and potato sample matrices spiked at two concentration levels of 10 and 100 μg kg(-1) . It exhibited recoveries between 71 and 117% for most pesticides with relative standard deviations lower than 15%. Matrix-matched calibrations were performed with the coefficients of determination greater than 0.995 for most studied pesticides between concentration levels of 10-500μg L(-1) . The limits of quantification for 40 pesticides ranged from 2 to 50 μg kg(-1) . The developed method was successfully applied to the determination of pesticide residues in market fruit and vegetable samples. This article is protected by copyright. All rights reserved. 23921349 Pharmacokinetics of an immunomodulating dose of levamisole in weaned pigs. Levamisole has been shown to stimulate the immune response in immunocompromised humans and animals. However, its use as an adjuvant in immunocompromised weaned pigs prone to colibacillosis has only been experimentally tested but not yet officially approved. Therefore, the aim of these studies was to study the pharmacokinetics (PK) of an immunomodulating dose of levamisole in weaned pigs. For that purpose, 20 weaned crossbred pigs were divided into two treatment groups. In this parallel-design study, a single dose of levamisole (2.5 mg/kg body weight) was administered by the intramuscular (i.m.) or oral (p.o.) route. Statistically significant differences between the i.m. and p.o. routes in terminal beta rate constant (β), maximum plasma concentration (Cmax), area under the curve (AUC) for plasma concentration-time curve from time zero to infinity (AUC0-inf), area under the plasma concentration-time curve from time 0 to the last quantifiable time point (AUC0-t) were determined. Further research is needed to establish a relationship between the PK and the immunomodulating effect of levamisole in pigs. 23901021 Morell mackenzie's the hygiene of the vocal organs - a practical handbook for singers and speakers - a study in longevity or durability. Morell Mackenzie's The Hygiene of the Vocal Organs - A Practical Handbook for Singers and Speakers is his only work that has been continually published into the 20th century. Why is this? The bibliographic history and details of all the editions from the first in 1886 until the 9th and last in 1928 were examined. Reviews and all other commentary about the book were ascertained though literature and library document searches. The book is still in use as the first edition is available online from the Cornell University library and that hard copy was last taken out from that library on December 19,1986 and returned with the fine paid on 8 January 1987. It was translated and published in Swedish, French, German and Spanish. All of the editions are small, inexpensively bound and printed on inexpensive paper so the cost was minimal in contradistinction to other works on the voice which are larger and expensive. To make it accessible for performers and practitioners, the contents of the earlier editions were modified by placing the technical, anatomical and physiological information as an appendix. The book was in part, criticized by Garcia in Semon's German journal. McKenzie answered these critiques in the 7th edition and noted that Garcia did not know German and the translator, Semon, was an antagonist. Mackenzie is emphatic in his advice to avoid singing when there's any sign of vocal difficulty. The medical advice was, on the whole, good common sense and provided substantial authority for a person to decline a performance - how grateful the singers must have been for that! The Hygiene of the Vocal Organs. A Practical Handbook for Singers and Speakers was, for the professional voice users - singers, actors, speakers, and for their teachers and physicians a useful, concise, small, inexpensive and authoritative book. With these virtues noted, we can well understand why it remained in circulation and use for a century. In terms of the dissemination of ideas, this heretofore neglected work may be Mackenzie's most long lasting contribution to laryngology. Laryngoscope, 2013. 23927332 A method to acquire CT organ dose map using OSL dosimeters and ATOM anthropomorphic phantoms. Purpose: To present the design and procedure of an experimental method for acquiring densely sampled organ dose map for CT applications, based on optically stimulated luminescence (OSL) dosimeters "nanoDots" and standard ATOM anthropomorphic phantoms; and to provide the results of applying the method-a dose data set with good statistics for the comparison with Monte Carlo simulation result in the future.Methods: A standard ATOM phantom has densely located holes (in 3 × 3 cm or 1.5 × 1.5 cm grids), which are too small (5 mm in diameter) to host many types of dosimeters, including the nanoDots. The authors modified the conventional way in which nanoDots are used, by removing the OSL disks from the holders before inserting them inside a standard ATOM phantom for dose measurements. The authors solved three technical difficulties introduced by this modification: (1) energy dependent dose calibration for raw OSL readings; (2) influence of the brief background exposure of OSL disks to dimmed room light; (3) correct pairing between the dose readings and measurement locations. The authors acquired 100 dose measurements at various positions in the phantom, which was scanned using a clinical chest protocol with both angular and z-axis tube current modulations.Results: Dose calibration was performed according to the beam qualities inside the phantom as determined from an established Monte Carlo model of the scanner. The influence of the brief exposure to dimmed room light was evaluated and deemed negligible. Pairing between the OSL readings and measurement locations was ensured by the experimental design. The organ doses measured for a routine adult chest scan protocol ranged from 9.4 to 18.8 mGy, depending on the composition, location, and surrounding anatomy of the organs. The dose distribution across different slices of the phantom strongly depended on the z-axis mA modulation. In the same slice, doses to the soft tissues other than the spinal cord demonstrated relatively small variations, with the maximum COV around 11.4%. This might be attributed to the angular mA modulation, the placement of the dosimeters, the chest cavity of the scanned region, and the size of the phantom. Doses to the spinal cord were consistently lower than those to other soft tissues.Conclusions: The method is suited for acquiring densely sampled organ dose maps, and can be used for studying dose distributions relevant to subject size, organ location, and clinical CT protocols. 23532375 ERP evidence suggests executive dysfunction in ecstasy polydrug users. BACKGROUND: Deficits in executive functions such as access to semantic/long-term memory have been shown in ecstasy users in previous research. Equally, there have been many reports of equivocal findings in this area. The current study sought to further investigate behavioural and electro-physiological measures of this executive function in ecstasy users. METHOD: Twenty ecstasy-polydrug users, 20 non-ecstasy-polydrug users and 20 drug-naïve controls were recruited. Participants completed background questionnaires about their drug use, sleep quality, fluid intelligence and mood state. Each individual also completed a semantic retrieval task whilst 64 channel Electroencephalography (EEG) measures were recorded. RESULTS: Analysis of Variance (ANOVA) revealed no between-group differences in behavioural performance on the task. Mixed ANOVA on event-related potential (ERP) components P2, N2 and P3 revealed significant between-group differences in the N2 component. Subsequent exploratory univariate ANOVAs on the N2 component revealed marginally significant between-group differences, generally showing greater negativity at occipito-parietal electrodes in ecstasy users compared to drug-naïve controls. Despite absence of behavioural differences, differences in N2 magnitude are evidence of abnormal executive functioning in ecstasy-polydrug users. 23865933 Chiral phosphoric Acid-catalyzed oxidative kinetic resolution of indolines based on transfer hydrogenation to imines. The oxidative kinetic resolution of 2-substituted indoline derivatives was achieved by hydrogen transfer to imines by means of a chiral phosphoric acid catalyst. The oxidative kinetic resolution was applicable to racemic alkyl- or aryl-substituted indolines, and the remaining indolines were obtained in good yields with excellent enantioselectivities. 23855741 Incidence of primary cutaneous T-cell lymphoma in Wales. Primary cutaneous T cell lymphoma (PCTCL) is a rare disease. The incidence of this disease has been studied in the USA and other countries but it has not previously been studied in Wales which has an estimated population of 3 million.(1) Our aim was to estimate the incidence rate of PCTCL in Wales which has a relatively homogenous population. All new cases of lymphoma diagnosed in Wales are reviewed by the 'All Wales Lymphoma Panel' which was established in 2002.(2) We hoped that identifying patients through this national pathology database would give an accurate reflection of the incidence of PCTCL in Wales. This article is protected by copyright. All rights reserved. 23845936 Prenatal exposure to environmental contaminants and behavioural problems at age 7-8years. Animal studies showed that the developing brain is particularly sensitive to chemical exposure. Human studies carried out in areas with high exposures have proven neurodevelopmental disorders in relation to e.g. lead and PCBs. Whether these chemicals are associated with behavioural problems in childhood at current environmental levels is not well known. Therefore, we assessed the association between prenatal exposure to lead, cadmium, PCBs, dioxin-like compounds, HCB and p,p'-DDE and behavioural problems in 7-8year old children. Prenatal exposure data were obtained from the Flemish mother-new-born cohort. Lead, cadmium, PCBs, dioxin-like compounds, HCB and p,p'-DDE were analysed in cord blood. When the child reached 7-8years, 270 mothers completed the Strengths and Difficulties Questionnaire assessing their children's behavioural health. We found that doubling the prenatal lead exposure (cord blood lead levels) was associated with a 3.43 times higher risk for hyperactivity in both boys and girls. In addition, total difficulties were 5.08 times more likely in the highest tertile for prenatal lead exposure compared to the lowest tertile. In girls, total difficulties were 4.92 more likely when doubling cord blood p,p'-DDE, whereas no significant association was found in boys. Further, we noted in boys a 1.53 times higher risk for emotional problems when doubling cord blood cadmium, whereas no significant association was found in girls. These results indicate that the presence of environmental contaminants influences the mental health of the next generation. 23270336 Highly ordered cobalt-phthalocyanine chains on fractional atomic steps: one-dimensionality and electron hybridization. Precisely controlled fabrication of low-dimensional molecular structures with tailored morphologies and electronic properties is at the heart of the nanotechnology research. Especially, the formation of one-dimensional (1D) structures has been strongly desired due to their expected high performance for information processing in electronic/magnetic devices. So far, however, they have been obtained by tough and slow methods such as manipulation of individual molecules, which are totally unsuited for mass production. Here we show that highly ordered cobalt-phthalocyanine chains can be self-assembled on a metal surface using fractional atomic steps as a template. We also demonstrate that the substrate surface electrons, which can be confined by cobalt-phthalocyanine molecules, can propagate along the step arrays and can hybridize with the molecular orbitals. These findings provide a significant step toward readily realization of 1D charge/spin transport, which can be mediated either directly by the molecules or by the surface electrons. 23589227 Regulation of the delta and alpha epithelial sodium channel (ENaC) by ubiquitination and Nedd8. The δ epithelial sodium channel (δENaC) is a proton-activated, sodium-selective, amiloride-sensitive ion channel in the ENaC/degenerin family of ion channels involved in blood pressure regulation and mechanosensation. Other ENaC family members are subject to ubiquitin modification leading to internalization from the cell surface, and degradation of the channel. Here, we show that δENaC is also modified by ubiquitin on three intracellular lysine residues. Absence of these lysines abolished ubiquitin modification of δENaC and increased cell surface levels of δENaC. Although the HECT-domain ubiquitin ligase Nedd4-2 reduced amiloride-sensitive current generated by δβγENaC-containing channels, δENaC does not contain a binding site for Nedd4-2; therefore, this effect is probably mediated by the βγENaC subunits. Nedd8, a ubiquitin-like protein that regulates RING-domain E3 ubiquitin ligases, promoted δENaC ubiquitination, decreased both the intracellular and cell surface δENaC populations, and decreased δβγENaC amiloride-sensitive short circuit current (Isc -amiloride) in a mammalian epithelium. Nedd8 also promoted α- and γENaC ubiquitination, decreased the cell surface pools, and decreased αβγENaC Isc -amiloride. Conversely, XIAP, a single subunit RING E3 ligase, decreased ubiquitinated δENaC, increased the δENaC cell surface pool and increased δβγENaC Isc -amiloride. Therefore δ- and α - βγENaC channel function may be influenced by RING-domain E3 ubiquitin ligases. J. Cell. Physiol. 228: 2190-2201, 2013. © 2013 Wiley Periodicals, Inc. 23664582 Expression of HvHMA2 in tobacco modifies Zn-Fe-Cd homeostasis. HvHMA2 is a plasma membrane P1B-ATPase from barley that functions in Zn/Cd root-to-shoot transport. To assess the usefulness of HvHMA2 for modifying the metal content in aerial plant parts, it was expressed in tobacco under the CaMV35S promoter. Transformation with HvHMA2 did not produce one unique pattern of Zn and Cd accumulation; instead it depended on external metal supply. Thus Zn and Cd root-to-shoot translocation was facilitated, but not at all applied Zn/Cd concentrations. Metal uptake was restricted in HvHMA2-transformed plants and the level in the shoot was not enhanced. It was shown that HvHMA2 localizes to the plasma membrane of tobacco cells, and overloads the apoplast with Zn, which could explain the overall decrease in metal uptake observed. Despite the lower levels in the shoot, HvHMA2 transformants showed increased Zn sensitivity. Moreover, introduction of HvHMA2 into tobacco interfered with Fe metabolism and Fe accumulation was modified in HvHMA2-transformants in a Zn- and Cd-concentration dependent manner. The results indicate that ectopic expression of the export protein HvHMA2 in tobacco interferes with tobacco metal Zn-Cd-Fe cross-homeostasis, inducing internal mechanisms regulating metal uptake and tolerance. 23698091 Genetic Markers of a Munc13 Protein Family Member, BAIAP3, Are Gender Specifically Associated with Anxiety and Benzodiazepine Abuse in Mice and Humans. Anxiety disorders and substance abuse, including benzodiazepine use disorder, frequently occur together. Unfortunately, treatment of anxiety disorders still includes benzodiazepines, and patients with an existing comorbid benzodiazepine use disorder or a genetic susceptibility for benzodiazepine use disorder may be at risk of adverse treatment outcomes. The identification of genetic predictors for anxiety disorders, and especially for benzodiazepine use disorder, could aid the selection of the best treatment option and improve clinical outcomes. The brain-specific angiogenesis inhibitor I-associated protein 3 (Baiap3) is a member of the mammalian uncoordinated 13 (Munc13) protein family of synaptic regulators of neurotransmitter exocytosis, with a striking expression pattern in amygdalae, hypothalamus and periaqueductal gray. Deletion of Baiap3 in mice leads to enhanced seizure propensity and increased anxiety, with the latter being more pronounced in female than in male animals. We hypothesized that genetic variation in human BAIAP3 may also be associated with anxiety. By using a phenotype-based genetic association study, we identified two human BAIAP3 single-nucleotide polymorphism risk genotypes (AA for rs2235632, TT for rs1132358) that show a significant association with anxiety in women and, surprisingly, with benzodiazepine abuse in men. Returning to mice, we found that male, but not female, Baiap3 knockout (KO) mice develop tolerance to diazepam more quickly than control animals. Analysis of cultured Baiap3 KO hypothalamus slices revealed an increase in basal network activity and an altered response to diazepam withdrawal. Thus, Baiap3/BAIAP3 is gender specifically associated with anxiety and benzodiazepine use disorder, and the analysis of Baiap3/BAIAP3-related functions may help elucidate mechanisms underlying the development of both disorders. 23411174 Comparison of extraction induced by emulsion breaking, ultrasonic extraction and wet digestion procedures for determination of metals in edible oil samples in Turkey using ICP-OES. The content of elements (Cd, Cr, Cu, Fe, Mn, Ni, Pb and Zn) in edible oils (sunflower, hazelnut, canola, corn and olive oils) from Turkey was determined using inductively coupled plasma optical emission spectrometry (ICP-OES) after ultrasonic extraction, wet digestion, and extraction induced by emulsion breaking procedures (EIEB). In order to evaluate the best sample preparation procedure, EIEB procedure was compared by ultrasonic extraction and wet digestion procedures. The results in the samples (minimum-maximum in mgkg(-1)) were : 0.022-0.058, Cr 0.126-7.106, Cu 0.570-4.504, Fe 8.004-12.588, Mn 0.035-0.054, Ni 0.908-2.182, Pb 0.099-0.134 and Zn 2.206-8.982. The EIEB procedure was found to be fast, reliable, simple, and excellent in comparison with the other studied procedures. The recovery test was performed by spiking the samples with known amounts of the metals in the form of organometallic standards and applying the EIEB procedure. The recoveries were in the range of 96-109%. 23608476 Differences in the detection of highly pathogenic avian influenza H5N1 virus in feather samples from 4-week-old and 24-week-old infected Pekin ducks (Anas platyrhynchos var. domestica). Previous studies have reported the detection of H5N1 HPAI virus in feathers from ducks naturally and experimentally infected and suggested that feather calami (FC) could be used as diagnostic samples for the early detection of H5N1 HPAI infections. Ducks are readily infected with H5N1 HPAI viruses although the development of clinical signs and deaths were reported as age-related with younger birds being more susceptible. The correlation between age and virus localisation in FC of infected ducks has not been studied to date. In the present study juvenile (4-week-old) and adult (24-week-old) Pekin ducks (Anas platyrhynchos var. domestica) were infected experimentally with a clade 2.2 H5N1 HPAI virus (A/duck/Nigeria/1071-23/2007). Tracheal (Tr) and cloacal (Cl) swabs and FC were collected at 3, 5, 7 and 10 days post infection and tested by RRT-PCR and a double antibody sandwich-ELISA (DAS-ELISA) developed in house. Virus was detected in swabs and FC of challenged ducks with a higher rate of detection in juvenile ducks. In this age group virus was detected over a longer period of time in FC compared to swabs. Our study showed that FC samples collected from young ducks are a valid diagnostic specimen for H5N1 HPAI virus detection. The DAS-ELISA on FC proved to be a suitable alternative diagnostic test when molecular and/or virus isolation techniques are not available therefore it could be useful in the diagnosis of H5N1 HPAI infections in under-resourced countries. 23922892 Prognostic value of radiological response to chemotherapy in patients with osteosarcoma. Chemotherapy is essential to improve the prognosis of the patients with osteosarcoma, and the response to chemotherapy is an important prognostic factor. In this study, the impact of various radiological examinations on overall survival (OS) and event-free survival (EFS) was evaluated. Eighty-two patients with high-grade osteosarcoma were included in this study, and we evaluated the following factors for prognostic significance: age (≥40 years), gender (male), tumor location (truncal site), metastatic disease, histological response to chemotherapy, radiological response to chemotherapy assessed using X-ray, angiography, CT, MRI, (201)Tl scintigraphy, and (99m)Tc-MIBI scintigraphy ((99m)Tc-MIBI), and combined radiological score (CRS). Univariate analyses revealed that metastatic disease, histological response, (99m)Tc-MIBI, and CRS were significantly correlated with OS. Multivariate analyses showed that metastatic disease (OS: HR 35.9, P<0.001; EFS: HR 17.32, P<0.001) was an independent predictor of OS and EFS. Tumor location (HR 36.1, P = 0.003), histological response (HR 31.1, P = 0.036), and (99m)Tc-MIBI (HR 18.4, P = 0.038) were significant prognostic factors for OS. Moreover, CRS was a marginally significant predictor of OS and EFS. The chemotherapeutic effects evaluated by (99m)Tc-MIBI and CRS could be considered as prognostic factors in osteosarcoma. 23712342 Comparison of stabilities in translucency, fluorescence and opalescence of direct and indirect composite resins. To evaluate translucency, fluorescence and opalescence stabilities of direct and indirect composite resins after aging. One direct (16 shades) and two indirect composite resins (16 and 26 shades) were investigated. Resins were filled in a mold (1 mm thick) and light cured; post-curings were performed for indirect resins. Color was measured before and after 5,000 cycles of thermocycling on a reflection spectrophotometer in reflectance and transmittance modes to calculate parameters for translucency (TP), fluorescence (FL) and opalescence (OP). Differences in the changes of TP, FL and OP after aging by the type of resin were determined by t test, and those were also determined by one-way ANOVA with the factor of the brand or the shade group (P < 0.05). Changes in TP, FL and OP were -1.2 to 0.7, -0.2 to 0.4 and -0.6 to 1.3, respectively, for direct resins; and were -2.0 to 1.8, -0.9 to 0.4 and -2.9 to 3.7, respectively, for indirect resins. Changes in TP were not significantly different by the type of resin, but those in FL and OP were different (P = 0.05). Changes in optical parameters were influenced by the brand or the shade group of the resins (P < 0.05). Stabilities in optical properties of resins varied depending on type, brand or shade group. Aging significantly affected fluorescence and opalescence, but not translucency, of indirect resins compared to those of direct resins. 23898411 Genera in Bionectriaceae, Hypocreaceae, and Nectriaceae (Hypocreales) proposed for acceptance or rejection. With the recent changes concerning pleomorphic fungi in the new International Code of Nomenclature for algae, fungi, and plants (ICN), it is necessary to propose the acceptance or protection of sexual morph-typified or asexual morph-typified generic names that do not have priority, or to propose the rejection or suppression of competing names. In addition, sexual morph-typified generic names, where widely used, must be proposed for rejection or suppression in favour of asexual morph-typified names that have priority, or the latter must be proposed for conservation or protection. Some pragmatic criteria used for deciding the acceptance or rejection of generic names include: the number of name changes required when one generic name is used over another, the clarity of the generic concept, their relative frequencies of use in the scientific literature, and a vote of interested mycologists. Here, twelve widely used generic names in three families of Hypocreales are proposed for acceptance, either by conservation or protection, despite their lack of priority of publication, or because they are widely used asexual morph-typified names. Each pair of generic names is evaluated, with a recommendation as to the generic name to be used, and safeguarded, either through conservation or protection. Four generic names typified by a species with a sexual morph as type that are younger than competing generic names typified by a species with an asexual morph type, are proposed for use. Eight older generic names typified by species with an asexual morph as type are proposed for use over younger competing generic names typified by a species with a sexual morph as type. Within Bionectriaceae, Clonostachys is recommended over Bionectria; in Hypocreaceae, Hypomyces is recommended over Cladobotryum, Sphaerostilbella over Gliocladium, and Trichoderma over Hypocrea; and in Nectriaceae, Actinostilbe is recommended over Lanatonectria, Cylindrocladiella over Nectricladiella, Fusarium over Gibberella, Gliocephalotrichum over Leuconectria, Gliocladiopsis over Glionectria, Nalanthamala over Rubrinectria, Nectria over Tubercularia, and Neonectria over Cylindrocarpon. 23939895 In Vitro Activity of Ceftolozane/Tazobactam versus Pseudomonas aeruginosa Isolates Obtained from Patients in Canadian Hospitals: CANWARD 2007-2012. The in vitro activity of ceftolozane in combination with tazobactam (fixed concentration of 4 μg/mL) was evaluated against 2435 Pseudomonas aeruginosa clinical isolates obtained from across Canada using Clinical and Laboratory Standards Institute broth microdilution methods. The MIC50 and MIC90 values for ceftolozane/tazobactam were 0.5 μg/mL and 1 μg/mL, respectively (32 fold lower MIC90 than for ceftazidime). Eighty-nine percent (141/158) of multidrug-resistant isolates were inhibited by ≤8 μg/mL of ceftolozane/tazobactam. 23554140 SiCN: SiCN Nanofibers with a Diameter Below 100 nm Synthesized via Concerted Block Copolymer Formation, Microphase Separation, and Crosslinking (Small 7/2013). SiCN fibers with a mean diameter of 50 nm and an aspect ratio of up to 100 are produced in a two-step process by R. Kempe and co-workers. The key step to fabricate the longitudinal and crosssectional views of the mesofibers shown here is a concerted block-copolymer synthesis, microphase separation, and cross linking at 140 °C followed by pyrolysis at 1100 °C. Inexpensive components like a commercially available silazane and polyethylene are linked. The fibers may find application in electronic devices, as components of ceramic matrix composites, as fiber beds in hightemperature nano-filtering like diesel fine dust removal, or as thermally robust and chemically inert catalyst supports. Furthermore, the SiCN nanofibers introduced on page 984 are a promising alternative to ultrathin carbon fibers, due to their oxidation resistance. 23548202 Formation of a tyrosine adduct involved in lignin degradation by Trametopsis cervina lignin peroxidase: A novel peroxidase activation mechanism. Lignin peroxidase (LiP) from Trametopsis cervina has an exposed catalytic tyrosine (Tyr-181) instead of the conserved tryptophan of other lignin-degrading peroxidases. Pristine LiP showed a lag period in veratryl alcohol (VA) oxidation. However, LiP after turnover with H2O2/VA (VA-LiP) lacked this lag, and H2O2-pretreated LiP (H2O2-LiP) was inactive. MS analyses revealed that VA-LiP includes one VA molecule covalently bound to the side-chain of Tyr-181, whereas H2O2-LiP contains hydroxylated Tyr-181. No adduct is formed by the Y171N variant. Molecular docking showed that VA binding is favored by sandwich π stacking with Tyr-181 and Phe-89. EPR spectroscopy after peroxide activation of the pretreated LiPs showed other protein radicals than the tyrosine radical found in pristine LiP, which were assigned to a tyrosine/VA adduct radical in VA-LiP and a dihydroxyphenyalanine radical in H2O2-LiP. Both radicals are able to oxidize large low redox-potential substrates, but H2O2-LiP is unable to oxidize high redox-potential substrates. Transient-state kinetics showed that the tyrosine/VA adduct strongly promotes (>100-fold) substrate oxidation by compound II, the rate-limiting step in catalysis. The novel activation mechanism is involved in ligninolysis, as demonstrated using lignin model substrates. This is the first report on autocatalytic modification, resulting in functional alteration, among class-II peroxidases. 23722921 Programming of the lung in early life by bacterial infections predisposes to chronic respiratory disease. There is emerging evidence that chronic respiratory diseases such as asthma and emphysema may originate in early life. Respiratory infections with certain bacterial pathogens such as Chlamydia, Haemophilus influenzae and Streptococcus pneumoniae in early life may promote permanent deleterious changes in immunity, lung structure, and function that predispose to, or increase the severity of chronic respiratory diseases in later life. For example, these infections increase immune responses, which drive subsequent asthma pathogenesis. Targeting the pathways involved with specific inhibitors or agonists may prevent these consequences of early-life infection. Vaccination and immunomodulatory therapies that control the infections and their sequelae may also be efficacious. 23927233 A higher-order tangent linear parabolic-equation solution of three-dimensional sound propagation. A higher-order square-root operator splitting algorithm is employed to derive a tangent linear solution for the three-dimensional parabolic wave equation due to small variations of the sound speed in the medium. The solution shown in this paper unifies other solutions obtained from less accurate approximations. Examples of three-dimensional acoustic ducts are presented to demonstrate the accuracy of the solution. Future work on the applications of associated adjoint models for acoustic inversions is proposed and discussed. 23962868 A systematic review on the effectiveness of school and community-based injury prevention programmes on risk behaviour and injury risk in 8-12 year old children. To review existing literature on the effectiveness of community-based and school-based physical activity related injury prevention programmes implemented to increase safety behaviour and decrease injury risk in 8-12 year old children, considering the methodological quality of the studies. A systematic review with quality assessment. A systematic search was performed using the CINAHL, Cochrane, EMBASE, PubMed and Sportdiscus databases. Inclusion criteria included the following: children aged 8-12 years; school- or community-based injury prevention programmes; an outcome defined as number of injuries, injury incidence or safety behaviour; published in an English language journal. Methodological quality was assessed for all included studies. The search yielded 5377 records, of which 11 were included in the review; four studies were considered as being of high quality. The focus of studies that were included was on the use of safety devices (8), pedestrian safety (2) and physical activity-related injury prevention (1). For safety device use, short term effects of school- and community-based interventions are promising for 8-12 year olds. Results regarding sustainability of the effect are inconsistent. A mediating effect on the distribution of safety devices was observed. Both financial and non-financial barriers seemed to prevent participants from purchasing a safety device. The short term effects for school- and community-based interventions using safety devices for 8-12 year olds are promising. More high quality research is, however warranted, preferably shifting focus from safety behaviour change to actual physical activity injury reduction. 23873705 Transcriptomic and phenotypic analysis of paralogous spx gene function in Bacillus anthracis Sterne. Spx of Bacillus subtilis is a redox-sensitive protein, which, under disulfide stress, interacts with RNA polymerase to activate genes required for maintaining thiol homeostasis. Spx orthologs are highly conserved among low %GC Gram-positive bacteria, and often exist in multiple paralogous forms. In this study, we used B. anthracis Sterne, which harbors two paralogous spx genes, spxA1 and spxA2, to examine the phenotypes of spx null mutations and to identify the genes regulated by each Spx paralog. Cells devoid of spxA1 were sensitive to diamide and hydrogen peroxide, while the spxA1 spoxA2 double mutant was hypersensitive to the thiol-specific oxidant, diamide. Bacillus anthracis Sterne strains expressing spxA1DD or spxA2DD alleles encoding protease-resistant products were used in microarray and quantitative real-time polymerase chain reaction (RT-qPCR) analyses in order to uncover genes under SpxA1, SpxA2, or SpxA1/SpxA2 control. Comparison of transcriptomes identified many genes that were upregulated when either SpxA1DD or SpxA2DD was produced, but several genes were uncovered whose transcript levels increased in only one of the two SpxADD-expression strains, suggesting that each Spx paralog governs a unique regulon. Among genes that were upregulated were those encoding orthologs of proteins that are specifically involved in maintaining intracellular thiol homeostasis or alleviating oxidative stress. Some of these genes have important roles in B. anthracis pathogenesis, and a large number of upregulated hypothetical genes have no homology outside of the B. cereus/thuringiensis group. Microarray and RT-qPCR analyses also unveiled a regulatory link that exists between the two spx paralogous genes. The data indicate that spxA1 and spxA2 are transcriptional regulators involved in relieving disulfide stress but also control a set of genes whose products function in other cellular processes. 23683597 Discovery of novel HCV inhibitors: synthesis and biological activity of 6-(indol-2-yl)pyridine-3-sulfonamides targeting hepatitis C virus NS4B. A novel series of 6-(indol-2-yl)pyridine-3-sulfonamides was prepared and evaluated for their ability to inhibit HCV RNA replication in the HCV replicon cell culture assay. Preliminary optimization of this series furnished compounds with low nanomolar potency against the HCV genotype 1b replicon. Among these, compound 8c has identified as a potent HCV replicon inhibitor (EC50=4 nM) with a selectivity index with respect to cellular GAPDH of more than 2500. Further, compound 8c had a good pharmacokinetic profile in rats with an IV half-life of 6h and oral bioavailability (F) of 62%. Selection of HCV replicon resistance identified an amino acid substitution in HCV NS4B that confers resistance to these compounds. These compounds hold promise as a new chemotype with anti-HCV activity mediated through an underexploited viral target. 23825092 Rationally designed coiled-coil DNA looping peptides control DNA topology. Artificial DNA looping peptides were engineered to study the roles of protein and DNA flexibility in controlling the geometry and stability of protein-mediated DNA loops. These LZD (leucine zipper dual-binding) peptides were derived by fusing a second, C-terminal, DNA-binding region onto the GCN4 bZip peptide. Two variants with different coiled-coil lengths were designed to control the relative orientations of DNA bound at each end. Electrophoretic mobility shift assays verified formation of a sandwich complex containing two DNAs and one peptide. Ring closure experiments demonstrated that looping requires a DNA-binding site separation of 310 bp, much longer than the length needed for natural loops. Systematic variation of binding site separation over a series of 10 constructs that cyclize to form 862-bp minicircles yielded positive and negative topoisomers because of two possible writhed geometries. Periodic variation in topoisomer abundance could be modeled using canonical DNA persistence length and torsional modulus values. The results confirm that the LZD peptides are stiffer than natural DNA looping proteins, and they suggest that formation of short DNA loops requires protein flexibility, not unusual DNA bendability. Small, stable, tunable looping peptides may be useful as synthetic transcriptional regulators or components of protein-DNA nanostructures. 22692766 Antidepressant use during pregnancy and serotonin transporter genotype (SLC6A4) affect newborn serum reelin levels. This study was undertaken to determine whether altered early serotonin signaling either via gestational serotonin reuptake inhibitor (SRI) exposure or genetic variations in the serotonin transporter promoter region (SLC6A4) alters levels of reelin, an important glycoprotein in neurodevelopment, in mothers and their neonates. Serum reelin protein expression was quantified by immunoblot from maternal and neonatal blood collected at delivery from women taking either an SRI during gestation or controls. SRI-exposed mothers had higher levels of one reelin fragment, while SRI-exposed neonates had lower total reelin levels, particularly in females and reelin levels differed with SLC6A4 genotype. Lower neonatal reelin levels predicted less time spent sleeping and more irritability during neonatal behavioral assessment on Day 6 of life. Our results suggest that prenatal SRI exposure and the SLC6A4 genotype influences reelin protein expression in both the mother and newborn and that this may be reflected in neonatal behavior. 23624290 In vitro binding affinities of a series of flavonoids for μ-opioid receptors. Antinociceptive effect of the synthetic flavonoid 3,3-dibromoflavanone in mice. The pharmacotherapy for the treatment of pain is an active area of investigation. There are effective drugs to treat this problem, but there is also a need to find alternative treatments free of undesirable side effects. In the present work the capacity of a series of flavonoids to bind to the μ opioid receptor was evaluated. The most active compound, 3,3-dibromoflavanone (31), a synthetic flavonoid, presented a significant inhibition of the binding of the selective μ opioid ligand [(3)H]DAMGO, with a Ki of 0.846 ± 0.263 μM. Flavanone 31 was further synthesized using a simple and cheap procedure with good yield. Its in vivo effects in mice, after acute treatments, were studied using antinociceptive and behavioral assays. It showed no sedative, anxiolytic, motor incoordination effects or inhibition of the gastrointestinal transit in mice at the doses tested. It evidenced antinociceptive activity on the acetic acid-induced nociception, hot plate and formalin tests (at 10 mg/kg and 30 mg/kg). The results showed that the 5-HT2 receptor and the adrenoceptors seem unlikely to be involved in its antinociceptive effects. Naltrexone, a nonselective opioid receptors antagonist, totally blocked compound 31 antinociceptive effects on the hot plate test, but naltrindole (δ opioid antagonist) and nor-binaltorphimine (κ opioid antagonist) did not. These findings demonstrated that 3,3-dibromoflavanone (31), at doses that did not interfere with the motor performance, exerted clear dose dependent antinociception when assessed in the chemical and thermal models of nociception in mice and it seems that its action is related to the activation of the μ opioid receptor. 23254193 Effect of lactation on postpartum cardiac function of pregnancy-associated hypertensive mice. Preeclampsia is a serious complication during pregnancy, and recent epidemiological studies indicate the association between preeclampsia and cardiac morbidity and mortality during the postpartum period. Although the risk of cardiovascular diseases in the postpartum period is affected by lactation, its role in maternal heart with a history of preeclampsia remains unclear. In this study, we investigated postpartum change in cardiac remodeling and function of pregnancy-associated hypertensive (PAH) mice with and without lactation. The systolic blood pressure was increased in PAH mice at day 19 of gestation (E19) and was reduced to normal levels in both lactating and nonlactating (NL) groups in the postpartum period. Histological analyses revealed that cardiac hypertrophy and macrophage infiltration in PAH mice at E19 were improved in both lactating and NL groups at 4 weeks postpartum (4W-PP), while marked fibrosis remained. Increased mRNA expression of profibrotic genes and proinflammatory cytokines in PAH mice at E19 was significantly reduced in both lactating and NL groups at 4W-PP. Echocardiographic analysis found no significant differences in fractional shortening between PAH mice and C57BL/6J mice at E19. On the other hand, at 4W-PP, NL PAH mice showed normal fractional shortening, but lactating PAH mice exhibited significant decreases in cardiac contractility compared with NL PAH mice. These results show that cardiac remodeling induced by hypertension during pregnancy are improved in the postpartum period except fibrosis, whereas lactation induces cardiac contractile dysfunction in mice with a history of pregnancy-associated hypertension. 23850356 Neotrofin reverses the effects of chronic unpredictable mild stress on behavior via regulating BDNF, PSD-95 and synaptophysin expression in rat. Depression is one of the most common neuropsychiatric disorders and has been associated with a wide range of neuronal structural changes in brain regions. Neotrofin, a neurotrophin agonist, has been demonstrated to exhibit neuroprotection in various in vivo and in vitro studies. The present study aimed to investigate the neuroprotective and ameliorating effects of neotrofin treatment in a rat model of chronic unpredictable mild stress (CUMS) induced depression. The results showed that CUMS was effective in producing depression-like behavior in rats as indicated by decreased responses in the sucrose preference test, and locomotor activity in the open-field test. Moreover, the expression of brain-derived neurotrophic factor (BDNF), PSD-95 and synaptophysin were decreased in the amygdala of CUMS rats. Chronic administration of neotrofin (60mg/kg, i.p., 5 weeks) significantly ameliorated all these behavioral and biochemical alterations associated with CUMS induced depression, which demonstrated that the expression changes of BDNF, PSD-95 and synaptophysin were correlated with the depression-like behaviors of CUMS rats. Taken together, the results of the present study highlight that neotrofin exhibits neuroprotective and antidepressant-like effects against CUMS induced depression, and suggest a possible mechanism for this protection via changes in synaptic plasticity within the amygdala. These findings reveal the therapeutic potential of neotrofin for use in clinical trials in the treatment of neuronal deterioration in depression. 23534826 Antifreeze (Glyco)protein Mimetic Behavior of Poly(vinyl alcohol): Detailed Structure Ice Recrystallization Inhibition Activity Study. This manuscript reports a detailed study on the ability of poly(vinyl alcohol) to act as a biomimetic surrogate for antifreeze(glyco)proteins, with a focus on the specific property of ice-recrystallization inhibition (IRI). Despite over 40 years of study, the underlying mechanisms that govern the action of biological antifreezes are still poorly understood, which is in part due to their limited availability and challenging synthesis. Poly(vinyl alcohol) (PVA) has been shown to display remarkable ice recrystallization inhibition activity despite its major structural differences to native antifreeze proteins. Here, controlled radical polymerization is used to synthesize well-defined PVA, which has enabled us to obtain the first quantitative structure-activity relationships, to probe the role of molecular weight and comonomers on IRI activity. Crucially, it was found that IRI activity is "switched on" when the polymer chain length increases from 10 and 20 repeat units. Substitution of the polymer side chains with hydrophilic or hydrophobic units was found to diminish activity. Hydrophobic modifications to the backbone were slightly more tolerated than side chain modifications, which implies an unbroken sequence of hydroxyl units is necessary for activity. These results highlight that, although hydrophobic domains are key components of IRI activity, the random inclusion of addition hydrophobic units does not guarantee an increase in activity and that the actual polymer conformation is important. 23645686 Symptomatic osteonecrosis in childhood leukemia survivors: prevalence, risk factors and impact on quality of life in adulthood. Corticosteroid can induce osteonecrosis in children with leukemia. Few studies have been designed to assess the influence of a wide range of cumulative steroid dose on this side effect. Prevalence, risk factors of symptomatic osteonecrosis and its impact on adults' Quality of Life were assessed in 943 patients enrolled in the French "Leucémies de l'Enfant et de l'Adolescent" (LEA) cohort of childhood leukemia survivors. During each medical visit, data on previous osteonecrosis diagnosis were retrospectively collected. Patients without a history but with suggestive symptoms were investigated with magnetic resonance imaging. The total steroid dose in equivalent of prednisone was calculated for each patient and its effect on osteonecrosis occurrence was studied in multivariate models. Cumulative incidence was 1.4% after chemotherapy alone versus 6.8% after transplantation (P<0.001). A higher cumulative steroid dose, age over ten years at diagnosis, and treatment with transplantation significantly increased the risk of osteonecrosis. A higher post-transplant steroid dose and age over ten years at time of transplantation were significant factors in the transplanted group. With patients grouped according to steroid dose quartile, cumulative incidence of osteonecrosis reached 3.8% in the chemotherapy group for a dose beyond 5835 mg/m(2) and 23.8% after transplantation for a post-transplant dose higher than 2055 mg/m(2). Mean physical composite score of Quality of Life was 44.3 in patients with osteonecrosis versus 54.8% in patients without (P<0.001). We conclude that total and post-transplant cumulative steroid dose may predict the risk of osteonecrosis, a rare late effect with a strong negative impact on physical domains of Quality of Life. 23252745 Development of new cathepsin B inhibitors: combining bioisosteric replacements and structure-based design to explore the structure-activity relationships of nitroxoline derivatives. Human cathepsin B has many house-keeping functions, such as protein turnover in lysosomes. However, dysregulation of its activity is associated with numerous diseases, including cancers. We present here the structure-based design and synthesis of new cathepsin B inhibitors using the cocrystal structure of 5-nitro-8-hydroxyquinoline in the cathepsin B active site. A focused library of over 50 compounds was prepared by modifying positions 5, 7, and 8 of the parent compound nitroxoline. The kinetic parameters and modes of inhibition were characterized, and the selectivities of the most promising inhibitors were determined. The best performing inhibitor 17 was effective in cell-based in vitro models of tumor invasion, where it significantly abrogated invasion of MCF-10A neoT cells. These data show that we have successfully explored the structure-activity relationships of nitroxoline derivatives to provide new inhibitors that could eventually lead to compounds with clinical usefulness against the deleterious effects of cathepsin B in cancer progression. 23881344 Odontoid infiltration and spinal compression in Farber Disease: reversal by haematopoietic stem cell transplantation. Farber disease (FD) is a lysosomal storage disorder caused by accumulation of ceramide in various organs and tissues, most notably the central nervous system, subcutaneous tissues and respiratory tract. We report a girl who developed major destructive bone involvement, which affected the odontoid process and produced spinal compression at 9 years of age. Bone involvement was proven histologically but resolved, as assessed by serial MRI scanning, following matched unrelated donor haematopoietic stem cell transplantation. This transplant resulted in only partial donor chimerism (less than 10 % donor cells in peripheral blood), yet this was sufficient to almost normalize acid ceramidase levels in leukocytes and to produce dramatic improvements in subcutaneous nodules and joint mobility as well as the beneficial effect on the involved bone. Unfortunately, the transplant was rejected after 2 years but the patient was rescued from an aplastic state by successful haploidentical peripheral blood stem cell transplantation and remained a full donor chimera without recurrence of the bone involvement and with steadily improving mobility at the age of 17 years. We describe an FD patient who presented with severe destruction of the odontoid by inflammatory tissue which was reversed after long-term control achieved by allogeneic hematopoietic stem cell transplantation. After extensive literature search, we believe that this is the first report of bony involvement in Farber disease. 23942256 Controlled growth of platinum nanowire arrays on sulfur doped graphene as high performance electrocatalyst. Graphene supported Pt nanostructures have great potential to be used as catalysts in electrochemical energy conversion and storage technologies; however the simultaneous control of Pt morphology and dispersion, along with ideally tailoring the physical properties of the catalyst support properties has proven very challenging. Using sulfur doped graphene (SG) as a support material, the heterogeneous dopant atoms could serve as nucleation sites allowing for the preparation of SG supported Pt nanowire arrays with ultra-thin diameters (2-5 nm) and dense surface coverage. Detailed investigation of the preparation technique reveals that the structure of the resulting composite could be readily controlled by fine tuning the Pt nanowire nucleation and growth reaction kinetics and the Pt-support interactions, whereby a mechanistic platinum nanowire array growth model is proposed. Electrochemical characterization demonstrates that the composite materials have 2-3 times higher catalytic activities toward the oxygen reduction and methanol oxidation reaction compared with commercial Pt/C catalyst. 23707647 Meta-analysis of prevention and treatment of toxoplasmic encephalitis in HIV-infected patients. Toxoplasmic encephalitis (TE) is one of the most common central nervous system (CNS) opportunistic infections in HIV-infected patients. It can be prevented and treated through drug regimen. However, drugs have serious adverse effects sometimes. The purpose of this review is to determine the most effective therapy for TE in HIV-infected patients. Different primary prophylaxis and treatment regimens have been compared with regard to episodes of TE, clinical response, morbidity, and serious adverse events. In September 2012, we searched PubMed, Google Scholar, EMBASE, and CENTRAL (the Cochrane Central Register of Controlled Trials) database for randomized and quasi-randomized controlled trials of any drug regimen for primary prophylaxis and treatment of TE in HIV-infected patients. We independently extracted data and assessed eligibility and risk of bias using a standardized data collection form, and resolved any disagreement through discussion. We combined dichotomous outcomes using odds ratio (OR), presenting with 95% confidence interval (CI). Eleven trials were found to meet the inclusion criteria. Six trials compared trimethoprim-sulfamethoxazole (TMP-SMX) with dapsone-pyrimethamine (D-P) were analyzed together for the outcome of episodes of TE, morbidity, and serious adverse events. The two treatment arms did not differ for episodes of TE (OR=0.98; 95% CI: 0.48-2.00). Compared with D-P, TMP-SMX showed a beneficial trend in terms of mortality despite a lack of statistical significance (OR=0.75; 95% CI: 0.53-1.06). However, TMP-SMX is still associated with substantial toxicity and intolerance (OR=1.47; 95% CI: 0.91-2.38). Three trials compared pyrimethamine-sulfadiazine (P-S) with pyrimethamine-clindamycin (P-C) were analyzed together for the outcome of clinical response, morbidity, and serious adverse events. Compared with P-C, P-S showed a beneficial trend in terms of clinical response (OR=1.63; 95% CI: 1.05-2.51); P-S also showed a beneficial trend in terms of mortality despite a lack of statistical significance (OR=0.66; 95% CI: 0.37-1.17). However, P-S is still associated with substantial toxicity and intolerance (OR=3.08; 95% CI: 1.82-5.24). Two trials compared P-S with TMP-SMX were analyzed together for the outcome of clinical response, morbidity, and serious adverse events. The two treatment arms did not differ for clinical response (OR=0.90; 95% CI: 0.39-2.06). Compared with TMP-SMX, P-S showed a beneficial trend in terms of mortality despite a lack of statistical significance (OR=0.12; 95% CI: 0.01-1.39). However, P-S is still associated with substantial toxicity and intolerance (OR=2.91; 95% CI: 0.99-8.55). The available evidence fails to identify any one superior regimen for the primary prophylaxis and treatment of TE. The choice of therapy will often be directed by available therapy. Although current evidence does not allow a definitive recommendation, administration of TMP-SMX for primary prophylaxis and treatment of TE in patients with HIV infection is consistent with the available data. 23735805 Molecular layer heterotopia of the cerebellar vermis in mutant and transgenic mouse models on a C57BL/6 background. C57BL/6 mice exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis (Tanaka and Marunouchi, 2005; Mangaru et al., 2013). Malformations are only found between folia VIII and IX and are indicative of deficits of neuronal migration during cerebellar development. In the present report we test the prediction that mutant and transgenic mouse models on a C57BL/6 background will also exhibit these same cerebellar malformations. Consistent with our hypothesis, we found that 2 spontaneous mutant models of Parkinson's disease on a C57BL/6 background had cerebellar malformations. In addition, we found that numerous transgenic mouse lines on a full or partial C57BL/6 background including eGFP-, YFP- and Cre-transgenic mice also exhibited heterotopia. These data suggest that histological analyses be performed in studies of cerebellar function or development when using C57BL/6 or other mice on this background in order for correct interpretation of research results. 23241370 Polyazamacrocycles as potential antitumor agents for human prostate cancer cells. Polyazamacrocycles are currently being studied and used in a variety of applications beyond their traditional place in supramolecular and co-ordination chemistry. This study suggests additional applications of these compounds with particular emphasis on their use as antiproliferative agents that could be potentially used to treat cancer. Four polyazamacrocycles were tested in human prostate cancer LNCaP and prostate epithelial PNTA1 cells to analyze changes in cell proliferation and cell death capabilities. Their intracellular localization was also evaluated by confocal microscopy. The results show a decrease in proliferation rate and cell viability of LNCaP and PNTA1, after treatment with these compounds. The decrease in the number of viable cells is similar for the majority of the compounds studied, and at higher concentration, the proliferation efficiency decreased significantly in the cell lines studied. Also, our results suggest that L and L2 induce early apoptosis in PNTA1 cells and late apoptosis/necrosis in LNCaP cells. The compounds did not induce a significant increase in necrosis of both cell types. Although the compounds did not localize in a unique organelle, all of them have as main target the Golgi apparatus and other localization profiles differed depending on the cell line. 23792965 The UDP-glucose Dehydrogenase of Escherichia coli K-12 Displays Substrate Inhibition by NAD That Is Relieved by Nucleotide Triphosphates. UDP-glucose dehydrogenase (Ugd) generates UDP-glucuronic acid, an important precursor for the production of many hexuronic acid-containing bacterial surface glycostructures. In Escherichia coli K-12, Ugd is important for biosynthesis of the environmentally regulated exopolysaccharide known as colanic acid, whereas in other E. coli isolates, the same enzyme is required for production of the constitutive group 1 capsular polysaccharides, which act as virulence determinants. Recent studies have implicated tyrosine phosphorylation in the activation of Ugd from E. coli K-12, although it is not known if this is a feature shared by bacterial Ugd proteins. The activities of Ugd from E. coli K-12 and from the group 1 capsule prototype (serotype K30) were compared. Surprisingly, for both enzymes, site-directed Tyr → Phe mutants affecting the previously proposed phosphorylation site retained similar kinetic properties to the wild-type protein. Purified Ugd from E. coli K-12 had significant levels of NAD substrate inhibition, which could be alleviated by the addition of ATP and several other nucleotide triphosphates. Mutations in a previously identified UDP-glucuronic acid allosteric binding site decreased the binding affinity of the nucleotide triphosphate. Ugd from E. coli serotype K30 was not inhibited by NAD, but its activity still increased in the presence of ATP. 22512576 Effects of synthetic peptides on the inflammatory response and their therapeutic potential. Recently, interest in small peptide molecules as potential drug candidates has revived. In this review, two series of synthetic peptides and their selective effects on the inflammatory response have been described, focusing on the intracellular pathways involved and on their therapeutic potential. A series of F(D)LF(D)LF analogs has been synthesized, including either N- t-Boc or different N-ureido substituents. The free acid derivatives as they are good candidates as antiinflammatory drugs are able to antagonize the multiple neutrophil functions evoked by N-formyl-L-methionyl-L-leucyl-Lphenylalanine (fMLF), i.e. chemotaxis, superoxide anion production and lysozyme release. Their methyl-ester derivatives are ineffective. The second series of peptides derives from the endogenous protein kinase C (PKC) inhibitor PKI55, a 55-amino acid protein, whose synthesis is induced by PKC activation, so that a feedback loop of inhibition is established. In vitro experiments showed that PKI55 inhibits recombinant PKC isoforms α, β1, β2, γ, δ, ζ, ; to identify the minimal amino acid sequence of PKI55 protein maintaining the inhibitory effects on PKC, peptides derived from both C- and N-terminal sequences have been synthesized. The N-terminal peptides 5 (MLYKLHDVCRQLWFSC), 8 (CRQLWFSC) and 9 (CRQLW), that in human neutrophils retain the inhibitory activity on PKC, decrease the chemotaxis, and, in mice, display anti-inflammatory and analgesic action, after both central and peripheral administration of very low doses. Furthermore, the peptide 5 shows neuroprotective activity in a model of cerebral ischemia in vitro, favouring the recovery of synaptic function. These findings suggest interesting possible therapeutic applications for these peptides. 23395730 A practical guide for the functional annotation of genetic variations using SNPnexus. Broader functional annotation of known as well as putative genetic variations is a valuable mean for prioritizing targets in disease studies and large-scale genotyping projects. In this article, we present a practical guide to SNPnexus, a web-based tool that provides an aggregate set of functional annotations for genomic variation data by characterizing related consequences at the transcriptome/proteome levels with in-depth analysis of potential deleterious effects, inferring physical and cytogenetic mapping, reporting related HapMap data, finding overlaps with potential regulatory, structural as well as conserved elements and retrieving links with previously reported genetic disease studies. We focus on the SNPnexus query system, its annotation categories and the biological interpretation of results. 23811781 The utility of the zebrafish model in conditioned place preference to assess the rewarding effects of drugs. Substance abuse is a significant public health concern both domestically and worldwide. The persistent use of substances regardless of aversive consequences forces the user to give higher priority to the drug than to normal activities and obligations. The harmful and hazardous use of psychoactive substances can lead to a dependence syndrome. In this regard, the genetic and neurobiological underpinnings of reward-seeking behavior need to be fully understood in order to develop effective pharmacotherapies and other methods of treatment. Animal models are often implemented in preclinical screening for testing the efficacy of novel treatments. Several paradigms exist that model various facets of addiction including sensitization, tolerance, withdrawal, drug seeking, extinction, and relapse. Self-administration and, most notably, conditioned place preference (CPP) are relatively simple tests that serve as indicators of the aforementioned aspects of addiction by means of behavioral quantification. CPP is a commonly used technique to evaluate the motivational effects of compounds and experiences that have been associated with a positive or negative reward, which capitalizes on the basic principles of Pavlovian conditioning. During training, the unconditioned stimulus is consistently paired with a neutral set of environmental stimuli, which obtain, during conditioning, secondary motivational properties that elicit approach behavior in the absence of the unconditioned stimulus. For over 50 years, rodents have been the primary test subjects. However, the zebrafish (Danio rerio) is gaining favor as a valuable model organism in the fields of biology, genetics, and behavioral neuroscience. This paper presents a discussion on the merits, advantages, and limitations of the zebrafish model and its utility in relation to CPP. 23917518 The BOLD signal and neurovascular coupling in autism. BOLD (blood oxygen level dependent) fMRI (functional magnetic resonance imaging) is commonly used to study differences in neuronal activity between human populations. As the BOLD response is an indirect measure of neuronal activity, meaningful interpretation of differences in BOLD responses between groups relies upon a stable relationship existing between neuronal activity and the BOLD response across these groups. However, this relationship can be altered by changes in neurovascular coupling or energy consumption, which would lead to problems in identifying differences in neuronal activity. In this review, we focus on fMRI studies of people with autism, and comparisons that are made of their BOLD responses with those of control groups. We examine neurophysiological differences in autism that may alter neurovascular coupling or energy use, discuss recent studies that have used fMRI to identify differences between participants with autism and control participants, and explore experimental approaches that could help attribute between-group differences in BOLD signals to either neuronal or neurovascular factors. 23680222 Introduction of routine polymerase chain reaction testing for Neisseria gonorrhoeae in a community laboratory. We introduced polymerase chain reaction (PCR) testing for Neisseria gonorrhoeae (NG) on the Cobas 4800 CT/NG assay for all samples received with a Chlamdyia trachomatis request in March 2012. From 1 March 2012 to 30 June 2012, all PCR-positive/culture-negative specimens had additional testing at another assay. A total of 40053 tests were performed. The estimated specificity and positive predictive value were 99.9% and 97.1%, respectively; thus routine additional testing is not required. 23883394 The (•)OH Radical Yield in the H2O2 + O3 (Peroxone) Reaction. The peroxone process is one of the AOPs that lead to (•)OH. Hitherto, it has been generally assumed that the (•)OH yield is unity with respect to O3 consumption. Here, experimental data are presented that suggest that it must be near 0.5. The first evidence is derived from competition experiments. The consumption of 4-chlorobenzoic acid (4-CBA), 4-nitrobenzoic acid (4-NBA) and atrazine present in trace amounts (1 μM) has been followed as a function of the O3 concentration in a solution containing H2O2 (1 mM) and tertiary butanol (tBuOH, 0.5 mM) in excess over the trace compounds. With authentic (•)OH generated by γ-radiolysis such a competition can be adequately fitted by known (•)OH rate constants. Fitting the peroxone data, however, the consumption of the trace indicators can only be rationalized if the (•)OH yield is near 0.5 (4-CBA: 0.56, 4-NBA: 0.49, atrazine: 0.6). Additional information for an (•)OH yield much below unity has been obtained by a product analysis of the reactions of tBuOH with (•)OH and dimethyl sulfoxide with (•)OH. The mechanistic interpretation for the low (•)OH yield is as follows (Merényi et al. Environ. Sci. Technol. 2010, 44, 3505-3507). In the reaction of O3 with HO2(-) an adduct (HO5(-)) is formed that decomposes into O3(•-) and HO2(•) in competition with 2 O2 + OH(-). The latter process reduces the free-radical yield. 23825388 Location, location, location: tissue-specific regulation of immune responses. Discovery of DCs and PRRs has contributed immensely to our understanding of induction of innate and adaptive immune responses. Activation of PRRs leads to secretion of inflammatory cytokines that regulate priming and differentiation of antigen-specific T and B lymphocytes. Pathogens enter the body via different routes, and although the same set of PRRs is likely to be activated, it is becoming clear that the route of immune challenge determines the nature of outcome of adaptive immunity. In addition to the signaling events initiated following innate-immune receptor activation, the cells of the immune system are influenced by the microenvironments in which they reside, and this has a direct impact on the resulting immune response. Specifically, immune responses could be influenced by specialized DCs, specific factors secreted by stromal cells, and also, by commensal microbiota present in certain organs. Following microbial detection, the complex interactions among DCs, stromal cells, and tissue-specific factors influence outcome of immune responses. In this review, we summarize recent findings on the phenotypic heterogeneity of innate and adaptive immune cells and how tissue-specific factors in the systemic and mucosal immune system influence the outcome of adaptive-immune responses. 23643893 Police AED programs: A systematic review and meta-analysis. Approximately 359,400 out-of-hospital cardiac arrests occur in the United States every year, and around 60% of them are treated by emergency medical services (EMS) personnel. In order to alleviate the impact of this public health burden, some communities have trained police officers as first responders so that they can provide cardiopulmonary resuscitation and defibrillation to cardiac arrest patients. This paper is a review of the current literature on the impact of police automated external defibrillators (AEDs) programs in these communities. A literature search of electronic journal databases was conducted to identify articles that evaluated police AED programs and quantified survival rates. The 10 articles that met the inclusion criteria were very heterogeneous in terms of study design, controlling for confounders, outcome definitions, and comparison groups. Two communities found a statistically significant difference in survival and 6 studies reported a statistically significant difference in time to defibrillation after the implementation of these programs. The weighted mean survival rate of the study groups was higher than that of the control groups (p<0.001), as was the weighted mean survival rate of the group first shocked by police compared to those first shocked by EMS (39.4% vs. 28.6%, p<0.001). The pooled relative risk of survival was 1.4 (95% CI: 1.3-1.6). Though there are many challenges in initiating these programs, this literature review shows that time to defibrillation decreased and survival from out-of-hospital cardiac arrests increased with the implementation of police AED programs. 23360490 The relation between social sharing and the duration of emotional experience. People often socially share their emotions to regulate them. Two-mode theory of social sharing states that cognitive sharing will contribute to emotional recovery, whereas socio-affective sharing will only temporarily alleviate emotional distress. Previous studies supporting this theory, measured emotional recovery in terms of residual emotional intensity. Until now, another important time-dynamic aspect of emotions, emotion duration, has been largely ignored. In two experience sampling studies we addressed this gap. In Study 1, participants reported on the duration of anger, fear, and sadness episodes; additionally time-varying information on the occurrence and mode of sharing was collected. This study revealed that sharing led to a shortening in emotion duration, in particular when it was socio-affective in nature. In Study 2 we investigated whether this result could be interpreted in terms of our measure of duration primarily reflecting emotional relief rather than recovery. In this study, the same method as in Study 1 was used; additionally, residual emotional intensity was measured three days after emotion onset. Study 2 largely replicated the findings from Study 1. Furthermore, duration appeared to be empirically distinct from residual intensity. Finally, no relation between sharing and residual intensity was found, even when considering the sharing mode. 23915803 Cross-Approximate Entropy parallel computation on GPUs for biomedical signal analysis. Application to MEG recordings. Cross-Approximate Entropy (Cross-ApEn) is a useful measure to quantify the statistical dissimilarity of two time series. In spite of the advantage of Cross-ApEn over its one-dimensional counterpart (Approximate Entropy), only a few studies have applied it to biomedical signals, mainly due to its high computational cost. In this paper, we propose a fast GPU-based implementation of the Cross-ApEn that makes feasible its use over a large amount of multidimensional data. The scheme followed is fully scalable, thus maximizes the use of the GPU despite of the number of neural signals being processed. The approach consists in processing many trials or epochs simultaneously, with independence of its origin. In the case of MEG data, these trials can proceed from different input channels or subjects. The proposed implementation achieves an average speedup greater than 250× against a CPU parallel version running on a processor containing six cores. A dataset of 30 subjects containing 148 MEG channels (49 epochs of 1024 samples per channel) can be analyzed using our development in about 30min. The same processing takes 5 days on six cores and 15 days when running on a single core. The speedup is much larger if compared to a basic sequential Matlab(®) implementation, that would need 58 days per subject. To our knowledge, this is the first contribution of Cross-ApEn measure computation using GPUs. This study demonstrates that this hardware is, to the day, the best option for the signal processing of biomedical data with Cross-ApEn. 23551028 Short Communication: High Natural Polymorphism in the gag Gene Cleavage Sites of non-B HIV Type 1 Isolates from Gabon. Abstract The main goal of the present study was to determine the frequency of substitutions in the cleavage sites (CS) of gag gene among non-B HIV-1 isolates from Gabon. Fifty plasma specimens, collected in 2010-2011, from HIV-1-infected patients failing first-line antiretroviral (ARV) regimens (constituted of two nucleoside reverse transcriptase inhibitors+one nonnucleoside reverse transcriptase inhibitor) (n=38) and from HIV-1-infected individuals untreated with ARV (n=12) were analyzed in the gag and gag-pol cleavage sites. Compared to HXB2 reference sequence, the total median number of substitutions in gag and gag-pol CS was 10 (range, 5-18). The cleavage site p2/NC was the most variable of the four gag CS with 100% (50/50) isolates carrying at least 1 substitution (range, 1-9). The two gag-pol TFP/p6(pol) and p6(pol)/PR CS sites were also highly variable (at least one substitution, 50/50, 100% in both cases). Substitutions at position G381 (p2/NC), L449 (p1/p6(gag)), and K444 (TFP/p6(pol)) were significantly more frequent in CRF02_AG strains, compared to other non-B strains (30.4% vs. 3.7%, p=0.03; 87.0% vs. 59.3%, p=0.03; and 91.3% vs. 59.3%, p=0.01, respectively). Other non-B subtypes were significantly more likely to harbor substitutions at position N487 (p6(pol)) (70.4%) than CRF02_AG (39.1%) (p=0.02). In Gabon, gag and gag-pol cleavage sites were highly polymorphic in protease inhibitor-naive patients harboring non-B HIV-1 strains. In sub-Saharan Africa, further studies are definitively required to better understand the impact of gag mutations among subjects receiving second-line LPV/r-containing regimens (monotherapy or triple combinations). 23707397 Acute inhalation toxicity of ammonia: revisiting the importance of RD50 and LCT01/50 relationships for setting emergency response guideline values. This study examined the acute median lethal concentration (LC(50)) and the non-lethal threshold concentration (LC(01)) of ammonia in male and female Wistar rats nose-only exposed at exposure durations of either 1 or 4 h. Additional attributes characterizing the acute toxicity of inhaled ammonia were determined during a post-exposure period of 2 weeks. The objective of this study is to further refine the methodology applied to derive Emergency Response Planning Guideline (ERPG) values on potent sensory irritants in a controlled rat bioassay. In the more susceptible male rats the 1- and 4-h LC(50) (LC(01)) were 12,303 (10,067) and 4923 (4028) mg/m(3), respectively. At sublethal exposure levels the ventilation of rats was about one third of normal breathing. This change in ventilation and inhalation dosimetry was adjusted for Cxt-dependent lethal endpoints whereas sensory irritation-related phenomena were C-dependently adjusted. In summary, the outcome of this study shows that C- and C × t-dependent causes of toxicity need to be appreciated when extrapolating across species with species-specific inhalation dosimetry. It also appears to be indispensable that each exposure metric must be disentangled when translating C × t-dependent lethality and reflexively-induced, sensation-based C-dependent point of departures. For one hour exposure periods, these PODs were derived to be 1500 and 500 ppm, respectively. 23951157 Light-Intensity Physical Activity and Cardiometabolic Biomarkers in US Adolescents. The minimal physical activity intensity that would confer health benefits among adolescents is unknown. The purpose of this study was to examine the associations of accelerometer-derived light-intensity (split into low and high) physical activity, and moderate- to vigorous-intensity physical activity with cardiometabolic biomarkers in a large population-based sample. The study is based on 1,731 adolescents, aged 12-19 years from the 2003/04 and 2005/06 National Health and Nutrition Examination Survey. Low light-intensity activity (100-799 counts/min), high light-intensity activity (800 counts/min to <4 METs) and moderate- to vigorous-intensity activity (≥4 METs, Freedson age-specific equation) were accelerometer-derived. Cardiometabolic biomarkers, including waist circumference, systolic blood pressure, diastolic blood pressure, HDL-cholesterol, and C-reactive protein were measured. Triglycerides, LDL- cholesterol, insulin, glucose, and homeostatic model assessments of β-cell function (HOMA-%B) and insulin sensitivity (HOMA-%S) were also measured in a fasting sub-sample (n = 807). Adjusted for confounders, each additional hour/day of low light-intensity activity was associated with 0.59 (95% CI: 1.18-0.01) mmHG lower diastolic blood pressure. Each additional hour/day of high light-intensity activity was associated with 1.67 (2.94-0.39) mmHG lower diastolic blood pressure and 0.04 (0.001-0.07) mmol/L higher HDL-cholesterol. Each additional hour/day of moderate- to vigorous-intensity activity was associated with 3.54 (5.73-1.35) mmHG lower systolic blood pressure, 5.49 (1.11-9.77)% lower waist circumference, 25.87 (6.08-49.34)% lower insulin, and 16.18 (4.92-28.53)% higher HOMA-%S. Time spent in low light-intensity physical activity and high light-intensity physical activity had some favorable associations with biomarkers. Consistent with current physical activity recommendations for adolescents, moderate- to vigorous-intensity activity had favorable associations with many cardiometabolic biomarkers. While increasing MVPA should still be a public health priority, further studies are needed to identify dose-response relationships for light-intensity activity thresholds to inform future recommendations and interventions for adolescents. 23720008 Molecular cytogenetic characterisation of Salix viminalis L. using repetitive DNA sequences. Salix viminalis L. (2n = 38) is a diploid dicot species belonging to the Salix genus of the Salicaceae family. This short-rotation woody crop is one of the most important renewable bioenergy resources worldwide. In breeding for high biomass productivity, limited knowledge is available on the molecular cytogenetics of willow, which could be combined with genetic linkage mapping. The present paper describes the adaptation of a fluorescence in situ hybridisation (FISH) protocol as a new approach to analyse the genomic constitution of Salix viminalis using the heterologous DNA clones pSc119.2, pTa71, pTa794, pAs1, Afa-family, pAl1, HT100.3, ZCF1 and the GAA microsatellite marker. Three of the nine probes showed unambiguous signals on the metaphase chromosomes. FISH analysis with the pTa71 probe detected one major 18S-5.8S-26S rDNA locus on the short arm of one chromosome pair; however, the pTa794 rDNA site was not visible. One chromosome pair showed a distinct signal around the centromeric region after FISH with the telomere-specific DNA clone HT100.3. Two chromosome pairs were found to have pAs1 FISH signals, which represent a D-genome-specific insert from Aegilops tauschii. Based on the FISH study, a set of chromosomes with characteristic patterns is presented, which could be used to establish the karyotype of willow species. 23253396 Hidden outpatient oncology clinical nursing minimum data set: findings from an Italian multi-method study. The main aim of this study was to present the hidden Clinical Nursing Minimum Data Set adopted by Italian nurses in outpatient oncology settings. A multi-method study design articulated in three phases was conducted from November 2009 to December 2010. A cross-sectional study design involving outpatient oncology centres located in the 20 Italian regions was undertaken in order to collect structured nursing records used by nurses in the documentation of daily nursing care. An evaluation of the items contained in each nursing record was performed in order to individuate homogeneities. A content analysis of the items was therefore undertaken in order to categorise them in assessment, problems, intervention, and outcomes. A total of 1080 different items from the structured nursing records were counted, comprising on average 29 items (range 8-175; ±40.4) for each record. A total of 330 (30.6%) out of 1080 were categorised as assessment items, 146 (13.5%) as problems, 583 (54.0%) as interventions and 21 (1.9%) as outcomes items. Italian nurses have developed a micro-system Clinical Nursing Minimum Data Set capturing and documenting several types of clinical data, following their implicit representation of what it is important to document: much consideration is given to nursing surveillance/monitoring and to at-risk problems, indicating the importance of the nursing role in the prevention and early recognition of a patient's clinical deterioration. However, there is a need to develop a macro-system national NMDS which will be useful for evaluating nursing outcomes and making decisions on workforce resources. 23870992 Beer classification by means of a potentiometric electronic tongue. In this work, an electronic tongue (ET) system based on an array of potentiometric ion-selective electrodes (ISEs) for the discrimination of different commercial beer types is presented. The array was formed by 21 ISEs combining both cationic and anionic sensors with others with generic response. For this purpose beer samples were analyzed with the ET without any pretreatment rather than the smooth agitation of the samples with a magnetic stirrer in order to reduce the foaming of samples, which could interfere into the measurements. Then, the obtained responses were evaluated using two different pattern recognition methods, principal component analysis (PCA), which allowed identifying some initial patterns, and linear discriminant analysis (LDA) in order to achieve the correct recognition of sample varieties (81.9% accuracy). In the case of LDA, a stepwise inclusion method for variable selection based on Mahalanobis distance criteria was used to select the most discriminating variables. In this respect, the results showed that the use of supervised pattern recognition methods such as LDA is a good alternative for the resolution of complex identification situations. In addition, in order to show an ET quantitative application, beer alcohol content was predicted from the array data employing an artificial neural network model (root mean square error for testing subset was 0.131 abv). 23414292 Bifunctional electrophiles cross-link thioredoxins with redox relay partners in cells. Thioredoxin protects cells against oxidative damage by reducing disulfide bonds in improperly oxidized proteins. Previously, we found that the baker's yeast cytosolic thioredoxin Trx2 undergoes cross-linking to form several protein-protein complexes in cells treated with the bifunctional electrophile divinyl sulfone (DVSF). Here, we report that the peroxiredoxin Tsa1 and the thioredoxin reductase Trr1, both of which function in a redox relay network with thioredoxin, become cross-linked in complexes with Trx2 upon DVSF treatment. Treatment of yeast with other bifunctional electrophiles, including diethyl acetylenedicarboxylate (DAD), mechlorethamine (HN2), and 1,2,3,4-diepoxybutane (DEB), resulted in the formation of similar cross-linked complexes. Cross-linking of Trx2 and Tsa1 to other proteins by DVSF and DAD is dependent on modification of the active site Cys residues within these proteins. In addition, the human cytosolic thioredoxin, cytosolic thioredoxin reductase, and peroxiredoxin 2 form cross-linked complexes to other proteins in the presence of DVSF, although each protein shows different susceptibilities to modification by DAD, HN2, and DEB. Taken together, our results indicate that bifunctional electrophiles potentially disrupt redox homeostasis in yeast and human cells by forming cross-linked complexes between thioredoxins and their redox partners. 23640681 Consistency of dominance rank order: A comparison of David's scores with I&SI and Bayesian methods in macaques. In nonhuman primate social groups, dominance ranks are usually assigned to individuals based on outcomes of dyadic agonistic encounters. Multiple approaches have been used, but currently there is no consensus. One approach, David's Scores (DS), offers dual advantages of yielding cardinal scores that may in turn be used to compute hierarchical steepness. Here we correlate rank orders yielded by DS with those yielded by both the traditionally used I&SI approach and the recently proposed parametric Bayesian approach. We use six datasets for female macaques (three despotic and three tolerant groups), and 90 artificially generated datasets modeling macaque groups. We also use the artificial datasets to determine the impact of three characteristics (group size, interaction frequency, and directional asymmetry of aggression) on the magnitude of correlation coefficients, and assess the relative utility of two indices used to compute DS: Dij versus Pij. DS-based rank orders were strongly positively correlated with those yielded by the other two approaches for five out of the six macaque datasets, and for the majority of artificial datasets. Magnitudes of correlation coefficients were unrelated to group size or interaction frequency, but increased with directional asymmetry, suggesting methodological inconsistencies were more likely when dyads had more frequent reversals in directions of aggression. Finally, rank orders calculated using the Dij and Pij indices were similarly consistent with orders from other methods. We conclude that DS offers consistent estimates of rank orders, except perhaps in groups with very low levels of aggression asymmetry. In such "tolerant" groups, we suggest that the relatively greater methodological variability in rank orders may reflect behavioral characteristics of tolerant groups rather than computational inconsistencies between methods. We hypothesize that this quality may be quantified using posterior probability scores of Bayesian rank orders and may also index macaque social styles. Am. J. Primatol. 75:959-971, 2013. © 2013 Wiley Periodicals, Inc. 23812052 Nursing implications for the lifelong management of tuberous sclerosis complex. Tuberous sclerosis complex (TSC) is a genetic disorder that can affect multiple organ systems, including the brain, heart, skin, kidney, and lung, by formation of benign hamartomas. It can be associated with autism, epilepsy, and other neurocognitive and behavioral disabilities. The incidence of TSC is approximately 1 in 6,000 live births, but it may be underdiagnosed. Mutations to either the TSC1 (coding for hamartin) or TSC2 (coding for tuberin) genes are present in 85% of patients with TSC. The TSC1/TSC2 protein dimer complex is a crucial inhibitory element in the mammalian target of rapamycin (mTOR) complex 1 pathway that regulates cell growth and proliferation. The manifestations of TSC usually require management over the entire life of the patient. Until recently, there were few options, other than surgical removal, for treating the symptoms of TSC related to growth of hamartomas. Increased understanding of the genetic cause of the disease and the underlying dysregulation of the mTOR pathway has led to clinical trials of mTOR inhibitors including sirolimus and everolimus. This article will review the various manifestations of TSC and describe treatment strategies, recommendations for surveillance, and use of mTOR inhibitors in their management. 23871367 Proteomic comparison of the probiotic bacterium Lactobacillus casei Zhang cultivated in milk and soy milk. Soy milk is regarded as a substitute for milk and has become popular in varied diets throughout the world. It has been shown that a newly characterized probiotic bacterium (Lactobacillus casei Zhang) actually grows faster in soy milk than in bovine milk. To elucidate the mechanism involved, we carried out a proteomic analysis to characterize bacterial proteins that varied upon growth in soy milk and bovine milk at 3 different growth phases, and compare their expression under these conditions. A total of 104 differentially expressed spots were identified from different phases using a peptide mass fingerprinting assay. Functional analysis revealed that a major part of these identified proteins is associated with transport and metabolism of carbohydrates, nucleotides, and amino acids as well. The results from our proteomic analysis were clarified by real-time quantitative PCR assay, which showed that Lb. casei Zhang loci involved in purine and pyrimidine biosynthesis were transcriptionally enhanced during growth in soy milk at lag phase (pH 6.4), whereas the loci involved in carbohydrate metabolism were upregulated in bovine milk. Particularly, our results showed that l-glutamine might play an important role in the growth of Lb. casei Zhang in soy milk and bovine milk, perhaps by contributing to purine, pyrimidine, and amino sugar metabolism. 23868438 Hepatocellular Carcinoma Screening Practices in the Department of Veterans Affairs: Findings from a National Facility Survey. Previous studies suggest low rates of hepatocellular carcinoma (HCC) screening in clinical practice. There is little information on the provider- and healthcare-facility-related factors that explain the use of HCC screening. We used data from the 2007 Survey to Assess Hepatitis C Care in Veterans Health Administration that collected information regarding the care of patients with hepatitis C virus (HCV) from 138 of 140 Veterans Administration healthcare facilities nationwide. All providers caring for veterans with HCV were invited to respond. In addition, each facility was asked to identify a lead HCV clinician to respond to facility-specific questions. Our outcome was a response concordant with HCC screening guidelines [HCC screening in patients with cirrhosis or in patients with chronic hepatitis B virus (HBV), and screening every 6 or 12 months]. A total of 268 providers responded (98 % facility participation rate). Of these, 190 respondents (70.9 %) reported recommending HCC screening with guideline-concordant risk groups and frequency. Providers reporting guideline-concordant HCC screening practices were significantly more likely to have expertise in liver disease (MD, gastroenterologists or hepatologists), routinely screen for varices, prescribe HCV treatment, and refer or manage patients with liver transplant. The availability of HCC-specific treatments on site was the main facility factor associated with guideline-concordant HCC screening. Self-reported rates of guideline-concordant HCC screening are considerably higher than those seen in routine VA practice. Provider expertise in liver disease and the perceived availability of HCC treatment including transplantation in the local facility are important factors driving self-reported HCC screening practices. 23318433 The cancer biology of whole-chromosome instability. One form of chromosome instability (CIN), the recurrent missegregation of whole chromosomes during cell division (W-CIN), leads to aneuploidy. Although W-CIN is a hallmark of most cancers, mutations in genes involved in chromosome segregation are exceedingly rare. We discuss an oncogene-induced mitotic stress model that provides a mechanistic framework to explain this paradox. We also review the tumor-promoting and tumor-suppressing consequences of W-CIN. Importantly, we do this in the context of cancer as a complex systemic disease, rather than as a simple linearly progressing disorder that arises from a single abnormal cell population. Accordingly, we highlight the often neglected effects of W-CIN on key non-cell-autonomous entities, such as the immune system and the tumor microenvironment. Distinct tissue-specific susceptibilities to W-CIN-induced tumorigenesis and the clinical implications of W-CIN are also discussed.Oncogene advance online publication, 14 January 2013; doi:10.1038/onc.2012.616. 23702950 Cooperation and the evolutionary ecology of bacterial virulence: The Bacillus cereus group as a novel study system. How significant is social evolution theory for the maintenance of virulence in natural populations? We assume that secreted, distantly acting virulence factors are highly likely to be cooperative public goods. Using this assumption, we discuss and critically assess the potential importance of social interactions for understanding the evolution, diversity and distribution of virulence in the Bacillus cereus group, a novel study system for microbial social biology. We conclude that dynamic equilibria in Cry toxin production, as well as strong spatial structure and population bottlenecks in hosts are the main ecological factors maintaining the cooperative secretion of virulence factors and argue that collective action has contributed to the evolution of narrow host range. Non-linearities in the benefits associated with public goods, as well as the lack of private secretion systems in the Firmicutes may also explain the prevalence and importance of distantly acting virulence factors in B. cereus and its relatives. 23851033 Attitudes and practices regarding resuscitation in emergency departments in Trinidad and Tobago. Ethical issues with regard to resuscitation are increasingly important. Understanding how emergency physicians deal with these problems is essential for the development of policies for resuscitative care. To identify the knowledge, opinions and practices of emergency physicians employed full time in public hospitals in Trinidad and Tobago, with respect to cardiopulmonary resuscitation. To compare the differences in responses between physicians in training and those who were not. In addition, to compare these responses with those expressed in a similar study in the USA in 2007. All emergency physicians (120) who fulfilled the eligibility criteria for the study were asked to record anonymous responses to survey questions about ethical issues regarding resuscitation. Of the 98 respondents, most (79.6%) had been practising emergency medicine for ≤5 years and about 38% had had some training in emergency medicine. Most respondents agreed that survival rates for cardiopulmonary resuscitation (CPR) were poor. However, 41.2% of respondents had performed CPR >10 times in the past 3 years despite expected futility. More participants in the US study than in the local study thought that the existence of an advance directive was important in making decisions about CPR and that legal concerns should not, but do, affect CPR decisions in practice. Local emergency physicians are as affected by legal and ethical CPR issues as are US emergency physicians. Education programmes and policies that deal with these concerns would better assist the emergency physician in dealing with them. 23703672 Synergistic dual activation catalysis by palladium nanoparticles for epoxide ring opening with phenols. Synergistic dual activation catalysis has been devised for epoxide phenolysis wherein palladium nanoparticles induce electrophilic activation via coordination with the epoxide oxygen followed by nucleophilic activation through anion-π interaction with the aromatic ring of the phenol, and water (reaction medium) also renders assistance through 'epoxide-phenol' dual activation. 23514728 Large pre- and postexercise rapid-acting insulin reductions preserve glycemia and prevent early- but not late-onset hypoglycemia in patients with type 1 diabetes. OBJECTIVE To examine the acute and 24-h glycemic responses to reductions in postexercise rapid-acting insulin dose in type 1 diabetic patients. RESEARCH DESIGN AND METHODS After preliminary testing, 11 male patients (24 ± 2 years, HbA1c 7.7 ± 0.3%; 61 ± 3.4 mmol/mol) attended the laboratory on three mornings. Patients consumed a standardized breakfast (1 g carbohydrate ⋅ kg(-1) BM; 380 ± 10 kcal) and self-administered a 25% rapid-acting insulin dose 60 min prior to performing 45 min of treadmill running at 72.5 ± 0.9% VO2peak. At 60 min postexercise, patients ingested a meal (1 g carbohydrate ⋅ kg(-1) BM; 660 ± 21 kcal) and administered a Full, 75%, or 50% rapid-acting insulin dose. Blood glucose concentrations were measured for 3 h postmeal. Interstitial glucose was recorded for 20 h after leaving the laboratory using a continuous glucose monitoring system. RESULTS All glycemic responses were similar across conditions up to 60 min postexercise. After the postexercise meal, blood glucose was preserved under 50%, but declined under Full and 75%. Thence at 3 h, blood glucose was highest under 50% (50% [10.4 ± 1.2] vs. Full [6.2 ± 0.7] and 75% [7.6 ± 1.2 mmol ⋅ L(-1)], P = 0.029); throughout this period, all patients were protected against hypoglycemia under 50% (blood glucose ≤3.9; Full, n = 5; 75%, n = 2; 50%, n = 0). Fifty percent continued to protect patients against hypoglycemia for a further 4 h under free-living conditions. However, late-evening and nocturnal glycemia were similar; as a consequence, late-onset hypoglycemia was experienced under all conditions. CONCLUSIONS A 25% pre-exercise and 50% postexercise rapid-acting insulin dose preserves glycemia and protects patients against early-onset hypoglycemia (≤8 h). However, this strategy does not protect against late-onset postexercise hypoglycemia. 23844237 Systemic inhibition of canonical notch signaling results in sustained callus inflammation and alters multiple phases of fracture healing. The Notch signaling pathway is an important regulator of embryological bone development, and many aspects of development are recapitulated during bone repair. We have previously reported that Notch signaling components are upregulated during bone fracture healing. However, the significance of the Notch pathway in bone regeneration has not been described. Therefore, the objective of this study was to determine the importance of Notch signaling in regulating bone fracture healing by using a temporally controlled inducible transgenic mouse model (Mx1-Cre;dnMAML(f/-)) to impair RBPjκ-mediated canonical Notch signaling. The Mx1 promoter was synthetically activated resulting in temporally regulated systemic dnMAML expression just prior to creation of bilateral tibial fractures. This allowed for mice to undergo unaltered embryological and post-natal skeletal development. Results showed that systemic Notch inhibition prolonged expression of inflammatory cytokines and neutrophil cell inflammation, and reduced the proportion of cartilage formation within the callus at 10 days-post-fracture (dpf) Notch inhibition did not affect early bone formation at 10dpf, but significantly altered bone maturation and remodeling at 20dpf. Increased bone volume fraction in dnMAML fractures, which was due to a moderate decrease in callus size with no change in bone mass, coincided with increased trabecular thickness but decreased connectivity density, indicating that patterning of bone was altered. Notch inhibition decreased total osteogenic cell density, which was comprised of more osteocytes rather than osteoblasts. dnMAML also decreased osteoclast density, suggesting that osteoclast activity may also be important for altered fracture healing. It is likely that systemic Notch inhibition had both direct effects within cell types as well as indirect effects initiated by temporally upstream events in the fracture healing cascade. Surprisingly, Notch inhibition did not alter cell proliferation. In conclusion, our results demonstrate that the Notch signaling pathway is required for the proper temporal progression of events required for successful bone fracture healing. 23717821 Prevalence of and risk factors for chronic bronchitis in a Canadian population: The Canadian Community Health Survey, 2007 to 2008. Chronic bronchitis (CB) represents one of the respiratory disease phenotypes that affect the Canadian health care system significantly. Presently, almost 6.5% of total health care costs are related to respiratory diseases. To determine the prevalence of self-reported CB and associated risk factors in the Canadian general population. Data regarding individuals ≥12 years of age from the Canadian Community Health Survey, 2007 to 2008, were analyzed. CB was determined through self-reported health professional diagnosis. Information regarding covariates of importance, such as demographics, lifestyle variables and socioeconomic status, was obtained. A weighted logistic regression analysis was performed with appropriate technique for clustering effects. RESULT<⁄strong>S: The prevalence of self-reported CB was 2.5%. A greater prevalence of self-reported CB associated with older age, female sex and white ethnic group was found. There were differences in the prevalence of self-reported CB among regions of Canada for household income, educational attainment and smoking status. The results suggest an association between ethnicity and the prevalence of CB. The associations between self-reported CB prevalence and household income, educational attainment and smoking status varied according to region of Canada. 23966628 Vascular Endothelial Growth Factor-D-Mediated Blockade of Regulatory T Cells within Tumors Is Induced by Hematopoietic Stem Cell Transplantation. Lymphopenia-induced homeostatic proliferation of T cells after autologous hematopoietic stem cell transplantation (HSCT) skews the T cell repertoire by engaging tumor-associated Ags, leading to an induction of antitumor immunity. However, how HSCT alters the immunosuppressive microenvironment in the tumors is unknown. In this study, we first analyzed the kinetics of regulatory T cells (Tregs) in the tumors after syngeneic HSCT. Unexpectedly, the frequency of CD4(+) cells expressing Foxp3 was increased in the spleens, whereas the frequency was clearly decreased in the tumors after HSCT. The origin of reconstituted CD4(+) and Foxp3(+) cells in the tumors was mainly from the expansion of transferred splenic T cells. Then, to examine the mechanism of Treg suppression after HSCT, we isolated CD11c(+) cells from tumors. A large amount of Treg-inhibitory cytokine IL-6 was secreted from the CD11c(+) cells in the tumors, but not in the spleens in the recipient mice. Furthermore, to understand what factor affects the activity of CD11c(+) cells in the tumors after HSCT, we analyzed the expression of various cytokines/chemokines with mouse cytokine Ab arrays, and noticed that VEGF-D concentration was increased in the tumors in the early period after HSCT. The CD11c(+) cells produced IL-6 in response to VEGF-D stimulation, and an administration of VEGF receptor-3 neutralizing Ab significantly suppressed the production of IL-6 from CD11c(+) cells accompanied with the increase of Tregs in the tumors of HSCT recipients. Autologous HSCT creates an environment that strongly supports the enhancement of antitumor immunity in reconstituted lymphopenic recipients through the suppression of Tregs. 23942111 Bilateral Asymmetry of Humeral Torsion and Length in African Apes and Humans. Few studies have directly compared human and African ape upper limb skeletal asymmetries despite the potential such comparisons have for understanding the origins of functional lateralization in humans and non-human primates. Here, we report the magnitude and direction of asymmetries in humeral torsion and humeral length in paired humeri of 40 Gorilla gorilla, 40 Pan troglodytes and 40 Homo sapiens. We test whether absolute and directional asymmetries differ between measurements, species and sexes. Our results show that humans are unique in being lateralized to the right for both measurements, consistent with human population-level handedness patterns, while apes show no significant directionality at the species level in either measurement. However, absolute torsion asymmetries in apes occur in the same magnitude as in humans, suggesting the existence of functional lateralization at the individual level. © 2013 S. Karger AG, Basel. 23541928 Osteochondral tissue regeneration using a bilayered composite hydrogel with modulating dual growth factor release kinetics in a rabbit model. Biodegradable oligo(poly(ethylene glycol) fumarate) (OPF) composite hydrogels have been investigated for the delivery of growth factors (GFs) with the aid of gelatin microparticles (GMPs) and stem cell populations for osteochondral tissue regeneration. In this study, a bilayered OPF composite hydrogel that mimics the distinctive hierarchical structure of native osteochondral tissue was utilized to investigate the effect of transforming growth factor-β3 (TGF-β3) with varying release kinetics and/or insulin-like growth factor-1 (IGF-1) on osteochondral tissue regeneration in a rabbit full-thickness osteochondral defect model. The four groups investigated included (i) a blank control (no GFs), (ii) GMP-loaded IGF-1 alone, (iii) GMP-loaded IGF-1 and gel-loaded TGF-β3, and (iv) GMP-loaded IGF-1 and GMP-loaded TGF-β3 in OPF composite hydrogels. The results of an in vitro release study demonstrated that TGF-β3 release kinetics could be modulated by the GF incorporation method. At 12weeks post-implantation, the quality of tissue repair in both chondral and subchondral layers was analyzed based on quantitative histological scoring. All groups incorporating GFs resulted in a significant improvement in cartilage morphology compared to the control. Single delivery of IGF-1 showed higher scores in subchondral bone morphology as well as chondrocyte and glycosaminoglycan amount in adjacent cartilage tissue when compared to a dual delivery of IGF-1 and TGF-β3, independent of the TGF-β3 release kinetics. The results suggest that although the dual delivery of TGF-β3 and IGF-1 may not synergistically enhance the quality of engineered tissue, the delivery of IGF-1 alone from bilayered composite hydrogels positively affects osteochondral tissue repair and holds promise for osteochondral tissue engineering applications. 22898496 Training your brain: Do mental and physical (MAP) training enhance cognition through the process of neurogenesis in the hippocampus? New neurons are produced each day in the hippocampus through the process of neurogenesis. Both mental and physical training can modify this process by increasing the number of new cells that mature into functional neurons in the adult brain. However, the mechanisms whereby these increases occur are not necessarily the same. Physical activity, especially aerobic exercise greatly increases the number of new neurons that are produced in the hippocampal formation. In contrast, mental training via skill learning increases the numbers that survive, particularly when the training goals are challenging. Both manipulations can increase cognitive performance in the future, some of which are reportedly mediated by the presence of new neurons in the adult hippocampus. Based on these data, we suggest that a combination of mental and physical training, referred to here as MAP training, is more beneficial for neuronal recruitment and overall mental health than either activity alone. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23946845 Mechanistic studies on the CAN-mediated intramolecular cyclization of δ-aryl-β-dicarbonyl compounds. The synthesis of 2-tetralones through the cyclization of δ-aryl-β-dicarbonyl substrates by using CAN is described. Appropriately functionalized aromatic substrates undergo intramolecular cyclizations generating 2-tetralone derivatives in moderate to good yields. DFT computational studies indicate that successful formation of 2-tetralones from δ-aryl-β-dicarbonyl radicals is dependent on the stability of the subsequent cyclohexadienyl radical intermediates. Furthermore, DFT computational studies were used to rationalize the observed site selectivity in the 2-tetralone products. 23628381 Surgical pathologic features of cerebral cortical lesions taken from 600 patients with intractable epilepsy. Objectives: To determine the scope of histopathological variation in lesions responsible for epileptogenesis, I retrospectively reviewed the features of surgical specimens taken consecutively from 600 patients with intractable epilepsy. Methods: The patients were divided into three groups on the basis of age at seizure onset: 94 patients with infantile onset (before 1year of age), 307 patients with juvenile onset (between 1 and 12years of age), and 199 patients with adolescent/adult onset (at 13years of age or beyond). Histological and immunohistochemical evaluations of the surgical specimens were performed. Results: In the infant group, seizure duration was significantly shorter than in the other groups, and malformations caused by abnormalities of cortical development, including focal cortical dysplasia (FCD) type IIa/b, tuberous sclerosis, hemimegalencephaly, and polymicrogyria were predominant, whereas in the juvenile and adolescent/adult groups, other lesions such as hippocampal sclerosis (HS), tumors, FCD type I, and vascular lesions were frequently observed. For patients with HS, seizure duration in the juvenile group was significantly longer than in the adolescent/adult group. FCD type IIIa was noted in nearly half of patient with HS in both juvenile and adolescent/adult groups. The causative tumors included dysembryoplastic neuroepithelial tumors, gangliogliomas, astrocytomas, and other glioneuronal and glial tumors. Conclusion: Various histopathological entities and types, showing clear predominance depending on the age at seizure onset, were observed in patients with epilepsy. These features appear to provide information on the pathomechanisms of the lesions and their clinical relevance in affected patients. 23938198 Ca(2+) released from calcium alginate gels can promote inflammatory responses in vitro and in vivo. In general, alginate hydrogels are considered to be biologically inert and are commonly used for biomedical purposes that require minimum inflammation. However, Ca(2+), which is commonly used to crosslink alginate, is a critical second messenger in immune cell signaling, and little has been done to understand its effect on immune cell fate when delivered as a component of alginate gels. We found that dendritic cells encapsulated in Ca(2+)-crosslinked alginate (calcium alginate) secreted at least fivefold more of the inflammatory cytokine IL-1β when compared to dendritic cells (DCs) encapsulated in agarose and collagen gels, as well as DCs plated on tissue-culture polystyrene (TCPS). Plating cells on TCPS with the alginate polymer could not reproduce these results, whereas culturing DCs on TCPS with increasing concentrations of Ca(2+) increased IL-1β, MHC class II and CD86 expression in a dose-dependent manner. In agreement with these findings, calcium alginate gels induced greater maturation of encapsulated DCs compared to barium alginate gels. When injected subcutaneously in mice, calcium alginate gels significantly upregulated IL-1β secretion from surrounding tissue relative to barium alginate gels, and similarly, the inflammatory effects of LPS were enhanced when it was delivered from calcium alginate gels rather than barium alginate gels. These results confirm that the Ca(2+) used to crosslink alginate gels can be immunostimulatory and suggest that it is important to take into account Ca(2+)'s bioactive effects on all exposed cells (both immune and non-immune) when using calcium alginate gels for biomedical purposes. This work may strongly impact the way people use alginate gels in the future as well as provide insights into past work utilizing alginate gels. 22922246 The value of selected in vitro and in silico methods to predict acute oral toxicity in a regulatory context: Results from the European Project ACuteTox. ACuteTox is a project within the 6th European Framework Programme which had as one of its goals to develop, optimise and prevalidate a non-animal testing strategy for predicting human acute oral toxicity. In its last 6months, a challenging exercise was conducted to assess the predictive capacity of the developed testing strategies and final identification of the most promising ones. Thirty-two chemicals were tested blind in the battery of in vitro and in silico methods selected during the first phase of the project. This paper describes the classification approaches studied: single step procedures and two step tiered testing strategies. In summary, four in vitro testing strategies were proposed as best performing in terms of predictive capacity with respect to the European acute oral toxicity classification. In addition, a heuristic testing strategy is suggested that combines the prediction results gained from the neutral red uptake assay performed in 3T3 cells, with information on neurotoxicity alerts identified by the primary rat brain aggregates test method. Octanol-water partition coefficients and in silico prediction of intestinal absorption and blood-brain barrier passage are also considered. This approach allows to reduce the number of chemicals wrongly predicted as not classified (LD50>2000mg/kg b.w.). 23435944 Multiple biological properties of macelignan and its pharmacological implications. Macelignan found in the nutmeg mace of Myristica fragrans obtains increasing attention as a new avenue in treating various diseases. Macelignan has been shown to possess a spectrum of pharmacological activities, including anti-bacterial, anti-inflammatory, anti-cancer, anti-diabetes, and hepatoprotective activities; recently, it has also been shown to have neuroprotective activities. This review summarizes the current research on the biological effects of macelignan derived from M. fragrans, with emphasis on the importance in understanding and treating complex diseases such as cancer and Alzheimer's disease. 23312278 Tipping the energy balance toward longevity. AMPK is a cellular energy sensor conserved across eukaryotes that in C. elegans prolongs life span and mimics dietary restriction. Stenesen and colleagues (2012) activate AMPK both directly and indirectly by altering AMP biosynthesis to slow aging in Drosophila, highlighting AMPK as a conserved life span modulator that links energy sensing to longevity. 23965389 Enteric methane production from beef cattle that vary in feed efficiency. We hypothesized that CH4 production will decrease with increased feed efficiency. Two experiments were conducted to determine CH4 production of cattle that differed in feed efficiency. Cattle in both studies were selected from larger contemporary groups. Animals furthest from the confidence ellipse that resulted from regressing BW gain on DMI were selected. In the first experiment, 113 crossbred steers were evaluated for feed efficiency for 64 d. Steers were 355 ± 1 d of age and weighed 456 ± 10 kg when they began the study. Steers were fed a ration that consisted of (dry matter basis) 82.8% corn, 12.8% corn silage, and 4.5% supplement (contains 0.065% monensin, 32% CP (28% NPN), 7.5% Ca, 0.8% P, 4.8% NaCl 1.8% K, and 55,116 IU/kg Vitamin A). Thirty-seven steers were selected to measure CH4 production. In the second experiment, 197 heifers were evaluated for feed efficiency for 64 d. Heifers were 286 ± 1 d of age and weighed 327 ± 2 kg when they began the study. Heifers were fed a ration that consisted of (dry matter basis) 60% corn silage, 30% alfalfa hay, and 10% wet distillers grains with solubles. Forty-seven heifers were selected to measure CH4 production. Methane production was measured with respiration calorimeters. In both experiments, cattle had ad libitum access to feed, and DMI consumed during the 24 h before CH4 production was measured. Methane production was collected for a 6-h period on untrained cattle; consequently, methane production is not a quantitative measure of daily methane production rather it is an index value to rank cattle. Multiple regression analysis was used to determine the relationship between either BW gain:DMI ratio or residual feed intake (RFI) on CH4 production after adjusting for the previous 24 h DMI. In the steers, gain:DMI ratio and previous 24 h feed intake accounted for little of the variance in CH4 production (R(2) = 0.009), nor did RFI and previous 24 h feed intake (R(2) = 0.001). In the heifers, the gain:DMI ratio contributed 28% toward the variance estimate and previous 24-h DMI contributed 72% toward the variance estimate (R(2) = 0.31). As the gain:DMI ratio increased daily CH4 production increased. The regression coefficient for RFI (P = 0.45) did not differ from zero for CH4 production. Our study does not support our original hypothesis that CH4 production decreases with increased feed efficiency, and suggests that CH4 production may increase with increased feed efficiency. 23872018 Vibrational spectral investigation and natural bond orbital analysis of pharmaceutical compound 7-Amino-2,4-dimethylquinolinium formate - DFT approach. The molecular geometry, the normal mode frequencies and corresponding vibrational assignments, natural bond orbital analysis and the HOMO-LUMO analysis of 7-Amino-2,4-dimethylquinolinium formate in the ground state were performed by B3LYP levels of theory using the 6-31G(d) basis set. The optimised bond lengths and bond angles are in good agreement with the X-ray data. The vibrational spectra of the title compound which is calculated by DFT method, reproduces vibrational wave numbers and intensities with an accuracy which allows reliable vibrational assignments. The possibility of N-H⋯O hydrogen bonding was identified using NBO analysis. Natural bond orbital analysis confirms the presence of intramolecular charge transfer and the hydrogen bonding interaction. 23818492 Identifying driver mutations from sequencing data of heterogeneous tumors in the era of personalized genome sequencing. Distinguishing driver mutations from passenger mutations is critical to the understanding of the molecular mechanisms of carcinogenesis and for identifying prognostic and diagnostic markers as well as therapeutic targets. We reviewed the current approaches and software for identifying driver mutations from passenger mutations including both biology-based approaches and machine-learning-based approaches. We also reviewed approaches to identify driver mutations in the context of pathways or gene sets. Finally, we discussed the challenges of predicting driver mutations considering the complexities of inter- and intra-tumor heterogeneity as well as the evolution and progression of tumors. 23912782 The interaction of influenza H5N1 viral hemagglutinin with sialic acid receptors leads to the activation of human γδ T cells. Highly pathogenic avian influenza H5N1 epidemics are a significant public health hazard. Genetically engineered H5N1 viruses with mammalian transmission activity highlight the potential risk of a human influenza H5N1 pandemic. Understanding the underlying principles of the innate immune system in response to influenza H5N1 viruses will lead to improved prevention and control of these potentially deadly viruses. γδ T cells act as the first line of defense against microbial infection and help initiate adaptive immune responses during the early stages of viral infection. In this study, we investigated the molecular mechanisms of γδ T cells in response to influenza H5N1 viral infection. We found that recombinant hemagglutinin (rHA) derived from three different strains of influenza H5N1 viruses elicited the activation of γδ T cells cultured in peripheral blood mononuclear cells (PBMCs). Both the cell surface expression of CD69, an early activation marker on γδ T cells, and the production of interferon-γ (IFN-γ) were significantly increased. Notably, the rHA protein-induced γδ T-cell activation was not mediated by TCRγδ, NKG2D or pattern recognition receptors (PRRs) or NKp46 receptors. The interaction of rHA proteins with sialic acid receptors may play a critical role in γδ T-cell activation. Our data may provide insight into the mechanisms underlying γδ T-cell activation in response to infection with H5N1 viruses.Cellular & Molecular Immunology advance online publication, 5 August 2013; doi:10.1038/cmi.2013.26. 23689999 Just like family: fictive kin relationships in the Netherlands. Objectives. This study examined the extent to which older adults in the Netherlands include a nonrelative as part of their family (create fictive kin), and whether this process is similar in other age groups. It assessed the importance of absence of close family ties and the experience of divorce in the family network for the creation of fictive kin. Method. Using data from the Netherlands Kinship Panel Study, logistic regression models for the different age groups tested the importance of absence of primary family relationships and the experience of divorce in the family among three age groups (18-40, 41-60, 61-79, N = 6,571). Prevalence of fictive kin relationships was higher in older age groups. Both the absence of close family relationships and the experience of divorce within the family were related to having fictive kin, although the latter was only found in the youngest age group. For older adults never having married, being widowed or divorced were important predictors of having fictive kin relationships. Discussion. The study provides support for the idea that the creation of fictive kin is a form of substitution for absent family members and shows that older adults in the Netherlands are active agents in the construction of their family network. 23846982 Sclerotherapy for Intra-abdominal Lymphatic Malformations in Children. Purpose Sclerotherapy is well described as a treatment for lymphatic malformations (LMs) in the head, neck, and other soft tissue areas. This study aims to evaluate the effectiveness of intralesional sclerotherapy as primary treatment for intra-abdominal LMs in children.Methods We conducted a retrospective review from 2008 to 2012 of all children with intra-abdominal LMs treated with sclerotherapy at our tertiary children's hospital.Results In this study, five patients underwent sclerotherapy as a primary intervention for intra-abdominal LMs. The ages of these patients ranged from 12 to 52 months at the time of initial treatment. Doxycycline was used as the primary sclerotherapy agent. The patients required between three and five (median 3) sclerosing treatments over a period that ranged from 5 to 366 days (median 28). No child has required an operation and all LMs have decreased in size. The median decease in maximum diameter is 62% (21-67). Complete resolution has not been attained but all have experienced symptomatic relief with a median follow-up of 3 (1-24) months.Conclusions Sclerotherapy is an effective first-line therapy for intra-abdominal LMs in the pediatric population and should be considered when treating these difficult lesions. 23933617 Carbon nanotubes in hyperthermia therapy. Thermal tumor ablation therapies are being developed with a variety of nanomaterials, including single- and multiwalled carbon nanotubes. Carbon nanotubes (CNTs) have attracted interest due to their potential for simultaneous imaging and therapy. In this review, we highlight in vivo applications of carbon nanotube-mediated thermal therapy (CNMTT) and examine the rationale for use of this treatment in recurrent tumors or those resistant to conventional cancer therapies. Additionally, we discuss strategies to localize and enhance the cancer selectivity of this treatment and briefly examine issues relating the toxicity and long term fate of CNTs. 23915819 Cytotoxicity and induction of DNA double-strand breaks by components leached from dental composites in primary human gingival fibroblasts. The public interest steadily increases in the biological adverse effects caused by components released from resin-based dental restorations. In this study, the cytotoxicity and the genotoxicity were investigated of following released components from dental resin restorations in human gingival fibroblasts (HGF): tetraethyleneglycol dimethacrylate (TEEGDMA), neopentylglycol dimethacrylate (Neopen), diphenyliodoniumchloride (DPIC), triphenyl-stibane (TPSB) and triphenylphosphane (TPP). XTT based cell viability assay was used for cytotoxicity screening of substances. γ-H2AX assay was used for genotoxicity screening. In the γ-H2AX assay, HGFs were exposed to the substances for 6h. Induced foci represent double DNA strand breaks (DSBs), which can induce ATM-dependent phosphorylation of the histone H2AX. Cell death effects (apoptosis and necrosis), induced by the substances were visually tested by the same investigator using the fluorescent microscope. All tested substances induced a dose-dependent loss of viability in HGFs. Following toxicity ranking among the substances at EC50-concentration were found in the XTT assay (mM, mean±SEM; n=5): DPIC>Neopen>TPSB>TPP>TEEGDMA. DSB-foci per HGF-cell were obtained, when HGFs were exposed to the EC50-concentration of each substance in the following order (mean±SEM; n=3): DPIC>Neopen>TPSB>TPP>TEEGDMA. Multi-foci cells (cells that contain more than 40 foci each) in 80 HGF-cells at EC50-concentration of each substance were found as follow (mean±SEM; n=3): DPIC>Neopen>TPP>TPSB>TEEGDMA. Cell apoptosis contained in each substance at EC50-concentration in the following order (mean±SEM; n=3): DPIC>Neopen>TPSB>TPP >TEEGDMA. Cell necrosis contained in each substance at EC50-concentration in the following order (mean±SEM; n=3): DPIC>Neopen>TPSB>TPP>TEEGDMA. Leached components from dental resin restorations can induce DNA DSBs and cell death effects in HGFs. 23847620 Autophagy, a novel pathway to regulate calcium mobilization in T lymphocytes. The T lymphocyte response initiates with the recognition of MHC/peptides on antigen presenting cells by the T cell receptor (TCR). After the TCR engagement, the proximal signaling pathways are activated for downstream cellular events. Among these pathways, the calcium-signaling flux is activated through the depletion of endoplasmic reticulum (ER) calcium stores and plays pivotal roles in T cell proliferation, cell survival, and apoptosis. In studying the roles of macroautophagy (hereafter referred to as autophagy) in T cell function, we found that a pathway for intracellular degradation, autophagy, regulates calcium signaling by developmentally maintaining the homeostasis of the ER. Using mouse genetic models with specific deletion of autophagy-related genes in T lymphocytes, we found that the calcium influx is defective and the calcium efflux is increased in autophagy-deficient T cells. The abnormal calcium flux is related to the expansion of the ER and higher calcium stores in the ER. Because of this, treatment with the ER sarco/ER Ca(2+)-ATPase pump inhibitor, thapsigargin, rescues the calcium influx defect in autophagy-deficient T cells. Therefore, autophagy regulates calcium mobilization in T lymphocytes through ER homeostasis. 23900718 Accounting for baseline differences and measurement error in the analysis of change over time. If change over time is compared in several groups, it is important to take into account baseline values so that the comparison is carried out under the same preconditions. As the observed baseline measurements are distorted by measurement error, it may not be sufficient to include them as covariate. By fitting a longitudinal mixed-effects model to all data including the baseline observations and subsequently calculating the expected change conditional on the underlying baseline value, a solution to this problem has been provided recently so that groups with the same baseline characteristics can be compared. In this article, we present an extended approach where a broader set of models can be used. Specifically, it is possible to include any desired set of interactions between the time variable and the other covariates, and also, time-dependent covariates can be included. Additionally, we extend the method to adjust for baseline measurement error of other time-varying covariates. We apply the methodology to data from the Swiss HIV Cohort Study to address the question if a joint infection with HIV-1 and hepatitis C virus leads to a slower increase of CD4 lymphocyte counts over time after the start of antiretroviral therapy. Copyright © 2013 John Wiley & Sons, Ltd. 23875866 One-year outcome of frailty indicators and activities of daily living following the randomised controlled trial; "Continuum of care for frail older people" Background; The intervention; "Continuum of Care for Frail Older People", was designed to create an integrated continuum of care from the hospital emergency department through the hospital and back to the older person's own home. The aim of this study is to evaluate the effects of the intervention on functional ability in terms of activities of daily living (ADL). Methods; The study is a non-blinded controlled trial with participants randomised to either the intervention group or a control group with follow-ups at three-, six- and 12 months. The intervention involved collaboration between a nurse with geriatric competence at the emergency department, the hospital wards and a multi-professional team for care and rehabilitation of the older people in the municipality with a case manager as the hub. Older people who sought care at the emergency department at Sahlgrenska University Hospital/Molndal and who were discharged to their own homes in the municipality of Molndal, Sweden were asked to participate. Inclusion criteria were age 80 and older or 65 to 79 with at least one chronic disease and dependent in at least one ADL. Analyses were made on the basis of the intention-to-treat principle. Outcome measures were ADL independence and eight frailty indicators. These were analysed, using Chi-square and odds ratio (OR). Results; A total of 161 participated in the study, 76 persons allocated to the control group and 85 to the intervention group were analysed throughout the study. There were no significant differences between the groups with regards to change in frailty compared to baseline at any follow-up. At both the three- and twelve-month follow-ups the intervention group had doubled their odds for improved ADL independence compared to the control (OR 2.37, 95% CI; 1.20 - 4.68) and (2.04, 95% CI; 1.03 - 4.06) respectively. At six months the intervention group had halved their odds for decreased ADL independence (OR 0.52, 95% CI; 0.27 - 0.98) compared to the control group. Conclusions; The intervention has the potential to reduce dependency in ADLs, a valuable benefit both for the individual and for society. Trial registration; ClinicalTrials.gov: NCT01260493 Keywords; integrated care, health care chain, rehabilitation, independence, aging in place, frail older people. 23949596 A Case of Spontaneous Extracranial Epidural Emphysema. Objective: To report a rare case of spontaneous extracranial epidural emphysema. Clinical Presentation and Intervention: An 18-year-old woman with a recent diagnosis of squamous cell carcinoma of the esophagus presented with acute onset of cough, dyspnea and subcutaneous emphysema. An esophageal endoscopy revealed an ulcerative lesion in the upper third of the esophagus that was diagnosed as squamous cell carcinoma. A computed tomographic scan of the chest showed spinal epidural emphysema in addition to pneumomediastinum and pneumoperitoneum. A few days later, the patient died of aspiration pneumonia and persistent epidural emphysema. Conclusion: The spontaneous extracranial epidural emphysema in our case resulted from a bout of cough with tracking of air from the pneumomediastinum through the emaciated tissue planes into the epidural space. © 2013 S. Karger AG, Basel. 23880856 MicroRNA-27a Is Induced by Leucine and Contributes to Leucine-Induced Proliferation Promotion in C2C12 Cells. Leucine, a branched chain amino acid, is well known to stimulate protein synthesis in skeletal muscle. However, the role of leucine in myoblast proliferation remains unclear. In this study, we found that leucine could promote proliferation of C2C12 cells. Moreover, expressions of miR-27a and myostatin (a bona fide target of miR-27a) were upregulated and downregulated, respectively, following leucine treatment. We also found that miR-27a loss-of-function by transfection of a miR-27a inhibitor suppressed the promotion of myoblast proliferation caused by leucine. Our results suggest that miR-27a is induced by leucine and contributes to leucine-induced proliferation promotion of myoblast. 23760855 Are there atheists in foxholes? Combat intensity and religious behavior. After battle, the moral and mortality stresses influence different soldiers in different ways. Using two large-scale surveys of World War II veterans, this research investigates the impact of combat on religiosity. Study 1 shows that as combat became more frightening, the percentage of soldiers who reported praying rose from 42 to 72%. Study 2 shows that 50 years later, many soldiers still exhibited religious behavior, but it varied by their war experience. Soldiers who faced heavy combat (vs. no combat) attended church 21% more often if they claimed their war experience was negative, but those who claimed their experience was positive attended 26% less often. The more a combat veteran disliked the war, the more religious they were 50 years later. While implications for counselors, clergy, support groups, and health practitioners are outlined, saying there are no atheists in foxholes may be less of an argument against atheism than it is against foxholes. 23955724 Relationship between mean platelet volume and retinopathy in patients with type 2 diabetes mellitus. To evaluate the effect of mean platelet volume (MPV) on diabetic retinopathy in patients with type 2 diabetes mellitus. In this study, ocular findings and MPV values were retrospectively reviewed in 192 patients with type 2 diabetes mellitus. The patients were classified into four groups according to ocular findings, as follows: group 1, diabetic patients without diabetic retinopathy (n = 70); group 2, diabetic patients with non-proliferative diabetic retinopathy (n = 64); group 3, diabetic patients with proliferative diabetic retinopathy (n = 58); and group 4, healthy controls (n = 100). A significant difference was found in MPV values between groups 2 and 4 (P = 0.001), between groups 3 and 4 (P = 0.001), and between groups 1 and 4 (P = 0.004). No significant difference was found in MPV values between groups 1 and 2 (P = 0.241) and between groups 2 and 3 (P = 0.460); whereas there was a statistically significant difference between groups 1 and 3 (P = 0.015). The three diabetic groups (groups 1, 2, and 3) were compared with each other. While there was a statistically significant difference between groups 1 and 3 (P = 0.015), there was no significance between groups 2 and 3 (P = 0.46), and between group 1 and 2 (P = 0.241). Logistic regression analysis found a 1.40-fold increase in the risk of retinopathy development (OR: 1.404; P = 0.002) and a 1.46-fold increase in the risk of proliferative diabetic retinopathy (OR: 1.466; P = 0.002) as the MPV value increased. In diabetic patients, the risk of retinopathy development increases with higher MPV values. 23770889 Effects of a trampoline exercise intervention on motor performance and balance ability of children with intellectual disabilities. Balance and motor impairments are most evident among inactive individuals with ID that might be particularly susceptible to a loss of basic functioning and further limit the person's autonomy in activities of daily living. The aim of the study was to assess the effect of a 12-week trampoline exercise intervention program on motor and balance ability of school aged children with intellectual disability (ID). Eighteen healthy schools aged children (mean age=10.3±1.6 years) with moderate ID were assigned either to an experimental group (n=9) or a control group (n=9). The experiment group attended a 12 weeks trampoline training intervention program consisting of daily individualized 20-min sessions, while the control group followed the regular school schedule. Balance was assessed using three tasks of increased difficulty (double-leg stance with eyes opened or closed, and one-leg stance with eyes opened) performed while standing on an electronic pressure platform (EPS). Motor performance of all participants was tested using sit and reach test and long and vertical jump tests all derived from the Eurofit Test Battery of physical fitness. Trampoline intervention resulted in significant improvements of participants' performance in all motor and balance tests. In conclusion, trampoline training can be an effective intervention for improving functional outcomes and can be recommended as an alternative mode of physical activity programming for improving balance and motor performance. Furthermore, it also supports the idea that individuals with ID require enjoyable and interesting intervention programs such as the trampoline program used in this study so as to remain active and consequently to facilitate their overall development and promote a more active and healthier way of life. 23812114 Comparative study of pregnancy outcomes between day 3 embryo transfer and day 5 blastocyst transfer in patients with progesterone elevation. To explore the effects of progesterone (P) elevation on pregnancy outcomes of day 3 embryo and day 5 blastocyst transfer. Clinical outcomes (pregnancy and ectopic pregnancy rates) following day 3 embryo and day 5 blastocyst transfer cycles were retrospectively analysed. Day 3 embryo and day 5 blastocyst transfer cycles were divided into normal P level (P ≤ 1.5 ng/ml) and P elevation group (P > 1.5 ng/ml), based on the serum P level on the day of human chorionic gonadotropin (hCG) administration. A total of 2868 cycles were analysed. In day 3 embryo transfer cycles (n = 2345), the clinical pregnancy rate was significantly higher in the normal P level group compared with the P elevation group (55.4% versus 46.7%, respectively) and the ectopic pregnancy rate was significantly lower in the normal P level group compared with the P elevation group (2.8% versus 7.9%, respectively). In day 5 blastocyst transfer cycles (n = 523), there were no significant differences in the clinical pregnancy and ectopic pregnancy rates between the two groups, based on the P level. These preliminary findings suggest that day 5 blastocyst transfer should be adopted for patients with P elevation on the day of hCG administration. 23696645 Redox Proteomics Uncovers Peroxynitrite-sensitive Proteins That Help Escherichia coli to Overcome Nitrosative Stress. Peroxynitrite is a highly reactive chemical species with antibacterial properties that are synthesized in immune cells. In a proteomic approach, we identified specific target proteins of peroxynitrite-induced modifications in Escherichia coli. Although peroxynitrite caused a fairly indiscriminate nitration of tyrosine residues, reversible modifications of protein thiols were highly specific. We used a quantitative redox proteomic method based on isotope-coded affinity tag chemistry and identified four proteins consistently thiol-modified in cells treated with peroxynitrite as follows: AsnB, FrmA, MaeB, and RidA. All four were required for peroxynitrite stress tolerance in vivo. Three of the identified proteins were modified at highly conserved cysteines, and MaeB and FrmA are known to be directly involved in the oxidative and nitrosative stress response in E. coli. In in vitro studies, we could show that the activity of RidA, a recently discovered enamine/imine deaminase, is regulated in a specific manner by the modification of its single conserved cysteine. Mutation of this cysteine 107 to serine generated a constitutively active protein that was not susceptible to peroxynitrite. 23194830 Effect of Two Weeks of rTMS on Brain Activity in Healthy Subjects During an n-Back Task: A Randomized Double Blind Study. Repetitive transcranial magnetic stimulation (rTMS) has shown significant efficiency in the treatment of several psychiatric disorders. In depressive disorders, the dorsolateral prefrontal cortex (DLPFC) is the main target for rTMS, but the effects of this stimulation on cognitive functions and their neural correlates are not well known. Previous works have established that the left DLPFC is reliably activated during the n-back working memory task. The aim of this randomized double-blind study was to determine the impact of rTMS applied to the DLPFC on brain activity during an n-back task in healthy subjects. After randomization, twenty subjects received either active treatment (10 sessions; 1 session a day; frequency = 10 Hz; intensity = 110% of motor threshold) or placebo treatment (sham coil). Subjects performed an n-back task during two functional magnetic resonance imaging sessions (one before stimulation, and one after 10 active or sham rTMS sessions). No significant changes, neither in mood nor in performance in the n-back task, were shown. A significant group-by-time interaction effect was found in the bilateral middle frontal gyrus and in the left caudate nucleus. These results show that rTMS applied on the left DLPFC had close and remote effects on brain areas involved in working memory. 23845964 Chromatin tandem affinity purification sequencing. Chromatin immunoprecipitation coupled with ultra-high-throughput sequencing (ChIP-seq) is a widely used method for mapping the interactions of proteins with DNA. However, the requirements for ChIP-grade antibodies impede wider application of this method, and variations in results can be high owing to differences in affinity and cross-reactivity of antibodies. Therefore, we developed chromatin tandem affinity purification (ChTAP) as an effective alternative to ChIP. Through the use of affinity tags and reagents that are identical for all proteins investigated, ChTAP enables one to directly compare the binding between different transcription factors and to directly assess the background in control experiments. Thus, ChTAP-seq can be used to rapidly map the genome-wide binding of multiple DNA-binding proteins in a wide range of cell types. ChTAP can be completed in 3-4 d, starting from cross-linking of chromatin to purification of ChIP DNA. 23879739 Cost of illness of the stomach cancer in Japan - a time trend and future projections. Stomach cancer is one of the leading causes of cancer deaths in Japan. The objectives of this study were to estimate and project the economic burden associated with stomach cancer in Japan, and to identify the key factors that drive the economic burden of stomach cancer. We calculated Cost of illness (COI) of 1996, 2002, 2008, 2014 and 2020 by using government office statistics and the COI method. We calculated direct cost and indirect cost (morbidity cost and mortality cost), and estimated the COI by summing them up. The number of deaths remained at approximately 50,000 in 1996-2008. COI was in downward trend from 1,293.5 billion yen in 1996 to 1,114.2 billion yen in 2008. Morbidity cost was 85.6 billion yen and 54.0 billion yen, mortality cost was 972.3 billion yen and 806.4 billion yen, and mortality cost per person was 19.4 million yen and 16.1 million yen in 1996 and 2008, respectively. Decrease of mortality cost that accounted for a large part of the COI (72.4% in 2008) was the major contributing factor. COI is predicted to decrease if the trend of health related indicators continues (442.8-1,056.1 billion yen depending on the model in 2020). Mortality cost per person is also predicted to decrease (9.5-12.5 million yen depending on the model in 2020). If the trend of health related indicators continues, it is estimated that COI of stomach cancer would decrease. "Aging", "change of the healthcare providing system" and "new medical technology" are considered as contributing factors of COI. 23793093 Effect of long term dietary supplementation with plant extract on carcass characteristics meat quality and oxidative stability in pork. The effects of dietary supplementation in pigs with plant extract (PE) from Lippia spp., titrated in verbascoside (5mg/kg feed), from weaning to slaughter (166days), on carcass characteristics, meat quality, collagen characteristics, oxidative stability and sensory attributes of Longissimus dorsi (LD) muscle were examined. Ten pigs per treatment were slaughter at a live weight of 109.5±1.4kg. No influence on carcass characteristics, LD meat quality parameters and collagen characteristics were observed. Dietary PE increased (P<0.001) α-tocopherol levels in LD muscle. Raw LD of pig fed PE showed lower (P<0.001) lipid oxidation levels than controls. A reduction (P=0.05) of fat odor and rancid flavor intensity in cooked LD muscle stored at 4°C for 24h was observed in the treated group. This study shows that PE is an effective antioxidant in pork meat, enhancing oxidative status and sensory attributes, without affecting other meat quality parameters. 23867721 Integrated virus-host methylome analysis in head and neck squamous cell carcinoma. One in six cancers worldwide is caused by infection and human papillomavirus (HPV) is one of the main culprits. To better understand the dynamics of HPV integration and its effect on both the viral and host methylomes, we conducted whole-genome DNA methylation analysis using MeDIP-seq of HPV+ and HPV- head and neck squamous cell carcinoma (HNSCC). We determined the viral subtype to be HPV-16 in all cases and show that HPV-16 integrates into the host genome at multiple random sites and that this process predominantly involves the transcriptional repressor gene (E2) in the viral genome. Comparative analysis identified 453 (FDR ≤ 0.01) differentially methylated regions (DMRs) in the HPV+ host methylome. Bioinformatics characterization of these DMRs confirmed the previously reported cadherin genes to be affected but also revealed new targets for HPV-mediated methylation changes at regions not covered by array-based platforms, including the recently identified super-enhancers. 23876718 Determination of renewable energy yield from mixed waste material from the use of novel image analysis methods. Two novel techniques are presented in this study which together aim to provide a system able to determine the renewable energy potential of mixed waste materials. An image analysis tool was applied to two waste samples prepared using known quantities of source-segregated recyclable materials. The technique was used to determine the composition of the wastes, where through the use of waste component properties the biogenic content of the samples was calculated. The percentage renewable energy determined by image analysis for each sample was accurate to within 5% of the actual values calculated. Microwave-based multiple-point imaging (AutoHarvest) was used to demonstrate the ability of such a technique to determine the moisture content of mixed samples. This proof-of-concept experiment was shown to produce moisture measurement accurate to within 10%. Overall, the image analysis tool was able to determine the renewable energy potential of the mixed samples, and the AutoHarvest should enable the net calorific value calculations through the provision of moisture content measurements. The proposed system is suitable for combustion facilities, and enables the operator to understand the renewable energy potential of the waste prior to combustion. 23887187 Local cortical dynamics of burst suppression in the anaesthetized brain. Burst suppression is an electroencephalogram pattern that consists of a quasi-periodic alternation between isoelectric 'suppressions' lasting seconds or minutes, and high-voltage 'bursts'. It is characteristic of a profoundly inactivated brain, occurring in conditions including hypothermia, deep general anaesthesia, infant encephalopathy and coma. It is also used in neurology as an electrophysiological endpoint in pharmacologically induced coma for brain protection after traumatic injury and during status epilepticus. Classically, burst suppression has been regarded as a 'global' state with synchronous activity throughout cortex. This assumption has influenced the clinical use of burst suppression as a way to broadly reduce neural activity. However, the extent of spatial homogeneity has not been fully explored due to the challenges in recording from multiple cortical sites simultaneously. The neurophysiological dynamics of large-scale cortical circuits during burst suppression are therefore not well understood. To address this question, we recorded intracranial electrocorticograms from patients who entered burst suppression while receiving propofol general anaesthesia. The electrodes were broadly distributed across cortex, enabling us to examine both the dynamics of burst suppression within local cortical regions and larger-scale network interactions. We found that in contrast to previous characterizations, bursts could be substantially asynchronous across the cortex. Furthermore, the state of burst suppression itself could occur in a limited cortical region while other areas exhibited ongoing continuous activity. In addition, we found a complex temporal structure within bursts, which recapitulated the spectral dynamics of the state preceding burst suppression, and evolved throughout the course of a single burst. Our observations imply that local cortical dynamics are not homogeneous, even during significant brain inactivation. Instead, cortical and, implicitly, subcortical circuits express seemingly different sensitivities to high doses of anaesthetics that suggest a hierarchy governing how the brain enters burst suppression, and emphasize the role of local dynamics in what has previously been regarded as a global state. These findings suggest a conceptual shift in how neurologists could assess the brain function of patients undergoing burst suppression. First, analysing spatial variation in burst suppression could provide insight into the circuit dysfunction underlying a given pathology, and could improve monitoring of medically-induced coma. Second, analysing the temporal dynamics within a burst could help assess the underlying brain state. This approach could be explored as a prognostic tool for recovery from coma, and for guiding treatment of status epilepticus. Overall, these results suggest new research directions and methods that could improve patient monitoring in clinical practice. 23563174 Critical role for inhibitory neurons in modulation of synaptic signaling in ex vivo neuronal networks. A number of laboratories have modeled aspects of synaptic plasticity using neuronal networks established on micro-electrode arrays. Such studies demonstrate that external stimulation can increase or hasten maturation of network signaling as evidenced an increase in complex bursts. Herein, we demonstrate that repetitive stimulation with a recorded synaptic signal was capable of increasing overall signaling, including the percentage of bursts, over a 5-day period, but that this increase was completely prevented by the presence of the GABAergic antagonist bicuculline. These findings demonstrate a critical role for inhibitory neurons in signal maturation following stimulation, which supports the purported role for inhibitory neuronal activity in long-term potentiation and learning in situ. 23966103 The role of Sep (O-phosphoserine) tRNA: Sec (selenocysteine) synthase (SEPSECS) in proliferation, apoptosis and hormone secretion of trophoblast cells. To investigate whether Sep (O-phosphoserine) tRNA: Sec (selenocysteine) synthase (SEPSECS), which plays an essential role in the synthesis of selenoprotein, affects proliferation, apoptosis and hormone secretion of human trophoblast cells. Human trophoblast JEG-3 cells were divided into four groups: control group, SEPSECS silenced-expression group, empty vector group and SEPSECS over-expression group. Over-expression and silenced-expression were achieved by transfection with plasmid DNA or RNA oligonucleotide, respectively. 3-[4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide (MTT) and colony formation assays were performed to investigate cell proliferation, while apoptosis was tested by annexin V-FITC, PI double staining and caspases-3 activation assays, enzyme-linked immunosorbent assay (ELISA) was used to determine the level of progesterone (PG) and human chorionic gonadotropin (hCG). SEPSECS silenced-expression clearly inhibited proliferation of JEG-3 cells (p < 0.05), significantly induced cell apoptosis (p < 0.01) and reduced the production of PG and hCG (p < 0.05). On the contrary, SEPSECS over-expression significantly promoted both cell proliferation (p < 0.01) and secretion of PG and hCG (p < 0.05). SEPSECS significantly affects proliferation, apoptosis and hormone secretion of human trophoblast cells, suggesting that a potential relationship exists among SEPSECS, cell proliferation, apoptosis and hormone production of human placental trophoblast cells. Furthermore, this may provide a clue to uncover the relationship between selenium and human placental in association with an emphasis on the importance of selenium adequacy during pregnancy. 23317117 A Fröhlich effect and representational gravity in memory for auditory pitch. Memory for the initial pitch of an auditory target that increased or decreased in auditory frequency was examined. Memory was displaced forward in the direction of pitch motion, and this is consistent with the Fröhlich effect previously observed for visual targets moving in visual physical space. The Fröhlich effect for pitch increased with faster target velocity and decreased if an auditory cue with the same pitch as the initial pitch of the target was presented before the target was presented. The Fröhlich effect was larger for descending pitch motion than for ascending pitch motion, and this is consistent with an influence of representational gravity. The data suggest that representation of auditory frequency space exhibits some of the same biases as representation of visual physical space, and implications for theories of attention in displacement and for crossmodal and multisensory representation of space are discussed. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23607518 Atopic dermatitis-mitigating effects of new Lactobacillus strain, Lactobacillus sakei probio 65 isolated from Kimchi. Atopic dermatitis (AD) is an inflammatory skin disease. Probiotics have been reported to modulate immune responses and thus are now being suggested as potential treatments for allergies. In this study, we investigated the inhibitory effects of Lactobacillus sakei probio 65 isolated from Kimchi on artificially inducing AD in NC/Nga mice. Oral administration of viable or heat-inactivated Lact. sakei probio 65 improved the condition of skin and reduced scratching frequency. Serum levels of IgE and cutaneous T-cell-attracting chemokine (CTACK) were significantly decreased by this therapy. Dead Lact. sakei probio 65 also decreased IL-4 and IL-6 serum concentrations. Moreover, both live and dead Lact. sakei probio 65 inhibited the expression of Thymus and activation-regulated chemokine and CTACK in AD-like skin lesions. The increased levels of Foxp3 expression in the lesional skin and ears were also suppressed by Lact. sakei probio 65. In addition, Lact. sakei probio 65 inhibited β-hexosaminidase release and the secretion of IL-4, TNF-α and IL-6 from RBL-2H3 cells. Oral treatment with both viable and heat-inactivated Lact. sakei probio 65 inhibits skin inflammation and AD-like skin lesions, as well as mast cell activation. Lactobacillus sakei probio 65 has an inhibitory effect on atopic dermatitis-like skin lesions and may represent an effective new anti-inflammatory agent. 22406206 A 90-day oral (dietary) toxicity study of arruva, an R, R-monatin salt isomer, in Crl:CD-1(ICR) mice. R,R-Monatin [2R,4R- isomer of 2-hydroxy-2-(indol-3-ylmethyl)-4-aminoglutaric acid] is one of four natural constituent isomers in the root bark of Sclerochitin ilicifolius; and "arruva" is the common/usual name that is proposed to represent R,R-monatin salt forms, which have potential use as high potency sweetener food ingredients. In the present study, groups of male and female Crl:CD-1(ICR) mice were exposed to 0 (control), 5000, 10,000, 20,000, or 35,000ppm of arruva in the diet for 90days. There were no toxicologically relevant clinical or histopathological findings in any of the test article-treated groups. Significantly lower mean body weights and cumulative body weight gains were noted in the 35,000ppm group when compared to the control group. Mean body weights in the 35,000ppm group males and females were 9% and 7% less than the control group, respectively, at week 13. In the absence of observations associated with systemic toxicity and in consideration of the magnitude of body weight difference, these effects were not considered toxicologically significant. Based on the results of this study, the dietary no-observed-adverse-effect level (NOAEL) of arruva for 90days in male and female mice was 35,000ppm (equivalent to an exposure level of 5764 and 8013mg/kg bw/day, respectively). 23315417 Differential Expression of p16(INK4A) and Cyclin D1 in Benign and Malignant Salivary Gland Tumors: A Study of 44 Cases. Salivary gland tumors (SGT) are a heterogeneous group of lesions. There is conflicting data concerning the molecular events involving the tumour suppressor retinoblastoma protein (pRb) pathway in these tumors. Few studies examined the alterations in components of the Rb pathway by immunohistochemical (IHC) methods in benign and malignant SGTs. Furthermore, recent evidence implicates human papillomavirus (HPV) in mucoepidermoid carcinoma (MEC) carcinogenesis. The purpose of our study is to examine p16(INK4A) and cyclin D1 expression in a variety of benign and malignant salivary gland tumors, and to investigate p16(INK4A) expression as a surrogate marker for HPV infection in MEC. Our series includes 30 malignant tumors [14 MEC, 6 acinic cell carcinomas (ACC), 5 polymorphous low grade adenocarcinomas (PLGA), 5 (AdCC)] and 14 benign tumors (4 benign cysts, 5 Warthin tumors and 5 pleomorphic adenomas (PA). All cases were tested by IHC for p16(INK4A) and cyclin D1. Testing for HPV wide spectrum (HPV-WS) was performed by in situ hybridization in all MEC cases. Staining intensity was recorded semi quantitatively (on a scale from 0 to 4+). Fisher's exact test and Pearson X(2) test with a p < 0.05 were used. Cyclin D1 and p16(INK4A) are expressed similarly in malignant and benign tumors (p = 0.146 and p = 0.543, respectively). None of the MEC cases showed nuclear reactivity for HPV-WS. Statistical analysis showed positive correlation between cyclin D1 and p16(INK4A) expression. Our findings suggest that p16(INK4A) overexpression is likely secondary to cyclin D1 gene upregulation or amplification. Further molecular studies are warranted. 23265513 Identification of xyloglucan endotransglucosylase/hydrolase genes (XTHs) and their expression in persimmon fruit as influenced by 1-methylcyclopropene and gibberellic acid during storage at ambient temperature. Xyloglucan endotransglucosylase/hydrolase (XTH) is thought to contribute to fruit softening by degrading xyloglucan that is a predominant hemicellulose in the cell wall. In this study, two full-length XTH genes (DKXTH1 and DKXTH2) were identified from 'Fupingjianshi' persimmon fruit, and the expression level of both XTH genes was investigated during softening for 18-24 d using RT-qPCR. Sequence analysis showed that DKXTH1 and DKXTH2 contained a putative open reading frame of 861 and 876 bp encoding polypeptides of 287 and 292 amino acid residues, respectively, which contained the conserved DEIDFEFLG motif of XTH, a potential N-linked glycosylation signal site. RT-qPCR analysis showed that DKXTH1 and DKXTH2 in untreated fruit had different expression patterns during fruit softening, in which maximum expression occurred on days 3 and 12 of ripening, respectively. 1-Methylcyclopropene (1-MCP) and gibberellic acid (GA(3)) treatments delayed the softening and ethylene peak of persimmon fruit, as well as suppressed the expression of both XTH genes, especially DKXTH1. These results indicated that the expression of both XTH genes might be ethylene dependent action, and closely related to softening of persimmon in the early (DKXTH1) and later (DKXTH2) ripening stages. 23239427 Longitudinal prediction of disruptive behavior disorders in adolescent males from multiple risk domains. The disruptive behavior disorders are among the most prevalent youth psychiatric disorders, and they predict numerous problematic outcomes in adulthood. This study examined multiple domains of risk during early childhood and early adolescence as longitudinal predictors of disruptive behavior disorder diagnoses among adolescent males. Early adolescent risks in the domains of sociodemographic factors, the caregiving context, and youth attributes were examined as mediators of associations between early childhood risks and disruptive behavior disorder diagnoses. Participants were 309 males from a longitudinal study of low-income mothers and their sons. Caregiving and youth risk during early adolescence each predicted the likelihood of receiving a disruptive behavior disorder diagnosis. Furthermore, sociodemographic and caregiving risk during early childhood were indirectly associated with disruptive behavior disorder diagnoses via their association with early adolescent risk. The findings suggest that preventive interventions targeting risk across domains may reduce the prevalence of disruptive behavior disorders. 23935392 Elastomeric Recombinant Protein-based Biomaterials. Elastomeric protein-based biomaterials, produced from elastin derivatives, are widely investigated as promising tissue engineering scaffolds due to their remarkable properties including substantial extensibility, long-term stability, self-assembly, high resilience upon stretching, low energy loss, and excellent biological activity. These elastomers are processed from different sources of soluble elastin such as animal-derived soluble elastin, recombinant human tropoelastin, and elastin-like polypeptides into various forms including three dimensional (3D) porous hydrogels, elastomeric films, and fibrous electrospun scaffolds. Elastin-based biomaterials have shown great potential for the engineering of elastic tissues such as skin, lung and vasculature. In this review, the synthesis and properties of various elastin-based elastomers with their applications in tissue engineering are described. 23542120 A rapid and inexpensive method for 226Ra and 228Ra measurements of high TDS groundwaters. A series of laboratory-scale studies was conducted by preconcentrating (226)Ra from spiked water test samples using Purolite ion-exchange resin to evaluate the adsorption efficiency of the resin under varying conditions. After removing the resin from the columns, it was sealed in gas-tight containers and measured via gamma spectrometry. The Purolite resin showed high radium uptake and retention from natural waters in the presence of high iron and total dissolved solids (TDS). This procedure allowed us to process a large number of high TDS samples at a typical rate of 15 samples/day using three germanium detectors. Quality assurance and method validation have been achieved by analyzing selected groundwater samples, with different (226)Ra activities and high TDS values, and comparing the results to those using alpha spectrometry with a (133)Ba yield tracer. There was very good agreement between the obtained (226)Ra activities by both methods. 23782703 CCAAT-enhancer-binding Protein β (C/EBPβ) and Downstream Human Placental Growth Hormone Genes Are Targets for Dysregulation in Pregnancies Complicated by Maternal Obesity. Human chorionic somatomammotropin (CS) and placental growth hormone variant (GH-V) act as metabolic adaptors in response to maternal insulin resistance, which occurs in "normal" pregnancy. Maternal obesity can exacerbate this "resistance," suggesting that CS, GH-V, or transcription factors that regulate their production might be targets. The human CS genes, hCS-A and hCS-B, flank the GH-V gene. A significant decrease in pre-term placental CS/GH-V RNA levels was observed in transgenic mice containing the CS/GH-V genes in a model of high fat diet (HFD)-induced maternal obesity. Similarly, a decrease in CS/GH-V RNA levels was detected in term placentas from obese (body mass index (BMI) ≥ 35 kg/m(2)) versus lean (BMI 20-25 kg/m(2)) women. A specific decrease in transcription factor CCAAT-enhancer-binding protein β (C/EBPβ) RNA levels was also seen with obesity; C/EBPβ is required for mouse placenta development and is expressed, like CS and GH-V, in syncytiotrophoblasts. Binding of C/EBPβ to the CS gene downstream enhancer regions, which by virtue of their position distally flank the GH-V gene, was reduced in placenta chromatin from mice on a HFD and in obese women; a corresponding decrease in RNA polymerase II associated with CS/GH-V promoters was also observed. Detection of decreased endogenous CS/GH-V RNA levels in human placental tumor cells treated with C/EBPβ siRNA is consistent with a direct effect. These data provide evidence for CS/GH-V dysregulation in acute HFD-induced obesity in mouse pregnancy and chronic obesity in human pregnancy and implicate C/EBPβ, a factor associated with CS regulation and placental development. 23906651 A qualitative study of patient choices in using emergency health care for long-term conditions: The importance of candidacy and recursivity. We aimed to explore how patients with long-term conditions choose between available healthcare options during a health crisis. Patients in North-West England with one or more of four long-term conditions were invited to take part in a questionnaire cohort study of healthcare use. Semi-structured interviews were conducted with a sub-sample of fifty consenting patients. Data were analysed qualitatively, using a framework approach. Patients described using emergency care only in response to perceived urgent need. Their judgements about urgency of need, and their choices about what services to use were guided by previous experiences of care, particularly how accessible services were and the perceived expertise of practitioners. Recursivity and candidacy provide a framework for understanding patient decision-making around emergency care use. Patients were knowledgeable and discriminating users of services, drawing on experiential knowledge of healthcare to choose between services. Their sense of 'candidacy' for specific emergency care services, was recursively shaped by previous experiences. Strategies that emphasise the need to educate patients about healthcare services use alone are unlikely to change care-seeking behaviour. Practitioners need to modify care experiences that recursively shape patients' judgements of candidacy and their perceptions of accessible expertise in alternative services. 23722875 A functional rattle-type microsphere with a magnetic-carbon double-layered shell for enhanced extraction of organic targets. A novel rattle-type sorbent with a surface-modified interior cavity and a magnetic Fe3O4-C double-layered shell was synthesized and first applied for magnetic solid-phase extraction. 23876444 Monitoring targeted therapy using dual-energy CT: semi-automatic RECIST plus supplementary functional information by quantifying iodine uptake of melanoma metastases. Aim: Supplementary functional information can contribute to assess response in targeted therapies. The aim of this study was to evaluate semi-automatic RECIST plus iodine uptake (IU) determination in melanoma metastases under BRAF inhibitor (vemurafenib) therapy using dual-energy computed tomography (DECT). Methods: Nine patients with stage IV melanoma treated with a BRAF inhibitor were included. Contrast-enhanced DECT was performed before and twice after treatment onset. Changes in tumor size were assessed according to RECIST. Quantification of IU (absolute value for total IU (mg) and volume-normalized IU (mg/ml)) was based on semi-automatic tumor volume segmentation. The decrease compared with baseline was calculated. Results: The mean change of RECIST diameter sum per patient was -47% at the first follow-up (FU), -56% at the second FU (P < 0.01). The mean normalized IU per patient was -21% at the first FU (P < 0.2) and -45% at the second FU (P < 0.01). Total IU per patient, combining both normalized IU and volume, showed the most pronounced decrease: -89% at the first FU and -90% at the second FU (P < 0.01). Conclusion: Semi-automatic RECIST plus IU quantification in DECT enables objective, easy and fast parameterization of tumor size and contrast medium uptake, thus providing 2 complementary pieces of information for response monitoring applicable in daily routine. 23194547 Rapid analysis of sugars in honey by processing Raman spectrum using chemometric methods and artificial neural networks. The aim of this study was to quantify glucose, fructose, sucrose and maltose contents of honey samples using Raman spectroscopy as a rapid method. By performing a single measurement, quantifications of sugar contents have been said to be unaffordable according to the molecular similarities between sugar molecules in honey matrix. This bottleneck was overcome by coupling Raman spectroscopy with chemometric methods (principal component analysis (PCA) and partial least squares (PLS)) and an artificial neural network (ANN). Model solutions of four sugars were processed with PCA and significant separation was observed. This operation, done with the spectral features by using PLS and ANN methods, led to the discriminant analysis of sugar contents. Models/trained networks were created using a calibration data set and evaluated using a validation data set. The correlation coefficient values between actual and predicted values of glucose, fructose, sucrose and maltose were determined as 0.964, 0.965, 0.968 and 0.949 for PLS and 0.965, 0.965, 0.978 and 0.956 for ANN, respectively. The requirement of rapid analysis of sugar contents of commercial honeys has been met by the data processed within this article. 23867514 PBRM1 and BAP1 as Novel Targets for Renal Cell Carcinoma. Technological advances in genome sequencing have led to the identification of novel driver genes mutated in renal cancer. Hitherto, 1 gene was known to be frequently mutated in renal cell carcinoma of clear cell type (ccRCC), the von Hippel-Lindau (VHL) gene. VHL was identified by positional cloning as the gene responsible for a familial syndrome with renal cancer predisposition, von Hippel-Lindau. Subsequently, VHL was found to be inactivated in approximately 90% of sporadic ccRCC. The discovery of VHL, together with the elucidation of its function, transformed the treatment of ccRCC leading to the introduction of 5 new drugs into the clinic. However, no other familial ccRCC predisposing genes are frequently mutated in sporadic ccRCC. With the development of massively parallel sequencing, a plethora of somatically mutated genes has been identified. Most genes are mutated at low frequencies, but 3 genes are mutated in more than 10% of ccRCC, PBRM1 (mutated in ∼50%), BAP1 (∼15%), and SETD2 (∼15%). Like VHL, all 3 genes are 2-hit tumor suppressor genes. Furthermore, these 3 genes are within a 50-Mb region on the short arm of chromosome 3p that encompasses VHL and is deleted in ∼90% of ccRCC. We discovered that PBRM1 mutations tend to anticorrelate with BAP1 mutations in ccRCC and that PBRM1- and BAP1-mutated tumors exhibit different biology and are associated with markedly different outcomes. This established the foundation for the first molecular genetic classification of sporadic ccRCC. Herein, I review the evidence that implicated PBRM1 and BAP1 as renal cancer driver genes, provide an update on the function of the gene products, and speculate on how mutations in these genes may be exploited therapeutically. 23883591 Natriuretic peptide receptors regulate cytoprotective effects in an ex vivo human 3D/bioreactor model. This study examined the effect of C-type natriuretic peptide (CNP) and biomechanical signals on anabolic and catabolic activities in chondrocyte/agarose constructs. Natriuretic peptide (Npr) 2 and 3 expression were compared in non-diseased (grade 0/1) and diseased (grade IV) human cartilage by immunofluoresence microscopy and western blotting. In separate experiments, constructs were cultured under free-swelling conditions or subjected to dynamic compression with CNP, interleukin-1beta (IL-1beta), the Npr2 antagonist P19 or the Npr3 agonist cANF4-23. Nitric oxide (NO) production, prostaglandin E2 (PGE2) release, glycosaminoglycan (GAG) synthesis and CNP concentration were quantified using biochemical assays. Gene expression of Npr2, Npr3, CNP, aggrecan and collagen type II were assessed by real-time qPCR. Two-way ANOVA and a post hoc Bonferroni-corrected t-test were used to analyse the data. This study demonstrates increased expression of natriuretic peptide receptors in diseased or older cartilage (age 70) when compared to non-diseased tissue (age 60) which showed minimal expression. There was strong parallelism in the actions of CNP on cyclic cyclic guanosine monophosphate (cGMP) induction resulting in enhanced GAG synthesis and reduction of NO and PGE2 release induced by IL-1beta. Inhibition of Npr2 with P19 maintained catabolic activities whilst specific agonism of Npr3 with cANF4-23 had the opposite effect and reduced NO and PGE2 release. Co-stimulation with CNP and dynamic compression enhanced anabolic activities and inhibited catabolic effects induced by IL-1beta. The presence of CNP and the Npr2 antagonist abolished the anabolic response to mechanical loading and prevented loading-induced inhibition of NO and PGE2 release. In contrast, the presence of the Npr3 agonist had the opposite effect and increased GAG synthesis and cGMP levels in response to mechanical loading and reduced NO and PGE2 release comparable to control samples. In addition, CNP concentration and natriuretic peptide receptor expression were increased with dynamic compression. Mechanical loading mediates endogenous CNP release leading to increased natriuretic peptide signalling. The loading-induced CNP/Npr2/cGMP signalling route mediates anabolic events and prevents catabolic activities induced by IL-1beta. The CNP pathway therefore represents a potentially chondroprotective intervention for patients with osteoarthritis, particularly when combined with physiotherapeutic approaches to stimulate biomechanical signals. 23644021 De novo sequencing and assembly of Centella asiatica leaf transcriptome for mapping of structural, functional and regulatory genes with special reference to secondary metabolism. Centella asiatica (L.) Urban is an important medicinal plant and has been used since ancient times in traditional systems of medicine. C. asiatica mainly contains ursane skeleton based triterpenoid sapogenins and saponins predominantly in its leaves. This investigation employed Illumina next generation sequencing (NGS) strategy on a pool of three cDNAs from expanding leaf of C. asiatica and developed an assembled transcriptome sequence resource of the plant. The short transcript reads (STRs) generated and assembled into contigs and singletons, representing majority of the genes expressed in C. asiatica, were termed as 'tentative unique transcripts' (TUTs). The TUT dataset was analyzed with the objectives of (i) development of a transcriptome assembly of C. asiatica, and (ii) classification/characterization of the genes into categories like structural, functional, regulatory etc. based on their function. Overall, 68.49% of the 46,171,131 reads generated in the NGS process could be assembled into a total of 79,041 contigs. Gene ontology and functional annotation of sequences resulted into the identification of genes related to different sets of cellular functions including identification of genes related to primary and secondary metabolism. The wet lab validation of seventeen assembled gene sequences identified to be involved in secondary metabolic pathways and control of reactive oxygen species (ROS) was established by semi-quantitative and real time PCR (qRT-PCR). The validation also included sequencing/size matching of a set of semi-quantitative PCR amplicons with their in silico assembled contig/gene. This confirmed the appropriateness of assembling the reads and contigs. Thus, the present study constitutes the largest report to date on C. asiatica transcriptome based gene resource that may contribute substantially to the understanding of the basal biological functions and biochemical pathways of secondary metabolites as well as the transcriptional regulatory elements and genetic markers. This work sets the stage for multi-faceted future improvement of the plant, through discovery of new genes, marker-assisted breeding or genetic engineering, on this species as well as for other species of Apiaceae and triterpene producing medicinal plants. 23763620 In vivo and in silico pharmacokinetics and biodistribution of a melanocortin receptor 1 targeted agent in preclinical models of melanoma. The melanocortin 1 receptor (MC1R) is overexpressed in most melanoma metastases, making it a promising target for imaging of melanomas. In this study, the expression of MC1R in a large fraction of patients with melanoma was confirmed using mRNA and tissue microarray. Here, we have characterized the in vivo tumor and tissue distribution and pharmacokinetics (PK) of uptake and clearance of a MC1R specific peptidomimetic ligand conjugated to a near-infrared fluorescent dye. We propose an interdisciplinary framework to bridge the different time and space scales of ligand-tumor-host interactions: intravital fluorescence microscopy to quantify probe internalization at the cellular level, a xenograft tumor model for whole body pharmacokinetics, and a computational pharmacokinetic model for integration and interpretation of experimental data. Administration of the probe into mice bearing tumors with high and low MC1R expression demonstrated normalized image intensities that correlated with expression levels (p < 0.05). The biodistribution study showed high kidney uptake as early as 30 min postinjection. The PK computational model predicted the presence of receptors in the kidneys with a lower affinity, but at higher numbers than in the tumors. As the mouse kidney is known to express the MC5R, this hypothesis was confirmed by both coinjection of a ligand with higher MC5R affinity compared to MC1R and by injection of lower probe concentrations (e.g., 1 nmol/kg), both leading to decreased kidney accumulation of the MC1R ligand. In addition, through this interdisciplinary approach we could predict the rates of ligand accumulation and clearance into and from organs and tumors, and the amount of injected ligand required to have maximum specific retention in tumors. These predictions have potential to aid in the translation of a targeted agent from lab to the clinic. In conclusion, the characterized MC1R-specific probe has excellent potential for in vivo detection of melanoma metastases. The process of cell-surface marker validation, targeted imaging probe development, and in vitro, in vivo, and in silico characterization described in this study can be generally applied to preclinical development of targeted agents. 23629387 The importance of an anthropological scene of crime investigation in the case of burnt remains in vehicles: 3 case studies. Inspection of a crime scene is a crucial step in forensic medicine, and even the methods taught by forensic anthropology are essential. Whereas a thorough inspection can provide crucial information, an approximate inspection can be useless or even harmful. This study reports 3 cases of burnt bodies found inside vehicles between 2006 and 2009 in the outskirts of Milan (Italy). In all 3 cases, the victim was killed by gunshot, and the body was burnt in the vehicle to destroy signs of skeletal injury and prevent identification. In every case, the assistance of forensic anthropologists was requested, but only after the inspection of the body at autopsy showed that the remains were incomplete, thus making it more difficult to determine the identity, cause, and manner of death. A second scene of crime inspection was therefore performed with strict anthropological and adapted archeological methods by forensic anthropologists to perform a more complete recovery, proving how much material had been left behind. These cases clearly show the importance of a proper recovery and of the application of forensic anthropology methods on badly charred bodies and the importance of recovering every fragment of bone: even the smallest fragment can provide essential information. Thus, a precise coordination, a correct and thorough recovery of bone fragments, and an anthropological approach are crucial for many issues: analysis of the scene of crime, reconstruction of the corpse, and reconstruction of the perimortem events. 23831706 Evaluating effects of penicillin treatment on the metabolome of rats. Penicillin (PEN) V, a well-known antibiotic widely used in the treatment of Gram-positive bacterial infections, was evaluated in this study. LC/MS- and NMR-based metabolic profiling were employed to examine the effects of PEN on the host's metabolic phenotype. Male Sprague Dawley rats were randomly divided into groups that were orally administered either 0.5% methylcellulose vehicle, 100 or 2400mg PEN/kg body weight once daily for up to 14 consecutive days. Urine, plasma and tissue were collected from groups sacrificed at 6h, 24h or 14d. The body fluids were subjected to clinical chemistry and metabolomics analysis; the tissue samples were processed for histopathology. The only notable clinical chemistry observation was that gamma glutamyltransferase (GGT) significantly decreased at 24h for both dose groups, and significantly decreased at 14d for the high-dose groups. Partial least squares discriminant analysis scores plots of the metabolomics data from urine and plasma samples showed dose- and time-dependent grouping patterns. Time- and dose-dependent decreases in urinary metabolites including indole-containing metabolites (such as 3-methyldioxyindole sulfate generated from bacterial metabolism of tryptophan), organic acids containing phenyl groups (such as hippuric acid, phenyllactic acid and 3-hydroxyanthranilic acid), and metabolites conjugated with sulfate or glucuronide (such as cresol sulfate and aminophenol sulfate) indicated that the gut microflora population was suppressed. Decreases in many host-gut microbiota urinary co-metabolites (indole- and phenyl-containing metabolites, amino acids, vitamins, nucleotides and bile acids) suggested gut microbiota play important roles in the regulation of host metabolism, including dietary nutrient absorption and reprocessing the absorbed nutrients. Decreases in urinary conjugated metabolites (sulfate, glucuronide and glycine conjugates) implied that gut microbiota might have an impact on chemical detoxification mechanisms. In all, these results clearly show that metabolic profiling is a useful tool to better understand the effects of the antibiotic penicillin has on the gut microbiota and the host. 23890020 Raman spectroscopy as a non-invasive technique for the quantification of melanins in feathers and hairs. The quantification of melanins is a complex task due to the chemical heterogeneity of the pigments and the difficulty of their isolation. The best accepted procedure currently consists in the chemical cleavage of melanins and the subsequent detection of degradation products by HPLC, which implies the destruction of samples. Here we show that Raman spectroscopy is a non-invasive technique that can be used to quantify melanins. We made parallel analyses of the characteristics of pheomelanin and eumelanin Raman spectra as measured by confocal Raman microscopy and of degradation products of pheomelanin (4-amino-3-hydroxyphenylalanine, 4-AHP) and eumelanin (pyrrole-2,3,5-tricarboxylic acid, PTCA) as measured by HPLC in feathers of red-legged partridges and hairs of wild boars and humans. We found strong correlations between the spectral Raman characteristics and 4-AHP and PTCA levels, which indicates that the Raman spectra of melanins can be used to determine their content. This article is protected by copyright. All rights reserved. 23826951 Measurement of tumour size with mammography, sonography and magnetic resonance imaging as compared to histological tumour size in primary breast cancer. Tumour size in breast cancer influences therapeutic decisions. The purpose of this study was to evaluate sizing of primary breast cancer using mammography, sonography and magnetic resonance imaging (MRI) and thereby establish which imaging method most accurately corresponds with the size of the histological result. Data from 121 patients with primary breast cancer were analysed in a retrospective study. The results were divided into the groups "ductal carcinoma in situ (DCIS)", invasive ductal carcinoma (IDC) + ductal carcinoma in situ (DCIS)", "invasive ductal carcinoma (IDC)", "invasive lobular carcinoma (ILC)" and "other tumours" (tubular, medullary, mucinous and papillary breast cancer). The largest tumour diameter was chosen as the sizing reference in each case. Bland-Altman analysis was used to determine to what extent the imaging tumour size correlated with the histopathological tumour sizes. Tumour size was found to be significantly underestimated with sonography, especially for the tumour groups IDC + DCIS, IDC and ILC. The greatest difference between sonographic sizing and actual histological tumour size was found with invasive lobular breast cancer. There was no significant difference between mammographic and histological sizing. MRI overestimated non-significantly the tumour size and is superior to the other imaging techniques in sizing of IDC + DCIS and ILC. The histological subtype should be included in imaging interpretation for planning surgery in order to estimate the histological tumour size as accurately as possible. 23661195 Characterization and functional analyses of the chitinase-encoding genes in the nematode-trapping fungus Arthrobotrys oligospora. Nematode-trapping fungi can secrete many extracellular hydrolytic enzymes such as serine proteases and chitinases to digest and penetrate nematode/egg-cuticles. However, little is known about the structure and function of chitinases in these fungi. In this study, 16 ORFs encoding putative chitinases, which all belong to glycoside hydrolase (GH) family 18, were identified from the Arthrobotrys oligospora genome. Bioinformatics analyses showed that these 16 putative chitinases differ in their functional domains, molecular weights and pI. Phylogenetic analysis grouped these A. oligospora chitinases into four clades: clades I, II, III and IV, respectively, including an A. oligospora-specific subclade (Clade IV-B) that contained high-molecular weight chitinases (≥100 kDa). Transcriptional analysis of A. oligospora chitinases suggested that the expression of most chitinases was repressed by carbon starvation, and all chitinases were up-regulated under nitrogen starvation. However, chitinase AO-190 was up-regulated under carbon and/or nitrogen starvation. Moreover, several chitinases (such as AO-59, AO-190 and AO-801) were up-regulated in the presence of chitinous substrates or a plant pathogenic fungus, indicating that they could play a role in biocontrol applications of A. oligospora. Our results provided a basis for further understanding the functions, diversities and evolutionary relationships between chitinase genes in nematode-trapping fungi. 23765524 Visualization of the leakage of pancreatic juice using a chymotrypsin-activated fluorescent probe. Pancreatic fistula (PF) remains the most serious complication after digestive surgery. It is difficult to prevent because of the inability to visualize the leakage of pancreatic juice during surgery or to evaluate the protease activity of leaked fluid, which is responsible for PF formation. The fluorescence intensities of a chymotrypsin probe (glutamyl-phenylalanine hydroxymethyl rhodamine green with added trypsin) in pancreatic juice and in intestinal or abdominal fluids drained after pancreatic resection were evaluated. The chymotrypsin probe was sprayed on to filter papers that had been placed on the resected pancreatic stump in patients undergoing pancreaticoduodenectomy or central pancreatectomy. The ability of this technique to visualize the leakage of pancreatic juice and predict postoperative PF formation was assessed. The fluorescence intensity of the chymotrypsin probe in 76 fluid samples correlated positively with amylase levels (rs  = 0·678, P < 0·001). The fluorescence patterns of the pancreatic stump were classified grossly into the three types: duct (fluorescence signal visualized only on the stump of the main pancreatic duct, 16 patients), diffuse (ductal stump and surrounding pancreatic parenchyma, 7) and negative (no fluorescence signal, 7). Symptomatic PFs developed in 13 of 23 patients with duct- or diffuse-type fluorescence, but in none of the seven patients with negative-type fluorescence (P = 0·008). The chymotrypsin probe enabled determination of the protease activity in drained pancreatic fluid samples and allowed real-time visualization of pancreatic juice leakage during surgery. 23907593 The Changing Composition of a Hospital Ethics Committee: A Tertiary Care Center's Experience. A growing body of research has demonstrated significant heterogeneity of hospital ethics committee (HEC) size, membership and training requirements, length of appointment, institutional support, clinical and policy roles, and predictors of self identified success. Because these studies have focused on HECs at a single point in time, however, little is known about how the composition of HECs changes over time and what impact these changes have on committee utilization. The current study presents 20 years of data on the evolution of the Massachusetts General Hospital HEC. Between 1993 and 2012, the average number of committee members per year was 38 ± 3 and the average length of membership was 4.8 ± 0.4 years. During that time, the committee performed 934 consults, averaging 47 ± 3 per year. Attendance rates fell from 61.5 to 23.8 % over the study period and were inversely correlated with the total number of members. Between 1993 and 2012, the committee saw substantial growth in the diversity of the professional backgrounds of its members. Multivariate analysis, however, suggests that substantial changes in committee composition did not impact its utilization and that other factors are more likely to explain fluctuations in consultation volume. 23925702 Passive Movement Improves the Learning and Memory Function of Rats with Cerebral Infarction by Inhibiting Neuron Cell Apoptosis. Passive movement has been found to improve evidently ischemic stroke patients' impaired capacity of learning and memory, but the optimal time window of initiating the therapy and the underlying mechanism are not fully understood. In this study, the effect of passive movement at different time windows on learning and memory of rats with cerebral infarction was detected. The results showed that the expression of caspase-3 and escape latency in the passive movement group were all considerably lower than those in the model group (P < 0.05), while the expression of Bcl-2 mRNA was significantly higher than those in the model group (P < 0.05). Moreover, we found that there were most significant changes of escape latency and expressions of Bcl-2 mRNA and caspase-3 when the therapy started at 24 h after focal cerebral infarction. These results suggest that passive movement is able to contribute to the recovery of learning and memory of rats with cerebral infarction, which is partially mediated by inhibiting neuron cell apoptosis, and the optimal therapeutic time is at 24 h after cerebral infarction. 23430704 Proteomic data from human cell cultures refine mechanisms of chaperone-mediated protein homeostasis. In the crowded environment of human cells, folding of nascent polypeptides and refolding of stress-unfolded proteins is error prone. Accumulation of cytotoxic misfolded and aggregated species may cause cell death, tissue loss, degenerative conformational diseases, and aging. Nevertheless, young cells effectively express a network of molecular chaperones and folding enzymes, termed here "the chaperome," which can prevent formation of potentially harmful misfolded protein conformers and use the energy of adenosine triphosphate (ATP) to rehabilitate already formed toxic aggregates into native functional proteins. In an attempt to extend knowledge of chaperome mechanisms in cellular proteostasis, we performed a meta-analysis of human chaperome using high-throughput proteomic data from 11 immortalized human cell lines. Chaperome polypeptides were about 10 % of total protein mass of human cells, half of which were Hsp90s and Hsp70s. Knowledge of cellular concentrations and ratios among chaperome polypeptides provided a novel basis to understand mechanisms by which the Hsp60, Hsp70, Hsp90, and small heat shock proteins (HSPs), in collaboration with cochaperones and folding enzymes, assist de novo protein folding, import polypeptides into organelles, unfold stress-destabilized toxic conformers, and control the conformal activity of native proteins in the crowded environment of the cell. Proteomic data also provided means to distinguish between stable components of chaperone core machineries and dynamic regulatory cochaperones. 23567950 Synthesis and biological evaluation of novel aliphatic amido-quaternary ammonium salts for anticancer chemotherapy: Part II. A series of novel aliphatic amido-quaternary ammonium salts were synthesized and evaluated for their anticancer effects involving induction of RhoB. Most of these compounds, featuring open-ring forms of aliphatic amido-quaternary ammonium salts, exhibited potent anti-proliferative activities in human cancer cell lines, including PC-3, NUGC-3, MDA-MB-231, ACHN, HCT-15, and NCI-H23. In further evaluation, the representative compound N,N-diethyl-N-(2-(N-methyltetradecanamido)ethyl)prop-2-en-1-aminium bromide (3b) exhibited potent pro-apoptotic activity, through RhoB activation, in HeLa cells. 23830745 Patient selection in outpatient surgery. Ambulatory surgery is commonplace for a multitude of procedures and a wide range of patients. The types of procedures performed in the ambulatory setting are becoming more work-intensive, and patients with comorbidities make for a challenging environment. For a safe environment for surgery in ambulatory facilities, the complex task of patient selection is necessary. Until an algorithm is created that includes provider, procedure, facility, and patient comorbidites, clinicians must rely on general guidelines rather than precise recommendations. 23935943 Prenatal exposure to dexamethasone in the mouse alters cardiac growth patterns and increases pulse pressure in aged male offspring. Exposure to synthetic glucocorticoids during development can result in later cardiovascular and renal disease in sheep and rats. Although prenatal glucocorticoid exposure is associated with impaired renal development, less is known about effects on the developing heart. This study aimed to examine the effects of a short-term exposure to dexamethasone (60 hours from embryonic day 12.5) on the developing mouse heart, and cardiovascular function in adult male offspring. Dexamethasone (DEX) exposed fetuses were growth restricted compared to saline treated controls (SAL) at E14.5, but there was no difference between groups at E17.5. Heart weights of the DEX fetuses also tended to be smaller at E14.5, but not different at E17.5. Cardiac AT1aR, Bax, and IGF-1 mRNA expression was significantly increased by DEX compared to SAL at E17.5. In 12-month-old offspring DEX exposure caused an increase in basal blood pressure of ∼3 mmHg. In addition, DEX exposed mice had a widened pulse pressure compared to SAL. DEX exposed males at 12 months had an approximate 25% reduction in nephron number compared to SAL, but no difference in cardiomyocyte number. Exposure to DEX in utero appears to adversely impact on nephrogenesis and heart growth but is not associated with a cardiomyocyte deficit in male mice in adulthood, possibly due to compensatory growth of the myocardium following the initial insult. However, the widened pulse pressure may be indicative of altered vascular compliance. 23897431 Erythropoietic Defect Associated with Reduced Cell Proliferation in Mice Lacking the 26S Proteasome Shuttling Factor Rad23b. Rad23a and Rad23b proteins are linked to nucleotide excision DNA repair (NER) via association with the DNA damage recognition protein Xeroderma Pigmentosum group C (XPC) and known to be implicated in protein turnover by the 26S proteasome. Rad23b null mice are NER proficient, likely due to the redundant function of its paralogue, Rad23a. However, Rad23b null mid-gestation embryos are anemic, and most embryos die before birth. Using an unbiased proteomics approach, we found that the majority of Rad23b interacting partners are associated with the Ubiquitin-Proteasome System (UPS). We tested the requirement for Rad23b-dependent UPS activity in cellular proliferation and more specifically in the process of erythropoiesis. In cultured fibroblasts derived from embryos lacking Rad23b, proliferation rates were reduced. In fetal livers of Rad23b null embryos, we observed reduced proliferation, accumulation of early erythroid progenitors and a block during erythroid maturation. In primary WT erythroid cells, knockdown of Rad23b or chemical inhibition of the proteasome reduced survival and differentiation capability. Finally, the defects linked to Rad23b loss specifically affected fetal definitive erythropoiesis and stress erythropoiesis in adult mice. Together, these data indicate a previously unappreciated requirement for Rad23b and the UPS in regulation of proliferation in different cell types. 23665185 Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites. For several years hepatologists have defined acute renal failure in patients with cirrhosis as an increase in serum creatinine (sCr) ⩾50% to a final value of sCr>1.5mg/dl (conventional criterion). Recently, the Acute Kidney Injury Network (AKIN) defined acute renal failure as acute kidney injury (AKI) on the basis of an absolute increase in sCr of 0.3mg/dl or a percentage increase in sCr⩾50% providing also a staging from 1 to 3. AKIN stage 1 was defined as an increase in sCr⩾0.3mg/dl or increase in sCr⩾1.5-fold to 2-fold from baseline. AKI diagnosed with the two different criteria was evaluated for the prediction of in-hospital mortality. Consecutive hospitalized patients with cirrhosis and ascites were included in the study and evaluated for the development of AKI. Conventional criterion was found to be more accurate than AKIN criteria in improving the prediction of in-hospital mortality in a model including age and Child-Turcotte-Pugh score. The addition of either progression of AKIN stage or a threshold value for sCr of 1.5mg/dl further improves the value of AKIN criteria in this model. More in detail, patients with AKIN stage 1 and sCr<1.5mg/dl had a lower mortality rate (p=0.03), a lower progression rate (p=0.01), and a higher improvement rate (p=0.025) than patients with AKIN stage 1 and sCr⩾1.5mg/dl. Conventional criterion is more accurate than AKIN criteria in the prediction of in-hospital mortality in patients with cirrhosis and ascites. The addition of either the progression of AKIN stage or the cut-off of sCr⩾1.5mg/dl to the AKIN criteria improves their prognostic accuracy. 23649169 Structural health and the politics of african american masculinity. This commentary describes ways in which notions of African American men's "health" attained by individual choice-embedded in the notion that African American men should visit doctors or engage in fewer risky behaviors-are at times in tension with larger cultural, economic, and political notions of "health." It argues that efforts to improve the health of Black men must take structural factors into account, and failure to do so circumvents even well-intentioned efforts to improve health outcomes. Using historical examples, the article shows how attempts to identify and intervene into what are now called social determinants of health are strengthened by addressing on-the-ground diagnostic disparities and also the structural violence and racism embedded within definitions of illness and health. And, that, as such, we need to monitor structural barriers to health that exist in institutions ostensibly set up to incarcerate or contain Black men and in institutions ostensibly set up to help them. 23800735 Improvement of fermentation ability under baking-associated stress conditions by altering the POG1 gene expression in baker's yeast. During the bread-making process, yeast cells are exposed to many types of baking-associated stress. There is thus a demand within the baking industry for yeast strains with high fermentation abilities under these stress conditions. The POG1 gene, encoding a putative transcription factor involved in cell cycle regulation, is a multicopy suppressor of the yeast Saccharomyces cerevisiae E3 ubiquitin ligase Rsp5 mutant. The pog1 mutant is sensitive to various stresses. Our results suggested that the POG1 gene is involved in stress tolerance in yeast cells. In this study, we showed that overexpression of the POG1 gene in baker's yeast conferred increased fermentation ability in high-sucrose-containing dough, which is used for sweet dough baking. Furthermore, deletion of the POG1 gene drastically increased the fermentation ability in bread dough after freeze-thaw stress, which would be a useful characteristic for frozen dough baking. Thus, the engineering of yeast strains to control the POG1 gene expression level would be a novel method for molecular breeding of baker's yeast. 23838648 Non-HLA antibodies in solid organ transplantation: recent concepts and clinical relevance. Humoral responses beyond major histocompatibility antigens continue to receive the attention of the transplantation community. We report on clinical studies testing clinical relevance of non-human leukocyte antigen (HLA) antigens in solid organ transplantation and provide an update on novel experimental findings. A conceptual framework on the role of graft microenvironment during initiation of non-HLA-related humoral immunity is addressed as well. Clinical relevance of antibodies targeting angiotensin type 1 receptor (AT1R-Abs) is broadly confirmed in renal and cardiac transplantation, where in addition antibodies against endothelin type A receptor (ETAR-Abs) were found. Obliterative lesions in lung allografts occur more commonly in the presence of antibodies directed against K-α 1 tubulin and collagen-V. Anti-perlecan antibodies are newly identified as accelerators of obliterative vascular lesions. Changes in the intragraft microenvironment, ischemia and alloimmunity seem to represent important permissive factors for non-HLA antibody responses. Confirmed clinical relevance of non-HLA humoral responses in solid organ transplantation emphasizes the need for revision of classical diagnostic approaches based solely on detection of HLA-donor-specific antibodies (DSA). A better understanding of intersections of HLA- and non-HLA-related mechanisms and identification of common effector mechanisms would represent an important step towards targeted therapies. 22727690 Developments in the systemic treatment of metastatic cervical cancer. Despite the available prevention and early detection strategies, advanced squamous-cell carcinoma of the uterine cervix remains a major concern for public health. Systemic treatment with cisplatin, either in combination with external beam irradiation for locally advanced disease, or as monotherapy for recurrent/metastatic disease has been the cornerstone of treatment for more than two decades. Cisplatin has been also combined with a number of agents including paclitaxel, topotecan, gemcitabine, vinorelbine and ifosfamide, leading to encouraging response rates and increases in progression-free survival in a series of randomized phase III trials. Platinum-based triplets have been also tested, albeit at the cost of substantial toxicity. More recently, combinations with molecular agents targeting critical pathways in cervical malignant transformation are being assessed in clinical trials. In the current review, we discuss all recent advances in the systemic treatment of metastatic cervical cancer with emphasis on the results of large randomized phase III trials. Concerns regarding treatment-related toxicity in the context of co-morbidities and the need for potent predictive biomarkers for individualized treatment are also addressed. 23922940 Cardiac complications associated with short-term mortality in schizophrenia patients hospitalized for pneumonia: a nationwide case-control study. Pneumonia is one of most prevalent infectious diseases worldwide and is associated with considerable mortality. In comparison to general population, schizophrenia patients hospitalized for pneumonia have poorer outcomes. We explored the risk factors of short-term mortality in this population because the information is lacking in the literature. In a nationwide schizophrenia cohort, derived from the National Health Insurance Research Database in Taiwan, that was hospitalized for pneumonia between 2000 and 2008 (n = 1,741), we identified 141 subjects who died during their hospitalizations or shortly after their discharges. Based on risk-set sampling in a 1∶4 ratio, 468 matched controls were selected from the study cohort (i.e., schizophrenia cohort with pneumonia). Physical illnesses were categorized as pre-existing and incident illnesses that developed after pneumonia respectively. Exposures to medications were categorized by type, duration, and defined daily dose. We used stepwise conditional logistic regression to explore the risk factors for short-term mortality. Pre-existing arrhythmia was associated with short-term mortality (adjusted risk ratio [RR] = 4.99, p<0.01). Several variables during hospitalization were associated with increased mortality risk, including incident arrhythmia (RR = 7.44, p<0.01), incident heart failure (RR = 5.49, p = 0.0183) and the use of hypoglycemic drugs (RR = 2.32, p<0.01). Furthermore, individual antipsychotic drugs (such as clozapine) known to induce pneumonia were not significantly associated with the risk. Incident cardiac complications following pneumonia are associated with increased short-term mortality. These findings have broad implications for clinical intervention and future studies are needed to clarify the mechanisms of the risk factors. 23907595 Intra-operative use of one-step nucleic acid amplification (OSNA) for detection of the tumor load of sentinel lymph nodes in breast cancer patients. The purpose of this single-center study was to determine the practicability of the intra-operative use of one-step nucleic acid amplification (OSNA) as the only method for detection of SLN. The OSNA system has been well described and is supposed to be as accurate as conventional histology. Three hundred and thirty SLNs from 143 breast cancer patients were analyzed in an intra-operative setting. The CK19-copy number was determined by OSNA and divided into 3 results ("-" no metastasis; "+" micrometastasis; "++" marcometastasis). If OSNA gave a positive result, an axillary lymph node dissection was carried out during the same session. The central 1-mm slice of each node was obtained for permanent histology. Additionally, the results were correlated to clinicopathological factors, and the time for the intra-operative use was evaluated. Thirty-nine of the 143 patients were OSNA positive, 22 with macrometastatic and 17 with micrometastatic spread. The mean time for the OSNA run with one SLN was 34.4 min. We could show a correlation between the tumor size and OSNA positivity as well as between the numbers of OSNA positive SLNs with the tumor load of associated non-SLNs. Furthermore, we found that a cutoff CK19 copy number of 7,900/μL indicates a positive non-SLN result with the highest sensitivity (91 %) and specificity (61 %). We found OSNA to be very helpful for the intra-operative determination of the tumor load of a SLN as a basis for decision-making concerning further surgical axillary intervention. OSNA allows precise differentiation of micro- from macrometastasis, and the CK19 copy number predicts the probability of tumor load in other axillary lymph nodes and might help to find adequate adjuvant treatment options. This objective method is well suitable for everyday use and may reduce the pathologic workload and the risk of secondary operative interventions with all associated costs and stress for the patients. 23937966 Multiple tuberculous nodules with metachronous changes: a case report. Spontaneous regression of lesions occurs in non-infectious benign diseases, such as sarcoidosis, as well as in infectious diseases, such as tuberculosis. Lung cancer and malignant lymphoma, on the other hand, rarely follow a similar course. We report a rare case of lung tuberculosis that presented with multiple nodules with metachronous changes in size. We describe the case of a 50-year-old immunocompetent Japanese man with pulmonary tuberculosis in the form of multifocal nodules. He came to our hospital because of a chest X-ray abnormality. During the course of observation, some nodules reduced while others enlarged in size. Two years after the first visit, fever and pleural effusion appeared. The sputum examination turned out to be positive for tuberculosis. A course of anti-tubercular agents resolved the pleural effusion and multifocal nodules. Differences in the manner of granuloma formation suggest that the local immune response can be different even in the same lung field. 23822111 Redox-Linked Conformational Control of Proton-Coupled Electron Transfer: Y122 in the Ribonucleotide Reductase β2 Subunit. Tyrosyl radicals play essential roles in biological proton-coupled electron transfer (PCET) reactions. Ribonucleotide reductase (RNR) catalyzes the reduction of ribonucleotides and is vital in DNA replication in all organisms. Class Ia RNRs consist of α2 and β2 homodimeric subunits. In class Ia RNR, such as the E. coli enzyme, an essential tyrosyl radical (Y122O(•))-diferric cofactor is located in β2. Although Y122O(•) is extremely stable in free β2, Y122O(•) is highly reactive in the quaternary substrate-α2β2 complex and serves as a radical initiator in catalytic PCET between β2 and α2. In this report, we investigate the structural interactions that control the reactivity of Y122O(•) in a model system, isolated E. coli β2. Y122O(•) was reduced with hydroxyurea (HU), a radical scavenger that quenches the radical in a clinically relevant reaction. In the difference FT-IR spectrum, associated with this PCET reaction, amide I (CO) and amide II (CN/NH) bands were observed. Specific (13)C-labeling of the tyrosine C1 carbon assigned a component of these bands to the Y122-T123 amide bond. Comparison to density functional calculations on a model dipeptide, tyrosine-threonine, and structural modeling demonstrated that PCET is associated with a Y122 rotation and a 7.2 Å translation of the Y122 phenolic oxygen. To test for the functional consequences of this structural change, a proton inventory defined the origin of the large solvent isotope effect (SIE = 16.7 ± 1.0 at 25 °C) on this reaction. These data suggest that the one-electron, HU-mediated reduction of Y122O(•) is associated with two, rate-limiting (full or partial) proton transfer reactions. One is attributable to HU oxidation (SIE = 11.9, net H atom transfer), and the other is attributable to coupled, hydrogen-bonding changes in the Y122O(•)-diferric cofactor (SIE = 1.4). These results illustrate the importance of redox-linked changes to backbone and ring dihedral angles in high potential PCET and provide evidence for rate-limiting, redox-linked hydrogen-bonding interactions between Y122O(•) and the iron cluster. 23833763 Carbon dots and chitosan composite film based biosensor for the sensitive and selective determination of dopamine. A simple, sensitive and reliable dopamine (DA) biosensor was developed based on a carbon dots (CDs) and chitosan (CS) composite film modified glassy carbon electrode (CDs-CS/GCE). Under optimal conditions, the CDs-CS/GCE showed a better electrochemical response for the detection of DA than that of the glassy carbon electrode (GCE). The oxidation peak current (Ipa) of DA was linear with the concentration of DA in the range from 0.1 μM to 30.0 μM with the limit of detection as 11.2 nM (3S/N). The CDs-CS/GCE was applied to the detection of DA content in an injection solution of DA with satisfactory results. 23686274 Comparative persistence of subgroups of F-specific RNA phages in river water. F-specific (F+) RNA phages are widely used as indicators for the presence of fecal contamination and/or enteric viruses in water, and identifying subgroups of F+ RNA phages provides an approach for microbial source tracking. Different survival characteristics of the F+ RNA phage subgroups result in a misinterpretation of their original proportion in water, thus giving misleading information when they are used for microbial source tracking. This study investigated the comparative persistence of subgroups of F+ RNA phages in river water under different conditions. Results suggested that temperature and pH are the major factors affecting the persistence of F+ RNA phages in river water, and organic substances promote phage survival. The comparative persistence patterns of subgroups of F+ RNA phages varied and may bias extrapolation of their initial proportions in surface water. Thus, the characteristics of water should be taken into consideration and the results should be carefully interpreted when F+ RNA phages are used for microbial source tracking. 23318685 Peginesatide clearance, distribution, metabolism, and excretion in monkeys following intravenous administration. Peginesatide, a polyethylene glycol (PEG)ylated peptide-based erythropoiesis-stimulating agent, stimulates the erythropoietin receptor dimer that governs erythropoiesis. Studies were designed to determine the erythropoietic response, pharmacokinetics (PK), tissue distribution, metabolism, and excretion of peginesatide in nonhuman primates following a single i.v. dose. The PK profile of peginesatide (0.1-5 mg/kg) is characterized by low, dose-dependent plasma clearance; small volume of distribution; and long half-life. The peginesatide PK profile following a single i.v. dose is consistent with the sustained erythropoiesis. Biodistribution quantitative whole-body autoradiography demonstrated high peginesatide levels in bone marrow (i.e., primary hematopoietic site) as well as other known hematopoietic sites persisting through at least 3 weeks at 2.1 mg/kg. Microautoradiography analysis at 48 hours postdose revealed uniform and high distribution of radioactivity in the bone marrow and splenic red pulp with less extensive distribution in the renal cortex (glomeruli, associated ducts, interstitial cells). Radioactivity in the kidney was most prominent in the outer medullary and papillary interstitium. At 2 weeks after dosing, cumulative radioactivity recovery in the urine and feces was 60 and 7% of the administered dose, respectively, with most of the radioactivity associated with the parent molecule. In conclusion, the PK characteristics are consistent with a PEGylated peptide of a 45-kDa molecular mass, specifically low volume of distribution and long half-life. Drug was localized principally to hematopoietic sites, and nonspecific tissue retention was not observed. The nonhuman primate data indicate that peginesatide is metabolically stable and primarily excreted in the urine. 23733003 Algibacter miyuki sp. nov., a member of the family Flavobacteriaceae isolated from leachate of a brown algae reservoir. A Gram-negative, aerobic, non-flagellated, non-gliding and rod-shaped bacterial strain, designated WS-MY6(T), was isolated from a brown algae reservoir in South Korea. Strain WS-MY6(T) grew optimally at 25 °C, at pH 7.0-8.0 and in the presence of 2 % (w/v) NaCl. Neighbour-joining, maximum-likelihood and maximum-parsimony phylogenetic trees based on 16S rRNA gene sequences showed that strain WS-MY6(T) clustered with the type strains of Algibacter lectus and 'Algibacter undariae', showing 16S rRNA gene sequence similarity values of 98.1 and 98.4 %, respectively. It exhibited sequence similarities of 95.4-96.7 % to the type strains of the other Algibacter species, Pontirhabdus pectinovorans and Marinivirga aestuarii, whose reclassification into the genus Algibacter has been recently proposed. Strain WS-MY6(T) contained MK-6 as the predominant menaquinone and iso-C15:1 G, anteiso-C15:0 and iso-C17:0 3-OH as the major fatty acids. It contained phosphatidylethanolamine and two unidentified lipids as the major polar lipids. The DNA G + C content of strain WS-MY6(T) was 35.3 mol% and its DNA-DNA relatedness values with A. lectus KCTC 12103(T) and 'A. undariae' WS-MY9(T) was 21 and 13 %, respectively. The phylogenetic and genetic distinctiveness and differential phenotypic properties revealed that strain WS-MY6(T) is separate from existing Algibacter species. On the basis of the data presented, strain WS-MY6(T) is considered to represent a novel species of the genus Algibacter, for which the name Algibacter miyuki sp. nov. is proposed. The type strain is WS-MY6(T) (=KCTC 32382(T) =CECT 8300(T)). 23877788 Block of P2X7 receptors could partly reverse the delayed neuronal death in area CA1 of the hippocampus after transient global cerebral ischemia. Transient global ischemia (which closely resembles clinical situations such as cardiac arrest, near drowning or severe systemic hypotension during surgical procedures), often induces delayed neuronal death in the brain, especially in the hippocampal CA1 region. The mechanism of ischemia/reperfusion (I/R) injury is not fully understood. In this study, we have shown that the P2X7 receptor antagonist, BBG, reduced delayed neuronal death in the hippocampal CA1 region after I/R injury; P2X7 receptor expression levels increased before delayed neuronal death after I/R injury; inhibition of the P2X7 receptor reduced I/R-induced microglial microvesicle-like components, IL-1β expression, P38 phosphorylation, and glial activation in hippocampal CA1 region after I/R injury. These results indicate that antagonism of the P2X7 receptor and signaling pathways of microglial MV shedding, such as src-protein tyrosine kinase, P38 MAP kinase and A-SMase, might be a promising therapeutic strategy for clinical treatment of transient global cerebral I/R injury. 23807242 Arterial hypertension and cardiovascular risk in HIV-infected patients. The dramatic change of the natural history of HIV-infected patients by highly active antiretroviral therapy (HAART) has exposed these patients to cardiovascular risk, including cardiovascular disease and hypertension. In HIV-infected patients, the development of arterial hypertension, at least in the medium-long term is an established feature, although recognized predictors of its development have not been clearly identified. In addition, conflicting data regarding the influence of antiretroviral therapy (ART) are reported. The presence of a proinflammatory state and oxidative stress-mediated endothelial dysfunction seem, however, to play a pathophysiologic role. In this review, we examine and provide a comprehensive, literature based, consideration of the pathophysiologic aspects of hypertension in these patients. HIV-infected patients, independently of the presence of hypertension, remain at very high cardiovascular risk due to the presence of the same cardiovascular risk factors recognized for the general population with, in addition, the indirect influence of the ART, essentially via its effect on lipid metabolism. This review based on the evidence from the literature, concludes that the management of HIV-infected patients in terms of cardiovascular prevention emerges as a priority. The consideration of cardiovascular risk in these patients should receive the same emphasis given for the general population at high cardiovascular risk, including adequate blood pressure control according to international guidelines. 23347146 T-cell memory differentiation: insights from transcriptional signatures and epigenetics. A critical component of vaccine design is to generate and maintain antigen-specific memory lymphocytes of sufficient quantity and quality to give the host life-long protection against re-infection. Therefore, it is important to understand how memory T cells acquire the ability for self-renewal while retaining a potential for heightened recall of effector functions. During acute viral infection or following vaccination, antigen-specific T cells undergo extensive phenotypic and functional changes during differentiation to the effector and memory phases of the immune response. The changes in cell phenotype that accompany memory T-cell differentiation are predominantly mediated through acquired transcriptional regulatory mechanisms, in part achieved through epigenetic modifications of DNA and histones. Here we review our current understanding of epigenetic mechanisms regulating the off-on-off expression of CD8 and CD4 T-cell effector molecules at naive, effector and memory stages of differentiation, respectively, and how covalent modifications to the genome may serve as a mechanism to preserve 'poised' transcriptional states in homeostatically dividing memory cells. We discuss the potential of such mechanisms to control genes that undergo on-off-on patterns of expression including homing and pro-survival genes, and the implications on the development of effector-memory and central-memory T-cell differentiation. Lastly, we review recent studies demonstrating epigenetic modifications as a mechanism for the progressive loss of transcriptional adaptation in antigen-specific T cells that undergo sustained high levels of T-cell receptor signalling. 23574453 Outcome of acquired haemophilia in France: the prospective SACHA (Surveillance des Auto antiCorps au cours de l'Hémophilie Acquise) registry. Although extremely rare, acquired haemophilia A (AHA) can cause severe bleeding, which may be fatal. The underlying causes of autoantibody development are not fully understood. Treatment goals are bleeding control and autoantibody eradication. At the time of our study, there was no consensus on a standard treatment strategy for AHA. Previous data were mainly retrospective or from single-centre cohorts. We conducted a prospective, controlled, registry-based study of patients with AHA in France. The prospective French registry (Surveillance des Auto antiCorps au cours de l'Hémophilie Acquise [SACHA]) collected data on prevalence, clinical course, disease associations and outcomes for haemostatic treatment and autoantibody eradication in 82 patients with a 1-year follow-up. Similar to earlier studies, the prevalence of AHA was higher in the elderly, with two thirds of patients aged >70 years. Around half of AHA cases were associated with underlying disease, most commonly autoimmune disease and cancer in younger and older patients respectively. Haemostatic treatment was initially administered to 46% of patients. Complete resolution or improvement of initial bleeding occurred in 22/27 (81%) rFVIIa-treated patients and in all six cases receiving pd-aPCC. The majority of patients (94%) received immunosuppressive therapy, with complete remission at 3 months in 61% (36/59) and in 98% (50/51) at 1 year. Overall mortality was 33%: secondary to bleeding in only three patients but to sepsis in 10. Bypassing agents were effective at controlling bleeding in patients with AHA. Immunosuppressive therapy should be used early but with caution, particularly in elderly patients. 23631796 Inhalation treatment with glutathione in patients with cystic fibrosis. A randomized clinical trial. Glutathione is the major antioxidant in the extracellular lining fluid of the lungs and depleted in patients with cystic fibrosis (CF). Objectives: We aimed to assess glutathione delivered by inhalation as a potential treatment for CF lung disease. This randomized, double-blind, placebo-controlled trial evaluated inhaled glutathione in subjects with CF 8 years of age and older and FEV1 of 40-90% of predicted. Subjects were randomized to receive 646 mg glutathione in 4 ml (n = 73) or placebo (n = 80) via an investigational eFlow nebulizer every 12 hours for 6 months. FEV1 (absolute values), both as pre-post differences (P = 0.180) and as area under the curves (P = 0.205), were the primary efficacy endpoints, and were not different between the glutathione group and the placebo group over the 6-month treatment period. Exploratory analysis showed an increase of FEV1 from baseline over placebo of 100 ml or 2.2% predicted; this was significant at 3 months, but not later. Subjects receiving glutathione had neither fewer pulmonary exacerbations, nor better scores for quality of life. Whereas increased glutathione and metabolites in sputum demonstrated significant delivery to the lungs, there was no indication of diminished oxidative stress to proteins or lipids, and no evidence for anti-inflammatory or antiproteolytic actions of glutathione supplemented to the airways. The adverse event incidence was similar between glutathione and placebo. Inhaled glutathione in the dose administered did not demonstrate clinically relevant improvements in lung function, pulmonary exacerbation frequency, or patient-reported outcomes. Glutathione delivery to the airways was not associated with changes in markers of oxidation, proteolysis, or inflammation. Clinical trial registered with www.clinicaltrials.gov (NCT00506688) and https://eudract.ema.europa.eu/index.html (EudraCT 2005-003870-88). 23465061 Isolation of Ciliatamide D from a Marine Sponge Stelletta sp. and a Reinvestigation of the Configuration of Ciliatamide A. A new lipopeptide, ciliatamide D (1), was isolated from a marine sponge Stelletta sp., collected at Oshimashinsone, together with the known compound ciliatamide A (2). Ciliatamide D (1) is a congener of 2, in which N-Me-Phe is replaced by N-Me-Met(O). Marfey's analysis of the acid hydrolysate of 1 demonstrated that the two constituent amino acids were both in the l-form. This result prompted us to carefully investigate the configuration of 2, resulting in the assignment of the l-form for both residues. 23821580 Possible roles of Robo1(+) ensheathing cells in guiding dorsal-zone olfactory sensory neurons in mouse. In the mouse olfactory system, the anatomical locations of olfactory sensory neurons (OSNs) correlate with their axonal projection sites along the dorsoventral axis of the olfactory bulb (OB). We have previously reported that Neuropilin-2 expressed by ventral-zone OSNs contributes to the segregation of dorsal and ventral OSN axons, and that Slit is acting as a negative land mark to restrict the projection of Robo2(+) , early-arriving OSN axons to the embryonic OB. Here, we report that another guidance receptor, Robo1, also plays an important role in guiding OSN axons. Knockout mice for Robo1 demonstrated defects in targeting of OSN axons to the OB. Although Robo1 is co-localized with dorsal-zone OSN axons, it is not produced by OSNs, but instead by olfactory ensheathing cells. These findings indicate a novel strategy of axon guidance in the mouse olfactory system during development. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013. 23714695 Effect of the position of nitrogen in pyridoindole on photophysical properties and device performances of α-, β-, γ-carboline based high triplet energy host materials for deep blue devices. Three carboline derivatives with nitrogen at different positions of the pyridoindole unit were synthesized and the effect of the position of nitrogen on the photophysical properties and device performances was investigated. β-Carboline was effective in obtaining high triplet energy and stabilizing energy levels, while α-carboline was better than other carbolines in terms of quantum efficiency. However, γ-carboline could not stabilize the LUMO level and low quantum efficiency was obtained. 23835621 Incorporation of metal-organic framework UiO-66 into porous polymer monoliths to enhance the liquid chromatographic separation of small molecules. UiO-66 incorporated monoliths were fabricated to enhance the liquid chromatographic separation of small molecules with high column efficiency and good reproducibility. 23218136 Effect of exercise on postprandial endothelial function in adolescent boys. The ingestion of high-fat meals induces a state of endothelial dysfunction in adults. This dysfunction is attenuated by prior exercise. The response of young people to these nutritional and physiological stressors has not been established. Thus, the purpose of the present study was to investigate if a bout of moderate-intensity exercise influenced endothelial function (as indicated by flow-mediated dilation (FMD)) following the ingestion of a high-fat breakfast and lunch in adolescent boys (aged 12·6-14·3 years). Two, 2 d main trials (control and exercise) were completed by thirteen adolescent boys in a counter-balanced, cross-over design. Participants were inactive on day 1 of the control trial, but completed 60 min of walking at 60 % peak oxygen uptake in the exercise trial. On day 2, endothelial function was assessed via FMD prior to, and following, ingestion of a high-fat breakfast and lunch. There was no difference in fasting FMD between the control and exercise trial (P= 0·449). In the control trial, FMD was reduced by 32 % following consumption of the high-fat breakfast and by 24 % following lunch. In the exercise trial, the corresponding reductions were 6 and 10 %, respectively (main effect trial, P= 0·002). These results demonstrate that moderate-intensity exercise can attenuate the decline in FMD seen following the consumption of high-fat meals in adolescent boys. 23787965 Ageing, cognitive disorders and professional practice. the workforce is ageing. The contribution of older workers is considerable. Their occupational health profiles differ from those of younger workers. we wished to establish whether consideration has been given by regulatory and professional bodies of the impact of ageing-related conditions such as dementia on professional practice. We e-mailed a questionnaire to 22 regulatory and professional bodies in the UK and the Republic of Ireland. We asked whether there are supports for their practitioners should they develop age-related diseases, (particularly cognitive disorders),whether the body considered that the practitioner was responsible for their own health, and whether the body has resources to arrange for medical review for their professionals if concerns arose regarding competence. Where bodies did not respond, information relating to the questions was extracted from their on-line resources. thirteen bodies responded. None of these had specific supports to assist older workers. Some knew of other supports (occupational health, employee assistance supports, benevolent funds or counselling services). All of the bodies who responded either have or are developing structures to deal with concerns regarding their practitioners. The absence of specific policies for age-related diseases, (particularly dementia), among professional and regulatory bodies is a challenge for an ageing workforce in the liberal professions. Closer working between geriatric medicine, old age psychiatry, occupational health and professional bodies is recommended to develop age-attuned policies and systems which protect the public while supporting the professionals in both work and timely transition from work. 23916972 Trends in Food and Beverage Sources among US Children and Adolescents: 1989-2010. Despite the historical rise and recent plateau of child overweight and obesity, levels remain exceedingly high. To understand these trends and identify targets for intervention it is important to examine concomitant trends in children's diets. The objective of our analysis was to describe 21-year trends in total energy intake and the major food and beverage sources of energy among 2- to 18-year-olds in the United States. Six nationally representative surveys were examined in 2012, the Continuing Survey of Food Intakes by Individuals (1989-1991 and 1994-1996, 1998) and the National Health and Nutrition Examination Survey (2003-2004, 2005-2006, 2007-2008, and 2009-2010). Total energy intake among US children and adolescents rose considerably from 1989 to 2004, and subsequently declined through 2010. Seven sources were consistently major contributors across all time points: sugar-sweetened beverages, pizza, full-fat milk, grain-based desserts, breads, pasta dishes, and savory snacks. Intakes of full-fat milk, meats and processed meat products, ready-to-eat cereals, burgers, fried potatoes, fruit juice, and vegetables decreased from 1989-2010 whereas intakes of nonfat milk, poultry, sweet snacks and candies, and tortilla- and corn-based dishes increased linearly over the 21-year period. Significant nonlinear time trends were observed with recent decreases in intakes of sugar-sweetened beverages, pizza, pasta dishes, breads and rolls, and savory snacks and recent increases in intake of fruit. Energy intakes of US children began to decline in 2003-2004 and continued to decline through 2009-2010. However, among preschool children (aged 2 to 5 years) and children from low-income families, total energy intakes in 2009-2010 still remained significantly higher than in 1989-1991. 23874763 Health and economic burden of obesity in Brazil. Higher and lower-middle income countries are increasingly affected by obesity. Obesity-related diseases are placing a substantial health and economic burden on Brazil. Our aim is to measure the future consequences of these trends on the associated disease burden and health care costs. A previously developed micro-simulation model is used to project the extent of obesity, obesity-related diseases and associated healthcare costs to 2050. In total, thirteen diseases were considered: coronary heart disease, stroke, hypertension, diabetes, osteoarthritis, and eight cancers. We simulated three hypothetical intervention scenarios: no intervention, 1% and 5% reduction in body mass index (BMI). In 2010, nearly 57% of the Brazilian male population was overweight or obese (BMI ≥25 kg/m(2)), but the model projects rates as high as 95% by 2050. A slightly less pessimistic picture is predicted for females, increasing from 43% in 2010 to 52% in 2050. Coronary heart disease, stroke, hypertension, cancers, osteoarthritis and diabetes prevalence cases are projected to at least double by 2050, reaching nearly 34,000 cases of hypertension by 2050 (per 100,000). 1% and 5% reduction in mean BMI will save over 800 prevalence cases and nearly 3,000 cases of hypertension by 2050 respectively (per 100,000). The health care costs will double from 2010 ($5.8 billion) in 2050 alone ($10.1 billion). Over 40 years costs will reach $330 billion. However, with effective interventions the costs can be reduced to $302 billion by 1% and to $273 billion by 5% reduction in mean BMI across the population. Obesity rates are rapidly increasing creating a high burden of disease and associated costs. However, an effective intervention to decrease obesity by just 1% will substantially reduce obesity burden and will have a significant effect on health care expenditure. 23546599 PTHrP is endogenous relaxant for spontaneous smooth muscle contraction in urinary bladder of female rat. Acute bladder distension causes various morphological and functional changes, in part through altered gene expression. We aimed to investigate the physiological role of PTHrP, which is upregulated in an acute bladder distension model in female rats. In the control Empty group, bladders were kept empty for 6 h, and in the Distension group, bladders were kept distended for 3 h after an artificial storing-voiding cycle for 3 h. In the Distention group bladder, upregulation of transcripts was noted for three genes reported to be upregulated by stretch in the cultured bladder smooth muscle cells (BSMC) in vitro. Further transcriptome analysis by microarray identified PTHrP as the 2second highest gene upregulated in Distension group bladder, among more than 27,000 genes. Localization of PTHrP and its functional receptor, PTH/PTHrP receptor 1(PTH1R), were analyzed in the untreated rat bladders and cultured bladder cells using real-time RT-PCR and immunoblotting, which revealed that PTH1R and PTHrP were more predominantly expressed in smooth muscle than in urothelium. Exogenous PTHrP peptide (1-34) increased intracellular cAMP level in cultured BSMC. In organ bath study using bladder strips, the PTHrP peptide caused a marked reduction in the amplitude of spontaneous contraction, but caused only modest suppression for carbachol-induced contraction. In in vivo functional study by cystometrogram, the PTHrP peptide decreased voiding pressure and increased bladder compliance. Thus, PTHrP is a potent endogenous relaxant of bladder contraction, and autocrine or paracrine mechanism of PTHrP-PTH1R axis is a physiologically relevant pathway functioning in the bladder. 23831332 Cholesterol load of microglia: Contribution of membrane architecture changes to neurotoxic power? Considerable evidence provides a link between hypercholesterolemia and ageing-related neurodegenerative diseases. The present study was aimed to provide a complex view on the effects caused by cholesterol- and cholesterol 5α,6α-epoxide-load in microglia, with particular emphasize put on membrane proteins. Prolonged application of oxysterol significantly enhanced LPS-stimulated association of cytosolic NADPH-oxidase factor p47[phox] with detergent-resistant microdomains (DRMs) in BV-2 cells. Although the treatment with both sterols does not influence the portion of CD36 receptor in DRMs, its apparent surface-cellular expression was altered. Even though sterol-treatment potentiated oxidant production by microglia, as well as their phagocytosis, these effects, however, appeared to be independent of cholesterol profusion in the membrane. In addition, oxysterol-treatment resulted in a loss of DRMs-associated activity of 26S proteasome, the protease critically regulating both protein homeostasis and immune signaling in microglia. Oxysterol relatively ameliorated cytotoxic effects of inflammed microglia on co-cultured PC12 cells. The outcomes of this study suggest that cholesterol and cholesterol oxides can differentially modulate microglia resulting either in impairment of their immune functionalities or enhanced neurotoxic power. Moreover, these findings shed light on possible complexity of this effect, produced by simultaneous affection of the levels, distribution and function of the critical proteins within microglial membrane compartments. 23545099 Comparative effectiveness review: prostate cancer antigen 3 testing for the diagnosis and management of prostate cancer. We compared the effectiveness of PCA3 (prostate cancer antigen 3) and select comparators for improving initial or repeat biopsy decision making in men at risk for prostate cancer, or treatment choices in men with prostate cancer. MEDLINE®, EMBASE®, Cochrane Database and gray literature were searched from January 1990 through May 2012. Included studies were matched, and measured PCA3 and comparator(s) within a cohort. No matched analyses were possible. Differences in independent performance estimates between PCA3 and comparators were computed within studies. Studies were assessed for quality using QUADAS (Quality Assessment of Diagnostic Accuracy Studies) and for strength of evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. Among 1,556 publications identified, 34 observational studies were analyzed (24 addressed diagnostic accuracy and 13 addressed treatment decisions). Most studies were conducted in opportunistic cohorts of men referred for procedures and were not designed to answer key questions. Two study biases (partial verification and sampling) were addressed by analyses, allowing some conclusions to be drawn. PCA3 was more discriminatory than total prostate specific antigen increases (eg at an observed 50% specificity, summary sensitivities were 77% and 57%, respectively). Analyses indicated that this finding holds for initial and repeat biopsies, and that the markers were independent predictors. For all other biopsy decision making comparisons and associated health outcomes, strength of evidence was insufficient. For treatment decision making, strength of evidence was insufficient for all outcomes and comparators. PCA3 had a higher diagnostic accuracy than total prostate specific antigen increases, but strength of evidence was low (limited confidence in effect estimates). Strength of evidence was insufficient to conclude that PCA3 testing leads to improved health outcomes. For all other outcomes and comparators, strength of evidence was insufficient. 23969858 Clinical Features of Takotsubo Cardiomyopathy - A Single-Center Experience. Takotsubo cardiomyopathy (TTC), also known as transient apical ballooning syndrome or stress-induced cardiomyopathy, is a distinctive reversible condition often affecting postmenopausal women after a stressful event. It is characterized by sudden temporary systolic dysfunction of the apical and/or mid-segments of the left ventricle. The underlying mechanisms have not yet been elucidated, but several hypotheses include catecholamine cardiotoxicity, microvascular dysfunction and coronary artery spasm. We conducted a retrospective descriptive study on patients with the discharge diagnosis of TTC from 2003 to 2012 at Danbury Hospital, Danbury, Conn., USA. A total of 78 patients met the Modified Mayo Criteria for the Diagnosis of TTC and were included in the study. Clinical characteristics at baseline, past surgical and medical history including psychiatric records were reviewed and recorded. The mean age was 70.5 ± 14 years, 87% (n = 68) were women, of which 11.7% (n = 8) were aged ≤55 years. Depression was present in 20.5% (n = 16) of the patients and anxiety in 30.8% (n = 24). Twenty-one patients (27.3%) reported a preceding emotional stressful event and 31 (40.3%) had a preceding physical stressor. Fifty patients (64.1%) presented with chest pain, 28 (35.9%) had ST-segment elevation upon admission and 5 (6.3%) died during their hospital stay. TTC is becoming an increasingly recognized condition and clinicians should include it in the differential diagnosis of patients presenting with a suspected acute coronary syndrome. It is frequent in postmenopausal women with preceding physical or emotional stress and overall prognosis is good among patients who survive the initial acute phase of heart failure. 23729639 Ancient DNA damage. Under favorable conditions DNA can survive for thousands of years in the remains of dead organisms. The DNA extracted from such remains is invariably degraded to a small average size by processes that at least partly involve depurination. It also contains large amounts of deaminated cytosine residues that are accumulated toward the ends of the molecules, as well as several other lesions that are less well characterized. 23834711 Extracorporeal Detoxification for Hepatic Failure Using Molecular Adsorbent Recirculating System: Depurative Efficiency and Clinical Results in a Long-Term Follow-Up. Acute liver failure and acute-on-chronic liver failure still show a poor prognosis. The molecular adsorbent recirculating system (MARS) has been extensively used as the most promising detoxifying therapy for patients with these conditions. Sixty-four patients with life-threatening liver failure were selected, and 269 MARS treatments were carried out as a bridge for orthotopic liver transplantation (OLT) or for liver function recovery. All patients were grouped according to the aim of MARS therapy. Group A consisted of 47 patients treated for liver function recovery (median age 59 years, range 23-82). Group B consisted of 11 patients on the waiting list who underwent OLT (median age 47 years, range 32-62). Group C consisted of 6 patients on the waiting list who did not undergo OLT (median age 45.5 years, range 36-54, P = 0.001). MARS depurative efficiency in terms of liver toxins, cytokines, and growth factors was assessed together with the clinical outcome of the patients during a 1-year follow-up. Total bilirubin reduction rate per session (RRs) for each MARS session was 23% (range 17-29); direct bilirubin RRs was 28% (21-35), and indirect bilirubin RRs was 8% (3-21). Ammonia RRs was 34% (12-86). Conjugated cholic acid RRs was 58% (48-61); chenodeoxycholic acid RRs was 34% (18-48). No differences were found between groups. Hepatocyte growth factor (HGF) values on starting MARS were 4.1 ng/mL (1.9-7.9) versus 7.9 ng/mL (3.2-14.1) at MARS end (P < 0.01). Cox regression analysis to determine the risk factors predicting patient outcomes showed that age, male gender, and Sequential Organ Failure Assessment score (but not Model for End-stage Liver Disease score) were factors predicting death, whereas the number of MARS sessions and the ΔHGF proved protective factors. Kaplan-Meier survival analysis was also used; after 12 months, 21.3% of patients in Group A survived, while 90.9% were alive in Group B and 16.7% in Group C (log rank = 0.002). In conclusion, MARS was clinically well tolerated by all patients and significantly reduced hepatic toxins. Better survival rates were linked to an OLT program, but patients' clinical characteristics on starting MARS therapy were the main factors predicting survival. The role of HGF should be evaluated in larger clinical trials. 23828503 Oropharyngeal cancer related to Human Papilloma Virus: incidence and prognosis in Madrid, Spain. To report the incidence of HPV-related oropharyngeal cancer (OC) in our region, and determine the influence of HPV status on survival among patients treated with chemoradiation (CRT). A total of 102 patients with stage II-IV OC treated by CRT at four hospitals in Madrid, Spain were retrospectively reviewed. Immunohistochemistry analysis was performed to evaluate p16 expression in pretreatment tumor block samples obtained from these patients. HPV-positive and HPV-negative patients were compared to assess differences in overall survival (OS), loco-regional control and disease-free survival. Of the tumor samples evaluated, 26.7 % were p16 positive. HPV-positive patients were younger (median age, 56 vs 59 years; p = 0.052). No significant differences were observed in terms of tumor stage, gender, or smoking habit between HPV+ and HPV- patients. HPV+ patients showed a trend towards better OS (67.4, vs 49.7 %; hazard ratio, 0.55; p = 0.095). Incidence of HPV-related OC in our region is similar to that reported in other regions in Europe, yet lower than in North America. We observed a trend for improved OS in patients with HPV+ oropharyngeal cancer. 23784074 Traits are represented in the medial prefrontal cortex: an fMRI adaptation study. Neuroimaging studies on trait inference about the self and others have found a network of brain areas, the critical part of which appears to be medial prefrontal cortex (mPFC). We investigated whether the mPFC plays an essential role in the neural representation of a trait code. To localize the trait code, we used functional magnetic resonance imaging (fMRI) adaptation, which is a rapid suppression of neuronal responses upon repeated presentation of the same underlying stimulus, in this case, the implied trait. Participants had to infer an agent's (social) trait from brief trait-implying behavioral descriptions. In each trial, the critical (target) sentence was preceded by a sentence (prime) that implied the same trait, the opposite trait, or no trait at all. The results revealed robust adaptation from prime to target in the ventral mPFC only during trait conditions, as expected. Adaptation was strongest after being primed with a similar trait, moderately strong after an opposite trait and much weaker after a trait-irrelevant prime. This adaptation pattern was found nowhere else in the brain. In line with previous research on fMRI adaptation, we interpret these findings as indicating that a trait code is represented in the ventral mPFC. 22459381 Bivalvular transcatheter treatment of high-surgical-risk patients with coexisting severe aortic stenosis and significant mitral regurgitation. In inoperable or high-surgical-risk patients, transcatheter aortic valve replacement (TAVR) and repair of the mitral valve using the MitraClip have emerged as novel treatment strategies. We sought to assess the feasibility and effectiveness of bivalvular transcatheter therapy in patients with coexisting aortic stenosis and mitral regurgitation. Out of 285 patients treated with TAVR and 226 patients who underwent MitraClip therapy at our institution, 11 patients (78±6years, 9 men [82%]) received both therapies. TAVR preceded MitraClip therapy in 10 patients, with 3 patients undergoing both interventions in a single session. TAVR via transapical (n=6) or transfemoral (n=5) access utilized the Sapien/Sapien XT and CoreValve prostheses in 7 and 4 patients, respectively. All TAVR procedures were successful, with significant increases in effective aortic orifice area and decreases in mean transvalvular pressure gradient. MitraClip therapy succeeded in reducing MR severity to <2+ in 10 patients. Periprocedurally, 1 patient sustained a stroke. At a median of 208days, 2 patients were in NYHA functional class II, with only 1 patient improved from before TAVR, and 6 patients were in class III (improvement in 1). Four patients had died at a median of 60days after MitraClip therapy. Bivalvular transcatheter treatment of patients with coexisting aortic stenosis and MR is technically feasible, even in a single session. Given the low prevalence of midterm functional improvement, factors predictive of clinical benefit from catheter-based double-valve intervention remain to be determined. 23940457 Par-1 regulates tissue growth by influencing hippo phosphorylation status and hippo-salvador association. The evolutionarily conserved Hippo (Hpo) signaling pathway plays a pivotal role in organ size control by balancing cell proliferation and cell death. Here, we reported the identification of Par-1 as a regulator of the Hpo signaling pathway using a gain-of-function EP screen in Drosophila melanogaster. Overexpression of Par-1 elevated Yorkie activity, resulting in increased Hpo target gene expression and tissue overgrowth, while loss of Par-1 diminished Hpo target gene expression and reduced organ size. We demonstrated that par-1 functioned downstream of fat and expanded and upstream of hpo and salvador (sav). In addition, we also found that Par-1 physically interacted with Hpo and Sav and regulated the phosphorylation of Hpo at Ser30 to restrict its activity. Par-1 also inhibited the association of Hpo and Sav, resulting in Sav dephosphorylation and destabilization. Furthermore, we provided evidence that Par-1-induced Hpo regulation is conserved in mammalian cells. Taken together, our findings identified Par-1 as a novel component of the Hpo signaling network. 23917653 Cognition, behavior and social competence of preterm low birth weight children at school age. The aim of this study was to assess the cognitive and behavioral development of preterm and low birth weight newborns living in a disadvantageous socioeconomic environment at school age. This cross-sectional study included children aged 6-7 from a historical birth cohort of preterm (gestational age <37 weeks) and low birth weight (<2,500 g) infants. The Wechsler Intelligence Scale for Children III (WISC-III) was administered by a psychologist while the parents completed the Child Behavior Checklist. The results were compared to the test's reference. The perinatal information and follow-up data were collected from the hospital files. The demographic data were collected from the parents. The current performance was compared with the results from the Denver II and Bayley II tests, which were administered during the first years of life. The total intelligence quotient varied from 70 to 140 (mean 98.7±15.8). The borderline intelligence quotient was observed in 9.3% of the children. The Child Behavior Checklist indicated a predominance of social competence problems (27.8%, CI 19.2 to 37.9) compared with behavioral problems (15.5%, CI 8.9 to 24.2). Both the Child Behavior Checklist domains, such as schooling, social and attention problems, and the cognitive scores were significantly associated with maternal education and family income. The results of the Denver and Bayley tests were associated with the cognitive performance (p<0.001) and the Child Behavior Checklist social profile, including aggressive and externalizing behavior (p<0.001). Our data suggest that even low-risk preterm newborns are at risk for developing disturbances in early school age, such as mild cognitive deficits and behavioral disorders. This risk might increase under unfavorable socioeconomic conditions. 23902985 Bone-marrow-derived mesenchymal stem cells attenuate cognitive deficits in an endothelin-1 rat model of stroke. Purpose: Stroke is the third leading cause of death and permanent disability in the United States, often producing long-term cognitive impairments, which are not easily recapitulated in animal models. The goals of this study were to assess whether: (1) the endothelin-1 (ET-1) model of chronic stroke produced discernable cognitive deficits; (2) a spatial operant reversal task (SORT) would accurately measure memory deficits in this model; and (3) bone-marrow-derived mesenchymal stem cells (BMMSCs) could reduce any observed deficits. Methods: Rats were given unilateral intracerebral injections of vehicle or ET-1, a stroke-inducing agent, near the middle cerebral artery. Seven days later, they were given intrastriatal injections of BMMSCs or vehicle, near the ischemic penumbra. The cognitive abilities of the rats were assessed on a novel SORT, which was designed to efficiently distinguish cognitive deficits from potential motoric confounds. Results: Rats given ET-1 had significantly more cognitive errors at six weeks post-stroke on the SORT, and that these deficits were attenuated by BMMSC transplants. Conclusions: These findings indicate that: (1) the ET-1 model produces chronic cognitive deficits; (2) the SORT efficiently measures cognitive deficits that are not confounded by motoric impairment; and (3) BMMSCs may be a viable treatment for stroke-induced cognitive dysfunction. 23940403 The epidemiology of child homicides in South Africa. To describe age- and sex-specific rates of child homicide in South Africa. A cross-sectional mortuary-based study was conducted in a national sample of 38 medicolegal laboratories operating in 2009. These were sampled in inverse proportion to the number that were operational in each of three strata defined by autopsy volume: < 500, 500-1499 or > 1499 annual autopsies. Child homicide data were collected from mortuary files, autopsy reports and police interviews. Cause of death, evidence of abuse and neglect or of sexual assault, perpetrator characteristics and circumstances surrounding the death were investigated. An estimated 1018 (95% confidence interval, CI: 843-1187) child homicides occurred in 2009, for a rate of 5.5 (95% CI: 4.6-6.4) homicides per 100 000 children younger than 18 years. The homicide rate was much higher in boys (6.9 per 100 000; 95% CI: 5.6-8.3) than in girls (3.9 per 100 000; 95% CI: 3.2-4.7). Child abuse and neglect had preceded nearly half (44.5%) of all homicides, but three times more often among girls than among boys. In children aged 15 to 17 years, the homicide rate among boys (21.7 per 100 000; 95% CI: 14.2-29.2) was nearly five times higher than the homicide rate among girls (4.6 per 100 000; 95% CI: 2.4-6.8). South Africa's child homicide rate is more than twice the global estimate. Since a background of child abuse and neglect is common, improvement of parenting skills should be part of primary prevention efforts. Abstract available from the publisher. Abstract available from the publisher. Abstract available from the publisher. Abstract available from the publisher. Abstract available from the publisher. 23747662 Plasmopara halstedii virus causes hypovirulence in Plasmopara halstedii, the downy mildew pathogen of the sunflower. Plasmopara halstedii virus (PhV) is an isometric virus recently found in the oomycete Plasmopara halstedii. The fully sequenced virus genome consists of two ss(+)RNA strands encoding for the virus polymerase and the coat protein, respectively. Most of previously screened field isolates of P. halstedii were found to harbor PhV, but effects of PhV on the pathogenicity and aggressiveness of the oomycete have not been investigated yet. To assess the influence of PhV on the infectivity of P. halstedii, virus-free isolates of the oomycete were searched for, cultivated on sunflower and used for single zoospore infection. Four genetically homogenous strains belonging to three different pathotypes (710, 730, 750) were established. Subcultures of each strain were successfully infected with PhV. This afforded pairs of isogenic strains with and without virus and allowed assessment of the pathogenicity (susceptibility to specific sunflower genotypes) and aggressiveness (intensity of infection, time scale and density of sporulation) in cultivation of sunflower. While no significant difference was found in the pathogenicity of P. halstedii strains with and without virus towards sunflower seedlings of different resistance (pathotype differentials), the aggressiveness of the oomycete was diminished by PhV. Compared to the virus-free strains, the time required for the first sporulation (latent period) increased by about 1day post inoculation. Progression of the pathogen from the hypocotyl into the epicotyl of sunflower (systemic infection) was reduced by about one third in the presence of virus. In the virus containing strains, the average density of sporangia produced per cm(2) cotyledon reached only 75% of the virus-free controls. In summary, the presence of PhV leads to hypovirulence effects by weakening the aggressiveness of P. halstedii. 23930880 Discrepancy in ABO Blood Grouping. Discrepancies in blood typing is one of the major reasons in eliciting a transfusion reaction. These discrepancies can be avoided through detailed analysis for the blood typing. Here, we report a subgroup of blood group type-B in the ABO system. Donor's blood was analyzed by employing commercial antisera for blood grouping. The results of forward (known antisera) and reverse (known antigen) reaction were not complimentary. A detailed analysis using the standard protocols by American Association of Blood Banking revealed the blood type as a variant of blood group-B instead of blood group-O. This is suggestive of the fact that blood group typing should be performed with extreme care and any divergence, if identified, should be properly resolved to avoid transfusion reactions. Moreover, a major study to determine the blood group variants in Pakistani population is needed. 23474365 Frank A. Beach Award: Programming of neuroendocrine function by early-life experience: A critical role for the immune system. Many neuropsychiatric disorders are associated with a strong dysregulation of the immune system, and several have a striking etiology in development as well. Our recent evidence using a rodent model of neonatal Escherichiacoli infection has revealed novel insight into the mechanisms underlying cognitive deficits in adulthood, and suggests that the early-life immune history of an individual may be critical to understanding the relative risk of developing later-life mental health disorders in humans. A single neonatal infection programs the function of immune cells within the brain, called microglia, for the life of the rodent such that an adult immune challenge results in exaggerated cytokine production within the brain and associated cognitive deficits. I describe the important role of the immune system, notably microglia, during brain development, and discuss some of the many ways in which immune activation during early brain development can affect the later-life outcomes of neural function, immune function, and cognition. 23708777 Comparison of victims' reports and court records of intimate partner violence perpetrators' criminal case outcomes. Intimate partner violence (IPV) victims often report feeling confused and uninformed about court proceedings, including even about the final disposition of the case against their partner. This is problematic because victims' decisions in responding to subsequent abuse may be significantly influenced by their beliefs about the outcomes of prior court experiences. Also, researchers often rely on victim report of court case outcomes; discrepancies between women's reports and official records may account for some of the conflicting findings in the empirical literature. In the current study, we compared the reports of case outcome given by 81 women recruited immediately after the final hearing of an IPV-related criminal case against their perpetrator with court records of case outcome. Findings revealed a fair level of agreement between women's reports and court files that was significantly different from the level of agreement expected by chance, but far from perfect. Level of agreement increased substantially when cases involving suspended sentences were removed. In reviewing these findings, we discuss the extent to which results can or cannot be interpreted as reflecting the accuracy of women's knowledge and review their implications for IPV researchers and court systems. 22891925 Coordination and bond activation in complexes of regioisomeric phenylpyridines with the nickel(II) chloride cation in the gas phase. Electrospray ionization of dilute solutions of phenylpyridines (phpy) in the presence of nickel(II) chloride leads to gaseous ions of the type [Ni(phpy)(m)](2+) with m = 3-5 and [NiCl(phpy)(n)](+) with n = 1-3, which are characterized by various gas-phase experiments in combination with calculations using density functional theory. Of the regioisomeric phpy's, 2-phpy behaves drastically different compared to 3- and 4-phpy. Ion mobility mass spectrometry allows a differentiation of the gaseous ions and an elucidation of characteristic properties of the metal complexes. For 2-phpy, C-H bond activation in the [NiCl(phpy)(2)](+) complex is significant, whereas this route is almost suppressed for the corresponding complexes of 3- and 4-phpy and only occurs at elevated energies. 23860321 A potentially functional polymorphism in the regulatory region of let-7a-2 is associated with an increased risk for diabetic nephropathy. Diabetic nephropathy (DN) is a major diabetic complication. However, the initiating molecular events triggering DN are unknown. MicroRNAs (miRNAs) have recently been identified as regulators that modulate the target gene expression and are involved in DN. However, the evidence of the mechanism is still insufficient in human samples. In this study, microRNA microarray assay was used to study gene differential expression profiles in DN and diabetes mellitus (DM) patients. One of the specific differentially expressed microRNAs, let-7a, was down-expressed in DN. Additionally, the expression of let-7a was also decreased in DN by real-time RT PCR in the patients' samples. Moreover, single nucleotide polymorphism (SNP) analysis was used to evaluate the relationship between three SNPs in the regulatory region of let-7a-2 gene and the risk of DN in the Chinese Han population by means of PCR-restriction fragment length polymorphism (RFLP-PCR). Also, the genotype and allele frequencies of let-7a-2 polymorphism were tested in 274 individuals, including 108 DN, 104 DM patients and 62 health control individuals (CON). It was found that a variant rs1143770 and the distributions of CT/TT genotypes were significantly different in three groups, and the CT+TT genotypes frequencies were significantly higher in DN and DM groups than that in CON group. In conclusion, let-7a-2 might participate in the regulation of the occurrence of DN, and a potential variant rs1143770 was significantly associated with the increased risk for DN. 23918167 A Preliminary Study of a Peruvian Diet Using Dietary Analysis and Hair Mineral Content as Indicators. Observations among former American residents living long-term in Peru suggested that hair health improved while in Peru. To determine if a Peruvian diet correlates with hair composition, dietary intake of nutrients and mineral content of hair were measured among Peruvian and matched US residents. Selected foods from Peru were also analyzed for mineral and antioxidant content and compared with equivalent foods available in the USA. Statistically significant differences between Peruvian and US residents' hair were found for sodium (decreased in Peru, p = 0.007) and vanadium (decreased in Peru, p = 0.03). Differences in hair composition between residencies may be explained by lower dietary sodium and vanadium intake among Peruvian residents or by lower concentrations of these minerals in Peruvian drinking water. Many significant mineral differences were also identified between Peruvian foods and their US equivalents. Although no statistically significant correlations between dietary intake and hair mineral content were found, results indicate that a Peruvian diet contributes differently to hair composition than a US diet. More research is needed to elucidate the link between a Peruvian diet and specific aspects of hair health. 23906026 Tolerance of a cow's milk-based hydrolyzed formula in patients with eosinophilic esophagitis triggered by milk. Cow's milk protein, a major food trigger for EoE in both children and adults, should be continuously avoided once identified as such. This study evaluates tolerance of a cow's milk-based extensively hydrolyzed formula (eHF) with regard to disease remission maintenance in adult patients with milk-triggered EoE. Seventeen adult patients in whom cow's milk was consecutively demonstrated to trigger EoE after an empiric six-food elimination diet-based study protocol and who subsequently maintained disease remission were prospectively recruited. They were given 400 ml of a cow's milk-based eHF daily for 8 weeks. Intraepithelial peak eosinophil and blood eosinophil counts, esophageal-related symptoms, serum total and specific IgE to major milk proteins, and eosinophil cationic protein were monitored before and after eHF intake. Thirteen male and four female patients aged 17-56 completed the study protocol. 15 patients (88.24%) achieved and maintained EoE remission, while an infiltration of ≥15 eosinophils/hpf reappeared in the remaining two patients. No differences in age, gender, symptoms, and endoscopic appearance at baseline conditions or personal/family allergic background were observed between those patients who tolerated the eHF and those who did not. Symptom scores did not significantly change after eHF intake and were significantly lower than those documented at baseline conditions or after cow's milk challenge. No differences were documented in blood eosinophil counts or serum markers after eHF intake. Most adult patients with EoE triggered by cow's milk tolerate a cow's milk-based eHF, thus providing them with a safe, economical alternative to cow's milk. 23657674 Percutaneous endoscopic transforaminal lumbar interbody fusion: is it worth it? Interbody spine fusion with cages was first described by Bagby and has been performed for a long time now in a variety of different conditions. We developed a percutaneous endoscopic lumbar fusion technique based on the principles of Kambin and an original titanium cage. From 2004 to 2010, 57 patients were operated on, 17 patients were male with a mean age of 50.29 years (range 34-71 years) and 40 were female with a mean age of 57.42 years (29-90 years). Nineteen patients had a previous operation. Patients were operated on under local anaesthesia in the prone position under image intensifier and a transforaminal percutaneous endoscopic approach. Fifty cases had a bilateral cage through a bilateral endoscopic approach, and seven cases had a unilateral endoscopic approach only; of those, three cases had only one cage. Eleven patients had a contemporary posterior plate fixation at the same time of the endoscopic cage fusion. Eight patients had a postoperative radicular pain with paresthesias. Asymptomatic migration of the cages occurred in two cases and symptomatic migration requiring a conventional secondary reoperation in 13 cases after a mean delay of eight months (range three to 36 months). The mean ODI after two years or more was 34.3 % (initial ODI 69.4 %). The technique was introduced in our practice to take care of difficult or grave co-morbidity patients, and some patients had excellent lasting results following a very short procedure and hospital stay. However, given the 36 % complication rate in this series, we do not recommend it unless decisive technical improvements are made. 23917655 Humeral internal rotation osteotomy for the treatment of Erb-Duchenne-type obstetric palsy: clinical and radiographic results. To evaluate the functional and radiographic results in patients undergoing shoulder anterior soft tissue stretching in association with open reduction and internal rotation osteotomy to centralize the humeral head as a treatment for Erb-Duchenne obstetric palsy sequelae. A total of 35 patients underwent this surgical treatment, and the mean follow-up was 4.6 years. The Mallet scale was applied before and after the surgical procedure. A total of 20 patients underwent computed tomography to assess the glenoid version and humeral head subluxation. Functional improvement was achieved, as evidenced by an increase in the Mallet scale score from 12.14 to 16.46 (p<0.001). The correction of retroversion was achieved once the glenoid version ranged from -21.4 to -12 degrees (p<0.001). The humeral head subluxation improved from 6.5 to 35.2% (p<0.001). Patients older than 6 years of age did not achieve glenohumeral joint improvement with respect to dysplastic abnormalities. Internal rotation osteotomy in association with the stretching of anterior soft tissues of the shoulder in patients under the age of 7 years provided improvements in the function, retroversion, and subluxation of the glenohumeral joint. 23225080 Impact of anemia on contrast-induced nephropathy (CIN) in patients undergoing percutaneous coronary interventions. The aim of the present study was to assess the influence of anemia on the risk of developing contrast-induced nephropathy after percutaneous coronary angioplasty. Serum creatinine values were measured before and within 48 h after the administration of contrast agents. Contrast-induced nephropathy (CIN) was defined as an increase of ≥0.5 mg/dl or ≥25 % in serum creatinine concentration over baseline within 48 h after administration. Anemia was defined as hemoglobin <120 g/l in women and <130 g/l in men. Among the 1,026 patients studied, 32 (3.1 %) developed CIN after procedure. CIN occurred in 6.3 % of the anemic patients and in 2.2 % of the non-anemic patients (P < 0.01). The incidence of CIN increased with decreasing of baseline estimated glomerular filtration rate (eGFR) in both the anemia and non-anemia groups. In patients with baseline eGFR <30 ml/min, a high proportion of both anemic and non-anemic patients experienced CIN (24.6 vs. 17.5 %). When baseline eGFR was 30-59 ml/min, the incidence of CIN in anemic patients was twofold higher than in non-anemic patients (7.9 vs. 3.8 %; P < 0.05). Multivariate logistic regression analysis found that baseline eGFR and baseline hemoglobin were independent predictors of CIN. Anemia is associated with a higher incidence of CIN in patients with moderate renal dysfunction. Patients with both preexisting renal insufficiency and anemia are at high risk of CIN. Baseline eGFR and baseline hemoglobin are independent predictors of CIN. 23916605 Phospholipase C zeta (PLCζ): Oocyte activation and clinical links to male factor infertility. Mounting scientific and clinical evidence supports the key role played by phospholipase C zeta (PLCζ), a sperm-specific protein, in the activation of oocytes following fertilisation. Lacking a pleckstrin homology domain, PLCζ remains the smallest known mammalian PLC and was first identified in 2002. Since then, PLCζ has been the target for a multitude of studies in both mammalian and non-mammalian species focused upon its fundamental biochemical activity and crucial role as the mediator of oocyte activation. The earliest event subsequent to gamete fusion is the onset of a series of intracellular calcium oscillations within the oocyte, which are known to modulate cortical granule exocytosis, release meiotic arrest, regulate gene expression, recruit maternal mRNA, and initiate embryogenesis. Collectively these processes are known as 'oocyte activation' and together, represent a fundamental mechanism for early embryonic development. Evidence suggests that these processes are initiated and controlled by calcium release from ooplasmic sources in response to PLCζ activity via the inositol-1,4,5-triphosphate (IP3) pathway. While the biochemical action of PLCζ has been extensively studied, especially in relation to the EF-hands, X-Y linker, and C2 domain, all of which play critical roles for in vivo activity, there are still key gaps in our knowledge, particularly in terms of regulation and interaction with other proteins within the oocyte. Moreover, increasing clinical evidence has revealed a strong correlation between certain types of male infertility and the aberrant expression, localisation, structure and function of PLCζ in human sperm, particularly in cases of recurrent intracytoplasmic sperm injection (ICSI) failure, globozoospermia, and oocyte activation deficiency (OAD). In addition, two heterozygous substitution mutations have been identified in the coding sequence of PLCζ in one particular patient causing disruption to the catalytic X and Y domains and resulting in infertility. Although, such cases can be treated via the use of artificial oocyte activators (AOAs) such as calcium ionophores, significant concern remains over the use of such chemical agents, largely due to the fact that calcium release manifests as a single transient, rather than a series of oscillations as observed during normal fertilisation. Current interest in PLCζ is thus to develop a series of prognostic, diagnostic and therapeutic approaches which could first identify male patients that are deficient in PLCζ and then rescue oocyte activation ability via assisted reproductive technology (ART) and a pure, functionally-active, recombinant human PLCζ protein. While significant progress has been made in such areas over recent years, there is a clear need to translate scientific findings to clinical settings in order to maximise successful outcome for patients. 23954406 Effects of sleep restriction on the human plasma metabolome. This study examined the effects of recurrent sleep restriction on the plasma metabolome of adults with familial risk of type 2 diabetes. Eleven healthy adults (6M/5F; mean [SD] age: 26 [3]years; BMI 23.5 [2.3]kg/m(2)) with parental history of type 2 diabetes participated in a two-condition, two-period randomized crossover study at the Clinical Resource Center at an academic hospital. Each participant completed two 8-night inpatient sessions with restricted (5.5-h time-in-bed) vs. adequate (8.5-h time-in-bed) sleep opportunity while daily food intake and physical activity were carefully controlled. A combination of two UHPLC/MS/MS platforms and one GC/MS platform was used to measure 362 biochemicals in fasting plasma samples collected from study participants the morning after each 8-night sleep treatment. Relative concentrations of 12 amino acids and related metabolites were increased when sleep was curtailed. Sleep restriction also induced elevations in several fatty acid, bile acid, steroid hormone, and tricarboxylic acid cycle intermediates. In contrast, circulating levels of glucose, some monosaccharides, gluconate, and five-carbon sugar alcohols tended to decline when sleep was reduced. Recurrent sleep curtailment affected multiple pathways of intermediary metabolism in adults at risk for type 2 diabetes. An elevation in plasma amino acids and related biochemicals was the most pronounced metabolic signature seen in response to 8 nights of sleep restriction. 23936345 Malaria hotspots drive hypoendemic transmission in the chittagong hill districts of bangladesh. Malaria is endemic in 13 of 64 districts of Bangladesh, representing a population at risk of about 27 million people. The highest rates of malaria in Bangladesh occur in the Chittagong Hill Districts, and Plasmodium falciparum (predominately chloroquine resistant) is the most prevalent species. The objective of this research was to describe the epidemiology of symptomatic P. falciparum malaria in an area of Bangladesh following the introduction of a national malaria control program. We carried out surveillance for symptomatic malaria due to P. falciparum in two demographically defined unions of the Chittagong Hill Districts in Bangladesh, bordering western Myanmar, between October 2009 and May 2012. The association between sociodemographics and temporal and climate factors with symptomatic P. falciparum infection over two years of surveillance data was assessed. Risk factors for infection were determined using a multivariate regression model. 472 cases of symptomatic P. falciparum malaria cases were identified among 23,372 residents during the study period. Greater than 85% of cases occurred during the rainy season from May to October, and cases were highly clustered geographically within these two unions with more than 80% of infections occurring in areas that contain approximately one-third of the total population. Risk factors statistically associated with infection in a multivariate logistic regression model were living in the areas of high incidence, young age, and having an occupation including jhum cultivation and/or daily labor. Use of long lasting insecticide-treated bed nets was high (89.3%), but its use was not associated with decreased incidence of infection. Here we show that P. falciparum malaria continues to be hypoendemic in the Chittagong Hill Districts of Bangladesh, is highly seasonal, and is much more common in certain geographically limited hot spots and among certain occupations. 23815998 Impact of magnetic resonance imaging in management of pediatric Crohn's disease. Crohn's disease (CD) is a chronic illness and radiographic evaluation is frequently used. Consequently, pediatric patients with CD who are diagnosed in childhood are at risk for high levels of radiation exposure during their lifetimes. We sought to evaluate the impact of magnetic resonance enterography (MRE) in management of pediatric patients with known or suspected Crohn's disease. A retrospective review of patients with known or suspected CD who underwent MRE for new onset of symptoms was conducted. All demographic data, clinical history, and results of all radiographic, endoscopic, and pathology studies were recorded. Twenty-eight patients with known or suspected CD underwent 31 MRE examinations. MRE showed active disease in 16 (52%), fistula or abscess in seven (22%), and no evidence of active disease in eight (26%). Sixty-five per cent of patients underwent MRE with no other radiation-based imaging used. Surgical intervention was deemed necessary after the MRE in 16 per cent. In all cases, surgical findings were consistent with MRE results. Nearly 60 per cent of patients with CD are managed based on the findings of MRE without additional radiographic evaluation. Based on the results of this retrospective study, we propose a clinical pathway for use of MRE in patients with known or suspected CD with new onset of symptoms. 23836565 Hantavirus Fever without Pulmonary Syndrome in Panama. In Panama, hantavirus pulmonary syndrome (HPS) is caused by Choclo virus, a species phylogenetically related to Andes and Maporal viruses. Up to 60% of the population has been positive for specific serum antibody in community-based surveys, but mortality is very uncommon. In four western Panama clinics, we tested individuals presenting with a severe febrile prodrome for acute hantavirus (HV) infection by immunoglobulin M enzyme-linked immunosorbent assay and reverse transcription polymerase chain reaction as well as clinically similar infections, such as dengue and leptospirosis. From 2006 to 2009, at least 21% of 117 patients diagnosed with HV infection had HV Fever (HF) with no evidence of pulmonary edema (no respiratory distress or radiographic lung infiltrates), and 44% of patients had very mild HPS (radiographic pulmonary edema but no respiratory insufficiency). HV infection caused by Choclo virus in Panama presents often as HF, which contrasts with HV in the Americas but is consistent with the high seroprevalence in endemic regions. 23793057 WURST-QCPMG sequence and "spin-lock" in (14)N nuclear quadrupole resonance. (14)N nuclear quadrupole resonance (NQR) is a promising method for the analysis of pharmaceuticals or for the detection of nitrogen based illicit compounds, but so far, the technique is still not widely used, mostly due to the very low sensitivity. This problem is already acute in the preliminary NQR stage, when a compound is being examined for the first time and the NQR frequencies are being searched for, by scanning a wide frequency range step-by-step. In the present work, we experimentally show how to increase the efficiency of this initial stage by using a combination of a wideband excitation achieved with frequency swept pulses (WURST) and a "spin-lock" state obtained with a quadrupolar-CPMG (QCPMG) sequence. In the first part we show that WURST pulses provide a much larger excitation bandwidth compared to common rectangular pulses. This increased bandwidth allows to increase the frequency step and reduces the total number of steps in a scanning stage. In the second part we show that the "spin-lock" decay time T2eff obtained with the WURST-QCPMG combination is practically identical with the T2eff obtained with the most common "spin-lock" sequence, the SLSE, despite a very different nature and length of excitation pulses. This allows for a substantial S/N increase through echo averaging in every individual step and really allows to exploit all the advantages of the wider excitation in the NQR frequency scanning stage. Our experimental results were obtained on a sample of trinitrotoluene, but identical behavior is expected for all compounds where a "spin-lock" state can be created. 23791467 Ancient cis-regulatory constraints and the evolution of genome architecture. The order of genes along metazoan chromosomes has generally been thought to be largely random, with few implications for organismal function. However, two recent studies, reporting hundreds of pairs of genes that have remained linked in diverse metazoan species over hundreds of millions of years of evolution, suggest widespread functional implications for gene order. These associations appear to largely reflect cis-regulatory constraints, with either (i) multiple genes sharing transcriptional regulatory elements, or (ii) regulatory elements for a developmental gene being found within a neighboring 'bystander' gene (known as a genomic regulatory block). We discuss implications, questions raised, and new research directions arising from these studies, as well as evidence for similar phenomena in other eukaryotic groups. 23799995 Graphene quantum dots as universal fluorophores and their use in revealing regulated trafficking of insulin receptors in adipocytes. Graphene quantum dots (GQDs) hold great promise as a new class of fluorophores for bioimaging, owing to their remarkable physicochemical properties including tunable photoluminescence, excellent photostability, and biocompatibility. Despite their highly anticipated potentials, GQDs have yet to be used to specifically label and track molecular targets involved in dynamic cellular processes in live cells. Here, we demonstrate that GQDs can serve as universal fluorophores for bioimaging because they can be readily conjugated with a wide range of biomolecules while preserving their functionalities. As a proof-of-concept demonstration, insulin-conjugated GQDs have been synthesized and utilized for specific labeling and dynamic tracking of insulin receptors in 3T3-L1 adipocytes. Our experiments reveal, for the first time, that the internalization and recycling of insulin receptors in adipocytes are oppositely regulated by apelin and TNFα, which may contribute to the regulations of these two cytokines in insulin sensitivity. 22885792 Size of TiO(2) nanoparticles influences their phototoxicity: an in vitro investigation. To uncover the size influence of TiO(2) nanoparticles on their potential toxicity, the cytotoxicity of different-sized TiO(2) nanoparticles with and without photoactivation was tested. It was demonstrated that without photoactivation, TiO(2) nanoparticles were inert up to 100 μg/ml. On the contrary, with photoactivation, the toxicity of TiO(2) nanoparticles significantly increased, which correlated well with the specific surface area of the particles. Our results also suggest that the generation of hydroxyl radicals and reactive oxygen species (ROS)-mediated damage to the surface-adsorbed biomolecules could be the two major reasons for the cytotoxicity of TiO(2) nanoparticles after photoactivation. Higher ROS generation from smaller particles was detected under both biotic and abiotic conditions. Smaller particles could adsorb more proteins, which was confirmed by thermogravimetric analysis. To further investigate the influence of the generation of hydroxyl radicals and adsorption of protein, poly (ethylene-alt-maleic anhydride) (PEMA) and chitosan were used to coat TiO(2) nanoparticles. The results confirmed that surface coating of TiO(2) nanoparticles could reduce such toxicity after photoactivation, by hindering adsorption of biomolecules and generation of hydroxyl radical (·OH) during photoactivation. 23966294 Targeting FSTL1 prevents tumor bone metastasis and consequent immune dysfunction. Bone metastasis greatly deteriorates the quality of life in cancer patients. While mechanisms have been widely investigated, the relationship between cancer bone metastasis and anti-tumor immunity in the host has been much less studied. Here we report a novel mechanism of bone metastasis mediated by FSTL1, a follistatin-like glycoprotein secreted by Snail+ tumor cells, which metastasize frequently to bone. We found that FSTL1 plays a dual role in bone metastasis, in one way by mediating tumor cell invasion and bone tropism but also in a second way by expanding a population of pluripotent mesenchymal stem-like CD45-ALCAM+ cells derived from bone marrow. CD45-ALCAM+ cells induced bone metastasis de novo, but they also generated CD8low T cells with weak CTL activity in the periphery, which also promoted bone metastasis in an indirect manner. RNAi-mediated attenuation of FSTL1 in tumor cells prevented bone metastasis along with the parallel increase in ALCAM+ cells andCD8 low T cells. These effects were accompanied by heightened anti-tumor immune responses in vitro and in vivo. In clinical specimens of advanced breast cancer, ALCAM+ cells increased with FSTL1 positivity in tumor tissues, but not in adjacent normal tissues, consistent with a causal connection between these molecules. Our findings define FSTL1 as an attractive candidate therapeutic target to prevent or treat bone metastasis, which remains a major challenge in cancer patients. 23697747 Antifungal Therapy and Management of Complications of Cryptococcosis due to Cryptococcus gattii. Background. We describe antifungal therapy and management of complications due to Cryptococcus gattii infection in 86 Australian patients followed for at least 12 months. Methods. Patient data from culture-confirmed cases (2000-2007) were recorded at diagnosis, 6 weeks, 6 months, and 12 months. Clinical, laboratory, and treatment variables associated with raised intracranial pressure (ICP) and immune reconstitution inflammatory syndrome (IRIS) were determined. Results. Seven of 10 patients with lung infection received amphotericin B (AMB) induction therapy (6 with 5-flucytosine [5-FC] for a median of 2 weeks); median duration of therapy including azole eradication therapy was 41 weeks, with a complete/partial clinical response in 78%. For neurologic disease, 88% of patients received AMB, 78% with 5-FC, for a median of 6 weeks. The median total course was 18 months. Nine patients receiving fluconazole induction therapy were reinduced with AMB plus 5-FC for clinical failure. Raised ICP (31 patients) was associated with initial abnormal neurology, and neurologic sequelae and/or death at 12 months (both P = .02); cerebrospinal fluid drains/shunts were placed in 58% of patients and in 64% of 22 patients with hydrocephalus. IRIS developed 2-12 months after starting antifungals in 8 patients, who presented with new/enlarging brain lesions. Risk factors included female sex, brain involvement at presentation, and higher median CD4 counts (all P < .05); corticosteroids reduced cryptococcoma-associated edema. Conclusions. Induction AMB plus 5-FC is indicated for C. gattii neurologic cryptococcosis (6 weeks) and when localized to lung (2 weeks). Shunting was often required to control raised ICP. IRIS presents with cerebral manifestations. 23964856 Study of the interaction among Notch pathway receptors, correlation with stemness, as well as their interaction with CD44, dipeptidyl peptidase-IV, hepatocyte growth factor receptor and the SETMAR transferase, in colon cancer stem cells. Abstract Context: The Notch signaling pathway is one of the most important pathways during normal development and implicated in self-renewal of adult stem cells and differentiation of progenitor cells. Abnormal expression of Notch receptors has been associated with many epithelial metaplastic and neoplastic lesions. Objective-materials and methods: In this particular study, it was determined the relative gene expression of Notch receptors after knockdown experiments in colon cancer stem cells (CSCs) and the gene expression changes in stemness transcription factors (Oct4, Sox2, Nanog), as well in dipeptidylpeptidase-4, CD44 antigen, Met proto-oncogene and in Metnase transposase. Results: In control CSCs Notch-2 had the higher expression, followed by Notch-1, Notch-3. Notch-4 demonstrated the lower gene expression among the receptors. The suppression of Notch-1 led to increased expression of Oct4 and Sox2, but in decreased gene expression of cMET, Setmar and CD44. The CD26 expression remained unchanged. The knockdown of Notch-2 led to decreased expression of all transcription factors. Notch-3 down regulation caused increased Oct4 gene expression, but decreased levels for the rest of the genes. Finally, the suppression of Notch-4 had the same effect as in receptor Notch-3. Discussion and conclusion: The above experimental data suggest the possible interaction between the four different receptors of Notch signaling pathway. The expression of CD26, cMET and N-methyltransferase Setmar was also changed. Finally, the stemness phenotype was changed in a different way each time, according to the receptor that was down regulated. All Notch receptors and particularly Notch-2 seem to play an important role in cancer stem cells. 23905784 Open visitation policies and practices in US ICUs: can we ever get there? Open visitation has been highly recommended by critical care groups but is not prevalent in practice. Here we discuss the present study on current visitation practices in US ICUs and discuss several factors affecting open visitation. We conclude with suggestions on achieving more liberal visitation practices. 23687378 Drosophila TRP and TRPL are assembled as homomultimeric channels in vivo. Family members of the cationic transient receptor potential (TRP) channels serve as sensors and transducers of environmental stimuli. The ability of different TRP channel isoforms of specific subfamilies to form heteromultimers and the structural requirements for channel assembly are still unresolved. Although heteromultimerization of different mammalian TRP channels within single subfamilies has been described, even within a subfamily (such as TRPC) not all members co-assemble with each other. In Drosophila photoreceptors two TRPC channels, TRP and TRP-like protein (TRPL) are expressed together in photoreceptors where they generate the light-induced current. The formation of functional TRP-TRPL heteromultimers in cell culture and in vitro has been reported. However, functional in vivo assays have shown that each channel functions independently of the other. Therefore, the issue of whether TRP and TRPL form heteromultimers in vivo is still unclear. In the present study we investigated the ability of TRP and TRPL to form heteromultimers, and the structural requirements for channel assembly, by studying assembly of GFP-tagged TRP and TRPL channels and chimeric TRP and TRPL channels, in vivo. Interaction studies of tagged and native channels as well as native and chimeric TRP-TRPL channels using co-immunoprecipitation, immunocytochemistry and electrophysiology, critically tested the ability of TRP and TRPL to interact. We found that TRP and TRPL assemble exclusively as homomultimeric channels in their native environment. The above analyses revealed that the transmembrane regions of TRP and TRPL do not determine assemble specificity of these channels. However, the C-terminal regions of both TRP and TRPL predominantly specify the assembly of homomeric TRP and TRPL channels. 23443650 A novel method for SLIPA™ size selection, for adult patients, on the basis of chamber length. Nowadays the size of the streamlined liner of the pharynx airway (SLIPA™) is selected by matching the width of the thyroid cartilage of the patient to the widest dimension of the SLIPA™. The objective of this work was to improve the method of selection by matching the distance between the otobasion inferius and the most inferior margin of the cricoid cartilage (O-C) to the length of the SLIPA™ chamber. 100 patients (ASAI-II) scheduled to undergo operations under general anesthesia were randomly divided into two groups, group A (size selected by matching O-C with SLIPAâ„¢ chamber length, n = 50) and group B (size selected by matching the width of the thyroid cartilage with the widest dimension of the SLIPAâ„¢, n = 50). We measured the distance between the nasopharynx and the interarytenoid fold (N-I) and investigated the correlation between O-C and N-I at the neutral head position. Number of attempts, insertion time, blood on the device, leakage, and the need to change sizes were assessed. A positive correlation (r = 0.68, p < 0.05) was detected between N-I and O-C. Leakage was observed in 6 % (n = 3) of group A patients and in 20 % (n = 10) of group B patients (p < 0.05). Compared with the classic size-selection method, matching the width of the thyroid cartilage with that of the SLIPA™, the size-selection method of matching SLIPA™ chamber length to O-C for adult patients is more accurate. 23649224 Veterans with diabetes receive arthroplasty more frequently and at a younger age. A future increase in total joint arthroplasties in patients with diabetes seems likely considering the prevalence of osteoarthritis and diabetes mellitus are increasing. However, the rates of arthroplasty in the population of patients with diabetes are unclear. We sought to determine whether lower extremity arthroplasties in a veteran population with diabetes is different from a similar population without diabetes. The following specific questions were asked: (1) Is the rate of TKA in veterans with diabetes higher than in those without diabetes? (2) Is the rate of THA in veterans with diabetes higher than in those without diabetes? (3) Are arthroplasty revision rates greater in veterans with diabetes than in veterans without diabetes? The US Department of Veterans Affairs Health administrative data from fiscal year 2000 was used to identify persons with primary or secondary TKA or THA. The rate of surgeries among a diabetic population was compared with that among a nondiabetic population. The diabetic cohort received total joint arthroplasties at a higher rate than the nondiabetic cohort at all ages younger than 66 years, with a range of odd ratios from 1.3 to 3.4. In answer to our specific questions, (1) the rate of TKA (95% CI, 2.1-3.7), (2) the rate of THA (95% CI, 1.0-2.6), and (3) the rates of arthroplasty revision (95% CI, 0.9-5.8 TKA and 0.7-6.8 THA) were higher in veterans with diabetes. Furthermore, those with diabetes in the youngest age group studied received total joint arthroplasties and revision surgeries at approximately double the rates of those without diabetes. If these findings hold true for the population as a whole, they imply that clinicians in the United States may see a sharp increase in younger diabetic candidates for joint arthroplasty. Level III, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. 23877526 Tips for a Physician in Getting the Right Job, Part III: Networking and Social Media, References, and Recruiters. It is important that physicians are appropriately aggressive in obtaining the best possible job, and not sitting back passively and expecting employers to come hunting for them. Networking is very important to learn of new job opportunities and in some cases to be introduced to prospective employers. Social media sites may be useful for networking and for researching job opportunities and the people in certain organizations. Recruiters can be helpful for many physicians in finding the right job. However, some recruiters can be bothersome and be more interested in making a commission than in obtaining the best match between the employer and employee. Having stellar references who will give an enthusiastic recommendation for the job seeker, both in writing and on the phone, is very important. 23943373 Antimuscarinic use among individuals with urinary incontinence who reside in long-term care facilities. To assess appropriateness of antimuscarinic use in long-term care facilities (LTCFs) among treated and untreated urinary incontinence (UI) residents from 2007 to 2009. We conducted a retrospective analysis using the AnalytiCare(SM) database consisting of minimum data sets (MDS) assessments and prescription records of 90,660 residents from 2007 to 2009. UI (MDS H1b â‰¥ 1) residents with ≥14-day LTCF stay were identified and categorized as treated if they had ≥1 antimuscarinic prescription and untreated if they had no antimuscarinics. A random sample of untreated residents was matched based on treated residents' type of MDS assessment. We defined appropriate antimuscarinic use if residents had adequate cognitive function [≤4 on the cognitive performance scale (0 = intact to 6 = very severe impairment)] and mobility [scoring <4 on mobility for toileting scale (MDS item G1iA 0 = independent to 4 = total dependent)]. Chi-square tests were used to detect statistical difference between cohorts. A total of 5,327 residents (2,840 treated; 2,487 untreated) were selected [mean age (standard deviation) 80 (8), 81 (8) years; female (76, 65 %), respectively]. On study-defined MDS assessment, 63 % of treated and 69 % of untreated residents had UI (P < 0.01). Approximately 84 % of treated and 74 % of untreated residents may have had cognitive function and mobility sufficient for appropriate antimuscarinic use (P < 0.01). Our study identified a high percentage of LTCF residents with UI who may have been candidates for antimuscarinics. However, due to the MDS limitation, we were unable to identify overactive bladder patients among these untreated residents with UI. It is possible that untreated control residents had UI due to other factors not amenable to treatment with antimuscarinic agents. Therefore, choice of treatment for each resident needs to be individualized and carefully monitored for efficacy and adverse effects. This retrospective analysis requires prospective confirmation. Proper patient selection for antimuscarinic treatment requires careful assessment of underlying physical status including cognitive function, mobility, and comorbidities. 23828498 Myeloid-derived suppressor cells in breast cancer. Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells defined by their suppressive actions on immune cells such as T cells, dendritic cells, and natural killer cells. MDSCs typically are positive for the markers CD33 and CD11b but express low levels of HLADR in humans. In mice, MDSCs are typically positive for both CD11b and Gr1. These cells exert their suppressive activity on the immune system via the production of reactive oxygen species, arginase, and cytokines. These factors subsequently inhibit the activity of multiple protein targets such as the T cell receptor, STAT1, and indoleamine-pyrrole 2,3-dioxygenase. The numbers of MDSCs tend to increase with cancer burden while inhibiting MDSCs improves disease outcome in murine models. MDSCs also inhibit immune cancer therapeutics. In light of the poor prognosis of metastatic breast cancer in women and the correlation of increasing levels of MDSCs with increasing disease burden, the purposes of this review are to (1) discuss why MDSCs may be important in breast cancer, (2) describe model systems used to study MDSCs in vitro and in vivo, (3) discuss mechanisms involved in MDSC induction/function in breast cancer, and (4) present pre-clinical and clinical studies that explore modulation of the MDSC-immune system interaction in breast cancer. MDSCs inhibit the host immune response in breast cancer patients and diminishing MDSC actions may improve therapeutic outcomes. 23958548 Diagnostic Utility of PLAG1 Immunohistochemical Determination in Salivary Gland Tumors. PLAG1 (pleomorphic adenoma gene 1) is a proto-oncogene whose overexpression is a crucial oncogenic event in salivary gland pleomorphic adenomas (PA), and in carcinoma ex-PA. The aim of the present study is to evaluate the sensitivity and the specificity of PLAG1 as a marker in the differential diagnosis of salivary gland benign and malignant tumors. We examined 101 cases, including 36 PAs, 8 myoepitheliomas, 3 basal cell adenomas, and 1 canalicular adenoma among benign tumors; 16 mucoepidermoid carcinomas, 10 adenoid cystic carcinomas, 8 acinic cell carcinomas, 8 polymorphous low-grade adenocarcinomas, 7 salivary duct carcinoma, and 4 epithelial-myoepithelial carcinoma among malignant tumors. PLAG1 was diffusely positive in 94.4% of PAs and in all myoepitheliomas, although with a lower staining intensity. Among malignant tumors, 2 (25%) polymorphous low-grade adenocarcinomas and 1 salivary duct carcinoma ex-PA were positive. In conclusion, PLAG1 is a marker with good specificity for PA and could be a useful diagnostic adjunct in the diagnosis of salivary gland tumors. In particular, this marker is negative in the most common salivary carcinomas, including adenoid cystic carcinoma, mucoepidermoid carcinoma, and acinic cell carcinoma. However, some mimickers of PA, like polymorphous low-grade adenocarcinoma, may show occasional positivity for PLAG1, thus limiting its diagnostic use. In addition, carcinoma ex-PA shows consistent positivity, and therefore should be considered as a diagnostic possibility in case of a malignant tumor with PLAG1 expression. 23566197 Novel sulfonamide compounds for inhibition of metastatic tumor growth (WO2012021963). A series of novel ureido-sulfonamides was prepared by reaction of aminobenzenesulfonamide with alkyl/aryl isocyanate. These compounds are claimed for use as therapeutic agents of metastatic tumors, which are poorly responsive to classical chemotherapies and constitute a conceptually novel approach for cancer treatment. 23949053 Selective use of low frequency stimulation in Parkinson's disease based on presence of tremor. High frequency stimulation (HFS) of the subthalamic nucleus is one of the most effective treatments for advanced Parkinson's disease (PD). HFS has provided beneficial improvements in the cardinal features of PD, but has not been proven as effective for addressing the axial predominant levodopa resistant symptoms, such as speech disturbances, gait disturbances, and postural instability. Recent studies have suggested that changes in stimulation parameters may influence differing PD symptoms. The purpose of this study was to compare the effects of low frequency stimulation (LFS) versus HFS on the Unified Parkinson's Disease Rating Scale (UPDRS), gait, balance, and verbal fluency. Eight tremor dominant and nine non-tremor dominant participants with bilateral deep brain stimulation of the subthalamic nucleus were tested off stimulation, during LFS, and during HFS. Results revealed that HFS significantly reduced UPDRS tremor score in the tremor dominant group; however no differences emerged within the non-tremor dominant group. No differences between groups or stimulation conditions were found for gait, balance, and verbal fluency measures. These results may suggest that HFS is better than LFS for reducing tremor in tremor dominant patients. However, patients with mild or no tremor show no acute differences in benefit from LFS as compared to HFS. 23932248 Click conjugated polymeric immuno-nanoparticles for targeted siRNA and antisense oligonucleotide delivery. Efficient and targeted cellular delivery of small interfering RNAs (siRNAs) and antisense oligonucleotides (AONs) is a major challenge facing oligonucleotide-based therapeutics. The majority of current delivery strategies employ either conjugated ligands or oligonucleotide encapsulation within delivery vehicles to facilitate cellular uptake. Chemical modification of the oligonucleotides (ONs) can improve potency and duration of activity, usually as a result of improved nuclease resistance. Here we take advantage of innovations in both polymeric delivery vehicles and ON stabilization to achieve receptor-mediated targeted delivery of siRNAs or AONs for gene silencing. Polymeric nanoparticles comprised of poly(lactide-co-2-methyl, 2-carboxytrimethylene carbonate)-g-polyethylene glycol-furan/azide are click-modified with both anti-HER2 antibodies and nucleic acids on the exterior PEG corona. Phosphorothioate (PS), 2'F-ANA, and 2'F-RNA backbone chemical modifications improve siRNA and AON potency and duration of activity. Importantly, delivery of these nucleic acids on the exterior of the polymeric immuno-nanoparticles are as efficient in gene silencing as lipofectamine transfection without the associated potential toxicity of the latter. 23899779 Discrepant partitioning of genetic diversity in mouse lemurs and dwarf lemurs - Biological reality or taxonomic bias? Unequal degrees of taxonomic subdivision can pose problems for research that relies on cross-taxon comparisons of biogeographic patterns. Numerous species of lemurs have been described in recent years. These descriptions were unevenly distributed over the genera of lemurs as exemplified by the closely related mouse lemurs (Microcebus spp.) and dwarf lemurs (Cheirogaleus spp.). According to previous studies, these genera display striking differences such as many versus few species, small versus large distributions, and small versus large mitochondrial divergence within and between species. We questioned if these differences reflect the biological reality or a biased taxonomic subdivision, which might be partially due to relatively small amounts of available genetic data from dwarf lemurs. We complemented existing datasets with genetic data from 51 dwarf lemurs from nine sites in southern Madagascar. We analyzed the mitochondrial cytb gene and the nuclear loci adora3, fiba, and vWF. Based on a comparison of mitochondrial genetic data from both genera, we delineated eight hypothetical subgroups within two recognized Cheirogaleus species. We used mitochondrial and nuclear data to reconstruct species trees and to estimate divergence times between Microcebus species and Cheirogaleus subgroups. We further performed Bayesian species delimitations based on nuclear sequence data from Cheirogaleus subgroups. Strong signals in mitochondrial and nuclear data indicate the existence of deeply divergent, distinct groups within recognized Cheirogaleus species. Based on several lines of evidence, we conclude that the species diversity in Cheirogaleus has been underestimated so far. We delineate six species among the eight subgroups and provide a formal description for one new Cheirogaleus species. 23872200 The GAG database: A new resource to gather genomic annotation cross-references. Several institutions provide genomic annotation data, and therefore these data show a significant segmentation and redundancy. Public databases allow access, through their own methods, to genomic and proteomic sequences and related annotation. Although some cross-reference tables are available, they don't cover the complete datasets provided by these databases. The Genomic Annotation Gathering project intends to unify annotation data provided by GenBank and Ensembl. We introduce an intra-species, cross-bank method. Generated results provide an enriched set of cross- references. This method allows for identifying an average of 30% of new cross-references that can be integrated to other utilities dedicated to analyzing related annotation data. By using only sequence comparison, we are able to unify two datasets that previously didn't share any stable cross-bank accession method. The whole process is hosted by the GenOuest platform to provide public access to newly generated cross-references and to allow for regular updates (http://gag.genouest.org). 23617417 Nicotiana benthamiana calreticulin 3a is required for the ethylene-mediated production of phytoalexins and disease resistance against oomycete pathogen Phytophthora infestans. Mature Nicotiana benthamiana shows strong resistance to the potato late blight pathogen Phytophthora infestans. By screening using virus-induced random gene silencing, we isolated a gene for plant-specific calreticulin NbCRT3a as a required gene for resistance of N. benthamiana against P. infestans. NbCRT3a encodes an endoplasmic reticulum quality-control (ERQC) chaperone for the maturation of glycoproteins, including glycosylated cell-surface receptors. NbCRT3a-silenced plants showed no detectable growth defects but resistance to P. infestans was significantly compromised. Defense responses induced by the treatment with INF1 (a secretory protein of P. infestans), such as production of reactive oxygen species and accumulation of phytoalexins, were suppressed in NbCRT3a-silenced N. benthamiana. Expression of an ethylene-regulated gene for phytoalexin biosynthesis, NbEAS, was reduced in NbCRT3a-silenced plants, whereas the expression of salicylic acid-regulated NbPR-1a was not affected. Consistently, induction of ethylene production by INF1 was suppressed in NbCRT3a-silenced plants. Resistance reactions induced by a hyphal wall components elicitor prepared from P. infestans were also impaired in NbCRT3a-silenced plants. However, cell death induced by active mitogen-activated protein kinase kinase (NbMEK2(DD)) was not affected by the silencing of NbCRT3a. Thus, NbCRT3a is required for the initiation of resistance reactions of N. benthamiana in response to elicitor molecules derived from P. infestans. 23138334 Alleviation effects of magnesium on copper toxicity and accumulation in grapevine roots evaluated with biotic ligand models. Copper toxicity and accumulation in plants are affected by physicochemical characteristics of soil solutions such as the concentrations of coexistent cations (e.g., Ca(2+), Mg(2+), K(+), Na(+), and H(+)). The biotic ligand model (BLM) approach has been proposed to predict metal phyto-toxicity and -accumulation by taking into account the effects of coexistent cations, given the assumption of the partition equilibrium of metal ions between soil solution and solid phase. The alleviation effects of Mg on Cu toxicity and accumulation in grapevine roots were the main concerns in this study and were investigated by using a hydroponic experiment of grapevine cuttings. The BLM approach, which incorporated competition of Mg(2+) with Cu(2+) to occupy the biotic ligands on root surfaces, was developed to predict Cu rhizotoxicity and accumulation by grapevine roots. In the results, the effective activity of Cu, {Cu (2+)}, resulting in a 50 % reduction of root elongation (EA (50)), linearly increased with increments of Mg activity, {Mg (2+)}. In addition, the Cu concentration in root, Cu ( root ), was retarded by an increase of {Mg (2+)}. The linear model was significantly fitted to the relationship between {Cu (2+)}/Cu ( root ) and {Mg (2+)}. According to the concept of BLM, the present results revealed that the amelioration effects of Mg on Cu toxicity and accumulation in roots could arise from competition between Mg(2+) and Cu(2+) on the binding sites (i.e., the biotic ligands). Then, the developed Cu-BLMs incorporating the Mg(2+) competition effectiveness were validated provide accurate predictions of Cu toxicity and accumulation in grapevine roots. To our knowledge this is the first report of the successful development of BLMs for a woody plant. This BLM approach shows promise of being widely applicable for various terrestrial plants. 23341342 A Robust Route to Enzymatically Functional, Hierarchically Self-Assembled Peptide Frameworks. The addition of enzyme biofunctionality to self-assembling peptide nanofibers is challenging since such additions can inhibit functionality or self-assembly. We introduce a method for peptide nanofiber enzyme functionalization, demonstrated by the attachment of a polymerization synthase to peptide nanofibers. The enzyme generates a biocompatible, biodegradable biopolyester coat on the fibers with applicablity in medical engineering. This approach provides a template for generation of functional bionanomaterials. 23916525 Efficacy and tolerability of lamotrigine in Juvenile Myoclonic Epilepsy in adults: A prospective, unblinded randomized controlled trial. Controlled randomized studies recommending the clinical use of lamotrigine in adult populations with the diagnosis of Juvenile Myoclonic Epilepsy are still lacking. To compare the efficacy and tolerability of lamotrigine versus valproate in adult patients with JME. This was a prospective, randomized, controlled, pragmatic, long-term and open-label treatment trial. Patients were randomized to use valproate or lamotrigine. The primary end points of the study were: (1) time from randomization to treatment failure (withdrawal); (2) time from randomization to seizures remission. Secondary ending points were: (1) frequency of clinically important adverse events and (2) change in the QOLIE-31 after randomization. The definition of seizure remission was based on disappearance of all seizure types and EEG discharges. We found that the time to withdraw treatment after randomization was not significantly different in lamotrigine and valproate groups. Long-term seizures freedom was equal in the both groups of the trial; only 8 (19.1%) patients randomized to lamotrigine and 6 (19.4%) randomized to valproate were not seizure free after 4 months of treatment. Between 17.03% (lamotrigine) and 35.3% (valproate) of patients reported adverse reactions at some point in the intention-to treat study (p=0.07). All subscales of the QOLIE-31 questionnaire, except that related to side effects of medication, improved more than 5 points with respect to baseline period in both groups CONCLUSION: Lamotrigine is effective in adult patients with Juvenile Myoclonic Epilepsy and better tolerated than valproate, although the incidence of idiosyncratic reactions could be a cause of concern. 23738909 Role of lysines in cytochrome c-cardiolipin interaction. Cytochrome c undergoes structural variations during the apoptotic process; such changes have been related to modifications occurring in the protein when it forms a complex with cardiolipin, one of the phospholipids constituting the mitochondrial membrane. Although several studies have been performed to identify the site(s) of the protein involved in the cytochrome c-cardiolipin interaction, to date the location of this hosting region(s) remains unidentified and is a matter of debate. To gain deeper insight into the reaction mechanism, we investigate the role that the Lys72, Lys73, and Lys79 residues play in the cytochrome c-cardiolipin interaction, as these side chains appear to be critical for cytochrome c-cardiolipin recognition. The Lys72Asn, Lys73Asn, Lys79Asn, Lys72/73Asn, and Lys72/73/79Asn mutants of horse heart cytochrome c were produced and characterized by circular dichroism, ultraviolet-visible, and resonance Raman spectroscopies, and the effects of the mutations on the interaction of the variants with cardiolipin have been investigated. The mutants are characterized by a subpopulation with non-native axial coordination and are less stable than the wild-type protein. Furthermore, the mutants lacking Lys72 and/or Lys79 do not bind cardiolipin, and those lacking Lys73, although they form a complex with the phospholipid, do not show any peroxidase activity. These observations indicate that the Lys72, Lys73, and Lys79 residues stabilize the native axial Met80-Fe(III) coordination as well as the tertiary structure of cytochrome c. Moreover, while Lys72 and Lys79 are critical for cytochrome c-cardiolipin recognition, the simultaneous presence of Lys72, Lys73, and Lys79 is necessary for the peroxidase activity of cardiolipin-bound cytochrome c. 23369254 Bioclimatic regions influence genetic structure of four Jordanian Stipa species. Strong environmental gradients can affect the genetic structure of plant populations, but little is known as to whether closely related species respond similarly or idiosyncratically to ecogeographic variation. We analysed the extent to which gradients in temperature and rainfall shape the genetic structure of four Stipa species in four bioclimatic regions in Jordan. Genetic diversity, differentiation and structure of Stipa species were investigated using amplified fragment length polymorphism (AFLP) molecular markers. For each of the four study species, we sampled 120 individuals from ten populations situated in distinct bioclimatic regions and assessed the degree of genetic diversity and genetic differentiation within and among populations. The widespread ruderals Stipa capensis and S. parviflora had higher genetic diversity than the geographically restricted semi-desert species S. arabica and S. lagascae. In three of the four species, genetic diversity strongly decreased with precipitation, while genetic diversity increased with temperature in S. capensis. Most genetic diversity resided among populations in the semi-desert species (ΦST  = 0.572/0.595 in S. arabica/lagascae) but within populations in the ruderal species (ΦST  = 0.355/0.387 S. capensis/parviflora). Principal coordinate analysis (PCoA) and STRUCTURE analysis showed that Stipa populations of all species clustered ecogeographically. A genome scan revealed that divergent selection at particular AFLP loci contributed to genetic differentiation. Irrespective of their different life histories, Stipa species responded similarly to the bioclimatic gradient in Jordan. We conclude that, in addition to predominant random processes, steep climatic gradients might shape the genetic structure of plant populations. 23938603 Vascular tumors have increased p70 S6-kinase activation and are inhibited by topical rapamycin. Vascular tumors are endothelial cell neoplasms whose cellular and molecular mechanisms, leading to tumor formation, are poorly understood, and current therapies have limited efficacy with significant side effects. We have investigated mechanistic (mammalian) target of rapamycin (mTOR) signaling in benign and malignant vascular tumors, and the effects of mTOR kinase inhibitor as a potential therapy for these lesions. Human vascular tumors (infantile hemangioma and angiosarcoma) were analyzed by immunohistochemical stains and western blot for the phosphorylation of p70 S6-kinase (S6K) and S6 ribosomal protein (S6), which are activated downstream of mTOR complex-1 (mTORC1). To assess the function of S6K, tumor cells with genetic knockdown of S6K were analyzed for cell proliferation and migration. The effects of topical rapamycin, an mTOR inhibitor, on mTORC1 and mTOR complex-2 (mTORC2) activities, as well as on tumor growth and migration, were determined. Vascular tumors showed increased activation of S6K and S6. Genetic knockdown of S6K resulted in reduced tumor cell proliferation and migration. Rapamycin fully inhibited mTORC1 and partially inhibited mTORC2 activities, including the phosphorylation of Akt (serine 473) and PKCα, in vascular tumor cells. Rapamycin significantly reduced vascular tumor growth in vitro and in vivo. As a potential localized therapy for cutaneous vascular tumors, topically applied rapamycin effectively reduced tumor growth with limited systemic drug absorption. These findings reveal the importance of mTOR signaling pathways in benign and malignant vascular tumors. The mTOR pathway is an important therapeutic target in vascular tumors, and topical mTOR inhibitors may provide an alternative and well-tolerated therapy for the treatment of cutaneous vascular lesions.Laboratory Investigation advance online publication, 12 August 2013; doi:10.1038/labinvest.2013.98. 23574281 Enhanced antioxidant and protective activities on retinal ganglion cells of carotenoids-overexpressing transgenic carrot. Carotenoids are considered to act as antioxidants and protect humans from serious disorders such as skin degeneration and ageing, cardiovascular disease, certain types of cancer, and age-related diseases of the eye. In this study, these chemopreventive activities of a carotenoids-overexpressing transgenic carrot were evaluated. The results of DPPH, hydroxyl, and superoxide radical scavenging tests demonstrate that the acetone extract obtained from the taproots of the carrot plants exhibits significant antioxidant activity. A higher activity was detected in the transgenic carrot extract compared with the wild-type extract. A chemopreventive activity test for degenerative diseases of the eye revealed that pretreatment with the carrot extract reduced cell death in a retinal ganglion cell line, RGC-5 cells exposed to 1-buthionine- (R,S)-sulfoximine and L-glutamic acid. 23915156 Geographic Genetic Structure in Two Laticaudine Sea Kraits, Laticauda laticaudata and Laticauda semifasciata (Serpentes: Elapidae), in the Ryukyu-Taiwan Region as Inferred from Mitochondrial Cytochrome b Sequences. The Ryukyu-Taiwan region is an island arch with intervening waters of varying distances and depths. This study examines the geographic genetic structure of two sympatric sea kraits, Laticauda laticaudata and L. semifasciata, in the region, to infer factors affecting the extent of dispersal and other biogeographical traits of these amphibious reptiles. Sequence analyses of the mitochondrial cytochrome b gene revealed four and 16 haplotypes for L. laticaudata (136 individuals) and L. semifasciata (177 individuals), respectively. For both species, population pairwise F ST analyses revealed significant genetic differentiations among islands and island groups, which are separated by deep straits, suggesting that deep waters serve as obstacles for dispersal in both species. Significant genetic differentiation was detected even among islands of the same basin in L. laticaudata, but not in L. semifasciata, and the isolation by distance analyses revealed no significant correlation between geographic and genetic distances in the former species. These results further suggest that L. laticaudata has stronger site fidelity or degree of philopatry than L. semifasciata. Based on the geographic genetic patterns, the historical biogeography of the two species in the Ryukyu-Taiwan region is also discussed. 23857372 Job stress and mortality in older age. This paper aims to assess the relationship between the determinants of the psychosocial work environment, as expressed in terms of JDC or ERI models, and all-cause mortality in older individuals. The baseline study was conducted on a cohort comprising a random sample of 65-year-old community-dwelling citizens of Kraków, Poland. All of the 727 participants (410 women, 317 men) were interviewed in their households in the period between 2001 and 2003; a structured questionnaire was used regarding their occupational activity history, which included indexes measuring particular dimensions of their psychosocial work environment based on Karasek's Job Demand-Control model and Siegrist's Effort-Reward Imbalance model, as well as health-related quality of life and demographic data. Mortality was ascertained by monitoring City Vital Records for 7 years. Analyses were conducted separately for men and women, with the multivariate Cox proportional hazard model. Results: During a 7-year follow-up period, 59 participants (8.1%) died, including 21 women (5.1% of total women) and 38 men (12%) (p < 0.05). Significant differences in the number of deaths occurred regarding disproportion between physical demands and control in men: those with low physical demands and low control died three times more often than those with high control, regardless of the level of demands. The multi-variate Cox proportional hazard model showed that significantly higher risk of death was observed only in men with low physical demands and low control, compared to those with low physical demands and high control (Exp(B) = 4.65, 95% CI: 1.64-13.2). Observed differences in mortality patterns are similar to the patterns of relationships observed in health-related quality of life (HRQoL) level at the beginning of old age; however, the relationship between efforts and rewards or demands and control and mortality was not fully confirmed. 23497904 Sensory quality and compositional characteristics of blackcurrant juices produced by different processes. Effects of enzymatic and non-enzymatic juice pressing on key orosensory and chemical quality factors of blackcurrant juices were studied in laboratory scale using berries of five different cultivars (Mortti, Mikael, Marski, Ola and Breed15). Enzymatic processing increased the juice yield by 10-22% and the content of various phenolic compounds in juice by 4-10-fold as compared to the non-enzymatic process. Higher intensity of the mouth-drying astringency of the enzyme-aided juice was the most significant orosensory difference between the processes. Juices of different blackcurrant cultivars varied in sweetness, sourness and bitterness. The most intensive sensory attributes of the juices were sourness and puckering astringency regardless of processing method. They correlated positively with each other and were contributed by acid content and pH. In enzyme-aided juices, the contents of flavonol glycosides and hydroxycinnamic acids were associated with mouth-drying astringency, and sugar/acid ratio correlated with sweetness. These correlations were less clear in non-enzyme juices possibly due to lower content of phenolic compounds and the high content of pectin. 23351136 Chemogenomics Approaches to Rationalizing the Mode-of-Action of Traditional Chinese and Ayurvedic Medicines. Traditional Chinese medicine (TCM) and Ayurveda have been used in humans for thousands of years. While the link to a particular indication has been established in man, the mode-of-action (MOA) of the formulations often remains unknown. In this study, we aim to understand the MOA of formulations used in traditional medicine using an in silico target prediction algorithm, which aims to predict protein targets (and hence MOAs), given the chemical structure of a compound. Following this approach we were able to establish several links between suggested MOAs and experimental evidence. In particular, compounds from the 'tonifying and replenishing medicinal' class from TCM exhibit a hypoglycemic effect which can be related to activity of the ingredients against the Sodium-Glucose Transporters (SGLT) 1 and 2 as well as Protein Tyrosine Phosphatase (PTP). Similar results were obtained for Ayurvedic anticancer drugs. Here, both primary anticancer targets (those directly involved in cancer pathogenesis) such as steroid-5-alpha-reductase 1 and 2 were predicted as well as targets which act synergistically with the primary target, such as the efflux pump P-glycoprotein (P-gp). In addition, we were able to elucidate some targets which may point us to novel MOAs as well as explain side effects. Most notably, GPBAR1, which was predicted as a target for both 'tonifying and replenishing medicinal' and anticancer classes, suggests an influence of the compounds on metabolism. Understanding the MOA of these compounds is beneficial as it provides a resource for NMEs with possibly higher efficacy in the clinic than those identified by single-target biochemical assays. 23834344 Oral, short-term exposure to titanium dioxide nanoparticles in Sprague-Dawley rat: focus on reproductive and endocrine systems and spleen. Abstract The study explored possible reproductive and endocrine effects of short-term (5 days) oral exposure to anatase TiO2 nanoparticles (0, 1, 2 mg/kg body weight per day) in rat. Nanoparticles were characterised by scanning electron microscopy (SEM) and transmission electron microscopy, and their presence in spleen, a target organ for bioaccumulation, was investigated by single-particle inductively coupled plasma mass spectrometry and SEM/energy-dispersive X-ray. Analyses included serum hormone levels (testosterone, 17-β-estradiol and triiodothyronine) and histopathology of thyroid, adrenals, ovary, uterus, testis and spleen. Increased total Ti tissue levels were found in spleen and ovaries. Sex-related histological alterations were observed at both dose levels in thyroid, adrenal medulla, adrenal cortex (females) and ovarian granulosa, without general toxicity. Altered thyroid function was indicated by reduced T3 (males). Testosterone levels increased in high-dose males and decreased in females. In the spleen of treated animals TiO2 aggregates and increased white pulp (high-dose females) were detected, even though Ti tissue levels remained low reflecting the low doses and the short exposure time. Our findings prompt to comprehensively assess endocrine and reproductive effects in the safety evaluation of nanomaterials. 23546999 Successful ganciclovir treatment of primary cytomegalovirus infection containing the UL97 mutation N510S in an intestinal graft recipient. In solid organ transplantation, human cytomegalovirus (HCMV) is considered to be the most important viral pathogen. We report a case of a CMV R-/D+ small intestine transplant recipient with a primary CMV infection on valganciclovir prophylaxis. Sequencing of the HCMV DNA for drug resistance-associated mutations revealed the UL97 mutation N510S. This mutation has been initially reported to confer ganciclovir resistance. Based on in vitro recombinant phenotyping, this assumption has recently been questioned. Switching the antiviral treatment to an intravenous regimen of ganciclovir eliminated HCMV DNAemia, showing the in vivo efficacy of ganciclovir for the UL97 mutation N510S. Hence, knowledge of drug efficacy is crucial for an adequate choice of antiviral medication, carefully balancing antiviral potency versus the risk of harmful side effects. 23874707 Linkage between Increased Nociception and Olfaction via a SCN9A Haplotype. Mutations reducing the function of Nav1.7 sodium channels entail diminished pain perception and olfactory acuity, suggesting a link between nociception and olfaction at ion channel level. We hypothesized that if such link exists, it should work in both directions and gain-of-function Nav1.7 mutations known to be associated with increased pain perception should also increase olfactory acuity. SCN9A variants were assessed known to enhance pain perception and found more frequently in the average population. Specifically, carriers of SCN9A variants rs41268673C>A (P610T; n = 14) or rs6746030C>T (R1150W; n = 21) were compared with non-carriers (n = 40). Olfactory function was quantified by assessing odor threshold, odor discrimination and odor identification using an established olfactory test. Nociception was assessed by measuring pain thresholds to experimental nociceptive stimuli (punctate and blunt mechanical pressure, heat and electrical stimuli). The number of carried alleles of the non-mutated SCN9A haplotype rs41268673C/rs6746030C was significantly associated with the comparatively highest olfactory threshold (0 alleles: threshold at phenylethylethanol dilution step 12 of 16 (n = 1), 1 allele: 10.6±2.6 (n = 34), 2 alleles: 9.5±2.1 (n = 40)). The same SCN9A haplotype determined the pain threshold to blunt pressure stimuli (0 alleles: 21.1 N/m(2), 1 allele: 29.8±10.4 N/m(2), 2 alleles: 33.5±10.2 N/m(2)). The findings established a working link between nociception and olfaction via Nav1.7 in the gain-of-function direction. Hence, together with the known reduced olfaction and pain in loss-of-function mutations, a bidirectional genetic functional association between nociception and olfaction exists at Nav1.7 level. 23092759 Upregulation of phagocyte-like NADPH oxidase by cytokines in pancreatic beta-cells: attenuation of oxidative and nitrosative stress by 2-bromopalmitate. Phagocyte-like NADPH oxidase (Nox2) has been shown to play regulatory roles in the metabolic dysfunction of the islet β-cell under the duress of glucolipotoxic conditions and exposure to proinflammatory cytokines. However, the precise mechanisms underlying Nox2 activation by these stimuli remain less understood. To this end, we report a time-dependent phosphorylation of p47phox, a cytosolic subunit of Nox2, by cytomix (IL-1β+TNFα+IFNγ) in insulin-secreting INS-1 832/13 cells. Furthermore, cytomix induced the expression of gp91phox, a membrane component of Nox2. 2-Bromopalmitate (2-BP), a known inhibitor of protein palmitoylation, markedly attenuated cytokine-induced, Nox2-mediated reactive oxygen species (ROS) generation and inducible nitric oxide synthase (iNOS)-mediated nitric oxide (NO) generation. However, 2-BP failed to exert any significant effects on cytomix-induced CHOP expression, a marker for endoplasmic reticulum stress. Together, our findings identify palmitoyltransferase as a target for inhibition of cytomix-induced oxidative (ROS generation) and nitrosative (NO generation) stress in the pancreatic β-cell. 23637088 Gene expression responses for detecting sublethal effects of xenobiotics and whole effluents on a Xenopus laevis embryo assay. In the present study, the authors investigated the effects of bisphenol A, chlorpyrifos, methylparaben, and 2 effluent samples from wastewater treatment plants located in the province of Madrid, Spain, on the messenger RNA expression of specific genes involved in early development (ESR1, pax6, bmp4, and myf5) and a gene involved in the general stress response (hsp70) during Xenopus laevis embryo development. Gene expression was analyzed after 4 h, 24 h, and 96 h of exposure by semiquantitative reverse-transcriptase-polymerase chain reaction. Concentration ranges of the compounds and dilutions for the samples were selected to cause morphological alterations in embryos after 96 h of exposure. Transcript levels of ESR1, pax6, and hsp70 were differentially altered at early developmental stages with patterns specific to the contaminant and the exposure time. However, further studies are needed to establish transcript levels of specific genes as biomarkers of sublethal effects in an environmental risk-assessment framework. Besides, studies including more generic responses, such as genes encoding antioxidant enzymes, together with genes related to embryonic development have to be developed to look for a battery of mechanistic endpoints for the evaluation of chemical exposure at the molecular level in a first-tier assessment. Environ Toxicol Chem 2013;32:2018-2025. © 2013 SETAC. 23871583 Managing uncontrolled postsplenectomy reactive thrombocytosis in idiopathic thrombocytopenic purpura: Role of thrombocytapheresis. Reactive thrombocytosis occurs in response to infection, trauma, or surgery. Splenectomy alone accounts for 19% of all possible causes of extreme thrombocytosis. We performed thrombocytapheresis in a young lady with chronic idiopathic thrombocytopenic purpura (ITP) who developed postsplenectomy reactive thrombocytosis. Her post splenectomy platelet count was 227×10(6)/ml which elevated to 1623×10(6)/ml on the 7th postoperative day. A single thrombocytapheresis procedure reduced her platelet to 403×10(6)/ml. She was discharged on the 10th postoperative day and then maintained a count of 204-238×10(6)/ml with aspirin. Thrombocytapheresis reduces the platelet count rapidly in thrombocytosis and prevents patients from having thrombotic events. However, such procedures should be performed very meticulously to ensure patient safety. 23912048 MicroRNA-106b regulates the tumor suppressor RUNX3 in laryngeal carcinoma cells. Our study focuses on a set of laryngeal tumors that show reduced RUNX3 expression in the absence of transcriptional silencing of tumor suppressor gene RUNX3 by aberrant methylation of CpG islands. We report that the loss of expression of RUNX3 correlates with up-regulation of miR-106b in human laryngeal carcinoma tissue. The downregulation of RUNX3 is mediated by miR-106b through binding of its 3'UTR. Moreover, miR-106b can promote the proliferation and invasion of laryngeal carcinoma cells by directly targeting RUNX3, and RUXN3 knockdown can abolish this phenotype. These results shed a new insight into the mechanism of miRNA regulation in laryngeal carcinoma. 23892745 The peptidoglycan hydrolase of the Staphylococcus aureus bacteriophage {Phi}11 plays a structural role in the viral particle. The role of virion-associated peptidoglycan hydrolases (VAPGH) in the phage infection cycle is not clear. Gp49, the VAPGH from Staphylococcus aureus phage Φ11 is not essential for phage growth but stabilizes the viral particles. Φ11Δ49 phages showed reduced burst size and delayed host lysis. Complementation of gp49 with HydH5 from bacteriophage vB_SauS-phiIPLA88 restored the wild type phenotype. 23746694 Efficacy of transvaginal ultrasound-guided twin reduction in the mare by embryonic or fetal stabbing compared with yolk sac or allantoic fluid aspiration. Transvaginal ultrasound-guided pregnancy reduction (TUGR) is a procedure described for the management of twins post-fixation in the horse. Success rates are often disappointing but are reported to be more favorable for bilaterally situated twins and when intervention takes place before day 35 of gestation. This study aimed to determine whether stabbing the embryo/fetus rather than aspirating conceptus fluids improved the likelihood of success, measured as the birth of a normal live singleton foal. Data from 103 TUGR interventions were analyzed by logistic regression analysis; method of treatment, relative conceptus location (i.e., uni- vs. bilateral), and stage of gestation were included as interdependent factors that potentially influence the outcome. Overall, 34/103 (33%) TUGR interventions resulted in a single live foal. There was no significant difference (P = 0.14) in the outcome between TUGR based on fetal stabbing (12/28: 42.9%) versus fluid aspiration (22/75: 29.3%). There was also no significant influence (P = 0.11) of the conceptuses being located unilaterally (19/65: 29.2%) versus bilaterally (15/38: 39.5%). However, TUGR was numerically more successful (P = 0.05) when performed ≤ Day 35 of gestation (21/53: 39.6%), as opposed to > Day 35 (13/50: 26%). Day 45 may represent an even more critical time point because only 2 out of 15 TUGRs (13.3%) performed beyond this day resulted in the birth of a live foal, compared with 11/35 (31.4%) performed between Days 36 and 45. Although the numbers are low, this suggests that TUGR is not the method of choice for reducing > Day 45 twins. Four pregnancy losses were recorded 1 to 7 months post-TUGR (4/38: 10.5%), and although it is tempting to attribute the losses to TUGR, this rate of late gestation pregnancy loss is normal. We conclude that TUGR by fetal stabbing does not offer significant advantages over fluid aspiration. However, TUGR should be performed before Day 35 of gestation and is considered primarily a salvage procedure to be used when re-breeding is not a viable alternative. 23747566 Plasma leptin, glucose and non-esterified fatty acid variations in dromedary camels exposed to prolonged periods of underfeeding or dehydration. The involvement of plasma leptin in the adaptation of dromedary camels to harsh conditions such as food or water shortages was studied through 2 experiments. In experiment 1, fourteen female camels were either fed at 68% of maintenance energy requirements (MER) during 112d (n=4) or overfed at 134% of MER during the first 56d and then underfed at 17% of MER the next 56d (OV-UN, n=5), or underfed and then overfed for the same durations and energy intake levels (UN-OV, n=5). Weekly plasma samples showed that leptin, glucose and non-esterified fatty acid (NEFA) concentrations were significantly modulated by energy intake level. NEFA increased sharply but transiently in underfed camels of the UN-OV or OV-UN groups, whereas glucose and leptin concentrations decreased with underfeeding and increased with overfeeding with more significant effects in camels that were previously overfed or underfed, respectively. In experiment 2 twelve female camels were either normally watered (n=6) or dehydrated (n=6) during 23d and then rehydrated during 4d. Dehydration specifically increased blood hematocrit, plasma NEFA and glucose whereas leptin decreased slightly. For both experiments, leptinemia was positively related to hump adipocyte volume. Taken together these results provide new data for a better understanding of lipid and energy metabolism in camels. 23891542 A novel mechanism of aluminium-induced cell death involving vacuolar processing enzyme and vacuolar collapse in tobacco cell line BY-2. The role of vacuole in the cell death mechanism induced by aluminium (Al) was investigated in tobacco (Nicotiana tabacum L.) cell line BY-2. Cells at logarithmic phase of growth were treated without (control) or with Al (up to 150μM) in a treatment medium containing CaCl2, sucrose and 2-(N-morpholino) ethanesulfonic acid (MES) buffer (pH5.0). After 18h treatment, both the integrity of the plasma membrane (estimated by Evans blue uptake) and growth capacity (estimated by post-Al treatment growth in nutrient medium) were decreased, while the activity of vacuolar processing enzyme (VPE) was increased, in the Al dose-dependent manner. The activity of the vacuole (estimated by neutral red uptake) was slightly increased at 50μM then decreased with an increase in Al concentration. Direct observation of morphological changes of vacuole in a transgenic BY-2 expressing GFP-AtVam3p fusion protein localized on tonoplast indicated Al-induced collapse of vacuole. Time-course experiments indicated that both an increase in VPE activity and a loss of growth capacity were clearly observed at 6h of the treatment time, prior to the loss of plasma membrane integrity. The presence of Ac-YVAD-CHO (an inhibitor effective to VPE) during Al treatment suppressed a loss of plasma membrane integrity. The expression of VPE genes (VPE-1a, VPE-1b) were significantly enhanced by Al treatment. Taken together, we conclude that an enhancement of VPE activity by Al is controlled at transcriptional level, and is a key factor leading to a loss of integrity of the plasma membrane and a loss of growth capacity. 23931372 Multiscale geometry and scaling of the turbulent-nonturbulent interface in high reynolds number boundary layers. The scaling and surface area properties of the wrinkled surface separating turbulent from nonturbulent regions in open shear flows are important to our understanding of entrainment mechanisms at the boundaries of turbulent flows. Particle image velocimetry data from high Reynolds number turbulent boundary layers covering three decades in scale are used to resolve the turbulent-nonturbulent interface experimentally and, for the first time, determine unambiguously whether such surfaces exhibit fractal scaling. Box counting of the interface intersection with the measurement plane exhibits power-law scaling, with an exponent between -1.3 and -1.4. A complementary analysis based on spatial filtering of the velocity fields also shows power-law behavior of the coarse-grained interface length as a function of filter width, with an exponent between -0.3 and -0.4. These results establish that the interface is fractal-like with a multiscale geometry and fractal dimension of D_{f}≈2.3-2.4. 23895089 Insight View on Possible Role of Fluoroquinolones in Cancer Therapy. Cancer is a disease without limits turning out to be prime cause for raising death toll around the world. Several treatment strategies including chemotherapy, surgery and radiotherapy are being employed worldwide to combat this disease. Due to the unwanted effects of currently available therapies, scientific community is immensely interested in exploring newer alternative pathways. Role of antibiotics in treatment of cancer is well established in the medical fraternity. Fluoroquinolones have been employed as potent anti-microbial agents for last few decades and now being looked up as potential therapeutic agents in the other ailments also. Several research endeavours are carried out in different parts of the world to focus on the prospective role of fluoroquinolones in carcinogenesis and mutagenesis. This article is an earnest attempt to present recent research work carried out on fluoroquinolones in the context to cancer treatment therapies. 23910379 Radiographic Diagnosis of Scapholunate Dissociation Among Intra-articular Fractures of the Distal Radius: Interobserver Reliability. To evaluate the reliability and accuracy of diagnosis of scapholunate dissociation (SLD) among AO type C (compression articular) fractures of the distal radius. A total of 217 surgeons evaluated 21 sets of radiographs with type C fractures of the distal radius for which the status of the scapholunate interosseous ligament was established by preoperative 3-compartment computed tomographic arthrography with direct operative visualization of diagnosed SLD (reference standard). Observers were asked whether SLD was present, and if yes, whether they would recommend operative treatment. Diagnostic performance characteristics were calculated with respect to the reference standard. We assessed interobserver reliability using the Fleiss generalized kappa. The interobserver agreement for radiographic diagnosis of SLD was moderate (κ = 0.44). Correct diagnosis for a given set of radiographs ranged from 8% to 98% (average, 79%) of observers. Diagnostic performance characteristics were: 69% sensitivity, 84% specificity, 84% accuracy, 68% positive predictive value, and 84% negative predictive value. Based on a prevalence of 5%, Bayes adjusted positive and negative predictive values were 18% and 98%, respectively. Raters recommended operative treatment in 74% to 100% of patients diagnosed with SLD. Radiographs are moderately reliable and are better at ruling out than ruling in SLD associated with type C fracture of the distal radius. Diagnostic III. 23576432 The cation-π box is a specific phosphatidylcholine membrane targeting motif. PPeripheral membrane proteins can be targeted to specific organelles or the plasma membrane by differential recognition of phospholipid headgroups. While molecular determinants of specificity for several headgroups, including phosphatidylserine and phosphoinositides are well defined, specific recognition of the headgroup of the zwitterionic phosphatidylcholine (PC) is less well understood. In cytosolic proteins the cation-π box provides a suitable receptor for choline recognition and binding through the trimethylammonium moiety. In PC, this moiety might provide a sufficient handle to bind to peripheral proteins via a cation-π cage, where the π systems of two or more aromatic residues are within 4-5 Å of the quaternary amine. We prove this hypothesis by engineering the cation-π box into secreted phosphatidylinositol-specific phospholipase C from Staphylococcus aureus, which lacks specific PC recognition. The N254Y/H258Y variant selectively binds PC-enriched vesicles, and X-ray crystallography reveals N254Y/H258Y binds choline and dibutyroylphosphatidylcholine within the cation-π motif. Such simple PC recognition motifs could be engineered into a wide variety of secondary structures providing a generally applicable method for specific recognition of PC. 23402628 Oxidation of tertiary amine-derivatized surfaces to control protein adhesion. Selective oxidation of ω-tertiary amine self-assembled thiol monolayers to tertiary amine N-oxides is shown to transform the adhesion of model proteins lysozyme and fibrinogen upon them. Efficient preparation of both secondary and tertiary linker amides as judged by X-ray photoelectron spectroscopy (XPS) and water droplet contact angle was achieved with an improved amide bond formation on gold quartz crystal microbalance (QCM) sensors using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate methanaminium uronium (HATU). Oxidation with hydrogen peroxide was similarly assessed, and adhesion of lysozyme and fibrinogen from phosphate buffered saline was then assayed by QCM and imaged by AFM. Tertiary amine-functionalized sensors adsorbed multilayers of aggregated lysozyme, whereas tertiary amine N-oxides and triethylene glycol-terminated monolayers are consistent with small protein aggregates. The surface containing a dimethylamine N-oxide headgroup and ethyl secondary amide linker showed the largest difference in adsorption of both proteins. Oxidation of tertiary amine decorated surfaces therefore holds the potential for selective deposition of proteins and cells through masking and other patterning techniques. 23890572 Utility of pelvic ultrasound following negative abdominal and pelvic CT in the emergency room. To determine the diagnostic value of pelvic ultrasound following negative abdominal/pelvic computed tomography (CT) in women presenting to the emergency room (ER) with abdominal/pelvic pain, and whether ultrasound altered clinical management in the acute-care setting. Between January 2005 to October 2010, 126 consecutive, non-pregnant women with abdominal/pelvic pain underwent pelvic ultrasound within 24 h following negative abdominal/pelvic CT in the ER. Imaging findings/reports for the CT and ultrasound examinations, and clinical data/outcomes were recorded. The time interval between the CT and ultrasound examinations was calculated. Mean length of stay (LOS) was compared to that of age-matched controls who did not have subsequent ultrasound using the t-test. Only 3% (four of 126 cases) of the pelvic ultrasound examinations showed positive findings, all of which were endometrial abnormalities. One patient was diagnosed with an endometrial polyp, whereas the others were lost to follow-up. In none of the four cases was the pelvic ultrasound finding relevant to the acute presentation or altered acute care. The average time between CT to ultrasound was 3 h and 4 min. Mean LOS was 22 h and 13 min for the cohort, and 16 h and 8 min for the age-matched controls, although this was not statistically significant (p = 0.29). Immediate ultrasound re-imaging of the pelvis following negative CT in women with acute abdominal/pelvic pain yields no additional diagnostic information and does not alter acute care. 23857053 Membrane Binding and Insertion of a pHLIP Peptide Studied by All-Atom Molecular Dynamics Simulations. Recent experiments in function mechanism study reported that a pH low-insertion peptide (pHLIP) can insert into a zwitterionic palmitoyloleoylphosphatidylcholine (POPC) lipid bilayer at acidic pH while binding to the bilayer surface at basic pH. However, the atomic details of the pH-dependent interaction of pHLIP with a POPC bilayer are not well understood. In this study, we investigate the detailed interactions of pHLIP with a POPC bilayer at acidic and basic pH conditions as those used in function mechanism study, using all-atom molecular dynamics (MD) simulations. Simulations have been performed by employing the initial configurations, where pHLIP is placed in aqueous solution, parallel to bilayer surface (system S), partially-inserted (system P), or fully-inserted (system F) in POPC bilayers. On the basis of multiple 200-ns MD simulations, we found (1) pHLIP in system S can spontaneously insert into a POPC bilayer at acidic pH, while binding to the membrane surface at basic pH; (2) pHLIP in system P can insert deep into a POPC bilayer at acidic pH, while it has a tendency to exit, and stays at bilayer surface at basic pH; (3) pHLIP in system F keeps in an α-helical structure at acidic pH while partially unfolding at basic pH. This study provides at atomic-level the pH-induced insertion of pHLIP into POPC bilayer. 23628198 Synthesis of Bi2O2CO3/Bi2S3 hierarchical microspheres with heterojunctions and their enhanced visible light-driven photocatalytic degradation of dye pollutants. Bismuth subcarbonate (Bi2O2CO3) microspheres were synthesized by a simple hydrothermal method using bismuth citrate and sodium hydrogen carbonate as precursors. Furthermore, through a facile ion exchange method between the Bi2O2CO3 microspheres and thioacetamide (TAA), bismuth subcarbonate/bismuth sulfide (Bi2O2CO3/Bi2S3) heterojunctions were fabricated. The structures and morphologies of the Bi2O2CO3 and Bi2O2CO3/Bi2S3 products were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The photocatalytic activities of the products were evaluated by decomposing rhodamine B (RhB) under visible light irradiation. In contrast with Bi2O2CO3, the Bi2O2CO3/Bi2S3 heterojunctions showed enhanced visible light photocatalytic properties. In addition, the effect of ion exchange reaction time on the photodegradation quality was studied, and the mechanism of the enhanced photocatalytic properties was proposed. 23464521 Peptides as the next generation of anti-infectives. Synthesis and large-scale manufacturing technologies are now available for the commercial production of even the most complex peptide anti-infectives. Married with the potential of this class of molecule as the next generation of effective, resistance-free and safe antimicrobials, and a much better understanding of their biology, pharmacology and pharmacodynamics, the first regulatory approvals and introduction into clinical practice of these promising drug candidates will likely be soon. This is a key juncture in the history/life cycle of peptide anti-infectives and, perhaps, their commercial and therapeutic potential is about to be realized. This review highlights the promise of these agents as the next generation of therapeutics and summarizes the challenges faced in, and lessons learned from, the past. 23870684 HGSA DNA Day Essay Contest Winner 60 Years On: Still Coding for Cutting-Edge Science. MESSAGE FROM THE EDUCATION COMMITTEE In 2013, the Education Committee of the Human Genetics Society of Australasia (HGSA) established the DNA Day Essay Contest in Australia and New Zealand. The contest was first established by the American Society of Human Genetics in 2005 and the HGSA DNA Day Essay Contest is adapted from this contest via a collaborative partnership. The aim of the contest is to engage high school students with important concepts in genetics through literature research and reflection. As 2013 marks the 60th anniversary of the discovery of the double helix of DNA by James Watson and Francis Crick and the 10th anniversary of the first sequencing of the human genome, the essay topic was to choose either of these breakthroughs and explain its broader impact on biotechnology, human health and disease, or our understanding of basic genetics, such as genetic variation or gene expression. The contest attracted 87 entrants in 2013, with the winning essay authored by Patrick Yates, a Year 12 student from Melbourne High School. Further details about the contest including the names and schools of the other finalists can be found at http://www.hgsa-essay.net.au/. The Education Committee would like to thank all the 2013 applicants and encourage students to enter in 2014. Joanne M. Lind, BSc, PhD Chair, HGSA Education Committee. 23928195 Proton magnetic resonance spectroscopy: technique for the neuroradiologist. Magnetic resonance spectroscopy (MRS) provides information on neuronal and axonal viability, energetics of cellular structures, and status of cellular membranes. Proton MRS appeals to clinicians and scientists because its application in the clinical setting can increase the specificity of MR imaging. The objective of this article is to provide descriptive concepts of the technique and its application in vivo for a variety of patient populations. When appropriately incorporating MRS into the neuroradiologic evaluation, this technique produces relevant information to radiologists and clinicians for their understanding of adult and pediatric neurologically based disease processes. 22637696 In situ validation of an intestinal stem cell signature in colorectal cancer. Wnt/Tcf, Lgr5, Ascl2 and/or Bmi1 signalling is believed to define the mouse intestinal stem cell niche(s) from which adenomas arise. The aim of this study was to determine the relevance of these putative intestinal stem cell markers to human colorectal cancer. 19 putative intestinal stem cell markers, including Ascl2 and Lgr5, were identified from published data and an evaluation of a human colorectal gene expression database. Associations between these genes were assessed by isotopic in situ hybridisation (ISH) in 57 colorectal adenocarcinomas. Multiplex fluorescent ISH and chromogenic non-isotopic ISH were performed to confirm expression patterns. The prognostic significance of Lgr5 was assessed in 891 colorectal adenocarcinomas. Ascl2 and Lgr5 were expressed in 85% and 74% of cancers respectively, and expression was positively correlated (p=0.003). Expression of Bmi1 was observed in 47% of cancers but was very weak in 98% of cases with expression. Both Ascl2 and/or Lgr5 were positively correlated with the majority of genes in the signature but neither was correlated with Cdk6, Gpx2, Olfm4 or Tnfrsf19. Lgr5 did not have prognostic significance. These data suggest that 74-85% of colorectal cancers express a Lgr5/Ascl2 associated signature and support the hypothesis that they derive from Lgr5(+)/Ascl2(+) crypt stem cells, not Bmi1(+) stem cells. However, Olfm4 was not found to be a useful marker of Lgr5(+) cells in normal colon or tumours. In this large series, Lgr5 expression is not associated with increased tumour aggressiveness, as might be expected from a cancer stem cell marker. 23879748 Setting priorities for stroke care and research. Recent publications describing the sobering global increase in stroke mortality and global life years lost due to stroke despite improvements in developed countries have drawn focus on the severe impact of stroke in the developing world. At the same time, three recent interventional trials that failed to demonstrate an important role for catheter-based therapies in acute stroke have called into question this expensive use of technology. Coupling all of this new data leads to the natural conclusion that a focus on stroke prevention for the developing world, and for the poor in developed countries, should be where we set our priorities for the foreseeable future. 23619346 The effects of ulipristal on Bax/Bcl-2, cytochrome C, Ki-67 and cyclooxygenase-2 expression in a rat model with surgically induced endometriosis. To evaluate the effect of ulipristal on Bax/Bcl-2, cytochrome C, Ki-67 and cyclooxygenase-2 expression in surgically induced endometriosis in a rat model. We conducted a prospective, randomized, controlled, experimental study at the Experimental Research Center of the Iuliu Hatieganu University of Medicine and Pharmacy in Cluj-Napoca, Romania. Endometriosis was induced in 40 female Wistar albino rats by transplanting two autologous fragments of uterine horn onto bowel mesentery. After a 4-week induction period, we formed two groups: the first group was treated with ulipristal (UPA+) for 8 weeks, while the second group was treated only with the vehicle used for ulipristal (UPA-). We measured the volumes and masses of the implants both before and after treatment. A pathologist examined the sections microscopically for histological hallmarks of endometriosis. Immunostaining for Bax/Bcl-2, cytochrome C, Ki-67 and cyclooxygenase-2 (COX-2) was assessed in both groups. Ulipristal reduced the average implant volume and mass, indicating that the drug is effective (P=0.01). The treatment induced a greater than 50% reduction in the volume and mass of endometrial implants, and the histological findings correspond to this result. The overall Bax positivity rate was higher in the group treated with ulipristal (42.37% vs. 21.05% for UPA+ and UPA-, respectively) (P=0.0062). The overall Bcl-2 positivity rate was smaller in the group treated with ulipristal (15% vs. 40% for UPA+ and UPA-, respectively) (P=0.0593). The cytochrome C global positivity rate was 5% in the UPA- group and increased to 50% in the UPA+ treatment group (P<0.0001). The COX-2 positivity rate decreased from 75% in the UPA- treatment group to 10% in the UPA+ treatment group (P<0.0001) and the Ki67 positivity rate also decreased from 55% in the UPA- group to 10% in the UPA+ treatment group (P<0.0002). Treatment with ulipristal contributed to the regression and atrophy of endometriotic lesions in rats. The immunohistochemical expression profiles of Bax/Bcl-2 and cytochrome C revealed a pro-apoptotic effect of ulipristal. We also observed a reduced cellular proliferation, indicated by a decrease in Ki-67 expression and an anti-inflammatory effect, shown by a decrease in COX-2 expression after treatment with ulipristal. 23450522 Ultrasensitive non-resonant detection of ultrasound with plasmonic metamaterials. Optical sensors for ultrasound detection provide high sensitivity and bandwidth, essential for photoacoustic imaging in clinical diagnostics and biomedical research. Implementing plasmonic metamaterials in a non-resonant regime facilitates sub-nanosecond, highly sensitive detectors while eliminating cumbersome optical alignment necessary for resonant sensors. 23759721 Report of 2 cases of primary epithelioid hemangioendothelioma of the external iliac vein. The epithelioid hemangioendothelioma (EHE) is a rare type of endothelial neoplasm found mainly in soft tissues and visceral organs and in extraordinary cases in large veins like the iliac veins. Currently, there is an active discussion in which EHE behavior, classification, new diagnostic tools, and treatment procedures are proposed. Here, we present 2 cases of EHE and discuss our experience in diagnosis and treatment of this neoplasm. 23955837 Choosing wisely in pediatric hospital medicine: Five opportunities for improved healthcare value. Despite estimates that waste constitutes up to 20% of healthcare expenditures in the United States, overuse of tests and therapies is significantly under-recognized in medicine, particularly in pediatrics. The American Board of Internal Medicine Foundation developed the Choosing Wisely campaign, which challenged medical societies to develop a list of 5 things physicians and patients should question. The Society of Hospital Medicine (SHM) joined this effort in the spring of 2012. This report provides the pediatric workgroup's results. A workgroup of experienced and geographically dispersed pediatric hospitalists was convened by the Quality and Safety Committee of the SHM. This group developed an initial list of 20 recommendations, which was pared down through a modified Delphi process to the final 5 listed below. The top 5 recommendations proposed for pediatric hospital medicine are: (1) Do not order chest radiographs in children with asthma or bronchiolitis. (2) Do not use systemic corticosteroids in children under 2 years of age with a lower respiratory tract infection. (3) Do not use bronchodilators in children with bronchiolitis. (4) Do not treat gastroesophageal reflux in infants routinely with acid suppression therapy. (5) Do not use continuous pulse oximetry routinely in children with acute respiratory illness unless they are on supplemental oxygen. We recommend that pediatric hospitalists use this list to prioritize quality improvement efforts and include issues of waste and overuse in their efforts to improve patient care. Journal of Hospital Medicine 2013. © 2013 Society of Hospital Medicine. 23945215 Characterization and in vitro properties of oral lactobacilli in breastfed infants. Lactobacillus species can contribute positively to general and oral health and are frequently acquired by breastfeeding in infancy. The present study aimed to identify oral lactobacilli in breast and formula-fed 4 month-old infants and to evaluate potential probiotic properties of the dominant Lactobacillus species detected. Saliva and oral swab samples were collected from 133 infants who were enrolled in a longitudinal study (n=240) examining the effect of a new infant formula on child growth and development. Saliva was cultured and Lactobacillus isolates were identified from 16S rRNA gene sequences. Five L. gasseri isolates that differed in 16S rRNA sequence were tested for their ability to inhibit growth of selected oral bacteria and for adhesion to oral tissues. Oral swab samples were analyzed by qPCR for Lactobacillus gasseri. 43 (32.3%) infants were breastfed and 90 (67.7%) were formula-fed with either a standard formula (43 out of 90) or formula supplemented with a milk fat globule membrane (MFGM) fraction (47 out of 90). Lactobacilli were cultured from saliva of 34.1% breastfed infants, but only in 4.7% of the standard and 9.3% of the MFGM supplemented formula-fed infants. L. gasseri was the most prevalent (88% of Lactobacillus positive infants) of six Lactobacillus species detected. L. gasseri isolates inhibited Streptococcus mutans binding to saliva-coated hydroxyapatite, and inhibited growth of S. mutans, Streptococcus sobrinus, Actinomyces naeslundii, Actinomyces oris, Candida albicans and Fusobacterium nucleatum in a concentration dependent fashion. L. gasseri isolates bound to parotid and submandibular saliva, salivary gp340 and MUC7, and purified MFGM, and adhered to epithelial cells. L. gasseri was detected by qPCR in 29.7% of the oral swabs. Breastfed infants had significantly higher mean DNA levels of L. gasseri (2.14 pg/uL) than infants fed the standard (0.363 pg/uL) or MFGM (0.697 pg/uL) formula. Lactobacilli colonized the oral cavity of breastfed infants significantly more frequently than formula-fed infants. The dominant Lactobacillus was L. gasseri, which was detected at higher levels in breastfed than formula-fed infants and displayed probiotic traits in vitro. 22962092 Improving safety and efficiency during emergent central venous catheter placement with a needleless securing clamp. To compare the needleless securing clamp to the traditional suture-secured clamp for central venous catheters. Compare the holding strength of each type of clamps by measuring the amount of kinetic energy absorbed, ask 20 physicians to evaluate the clamp placement using sutures or staples, and summarise the clamps effectiveness and complications in 10 patients. Compared to sutured clamp, the needleless clamp was more secure. The needleless clamp was also significantly better with regard to ease of use, safety, perceived strength (p value <0.002), and insertion time was reduced by 63%. No adverse events or skin infections occurred while using the needleless clamps. Without incurring complications or increasing risk to patients, the needleless clamp is secure and improves safety and efficiency for physicians. 23526801 How many genetic options for evolving insecticide resistance in heliothine and spodopteran pests? The widely accepted paradigm for the development of insecticide resistance in field populations of insects is of selection for one or a very few genes of major effect. Limited genetic mapping data for organophosphate and pyrethroid resistance in heliothine and spodopteran pests generally agrees with this paradigm. However, other biochemical and transcriptomic data suggest a more complex set of changes in multiple P450 and esterase gene/enzyme systems in resistant strains of these species. We discuss possible explanations for this paradox, including the likely embedding of these genes in regulatory cascades and emerging evidence for their arrangement in large clusters of closely related genes. We conclude that there could indeed be an unusually large number of genetic options for evolving resistance in these species. © 2013 Society of Chemical Industry. 23873600 DockRank: ranking docked conformations using partner-specific sequence homology based protein interface prediction. Selecting near-native conformations from the immense number of conformations generated by docking programs remains a major challenge in molecular docking. We introduce DockRank, a novel approach to scoring docked conformations based on the degree to which the interface residues of the docked conformation match a set of predicted interface residues. DockRank uses interface residues predicted by PS-HomPPI, a sequence homology based partner-specific protein-protein interface predictor, which predicts the interface residues of a query protein with a specific interaction partner. We compared the performance of DockRank with several state-of-the-art docking scoring functions using Success Rate (the percentage of cases that have at least one near-native among the top m conformations) and Hit Rate (the percentage of near-native conformations that are included among the top m conformations). In cases where it is possible to obtain partner-specific (PS) interface predictions from PS-HomPPI, DockRank consistently outperforms both (i) ZRank and IRAD, two state-of-the-art energy-based scoring functions (improving Success Rate by up to 4-fold); and (ii) Variants of DockRank that use predicted interface residues obtained from several protein interface predictors that do not take into account the binding partner in making interface predictions (improving Success Rate by up to 39-fold). The latter result underscores the importance of using partner-specific interface residues in scoring docked conformations. We show that DockRank, when used to re-rank the conformations returned by ClusPro, improves upon the original ClusPro rankings in terms of both Success Rate and Hit Rate. DockRank is available as a server at http://einstein.cs.iastate.edu/DockRank/. © Proteins 2013;. © 2013 Wiley Periodicals, Inc. 23951150 Human Umbilical Cord Matrix Stem Cells Maintain Multilineage Differentiation Abilities and Do Not Transform during Long-Term Culture. Umbilical cord matrix stem cells (UCMSC) have generated great interest in various therapeutic approaches, including liver regeneration. This article aims to analyze the specific characteristics and the potential occurrence of premalignant alterations of UCMSC during long-term expansion, which are important issues for clinical applications. UCMSC were isolated from the umbilical cord of 14 full-term newborns and expanded in vitro until senescence. We examined the long-term growth potential, senescence characteristics, immunophenotype and multilineage differentiation capacity of these cells. In addition, their genetic stability was assessed through karyotyping, telomerase maintenance mechanisms and analysis of expression and functionality of cell cycle regulation genes. The tumorigenic potential was also studied in immunocompromised mice. In vitro, UCMSC reached up to 33.7±2.1 cumulative population doublings before entering replicative senescence. Their immunophenotype and differentiation potential, notably into hepatocyte-like cells, remained stable over time. Cytogenetic analyses did not reveal any chromosomal abnormality and the expression of oncogenes was not induced. Telomere maintenance mechanisms were not activated. Just as UCMSC lacked transformed features in vitro, they could not give rise to tumors in vivo. UCMSC could be expanded in long-term cultures while maintaining stable genetic features and endodermal differentiation potential. UCMSC therefore represent safe candidates for liver regenerative medicine. 23648572 A pH-sensitive charge-conversion system for doxorubicin delivery. A novel pH-sensitive charge-conversion shielding system was designed by the electrostatic binding of polyethylenimine (PEI)-poly(l-lysine)-poly(l-glutamic acid) (PELG), PEI, and cis-aconityl-doxorubicin (CAD). Doxorubicin (DOX) was modified by cis-aconityl linkage to form acid-sensitive CAD, which was then adsorbed by the positively charged PEI. The PEI/CAD complexes were subsequently shielded with the pH-responsive charge-conversion PELG. In normal tissues, the PELG/PEI/CAD complexes were negatively charged; in acidic tumor tissues, the shielding PELG was positively charged and detached from the PELG/PEI/CAD complexes. The resulting positively charged PEI/CAD complexes thus became exposed and were endocytosed. CAD was then cleaved in the acidic intracellular environment of endosomes and lysosomes, and converted back into DOX. The charge reversal of the PELG/PEI/CAD complexes was verified by zeta potential analysis at different pH values. Moreover, DOX release increased with decreasing pH. Cell uptake and confocal laser scanning microscopy analyses showed that, at pH 6.8, PELG/PEI/CAD had the highest endocytosis rate and more DOX entered cell nuclei. More importantly, the system showed remarkable cytotoxicity against cancer cells. These results revealed that the combination of pH-sensitive charge-conversion shielding with pH-sensitive drug release is a potential drug delivery system for tumor treatment. 23412052 Microfluidic origami: a new device format for in-line reaction monitoring by nanoelectrospray ionization mass spectrometry. Microfluidics is an attractive platform for chemical synthesis because it offers fast reaction times, reduced reagent usage, and the ability to integrate multiple functions on a single device. Digital Microfluidics (DMF) is particularly well-suited for microscale chemical synthesis, as it permits discretized sample handling, allowing for total process control. However, a limitation of DMF-based synthesis is analysis, which is often performed offline. To this end, we have developed "microfluidic origami", a new device format that integrates DMF with in-line analysis by mass spectrometry (MS). This format comprises a DMF platform and a folded nanoelectrospray ionization (nanoESI) emitter formed on a single flexible polyimide film substrate. Additionally, the device contains a two-plate-to-one-plate DMF interface, which allows for straightforward coupling of micro-reaction operations and product delivery to the emitter for analysis. The integrated platform was used to perform the Morita-Baylis-Hillman (MBH) reaction using DMF followed by inline MS analysis for monitoring the reaction progress in real-time. We propose that this platform has potential as a new tool for real-time monitoring of reaction rates and reaction pathways and could be a useful addition to the synthetic organic chemistry laboratory. 23515837 Improvement of gougerotin and nikkomycin production by engineering their biosynthetic gene clusters. Nikkomycins and gougerotin are peptidyl nucleoside antibiotics with broad biological activities. The nikkomycin biosynthetic gene cluster comprises one pathway-specific regulatory gene (sanG) and 21 structural genes, whereas the gene cluster for gougerotin biosynthesis includes one putative regulatory gene, one major facilitator superfamily transporter gene, and 13 structural genes. In the present study, we introduced sanG driven by six different promoters into Streptomyces ansochromogenes TH322. Nikkomycin production was increased significantly with the highest increase in engineered strain harboring hrdB promoter-driven sanG. In the meantime, we replaced the native promoter of key structural genes in the gougerotin (gou) gene cluster with the hrdB promoters. The heterologous producer Streptomyces coelicolor M1146 harboring the modified gene cluster produced gougerotin up to 10-fold more than strains carrying the unmodified cluster. Therefore, genetic manipulations of genes involved in antibiotics biosynthesis with the constitutive hrdB promoter present a robust, easy-to-use system generally useful for the improvement of antibiotics production in Streptomyces. 23848220 Review article: a clinician's guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease. Tumour necrosis factor (TNF)-antagonists have an established role in the treatment of inflammatory bowel diseases (IBDs), however, subtherapeutic drug levels and the formation of anti-drug antibodies (ADAs) may decrease their efficacy. The evidence supporting the use of therapeutic drug monitoring (TDM) based clinical algorithms for infliximab (IFX) and their role in clinical practice will be discussed. The literature was reviewed to identify relevant articles on the measurement of IFX levels and antibodies-to-infliximab. Treatment algorithms for IBD have evolved from episodic monotherapy used in patients refractory to all other treatments, to long-term combination therapy initiated early in the disease course. Improved remission rates have been observed with this paradigm shift, nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence-based manner and are probably not cost-effective. Multiple TDM-based algorithms have been developed to identify patients that may benefit from measurement of IFX and ADA levels to guide adjustments to therapy. Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX. This concept has gained momentum based on evidence from case series, cohort studies and post-hoc analyses of randomised controlled trials. 23912926 A patient with ventricular tachycardia due to a novel mutation of the lamin a/c gene: case presentation and mini review. Lamin A/C is a major constituent of the nuclear lamina, the proteinaceous meshwork underlying the inner nuclear membrane. Laminopathies are a group of diseases with heterogeneous clinical presentation. Lamin A/C mutations are a well-established cause of dilated cardiomyopathy. In our case, a novel mutation of lamin A/C presented in the typical form of cardiolaminopathy with ventricular tachycardia and mild myocardial dysfunction in an apparently healthy, middle-aged individual. 23918405 Development of the rat larynx: A histological study. To evaluate and describe the cartilaginous and muscular development of the rat larynx. Histologic evaluation. The larynges of Sprague Dawley rats of embryonic day (E) 13, 15, 17, 19, 21, postnatal day 0, 14, and adult of 250 gm were collected. Four larynges of each age were harvested, cut into 15-μm serial sections, stained with hematoxylin and eosin, and evaluated under light microscopy. Representative digital images were recorded and evaluated at the preglottic (supraglottic in humans), glottic, and postglottic (subglottic in humans) levels. Brachial arches were observed at E13. At E17, immature structures of the larynx, including skeletal muscle, cartilage, and the lumen were identifiable. Chondrification and muscle formation were clearly seen by E19. The muscular and cartilagenous components of the larynx were well established by E21. During the span between birth and adult maturation, the size of the larynx increased from a height of 1.10 mm to 2.90 mm, and from a width of 1.80 mm to 5.40 mm, and from a length of 1.38 mm to 4.77 mm in the stained section. Although developed at E21, the laryngeal structures continued to grow by approximately 30%. Rat laryngeal development parallels that in mice and humans. In the rat, at E17 immature structures of the larynx are identifiable, they are well developed at birth and grow by approximately 30% into adulthood. Understanding the chronology and morphology of the embryogenesis of the rat laryngeal musculature is essential and will allow for further evaluation of the embryologic innervation of these muscles. N/A. Laryngoscope, 2013. 22773383 Severity of coronary artery disease affects prognosis of patients with peripheral artery disease. It remains unclear whether severity of coronary artery disease (CAD) affects the prognosis of patients with peripheral artery disease (PAD). In this retrospective, multicenter study, we analyzed 537 consecutive patients with symptomatic PAD who underwent both peripheral artery revascularization and coronary angiography (CAG) prior to revascularization. We classified patients into 3 groups based on CAG: no-CAD group, intermediate CAD group (1-2 diseased vessels), and triple-vessel disease (TVD) group. We evaluated clinical outcome including all-cause death, major adverse cardiac events (MACEs), and amputation. The no-CAD, intermediate CAD, and TVD groups comprised 204, 268, and 65 patients, respectively. Mean follow-up duration was 952 ± 497 days. Freedom from any adverse outcome was highest in the no-CAD group and lowest in the TVD group (all-cause death: 86% vs 77% vs 65%, P = .043; MACE: 95% vs 87% vs 78%, P = .044; amputation: 96% vs 92% vs 83%, P = .0015). Severity of CAD affected prognosis of patients with PAD. 23828393 Interleukin-6 but not tumour necrosis factor-alpha predicts survival in patients with advanced cancer. The purpose of this study was to evaluate the prognostic role of interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) in the survival of patients with advanced cancer. In this prospective cohort study between three hospice and palliative care centres in South Korea, we followed 98 advanced cancer patients until death or the end of the study. Approximately 60 % of the patients had poor functional status (Eastern Cooperative Oncology Group score ≥3). We investigated the symptoms of cancer cachexia anorexia syndrome, possible cytokine-related confounders such as infection and medication records. Influence from clinical variables was adjusted using the Cox proportional hazard model. The median survival time was 27 days. On multivariate analysis, elevated IL-6 (hazard ratio, 2.139; p = 0.003) was found to be an independent significant prognostic factor. TNF-α was not a significant factor. Poor performance status and male gender were also independently related to shortened survival. IL-6 level can be a useful indicator of survival time of patients with advanced cancer at the very end of life. In contrast, the prognostic role of TNF-α requires further study. 23714171 Tubular Secretion of Creatinine in Autosomal Dominant Polycystic Kidney Disease: Consequences for Cross-sectional and Longitudinal Performance of Kidney Function Estimating Equations. Autosomal dominant polycystic kidney disease (ADPKD) is characterized by renal tubular cell proliferation and dedifferentiation, which may influence tubular secretion of creatinine (CCr[TS]). Diagnostic test study. We therefore investigated CCr(TS) in patients with ADPKD and controls and studied consequences for the performance of glomerular filtration rate (GFR) estimating equations. In patients with ADPKD and healthy controls, we measured GFR as (125)I-iothalamate clearance while simultaneously determining creatinine clearance. 24-hour urinary albumin excretion. In 121 patients with ADPKD (56% men; mean age, 40 ± 11 [SD] years) and 215 controls (48% men; mean age, 53 ± 10 years), measured GFR (mGFR) was 78 ± 30 and 98 ± 17 mL/min/1.73 m(2), respectively, and CCr(TS) was 15.9 ± 10.8 and 10.9 ± 10.6 mL/min/1.73 m(2), respectively (P < 0.001). The higher CCr(TS) in patients with ADPKD remained significant after adjustment for covariates and appeared to be dependent on mGFR. Correlation and accuracy between mGFR and CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) estimated GFR (eGFR) were 0.95 and 99%, respectively; between mGFR and MDRD (Modification of Diet in Renal Disease) Study eGFR, they were 0.93 and 97%, respectively. Values for bias, precision, and accuracy were similar or slightly better than in controls. In addition, change in mGFR during 3 years of follow-up in 45 patients with ADPKD correlated well with change in eGFR. Cross-sectional, single center. CCr(TS) in patients with ADPKD is higher than that in controls, but this effect is limited and observed at only high-normal mGFR. Consequently, the CKD-EPI and MDRD Study equations perform relatively well in estimating GFR and change in GFR in patients with ADPKD. 23968090 An ab initio study of the ground and low-lying excited states of KBe with the effect of inner-shell electrons. The potential energy curves (PECs) of 1(2)Σ(+), 2(2)Σ(+), 1(2)Π, and 2(2)Π states of KBe are calculated using multireference configuration interaction method and large all-electron basis sets. Four sets of frozen core orbitals (FCOs) are considered to examine the effect of inner-shell correlation electrons on the molecular properties. The ro-vibrational energy levels are obtained by solving the Schrödinger equation of nuclear motion based on the ab initio PECs. The spectroscopic parameters are determined from the ro-vibrational levels with Dunham expansion. The PECs are fitted into analytical potential energy functions using the Morse long-range potential function. The dipole moment functions of the states for KBe calculated with different FCOs are presented. The transition dipole moments for KBe between 1(2)Σ(+) and 2(2)Σ(+) states, 1(2)Π and 1(2)Σ(+) states, and 2(2)Π and 1(2)Σ(+) states are also obtained. 23903830 Mice lacking functional STAT1 are highly susceptible to lethal infection with Lassa virus. Lassa fever (LF) is a potentially lethal human disease that is caused by the arenavirus, Lassa virus (LASV). Annually, around 300,000 infections with up to 10,000 deaths occur in endemic regions of West Africa. Here we demonstrate that mice lacking a functional STAT1 pathway are highly susceptible to infection with LASV and develop lethal disease with pathology similar to that reported in humans. 23801546 Distinct solid and solution state self-assembly pathways of RADA16-I designer peptide. Solid state NMR measurements on selectively (13) C-labeled RADA16-I peptide (COCH3 -RADARADARADARADA-NH2 ) were used to obtain new molecular level information on the conversion of α-helices to β-sheets through self-assembly in the solid state with increasing temperature. Isotopic labeling at the A4 Cβ site enabled rapid detection of (13) C NMR signals. Heating to 344-363 K with simultaneous NMR detection allowed production of samples with systematic variation of α-helix and β-strand content. These samples were then probed at room temperature for intermolecular (13) C-(13) C nuclear dipolar couplings with the PITHIRDS-CT NMR experiment. The structural transition was also characterized by Fourier transform infrared spectroscopy and wide angle X-ray diffraction. Independence of PITHIRDS-CT decay shapes on overall α-helical and β-strand content infers that β-strands are not observed without association with β-sheets, indicating that β-sheets are formed at elevated temperatures on a timescale that is fast relative to the NMR experiment. PITHIRDS-CT NMR data were compared with results of similar measurements on RADA16-I nanofibers produced by self-assembly in aqueous salt solution. We report that β-sheets formed through self-assembly in the solid state have a structure that differs from those formed through self-assembly in the solution state. Specifically, solid state RADA16-I self-assembly produces in-register parallel β-sheets, whereas nanofibers are composed of stacked parallel β-sheets with registry shifts between adjacent β-strands in each β-sheet. These results provide evidence for environment-dependent self-assembly mechanisms for RADA16-I β-sheets as well as new constraints on solid state self-assembled structures, which must be avoided to maximize solution solubility and nanofiber yields. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd. 23256624 Evaluation of low background liquid scintillation counter for non-clinical ADME studies. 1. The performance of low background (BG) liquid scintillation counter (LSC) was evaluated for practical purposes of non-clinical drug absorption, distribution, metabolism and excretion (ADME) studies. The measurement conditions for the radioactivity for low BG LSC were investigated and metabolite profiling in rat plasma after single oral administration of (14)C-labeled compounds was performed. Metabolite profiling was also conducted using conventional LSC and accelerator mass spectrometer (AMS), and the performances of these measuring instruments were compared. 2. The established measurement conditions showed good linearity of the calibration curve over the concentration range from 3 to 300 dpm/vial. Metabolite profiling using low BG LSC for the plasma samples diluted to 5-55 times was comparable to that using conventional LSC for the undiluted plasma samples. Meanwhile, metabolite profiling using AMS for the plasma samples diluted to 250-2000 times was comparable to that using conventional LSC. 3. These results suggest that the application of low BG LSC is one of the useful tools for non-clinical ADME studies and that it is possible to select conventional LSC, low BG LSC or AMS for radioactivity measurement by considering the specific radioactivity of the compounds and the predicted concentrations of radioactivity in biological samples in ADME studies. 23901952 Communication: Fundamental equation of state correlation with hybrid data sets. A strategy is proposed for empirical fundamental equation of state correlations for pure fluids on the basis of hybrid data sets, composed of experimental and molecular simulation data. Argon and hydrogen chloride are used as examples. 23873586 Effect of different bone marrow stimulation techniques (BSTs) on MSCs mobilization. The therapeutic effect of bone marrow stimulation techniques (BSTs) is mainly attributed to the role of mesenchymal stem cells (MSCs) from the bone marrow. However, no studies have directly shown the amount of MSCs drained by BSTs. This study hypothesized that differences in the opening of subchondral bone affect the number of MSCs drained from the bone marrow. We purposed that as the exposed area and hole size of BSTs vary, the number of MSCs drained out was measured. Three groups of different BSTs were designed that have variations in the sizes of total exposed area and individual holes. Three different BSTs using a curette, 1.5- and 0.8-mm awls were carried out on the full-thickness femoral cartilage defect of young rabbits. After BST, the number of MSCs in the blood clot was measured by CFU-Fs assay. As the size of the total exposed area increased, so did the number of MSCs obtained. The number of MSCs drained from bone marrow may vary depending on different BSTs and this could affect therapeutic efficacy of cartilage defect. As current microfracture (MF) method cannot drain the most MSCs clinically, more improved surgery technique is needed. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 9999:1-6, 2013. 23846190 Pediatric nasolacrimal duct obstruction. Review the current management for pediatric nasolacrimal duct obstruction and congenital dacryocele. Early probing in the office, and probing beyond 1 year of age in a facility with general anesthesia are equally effective. Congenital nasolacrimal duct obstruction is associated with anisometropic amblyopia. Infants with unilateral dacryocele are at risk for developing a dacryocele on the unaffected side. The decision to probe early in the office or continue medical management and probe beyond a year of age in a facility with a general anesthetic is at the discretion of the ophthalmologist. Failed probings should be treated in a facility under general anesthesia with a balloon catheter or intubation. Children with congenital nasolacrimal duct obstruction need to be followed to make certain they do not develop anisometropic amblyopia. 23459067 Synthesis of a paraffin phase change material microencapsulated in a siloxane polymer. The coemulsification method suitable for the formulation of microcapsules of n-eicosane coated with a polysiloxane is developed. This method allows to synthesize core-shell microcapsules of paraffin which have the shape of spheres or distorted spheres and are designed for the use as phase change materials. The microcapsules are formed in aqueous phase by the precipitation of n-eicosane together with modified polyhydromethylsiloxane from a common solvent which is miscible with aqueous media. The polysiloxane is modified by the attachment of silylvinyl and alkoxy functions before coemulsification with the paraffin. It also contains the Pt(0) Karstedt catalyst. The microcapsules formed by coemulsification are stabilized by the in situ cross-linking of the polysiloxane shell. The shell is additionally modified by the in situ generation of silanol groups which provide colloidal stabilization of microspheres in aqueous phase. Microcapsules were studied by DSC, SEM, optical polarized microscope, and by thermooptical analysis (TOA). 23553987 Haemostatic role of intermediate filaments in adhered platelets: Importance of the membranous system stability. The role of platelets in coagulation and the haemostatic process was initially suggested two centuries ago, and under appropriate physiological stimuli, these undergo abrupt morphological changes, attaching and spreading on damaged endothelium, preventing bleeding. During the adhesion process, platelet cytoskeleton reorganizes generating compartments in which actin filaments, microtubules, and associated proteins are arranged in characteristic patterns mediating crucial events, such as centralization of their organelles, secretion of granule contents, aggregation with one another to form a haemostatic plug, and retraction of these aggregates. However, the role of Intermediate filaments during the platelet adhesion process has not been explored. J. Cell. Biochem. 114: 2050-2060, 2013. © 2013 Wiley Periodicals, Inc. 23313622 In-line monitoring of the drug content of powder mixtures and tablets by near-infrared spectroscopy during the continuous direct compression tableting process. Continuous manufacturing methods offer economic and quality advantages when compared with batch manufacturing methods. In continuous manufacturing, one requires real time assurance of quality of product via the implementation of PAT tools. This study focuses on an in-line near-infrared (NIR) spectroscopic method for determining the drug content of powder mixtures and tablets during a continuous tableting process. Tablets consisting of acetaminophen (20-30%), lactose (69.07-78.93%) and magnesium stearate (0.93-1.07%) were prepared in a continuous direct compression line that consisted of two loss-in-weight feeders, one for acetaminophen and one for premixed lactose and magnesium stearate, and a continuous mixer followed by a rotary tablet press. NIR spectroscopy was applied to the continuous mixer and tablet press to perform a 100% product check at full tableting speed. The UV-spectrophotometric method was used as an off-line reference method to determine the acetaminophen content in the samples. The powder mixture and tablet samples were taken during the process for the calibration of continuous mixer and tablet press, respectively. For the continuous mixer, model creation with the PLS method yielded R-Square and RMSEC (root mean square error of calibration) values of 0.975% and 0.56%, respectively. For the tablet press, the corresponding R-Square and RMSEC values were 0.943% and 0.75%, respectively. A test run demonstrated good predictability in the estimation of the API content in the powder mixtures and tablets during the continuous tableting process. For the continuous mixer and tablet press, the RMSEP (root mean square error of prediction) values were 0.96% and 1.37%, respectively. This study demonstrates that an NIR instrument capable of fast spectra acquisition can be a valuable tool for the in-line monitoring of the continuous mixing and tableting processes. 23838361 Is gait variability reliable? An assessment of spatio-temporal parameters of gait variability during continuous overground walking. The assessment of gait variability has become an important indicator for quantifying motor performance. However, the use of treadmills is known to influence the temporal rhythm of gait, while non-continuous (i.e. stop-start) overground walking alters gait variability, leading to erroneous results. Through establishing the "8-walk", an overground walking protocol that allows the collection of a high number of consecutive gait cycles, the aim of this study was to determine the conditions under which gait variability can be assessed reliably. Twelve healthy subjects performed continuous barefoot walking at their preferred speed in a path shaped as an "8". Kinematic data of the dominant foot was collected while subjects walked along the straight 10m sections of the 8-walk during sessions on two different days. Mean spatio-temporal parameters of gait and gait variability were computed for 10, 20, 30, 40, 50 and 60 consecutive cycles. All mean parameters of gait showed excellent reliability (ICC: 0.88-0.98) with only 10 cycles included in the analysis. However, the reliability of spatial and temporal parameters of gait variability improved with increasing number of cycles (ICC: 0.60-0.90) but levelled-off after 50 consecutive cycles, revealing an inter-day test-retest variability of ∼13%. To reliably assess gait variability and evaluate human motor performance, we propose the collection of at least 50 cycles and the use of an 8-walk protocol, which avoids the limitations of treadmill and non-consecutive walking protocols. 23445875 Hepcidin level predicts hemoglobin concentration in individuals undergoing repeated phlebotomy. Dietary iron absorption is regulated by hepcidin, an iron regulatory protein produced by the liver. Hepcidin production is regulated by iron stores, erythropoiesis and inflammation, but its physiology when repeated blood loss occurs has not been characterized. Hepcidin was assayed in plasma samples obtained from 114 first-time/reactivated (no blood donations in preceding 2 years) female donors and 34 frequent (≥3 red blood cell donations in preceding 12 months) male donors as they were phlebotomized ≥4 times over 18-24 months. Hepcidin levels were compared to ferritin and hemoglobin levels using multivariable repeated measures regression models. Hepcidin, ferritin and hemoglobin levels declined with increasing frequency of donation in the first-time/reactivated females. Hepcidin and ferritin levels correlated well with each other (Spearman's correlation of 0.74), but on average hepcidin varied more between donations for a given donor relative to ferritin. In a multivariable repeated measures regression model the predicted inter-donation decline in hemoglobin varied as a function of hepcidin and ferritin; hemoglobin was 0.51 g/dL lower for subjects with low (>45.7 ng/mL) or decreasing hepcidin and low ferritin (>26 ng/mL), and was essentially zero for other subjects including those with high (>45.7 ng/mL) or increasing hepcidin and low ferritin (>26 ng/mL) levels (P<0.001). In conclusion, hepcidin levels change rapidly in response to dietary iron needed for erythropoiesis. The dynamic regulation of hepcidin in the presence of a low levels of ferritin suggests that plasma hepcidin concentration may provide clinically useful information about an individual's iron status (and hence capacity to tolerate repeated blood donations) beyond that of ferritin alone. Clinicaltrials.gov identifier: NCT00097006. 23958783 The delayed addition of human MSCs to pre-formed endothelial cell networks results in functional vascularisation of a collagen-GAG scaffold in vivo. This article demonstrates a method to engineer, in vitro, a nascent microvasculature within a collagen-GAG scaffold with a view to overcoming the major issue of graft failure due to avascular necrosis of tissue engineered constructs. Human umbilical vein endothelial cells (ECs) were cultured alone and in various co-culture combinations with human mesenchymal stem cells (MSCs) to determine their vasculogenic abilities in vitro. Results demonstrated that the delayed addition of MSCs to pre-formed EC networks, whereby MSCs act as pericytes to the nascent vessels, resulted in the best developed vasculature. The results also demonstrate that the crosstalk between ECs and MSCs during microvessel formation occurs in a highly regulated, spatio-temporal fashion, whereby the initial seeding of ECs results in platelet derived growth factor (PDGF) release; the subsequent addition of MSCs 3 days later leads to a cessation in PDGF production, coinciding with increased vascular endothelial cell growth factor expression and enhanced vessel formation. Functional assessment of these pre-engineered constructs in a subcutaneous rat implant model demonstrated anastomosis between the in vitro engineered vessels and the host vasculature, with significantly increased vascularisation occurring in the co-culture group. This study has thus provided new information on the process of in vitro vasculogenesis within a 3D porous scaffold for tissue engineering and demonstrates the potential for using these vascularised scaffolds in the repair of critical sized bone defects. 23867390 Evaluation of novel aryloxyalkyl derivatives of imidazole and 1,2,4-triazole as heme oxygenase-1 (HO-1) inhibitors and their antitumor properties. A novel series of aryloxyalkyl derivatives of imidazole and 1,2,4-triazole, 17-31, was designed and synthesized as inhibitors of heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2). Some of these compounds were found to be good inhibitors of HO-1, in particular those carrying an imidazole moiety as azolyl group and a 3-bromo or 4-iodophenyl as aryl moiety. The most potent compounds 6 and 30 were selected and studied for their antitumor properties in a model of LAMA-84 R cell line overexpressing HO-1 and resistant to imatinib mesylate (IM), a tyrosine-kinase inhibitor used in the treatment of multiple types of cancer, most notably Philadelphia Chromosome positive (Ph(+)) Chronic Myelogenous Leukemia (CML). Results show that both 6 and 30 sensitized LAMA-84 R cell line to antitumor properties of IM. 23314053 Antimicrobial activity of various 4- and 5-substituted 1-phenylnaphthalenes. Bacterial cell division occurs in conjunction with the formation of a cytokinetic Z-ring structure comprised of FtsZ subunits. Agents that can disrupt Z-ring formation have the potential, through this unique mechanism, to be effective against several of the newly emerging multi-drug resistant strains of infectious bacteria. 1- and 12-Aryl substituted benzo[c]phenanthridines have been identified as antibacterial agents that could exert their activity by disruption of Z-ring formation. Substituted 4- and 5-amino-1-phenylnaphthalenes represent substructures within the pharmacophore of these benzo[c]phenanthridines. Several 4- and 5-substituted 1-phenylnaphthalenes were synthesized and evaluated for antibacterial activity against Staphylococcus aureus and Enterococcus faecalis. The impact of select compounds on the polymerization dynamics of S. aureus FtsZ was also assessed. 23444962 In vivo genotoxicity and oxidative stress evaluation of an ethanolic extract from piquiá (Caryocar villosum) pulp. In this study, the ethanolic extract obtained from piquiá pulp was assessed for genotoxicity and oxidative stress by employing the micronucleus test in bone marrow and peripheral blood cells in addition to comet, thiobarbituric-acid-reactive substances (TBARS), and reduced glutathione assays in the liver, kidney, and heart. Additionally, phytochemical analyses were performed to identify and quantify the chemical constituents of the piquiá extract. Wistar rats were treated by gavage with an ethanolic extract from piquiá pulp (75 mg/kg body weight) for 14 days, and 24 h prior to euthanasia, they received an injection of saline or doxorubicin (15 mg/kg body weight, intraperoneally). The results demonstrated that piquiá extract at the tested dose was genotoxic but not mutagenic, and it increased the TBARS levels in the heart. Further studies are required to fully elucidate how the properties of ethanolic extract of piquiá pulp can affect human health. 23510375 Clinical studies of innovative medical devices: what level of evidence for hospital-based health technology assessment? Like health technology assessment (HTA) agencies, hospitals are faced with requests for innovative and costly medical devices. However, local decision makers are frequently confronted with a lack of high-quality clinical data when assessing the effectiveness of innovative medical devices. The aim of this study was to quantify the level of evidence available for innovative medical devices in the context of hospital-based HTA. We searched the Medline, Embase and Cochrane Library databases for articles, letters and reports relating to 32 innovative medical devices requested at our hospital between January 2008 and March 2012. All clinical studies retrieved were screened and classified according to the Sackett 5-point level-of-evidence scale. We screened and classified 217 studies: 215 clinical trials and 2 cost-effectiveness studies. Only 47 of the 215 clinical studies (22%) provided high-level clinical evidence (levels 1-2); 33 (15%) were randomized controlled trials (RCTs). More than half of the 215 studies (52.1%) included fewer than 30 patients. Only 14 of the 47 high-quality studies reported the amount of missing data. For implantable medical devices, 84 (71.8%) studies specified the follow-up period and the mean follow-up period was 18.9 months. Finally, methodological quality did not increase with the risk level of the medical device. Our findings confirm that only a few studies of innovative medical devices provide high-level clinical evidence. Nevertheless, RCT may be the 'gold standard' for drugs, but it is not always appropriate for medical devices. Changes to the European regulation of medical devices, with the requirement for a demonstration of clinical efficacy and safety before release onto the European market, have raised expectations. 23916833 Inhibition of LRRK2 kinase activity stimulates macroautophagy. Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most important genetic contributors to Parkinson's disease. LRRK2 has been implicated in a number of cellular processes, including macroautophagy. To test whether LRRK2 has a role in regulating autophagy, a specific inhibitor of the kinase activity of LRRK2 was applied to human neuroglioma cells and downstream readouts of autophagy examined. The resulting data demonstrate that inhibition of LRRK2 kinase activity stimulates macroautophagy in the absence of any alteration in the translational targets of mTORC1, suggesting that LRRK2 regulates autophagic vesicle formation independent of canonical mTORC1 signaling. This study represents the first pharmacological dissection of the role LRRK2 plays in the autophagy/lysosomal pathway, emphasizing the importance of this pathway as a marker for LRRK2 physiological function. Moreover it highlights the need to dissect autophagy and lysosomal activities in the context of LRRK2 related pathologies with the final aim of understanding their aetiology and identifying specific targets for disease modifying therapies in patients. 23763594 Encapsulation of enzymes in Layer-by-Layer (LbL) structures: latest advances and applications. Layer-by-Layer (LbL) technology has become an active area of research and is currently considered a hot topic with many potential applications, especially in the pharmaceutical and biopharmaceutical fields. This review is providing an overview of current approaches and applications of LbL designs used to immobilize and/or encapsulate various enzymes. One aim was to show the versatility and the potential of this technique in obtaining different designs and architectures fulfilling a wide range of needs and applications. Another important aim was to shed light on the techniques commonly used to characterize LbL structures and to monitor the process of layer deposition. Special attention was given to LbL structures encapsulating multiple enzymes where the function depends on the sequential activities of encapsulated enzymes. 23871316 What Is in a Name? Oral and Maxillofacial Surgeon Versus Oral Surgeon. In 1975, the American Society of Oral Surgeons officially changed its name to the American Association of Oral and Maxillofacial Surgeons. This change was intended to address the specialty's expanding surgical scope. However, today, many health care professionals continue to use the term oral surgeon. This study was undertaken to determine if students' perception of the oral and maxillofacial surgeon's (OMS) surgical scope would change when oral and maxillofacial surgeon was used instead of oral surgeon. This cross-sectional study surveyed undergraduate and dental students' choice of specialist to treat 21 different conditions. The independent variable was the specialty term (oral and maxillofacial surgeon vs oral surgeon). The dependent variables were specialists chosen for the procedure (ear, nose, and throat surgeon; plastic surgeon; OMS or oral surgeon; periodontist; other). The test of proportions (z test) with the Yates correction was performed for data analysis. Of the 280 senior dental students who were surveyed, 258 surveys were included in the study. Dental students' perception of the OMS's surgical scope increased significantly from 51% to 55% when oral and maxillofacial surgeon was used instead of oral surgeon. Of the 530 undergraduate upper division science students who were surveyed, 488 surveys were included in the study. Undergraduate upper division science students' perception of the OMS's surgical scope increased significantly from 23% to 31% when oral and maxillofacial surgeon was used as an option instead of oral surgeon. The use of oral and maxillofacial surgeon increased students' perception of the OMS's surgical scope. This study also suggested that students were not fully aware of the magnitude of the OMS's scope of practice. The current dichotomy and inconsistent use of the specialty's official term adds to the confusion and to misunderstanding. Therefore, OMSs should universally refer to themselves as oral and maxillofacial surgeons and help educate others of their scope. 23962806 Physiological and proteomics analyses of Holm oak (Quercus ilex subsp. ballota [Desf.] Samp.) responses to Phytophthora cinnamomi. Phytophthora cinnamomi is one of the agents that trigger the decline syndrome in Quercus spp., this being a serious threat to Mediterranean Holm oak forest sustainability and reforestation programs. Quercus ilex responses to Phytophthora cinnamomi have been studied in one-year olds seedlings from two Andalucía provenances, assessing the physiological water status and photosynthesis-related parameters. Upon inoculation with mycelium a reduction in water content, chlorophyll fluorescence, stomatal conductance and gas exchange was observed along a 90 days post inoculation period in both provenances. The reduction was higher in the most susceptible (SSA) provenance, than in the most tolerant (PCO), being these typical plant responses to drought stress. Leaf protein profiles were analyzed in non-inoculated and inoculated seedlings from the two provenances by using a 2-DE coupled to MS proteomics strategy. Ninety seven proteins changing in abundance in response to the inoculation were successfully identified after MALDI-TOF-TOF analyses. The largest group of variable identified proteins were chloroplasts ones, and they were involved in the photosynthesis, Calvin cycle and carbohydrate metabolism. It was noted that a general tendency was a decrease in the protein abundance as a consequence of the inoculation, being it less accused in the least susceptible, the Northern provenance (PCO), than in the most susceptible, the Southern provenance (SSA). This trend is clearly manifested in photosynthesis, amino acid metabolism and stress/defence proteins. On the contrary, some proteins related to starch biosynthesis, glycolysis and stress related peroxiredoxin showed an increase upon inoculation. These changes in protein abundance were correlated to the estimated physiological parameters and have been frequently observed in plants subjected to drought stress. 23922962 Cognitive reactivity, implicit associations, and the incidence of depression: a two-year prospective study. Cognitive reactivity to sad mood is a vulnerability marker of depression. Implicit self-depressed associations are related to depression status and reduced remission probability. It is unknown whether these cognitive vulnerabilities precede the first onset of depression. To test the predictive value of cognitive reactivity and implicit self-depressed associations for the incidence of depressive disorders. Prospective cohort study of 834 never-depressed individuals, followed over a two-year period. The predictive value of cognitive reactivity and implicit self-depressed associations for the onset of depressive disorders was assessed using binomial logistic regression. The multivariate model corrected for baseline levels of subclinical depressive symptoms, neuroticism, for the presence of a history of anxiety disorders, for family history of depressive or anxiety disorders, and for the incidence of negative life events. As single predictors, both cognitive reactivity and implicit self-depressed associations were significantly associated with depression incidence. In the multivariate model, cognitive reactivity was significantly associated with depression incidence, together with baseline depressive symptoms and the number of negative life events, whereas implicit self-depressed associations were not. Cognitive reactivity to sad mood is associated with the incidence of depressive disorders, also when various other depression-related variables are controlled for. Implicit self-depressed associations predicted depression incidence in a bivariate test, but not when controlling for other predictors. 23939785 Castration-induced upregulation of muscle ERα supports estrogen sensitivity of motoneuron dendrites in a sexually dimorphic neuromuscular system. The spinal cord of rats contains the sexually dimorphic motoneurons of the spinal nucleus of the bulbocavernosus (SNB). In males, SNB dendrites fail to grow after castration, but androgen or estrogen treatment supports dendritic growth in castrated males. Estrogenic support of SNB dendrite growth is mediated by estrogen receptors (ER) in the target muscle. ERα expression in cells lacking a basal lamina (referred to as "extra-muscle fiber cells") of the SNB target musculature coincides with the period of estrogen-dependent SNB dendrite growth. In the SNB target muscle, extra-muscle fiber ERα expression declines with age and is typically absent after postnatal (P) day 21 (P21). Given that estradiol downregulates ERα in skeletal muscle, we tested the hypothesis that depleting gonadal hormones would prevent the postnatal decline in ERα expression in the SNB target musculature. We castrated male rats at P7 and assessed ERα immunolabeling at P21; ERα expression was significantly greater in castrated males compared with normal animals. Because ERα expression in SNB target muscles mediates estrogen-dependent SNB dendrogenesis, we further hypothesized that the castration-induced increase in muscle ERα would heighten the estrogen sensitivity of SNB dendrites. Male rats were castrated at P7 and treated with estradiol from P21 to P28; estradiol treatment in castrates resulted in dendritic hypertrophy in SNB motoneurons compared with normal males. We conclude that early castration results in an increase in ERα expression in the SNB target muscle, and this upregulation of ERα supports estrogen sensitivity of SNB dendrites, allowing for hypermasculinization of SNB dendritic arbors. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013. 23115222 The antinociceptive effects of nicotinic receptors α7-positive allosteric modulators in murine acute and tonic pain models. The α7 nicotinic acetylcholine receptor (nAChR) subtype is abundantly expressed in the central nervous system and in the periphery. Recent evidence suggests that α7 nAChR subtypes, which can be activated by an endogenous cholinergic tone, comprising acetylcholine and the α7 nAChR agonist choline, play an important role in subchronic pain and inflammation. This study's objective was to test whether α7 nAChR positive allosteric modulators (PAMs) produce antinociception in in vivo mouse models of acute and persistent pain. Testing type I [N-(5-chloro-2-hydroxyphenyl)-N'-[2-chloro-5-(trifluoromethyl)phenyl] (NS1738)] and type II [1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl) (PNU-120596)] α7 nAChR PAMs in acute and persistent pain, we found that, although neither reduced acute thermal pain, only PNU-120596 dose-dependently attenuated paw-licking behavior in the formalin test. The long-acting effect of PNU-120596 in this test was in discordance with its pharmacokinetic profile in mice, which suggests the involvement of postreceptor signaling mechanisms. Our results with selective mitogen-activated protein kinase kinase inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene monoethanolate (U0126) argues for an important role of extracellular signal-regulated kinase-1/2 pathways activation in PNU-120596's antinociceptive effects. The α7 antagonist MLA, administered intrathecally, reversed PNU-120596's effects, confirming PNU-120596's action, in part, through central α7 nAChRs. Importantly, tolerance to PNU-120596 was not developed after subchronic treatment of the drug. Surprisingly, PNU-120596's antinociceptive effects were blocked by NS1738. Our results indicate that type II α7 nAChR PAM PNU-120596, but not type I α7 nAChR PAM NS1738, shows significant antinociception effects in persistent pain models in mice. 23892084 Histone H3 lysine 9 methyltransferases, G9a and GLP are essential for cardiac morphogenesis. Lysine methylation of the histone tail is involved in a variety of biological events. G9a and GLP are known as major H3-K9 methyltransferases and contribute to transcriptional silencing. The functions of these genes in organogenesis remain largely unknown. Here, we analyzed the phenotypes of cardiomyocyte specific GLP knockout and G9a knockdown (GLP-KO/G9a-KD) mice. The H3-K9 di-methylation level decreased markedly in the nuclei of the cardiomyocytes of GLP-KO/G9a-KD mice, but not single G9a or GLP knockout mice. In addition, GLP-KO/G9a-KD mice showed neonatal lethality and severe cardiac defects (atrioventricular septal defects, AVSD). We also showed that hypoplasia in the atrioventricular cushion, which is a main part of the atrioventricular septum, caused AVSD. Expression analysis revealed downregulation of 2 AVSD related genes and upregulation of several non-cardiac specific genes in the hearts of GLP-KO/G9a-KD mice. These data indicate that G9a and GLP are required for sufficient H3-K9 di-methylation in cardiomyocytes and regulation of expression levels in multiple genes. Moreover, our findings show that G9a and GLP have an essential role in normal morphogenesis of the atrioventricular septum through regulation of the size of the atrioventricular cushion. 23529067 The effect of sodium selenite on lead induced cognitive dysfunction. The effect of lead (Pb) on spatial memory and hippocampal long-term potentiation (LTP) as a key risk factor has been widely recognized and the oxidative damage has been proposed as a possible mechanism of lead neurotoxicity. Selenium (Se) is a nutritionally essential trace element with known antioxidant potential. In this study we investigated the effect and the underlying mechanisms of Se supplementary on Pb induced cognition and synaptic plasticity impairment. Lactating Sprague-Dawley rats (SD rats) were randomly divided to four groups: 0ppm lead acetate (Pb); 0ppm Pb and 0.2ppm sodium selenite (Se); 100ppm Pb; 100ppm Pb and 0.2ppm Se. Lactating rats were treated with or without Pb and/or Se throughout lactation until weaning. The levels of hippocampal LTP, the spatial memory, the apoptosis of hippocampal neurons, the levels of lactate dehydrogenase (LDH) release, and the serum level of superoxide dismutase (SOD) and malondialdehyde (MDA) were assayed. It had been observed that in Pb group the spatial memory, the induce level of LTP, the serum SOD level decreased, the LDH release level, the neurons apoptosis level, the serum MDA level increased, while in the Se supplements groups, the spatial memory, the induce level of LTP increased significantly. Compared with the Pb group, Se supplements shown down regulated the level of LDH, the neurons apoptosis and the serum MDA, and up regulated the level of serum SOD. We could draw the conclusion that Se supplements could alleviate toxic effect of lead on hippocampal LTP and spatial memory. The treated with selenium around 0.2ppm may protect against spatial memory dysfunction induced by lead exposure. 23845188 Mesenchymal stromal cells augment CD4+ and CD8+ T-cell proliferation through a CCL2 pathway. Mesenchymal stromal cells (MSC) derived from bone marrow are immunosuppressive in vitro and in vivo. Recent evidence, however, has shown that in certain settings, MSC can also be immunostimulatory. The mechanisms involved in this process are largely unknown. Mouse spleen T cells were stimulated with allogeneic mixed lymphocyte reaction (MLR) or anti-CD3/CD28 beads and treated with autologous bone marrow MSC or MSC-conditioned medium. CD4+ and CD8+ T-cell proliferation was analyzed after treatment. We show that MSC have both suppressive and stimulatory functions toward T cells after stimulation with anti-CD3/CD28 beads or in an MLR. This depended on the ratio of MSC to responder T cells, with low numbers of MSC increasing and higher numbers inhibiting T-cell proliferation. Immunostimulatory function was mediated, in part, by soluble factors. MSC immunosuppression of the MLR was indirect and related to inhibition of antigen-presenting cell maturation. Direct effects of MSC-conditioned medium during anti-CD3/CD28 stimulated proliferation were entirely stimulatory and required the presence of the T-cell receptor. MSC supernatant contained both CCL2 and CCL5 at high levels, but only CCL2 level correlated with the ability to augment proliferation. An anti-CCL2 antibody blocked this proliferative activity. CCL2 plays an important role in the immunostimulatory function of MSC, and we further hypothesize that the immunomodulatory role of MSC is determined by a balance between inhibitory and stimulatory factors, suggesting the need for caution when these cells are investigated in clinical protocols. 23910686 Hyponatremia in Children with Bronchiolitis Admitted to the Pediatric Intensive Care Unit Is Associated with Worse Outcomes. To characterize the relationship between hyponatremia (serum sodium <135 mEq/L) and clinical outcomes in children ages 1 month to 2 years admitted to the pediatric intensive care unit (PICU) with bronchiolitis. Single-center retrospective cohort study comprising children who were admitted to the PICU between January 2009 and April 2011. Serum sodium concentrations, collected within the first 2 hours after admission to the PICU, were recorded and associations with clinical outcomes were calculated. Quantitative data are presented as mean ± SD or percentage. Student t-test, Fisher exact test, and χ(2) analyses were performed as appropriate. Subjects were excluded if they were previously diagnosed with chronic disease that would affect initial serum sodium concentration. Children with bronchiolitis were enrolled (n = 102; age = 10.7 ± 6.7 months). Twenty-three patients (22%) were diagnosed with hyponatremia within 2 hours of admission. Mortality (13% vs 0%; P = .011), ventilator time (8.41 ± 2 days vs 4.11 ± 2 days; P = .001), duration of stay in the PICU (10.63 ± 2.5 days vs 5.82 ± 2.09 days; P = .007), and noninvasive ventilator support (65% vs 24%; P = .007) were significantly different between subjects with hyponatremia vs those without. There were no differences in the number of patients with seizures, bronchodilator use, steroid use, intubation requirement, oxygen use at discharge, or hospital readmission. Pediatric patients diagnosed with bronchiolitis who present with a serum sodium concentration less than 135 mEq/L within 2 hours of admission to the PICU fare worse than their cohorts with normonatremia. A prospective study to evaluate the effects of hyponatremia appears justified. 23859379 Swift Nanopattern Formation of PS-b-PMMA and PS-b-PDMS Block Copolymer Films Using a Microwave Assisted Technique. Microphase separation of block copolymer (BCPs) thin films has high potential as a surface patterning technique. However, the process times (during thermal or solvent anneal) can be inordinately long, and for it to be introduced into manufacturing, there is a need to reduce these times from hours to minutes. We report here BCP self-assembly on two different systems, polystyrene-b-polymethylmethacrylate (PS-b-PMMA) (lamellar- and cylinder-forming) and polystyrene-b-polydimethylsiloxane (PS-b-PDMS) (cylinder-forming) by microwave irradiation to achieve ordering in short times. Unlike previous reports of microwave assisted microphase segregation, the microwave annealing method reported here was undertaken without addition of solvents. Factors such as the anneal time and temperature, BCP film thickness, substrate surface type, etc. were investigated for their effect of the ordering behavior. The microwave technique was found to be compatible with graphoepitaxy, and in the case of the PS-b-PDMS system, long-range translational alignment of the BCP domains was observed within the topographic patterns. To demonstrate the usefulness of the method, the BCP nanopatterns were turned into an 'on-chip' resist by an initial plasma etch and these were used to transfer the pattern into the substrate. 23884368 Pacemaking Kisspeptin Neurons. Kisspeptin (Kiss1) neurons are vital for reproduction. GnRH neurons express the kisspeptin receptor, GPR 54, and kisspeptins potently stimulate the release of GnRH by depolarising and inducing sustained action potential firing in GnRH neurons. As such Kiss1 neurons may be the pre-synaptic pacemaker neurons in the hypothalamic circuitry that controls reproduction. There are at least two different populations of Kiss1 neurons: one in the rostral periventricular area (RP3V) that is stimulated by oestrogens and the other in the arcuate nucleus that is inhibited by oestrogens. How each of these Kiss1 neuronal populations participate in the regulation of the reproductive cycle is currently under intense investigation. Based on electrophysiological studies in the guinea pig and mouse, Kiss1 neurons in general are capable of generating burst firing behavior. Essentially all Kiss1 neurons, which have been studied thus far in the arcuate nucleus, express the ion channels necessary for burst firing, which include hyperpolarization-activated, cyclic nucleotide gated cation (HCN) channels and the T-type calcium (Cav3.1) channels. Under voltage clamp conditions, these channels produce distinct currents that under current clamp conditions can generate burst firing behavior. The future challenge is to identify other key channels and synaptic inputs involved in the regulation of the firing properties of Kiss1 neurons and the physiological regulation of the expression of these channels and receptors by oestrogens and other hormones. The ultimate goal is to understand how Kiss1 neurons control the different phases of GnRH neurosecretion and hence reproduction. 23910746 Factor structure and psychometric properties of the Spanish version of the Alabama Parenting Questionnaire (APQ) for children. Background: The Alabama Child Parenting Questionnaire (APQ) is a multi-source and multi-method instrument created to assess the most relevant parenting practices from a bidirectional perspective. Despite its advantages, the APQ has not been validated with a Spanish population. The objective of this study was to analyse the psychometric properties and factor structure of the APQ, child self-report version, in a community sample of Spanish children. Method: The participants were 423 Spanish children (58.9% boys) aged between 8 and 12 years. Results: Exploratory factor analysis suggested a version of the questionnaire that consists of 16 items with a four-factor structure: Parental Involvement, Positive Parenting, Inconsistent Discipline, and Poor Supervision. The internal consistency of the subscales was moderate, except for the father's Parental Involvement factor, which reached acceptable reliability. Convergent validity with a measure of quality of life was adequate. Gender differences were only found in Poor Supervision, with higher scores in boys than in girls. Conclusions: Overall, these findings provide support for the use of the APQ to measure parenting practices perceived by Spanish children. 23928602 The effect of immediate and delayed post-space preparation using extended working time root canal sealers on apical leakage. Even when using an extended working time (EWT) sealer, post-spaces can be prepared immediately following root canal obturation. 23910944 The Importance of Self-Perceptions to Psychosocial Adjustment in Adolescents With Heart Disease. This study examined the importance of self-perceptions as determinants of psychosocial adjustment reported by adolescents with heart disease and compared adolescents with heart disease to healthy norms. Ninety-two adolescents with heart disease from a single Midwestern institution provided reports of self-perceptions (health, self-worth, competence, and importance), internalizing behavior problems (IPs; e.g., anxiety and depression) and externalizing behavior problems (EPs; e.g., attention problems and aggression), and health-related quality of life (HRQOL). Hierarchical linear regression was used to assess the impact of self-perceptions, as well as clinical factors (e.g., illness severity, time since last hospitalization, and medications) and demographic characteristics on outcomes. Self-perceptions explained the most variance in behavioral and HRQOL outcomes (R(2)adj = 0.34 for IP, 0.24 for EP, and 0.33 for HRQOL, p < .001). Male gender and lower household income were associated with more behavior problems. Clinical variables were only related to HRQOL. Compared with healthy norms, IPs were significantly more common in male adolescents and HRQOL was lower (p < .001). Adolescents with heart disease are at risk for internalizing behavior problems and reduced HRQOL; however, positive self-perceptions appear to be protective. Self-perceptions are critical and should be addressed by clinicians. 23618394 In-situ studies of nanocatalysis. A heterogeneous catalyst in industry consists of nanoparticles with variable crystallite sizes, shapes, and compositions. Its catalytic performance (activity, selectivity, and durability) derives from surface chemistry of catalyst nanoparticles during catalysis. However, the surface chemistry of the catalyst particles during catalysis, termed in-situ information, is a "black box" because of the challenges in characterizing the catalysts during catalysis. The lack of such in-situ information about catalysts has limited the understanding of catalytic mechanisms and the development of catalysts with high selectivity and activity. The challenges in understanding heterogeneous catalysis include measurement of reaction kinetics, identification of reaction intermediates, bridging pressure gap and materials gap. The pressure gap is the difference in surface structure and chemistry between a catalyst during catalysis and under an ultrahigh vacuum (UHV) condition. The materials gap represents the difference between the structural and compositional complexity of industrial catalysts and the well-defined surface of model catalysts of metals or oxides. Development of in-situ characterization using electron spectroscopy and electron microscopy in recent decades has made possible studies of surface chemistry and structure of nanocatalysts under reaction conditions or during catalysis at near ambient pressure. In this Account, we review the new chemistries and structures of nanocatalysts during reactions revealed with in-situ analytical techniques. We discuss changes observed during catalysis including the evolution of composition, oxidation state, phase, and geometric structure of the catalyst surface, and the sintering of catalysts. These surface chemistries and structures have allowed researchers to build a correlation between surface chemistry and structure of active nanocatalysts and their corresponding catalytic performances. Such a correlation provides critical insights for understanding catalysis, optimization of existing nanocatalysts, and development of new nanocatalysts with high activity and selectivity. 23423383 Hedgehog-Gli Activators Direct Osteo-chondrogenic Function of Bone Morphogenetic Protein toward Osteogenesis in the Perichondrium. Specification of progenitors into the osteoblast lineage is an essential event for skeletogenesis. During endochondral ossification, cells in the perichondrium give rise to osteoblast precursors. Hedgehog (Hh) and bone morphogenetic protein (BMP) are suggested to regulate the commitment of these cells. However, properties of perichondrial cells and regulatory mechanisms of the specification process are still poorly understood. Here, we investigated the machineries by combining a novel organ culture system and single-cell expression analysis with mouse genetics and biochemical analyses. In a metatarsal organ culture reproducing bone collar formation, activation of BMP signaling enhanced the bone collar formation cooperatively with Hh input, whereas the signaling induced ectopic chondrocyte formation in the perichondrium without Hh input. Similar phenotypes were also observed in compound mutant mice, where signaling activities of Hh and BMP were genetically manipulated. Single-cell quantitative RT-PCR analyses showed heterogeneity of perichondrial cells in terms of natural characteristics and responsiveness to Hh input. In vitro analyses revealed that Hh signaling suppressed BMP-induced chondrogenic differentiation; Gli1 inhibited the expression of Sox5, Sox6, and Sox9 (SRY box-containing gene 9) as well as transactivation by Sox9. Indeed, ectopic expression of chondrocyte maker genes were observed in the perichondrium of metatarsals in Gli1(-/-) fetuses, and the phenotype was more severe in Gli1(-/-);Gli2(-/-) newborns. These data suggest that Hh-Gli activators alter the function of BMP to specify perichondrial cells into osteoblasts; the timing of Hh input and its target populations are critical for BMP function. 23793259 Ernst Chain: a great man of science. This paper is a tribute to the scientific accomplishments of Ernst Chain and the influence he exerted over the fields of industrial microbiology and biotechnology. Chain is the father of the modern antibiotic era and all the benefits that these therapeutic agents have brought, i.e., longer life spans, greater levels of public health, widespread modern surgery, and control of debilitating infectious diseases, including tuberculosis, gonorrhea, syphilis, etc. Penicillin was the first antibiotic to become commercially available, and its use ushered in the age of antibiotics. The discovery of penicillin's bactericidal action had been made by Alexander Fleming in London in 1928. After publishing his observations in 1929, no further progress was made until the work was picked up in 1939 by scientists at Oxford University. The group was headed by Howard Florey, and Chain was the group's lead scientist. Chain was born and educated in Germany, and he fled in 1933 as a Jewish refugee from Nazism to England. Other important members of the Oxford research team were Norman Heatley and Edward Abraham. The team was able to produce and isolate penicillin under conditions of scarce resources and many technical challenges. Sufficient material was collected and tested on mice to successfully demonstrate penicillin's bactericidal action on pathogens, while being nontoxic to mammals. Chain directed the microbiological methods for producing penicillin and the chemical engineering methods to extract the material. This technology was transferred to US government facilities in 1941 for commercial production of penicillin, becoming an important element in the Allied war effort. In 1945, the Nobel Prize for medicine was shared by Fleming, Florey, and Chain in recognition of their work in developing penicillin as a therapeutic agent. After World War II, Chain tried to persuade the British government to fund a new national antibiotic industry with both research and production facilities. As resources were scarce in postwar Britain, the British government declined the project. Chain then took a post in 1948 at Rome's Instituto Superiore di Sanitá, establishing a new biochemistry department with a pilot plant. During that period, his department developed important new antibiotics (including the first semisynthetic antibiotics) as well as improved technological processes to produce a wide variety of important microbial metabolites that are still in wide use today. Chain was also responsible for helping several countries to start up a modern penicillin industry following World War II, including the Soviet Union and the People's Republic of China. In 1964, Chain returned to England to establish a new biochemistry department and industrial scale fermentation pilot plant at Imperial College in London. Imperial College became the preeminent biochemical department in Europe. Chain was also a pioneer in changing the relationship between government, private universities, and private industry for collaboration and funding to support medical research. Ernst Chain has left a lasting impact as a great scientist and internationalist. 23446140 Influence of general anesthesia with isoflurane following propofol-induction on natural killer cell cytotoxic activities of peripheral blood lymphocytes in dogs. To investigate influence of general anesthesia on immunological anti-tumor activity, the natural killer (NK) cytotoxic activity of peripheral lymphocytes (PBLs) was measured in 7 dogs anesthetized for 3 hr with isoflurane following propofol-induction (anesthesia group) and 6 dogs without anesthesia (control group). Blood samples were collected before (baseline) and 24, 120 and 192 hr after the anesthesia. The PBLs were isolated via centrifugation with Ficoll-Hypaque solution (density, 1.073), and adherent cells were removed. The NK cytotoxic activity of the isolated PBLs against canine thyroid cancer cells was detected by the colorimetric rose Bengal assay. Significant decrease in the NK cytotoxic activity was observed at 24 hr after the anesthesia, compared with the baseline values and the control group. The NK cytotoxic activities were recovered to the baseline values until 120 hr after the anesthesia. The general anesthesia with isoflurane following propofol-induction decreased the NK cytotoxic activities of PBLs in dogs. This finding has a clinical relevance to the risk of tumor recurrence or metastasis induced by the suppression of immunological anti-tumor activity after general anesthesia in dogs. The results further emphasized the importance of the need to evaluate immune suppression following general anesthesia in animals. 23891026 Postural prioritization is differentially altered in healthy older compared to younger adults during visual and auditory coded spatial multitasking. Many daily activities require appropriate allocation of attention between postural and cognitive tasks (i.e. dual-tasking) to be carried out effectively. Processing multiple streams of spatial information is important for everyday tasks such as road crossing. Fifteen community-dwelling healthy older (mean age=78.3, male=1) and twenty younger adults (mean age=25.3, male=6) completed a novel bimodal spatial multi-task test providing contextually similar spatial information via separate sensory modalities to investigate effects on postural prioritization. Two tasks, a temporally random visually coded spatial step navigation task (VS) and a regular auditory-coded spatial congruency task (AS) were performed independently (single task) and in combination (multi-task). Response time, accuracy and dual-task costs (% change in multi-task condition) were determined. Results showed a significant 3-way interaction between task type (VS vs. AS), complexity (single vs. multi) and age group for both response time (p≤0.01) and response accuracy (p≤0.05) with older adults performing significantly worse than younger adults. Dual-task costs were significantly greater for older compared to younger adults in the VS step task for both response time (p≤0.01) and accuracy (p≤0.05) indicating prioritization of the AS over the VS stepping task in older adults. Younger adults display greater AS task response time dual task costs compared to older adults (p≤0.05) indicating VS task prioritization in agreement with the posture first strategy. Findings suggest that novel dual modality spatial testing may lead to adoption of postural strategies that deviate from posture first, particularly in older people. Adoption of previously unreported postural prioritization strategies may influence balance control in older people. 23642492 Levetiracetam vs. sulthiame in benign epilepsy with centrotemporal spikes in childhood: A double-blinded, randomized, controlled trial (German HEAD Study). To show non-inferiority of levetiracetam to sulthiame with respect to efficacy, tolerability and safety in benign epilepsy with centrotemporal spikes in a prospective, double-blinded randomized controlled trial. A sample size of 60 subjects (treatment group) was calculated to show reliable statistical results for non-inferiority. A total of 44 patients could be randomly allocated to either (LEV or STM) treatment group. Explorative data analysis was performed to investigate differences in the number of treatment failure events (occurrence of a seizure during the observation period of 6 months) and total dropouts. In addition, information of the occurrence of adverse events was collected. 43 patients were analyzed. One patient had to be excluded due to protocol violation. Treatment failure events occurred in four patients (19.0%) in the LEV treatment group and in two patients (9.1%) in the STM treatment group, respectively, (p = 0.412). The number of dropouts due to adverse reactions was five in the LEV treatment group and one in STM treatment group (23.8% vs. 4.5%, respectively, p = 0.095). Severe adverse events occurred in patients treated with LEV (n = 2, 9.5%). The total number of dropouts due to either seizure recurrence or adverse events was significantly higher in the LEV group (n = 9, 42.9%) compared to the STM group (n = 3, 13.6%, p = 0.03). The study results concerning non-inferiority were not conclusive, as the calculated sample size was not reached to support sufficient statistical power due to limited recruitment in a 26 months period. The rates of seizure free patients were [relatively] high in both groups. However, the results indicate that termination of drug treatment due to seizure recurrence or adverse events occurred more frequently in the LEV group compared to STM. Behavioral disturbances were the most common adverse event causing study termination. 23934688 Conductive, Monodisperse Polyaniline Nanofibers of Controlled Length Using Well-Defined Cylindrical Block Copolymer Micelles as Templates. Stable colloidal dispersions of polyaniline (PAni) nanofibers with controlled lengths from about 200 nm-1.1 μm and narrow length distributions (Lw /Ln <1.04; Lw =weight average micelle length, Ln =number average micelle length) were prepared through the template-directed synthesis of PAni using monodisperse, solution-self-assembled, cylindrical, block copolymer micelles as nanoscale templates. These micelles were prepared through a crystallization-driven living self-assembly method from a poly(ferrocenyldimethylsilane)-b-poly(2-vinylpyridine) block copolymer (PFS25 -b-P2VP425 ). This material was initially self-assembled in iPrOH to form cylindrical micelles with a crystalline PFS core and a P2VP corona and lengths of up to several micrometers. Sonication of this sample then yielded short cylinders with average lengths of 90 nm and a broad length distribution (Lw /Ln =1.32). Cylindrical micelles of PFS25 -b-P2VP425 with controlled lengths and narrow length distributions (Lw /Ln <1.04) were subsequently prepared using thermal treatment at specific temperatures between 83.5 and 92.0 °C using a 1D self-seeding process. These samples were then employed in the template-directed synthesis of PAni nanofibers through a two-step procedure, where the micellar template was initially stabilised by deposition of an oligoaniline coating followed by addition of a polymeric acid dopant, resulting in PAni nanofibers in the emeraldine salt (ES) state. The ES-PAni nanofibers were shown to be conductive by scanning conductance microscopy, whereas the precursor PFS25 -b-P2VP425 micelle templates were found to be dielectric in character. 22284538 Structural basis for protein phosphatase 1 regulation and specificity. The ubiquitous serine/threonine protein phosphatase 1 (PP1) regulates diverse, essential cellular processes such as cell cycle progression, protein synthesis, muscle contraction, carbohydrate metabolism, transcription and neuronal signaling. However, the free catalytic subunit of PP1, while an effective enzyme, lacks substrate specificity. Instead, it depends on a diverse set of regulatory proteins (≥ 200) to confer specificity towards distinct substrates. Here, we discuss recent advances in structural studies of PP1 holoenzyme complexes and summarize the new insights these studies have provided into the molecular basis of PP1 regulation and specificity. 23962988 Kinetics and thermodynamics of metal binding to the N-terminus of a human copper transporter, hCTR1. The N-terminus of hCTR1 was demonstrated to bind three Cu(+) ions tightly (log K = 14.92) and reversibly via its Met-rich motifs. Ag(+) binds to the protein with the same stoichiometry but much lower affinities than Cu(+). The protein also coordinates two Cu(2+) ions through its ATCUN motif and His-rich motif with lower affinity. This study provides an insight into the selectivity of the transporter. 23929090 Serum uric acid levels and long-term outcomes in chronic kidney disease. Hyperuricemia is common in chronic kidney disease (CKD), but data regarding the relationship between serum uric acid levels and the long-term outcomes of CKD patients have been limited. The present study evaluated the associations between baseline serum uric acid levels with mortality and end-stage renal disease (ESRD). The subjects of this study were 551 stage 2-4 CKD patients. Cox proportional hazards models were used to evaluate the relationship between serum uric acid tertiles and all-cause mortality, cardiovascular disease (CVD) mortality, 50 % reduction in estimated glomerular filtration rate (eGFR), and development of ESRD, initially without adjustment, and then after adjusting for several groups of covariates. The mean age of the study subjects was 58.5 years, 59.3 % were men, and 10.0 % had diabetes. The mean eGFR was 42.02 ± 18.52 ml/min/1.73 m(2). In all subjects, the mean serum uric acid level was 6.57 ± 1.35 mg/dl, and 52.2 % of study subjects were on hypouricemic therapy (allopurinol; 48.3 %) at baseline. Thirty-one patients (6.1 %) died during a follow-up period of approximately 6 years. There was no significant association between serum uric acid level and all-cause mortality, CVD mortality, development of ESRD and 50 % reduction in eGFR in the unadjusted Cox models. In the adjusted models, hyperuricemia was found to be associated with all-cause mortality and CVD mortality after adjustment with CVD risk factors, kidney disease factors, and allopurinol, but not associated with development of ESRD and 50 % reduction in eGFR. The results of this study showed that hyperuricemia but not serum uric acid levels were associated with all-cause mortality, CVD mortality after adjustments with CVD risk factors, kidney disease factors, and allopurinol in stage 2-4 CKD patients. 23292358 Northeast Red Beans Produce a Thermostable and pH-Stable Defensin-Like Peptide with Potent Antifungal Activity. A 5.4-kDa antifungal peptide was purified from Phaseolus vulgaris L. cv. "northeast red bean" using a protocol that entailed affinity chromatography, ion exchange chromatography, and gel filtration. The molecular mass was determined by matrix-assisted laser desorption ionization time-of-flight. The N-terminal amino acid sequence of the peptide was highly homologous to defensins and defensin-like peptides from several plant species. The peptide impeded the growth of a number of pathogenic fungi, including Mycosphaerella arachidicola Khokhr. (IC50 = 1.7 Î¼M), Setosphaeria turcica Luttr., Fusarium oxysporum Schltdl., and Valsa mali Miyabe & G. Yamada. Antifungal activity of the peptide was fully preserved at temperatures up to 100 °C and pH values from 0 to 12. Congo red deposition at the hyphal tip of M. arachidicola was detected after exposure to the peptide, signifying that the peptide had suppressed hyphal growth. The antifungal peptide did not manifest antiproliferative activity toward human breast cancer MCF7 cells and hepatoma HepG2 cells, in contradiction to the bulk of previously reported plant defensins. The data suggest distinct structural requirements for antifungal and antiproliferative activities. 23899981 Neurologic complications of cancer and cancer therapy. When neurologic complications occur as a result of systemic cancer and cancer treatment, they can be more disabling for patients than their primary cancer and significantly impair functioning in varied domains. However, recognizing neurologic signs and symptoms as complications of cancer and its treatment can pose a challenge for healthcare providers. Oncology nurses must develop a high index of suspicion for neurologic complications when examining or interviewing patients who present with neurologic symptoms or deficits and have a known systemic cancer. The purpose of this article is to help oncology nurses identify the common presentations of those complications and understand the ways in which they occur, with the hope that early identification will facilitate appropriate medical intervention and slow the progression of neurologic deficits and systemic decline. 23890400 Occult primary breast cancer at a comprehensive cancer center. Management of occult primary breast cancer (OPBC), that is, breast cancer that first presents through regional nodal or distant disease without clinical or mammographic evidence of disease in the breast, has been controversial and inconsistent. Here, we review OPBC patients treated at our institution. We conducted a retrospective review of women diagnosed with a first primary breast cancer between March 1999 and September 2010 to identify patients who presented with isolated axillary lymphadenopathy proven to be histologically consistent with primary breast malignancy but had no evidence of a breast mass on physical examination, mammography, or ultrasound. Descriptions of treatments received, recurrence, morbidity, and mortality as of October 2012 are reported. Of 5533 patients reviewed, seven (0.1%) patients were identified. The median age was 65 y old (range, 40-72), and the median length of follow-up was 86 mo (range, 42-124). Four patients underwent modified radical mastectomy, one patient had a lumpectomy and axillary lymph node dissection, and two patients had axillary lymph node dissection without breast surgery. Four patients received adjuvant radiation therapy. All seven patients received chemotherapy. Three patients received endocrine therapy, and two patients received anti-HER2 therapy. At the last follow-up, all seven patients were alive with no evidence of disease. Although there was some variation in the management of OPBC at our institution, our patients had excellent outcomes after multimodal treatment. Our results support a curative intent approach to the treatment of OPBC and illustrate the need for individualized treatment algorithms based on tumor biology and extent of the disease at diagnosis. 22999652 Altering the way the optic nerve head responds to intraocular pressure-a potential approach to glaucoma therapy. Over the past decade, engineering principles have been used to explain why a mechanical load, intraocular pressure, can lead to the development of glaucomatous optic neuropathy. This has led to the 'biomechanical theory' of glaucoma, which posits that the behavior of optic nerve head connective tissues (specifically within the peripapillary sclera and lamina cribrosa) in response to intraocular pressure (regardless of its magnitude) can directly and indirectly influence the physiology and pathophysiology of the optic nerve head. Given that the biomechanics of the sclera and lamina cribrosa probably influence retinal ganglion cell loss in glaucoma, the idea that altering biomechanical behavior might be protective against glaucoma is an appealing notion. There is some evidence to suggest that stiffening the peripapillary sclera may be protective against the development of glaucoma in an animal model. It is technically possible to stiffen the sclera in vivo using collagen cross-linking techniques already applied in vivo to the cornea in the treatment of keratoconus. It has yet to be established whether scleral cross-linking is safe in humans and that it confers anything more than a theoretical advantage in terms of reducing the risk of glaucomatous damage. 23794236 Interstitial 6q microdeletion syndrome and epilepsy: A new patient and review of the literature. Interstitial deletions of the long arm of chromosome 6 represent a rare genomic disorder. Variable phenotypes has been reported in patients carrying this deletion, including facial dysmorphisms, intellectual disability/developmental delay, growth retardation and hypotonia, upper limb and cardiac malformations, and Prader-Willi (PWS)-like features. We describe a new patient with an interstitial 6q deletion of 11.58 Mb detected by CGH-Array, who showed facial dysmorphic features, small hands and feet, and severe dorsal scoliosis. Ataxic gait and frequent hand stereotypies were also noted. She started having seizures at 14 years, characterized by loss of consciousness, clonic jerks of the limbs, roaring breathing, fixed gaze, and generalized hypotonia. In the course of the disease she experienced cluster of seizures requiring intensive treatment. The electroencephalographic recording showed slowing of the background activity and bilateral paroxysmal activity over the posterior regions. Review of the literature done to pinpoint the epileptological features of the syndrome identified heterogeneous descriptions of the electro-clinical picture in patients with interstitial 6q deletions. Genotype-phenotype correlations of this syndrome have been lacking until recently, when patients can be characterized with microarray-based comparative genomic hybridization. Description of additional patients with interstitial 6q deletions will help to delineate candidate genes associated with particular phenotypes. © 2013 Wiley Periodicals, Inc. 23902597 Central 5-HT1A receptor-mediated modulation of heart rate dynamics and its adjustment by conditioned and unconditioned fear in mice. The beat-by-beat fluctuation (dynamics) of heart rate (HR) depends on centrally mediated autonomic nervous system (ANS) control reflecting the physiological state of an organism. 5-HT1A receptors are implicated in affective disorders that are associated with ANS dysregulation which increases cardiac risk and their role in autonomic HR regulation under physiological condition is insufficiently characterized. The effects of subcutaneously administered 5-HT1A receptor ligands were investigated on HR dynamics in C57BL/6 mice during baseline stress-free conditions and emotional challenge (recall of fear conditioned to an auditory stimulus and novelty exposure) using time domain and nonlinear HR analyses. Pre-training injection of 8-OH-DPAT (0.5 mg·kg(-1) ) prevented the conditioned tachycardia in the retention test indicating impaired fear memory. Pretest 5-HT1A receptor activation by 8-OH-DPAT (0.5 but not 0.1 and 0.02 mg·kg(-1) ) caused bradycardia and increased HR variability. 8-OH-DPAT (0.5 mg·kg(-1) ) lowered the unconditioned and conditioned tachycardia from ∼750 bpm to ∼550 bpm without changing the expression of the conditioned HR response to the sound. 8-OH-DPAT induced profound QT prolongation and bradyarrhythmic episodes. Nonlinear analysis indicated a pathological state of HR dynamics after 8-OH-DPAT (0.5 mg·kg(-1) ) with ANS hyperactivation impairing HR adaptability. The 5-HT1A receptor antagonist WAY-100635 (0.03 mg·kg(-1) ) blocked the 8-OH-DPAT-mediated effects. Pre-training 5-HT1A receptor activation by 8-OH-DPAT (0.5 mg·kg(-1) ) impairs memory of conditioned auditory fear based on an attenuated HR increase, whereas pretest administration does not prevent the fear-conditioned HR increase but induces pathological HR dynamics through central ANS dysregulation with cardiac effects similar to acute SSRI overdosing. 23845586 Using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement to Assess Reporting of Observational Trials in Hand Surgery. To use the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement checklist to critically evaluate the change in quality of observational trial reporting in the Journal of Hand Surgery American between 2005 and 2011. A cross-sectional analysis of observational studies published in the Journal of Hand Surgery American was designed to sample 2 6-month periods of publication (March 2005 to August 2005 and June 2011 to November 2011). Fifty-one items were extracted from the STROBE statement for evaluation. Overall STROBE compliance rates for articles and specific checklist items were determined. Final compliance percentages from each period were compared by Student t-testing. Changes in item compliance over time were quantified. Overall compliance with the STROBE statement was 38% (range, 10%-54%) in 2005 and 58% (range, 39%-85%) for 2011 manuscripts representing a significant improvement. Seventy-five percent or greater of articles (2005/2011) provided the explicit reporting of background (100%/97%), follow-up time (85%/94%), overall interpretation of data (100%/94%), and results of similar studies (95%/89%). Twenty-five percent or less of articles provided the study design in the abstract (10%/20%), a clear description of the study's setting (10%/23%), the handling of missing data (0%/6%), the potential directions of bias (5%/11%), and the use of a power analysis (0%/17%). Eighty-six percent (44/51) of items were more frequently satisfied in 2011 articles than in 2005 publications. Absolute increases in compliance rates of 40% or greater were noted in 10 items (20%) with no worsening in compliance for an individual item over 6%. The overall quality of the reporting of observational trials in the Journal of Hand Surgery American improved from 2005 to 2011. Current observational trials in hand surgery could still benefit from increased reporting of methodological details including the use of power analyses, the handling of missing data, and consideration of potential bias. Diagnostic III. 23770054 Molecular epidemiology of PRRSV in South China from 2007 to 2011 based on the genetic analysis of ORF5. Porcine reproductive and respiratory syndrome virus (PRRSV) has proven to be highly genetically variable; however, comprehensive information regarding the virus's genetic diversity in South China is limited. In this study, a total of 3199 clinical samples were collected from 267 pig farms suspected of PRRSV infection between 2007 and 2011. The ORF5 genes of 51 PRRSV-positive samples were sequenced and analyzed. The 51 study strains were divided into three primary subgenotypes. Fourty-five of the strains belonged to subgenotype I and were closely related to the highly pathogenic PRRSV (HP-PRRSV) strains. The subgenotype I strains were generally clustered into genetically similar groups by year. Only one of the strains belonged to subgenotype II, clustering with the classical North American type, VR2332. Five of the strains were grouped into subgenotype III, which occupied a separate branch and was closely related to the recently isolated novel field strains, QYYZ and GM2. The 5 subgenotype III strains shared an amino acid identity with the remaining 46 study strains ranging from 79.6%-83.6%. Amino acid analysis showed extensive mutations in subgenotype III; the diverse genetic mutations of these novel strains are of great concern. 23867576 The Role of Matrix Metalloproteinase-2 in the Treatment of Atrial Fibrillation Recurrence after a Radiofrequency Modified Maze Procedure. Background and Objective: Our study aimed to elucidate the potential clinical and molecular issues in recurrent atrial fibrillation (AF) following a radiofrequency modified maze procedure in patients with rheumatic valvular disease and persistent AF. Methods and Results: Eighty patients with rheumatic valvular disease and persistent AF (lasting more than 6 months) who had undergone a radiofrequency modified maze procedure and mitral valve replacement were enrolled into this single-center pilot study and were followed up for another 6 months. Their clinical characteristics were analyzed and the expression of matrix metalloproteinase (MMP)-2 including its specific inhibitor and collagen volume fraction (CVF) was also assessed. During the 6-month follow-up, 24 subjects had recurrent AF. Among them, the left atrial diameter was larger compared to that achieved in sinus rhythm (SR). The mRNA and protein expression of MMP-2 was significantly increased in recurrent AF patients, while its specific inhibitor did not show a significant difference (p > 0.05). The CVF of type I collagen increased significantly in the recurrent AF patients compared to SR patients (18.16 ± 3.22 vs. 11.66 ± 3.38, p < 0.001), whereas the CVF of type III collagen showed no significant difference (8.33 ± 3.44 vs. 9.55 ± 3.67, p > 0.05). Conclusion: This study suggests that the overexpression of MMP-2 is associated with CVF-I in the left atrial appendage which potentially leads to the recurrence of AF following a radiofrequency modified maze procedure in patients with rheumatic valve disease. 22378588 Writing affects the brain network of reading in Chinese: a functional magnetic resonance imaging study. We examined the hypothesis that learning to write Chinese characters influences the brain's reading network for characters. Students from a college Chinese class learned 30 characters in a character-writing condition and 30 characters in a pinyin-writing condition. After learning, functional magnetic resonance imaging collected during passive viewing showed different networks for reading Chinese characters and English words, suggesting accommodation to the demands of the new writing system through short-term learning. Beyond these expected differences, we found specific effects of character writing in greater activation (relative to pinyin writing) in bilateral superior parietal lobules and bilateral lingual gyri in both a lexical decision and an implicit writing task. These findings suggest that character writing establishes a higher quality representation of the visual-spatial structure of the character and its orthography. We found a greater involvement of bilateral sensori-motor cortex (SMC) for character-writing trained characters than pinyin-writing trained characters in the lexical decision task, suggesting that learning by doing invokes greater interaction with sensori-motor information during character recognition. Furthermore, we found a correlation of recognition accuracy with activation in right superior parietal lobule, right lingual gyrus, and left SMC, suggesting that these areas support the facilitative effect character writing has on reading. Finally, consistent with previous behavioral studies, we found character-writing training facilitates connections with semantics by producing greater activation in bilateral middle temporal gyri, whereas pinyin-writing training facilitates connections with phonology by producing greater activation in right inferior frontal gyrus. 23557213 Sex differences in trajectories of depressive symptoms among older Taiwanese: the contribution of selected stressors and social factors. Objectives: We assessed female-male differences in depressive symptoms among older Taiwanese and quantified the contribution of sex differences in exposure and response to selected covariates in explaining the gap. Methods: Using data from six survey waves over 18 years for a nationally representative cohort of 4049 Taiwanese aged 60+, we employed growth curve analysis to model individual-level trajectories of depressive symptoms across age. Results: Among older Taiwanese, women's disadvantage with respect to social position and employment accounted for about 40% of the sex difference in depressive symptoms. Sex differences in decision control and exposure to widowhood and financial decline played surprisingly little role. Although we found no evidence that the effects of marriage, recent widowhood or recent child death varied by sex, living apart from one's children appeared to be more detrimental for women than for men in this society. Moreover, the effect of living with children depended on the arrangement: living with an unmarried son was more strongly associated with depressive symptoms than living with a married son and daughter-in-law. Conclusion: Sex differentials in social position and employment are major contributors to the sex difference in depressive symptoms among older Taiwanese, yet sex differences in exposure or response to selected stressors appear to play little role. Differential vulnerabilities to particular living arrangements may also contribute to women's excess psychological distress, although more research is needed to elucidate the mechanisms by which living arrangements influence depressive symptoms in Taiwan. 23414381 Bioanalytical LC separation techniques for quantitative analysis of free amino acids in human plasma. The quantitative analysis of free amino acids in human plasma has become an important and essential analysis parameter in different areas of life sciences. Free amino acid concentrations in human plasma samples are generally determined by means of GC or LC after chemical derivatization followed by UV, fluorescent or MS detection of the amino acid derivatives. Derivatization of free amino acids is done either pre- or post-column, and the amino acid derivatives obtained posess improved chromatographic behavior, increased detection sensitivity and selectivity compared with non-derivatized free amino acids. This work gives an overview of different chemical derivatization methods applied and their liquid separation techniques in bioanalytical assays for quantitative free amino acid analysis in human plasma samples. Important plasma preparation procedures, pre- and post-column derivatization, and different LC separation techniques are presented. 23043184 Interactions between CYP2E1 and CYP2B4: effects on affinity for NADPH-cytochrome P450 reductase and substrate metabolism. Studies in microsomal and reconstituted systems have shown that the presence of one cytochrome P450 isoform can significantly influence the catalytic activity of another isoform. In this study, we assessed whether CYP2E1 could influence the catalytic activity of CYP2B4 under steady-state turnover conditions. The results show that CYP2E1 inhibits CYP2B4-mediated metabolism of benzphetamine (BNZ) with a K(i) of 0.04 µM. However, CYP2B4 is not an inhibitor of CYP2E1-mediated p-nitrophenol hydroxylation. When these inhibition studies were performed with the artificial oxidant tert-butyl hydroperoxide, CYP2E1 did not significantly inhibit CYP2B4 activity. Determinations of the apparent K(M) and k(cat) of CYP2B4 for CPR in the presence of increasing concentrations of CYP2E1 revealed a mixed inhibition of CYP2B4 by CYP2E1. At low concentrations of CYP2E1, the apparent K(M) of CYP2B4 for CPR increased up to 23-fold with virtually no change in the k(cat) for the reaction, however, at higher concentrations of CYP2E1, the apparent K(M) of CYP2B4 for CPR decreased to levels similar to those observed in the absence of CYP2E1 and the k(cat) also decreased by 11-fold. Additionally, CYP2E1 increased the apparent K(M) of CYP2B4 for BNZ by 8-fold and the apparent K(M) did not decrease to its original value when saturating concentrations of CPR were used. While the individual apparent K(M) values of CYP2B4 and CYP2E1 for CPR are similar, the apparent K(M) of CYP2E1 for CPR in the presence of CYP2B4 decreased significantly, thus suggesting that CYP2B4 enhances the affinity of CYP2E1 for CPR and this may allow CYP2E1 to out-compete CYP2B4 for CPR. 23883299 Microscopic observation of metal-containing particles from chinese continental outflow observed from a non-industrial site. Atmospheric metal-containing particles adversely affect human health because of their physiological toxicity. Mixing state, size, phase, aspect ratio, and sphericity of individual metal-containing particles collected in Hong Kong air in winter are examined through transmission electron microscopy (TEM). Eighteen percent of the sulfate particles have one or more tiny metal inclusions. Size distributions of metal and fly ash particles (or inclusions) with diameters from 15 nm to 2.7 μm show the same peak at 210 nm. The major metal particles were classified as Fe-rich (e.g., hematite), Zn-rich (e.g., zinc sulfate and zinc oxide), Pb-rich (e.g., anglesite), Mn-rich, and As-rich, which were likely emitted from industries and coal-fired power plants at high temperatures in mainland China. Compared to fly ash and S-rich particles, metal particles display a lower sphericity of 0.51 and a higher aspect ratio of 1.47, which means their shapes are poorly defined. The elemental mapping of individual particles reveal that sulfate areas without metal inclusions also contain minor Fe, Mn, or Zn. Therefore, the internal mixing of metals and acidic constituents likely solubilize metals and modify metal inclusion shapes. Solubilization of metals in airborne particles can extend their toxicity into nontoxicity parts in the particles. The structure of the metal-containing particles may provide important information for assessing health effects of fine sulfate and nitrate particles with metal inclusions in urban areas. 23275540 Structure, stability and function of 5-chlorouracil modified A:U and G:U base pairs. The thymine analog 5-chlorouridine, first reported in the 1950s as anti-tumor agent, is known as an effective mutagen, clastogen and toxicant as well as an effective inducer of sister-chromatid exchange. Recently, the first microorganism with a chemically different genome was reported; the selected Escherichia coli strain relies on the four building blocks 5-chloro-2'-deoxyuridine (ClU), A, C and G instead of the standard T, A, C, G alphabet [Marlière,P., Patrouix,J., Döring,V., Herdewijn,P., Tricot,S., Cruveiller,S., Bouzon,M. and Mutzel,R. (2011) Chemical evolution of a bacterium's genome. Angew. Chem. Int. Ed., 50, 7109-7114]. The residual fraction of T in the DNA of adapted bacteria was <2% and the switch from T to ClU was accompanied by a massive number of mutations, including >1500 A to G or G to A transitions in a culture. The former is most likely due to wobble base pairing between ClU and G, which may be more common for ClU than T. To identify potential changes in the geometries of base pairs and duplexes as a result of replacement of T by ClU, we determined four crystal structures of a B-form DNA dodecamer duplex containing ClU:A or ClU:G base pairs. The structures reveal nearly identical geometries of these pairs compared with T:A or T:G, respectively, and no consequences for stability and cleavage by an endonuclease (EcoRI). The lack of significant changes in the geometry of ClU:A and ClU:G base pairs relative to the corresponding native pairs is consistent with the sustained unlimited self-reproduction of E. coli strains with virtually complete T→ClU genome substitution. 23819593 Clinical bond failure rates of adhesive precoated self-ligating brackets using a self-etching primer. Abstract Objective: To comparatively assess the failure rate of adhesive precoated (APC) self-ligating metal brackets bonded with two different enamel surface preparation techniques: self-etching primer (SEP) and conventional two-step etch and primer method (CM). Materials and Methods: Fifty-seven patients with complete permanent dentition were included in this study. A total of 1140 APC self-ligating brackets (3M Unitek, Monrovia, Calif) were bonded using a split-mouth design. For each patient, SEP (Transbond Plus SEP, 3M Unitek) and CM (37% phosphoric acid) were used in alternate quadrants. All brackets were bonded by the same investigator after pumicing and rinsing of all of the teeth. The number, site, and date of first-time bracket failures were monitored throughout orthodontic treatment (mean, 22 months). The survival rates of the brackets were estimated by Kaplan-Meier and log-rank tests (P < .05). The adhesive remnant index was used to determine the bond failure interface. Results: The bond failure rates were 2.97% and 2.18% for the CM and SEP, respectively. No statistically significant difference in failure rates was found between the groups. The bond failure sites were predominantly at the enamel-adhesive interface in both groups. Conclusion: This long-term in vivo study showed that the combined use of SEP and the APC bracket system can be used effectively for bonding brackets after pumicing the enamel surfaces in clinical orthodontics. 23902316 Moderate weight loss is sufficient to affect thyroid hormone homeostasis and inhibit its peripheral conversion. Background: Thyroid hormones are important determinants of energy expenditure and in rodents adipose tissue affects thyroid hormone homeostasis via leptin signaling. The relationship between thyroid hormones and nutritional status in humans has been assessed primarily in drastic dietary or bariatric surgery interventions, while limited information is available on serial assessment of this axis during moderate, prolonged dietary restriction. Methods: To evaluate the effects of moderate dietary restriction on thyroid hormone homeostasis, forty-seven subjects BMI ≥25≤45 Kg/m2 were enrolled in a longitudinal intervention study; thirty non-overweight volunteers were also enrolled as controls. Overweight and obese subjects underwent a twelve-month individualized dietary intervention aimed at achieving a 5-10% weight loss. Results: The intervention resulted in a 6.3±0.9 kg (6.5±1.0%) weight loss. At baseline, TSH and T3 concentrations correlated significantly with fat mass (R=0.257, p=0.024 and R=0.318, p=0.005, respectively). After weight loss, T3 decreased significantly (from 112.7±3.1 to 101.8±2.6 ng/dL p<0.001) in the absence of significant changes in TSH or free T4. The decrease in serum T3 correlated with the decrease in weight (R=0.294, p<0.001). T3:free T4 ratio decreased significantly (p=0.02) in individuals who lost >5% body weight. Conclusions: T3 concentration closely correlates with individual nutritional status, and moderate weight loss results in a decrease in T3 with minimal changes in other thyroid hormone homeostasis parameters. The data suggest that a decrease in peripheral conversion of the pro-hormone T4 into its hormonally active metabolite T3 is at least in part responsible for the changes in thyroid hormone homeostasis. 23096773 The Scientist's Education and a Civic Conscience. A civic science curriculum is advocated. We discuss practical mechanisms for (and highlight the possible benefits of) addressing the relationship between scientific knowledge and civic responsibility coextensively with rigorous scientific content. As a strategy, we suggest an in-course treatment of well known (and relevant) historical and contemporary controversies among scientists over science policy or the use of sciences. The scientific content of the course is used to understand the controversy and to inform the debate while allowing students to see the role of scientists in shaping public perceptions of science and the value of scientific inquiry, discoveries and technology in society. The examples of the activism of Linus Pauling, Alfred Nobel and Joseph Rotblat as scientists and engaged citizens are cited. We discuss the role of science professors in informing the social conscience of students and consider ways in which a treatment of the function of science in society may find, coherently, a meaningful space in a science curriculum at the college level. Strategies for helping students to recognize early the crucial contributions that science can make in informing public policy and global governance are discussed. 23832097 Tuning the layer-dependent doping effect of graphenes by C60. In this work, the doping of n-layer graphenes with C60 is investigated via Raman spectroscopy. The results indicate that C60 can induce hole doping in graphenes, and that the doping level is closely related to the layer number of the graphenes. Moreover, the level of doping in the hybrid of C60 on graphene (C60/G) is more significant than that in the hybrid of graphene on C60 (G/C60). 23047321 Nanoengineered colloidal probes for Raman-based detection of biomolecules inside living cells. Gold nanoparticle aggregate carbon nanotube functionalized colloidal particles serve as an efficient platform for probing the intracellular environment. The probes provide the means of effective localization of signal and detection of molecular fingerprints of biomolecules in living cells. The approach demonstrated in this work opens significant opportunities in molecular imaging as well as intracellular sensing and trafficking. 23178416 Life-Threatening ACE Inhibitor-Induced Angioedema After Eleven Years on Lisinopril. Angiotensin-converting enzyme inhibitors (ACE-Is) are the primary medication class implicated in drug-associated angioedema. Angioedema is most common early in ACE-I therapy, yet episodes can occur late in therapy and have been reported even as late as 10 years after single treatment initiation. We present a case of a 65-year-old African American woman who experienced 2 episodes of angioedema, with the second being life threatening after receiving several concomitant agents known to cause angioedema, most notably lisinopril for 11 years. 23763575 A Sensitive Assay Using a Native Protein Substrate for Screening HIV-1 Maturation Inhibitors Targeting the Protease Cleavage Site between the Matrix and Capsid. The matrix/capsid processing site in the HIV-1 Gag precursor is likely the most sensitive target to inhibit HIV-1 replication. We have previously shown that modest incomplete processing at the site leads to a complete loss of virion infectivity. In the study presented here, a sensitive assay based on fluorescence polarization that can monitor cleavage at the MA/CA site in the context of the folded protein substrate is described. The substrate, an MA/CA fusion protein, was labeled with the fluorescein-based FlAsH (fluorescein arsenical hairpin) reagent that binds to a tetracysteine motif (CCGPCC) that was introduced within the N-terminal domain of CA. By limiting the size of CA and increasing the size of MA (with an N-terminal GST fusion), we were able to measure significant differences in polarization values as a function of HIV-1 protease cleavage. The sensitivity of the assay was tested in the presence of increasing amounts of an HIV-1 protease inhibitor, which resulted in a gradual decrease in the fluorescence polarization values demonstrating that the assay is sensitive in discerning changes in protease processing. The high-throughput screening assay validation in 384-well plates showed that the assay is reproducible and robust with an average Z' value of 0.79 and average coefficient of variation values of <3%. The robustness and reproducibility of the assay were further validated using the LOPAC(1280) compound library, demonstrating that the assay provides a sensitive high-throughput screening platform that can be used with large compound libraries for identifying novel maturation inhibitors targeting the MA/CA site of the HIV-1 Gag polyprotein. 23331337 Isolation and characterization of quorum-sensing signalling molecules in Pseudomonas aeruginosa isolates recovered from nosocomial infections. Pseudomonas aeruginosa is one of the most common pathogens in nosocomial infections. Many studies have documented the role of quorum-sensing (QS) systems in antibiotic tolerance of P. aeruginosa. N-acyl homoserine lactones (AHLs) serve as QS signalling molecules and can be a target for modulating bacterial pathogenicity. In this study, nosocomial isolates of P. aeruginosa were characterized for the presence of different types of QS signalling molecules. AHLs were solvent extracted and quantified by determination of β-galactosidase activity using the Escherichia coli MG4 reporter strain. Further characterization was performed by analytical thin layer chromatography coupled with detection using the Agrobacterium tumefaciens A136 biosensor strain. All P. aeruginosa isolates produced AHLs, but there were differences in the quantity and nature of AHLs. We identified AHLs belonging to C4-homoserine lactone (HSL), C6-HSL, C8-HSL, C10-HSL and C12-HSL. AHL profiling of P. aeruginosa isolates showed differences in the amounts and types of AHLs, suggesting differences in the virulence factors and the potential for infection. Our results may be investigated further using animal model systems. 23970893 A population-based analysis of clustering identifies a strong genetic contribution to lethal prostate cancer. Background: Prostate cancer is a common and often deadly cancer. Decades of study have yet to identify genes that explain much familial prostate cancer. Traditional linkage analysis of pedigrees has yielded results that are rarely validated. We hypothesize that there are rare segregating variants responsible for high-risk prostate cancer pedigrees, but recognize that within-pedigree heterogeneity is responsible for significant noise that overwhelms signal. Here we introduce a method to identify homogeneous subsets of prostate cancer, based on cancer characteristics, which show the best evidence for an inherited contribution. Methods: We have modified an existing method, the Genealogical Index of Familiality (GIF) used to show evidence for significant familial clustering. The modification allows a test for excess familial clustering of a subset of prostate cancer cases when compared to all prostate cancer cases. Results: Consideration of the familial clustering of eight clinical subsets of prostate cancer cases compared to the expected familial clustering of all prostate cancer cases identified three subsets of prostate cancer cases with evidence for familial clustering significantly in excess of expected. These subsets include prostate cancer cases diagnosed before age 50 years, prostate cancer cases with body mass index (BMI) greater than or equal to 30, and prostate cancer cases for whom prostate cancer contributed to death. Conclusions: This analysis identified several subsets of prostate cancer cases that cluster significantly more than expected when compared to all prostate cancer familial clustering. A focus on high-risk prostate cancer cases or pedigrees with these characteristics will reduce noise and could allow identification of the rare predisposition genes or variants responsible. 23699927 Changes in sodium levels in processed and restaurant foods, 2005 to 2011. IMPORTANCE Excess consumption of sodium is an important cause of hypertension, a major risk factor for heart disease and stroke. The higher the level of consumption, the greater is a person's likelihood of developing hypertension. Numerous organizations have recommended reductions in sodium intake in the United States. Roughly 80% of the sodium consumed by Americans has been added by food manufacturers and restaurants. OBJECTIVE To compare the mean (SD) levels of sodium for identical products ascertained in 2005, 2008, and 2011. DESIGN AND SETTING Comparison study in an academic research setting. PARTICIPANTS AND EXPOSURES Center for Science in the Public Interest staff have monitored sodium levels in selected processed foods and fast-food restaurant foods for many years. MAIN OUTCOMES AND MEASURES The sodium content in identical foods, as measured in 2005, 2008, and 2011. RESULTS Between 2005 and 2011, the sodium content in 402 processed foods declined by approximately 3.5%, while the sodium content in 78 fast-food restaurant products increased by 2.6%. Although some products showed decreases of at least 30%, a greater number of products showed increases of at least 30%. The predominant finding is the absence of any appreciable or statistically significant changes in sodium content during 6 years. CONCLUSIONS AND RELEVANCE Based on our sample, reductions in sodium levels in processed and restaurant foods are inconsistent and slow. These findings are in accord with other data indicating the slow pace of voluntary reductions in sodium levels in processed and restaurant foods. Stronger action (eg, phased-in limits on sodium levels set by the federal government) is needed to lower sodium levels and reduce the prevalence of hypertension and cardiovascular diseases. 23958604 The experience of presence among telehealth nurses. Telehealth technology allows for the provision of nursing care even when the patient and nurse are physically separated from each other. Telehealth has shown positive effects on healthcare costs and healthcare access. Although it can increase healthcare access and decrease healthcare costs, the use of telehealth has altered the typical pattern of nurse-patient proximity. It is unknown how the physical separation related to telehealth use may affect the experience of presence among nurses during nurse-patient interactions. The purpose of the research was to gain knowledge about the ways that nurses experience presence during interactions with patients using telehealth technology. A qualitative descriptive design with convenience sampling was used for this study. Sample inclusion criteria included being a registered nurse with at least 1 year of experience using telehealth technology and working in telehealth at the time of the study. Institutional review board approval was received before beginning data collection. Participants (n = 6) provided informed consent. Qualitative data were obtained by individual, audiotaped, semistructured interviews. The data were transcribed and analyzed deductively for the existence of presence. Ethnograph version 6.0 software was used to assist in organizing and analyzing the data. Two examples of presence during telehealth nurse-patient interactions were described by participants. This study documented for the first time the experience of presence among nurses who interact with their patients using only nonvideo telehealth technology. 23941906 Candida albicans and Enterococcus faecalis in the gut: Synergy in commensalism? The fungus Candida albicans and the Gram-positive bacterium Enterococcus faecalis are both normal residents of the human gut microbiome and cause opportunistic disseminated infections in immunocompromised individuals. Using a nematode infection model, we recently showed that co-infection resulted in less pathology and less mortality than infection with either species alone and this was partly explained by an interkingdom signaling event in which a bacterial-derived product inhibits hyphal morphogenesis of C. albicans. In this addendum we discuss these findings in the contest of other described bacterial-fungal interactions and recent data suggesting a potentially synergistic relationship between these two species in the mouse gut as well. We suggest that E. faecalis and C. albicans promote a mutually beneficial association with the host, in effect choosing a commensal lifestyle over a pathogenic one. 23789986 Water-wettable polypropylene fibers by facile surface treatment based on soy proteins. Modification of the wetting behavior of hydrophobic surfaces is essential in a variety of materials, including textiles and membranes that require control of fluid interactions, adhesion, transport processes, sensing, etc. This investigation examines the enhancement of wettability of an important class of textile materials, viz., polypropylene (PP) fibers, by surface adsorption of different proteins from soybeans, including soy flour, isolate,glycinin, and β-conglycinin. Detailed investigations of soy adsorption from aqueous solution (pH 7.4, 25 °C) on polypropylene thin films is carried out using quartz crystal microbalance (QCM) and surface plasmon resonance (SPR). A significant amount of protein adsorbs onto the PP surfaces primarily due to hydrophobic interactions. We establish that adsorption of a cationic surfactant, dioctadecyldimethylammonium bromide (DODA) onto PP surfaces prior to the protein deposition dramatically enhances its adsorption. The adsorption of proteins from native (PBS buffer, pH 7.4, 25 °C) and denatured conditions (PBS buffer, pH 7.4, 95 °C) onto DODA-treated PP leads to a high coverage of the proteins on the PP surface as confirmed by a significant improvement in water wettability. A shift in the contact angle from 128° to completely wettable surfaces (≈0°) is observed and confirmed by imaging experiments conducted with fluorescence tags. Furthermore, the results from wicking tests indicate that hydrophobic PP nonwovens absorb a significant amount of water after protein treatment, i.e., the PP-modified surfaces become completely hydrophilic. 23871919 Differential expression of cathepsins K, S and V between young and aged Caucasian women skin epidermis. Cutaneous aging translates drastic structural and functional alterations in the extracellular matrix (ECM). Multiple mechanisms are involved, including changes in protease levels. We investigated the age-related protein expression and activity of cysteine cathepsins and the expression of two endogenous protein inhibitors in young and aged Caucasian women skin epidermis. Immunofluorescence studies indicate that the expression of cathepsins K, S and V, as well as cystatins A and M/E within keratinocytes is reduced in photoprotected skin of aged women. Furthermore, the overall endopeptidase activity of cysteine cathepsins in epidermis lysates decreased with age. Albeit dermal elastic fiber and laminin expression is reduced in aged skin, staining of nidogen-1, a key protein in BM assembly that is sensitive to proteolysis by cysteine, metallo- and serine proteases, has a similar pattern in both young and aged skin. Since cathepsins contribute to the hydrolysis and turnover of ECM/basement membrane components, the abnormal protein degradation and deposition during aging process may be related in part to a decline of lysosomal/endosomal cathepsin K, S and V activity. 23867960 The effects of umbilical cord milking in extremely preterm infants: a randomized controlled trial. Objective:Delayed cord clamping has been shown to decrease the need for transfusion in preterm neonates, but may delay resuscitation. The aim of this study was to determine whether umbilical cord milking compared with immediate cord clamping in extremely preterm deliveries reduces the need for neonatal red blood cell transfusion.Study design:Women admitted to a tertiary care center and expected to deliver between 24 to 28 completed weeks of gestation were randomized to cord milking before clamping or immediate cord clamping. The primary outcome was the risk of neonatal transfusion, reported as risk ratio (RR) and 95% confidence interval (CI).Result:Of 113 women who were enrolled and randomized, 56 were assigned to cord milking with 36 remaining eligible and completing the study and 57 were assigned to the control group with 39 remaining eligible and completing the study. Albeit not statistically significant, neonates in the cord milking group were less likely to require transfusion compared with those in the control group (RR: 0.86; 95% CI: 0.73 to 1.0). Neonates whose cords were milked had higher hematocrits at birth (P=0.004) and were less likely to develop an intraventricular hemorrhage (P=0.0195).Conclusion:Milking the umbilical cord of a preterm neonate is an easy intervention with the potential to improve perinatal outcomes. Our results suggest that milking of the cord increases the neonate's initial hematocrit and may lessen the need for transfusion in the neonatal period. The observed reduction in the incidence of intraventricular hemorrhage may have important long-term implications that warrant further study.Journal of Perinatology advance online publication, 18 July 2013; doi:10.1038/jp.2013.70. 23892168 Degradation of antipyrine by UV, UV/H2O2 and UV/PS. Degradation of antipyrine (AP) in water by three UV-based photolysis processes (i.e., direct UV, UV/H2O2, UV/persulfate (UV/PS)) was studied. For all the oxidation processes, the AP decomposition exhibited a pseudo-first-order kinetics pattern. Generally, UV/H2O2 and UV/PS significantly improved the degradation rate relevant to UV treatment alone. The pseudo-first-order degradation rate constants (kobs) were, to different degrees, affected by initial AP concentration, oxidant dose, pH, UV irradiation intensity, and co-existing chemicals such as humic acid, chloride, bicarbonate, carbonate and nitrate. The three oxidation processes followed the order in terms of treatment costs: UV/PS>UV>UV/H2O2 if the energy and chemical costs are considered. Finally, the AP degradation pathways in the UV/H2O2 and UV/PS processes are proposed. Results demonstrated that UV/H2O2 and UV/PS are potential alternatives to control water pollution caused by emerging contaminants such as AP. 23537583 Dysfunctions of the translational machinery in digestive glands of mussels exposed to mercury ions. Mercury is an element naturally occurring in the biosphere, but is also released into the environment by human activities, such as mining, smelting, and industrial discharge. Mercury is a biologically harmful element and any exposure of living organisms mainly due to contamination, can cause severe or even lethal side effects. In every form detected, elemental, inorganic, or organic, mercury exhibits toxicity associated with induced oxidative stress. Although the genotoxicity of mercury has been well demonstrated in mussels, little is known about its toxic effects on the translational machinery at the molecular level. To investigate possible effects, we exposed the common mussel Mytilus galloprovincialis in seawater supplemented by 30μg/L Hg(2+) for 15 days. We observed that Hg(2+) was significantly accumulated in the digestive glands of mussels, reaching a level around 80μg/g tissue (dry weight) at the 15th day of exposure. Exposure of mussels to Hg(2+) resulted in failure of redox homeostasis, as reflected on lipid peroxidation levels and superoxide dismutase activity in glands, and micronucleus frequency in gills. Extracts from digestive glands after 15-day exposure to Hg(2+) exhibited decreased tRNA aminoacylation ability and, moreover, a 70% reduction in the ability of 40S ribosomal subunits to form the 48S initiation ribosomal complex. A similar reduction was detected in the ability of ribosomes to translocate peptidyl-tRNA from the A-site to the P-site, an observation coinciding with the notion that regulation of protein synthesis by Hg(2+) mainly occurs at the initiation and elongation stages of translation. A-site binding, peptidyl transferase activity, and termination of peptide chain synthesis underwent less pronounced but measurable reductions, a finding which explains why poly(Phe)-synthesis in ribosomes isolated from exposed mussels is reduced by 70%. In conclusion, Hg(2+) apart from being a genotoxic ion acts as a modulator of protein synthesis in mussels, an observation probably related with its ability to induce oxidative stress. 23900622 Knowledge and Perspectives of Breast and Cervical Cancer Screening Among Female African Immigrants in the Washington D.C. Metropolitan Area. Black women in the USA have both a higher percentage of late-stage diagnoses as well as the highest rates of mortality from breast cancer when compared to women of other ethnic subgroups. Additionally, Black women have the second highest prevalence of cervical cancer. Many reports evaluating the cancer outcomes of Black women combine data on African-born immigrants and US-born Blacks. This categorization ignores subtle yet important cultural differences between the two groups, which may ultimately affect breast and cervical cancer screening practices. Therefore, this study investigated knowledge and awareness levels of breast and cervical cancer screening practices among female African-born immigrants to the USA residing in the Washington D.C. metropolitan area. Data were collected from 38 participants through key informant interviews, focus group sessions, and a sociodemographic questionnaire over a 3-month study period. Results suggest that fatalism, stigma, and privacy are among the major factors that affect the decision to seek preventative screening measures for breast and cervical cancer among this population. Additionally, the study implies that cervical cancer awareness is significantly lower among this population when compared to breast cancer. This study highlights differences between women of African descent residing in the USA and the need for continued research to increase understanding of the manner in which immigrant status affects health-seeking behavior. This information is critical for researchers, physicians, and public health educators aiming to design culturally appropriate interventions to effectively reduce the prevalence of breast and cervical cancer among female African immigrants living in the USA. 23827769 Disrupted amygdala-prefrontal functional connectivity in civilian women with posttraumatic stress disorder. Many features of posttraumatic stress disorder (PTSD) can be linked to exaggerated and dysregulated emotional responses. Central to the neurocircuitry regulating emotion are functional interactions between the amygdala and the ventromedial prefrontal cortex (vmPFC). Findings from human and animal studies suggest that disruption of this circuit predicts individual differences in emotion regulation. However, only a few studies have examined amygdala-vmPFC connectivity in the context of emotional processing in PTSD. The aim of the present research was to investigate the hypothesis that PTSD is associated with disrupted functional connectivity of the amygdala and vmPFC in response to emotional stimuli, extending previous findings by demonstrating such links in an understudied, highly traumatized, civilian population. 40 African-American women with civilian trauma (20 with PTSD and 20 non-PTSD controls) were recruited from a large urban hospital. Participants viewed fearful and neutral face stimuli during functional magnetic resonance imaging (fMRI). Relative to controls, participants with PTSD showed an increased right amygdala response to fearful stimuli (pcorr < .05). Right amygdala activation correlated positively with the severity of hyperarousal symptoms in the PTSD group. Participants with PTSD showed decreased functional connectivity between the right amygdala and left vmPFC (pcorr < .05). The findings are consistent with previous findings showing PTSD is associated with an exaggerated response of amygdala-mediated emotional arousal systems. This is the first study to show that the amygdala response may be accompanied by disruption of an amygdala-vmPFC functional circuit that is hypothesized to be involved in prefrontal cortical regulation of amygdala responsivity. 23017424 Purification and characterisation of antibacterial peptide-containing compound derived from palm kernel cake. Palm kernel cake (PKC), the most useful by-product resulted from palm kernel oil production. In this study, PKC-derived protein product was found suitable for use as an antimicrobial agent with potent antibacterial activity, particularly against Bacillus species, after enzymatic hydrolysis with alcalase. The hydrolysate was further purified by gel filtration chromatography. The purified fraction was found to have 14.63±0.70% (w/w) protein, a molecular mass of 2.4kDa and low hemolytic activity (<50% hemolysis of human erythrocytes at concentration of 1000μg/ml). The presence of lysine and the major component lauric acid derivative, as indicated by electrospray ionisation-mass spectrometry (ESI-MS) direct infusion and nuclear magnetic resonance (NMR) spectroscopy, may have contributed to the antibacterial effect of purified PKC fraction. This study suggests that the antibacterial PKC compound may be not a pure peptide but instead a peptide-containing compound high in lauric acid derivative. 23959450 High-dose methotrexate, high-dose cytarabine and temozolomide for the treatment of primary central nervous system lymphoma (PCNSL). Treatment of primary central nervous system lymphoma (PCNSL) associates with low response rates and poor survival using conventional radio and chemotherapy. Due to its favorable toxicity profile, temozolomide has emerged as a new option for treatment of PCNSL in young patients. In this study, we report a series of PCNSL patients treated with an innovative regimen combining high dose of both cytarabine and methotrexate with temozolomide without radiotherapy or intrathecal chemotherapy. To evaluate a new intensive chemotherapy with temozolomide, trying to assess response and progression-free survival rates and if the results are promising, we are aiming at evaluating the overall survival (OS) taking into consideration the toxicity profile. The study was performed at Al Mowassa Charity Hospital in Damascus (Syria). Forty patients with histologically confirmed PCNSL median age 52 years (range 20-65) years were included. Biopsies were cultured, and a karyotyping was made in 32 patients. An induction chemotherapy was started, and methotrexate 3 gr/m² over 12 h on day 1, cytarabine 3 gr/m² every 12 h on day 1 and temozolomide 150 mg/m² from day 2 through day 6 with a total of 6 cycles were given on a monthly basis. Among the 40 patients included in the study, a complete response was observed in 34 patients (85 %) and a partial response in the remaining 6 patients (15 %). Disease progressed in 8 out of 40 patients (20 %) while 32 patients are still living at 5 years making the OS reaching 77 %. Grade II nephrotoxicity was observed in 2 patients while grade III and IV hematotoxicity was observed in 5 patients. High dose of both Ara-C and MTX combined with temozolomide appears to be a good choice in the treatment of PCNSL, in the light of good response and OS rates, taking into consideration the acceptable toxicity profile. However, a larger trial is needed to make it an acceptable new combination as a first line for PCNSL patients. 23903593 Firearm homicides and suicides in major metropolitan areas - United States, 2006-2007 and 2009-2010. Firearm homicides and suicides are a continuing public health concern in the United States. During 2009-2010, a total of 22,571 firearm homicides and 38,126 firearm suicides occurred among U.S. residents. This includes 3,397 firearm homicides and 1,548 firearm suicides among persons aged 10-19 years; the firearm homicide rate for this age group was slightly above the all-ages rate. This report updates an earlier report that provided statistics on firearm homicides and suicides in major metropolitan areas for 2006-2007, with special emphasis on persons aged 10-19 years in recognition of the importance of early prevention efforts. Firearm homicide and suicide rates were calculated for the 50 most populous U.S. metropolitan statistical areas (MSAs) for 2009-2010 using mortality data from the National Vital Statistics System (NVSS) and population data from the U.S. Census Bureau. Comparison statistics were recalculated for 2006-2007 to reflect revisions to MSA delineations and population estimates subsequent to the earlier report. Although the firearm homicide rate for large MSAs collectively remained above the national rate during 2009-2010, more than 75% of these MSAs showed a decreased rate from 2006-2007, largely accounting for a national decrease. The firearm homicide rate for persons aged 10-19 years exceeded the all-ages rate in many of these MSAs during 2009-2010, similar to the earlier reporting period. Conversely, although the firearm suicide rate for large MSAs collectively remained below the national rate during 2009-2010, nearly 75% of these MSAs showed an increased rate from 2006-2007, paralleling the national trend. Firearm suicide rates among persons aged 10-19 years were low compared with all-ages rates during both periods. These patterns can inform the development and monitoring of strategies directed at reducing firearm-related violence. 23868976 Promoter occupancy of MLL1 histone methyltransferase seems to specify the proliferative and apoptotic functions of E2F1 in a tumour microenvironment. The E2F family of transcription factors are considered versatile modulators poised at biological crossroads to execute diverse cellular functions. Despite extensive studies on E2F, the molecular mechanisms that control specific biological functions of E2F1 transcription factor is still not fully understood. Here we have addressed the molecular underpinnings of paradoxical functions of E2F1 in a tumour microenvironment using the 'X15-myc' oncomouse model of hepatocellular carcinoma. We observed that the HBx oncoprotein of hepatitis B virus regulates E2F1 functions by interfering with its binding to Skp2 E3 ubiquitin ligase. The HBx-Skp2 interaction led to the accumulation of transcriptionally active E2F1 and histone methyltransferase mixed lineage leukemia 1 (MLL1) protein. During early stages of hepatocarcinogenesis, the increased E2F1 activity promoted cellular proliferation by stimulating the genes involved in cell cycle control and replication. However, during the late stages, E2F1 triggered replicational stress-induced DNA damage and sensitized cells to apoptotic death in a p53-independent manner. Interestingly, the differential promoter occupancy of MLL1 during the early and late stages of tumour development seemed to specify the proliferative and apoptotic functions of E2F1 through its dynamic interaction with co-activator CBP or co-repressor Brg1. Thus, the temporally-regulated promoter occupancy of histone methyltransferase could be a novel regulatory mechanism associated with diverse cellular functions of E2F family of transcription factors. 23662714 Growth in prepubertal Nigerian children is highly dependent on socio-economic status. To relate height, weight and body mass index (BMI) of prepubertal children in Sagamu, Nigeria, to parental socio-economic class (SEC). Cross-sectional study of 1606 children aged 5-11 years from eight public and eight private primary schools. Height, weight and BMI from 1557 prepubertal children were standardized using two references: US-CDC birth cohorts 1929-1974 and Swedish birth cohort 1974. Children in private schools were taller and heavier than those in public schools (p < 0.0001). Most children (73.2%) belonged to lower SEC, 17.6% to middle and 9.2% to upper. HeightSDS , weightSDS and BMISDS increased with increasing parental SEC. Upper SEC children were taller and heavier with higher BMIs than those from lower SEC (p < 0.0001). HeightSDS , weightSDS and BMISDS were below '0' in all SEC and gender groups (all p < 0.002). Younger children were taller and heavier than the older (p < 0.0001). Fathers/mothers with higher education/occupation had taller and heavier children with higher BMI than other groups. Children in private schools were taller and heavier than children in public schools. Disparities in parental SEC still constrain optimal child growth in Nigeria: whereas height and weight of children of upper SEC were close to the US-CDC29-74 reference mean, they were still below Swedish74 reference mean representing more optimal growth. 23506455 Targeting TRP Channels in Airway Disorders. Novel effective therapeutic agents are actively sought for the treatment of a broad spectrum of respiratory diseases which collectively significantly impact on mortality, morbidity and quality of life of hundreds of millions of people world-wide. These include asthma, allergic rhinitis, chronic obstructive pulmonary disease, cough, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, cystic fibrosis and acute lung injury. TRP channels are broadly distributed throughout the respiratory tract and play an important physiological role in sensing and subsequently responding to a wide variety of stimuli, for example temperature, osmolarity and oxidant stress. In the context of respiratory disease however TRP channel function may be altered, eg: under conditions of oxidative stress, inflammation, hypoxia and mechanical stress. In addition there is evidence that the expression/activity of TRP channels can be affected in the disease setting. Modulators of TRP channel function are therefore under investigation for a range of diseases including disorders of the respiratory system. Several excellent review articles have discussed in detail evidence that modulation of specific TRP channels may be of benefit in specific respiratory diseases. In this article we have taken the approach of reviewing evidence that modulation of TRP channel function may be able to affect common and over-lapping characteristic features of respiratory diseases, for example bronchoconstriction, airways hyper-responsiveness, cough, airways inflammation, mucus hyper-secretion, exacerbations, lung injury, hypoxia and airways re-modelling. The therapeutic potential of TRP channel modulators, the status of these agents in the clinic along with the challenges posed in this rapidly advancing field are also discussed in this review. 23750001 Sirtuin-7 Inhibits the Activity of Hypoxia-inducible Factors. Hypoxia-inducible factor (HIF) 1 and HIF-2 are heterodimeric proteins composed of an oxygen-regulated HIF-1α or HIF-2α subunit, respectively, and a constitutively expressed HIF-1β subunit, which mediate adaptive transcriptional responses to hypoxia. Here, we report that Sirt7 (sirtuin-7) negatively regulates HIF-1α and HIF-2α protein levels by a mechanism that is independent of prolyl hydroxylation and that does not involve proteasomal or lysosomal degradation. The effect of Sirt7 was maintained in the presence of the sirtuin inhibitor nicotinamide and upon deletion or mutation of its deacetylase domain, indicating a non-catalytic function. Knockdown of Sirt7 led to an increase in HIF-1α and HIF-2α protein levels and an increase in HIF-1 and HIF-2 transcriptional activity. Thus, we identify a novel molecular function of Sirt7 as a negative regulator of HIF signaling. 23747583 Thin slice ratings of client characteristics in intake assessments: predicting symptom change and dropout in cognitive therapy for depression. Thin slice ratings of personality have been shown to predict a number of outcomes, but have yet to be examined in the context of psychotherapy. In a sample of 66 clients participating in cognitive therapy for depression, we examined the predictive utility of thin slice rated pre-treatment client traits. On the basis of short video clip excerpts (i.e., thin slices) of intake assessments, trained observers rated clients on personality characteristics and specific personality disorder (PD) traits. Clients' therapy interest and neuroticism predicted lower odds of dropout. Ratings of extraversion predicted greater symptom change across treatment; ratings of clients' Avoidant and Schizoid PD traits predicted less marked symptom improvement. Ratings of agreeableness and likeability also predicted greater symptom change, but these relations were only significant in one of two analytic approaches used. Evidence for the predictive validity of thin slice ratings was generally stronger than that observed for self-reported PD traits and PD status. Moreover, these self-report and diagnostic assessments failed to account for the thin slice-outcome relations identified. Findings support the clinical utility of quick, thin slice impressions of clients, as these ratings could be used to identify clients with a high risk of dropout or poor treatment outcome. 23545708 Direct Effects of Exendin-(9,39) and GLP-1-(9,36)amide on Insulin Action, β-Cell Function, and Glucose Metabolism in Nondiabetic Subjects. Exendin-(9,39) is a competitive antagonist of glucagon-like peptide-1 (GLP-1) at its receptor. However, it is unclear if it has direct and unique effects of its own. We tested the hypothesis that exendin-(9,39) and GLP-1-(9,36)amide have direct effects on hormone secretion and β-cell function as well as glucose metabolism in healthy subjects. Glucose containing [3-(3)H]glucose was infused to mimic the systemic appearance of glucose after a meal. Saline, GLP-1-(9,36)amide, or exendin-(9,39) at 30 pmol/kg/min (Ex 30) or 300 pmol/kg/min (Ex 300) were infused in random order on separate days. Integrated glucose concentrations were slightly but significantly increased by exendin-(9,39) (365 ± 43 vs. 383 ± 35 vs. 492 ± 49 vs. 337 ± 50 mmol per 6 h, saline, Ex 30, Ex 300, and GLP-1-[9,36]amide, respectively; P = 0.05). Insulin secretion did not differ among groups. However, insulin action was lowered by exendin-(9,39) (25 ± 4 vs. 20 ± 4 vs. 18 ± 3 vs. 21 ± 4 10(-4) dL/kg[min per μU/mL]; P = 0.02), resulting in a lower disposition index (DI) during exendin-(9,39) infusion (1,118 ± 118 vs. 816 ± 83 vs. 725 ± 127 vs. 955 ± 166 10(-14) dL/kg/min(2) per pmol/L; P = 0.003). Endogenous glucose production and glucose disappearance did not differ significantly among groups. We conclude that exendin-(9,39), but not GLP-1-(9,36)amide, decreases insulin action and DI in healthy humans. 22748603 Concomitant carotid plaque development and brachial artery diameter enlargement: A retrospective, recall-based study in postmenopausal women. To verify if the carotid plaque development is concomitant to brachial artery diameter enlargement, in healthy postmenopausal women. This is a retrospective, recall study. We enrolled 40 postmenopausal women, selected from a database for the period 2000-2008, not affected by subclinical carotid atherosclerosis and without risk factors for cardiovascular disease. At the recall visit, carotid and brachial duplex scan was again obtained. The incidence of plaque was 30% after a mean follow-up period of 60 months. There were no differences in baseline characteristics between subjects developing carotid atherosclerosis and subjects who did not, except for the brachial diameter change, follow-up and heart rate. The logistic-regression analysis confirmed that only brachial diameter change resulted to be correlated with the development of carotid atherosclerosis. Brachial artery diameter increase is concomitant to carotid plaque development. Vascular enlargement could not be a focal change but a systemic process associated with atherosclerotic plaque development. Brachial diameter could be a tool with a predictive significance. 23851136 Examining the Measurement Precision and Invariance of the Revised Get Ready to Read! Children's emergent literacy skills are highly predictive of later reading abilities. To determine which children have weaker emergent literacy skills and are in need of intervention, it is necessary to assess emergent literacy skills accurately and reliably. In this study, 1,351 children were administered the Revised Get Ready to Read! (GRTR-R), and an item response theory analysis was used to evaluate the item-level reliability of the measure. Differential item functioning (DIF) analyses were conducted to examine whether items function similarly between subpopulations of children. The GRTR-R had acceptable reliability for children whose ability level was just below the mean. DIF for a small number of items was present for only two comparisons-children who were older versus younger and children who were White versus African American. These results demonstrate that the GRTR-R has acceptable reliability and limited DIF, enabling the screener to identify those at risk for developing reading problems. 23950206 Clinical response to a lapatinib-based therapy of a Li-Fraumeni Syndrome patient with a novel HER2-V659E mutation. Genomic characterization of recurrent breast and lung tumors developed over the course of 10 years in a 29-year-old patient with a germline p53 mutation (Li-Fraumeni Syndrome) identified oncogenic alterations in the HER2 and EGFR genes across all tumors, including HER2 amplifications, an EGFR-exon 20 insertion, and the first-in-human HER2-V659E mutation showing a phenotypic convergent evolution towards HER2 and EGFR alterations. Following the identification of HER2-activating events in the most recent lung carcinoma and in circulating tumor cells, we treated the reminiscent metastatic lesions with a lapatinib-based therapy. A clinical response both symptomatic and radiologic was achieved. HER2-V659E sensitivity to lapatinib was confirmed in the laboratory. 23521174 Comparison of transcriptomic signature of post-Chernobyl and post-radiotherapy thyroid tumors. Background: We previously identified two highly discriminating and predictive radiation-induced transcriptomic signatures by comparing series of sporadic and post-radiotherapy thyroid tumors (322-gene signature), and by re-analyzing a previously published dataset of sporadic and post-Chernobyl thyroid tumors (106-gene signature). The aim of the present work was 1) to compare the two signatures in terms of gene expression deregulations and molecular features/pathways and 2) to test the capacity of the post-radiotherapy signature in classifying the post-Chernobyl series of tumors and reciprocally of the post Chernobyl signature in classifying the post-radiotherapy induced tumors. Methods: We now explored if post-radiotherapy and post-Chernobyl thyroid papillary carcinomas (PTC) display common molecular features by comparing molecular pathways deregulated in the two tumor series and test the potential of gene subsets of the post-radiotherapy signature to classify the post-Chernobyl series (14 sporadic and 12 post-Chernobyl PTC), and reciprocally of gene subsets of the post-Chernobyl signature to classify the post-radiotherapy series (15 sporadic and 12 post-radiotherapy PTC), by using conventional Principal Component Analysis. Results: We found that the 5 genes common to the two signatures classified the learning/training tumors (used to search these signatures) of both the post-radiotherapy (7 PTC) and the post-Chernobyl (6 PTC) thyroid tumor series as compared with the sporadic tumors (7 sporadic PTC in each series). Importantly, these 5 genes were also effective for classifying independent series of post-radiotherapy (5 PTC) and post-Chernobyl (6 PTC) tumors compared to independent series of sporadic tumors (8 PTC and 6 PTC, respectively) (testing tumors) Moreover, part of each post-radiotherapy (32 genes) and post-Chernobyl signature (16 genes) cross-classified the respective series of thyroid tumors. Finally, several molecular pathways deregulated in post-Chernobyl tumors matched those found to be deregulated in post-radiotherapy tumors. Conclusions Overall, our data suggest that thyroid tumors that developed following either external exposure or internal 131I contamination shared common molecular features, related to DNA repair, oxidative and endoplasmic reticulum stresses, allowing their classification as radiation-induced tumors in comparison with sporadic counterparts, independently of doses and dose rates, which suggests there may be a "general" radiation-induced signature of thyroid tumors. 23792190 Directed phenotype switching as an effective antimelanoma strategy. Therapeutic resistance in melanoma and other cancers arises via irreversible genetic, and dynamic phenotypic, heterogeneity. Here, we use directed phenotype switching in melanoma to sensitize melanoma cells to lineage-specific therapy. We show that methotrexate (MTX) induces microphthalmia-associated transcription factor (MITF) expression to inhibit invasiveness and promote differentiation-associated expression of the melanocyte-specific Tyrosinase gene. Consequently, MTX sensitizes melanomas to a tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin (TMECG), that inhibits the essential enzyme DHFR with high affinity. The combination of MTX and TMECG leads to depletion of thymidine pools, double-strand DNA breaks, and highly efficient E2F1-mediated apoptosis in culture and in vivo. Importantly, this drug combination delivers an effective and tissue-restricted antimelanoma therapy in vitro and in vivo irrespective of BRAF, MEK, or p53 status. 23907102 Quantitative Evaluation of Computed High b Value Diffusion-Weighted Magnetic Resonance Imaging of the Prostate. Computed diffusion-weighted magnetic resonance imaging (cDWI) refers to the synthesizing of arbitrary b value diffusion-weighted images (DWI) from a set of measured b value images by voxelwise fitting. The objectives of this study were to quantitatively analyze the noise and the contrast-to-noise ratio (CNR) in cDWI as a function of b value by numerical simulations and by measurements in patients with prostate cancer and to compare cDWI to directly measured DWI at a b value of 1400 s/mm. Numerical simulations were performed to assess image noise and CNR in both cDWI and regular DWI. Forty-two patients with prostate cancer (age, 51-73 years; prostate specific antigen level, 0.5-30 ng/mL; and biopsy Gleason score, 6-9) received 2 DWI examinations at 3.0 T (one with b values of 100, 500, and 1400 s/mm and another with b values of 0, 100, 400, and 800 s/mm) to create cDWI images at arbitrary b values, both with and without incorporating a b value of 0 s/mm in their calculation. Regions of interest were drawn to compare the scan time adjusted CNR (CNReff) between cDWI and directly measured DWI at b = 1400 s/mm on tumor-suspicious lesions and normal-appearing regions. In the numerical simulations, noise depended strongly on the b value, the diffusion coefficient, and the signal intensity at a b value of 0 s/mm in cDWI but not in regular DWI. The CNR between simulated tumor and normal regions showed a continuous increase with increasing b value. Both these findings were also observed in tumor-suspicious and normal-appearing regions in in vivo data. In vivo prostate DWI at a b value of 1400 s/mm showed a similar CNReff between the tumor-suspicious regions and the normal-appearing tissue in cDWI as in the directly measured DWI (P = 0.395). The CNReff between tumor-suspicious and normal-appearing prostate tissue in DWI images at a b value of 1400 s/mm is comparable in cDWI and directly measured DWI. Computed DWI at even higher b values, calculated from measured images with b values between 0 and 800 s/mm, yields higher CNReff than measured DWI, which may be of clinical aid in the management of prostate cancer. 22461372 Altered white matter connectivity in never-medicated patients with schizophrenia. Numerous diffusion tensor imaging (DTI) studies have implicated white matter brain tissue abnormalities in schizophrenia. However, the vast majority of these studies included patient populations that use antipsychotic medication. Previous research showed that medication intake can affect brain morphology and the question therefore arises to what extent the reported white matter aberrations can be attributed to the disease rather than to the use of medication. In this study we included 16 medication-naïve patients with schizophrenia and compared them to 23 healthy controls to exclude antipsychotic medication use as a confounding factor. For each subject DTI scans and magnetization transfer imaging (MTI) scans were acquired. A new tract-based analysis was used that combines fractional anisoptropy (FA), mean diffusivity (MD) and magnetization transfer ratio (MTR) to examine group differences in 12 major white matter fiber bundles. Significant group differences in combined FA, MD, MTR values were found for the right uncinate fasciculus and the left arcuate fasciculus. Additional analysis revealed that the largest part of both tracts showed an increase in MTR in combination with an increase in MD for patients with schizophrenia. We interpret these group-related differences as disease-related axonal or glial aberrations that cannot be attributed to antipsychotic medication use. Hum Brain Mapp 34:2353-2365, 2013. © 2012 Wiley Periodicals, Inc. 23433976 Effective biochemical decomposition of chlorinated aromatic hydrocarbons with a biocatalyst immobilized on a natural enzyme support. The enzymatic decomposition of 4-chlorophenol metabolites using an immobilized biocatalyst was investigated in this study. Catechol 1,2-dioxygenase for ortho ring cleavage obtained via cloning of the corresponding gene cphA-I from Arthrobacter chlorophenolicus A6 was overexpressed and purified. It was found that the cphA-I enzyme could catalyze the degradation of catechol, 4-chlorocatechol, and 3-methylcatechol. The expressed enzyme was immobilized onto a natural enzyme support, fulvic acid-activated montmorillonite. The immobilization yield was as high as 63%, and the immobilized enzyme maintained high substrate utilization activity, with only a 15-24% reduction in the specific activity. Kinetic analysis demonstrated marginal differences in νmax and KM values for the free and immobilized enzymes, indicating that inactivation of the immobilized enzyme was minimal. The immobilized enzyme exhibited notably increased stability against changes in the surrounding environment (temperature, pH, and ionic strength). Our results provide useful information for the effective enzymatic biochemical treatment of hazardous organic compounds. 23829877 Dropped head sign induced by transdermal application of the dopamine agonist rotigotine in parkinsonian syndrome: a case report. 'Dropped head sign' relates to a severe disproportionate antecollis in parkinsonism. We present the first report of a rotigotine-induced dropped head sign in a patient with suspected idiopathic Parkinson's disease, which was later defined as multiple system atrophy. The 'dropped head sign' is considered a rare symptom of unknown etiology in parkinsonian disorders, though a disproportionate antecollis is frequently observed in multiple system atrophy. It has also been described as a side effect of dopamine agonist medication with cabergoline and pramipexole. Rotigotine is a transdermally applied, non-ergot dopamine agonist, resulting in a continuous stimulation of dopamine receptors, which is widely used in the treatment of patients with Parkinson's disease. We report a case of a 64-year-old Caucasian woman with a rapidly progressive two-and-a-half-year history of a hypokinetic Parkinson's syndrome with asymmetric development of symptoms and an initially good response to levodopa medication. Due to side effects of other dopamimetic medications the patient was switched to rotigotine medication five weeks before clinical admission. Progressive antecollis without muscle weakness and prominent paraspinal muscle contraction developed within two weeks of treatment and resolved within a week after discontinuation of rotigotine and initiation of levodopa/cabergoline medication. While the pathophysiology still remains unresolved, this case supports the concept of a dopaminergic imbalance as a cause of certain axial dystonias like disproportionate antecollis including the 'dropped head sign'. We believe this case is specifically useful for neurologists and general practitioners, as the easily recognizable symptom should prompt a thorough reevaluation of diagnosis and medication in patients with Parkinson's disease. 23968744 Randomized Trial of Exclusive Human Milk versus Preterm Formula Diets in Extremely Premature Infants. To compare the duration of parenteral nutrition, growth, and morbidity in extremely premature infants fed exclusive diets of either bovine milk-based preterm formula (BOV) or donor human milk and human milk-based human milk fortifier (HUM), in a randomized trial of formula vs human milk. Multicenter randomized controlled trial. The authors studied extremely preterm infants whose mothers did not provide their milk. Infants were fed either BOV or an exclusive human milk diet of pasteurized donor human milk and HUM. The major outcome was duration of parenteral nutrition. Secondary outcomes were growth, respiratory support, and necrotizing enterocolitis (NEC). Birth weight (983 vs 996 g) and gestational age (27.5 vs 27.7 wk), in BOV and HUM, respectively, were similar. There was a significant difference in median parenteral nutrition days: 36 vs 27, in BOV vs HUM, respectively (P = .04). The incidence of NEC in BOV was 21% (5 cases) vs 3% in HUM (1 case), P = .08; surgical NEC was significantly higher in BOV (4 cases) than HUM (0 cases), P = .04. In extremely preterm infants given exclusive diets of preterm formula vs human milk, there was a significantly greater duration of parenteral nutrition and higher rate of surgical NEC in infants receiving preterm formula. This trial supports the use of an exclusive human milk diet to nourish extremely preterm infants in the neonatal intensive care unit. 23660025 Anisotropic photoelectric film assembled from mesoporous silica (MS)@CuO@FeS2 composite microspheres for improving photoelectric conversion. We report a novel strategy for the fabrication of mesoporous silica (MS)@CuO@FeS2 composite microsphere-based anisotropic films that combine the advantages of the CuO and FeS2 materials to improve photoelectric conversion. This was achieved by aligning MS@CuO@FeS2 composite microspheres in a cross-linked gel under a homogeneous magnetic field. The MS@CuO@FeS2 composite microspheres, which were synthesized by a simple layer-by-layer (LbL) self-assembly technique together with a solvothermal method, can absorb a wide range of light and exhibit ferromagnetic properties. In addition, the resulting MS@CuO@FeS2 composite microsphere-based anisotropic film shows photoelectric anisotropy. Such systems are promising for improving the performance of solar cells. 22566066 The synergistic apoptotic interaction of panaxadiol and epigallocatechin gallate in human colorectal cancer cells. Panaxadiol (PD) is a purified sapogenin of ginseng saponins, which exhibits anticancer activity. Epigallocatechin gallate (EGCG), a major catechin in green tea, is a strong botanical antioxidant. In this study, we investigated the possible synergistic anticancer effects of PD and EGCG on human colorectal cancer cells and explored the potential role of apoptosis in the synergistic activities. Effects of selected compounds on HCT-116 and SW-480 human colorectal cancer cells were evaluated by a modified trichrome stain cell proliferation analysis. Cell cycle distribution and apoptotic effects were analyzed by flow cytometry after staining with PI/RNase or annexin V/PI. Cell growth was suppressed after treatment with PD (10 and 20 µm) for 48 h. When PD (10 and 20 µm) was combined with EGCG (10, 20, and 30 µm), significantly enhanced antiproliferative effects were observed in both cell lines. Combining 20 µm of PD with 20 and 30 µm of EGCG significantly decreased S-phase fractions of cells. In the apoptotic assay, the combination of PD and EGCG significantly increased the percentage of apoptotic cells compared with PD alone (p < 0.01). The synergistic apoptotic effects were also supported by docking analysis, which demonstrated that PD and EGCG bound in two different sites of the annexin V protein. Data from this study suggested that apoptosis might play an important role in the EGCG-enhanced antiproliferative effects of PD on human colorectal cancer cells. 23916060 Cryptosporidium suis and Cryptosporidium scrofarum in Eurasian wild boars (Sus scrofa) in Central Europe. From 2011 to 2012, to identify Cryptosporidium spp. occurrence in Eurasian wild boars (Sus scrofa) 29 randomly selected localities (both forest areas and enclosures) across the Central European countries of Austria, the Czech Republic, Poland, and the Slovak Republic were investigated. Cryptosporidium oocysts were microscopicaly detected in 11 out of 460 faecal samples examined using aniline-carbol-methyl violet staining. Sixty-one Cryptosporidium infections, including the 11 infections that were detected by microscopy, were detected using genus- or species-specific nested PCR amplification of SSU rDNA. This represents a 5.5 fold greater sensitivity for PCR relative to microscopy. Combining genus- and species-specific PCR tools significantly changes the perspective on the occurrence of Cryptosporidium spp. in wild boars. While RFLP and direct sequencing of genus specific PCR-amplified products revealed 56 C. suis (20) and C. scrofarum (36) monoinfections and only 5 mixed infections of these species, species-specific molecular tools showed 44 monoinfections and 17 mixed infections with these species. PCR analysis of the gp60 gene did not reveal any other Cryptosporidium infections. Similar to domestic pigs, C. scrofarum was detected as a dominant species infecting adult Eurasian wild boars (Sus scrofa). Cryptosporidium infected wild boars did not show signs of clinical disease. This report is perhaps the most comprehensive survey of cryptosporidial infection in wild boars. 23725222 Surface plasmon resonance-based real-time bioaerosol detection. Rapid and precise bioaerosol detection in different environments has become an important research and technological issue over last decades. Previously, we employed a real-time PCR protocol in conjunction with personal bioaerosol sampler for rapid detection of airborne viruses. The approach has been proved to be specific and sensitive. However, a period of time required for entire procedure was in manner of hours. Some new developments are required to decrease the detection time down to real-time protocols. Presently, a surface plasmon resonance (SPR)-based immunosensor that coupled with a specific antigen-antibody reaction could offer sensitive, specific, rapid and label-free detection. This study describes the possibility of combining the personal sampler with SPR technology for qualitative and extremely rapid detection of airborne micro-organisms. Common viral surrogate MS2 bacteriophage, frequently used in bioaerosol studies, was employed as a model organism. The results of the sensor functionalizing procedure with monoclonal anti-MS2 antibody and optimization of the chip performance are presented. The SPR-based detection of the airborne virus was found to be very fast; the viral presence was detected in less than 2 min, and the entire procedure (sampling and analysis) was undertaken in 6 min, which could be considered as real-time detection for this type of measurements. The combination of SPR with the personal sampler targeted towards bioaerosol detection was proven to be feasible. The SPR sensor was found to be highly stable and suitable for multiple utilizations without significant decrease in response. The suggested approach opens new possibilities for the development of portable and rapid (almost real time) bioaerosol monitors. This technology is the first in the world real-time bioaerosol monitor. This outcome would be of strong interest to individuals representing public health, biosecurity, defence forces, environmental sciences and many others. 23376211 New insights toward the discovery of antibacterial agents: multi-tasking QSBER model for the simultaneous prediction of anti-tuberculosis activity and toxicological profiles of drugs. Tuberculosis (TB) constitutes one of the most dangerous and serious health problems around the world. It is a very lethal disease caused by microorganisms of the genus mycobacterium, principally Mycobacterium tuberculosis (MTB) which affects humans. A very active field for the search of more efficient anti-TB chemotherapies is the use in silico methodologies for the discovery of potent anti-TB agents. The battle against MTB by using antimicrobial chemotherapies will depend on the design of new chemicals with high anti-TB activity and low toxicity as possible. Multi-target methodologies focused on quantitative-structure activity relationships (mt-QSAR) have played a very important role for the rationalization of drug design, providing a better understanding about the molecular patterns related with diverse pharmacological profiles including antimicrobial activity. Nowadays, almost all mt-QSAR models have considered the study of biological activity or toxicity separately. In the present study, we develop by the first time, a unified multitasking model based on quantitative-structure biological effect relationships (mtk-QSBER) for the simultaneous prediction of anti-TB activity and toxicity against Mus musculus and Rattus norvegicus. The mtk-QSBER model was created by using linear discriminant analysis (LDA) for the classification of compounds as positive (high biological activity and/or low toxicity) or negative (otherwise) under many experimental conditions. Our mtk-QSBER model, correctly classified more than 90% of the case in the whole database (more than 12,000 cases), serving as a powerful tool for the computer-assisted screening of potent and safe anti-TB drugs. 23897185 IgM nephropathy in children: clinicopathologic analysis. Introduction: IgM nephropathy (IgMN) is a glomerulonephritis characterised by diffuse mesangial immunoglobulin M (IgM) deposits. It usually presents with nephrotic range proteinuria and, according to some previous work, it occurs most often in patients who are resistant to or dependent on steroid treatment. Objective: To perform a clinical, histological and immunopathological description and assess the response to steroid treatment of paediatric patients diagnosed with nephrotic syndrome and diffuse mesangial IgM deposits. Method: This is a descriptive, retrospective study carried out in two hospitals, where the clinical records of paediatric patients with IgMN were analysed and the histological sections were re-assessed. Results: thirteen children were included in this study. IgMN corresponded to 5.17% of all paediatric renal biopsies. The age of patients ranged from 1 year to 12 years (median: 2 years), 46.7% were women. The most common morphological finding was diffuse mesangial hypercellularity (46.1%), followed by focal segmental glomerulosclerosis (30.8%) and minimal glomerular changes (23.1%). All patients received steroids; in 4 cases (30.7%) as the only immunosuppressant medication, 3 (23.1%) also received cyclophosphamide, 5 (38.4%) mycophenolate, and 1 (7.7%) cyclosporine. Seven patients (53.8%) had frequent relapses, 5 (38.5%) were cortico-resistant and 1 (7.7%) cortico-dependent. Two patients (15.38%) had chronic impairment of renal function. Conclusion: The presence of diffuse mesangial IgM in paediatric patients with nephrotic syndrome is not a very uncommon finding; its clinical presentation has been associated with lower response to steroids. However, the long-term prognosis of these patients is still unknown. 23665316 Nano-titanium dioxide induced cardiac injury in rat under oxidative stress. Heart diseases, which are related to oxidative stress (OS), negatively affect millions of people from kids to the elderly. Titanium dioxide (TiO2) has widespread applications in our daily life, especially nanoscale TiO2. Compared to the high risk of particulate matter (⩽2.5μm) in air to heart disease patients, related research of TiO2 on diseased body is still unknown, which suggest us to explore the potential effects of nanoscale and microscale TiO2 to heart under OS conditions. Here, we used alloxan to induce OS conditions in rat, and investigated the response of heart tissue to TiO2 in healthy and alloxan treated rats. Compared with NMs treatment only, the synergistic interaction between OS conditions and nano-TiO2 significantly reduced the heart-related function indexes, inducing pathological changes of myocardium with significantly increased levels of cardiac troponin I and creatine kinase-MB. In contrast with the void response of micro-TiO2 to heart functions in alloxan treated rats, aggravation of OS conditions might play an important role in cardiac injury after alloxan and nano-TiO2 dual exposure. Our results demonstrated that OS conditions enhanced the adverse effects of nano-TiO2 to heart, suggesting that the use of NMs in stressed conditions (e.g., drug delivery) needs to be carefully monitored. 23618757 Cholesterol and perhaps estradiol protect against corticosterone-induced hippocampal CA3 dendritic retraction in gonadectomized female and male rats. Chronic stress or glucocorticoid exposure simplifies hippocampal Cornu Ammonis region 3 (CA3) apical dendritic arbors in male rats. In contrast to males, chronic stress either reduces CA3 basal branching or exerts no observable morphological effects in gonadally intact female rats. Under conditions that females display stress-induced CA3 dendritic retraction, such as that following ovariectomy, chronic exposure to 17β-estradiol or cholesterol can negate these changes. Whether glucocorticoids produce CA3 dendritic retraction in ovariectomized females and whether neuroprotection from 17β-estradiol or cholesterol is sex-specific remains unknown. The current study examined the effects of chronic glucocorticoid exposure, in conjunction with 17β-estradiol or cholesterol administration, on hippocampal CA3 dendritic complexity. Adult male and female Sprague-Dawley rats were gonadectomized and implanted with 25% 17β-estradiol in cholesterol, 100% cholesterol, or blank Silastic capsules. Rats were then assigned to either a 21-day corticosterone (CORT) drink (400μg/ml CORT, 2.4% ethanol in tap water) or tap water (Tap, 2.4% ethanol in tap water) treatment. Brains were processed for Golgi staining, and hippocampal CA3 dendritic architecture was quantified. Results showed 21-day CORT administration reduced hippocampal CA3 apical dendritic branch points, CA3 apical dendritic length, body weight gain, and adrenal weights compared to male and female control counterparts. Furthermore, male and female rats implanted with Silastic capsules containing cholesterol or 25% 17β-estradiol in cholesterol were protected from CORT-induced CA3 apical dendritic branch reduction. No effects were observed in the CA3 basal dendritic arbors. The present results demonstrate that CORT produces hippocampal CA3 dendritic retraction in gonadectomized male and female rats and that cholesterol and 25% 17β-estradiol in cholesterol prevent this dendritic simplification. 23279197 Haemoglobin S and C affect the motion of Maurer's clefts in Plasmodium falciparum-infected erythrocytes. The haemoglobinopathies S and C protect carriers from severe Plasmodium falciparum malaria. We have recently shown that haemoglobin S and C interfere with host-actin remodelling in parasitized erythrocytes and the generation of an actin network that seems to be required for vesicular protein trafficking from the Maurer's clefts (a parasite-derived intermediary protein secretory organelle) to the erythrocyte surface. Here we show that the actin network exerts skeletal functions by anchoring the Maurer's clefts within the erythrocyte cytoplasm. Using a customized tracking tool to investigate the motion of single Maurer's clefts, we found that a functional actin network restrains Brownian motion of this organelle. Maurer's clefts moved significantly faster in wild-type erythrocytes treated with the actin depolymerizing agent cytochalasin D and in erythrocytes containing the haemoglobin variants S and C. Our data support the model of an impaired actin network being an underpinning cause of cellular malfunctioning in parasitized erythrocytes containing haemoglobin S or C, and, possibly, for the protective role of these haemoglobin variants against severe malaria. 23583540 Xiaoxuming decoction for acute ischemic stroke: A systematic review and meta-analysis. ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoxuming decoction (XXMD) is a well-known traditional Chinese herbal prescription in treatment of patients with stroke. The objective of this study is to assess the efficacy and safety of XXMD for acute ischemic stroke. MATERIALS AND METHODS: A systematic literature search was conducted in 6 databases until June 2012 to identify randomized controlled trials (RCTs) of XXMD for acute ischemic stroke compared with western conventional medicine (WCM). The primary outcome measures were National Institutes of Health Stroke Scale (NIHSS) scores and modified Rankin Scale (mRS) scores. The secondary outcome measures were the clinical effective rate and adverse events at the end of treatment course. The methodological quality of RCTs was assessed independently using 12-item criteria according to the Cochrane Back Review Group. All data were analyzed using Review Manager 5.0 software. RESULTS: Eight RCTs with 601 individuals published from 1992 to 2012 were identified. The studies were deemed to have a high risk of bias. Compared with WCM, 1 RCT showed significant effects of XXMD for improving mRS after stroke (p<0.05); 3 RCTs for improving NIHSS scores [n=186, weighted mean difference (WMD): -1.86, 95% CI: -3.25 to -0.48, z=2.63, p<0.01]; 7 RCTs for improving the clinical effective rate [n=531, risk ratio (RR)=1.17, 95% CI, 1.09 to 1.26, z=4.38, p<0.01]. Five trials contained safety assessments and stated that no adverse event was found, whereas the other 3 trials did not provide the information about adverse events. CONCLUSIONS: This systematic review showed positive but weak evidence of XXMD for acute ischemic stroke because of the poor methodological quality and the small quantity of the included trials. The difficulties of fitting Chinese herbal medicine (CHM) into the double blinded RCTs have raised as follows: (A) traditional Chinese medicine (TCM) as whole systems of healthcare offers unique methodological and theoretical challenges for RCTs; (B) suspicions against the placebo and unwillingness to stop taking other CHMs make recruitment more difficulty, time-consumption, and cost; (C) the shortcomings of the TCM diagnostic process includes the lack of standardization in terminology, disagreement of pattern differentiation (Bianzheng), and neglect of formula corresponding to syndrome (TCM Zheng); (D) It is difficult to design credible herbal placebos with similar appearance, smells and tastes to the experimental CHM and at the same time is absent of any pharmacological activity; (E) the achieving efficacy of CHM complex interventions is often nonspecific and the outcome measures is subjective using Chinese quantitative instrument. 23640331 Progesterone receptor induces bcl-x expression through intragenic binding sites favoring RNA polymerase II elongation. Steroid receptors were classically described for regulating transcription by binding to target gene promoters. However, genome-wide studies reveal that steroid receptors-binding sites are mainly located at intragenic regions. To determine the role of these sites, we examined the effect of progestins on the transcription of the bcl-x gene, where only intragenic progesterone receptor-binding sites (PRbs) were identified. We found that in response to hormone treatment, the PR is recruited to these sites along with two histone acetyltransferases CREB-binding protein (CBP) and GCN5, leading to an increase in histone H3 and H4 acetylation and to the binding of the SWI/SNF complex. Concomitant, a more relaxed chromatin was detected along bcl-x gene mainly in the regions surrounding the intragenic PRbs. PR also mediated the recruitment of the positive elongation factor pTEFb, favoring RNA polymerase II (Pol II) elongation activity. Together these events promoted the re-distribution of the active Pol II toward the 3'-end of the gene and a decrease in the ratio between proximal and distal transcription. These results suggest a novel mechanism by which PR regulates gene expression by facilitating the proper passage of the polymerase along hormone-dependent genes. 23922410 Brain networks in human epilepsy. Mark Richardson is a neurologist specialising in epilepsy. He is Paul Getty III Professor of Epilepsy and Head of the Department of Clinical Neuroscience at King's College London. Professor Richardson studied medicine at Oxford and trained in neurology in London. He began his research career as a PhD student at the Institute of Neurology, joining the faculty there in 2000 as an MRC Clinician Scientist Fellow. He moved to King's in 2005. Professor Richardson's clinical practice spans all aspects of epilepsy, from first presentation to complex treatment-resistant epilepsy. His lab studies people with epilepsy using neuroimaging and neurophysiological techniques. Current work aims to understand the brain networks underlying epilepsy, how seizures might arise in these networks, how these network abnormalities affect cognition, and whether interventions targeting specific components of the network can improve epilepsy. He collaborates with mathematicians and engineers in developing computational models to explain phenomena associated with epilepsy. This contribution aims to introduce the concept of epilepsy as a network disorder. I will provide an overview of how neuroimaging and EEG might contribute to describing brain network structure, and describe how dynamic models may be introduced into network structures to reveal how seizures emerge. I will provide examples of how conventional MRI may be used to reveal network abnormalities. Lastly, I will show an example of how data from human subjects may be used to derive network structures, and combined with dynamic modelling, to cast light on how seizure susceptibility varies between individuals. 23838146 Experimental infection studies demonstrating Atlantic salmon as a host and reservoir of viral hemorrhagic septicemia virus type IVa with insights into pathology and host immunity. In British Columbia, Canada (BC), aquaculture of finfish in ocean netpens has the potential for pathogen transmission between wild and farmed species due to the sharing of an aquatic environment. Viral hemorrhagic septicemia virus (VHSV) is enzootic in BC and causes serious disease in wild Pacific herring, Clupea pallasii, which often enter and remain in Atlantic salmon, Salmo salar, netpens. Isolation of VHSV from farmed Atlantic salmon has been previously documented, but the effects on the health of farmed salmon and the wild fish sharing the environment are unknown. To determine their susceptibility, Atlantic salmon were exposed to a pool of 9 isolates of VHSV obtained from farmed Atlantic salmon in BC by IP-injection or by waterborne exposure and cohabitation with diseased Pacific herring. Disease intensity was quantified by recording mortality, clinical signs, histopathological changes, cellular sites of viral replication, expression of interferon-related genes, and viral tissue titers. Disease ensued in Atlantic salmon after both VHSV exposure methods. Fish demonstrated gross disease signs including darkening of the dorsal skin, bilateral exophthalmia, light cutaneous hemorrhage, and lethargy. The virus replicated within endothelial cells causing endothelial cell necrosis and extensive hemorrhage in anterior kidney. Infected fish demonstrated a type I interferon response as seen by up-regulation of genes for IFNα, Mx, and ISG15. In a separate trial infected salmon transmitted the virus to sympatric Pacific herring. The results demonstrate that farmed Atlantic salmon can develop clinical VHS and virus can persist in the tissues for at least 10 weeks. Avoiding VHS epizootics in Atlantic salmon farms would limit the potential of VHS in farmed Atlantic salmon, the possibility for further host adaptation in this species, and virus spillback to sympatric wild fishes. 23927970 Synthesis, cytotoxicity and DNA-binding properties of Pd(II), Cu(II) and Zn(II) complexes with 4'-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-2,2':6',2″-terpyridine. Pd(II), Cu(II) and Zn(II) complexes (1-3) based on 4'-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-2,2':6',2″-terpyridine were synthesized and characterized by UV, IR, NMR, EPR, HRMS, elemental analyses, and molar conductivity measurements. The cytotoxicity of these complexes against HL-60, BGC-823, KB, Bel-7402, A549, Hela, K562 and MCF-7 cell lines in vitro was measured by MTT method. The DNA binding property of the complexes was evaluated by UV, fluorescence, CD spectroscopies and thermal denaturation. The cytotoxicity of complexes 1 and 3 against all the tested cell lines is better than that of cisplatin. Complexes 1 and 2 exhibit 7- and 4-folds higher cytotoxicity than cisplatin against Bel-7402 cell line. Complex 3 displays the highest cytotoxicity against all the cell lines tested, and shows 7-, 14-, 8-, 11- and 8-folds higher cytotoxicity than cisplatin against Bel-7402, A549, Hela, K562 and MCF-7 cell lines. The complexes bind to DNA via intercalation mode and complex 3 stabilizes the G-quadruplex. The results reveal that all the complexes display high cytotoxicity against all the tested cancer cell lines, and complex 3 is selective for G-quadruplex over duplex DNA. 23725091 Effects of carbohydrates on the oNPG converting activity of β-galactosidases. The effects of high concentrations of carbohydrates on the o-nitrophenyl β-d-galactopyranoside (oNPG) converting activity of β-galactosidase from Bacillus circulans are studied to get a better understanding of the enzyme behavior in concentrated and complicated systems in which enzymatic synthesis of galacto-oligosaccharides is usually performed. The components that were tested were glucose, galactose, lactose, sucrose, trehalose, raffinose, Vivinal GOS, dextran-6000, dextran-70,000, and sarcosine. Small carbohydrates act as acceptors in the reaction. This speeds up the limiting step, which is binding of the galactose residue with the acceptor and release of the product. Simultaneously, both inert and reacting additives seem to cause some molecular crowding, which results in a higher enzyme affinity for the substrate. The effect of molecular crowding on the enzyme activity is small compared to the effect of carbohydrates acting in the reactions as acceptors. The effects of reactants on β-galactosidases from B. circulans, A. oryzae, and K. lactis are compared. 23876366 Rapid and sensitive detection of shrimp infectious myonecrosis virus using a reverse transcription loop-mediated isothermal amplification and visual colorogenic nanogold hybridization probe assay. This study reports a novel strategy for the detection of reverse transcription loop-mediated isothermal amplification (RT-LAMP) products derived from infectious myonecrosis virus (IMNV), causes a serious myonecrosis in Penaeus (Litopenaeus) vannamei, by using a ssDNA-labeled with gold nanoparticle (AuNP) probe. This technique relies on a self-aggregation method, when the AuNP aggregation is induced by an increasing of salt concentrations with visual detection. The presence of IMNV-LAMP target prevented an AuNP aggregation and a solution remained as pink color of AuNP, while non-complementary targets cannot prevent AuNP aggregation, resulting in a visible color change to purple color after addition of salt. By using the combination of LAMP and AuNP probe system, the total assay interval required approximately 50min (exclude RNA preparation). Detection limit was 10copies of IMNV RNA in vitro transcript that comparable to that of LAMP followed by LFD and nested RT-PCR, but it was 100-times more sensitive than RT-PCR methods. This assay can be adapted easily for rapid detection of other shrimp infectious diseases agents at low-cost with robust reagents and using a simple colorimetric detection method. 23748100 Gremlin utilizes canonical and non-canonical TGFβ signaling to induce lysyl oxidase (LOX) genes in human trabecular meshwork cells. The TGFβ/BMP signaling pathways are involved in glaucomatous damage to the trabecular meshwork (TM) leading to elevated intraocular pressure (IOP), which is a major risk factor for the development and progression of glaucoma. The BMP antagonist gremlin is elevated in glaucomatous TM cells and tissues and can directly elevate IOP. Gremlin utilizes the TGFβ2/SMAD pathway to induce TM extracellular matrix (ECM) proteins. The purpose of this study is to determine whether expression of the ECM cross-linking lysyl oxidase (LOX) genes is regulated by gremlin in cultured human TM cells. Human TM cells were treated with recombinant gremlin, and expression of the LOX genes was examined by quantitative RT-PCR and western immunoblotting. TM cells were pretreated with TGFBR inhibitors (LY364947 or SB431542), an inhibitor of the SMAD signaling pathway (SIS3), or with JNK (SP600125) and p38 MAPK (SB203580) inhibitors to identify the signaling pathway(s) involved in gremlin induction of LOX protein expression. All five LOX genes (LOX and LOXL1-4) were induced by gremlin. Gremlin induction of LOX genes and protein expression was blocked by TGFBR inhibitors as well as by inhibitors of the SMAD3, JNK and p38 MAPK signaling pathways. We conclude that gremlin employs both canonical TGFβ/SMAD and the non-canonical JNK and p38 MAPK signaling pathways to induce LOX genes and proteins in cultured human TM cells. Increased LOX levels may be at least partially responsible for gremlin-mediated IOP elevation and increased aqueous humor outflow resistance leading to glaucoma. 23795961 Photodissociation of Ozone from 321 to 329 nm: The Relative Yields of O((3)P2) with O2(X (3)Σg(-)), O2(a (1)Δg) and O2(b (1)Σg(+)). Product imaging of O((3)P2) following dissociation of ozone has been used to determine the relative yields of the product channels O((3)P2) + O2(X (3)Σg(-)) of ozone. All three channels are prominent at all wavelengths investigated. O2 vibrational distributions for each channel and each wavelength are also estimated assuming Boltzmann rotational distributions. Averaged over wavelength in the measured range, the yields of the O((3)P2) + O2(X (3)Σg(-)), O((3)P2) + O2(a (1)Δg), and O((3)P2) + O2(b (1)Σg(+)) channels are 0.36, 0.31,and 0.34, respectively. Photofragment distributions in the spin-allowed channel O((3)P) + O2(X (3)Σg(-)) are compared with the results of quantum mechanical calculations on the vibronically coupled PESs of the singlet states B (optically bright) and R (repulsive). The experiments suggest that considerably more vibrational excitation and less rotational excitation occur than predicted by the quantum calculations. The rotational distributions, adjusted to fit the experimental images, suggest that the dissociation takes place from a more linear configuration than the Franck-Condon bending angle of 117°. The dissociation at most wavelengths results in a positive value of the anisotropy parameter, β, both in the experiment and in the calculations. Calculations indicate that both nonadiabatic transitions and intersystem crossings substantially reduce β below the nominal value of 2. 23940024 Mystery Case: An unexpected complication of IV thrombolysis for acute ischemic stroke. A 46-year-old man with psoriasis and morbid obesity developed acute aphasia and right hemiplegia. As a result of his weakness, he had fallen and struck his right eye on a desk. His presenting examination demonstrated right periorbital ecchymosis without accompanying ptosis, expressive aphasia, left gaze deviation with corresponding hemianopsia, and dense right hemiplegia, summating an NIH Stroke Scale score of 13. 23743717 The interactive effects of physical fitness and acute aerobic exercise on electrophysiological coherence and cognitive performance in adolescents. The current study examined the effects of physical fitness and aerobic exercise on cognitive functioning and coherence of the electroencephalogram in 30 adolescents between the ages of 13 and 14 years. Participants were first classified as fit or unfit and then performed a modified Eriksen flanker task after a bout of acute exercise and after a period of relaxation. Analysis of behavioural differences between the fit and unfit groups revealed an interaction between fitness levels and acute physical exercise. Specifically, fit participants had significantly faster reaction times in the exercise condition in comparison with the rest condition; unfit, but not fit, participants had higher error rates for NoGo relative to Go trials in the rest condition. Furthermore, unfit participants had higher levels of lower alpha, upper alpha, and beta coherence in the resting condition for NoGo trials, possibly indicating a greater allocation of cognitive resources to the task demands. The higher levels of alpha coherence are of particular interest in light of its reported role in inhibition and effortful attention. The results suggest that physical fitness and acute exercise may enhance cognition by increasing the efficacy of the attentional system. 23368743 Zinc-dependent lysosomal enlargement in TRPML1-deficient cells involves MTF-1 transcription factor and ZnT4 (Slc30a4) transporter. Zinc is critical for a multitude of cellular processes, including gene expression, secretion and enzymatic activities. Cellular zinc is controlled by zinc-chelating proteins and by zinc transporters. The recent identification of zinc permeability of the lysosomal ion channel TRPML1 (transient receptor potential mucolipin 1), and the evidence of abnormal zinc levels in cells deficient in TRPML1, suggested a role for TRPML1 in zinc transport. In the present study we provide new evidence for such a role and identify additional cellular components responsible for it. In agreement with the previously published data, an acute siRNA (small interfering RNA)-driven TRPML1 KD (knockdown) leads to the build-up of large cytoplasmic vesicles positive for LysoTracker™ and zinc staining, when cells are exposed to high concentrations of zinc. We now show that lysosomal enlargement and zinc build-up in TRPML1-KD cells exposed to zinc are ameliorated by KD of the zinc-sensitive transcription factor MTF-1 (metal-regulatory-element-binding transcription factor-1) or the zinc transporter ZnT4. TRPML1 KD is associated with a build-up of cytoplasmic zinc and with enhanced transcriptional response of mRNA for MT2a (metallothionein 2a). TRPML1 KD did not suppress lysosomal secretion, but it did delay zinc leak from the lysosomes into the cytoplasm. These results underscore a role for TRPML1 in zinc metabolism. Furthermore, they suggest that TRPML1 works in concert with ZnT4 to regulate zinc translocation between the cytoplasm and lysosomes. 23861330 Cytopathology fellowship outcomes assessment: Milestones and evaluation toolboxes. The Accreditation Council for Graduate Medical Education will begin using milestones, outcomes assessment, and continuous accreditation to assess cytopathology fellowship programs. Additional assessment tools, including gynecologic cytopathology interobserver agreement between fellows and faculty, will be useful in establishing benchmarks for training cytopathologists who are competent and ready for safe independent practice. Cancer (Cancer Cytopathol) 2013. © 2013 American Cancer Society. 23961801 Using a knowledge utilization framework to explore how findings from one study can be applied to other nursing contexts. To discuss the complexities of moving research into practice and through a case example, explore how empirical findings from one specific study could be applied to nursing in other contexts. The processes of moving research findings into practice are complex and multidimensional. In this paper, an innovative approach to social support, network-focused nursing (NFN), is used as a case example to illustrate these complexities. Social support is associated with better recovery and survival after illness and based on this, a NFN programme was developed in a Danish oncology youth unit. Subsequently, a research study was undertaken to investigate the programme and based on the findings, the concept NFN was developed. A knowledge utilization framework is used to explore how empirical findings from the NFN study could be applied to nursing more generally. Aligned with this, the specific considerations for implementing NFN are explicated. Strong leadership, education, management support and effective communication are critical factors for research utilization. Moving research into practice requires openness to new ideas. Nursing and healthcare policies therefore need to support environments in which creativity and innovation can flourish. NFN was developed in teenager and young adult cancer care, but its principles may be transferable to other clinical environments. It is important that nurse managers and policy makers ensure that support and education are available to nurses to facilitate moving research into practice. Moreover, resources need to be considered, particularly in countries where financial and organizational infrastructures may be weak. 23065799 Resonance Raman spectral imaging of intracellular uptake of β-carotene loaded poly(D,L-lactide-co-glycolide) nanoparticles. The use of nanoparticles for drug delivery has been drawing considerable attention in pharmaceutical research. With increasing diversity and potential of various carrier systems, it is important to study the impact of nanocarriers on sub-cellular metabolic processes and organelles, since the delivery of a drug usually involves intra-cellular internalization. Herein, we employ Raman microscopy as a non-invasive method for cellular and sub-cellular imaging, to monitor the uptake and translocation patterns of particles based on poly(D,L-lactide-co-glycolide) over time. As the technique detects inherent signals from the molecules of interest, it does not rely on external labels or dyes, which is an advantage over fluorescence labeling. For this purpose, the particles were loaded with β-carotene. The conjugated π-system of the molecule has a large Raman scattering cross-section and gives rise to resonance Raman effects, which can enhance the sensitivity by orders of magnitude. β-Carotene as a provitamin is not soluble in water and is thus usually of low bioavailability, which is enhanced by encapsulation into the nanoparticles. 23785122 Antiviral vaccines license T cell responses by suppressing granzyme B levels in human plasmacytoid dendritic cells. Human plasmacytoid dendritic cells (pDC) are important modulators of adaptive T cell responses during viral infections. Recently, we found that human pDC produce the serine protease granzyme B (GrB), thereby regulating T cell proliferation in a GrB-dependent manner. In this study, we demonstrate that intrinsic GrB production by pDC is significantly inhibited in vitro and in vivo by clinically used vaccines against viral infections such as tick-borne encephalitis. We show that pDC GrB levels inversely correlate with the proliferative response of coincubated T cells and that GrB suppression by a specific Ab or a GrB substrate inhibitor results in enhanced T cell proliferation, suggesting a predominant role of GrB in pDC-dependent T cell licensing. Functionally, we demonstrate that GrB(high) but not GrB(low) pDC transfer GrB to T cells and may degrade the ζ-chain of the TCR in a GrB-dependent fashion, thereby providing a possible explanation for the observed T cell suppression by GrB-expressing pDC. Modulation of pDC-derived GrB activity represents a previously unknown mechanism by which both antiviral and vaccine-induced T cell responses may be regulated in vivo. Our results provide novel insights into pDC biology during vaccinations and may contribute to an improvement of prophylactic and therapeutic vaccines. 23795791 Renal function and cardiovascular outcomes after living donor nephrectomy in the UK: quality and safety revisited. To determine renal function and cardiovascular outcomes after living donor nephrectomy (LDN). Living donor kidney transplantation has become established as the treatment of choice for end-stage renal failure. Benefits to the recipient have to be balanced against perioperative and long-term health risks to the donor. The UK Transplant Registry (UKTR) was used to identify 4586 living donors who had donated a kidney for transplantation in the UK between 2001 and 2008. This study was conducted with the consent and support of the NHS Blood and Transplant (NHSBT) Kidney and Pancreas Research Group. The mean glomerular filtration rate (GFR) fell from 103 mL/min/1.73 m(2) before LDN to 58 mL/min/1.73 m(2) 1 year after LDN. At 1 year after LDN 60% of donors had a GFR of <60 mL/min/1.73 m(2). A GFR of <60 mL/min/1.73 m(2) after LDN was associated with older age, females, lower GFR before LDN, White ethnicity, earlier LDN period, unrelated donor type and body mass index of >25 kg/m(2). Over a 2-year period after LDN there was an overall mortality rate of 0.39%, cardiovascular death in one patient (mortality rate of 0.02%) and a major cardiovascular event rate of 0.44%. In this study we show that mild renal dysfunction is common after LDN; however, due to the short duration of follow-up we are unable to comment on whether this subsequently leads to an increased risk of developing of cardiovascular disease. 23897032 Dynamics of exocyclic groups in the Escherichia coli O91 O-antigen polysaccharide in solution studied by carbon-13 NMR relaxation. Carbon-13 relaxation data are reported for exocyclic groups of hexopyranosyl sugar residues in the repeating unit within the Escherichia coli O91 O-antigen polysaccharide in a dilute D2O solution. The measurements of T 1, T 2 and heteronuclear nuclear Overhauser enhancements were carried out at 310 K at two magnetic fields (16.4 T, 21.1 T). The data were analyzed using the standard and extended Lipari-Szabo models, as well as a conformational jump model. The extended version of the Lipari-Szabo and the two-site jump models were most successful for the hydroxymethyl groups of Gal and GlcNAc sugar residues. Different dynamics was found for the hydroxymethyl groups associated with different configurations (D-gluco, D-galacto) of the sugar residues, the latter being faster than the former. 23856621 Advances in Molecular Modeling of Human Cytochrome P450 Polymorphism. Cytochrome P450 (CYP) is a supergene family of metabolizing enzymes involved in the phase I metabolism of drugs and endogenous compounds. CYP oxidation often leads to inactive drug metabolites or to highly toxic or carcinogenic metabolites involved in adverse drug reactions (ADR). During the last decade, the impact of CYP polymorphism in various drug responses and ADR has been demonstrated. Of the drugs involved in ADR, 56% are metabolized by polymorphic phase I metabolizing enzymes, 86% among them being CYP. Here, we review the major CYP polymorphic forms, their impact for drug response and current advances in molecular modeling of CYP polymorphism. We focus on recent studies exploring CYP polymorphism performed by the use of sequence-based and/or protein-structure-based computational approaches. The importance of understanding the molecular mechanisms related to CYP polymorphism and drug response at the atomic level is outlined. 23727667 Simple spectrophotometric method for determination of melamine in liquid milks based on green Mannich reaction. A new and simple spectrophotometric method has been developed and validated for measuring the contamination of melamine in different milk products. The method is based upon measuring the absorption of the complex formed from melamine, 4-hydroxyacetophenone (Hap) and 1-pyrene carboxaldehyde (Pcd), which was adapted from the Mannich reaction. Quantitative analysis was done at a wavelength of 236nm within a few minutes. The reaction was optimized by focusing on both obtaining high performance of the method and to concern the volatility and toxicity of used reagents. This method provided a linear dynamic range, limit of detection and limit of quantification of 0.100-3.78, 0.08 and 0.14mgL(-1), respectively. The relative standard deviation (RSD) was 3.6% (n=10). The recoveries of melamine spiked liquid milk samples, with melamine concentrations of 0.63, 1.26, 1.89 and 2.52mgL(-1), were 87.7±3.7%, 91.1±8.8%, 89.2±4.4% and 90.6±3.6% (n=3), respectively. 23913616 Stent-assisted coil embolization of coronary artery aneurysm. Coronary artery aneurysms are uncommon diseases with potential complications including rupture and ischemia from embolic events or thrombosis. No consensus has been established regarding the optimal therapy for coronary artery aneurysms. Percutaneous catheter-based treatments using membrane-covered stents and coil embolization have been described. However, only few reports of stent-assisted coil embolization for coronary artery aneurysms have been published to date. Therefore, we report a case of coronary artery aneurysm successfully treated with stent-assisted coil embolization. 23153547 New developments in the pharmacological modulation of wound healing after glaucoma filtration surgery. Despite the advent of many new devices for glaucoma surgery, scarring is the main cause of suboptimal pressure control and surgical failure in all forms of surgery. The cytotoxic antimetabolites, 5-flurouracil and mitomycin C both prolong success but with the increased risk of blinding complications. A greater understanding of the cellular mechanisms of the wound healing response has led to the identification and modulation of potential therapeutic targets. These include transforming factor β, inflammatory mediators, the acute phase protein serum amyloid P, vascular endothelial growth factor and the matrix metallaproteinases. While optimal drug delivery is still a major challenge, modulating these effects either directly or through downstream signalling promises to yield anti-scarring efficacy, while minimising side effects. 23490587 Peripubertal female athletes in high-impact sports show improved bone mass acquisition and bone geometry. OBJECTIVE: Intensive physical training may have a sport-dependent effect on bone mass acquisition. This cross-sectional study evaluated bone mass acquisition in girls practicing sports that put different mechanical loads on bone. MATERIALS/METHODS: Eighty girls from 10.7 to 18.0years old (mean 13.83±1.97) were recruited: 20 artistic gymnasts (AG; high-impact activity), 20 rhythmic gymnasts (RG; medium-impact activity), 20 swimmers (SW, no-impact activity), and 20 age-matched controls (CON; leisure physical activity <3h/wk). Areal bone mineral density (aBMD) was determined using DEXA. Hip structural analysis applied at the femur evaluated cross-sectional area (CSA, cm(2)), section modulus (Z, cm(3)), and buckling ratio. Bone turnover markers and OPG/RANKL levels were analyzed. RESULTS: AG had higher aBMD than SW and CON at all bone sites and higher values than RG in the lumbar spine and radius. RG had higher aBMD than SW and CON only in the femoral region. CSA and mean cortical thickness were significantly higher and the buckling ratio was significantly lower in both gymnast groups compared with SW and CON. In RG only, endocortical diameter and width were reduced, while Z was only increased in AG compared with SW and CON. Reduced bone remodeling was observed in RG compared with AG only when groups were subdivided according to menarcheal status. All groups showed similar OPG concentrations, while RANKL concentrations increased with age and were decreased in SW. CONCLUSION: High-impact activity clearly had a favorable effect on aBMD and bone geometry during the growth period, although the bone health benefits seem to be more marked after menarche. 23499735 Angiotensin-(1-7) inhibits autophagy in the brain of spontaneously hypertensive rats. Autophagy is an important cellular process that mediates lysosomal degradation of damaged organelles, which is activated in response to a variety of stress-related diseases, including hypertension. The basal level of autophagy plays an important role in the maintenance of cellular homeostasis, whereas excessive autophagic activity leads to cell death and is considered as a contributing factor to several disorders. Recent works have demonstrated that Angiotensin-(1-7) [Ang-(1-7)] exerted its neuroprotective effects by modulating classic components of renin-angiotensin system associated with reducing oxidative stress and apoptosis in brains of spontaneously hypertensive rats (SHRs). However, the effect of Ang-(1-7) on autophagic activity in brain of hypertensive individual remains unclear. In this study, Wistar-Kyoto rats received intracerebroventricular (I.C.V.) infusion of artificial cerebrospinal fluid (aCSF) while SHRs received I.C.V. infusion of aCSF, Ang-(1-7), Mas receptor antagonist A-779, or angiotensin II type 2 receptor antagonist PD123319 for 4 weeks. Brain tissues were collected and analyzed by western blotting analysis, immunofluorescence assay, and transmission electron microscopic examination. Our study showed that infusion of Ang-(1-7) for 4 weeks inhibited the increase of microtubule-associated protein 1 light chain 3 (LC3)-II and Beclin-1 levels, as well as the autophagosome formation in SHR brain. Meanwhile, the reduction of p62 expression in SHR brain was also reversed by Ang-(1-7). Of note, the anti-autophagic effects of Ang-(1-7) were independent of blood pressure reduction and can be inhibited by A-779 and PD123319. These findings suggest that treatment with Ang-(1-7) may be useful to prevent hypertension-induced excessive autophagic activation in brain. 23937659 Direct Catalytic Asymmetric Reductive Amination of Simple Aromatic Ketones. A green method for chiral amine synthesis, the direct catalytic asymmetric reductive amination, was developed. Phenylhydrazide is an ideal nitrogen source for reductive amination. Molecular sieves play dual roles in this reaction. They help to remove H2O to form imine, as well as promote an imine reduction. f-Binaphane minimizes the inhibition effect from amines and helps the coordination of sterically demanding imines to the iridium center, thus leading to a smooth reaction. 23709268 A Model of the Membrane-bound Cytochrome b5-Cytochrome P450 Complex from NMR and Mutagenesis Data. Microsomal cytochrome b5 (cytb5) is a membrane-bound protein that modulates the catalytic activity of its redox partner, cytochrome P4502B4 (cytP450). Here, we report the first structure of full-length rabbit ferric microsomal cytb5 (16 kDa), incorporated in two different membrane mimetics (detergent micelles and lipid bicelles). Differential line broadening of the cytb5 NMR resonances and site-directed mutagenesis data were used to characterize the cytb5 interaction epitope recognized by ferric microsomal cytP450 (56 kDa). Subsequently, a data-driven docking algorithm, HADDOCK (high ambiguity driven biomolecular docking), was used to generate the structure of the complex between cytP4502B4 and cytb5 using experimentally derived restraints from NMR, mutagenesis, and the double mutant cycle data obtained on the full-length proteins. Our docking and experimental results point to the formation of a dynamic electron transfer complex between the acidic convex surface of cytb5 and the concave basic proximal surface of cytP4502B4. The majority of the binding energy for the complex is provided by interactions between residues on the C-helix and β-bulge of cytP450 and residues at the end of helix α4 of cytb5. The structure of the complex allows us to propose an interprotein electron transfer pathway involving the highly conserved Arg-125 on cytP450 serving as a salt bridge between the heme propionates of cytP450 and cytb5. We have also shown that the addition of a substrate to cytP450 likely strengthens the cytb5-cytP450 interaction. This study paves the way to obtaining valuable structural, functional, and dynamic information on membrane-bound complexes. 23830970 Compulsory drug detention in East and Southeast Asia: Evolving government, UN and donor responses. According to official accounts, more than 235,000 people are detained in over 1000 compulsory drug detention centers in East and South East Asia. Individuals in such centers are held for periods of months to years, and can experience a wide range of human rights abuses, including violation of the rights to freedom from torture and cruel, inhuman and degrading treatment; freedom from arbitrary arrest and detention; a fair trial; privacy; the highest attainable standard of health; and freedom from forced labor. Since 2010, an increasing number of United Nations agencies, human rights experts, and others have expressed concerns about rights abuses associated with compulsory drug detention centers, and since 2012, called for their closure. Although they do not represent a complete break from the past, these calls mark a significant shift from past engagement with drug detention, which included direct and indirect funding of detention centers and activities in detention centers by some donors. However, the lack of transparent governance, restrictions on free speech and prohibitions on monitoring by independent, international human rights organizations make assessing the evolving laws, policies and practices, as well as the attitudes of key governments officials, difficult. Looking specifically at publicly announced reforms and statements by government officials in China, Cambodia, Vietnam and Lao PDR reveals possible improvements in respect for the rights of drug users, and on-going challenges. 22687556 Environmental impact assessment of radionuclide and metal contamination at the former U sites Taboshar and Digmai, Tajikistan. Uranium (U) ore mining and processing were initiated in the former Soviet Republics of Tajikistan after the Second World War as part of the USSR nuclear weapon programme. The U mine in Taboshar was opened in 1936, and mining took place from 1945 to 1965, while the Digmai tailings dump was exploited during 1963-1993. The mining, milling and extraction activities have resulted in large amounts of waste rock deposits and U tailing materials placed in the vicinity of inhabited areas. To assess the environmental impact of radionuclides and trace metals in the Taboshar and Digmai mining and tailing sites in Tajikistan, field expeditions were performed in 2006 and 2008. In addition to in situ gamma and radon dose rate measurements, sampling of water, fish, sediments, soils and vegetation including in situ fractionation of water were performed. The U concentrations in water from Taboshar Pit Lake (2.0 mg U/L) were higher than in waters collected in the Digmai area. The Pit Lake and the stream water from the tailing mountain were also characterised by elevated concentrations of As, Mo, Mn and Fe, exceeding the WHO recommended values for drinking water. Uranium, As, Mo and Ni were present as low molecular mass species in the waters, and are therefore considered mobile and potentially bioavailable. The (238)U concentrations in sediments and soils varied between the sites; with peak concentrations (6 kBq/kg dw) in sediments from the Pit Lake, while the soil concentrations were significantly lower (296-590 Bq/kg dw). In contrast, high levels of the radium isotopes ((226)Ra and (228)Ra) were found in the Digmai soil (17-32 kBq/kg dw). Based on sequential extraction results, both U and Pb were found to be quite mobile at the Pit Lake site, showing that these elements were associated with the pH sensitive and redox sensitive amorphous fractions. In tailings, U was found to be quite mobile, but here Pb was rather inert. The transfer of radionuclides and metals from sediments to waters was in general low. In the Pit Lake, U was quite mobile (Kd = 90 L/kg), followed by Ni (1.5 Ã— 10(3) L/kg) and As (6 Ã— 10(3) L/kg), Cu and Cd (1.5 Ã— 10(4) L/kg), while Pb (3 Ã— 10(5) L/kg) was rather inert. The transfer from soil to plant, TFs (kg/kg dw), was in general low, while the bioconcentration factor for water living Poaceae and for fish from water was relatively high (Pb 1.8 Ã— 10(5) and Cd 1 Ã— 10(4)). These legacy sites, containing enhanced levels of natural radioactive material (TENORM) as well as heavy metals, may represent a hazard having a potential radiological and chemical impact on man and the environment, and measures should be taken to reduce the environmental risk to man and biota. 23880933 Proteomic investigation of the sinulariolide-treated melanoma cells A375: effects on the cell apoptosis through mitochondrial-related pathway and activation of caspase cascade. Sinulariolide is an active compound isolated from the cultured soft coral Sinularia flexibilis. In this study, we investigated the effects of sinulariolide on A375 melanoma cell growth and protein expression. Sinulariolide suppressed the proliferation and migration of melanoma cells in a concentration-dependent manner and was found to induce both early and late apoptosis by flow cytometric analysis. Comparative proteomic analysis was conducted to investigate the effects of sinulariolide at the molecular level by comparison between the protein profiles of melanoma cells treated with sinulariolide and those without treatment. Two-dimensional gel electrophoresis (2-DE) master maps of control and treated A375 cells were generated by analysis with PDQuest software. Comparison between these maps showed up- and downregulation of 21 proteins, seven of which were upregulated and 14 were downregulated. The proteomics studies described here identify some proteins that are involved in mitochondrial dysfunction and apoptosis-associated proteins, including heat shock protein 60, heat shock protein beta-1, ubiquinol cytochrome c reductase complex core protein 1, isocitrate dehydrogenase (NAD) subunit alpha (down-regulated), and prohibitin (up-regulated), in A375 melanoma cells exposed to sinulariolide. Sinulariolide-induced apoptosis is relevant to mitochondrial-mediated apoptosis via caspase-dependent pathways, elucidated by the loss of mitochondrial membrane potential, release of cytochrome c, and activation of Bax, Bad and caspase-3/-9, as well as suppression of p-Bad, Bcl-xL and Bcl-2. Taken together, our results show that sinulariolide-induced apoptosis might be related to activation of the caspase cascade and mitochondria dysfunction pathways. Our results suggest that sinulariolide merits further evaluation as a chemotherapeutic agent for human melanoma. 23415795 Cryptosporidial infection in children with inflammatory bowel disease. Cryptosporidiosis is usually a self-limiting illness in healthy patients. However, it can cause severe life threatening complications in immunocompromised patients. The effect of cryptosporidial infection on inflammatory bowel disease (IBD) has not been well studied and available literature is largely restricted to adult case reports. The purpose of this study is to describe the clinical characteristics of cryptosporidial infection in children with IBD. Stool studies from children with IBD presenting with presumed relapse during the period 2005-2011 were reviewed retrospectively. Cryptosporidial infection was diagnosed by stool enzyme immunoassay. An age matched control group of IBD patients without cryptosporidial infection was used for comparison. Medical records of 170 IBD patients were reviewed and a total of 149 presumed relapses were identified. Cryptosporidial infection was found in seven of the 39 patients with positive stool studies (four ulcerative colitis/three Crohn's disease) presenting with relapse. The median age was 13years (range: 3-17) and five patients were female. The median duration of the IBD was 18months (range 2-48months). All but one patient had stable disease prior to acquiring infection. Five patients required hospitalization due to significant dehydration. Three of the five patients treated with nitazoxanide had significant clinical improvement in 3days. All patients had complete resolution of symptoms by three weeks and no infection related complications were noted. In comparison to patients with cryptosporidial infection, the control group required an increased need for escalation of therapy (71% vs. 0.0%, p=001) and higher re-hospitalization rates (24% Vs.0.0%, p=0.54) within 6months following indexed relapse. In IBD patients, cryptosporidiosis can cause significant illness leading to increased need for hospitalization. In the absence of appropriate stool studies, cryptosporidiosis can be misdiagnosed as disease relapse and lead to inappropriate therapy. Nitazoxanide appears to be effective along with supportive therapy. 23763302 Boron-doped diamond electrodes for the electrochemical oxidation and cleavage of peptides. Electrochemical oxidation of peptides and proteins is traditionally performed on carbon-based electrodes. Adsorption caused by the affinity of hydrophobic and aromatic amino acids toward these surfaces leads to electrode fouling. We compared the performance of boron-doped diamond (BDD) and glassy carbon (GC) electrodes for the electrochemical oxidation and cleavage of peptides. An optimal working potential of 2000 mV was chosen to ensure oxidation of peptides on BDD by electron transfer processes only. Oxidation by electrogenerated OH radicals took place above 2500 mV on BDD, which is undesirable if cleavage of a peptide is to be achieved. BDD showed improved cleavage yield and reduced adsorption for a set of small peptides, some of which had been previously shown to undergo electrochemical cleavage C-terminal to tyrosine (Tyr) and tryptophan (Trp) on porous carbon electrodes. Repeated oxidation with BDD electrodes resulted in progressively lower conversion yields due to a change in surface termination. Cathodic pretreatment of BDD at a negative potential in an acidic environment successfully regenerated the electrode surface and allowed for repeatable reactions over extended periods of time. BDD electrodes are a promising alternative to GC electrodes in terms of reduced adsorption and fouling and the possibility to regenerate them for consistent high-yield electrochemical cleavage of peptides. The fact that OH-radicals can be produced by anodic oxidation of water at elevated positive potentials is an additional advantage as they allow another set of oxidative reactions in analogy to the Fenton reaction, thus widening the scope of electrochemistry in protein and peptide chemistry and analytics. 23523582 How to improve care in outpatients with cirrhosis and ascites: A new model of care coordination by consultant hepatologists. The development of ascites in patients with cirrhosis is associated with a high rate of health care utilization. New models of specialized caregiving support are necessary to optimize its management. The aim of the study was to evaluate the efficacy and financial sustainability of the "Care management check-up" as a new model of specialized caregiving support based on a series of diagnostic facilities performed in real time and on the integrated activity of consultant hepatologists at the hospital unit for outpatients, dedicated nurses, physicians in training and primary physicians, compared to standard care in outpatients with cirrhosis and ascites. 100 cirrhotic patients admitted to our hospital were allocated, after discharge, to the "Care management check-up" group (group 1), or to the "Standard outpatient care" group (group 2), and followed prospectively as outpatients up to death or for at least 12months. Patients of the two groups could also access to a "Day hospital" when an invasive procedure was required. In group 1, the "Care management check-up" and the "Day hospital" taken together defined the "Care management program". Twelve-month mortality was higher in group 2 than in group 1 (45.7% vs. 23.1%, p<0.025). The rate of 30-day readmission was also higher in group 2 (42.4% vs. 15.4%, p<0.01). The global cost attributable to the management per patient-month of life was lower (1479.19±2184.43€) in group 1 than (2816.13±3893.03€) in group 2 (p<0.05). The study suggests that this new model of specialized caregiving reduces 12-month mortality in patients with cirrhosis and ascites as well as the global health care costs for their management. 23846102 Wetting of porous solids. This paper presents a simple, three stage method to simulate the mechanics of wetting of porous solid objects, like sponges and cloth, when they interact with a fluid. In the first stage, we model the absorption of fluid by the object when it comes in contact with the fluid. In the second stage, we model the transport of absorbed fluid inside the object, due to diffusion, as a flow in a deforming, unstructured mesh. The fluid diffuses within the object depending on saturation of its various parts and other body forces. Finally, in the third stage, oversaturated parts of the object shed extra fluid by dripping. The simulation model is motivated by the physics of imbibition of fluids into porous solids in the presence of gravity. It is phenomenologically capable of simulating wicking and imbibition, dripping, surface flows over wet media, material weakening, and volume expansion due to wetting. The model is inherently mass conserving and works for both thin 2D objects like cloth and for 3D volumetric objects like sponges. It is also designed to be computationally efficient and can be easily added to existing cloth, soft body, and fluid simulation pipelines. 23122063 Preparative separation and purification of sulforaphene from radish seeds by high-speed countercurrent chromatography. Sulforaphene, a kind of isothiocyanates, derived from glucoraphenin which is the important ingredient of radish (Raphanus sativus L.) seeds, has shown significant pharmacological activities. In this paper, the separation and purification of sulforaphene from radish seeds, was achieved by high-speed countercurrent chromatography (HSCCC). A two-phase solvent system consisted of n-hexane-ethyl acetate-methanol-water (35:100:35:100, v/v/v/v) was applied. The revolution speed of the separation column, flow rate of the mobile phase and separation temperature were 800 rpm, 2 ml/min and 30°C, respectively. From about 1000 mg amount of the crude plant extract, 249.4 mg of pure sulforaphene was obtained by one-step separation on a 280 ml HSCCC column. The purified sulforaphene was at a high purity of 96.9% and the mass recovery was more than 95%. The purity of sulforaphene was determined by HPLC analysis and its chemical structure was assessed by MS, (1)H NMR, (13)C NMR and DEPT-135 NMR. 23427872 Composite lymphoma of nodular lymphocyte-predominant and classical Hodgkin lymphoma-Epstein-Barr virus association suggests divergent pathogenesis despite clonal relatedness. Nodular lymphocyte-predominant Hodgkin lymphoma and classical Hodgkin lymphoma are considered 2 distinct entities whose co-occurrence in 1 patient is extremely rare. We report a case of nodular lymphocyte-predominant Hodgkin lymphoma and classical Hodgkin lymphoma concurrently affecting the same lymph nodes in a 48-year-old male patient. Amplification and sequencing of the rearranged immunoglobulin heavy chain genes in tumor cells isolated by laser-assisted microdissection revealed identical variable, diverse and joining segment rearrangements and somatic hypermutation events, demonstrating a clonal relationship between the 2 lymphomas. The Epstein-Barr virus-encoded RNA and latent membrane protein 1 were present in the Hodgkin/Reed-Sternberg cells of the classical Hodgkin lymphoma but not in the tumor cells of the nodular lymphocyte-predominant Hodgkin lymphoma, pointing to a common precursor cell but differences in the early steps of pathogenesis. 23690044 Development of a chloroplast DNA marker for monitoring of transgene introgression in Brassica napus L. Chloroplast molecular markers can provide useful information for high-resolution analysis of inter- and intra-specific variation in Brassicaceae and for differentiation between its species. Combining data generated from nuclear and chloroplast markers enables the study of seed and pollen movement, and assists in the assessment of gene-flow from genetically modified (GM) plants through hybridization studies. To develop chloroplast DNA markers for monitoring of transgene introgression in Brassica napus L., we searched for sequence variations in the chloroplast (cp) genome, and developed a simple cpDNA marker that is reliable, time-saving, and easily discriminates among 4 species (B. napus, B. rapa, Raphanus sativus, and Sinapis alba) based on PCR-product length polymorphism. This marker will be useful to identify maternal lineages and to estimate transgene movement of GM canola. 23335345 Factors associated with attrition in a longitudinal rheumatoid arthritis registry. Loss of participants in longitudinal data collection can affect the validity of outcomes in rheumatoid arthritis (RA) registries. Prior research indicates that demographics and socioeconomic and psychosocial factors contribute to attrition. This study analyzed the characteristics of an RA registry that may contribute to attrition in a hospital-based population. Subjects consisted of RA patients enrolled in the Brigham and Women's Rheumatoid Arthritis Sequential Study. Demographics and clinical and psychological factors were evaluated in univariate analyses to determine differences between participants who dropped out and those who completed 5 years of followup. Univariate factors with a P value <0.1 were used in a survival analysis to determine significant factors associated with attrition. A secondary analysis looked at patients who dropped out during the first year. A total of 1,144 RA participants were enrolled (509 completed 5 years of followup, 227 were still actively enrolled, and 408 dropped out). The attrition rate was 4.31% per 6-month cycle. Shorter disease duration, higher disease activity (3-variable Disease Activity Score in 28 joints using the C-reactive protein level), less education, RA drug therapy, and lower arthritis self-efficacy were statistically significant in multivariate survival analyses. In a secondary analysis, sex and age were the only additional factors found that contributed to attrition. The attrition rate for this registry was similar to rates reported by other registries. Shorter disease duration, higher disease activity, and several other socioeconomic factors were associated. Men and younger patients tended to drop out during the first year. Population differences in each registry may result in different attrition patterns and ultimately, each longitudinal registry should consider conducting its own analyses. 23896386 Comparing the effect of auditory-only and auditory-visual modes in two groups of Persian children using cochlear implants: A randomized clinical trial. Since the introduction of cochlear implantation, researchers have considered children's communication and educational success before and after implantation. Therefore, the present study aimed to compare auditory, speech, and language development scores following one-sided cochlear implantation between two groups of prelingual deaf children educated through either auditory-only (unisensory) or auditory-visual (bisensory) modes. A randomized controlled trial with a single-factor experimental design was used. The study was conducted in the Instruction and Rehabilitation Private Centre of Hearing Impaired Children and their Family, called Soroosh in Shiraz, Iran. We assessed 30 Persian deaf children for eligibility and 22 children qualified to enter the study. They were aged between 27 and 66 months old and had been implanted between the ages of 15 and 63 months. The sample of 22 children was randomly assigned to two groups: auditory-only mode and auditory-visual mode; 11 participants in each group were analyzed. In both groups, the development of auditory perception, receptive language, expressive language, speech, and speech intelligibility was assessed pre- and post-intervention by means of instruments which were validated and standardized in the Persian population. No significant differences were found between the two groups. The children with cochlear implants who had been instructed using either the auditory-only or auditory-visual modes acquired auditory, receptive language, expressive language, and speech skills at the same rate. Overall, spoken language significantly developed in both the unisensory group and the bisensory group. Thus, both the auditory-only mode and the auditory-visual mode were effective. Therefore, it is not essential to limit access to the visual modality and to rely solely on the auditory modality when instructing hearing, language, and speech in children with cochlear implants who are exposed to spoken language both at home and at school when communicating with their parents and educators prior to and after implantation. The trial has been registered at IRCT.ir, number IRCT201109267637N1. 23397934 Busy lifestyles and mammography screening: Time pressure and women's reattendance likelihood. Time pressure is often cited as a reason for non-attendance at mammography screening, although evidence from other areas of psychology suggests that time pressure can improve performance when barriers such as time pressure provide a challenge. We predicted that time pressure would negatively predict attendance in women whose self-efficacy for overcoming time pressure is low, but positively predict attendance when self-efficacy is high. Time pressure was operationalised as the self-reported number of dependent children and others, and average number of working hours per week. Australian women were surveyed after being invited to attend second or subsequent screenings at a free public screening service, and subsequent attendance monitored until six months after screening was due. The majority (87.5%) attended screening. Women with more dependent children and higher self-efficacy showed greater attendance likelihood, and women with fewer non-child dependants and lower self-efficacy were less likely to attend. Working hours did not predict attendance. Findings provide partial support for the idea that time pressure acts as a challenge for women with high self-efficacy. 23946468 Selective targeting of the cysteine proteome by thioredoxin and glutathione redox systems. Thioredoxin (Trx) and GSH are the major thiol antioxidants protecting cells from oxidative stress-induced cytotoxicity. Redox states of Trx and GSH have been used as indicators of oxidative stress. Accumulating studies suggest that Trx and GSH redox systems regulate cell signaling and metabolic pathways differently and independently during diverse stressful conditions. In the current study, we used a mass spectrometry-based redox proteomics approach to test responses of the cysteine (Cys) proteome to selective disruption of the Trx- and GSH-dependent systems. Auranofin (ARF) was used to inhibit Trx reductase without detectable oxidation of the GSH/GSSG couple, and buthionine sulfoximine (BSO) was used to deplete GSH without detectable oxidation of Trx1. Results for 606 Cys-containing peptides (peptidyl Cys) showed that 36% were oxidized more than 1.3-fold by ARF, while BSO-induced oxidation of peptidyl Cys was only 10%. Mean fold oxidation of these peptides was also higher by ARF than BSO treatment. Analysis of potential functional pathways showed that ARF oxidized peptides associated with glycolysis, cytoskeleton remodeling, translation and cell adhesion. Of 60 peptidyl Cys oxidized due to depletion of GSH, 41 were also oxidized by ARF and included proteins of translation and cell adhesion but not glycolysis or cytoskeletal remodeling. Studies to test functional correlates showed that pyruvate kinase activity and lactate levels were decreased with ARF but not BSO, confirming the effects on glycolysis-associated proteins are sensitive to oxidation by ARF. These data show that the Trx system regulates a broader range of proteins than the GSH system, support distinct function of Trx and GSH in cellular redox control, and show for the first time in mammalian cells selective targeting peptidyl Cys and biological pathways due to deficient function of the Trx system. 23967010 GraphML specializations to codify ancestral recombinant graphs. Software which simulates, infers, or analyzes ancestral recombination graphs (ARGs) faces the problem of communicating them. Existing formats omit information either about the location of recombinations along the chromosome or the position of recombinations relative to the branching topology. We present a specialization of GraphML, an XML-based standard for mathematical graphs, for communication of ARGs. The GraphML type is specialized to contain the node type, time, recombination location, and name. The GraphML type is specialized to contain the ancestral material passed along that edge. This approach, which we call ArgML, retains all information in the original ARG. Due to its use of established formats ArgML can be parsed, checked and displayed by existing software. 23671024 Design and synthesis of 4-(2,4,5-trifluorophenyl)butane-1,3-diamines as dipeptidyl peptidase IV inhibitors. The worldwide prevalence of diabetes has spurred numerous studies on the development of new antidiabetic medicines. As a result, dipeptidyl peptidase IV (DPP4) has been recognized as a validated target. In our efforts to discover new DPP4 inhibitors, we analyzed the complexed structures of DPP4 available in Protein Data Bank and designed a series of triazole compounds. After enzyme activity assays and crystallographic verification of the binding interaction patterns, we found that the triazole compounds can inhibit DPP4 with micromolar IC50 values. Liver microsome stability and cytochrome P450 metabolic tests were performed on this series, revealing undesirable pharmacokinetic profiles for the triazole compounds. To overcome this liability, we substituted the triazole ring with an amide or urea group to produce a new series of DPP4 inhibitors. Based on its enzyme activity, metabolic stability, and selectivity over DPP8 and DPP9, we selected compound 21 r for further study of its in vivo effects in mice using an oral glucose tolerance test (OGTT). The results show that 21 r has efficacy similar to that of sitagliptin at a dose of 3 mg kg(-1) . The crystal structure of 21 r bound to DPP4 also reveals that the trifluoromethyl group is directed toward a subpocket different from the subsite bound by sitagliptin, providing clues for the design of new DPP4 inhibitors. 23883409 Pseudonymization of patient identifiers for translational research. The usage of patient data for research poses risks concerning the patients' privacy and informational self-determination. Next-generation-sequencing technologies and various other methods gain data from biospecimen, both for translational research and personalized medicine. If these biospecimen are anonymized, individual research results from genomic research, which should be offered to patients in a clinically relevant timeframe, cannot be associated back to the individual. This raises an ethical concern and challenges the legitimacy of anonymized patient samples. In this paper we present a new approach which supports both data privacy and the possibility to give feedback to patients about their individual research results. We examined previously published privacy concepts regarding a streamlined de-pseudonymization process and a patient-based pseudonym as applicable to research with genomic data and warehousing approaches. All concepts identified in the literature review were compared to each other and analyzed for their applicability to translational research projects. We evaluated how these concepts cope with challenges implicated by personalized medicine. Therefore, both person-centricity issues and a separation of pseudonymization and de-pseudonymization stood out as a central theme in our examination. This motivated us to enhance an existing pseudonymization method regarding a separation of duties. The existing concepts rely on external trusted third parties, making de-pseudonymization a multistage process involving additional interpersonal communication, which might cause critical delays in patient care. Therefore we propose an enhanced method with an asymmetric encryption scheme separating the duties of pseudonymization and de-pseudonymization. The pseudonymization service provider is unable to conclude the patient identifier from the pseudonym, but assigns this ability to an authorized third party (ombudsman) instead. To solve person-centricity issues, a collision-resistant function is incorporated into the method. These two facts combined enable us to address essential challenges in translational research. A productive software prototype was implemented to prove the functionality of the suggested translational, data privacy-preserving method. Eventually, we performed a threat analysis to evaluate potential hazards connected with this pseudonymization method. The proposed method offers sustainable organizational simplification regarding an ethically indicated, but secure and controlled process of de-pseudonymizing patients. A pseudonym is patient-centered to allow correlating separate datasets from one patient. Therefore, this method bridges the gap between bench and bedside in translational research while preserving patient privacy. Assigned ombudsmen are able to de-pseudonymize a patient, if an individual research result is clinically relevant. 23664228 Anesthetic emergencies in oral surgery: malignant hyperthermia, endocrinopathy, and neurologic events. Despite the impressive safety of office-based anesthesia, serious emergencies still occur. Early and appropriate treatment is likely to improve outcomes. This article discusses selected emergencies with backgrounds and rationale for emergent treatment. 23339339 Graphene nanoribbons as an advanced precursor for making carbon fiber. Graphene oxide nanoribbons (GONRs) and chemically reduced graphene nanoribbons (crGNRs) were dispersed at high concentrations in chlorosulfonic acid to form anisotropic liquid crystal phases. The liquid crystal solutions were spun directly into hundreds of meters of continuous macroscopic fibers. The relationship of fiber morphology to coagulation bath conditions was studied. The effects of colloid concentration, annealing temperature, spinning air gap, and pretension during annealing on the fibers' performance were also investigated. Heat treatment of the as-spun GONR fibers at 1500 °C produced thermally reduced graphene nanoribbon (trGNR) fibers with a tensile strength of 378 MPa, Young's modulus of 36.2 GPa, and electrical conductivity of 285 S/cm, which is considerably higher than that in other reported graphene-derived fibers. This better trGNR fiber performance was due to the air gap spinning and annealing with pretension that produced higher molecular alignment within the fibers, as determined by X-ray diffraction and scanning electron microscopy. The specific modulus of trGNR fibers is higher than that of the commercial general purpose carbon fibers and commonly used metals such as Al, Cu, and steel. The properties of trGNR fibers can be further improved by optimizing the spinning conditions with higher draw ratio, annealing conditions with higher pretensions, and using longer flake GONRs. This technique is a new high-carbon-yield approach to make the next generation carbon fibers based on solution-based liquid crystal phase spinning. 23904619 Short-term learning induces white matter plasticity in the fornix. Magnetic resonance imaging (MRI) has greatly extended the exploration of neuroplasticity in behaving animals and humans. Imaging studies recently uncovered structural changes that occur in gray and white matter, mainly after long-term training. A recent diffusion tensor imaging (DTI) study showed that training in a car racing game for 2 h induces changes in the hippocampus and parahippocampal gyri. However, the effect of short-term training on the white matter microstructure is unknown. Here we investigated the influence of short learning tasks on structural plasticity in the white matter, and specifically in the fornix, in humans and rats. Human subjects performed a 2 h spatial learning task, and rats underwent training for 1 d in a Morris water maze. Between tasks, subjects were scanned with DTI, a diffusion MRI framework sensitive to tissue microstructure. Using tract-based spatial statistics, we found changes in diffusivity indices in both humans and rats. In both species, changes in diffusion in the fornix were correlated with diffusion changes in the hippocampus, as well as with behavioral measures of improvement in the learning tasks. These results, which provide the first indication of short-term white matter plasticity in the human brain, suggest that the adult brain white matter preserves dynamic characteristics and can be modified by short-term learning experiences. The extent of change in white matter was correlated with their extent in gray matter, suggesting that all components of the neural network are capable of rapid remodeling in response to cognitive experiences. 23534618 Effect of surface charge density on the affinity of oxide nanoparticles for the vapor-water interface. Using in-situ X-ray photoelectron spectroscopy at the vapor-water interface, the affinity of nanometer-sized silica colloids to adsorb at the interface is shown to depend on colloid surface charge density. In aqueous suspensions at pH 10 corrected Debye-Hückel theory for surface complexation calculations predict that smaller silica colloids have increased negative surface charge density that originates from enhanced screening of deprotonated silanol groups (≡Si-O(-)) by counterions in the condensed ion layer. The increased negative surface charge density results in an electrostatic repulsion from the vapor-water interface that is seen to a lesser extent for larger particles that have a reduced charge density in the XPS measurements. We compare the results and interpretation of the in-situ XPS and corrected Debye-Hückel theory for surface complexation calculations with traditional surface tension measurements. Our results show that controlling the surface charge density of colloid particles can regulate their adsorption to the interface between two dielectrics. 23838556 Relation of serum uric acid and body mass index to mortality in high-risk patients with established coronary artery disease: A report from the ET-CHD registry, 1997-2006. Hyperuricemia is associated with a higher risk of death in patients with coronary artery disease (CAD). In contrast, overweight or obesity was associated with survival benefits in this population. However, the relation of body mass index (BMI) and serum uric acid (SUA) to mortality has not been clarified in this population. We studied a cohort of 1202 patients with angiographic CAD from the ET-CHD registry during 1997-2003 in Taiwan. To evaluate the relation of BMI and SUA on mortality, the subjects were categorized into 4 groups by BMI≧25kg/m(2) (overweight or obesity) or BMI<25kg/m(2) (normal- or under-weight), and SUA levels higher or lower than the median of 6.6mg/dl. At a median follow-up of 5.4 years, cardiac and all-cause deaths were the primary end points. Multivariate analyses demonstrated that high SUA group had a significantly higher cardiac mortality [hazard ratio (HR): 1.79, 95% confidence interval (CI): 1.14-2.82, p=0.023] and overall mortality (HR: 1.68, 95% CI: 1.19-2.36, p=0.003) than low SUA group only in overweight or obese patients. Additionally, high BMI was associated with a significantly lower cardiac mortality (HR: 0.58, 95% CI: 0.38-0.99, p=0.023) and overall mortality (HR: 0.62, 95% CI: 0.41-0.82, p=0.003) than low BMI in patients with low SUA levels. Furthermore, normal-low weight and underweight patients (BMI<21kg/m(2)) were found to have a higher risk of mortality regardless of SUA levels. Among patients with established CAD, SUA may be a potent predictor to mortality in overweight or obese patients. Moreover, the obesity-mortality paradox phenomenon was mainly driven by higher mortality risk in underweight patients and lower mortality risk in overweight and obese patients with low SUA. 23957728 Synthesis of Polymer-Lipid Nanoparticles for Image-Guided Delivery of Dual Modality Therapy. For advanced treatment of diseases such as cancer, multicomponent, multifunctional nanoparticles hold great promise. In the current study we report the synthesis of a complex nanoparticle (NP) system with dual drug loading as well as diagnostic properties. To that aim we present a methodology where chemically modified poly(lactic-co-glycolic) acid (PLGA) polymer is formulated into a polymer-lipid NP that contains a cytotoxic drug doxorubicin (DOX) in the polymeric core and an anti-angiogenic drug sorafenib (SRF) in the lipidic corona. The NP core also contains gold nanocrystals (AuNCs) for imaging purposes and cyclodextrin molecules to maximize the DOX encapsulation in the NP core. In addition, a near-infrared (NIR) Cy7 dye was incorporated in the coating. To fabricate the NP we used a microfluidics-based technique that offers unique NP synthesis conditions, which allowed for encapsulation and fine-tuning of optimal ratios of all the NP components. NP phantoms could be visualized with computed tomography (CT) and near-infrared (NIR) fluorescence imaging. We observed timed release of the encapsulated drugs, with fast release of the corona drug SRF and delayed release of a core drug DOX. In tumor bearing mice intravenously administered NPs were found to accumulate at the tumor site by fluorescence imaging. 23823977 Rudimentary substrates for vocal learning in a suboscine. Vocal learning has evolved in only a few groups of mammals and birds. The key neuroanatomical and behavioural links bridging vocal learners and non-learners are still unknown. Here we show that a non-vocal-learning suboscine, the eastern phoebe, expresses neural and behavioural substrates that are associated with vocal learning in closely related oscine songbirds. In phoebes, a specialized forebrain region in the intermediate arcopallium seems homologous to the oscine song nucleus RA (robust nucleus of arcopallium) by its neural connections, expression of glutamate receptors and singing-dependent immediate-early gene expression. Lesion of this RA-like region induces subtle but consistent song changes. Moreover, the unlearned phoebe song unexpectedly develops through a protracted ontogeny. These features provide the first evidence of forebrain vocal-motor control in suboscines, which has not been encountered in other avian non-vocal-learners, and offer a potential configuration of brain and behaviour from which vocal learning might have evolved. 23550625 Activation of PPARγ by Pioglitazone Potentiates the Effects of Naltrexone on Alcohol Drinking and Relapse in msP Rats. Pioglitazone is a selective peroxisome proliferator-activated receptor γ (PPARγ) agonist used for the treatment of insulin resistance and type 2 diabetes. Previous studies conducted in our laboratory showed that activation of PPARγ by pioglitazone reduces alcohol drinking, stress-induced relapse, and alcohol withdrawal syndrome in rats. Pioglitazone was not able to prevent relapse elicited by alcohol cues. Conversely, the nonselective opioid antagonist naltrexone has been shown to reduce alcohol drinking and cue- but not stress-induced relapse in rodents. Based on these findings, this study was sought to determine the efficacy of pioglitazone and naltrexone combination on alcohol intake and relapse behavior. Genetically selected alcohol-preferring Marchigian Sardinian (msP) rats were used for the study. Pioglitazone (10 and 30 mg/kg) and naltrexone (0.25 and 1.0 mg/kg) each individually reduced alcohol drinking in msP rats. The combination of the 2 drugs resulted in a more potent alcohol drinking reduction than single agents. Confirming previous studies, pioglitazone (10 and 30 mg/kg) significantly reduced relapse induced by the pharmacological stressor yohimbine (1.25 mg/kg) but not by cues predictive of alcohol availability. Conversely, naltrexone reduced reinstatement of drug seeking elicited by alcohol cues but not by yohimbine. The drug combination was effective in reducing both relapse behaviors. These findings open new vistas in the use pioglitazone in combination with naltrexone for the treatment of alcoholism. 23523202 Targeting kinases: a new approach to treating inflammatory rheumatic diseases. After two decades of research and development activity focussed on orally active kinase inhibitors, the first such drug (the JAK inhibitor Xeljanz, tofacitinib) was approved by the FDA in November 2012 for the treatment of rheumatoid arthritis (RA). There is an intense activity in many companies both on expanding the utility of JAK inhibitors in other auto-immune indications and in discovering inhibitors of the JAK family with different and more selective profiles. Progress is also being made with orally active Syk inhibitors. One such inhibitor (fostamatinib) is currently in large-scale phase 3 trials, and there are others in clinical development. The last two to three years have been transformative for kinase inhibitors in auto-immune diseases, as several inhibitors have finally progressed beyond phase 2 trials after so many failures on other targets. Thus, there are new treatment options for RA patients beyond existing oral DMARDs and parenteral biologics. 22889703 Sudden cardiac death in non-ischemic dilated cardiomyopathy: a critical appraisal of existing and potential risk stratification tools. Non ischemic dilated cardiomyopathy poses a significant risk of malignant ventricular arrhythmias and subsequent sudden cardiac death. The pathologic and electrophysiological substrate implicated to arrhythmogenesis has been quite adequately defined over the last decades and multiple forms of myocardial fibrosis - diffuse, patchy or gross scarring - are being studied regarding their arrhythmogenic potential. Moreover, the recent demonstration and continuous expansion of knowledge regarding causative genes in dilated cardiomyopathy open a new chapter in the field of diagnosis and prognosis of these patients. Numerous noninvasive and invasive methods have been used to stratify patients according to sudden cardiac death level of risk. Severely reduced left ventricular systolic myocardial function, expressed mostly by left ventricular ejection function, NYHA functional class, syncope and invasive electrophysiological study with programmed electrical stimulation have been incorporated into international guidelines, though leaving significant proportions of primary prevention patients out of stratification schemes. Electrocardiographic markers, signal-averaged ECG, heart rate variability, heart rate turbulence, baroreflex sensitivity, heart rate recovery and T-wave alternans have given conflicting results in non ischemic dilated cardiomyopathy. During the last decade, cardiac magnetic resonance, especially with gadolinium enhancement, has made a step forward in defining the fibrotic substrate of such patients. Prospective studies have given promising results, demonstrating correlation between late gadolinium enhancement and ventricular arrhythmogenesis. Identification of patients with genetically caused dilated cardiomyopathy prone to sudden cardiac death and large prospective trials investigating cardiac magnetic resonance and its prognostic potential may be able to establish a new era in stratification schemes. 23771245 Population-Level Analysis of Pancreatic Neuroendocrine Tumors 2 cm or Less in Size. There is a paucity of evidence regarding incidence and predictors of survival in pancreatic neuroendocrine tumors (PNETs) ≤2 cm in size. Patients having undergone resection for nonfunctioning PNETs were selected from the SEER database (1988-2009) and an institutional pathology database (1996-2012). PNETs ≤2 cm were compared with PNETs >2 cm. Data were analyzed with χ (2) tests, ANOVA, the Kaplan-Meier method, log rank tests, and Cox proportional hazard, and binary logistic regression. The incidence of PNETs ≤2 cm in the United States has increased by 710.4 % over the last 22 years. Rates of extrapancreatic extension, nodal metastasis, and distant metastasis in PNETs ≤2 cm in the SEER database were 17.9, 27.3, and 9.1 %, respectively. The rate of nodal metastasis in our institutional series was 5.7 %. Disease-specific survival at 5, 10, and 15 years for PNETs ≤2 cm was 91.5, 84.0, and 76.8 %. Decreased disease-specific survival was not associated with nodal metastasis, but rather with high grade [moderately differentiated, hazard ratio (HR) 37.2, 95 % confidence interval (CI) 2.7-518.8; poorly differentiated, HR 94.2, 95 % CI 4.9-1,794.4; reference, well differentiated], and minority race (Asian, HR 30.2, 95 % CI 3.1-291.7; Black, HR 60.1, 95 % CI 2.1-1,027.9; reference, White). Pancreatic neuroendocrine tumors ≤2 cm are increasingly common, and the most significant predictors of disease-specific survival are grade and race. The SEER database excludes PNETs considered to be benign, and rates of extrapancreatic extension, nodal metastasis, and distant metastasis are overestimated. Small size, however, does not preclude malignant behavior. 23970472 A Negative Dielectrophoresis and Gravity-Driven Flow-Based High-Throughput and High-Efficiency Cell-Sorting System. We present a negative dielectrophoresis (n-DEP)-based cell separation system for high-throughput and high-efficiency cell separation. To achieve a high throughput, the proposed system comprises macro-sized channel and cantilever-type electrode (CE) arrays (L × W × H = 150 µm × 500 µm × 50 µm) to generate n-DEP force. For high efficiency, double separation modules, which have macro-sized channels and CE arrays in each separation module, are employed. In addition, flow regulators to precisely control the hydrodynamic force are allocated for each outlet. Because the hydrodynamic force and the n-DEP force acting on the target cell are the main determinants of the separation efficiency, we evaluate the theoretical amount of hydrodynamic force and n-DEP force acting on each target cell. Based on theoretical results, separation conditions are experimentally investigated. Finally, to demonstrate the separation performance, we performed the separation of target cells (live K562) from nontarget cells (dead K562) under conditions of low voltage (7Vp-p with 100 kHz) and a flow rate of 15 µL•min(-1), 6 µL•min(-1), and 8 µL•min(-1) in outlets 1, 2, and 3, respectively. The system can separate target cells with 95% separation efficiency in the case of the ratio of 5:1 (live K562:dead K562). 22341693 Incidence rates and predictors of major and minor depression in patients with heart failure. Depression is common in heart failure (HF) and associated with adverse outcomes. This study aimed to investigate incidence rates and predictors of depression in patients sampled from four subprojects of the German Competence Network Heart Failure. Eight hundred thirty nine symptomatic HF patients free of depression at baseline underwent repeat depression screening (Patient Health Questionnaire, PHQ-9) after 12 months. Ordered logistic regression analysis was employed to search for predictors of incident depression. Incident minor (major) depression was observed in 61 (7.3%) and 47 (5.6%) of the population. Depression was recurrent in 15 (25%) and 16 (34%), respectively. Multiple regression analysis revealed seven variables predicting minor or major depression: Previous depressive episode (odds ratio [OR] 4.04, 95% confidence interval [CI] 2.37-6.89, p ≤ 0.001), previous resuscitation (OR 2.44, CI 1.23-4.81, p=0.010), current smoking (OR 2.06, CI 1.08-3.50, p=0.008), >4 visits/year to general practitioner (OR 1.67, CI 1.06-2.63, p=0.026), New York Heart Association class (OR 1.54/class, 95% CI 1.05-2.25, p=0.027), PHQ-9 baseline sum-score (OR 1.18/point, CI 1.11-1.27, p<0.001), and SF-36 physical functioning (OR 1.08/-5 points, CI 1.03-1.13, p=0.002). In these HF patients initially free of depression annual incidence rates were high. Several independent predictors allowed identification of patients at particular risk. Although obtained in a selected cohort these findings call, in view of the grave prognosis of HF patients with comorbid depression, for regular depression screening and development of specific supportive strategies to improve patient care and outcomes in HF. 23897539 Size and location of thyroid gland in the fetal period. The present study's purpose was to examine the size and location of the thyroid gland using anatomic dissection methods on fetal cadavers. This study was performed on 200 spontaneously aborted human fetuses (100 males and 100 females) aged between 9 and 40 weeks of gestation. Fetuses without any external and internal pathology or anomaly were included in this study. Fetuses were divided into four groups based on gestational ages as follows: first group 9-12 weeks (first trimester), second group 13-25 weeks (second trimester), third group 26-37 weeks (third trimester) and fourth group 38-40 weeks (full term). The fetuses were also grouped into monthly cohorts as follows: 9-12 weeks, 3rd month; 13-16 weeks, 4th month; 17-20 weeks, 5th month; 21-24 weeks, 6th month; 25-28 weeks, 7th month; 29-32 weeks, 8th month; 33-36 weeks, 9th month; and 37-40 weeks, 10th month. The anterior necks of fetuses were dissected and the thyroid glands exposed. Vertebral and laryngeal levels and the dimensions (width, length, thickness and weight) of the fetal thyroid glands were determined by anatomical dissection methods. The dimensions and ratios of the fetal thyroid gland (weight/fetal body weight) were evaluated. The mean values and standard deviations of all parameters by gestational weeks, months, and trimesters were calculated. It was found that all parameters increased with gestational age. No significant differences were observed between genders in all parameters (P > 0.05). There were no significant differences between the right and the left sides for parameters of the thyroid glands. The levels of the superior poles of the thyroid lobes were located at the cervical (C) C1-C3 vertebral bodies. The levels of the inferior poles of the thyroid lobes were located at C4-C5 vertebral bodies. The levels of the superior poles of thyroid lobes were located between the upper ½ and lower ½ of the thyroid cartilage or cricoid cartilage. The levels of the inferior poles of the thyroid lobes were located between the second and sixth tracheal rings. The distance between the superior poles of the thyroid gland and the hyoid bone increased throughout the fetal period. The dimensions of fetal thyroid glands increased with gestational age. The ratio between thyroid gland weights and fetal body weights was unchanged during the fetal period. We believe that the results obtained from this study will be useful in monitoring thyroid glands in the intrauterine period as well as recognizing early diagnosis and treatment of thyroid anomalies. It will also contribute to future studies in obstetrics, perinatology, and fetopathology. 23955169 Completion of Primary Care Referrals Among New York State Refugees. An important component of the New York State Refugee Health Program's (NYSRHP) mission is to ensure refugees with identified medial conditions are referred to primary and specialty care. A programmatic evaluation was conducted to assess the completion rate for primary care referral appointments made during the initial domestic health assessment among refugees in NYS (exclusive of New York City). Upon arrival in NYS, refugees may receive a domestic health assessment by one of NYSRHP contracted providers. As part of the assessment, referrals for primary and specialty care may be assigned. From July 2010 to June 2011, 69 % of NYS-bound refugees that received a primary care referral by a NYSRHP contracted provider completed their appointment. 23899272 Molecular nanostamp based on one-dimensional porphyrin polymers. Surface design with unique functional molecules by a convenient one-pot treatment is an attractive project for the creation of smart molecular devices. We have employed a silane coupling reaction of porphyrin derivatives that form one-dimensional polymer wires on substrates. Our simple one-pot treatment of a substrate with porphyrin has successfully achieved the construction of nanoscale bamboo shoot structures. The nanoscale bamboo shoots on the substrates were characterized by atomic force microscopy (AFM), UV-vis spectra, and X-ray diffraction (XRD) measurements. The uneven and rigid nanoscale structure has been used as a stamp for constructing bamboo shoot structures of fullerene. 23889859 Increasing pregnancy-related use of prescribed opioid analgesics. To quantify the prevalence of prescribed opioid analgesics among pregnant women enrolled in Tennessee Medicaid from 1995 to 2009. Retrospective cohort study of 277,555 pregnancies identified from birth and fetal death certificates, and linked to previously validated, computerized pharmacy records. Poisson regression was used to estimate trends over time, rate ratios, and 95% confidence intervals (CI). During the study period, 29% of pregnant women filled a prescription for an opioid analgesic. From 1995 to 2009, any pregnancy-related use increased 1.90-fold (95% CI, 1.83-1.98), first trimester use increased 2.27-fold (95% CI, 2.14-2.41), and second or third trimester use increased 2.02-fold (95% CI, 1.93-2.12), after adjusting for maternal characteristics. Any pregnancy-related, first trimester, and second or third trimester use were each more likely among mothers who were at least 21 years old, white, non-Hispanic, prima gravid, resided in nonurban areas, enrolled in Medicaid owing to disability, and who had less than a high school education. Opioid analgesic use by Tennessee Medicaid-insured pregnant women increased nearly 2-fold from 1995 to 2009. Additional study is warranted to understand the implications of this increased use. 23921077 G protein-coupled estrogen receptor (GPER) expression in endometrial adenocarcinoma and effect of agonist G-1 on growth of endometrial adenocarcinoma cell lines. The G protein-coupled estrogen receptor (GPER, GPR30) is suggested to be involved in non-nuclear estrogen signaling and is expressed in a variety of hormone dependent cancer entities. This study was performed to further elucidate the role of this receptor in endometrial adenocarcinoma. We first analyzed GPER expression at the mRNA level in 88 endometrial cancer or normal endometrial tissue samples and compared it to those of nuclear steroid hormone receptors. GPER transcript levels were found to be about 6-fold reduced, but still present in endometrial cancer. Expression of this receptor was decreased in all grading subgroups when compared to pre- or postmenopausal endometrium. GPER mRNA expression was associated with PR mRNA levels (Spearman's rho 0.4610, p<0.001). We then tested the effect of the GPER ligand G-1 on growth of three endometrial cancer cell lines with different GPER expression. GPER protein levels were highest in RL95-2 cells, moderate in HEC-1A cells and not detectable in HEC-1B cells. The moderate expression level in HEC-1A cells was similar to average tumor tissue expression. Treatment with G-1 significantly inhibited growth of the GPER-positive cell lines RL95-2 and HEC-1A in a dose-dependent manner, whereas the GPER-negative line HEC-1B was not affected. Though GPER transcript levels were found to be reduced in endometrial cancer, our in vitro data suggest that moderate GPER expression might be sufficient to mediate growth-inhibitory effects triggered by its agonist G-1. 23598702 Comparison between a new implantable transcutaneous bone conductor and percutaneous bone-conduction hearing implant. Despite good results on osseointegration and limited skin reactions with percutaneous bone conductors, there remains room for improvement. Especially in children, adverse events with percutaneous bone conductors might occur more frequently. Transcutaneous bone conductors, if powerful enough, can provide a solution that minimizes adverse events and implant loss. This study compares a new transcutaneous bone conduction hearing aid, the Sophono Alpha 1 (Sophono), with the percutaneous BAHA system (BAHA). In our tertiary referral center, 12 patients (age 5-12 yr) with congenital unilateral conductive hearing loss were enrolled in the study as follows: 6 patients with the Sophono and 6 with the BAHA. Both clinical results and audiologic data were gathered. For an objective audiologic comparison between both systems, we used a skull simulator. The skin reactions were comparable between both groups, in 1 implant was lost 1 month after second phase surgery (BAHA). The users received audiologic benefits from both systems. The BAHA-based outcome was slightly better compared with Sophono-based results in sound field thresholds, speech recognition threshold, and speech comprehension at 65 dB. The skull simulator demonstrated that the BAHA device has an output that is 10 to 15 dB higher compared with the Sophono device. The Sophono offers appealing clinical benefits of transcutaneous bone conduction hearing; however, the audiologic challenges of transcutaneous application remain, as the Sophono does not exceed percutaneous application regarding audiologic output. 23220294 Food reward-sensitive interaction of ghrelin and opioid receptor pathways in mesolimbic dopamine system. Ghrelin is a stomach-derived orexigenic peptide. The goal of the study was to investigate the roles of mu and kappa opioid receptors in systemic ghrelin-mediated regulation of the mesolimbic dopamine system. To evaluate the interaction of systemic ghrelin with values of food reward, rats were exposed to food removal, regular food or palatable food after systemic ghrelin administration. Extracellular dopamine levels were quantified in the nucleus accumbens (NAc) and receptor-specific compounds were infused into the ventral tegmental area (VTA) using dual-probe microdialysis. Consumption of regular or palatable food without systemic ghrelin administration induced an increase in dopamine levels in the NAc via activation of mu opioid receptors in the VTA. Systemic ghrelin administration (3 nmol, i.v.) followed by no food induced a decrease in dopamine levels via activation of kappa opioid receptors in the VTA. Systemic ghrelin administration followed by consumption of regular food induced an increase in dopamine levels via preferential activation of mu opioid receptors, whereas systemic ghrelin administration followed by consumption of palatable food suppressed the increase in dopamine levels via preferential activation of kappa opioid receptors. Thus, natural food reward and systemic ghrelin activate mu and kappa opioid receptor pathways in the VTA, respectively, resulting in opposite influences on dopamine release in the NAc. Furthermore, systemic ghrelin induces switching of the dominant opioid receptor pathway for highly rewarding food from mu to kappa, resulting in suppression of the mesolimbic dopamine system. These novel findings might provide insights into the neural pathways involved in eating disorders. 23839958 Delivery of a Therapeutic Protein for Bone Regeneration from a Substrate Coated with Graphene Oxide. The therapeutic efficacy of drugs often depends on the drug delivery carrier. For efficient delivery of therapeutic proteins, delivery carriers should enable the loading of large doses, sustained release, and retention of the bioactivity of the therapeutic proteins. Here, it is demonstrated that graphene oxide (GO) is an efficient carrier for delivery of therapeutic proteins. Titanium (Ti) substrates are coated with GO through layer-by-layer assembly of positively (GO-NH3 (+) ) and negatively (GO-COO(-) ) charged GO sheets. Subsequently, a therapeutic protein (bone morphogenetic protein-2, BMP-2) is loaded on the GO-coated Ti substrate with the outermost coating layer of GO-COO(-) (Ti/GO-). The GO coating on Ti substrate enables loading of large doses and the sustained release of BMP-2 with preservation of the structure and bioactivity of the drug. The extent of in vitro osteogenic differentiation of human bone marrow-derived mesenchymal stem cells is higher when they are cultured on Ti/GO- carrying BMP-2 than when they are cultured on Ti with BMP-2. Eight weeks after implantation in mouse models of calvarial defects, the Ti/GO-/BMP-2 implants show more robust new bone formation compared with Ti, Ti/GO-, or Ti/BMP-2 implants. Therefore, GO is an effective carrier for the controlled delivery of therapeutic proteins, such as BMP-2, which promotes osteointegration of orthopedic or dental Ti implants. 23586585 Dynamic and Electronic Transport Properties of DNA Translocation through Graphene Nanopores. Graphene layers have been targeted in the last years as excellent host materials for sensing a remarkable variety of gases and molecules. Such sensing abilities can also benefit other important scientific fields such as medicine and biology. This has automatically led scientists to probe graphene as a potential platform for sequencing DNA strands. In this work, we use robust numerical tools to model the dynamic and electronic properties of molecular sensor devices composed of a graphene nanopore through which DNA molecules are driven by external electric fields. We performed molecular dynamic simulations to determine the relation between the intensity of the electric field and the translocation time spent by the DNA to pass through the pore. Our results reveal that one can have extra control on the DNA passage when four additional graphene layers are deposited on the top of the main graphene platform containing the pore in a 2 × 2 grid arrangement. In addition to the dynamic analysis, we carried electronic transport calculations on realistic pore structures with diameters reaching nanometer scales. The transmission obtained along the graphene sensor at the Fermi level is affected by the presence of the DNA. However, it is rather hard to distinguish the respective nucleobases. This scenario can be significantly altered when the transport is conducted away from the Fermi level of the graphene platform. Under an energy shift, we observed that the graphene pore manifests selectiveness toward DNA nucleobases. 23839801 Validation of a Proposed Warfarin Dosing Algorithm Based on the Genetic Make-Up of Egyptian Patients. Warfarin is the most frequently prescribed oral anticoagulant worldwide. Due to its narrow therapeutic index and inter-patient variability in dose requirement, this drug has been considered an ideal target for personalised medicine. Several warfarin dosing algorithms have been proposed to tailor the warfarin dosage in the European, Asian and African-American populations. However, minimal interest was directed towards Middle East countries. The factors affecting warfarin dose requirement could be different in patients from different geographical and ethnic groups, limiting the value of published dosing algorithms. The first objective of this study was to examine the contribution of genetic and nongenetic factors on the variability of warfarin dose requirements in the Egyptian population using an easy, cost-effective and rapid analysis of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 (CYP) 2C9 single nucleotide polymorphism (SNP) genotyping of patients. A second objective was to develop and validate an algorithm for warfarin dose prediction that is tailored to Egyptian patients. Eighty-four patients, 41 males and 43 females, with a median (25th-75th percentiles) age of 39 (31-48) years were recruited in this study. Fifty patients whose international normalised ratio (INR) was in the range of 2-3 were allocated to a study cohort. SYBR Green-based multiplex allele-specific real-time PCR was used for genotyping of CYP2C9 (1075A>C) and VKORC1 (1173C>T) polymorphisms. Linear regression analysis, including the variables age, gender, CYP2C9 and VKORC1 SNP genotypes, was run to derive the best model for estimating the warfarin dose that achieves an INR of 2-3. The new warfarin dosing algorithm was examined in a second cohort of patients (n = 34) to check its validity. The predicted dose requirements for a subgroup of our patients were calculated according to Gage and International Warfarin Pharmacogenetics Consortium (IWPC) algorithms available at http://www.warfarindosing.org. In the study cohort, warfarin dose/week in VKORC1 TT subjects was statistically significantly lower than in VKORC1 CC/CT subjects (p = 0.032), while there was no statistically significant difference in warfarin dose/week between CYP2C9*1*1 and *1*3 (p = 0.925). A multivariate stepwise linear regression analysis revealed that age and VKORC1 had independent and significant contributions to the overall variability in warfarin dose with a p-value = 0.013 and 0.042, respectively. Maintenance dose (mg/week) = 65.226 - 0.422 Ã— (age) - 9.474 Ã— (VKORC1). The estimated regression equation was able to account for 20.5 % of the overall variability in warfarin maintenance dose. A significant positive correlation, with sufficient strength, was observed between the predicted warfarin dose and the actual prescribed dose (r = 0.453, p = 0.001). In the validation cohort, after application of the dosing algorithm, correlation between predicted and actual dose was statistically significant (p = 0.023). The equation was particularly successful among patients with a dose ≥35 mg/week. The correlation coefficient between the actual and predicted doses for IWPC and Gage were 0.304 and 0.276, respectively. When compared with our algorithm (r = 0.279), the difference was non-significant: p = 0.903 and 0.990, respectively. VKORC1 (1173C>T) contributes to the warfarin dose variability. Patients' age and genetic variants of VKORC1 account for nearly 20.5 % of the variability in warfarin dose required to achieve an INR of 2-3. The success of a prediction equation based on these variables was proved in a different cohort: the predicted dose correlated significantly with the maintenance dose and the equation was more successful among patients with a dose ≥35 mg/week. The results of the warfarin algorithm we developed were comparable with those of the IWPC and Gage algorithms with the advantage of using one SNP (VKORC1 1173C>T) only. This represents an economic advantage in our community. Replication of this study in a larger cohort of patients is necessary before translation of this knowledge into clinical guidelines for warfarin prescription. 23290008 Use of potassium channel tetramerization domain-containing 12 as a biomarker for diagnosis and prognosis of gastrointestinal stromal tumor. Previously, we showed that the expression of potassium channel tetramerization domain-containing 12 (KCTD12), which was discovered by a proteomics approach, is associated with high-risk behavior of gastrointestinal stromal tumors (GISTs). Here, we examined the distribution and expression of this protein by immunostaining with a commercially available polyclonal KCTD12 antibody in GISTs (n = 64) and other types of malignancy (n = 168) to clarify its diagnostic and clinical significance. Diffuse KCTD12 immunoreactivity was found in most GISTs (52 cases; 81%). KCTD12 expression was observed primarily in vascular endothelial cells, Purkinje cells of the cerebellum, and some neurons scattered throughout the cerebral cortex. KCTD12 was absent from not only the interstitial cells of Cajal but also interstitial cells of Cajal hyperplasia that was encountered incidentally in colon diverticulitis. KCTD12 immunostaining was also seen in malignant peripheral nerve sheath tumors (2/10 cases; 20%), synovial sarcomas (2/10; 20%), solitary fibrous tumor (1/8; 13%), angiosarcoma (1/7; 14%), and colon adenocarcinoma (1/24; 4%). In survival analyses, the 5-year recurrence-free survival rate of patients without KCTD12 expression was only 16.7% compared with 95.6% in those with KCTD12 expression (P < .0001). Ki-67 and KCTD12 were significant predictors of recurrence-free survival, and KCTD12 expression provided additional information about recurrence-free survival after accounting for Ki-67 status. Overall, KCTD12 expression was specific for GISTs from neoplastic and nonneoplastic adult tissues other than brain and served as a predictor of GIST recurrence. These findings suggest that KCTD12 is a useful and reliable biomarker for both the diagnosis and prognosis of GIST. 23857257 Experimental results of underwater cooperative source localization using a single acoustic vector sensor. This paper aims at estimating the azimuth, range and depth of a cooperative broadband acoustic source with a single vector sensor in a multipath underwater environment, where the received signal is assumed to be a linear combination of echoes of the source emitted waveform. A vector sensor is a device that measures the scalar acoustic pressure field and the vectorial acoustic particle velocity field at a single location in space. The amplitudes of the echoes in the vector sensor components allow one to determine their azimuth and elevation. Assuming that the environmental conditions of the channel are known, source range and depth are obtained from the estimates of elevation and relative time delays of the different echoes using a ray-based backpropagation algorithm. The proposed method is tested using simulated data and is further applied to experimental data from the Makai'05 experiment, where 8-14 kHz chirp signals were acquired by a vector sensor array. It is shown that for short ranges, the position of the source is estimated in agreement with the geometry of the experiment. The method is low computational demanding, thus well-suited to be used in mobile and light platforms, where space and power requirements are limited. 23885802 Temperature dependence of the electrical transport properties in few-layer graphene interconnects. We report a systematic investigation of the temperature dependence of electrical resistance behaviours in tri- and four-layer graphene interconnects. Nonlinear current-voltage characteristics were observed at different temperatures, which are attributed to the heating effect. With the resistance curve derivative analysis method, our experimental results suggest that Coulomb interactions play an essential role in our devices. The room temperature measurements further indicate that the graphene layers exhibit the characteristics of semiconductors mainly due to the Coulomb scattering effects. By combining the Coulomb and short-range scattering theory, we derive an analytical model to explain the temperature dependence of the resistance, which agrees well with the experimental results. 23968720 Attenuation of fibroblast growth factor signaling by poly-N-acatyllactosamine type glycans. Fibroblast growth factors (FGFs) and their receptors are expressed in a variety of mammalian tissues, playing a role in development and cell proliferation. While analyzing human sperm motility, we found that sperm treated with endo-β-galactosidase (EBG), which specifically hydrolyzes poly-N-acetyllactosamine type glycans (polyLacs), enhanced motility. Mass spectrometry analysis revealed that sperm-associated polyLacs are heavily fucosylated, consistent with Lewis Y antigen. Immunohistochemistry of epididymis using an anti-Lewis Y antibody before and after EBG treatment suggested that polyLacs carrying the Lewis Y epitope are synthesized in epididymal epithelia and secreted to seminal fluid. EBG-treated sperm elevated cAMP levels and calcium influx, indicating activation of fibroblast growth factor signaling. Seminal fluid polyLacs bound to FGFs in vitro, and impaired FGF-mediated signaling in HEK293T cells. 23816336 A rare case of Endometriosis in vaginal hysterectomy scar. Presented hereunder is probably the first reported case of endometriosis at the vaginal apex following vaginal hysterectomy. No other similar case could be traced in the review of the literature. 23601576 Usefulness of monocyte chemoattractant protein-1 to predict no-reflow and three-year mortality in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Although monocyte chemoattractant protein-1 (MCP-1) levels are increased in patients with ST-segment elevation myocardial infarction, the prognostic value of MCP-1 in primary percutaneous coronary intervention (pPCI) is not clear. The goal of the present study was to investigate the association of MCP-1 levels with myocardial perfusion and prognosis in patients with ST-segment elevation myocardial infarction undergoing pPCI. Consecutive pPCI patients (n = 192) were assigned to tertiles according to their admission serum MCP-1 levels. Angiographic no-reflow, Thrombolysis In Myocardial Infarction flow grade, myocardial blush grade, and ST-segment resolution were assessed. Mortality and major adverse cardiac events were evaluated during hospitalization and at the 3-year clinical follow-up visit. Failure of ST resolution was associated with greater admission MCP-1 levels. The risk of no-reflow (Thrombolysis In Myocardial Infarction flow ≤2 or Thrombolysis In Myocardial Infarction flow 3 with final myocardial blush grade ≤2 after pPCI and ST resolution <30%) increased as the admission MCP-1 increased. The 3-year mortality increased as the MCP-1 level increased (8% vs 22% vs 28% for the 3 tertiles, p <0.01). Multivariate logistic regression analysis demonstrated that MCP-1 levels at admission are a significant independent correlate of 3-year mortality in patients with no-reflow as detected by myocardial blush grade. A receiver operating characteristics analysis identified an optimum cut point of ≥254 pg/ml, which was associated with a negative predictive value of 95% in association with 1-year mortality. In conclusion, the plasma MCP-1 levels at admission are independently associated with the development of no-reflow and 3-year mortality in patients with ST-segment elevation myocardial infarction undergoing pPCI. 23355020 Effect of power plant emission reductions on a nearby wilderness area: a case study in northwestern Colorado. This study evaluates the effect of emission reductions at two coal-fired power plants in northwestern Colorado on a nearby wilderness area. Control equipment was installed at both plants during 1999-2004 to reduce SO2 and NOx emissions. One challenge was separating the effects of local from regional emissions, which also declined during the study period. The long-term datasets examined confirm that emission reductions had a beneficial effect on air and water quality in the wilderness. Despite a 75 % reduction in SO2 emissions, sulfate aerosols measured in the wilderness decreased by only 20 %. Because the site is relatively close to the power plants (<75 km), the slow rate of conversion of SO2 to sulfate, particularly under conditions of low relative humidity, might account for this less than one-to-one response. On the clearest days, emissions controls appeared to improve visibility by about 1 deciview, which is a small but perceptible improvement. On the haziest days, however, there was little improvement perhaps reflecting the dominance of regional haze and other components of visibility degradation particularly organic carbon and dust. Sulfate and acidity in atmospheric deposition decreased by 50 % near the southern end of the wilderness of which 60 % was attributed to power plant controls and the remainder to reductions in regional sources. Lake water sulfate responded rapidly to trends in deposition declining at 28 lakes monitored in and near the wilderness. Although no change in the acid-base status was observed, few of the lakes appear to be at risk from chronic or episodic acidification. 23903014 A Randomized Pilot Study of Donor Stem Cell Infusion in Living-Related Kidney Transplant Recipients Receiving Alemtuzumab. Transplant tolerance would remove the need for maintenance immunosuppression while improving survival and quality of life. A prospective, randomized pilot study was undertaken to assess the safety and efficacy of donor stem cell infusion (DSCI) in living-related kidney transplant recipients treated with alemtuzumab (C1H) induction and tacrolimus and mycophenolate maintenance with switch to sirolimus and weaning over 2 years. Four patients received DSCI; five patients were controls. Graft failure occurred in two patients in the DSCI arm. Recurrence of glomerular disease occurred in two DSCI recipients, leading to graft loss in one. Biopsy-proven acute rejection episodes occurred in three patients (two in the DSCI vs. one in the control). One DSCI patient, with recurrence, subsequently developed antibody-mediated rejection leading to graft failure. In the remaining two DSCI patients, weaning was attempted but was not successful. All (4 of 4) DSCI patients had biopsy-proven chronic allograft injury and/or recurrence. DSCI with C1H induction and a steroid-free maintenance regimen in a small group of patients failed to induce tolerance, with suboptimal patient and graft survival. The results do not justify extension of this particular trial and underscore the importance of patient selection, specifically avoidance of patients with glomerulopathies whose recurrence may obscure potential benefit. 23951024 Cannabinoid Receptor CB2 Modulates Axon Guidance. Navigation of retinal projections towards their targets is regulated by guidance molecules and growth cone transduction mechanisms. Here, we present in vitro and in vivo evidences that the cannabinoid receptor 2 (CB2R) is expressed along the retino-thalamic pathway and exerts a modulatory action on axon guidance. These effects are specific to CB2R since no changes were observed in mice where the gene coding for this receptor was altered (cnr2 (-/-)). The CB2R induced morphological changes observed at the growth cone are PKA dependent and require the presence of the netrin-1 receptor, Deleted in Colorectal Cancer. Interfering with endogenous CB2R signalling using pharmacological agents increased retinal axon length and induced aberrant projections. Additionally, cnr2 (-/-) mice showed abnormal eye-specific segregation of retinal projections in the dorsal lateral geniculate nucleus (dLGN) indicating CB2R's implication in retinothalamic development. Overall, this study demonstrates that the contribution of endocannabinoids to brain development is not solely mediated by CB1R, but also involves CB2R. 23547794 Discovery of the First C-Nucleoside HCV Polymerase Inhibitor (GS-6620) with Demonstrated Antiviral Response in HCV Infected Patients. Hepatitis C virus (HCV) infection presents an unmet medical need requiring more effective treatment options. Nucleoside inhibitors (NI) of HCV polymerase (NS5B) have demonstrated pan-genotypic activity and durable antiviral response in the clinic, and they are likely to become a key component of future treatment regimens. NI candidates that have entered clinical development thus far have all been N-nucleoside derivatives. Herein, we report the discovery of a C-nucleoside class of NS5B inhibitors. Exploration of adenosine analogs in this class identified 1'-cyano-2'-C-methyl 4-aza-7,9-dideaza adenosine as a potent and selective inhibitor of NS5B. A monophosphate prodrug approach afforded a series of compounds showing submicromolar activity in HCV replicon assays. Further pharmacokinetic optimization for sufficient oral absorption and liver triphosphate loading led to identification of a clinical development candidate GS-6620. In a phase I clinical study, the potential for potent activity was demonstrated but with high intra- and interpatient pharmacokinetic and pharmacodynamic variability. 23666901 Implementing telemonitoring in heart failure care: barriers from the perspectives of patients, healthcare professionals and healthcare organizations. The increasing prevalence of chronic diseases, such as heart failure, presents a substantial challenge to healthcare systems. Telemonitoring is believed to be a useful instrument in the delivery of heart failure care. However, a widespread use of telemonitoring is currently failing for various reasons. This article provides an overview of the barriers for the implementation of telemonitoring in heart failure patients from the perspectives of its users: patients, healthcare professionals and healthcare organisations. In doing so, identified barriers are grouped according to the perceived attributes of innovation by Rogers. Recommendations are provided as to how research can improve the implementation of telemonitoring in heart failure. 23441583 Twenty-first century mast cell stabilizers. Mast cell stabilizing drugs inhibit the release of allergic mediators from mast cells and are used clinically to prevent allergic reactions to common allergens. Despite the relative success of the most commonly prescribed mast cell stabilizer, disodium cromoglycate, in use for the preventative treatment of bronchial asthma, allergic conjunctivitis and vernal keratoconjunctivitis, there still remains an urgent need to design new substances that are less expensive and require less frequent dosing schedules. In this regard, recent developments towards the discovery of the next generation of mast cell stabilizing drugs has included studies on substances isolated from natural sources, biological, newly synthesized compounds and drugs licensed for other indications. The diversity of natural products evaluated range from simple phenols, alkaloids, terpenes to simple amino acids. While in some cases their precise mode of action remains unknown it has nevertheless sparked interest in the development of synthetic derivatives with improved pharmacological properties. Within the purely synthetic class of inhibitors, particular attention has been devoted to the inhibition of important signalling molecules including spleen TK and JAK3. The statin class of cholesterol-lowering drugs as well as nilotinib, a TK inhibitor, are just some examples of clinically used drugs that have been evaluated for their anti-allergic properties. Here, we examine each approach under investigation, summarize the test data generated and offer suggestions for further preclinical evaluation before their therapeutic potential can be realized. This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1. 23815262 The Dimensions of Mastery Questionnaire in School-Aged Children with Congenital Hemiplegia: Test-Retest Reproducibility and Parent-Child Concordance. ABSTRACT Aim: To examine internal consistency, test-retest reproducibility, and parent-child concordance of the Dimensions of Mastery Questionnaire 17.0 (DMQ) in school-aged children with congenital hemiplegia. Method: Forty-two children (8.24 ± 2.38 years, Manual Ability Classification System (MACS) I = 23, MACS II = 19) and their parents completed the DMQ, and a subset on two occasions 2-30 days apart (n = 27). Cronbach's alpha (α), intraclass correlation coefficients (ICCs), standard error of measurement (SEM), and 95% limits of agreement were calculated. Results: Internal consistency for child self-report was variable (α = 0.57-0.90). Cronbach's alphas for parent proxy report were good (α = 0.69-0.86). Test-retest reproducibility for instrumental aspect (ICC = 0.86) and total motivation (ICC = 0.84) were excellent with subscales ranging from 0.70 to 0.91. The SEM for total motivation was 0.23 points. Parent-child concordance was poor across all scores (ICC = -0.04 to 0.42) with a large SEM (0.50-0.91). Interpretation: The DMQ parent report has good test-retest reproducibility for subscales, instrumental, and total motivation scores in school-aged children with congenital hemiplegia. Parent-child concordance was low highlighting differences in individual and contextual perspectives. 23918044 A multicenter phase II study of belotecan, a new camptothecin analogue, in elderly patients with previously untreated, extensive-stage small cell lung cancer. Belotecan is a new camptothecin analogue and a potent topoisomerase I inhibitor. The aim of this phase II study was to investigate the efficacy and toxicity of belotecan in previously untreated elderly patients with small cell lung cancer (SCLC). A total of 26 patients, aged ≥65 years, with previously untreated, extensive-stage SCLC were enrolled in the study. Belotecan was administered by daily intravenous infusion at 0.5 mg/m(2)/day for 5 consecutive days every 3 weeks. The overall response rate and disease control rate of chemotherapy on an intention-to-treat basis were 35 and 54 %, respectively. The median overall survival was 6.4 months, and the median time to progression was 2.8 months. The most common toxicity was hematologic. Grade 3 or 4 neutropenia occurred in 80.8 % of patients, and grade 3 or 4 thrombocytopenia in 15.3 %. Non-hematologic toxic effects of grade 3 or 4 were uncommon. Belotecan had modest efficacy and well-tolerated toxicity in previously untreated, elderly SCLC patients. Single belotecan could be a promising treatment option, considering its lower toxicity in elderly patients who are unsuitable candidates for platinum plus etoposide chemotherapy. 23942633 Wavelet-based data and solution compression for efficient image reconstruction in fluorescence diffuse optical tomography. ABSTRACT. Current fluorescence diffuse optical tomography (fDOT) systems can provide large data sets and, in addition, the unknown parameters to be estimated are so numerous that the sensitivity matrix is too large to store. Alternatively, iterative methods can be used, but they can be extremely slow at converging when dealing with large matrices. A few approaches suitable for the reconstruction of images from very large data sets have been developed. However, they either require explicit construction of the sensitivity matrix, suffer from slow computation times, or can only be applied to restricted geometries. We introduce a method for fast reconstruction in fDOT with large data and solution spaces, which preserves the resolution of the forward operator whilst compressing its representation. The method does not require construction of the full matrix, and thus allows storage and direct inversion of the explicitly constructed compressed system matrix. The method is tested using simulated and experimental data. Results show that the fDOT image reconstruction problem can be effectively compressed without significant loss of information and with the added advantage of reducing image noise. 23349483 Reduction of reactive oxygen species ameliorates metabolism-secretion coupling in islets of diabetic GK rats by suppressing lactate overproduction. We previously demonstrated that impaired glucose-induced insulin secretion (IS) and ATP elevation in islets of Goto-Kakizaki (GK) rats, a non-obese model of diabetes, were significantly restored by 30∼60 min suppression of endogenous reactive oxygen species (ROS) overproduction. In this study, we investigated the effect of longer (12 h) suppression of ROS on metabolism-secretion coupling in β-cells by exposure to tempol, a superoxide dismutase mimic, plus ebselen, a glutathione peroxidase mimic (TE-treatment). In GK islets, both H(2)O(2) and superoxide were sufficiently reduced and glucose-induced IS and ATP elevation were improved by TE-treatment. Glucose oxidation, an indicator of Krebs cycle velocity, also was improved by TE-treatment at high glucose, whereas glucokinase activity, which determines glycolytic velocity, was not affected. Lactate production was markedly increased in GK islets and TE-treatment reduced lactate production and protein expression of lactate dehydrogenase and hypoxia-inducible factor 1α (HIF1α). These results indicate that the Warburg-like effect, which is characteristic of aerobic metabolism in cancer cells by which lactate is overproduced with reduced linking to mitochondria metabolism, plays an important role in impaired metabolism-secretion coupling in diabetic β-cells and suggest that ROS reduction can improve mitochondrial metabolism by suppressinglactate overproduction through inhibition of HIF1α stabilization. 23913107 Prevalence and Risk Factors of Type 2 Diabetes in Older Vietnam-Born Australians. Vietnamese immigrants in Australia represent the second largest Vietnamese community in developed countries, following the United States. However, limited information is available about prevalence of type 2 diabetes (T2D) and the relative roles of socio-demographic characteristics, lifestyle factors, and Vietnamese ethnicity per se in this population. This study investigated the prevalence of T2D and its risk factors in older Vietnam-born Australians, in comparison to native-born Australians. The study used baseline questionnaire data from 787 Vietnam- and 196,866 Australia-born individuals (≥45 years), who participated in the 45 and Up Study, which is Australia's largest population-based cohort study. Country of birth specific prevalence of T2D and its risk factors were age-standardised to the 2006 Australian population (≥45 years). Multivariable logistic regression models were built for each group to assess the relationship between T2D and socio-demographic characteristics, family history of diabetes, lifestyle factors and health status. Compared to Australia-born counterparts, Vietnam-born individuals had significantly (p < 0.001) higher age-standardised prevalence of T2D (14.7 vs 7.4 %) and significantly (p < 0.001) lower levels of vegetable consumption (≥5 serves/day, 19.4 vs 33.5 %), physical activity (≥5 sessions/week, 68.7 vs 78.5 %) and overweight and obesity (body mass index ≥25 kg/m(2), 21.5 vs 62.7 %). The increased risk of T2D associated with a family history of diabetes for Vietnam-born people [adjusted odds ratio (OR) 7.14, 95 % CI 4.15-12.28] was almost double that for Australia-born people (OR 3.77, 95 % CI 3.63-3.90). The patterns of association between T2D and other factors were similar between the two groups. The findings suggest a genetic predisposition to T2D in people of Vietnamese ethnicity. Reducing lifestyle risk factors for diabetes and better management of diabetes are priorities for Vietnam-born populations. 23928002 A systematic approach for designing a HBM Pilot Study for Europe. The objective of COPHES (Consortium to Perform Human biomonitoring on a European Scale) was to develop a harmonised approach to conduct human biomonitoring on a European scale. COPHES developed a systematic approach for designing and conducting a pilot study for an EU-wide cross-sectional human biomonitoring (HBM) study and for the implementation of the fieldwork procedures. The approach gave the basis for discussion of the main aspects of study design and conduct, and provided a decision making tool which can be applied to many other studies. Each decision that had to be taken was listed in a table of options with their advantages and disadvantages. Based on this the rationale of the decisions could be explained and be transparent. This was important because an EU-wide HBM study demands openness of all decisions taken to encourage as many countries as possible to participate and accept the initiative undertaken. Based on this approach the following study design was suggested: a cross-sectional study including 120 children aged 6-11 years and their mothers aged up to 45 years from each participating country. For the pilot study the children should be sampled in equal shares in an urban and a rural location. Only healthy children and mothers (no metabolic disturbances) should be included, who have a sufficient knowledge of the local language and have been living at least for 5 years at the sampling location. Occupational exposure should not be an exclusion criterion. Recruitment should be performed via inhabitant registries or schools as an alternative option. Measures suitable to increase the response rate should be applied. Preferably, the families should be visited at home and interviewed face-to-face. Various quality control measures to guarantee a good fieldwork performance were recommended. This comprehensive overview aims to provide scientists, EU officials, partners and stakeholders involved in the EU implementation process full transparency of the work carried out in COPHES. Thus this report presents the discussion and consensus in COPHES on the main aspects of designing and conducting fieldwork of a human biomonitoring study. Furthermore, it provides an example for a systematic approach that may be useful to other research groups or pan-European research initiatives. In the study protocol that will be published elsewhere these aspects are elaborated and additional aspects are covered (Casteleyn et al., 2012). Meanwhile the respective pilot study DEMOCOPHES had been conducted and assessed. The results and lessons learned will be published elsewhere. 23684384 Altered regional homogeneity patterns in adults with attention-deficit hyperactivity disorder. Investigating the discriminative brain map for patients with attention-deficit/hyperactivity disorder (ADHD) based on feature selection and classifier; and identifying patients with ADHD based on the discriminative model. A dataset of resting state fMRI contains 23 patients with ADHD and 23 healthy subjects were analyzed. Regional homogeneity (ReHo) was extracted from resting state fMRI signals and used as model inputs. Raw ReHo features were ranked and selected in a loop according to their p values. Selected features were trained and tested by support vector machines (SVM) in a cross validation procedure. Cross validation was repeated in feature selection loop to produce optimized model. Optimized discriminative map indicated that the ADHD brains exhibit more increased activities than normal controls in bilateral occipital lobes and left front lobe. The altered brain regions included portions of basal ganglia, insula, precuneus, anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), thalamus, and cerebellum. Correlation coefficients indicated significant positive correlation of inattentive scores with bilateral cuneus and precuneus, and significant negative correlation of hyperactive/impulsive scores with bilateral insula and claustrum. Additionally, the optimized model produced total accuracy of 80% and sensitivity of 87%. ADHD brain regions were more activated than normal controls during resting state. Linear support vector classifier can provide useful discriminative information of altered ReHo patterns for ADHD; and feature selection can improve the performances of classification. 23212949 Nonallelic homologous recombination between retrotransposable elements is a driver of de novo unbalanced translocations. Large-scale analysis of balanced chromosomal translocation breakpoints has shown nonhomologous end joining and microhomology-mediated repair to be the main drivers of interchromosomal structural aberrations. Breakpoint sequences of de novo unbalanced translocations have not yet been investigated systematically. We analyzed 12 de novo unbalanced translocations and mapped the breakpoints in nine. Surprisingly, in contrast to balanced translocations, we identify nonallelic homologous recombination (NAHR) between (retro)transposable elements and especially long interspersed elements (LINEs) as the main mutational mechanism. This finding shows yet another involvement of (retro)transposons in genomic rearrangements and exposes a profoundly different mutational mechanism compared with balanced chromosomal translocations. Furthermore, we show the existence of compound maternal/paternal derivative chromosomes, reinforcing the hypothesis that human cleavage stage embryogenesis is a cradle of chromosomal rearrangements. 23393214 Impact of Baseline Insulin Regimen on Glycemic Response to a Group Medical Clinic Intervention. OBJECTIVEGroup medical clinics (GMC) combine medication management and self-management training, and may improve diabetes outcomes. It remains unclear which patients benefit most from GMC. This secondary analysis examined the impact of baseline insulin regimen on GMC response.RESEARCH DESIGN AND METHODSWe analyzed a trial of 239 veterans with type 2 diabetes randomized to GMC or usual care (UC). We categorized baseline insulin regimen as the following: no insulin; basal insulin only; or complex insulin (basal-prandial or mixed regimens). Using linear mixed models adjusted for clustering within GMC, we evaluated the differential impact of GMC relative to UC on hemoglobin A(1c) (HbA(1c)) and self-efficacy among patients on different baseline insulin regimens.RESULTSFrom linear mixed models, the effect of GMC on HbA(1c) differed by baseline insulin regimen versus UC (P = 0.05); there was no differential effect on self-efficacy (P = 0.29). Among those using complex insulin regimens at baseline, GMC reduced HbA(1c) by study end compared with UC (-1.0%; 95% CI -1.8 to -0.2; P = 0.01). We found no such HbA(1c) difference between GMC and UC patients using no insulin (P = 0.65) or basal insulin only (P = 0.71). There were no clinically significant differences in hypoglycemia by baseline insulin regimen and intervention group.CONCLUSIONSWe found that compared with UC, GMC lowered HbA(1c) specifically among patients using complex insulin regimens at study baseline, which may relate to this group's demanding medication and self-management requirements. Implementing GMC among patients using complex insulin regimens may maximize this care delivery strategy's potential. 23789650 Nanofibrillar micelles and entrapped vesicles from biodegradable block copolymer/polyelectrolyte complexes in aqueous media. Here we report a viable route to fibrillar micelles and entrapped vesicles in aqueous solutions. Nanofibrillar micelles and entrapped vesicles were prepared from complexes of a biodegradable block copolymer poly(ethylene oxide)-block-poly(lactide) (PEO-b-PLA) and a polyelectrolyte poly(acrylic acid) (PAA) in aqueous media and directly visualized using cryogenic transmission electron microscopy (cryo-TEM). The self-assembly and the morphological changes in the complexes were induced by the addition of PAA/water solution into the PEO-b-PLA in tetrahydrofuran followed by dialysis against water. A variety of morphologies including spherical wormlike and fibrillar micelles, and both unilamellar and entrapped vesicles, were observed, depending on the composition, complementary binding sites of PAA and PEO, and the change in the interfacial energy. Increasing the water content in each [AA]/[EO] ratio led to a morphological transition from spheres to vesicles, displaying both the composition- and dilution-dependent micellar-to-vesicular morphological transitions. 23455948 A qualitative study exploring patients' and carers' experiences of Early Supported Discharge services after stroke. Objective: To investigate patients' and carers' experiences of Early Supported Discharge services and inform future Early Supported Discharge service development and provision. Design and subjects: Semi-structured interviews were completed with 27 stroke patients and 15 carers in the Nottinghamshire region who met evidence-based Early Supported Discharge service eligibility criteria. Participants were either receiving Early Supported Discharge or conventional services. Setting: Community stroke services in Nottinghamshire, UK. Results: A thematic analysis process was applied to identify similarities and differences across datasets. Themes specific to participants receiving Early Supported Discharge services were: the home-based form of rehabilitation; speed of response; intensity and duration of therapy; respite time for the carer; rehabilitation exercises and provision of technical equipment; disjointed transition between Early Supported Discharge and ongoing rehabilitation services. Participants receiving Early Supported Discharge or conventional community services experienced difficulties related to: limited support in dealing with carer strain; lack of education and training of carers; inadequate provision and delivery of stroke-related information; disjointed transition between Early Supported Discharge and ongoing rehabilitation services. Conclusions: Accelerated hospital discharge and home-based rehabilitation was perceived positively by service users. The study findings highlight the need for Early Supported Discharge teams to address information and support needs of patients and carers and to monitor their impact on carers in addition to patients, using robust outcome measures. 23836910 Structural and Functional Analysis of Transmembrane Segment IV of the Salt Tolerance Protein Sod2. Sod2 is the plasma membrane Na(+)/H(+) exchanger of the fission yeast Schizosaccharomyces pombe. It provides salt tolerance by removing excess intracellular sodium (or lithium) in exchange for protons. We examined the role of amino acid residues of transmembrane segment IV (TM IV) ((126)FPQINFLGSLLIAGCITSTDPVLSALI(152)) in activity by using alanine scanning mutagenesis and examining salt tolerance in sod2-deficient S. pombe. Two amino acids were critical for function. Mutations T144A and V147A resulted in defective proteins that did not confer salt tolerance when reintroduced into S. pombe. Sod2 protein with other alanine mutations in TM IV had little or no effect. T144D and T144K mutant proteins were inactive; however, a T144S protein was functional and provided lithium, but not sodium, tolerance and transport. Analysis of sensitivity to trypsin indicated that the mutations caused a conformational change in the Sod2 protein. We expressed and purified TM IV (amino acids 125-154). NMR analysis yielded a model with two helical regions (amino acids 128-142 and 147-154) separated by an unwound region (amino acids 143-146). Molecular modeling of the entire Sod2 protein suggested that TM IV has a structure similar to that deduced by NMR analysis and an overall structure similar to that of Escherichia coli NhaA. TM IV of Sod2 has similarities to TM V of the Zygosaccharomyces rouxii Na(+)/H(+) exchanger and TM VI of isoform 1 of mammalian Na(+)/H(+) exchanger. TM IV of Sod2 is critical to transport and may be involved in cation binding or conformational changes of the protein. 23860903 Primary migration of a mini-implant under a functional orthodontic loading. The objective of this study was to examine whether cortical bone thickness and bone mineral density (BMD) can explain the primary migration of a mini-implant under a functional orthodontic tangential loading at the early stage following implantation. Mini-implants were installed in human mandibular sections. A constant tangential load (2 N) was applied to the mini-implant under hydration. Creep, which is a time-dependent viscoelastic displacement in the bone surrounding the mini-implant, was assessed as the change in displacement during 2 h of loading. The total migration was measured as a maximum displacement that combined an initial elastic displacement and creep. After removal of the mini-implant, all specimens were scanned together by cone beam computed tomography. Cortical bone thickness and BMD were measured for the bone voxels surrounding the implant site. BMD had significant correlations with the displacement parameters (p < 0.019), but the cortical bone thickness did not (p > 0.272). Permanent bone deformation adjacent to the implant was observed to be resulting from substantial creep development under the orthodontic functional loading level. BMD controls the primary migration of the mini-implant system in mandibular bone. Viscoelastic creep can develop at a small constant functional loading level, leading to migration of the mini-implant. The current results indicated that mini-implant migration can develop under the small level of functional orthodontic load used in clinic. If the active bone remodeling around the mini-implant accelerates the migration, the risk of causing damage in vital organs next to the mini-implant increases. 23948944 Can Rituximab Induce Long-Term Disease Remission in Patients with Intra-Ocular Non-Infectious Inflammation? Treatment of non-infectious uveitis is based primarily on the use of systemic corticosteroids and second-line immunosuppressive drugs. However, their extensive side effect profile, particularly for steroids, has led to the increased use of other immunosuppressive drugs, as sparing capacity agents. Rituximab is an anti-CD20 chimeric antibody, often given as a single course of 2 infusions, resulting in complete depletion of peripheral mature B cells. While it is licensed to treat refractory systemic lymphoma patients, it has also shown promising results in systemic auto-immune diseases, where a single course of treatment is able to achieve long-term clinical remission. Treatment with rituximab has been reported for various ocular conditions, suggesting it may be effective in inducing long-term disease control and other systemic immunosuppressive agents can be reduced or discontinued. When disease relapse occurs, a further course or courses can be given with good results. This review summarizes the current evidence regarding the role of rituximab in treating non-infectious uveitis. 23712095 Antitumor activity and toxicity relationship of annonaceous acetogenins. Annonaceous acetogenins (ACGs) are one of the most interesting classes of natural products appearing in the past two decades. Here, we studied the antitumor activity and toxicity relationship of ACGs including annosquamin B (1), bullatacin (2) and annosquatin B (3) in vivo. A single intraperitoneal (i.p.) injection of 100μg/kg of annosquamin B, bullatacin and annosquatin B did not cause side effects in normal mice. Bullatacin treatment with five doses of 25 and 50μg/kg in H22 hepatoma cells bearing mice resulted in about 61% reduction in tumor growth with hematologic parameters increased significantly in normal mice. Annosquamin B and annosquatin B treatments with 10 doses of 25, 50 and 100μg/kg in the H22 hepatoma cells transplantation tumor model mice resulted in maximum 53.7% and 58.7% reduction in tumor growth, respectively, and did not cause severe side effects in normal mice. This study provided the evidence that adjacent bis-THF ACGs showed higher antitumor activity and toxicity than mono-THF and nonadjacent bis-THF ACGs in vivo. Furthermore, it was found that bullatacin led to liver and kidney toxicity via increasing calcium concentration, ROS production, and Bax expression and Bax/Bcl-2 ratio in rats with repeated treatment with bullatacin for 3weeks. 23887958 Evaluation of the particulate concentration in a gelatin-based phantom for sonographically guided lesion biopsy. Objectives- The purpose of this study was to determine the particulate concentration in a gelatin-based ultrasound phantom for lesion biopsy at 6 cm in depth to reduce visualization of the biopsy needle in the near field, simulating subcutaneous fat and tissue echogenicity, and maintain target lesion visualization. Methods- Four gelatin-based phantoms with cornstarch at concentrations of 4, 8, 12, and 16 g/L and an anechoic gelatin target at 7 cm in depth were rated on a 5-point scale by readers for visibility of the target lesion, similarity of near-field to abdominal subcutaneous fat echogenicity, and visibility of a 22-gauge spinal needle in the phantom. A timed sonographically guided localization task was performed on the anechoic target by 4 radiology residents using the 22-gauge spinal needle. Results were analyzed by comparative statistical analysis. Results- An increasing particulate concentration did not alter the similarity of near-field to abdominal subcutaneous fat echogenicity (P = .6) but did significantly reduce visibility of the anechoic target at a cornstarch concentration of 16 g/L (P = .04) and the 22-gauge needle at 12 g/L (P = .03). Decreased visualization of the needle or target lesion did not affect the time for needle localization of the anechoic target (P = .96). Conclusions- The optimal ultrasound phantom cornstarch concentration was 12 g/L to reduce visualization of the spinal needle, simulating subcutaneous fat echogenicity while maintaining target lesion visualization. 23883111 Mitochondrial Polymorphisms Impact Outcomes after Severe Traumatic Brain Injury. Patient outcomes are variable following severe traumatic brain injury (TBI); however the biological underpinnings explaining this variability are unclear. Mitochondrial dysfunction after TBI is well documented, particularly in animal studies. The aim of this study was to investigate the role of mitochondrial polymorphisms on mitochondrial function and patient outcomes out to 1 year after a severe TBI in a human adult population. The Human MitoChip V2.0 was used to evaluate mitochondrial variants in an initial set of n=136 subjects. SNPs found to be significantly associated with patient outcomes [Glasgow Outcome Scale (GOS), Neurobehavioral Rating Scale (NRS), Disability Rating Scale (DRS), in-hospital mortality, and hospital length of stay] or neurochemical level (lactate:pyruvate ratio from cerebrospinal fluid) were further evaluated in an expanded sample of n=336 subjects. A10398G was associated with DRS at 6 and 12 months (p=0.02) and a significant time by SNP interaction for DRS was found (p=0.0013). The A10398 allele was associated with greater disability over time. There was a T195C by sex interaction for GOS (p=0.03) with the T195 allele associated with poorer outcomes in females. This is consistent with our findings that the T195 allele was associated with mitochondrial dysfunction (p=0.01) but only in females. This is the first study associating mitochondrial DNA variation with both mitochondrial function and neurobehavioral outcomes after TBI in humans. Our findings indicate that mitochondrial DNA variation may impact patient outcomes after a TBI potentially by influencing mitochondrial function and that sex of the patient may be important in evaluating these associations in future studies. 23747701 Induction of Biofilm Formation in the Betaproteobacterium Burkholderia unamae CK43B Exposed to Exogenous Indole and Gallic Acid. Burkholderia unamae CK43B, a member of the Betaproteobacteria that was isolated from the rhizosphere of a Shorea balangeran sapling in a tropical peat swamp forest, produces neither indole nor extracellular polymeric substances associated with biofilm formation. When cultured in a modified Winogradsky's medium supplemented with up to 1.7 mM indole, B. unamae CK43B maintains its planktonic state by cell swelling and effectively degrades exogenous indole. However, in medium supplemented with 1.7 mM exogenous indole and 1.0 mM gallic acid, B. unamae CK43B produced extracellular polymeric substances and formed a biofilm. The concentration indicated above of gallic acid alone had no effect on either the growth or the differentiation of B. unamae CK43B cells above a certain concentration threshold, whereas it inhibited indole degradation by B. unamae CK43B to 3-hydroxyindoxyl. In addition, coculture of B. unamae CK43B with indole-producing Escherichia coli in nutrient-rich Luria-Bertani medium supplemented with 1.0 mM gallic acid led to the formation of mixed cell aggregates. The viability and active growth of B. unamae CK43B cells in a coculture system with Escherichia coli were evidenced by fluorescence in situ hybridization. Our data thus suggest that indole facilitates intergenus communication between indole-producing gammaproteobacteria and some indole-degrading bacteria, particularly in gallic acid-rich environments. 23789726 A cross-sectional study of hepatitis e virus infection in pigs in different-sized farms in northern Thailand. Abstract Pigs are an important reservoir of hepatitis E virus (HEV) in many countries throughout the world. We evaluated the association between farm size and presence of serum antibodies against HEV, as well as other risk factors for infection in pigs raised in Nan Province, Thailand in a cross-sectional study. The sampling frame was a total-population census of all pig herds, stratified into three classes of the farm size according to criteria developed by the Nan provincial livestock health office. One-eighth of all pigs in each farm were sampled randomly. All pig-farm owners were interviewed to elicit information on general characteristics of their farms, biosecurity and hygienic procedures, and farm management. We obtained sera and fecal samples from 879 pigs to test for antibodies to HEV and HEV RNA. Odds ratios (OR) and 95% confidence intervals (CI) for risk factors for HEV seroprevalence were estimated by multivariate logistic regression. The overall prevalence of anti-HEV immunoglobulin G antibodies was 9.9%. Pigs studied from medium-sized farms had a higher HEV seroprevalence than those from larger farms (adjusted OR 4.95, 95% CI: 1.79, 13.70). Factors associated with HEV seropositivity included feeding pigs with agro-industrial byproducts, having veterinarians on farms, and presence of other pig farms within 100 m. Twenty-five (2.9%) of 875 sampled pig stools were positive for HEV RNA. Phylogenetic analysis revealed that all HEV isolates clustered to HEV genotype 3. 23879887 Monitoring Avian Influenza A(H7N9) Virus through National Influenza-like Illness Surveillance, China. In China during March 4-April 28, 2013, avian influenza A(H7N9) virus testing was performed on 20,739 specimens from patients with influenza-like illness in 10 provinces with confirmed human cases: 6 (0.03%) were positive, and increased numbers of unsubtypeable influenza-positive specimens were not seen. Careful monitoring and rapid characterization of influenza A(H7N9) and other influenza viruses remain critical. 23494513 Covered self-expandable metal stents are more associated with complications in the management of malignant colorectal obstruction. The use of self-expandable metal stents (SEMS) for the treatment of malignant colorectal obstruction is increasing. However, results of risk factors for its complications are inconsistent. This study aimed to examine the clinical effectiveness of the procedure as well as the complications and risk factors associated with the complications. Medical records of patients with malignant colorectal obstruction who underwent endoscopic placement of covered or uncovered SEMS were reviewed retrospectively. The procedure was performed by two endoscopists with experience in pancreatobiliary endoscopy. A total of 152 patients were included (102 men; mean age, 70 ± 12.5 years). The procedure was performed for palliative management in 83 patients and performed as a bridge to surgery in 69 patients. There were 111 uncovered stents and 41 covered stents. The technical success rate was 100 % and the clinical success rate 94.1 %. Overall complications were observed in 49 patients (32.2 %) during the follow-up period (median, 98 days; interquartile range, 19-302 days). Obstruction (17.1 %), migration (7.9 %), perforation (5.2 %), bleeding (1.3 %), and tenesmus (0.7 %) were the causes of the complications. Stage IV disease, carcinomatosis peritonei, complete obstruction of the colon, palliative intention, and covered stents increased the complications based on the univariate analysis. Multivariate analysis revealed that complete obstruction of the colon and covered stents were significantly independent risk factors for complications. In the palliative group, Kaplan-Meier analysis showed significantly shorter median duration to the onset of complications in the covered stent group than in the uncovered stent group. Although SEMS in patients with malignant colorectal obstruction is effective both as palliative therapy and as a bridge to surgery, one-third of patients experienced complications. Severity of obstruction and stent type can influence outcomes. 23836528 Comparative proteomics of glioma stem cells and differentiated tumor cells identifies S100A9 as a potential therapeutic target. Recent studies have suggested the existence of a small subset of cancer cells called cancer stem cells(CSCs), which possess the ability to initiate malignancies, promote tumor formation, drive metastasis, and evade conventional chemotherapies. Elucidation of the specific signaling pathway and mechanism underlying the action of CSCs might improve the efficacy of cancer treatments. In this study, we analyzed differentially expressed proteins between glioma stem cells and differentiated tumor cells isolated from the human glioma cell line, U251, via iTRAQ-tagging combined with two dimensional liquid chromatography tandem MS analysis to identify proteins correlated with specific features of CSCs. Out of a total data set of 559 identified proteins, 29 proteins were up-regulated in the glioma stem cells when compared with the differentiated cells. Interestingly, The expression level of S100A9 was 5-fold higher in glioma stem cells than differentiated cells. Similar results were also observed in glioma stem cells derived from other glioma cells. More importantly, knockdown of S100A9 by RNA interference suppressed the proliferation of glioma stem cell line and decreased the growth of xenograft tumors in vivo. Taken together, these results indicate that the tumorigenesis potential of CSCs arises from highly expressed S100A9. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc. 23880570 Haemorrhagic stroke or hyperglycaemia? A 56-year-old woman with no medical history was admitted with acute onset hemiballistic-choreiform movements of right extremity. On admission, her serum glucose and osmolality were elevated. Her glycosylated haemoblobin (HbA1c) was 17.9 with average blood sugars of 467 mg/dL. A CT scan of the brain revealed unilateral hyperintensities in the basal ganglia. A complete stroke work-up, including MRI and MR angiography of brain was otherwise unrevealing. Subcutaneous insulin was instituted, which led to complete resolution of her symptoms within 48 h of hospital admission. She was readmitted 4 weeks after her initial discharge for similar, but less severe, symptoms. This time her HbA1c was 13.9 with an average blood sugar of 352 mg/dL. A repeat MRI demonstrated a persistent abnormal signal within the left basal ganglia without infarct. She was started on subcutaneous insulin. Her symptoms improved but did not resolve. Haloperidol and gabapentin were initiated and she was again discharged after stabilisation to a rehabilitation centre as per physiotherapy recommendations. 23861837 Functional Divergence in Shrimp Anti-Lipopolysaccharide Factors (ALFs): From Recognition of Cell Wall Components to Antimicrobial Activity. Antilipopolysaccharide factors (ALFs) have been described as highly cationic polypeptides with a broad spectrum of potent antimicrobial activities. In addition, ALFs have been shown to recognize LPS, a major component of the Gram-negative bacteria cell wall, through conserved amino acid residues exposed in the four-stranded β-sheet of their three dimensional structure. In penaeid shrimp, ALFs form a diverse family of antimicrobial peptides composed by three main variants, classified as ALF Groups A to C. Here, we identified a novel group of ALFs in shrimp (Group D ALFs), which corresponds to anionic polypeptides in which many residues of the LPS binding site are lacking. Both Group B (cationic) and Group D (anionic) shrimp ALFs were produced in a heterologous expression system. Group D ALFs were found to have impaired LPS-binding activities and only limited antimicrobial activity compared to Group B ALFs. Interestingly, all four ALF groups were shown to be simultaneously expressed in an individual shrimp and to follow different patterns of gene expression in response to a microbial infection. Group B was by far the more expressed of the ALF genes. From our results, nucleotide sequence variations in shrimp ALFs result in functional divergence, with significant differences in LPS-binding and antimicrobial activities. To our knowledge, this is the first functional characterization of the sequence diversity found in the ALF family. 23949622 Functional Polymorphisms in the Regulatory Regions of the VNN1 Gene Are Associated with Susceptibility to Inflammatory Bowel Diseases. Vanin-1 is an epithelial pantetheinase, which regulates intestinal inflammation in mouse. We investigated whether human VNN1 levels could be associated to the susceptibility to inflammatory bowel diseases (IBD) and explored the participation of PPARg to these processes. We studied VNN1 expression in colon biopsies from IBD patients. We investigated polymorphisms in the regulatory regions of the VNN1 gene and examined their genetic association with the disease. Functional relevance of these single-nucleotide polymorphisms (SNPs) was assayed, and we tested PPARg in nuclear complexes associated with specific VNN1 polymorphic sequences. In mouse, we examined Vanin-1 expression in gut and feces during dextran sulfate sodium-induced colitis and assayed the effect of PPARg on Vanin-1 regulation. VNN1 is expressed by enterocytes and is upregulated in IBD. Three SNPs are statistically associated to IBD. The regions containing these SNPs specifically bind nuclear complexes and are correlated with the VNN1 transcript abundance in colon in an allele-dependent manner. One rare SNP is associated to severe ulcerative colitis with strong VNN1 and dropped PPARg levels. PPARg is involved in nuclear complexes that bound to VNN1 regulatory sites. Similarly, Vanin-1 is tightly regulated in the mouse gut in normal and colitis conditions and PPARg regulates its expression. VNN1 is a marker for IBD. Polymorphic positions in the VNN1 locus are direct targets for nuclear factors that might regulate the level of VNN1 in colon, and this could be linked to IBD susceptibility. It is hoped that modulating locally VNN1 expression or activity can be exploited to develop future therapeutic strategies against IBD. 23424216 Cytotoxic, genotoxic and antigenotoxic potencies of oligorutins. Rutin has been enzymatically oligomerized by laccase from Trametes versicolor. Five fractions of oligomers were obtained from the monomers having high solubility in water, which can reach 351-times that of rutin. Cytotoxicity of rutin and oligorutin fractions was evaluated towards K562 cells. Oligorutin fractions showed a lower antiproliferative effect compared with its monomer. The genotoxic potential of rutin and oligorutin fractions was assessed, at the limit of the solubility of each molecule, using the comet test. None of the tested concentrations of either rutin or oligorutin fractions has showed a genotoxic effect. Similarly, the antigenotoxic effect of these flavonoids was tested using the same assay. The obtained results showed a higher ability of oligorutin fractions to reduce the genotoxicity induced by hydrogen peroxide compared with monomeric rutin. 22512726 The effect of some antineoplastic agents on glutathione S-transferase from human erythrocytes. Glutathione S-transferase was purified from human erythrocytes and effects of some antineoplastic agents were investigated on the enzyme activity. The purification procedure was composed of Glutathione-Agarose affinity chromatography after preparation of erythrocytes hemolysate. Using this procedure, the enzyme, having the specific activity of 16.00 EU/mg proteins, was purified 1143-fold with a yield of 80%. The purified enzyme showed a single band on the SDS-PAGE. The effects of paclitaxel, cyclophosphamide, and gemcitabine, are antineoplastic agents, were examined on the in vitro enzyme activity of glutathione S-transferase and were determined to be inhibitors for the enzyme. IC50 values were 0.23 mM for paclitaxel, 5.57 mm for cyclophosphamide, and 6.35 mM for gemcitabine. These constants were 0.182 ± 0.028 mM and 0.162 ± 0.062 mM for paclitaxel, 6.97 ± 0.49 mM and 10.50 ± 5.43 mM for cyclophosphamide, and 6.71 mM and 7.93 mM for gemcitabine, with GSH and CDNB substrates, respectively. Inhibition types of all inhibitors were noncompetitive. 22575631 Choosing between velocity-time-integral ratio and peak velocity ratio for calculation of the dimensionless index (or aortic valve area) in serial follow-up of aortic stenosis. It remains unclear which echocardiographic measure is most suitable for serial measurement in real-world aortic stenosis (AS) follow-up. We determine whether the dimensionless index (DI) between aortic valve and left ventricular outflow tract velocities is measured more consistently using velocity-time-integral (VTI) or peak velocities (Vpeak) in real life. Serial echocardiograms acquired within 6months in subjects with AS were analysed with blinding, to compare the variability over time of DI calculated using Vpeak, with that of DI calculated using VTI. Paired echocardiograms, acquired on average 72days apart, were analysed from 70 patients with a range of severities of AS (59% severe). DI, calculated using either Vpeak or VTI, did not significantly change over this short time. Coefficient of variation was significantly better when DI was calculated using Vpeak than VTI (12.6 versus 25.4%, p<0.0001). The variabilities of mean and peak trans-aortic valve 4v(2) and left ventricular outflow tract VTI were no better: 26.9%, 19.1% and 22.1% respectively. Serially-followed variables require minimal noise to maximise detection of genuine change. For AS surveillance, calculating DI - or effective orifice area - from the ratio of Vpeak rather than VTIs would reduce 95% confidence intervals from ±51% to a still-disappointing ±25%. Guidelines recommend noisy surveillance measures, causing conscientious echocardiographers to 'peek' at previous values, and impairing clinicians' faith in echocardiographically-observed changes when making clinical decisions. For us in echocardiography to improve our ability to contribute to AS follow-up requires us to first acknowledge and discuss this honestly. 23330726 Multilayered hierarchical capsules providing cell adhesion sites. Liquified capsules featuring (i) an external shell by layer-by-layer assembly of poly(l-lysine), alginate, and chitosan, and encapsulating (ii) surface functionalized poly(l-lactic acid) (PLLA) microparticles were developed. We hypothesize that, while the liquified environment enhances the diffusion of essential molecules for cell survival, microparticles dispersed in the liquified core of capsules provide the physical support required for cellular functions of anchorage-dependent cells. The influence of the incorporation of PLL on the regime growth, thickness, and stability was analyzed. Results show a more resistant and thicker film with an exponential build-up growth regime. Moreover, capsules ability to support cell survival was assessed. Capsules containing microparticles revealed an enhanced biological outcome in cell metabolic activity and proliferation, suggesting their potential to boost the development of innovative biomaterial designs for bioencapsulation systems and tissue engineering products. 23955520 Immunochemical characterization of synthetic hexa-, octa- and decasaccharide conjugate vaccines for Vibrio cholerae O:1 Serotype Ogawa with emphasis on antigenic density and chain length. Cholera remains to be a global health problem without suitable vaccines for endemic control or outbreak relief. Here we describe a new parenteral vaccine based on neoglyco-conjugate of synthetic fragments of O-specific polysaccharide (O-SP) of Vibrio cholerae O1, serotype Ogawa. Hexa-, octa- and decasaccharides of the O-SP with carboxylic acid at the reducing end were chemically synthesized and conjugated to tetanus toxoid (TT). The conjugates prepared by a novel linking scheme consisted of 17-atom linker of hydrazide and alkyl bonds elicited robust serum IgG anti-LPS responses with vibriocidal activities in mice. There is a length dependence in immune response with decasaccharide conjugates elicited the highest anti-LPS IgG. There seems to be an indication that regardless of the carbohydrate chain length, a molar ratio of 230 ± 10 monosaccharide units per TT induced high antibody response. The conjugates also elicited cross-reactive antibodies to serotype Inaba. The formulation of the proposed cholera conjugate vaccine, similar to other licensed polysaccharide vaccine, is suitable for children immunization. A parenteral cholera vaccine could overcome the diminishing immunogenicity in most of oral vaccines due to the gastrointestinal complexity and environmental enteropathy in children living in impoverished environment and could be considered for global cholera immunization. 23660444 Cortisol treatment of prespawning female cod affects cytogenesis related factors in eggs and embryos. A stable supply of viable eggs and embryos is crucial for successful farming of Atlantic cod. Stress during broodstock rearing can have negative effects on offspring, but little is known about the molecular mechanisms that cause abnormal development. Maternally transferred mRNAs have been shown to be essential for normal development, and stress may therefore influence their expression and the subsequent embryonic development. We investigated if mimicked stress in cod females affects mRNA concentrations in eggs/embryos, and if this can be linked to viability of embryos. Three weeks before peak spawning, 20 fish were intraperitoneally implanted with either cortisol-containing or cortisol-free (sham) osmotic pumps. At peak spawning all individuals were stripped and eggs were fertilized and incubated until hatching. Samples were collected from unfertilized eggs and embryos for analysis of gene expression (microarray), viability, steroids and vitellogenin. Plasma concentration of cortisol (ng/ml) in treated females was significantly higher at spawning (127.1±20.9) than that of sham control (11.3±6.7). This difference was also reflected in eggs and embryos. Percent fertilization, asymmetric cell division and hatching were not affected. However, numerous genes were differentially expressed in eggs and embryos in response to elevated cortisol, especially in maternal (oocyte and blastula) stages. Among these differentially expressed genes, some were found to be linked to cytogenesis (stxbp6, fbxw2, capn12, thbs4, sytl2, coro1c, sel1l3), induction of mesodermal fate (fgfrl1) and import of the glucocorticoid receptor to the cell nucleus (ipo7). Gene ontology overrepresentation analysis on the whole set of differentially expressed genes at maternal stages (539 genes) revealed enriched activity in membrane associated regions, which largely corresponds to cytogenesis related processes. These results suggest that despite no visible phenotypic effects in early embryos, broodstock stress affects the egg/embryonic transcriptome, especially in relation to cytogenesis. Furthermore, effects related to egg/embryo phenotypes are difficult to measure at early stages of development, and instead might become apparent at later life stages. 23941307 Early postoperative complications after stapled versus handsewn restorative proctocolectomy with ileal pouch-anal anastomosis in 148 patients with familial adenomatous polyposis coli (FAP):a matched pair analysis. Restorative proctocolectomy with Ileal pouch-anal anastomosis for patients with familial polyposis coli (FAP) and ulcerative colitis (UC), has been modified from a transanal hand-suture after mucosectomy to a stapled ileo-anal anastomosis (IAA) without mucosectomy. Better functional results favour stapled anastomosis, which, however, results in higher rates of adenomas in persisting anorectal mucosa The purpose of this study was to compare the two techniques of pouch-anal anastomosis with respect to early postoperative complications in a collective of FAP-patients. The study was performed as a matched-pair analysis. Data were obtained from a prospectively collected database. The overall rate of postoperative complications was higher after stapled IAA (31% stapled vs. 23% handsewn); with anastomotic stricture occurring in 24.3% and 16.2%. [p=0.22]). Any leakage or pelvic abscess formation after stapled anastomosis occurred within 30 days in almost all cases, whereas after handsewn IAA they were mainly diagnosed between 30 days and six months. A laparoscopic approach was used in 56.7% in the stapled group and in only two patients in the handsewn group. Intraoperative blood loss was significantly higher in the handsewn group (mean 699ml, SD 511ml vs. 369 ml, SD 343 ml; p<0.0001), as was the volume of blood transfusion (mean 205ml, SD 365ml vs. 8ml, SD 49ml; p<0.0001). Function did not differ between both groups. There was a non-statistically significant tendency towards a higher rate of early postoperative complications after stapled IAA. The timing of anastomotic leakage and abscess formation differed between both groups. This article is protected by copyright. All rights reserved. 23965826 Enhanced potassium selectivity in a bioinspired solid nanopore. Biological ion channels present unique ionic properties. They can be highly permeable to ions, while selecting only one type of ions, without external energy supply. An important research field has been developed to transfer these properties to solid state nanoporous membranes in order to develop artificial biomimetic nanofilters. One of the promising ways to develop biomimetic structures is based on the direct insertion of the gramicidin A, i.e. an ionic channel, inside a nanopore. Experiments have recently proved the feasibility of such a hybrid membrane with very interesting results regarding the ionic selectivity. Here, we propose to interpret these experiments using theoretical molecular dynamic simulations which allow us to analyze more profoundly the structures of the proteins confined inside the nanopore and the relation between their conformation and the observed ionic properties. 23947620 Modelling organelle transport after traumatic axonal injury. This paper is motivated by recent experimental research (Tang-Schomer et al. 2012) on the formation of periodic varicosities in axons after traumatic brain injury (TBI). TBI leads to the formation of undulated distortions in the axons due to their dynamic deformation. These distortions result in the breakage of some microtubules (MTs) near the peaks of undulations. The breakage is followed by catastrophic MT depolymerisation around the broken ends. Although after relaxation axons regain their straight geometry, the structure of the axon after TBI is characterised by the presence of periodic regions where the density of MTs has been decreased due to depolymerisation. We modelled organelle transport in an axon segment with such a damaged MT structure and investigated how this structure affects the distributions of organelle concentrations and fluxes. The modelling results suggest that organelles accumulate at the boundaries of the region where the density of MTs has been decreased by depolymerisation. According to the model, the presence of such damaged regions decreases the organelle flux by only about 12%. This provides evidence that axon degradation after TBI may be caused by organelle accumulation rather than by starvation due to insufficient organelle flux. 23126331 Mating in the pseudogamic apomictic Anemopaegma acutifolium DC: another case of pseudo-self-compatibility in Bignoniaceae? Self-compatibility in apomictic pseudogamic species is considered fundamental to assure reproduction by seeds in extreme situations, making apomictic species more advantageous than sexual ones in these scenarios. Anemopaegma acutifolium is a polyploidy, apomictic sporophytic species with no endosperm development in ovules of unpollinated pistils, which indicates obligate pseudogamy. Thus, the aim of the present work is to study the breeding system and post-pollination events to test if there is similar pseudogamous development irrespective of pollination treatment. We analysed fruit and seed set obtained in controlled experimental pollinations, as well as embryo number per seed, and the progress of ovule penetration, fertilisation and early endosperm development between self- and cross-pollinated pistils. We found that the species is self-fertile and that spontaneous selfing fruit set is also possible, although emasculated flowers never form fruits. Selfed pistils were as efficient as crossed ones for all parameters analysed, except for a delay in endosperm development observed in the former that may be an effect of the late-acting self-incompatibility. Therefore, the avoidance of selfed pistil abortion seems to be promoted by the presence of adventitious embryos and a normal endosperm. We conclude that A. acutifolium shows apomixis-related pseudo-self-compatibility, as in other self-fertile apomictic species of Bignoniaceae, which confer reproductive assurance and increases fruit-set and persistence ability in fast-changing tropical habitats. 23831069 The Efficacy of Bupivacaine Infiltration on the Nephrostomy Tract in Tubeless and Standard Percutaneous Nephrolithotomy: A Prospective, Randomized, Multicenter Study. To assess the analgesic efficacy of bupivacaine infiltrations into the nephrostomy tract in tubeless and standard percutaneous nephrolithotomy (PCNL). This prospective, randomized controlled study enrolled 121 patients. Patients were randomized to receive a 20-mL infiltration of 0.25% bupivacaine into the nephrostomy tract after PCNL. Patients were divided into 2 groups. The group 1 patients received bupivacaine infiltrations, whereas group 2 did not. Patients' visual analog scale (VAS) pain scores were evaluated at 6, 12, and 24 hours postoperatively. Pain in the postoperative period was managed with intramuscular diclofenac sodium (75 mg) or meperidine (pethidine) hydrochloride (50 mg), as requested by the patients. The patients were a mean age of 43.2 ± 12.7 years (range, 18-74 years). The VAS pain scores at 6, 12, and 24 hours postoperatively and the amount of diclofenac sodium needed were significantly less in the group with bupivacaine infiltration than in those that did not receive the infiltration (P <.05). The VAS pain scores in patients with tubeless PCNL were significantly lower than those in patients with standard PCNL (P <.05). The pain after tubeless and standard PCNL may be decreased by bupivacaine infiltration into the nephrostomy tract. The findings of the present study reveal that a tubeless procedure and local analgesic infiltration into the nephrostomy tract after the PCNL is the more comfortable procedure for the patients. 23528656 Learning curve of virtual chromoendoscopy for the prediction of hyperplastic and adenomatous colorectal lesions: a prospective 2-center study. Computed virtual chromoendoscopy (CVC) enables high-definition imaging of mucosal lesions with improved tissue contrast. Previous studies have shown that CVC yields an improved detection rate of colorectal lesions. However, the learning curve for interpretation of CVC images is unknown. To examine the learning curve of correctly identifying hyperplastic and adenomatous colorectal lesions by using CVC. Prospective, 2-center study. Consecutive patients undergoing screening colonoscopy were included. CVC images were analyzed by using corresponding polypectomies as the reference standard followed by a prospective, double-blind review of i-scan images. A training set containing 20 images with known histology was reviewed to standardize image interpretation, followed by a blind review of 110 unknown images. Overall, 4 endoscopists from 2 different endoscopy centers evaluated the images, which were obtained by 1 endoscopist using high-definition endoscopy with CVC. Patients were included in a prospective fashion. Seventy-seven of 110 colorectal lesions were adenomas and 33 were hyperplastic lesions. Mean diameter of colonic polyps was 4 mm (range, 2-20 mm). Overall accuracy for the group was 73.9% for lesions 1 to 22, 79.6% for lesions 23 to 44, 84.1% for lesions 45 to 66, 87.5% for lesions 67 to 88, and 94.3% for lesions 89 to 110. Accuracy of i-scan for prediction of polyp histology was not dependent on polyp size (≤5 mm, 6-10 mm, or > 10 mm). The ability to obtain high-quality images was stable over time, and high-quality images were constantly produced. Post-hoc assessment. Accurate interpretation of CVC images for prediction of hyperplastic and adenomatous colorectal lesions follows a learning curve but can be learned rapidly. 23868550 Impact of the HPV-positivity definition on the prognostic value of HPV status in patients with locally advanced squamous cell carcinoma of the head and neck. This study re-evaluated the prognostic value of HPV status for loco-regional control (LRC), metastases-free survival (MFS), and survival (OS) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). A modified definition of HPV positivity was used in the current study compared to the authors' previous study. In the previous study of the same 170 patients, a tumor was defined as HPV-positive if it showed a positive in situ hybridization result in ≥ 10 % of tumor cells and/or positive p16 immunostaining. In the current analysis, tumors were considered HPV-positive only if they showed positive results for both in situ hybridization and p16 immunostaining. In addition to HPV status, the same 11 potential prognostic factors were investigated for treatment outcomes as in the preceding study. In the multivariate analysis of the current study, HPV positivity was significantly associated with improved LRC [risk ratio (RR) 9.78; p < 0.001], MFS (RR 7.17; p = 0.008), and OS (RR 6.61; p < 0.001). In the previous study, HPV positivity was associated with LRC (RR 2.34; p = 0.014) and OS (RR 2.19; p = 0.019), but not with MFS (RR 2.04; p = 0.11). Applying the new definition of HPV positivity, the impact of HPV status on the prognosis of patients irradiated for locally advanced SCCHN was more prominent than in our previous study and associated with all three investigated endpoints. 23838815 (1)H, (13)C, and (15)N backbone and side-chain chemical shift assignments of the free and bound forms of the human PTPN11 second SH2 domain. Src homology 2 (SH2) domains have an important role in the regulation of protein activity and intracellular signaling processes. They are geared to bind to specific phosphotyrosine (pY) motifs, with a substrate sequence specificity depending on the three amino acids immediately C-terminal to the pY. Here we report for the first time the (1)H, (15)N and (13)C backbone and side-chain chemical shift assignments for the C-terminal SH2 domain of the human protein tyrosine phosphatase PTPN11, both in its free and bound forms, where the ligand in the latter corresponds to a specific sequence of the human erythropoietin receptor. 23852724 Amniotic Fluid Stem Cells Prevent Development of Ascites in a Neonatal Rat Model of Necrotizing Enterocolitis. Aim It has been demonstrated that in a neonatal rat model of necrotizing enterocolitis (NEC), amniotic fluid stem (AFS) cells decrease intestinal damage and improve survival via modulation of stromal cells expressing cyclooxygenase 2 in the lamina propria. Herein, we aimed to evaluate the effect of AFS cells on body weight and fluid retention in this NEC model.Methods AFS cells were obtained from green fluorescent protein (GFP) + pregnant rats at E16 and expanded in culture. A total of 185 neonatal rats had NEC induced by gavage feeding of hypertonic formula + hypoxia + oral lipopolysaccharide (4 mg/kg/d) and were randomized to intraperitoneal phosphate buffered saline (PBS, n = 93) or AFS cells (n = 92). A total of 36 breastfed (BF) rats were used as controls. All rats were being killed at 96 hours of life. Groups were compared for body weight and presence of free intraperitoneal fluid using nonparametric and contingency tests. Data are expressed as mean ± standard deviation.Results There were no differences in birth weight among the groups (PBS = 5.6 ± 0. 3 g; AFS cells = 5.6 ± 0. 3 g; BF = 5.6 ± 0. 3 g; p = 1). The body weight at randomization was not different between PBS (5.61 ± 0. 5 g) and AFS cells (5.60 ± 0. 5; p = 1) rats. After the rats were killed, BF rats were significantly heavier (12.5 ± 0.1 g) than PBS (5.12 ± 0.4 g) and AFS cell rats (4.95 ± 0.3; p < 0.0001). From randomization to being killed, PBS rats had 9% of weight loss in comparison with 12% in AFS cell rats (p = 0.08). After the rats were killed, 42 (45%) PBS rats developed ascites with evident abdominal distension in comparison with 19 (21%) AFS cells (p = 0.0005). None of BF animals had ascites.Conclusion Gavage feeding and undernutrition severely affect growth in this model of NEC. Administration of AFS cells result in lower incidence of ascites than in PBS rats. This could explain the differences in body weight between the two groups of rats that were killed. Furthermore, studies on liver function and fluid composition are needed to investigate our speculation. 23573951 Gelation-induced visible supramolecular chiral recognition by fluorescent metal complexes of quinolinol-glutamide. Three metal complexes consisting of Li(+), Zn(2+), and Al(3+) and quinolinol-functionalized l-glutamides (HQLG), (abbreviated as LiHQLG, Zn(HQLG)2, and Al(HQLG)3) were found to form fluorescent metallogels in several organic solvents. In solution, these chiral complexes showed neither any CD signal in the chromophore region nor chiral recognition of the chiral species. However, upon gel formation, the supramolecular chirality emerged because of the self-assembled nanostructures, which provided an opportunity for the chiral recognition of enantiomeric ligands. The metallogels showed different fluorescence changes when they met with enantiomeric (R,R)- or (S,S)-1,2-diaminocyclohexane. Among them, the Al(HQLG)3 metallogels did not show any change whereas the LiHQLG gels exhibited the same decrease in fluorescence. Interestingly, the Zn(HQLG)2 gels showed obviously different fluorescent color with respect to (R,R)- and (S,S)-1,2-diaminocyclohexane, thus providing visible chiral recognition via the naked eye. Such different recognition ability was discussed on the basis of the assembled chiral nanostructures and the primary molecular structures of the metal complexes. It was shown that both of them played important roles in chiral recognition. 23582239 Numerical simulation of effective phase velocity and attenuation of shear elastic wave propagation in unidirectional composite materials. In this paper, a simple simulation approach is presented for calculating the effective phase velocity and attenuation coefficient of elastic shear waves propagating in composite materials with randomly distributed unidirectional inclusions. As an application of the developed numerical approach, the phase velocities and attenuation coefficients of the coherent waves in four different types of composite material are simulated for various incident frequencies up to π. Numerical results are compared with theoretical predictions obtained from three representative theoretical models. While all theoretical results agree very well with numerical values at low incident frequencies, the discrepancies increase with the increased incident frequency and volume fraction of inclusions. It has been found that within the frequency and volume fraction ranges considered in this work, the generalized self-consistent model by Kanaun and Levin [18] seems to provide the most accurate estimations. 23165625 A VUV photoionization study of the multichannel reaction of phenyl radicals with 1,3-butadiene under combustion relevant conditions. We studied the reaction of phenyl radicals (C(6)H(5)) with 1,3-butadiene (H(2)CCHCHCH(2)) exploiting a high temperature chemical reactor under combustion-like conditions (300 Torr, 873 K). The reaction products were probed in a supersonic beam by utilizing VUV radiation from the Advanced Light Source and by recording the experimental PIE curves at mass-to-charge ratios of m/z = 130 (C(10)H(10)(+)), 116 (C(9)H(8)(+)), and 104 (C(8)H(8)(+)). Our data suggest that the atomic hydrogen (H), methyl (CH(3)), and vinyl (C(2)H(3)) losses are open with estimated branching ratios of about 86 ± 4%, 8 ± 2%, and 6 ± 2%, respectively. The isomer distributions were probed further by fitting the experimentally recorded PIE curves with a linear combination of the PIE curves of individual C(10)H(10), C(9)H(8), and C(8)H(8) isomers. These fits indicate the formation of three C(10)H(10) isomers (trans-1,3-butadienylbenzene, 1,4-dihydronaphthalene, 1-methylindene), three C(9)H(8) isomers (indene, phenylallene, 1-phenyl-1-methylacetylene), and a C(8)H(8) isomer (styrene). A comparison with results from recent crossed molecular beam studies of the 1,3-butadiene-phenyl radical reaction and electronic structure calculations suggests that trans-1,3-butadienylbenzene (130 amu), 1,4-dihydronaphthalene (130 amu), and styrene (104 amu) are reaction products formed as a consequence of a bimolecular reaction between the phenyl radical and 1,3-butadiene. 1-Methylindene (130 amu), indene (116 amu), phenylallene (116 amu), and 1-phenyl-1-methylacetylene (116 amu) are synthesized upon reaction of the phenyl radical with three C(4)H(6) isomers: 1,2-butadiene (H(2)CCCH(CH(3))), 1-butyne (HCCC(2)H(5)), and 2-butyne (CH(3)CCCH(3)); these C(4)H(6) isomers can be formed from 1,3-butadiene via hydrogen atom assisted isomerization reactions or via thermal rearrangements of 1,3-butadiene involving hydrogen shifts in the high temperature chemical reactor. 23968195 Luminescence of [Ru(bpy)2(dppz)](2+) Bound to RNA Mismatches. The luminescence of rac-[Ru(bpy)2(dppz)](2+) (bpy = 2,2'-bipyridine and dppz = dipyrido[3,2-a:2',3'-c]phenazine) was explored in the presence of RNA oligonucleotides containing a single RNA mismatch (CA and GG) in order to develop a probe for RNA mismatches. While there is minimal luminescence of [Ru(bpy)2(dppz)](2+) in the presence of matched RNA due to weak binding, the luminescence is significantly enhanced in the presence of a single CA mismatch. The luminescence differential between CA mismatched and matched RNA is substantially higher compared to the DNA analogue, and therefore, [Ru(bpy)2(dppz)](2+) appears to be also a sensitive light switch probe for a CA mismatch in duplex RNA. Although the luminescence intensity is lower in the presence of RNA than DNA, Förster resonance energy transfer (FRET) between the donor ruthenium complex and FRET acceptor SYTO 61 is successfully exploited to amplify the luminescence in the presence of the mismatch. Luminescence and quenching studies with sodium iodide suggest that [Ru(bpy)2(dppz)](2+) binds to these mismatches via metalloinsertion from the minor groove. This work provides further evidence that metalloinsertion is a general binding mode of octahedral metal complexes to thermodynamically destabilized mismatches not only in DNA but also in RNA. 23640861 Environmental toxin-linked nonalcoholic steatohepatitis and hepatic metabolic reprogramming in obese mice. Obesity is associated with strong risks of development of chronic inflammatory liver disease and metabolic syndrome following a second hit. This study tests the hypothesis that free radical metabolism of low chronic exposure to bromodichloromethane (BDCM), a disinfection byproduct of drinking water, causes nonalcoholic steatohepatitis (NASH), mediated by cytochrome P450 isoform CYP2E1 and adipokine leptin. Using diet-induced obese mice (DIO), mice deficient in CYP2E1, and mice with spontaneous knockout of the leptin gene, we show that BDCM caused increased lipid peroxidation and increased tyrosine nitration in DIO mice, events dependent on reductive metabolism by CYP2E1. DIO mice, exposed to BDCM, exhibited increased hepatic leptin levels and higher levels of proinflammatory gene expression and Kupffer cell activation. Obese mice exposed to BDCM also showed profound hepatic necrosis, Mallory body formation, collagen deposition, and higher alpha smooth muscle actin expression, events that are hallmarks of NASH. The absence of CYP2E1 gene in mice that were fed with a high-fat diet did not show NASH symptoms and were also protected from hepatic metabolic alterations in Glut-1, Glut-4, phosphofructokinase and phosphoenolpyruvate carboxykinase gene expressions (involved in carbohydrate metabolism), and UCP-1, PGC-1α, SREBP-1c, and PPAR-γ genes (involved in hepatic fat metabolism). Mice lacking the leptin gene were significantly protected from both NASH and metabolic alterations following BDCM exposure, suggesting that higher levels of leptin induction by BDCM in the liver contribute to the development of NASH and metabolic alterations in obesity. These results provide novel insights into BDCM-induced NASH and hepatic metabolic reprogramming and show the regulation of obesity-linked susceptibility to NASH by environmental factors, CYP2E1, and leptin. 23522328 Platelet-to-lymphocyte ratio better predicts inflammation than neutrophil-to-lymphocyte ratio in end-stage renal disease patients. Neutrophil-to-lymphocyte ratio (NLR) was introduced as a potential marker to determine inflammation in end-stage renal disease (ESRD) patients. Recently, platelet-to-lymphocyte ratio (PLR) and NLR were found to positively correlated with inflammatory markers including tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 in cardiac and noncardiac patients. Data regarding PLR and its association with inflammation are lacking in hemodialysis (HD) and peritoneal dialysis (PD) patients. Hence, we aimed to determine the relationship between PLR, NLR, and inflammation in ESRD patients. This was a cross-sectional study involving 62 ESRD patients (29 females, 33 males; mean age, 49.6 ± 14.6 years) receiving PD or HD for ≥6 months in the Dialysis Unit of Necmettin Erbakan University. PLR, NLR, C-reactive protein, TNF-α, IL-6 levels were measured. PLR, NLR, serum high sensitive C-reactive protein, IL-6, and TNF-α levels were significantly higher in PD patients when compared with HD patients. ESRD patients with PLR ≥ 140 had significantly higher NLR, IL-6, and TNF-α levels when compared to patients with PLR < 139. In the bivariate correlation analysis, PLR was positively correlated with NLR, IL-6, and TNF-α in this population. When we compared the association of PLR and NLR with IL-6 (r = 0.371, P = 0.003 vs. r = 0.263, P = 0.04, respectively) and TNF-α (r = 0.334, P = 0.008 vs. r = 0.273, P = 0.032, respectively), PLR was found to be superior to NLR in terms of inflammation in ESRD patients. Simple calculation of PLR can predict inflammation better than NLR in ESRD patients. 23962526 Development of a novel device for applying uniform doses of electron beam irradiation on carcasses. The Maxim's Electron Scatter Chamber (Maxim Chamber) was developed to obtain uniform dose distribution when applying electron beam (e-beam) irradiation to materials of irregular surface. This was achieved by placing a stainless steel mesh surrounding a cylindrical area where the target sample was placed. Upon contact with the mesh, electrons scatter and are directed onto the target from multiple angles, eliminating the e-beam linearity and resulting in a uniform dose distribution over the target surface. The effect of irradiation in the Maxim Chamber on dose distribution and pathogen reduction was tested on rabbit carcasses to simulate other larger carcasses. The dose uniformity ratio (DUR) on the rabbit carcasses was 1.8, indicating an acceptable dose distribution. On inoculated carcasses, this treatment reduced Escherichia coli O157:H7 by >5 log cycles. These results indicate that carcass irradiation using e-beam is feasible using the Maxim's electron scattering chamber. Appropriate adjustments will be further needed for commercial application on beef and other animal carcasses. 23907532 Recurrent insect outbreaks caused by temperature-driven changes in system stability. Insects often undergo regular outbreaks in population density but identifying the causal mechanism for such outbreaks in any particular species has proven difficult. Here, we show that outbreak cycles in the tea tortrix Adoxophyes honmai can be explained by temperature-driven changes in system stability. Wavelet analysis of a 51-year time series spanning more than 200 outbreaks reveals a threshold in outbreak amplitude each spring when temperature exceeds 15°C and a secession of outbreaks each fall as temperature decreases. This is in close agreement with our independently parameterized mathematical model that predicts the system crosses a Hopf bifurcation from stability to sustained cycles as temperature increases. These results suggest that temperature can alter system stability and provide an explanation for generation cycles in multivoltine insects. 23511196 Is there a link between neutrophil-lymphocyte ratio and microvascular complications in geriatric diabetic patients? Background: Chronic inflammation plays an important role on development and progression of type 2 diabetes through immunologic inflammatory mechanisms. Neutrophil to lymphocyte ratio (NLR) is a new, simple and cheap marker of subclinical inflammation. NLR has recently been used as a systemic inflammation marker in chronic diseases as well as a predictor of prognosis in cardiovascular diseases and malignancies. Aim: The objective of the present study was to investigate the relationship between NLR and microvascular complications of diabetes mellitus in elderly population. Subjects and methods: Two hundred and forty-two patients with DM (145 diabetic patients with complications, 97 diabetic patients without complications) and 218 control subjects were enrolled in this study. NLR and microvascular complications because of diabetes mellitus were evaluated and compared with other inflammatory markers. Results: NLR was higher in the diabetic group (2.21 ± 1.14) than in the controls (2.18 ± 0.76). Furthermore, there was a statistically significant difference between NLR levels in diabetic patients with and without complications (2.46 ± 1.26 vs. 2.04 ± 0.51, respectively; P < 0.001). The results of the multiple logistic regression analysis depicted that NLR is also an independent predictor for microvascular complications (OR=2.217; 95%=1.086-4.526, P = 0.029). ROC curve analysis suggested that the optimum NLR cut-off point for microvascular complication was 2.89 with 96.72 % specificity, 94.4 % positive predictive value. Conclusion: Increased NLR levels may be associated with microvascular complications of diabetes mellitus in the elderly population. 23551253 Expression of the collagen adhesin ace by Enterococcus faecalis strain OG1RF is not repressed by Ers but requires the Ers box. Expression of adhesin to collagen of Enterococcus faecalis (ace), a known virulence factor, is increased by environmental signals such as the presence of serum, high temperature, and bile salts. Currently, the enterococcal regulator of survival (Ers) of E. faecalis strain JH2-2 is the only reported repressor of ace. Here, we show that for strain OG1RF, Ers is not involved in the regulation of ace. Our data showed similar levels of ace expression by OG1RF and its Δers derivative in the presence of bile salts, serum, and high temperature. Using ace promoter-lacZ fusions and site-directed mutagenesis, we confirmed these results and further showed that, while the previously designated Ers box is important for increased expression from the ace promoter of OG1RF, the region responsible for the increase is bigger than the Ers box. In summary, these results indicate that, in strain OG1RF, Ers is not a repressor of ace expression. Although JH2-2 and OG1RF differ by six nucleotides in the region upstream of ace as well as in production of Fsr and gelatinase, the reason(s) for the difference in ace expression between JH2-2 and OG1RF and for increased ace expression in bile, serum and at 46 °C remain(s) to be determined. 23747965 Mechanisms of increased right and left ventricular oxygen uptake during inotropic stimulation. Few studies have investigated oxygen supply/demand relations in right ventricle (RV). The current study compared changes in myocardial oxygen uptake (MVO2) and its determinants, myocardial blood flow (MBF) and oxygen extraction (EO2), in RV and left ventricle (LV) during stimulation with inotropic drugs. Twenty-one anesthetized dogs were studied. MBF was measured with radioactive microspheres. A-VO2 difference was determined separately for RV and LV, and used to calculate MVO2 (Fick equation) and EO2. Responses to iv. infusions of isoproterenol (0.1μg/kg/min), dobutamine (5μg/kg/min), and amrinone (1mg/kg+10μg/kg/min) were assessed. Baseline MVO2 in RV was 50-60% of that in LV. The inotropes increased MVO2 in both RV and LV (range 32-63%; P<0.05). With isoproterenol, the increased MVO2 in the RV was due to increases in both MBF and EO2, whereas in LV it was due only to increases in MBF. With dobutamine and amrinone, the increased MVO2 in RV was due to increased MBF while EO2 was constant (dobutamine) or decreased (amrinone), and that in the LV was due to increased MBF while EO2 decreased. RV possesses EO2 reserve that contributed to increased MVO2 during isoproterenol infusion, whereas LV depended on increased MBF alone. Because dobutamine and amrinone caused direct coronary vasodilation, i.e., "luxuriant perfusion," it was not necessary to recruit the EO2 reserve. Thus, it remained available to meet further increases in MVO2 or to maintain MVO2 in the face of reductions in MBF. 23853020 Bilateral renal cell carcinoma in a paediatric patient with tuberous sclerosis complex. Tuberous sclerosis complex (TSC) is a genetic neurocutaneous disorder characterised by seizures, mental retardation and hamartoma formation in multiple organs, mainly in the brain, skin, kidney, liver, lung and heart. Renal manifestations occur in about 60-80% of all patients with TSC and their rate increases with age. We report the case of a 17-year-old boy with tuberous sclerosis who presented with abdominal pain associated with kidney failure. Investigation revealed bilateral renal lesions, suggesting angiomyolipomas. On further work-up, malignancy was suspected and the patient underwent bilateral partial nephrectomy with histological diagnosis of bilateral renal cell carcinoma. This is a rare complication of TSC, particularly in a paediatric setting. Adequate surveillance of kidney disorders in patients with TSC is warranted, to guarantee an early diagnosis and treatment. 23187787 Azadirachta indica mitigates behavioral impairments, oxidative damage, histological alterations and apoptosis in focal cerebral ischemia-reperfusion model of rats. Azadirachta indica Linn. (Meliaceae) has been used from ancient times as a remedy for various ailments. The present study was designed to investigate the antioxidant and anti-apoptotic properties of A. indica seed extract (ASE) in transient middle cerebral artery occlusion (MCAO) rat model. Antioxidant potential of ASE was determined in vitro. Further, ASE was evaluated against neurological deficits, histological alterations (TTC, CV and H&E) and oxidative damage (TBARS, GSH and nitrite) in MCAO rats. Moreover, caspase-3 and -9 were analyzed to evaluate the anti-apoptotic activity of ASE. ASE has shown potent in vitro reducing power (126.2 mg AsAE/g extract) and free radical scavenging activities (DPPH 171.0 and NO 176.0 Î¼g/ml). Furthermore, ASE inhibited oxidative stress and decreased the activities of caspase-3 (26.7 %, p < 0.05) and caspase-9 (31.2 %, p < 0.01) thus, reduced neuronal loss in MCAO rats. Our data revealed that ASE has potent antioxidant and anti-apoptotic properties, and may be explored for its active constituents against neurodegenerative diseases. 23751845 Outcome after liver transplantation for cirrhosis due to alcohol and hepatitis C: comparison to alcoholic cirrhosis and hepatitis C cirrhosis. Data on outcome of patients after liver transplantation (LT) for cirrhosis due to hepatitis C virus (HCV+) alcohol are limited. Analysis from United Network for Organ sharing data set (1991 to 2010) for cirrhotics with first LT for HCV (group I, N=17,722), alcohol or alcoholic cirrhosis (AC; group II, N=9617), and alcohol+HCV (group III, N=6822). Five-year graft and patient survival for group III were similar to group I (73% vs. 69%; P=0.33 and 76% vs. 76%; P=0.87) and worse than group II (70% vs. 74%; P<0.0001 and 76% vs. 79%; P<0.0001). Cox regression analysis adjusted for recipient and donor characteristics showed (a) graft survival for group III similar to group I [hazard ratio (HR) 1.03 (95% confidence interval (CI), 0.97-1.09)] and worse than group II [HR 1.27 (95% CI, 1.19-1.35)] and (b) patient survival for group III worse than both groups I [HR 1.09 (95% CI, 1.02-1.15)] and II [HR 1.27 (95% CI, 1.19-1.36)]. In group III, graft failure was common for graft and patient loss and de novo malignancy more common compared with group I. Patients undergoing LT for cirrhosis due to combined alcohol and HCV have (a) graft survival similar to patients with HCV cirrhosis and worse than AC and (b) worse patient survival compared with AC and HCV cirrhosis. Better strategies for anti-HCV treatment and screening for tumors are needed for patients undergoing LT for combined alcohol and HCV. 23826961 Improvement of capture efficacy of immunomagnetic beads for Campylobacter jejuni using reagents that alter its motility. Previous studies using the immunomagnetic beads separation (IMS) technique have shown high detection limits of live campylobacters but low detection limits of formalin-killed campylobacters. The present study investigated if the addition of various concentrations of reagents that alter the motility of live Campylobacter jejuni could enhance the recovery of the organisms by IMS. The addition of 5% glycerol, 0.001% formalin, 10% polyethylene glycol, or 0.001% agarose in a buffer slowed down the movement of C. jejuni and increased the recovery of live C. jejuni, using beads coated with specific monoclonal antibodies (mAbs). The highest recovery yielded was 5.2- ± 3.3-fold with 5% glycerol at 10(5) colony-forming units (CFU)·mL(-1). The addition of 5% glycerol also improved isolation at lower concentrations of C. jejuni (10(2) to 10(4) CFU·mL(-1)) in buffer. The recovery by IMS of C. jejuni killed by 1% formalin was increased up to as high as 17-fold compared with the recovery of live organisms, as detected using a real-time polymerase chain reaction assay. The reagents investigated did not enhance the immunological reactivity of the mAbs to this organism. These results indicate that the addition of several reagents enhanced the capture of C. jejuni by IMS, which could be partially due to the slowing down of the movement or the altering of the motility of C. jejuni and to the increasing of the contact time between C. jejuni and immunomagnetic beads. 23887311 Characteristics and Outcomes of Dialysis Patients with Infective Endocarditis. Background: The incidence of infective endocarditis (IE) in dialysis patients is higher than the general population. Dialysis patients who develop endocarditis are thought to have a poorer prognosis than other patients with IE. Aim: To examine the risk profiles, clinical features, and outcomes of patients on dialysis who developed IE in a large cohort. Design and Methods: A retrospective analysis of all patients developing IE on dialysis (using the modified Duke criteria) was undertaken between 1998 and 2011. Patients were identified from a prospectively collected clinical database. Results: 42 patients developed IE out of a total incident dialysis population of 1,500 over 13 years. 95% of the patients (40/42) were on long-term haemodialysis (HD) and 5% (2/42) on peritoneal dialysis. Mean patient age was 55.2 years (IQR: 43-69), and mean duration of HD prior to IE was 57.4 months. Primary HD access at the time of diagnosis was an arteriovenous fistula in 35% (14/40), a dual-lumen tunnelled catheter in 55% (22/40), and a dual-lumen non-tunnelled catheter in 10% (4/40). Staphylococcus aureus (including methicillin-resistant S. aureus) was present in 57.1% (24/42). The aortic valve was affected in 42.8% of the patients (18/42), the mitral valve in 30.9% (13/42), and both valves in 9.5% (4/42). 33.3% of the patients had an abnormal valve before the episode of IE. In 21.4% (9/42), valve surgery was performed and mortality was lower in the surgical group compared to the group managed medically during hospitalisation (11.1 vs. 15.2%, p = 0.892), at 3 months (13.1 vs. 19.6%, p = 0.501), and during follow-up (p = 0.207), but this difference did not reach statistical significance. Age >60 years, septic emboli, and methicillin-resistant S. aureus were all adverse prognostic factors. Patients receiving surgery were younger (mean 47.1 ± 14.4 years vs. 57.4 ± 14.3, p = 0.049) and less likely to be infected with S. aureus (surgery 33.3% vs. antibiotics 63.6%, p = 0.046). Conclusion: This is one of the largest reported series of IE in dialysis patients. The incidence of IE remains high and the prognosis poor in dialysis patients, although patients selected for early valve surgery have good 1-year survival. 23843573 Prevention of suicidal behavior in adolescents with post-traumatic stress disorder. Abstract Post-traumatic stress disorder (PTSD) is significantly associated with an increased risk for suicidal behavior among adolescents. Suicide is one of the top three causes of adolescent deaths worldwide. Despite the strong relationship between PTSD and suicidal behavior, precise causal pathways linking PTSD to suicide in adolescents remains unclear. A slew of mediating factors and variables commonly present themselves with both suicide and PTSD, including co-morbid psychiatric disorders, exposure to different forms of trauma and stressful life events, core neurobiological changes, and mental, emotional, and physiological states such as hyperarousal, impulsivity, and aggression. Because youth is such a critical stage of development, it is very important that at-risk adolescents are identified and referred for treatment. With many treatment challenges in these populations, effective implementation and use of prevention methods are of increasing importance. The most proven prevention methods include physician education, means restriction, and gatekeeper training. Other strategies that have received empirical support are public education campaigns and implementing guidelines for the media, including those for television, print media, and the Internet. 23945279 Infectious neuropathies. Infectious neuropathies are heterogeneous neuropathies with multiple causes. They still represent an important world health burden and some of them have no current available therapy. Leprosy incidence has decreased by 50% during the last years, but leprosy-related neuropathies still cause severe disability. The pure neuritic leprosy is a diagnostic challenge that may require nerve biopsy or nerve aspiration cytology. The treatment itself may lead to a 'reversal reaction', which further causes injuries to the nerve. HCV-related neuropathies may be related or not to the presence of cryoglobulins. The absence of vasculitis, the most frequent form is a peripheral sensory neuropathy involving small nerve fibers, and more accurately diagnosed by pain-related evoked potentials. HIV-related neuropathy has become the major neurological complication of HIV infection. Both HIV-induced neuropathy and antiretroviral toxic neuropathy are clinically indistinguishable. The existence of an isolated chronic polyneuropathy due to Borrelia burgdorferi remains highly controversial. Lastly, an active infectious ganglioneuritis caused by varicella zoster virus, producing shingles, is the most frequent infectious neuropathy in the world and may cause various neurological complications. Zoster sine herpete remains frequently undiagnosed. Recent data have improved our knowledge and diagnostic tools of infectious neuropathies. Treatment of the injured nerves is not yet available, and prevention and rapid diagnosis remain the main priorities for the clinician. 23884715 Community Composition of NirS-Type Denitrifier in a Shallow Eutrophic Lake. Denitrification is a major biological process to reduce nitrate to molecular nitrogen (N2). In shallow eutrophic lakes, this process can remove the largest portion of fixed nitrogen and plays an important role in self-purification of this ecosystem. To understand the structure of denitrifying communities in a shallow eutrophic lake, denitrifier communities in four sub-lakes of East Lake in Wuhan, China, were explored by restriction fragment length polymorphisms (RFLP) analysis and sequencing of nirS gene clone libraries. nirS is a functional marker gene for denitrification encoding cytochrome cd 1-containing nitrite reductase, which catalyzes the reduction of nitrite to nitric oxide. Both RFLP fingerprints clustering analysis and phylogeny analysis based on the amino acid sequences of NirS revealed that NirS-type communities in East Lake sediment could be roughly divided into three clusters. Cluster I accounted for 74-82 % of clones from the moderately eutrophic sub-lakes Tuan, Tang Ling, and Guo Zheng. Cluster II accounted for 76 % of the communities in hypertrophic sub-lake Miao Lake and cluster III as a minor group (7 % of the total), mainly presented in Miao Lake. Phylogenetic analysis revealed that cluster I was related to the reference clones from a broad range of ecological environments, and clusters II and III were more phylogenetically related to the reference clones from entrophic environments. Canonical correspondence analysis indicated that total nitrogen, total phosphate, total organic carbon, and NH4-N and NO2-N were important environmental factors affecting the dispersion of NirS-type denitrifier in the sediments. Cluster I showed a weak relationship with the nutrient content, while cluster II and III were positively related with the nutrient content. Principal coordinates analysis indicated that NirS-type communities from Tuan Lake, Tang Ling Lake, and Guo Zheng Lake sediments were divergent from those found in river, estuary sediment, and forest soil but similar to communities in constructed wetland sediment despite large geographic distances. The communities from the hypertrophic sub-lake Miao Lake deviated from other sub-lakes and the reference communities and clustered independently. Our results support the argument that environmental factors regulate the composition and distribution of the functional bacterial groups. 23833301 Memantine protects rats treated with intrathecal methotrexate from developing spatial memory deficits. To test whether memantine can prevent methotrexate-induced cognitive deficits in a preclinical model. After noting that methotrexate exposure induces prolonged elevations of the glutamate analog homocysteic acid (HCA) within cerebrospinal fluid, we tested whether intrathecal injection of HCA would produce memory deficits similar to those observed after intrathecal methotrexate. We then tested whether memantine, an antagonist of the N-methyl-d-aspartate (NMDA) subclass of glutamate receptors, could protect animals treated with clinically relevant doses of intrathecal methotrexate against developing memory deficits. Finally, we asked whether memantine affected this pathway beyond inhibiting the NMDA receptor by altering expression of the NMDA receptor or affecting concentrations of HCA or glutamate within the central nervous system. Four intrathecal doses of methotrexate induced deficits in spatial memory, persisting at least one month following the final injection. Intrathecal HCA was sufficient to reproduce this deficit. Concurrent administration of memantine during the period of methotrexate exposure was protective, decreasing the incidence of methotrexate-induced spatial memory deficits from 56% to 20% (P < 0.05). Memantine neither altered expression of NMDA receptors within the hippocampus nor blunted the methotrexate-induced increases in glutamate or HCA. Excitotoxic glutamate analogs including HCA contribute to cognitive deficits observed after intrathecal methotrexate. Memantine, an NMDA receptor antagonist, reduces the incidence of cognitive deficits in rats treated with intrathecal methotrexate, and may therefore benefit patients with cancer receiving similar treatment. Clin Cancer Res; 19(16); 4446-54. ©2013 AACR. 23712969 Proteomic approach toward molecular backgrounds of drug resistance of osteosarcoma cells in spheroid culture system. Chemoresistance is one of the most critical prognostic factors in osteosarcoma, and elucidation of the molecular backgrounds of chemoresistance may lead to better clinical outcomes. Spheroid cells resemble in vivo cells and are considered an in vitro model for the drug discovery. We found that spheroid cells displayed more chemoresistance than conventional monolayer cells across 11 osteosarcoma cell lines. To investigate the molecular mechanisms underlying the resistance to chemotherapy, we examined the proteomic differences between the monolayer and spheroid cells by 2D-DIGE. Of the 4762 protein species observed, we further investigated 435 species with annotated mass spectra in the public proteome database, Genome Medicine Database of Japan Proteomics. Among the 435 protein species, we found that 17 species exhibited expression level differences when the cells formed spheroids in more than five cell lines and four species out of these 17 were associated with spheroid-formation associated resistance to doxorubicin. We confirmed the upregulation of cathepsin D in spheroid cells by western blotting. Cathepsin D has been implicated in chemoresistance of various malignancies but has not previously been implemented in osteosarcoma. Our study suggested that the spheroid system may be a useful tool to reveal the molecular backgrounds of chemoresistance in osteosarcoma. 23849779 Using EAE to better understand principles of immune function and autoimmune pathology. Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) in which myelin becomes the target of attack by autoreactive T cells. The immune components of the disease are recapitulated in mice using the experimental autoimmune encephalomyelitis (EAE) model. EAE is classically induced by the immunization of mice with encephalitogenic antigens derived from CNS proteins such as proteolipid protein (PLP), myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG). Immunization of susceptible mouse strains with these antigens will induce autoreactive inflammatory T cell infiltration of the CNS. More recently, the advent of clonal T cell receptor transgenic mice has led to the development of adoptive transfer protocols in which myelin-specific T cells may induce disease upon transfer into naïve recipient animals. When used in concert with gene knockout strains, these protocols are powerful tools by which to dissect the molecular pathways that promote inflammatory T cells responses in the central nervous system (CNS). Further, myelin-antigen-specific transgenic T cells may be cultured in vitro under a variety of conditions prior to adoptive transfer, allowing one to study the effects of soluble factors or pharmacologic compounds on T cell pathogenicity. In this review, we describe many of the existing models of EAE, and discuss the contributions that use of these models has made in understanding both T helper cell differentiation and the function of inhibitory T cell receptors. We focus on the  step-by-step elucidation of the network of signals required for T helper 17 (Th17) cell differentiation, as well as the molecular dissection of the Tim-3 negative regulatory signaling pathway in Th1 cells. 23948816 A mutation in the gene for polynucleotide kinase of bacteriophage T4 K10 affects mRNA processing. The bacteriophage T4 insertion-substitution (I/S) vector system has become one of the most important tools for the introduction of site-directed mutations into the T4 genome. In this study, we show that the I/S phage T4 K10 carries two point mutations within the gene for polynucleotide kinase pseT, resulting in amino acid substitutions G14D and R229H. The G14D mutation impairs 5'-kinase activity in vivo as well as in vitro and leads to diminished processing at secondary sites of several RegB-cleaved transcripts. 23322906 A genome-wide siRNA screen reveals positive and negative regulators of the NOD2 and NF-κB signaling pathways. The cytoplasmic receptor NOD2 (nucleotide-binding oligomerization domain 2) senses peptidoglycan fragments and triggers host defense pathways, including activation of nuclear factor κB (NF-κB) signaling, which lead to inflammatory immune responses. Dysregulation of NOD2 signaling is associated with inflammatory diseases, such as Crohn's disease and Blau syndrome. We used a genome-wide small interfering RNA screen to identify regulators of the NOD2 signaling pathway. Several genes associated with Crohn's disease risk were identified in the screen. A comparison of candidates from this screen with other "omics" data sets revealed interconnected networks of genes implicated in NF-κB signaling, thus supporting a role for NOD2 and NF-κB pathways in the pathogenesis of Crohn's disease. Many of these regulators were validated in secondary assays, such as measurement of interleukin-8 secretion, which is partially dependent on NF-κB. Knockdown of putative regulators in human embryonic kidney 293 cells followed by stimulation with tumor necrosis factor-α revealed that most of the genes identified were general regulators of NF-κB signaling. Overall, the genes identified here provide a resource to facilitate the elucidation of the molecular mechanisms that regulate NOD2- and NF-κB-mediated inflammation. 23926154 From trickle to flood: the large-scale, cryptic invasion of California by tropical fruit flies. Since 1954, when the first tropical tephritid fruit fly was detected in California, a total of 17 species in four genera and 11 386 individuals (adults/larvae) have been detected in the state at more than 3348 locations in 330 cities. We conclude from spatial mapping analyses of historical capture patterns and modelling that, despite the 250+ emergency eradication projects that have been directed against these pests by state and federal agencies, a minimum of five and as many as nine or more tephritid species are established and widespread, including the Mediterranean, Mexican and oriental fruit flies, and possibly the peach, guava and melon fruit flies. We outline and discuss the evidence for our conclusions, with particular attention to the incremental, chronic and insidious nature of the invasion, which involves ultra-small, barely detectable populations. We finish by considering the implications of our results for invasion biology and for science-based invasion policy. 23968485 Design, Synthesis and Characterization of Novel Tetrahydropyran-based Bacterial Topoisomerase Inhibitors with Potent Anti-Gram Positive Activity. There is an urgent need for new antibacterial drugs that are effective against infections caused by multi-drug resistant pathogens. Novel non-fluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) have the potential to become such drugs as they display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. Bacterial topoisomerase inhibitors that are built on a tetrahydropyran ring linked to a bicyclic aromatic moiety through a syn-diol linker, show potent anti Gram-positive activity, covering isolates with clinically relevant resistance phenotypes. For instance, analog 49c was found to be a dual DNA gyrase-topoisomerase IV inhibitor, with broad antibacterial activity and low propensity for spontaneous resistance development, but suffered from high hERG K+ channel block. On the other hand, analog 49e displayed lower hERG K+ channel block, while retaining potent in vitro antibacterial activity and acceptable frequency for resistance development. Furthermore, analog 49e showed moderate clearance in rat and promising in vivo efficacy against Staphylococcus aureus in a murine infection model. 23194561 Isotopic analysis of eggs: evaluating sample collection and preparation. Egg traceability/authenticity is a worldwide concern. Stable isotope techniques have been suggested as a tool to address this issue. To further validate the use of these techniques, a research project was undertaken to evaluate what effect sample collection and preparation have on the measured isotopic composition of egg components. The timing of egg collection, the timing of egg preparation after collection, and the use of pasteurisation were investigated. The C, N, O, and S isotopic compositions of egg components from 7 different production systems were measured. Two sets of eggs were collected (4 months apart). It was found that the 'isotopic fingerprint' of a particular production system was maintained over time, and that it may be possible to trace liquid egg products based on isotopic data from fresh eggs. The findings from this study support the integration of stable isotope techniques in egg traceability/authenticity systems. 23851022 Genetic characterization of a rare bovine-like human VP4 mono-reassortant G6P[8] rotavirus strain detected from an infant in Bangladesh. During an ongoing diarrhea etiology surveillance in Mirzapur, Bangladesh, a rare human G6P[8] RVA strain (RVA/Human-wt/BGD/KH2288/2011/G6P[8]) was detected in a stool sample of a 7-month-old infant with acute diarrhea. Complete genotype analyses revealed that KH2288 possessed the G6-P[8]-I2-R2-C2-M2-A11-N2-T6-E2-H3 genotype constellation. Sequence analysis of the VP7 gene revealed a close phylogenetic relationship with bovine G6 strains from India, whereas, the VP4 gene segment was nearly identical to typical human P[8] strain circulating in Bangladesh and the rest of the world. Phylogenetic analysis of the remaining nine gene segments revealed a close relatedness to either animal or animal derived human RVA strain. We speculated that, strain KH2288 was a monoreassortant between a human RVA strain and a RVA strain typically infecting member of the Artiodactyla, such as cattle, goat or sheep. To our knowledge, this is the first complete genotyping report of a naturally occurring G6P[8] RVA strain, worldwide. 23838581 Specific and quantitative detection and identification of Cryptosporidium hominis andC. parvum in clinical and environmental samples. Cryptosporidium is an enteric protozoan parasite that is resistant to inactivation by commonly used drinking water disinfectants. Between 2004 and 2010, it was responsible for 60% of all waterborne protozoan parasitic outbreaks reported worldwide. Most sporadic infections in humans and almost all outbreaks are caused by Cryptosporidium parvum and Cryptosporidium hominis. We report the development and validation of a quantitative qPCR assay using minor groove binder (MGB)-probes targeting a unique Cryptosporidium specific protein-coding gene, that directly detects, quantitates and identifies C. hominis and C. parvum in environmental and faecal samples. An internal amplification control (IAC) was also developed and included in this assay. The qPCR assay was compared with an 18S nested PCR assay for sensitivity and specificity. The analytical sensitivity for the qPCR assay was 1 oocyst and 1-10 oocysts for the 18S assay. Evaluation of analytical specificity of the qPCR assay revealed no cross-reactions with other genera and detected all C. parvum and C. hominis isolates correctly. The diagnostic sensitivity and specificity of the qPCR was 100% compared to 96.9% and 98.4%, respectively for the 18S assay. The qPCR assay was also highly reproducible with RSD (relative standard deviation) values of 1.4-9.4%, when the assay was performed by four different technicians. When tested on water samples, the qPCR assay was more sensitive than the 18S assay, detecting positives in 37 of 138 water samples compared to 35 for the 18S locus. This qPCR assay should be a valuable tool for the detection and differentiation of C. hominis and C. parvum in both clinical and environmental samples. 22851670 Rescuer fatigue under the 2010 ERC guidelines, and its effect on cardiopulmonary resuscitation (CPR) performance. Updated life-support guidelines were published by the European Resuscitation Council (ERC) in 2010, increasing the required depth and rate of chest compression delivery. This study sought to determine the impact of these guidelines on rescuer fatigue and cardiopulmonary resuscitation (CPR) performance. 62 Health science students performed 5 min of conventional CPR in accordance with the 2010 ERC guidelines. A SkillReporter manikin was used to objectively assess temporal change in determinants of CPR quality. Participants subjectively reported their end-fatigue levels, using a visual analogue scale, and the point at which they believed fatigue was affecting CPR delivery. 49 (79%) participants reported that fatigue affected their CPR performance, at an average of 167 s. End fatigue averaged 49.5/100 (range 0-95). The proportion of chest compressions delivered correctly decreased from 52% in min 1 to 39% in min 5, approaching significance (p=0.071). A significant decline in chest compressions reaching the recommended depth occurred between the first (53%) and fifth (38%) min (p=0.012). Almost half this decline (6%) was between the first and second minutes of CPR. Neither chest compression rate, nor rescue breath volume, were affected by rescuer fatigue. Fatigue affects chest compression delivery within the second minute of CPR under the 2010 ERC guidelines, and is poorly judged by rescuers. Rescuers should, therefore, be encouraged to interchange after 2 min of CPR delivery. Team leaders should be advised to not rely on rescuers to self-report fatigue, and should, instead, monitor for its effects. 23906878 Weight six years after childbirth: A follow-up of obese women in a weight-gain restriction programmme. to compare weight development in an intervention group and a control group, six years after participation in a gestational weight-gain restriction programme. follow-up of a prospective intervention study. antenatal care clinics. a total of 129 women (88.4%) from the original intervention group and 166 women (88.8%) from the original control group. the women answered a study specific questionnaire, covering socio-demographic data and health- and weight status. after adjusting for socio-demographic factors, the mean weight was lower (4.1kg) among the women in the intervention group, compared to the controls (p=0.028). Furthermore, the mean weight change, e.g. the weight at the six year assessment compared with the weight at the start of the intervention at the first antenatal care visit, was greater in the intervention group than in the control group. The women in the intervention group had a larger mean weight change (-5.2kg), e.g. weighed less than the women in the control group (-1.9kg) (p=0.046). Mean weight change expressed in 5kg classes also showed a significant difference between the two groups (p=0.030). the results indicate that attending a gestational weight-gain-restriction programme can have a positive effect on weight up to six years after the intervention. a restrictive gestational weight gain can result in a positive weight development during the first years after childbirth. It might provide both short- and long term medical health benefits for the mother as well as the child. 23623625 Incidence of symptomatic deep venous thrombosis after achilles tendon rupture. Deep venous thrombosis (DVT) is a significant source of morbidity and mortality and is associated with many orthopedic procedures. Previous studies have reported highly variable DVT rates in patients with Achilles tendon rupture undergoing operative and nonoperative treatment. We performed a retrospective chart review for all patients who underwent Achilles tendon repair at our institution from January 2006 to February 2012. Patient data were collected from the electronic medical record system. A total of 115 patients were eligible for the present study. Of these patients, 27 (23.47%) with a surgically treated Achilles tendon rupture developed a symptomatic DVT either while waiting for, or after, surgical intervention, with approximately one third of these diagnosed before surgical intervention. Of the 27 patients with DVT, 3 had a proximal DVT and 24 had a distal DVT. One patient developed a pulmonary embolism. The DVT incidence was greater in the 2 older age groups (40 to 59 and 60 to 79 years) compared individually with the younger age group (20 to 39 years; p < .0026 and p < .0014, respectively). We have shown a high incidence of DVT after Achilles tendon rupture. We recommend a high level of suspicion for the signs and symptoms of DVT during the follow-up period. In addition, patient education and early mobilization should be advocated, especially for patients older than 40 years. Additional randomized controlled trials investigating any benefits to pharmaceutical DVT prophylaxis in this population are needed to establish evidence-based recommendations. 23806814 Using machine learning for improving knowledge on antibacterial effect of bioactive glass. The aim of this work was to find relationships between critical bioactive glass characteristics and their antibacterial behaviour using an artificial intelligence tool. A large dataset including ingredients and process variables of the bioactive glasses production, bacterial characteristics and microbiological experimental conditions was generated from literature and analyzed by neurofuzzy logic technology. Our findings allow an explanation on the variability in antibacterial behaviour found by different authors and to obtain general conclusions about critical parameters of bioactive glasses to be considered in order to achieve activity against some of the most common skin and implant surgery pathogens. 23771800 Phase II study of weekly PM00104 (ZALYPSIS(®)) in patients with pretreated advanced/metastatic endometrial or cervical cancer. This open-label, two-arm, phase II clinical trial evaluated the antitumor activity and safety profile of PM00104 (Zalypsis(®)) administered as a 1-h, weekly, intravenous infusion (days 1, 8 and 15; every 4 weeks) at a dose of 2 mg/m(2) to patients with advanced and/or metastatic endometrial (EC) or cervical cancer (CC) after one previous line of systemic chemotherapy. Twelve patients (median age, 61.5 years) with pretreated EC received a median of 2 treatment cycles (range 1-5) and seven patients (median age, 38 years) with pretreated CC received 2 treatment cycles. None achieved objective tumor response. Median progression-free survival (PFS) was 1.8 months, and median overall survival (OS) was 5.5 months in EC (median follow-up = 20.1 months); median PFS was 1.5 months, and median OS was 5.6 months in CC (median follow-up = 17.1 months). The most common toxicities reported were mild to moderate asthenia, nausea, vomiting and diarrhea. Despite PM00104 showing mostly mild, predictable, manageable and reversible toxicity, protocol criteria for further recruitment were not met in EC, a futility analysis was done and recruitment was stopped; a low patient recruitment rate together with no evidence of activity in CC resulted in early study closure. 23917809 Effectiveness and Safety of Phosphodiesterase 5 Inhibitors in Patients with Cardiovascular Disease and Hypertension. Phosphodiesterase 5 (PDE 5) inhibitors are selective inhibitors of the enzyme PDE 5, which catalyzes the hydrolysis of cyclic guanosine monophosphate (cGMP), a potent vasodilator and nitric oxide (NO) donor, to its corresponding metabolites (monophosphates). The enzyme PDE 5 is widely distributed in the body, including the heart and blood vessels. Because of its distribution, it was hypothesized that its inhibition could lead to significant coronary vasodilation, which would benefit patients with coronary artery disease (CAD). This hypothesis led to the development of PDE 5 inhibitors with the first being sildenafil citrate. Subsequent studies with sildenafil in patients with CAD demonstrated a modest cardiovascular effect, but a potent action on penile erection in men, resulting in sildenafil becoming a first-line therapy of erectile dysfunction (ED). Subsequently, two more PDE 5 inhibitors (vardenafil and tadalafil) were developed and approved by the Food and Drug Administration (FDA) for the treatment of ED. Recent studies have shown several pleiotropic beneficial effects of PDE 5 inhibitors in patients with CAD, hypertension, heart failure, pulmonary arterial hypertension, diabetes mellitus and Raynaud's phenomenon. Side effects and interactions of PDE 5 inhibitors with other drugs have been minimal, with the exception of their coadministration with nitrates, which could lead to severe vasodilation and hypotension and therefore, their coadministration is prohibited. All these pleiotropic cardiovascular effects of PDE 5 inhibitors and their drug interactions will be discussed in this concise review in the context of the American College of Cardiology / American Heart Association guidelines and the recent developments in this field. 23291121 Antioxidant activities of thiosemicarbazones from substituted benzaldehydes and N-(tetra-O-acetyl-β-D-galactopyranosyl)thiosemicarbazide. Reaction of N-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)thiosemicarbazide and different substituted benzaldehydes gave some new substituted benzaldehyde N-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)thiosemicarbazones. The reaction was performed using conventional and microwave-assisted heating methods. The structures of thiosemicarbazones were confirmed by spectroscopic (IR, (1)H NMR, (13)C NMR and ESI-MS) method. The antioxidant activity of these thiosemicarbazones was evaluated in vitro and in vivo, and it's shown that some of these compounds had significant antioxidant activity. Amongst the compounds screened for antioxidant activity, thiosemicarbazones 4a, 4b and 4c showed good antioxidant activity on DPPH. The compounds 4g, 4i, 4l caused significant elevation of SOD activity and 4e, 4g, 4i, 4l had higher catalase activity, and only compounds 4c and 4f expressed the GSH-Px activity. 23899923 Emissions from soil fumigation in two raised bed production systems tarped with low permeability films. Raised beds are used to produce some high-value annual fruit and vegetable crops such as strawberry in California (CA) and tomato in Florida (FL), USA. Pre-plant soil fumigation is an important tool to control soil-borne pests in the raised beds. However, fumigant emissions have detrimental environmental consequences. Field trials were conducted to evaluate emissions of 1,3-dichloropropene (1,3-D) and chloropicrin (CP) in two different production systems with raised beds covered by different tarps. In the CA trial, InLine (60.8% 1,3-D and 33.3% CP) was drip-applied at 340kgha(-1) to 5cm deep in the beds (30cm high and 107cm wide) tarped with polyethylene (PE) or virtually impermeable film (VIF). In the FL trial, carbonated Telone C35 (63.4% 1,3-D and 34.7% CP) was shank-applied at 151kgha(-1) to 20cm deep in the beds (22cm high and 76cm wide) tarped with totally impermeable film (TIF). Emissions from tarped beds relative to furrows were contrary between the two trials. For the CA trial, the emission was 47% of applied 1,3-D and 27% of applied CP from PE tarped beds and 31% of applied 1,3-D and 15% of applied CP from VIF tarped beds, while that from uncovered furrows was<0.4% for both chemicals in both fields. In the FL trial, only 0.1% 1,3-D was emitted from the TIF tarped beds, but 27% was measured from the uncovered furrows. Factors contributing to the differences in emissions were chiefly raised-bed configuration, tarp permeability, fumigant application method, soil properties, soil water content, and fumigant carbonation. The results indicate that strategies for emission reduction must consider the differences in agronomic production systems. Modifying raised bed configuration and fumigant application technique in coarse textured soils with TIF tarping can maximize fumigation efficiency and emission reduction. 23481641 Preclinical Activity of Simvastatin Induces Cell Cycle Arrest in G1 via Blockade of Cyclin D-Cdk4 Expression in Non-Small Cell Lung Cancer (NSCLC). Lung cancer is the most common cause of cancer-related death. Nonetheless, a decrease in overall incidence and mortality has been observed in the last 30 years due to prevention strategies and improvements in the use of chemotherapeutic agents. In recent studies, Simvastatin (SIM) has demonstrated anti-tumor activity, as well as potent chemopreventive action. As an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA), SIM has been shown to stimulate apoptotic cell death. In this study, an MTT assay revealed the cytotoxic activity of SIM against human large cell lung cancer (Non-small cell lung cancer; NSCLC) cells (NCI-H460); however, induced apoptosis was not observed in NCI-H460 cells. Protein expression levels of cell cycle regulating proteins Cdk4, Cyclin D1, p16 and p27 were markedly altered by SIM. Collectively, our results indicate that SIM inhibits cell proliferation and arrests NCI-H460 cell cycle progression via inhibition of cyclin-dependent kinases and cyclins and the enhancement of CDK inhibitors p16 and p27. Our findings suggest that, in addition to the known effects on hypercholesterolemia therapy, SIM may also provide antitumor activity in established NSCLC. 23545900 Beneficial influence of topical extra virgin olive oil application on an experimental model of penile fracture in rats. Penile fracture (PF) is known as a traumatic rupture of the tunica albuginea of corpus cavernosum. In this study, we aimed to investigate the healing influence of topical extra virgin olive oil (EVOO) on PF through evaluating levels of some oxidative stress biomarkers for the first time. Histopathological evaluation was also realized. A total of 18 male Sprague-Dawley albino rats were divided into three groups of six rats each as control group, in PF (alone) group, and PF + EVOO group. Experimental PF was formed via incising from the proximal dorsal side of the penis in the rats of all groups except control. While in PF (alone) group, fracture was formed and the incision was primarily closed, in PF + EVOO group in addition to foregoing processes, EVOO was also administrated topically twice a day for 3 weeks. At the end of the experiment, all rats were killed and penectomy was carried out. While malondialdehyde, myeloperoxidase, lipid hyroperoxide, and total oxidant status significantly (p < 0.05) increased, reduced glutathione and total free sulfhydryl groups markedly (p < 0.05) decreased in PF (alone) group when compared with PF + EVOO group. Levels of these parameters were reversed to nearly normal values by topical EVOO application. Protection by EVOO is further substantiated via the improved histological findings in PF + EVOO group as against degenerative changes in the rats of PF (alone) group. Our data revealed that EVOO has protective effect in penile cavernosal tissue through probably its antioxidant, free radical defusing, anti-inflammatory, and antimicrobial effects. 23872920 Apoptotic cell administration enhances pancreatic islet engraftment by induction of regulatory T cells and tolerogenic dendritic cells. Apoptotic cell transfer has been found to be able to facilitate engraftment of allograft. However, the underlying mechanisms remain to be fully understood. Here we demonstrate that intravenous administration of donor apoptotic splenocytes can promote pancreatic islet engraftment by inducing generation of tolerogenic dendritic cells (Tol-DCs) and expansion of CD4(+)Foxp3(+) regulatory T cells (Tregs). In vivo clearance of either dendritic cells (DCs) or Tregs prevented the induction of immune tolerance by apoptotic cell administration. Transient elimination of Tregs using anti-CD25, monoclonal antibody (mAb) abrogated the generation of Tol-DCs after administration of apoptotic splenocytes. Reciprocally, depletion of DCs within CD11c-DTR mice using diphtheria toxin (DT) prevented the generation of Tregs in the recipients with administration of apoptotic splenocytes. Induction of Tregs by Tol-DCs required direct cell contact between the two cell types, and programmed death 1 ligand (PD-L1) played important role in the Tregs expansion. Apoptotic cell administration failed to induce Tol-DCs in IL-10-deficient and Smad3-deficient mice, suggesting that IL-10 and transforming growth factor-β (TGF-β) are needed to maintain DCs in the tolerogenic state. Therefore, we demonstrate that Tol-DCs promote the expansion of Tregs via PD-L1 on their surface and reciprocally Tregs facilitate Tol-DCs to maintain transplantation tolerance induced by apoptotic cells via secreting IL-10 and TGF-β.Cellular & Molecular Immunology advance online publication, 22 July 2013; doi:10.1038/cmi.2013.16. 23904472 Individualised exercise improves endothelial function in patients with rheumatoid arthritis. We investigated the effects of individualised combined resistance and aerobic exercise on microvascular and macrovascular function in rheumatoid arthritis (RA) patients. Forty age-matched, gender-matched and body mass index (BMI)-matched patients were allocated to either an exercise group, receiving a 6 months tailored aerobic and resistance exercise intervention, or controls receiving only information about the benefits of exercise. Participants were assessed for microvascular (acetylcholine (Ach) and sodium nitroprusside (SNP)) and macrovascular (flow-mediated dilatation (FMD) and glyceryl trinitrate (GTN)) endothelial function, maximal oxygen uptake, disease activity and severity (C-reactive protein (CRP), disease activity score 28 and health assessment questionnaire). Data were collected at baseline, 3 months and at the end of the intervention (6 months). At baseline, demographic, anthropometric, disease-related characteristics and endothelial function parameters were similar between the exercise and control groups (p>0.05). Repeated measures analysis of variance revealed a significant improvement in endothelial function parameters at 3 (GTN: p<0.001) or 6 months (Ach: p=0.016, SNP: p=0.045, FMD: p=0.016) in the exercise but not in the control group. Generalised estimated equations detected that maximal oxygen uptake was a strong predictor for the observed changes in Ach (p=0.009) and GTN (p<0.001) whereas logCRP for SNP (p=0.017) and GTN (p=0.008). An exercise programme designed to meet individual needs and physical abilities significantly improves microvascular and macrovascular function in parallel with disease-related characteristics in RA patients. The potential long-term beneficial effects of such interventions at reducing cardiovascular risk in these patients merit further exploration. ISRCTN50861407. 23703031 Ultrasensitive surface-enhanced Raman scattering detection of trypsin based on anti-aggregation of 4-mercaptopyridine-functionalized silver nanoparticles: an optical sensing platform toward proteases. In this work, a simple and sensitive surface-enhanced Raman scattering (SERS) strategy was developed for recognition and detection of trypsin, by using anti-aggregation of 4-mercaptopyridine (4-MPY)-functionalized silver nanoparticles (AgNPs) based on the interaction between protamine and trypsin. The polycationic protamine not only served as a substrate for enzyme hydrolysis but also worked as a medium for SERS enhancement, which could bind negatively charged 4-MPY-functionalized AgNPs and induce their aggregation. The hydrolysis catalyzed with trypsin in sample solution decreased the concentration of free protamine, resulting in the dispersion of AgNPs and thus decreasing the Raman intensity of 4-MPY, by which the trypsin could be sensed optically. A detection level down to 0.1 ng mL(-1) for trypsin was obtained. The induced accumulation of AgNPs modified with Raman reporter 4-MPY largely enhanced the SERS responses. A good linearity was found within the wide range over five orders of magnitude and reasonable relative standard deviations (between 2.4 and 11.6%) were attained. By using trypsin as a model, the new concept can provide an excellent platform for ultrasensitive SERS measurements of various proteases/enzymes which can lead to nanoparticles stability change through catalyzed hydrolysis toward substrate. 23731122 Effect of injection routes on the biodistribution, clearance, and tumor uptake of carbon dots. The emergence of photoluminescent carbon-based nanomaterials has shown exciting potential in the development of benign nanoprobes. However, the in vivo kinetic behaviors of these particles that are necessary for clinical translation are poorly understood to date. In this study, fluorescent carbon dots (C-dots) were synthesized and the effect of three injection routes on their fate in vivo was explored by using both near-infrared fluorescence and positron emission tomography imaging techniques. We found that C-dots are efficiently and rapidly excreted from the body after all three injection routes. The clearance rate of C-dots is ranked as intravenous > intramuscular > subcutaneous. The particles had relatively low retention in the reticuloendothelial system and showed high tumor-to-background contrast. Furthermore, different injection routes also resulted in different blood clearance patterns and tumor uptakes of C-dots. These results satisfy the need for clinical translation and should promote efforts to further investigate the possibility of using carbon-based nanoprobes in a clinical setting. More broadly, we provide a testing blueprint for in vivo behavior of nanoplatforms under various injection routes, an important step forward toward safety and efficacy analysis of nanoparticles. 23963175 Transcriptional Profiling of Staphylococcus aureus During Growth in 2 M NaCl Leads to Clarification of Physiological Roles for Kdp and Ktr K+ Uptake Systems. ABSTRACT Staphylococcus aureus exhibits an unusually high level of osmotolerance and Na(+) tolerance, properties that support survival in various host niches and in preserved foods. The genetic basis of these traits is not well understood. We compared the transcriptional profiles of S. aureus grown in complex medium with and without 2 M NaCl. The stimulon for growth in high-osmolality media and Na(+) included genes involved in uptake of K(+), other compatible solutes, sialic acid, and sugars; capsule biosynthesis; and amino acid and central metabolism. Quantitative PCR analysis revealed that the loci responded differently from each other to high osmolality imposed by elevated NaCl versus sucrose. High-affinity K(+) uptake (kdp) genes and capsule biosynthesis (cap5) genes required the two-component system KdpDE for full induction by osmotic stress, with kdpA induced more by NaCl and cap5B induced more by sucrose. Focusing on K(+) importers, we identified three S. aureus genes belonging to the lower-affinity Trk/Ktr family that encode two membrane proteins (KtrB and KtrD) and one accessory protein (KtrC). In the absence of osmotic stress, the ktr gene transcripts were much more abundant than the kdpA transcript. Disruption of S. aureus kdpA caused a growth defect under low-K(+) conditions, disruption of ktrC resulted in a significant defect in 2 M NaCl, and a ΔktrC ΔkdpA double mutant exhibited both phenotypes. Protective effects of S. aureus Ktr transporters at elevated NaCl are consistent with previous indications that both Na(+) and osmolality challenges are mitigated by the maintenance of a high cytoplasmic K(+) concentration. IMPORTANCE There is general agreement that the osmotolerance and Na(+) tolerance of Staphylococcus aureus are unusually high for a nonhalophile and support its capacity for human colonization, pathogenesis, and growth in food. Nonetheless, the molecular basis for these properties is not well defined. The genome-wide response of S. aureus to a high concentration, 2 M, of NaCl revealed the upregulation of expected genes, such as those for transporters of compatible solutes that are widely implicated in supporting osmotolerance. A high-affinity potassium uptake system, KdpFABC, was upregulated, although it generally plays a physiological role under very low K(+) conditions. At higher K(+) concentrations, a lower-affinity and more highly expressed type of K(+) transporter system, Ktr transporters, was shown to play a significant role in high Na(+) tolerance. This study illustrates the importance of the K(+) status of the cell for tolerance of Na(+) by S. aureus and underscores the importance of monovalent cation cycles in this pathogen. 23683497 Activation of p53 with Nutlin-3a radiosensitizes lung cancer cells via enhancing radiation-induced premature senescence. Radiotherapy is routinely used for the treatment of lung cancer. However, the mechanisms underlying ionizing radiation (IR)-induced senescence and its role in lung cancer treatment are poorly understood. Here, we show that IR suppresses the proliferation of human non-small cell lung cancer (NSCLC) cells via an apoptosis-independent mechanism. Further investigations reveal that the anticancer effect of irradiation correlates well with IR-induced premature senescence, as evidenced by increased senescence-associated β-glactosidase (SA-β-gal) staining, decreased BrdU incorporation and elevated expression of p16(INK4a) (p16) in irradiated NSCLC cells. Mechanistic studies indicate that the induction of senescence is associated with activation of the p53-p21 pathway, and that inhibition of p53 transcriptional activity by PFT-α attenuates IR-induced tumor cell killing and senescence. Gain-of-function assays demonstrate that restoration of p53 expression sensitizes H1299 cells to irradiation, whereas knockdown of p53 expression by siRNA inhibits IR-induced senescence in H460 cells. Furthermore, treatment with Nutlin-3a, a small molecule inhibitor of MDM2, enhances IR-induced tumor cell killing and senescence by stabilizing the activation of the p53-p21 signaling pathway. Taken together, these findings demonstrate for the first time that pharmacological activation of p53 by Nutlin-3a can sensitize lung cancer cells to radiation therapy via promoting IR-induced premature senescence. 23840138 Treatment options of inflammatory appendiceal masses in adults. At present, the treatment of choice for uncomplicated acute appendicitis in adults continues to be surgical. The inflammation in acute appendicitis may sometimes be enclosed by the patient's own defense mechanisms, by the formation of an inflammatory phlegmon or a circumscribed abscess. The management of these patients is controversial. Immediate appendectomy may be technically demanding. The exploration often ends up in an ileocecal resection or a right-sided hemicolectomy. Recently, the conditions for conservative management of these patients have changed due to the development of computed tomography and ultrasound, which has improved the diagnosis of enclosed inflammation and made drainage of intra-abdominal abscesses easier. New efficient antibiotics have also given new opportunities for nonsurgical treatment of complicated appendicitis. The traditional management of these patients is nonsurgical treatment followed by interval appendectomy to prevent recurrence. The need for interval appendectomy after successful nonsurgical treatment has recently been questioned because the risk of recurrence is relatively small. After successful nonsurgical treatment of an appendiceal mass, the true diagnosis is uncertain in some cases and an underlying diagnosis of cancer or Crohn's disease may be delayed. This report aims at reviewing the treatment options of patients with enclosed appendiceal inflammation, with emphasis on the success rate of nonsurgical treatment, the need for drainage of abscesses, the risk of undetected serious disease, and the need for interval appendectomy to prevent recurrence. 23830283 Dilute nanoemulsions via separation of satellite droplets. A facile method is suggested for fabrication of dilute nanoemulsions. In a typical emulsification process, drops are usually accompanied by off-grade satellite droplets. The size of these satellite droplets ranges from hundreds of nanometers to above microns. Experiments were carried out to assess the possibility of separation of nanodrops from macroemulsions made via a conventional method in order to produce nanoemulsions. A low-power homogenizer was used to produce parent emulsions which were then injected from the bottom to a glass column containing water and allowed to cream. By monitoring drops remaining in the bottom of the column, it is clearly shown how progressively smaller they become with time yielding eventually dilute nanoemulsions. The average diameter of drops reduced to 100nm when oil with high viscosity was used. The concentration of resulting nanoemulsions increased with increasing viscosity and ratio of the disperse phase of parent emulsions. 23859763 Effects of radiation on the incidence of prostate cancer among Nagasaki atomic bomb survivors. Atomic bomb survivors have been reported to have an increased risk of some cancers, especially leukemia. However, the risk of prostate cancer in atomic bomb survivors is not known to have been examined previously. This study examined the association between atomic bomb radiation and the incidence of prostate cancer among male Nagasaki atomic bomb survivors. The subjects were classified by distance from the hypocenter into a proximal group (<2 km), a distal group (≥2 km), and an early entrance group (those who entered the region <2 km from the hypocenter within 2 weeks after the explosion). Between 1996 and 2009, 631 new cases of prostate cancer were identified among approximately 18 400 male Nagasaki atomic bomb survivors who were alive in 1996. The Cox proportional hazard model was used to estimate the risk of prostate cancer development, with adjustment for age at atomic bomb explosion, attained age, smoking status, and alcohol consumption. Compared with the distal group, the proximal group had significant increased risks of total, localized, and high-grade prostate cancer (relative risk and 95% confidence interval: 1.51 [1.21-1.89]; 1.80 [1.26-2.57]; and 1.88 [1.20-2.94], respectively). This report is the first known to reveal a significant relationship between atomic bomb radiation and prostate cancer. 23944828 Notice board. Courses, events, grants, and awards to progress your career. 23229277 Sequential optimal monitoring network design and iterative spatial estimation of pollutant concentration for identification of unknown groundwater pollution source locations. One of the difficulties in accurate characterization of unknown groundwater pollution sources is the uncertainty regarding the number and the location of such sources. Only when the number of source locations is estimated with some degree of certainty that the characterization of the sources in terms of location, magnitude, and activity duration can be meaningful. A fairly good knowledge of source locations can substantially decrease the degree of nonuniqueness in the set of possible aquifer responses to subjected geochemical stresses. A methodology is developed to use a sequence of dedicated monitoring network design and implementation and to screen and identify the possible source locations. The proposed methodology utilizes a combination of spatial interpolation of concentration measurements and simulated annealing as optimization algorithm for optimal design of the monitoring network. These monitoring networks are to be designed and implemented sequentially. The sequential design is based on iterative pollutant concentration measurement information from the sequentially designed monitoring networks. The optimal monitoring network design utilizes concentration gradient information from the monitoring network at previous iteration to define the objective function. The capability of the feedback information based iterative methodology is shown to be effective in estimating the source locations when no such information is initially available. This unknown pollution source locations identification methodology should be very useful as a screening model for subsequent accurate estimation of the unknown pollution sources in terms of location, magnitude, and activity duration. 23907185 A Synaptic Function Approach to Investigating Complex Psychiatric Diseases. The 22q11 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans and presents with a complex and variable psychiatric phenotype. Patients show cognitive impairment and have a higher probability of psychiatric disorders. As much as 30% of patients with 22q11DS suffer from schizophrenia, the strongest association between any mutation and the disease. Schizophrenia is a complex psychiatric disease that affects multiple brain regions, giving rise to a constellation of seemingly unrelated symptoms including hallucinations, social withdrawal, and memory deficits. Synaptic or neuronal malfunctions within certain physiological circuits appear to be at the core of these symptoms. Understanding disease at the synaptic level requires genetic model systems where intact neural circuits can be interrogated for functional deficits. Because of the overlap between 22q11DS and schizophrenia, models of 22q11DS may be key genetic tools for investigating both diseases. Here we discuss the advantages of using a synaptic function approach to studying mouse models of 22q11DS, review recent findings, and discuss them in the broader context of 22q11DS and schizophrenia. 23811820 Formation of an iron phosphine-borane complex by formal insertion of BH3 into the Fe-P bond. A unique hydrido phosphine-borane iron(ii) complex [(dppa)(Ph2P-N-P(BH3)Ph2)Fe(H)] () was obtained by the reaction of iron(ii) chloride and two equivalents of bis(diphenylphosphino)amine (dppa) with an excess of sodium borohydride in acetonitrile-ethanol mixtures. Detailed investigations of the reaction revealed that a mixture of cis- and trans-[(dppa)2Fe(NCMe)2](2+) is formed prior to the reduction by sodium borohydride. Depending on the solvent, different products were obtained by the reduction: in acetonitrile-ethanol mixtures the hydrido phosphine-borane complex is formed by formal insertion of BH3, while the reduction in pure acetonitrile results in the formation of the cationic complex trans-[(dppa)2Fe(H)(NCMe)](BH4) (). Complex is remarkably stable in ethanol and does not undergo phosphine-borane formation, even in the presence of excess sodium borohydride. This observation suggests that the phosphine-borane complex is generated by the reaction with the first equivalent of sodium borohydride with the participation of ethanol, followed by deprotonation or dihydrogen elimination. Experiments with similar diphosphine ligands, such as bis(diphenylphosphino)methane, did not yield a phosphine-borane complex, indicating the crucial role of the amine group in the observed reactivity. 23774162 Silver nanowire-based electrochemical immunoassay for sensing immunoglobulin G with signal amplification using strawberry-like ZnO nanostructures as labels. The quick development of nanoscience and nanotechnology has paved the way for ultrasensitive biosensing and analysis. In this work, an ultrasensitive electrochemical immunosensor was developed for the detection of human immunoglobulin G (IgG) by combining with a newly designed trace tag on a disposable immunosensor array. The array was prepared by immobilizing captured antibodies on ultralong Ag nanowires, whilst the trace tag was prepared by loading horseradish peroxidase (HRP)-labeled goat anti-human IgG (HRP-anti-IgG) on thionine (TH)-doped mesoporous ZnO nanostrawberries (MP-ZnO). With a sandwich-type immunoassay format, mainly due to crystalline framework and high surface area of the mesoporous (MP) materials, as well as the superconductivity of silver nanowires, the electrochemical signal was significantly amplified. The linear range of the developed immunosensor is 0.01-200ngmL(-1) and the detection limit is 4pgmL(-1) IgG, which make the hierarchically nanostructured composites very promising candidates for the next-generation sandwich-type electrochemical immunoassays. 23647244 Targeting cAMP in chronic lymphocytic leukemia: a pathway-dependent approach for the treatment of leukemia and lymphoma. Introduction: Cyclic AMP (cAMP) promotes growth arrest and/or apoptosis of various types of lymphoma, in particular chronic lymphocytic leukemia (CLL). These responses have spurred the interest in developing agents that increase cAMP to treat such malignancies and to identify mechanisms of the responses. Areas covered: The murine T-lymphoma cell line S49, has provided an important, pioneering model to define mechanisms of cAMP-mediated lymphoid cell death. Studies with S49 cells demonstrated that cAMP, acting via protein kinase A (PKA), is pro-apoptotic through a mitochondria-dependent pathway and identified cAMP/PKA-regulated targets involved in apoptosis. Akin to such findings, cAMP promotes apoptosis via PKA of cells from patients with CLL. Analysis of mediators of cAMP accumulation and cAMP-promoted apoptosis in CLL cells has revealed approaches to increase cAMP and engage its pro-apoptotic action. Expert opinion: This 'pathway approach' targeted to cAMP has identified GPCR agonists/antagonists, AC activators (e.g., AC7), PDE inhibitors (e.g., PDE7B) and/or activators or inhibitors of downstream mediators (PKA and Epac, respectively), which might be utilized therapeutically in CLL. Therapy directed at such targets may prove to be clinically useful and may also provide a proof-of-principle of the utility of targeting cAMP signaling in other types of cancer. 23815768 Surgical approach to a vulval-pubic cartilaginous cyst: A case report and review of published work. Cartilaginous cyst of symphysis pubis is rare and to our knowledge 12 cases have been reported in the published work. Although cartilaginous cysts of the vulva and pubis are likely to present to a gynecologist as a vulval-pubic mass, their diagnosis and management warrants a multidisciplinary team approach because of their rarity and anatomical location. Non-invasive diagnosis includes magnetic resonance imaging and ultrasound scan, while the invasive preoperative biopsy is reserved for cases with a high index of suspicion of malignancy. The surgical approach for the management of vulval-pubic cartilaginous cyst is not well established. The current case demonstrates a joint surgical approach involving a gynecologist and orthopedic surgeon in management of a degenerative cartilaginous cyst. As this condition is benign, every effort should be made to preserve the stability of the pubic symphysis. Symphyseal dysfunction from surgery remains a potential complication for which treatment is not straightforward. 23957271 Emotional availability in psychotherapy: The usefulness and validity of the Emotional Availability Scales for analyzing the psychotherapeutic relationship. Abstract The aim of this study was to assess whether a modified version of the Emotional Availability Scales (EAS), created to assess interaction quality between parents and children, could be applied to psychotherapy sessions and whether emotional availability (EA), as assessed by the modified EAS-T, was associated with client- and therapist-rated working alliance. EAS-T was used to assess 42 sessions from 16 therapies. The therapies came from the LURIPP project, comparing IPT with BRT for depressed clients. The results showed that sessions could be reliably rated with EAS-T. Most rating scales had acceptable variance. The client's perception of task alliance was associated with several of the EA subscales (sensitivity, nonhostility, responsiveness) assessed over therapies, whereas the perception of bond was associated with Structure on EAS. 23788080 Surface properties of alumino-silicate single-walled nanotubes of the imogolite type. An IR spectroscopy study is reported on the nature and accessibility of external and internal surfaces of single-walled alumino-silicate nanotubes (NTs) of the imogolite type. NTs form bundles with hexagonal symmetry, in which three kinds of surfaces may be figured out: surface A is the inner surface of NTs; surface B is that between three aligned NTs in the hexagonal packing; and surface C arises from slit mesopores between bundles. Two materials were considered: proper imogolite (IMO, (OH)3Al2O3SiOH) and its methylated analogue, (Me-IMO, (OH)3Al2O3SiCH3). The chemical nature of the outer surface of NTs is the same in both materials, i.e. a curved gibbsite sheet with both Al-OH-Al and Al-O-Al groups and an amphoteric character. The inner surface is very hydrophilic in IMO NTs, lined by closely packed silanols, and hydrophobic in Me-IMO, all silanols being replaced by -SiCH3 groups. The change in chemical composition is accompanied by an increment in pore size, about 1.0 nm in IMO, and ca. 2.0 nm in Me-IMO, which implies a change in the accessibility of the B surface, not available to any molecule in IMO, and accessible in Me-IMO to small molecules like water, due to larger pores between NTs. Aluminol species at the B surface display an acidic nature, in contrast with that of the same species at surface C, because of a confinement effect. 23965249 A randomized controlled trial on preweaning morbidity, growth and mortality in Holstein heifers fed a lacteal-derived colostrum replacer or pooled maternal colostrum. The objective of this randomized controlled trial was to determine the effect of feeding a commercial lacteal-derived colostrum replacer (CR) or pooled maternal colostrum (MC) on preweaning morbidity, growth and mortality in Holstein heifer calves. A total of 568 calves were randomly assigned to be fed either 3.8 L of pooled MC or two doses (200 g IgG) of a CR. Calves were monitored daily for preweaning morbidity until weaning at 60 d old. Birth and weaning weights were measured to estimate growth rates. Calves fed CR were significantly less likely to be affected with a diarrhea event (OR = 0.58; 95% CI, 0.38 to 0.88; P value = 0.011) and had a higher rate of daily weight gain (0.051 kg/day; 95% CI, 0.03 to 0.08; P value <0.001) compared to calves fed pooled MC. Use of lacteal-derived colostrum replacer was not significantly associated with respiratory disease (OR = 1.01; 95% CI 0.67 to 1.51; P value = 0.974 ), omphalitis (OR = 0.93; 95% CI 0.06 to 14.86; P value = 0.956), or mortality (HR = 0.71; 95% CI 0.27 to 1.92; P value = 0.505) in the study calves. The lacteal-derived CR fed at the study dose was a viable colostrum alternative in the event of poor quality pooled MC for the prevention of preweaning diarrhea and resulted in higher growth rates in comparison to calves fed pooled MC in the study herd. 23422021 Medico-legal issues in cardiology. The aim of this article is to educate physicians about the current litigation climate in cardiology and cardiac surgery, with a focus on the most frequently litigated areas of practice, including failure to diagnose and treat myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary intervention, and the use of tissue plasminogen activator. Empirical research on cardiology malpractice is presented, along with a sampling of up-to-date cases designed to illustrate common issues and important themes. The principles for reducing legal liability are also discussed, including the informed consent process, spoliation of records, and the role of documentation. Finally, practical recommendations are provided for cardiologists and cardiac surgeons to limit their legal liability. 23740751 High-throughput instant quantification of protein expression and purity based on photoactive yellow protein turn off/on label. Quantifying the concentration and purity of a target protein is essential for high-throughput protein expression test and rapid screening of highly soluble proteins. However, conventional methods such as PAGE and dot blot assay generally involve multiple time-consuming tasks requiring hours or do not allow instant quantification. Here, we demonstrate a new method based on the Photoactive yellow protein turn Off/On Label (POOL) system that can instantly quantify the concentration and purity of a target protein. The main idea of POOL is to use Photoactive Yellow Protein (PYP), or its miniaturized version, as a fusion partner of the target protein. The characteristic blue light absorption and the consequent yellow color of PYP is absent when initially expressed without its chromophore, but can be turned on by binding its chromophore, p-coumaric acid. The appearance of yellow color upon adding a precursor of chromophore to the co-expressed PYP can be used to check the expression amount of the target protein via visual inspection within a few seconds as well as to quantify its concentration and purity with the aid of a spectrometer within a few minutes. The concentrations measured by the POOL method, which usually takes a few minutes, show excellent agreement with those by the BCA Kit, which usually takes ∼1 h. We demonstrate the applicability of POOL in E. coli, insect, and mammalian cells, and for high-throughput protein expression screening. 23704275 Genetic characterization of novel putative rhabdovirus and dsRNA virus from Japanese persimmon. Deep-sequencing analysis of nucleic acids from leaf tissue of Japanese persimmon trees exhibiting fruit apex disorder in some fruits detected two molecules that were graft transmitted to healthy seedlings. One of the complete genomes consisted of 13 467 nt and encoded six genes similar to those of plant rhabdoviruses. The virus formed a distinct cluster in the genus Cytorhabdovirus with lettuce necrotic yellows virus, lettuce yellow mottle virus and strawberry crinkle virus in a phylogenetic tree based on the L protein (RNA-dependent RNA polymerase, RdRp). The other consisted of 7475 nt and shared a genome organization similar to those of some insect and fungal viruses having dsRNA genomes. In a phylogenetic tree using the RdRp sequence of several unassigned dsRNA viruses, the virus formed a possible new genus cluster with two insect viruses, Circulifer tenellus virus 1 and Spissistilus festinus virus 1, and one plant virus, cucurbit yellows-associated virus. 23953513 Microstructural characterization of TFA-MOD processed Y1-xGdxBa2Cu3O7-y with BaZrO3. Y1-xGdxBa2Cu3O7-y with BaZrO3 film was fabricated on CeO2 buffered LaMnO3/ion beam assisted deposition-MgO/Gd2Zr2O7/Hastelloy C276TM substrates by the metal organic deposition process using trifluoroacetates. Both microstructural and analytical characterizations were performed by transmission electron microscopy with selected area electron diffraction method and energy dispersive X-ray spectroscopy. The thickness of Y1-xGdxBa2Cu3O7-y with BaZrO3 film was found approximately 700nm and the film was composed of c-axis oriented Y1-xGdxBa2Cu3O7-y grains. Several types of particles, (Y,Gd)2Cu2O5, CuO and BaZrO3, were formed within the Y1-xGdxBa2Cu3O7-y film, whose sizes were about 100-200nm for (Y,Gd)2Cu2O5 and CuO particles, and about 10-20nm for BaZrO3 particles, respectively. In the Y1-xGdxBa2Cu3O7-y film, (Y,Gd)2Cu2O5 and CuO particles were dispersed heterogeneously, whereas BaZrO3 nanoparticles were found dispersed homogeneously with random orientation. In addition, electron tomographic observation was carried out to attain the three-dimensional information of polyhedral BaZrO3 nanoparticles. 23053787 Contamination by metals and pharmaceuticals in northern Taihu Lake (China) and its relation to integrated biomarker response in fish. Taihu Lake is the largest shallow freshwater lake in eastern China and is suffering not only from an increasingly serious threat of eutrophication but also potential ecological risk due to the input of emerging contaminants. Active biomonitoring was conducted in Taihu Lake using transplanted goldfish (Carassius auratus) to determine the contamination by pharmaceuticals and metals and to assess the potential ecological risk. A suite of biomarkers including acetylcholinesterase, ethoxyresorufin O-deethylase, glutathione S-transferase, glutathione peroxidase and superoxide dismutase activities in fish after 7, 14, 21 and 28 days of exposure in situ, as well as pharmaceuticals and metals in water, were determined during the field exposure period. The results indicate that pharmaceuticals exist mainly in Zhushan Bay and Meiliang Bay, while metals are present mainly in Gong Bay. An integrated biomarker response (IBR) was calculated and used to evaluate the ecological risk of the polluted area of Taihu Lake. It was found that Zhushan Bay might present higher risk to fish, followed by Meiliang Bay. IBR values were in good agreement with copper and caffeine concentrations. 23954400 Parp1 deficient mice are protected from streptozotocin-induced diabetes but not caerulein-induced pancreatitis, independent of the induction of Reg family genes. Poly(ADP-ribose) polymerase (Parp) 1 is a key regulator of cell death, its inhibition prevented streptozotocin-induced diabetes and attenuated caerulein-induced acute pancreatitis. Reg family proteins are significantly induced by Parp1 inhibitor, experimental diabetes and/or acute pancreatitis. We propose that Reg proteins are involved in the protection of pancreatic cells by Parp1 inhibition. To test this possibility, Parp1-/- and wild-type mice were injected with streptozotocin to induce diabetes. Separately, acute pancreatitis was induced with repeated injections of caerulein. Upon streptozotocin administration, Parp1-/- mice displayed much decreased hyperglycemia and preserved serum insulin level. The treatment induced similar levels of Reg1, -2, -3α and -3β genes in the pancreas of both wild-type and Parp1-/- mice, suggesting that the upregulation of Reg family genes during streptozotocin-induced diabetes was independent of Parp1 ablation. In caerulein-induced pancreatitis, unlike being reported, Parp1 knockout caused no relief on the severity of pancreatitis; the upregulation of pancreatic Reg1, -2, -3α and -3β genes upon caerulein was unaffected by Parp1 deletion. Our results reconfirmed the protective effect of Parp1 gene deletion on islet β-cells but questioned its effect on the acinar cells. In either case, the significant induction of Reg family genes seemed independent of Parp1-mediated cell death. 23952607 European deciduous trees exhibit similar safety margins against damage by spring freeze events along elevational gradients. Minimum temperature is assumed to be an important driver of tree species range limits. We investigated during which period of the year trees are most vulnerable to freezing damage and whether the pressure of freezing events increases with increasing elevation. We assessed the course of freezing resistance of buds and leaves from winter to summer at the upper elevational limits of eight deciduous tree species in the Swiss Alps. By reconstructing the spring phenology of these species over the last eight decades using a thermal time model, we linked freezing resistance with long-term minimum temperature data along elevational gradients. Counter-intuitively, the pressure of freeze events does not increase with elevation, but deciduous temperate tree species exhibit a constant safety margin (5-8.5 K) against damage by spring freeze events along elevational gradients, as a result of the later flushing at higher elevation. Absolute minimum temperatures in winter and summer are unlikely to critically injure trees. Our study shows that freezing temperatures in spring are the main selective pressure controlling the timing of flushing, leading to a shorter growing season at higher elevation and potentially driving species distribution limits. Such mechanistic knowledge is important to improve predictions of tree species range limits. 23651917 Framework for combining REACH and national regulations to obtain equal protection levels of human health and the environment in different countries - comparative study of Denmark and Korea. The aim of this paper is to present a conceptual framework for a systems approach to protect the environment and human health by taking into account differences in the cumulative risks of total human exposure in a territorial context. To this end the measures that are available and that can be included in REACH exposure scenarios in order to obtain territorially relevant chemical safety assessments (CSAs) were explored. The advantage of linking the REACH exposure scenarios with background environmental quality data reported under other national regulations is discussed. The main question is how REACH may be improved to protect the environment and human health inside and outside the EU. This question is exemplified in a comparative case study of two countries, Denmark and Korea, each with its own set of different environmental qualities and national regulations. As a member of the EU Denmark is obliged to adopt REACH, while Korea implemented REACH to improve the competitiveness of Korean industry within the EU market. It is presented how differences in national regulations and environmental qualities in these two countries affect background human exposure concentrations. Choosing lead as a model compound, the territorial differences in background exposure to endocrine and neurological interfering stressors were modelled. It is concluded that the different territorial soil and air lead pollution levels contribute differently to the total childhood lead exposure in the two countries. As such, the probability of the total exposure from air and soil exceeding 10% of the provisional Total Daily Intake (PTDI) is estimated to be 55.3% in Denmark and 8.2% in Korea. The relative contribution from air inhalation and soil ingestion to childhood lead exposure is estimated to be 1-99% in Denmark while it is 83-17% in Korea. 23581495 Recurrence of preterm birth and perinatal mortality in northern Tanzania: registry-based cohort study. To estimate the recurrence risk of preterm delivery and estimate the perinatal mortality in repeated preterm deliveries. Prospective study in Tanzania of 18 176 women who delivered a singleton between 2000 and 2008 at KCMC hospital. The women were followed up to 2010 for consecutive births. A total of 3359 women were identified with a total of 3867 subsequent deliveries in the follow-up period. Recurrence risk of preterm birth and perinatal mortality was estimated using log-binomial regression and adjusted for potential confounders. For women with a previous preterm birth, the risk of preterm birth in a subsequent pregnancy was 17%. This recurrence risk was estimated to be 2.7-fold (95% CI: 2.1-3.4) of the risk of women with a previous term birth. The perinatal mortality of babies in a second preterm birth of the same woman was 15%. Babies born at term who had an older sibling that was born preterm had a perinatal mortality of 10%. Babies born at term who had an older sibling who was also born at term had a perinatal mortality of 1.7%. Previous delivery of a preterm infant is a strong predictor of future preterm births in Tanzania. Previous or repeated preterm births increase the risk of perinatal death substantially in the subsequent pregnancy. 23936877 Diagnostic value of stool DNA testing for multiple markers of colorectal cancer and advanced adenoma: A meta-analysis. The diagnostic value of stool DNA (sDNA) testing for colorectal neoplasms remains controversial. To compensate for the lack of large-scale unbiased population studies, a meta-analysis was performed to evaluate the diagnostic value of sDNA testing for multiple markers of colorectal cancer (CRC) and advanced adenoma. The PubMed, Science Direct, Biosis Review, Cochrane Library and Embase databases were systematically searched in January 2012 without time restriction. Meta-analysis was performed using a random-effects model using sensitivity, specificity, diagnostic OR (DOR), summary ROC curves, area under the curve (AUC), and 95% CIs as effect measures. Heterogeneity was measured using the χ2 test and Q statistic; subgroup analysis was also conducted. A total of 20 studies comprising 5876 individuals were eligible. There was no heterogeneity for CRC, but adenoma and advanced adenoma harboured considerable heterogeneity influenced by risk classification and various detection markers. Stratification analysis according to risk classification showed that multiple markers had a high DOR for the high-risk subgroups of both CRC (sensitivity 0.759 [95% CI 0.711 to 0.804]; specificity 0.883 [95% CI 0.846 to 0.913]; AUC 0.906) and advanced adenoma (sensitivity 0.683 [95% CI 0.584 to 0.771]; specificity 0.918 [95% CI 0.866 to 0.954]; AUC 0.946) but not for the average-risk subgroups of either. In the methylation subgroup, sDNA testing had significantly higher DOR for CRC (sensitivity 0.753 [95% CI 0.685 to 0.812]; specificity 0.913 [95% CI 0.860 to 0.950]; AUC 0.918) and advanced adenoma (sensitivity 0.623 [95% CI 0.527 to 0.712]; specificity 0.926 [95% CI 0.882 to 0.958]; AUC 0.910) compared with the mutation subgroup. There was no significant heterogeneity among studies for subgroup analysis. sDNA testing for multiple markers had strong diagnostic significance for CRC and advanced adenoma in high-risk subjects. Methylation makers had more diagnostic value than mutation markers. 23962132 Effects of Reduced Sulfur Compounds on Pd-catalytic Hydrodechlorination of TCE in Groundwater by Cathodic H2 under Electrochemically-induced Oxidizing Conditions. Reduced sulfur compounds (RSCs) poison Pd catalysts for catalytic hydrodechlorination of contaminants in anoxic groundwater. This study investigates the effects of RSCs on Pd-catalytic hydrodechlorination of trichloroethylene (TCE) in oxic groundwater. Water electrolysis in an undivided electrolytic cell is used to produce H2 for TCE hydrodechlorination under oxidizing conditions. TCE is efficiently hydrodechlorinated to ethane, with significant accumulation of H2O2 under acidic conditions. Presence of sulfide at concentrations less than 93.8 μM moderately inhibits TCE hydrodechlorination and H2O2 production. Presence of sulfite at low concentrations (≤ 1 mM) significantly enhances TCE decay, while at high concentration (3 mM) inhibits initially and enhances afterwards when sulfite concentration declines to less than 1 mM. Using radical scavenging experiments and electron spin resonance assay, SO3•- which is generated from sulfite under oxidizing conditions is validated as the new reactive species contributing to the enhancement. This study reveals a distinct mechanism of effect of sulfite on TCE hydrodechlorination by Pd and H2 in oxic groundwater and presents an alternative approach to increasing resistance of Pd to RSCs poisoning. 23862962 Tailoring relaxation time spectrum in soft glassy materials. Physical properties of out of equilibrium soft materials depend on time as well as deformation history. In this work we propose to transform this major shortcoming into gain by applying controlled deformation field to tailor the rheological properties. We take advantage of the fact that deformation field of a certain magnitude can prevent particles in an aging soft glassy material from occupying energy wells up to a certain depth, thereby populating only the deeper wells. We employ two soft glassy materials with dissimilar microstructures and demonstrate that increase in strength of deformation field while aging leads to narrowing of spectrum of relaxation times. We believe that, in principle, this philosophy can be universally applied to different kinds of glassy materials by changing nature and strength of impetus. 23900703 Sodium ((23)Na) ultra-short echo time imaging in the human brain using a 3D-Cones trajectory. Sodium magnetic resonance imaging ((23)Na-MRI) of the brain has shown changes in (23)Na signal as a hallmark of various neurological diseases such as stroke, Alzheimer's disease, Multiple Sclerosis and Huntington's disease. To improve scan times and image quality, we have implemented the 3D-Cones (CN) sequence for in vivo (23)Na brain MRI. Using signal-to-noise (SNR) as a measurement of sequence performance, CN is compared against more established 3D-radial k-space sampling schemes featuring cylindrical stack-of-stars (SOS) and 3D-spokes kooshball (KB) trajectories, on five healthy volunteers in a clinical setting. Resolution was evaluated by simulating the point-spread-functions (PSFs) and experimental measures on a phantom. All sequences were shown to have a similar SNR arbitrary units (AU) of 6-6.5 in brain white matter, 7-9 in gray matter and 17-18 AU in cerebrospinal fluid. SNR between white and gray matter were significantly different for KB and CN (p = 0.046 and <0.001 respectively), but not for SOS (p = 0.1). Group mean standard deviations were significantly smaller for CN (p = 0.016). Theoretical full-width at half-maximum linewidth of the PSF for CN is broadened by only 0.1, compared to 0.3 and 0.8 pixels for SOS and KB respectively. Actual image resolution is estimated as 8, 9 and 6.3 mm for SOS, KB and CN respectively. The CN sequence provides stronger tissue contrast than both SOS and KB, with more reproducible SNR measurements compared to KB. For CN, a higher true resolution in the same amount of time with no significant trade-off in SNR is achieved. CN is therefore more suitable for (23)Na-MRI in the brain. 23584593 Omega-3 polyunsaturated Fatty acids increase plasma adiponectin to leptin ratio in stable coronary artery disease. Growing evidence suggests a cardioprotective role of omega-3 polyunsaturated fatty acids (PUFA). However, the exact mechanisms underlying the effects of omega-3 PUFA in humans have not yet been fully clarified. We sought to evaluate omega-3 PUFA-mediated effects on adipokines in patients with stable coronary artery disease (CAD) undergoing elective percutaneous coronary intervention (PCI). We conducted a prospective, double-blind, placebo-controlled, randomized study, in which adiponectin, leptin and resistin were determined at baseline, 3-5 days and 30 days during administration of omega-3 PUFA 1 g/day (n = 20) or placebo (n = 28). As compared to controls administration of omega-3 PUFA resulted in increase of adiponectin by 13.4 % (P < 0.0001), reduction of leptin by 22 % (P < 0.0001) and increase of adiponectin to leptin (A/L) ratio by 45.5 % (P < 0.0001) at 30 days, but not at 3-5 days. Compared with placebo adiponectin was 12.7 % higher (P = 0.0042), leptin was 16.7 % lower (P < 0.0001) and A/L ratio was 33.3 % higher (P < 0.0001) in the omega-3 PUFA group at 30 days. Resistin decreased similarly in both groups after 1 month, without intergroup differences (P = 0.32). The multivariate model showed that the independent predictors of changes in adiponectin at 1 month (P < 0.001) were: omega-3 PUFA treatment, baseline platelet count, total cholesterol and those in leptin (P < 0.0001) were: omega-3 PUFA treatment and waist circumference. Independent predictors of A/L ratio changes (P < 0.0001) were: assigned treatment, current smoking and hyperlipidemia. In high risk stable coronary patients after PCI omega-3 PUFA supplementation improves adipokine profile in circulating blood. This might be a novel, favourable mechanism of omega-3 PUFA action. 23629935 Seeking care for pediatric diarrheal illness from traditional healers in bamako, mali. Abstract. Diarrhea is a leading cause of child mortality worldwide. Early recognition of symptoms and referral to medical treatment are essential. In 2007, we conducted a Healthcare Utilization and Attitudes Survey (HUAS) of 1,000 children randomly selected from a population census to define care-seeking patterns for diarrheal disease in Bamako, Mali, in preparation for the Global Enteric Multicenter Study (GEMS). We found that 57% of caretakers sought care for their child's diarrheal illness from traditional healers, and 27% of caretakers sought care from the government health center (GHC). Weighted logistic regression showed that seeking care from a traditional healer was associated with more severe reported diarrheal disease, like decreased urination (odds ratio [OR] = 3.35, 95% confidence interval [95% CI] = 1.19-9.41) and mucus or pus in stool (OR = 4.42, 95% CI = 1.35-14.51), along with other indicators of perceived susceptibility. A locally designed traditional healer referral system was, therefore, created that emphasized more severe disease. This system may serve as a model for health systems in West Africa. 23856363 Clinical features and outcomes of foot keloids treated using complete surgical excision and full thickness skin grafting followed by corticosteroid injections. Keloids are often resistant to treatment and have high recurrence rates. To the best of the authors' knowledge, however, there have been very few case reports related to foot keloids. The purpose of this retrospective case-series was to summarize the baseline characteristics of a cohort of patients, introduce our treatment regimen for the successful treatment of foot keloids. Patients were treated with surgical excision followed by full thickness skin grafting combined with postoperative steroid injections combined with silicone gel sheeting over a period of eight years from December 2004 to November 2012 at our institution. Subjective outcome was evaluated using Patient Scar Assessment Scales. The final objective outcome was judged by two independent physicians at the time of 12 months after treatment as recurrence or non-recurrence. Of 79 patients, 75 (94.9%) were women and 4 (5.1%) were men. The average age was 18 (range 7-43) years. The average pretreatment total size of the lesions was 50 (range 18-150) cm. The number of patients treated for a primary foot keloid was 29 (36.7%), and 70 patients (63.3%) were treated for a recurrent keloid that failed to respond to prior treatments. Prior treatments included single therapies such as surgical excision alone (4 patients, 5.1%), prior steroid injection alone (33 patients, 41.8%), and laser therapy (2 patients, 2.5%). Other therapies included combination treatments (11 patients, 13.9%). Most patients reported improved Patient Scar Assessment Scale by lapse of time. All patients completed the treatment regimen and follow-up of 12 months. Of these patients, 62 patients (78.5%) achieved successful treatment, while the remaining 17 (21.5%) experienced recurrence. We successfully treated foot keloids using complete surgical excision and full thickness skin grafting followed by four corticosteroid injections (at one month intervals). 23557989 A new method for stranded whole transcriptome RNA-seq. This report describes an improved protocol to generate stranded, barcoded RNA-seq libraries to capture the whole transcriptome. By optimizing the use of duplex specific nuclease (DSN) to remove ribosomal RNA reads from stranded barcoded libraries, we demonstrate improved efficiency of multiplexed next generation sequencing (NGS). This approach detects expression profiles of all RNA types, including miRNA (microRNA), piRNA (Piwi-interacting RNA), snoRNA (small nucleolar RNA), lincRNA (long non-coding RNA), mtRNA (mitochondrial RNA) and mRNA (messenger RNA) without the use of gel electrophoresis. The improved protocol generates high quality data that can be used to identify differential expression in known and novel coding and non-coding transcripts, splice variants, mitochondrial genes and SNPs (single nucleotide polymorphisms). 23954162 DrGaP: A Powerful Tool for Identifying Driver Genes and Pathways in Cancer Sequencing Studies. Cancers are caused by the accumulation of genomic alterations. Driver mutations are required for the cancer phenotype, whereas passenger mutations are irrelevant to tumor development and accumulate through DNA replication. A major challenge facing the field of cancer genome sequencing is to identify cancer-associated genes with mutations that drive the cancer phenotype. Here, we describe a powerful and flexible statistical framework for identifying driver genes and driver signaling pathways in cancer genome-sequencing studies. Biological knowledge of the mutational process in tumors is fully integrated into our statistical models and includes such variables as the length of protein-coding regions, transcript isoforms, variation in mutation types, differences in background mutation rates, the redundancy of genetic code, and multiple mutations in one gene. This framework provides several significant features that are not addressed or naively obtained by previous methods. In particular, on the observation of low prevalence of somatic mutations in individual tumors, we propose a heuristic strategy to estimate the mixture proportion of chi-square distribution of likelihood ratio test (LRT) statistics. This provides significantly increased statistical power compared to regular LRT. Through a combination of simulation and analysis of TCGA cancer sequencing study data, we demonstrate high accuracy and sensitivity in our methods. Our statistical methods and several auxiliary bioinformatics tools have been incorporated into a computational tool, DrGaP. The newly developed tool is immediately applicable to cancer genome-sequencing studies and will lead to a more complete identification of altered driver genes and driver signaling pathways in cancer. 23922720 Childhood chronic physical aggression associates with adult cytokine levels in plasma. An increasing number of animal and human studies are indicating that inflammation is associated with behavioral disorders including aggression. This study investigates the association between chronic physical aggression during childhood and plasma cytokine levels in early adulthood. Two longitudinal studies were used to select males on a chronic physical aggression trajectory from childhood to adolescence (n = 7) and a control group from the same background (n = 25). Physical aggression was assessed yearly by teachers from childhood to adolescence and plasma levels of 10 inflammatory cytokines were assessed at age 26 and 28 years. Compared to the control group, males on a chronic physical aggression trajectory from childhood to adolescence had consistently lower plasma levels of five cytokines: lower pro-inflammatory interleukins IL-1α (T(28.7) = 3.48, P = 0.002) and IL-6 (T(26.9) = 3.76, P = 0.001), lower anti-inflammatory interleukin IL-4 (T(27.1) = 4.91, P = 0.00004) and IL-10 (T(29.8) = 2.84, P = 0.008) and lower chemokine IL-8 (T(26) = 3.69, P = 0.001). The plasma levels of four cytokines accurately predicted aggressive and control group membership for all subjects. Physical aggression of boys during childhood is a strong predictor of reduced plasma levels of cytokines in early adulthood. The causal and physiological relations underlying this association should be further investigated since animal data suggest that some cytokines such as IL-6 and IL-1β play a causal role in aggression. 23877510 Unexpected Detection of Brain Metastases by 18F-NaF PET/CT in a Patient With Lung Cancer. In recent years, the inconsistent supply of Tc and the increasingly widespread use of PET/CT have led to a renewed interest in PET/CT bone scans using F-NaF. Recently, a 64-year-old man with biopsy-proven lung cancer underwent an F-NaF PET/CT bone scan due to a shortage of Tc. Unexpectedly, multiple nodular foci of increased tracer uptake were present in the brain, whereas there were no definitive bone metastases detected. Subsequently, brain MRI confirmed the presence of brain metastases. 23674436 White blood cell count and mortality in patients with acute pulmonary embolism. Although associated with adverse outcomes in other cardiovascular diseases, the prognostic value of an elevated white blood cell (WBC) count, a marker of inflammation and hypercoagulability, is uncertain in patients with pulmonary embolism (PE). We therefore sought to assess the prognostic impact of the WBC in a large, state-wide retrospective cohort of patients with PE. We evaluated 14,228 patient discharges with a primary diagnosis of PE from 186 hospitals in Pennsylvania. We used random-intercept logistic regression to assess the independent association between WBC count levels at the time of presentation and mortality and hospital readmission within 30 days, adjusting for patient and hospital characteristics. Patients with an admission WBC count <5.0, 5.0-7.8, 7.9-9.8, 9.9-12.6, and >12.6 × 10(9) /L had a cumulative 30-day mortality of 10.9%, 6.2%, 5.4%, 8.3%, and 16.3% (P < 0.001), and a readmission rate of 17.6%, 11.9%, 10.9%, 11.5%, and 15.0%, respectively (P < 0.001). Compared with patients with a WBC count 7.9-9.8 × 10(9) /L, adjusted odds of 30-day mortality were significantly greater for patients with a WBC count <5.0 × 10(9) /L (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.14-2.03), 9.9-12.6 × 10(9) /L (OR 1.55, 95% CI 1.26-1.91), or >12.6 × 10(9) /L (OR 2.22, 95% CI 1.83-2.69), respectively. The adjusted odds of readmission were also significantly increased for patients with a WBC count <5.0 × 10(9) /L (OR 1.34, 95% CI 1.07-1.68) or >12.6 × 10(9) /L (OR 1.29, 95% CI 1.10-1.51). In patients presenting with PE, WBC count is an independent predictor of short-term mortality and hospital readmission. Am. J. Hematol. 88:677-681, 2013. © 2013 Wiley Periodicals, Inc. 23557932 Antitumor effect of 5-fluorouracil is enhanced by rosemary extract in both drug sensitive and resistant colon cancer cells. 5-Fluorouracil (5-FU) is the most used chemotherapeutic agent in colorectal cancer. However, resistance to this drug is relatively frequent, and new strategies to overcome it are urgently needed. The aim of this work was to determine the antitumor properties of a supercritical fluid rosemary extract (SFRE), alone and in combination with 5-FU, as a potential adjuvant therapy useful for colon cancer patients. This extract has been recognized as a healthy component by the European Food Safety Authority (EFSA). The effects of SFRE both alone and in combination with 5-FU were evaluated in different human colon cancer cells in terms of cell viability, cytotoxicity, and cell transformation. Additionally, colon cancer cells resistant to 5-FU were used to assay the effects of SFRE on drug resistance. Finally, qRT-PCR was performed to ascertain the mechanism by which SFRE potentiates the effect of 5-FU. Our results show that SFRE displays dose-dependent antitumor activities and exerts a synergistic effect in combination with 5-FU on colon cancer cells. Furthermore, SFRE sensitizes 5-FU-resistant cells to the therapeutic activity of this drug, constituting a beneficial agent against both 5-FU sensitive and resistant tumor cells. Gene expression analysis indicates that the enhancement of the effect of 5-FU by SFRE might be explained by the downregulation of TYMS and TK1, enzymes related to 5-FU resistance. 23904146 Social Network Composition and Sexual Risk-Taking Among Gay and Bisexual Men in Atlanta, GA. Social network composition is known to effect patterns of reported sexual risk-taking among men who have sex with men (MSM); however, consensus as to the directionality and size of these effects is lacking. We examined the relationships between novel aspects of social network composition and sexual risk-taking using a cross-sectional survey of 870 MSM. Social network composition was found to have mixed effects on reported sexual risk-taking: reporting proportionally more lesbian, gay, or bisexual (LGB)-identified friends and reporting friends who were on average significantly older than the respondent were both associated with reporting increased sexual risk, while reporting proportionally more LGB-identified friends in relationships and reporting a social network proportionally more aware of the respondent's homosexuality/bisexuality were both associated with reporting decreased sexual risk. The support structures created by differing social network compositions-and particularly the presence of LGB couples-may be a potential area for targeting sexual risk-reduction interventions for MSM. 23870898 Effect of sorbitan monostearate on the physical characteristics and whipping properties of whipped cream. In this work, the effects of sorbitan monostearate (Span 60) level on the particle size distribution, microstructure and apparent viscosity of the emulsion were investigated. Average particle size (d4,3), surface protein concentration, partial coalescence of fat and overrun of whipped cream during whipping were also determined. As Span 60 level increased (0-0.8%) in emulsion, the apparent viscosity was increased gradually, and the particle size range was narrowed, which was also detected by microstructure. A positive effect of whipping time was observed on the average particle size, partial coalescence of fat, surface protein concentration and overrun during whipping, respectively. An increase of Span 60 level resulted in a reduction of d4,3 values and partial coalescence of fat during 0-1min whipping, then increasing after whipping for 2-5min (0.6% Span 60 as the critical level). A negative behaviour was observed between surface protein concentration and Span 60. Moreover, Span 60 could improve the overrun and organoleptic properties of whipped cream efficiently. 23872847 Targeting H3K4 trimethylation in Huntington disease. Transcriptional dysregulation is an early feature of Huntington disease (HD). We observed gene-specific changes in histone H3 lysine 4 trimethylation (H3K4me3) at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective. Therefore, targeting this epigenetic signature may be an effective strategy to ameliorate the consequences of HD. 23962168 The Escherichia coli divisome: born to divide. Septation in Escherichia coli involves complex molecular mechanisms that contribute to the accuracy of bacterial division. The proto-ring, a complex made up by the FtsZ, FtsA and ZipA proteins, forms at the beginning of the process and directs the assembly of the full divisome. Central to this complex is the FtsZ protein, a GTPase able to assemble into a ring-like structure that responds to several modulatory inputs including mechanisms to position the septum at midcell. The connection with the cell wall synthesising machinery stabilizes the constriction of the cytoplasmic membrane. Although a substantial amount of evidence supports this description, many details on how individual divisome elements are structured or how they function are subjected to controversial interpretations. We discuss these discrepancies arising from incomplete data and from technical difficulties imposed by the small size of bacteria. Future work, including more powerful imaging and reconstruction technologies, will help to clarify the missing details on the architecture and function of the bacterial division machinery. 23222201 Diaphragmatic hernia after esophagectomy for esophageal malignancy. Diaphragmatic hernia (DH) is an uncommon complication after esophagectomy, with <150 cases reported in the literature. The objective of our study was to determine the incidence and clinical presentation of this condition and to describe the prospective recognition of this finding in radiologic reports. Cross-sectional imaging studies of all patients who underwent an esophagectomy between January 2001 and December 2007 at a single tertiary care center were retrospectively reviewed by 2 radiologists who were blinded to the clinical information and radiologic reports. Patients with DH were identified and their demographics, characteristics of hernia, and patient outcome were recorded. Radiology reports issued at the time of study were reviewed independently by a third reviewer to assess whether the hernia was prospectively reported. A total of 458 patients underwent esophagectomy during the study time period, of whom 440 patients were eligible to be included in the study. Forty-four patients developed postesophagectomy DH. Thirty-six patients with DH were asymptomatic, whereas 8 had hernia-related symptoms. Only 7 cases were prospectively reported by the radiologists. Of the 37 cases not reported by the radiologists, 6 required surgical intervention during the follow-up. Postesophagectomy DH is difficult to diagnose clinically but is usually apparent on cross-sectional imaging. Some asymptomatic patients may develop hernia-related complications, which significantly increases the mortality rate. Hence, radiologists need to be aware of this rare postoperative complication and should report this finding so that affected patients can be optimally managed by surgeons. 23696422 Views and preferences for the implementation of non-invasive prenatal diagnosis for single gene disorders from health professionals in the United Kingdom. Non-invasive prenatal diagnosis (NIPD) will offer new options in prenatal diagnosis for carriers of single gene disorders. This will affect carrier couples and health professionals involved in prenatal care. The aim of this study was to determine health professional opinions on NIPD for single gene disorders to guide development of infrastructure required for implementation. A qualitative approach was adopted using focus groups (N = 17) and one-to-one interviews (N = 30) with health professionals from a range of backgrounds involved in caring for carriers of single gene disorders. Data were digitally recorded, transcribed verbatim and analyzed using thematic analysis. Participants were very positive about the introduction of NIPD, describing benefits arising from no risk of miscarriage, earlier testing and a simple procedure. A number of concerns for implementation were raised. Participants emphasized the need for the new test to be highly accurate and thoroughly validated. There was concern that people may not give as much thought to having a blood test compared to an invasive test or that it may be viewed as routine and as such NIPD may negatively impact on informed consent. In addition there was concern that the simplicity of a blood test may lead to increased pressure to test and terminate. However, participants felt these concerns could be overcome with thorough pre- and post-test counseling. To ensure high quality care, offering NIPD through genetics or other specialist services is essential. Ongoing education and training of health professionals will be important, and guidelines and regulation are needed for effective implementation. 23392565 Differences in the Pattern of Structural Abnormalities on CT Scan in Patients With Cystic Fibrosis and Pancreatic Sufficiency or Insufficiency. Cystic fibrosis (CF) genotypes characterized by pancreatic sufficiency (PS) are generally associated with milder disease vs genotypes characterized by pancreatic insufficiency (PI); however, the correlation between pancreatic status and type and severity of structural lung changes has not been studied. We aimed to evaluate differences in the severity and distribution of pulmonary manifestations of CF in patients with PS vs PI. We retrospectively evaluated changes in individual lobes and the whole lung on chest CT scan with the modified Brody score. The study population included 84 (39 female, 45 male) patients with CF aged 4 to 68 years (mean, 20.5) treated from 2000 to 2010. Our institutional review board waived the requirement for informed consent. The severity of lung changes and distribution of pulmonary disease were compared by Student t test, nonparametric Pearson χ2 test, or mixed-design analysis of variance for 28 patients with CF-PS and 56 with CF-PI. Correlations were evaluated with the Pearson (continuous variables) or Spearman ρ (nonparametric variables) tests. A linear regression model was used for multivariate analyses. Compared with patients with CF-PS, those with CF-PI had more-severe lung disease (P = .001) with predominant upper lobe involvement (P = .002) and significant differences in Brody scores for bronchiectasis and bronchial wall thickening. Lung manifestations in patients with CF-PS did not show predominant involvement of any one area (P = .133). In patients with CF-PI, structural lung changes are more severe with upper lobe predominance, prominent bronchiectasis, and bronchial wall thickening vs lower severity and more general distribution of changes in those with CF-PS. 23279101 Statistical analyses of protein sequence alignments identify structures and mechanisms in signal activation of sensor histidine kinases. Statistical analyses of genome sequence-derived protein sequence data can identify amino acid residues that interact between proteins or between domains of a protein. These statistical methods are based on evolution-directed amino acid variation responding to structural and functional constraints in proteins. The identified residues form a basis for determining structure and folding of proteins as well as inferring mechanisms of protein function. When applied to two-component systems, several research groups have shown they can be used to identify the amino acid interactions between response regulators and histidine kinases and the specificity therein. Recently, statistical studies between the HisKA and HATPase-ATP-binding domains of histidine kinases identified amino acid interactions for both the inactive and the active catalytic states of such kinases. The identified interactions generated a model structure for the domain conformation of the active state. This conformation requires an unwinding of a portion of the C-terminal helix of the HisKA domain that destroys the inactive state residue contacts and suggests how signal-binding determines the equilibrium between the inactive and active states of histidine kinases. The rapidly accumulating protein sequence databases from genome, metagenome and microbiome studies are an important resource for functional and structural understanding of proteins and protein complexes in microbes. 23886077 New uses for old drugs: attempts to convert quinolone antibacterials into potential anticancer agents containing ruthenium. Continuing the study of the physicochemical and biological properties of ruthenium-quinolone adducts, four novel complexes with the general formula [Ru([9]aneS3)(dmso-κS)(quinolonato-κ(2)O,O)](PF6), containing the quinolones levofloxacin (1), nalidixic acid (2), oxolinic acid (3), and cinoxacin (4), were prepared and characterized in solid state as well as in solution. Contrary to their organoruthenium analogues, these complexes are generally relatively stable in aqueous solution as substitution of the dimethylsulfoxide (dmso) ligand is slow and not quantitative, and a minor release of the quinolonato ligand is observed only in the case of 4. The complexes bind to serum proteins displaying relatively high binding constants. DNA binding was studied using UV-vis spectroscopy, cyclic voltammetry, and performing viscosity measurements of CT DNA solutions in the presence of complexes 1-4. These experiments show that the ruthenium complexes interact with DNA via intercalation. Possible electrostatic interactions occur in the case of compound 4, which also shows the most pronounced rate of hydrolysis. Compounds 2 and 4 also exhibit a weak inhibition of cathepsins B and S, which are involved in the progression of a number of diseases, including cancer. Furthermore, complex 2 displayed moderate cytotoxicity when tested on the HeLa cell line. 23504603 Immunotherapy and endothelin receptor antagonists for treatment of castration-resistant prostate cancer. Recently, novel therapies of prostate cancer, such as immunotherapy, endothelin receptor antagonists, novel androgen receptor antagonist and novel taxanes, and others have been introduced into clinical practice. This study was performed to summarize these results of immunotherapy and endothelin receptor antagonists in the treatment of castration-resistant prostate cancer (CRPC) and derive a more precise estimation of their effect on future treatment. The PubMed database, references of published trials, and review articles were searched. Two reviewers independently extracted data of these trials. We used hazard ratios (HRs) to assess the effects on overall survival (OS), progression-free survival (PFS), or time to disease progression (TTP), and relative risk (RR) for the different types of toxicity. In addition, 95% confidence intervals (CIs) give a sense of the precision of the estimate. Nine randomized controlled trials were ultimately identified. The pooled HR showed that immunotherapy could prolong OS significantly in patients with CRPC compared to placebo (HR = 0.70, 95% CI: 0.58-0.83, p < 0.001). Endothelin receptor antagonists also had modest benefits (HR = 0.90, 95% CI: 0.82-1.00, p = 0.046). Nevertheless, there were no significant benefits from both therapies on PFS or TTP. In addition, immunotherapy led to more fatigue, pyrexia, chills, and endothelin receptor antagonists led to more peripheral edema, anemia, and dyspnea. Our article suggested that the very acceptable toxicity and improving OS in patients with CRPC made immunotherapy an attractive option for such patients. However, future studies with thoughtful clinical trial designs are warranted. 23842804 Allosite: a method for predicting allosteric sites. The use of allosteric modulators as preferred therapeutic agents against classic orthosteric ligands has colossal advantages, including higher specificity, fewer side effects and lower toxicity. Therefore, the computational prediction of allosteric sites in proteins is receiving increased attention in the field of drug discovery. Allosite is a newly developed automatic tool for the prediction of allosteric sites in proteins of interest and is now available through a web server. The Allosite server and tutorials are freely available at http://mdl.shsmu.edu.cn/AST CONTACT: jian.zhang@sjtu.edu.cn Supplementary data are available at Bioinformatics online. 23937053 Facile Method for Site-specific Gene Integration in Lysobacter enzymogenes for Yield Improvement of the Anti-MRSA Antibiotics WAP-8294A and the Antifungal Antibiotic HSAF. Lysobacter is a genus of Gram-negative gliding bacteria that are emerged as novel biocontrol agents and new sources of bioactive natural products. The bacteria are naturally resistant to many antibiotics commonly used in transformant selection, which has hampered the genetic manipulations. Here, we described a facile method for quick-and-easy identification of the target transformants from a large population of the wild type and nontarget transformants. The method is based on a distinct yellow-to-black color change as a visual selection marker for site-specific integration of the gene of interest. Through transposon random mutagenesis, we identified a black-colored strain from the yellow-colored L. enzymogenes . The black strain was resulted from a disruption of hmgA, a gene required for tyrosine/phenylalanine metabolism. The disruption of hmgA led to accumulation of dark brown pigments. As proof of principle, we constructed a series of expression vectors for a regulator gene found within the WAP-8294A biosynthetic gene cluster. The yield of WAP-8294A in the black strains increased by 2 fold compared to the wild type. Interestingly, the yield of another antibiotic (HSAF) increased up to 7 fold in the black strains. WAP-8294A is a family of potent anti-MRSA antibiotics and is currently in clinical studies, and HSAF is an antifungal compound with distinct structural features and a novel mode of action. This work represents the first successful metabolic engineering in Lysobacter. The development of this facile method opens a way toward manipulating antibiotic production in the largely unexplored sources. 23883377 Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. Riociguat, a member of a new class of compounds (soluble guanylate cyclase stimulators), has been shown in previous clinical studies to be beneficial in the treatment of chronic thromboembolic pulmonary hypertension. In this phase 3, multicenter, randomized, double-blind, placebo-controlled study, we randomly assigned 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive placebo or riociguat. The primary end point was the change from baseline to the end of week 16 in the distance walked in 6 minutes. Secondary end points included changes from baseline in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) level, World Health Organization (WHO) functional class, time to clinical worsening, Borg dyspnea score, quality-of-life variables, and safety. By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group (least-squares mean difference, 46 m; 95% confidence interval [CI], 25 to 67; P<0.001). Pulmonary vascular resistance decreased by 226 dyn·sec·cm(-5) in the riociguat group and increased by 23 dyn·sec·cm(-5) in the placebo group (least-squares mean difference, -246 dyn·sec·cm(-5); 95% CI, -303 to -190; P<0.001). Riociguat was also associated with significant improvements in the NT-proBNP level (P<0.001) and WHO functional class (P=0.003). The most common serious adverse events were right ventricular failure (in 3% of patients in each group) and syncope (in 2% of the riociguat group and in 3% of the placebo group). Riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension. (Funded by Bayer HealthCare; CHEST-1 and CHEST-2 ClinicalTrials.gov numbers, NCT00855465 and NCT00910429, respectively.) 23558794 Fractured neck of femur patient care improved by simulated fast-track system. Fractured neck of femur patients represent a large demand on trauma services, and timely management results in improvements in morbidity and mortality. NICE guidance, advocating surgery on the day of admission or the following day, emphasises this. We set out to investigate whether a simulated fast-track management system could improve neck of femur fracture patient care. This prospective study was performed in a district general hospital in South West England, following a change in practise. We studied 429 patients over a 1-year period. Patients were phoned through, by the ambulance crew, to a trauma coordinator who arranged prompt radiological assessment and review. Patients with confirmed fractures were transferred to an optimisation area for orthopaedic and anaesthetic assessment prior to surgery the same day or early the following day. Our primary outcome measures were time to theatre (h) and length of hospital stay (days/h). Time to theatre reduced from 44.95 (±27.42) to 29.28 (±21.23) h. Length of stay reduced from 10 days (245.92 (±131.02) h) to 9 days (225.30 (±128.75) h). Both of these improvements were statistically significant (P < 0.05). Despite operating on virtually all patients, no increase in adverse events was seen, there was no increase in 30-day mortality and there were no perioperative deaths. This coordinated management pathway improves the efficiency of the service and reduces inpatient length of stay. Increased productivity may lead to financial savings and improve our ability to meet guidelines. 23834661 Recommencement of anticoagulation in chronic subdural haematoma: a systematic review and meta-analysis. Objective. Chronic subdural haematoma (CSDH) is becoming an increasingly important neurosurgical condition, especially given the aging world population and the increasing use of anticoagulant and antiplatelet medication. Clinicians regularly confront the dilemma of whether or not to restart anticoagulant and antiplatelet medication after CSDH, yet there is little evidence to support the decision-making process. This systematic review and meta-analysis aims to address this specific question. Methods. This systematic review and meta-analysis was conducted according to the PRISMA guidelines and has been registered with the PROSPERO international prospective register of systematic reviews (registration number CRD42012002509). Databases including MEDLINE, Cochrane, ISI Web of Knowledge, Embase and Google Scholar were searched for retrospective and prospective studies looking specifically at patients presenting with CSDH whilst on anticoagulant or antiplatelet medication which had data on subsequent recurrence and thromboembolic events. Results. Three relevant studies were found, totalling to 64 patients. In those restarted on anticoagulation, 11.1% experienced recurrences and 2.2% experienced thromboembolic events. In the control group that was not restarted on anticoagulation, 22.2% experienced recurrences and no patient experienced thromboembolic events. All recurrences and thromboembolic events occurred within the first 4 weeks of the initial surgical evacuation. Conclusions. The review seems to paradoxically suggest a lower bleeding risk and a higher thromboembolism risk when anticoagulation is restarted, although few concrete conclusions can be drawn from a pool of 64 patients. The decision on whether or not to restart anticoagulation in patients who present with CSDH whilst on anticoagulation has little empirical evidence to support a decision either way; more data are required to allow clinicians to make informed decisions about whether or not to restart anticoagulation, and if so, which drug, at what time-point and at what dose/therapeutic target. 23172286 WDDD: Worm Developmental Dynamics Database. During animal development, cells undergo dynamic changes in position and gene expression. A collection of quantitative information about morphological dynamics under a wide variety of gene perturbations would provide a rich resource for understanding the molecular mechanisms of development. Here, we created a database, the Worm Developmental Dynamics Database (http://so.qbic.riken.jp/wddd/), which stores a collection of quantitative information about cell division dynamics in early Caenorhabditis elegans embryos with single genes silenced by RNA-mediated interference. The information contains the three-dimensional coordinate values of the outlines of nuclear regions and the dynamics of the outlines over time. The database provides free access to 50 sets of quantitative data for wild-type embryos and 136 sets of quantitative data for RNA-mediated interference embryos corresponding to 72 of the 97 essential embryonic genes on chromosome III. The database also provides sets of four-dimensional differential interference contrast microscopy images on which the quantitative data were based. The database will provide a novel opportunity for the development of computational methods to obtain fresh insights into the mechanisms of development. The quantitative information and microscopy images can be synchronously viewed through a web browser, which is designed for easy access by experimental biologists. 23874387 Transcriptional Repression of Bim by a Novel YY1-RelA Complex Is Essential for the Survival and Growth of Multiple Myeloma. Multiple Myeloma (MM) is an incurable plasma cell cancer that is caused by several chromosomal translocations and gene deletions. Although deregulation of several signaling pathways including the Nuclear Factor-Kappa B (NF-κB) pathway has been reported in MM, the molecular requirement and the crosstalk between NF-κB and its target genes in MM cell survival has been largely unclear. Here, we report that Yin Yang1 (YY1), a target gene for NF-κB, is hyperexpressed in most MM tumor cells obtained from human patients, exhibits constitutive nuclear localization, and is essential for survival of MM cells. Mechanistically, we report a novel YY1-RelA complex formation, which is essential to transcriptionally repress a proapoptotic gene Bim. In line with this, depletion of YY1 or RelA resulted in elevated levels of Bim and apoptosis. Moreover, both YY1 and RelA are recruited to the Bim promoter and are required to repress the Bim promoter. Importantly, depletion of YY1 or RelA almost completely impaired the colony forming ability of MM progenitor cells suggesting that both RelA and YY1 are essential for the survival and growth of MM progenitor cells. Moreover, depletion of either YY1 or RelA completely inhibited MM tumor growth in xenograft models for human myeloma. Thus, a novel RelA-YY1 transcriptional repression complex is an attractive drug target in MM. 23895656 Combining genomic and proteomic approaches for epigenetics research. Epigenetics is the study of changes in gene expression or cellular phenotype that do not change the DNA sequence. In this review, current methods, both genomic and proteomic, associated with epigenetics research are discussed. Among them, chromatin immunoprecipitation (ChIP) followed by sequencing and other ChIP-based techniques are powerful techniques for genome-wide profiling of DNA-binding proteins, histone post-translational modifications or nucleosome positions. However, mass spectrometry-based proteomics is increasingly being used in functional biological studies and has proved to be an indispensable tool to characterize histone modifications, as well as DNA-protein and protein-protein interactions. With the development of genomic and proteomic approaches, combination of ChIP and mass spectrometry has the potential to expand our knowledge of epigenetics research to a higher level. 23720751 Pentalysine Clusters Mediate Silica Targeting of Silaffins in Thalassiosira pseudonana. The biological formation of inorganic materials (biomineralization) often occurs in specialized intracellular vesicles. Prominent examples are diatoms, a group of single-celled eukaryotic microalgae that produce their SiO2 (silica)-based cell walls within intracellular silica deposition vesicles (SDVs). SDVs contain protein-based organic matrices that control silica formation, resulting in species specifically nanopatterned biosilica, an organic-inorganic composite material. So far no information is available regarding the molecular mechanisms of SDV biogenesis. Here we have investigated by fluorescence microscopy and subcellular membrane fractionation the intracellular transport of silaffin Sil3. Silaffins are a group of phosphoproteins constituting the main components of the organic matrix of diatom biosilica. We demonstrate that the N-terminal signal peptide of Sil3 mediates import into a specific subregion of the endoplasmic reticulum. Additional segments from the mature part of Sil3 are required to reach post-endoplasmic reticulum compartments. Further transport of Sil3 and incorporation into the biosilica (silica targeting) require protein segments that contain a high density of modified lysine residues and phosphoserines. Silica targeting of Sil3 is not dependent on a particular peptide sequence, yet a lysine-rich 12-14-amino acid peptide motif (pentalysine cluster), which is conserved in all silaffins, strongly promotes silica targeting. The results of the present work provide the first insight into the molecular mechanisms for biogenesis of mineral-forming vesicles from an eukaryotic organism. 23957693 Multigenerational transmission of family size in contemporary Sweden. The study of the intergenerational transmission of fertility has a long history in demography, but until now research has focused primarily on parents' influence on their children's fertility patterns and has largely overlooked the possible influence of other kin. This study examines the transmission of fertility patterns from parents, grandparents, uncles, and aunts, using event history models to determine the risk of first, second, and third births. Swedish register data are used to study the 1970-82 birth cohorts. The findings indicate strong associations between the fertility of index persons and that of their parents, and also independent associations between the completed fertility of index persons and that of their grandparents and parents' siblings. The results suggest that, when examining background effects in fertility research, it is relevant to take a multigenerational perspective and to consider the characteristics of extended kin. 23937683 Covering Surface Nanobubbles with a NaCl Nanoblanket. By letting a NaCl aqueous solution of low (0.01 M) concentration evaporate on a highly oriented pyrolytic graphite (HOPG) surface, it is possible to form a thin film of salt. However, pre-existing surface nanobubbles prevent the homogeneous coverage of the surface with the salt, keeping the footprint areas on the substrate pristine. Comparing the surface nanobubbles in the salt solution with their associated footprint after drying, provides information on the shrinkage of nanobubbles during the hours-long process of drying the liquid film. At a slightly higher NaCl concentration and thus salt layer thickness, the nanobubbles are covered with a thin blanket of salt. Once the liquid film has evaporated until a water film remains that is smaller than the height of the nanobubbles, the blanket of salt cracks and unfolds into a flower-like pattern of salt flakes that is located at the rim of the nanobubble footprint. The formation of a blanket of salt covering the nanobubbles is likely to considerably or even completely block the gas out-flux from the nanobubble, partially stabilizing the nanobubbles against dissolution. 23873776 Dietary acid load is associated with lower bone mineral density in men with low intake of dietary calcium. High dietary acid load (DAL) may be detrimental to bone mineral density (BMD). The objectives of the study were to: 1) evaluate the cross-sectional relation between DAL and BMD; 2) determine whether calcium intake modifies this association. Men (n = 1218) and women (n = 907) ≥60y were included from the National Health and Nutrition Examination Survey 2005-2008. Nutrient intake from 2-24h recalls was used to calculate net endogenous acid production (NEAP) and potential renal acid load (PRAL) (mEq/d). PRAL was calculated from dietary calcium (PRALdiet ) and diet + supplemental calcium (PRALtotal ). Tests for linear trend in adjusted mean BMD of the hip and lumbar spine were performed across energy adjusted NEAP and PRAL quartiles. Modification by calcium intake (dietary or total) above or below 800 mg/d was assessed by interaction terms. Overall, mean age was 69 ± 0.3y. Among women, there was no association between NEAP and BMD. PRALdiet was positively associated with proximal femur BMD (p trend = 0.04). No associations were observed with PRALtotal at any BMD site (P-range: 0.38-0.82). Among men, no significant associations were observed of BMD with NEAP or PRAL. However, an interaction between PRALdiet and calcium intake was observed with proximal femur BMD (p = 0.08). An inverse association between PRALdiet and proximal femur BMD was detected among men <800 mg/d dietary calcium (p = 0.02); and no associations ≥800 mg/d (p = 0.98). A significant interaction with PRALtotal was not observed. In conclusion, when supplemental calcium is considered, there is no association between DAL and BMD among adults. Men with low dietary calcium showed an inverse relation with PRAL at the proximal femur; in women no interaction was observed. This study highlights the importance of calcium intakes in counteracting the adverse effect of DAL on bone health. Further research should determine the relation between DAL and change in BMD with very low calcium intake. 23579021 Phenotypic flexibility in body mass, basal metabolic rate and summit metabolism in southern red bishops (Euplectes orix): responses to short term thermal acclimation. Avian basal metabolic rate (BMR) and summit metabolism (Msum) vary within individuals in response to seasonal acclimatization in free-ranging birds, and thermal acclimation under laboratory conditions. We examined relationships between acclimation air temperature (Tacc) and body mass (Mb), BMR and Msum in female southern red bishops (Euplectes orix) from a relatively mild coastal site and a seasonally colder, inland site. Following acclimation for 21days to Tacc=10, 22 or 35°C, Mb, BMR and Msum were all significantly and negatively related to Tacc. The significant relationship between BMR and Tacc did not remain after Mb was included as a covariate, whereas that between Msum and Tacc did. A subsequent reverse acclimation protocol, where bishops were acclimated to a second Tacc value and then re-acclimated to the first, revealed that short-term changes in Mb and BMR were completely reversible, but changes in Msum were only partially reversible. Following the reverse-acclimation protocol, metabolic expansibility (Msum/BMR) varied significantly with air temperature, being greatest at Tacc=35°C. Our data suggest that the intraspecific variation in seasonal metabolic variation previously reported for this species is at least partly driven by factors other than temperature. 23696328 Prevalence of Sensory Modulation Disorder among Puerto Rican Preschoolers: An Analysis Focused on Socioeconomic Status Variables. The purposes of this study were to determine the prevalence of sensory modulation disorder (SMD) in a sample of Puerto Rican preschoolers and to examine differences in the prevalence of SMD based on socioeconomic status (SES) variables. Caregivers of children from Head Start programs and private preschools were recruited from three regions in Puerto Rico (PR) to participate in the study. Each caregiver completed a Short Sensory Profile (SSP) and a demographic data sheet. Total scores on the SSP were used to establish diagnosis of SMD. The total sample included 141 participants (response rate of 64%). Prevalence of SMD among the total PR sample (19.9%) was higher than previously reported estimates on the US mainland (5-16%). Statistical results indicated no difference in the overall prevalence of SMD based on SES. However, significant differences in scores based on caregivers' educational degree were found on the SSP sub-domain of Movement sensitivity and Under-responsive/seeks sensation; differences in scores based on caregiver household income were also found for the SSP sub-domain of Under-responsive/seeks. Although SMD appears to be prevalent in preschoolers in PR, variables associated with SES do not appear to contribute to an overall SMD diagnosis. However, additional research linking specific sub-domains of SMD to SES variables may be warranted. Copyright © 2013 John Wiley & Sons, Ltd. 23223414 Effect of nuclear vibrations, temperature, co-adsorbed water, and dye orientation on light absorption, charge injection and recombination conditions in organic dyes on TiO2. We study the effect of nuclear motions at different temperatures, including the effect of a dye molecule's orientation with respect to the oxide surface, on factors determining the performance of dye sensitized solar cells: light absorption, electron injection, and back-donation. We perform ab initio molecular dynamics simulations of aminophenyl acid dyes NK1 and NK7, differing by the electron donating group, in a vacuum and adsorbed in mono- and bi-dentate modes on a dry and a water-covered anatase (101) surface of TiO(2), at 300 and 350 K. Nuclear vibrations and an increase of temperature cause a red shift in the absorption spectra of free dyes. This effect is preserved in dyes on dry TiO(2) but largely disappears in the presence of water. Averaged over nuclear vibrations, the driving force to injection, ΔG, differs from the static estimate. It depends on the adsorption mode and the presence of H(2)O but is almost the same for 300 and 350 K. Recombination to the dye cation is expected to be much enhanced by the approach of the dye oxidation equivalent hole to the surface during dye wagging around TiO(2). This effect is somewhat mitigated by the co-adsorbed water. The dynamics of ΔG(t) are explained by uncorrelated evolution of the energies of the dye excited state and the conduction band minimum of the oxide due to their respective vibrations, and are almost independent of dye orientation. It may therefore be possible to independently control the conditions of recombination and of injection. 23922019 Takotsubo cardiomyopathy complicated by cardiac tamponade. We describe a 76-year-old patient with takotsubo cardiomyopathy complicated by cardiac tamponade. Pericardial effusion in takotsubo cardiomyopthy is common but a cardiac tamponade is very rare. The use of anticoagulants may increase the risk of pericardial effusion and should be considered with care. 23584195 The moderating effect of family involvement on substance use risk factors in adolescents with severe emotional and behavioral challenges. The current study longitudinally examined the moderating effects of family involvement, which previous research has shown to be a protective factor against adolescents' substance use involvement, on the associations between internalizing and externalizing problems, respectively, and substance use (alcohol, marijuana, and tobacco) and problems in a unique sample of adolescents with severe emotional and behavioral problems. Adolescents (n=4786) and their parents were assessed at three waves over a 1-year period as part of the SAMHSA funded Comprehensive Community Mental Health Initiative (CMHI). Multilevel growth curve models were estimated using Hierarchical Linear Modeling (HLM) to examine the associations between time-varying internalizing and externalizing problems, respectively, and substance use involvement over time as a function of family involvement at baseline. Results supported the hypothesis that family involvement protects against adolescent substance use involvement by buffering the adverse effects of both internalizing and externalizing problems. Specifically, for alcohol use, family involvement buffered the negative effects of high externalizing problems. For tobacco use, family involvement buffered the negative effects of both internalizing and externalizing problems, respectively. For substance use problems, family involvement buffered the effects of only internalizing problems. Family involvement did not moderate effects of emotional and behavioral problems on marijuana use, however, a significant main effect was observed such that family involvement was negatively related to marijuana use. Results suggest that the beneficial effects of family involvement on at-risk adolescents' substance use involvement are dependent on the type of emotional and behavioral problems the adolescent experiences as well as the type of substance the adolescent uses. Implications for family- and adolescent-focused treatment are discussed. 23821649 The signal within the noise: efficient inference of stochastic gene regulation models using fluorescence histograms and stochastic simulations. In the noisy cellular environment, stochastic fluctuations at the molecular level manifest as cell-cell variability at the population level that is quantifiable using high-throughput single-cell measurements. Such variability is rich with information about the cell's underlying gene regulatory networks, their architecture and the parameters of the biochemical reactions at their core. We report a novel method, called Inference for Networks of Stochastic Interactions among Genes using High-Throughput data (INSIGHT), for systematically combining high-throughput time-course flow cytometry measurements with computer-generated stochastic simulations of candidate gene network models to infer the network's stochastic model and all its parameters. By exploiting the mathematical relationships between experimental and simulated population histograms, INSIGHT achieves scalability, efficiency and accuracy while entirely avoiding approximate stochastic methods. We demonstrate our method on a synthetic gene network in bacteria and show that a detailed mechanistic model of this network can be estimated with high accuracy and high efficiency. Our method is completely general and can be used to infer models of signal-activated gene networks in any organism based solely on flow cytometry data and stochastic simulations. A free C source code implementing the INSIGHT algorithm, together with test data is available from the authors. mustafa.khammash@bsse.ethz.ch Supplementary data are available at Bioinformatics online. 23913537 Solid-Solid Heterogeneous Catalysis: The Role of Potassium in Promoting the Dehydrogenation of the Mg(NH2 )2 /2 LiH Composite. Considerable efforts have been devoted to the catalytic modification of hydrogen storage materials. The K-modified Mg(NH2 )2 /2 LiH composite is a typical model for such studies. In this work, we analyze the origin of the kinetic barrier in the first step of the dehydrogenation and investigate how K catalyzes this heterogeneous solid-state reaction. Our results indicate that the interface reaction of Mg(NH2 )2 and LiH is the main source of the kinetic barrier at the early stage of the dehydrogenation for the intensively ball-milled Mg(NH2 )2 /2 LiH sample. K can effectively activate Mg(NH2 )2 as well as promote LiH to participate in the dehydrogenation. Three K species of KH, K2 Mg(NH2 )4 , and Li3 K(NH2 )4 likely transform circularly in the dehydrogenation (KH↔K2 Mg(NH2 )4 ↔KLi3 (NH2 )4 ), which creates a more energy-favorable pathway and thus leads to the overall kinetic enhancement. This catalytic role of K in the amide/hydride system is different from the conventional catalysis of transition metals in the alanate system. 23608957 Association of PON1 genotype and haplotype with susceptibility to coronary artery disease and clinical outcomes in dual antiplatelet-treated Han Chinese patients. PURPOSE: The aim of this study was to evaluate the association of PON1 genetic variants with the susceptibility to coronary artery disease (CAD) and with the clinical endpoints in aspirin and clopidogrel (dual antiplatelet therapy)-treated Han Chinese patients with CAD after percutaneous coronary intervention (PCI). METHODS: A total of 538 Han Chinese patients undergoing PCI and receiving dual-antiplatelet therapy were sequentially recruited to the study and followed for up to 1 year. Healthy controls (n = 539) were enrolled during the same period. All study participants were genotyped for five genetic variants in PON1 and the cytochrome P450 2C19*2 mutation (CYP2C19*2). The effect of genetic variants on disease risk and clinical outcome of major adverse cardiac events (MACE) within 1 year or bleeding within 6 months was assessed. RESULTS: CYP2C19*2 was associated with a higher risk of MACE (adjusted P = 0.0098), but a lower risk of bleeding events (adjusted P = 0.0016). The PON1 Q192R polymorphism was significantly associated with a lower risk of bleeding events [odds ratio (OR) 0.61, 95% confidence interval (CI) 0.43-0.87, adjusted P = 0.0066). The haplotype bearing the PON1 -126C allele was associated with a higher risk to CAD (OR 1.48, 95% CI 1.04-2.09, P = 0.029) and a higher risk of bleeding events (OR 1.68, 95% CI 1.10-2.56, P = 0.017) compared to the most frequent haplotype. The transcription activity of haplotype p-162A-126C-108C in the PON1 promoter was 2.6-fold higher than that of the most frequent haplotype (p-162G-126G-108T). CONCLUSIONS: Based on these results, we suggest that the haplotype-bearing PON1 -126C allele contributes to the disease risk and the risk of bleeding events in dual antiplatelet-treated CAD patients after PCI. 23739175 Attack on Australia: Tobacco industry challenges to plain packaging. In 2011, the Australian Government passed landmark legislation requiring tobacco manufacturers to adopt 'plain packaging', a government-mandated design standardized across all brands of tobacco products. In response, plain packaging policy in Australia has faced multiple, simultaneous challenges from a global, well-resourced industry able to use all available fora to seek redress. Generalizing from the Australian experience, we analyze four types of challenges to plain packaging from the tobacco industry. We characterize three ways in which industry questions public health policies through international trade and investment law, on: (i) the intent or purpose of the policy; (ii) the economic consequences of it; and (iii) the regulatory authority behind it. We make recommendations and suggest that public health policymakers can know with some precision what attacks will be launched on tobacco control policies, and prepare their strategies and legislation accordingly. 23836546 Atropine-sensitive theta rhythm in the posterior hypothalamic area: In vivo and in vitro studies. Theta rhythm is the largest, most prominent, and well-documented electroencephalography activity present in a number of mammals, including humans. Spontaneous theta activity recorded locally in the posterior hypothalamic area (PHa) has never been the subject of detailed studies. The authors have shown that local theta field potentials could be generated in urethane-anesthetized rats in the supramammillary (SuM) nuclei and posterior hypothalamic (PH) nuclei. Theta recorded in the PHa was produced independently of simultaneously occurring hippocampal theta. These data were confirmed in the PHa maintained in vitro. Local theta field activity was recorded in the SuM and PH nuclei of PHa slice preparations perfused with cholinergic agonist carbachol. Both in vivo and in vitro recorded PHa theta rhythmicity had a cholinergic-muscarinic profile, that is, it was antagonized by muscarinic antagonist atropine sulfate. © 2013 Wiley Periodicals, Inc. 23970341 Quantitative Analysis of Localized Retinal Nerve Fiber Layer Defects Using Spectral Domain Optical Coherence Tomography. To compare the topographic features of localized retinal nerve fiber layer (RNFL) defects presented in red-free RNFL photography and spectral domain optical coherence tomography (SD-OCT), and to evaluate the correlation with structural and functional parameters. Sixty eyes with localized RNFL defects in red-free RNFL photographs were included. RNFL thickness map and significance map were obtained by SD-OCT. The angular location, angular width, and area of localized RNFL defects were measured and compared among RNFL thickness map, significance map (red, <1% level; yellow, <5% level), and RNFL photograph. The RNFL defect areas were analyzed by their correlations with structural and functional parameters. The RNFL defect area of RNFL thickness map was significantly greater than those of red significance map, and smaller than those of RNFL photograph and yellow significance map (all P<0.001). RNFL thickness map showed a significantly narrower angular width than RNFL photograph and yellow significance map (all P<0.001). The area, angular width, and angular location of localized RNFL defects in RNFL photographs strongly correlated with those of RNFL thickness maps and significance maps (all r≥0.741, P<0.001). The relationship between RNFL defect area and structural-functional parameters was also significant. The high topographic correlations in RNFL defects between RNFL photography and SD-OCT RNFL maps suggest the validity of SD-OCT RNFL imaging for detecting localized glaucomatous RNFL damage. In addition, structural and functional parameters are closely related to RNFL defect areas. Quantitative measurements of RNFL defects might be valuable for glaucoma diagnosis. 23816928 Overexpression of Arachis hypogaea NAC3 in tobacco enhances dehydration and drought tolerance by increasing superoxide scavenging. Drought stress can severely affect plant growth and substantially diminish crop yields. We previously isolated Arachis hypogaea NAC3 (AhNAC3), a dehydration-induced NAM/ATAF/CUC (NAC) gene from peanut. In this study, to examine the role of AhNAC3 in stress tolerance, we constructed transgenic tobacco lines overexpressing AhNAC3. The transgenic plants showed hyper-resistance to dehydration and drought stresses and accumulated more proline and less superoxide anion (O2(-)) than wild type under dehydration and drought conditions. Moreover, the transgenic plants showed upregulation of four functional genes, superoxide dismutase (SOD), pyrroline-5-carboxylate synthetase (P5SC), late embryogenic abundant proteins (LEA), and early response to drought 10 (ERD10C). Protein localization and transactivation analysis suggested that AhNAC3 activates its specific targets in the nucleus. These results suggest that AhNAC3 is a dehydration-induced transcription factor that improves water stress tolerance by increasing superoxide scavenging and promoting the accumulation of various protective molecules. 23292239 Intermediate-dose Ara-C plus G-CSF for stem cell mobilization in patients with lymphoid malignancies, including predicted poor mobilizers. The optimal protocol for mobilization of hematopoietic stem cells in patients with lymphoid malignancies has not been determined so far. We retrospectively analyzed the efficacy and safety of Ara-C at a dose of 1.6 g/m(2) compared with CY at a dose of 4.0 g/m(2), both combined with filgrastim. Seventy and forty-five patients, respectively, were included, among whom 60% were defined as 'predicted poor mobilizers'. The use of Ara-C was associated with significantly higher peak number of circulating CD34(+) cells compared with CY (P<0.0001). In the Ara-C group, 95% of patients with multiple myeloma (MM) collected at least 5 × 10(6) CD34(+) cells/kg required for tandem transplantation, and 97% of lymphoma patients collected at least 2 × 10(6) CD34(+) cells/kg, needed for a single autologous hematopoietic SCT (autoHSCT), which was achieved with a single leukapheresis in 91% of cases. Results for the CY group were significantly inferior (P<0.0001). No patient mobilized with Ara-C experienced febrile neutropenia, whereas 35% required platelet transfusions. Among patients who proceeded to autoHSCT, the time of both neutrophil and platelet recovery was significantly shorter for those mobilized with Ara-C than CY. We conclude that intermediate-dose Ara-C+filgrastim is a very effective and relatively safe mobilization protocol for patients with lymphoid malignancies. 23932515 The association between health literacy and indicators of cognitive impairment in a diverse sample of primary care patients. To confirm the association of health literacy scores as measured by Health Literacy Assessment Using Talking Touchscreen Technology (Health LiTT) with cognitive ability and education. To determine whether this association differs by cognitive task. Cognitive impairment was measured using the Mini-Cog, which combines a delayed word recall task (WRT) and a clock drawing task (CDT) to yield an overall classification of normal versus cognitively impaired. Participants were recruited from primary care clinics that provide care to underserved patients. Participants (n=574) were predominantly non-Hispanic black (67%) with a mean age of 46 years, 50% did not have health insurance, 56% had a high school education or less and 21% screened positive for cognitive impairment. Overall cognitive ability and education were significantly associated with health literacy after adjusting for other variables, including race/ethnicity and physical health. We observed a stronger association between the CDT and health literacy than between the WRT and health literacy. By confirming hypothesized associations, this study provides additional support of the validity of Health LiTT. Health LiTT is a reliable and valid tool that researchers and clinicians can use to identify individuals who might have difficulty understanding health information. 23461598 Quantitative physiology of Lactococcus lactis at extreme low-growth rates. This paper describes the metabolic adaptation of Lactococcus lactis during the transition from a growing to a non-growing state using retentostat cultivation. Under retentostat cultivation, the specific growth rate decreased from 0.025 h(-1) to 0.0001 h(-1) in 42 days, while doubling time increased to more than 260 days. Viability of the overall culture was maintained above 90% but included approximately 20% damaged cells, which had lost their colony forming capacity on solid media. Although culture biomass and viability had reached a steady-state after 14 days of retentostat cultivation, the morphology of the cells changed from coccus-to-rod shape at later stages of retentostat cultivation, by which the cell's surface to volume ratio was estimated to increase 2.4-fold. Furthermore, the metabolic patterns switched between homolactic and mixed-acid fermentation during the retentostat cultivation. Retentostat cultivation enabled the calculation of accurate substrate- and energy-related maintenance coefficients and biomass yields under non-growing conditions, which were in good agreement with those calculated by extrapolation from chemostat cultivations at high dilution rates. In this study, we illustrate how retentostat cultivation allows decoupling of growth and non-growth associated processes in L. lactis, enabling the analysis of quantitative physiological responses of this bacterium to near zero-specific growth rates. 23886606 The unnatural history of an atrial septal defect: Longitudinal 35 year follow up after surgical closure at young age. To describe the very long-term outcome after surgical closure of an atrial septal defect (ASD). Longitudinal cohort study of 135 consecutive patients who underwent surgical ASD repair at age <15 years between 1968 and 1980. The study protocol included ECG, echocardiography, exercise testing, N-terminal prohormone of brain natriuretic hormone, Holter monitoring and cardiac MRI. Survival, major events (cardiac reinterventions, stroke, symptomatic arrhythmia or heart failure) and ventricular function. After 35 years (range 30-41), survival status was obtained in 131 of 135 patients (97%): five died (4%), including two sudden deaths in the last decade. Fourteen patients (16%) had symptomatic supraventricular tachyarrhythmias and six (6%) had a pacemaker implanted which was predicted by early postoperative arrhythmias. Two reoperations were performed. One ischaemic stroke occurred. Left ventricular (LV) and right ventricular (RV) ejection fractions (EF) were 58±7% and 51±6%, respectively. RVEF was diminished in 17 patients (31%) and in 11 (20%) the RV was dilated. Exercise capacity and quality of life were comparable to the normal population. No clear differences were found between ASD-II or sinus venosus type ASD. Very long-term outcome after surgical ASD closure in childhood shows good survival and low morbidity. Early surgical closure prevents pulmonary hypertension and reduces the occurrence of supraventricular arrhythmias. Early postoperative arrhythmias are predictive for the need for pacemaker implantation during early follow-up, but the rate of late pacemaker implantation remains low. Although RVEF was unexpectedly found to be decreased in one-third of patients, the functional status remains excellent. 23923970 Short-term evaluation of autologous transplantation of bone marrow-derived mesenchymal stem cells in patients with cirrhosis: Egyptian study. Stem cell-based therapy has received attention as a possible alternative to organ transplantation. The aim of this study was to assess the safety and efficacy of autologous transplantation of bone marrow (BM)-derived stromal cells in post-HCV liver cirrhosis patients. 10 Ã— 10(6) of isolated human bone marrow (HBM)-stromal cells in 10 mL normal saline were injected in the spleen of 20 patients with end-stage liver cirrhosis guided by the ultrasonography, and then patients were followed up on monthly basis for six months. A statistically significant decrease was detected in the total bilirubin, aspartate transaminase (AST), alanine transaminase (ALT) (p-value<0.01), prothrombin time (PT), and international normalized ratio (INR) levels (p-value<0.05), while a statistically significant increase in the albumin and PC (p-value<0.05) after follow-up. This study suggested the safety, feasibility, and efficacy of the intrasplenic injection of autologous BM stromal cells in improving liver function in Egyptian patients with cirrhosis. 23911612 High sensitivity capillary zone electrophoresis-electrospray ionization-tandem mass spectrometry for the rapid analysis of complex proteomes. The vast majority of bottom-up proteomic studies employ reversed-phase separation of tryptic digests coupled with electrospray ionization tandem mass spectrometry. These studies are remarkably successful for the analysis of samples containing micrograms of protein. However, liquid chromatography tends to perform poorly for samples containing nanogram amounts of protein, presumably due to loss of trace-level peptides within the chromatographic system. Capillary zone electrophoresis provides a much simpler flow system and would appear to be an attractive alternative to liquid chromatography for separation of small peptide samples before electrospray ionization and mass spectrometry detection. However, capillary zone electrophoresis has received very little attention as a tool for analysis of complex proteomes. In 2012, we reported the use of capillary zone electrophoresis for the analysis of the secretome of Mycobacterium marinum, a model system for tuberculosis. Roughly 400 peptides and over 100 proteins were identified from this medium-complexity proteome; this identification required analysis of a set of 11 fractions and occupied three hours of mass spectrometer time. We have recently employed an improved capillary zone electrophoresis system for the analysis of 100ng of the Escherichia coli proteome and observed over 1300 peptides and nearly 350 proteins in a single separation. More interestingly, analysis of 1ng of the E. coli proteome yielded over 600 peptide and 140 protein groups. This sample size approaches that of a large eukaryotic cell, suggesting that capillary zone electrophoresis may ultimately be a useful tool for chemical cytometry. 23329698 Recognition of viral RNA stem-loops by the tandem double-stranded RNA binding domains of PKR. In humans, the double-stranded RNA (dsRNA)-activated protein kinase (PKR) is expressed in late stages of the innate immune response to viral infection by the interferon pathway. PKR consists of tandem dsRNA binding motifs (dsRBMs) connected via a flexible linker to a Ser/Thr kinase domain. Upon interaction with viral dsRNA, PKR is converted into a catalytically active enzyme capable of phosphorylating a number of target proteins that often results in host cell translational repression. A number of high-resolution structural studies involving individual dsRBMs from proteins other than PKR have highlighted the key features required for interaction with perfectly duplexed RNA substrates. However, viral dsRNA molecules are highly structured and often contain deviations from perfect A-form RNA helices. By use of small-angle X-ray scattering (SAXS), we present solution conformations of the tandem dsRBMs of PKR in complex with two imperfectly base-paired viral dsRNA stem-loops; HIV-1 TAR and adenovirus VA(I)-AS. Both individual components and complexes were purified by size exclusion chromatography and characterized by dynamic light scattering at multiple concentrations to ensure monodispersity. SAXS ab initio solution conformations of the individual components and RNA-protein complexes were determined and highlight the potential of PKR to interact with both stem and loop regions of the RNA. Excellent agreement between experimental and model-based hydrodynamic parameter determination heightens our confidence in the obtained models. Taken together, these data support and provide a framework for the existing biochemical data regarding the tolerance of imperfectly base-paired viral dsRNA by PKR. 23857582 Heterogeneous Nuclear Ribonucleoprotein (HnRNP) K Genome-wide Binding Survey Reveals Its Role in Regulating 3'-End RNA Processing and Transcription Termination at the Early Growth Response 1 (EGR1) Gene through XRN2 Exonuclease. The heterogeneous nuclear ribonucleoprotein K (hnRNPK) is a nucleic acid-binding protein that acts as a docking platform integrating signal transduction pathways to nucleic acid-related processes. Given that hnRNPK could be involved in other steps that compose gene expression the definition of its genome-wide occupancy is important to better understand its role in transcription and co-transcriptional processes. Here, we used chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) to analyze the genome-wide hnRNPK-DNA interaction in colon cancer cell line HCT116. 9.1/3.6 and 7.0/3.4 million tags were sequenced/mapped, then 1809 and 642 hnRNPK binding sites were detected in quiescent and 30-min serum-stimulated cells, respectively. The inspection of sequencing tracks revealed inducible hnRNPK recruitment along a number of immediate early gene loci, including EGR1 and ZFP36, with the highest densities present at the transcription termination sites. Strikingly, hnRNPK knockdown with siRNA resulted in increased pre-RNA levels transcribed downstream of the EGR1 polyadenylation (A) site suggesting altered 3'-end pre-RNA degradation. Further ChIP survey of hnRNPK knockdown uncovered decreased recruitment of the 5'-3' exonuclease XRN2 along EGR1 and downstream of the poly(A) signal without altering RNA polymerase II density at these sites. Immunoprecipitation of hnRNPK and XRN2 from intact and RNase A-treated nuclear extracts followed by shotgun mass spectrometry revealed the presence of hnRNPK and XRN2 in the same complexes along with other spliceosome-related proteins. Our data suggest that hnRNPK may play a role in recruitment of XRN2 to gene loci thus regulating coupling 3'-end pre-mRNA processing to transcription termination. 23703297 Caloric restriction reduces edema and prolongs survival in a mouse glioma model. Regardless of their cell type of origin, all aggressive brain tumors, such as malignant gliomas and metastatic tumors produce brain edema, which is an important cause of patient morbidity and mortality. Caloric restriction (CR) has long been recognized as a natural therapy that improves health, promotes longevity, and significantly reduces both the incidence and growth of many tumor types. The aim of present work was to investigate the effect of CR on edema and survival in the mice implanted with U87 gliomas. We found that CR significantly inhibited the intracerebral tumor growth, attenuated brain edema, and ultimately prolonged survival of mice with U87 gliomas. Plasma corticosterone level was found higher and serum VEGF and IGF-1 levels were found lower in CR, when compared to AL group. CR upregulated tight junction proteins including claudin-1, claudin-5 and ZO-1, downregulated VEGF and VEGFR2, enhanced α-SMA expression, and reduced AQP1 expression in U87 gliomas. In addition, CR suppressed inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) formation in U87 gliomas. In conclusion, CR attenuated edema in U87 orthotopic mouse glioma model associated with elevation of corticosterone, suppression of VEGF/VEGFR2, improvement of tight junctions, and suppression of iNOS expression and NO formation. Our results suggested that CR might be an effective therapy for recurrent malignant brain cancers through alleviating associated edema. 23955045 Combined measurement of X-ray photon correlation spectroscopy and diffracted X-ray tracking using pink beam X-rays. Combined X-ray photon correlation spectroscopy (XPCS) and diffracted X-ray tracking (DXT) measurements of carbon-black nanocrystals embedded in styrene-butadiene rubber were performed. From the intensity fluctuation of speckle patterns in a small-angle scattering region (XPCS), dynamical information relating to the translational motion can be obtained, and the rotational motion is observed through the changes in the positions of DXT diffraction spots. Graphitized carbon-black nanocrystals in unvulcanized styrene-butadiene rubber showed an apparent discrepancy between their translational and rotational motions; this result seems to support a stress-relaxation model for the origin of super-diffusive particle motion that is widely observed in nanocolloidal systems. Combined measurements using these two techniques will give new insights into nanoscopic dynamics, and will be useful as a microrheology technique. 23488982 Iodine Status in Pregnant Women in the United States: National Children's Study and National Health and Nutrition Examination Survey. Background: This report presents iodine data from NHANES and from a sample of pregnant women in the National Children's Study (NCS) Vanguard Study. Methods: UI was measured in a one third subsample of NHANES 2005-2006, and 2009-2010 participants and in all 2007-2008 participants age six years and older. These measurements are representative of the general U.S. population. UI was also measured in a convenience sample of 501 pregnant women enrolled in the NCS initial Vanguard Study from seven study sites across the U.S. Results: NHANES median UI concentration in 2009-2010 (144 µg/L) was significantly lower than in 2007-2008 (164 µg/L). Non-Hispanic blacks had the lowest UI concentrations (131µg/L) compared to non-Hispanic whites or Hispanics (147 and 148 µg/L, respectively). The median for all pregnant women in NHANES 2005-2010 was less than adequate (129 µg/L), the third trimester women had UI concentrations that were adequate ( median UI 172 µg/L). Third trimester women participating in the NCS study similarly had an adequate level of iodine intake, with a median UI concentration of 167µg/L. Furthermore, NCS median UI concentrations varied by geographic location. Conclusions: Dairy, but not salt, seafood or grain consumption, was significantly positively associated with median UI concentration in women of childbearing age. Pregnant women in their third trimester in the NHANES 2005-2010 had adequate median UI concentrations, but pregnant women in NHANES who were in their first or second trimesters had median UI concentrations that were less than adequate. Non-Hispanic black pregnant women from both the NHANES 2005-20010 and the NCS consistently had lower UI median concentrations than non-Hispanic whites or Hispanics. 23712465 Treatment with atorvastatin is associated with a better prognosis in chronic heart failure with systolic dysfunction: results from The Daunia Heart Failure Registry. Few works have evaluated the effect of statins on left ventricular dysfunction in patients with chronic heart failure (CHF), by using tissue Doppler imaging (TDI). We therefore aimed to investigate whether atorvastatin treatment may influence prognosis and myocardial performance evaluated by TDI in subjects with CHF. Five hundred thirty-two consecutive CHF outpatients enrolled in a local registry, the Daunia Heart Failure Registry, were prospectively analysed. 195 patients with CHF and left ventricular ejection fraction (LVEF) ≤40 %, either in treatment with atorvastatin (N: 114) or without statins (N: 81), underwent TDI examination. Adverse events were evaluated during follow-up. The atorvastatin group showed a lower incidence of adverse events (cardiac death: 0 % vs 7 %, p < 0.01), and better TDI performance (E/E' 15 ±â€‰5.7 vs 18 ±â€‰8.3, p < 001) than controls. Ischaemic CHF patients in treatment with atorvastatin also showed a lower incidence of adverse events (death: 10 % vs 26 %, p < 0.05; sustained ventricular arrhythmias: 5 % vs 19 %, p < 0.05, cardiac death: 0 vs 8 %, p < 0.05) and better TDI performance (E/E' ratio: 15.00 ±â€‰5.68 vs 19.72 ±â€‰9.14, p < 0.01; St: 353.70 ±â€‰48.96 vs 303.33 ±â€‰68.52 msec, p < 0.01) than controls. The association between atorvastatin and lower rates of cardiac death remained statistically significant even after correction in a multivariable analysis (RR 0.83, 95 % CI 0.71-0.96, p < 0.05 in CHF with LVEF ≤40 %; RR 0.77, 95 % CI 0.62-0.95, p < 0.05 in ischaemic CHF with LVEF ≤40 %). Treatment with atorvastatin in outpatients with systolic CHF is associated with fewer cardiac deaths, and a better left ventricular performance, as assessed by TDI. 23412815 Amplatzer left atrial appendage occlusion: Single center 10-year experience. To report a 10-year single center experience with Amplatzer devices for left atrial appendage (LAA) occlusion. Intermediate-term outcome data following LAA occlusion are scarce. Short- and intermediate-term outcomes of patients who underwent LAA occlusion were assessed. All procedures were performed under local aesthesia without transesophageal echocardiography. Patients were discharged on acetylsalicylic acid and clopidogrel for 1-6 months. LAA occlusion was attempted in 152 patients (105 males, age 72 ± 10 years, CHA2 DS2 -Vasc-score 3.4 ± 1.7, HAS-BLED-score 2.4 ± 1.2). Nondedicated devices were used in 32 patients (21%, ND group) and dedicated Amplatzer Cardiac Plugs were used in 120 patients (79%, ACP group). A patent foramen ovale or atrial septal defect was used for left atrial access and closed at the end of LAA occlusion in 40 patients. The short-term safety endpoints (procedural complications, bleeds) occurred in 15 (9.8%) and the efficacy endpoints (death, stroke, systemic embolization) in 0 patients. Device embolization occurred more frequently in the ND as compared to the ACP group (5 patients or 12% vs. 2 patients or 2%). Mean intermediate-term follow up of the study population was 32 months (range 1-120). Late deaths occurred in 15 patients (5 cardiovascular, 7 noncardiac, 3 unexplained). Neurologic events occurred in 2, peripheral embolism in 1, and major bleeding in 4 patients. The composite efficacy and safety endpoint occurred in 7% and 12% of patients. LAA closure may be a good alternative to oral anticoagulation. This hypothesis needs to be tested in a randomized clinical trial to ensure that all potential biases of this observational study are accounted for. © 2013 Wiley Periodicals, Inc. 23434833 Identification of three genes encoding for the late acyltransferases of lipid A in Cronobacter sakazakii. Lipid A, the hydrophobic anchor of lipopolysaccharide, is an essential component in the outer membrane of most Gram-negative bacteria. Food-borne pathogen Cronobacter sakazakii synthesizes two lipid A species, differing by the length of the secondary acyl chain. In this work, we identified three genes ESA02293, ESA02951 and ESA01386 encoding for the late acyltransferases of lipid A biosynthesis pathway in C. sakazakii. Based on the sequence alignment, proteins YP_001438378.1 encoded by ESA02293, YP_001439016.1 encoded by ESA02951, and YP_001437482.1 encoded by ESA01386 are homologous to E. coli LpxL, LpxP and LpxM, respectively. Functions of the three acyltransferases were confirmed by overexpressing the genes in E. coli, isolating lipid As and analyzing their structures using an ESI/MS. C. sakazakii LpxL and LpxM transfer a C14:0 secondary acyl chain to the 2'- and 3'-position of lipid A, respectively. C. sakazakii LpxP can transfer either a C16:1 or a C14:0 secondary acyl chains to the 2'-position of lipid A. 23943500 Apparent causality affects perceived simultaneity. The present research addresses the question of how visual predictive information and implied causality affect audio-visual synchrony perception. Previous research has shown a systematic shift in the likelihood of observers to accept audio-leading stimulus pairs as being apparently simultaneous in variants of audio-visual stimulus pairs that differ in (1) the amount of visual predictive information available and (2) the apparent causal relation between the auditory and visual components. An experiment was designed to separate the predictability and causality explanations, and the results indicated that shifts in subjective simultaneity were explained completely by changes in the implied causal relations in the stimuli and that predictability had no added value. Together with earlier findings, these results further indicate that the observed shifts in subjective simultaneity due to causal relations among auditory and visual events do not reflect a mere change in response strategy, but rather result from early multimodal integration processes in event perception. 23556343 Biological activities of selected basidiomycetes from Yemen. In a previous paper we demonstrated the results of biological screening of Yemeni basidiomycetes. The present study was aimed to investigate the antimicrobial and the antioxidant activity of further basidiomycetes collected in Yemen. Dichloromethane, methanol and aqueous extracts of the fruiting bodies of 25 species were screened in vitro for their antibacterial activities against three Gram-positive bacteria (Staphyloccocus aureus, Bacillus subtilis, Micrococcus flavus) and two Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa), against six human fungal pathogens (Candida albicans, Candida krusei, Aspergillus fumigatus, Mucor sp., Microsporum gypseum, Trichophyton mentagrophytes) and against one non human pathogenic fungus (Candida maltosa). The results indicated that 75 extracts exhibited activity against one or more of the bacteria. The methanol extracts of Agaricus cf. bernardii, Agrocybe pediades, Chlorophyllum molybdites, Coriolopsis polyzona, Ganoderma xylonoides, Pycnoporus sanguineus, Trametes lactinea and Trametes cingulata showed activity against all tested bacteria. The highest antibacterial activity was exhibited by methanol extracts from Chlorophyllum molybdites, Ganoderma xylonoides and Trametes cingulata and Agaricus cf. bernardii, Agrocybe pediades, Coriolopsis polyzona, Pycnoporus sanguineus and Trametes lactinea. The methanol extracts of Chlorophyllum molybdites, Ganoderma xylonoides and Pycnoporus sanguineus showed considerable antifungal activities against the tested fungal strains. Strong antioxidative effects employing the DPPH assay were exhibited by methanol extracts from Chlorophyllum molybdites, Ganoderma xylonoides, Hexagonia velutina, Pycnoporus sanguineus, Trametes lactinea and Trametes cingulata. Our previous and presented studies about 48 basidiomycetes collected in Yemen provide evidence that basidiomycetes from the Arabic region so far should attract more attention as potential source for new biologically active agents. 23922725 Effects of dietary arginine and glutamine on alleviating the impairment induced by deoxynivalenol stress and immune relevant cytokines in growing pigs. Deoxynivalenol (DON) is a mycotoxin that reduces feed intake and animal performance, especially in swine. Arginine and glutamine play important roles in swine nutrition. The objective of this study was to determine the effects of dietary supplementation with arginine and glutamine on both the impairment induced by DON stress and immune relevant cytokines in growing pigs. A total of forty 60-d-old healthy growing pigs with a mean body weight of 16.28±1.54 kg were randomly divided into 5 groups, and assigned to 3 amino acid treatments fed 1.0% arginine (Arg), 1.0% glutamine (Gln) and 0.5% Arg+0.5% Gln, respectively, plus a toxin control and a non-toxin control. Pigs in the 3 amino acid treatments were fed the corresponding amino acids, and those in non-toxin control and toxin control were fed commercial diet with 1.64% Alanine as isonitrogenous control for 7 days. The toxin control and amino acid treatments were then challenged by feeding DON-contaminated diet with a final DON concentration of 6 mg/kg of diet for 21 days. No significant differences were observed between toxin control and the amino acid groups with regard to the average daily gain (ADG), although the values for average daily feed intake (ADFI) in the amino acid groups were significantly higher than that in toxin control (P<0.01). The relative liver weight in toxin control was significantly greater than those in non-toxin control, arginine and Arg+Glu groups (P<0.01), but there were no significant differences in other organs. With regard to serum biochemistry, the values of BUN, ALP, ALT and AST in the amino acid groups were lower than those in toxin control. IGF1, GH and SOD in the amino acid groups were significantly higher than those in toxin control (P<0.01). The IL-2 and TNFα values in the amino acid groups were similar to those in non-toxin control, and significantly lower than those in toxin control (P<0.01). These results showed the effects of dietary supplementation with arginine and glutamine on alleviating the impairment induced by DON stress and immune relevant cytokines in growing pigs. 23327656 Selective inhibition of extracellular thioredoxin by asymmetric disulfides. Whereas the role of mammalian thioredoxin (Trx) as an intracellular protein cofactor is widely appreciated, its function in the extracellular environment is not well-understood. Only few extracellular targets of Trx-mediated thiol-disulfide exchange are known. For example, Trx activates extracellular transglutaminase 2 (TG2) via reduction of an intramolecular disulfide bond. Because hyperactive TG2 is thought to play a role in various diseases, understanding the biological role of extracellular Trx may provide critical insight into the pathogenesis of these disorders. Starting from a clinical-stage asymmetric disulfide lead, we have identified analogs with >100-fold specificity for Trx. Structure-activity relationship and computational docking model analyses have provided insights into the features important for enhancing potency and specificity. The most active compound identified had an IC(50) below 0.1 μM in cell culture and may be appropriate for in vivo use to interrogate the role of extracellular Trx in health and disease. 23965297 Relationship between Seizure Episode and Sudden Cardiac Arrest in Patients with Epilepsy: A Community-Based Study. -Among patients with epilepsy, SCA is a major cause of death. It is commonly thought that SCA in epilepsy occurs following a seizure, though the strength of evidence supporting this is limited. We sought to evaluate the relationship between seizures and sudden cardiac arrest (SCA) in patients with epilepsy. -From the ongoing Oregon Sudden Unexpected Death Study, cases of SCA identified using prospective, multi-source ascertainment (Portland, Oregon metropolitan area population approximately 1 million; February, 1 2002 to March 1, 2012) were evaluated for history of epilepsy. In the subset with witnessed SCA, clinical presentations were analyzed for evidence of seizure activity immediately preceding the event as well as lifetime clinical history including nature of seizures preceding SCA. Only 34% of patients with history of epilepsy and a witnessed arrest had evidence of seizure activity prior to the arrest. Rates of survival to hospital discharge following attempted resuscitation were 2.7% in patients with history of epilepsy versus 11.9% for patients without epilepsy (p=0.014). Patients with epilepsy had a significantly lower rate of presentation with ventricular tachycardia / ventricular fibrillation as opposed to pulseless electrical activity / asystole (epilepsy - 26%, no epilepsy - 44%; p=0.002); despite nearly identical response times. -In the majority (66%) of epilepsy patients there was no relationship between seizure and SCA, implying that SCA in epilepsy patients often may not involve seizure as a trigger. The significantly worse rate of survival from SCA in epilepsy patients warrants urgent investigation. 23952849 Risk factors for long-term brain dysfunction after chronic critical illness. Rationale: Factors associated with long-term brain dysfunction (LTBD) in survivors of chronic critical illness (CCI) have not been explored but may be important for clinical practice and planning by patients, families, and providers. Objectives: To identify risk factors for LTBD after treatment for CCI and to explore the association between acute delirium and coma during hospital treatment and LTBD. Methods: A prospective cohort study of adults admitted to a respiratory care unit for treatment of CCI. Measurements and Main Results: Using the Confusion Assessment Method for ICU and the Richmond Agitation and Sedation Scale, we evaluated patients for delirium and coma during their hospital treatment for CCI. We collected data on other potential risk factors for LTBD by prospectively reviewing the patients' medical records and interviewing surrogates. We contacted survivors by telephone at 6 months after discharge to assess brain function using the telephone Confusion Assessment Method. Among 385 patients treated for CCI, 213 (56.1%) were dead at 6 months, and 108 of 167 (64.7%) of survivors were impaired. We used multinomial logistic regression in which the outcomes were (1) death, (2) brain dysfunction, and (3) survival without LTBD. Older patients, patients with higher Acute Physiology Score, and those with multiple complications during treatment for CCI were more likely to have LTBD. Acute brain dysfunction during hospital treatment was also associated with an increased risk of LTBD (odds ratio, 2.14; 95% confidence interval, 1.02-4.52). Conclusions: LTBD after treatment for CCI is associated with brain dysfunction during such treatment as well as with older age and higher severity of illness of the patients. 23948669 Feasibility and safety of endovascular treatment for chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. Chronic cerebrospinal venous insufficiency (CCSVI) is a recently discovered syndrome mainly due to stenoses of internal jugular (IJV) and/or azygos (AZ) veins. The present study retrospectively evaluates the feasibility and safety of endovascular treatment for CCSVI in a cohort of patients with multiple sclerosis (MS). From September 2010 to October 2012, 1202 consecutive patients were admitted to undergo phlebograpy ± endovascular treatment for CCSVI. All the patients had previously been found positive at color Doppler sonography (CDS) for at least two Zamboni criteria for CCSVI and had a neurologist-confirmed diagnosis of MS. Only symptomatic MS were considered for treatment. Percutaneous transluminal angioplasty was carried out as an outpatient procedure at two different institutes. Primary procedures, regarded as the first balloon angioplasty ever performed for CCSVI, and secondary (reintervention) procedures, regarded as interventions performed after venous disease recurrence, were carried out in 86.5% (1037 of 1199) and 13.5% (162 of 1199) of patients, respectively. Procedural success and complications within 30 days were recorded. Phlebography followed by endovascular recanalization was carried out in 1999 patients consisting of 1219 interventions. Balloon angioplasty alone was performed in 1205 out of 1219 (98.9%) procedures, whereas additional stent placement was required in the remaining 14 procedures (1.1%) following unsuccessful attempts at AZ dilatation. No stents were ever implanted in the IJV. The feasibility rate was as high as 99.2% (1209 interventions). Major complications included one (0.1%) AZ rupture occurring during balloon dilatation and requiring blood transfusion, one (0.1%) severe bleeding in the groin requiring open surgery, two (0.2%) surgical openings of the common femoral vein to remove balloon fragments, and three (0.2%) left IJV thromboses. The overall major and minor complication rates at 30 days were 0.6% and 2.5%, respectively. Endovascular treatment for CCSVI appears feasible and safe. However, a proper learning curve can dramatically lower the rate of adverse events. In our experience, the vast majority of complications occurred in the first 400 cases performed. 23917164 Cytotoxicity and the induction of the stress protein Hsp 70 in Chang liver cells in response to zearalenone-induced oxidative stress. Zearalenone (ZEN) has been implicated in several cases of mycotoxicosis in farm animals and humans. The toxic effects of ZEN have been well characterized, but little is known regarding the mechanisms of ZEN toxicity, including the involvement of the oxidative stress pathway. Using Chang liver cells as a model, the aim of this study was to determine if ZEN could elevate the expression of the heat shock protein Hsp 70, induce cytotoxicity and modulate the levels of glutathione (GSH) and thiobarbituric acid reactive substance (TBARS). In addition, the cytoprotective effects of N-acetylcysteine amide (NACA) pre-treatment were assessed. Finally, the involvement of oxidative stress in ZEN-induced toxicity was confirmed. The results of this study demonstrated that ZEN-induced Hsp 70 expression in a dose- and time-dependent manners. This effect occurred at low-ZEN concentrations, and could therefore be considered a biomarker of ZEN-induced toxicity. The cytotoxicity was reduced when Chang liver cells were exposed to sub-lethal heat shock prior to ZEN treatment, demonstrating a cytoprotective effect of Hsp 70. This cytoprotective effect suggested that Hsp 70 might play a key role in the cellular defense mechanism. When cells were pre-treated with NACA prior to ZEN treatment, the cells were also protected from toxicity. This NACA cytoprotective effect suggested the involvement of oxidative stress in ZEN-induced toxicity, and this mechanism was supported by reduced Hsp 70 expression, inhibited cytolethality, increased GSH levels and decreased TBARS formation when cells were pre-treated with NACA prior to ZEN exposure. Our data clearly demonstrated that ZEN induced cytotoxicity in Chang liver cells by inhibiting cell proliferation, decreasing GSH levels and increasing TBARS formation in a dose-dependent manner. ZEN also, induced Hsp 70 expression, and the side effects of ZEN were significantly alleviated by pre-treatment with NACA. Oxidative stress is likely to be one of the primary pathways of ZEN toxicity. This oxidative stress may contribute, at least in part, to the mechanism of ZEN-induced cytotoxicity. 23884069 Enhancing assessment and treatment of hepatitis C in the custodial setting. Acute and chronic hepatitis C (HCV) infections are prevalent in custodial settings worldwide, yet provision of antiviral therapies is uncommon. This disparity between the burden of disease and hepatitis service delivery reflects the marginalized patient population, which features high rates of injection drug use and poor mental health. In addition, the prison environment is intended for deprivation of liberty and not healthcare. Screening for HCV infections is provided in most jurisdictions, but uptake rates remain low. Assessment and treatment of inmates is often provided only by community-based services. Despite these challenges, assessment and treatment of inmates with chronic HCV via prison-based services has been shown to be feasible and effective. These services offer the potential to substantively increase HCV treatment uptake and reduce the burden of disease for the community at large. Improvements in the efficacy of HCV therapies via direct-acting antivirals, which also offer reduced treatment duration and decreased toxicities, mean that prison health services will be well placed for the treatment of large numbers of people with HCV who do not access health services in the community. 23944867 ICR SS Protozoan Data Site-by-Site--A Picture of Cryptosporidium & Giardia in USA Surface Water. The USEPA Information Collection Rule Supplemental Survey (ICR SS) required analysis of Cryptosporidium and Giardia in 10 L surface water samples twice a week for a year by USEPA Method 1623 at 80 representative USA public water systems (PWS). The resulting data are examined site-by-site in relation to objectives of the Federal drinking water regulation, The Long Term (2) Enhanced Surface Water Treatment Rule (LT2), currently under formal 6-year review by the USEPA. The data describe Cryptosporidium and Giardia in watersheds nation-wide over a single annual cycle. Due to limited recovery efficiency measurement results are not fully quantified. In the required sample volumes of 10 L no Cryptosporidium were found in 86% of samples and no Giardia were found in 67% of samples. Yet, organisms were found in enough samples at 34 of 80 sites to detail a specrtum of occurrence and variability for both organisms. The data are shown to describe indivudual site risk essential for guidance of watershed and water treatment management by PWSs. The span of median occurrence for both organisms was about two orders of magnitude above the limit of detection (LD), ca. 0.05 raw no's/L for Cryptosporidium and ca 0.10 raw no's/L for Giardia. Data analysis illustrates key features of Cryptosporidium and Giardia in surface water: presence is continuous not intermittent; zeros indicate presence below the LD; occurrence level and variations depend on watershed sources; risk depends on both magnitude and variability of concentration; accurate estimation of risk requires routine measurement of recovery efficiency and calculation of concentration. The data and analysis illustrate features of Crytpsporidium and Giardia occurrence in surface water relevant to their effective regulation for public health protection. 23716465 Prenatal exposure to nitrosatable drugs, vitamin C, and risk of selected birth defects. Nitrosatable drugs, such as secondary or tertiary amines and amides react with nitrite in an acidic environment to form N-nitroso compounds, teratogens in animal models. Vitamin C is a known nitrosation inhibitor. Using data from the National Birth Defects Prevention Study, we assessed nitrosatable drug exposure and vitamin C intake during the first trimester among 11,606 case-mothers of infants with oral clefts, limb deficiencies (LDs), or congenital heart defects and 6807 control-mothers of infants without major birth defects during 1997-2005. Daily intake of vitamin C was estimated from maternal interviews that elicited information about supplement use and dietary intake. With no reported use of nitrosatable drugs as the referent group, a lower odds ratio (OR) was observed for transverse LDs among births to mothers exposed to secondary amine drugs and daily vitamin C supplementation (adjusted odds ratio [aOR] 1.2, 95% confidence interval [CI] 0.83-1.8) compared with women taking these drugs and no supplementation (aOR 2.7, 95% CI 1.5-4.6). The OR for longitudinal LDs associated with secondary amine exposure was lower with daily dietary vitamin C intake ≥85 mg (aOR 1.2, 95% CI 0.68-2.0) compared with <85 mg (aOR 1.9, 95% CI 1.2-3.1). Daily vitamin C supplementation in combination with higher dietary vitamin C intake reduced associations between nitrosatable drug exposures and limb deficiencies and atrial septal defects not otherwise specified. Prenatal dietary and vitamin C supplement intake may diminish the association between nitrosatable drug exposure during pregnancy and selected birth defects. Birth Defects Research (Part A) 97:515-531, 2013. © 2013 Wiley Periodicals, Inc. 23828729 Natural and enhanced biodegradation of propylene glycol in airport soil. Aircraft de-icing fluids (ADF) are a source of water and soil pollution in airport sites. Propylene glycol (PG) is a main component in several commercial formulations of ADFs. Even though PG is biodegradable in soil, seasonal overloads may result in occasional groundwater contamination. Feasibility studies for the biostimulation of PG degradation in soil have been carried out in soil slurries, soil microcosms and enrichment cultures with and without the addition of nutrients (N and P sources, oligoelements), alternative electron acceptors (nitrate, oxygen releasing compounds) and adsorbents (activated carbon). Soil samples have been taken from the contaminated area of Gardermoen Airport Oslo. Under aerobic conditions and in the absence of added nutrients, no or scarce biomass growth is observed and PG degradation occurs by maintenance metabolism at constant removal rate by the original population of PG degraders. With the addition of nutrient, biomass exponential growth enhances aerobic PG degradation also at low temperatures (4 ° C) that occur at the high season of snowmelt. Anaerobic PG degradation without added nutrients still proceeds at constant rate (i.e. no biomass growth) and gives rise to reduced fermentation product (propionic acid, reduced Fe and Mn, methane). The addition of nitrate does not promote biomass growth but allows full PG mineralization without reduced by-products. Further exploitation on the field is necessary to fully evaluate the effect of oxygen releasing compounds and adsorbents. 23693125 DNA functionalized gold nanorods/nanoplates assembly as sensitive LSPR-based sensor for label-free detection of mercury ions. Core-satellite assembly, i.e., gold nanoplates (AuNPs) surrounded by gold nanorods (AuNRs), has been obtained by Thymine-Hg(2+)-Thymine (T-Hg(2+)-T) coordination. A novel label-free localized surface plasmon resonance (LSPR) detection of mercury ions can be performed via the core-satellite assembly. The proposed detection protocol exhibits good linear correlation between wavelength shifts of the plasmon band and concentrations of mercury ions over the range from 10nM to 0.2μM. Moreover, the detection limit (3σ) for the probes is 2.2nM, which is better than colorimetric detection via random aggregation of gold nanoparticles. 23534857 Skin Sensitization of Epoxyaldehydes: Importance of Conjugation. Structure-activity relationship (SAR) models are important tools for predicting the skin sensitization potential of new compounds without animal testing. In compounds possessing a structural alert (aldehyde) and an activation alert (double bond), it is important to consider bioactivation/autoxidation (e.g., epoxidation). In the present study, we have explored a series of aldehydes with regard to contact allergy. The chemical reactivity of these 6 aldehydes toward a model hexapeptide was investigated, and their skin sensitization potencies were evaluated using the local lymph node assay (LLNA). Overall, we observed a similar trend for the in vitro reactivity and the in vivo sensitization potency for the structural analogues in this study. The highly reactive conjugated aldehydes (α,β-unsaturated aldehydes and 2,3-epoxyaldehydes) are sensitizing moieties, while nonconjugated aldehydes and nonterminal aliphatic epoxides show low reactivity and low sensitization potency. Our data show the importance of not only double bond conjugation to aldehyde but also epoxide-aldehyde conjugation. The observations indicate that the formation of nonconjugated epoxides by bioactivation or autoxidation is not sufficient to significantly increase the sensitization potency of weakly sensitizing parent compounds. 23942056 Phenotypic and metabolic aspects of prostatic epithelial cells in aged gerbils after antisteroidal therapy: Turnover in the state of chromatin condensation and androgen-independent cell replacement. The gerbil is a rodent considered a good model for studies of prostatic morphophysiology under different experimental conditions. Studies involving castration and steroidal blockers of aged gerbils showed that the glandular epithelium persists after long-term therapy, preventing the organ atrophy. Thus, the objective of this study was to evaluate the phenotypic characteristics and behavior of prostatic epithelial cells that remained after different periods of hormone ablation in aged gerbils. The identification of elements that influenced the survival of this cell type was performed by morphometric, nuclear phenotypes, ultrastructural and immune histochemical analysis. The most significant responses to treatment, by analyzing morphometric features, were observed during the first three time points (day 1, day 3, and day 7), after which there appeared to be an adjustment of the gland to the hormone ablation. All treatments led to changes in the state of chromatin condensation, DNA methylation pattern and phenotypic changes indicated cell senescence. Additionally, an increase in the basal cells seemed to guarantee self-renewal properties to the epithelium. These data indicate that changes occur at many levels, including gene expression and nuclear architecture in the epithelial cells, when aging and steroidal blockade are associated. These aspects are important when considering castration-resistant prostate cancer, a malignant tumor posing difficult therapeutic intervention. 23542683 Notch3 induces epithelial-mesenchymal transition and attenuates carboplatin-induced apoptosis in ovarian cancer cells. Notch3 is implicated in chemoresistance of ovarian cancer, yet the molecular mechanism underlying Notch3-mediated drug resistance remains to be elucidated. Here, we investigated the role of Notch3 in carboplatin-induced apoptosis in ovarian cancer cells. Ovarian cancer cell line OVCA429 cells were stably transduced with an empty vector or a retroviral vector expressing the Notch3 intracellular domain (NICD3, the constitutively active form of Notch3) to generate OVCA429/vector and OVCA429/NICD3 cells. Epithelial-mesenchymal transition (EMT) was determined by morphological change and expression of the EMT markers. Carboplatin-induced cytotoxicity was determined by the neutral red uptake assay. Apoptosis was determined by Annexin V staining and Western blotting. Carboplatin-induced phosphorylation of extracellular signal-regulated kinase (ERK) was identified by a phospho-kinase array and confirmed by Western blotting. Activation of Notch3 in OVCA429 cells causes a spindle and fibroblast-like morphology, induces the expression of smooth muscle α-actin, Slug and Snail, but decreases the expression of E-cadherin, indicating that Notch3 activation induces EMT in OVCA429 cells. Furthermore, Notch3 activation renders OVCA429 cells more resistant to carboplatin-induced cytotoxicity and attenuates carboplatin-induced apoptosis in these cells. Our results indicate that phosphorylation of ERK is a positive regulator of carboplatin-induced apoptosis in OVCA429 cells. Interestingly, carboplatin-induced ERK phosphorylation is inhibited by Notch3 activation. Notch3 activation induces EMT and attenuates carboplatin-induced apoptosis in OVCA429 cells. ERK phosphorylation plays a pro-apoptotic role in carboplatin-induced apoptosis in OVCA429 cells. Interestingly, Notch3 activation attenuates carboplatin-induced ERK phosphorylation in these cells. 23567839 Brain edema in acute liver failure: Role of neurosteroids. Brain edema is a major neurological complication of acute liver failure (ALF) and swelling of astrocytes (cytotoxic brain edema) is the most prominent neuropathological abnormality in this condition. Elevated brain ammonia level has been strongly implicated as an important factor in the mechanism of astrocyte swelling/brain edema in ALF. Recent studies, however, have suggested the possibility of a vasogenic component in the mechanism in ALF. We therefore examined the effect of ammonia on blood-brain barrier (BBB) integrity in an in vitro co-culture model of the BBB (consisting of primary cultures of rat brain endothelial cells and astrocytes). We found a minor degree of endothelial permeability to dextran fluorescein (16.2%) when the co-culture BBB model was exposed to a pathophysiological concentration of ammonia (5mM). By contrast, lipopolysaccharide (LPS), a molecule well-known to disrupt the BBB, resulted in an 87% increase in permeability. Since increased neurosteroid biosynthesis has been reported to occur in brain in ALF, and since neurosteroids are known to protect against BBB breakdown, we examined whether neurosteroids exerted any protective effect on the slight permeability of the BBB after exposure to ammonia. We found that a nanomolar concentration (10nM) of the neurosteroids allopregnanolone (THP) and tetrahydrodeoxycorticosterone (THDOC) significantly reduced the ammonia-induced increase in BBB permeability (69.13 and 58.64%, respectively). On the other hand, we found a marked disruption of the BBB when the co-culture model was exposed to the hepatotoxin azoxymethane (218.4%), but not with other liver toxins commonly used as models of ALF (thioacetamide and galactosamine, showed a 29.3 and 30.67% increase in permeability, respectively). Additionally, THP and THDOC reduced the effect of TAA and galactosamine on BBB permeability, while no BBB protective effect was observed following treatment with azoxymethane. These findings suggest that ammonia does not cause a significant BBB disruption, and that the BBB is intact in the TAA or galactosamine-induced animal models of ALF, likely due to the protective effect of neurosteroids that are synthesized in brain in the setting of ALF. However, caution should be exercised when using azoxymethane as an experimental model of ALF as it caused a severe breakdown of the BBB, and neurosteriods failed to protect against this breakdown. 23263913 A study of circulating anti-CD25 antibodies in non-small cell lung cancer. Tumors can trigger specific immune response to tumor-associated antigens but the precise mechanism remains unclear. Since regulatory T-lymphocytes (Treg) play a crucial role in controlling autoimmune responses, the present work was undertaken to test whether dysfunction of Treg cells could be involved in developing autoimmunity in patients with lung cancer. In this study, we developed an in-house enzyme-linked immunosorbent assay to test circulating anti-CD25 autoantibodies among 272 patients with non-small cell lung cancer (NSCLC) and 226 control subjects matched in age, gender and smoking history. Mann-Whitney U test showed that the anti-CD25 IgG level was significantly higher in patients with NSCLC than control subjects (Z = -7.48, P < 0.001) while the anti-CD25 IgA level was not significantly changed in the patient group as compared with the control group (Z = -1.34, P = 0.181). Spearman correlation analysis failed to reveal a significant correlation between the levels of anti-CD25 IgG and IgA either in patients with NSCLC (r = -0.034, P = 0.578) or in control subjects (r = 0.055, P = 0.429). ROC analysis showed an AUC of 0.70 for anti-CD25 IgG, in which NSCLC at stage III had the highest AUC (0.75). The sensitivity against a specificity of >90 % was 35.0 % for anti-CD25 IgG assay with an inter-assay deviation of 9.4 %, and 4.0 % for anti-CD25 IgA assay with an inter-assay deviation of 13.0 %. Circulating anti-CD25 IgG antibody may be a useful biomarker for prognosis of lung cancer. 23872450 Non-invasive brain stimulation (rTMS and tDCS) in patients with aphasia: Mode of action at the cellular level. A high proportion of patients who have suffered a stroke also suffer from aphasia. Approximately half of those affected will remain in this state despite intensive language therapy. Non-invasive brain stimulation allows us to directly and focally stimulate areas of the brain. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), methods used in the treatment of aphasia, are based on an imbalance of mutual interhemispheric inhibition. In open and sham-controlled studies, a low-frequency, 1Hz stimulation of the non-lesioned hemisphere (the homologue of Broca's area) for a week or more significantly improved spontaneous speech and anomia in patients with non-fluent aphasia. These positive outcomes from rTMS stimulation developed slowly, often over months following treatment, and persisted. Effects of intermittent theta burst stimulation (iTBS) developed faster than the low-frequency stimulation, and high-activity enhancement was detected in the left hemisphere after the stimulation of Broca's region. Both types of tDCS stimulation resulted in improved comprehension and reduced anomia, their primary modes of action are distinct, however, both share a common site of action with regard to the balance that occurs between inhibitory and excitatory neurotransmitters (synaptic and non-synaptic). Both types of non-invasive stimulation prepare the lesioned brain for better outcome. 23959202 Brain mitochondrial oxidative metabolism during and after cerebral hypoxia-ischemia studied by simultaneous phosphorus magnetic-resonance and broadband near-infrared spectroscopy. Multimodal measurements combining broadband near-infrared spectroscopy (NIRS) and phosphorus magnetic resonance spectroscopy ((31)P MRS) assessed associations between changes in the oxidation state of cerebral mitochondrial cytochrome-c-oxidase (Δ[oxCCO]) and (31)P metabolite peak-area ratios during and after transient cerebral hypoxia-ischemia (HI) in the newborn piglet. Twenty-four piglets (aged<24h) underwent transient HI (inspired oxygen fraction 9% and bilateral carotid artery occlusion for ~20min). Whole-brain (31)P MRS and NIRS data were acquired every minute. Inorganic phosphate (Pi)/epp, phosphocreatine (PCr)/epp, and total nucleotide triphosphate (NTP)/epp were measured by (31)P MRS and were plotted against Δ[oxCCO] during HI and recovery (epp=exchangeable phosphate pool=Pi+PCr+2γ-NTP+β-NTP). During HI Δ[oxCCO], PCr/epp and NTP/epp declined and Pi/epp increased. Significant correlations were seen between (31)P ratios and Δ[oxCCO]; during HI a threshold point was identified where the relationship between Δ[oxCCO] and both NTP/epp and Pi/epp changed significantly. Outcome at 48h related to recovery of Δ[oxCCO] and (31)P ratios 1h post-HI (survived: 1-h NTP/epp 0.22±0.02, Δ[oxCCO] -0.29±0.50μM; died: 1-h NTP/epp 0.10±0.04, Δ[oxCCO] -2.41±1.48μM). Both lowered Δ[oxCCO] and NTP/epp 1h post-HI indicated mitochondrial impairment. Animals dying before 48h had slower recovery of both Δ[oxCCO] and (31)P ratios by 1h after HI. 23354951 Alternative splicing of BRAF transcripts and characterization of C-terminally truncated B-Raf isoforms in colorectal cancer. The BRAF proto-oncogene is mutated in a subset of human tumors, including colorectal cancer. A splicing variant lacking exons 14 and 15 (BRAF del E14/15) has been described recently. However, the frequency of the variant, the kinase activity of the protein isoform, its biological function, and which allele it is derived from remains unknown. BRAF mRNA from colorectal cancer cell lines and colonic epithelium was reversely transcribed, subcloned, and screened for alternative splicing. New transcript variants and allelic origin of alternatively spliced transcripts were analyzed by DNA sequencing. Kinase activity of the B-Raf isoforms was determined by Western blotting after transfections with expression constructs of the different BRAF variants. Four additional BRAF transcript variants resulting in C-terminal truncation of the gene product were found. Alternative splicing was found at frequencies from 4.7 to 16.7% in normal and neoplastic colorectal cells. Alternative transcripts were shown to be derived from both wild-type and V600E alleles. All nonconsensus B-Raf protein variants were found to be kinase-dead and failed to coactivate full-length B-Raf. In conclusion, we present a highly sensitive method for the detection of aberrantly spliced transcripts. Alternative splicing of exons 14, 15, 15b, 16b and 16c occurs in a considerable fraction of BRAF mRNA in normal colon and colorectal cancer cells and is independent of the V600E mutational status of the parental allele. Splicing of nonfunctional transcripts affects overall cellular B-Raf activity and might represent a mechanism to decrease sensitivity to growth signals. 23906320 Troponin T autoantibodies correlate with chronic cardiomyopathy in human Chagas disease. To evaluate the potential involvement of anti-Trypanosoma cruzi and cardiac protein antibody (IgG total and isotypes) production and their possible association with different clinical forms of human chronic Chagas disease. IgG total and isotypes were measured by ELISA, using epimastigote and trypomastigote forms of T. cruzi as antigens and human cardiac proteins (myosin and troponin T) in sera of patients with indeterminate (IND, n = 72), cardiac (CARD, n = 47) and digestive/cardiodigestive (DIG/CARD-DIG, n = 12) clinical forms of the disease. Samples from uninfected health individuals (CONT, n = 30) and patients with ischaemic cardiomyopathy (ISCH, n = 15) were used as controls. Autoantibody levels were correlated with parameters of cardiac function obtained by electrocardiographic, radiographic and echocardiographic examinations. Fifty five per cent of patients were classified as IND, 35.9% as CARD and 9.1% as DIG/CARD-DIG. Greater total IgG production was observed in IND, CARD and DIG/CARD-DIG chagasic patients than in CONT and ISCH, using trypomastigote, epimastigote and cardiac antigens. Moreover, patients with CARD and DIG/CARD-DIG presented greater total IgG production (trypomastigote and epimastigote antigen) than IND, and a negative correlation was determined between total IgG and left ventricular ejection fraction (LVEF). Patients with IND and CARD presented similar higher levels of total IgG specific to troponin T and myosin than CONT and ISCH individuals. Patients with chronic Chagas disease presented a negative correlation between left ventricular ejection fraction (LVEF) and the production of anti-myosin and troponin T autoantibodies. When grouped as low and high antibody producers and compared with LVEF, we observed that high anti-troponin T (P = 0.042) and myosin (P = 0.013) producers presented lower LVEF than low producers. Moreover, there was a positive correlation (r = 0.9508, P = 0.0001) between the production of troponin T and myosin autoantibodies. These findings indicate that increased production of anti-cardiac troponin T and myosin autoantibodies probably influences the left ventricular ejection fraction and could be related to chagasic cardiomyopathy. 23468458 Hydrogen-bond reinforced vanadia nanofiber paper of high stiffness. Low-temperature, solution-based self-assembly of vanadia nanofibers yields a free-standing, ceramic paper with an outstanding combination of high strength, stiffness, and macroscopic flexibility. Its excellent mechanical performance results from a brick-and-mortar like architecture, which combines strong covalent bonding within the single-crystalline nanofibers with an intricate hydrogen bonding network between them. 23959785 Suboptimal effect of different vitamin D3 supplementations and doses adapted to baseline serum 25(OH)D on achieved 25(OH)D levels in patients with a recent fracture: a prospective observational study. Guidelines on the need of dose adaptation of vitamin D3 supplementation according to baseline serum 25(OH)D are inconclusive. The effects of increasing doses of vitamin D3 at lower baseline serum 25(OH)D values on the serum 25(OH)D after 4.2 and 11 months were determined in an observational study. a prospective observational study METHODS: Out of 1481 consecutive women and men with a recent clinical fracture, 707 had a baseline 25(OH)D level <50 nmol/L and were supplemented with increasing doses of vitamin D3 (400, 800, 1700, ≥3500IU/day) according to the lower baseline 25(OH)D. Final analysis was restricted to the 221 participants who had full follow-up data available for 11 months. Serum 25(OH)D ≥50 nmol/L was achieved in 57-76% of patients after 4.2months and in 73-79% after 11 months. These percentages were similar for all doses (p=0.06 and p=0.91, respectively). The mean achieved 25(OH)D was similar for all dose groups (56.1-64.0 nmol/L after 4.2 months and 60.2-76.3 nmol/L after 11 months). With multivariate analysis, the increase in 25(OH)D (17±32.0 after 4.2 months and 24.3±34.0 nmol/L after 11 months) was dependent on the baseline 25(OH)D (p<0.001), not on supplementation dose, season, age, BMI or gender. The increase in serum 25(OH)D was significantly larger with higher vitamin D3 supplementation doses. However, this dose-effect response was mainly explained by the baseline 25(OH)D, not the supplementation dose, with a greater magnitude of response at lower baseline 25(OH)D concentrations. In 21-27% of patients serum 25(OH)D3 levels did not reach 50 nmol/L after 11 months, at any dose. Further studies are needed order to identify possible causes of suboptimal response such as non-compliance, undiagnosed malabsorption syndromes or variability in cholecalciferol content of the vitamin D supplements. 23174266 Beneficial effects of polyphenols on cardiovascular disease. In recent years, numerous studies have demonstrated the health benefits of polyphenols, and special attention has been paid to their beneficial effects against cardiovascular disease, the leading cause of death in the world today. Polyphenols present vasodilator effects and are able to improve lipid profiles and attenuate the oxidation of low density lipoproteins. In addition, they present clear anti-inflammatory effects and can modulate apoptotic processes in the vascular endothelium. It has been suggested that most of these effects are a consequence of the antioxidant properties of polyphenols, but this idea is not completely accepted, and many other mechanisms have been proposed recently to explain the health effects of these compounds. In fact, different signaling pathways have been linked to polyphenols. This review brings together some recent studies which establish the beneficial properties of polyphenols for cardiovascular disease and analyzes the mechanisms involved in these properties. 23954358 Developmental exposure of fetal ovaries and fetal germ cells to endometriosis in an endometriosis model causes differential gene expression in the preimplantation embryos of the first-generation and second-generation embryos. To characterize multigenerational gene expression anomalies in eight-cell stage embryos associated with developmental exposure to endometriosis. Using an endometriosis model in rats (F0 founder generation) to evaluate gene expression in F1 (fetal exposure) and F2 (fetal germ cell exposure) generation eight-cell stage embryos. Laboratory. Endometriosis model in rats (Endo) and controls (Sham). F0 Endo and Sham rats were bred; half the pregnant rats were killed on gestational day 3 to collect F1 eight-cell stage embryos and the others gestated to term (F1 females). Adult F1 females bred; F2 eight-cell embryos collected. Maintenance of differential gene expression in F1 and F2 generation eight-cell embryos in endometriosis. Developmental exposure to endometriosis altered the gene signaling pathways, with changes found in apoptosis, the cell cycle process, the response to oxidative stress, negative regulation of molecular function, and RNA processing. The apoptotic genes Diablo, Casp3, Parp1, Cad, and Dnaja3 were increased and the Nfkbia transcripts were decreased in F1 Endo versus F1 Sham embryos. In F2 Endo versus Sham embryos, Casp3 and Cad were statistically significantly increased, and Parp1 and Nfkbia tended to be elevated. Fetal and germ cell exposure to endometriosis alters apoptotic gene expression in first- and second-generation eight-cell stage embryos, supporting the hypothesis of multigenerational inheritance resulting from exposure to endometriosis in utero. 23844915 Breast cancer as a systemic disease: a view of metastasis. Breast cancer is now the most frequently diagnosed cancer and leading cause of cancer death in women worldwide. Strategies targeting the primary tumour have markedly improved, but systemic treatments to prevent metastasis are less effective; metastatic disease remains the underlying cause of death in the majority of patients with breast cancer who succumb to their disease. The long latency period between initial treatment and eventual recurrence in some patients suggests that a tumour may both alter and respond to the host systemic environment to facilitate and sustain disease progression. Results from studies in animal models suggest that specific subtypes of breast cancer may direct metastasis through recruitment and activation of haematopoietic cells. In this review, we focus on data implicating breast cancer as a systemic disease. 23416701 Maternal exposure to airborne particulate matter causes postnatal immunological dysfunction in mice offspring. Evidence suggests that prenatal exposure to air pollution affects the ontogeny and development of the fetal immune system. The aim of this study was to investigate the effect of maternal exposure to airborne particulate matter (PM) on immune function in postnatal offspring. Pregnant female ICR mice were intralaryngopharyngeally administered with 30μl of phosphate buffered solution (the control group) or resuspended PM of Standard Reference Material 1649a at 0.09 (low), 0.28 (medium), 1.85 (high) or 6.92 (overdose) μg/μl once every three days from day 0 to 18 of pregnancy (n=8-10). Offspring were sacrificed on postnatal day 30. Interleukin-4 and interferon-γ levels in plasma and splenocytes, splenic lymphocyte proliferation, and expressions of GATA-3 and T-bet mRNA in the spleen were tested. The spleen and thymus were histopathologically examined. The offspring of the medium, high and overdose PM-exposed dams showed significantly suppressed splenocyte proliferation. Decreased interferon-γ and increased interleukin-4 levels in the blood and splenocytes, and lowered T-bet and elevated GATA-3 mRNA expressions were found in the spleen in the medium, high and overdose groups when compared with the control or low dose group (P<0.05). Histopathology revealed prominent tissue damage in the spleen and thymus in the overdose group. These results suggest that exposure of pregnant mice to PM modulates the fetal immune system, resulting in postnatal immune dysfunction by exacerbation of Thl/Th2 deviation. This deviation is associated with altered T-bet and GATA-3 gene expressions. 23543412 Nicotine-Induced Structural Plasticity in Mesencephalic Dopaminergic Neurons Is Mediated by Dopamine D3 Receptors and Akt-mTORC1 Signalling. Though long-term exposure to nicotine is highly addictive, one "beneficial" consequence of chronic tobacco use is a reduced risk for Parkinson's disease. Interestingly, these effects both reflect structural and functional plasticity of brain circuits controlling reward and motor behavior, and specifically recruitment of nicotinic acetylcholine receptors (nAChR) in mesencephalic dopaminergic neurons. Since the underlying cellular mechanisms are poorly understood, we addressed this issue employing primary cultures of mouse mesencephalic dopaminergic neurons. Exposure to nicotine (1-10 μM) for 72 hr in vitro increased dendritic arborization and soma size in primary cultures. These effects were blocked by mecamylamine and dihydro-β-erythroidine, but not methyllycaconitine. The involvement of α4β2 nAChR was supported by the lack of nicotine-induced structural remodeling in neurons from α4 null mutant mice (KO). Challenge with nicotine triggered phosphorylation of the extracellular signal-regulated kinase (ERK) and the thymoma viral proto-oncogene (Akt) followed by activation of the mTORC1-dependent p70 ribosomal S6 protein kinase. Upstream pathway blockade using the phosphatidylinositol 3-kinase inhibitor LY294002 resulted in suppression of nicotine-induced phosphorylations and structural plasticity. These effects were dependent upon functional DA D3 receptor (D3R) since nicotine was inactive both in cultures from D3R KO mice and following pharmacologic blockade with D3R antagonist SB-277011-A (50 nM). Finally, exposure to nicotine in utero (5 mg/kg/day for 5 days) resulted in increased soma area of DAergic neurons of newborn mice, effects not observed in D3KO mice. These findings indicate that nicotine-induced structural plasticity in mesencephalic dopaminergic neurons involves α4β2 nAChRs together with dopamine D3R-mediated recruitment of ERK/Akt-mTORC1 signaling. 23918691 Treatment with the Nitric Oxide Donor SNP Increases Triiodothyronine Levels in Hyper- and Hypothyroid Sprague-Dawley Rats. Nitric oxide pathway might play a crucial role in the pathophysiology of thyroid dysfunctions. This study aimed to investigate the impact of nitric oxide (NO) on hypothyroid and hyperthyroid Sprague-Dawley rats under controlled diet. Furthermore, the effects of the nitric oxide donor sodium nitroprusside (SNP) on thyroid dysfunctions were also assessed. Sprague-Dawley rats (n=107) were subdivided into normal diet and high-fat diet (HFD) groups and grouped into controls, hypothyroid, hyperthyroid, and SNP treated groups. Hypothyroidism was induced through propylthiouracil, whereas hyperthyroidism by triiodothyronine (T3). After 12 weeks of T3 treatment, serum nitric oxides (NOX), endogenous asymmetric dimethylarginine (ADMA), body weight and food intake were analyzed. Hypothyroid rats showed decreased serum T3 levels, hyperthyroid rats increased T3 compared to controls. Diet had no impact on T3. Thyroid dysfunctions were accompanied by changes in calorie intake and body weight. Serum NOX was significantly reduced in normal diet hypothyroid rats. SNP administration compensated the decrease and markedly increased T3. NO synthase inhibitor ADMA levels were significantly higher in the HFD control group than in the normal diet controls. ADMA was declined in both hypothyroid groups and increased in normal diet hyperthyroid rats. An association of thyroid dysfunctions with reduced bioavailability of NO and alterations of ADMA levels could be established. Treatment with the NO donor SNP resulted in an increase of serum T3 levels. These results demonstrate that the NO pathway is implicated in thyroid dysfunctions, which may be of clinical relevance. 23801662 Relationship between diet and plasma long-chain n-3 PUFAs in older people: impact of apolipoprotein E genotype. The main risk factors for Alzheimer's disease, age and the ε4 allele of the APOE gene (APOE4), might modify the metabolism of n-3 PUFAs and in turn, their impact on cognition. The aim of this study was to investigate the association between dietary fat and plasma concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in elderly persons, taking the APOE4 genotype into account. The sample was composed of 1,135 participants from the Three-City study aged 65 years and over, of whom 19% were APOE4 carriers. Mean plasma proportions of EPA [1.01%, standard deviation (SD) 0.60] and DHA (2.41%, SD 0.81) did not differ according to APOE4. In multivariate models, plasma EPA increased with frequency of fish consumption (P < 0.0001), alcohol intake (P = 0.0006), and female gender (P = 0.02), and decreased with intensive consumption of n-6 oils (P = 0.02). The positive association between fish consumption and plasma DHA was highly significant whatever the APOE genotype (P < 0.0001) but stronger in APOE4 noncarriers than in carriers (P = 0.06 for interaction). Plasma DHA increased significantly with age (P = 0.009) in APOE4 noncarriers only. These findings suggest that dietary habits, gender, and APOE4 genotype should be considered when designing interventions to increase n-3 PUFA blood levels in older people. 23933726 Adaptive Phenotypic Diversification along a Temperature-Depth Gradient. Abstract Theoretical models suggest that sympatric speciation along environmental gradients might be common in nature. Here we present the first data-based model of evolutionary diversification along a continuous environmental gradient. On the basis of genetic analyses, it has been suggested that a pair of coregonid fishes (Coregonus spp.) in a postglacial German lake originated by sympatric speciation. Within this lake, the two species segregate vertically and show metabolic adaptations to, as well as behavioral preferences for, correspondingly different temperatures. We test the plausibility of the hypothesis that this diversifying process has been driven by adaptations to different thermal microhabitats along the lake's temperature-depth gradient. Using an adaptive-dynamics model that is calibrated with empirical data and allows the gradual evolution of a quantitative trait describing optimal foraging temperature, we show that under the specific environmental conditions in the lake, evolutionary branching of a hypothetical ancestral population into two distinct phenotypes may have occurred. We also show that the resultant evolutionary diversification yields two stably coexisting populations with trait values and depth distributions that are in agreement with those currently observed in the lake. We conclude that divergent thermal adaptations along the temperature-depth gradient might have brought about the two species observed today. 23913417 Association of twinning and maternal age with major structural birth defects in Utah, 1999 to 2008. Twinning is a risk factor for birth defects. Using population-based data from the Utah Birth Defect Network and the Utah Department of Health Vital Records, we investigated whether twinning increases the risk of major structural birth defects in live-born opposite-sex (OS) and same-sex (SS) twins as proxies for monozygotic and dizygotic twins, respectively. We also assessed whether maternal age modified the association between twinning and birth defects. All resident live-born singleton (n = 492,143) and twin (n = 13,596) infants issued a Utah birth certificate and delivered from 1999 through 2008 were included. Unadjusted and adjusted odds ratios (aORs) with 95% confidence intervals were calculated for each birth defect using unconditional logistic regression. Birth defects were slightly more likely to occur in SS (aOR = 1.94; 95% confidence interval, 1.70-2.21) than OS (aOR = 1.55; 95% confidence interval, 1.27-1.90) twins. The aORs stratified by maternal age did not show a trend for any twin type when calculated for all birth defects combined. However, trends were observed for coarctation, pyloric stenosis, and shaft or penoscrotal hypospadias in OS twins; microcephaly, anotia/microtia, conotruncal defects, membranous ventricular septal defects, pyloric stenosis, all hypospadias, and craniosynostosis in SS twins; and tetralogy of Fallot, right ventricular outflow tract obstructions, renal agenesis/hypoplasia, and craniosynostosis in all twins. All twin types have an increased risk for birth defects compared with singletons. SS twins have the highest risk, presumably due to the influence of monozygotic twins. The risk for birth defects in twins was not significantly modified by the mother's age. Birth Defects Research (Part A) 97:554-563, 2013. © 2013 Wiley Periodicals, Inc. 23567313 Chloroquine causes similar electroretinogram modifications, neuronal phospholipidosis and marked impairment of synaptic vesicle transport in Albino and Pigmented Rats. Retinal toxicity of chloroquine has been known for several years, but the mechanism(s) of toxicity remain controversial; some author support the idea that the binding of chloroquine to melanin pigments in the retinal pigmented epithelium (RPE) play a major toxic role by concentrating the drug in the eye. In our study, 12 albinos Sprague-Dawley (SD) and 12 pigmented Brown Norway (BN) rats were treated orally for 3 months with chloroquine to compare functional and pathological findings. On Flash electroretinograms (ERG) performed in scotopic conditions, similar and progressive (time-dependent) delayed onset and decreased amplitudes of oscillatory potentials (from Day 71) and b-waves (on Day 92) were identified in both BN and SD rats. In both strains, identical morphological changes consisted of neuronal phospholipidosis associated with UV auto-fluorescence without evidence of retinal degeneration and gliosis; the RPE did not show any morphological lesions or autofluorescence. IHC analyses demonstrated a decrease in GABA expression in the inner nuclear layer. In addition, a marked accumulation of synaptic vesicles coupled with a marked disruption of neurofilaments in the optic nerve fibers was identified. In conclusion, ERG observations were very similar to those described in humans. Comparable ERG modifications, histopathology and immunohistochemistry findings were observed in the retina of both rat strains suggesting that melanin pigment is unlikely involved. chloroquine-induced impairment of synaptic vesicle transport, likely related to disruption of neurofilaments was identified and non-previously reported. This new mechanism of toxicity may also be responsible for the burry vision described in humans chronically treated with chloroquine. 23649493 Burden of disease from toxic waste sites in India, indonesia, and the Philippines in 2010. Prior calculations of the burden of disease from toxic exposures have not included estimates of the burden from toxic waste sites due to the absence of exposure data. We developed a disability-adjusted life year (DALY)-based estimate of the disease burden attributable to toxic waste sites. We focused on three low- and middle-income countries (LMICs): India, Indonesia, and the Philippines. Sites were identified through the Blacksmith Institute's Toxic Sites Identification Program, a global effort to identify waste sites in LMICs. At least one of eight toxic chemicals was sampled in environmental media at each site, and the population at risk estimated. By combining estimates of disease incidence from these exposures with population data, we calculated the DALYs attributable to exposures at each site. We estimated that in 2010, 8,629,750 persons were at risk of exposure to industrial pollutants at 373 toxic waste sites in the three countries, and that these exposures resulted in 828,722 DALYs, with a range of 814,934-1,557,121 DALYs, depending on the weighting factor used. This disease burden is comparable to estimated burdens for outdoor air pollution (1,448,612 DALYs) and malaria (725,000 DALYs) in these countries. Lead and hexavalent chromium collectively accounted for 99.2% of the total DALYs for the chemicals evaluated. Toxic waste sites are responsible for a significant burden of disease in LMICs. Although some factors, such as unidentified and unscreened sites, may cause our estimate to be an underestimate of the actual burden of disease, other factors, such as extrapolation of environmental sampling to the entire exposed population, may result in an overestimate of the burden of disease attributable to these sites. Toxic waste sites are a major, and heretofore underrecognized, global health problem. 23831745 Nitrogen removal in intermittently aerated vertical flow constructed wetlands: Impact of influent COD/N ratios. The performance response of eight vertical flow constructed wetlands (VFCWs) to different influent COD/N ratios and intermittent aeration in domestic wastewater treatment was investigated. Almost complete nitrification was obtained by intermittent aeration, which well developed alternate anaerobic and aerobic conditions for nitrification and denitrification. Sufficient carbon source supply resulted from influent COD/N ratio of 10 simultaneously obtained high removals of COD (96%), ammonia nitrogen (99%) and total nitrogen (90%) in intermittently aerated VFCWs. In all non-aerated VFCWs, poor nitrification was observed due to oxygen deficiency whilst high COD/N ratios further led to lower COD and nitrogen removal efficiency. The results suggest that intermittent aeration combined with high influent COD/N ratios could achieve high nitrogen removal in VFCWs. 23684838 Hepatitis B virus vaccination in children with steroid sensitive nephrotic syndrome: immunogenicity and safety? We investigated the efficacy and safety of Hepatitis B vaccine (HBVac) in steroid sensitive nephrotic syndrome (SSNS) children. 41 patients with SSNS and 30 controls were vaccinated with HBVac(Engerix B(®)). Patients were divided into 3 subgroups:full dose steroid users, alternate-day steroid users and steroid non-users. Seroconversion rate was lower in steroid users than non-users at the 6th(p=0.015) and 12th(p=0.036) months. Antibody to Hepatitis B surface antigen(HBsAb) titers were significantly different between subgroups and controls at the 15th month. However, HBsAb and response rates were not different between subgroups at the 12th and 15th months (p>0.05). Five patients were unresponsive to HBVac. Relapse rates after the vaccination were higher than those in the prevaccination period (p=0.002). HBVac is less effective in producing immune response in SSNS children with steroid therapy. HBVac may trigger relapse in some patients. We recommend HBVac to SSNS children with low dose steroid therapy or after steroids are discontinued. 23373756 Heavy-enzyme kinetic isotope effects on proton transfer in alanine racemase. The catalytic effects of perdeuterating the pyridoxal phosphate-dependent enzyme alanine racemase from Geobacillus stearothermophilus are reported. The mass of the heavy perdeuterated form is ~5.5% greater than that of the protiated form, causing kinetic isotope effects (KIEs) of ~1.3 on k(cat) and k(cat)/K(M) for both L- and D-alanine. These values increase when Cα-deuterated alanine is used as the substrate. The heavy-enzyme KIEs of ~3 on k(cat)/K(M) with deuterated substrates are greater than the product of the individual heavy-enzyme and primary substrate KIEs. This breakdown of the rule of the geometric mean is likely due to coupled motion between the protein and the proton-transfer reaction coordinate in the rate-limiting step. These data implicate a direct role for protein vibrational motions in barrier crossing for proton-transfer steps in alanine racemase. 23687223 Plasma Viral MicroRNA Profiles Reveal Potential Biomarkers for Chronic Active Epstein-Barr Virus Infection. Background. Chronic active Epstein-Barr virus (CAEBV) infection has high mortality and morbidity, and biomarkers for disease severity and prognosis are required. MicroRNAs (miRNAs) are small noncoding RNAs, and EBV encodes multiple miRNAs. Because plasma contains sufficiently stable miRNAs, circulating EBV-associated miRNA profiles were investigated as novel biomarkers in CAEBV infection. Methods. Plasma miRNA expression was assessed for 12 miRNAs encoded within 2 EBV open reading frames (BART and BHRF). Expression levels were investigated in 19 patients with CAEBV infection, 14 patients with infectious mononucleosis, and 11 healthy controls. Relative expression levels of plasma miRNAs were determined by TaqMan probe-based quantitative assay. Results. Plasma miR-BART1-5p, 2-5p, 5, and 22 levels in patients with CAEBV infection were significantly greater than those in patients with infectious mononucleosis and in controls. Plasma miR-BART2-5p, 4, 7, 13, 15, and 22 levels were significantly elevated in patients with CAEBV infection with systemic symptoms, compared with levels in patients with no systemic symptoms. The levels of miR-BART2-5p, 13, and 15 showed clinical cutoff values associated with specific clinical conditions, in contrast to plasma EBV loads. Conclusions. Levels of specific plasma EBV miRNAs were elevated differentially in patients with CAEBV infection. Several EBV miRNAs, particularly miR-BART2-5p, 13, and 15, are potentially biomarkers of disease severity or prognosis. 23893652 Use of OMIC technologies to study arsenic exposure in human populations. Exposure to arsenic (As) in drinking water is a major health concern. More than 100 million individuals are exposed to levels over the current World Health Organization standard of 10 µg/L worldwide. Arsenic is one of the few agents established as a human carcinogen prior to understanding its mechanism of carcinogenicity. OMIC technologies have enabled researchers to utilize agnostic approaches to explore new, unknown mechanisms through which As causes disease in exposed human populations. In this article, we present recent studies in which OMIC technologies have been used to explore differences in human biological samples to identify markers of exposure, disease susceptibility, and effect in As-exposed and/or diseased tissues. Environ. Mol. Mutagen. 54:589-595, 2013. © 2013 Wiley Periodicals, Inc. 23768076 Further acylated flavonol bisdesmosides from Sinocrassula indica. Further investigation on the whole herbs of Sinocrassula indica (Crassulaceae) led to the isolation of four new acylated flavonol bisdesmosides, sinocrassosides A13 (1), B6 (2), B7 (3), and D4 (4), together with kaempferol 3-O-β-d-(6-O-acetyl)glucopyranosyl-7-O-α-l-rhamnopyranoside (5). Their structures were established by spectral and chemical methods. 23942746 Isolated hepatobiliary cryptococcosis manifesting as obstructive jaundice in an immunocompetent child: case report and review of the literature. The majority of patients with symptomatic cryptococcosis have an underlying immunocompromising condition. In the absence of coexisting immunocompromising condition, Cryptococcus neoformans is rarely considered in the differential diagnosis of obstructive jaundice that occurs in children with hilar masslike lesion. Here, we report a 5-year-old boy without immunoglobulin or lymphocyte abnormalities who developed a hepatobiliary infection with C. neoformans. Ultrasonography and computed tomography showed dilatation of the bilateral intrahepatic bile ducts and a low-attenuated mass in the hepatic hilum. Microscopic examination of tissue samples revealed abundant numbers of encapsulated yeast cell suggestive of C. neoformans. After 4 months of antifungal therapy (liposomal amphotericin B for 2 weeks and oral fluconazole for 3 months), the disease was effectively controlled. Unnecessary operation could be avoided by an early and accurate diagnosis. By sharing our experience, we suggest hepatobiliary surgeons and gastroenterologists should have a suspicion of this unusual entity to make earlier diagnosis and treatment. 23878230 Exosome-mediated transmission of hepatitis C virus between human hepatoma Huh7.5 cells. Recent evidence indicates there is a role for small membrane vesicles, including exosomes, as vehicles for intercellular communication. Exosomes secreted by most cell types can mediate transfer of proteins, mRNAs, and microRNAs, but their role in the transmission of infectious agents is less established. Recent studies have shown that hepatocyte-derived exosomes containing hepatitis C virus (HCV) RNA can activate innate immune cells, but the role of exosomes in the transmission of HCV between hepatocytes remains unknown. In this study, we investigated whether exosomes transfer HCV in the presence of neutralizing antibodies. Purified exosomes isolated from HCV-infected human hepatoma Huh7.5.1 cells were shown to contain full-length viral RNA, viral protein, and particles, as determined by RT-PCR, mass spectrometry, and transmission electron microscopy. Exosomes from HCV-infected cells were capable of transmitting infection to naive human hepatoma Huh7.5.1 cells and establishing a productive infection. Even with subgenomic replicons, lacking structural viral proteins, exosome-mediated transmission of HCV RNA was observed. Treatment with patient-derived IgGs showed a variable degree of neutralization of exosome-mediated infection compared with free virus. In conclusion, this study showed that hepatic exosomes can transmit productive HCV infection in vitro and are partially resistant to antibody neutralization. This discovery sheds light on neutralizing antibodies resistant to HCV transmission by exosomes as a potential immune evasion mechanism. 23589254 A comprehensive investigation and assessment of mercury in intertidal sediment in continental coast of Shanghai. The aims of this paper were to survey the total Hg levels and distribution character in intertidal sediment in continental coast of Shanghai, and identify the environment factors that might influence the sediment Hg concentrations, and to assess the pollution degree and potential ecological risk of Hg in sediment. Eighty-eight surface sediment samples and 18 sediment cores were collected for Hg contamination analysis. Physicochemical properties including Eh, particle size, content of total organic carbon (TOC), and acid volatile sulfide (AVS) were also measured. Index of geo-accumulation (I geo) and potential ecological risk index were used respectively to assess the pollution levels and the ecological risk of sediment Hg. The average of total Hg concentrations in surface sediments was 107.4 ±â€‰90.9 ng/g with the range from 0 to 465.9 ng/g. Higher Hg concentrations were generally found in surface sediments near sewage outfalls and the mouth of rivers. Total Hg concentrations were significantly correlated with TOC (p < 0.05) both in surface (r = 0.24) and core (r = 0.29) sediments, but not with the other environment factors (Eh, AVS, and particle size). Geo-accumulation index indicated that Hg contamination in intertidal sediments was generally at none to moderate degree, while potential ecological risk index demonstrated that the risk caused by Hg were at moderate to considerable level. Intertidal sediment in continental coast of Shanghai has generally been contaminated by Hg, and it might pose moderate to considerable risk to the local ecosystem. The Hg contamination is related more to the coastal pollution sources and complicated hydrodynamic and sedimentary conditions than the other environment factors studied. 23947330 The Importance of Increased Asthma Education. The article by Clark et al.(1) was very compelling to me on a personal level. I am a registered nurse at a children's hospital in South Florida, and I work in the pediatric intensive care unit (PICU). Unfortunately, asthma patients are very common on my unit and a large number of our patient population come from low-income families. We recently had an adolescent patient who died. He had an asthma exacerbation, but the patient had coded several times before arriving to the hospital and in the emergency room as well. The patient suffered a significantly devastating loss of brain function and was pronounced brain dead. I believe the saddest part of this whole story is the simple fact that it could have all been prevented with education and medication compliance. Asthma education is extremely important and mandatory to all asthma patients that are treated at our facility. The asthma action plan is an excellent tool and is thoroughly reviewed with each asthma patient and their family before discharge. Unfortunately, a lack of education and medication noncompliance is perhaps one of the greatest reasons why most of the children with asthma exacerbations end up in the PICU. (Am J Public Health. Published online ahead of print August 15, 2013: e1. doi:10.2105/AJPH.2013.301536). 23180324 Safety and efficacy of the Gunther Tulip retrievable vena cava filter: midterm outcomes. To evaluate of the medium-term integrity, efficacy, and complication rate associated with the Gunther Tulip vena cava filter. A retrospective study was performed of 369 consecutive patients who had infrarenal Gunther Tulip inferior vena cava filters placed over a 5-year period. The mean patient age was 61.8 years, and 59% were men. Venous thromboembolic disease and a contraindication to or complication of anticoagulation were the indications for filter placement in 86% of patients; 14% were placed for prophylaxis in patients with a mean of 2.3 risk factors. Follow-up was obtained by review of medical and radiologic records. Mean clinical follow-up was 780 days. New or recurrent pulmonary embolus occurred in 12 patients (3.3%). New or recurrent deep-vein thrombosis occurred in 53 patients (14.4%). There were no symptomatic fractures, migrations, or caval perforations. Imaging follow-up in 287 patients (77.8%) at a mean of 731 days revealed a single (0.3%) asymptomatic fracture, migration greater than 2 cm in 36 patients (12.5%), and no case of embolization. Of 122 patients with CT scans, asymptomatic perforations were identified in 53 patients (43.4%) at a mean 757 days. The Gunther Tulip filter was safe and effective at 2-year follow-up. Complication rates were similar to those reported for permanent inferior vena cava filters. 23140136 Comparative analysis of four oxidized guanine lesions from reactions of DNA with peroxynitrite, singlet oxygen, and γ-radiation. Oxidative damage to DNA has many origins, including irradiation, inflammation, and oxidative stress, but the chemistries are not the same. The most oxidizable base in DNA is 2-deoxyguanosine (dG), and the primary oxidation products are 8-oxodG and 2-amino-imidazolone. The latter rapidly converts to 2,2-diamino-oxazolone (Ox), and 8-oxodG is further oxidized to spiroiminodihydantoin (Sp) and guanidinohydantoin (Gh). In this study, we have examined the dose-response relationship for the formation of the above four products arising in calf thymus DNA exposed to gamma irradiation, photoactivated rose bengal, and two sources of peroxynitrite. In order to carry out these experiments, we developed a chromatographic system and synthesized isotopomeric internal standards to enable accurate and precise analysis based upon selected reaction monitoring mass spectrometry. 8-OxodG was the most abundant products in all cases, but its accumulation was highly dependent on the nature of the oxidizing agent and the subsequent conversion to Sp and Gh. Among the other oxidation products, Ox was the most abundant, and Sp was formed in significantly greater yield than Gh. 23868473 Chemoenzymatic Synthesis of the Immunoglobulin Domain of Tim-3 Carrying a Complex-Type N-Glycan by Using a One-pot Ligation. Ligations: The title immunoglobin (Ig) domain was chemoenzymatically synthesized. The domain was divided into three segments and N- and S-protected peptide thioesters were synthesized by solid-phase peptide synthesis. The one-pot sequential ligation was achieved by using Ag(+) -free and Ag(+) -assisted activation of the thioester. After folding and enzymatic transfer of the synthetic glycan, the desired Ig domain carrying a nonasaccharide was successfully obtained. 23649771 Genetic variation of the CYP17 and susceptibility to endometrial cancer: a meta-analysis. Excessive estrogenic influence is known to be associated with initiation/promotion of endometrial cancer (EC). Common variants among genes coding for enzymes in sex steroid biosynthetic pathways may influence the risk of EC. Cytochrome P450c17α (CYP17), a gene that codes for a key enzyme (cytochrome P450c17α) in a rate-limiting step of estrogen biosynthesis has attracted considerable attention as a candidate gene for EC. The relationship between CYP17 and EC has been reported in various ethnic groups; however, these studies have yielded contradictory results. To investigate this inconsistency, we performed a meta-analysis of 13 studies involving a total of 3,258 cases and 4,614 controls for -34T>C (rs743572) polymorphism of the CYP17 gene to evaluate the effect of CYP17 on genetic susceptibility for EC. An overall random effects odds ratio of 0.71 (95 % confidence interval 0.58-0.88, P = 0.001) was found under recessive genetic model. Stratified analysis based on ethnicity, sample size and Hardy-Weinberg equilibrium status was conducted to explore potential heterogeneity. This meta-analysis demonstrated that the C allele of -34T>C in CYP17 is a protective factor associated with decreased EC susceptibility, but these associations vary in different ethnic populations. 23640214 Acute lymphocytic leukemia presented as back pain and revealed by bone scintigraphy. A previously healthy 8-year-old girl underwent MDP bone scintigraphy to evaluate possible spondylolysis due to worsening back pain. Unexpectedly, the bone scan images revealed intense activity in several thoracic and lumbar vertebrae, which was not consistent with spondylolysis. Further examinations proved that the patient had acute lymphocytic leukemia. 23958432 CT imaging with fistulography for perianal fistula: does it really help the surgeon? To prospectively evaluate the relative accuracy of computed tomography (CT) fistulography for preoperative assessment of fistula in ano. Ethical committee approval and informed consent were obtained. A total of 22 patients (15 male and 7 female, age 21-58 years) who were suspected of having fistula in ano underwent preoperative CT fistulography (CTF). The CT images of 0.6 mm were obtained respectively before and after fistulography; contrast-enhanced CT scan was also performed in 22 patients. CTF images were evaluated by two expert radiologists to assess the fistulas in the following respects: (a) the volume-rendered imaging; (b) the extensions of active inflammatory tissue; (c) the internal opening and external opening; (d) the hidden areas of tract or abscess; and (e) the deep abscess adjacent to fistula. CT findings in 18 patients were compared with surgical findings or exam under anesthesia. The CTF findings in 18 cases were basically in accordance with the surgical findings and/or examination findings under anesthesia. Both coronal and transverse planes were useful in assessing the location and direction of tracts or abscesses. Complicated spatial information within the perianal soft tissue about the fistula with secondary ramifications or abscesses can be easily demonstrated to the surgeons. Contrast-enhanced images were useful in assessing the inflammatory lesion activity and infiltrated area. CTF exquisitely depicts the perianal anatomy and shows the fistulous tracks with their associated ramifications, enables selection of the most appropriate surgical treatment, and therefore minimizes all chances of recurrence. 23885909 Personalized oncology in interventional radiology. As personalized medicine becomes more applicable to oncologic practice, image-guided biopsies will be integral for enabling predictive and pharmacodynamic molecular pathology. Interventional radiology has a key role in defining patient-specific management. Advances in diagnostic techniques, genomics, and proteomics enable a window into subcellular mechanisms driving hyperproliferation, metastatic capabilities, and tumor angiogenesis. A new era of personalized medicine has evolved whereby clinical decisions are adjusted according to a patient's molecular profile. Several mutations and key markers already have been introduced into standard oncologic practice. A broader understanding of personalized oncology will help interventionalists play a greater role in therapy selection and discovery. 23962440 Treatment of depression in diagnosed diabetes: common cause or detection bias? This study examined two competing hypotheses concerning the association between diabetes and treatment for depression: (1) the detection/ascertainment bias hypothesis suggesting that those with diabetes are more likely to be diagnosed with and treated for depression because of increased medical attention and (2) a hypothesis assuming that diabetes and depression share common underlying pathophysiological pathways. The study population included all persons aged 35-65 years in Finland with any record of type 2 diabetes in the national health and population registers from 1999 to 2002 and for whom register-based data on depression treatment (antidepressant medication use and hospitalizations for depression) were available at least 2 years before and after the diagnosis of diabetes (n = 18 217). Sociodemographic data were individually linked to the study population. Associations between diabetes diagnosis and time and indicators of depression care were assessed with population-averaged multilevel logistic models. Within the year following diagnosis diabetes, there was a 5% increase in antidepressant medication use but not in hospitalization for depression. The longitudinal change in antidepressant use over time was less steep after the diabetes diagnosis, and hospitalization risk decreased after the diagnosis. These associations between diabetes diagnosis and depression treatment were not modified by the participant's socio-economic position (SEP). These findings support the common cause hypothesis that treatment for diabetes is beneficial to the prevention of depression rather than the detection/ascertainment hypothesis that individuals with diabetes have higher rates of depression because they receive more medical attention in general. 23931567 Enigmas regarding the true extent and impact of tyrosine kinase inhibitor-related cardiotoxicity. Cardiac sequelae of anticancer treatment remains a major concern among both oncologists and cardiologists caring for patients treated with potentially cardiotoxic regimens. While the toxicity of anthracyclines is well understood to destroy myocytes, the scenario with regard to newer agents, both monoclonal antibodies and small-molecule tyrosine kinase inhibitors, is substantially different. This article differentiates the toxicity of agents that directly destroy myocytes (type I agents) from those that are associated with cardiac damage more indirectly (type II agents). Some mechanistic considerations regarding type II toxicity, albeit not categorically proven, are presented. 23951343 Leukocyte proliferation and immune modulator production in patients with chronic kidney disease. In Chronic Kidney Disease (CKD), immune cells are affected by uremic retention toxins. Given this effect, we analyzed lymphocyte proliferative response and immune modulators production following in vitro stimulation. Whole blood was drawn from healthy controls, patients with eGFR <20 ml/min/1.73 m(2) (Pre-dialysis, CKD stages 4 and 5) and hemodialysis patients (stage 5D). Peripheral cells were incubated for six days with pokeweed mitogen, concanavalin A, Staphylococcus enterotoxin A or influenza A vaccine. Peripheral lymphocyte proliferation was then analyzed by the "Flow-cytometric Assay of Specific Cell-mediated Immune response in Activated whole blood" (FASCIA) method, and cytokine profile in the cell supernatants was analyzed by the Milliplex multi-array method. The absolute number of lymphoblasts in response to mitogenic stimulation and the number of cells in each CD4+ and CD8+ subpopulation were similar comparing the three groups, except for a single decline in number of lymphoblasts after stimulation with Staphylococcus enterotoxin A, comparing dialysis patients with healthy controls. Levels of interleukin (IL)-2 (p=0.026), -10 (p=0.019) and -15 (p=0.027) in the Staphylococcus enterotoxin A-stimulated supernatant were lower in hemodialysis patients compared to healthy controls. Levels of IL-15 (p=0.017) from pre-dialysis patients and levels of IL-5 (p=0.019) from hemodialysis patients in influenza A vaccine-stimulated supernatants were also lower compared to controls. In pokeweed mitogen-stimulated supernatant, IL-2 levels (p=0.013) were lower in hemodialysis patients compared to pre-dialysis patients. TNF-α, IL-10, IL-12, IL-15, IL-8, MCP-1, IP-10, IFN-α2, IL-1α and eotaxin levels were all significantly higher in plasma obtained from CKD patients. Our results suggest that T-cells from CKD patients have similar proliferative response to stimulation compared with healthy individuals. Moreover, however the immune cells show inability to produce selected cytokines, most likely due to the uremic milieu or dialysis procedure. 23896023 The influence of smoking intensity on the clinicopathologic features and survival of patients with surgically treated non-small cell lung cancer. Smoking is a well-known carcinogen for lung cancer. However, whether smoking affects the biological behavior of lung cancer remains uncertain. This study aimed to investigate the influences of smoking intensity on the clinicopathologic characteristics of and survival in non-small cell lung cancer (NSCLC). We retrospectively reviewed 2238 consecutive patients who underwent surgical resection for NSCLC between 1990 and 2010. Smoking intensity was defined as pack-years (PY). The patients were divided into three groups according to the median value of smoking intensity (40 PY): group A (never smokers), group B (smoking intensity less than 40 PY) and group C (smoking intensity more than 40 PY). There were 1629 (72.8%) male patients, and the mean age was 61.71±13.17 years. Adenocarcinoma was reported in 1058 (47.3%) patients. The median follow-up period was 30.7 months (range: 0.0-261.7 months). The 5-year overall survivals for groups A, B and C were 60.1%, 51.6% and 43.2%, respectively (p<0.001). In subset analysis by histology, the 5-year overall survival was significantly different according to smoking intensity in adenocarcinoma (p<0.001), but there was no difference in the non-adenocarcinoma. In adenocarcinoma, the incidences of vascular invasion (p=0.028), pleural invasion (p=0.013) and poor differentiation (p<0.001) were higher and tumor sizes (p<0.001) were greater in group C than others. On multivariate analysis, smoking intensity was an adverse risk factor for overall survival in surgically treated adenocarcinoma patients (hazard ratio=1.008, p=0.028). Smoking intensity was an adverse prognostic factor after surgical resection of adenocarcinoma. Heavy smoking was correlated with poor pathologic characteristics in adenocarcinoma. 23477884 Survival after partial breast brachytherapy in elderly patients with nonmetastatic breast cancer. Despite growing utilization of accelerated partial breast irradiation using brachytherapy (APBI-Brachy) for elderly breast cancer patients, there are limited data from randomized Phase III trials to support its routine use. This study uses population-based data to examine whether APBI-Brachy results in comparable survival rates compared with whole breast irradiation (WBI). A sample of 29,647 female patients diagnosed with nonmetastatic breast cancer in 2002-2007 treated with breast-conserving surgery and radiotherapy was identified in the Surveillance, Epidemiology, and End Results Program-Medicare data set. Log-rank tests, Cox proportional hazards models, instrumental variable analysis, and subgroup analysis were used to study the comparative effectiveness of APBI-Brachy and WBI. During a median followup of 3.6 and 4.8 years, 123 (7.7%) and 3438 (13.6%) patients died after APBI-Brachy and WBI, respectively. Recurrence-free survival (p = 0.9711) and overall survival rates (p = 0.0551) did not differ significantly between the two radiation modalities. After accounting for tumor characteristics, patient characteristics, community factors, and comorbidities, the recurrence-free survival (hazard ratio, 1.05; 95% confidence interval, 0.90-1.23; p = 0.5125) and overall survival (hazard ratio, 0.87; 95% confidence interval, 0.72-1.04; p = 0.1332) rates were still not significantly different between patients treated with APBI-Brachy and WBI. Partial breast brachytherapy and WBI resulted in similar recurrence-free and overall survival rates in this cohort of elderly breast cancer patients, even after adjustment for the more favorable characteristics of patients in the former group. These findings will need to be confirmed by the randomized trials comparing these modalities. 23881702 Isoalantolactone, a sesquiterpene lactone, induces apoptosis in SGC-7901 cells via mitochondrial and phosphatidylinositol 3-kinase/Akt signaling pathways. Isoalantolactone, a sesquiterpene lactone, possesses anti-fungal as well as cytotoxic properties. In this study, the effects of Isoalantolactone on cell viability, cell cycle, and apoptosis were investigated in human gastric adenocarcinoma SGC-7901 cells. The results demonstrated that Isoalantolactone induced morphological changes and decreased cell viability. Subsequently, we found that Isoalantolactone induced G2/M and S phase arrest, which was associated with a decrease in the expression level of cyclin B1. Apoptosis triggered by Isoalantolactone was visualized using propidium iodide (PI) and Annexin V-FITC/PI staining. Isoalantolactone-induced apoptosis of SGC-7901 cells was associated with the dissipation of mitochondrial membrane potential (ΔΨ m) that was due to the down-regulation of Bcl-2 and up-regulation of Bax that led to the cleavage of caspase-3. Additionally, it was found that Isoalantolactone was involved in the inhibition of phosphorylation of PI3K/Akt. Isoalantolactone-induced cytotoxicity and apoptosis of SGC-7901 cells involve mitochondria-caspase and PI3K/Akt dependent pathways, which gives the rationale for in vivo studies on the utilization of Isoalantolactone as a potential cancer therapeutic compound. 23830746 Conscious sedation/local anesthesia in the office-based surgical and procedural facility. The safety, efficacy, and rapid recovery of conscious sedation/local anesthesia make this anesthetic technique useful in the ambulatory setting. The care of the sedated patient requires a team effort. The individual role and responsibility of patient, surgeon, anesthesia provider, and nursing staff are discussed. Using data obtained from a series of 1400 consecutive cases, the authors' experience with conscious sedation/local anesthesia is presented. The current technique, using low-dose propofol, is described in detail. Using conscious sedation, the patient's level of consciousness is depressed, but respiratory drive and airway reflexes are maintained and anesthesia is provided by infiltration of local anesthetic. 23947517 An official american thoracic society/european respiratory society statement: the role of the pulmonologist in the diagnosis and management of lung cancer. Background: Lung cancer is a common problem seen by pulmonologists. The American Thoracic Society (ATS) and European Respiratory Society (ERS) are professional organizations whose memberships are composed of large numbers of pulmonologists. Purpose: This document describes the key role of pulmonologists in the prevention, early diagnosis, and management of lung cancer. Methods: A committee of ATS and ERS leaders and their oncology groups discussed the activities of pulmonologists in relation to lung cancer in various settings and reviewed available literature on the topic. The content of this statement was approved by the board of directors of both the ATS and ERS. Results: Optimal lung cancer care requires a multidisciplinary team of specialists who care for a significant number of patients on a regular basis. Pulmonologists are responsible for and involved with patients from their initial diagnosis and staging through treatment and restaging. They are often involved with complications, palliative care, and end-of-life care, and thus have an important role in team leadership. Conclusions: Lung cancer is a disease with high mortality, profound effects on the quality of the lives of patients and their families, and an enormous cost and impact on society. To treat lung cancer optimally, care must be prompt, multidisciplinary, and patient-centered. In the entire process, pulmonologists have a key role. Pulmonologists and their professional societies should also enhance lung cancer research and education to provide better treatment options and patient care. 23829303 Cardiac involvements in myasthenia gravis associated with anti-Kv1.4 antibodies. There is no general consensus as to whether autoimmune myasthenia gravis (MG) is associated with heart diseases, despite the fact that myocarditis, a serious cardiac involvement treatable by immunotherapy, is a complication of MG. It has been observed previously that MG patients with clinically suspected myocarditis had anti-Kv1.4 antibodies. The purpose of this study was to disclose the association between anti-Kv1.4 antibodies and cardiac involvements in MG patients. Anti-Kv1.4 antibody was detected by an immunoprecipitation assay using (35) S-labeled rhabdomyosarcome cellular extract as the antigen source. Cardiac findings including electrocardiography (ECG) and clinical features of clinically suspected myocarditis in MG patients with anti-Kv1.4 antibodies were investigated. Ultrasound echocardiography (UCG) of ex vivo chick embryos was performed to determine the suppressive effects of sera with or without anti-Kv1.4 antibodies on heart muscle functions. Seventy (10.8%) of 650 MG patients had anti-Kv1.4 antibodies and 60% of them had abnormal ECG findings with high frequencies of T-wave abnormality and QT prolongation. Clinically suspected myocarditis was found in eight MG patients with anti-Kv1.4 antibodies but in none of the MG patients without anti-Kv1.4 antibodies. Most patients showed rapid deterioration with lethal arrhythmias such as ventricular tachycardia, sick sinus syndrome, or complete atrial ventricular block and severe heart failure. It was concluded using UCG of ex vivo chick embryos that MG serum with anti-Kv1.4 antibodies suppressed heart muscle functions. It has been demonstrated that anti-Kv1.4 antibodies are possible markers for cardiac involvements in MG patients. 23583635 Insights into mast cell functions in asthma using mouse models. Therapeutics targeting specific mechanisms of asthma have shown promising results in mouse models of asthma. However, these successes have not transferred well to the clinic or to the treatment of asthma sufferers. We suggest a reason for this incongruity is that mast cell-dependent responses, which may play an important role in the pathogenesis of both atopic and non-atopic asthma, are not a key component in most of the current asthma mouse models. Two reasons for this are that wild type mice have, in contrast to humans, a negligible number of mast cells localized in the smaller airways and in the parenchyma, and that only specific protocols show mast cell-dependent reactions. The development of mast cell-deficient mice and the reconstitution of mast cells within these mice have opened up the possibility to generate mouse models of asthma with a marked role of mast cells. In addition, mast cell-deficient mice engrafted with mast cells have a distribution of mast cells more similar to humans. In this article we review and highlight the mast cell-dependent and -independent responses with respect to airway hyperresponsiveness and inflammation in asthma models using mast cell-deficient and mast cell-engrafted mice. 23907592 Locating Pb(2+) and Zn (2+) in Zinc Finger-Like Peptides Using Mass Spectrometry. The binding preferences of Pb(2+)and Zn(2+) in doubly charged complexes with zinc finger-like 12-residue peptides (Pep), [Mn(Pep-2(n-1)H)](2+) have been explored using tandem mass spectrometry. The peptides were synthesized strategically by blocking the N-terminus with an acetyl group and with four cysteine and/or histidine residues in positions 2, 5, 8, and 11, arranged in different motifs: CCHH, CHCH, and CCCC. The MS(2) spectra of the Pb(2+) and Zn(2+) complexes show multiple losses of water and a single methane loss and these provide a sensitive method for locating the metal dication and so elucidating its coordination. The elimination of a methane molecule indicated the position of the metal at the Cys2 residue. Whereas lead was observed to preferentially bind to cysteine residues, zinc was found to primarily bind to histidine residues and secondarily to cysteine residues. Preferential binding of lead to cysteine is preserved in the complexes with more than one Pb(2+). Key to the mechanism of the loss of water and methane is the metal dication withdrawing electrons from the proximal amidic nitrogen. This acidic nitrogen loses its hydrogen to an amidic oxygen situated four atoms away leading to formation of a five-member ring and the elimination of water. 23949645 Interventions to Improve the Physical Function of ICU Survivors - A Systematic Review. Intensive care unit admissions are ever increasing across the US. Following critical illness, physical functioning (PF) may be impaired for up to 5 years. We performed a systematic review of randomized controlled trials (RCT) evaluating the efficacy of interventions targeting PF among ICU survivors. To identify effective interventions that improve long-term PF in ICU survivors. MEDLINE, EMBASE, CINAHL and PEDro were searched between 1990 and 2012. Two reviewers independently evaluated studies for eligibility; critically appraised the included studies; and extracted data into standardized evidence tables. Fourteen studies met the inclusion criteria. Interventions included exercise/physical therapy (PT), parenteral nutrition, nurse-led follow-up, spontaneous awakening trials, absence of sedation during mechanical ventilation, and early tracheotomy. Ten studies failed to demonstrate efficacy on PF of the ICU survivors. However, early physical exercise and PT based interventions had a positive effect on long-term PF. The only effective intervention to improve long-term PF in critically ill patients is exercise/PT; its benefit may be higher if started earlier. Further research in this area comparing different interventions and timing is needed. 23921786 Can serum angiogenin be used to improve the diagnostic performance in prostate cancer screening? Several biomarkers have been studied to avoid unnecessary biopsies resulting from suboptimal performance of prostate-specific antigen (PSA) testing. We aimed to assess the use of serum angiogenin as a prostate cancer diagnostic tool among candidates for biopsy. We selected 252 patients referred for ultrasound-guided transrectal prostate biopsy on the basis of an abnormal digital rectal examination and/or elevated total PSA. Serum angiogenin was quantitatively analyzed by solid-phase enzyme-linked immunosorbent assay. Results of the prostatic pathology assessment (cancer vs. noncancer) were defined by biopsy. The median serum angiogenin levels were significantly higher in patients with prostate cancer (median: 487 500 vs. 414 800 pg/ml, P=0.008). Among patients with baseline tPSA of 4.0 ng/ml or less, 37.5% had serum angiogenin less than 389 000 pg/ml (sensitivity: 88.9%; specificity: 45.2%), and the probability of having prostate cancer varied from 22.5% before testing to 6.7% among those with low angiogenin levels. When further restricting the analyses to a group of patients with even lower probability of having cancer, on the basis of tPSA and f/t PSA values, the evaluation of serum angiogenin did not contribute toward a meaningful variation in the post-test probability of cancer. In conclusion, serum angiogenin levels may be useful to distinguish between cancer and noncancer patients among the candidates for prostatic biopsy in regular clinical practice. Further investigation is needed among patients with low PSA levels and to understand the relation between this biomarker and the long-term survival of prostate cancer patients. 23587917 ERp57/PDIA3 binds specific DNA fragments in a melanoma cell line. ERp57/PDIA3 is a ubiquitously expressed disulfide isomerase protein, which acts in concert with calreticulin and calnexin in the folding of glycoproteins destined to the plasma membrane or to be secreted. Its canonical compartment is the endoplasmic reticulum, where it acts as a chaperone and redox catalyst, but non canonical locations have been described as well, and ERp57 has been found associated with DNA and nuclear proteins. In previous work performed in HeLa cells, ERp57 has been demonstrated to bind specific DNA sequences involved in the stress response. The direct interaction with the DNA sequences identified as ERp57-targeted regions in HeLa cells has now been confirmed in a melanoma cell line. Furthermore, the ERp57 silencing, achieved by RNA interference, has produced a significant down-regulation of the expression of target genes. The possible involvement of other proteins in complex with ERp57 has been studied by an in vitro biotin-streptavidin based binding assay and the interacting protein APE/Ref-1 has been also assessed for its direct association with the ERp57 target regions. In conclusion, nuclear ERp57 interacts in vivo with DNA fragments in melanoma cells and is potentially involved in the transcriptional regulation of its target genes. 23815597 Innate Type 2 Immunity is Associated with Eosinophilic Pleural Effusion in Primary Spontaneous Pneumothorax. Rationale: Eosinophilic pleural effusion (EPE) is characterized by greater than 10% eosinophilia and is frequently associated with air and/or blood in the pleural cavity. Primary spontaneous pneumothorax (PSP), defined as the spontaneous presence of air in the pleural space, is one of the most common causes of EPE. Recent studies have shown that type 2 immune responses play important roles in eosinophilic airway inflammation resulting in pleural pathology. Objective: To determine the predominant immune responses associated with PSP in humans, and to examine whether interleukin (IL)-33, thymic stromal lymphopoietin (TSLP), or type 2 innate lymphoid cell (ILC2) mediated-immune responses are associated factors. Methods: Eosinophil-associated cytokines were measured in the pleural fluid of PSP patients and control subjects. Th2 cell and ILC2 responses in the pleural cavity and peripheral blood were also evaluated by in vitro restimulation and intracellular cytokine staining of T cells and ILC2s in patients with PSP (n=62) and control subjects (n=33). IL-33-mediated IL-5 production by ILC2s was also evaluated. Results: Significantly higher concentrations of IL-5 and eotaxin-3 were detected in the pleural fluid of PSP patients, in addition to significantly higher concentrations of IL-33 and TSLP. Although IL-5 production was induced by IL-33 treatment of ILC2s, other Th2 cell-mediated immune responses were not detected. Conclusions: Our results indicate that innate immune responses characterized by the production of IL-33, TSLP, and IL-5 are associated with the development of EPE in PSP via an ILC2-dependent and Th2-independent mechanism. 23933309 Developmental and hypoxia-induced cell death share common ultrastructural and biochemical apoptotic features in the central nervous system. Hypoxic insults during the perinatal period lead to motor and cognitive impairments that later appear during childhood. In the adult brain, hypoxic events often lead to necrotic neuronal death, depending on the region and intensity of the event. During development an active apoptotic cell death occurs and could be an important variable affecting the hypoxic insult outcome. In the present work we performed a comparative study, in a chick embryo model, of the phenotypes and molecular markers exhibited during developmental and hypoxic cell death (HxCD). Ultrastructural analysis of optic tectum cells of embryos subjected to hypoxia (8% O2, 60min) revealed a clear apoptotic morphology that did not differ from the one exhibited during developmental cell death. Integrity of plasma membrane, condensation of chromatin in round well-defined bodies, and gradual shrinkage of the cell are all hallmarks of the apoptotic process and were present in both control and hypoxic cells. To elucidate if hypoxic and developmental cell deaths share a common mechanism we evaluated the activation of both intrinsic and extrinsic apoptotic pathways. A basal cleavage of caspase-9 and cytochrome c release was observed by co-immunofluorescence in control embryos, but hypoxic insult significantly increased the incidence of this colocalization. Caspase-8 cleavage remained unchanged after the hypoxic insult, suggesting that the extrinsic pathway would not be involved in hypoxic death. We also observed a significant decrease of Akt activation immediately after hypoxia, possibly facilitating the later release of cytochrome c. In addition we analyzed the influence of retinal ganglion cells (RGC) in neuronal survival. Transection of RGC fibers at embryonic day (ED) 3 did not induce any change in developmental and HxCD at ED12. In conclusion, our findings demonstrate that a hypoxic insult in the developing brain triggers the same apoptotic pathway as the active developmental death. 23954274 Comparison of meat quality between eland (Taurotragus oryx) and cattle (Bos taurus) raised under similar conditions. Physical, chemical and sensory characteristics of meat were compared between non-domestic eland (Taurotragus oryx) bulls (n=6) and domestic Fleckvieh (Bos taurus) bulls (n=6) which were finished under controlled conditions of feeding and management. Musculus longissimus lumborum from eland were darker and less yellow in colour, with a higher pH24 and lower contents of intramuscular fat and total collagen, compared to cattle. Contents (mg/100g muscle tissue) and proportions (g/100g of FA determined) of SFA and MUFA were higher (P<0.01) in cattle. Although the proportion of total PUFA were higher (P<0.001) in eland, contents of PUFA were similar between species. Meat from cattle was consistently scored higher (P<0.05) for sensory texture characteristics, juiciness, flavour, and overall acceptance. We concluded that bulls of eland provided low-fat meat with a beneficial fatty acid composition from a human nutrition perspective, but with lower sensory scores, compared to bull beef. 23022015 Developmental effects of prenatal di-n-hexyl phthalate and dicyclohexyl phthalate exposure on reproductive tract of male rats: Postnatal outcomes. The present study is to investigate the effects of in utero di-n-hexyl phthalate (DHP) and dicyclohexyl phthalate exposure (DCHP) on the development of male reproductive tract at prepubertal, pubertal and adult stages. Pregnant rats were exposed to DHP and DCHP at doses of 0, 20, 100 and 500mg/kg/day, by gavage, on gestational days (GD) 6-19. Testosterone (T) levels of prepubertal rats diminished at high dose DHP and middle dose DCHP groups. MIS/AMH levels elevated in DHP and DCHP groups. T levels of pubertal rats decreased in low and high dose DHP and DCHP groups. Inhibin B levels of adult rats diminished in DCHP groups. Atrophic and amorphous tubules, spermatogenic cell debris, apoptotic cells, adherent tubules, Sertoli cell vacuolisation, prostatic atrophic tubules and prostatic intraepithelial neoplasia (PIN) were observed in the reproductive organs of treated animals at all developmental stages. There was an increase in immunoexpression of MIS/AMH in testes of treated rats. There were no changes in sperm head count but percentages of abnormal sperms increased. The diameters of seminiferous and epididymal tubules in treatment groups were significantly lower. This study shows that DHP and DCHP may have antiandrogenic effects on male reproductive development before and after birth. 23522926 Antitumor effects obtained by autologous Lewis lung cancer cell vaccine engineered to secrete mouse interleukin 27 by means of cationic liposome. Interleukin-27 (IL-27), a novel IL-6/IL-12 family cytokine, plays an important role in the early regulation of Th1 responses. The cytokine IL-27 can exert a variety of immune-regulatory functions including cytotoxic T lymphocyte (CTL), CD4+, CD8+ T lymphocytes activation and interferon-γ (IFN-γ) production. In this study, we developed an effective and gene modified tumor cell vaccine. Lewis lung cancer cell LL/2 transfected with the DOTAP:cholesterol cationic liposome could express the mouse IL-27 (mIL-27) gene at a relative high level. The resultant transfectants were then irradiated with X-ray and used as a tumor cell vaccine. This tumor cell vaccine not only contained tumor associated antigen (TAA) of LL/2 cells but also secreted mIL-27 which could induce immune response in mice. The mice vaccinated with LL/2-mIL-27 performed strong tumor inhibiting effect accompanied with a high IFN-γ production. Both CD4+ and CD8+ T lymphocytes were significantly elevated in these mice vaccinated with LL/2-mIL-27 cell vaccine. Moreover, after depletion of CD4+, CD8+ T lymphocytes by injection of antibodies against CD4 and CD8, the vaccinated mice inoculated with autologous LL/2 cells were not protected from tumor challenge. In contrast, vaccinated mice inoculated with autologous LL/2 cells were treated with antibody against natural killer (NK)cells or normal rat IgG still possessed strong antitumor activity. Our data suggested that DOTAP:cholesterol cationic liposome was quite useful in generating an autologous tumor cell vaccine and mIL-27 could be therapeutically used to potentiate the host antitumor immunity. 23556444 Institutional Profile: Jayne Haines Center for Pharmacogenomics and Drug Safety: educating future generations of healthcare professionals. The Jayne Haines Center for Pharmacogenomics and Drug Safety operates in the Temple University School of Pharmacy and serves as an educational and research facility for professional pharmacy students, graduate students, residents, postdoctoral fellows and faculties. The Center is involved in educational and investigational projects in a setting that includes an inner city research/teaching hospital and the Temple University Schools of Pharmacy, Medicine, Dentistry and Health Professions. The mission of the Haines Center is to facilitate the basic science approach to the problems of pharmacotherapy, and to provide education for future healthcare professionals in the genetics of drug response. With the expanding role of genetic analysis in preventing adverse effects of pharmacotherapy, we are working towards truly personalized pharmacotherapy that fully exploits the advances of modern biomedical science. 23917643 Magnetic Resonance Imaging Morphology and Morphometry of the Coccyx in Coccydynia. Study Design. Retrospective case-control study.Objective. To determine if differences exists between the bony anatomy of the coccyx in patients with coccydynia and that in subjects with no known coccygeal pathology.Summary of Background Data. Numerous bony characteristics of the coccyx have been described in patients with coccydynia but their significance is uncertain. This study aimed to evaluate these in patients with coccydynia and compare them with normal coccyges.Methods. Magnetic resonance scans of the coccyx from 107 adults (mean age 43 ± 12 years; 84 females) with clinically diagnosed coccydynia were retrospectively analysed and compared with 112 CT scans from sex-matched adults with normal coccyges. The following were assessed: coccygeal segmentation; sacrococcygeal and intercoccygeal joint fusion, angles and curvature; bony spicule formation; and subluxation.Results. Compared to normal, women with coccydynia had a more ventrally curved coccyx (curvature index 85 ± 7 versus 90 ± 5; P<0.01), a lower prevalence of sacrococcygeal joint fusion (27% versus 58%, P<0.01), and a higher frequency of bony spicule formation (44% versus 19%, P<0.01). Men with coccydynia showed a trend towards a more ventrally curved coccyx (curvature index: 86 ± 6 versus 89 ± 5, P<0.08), and a lower prevalence of sacrococcygeal (27% versus 60%, P<0.02) and intercoccygeal (0% versus 22%, P<0.02) joint fusion. Combining statistically significant coccygeal parameters in a logistic regression model yielded sensitivity, specificity and positive predictive values of 72%, 71% and 73%, respectively in females and 52%, 92% and 73%, respectively in males.Conclusions. This is the most detailed comparison of coccygeal morphology and morphometry in adults with and without coccydynia investigated using cross-sectional imaging. Anatomical differences in joint fusion and coccygeal curvature may either predispose to the development of coccydynia or arise as a result of this condition. 23837771 Development and feasibility testing of a smart phone based attentive eating intervention. Attentive eating means eating devoid of distraction and increasing awareness and memory for food being consumed. Encouraging individuals to eat more attentively could help reduce calorie intake, as a strong evidence base suggests that memory and awareness of food being consumed substantially influence energy intake. The development and feasibility testing of a smartphone based attentive eating intervention is reported. Informed by models of behavioral change, a smartphone application was developed. Feasibility was tested in twelve overweight and obese volunteers, sampled from university staff. Participants used the application during a four week trial and semi-structured interviews were conducted to assess acceptability and to identify barriers to usage. We also recorded adherence by downloading application usage data from participants' phones at the end of the trial. Adherence data indicated that participants used the application regularly. Participants also felt the application was easy to use and lost weight during the trial. Thematic analysis indicated that participants felt that the application raised their awareness of what they were eating. Analysis also indicated barriers to using a smartphone application to change dietary behavior. An attentive eating based intervention using smartphone technology is feasible and testing of its effectiveness for dietary change and weight loss is warranted. 23359490 Effects of short elastin-like peptides on filamentous particles and their transition behavior. While elastin-like polypeptides and peptides (ELPs) have been used for various stimulus-responsive applications, details of their switching remain unclear. We therefore constructed a novel series of filamentous phage particles displaying a high surface density of short ELPs. The surface display of ELPs did not disrupt either particle shape or dimensions, and the resulting ELP-phage particles were colloidally stable over several weeks. However, in spite of a saturating surface density, macroscopic aggregation of ELP-phages cannot be triggered in water. To investigate the underlying mechanisms we examined conformational changes in the secondary structure of the phage proteins by circular dichroism and tryptophan fluorescence, which indicate partial protein unfolding in ELP-phage particles. To gain further insight into the ELP itself, analogous "free" ELP peptides were synthesized and characterized. Circular dichroism of these peptides shows the onset of β-type conformations with increasing temperature, consistent with the accepted view of the microscopic transition that underlies the inverse phase behavior of ELPs. Increased guest residue hydrophobicity was found to depress the microscopic transition temperature of the peptides, also consistent with a previously proposed intramolecular hydrogen-bonding mechanism. Importantly, our results indicate that although the nanoscale presentation state can suppress macroscopic aggregation of ELPs, microscopic transitions of the ELP can still occur. Given the growing use of ELPs within supra-molecular scaffolds, such effects are important design considerations for future applications. 23791144 Evaluating the performance of different multicolumn setups for chromatographic separation of proteins on hydrophobic interaction chromatography media by a numerical study. A theoretical study has been performed on the effectiveness of isolating a target component out of a multi-component protein mixture using different arrangements of chromatographic columns. Three continuous systems have been considered which were able to perform solvent gradient separations, such as: open loop simulated moving bed, countercurrent solvent gradient purification and carousel multicolumn setup. The performance of the continuous processes was examined with respect to productivity, yield and eluent consumption and compared to a single-column batch system. As a case study separation of a ternary mixture of proteins on HIC media has been selected. Two separation problems have been analyzed referring to the situation when the target component was the most strongly adsorbed as well as when it exhibited intermediate adsorption strength. A mathematical model has been used to simulate the process dynamics and to optimize operating conditions for the separation. The numerical study indicated that batch column arrangements can outperform SMB-based configurations regarding all performance indicators considered, which has been attributed to solvent mixing in the recycled streams and distortion of the gradient shape in SMB units. It has been concluded that the performance of complex multicolumn systems should be verified vs. batch column operations prior to the realization of the separation process. 23404373 Metabolism-Dependent Inhibition of CYP3A4 by Lapatinib: Evidence for Formation of a Metabolic Intermediate Complex with a Nitroso/Oxime Metabolite Formed via a Nitrone Intermediate. Metabolism-dependent inhibition (MDI) of cytochrome P450 (P450) enzymes has the potential to cause clinically relevant drug-drug interactions. In the case of several alkylamine drugs, MDI of P450 involves formation of a metabolite that binds quasi-irreversibly to the ferrous heme iron to form a metabolic intermediate (MI) complex. The specific metabolites coordinately bound to ferrous iron and the pathways leading to MI complex formation are the subject of debate. We describe an approach combining heme iron oxidation with potassium ferricyanide and metabolite profiling to probe the mechanism of MI complex-based CYP3A4 inactivation by the secondary alkylamine drug lapatinib. Ten metabolites formed from lapatinib by CYP3A4-mediated heteroatom dealkylation, C-hydroxylation, N-oxygenation with or without further oxidation, or a combination thereof, were detected by accurate mass spectrometry. The abundance of one metabolite, the N-dealkylated nitroso/oxime lapatinib metabolite (M9), correlated directly with the prevalence or the disruption of the MI complex with CYP3A4. Nitroso/oxime metabolite formation from secondary alkylamines has been proposed to occur through two possible pathways: (1) sequential N-dealkylation, N-hydroxylation, and dehydrogenation (primary hydroxylamine pathway) or (2) N-hydroxylation with dehydrogenation to yield a nitrone followed by N-dealkylation (secondary hydroxylamine pathway). All intermediates for the secondary hydroxylamine pathway were detected but the primary N-hydroxylamine intermediate of the primary hydroxylamine pathway was not. Our findings support the mechanism of lapatinib CYP3A4 inactivation as MI complex formation with the nitroso metabolite formed through the secondary hydroxylamine and nitrone pathway, rather than by N-dealkylation to the primary amine followed by N-hydroxylation and dehydrogenation as is usually assumed. 23899089 Autocatalytic-Assisted Photorelease of a Sensitizer Drug Bound to a Silica Support. The photorelease of a sensitizer from a fluorinated silica surface occurs by a reaction of singlet oxygen with the vinyl ether bond linker with scission of a dioxetane intermediate. Irradiation of the released sensitizer generates singlet oxygen, which accelerates the release of more sensitizer via an autocatalytic reaction. Sigmoidal behavior of sensitizer release in n-butanol and n-octanol occurs at an optimal temperature of 20 °C. The photorelease efficiency was reduced at low temperatures, where the sensitizer was retained on the surface due to a long-lived dioxetane with inefficient scission, and also reduced at high temperatures, due to a slower reaction of (1)O2 with the vinyl ether bond. Immediate acceleration is a result of released sensitizer being used as a dopant to eliminate the induction step, further implicating an autocatalytic mechanism. However, the sigmoidal sensitizer release was not correlated to solvent viscosity, heat, or light from the dioxetane decomposition or to minor O2 solubility enhancements caused by the fluorinated silica. The mechanistic information collected here can be used to help control the pace of drug release; however, it remains to be seen whether an autocatalytic-based drug delivery system has an advantage to those with non-sigmoidal kinetics. 23894273 A microfluidic device for preparing next generation DNA sequencing libraries and for automating other laboratory protocols that require one or more column chromatography steps. Library preparation for next-generation DNA sequencing (NGS) remains a key bottleneck in the sequencing process which can be relieved through improved automation and miniaturization. We describe a microfluidic device for automating laboratory protocols that require one or more column chromatography steps and demonstrate its utility for preparing Next Generation sequencing libraries for the Illumina and Ion Torrent platforms. Sixteen different libraries can be generated simultaneously with significantly reduced reagent cost and hands-on time compared to manual library preparation. Using an appropriate column matrix and buffers, size selection can be performed on-chip following end-repair, dA tailing, and linker ligation, so that the libraries eluted from the chip are ready for sequencing. The core architecture of the device ensures uniform, reproducible column packing without user supervision and accommodates multiple routine protocol steps in any sequence, such as reagent mixing and incubation; column packing, loading, washing, elution, and regeneration; capture of eluted material for use as a substrate in a later step of the protocol; and removal of one column matrix so that two or more column matrices with different functional properties can be used in the same protocol. The microfluidic device is mounted on a plastic carrier so that reagents and products can be aliquoted and recovered using standard pipettors and liquid handling robots. The carrier-mounted device is operated using a benchtop controller that seals and operates the device with programmable temperature control, eliminating any requirement for the user to manually attach tubing or connectors. In addition to NGS library preparation, the device and controller are suitable for automating other time-consuming and error-prone laboratory protocols requiring column chromatography steps, such as chromatin immunoprecipitation. 23952898 Symptom profile and outcome of delirium associated with alcohol withdrawal syndrome: A study from India. To study the profile of delirium associated with alcohol withdrawal syndrome (AWS) in a developing country in terms of symptomatology, associated risk factors/physical complications, and outcome. Using a prospective design, 112 patients in whom delirium could be attributed to AWS as either the sole or a contributory cause were assessed by Delirium Rating Scale-Revised-98 and the associated etiological factors were assessed by using delirium etiology checklist. In all patients, delirium was acute in onset and all patients had disturbance of sleep-wake cycle and inattention. Other common symptoms were: disorientation (99.1%), fluctuation in symptoms (97.3%), motor agitation (94.6%), and short-term memory disturbance (92.9%). In terms of delirium etiology checklist etiological categories, besides alcohol withdrawal, the most common factors were metabolic/endocrine abnormalities (76%), followed by organ insufficiency and infection (37% and 35%, respectively). Most patients (67%) improved or recovered completely from delirium during the short stay of 4 days. During the short stay of mean duration of 4 days 13.4% of the patients died during the hospital stay. Delirium associated with alcohol withdrawal is characterized by an acute onset of symptoms with high prevalence of disturbance of sleep-wake cycle, inattention, disorientation, fluctuation in symptoms, motor agitation, and disturbance in short-term memory. There are certain differences in the symptom profile of delirium associated with alcohol withdrawal and that associated with medical-surgical causes. About one-sixth of the patients developing delirium due to alcohol withdrawal die during the short hospital stay of 4 days. (Am J Addict 2013;22:503-509). 23030240 Treatment of supra-alveolar-type defects by a simplified papilla preservation technique for access flap surgery with or without enamel matrix proteins. Background: In this study, we compare the effectiveness of enamel matrix derivative (EMD) associated with a simplified papilla preservation flap (SPPF) technique to SPPF alone when surgically treating supra-alveolar-type defects. Methods: Fifty patients, from 54 initially selected, presenting horizontal bone loss around ≥4 adjacent teeth, were treated by an SPPF technique; 25 participants also received EMD (test group) and 25 patients underwent flap surgery alone (control group). A complete clinical and radiographic examination was performed at baseline and 12 months after treatment. Pre- and post-therapy probing depth (PD), clinical attachment level (CAL), gingival recession (GR), and radiographic bone level (BL) were compared between treatments. Results: After 12 months, PD, CAL, and GR in both groups showed significant differences from baseline (P <0.001). No differences in BL scores were observed within the groups at the 12-month examination. After 1 year, the test group showed significantly (P <0.001) greater PD reduction (3.4 ± 0.7 mm) and CAL gain (2.8 ± 0.8 mm) and a smaller GR increase (0.6 ± 0.4 mm) compared to the control group (PD, 2.2 ± 0.8 mm; CAL, 1.0 ± 0.6 mm; GR, 1.2 ± 0.7 mm.) BL changes did not significantly differ between the experimental groups. Conclusion: The results of this study suggest that combining EMD and SPPF in the treatment of suprabony defects may lead to a greater clinical improvement compared to SPPF alone. 23841731 Delayed puberty and estrogen resistance in a woman with estrogen receptor α variant. Although androgen resistance has been characterized in men with a normal chromosome complement and mutations in the androgen-receptor gene, a mutation in the gene encoding estrogen receptor α (ESR1) was previously described only in one man and not, to our knowledge, in a woman. We now describe an 18-year-old woman without breast development and with markedly elevated serum levels of estrogens and bilateral multicystic ovaries. She was found to have a homozygous loss-of-function ESR1 mutation in a completely conserved residue that interferes with estrogen signaling. Her clinical presentation was similar to that in the mouse orthologue knockout. This case shows that disruption of ESR1 causes profound estrogen resistance in women. (Funded by the National Institutes of Health.). 23899828 Efficacy of exercise for menopausal symptoms: a randomized controlled trial. This study aims to determine the efficacy of exercise training for alleviating vasomotor and other menopausal symptoms. Late perimenopausal and postmenopausal sedentary women with frequent vasomotor symptoms (VMS) participated in a randomized controlled trial conducted in three sites: 106 women randomized to exercise and 142 women randomized to usual activity. The exercise intervention consisted of individual facility-based aerobic exercise training three times per week for 12 weeks. VMS frequency and bother were recorded on daily diaries at baseline and on weeks 6 and 12. Intent-to-treat analyses compared between-group differences in changes in VMS frequency and bother, sleep symptoms (Insomnia Severity Index and Pittsburgh Sleep Quality Index), and mood (Patient Health Questionnaire-8 and Generalized Anxiety Disorder-7 questionnaire). At the end of week 12, changes in VMS frequency in the exercise group (mean change, -2.4 VMS/d; 95% CI, -3.0 to -1.7) and VMS bother (mean change on a four-point scale, -0.5; 95% CI, -0.6 to -0.4) were not significantly different from those in the control group (-2.6 VMS/d; 95% CI, -3.2 to -2.0; P = 0.43; -0.5 points; 95% CI, -0.6 to -0.4; P = 0.75). The exercise group reported greater improvement in insomnia symptoms (P = 0.03), subjective sleep quality (P = 0.01), and depressive symptoms (P = 0.04), but differences were small and not statistically significant when P values were adjusted for multiple comparisons. Results were similar when considering treatment-adherent women only. These findings provide strong evidence that 12 weeks of moderate-intensity aerobic exercise do not alleviate VMS but may result in small improvements in sleep quality, insomnia, and depression in midlife sedentary women. 23900936 Differential proinflammatory responses induced by diesel exhaust particles with contrasting PAH and metal content. Exposure to diesel engine exhaust particles (DEPs), representing a complex and variable mixture of components, has been linked with cellular production and release of several types of mediators related to pulmonary inflammation. A key challenge is to identify the specific components, which may be responsible for these effects. The aim of this study was to compare the proinflammatory potential of two DEP-samples with contrasting contents of polycyclic aromatic hydrocarbons (PAHs) and metals. The DEP-samples were compared with respect to their ability to induce cytotoxicity, expression and release of proinflammatory mediators (IL-6, IL-8), activation of mitogen-activated protein kinases (MAPKs) and expression of CYP1A1 and heme oxygenase-1 (HO-1) in human bronchial epithelial (BEAS-2B) cells. In addition, dithiothreitol and ascorbic acid assays were performed in order to examine the oxidative potential of the PM samples. The DEP-sample with the highest PAH and lowest metal content was more potent with respect to cytotoxicity and expression and release of proinflammatory mediators, CYP1A1 and HO-1 expression and MAPK activation, than the DEP-sample with lower PAH and higher metal content. The DEP-sample with the highest PAH and lowest metal content also possessed a greater oxidative potential. The present results indicate that the content of organic components may be determinant for the proinflammatory effects of DEP. The findings underscore the importance of considering the chemical composition of particulate matter-emissions, when evaluating the potential health impact and implementation of air pollution regulations. © 2013 Wiley Periodicals, Inc. Environ Toxicol, 2013. 23897550 Key intermediates of iodine-mediated electrophilic cyclization: isolation and characterization in an osmabenzene system. Caught in the act: Key intermediates in an iodine-mediated electrophilic cyclization reaction was isolated by introducing metallabenzenes as the starting material. The unique structure of the intermediate should be described as the intimate ion pair form, instead of the widely accepted iodonium ion form. 23266270 Anti-inflammatory effects of trans-1,3-diphenyl-2,3-epoxypropane-1-one mediated by suppression of inflammatory mediators in LPS-stimulated RAW 264.7 macrophages. To assess the potential therapeutic properties of trans-1,3-diphenyl-2,3-epoxypropane-1-one (DPEP), its anti-inflammatory effects were investigated in lipopolysaccharide (LPS)-stimulated mouse macrophage (RAW 264.7) cells. DPEP induced dose-dependent reduction of the protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and concomitant reduction in the production of NO and prostaglandin E(2) (PGE(2)). Additionally, DPEP suppressed the production of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6. We investigated the mechanism by which DPEP inhibits NO and PGE(2) by examining the level of nuclear factor-κB (NF-κB) activation within the mitogen-activated protein kinase (MAPK) pathway, which is an inflammation-induced signaling pathway in RAW 264.7 cells. DPEP inhibited LPS-induced phosphorylation of ERK, JNK, and p38. Furthermore, DPEP inhibited the LPS-induced phosphorylation of inhibitor κB (IκB)-α and NF-κB p50. Taken together, the results of this study demonstrate that DPEP inhibits LPS-stimulated inflammation by blocking the NF-κB and MAPK pathways in macrophages. 23968455 Simultaneous Light-Directed Synthesis of Mirror-Image Microarrays in a Photochemical Reaction Cell with Flare Suppression. The use of photolabile protecting groups is a versatile and well-established means of synthesizing high complexity microarrays of biopolymers-such as nucleic acids and peptides-for high-throughput analysis. The synthesis takes place in a photochemical reaction cell which positions the microarray substrate at the focus of the optical system delivering the light, and which can be connected to a fluidics system which delivers appropriate reagents to the surface in synchrony with the light exposure. Here we describe a novel photochemical reaction cell which allows for the simultaneous synthesis of microarrays on two substrates. The reaction cell positions both substrates within the limited depth-of-focus of the optical system while maintaining the necessary reagent flow conditions. The resulting microarrays are mirror images of each other, but otherwise essentially identical. The new reaction cell doubles the throughput of microarray synthesis without increasing the consumption of reagents. In addition, a secondary flow chamber behind the reaction cell can be filled with an absorbent and index-matching fluid to eliminate reflections from light exiting the reaction cell assembly, greatly reducing unintended light exposure that reduces the sequence fidelity of the microarray probes. 23918563 Late-presenting congenital diaphragmatic hernia in children: the experience of single institution in Korea. Purpose: Late-presenting congenital diaphragmatic hernia (CDH) beyond the neonatal period is rare and often misdiagnosed, with delayed treatment. Materials and Methods: We retrospectively reviewed our experience with late-presenting CDH over 30 years at a single institution to determine the characteristics of late-presenting CDH for early diagnosis. Results: Seven patients had operations due to late-presenting CHD in our institution over 30 years. The patients' ages ranged from 2.5 months to 16 years. There were six boys and one girl. Five hernias were left-sided, one was right-sided and one was a retrosternal hernia. All patients had normal intestinal rotation. Non-specific gastrointestinal or respiratory symptoms and signs were usually presented. Intestinal malrotations were absent; therefore, only organs adjacent to the defect or relatively movable organs such as the small bowel and transverse colon were herniated. Two cases were accompanied by stomach herniation with the volvulus and liver, respectively. The duration from presentation to diagnosis varied from 5 days to 1 year. Diagnoses were made by chest X-ray, upper gastrointestinal series and chest computed tomography. All patients underwent primary repair with interrupted non-absorbable sutures by a transabdominal approach. None had postoperative complications. The follow-up period in six patients ranged from 4 months to 20 years (median 3.8 years). There was no recurrence in any of the patients on follow-up. Conclusion: A high index of suspicion is important for the diagnosis of late-presenting CDH because it can be a life-threatening condition such as CDH with a gastric volvulus. Early diagnosis and appropriate treatment can lead to a good prognosis. 23311998 Covalent Layer-by-Layer Assembly of Redox-Active Polymer Multilayers. Poly(ferrocenyl(3-bromopropyl)methylsilane) and poly(ethylene imine) are employed in a layer-by-layer deposition process to form covalently connected, redox-active multilayer thin films by means of an amine alkylation reaction. The stepwise buildup of these multilayers on silicon, ITO, and quartz substrates was monitored by UV-vis absorption spectroscopy, Fourier transform infrared spectroscopy (FTIR), static contact angle measurements, surface plasmon resonance (SPR), atomic force microscopy, ellipsometry, and cyclic voltammetry, which provide evidence for a linear increase in multilayer thickness with the number of deposited bilayers. Upon oxidation and reduction, these covalently interconnected layers do not disassemble, in contrast to poly(ferrocenylsilane) (PFS) layers featuring similar backbone structures that are held together by electrostatic forces. The PFS/PEI multilayers are effective for the electrochemical sensing of ascorbic acid and hydrogen peroxide and show improved sensing performance at higher bilayer numbers. These covalently linked layers are readily derivatized further and can therefore be regarded as a versatile platform for creating robust, tailorable, redox-active interfaces with applications in sensing and biofuel cells. 23757404 Export of Salicylic Acid from the Chloroplast Requires the Multidrug and Toxin Extrusion-Like Transporter EDS5. Salicylic acid (SA) is central for the defense of plants to pathogens and abiotic stress. SA is synthesized in chloroplasts from chorismic acid by an isochorismate synthase (ICS1); SA biosynthesis is negatively regulated by autoinhibitory feedback at ICS1. Genetic studies indicated that the multidrug and toxin extrusion transporter ENHANCED DISEASE SUSCEPTIBILITY5 (EDS5) of Arabidopsis (Arabidopsis thaliana) is necessary for SA accumulation after biotic and abiotic stress, but so far it is not understood how EDS5 controls the biosynthesis of SA. Here, we show that EDS5 colocalizes with a marker of the chloroplast envelope and that EDS5 functions as a multidrug and toxin extrusion-like transporter in the export of SA from the chloroplast to the cytoplasm in Arabidopsis, where it controls the innate immune response. The location at the chloroplast envelope supports a model of the effect of EDS5 on SA biosynthesis: in the eds5 mutant, stress-induced SA is trapped in the chloroplast and inhibits its own accumulation by autoinhibitory feedback. 23951092 Inhibition of PPARα Induces Cell Cycle Arrest and Apoptosis, and Synergizes with Glycolysis Inhibition in Kidney Cancer Cells. Renal cell carcinoma (RCC) is the sixth most common cancer in the US. While RCC is highly metastatic, there are few therapeutics options available for patients with metastatic RCC, and progression-free survival of patients even with the newest targeted therapeutics is only up to two years. Thus, novel therapeutic targets for this disease are desperately needed. Based on our previous metabolomics studies showing alteration of peroxisome proliferator-activated receptor α (PPARα) related events in both RCC patient and xenograft mice materials, this pathway was further examined in the current study in the setting of RCC. PPARα is a nuclear receptor protein that functions as a transcription factor for genes including those encoding enzymes involved in energy metabolism; while PPARα has been reported to regulate tumor growth in several cancers, it has not been evaluated in RCC. A specific PPARα antagonist, GW6471, induced both apoptosis and cell cycle arrest at G0/G1 in VHL(+) and VHL(-) RCC cell lines (786-O and Caki-1) associated with attenuation of the cell cycle regulatory proteins c-Myc, Cyclin D1, and CDK4; this data was confirmed as specific to PPARα antagonism by siRNA methods. Interestingly, when glycolysis was blocked by several methods, the cytotoxicity of GW6471 was synergistically increased, suggesting a switch to fatty acid oxidation from glycolysis and providing an entirely novel therapeutic approach for RCC. 23831521 Recombinant soluble neprilysin reduces amyloid-beta accumulation and improves memory impairment in Alzheimer's disease mice. Accumulation of amyloid-β (Aβ) is thought to be a central pathology in the brain of patients with Alzheimer's disease (AD). Neprilysin (NEP), a plasma membrane glycoprotein of the neutral zinc metalloendopeptidase family, is known as a major Aβ-degrading enzyme in the brain. The level of NEP is reduced in the brains of patients with AD; therefore, NEP is under intense investigation as a potential therapeutic source for degradation of deposited Aβ in AD. Previous studies have utilized viral vectors expressing NEP for reduction of Aβ deposition in the brain. However, viral vectors have disadvantages regarding difficulty in control of insert size, expression desired (short- or long-term), and target cell type. Here, in order to overcome these disadvantages, we produced recombinant soluble NEP from insect cells using an NEP expression vector, which was administered by intracerebral injection into AD mice, resulting in significantly reduced accumulation of Aβ. In addition, AD mice treated with NEP showed improved behavioral performance on the water maze test. These data support a role of recombinant soluble NEP in improving memory impairment by regulation of Aβ deposition and suggest the possibility that approaches using protein therapy might have potential for development of alternative therapies for treatment of AD. 23014811 Medium and high oxidation state metal/non-metal fluoride and oxide-fluoride complexes with neutral donor ligands. While most high and medium oxidation state (O.S. ≥ 3) metal and non-metal fluorides and oxide fluorides are strong Lewis acids, exploration of their coordination chemistry with neutral ligands has been limited and mostly non-systematic. This is despite the very different properties conferred on the acceptor centre by the small electronegative fluoride ligands compared to the heavier halides. This article sets out these key differences, discusses possible synthetic routes, the key characterisation techniques, and appropriate bonding models. Current knowledge of the coordination chemistry of d, f and p-block fluorides and oxide fluorides with neutral ligands (with donor atoms drawn from Groups 15 and 16 and including N-heterocyclic carbenes) is then presented and discussed, and the differences in properties compared to complexes containing the heavier halides are illustrated. The emphasis is on work published post 1990, but earlier work is also included as essential background and where no more recent information exists. Attention is drawn to unexplored areas meriting investigation and to possible applications of these complexes. 23639189 Lippia alba (Mill.) N. E. Brown hydroethanolic extract of the leaves is effective in the treatment of migraine in women. There is no universally accepted and effective prophylaxis of migraine headache episodes. We aimed to investigate the effects of Lippia alba (Mill.) N. E. Brown (chemotype geranial-carvenone) in the treatment of migraine patients. Twenty-one women were enrolled in a prospective, phase 2, non-controlled cohort study to orally receive hydroethanolic extract of L. alba leaves. Symptom intensity and impact were assessed using MIDAS and HIT-6 instruments before and after 2 months of treatment. We observed a significant decrease on HIT-6 total score, as well as MIDAS number of missed days, number of headache days, and pain intensity. More than 70% of patients experienced a minimum 50% reduction on pain frequency. Treatment with L. alba leaves (geranial-carvenone) hydroethanolic extract is a cheap, safe, widely available, highly effective therapy to reduce both the intensity and the frequency of headache episodes of women with migraine. ClinicalTrials.gov Identifier: NCT01259947. 23182463 Assessing the chemical accuracy of protein structures via peptide acidity. Although the protein native state is a Boltzmann conformational ensemble, practical applications often require a representative model from the most populated region of that distribution. The acidity of the backbone amides, as reflected in hydrogen exchange rates, is exquisitely sensitive to the surrounding charge and dielectric volume distribution. For each of four proteins, three independently determined X-ray structures of differing crystallographic resolution were used to predict exchange for the static solvent-exposed amide hydrogens. The average correlation coefficients range from 0.74 for ubiquitin to 0.93 for Pyrococcus furiosus rubredoxin, reflecting the larger range of experimental exchange rates exhibited by the latter protein. The exchange prediction errors modestly correlate with the crystallographic resolution. MODELLER 9v6-derived homology models at ~60% sequence identity (36% identity for chymotrypsin inhibitor CI2) yielded correlation coefficients that are ~0.1 smaller than for the cognate X-ray structures. The most recently deposited NOE-based ubiquitin structure and the original NMR structure of CI2 fail to provide statistically significant predictions of hydrogen exchange. However, the more recent RECOORD refinement study of CI2 yielded predictions comparable to the X-ray and homology model-based analyses. 23850529 Methylergonovine maleate and the risk of myocardial ischemia and infarction. The purpose of this study was to examine the risk of acute coronary syndrome (ACS) and acute myocardial infarction (AMI) that are associated with methylergonovine maleate (Methergine; Novartis Pharmaceuticals Corporation, Plantation, FL) use in a large database of inpatient delivery admissions in the United States. We conducted a retrospective cohort study using data from the Premier Perspective Database and identified 2,233,630 women who were hospitalized for delivery between 2007 and 2011 (approximately one-seventh of all US deliveries during this period). Exposure was defined by a charge code for methylergonovine during the delivery hospitalization. Study outcomes included ACS and AMI. Propensity score matching was used to address potential confounding. Methylergonovine was administered to 139,617 patients (6.3%). Overall, 6 patients (0.004%) who were exposed to methylergonovine and 52 patients (0.002%) who were not exposed to methylergonovine had an ACS. Four patients (0.003%) who were exposed to methylergonovine and 44 patients (0.002%) in the not-exposed group had an AMI. After propensity score matching, the relative risk for ACS that was associated with methylergonovine exposure was 1.67 (95% confidence interval [CI], 0.40-6.97), and the risk difference was 1.44 per 100,000 patients (95% CI, -2.56 to 5.45); the relative risk for AMI that was associated with methylergonovine exposure was 1.00 (95% CI, 0.20-4.95), and the risk difference was 0.00 per 100,000 patients (95% CI, -3.47 to 3.47). Despite studying a very large proportion of US deliveries, we did not find a significant increase in the risk of ACS or AMI in women who received methylergonovine compared with those who did not; estimates were increased only modestly or not at all. The upper limit of the 95% CI of our analysis suggests that treatment with methylergonovine would result in no more than 5 additional cases of ACS and 3 additional cases of AMI per 100,000 exposed patients. 23828664 Tracking the Down-Regulation of Folate Receptor-α in Cancer Cells through Target Specific Delivery of Quantum Dots Coupled with Antisense Oligonucleotide and Targeted Peptide. Based on the multivalent binding capability of streptavidin (SA) to biotin, a multifunctional quantum dot probe (QD-(AS-ODN+p160)) coupled with antisense oligonucleotide (AS-ODN) and peptide p160 is designed for real-time tracking of targeted delivery of AS-ODN and regulation of folate receptor-α (hFR-α) in MCF-7 breast cancer cells. Fluorescence spectra, capillary electrophoresis (CE) and dynamic light scattering (DLS) are used to characterize the conjugation of AS-ODN and p160 with quantum dots (QDs), DLS results confirm the well stability of the probe in aqueous media. Confocal imaging and quantitative flow cytometry show that QD-(AS-ODN+p160) is able to specifically target human breast cancer MCF-7 cells. Low temperature and ATP depletion treatments reveal the cellular uptake of QD-(AS-ODN+p160) is energy-dependent, and the effects of inhibition agents and co-localization imaging further confirm the endocytic pathway is mainly receptor-mediated. Transmission electron microscopy (TEM) shows the intracellular delivery and endosomal escape of QD probe along with incubation time extended. Two transfection concentrations of QD probe (10 nM and 50 nM) below half inhibitory concentration (IC50 ) value are chosen according to MTT assay. Real-time PCR shows at these two concentration cases the relative mRNA expression levels of hFR-α reduce to 72.5 ± 3.9% and 17.6 ± 1.0%, respectively. However, western blot and quantitative ELISA analysis show the expression level of hFR-α protein has a significant decrease only at 50 nM, indicating that gene silence is concentration-dependent. These results demonstrate that the QD-(AS-ODN+p160) probe not only achieves gene silence in a cell-specific manner but also achieves real-time tracking during AS-ODN intracellular delivery. 23871980 Investigation of interaction of nuclear fast red with human serum albumin by experimental and computational approaches. For the first time, interaction of nuclear fast red (NFR) with human serum albumin (HSA) was studied by experimental and computational approaches. Firstly, experimental measurements including fluorescence spectroscopy (F), UVvis spectrophotometry (UVvis), cyclic voltammetry (CV), differential pulse voltammetry (DPV) and linear sweep voltammetry (LSV) were separately used to investigate the interaction of NFR with HSA and interesting thermodynamics information was obtained from these studies. Secondly, new information including electrochemical behavior of NFR-HSA complex species, relative concentrations of the various reacting species and effects of NFR on the sub-structure of HSA was obtained by applying multivariate curve resolution-alternating least squares (MCR-ALS). In this case, a row- and column-wise augmented matrix was built with DPV, LSV, F and UVvis sub-matrices and resolved by MCR-ALS. Surprisingly, by this method two NFR-HSA complex species with different stoichiometries and different electrochemical behaviors were found. Furthermore, by the use of the recorded voltammetric and spectroscopic data the binding constants of complex species were computed by EQUISPEC (a hard-modeling algorithm). Finally, the binding of NFR to HSA was modeled by molecular modeling and molecular dynamics (MD) simulations methods. Excellent agreement was found between experimental and computational results. Both experimental and computational results suggested that the NFR binds mainly to the sub-domain IIA of HSA. 23776225 General approach to reversing ketol-acid reductoisomerase cofactor dependence from NADPH to NADH. To date, efforts to switch the cofactor specificity of oxidoreductases from nicotinamide adenine dinucleotide phosphate (NADPH) to nicotinamide adenine dinucleotide (NADH) have been made on a case-by-case basis with varying degrees of success. Here we present a straightforward recipe for altering the cofactor specificity of a class of NADPH-dependent oxidoreductases, the ketol-acid reductoisomerases (KARIs). Combining previous results for an engineered NADH-dependent variant of Escherichia coli KARI with available KARI crystal structures and a comprehensive KARI-sequence alignment, we identified key cofactor specificity determinants and used this information to construct five KARIs with reversed cofactor preference. Additional directed evolution generated two enzymes having NADH-dependent catalytic efficiencies that are greater than the wild-type enzymes with NADPH. High-resolution structures of a wild-type/variant pair reveal the molecular basis of the cofactor switch. 23497170 H2-driven cofactor regeneration with NAD(P)+-reducing hydrogenases. A large number of industrially relevant enzymes depend upon nicotinamide cofactors, which are too expensive to be added in stoichiometric amounts. Existing NAD(P)H-recycling systems suffer from low activity, or the generation of side products. H2-driven cofactor regeneration has the advantage of 100% atom efficiency and the use of H2 as a cheap reducing agent, in a world where sustainable energy carriers are increasingly attractive. The state of development of H2-driven cofactor-recycling systems and examples of their integration with enzyme reactions are summarized in this article. The O2-tolerant NAD(+)-reducing hydrogenase from Ralstonia eutropha is a particularly attractive candidate for this approach, and we therefore discuss its catalytic properties that are relevant for technical applications. 23411319 Evolution of flavonoids in Mouratón berries taken from both bunch halves. Galicia (N.W. Spain) is a Spanish region with several old-traditional winegrowing areas. There are autochthonous grapevine varieties, such as Vitis vinifera L. cv. Mouratón, considered a biodiversity resource in viticulture and an opportunity for Galician sustainable wine production. Therefore, it is necessary to assess the potential of traditional cultivars to produce quality red wines. In this work, anthocyanin and flavonol evolution was followed in red berries from V. vinifera L. cv. Mouratón. The novelty of this study is that grapes were separately collected from two different positions (tips and shoulders) within the cluster, over ripening to examine the effects of berry position within the fruit cluster on the flavonoid compounds. Derivatives of five anthocyanins (malvidin, peonidin, petunidin, delphinidin and cyanidin) and derivatives of six flavonols (quercetin, myricetin, kaempherol, laricitrin isorhamnetin and syringetin) were detected in both positions within the cluster. Dynamic of anthocyanins (from 819 mg/kg to 1206 mg/kg in tips; and from 786 mg/kg to 1077 mg/kg in shoulders) and dynamic of flavonols (from 25mg/kg to 41 mg/kg in tips; and from 18 mg/kg to 21 mg/kg in shoulders) confirmed their upward trends over ripening. Grapes located inside the shoulder bunch receive less sunlight radiation than those located inside the tip bunch and this fact could explain the different accumulation observed for both positions. These results can be useful for winemakers in order to obtain different final red wine quality. 23959566 Consumption of a Diet Low in Advanced Glycation Endproducts for 4 weeks Improves Insulin Sensitivity in Overweight Women. ObjectiveHigh heat cooking of food induces formation of advanced glycation endproducts (AGEs), which are thought to impair glucose metabolism in type 2 diabetic patients. High intake of fructose might additionally affect endogenous formation of AGEs. This parallel intervention study investigated whether addition of fructose or cooking methods influencing the AGE content of food affect insulin sensitivity in overweight individuals.Research design and methodsSeventy-four overweight women were randomized to follow either a high- or low-AGE diet for 4 weeks, together with either fructose or glucose drinks. Glucose and insulin concentrations - fasting and 2-h after an oral glucose tolerance test - were measured before and after the intervention. Homeostasis model assessment of insulin resistance (HOMA-IR) and insulin sensitivity index (ISI0,120) were calculated. Dietary and urinary AGE concentrations were measured (LC-MS/MS) to estimate AGE intake and excretion.ResultsWhen adjusted for changes in anthropometric measures during the intervention the low-AGE diet decreased urinary AGEs, fasting insulin, and HOMA-IR, compared with the high-AGE diet. Addition of fructose did not affect any outcomes.ConclusionsDiets with high AGE content may increase development of insulin resistance. AGEs can be reduced by modulation of cooking methods but is unaffected by moderate fructose intake. 23904860 Pathogenic mechanisms linking benign prostatic hyperplasia, lower urinary tract symptoms and erectile dysfunction. Erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) are clinical entities very prevalent in men aged over 50 years. There is evidence that both may have a common pathophysiology. The objective of this study was to conduct a literature review aiming to show theories and hypotheses that justify a single pathophysiology for ED and LUTS/BPH. A search in Medline using the keywords of the Medical Subject Headings (MESH) 'erectile dysfunction' and 'lower urinary tract symptoms' in all fields of the database up to 15 December 2012. This search found 198 relevant articles that were analyzed. The data and articles were divided according to the type of evidence found. There are strong epidemiological data showing that LUTS/BPH is a risk factor for developing ED. Several experimental models demonstrated partial obstruction of the bladder in animals causes voiding disorders as well as a negative impact on erectile function of the operated animals. The increased adrenergic tonus in animals leads to prostate growth and urodynamic conditions similar to those found in men with LUTS and ED. Arteriosclerosis may lead to loss of vesical complacency, urinary tract obstruction and fibrosis of the cavernous bodies. The use of phosphodiesterase type 5 inhibitors (PDE-5i) and/or alpha-adrenergic blockers to treat ED and LUTS/BPH reinforces the hypothesis that, at least in some patients, both clinical pictures may have the same pathophysiology. 23846815 Synthesis and onwards coordination of an as(i) centered zwitterion. The bis(phosphino)borate ligand class is used as an anionic anchor to stabilize reactive, low coordinate arsenic centers. The neutral, zwitterionic As(I) species, 2, is formed very cleanly, and isolated in good yields using cyclohexene as a halogen scavenger. The uniqueness of this heterocyclic As(I) compound is on display with the coordination to Group 6 metal centers, (2 M(CO)5 ; M=Cr, Mo, W). The arsenicmetal bond lengths are longer than the related AsPh3 complexes suggesting that compound 2 is a weak sigma donor. The metal complexes reveal a trigonal pyramidal arsenic atom, which provides the first experimental evidence for the presence of two "lone pairs" of electrons on the As(I) center. When more flexible and more electron-donating isopropyl substituents were used, an intermediate (compound 5) in the formation of low coordinate pnictogen compounds was crystallographically characterized. This structure, formally a base-stabilized dichloroarsenium cation, provides an alternative mechanistic proposal to the one described in the literature. 23879481 Interprofessional education in community-based Alzheimer's disease diagnosis and treatment. Abstract As the population ages and understanding of Alzheimer's disease (AD) improves, the number of older adults diagnosed and treated for AD and related dementias is projected to increase. Dementia diagnosis, treatment and patient and family education are complex processes best done through collaboration among healthcare professions. The educational program described in this article aimed to create an interprofessional team approach to the diagnosis and treatment of dementia involving medical and family nurse practitioner students. A two-group treatment/control pretest posttest design was used to measure changes in knowledge, attitudes and appreciation for an interprofessional team approach to patient care. Findings from this interprofessional program demonstrated that nurse practitioner students gained higher levels of knowledge regarding AD, and medical students gained more positive attitudes toward these patients and their caregivers. Comments from students indicated that both medical and nursing students found the experience valuable. Understanding the roles that various providers play will help healthcare professional meet the challenge of caring for the increasing number of patients with memory loss and for their families. 23241678 The iron regulatory hormone hepcidin is decreased in pregnancy: a prospective longitudinal study. Iron deficiency is a commonly encountered problem in pregnancy and a frequently observed cause of pregnancy-associated anemia. We longitudinally assessed the iron regulatory hormone hepcidin during gestation and postpartum and related hepcidin to conventional indicators of iron status and inflammation. Thirty-one healthy pregnant women were included and 81 blood samples from the three trimesters, directly and 6 weeks postpartum were analyzed for hemoglobin, the iron parameters: iron, total iron binding capacity, transferrin saturation, ferritin, soluble transferrin receptor and hepcidin, and CRP and leucocytes as markers of inflammation. Hepcidin concentration decreased gradually from the first to the second and third trimester to undetectable levels (≤ 0.5 nmol/L) which was paralleled by decreasing hemoglobin levels and changes in iron parameters indicative for iron deficiency. During gestation hepcidin levels correlated with iron parameters, but not with inflammatory markers. Postpartum, hepcidin increased immediately to levels similar as assessed at early pregnancy. We conclude that hepcidin levels were suppressed during the second and third trimester of pregnancy, which was likely determined by the occurrence of iron deficiency. These data give insight in iron homeostasis during normal pregnancy. 23720487 Ethnicity and stroke risk in patients with atrial fibrillation. To examine the prevalence of atrial fibrillation (AF) and stroke risk by ethnic group in south and east London; to compare classification with CHA2DS2VASc and CHADS2; to examine the appropriateness of anticoagulant treatment and historic trends in prescribing by gender, age, and ethnicity. Cross-sectional study. Routine general practice records from south and east London. Patients aged 18 years or over with AF. Risk of stroke by CHA2DS2VASc and CHADS2 score, and prescription of anticoagulant. In 2011, we identified 6292 patients with AF, with an age adjusted prevalence of 0.63% (1.2% white, 0.4% black African/Caribbean and 0.2% South Asian). 93% of the AF population were at high risk of stroke with a CHA2DS2VASc score ≥1, of whom 54% were on warfarin. South Asian patients were at higher stroke risk than white patients (OR 1.67, 95% CI 1.02 to 2.73). Warfarin under-prescribing in people over 80 years of age persisted without improvement throughout 2008-2011. There were no clear differences in warfarin use by ethnic group. Despite a reduced prevalence of AF among South Asian patients, their risk of stroke is higher than for white patients or black African/Caribbean patients in association with diabetes, cardiovascular disease, and hypertension. Under-prescription of anticoagulation persists in all ethnic groups, a deficit most pronounced in the elderly. Use of the CHA2DS2VASc score would enhance optimal management in primary care. 23541434 Pharmacological study of a new Asp49 phospholipase A2 (Bbil-TX) isolated from Bothriopsis bilineata smargadina (forest viper) venom in vertebrate neuromuscular preparations. The neuromuscular activity of Bbil-TX, a PLA2 with catalytic activity isolated from Bothriopsis bilineata smargadina venom, was examined in chick biventer cervicis (BC) and mouse phrenic nerve-diaphragm (PND) preparations. In BC preparations, Bbil-TX (0.5-10 μg/ml) caused time- and concentration-dependent blockade that was not reversed by washing; the times for 50% blockade were 87 ± 7, 41 ± 7 and 19 ± 2 min (mean ± SEM; n = 4-6) for 1, 5 and 10 μg/ml, respectively. Muscle contractures to exogenous ACh and KCl were unaffected. The toxin (10 μg/ml) also did not affect the twitch-tension of directly-stimulated, curarized (10 μg/ml) BC preparations. However, Bbil-TX (10 μg/ml) produced mild morphological alterations (edematous and/or hyperchromic fibers) in BC; there was also a progressive release of CK (from 116 ± 17 IU/ml (basal) to 710 ± 91 IU/ml after 45 min). Bbil-TX (5 μg/ml)-induced blockade was markedly inhibited at 22-24 °C and pretreatment with p-bromophenacyl bromide (p-BPB) abolished the neuromuscular blockade. Bbil-TX (3-30 μg/ml, n = 4-6) caused partial time- and concentration-dependent blockade in PND preparations (52 ± 2% at the highest concentration). Bbil-TX (30 μg/ml) also markedly reduced the MEPPs frequency [from 26 ± 2.5 (basal) to 10 ± 1 after 60 min; n = 5; p < 0.05] and the quantal content [from 94 ± 14 (basal) to 24 ± 3 after 60 min; n = 5; p < 0.05] of PND preparations, but caused only minor depolarization of the membrane resting potential [from -80 ± 1 mV (basal) to -66 ± 2 mV after 120 min; n = 5; p < 0.05], with no significant change in the depolarizing response to exogenous carbachol. These results show that Bbil-TX is a presynaptic PLA2 that contributes to the neuromuscular blockade caused by B. b. smargadina venom. 23880847 (Healthy) ageing: focus on iodothyronines. The activity of the thyroid gland diminishes during ageing, but a certain tissue reserve of T3 and its metabolites is maintained. This reserve is thought to play a regulatory role in energy homeostasis during ageing. This review critically assesses this notion. T3 was thought to act predominantly through pathways that require transcriptional regulation by thyroid hormone receptors (TRs). However, in recent years, it has emerged that T3 and its metabolites can also act through non-genomic mechanisms, including cytosolic signaling. Interestingly, differences may exist in the non-genomic pathways utilized by thyroid hormone metabolites and T3. For instance, one particular thyroid hormone metabolite, namely 3,5-diiodo-L-thyronine (T2), increases the activity of the redox-sensitive protein deacetylase SIRT1, which has been associated with improvements in healthy ageing, whereas evidence exists that T3 may have the opposite effect. Findings suggesting that T3, T2, and their signaling pathways, such as those involving SIRT1 and AMP-activated protein kinase (AMPK), are associated with improvements in diet-induced obesity and insulin resistance emphasize the potential importance of the thyroid during ageing and in ageing-associated metabolic diseases. 23842103 PENTRAXIN 3 AND OTHER INFLAMMATORY FACTORS IN CENTRAL RETINAL VEIN OCCLUSION AND MACULAR EDEMA. To evaluate the association between vitreous fluid levels of inflammatory factors and macular edema in patients with central retinal vein occlusion (CRVO). In 30 CRVO patients with macular edema and 29 controls with idiopathic macular hole, vitreous fluid samples were obtained during vitreoretinal surgery. Retinal ischemia was evaluated from capillary nonperfusion on fluorescein angiography. Macular edema was examined by optical coherence tomography. Vitreous fluid levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor 2 (sVEGFR-2), soluble intercellular adhesion molecule 1 (sICAM-1), interleukin 6 (IL-6), monocyte chemotactic protein 1 (MCP-1), and pentraxin 3 (PTX3) were significantly higher in CRVO patients than in macular hole patients. Vitreous fluid levels of VEGF, sICAM-1, IL-6, MCP-1, and PTX3 were significantly correlated with the retinal thickness at the central fovea. There were significant correlations between the vitreous fluid level of VEGF and the levels of sICAM-1, IL-6, and MCP-1 in the CRVO patients. There was also a significant correlation between sVEGFR-2 and PTX3 but not between VEGF and PTX3. These findings suggest the importance of VEGF, its signal transduction pathways, and the cytokine network and may be useful for understanding the mechanism of macular edema in CRVO and developing new treatments. 23220410 Organochlorines and metals induce changes in the mitochondria-rich cells of fish gills: an integrative field study involving chemical, biochemical and morphological analyses. Through integrating chemical, biochemical and morphological analyses, this study investigated the effects of multiple pollutants on the gill mitochondria-rich cells (MRCs) in two fish species, Astyanax fasciatus and Pimelodus maculatus, collected from five sites (FU10, FU20, FU30, FU40 and FU50) in the Furnas Hydroelectric Power Station reservoir. Water analyses revealed aluminum, iron and zinc as well as organochlorine (aldrin/dieldrin, endosulfan, heptachlor/heptachlor epoxide and metolachlor) contamination at all of the sites, with the exception of FU10. Copper, chrome, iron and zinc were detected in the gills of both species, and aldrin/dieldrin, endosulfan and heptachlor/heptachlor epoxide were detected in the gills of fish from all of the sites, with the exception of FU10. Fish collected at FU20, FU30 and FU50 exhibited numerous alterations in the surface architecture of their pavement cells and MRCs. The surface MRC density and MRC fractional area were lower in fish from FU20, FU30, FU40 and FU50 than in those from the reference site (FU10) in the winter, and some variability between the sites was observed in the summer. The organochlorine contamination at FU20 and FU50 was associated with variable changes in the MRCs and inhibition of Na(+)/K(+)-ATPase (NKA) activity, especially in P. maculatus. At FU30, the alterations in the MRCs were associated with the contaminants present, especially metals. A multivariate analysis demonstrated a positive association between the biological responses of both species and environmental contamination, indicating that under realistic conditions, a mixture of organochlorines and metals affected the MRCs by inhibiting NKA activity and inducing morphological changes, which may cause an ionic imbalance. 23648812 Association between respiratory tract infections and incidence of falls in nursing home residents. Falls are complex incidents caused by a combination of intrinsic impairments and disabilities with or without accompanying environmental hazards. The aim of the study was to assess the relationship between respiratory tract infections (RTIs) and the incidence of falls, and to further link the history of falls to functional status in nursing homes residents. The study involved 255 residents at 3 nursing homes aged 65 years and older. Falls and RTIs were registered during 1 year, and, afterwards, a comprehensive geriatric assessment was performed in each subject. Falls occurred in 104 subjects, and 17 falls resulted in a fracture. The waist‑to‑hip ratio (WHR) was lower among subjects with fractures compared with those without fractures. Subjects with a fracture in history had a significantly worse functional status in terms both of basic and instrumental daily activities. Nursing home residents with a history of falls more often suffered from infections than those without such history (1.53 ±1.31 vs. 1.03 ±1.17, respectively, P <0.001). Similarly, subjects with a history of fractures more often suffered from infections than those without such history (1.82 ±1.07 vs. 1.19 ±1.26; P = 0.012). After adjustment for other covariates in a multivariate model, RTIs remained an independent predictor of falls and fractures. The risk of falls and fractures in nursing home residents is associated with the occurrence of RTIs. A low WHR is a risk factor for falls with fractures. Older subjects with a history of fracture are characterized by a worse functional status. Preventing infections may probably reduce the number of falls and fractures in older nursing homes residents. 23849603 Effects of traditional Chinese medicine Xin-Ji-Er-Kang formula on 2K1C hypertensive rats: role of oxidative stress and endothelial dysfunction. XinJiErKang (XJEK), a Chinese herbal formula, is identified as an effective preparation to treat coronary heart disease and myocarditis. The aim of the study is to investigate the anti-hypertensive effects of XJEK by oral administration and also to find out whether the drug has any role in oxidative stress and vascular endothelial function. Clipping of the renal artery resulted in gradual elevation of the systolic blood pressure (SBP) which reached a plateau after 4 weeks of surgery. Treatment of hypertensive rats (20 mmHg higher than basic systolic blood pressure) with XJEK (6, 12, 24 g/kg/day) and fosinopril (15 mg/kg/day) respectively by intragastric administration started 4 weeks after surgery and continued for 4 weeks. The sham-operated (Sh-Op) controls received drinking water. BP was monitored weekly using tail-cuff apparatus. At the end of 8 wk, left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), rate of rise of left ventricular pressure (+/-dp/dtmax) were examined (PowerLab 8/30, AD Instruments, Australia). The myocardial hypertrophy index was expressed as heart weight/body weight (HW/BW), the histological changes were investigated by hematoxylin and eosin (HE) and Van Gieson (VG) stain. Endothelium-dependent relaxations due to acetylcholine were observed in isolated rat thoracic aortic ring preparation. Superoxide dismutase (SOD) activity, malondialdehyde (MDA) and nitric oxide (NO) content in serum, contents of hydroxyproline (Hyp) in the ventricular tissue were assayed by xanthin oxidase method, thiobarbituric acid (TBA) method, Griess method and alkaline hydrolysis method, respectively. Angiotensin II (Ang II) content in serum was detected by radioimmunoasssay method. XJEK therapy potently improved cardiac function, inhibited myocardial hypertrophy, improved cardiac pathology change, decreased the myocardial cross-section area (CSA), collagen volume fraction (CVF) and perivascular circumferential collagen area (PVCA), reduced the content of Hyp in the left ventricular tissue, inhibited the decrease of SOD activity and increase of MDA, Ang II content in serum. Moreover, treatment with XJEK improved endothelial dysfunction (ED) manifested by promoting endothelial-dependent vasodilation of thoracic aortic rings and enhancing the NO activity in serum. These findings suggest that administration of XJEK possess protective effects against 2K1C induced hypertension and cardiac remodeling in rats, preserve NO activity and endothelial function. 23859647 Neural and Psychological Maturation of Decision-making in Adolescence and Young Adulthood. We examined the maturation of decision-making from early adolescence to midadulthood using fMRI of a variant of the Iowa gambling task. We have previously shown that performance in this task relies on sensitivity to accumulating negative outcomes in ventromedial pFC and dorsolateral pFC. Here, we further formalize outcome evaluation (as driven by prediction errors [PE], using a reinforcement learning model) and examine its development. Task performance improved significantly during adolescence, stabilizing in adulthood. Performance relied on greater impact of negative compared with positive PEs, the relative impact of which matured from adolescence into adulthood. Adolescents also showed increased exploratory behavior, expressed as a propensity to shift responding between options independently of outcome quality, whereas adults showed no systematic shifting patterns. The correlation between PE representation and improved performance strengthened with age for activation in ventral and dorsal pFC, ventral striatum, and temporal and parietal cortices. There was a medial-lateral distinction in the prefrontal substrates of effective PE utilization between adults and adolescents: Increased utilization of negative PEs, a hallmark of successful performance in the task, was associated with increased activation in ventromedial pFC in adults, but decreased activation in ventrolateral pFC and striatum in adolescents. These results suggest that adults and adolescents engage qualitatively distinct neural and psychological processes during decision-making, the development of which is not exclusively dependent on reward-processing maturation. 23938316 Abundant sequence divergence in the native Japanese cattle Mishima-Ushi (Bos taurus) detected using whole-genome sequencing. The native Japanese cattle Mishima-Ushi, a designated national natural treasure, are bred on a remote island, which has resulted in the conservation of their genealogy. We examined the genetic characteristics of 8 Mishima-Ushi individuals by using single nucleotide polymorphisms (SNPs), insertions, and deletions obtained by whole-genome sequencing. Mapping analysis with various criteria showed that predicted heterozygous SNPs were more prevalent than predicted homozygous SNPs in the exonic region, especially non-synonymous SNPs. From the identified 6.54million polymorphisms, we found 400 non-synonymous SNPs in 313 genes specific to each of the 8 Mishima-Ushi individuals. Additionally, 3,170,833 polymorphisms were found between the 8 Mishima-Ushi individuals. Phylogenetic analysis confirmed that the Mishima-Ushi population diverged from another strain of Japanese cattle. This study provides a framework for further genetic studies of Mishima-Ushi and research on the function of SNP-containing genes as well as understanding the genetic relationship between the domestic and native Japanese cattle breeds. 23582909 Sensitization to Cor a 9 and Cor a 14 is highly specific for a hazelnut allergy with objective symptoms in Dutch children and adults. Component-resolved diagnosis has been shown to improve the diagnosis of food allergy. We sought to evaluate whether component-resolved diagnosis might help to identify patients at risk of objective allergic reactions to hazelnut. A total of 161 hazelnut-sensitized patients were included: 40 children and 15 adults with objective symptoms on double-blind, placebo-controlled food challenges (DBPCFCs) and 24 adults with a convincing objective history were compared with 41 children and 41 adults with no or subjective symptoms on DBPCFCs (grouped together). IgE levels to hazelnut extract and single components were analyzed with ImmunoCAP. IgE levels to hazelnut extract were significantly higher in children with objective than with no or subjective symptoms. In 13% of children and 49% of adults with hazelnut allergy with objective symptoms, only sensitization to rCor a 1.04 was observed and not to other water-soluble allergens. Sensitization to rCor a 8 was rare, which is in contrast to rCor a 1. Sensitization to nCor a 9, rCor a 14, or both was strongly associated with hazelnut allergy with objective symptoms. By using adapted cutoff levels, a diagnostic discrimination between severity groups was obtained. IgE levels to either nCor a 9 of 1 kUA/L or greater or rCor a 14 of 5 kUA/L or greater (children) and IgE levels to either nCor a 9 of 1 kUA/L or greater or rCor a 14 of 1 kUA/L or greater (adults) had a specificity of greater than 90% and accounted for 83% of children and 44% of adults with hazelnut allergy with objective symptoms. Sensitization to Cor a 9 and Cor a 14 is highly specific for patients with objective symptoms in DBPCFCs as a marker for a more severe hazelnut allergic phenotype. 23926418 Evolutionary Modeling of Genotype-Phenotype Associations, and Application to Primate Coding and Non-coding mtDNA Rate Variation. Variation in substitution rates across a phylogeny can be indicative of shifts in the evolutionary dynamics of a protein or non-protein coding regions. One way to understand these signals is to seek the phenotypic correlates of rate variation. Here, we extended a previously published likelihood method designed to detect evolutionary associations between genotypic evolutionary rate and phenotype over a phylogeny. In simulation with two discrete categories of phenotype, the method has a low false-positive rate and detects greater than 80% of true-positives with a tree length of three or greater and a three-fold or greater change in substitution rate given the phenotype. In addition, we successfully extend the test from two to four phenotype categories and evaluated its performance. We then applied the method to two major hypotheses for rate variation in the mitochondrial genome of primates-longevity and generation time as well as body mass which is correlated with many aspects of life history-using three categories of phenotype through discretization of continuous values. Similar to previous results for mammals, we find that the majority of mitochondrial protein-coding genes show associations consistent with the longevity and body mass predictions and that the predominant signal of association comes from the third codon position. We also found a significant association between maximum lifespan and the evolutionary rate of the control region of the mtDNA. In contrast, 24 protein-coding genes from the nuclear genome do not show a consistent pattern of association, which is inconsistent with the generation time hypothesis. These results show the extended method can robustly identify genotype-phenotype associations up to at least four phenotypic categories, and demonstrate the successful application of the method to study factors affecting neutral evolutionary rate in protein-coding and non-coding loci. 23877994 Orientational Fluctuations Near the Smectic A to Smectic C Phase Transition in Two "de Vries"-Type Liquid Crystals. On the basis of thorough analysis of 2D X-ray diffraction patterns from smectic monodomains, we examine the influence of orientational fluctuations on the weakly first-order smectic A (SmA) to smectic C (SmC) transitions in two nonchiral organosiloxane "de Vries"-type liquid crystals. We find that these materials exhibit very large molecular tilt fluctuations with magnitudes of up to 35°-thus larger than the average tilt itself. This is essential to understand the underlying molecular mechanism behind the practical absence of smectic layer contraction in these materials: in the SmA phase, the nematic order parameter is very low (molecular fluctuations correspondingly high), and the expected layer shrinkage at the SmA to SmC transition is almost fully compensated by the increase in orientational order, as the fluctuations diminish with decreasing temperature. In addition to the general tilt fluctuations, we observe intrinsic soft-mode fluctuations. They have a λ-shaped temperature dependence that peaks at the SmA-SmC transition with a maximum amplitude of about 2°. 23907543 The Brain-Derived Neurotrophic Factor Val66Met Polymorphism Moderates an Effect of Physical Activity on Working Memory Performance. Physical activity enhances cognitive performance, yet individual variability in its effectiveness limits its widespread therapeutic application. Genetic differences might be one source of this variation. For example, carriers of the methionine-specifying (Met) allele of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have reduced secretion of BDNF and poorer memory, yet physical activity increases BDNF levels. To determine whether the BDNF polymorphism moderated an association of physical activity with cognitive functioning among 1,032 midlife volunteers (mean age = 44.59 years), we evaluated participants' performance on a battery of tests assessing memory, learning, and executive processes, and evaluated their physical activity with the Paffenbarger Physical Activity Questionnaire. BDNF genotype interacted robustly with physical activity to affect working memory, but not other areas of cognitive functioning. In particular, greater levels of physical activity offset a deleterious effect of the Met allele on working memory performance. These findings suggest that physical activity can modulate domain-specific genetic (BDNF) effects on cognition. 23932619 Mathematical modelling of gubernaculum during inguino-scrotal migration shows limb bud characteristics. The gubernaculum is postulated to grow like an embryonic limb bud during inguinoscrotal descent in rodents. Recently, modelling of limb bud growth suggests the undifferentiated, distal "progress zone" provides molecular morphogenic signals, rather than cell division, as previously thought. We aimed to develop a mathematical gubernacular growth model, hypothesising that it would mimic limb buds through evolutionary conservation. Histology was done on Sprague-Dawley rats (day 2, 8; n=7/group) to determine gubernacular length, width, cell density in distal growth centre, middle and proximal cremaster muscle. Analysis of measurements enabled gubernacular growth modelling under variable growth centre sizes/densities, assuming no apoptosis. Modelling found that gubernacular growth occurred mostly within cremaster muscle, rather than primarily in the undifferentiated mesenchymal tip, despite its higher mitotic rate. The growth centre accounted for≤10% of total gubernacular enlargement/elongation. These results suggest the gubernaculum elongates by proliferation throughout cremaster muscle like a limb bud. The distal undifferentiated tip may provide signalling molecules for growth, which could be a fruitful source for causes of failed migration/elongation in cryptorchidism. 23643861 Cloning and characterization of a novel human BRMS1 transcript variant in hepatocellular carcinoma cells. Breast cancer metastasis suppressor 1 (BRMS1) is able to suppress tumor metastasis without affecting primary tumor growth in various cancers. Here, we report a novel transcript variant of human BRMS1, termed BRMS1.vh. BRMS1.vh is identical to the major BRMS1 variant (BRMS1.v1) except for missing base pairs 683-775, encoding a 215-amino acid protein lacking a functional nuclear localization sequence. Expression of BRMS1.vh in hepatocellular carcinoma (HCC) cells suppressed NF-κB signaling pathway, sensitized cells to apoptotic stimuli, leading to suppressed tumor growth. Taken together, our results suggest a potential role for BRMS1.vh in regulating cell apoptosis and tumor growth in HCC. 22717325 Sonoluminescence quenching and cavitation bubble temperature measurements in an ionic liquid. A comparison between the temperatures within imploding acoustic cavitation bubbles and the extent of sonoluminescence (SL) quenching by C(1)-C(5) aliphatic alcohols in 1-ethyl-3-methylimidazolium ethylsulfate ([EMIM][EtSO(4)], a well known imidazolium based room temperature ionic liquid (RTIL)), has been made at an ultrasound frequency of 213 kHz. The temperatures obtained ranged from 3500 ± 200K, in neat [EMIM][EtSO(4)], to about 3200 ± 200K in RTIL-alcohol containing solutions. It was also found that the SL intensity decreased with increasing concentration (up to 1M) of the alcohols to a greater extent compared with the relative changes to the bubble temperatures. Both the extent of the reduction in the bubble temperatures and the SL quenching were much smaller than those obtained in comparable aqueous solutions containing aliphatic alcohols. Possible reasons for the differences in the observed trends between water/alcohol and [EMIM][EtSO(4)]/alcohol systems under sonication at 213 kHz are discussed. 23633189 Involvement of PARP-1 Val762Ala Polymorphism in the Onset of Cervical Cancer in Caucasian Women. Data on the Val762Ala (rs1136410) polymorphism in the poly(adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP-1) gene as a risk factor for various types of cancers in different ethnicities are inconsistent. We studied this association in a Caucasian population. Using high-resolution melting curve analysis (HRM), we studied the distribution of the PARP-1 Val762Ala polymorphism in patients with cervical cancer (n = 446) and in controls (n = 491). Logistic regression analysis adjusting for age, pregnancy, oral contraceptive use, tobacco smoking, and menopausal status demonstrated that the PARP-1 Val762Ala polymorphism was associated with an increased risk of cervical cancer. The adjusted odds ratio (OR) for patients with the Ala/Val genotype versus the Val/Val genotype was 1.381 (95 % CI = 1.025-1.859, p = 0.033), and the adjusted OR for the Ala/Ala or Ala/Val genotype versus the Val/Val genotype was 1.403 (95 % CI = 1.057-1.863, p = 0.019). The p value from the chi-square test of the trend observed for the PARP-1 Val762Ala polymorphism was statistically significant (p trend = 0.0123). Stratified analyses of the PARP-1 Val762Ala genotype distribution and cervical cancer risk showed that the age-adjusted OR of Ala/Ala or Ala/Val vs Val/Val for pregnancy was 1.388 (95 % CI = 1.027-1.877, p = 0.0328), 1.773 (95 % CI = 1.145-2.745, p = 0.0100) for contraceptive use, and 1.604 (95 % CI = 1.132-2.272, p = 0.0077) for postmenopausal women. The age-adjusted OR of Ala/Val vs Val/Val for contraceptive use was 1.769 (95 % CI = 1.114-2.809, p = 0.0154) and for postmenopausal women was 1.577 (95 % CI = 1.094-2.272, p = 0.0143). Our studies suggest that the PARP-1 Val762Ala polymorphism may be a genetic risk factor for cervical cancer. 23707963 Engineering poly(ethylene oxide) buccal films with cyclodextrin: a novel role for an old excipient? Inspired by the multiple roles cyclodextrins can play in polymeric systems, here we engineered poly(ethylene oxide) (PEO) films with (2-hydroxypropyl)-β-cyclodextrin (CD) as multipurpose ingredient. To shed light on the potential of CD in formulating PEO buccal films for the delivery of poorly water-soluble drugs, we preliminarily assessed thermal and mechanical properties as well as wettability of films prepared at different PEO/CD ratios. PEO/CD platform containing 54% by weight of CD was chosen as the optimized composition since it matched acceptable mechanical properties, in terms of tensile strength and elasticity, with a good wettability. The platform was tested as buccal delivery system for triamcinolone acetonide (TrA), a lipophilic synthetic corticosteroid sparely water soluble. Confocal Raman imaging clearly showed that CD was homogeneously (i.e. molecularly) dispersed in PEO. Nevertheless, homogenous drug distribution in the film without TrA crystallization occurred only in the presence of CD. Finally, CD-containing PEO film placed in simulated buccal fluids provided a useful speed-up of TrA release rate while showing slower dissolution as compared to PEO film. These results, as well as compliance with quality specifications of pharmaceutical manufacturing products, strongly support the soundness of the strategy and prompt toward further applications of PEO/CD films in buccal drug delivery. 23430569 Deep circumflex iliac artery flap with osseointegrated implants for reconstruction of mandibular benign lesions: clinical experience of 33 cases. A variety of free flaps have been successfully used for mandible reconstruction. The iliac crest has similar dimensions and form to the lateral mandible. The success rate and complication rate of deep circumflex iliac artery flap transplants had no significant difference to those of other microvascular bone transplants. The purpose of this study was to evaluate our experience with the use of the vascularized free iliac flap for the reconstruction of mandibular defects following surgical resection. Data from 33 patients who underwent operations, including segmental mandibulectomy, immediate mandibular reconstruction and second-stage surgery, were retrospectively analysed. The size of segmental mandible defects ranged from 6 to 13 cm. Surgicase for cranio-maxillofacial reconstruction software was used for patients with mandible defects greater than 10 cm. One flap loss occurred related to vascular thrombosis. The survival rate was 96.97%, and the mean follow-up was 26 months. A total of 81 osseointegrated dental implants were placed in 25 patients with adequate outcomes; 21 patients (63.64%) showed complete recovery, and in 18 out of these 21 patients, occlusion rehabilitation with fixed dentures benefitted from an appropriate distance between upper teeth and new alveolar bone. Donor-site morbidity was moderate, and most of the patients were satisfied with their functional and aesthetic results. Our results show that deep circumflex iliac artery is a reliable method for reconstructing hemimandibular body defects with an acceptably low rate of morbidity. The iliac crest is a safe foundation for the placement of osseointegrated implants, which enable good reconstruction and further improve life quality of patients. 23330562 Bioanalytical assay strategies for the development of antibody-drug conjugate biotherapeutics. Antibody-drug conjugates (ADCs) are monoclonal antibodies with covalently bound cytotoxic drugs. They are designed to target tumor antigens selectively and offer the hope of cancer treatment without the debilitating side-effects of conventional therapies. The concept of ADCs is not new; however, development of these therapeutics is challenging and only recently are promising clinical data emerging. These challenges include ADC bioanalysis, such as quantifying in serum/plasma for PK studies and strategies for assessing immunogenicity. ADCs have complex molecular structures incorporating large- and small-molecule characteristics and require diverse analytical methods, including ligand-binding assays and MS-based methods. ADCs are typically mixtures with a range of drug-to-antibody ratios. Biotransformations in vivo can lead to additional changes in drug-to-antibody ratios resulting in dynamically changing mixtures. Thus, a standard calibration curve consisting of the reference standard may not be appropriate for quantification of analytes in vivo and represents a unique challenge. This paper will share our perspective on why ADC bioanalysis is so complex and describe the strategies and rationale that we have used for ADCs, with highlights of original data from a variety of nonclinical and clinical case studies. Our strategy has involved novel protein structural characterization tools to help understand ADC biotransformations in vivo and use of the analyte knowledge gained to guide the development of quantitative bioanalytical assays. 23347396 Adsorption and dilational rheology of mixed β-casein/DoTAB layers formed by sequential and simultaneous adsorption at the water/hexane interface. The interfacial behavior of β-casein (βCS) has been investigated in presence of the cationic surfactant dodecyl trimethyl ammonium bromide (DoTAB) at the water/hexane interface and compared to that obtained for the water/air interface. The used experimental technique is a drop profile analysis tensiometer specially equipped with a coaxial double capillary, which allows investigation of sequential adsorption of individual components besides the traditional simultaneous adsorption of two species. This method also provides the dilational rheological measurements based on low frequency harmonic drop oscillations. The tensiometric results show that the equilibrium states of the mixed βCS/DoTAB layers built up on the two different routes do not differ significantly, that is, the general compositions of the mixed layers are similar. However, the results of dilational rheology for the two adsorption strategies are remarkably different indicating different dynamic characteristics of the adsorbed layers. These findings suggest that the respective mixed layers are more proteinlike if they are formed via sequential adsorption and more surfactant-like after simultaneous adsorption. In contrast to the W/A interface, at the W/H interface proteins remain at the interface once adsorbed and cannot be displaced just by competitive adsorption of surfactants. 23448807 Global, multicenter, randomized, phase II trial of gemcitabine and gemcitabine plus AGS-1C4D4 in patients with previously untreated, metastatic pancreatic cancer. We evaluated AGS-1C4D4, a fully human monoclonal antibody to prostate stem cell antigen (PSCA), with gemcitabine in a randomized, phase II study of metastatic pancreatic cancer. Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0/1 and previously untreated, metastatic pancreatic adenocarcinoma were randomly assigned 1:2 to gemcitabine (1000 mg/m(2) weekly seven times, 1 week rest, weekly three times q4weeks) or gemcitabine plus AGS-1C4D4 (48 mg/kg loading dose, then 24 mg/kg q3weeks IV). The primary end point was 6-month survival rate (SR). Archived tumor samples were collected for pre-planned analyses by PSCA expression. Between April 2009 and May 2010, 196 patients were randomly assigned to gemcitabine (n = 63) or gemcitabine plus AGS-1C4D4 (n = 133). The 6-month SR was 44.4% (95% CI, 31.9-57.5) in the gemcitabine arm and 60.9% (95% CI, 52.1-69.2) in the gemcitabine plus AGS-1C4D4 arm (P = 0.03), while the median survival was 5.5 versus 7.6 months and the response rate was 13.1% versus 21.6% in the two arms, respectively. The 6-month SR was 57.1% in the gemcitabine arm versus 79.5% in the gemcitabine plus AGS-1C4D4 arm among the PSCA-positive subgroup and 31.6% versus 46.2% among the PSCA-negative subgroup. This randomized, phase II study achieved its primary end point, demonstrating an improved 6-month SR with addition of AGS-1C4D4 to gemcitabine among patients with previously untreated, metastatic pancreatic adenocarcinoma. ClinicalTrials.gov identifier: NCT00902291. 22447194 Indoor air quality in Virginia waterpipe cafes. A revised indoor air quality law has been implemented in Virginia to protect the public from the harmful effects of secondhand smoke exposure. This legislation contains exemptions that include allowances for smoking in a room that is structurally separated and separately ventilated. The objective of the current study was to examine the impact of this law on air quality in waterpipe cafés, as well as to compare the air quality in these cafés to restaurants that allow cigarette smoking and those where no smoking is permitted. Indoor air quality in 28 venues (17 waterpipe cafés, five cigarette smoking-permitted restaurants and six smoke-free restaurants (five with valid data)) in Virginia was assessed during 4 March to 27 May 2011. Real-time measurements of particulate matter (PM) with 2.5 μm aerodynamic diameter or smaller (PM2.5) were obtained and occupant behaviour/venue characteristics were assessed. The highest mean PM2.5 concentration was observed for waterpipe café smoking rooms (374 μg/m(3), n=17) followed by waterpipe café non-smoking rooms (123 μg/m(3), n=11), cigarette smoking-permitted restaurant smoking rooms (119 μg/m(3), n=5), cigarette smoking-permitted restaurant non-smoking rooms (26 μg/m(3), n=5) and smoke-free restaurants (9 μg/m(3), n=5). Smoking density was positively correlated with PM2.5 across smoking rooms and the smoke-free restaurants. In addition, PM2.5 was positively correlated between smoking and non-smoking rooms of venues. The PM2.5 concentrations observed among the waterpipe cafés sampled here indicated air quality in the waterpipe café smoking rooms was worse than restaurant rooms in which cigarette smoking was permitted, and state-required non-smoking rooms in waterpipe cafés may expose patrons and employees to PM2.5 concentrations above national and international air quality standards. Reducing the health risks of secondhand smoke may require smoke-free establishments in which tobacco smoking sources such as water pipes are, like cigarettes, prohibited. 23427277 Expansion of Secretin-Like G Protein-Coupled Receptors and Their Peptide Ligands via Local Duplications Before and After Two Rounds of Whole-Genome Duplication. In humans, the secretin-like G protein-coupled receptor (GPCR) family comprises 15 members with 18 corresponding peptide ligand genes. Although members have been identified in a large variety of vertebrate and nonvertebrate species, the origin and relationship of these proteins remain unresolved. To address this issue, we employed large-scale genome comparisons to identify genome fragments with conserved synteny and matched these fragments to linkage groups in reconstructed early gnathostome ancestral chromosomes (GAC). This genome comparison revealed that most receptor and peptide genes were clustered in three GAC linkage groups and suggested that the ancestral forms of five peptide subfamilies (corticotropin-releasing hormone-like, calcitonin-like, parathyroid hormone-like, glucagon-like, and growth hormone-releasing hormone-like) and their cognate receptor families emerged through tandem local gene duplications before two rounds (2R) of whole-genome duplication. These subfamily genes have, then, been amplified by 2R whole-genome duplication, followed by additional local duplications and gene loss prior to the divergence of land vertebrates and teleosts. This study delineates a possible evolutionary scenario for whole secretin-like peptide and receptor family members and may shed light on evolutionary mechanisms for expansion of a gene family with a large number of paralogs. 23642486 Transit of micro-bubbles through the pulmonary circulation of Thoroughbred horses during exercise. It has been observed that microbubbles may pass through the pulmonary circulation of dogs and humans during exercise. In humans, this phenomenon has been associated with lower pulmonary artery pressures, enhanced right ventricular function and greater exercise capacity. In the exercising Thoroughbred horse, extraordinarily high cardiac outputs exert significant pulmonary vascular stresses. The aim of this study was to determine, using contrast echocardiography, whether Thoroughbred horses performing strenuous exercise developed pulmonary transit of agitated contrast microbubbles (PTAC). At rest, agitated contrast was observed in the right ventricle, but not in the left ventricle. However, post-exercise microbubbles were observed in the left ventricle, confirming the occurrence of PTAC with exercise but not at rest. Further investigation is warranted to investigate whether this phenomenon may be associated with superior physiology and performance measures as has been implicated in other species. 23623845 Biological effects induced by BSA-stabilized silica nanoparticles in mammalian cell lines. Much of the concerns regarding engineered nanoparticle (NP) toxicity are based on knowledge from previous studies on particles in ambient air or occupational situations. E.g., the effects of exposure to silica dust particles have been studied intensely due to the carcinogenicity of crystalline silica. However, the increasing usage of engineered amorphous silica NPs has emphasized the need for further mechanistic insight to predict the consequences of exposure to the amorphous type of silica NPs. The present study focused on the in vitro biological effects following exposure to well-dispersed, BSA-stabilized, amorphous silica NPs whereas unmodified silica NPs where included for reasons of comparison. The cytotoxicity of the silica NPs was investigated in six different cell lines (A549, THP-1, CaCo-2, ASB-XIV, J-774A.1, and Colon-26) selected to explore the significance of organ and species sensitivity in vitro. Viability data demonstrated that macrophages were most sensitive to silica NP and interestingly, murine cell lines were generally found to be more sensitive than comparable human cell lines. Further studies were conducted in the human epithelial lung cell line, A549, to explore the molecular mechanism of silica toxicity. Generation of reactive oxygen species, one of the proposed toxicological mechanisms of NPs, was investigated in A549 cells by the dichlorofluorescin (DCF) assay to be significantly induced at NP concentrations above 113μg/mL. However, induction of oxidative stress related pathways was not found after silica NP exposure for 24h in gene array studies conducted in A549 cells at a relatively low NP concentration (EC20). Up-regulated genes (more than 2-fold) were primarily related to lipid metabolism and biosynthesis whereas down-regulated genes included several processes such as transcription, cell junction, extra cellular matrix (ECM)-receptor interaction and others. Thus, gene expression data proposes that several cellular processes other than oxidative stress could be affected by exposure to silica NPs. 23922330 PET-guided biopsy with needle navigation facilitates diagnosis of angiosarcoma in neurofibromatosis type 1. Malignant degeneration frequently arises from preexisting plexiform neurofibroma in patients with neurofibromatosis type 1 (NF1). Image guided biopsy for diagnostic purposes, such as with CT guidance, can be technically challenging in these patients, as CT cannot distinguish malignant from benign areas within the same tumor. Navigation with multi-modality (PET, CT, and ultrasound) image fusion facilitated the successful biopsy and diagnosis of angiosarcoma arising from a pelvic neurofibroma in a patient with NF1. Successful targeting assisted treatment selection in this case. This novel navigation technique may facilitate the otherwise difficult diagnosis of malignancy in patients with NF1. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc. 23176171 Fast Monolayer Adsorption and Slow Energy Transfer in CdSe Quantum Dot Sensitized ZnO Nanowires. A method for CdSe quantum dot (QD) sensitization of ZnO nanowires (NW) with fast adsorption rate is applied. Photoinduced excited state dynamics of the quantum dots in the case of more than monolayer coverage of the nanowires is studied. Transient absorption kinetics reveals an excitation depopulation process of indirectly attached quantum dots with a lifetime of ∼4 ns. Photoluminescence and incident photon-to-electron conversion efficiency show that this process consists of both radiative e-h recombination and nonradiative excitation-to-charge conversion. We argue that the latter occurs via interdot energy transfer from the indirectly attached QDs to the dots with direct contact to the nanowires. From the latter, fast electron injection into ZnO occurs. The energy transfer time constant is found to be around 5 ns. 23800777 Structural elucidation and spectral characterizations of Co3O4 nanoflakes. A facile solvothermal process is successfully developed to prepare F-center cubic Co3O4 nanoflakes in ethylene-glycol-water solvent. Cobalt acetate [Co(Ac)2⋅4H2O] is directly used as precursor and ethylene glycol performs a reducer and modifying agent in the system. The as obtained products were characterized by XRD, FT-IR, UV-Vis-DRS, SEM, EDAX, XPS and HR-TEM. XRD studies indicate that the nanoflakes have the same crystal structure found in cubic form of Co3O4. The lattice parameter, X-ray density and the specific area of nanoflakes were also estimated from XRD pattern. The various functional groups present in Co3O4 nanoflakes were identified by FTIR analysis. The band gap energy of Co3O4 nanoflakes was calculated from UV-Vis-DRS spectral studies. SEM analyses ascertain that Co3O4 nanocrystals are nanoflakes in nature and the particle size in SEM is exactly consistent with XRD results. The elemental composition was determined using the energy dispersive X-ray spectroscopy was performed at several points in the region and averaged to obtain the representative results. The atomic composition of the Co3O4 was detected by X-ray photoelectron spectroscopy (XPS). The nanoscale structures were observed using high-resolution transmission electron microscopy. 23964137 Portal hypertension and gastrointestinal bleeding: Diagnosis, prevention and management. Bleeding from esophageal varices is a life threatening complication of portal hypertension. Primary prevention of bleeding in patients at risk for a first bleeding episode is therefore a major goal. Medical prophylaxis consists of non-selective beta-blockers like propranolol or carvedilol. Variceal endoscopic band ligation is equally effective but procedure related morbidity is a drawback of the method. Therapy of acute bleeding is based on three strategies: vasopressor drugs like terlipressin, antibiotics and endoscopic therapy. In refractory bleeding, self-expandable stents offer an option for bridging to definite treatments like transjugular intrahepatic portosystemic shunt (TIPS). Treatment of bleeding from gastric varices depends on vasopressor drugs and on injection of varices with cyanoacrylate. Strategies for primary or secondary prevention are based on non-selective beta-blockers but data from large clinical trials is lacking. Therapy of refractory bleeding relies on shunt-procedures like TIPS. Bleeding from ectopic varices, portal hypertensive gastropathy and gastric antral vascular ectasia-syndrome is less common. Possible medical and endoscopic treatment options are discussed. 23338232 Controversies in ocular trauma classification and management: review. Ocular trauma is a topic of unresolved controversies and there are continuous controversial and debatable management strategies for open-globe injuries (OGIs). International classification of ocular trauma proposed almost 15 years ago needs to be reviewed and to be more robust in predicting the outcome in the setting of OGIs. Anterior segment trauma involves controversies related to patching for corneal abrasion, corneal laceration repair, and medical management of hyphema. Timing of cataract surgery and intraocular lens implantation in the setting of trauma is still debated worldwide. There are unresolved issues regarding the management of OGIs involving the posterior segment. Timing of vitrectomy has been and will continue to be debated by proponents of early versus delayed intervention. The use of prophylactic cryotherapy and scleral buckle is still practiced differently throughout the world. The role of intravitreal antibiotics in posterior segment trauma in the absence of infection is still debated. Similarly, the use of vitrectomy versus vitreous tap in the setting of traumatic endophthalmitis is not fully resolved. In optic neuropathy, the role of intravenous methylprednisolone versus conservative management is always debated and still there are no evidence-based guidelines about the beneficial role of pulse steroid therapy. The role of optic canal decompression in the setting of acute traumatic optic neuropathy is also not conclusive. Orbital and adnexal trauma has been shown to adversely affect the outcome of OGI patients but both lids and orbital injury are not taken as preoperative variables in international ocular trauma classification. The timing of intervention in blow-out fracture is still debated. The pediatric age group, owing to the high risk of amblyopia and intraocular inflammation as well as strong vitreoretinal adhesions, has to be managed by different principles. Although the risk of sympathetic ophthalmia is very rare, it is always one of the key debated issues while managing traumatized eyes with no light perception vision. Prospective, controlled clinical studies are not possible in the OGI setting and this article reviews pertinent data regarding these management issues and controversies, and provides recommendations for treatment based on the available published data and the authors' personal experience. 23748799 Is there a relationship between attention deficit/hyperactivity disorder and Osgood-Schlatter disease? The purpose of this prospective study is to investigate the relationship between Osgood-Schlatter disease (OSD) and attention deficit/hyperactivity disorder (ADHD). Seventy-four children with a diagnosis of OSD were referred to child and adolescent psychiatry department for the evaluation of ADHD. Diagnostic and Statistical Manual of Mental Disorders was used for diagnostic criteria. Diagnosis of ADHD was made in 56 (75.6 %) out of 74 children. Results of this study suggest that ADHD is a significant risk factor for OSD. During the evaluation of a patient with OSD, a thorough history should be obtained about the behavioral symptoms that indicate underlying ADHD. In case of suspicion, these patients should be referred for an additional evaluation by a child psychiatrist. II. 23906279 Electron-Hole Transfer in G-Quadruplexes with Different Tetrad Stacking Geometries: A Combined QM and MD Study. G-quadruplex nucleic acids represent a unique avenue for the building of electrically conductive wires. These four-stranded structures are formed through the stacking of multiple planar guanine assemblies termed G-tetrads. The diverse folding patterns of G-quadruplexes allow for several geometries to be adopted by stacked guanine bases within the core and at the dimeric interface of these structures. It is currently not clear how different G-tetrad stacking arrangements affect electron hole mobility through a G-quadruplex wire. Using a combined quantum mechanics and molecular dynamics approach, we demonstrate that the electron-hole transfer rates within the G-tetrad stacks vary greatly for different stacking geometries. We identify a distinguished structure that allows for strong electronic coupling and thus enhanced molecular electric conductance. We also demonstrate the importance of sampling a large number of geometries when considering the bulk properties of such systems. Hole hopping within single G-tetrads is slower by at least two orders of magnitude than between stacked guanines; therefore, hole jumping within individual tetrads should not affect the hole mobility in G-quadruplexes. The results of this study suggest engineering G-tetrads with continuous 5/6-ring stacking from an assembly of single guanosine analogs or through modification of the backbone in G-rich DNA sequences. 23818248 Reversing Bone Loss by Directing Mesenchymal Stem Cells to the Bone. Bone regeneration by systemic transplantation of mesenchymal stem cells (MSCs) is problematic due to the inability to control the MSCs' commitment, growth and differentiation into functional osteoblasts on the bone surface. Our research group has developed a method to direct the MSCs to the bone surface by conjugating a synthetic peptidomimetic ligand (LLP2A) that has high affinity for activated α4β1 integrin on the MSC surface, with a bisphosphonates (alendronate) that has high affinity for bone (LLP2A-Ale), to direct the transplanted MSCs to bone. Our in vitro experiments demonstrated that mobilization of LLP2A-Ale to hydroxyapatite accelerated MSC migration that was associated with an increase in the phosphorylation of Akt kinase and osteoblastogenesis. LLP2A-Ale increased the homing of the transplanted MSCs to bone as well as the osteoblast surface, significantly increased the rate of bone formation and restored both trabecular and cortical bone loss induced by estrogen deficiency or advanced age in mice. These results support LLP2A-Ale as a novel therapeutic option to direct the transplanted MSCs to bone for the treatment of established bone loss related to hormone deficiency and aging. 23139061 Hierarchical porous materials: catalytic applications. In this review, we discuss the phenomenon of complementary macropore incorporation into mesoporous and/or microporous solids in order to enhance their catalytic performance in fuels and chemicals synthesis. 23790915 Proteolysis of noncollagenous proteins in sea cucumber, Stichopus japonicus, body wall: characterisation and the effects of cysteine protease inhibitors. Proteolysis of noncollagenous proteins in sea cucumber, Stichopus Japonicus, body wall (sjBW) was investigated. The proteins removed from sjBW by SDS and urea extraction were mainly noncollagenous proteins with molecular weights about 200kDa (Band I) and 44kDa (Band II), respectively. Band I and Band II were identified as major yolk protein (MYP) and actin, respectively, from holothurian species by liquid chromatography-mass spectrometry (LC-MS/MS) with significant scores. Based on TCA-soluble oligopeptide assay, the optimum proteolysis condition of noncollagenous proteins was at 46.3°C and pH 6.1, by response surface methodology. The proteolysis of MYP, and actin, was partially inhibited by cysteine protease inhibitors, including Trans-epoxysuccinyl-l-leucyl-amido (4-guanidino) butane (E-64), iodoacetic acid, antipain and whey protein concentrate. These results suggest that cysteine proteases are partially involved in the proteolysis of noncollagenous proteins in body wall of sea cucumber, S. japonicus. 23681957 Nonfitting protein-ligand interaction scoring function based on first-principles theoretical chemistry methods: development and application on kinase inhibitors. Targeted therapy is currently a hot topic in the fields of cancer research and drug design. An important requirement for this approach is the development of potent and selective inhibitors for the identified target protein. However, current ways to estimate inhibitor efficacy rely on empirical protein-ligand interaction scoring functions which, suffering from their heavy parameterizations, often lead to a low accuracy. In this work, we develop a nonfitting scoring function, which consists of three terms: (1) gas-phase protein-ligand binding enthalpy obtained by the eXtended ONIOM hybrid method based on an integration of density functional theory (DFT) methods (XYG3 and ωB97X-D) and the semiempirical PM6 method, (2) solvation free energy based on DFT-SMD solvation model, and (3) entropy effect estimated by using DFT frequency analysis. The new scoring function is tested on a cyclin-dependent kinase 2 (CDK2) inhibitor database including 76 CDK2 protein inhibitors and a p21-activated kinase 1 (PAK1) inhibitor database including 20 organometallic PAK1 protein inhibitors. From the results, good correlations are found between the calculated scores and the experimental inhibitor efficacies with the square of correlation coefficient R(2) of 0.76-0.88. This suggests a good predictive power of this scoring function. To the best of our knowledge, this is the first high level theory-based nonfitting scoring function with such a good level of performance. This scoring function is recommended to be used in the final screening of lead structure derivatives. 23729486 Ezrin/radixin/moesin proteins differentially regulate endothelial hyperpermeability after thrombin. Endothelial cell (EC) barrier disruption induced by inflammatory agonists such as thrombin leads to potentially lethal physiological dysfunction such as alveolar flooding, hypoxemia, and pulmonary edema. Thrombin stimulates paracellular gap and F-actin stress fiber formation, triggers actomyosin contraction, and alters EC permeability through multiple mechanisms that include protein kinase C (PKC) activation. We previously have shown that the ezrin, radixin, and moesin (ERM) actin-binding proteins differentially participate in sphingosine-1 phosphate-induced EC barrier enhancement. Phosphorylation of a conserved threonine residue in the COOH-terminus of ERM proteins causes conformational changes in ERM to unmask binding sites and is considered a hallmark of ERM activation. In the present study we test the hypothesis that ERM proteins are phosphorylated on this critical threonine residue by thrombin-induced signaling events and explore the role of the ERM family in modulating thrombin-induced cytoskeletal rearrangement and EC barrier function. Thrombin promotes ERM phosphorylation at this threonine residue (ezrin Thr567, radixin Thr564, moesin Thr558) in a PKC-dependent fashion and induces translocation of phosphorylated ERM to the EC periphery. Thrombin-induced ERM threonine phosphorylation is likely synergistically mediated by protease-activated receptors PAR1 and PAR2. Using the siRNA approach, depletion of either moesin alone or of all three ERM proteins significantly attenuates thrombin-induced increase in EC barrier permeability (transendothelial electrical resistance), cytoskeletal rearrangements, paracellular gap formation, and accumulation of phospho-myosin light chain. In contrast, radixin depletion exerts opposing effects on these indexes. These data suggest that ERM proteins play important differential roles in the thrombin-induced modulation of EC permeability, with moesin promoting barrier dysfunction and radixin opposing it. 23616105 High-fat diet changes the temporal profile of GLP-1 receptor-mediated hypophagia in rats. Overconsumption of a high-fat diet promotes weight gain that can result in obesity and associated comorbidities, including Type 2 diabetes mellitus. Consumption of a high-fat diet also alters gut-brain communication. Glucagon-like peptide 1 (GLP-1) is an important gastrointestinal signal that modulates both short- and long-term energy balance and is integral in maintenance of glucose homeostasis. In the current study, we investigated whether high-fat diets (40% or 81% kcal from fat) modulated the ability of the GLP-1 receptor (GLP-1r) agonists exendin-4 (Ex4) and liraglutide to reduce food intake and body weight. We observed that rats maintained on high-fat diets had a delayed acute anorexic response to peripheral administration of Ex4 or liraglutide compared with low-fat diet-fed rats (17% kcal from fat). However, once suppression of food intake in response to Ex4 or liraglutide started, the effect persisted for a longer time in the high-fat diet-fed rats compared with low-fat diet-fed rats. In contrast, centrally administered Ex4 suppressed food intake similarly between high-fat diet-fed and low-fat diet-fed rats. Chronic consumption of a high-fat diet did not change the pharmacokinetics of Ex4 but increased intestinal Glp1r expression and decreased hindbrain Glp1r expression. Taken together, these findings demonstrate that dietary composition alters the temporal profile of the anorectic response to exogenous GLP-1r agonists. 23443358 Control of 10 nm scale cylinder orientation in self-organized sugar-based block copolymer thin films. The present paper describes the orientational control of 10 nm scale cylinders in sugar-based block copolymer thin films by simply varying the composition of the annealing co-solvent. The affinity of the block copolymer to the solvent vapor could be systematically adjusted in this way. 23567349 Dietary fiber intake reduces risk for gastric cancer: a meta-analysis. The association between dietary fiber intake and gastric cancer risk has been investigated by many studies, with inconclusive results. We conducted a meta-analysis of case-control and cohort studies to analyze this association. Relevant studies were identified by searching PubMed and Embase through October 2012. We analyzed 21 articles, which included 580,064 subjects. Random-effects models were used to estimate summary relative risks. Dose-response, subgroup, sensitivity, meta-regression, and publication bias analyses were performed. The summary odds ratios of gastric cancer for the highest, compared with the lowest, dietary fiber intake was 0.58 (95% confidence interval, 0.49-0.67) with significant heterogeneity among studies (P < .001, I(2) = 62.2%). Stratified analysis for study design, geographic area, source and type of fiber, Lauren's classification, publication year, sample size, and quality score of study yielded consistent results. Dose-response analysis associated a 10-g/day increment in fiber intake with a significant (44%) reduction in gastric cancer risk. Sensitivity analysis restricted to studies with control for conventional risk factors produced similar results, and omission of any single study had little effect on the combined risk estimate. In a meta-analysis, we show that dietary fiber intake is associated inversely with gastric cancer risk; the effect probably is independent of conventional risk factors. The direction of the protective association of dietary fiber was consistent among all studies, but the absolute magnitude was less certain because of heterogeneity among the studies. Further studies therefore are required to establish this association. 23906815 Noninvasive ventilation for acute respiratory distress in children with central nervous system disorders. Acute respiratory distress (ARD) is a relatively frequent occurrence in patients suffering from central nervous system disorders (CNSD) and moderate to severe mental retardation. Whenever conventional therapy is little effective, noninvasive mechanical ventilation (NIV) is the additional treatment in patients with diseases of the peripheral nervous system. However, NIV is traditionally little employed in the acute phase in patients suffering from CNSD. In the latter, either conventional therapy is maintained or invasive mechanical ventilation is instituted if the patient's condition worsens severely. To challenge the traditional view, we conducted the study to prove that NIV is both applicable and effective in the treatment of ARD also in children with moderate to severe mental retardation. We studied 44 children with ARD secondary to pneumonia and CNSD causing moderate to severe mental retardation. The children were divided in two groups. One group received conventional therapy and NIV, the other conventional therapy only, before being advanced to invasive ventilator support when nonresponding. On admission to hospital and one hour following admission we registered pH, PaCO2, PaO2, A - a DO2 and the PaO2/FiO2 ratio. The mean hospital stay was also recorded. After one hour on NIV PaO2 and pH increased, PaCO2 decreased, A - a DO2 and PaO2/FiO2 ratio improved. No changes in the above parameters were observed in children on conventional therapy only. Hospital stay was shorter when NIV was instituted. NIV is both applicable and beneficial in stabilizing blood gases, respiratory and cardiovascular parameters also in children with CNSD. Moreover its use shortens the hospital stay. 23839489 DUSP6 regulates drug sensitivity by modulating DNA damage response. Background:Dual specificity phosphatase 6 (DUSP6) is a member of a family of mitogen-activated protein kinase phosphatases that dephosphorylates and inhibits activated ERK1/2. Dual specificity phosphatase 6 is dynamically regulated in developmental and pathological conditions such as cancer.Methods:Cancer cell lines were made deficient in DUSP6 by siRNA and shRNA silencing. Sensitivity to anti-EGFR and chemotherapeutic agents was determined in viability and apoptosis assays, and in xenografts established in SCID mice. Cellular effects of DUSP6 inactivation were analysed by proteomic methods, followed by analysis of markers of DNA damage response (DDR) and cell cycle.Results:We determined that depletion of DUSP6 reduced the viability of cancer cell lines and increased the cytotoxicity of EGFR and other targeted inhibitors, and cytotoxic agents, in vitro and in vivo. Subsequent phosphoproteomic analysis indicated DUSP6 depletion significantly activated CHEK2 and p38, which function in the DDR pathway, and elevated levels of phosphorylated H2AX, ATM, and CHEK2, for the first time identifying a role for DUSP6 in regulating DDR.Conclusion:Our results provide a novel insight into the DUSP6 function in regulating genomic integrity and sensitivity to chemotherapy in cancer. 23912578 Transcranial magnetic stimulation-may be useful as a preoperative screen of motor tract function. Transcranial motor stimulation with noninvasive cortical surface stimulation, using a high-intensity magnetic field referred to as transcranial magnetic stimulation generally, is considered a nonpainful technique. In contrast, transcranial electric stimulation of the motor tracts typically cannot be done in unanesthesized patients. Intraoperative monitoring of motor tract function with transcranial electric stimulation is considered a standard practice in many institutions for patients during surgical procedures in which there is potential risk of motor tract impairment so that the risk of paraplegia or paraparesis can be reduced. Because transcranial electric stimulation cannot be typically done in the outpatient setting, transcranial magnetic stimulation may be able to provide a well-tolerated method for evaluation of the corticospinal motor tracts before surgery. One hundred fifty-five patients aged 5 to 20 years were evaluated preoperatively with single-stimulation nonrepetitive transcranial magnetic stimulation for preoperative assessment. The presence of responses to transcranial magnetic stimulation reliably predicted the presence of responses to transcranial electric stimulation intraoperatively. No complications occurred during the testing, and findings were correlated to the clinical history and used in the setup of the surgical monitoring. 23756159 Crystal Structures of the First Condensation Domain of CDA Synthetase Suggest Conformational Changes during the Synthetic Cycle of Nonribosomal Peptide Synthetases. Nonribosomal peptide synthetases (NRPSs) are large modular macromolecular machines that produce small peptide molecules with wide-ranging biological activities, such as antibiotics and green chemicals. The condensation (C) domain is responsible for amide bond formation, the central chemical step in nonribosomal peptide synthesis. Here we present two crystal structures of the first condensation domain of the calcium-dependent antibiotic (CDA) synthetase (CDA-C1) from Streptomyces coelicolor, determined at resolutions 1.8Å and 2.4Å. The conformations adopted by CDA-C1 are quite similar in these two structures yet distinct from those seen in other NRPS C domain structures. HPLC-based reaction assays show that this CDA-C1 construct is catalytically active, and small-angle X-ray scattering experiments suggest that the conformation observed in these crystal structures could faithfully represent the conformation in solution. We have performed targeted molecular dynamics simulations, normal mode analyses and energy-minimized linear interpolation to investigate the conformational changes required to transition between the observed structures. We discuss the implications of these conformational changes in the synthetic cycle and of the observation that the "latch" that covers the active site is consistently formed in all studied C domains. 23296984 Biomimetic Methodology to Produce Polymeric Multilayered Particles for Biotechnological and Biomedical Applications. The production of multi-compartmented particles for biomedical and biotechnological applications is challenging and the existing methods usually involve wet and aggressive conditions that compromise the encapsulation efficiency of bioactive agents and the viability of cells. Biomimetic superhydrophobic surfaces allow construction of concentric multilayered polymeric systems, adding sequential layers where molecules or cells may be separately confined in compartments with high efficiency. 23838355 Influence and Pathophysiological Mechanisms of Simvastatin on Prostatic Hyperplasia in Spontaneously Hypertensive Rats. Objective: To explore the effects and mechanisms of simvastatin on prostate hyperplasia in spontaneously hypertensive rats (SHRs). Methods: Thirty-six male SHRs were randomly divided into three groups: the 10 and the 20 mg/kg/d simvastatin group and the control group. After 6 weeks the ultra-microscopic prostate structures were observed. The serum levels of interleukin-6 (IL-6), insulin-like growth factor (IGF-1) and angiotensin II (Ang-II) were measured by enzyme-linked immunosorbent assays. The endothelium-derived nitric oxide synthase (eNOS) expression was evaluated with immunohistochemistry. Results: Compared to the control group, the 20 mg/kg/d simvastatin group presented with lower absolute (p = 0.005) and relative prostate weight (p = 0.009). The basal cells and columnar cells presented with edema, condensed heterochromatin in interstitial fibroblast nuclei, widened nucleus gaps, and decreased mitochondria and endoplasmic reticulum in the 10 mg/kg/d simvastatin group, these changes were more pronounced in the 20 mg/kg/d simvastatin group. The IL-6 levels in the 10 and 20 mg/kg/d simvastatin groups were lower than those of the controls (p = 0.005 and p = 0.008). The IGF-1 levels of the 20 mg/kg/d simvastatin group were reduced compared to the control group (p = 0.016). Conclusions: Simvastatin can delay and inhibit prostatic hyperplasia and progression in SHR. These actions may be mediated through the suppression of inflammatory and growth factors. 23941588 Radiofrequency volumetric thermal ablation of fibroids: a prospective, clinical analysis of two years' outcome from the Halt trial. Although most myomas are asymptomatic, quality of life is compromised for many women with uterine fibroid disease. Twelve-month outcomes from the Halt Trial have been reported in the literature. Here we analyze the clinical success of radiofrequency volumetric thermal ablation (RFVTA) of symptomatic uterine fibroids at two years of follow up. Prospective, multicenter, outpatient interventional clinical trial of fibroid treatment by RFVTA in 124 premenopausal women (mean age, 42.4 ± 4.4 years) with symptomatic uterine fibroids and objectively confirmed heavy menstrual bleeding (≥160 to ≤500 mL).Outcome measures included: subject responses to validated questionnaires, treatment-emergent adverse events, and surgical re-intervention for fibroids at 24 months postprocedure. Continuous and categorical variables were summarized using descriptive statistics and means and percentages. Comparisons between visits were based on t-tests using repeated measures models. P-values < 0.05, adjusted for multiplicity, were statistically significant. One hundred twelve subjects were followed through 24 months. Change in symptom severity from baseline was -35.7 (95% CI, -40.1 to -31.4; p<.001). Change in health-related quality of life (HRQL) was 40.9 (95% CI, 36.2 to 45.6; p < .001). HRQL subscores also improved significantly from baseline to 24 months in all categories (concern, activities, energy/mood, control, self-consciousness, and sexual function) [p<.001]. Six patients underwent surgical re-intervention for fibroid-related bleeding between 12 and 24 months providing a re-intervention rate of 4.8% (6/124). Radiofrequency volumetric thermal ablation of myomas significantly reduces symptom severity and improves quality of life with low surgical re-intervention through 24 months of follow up. ClinicalTrials.gov: NCT00874029. 23265520 Grape seed procyanidin extract modulates proliferation and apoptosis of pancreatic beta-cells. Grape seed procyanidin extract (GSPE) modulates glucose homeostasis and insulinemia in several animal models. Under pathological conditions, insulin levels are dependent on pancreatic beta-cell functionality, as well as on the beta-cell mass expansion or apoptosis in the pancreas. In this study, we analysed the effects of GSPE on modulating apoptosis and proliferation in beta-cells. We tested the effects of GSPE in the INS-1E pancreatic beta-cell line, either under basal or altered conditions with high glucose, insulin or palmitate levels. GSPE enhanced the pro-apoptotic effect of high glucose and showed clear antiproliferative effects under high glucose, insulin and palmitate conditions. These antiproliferative effects are likely due to high molecular weight compounds contained in the extract. GSPE also modulated pro- and anti-apoptotic markers in the pancreas of rats fed a cafeteria diet, with the effect depending on the dose of GSPE and duration of treatment. Thus, GSPE is able to modulate apoptosis and proliferation of beta-cells under altered, but not basal, conditions. 23479391 Flavonoids and 3-Arylcoumarin from Pterocarpus soyauxii. Phytochemical study on the constituents of the heartwood of Pterocarpus soyauxii led to the isolation of five new isoflavonoids and one new 3-arylcoumarin, pterosonins A-F (1-6), together with 17 known analogues, among which 8, 9, and 18 were reported as natural products for the first time. Structure elucidation was achieved by way of spectroscopic measurements as well as by comparison with literature data. Only Compound 6 showed potent cytotoxicity against human non-small cell lung cancer (A549), pancreatic cancer (Panc-28), and colon carcinoma (HCT-116) cells with GI50 values at 7.39, 25, and 19.17 µM, respectively; the other isolates showed no cytotoxicity against the above tested cell lines with GI50 values > 50 µM. 23873266 Thermodynamic parameters for Eu(III) binding to Datura innoxia root material. Plants offer the potential for selective removal and sequestration of toxic heavy metals from contaminated soil. Phytoextraction of metal ions involve their transport through the plant's root system and into its shoots and leaves. This study investigates the thermodynamics of Eu(III) ion chemical interactions with Datura innoxia plant root materials under solution conditions of pH 4.0 and 5.0. Both changes in enthalpies (∆H) and entropies (∆S) of metal binding were elucidated from isotherms collected under varied temperature conditions using regularized regression data analysis and conditional affinity spectra. ∆H values for binding to root materials at pH 4.0 and 5.0 were each calculated to be +30 kJ/mol. Values of ΔS for these same materials were found to be +170 and +153 J/mol K for solution conditions of pH 4.0 and 5.0, respectively. These results suggest binding to the root material to be entropically driven (∆S° > 0 and ΔH > 0) through possible displacement of waters of solvation. 23873756 Electronic health record-based triggers to detect potential delays in cancer diagnosis. Delayed diagnosis of cancer can lead to patient harm, and strategies are needed to proactively and efficiently detect such delays in care. We aimed to develop and evaluate 'trigger' algorithms to electronically flag medical records of patients with potential delays in prostate and colorectal cancer (CRC) diagnosis. We mined retrospective data from two large integrated health systems with comprehensive electronic health records (EHR) to iteratively develop triggers. Data mining algorithms identified all patient records with specific demographics and a lack of appropriate and timely follow-up actions on four diagnostic clues that were newly documented in the EHR: abnormal prostate-specific antigen (PSA), positive faecal occult blood test (FOBT), iron-deficiency anaemia (IDA), and haematochezia. Triggers subsequently excluded patients not needing follow-up (eg, terminal illness) or who had already received appropriate and timely care. Each of the four final triggers was applied to a test cohort, and chart reviews of randomly selected records identified by the triggers were used to calculate positive predictive values (PPV). The PSA trigger was applied to records of 292 587 patients seen between 1 January 2009 and 31 December 2009, and the CRC triggers were applied to 291 773 patients seen between 1 March 2009 and 28 February 2010. Overall, 1564 trigger positive patients were identified (426 PSA, 355 FOBT, 610 IDA and 173 haematochezia). Record reviews revealed PPVs of 70.2%, 66.7%, 67.5%, and 58.3% for the PSA, FOBT, IDA and haematochezia triggers, respectively. Use of all four triggers at the study sites could detect an estimated 1048 instances of delayed or missed follow-up of abnormal findings annually and 47 high-grade cancers. EHR-based triggers can be used successfully to flag patient records lacking follow-up of abnormal clinical findings suspicious for cancer. 23850290 A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Microglia are resident immune cells of the CNS that are activated by infection, neuronal injury, and inflammation. Here, we utilize flow cytometry and deep RNA sequencing of acutely isolated spinal cord microglia to define their activation in vivo. Analysis of resting microglia identified 29 genes that distinguish microglia from other CNS cells and peripheral macrophages/monocytes. We then analyzed molecular changes in microglia during neurodegenerative disease activation using the SOD1(G93A) mouse model of amyotrophic lateral sclerosis (ALS). We found that SOD1(G93A) microglia are not derived from infiltrating monocytes, and that both potentially neuroprotective and toxic factors, including Alzheimer's disease genes, are concurrently upregulated. Mutant microglia differed from SOD1(WT), lipopolysaccharide-activated microglia, and M1/M2 macrophages, defining an ALS-specific phenotype. Concurrent messenger RNA/fluorescence-activated cell sorting analysis revealed posttranscriptional regulation of microglia surface receptors and T cell-associated changes in the transcriptome. These results provide insights into microglia biology and establish a resource for future studies of neuroinflammation. 23927274 Thermodynamic and structural signatures of water-driven methane-methane attraction in coarse-grained mW water. Hydrophobic interactions are responsible for water-driven processes such as protein folding and self-assembly of biomolecules. Microscopic theories and molecular simulations have been used to study association of a pair of methanes in water, the paradigmatic example of hydrophobic attraction, and determined that entropy is the driving force for the association of the methane pair, while the enthalpy disfavors it. An open question is to which extent coarse-grained water models can still produce correct thermodynamic and structural signatures of hydrophobic interaction. In this work, we investigate the hydrophobic interaction between a methane pair in water at temperatures from 260 to 340 K through molecular dynamics simulations with the coarse-grained monatomic water model mW. We find that the coarse-grained model correctly represents the free energy of association of the methane pair, the temperature dependence of free energy, and the positive change in entropy and enthalpy upon association. We investigate the relationship between thermodynamic signatures and structural order of water through the analysis of the spatial distribution of the density, energy, and tetrahedral order parameter Qt of water. The simulations reveal an enhancement of tetrahedral order in the region between the first and second hydration shells of the methane molecules. The increase in tetrahedral order, however, is far from what would be expected for a clathrate-like or ice-like shell around the solutes. This work shows that the mW water model reproduces the key signatures of hydrophobic interaction without long ranged electrostatics or the need to be re-parameterized for different thermodynamic states. These characteristics, and its hundred-fold increase in efficiency with respect to atomistic models, make mW a promising water model for studying water-driven hydrophobic processes in more complex systems. 23312126 The clinical quandary of counseling the moribund critical care patient-a registry analysis of postsurgical outcomes. To provide outcomes data to intensivists and surgeons for counseling patients and family members when considering a surgical intervention in a moribund patient. Retrospective analysis of prospectively collected data from the American College of Surgeons National Surgical Quality Improvement Program database in moribund patients undergoing general surgical procedures. Out of 633,262 patients available in the national registry, 2063 (0.3%) were of moribund status. Post-operative mortality was 52.8% for moribund patients. Those who died had higher rates of compromised respiratory, renal and cognitive dysfunction, were older, less independent prior to surgery and had generally longer surgeries. 83% of patients experienced a major complication including mortality and 17 % of patients experienced minor complications. The moribund patient is not as grave as once thought and surgery on these patients may not be futile given the 47% survival rate at 30 days. Postoperative complication rates are high. The data presented provide a meaningful tool for the clinicians in counseling patients and families on the expectations when considering a surgical intervention for moribund patients. 23865662 The Association Between Client Characteristics and Recovery in California's Comprehensive Community Mental Health Programs. Objectives. In November 2004, California voters passed the Mental Health Services Act, which allocated more than $3 billion for comprehensive community mental health programs. We examined whether these county-level programs, known as "full service partnerships," promoted independent living arrangements (i.e., recovery) among their clients. Methods. We used Markov chain models to identify probabilities of residential transitions among 8 living arrangements (n = 9208 adults followed up to 4 years). We modeled these transitions on the basis of patterns of program participation and clinical and sociodemographic characteristics. Results. Interrupted program participation and substance abuse were significantly associated with a reduced likelihood of independent living and a greater probability of homelessness and incarceration. Persons with schizophrenia were the least likely to live independently, followed by persons with bipolar disorder. Compared with Whites, non-Whites were more frequently found to be homeless or in jail. Conclusions. Clients with sustained enrollment in California's comprehensive community mental health programs appear most likely to transition to independent living. The likelihood of this transition, however, shows a disparity in that ethnic minority clients appear least likely to transition to independent living. (Am J Public Health. Published online ahead of print July 18, 2013: e1-e7. doi:10.2105/AJPH.2013.301233). 22533311 Dietary supplementation of Zingiber officinale and Zingiber zerumbet to heat-stressed broiler chickens and its effect on heat shock protein 70 expression, blood parameters and body temperature. The present study was conducted to assess the effects of dietary supplementation of Zingiber officinale and Zingiber zerumbet and to heat-stressed broiler chickens on heat shock protein (HSP) 70 density, plasma corticosterone concentration (CORT), heterophil to lymphocyte ratio (HLR) and body temperature. Beginning from day 28, chicks were divided into five dietary groups: (i) basal diet (control), (ii) basal diet +1%Z. zerumbet powder (ZZ1%), (iii) basal diet +2%Z. zerumbet powder (ZZ2%), (iv) basal diet +1%Z. officinale powder (ZO1%) and (v) basal diet +2%Z. officinale powder (ZO2%). From day 35-42, heat stress was induced by exposing birds to 38 ±â€ƒ1 °C and 80% RH for 2 h/day. Irrespective of diet, heat challenge elevated HSP70 expression, CORT and HLR on day 42. On day 42, following heat challenge, the ZZ1% birds showed lower body temperatures than those of control, ZO1% and ZO2%. Neither CORT nor HLR was significantly affected by diet. The ZO2% and ZZ2% diets enhanced HSP70 expression when compared to the control groups. We concluded that dietary supplementation of Z. officinale and Z. zerumbet powder may induce HSP70 reaction in broiler chickens exposed to heat stress. 23902799 Cross-linking of IgGs bound on circulating neutrophils leads to an activation of endothelial cells: possible role of rheumatoid factors in rheumatoid arthritis-associated vascular dysfunction. Rheumatoid arthritis is characterized by the presence of circulating auto-antibodies, including rheumatoid factors, which recognize the Fc portion of IgGs. The neutrophil is the most abundant circulating leukocyte and it expresses high levels of FcγRs on its surface. The aim of the present study was to examine the capacity of circulating human neutrophils to be activated by rheumatoid factors and the consequences of these events on endothelium. Neutrophil-bound IgGs were cross-linked with anti-human IgGs to mimick the presence of circulating rheumatoid factors and FcγRs-dependent signalling events and functions were examined. The IgG and IgM composition of rheumatoid factors isolated from the serum of RA patients was characterized. Adhesion of neutrophils to endothelial cells was quantified in response to the addition of rheumatoid factors. Cross-linking of IgGs bound on neutrophils leads to FcγRs-dependent tyrosine phosphorylation, mobilisation of intracellular calcium and the extracellular release of superoxide anions and lysozyme. Incubation of endothelial cells with the supernatant of activated neutrophils increases ICAM-1 expression and IL-8 production by endothelial cells. Finally, rheumatoid factors enhance neutrophil adhesion to endothelial cells. Our results show that activation of neutrophils' FcγRs by rheumatoid factors could participate in rheumatoid arthritis-associated vascular damage. 23685136 Photocatalytic degradation of a widely used insecticide Thiamethoxam in aqueous suspension of TiO2: adsorption, kinetics, product analysis and toxicity assessment. This paper deals with the study of photocatalyzed degradation of an insecticide, Thiamethoxam in aqueous suspension of TiO2. The adsorption of Thiamethoxam on TiO2 surface under dark conditions was also investigated in order to find out equilibrium adsorption constant. The degradation kinetics was studied using spectrophotometric method under various conditions such as substrate concentration, type of catalyst, catalyst dosage, pH, and in the presence of electron acceptors such as hydrogen peroxide, potassium bromate, and ammonium persulphate under continuous purging of atmospheric oxygen, and the degradation rates were found to be strongly influenced by these parameters. The results manifested that the photocatalysis of Thiamethoxam follows pseudo-first-order kinetics. The toxicity assessments of the irradiated samples were carried out using human erythrocytes as a model system under in vitro conditions. GC-MS study showed the formation of several intermediate products which were characterised based on their molecular mass and mass fragmentation pattern. A probable mechanism for the formation of various products formed during the photocatalytic process of Thiamethoxam was also proposed. 23727447 What basal ganglia changes underlie the parkinsonian state? The significance of neuronal oscillatory activity. One well accepted functional feature of the parkinsonian state is the recording of enhanced beta oscillatory activity in the basal ganglia. This has been demonstrated in patients with Parkinson's disease (PD) and in animal models such as the rat with 6-hydroxydopamine (6-OHDA)-induced lesion and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, all of which are associated with severe striatal dopamine depletion. Neuronal hyper-synchronization in the beta (or any other) band is not present despite the presence of bradykinetic features in the rat and monkey models, suggesting that increased beta band power may arise when nigro-striatal lesion is advanced and that it is not an essential feature of the early parkinsonian state. Similar observations and conclusions have been previously made for increased neuronal firing rate in the subthalamic and globus pallidus pars interna nuclei. Accordingly, it is suggested that early parkinsonism may be associated with dynamic changes in basal ganglia output activity leading to reduced movement facilitation that may be an earlier feature of the parkinsonian state. 23455616 Complete genotyping in conservation genetics, a case study of a critically endangered shrub, Stachyurus macrocarpus var. prunifolius (Stachyuraceae) in the Ogasawara Islands, Japan. More than 3,000 species are listed as critically endangered worldwide, and various conservation measures such as habitat restoration, assisted reproduction and establishment of ex situ populations would be required to prevent their extinction. We determined the genotype of all 15 known wild clumps using nuclear microsatellite markers for Stachyurus macrocarpus var. prunifolius, a critically endangered shrub endemic to the Ogasawara (Bonin) Islands of Japan. In addition, the seedlings propagated from seeds taken from one wild clumps were genotyped. The results of complete genotyping showed that both wild and nursery populations had population-specific alleles. Two alleles were detected only in the nursery population, indicating the existence of undiscovered mature individuals in the wild. Four alleles were found only in the wild and were detected in two geographically isolated clumps, and this finding may propose that re-introduction and transplantation between different sites requires sensitive handling in terms of the conservation of evolutionary significant units. These results show that complete genotyping can provide essential genetic and ecological information for effective management of endangered species. 23543084 XRCC1 Arg399Gln, Arg194Trp, and Arg280His polymorphisms in esophageal cancer risk: a meta-analysis. The X-ray repair cross-complementation group 1 (XRCC1) protein plays an important role in base excision repair. To elucidate the role of XRCC1 Arg399Gln, Arg194Trp and Arg280His genotypes in esophageal cancer risk, all available studies were considered in the present meta-analysis. Eligible studies were identified by searching several electronic databases for relevant reports published before June 2012. According to the inclusion criteria and exclusion criteria, a total of 21 eligible studies were included in the pooled analyses. Among the 21 studies, 18 focused on Arg399Gln polymorphism, 11 described the Arg194Trp, and 4 articles investigated on Arg280His. Our analysis suggested that there was no evidence of significant association between XRCC1 Arg399Gln polymorphism and esophageal cancer risk in any genetic model. In the stratified analysis by ethnicity for Arg399Gln polymorphism and esophageal cancer, the results showed that Arg399Gln polymorphism was not associated with esophageal cancer risk. Only 4 studies analyzed the relationship between XRCC1 Arg280His polymorphism and the risk of esophageal cancer. The Arg/His and His/His genotypes were not significantly associated with increased risk of EC. A similar negative association was maintained in dominant and recessive models. However, for XRCC1 Arg194Trp polymorphism, our study showed individuals carrying the variant genotype Trp/Trp had a significant increased risk of esophageal cancer (OR = 1.295, 95 % CI 1.053-1.591, P = 0.014). In addition, increased associations were found in recessive model (OR = 1.332, 95 % CI 1.093-1.624, P = 0.005). Our meta-analysis suggested that Arg194Trp Trp allele might act as a risk allele in its association with esophageal cancer. 23668599 rs2072135, a low-penetrance variant for chronic lymphocytic leukaemia? Recent multi-stage genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) that are robustly associated with chronic lymphocytic leukaemia (CLL) risk. Given that most of these SNPs map to non-coding regions of the genome, it suggests that the functional basis of many GWAS signals will be through differential gene expression. By referencing publically accessible expression quantitative trait loci (eQTL) data on lymphoblastoid cells lines (LCLs) we have globally demonstrated an association between GWAS P-values and eQTLs, consistent with much of the variation in CLL risk being defined by variants impacting on gene expression. To explore using eQTL data to select GWAS SNPs for replication, we genotyped rs2072135 (GWAS P-value = 0·0024, eQTL P-value = 1·510(-19)) in five independent case-control series totalling 1968 cases and 3538 controls. While not attaining statistical significance (combined P-value = 1 × 10(-4)), rs2072135 defines a promising risk locus for CLL. Incorporating eQTL information offers an attractive strategy for selecting SNPs from GWAS for validation. 23590300 A Decoy Oligonucleotide to NF-κB Delivered through Inhalable Particles Prevents LPS-Induced Rat Airway Inflammation. The inflammatory process plays a crucial role in the onset and progression of several lung pathologies, including cystic fibrosis (CF), and the involvement of NF-κB is widely recognized. The specific inhibition of NF-κB by decoy oligonucleotides delivered within the lung may be beneficial, although rationally designed systems are needed to optimize their pharmacological response. Prompted by this need, we have developed and tested in vivo an inhalable dry powder for the prolonged delivery of a decoy oligodeoxynucleotide to NF-κB (dec-ODN), consisting of large porous particles (LPPs) based on poly(lactic-co-glycolic) acid. First, LPPs containing dec-ODN (dec-ODN LPPs) were engineered to meet the aerodynamic criteria crucial for pulmonary delivery, to gain an effective loading of dec-ODN, to sustain its release, and to preserve its structural integrity in lung lining fluids. We then investigated the effects of dec-ODN LPPs in a rat model of lung inflammation induced by the intratracheal aerosolization of LPS from Pseudomonas aeruginosa. The results show that a single intratracheal insufflation of dec-ODN LPPs reduced the bronchoalveolar neutrophil infiltration induced by LPS for up to 72 hours, whereas naked dec-ODN was able to inhibit it only at 6 hours. The persistent inhibition of neutrophil infiltrate was associated with reduced NF-κB/DNA binding activity, as well as reduced IL-6, IL-8, and mucin-2 mRNA expression in lung homogenates. We consider it noteworthy that the developed LPPs, preventing the accumulation of neutrophils and NF-κB-related gene expression, may provide a new therapeutic option for the local treatment of inflammation associated with lung disease. 23899319 Localized versus generalist phenotypes in a broadly distributed tropical mammal: how is intraspecific variation distributed across disparate environments? The extent of phenotypic differentiation in response to local environmental conditions is a key component of species adaptation and persistence. Understanding the structuring of phenotypic diversity in response to local environmental pressures can provide important insights into species evolutionary dynamics and responses to environmental change. This work examines the influence of steep environmental gradients on intraspecific phenotypic variation and tests two hypotheses about how the tropical soft grass mouse, Akodon mollis (Cricetidae, Rodentia), contends with the disparate environmental conditions encompassed by its broad distribution. Specifically, we test if the species expresses a geographically unstructured, or generalist, phenotype throughout its range or if it shows geographically localized morphological differentiation across disparate environments. Using geometric morphometric and ecomorphological analyses of skull shape variation we found that despite distinct environmental conditions, geographically structured morphological variation is limited, with the notable exception of a distinct morphological disjunction at the high-elevation forest-grassland transition in the southern portion of A. mollis distribution. Based on genetic analyses, geographic isolation alone does not explain this localized phenotype, given that similar levels of genetic differentiation were also observed among individuals inhabiting other ecosystems that are nonetheless not distinct morphologically. Instead of phenotypic specialization across environments in these tropical mountains, there was limited differentiation of skull shape and size across the broad range of A. mollis, with the exception of individuals from the puna, the highest-elevation ecosystem. The high morphological variance among individuals, together with a weak association with local environmental conditions, not only highlights the flexibility of A. mollis' skull, but also highlights the need for further study to understand what maintains the observed morphological patterns. The work also indicates that mechanisms other than processes linked to local ecological specialization as a driver of diversification may contribute to the high diversity of this tropical region. 23229518 Relative oral bioavailability of 3-MCPD from 3-MCPD fatty acid esters in rats. In order to quantify the relative oral bioavailability of 3-chloropropane-1,2-diol (3-MCPD) from 3-MCPD fatty acid diesters in vivo, 1,2-dipalmitoyl-3-chloropropane-1,2-diol (3-MCPD diester) and 3-MCPD were orally applied to rats in equimolar doses. In both cases, the time courses of 3-MCPD concentrations were measured in blood, various organs, tissues and intestinal luminal contents. The results show that 3-MCPD is released by enzymatic hydrolysis from the 3-MCPD diester in the gastrointestinal tract and distributed to blood, organs and tissues. Based on the measurements in blood, the areas under the curve (AUC) for 3-MCPD were calculated. By comparing both AUC, the relative amount of 3-MCPD bioavailable from the 3-MCPD diester was calculated to be 86 % on average of the amount bioavailable following administration of 3-MCPD. In view of limited experimental data, it is justified for the purpose of risk assessment to assume complete hydrolysis of the diesters in the gastro-intestinal tract. Therefore, assessment of the extent of exposure to 3-MCPD released from its fatty acid esters should be performed in the same way as exposure to the same molar quantity of 3-MCPD. 23851426 A robust transparent and anti-fingerprint superhydrophobic film. A thin film of polyaniline (PANI) nanofibers on the stainless steels with fluoro-thiol modification was prepared through an optimal polymerization time of aniline using HClO4 as a dopant, showing robust superhydrophobic, transparent and anti-fingerprint properties. 23231586 New iridoid glycoside and triterpenoid glycoside from Premna fulva. Liquid chromatography-photodiode array detector-mass spectrometry-based chemical investigation of the leaves and stems of Premna fulva yielded one new iridoid glycoside (1), one new triterpenoid glycoside (2) along with six known compounds isolated for the first time from the genus. Their structures were established on the basis of extensive spectroscopic data analyses and chemical methods. 23918359 Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice. Transgenic mice expressing the mouse interleukin 33 (IL-33) gene driven by a keratin 14 promoter were generated. The skin-selective expression of the IL-33 gene was enhanced, and intense immunofluorescence for IL-33 was evident in the nuclei of the epidermis. Spontaneous itchy dermatitis developed in those mice at 6-8 wk of age in specific pathogen-free conditions. In the lesional skin, the epidermis was thickened and the eosinophils were infiltrated with increased expression of the eosinophil peroxidase and major basic protein genes. Mast cells were also abundant there, and blood histamine and total IgE levels were high. Those phenotypes closely resemble the features of atopic dermatitis. In peripheral blood and lesional skin, IL-5, IL-13, regulated upon activation, normally T-expressed, and presumably secreted (RANTES)/CCL5, and Eotaxin 1/CCL11 were increased, whereas TNF-α, IFN-γ, and thymic stromal lymphopoietin (TSLP) were unaltered. Furthermore, the proportion of group 2 innate lymphoid cells (ILC2s), which produce IL-5, were significantly increased in the lesional skin, peripheral blood, and regional lymph nodes. The dermatitis with eosinophil infiltration was improved by the administration of an anti-IL-5 antibody. These results suggest that the expression of IL-33 in the skin activates an immune response involving ILC2 and that this process might play a crucial role in the pathogenesis of allergic inflammation that is characteristic of atopic dermatitis. 23312348 Quantitative photoacoustic imaging of nanoparticles in cells and tissues. Quantitative visualization of nanoparticles in cells and tissues, while preserving the spatial information, is very challenging. A photoacoustic imaging technique to depict the presence and quantity of nanoparticles is presented. This technique is based on the dependence of the photoacoustic signal on both the nanoparticle quantity and the laser fluence. Quantitative photoacoustic imaging is a robust technique that does not require knowledge of the local fluence, but a relative change in the fluence. This eliminates the need for sophisticated methods or models to determine the energy distribution of light in turbid media. Quantitative photoacoustic imaging was first applied to nanoparticle-loaded cells, and quantitation was validated by inductively coupled plasma mass spectrometry. Quantitative photoacoustic imaging was then extended to xenograft tumor tissue sections, and excellent agreement with traditional histopathological analysis was demonstrated. Our results suggest that quantitative photoacoustic imaging may be used in many applications including the determination of the efficiency and effectiveness of molecular targeting strategies for cell studies and animal models, the quantitative assessment of photoacoustic contrast agent biodistribution, and the validation of in vivo photoacoustic imaging. 23937148 Carbon-Sulfur Bond Formation Catalyzed by [Pd(IPr*OMe)(cin)Cl] (cin = cinnamyl). The newly prepared [Pd(IPr*OMe)(cin)(Cl)] provides high catalytic activity for carbon-sulfur cross-coupling reactions. Non-activated and deactivated aryl halides were successfully coupled with a large variety of aryl- and alkylthiols by using this well-defined palladium N-heterocyclic carbene (NHC) complex. 23660252 An ex-vivo multiple sclerosis model of inflammatory demyelination using hyperbranched polymer. Multiple sclerosis (MS) is characterized by the presence of inflammatory demyelinating foci throughout the brain and spinal cord, accompanied by axonal and neuronal damage. Although inflammatory processes are thought to underlie the pathological changes, the individual mediators of this damage are unclear. In order to study the role of pro-inflammatory cytokines in demyelination in the central nervous system, we have utilized a hyperbranched poly(2-dimethyl-aminoethylmethacrylate) based non-viral gene transfection system to establish an inflammatory demyelinating model of MS in an ex-vivo environment. The synthesized non-viral gene transfection system was optimized for efficient transfection with minimal cytotoxicity. Organotypic brain slices were then successfully transfected with the TNF or IFNγ genes. TNF and IFNγ expression and release in cerebellar slices via non-viral gene delivery approach resulted in inflammation mediated myelin loss, thus making it a promising ex-vivo approach for studying the underlying mechanisms of demyelination in myelin-related diseases such as MS. 23774334 Preparation and characterization of lignin based macromonomer and its copolymers with butyl methacrylate. Copolymerization of butyl methacrylate (BMA) with biobutanol lignin (BBL) was achieved by free-radical polymerization (FRP) using a lignin-based macromonomer. The lignin-based macromonomer containing acrylic groups was prepared by reacting acryloyl chloride with biobutanol lignin using triethylamine (TEA) as absorb acid agentin. From the results of elemental analysis and GPC, the average degree of polymerization (DP) of BBL was estimated to be five. A detailed molecular characterization has been performed, including techniques such as (1)H NMR, (13)C NMR and UV-vis spectroscopies, which provided quantitative information about the composition of the copolymers. The changes in the solubility of lignin-g-poly(BMA) copolymers in ethyl ether were dependent on the length of poly(BMA) side chain. TGA analysis indicated that the lignin-containing poly(BMA) graft copolymers exhibited high thermal stability. The bulky aromatic group of lignin increased the glass-transition temperature of poly(BMA). In order to confirm the main structure of copolymer, (AC-g-BBL)-co-BMA copolymer was also synthesized by atom transfer radical polymerization (ATRP), and the results revealed that the copolymer prepared by ATRP had the same solution behavior as that prepared by FRP, and the lignin-based macromonomer showed no homopolymerizability due to the steric hindrance. In addition, the lignin-co-BMA copolymer had a surprisingly higher molecular weight than poly(BMA) under the same reaction condition, suggesting that a branched lignin based polymer could be formed. 23919353 Polypharmacology - Foe or Friend? Polypharmacology describes the activity of compounds at multiple targets. Current research focuses on two aspects of polypharmacology: (1) unintended polypharmacology can lead to adverse effects; (2) polypharmacology across several disease-relevant targets can improve therapeutic efficacy, prevent drug resistance, or reduce therapeutic-target-related adverse effects. This perspective reviews these interconnected aspects of polypharmacology. The first part discusses the relevance of polypharmacology for the safety of drugs, the mitigation of safety risks, and methods to identify polypharmacological compounds early in the drug discovery process. The second part discusses the advantages of polypharmacology in the treatment of multigenic diseases and infections, and opportunities for drug discovery and drug repurposing. This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy. 23620485 Variability in P-Glycoprotein Inhibitory Potency (IC50) Using Various In Vitro Experimental Systems: Implications for Universal Digoxin DDI Risk Assessment Decision Criteria. A P-glycoprotein (P-gp) IC50 working group was established with twenty-three participating pharmaceutical and contract research laboratories and one academic institution to assess inter-laboratory variability in P-gp IC50 determinations. Each lab followed their in-house protocol to determine in vitro IC50 values for sixteen inhibitors using four different test systems: Caco-2 (11 labs), MDCKII-MDR1 (6 labs) and LLC-PK1-MDR1 (4 labs) cells, and membrane vesicles containing human P-gp (5 labs). For cell models, various equations to calculate remaining transport activity (e.g. efflux ratio, unidirectional flux, net secretory flux) were also evaluated. The difference in IC50 values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC50 values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC50 values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratio based-equation generally resulted in several fold lower IC50 values compared to unidirectional or net-secretory flux equations. Statistical analysis indicated that variability in IC50 values was mainly due to inter-laboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC50 determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion paper and recommendations are provided. 23916474 An isolation technique to prevent the spread of tumor cells during radical gastrectomy for gastric carcinoma located on the anterior wall of the gastric antrum. To report an isolation technique for reducing the spread of tumor cells during radical gastrectomy for lesions located on the anterior wall of the gastric antrum. The isolation technique involves using linear cutting staplers and a waterproof membrane to completely "block" and isolate the area to be resected. Blood samples from the portal vein and peritoneal wash samples were obtained immediately after laparotomy and during surgical resection. RT-PCR was used to determine levels of carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20). Carbon nanoparticles were injected into the subserosa of the blocked region before resection to determine lymph flow out of the region. A total of 76 patients (median age, 59 years; range, 22-73 years), with tumors on the anterior wall of the gastric antrum were included (blocking group, n = 40; non-blocking group, n = 36). In the blocking group, the carbon nanoparticles did not flow beyond the blocking line. There were no significant differences between the groups in CEA or CK20 mRNA levels in portal vein blood or peritoneal wash fluid immediately after laparotomy. CEA and CK20 levels were significantly lower in portal vein blood in the blocking group during tumor resection. During a median follow-up of 30 months, the incidence of metastasis or recurrence in the blocking group was lower than the non-blocking group, although it did not reach statistical significance (17.9% vs. 25.0%, respectively). The blocking technique can reduce hematogenous and lymphatic spread of tumor cells into the systemic circulation, and may prevent metastasis or recurrence after radical gastrectomy for gastric carcinoma. 23891339 Skin Dimpling after a Closed Proximal Humerus Fracture. Skin dimpling, also known as skin puckering, is a rare occurrence after closed proximal humerus fractures. This finding is suggestive of incarceration of the skin at the fracture site and may lead to necrosis and conversion to an open fracture. Our goal is to describe our experience with skin dimpling after a proximal humerus fracture to increase awareness and recognition of this clinical presentation in the Emergency Department (ED). We report a case of a 46-year-old woman who presented to the ED with left shoulder pain and swelling after a fall. She was found to have skin dimpling over the anterior aspect of the shoulder on further examination and was diagnosed with a proximal humerus fracture after imaging. Skin dimpling is an uncommon sign associated with proximal humerus fractures that can help in diagnosis and determining course of treatment. Devastating soft tissue injury can occur if the fracture is not immediately reduced. Therefore, it is imperative that physicians be able to promptly identify the clinical presentation to prevent unwanted sequelae. 23706626 The rubber hand illusion in complex regional pain syndrome: Preserved ability to integrate a rubber hand indicates intact multisensory integration. In patients with complex regional pain syndrome (CRPS) type 1, processing of static tactile stimuli is impaired, whereas more complex sensory integration functions appear preserved. This study investigated higher order multisensory integration of body-relevant stimuli using the rubber hand illusion in CRPS patients. Subjective self-reports and skin conductance responses to watching the rubber hand being harmed were compared among CRPS patients (N=24), patients with upper limb pain of other origin (N=21, clinical control group), and healthy subjects (N=24). Additionally, the influence of body representation (body plasticity [Trinity Assessment of Body Plasticity], neglect-like severity symptoms), and clinical signs of illusion strength were investigated. For statistical analysis, 1-way analysis of variance, t test, Pearson correlation, with α=0.05 were used. CRPS patients did not differ from healthy subjects and the control group with regard to their illusion strength as assessed by subjective reports or skin conductance response values. Stronger left-sided rubber hand illusions were reported by healthy subjects and left-side-affected CRPS patients. Moreover, for this subgroup, illness duration and illusion strength were negatively correlated. Overall, severity of neglect-like symptoms and clinical signs were not related to illusion strength. However, patients with CRPS of the right hand reported significantly stronger neglect-like symptoms and significantly lower illusion strength of the affected hand than patients with CRPS of the left hand. The weaker illusion of CRPS patients with strong neglect-like symptoms on the affected hand supports the role of top-down processes modulating body ownership. Moreover, the intact ability to perceive illusory ownership confirms the notion that, despite impaired processing of proprioceptive or tactile input, higher order multisensory integration is unaffected in CRPS. 23905575 Handling of Diskus Dry Powder Inhaler in Chinese Chronic Obstructive Pulmonary Disease Patients. Abstract Background: The incorrect handling of Diskus inhalers in Chinese patients with chronic obstructive pulmonary disease (COPD) is not well documented. Objective: The present study was conducted to evaluate in detail the handling errors related to the Diskus device, and to elucidate the importance of educating COPD patients on the proper use of the device. Methods: A total of 384 COPD patients from a pulmonary clinic in China over a period of 5 years were included in the study. The compliance of COPD patients to the 13 discrete steps of Diskus usage were scored and analyzed by three measures: (1) On day 0, patients were given only a package insert on Diskus, and the handling error rate was assessed. Then the patients were given instruction on the 13-step Diskus procedure until they could demonstrate the proper technique. (2) On days 1, 2, and 3, the observation group was continuously educated on a 13-step procedure, and the percentage of patients who scored 100% for each step was recorded. The control group had no such training. (3) On days 10, 20, and 30, the percentage of all subjects correctly performing the Diskus 13-step inhalation procedure was assessed. Results: Incorrect handling techniques on Diskus usage were widely distributed among Chinese COPD patients. Step 8 ("Inhale forcefully from the beginning, slowly, deeply, and uniformly during the inspiratory phase until the lungs are full") was the most commonly mishandled step (93.8%). The total score and individual step scores of the patients from the observation group were significantly improved during 3-day continuous education. There was also a significantly higher percentage of correctly performed steps in the observation group than in the control group upon assessment on day 10 (96.24% vs. 85.63%, respectively; p<0.01), day 20 (97.31% vs. 86.09%, respectively; p<0.01), and day 30 (98.19% vs. 87.39%, respectively; p<0.01). Conclusion: Handling errors of the Diskus 13-step inhalation procedure were commonly observed in Chinese COPD patients. Continuous educational interventions and regular supervision by health-care providers are therefore crucial for the optimum use of the Diskus inhaler. 23192568 Developments in IVF legislation in a Catholic country. Some time ago an article was published in this journal relating the difficulties of legislating for InVitro Fertilization in a Catholic country and the issues and side issues which had to be faced. Since then one has approached closer to having a law which regulates this technology. However several issues continue to challenge the country. The main concern, other than IVF not being a natural method of having children is the status of the embryo. The normative values of the country in fact induces politicians to discuss an 'embryology act' rather than a 'reproductive medicine' act. At the eleventh hour Bishops continue to launch concerns which raises queries on how the debate moved forward over the past two decades. This paper tackles these issues and other more recent concerns and suggestions and takes a look at how such processes can be improved through a more rigorous understanding and logistic of dialogue, as certainly such debates should have implications for bioethics in general. Although the Church's document Donum Vitae's instructions for politicians where legislation for this technology has to occur has been vindicated, I seems that whilst many disputes have been resolved, the main conflict--that of the value of the conjugal act--has not. 23884100 Genetic variants and signatures of selective sweep of Hanwoo population (Korean native cattle). Although there have been many studies of native Korean cattle, Hanwoo, there have been no selective sweep studies in these animals. This study was performed to characterize genetic variation and identify selective signatures. We sequenced the genomes of 12 cattle, and identified 15125420 SNPs, 1768114 INDELs, and 3445 CNVs. The SNPs, INDELs, and CNVs were similarly distributed throughout the genome, and highly variable regions were shown to contain the BoLA family and GPR180, which are related to adaptive immunity. We also identified the domestication footprints of the Hanwoo population by searching for selective sweep signatures, which revealed the RCN2 gene related to BPV resistance. The results of this study may contribute to genetic improvement of the Hanwoo population in Korea. [BMB Reports 2013; 46(7): 346-351]. 23898039 T Lymphocytes Sense Antigens within Seconds and Make a Decision within One Minute. Adaptive immune responses are triggered by the rapid and sensitive detection of MHC-bound peptides by TCRs. The kinetics of early TCR/APC contacts are incompletely known. In this study, we used total internal reflection fluorescence microscopy to image human T cell membranes near model surfaces: contact was mediated by mobile protrusions of <0.4 μm diameter. The mean lifetime of contacts with a neutral surface was 8.6 s. Adhesive interactions increased mean contact time to 27.6 s. Additional presence of TCR ligands dramatically decreased contact to 13.7 s, thus evidencing TCR-mediated triggering of a pulling motion within seconds after ligand encounter. After an interaction typically involving 30-40 contacts formed during a 1-min observation period, TCR stimulation triggered a rapid and active cell spreading. Pulling events and cell spreading were mimicked by pharmacological phospholipase Cγ1 activation, and they were prevented by phospholipase Cγ1 inhibition. These results provide a quantitative basis for elucidating the earliest cell response to the detection of foreign Ags. 23618851 Investigation of design parameters in ultrasound reactors with confined channels. This paper presents a three-dimensional numercial simulation of sonochemical degradation upon cavitational activity. The model relates the simulation of the acoustic pressure distribution to the sonochemical reaction rate. As a case study, the thermal degradation of carbon tetrachloride during sonication is studied in a tubular milliscale reactor. The model is used to optimize the reactor diameter, ultrasound frequency and power dissipated to the ultrasound transducers. The results indicate that multiple transducers at a moderate power level are more efficient than one transducer with high power level. Furthermore, the average cavity volume fraction is proposed as a reaction independent parameter to estimate the optimal reactor design. Within the results obtained in this paper, it appears possible to optimise reactor design based on this parameter. 23925967 The social information processing model as a framework for explaining frequent aggression in adults with mild to moderate intellectual disabilities: a systematic review of the evidence. There is an established evidence base con-cerning the use of anger management interventions with violent offenders who have intellectual disabilities. However, there has been limited research investigating the role of social cognitive factors underpinning problems of aggression. Psychosocial sources of agg-ression in the non-disabled population are generally discussed using Social Information Processing (SIP) models. A systematic review of the available evidence was carried out to establish whether SIP offers a useful explanatory model for understanding the contribution of social cognitive factors to problems of aggression presented by people with intellectual disabilities. Whilst research relating to the SIP model remains sparse for this population, there was evidence for different patterns of processing between aggressive and non-aggressive individuals. Group diff-erences included interpretation of emotional cues, inter-personal attributions and beliefs about the outcomes of aggressive behaviour. The future direction of SIP research with people who have intellectual disabilities is discussed, along with the possibility of using this framework to help build on current initiatives to develop individually tailored interventions to work at a cognitive level with those who are aggressive and offend. 23731382 Protein-serine/threonine/tyrosine kinases in bacterial signaling and regulation. In this review, we address some recent developments in the field of bacterial protein phosphorylation, focusing specifically on serine/threonine and tyrosine kinases. We present an overview of recent studies outlining the scope of physiological processes that are regulated by phosphorylation, ranging from cell cycle, growth, cell morphology, to metabolism, developmental phenomena, and virulence. Specific emphasis is placed on Mycobacterium tuberculosis as a showcase organism for serine/threonine kinases, and Bacillus subtilis to illustrate the importance of protein phosphorylation in developmental processes. We argue that bacterial serine/threonine and tyrosine kinases have a distinctive feature of phosphorylating multiple substrates and might thus represent integration nodes in the signaling network. Some open questions regarding the evolutionary benefits of relaxed substrate selectivity of these kinases are treated, as well as the notion of nonfunctional 'background' phosphorylation of cellular proteins. We also argue that phosphorylation events for which an immediate regulatory effect is not clearly established should not be dismissed as unimportant, as they may have a role in cross-talk with other post-translational modifications. Finally, recently developed methods for studying protein phosphorylation networks in bacteria are briefly discussed. 23394857 Enterococcus spp on fomites and hands indicate increased risk of respiratory illness in child care centers. Surface-mediated transmission is a potential route for respiratory disease in child care centers, but evidence of its importance relative to other routes (eg, airborne) is limited. We tracked respiratory disease and monitored bacteria contamination on hands and fomites over 4 months during 64 visits at 2 child care centers. Staff monitored health daily by recording respiratory symptoms. We measured concentrations of Escherichia coli, Enterococcus spp, and fecal coliform in hand rinses and on select fomites. We demonstrated that symptomatic respiratory illness was positively associated with microbial contamination on hands and fomites, as measured using Enterococcus spp. Enterococcus spp were 0.28 (95% confidence interval: 0.08-0.48)-log10 (colony-forming units per 2 hands) higher when an individual had symptomatic respiratory illness. Susceptible individuals were 1.62 (95% confidence interval: 1.06-2.46) times more likely to develop respiratory illness within 4 days with every log10 increase of Enterococcus spp on hands. The findings imply that hand contamination as measured using Enterococcus spp is a risk factor for onset of respiratory illness and highlight the utility of fecal indicator bacteria as a metric for hand and fomite contamination. 23377699 Association between bisphenol A and abnormal free thyroxine level in men. Bisphenol A (BPA) is a chemical that is used in a variety of consumer products, and exposure to BPA is widespread among the general population. Recent studies have suggested that BPA may affect the thyroid and related pathways. However, human studies are still limited. The aim of this study was to determine the relationship between BPA exposure and thyroid function. We obtained survey data and blood samples from The Thai National Health Examination Survey IV 2009, a nationally representative cross-sectional survey using a multistage, stratified sampling of the Thai population. A total of 2,340 subjects aged 18-94 years were sampled for the present study. Serum BPA, TSH, FT(4), and related covariates were measured. BPA was log-transformed prior to analysis. BPA was detected in 52.8 % of serum samples with a median concentration of 0.33 (range 0-66.91) ng/mL. We excluded subjects who tested positive for thyroid autoantibody and then stratified the remaining subjects by gender; the analysis showed a significantly negative correlation between serum BPA and FT(4) levels in males (r = -0.14, P < 0.001). In contrast, no association was observed in females. BPA was not associated with TSH in either gender. This gender-related discrepancy is possibly related to androgen-related differences in the metabolism of BPA. Our preliminary results provide evidence of a negative association between BPA and FT(4) levels. Additional detailed studies are needed to investigate the temporal relationship and potential public health implications of such an association. 23873480 Quantity matching by an orangutan (Pongo abelii). An adult male orangutan (Pongo abelii) was presented with a series of delayed matching-to-sample (DMTS) tasks in which he was to match images based on (a) the number of individual animals depicted in the photograph (from 1 to 4), (b) the number of abstract shapes presented in the stimulus (from 1 to 4), or (c) the number of dots presented in the stimulus (from 1 to 4, 4-7, or 7-10). The spatial arrangement of the dots and the background color of the stimuli varied, and the size of the dots was manipulated to control for overall ratio of foreground to background. The subject's performance was not affected by these perceptual features, but was affected by the absolute difference and ratio between number of elements in the comparison stimuli. However, the relationship between these variables and his performance was not always linear as predicted by the analog magnitude model. In addition, the subject showed a high degree of transfer to novel numerosities up to ten, indicating that orangutans are capable of estimating quantity for a greater number of items than can presumably be subtilized by humans. 23835520 Analysis of worldwide Regulatory Guidance Values for less frequently regulated elemental surface soil contaminants. Guidance values are used to regulate exposure to surface soil contamination. In the United States, element guidance values have been promulgated by at least 6 federal agencies, 46 states, and several regional, city, county, territorial, and autonomous Native American jurisdictions. Guidance values have also been promulgated in at least 74 other United Nations member states. A companion manuscript examined the values applied to the eight most frequently regulated elements (Pb, Cd, As, Ni, Cr, Hg, Cu, and Zn) each for which there are at least 300 guidance values. This manuscript extends analysis to the second tier of contaminants (Sb, Ba, Be, Co, F, Mn, Mo, Se, Ag, Tl, Sn, and V) each for which there are at least 100 guidance values. These values span from 3.4 (for Sn) to 6.1 (for Be) orders of magnitude. Their distributions resemble those of lognormal random variables, but also contain non-random value clusters. On average, with the exception of cobalt, the values used in the U.S. are higher (less conservative) than those used elsewhere. Only about 44% of U.S. values and 31% of all values fall within uncertainty bounds computed for the U.S. Environmental Protection Agency health risk model applied to the elements considered. 23899356 Ciprofloxacin prophylaxis in high risk neutropenic patients: effects on outcomes, antimicrobial therapy and resistance. The use of quinolone prophylaxis in high-risk neutropenic patients is considered standard of care but the development of resistance is a concern. Previous studies have focused mainly on quinolone resistance among patients receiving prophylaxis, with very few data reporting its impact on the hospital microbial epidemiology. We analyzed a cohort of 329 episodes of chemotherapy-induced neutropenia in adults, and compared two periods: 2005 (period 1, no prophylaxis, n=110) and 2006-2008 (period 2, ciprofloxacin prophylaxis, n=219). Outcomes analyzed were the frequency of febrile neutropenia, bacteremia, duration of antibiotic therapy and hospitalization, and antimicrobial resistance to ciprofloxacin and extended-spectrum beta-lactamase [ESBL] production. We analyzed resistance rates (by patients-day) in the cohort, as well as in other patients (neutropenic and non-neutropenic, 11,975 patients-day) admitted to the hematology unit in the same period, taking into consideration the general resistance patterns in the hospital. Quinolone prophylaxis (period 2) resulted in fewer episodes of febrile neutropenia (159/219 [73%] vs. 102/110 [93%], Chi-square 18.09, p = 0.00002), and bacteremia (49/219 [22] vs. 36/110 [33%], Chi-square 4.10, p = 0.04), shorter duration of antibiotic therapy (p = 0.0002) and hospitalization (p = 0.002), but more frequent use of carbapenems (79/219 [36%] vs. 15/110 [14%], Chi-square 18.06, p = 0.0002). In addition, period 2 was associated with higher rates of quinolone resistance (6.77 vs. 3.02 per 1,000 patients-day, p = 0.03). The rate of ESBL-producing enterobacteria in the two periods was slightly higher in patients receiving quinolone prophylaxis (1.27 vs. 0.38 per 1,000 patients-day, p = 0.26) as well as in the hematology unit overall (1.59 vs. 0.53 per 1,000 patients-day, p = 0.08), but remained stable in the whole hospital (0.53 vs. 0.56 per 1,000 patients-day, p = 0.74). Ciprofloxacin prophylaxis was beneficial in high risk neutropenic patients, but important modifications in the prescription of carbapenems and on antimicrobial resistance patterns of isolates were observed. The importance of hospital or ward ecology must be taken into account when deciding for quinolone prophylaxis in high-risk neutropenic patients. 23928827 The impact of memantine in combination with acetylcholinesterase inhibitors on admission of patients with Alzheimer's disease to nursing homes: cost-effectiveness analysis in France. The costs associated with the care of Alzheimer's disease patients are very high, particularly those associated with nursing home placement. The combination of a cholinesterase inhibitor (ChEI) and memantine has been shown to significantly delay admission to nursing homes as compared to treatment with a ChEI alone. The objective of this cost-effectiveness analysis was to evaluate the economic impact of the concomitant use of memantine and ChEI compared to ChEI alone. Markov modelling was used in order to simulate transitions over time among three discrete health states (non-institutionalised, institutionalised and deceased). Transition probabilities were obtained from observational studies and French national statistics, utilities from a previous US survey and costs from French national statistics. The analysis was conducted from societal and healthcare system perspectives. Mean time to nursing home admission was 4.57 years for ChEIs alone and 5.54 years for combination therapy, corresponding to 0.98 additional years, corresponding to a gain in quality adjusted life years (QALYs) of 0.25. From a healthcare system perspective, overall costs were 98,609 for ChEIs alone and 90,268 for combination therapy, representing cost savings of 8,341. From a societal perspective, overall costs were 122,039 and 118,721, respectively, representing cost savings of 3,318. Deterministic and probabilistic (Monte Carlo simulations) sensitivity analyses indicated that combination therapy would be the dominant strategy in most scenarios. In conclusion, combination therapy with memantine and a ChEI is a cost-saving alternative compared to ChEI alone as it is associated with lower cost and increased QALYs from both a societal and a healthcare perspective. 23225148 Factors limiting device efficiency in organic photovoltaics. The power conversion efficiency of the most efficient organic photovoltaic (OPV) cells has recently increased to over 10%. To enable further increases, the factors limiting the device efficiency in OPV must be identified. In this review, the operational mechanism of OPV cells is explained and the detailed balance limit to photovoltaic energy conversion, as developed by Shockley and Queisser, is outlined. The various approaches that have been developed to estimate the maximum practically achievable efficiency in OPV are then discussed, based on empirical knowledge of organic semiconductor materials. Subsequently, approaches made to adapt the detailed balance theory to incorporate some of the fundamentally different processes in organic solar cells that originate from using a combination of two complementary, donor and acceptor, organic semiconductors using thermodynamic and kinetic approaches are described. The more empirical formulations to the efficiency limits provide estimates of 10-12%, but the more fundamental descriptions suggest limits of 20-24% to be reachable in single junctions, similar to the highest efficiencies obtained for crystalline silicon p-n junction solar cells. Closing this gap sets the stage for future materials research and development of OPV. 23835089 Assessing risks of multiple sclerosis therapies. Over the last two decades, thanks to the discovery of several pharmaceutical agents, multiple sclerosis (MS) has been transformed into a treatable disorder although the degree of therapeutic response may vary considerably. As more medications find their entry into the MS market, a clinician faces a mounting challenge of comparing risk and benefit profiles of various agents in an attempt to find the best treatment approach for each individual patient. In this review, we aim to summarize the available data on safety profiles of available MS therapies while focusing mostly on serious medication specific potential adverse events without discussing the teratogenic potential of each agent (unless there is a black box warning) or hypersensitivity reactions. Our goal is to provide a clinician with guidance on assuring the appropriate safety monitoring for patients treated with one of the agents discussed. We also comment on the future of risk management in MS and discuss possible enhancements to the current model of drug approval process and general strategies to improve the patient safety. 23026356 Assessing spatial uncertainties of land allocation using a scenario approach and sensitivity analysis: A study for land use in Europe. Land change model outcomes are vulnerable to multiple types of uncertainty, including uncertainty in input data, structural uncertainties in the model and uncertainties in model parameters. In coupled model systems the uncertainties propagate between the models. This paper assesses uncertainty of changes in future spatial allocation of agricultural land in Europe as they arise from a general equilibrium model coupled to a spatial land use allocation model. Two contrasting scenarios are used to capture some of the uncertainty in the development of typical combinations of economic, demographic and policy variables. The scenario storylines include different measurable assumptions concerning scenario specific drivers (variables) and parameters. Many of these assumptions are estimations and thus include a certain level of uncertainty regarding their true values. This leads to uncertainty within the scenario outcomes. In this study we have explored how uncertainty in national-level assumptions within the contrasting scenario assumptions translates into uncertainty in the location of changes in agricultural land use in Europe. The results indicate that uncertainty in coarse-scale assumptions does not translate into a homogeneous spread of the uncertainty within Europe. Some regions are more certain than others in facing specific land change trajectories irrespective of the uncertainty in the macro-level assumptions. The spatial spread of certain and more uncertain locations of land change is dependent on location conditions as well as on the overall scenario conditions. Translating macro-level uncertainties to uncertainties in spatial patterns of land change makes it possible to better understand and visualize the land change consequences of uncertainties in model input variables. 23648170 Tankyrases as drug targets. Tankyrase 1 and tankyrase 2 are poly(ADP-ribosyl)ases that are distinguishable from other members of the enzyme family by the structural features of the catalytic domain, and the presence of a sterile α-motif multimerization domain and an ankyrin repeat protein-interaction domain. Tankyrases are implicated in a multitude of cellular functions, including telomere homeostasis, mitotic spindle formation, vesicle transport linked to glucose metabolism, Wnt-β-catenin signaling, and viral replication. In these processes, tankyrases interact with target proteins, catalyze poly(ADP-ribosyl)ation, and regulate protein interactions and stability. The proposed roles of tankyrases in disease-relevant cellular processes have made them attractive drug targets. Recently, several inhibitors have been identified. The selectivity and potency of these small molecules can be rationalized by how they fit within the NAD(+) -binding groove of the catalytic domain. Some molecules bind to the nicotinamide subsite, such as generic diphtheria toxin-like ADP-ribosyltransferase inhibitors, whereas others bind to a distinct adenosine subsite that diverges from other diphtheria toxin-like ADP-ribosyltransferases and confers specificity. A highly potent dual-site inhibitor is also available. Within the last few years, tankyrase inhibitors have proved to be useful chemical probes and potential lead compounds, especially for specific cancers. 23835695 Inpatient Diabetes Education Is Associated With Less Frequent Hospital Readmission Among Patients With Poor Glycemic Control. OBJECTIVETo explore the relationship between inpatient diabetes education (IDE) and hospital readmissions in patients with poorly controlled diabetes.RESEARCH DESIGN AND METHODSPatients with a discharge diagnosis of diabetes (ICD-9 code 250.x) and HbA1c >9% who were hospitalized between 2008 and 2010 were retrospectively identified. All-cause first readmissions were determined within 30 days and 180 days after discharge. IDE was conducted by a certified diabetes educator or trainee. Relationships between IDE and hospital readmission were analyzed with stepwise backward logistic regression models.RESULTSIn all, 2,265 patients were included in the 30-day analysis and 2,069 patients were included in the 180-day analysis. Patients who received IDE had a lower frequency of readmission within 30 days than did those who did not (11 vs. 16%; P = 0.0001). This relationship persisted after adjustment for sociodemographic and illness-related factors (odds ratio 0.66 [95% CI 0.51-0.85]; P = 0.001). Medicaid insurance and longer stay were also independent predictors in this model. IDE was also associated with reduced readmissions within 180 days, although the relationship was attenuated. In the final 180-day model, no IDE, African American race, Medicaid or Medicare insurance, longer stay, and lower HbA1c were independently associated with increased hospital readmission. Further analysis determined that higher HbA1c was associated with lower frequency of readmission only among patients who received a diabetes education consult.CONCLUSIONSFormal IDE was independently associated with a lower frequency of all-cause hospital readmission within 30 days; this relationship was attenuated by 180 days. Prospective studies are needed to confirm this association. 23962981 Potential Pathological and Functional Links Between Long Noncoding RNAs and Hematopoiesis. Differential abundance and activity of long noncoding RNAs (lncRNAs) are recognized as the hallmark features in various diseases. We highlight the lncRNAs that play a functional role in the development of blood cells. Many lncRNAs and the protein complexes within which they interact have been implicated in various types of cancers. Multiple lncRNAs participate in normal and may be implicated in malignant hematopoiesis associated with blood cell cancers, such as leukemia, by regulating gene expression through such mechanisms as redirecting chromatin remodeling complexes and activating epigenetic silencing, either of which can inactivate tumor suppressor genes or activate oncogenes. Because of their potential importance in cancers of the blood, lncRNAs may be useful as diagnostic and prognostic markers, and it may be possible to develop lncRNA-mediated therapy. 23385390 Throwing a monkey wrench in the motor: targeting DExH/D box proteins with small molecule inhibitors. DExH/D box proteins are molecular motors that utilize the energy derived from NTP hydrolysis to perform work - from helicases that remodel RNA to RNPases that alter RNA-protein complexes. Members of this class of proteins are uniquely placed along the RNA information highway to regulate the flow of genetic information. They have been implicated in a number of nodal points encompassing nuclear, cytoplasmic, and organellar RNA-based processes. The identification and characterization of three unique natural products that selectively inhibit the activity of eukaryotic initiation factor (eIF)4A (DDX2) has provided proof-of-principle that the activity of DExH/D box family members can be selectively targeted. Extending these achievements to other DExH/D box proteins is an important future challenge for drugging this family of proteins. This article is part of a Special Issue entitled: The Biology of RNA helicases - Modulation for life. 23828293 Sex differences in blood flow restricted isotonic knee extensions to fatigue. Aim: It has been shown that females have greater muscular endurance than males and that this advantage is eliminated when blood flow is restricted. It is unknown if sex differences in dynamic endurance exist during low-load blood flow restricted (BFR) resistance exercise. The purpose of this study was to investigate sex differences in quadriceps femoris fatigability during isotonic knee extension exercise coupled with a blood flow restriction. Methods: Ten males and ten females completed three sets of low-load isotonic knee extension exercises (20% of peak torque) to volitional failure under two conditions: blood flow restricted (BFR) and non-restricted free flow (FF). The number of repetitions, exercise volume, post-exercise strength loss and surface electromyography (EMG) were measured. Results: Females performed more repetitions than males in the FF (252±37 vs. 112±17 repetitions; P<0.01) and BFR conditions (165±29 vs. 79±8 repetitions; P<0.01). Both sexes performed ~30% fewer repetitions during the BFR condition. MVC torque decreased approximately 37% following both conditions (P<0.01) and EMG activity increased (P<0.05) during the exercise bouts. Conclusion: Similar fatigue characteristics were evident in FF and BFR conditions for both sexes, and females demonstrated greater endurance, as determined by the number of repetitions completed, in both conditions. It may be beneficial to increase the relative exercise load for females in order to decrease the time under BFR. 23949447 A hierarchical three-dimensional NiCo2O4 nanowire array/carbon cloth as an air electrode for nonaqueous Li-air batteries. A 3D NiCo2O4 nanowire array/carbon cloth (NCONW/CC) was employed as the cathode for Li-air batteries with a non-aqueous electrolyte. After its discharge, novel porous ball-like Li2O2 was found to be deposited on the tip of NiCo2O4 nanowires. The special structure of Li2O2 and active sites of catalysts are also discussed. 23577302 A review on the role of quinones in renal disorders. Quinones are electron and proton carriers that play a primary role in the aerobic metabolism of virtually every cell in nature. Most physiological quinones are benzoquinones. They undergo highly regulated redox reactions in the mitochondria, Golgi apparatus, plasma membrane and endoplasmic reticulum. Important consequences of these electron transfer reactions are the production of and protection against reactive oxygen species (ROS). Quinones have been extensively studied for both their cytotoxic as well as cellular protective properties and they have been particularly useful in rational drug design. The role of quinones in medicine is explored in this literature review with a particular focus on renal diseases. Due to their high basal metabolism and detoxification role, the kidneys are particularly sensitive to oxidative stress. Regardless of the underlying etiology, ROS plays an important role in both acute kidney injury (AKI) and chronic kidney diseases (CKD). Depending on the oxidative state of the kidney, quinones can be nephrotoxoic or nephro-protective. Many factors play a role in the interaction between quinones and the kidney and the consequences of this are just beginning to be explored. 23961848 Goal or movement? Action representation within the primary motor cortex. Although facilitation of the cortico-spinal system during action observation is widely accepted, it remains controversial whether this facilitation reflects a replica of the observed movements or the goal of the observed motor acts. In the present transcranial magnetic stimulation study, we recorded motor evoked potentials from two hand muscles (first dorsal interosseous and abductor digiti minimi) while 22 healthy participants observed a hand reaching towards and grasping a bottle. To test for alternative coding levels (goal vs. movement), three relevant aspects were systematically manipulated: the type of observed movement (precision grip or whole hand grasping), situational context (bottle positioned in front of or behind a wall-like barrier), and processing stage (transcranial magnetic stimulation pulse delivered at the onset of the movement or at the moment of contact between the fingers and the object). At movement onset, motor evoked potential responses reflected the program necessary to achieve the action goal within the situational context. During movement observation, however, the type of observed movement was taken into account and a transition towards a movement-related modulation was observed. These results suggest that, rather than being exclusive alternatives, goal coding and movement coding may relate to different processing stages. 23919738 Development and validation of a patient-reported outcome instrument in partial responders to proton pump inhibitors. Abstract Objective. The Reflux Symptom Questionnaire 7-day recall (RESQ-7) was developed, in line with the US Food and Drug Administration (FDA) guidelines, to address the need for a patient-reported outcome (PRO) instrument assessing symptoms specifically in patients with gastroesophageal reflux disease (GERD) who are only partially responsive to proton pump inhibitor (PPI) therapy. Materials and methods. The RESQ-7 was constructed using patient interviews and expert consensus. The instrument was psychometrically validated in a clinical trial setting in patients with persistent GERD symptoms despite PPI therapy. Results. Evaluation of content validity yielded a 13-item structure for the RESQ-7, incorporating symptoms overlooked by existing GERD questionnaires, such as hoarseness, cough, difficulty swallowing and burping. Principal component analysis suggested a four-domain structure. All domains had a high inter-item correlation (Cronbach's α lower 95% confidence limits: 0.77-0.87 for intensity; 0.72-0.82 for frequency). Test-retest reliability was fair-to-good or excellent (intraclass correlation coefficient lower 95% confidence limits: 0.70-0.78 for intensity; 0.65-0.75 for frequency). Convergent and discriminant validity were confirmed by correlation comparisons with the Gastrointestinal Symptom Rating Scale. Discussion. The RESQ-7 demonstrated good content validity and psychometric properties in patients with GERD and a partial response to PPIs. The weekly recall makes the RESQ-7 appropriate for use in routine clinical care. The authors believe that it is the first instrument to be developed specifically for patients with a partial response to PPI therapy in line with FDA guidelines on PROs (ClinicalTrials.gov identifier: NCT00703534). 23933220 Cost effectiveness in site selection to protect native plant communities from the weed, bitou bush, in New South Wales, Australia. Government funding to protect native plant communities is usually limited. For cost effectiveness, priority sites for conservation must therefore be identified and funds allocated to protect these sites according to the quantity of communities conserved per dollar of cost. In 1999, invasion of coastal vegetation in New South Wales (NSW) by bitou bush was listed as a key threatening process under the NSW Threatened Species Conservation Act 1995. In accordance with the Act, a Threat Abatement Plan (TAP) was prepared to reduce the impacts of the weed to threatened biodiversity at priority sites. In the present study, data collected for the TAP were analysed by linear programming to determine the feasibility of achieving cost effectiveness in identifying sites and allocating funds, and to explore the impact of associated economic issues on the quantity of native plant communities that are protected. In addition to the total funds and costs per site, the quantity was influenced by alternative funding policies and different site selection strategies. Allocations that recognise these issues can enhance protection outcomes, and promote the cost effectiveness of weed management. 23335586 Sternoclavicular joint involvement in rheumatoid arthritis: clinical and ultrasound findings of a neglected joint. To describe the prevalence of sternoclavicular (SC) joint involvement and the relationship between clinical and ultrasound (US) findings in patients with rheumatoid arthritis (RA). One hundred three consecutive patients with RA and 103 age- and sex-matched healthy individuals were enrolled. Clinical evaluation and blinded US examinations of the SC joint were performed bilaterally in both groups. The presence of gray-scale synovitis, osteophytes, erosions, and intraarticular power Doppler (PD) was recorded. Interobserver agreement was calculated. A total of 412 SC joints were evaluated: 206 from patients with RA and 206 from healthy controls. In the RA group, 39 joints (19%) were found to be clinically involved (pain/swelling), in contrast to only 4 (1.9%) in the control group (P = 0.0001). In the RA group, US abnormalities were recorded in 89 SC joints (43%) compared with 36 (17%) in the healthy control group (P = 0.0001), comprising osteophytes in 59 (29%) versus 25 (12%; P = 0.0001), synovitis in 31 (15%) versus 5 (2%; P = 0.0001), erosions in 23 (11%) versus none (P = 0.0001), and intraarticular PD in 5 (2%) versus none (P = 0.03). Furthermore, a correlation between the presence of US synovitis (P < 0.001) and intraarticular PD (P < 0.0001) with a higher Disease Activity Score in 28 joints (DAS28) was found. In patients with RA, US detected a higher number of involved SC joints than with clinical assessment. Our results indicate that both gray-scale and PD US findings were more prevalent in patients with RA than in healthy controls. US synovitis and synovial hyperperfusion correlated with the DAS28, suggesting that SC joints actively participate in the systemic inflammatory process of RA. 23747777 The ATLAS ACS 2-TIMI 51 Trial and the Burden of Missing Data: (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome ACS 2-Thrombolysis In Myocardial Infarction 51). Rivaroxaban is a factor Xa inhibitor that was recently reviewed by the Food and Drug Administration as a potential therapy to reduce the risk of recurrent atherothrombotic events in patients with acute coronary syndromes. Approval of this drug would represent a paradigm shift away from dual antiplatelet therapy toward long-term triple antithrombotic therapy. However, to date, no other experimental anticoagulant agent has demonstrated a favorable risk-benefit profile in this population, in part because of the expected increased risk in major bleeding by combining aspirin, a P2Y12 receptor inhibitor, and an anticoagulant. Approvability of rivaroxaban was considered largely on the basis of the ATLAS ACS 2-TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome ACS 2-Thrombolysis In Myocardial Infarction 51) trial, which demonstrated a significant reduction in a composite of cardiovascular death, myocardial infarction, and stroke. Although the primary efficacy endpoint was met, a substantial amount of missing data was observed. We discuss the impact of missing data in this trial, its implications for informative censoring of safety events (major bleeding), and implications for future cardiovascular outcomes trials. 23643924 Spatio-temporal Granger causality: a new framework. That physiological oscillations of various frequencies are present in fMRI signals is the rule, not the exception. Herein, we propose a novel theoretical framework, spatio-temporal Granger causality, which allows us to more reliably and precisely estimate the Granger causality from experimental datasets possessing time-varying properties caused by physiological oscillations. Within this framework, Granger causality is redefined as a global index measuring the directed information flow between two time series with time-varying properties. Both theoretical analyses and numerical examples demonstrate that Granger causality is a monotonically increasing function of the temporal resolution used in the estimation. This is consistent with the general principle of coarse graining, which causes information loss by smoothing out very fine-scale details in time and space. Our results confirm that the Granger causality at the finer spatio-temporal scales considerably outperforms the traditional approach in terms of an improved consistency between two resting-state scans of the same subject. To optimally estimate the Granger causality, the proposed theoretical framework is implemented through a combination of several approaches, such as dividing the optimal time window and estimating the parameters at the fine temporal and spatial scales. Taken together, our approach provides a novel and robust framework for estimating the Granger causality from fMRI, EEG, and other related data. 23949951 The translocation t(2;11)(p21;q23) without MLL gene rearrangement-a possible marker of good prognosis in myelodysplastic syndrome patients. The translocation t(2;11)(p21;q23) is associated with de novo myelodysplastic syndromes (MDS) and has an overall frequency of approximately 1%. The outcome of MDS patients with this translocation is not clear until now, because most of the clinical data addressing the t(2;11)(p21;q23) has been collected without investigating the status of the mixed lineage leukemia (MLL) gene. In this report, we present seven new patients with MDS diagnosis and the t(2;11)(p21;q23) in bone marrow cells; all of them without MLL gene rearrangement. They were found in two databases consisting of 1185 patients of two Czech institutions. These patients tended to be younger and showed a strong male predominance. A cytological and histological assessment of bone marrow at diagnosis revealed only mild MDS with marked dysplasia in megakaryopoiesis. Similar to other primary abnormalities in MDS (e.g. deletion of 11q), the t(2;11)(p21;q23) was frequently associated with deletion of 5q. Our results stress the common clinicopathological features of this entity and indicate that the t(2;11)(p21;q23) may be associated with a good prognosis for MDS patients (median survival 72 months). Copyright © 2013 John Wiley & Sons, Ltd. 23246690 Macrophages and fibrosis: How resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repair. Certain macrophage phenotypes contribute to tissue fibrosis, but why? Tissues host resident mononuclear phagocytes for their support to maintain homeostasis. Upon injury the changing tissue microenvironment alters their phenotype and primes infiltrating monocytes toward pro-inflammatory macrophages. Several mechanisms contribute to their deactivation and macrophage priming toward anti-inflammatory and pro-regenerative macrophages that produce multiple cytokines that display immunosuppressive as well as pro-regeneratory effects, such as IL-10 and TGF-beta1. Insufficient parenchymal repair creates a tissue microenvironment that becomes dominated by multiple growth factors that promote the pro-fibrotic macrophage phenotype that itself produces large amounts of such growth factors that further support fibrogenesis. However, the contribution of resident mononuclear phagocytes to physiological extracellular matrix turnover implies also their fibrolytic effects in the late stage of tissue scaring. Fibrolytic macrophages break down fibrous tissue, but their phenotypic characteristics remain to be described in more detail. Together, macrophages contribute to tissue fibrosis because the changing tissue environments prime them to assist and orchestrate all phases of tissue injury and repair. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. 23720053 Cancer research advocacy: past, present, and future. In this article, we present a brief history of cancer advocacy and discuss the variety of ways advocates have become involved in cancer research and subsequently present principles that establish a framework for successful research advocacy based on a review of many early initiatives coupled with our knowledge as long-time cancer advocates. Challenges to effective advocacy are described, and recommendations for increasing meaningful contributions by research advocates are proposed. The purpose of this article is to discuss the exciting field of research advocacy and to help shape a more productive future for advocates and their scientific collaborators. Cancer Res; 73(15); 4611-5. ©2013 AACR. 22128867 Attitude, knowledge and behaviour towards evidence-based medicine of physical therapists, students, teachers and supervisors in the Netherlands: a survey. Rationale, aims and objectives  Evidence-based medicine (EBM) has gained widespread acceptance in physical therapy. However, because little is known about the attitudes, knowledge and behaviour of physical therapists towards EBM, and their participation in research to generate EBM, we explored these aspects among physical therapy students, teachers, supervisors and practising physical therapists. Methods  This is a cross-sectional survey in which participants completed a web-based questionnaire to determine their attitudes, knowledge and behaviour regarding EBM, and their participation in research. Results  Questionnaires were sent to 814 participants of which 165 were returned. The overall mean score for attitude was 4.3 [standard deviation (SD) 1.0; range 1-7], which indicates a weak positive attitude. Teachers scored the highest (4.9, SD 1.2) and students the lowest (4.1, SD 0.8). Although most participants had some understanding of the technical terms used in EBM, only teachers felt able to explain these terms to others. Of the students, 45% rated their perceived EBM knowledge as bad and 45% as average, whereas 78% of the teachers considered that they had good knowledge. To answer clinical questions, most students generally use textbooks (96%) and the opinion of their supervisors (87.7%). Conclusions  There is a weak positive attitude of physical therapists, teachers, supervisors and students towards participating in research in general practice, but there is a lack of knowledge and active behaviour regarding EBM, especially among physical therapy students. 23772613 The oral mucosa immune environment and oral transmission of HIV/SIV. The global spread of human immunodeficiency virus (HIV) is dependent on the ability of this virus to efficiently cross from one host to the next by traversing a mucosal membrane. Unraveling how mucosal exposure of HIV results in systemic infection is critical for the development of effective therapeutic strategies. This review focuses on understanding the immune events associated with the oral route of transmission (via breastfeeding or sexual oral intercourse), which occurs across the oral and/or gastrointestinal mucosa. Studies in both humans and simian immunodeficiency virus (SIV) monkey models have identified viral changes and immune events associated with oral HIV/SIV exposure. This review covers our current knowledge of HIV oral transmission in both infants and adults, the use of SIV models in understanding early immune events, oral immune factors that modulate HIV/SIV susceptibility (including mucosal inflammation), and interventions that may impact oral HIV transmission rates. Understanding the factors that influence oral HIV transmission will provide the foundation for developing immune therapeutic and vaccine strategies that can protect both infants and adults from oral HIV transmission. 23958517 Current understanding of molecular and cellular mechanisms in fibroplasia and angiogenesis during acute wound healing. Cutaneous wound healing ultimately functions to facilitate barrier restoration following injury-induced loss of skin integrity. It is an evolutionarily conserved, multi-cellular, multi-molecular process involving co-ordinated inter-play between complex signalling networks. Cellular proliferation is recognised as the third stage of this sequence. Within this phase, fibroplasia and angiogenesis are co-dependent processes which must be successfully completed in order to form an evolving extracellular matrix and granulation tissue. The resultant structures guide cellular infiltration, differentiation and secretory profile within the wound environment and consequently have major influence on the success or failure of wound healing. This review integrates in vitro, animal and human in vivo studies, to provide up to date descriptions of molecular and cellular interactions involved in fibroplasia and angiogenesis. Significant molecular networks include adhesion molecules, proteinases, cytokines and chemokines as well as a plethora of growth factors. These signals are produced by, and affect behaviour of, cells including fibroblasts, fibrocytes, keratinocytes, endothelial cells and inflammatory cells resulting in significant cellular phenotypic and functional plasticity, as well as controlling composition and remodelling of structural proteins including collagen and fibronectin. The interdependent relationship between angiogenesis and fibroplasia relies on dynamic reciprocity between cellular components, matrix proteins and bioactive molecules. Unbalanced regulation of any one component can have significant consequences resulting in delayed healing, chronic wounds or abnormal scar formation. Greater understanding of angiogenic and fibroplastic mechanisms underlying chronic wound pathogenesis has identified novel therapeutic targets and enabled development of improved treatment strategies including topical growth factors and skin substitutes. 23425029 Accurate semiexperimental structure of 1,3,4-oxadiazole by the mixed estimation method. In order to determine an accurate equilibrium structure for 1,3,4-oxadiazole, microwave transitions and ground-state rotational constants are reported for the parent species and for the (18)O isotopologue measured in natural abundance. These rotational constants along with those of the (13)C, (15)N, and D1 species were used together with vibration-rotation constants calculated from a cubic force field calculated at the B3LYP/6-311+G(3df,2pd) level of theory to derive a semiexperimental equilibrium structure. However, the results of this fit were not satisfactory; therefore, the structure was later significantly improved by the mixed estimation method. In this method, internal coordinates from good-quality quantum chemical calculations (with appropriate uncertainties) are fitted simultaneously with moments of inertia of the full set of isotopologues. The accuracy of this structure has been confirmed by using an extrapolation technique. All elements of the (14)N nuclear quadrupole coupling tensor have been determined. 23566055 Combinatorial Treatment of Tart Cherry Extract and Essential Fatty Acids Reduces Cognitive Impairments and Inflammation in the mu-p75 Saporin-Induced Mouse Model of Alzheimer's Disease. Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects more than five million Americans and is characterized by a progressive loss of memory, loss of cholinergic neurons in the basal forebrain, formation of amyloid plaques and neurofibrillary tangles, and an increase in oxidative stress. Recent studies indicate that dietary supplements of antioxidants and omega-3 and omega-6 fatty acids may reduce the cognitive deficits in AD patients. The current study tested a combinatorial treatment of antioxidants from tart cherry extract and essential fatty acids from Nordic fish and emu oils for reducing cognitive deficits in the mu-p75 saporin (SAP)-induced mouse model of AD. Mice were given daily gavage treatments of Cerise(®) Total-Body-Rhythm™ (TBR; containing tart cherry extract, Nordic fish oil, and refined emu oil) or vehicle (methylcellulose) for 2 weeks before intracerebroventricular injections of the cholinergic toxin, mu-p75 SAP, or phosphate-buffered saline. The TBR treatments continued for an additional 17 days, when the mice were tested on a battery of cognitive and motor tasks. Results indicate that TBR decreased the SAP-induced cognitive deficits assessed by the object-recognition, place-recognition, and Morris-water-maze tasks. Histological examination of the brain tissue indicated that TBR protected against SAP-induced inflammatory response and loss of cholinergic neurons in the area around the medial septum. These findings indicate that TBR has the potential to serve as an adjunctive treatment which may help reduce the severity of cognitive deficits in disorders involving cholinergic deficits, such as AD. 22714651 Studying the recovery procedure for the time-dependent transmission rate(s) in epidemic models. Determining the time-dependent transmission function that exactly reproduces disease incidence data can yield useful information about disease outbreaks, including a range potential values for the recovery rate of the disease and could offer a method to test the "school year" hypothesis (seasonality) for disease transmission. Recently two procedures have been developed to recover the time-dependent transmission function, β(t), for classical disease models given the disease incidence data. We first review the β(t) recovery procedures and give the resulting formulas, using both methods, for the susceptible-infected-recovered (SIR) and susceptible-exposed-infected-recovered (SEIR) models. We present a modification of one procedure, which is then shown to be identical to the other. Second, we explore several technical issues that appear when implementing the procedure for the SIR model; these are important when generating the time-dependent transmission function for real-world disease data. Third, we extend the recovery method to heterogeneous populations modeled with a certain SIR-type model with multiple time-dependent transmission functions. Finally, we apply the β(t) recovery procedure to data from the 2002-2003 influenza season and for the six seasons from 2002-2003 through 2007-2008, for both one population class and for two age classes. We discuss the consequences of the technical conditions of the procedure applied to the influenza data. We show that the method is robust in the heterogeneous cases, producing comparable results under two different hypotheses. We perform a frequency analysis, which shows a dominant 1-year period for the multi-year influenza transmission function(s). 22914798 Group II metabotropic glutamate receptor type 2 allosteric potentiators prevent sodium lactate-induced panic-like response in panic-vulnerable rats. Rats with chronic inhibition of GABA synthesis by infusion of l-allyglycine, a glutamic acid decarboxylase inhibitor, into their dorsomedial/perifornical hypothalamus are anxious and exhibit panic-like cardio-respiratory responses to treatment with intravenous (i.v.) sodium lactate (NaLac) infusions, in a manner similar to what occurs in patients with panic disorder. We previously showed that either NMDA receptor antagonists or metabotropic glutamate receptor type 2/3 receptor agonists can block such a NaLac response, suggesting that a glutamate mechanism is contributing to this panic-like state. Using this animal model of panic, we tested the efficacy of CBiPES and THIIC, which are selective group II metabotropic glutamate type 2 receptor allosteric potentiators (at 10-30 mg/kg i.p.), in preventing NaLac-induced panic-like behavioral and cardiovascular responses. The positive control was alprazolam (3mg/kg i.p.), a clinically effective anti-panic benzodiazepine. As predicted, panic-prone rats given a NaLac challenge displayed NaLac-induced panic-like cardiovascular (i.e. tachycardia and hypertensive) responses and "anxiety" (i.e. decreased social interaction time) and "flight" (i.e. increased locomotion) -associated behaviors; however, systemic injection of the panic-prone rats with CBiPES, THIIC or alprazolam prior to the NaLac dose blocked all NaLac-induced panic-like behaviors and cardiovascular responses. These data suggested that in a rat animal model, selective group II metabotropic glutamate type 2 receptor allosteric potentiators show an anti-panic efficacy similar to alprazolam. 23849273 Immigrant enclaves and obesity in preschool-aged children in Los Angeles County. While neighborhood environments are increasingly recognized as important contributors to obesity risk, less has been reported on the socio-cultural aspects of neighborhoods that influence obesity development. This is especially true among immigrants, who may lack the necessary language skills to navigate their new living environments. In this study, we tested the hypothesis that young children of immigrants would be at lower obesity risk if they lived in neighborhoods where neighbors share the same language and culture. Using 2000 Census data and 2003-2009 data from the Special Supplemental Nutrition Program for Women, Infants and Children in Los Angeles County, we examined the relation between BMI z-scores in low-income children aged 2-5 years (N = 250,029) and the concentration of neighborhood residents who spoke the same language as the children's mothers. Using multi-level modeling and adjusting for child's gender and race/ethnicity, household education, neighborhood socioeconomic status, and year the child was examined, we found that percent of neighborhood residents who spoke the same language as the child's mother was negatively associated with BMI z-scores. This relation varied by child's race/ethnicity and mother's preferred language. The relation was linear and negative among children of English-speaking Hispanic mothers and Chinese-speaking mothers. However, for Hispanic children of Spanish-speaking mothers the relation was curvilinear, initially exhibiting a positive relation which reversed at higher neighborhood concentrations of Spanish-speaking residents. Our findings suggest that living in neighborhoods where residents share the same language may influence obesity-related behaviors (namely diet and physical activity) possibly through mechanisms involving social networks, support, and norms. 23902566 Iron restriction prevents diabetic nephropathy in Otsuka Long-Evans Tokushima fatty rat. Abstract High body iron levels are found in type 2 diabetes mellitus (DM). Iron excess leads to tissue injury through free radical formation. We investigated the effect of iron restriction on renal damage in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 DM. OLETF rats (n = 18) were divided into three groups at 10 weeks of age: high fat diet containing 8% NaCl (HFS, n = 6), HFS diet with iron restricted (HFS + IR, n = 6), and HFS with hydralazine (HFS + Hyd, n = 6). Long-Evans Tokushima (LETO) rats served as control. Iron restriction decreased hemoglobin levels, systolic blood pressure, and urinary excretion of protein and 8-hydroxy-2'-deoxyguanosine in the OLETF rats fed with HFS diet. Compared to the HFS group, the expression of desmin, renal glomerular injury marker and iron deposition in the renal tubules were attenuated in the HFS + IR group but not in the HFS + Hyd group at 26 weeks of age. Moreover, renal hypoxia (evaluated as pimonidazole adducts) was improved in the HFS + IR group compared to the HFS group in spite of anemia. Iron restriction prevented the production of reactive oxygen species and the development of early stage nephropathy in OLETF rats. Iron restriction may be beneficial in prevention of nephropathy in type 2 DM. 23842557 Test-Retest-Reliability of Navigated Transcranial Magnetic Stimulation of the Motor Cortex. Since navigated transcranial magnetic stimulation (nTMS) is increasingly used in neurosurgical research, interpretation of its results is of utmost importance. To evaluate test-retest-reliability of nTMS. 12 healthy participants underwent nTMS at two different sessions, separated by 10.3 ± 9.6 days. Investigated parameters comprised resting motor thresholds (RMT), hotspots (HS) and centers of gravity (CoG), being calculated for the first dorsal interosseous, abductor pollicis brevis, extensor digitorum, tibial anterior and abductor hallucis muscles. Excellent reliability of RMTs was observed. HS and CoGs showed moderate to excellent repeatability along the anteroposterior axis (ICC = 0.54 - 0.89), whereas the X-coordinate presented mainly poor to moderate stability (ICC = 0.11 - 0.89). Movement of CoGs over sessions was 0.57 ± 0.32 cm and HS laid 0.79 ± 0.47 cm apart. Calculation of coefficient of variation (CV) revealed high reliability of investigated parameters in upper extremities; in lower extremity muscles high variation across sessions was observed. nTMS can be considered as a reliable tool, thus opening new fields of non-invasive investigations in neurosurgery. Presented results should be considered when interpreting individual nTMS results. 23921535 Quantitative multiplex PCR of short fluorescent fragments for the detection of large intragenic POLG rearrangements in a large French cohort. Polymerase gamma (POLG) is the gene most commonly involved in mitochondrial disorders with mitochondrial DNA instability and causes a wide range of diseases with recessive or dominant transmission. More than 170 mutations have been reported. Most of them are missense mutations, although nonsense mutations, splice-site mutations, small deletions and insertions have also been identified. However, to date, only one large-scale rearrangement has been described in a child with Alpers syndrome. Below, we report a large cohort of 160 patients with clinical, molecular and/or biochemical presentation suggestive of POLG deficiency. Using sequencing, we identified POLG variants in 22 patients (18 kindreds) including five novel pathogenic mutations. Two patients with novel mutations had unusual clinical presentation: the first exhibited an isolated ataxic neuropathy and the second was a child who presented with endocrine signs. We completed the sequencing step by quantitative multiplex PCR of short fluorescent fragments (QMPSF) analysis in 37 patients with either only one POLG heterozygous variant or a family history suggesting a dominant transmission. We identified a large intragenic deletion encompassing part of intron 21 and exon 22 of POLG in a child with refractory epilepsia partialis continua. In conclusion, we describe the first large French cohort of patients with POLG mutations, expanding the wide clinical and molecular spectrum observed in POLG disease. We confirm that large deletions in the POLG gene are rare events and we highlight the importance of QMPSF in patients with a single heterozygous POLG mutation, particularly in severe infantile phenotypes.European Journal of Human Genetics advance online publication, 7 August 2013; doi:10.1038/ejhg.2013.171. 23598697 Otopathology in congenital toxoplasmosis. To describe the temporal bone histopathology in children with congenital toxoplasmosis. Toxoplasmosis is a parasitic infection caused by Toxoplasma gondii. If fetal infection occurs early in gestation, severe inflammation and necrosis can cause brain lesions, chorioretinitis, and hearing loss. Hearing loss in congenital toxoplasmosis may be preventable with early diagnosis and treatment. The temporal bones of 9 subjects with congenital toxoplasmosis were removed at autopsy and studied under light microscopy. Cytocochleograms were constructed for hair cells, the stria vascularis, and cochlear neuronal cells. Three (33%) of 9 subjects were found to have parasites in the temporal bone. The organism was identified in the internal auditory canal, the spiral ligament, stria vascularis, and saccular macula. The cystic form of the parasite was not associated with the inflammatory response seen in the active tachyzoite form. We infer that the hearing loss of toxoplasmosis is likely the result of a postnatal inflammatory response to the tachyzoite form of T. gondii. Our findings have implications for the early identification and management of Toxoplasmosis. 22531366 Low-density lipoprotein cholesterol, apolipoprotein B, and risk of coronary heart disease: from familial hyperlipidemia to genomics. Coronary heart disease (CHD) affects 17 million people in the United States and accounts for over a million hospital stays each year. Technological advances, especially in genetics and genomics, have changed our understanding of the risk factors for developing CHD. The purpose of this article is to review low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), and risk of CHD. The article focuses on five topics: (1) a description of lipoprotein classes, normal lipoprotein metabolism, and the biological mechanism of atherosclerosis; (2) a review of selected epidemiologic and clinical trial studies examining the associations between elevated LDL-C and apo B with CHD; (3) a brief review of the familial forms of hyperlipidemia; (4) a description of variants in genes that have been associated with higher LDL-C levels in candidate gene studies and genome-wide association studies (GWAS); and (5) nursing implications, including a discussion on how genetic tests are evaluated and the current clinical utility and validity of genetic tests for CHD. 23478083 Suppression of acute rejection by administration of prostaglandin E2 receptor subtype 4 agonist in rat organ transplantation models. Prostaglandin E2 (PGE2) receptor subtype 4 (EP4) signaling is known to modulate the inflammation process. Several studies have demonstrated the potential utility of EP4-selective agonists for the management of autoimmune and inflammatory diseases. In the present study, we assessed the immunosuppressive efficacy of a selective EP4 agonist in experimental rat organ transplantation models. We continuously injected a selective EP4 agonist (CAY10580) by subcutaneous insertion of infuser pumps into recipient rats that underwent heterotopic heart and small bowel transplantation. The administration of EP4 agonist significantly delayed cardiac allograft survival and delayed the onset of rejection in both the cardiac and intestinal allografts. Expression of proinflammatory cytokines of interferon-gamma was suppressed by the treatment compared with the vehicle-treated group. Furthermore, the expression of suppressor of cytokine signaling-1, a known intracellular regulation factor of IFN-gamma, was also down-regulated compared with the control group. These results suggest that selective EP4 agonists represent a novel class of immune-modulator drugs that could be useful for the management of acute allogeneic rejection. 23230273 The yeast cap binding complex modulates transcription factor recruitment and establishes proper histone H3K36 trimethylation during active transcription. Recent studies have revealed a close relationship between transcription, histone modification, and RNA processing. In fact, genome-wide analyses that correlate histone marks with RNA processing signals raise the possibility that specific RNA processing factors may modulate transcription and help to "write" chromatin marks. Here we show that the nuclear cap binding complex (CBC) directs recruitment of transcription elongation factors and establishes proper histone marks during active transcription. A directed genetic screen revealed that deletion of either subunit of the CBC confers a synthetic growth defect when combined with deletion of genes encoding either Ctk2 or Bur2, a component of the Saccharomyces cerevisiae ortholog of P-TEFb. The CBC physically associates with these complexes to recruit them during transcription and mediates phosphorylation at Ser-2 of the C-terminal domain (CTD) of RNA polymerase II. To understand how these interactions influence downstream events, histone H3K36me3 was examined, and we demonstrate that CBCΔ affects proper Set2-dependent H3K36me3. Consistent with this, the CBC and Set2 have similar effects on the ability to rapidly induce and sustain activated gene expression, and these effects are distinct from other histone methyltransferases. This work provides evidence for an emerging model that RNA processing factors can modulate the recruitment of transcription factors and influence histone modification during elongation. 23281099 Effect of molecular crowding on the temperature-pressure stability diagram of ribonuclease A. FT-IR spectroscopic and thermodynamic measurements were designed to explore the effect of a macromolecular crowder, dextran, on the temperature and pressure-dependent phase diagram of the protein Ribonuclease A (RNase A), and we compare the experimental data with approximate theoretical predictions based on configuration entropy. Exploring the crowding effect on the pressure-induced unfolding of proteins provides insight in protein stability and folding under cell-like dense conditions, since pressure is a fundamental thermodynamic variable linked to molecular volume. Moreover, these studies are of relevance for understanding protein stability in deep-sea organisms, which have to cope with pressures in the kbar range. We found that not only temperature-induced equilibrium unfolding of RNase A, but also unfolding induced by pressure is markedly prohibited in the crowded dextran solutions, suggesting that crowded environments such as those found intracellularly, will also oppress high-pressure protein unfolding. The FT-IR spectroscopic measurements revealed a marked increase in unfolding pressure of 2 kbar in the presence of 30 wt % dextran. Whereas the structural changes upon thermal unfolding of the protein are not significantly influenced in the presence of the crowding agent, through stabilization by dextran the pressure-unfolded state of the protein retains more ordered secondary structure elements, which seems to be a manifestation of the entropic destabilization of the unfolded state by crowding. 23712443 The mitochondrial Italian Human Proteome Project initiative (mt-HPP). Mitochondria carry maternally inherited genetic material, called the mitochondrial genome (mtDNA), which can be defined as the 25th human chromosome. The chromosome-centric Human Proteome Project (c-HPP) has initially focused its activities addressing the characterization and quantification of the nuclear encoded proteins. Following the last International HUPO Congress in Boston (September 2012) it was clear that however small the mitochondrial chromosome is, it plays an important role in many biological and physiopathological functions. Mutations in the mtDNA have been shown to be associated with dozens of unexplained disorders and the information contained in the mtDNA should be of major relevance to the understanding of many human diseases. Within this paper we describe the Italian initiative of the Human Proteome Project dedicated to mitochondria as part of both programs: chromosome-centric (c-HPP) and Biology/Disease (B/D-HPP). The mt-HPP has finally shifted the attention of the HUPO community outside the nuclear chromosomes with the general purpose to highlight the mitochondrial processes influencing the human health. Following this vision and considering the large interest and evidence collected on the non-Mendelian heredity of Homo sapiens associated with mt-chromosome and with the microbial commensal ecosystem constituting our organism we may speculate that this program will represent an initial step toward other HPP initiatives focusing on human phenotypic heredity. 23492812 Polybrominated Dibenzo-p-dioxins (PBDDs), Dibenzofurans (PBDFs) and Biphenyls (PBBs) - Inclusion in the Toxicity Equivalency Factor Concept for Dioxin-like Compounds - In 2011 a joint World Health Organization (WHO) and United Nations Environment Programme (UNEP) expert consultation took place, during which the possible inclusion of brominated analogues of the dioxin-like compounds in the WHO Toxicity Equivalency Factor (TEF) scheme were evaluated. The expert panel concluded that polybrominated dibenzo-p-dioxins (PBDDs), dibenzofurans (PBDFs), and some dioxin-like biphenyls (dl-PBBs) may contribute significantly in daily human background exposure to the total dioxin toxic equivalencies (TEQs). These compounds are also commonly found in the aquatic environment. Available data for fish toxicity were evaluated for possible inclusion in the WHO-UNEP TEF scheme (Van den Berg et al., 1998). Because of the limited database it was decided not to derive specific WHO-UNEP TEFs for fish, but for ecotoxicological risk assessment the use of specific relative effect potencies (REPs) from fish embryo assays is recommended. Based on the limited mammalian REP database for these brominated compounds, it was concluded that sufficient differentiation from the present TEF values of the chlorinated analogues (Van den Berg et al., 2005) was not possible. However, the REPs for PBDDs, PBDFs, and non-ortho dl-PBBs in mammals closely follow those of the chlorinated analogues, at least within one order of magnitude. Therefore, the use of similar interim TEF values for brominated and chlorinated congeners for human risk assessment is recommended, pending more detailed information in the future. 23913792 A novel isoform of the B cell tyrosine kinase BTK protects breast cancer cells from apoptosis. Tyrosine kinases orchestrate key cellular signaling pathways and their dysregulation is often associated with cellular transformation. Several recent cases in which inhibitors of tyrosine kinases have been successfully used as anticancer agents have underscored the importance of this class of proteins in the development of targeted cancer therapies. We have carried out a large-scale loss-of-function analysis of the human tyrosine kinases using RNA interference to identify novel survival factors for breast cancer cells. In addition to kinases with known roles in breast and other cancers, we identified several kinases that were previously unknown to be required for breast cancer cell survival. The most surprising of these was the cytosolic, nonreceptor tyrosine kinase, Bruton's tyrosine kinase (BTK), which has been extensively studied in B cell development. Down regulation of this protein with RNAi or inhibition with pharmacological inhibitors causes apoptosis; overexpression inhibits apoptosis induced by Doxorubicin in breast cancer cells. Our results surprisingly show that BTK is expressed in several breast cancer cell lines and tumors. The predominant form of BTK found in tumor cells is transcribed from an alternative promoter and results in a protein with an amino-terminal extension. This alternate form of BTK is expressed at significantly higher levels in tumorigenic breast cells than in normal breast cells. Since this protein is a survival factor for these cells, it represents both a potential marker and novel therapeutic target for breast cancer. © 2013 Wiley Periodicals, Inc. 23583863 Nifurtimox therapy for Chagas disease does not cause hypersensitivity reactions in patients with such previous adverse reactions during benznidazole treatment. Currently, only two drugs are approved for treating Trypanosoma cruzi infection: benznidazole and nifurtimox. Adverse reactions are frequent with both drugs: they have chemical similarities and common metabolic pathways making cross reactions a possibility. Our objective was to describe the safety/tolerability profile of nifurtimox in patients who had previously discontinued benznidazole due to hypersensitivity reactions. We performed a prospective observational study from September 2009 to December 2011. Patients who discontinued benznidazole therapy due to hypersensitivity reactions (HR) and were later treated with nifurtimox were included. HR to benznidazole were defined as presence of a rash with or without mucosal involvement, fever or laboratory abnormalities (such as eosinophilia, leucopaenia or impaired liver function tests). The drugs were prescribed for 60 days (benznidazole) or 60-90 days (nifurtimox). The National Cancer Institute criteria (CTCAE, 2006, Version 3.0) were used for grading and reporting of adverse reactions (AR). Eighteen patients (16 females, two males, median age 35.5 years, range 15-50 years) with asymptomatic late chronic infection, were included. Median time between benznidazole interruption and start of therapy with nifurtimox was 121.5 days (IQR 72-223 days). Fifteen patients (83.3%) developed an AR to nifurtimox, gastrointestinal complaints and anorexia being the most common, and 13 patients (72%) completed the treatment schedule. Five patients interrupted therapy (27.8%) mainly because of gastrointestinal intolerance and/or nervous system toxicity. Only one patient developed skin lesions, a mild maculopapular rash not requiring specific therapy or treatment withdrawal. There was no severe AR. Nifurtimox as second line therapy in patients who discontinued benznidazole specifically due to HR appears to be safe and does not seem to be associated with a higher incidence of AR. 23376033 Further evidence of the trypanocidal action of eupomatenoid-5: confirmation of involvement of reactive oxygen species and mitochondria owing to a reduction in trypanothione reductase activity. Our group assays natural products that are less toxic and more effective than available nitroheterocycles as promising therapeutic options for patients with Chagas disease. Our previous study reported the trypanocidal activity of eupomatenoid-5, a neolignan isolated from the leaves of Piper regnellii var. pallescens, against the three main parasitic forms of Trypanosoma cruzi. The present study further characterizes the biochemical and morphological alterations induced by this compound to elucidate the mechanisms of action involved in the cell death of T. cruzi. We show that eupomatenoid-5 induced oxidative imbalance in the three parasitic forms, especially trypomastigotes, reflected by a decrease in the activity of trypanothione reductase and increase in the formation of reactive oxygen species (ROS). A reduction of mitochondrial membrane potential was then triggered, further impairing the cell redox system through the production of more ROS and reactive nitrogen species. Altogether, these effects led to oxidative stress, reflected by lipid peroxidation and DNA fragmentation. These alterations are key events in the induction of parasite death through various pathways, including apoptosis, necrosis, and autophagy. 23906040 The osmium-silicon triple bond: synthesis, characterization, and reactivity of an osmium silylyne complex. The first silylyne complex of a metal beyond group 6, [Cp*((i)Pr3P)(H)Os≡Si(Trip)][HB(C6F5)3], was prepared by a new synthetic route involving hydride abstraction from silicon. NMR and DFT computations support the presence of a silylyne ligand, and NBO and ETS-NOCV analysis revealed the nature of this Os-Si interaction as a triple bond consisting of a covalent σ bond and two strong π back-donations. The discovery of this complex allowed observations of the first cycloadditions involving a silylyne complex, and terminal alkynes are shown to react via C-H bond additions across the Os≡Si bond. 23903078 Periorbital Reconstruction With the Expanded Pedicled Forehead Flap. The complexity of structures within the periorbital region makes reconstruction of this area particularly a challenging endeavor. Within the literature, different techniques have been described for reconstruction of the external lamellae of the upper and lower eyelids as well as the medial and lateral canthal regions.Herein, we present the expanded pedicled forehead flap as a versatile and useful surgical option for reconstruction of various defects around the eye globe. A tissue expander is inserted underneath the forehead skin and serially expanded. The pedicle of the expanded pedicled flap is designed either from the superior portion of the expanded skin and interpolated to reconstruct the upper and lower eyelids, and the medial or lateral canthal areas; or from the inferior portion of the expanded skin and interpolated over the eyebrow to reconstruct the area between the upper eyelid crease and eyebrow.Fifteen patients with periorbital nevi or severe scarring were treated using the expanded forehead flap between the years 2003 and 2012. Thirteen patients had complex periorbital defects involving multiple anatomic areas, and 2 patients had defects confined to the upper eyelid area only. Operative and postoperative course for 13 patients was uneventful. One patient had a late infection of the tissue expander but nonetheless continued with the reconstructive process. In 1 patient, the tissue expander was removed due to infection, and subsequent reconstruction was not carried out. The aesthetic and functional results of reconstruction were very good, and with excellent skin color and thickness match. In 1 patient, the flap was defattened in an ancillary procedure. No partial or complete flap loss was observed in this study. We conclude that the expanded pedicled forehead flap is a safe and reliable method for reconstruction of different segments of the periorbital region, while providing good aesthetic and functional reconstructive results with minimal donor-site morbidity. 23176149 Induced Optical Activity of DNA-Templated Cyanine Dye Aggregates: Exciton Coupling Theory and TD-DFT Studies. Certain cyanine dye molecules have been observed to self-assemble in DNA templates to form large chiral aggregates, which exhibit induced circular dichroism. The structure and circular dichroism (CD) of one such system, aggregates of a cationic DiSC2(5) cyanine dye, are investigated using the time-dependent Kohn-Sham density functional theory (TD-DFT) and exciton coupling model. A series of TD-DFT calculations on the aggregates with one, two, and four dye molecules clearly shows the onset of CD induced by the helically twisted structure compatible with the minor groove of DNA templates. More simplified exciton coupling model analysis successfully reproduces the major positive Cotton effect observed in the experiment as well as the TD-DFT calculations, but it is unable to capture minor features of the CD spectrum that are closely related to absolute configurations of constituent dyes in the complex. We assess the performance of various methods used for evaluation of the electronic coupling energies between interacting chromophores. Our results confirm that the interchromophore interactions in cyanine dye aggregates are primarily electrostatic in nature and indicate that the exciton coupling model is adequate for studying induced CD of self-assembled aggregates of cyanine dye molecules. 23122071 Separation and quantification of water buffalo milk protein fractions and genetic variants by RP-HPLC. A RP-HPLC method, developed for the separation and quantification of the most common genetic variants of bovine milk proteins, was successfully applied to the analysis of water buffalo milk. All the most common buffalo casein and whey proteins fractions, as well as their genetic variants, were detected and separated simultaneously in 40 min. Purified buffalo proteins were used as calibration standards and a total of 536 individual milk samples were analysed for protein composition. α(S1)-, α(S2)-, βγ-, and κ-casein were 32.2%, 15.8%, 36.5%, and 15.5%, respectively, of total casein content, whereas content of β-Lactoglobulin was approximately 1.3 times as high as that of α-Lactalbumin. The existence of a polymorphism of κ-casein was demonstrated in Mediterranean water buffalo and α(S1)- and κ-casein genetic variants were successfully detected by RP-HPLC. 23950795 Correction: Dietary Glycemic Index during Pregnancy Is Associated with Biomarkers of the Metabolic Syndrome in Offspring at Age 20 Years. [This corrects the article on p. e64887 in vol. 8.]. 23869204 A standardized vascular disease health check in europe: a cost-effectiveness analysis. No clinical trials have assessed the effects or cost-effectiveness of health check strategies to detect and manage vascular disease. We used a mathematical model to estimate the cost-effectiveness of several health check strategies in six European countries. We used country-specific data from Denmark, France, Germany, Italy, Poland, and the United Kingdom to generate simulated populations of individuals aged 40-75 eligible for health checks in those countries (e.g. individuals without a previous diagnosis of diabetes, myocardial infarction, stroke, or serious chronic kidney disease). For each country, we used the Archimedes model to compare seven health check strategies consisting of assessments for diabetes, hypertension, lipids, and smoking. For patients diagnosed with vascular disease, treatment was simulated in a standard manner. We calculated the effects of each strategy on the incidence of type 2 diabetes, major adverse cardiovascular events (MACE), and microvascular complications in addition to quality of life, costs, and cost per quality-adjusted life-year (QALY). Compared with current care, health checks reduced the incidence of MACE (6-17 events prevented per 1000 people screened) and diabetes related microvasular complications (5-11 events prevented per 1000 people screened), and increased QALYs (31-59 discounted QALYs) over 30 years, in all countries. The cost per QALY of offering a health check to all individuals in the study cohort ranged from €14903 (France) to cost saving (Poland). Pre-screening the population and offering health checks only to higher risk individuals lowered the cost per QALY. Pre-screening on the basis of obesity had a cost per QALY of €10200 (France) or less, and pre-screening with a non-invasive risk score was similar. A vascular disease health check would likely be cost effective at 30 years in Denmark, France, Germany, Italy, Poland, and the United Kingdom. 23690034 Enhanced transesterification of ethyl ferulate with glycerol for preparing glyceryl diferulate using a lipase in ionic liquids as reaction medium. Glyceryl diferulate (DFG) is a water-soluble ester of ferulic acid. A novel ionic liquid (IL) system for enzymatic transesterification of ethyl ferulate (EF) with glycerol to produce DFG was developed. Of three ILs with different anions (BF4 (-), PF6 (-) and TF2N(-)) and cations (BDMIM, OMIM, HMIM, BMIM, and EMIM), EMIMTF2N proved the best using a commercial lipase. It had a significant protective effect against thermal inactivation of the enzyme. High EF conversion (~100 %) and DFG yield (45 %) were achieved using 45 mg enzyme/ml; temperature, 70 °C; reaction time, 12 h. 23838802 High expression of M3 muscarinic acetylcholine receptor is a novel biomarker of poor prognostic in patients with non-small cell lung cancer. We assessed the expression of M3 receptor in non-small cell lung cancer (NSCLC) and determined its relationship with clinicopathological features and its impact on patient outcome. Specimens from 192 patients with NSCLC were investigated by immunohistochemistry for M3 receptor and Ki67 expression. Correlation between the expression of M3 receptor and Ki67 and various clinicopathological features of NSCLC patients was analyzed. We found that M3 receptor expression was gradually elevated from normal to metaplasia/dysplasia tissues to cancer tissues. Furthermore, there was a similar trend for Ki67 expression. Statistical analysis revealed that M3 receptor expression in tumor cells were correlated significantly with stage (P < 0.0001), histology type (P = 0.0003), Ki67 expression (P < 0.0001), tumor size (P < 0.0001), lymph node status (P < 0.0001), LVS invasion (P = 0.0002), and histology grade (P < 0.0001). Patients with M3 receptor high expression showed far lower disease-free survival (DFS) and overall survival (OS) rates than those with M3 receptor low expression. Multivariate Cox regression analysis demonstrated that high M3 receptor expression was an independent prognostic factor for both DFS and OS. High M3 receptor expression correlates with poor survival in NSCLC patients. M3 receptor expression may be related with tumor progression in NSCLC, indicating that M3 receptor may be a novel antineoplastic target in the future. 23358194 Transcriptome alterations following developmental atrazine exposure in zebrafish are associated with disruption of neuroendocrine and reproductive system function, cell cycle, and carcinogenesis. Atrazine, a herbicide commonly applied to agricultural areas and a common contaminant of potable water supplies, is implicated as an endocrine-disrupting chemical (EDC) and potential carcinogen. Studies show that EDCs can cause irreversible changes in tissue formation, decreased reproductive potential, obesity, and cancer. The U.S. Environmental Protection Agency considers an atrazine concentration of ≤ 3 ppb in drinking water safe for consumption. The specific adverse human health effects associated with a developmental atrazine exposure and the underlying genetic mechanisms of these effects are not well defined. In this study, zebrafish embryos were exposed to a range of atrazine concentrations to establish toxicity. Morphological, transcriptomic, and protein alterations were then assessed at 72h postfertilization following developmental atrazine exposure at 0, 0.3, 3, or 30 ppb. A significant increase in head length was observed in all three atrazine treatments. Transcriptomic profiles revealed 21, 62, and 64 genes with altered expression in the 0.3, 3, and 30 ppb atrazine treatments, respectively. Altered genes were associated with neuroendocrine and reproductive system development, function, and disease; cell cycle control; and carcinogenesis. There was a significant overlap (42 genes) between the 3 and 30 ppb differentially expressed gene lists, with two of these genes (CYP17A1 and SAMHD1) present in all three atrazine treatments. Increased transcript levels were translated to significant upregulation in protein expression. Overall, this study identifies genetic and molecular targets altered in response to a developmental atrazine exposure to further define the biological pathways and mechanisms of toxicity. 23824470 Influence of assessment instrument on ADHD diagnosis. We compared four instruments commonly used to screen for and diagnose Attention-Deficit/Hyperactivity Disorder (ADHD) in children. The Bergen Child Study included a DSM-IV ADHD symptom list and the Strengths and Difficulties Questionnaire (SDQ) as screen in Phase one. Phase two included the parent Development and Well-Being Assessment (DAWBA), whereas Phase three comprised in-depth clinical assessment, including the Schedule for Affective Disorders and Schizophrenia for School Aged Children (K-SADS). We compared ADHD as diagnosed by the four instruments in the children with normal intellectual functioning participating in all three phases (N = 234). The DSM-IV ADHD symptom list showed moderate agreement with all other instruments (κ = 0.53-0.57), whereas there was fair agreement between the K-SADS-DAWBA (κ = 0.31) and between SDQ-DAWBA (κ = 0.33). The DAWBA diagnosed fewer children with ADHD than did the other instruments. Implications for use of the instruments are discussed. 23498839 Inverted left atrial appendage bonded to atrial septum. Inverted left atrial appendage (LAA) is a rare surgical complication. Our patient, a boy aged 2 years, was diagnosed with a partial atrioventricular defect with mild regurgitation of the left atrioventricular valve and a large primum atrial septal defect. Direct postoperative transesophageal echocardiography revealed a new left atrial mass attached to the atrial septum, without left ventricle inflow obstruction. Out of concern about the nature of this mass, we chose surgical direct examination. Intraoperatively, we diagnosed it as an inverted LAA accidentally attached to the atrial septum suture line. Awareness of this condition can avoid unnecessary diagnostic and therapeutic procedures. 23938764 Comparative antioxidant responses in liver of Carassius auratus exposed to phthalates: An integrated biomarker approach. Phthalates (PAEs) are chemical agents typically used as plasticizers in numerous industrial products. They have become ubiquitous contaminants due to their tendency to release into the environment. The present study was conducted to investigate the comparative antioxidant responses in liver of freshwater goldfish Carassius auratus injected intraperitoneally with 17 different PAEs at a concentration of 10mg/kg for 10 days. The results indicated that these PAEs can adversely affect the antioxidant status, confirmed by the significantly inhibited activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase). Especially, the latter two enzymes constituted the most affected antioxidant enzymes after the exposure, and the lowest values were recorded for the catalase activity. The toxicity order was proposed via the integrated biomarker response, with dicyclohexyl phthalate the most toxic and diethyl phthalate the least. Overall, these findings may contribute to the risk assessments of these chemicals on aquatic species. 23648416 Association of periodontitis with carotid artery intima-media thickness and arterial stiffness in community-dwelling people in Japan: the Nagasaki Islands study. Recent studies have suggested an association between periodontitis and atherosclerosis; however, the relationship between periodontal status and arterial alterations should be clarified. The purpose of this study was to examine associations between periodontal status and carotid intima-media thickness (cIMT) and arterial stiffness using the cardio-ankle vascular index (CAVI) in community dwellers. A community-based cross-sectional study of 1053 subjects ≥40 years with 10 teeth or more was conducted in Goto, Japan from 2008 to 2010. In a multiple linear regression analysis adjusted for age, sex, number of present teeth, and other confounders, each 1-mm increase in mean periodontal pocket depth corresponded to a 0.02-mm increase in maximal cIMT (β = 0.018; P = 0.049) and also to a 0.1 increase in mean CAVI (β = 0.133; P = 0.040). In addition, each 1-mm increase in the mean periodontal attachment loss corresponded to a 0.01-mm increase in maximal cIMT (β = 0.013; P = 0.040). A multiple logistic regression analysis revealed that each 1-mm increase in mean periodontal pocket depth was associated with an increased risk of a maximal cIMT >1 mm (adjusted odds ratio [OR], 1.430; 95% confidence interval [CI], 1.067-1.918; P = 0.017) and mean CAVI of ≥8 (OR, 1.323; 95% CI, 1.003-1.743; P = 0.047). Furthermore, each 1-mm increase in mean periodontal attachment loss was associated with an increased risk of a maximal cIMT >1 mm (OR, 1.251; 95% CI, 1.032-1.516; P = 0.022). A linear, dose-dependent relationship was found between periodontal pocket depth, cIMT, and arterial stiffness. 23739685 Changes in circulating biomarkers of muscle atrophy, inflammation, and cartilage turnover in patients undergoing anterior cruciate ligament reconstruction and rehabilitation. After anterior cruciate ligament (ACL) reconstruction, there is significant atrophy of the quadriceps muscles that can limit full recovery and place athletes at risk for recurrent injuries with return to play. The cause of this muscle atrophy is not fully understood. Circulating levels of proatrophy, proinflammatory, and cartilage turnover cytokines and biomarkers would increase after ACL reconstruction. Descriptive laboratory study. Patients (N = 18; mean age, 28 ± 2.4 years) underwent surgical reconstruction of the ACL after a noncontact athletic injury. Circulating levels of biomarkers were measured along with Short Form-12, International Knee Documentation Committee, and objective knee strength measures preoperatively and at 6 postoperative visits. Differences were tested using repeated-measures 1-way analysis of variance. Myostatin, TGF-β, and C-reactive protein levels were significantly increased in the early postoperative period and returned to baseline. Cartilage oligomeric matrix protein levels decreased immediately after surgery and then returned to baseline. CCL2, CCL3, CCL4, CCL5, EGF, FGF-2, IGF-1, IL-10, IL-1α, IL-1β, IL-1ra, IL-6, myoglobin, and TNF-α were not different over the course of the study. An increase in potent atrophy-inducing cytokines and corresponding changes in knee strength and functional scores were observed after ACL reconstruction. Although further studies are necessary, the therapeutic inhibition of myostatin may help prevent the muscle atrophy that occurs after ACL reconstruction and provide an accelerated return of patients to sport. 23929924 Determinants and Changes Associated with Aldosterone Breakthrough after Angiotensin II Receptor Blockade in Patients with Type 2 Diabetes with Overt Nephropathy. Inhibition of the renin-angiotensin-aldosterone system decreases proteinuria and slows estimated GFR decline in patients with type 2 diabetes mellitus with overt nephropathy. Serum aldosterone levels may increase during renin-angiotensin-aldosterone system blockade. The determinants and consequences of this aldosterone breakthrough remain unknown. This study examined the incidence, determinants, and changes associated with aldosterone breakthrough in a posthoc analysis of a randomized study that compared the effect of two angiotensin II receptor blockers in patients with type 2 diabetes mellitus with overt nephropathy. Of 567 of 860 participants included in this posthoc analysis, 28% of participants developed aldosterone breakthrough, which was defined by an increase greater than 10% over baseline values of serum aldosterone levels after 1 year of angiotensin II receptor blocker treatment. Factors independently associated with aldosterone breakthrough at 1 year were lower serum aldosterone and potassium levels at baseline, higher decreases in sodium intake, systolic BP, and estimated GFR from baseline to 1 year, and use of losartan versus telmisartan. Aldosterone breakthrough at 6 months was not sustained at 1 year in 69% of cases, and it did not predict estimated GFR decrease and proteinuria increase between 6 months and 1 year. Aldosterone breakthrough is a frequent event 1 year after initiating renin-angiotensin-aldosterone system blockade, particularly in participants exposed to intensive lowering of BP with sodium depletion and short-acting angiotensin II receptor blockers. Short-term serum aldosterone level increases at 6 months are not associated with negative kidney outcomes between 6 months and 1 year. 23787763 Inhibition of glioma growth by minocycline is mediated through endoplasmic reticulum stress-induced apoptosis and autophagic cell death. Background We have reported that minocycline (Mino) induced autophagic death in glioma cells. In the present study, we characterize the upstream regulators that control autophagy and switch cell death from autophagic to apoptotic. Methods Western blotting and immunofluorescence were used to detect the expressions of eukaryotic translation initiation factor 2α (eIF2α), transcription factor GADD153 (CHOP), and glucose-regulated protein 78 (GRP78). Short hairpin (sh)RNA was used to knock down eIF2α or CHOP expression. Autophagy was assessed by the conversion of light chain (LC)3-I to LC3-II and green fluorescent protein puncta formation. An intracranial mouse model and bioluminescent imaging were used to assess the effect of Mino on tumor growth and survival time of mice. Results The expression of GRP78 in glioma was high, whereas in normal glia it was low. Mino treatment increased GRP78 expression and reduced binding of GRP78 with protein kinase-like endoplasmic reticulum kinase. Subsequently, Mino increased eIF2α phosphorylation and CHOP expression. Knockdown of eIF2α or CHOP reduced Mino-induced LC3-II conversion and glioma cell death. When autophagy was inhibited, Mino induced cell death in a caspase-dependent manner. Rapamycin in combination with Mino produced synergistic effects on LC3 conversion, reduction of the Akt/mTOR/p70S6K pathway, and glioma cell death. Bioluminescent imaging showed that Mino inhibited the growth of glioma and prolonged survival time and that these effects were blocked by shCHOP. Conclusions Mino induced autophagy by eliciting endoplasmic reticulum stress response and switched cell death from autophagy to apoptosis when autophagy was blocked. These results coupled with clinical availability and a safe track record make Mino a promising agent for the treatment of malignant gliomas. 23822294 Going beyond "no-pair relativistic quantum chemistry". The current field of relativistic quantum chemistry (RQC) has been built upon the no-pair and no-retardation approximations. While retardation effects must be treated in a time-dependent manner through quantum electrodynamics (QED) and are hence outside RQC, the no-pair approximation (NPA) has to be removed from RQC for it has some fundamental defects. Both configuration space and Fock space formulations have been proposed in the literature to do this. However, the former is simply wrong, whereas the latter is still incomplete. To resolve the old problems pertinent to the NPA itself and new problems beyond the NPA, we propose here an effective many-body (EMB) QED approach that is in full accordance with standard methodologies of electronic structure. As a first application, the full second order energy E2 of a closed-shell many-electron system subject to the instantaneous Coulomb-Breit interaction is derived, both algebraically and diagrammatically. It is shown that the same E2 can be obtained by means of 3 Goldstone-like diagrams through the standard many-body perturbation theory or 28 Feynman diagrams through the S-matrix technique. The NPA arises naturally by retaining only the terms involving the positive energy states. The potential dependence of the NPA can be removed by adding in the QED one-body counter terms involving the negative energy states, thereby leading to a "potential-independent no-pair approximation" (PI-NPA). The NPA, PI-NPA, EMB-QED, and full QED then span a continuous spectrum of relativistic molecular quantum mechanics. 23828271 Antihyperglycemic and Antihyperlipidemic Effects of Newly Synthesized Glibenclamide Analogues on Streptozotocin-diabetic Rats. In this study, new glibenclamide analogues (5a-d) with substituted pharmacological triethoxysilyl propan, allyl and ethoxyphenyl groups for cyclohexyl moiety have been synthesized by condensing sulfonamide (4) with related isocyanate or isothiocyanate's compounds. The newly synthesized drugs were evaluated for their antihyperglycemic and antihyperlipidemic activities with streptozotocin (STZ)-induced diabetic rats. All showed hypoglycemic and hypolipidemic activities compared to the control animals but 5c and 5d exhibited more and significant lowering blood activities similar to glibenclamide. This was concerned with identical affinities to bind with SUR1 receptor. Moreover, the new drugs displayed high efficiency for reducing serum LDL level which resulted in a high HDL/LDL ratio as a good lipid profile compared to other groups. 23499630 Prevalence, characteristics, and prognosis role of type 1 ST elevation in the peripheral ECG leads in patients with Brugada syndrome. Despite isolated reports of Brugada syndrome (BrS) in the inferior or lateral leads, the prevalence and prognostic value of ST elevation in the peripheral electrocardiographic (ECG) leads in patients with BrS remain poorly known. To study the prevalence, characteristics, and prognostic value of type 1 ST elevation and ST depression in the peripheral ECG leads in a large cohort of patients with BrS. ECGs from 323 patients with BrS (age 47 ± 13 years; 257 men) with spontaneous (n = 141) or drug-induced (n = 182) type 1 ECG were retrospectively reviewed. Two hundred twenty-five (70%) patients were asymptomatic, 72 (22%) patients presented with unexplained syncope, and 26 (8%) patients presented with sudden death (12 patients) or appropriated implantable cardioverter-defibrillator therapies (14 patients) at diagnosis or over a mean follow-up of 48 ± 34 months. Thirty (9%) patients presented with type 1 ST elevation in at least 1 peripheral lead (22 patients in the aVR leads, 2 in the inferior leads, 5 in both aVR and inferior leads, and 1 in the aVR and VL leads). Patients with type 1 ST elevation in the peripheral leads more often had mutations in the SCN5A gene, were more often inducible, had slower heart rate, and higher J-wave amplitude in the right precordial leads. Twenty-seven percent (8 of 30) of the patients with type 1 ST elevation in the peripheral leads experimented sudden death/appropriate implantable cardioverter-defibrillator therapy, whereas it occurred in only 6% (18 of 293) of other patients (P < .0001). In multivariate analysis, type 1 ECG in the peripheral leads was independently associated with malignant arrhythmic events (odds ratio 4.58; 95% confidence interval 1.7-12.32; P = .0025). Type 1 ST elevation in the peripheral ECG leads can be seen in 10% of the patients with BrS and is an independent predictor for a malignant arrhythmic event. 23927872 Low voltage EELS-How low? Using low beam energies in a (scanning) transmission electron microscope (S/TEM) has numerous advantages over higher beam energies. We discuss the performance of commonly available electron microscopes when being operated at reduced beam energies. Further on, we discuss the merits of low beam energies concerning the determination of the optical properties of Si as well as of buried quantum structures. For this purpose we have aligned a conventional S/TEM and the attached energy loss spectrometer for 13keV and 60keV, respectively. Finally we identify the key parameters for setting up a low voltage electron energy loss spectrometry (EELS) experiment. 23891213 The evaluation of 25 chiral stationary phases and the utilization of sub-2.0μm coated polysaccharide chiral stationary phases via supercritical fluid chromatography. A rapid screening method to identify the best conditions for chiral separations is described. We analyzed a representative set of 80 racemic compounds against 25 different chiral stationary phases with three different mobile phases to identify the combination of columns and mobile phases that will separate the most compounds on the initial screen. While the OD separated the largest number of compounds, we found the best combination of six columns to be the AD, AS, AY, CC4, ID and Whelk-O1. The second team included the CCC, Cellulose-1, Cellulose-3 or OJ, IA, IE and IF. All 80 compounds were separated with a resolution range of 0.65-15.36. Screening the covalently bonded phases provided separation for 79 of the 80 compounds. We also found ethanol (0.1% NH4OH) separated more compounds than methanol (0.1% NH4OH) or isopropanol (0.1% NH4OH). As part of this study, we also compared the effectiveness of stationary phases that have the same chiral selector. Finally, we demonstrated the effectiveness of using a fast, 1.5-min screening method that utilizes a 1.7μm coated polysaccharide chiral stationary phase. 23921337 Sleeving nanocelluloses by admicellar polymerization. This investigation reports the first application of admicellar polymerization to cellulose nanofibers in the form of bacterial cellulose, microfibrillated cellulose, and cellulose nanowhiskers using styrene and ethyl acrylate. The success of this physical sleeving was assessed by SEM, FTIR, and contact angle measurements, providing an original and simple approach to the modification of cellulose nanofibers in their pristine aqueous environment. 23876198 Chevron Nails: A Normal Variant in the Pediatric Population. A 7-month-old girl was evaluated for V-shaped ridging of the fingernails consistent with chevron nails. Chevron nails are a normal variant in the pediatric population that is frequently outgrown. This case nicely demonstrates this normal finding that has so rarely been reported in the literature. 23909578 Atopy, the barrier, urine and genital lichen sclerosus (LS). From their interesting data Becker et al (Br J Dermatol 2013;168:362-6) induce that … 'AD seems to be a priming precondition for the development of LS in boys' … consistent with … a permissive effect of atopy facilitating the development of LS' …. Not unreasonably, they continue … 'genetic defects causing a lack of filaggrin have been reported in 50% of all AD cases, underlining the pathogenetic hypothesis that a disturbed atopic skin barrier is more susceptible to infectious and allergic and possibly LS-triggering agents' …, but then take a tendentious wrong-turning to conclude that … 'further studies are needed to illuminate the underlying immunological mechanisms in both entities to clarify the linkage between AD and LS'. This article is protected by copyright. All rights reserved. 23826985 School-based eating disorder prevention: a pilot effectiveness trial of teacher-delivered Media Smart. This pilot study tested teacher-delivered Media Smart, a school-based eating disorder prevention program that has achieved significant benefits when delivered by health professionals. Two Grade 7 classes (N = 51; M age = 12.43 years) participated, with one randomly allocated to Media Smart (n = 27; 67% girls) and the other to a control condition of usual lessons (n = 24; 37% girls). Program feasibility was assessed by teacher self-report, whereas student self-report of shape and weight concern (primary outcome variable) and seven additional risk factors were measured at baseline, post-program and 6-month follow up. Teacher ratings of program feasibility revealed that 25 of the 29 (86.2%) program activities were taught with 96% of activities rated as either highly (19 activities) or moderately (5 activities) valuable for students. Mixed model analyses were conducted using a 2 (group: Media Smart, control) × 2 (time: post-program, 6-month follow up) × 2 (gender: girls, boys) design, with baseline scores as a covariate. A not-significant trend for group favouring Media Smart was observed for shape and weight concern (Cohen's d effect size [d] = 0.32), whereas significant effects were found for feelings of ineffectiveness (d = 0.52) and weight-related peer teasing (d = 0.68). The program was feasible for teacher delivery and showed some promising results, supporting a more substantial randomized-controlled effectiveness trial. 23292357 Interaction of L-SIGN with Hepatitis C Virus Envelope Protein E2 Up-Regulates Raf-MEK-ERK Pathway. Liver/lymph node-specific intercellular adhesion molecule-3-grabbing integrin (L-SIGN) facilitates hepatitis C virus (HCV) infection through interaction with HCV envelope protein E2. Signaling events triggered by the E2 via L-SIGN are poorly understood. Here, kinase cascades of Raf-MEK-ERK pathway were defined upon the E2 treatment in NIH3T3 cells with stable expression of L-SIGN. The E2 bound to the cells through interaction with L-SIGN and such binding subsequently resulted in phosphorylation and activation of Raf, MEK, and ERK. Blockage of L-SIGN with antibody against L-SIGN reduced the E2-induced phosphorylation of Raf, MEK, and ERK. In the cells infected with cell culture-derived HCV, phosphorylation of these kinases was enhanced by the E2. Up-regulation of Raf-MEK-ERK pathway by HCV E2 via L-SIGN provides new insights into signaling cascade of L-SIGN, and might be a potential target for control and prevention of HCV infection. 23930872 Effect of early release of tourniquet in total knee arthroplasty. Objective: To evaluate whether tourniquet release intraoperatively is better than postoperative release in reducing overall blood loss, duration of surgery, duration of tourniquet, length of hospital stay, wound related complications and transfusion requirement. Study Design: Comparative study. Place and Duration of Study: Department of Surgery, The Aga Khan University Hospital, Karachi, from January 2004 to June 2007. Methodology: One hundred and thirty patient files were reviewed retrospectively. Patients were divided into two groups. Group-A consisted of 65 patients with early deflation of tourniquet and group-B comprised of 65 patients with the release of tourniquet after applying compressive dressing. Total blood loss (determined by Gross method) and other study variables were noted as per objective and computed. Results: There were 22 males and 108 females with comparable BMI. All had undergone posterior stabilized cemented total knee replacement. Calculated blood loss was 1.208 L and 1.108 L in group-A and B respectively (p = 0.27). Significant increase in duration of surgery was noted in group-A patients. Four patients in group-B showed complication related to wound with 3 being minor and 1 requiring additional operation room visit. Mean length of hospital stay was 9 days. Transfusion frequency was higher in group-B despite comparable postoperative haemoglobin values. Conclusion: Intraoperative tourniquet release does not reduce overall blood loss with no effect in conserving blood after total knee replacement, however, this group had relatively shorter hospital stay. 23643726 Thermodynamically accurate modeling of the catalytic cycle of photosynthetic oxygen evolution: a mathematical solution to asymmetric Markov chains. Forty-three years ago, Kok and coworkers introduced a phenomenological model describing period-four oscillations in O2 flash yields during photosynthetic water oxidation (WOC), which had been first reported by Joliot and coworkers. The original two-parameter Kok model was subsequently extended in its level of complexity to better simulate diverse data sets, including intact cells and isolated PSII-WOCs, but at the expense of introducing physically unrealistic assumptions necessary to enable numerical solutions. To date, analytical solutions have been found only for symmetric Kok models (inefficiencies are equally probable for all intermediates, called "S-states"). However, it is widely accepted that S-state reaction steps are not identical and some are not reversible (by thermodynamic restraints) thereby causing asymmetric cycles. We have developed a mathematically more rigorous foundation that eliminates unphysical assumptions known to be in conflict with experiments and adopts a new experimental constraint on solutions. This new algorithm termed STEAMM for S-state Transition Eigenvalues of Asymmetric Markov Models enables solutions to models having fewer adjustable parameters and uses automated fitting to experimental data sets, yielding higher accuracy and precision than the classic Kok or extended Kok models. This new tool provides a general mathematical framework for analyzing damped oscillations arising from any cycle period using any appropriate Markov model, regardless of symmetry. We illustrate applications of STEAMM that better describe the intrinsic inefficiencies for photon-to-charge conversion within PSII-WOCs that are responsible for damped period-four and period-two oscillations of flash O2 yields across diverse species, while using simpler Markov models free from unrealistic assumptions. 23827680 Observing a DNA polymerase choose right from wrong. DNA polymerase (pol) β is a model polymerase involved in gap-filling DNA synthesis utilizing two metals to facilitate nucleotidyl transfer. Previous structural studies have trapped catalytic intermediates by utilizing substrate analogs (dideoxy-terminated primer or nonhydrolysable incoming nucleotide). To identify additional intermediates during catalysis, we now employ natural substrates (correct and incorrect nucleotides) and follow product formation in real time with 15 different crystal structures. We are able to observe molecular adjustments at the active site that hasten correct nucleotide insertion and deter incorrect insertion not appreciated previously. A third metal binding site is transiently formed during correct, but not incorrect, nucleotide insertion. Additionally, long incubations indicate that pyrophosphate more easily dissociates after incorrect, compared to correct, nucleotide insertion. This appears to be coupled to subdomain repositioning that is required for catalytic activation/deactivation. The structures provide insights into a fundamental chemical reaction that impacts polymerase fidelity and genome stability. 23887206 Mast Cell Positivity to Tryptase Correlates with Metastatic Lymph Nodes in Gastrointestinal Cancer Patients Treated Surgically. Background: Angiogenesis has been found to be a reliable prognostic indicator for several types of malignancies. Tryptase is a serine protease stored in mast cell (MC) granules, which plays a role in tumor angiogenesis. MCs can release tryptase following c-Kit receptor activation. Method: In this study, immunohistochemistry, image analysis methods and clinical aspects were employed in a series of 41 gastrointestinal cancer patients with stage T3-4N2a-bM0 (by the American Joint Committee on Cancer, AJCC, for colorectal cancer, 7th edition) and T3N2-3M0 (by AJCC for gastric cancer, 7th edition) to evaluate the possible correlation between MCs positive to tryptase (MCPT) in tumor tissue and the number of metastatic lymph nodes harvested. Results: Data demonstrated a positive correlation between MCPT in tumor tissue and the number of metastatic lymph nodes; the validity of these data needs confirmation in larger patient cohorts. Conclusion: This is the first report considering MCPT in tumor tissue as a potential tool for a valid indication of the type of surgical treatment and its radicality, and it might be considered for the prognosis of patients before radical surgical treatment. Our pilot data need confirmation in a larger patient cohort. 23630044 Fallback foods, preferred foods, adaptive zones, and primate origins. Appreciation has grown for the impact of tropical forest seasonality and fallback foods on primate diets, behaviors, and morphology. As critically important resources in times of shortage, seasonal fallback foods may have an outsized role in selecting for form and function while the diversity of preferred plant foods has played an equally prominent role in shaping primate evolution. Here, hypotheses of primate origins are examined in the context of food choice models developed by Marshall and Wrangham [2007] and related to the broader concepts of adaptive zones and radiations. The integrated evolution of primate diet and positional behavior is consistent with a growing reliance on angiosperm products-not prey-as preferred and seasonal fallback foods, temporally and phylogenetically coordinated with evolutionary phases of the angiosperm adaptive radiation. Selection for an incisor oriented but non-specialized heterodont dentition, in contrast with most other orders, attests to the universal role of a highly varied vegetation diet as the primates' primary food resource, with diverse physical properties, phenology and high seasonality. A preference by plesiadapiforms for eating small protein- and lipid-rich seeds may have predisposed the primates and advanced angiosperms to diversify their evolving ecological interdependence, which established the primate adaptive zone and became realized more fully with the rise of the modern euprimate and angiosperm phenotypes. The "narrow niche" hypothesis, a recent challenge to the angiosperm co-evolution hypothesis, is evaluated further. Finally, I note support for visual predation as a core adaptive breakthrough for primates or euprimates remains elusive and problematic, especially considering the theoretical framework provided by the Marshall-Wrangham model, updated evidence of primate feeding habits and the counterpoint lessons of the most successful primate predators, the tarsiiforms. Am. J. Primatol. 75:883-890, 2013. © 2013 Wiley Periodicals, Inc. 23830429 Multicommutated flow analysis system for determination of creatinine in physiological fluids by Jaffe method. For the needs of photometric determination of creatinine according to Jaffe protocol a dedicated paired emitter detector diode (PEDD) detector has been developed. This PEDD device has been constructed in the compact form of flow-through cell (30 μL total volume and 7 mm optical pathlength) integrated with 505 nm LED-based emitter and 525 nm LED-based detector compatible with multicommutated flow analysis (MCFA) system. This fully mechanized MCFA system configured of microsolenoid valves and pumps is operating under microprocessor control. The developed analytical system offers determination of creatinine in the submillimolar range of concentrations with detection limit at ppm level. The throughput offered by the system operating according to multi-point fixed-time procedure for kinetic measurements is 15-40 samples per hour depending on the mode of measurements. The developed PEDD-based MCFA system has been successfully applied for the determination of creatinine in real samples of human urine as well as serum. The developed sampling unit used the system is free from effects caused by differences in sample viscosity. 23899650 Range of motion and function are not affected by increased post constraint in patients undergoing posterior stabilized total knee arthroplasty. Constrained primary total knee arthroplasty (TKA) can provide stability in the face of incompetent collateral structures or irreconcilable flexion-extension imbalances. However, little is known about its effect on overall knee range of motion (ROM). This study determines whether TKA with increased constraint affects postoperative ROM. Patients undergoing primary TKA using either posterior stabilized (PS) or constrained condylar knee (CCK) inserts were match-paired based on body mass index, preoperative ROM, and direction and severity of the coronal deformity, yielding 68 pairs. ROM and Knee Society Score (KSS) were obtained preoperatively and at 6weeks, 4months, and 1year. When the 68 matched pairs were considered, all outcome variables related to ROM between the PS and CCK groups at each of the postoperative intervals were similar. Additionally, both the individual items and combined scores of the KSS were similar between groups at all time points. We demonstrate that the use of increased constraint does not affect ROM, relief of pain, or function after TKA. Level III (retrospective case-controlled study, based on prospectively collected data). 23966067 Varenicline and Cytisine Diminish the Dysphoric-Like State Associated with Spontaneous Nicotine Withdrawal in Rats. Tobacco addiction is characterized by a negative mood state upon smoking cessation and relapse after periods of abstinence. Clinical studies indicate that negative mood states lead to craving and relapse. The partial α4/α6/β2* nicotinic acetylcholine receptor (nAChR) agonists varenicline and cytisine are widely used as smoking cessation treatments. Varenicline has been approved in the US for smoking cessation and cytisine is used in Eastern European countries. Despite the widespread use of these compounds very little is known about their effects on mood states. These studies investigated the effects of varenicline, cytisine, and the cytisine-derivative 3-(pyridin-3'-yl)-cytisine (3-pyr-Cyt) on brain reward function in nicotine-naïve and nicotine withdrawing rats. The cytisine-derivative 3-pyr-Cyt is a very weak α4β2* nAChR partial agonist and like cytisine and varenicline has antidepressant-like effects in animal models. The intracranial self-stimulation (ICSS) procedure was used to investigate the effects of these compounds on brain reward function. Elevations in ICSS thresholds reflect a dysphoric state and a lowering of thresholds is indicative of a potentiation of brain reward function. It was shown that acute administration of nicotine and varenicline lowered ICSS thresholds. Acute administration of cytisine or 3-pyr-Cyt did not affect ICSS thresholds. Discontinuation of chronic, 14-days, nicotine administration led to elevations in ICSS thresholds that lasted for about 2 days. Varenicline and cytisine, but not 3-pyr-Cyt, diminished the nicotine withdrawal-induced elevations in ICSS thresholds. In conclusion, these studies indicate that varenicline and cytisine diminish the dysphoric-like state associated with nicotine withdrawal and may thereby prevent relapse to smoking in humans.Neuropsychopharmacology accepted article preview online, 21 August 2013. doi:10.1038/npp.2013.216. 23554102 Emerging mechanisms of glutathione-dependent chemistry in biology and disease. Glutathione has traditionally been considered as an antioxidant that protects cells against oxidative stress. Hence, the loss of reduced glutathione and formation of glutathione disulfide is considered a classical parameter of oxidative stress that is increased in diseases. Recent studies have emerged that demonstrate that glutathione plays a more direct role in biological and pathophysiological processes through covalent modification to reactive cysteines within proteins, a process known as S-glutathionylation. The formation of an S-glutathionylated moiety within the protein can lead to structural and functional modifications. Activation, inactivation, loss of function, and gain of function have all been attributed to S-glutathionylation. In pathophysiological settings, S-glutathionylation is tightly regulated. This perspective offers a concise overview of the emerging field of protein thiol redox modifications. We will also cover newly developed methodology to detect S-glutathionylation in situ, which will enable further discovery into the role of S-glutathionylation in biology and disease. J. Cell. Biochem. 114: 1962-1968, 2013. © 2013 Wiley Periodicals, Inc. 23444334 Protective effect of butylated hydroxytoluene on ferric nitrilotriacetate induced hepatotoxicity and oxidative stress in mice. The present study was undertaken to evaluate the possible ameliorating effect of butylated hydroxyl toluene (BHT), associated with ferric nitrilotriacetate (Fe-NTA)-induced oxidative stress and liver injury in mice. The treatment of mice with Fe-NTA alone enhances ornithine decarboxylase activity to 4.6 folds, protein carbonyl formation increased up to 2.9 folds and DNA synthesis expressed in terms of [(3)H] thymidine incorporation increased to 3.2 folds, and antioxidants and antioxidant enzymes decreased to 1.8-2.5 folds, compared with the corresponding saline-treated controls. These changes were reversed significantly (p < 0.001) in animals receiving a pretreatment of BHT. Our data show that BHT can reciprocate the toxic effects of Fe-NTA and can serve as a potent chemopreventive agent. 23305962 Slow accrual of elderly patients with metastatic breast cancer in the Dutch multicentre OMEGA study. In a Dutch multicentre study, elderly (65 + year) metastatic breast cancer patients, eligible for first-line chemotherapy, were randomised between two types of single-agent chemotherapy. As accrual was slow, with 78 randomised patients between April 2007 and September 2011, we explored potential barriers in the accrual process and their consequences for characteristics of included patients. We sent surveys on the reasons for non-inclusion to all coordinating investigators. We also examined inclusion in a concurrent, non-elderly breast cancer study of the trialists' group and analysed baseline geriatric characteristics of included patients. Investigators from fifteen participating centres returned the survey. Most commonly reported barriers to inclusion were: patient's refusal of chemotherapy (n = 8) or of randomisation (n = 9), impaired cognition (n = 3) and insufficient cardiac function (n = 2). Oncologists' preference for combination regimens over single-agent chemotherapy was reported twice. Twenty-eight potentially eligible patients, aged 65-71 years, were included in a concurrent, study investigating combination chemotherapy in fit non-elderly patients with metastatic breast cancer. However, baseline characteristics of the included patients showed that the OMEGA study succeeded in including frail and older patients, with a performance status of 2 in 22% of patients and 54% of patients aged 75 years or older. Accrual in this study was mainly hampered by patient's refusal or preference for a particular type of treatment, and an overall condition considered as too fit or too frail for inclusion. Future trials in elderly metastatic breast cancer patients should focus on non-restrictive inclusion criteria as well as on education of physicians and elderly patients on the advantages of trial participation. 23639586 Gene expression profiling and pathway analysis of hepatotoxicity induced by triptolide in Wistar rats. Triptolide (TP), a major component of TWHF, is widely used to treat rheumatoid arthritis, systemic lupus erythematosus, nephritis and leprosy. However, its clinical use is limited by hepatotoxicity. To further elucidate the underlying mechanism of its hepatotoxic effects, hepatic gene expression profiles were analyzed. TP (1000 and 300μg/kg) was orally administered to Wistar rats for 14days. Current study indicated that female rats were more sensitive to TP-induced hepatotoxicity than males. Genome-wide microarray analyses identified 3329 differentially expressed genes in liver of female rats. Analyses of these genes identified over-represented functions associated with insulin signaling pathway, glucose metabolism, cell cycle, oxidative stress and apoptosis, which were consistent with the results of significant increase of Caspase-3 activity and reduction of serum glucose, GSH/GSSG ratio, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities, liver glycogen. In addition, it was observed for the first time that glucocorticoids and IGF1 might get involved in TP-induced hepatotoxicity. These data suggest that TP treatment could alter the hepatic redox status, reduce serum glucose and induce hepatocyte apoptosis, consistent with the differential expression of genes involved in insulin signaling pathway, glucose metabolism pathway and cell stress pathway, all of which might contribute to the overall TP-induced hepatotoxicity. 23964629 Advances in and the potential of vaccines for respiratory syncytial virus. Respiratory syncytial virus (RSV) is the leading cause of serious lower respiratory track illness causing bronchiolitis and some mortality in infants and the elderly. Despite decades of research there is no licensed RSV vaccine. To enable the development of RSV vaccines, several major obstacles must be overcome including immature and waning immunity to RSV infection, the capacity of RSV to evade immunity and the failure of RSV infection to induce robust enduring immunity. Since the failure of the formalin-inactivated RSV vaccine trial, more cautious and deliberate progress has been made toward RSV vaccine development using a variety of experimental approaches. The scientific rational and the state of development of these approaches are reviewed in this article. 23489622 Anti-influenza active and low toxic N-phenyl-substituted β-amidoamidines structurally related to natural antibiotic amidinomycin. A set of racemic N-phenyl-substituted β-amidoamidines hydrochlorides 4, which are structurally related to natural antiviral agent amidinomycin (1), was synthesized in four steps starting from methacryloyl anilide (5). In the final step of the synthetic route, an uncommon monoacylation of β-aminoamidine 8 at the less reactive β-phenylamino-group took place. To rationalize this result, a mechanism which involves initial acylation at the more active amidine-function followed by intramolecular acyl-group transfer to β-phenylamino-group was suggested. All three β-amidoamidines 4d-f bearing long linear aliphatic chain (from n-C8H17 to n-C12H25) revealed significant in vitro activity against influenza A virus (H3N2) and modest cytotoxicity. The in vitro antiviral potency of 4d,e is 6-20 times greater than that of commercial rimantadine with lower EC50 values and higher therapeutic index. The non-toxic in vivo compounds 4d-f showed a beneficial protective effect in influenza A (H3N2) infected mice. 23551297 Spontaneous formation of hydrophobic domains in isolated peptides. Aromatic amino acids are known for their hydrophobicity and the active role they play in protein folding. Here, we investigate the intrinsic propensity of small peptides to form hydrophobic domains in the absence of solvent water molecules. The structures of three aromatic-rich isolated peptides, Ac-Phe-Phe-NH2 (FF), Ac-Trp-Tyr-NH2 (WY), and Ac-Phe-Phe-Phe-NH2 (FFF), all in the gas phase, have been studied by infrared-ultraviolet (IR/UV) double resonance laser spectroscopy, aided by dispersion-corrected density functional theory (DFT-D) calculations. Spontaneous formation of hydrophobic domains is systematically observed, whatever the secondary structure adopted by the backbone. Various types of aromatic-aromatic arrangements have been identified and associated to specific secondary structures, illustrating the interplay between the hydrophobic clusters and the backbone. Backbone NH amide groups surrounded by aromatic rings have also been evidenced and are found to contribute significantly to the stabilization of aromatic pairs. These results suggest that the formation of aromatic clusters involving contiguous residues might be a very efficient process leading to the formation of hydrophobic domains in the early stages of protein folding, well before a hydrophobic collapse into the tertiary structure. 23618622 Two differential flows in a bioreactor promoted platelet generation from human pluripotent stem cell-derived megakaryocytes. Induced pluripotent stem cell (iPSC) technology enables us to investigate various potential iPSC-based therapies. Although the safety of iPSC derivation has not been completely validated, anucleate cells, such as platelets or erythrocytes, derived from iPSCs are promising targets. However, the efficiency of in vitro platelet generation from megakaryocytes (MKs) under static culture conditions is lower than is seen in vivo. In this study, we demonstrate the proof of concept by a two-dimensional flow culture system that enabled us to increase platelet yield from human embryonic stem cell or iPSC-derived MKs using a biomimetic artificial blood vessel system. The bioreactor was composed of biodegradable scaffolds with ordered arrays of pores made to mimic in vivo bone marrow through salt leaching. Within the system, two flows in different directions in which the angle between the directions of flow is 60 degrees but not 90 degrees contributed to suitable pressure and shear stress applied to MKs to promote platelet generation. Generated platelets derived from human embryonic stem cells or human induced pluripotent stem cells through the bioreactor with a 60-degree angle revealed intact integrin αIIbβ3 activation after agonist stimulation. Collectively, our findings indicate that two flows in different directions of two-dimensional flow culture may be a feasible system for in vitro generation of platelets from pluripotent stem cells (i.e., iPSC-derived MKs) in numbers sufficient for transfusion therapy. 22983720 Are your asset data as good as you think? Conducting a comprehensive census of built assets to improve urban population health. Secondary data sources are widely used to measure the built asset environment, although their validity for this purpose is not well-established. Using community-engaged research methodology, this study conducted a census of public-facing, built assets via direct observation and then tested the performance of these data against widely used secondary datasets. After engaging community organizations, a community education campaign was implemented. Using web-enabled cell phones and a web-based application prepopulated with the secondary data, census workers verified, modified, and/or added assets using street-level observation, supplementing data with web searches and telephone calls. Data were uploaded to http://www.SouthSideHealth.org . Using direct observation as the criterion standard, the sensitivity of secondary datasets was calculated. Of 5,773 assets on the prepopulated list, direct observation of public-facing assets verified 1,612 as operating; another 653 operating assets were newly identified. Sensitivity of the commercial list for nonresidential, operating assets was 61 %. Using the asset census as the criterion standard, secondary datasets were incomplete and inaccurate. Comprehensive, accurate built asset data are needed to advance urban health research, inform policy, and improve individuals' access to assets. 23650168 Phosphatidylinositol 4-kinase III beta is essential for replication of human rhinovirus and its inhibition causes a lethal phenotype in vivo. Human rhinovirus (HRV) is the predominant cause of the common cold, but more importantly, infection may have serious repercussions in asthmatics and chronic obstructive pulmonary disorder (COPD) patients. A cell-based antiviral screen against HRV was performed with a subset of our proprietary compound collection, and an aminothiazole series with pan-HRV species and enteroviral activity was identified. The series was found to act at the level of replication in the HRV infectious cycle. In vitro selection and sequencing of aminothiazole series-resistant HRV variants revealed a single-nucleotide mutation leading to the amino acid change I42V in the essential HRV 3A protein. This same mutation has been previously implicated in resistance to enviroxime, a former clinical-stage antipicornavirus agent. Enviroxime-like compounds have recently been shown to target the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIβ). A good correlation between PI4KIIIβ activity and HRV antiviral potency was found when analyzing the data over 80 compounds of the aminothiazole series, covering a 750-fold potency range. The mechanism of action through PI4KIIIβ inhibition was further demonstrated by small interfering RNA (siRNA) knockdown of PI4KB, which reduced HRV replication and also increased the potency of the PI4KIIIβ inhibitors. Inhibitors from two different structural classes with promising pharmacokinetic profiles and with very good selectivity for PI4KIIIβ were used to dissociate compound-related toxicity from target-related toxicity. Mortality was seen in all dosing groups of mice treated with either compound, therefore suggesting that short-term inhibition of PI4KIIIβ is deleterious. 23813653 Challenges of using primary care electronic medical records in the UK to study medications in pregnancy. This paper aimed to assess the prescription of medications during pregnancy by primary care physicians in the UK. We identified both completed pregnancies and pregnancies losses (ectopic pregnancies, miscarriages, terminations, and stillbirths) in women aged 13-49 years enrolled in The Health Improvement Network (THIN) between 1996 and 2010 following an algorithm with three sequential cycles that searched for Read Code groups in hierarchical order: (1) indicators of conception; (2) delivery or pregnancy loss; and (3) other codes suggestive of pregnancy. Completed pregnancies were linked to liveborn infants by means of the family identification number and date of birth. Prescription of specific drugs during the first trimester and time trends during the last decade were calculated. A total of 191 000 pregnancies were identified, including 148 544 completed pregnancies and 42 456 (22.2%) pregnancies losses (ectopic pregnancies, miscarriages, terminations, and stillbirths). Of the completed pregnancies, 131670 (88.6%) were successfully linked with the offspring. The most commonly prescribed drugs were antibiotics, antimycotics, asthma/allergy medications, and analgesics. From 1996 to 2010, the proportion of completed pregnancies with at least one prescription during the first trimester increased for antidepressants (1.8% to 4.2%), thyroid hormones (0.7% to 1.6%), and opiods (1.5% to 2.6%), among other drugs. In conclusion, the prescription of several medications by primary care physicians during the first trimester of pregnancy has risen in the UK during the last decade. We discuss how, when important challenges are considered, THIN may be a promising resource to study specific therapies during pregnancy. Copyright © 2013 John Wiley & Sons, Ltd. 23946043 Use of natural health products in children: Survey of parents in waiting rooms. To determine how common it is for parents to give natural health products (NHPs) to their children, which NHPs are being used, why they are being used, and parents' assessments of the benefits and side effects of NHPs. Survey. Newfoundland and Labrador. Parents waiting in their family doctors' offices. Parent and child demographic characteristics; pediatric chronic medical conditions affecting the children; prescribed medications, over-the-counter medications, and NHPs used by the children; why the medications and NHPs were being used, the dose, and parents' assessments of the effectiveness and side effects; and where parents had heard about the NHPs, whether they had told their physicians that the children were taking the products, and where they had obtained the products. A total of 202 (53.4%) of the 378 eligible adults who were approached completed the survey. This represented 333 children. Mean (SD) age of the children was 5.1 (3.3) years. Overall, 28.7% of parents reported using nonvitamin NHPs for their children. A total of 137 children (41.1%) had taken NHPs (including vitamins); 61.1% of the NHPs being used were vitamins. The remainder fell under teas (primarily chamomile and green teas), echinacea, fish or omega-3 oils, and a large category of "other" products. These NHPs were most commonly used to improve general health, improve immunity, and prevent colds and infections. Approximately half of the parents (51.7%) believed their children had benefited from taking NHPs, and 4.4% believed their children had experienced adverse side effects. Slightly less than half of the parents (45.0%) had informed their physicians that their children were taking NHPs. Overall, 45.5% of parents attending physicians' offices reported using NHPs in their children. If vitamins are not included in the definition of NHPs, this rate drops to 28.7%. Parents most commonly use NHPs to maintain the general health of their children, to prevent colds, and to boost children's immune systems. About half of the parents believed the NHPs helped, very few had noticed any side effects, and approximately half had informed their physicians that they were giving their children NHPs. 23157629 Serotonin receptors of type 6 (5-HT6): from neuroscience to clinical pharmacology. The serotonin (5-HT) receptors of type 6 (5-HT6) are quite different from all other 5-HT receptors, as they include a short third cytoplasmatic loop and a long C-terminal tail, and one intron located in the middle of the third cytoplasmatic loop. A lot of controversies still exist regarding their binding affinity, effects of 5-HT6 ligands on brain catecholamines, behavioral syndromes regulated by them, and brain distribution. In spite of the lack of information on metabolic pattern of the various compounds, some of 5-HT6 receptor ligands entered the clinical development as potential anti-dementia, antipsychotic, antidepressant and anti-obese drugs. The present paper is a comprehensive review on the state of art of the 5-HT6 receptors, while highlighting the potential clinical applications of 5-HT6 receptor agonists/antagonists. 23708526 The potential of stem cell research for the treatment of neuronal damage in glaucoma. Stem cell research offers a wide variety of approaches for the advancement of our understanding of basic mechanisms of neurodegeneration and tissue regeneration and for the discovery and development of new therapeutic strategies to prevent and restore neuronal cell loss. Similar to most other regions of our central nervous system, degenerative diseases of the retina lead to the loss of neurons, which are not replaced. Recent work in animals has provided proof-of-concept evidence for the restoration of photoreceptor cells by cell transplantation and neuronal cell replacement by regeneration from endogenous cell sources. However, efficient therapeutic prevention of neuronal cell loss has not been achieved. Moreover, successful cell replacement of retinal neurons in humans, including that of ganglion cells, remains a major challenge. Future successes in the discovery and translation of neuroprotective drug and gene therapies and of cell-based regenerative therapies will depend on a better understanding of the underlying disease pathomechanisms. Existing stem cell and cell-reprogramming technologies offer the potential to generate human retina cells, to develop specific human-cell-based retina disease models, and to open up novel therapeutic strategies. Further, we might glean substantial knowledge from species that can or cannot regenerate their neuronal retina, in the search for new therapeutic approaches. Thus, stem cell research will pave the way toward clinical translation. In this review, I address some of the major possibilities presently on offer and speculate about the power of stem cell research to gain further insights into the pathomechanisms of retinal neurodegeneration (with special emphasis on glaucoma) and to advance our therapeutic options. 23927554 Interventionally implanted port catheter systems for hepatic arterial infusion of chemotherapy in patients with primary liver cancer: A phase II-study (NCT00356161). Hepatic arterial infusion (HAI) of chemotherapy requires the implantation of a transcatheter application system which is traditionally performed by surgery. This procedure, but particularly the adjacent drug application via pump or port is often hampered by specific complications and device failure. Interventionally implanted port catheter systems (IIPCS) facilitate the commencement of HAI without need for laparatomy, and are associated with favorable complication rates. We here present an evaluation of the most important technical endpoints associated with the use of IIPCS for HAI in patients with primary liver cancers. 70 patients (pts) with hepatocellular (HCC, n=33) and biliary tract cancer (BTC, n=37) were enrolled into a phase II -study. Of those, n=43 had recurrent disease and n=31 suffered from liver-predominant UICC-stage IVb. All pts were provided with IIPCSs before being treated with biweekly, intraarterial chemotherapy (oxaliplatin, 5-Flourouracil, folinic acid). The primary objective of the trial was defined as evaluation of device-related complications and port duration. Implantation of port catheters was successful in all patients. Mean treatment duration was 5.8 months, and median duration of port patency was not reached. Disease-progression was the most common reason for treatment discontinuation (44 pts., 63%), followed by chemotherapy-related toxicity (12 pts., 17%), and irreversible device failure (5 pts., 7%). A total of 28 port complications occurred in 21 pts (30%). No unexpected complications were observed. HAI via interventionally implanted port catheters can be safely applied to patients with primary liver tumors far advanced or/and pretreated. 23694902 3D matrix microenvironment for targeted differentiation of embryonic stem cells into neural and glial lineages. The onset of neurodegenerative disorders is characterized by the progressive dysfunction and loss of subpopulations of specialized cells within specific regions of the central nervous system (CNS). Since CNS has a limited ability for self-repair and regeneration under such conditions, clinical transplantation of stem cells has been explored as an alternative. Although embryonic stem cells (ESCs) offer a promising therapeutic platform to treat a variety of neurodegenerative disorders, the niche microenvironment, which could regulate their differentiation into specialized lineages on demand, needs to be optimized for successful clinical transplantation. Here, we evaluated the synergistic role of matrix microenvironment (type, architecture, composition, stiffness) and signaling molecules (type, dosage) on murine ESC differentiation into specific neural and glial lineages. ESCs were cultured as embryoid bodies on either 2D substrates or within 3D scaffolds, in the presence or absence of retinoic acid (RA) and sonic hedgehog (Shh). Results showed that ESCs maintained their stemness even after 4 days in the absence of exogenous signaling molecules, as evidenced by Oct-4 staining. RA at 1 μM dosage was deemed optimal for neural differentiation and neurite outgrowth on collagen-1 coated substrates. Significant neural differentiation with robust neurite outgrowth and branching was evident only on collagen-1 coated 2D substrates and within 3D matrigel scaffolds, in the presence of 1 μM RA. Blocking α6 or β1 integrin subunits on differentiating cells inhibited matrigel-induced effects on neural differentiation and neurite outgrowth. Hydrogel concentration strongly regulated formation of neural and astrocyte lineages in 1 μM RA additive cultures. When RA and Shh were provided, either alone or together, 3D collagen-1 scaffolds enhanced significant motor neuron formation, while 3D matrigel stimulated dopaminergic neuron differentiation. These results suggest a synergistic role of microenvironmental cues for ESC differentiation and maturation, with potential applications in cell transplantation therapy. 23932304 Uterine necrosis following pelvic arterial embolization for post-partum hemorrhage: review of the literature. Uterine necrosis is one of the rarest complications following pelvic arterial embolization for postpartum hemorrhage (PPH). With the increasing incidence of cesarean section and abnormal placental localization (placenta previa) or placental invasion (placenta accreta/increta/percreta), more and more cases of uterine necrosis after embolization are being diagnosed and reported. Pelvic computed tomography or magnetic resonance imaging provides high diagnostic accuracy, and surgical management includes hysterectomy. We performed a Medline database query following the first description of uterine necrosis after pelvic embolization (between January 1985 and January 2013). Medical subheading search words were the following: "uterine necrosis"; "embolization"; "postpartum hemorrhage". Seventeen citations reporting at least one case of uterine necrosis after pelvic embolization for PPH were included, with a total of 19 cases. This literature review discusses the etiopathogenesis, clinical and therapeutic aspects of uterine necrosis following pelvic arterial embolization, and guidelines are detailed. The mean time interval between pelvic embolization and diagnosis of uterine necrosis was 21 days (range 9-730). The main symptoms of uterine necrosis were fever, abdominal pain, menorrhagia and leukorrhea. Surgical management included total hysterectomy (n=15, 78%) or subtotal hysterectomy (n=2, 10%) and partial cystectomy with excision of the necrotic portion in three cases of associated bladder necrosis (15%). Uterine necrosis was partial in four cases (21%). Regarding the pathophysiology, four factors may be involved in uterine necrosis: the size and nature of the embolizing agent, the presence of the anastomotic vascular system and the embolization technique itself with the use of free flow embolization. 23643608 Wear and abrasion resistance selection maps of biological materials. The mechanical design of biological materials has generated widespread interest in recent years, providing many insights into their intriguing structure-property relationships. A critical characteristic of load-bearing materials, which is central to the survival of many species, is their wear and abrasion tolerance. In order to be fully functional, protective armors, dentitious structures and dynamic appendages must be able to tolerate repetitive contact loads without significant loss of materials or internal damage. However, very little is known about this tribological performance. Using a contact mechanics framework, we have constructed materials selection charts that provide general predictions about the wear performance of biological materials as a function of their fundamental mechanical properties. One key assumption in constructing these selection charts is that abrasion tolerance is governed by the first irreversible damage at the contact point. The maps were generated using comprehensive data from the literature and encompass a wide range of materials, from heavily mineralized to fully organic materials. Our analysis shows that the tolerance of biological materials against abrasion depends on contact geometry, which is ultimately correlated to environmental and selective pressures. Comparisons with experimental data from nanoindentation experiments are also drawn in order to verify our predictions. With the increasing amount of data available for biological materials also comes the challenge of selecting relevant model systems for bioinspired materials engineering. We suggest that these maps will be able to guide this selection by providing an overview of biological materials that are predicted to exhibit the best abrasion tolerance, which is of fundamental interest for a wide range of applications, for instance in restorative implants and protective devices. 23830875 A case of an adoptive girl with precocious puberty: The problem of age estimation. Age estimation is one of the main tasks of forensic anthropology and odontology, both on the dead and the living. In living subjects, age estimation may be used to establish an individual's status as a minor in cases involving adoption, criminal responsibility, child pornography, and those seeking asylum, especially where adequate identification documents are lacking. The authors report a case about age assessment of a girl born in Mbujimayi (Democratic Republic of Congo) and later adopted in Italy. The birth certificate issued after finding the child in a state of abandonment (in December 2007), bore date of 12.12.2004, but this was in contrast with the year of birth - 2003 - stated on the certification available to the center that had provided accommodation to the girl in Africa. Her adoptive parents reported that the child had been diagnosed with precocious puberty and was thus under treatment. She weighed 32.5kg and was 132.5cm tall. Body mass index (BMI) corresponded to the range between 9.5 and 14 years of age. The assessment of maturity indicators (sexual characteristics) placed the child at the lower limits of Stage II of Tanner's classification (sparse growth of long, slightly darkened, downy straight pubic hair; elevation of the breast and nipple as a small mound with increased diameter of the areolae). The skeletal age was determined by taking X-rays of the hand and wrist using Fels, TW2 and Greulich and Pyle methods. Dental growth was assessed through orthopantomogram using Demirjian's technique. The methods applied were adjusted considering the studies on African population found in the literature, and a skeletal and dental age of 10 years was established. Afterwards, the wrist X-rays performed at the Children's Hospital of Bari, 7 months before our investigation, revealed a skeletal age of 7 years. This evidence showed that, despite the treatment the child had promptly initiated, early puberty had influenced the skeletal growth with an acceleration of about 2 years. Therefore, the age we detected (10 years) was the result of precocious puberty. Then, we backdated the girl's birth (by about 2 years, based on current studies), stating that she was about 8 at the time of our investigation. This case is significant both for the racial differences that need to be considered in age assessment, and for the importance of any pathology (growth disorders) that may affect physiological development and make the applied methods poorly reliable. 23842760 Thoracoscopic oesophageal mobilization during thoracolaparoscopy three-stage oesophagectomy: a comparison of lateral decubitus versus semiprone positions. OBJECTIVESThe aim of this study is to compare thoracoscopic mobilization of the oesophagus in the lateral decubitus position and the semiprone position and to identify potential differences between the two techniques.METHODA retrospective review of a prospectively maintained oesophagectomy database identified 150 patients undergoing combined thoracoscopic and laparoscopic oesophagectomy (TLO). Of these, 90 cases underwent thoracoscopic oesophageal mobilization in the left lateral decubitus position. The remaining 60 cases underwent thoracoscopic oesophageal mobilization in the semiprone position.RESULTThere were no differences in the clinicopathological factors and tumour characteristics between the two groups. There was no significant difference in the blood loss, operation time, the incidence of conversion, length of hospital stay or in the number of retrieved mediastinal and abdominal nodes between the two groups. There was no significant difference with regard to the incidence of respiratory complications, anastomotic leaks, vocal cord palsy, chylothorax, delayed gastric emptying, arrhythmia and intestinal obstruction between the two groups.CONCLUSIONThe semiprone and lateral decubitus positions each have their inherent advantages and disadvantages. Our initial experience confirmed that while the semiprone position is associated with superior surgical ergonomics and better exposure of the posterior mediastinum, there is no convincing evidence that semiprone thoracoscopic oesophagectomy is superior to the left lateral decubitus positioning with respect to the major surgical outcomes and oncological clearance. 23927920 Influence of on-farm production practices on sensory and technological quality characteristics of pork loin. Quality of pork from pigs raised either traditionally (outdoor access or bedded settings with no sub-therapeutic antibiotics or growth promotants in feed) or conventionally (commercial indoor) was evaluated. Pork loins (m. longissimus thoracis et lumborum, LTL) from four hundred pigs from either traditional or conventional production systems (n=200) fed commercially formulated diets ad libitum were harvested at slaughter. Intramuscular crude fat content and lean color (L* and b*) values were significantly decreased in conventional pork loins. LTL from conventionally-raised pig carcasses showed increased (P<0.05) mean pH, moisture content and reduced cooking loss and shear force values and had increased tenderness and juiciness scores compared to those from traditionally-raised pig carcasses. Results indicated that pork from conventionally raised pigs was superior to that from traditionally raised pigs in terms of tenderness and juiciness, suggesting that consumers may value pork from traditionally raised pigs on the basis of factors other than eating quality and appearance. 23736066 Imino phenoxide complexes of niobium and tantalum as catalysts for the polymerization of lactides, ε-caprolactone and ethylene. Imino phenoxide complexes of Nb and Ta show precise control towards the solvent free ring-opening polymerization of lactides (LA) and ε-caprolactone (CL). There is a close proximity between the observed number average molecular weight (M(n)) and theoretical molecular weight and the molecular weight distributions (MWDs) were found to be narrow. Analysis of low molecular weight oligomers of LA synthesized from these compounds revealed that the ligand is incorporated as one of the end terminal groups in the polymer chain. In addition, these complexes were realized to be precatalysts for the polymerization of ethylene. 23539642 Amphetamine, past and present - a pharmacological and clinical perspective. Amphetamine was discovered over 100 years ago. Since then, it has transformed from a drug that was freely available without prescription as a panacea for a broad range of disorders into a highly restricted Controlled Drug with therapeutic applications restricted to attention deficit hyperactivity disorder (ADHD) and narcolepsy. This review describes the relationship between chemical structure and pharmacology of amphetamine and its congeners. Amphetamine's diverse pharmacological actions translate not only into therapeutic efficacy, but also into the production of adverse events and liability for recreational abuse. Accordingly, the balance of benefit/risk is the key challenge for its clinical use. The review charts advances in pharmaceutical development from the introduction of once-daily formulations of amphetamine through to lisdexamfetamine, which is the first d-amphetamine prodrug approved for the management of ADHD in children, adolescents and adults. The unusual metabolic route for lisdexamfetamine to deliver d-amphetamine makes an important contribution to its pharmacology. How lisdexamfetamine's distinctive pharmacokinetic/pharmacodynamic profile translates into sustained efficacy as a treatment for ADHD and its reduced potential for recreational abuse is also discussed. 23346866 Synthesis of antioxidants for prevention of age-related macular degeneration. Photooxidation of A2E may be involved in diseases of the macula, and antioxidants could serve as therapeutic agents for these diseases. Inhibitors of A2E photooxidation were prepared by Mannich reaction of the antioxidant quercetin. These compounds contain water-solubilizing amine groups, and several were more potent inhibitors of A2E photooxidation than quercetin. 23839028 Abuse liability of novel 'legal high' designer stimulants: evidence from animal models. In the last few years, the variety and recreational use of 'legal high' designer stimulants has increased to unprecedented levels. Since their rapid emergence in drug markets, numerous adverse physical and psychological effects have been extensively reported. However, less is understood about the potential for compulsive use of and addiction to these drugs. Recently, a small collection of scientific studies assessing the abuse liability of these drugs has emerged. This new knowledge has been derived primarily from animal studies using behaviorally based procedures which include intravenous self-administration, conditioned place preference, intracranial self-stimulation, and drug discrimination. In this review we present a brief history of the recent rise in designer stimulant use followed by a short methodological description of the aforementioned procedures. We then review neurochemical and abuse liability studies on designer stimulants that have been examined to date. Finally, we conclude with a discussion of these collective findings, our current understanding of the abuse liability of these drugs in relation to each other and the illicit drugs they are designed to mimic, and recommend future research directions. 23906762 Colorful quality control of chromatographic sample preparation. Multidimensional chromatographic separation for proteomic biomarker search generates sets of several hundred homologous fractions, which have to be compared. Due to the high number of sequential steps, deviations between samples may be produced randomly by slight processing differences. These deviations may falsify proteomic results. In order to overcome this problem, we tested the applicability of quality control by colored phycobilins as internal standards. The elution of the used protein standards themselves shows a high reproducibility since their main peak location is practically constant under proper performance of size exclusion and anion exchange chromatography. This applies to runs of one phycobilin alone, combined with another phycobilin, or combined with plasma proteins. Thus, these protein standards do not disturb sample processing. Characteristic peak shifts of phycobilins allow easy observation of deviations caused by typical failures in the elution protocol (aberrant step number, buffer permutation). Mass spectrometric analysis is not influenced by their presence since protein coverage, peptide numbers, and protein numbers are not altered. Thus, colored protein standards may be used for quality control and evaluation of robustness of various chromatographic applications. 23203512 Outcomes of total knee replacement after patellofemoral arthroplasty. There is increasing interest in the use of patellofemoral joint replacements and the cohort receiving them are the youngest of any of the groups of patients undergoing a knee arthroplasty. With more contemporary prostheses, progression of arthritis in other parts of the knee joint is becoming the predominant mechanism of failure. We conducted a multicenter retrospective comparative cohort study to discover whether the outcome of total knee replacement is compromised by prior patellofemoral joint arthroplasty. A total of 21 patients with a mean age of 61 years, who were revised from a patellofemoral joint replacement to a total knee replacement, were compared with a matched cohort of patients who underwent primary total knee replacement. At a mean follow-up of 2.4 years, the primary total knee replacement cohort had significantly better Oxford Knee Scores, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function scores, pain visual analog scores, and EQ-5D scores. There was no significant difference in patient satisfaction or EQ-5D visual analog scale.Our results indicate that although the revision of a patellofemoral joint replacement to a total knee replacement is a technically straightforward procedure, the eventual outcome may be less satisfactory when compared with a primary total knee replacement. 23864784 Metabonomic studies of pancreatic cancer response to radiotherapy in a mouse xenograft model using magnetic resonance spectroscopy and principal components analysis. To investigate the metabolic profiles of xenograft pancreatic cancer before and after radiotherapy by high-resolution magic angle spinning proton magnetic resonance spectroscopy (HRMAS (1)H NMR) combined with principal components analysis (PCA) and evaluate the radiotherapeutic effect. The nude mouse xenograft model of human pancreatic cancer was established by injecting human pancreatic cancer cell SW1990 subcutaneously into the nude mice. When the tumors volume reached 800 mm(3), the mice received various radiation doses. Two weeks later, tumor tissue sections were prepared for running the NMR measurements. (1)H NMR and PCA were used to determine the changes in the metabolic profiles of tumor tissues after radiotherapy. Metabolic profiles of normal pancreas, pancreatic tumor tissues, and radiation- treated pancreatic tumor tissues were compared. Compared with (1)H NMR spectra of the normal nude mouse pancreas, the levels of choline, taurine, alanine, isoleucine, leucine, valine, lactate, and glutamic acid of the pancreatic cancer group were increased, whereas an opposite trend for phosphocholine, glycerophosphocholine, and betaine was observed. The ratio of phosphocholine to creatine, and glycerophosphocholine to creatine showed noticeable decrease in the pancreatic cancer group. After further evaluation of the tissue metabolic profile after treatment with three different radiation doses, no significant change in metabolites was observed in the (1)H NMR spectra, while the inhibition of tumor growth was in proportion to the radiation doses. However, PCA results showed that the levels of choline and betaine were decreased with the increased radiation dose, and conversely, the level of acetic acid was dramatically increased. The combined methods were demonstrated to have the potential for allowing early diagnosis and assessment of pancreatic cancer response to radiotherapy. 23619606 Exposure to DEHP decreased four fatty acid levels in plasma of prepartum mice. Maternal exposure to di(2-ethylhexyl) phthalate (DEHP) decreased the plasma triglyceride in prepartum mice. To identify the fatty acid (FA) species involved and to understand the underlying mechanisms, pregnant Sv/129 wild-type (mPPARα), peroxisome proliferator-activated receptor α-null (Pparα-null) and humanized PPARα (hPPARα) mice were treated with diets containing 0%, 0.01%, 0.05% or 0.1% DEHP. Dams were dissected on gestational day 18 together with fetuses, and on postnatal day 2 together with newborns. n-3/n-6 polyunsaturated, saturated, and monounsaturated FAs in maternal plasma and in liver of wild-type offspring, and representative enzymes for FA desaturation and elongation in maternal liver, were measured. The plasma levels of linoleic acid, α-linolenic acid, palmitic acid and oleic acid were higher in the pregnant control mPPARa mice than in Ppara-null and hPPARa mice. DEHP exposure significantly decreased the levels of these four FAs only in pregnant mPPARα mice. Plasma levels of many FAs were higher in pregnant mice than in postpartum ones in a genotype-independent manner, while it was lower in the livers of fetuses than pups. DEHP exposure slightly increased hepatic arachidonic acid, α-linolenic acid, palmitoleic acid and oleic acid in fetuses, but not in pups. However, DEHP exposure did not clearly influence FA desaturase 1 and 2 nor elongase 2 and 5 expressions in the liver of all maternal mice. Taken together, the levels of plasma four FAs with shorter carbon chains were higher in pregnant mPPARα mice than in other genotypes, and DEHP exposure decreased these specific FA concentrations only in mPPARα mice, similarly to triglyceride levels. 23803769 Biomimetic assembly and activation of [FeFe]-hydrogenases. Hydrogenases are the most active molecular catalysts for hydrogen production and uptake, and could therefore facilitate the development of new types of fuel cell. In [FeFe]-hydrogenases, catalysis takes place at a unique di-iron centre (the [2Fe] subsite), which contains a bridging dithiolate ligand, three CO ligands and two CN(-) ligands. Through a complex multienzymatic biosynthetic process, this [2Fe] subsite is first assembled on a maturation enzyme, HydF, and then delivered to the apo-hydrogenase for activation. Synthetic chemistry has been used to prepare remarkably similar mimics of that subsite, but it has failed to reproduce the natural enzymatic activities thus far. Here we show that three synthetic mimics (containing different bridging dithiolate ligands) can be loaded onto bacterial Thermotoga maritima HydF and then transferred to apo-HydA1, one of the hydrogenases of Chlamydomonas reinhardtii algae. Full activation of HydA1 was achieved only when using the HydF hybrid protein containing the mimic with an azadithiolate bridge, confirming the presence of this ligand in the active site of native [FeFe]-hydrogenases. This is an example of controlled metalloenzyme activation using the combination of a specific protein scaffold and active-site synthetic analogues. This simple methodology provides both new mechanistic and structural insight into hydrogenase maturation and a unique tool for producing recombinant wild-type and variant [FeFe]-hydrogenases, with no requirement for the complete maturation machinery. 23468320 Preventive dental care among New York City children, 2009. This study aims to describe the prevalence of preventive dental care among New York City (NYC) children, including disparities by race/ethnicity or poverty and to identify health care utilization factors associated with these outcomes. Data were obtained from the 2009 NYC Child Community Health Survey. Descriptive statistics were calculated for preventive dental visits in the past 12 months among children aged 2-12 years (n = 2,435) and receipt of sealants among children aged 6-12 years (n = 1,416). Multivariable logistic regression was used to compute adjusted prevalence ratios (aPRs). One in four (23.3 %) NYC children aged 2-12 years, including 57.3 % of 2-3-year olds, had no preventive dental visit in the past 12 months. Lack of preventive visits was more prevalent among Asian/Pacific Islander children compared with non-Hispanic white children (aPR 1.42 [95 % CI 1.07-1.89]), and among children living in poorer households compared with wealthier households (aPR 1.47 [95 % CI 1.13-1.92]). Two-thirds (64.5 %) of children aged 6-12 years never had sealants. Compared with non-Hispanic white children, Asian/Pacific Islander (aPR 1.26 [95 % CI 1.01-1.56]), non-Hispanic black (aPR 1.24 [95 % CI 1.06-1.46]), and Hispanic (aPR 1.21 [95 % CI 1.04-1.41]) children were more likely not to have sealants, as were children without a personal health care provider compared with children with a provider (aPR 1.33 [95 % CI 1.14-1.56]). Disparities in preventive dental care exist by race/ethnicity, poverty, and health care utilization. Personal health care providers may improve children's oral health by linking them to preventive dental care and promoting sealant application. 23898064 Polycyclic Aromatic Hydrocarbon-induced Oxidative Stress, Antioxidant Capacity, and the Risk of Lung Cancer: A Pilot Nested Case-control Study. Aim: We conducted a pilot nested case-control study to prospectively evaluate the effects of polycyclic aromatic hydrocarbons (PAH) exposure, antioxidant capacity, and oxidative stress on lung carcinogenesis. Thirty-five patients with lung cancer and 140 age- and sex-matched controls were selected from a sub-cohort of the Korean Multi-center Cancer Cohort. PAH metabolites (1-hydroxypyrene and 2-naphthol), oxidative stress markers, and total antioxidant capacity (TAC) were assessed using urine samples collected at baseline. The levels of urinary PAH metabolites and oxidative stress were not different between cases and controls. Urinary 1-hydroxypyrene and 2-naphthol levels were significantly associated with urinary oxidative stress markers only in lung cancer cases. Individuals with low urinary TAC and high urinary oxidative stress levels had significantly higher risk of lung cancer compared to those with high urinary TAC and low urinary oxidative stress levels. Oxidative stress induced by PAH exposure and TAC may be important determinants for the susceptibility to lung cancer. 23811745 Invasive Pneumococcal Disease among Children with and without Sickle Cell Disease in the United States, 1998-2009. Children with sickle cell disease (SCD) are at increased risk of illness and death from invasive pneumococcal disease (IPD). The introduction in 2000 of the 7-valent pneumococcal conjugate vaccine (PCV7) and penicillin prophylaxis for children with SCD has greatly reduced the incidence of IPD in this population. However, a recent report suggested an increase in cases of IPD in children with SCD. Using data from Active Bacterial Core Surveillance (ABCs), we analyzed trends in hospitalizations, mortality, and serotype among children with SCD compared with other children. We used neonatal screening data to estimate SCD population denominators for each ABCs site. From 1998-2009, 3,069 cases of IPD occurred among African-American children less than 18 years of age in the ABCs catchment area. Of these, 127 (4.1%) had SCD identified by medical chart review and 185 (6.0%) had one or more IPD risk factors, excluding SCD. Rates of IPD among children with SCD declined by 53% (1,118 versus 530 per 100,000) while the overall rates among African-American children declined by 74% (54 to 14 per 100,000). For all time periods, children with SCD and IPD were more likely to be hospitalized (84%-92% versus 31%-56%) and more likely to die (6%-17% versus 1%-2%) than children with no risk factors. While the rate of IPD in children with SCD has dropped dramatically since PCV7 introduction, the rate of IPD in children with SCD remains higher than that of the general population of African-American children, pointing to the need for more effective prevention efforts to prevent IPD in children with SCD. 23901921 The complete mitochondrial genome of the Java fat-nose goby Pseudogobius javanicus (Teleostei, Gobiidae). Abstract In this study, the complete mitochondrial genome of the fat-nose goby Pseudogobius javanicus has been amplified. P. javanicus is widely contributed species in Southeast to East Asia. The complete mitochondrial genome is 16,493 base pairs (bp) in total length, had the typical vertebrate mitochondrial gene arrangement, including 13 protein-coding genes, 2 rRNAs, 22 tRNAs, 1 control region (CR) and 1 light-strand replication origin (OL). The overall base composition of P. javanicus is 27.1% for A, 27.3% for T, 28.6% for C, 17.0% for G, with higher AT content of 54.4%. This study will contribute for understanding the phylogenetic approach in genus Pseudogobius. 23970382 microRNA-18b is upregulated in breast cancer and modulates genes involved in cell migration. microRNAs are small non-coding RNAs of ~22 nucleotides that function at post-transcriptional level as negative regulators of gene expression. Aberrant expression of microRNAs could promote uncontrolled proliferation, migration and invasion of human cancer cells. In this study, we analyzed the expression of microRNA-18b (miR-18b) in breast cancer cell lines and in a set of clinical specimens. Our results showed that miR-18b was upregulated in four out of five breast cancer cell lines and also in breast tumors. In order to identify potential gene targets, we carried out transcriptional profiling of MDA-MB-231 breast cancer cells that ectopically expressed miR-18b. Our results showed that 263 genes were significantly modulated in miR-18b-deficient cells (fold change >1.5; P≤0.05). We found that knock-down of miR-18b induced the upregulation of 55 olfactory receptor (OR) genes and nine genes (NLRP7, KLK3, OLFM3, POSTN, MAGED4B, KIR3DL3, CRX, SEMG1 and CEACAM5) with key roles in cell migration and metastasis. Consistently, we found that ectopic inhibition of miR-18b suppressed the migration of two breast cancer cell models in vitro. In conclusion, we have uncovered genes directly or indirectly modulated by miR-18b which may represent potential therapeutic targets in breast cancer. Our data also pointed out a role of miR-18b in migration of breast cancer cells. 23791456 Extreme attributions predict transition from depression to mania or hypomania in bipolar disorder. Relatively little is known about psychological predictors of the onset of mania among individuals with bipolar disorder, particularly during episodes of depression. In the present study we investigated attributional style as a predictor of onset of hypomanic, manic or mixed episodes among bipolar adults receiving psychosocial treatment for depression. We hypothesized that "extreme" (i.e., excessively pessimistic or optimistic) attributions would predict a greater likelihood of developing an episode of mood elevation. Outpatients with DSM-IV bipolar I or II disorder (N = 105) enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were randomly allocated to one of three types of intensive psychotherapy for depression or a brief psychoeducational intervention. Patients completed a measure of attributional style at baseline and were followed prospectively for up to one year. All analyses were by intent to treat. Logistic regressions and Cox proportional hazards models indicated that extreme (both positively- and negatively-valenced) attributions predicted a higher likelihood of (and shorter time until) transition from depression to a (hypo)manic or mixed episode (ps < .04), independent of the effects of manic or depressive symptom severity at baseline. Extreme attributions were also retrospectively associated with more lifetime episodes of (hypo)mania and depression (ps < .05). Evaluating extreme attributions may help clinicians to identify patients who are at risk for experiencing a more severe course of bipolar illness, and who may benefit from treatments that introduce greater cognitive flexibility. 23535827 Force nanoscopy of cell mechanics and cell adhesion. Cells are constantly exposed to mechanical stimuli in their environment and have several evolved mechanisms to sense and respond to these cues. It is becoming increasingly recognized that many cell types, from bacteria to mammalian cells, possess a diverse set of proteins to translate mechanical cues into biochemical signalling and to mediate cell surface interactions such as cell adhesion. Moreover, the mechanical properties of cells are involved in regulating cell function as well as serving as indicators of disease states. Importantly, the recent development of biophysical tools and nanoscale methods has facilitated a deeper understanding of the role that physical forces play in modulating cell mechanics and cell adhesion. Here, we discuss how atomic force microscopy (AFM) has recently been used to investigate cell mechanics and cell adhesion at the single-cell and single-molecule levels. This knowledge is critical to our understanding of the molecular mechanisms that govern mechanosensing, mechanotransduction, and mechanoresponse in living cells. While pushing living cells with the AFM tip provides a means to quantify their mechanical properties and examine their response to nanoscale forces, pulling single surface proteins with a functionalized tip allows one to understand their role in sensing and adhesion. The combination of these nanoscale techniques with modern molecular biology approaches, genetic engineering and optical microscopies provides a powerful platform for understanding the sophisticated functions of the cell surface machinery, and its role in the onset and progression of complex diseases. 23583803 Melanoidins isolated from heated potato fiber (Potex) affect human colon cancer cells growth via modulation of cell cycle and proliferation regulatory proteins. Melanoidins are brown, nitrogen containing, high molecular weight end products of Maillard reaction with poorly established activity towards tumor cells. The goal of present study was to verify whether both heated potato fiber Potex extract (180°C for 2h) and melanoidins isolated from the extract exerts growth-inhibiting activity in human colon cancer cells in vitro. The cells of LS180 colon cancer cell line were tested upon treatment with roasted potato fiber extract (AM4) as well as with high (HMW) and low (LMW) molecular weight fractions isolated from the extract, since both may be regarded as/or contain melanoidins. The tested compounds at concentration of 1000μg/ml reduced cell growth down to 45%, 69% and 54%, respectively. Furthermore, deregulated ERK1/2 signaling was revealed upon treatment. Moreover, multiple alternations in cell cycle regulators activity were found (i.e. cyclinD1, cyclin-dependent kinase 4 and 6, p21, p27, p53, pRb) leading to cell cycle cessation in G0 phase. Importantly, LMW compounds revealed markedly stronger potential to alter specific molecular targets comparing to HMW compounds. Summarizing, the results emphasize that both high and low molecular weight melanoidins contribute to antiproliferative activity of heated potato fiber in LS180 colon cancer cells in vitro. 23938394 Stem cell function and maintenance - ends that matter: Role of telomeres and telomerase. Stem cell research holds a promise to treat and prevent age-related degenerative changes in humans. Literature is replete with studies showing that stem cell function declines with aging, especially in highly proliferative tissues/ organs. Among others, telomerase and telomere damage is one of the intrinsic physical instigators that drive agerelated degenerative changes. In this review we provide brief overview of telomerase-deficient aging affects in diverse stem cells populations. Furthermore, potential disease phenotypes associated with telomerase dysregulation in a specific stem cell population is also discussed in this review. Additionally, the role of telomerase in stem cell driven cancer is also briefly touched upon. 23887562 A dynamic mass casualty incident at sea: Lessons learned from the Mavi Marmara. Mass casualty incidents (MCIs) represent one of the most difficult prehospital challenges faced by medical personnel. When they occur at sea, this challenge may be further complicated by isolation, distance, vessel structure, number of passengers, and limited evacuation means. We describe our experience and lessons learned from a dynamic MCI in an austere environment at sea. Following an armed attack on navy operators boarding the MV Mavi Marmara, a vessel heading for Gaza, the Israel Defense Forces' medical teams triaged and cared for 62 casualties, among them 9 soldiers; 9 additional casualties were declared dead at the scene. The injured, including 10 triaged as severely wounded, were all evacuated to Israeli hospitals within several hours of the start of the event. Despite the austere conditions and the severity of injuries, all of the injured passengers were able to return to their home countries, and all soldiers returned to duty. Multiple issues were identified as requiring changes or heightened awareness so as to be better prepared for future events of this special nature. The primary lessons learned related to difficulties in functioning without effective communication, maintaining command and control, coordinating serial evacuation of casualties who were being triaged in parallel, planning for an event with lengthy evacuation times, resolving real-time ethical dilemmas, and preparing our providers mentally. As MCIs tend to be unexpected, preplanning, using preestablished manuals, and drilling for them may prove crucial in such extreme events. Importantly, the lessons learned from this event, with its unique synthesis of multiple contributing factors, remain relevant even in less austere settings. Care management, level V. 23559029 Effect of Positive End-expiratory Pressure on Regional Ventilation Distribution during Mechanical Ventilation after Surfactant Depletion. Ventilator-induced lung injury occurs due to exaggerated local stresses, repeated collapse, and opening of terminal air spaces in poorly aerated dependent lung, and increased stretch in nondependent lung. The aim of this study was to quantify the functional behavior of peripheral lung units in whole-lung lavage-induced surfactant depletion, and to assess the effect of positive end-expiratory pressure. The authors used synchrotron imaging to measure lung aeration and regional specific ventilation at positive end-expiratory pressure of 3 and 9 cm H2O, before and after whole-lung lavage in rabbits. Respiratory mechanical parameters were measured, and helium-washout was used to assess end-expiratory lung volume. Atelectatic, poorly, normally aerated, hyperinflated, and trapped regions could be identified using the imaging technique used in this study. Surfactant depletion significantly increased atelectasis (6.3 ± 3.3 [mean ± SEM]% total lung area; P = 0.04 vs. control) and poor aeration in dependent lung. Regional ventilation was distributed to poorly aerated regions with high (16.4 ± 4.4%; P < 0.001), normal (20.7 ± 5.9%; P < 0.001 vs. control), and low (5.7 ± 1.2%; P < 0.05 vs. control) specific ventilation. Significant redistribution of ventilation to normally aerated nondependent lung regions occurred (41.0 ± 9.6%; P = 0.03 vs. control). Increasing positive end-expiratory pressure level to 9 cm H2O significantly reduced poor aeration and recruited atelectasis, but ventilation redistribution persisted (39.2 ± 9.5%; P < 0.001 vs. control). Ventilation of poorly aerated dependent lung regions, which can promote the local concentration of mechanical stresses, was the predominant functional behavior in surfactant-depleted lung. Potential tidal recruitment of atelectatic lung regions involved a smaller fraction of the imaged lung. Significant ventilation redistribution to aerated lung regions places these at risk of increased stretch injury. 23625542 Imagination as expansion of experience. This paper proposes a developmental view on imagination: from this perspective, imagination can be seen as triggered by some disrupting event, which generates a disjunction from the person's unfolding experience of the "real" world, and as unfolding as a loop, which eventually comes back to the actual experience. Examining recent and classical theorization of imagination in psychology, the paper opposes a deficitary view of imagination to an expansive notion of imagination. The paper explores Piaget, Vygotsky, Harris and Pelaprat & Cole consider: 1) What does provoke a "rupture" or disjunction? 2) What are the psychological processes involved in the imaginary loop? 3) What nourishes such processes? 4) What are the consequences of such imaginary loop, or what does it enable doing? The paper proposes to adopt an expansive view of imagination, as Vygotsky proposed-a perspective that has been under-explored empirically since his seminal work. To stimulate such sociocultural psychology of imagination, two empirical examples are provided, one showing how children make sense of metaphor in an experimental setting, the other showing a young person using a novel met at school as symbolic resource. 23818523 Pigment Epithelium-derived Factor (PEDF) Prevents Retinal Cell Death via PEDF Receptor (PEDF-R): IDENTIFICATION OF A FUNCTIONAL LIGAND BINDING SITE. The extracellular pigment epithelium-derived factor (PEDF) displays retina survival activity by interacting with receptor proteins on cell surfaces. We have previously reported that PEDF binds and stimulates PEDF receptor (PEDF-R), a transmembrane phospholipase. However, the PEDF binding site of PEDF-R and its involvement in survival activity have not been identified. The purpose of this work is to identify a biologically relevant ligand-binding site on PEDF-R. PEDF bound the PEDF-R ectodomain L4 (Leu(159)-Met(325)) with affinity similar to the full-length PEDF-R (Met(1)-Leu(504)). Binding assays using synthetic peptides spanning L4 showed that PEDF selectively bound E5b (Ile(193)-Leu(232)) and P1 (Thr(210)-Leu(249)) peptides. Recombinant C-terminal truncated PEDF-R4 (Met(1)-Leu(232)) and internally truncated PEDF-R and PEDF-R4 (ΔHis(203)-Leu(232)) retained phospholipase activity of the full-length PEDF-R. However, PEDF-R polypeptides without the His(203)-Leu(232) region lost the PEDF affinity that stimulated their enzymatic activity. Cell surface labeling showed that PEDF-R is present in the plasma membranes of retina cells. Using siRNA to selectively knock down PEDF-R in retina cells, we demonstrated that PEDF-R is essential for PEDF-mediated cell survival and antiapoptotic activities. Furthermore, preincubation of PEDF with P1 and E5b peptides blocked the PEDF·PEDF-R-mediated retina cell survival activity, implying that peptide binding to PEDF excluded ligand-receptor interactions on the cell surface. Our findings establish that PEDF-R is required for the survival and antiapoptotic effects of PEDF on retina cells and has determinants for PEDF binding within its L4 ectodomain that are critical for enzymatic stimulation. 23817387 Nanomaterial modified electrodes: evaluating oxygen reduction catalysts. Intense current research is directed at the evaluation of nanomaterials as catalysts for the oxygen reduction reaction. This is commonly undertaken by means of voltammetric measurements supported on an electrode surface presumed inert other than for providing electrical contact. At their basis these factors usually involve measurement of a current or current density, measured at a fixed potential. However we now report that the current/current density at a fixed potential can vary with the surface coverage of the nanoparticles in the catalyst, without any change in fundamental kinetic or thermodynamic parameters, even though the voltammetric signal shows that the reduction is fully transport controlled. This finding leads us to the conclusion that caution should be expressed when comparing catalysts in this way. In particular the essential need is emphasised for characterising the coverage, porosity and particle size, when inferring inherent electrochemical activity and using a suitable physical model to extract catalytic parameters. 23273764 Long-term results of endolymphatic sac drainage with local steroids for intractable Meniere's disease. Meniere's disease is a common inner ear disease characterized by vertigo, hearing loss and tinnitus. Since Meniere's disease is thought to be triggered by an immune insult to inner ear hydrops, we examined endolymphatic sac drainage with intra-endolymphatic sac application of large doses of steroids for intractable Meniere's patients and observed long-term results from 2 years to over a decade until 13 years. Between 1998 and 2009, we enrolled and assigned 286 intractable Meniere's patients to two groups: group-I (G-I) included patients who underwent endolymphatic sac drainage with steroid instillation and group-II (G-II) included those who declined endolymphatic sac drainage. Definitive spells and hearing improvement in these two groups were determined for 2-13 years after treatment. According to the established criteria, vertigo was completely controlled in 88% of patients in G-I in the 2nd year, in 73% in the 12th year and in 70% in the 13th year. These results in G-I were significantly better than those in G-II for 13 years after treatment. Hearing was improved in 49% of patients in G-I in the 2nd year, in 27% in the 12th year and in 25% in the 13th year. These results in G-I were significantly better than those in G-II for 12 years after treatment, but this was not significant in the 13th year. Endolymphatic sac drainage with intra-endolymphatic sac application of large doses of steroids could improve long-term follow-up results of hearing as well as vertigo control. This means that the drainage with local steroids could also improve patients' long-term quality in the prime of life. 23347261 Distinguishing ecological from evolutionary approaches to transposable elements. Considerable variation exists not only in the kinds of transposable elements (TEs) occurring within the genomes of different species, but also in their abundance and distribution. Noting a similarity to the assortment of organisms among ecosystems, some researchers have called for an ecological approach to the study of transposon dynamics. However, there are several ways to adopt such an approach, and it is sometimes unclear what an ecological perspective will add to the existing co-evolutionary framework for explaining transposon-host interactions. This review aims to clarify the conceptual foundations of transposon ecology in order to evaluate its explanatory prospects. We begin by identifying three unanswered questions regarding the abundance and distribution of TEs that potentially call for an ecological explanation. We then offer an operational distinction between evolutionary and ecological approaches to these questions. By determining the amount of variance in transposon abundance and distribution that is explained by ecological and evolutionary factors, respectively, it is possible empirically to assess the prospects for each of these explanatory frameworks. To illustrate how this methodology applies to a concrete example, we analyzed whole-genome data for one set of distantly related mammals and another more closely related group of arthropods. Our expectation was that ecological factors are most informative for explaining differences among individual TE lineages, rather than TE families, and for explaining their distribution among closely related as opposed to distantly related host genomes. We found that, in these data sets, ecological factors do in fact explain most of the variation in TE abundance and distribution among TE lineages across less distantly related host organisms. Evolutionary factors were not significant at these levels. However, the explanatory roles of evolution and ecology become inverted at the level of TE families or among more distantly related genomes. Not only does this example demonstrate the utility of our distinction between ecological and evolutionary perspectives, it further suggests an appropriate explanatory domain for the burgeoning discipline of transposon ecology. The fact that ecological processes appear to be impacting TE lineages over relatively short time scales further raises the possibility that transposons might serve as useful model systems for testing more general hypotheses in ecology. 23916044 Efficacy and tolerability exposure-response relationship of retigabine (ezogabine) immediate-release tablets in patients with partial-onset seizures. Retigabine (international nonproprietary name)/ezogabine (United States adopted name) is an antiepileptic drug (AED) that enhances KCNQ (Kv7) potassium channel activity. The aim of this study was to explore the relationship between retigabine/ezogabine systemic exposure and efficacy and adverse events (AEs) of retigabine/ezogabine from Phase III clinical trials. Data were combined from Studies 301 and 302, which were both randomized, double-blind, placebo-controlled, multicenter, parallel-group studies with similar inclusion and exclusion criteria. All patients had partial-onset seizures and were receiving 1 to 3 concomitant AEDs. Systemic exposure was predicted for each patient as the average steady-state AUC0-τ during the 12-week maintenance phase, based on a population pharmacokinetic model developed for retigabine/ezogabine. Efficacy end points included reduction in total partial-seizure frequency from baseline and probability of ≥50% reduction from baseline in seizure frequency. The probabilities of occurrence of 6 AEs were also evaluated. AUC0-τ values increased linearly over the 600- to 1200-mg/d dose range. Over the entire AUC0-τ range, the probability of efficacy was greater than that for any AE. The slopes of the exposure-response relationship for probability of dizziness and abnormal coordination were similar to that for efficacy, whereas the slopes for dysarthria, somnolence, tremor, and blurred vision were shallower, indicating that the probability of these events occurring was less affected than the probability of efficacy by increases in retigabine/ezogabine AUC0-τ. Based on the summary statistics of pharmacokinetic parameters, systemic exposure to retigabine/ezogabine increased linearly with dose (600-1200 mg/d). Population pharmacokinetics and pharmacodynamics showed that the probability of efficacy and AEs increased with increasing systemic retigabine/ezogabine exposure, and the probability of efficacy was higher than the probability of any of the AEs. The 35%-50% between-patient variability and overlap between retigabine/ezogabine dose levels in AUC0-τ values indicate that, as with other AEDs, doses should be individually titrated based on a balance between efficacy and tolerability. 23903825 Ultralow-power and ultrafast all-optical tunable plasmon-induced transparency in metamaterials at optical communication range. Actively all-optical tunable plasmon-induced transparency in metamaterials paves the way for achieving ultrahigh-speed quantum information processing chips. Unfortunately, up to now, very small experimental progress has been made for all-optical tunable plasmon-induced transparency in metamaterials in the visible and near-infrared range because of small third-order optical nonlinearity of conventional materials. The achieved operating pump intensity was as high as several GW/cm(2) order. Here, we report an ultralow-power and ultrafast all-optical tunable plasmon-induced transparency in metamaterials coated on polycrystalline indium-tin oxide layer at the optical communication range. Compared with previous reports, the threshold pump intensity is reduced by four orders of magnitude, while an ultrafast response time of picoseconds order is maintained. This work not only offers a way to constructing photonic materials with large nonlinearity and ultrafast response, but also opens up the possibility for realizing quantum solid chips and ultrafast integrated photonic devices based on metamaterials. 23263221 Impact of collagen crosslinking on corneal sensitivity in keratoconus patients. To evaluate changes in corneal sensitivity after corneal collagen crosslinking in patients having progressive keratoconus. Thirty-six consecutive patients having progressive keratoconus were included in the study. The crosslinking surgery was performed in one eye of each patient (study group) and the opposite eye was used as control (control group). The following steps were done in the procedure: central cornea epithelial debridement, riboflavin solution dropping (1 drop every 5 minutes) for 30 minutes, and subsequently, corneal surface irradiation with Ultraviolet A for 30 minutes, keeping the riboflavin instillation while irradiating. The analysis of corneal tactile sensitivity in each patient was performed using the Cochet-Bonnet aesthesiometer at 5 time points: preoperative and 7, 30, 90, and 180 days after surgery. The study enrolled 72 eyes of 36 patients. Considering the eyes submitted to crosslinking, there was a significant statistical difference concerning the tactile corneal sensitivity at all 5 evaluated moments. The median sensitivity at each time point studied was: preoperative, 52.5 mm (range, 25-60 mm); 7 days, 20.0 mm (range, 5-60 mm); 30 days, 32.5 mm (range, 5-60 mm); 90 days, 40.0 mm (range, 10-60 mm) and 180 days, 45.0 mm (range, 25-60 mm) (P < 0.001). The control group showed no statistical difference among all 5 time points (P = 0.160). Corneal crosslinking performed in keratoconus patients induced a considerable decrease in corneal sensitivity. This decrease was more intense at the first week after the procedure, with a progressive recovery up to 6 months. 23892592 Association of Genetic Variants in CDK6 and XRCC1 with The Risk of Dysplastic Nevi in Melanoma-Prone Families. Dysplastic nevi (DN) is a strong risk factor for cutaneous malignant melanoma (CMM), and it frequently occurs in melanoma-prone families. To identify genetic variants for DN, we genotyped 677 tagSNPs in 38 melanoma candidate genes that are involved in pigmentation, DNA repair, cell cycle control, and melanocyte proliferation pathways in a total of 504 individuals (310 with DN, 194 without DN) from 53 melanoma-prone families (23 CDKN2A mutation positive and 30 negative). Conditional logistic regression, conditioning on families, was used to estimate the association between DN and each SNP separately, adjusted for age, sex, CMM and CDKN2A status. P-values for SNPs in the same gene were combined to yield gene-specific p-values. Two genes, CDK6 and XRCC1, were significantly associated with DN after Bonferroni correction for multiple testing (P=0.0001 and 0.00025, respectively), whereas neither gene was significantly associated with CMM. Associations for CDK6 SNPs were stronger in CDKN2A mutation positive families (rs2079147, Pinteraction=0.0033), whereas XRCC1 SNPs had similar effects in mutation-positive and negative families. The association for one of the associated SNPs in XRCC1 (rs25487) was replicated in two independent datasets (random effect meta-analysis: P<0.0001). Our findings suggest that some genetic variants may contribute to DN risk independently of their association with CMM in melanoma-prone families.Journal of Investigative Dermatology accepted article preview online, 26 July 2013. doi:10.1038/jid.2013.316. 23719194 Efficient secretion of (R)-3-hydroxybutyric acid from Halomonas sp. KM-1 cultured with saccharified Japanese cedar under microaerobic conditions. In the presence of d-glucose, consumption of pentoses such as d-xylose is somewhat repressed by most bacteria. However, in Halomonas sp. KM-1, simultaneous utilization of a pure hexose and pentose for growth and PHB production has been observed. Moreover, this strain has been shown to preferentially utilize d-xylose from a mixture of hexose and pentose. In addition, the KM-1 strain produced (R)-3-hydroxybutyric acid ((R)-3-HB) by using saccharified Japanese cedar (Cryptomeria japonica) wood. The concentration of intracellular PHB after aerobic cultivation for 24h was 8.4 g/L, and after shifting to microaerobic conditions and further cultivation for 18 h, the concentration of (R)-3-HB in the medium reached 8.0 g/L. These results show that the KM-1 strain can efficiently utilize saccharified Japanese cedar and secreted (R)-3-HB under microaerobic conditions. 23759932 Clonally related follicular lymphomas and Langerhans cell neoplasms: expanding the spectrum of transdifferentiation. The traditional model of hematopoiesis is based on unidirectional maturation of hematopoietic precursors into lineage-committed cells. However, recent studies indicate that mature B lymphocytes may demonstrate significant lineage plasticity. We and others have reported transdifferentiation of follicular lymphomas (FLs) into clonally related histiocytic/dendritic cell neoplasms. Here, we describe 2 patients with FL who developed clonally related Langerhans cell neoplasms. The first was a 52-year-old man diagnosed with FL, grade 1. He received immunochemotherapy and had stable disease for 8 years. He then developed increasing lymphadenopathy, and lymph node biopsy showed Langerhans cell sarcoma with no evidence of FL. The second patient was a 77-year-old woman who presented with lymphadenopathy, an abdominal mass, and pulmonary nodules. Lymph node biopsy showed both Langerhans cell histiocytosis and minimal involvement by FL, grade 1. In each case, a combination of immunoglobulin gene rearrangement and fluorescence in situ hybridization studies provided evidence to support a clonal relationship between the FL and Langerhans cell neoplasm. These cases provide striking examples of neoplastic transdifferentiation and expand the spectrum of lesions clonally identical to otherwise typical FL. Awareness of this phenomenon may aid in diagnosis when histologically dissimilar tumors arise synchronously or metachronously in patients with lymphoma. 22951230 Isolation and characterization of a novel antibacterial peptide derived from hemoglobin alpha in the liver of Japanese eel, Anguilla japonica. We isolated and characterized a novel antibacterial peptide, AJHbα, derived from hemoglobin alpha in the liver of Japanese eel, Anguilla japonica. It with concentration of 11.30 Î¼M exhibited stronger antibacterial activity against pathogenic bacterium 1 Ã— 10(6) cell ml(-1)Edwardsiella tarda than other two bacteria. The extraction procedure for AJHbα included extraction with acetate acid, ultrafiltration, cation-exchange chromatography on HiTrapâ„¢ CM FF, reverse-phase liquid chromatography on Source 5R RPC and C18 RP-HPLC. MALDI-TOF MS suggested that the peptide had an observed molecular weight of 2388.05 Da. Its amino acid sequence determined by Edman degradation was similar to those of hemoglobin alpha chain in other fish by BLAST analysis. A complete N-terminal amino acid sequence of the AJHbα was FAHWPDLGPGSPSVKKHGKVIM corresponding to the cDNA sequence by RACE amplification. Its synthetic peptide had strong antibacterial activities against ten Gram-positive or negative bacteria. To our knowledge, AJHbα was the first identified fragment of hemoglobin alpha chain with strong antibacterial activity in fish. 23837609 Expanding the Structural Diversity of Polyketides by Exploring the Cofactor Tolerance of an Inline Methyltransferase Domain. A strategy for introducing structural diversity into polyketides by exploiting the promiscuity of an in-line methyltransferase domain in a multidomain polyketide synthase is reported. In vitro investigations using the highly-reducing fungal polyketide synthase CazF revealed that its methyltransferase domain accepts the nonnatural cofactor propargylic Se-adenosyl-l-methionine and can transfer the propargyl moiety onto its growing polyketide chain. This propargylated polyketide product can then be further chain-extended and cyclized to form propargyl-α pyrone or be processed fully into the alkyne-containing 4'-propargyl-chaetoviridin A. 23305894 Effects of OLRs and HRTs on hydrogen production from high salinity substrate by halophilic hydrogen producing bacterium (HHPB). The effects of hydraulic retention time (HRT) and organic loading rate (OLR) on hydrogen production were investigated with glucose medium containing 2% NaCl. Halophilic hydrogen producing bacterium (HHPB) Clostridium bifermentans 3AT-ma, which can survive under high salt conditions, was used. Sponge media were used as 20% of working volume. The OLR and HRT were varied in 10-60 g-glucose/L-reactor/day and 24-6h. With OLR of 20 g-glucose/L/day, shorter HRT resulted in higher hydrogen producing rate and yield. When the OLR was increased from 20 to 60 g-glucose/L-reactor/day at HRT 6h, the hydrogen production rate increased, while the hydrogen production yield decreased due to the increase and accumulation of volatile fatty acids. Biohydrogen production was possible from the salinity substrate using HHPB, and the maximum hydrogen production yield was 1.1 mol-H₂/mol-glucose with optimal conditions of OLR of 20 g-glucose/L/day and HRT of 12h. 23552828 Rapid self-healable poly(ethylene glycol) hydrogels formed by selective metal-phosphate interactions. Rapid self-healable and biocompatible hydrogels were prepared using the selective formation of metal-ligand interactions between selected metal ions and phosphate end groups of poly(ethylene glycol) (PEG). The phosphate-terminated branch of PEG was synthesized via a substitution reaction of the hydroxyl end groups using phosphoryl chloride. The gelation and gel properties including rheological properties can be tuned by the careful selection of metal ions, branch numbers, and temperature. Especially, the gels rapidly formed by trivalent metal ions such as Fe(3+), V(3+), Al(3+), Ti(3+), and Ga(3+) have relatively small ionic radii. The ligand substitution rates also affected the repeatable autonomic healing ability. We have also demonstrated a gel-sol/sol-gel transition by switching the redox states of Fe(3+)/Fe(2+) ions. Learning from biological systems, the proposed phosphate-metal ion based self-healable hydrogels could become an attractive candidate for various biomedical and environmental applications. 23276752 Generating thermal stable variants of protein domains through phage display. Often in protein design research, one desires to generate thermally stable variants of a protein or domain. One route to identifying mutations that yield domains that remain folded and active at a higher temperature is through the use of directed evolution. A library of protein domain variants can be generated by mutagenic PCR, expressed on the surface of bacteriophage M13, and subjected to heat, such that the unfolded forms of the domain, showing reduced or no binding activity, are lost during subsequent affinity selection, whereas variants that still retain binding to their target are selected and enriched with each subsequent round of affinity selection. This approach takes advantage of the fact that bacteriophage M13 particles are heat stable and resistant to many proteases and protein denaturants. We present the application of this general approach to generating thermally stable variants of a eukaryotic peptide-binding domain. The benefits of producing such variants are that they typically express at high levels in Escherichia coli (30-60mg/L shake flask) and remain soluble in solution at higher concentrations for longer periods of time than the wild-type form of the domain. The process of library generation and screening generally requires about one month of effort, and yields variants with >10°C increase in thermal stability, as measured in a simple fluorescence-based thermal shift assay. It is anticipated that thermally stable variants will serve as excellent scaffolds for generating affinity reagents to a variety of targets of interest. 23678026 Anti-inflammatory salicylate treatment alters the metabolic adaptations to lactation in dairy cattle. Adapting to the lactating state requires metabolic adjustments in multiple tissues, especially in the dairy cow, which must meet glucose demands that can exceed 5 kg/day in the face of negligible gastrointestinal glucose absorption. These challenges are met through the process of homeorhesis, the alteration of metabolic setpoints to adapt to a shift in physiological state. To investigate the role of inflammation-associated pathways in these homeorhetic adaptations, we treated cows with the nonsteroidal anti-inflammatory drug sodium salicylate (SS) for the first 7 days of lactation. Administration of SS decreased liver TNF-α mRNA and marginally decreased plasma TNF-α concentration, but plasma eicosanoids and liver NF-κB activity were unaltered during treatment. Despite the mild impact on these inflammatory markers, SS clearly altered metabolic function. Plasma glucose concentration was decreased by SS, but this was not explained by a shift in hepatic gluconeogenic gene expression or by altered milk lactose secretion. Insulin concentrations decreased in SS-treated cows on day 7 compared with controls, which was consistent with the decline in plasma glucose concentration. The revised quantitative insulin sensitivity check index (RQUICKI) was then used to assess whether altered insulin sensitivity may have influenced glucose utilization rate with SS. The RQUICKI estimate of insulin sensitivity was significantly elevated by SS on day 7, coincident with the decline in plasma glucose concentration. Salicylate prevented postpartum insulin resistance, likely causing excessive glucose utilization in peripheral tissues and hypoglycemia. These results represent the first evidence that inflammation-associated pathways are involved in homeorhetic adaptations to lactation. 23916248 Frequency domains of resting state default mode network activity in schizophrenia. Probabilistic independent component analysis was applied to identify the default mode network (DMN) in resting state data obtained with functional magnetic resonance imaging from 25 DSM-IV schizophrenia and 25 matched healthy subjects. Power spectrum analysis showed a significant diagnosis×frequency interaction and higher power in one frequency band, indicating an alteration of DMN frequency spectrum in schizophrenia. 23666472 Palliative sedation in end-of-life care. The aim of this review was to present and comment on recent data published on palliative sedation in palliative and end-of-life care. Palliative sedation is a medical procedure used to deal with the refractory symptoms occurring in the advanced stages of cancer. It has clinical, nursing, relational and ethical implications, making it a highly sensitive issue. Over the last 12 months, a number of authors have published interesting new findings on different areas of palliative sedation, that is prevalence, indications, monitoring, duration and choice of drugs. In particular, a clear definition of palliative sedation and of its more pronounced form, deep continuous sedation (DCS), has emerged. It has been confirmed that, when performed in the correct way and with the right aims, palliative sedation does not have a detrimental impact on survival. Recent findings confirm that palliative sedation is an integral part of a medical palliative care approach and is needed in certain clinical situations. It is a legitimate clinical practice from any ethical point of view. While oncologists should have a basic knowledge of the procedure, its in depth study is a core competency for palliative care physicians. 23677523 Depressive symptoms are a risk factor for all-cause mortality: results from a prospective population-based study among 3,080 cancer survivors from the PROFILES registry. The goal of this large prospective population-based study was to examine the association between depressive symptoms and all-cause mortality among cancer survivors up to 10 years post-diagnosis. All currently alive individuals diagnosed with endometrial or colorectal cancer (CRC) between 1998 and 2007 or with lymphoma or multiple myeloma between 1999 and 2008, as registered in the Eindhoven Cancer Registry, received a questionnaire on depressive symptoms (Hospital Anxiety and Depression Scale (HADS)) in 2008 or 2009, respectively; 69 % (n = 3,080) responded. Survival status was obtained from the Central Bureau for Genealogy. Clinically elevated levels of depressive symptoms (HADS cutoff value ≥8) were more prevalent in those who died compared to those who survived (38 vs. 19 %, respectively; p < 0.0001). This was also evident across different types of cancer. After adjustment for independent predictors of all-cause mortality, 1-10-year survivors with depressive symptoms had an increased risk of death (hazard ratio (HR) 2.07; 95 % confidence interval (CI) 1.56-2.74; p < 0.0001), and this was also found among 1-2-year survivors (HR, 2.20; 95 % CI, 1.41-3.43; p < 0.001). Sub-analyses among CRC survivors gave the opportunity to adjust for metastasis and showed that depressive symptoms among 1-10-year CRC survivors and 1-2-year CRC survivors increased the risk of death (HR, 1.88; 95 % CI, 1.24-2.83; p < 0.01 and HR, 2.55; 95 % CI, 1.44-4.51; p < 0.001, respectively). This study showed that patients with depressive symptoms had twofold risk for all-cause mortality, even after adjustment for major clinical predictors. Paying more attention to the recognition and treatment of depressive symptoms seems warranted since depressive symptoms are often underdiagnosed and undertreated in cancer patients. 23796856 Evaluation of an endorectal electrode for performing focused irreversible electroporation ablations in the Swine rectum. To study the feasibility of a novel endorectal electrode for the creation of focal ablations of the rectal wall with the use of irreversible electroporation (IRE). A monopolar electrode with a grounding pad (10 ablations in five pigs) and a bipolar electrode (two ablations in one pig) were evaluated in healthy swine rectum. A two-dimensional model of the electrode in the rectum was created and used to solve the Laplace equation to determine field strength. Simulation was used to identify treatment settings for superficial ablation (mucosal layers) or transmural ablation of rectal wall. Animals were euthanized within 4 hours after treatment. Treatment was successfully completed without treatment-related complications. Eleven of 12 lesions were successfully located and extracted for pathologic analysis. All lesions were characterized by necrotic cell death with mild inflammation and hyperemia, with a sharp demarcation between ablated and adjacent normal tissue. Depth of lesions corresponded with numeric simulation. Histologic analysis and measurements indicated that lesion creation with the superficial treatment setting resulted in ablation of mucosal and submucosal layers with superficial or no injury to the muscularis propria (9.97 mm ± 0.31 length, 3.3 mm ± 2.92 depth), and that lesion creation with the transmural treatment setting resulted in full-thickness ablation (12.43 mm ± 3.85 length, 4.97 mm ± 2.89 depth) of the rectal wall. An endorectal electrode can be used to deliver IRE and create limited focal ablations in the rectal wall. Treatment parameters can be determined through numeric modeling to control the depth of penetration of ablation. 23932999 Whole-body posture planning in anticipation of a manual prehension task: Prospective and retrospective effects. This study examined the extent to which the anticipation of a manual action task influences whole-body postural planning and orientation. Our participants walked up to a drawer, opened the drawer, then grasped and moved an object in the drawer to another location in the same drawer. The starting placement of the object within the drawer and the final placement of the object in the drawer were varied across trials in either a blocked design (i.e., in trials where the same start and end location were repeated consecutively) or in a mixed fashion. Of primary interest was the posture adopted at the moment of grasping the drawer handle before pulling it out prior to the object manipulation task. Of secondary interest was whether there were sequential effects such that postures adopted in preceding trials influenced postures in subsequent trials. The results indicated that the spatial properties of the forthcoming object manipulation influenced both the postures adopted by the participants and the degree to which the drawer was opened, suggesting a prospective effect. In addition, the adopted postures were more consistent in blocked trials than in mixed trials, suggesting an additional retrospective effect. Overall, our findings suggest that motor planning occurs at the level of the whole body, and reflects both prospective and retrospective influences. 23896813 Genetic and phenotypic characterization of a Japanese wild-derived DOB/Oda rat strain. Wild-derived rat strains can provide novel genome resources that are not available in standard laboratory strains. Genetic backgrounds of wild-derived strains can facilitate effective genetic linkage analyses and often modulate the expression of mutant phenotypes. Here we describe the development and characterization of a new inbred rat strain, DOB/Oda, from wild rats (Rattus norvegicus) captured in Shitara, Aichi, Japan. Phenotype analysis of 109 parameters revealed that the DOB/Oda rats had small body weight, preference for darkness, and high locomotor activity compared with the rat strains in the National BioResource Project for the Rat (NBRP-Rat) database. Genome analysis with 357 SSLP markers identified DOB/Oda-specific alleles in 70 markers. The percentage of SSLP markers that showed polymorphism between the DOB/Oda strain and any of 132 laboratory strains from NBRP-Rat varied from 89 to 95 %. The polymorphic rate (average of the values of the percentage) for the DOB/Oda strain was 91.6 %, much higher than the rates for available wild-derived strains such as the Brown Norway rat. A phylogenic tree constructed with DOB/Oda and all the strains in NBRP-Rat showed that the DOB/Oda strain localized within the wild rat groups, apparently separate from the laboratory strains. Together, these findings indicated that the DOB/Oda rat has a unique genome that is not available in the laboratory strains. Therefore, the new DOB/Oda strain will provide an important genome resource that will be useful for designing genetic experiments and for the discovery of genes that modulate mutant phenotypes. 23819599 Deciphering the response of Mycobacterium smegmatis to nitrogen stress using bipartite active modules. The ability to adapt to environments with fluctuating nutrient availability is vital for bacterial survival. Although essential for growth, few nitrogen metabolism genes have been identified or fully characterised in mycobacteria and nitrogen stress survival mechanisms are unknown. A global transcriptional analysis of the mycobacterial response to nitrogen stress, showed a significant change in the differential expression of 16% of the Mycobacterium smegmatis genome. Gene expression changes were mapped onto the metabolic network using Active Modules for Bipartite Networks (AMBIENT) to identify metabolic pathways showing coordinated transcriptional responses to the stress. AMBIENT revealed several key features of the metabolic response not identified by KEGG enrichment alone. Down regulated reactions were associated with the general reduction in cellular metabolism as a consequence of reduced growth rate. Up-regulated modules highlighted metabolic changes in nitrogen assimilation and scavenging, as well as reactions involved in hydrogen peroxide metabolism, carbon scavenging and energy generation. Application of an Active Modules algorithm to transcriptomic data identified key metabolic reactions and pathways altered in response to nitrogen stress, which are central to survival under nitrogen limiting environments. 23882408 A case of apical ballooning syndrome in a male with status asthmaticus; highlighting the role of B2 agonists in the pathophysiology of a reversible cardiomyopathy. Apical ballooning syndrome (ABS), also known as Takotsubo cardiomyopathy, was first reported by Dote and colleagues in Japanese literature in 1991 in a review of five cases. Case series have highlighted the association of severe psychological stressors as the major precipitating factors of this syndrome. Status Epilepticus and Sub-Arachnoid hemorrhage are also now established independent etiologies for this phenomenon in patients without coronary artery disease. We report a case of reversible apical ventricular dysfunction in a 50-year-old male presenting with status asthmaticus who quickly underwent intubation. Following this, he had ST elevations in precordial leads with mild cardiac enzyme leak. Subsequent cardiac catheterization revealed a left ventricular ejection fraction of 25-30% with apical aneurismal segment. No obstructive disease was observed. Three days later there was marked clinical improvement; the patient was extubated and repeat echocardiography revealed a remarkable return to normal ventricular size and systolic function. Our case demonstrates that excess use of beta-agonists may be a potential risk factor for ABS and raises the possibility of cathecholamine cardiotoxicity being mediated via beta-receptors. Furthermore, it also negates the propensity of apical ballooning so far reported only in women with respiratory distress without confounding emotional stressors. 23928865 Endoplasmic Reticulum Stress Participates in Aortic Valve Calcification in Hypercholesterolemic Animals. Aortic valve (AV) calcification occurs via a pathophysiological process that includes lipoprotein deposition, inflammation, and osteoblastic differentiation of valvular interstitial cells. Here, we investigated the association between endoplasmic reticulum (ER) stress and AV calcification. We identified ER stress activation in AV of patients with calcified AV stenosis. We generated an AV calcification model in hypercholesterolemic rabbits and mice, respectively, and found marked AV ER stress induction. Classical ER stress inhibitor, tauroursodeoxycholic acid, administration markedly prevented AV calcification, and attenuated AV osteoblastic differentiation and inflammation in both rabbit and mouse models of AV calcification via inhibition of ER stress. In cultured valvular interstitial cells, we found that oxidized low-density lipoprotein caused ER stress in a cytosolic [Ca](2+)i-dependent manner. Oxidized low-density lipoprotein promoted osteoblastic differentiation via ER-stress-mediated protein kinase-like ER kinase/activation of transcription factor 4/osteocalcin and inositol-requiring transmembrane kinase and endonuclease-1α/spliced X-box-binding protein 1/Runx2 pathway, and induced inflammatory responses through inositol-requiring transmembrane kinase and endonuclease-1α/c-Jun N-terminal kinase and inositol-requiring transmembrane kinase and endonuclease-1α/nuclear factor-κB signaling in valvular interstitial cells. Inhibition of ER stress by either tauroursodeoxycholic acid or 4-phenyl butyric acid could both suppress oxidized low-density lipoprotein-induced osteoblastic differentiation and inflammatory responses in valvular interstitial cells. These data provide novel evidence that ER stress participates in AV calcification development, and suggest that ER stress may be a novel target for AV calcification prevention and treatment. 23910782 Structural relationships among attachment insecurity, alexithymia, and body esteem in women with eating disorders. Patients with eating disorders tend to experience low levels of body esteem. To assess the psychosocial processes that may predict low body esteem in these individuals, we assessed the structural interrelations among attachment anxiety, attachment avoidance, alexithymia, and body esteem in a cross-sectional sample of patients with eating disorders. We tested a model in which alexithymia mediates the relationship between attachment insecurity and body esteem. Participants were 300 women with anorexia nervosa (n=109), bulimia nervosa (n=130), and eating disorders not otherwise specified (n=61) who completed pretreatment self-report questionnaires at intake for a day hospital treatment program. We found a direct and negative relationship between attachment anxiety and body esteem. Additionally, attachment avoidance had an indirect negative relationship to body esteem through alexithymia. These results indicate that therapists may attend to attachment insecurity and affective regulation strategies when addressing body image issues in patients with eating disorders. 23063671 Emerging Fusarium mycotoxins in organic and conventional pasta collected in Spain. One of the main sources of emerging Fusarium mycotoxins in human nutrition is the cereals and cereal products. In this study, an analytical method to determine enniatins A, A1, B and B1 (ENs), beauvericin (BEA) and fusaproliferin (FUS) based on Ultra-Turrax extraction followed by liquid chromatography coupled to triple quadrupole mass spectrometer detector (MS/MS QqQ), was applied for the analysis of pasta. For this purpose, 114 commercial samples of pasta were acquired from supermarkets located in Valencia. The results showed higher frequencies of contamination in organic pasta than in conventional pasta, while the concentration levels were variable for both types of pasta. In positive samples, BEA levels varied from 0.10 to 20.96μg/kg and FUS levels varied from 0.05 to 8.02μg/kg. ENs levels ranged from 0.25 to 979.56μg/kg, though the majority of the values were below 25μg/kg. Besides, it was observed the simultaneous presence of two or more mycotoxins in a high percentage of the samples. Finally, an evaluation of the dietary exposure of the emerging Fusarium mycotoxins was performed in the Spanish population. The prevalence of ENs, BEA and FUS in cereal products suggests that the toxins may pose a health risk to Spanish population. 23279351 Electroretinographical and histological study of mouse retina after optic nerve section: a comparison between wild-type and retinal degeneration 1 mice. Retinal ganglion cell death underlies the pathophysiology of neurodegenerative disorders such as glaucoma or optic nerve trauma. To assess the potential influence of photoreceptor degeneration on retinal ganglion cell survival, and to evaluate functionality, we took advantage of the optic nerve section mouse model. Surviving retinal ganglion cells were double-stained by exposing both superior colliculi to fluorogold, and by applying dextran-tetramethylrhodamine to the injured optic nerve stump. To assess retinal function in wild-type animals, electroretinograms were recorded on the injured eyes and compared with the contralateral. Similar labelling experiments were carried out on retinal degeneration 1 mice. Surviving retinal ganglion cells were counted 21 days after axotomy and compared with wild-type mice. No functional experiments were performed on retinal degeneration 1 animals because they do not develop normal electroretinographical responses. A significant decrease in retinal ganglion cell density was observed 6 days after axotomy in the wild type. Functional studies revealed that, in scotopic conditions, axotomy induced a significant amplitude decrease in the positive scotopic threshold response component of the electroretinogram. Such decrease paralleled cell loss, suggesting it may be an appropriate technique to evaluate functionality. When comparing retinal ganglion cell densities in wild-type and retinal degeneration 1 mice, a significant greater survival was observed on the latter. After optic nerve section, electroretinographical recordings exhibited a progressive decrease in the amplitude of the positive scotopic threshold response wave, reflecting ganglion cell loss. Interestingly, rod degeneration seemed, at least initially, to protect from axotomy-driven damage. 23893984 Effects of glycerin on receiving performance and health status of beef steers and nutrient digestibility and rumen fermentation characteristics of growing steers. One experiment was conducted to evaluate the influence of glycerin (GLY) on animal performance and health when used as a partial replacement for roughage in receiving diets. The second experiment was conducted using ruminally and duodenally cannulated steers in a 4 × 4 Latin square to determine the site of nutrient digestion and ruminal fermentation characteristics when GLY replaced roughage at 0%, 2.5%, 5%, and 10% of diet DM. In Exp. 1, steers (initial BW = 245 ± 2.3 kg) were fed treatment diets over a 42-d period that consisted of a control diet based on steam-flaked corn with GLY inclusion in replacement of dietary roughage at 0%, 5%, and 10% of diet DM. A linear reduction in DMI was observed as GLY increased (P = 0.01). Glycerin incorporation tended to improve G:F in a linear manner (P = 0.07); efficiency was improved 5.4% and 4.7% at 5% and 10% GLY. The number of animals receiving treatment for bovine respiratory disease did not differ among treatments. Furthermore, there were no differences among treatments for mortality or the frequency of steers that were seropositive for serum antibody titers to infectious bovine rhinotracheitis on d 28. In Exp. 2, apparent OM and apparent and true starch digestibility increased linearly (P < 0.05) as GLY concentration increased, whereas true OM digestibility responded in a quadratic (P < 0.01) manner. Bacterial OM and bacterial starch flow responded quadratically (P ≤ 0.02), and flow increased from 0% to 5% GLY inclusion and decreased thereafter. Feed OM flow responded quadratically (P ≤ 0.05), where it decreased from 0% to 2.5% GLY and increased from 2.5% to 10% GLY inclusion. Feed starch (P = 0.02) and total starch (P = 0.02) flow from the duodenum decreased linearly as the concentration of GLY increased in the diet. Bacterial N flow to the duodenum responded quadratically (P < 0.01); it increased with increasing GLY in the diet up to 5% and then decreased from 5% to 10%. The acetate to propionate (A:P) ratio in the ruminal fluid decreased (P < 0.05) as the concentration of GLY in the diet increased, which could have implications on improved G:F. The decrease in the A:P ratio as GLY increased in the diet, coupled with the linear decrease in DMI and improvement in G:F with GLY addition up to 5% of DM in place of roughage, implies that GLY is a viable dietary ingredient in growing and receiving diets. 23834013 Vibronic Coupling Dominates the Electronic Circular Dichroism of the Benzene Chromophore (1)Lb band. The alkylbenzene derivatives (R)-PhCH(CH3)(t)Bu (1) and (R)-PhCH(CH3)(i)Pr (2) were taken as paradigms of chiral benzene compounds and their vibronic electronic circular dichroism (ECD) spectrum in the (1)Lb band region analyzed in detail. The (1)Lb ECD band of chiral benzene compounds is often used to assign absolute configurations on the basis of sector rules. However, (1)Lb ECD bands of several benzene derivatives are associated with a forbidden character and show marked vibrational progressions strongly modulating their shape. This is also true for compounds 1 and 2, the latter also showing a peculiar thermochromism. The low-temperature ECD spectrum of 2 displays in fact an alternation of positive and negative ECD maxima. Vibronic ECD calculations performed within a TDDFT scheme allowed a full rationalization of the observed ECD spectra of 1 and 2. Especially in the case of 2, the ECD spectrum in the (1)Lb band region results from a complex balance of Franck-Condon and Herzberg-Teller effects, as well as of conformational factors. Therefore, straightforward sector rules cannot be safely used to assign the absolute configuration of even these simple derivatives. 23740839 Correlating transcriptional networks to breast cancer survival: a large-scale coexpression analysis. Weighted gene coexpression network analysis (WGCNA) is a powerful 'guilt-by-association'-based method to extract coexpressed groups of genes from large heterogeneous messenger RNA expression data sets. We have utilized WGCNA to identify 11 coregulated gene clusters across 2342 breast cancer samples from 13 microarray-based gene expression studies. A number of these transcriptional modules were found to be correlated to clinicopathological variables (e.g. tumor grade), survival endpoints for breast cancer as a whole (disease-free survival, distant disease-free survival and overall survival) and also its molecular subtypes (luminal A, luminal B, HER2+ and basal-like). Examples of findings arising from this work include the identification of a cluster of proliferation-related genes that when upregulated correlated to increased tumor grade and were associated with poor survival in general. The prognostic potential of novel genes, for example, ubiquitin-conjugating enzyme E2S (UBE2S) within this group was confirmed in an independent data set. In addition, gene clusters were also associated with survival for breast cancer molecular subtypes including a cluster of genes that was found to correlate with prognosis exclusively for basal-like breast cancer. The upregulation of several single genes within this coexpression cluster, for example, the potassium channel, subfamily K, member 5 (KCNK5) was associated with poor outcome for the basal-like molecular subtype. We have developed an online database to allow user-friendly access to the coexpression patterns and the survival analysis outputs uncovered in this study (available at http://glados.ucd.ie/Coexpression/). 23216672 Leptin therapy in type 2 diabetes. There is a pressing need for new effective therapeutic strategies for addressing the epidemic of type 2 diabetes. Leptin has been shown to reduce hyperglycaemia in rodent models of type 1 diabetes and has recently been shown to normalize fasting plasma glucose concentrations in a rodent model of polygenic obesity and type 2 diabetes. Overall, these findings suggest that leptin may be an effective therapeutic option for both type 1 and type 2 diabetes. However, short-term human clinical studies in overweight and obese patients with recently diagnosed type 2 diabetes have reported minimal efficacy of leptin administration to lower blood glucose levels. Herein, the role of leptin in the maintenance of glucose homeostasis and the potential use of leptin in the treatment of type 2 diabetes are discussed. 23395634 Synthesis and characterization of novel quick-release propofol prodrug via lactonization. The water-soluble derivatives of propofol have gained attention as a method to increase solubility of propofol. According to the principle of lactonization, the lead compound HX0969 was synthesized first and then the pharmacological features of HX0969 were evaluated in a comparison with those of propofol in the SD rats. Then, HX0969 disodium phosphate monoester (HX0969W) and glycine ester trifluoroacetic acid salt (HX101230) were synthesized, and their pharmacological features were compared with those of Lusedra®, which has been recognized and marketed as a water-soluble prodrug of propofol since 2008. The results showed that HX0969 could produce an anesthetic effect within a few seconds (3.6±3.0s) and its therapeutic index was 4.66 in the SD rat. The pharmacodynamic characteristics of HX0969W were similar to those of the Lusedra®. HX101230 could still produce an anesthetic effect within 60s in the rats though its therapeutic index was not so high (TI=2.96). Therefore, our study has indicated that HX0969 is a potentially useful lead compound of propofol derivative. Its rapid anesthetic effect is probably associated with lactonization. 23845707 Variations of natremia in sea kraits (Laticauda spp.) kept in seawater and fresh water. Marine tetrapods evolved specific excretory structures (e.g. salt glands) that maintain salt concentrations within a narrow range of variation. However, recent investigations showed that in some lineages (sea snakes), individuals dehydrate in seawater and cannot equilibrate their hydromineral balance without access to fresh water. How these marine species cope with salt gain is therefore puzzling. We sampled two species of amphibious sea kraits (Laticauda saintgironsi and L. laticaudata) in the field. We also experimentally investigated patterns of salt regulation, specifically variations in natremia (plasma sodium) and body mass (net water flow), in individuals transferred first to fresh water and then to seawater. Our results show that free-ranging sea kraits display hypernatremia (up to 205mmol·l(-1)). Experimental data showed that natremia markedly decreased in snakes exposed to fresh water and increased when they were transferred to saltwater, thereby demonstrating a marked flexibility in their relation to environmental conditions. A literature survey indicated that all free-ranging marine snake species usually display hypernatremia despite having functional salt glands. Overall, sea snakes exhibit a marked tolerance to salt load compared to other marine tetrapods and apparently trigger substantial salt excretion only once natremia exceeds a high threshold. We hypothesise that this high tolerance significantly decreases energetic costs linked to salt gland functioning. 23641914 Copolymerization of 2-methylene-1,3-dioxepane and glycidyl methacrylate, a well-defined and efficient process for achieving functionalized polyesters for covalent binding of bioactive molecules. The understanding of cell-material interactions is important for creating personalized implants for tissue engineering. This has resulted in an interest in developing polymers with functional groups with the possibility of controlling the macromolecular surface. We have in a one-pot reaction synthesized a series of amorphous and degradable polyester-based copolymers with active functional groups by copolymerization of 2-methylene-1,3-dioxepane and glycidyl methacrylate. The properties of the final polymers were varied by varying the feed ratios of the monomers and it was seen that it was possible to control the amount of active functional groups. The resulting epoxy-functionalized polyester was further modified by covalent immobilization of heparin. The heparinization was done in order, in a future aspect, to enhance the osteogenic differentiation of mesenchymal stem cells. Heparin binds directly with the growth factor bone morphogenetic protein-2 and helps to retain its activity. The molecular structure of the copolymers was characterized by nuclear magnetic resonance, size exclusion chromatography, and fourier transform infrared spectroscopy. Differential scanning calorimetry and tensile testing showed that the monomer feed ratio had a great influence on the properties of the final polymer and that it thus was possible to control the mechanical properties to suit an intended application. The presence of heparin was verified by toluidine blue staining and all the films tested showed positive signals for heparin. 23500481 Identification, assessment and management of "endocrine disruptors" in wildlife in the EU substance legislation-Discussion paper from the German Federal Environment Agency (UBA). A discussion paper was developed by a panel of experts of the German Federal Environment Agency (UBA) contributing to the on-going debate on the identification, assessment and management of endocrine disruptors with a view to protect wildlife according to the EU substance legislation (plant protection products, biocides, industrial chemicals). Based on a critical synthesis of the state-of-the-art regarding regulatory requirements, testing methods, assessment schemes, decision-making criteria and risk management options, we advise an appropriate and consistent implementation of this important subject into existing chemicals legislation in Europe. Our proposal for a balanced risk management of endocrine disruptors essentially advocates transparent regulatory decision making based on a scientifically robust weight of evidence approach and an adequate risk management consistent across different legislations. With respect to the latter, a more explicit consideration of the principle of proportionality of regulatory decision making and socio-economic benefits in the on-going debate is further encouraged. 23758070 Stabilizing and retaining a quality nursing work force through the use of the Married State Preceptorship Model. The nursing shortage requires new graduate registered nurses (RNs) to work at the bedside, often leading to a shortened orientation period and increased stress. In the Married State Preceptorship Model (MSPM), the preceptor and the preceptee work together as the new graduate RN transitions to the bedside while maintaining safety and quality. This study explored first-year turnover rates of new graduate RNs and new graduate RNs' and preceptors' perceptions of the MSPM in transitioning new graduate RNs to practice. Focus groups and surveys were used with 108 new graduate RNs and 100 preceptors. Four themes emerged for new graduate RNs: partnership, critical thinking, learning, and transition. A statistically significant decrease in turnover rates was seen with MSPM versus traditional precepting. Survey data found that new graduate RNs and preceptors perceived the MSPM as promoting safety and reducing anxiety. The MSPM allows organizations to retain a quality nursing work force focused on safety patient care by transitioning new graduate RNs into the practice setting. 23849877 Tailoring enzyme activity and stability using polymer-based protein engineering. Polymer-based protein engineering (PBPE) offers an attractive method to predictably modify and enhance enzyme structure and function. Using polymers that respond to stimuli such as temperature and pH, enzyme activity and stability can be predictably modified without a dependence on molecular biology. Herein, we demonstrate that temperature responsive enzyme-polymer conjugates show increased stability while retaining bioactivity and substrate affinity. The bioconjugates were synthesized using a "grafting from" approach, where polymers were grown from a novel water-soluble initiator on the surface of a protein using atom transfer radical polymerization. Prior to polymer synthesis, the polymerization initiating molecule was covalently attached to surface accessible primary amines (lysine, N-terminal) of chymotrypsin, forming a macroinitiator. Poly(N-isopropylacrylamide) and poly[N,N'-dimethyl(methacryloylethyl) ammonium propane sulfonate] were grown separately from the initiator modified chymotrypsin. Both polymers were selected because of their temperature-dependent conformations. We observed that the enzyme-polymer conjugates retained temperature-dependent changes in conformation while still maintaining enzyme function. The conjugates exhibited dramatic increases in enzyme stability over a wide range of temperatures. We can now predictably manipulate enzyme kinetics and stability using polymer-based protein engineering without the need for molecular biology dependent mutagenesis. 23739535 A morphine conjugate vaccine attenuates the behavioral effects of morphine in rats. Vaccines for opioid dependence may provide a treatment that would reduce or slow the distribution of the drug to brain, thus reducing the drug's reinforcing effects. We tested whether a conjugate vaccine against morphine (keyhole limpet hemocyanin-6-succinylmorphine; KLH-6-SM) administered to rats would produce antibodies and show specificity for morphine or other heroin metabolites. The functional effects of the vaccine were tested with antinociceptive and conditioned place preference (CPP) tests. Rats were either vaccinated with KLH-6-SM and received two boosts 3 and 16weeks later or served as controls and received KLH alone. Anti-morphine antibodies were produced in vaccinated rats; levels increased and were sustained at moderate levels through 24weeks. Antibody binding was inhibited by free morphine and other heroin metabolites as demonstrated by competitive inhibition ELISA. Vaccinated rats showed reduced morphine CPP, tested during weeks 4 to 6, and decreased antinociceptive responses to morphine, tested at week 7. Brain morphine levels, assessed using gas-chromatography coupled to mass spectrometry (GC-MS) on samples obtained at 26weeks, were significantly lower in vaccinated rats. This suggests that morphine entry into the brain was reduced or slowed. These results provide support for KLH-6-SM as a candidate vaccine for opioid dependence. 23602054 Antibacterial serrulatane diterpenes from the Australian native plant Eremophila microtheca. Chemical investigations of the aerial parts of the Australian plant Eremophila microtheca resulted in the isolation of three serrulatane diterpenoids, 3-acetoxy-7,8-dihydroxyserrulat-14-en-19-oic acid (1), 3,7,8-trihydroxyserrulat-14-en-19-oic acid (2) and 3,19-diacetoxy-8-hydroxyserrulat-14-ene (3) as well as the previously reported compounds verbascoside (4) and jaceosidin (5). Acetylation and methylation of the major serrulatane diterpenoid 2 afforded 3,8-diacetoxy-7-hydroxyserrulat-14-en-19-oic acid (6) and 3,7,8-trihydroxyserrulat-14-en-19-oic acid methyl ester (7), respectively. The antibacterial activity of 1-7 was assessed against a panel of Gram-positive and Gram-negative bacterial isolates. All of the serrulatane compounds exhibited moderate activity against Streptococcus pyogenes (ATCC 12344) with minimum inhibitory concentrations (MICs) ranging from 64-128μg/mL. Serrulatane 1 demonstrated activity against all Gram-positive bacterial strains (MICs 64-128μg/mL) except for Enterococcus faecalis and Enterococcus faecium. This is the first report of natural products from E. microtheca. 22963453 Obesity and outcomes in patients hospitalized with pneumonia. Studies suggest obesity is paradoxically associated with better outcomes for patients with pneumonia. Therefore, we examined the impact of obesity on short-term mortality in patients hospitalized with pneumonia. For 2 years clinical and radiographic data were prospectively collected on all consecutive adults admitted with pneumonia to six hospitals in Edmonton, Alberta, Canada. We identified 907 patients who also had body mass index (BMI, kg/m(2) ) collected and categorized them as underweight (BMI < 18.5), normal (18.5 to <25), overweight (25 to <30) and obese (>30). Overall, 65% were >65 years, 52% were female, and 15% reported recent weight loss. Eighty-four (9%) were underweight, 358 (39%) normal, 228 (25%) overweight, and 237 (26%) obese. Two-thirds had severe pneumonia (63% PSI Class IV/V) and 79 (9%) patients died. In-hospital mortality was greatest among those that were underweight (12 [14%]) compared with normal (36 [10%]), overweight (21 [9%]) or obese (10 [4%], p <0.001 for trend). Compared with those of normal weight, obese patients had significantly lower rates of in-hospital mortality in multivariable logistic regression analyses: adjusted odds ratio (OR), 0.46; 95% CI, 0.22-0.97; p 0.04. However, compared with patients with normal weight, neither underweight (adjusted OR, 1.13; 95% CI, 0.54-2.4; p 0.7) nor overweight (adjusted OR, 0.94; 95% CI, 0.52-1.69; p 0.8) were associated with in-hospital mortality. In conclusion, in patients hospitalized with pneumonia, obesity was independently associated with lower short-term mortality, while neither being underweight nor overweight were. This suggests a protective influence of BMIs > 30 kg/m(2) that requires better mechanistic understanding. 23628393 Characterization and specification of microsatellite markers in the HLA-DRB1 gene region: a revision to major histocompatibility complex database. Association between HLA-DRB1 and a large number of diseases such as multiple sclerosis, type I diabetes and rheumatoid arthritis has been demonstrated. In the present study, we attempted to identify and characterize potential microsatellites in the HLA-DRB1 gene region to find specific markers for genotyping and linkage analysis of this gene. The microsatellites including M2_3_22, M2_2_36, D6S2878, D6S2805, D6S2879 and D6S2880 were selected from microsatellite resource in the Major Histocompatibility Complex database (dbMHC). In silico analysis showed that only M2_3_22 was specific for HLA-DRB1. Moreover, our findings revealed some more accurate characteristics of the other investigated microsatellites. M2_3_22 existed as a single copy in all the MHC haplotype sequences and was located next to HLA-DRB1. Therefore, a new set of primers compatible with all the last published MHC haplotype sequences were designed and used to amplify M2_3_22 in 164 DNA samples obtained from unrelated Iranian individuals. M2_3_22 was successfully amplified in all DNA samples and three different alleles were identified. This locus was found in the Hardy-Weinberg equilibrium (P>0.05) in the studied population. Together, the findings suggested that M2_3_22 could be introduced as a specific locus in the HLA-DRB1 gene region for linkage analysis and disease association studies. 23963508 Prescription n-3 Fatty Acids, But Not Eicosapentaenoic Acid Alone, Improve Reference Memory-Related Learning Ability by Increasing Brain-Derived Neurotrophic Factor Levels in SHR.Cg-Lepr (cp) /NDmcr rats, A Metabolic Syndrome Model. Metabolic syndrome is implicated in the decline of cognitive ability. We investigated whether the prescription n-3 fatty acid administration improves cognitive learning ability in SHR.Cg-Lepr (cp) /NDmcr (SHR-cp) rats, a metabolic syndrome model, in comparison with administration of eicosapentaenoic acid (EPA, C20:5, n-3) alone. Administration of TAK-085 [highly purified and concentrated n-3 fatty acid formulation containing EPA ethyl ester and docosahexaenoic acid (DHA, C22:6, n-3) ethyl ester] at 300 mg/kg body weight per day for 13 weeks reduced the number of reference memory-related errors in SHR-cp rats, but EPA alone had no effect, suggesting that long-term TAK-085 administration improves cognitive learning ability in a rat model of metabolic syndrome. However, the working memory-related errors were not affected in either of the rat groups. TAK-085 and EPA administration increased plasma EPA and DHA levels of SHR-cp rats, associating with an increase in EPA and DHA in the cerebral cortex. The TAK-085 administration decreased the lipid peroxide levels and reactive oxygen species in the cerebral cortex and hippocampus of SHR-cp rats, suggesting that TAK-085 increases antioxidative defenses. Its administration also increased the brain-derived neurotrophic factor levels in the cortical and hippocampal tissues of TAK-085-administered rats. The present study suggests that long-term TAK-085 administration is a possible therapeutic strategy for protecting against metabolic syndrome-induced learning decline. 23533261 Histochemical detection of platelet esterase activity in the bone marrow postmortem: can megakaryocytes serve as indicators for time since death? α-Naphthyl acetate esterase (ANAE) is one of the few enzymes that are histochemically detectable on formalin-fixed paraffin-embedded tissue. In bone marrow (BM) biopsies, ANAE staining highlights megakaryocytes. We investigated autopsy BM to determine whether ANAE staining intensity (SI) was associated with postmortem intervals (PMI, period between death and autopsy), and thus could allow the time of death of a patient to be deduced. ANAE-stained BM slides of 74 forensic and pathology autopsies as well as 22 biopsies were histologically evaluated and their SIs semiquantitatively graded. ANAE-SIs did not differ between men and women and slightly decreased with age. Biopsies had significantly higher ANAE-SIs than pathology cases. In autopsies, ANAE-SIs were not associated with PMI, except for cases with PMI ≥7 days which were consistently ANAE-negative. ANAE-SIs in postmortem BM samples were independent of PMI. Thus, ANAE staining of BM megakaryocytes cannot serve as an indicator for time-since-death of a patient. 23708432 Mass spectrometric glycoform profiling of the innovator and biosimilar erythropoietin and darbepoetin by LC/ESI-MS. The recent patent expirations of erythropoietin (EPO) have promoted the development of biosimilars. Two and one biosimilar EPO products were approved in 2007 in Europe and in 2010 in Japan, respectively. Glycosylation heterogeneity of EPO is very complex, and its pattern has a large impact on its in vivo activity. In this study, glycoform profilings of biosimilar and innovator EPO products were performed using LC/ESI-MS. Glycoforms of EPO were detected within the range of m/z 1700-3600 at the 10(+)-16(+) charge states. The charge-deconvoluted spectra showed complex glycoform mass profiles at 28,000-32,000 Da, and most of the observed peaks were assigned to the peptide (18,236 Da)+glycans with the compositions of NeuAc10-14Hexn+3HexNAcnFuc3 (n=16-26) with or without some O-acetylations (+42 Da) and attachment of NeuGc for NeuAc or oxidation (+16 Da). Analysis of de-N-glycosylated EPO showed the distributions of O-glycans of NeuAc1-2Hex1HexNAc1 and site occupancy. Each EPO product showed a characteristic glycoform profile with respect to sialylation, glycan size, O-acetylation of sialic acids and O-glycosylation. Analysis of darbepoetin suggested that glycans of darbepoetin were highly sialylated and O-acetylated. LC/ESI-MS was shown to be useful to evaluate the similarity of the glycoform profiles of EPO. 23886837 Rasip1 regulates vertebrate vascular endothelial junction stability through Epac1-Rap1 signaling. Establishment and stabilization of endothelial tubes with patent lumens is vital during vertebrate development. Ras-interacting protein 1 (RASIP1) has been described as an essential regulator of de novo lumenogenesis through modulation of endothelial cell (EC) adhesion to extracellular matrix (ECM). Here, we show that in mouse and zebrafish embryos, Rasip1-deficient vessels transition from an angioblast cord to a hollow tube, permit circulation of primitive erythrocytes, but ultimately collapse, leading to hemorrhage and embryonic lethality. Knockdown of RASIP1 does not alter EC-ECM adhesion, but causes cell-cell detachment and increases permeability of EC monolayers in vitro. We also found that endogenous RASIP1 in ECs binds RAP1, but not RHOA or CDC42. Using an EPAC1-RAP1 dependent model of nascent junction formation, we demonstrate that a fraction of the RASIP1 protein pool localizes to cell-cell contacts. Loss of RASIP1 phenocopies loss of RAP1 or EPAC1 in ECs by altering junctional actin organization, localization of the actin-bundling protein non-muscle myosin heavy chain IIB, and junction remodeling. Our data show that RASIP1 regulates the integrity of newly formed blood vessels as an effector of EPAC1-RAP1 signaling. 23881500 The Janus-faced role of external forces in mechanochemical disulfide bond cleavage. Recent force microscopy measurements on the mechanically activated cleavage of a protein disulfide bond through reaction with hydroxide ions revealed that for forces greater than 0.5 nN, the acceleration of the reaction rate is substantially reduced. Here, using ab initio simulations, we trace this 'reactivity switch' back to a dual role played by the mechanical force, which leads to antagonistic effects. On the one hand, the force performs work on the system, and thereby accelerates the reaction. On the other hand, the force also induces a conformational distortion that involves the S-S-C-C dihedral angle, which drives the disulfide into a conformation that is shielded against nucleophilic attack because of steric hindrance. The discovery of force-induced conformational changes that steer chemical reactivity provides a new key concept that is expected to be relevant beyond this specific case, for example in understanding how 'disulfide switches' regulate protein function and for the rational design of mechanoresponsive materials. 23842764 Tunable scattered colors over a wide spectrum from a single nanoparticle. By controlling the thickness of the silver shell, Au-Ag core-shell nanorods with quadruple plasmonic peaks corresponding to red, green, violet and deep violet regions have been prepared. Additionally, under polarized light, we achieved tunability of scattered colors from a single nanoparticle over an exceptionally wide wavelength range. The observed colors include red, orange, yellow, green, blue and purple. 23928088 From gaze cueing to dual eye-tracking: Novel approaches to investigate the neural correlates of gaze in social interaction. Tracking eye-movements provides easy access to cognitive processes involved in visual and sensorimotor processing. More recently, the underlying neural mechanisms have been examined by combining eye-tracking and functional neuroimaging methods. Apart from extracting visual information, gaze also serves important functions in social interactions. As a deictic cue, gaze can be used to direct the attention of another person to an object. Conversely, by following other persons' gaze we gain access to their attentional focus, which is essential for understanding their mental states. Social gaze has therefore been studied extensively to understand the social brain. In this endeavor, gaze has mostly been studied from an observational perspective using static displays of faces and eyes. However, there is growing consent that observational paradigms are insufficient for an understanding of the neural mechanisms of social gaze behavior, which typically involve active engagement in social interactions. Recent methodological advances have allowed increasing ecological validity by studying gaze in face-to-face encounters in real-time. Such improvements include interactions using virtual agents in gaze-contingent eye-tracking paradigms, live interactions via video feeds, and dual eye-tracking in two-person setups. These novel approaches can be used to analyze brain activity related to social gaze behavior. This review introduces these methodologies and discusses recent findings on the behavioral functions and neural mechanisms of gaze processing in social interaction. 23058815 The 2010 U.S. health care reform: approaching and avoiding how other countries finance health care. This article describes and analyzes the U.S. health care legislation of 2010 by asking how far it was designed to move the U.S. system in the direction of practices in all other rich democracies. The enacted U.S. reform could be described, extremely roughly, as Japanese pooling with Swiss and American problems at American prices. Its policies are distinctive, yet nevertheless somewhat similar to examples in other rich democracies, on two important dimensions: how risks are pooled and the amount of funds redistributed to subsidize care for people with lower incomes. Policies about compelling people to contribute to a finance system would be further from international norms, as would the degree to which coverage is set by clear and common substantive standards--that is, standardization of benefits. The reform would do least, however, to move the United States toward international practices for controlling spending. This in turn is a major reason why the results would include less standard benefits and incomplete coverage. In short, the United States would remain an outlier on coverage less because of a failure to make an effort to redistribute--a lack of solidarity--than due to a failure to control costs. 23494481 Neuroprotection against neuroblastoma cell death induced by depletion of mitochondrial glutathione. Mitochondrial glutathione pool is vital in protecting cells against oxidative stress as the majority of the cellular reactive oxygen species are generated in mitochondria. Oxidative stress is implicated as a causative factor in neuronal death in neurodegenerative disorders. We hypothesized that depletion of mitochondrial glutathione leads to mitochondrial dysfunction and apoptotic death of SK-N-SH (human neuroblastoma) cells and investigated the neuroprotective strategies against GSH depletion. SK-N-SH cells were treated with two distinct inhibitors of glutathione metabolism: L-buthionine-(S, R)-sulfoximine (BSO) and ethacrynic acid (EA). EA treatment caused depletion of both the total and mitochondrial glutathione (while BSO had no effect on mitochondrial glutathione), enhanced rotenone-induced ROS production, and reduced the viability of SK-N-SH cells. Glutathione depletion by BSO or EA demonstrated positive features of mitochondria-mediated apoptosis in neuroblastoma cell death. Prevention of apoptosis by Bcl2 overexpression or use of antioxidant ebselen did not confer neuroprotection. Co-culture with U-87 (human glioblastoma) cells protected SK-N-SH cells from the cell death. Our data suggest that depletion of mitochondrial glutathione leads to mitochondrial dysfunction and apoptosis. The study indicates that preventing mitochondrial glutathione depletion could become a novel strategy for the development of neuroprotective therapeutics in neurodegenerative disorders. 23895111 Does stress enhance or impair memory consolidation? Three experiments examined the hypothesis that stress-induced arousal enhances long-term memory for experiences associated with arousing events. Contrary to expectations, in each experiment exposure to a stressor (arm immersion in ice water) interfered with, rather than enhanced, long-term memory for associated material. Despite varying the stimuli (words, pictures), their emotional value (positive, negative, neutral), the time between learning and stress inductions (0 to 1 minute), and opportunities for post-learning rehearsal, each experiment produced a significant reversal of the hypothesised effect. That is, in each experiment, exposure to a stressor interfered with, rather than enhanced, long-term memory for associated material. We conclude that the relationship between stress and memory consolidation is more bounded than previously believed. 23946439 Differential roles for 3-OSTs in the regulation of cilia length and motility. As cells integrate molecular signals from their environment, cell surface receptors require modified proteoglycans for the robust activation of signaling pathways. Heparan sulfate proteoglycans (HSPGs) have long unbranched chains of repetitive disaccharide units that can be sulfated at specific positions by heparan sulfate O-sulfotransferase (OST) families. Here, we show that two members of the 3-OST family are required in distinct signaling pathways to control left-right (LR) patterning through control of Kupffer's vesicle (KV) cilia length and motility. 3-OST-5 functions in the fibroblast growth factor pathway to control cilia length via the ciliogenic transcription factors FoxJ1a and Rfx2. By contrast, a second 3-OST family member, 3-OST-6, does not regulate cilia length, but regulates cilia motility via kinesin motor molecule (Kif3b) expression and cilia arm dynein assembly. Thus, two 3-OST family members cell-autonomously control LR patterning through distinct pathways that regulate KV fluid flow. We propose that individual 3-OST isozymes create distinct modified domains or 'glycocodes' on cell surface proteoglycans, which in turn regulate the response to diverse cell signaling pathways. 23306547 Biomarkers to help guide management of patients with pulmonary nodules. Rationale: Indeterminate pulmonary nodules are a common radiographic finding and require further evaluation because of the concern for lung cancer. Objectives: We developed an algorithm to assign patients to a low- or high-risk category for lung cancer, based on a combination of serum biomarker levels and nodule size. Methods: For the serum biomarker assay, we determined levels of carcinoembryonic antigen, α1-antitrypsin, and squamous cell carcinoma antigen. Serum data and nodule size from a training set of 509 patients with (n = 298) and without (n = 211) lung cancer were subjected to classification and regression tree and logistic regression analyses. Multiple models were developed and tested in an independent, masked validation set for their ability to categorize patients with (n = 203) or without (n = 196) lung cancer as being low- or high-risk for lung cancer. Measurements and Main Results: In all models, a large percentage of individuals in the validation study with small nodules (<1 cm) were assigned to the low-risk group, and a large percentage of individuals with large nodules (≥3 cm) were assigned to the high-risk group. In the validation study, the classification and regression tree algorithm had overall sensitivity, specificity, and positive and negative predictive values for determining lung cancer of 88%, 82%, 84%, and 87%, respectively. The logistic regression model had overall sensitivity, specificity, and positive and negative predictive values of 80%, 89%, 89%, and 81%, respectively. Conclusion: Integration of biomarkers with lung nodule size has the potential to help guide the management of patients with indeterminate pulmonary nodules. 23628649 A modified technique for implantation of the HeartWare™ left ventricular assist device when using bivalirudin anticoagulation in patients with acute heparin-induced thrombocytopenia. In patients with acute heparin-induced thrombocytopenia (HIT) needing urgent cardiac surgery, bivalirudin is recommended as a first-line strategy for intraoperative anticoagulation. However, due to the unique elimination process of bivalirudin, careful adjustment of the perfusion and surgical strategy is mandatory as blood stasis in the circuit or prolonged interruption of areas or compartments containing blood from the systemic circulation may result in thrombus formation. We report here a modified surgical strategy for the implantation of the HeartWare™ left ventricular assist device, which avoids prolonged disconnection of the blood-filled device from the systemic blood flow, so that bivalirudin can be safely used as anticoagulant. 23874924 Is the pathogenic ergot fungus a conditional defensive mutualist for its host grass? It is well recognized, that outcomes of mutualistic plant-microorganism interactions are often context dependent and can range from mutualistic to antagonistic depending on conditions. Instead, seemingly pathogenic associations are generally considered only harmful to plants. The ergot fungus (Claviceps purpurea) is a common seed pathogen of grasses and cereals. Ergot sclerotia contain alkaloids which can cause severe toxicity in mammals when ingested, and thus the fungal infection might provide protection for the host plant against mammalian herbivores. Theoretically, the net effect of ergot infection would positively affect host seed set if the cost is not too high and the defensive effect is strong enough. According to our empirical data, this situation is plausible. First, we found no statistically significant seed loss in wild red fescue (Festuca rubra) inflorescences due to ergot infection, but the seed succession decreased along increasing number of sclerotia. Second, in a food choice experiment, sheep showed avoidance against forage containing ergot. Third, the frequency of ergot-infected inflorescences was higher in sheep pastures than surrounding ungrazed areas, indicating a protective effect against mammalian grazing. We conclude that, although ergot can primarily be categorized as a plant pathogen, ergot infection may sometimes represent indirect beneficial effects for the host plant. Ergot may thus serve as a conditional defensive mutualist for its host grass, and the pathogenic interaction may range from antagonistic to mutualistic depending on the situation. 23305122 Modelling the reaction mechanism of ribulose-1,5-bisphosphate carboxylase/oxygenase and consequences for kinetic parameters. Although ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) was discovered nearly 60 years ago, the associated chemical mechanism of the reaction is still incompletely understood. The catalytic cycle consists of four major steps: ribulose-1,5-bisphosphate binding, enolization, CO2 or O2 addition and hydration, and cleavage of the intermediate. The use of individual rate constants for these elemental steps yields mathematical expressions for usual kinetic constants (kcat , Km ), CO2 versus O2 specificity (Sc/o ) as well as other chemical parameters such as the (12) C/(13) C isotope effect. That said, most of them are not simple and thus the interpretation of experimental and observed values of kcat , Km and Sc/o may be more complicated than expected. That is, Rubisco effective catalysis depends on several kinetic parameters that are influenced by both the biological origin and the cellular medium (which, in turn, can vary with environmental conditions). In this brief review, we present the basic model of Rubisco kinetics and describe how subtle biochemical changes (which may have occurred along Evolution) can easily modify Rubisco catalysis. 22690946 Hyperinakin, a new anti-inflammatory phloroglucinol derivative from Hypericum nakamurai. Phytochemical investigation of Hypericum nakamurai (Masamune) Robson has led to the isolation of three phloroglucinol derivatives 1-3. The structures of these compounds were determined by the analysis of their spectroscopic data (IR, mass and UV), and by the application of 1-D and 2-D-NMR techniques. Hyperinakin (1) is a new compound. The anti-inflammatory activities of compounds 1-3 were also tested and evaluated. A biogenetic pathway for compounds 1-3 was also proposed. 23947617 Cooperative Slowdown of Water Rotation Near Densely Charged Ions is Intense but Short-Ranged. We investigate the reorientation dynamics of water at 300 K in solutions of magnesium sulfate and cesium chloride from classical atomistic molecular dynamics simulations using the "simple water model with four sites and negative Drude polarizability" (SWM4-NDP) and accompanying ion models; for sulfate, we derive SWM4-NDP-compatible parameters. Results indicate that pairs of ions have a cooperative effect on water rotation, but do not support the model based on experiment whereby ion cooperativity increases the number of very slow water molecules well beyond the ions' first hydration shell. Instead, we find that cooperative slowdown beyond the first hydration shell is weak. Intense cooperative slowdown is limited to the first hydration shells, the magnitude of the slowdown being stronger for the multivalent ions. Cooperative effects for different salts differ in both the magnitude of rotational slowdown and the spatial range of the affected water subpopulations. 23104320 The effect of preemptive analgesia with bupivacaine on postoperative pain of inguinal hernia repair under spinal anesthesia: a randomized clinical trial. In the absence of any study on the use of bupivacaine as a long acting local anesthetic for the purpose of inducing preemptive analgesia in patients undergoing inguinal hernia repair under spinal anesthesia, this study was conducted to provide some evidence for possible benefits of such practice. In this randomized clinical trial, local infiltration of bupivacaine in patients undergoing inguinal hernia repair under spinal anesthesia was compared with placebo. The patients were randomly divided to two groups of 30 including the case group who received 10 cc of 0.5 % bupivacaine and the control group who received 10 cc of normal saline in the operation site before surgical incision. At the end of spinal block effect, patients were followed for symptoms of pain intensity according to numerical rating scale method, nausea, vomiting and opioid use for 24 h past the operation. The pain scores, nausea, vomiting and postoperative opioid use were 69.6, 76.5, 83.2 and 80 % respectively lower in first 24 h among the case group (P < 0.001, P = 0.005, P = 0.001 and P < 0.001). The number of patients with at least one analgesic request in first 24 h after operation was 64.2 % lower in case group, while time of first analgesic request was 67 % longer in treatment group (P < 0.001 and P < 0.001). The pre-operative local infiltration of bupivacaine reduces pain, nausea, vomiting and opioid use in the first 24 h after inguinal hernia surgery under spinal anesthesia. Therefore, further evaluation of the efficacy of this technique as a modality of preemptive analgesia is suggested. 23436754 Fabrication and characterization of regenerated silk scaffolds reinforced with natural silk fibers for bone tissue engineering. We introduce a novel Bombyx mori silk-based composite material developed for bone tissue engineering. Three-dimensional scaffolds were fabricated by embedding of natural degummed silk fibers in a matrix of regenerated fibroin, followed by freeze-drying. Different ratios of fibers to fibroin were investigated with respect to their influence on mechanical and biological properties. For all scaffold types, an interconnected porous structure suitable for cell penetration was proven by scanning electron microscopy. Compressive tests, carried out in static and cyclic mode under dry as well as wet conditions, revealed a strong impact of fiber reinforcement on compressive modulus and compressive stress. Cell culture experiments with human mesenchymal stem cells demonstrated that the fiber/fibroin composite scaffolds support cell attachment, proliferation, as well as differentiation along the osteoblastic lineage. Considering the excellent mechanical and biological properties, novel fiber/fibroin scaffolds appear to be an interesting structure for prospect studies in bone tissue engineering. 22566106 HPLC analysis of Stephania rotunda extracts and correlation with antiplasmodial activity. Stephania rotunda (Menispermaceae), a creeper commonly found in the mountainous areas of Cambodia, has been mainly used for the treatment of fever and malaria. Thus, the aim of this study is to investigate the chemical composition and antiplasmodial activity of different samples of S. rotunda and compare their antiplasmodial activity with their alkaloid content. Sixteen samples from different parts (roots, stem, and tuber) of S. rotunda were collected from four regions of Cambodia (Battambang, Pailin, Siem Reap, and Kampot). Reversed-phase HPLC was used to determine the content of three bioactive alkaloids (cepharanthine, tetrahydropalmatine, and xylopinine). These three alkaloids have been found in all samples from Battambang and Pailin (samples I-IX), whereas only tetrahydropalmatine was present in samples from Siem Reap and Kampot (samples X-XVI). The analyzed extracts were evaluated for their antiplasmodial activity on W2 strain of Plasmodium falciparum. Among them, 13 extracts were significantly active with inhibitory concentration 50 (IC(50) ) from 1.2 to 3.7 µg/mL and 2 extracts were moderately active (IC(50)  = 6.1 and 10 µg/mL, respectively), whereas sample XI was not active (IC(50)  = 19.6 µg/mL). A comparison between antiplasmodial activity and concentration of the three bioactive alkaloids in S. rotunda extracts has been realized. 23881697 Risk of heart failure associated with dopamine agonists: a nested case-control study. Recent evidence has emerged that a dopamine agonist, pramipexole, may increase the risk of heart failure among Caucasian patients, but the association has not been examined among Asian patients. The aim of this study was to explore the relationship between use of dopamine agonists and the risk of heart failure. Using data from Taiwan's National Health Insurance research database (NHIRD), we identified a population-based cohort comprising 27,135 patients who were prescribed anti-parkinsonian drugs between 2001 and 2010. We conducted a nested case-control study in which 1,707 cases of newly diagnosed heart failure were matched to 3,414 controls (1:2 matched according to age, gender and cohort entry year) within this cohort. Multivariable conditional logistic regressions were used to estimate the association between use of dopamine agonists and heart failure. An increased risk of heart failure was observed with current use of ergot-derived dopamine agonists (adjusted odds ratio [OR] 1.46, 95 % confidence interval [CI] 1.00-2.12) but not with current use of non-ergot-derived dopamine agonists (adjusted OR 1.24, 95 % CI 0.84-1.82). Among non-ergot-derived dopamine agonists, both pramipexole (adjusted OR 1.40, 95 % CI 0.75-2.61) and ropinirole (adjusted OR 1.22, 95 % CI 0.76-1.95) showed a non-significantly increased heart failure risk. Although the findings of our study were limited by lack of statistical power, a clear pattern of an increased duration of pramipexole use and an increased risk of heart failure were observed. Use of dopamine agonists, including pramipexole, was associated with non-significantly increased risks of heart failure in this population-based study in Taiwan. Further investigation is needed to clarify this potential association. 23237718 Positive and negative affect, depression, and cognitive processes in the Cognition in the Study of Tamoxifen and Raloxifene (Co-STAR) Trial. ABSTRACT Objectives: This study examined the relationship between positive and negative affect, depressive symptoms, and cognitive performance. Methods: The sample consisted of 1479 non-demented, postmenopausal women (mean age = 67 years) at increased risk of breast cancer enrolled in the National Surgical Adjuvant Breast and Bowel Project's Study of Tamoxifen and Raloxifene. At each annual visit, women completed a standardized neuropsychological battery and self-report measures of affect and depression. Data from three visits were used in linear mixed models for repeated measures using likelihood ratio tests. Separate analyses were performed to relate positive/negative affect and depression to each cognitive measure. Results: Higher positive affect was associated with better letter fluency (p = .006) and category fluency (p < .0001). Higher negative affect was associated with worse global cognitive function (p < .0001), verbal memory (CVLT List B; p = .002), and spatial ability (p < .0001). Depressive symptoms were negatively associated with verbal knowledge (p = .004), figural memory (p < .0001), and verbal memory (p's ≤ .0001). Discussion: Findings are consistent with some prior research demonstrating a link between positive affect and increased verbal fluency and between depressive symptoms and decreased memory. The most novel finding shows that negative affect is related to decreased global cognition and visuospatial ability. Overall, this research in a large, longitudinal sample supports the notion that positive affect is related to increases and negative affect to decreases in performance on distinct cognitive measures. 23279922 Lower respiratory tract hemorrhage associated with 2009 pandemic influenza A (H1N1) virus infection. Please cite this paper as: Kennedy et al. for the 2009 Pandemic H1N1 Influenza-Associated Lower Respiratory Tract Hemorrhage Working Group. (2012) Lower respiratory tract hemorrhage associated with 2009 pandemic influenza A (H1N1) virus infection. Influenza and Other Respiratory Viruses DOI: 10.1111/irv.12022. Background  Influenza-associated lower respiratory tract hemorrhage (LRTH) has been reported in previous pandemics and is a rare complication of seasonal influenza virus infection. We describe patients with LRTH associated with 2009 pandemic influenza A (H1N1) (pH1N1) virus infection identified from April 2009 to April 2010 in the United States. Methods  We ascertained patients with pH1N1-associated LRTH through state and local surveillance, the Emerging Infections Program, and CDCs Infectious Diseases Pathology Branch. All patients had influenza A, evidence of pneumonia, and evidence of LRTH. Results  We identified 44 cases; the median number of days from illness onset to clinical signs of LRTH was one. Hemoptysis or respiratory tract bleeding was documented in 40% of pH1N1-associated LRTH cases, often present early during the course of illness. Twenty-one (48%) patients with LRTH had no other hemorrhagic diatheses. Seven (23%) patients with LRTH received antiviral treatment within two days of illness onset. Conclusions  During influenza season, clinicians should consider influenza infection in the differential diagnosis for patients presenting with hemoptysis or other signs or symptoms of LRTH. While the impact of timing of antiviral therapy on this complication has not been studied, the rapid progression of LRTH may support use of early empiric therapy. Continued investigation is necessary to betterdefine the clinical spectrum of both seasonal influenza- and pH1N1-associated LRTH. 23373466 Effect of phospholipid composition and phase on nanodisc films at the solid-liquid interface as studied by neutron reflectivity. Nanodiscs are disc-like self-assembled structures formed by phospholipids and amphipatic proteins. The proteins wrap like a belt around the hydrophobic part of the lipids, basically producing nanometer-sized patches of lipid bilayers. The bilayer in the nanodisc constitutes a native-like model of the cell membrane and can act as a nanometer-sized container for functional single membrane proteins. In this study, we present a general nanodisc-based system, intended for structural and functional studies of membrane proteins. In this method, the nanodiscs are aligned at a solid surface, providing the ability to determine the average structure of the film along an axis perpendicular to the interface as measured by neutron reflectivity. The nanodisc film was optimized in terms of nanodisc coverage, reduced film roughness, and stability for time-consuming studies. This was achieved by a systematic variation of the lipid phase, charge, and length of lipid tails. Herein, we show that, although all studied nanodiscs align with their lipid bilayer parallel to the interface, gel-phase DMPC nanodiscs form the most suitable film for future membrane protein studies since they yield a dense irreversibly adsorbed film with low roughness and high stability over time. This may be explained by the appropriate matching between the thickness of the hydrophobic lipid core of gel phase DMPC and the height of the belt protein. Moreover, once formed the gel-phase DMPC nanodiscs film can be heated up to melt the lipid bilayer, thus providing a more biologically friendly environment for membrane proteins. 23912895 Effects of N-acetylcysteine on isolated mouse skeletal muscle: contractile properties, temperature dependence, and metabolism. The effects of the general antioxidant N-acetylcysteine (NAC) on muscle function and metabolism were examined. Isolated paired mouse extensor digitorum longus muscles were studied in the absence or presence of 20 mM NAC. Muscles were electrically stimulated to perform 100 isometric tetanic contractions (300 ms duration) at frequencies resulting in ∼85 % of maximal force (70-150 Hz at 25-40 °C). NAC did not significantly affect peak force in the unfatigued state at any temperature but significantly slowed tetanic force development in a temperature-dependent fashion (e.g., time to 50 % of peak tension averaged 35 ±â€‰2 ms [control] and 37 ±â€‰1 ms [NAC] at 25 °C vs. 21 ±â€‰1 ms [control] and 52 ±â€‰6 ms [NAC, P < 0.01] at 40 °C). During repeated contractions, NAC maximally enhanced peak force by the fifth tetanus at all temperatures (by ∼30 %). Thereafter, the effect of NAC disappeared rapidly at high temperatures (35-40 °C) and more slowly at the lower temperatures (25-30 °C). At all temperatures, the enhancing effect of NAC on peak force was associated with a slowing of relaxation. NAC did not significantly affect myosin light chain phosphorylation at rest or after five contractions (∼50 % increase vs. rest). After five tetani, lactate and inorganic phosphate increased about 20-fold and 2-fold, respectively, both in control and NAC-treated muscles. Interestingly, after five tetani, the increase in glucose 6-P was ∼2-fold greater, whereas the increase in malate was inhibited by ∼75 % with NAC vs. control, illustrating the metabolic effects of NAC. NAC slightly decreased the maximum shortening velocity in early fatigue (five to seven repeated tetani). These data demonstrate that the antioxidant NAC transiently enhances muscle force generation by a mechanism that is independent of changes in myosin light chain phosphorylation and inorganic phosphate. The slowing of relaxation suggests that NAC enhances isometric force by facilitating fusion (i.e., delaying force decline between pulses). The initial slowing of tension development and subsequent slowing of relaxation suggest that NAC would result in impaired performance during a high-intensity dynamic exercise. 23576235 A Platform for Large-Scale Graphene Electronics - CVD Growth of Single-Layer Graphene on CVD-Grown Hexagonal Boron Nitride. Direct chemical vapor deposition (CVD) growth of single-layer graphene on CVD-grown hexagonal boron nitride (h-BN) film can suggest a large-scale and high-quality graphene/h-BN film hybrid structure with a defect-free interface. This sequentially grown graphene/h-BN film shows better electronic properties than that of graphene/SiO2 or graphene transferred on h-BN film, and suggests a new promising template for graphene device fabrication. 23849015 Transplantation in the elderly patient. During the last 2 decades, the number of kidney transplants performed in the candidates older than 65 years has grown dramatically. For selected geriatric patients with end-stage kidney failure, kidney transplantation has emerged as a potential option for treatment of their end organ failure. Aging is associated with functional changes to the immune system known as immunosenescence, and this age-related decline in immune function has important implications for immunosuppression in this subgroup of kidney transplant recipients. 23902710 Targeting mixed lineage kinases in ER-positive breast cancer cells leads to G2/M cell cycle arrest and apoptosis. Estrogen receptor (ER)-positive tumors represent the most common type of breast cancer, and ER-targeted therapies such as antiestrogens and aromatase inhibitors have therefore been widely used in breast cancer treatment. While many patients have benefited from these therapies, both innate and acquired resistance continue to be causes of treatment failure. Novel targeted therapeutics that could be used alone or in combination with endocrine agents to treat resistant tumors or to prevent their development are therefore needed. In this report, we examined the effects of inhibiting mixed-lineage kinase (MLK) activity on ER-positive breast cancer cells and non-tumorigenic mammary epithelial cells. Inhibition of MLK activity with the pan-MLK inhibitor CEP-1347 blocked cell cycle progression in G2 and early M phase, and induced apoptosis in three ER-positive breast cancer cell lines, including one with acquired antiestrogen resistance. In contrast, it had no effect on the cell cycle or apoptosis in two non-tumorigenic mammary epithelial cell lines. CEP-1347 treatment did not decrease the level of active ERK or p38 in any of the cell lines tested. However, it resulted in decreased JNK and NF-κB activity in the breast cancer cell lines. A JNK inhibitor mimicked the effects of CEP-1347 in breast cancer cells, and overexpression of c-Jun rescued CEP-1347-induced Bax expression. These results indicate that proliferation and survival of ER-positive breast cancer cells are highly dependent on MLK activity, and suggest that MLK inhibitors may have therapeutic efficacy for ER-positive breast tumors, including ones that are resistant to current endocrine therapies. 23809625 The Kiss1 system and polycystic ovary syndrome: lessons from physiology and putative pathophysiologic implications. Polycystic ovary syndrome (PCOS) is a highly prevalent heterogeneous disease characterized by ovulatory dysfunction, hyperandrogenism, and metabolic alterations. Women with PCOS commonly display dysregulated gonadotropin secretion with higher LH pulsatility and perturbed LH-FSH ratios, which likely contributes to the ovarian phenotype and might be indicative of disrupted GnRH secretory activity. Although the involvement of altered androgen and insulin levels in the pathogenesis of the neuroendocrine alterations of PCOS has been explored in various experimental and clinical settings, the ultimate mechanisms whereby such neurohormonal perturbations take place remain partially unknown. In recent years, kisspeptins, the products of the Kiss1 gene that operate via the surface receptor Gpr54, have emerged as essential elements of the reproductive brain that play an indispensable role in the control of gonadotropin secretion and ovulation. In addition, Kiss1 neurons in the brain are targets and transmitters of the regulatory actions of sex steroids and metabolic cues on the reproductive axis during early organizing periods and adulthood. Furthermore, Kiss1/kisspeptin expression has been documented in the ovary in various species, including humans; yet clear evidence for the involvement of kisspeptin signaling in the control of ovulation, or its alterations, is still pending. Based on these physiologic features, we discuss the putative pathophysiologic implications of alterations of the Kiss1 system in the generation of PCOS and summarize the scarce experimental and clinical evidence that might support such a role. 23715651 Percentage of future liver remnant volume before portal vein embolization influences the degree of liver regeneration after hepatectomy. Clinical determinants of liver regeneration induced by portal vein embolization (PVE) and hepatectomy remain unclear. The aims of this study were to investigate how liver regeneration occurs after PVE followed by hepatectomy and to determine which factors strongly promote liver regeneration. Thirty-six patients who underwent both preoperative PVE and major hepatectomy were enrolled in this study. Percentage of future liver remnant volume before PVE (%FLR-pre) was compared with the remnant liver volume after PVE (%FLR-post-PVE) and on postoperative day 7 after hepatic resection (%FLR-post-HR). Clinical indicators contributing to liver regeneration induced by both PVE and hepatectomy were examined by logistic regression analysis. PVE and hepatectomy caused a two-step regeneration. FLR-pre, FLR-post-PVE, and FLR-post-HR were 448, 579, and 761 cm(3), respectively. The %FLR-pre was significantly associated with liver regeneration induced by both PVE and hepatectomy (r = 0.63, p < 0.0001). Multiple regression analysis showed that only %FLR-pre was independently correlated with posthepatectomy liver regeneration (p = 0.027, odds ratio = 13.8). After PVE and the subsequent hepatectomy, liver regeneration was accomplished in a two-step manner. Liver regeneration was strongly influenced by the %FLR-pre. 23321619 Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes. The recent finding that the neuronal cadherin gene CDH2 confers a highly significant risk for canine compulsive disorder led us to investigate whether missense variants within the human ortholog CDH2 are associated with altered susceptibility to obsessive-compulsive disorder (OCD), Tourette disorder (TD) and related disorders. Exon resequencing of CDH2 in 320 individuals identified four non-synonymous single-nucleotide variants, which were subsequently genotyped in OCD probands, Tourette disorder probands and relatives, and healthy controls (total N=1161). None of the four variants was significantly associated with either OCD or TD. One variant, N706S, was found only in the OCD/TD groups, but not in controls. By examining clinical data, we found there were significant TD-related phenotype differences between those OCD probands with and without the N845S variant with regard to the co-occurrence of TD (Fisher's exact test P=0.014, OR=6.03). Both N706S and N845S variants conferred reduced CDH2 protein expression in transfected cells. Although our data provide no overall support for association of CDH2 rare variants in these disorders considered as single entities, the clinical features and severity of probands carrying the uncommon non-synonymous variants suggest that CDH2, along with other cadherin and cell adhesion genes, is an interesting gene to pursue as a plausible contributor to OCD, TD and related disorders with repetitive behaviors, including autism spectrum disorders. 23901972 Comparison of volume and surface area nonpolar solvation free energy terms for implicit solvent simulations. Implicit solvent models for molecular dynamics simulations are often composed of polar and nonpolar terms. Typically, the nonpolar solvation free energy is approximated by the solvent-accessible-surface area times a constant factor. More sophisticated approaches incorporate an estimate of the attractive dispersion forces of the solvent and∕or a solvent-accessible volume cavitation term. In this work, we confirm that a single volume-based nonpolar term most closely fits the dispersion and cavitation forces obtained from benchmark explicit solvent simulations of fixed protein conformations. Next, we incorporated the volume term into molecular dynamics simulations and find the term is not universally suitable for folding up small proteins. We surmise that while mean-field cavitation terms such as volume and SASA often tilt the energy landscape towards native-like folds, they also may sporadically introduce bottlenecks into the folding pathway that hinder the progression towards the native state. 23389043 Oxidative Stress and DNA Damage in Human Gastric Carcinoma: 8-Oxo-7'8-dihydro-2'-deoxyguanosine (8-oxo-dG) as a Possible Tumor Marker. We characterized the oxidative stress (OS) status by the levels of reduced/oxidized glutathione (GSH/GSSG), malondialdehyde (MDA) and the mutagenic base 8-oxo-7'8-dihydro-2'-deoxyguanosine (8-oxo-dG) in human gastric carcinoma (HGC) samples and compared the results with normal tissue from the same patients. We also analyzed 8-oxo-dG in peripheral mononuclear cells (PMNC) and urine from healthy control subjects and in affected patients in the basal state and one, three, six, nine and twelve months after tumor resection. The levels of DNA repair enzyme mRNA expression (hOGG1, RAD51, MUYTH and MTH1) were determined in tumor specimens and compared with normal mucosa. Tumor specimens exhibited increased levels of MDA and 8-oxo-dG compared with normal gastric tissue. GSH levels were also increased, while GSSG levels remained stable. DNA repair enzyme mRNA expression was induced in the tumor tissues. Levels of 8-oxo-dG were significantly elevated in both urine and PMNC of gastric cancer patients compared with healthy controls. After gastrectomy, the levels of the damaged base in urine and PMNC decreased progressively to values close to those found in the healthy population. The high levels of 8-oxo-dG in urine may be related to the increased induction of DNA repair activity in tumor tissue, and the changes observed after tumor resection support its potential use as a tumor marker. 23934957 Directly Deposited Quantum Dot Solids Using a Colloidally Stable Nanoparticle Ink. We develop a photovoltaic colloidal quantum dot ink that allows for lossless, single-step coating of large areas in a manufacturing-compatible process. Our materials strategy involves a solution-phase ligand exchange to transport compatible linkers that yields 1-thioglycerol-capped PbS quantum dots in dimethyl sulfoxide with a photoluminescence quantum yield of 24%. A proof-of-principle solar cell made from the ink exhibits 2.1% power conversion efficiency. 23911812 Microbial community acclimation enhances waste hydrolysis rates under elevated ammonia and salinity conditions. Hydrolysis rates under potentially inhibitory concentrations of ammonia and salinity were investigated for two model feedstocks (manure and food waste). Rates were determined under a range of ammonia and salinity concentrations (1.0-10.0g TAN [total ammonia nitrogen] L(-1) and 3.9-20.0g sodiumL(-1)) with unacclimated and acclimated microbial inocula. Microbial community changes as a function of acclimation and feedstock were also investigated. Using unacclimated inocula, hydrolysis was found to be severely inhibited for elevated ammonia and salinity (∼4 to 10-fold, respectively) or hydrolysis was not detected. However, for inocula acclimated over 2-4months, statistically significant inhibition generally was not detectable. Molecular analyses demonstrated that microbial community composition changed during acclimation, and bacterial communities under elevated ammonia were distinct from communities under elevated salinity. Feedstock source also had a major influence on bacterial community structure. 23953968 The Association Between Neonatal Abo Blood Group And Intraventricular Hemorrhage In Extremely Low Birth Weight Infants: a reply to a comment. We would like to thank Aksoy and colleagues for their observations [1], which confirm, also in a younger subset of patients, the results of our previous research documenting the lack of association between ABO blood group and the risk of intracranial haemorrhage (ICH) [2]. ABO blood group has a profound influence on hemostasis, as it is a major determinant of VWF and, consequently, of FVIII plasma levels and non-O blood group individuals usually have VWF and FVIII levels approximately 25% higher than O blood group subjects [3]. However, while nowadays there is robust evidence from the literature on the positive association between non-O blood group and the risk of developing thrombotic events, and in particular venous thromboembolic events [4,5], there is still a degree of uncertainty regarding the association between hemorrhagic risk and ABO blood group, mostly due to the lack of well-conducted studies. In a recently published meta-analysis of the literature, we found a slight, but statistically significant, O group-related increased hemorrhagic risk (OR 1.33; 95% CI 1.25-1.42) [6]. This article is protected by copyright. All rights reserved. 23916402 'Midwives are the backbone of our health system': Lessons from Afghanistan to guide expansion of midwifery in challenging settings. over the last decade Afghanistan has made large investments in scaling up the number of midwives to address access to skilled care and the high burden of maternal and newborn mortality. at the request of the Ministry of Public Health (MOPH) an evaluation was undertaken to improve the pre-service midwifery education programme through identification of its strengths and weaknesses. The qualitative component of the evaluation specifically examined: (1) programme strengths; (2) programme weaknesses; (3) perceptions of the programme's community impact; (4) barriers to provision of care and challenges to impact; (5) perceptions of the recently graduated midwife's field experience, and (6) recommendations for programme improvement. the evaluation used a mixed methods approach that included qualitative and quantitative components. This paper focuses on the qualitative components which included in-depth interviews with 138 graduated midwives and 20 key informants as well as 24 focus group discussions with women. eight provinces in Afghanistan with functioning and accredited midwifery schools between June 2008 and November 2010. midwives graduated from one of the two national midwifery programmes: Institute of Health Sciences and Community Midwifery Education. Key informants comprised of stakeholders and female residents of the midwives catchment areas. midwives described overall satisfaction with the quality of their education. Midwives and stakeholders perceived that women were more likely to use maternal and child health services in communities where midwives had been deployed. Strengths included evidence-based content, standardised materials, clinical training, and supportive learning environment. Self-reported aspects of the quality education in respect to midwives empowerment included feeling competent and confident as demonstrated by respect shown by co-workers. Weaknesses of the programme included perceived low educational requirement to enter the programme and readiness of programmes to commence education. Insecurity and geographical remoteness are perceived as challenges with clients' access to care and the ability of midwives to make home visits. the depth of midwives' contribution in Afghanistan - from increased maternal health care service utilisation to changing community's perceptions of women's education and professional independence - is overwhelmingly positive. Lessons learned can serve as a model to other low resource, post-conflict settings that are striving to increase the workforce of skilled providers. 23757509 Alteration of the intestinal barrier and GLP2 secretion in Berberine-treated type 2 diabetic rats. For centuries, Berberine has been used in the treatment of enteritis in China, and it is also known to have anti-hyperglycemic effects in type 2 diabetic patients. However, as Berberine is insoluble and rarely absorbed in gastrointestinal tract, the mechanism by which it works is unclear. We hypothesized that it may act locally by ameliorating intestinal barrier abnormalities and endotoxemia. A high-fat diet combined with low-dose streptozotocin was used to induce type 2 diabetes in male Sprague Dawley rats. Berberine (100 mg/kg) was administered by lavage to diabetic rats for 2 weeks and saline was given to controls. Hyperinsulinemia and insulin resistance improved in the Berberine group, although there was no significant decrease in blood glucose. Berberine treatment also led to a notable restoration of intestinal villi/mucosa structure and less infiltration of inflammatory cells, along with a decrease in plasma lipopolysaccharide (LPS) level. Tight junction protein zonula occludens 1 (ZO1) was also decreased in diabetic rats but was restored by Berberine treatment. Glutamine-induced glucagon-like peptide 2 (GLP2) secretion from ileal tissue decreased dramatically in the diabetic group but was restored by Berberine treatment. Fasting insulin, insulin resistance index, plasma LPS level, and ZO1 expression were significantly correlated with GLP2 level. In type 2 diabetic rats, Berberine treatment not only augments GLP2 secretion and improves diabetes but is also effective in repairing the damaged intestinal mucosa, restoring intestinal permeability, and improving endotoxemia. Whether these effects are mechanistically related will require further studies, but they certainly support the hypothesis that Berberine acts via modulation of intestinal function. 23957789 Molecular signatures of mammalian hibernation: comparisons with alternative phenotypes. Mammalian hibernators display phenotypes similar to physiological responses to calorie restriction and fasting, sleep, cold exposure, and ischemia-reperfusion in non-hibernating species. Whether biochemical changes evident during hibernation have parallels in non-hibernating systems on molecular and genetic levels is unclear. We identified the molecular signatures of torpor and arousal episodes during hibernation using a custom-designed microarray for the Arctic ground squirrel (Urocitellus parryii) and compared them with molecular signatures of selected mouse phenotypes. Our results indicate that differential gene expression related to metabolism during hibernation is associated with that during calorie restriction and that the nuclear receptor protein PPARα is potentially crucial for metabolic remodeling in torpor. Sleep-wake cycle-related and temperature response genes follow the same expression changes as during the torpor-arousal cycle. Increased fatty acid metabolism occurs during hibernation but not during ischemia-reperfusion injury in mice and, thus, might contribute to protection against ischemia-reperfusion during hibernation. In this study, we systematically compared hibernation with alternative phenotypes to reveal novel mechanisms that might be used therapeutically in human pathological conditions. 23344447 Catalytic transformation of alcohols to carboxylic acid salts and H2 using water as the oxygen atom source. The oxidation of alcohols to carboxylic acids is an important industrial reaction used in the synthesis of bulk and fine chemicals. Most current processes are performed by making use of either stoichiometric amounts of toxic oxidizing agents or the use of pressurized dioxygen. Here, we describe an alternative dehydrogenative pathway effected by water and base with the concomitant generation of hydrogen gas. A homogeneous ruthenium complex catalyses the transformation of primary alcohols to carboxylic acid salts at low catalyst loadings (0.2 mol%) in basic aqueous solution. A consequence of this finding could be a safer and cleaner process for the synthesis of carboxylic acids and their derivatives at both laboratory and industrial scales. 23838298 Kaposi's Sarcoma and Pregnancy: Case Report and Literature Review. We report the observation of cutaneous Kaposi's sarcoma (KS) worsening during the second trimester of pregnancy in 2 African women. Both patients were tested seronegative for HIV. They had no complication during their pregnancy, and no evidence of extracutaneous disease was found, allowing therapeutic abstention. They gave birth to healthy children showing no clinical evidence of human herpesvirus 8 (HHV-8) infection. Based on these observations and on the review of the literature, we discuss the risk of vertical transmission of HHV-8 as well as the impact of pregnancy on KS. 23382381 Supervillin-mediated suppression of p53 protein enhances cell survival. Integrin-based adhesions promote cell survival as well as cell motility and invasion. We show here that the adhesion regulatory protein supervillin increases cell survival by decreasing levels of the tumor suppressor protein p53 and downstream target genes. RNAi-mediated knockdown of a new splice form of supervillin (isoform 4) or both isoforms 1 and 4 increases the amount of p53 and cell death, whereas p53 levels decrease after overexpression of either supervillin isoform. Cellular responses to DNA damage induced by etoposide or doxorubicin include down-regulation of endogenous supervillin coincident with increases in p53. In DNA-damaged supervillin knockdown cells, p53 knockdown or inhibition partially rescues the loss of cell metabolic activity, a measure of cell proliferation. Knockdown of the p53 deubiquitinating enzyme USP7/HAUSP also reverses the supervillin phenotype, blocking the increase in p53 levels seen after supervillin knockdown and accentuating the decrease in p53 levels triggered by supervillin overexpression. Conversely, supervillin overexpression decreases the association of USP7 and p53 and attenuates USP7-mediated p53 deubiquitination. USP7 binds directly to the supervillin N terminus and can deubiquitinate and stabilize supervillin. Supervillin also is stabilized by derivatization with the ubiquitin-like protein SUMO1. These results show that supervillin regulates cell survival through control of p53 levels and suggest that supervillin and its interaction partners at sites of cell-substrate adhesion constitute a locus for cross-talk between survival signaling and cell motility pathways. 23884172 Enantioselective synthesis of benzofurans and benzoxazines via an olefin cross-metathesis-intramolecular oxo-Michael reaction. Chiral phosphoric acid and Hoveyda-Grubbs II were found to catalyze an olefin cross-metathesis-intramolecular oxo-Michael cascade reaction of the ortho-allylphenols and enones to provide a variety of benzofuran and benzoxazine derivatives in moderate to good yields and enantioselectivity. 23938374 Clinical and toxicity predictors of response and progression to temsirolimus in women with recurrent or metastatic endometrial cancer. Temsirolimus (TEM) has recently shown activity (NCIC CTG phase II trial) in endometrial cancer (EC). Despite EC having a high rate of PTEN mutation, in this trial activity was independent of PTEN and other molecular markers. We explored whether treatment related toxicity occurring in cycle one was predictive of outcomes. Patients were those enrolled on two sequential phase II studies of the NCIC CTG that evaluated single agent TEM in women with recurrent or metastatic chemotherapy naïve or treated EC. An exploratory landmark analysis examined the relationship between early treatment related toxicities as well as prior chemotherapy and efficacy outcomes (response, progression, and tumor size shrinkage) in univariate and multivariate analyses. The relationship between molecular markers and outcomes was also reexamined in patients. Mucositis, diarrhea, decreased absolute neutrophil count, as well as elevated glucose, or cholesterol were not independent predictors of response or progression. Highest fasting triglyceride predicted for a 3.5% tumor shrinkage from baseline. Women previously treated with chemotherapy were at 7.37 times greater risk of progression and experienced 20.9% increased tumor growth compared to chemotherapy naïve women. Molecular markers were not predictors of response or progression. Except for elevation in fasting triglyceride being associated with minimal tumor shrinkage, no other relationship between efficacy and TEM induced adverse events was found. mTOR inhibition activity in EC seems greatest in chemo-naïve patients. Future studies of mTOR inhibitors in EC should focus on women without prior chemotherapy while continuing to explore molecular mechanisms of benefit. 23354525 Trichomonas vaginalis infection in men who submit self-collected penile swabs after internet recruitment. Submission of self-collected penile samples collected at home could remove barriers that men face in getting tested for sexually transmitted infections (STIs). From December 2006 to July 2012, sexually active men aged ≥14 years were recruited by an educational internet program (http://www.iwantthekit.org) which offered free testing for Trichomonas vaginalis infection. Kits were ordered online and swabs were sent via US mail to the laboratory and tested by nucleic acid amplification tests. Demographics and sexual risk factors were accessed by questionnaires. Men called or were contacted to receive their results. Risk factors for trichomonas infection were determined by multivariate logistic regression Of 4398 men requesting kits, 1699 (38.6%) returned swabs by mail (55.4% returned in 2012). Forty-one percent of men were aged <25 years, 43% were black subjects and 45% were white. The overall prevalence for trichomonas in the 1699 men was 3.7%; the highest prevalence by age group was for men aged 40-49 years (5.2%) and, by year, 216 men screened in 2008 had the highest prevalence (12.5%). Risk factors for 919 men whose risk information was collected by questionnaire (prevalence 6.0%) indicated that 9.6% had a concurrent chlamydia infection. Significantly associated risks factors included: black race (adjusted OR 2.67), residence in Illinois (OR 12.02), age 30-39 years (OR 6.63) and age >40 years (OR 5.31). A fairly high prevalence of trichomonas and sexual risk factors were demonstrated from internet recruitment of men. This method of engaging men to get screened for trichomonas may augment screening in STI clinics. 23756167 Association of interleukin (IL)-4 gene intron 3 VNTR polymorphism with multiple sclerosis in Turkish population. Genetic risk factors are known to contribute to the etiology of multiple sclerosis (MS). Interleukin (IL)-4 gene polymorphisms have been associated with immune-mediated diseases. The aim of this study was to explore the frequency of IL-4 gene intron 3 VNTR (variable number tandem repeat) polymorphism in a cohort of Turkish patients with MS. The study included 125 patients with MS and 160 healthy controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR) analyses for the IL-4 gene intron 3 VNTR polymorphism. The distribution of genotype and allele frequencies of IL-4 gene intron 3 VNTR polymorphism was statistically different between MS patients and control group (p=0.003 and p=0.002, respectively). There were no statistically significant association between IL-4 VNTR polymorphism and clinical and demographical characteristics of MS patients. The results of this study suggest that intron 3 VNTR polymorphism of the IL-4 gene was positively associated with predisposition to develop MS in Turkish population. 23913620 Phase contrast without phase plates and phase rings-optical solutions for improved imaging of phase structures. Using the optical methods described, phase specimens can be observed with a modified light microscope in enhanced clarity, purified from typical artifacts which are apparent in standard phase contrast illumination. In particular, haloing and shade-off are absent, lateral and vertical resolution are maximized and the image quality remains constant even in problematic preparations which cannot be well examined in normal phase contrast, such as specimens beyond a critical thickness or covered by obliquely situated cover slips. The background brightness and thus the range of contrast can be continuously modulated and specimens can be illuminated in concentric-peripheral, axial or paraxial light. Additional contrast effects can be achieved by spectral color separation. Normal glass or mirror lenses can be used; they do not need to be fitted with a phase plate or a phase ring. The methods described should be of general interest for all disciplines using phase microscopy. Microsc. Res. Tech., 2013. © 2013 Wiley Periodicals, Inc. 23588305 Emerging Transporters of Clinical Importance: An Update from the International Transporter Consortium. The International Transporter Consortium (ITC) has described recently seven transporters of particular relevance for drug development (Giacomini et al., Nat. Rev. Drug Discov. 9: 215-236, 2010). Based on the second ITC transporter workshop in 2012, we have identified additional transporters of emerging importance in pharmacokinetics, interference of drugs with transport of endogenous compounds and drug-drug interactions in humans. The multidrug and toxin extrusion proteins (MATEs, gene symbol SLC47A) mediate excretion of organic cations into bile and urine. MATEs are important in renal drug-drug interactions. Multidrug resistance proteins (MRPs or ABCCs) are drug and conjugate efflux pumps, and impaired activity of MRP2 results in conjugated hyperbilirubinemia. The bile salt export pump (BSEP or ABCB11) prevents accumulation of toxic bile salt concentrations in hepatocytes, and BSEP inhibition or deficiency may cause cholestasis and liver injury. Additionally, examples are presented on the roles of nucleoside and peptide transporters in drug targeting and disposition.Clinical Pharmacology & Therapeutics (2013); accepted article preview online 8 April 2013 doi:10.1038/clpt.2013.74. 23537203 Molecular Mechanism of the Inhibition of EGCG on the Alzheimer Aβ1-42 Dimer. Growing evidence supports that amyloid β (Aβ) oligomers are the major causative agents leading to neural cell death in Alzheimer's disease. The polyphenol (-)-epigallocatechin gallate (EGCG) was recently reported to inhibit Aβ fibrillization and redirect Aβ aggregation into unstructured, off-pathway oligomers. Given the experimental challenge to characterize the structures of Aβ/EGCG complexes, we performed extensive atomistic replica exchange molecular dynamics simulations of Aβ1-42 dimer in the present and absence of EGCG in explicit solvent. Our equilibrium Aβ dimeric structures free of EGCG are consistent with the collision cross section from ion-mobility mass spectrometry and the secondary structure composition from circular dichroism experiment. In the presence of EGCG, the Aβ structures are characterized by increased inter-center-of-mass distances, reduced interchain and intrachain contacts, reduced β-sheet content, and increased coil and α-helix contents. Analysis of the free energy surfaces reveals that the Aβ dimer with EGCG adopts new conformations, affecting therefore its propensity to adopt fibril-prone states. Overall, this study provides, for the first time, insights on the equilibrium structures of Aβ1-42 dimer in explicit aqueous solution and an atomic picture of the EGCG-mediated conformational change on Aβ dimer. 23755994 Enhanced adsorption of hydrogen sulfide on mixed zinc/cobalt hydroxides: effect of morphology and an increased number of surface hydroxyl groups. Mixed zinc and cobalt hydroxides were synthesized using a precipitation method and tested as adsorbents of hydrogen sulfide from either dry or moist air. The adsorption capacity increased with an increase in the content of cobalt in the structure of mixed hydroxides. The synergistic effect was demonstrated by a fourfold increase in the amount of hydrogen sulfide adsorbed on the surface of the best performing mixed hydroxide in comparison with the hypothetical mixture of the two hydroxides. The initial and exhausted materials were characterized by FTIR, thermal analysis, potentiometric titration, X-ray diffraction, SEM/EDX, and adsorption of nitrogen. The results obtained suggest that an increase in the content of cobalt results in an increase in amorphicity level and in an increase in the number of hydroxyl groups. These groups, besides providing higher basicity thereby increasing the extent of H2S dissociation in the presence of water, are the main active centers reacting with hydrogen sulfide. Defects in the structure and oxygen vacancies result in the oxidation of some H2S to sulfites and sulfates. 23041257 Apoptosis induced neurotoxicity of Di-n-butyl-di-(4-chlorobenzohydroxamato) Tin (IV) via mitochondria-mediated pathway in PC12 cells. The severe toxicity of antitumor organotin (IV) compounds limits their application in clinic, however, the toxic mechanism is still unclear. Di-n-butyl-di-(4-chlorobenzohydroxamato) Tin (IV) (DBDCT), an antitumor agent with high activity and obvious neurotoxicity was chosen as a typical diorganotin (IV) compound to investigate its neurotoxic mechanism using PC12 cells and comprehensive methods. Treatment with DBDCT resulted in a dose- and time-dependent growth inhibition of PC12 cells. The changes in cell morphology were observed using light microscopy, fluorescence microscopy and transmission electron microscopy. PC12 cell apoptosis induced by DBDCT was confirmed by annexin V/propidium iodide staining, and characterized by cleavage of caspase-9 and caspase-3 proteins. DBDCT induced the release of cytochrome c from the mitochondria to the cytosol and the generation of reactive oxygen species. DBDCT up-regulated the expression of Bax, down-regulated the expression of Bcl-2, and significantly increased the ratio of Bax/Bcl-2. DBDCT also caused the phosphorylation of JNK and p38(MAPK). In rats exposed to DBDCT, apoptosis was also observed in brain, as shown by the detection of cleaved caspase-9 and caspase-3 proteins and increased TUNEL positive staining. In conclusion, the results demonstrated that DBDCT caused the neurotoxicity by inducing apoptosis via mitochondria-mediated pathway. 23468187 Feasibility of reduced-intensity allogeneic stem cell transplantation with imatinib in children with philadelphia chromosome-positive acute lymphoblastic leukemia. Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) in children is one of the highest-risk ALL groups. Improved outcome in combination with imatinib has been reported. However, intensive chemotherapy or myeloablative conditioning followed by hematopoietic stem cell transplantation (HSCT) can be associated with significant adverse late effects. We report a case series of five children with Ph + ALL underwent reduced-intensity allogeneic HSCT (RIST) after induction and consolidation in chemotherapy combined with imatinib. Four of the five patients remain first complete remission for a median of 3.1 years after RIST. These results are preliminary, but suggest the feasibility and effectiveness of RIST with imatinib. 23895703 Phospholamban Antisense RNA Improves SR Ca2+-ATPase Activity and Left Ventricular Function in STZ-induced Diabetic Rats. To study the effect of phospholamban antisense RNA (asPLB) on sarcoplasmic reticulum Ca2+-ATPase activity and cardiac function in rats with diabetes mellitus (DM) mediated by recombinant adeno-associated virus (rAAV) vector. Six weeks after the induction of DM by streptozotocin injected intraperitoneally, the rats were divided into three groups, namely: DM-rAAV-asPLB group, DM-saline group and DM group (control group). The rats in the DM-rAAV-asPLB group were intramyocardially injected with rAAV-asPLB, the rats in the DM-saline group were injected with saline, and those in the control group did not receive any treatment. Six weeks after gene transfer, the expressions of PLB protein and PLB phosphorylation were detected by Western-blot, while the activity of sarcoplasmic reticulum (SR) Ca2+-ATPase and left ventricular function were measured. The PLB protein expression level was significantly higher whereas the PLB phosphorylation, SR Ca2+-ATPase activity and left ventricular function were significantly lower in the DM-saline group than in the control group. No significant difference was found in PLB protein expression level, PLB phosphorylation or SR Ca2+-ATPase activity between the DM-rAAV-asPLB group and the control group. The left ventricular function in the DM-rAAV-asPLB group was poorer than in the control group and was better than in the DM-saline group. rAAV-asPLB can down-regulate PLB protein expression and up-regulate PLB phosphorylation and SR Ca2+-ATPase activity, thus contributing to the improvement of in vivo left ventricular function. 23782941 Leptin action in the ventromedial hypothalamic nucleus is sufficient, but not necessary, to normalize diabetic hyperglycemia. In rodent models of type 1 diabetes, leptin administration into brain ventricles normalizes blood glucose at doses that have no effect when given peripherally. The ventromedial nucleus of the hypothalamus (VMN) is a potential target for leptin's antidiabetic effects because leptin-sensitive neurons in this brain area are implicated in glucose homeostasis. To test this hypothesis, we injected leptin directly into the bilateral VMN of rats with streptozotocin-induced uncontrolled diabetes mellitus. This intervention completely normalized both hyperglycemia and the elevated rates of hepatic glucose production and plasma glucagon levels but had no effect on tissue glucose uptake in the skeletal muscle or brown adipose tissue as measured using tracer dilution techniques during a basal clamp. To determine whether VMN leptin signaling is required for leptin-mediated normalization of diabetic hyperglycemia, we studied mice in which the leptin receptor gene was deleted in VMN steroidogenic factor 1 neurons using cre-loxP technology. Our findings indicate leptin action within these neurons is not required for the correction of diabetic hyperglycemia by central leptin infusion. We conclude that leptin signaling in the VMN is sufficient to mediate leptin's antidiabetic action but may not be necessary for this effect. Leptin action within a distributed neuronal network may mediate its effects on glucose homeostasis. 23409747 Erythrocyte membrane-cloaked polymeric nanoparticles for controlled drug loading and release. Aim: Polymeric nanoparticles (NPs) cloaked by red blood cell membrane (RBCm) confer the combined advantage of both long circulation lifetime and controlled drug release. The authors carried out studies to gain a better understanding of the drug loading, drug-release kinetics and cell-based efficacy of RBCm-cloaked NPs. Materials & methods: Two strategies for loading doxorubicin into the RBCm-cloaked NPs were compared: physical encapsulation and chemical conjugation. In vitro efficacy was examined using the acute myeloid leukemia cell line, Kasumi-1. Results: It was found that the chemical conjugation strategy resulted in a more sustained drug release profile, and that the RBCm cloak provided a barrier, retarding the outward diffusion of encapsulated drug molecules. It was also demonstrated that RBCm-cloaked NPs exhibit higher toxicity in comparison with free doxorubicin. Conclusion: These results indicate that the RBCm-cloaked NPs hold great promise to become a valuable drug-delivery platform for the treatment of various diseases such as blood cancers. Original submitted 27 February 2012; Revised submitted 27 August 2012; Published online 14 February 2013. 23844867 Randomized in vivo trial evaluating plaque inhibition benefits of an advanced stannous-containing sodium fluoride dentifrice used in conjunction with power brush technology. To compare the plaque inhibition efficacy of a novel stannous-containing sodium fluoride test dentifrice to a standard anticavity negative control dentifrice, when both were used in conjunction with an advanced oscillating-rotating (O/R) power toothbrush. This was a randomized, two-treatment, three-period, double-blind crossover study conducted in a population using an O/R power brush. Subjects brushed twice per day with their assigned dentifrice during the three-treatment periods, each lasting for 17 consecutive days. Each period was separated by a 4-day washout period during which subjects continued to use their O/R power toothbrush. Plaque levels were assessed and averaged amongst three assessments taken on days 15, 16 and 17 at the end of each treatment period using digital plaque imaging analysis. Assessments were carried out on the facial anterior tooth surfaces in the morning before brushing (A.M. prebrush) following whole-mouth brushing (30 s per quadrant) with the assigned dentifrice (A.M. post-brush) and in the afternoon (P.M.). Twenty-seven subjects were randomized and completed the study. During the 17-day usage period, the stannous-containing test NaF dentifrice demonstrated a statistically significant lower mean plaque area versus the negative control dentifrice at each assessment timepoint; overnight A.M. prebrush was 33.8% lower (P < 0.0001), A.M. post-brush was 21.8% lower (P < 0.01), and P.M. was 29.2% lower (P < 0.0001). A population of O/R power toothbrush users had significantly less plaque coverage for all three measurements when using a stannous-containing NaF dentifrice than when using a negative control (fluoride) dentifrice. 23875803 The Genetics of Melanoma: Recent Advances. Cutaneous malignant melanoma results from the interplay of genetic, host, and environmental factors. Genetic factors implicated in melanoma etiology include inherited high-, intermediate-, and low-risk susceptibility genes as well as numerous somatic mutations in melanoma tumors. CDKN2A is the major high-risk melanoma susceptibility gene identified to date. Recent identification of low-risk loci has been accomplished predominantly through genome-wide association studies. Whole-exome and whole-genome studies have identified numerous genes somatically altered in melanoma tumors and highlighted a higher mutation load in melanoma tumors compared with those in other cancers. This higher load is believed to be attributable to the preponderance of thymine-to-cytosine nucleotide substitutions as a result of UV radiation exposure. Technological advances, particularly next-generation sequencing, have increased the opportunities for germline and somatic gene discovery in melanoma and are opening up new avenues for understanding melanoma pathogenesis as well as leading to new opportunities for treatment. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 14 is August 31, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates. 23399382 Nicotine enhances antisaccade performance in schizophrenia patients and healthy controls. Nicotine has been proposed to be a cognitive enhancer, particularly in schizophrenia patients. So far, the published studies of nicotine effects on antisaccade performance in schizophrenia patients only tested participants who were deprived smokers. Thus, we aimed to test both smoking and non-smoking patients as well as healthy controls in order to extend previous findings. Moreover, we employed a paradigm using standard and delayed trials. We hypothesized that, if nicotine is a genuine cognitive enhancer, its administration would improve antisaccade performance both in smoking and non-smoking participants. A total of 22 patients with schizophrenia (12 smokers and 10 non-smokers) and 26 controls (14 smokers and 12 non-smokers) completed the study. The effects of a nicotine patch (14 mg for smokers, 7 mg for non-smokers) on antisaccade performance were tested in a randomized, double-blind, placebo-controlled, cross-over trial. Schizophrenia patients made significantly more antisaccade errors than controls (p = 0.03). Both patients and controls made fewer antisaccade errors in the delayed trials than in the standard trials (p < 0.0001). Nicotine significantly reduced antisaccade error rate in the standard trials, but not in the delayed trials (p = 0.02). Smoking status did not influence the nicotine effect on antisaccade error rate (p = 0.10) indicating an equal procognitive effect of nicotine in smokers and non-smokers. Overall the present findings indicate that beneficial effects of nicotine on antisaccade performance are not confined to smoking schizophrenia patients. Instead, the findings likely represent genuine nicotine-induced enhancement of cognitive performance. 23726552 Snapin accelerates exocytosis at low intracellular calcium concentration in mouse chromaffin cells. Snapin associates with SNAP-25 and with assembled SNARE complexes, stabilizing the coupling between Synaptotagmin-1 and SNAP-25. Deletion of Snapin reduces releasable pools of vesicles in chromaffin cells and reduces synchronous release of neurotransmitter in cortical neurons. Snapin deletion leads to a deficit in exocytosis at low calcium concentration with no change in the threshold calcium concentration for exocytosis in chromaffin cells. In order to determine whether Snapin deletion alters release rates or calcium dependence, we examined the effect of overexpression of wild type Snapin on readily releasable pool kinetics and pool size in mouse chromaffin cells. Modest increases in intracellular calcium induced by flash-photolysis unmasked a rapidly releasing component of secretion which was enhanced when Snapin was overexpressed. This result indicates that Snapin allows rapid release at lower intracellular calcium levels at which release of the remaining RRP occurs more slowly. 23685277 What causes relapses of autoimmune diseases? The etiological role of autoreactive T cells. Most human autoimmune diseases have a relapsing-remitting or a chronic progressive course, while animal models are usually acute and monophasic. In our experimental animal model the disease can be either monophasic or remitting, depending on the autoantigen used for induction, and it appears to lie in the effector phenotype of the elicited T helper cell response. Since both, monophasic and relapsing courses of disease are induced by immunization as well as by adoptive transfer of peptide-specific, CD4(+) T cells, we were able to directly compare the transcriptomes of pathogenic T cell lines by gene array analysis and qPCR as well as protein expression. Upregulated genes were only determined in T cells inducing relapsing uveitis and belong to certain pathways of antigen presentation, activation, inflammation, migration and survival, comprising WNT, Hedgehog, MAP-kinase and JAK/STAT-pathways. These pathways are partially interacting with each other, and the central molecule upregulated in T cells causing relapsing disease was found to be IFN-γ. Here the course of the autoimmune diseases strictly depends on the characteristics of the autoreactive T cells, which are already determined at their early stage of antigen-specific activation. Our rat models of experimental autoimmune uveitis could help elucidating the immune mechanisms behind relapsing autoimmunity in order to develop better therapeutic strategies. 22522972 Stratified medicine in psychiatry: a worrying example or new opportunity in the treatment of anxiety? Stratified medicine is a new term that figures highly in current MRC and NHS strategy. It has developed from the earlier terms individualised or personalised medicine and refers to the use of genetic and/or endophenotypic measures to allow better targeting of treatments. The best exemplar is HER2 positivity in breast cancer to determine the efficacy of Herceptin. Clinical trials of this anti-cancer drug were initially unpromising, but once the HER2 positive subgroup was identified it was found, in this subgroup only, to be highly effective. It is presumed that similar subgroups will be found for many common disorders not just cancers, and that these will lead to much better targeted treatments. Such an advance may be necessary to develop new treatments in certain fields where the development of broad-spectrum/blockbuster treatments appears to have reached the end of the road; a particular example of this is in psychiatry. In this paper we discuss this issue in relation to psychiatry using a new and interesting example of how genotyping might help rescue an apparently failed novel treatment in anxiety disorders. 23960050 Intravitreal bevacizumab for the treatment of retinopathy of prematurity: a case report. We report the first case in Scotland of a premature infant treated for retinopathy of prematurity with bevacizumab. A case report and a review of the literature are presented. Retinopathy of prematurity is a leading worldwide cause of childhood blindness. Conventional laser treatment results in destruction of the peripheral retina and does not prevent all cases of vision loss, particularly in Zone I disease. We present the case of a baby born at 26(+3) weeks who developed stage 3+ disease located in Zone I of the retina. The patient was treated with bilateral bevacizumab injections and achieved complete resolution of his retinopathy. Bevacizumab therapy for the treatment of retinopathy of prematurity is an effective and inexpensive treatment that can readily and quickly be administered by a competent ophthalmologist without the need for specialist equipment. 22760160 Bilateral abdominoscrotal hydrocele in a 5-month-old infant presented with a left leg edema and cyanosis. A 5-month-old infant presented with bilateral abdominoscrotal hydroceles since birth and left leg edema and cyanosis. An ultrasound of the abdomen showed a cystic mass. Computed tomography showed a fluid filled mass extending intra-abdominally through the inguinal canal from the scrotum. A bilateral hydrocelectomy was performed, and the proximal sac was completely excised through the inguinal incision. The edema of the left leg resolved 2 days after surgery. The postoperative course was uneventful, without complication. 23811515 Host Association of Cryptosporidium parvum Populations Infecting Domestic Ruminants in Spain. A stock of 148 Cryptosporidium parvum DNA extracts from lambs and goat kids selected from a previous study examining the occurrence of Cryptosporidium species and GP60 subtypes in diarrheic lambs and goat kids in northeastern Spain was further characterized by a multilocus fragment typing approach with six mini- and microsatellite loci. Various degrees of polymorphism were seen at all but the MS5 locus, although all markers exhibited two major alleles accounting for more than 75% of isolates. A total of 56 multilocus subtypes (MLTs) from lambs (48 MLTs) and goat kids (11 MLTs) were identified. Individual isolates with mixed MLTs were detected on more than 25% of the farms, but most MLTs (33) were distinctive for individual farms, revealing the endemicity of cryptosporidial infections on sheep and goat farms. Comparison with a previous study in calves in northern Spain using the same six-locus subtyping scheme showed the presence of host-associated alleles, differences in the identity of major alleles, and very little overlap in MLTs between C. parvum isolates from lambs and those from calves (1 MLT) or isolates from lambs and those from goat kids (3 MLTs). The Hunter-Gaston index of the multilocus technique was 0.976 (95% confidence interval [CI], 0.970 to 0.982), which supports its high discriminatory power for strain typing and epidemiological tracking. Population analyses revealed the presence of two host-associated subpopulations showing epidemic clonality among the C. parvum isolates infecting calves and lambs/goat kids, respectively, although evidence of genetic flow between the two subpopulations was also detected. 23940079 Changes in the NMR characteristics of 3,6-di-tert-butylquinone on formation of paramagnetic complexes. High-resolution NMR spectra of 3,6-di-tert-butylquinone were recorded and analyzed for the first time in a wide range of temperatures. The spectra were transformed by paramagnetic additives of cobalt, nickel, and copper complexes synthesized on the basis of metal semiquinolates. Chloroform, dimethylsulfoxide, toluene, and acetone were used as solvents. It was shown that the spectra changed by paramagnetic additives can contain valuable information on the nature of a superfine interaction in paramagnetic complexes and on peculiarities of intramolecular dynamics inherent in these compounds. Copyright © 2013 John Wiley & Sons, Ltd. 23822155 Determinants of maternal health care utilization in Holeta town, central Ethiopia. In developing countries a large number of women are dying due to factors related to pregnancy and child birth. Implementing and assuring utilization of maternal health care services is potentially one of the most effective health interventions for preventing maternal morbidity and mortality. However, in Ethiopia the utilization of maternal health care is low. A cross-sectional study was conducted from January 20 to February 20, 2012 in Holeta town, central Ethiopia, to assess the determinants of maternal health care utilization among women who had given birth in the past three years prior to the survey. Structured questionnaire and focus group discussion guides were used for data collection. Data were collected from a sample of 422 women in the town. Descriptive, bivariate and multivariate logistic regression analyses were conducted. Statistical tests were done at a level of significance of p < 0.05. The study revealed that 87% of the women had at least one antenatal visit during their last pregnancy. Among the antenatal service users, 33.7% had less than four antenatal visits. More than half of the antenatal care (ANC) attendants made their first visit during their second and third trimester of pregnancy although WHO recommended ANC should be started at the first trimester of the pregnancy. There was a significant association (P<0.05) between ANC attendance and some demographic, socio-economic and health related factors (age at last birth, literacy status of women, average monthly family income, media exposure, attitude towards pregnancy, knowledge on danger signs of pregnancy and presence of husband approval on ANC). The study also revealed that about 61.6% of the women had given birth in the health institutions. Parity, literacy status of women, average monthly family income, media exposure, decision where to give birth, perception of distance to health institutions (HI) and ANC attendance were found to be significantly associated (P<0.05) with delivery care (DC) attendance. The utilization of ANC and DC service is inadequate in the town. The utilization of ANC and DC were influenced by demographic, socio-economic and health related factors. Improving the status of women by expanding educational opportunities, strengthening promotion of antenatal and delivery care by enhancing community awareness about the importance of ANC and DC are recommended. 23919955 Profile and predictors of global distress: Can the DT guide nursing practice in prostate cancer? Objective: This study examines the ability of the distress thermometer to accurately identify patients with higher symptoms, unmet needs and psychological morbidity. Methods: Baseline data collected as part of a randomized controlled trial evaluating a nurse-led supportive care intervention for men with prostate cancer commencing radiotherapy at a specialist cancer hospital in Melbourne, Australia. Measures assessed global distress (DT), anxious and depressive symptomatology (HADS), prostate-cancer specific quality of life (EPIC-26), unmet supportive care needs (SCNS-SF34R) and cancer treatment-related concerns (CATS). Following descriptive and correlational analysis, hierarchical multiple regression was employed to examine the contribution of variable sets to explaining variance in DT scores. Results: Less than 20% of men reported DT scores of 4 or higher, indicating overall low distress. The DT accurately identified almost all men reporting HADS score indicative of anxious or depressive symptomatology, suggesting it accurately identifies psychological morbidity. Importantly, the DT identified a further group of distressed men, not identified by HADS, whose distress related to unmet needs and prostate cancer-specific issues, indicating the DT is superior in identifying other forms of distress. While the hierarchical multiple regression confirmed anxious and depressive symptomatology as the best predictor of distress score, many other scales are also good predictors of DT scores, supporting the argument that distress is multi-determined. Significance of results: Nurses can be confident that the DT accurately identifies patients with psychological morbidity and importantly identifies other patients with distress who may require intervention. A distress score of 4 or higher identified participants with higher physical symptomatology, higher unmet needs, more concerns about treatment and poorer quality of life. The low prevalence of distress reaching cut off scores suggests nurses would not be overwhelmed by the outcomes of screening and could use the score to prioritise the patients who need greater attention at entry to radiotherapy services. 23508847 Issues, challenges, and opportunities in model-based drug development for monoclonal antibodies. Over the last two decades, there has been a simultaneous explosion in the levels of activity and capability in both monoclonal antibody (mAb) drug development and in the use of quantitative pharmacologic models to facilitate drug development. Both of these topics are currently areas of great interest to academia, the pharmaceutical and biotechnology industries, and to regulatory authorities. In this article, we summarize convergence of these two areas and discuss some of the current and historical applications of the use of mathematical-model-based techniques to facilitate the discovery and development of mAb therapeutics. We also consider some of the current issues and limitations in model-based antibody discovery/development and highlight areas of further opportunity. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2898-2908, 2013. 23969693 Zebrafish cancer: the state of the art and the path forward. The zebrafish is a recent addition to animal models of human cancer, and studies using this model are rapidly contributing major insights. Zebrafish develop cancer spontaneously, after mutagen exposure and through transgenesis. The tumours resemble human cancers at the histological, gene expression and genomic levels. The ability to carry out in vivo imaging, chemical and genetic screens, and high-throughput transgenesis offers a unique opportunity to functionally characterize the cancer genome. Moreover, increasingly sophisticated modelling of combinations of genetic and epigenetic alterations will allow the zebrafish to complement what can be achieved in other models, such as mouse and human cell culture systems. 22713812 A newly identified locus for benign adult familial myoclonic epilepsy on chromosome 3q26.32-3q28. Benign Adult Familial Myoclonic Epilepsy (BAFME) is an autosomal dominant disorder characterized by adult-onset cortical tremor or action myoclonus predominantly in the upper limbs, and generalized seizures. We investigated a Thai BAFME family. Clinical and electrophysiological studies revealed that 13 were affected with BAFME. There were a total of 24 individuals studied. Genetic analysis by genome-wide linkage study (GWLS) was performed using 400 microsatellite markers and excluded linkage of the previous BAFME loci, 8q23.3-q24.1, and 2p11.1-q12.2. GWLS showed that the disease-associated region in our Thai family was linked to a newly identified locus on chromosome 3q26.32-3q28. This locus represents the fourth chromosomal region for BAFME. 23280061 The dynamics of infection and the persistence of immunity to A(H1N1)pdm09 virus in Israel. Influenza virus A(H1N1)pdm09 first appeared in Israel in late April 2009, disappeared in mid-March 2010, and reappeared in late October 2010. Symptoms were mostly mild without need for medical care. To provide targets for future pandemic preparedness and response by evaluating the dynamics and cumulative incidence of A(H1N1)pdm09 infection, the virus-specific seroprevalence (HI antibody titer >1:40) at the height of the pandemic, during its decline and thereafter. A cross-sectional seroepidemiological study was conducted on 6911 serum samples collected before, during, and after the pandemic. Cumulative incidence of infection derived from the differences between post- and pre-pandemic seroprevalence was 54·1%, 32·9%, 22·9%, 14·8%, and 6·3% in age-groups 0-9, 10-19, 20-49, 50-79, and ≥80 years, respectively, and 28·5% for all age-groups combined. Vaccination could have contributed at the most 4·6% to the post-pandemic population seroprevalence. High pre-pandemic immune response (47·4%) found in a cohort aged 15-18 year was strongly associated with birth years 1990-1993. Morbidity began to decline in mid-November 2009 at 32·8% population seroprevalence (45% in ages 0-19 year) and stopped in March 2010 at 43·4% population seroprevalence in February 2010 (70% in ages 0-19 year). Between February and September 2010, seroprevalence declined by 12·2% allowing virus recirculation from October 2010. Our study provides targets for controlling future influenza pandemics in Israel. Vaccination should focus on the younger age-groups (0-19 year) which played a key role in transmission of the A(H1N1)pdm09 due to lack of background immunity (ages 0-9 year) and high exposure rates (ages 10-19 year). 23483722 Comparison of different MRI sequences in lesion detection and early response evaluation of diffuse large B-cell lymphoma - a whole-body MRI and diffusion-weighted imaging study. To compare different MRI sequences for the detection of lesions and the evaluation of response to chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL), 18 patients with histology-confirmed DLBCL underwent 3-T MRI scanning prior to and 1 week after chemotherapy. The MRI sequences included T1 -weighted pre- and post-contrast, T2 -weighted with and without fat suppression, and a single-shot echo-planar diffusion-weighted imaging (DWI) with two b values (0 and 800 s/mm(2) ). Conventional MRI sequence comparisons were performed using the contrast ratio between tumor and normal vertebral body instead of signal intensity. The apparent diffusion coefficient (ADC) of the tumor was measured directly on the parametric ADC map. The tumor volume was used as a reference for the evaluation of chemotherapy response. The mean tumor volume was 374 mL at baseline, and decreased by 65% 1 week after chemotherapy (p < 0.01). The T2 -weighted image with fat suppression showed a significantly higher contrast ratio compared with images from all other conventional MRI sequences, both before and after treatment (p < 0.01, respectively). The contrast ratio of the T2 -weighted image with fat suppression decreased significantly (p < 0.01), and that of the T1 -weighted pre-contrast image increased significantly (p < 0.01), after treatment. However, there was no correlation between the change in contrast ratio and tumor volume. The mean ADC value was 0.68 × 10(-3) mm(2) /s at baseline; it increased by 89% after chemotherapy (p < 0.001), and the change in ADC value correlated with the change in tumor volume (r = 0.66, p < 0.01). The baseline ADC value also correlated inversely with the percentage change in ADC after treatment (r = -0.62, p < 0.01). In conclusion, this study indicates that T2 -weighted imaging with fat suppression is the best conventional sequence for the detection of lesions and evaluation of the efficacy of chemotherapy in DLBCL. DWI with ADC mapping is an imaging modality with both diagnostic and prognostic value that could complement conventional MRI. Copyright © 2013 John Wiley & Sons, Ltd. 23720160 Development of an SDS-gel electrophoresis method on SU-8 microchips for protein separation with LIF detection: Application to the analysis of whey proteins. This work describes the development of an SDS-gel electrophoresis method for the analysis of major whey proteins (α-lactalbumin, β-lactoglobulin, and BSA) carried out in SU-8 microchips. The method uses a low-viscosity solution of dextran as a sieving polymer. A commercial coating agent (EOTrol LN) was added to the separation buffer to control the EOF of the chips. The potential of this coating agent to prevent protein adsorption on the walls of the SU-8 channels was also evaluated. Additionally, the fluorescence background of the SU-8 material was studied to improve the sensitivity of the method. By selecting an excitation wavelength of 532 nm at which the background fluorescence remains low and by replacing the mercury arc lamp by a laser in the detection system, an LOD in the nanomolar range was achieved for proteins derivatized with the fluorogenic reagent Chromeo P540. Finally, the method was applied to the analysis of milk samples, demonstrating the potential of SU-8 microchips for the analysis of proteins in complex food samples. 23850022 Further isolation of Mycobacterium abscessus subsp. abscessus and subsp. bolletii in different regions of Japan and susceptibility of these isolates to antimicrobial agents. The aim of this study was to genetically analyse Mycobacterium abscessus subsp. abscessus (hereafter M. abscessus) and M. abscessus subsp. bolletii (hereafter M. bolletii) isolates from six different regions of Japan and to determine the antimicrobial susceptibility of these isolates. Subspeciation of 143 clinical isolates of M. abscessus group was done by comparative sequence analysis of the rpoB and hsp65 genes and the internal transcribed spacer (ITS) region. Genetic analysis led to the identification of 90 M. abscessus (62.9%) and 53 M. bolletii (37.1%; comprising 50 'M. massiliense' and 3 'M. bolletii' in the old nomenclature). No significant differences were found between the M. abscessus and M. bolletii isolates in any characteristics. Susceptibility to clarithromycin and linezolid for M. bolletii isolates was significantly higher than that for M. abscessus (P<0.05). Moreover, the results demonstrated that 82 M. abscessus isolates with T28 sequevar were resistant to clarithromycin owing to the expression of erm(41), which was induced by clarithromycin, whilst 8 isolates with C28 sequevar were susceptible. Acquired clarithromycin resistance in 'M. bolletii' isolates was significantly associated with previous Mycobacterium avium complex (MAC) treatment compared with that of M. abscessus isolates; however, intrinsic inducible susceptibility of M. abscessus isolates was not associated with MAC treatment. However, acquired resistance to clarithromycin by mutation in the rrl gene encoding 23S rRNA did not occur in 14 of 18 resistant isolates. Strains with acquired resistance to clarithromycin and mutation in rrl consisted of two M. bolletii (one 'M. massiliense' and one 'M. bolletii') and two M. abscessus T28 sequevar. 23788633 Caspase substrates and inhibitors. Caspases are proteases at the heart of networks that govern apoptosis and inflammation. The past decade has seen huge leaps in understanding the biology and chemistry of the caspases, largely through the development of synthetic substrates and inhibitors. Such agents are used to define the role of caspases in transmitting life and death signals, in imaging caspases in situ and in vivo, and in deconvoluting the networks that govern cell behavior. Additionally, focused proteomics methods have begun to reveal the natural substrates of caspases in the thousands. Together, these chemical and proteomics technologies are setting the scene for designing and implementing control of caspase activity as appropriate targets for disease therapy. 23880455 A comparison of immediate postoperative rigid and soft dressings for below-knee amputations. A variety of postsurgical dressings are used after a below-knee amputation (BKA), but there is no evidence-based guideline on which dressing to use. The purpose of this study was to compare the application of immediate postoperative rigid dressings or soft dressings on the healing times of BKA. In this retrospective analysis we compared 151 patients who underwent BKA from 2000 to 2012 at Yale New Haven Hospital. Patient demographics were collected and the type of postoperative dressing utilized was recorded. Ninety-one patients received a rigid plaster or plastic dressing and 60 received a soft gauze dressing with knee immobilizer. Time was measured between amputation and initial casting of prosthesis. Average age for the rigid dressing group was 58.6 years, with 78.2% presenting with diabetes mellitus, compared with the soft dressing group of 61.0 years, with 82.8%, respectively. Using a Kaplan-Meier analysis, patients fit with a rigid dressing demonstrated significantly decreased healing time from BKA to initial casting for a prosthesis (P = 0.02). After the first 60 days, 58.24% of patients who received a rigid dressing were ready to be cast, compared with 38.33% of patients receiving a soft dressing (P = 0.03). Below-knee amputees had a significantly quicker healing time, as measured by the time to be cast for prosthesis, when a rigid dressing was used compared with a soft dressing. Consideration should be given to the use of a rigid dressing after BKA to expedite healing and promote earlier ambulation. 23867730 Oxidized linoleic acid metabolite-cytochrome P450 system is active in biopsy samples from patients with inflammatory dental pain. Endogenous TRPV1 agonists such as oxidized linoleic acid metabolites (OLAMs) and the enzymes releasing them [eg, cytochrome P450 (CYP)] are up-regulated after inflammation in the rat. However, it is not known whether such agonists are elevated in human inflammatory pain conditions. Because TRPV1 is expressed in human dental pulp nociceptors, we hypothesized that OLAM-CYP machinery is active in this tissue type and is increased under painful inflammatory conditions such as irreversible pulpitis (IP). The aim of this study was to compare CYP expression and linoleic acid (LA) metabolism in normal vs inflamed human dental pulp. Our data showed that exogenous LA metabolism was significantly increased in IP tissues compared to normal tissues and that pretreatment with a CYP inhibitor, ketoconazole, significantly inhibited LA metabolism. Additionally, extracts obtained from LA-treated inflamed tissues evoked significant inward currents in trigeminal ganglia neurons and were blocked by pretreatment with the TRPV1 antagonist IRTX. Moreover, extracts obtained from ketoconazole-pretreated inflamed tissues significantly reduced inward currents in trigeminal ganglia neurons. These data suggest that LA metabolites produced in human inflamed tissues act as TRPV1 agonists and that the metabolite production can be targeted by CYP inhibition. In addition, immunohistochemical analysis of 2 CYP isoforms, CYP2J and CYP3A1, were shown to be predominately expressed in immune cells infiltrating the inflamed dental pulp, emphasizing the paracrine role of CYP enzymes in OLAM regulation. Collectively, our data indicate that the machinery responsible for OLAM production is up-regulated during inflammation and can be targeted to develop potential analgesics for inflammatory-induced dental pain. 23809856 Abrupt transition to heightened poliomyelitis epidemicity in England and Wales, 1947-1957, associated with a pronounced increase in the geographical rate of disease propagation. SUMMARY The abrupt transition to heightened poliomyelitis epidemicity in England and Wales, 1947-1957, was associated with a profound change in the spatial dynamics of the disease. Drawing on the complete record of poliomyelitis notifications in England and Wales, we use a robust method of spatial epidemiological analysis (swash-backwash model) to evaluate the geographical rate of disease propagation in successive poliomyelitis seasons, 1940-1964. Comparisons with earlier and later time periods show that the period of heightened poliomyelitis epidemicity corresponded with a sudden and pronounced increase in the spatial rate of disease propagation. This change was observed for both urban and rural areas and points to an abrupt enhancement in the propensity for the geographical spread of polioviruses. Competing theories of the epidemic emergence of poliomyelitis in England and Wales should be assessed in the light of this evidence. 23832448 Free cholesterol accumulation in hepatic stellate cells: Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. Although nonalcoholic steatohepatitis (NASH) is associated with hypercholesterolemia, the underlying mechanisms of this association have not been clarified. We aimed to elucidate the precise role of cholesterol in the pathophysiology of NASH. C57BL/6 mice were fed a control, high-cholesterol (HC), methionine-choline-deficient (MCD), or MCD+HC diet for 12 wk or a control, HC, high-fat (HF), or HF+HC diet for 24 wk. Increased cholesterol intake accelerated liver fibrosis in both the mouse models without affecting the degree of hepatocellular injury or Kupffer cell activation. The major causes of the accelerated liver fibrosis involved free cholesterol (FC) accumulation in hepatic stellate cells (HSCs), which increased Toll-like receptor 4 protein (TLR4) levels through suppression of the endosomal-lysosomal degradation pathway of TLR4, and thereby sensitized the cells to transforming growth factor (TGF)β-induced activation by downregulating the expression of bone morphogenetic protein and activin membrane-bound inhibitor. Mammalian-cell cholesterol levels are regulated via a feedback mechanism mediated by sterol regulatory element-binding protein 2 (SREBP2), maintaining cellular cholesterol homeostasis. Nevertheless, HSCs were sensitive to FC accumulation because the high intracellular expression ratio of SREBP cleavage-activating protein (Scap) to insulin-induced gene (Insig) disrupted the SREBP2-mediated feedback regulation of cholesterol homeostasis in these cells. HSC activation subsequently enhanced the disruption of the feedback system by Insig-1 downregulation. In addition, the suppression of peroxisome proliferator-activated receptor γ signaling accompanying HSC activation enhanced both SREBP2 and microRNA-33a signaling. Consequently, FC accumulation in HSCs increased and further sensitized these cells to TGFβ-induced activation in a vicious cycle, leading to exaggerated liver fibrosis in NASH. Conclusion: These characteristic mechanisms of FC accumulation in HSCs are potential targets to treat liver fibrosis in liver diseases including NASH. (Hepatology 2013;). 23563272 Mitochondrial genomes to the rescue--Diurodrilidae in the myzostomid trap. Diurodrilidae is a taxon of Lophotrochozoa comprising about six, exclusively interstitial species, which are up to 500μm long and dorsoventrally flattened. Traditionally, Diurodrilidae had been regarded as an annelid family. However, recently Diurodrilidae had been excluded from Annelida and been placed in closer relationship to platyzoan taxa based on both morphological and nuclear rRNA data. Since both, Diurodrilidae and platyzoan taxa, exhibit long branches in the molecular analyses, the close relationship might be due to a long branch attraction artifact. The annelid taxon Myzostomida had been trapped in a similar long branch attraction artifact with platyzoan taxa using nuclear rRNA data, but determination of the nearly complete mitochondrial genome of myzostomids revealed their annelid affinity. Therefore, we determined the nearly complete mitochondrial genome of Diurodrilus subterraneus as well as new nuclear rRNA data for D. subterraneus and some platyzoan taxa. All our analyses of nuclear rRNA and mitochondrial sequence and gene order data presented herein clearly place Diurodrilidae within Annelida and with strong nodal support values in some analyses. Therefore, the previously suggested exclusion of Diurodrilidae from Annelida and its close relationship with platyzoan taxa can be attributed to a long branch artifact. Morphological data do not unambiguously support a platyzoan affinity of Diurodrilidae, but instead would also be in line with a progenetic origin of Diurodrilidae within Annelida. 23851103 Statin-induced necrotizing myositis - A discrete autoimmune entity within the "statin-induced myopathy spectrum" Statin-induced necrotizing myositis is increasingly being recognised as part of the "statin-induced myopathy spectrum". As in other immune-mediated necrotizing myopathies, statin-induced myositis is characterised by proximal muscle weakness with marked serum creatinine kinase elevations and histological evidence of myonecrosis, with little or no inflammatory cell infiltration. Unlike other necrotizing myopathies, statin-induced myopathy is associated with the presence of autoantibodies directed against 3-hydroxy-3-methylglutaryl- coenzyme A reductase (the enzyme target of statin therapies), and with Human Leukocyte Antigen-DRB1*11. This article summarises the clinical presentation, investigations and management of this rare, but serious complication of statin therapy. 23354393 Bioactive microconstituents and antioxidant properties of wild edible mushrooms from the island of Lesvos, Greece. Crude composition, fatty acids, sterols, total phenolic content (TPC), individual polyphenols and terpenic acids were determined in five wild edible mushrooms species (Lactarius deliciosus, Lactarius sanguifluus, Lactarius semisanguifluus, Russula delica, Suillus bellinii) from Lesvos Island, Greece. In addition, the DPPH scavenging capacity, the ferric ion reducing power (FRAP) and the ferrous ion chelating activity of mushroom methanolic extracts were assessed. Among sterols, ergosterol predominated at concentrations 9.2-18.0mg/100g fw. Total phenolic content of mushroom extracts ranged from 6.0 to 20.8mg GAE/100g fw. Up to 19 simple polyphenols were determined in mushrooms extracts, the more abundant being p-OH-benzoic acid, p-OH-phenylacetic acid, o-coumaric acid, ferulic acid and chrysin. In addition, the triterpenic acids oleanolic and ursolic were detected for the first time in mushrooms. All species exerted antioxidant activity and ferrous ion chelating capacity. Principal component analysis revealed good correlations between TPC, DPPH and FRAP but not with metal chelating activity. It seems that mushrooms polyphenols exert antiradical and reducing activities, but they are not strong metal chelators, the observed chelating ability being probably due to other classes of compounds. To our knowledge, this is the first report on the bioactive microconstituents and antioxidant activity of wild Greek edible mushrooms. 23887885 Proteolytic post translational modification ofproteins: proteomic tools and methodology. Proteolytic processing is a ubiquitous and irreversible post-translational modification involving limited and highly specific hydrolysis of peptide and isopeptide bonds of a protein by a protease. Cleavage generates shorter protein chains displaying neo- N- and C-termini, often with new or modified biological activities. Within the past decade, degradomics and terminomics have emerged as significant proteomics subfields dedicated to characterizing proteolysis products as well as natural protein N- and C-termini. Here we provide an overview of contemporary proteomics-based methods including specific quantitation, data analysis and curation considerations and highlight exciting new and emerging applications within these fields enabling in vivo analysis of proteolytic events. 23956253 Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society. The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD). Of the theoretical estimated prevalence of 1/500 for heterozygous FH, <1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, low-density lipoprotein cholesterol targets are <3.5 mmol/L(<135 mg/dL) for children, <2.5 mmol/L(<100 mg/dL) for adults, and <1.8 mmol/L(<70 mg/dL) for adults with known CHD or diabetes. In addition to lifestyle and dietary counselling, treatment priorities are (i) in children, statins, ezetimibe, and bile acid binding resins, and (ii) in adults, maximal potent statin dose, ezetimibe, and bile acid binding resins. Lipoprotein apheresis can be offered in homozygotes and in treatment-resistant heterozygotes with CHD. Owing to severe underdiagnosis and undertreatment of FH, there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition. 23816003 Associated injuries in traumatic sternal fractures: a review of the National Trauma Data Bank. Sternal fractures occur infrequently with blunt force trauma. The demographics and epidemiology of associated injuries have not been well characterized from a national trauma database. The National Trauma Data Bank was queried for patients with closed sternal fractures. The demographics were analyzed by age, gender, mechanism and indicators of anatomic and physiologic injuries. Types of commonly associated injuries were also determined. A total of 23,985 records were analyzed. Males accounted for 68.3 per cent and whites 70.9 per cent. Motor vehicle crash was the leading mechanism. More than 56 per cent had severe injuries based on Injury Severity Score (greater than 15) and 17 per cent with Glasgow Coma Score 8 or less. Crude mortality was 7.9 per cent. The majority (57.8%) and approximately one-third (33.7%) of the patients had rib fractures and lung contusions, respectively, 22.0 per cent with closed pneumothorax, 21.6 per cent had a closed thoracic vertebra fracture, 16.9 per cent with lumbar spine fracture, 3.9 per cent with concussion, and blunt cardiac injury in 3.6 per cent. Sternal fractures are usually associated with severe blunt trauma. Lung contusion remains the leading associated injury followed by vertebral spine fractures. Cardiac injuries are less frequent and vascular injuries less so. Mechanism of injury and presence of sternal fractures should alert providers to these potential associated injuries. 23515166 Associations between valve repair and reduced operative mortality in 21 056 mitral/tricuspid double valve procedures. Repair of either the mitral (M) or tricuspid (T) valve in single valve surgery is associated with reduced operative mortality. It is unclear, however, how valve repair influences mortality in combined MT procedures. This topic was evaluated in the Society of Thoracic Surgeons database. From 1993 through 2007, 21 056 patients underwent concomitant MT valve surgery. Group I had M&T replacement (n = 1130), Group II had M repair and T replacement (n = 216), Group III had M replacement and T repair (n = 11 448) and Group IV had both M&T repair (n = 8262). Unadjusted operative mortalities (UOMs) and morbidities of Groups I-IV were assessed, and logistic regression analysis adjusted for differences in baseline patient profiles. Surgical outcomes were expressed as UOMs, and also adjusted odds ratios (ORs) for mortality. Group IV was older with more coronary artery bypass grafting and generally less comorbidity, and Group I had more endocarditis, mitral stenosis and reoperation. UOM values were: Group I = 16.8, Group II = 10.2, Group III = 10.3 and Group IV = 8.0%. In the multivariable model, factors influencing mortality included: age (per 5-year increase, OR = 1.15), renal failure with dialysis (OR = 3.22), emergency status (OR = 3.14), second or more reoperations (OR = 1.92) and later surgical date (OR = 0.63). Both M and T repair were independently associated with lower operative mortalities vs prosthetic valve replacement (OR = 0.83 and 0.60, respectively, P < 0.003). In MT double valve surgery, repair of either valve is associated with lower risk-adjusted mortality when compared with replacement and, when feasible, multiple valve repair should be considered the optimal treatment. Within the limitations of observational analysis, these data support continued efforts to increase M&T repair rates. 23849160 Super learning to hedge against incorrect inference from arbitrary parametric assumptions in marginal structural modeling. Clinical trials are unlikely to ever be launched for many comparative effectiveness research (CER) questions. Inferences from hypothetical randomized trials may however be emulated with marginal structural modeling (MSM) using observational data, but success in adjusting for time-dependent confounding and selection bias typically relies on parametric modeling assumptions. If these assumptions are violated, inferences from MSM may be inaccurate. In this article, we motivate the application of a data-adaptive estimation approach called super learning (SL) to avoid reliance on arbitrary parametric assumptions in CER. Using the electronic health records data from adults with new-onset type 2 diabetes, we implemented MSM with inverse probability weighting (IPW) estimation to evaluate the effect of three oral antidiabetic therapies on the worsening of glomerular filtration rate. Inferences from IPW estimation were noticeably sensitive to the parametric assumptions about the associations between both the exposure and censoring processes and the main suspected source of confounding, that is, time-dependent measurements of hemoglobin A1c. SL was successfully implemented to harness flexible confounding and selection bias adjustment from existing machine learning algorithms. Erroneous IPW inference about clinical effectiveness because of arbitrary and incorrect modeling decisions may be avoided with SL. 23880144 Dynamic expression of neurexophilin1 during zebrafish embryonic development. Neurexophilin 1 (Nxph1) is a specific endoligand of α-neurexins that is essential for trans-synaptic activation. Here, we report its dynamic expression during development in zebrafish. Our study revealed an early onset of expression of nxph1. RT-PCR on a series of embryonic stages showed that it is maternally deposited, although only readily detectable by whole mount in situ hybridization by 22hpf. During embryogenesis and larval stages, the zygotic transcript is expressed dynamically in various clusters of post-mitotic neurons and in glia in the central nervous system. 23886226 Very low birth weight and respiratory outcome: association between airway inflammation and hyperresponsiveness. The respiratory outcomes after preterm birth have changed, and it is unclear whether increased airway hyperresponsiveness (AHR) later in childhood is associated with airway inflammation. To investigate the association between AHR and fractional exhaled nitric oxide (FeNO), including the alveolar concentration of nitric oxide, in school-age children with very low birth weight (VLBW). Twenty-nine children with VLBW, 33 children with a history of early wheeze, and 60 healthy controls underwent a FeNO measurement and bronchial challenge test with histamine. Atopy was assessed with skin prick tests. Children with VLBW had well-preserved baseline lung function but significantly increased AHR, expressed as the dose response slope (P < .001). Geometric mean FeNO levels were similar between VLBW children and healthy controls, and a history of bronchopulmonary dysplasia had no effect. In the VLBW and early wheeze groups, AHR was associated with FeNO (r = 0.47, P = .01, and r = 0.43, P = .013, respectively), but in a stratified analysis, this association was significant only in atopic individuals. By using the multiple flow FeNO technique, the bronchial nitric oxide flux rather than alveolar nitric oxide concentrations were associated with AHR in both children with early wheeze and VLBW. We conclude that in VLBW children AHR is related to FeNO but only in atopic individuals. Similar to children with early wheeze, this association is dependent on bronchial flux rather than alveolar nitric oxide concentration. It is likely that AHR is modified by atopic inflammation rather than by inflammatory process due to prematurity. 23517413 Novel Plasmodium falciparum Maurer's clefts protein families implicated in the release of infectious merozoites. The pathogenicity of the most deadly human malaria parasite, Plasmodium falciparum, relies on the export of virulence factors to the surface of infected erythrocytes. A novel membrane compartment, referred to as Maurer's clefts, is transposed to the host erythrocyte, acting as a marshal platform in the red blood cell cytoplasm, for exported parasite proteins addressed to the host cell plasma membrane. We report here the characterization of three new P. falciparum multigene families organized in 9 highly conserved clusters with the Pfmc-2tm genes in the subtelomeric regions of parasite's chromosomes and expressed at early trophozoite stages. Like the PfMC-2TM proteins, the PfEPF1, 3 and 4 proteins encoded by these families are exported to the Maurer's clefts, as peripheral or integral proteins of the Maurer's cleft membrane and largely exposed to the red cell cytosolic face of this membrane. A promoter titration approach was used to question the biological roles of these P. falciparum-specific exported proteins. Using the Pfepf1 family promoter, we observed the specific downregulation of all four families, correlating with the inefficient release of merozoites while the parasite intra-erythrocytic maturation and Maurer's clefts morphology were not impacted. 23932627 A simple method for percutaneous endoscopic gastrostomy tube removal: "Tie and retrograde pull". Various techniques have been presented to remove the percutaneous endoscopically placed gastrostomy tube in children, but tubes with semi-rigid internal retaining discs are difficult or impossible to remove by external traction. We describe a simple and effective endoscopic removal technique that should be applicable to any type of percutaneous endoscopic gastrostomy tube. Percutaneous endoscopic gastrostomy tube removal was performed with the "tie and retrograde pull" technique. After a polypropylene suture was placed and tied 1cm over the skin level, the percutaneous endoscopic gastrostomy tube was cut 0.5cm over the knot. The suture was cut from the connection point between the needle and the suture. The distal end of the suture was pushed through the stoma into the stomach. Then a forceps was inserted through the gastroscope. The suture was caught, and the residual percutaneous endoscopic gastrostomy portion was retrieved via retrograde traction on the suture. The causes of exchange were determined to be planned tube replacement in 9, buried bumper syndrome in 1, and tube occlusion in 3 patients. The mean tube dwell time was 10.8±3.9months. Esophageal mucosal tear developed in 1 patient with epidermolysis bullosa during removal. No other complications occurred during PEG tube exchanges. This is a rapid and useful technique that does not require any complex endoscopic devices. 23940336 Communicating science in politicized environments. Many members of the scientific community attempt to convey information to policymakers and the public. Much of this information is ignored or misinterpreted. This article describes why these outcomes occur and how science communicators can achieve better outcomes. The article focuses on two challenges associated with communicating scientific information to such audiences. One challenge is that people have less capacity to pay attention to scientific presentations than many communicators anticipate. A second challenge is that people in politicized environments often make different choices about whom to believe than do people in other settings. Together, these challenges cause policymakers and the public to be less responsive to scientific information than many communicators desire. Research on attention and source credibility can help science communicators better adapt to these challenges. Attention research clarifies when, and to what type of stimuli, people do (and do not) pay attention. Source credibility research clarifies the conditions under which an audience will believe scientists' descriptions of phenomena rather than the descriptions of less-valid sources. Such research can help communicators stay true to their science while making their findings more memorable and more believable to more audiences. 23528018 The experience of chemotherapy-induced alopecia for Australian women with ovarian cancer. This article describes the experience of chemotherapy-induced alopecia. Data resulted from an ongoing study, which sought to explore the experience of Australian women with a primary diagnosis of ovarian cancer. Phenomenological analysis of written accounts or interviews with 15 Australian women resulted in 13 of these 15 women giving priority to describing their experience of alopecia. The women described alopecia as the most distressing corporeal feature of the ovarian cancer experience. Factors which contributed to women's distress included: loss of sense of self and altered body image; reminder of their illness and potential for an early death; public statement about their private life, practical issues and re-growth. No literature was located, worldwide, which specifically explores the experience of alopecia for women with ovarian cancer. This article presents the first in-depth exploration of the experience of alopecia for Australian women with ovarian cancer. Insight gained from this study will inform understanding of the issues associated with alopecia for women with ovarian cancer and may facilitate the provision of optimal supportive care provided by health care professionals for female cancer patients with chemotherapy-induced alopecia. 23438080 Expression of Gα12 predicts progression and prognosis of oral squamous cell carcinomas in Taiwan. Expression of Gα12 is found to be associated with cancer cell proliferation, migration, invasion, and metastasis. This study used immunohistochemistry to examine the expression of Gα12 protein in 100 specimens of oral squamous cell carcinoma (OSCC), 45 specimens of oral epithelial dysplasia (OED), and 36 specimens of normal oral mucosa (NOM). The mean Gα12 labeling indices (LIs, defined as the percentage of positive cells in total cells) increased significantly from NOM (7 ± 11%) through OED (21 ± 20%) to OSCC samples (53 ± 33%, P < 0.001). The higher mean Gα12 LI was significantly associated with OSCCs with larger tumor size (P = 0.003), positive lymph node metastasis (P = 0.002), or more advanced clinical stages (P = 0.003). Positive lymph node metastasis (P = 0.039) and Gα12 LI > 50% (P = 0.009) were identified as independent unfavorable prognosis factors by multivariate analyses with Cox regression model. Moreover, Kaplan-Meier curve showed that OSCC patients with a Gα12 LI > 50% had a significantly poorer cumulative survival than those with a Gα12 LI â‰¤ 50% (log-rank test, P = 0.009). Our results showed a stepwise and significant elevation in Gα12 protein expression from NOM through OED to OSCCs, suggesting that overexpression of Gα12 protein may be an early event in oral carcinogenesis and may play a pivotal role in oral cancer development. Moreover, the Gα12 protein can be a biomarker for prediction of the progression of OSCCs and the prognosis of patients with OSCC in Taiwan. 23702466 When should cardiopulmonary bypass be used in the setting of severe hypothermic cardiac arrest? A best evidence topic was written according to a structured protocol. The question addressed was regarding the indication and timing of the use of cardiopulmonary bypass (CPB), following severe hypothermic cardiac arrest. A total of 284 papers were found using the reported searches, of which nine represented the best evidence to answer the clinical question. The authors, date, journal, study type, population, main outcome measures and results are tabulated. Reported measures were survival, rewarming speed, incidence of arrhythmia during rewarming, resolution of full neurological function, long-term neurological function, evidence of damage on neurological imaging and venous metabolic parameters in hypothermic patients. The most recent of the best evidence studies, a retrospective comparative study of 68 patients, demonstrated CPB rewarming to be far superior to conventional methods of rewarming, with mortality rates of 15.8 and 53.3%, respectively. Another study of similar size, comparing CPB with extracorporeal membrane oxygenation (ECMO) for rewarming, revealed superior survival rates with ECMO, 75 vs 34%. A systematic review of 68 patients demonstrated an overall survival of 60%, and 80% of survivors returning to a previous level of activity. Two smaller observational studies reported survival rates of 73.1 and 45.5%, respectively. A retrospective study analysing long-term neurological outcomes of survivors reported normal history and physical examination in 93.3%, normal neurovascular ultrasound in 100%, normal neuropsychological findings in 93.3% and normal brain magnetic resonance imaging in 86.7%. A small comparative study demonstrated a significant survival benefit when CPB was preceded with emergency thoracotomy, internal cardiac massage and warm mediastinal irrigation compared with CPB alone. We conclude that, following deep hypothermic circulatory arrest, the urgent use of cardiopulmonary bypass is widely indicated for rewarming where it has been shown to provide good survival and neurological outcomes far superior in comparison with conventional methods of rewarming. 23940721 Exogenous Calcium Alleviates Photoinhibition of PSII by Improving the Xanthophyll Cycle in Peanut (Arachis Hypogaea) Leaves during Heat Stress under High Irradiance. Peanut is one of the calciphilous plants. Calcium (Ca) serves as a ubiquitous central hub in a large number of signaling pathways. The effect of exogenous calcium nitrate [Ca(NO3)2] (6 mM) on the dissipation of excess excitation energy in the photosystem II (PSII) antenna, especially on the level of D1 protein and the xanthophyll cycle in peanut plants under heat (40°C) and high irradiance (HI) (1 200 µmol m(-2) s(-1)) stress were investigated. Compared with the control plants [cultivated in 0 mM Ca(NO3)2 medium], the maximal photochemical efficiency of PSII (Fv/Fm) in Ca(2+)-treated plants showed a slighter decrease after 5 h of stress, accompanied by higher non-photochemical quenching (NPQ), higher expression of antioxidative genes and less reactive oxygen species (ROS) accumulation. Meanwhile, higher content of D1 protein and higher ratio of (A+Z)/(V+A+Z) were also detected in Ca(2+)-treated plants under such stress. These results showed that Ca(2+) could help protect the peanut photosynthetic system from severe photoinhibition under heat and HI stress by accelerating the repair of D1 protein and improving the de-epoxidation ratio of the xanthophyll cycle. Furthermore, EGTA (a chelant of Ca ion), LaCl3 (a blocker of Ca(2+) channel in cytoplasmic membrane), and CPZ [a calmodulin (CaM) antagonist] were used to analyze the effects of Ca(2+)/CaM on the variation of (A+Z)/(V+A+Z) (%) and the expression of violaxanthin de-epoxidase (VDE). The results indicated that CaM, an important component of the Ca(2+) signal transduction pathway, mediated the expression of the VDE gene in the presence of Ca to improve the xanthophyll cycle. 23888063 Sclerosis and varicocele embolization with N-butyl cyanoacrylate: experience in 41 patients. Embolization is an established treatment for varicocele. Coils are most frequently used in the procedure. Liquid embolic and sclerosing agents seem to have a number of advantages over coils. To report our experience and explain the technique of using N-2-butyl-cyanoacrylate (N2BCA) in varicocele treatment. From January 2010 to July 2011, 42 gonadal veins in 41 consecutive patients (age range, 11-41 years; mean, 18 years) with a diagnosis of varicocele were treated with N2BCA as an embolic agent. The clinical diagnosis was confirmed by Doppler ultrasound in all patients. Institutional review board approval was obtained, and all the patients signed informed consent for this retrospective review. In all cases, a 4-F hydrophilic catheter was used to catheterize the distal portion of the gonadal vein through which N2BCA, emulsified with lipiodol, was injected. The technical success was 100%. No complications or non-targeted embolizations were reported. Seven patients reported moderate post-embolization pain that required oral analgesic treatment for 7-10 days. After 12-month follow-up, all patients exhibited varicocele resolution in the Doppler ultrasound examination as well as relief of all previous symptoms. We have no fertility-related data for patients treated for this condition. N2BCA as an embolic agent is a therapeutic alternative for the endovascular treatment of varicocele. This technique is uncomplicated, inexpensive, efficient, and safe. 23952780 Degradation of Norgestrel by Bacteria from Activated Sludge: Comparison to Progesterone. Natural and synthetic progestagens in the environment have become a concern due to their adverse effects on aquatic organisms. Laboratory studies were performed to investigate aerobic biodegradation of norgestrel by bacteria from activated sludge in comparison with progesterone, and to identify their degradation products and biotransformation pathways. The degradation of norgestrel followed first order reaction kinetics (T1/2 = 12.5 d), while progesterone followed zero order reaction kinetics (T1/2 = 4.3 h). Four and eight degradation products were identified for norgestrel and progesterone, respectively. Six norgestrel-degrading bacterial strains (Enterobacter ludwigii, Aeromonas hydrophila subsp. dhakensis, Pseudomonas monteilii, Comamonas testosteroni, Exiguobacterium acetylicum, and Chryseobacterium indologenes) and one progesterone-degrading bacterial strain (Comamonas testosteroni) were successfully isolated from the enrichment culture inoculated with aerobic activated sludge. To our best knowledge, this is the first report on the biodegradation products and degrading bacteria for norgestrel under aerobic conditions. 23906199 Stability and Hopf bifurcation in a diffusive predator-prey system incorporating a prey refuge. A diffusive predator-prey model with Holling type II functional response and the no-flux boundary condition incorporating a constant prey refuge is considered. Globally asymptotically stability of the positive equilibrium is obtained. Regarding the constant number of prey refuge m as a bifurcation parameter, by analyzing the distribution of the eigenvalues, the existence of Hopf bifurcation is given. Employing the center manifold theory and normal form method, an algorithm for determining the properties of the Hopf bifurcation is derived. Some numerical simulations for illustrating the analysis results are carried out. 23964827 Increased visfatin in hemodialysis patients is associated with decreased demands for recombinant human erythropoietin. Abstract Background: Studies detected an association between visfatin and markers of iron metabolism in patients with insulin resistance. In this study, such a relation was evaluated in hemodialysis (HD) patients. Also relations between visfatin and hepcidin, demands for recombinant human erythropoietin (rHuEpo), inflammation, and situations characterized by insulin resistance were evaluated. Methods: After a four-week washout period from iron treatment, 33 HD patients and 20 healthy volunteers enrolled in the study. Serum visfatin, hepcidin, and interleukin-6 (IL-6) were assessed by means of enzyme-linked immunosorbent assay. Hemoglobin, serum iron, ferritin, and transferrin saturation (TSAT) were also measured. Results: Visfatin was markedly increased in HD patients. Visfatin levels did not differ between diabetics and non-diabetics. No relation was detected between visfatin and body mass index or IL-6 in HD patients. From the markers of iron metabolism, the hepcidin included, visfatin was related only to TSAT. A strong positive relation was revealed between visfatin and hemoglobin, whereas visfatin was inversely related to rHuEpo dose. Resistance to rHuEpo index was inversely and independently of TSAT related to visfatin. Conclusion: Visfatin is increased in HD patients and it is associated with decreased demands for rHuEpo. 23558694 Reduced work capacity in individuals with down syndrome: a consequence of autonomic dysfunction? Low work capacity and V˙O2peak commonly are described phenomena in Down syndrome. This is accompanied by chronotropic incompetence and a high incidence of obesity. Although many causes of low work capacity in Down syndrome have been proposed, little scientific support exists. Our working hypothesis is that autonomic dysfunction is the major contributor to the low levels of work capacity in this population. 23685165 Evidence for constitutive protein synthesis in hippocampal LTP stabilization. The notion that blockade of constitutive protein synthesis underlies the effect of protein synthesis inhibitors (PSIs) on long-term potentiation (LTP) stabilization was examined using the rat hippocampal CA3-CA1 synapse. Using a biochemical assay we found protein synthesis rate largely recovered 1h after wash-out of cycloheximide (CHX). Nonetheless, a 4-h CHX application followed by wash-out 1h prior to LTP resulted in a significant decrement of LTP stabilization. Wash-out initiated just prior to LTP, thus extending protein synthesis inhibition well into the post-LTP period, resulted in no further effect on LTP. However, short pre- and continuous post-tetanization application of PSIs failed to influence LTP persistence for up to 7 h. Addition of hydrogen peroxide (H₂O₂) 5-25 min following LTP induction resulted in parallel depression of potentiated and non-potentiated inputs, leaving LTP seemingly unaltered. However, in the presence of cyxloheximide the H₂O₂ application resulted in a significant reduction of LTP. In conclusion: LTP stabilization was impaired by pre-LTP application of protein synthesis inhibition but not by post-LTP application unless the slices were exposed to oxidative stress. We submit that these results favor the notion that constitutive rather than triggered protein synthesis is important for LTP stabilization. 23793447 Correlation analysis as a tool to investigate the bioaccessibility of nickel, vanadium and zinc in Northern Ireland soils. Correlation analyses were conducted on nickel (Ni), vanadium (V) and zinc (Zn) oral bioaccessible fractions (BAFs) and selected geochemistry parameters to identify specific controls exerted over trace element bioaccessibility. BAFs were determined by previous research using the unified BARGE method. Total trace element concentrations and soil geochemical parameters were analysed as part of the Geological Survey of Northern Ireland Tellus Project. Correlation analysis included Ni, V and Zn BAFs against their total concentrations, pH, estimated soil organic carbon (SOC) and a further eight element oxides. BAF data were divided into three separate generic bedrock classifications of basalt, lithic arenite and mudstone prior to analysis, resulting in an increase in average correlation coefficients between BAFs and geochemical parameters. Sulphur trioxide and SOC, spatially correlated with upland peat soils, exhibited significant positive correlations with all BAFs in gastric and gastro-intestinal digestion phases, with such effects being strongest in the lithic arenite bedrock group. Significant negative relationships with bioaccessible Ni, V and Zn and their associated total concentrations were observed for the basalt group. Major element oxides were associated with reduced oral trace element bioaccessibility, with Al2O3 resulting in the highest number of significant negative correlations followed by Fe2O3. spatial mapping showed that metal oxides were present at reduced levels in peat soils. The findings illustrate how specific geology and soil geochemistry exert controls over trace element bioaccessibility, with soil chemical factors having a stronger influence on BAF results than relative geogenic abundance. In general, higher Ni, V and Zn bioaccessibility is expected in peat soil types. 23831306 Pyroptosis: An inflammatory cell death implicates in atherosclerosis. Cell death and inflammation are the fundamental biological processes in both normal physiology and pathology. Apoptosis is the most well-studied process of cell death, but there are also many other forms of cell death such as necrosis, autophagy and pyroptosis. Cell death could be observed throughout atherosclerosis and plays an important role in determining the fate of atherosclerotic lesion. Inflammation, the primary response of innate immunity, is considered essential in initiating and driving atherosclerosis. Apoptosis and autophagy had been reported in atherosclerosis, however, the mechanism of cell death involved in atherosclerosis still remain largely unknown. Cell death and inflammation are inextricably linked with their effectors modulating the process of atherosclerosis. Therefore, we proposed hypothesis that pyroptosis, an inflammatory form of cell death, may be implicated in atherosclerosis and play an important role in lesion instability. 23843026 Impact of Human Papillomavirus Vaccination on Cervical Cytology Screening, Colposcopy, and Treatment. The impact of human papillomavirus (HPV) vaccination on cervical screening, colposcopy, and treatment is incompletely understood. In 2004-2005, investigators in the Costa Rica Vaccine Trial randomized 7,466 women aged 18-25 years, 1:1, to receive HPV vaccination or hepatitis A vaccination. The worst-ever cytology diagnosis and the 4-year cumulative proportions of colposcopy referral and treatment by vaccination arm were compared for 2 cohorts. The total vaccinated cohort included 6,844 women who provided cervical samples. The naive cohort included 2,284 women with no evidence of previous HPV exposure. In the total vaccinated cohort, HPV-vaccinated women had a significant (P = 0.01) reduction in cytological abnormalities: 12.4% for high-grade lesions and 5.9% for minor lesions. Colposcopy referral was reduced by 7.9% (P = 0.03) and treatment by 11.3% (P = 0.24). Greater relative reductions in abnormal cytology (P < 0.001) were observed for HPV-vaccinated women in the naive cohort: 49.2% for high-grade lesions and 18.1% for minor lesions. Colposcopy referral and treatment were reduced by 21.3% (P = 0.01) and 45.6% (P = 0.08), respectively, in the naive cohort. The overall impact on health services will be modest in the first years after vaccine introduction among young adult women, even in regions with high coverage. 23773213 Removal of N-Alkyl Modifications from N(2)-Alkylguanine and N(4)-Alkylcytosine in DNA by the Adaptive Response Protein AlkB. The AlkB enzyme is an Fe(II)- and α-ketoglutarate-dependent dioxygenase that repairs DNA alkyl lesions by a direct reversal of damage mechanism as part of the adaptive response in E. coli. The reported substrate scope of AlkB includes simple DNA alkyl adducts, such as 1-methyladenine, 3-methylcytosine, 3-ethylcytosine, 1-methylguanine, 3-methylthymine, and N(6)-methyladenine, as well as more complex DNA adducts, such as 1,N(6)-ethenoadenine, 3,N(4)-ethenocytosine, and 1,N(6)-ethanoadenine. Previous studies have revealed, in a piecemeal way, that AlkB has an impressive repertoire of substrates. The present study makes two additions to this list, showing that alkyl adducts on the N(2) position of guanine and N(4) position of cytosine are also substrates for AlkB. Using high resolution ESI-TOF mass spectrometry, we show that AlkB has the biochemical capability to repair in vitro N(2)-methylguanine, N(2)-ethylguanine, N(2)-furan-2-yl-methylguanine, N(2)-tetrahydrofuran-2-yl-methylguanine, and N(4)-methylcytosine in ssDNA but not in dsDNA. When viewed together with previous work, the experimental data herein demonstrate that AlkB is able to repair all simple N-alkyl adducts occurring at the Watson-Crick base pairing interface of the four DNA bases, confirming AlkB as a versatile gatekeeper of genomic integrity under alkylation stress. 23437929 Balance of coordination and hydrophobic interaction in the formation of bilayers in metal-coordinated surfactant mixtures. Metal-ligand coordination and hydrophobic interaction are two significant driving forces in the aggregation of mixtures of M(n+) surfactants and alkyldimethylamine oxide (CnDMAO) in aqueous solutions. The coordinated systems exhibit rich aggregation behavior. This study investigated the effect of M(n+) ions (Zn(2+), Ca(2+), Ba(2+), Al(3+), Fe(3+), La(3+), Eu(3+), and Tb(3+)) and hydrophobic chains (hydrocarbon and fluorocarbon) on the formation of metal-coordinated bilayers. We found that fluorocarbon chains and branched hydrocarbon chains are preferable to the corresponding linear hydrocarbon chains for the formation of an Lα phase. Moreover, Lα phases formed by fluorocarbon chains exhibited higher viscoelasticity than ones formed by the hydrocarbons, and the bilayers formed by branched chains were rather flexible, revealing obvious undulation. The construction of bilayers was also strongly affected by metal ions due to their variable coordination ability with CnDMAO. Our results contribute to the understanding of the formation of metal-coordinated bilayers, which is driven by the interplay of noncovalent forces. 23768371 Coumestrol induces senescence through protein kinase CKII inhibition-mediated reactive oxygen species production in human breast cancer and colon cancer cells. An inhibitor of the protein kinase CKII (CKII) was purified from leaves of Glycine max (L.) Merrill and was identified as coumestrol by structural analysis. Coumestrol inhibited the phosphotransferase activity of CKII toward β-casein, with an IC50 of about 5 μM. It acted as a competitive inhibitor with respect to ATP as a substrate, with an apparent Ki value of 7.67 μM. Coumestrol at 50μM resulted in 50% and 30% growth inhibition of human breast cancer MCF-7 and colorectal cancer HCT116 cells, respectively. Coumestrol promoted senescence through the p53-p21(Cip1/WAF1) pathway by inducing reactive oxygen species (ROS) production in MCF-7 and HCT116 cells. The ROS scavenger N-acetyl-l-cysteine (NAC), NADPH oxidase inhibitor apocynin and p22(phox) siRNA almost completely abolished this event. Overexpression of CKIIα antagonised cellular senescence mediated by coumestrol, indicating that this compound induced senescence via a CKII-dependent pathway. Since senescence is an important tumour suppression process in vivo, these results suggest that coumestrol can function by inhibiting oncogenic disease, at least in part, through CKII inhibition-mediated cellular senescence. 23860600 Focal uncaging of GABA reveals a temporally defined role for GABAergic inhibition during appetitive associative olfactory conditioning in honeybees. Throughout the animal kingdom, the inhibitory neurotransmitter γ-aminobutyric acid (GABA) is a key modulator of physiological processes including learning. With respect to associative learning, the exact time in which GABA interferes with the molecular events of learning has not yet been clearly defined. To address this issue, we used two different approaches to activate GABA receptors during appetitive olfactory conditioning in the honeybee. Injection of GABA-A receptor agonist muscimol 20 min before but not 20 min after associative conditioning affects memory performance. These memory deficits were attenuated by additional training sessions. Muscimol has no effect on sensory perception, odor generalization, and nonassociative learning, indicating a specific role of GABA during associative conditioning. We used photolytic uncaging of GABA to identify the GABA-sensitive time window during the short pairing of the conditioned stimulus (CS) and the unconditioned stimulus (US) that lasts only seconds. Either uncaging of GABA in the antennal lobes or the mushroom bodies during the CS presentation of the CS-US pairing impairs memory formation, while uncaging GABA during the US phase has no effect on memory. Uncaging GABA during the CS presentation in memory retrieval also has no effect. Thus, in honeybee appetitive olfactory learning GABA specifically interferes with the integration of CS and US during associative conditioning and exerts a modulatory role in memory formation depending on the training strength. 23924172 Meditation and neurodegenerative diseases. Neurodegenerative diseases pose a significant problem for the healthcare system, doctors, and patients. With an aging population, more and more individuals are developing neurodegenerative diseases and there are few treatment options at the present time. Meditation techniques present an interesting potential adjuvant treatment for patients with neurodegenerative diseases and have the advantage of being inexpensive, and easy to teach and perform. There is increasing research evidence to support the application of meditation techniques to help improve cognition and memory in patients with neurodegenerative diseases. This review discusses the current data on meditation, memory, and attention, and the potential applications of meditation techniques in patients with neurodegenerative diseases. 23629936 Determinants of health care seeking for diarrheal illness in young children in urban slums of kolkata, India. Abstract. Maternal practices regarding children's health care have been recognized as an important factor associated with mortality rates among children < 5 years of age. We focused on health care-seeking practices of primary caretakers of children < 5 years of age with diarrheal disease in Kolkata. We interviewed caretakers of 1,058 children in a baseline survey and 6,077 children on six subsequent surveys. The prevalence of diarrhea during the preceding 2 weeks was 7.9% in the baseline survey and 5.7% (lowest 3.5% to highest 7.8%) in subsequent surveys. Multivariate logistic regression showed that formal education of primary caretakers was associated with seeking care outside the home (odds ratio [OR] = 15.5; 95% confidence interval [CI] [2.5-85.7]; P = 0.002). Multinomial logistic regression showed that formal education of the primary caretaker (OR = 21.4; 95% CI [3.2-139.0]; P = 0.002) and presence of dry mouth during diarrhea (OR = 17.3; 95% CI [2.7-110.9]; P = 0.003) were associated with seeking care from licensed providers compared with the children for whom care was not sought outside of the home. This health care utilization and attitudes survey (HUAS) can serve as a tool to identify the factors that influence a better health care-seeking pattern in urban slums of Kolkata. 23738749 Edelfosine and miltefosine effects on lipid raft properties: membrane biophysics in cell death by antitumor lipids. Edelfosine (1-O-octadecyl-2-O-methyl-sn-glycero-phosphocholine) and miltefosine (hexadecylphosphocholine) are synthetic alkylphospholipids (ALPs) that are reported to selectively accumulate in tumor cell membranes, inducing Fas clustering and activation on lipid rafts, triggering apoptosis. However, the exact mechanism by which these lipids elicit these events is still not fully understood. Recent studies propose that their mode of action might be related with alterations of lipid rafts biophysical properties caused by these lipid drugs. To achieve a clear understanding of this mechanism, we studied the effects of pharmacologically relevant amounts of edelfosine and miltefosine in the properties of model and cellular membranes. The influence of these molecules on membrane order, lateral organization, and lipid rafts molar fraction and size were studied by steady-state and time-resolved fluorescence methods, Förster resonance energy transfer (FRET), confocal and fluorescence lifetime imaging microscopy (FLIM). We found that the global membrane and lipid rafts biophysical properties of both model and cellular membranes were not significantly affected by both the ALPs. Nonetheless, in model membranes, a mild increase in membrane fluidity induced by both alkyl lipids was detected, although this effect was more noticeable for edelfosine than miltefosine. This absence of drastic alterations shows for the first time that ALPs mode of action is unlikely to be directly linked to alterations of lipid rafts biophysical properties caused by these drugs. The biological implications of this result are discussed in the context of ALPs effects on lipid metabolism, mitochondria homeostasis modulation, and their relationship with tumor cell death. 23787111 Low-modulus Mg/PCL hybrid bone substitute for osteoporotic fracture fixation. In this paper, we describe a new biodegradable composite composed of polycaprolactone and magnesium. Incorporation of magnesium micro-particles into the polycaprolactone matrix yields mechanical properties close to those of human cancellous bone, and in vitro studies indicate that the silane-coated Mg/PCL composites have excellent cytocompatibility and osteoblastic differentiation properties. The bioactivity of the composites is manifested by the formation of calcium and phosphate after immersion in simulated body fluids. The bulk mechanical properties can be maintained for 2 months before obvious degradation takes place. The in vivo animal study reveals a larger amount of new bone formation on the silane-coated Mg/PCL composites compared to conventional PMMA and pure polycaprolactone and our results suggest potential clinical applications of the sliane-coated Mg/PCL composites. 23847315 Theoretical analysis of vascular regulatory mechanisms contributing to retinal blood flow autoregulation. To study whether impaired retinal autoregulation is a risk factor for glaucoma, the relationship between vascular regulatory mechanisms and glaucoma progression needs to be investigated. In this study, a vascular wall mechanics model is used to predict the relative importance of regulatory mechanisms in achieving retinal autoregulation. Resistance vessels are assumed to respond to changes in pressure, shear stress, carbon dioxide (CO2), and the downstream metabolic state communicated via conducted responses. Model parameters governing wall tension are fit to pressure and diameter data from porcine retinal arterioles. The autoregulation pressure range for control and elevated levels of IOP is predicted. The factor by which flow changes as the blood pressure exiting the central retinal artery is varied between 28 and 40 mm Hg is used to indicate the degree of autoregulation (1 indicates perfect autoregulation). In the presence of only the myogenic response mechanism, the factor is 2.06. In the presence of the myogenic and CO2 responses, the factor is 1.22. The combination of myogenic, shear, CO2, and metabolic responses yields the best autoregulation (factor of 1.10). Model results are compared with flow and pressure data from multiple patient studies, and the combined effects of the metabolic and CO2 responses are predicted to be critical for achieving retinal autoregulation. When IOP is elevated, the model predicts a decrease in the autoregulation range toward low perfusion pressure, which is consistent with observations that glaucoma is associated with decreased perfusion pressure. 23210776 New molecular and cellular targets for chemoprevention and treatment of skin tumors by plant polyphenols: a critical review. As the incidence of skin tumors has been steadily growing, there is an urgent need for the preventive measures as well as the improved therapeutic approaches. In the last two decades, natural plant derived polyphenols (PPs, resveratrol, silibinin, green tea polyphenols, flavonoids, anthocyanins, etc.) have been drawing particular interest as emerging active substances in dermatological/cosmeceutical compositions for the prevention, slowing, or reversion of skin tumorigenesis (chemoprevention). When chronically applied to the skin, they supposedly would not damage normal skin cells or negatively affect their functions while they would suppress tumorigenic cell transformation, inhibit tumor cell proliferation, and activate tumor cell apoptosis. PPs are also reported to synergize with conventional anti-cancer therapies. The major aim of this critical review is to provide recent updates on the molecular and cellular targets for the prevention and therapy of skin tumors with a special focus on the crossroad between inflammation and carcinogenesis as the most promising approach to chemoprevention. Novel therapeutic targets as different as epidermal stem cells, cellular senescence, epigenetic enzymes involved in carcinogenesis, epidermal growth factor and aryl hydrocarbon receptors, and metabolic CYP1 subfamily enzymes are highlighted. The mechanisms of PPs interaction with these molecular and cellular targets are reviewed. The feasibility of PPs to prevent/ cure specific cutaneous toxicity connected to anti-EGFR therapy and to reduce multidrug resistance of skin tumors is also discussed. 23824320 Drastic sensitivity enhancement in (29)Si MAS NMR of zeolites and mesoporous silica materials by paramagnetic doping of Cu(2+). The paramagnetic doping of Cu(2+) in both mesoporous silica materials and microporous silicate crystals (zeolites) can be used effectively to enhance the signal intensity of (29)Si solid state magic angle spinning NMR, as a result of shortening of the spin-lattice relaxation time, T1, by the paramagnetic effect, because of the Cu(2+) electronic relaxation time in the range of 10(-8) s. This leads to drastically reduced data-collection times, typically 80-fold shorter than that in mesoporous silica. We found that the estimated range of the paramagnetic effect of Cu(2+) doping in porous silicates was at least 1 nm. 23827486 Digital arthrodesis. For lesser toe deformities, fusion of the proximal interphalangeal joint offers good long-term correction and predictability. Digital arthrodesis has been described for longer than 100 years in the literature, and current techniques closely resemble those described in early accounts. However, many implants currently being used take advantage of the latest metallurgic and polymeric innovations, with implants being composed of nitinol, polylactic or polyglycolic acids, and polydioxanone. Newer implants offer easy insertion and good stability, with no percutaneous wires. Pin-tract infection rates from exposed Kirschner wires may be as high as 18%, and newer implants help to mitigate this problem. 23950627 Empathy without borders? Cross-cultural heart and mind-reading in first-year medical students. This cross-cultural study was designed to examine cultural differences in empathy levels of first-year medical students. A total of 257 students from the academic year 2010/11, 131 at Jimma University, Ethiopia, and 126 at the Ludwig Maximilian University, Munich, Germany, completed the Balanced Emotional Empathy Scale (BEES), the Reading the Mind in the Eyes (RME-R) test, and a questionnaire on sociodemographic and cultural characteristics. Furthermore, we conducted a qualitative analysis of the students' personal views on the definition of empathy and possible influencing factors. Group comparisons and correlation analyses of empathy scores were performed for the entire cohort and for the Jimma and Munich students separately. We used a regression tree analysis to identify factors influencing the BEES. The male students in Jimma (39.1 ± 22.3) scored significantly higher in the BEES than those male students from Munich (27.2 ± 22.6; p = 0.0002). There was no significant difference between the female groups. We found a moderate, positive correlation between the BEES and RME-R test, i.e. between emotional and cognitive empathy, within each university. Nevertheless, the RME-R test, which shows only Caucasian eyes, appears not to be suitable for use in other cultures. The main findings of our study were the influence of culture, religion, specialization choice, and gender on emotional empathy (assessed with the BEES) and cognitive empathy (assessed with the RME-R test) in first-year medical students. Further research is required into the nature of empathy in worldwide medical curricula. 23817891 Comparative survival following different treatment modalities for stage T2 bladder cancer in octogenarians. A higher rate of comorbidities and an anticipated higher operative risk in octogenarians may influence urologists in opting for less aggressive and less effective treatment modalities for muscle-invasive bladder cancer. This study was performed to compare survival after different treatment modalities in octogenarians with stage T2 bladder cancer. Patients that were 80 years or older with a diagnosis of transitional cell carcinoma of the bladder were identified using the Surveillance, Epidemiology, and End Results-17 registry database between 1988 and 2007. Patients were analyzed for treatment method and outcomes, including overall survival (OS) and cancer-specific survival (CSS). A total of 3,232 patients met inclusion criteria. Of these, 69 % (N = 2,216) underwent only transurethral resection (TURBT), 23 % (N = 733) underwent pelvic radiation therapy (RT), and 9 % (N = 283) underwent definitive surgical therapy. The 3-, 5-, and 10-year OS rates were 22.2, 15.0, and 4.4 %, respectively, for TURBT; 27.8, 18.3, and 3.5 % for RT; and 52.7, 39.1, and 17.2 % for definitive surgery. The 3-, 5-, and 10-year CSS rates were 38.3, 33.4, and 27.4 %, respectively, for TURBT; 41.6, 35.0, and 27.2 % for RT; and 66.6, 55.5, and 49.9 % for definitive surgery. Both partial and radical cystectomy had significantly longer CSS rates at 3 and 5 years when compared to RT (p â‰¤ 0.001). Compared to other treatment modalities, surgery, either radical cystectomy or partial cystectomy, offers the best OS and CSS for men aged 80 years or older with T2 bladder cancer. 23963244 Flexible access to conformationally-locked bicyclic morpholines. A preparatively accessible route to a series of conformationally-locked bicyclic morpholines has been developed. This flexible approach allows for diversification in order for a small array of lead-like scaffolds to be synthesised from readily available key building blocks. 23896118 Secondary hypertension caused by massive renal lymphangiomatosis. Renal lymphangiomatosis is a rare disease characterized by lymphatic vessel proliferation. We present a case of an adult patient with chronic flank pain, hypertension, and a right kidney mass. The magnetic resonance imaging findings were consistent with unilateral renal lymphangiomatosis. Technetium-99m dimercaptosuccinic acid renal scintilography revealed decreased ipsilateral renal function. From these findings, the patient underwent right nephrectomy, which resulted in complete remission of his hypertension and pain. 22634112 cAMP regulation of airway smooth muscle function. Agonists activating β(2)-adrenoceptors (β(2)ARs) on airway smooth muscle (ASM) are the drug of choice for rescue from acute bronchoconstriction in patients with both asthma and chronic obstructive pulmonary disease (COPD). Moreover, the use of long-acting β-agonists combined with inhaled corticosteroids constitutes an important maintenance therapy for these diseases. β-Agonists are effective bronchodilators due primarily to their ability to antagonize ASM contraction. The presumed cellular mechanism of action involves the generation of intracellular cAMP, which in turn can activate the effector molecules cAMP-dependent protein kinase (PKA) and Epac. Other agents such as prostaglandin E(2) and phosphodiesterase inhibitors that also increase intracellular cAMP levels in ASM, can also antagonize ASM contraction, and inhibit other ASM functions including proliferation and migration. Therefore, β(2)ARs and cAMP are key players in combating the pathophysiology of airway narrowing and remodeling. However, limitations of β-agonist therapy due to drug tachyphylaxis related to β(2)AR desensitization, and recent findings regarding the manner in which β(2)ARs and cAMP signal, have raised new and interesting questions about these well-studied molecules. In this review we discuss current concepts regarding β(2)ARs and cAMP in the regulation of ASM cell functions and their therapeutic roles in asthma and COPD. 23230214 Expression and activity of nitric oxide synthase isoforms in methamphetamine-induced striatal dopamine toxicity. Nitric oxide is implicated in methamphetamine (METH)-induced neurotoxicity; however, the source of the nitric oxide has not been identified. Previous work has also revealed that animals with partial dopamine loss induced by a neurotoxic regimen of methamphetamine fail to exhibit further decreases in striatal dopamine when re-exposed to methamphetamine 7-30 days later. The current study examined nitric oxide synthase expression and activity and protein nitration in striata of animals administered saline or neurotoxic regimens of methamphetamine at postnatal days 60 and/or 90, resulting in four treatment groups: Saline:Saline, METH:Saline, Saline:METH, and METH:METH. Acute administration of methamphetamine on postnatal day 90 (Saline:METH and METH:METH) increased nitric oxide production, as evidenced by increased protein nitration. Methamphetamine did not, however, change the expression of endothelial or inducible isoforms of nitric oxide synthase, nor did it change the number of cells positive for neuronal nitric oxide synthase mRNA expression or the amount of neuronal nitric oxide synthase mRNA per cell. However, nitric oxide synthase activity in striatal interneurons was increased in the Saline:METH and METH:METH animals. These data suggest that increased nitric oxide production after a neurotoxic regimen of methamphetamine results from increased nitric oxide synthase activity, rather than an induction of mRNA, and that constitutively expressed neuronal nitric oxide synthase is the most likely source of nitric oxide after methamphetamine administration. Of interest, animals rendered resistant to further methamphetamine-induced dopamine depletions still show equivalent degrees of methamphetamine-induced nitric oxide production, suggesting that nitric oxide production alone in response to methamphetamine is not sufficient to induce acute neurotoxic injury. 23861944 An Innovative Cloning Platform Enables Large-Scale Production and Maturation of an Oxygen-Tolerant [NiFe]-Hydrogenase from Cupriavidus necator in Escherichia coli. Expression of multiple heterologous genes in a dedicated host is a prerequisite for approaches in synthetic biology, spanning from the production of recombinant multiprotein complexes to the transfer of tailor-made metabolic pathways. Such attempts are often exacerbated, due in most cases to a lack of proper directional, robust and readily accessible genetic tools. Here, we introduce an innovative system for cloning and expression of multiple genes in Escherichia coli BL21 (DE3). Using the novel methodology, genes are equipped with individual promoters and terminators and subsequently assembled. The resulting multiple gene cassettes may either be placed in one vector or alternatively distributed among a set of compatible plasmids. We demonstrate the effectiveness of the developed tool by production and maturation of the NAD(+)reducing soluble [NiFe]-hydrogenase (SH) from Cupriavidus necator H16 (formerly Ralstonia eutropha H16) in E. coli BL21Star™ (DE3). The SH (encoded in hoxFUYHI) was successfully matured by co-expression of a dedicated set of auxiliary genes, comprising seven hyp genes (hypC1D1E1A2B2F2X) along with hoxW, which encodes a specific endopeptidase. Deletion of genes involved in SH maturation reduced maturation efficiency substantially. Further addition of hoxN1, encoding a high-affinity nickel permease from C. necator, considerably increased maturation efficiency in E. coli. Carefully balanced growth conditions enabled hydrogenase production at high cell-densities, scoring mg·(Liter culture)(-1) yields of purified functional SH. Specific activities of up to 7.2±1.15 U·mg(-1) were obtained in cell-free extracts, which is in the range of the highest activities ever determined in C. necator extracts. The recombinant enzyme was isolated in equal purity and stability as previously achieved with the native form, yielding ultrapure preparations with anaerobic specific activities of up to 230 U·mg(-1). Owing to the combinatorial power exhibited by the presented cloning platform, the system might represent an important step towards new routes in synthetic biology. 23561186 Structures and reactions of compounds involved in pink discolouration of onion. In "pinking" of onion, E-(+)-S-(1-propenyl)-l-cysteine sulfoxide is first cleaved by alliinase to yield colour developers (CDs), which react with amino acids, such as valine, to form pigment precursors (PPs). The PPs react with naturally occurring carbonyls (NOCs) to form pigments. By inducing a PP from previously isolated cepathiolanes and l-valine, it was confirmed that cepathiolanes constitute at least a part of the CDs. From the PP and formaldehyde as a NOC, two colourless and two pink compounds were derived. The structure of one of the colourless compounds was established as 2-(2-(1-(1-carboxy-2-methylpropyl)-3,4-dimethyl-1H-pyrrol-2-yl)methyl-3,4-dimethyl-1H-pyrrol-1-yl)-3-methylbutanoic acid. The structures of the other colourless compound and the pink pigments were predicted based on their molecular formula and the MS(n) spectral data. A trimeric pigment structure was predicted for one of the pink pigments, which was believed to be the first to be reported in the literature. With these, a new reaction scheme for "pinking" of onion is proposed. 23619740 Prevalence and effect of fever on outcome following resuscitation from cardiac arrest. Evaluate the prevalence of fever in the first 48h after cardiac arrest and its effect on outcomes. Review of patients treated between 1/1/2005 and 6/30/2010. Fever was defined as T≥38.0°C. We classified categories of post-cardiac arrest illness severity as (I) awake, (II) coma+mild cardiopulmonary dysfunction (SOFA cardiac+respiratory score <4), (III) coma+moderate-severe cardiopulmonary dysfunction, and (IV) deep coma. Associations between fever and survival or good neurologic outcome were examined between hypothermia (TH) and non-TH groups. In 336 patients, mean age was 60 years (SD 16), 63% experienced out-of-hospital cardiac arrest and 65% received TH. A shockable rhythm was present in 40%. Post arrest illness severity was category II in 38%, category III in 20%, and category IV in 42%. Fever was present in 42% of subjects, with a post-arrest median onset of 15h in the non-TH cohort and 36h in TH cohort. Fever was not associated with survival within the whole cohort (OR 0.32, CI 0.15, 0.68) or TH cohort (OR 1.21, CI 0.69, 2.14), but was associated with survival in non-TH cohort (OR 0.47, CI 0.20, 1.10). Fever was not associated with good outcomes in the whole cohort (OR 0.83, CI 0.49, 1.40), TH cohort (OR 1.09, CI 0.56, 2.12) or non-TH cohort (OR 0.34, CI 0.11, 1.06). The development of fever within the first 48h after ROSC is common. Fever is associated with death in non-TH patients. TH treatment appears to mitigate this effect, perhaps by delaying fever onset. 23829455 Development of a complex hydrogel of hyaluronan and PVA embedded with silver nanoparticles and its facile studies on Escherichia coli. Novel nanocomposite hydrogels composed of hyaluronan (HA), poly(vinyl alcohol) (PVA) and silver nanoparticles were prepared by several cycles of freezing and thawing. The nanocomposite was then characterised using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), wide-angle X-ray diffraction (XRD) and scanning electron microscopy (SEM). The complex hydrogels consisted of semi-interpenetrating network structures, with PVA microcrystallines as junction zones. By increasing the HA content, the crystallinity and melting temperature of the complex hydrogels decreased, whereas the glass transition temperatures of these materials increased because of the steric hindrance of HA and the occurrence of intermolecular interactions through hydrogen bonding between HA and PVA in the complex hydrogels. Swelling studies showed that in comparison with the swelling properties of the cryogels from PVA alone, those of the complex hydrogels can be significantly improved and presented in a pH-sensitive manner. In addition, silver nanoparticles were synthesised through UV-initiated photoreduction with HA functioning as a reducing agent and stabiliser. The silver nanoparticles were then incorporated in situ into the HA/PVA complex hydrogel matrix. The size and morphology of the as-prepared Ag nanoparticles were investigated through ultraviolet-visible light spectroscopy, transmission electron microscopy, XRD and thermogravimetric analysis. The experimental results indicated that silver nanoparticles 20-50 nm in size were uniformly dispersed in the hydrogel matrix. The antibacterial effects of the HA/PVA/Ag nanocomposite hydrogel against Escherichia coli were evaluated. The results show that this nanocomposite hydrogel possesses high antibacterial property and has a potential application as a wound dressing material. 23416841 Hypothetical physiological and molecular basis for the effect of acupuncture in the treatment of polycystic ovary syndrome. Clinical and experimental evidence indicates that acupuncture may be a safe alternative or complement in the treatment of endocrine and reproductive function in women with polycystic ovary syndrome (PCOS). This review describes potential etiological factors of PCOS with the aim to support potential mechanism of action of acupuncture to relieve PCOS related symptoms. The theory that increased sympathetic activity contributes to the development and maintenance of PCOS is presented, and that the effects of acupuncture are, at least in part, mediated by modulation of sympathetic outflow. While there are no relevant randomized controlled studies on the use of acupuncture to treat metabolic abnormalities in women with PCOS, a number of experimental studies indicate that acupuncture may improve metabolic dysfunction. For each aspect of PCOS, it is important to pursue new treatment strategies that have fewer negative side effects than drug treatments, as women with PCOS often require prolonged treatment. 23959663 Differential contributions of the latch in Thermotoga maritima reverse gyrase to binding of single-stranded DNA before and after ATP hydrolysis. Abstract Reverse gyrase catalyzes the ATP-dependent introduction of positive supercoils into DNA. Supercoiling requires the functional cooperation of its N-terminal helicase domain with the C-terminal topoisomerase domain. The helicase domain contains a superfamily 2 helicase core formed by two RecA domains, H1 and H2. We show here that a helicase domain lacking the latch, an insertion in H2, fails to close the cleft in the helicase core in response to nucleotide and DNA binding at the beginning of the catalytic cycle. In the presence of the pre-hydrolysis ATP analog ADP BeFx, however, the closed conformer can still be formed in the absence of the latch. The helicase domain lacking the latch exhibits reduced DNA affinities. The energetic difference between the two nucleotide states involved in duplex separation is diminished, rationalizing the unwinding deficiency of reverse gyrase lacking the latch. The latch most strongly contributes to binding of single-stranded DNA in the post-hydrolysis state, before phosphate release. Our results are in line with contributions of the latch in determining the direction of strand passage, and in orienting the cleaved ssDNA for religation. At the same time, the latch may coordinate the religation reaction with strand passage and with the nucleotide cycle. 23958007 Effects of prolonged nutrient restriction on baseline and periprandial plasma ghrelin concentrations of postpubertal Holstein heifers. Objectives of this study were to measure both daily and periprandial plasma ghrelin concentrations of postpubertal Holstein heifers during prolonged undernutrition. Following an acclimation period, Holstein heifers [n = 10; 339.5 ± 8.6 kg of body weight (BW)] were fed ad libitum [well fed (WF); n = 5] or restricted to 50% of ad libitum intake [underfed (UF); n = 5) for 8 wk. Body condition scores (BCS) were recorded at the beginning and end of the treatment period, and weekly measurements of BW, plasma ghrelin, progesterone, and nonesterified fatty acids (NEFA) concentrations were obtained. Ovarian follicular and luteal structures were measured twice weekly via transrectal ultrasonography. Plasma ghrelin concentrations were also measured during a periprandial window bleed conducted at the end of the experiment. During the window bleed, samples were collected every 15 min between 0500 and 0900 h, with feed offered at 0700 h. Underfed heifers lost BW and BCS, whereas WF heifers gained weight and either increased or maintained BCS. Chronic underfeeding increased circulating ghrelin and NEFA concentrations. By wk 4 of the treatment period, circulating ghrelin concentrations of the UF heifers reached a plateau. Periprandial fluctuations in ghrelin concentrations were apparent as plasma ghrelin concentrations changed over time. Overall differences in periprandial plasma ghrelin concentrations were primarily due to prefeeding effects of plane of nutrition. Plasma ghrelin concentrations and change in BCS were negatively correlated such that heifers that lost the most BCS had the highest concentrations of circulating ghrelin. Two of the 5 UF heifers became anestrus by wk 3 of the treatment period. Despite being of similar age, the heifers that became anestrus had lower BW and plasma ghrelin concentrations than the UF heifers that continued to ovulate. In the current experiment, long-term undernutrition elicited ghrelin responses similar to those reported for shorter durations of nutrient restriction in cattle and other ruminants. These results demonstrate that plane of nutrition is a chronic regulator of plasma ghrelin concentrations, and that these concentrations can be experimentally manipulated in postpubertal heifers for up to 8 wk with no evidence of an adaptive response. 23321433 Short-term experience of porcine small intestinal submucosa patches in paediatric cardiovascular surgery. Surgical reconstructions or palliations of congenital heart defects often require the utilization of patches, of which the ideal material has yet to be discovered. Recently, porcine small intestinal submucosa extracellular matrix (SIS-ECM) has been advocated as an alternative to conventional synthetic or biological patch material. Here, we present our initial experience with SIS-ECM in paediatric cardiovascular reconstructions. A retrospective review of all patients <18 years of age who had SIS-ECM implanted during surgery from July 2009 to September 2011 was performed. Chart review consisted of assessment of heart defect, operative procedures, implant location, echocardiograms, reinterventions and pathology studies related to any explanted SIS-ECM. During the study period, 37 paediatric patients had SIS-ECM implanted during a cardiovascular reconstruction. Mean length of follow-up was 411 days (range 6-757 days). SIS-ECM was implanted in 48 cardiac locations as patches for septal defects (n = 13), vascular augmentation (n = 26), outflow tract augmentation (n = 7) and valve reconstruction (n = 3). Eight of the patients required SIS-ECM patches in multiple locations. There was progressive stenosis in one RVOT patch requiring reoperation. Progressive stenosis in a near-circumferential pulmonary artery patch was present in 1 patient, requiring stent placement. All other patched structures remained patent. SIS-ECM is suitable for the closure of septal defects. Use of SIS-ECM for the reconstructions of outflow tracts and great vessels carries a small risk of stenosis, especially in patches that form the majority of the vessel circumference. The long-term follow-up is needed to determine the risk of late stenosis. 23735697 High glucose modulates IL-6 mediated immune homeostasis through impeding neutrophil extracellular trap formation. Neutrophils serve as an active constituent of innate immunity and are endowed with distinct ability for producing neutrophil extracellular traps (NETs) to eliminate pathogens. Earlier studies have demonstrated a dysfunction of the innate immune system in diabetic subjects leading to increased susceptibility to infections; however, the influence of hyperglycemic conditions on NETs is unknown. In the present study we demonstrate that (a) NETs are influenced by glucose homeostasis, (b) IL-6 is a potent inducer of energy dependent NET formation and (c) hyperglycemia mimics a state of constitutively active pro-inflammatory condition in neutrophils leading to reduced response to external stimuli making diabetic subjects susceptible to infections. 23966964 Pros and cons of a wandering mind: a prospective study. Mind wandering (MW) has recently been associated with both adaptive (e.g., creativity enhancement) and maladaptive (e.g., mood worsening) consequences. This study aimed at investigating whether proneness to MW was prospectively associated with negative health outcomes. At time 0, 21 women, 19 men; mean age = 24.5 (4.9) underwent a 5-min baseline electrocardiogram (ECG), a 20-min laboratory tracking task with thought probes, and personality questionnaires. At time 1 (1 year follow-up), the same participants underwent a 24-h Ecological Momentary Assessment characterized by ambulatory ECG recording and electronic diaries. First, we examined if the likelihood of being a "mind wanderer" was associated with specific personality dispositions. Then, we tested if the occurrence of episodes of MW in the lab would be correlated with frequency of MW in daily life. Finally, multiple regression models were used to test if MW longitudinally acted as a risk factor for health, accounting for the effects of biobehavioral variables. Among dispositional traits, the frequency of MW episodes in daily life was inversely associated with the capacity of being mindful (i.e., aware of the present moment and non-judging). There was a positive correlation between frequency of MW in the lab and in daily life, suggesting that it is a stable disposition of the individual. When differentiated from perseverative cognition (i.e., rumination and worry), MW did not predict the presence of health risk factors 1 year later, however, a higher occurrence of episodes of MW was associated with short-term adverse consequences, such as increased 24-h heart rate (HR) on the same day and difficulty falling asleep the subsequent night. Present findings suggest that MW may be associated with short term "side effects" but argue against a long term dysfunctional view of this cognitive process. 23508828 Accuracy of sexually violent person assessments of juveniles adjudicated for sexual offenses. This study reviewed the records of 198 juveniles who were committed to secured custody after being adjudicated delinquent for a sexually violent offense that qualified them for possible commitment under a Sexually Violent Person's (SVP) civil commitment law. For an individual to be committed, the statute requires that the individual have a qualifying mental disorder and is "likely," to commit a future act of sexual violence. Each youth was screened by at least two expert examiners in a two-step process. Fifty-four of the youth were found to meet the commitment criteria in an initial examination and were subject to an SVP petition. The remaining 144 were screened out. Subsequent criminal charges were collected over a 4.97-year mean follow-up. The results showed that the prevalence rates for general sexual offending and felony sexual offending did not differ between youth who were screened out and those who were subject to a petition. Among petitioned youth, 11.76% were charged with a new sexual offense including 9.80% who were charged with a felony sexual assault. By comparison, 17.36% of the youth that were screened out were charged with a sexual offense including 13.19% who were charged with a felony sexual assault, a nonsignificant difference. 23166320 Molecular interaction studies of HIV-1 matrix protein p17 and heparin: identification of the heparin-binding motif of p17 as a target for the development of multitarget antagonists. Once released by HIV(+) cells, p17 binds heparan sulfate proteoglycans (HSPGs) and CXCR1 on leukocytes causing their dysfunction. By exploiting an approach integrating computational modeling, site-directed mutagenesis of p17, chemical desulfation of heparin, and surface plasmon resonance, we characterized the interaction of p17 with heparin, a HSPG structural analog, and CXCR1. p17 binds to heparin with an affinity (K(d) = 190 nm) that is similar to those of other heparin-binding viral proteins. Two stretches of basic amino acids (basic motifs) are present in p17 N and C termini. Neutralization (Arg→Ala substitution) of the N-terminal, but not of the C-terminal basic motif, causes the loss of p17 heparin-binding capacity. The N-terminal heparin-binding motif of p17 partially overlaps the CXCR1-binding domain. Accordingly, its neutralization prevents also p17 binding to the chemochine receptor. Competition experiments demonstrated that free heparin and heparan sulfate (HS), but not selectively 2-O-, 6-O-, and N-O desulfated heparins, prevent p17 binding to substrate-immobilized heparin, indicating that the sulfate groups of the glycosaminoglycan mediate p17 interaction. Evaluation of the p17 antagonist activity of a panel of biotechnological heparins derived by chemical sulfation of the Escherichia coli K5 polysaccharide revealed that the highly N,O-sulfated derivative prevents the binding of p17 to both heparin and CXCR1, thus inhibiting p17-driven chemotactic migration of human monocytes with an efficiency that is higher than those of heparin and HS. Here, we characterized at a molecular level the interaction of p17 with its cellular receptors, laying the basis for the development of heparin-mimicking p17 antagonists. 23824824 Influences on Trimerization and Aggregation of Soluble, Cleaved HIV-1 SOSIP Envelope Glycoprotein. We describe methods to improve the properties of soluble, cleaved gp140 trimers of the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) for use in structural studies and as immunogens. In the absence of nonionic detergents, gp140 of the KNH1144 genotype, terminating at residue 681 in gp41 (SOSIP.681), has a tendency to form higher-order complexes or aggregates, which is particularly undesirable for structure-based research. We found that this aggregation in the absence of detergent does not involve the V1, V2, or V3 variable regions of gp120. Moreover, we observed that detergent forms micelles around the membrane-proximal external region (MPER) of the SOSIP.681 gp140 trimers, whereas deletion of most of the MPER residues by terminating the gp140 at residue 664 (SOSIP.664) prevented the aggregation that otherwise occurs in SOSIP.681 in the absence of detergent. Although the MPER can contribute to trimer formation, truncation of most of it only modestly reduced trimerization and lacked global adverse effects on antigenicity. Thus, the MPER deletion minimally influenced the kinetics of the binding of soluble CD4 and a CD4-binding site antibody to immobilized trimers, as detected by surface plasmon resonance. Furthermore, the MPER deletion did not alter the overall three-dimensional structure of the trimers, as viewed by negative-stain electron microscopy. Homogeneous and aggregate-free MPER-truncated SOSIP Env trimers are therefore useful for immunogenicity and structural studies. 23207249 Silexan, an essential oil from flowers of Lavandula angustifolia, is not recognized as benzodiazepine-like in rats trained to discriminate a diazepam cue. Recently, an essential oil of selected quality produced from the flowering tops of Lavandula angustifolia Mill. by steam distillation (Silexan) has been approved in Germany for the treatment of restlessness in case of anxious mood. Based on the observed clinical effects, it has been speculated that lavender oil may exert benzodiazepine-like action including the known dependence and abuse potential of this class of drugs. Although no evidence for such an activity was generated during the long-standing medicinal use of lavender oil, further preclinical investigations were now conducted to evaluate this potential side effect in more detail. Twelve adult, male, Sprague-Dawley rats were trained to discriminate the benzodiazepine drug diazepam (2 mg/kg i.p.) from saline using a two-lever operant procedure. After approximately 40 training sessions the majority of rats learned the discrimination and pre-treatment with ascending doses of diazepam (0.3-2 mg/kg i.p.) produced a dose related generalization to the diazepam cue. In these same animals Silexan was administered to see if animals recognized the drug as "diazepam-like" i.e. generalized to diazepam or "saline-like". Silexan tested at doses 3-30 mg/kg i.p. produced almost exclusively (>90%) saline-like responding. Also there was no effect of Silexan on response rate, i.e. rate of lever pressing, at any dose suggesting that the test article is well tolerated and does not exert a sedating effect. In sum, Silexan has no diazepam-like interoceptive property in adult, male rats. This suggests that Silexan does not share the potential of benzodiazepines to induce the development of tolerance, dependence and addiction. 23554352 Development of a checklist of safe discharge practices for hospital patients. Discharge from hospital can be a vulnerable period for patients. Multifaceted "discharge bundles" facilitate care transitions and possibly decrease adverse outcomes. We describe a structured approach to discharge planning, starting from admission and proceeding through discharge, using a standardized checklist of tasks to be performed for each hospitalization day. To create an evidence-based checklist of safe discharge practices for hospital patients. In the province of Ontario, the Ministry of Health and Long-Term Care convened a panel of expert members from multiple disciplines and across several healthcare sectors. The panel conducted a systematic search of the literature and used a structured approach to review evidence-based practices that ensure efficient, effective, safe, and patient-centered care transitions. A discharge-checklist tool was created to facilitate safe discharge from hospital. The final checklist describes the processes necessary for a safe and optimal discharge and recommended timeline of when to complete each step, starting from the first day of admission. The checklist domains include (1) indication for hospitalization, (2) primary care, (3) medication safety, (4) follow-up plans, (5) home-care referral, (6) communication with outpatient providers, and (7) patient education. The Checklist of Safe Discharge Practices for Hospital Patients summarizes the sequence of events that need to be completed throughout a typical hospitalization. Standardizing discharge planning and initiating processes early on in a patient's hospital stay may ensure a safe transition home. Journal of Hospital Medicine 2013;8:444-449. © 2013 Society of Hospital Medicine. 23958002 Meta-analysis of the effect of pasture allowance on pasture intake, milk production, and grazing behavior of dairy cows grazing temperate grasslands. Daily pasture allowance (PA) is defined as the product of pregrazing pasture mass and offered area, and is the major grazing management factor determining pasture utilization per unit area and daily performance of grazing dairy cows. The objective of the present study was to perform a meta-analysis reviewing the effect of PA on pasture intake, milk production, milk composition, and grazing behavior of dairy cows. Experiments studying the effect of PA on pasture intake or milk production, which eventually included milk composition or grazing behavior data, or both, were selected to create a database. Papers were selected only if at least 2 PA were compared under the same experimental conditions, particularly the same pasture mass (i.e., where PA levels were only obtained through changes in daily offered area). The final database included 97 PA comparisons reported in 56 papers. For analytical purposes, the database was subdivided into 3 subsets that varied according to the estimation height (EH) at which PA was determined; that is, PA above ground level (PA0 subset), PA above 2.5 to 3.5 cm (PA3 subset), and PA above 4 to 5 cm (PA5 subset). Statistical analyses were conducted independently on the PA0, PA3, and PA5 subsets and on the whole database (global analysis) by using linear and nonlinear mixed-model procedures. The curves, either exponential, quadratic, or linear, describing the effects of PA on pasture intake, milk production, or grazing behavior of dairy cows are conceptually similar, whatever the EH. The equations describing these curves are, however, specific for each EH. Accordingly, from typical low to high PA, the increase in pasture intake (0.13 vs. 0.21 vs. 0.28 kg/kg of PA), milk production (0.11 vs. 0.17 vs. 0.24 kg/kg of PA), and milk solids production (0.008 vs. 0.010 vs. 0.013 kg/kg of PA) per kilogram of increase in PA was lower for PA0 than for PA3, and for PA3 than for PA5. Grazing time increased from low to medium PA and did not vary from medium to high PA. Pasture intake rate seemed to increase from low to medium PA because of greater bite mass, whereas it increased from medium to high PA because of greater biting rate. The present meta-analysis demonstrated that the general relationship between PA and any dependent variable is quite strong and independent of EH. This suggests no specific relationship for some parts of the world or methodology approach, with a high portability of the global equations calculated here. These results are useful for improving grazing management and modeling on pasture-based dairy systems. 23926338 Lack of B cell dysfunction is associated with functional, gp120-dominant antibody responses in breast milk of simian immunodeficiency virus-infected African green monkeys. The design of an effective vaccine to reduce the incidence of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) via breastfeeding will require identification of protective immune responses that block postnatal virus acquisition. Natural hosts of simian immunodeficiency virus (SIV) sustain nonpathogenic infection and rarely transmit the virus to their infants, despite high milk virus RNA loads. This is in contrast to HIV-infected women and SIV-infected rhesus macaques (RhMs), non-natural hosts which exhibit higher rates of postnatal virus transmission. In this study, we compared the systemic and mucosal B cell responses of lactating, SIV-infected African green monkeys (AGMs), a natural host species, to that of SIV-infected RhMs and HIV-infected women. AGMs did not demonstrate hypergammaglobulinemia or accumulate circulating memory B cells during chronic SIV infection. Moreover, the milk of SIV-infected AGMs contained higher proportions of naive B cells compared to RhMs. Interestingly, AGMs exhibited robust milk and plasma Env binding antibody responses that were one to two logs higher than in RhMs and humans and demonstrated autologous neutralizing responses in milk at one year post infection. Furthermore, the plasma and milk Env gp120-binding antibody responses were equivalent to or predominant over Env gp140-binding antibody responses in AGMs, in contrast to that in RhMs and humans. The strong gp120-specific, functional antibody responses in the milk of SIV-infected AGMs may contribute to the rarity of postnatal transmission observed in natural SIV hosts. 23398573 Supporting the care of children with diabetes in school: a qualitative study of nurses in the UK. Intensification of diabetes management in children and young people has implications for schools. The aim of this study was to examine the role of nurses in supporting care of children with diabetes in schools and early years settings. The qualitative design incorporated focus groups and individual telephone interviews with nurses who were unavailable to participate in focus groups. A purposive sample of 47 nurses from acute and community settings, participated in eight focus groups and eight telephone interviews. Data were analysed through a process of constant comparison. Nurses identified an ambiguous and inadequate legal and policy framework. The responses of schools were variable and unpredictable because the views of head teachers determined the level of cooperation. School staff could lack basic knowledge about Type 1 diabetes. Relationships between school staff and parents could also affect their willingness to provide support for diabetes care. The skills of negotiating appropriate support for children with diabetes were learnt by experience rather than through formal training or evidence-based guidance. Nurses' accounts demonstrated uncertainties about: what could be required of schools; how schools would respond; individual responsibilities; and about what constituted best practice. There is a need for more evidence about how healthcare providers can influence schools and about the most cost-effective use of nurses to support the management of children with diabetes in schools. 23582307 Colloidal stability of suspended and agglomerate structures of settled carbon nanotubes in different aqueous matrices. Carbon nanotubes (CNTs) are often processed in suspended form and therefore a release of CNT-suspensions into the aquatic environment is plausible. In this study, the behaviour of two physico-chemically very different CNT types in the presence of varying, environmentally relevant calcium-containing media was investigated, including the long-term colloidal stability and the sedimentary structures of settled CNTs. Calcium induced CNT flocculation, however, the stability of the CNTs in the medium did not monotonously decrease with increasing calcium concentration. At intermediate calcium concentrations (0.5-1.5 mM Ca) pre-dispersed CNTs were stabilized in humic acid medium to similar, temporarily even to higher degree than in the absence of calcium. Between pH 5 and 8 only at the highest pH an influence on CNT stability was observed by either promoting flocculation or stabilisation depending on the CNT type. Humic acid stabilized CNTs much better than fulvic acid. Generally, the colloidal stability of the long, thick CNTs with higher surface oxygen content was less affected by the media composition. An investigation of the settled CNT material using analytical electron microscopy revealed the presence of spheroidal, bundle-like and net like CNT-agglomerate structures. Calcium possibly acted as bridging agent linking CNTs in a network like manner, temporarily increasing the CNT concentrations stabilized in the supernatants due to the low density of these structures. With increasing settling time the CNTs formed a fluffy sediment layer at the bottom of the reaction vessels. Bundle-like CNT agglomerates were also observed within that layer of settled CNTs, possibly caused by calcium neutralizing the surface charges. Furthermore, the CNT suspensions contained spheroidal CNT agglomerates, most likely residues from the original dry powder that were not disaggregated. The analysis of settled CNT material is a novelty and illustrates CNT agglomerate structures possibly accumulating in the sediments of aquatic systems subsequent to CNT emissions. 23250742 Regulation of H2O2 stress-responsive genes through a novel transcription factor in the protozoan pathogen Entamoeba histolytica. Outcome of infection depends upon complex interactions between the invading pathogen and the host. As part of the host's innate immune response, the release of reactive oxygen and nitrogen species by phagocytes represents a major obstacle to the establishment of infection. The ability of the human parasite Entamoeba histolytica to survive reactive oxygen and nitrogen species is central to its pathogenic potential and contributes to disease outcome. In order to define the transcriptional network associated with oxidative stress, we utilized the MEME and MAST programs to analyze the promoter regions of 57 amoebic genes that had increased expression specifically in response to H(2)O(2) exposure. We functionally characterized an H(2)O(2)-regulatory motif (HRM) ((1)AAACCTCAATGAAGA(15)), which was enriched in these promoters and specifically bound amoebic nuclear protein(s). Assays with promoter-luciferase fusions established the importance of key residues and that the HRM motif directly impacted the ability of H(2)O(2)-responsive promoters to drive gene expression. DNA affinity chromatography and mass spectrometry identified EHI_108720 as an HRM DNA-binding protein. Overexpression and down-regulation of EHI_108720 demonstrated the specificity of EHI_108720 protein binding to the HRM, and overexpression increased basal expression from an H(2)O(2)-responsive wild-type promoter but not from its mutant counterpart. Thus, EHI_108720, or HRM-binding protein, represents a new stress-responsive transcription factor in E. histolytica that controls a transcriptional regulatory network associated with oxidative stress. Overexpression of EHI_108720 increased parasite virulence. Insight into how E. histolytica responds to oxidative stress increases our understanding of how this important human pathogen establishes invasive disease. 23821359 Intravenous immunoglobulin for suspected or proven infection in neonates. Neonates are at higher risk of infection due to immuno-incompetence. Maternal transport of immunoglobulins to the fetus mainly occurs after 32 weeks' gestation, and endogenous synthesis begins several months after birth. Administration of intravenous immunoglobulin (IVIG) provides immunoglobulin G (IgG) that can bind to cell surface receptors, provide opsonic activity, activate complement, promote antibody-dependent cytotoxicity and improve neutrophilic chemo-luminescence. Theoretically, infectious morbidity and mortality could be reduced by the administration of IVIG. To assess the effects of IVIG on mortality/morbidity caused by suspected or proven infection at study entry in neonates. To assess in a subgroup analysis the effects of IgM-enriched IVIG on mortality from suspected infection. For this update, MEDLINE, EMBASE, The Cochrane Library, CINAHL, trial registries, Web of Science, reference lists of identified studies, meta-analyses and personal files were searched in 2013. No language restrictions were applied. Randomised or quasi-randomised controlled trials; newborn infants (< 28 days old); IVIG for treatment of suspected or proven bacterial/fungal infection compared with placebo or no intervention; one of the following outcomes was reported: mortality, length of hospital stay or psychomotor development at follow-up. Statistical analyses included typical risk ratio (RR), risk difference (RD), weighted mean difference (WMD), number needed to treat for an additional beneficial outcome (NNTB) or an additional harmful outcome (NNTH) (all with 95% confidence intervals (CIs) and the I-squared (I(2)) statistic to examine for statistical heterogeneity). The updated search identified one published study and one ongoing study. A total of eight studies evaluating 3871 infants are included in this review.Mortality during hospital stay in infants with clinically suspected infection at trial entry was not significantly different after IVIG treatment (8 studies (n = 2425); typical RR 0.94, 95% CI 0.80 to 1.12; typical RD -0.01, 95% CI - 0.04 to 0.02 I(2) = 28% for RR and 32% for RD). Death or major disability at 2 years corrected age was not significantly different in infants with suspected infection after IVIG treatment (one study (n = 1985); RR 0.98, 95% CI 0.88 to 1.09 RD -0.01, 95% CI -0.05 to 0.03). Mortality during hospital stay was not significantly different after IVIG treatment in infants with proven infection at trial entry (RR 0.95, 95% CI 0.74 to 1.21 RD -0.01, 95% CI -0.04 to 0.03). Death or major disability at 2 years corrected age was not significantly different after IVIG treatment in infants with proven infection at trial entry (RR 1.03, 95% CI 0.91 to 1.18; RD 0.01, 95% CI -0.04 to 0.06). Mortality during hospital stay in infants with clinically suspected or proven infection at trial entry was not significantly different after IVIG treatment (1 study (n = 3493); RR 1.00, 95% CI 0.86 to 1.16; RD 0.00, 95% CI - 0.02 to 0.03). Death or major disability at 2 years corrected age was not significantly different after IVIG treatment in infants with suspected or proven infection at trial entry (1 study (n = 3493); RR 1.00, 95% CI 0.92 to 1.09; RD -0.00, 95% CI -0.03 to 0.03). Length of hospital stay was not reduced for infants with suspected/proven infection at trial entry (1 study (n = 3493); mean difference (MD) 0.00 days, 95% CI -0.61 to 0.61). No significant difference in mortality during hospital stay after IgM-enriched IVIG treatment for suspected infection was reported at trial entry (3 studies (n = 164); typical RR 0.57, 95% CI 0.31 to 1.04; RD -0.12, 95% CI -0.24 to 0.00 ; P = 0.06); I(2) = 2% for RR and 0% for RD). In previous reviews, we encouraged researchers to undertake well-designed trials to confirm or refute the effectiveness of IVIG in reducing adverse outcomes in neonates with suspected infection. Such a trial has been undertaken. Results of the INIS trial, which enrolled 3493 infants, carry a heavy weight in the current update of this review, and the undisputed results show no reduction in death or major disability at 2 years of age. Routine administration of IVIG to prevent mortality in infants with suspected or proven neonatal infection is not recommended. 23893384 RACK1 promoted the growth and migration of the cancer cells in the progression of esophageal squamous cell carcinoma. Dysregulation of hedgehog signaling has been involved in esophageal squamous cell carcinoma (ESCC) by the mechanisms that are not fully understood. The receptor for activated protein kinase C (RACK1) is involved in the progression of multiple cancers. However, its expression and function in ESCC have not been investigated. Here, we found that the expression of RACK1 was upregulated in ESCC clinical samples. Moreover, over-expression of RACK1 in ESCC cells promoted cell proliferation and migration, while downregulation of RACK1 impaired the proliferation and migration of ESCC cells in vitro and in vivo. Mechanistically, RACK1 promoted the proliferation and migration of ESCC cells by activating hedgehog signaling. Taken together, our study suggested RACK1 might be an important therapeutic target in ESCC. 23895697 Secular Changes on the Distribution of Body Mass Index among Chinese Children and Adolescents, 1985-2010. To analyze the change in Body Mass Index (BMI) distribution among Chinese children and adolescents for the development of more effective intervention for childhood obesity. Data on the national students' constitution and health survey between 1985 and 2010 was used for this study. Subjects were students aged 7-18 randomly selected from 30 provinces in China. BMI for-age curves were developed by LMS method, and the trend of BMI distribution was determined by comparing the upper BMI percentiles and analyzing the skew shift of distribution between 1985 and 2010. An overall positive swift trend of BMI between 1985 and 2010 was observed among the Chinese school-age children and adolescents. The average median of the BMI increased from 16.8 and 17.0 kg/m2 to 18.2 and 17.9 kg/m2 in 25 years, with increments 0.56 and 0.36 kg/m2 per decade for males and females, respectively. The more obvious increments were found at the high BMI. The total increments of BMI in this period were 4.03 and 2.20 kg/m2 at the 85th, 6.14 and 3.57 kg/m2 at the 95th, and 6.99 and 4.27 kg/m2 at the 97th percentiles, for males and females, respectively. Obvious increments were observed at high BMI of the Chinese children and adolescents. More effective interventions should be taken for control and prevention of obesity and its health consequence for these subgroups. It is necessary to establish a risk-complex system consisting of the identification of BMI scope, the screen of the disease risk factors and the assessment of excessive adiposity. 23333709 Bottom-up approaches for preparing drug nanocrystals: Formulations and factors affecting particle size. The solubility dependent bioavailability problem has become a major hurdle in drug development processes. Drug nanocrystals have been widely accepted by the pharmaceutical industry to improve the bioavailability of poorly water-soluble compounds. Top-down and bottom-up technologies are the two primary technical approaches of drug nanocrystal production. Though the top-down approach has been hugely successful on the commercial front, it has some inherent drawbacks that necessitate the emergence of alternate approaches. The bottom-up approach has not yet been established as a successful commercial technology. However, it has the potential to produce small size drug nanocrystals with less energy demanding processes. The bottom-up approach is commonly known as precipitation technique. It would be possible to stabilize particles at an early stage of precipitation and to generate drug nanocrystals. In the first part of this review article, we have discussed various bottom-up technologies that are currently in use. This has been followed by description and analysis of various process parameters that can affect the final particle size of the drug nanocrystals. 22931533 Cholinergic modulation by opioid receptor ligands: potential application to Alzheimer's disease. Morphinans have a storied history in medicinal chemistry as pain management drugs but have received attention as modulators of cholinergic signaling for the treatment of Alzheimer's Disease (AD). Galantamine is a reversible, competitive acetylcholinesterase (AChE) inhibitor and allosteric potentiating ligand of nicotinic acetylcholine receptors (nAChR-APL) that shares many common structural elements with morphinan-based opioids. The structurally diverse opioids codeine and eseroline, like galantamine, are also nAChR-APL that have greatly diminished affinity for AChE, representing potential lead compounds for selective nAChR-APL development. In accordance with the emerging repurposing trend of evaluating known compounds for novel pharmacological activity, ongoing research on augmentation of cholinergic signaling that has been aided by the use of opioids will be reviewed. 23886586 Worldwide human papillomavirus genotype attribution in over 2000 cases of intraepithelial and invasive lesions of the vulva. Human papillomavirus (HPV) contribution in vulvar intraepithelial lesions (VIN) and invasive vulvar cancer (IVC) is not clearly established. This study provides novel data on HPV markers in a large series of VIN and IVC lesions. Histologically confirmed VIN and IVC from 39 countries were assembled at the Catalan Institute of Oncology (ICO). HPV-DNA detection was done by polymerase chain reaction using SPF-10 broad-spectrum primers and genotyping by reverse hybridisation line probe assay (LiPA25) (version 1). IVC cases were tested for p16(INK4a) by immunohistochemistry (CINtec histology kit, ROCHE). An IVC was considered HPV driven if both HPV-DNA and p16(INK4a) overexpression were observed simultaneously. Data analyses included algorithms allocating multiple infections to calculate type-specific contribution and logistic regression models to estimate adjusted prevalence (AP) and its 95% confidence intervals (CI). Of 2296 cases, 587 were VIN and 1709 IVC. HPV-DNA was detected in 86.7% and 28.6% of the cases respectively. Amongst IVC cases, 25.1% were both HPV-DNA and p16(INK4a) positive. IVC cases were largely keratinising squamous cell carcinoma (KSCC) (N=1234). Overall prevalence of HPV related IVC cases was highest in younger women for any histological subtype. SCC with warty or basaloid features (SCC_WB) (N=326) were more likely to be HPV and p16(INK4a) positive (AP=69.5%, CI=63.6-74.8) versus KSCC (AP=11.5%, CI=9.7-13.5). HPV 16 was the commonest type (72.5%) followed by HPV 33 (6.5%) and HPV 18 (4.6%). Enrichment from VIN to IVC was significantly high for HPV 45 (8.5-fold). Combined data from HPV-DNA and p16(INK4a) testing are likely to represent a closer estimate of the real fraction of IVC induced by HPV. Our results indicate that HPV contribution in invasive vulvar cancer has probably been overestimated. HPV 16 remains the major player worldwide. 23696679 Medial Posterior Meniscal Root Tears Are Associated with Development or Worsening of Medial Tibiofemoral Cartilage Damage: The Multicenter Osteoarthritis Study. Purpose: To assess the association of meniscal root tear with the development or worsening of tibiofemoral cartilage damage. Materials and Methods: Institutional review board approval and written informed consent from all subjects were obtained. A total of 596 knees with radiographically depicted osteoarthritis were randomly selected from the Multicenter Osteoarthritis study cohort. Cartilage damage was semiquantitatively assessed by using the Whole-Organ Magnetic Resonance Imaging Score (WORMS) system (grades 0-6). Subjects were separated into three groups: root tear only, meniscal tear without root tear, and neither meniscal nor root tear. A log-binomial regression model was used to calculate the relative risks for knees to develop incident or progressing cartilage damage in the root tear group and the meniscal tear group, with the no tear group serving as a reference. Results: In the medial tibiofemoral joint, there were 37 knees with isolated medial posterior root tear, 294 with meniscal tear without root tear, and 264 without meniscal or root tear. There were only two lateral posterior root tears, and no anterior root tears were found. Thus, the focus was on the medial posterior root tear. The frequency of severe cartilage damage (WORMS ≥5) was higher in the group with root tear than in the group without root or meniscal tear (76.7% vs 19.7%, P < .0001) but not in the group with meniscal but no root tear (76.7% vs 65.2%, P = .055). Longitudinal analyses included 33 knees with isolated medial posterior root tear, 270 with meniscal tear, and 245 with no tear. Adjusted relative risk of cartilage loss was 2.03 (95% confidence interval [CI]: 1.18, 3.48) for the root tear group and 1.84 (95% CI: 1.32, 2.58) for the meniscal tear group. Conclusion: Isolated medial posterior meniscal root tear is associated with incident and progressive medial tibiofemoral cartilage loss. © RSNA, 2013. 23920056 Longitudinal analysis of serological tests officially adopted by the Brazilian Ministry of Health for the diagnosis of canine visceral leishmaniasis in dogs vaccinated with Leishmune(®) Development of vaccines against canine visceral leishmaniasis (CVL) may provide a prophylactic barrier, but antibody response detected by standard diagnostic techniques may not separate vaccinated from naturally infected dogs. Moreover, anti-Leishmania antibody levels in vaccinated dogs may be detectable for months. Accordingly, the aim of the present study was to comparatively evaluate an "in-house" ELISA with three serological tests officially adopted by the Brazilian Ministry of Health for the diagnosis of CVL in dogs vaccinated with Leishmune(®). A total of 18 mongrel dogs were submitted to a complete protocol of the vaccine, monitored and evaluated in 5 times (T0-T4) up to 180 days after T0. Twenty-one days after the first dose (T1), 50% of the dogs were seropositive by the "in-house" ELISA and 5.5% by IFAT, while by the official ELISA and DPP(®) CVL rapid test all dogs tested negative. At time T2, 42 days after of the first dose, 100%, 83.3%, 11.1%, and 5.5% of the dogs were seropositive by the "in-house" ELISA, IFAT, official ELISA kit and the DPP(®) CVL rapid test, respectively. Ninety days after the first dose (T3), 100%, 83.3%, 72.2% and 33.3% of the dogs were seropositive by the "in-house" ELISA, official ELISA kit, IFAT, and the DPP(®) CVL rapid test, respectively. Finally, at time T4, 88.8%, 33.3%, 11.1% and 5.5% of the dogs were seropositive by the "in-house" ELISA, official ELISA kit, DPP(®) CVL rapid test and IFAT, respectively. In conclusion, dogs vaccinated with Leishmune(®) cross-react by an "in-house" ELISA and by the three official Brazilian serological tests for the diagnosis of canine visceral leishmaniasis up to six months after the first vaccine dose, and may be mistakenly diagnosed and removed. 23797952 Financial crisis and collapsed banks: Psychological distress and work related factors among surviving employees-A nation-wide study. The study considered psychological distress among surviving bank employees differently entangled in downsizing and restructuring following the financial crisis of 2008. A cross-sectional, nationwide study was conducted among surviving employees (N = 1880, response rate 68%). Multivariate analysis was conducted to assess factors associated with psychological distress. In the banks, where all employees experienced rapid and unpredictable organizational changes, psychological distress was higher among employees most entangled in the downsizing and restructuring process. Being subjected to downsizing within own department, salary cut, and transfer to another department, was directly related to increased psychological distress, controlling for background factors. The associations between downsizing, restructuring, and distress were reduced somewhat by adding job demands, job control, and empowering leadership to the model, however, adding social support had little effect on these associations. Employees most entangled in organizational changes are the most vulnerable and should be prioritized in workplace interventions during organizational changes. Am. J. Ind. Med. 56:1095-1106, 2013. © 2013 Wiley Periodicals, Inc. 23830901 Single point biochemical measurement algorithm for early diagnosis of ectopic pregnancy. Tubal rupture as a result of an ectopic pregnancy is the leading cause of first trimester maternal mortality. Currently, the diagnosis of ectopic pregnancy depends on transvaginal ultrasound and serial serum measurements of human chorionic gonadotrophin (hCG), which requires follow up. The objective of this study was to examine whether single point measurements at presentation could distinguish between women with ectopic pregnancy, viable pregnancy, and spontaneous miscarriage. Serum total hCG (hCGt), hyperglycosylated hCG (hCGh), free beta subunit of hCG (hCGβ), progesterone (P), and CA-125 were measured by chemiluminescence immunoassay over a 3month period in 441 women presenting at the emergency room with abdominal pain and a positive pregnancy test. Patient outcomes were followed and confirmed by histology. 65 samples were excluded due to poor sample storage, or lost to follow up. The pregnancy outcomes were 175 viable pregnancies, 175 spontaneous miscarriages, and 26 ectopic pregnancies. A serum hCGt <3736mIU/mL cut off was 100% sensitive, with 76% specificity, for distinguishing ectopic pregnancy from viable pregnancy; but did not differentiate spontaneous miscarriage. Serum CA125 <41.98U/mL produced 100% sensitivity and 43% specificity in distinguishing ectopic pregnancy from spontaneous miscarriage. Sequential application of hCGt and CA-125 cut off followed by ultrasound could detect 100% of ectopic pregnancies with 87% specificity for all intrauterine pregnancies. The combination of serum hCGt <3736mIU/mL, followed by CA125 <41.98U/mL is a promising algorithm for detecting all ectopic pregnancy at initial presentation. 23830192 New small molecule inhibitors of UPR activation demonstrate that PERK, but not IRE1α signaling is essential for promoting adaptation and survival to hypoxia. The unfolded protein response (UPR) is activated in response to hypoxia-induced stress in the endoplasmic reticulum (ER) and consists of three distinct signaling arms. Here we explore the potential of targeting two of these arms with new potent small-molecule inhibitors designed against IRE1α and PERK. We utilized shRNAs and small-molecule inhibitors of IRE1α (4μ8c) and PERK (GSK-compound 39). XBP1 splicing and DNAJB9 mRNA was measured by qPCR and was used to monitor IRE1α activity. PERK activity was monitored by immunoblotting eIF2α phosphorylation and qPCR of DDIT3 mRNA. Hypoxia tolerance was measured using proliferation and clonogenic cell survival assays of cells exposed to mild or severe hypoxia in the presence of the inhibitors. Using knockdown experiments we show that PERK is essential for survival of KP4 cells while knockdown of IRE1α dramatically decreases the proliferation and survival of HCT116 during hypoxia. Further, we show that in response to both hypoxia and other ER stress-inducing agents both 4μ8c and the PERK inhibitor are selective and potent inhibitors of IRE1α and PERK activation, respectively. However, despite potent inhibition of IRE1α activation, 4μ8c had no effect on cell proliferation or clonogenic survival of cells exposed to hypoxia. This was in contrast to the inactivation of PERK signaling with the PERK inhibitor, which reduced tolerance to hypoxia and other ER stress inducing agents. Our results demonstrate that IRE1α but not its splicing activity is important for hypoxic cell survival. The PERK signaling arm is uniquely important for promoting adaptation and survival during hypoxia-induced ER stress and should be the focus of future therapeutic efforts. 23939491 Overexpression of microRNA-1 promotes cardiomyocyte commitment from human cardiovascular progenitors via suppressing WNT and FGF signaling pathways. Early heart development takes place through a complex series of steps, including the induction of cardiac mesoderm, formation of the cardiovascular progenitor cells and the commitment of cardiovascular lineage cells, such as cardiomyocytes (CMs), smooth muscle cells (SMCs) and endothelial cells (ECs). Recently, microRNAs, a family of endogenous, small non-coding RNAs, have been identified as critical regulators in cardiogenesis and cardiovascular disease. Previous studies demonstrated that microRNA-1 (miR-1) could promote cardiac differentiation from mouse and human embryonic stem (ES) cells. However, the underlying mechanism remained largely unclear. We performed microRNA deep sequencing among human ES cells, ES cell derived-multipotent cardiovascular progenitors (MCPs), and MCP-specified CMs, ECs, and SMCs. A specific enrichment of miR-1 was found in CMs, not in SMCs or ECs, implying a key role of miR-1 in determining cardiovascular commitment from MCPs. When overexpressed in human pluripotent stem cells, miR-1 enhanced the expression of key cardiac transcriptional factors and sarcomeric genes. Importantly, we found miR-1 promoted CM differentiation and suppressed EC commitment from MCPs by modulating the activities of WNT and FGF signaling pathways. FZD7 and FRS2 were confirmed as miR-1 targets using luciferase reporter assay and western blot. Overall, this study reveals a fate-switching role of miR-1 at early human cardiovascular commitment stage via suppressing both WNT and FGF signaling pathways. 23443753 Estimation of renal cell carcinoma treatment effects from disease progression modeling. To improve future drug development efficiency in renal cell carcinoma (RCC), a disease-progression model was developed with longitudinal tumor size data from a phase III trial of sorafenib in RCC. The best-fit model was externally evaluated on 145 placebo-treated patients in a phase III trial of pazopanib; the model incorporated baseline tumor size, a linear disease-progression component, and an exponential drug effect (DE) parameter. With the model-estimated effect of sorafenib on RCC growth, we calculated the power of randomized phase II trials between sorafenib and hypothetical comparators over a range of effects. A hypothetical comparator with 80% greater DE than sorafenib would have 82% power (one-sided α = 0.1) with 50 patients per arm. Model-based quantitation of treatment effect with computed tomography (CT) imaging offers a scaffold on which to develop new, more efficient, phase II trial end points and analytic strategies for RCC. 23425956 Irbesartan, an angiotensin receptor blocker, exhibits metabolic, anti-inflammatory and antioxidative effects in patients with high-risk hypertension. Irbesartan, an angiotensin II receptor blocker (ARB), acts as a selective PPAR-γ (peroxisome proliferator-activated receptor-γ) modulator, and thus may have anti-inflammatory and antioxidative effects, as well as beneficial effects on glucose and lipid metabolism. We enrolled 118 high-risk hypertensive outpatients, defined as those with the presence of at least one complication such as coronary artery disease, cerebrovascular disease or diabetes, and who were receiving any ARB except for irbesartan (67±10 years, 80% male subjects). After a 4-week control period, all ARBs were switched to an equivalent dose of irbesartan. We evaluated changes in lipid parameters, inflammatory markers and derivatives of reactive oxygen metabolites (d-ROMs) as an oxidative stress index. After 12 weeks of irbesartan, there were significant decreases in triglycerides (138±73 versus 123±65 mg dl(-1), P<0.05), high-sensitivity C-reactive protein (hs-CRP) (2.80±0.53 versus 2.66±0.50, log (ng ml(-1)), P<0.05) and d-ROMs (338±74 versus 305±62 U.CARR, P<0.001). There were significant increases in high-density lipoprotein cholesterol (50±13 versus 52±14 mg dl(-1), P<0.01) and adiponectin (9.4±6.2 versus 16.6±13.4 ng ml(-1), P<0.05). There were no significant changes in systolic and diastolic blood pressure. The change in d-ROMs from baseline to 12 weeks was positively correlated with the change in hs-CRP (R=0.34, P<0.01). Irbesartan appears to exert beneficial effects on oxidative stress, inflammation, lipid metabolism and metabolic syndrome, indicating that it may be useful in high-risk hypertensive patients. 23844165 Anti-aggregating effect of the naturally occurring dipeptide carnosine on aβ1-42 fibril formation. Carnosine is an endogenous dipeptide abundant in the central nervous system, where by acting as intracellular pH buffering molecule, Zn/Cu ion chelator, antioxidant and anti-crosslinking agent, it exerts a well-recognized multi-protective homeostatic function for neuronal and non-neuronal cells. Carnosine seems to counteract proteotoxicity and protein accumulation in neurodegenerative conditions, such as Alzheimer's Disease (AD). However, its direct impact on the dynamics of AD-related fibril formation remains uninvestigated. We considered the effects of carnosine on the formation of fibrils/aggregates of the amyloidogenic peptide fragment Aβ1-42, a major hallmark of AD injury. Atomic force microscopy and thioflavin T assays showed inhibition of Aβ1-42 fibrillogenesis in vitro and differences in the aggregation state of Aβ1-42 small pre-fibrillar structures (monomers and small oligomers) in the presence of carnosine. in silico molecular docking supported the experimental data, calculating possible conformational carnosine/Aβ1-42 interactions. Overall, our results suggest an effective role of carnosine against Aβ1-42 aggregation. 23392852 Test sensitivity is important for detecting variability in pointing comprehension in canines. Several articles have been recently published on dogs' (Canis familiaris) performance in two-way object choice experiments in which subjects had to find hidden food by utilizing human pointing. The interpretation of results has led to a vivid theoretical debate about the cognitive background of human gestural signal understanding in dogs, despite the fact that many important details of the testing method have not yet been standardized. We report three experiments that aim to reveal how some procedural differences influence adult companion dogs' performance in these tests. Utilizing a large sample in Experiment 1, we provide evidence that neither the keeping conditions (garden/house) nor the location of the testing (outdoor/indoor) affect a dogs' performance. In Experiment 2, we compare dogs' performance using three different types of pointing gestures. Dogs' performance varied between momentary distal and momentary cross-pointing but "low" and "high" performer dogs chose uniformly better than chance level if they responded to sustained pointing gestures with reinforcement (food reward and a clicking sound; "clicker pointing"). In Experiment 3, we show that single features of the aforementioned "clicker pointing" method can slightly improve dogs' success rate if they were added one by one to the momentary distal pointing method. These results provide evidence that although companion dogs show a robust performance at different testing locations regardless of their keeping conditions, the exact execution of the human gesture and additional reinforcement techniques have substantial effect on the outcomes. Consequently, researchers should standardize their methodology before engaging in debates on the comparative aspects of socio-cognitive skills because the procedures they utilize may differ in sensitivity for detecting differences. 23479255 Endoscopic resection of granular cell tumors in the gastrointestinal tract: a single center experience. The frequency of granular cell tumors (GCTs) identified in the gastrointestinal tract has recently increased with the increased use of routine endoscopy. Endoscopic treatment is increasingly used as an alternative to traditional surgical resection, but there are few reports on the efficacy, safety, and long-term prognosis of endoscopic treatment for GCTs. The aim of this study was to assess the efficacy, safety, and long-term prognosis of endoscopic resection for the gastrointestinal GCTs. We examined a total of 27 GCTs in 25 patients who were treated by endoscopic resection from January 2007 to February 2011. For endoscopic resection, endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) was used. Twenty GCTs were located in the esophagus, 5 in the stomach, and 2 in the colon. The median size of the GCTs was 10 mm; the largest size, located in the ascending colon, measured 18 mm. EMR with a ligation device was performed in 20 cases, conventional EMR in 5 cases, and ESD in 2 cases. En bloc resection was performed in 25 cases (92.6 %), and endoscopic complete resection piecemeal resection was achieved in 25 cases (92.6 %). Pathologic complete resection was achieved in 22 lesions (81.5 %). Intraprocedural bleeding was noted in three patients, with no occurrence of perforation or postprocedure stricture. No recurrence was observed during the mean follow-up period of 15 months (range 9-31 months). Endoscopic resection appears to be a safe and effective treatment for GCTs in the gastrointestinal tract. 23818321 IRRITABILITY IN CHILD AND ADOLESCENT ANXIETY DISORDERS. Our objective was to compare self- and parent-reported irritability in youths with anxiety disorders, healthy youths, and those with mood disorders characterized by irritability. Irritability is a common but relatively understudied psychiatric symptom in child and adolescent anxiety disorders. In anxious youths, little is known about the severity of irritability, its impact on functioning, or the effect of informant source on reports of irritability. We compared parent- and self-report forms of the Affective Reactivity Index (ARI), a validated measure of irritability, in youths ages 8-17 years with no psychopathology (healthy comparison, HC; n = 38), anxiety disorders (ANX; n = 42), bipolar disorder (BD; n = 35), or severe mood dysregulation (SMD; n = 61; a phenotype characterized by chronic, severely impairing irritability). Irritability was significantly higher in ANX than HC youths by both parent and self-report (partial η(2) = 0.24 and 0.22, respectively, P's < 0.001). Informant effects differed among ANX, BD, and SMD. Overall, parent-reported irritability was higher in BD with comorbid anxiety disorders and SMD with or without comorbid anxiety disorders than ANX (P's < 0.007), but self-reported irritability was not significantly different among the three patient groups. By both parent and self-report, youths with anxiety disorders exhibit significantly more irritability and associated impairment than healthy subjects. Self-reported irritability in youths with anxiety disorders is comparable to that observed in youths with severe mood disorders, although parental reports of irritability differ among the disorders. Future research should examine the pathophysiology of anxiety-associated irritability, as well as its prognostic and treatment implications. 23903154 Quasi-periodic gratings: diffraction orders accelerate along curves. Light diffracting to different diffraction orders of a periodic grating generally propagates along a set of straight trajectories. Here we show that certain quasi-periodic gratings can produce curved diffraction orders. These curved lobes are created by the caustic interference of the originally straight diffraction orders and manifest themselves as accelerating beams. Both numerical simulations and experimental results demonstrate the validity of multiple accelerating beam generation with a single binary grating. Our work makes a quantitative link between the quasi-periodicity of a grating and the resulting caustic diffraction orders. Furthermore, the use of binary devices has important applications in acoustics, x-ray optics, and electron beam engineering and is also useful when high optical power is needed. 23798576 Minireview: Toward the Establishment of a Link between Melatonin and Glucose Homeostasis: Association of Melatonin MT2 Receptor Variants with Type 2 Diabetes. The existence of interindividual variations in G protein-coupled receptor sequences has been recognized early on. Recent advances in large-scale exon sequencing techniques are expected to dramatically increase the number of variants identified in G protein-coupled receptors, giving rise to new challenges regarding their functional characterization. The current minireview will illustrate these challenges based on the MTNR1B gene, which encodes the melatonin MT2 receptor, for which exon sequencing revealed 40 rare nonsynonymous variants in the general population and in type 2 diabetes (T2D) cohorts. Functional characterization of these MT2 mutants revealed 14 mutants with loss of Gi protein activation that associate with increased risk of T2D development. This repertoire of disease-associated mutants is a rich source for structure-activity studies and will help to define the still poorly understood role of melatonin in glucose homeostasis and T2D development in humans. Defining the functional defects in carriers of rare MT2 mutations will help to provide personalized therapies to these patients in the future. 23948434 Comprehensive overview of recent preparation and application trends of various open tubular capillary columns in separation science. Open tubular (OT) capillary columns have been increasingly used in a variety of fields of separation science such as CEC, LC, and SPE. Especially their application in CEC has attracted a lot of attention for their outstanding separation performance. Various forms of OT stationary phase materials have been employed such as in-situ prepared polymers, molecular imprinted polymers (MIPs), brush ligands, host ligands, block copolymers, aptamers, carbon nanotubes, polysaccharides, proteins, tentacles, nanoparticles, monoliths, and polyelectrolyte multi-layers. They have been prepared either in the chemically bound format or physically adsorbed format. Sol-gel technologies and nanoparticles have been sometimes involved in their preparation. There have been also some unique miscellaneous studies, for example, adopting preferentially adsorbed mobile phase components as stationary phases. In this review, recent progresses since mostly 2007 will be critically discussed in detail with some summarized descriptions for the work before the date. 23904840 Eosinophilic gastroenteritis: review of a rare and treatable disease of the gastrointestinal tract. Eosinophilic gastroenteritis is a rare disease of the gastrointestinal tract characterized by crampy abdominal pain, nausea, vomiting, diarrhea, gastrointestinal bleeding, and weight loss associated with peripheral eosinophilia leading to eosinophilic infiltrates in stomach and intestine, usually in a patient with a prior history of atopy. In this article, we describe our encounter with a 59-year-old female presenting with severe abdominal pain, nausea, vomiting, and weight loss with an extensive evaluation including an upper endoscopy with biopsies resulting in a diagnosis of eosinophilic gastroenteritis. The patient was eventually treated with oral prednisone for three weeks with complete resolution of her symptoms. 23970098 The Stable Microbubble Test for Determining Continuous Positive Airway Pressure (CPAP) Success in Very Preterm Infants Receiving Nasal CPAP from Birth. Background: Very preterm infants can be treated with nasal continuous positive airway pressure (CPAP) from birth, but some fail. A rapid test, such as the stable microbubble test (SMT) on gastric aspirate, may identify those who can be managed successfully using CPAP. Objective: To determine if SMT can identify soon after birth, very preterm infants who may be successfully managed on CPAP alone. Methods: Stable microbubbles (diameter <15 µm) were counted in gastric aspirates taken <1 h of age from infants <30 weeks' gestation, who received CPAP from birth. Infants failed CPAP if intubated at <72 h of age. Clinicians were masked to SMT results. A receiver operating characteristic curve was generated to determine the relationship between number of microbubbles/mm(2) and subsequent intubation. Results: 68 infants of mean (SD) 28.1 (1.4) weeks' gestation received CPAP in the delivery room at a median (interquartile range) pressure 7 (6-8) cmH2O and FiO2 0.25 (0.21-0.3). Gastric aspirates were taken at a median (interquartile range) age of 0.5 (0.3-0.6) hours. The best cut-off point for predicting CPAP success or failure was a SMT count of 8 microbubbles/mm(2). The area under the receiver operating characteristic curve was 0.8 (95% CI 0.7-0.9). A SMT count ≥8 microbubbles/mm(2) had a sensitivity of 53%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 60% for predicting CPAP success. Conclusion: Infants treated with CPAP from birth, who had SMT counts ≥8 microbubbles/mm(2) on their gastric aspirate, did not fail CPAP. 23107164 Overattachment and perceived disability in chronic migraineurs. The aim of this cross-sectional study was to assess whether stagnation dimensions and depression were associated with perceived disability in chronic migraineurs. Participants were 69 consecutive adult outpatients admitted to the Regional Referral Headache Centre of the Sant'Andrea Hospital in Rome, Italy. Patients were administered the Center for Epidemiologic Studies Depression Scale, the Stagnation Scale, and the Italian Perceived Disability Scale. They also compiled a headache diary to compute headache frequency. Patients with higher perceived disability (compared to patients with lower perceived disability) reported higher depression and higher symptoms of stagnation. The effect of Overattachment, a dimension of the Stagnation Scale, on perceived disability was only in part mediated by the severity of depressive symptoms. Our results confirm that many patients with chronic migraine report symptoms of stagnation, and that investigating the presence of the stagnation syndrome may be useful for understanding the psychology of chronic migraineurs. 23636447 Individual multi-locus heterozygosity is associated with lower morning plasma cortisol concentration. OBJECTIVE. STRESS IS IMPLICATED AS A RISK FACTOR FOR NUMEROUS ILLNESSES IN HUMANS, PUTATIVELY IN PART MEDIATED BY BIOLOGICAL RESPONSES TO STRESS, SUCH AS ELEVATED CORTISOL. THE THEORY OF GENETIC HOMEOSTASIS SUGGESTS THAT INDIVIDUAL HETEROZYGOSITY FACILITATES COMPENSATION FOR ENVIRONMENTAL STRESSES. WE HYPOTHESIZED THAT HETEROZYGOSITY AMELIORATES THE BIOLOGICAL RESPONSE TO A GIVEN LEVEL OF PERCEIVED STRESS, REFLECTED IN LOWER PLASMA CORTISOL CONCENTRATIONS.DESIGN. WE EXAMINE THE ROLE OF HETEROZYGOSITY ON THE ASSOCIATION BETWEEN PERCEIVED PSYCHOLOGICAL STRESS AND MORNING CORTISOL CONCENTRATIONS IN 854 INDIVIDUALS FROM THE ISOLATED ISLAND OF VIS, CROATIA.METHODS. CORTISOL WAS MEASURED IN MORNING PLASMA SAMPLES. 1184 AUTOSOMAL MICROSATELLITE MARKERS WERE GENOTYPED AND INDIVIDUAL MULTI-LOCUS HETEROZYGOSITY WAS CALCULATED AS THE PROPORTION OF HETEROZYGOUS MARKERS. GENERAL HEALTH QUESTIONNAIRE (GHQ-30) WAS USED TO ASSESS THE DEGREE OF PSYCHOLOGICAL DISTRESS.RESULTS. MEAN MULTI-LOCUS HETEROZYGOSITY WAS 34.850.45% (RANGE: 31.97-36.22%). Psychological distress (GHQ Likert score >31) was more prevalent in women (37% versus 18% in men, p<0.0001), in less educated people (β=-0.35 per year in school, p<0.001) and in lower socio-economic classes (β=-3.59, p<0.0001). Cortisol was positively associated with psychological distress (β=2.20, p=0.01). In a regression model adjusting for age, BMI, education and GHQ-30 score, multi-locus heterozygosity was independently and inversely associated with morning plasma cortisol (p=0.005).Conclusion. More heterozygous individuals, as measured by microsatellite markers, had lower morning plasma cortisol concentrations for a given level of perceived psychological stress. This may be important, as higher cortisol concentrations may increase allostatic load and be associated with higher risk of stress-related illness. 23411246 Iron and zinc bioavailability in Caco-2 cells: influence of caseinophosphopeptides. A study has been made of the influence of two pools of caseinophosphopeptides (CPPs) obtained from α(s)- and β-casein (CN) fractions, and of three specific CPPs (β-CN(1-25)4P, α(s1)-CN(64-74)4P and α(s2)-CN(1-19)4P), on iron bioavailability (ferritin synthesis) and zinc bioavailability (retention, transport and uptake of zinc) in Caco-2 cells. α-CPP and β-CPP pools did not improve ferritin synthesis, but the three specific CPPs showed an increase in ferritin synthesis in Caco-2 cells versus iron sulphate, β-CN(1-25)4P being the most effective. In relation to zinc bioavailability, α-CPPs, β-CPPs, α(s1)-CN(64-74)4P and β-CN(1-25)4P increased zinc uptake. However, this increase was of the same order as the increase due to the presence of zinc sulphate. 23587853 Repeatability of Gallium-68 DOTATOC Positron Emission Tomographic Imaging in Neuroendocrine Tumors. To evaluate the repeatability of gallium-68 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic (DOTA)-D-Phe-Try-octreotide (Ga-DOTATOC) positron emission tomography (PET) in neuroendocrine tumors. Five patients with neuroendocrine tumors were imaged with Ga-DOTATOC PET twice within 5 days. Maximum and mean standardized uptake values (SUVmax and SUVmean) and kinetic parameters (K-Patlak and K-influx) of target lesions were measured. The repeatability of these measurements was investigated. Forty-seven target lesions were identified on whole-body PET and 21 lesions on dynamic images. There was excellent repeatability with intraclass correlation coefficient of 0.99 for SUVmax, SUVmean, and K-Patlak, and 0.85 for K-influx. The median absolute percent differences and the interquartile ranges (IQR) between 2 scans for SUVmax and SUVmean were 7.4% (IQR, 14.1%) and 9.3% (IQR, 10.6%), respectively. The median absolute percent differences for K-Patlak and K-influx were 12.5% (IQR, 12.6%) and 29.9% (IQR, 22.4%), respectively. The SUVmax of target lesions did not differ by more than 25% between the 2 scans. Ga-DOTATOC PET imaging of neuroendocrine tumors is highly reproducible. A difference of more than 25% in SUVmax represents a change that is larger than the measurement error observed on repeated studies and should reflect a significant change in the biological character of the tumor. 23480027 Sirolimus ameliorates inflammatory responses by switching the regulatory T/T helper type 17 profile in murine colitis. Inflammatory bowel disease is characterized by dysregulated immune responses in inflamed intestine, with dominance of interleukin-17 (IL-17)--producing cells and deficiency of regulatory T (Treg) cells. The aim of this study was to investigate the effect and mechanisms of sirolimus, an inhibitor of the mammalian target of rapamycin, on immune responses in a murine model of Crohn's disease. Murine colitis was induced by intrarectal administration of 2,4,6-trinitrobenzene sulphonic acid at day 0. Mice were then treated intraperitoneally with sirolimus daily for 3 days. The gross and histological appearances of the colon and the numbers, phenotype and cytokine production of lymphocytes were compared with these characteristics in a control group. Sirolimus treatment significantly decreased all macroscopic, microscopic and histopathological parameters of colitis that were analysed. The therapeutic effects of sirolimus were associated with a down-regulation of pro-inflammatory cytokines tumour necrosis factor-α, IL-6 and IL-17A. Intriguingly, sirolimus administration resulted in a prominent up-regulation of the regulatory cytokine transforming growth factor-β. Supporting the hypothesis that sirolimus directly affects the functional activity of CD4+ CD25+ Treg cells, we observed a remarkable enhancement of FoxP3 expression in colon tissues and isolated CD4+ T cells of sirolimus-treated mice. Simultaneously, sirolimus treatment led to a significant reduction in the number of CD4+ IL-17A+ T cells in the mesenteric lymph node cells as well as IL-17A production in mesenteric lymph node cells. Therefore, sirolimus may offer a promising new therapeutic strategy for the treatment of inflammatory bowel disease. 23876784 Is the length of time in acute burn surgery associated with poorer outcomes? Acute wound closure surgery improves outcomes, after burn particularly mortality, but also imposes physiological stress on the patient. The duration of surgery is associated with adverse outcomes in other populations. This study aimed to examine if extended acute burn surgery duration was associated with poorer in-hospital outcomes. This retrospective cohort study included adult burn patients who required a single wound closure surgery at Royal Perth Hospital between 2004 and 2011. Multivariable regression analyses were used to assess the influence of patient and injury factors on surgery duration and length of stay (LOS). Surgery duration independently increased LOS (incidence rate ratio [IRR]=1.004, p<0.001). This translates to a predicted 13% increase in LOS for a 30min increase in surgery 'knife to skin' time. Total body surface area (TBSA) was identified as a significant predictor of surgery duration (IRR=1.047, p<0.001), estimating that a 10% TBSA increase results in a 59% increase in surgery duration. The results show that surgery duration is associated with LOS after adjusting for size of burn and other factors. The study justifies the need to explore strategies to reduce acute burn surgery duration. 23861846 Conformational dynamics of a ligand-free adenylate kinase. Adenylate kinase (AdK) is a phosphoryl-transfer enzyme with important physiological functions. Based on a ligand-free open structure and a ligand-bound closed structure solved by crystallography, here we use molecular dynamics simulations to examine the stability and dynamics of AdK conformations in the absence of ligands. We first perform multiple simulations starting from the open or the closed structure, and observe their free evolutions during a simulation time of 100 or 200 nanoseconds. In all seven simulations starting from the open structure, AdK remained stable near the initial conformation. The eight simulations initiated from the closed structure, in contrast, exhibited large variation in the subsequent evolutions, with most (seven) undergoing large-scale spontaneous conformational changes and approaching or reaching the open state. To characterize the thermodynamics of the transition, we propose and apply a new sampling method that employs a series of restrained simulations to calculate a one-dimensional free energy along a curved pathway in the high-dimensional conformational space. Our calculated free energy profile features a single minimum at the open conformation, and indicates that the closed state, with a high (∼13 kcal/mol) free energy, is not metastable, consistent with the observed behaviors of the unrestrained simulations. Collectively, our simulations suggest that it is energetically unfavorable for the ligand-free AdK to access the closed conformation, and imply that ligand binding may precede the closure of the enzyme. 23298452 Ocular diurnal rhythms and eye growth regulation: Where we are 50 years after Lauber. Many ocular processes show diurnal oscillations that optimize retinal function under the different conditions of ambient illumination encountered over the course of the 24 h light/dark cycle. Abolishing the diurnal cues by the use of constant darkness or constant light results in excessive ocular elongation, corneal flattening, and attendant refractive errors. A prevailing hypothesis is that the absence of the Zeitgeber of light and dark alters ocular circadian rhythms in some manner, and results in an inability of the eye to regulate its growth in order to achieve emmetropia, the matching of the front optics to eye length. Another visual manipulation that results in the eye growth system going into a "default" mode of excessive growth is form deprivation, in which a translucent diffuser deprives the eye of visual transients (spatial or temporal) while not significantly reducing light levels; these eyes rapidly elongate and become myopic. It has been hypothesized that form deprivation might constitute a type of "constant condition" whereby the absence of visual transients drives the eye into a similar default mode as that in response to constant light or dark. Interest in the potential influence of light cycles and ambient lighting in human myopia development has been spurred by a recent study showing a positive association between the amount of time that children spent outdoors and a reduced prevalence of myopia. The growing eyes of chickens and monkeys show a diurnal rhythm in axial length: Eyes elongate more during the day than during the night. There is also a rhythm in choroidal thickness that is in approximate anti-phase to the rhythm in eye length. The phases are altered in eyes growing too fast, in response to form deprivation or negative lenses, or too slowly, in response to myopic defocus, suggesting an influence of phase on the emmetropization system. Other potential rhythmic influences include dopamine and melatonin, which form a reciprocal feedback loop, and signal "day" and "night" respectively. Retinal dopamine is reduced during the day in form deprived myopic eyes, and dopamine D2 agonists inhibit ocular growth in animal models. Rhythms in intraocular pressure as well, may influence eye growth, perhaps as a mechanical stimulus triggering changes in scleral extracellular matrix synthesis. Finally, evidence shows varying influences of environmental lighting parameters on the emmetropization system, such as high intensity light being protective against myopia in chickens. This review will cover the evidence for the possible influence of these various factors on ocular growth. The recognition that ocular rhythms may play a role in emmetropization is a first step toward understanding how they may be manipulated in treatment therapies to prevent myopia in humans. 23895785 Aquaculture-derived enrichment of hexachlorocyclohexanes (HCHs) and dichlorodiphenyltrichloroethanes (DDTs) in coastal sediments of Hong Kong and adjacent mainland China. To evaluate contamination of sediments along the coast of Hong Kong and adjacent mainland China, concentrations of hexachlorocyclohexanes (HCHs) and dichlorodiphenyltrichloroethanes (DDTs) in surface and core sediments were measured in six mariculture zones. In surface sediments (0 to 5cm), concentrations of ∑HCHs and ∑DDTs in mariculture sediments were approximately 1.3- and 7.7-fold greater, respectively, than those detected in sediments at corresponding reference sites, which were 1 to 2km away in areas where there was no mariculture. Similarly, in cores of sediments, concentrations of ∑HCHs and ∑DDTs were 1.2- and 14-fold greater in mariculture zones, respectively. Enrichment relative to regional background concentrations, expressed as percentages was as large as 8.67×10(3)% for o,p'-DDD. The major sources of the enriched organochlorine pesticides (OCPs) were hypothesized to be derived from the use of contaminated fish feeds and anti-fouling paints for maintaining fish cages. Results of ecological risk assessments revealed that enriched OCPs had a large potential to contaminate the surrounding marine environment and lead to adverse effects on the associated biota. To our knowledge, this is the first study to evaluate the differences of OCP contaminations between mariculture and natural coastal sediments. 23625284 Granulomas of intestinal tuberculosis and Crohn's disease can be differentiated by CD73 cell surface marker expression: a pilot study. Intestinal tuberculosis (ITB) and Crohn's disease are similar granulomatous disorders. Granulomas are present in both and difficult to differentiate on histopathology alone. A recent study demonstrated recruitment of mesenchymal cells (MSCs) at the periphery of granulomas in lymph node tuberculosis which suppressed T cell responses. We hypothesized that granulomas of ITB would also recruit MSCs to evade host immune response. The purpose of this study was to demonstrate MSC markers in granulomas of ITB and evaluate whether distribution of MSC markers could differentiate between granulomas of Crohn's and ITB. We initially retrospectively enrolled 17 patients with confirmed ITB (8) or Crohn's (9) with granulomas on histopathology. Tissues were evaluated by immunofluorescence for MSC markers CD29, CD90, CD73 and absence of haematopoietic markers CD31, CD34, CD45 and CD14. Double-staining was done to confirm presence of MSCs. Subsequently, 23 postoperative specimens of Crohn's (18) and ITB (5) were analyzed for validation. Overall, 27 Crohn's and 13 ITB cases were assessed. CD29 and CD90 positive cells were noted around both ITB and Crohn's granulomas. MSC marker CD73 was expressed around the granulomas of ITB alone and was completely absent in the Crohn's. The subsequent assessment of granulomas in postoperative specimens of Crohn's and ITB also showed similar results. Granulomas of ITB and Crohn's disease can be differentiated by CD73 MSC surface marker expression. The differential CD73 expression around ITB granuloma indicates that Mycobacterium tuberculosis evades host immunity by recruiting MSCs with CD73 expression. MSCs with increased CD73 expression could be the future for therapeutic intervention in Crohn's. 23715291 Thoracic duct embolization for the management of chylothoraces. The aim is to inform the reader on the recent advancements in the minimally invasive treatment of chylothorax. Intranodal lymphangiography has been demonstrated to be a superior alternative to traditional pedal lymphangiography for thoracic duct embolization (TDE). TDE is associated with less morbidity and better clinical success than conservative management or surgical intervention in both traumatic and nontraumatic causes of chylothorax. TDE embolization in the pediatric population was found to be feasible. Recent advances in the lymphangiography techniques and the accumulation of experience in treating chylous effusions have significantly broadened the adoption of TDE to treat chylothorax. TDE for traumatic chylothorax has been demonstrated to be less morbid and more effective than surgical and conservative treatment. In cases of nontraumatic chylothorax, the patient has to be evaluated by MRI and lymphangiography to exclude causes of chylothorax which cannot be managed by interruption of the thoracic duct (e.g. lymphatic malformations or chylous ascites). Future advancements in noninvasive imaging of the thoracic duct and imaging guidance during TDE will continue to refine the percutaneous management of chylous effusions. 23940670 Downscaling the analysis of complex transmembrane signaling cascades to closed attoliter volumes. Cellular signaling is classically investigated by measuring optical or electrical properties of single or populations of living cells. Here we show that ligand binding to cell surface receptors and subsequent activation of signaling cascades can be monitored in single, (sub-)micrometer sized native vesicles with single-molecule sensitivity. The vesicles are derived from live mammalian cells using chemicals or optical tweezers. They comprise parts of a cell's plasma membrane and cytosol and represent the smallest autonomous containers performing cellular signaling reactions thus functioning like minimized cells. Using fluorescence microscopies, we measured in individual vesicles the different steps of G-protein-coupled receptor mediated signaling like ligand binding to receptors, subsequent G-protein activation and finally arrestin translocation indicating receptor deactivation. Observing cellular signaling reactions in individual vesicles opens the door for downscaling bioanalysis of cellular functions to the attoliter range, multiplexing single cell analysis, and investigating receptor mediated signaling in multiarray format. 23400964 Rash associated with dabigatran etexilate. Patients experiencing atrial fibrillation are at an increased risk for thromboembolic events. Therefore, anticoagulation therapy is imperative to prevent thrombus formation and stroke. Dabigatran etexilate was approved by the Food and Drug Administration in 2010 as anticoagulant prophylaxis for patients with nonvalvular atrial fibrillation. The frequency of dermatologic reactions to dabigatran etexilate is estimated in the product labeling to be less than 0.1%. To date, five cases of dabigatran etexilate-associated rash have reported, including three published cases. We describe the sixth reported case of dabigatran etexilate-associated rash, in a 59-year-old man with a history of atrial fibrillation who received dabigatran etexilate 150 mg twice/day for atrial flutter before cardioversion. The patient had taken dabigatran etexilate for 5 days before the rash was noted on hospital admission. He had no known previous drug allergies, and his platelet count, serum creatinine concentration, and hepatic function were normal. The rash resolved 7 days after the discontinuation of dabigatran etexilate, and the patient was stabilized on warfarin therapy. Use of the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 5) between the patient's development of the rash and dabigatran etexilate therapy. Clinicians should be aware of this adverse effect of dabigatran etexilate and monitor for dermatologic reactions during follow-up visits. 23949686 Spin-triplet excitons in 1,3-diphenyl-7-(fur-2-yl)-1,4-dihydro-1,2,4-benzotriazin-4-yl. 7-(Fur-2-yl)benzotriazinyl is the first example of a hydrazyl radical dimer with a thermally accessible triplet state. The triplet exciton (|D| = 0.018 cm(-1), |E| = 0.001 cm(-1)) was observed by solid-state VT-EPR spectroscopy between 5 and 140 K. VT crystallography, DFT calculations and magnetic susceptibility studies reveal a strong temperature dependence of the intra-dimer exchange interaction with J/k ∼ -254 + 0.0007T(2). 23256441 Bamboo salt has in vitro anticancer activity in HCT-116 cells and exerts anti-metastatic effects in vivo. Bamboo salt is a traditional food widely used in Korea. The in vitro anticancer effects of this salt were evaluated in HCT-116 human colon cancer cells using a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay. A 1% salt concentration of bamboo salt baked nine times (9×) inhibited the growth of HCT-116 cells by 53%, which was higher than salt baked three times (3×) or once (1×; 44% and 41%, respectively) and much higher than solar sea salt (Korean sea salt) and purified salt (22% and 18%, respectively). To elucidate the inhibitory mechanisms underlying the anticancer effect of the salt samples in cancer cells, expression of genes associated with apoptosis, inflammation, and metastasis was measured with reverse transcription-polymerase chain reaction and Western blotting. Bamboo salt (9×) significantly induced apoptosis in cancer cells (P<.05) by upregulating Bax, caspase-9, and caspase-3, and downregulating Bcl-2. The expression of genes associated with inflammation (NF-κB, iNOS, and COX-2) was significantly downregulated (P<.05) by 9× bamboo salt, demonstrating its anti-inflammatory properties. The 9× bamboo salt also exerted a greater anti-metastatic effect on cancer cells than the other salts as demonstrated by decreased mRNA expression of MMP genes and increased expression of tissue inhibitors of metalloproteinases, which was confirmed by the inhibition of tumor metastasis induced in colon 26-M3.1 cells in BALB/c mice. In contrast, purified and solar salts increased metastasis in the mice. Our results demonstrated that 9× bamboo salt had the most potent in vitro anticancer effect, induced apoptosis, had anti-inflammatory activities, and exerted in vivo anti-metastatic effects. Additionally, the anticancer, anti-inflammatory, and anti-metastatic effects of the 1× and 3× bamboo salts were stronger than those of the purified and solar salts. 23881381 Dietary Intake and Food Sources of EPA, DPA and DHA in Australian Children. Secondary analysis of the 2007 Australian National Children's Nutrition and Physical Activity survey was undertaken to assess the intake and food sources of EPA, DPA and DHA (excluding supplements) in 4,487 children aged 2-16 years. An average of two 24-h dietary recalls was analysed for each child and food sources of EPA, DPA and DHA were assessed using the Australian nutrient composition database called AUSNUT 2007. Median (inter quartile range, IQR) for EPA, DPA and DHA intakes (mg/day) for 2-3, 4-8, 9-13, 14-16 year were: EPA 5.3 (1.5-14), 6.7 (1.8-18), 8.7 (2.6-23), 9.8 (2.7-28) respectively; DPA 6.2 (2.2-14), 8.2 (3.3-18), 10.8 (4.3-24), 12.2 (5-29) respectively; and DHA 3.9 (0.6-24), 5.1 (0.9-26), 6.8 (1.1-27), 7.8 (1.5-33) respectively. Energy-adjusted intakes of EPA, DPA and DHA in children who ate fish were 7.5, 2 and 16-fold higher, respectively (P < 0.001) compared to those who did not eat fish during the 2 days of the survey. Intake of total long chain n-3 PUFA was compared to the energy adjusted suggested dietary target (SDT) for Australian children and 20 % of children who ate fish during the 2 days of the survey met the SDT. Fish and seafood products were the largest contributors to DHA (76 %) and EPA (59 %) intake, while meat, poultry and game contributed to 56 % DPA. Meat consumption was 8.5 times greater than that for fish/seafood. Australian children do not consume the recommended amounts of long chain omega-3 fatty acids, especially DHA, which could be explained by low fish consumption. 23892885 Numerical acuity of fish is improved in the presence of moving targets, but only in the subitizing range. There is controversy in comparative psychology about whether on the one hand non-symbolic number estimation of small (≤4) and large numbers involves a single mechanism (an approximate number system), or whether on the other hand enumeration of the numbers 1-4 is accomplished by a separate mechanism, an object tracking system. To date, support for the latter hypothesis has come only from the different ratio-dependency of performance seen in the two numerical ranges, a reading that has been criticized on several grounds. In humans, the two-system hypothesis is supported by evidence showing that manipulation of the physical properties of the stimuli (e.g., the motion of the items) has dissimilar effects on small- and large-number discrimination. In this research, we studied this effect on guppies. Initially, fish were trained to simultaneously discriminate two numerical contrasts having the same easy ratio (0.50): one in the small-number (2 vs. 4) range and one in the large-number (6 vs. 12) range. Half of the fish were presented with moving items; the other half were shown the same stimuli without motion. Fish were then subjected to non-reinforced probe trials in the presence of a more difficult ratio (0.75: 3 vs. 4 and 9 vs. 12). Under both static and moving conditions, the fish significantly discriminated 6 versus 12, but not 9 versus 12 items. As regards small numbers, both groups learned to discriminate a 0.50 ratio, but only fish tested with moving stimuli also discriminated 3 and 4 items. This differential effect suggests that fish may possess two separate systems for small- and large-number discrimination. 23802607 A Novel Role for Coenzyme A during Hydride Transfer in 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase. In this study, we take advantage of the ability of HMG-CoA reductase (HMGR) from Pseudomonas mevalonii to remain active while in its crystallized form to study the changing interactions between the ligands and protein as the first reaction intermediate is created. HMG-CoA reductase catalyzes one of the few double oxidation-reduction reactions in intermediary metabolism that take place in a single active site. Our laboratory has undertaken an exploration of this reaction space using structures of HMG-CoA reductase complexed with various substrate, nucleotide, product, and inhibitor combinations. With a focus in this publication on the first hydride transfer, our structures follow this reduction reaction as the enzyme converts the HMG-CoA thioester from a flat sp(2)-like geometry to a pyramidal thiohemiacetal configuration consistent with a transition to an sp(3) orbital. This change in the geometry propagates through the coenzyme A (CoA) ligand whose first amide bond is rotated 180° where it anchors a web of hydrogen bonds that weave together the nucleotide, the reaction intermediate, the enzyme, and the catalytic residues. This creates a stable intermediate structure prepared for nucleotide exchange and the second reduction reaction within the HMG-CoA reductase active site. Identification of this reaction intermediate provides a template for the development of an inhibitor that would act as an antibiotic effective against the HMG-CoA reductase of methicillin-resistant Staphylococcus aureus. 23875661 Complications of prostate biopsy. Biopsy of the prostate is a common procedure with minor complications that are usually self-limited. However, if one considers that millions of men undergo biopsy worldwide, one realizes that although complication rate is low, the number of patients suffering from biopsy complications should not be underestimated and can be a clinically relevant problem for healthcare professionals. In this review, the authors present diagnosis and management of postbiopsy of prostate complications. Bleeding is the most common complication observed after prostate biopsy, but the use of aspirin or nonsteroidal anti-inflammatory drugs is not an absolute contraindication to prostate biopsy. Emerging resistance to ciprofloxacin is the most probable cause of the increasing risk of infectious complications after prostate biopsy. Even though extremely rare, fatal complications are possible and were described in case reports. 23587216 Enhanced ultrasonically assisted turning of a β-titanium alloy. Although titanium alloys have outstanding mechanical properties such as high hot hardness, a good strength-to-weight ratio and high corrosion resistance; their low thermal conductivity, high chemical affinity to tool materials severely impair their machinability. Ultrasonically assisted machining (UAM) is an advanced machining technique, which has been shown to improve machinability of a β-titanium alloy, namely, Ti-15-3-3-3, when compared to conventional turning processes. 23761351 Detection of adverse drug reactions using hospital databases-a nationwide study in Portugal. This study aimed to detect and characterize adverse drug reactions (ADRs) that occurred during hospitalization (ADRIn ) and ADRs associated with admission (ADRAd ) in Portugal from 2000 to 2009. We also intended to compare the results of this methodology with spontaneous reporting. We conducted a nationwide study using a hospital administrative database that included all acute care public hospitalizations in Portugal, from 2000 to 2009. We used International Classification of Diseases-9(th) Revision-Clinical Modification coding data for the detection of ADRs. Codes searched included "E" codes (E930 to E949.9, codes that exclude poisonings and errors) and five groups of diagnoses codes associated with high prevalence of ADR as found in a previous study: hypoglycemia, drug-induced neutropenia, hepatitis unspecified, anaphylactic shock due to drugs, and shock due to anesthesia. From 9 271 122 hospitalizations within that period, 116 720 ADRs were detected through the database methodology, representing 1.26% from all hospitalizations. Of the ADRs, 97.3% occurred during hospitalization (ADRIn ), whereas 2.7% were associated with admission. Age, female sex, and comorbidities such as pneumonia, heart failure, diabetes, and malignancies were associated with ADRs (all with differences statistically significant). There were 13 562 spontaneous reports from 2000 to 2009. Several methods have been used for the detection of ADRs, but they are difficult to apply at a national level. Spontaneous reporting is widely used but grossly underestimates the frequency of ADRs. The database methodology can be very useful to estimate ADRs frequency and to perform a simple characterization of ADRs nationwide. Copyright © 2013 John Wiley & Sons, Ltd. 23607456 L-DOPA attenuates prolactin secretion in response to isolation stress in Holstein steers. To clarify endocrine responses to psychological stressors in cattle, the effects of isolation from familiar peers on plasma prolactin (PRL) and cortisol (CORT) concentrations, and the effect of 3,4-dihydroxy-L-phenylalanine (L-DOPA), a precursor of dopamine (DA), on stress-induced PRL secretion were determined in Holstein steers. First, the potency of peripheral L-DOPA administration on attenuation of central DA levels was confirmed. Cerebrospinal fluid (CSF) collected from a chronic cannula in the third ventricle and plasma were sampled 1 h before and 3 h after intravenous injection of L-DOPA (100 mg/head). DA concentrations in CSF increased just after L-DOPA injection with subsequent decrease in PRL secretion. Injection of L-DOPA increased CORT secretion. Second, one experimental steer was isolated in its stall by removing its peers for 2 h with or without- pre-injection of L-DOPA. The concentration of PRL was elevated by isolation treatment, whereas the effect of isolation on CORT concentration could not be detected. The increase in PRL concentration after isolation was abolished by pre-injection of L-DOPA. These results suggest that PRL responds to isolation and that DA neurons in the central nervous system may regulate stress-induced PRL secretion in steers. 23966061 Designing cooperativity into the designed protein Top7. The topology of the designed protein Top7 is not found in natural proteins. Top7 shows signatures of non-cooperative folding in both experimental studies and computer simulations. In particular, molecular dynamics of coarse-grained structure-based models of Top7 show a well-populated C-terminal folding-intermediate. Since most similarly sized globular proteins are cooperative folders, the non-natural topology of Top7 has been suggested as a reason for its non-cooperative folding. Here, we computationally examine the folding of Top7 with the intent of making it cooperative. We find that its folding cooperativity can be increased in two ways: (a) Optimization of packing interactions in the N-terminal half of the protein enables further folding of the C-terminal intermediate. (b) Reduction in the packing density of the C-terminal region destabilizes the intermediate. In practice, these strategies are implemented in our Top7 model through modifications to the contact-map. These modifications do not alter the topology of Top7 but result in cooperative folding. Amino-acid mutations that mimic these modifications also lead to a significant increase in folding cooperativity. Finally, we devise a method to randomize the sizes of amino-acids within the same topology, and confirm that the structure of Top7 makes its folding sensitive to packing interactions. In contrast, the ribosomal protein S6, which has secondary structure similar to Top7, has folding which is much less sensitive to packing perturbations. Thus, it should be possible to make a sequence fold cooperatively to the structure of Top7, but to do so its side-chain packing needs to be carefully designed. © Proteins 2013;. © 2013 Wiley Periodicals, Inc. 23244065 Profiling genome-wide chromatin methylation with engineered posttranslation apparatus within living cells. Protein methyltransferases (PMTs) have emerged as important epigenetic regulators in myriad biological processes in both normal physiology and disease conditions. However, elucidating PMT-regulated epigenetic processes has been hampered by ambiguous knowledge about in vivo activities of individual PMTs particularly because of their overlapping but nonredundant functions. To address limitations of conventional approaches in mapping chromatin modification of specific PMTs, we have engineered the chromatin-modifying apparatus and formulated a novel technology, termed clickable chromatin enrichment with parallel DNA sequencing (CliEn-seq), to probe genome-wide chromatin modification within living cells. The three-step approach of CliEn-seq involves in vivo synthesis of S-adenosyl-L-methionine (SAM) analogues from cell-permeable methionine analogues by engineered SAM synthetase (methionine adenosyltransferase or MAT), in situ chromatin modification by engineered PMTs, subsequent enrichment and sequencing of the uniquely modified chromatins. Given critical roles of the chromatin-modifying enzymes in epigenetics and structural similarity among many PMTs, we envision that the CliEn-seq technology is generally applicable in deciphering chromatin methylation events of individual PMTs in diverse biological settings. 23509235 Does the addition of a radial artery graft improve survival after higher risk coronary artery bypass grafting? A propensity-score analysis of a multicentre database. The use of the radial artery as a second arterial graft during coronary surgery has grown in popularity due to high patency and low harvest site complication rates. We sought to assess whether higher risk patients derive prognostic benefit. From 2001 to 2009, 11 388 patients underwent isolated primary multivessel coronary surgery. We identified a higher risk subgroup (n = 2581) according to emergent status, coronary instability, low ejection fraction and/or aortic counterpulsation. Among these, 1832 (71%) received at least one radial artery graft in addition to a left internal thoracic artery (LITA). The remaining 749 (29%) received LITA and veins only. Patients not receiving a radial artery were more likely to be elderly, female, have poor left ventricular function or be of emergent status. These patients experienced higher unadjusted 30-day mortality (radial: 2% vs vein: 8%, P < 0.0001) with lower unadjusted 7-year survival (80 ± 1.3 vs 67 ± 2.4%, P < 0.0001). Subsequently, 515 patients in the radial group were propensity-matched to 515 receiving LITA + veins (mean logistic EuroSCORE, radial: 11.6 ± 9.7% vs vein: 11.6 ± 10.3%, P = 0.99). At 30 days, there were comparable rates of mortality (radial: 4% vs vein: 3%, P > 0.99), stroke (1 vs 1%, P > 0.99), myocardial infarction (1 vs 2%, P = 0.79), and any morbidity/mortality (34 vs 35%, P = 0.95). At 7 years, survival rates between the radial and vein groups were similar (radial: 75 ± 2.6% vs vein: 74 ± 2.9%, P = 0.65). Patients with the greatest coronary instability, urgency of surgery or impairment of ventricular function are not disadvantaged in early outcomes or mid-term survival by the use of only a single arterial graft. 23953273 Theoretical and experimental indicators of falls during pregnancy as assessed by postural perturbations. Throughout pregnancy, women experience physical, physiological, and hormonal alterations that are often accompanied by decreased postural control. According to one study, nearly 27% of pregnant women fell while pregnant. This study had two objectives: (1) to characterize the postural responses of pregnant fallers, nonfallers, and controls to surface perturbations, and (2) to develop a mathematical model to gain insights into the postural control strategies of each group. This retrospective analysis used experimental data obtained from 15 women with a fall history during pregnancy, 14 women without a fall history during pregnancy, and 40 nonpregnant controls. Small, medium, and large translational support surface perturbations in the anterior and posterior directions were performed during the pregnant participants' second and third trimesters. A two-segmented mathematical model of bipedal stance was developed and parameterized, and optimization tools were used to identify ankle and hip stiffness, viscosity, and the feedback time delay by searching for the best fits to experimental COP data. The peak differences between the center of pressure and center of gravity (COP-COG) values were significantly smaller for the pregnant fallers compared with the pregnant nonfallers and controls (p<0.01). Perturbation magnitude was a significant factor (p<0.01), but perturbation direction was not (p=0.24). Model fits were obtained with a mean goodness of fit value of R(2)=0.92. Theoretical results indicated that pregnant nonfallers had higher ankle stiffness compared with the pregnant fallers and the controls, which suggests that ankle stiffness itself may be the dominant reason for the different dynamic response characteristics (e.g., peak COP-COG) observed. We conclude that increasing ankle stiffness could be an important strategy to prevent falling by pregnant women. 23500469 Fabrication of an ultrasensitive electrochemical immunosensor for CEA based on conducting long-chain polythiols. A conducting long-chain polythiols (poly (2-aminothiophenol), PATP) was synthesized by a chemical polymerization process and combined with Au nanoparticles (AuNPs) to prepare a novel, sensitive and label-free electrochemical biosensor by adsorption of carcinoembryonic antibody (anti-CEA) on the PATP-AuNPs modified gold electrode. Differential pulse voltammetry (DPV) was used to characterize the recognition of carcinoembryonic antigen (CEA). Under the optimized conditions, the proposed immunosensor displayed a good amperometric response to CEA with linear range from 1 fg mL(-1) to 10 ng mL(-1) and a detection limit of 0.015 fg mL(-1) (signal/noise=3). The results demonstrated that the immunosensor has advantages of high sensitivity, wide linear range, good repeatability, and good selectivity. Importantly, the results of the detection of clinical serum specimens with the proposed sensor were well consistent with the data determined by micropartical enzyme immunoassay (MPEI), showing that the present work provides a promising ultrasensitive immunoassay strategy for clinical applications. 23955990 Developing Functionalized Dendrimer-Like Silica Nanoparticles with Hierarchical Pores as Advanced Delivery Nanocarriers. Functionalized dendrimer-like hybrid silica nanoparticles with hierarchical pores are designed and synthesized. The unique structure, large surface area, and excellent biocompability render such materials attractive nanocarriers for the advanced delivery of various sized drugs and genes simultaneously. 23939134 Hide and seek: Placing and finding an optimal tree for thousands of homoplasy-rich sequences. Finding optimal evolutionary trees from sequence data is typically an intractable problem, and there is usually no way of knowing how close to optimal the best tree from some search truly is. The problem would seem to be particularly acute when we have many taxa and when that data has high levels of homoplasy, in which the individual characters require many changes to fit on the best tree. However, a recent mathematical result has provided a precise tool to generate a short number of high-homoplasy characters for any given tree, so that this tree is provably the optimal tree under the maximum parsimony criterion. This provides, for the first time, a rigorous way to test tree search algorithms on homoplasy-rich data, where we know in advance what the 'best' tree is. In this short note we consider just one search program (TNT) but show that it is able to locate the globally optimal tree correctly for 32,768 taxa, even though the characters in the dataset require, on average, 1148 state-changes each to fit on this tree, and the number of characters is only 57. 23951291 670nm Photobiomodulation as a Novel Protection against Retinopathy of Prematurity: Evidence from Oxygen Induced Retinopathy Models. To investigate the validity of using 670nm red light as a preventative treatment for Retinopathy of Prematurity in two animal models of oxygen-induced retinopathy (OIR). During and post exposure to hyperoxia, C57BL/6J mice or Sprague-Dawley rats were exposed to 670nm light for 3 minutes a day (9J/cm(2)). Whole mounted retinas were investigated for evidence of vascular abnormalities, while sections of neural retina were used to quantify levels of cell death using the TUNEL technique. Organs were removed, weighed and independent histopathology examination performed. 670nm light reduced neovascularisation, vaso-obliteration and abnormal peripheral branching patterns of retinal vessels in OIR. The neural retina was also protected against OIR by 670nm light exposure. OIR-exposed animals had severe lung pathology, including haemorrhage and oedema, that was significantly reduced in 670nm+OIR light-exposed animals. There were no significance differences in the organ weights of animals in the 670nm light-exposed animals, and no adverse effects of exposure to 670nm light were detected. Low levels of exposure to 670nm light protects against OIR and lung damage associated with exposure to high levels of oxygen, and may prove to be a non-invasive and inexpensive preventative treatment for ROP and chronic lung disease associated with prematurity. 23890943 Has the association between hysterectomy and ovarian cancer changed over time? A systematic review and meta-analysis. Until recently most studies suggested that hysterectomy with ovarian conservation was associated with a decreased risk of ovarian cancer. However, several recent studies have reported modestly increased risks of ovarian cancer following hysterectomy. Given that as many as 35% of women will have a hysterectomy, the nature of the association requires clarification. We conducted a systematic review and meta-analysis of the published literature on the relationship between hysterectomy and ovarian cancer to investigate whether there has been a temporal change in the association. Twenty observational studies that have reported a quantitative assessment of the association between hysterectomy and risk of histologically-confirmed ovarian cancer were included in the meta-analysis. The overall relative risk (RR) estimate was 0.81 (95% confidence interval (CI) 0.72-0.92) suggesting hysterectomy decreases the risk of ovarian cancer. However, there was significant heterogeneity in the results (I(2)=74%). Our exploration of sources of heterogeneity and metaregression showed that median year of cancer diagnosis of included cases explained most of the heterogeneity relative risk (RR=0.70 (95% CI 0.65-0.76) for median year diagnosis pre 2000; RR=1.18 (95% CI 1.06-1.31) for post 2000). This study shows that there has been a temporal shift in the association between hysterectomy and risk of ovarian cancer. One explanation may be the trend away from hysterectomy in younger women. Other speculative possibilities include the decline in oophorectomy rates and the use of oestrogen-only hormone replacement therapy in hysterectomised women. Until further evidence becomes available, clinicians should not advise women that a hysterectomy without salpingo-oophorectomy will favourably influence their future risk of ovarian cancer. 23266505 Activation of an apoptotic signal transduction pathway involved in the upregulation of calpain and apoptosis-inducing factor in aldosterone-induced primary cultured cardiomyocytes. In this study, aldosterone (ALD)-induced apoptosis of cardiomyocyte was evaluated based on the previous studies, and the roles of calpain signaling were clarified. Primary cultured rat cardiomyocytes were injured by ALD (0.01-10 μM) for varying time periods. Then, the effects of ethylene glycol tetraacetic acid (EGTA) (0.5 mM), calpeptin (2.5 μM), and spironoclactone (10 μM) were evaluated on cardiomyocytes activated by ALD. Cardiomyocytes that were injured by ALD were assayed by the MTT and LDH leakage ratio. Apoptosis was evaluated by a TUNEL assay, annexin V/PI staining, and caspase-3 activity. The expression of cleavage of Bid (tBid), calpain and apoptosis-inducing factor (AIF) was evaluated by western blot analysis. ALD increased calpain expression and caspase-3 activity and promoted Bid cleavage. It also induced the release of AIF from mitochondria into the cytosol. The upregulation of calpain, tBid and caspase-3 activity were further inhibited by treatment with EGTA in the presence of ALD. Additionally, AIF levels in the cytosol decreased due to EGTA but not due to calpeptin. This was also accompanied by a significant decrease in apoptosis. Furthermore, treatment with spironoclactone not only attenuated the pro-apoptotic effect of ALD but reversed the ALD-induced increase of calpain and AIF levels. 23850471 Anoxia-responsive regulation of the FoxO transcription factors in freshwater turtles, Trachemys scripta elegans. The forkhead class O (FoxO) transcription factors are important regulators of multiple aspects of cellular metabolism. We hypothesized that activation of these transcription factors could play crucial roles in low oxygen survival in the anoxia-tolerant turtle, Trachemys scripta elegans. Two FoxOs, FoxO1 and FoxO3, were examined in turtle tissues in response to 5 and 20h of anoxic submergence using techniques of RT-PCR, western immunoblotting and DNA-binding assays to assess activation. Transcript levels of FoxO-responsive genes were also quantified using RT-PCR. FoxO1 was anoxia-responsive in the liver, with increases in transcript levels, protein levels, nuclear levels and DNA-binding of 1.7-4.8fold in response to anoxia. Levels of phosphorylated FoxO1 also decreased to 57% of control values in response to 5h of anoxia, indicating activation. FoxO3 was activated in the heart, kidney and liver in response to anoxia, with nuclear levels increasing by 1.5-3.7fold and DNA-binding activity increasing by 1.3-2.9fold. Transcript levels of two FoxO-target genes, p27kip1 and catalase, also rose by 2.4-2.5fold in the turtle liver under anoxia. The results suggest that the FoxO transcription factors are activated in response to anoxia in T. scripta elegans, potentially contributing to the regulation of stress resistance and metabolic depression. This study provides the first demonstration of activation of FoxOs in a natural model for vertebrate anoxia tolerance, further improving understanding of how tissues can survive without oxygen. 23951269 The effect of the physical presence of co-players on perceived ostracism and event-related brain potentials in the cyberball paradigm. The affective and cognitive mechanisms elicited by the experience of social exclusion-or ostracism-have recently been explored using behavioral and neurocognitive methods. Most of the studies took advantage of the Cyberball paradigm, a virtual ball tossing game with presumed co-players connected via the internet. Consistent behavioral findings indicate that exclusion obviously threatens fundamental social needs (belonging, self-esteem, meaningful existence, and control) and lowers mood. In this study, we followed the question whether the credibility of the setting affects the processing of social exclusion. In contrast to a control group (standard Cyberball setup), co-players were physically present in an experimental group. Although the credibility of the virtual ball tossing game was significantly enhanced in the experimental group, self-reported negative mood and need threat were not enhanced compared to the control group. Event-related brain potentials (ERPs), however, indicated a differential processing of social exclusion. The N2 amplitude triggered by occasional ball receptions was significantly reduced in the experimental group. This effect was restricted for an early time range (130-210 ms), and did not extend to the following P3 components. The ERP effect in the N2 time range can be related to a differential social reward processing in ostracism if co-players are physically present. The lack of a corresponding correlate in the behavioral data indicates that some facets of ostracism processing are not covered by questionnaire data. 23676825 Structure-activity relationship of memapsin 2: implications on physiological functions and Alzheimer's disease. Memapsin 2 (BACE1, β-secretase), a membrane aspartic protease, functions in the cleavage of the type I transmembrane protein, β-amyloid precursor protein (APP), leading to the production of amyloid β (Aβ) in the brain. Since Aβ is closely associated with the pathogenesis of Alzheimer's disease, understanding the biological function, particularly the catalytic activities of memapsin 2, would assist in a better understanding of the disease and the development of its inhibitors. The transmembrane and cytosolic domains of memapsin 2 function in cellular transport and localization, which are important regulatory mechanisms for its activity. The catalytic ectodomain contains a long substrate cleft that is responsible for substrate recognition, specificity, and peptide bond hydrolysis. The substrate cleft accommodates 11 residues of the substrate in separate binding subsites. Besides APP, a number of membrane proteins have been reported to be substrates of memapsin 2. The elucidation for the specificity of these subsites and the amino acid sequences surrounding the memapsin 2 cleavage site in these proteins has led to the establishment of a predictive model that can quantitatively estimate the efficiency of cleavage for any potential substrates. Such tools may be employed for future studies of memapsin 2 about its biological function. Herein, we review the current knowledge on the structure-function relationship of memapsin 2 and its relationship in the biological function. 23897619 Development of Severe Pathology in Immunized Pregnant Mice Challenged with Lethal Malaria Parasites. Pregnant women are highly susceptible to malaria infection because of their low immunity, and are at increased risk of maternal illness or death, in addition to spontaneous abortion, stillbirth, premature delivery and low birth weight. However, the detailed pathogenesis of maternal malaria remains unclear. In this study, we evaluated a mouse model that shows similar severe pathological features of pregnant women during Plasmodium falciparum infection and investigated the pathogenesis of maternal malaria. Pregnant mice immunized by infection with an attenuated parasite, P. berghei XAT, were more susceptible to virulent P. berghei NK65 challenge/infection than nonpregnant mice and showed high levels of parasitemia and a poor pregnancy outcome associated with placental pathology, such as accumulation of parasitized red blood cells, in the late phase of pregnancy. Notably, the pregnant immune mice challenged/infected with P. berghei NK65 developed liver injury associated with microvesicular fatty infiltration in late pregnancy. The pathological features were similar to acute fatty liver of pregnancy. Higher levels of interferon-γ and NO were found in plasma from pregnant immune mice infected with P. berghei NK65 compared with those in nonpregnant mice. These findings suggest that development of liver injury and placental pathology in pregnant immune mice challenged/infected with P. berghei NK65 is accompanied by enhanced production of proinflammatory cytokines. 23561509 Different patterns of gray matter atrophy in early- and late-onset Alzheimer's disease. We assessed patterns of gray matter atrophy according to-age-at-onset in a large sample of 215 Alzheimer's disease (AD) patients and 129 control subjects with voxel-based morphometry using 3-Tesla 3D T1-weighted magnetic resonance imaging. Local gray matter amounts were compared between late- and early-onset AD patients and older and younger control subjects, taking into account the effect of apolipoprotein E. Additionally, combined effects of age and diagnosis on volumes of hippocampus and precuneus were assessed. Compared with age-matched control subjects, late-onset AD patients exhibited atrophy of the hippocampus, right temporal lobe, and cerebellum, whereas early-onset AD patients showed gray matter atrophy in hippocampus, temporal lobes, precuneus, cingulate gyrus, and inferior frontal cortex. Direct comparisons between late- and early-onset AD patients revealed more pronounced atrophy of precuneus in early-onset AD patients and more severe atrophy in medial temporal lobe in late-onset AD patients. Age and diagnosis independently affected the hippocampus; moreover, the interaction between age and diagnosis showed that precuneus atrophy was most prominent in early-onset AD patients. Our results suggest that patterns of atrophy might vary in the spectrum of AD. 23899302 Fate and ecological effects of decabromodiphenyl ether in a field lysimeter. Flame-retardant polybrominated diphenyl ethers (PBDEs) are environmental contaminants. Deca-BDE is increasingly used commercially, but little is known about the long-term fate and impact of its major component, decabromodiphenyl ether (BDE-209), on the soil environment. In this study, we investigated the fate and ecological effect of BDE-209 over 4 years in outdoor lysimeters in a field planted with a rice-wheat rotation. BDE-209 and six lower-brominated PBDEs (BDE-28, -47, -99, -153, -154, and -183) were detected in soil layers of the test lysimeter. We calculated an average BDE-209 migration rate of 1.54 mg·m(-2)·yr(-1). In samples collected in May 2008, November 2008, November 2009, November 2010, and November 2011, 95.5%, 94.3%, 108.1%, 33.8%, and 35.5% of the spiked BDE-209 were recovered, respectively. We predicted the major pathway for debromination of BDE-209 in soil to be: BDE-209→BDE-183→BDE-153/BDE-154→BDE-99→BDE-47→BDE-28. In plants, BDE-209 and seven lower-brominated PBDEs (BDE-28, -47, -99, -100, -153, -154, and -183) were detected. BDE-100 was mainly derived from the debromination of BDE-154 in plants, but sources of other lower-brominated PBDEs were still difficult to determine. In soils containing BDE-209 for 4 years, soil urease activity increased, and soil protease activity slightly decreased. Our results provide important insights for understanding the behavior of BDE-209 in agricultural soils. 23331067 The transcription factor Pitx3 is expressed selectively in midbrain dopaminergic neurons susceptible to neurodegenerative stress. The homeodomain transcription factor Pitx3 is critical for the survival of midbrain dopaminergic (mDA) neurons. Pitx3-deficient mice exhibit severe but selective developmental loss of mDA neurons, with accompanying locomotor deficits resembling those seen in Parkinson's disease (PD) models. Here, we identify specific mDA cell subpopulations that are consistently spared in adult Pitx3-hypomorphic (aphakia) mice, demonstrating that Pitx3 is not indiscriminately required by all mDA neurons for their survival. In aphakia mice, virtually all surviving mDA neurons in the substantia nigra (SN) and the majority of neurons in the adjacent ventral tegmental area (VTA) also express calbindin-D28k, a calcium-binding protein previously associated with resistance to injury in PD and in animal models. Cell-mapping studies in wild-type mice revealed that Pitx3 is primarily expressed in the ventral SN, a region particularly susceptible to MPTP and other dopaminergic neurotoxins. Furthermore, Pitx3-expressing SN cells are preferentially lost following MPTP treatment. Finally, SN mDA neurons in Pitx3 hemizygous mice show increased sensitivity when exposed to MPTP. Thus, SN mDA neurons are represented by at least two distinct subpopulations including MPTP-resistant Pitx3-autonomous, calbindin-positive neurons, and calbindin-negative Pitx-3-dependent cells that display elevated vulnerability to toxic injury, and probably correspond to the subpopulation that degenerates in PD. Impairment of Pitx3-dependent pathways therefore increases vulnerability of mDA neurons to toxic injury. Together, these data suggest a novel link between Pitx3 function and the selective pattern of mDA cell loss observed in PD. 23852223 Immunohistochemical BAG1 expression improves the estimation of residual risk by IHC4 in postmenopausal patients treated with anastrazole or tamoxifen: a TransATAC study. BAG1 is a multifunctional anti-apoptotic protein located on chromosome 9q12, which binds to Bcl-2. BAG1 is present as a separate module in the GHI-RS 21-gene panel. It may provide additional prognostic information as an immunohistochemical marker when added to IHC4. Analysis of BAG1 was performed on archival tumour blocks from patients from the anastrozole and tamoxifen arms of the ATAC trial of 5 years endocrine therapy in postmenopausal women with oestrogen receptor (ER)-positive primary breast cancer. Staining was scored separately as nuclear or cytoplasmic. Statistical analyses were performed on data from median 10-year follow-up with distant recurrence as primary endpoint. Data on both nuclear and cytoplasmic BAG1 as well as the IHC4 markers (ER, PgR, HER2 and Ki67) were available on 963 ER-positive cases of which 860 were HER2-negative. Cytoplasmic and nuclear BAG1 were highly correlated (Spearman r = 0.79, p < 00001). Women with higher BAG1 expression developed 30 % fewer distant recurrences compared to those with low expression. Nuclear BAG1 contributed significantly to the clinical and IHC4 models with added information being greater in node-positive cases. Similar results were seen if all recurrences were the endpoints. BAG1 expression provides significant prognostic information when added to the classical clinicopathological parameters and IHC4, particularly in node-positive patients. 23375059 Vitamin D metabolism in human bone marrow stromal (mesenchymal stem) cells. There are many human extra-renal tissues and cells that biosynthesize 1α,25-dihydroxyvitamin D (1α,25(OH)(2)D) by the action of CYP27B1/1α-hydroxylase. Human marrow stromal cells (hMSCs), also known as mesenchymal stem cells, were isolated from marrow discarded from well-characterized, consented subjects during common orthopedic procedures. Human MSCs can give rise to osteoblasts, chondrocytes, adipocytes, and other lineages. Their in vitro differentiation to osteoblasts is stimulated by 1α,25(OH)(2)D, and recent evidence indicates that they have the capacity to metabolize vitamin D in a regulated manner. Human MSCs express the vitamin D receptor, 25-hydroxylases, 1α-hydroxylase, and 24-hydroxylase; stimulation of in vitro osteoblastogenesis by 25(OH)D depends on the activity of CYP27B1/1α-hydroxylase. The finding that hMSCs are a both a producer and target of 1α,25(OH)(2)D suggests a potential autocrine/paracrine role of vitamin D metabolism in osteoblast differentiation. Expression and enzyme activity of CYP27B1/1α-hydroxylase are upregulated by substrate 25(OH)D and Parathyroid Hormone (PTH) and are downregulated by 1α,25(OH)(2)D. With subject age, there are decreases in basal osteoblast potential and in stimulation of osteoblastogenesis by 1α,25(OH)(2)D, 25(OH)D, and PTH. In vitro treatment with a combination of 25(OH)D and PTH rejuvenated osteoblastogenesis with hMSCs from elders; this was attributable to increases in CYP27B1/1α-hydroxylase and in receptor for each hormone by the reciprocal factor. Other clinical variables beside age, i.e. low serum 25(OH)D or low estimated glomerular filtration rate, are correlated with reduced osteoblastogenesis. These studies suggest that osteoblastogenesis may not be optimal unless there is sufficient serum 25(OH)D substrate for hMSCs to synthesize and respond to local 1α,25(OH)(2)D. 23838388 Opportunities and challenges from current investigations into the biosynthetic logic of nosiheptide-represented thiopeptide antibiotics. Nosiheptide is an archetypal thiopeptide antibiotic, possessing a characteristic macrocyclic core that contains a 6-membered heterocycle central to multiple azol(in)es and dehydroamino acids. The discovery of the ribosomal origin of thiopeptides revealed a unifying theme, showing that the structural complexity arises from post-translational modifications (PTMs) of precursor peptides. Thiopeptide framework formation proceeds via cyclodehydration/dehydrogenation (for azol(in)es), dehydration (for dehydroamino acids), and cycloaddition (for the central heterocycle domain). This common process has not been reproduced in vitro, partly due to the poorly understood logic of thiopeptide biosynthetic pathways. Utilizing nosiheptide biosynthesis as a model system, we herein consider how nature coordinates a number of highly interwined, common and specific PTMs to accomplish the complexity of ribosomally synthesized and post-translationally modified peptides. 23889820 Prevalence of onychectomy in cats presented for veterinary care near Raleigh, NC and educational attitudes toward the procedure. The current prevalence of onychectomy (declawing) in cats is unknown, and education regarding the procedure appears to vary greatly among veterinary schools. The purpose of this project was to determine the prevalence of onychectomized cats near Raleigh, NC and to document the frequency and style (laboratory or lecture) with which the procedure is taught in USA veterinary schools. One thousand seven hundred ninety four cats ranging in age from 8 days to 21 years, of which 938 (52.3%) were female and 1719 (95.8%) were sterilized. Data were collected over a 10-week period regarding cats seen for appointments in five veterinary facilities (two cat-only, two general, and one tertiary). Data collection included signalment and onychectomy status. During this time, 28 veterinary schools were polled regarding education of veterinary students in onychectomy. Three hundred and seventy four (20.8%) cats had undergone onychectomy. A significantly higher percentage of declawed cats were seen in the general practices compared with the other practice types (p < 0.030). Younger cats had a higher rate of onychectomy (p < 0.001). Twenty-six veterinary schools responded to the survey (93%). Fourteen (54%) of the responding schools did not include in their core curriculum a lecture or surgical laboratory providing instruction in the onychectomy procedure. Almost 21% of cats seen in veterinary hospitals near Raleigh, NC were declawed. Less than 50% of veterinary schools in the USA include a mandatory lecture or laboratory to teach the procedure. There appears to be a discrepancy between the popularity of the onychectomy procedure and the emphasis placed on relevant instruction in veterinary schools in the USA. 23939888 Mutations of the ompK36 porin gene and promoter impact responses of ST258, KPC-2-producing Klebsiella pneumoniae strains to doripenem and doripenem-colistin. Doripenem-colistin exerts synergy against some, but not all Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae strains in vitro. We determined if doripenem MICs and/or ompK36 porin gene mutations impacted the responses of 23 ST258, KPC-2-producing strains to the combination of doripenem (8 μg/ml) and colistin (2 μg/ml) during time kill assays. Median doripenem and colistin MICs were 32 and 4 μg/ml. Doripenem MICs did not correlate with KPC-2 expression levels. Five and 18 strains had wild-type and mutant ompK36, respectively. The most common mutations were IS5 promoter insertions (n=7) and insertions encoding glycine and aspartic acid at amino acid positions 134-135 (ins AA134-135 GD; n=8), which were associated with higher doripenem MICs than other mutations or wild-type ompK36 (all p-values ≤0.04). Bactericidal activity (24 hours) was achieved by doripenem-colistin against 12%, 43% and 75% of ins AA134-135 GD, IS5 and wild-type/other mutants, respectively (p=0.04). Doripenem-colistin was more active in time-kills than colistin at 12 and 24 hours if doripenem MIC was ≤8 μg/ml (p=0.0007 and 0.09, respectively), but not if MIC was >8 μg/ml (p=0.10 and 0.16). Likewise, doripenem-colistin was more active at 12 and 24 hours against wild-type/other mutants than ins AA134-135 GD or IS5 mutants (p=0.007 and 0.0007). By multivariate analysis, the absence of ins AA134-135 GD or IS5 mutations was the only independent predictor of doripenem-colistin responses at 24 hours (p=0.002). In conclusion, ompK36 genotypes identified ST258 KPC-K. pneumoniae strains that were most likely to respond to doripenem-colistin. 23400739 Population pharmacokinetic/pharmacodynamic modeling to assist dosing schedule selection for dovitinib. Dovitinib is an oral multitargeted kinase inhibitor with potent activity against receptors for vascular endothelial growth factor, platelet-derived growth factor, and basic fibroblast growth factor. Initial phase 1 to 2 studies of dovitinib using a continuous daily dosing schedule has shown that dovitinib exhibits a prolonged and overproportional increase in dose and exposure relationship above 400 mg/d. To address this, intermittent dosing schedules were explored using a model-based approach. A semi-mechanistic population pharmcokinetic/pharmacodynamic (PD) model was developed from 4 dovitinib phase 1 studies with daily dosing schedules. Autoinduction of cytochrome P450 1A (CYP1A) responsible for dovitinib metabolism was described using an indirect response model. Simulation of dovitinib plasma concentration profiles following 4 intermittent dosing schedules suggested that intermittent dosing could prevent prolonged drug accumulation. Based on the simulated plasma profiles, PD response, and patient compliance, a 5-days-on/2-days-off intermittent dosing schedule was selected for a phase 1 to 2 clinical study. The observed dovitinib plasma concentrations in this study confirmed the model predictions. Furthermore, dovitinib was well tolerated, and antitumor activity was observed as well in this new study. The 5-days-on/2-days-off dosing schedule is currently used in a dovitinib registration trial and other clinical trials. 23687372 New roles of the fission yeast eIF2α kinases Hri1 and Gcn2 in response to nutritional stress. In fission yeast, three distinct eukaryotic initiation factor 2α (eIF2α) kinases (Hri1, Hri2 and Gcn2), regulate protein synthesis in response to various environmental stresses. Thus, Gcn2 is activated early after exposure to hydrogen peroxide (H2O2) and methyl methanesulfonate (MMS), whereas Hri2 is the primary activated eIF2α kinase in response to heat shock. The function of Hri1 is still not completely understood. It is also known that the mitogen-activated protein kinase Sty1 negatively regulates Gcn2 and Hri2 activities under oxidative stress. In this study, we demonstrate that Hri1 is mainly activated, and its expression upregulated, during transition from exponential growth to the stationary phase in response to nutritional limitation. Accordingly, both Hri1 and Gcn2, but not Hri2, are activated upon nitrogen source deprivation. In contrast, Hri2 is stimulated early during glucose starvation. We also found that Gcn2 is implicated in nitrogen starvation-induced growth arrest in the cell cycle G1 phase as well as in the non-selective protein degradation process caused upon this particular cellular stress. Moreover, Gcn2, but not Hri1 or Hri2, is essential for survival of cells growing in minimal medium, upon oxidative stress or glucose limitation. We further show that eIF2α phosphorylation at serine 52 by the eIF2α kinases is necessary for efficient cell cycle arrest in the G1 phase, for the consequent protein degradation and for sexual differentiation, under nitrogen starvation. Therefore, the eIF2α kinase signalling pathway modulates G1 phase cell cycle arrest, cell survival and mating under nutritional stress in the fission yeast Schizosaccharomyces pombe. 23804709 Myeloid-derived suppressor cells play crucial roles in the regulation of mouse collagen-induced arthritis. Myeloid-derived suppressor cells (MDSCs) are of myeloid origin and are able to suppress T cell responses. The role of MDSCs in autoimmune diseases remains controversial, and little is known about the function of MDSCs in autoimmune arthritis. In this study, we clarify that MDSCs play crucial roles in the regulation of proinflammatory immune response in a collagen-induced arthritis (CIA) mouse model. MDSCs accumulated in the spleens of mice with CIA when arthritis severity peaked. These MDSCs inhibited the proliferation of CD4(+) T cells and their differentiation into Th17 cells in vitro. Moreover, MDSCs inhibited the production of IFN-γ, IL-2, TNF-α, and IL-6 by CD4(+) T cells in vitro, whereas they promoted the production of IL-10. Adoptive transfer of MDSCs reduced the severity of CIA in vivo, which was accompanied by a decrease in the number of CD4(+) T cells and Th17 cells in the draining lymph nodes. However, depletion of MDSCs abrogated the spontaneous improvement of CIA. In conclusion, MDSCs in CIA suppress the progression of CIA by inhibiting the proinflammatory immune response of CD4(+) T cells. These observations suggest that MDSCs play crucial roles in the regulation of autoimmune arthritis, which could be exploited in new cell-based therapies for human rheumatoid arthritis. 23183327 Alterations of body mass index and body composition in atomic bomb survivors. Objective:Obesity, underweight, sarcopenia and excess accumulation of abdominal fat are associated with a risk of death and adverse health outcomes. Our aim was to determine whether body mass index (BMI) and body composition, assessed with dual-energy X-ray absorptiometry (DXA), are associated with radiation exposure among atomic bomb (A-bomb) survivors.Design:This was a cross-sectional study conducted in the Adult Health Study of the Radiation Effects Research Foundation.Subjects:We examined 2686 subjects (834 men and 1852 women), aged 48-89 years (0-40 years at A-bomb exposure), for BMI analysis. Among them, 550 men and 1179 women underwent DXA in 1994-1996 and were eligible for a body composition study.Results:After being adjusted for age and other potential confounding factors, A-bomb radiation dose was associated significantly and negatively with BMI in both sexes (P=0.01 in men, P=0.03 in women) and appendicular lean mass (P<0.001 in men, P=0.05 in women). It was positively associated with trunk-to-limb fat ratio in women who were less than 15 years old at the time of exposure (P=0.03).Conclusions:This is the first study to report a significant dose response for BMI and body composition 50 years after A-bomb radiation exposure. We will need to conduct further studies to evaluate whether these alterations affect health status. 23297412 Resveratrol improves cardiomyopathy in dystrophin-deficient mice through SIRT1 protein-mediated modulation of p300 protein. Cardiomyopathy is the main cause of death in Duchenne muscular dystrophy. Here, we show that oral administration of resveratrol, which leads to activation of an NAD(+)-dependent protein deacetylase SIRT1, suppresses cardiac hypertrophy and fibrosis and restores cardiac diastolic function in dystrophin-deficient mdx mice. The pro-hypertrophic co-activator p300 protein but not p300 mRNA was up-regulated in the mdx heart, and resveratrol administration down-regulated the p300 protein level. In cultured cardiomyocytes, cardiomyocyte hypertrophy induced by the α(1)-agonist phenylephrine was inhibited by the overexpression of SIRT1 as well as resveratrol, both of which down-regulated p300 protein levels but not p300 mRNA levels. In addition, activation of atrial natriuretic peptide promoter by p300 was inhibited by SIRT1. We found that SIRT1 induced p300 down-regulation via the ubiquitin-proteasome pathway by deacetylation of lysine residues for ubiquitination. These findings indicate the pathological significance of p300 up-regulation in the dystrophic heart and indicate that SIRT1 activation has therapeutic potential for dystrophic cardiomyopathy. 23825872 Technology transfer aids hearing. India is one of a growing number of countries looking at technology transfer to improve access to reliable, low-cost, digital hearing devices. Gary Humphreys reports. 23965037 Mosaic-like Monolayer of Graphene Oxide Sheets Decorated with Tetrabutylammonium Ions. We report the fabrication of mosaic-like monolayers of graphene oxide (G-O) coated with tetrabutylammonium ions (TBA) using a simple spin-coating method. The TBA-coated G-O (TG-O) sheets were prepared by "spontaneous exfoliation" of graphite oxide intercalated with tetrabutylammonium hydroxide (TBAOH) in the wet state, without the need for sonication. Mosaic-like monolayers could be formed on a variety of substrates such as Si wafer (coated with the thin native oxide), SiO2/Si wafer, graphene grown by chemical vapor deposition and then transferred on SiO2/Si wafer, Au film on Si wafer, and Cu foil. The mosaic-like monolayer of TG-O was compared with monolayers of G-O and TG-O prepared using a Langmuir-Blodgett (LB) trough. The formation of the mosaic-like TG-O monolayer films was attributed to (1) weakening of the electrostatic repulsion between G-O sheets by TBA, and (2) prevention of the overlap and stacking of TG-O sheets by disruption of the hydrogen bonding between the basal plane of one sheet and the basal plane or edge of another, by adsorbed TBA. External reflection FTIR spectroscopy showed that spectral features of the mosaic-like monolayer of TG-O made by simple spin-coating were the same as those for the monolayer fabricated using the LB assembly, indicating the same spatial orientations of functional groups. This study provides a very simple route to a complete monolayer of G-O without the need for an LB trough. 23603670 Anti-inflammatory BmAFI of Brugia malayi modulates IgE, histamine and histamine receptor responses in Mastomys coucha. We recently reported that BmAFI, an anti-inflammatory fraction of Brugia malayi adult worm supports parasite development in the hostile peritoneal cavity (p.c.) of Mastomys coucha through a modified Th2 type of response that includes IL-13 and IgE response and anti-inflammatory IL-10 cytokine milieu. In the present study we investigated IgE related responses such as histamine release and modulation of histamine receptors 1 and 2 (HR1 and HR2) by presensitization with BmAFI of M. coucha infected with B. malayi. Sensitization with BmAFI alone enhanced IgE, histamine and HR2, but decreased HR1. Exposure of these animals to infection produced an IgE response that was inversely related to the parasite burden, and decreased histamine conc., and HR1 and HR2 expression. However, there was an early small increase in HR1 expression for a short period after exposure to infection. As expected, BmAFI sensitization supported parasite survival and development in the hostile p.c. of the host. These findings further establish that BmAFI decreases inflammatory/Th1 response and modulates Th2 responses to favour survival and development of the parasite in the hostile p.c. of the host and that IgE and histamine play an important role in this. 23777864 Exopolysaccharides protect Synechocystis against the deleterious effects of titanium dioxide nanoparticles in natural and artificial waters. We have studied the effect of TiO2 nanoparticles (NPs) on the model cyanobacteria Synechocystis PCC6803. We used well-characterized NPs suspensions in artificial and natural (Seine River, France) waters. We report that NPs trigger direct (cell killing) and indirect (cell sedimentation precluding the capture of light, which is crucial to photosynthesis) deleterious effects. Both toxic effects increase with NPs concentration and are exacerbated by the presence of UVAs that increase the production of Reactive Oxygen Species (hydroxyl and superoxide radicals) by TiO2 NPs. Furthermore, we compared the responses of the wild-type strain of Synechocystis, which possesses abundant exopolysaccharides surrounding the cells, to that of an EPS-depleted mutant. We show, for the first time, that the exopolysaccharides play a crucial role in Synechocystis protection against cell killing caused by TiO2 NPs. 23413834 Effects of varenicline on ethanol- and food-maintained responding in a concurrent access procedure. Varenicline has been reported to reduce drinking in smokers and to selectively decrease responding for ethanol (EtOH) versus alternatives in preclinical studies. Such selectivity may reflect potential therapeutic effects and the involvement of nicotinic receptors in EtOH reinforcement. However, these studies have been conducted with EtOH and an alternative available in isolation or in separate groups, and selectivity can depend on the context in which reinforcement occurs. Whether varenicline selectivity is maintained when EtOH and an alternative are concurrently available has not been reported. To examine the effects of varenicline on EtOH self-administration when an alternative is concurrently available, male Lewis rats (n = 5) were trained to respond for EtOH and food under a concurrent FR5 FRX schedule where the fixed ratio (FR) for food was adjusted (FR = 25 or 35 for each subject) to provide similar numbers of EtOH and food deliveries during a 30-minute session. Doses of varenicline (0.56 to 5.6 mg/kg, i.p.) or vehicle were administered 30 minutes before sessions. Effects of varenicline on responding across the session and during each tenth of the session were compared to responding following vehicle treatment. Lower doses (0.56 to 1.0 mg/kg) of varenicline increased responding for EtOH without affecting responding for food. Higher doses disrupted responding for EtOH and food similarly. Previous reports of varenicline selectivity on EtOH-maintained responding do not generalize to other experimental conditions such as a concurrent schedule. The increase in responding for EtOH following lower doses might be due to enhanced EtOH reinforcement, decreased food reinforcement, rate dependency, or greater perseverance on the initial, EtOH response. 23552514 Chinese herbal formulas for treating hypertension in traditional Chinese medicine: perspective of modern science. Hypertension, which directly threatens quality of life, is a major contributor to cardiovascular and cerebrovascular events. Over the past two decades, domestic and foreign scholars have agreed upon various standards in the treatment of hypertension, and considerable progress has been made in the field of antihypertensive drugs. Oral antihypertensive drugs represent a milestone in hypertension therapy. However, the blood pressure standard for patients with hypertension is far from satisfactory. The study of Chinese herbal formulas for treating hypertension has received much research attention. These studies seek to integrate traditional and Western medicine in China. Currently, Chinese herbal formulas are known to have an outstanding advantage with regard to bodily regulation. Research shows that Chinese medicine has many protective mechanisms. This paper addresses the process of the antihypertensive mechanisms in Chinese herbal formulas for treating hypertension. These mechanisms are to be discussed in future research. 23430086 Exploring the automatic undercurrents of sexual narcissism: individual differences in the sex-aggression link. Sexual narcissism (SN) has recently been proposed to be a specific risk factor for the perpetration of sexual coercion based on both self-reports of previous behavior and self-estimated likelihood of engaging in acts of sexual violence. To explore one of the potential underlying mechanisms of SN, we tested whether for highly sexually narcissistic males (measured with the German language version of the Sexual Narcissism Scale) the subtle priming of sexual concepts would evoke aggressive behavior in a standard measure of aggressive behavior, the Taylor Aggression Paradigm. Results showed that only for sexually narcissistic men did a subtle priming with mildly erotic words lead to an increase in shock volumes administered to the alleged competitor on this task. For women, it was postulated that physical force would not be represented as a functional behavioral script for sexually narcissistic females and, in line with this hypothesis, no effects were found for women. The results were discussed with regard to the underlying processes of SN and the importance of an individual difference perspective in sex-aggression links. 23726971 Phase II study of pemetrexed in combination with cisplatin and cetuximab in recurrent or metastatic squamous cell carcinoma of the head and neck. Platinum/5-fluorouracil plus cetuximab is a standard systemic treatment for recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Pemetrexed has shown activity in SCCHN. This phase II study evaluated pemetrexed with cisplatin and cetuximab in recurrent/metastatic SCCHN. Patients received cetuximab 250mg/m(2) (loading dose: 400mg/m(2))days 1, 8 and 15; pemetrexed 500mg/m(2)+cisplatin 75mg/m(2) on day 1, q3w up to six cycles and folic acid, vitamin B12 and prophylactic medications. After a minimum of four cycles, responding patients were eligible for maintenance with pemetrexed and cetuximab, or either as monotherapy, until progression or toxicity. Efficacy (primary end-point: progression-free survival [PFS]) and toxicity were evaluated. Sixty-six patients received ⩾1 cycle of the triplet. Most patients were male (80.3%), with a median age of 62years and Eastern Cooperative Oncology Group (ECOG) performance status of 1 (71.2%). Diagnoses included oropharynx (45.5%) and larynx (24.2%) cancers, with locoregional disease (51.5%) alone, or combined with distant metastases (48.5%). Median (m) PFS was 4.4months (95% confidence interval [CI]: 3.6, 5.4); median overall survival was 9.7months (95% CI: 6.5, 13.1). Objective response rate was 29.3%; 23 patients had stable disease (39.7%). Drug-related grade 3/4 toxicities included neutropaenia (33.3%), fatigue (24.2%), anorexia (12.1%) and infection (10.6%). Five treatment-related deaths (7.6%) occurred. Efficacy results were consistent with current standard treatment for this patient population, but the pre-specified mPFS of 5.5months was not achieved. Grade 3/4 toxicities were also consistent with standard treatment, although treatment-related deaths were higher than expected. 23829403 Social support, coping strategies and health-related quality of life among primary caregivers of stroke survivors in China. To examine the relationships of social support and coping strategies to health-related quality of life among primary caregivers of stroke survivors in China. Caring for a stroke survivor is highly stressful, which can negatively affect a caregiver's physical and psychological well-being. Stroke caregivers generally report more somatic symptoms, depressive symptoms, sleep disorders and social isolation. They generally have poorer quality of life than the general population. A cross-sectional, descriptive, correlational study. A quasi-random, point of reference sample of 121 survivor-caregiver dyads was recruited from three community health centres and six health service stations in a city in central China. Data were collected in face-to-face interviews at participants' homes using structured questionnaires. Higher educational levels, planning and active coping were positively associated with health-related quality of life. The number of chronic conditions, hours of care per day and functional dependence of the survivor were negatively related to quality of life. Active coping strategies predicted better health-related quality of life. Findings suggest that intervention programmes should be developed to enhance caregivers of stroke survivors' coping skills and improve social support for these caregivers in China. Community healthcare providers may need to help caregivers strengthen strategies that are effective (planning, active coping, seeking instrumental and emotional support) and change those that are not helpful (venting, denial and self-blame). 23344121 Microarray analysis of gene expression profiles in the rat kidney demonstrates a local inflammatory response induced by cardiopulmonary bypass. Cardiopulmonary bypass (CPB) is a commonly used technique in cardiac surgery but is associated with acute, transient, renal dysfunction that has a negative impact on long-term survival. To unravel the molecular pathogenesis of renal injury following CPB. To obtain insight into the pathogenesis of renal dysfunction following CPB, we performed a microarray analysis of renal gene expression in the rat. University Medical Centre Groningen. Rats underwent CPB or a sham procedure for 60 min and were sacrificed at 60 min, 1 and 5 days after the procedure. Renal gene expression profile as determined by microarray analysis. Expression of 420 genes was significantly altered in CPB compared to the sham procedure, and in 407 genes, this was evident in the acute phase (60 min) following CPB. Gene ontology analysis revealed 28 of these genes were involved in inflammatory responses, with high expression of genes downstream of mitogen-activated protein-kinase (MAP-kinase) signalling pathways. Potent inducers identified are from the interleukin-6 cytokine family that consists of interleukin-6 and oncostatin M (OSM), which signal through the gp130-cytokine receptor complex. The plasma concentration of interleukin-6 was hugely increased by CPB as measured by ELISA. Expression of genes downstream of these signalling pathways that lead to production of chemokines, adhesion molecules and molecules involved in coagulative pathways, was upregulated. CPB induces an acute and local inflammatory response in the kidney, which might contribute to renal injury. The signalling pathways involved identified by gene expression analysis may represent pharmacological targets to limit renal injury following CPB. 23698309 Nonconserved tryptophan 38 of the cell surface receptor for subgroup j avian leukosis virus discriminates sensitive from resistant avian species. Subgroup J avian leukosis virus (ALV-J) is unique among the avian sarcoma and leukosis viruses in using the multimembrane-spanning cell surface protein Na(+)/H(+) exchanger type 1 (NHE1) as a receptor. The precise localization of amino acids critical for NHE1 receptor activity is key in understanding the virus-receptor interaction and potential interference with virus entry. Because no resistant chicken lines have been described until now, we compared the NHE1 amino acid sequences from permissive and resistant galliform species. In all resistant species, the deletion or substitution of W38 within the first extracellular loop was observed either alone or in the presence of other incidental amino acid changes. Using the ectopic expression of wild-type or mutated chicken NHE1 in resistant cells and infection with a reporter recombinant retrovirus of subgroup J specificity, we studied the effect of individual mutations on the NHE1 receptor capacity. We suggest that the absence of W38 abrogates binding of the subgroup J envelope glycoprotein to ALV-J-resistant cells. Altogether, we describe the functional importance of W38 for virus entry and conclude that natural polymorphisms in NHE1 can be a source of host resistance to ALV-J. 23607366 Intrinsic hyporesponsiveness of invariant natural killer T cells precedes the onset of lupus. Patients with systemic lupus erythematosus (SLE) display reduced numbers and functions of invariant natural killer T (iNK T) cells, which are restored upon treatment with corticosteroids and rituximab. It is unclear whether the iNK T cell insufficiency is a consequence of disease or is a primary abnormality that precedes the onset of disease. To address this, we analysed iNK T cell function at different stages of disease development using the genetically lupus-susceptible NZB × NZW F1 (BWF(1)) model. We found that iNK T cell in-vivo cytokine responses to an iNK T cell ligand α-galactosylceramide (α-GalCer) were lower in BWF(1) mice than in non-autoimmune BALB/c and major histocompatibility complex (MHC)-matched NZB × N/B10.PL F1 mice, although iNK T cell numbers in the periphery were unchanged in BWF(1) mice compared to control mice. Such iNK T cell hyporesponsiveness in BWF(1) mice was detected at a young age long before the animals exhibited any sign of autoimmunity. In-vivo activation of iNK T cells is known to transactivate other immune cells. Such transactivated T and B cell activation markers and/or cytokine responses were also lower in BWF(1) mice than in BALB/c controls. Finally, we show that iNK T cell responses were markedly deficient in the NZB parent but not in NZW parent of BWF(1) mice, suggesting that BWF(1) might inherit the iNK T cell defect from NZB mice. Thus, iNK T cells are functionally insufficient in lupus-prone BWF(1) mice. Such iNK T cell insufficiency precedes the onset of disease and may play a pathogenic role during early stages of disease development in SLE. 23876217 The 5'-untranslated region regulates ATF5 mRNA stability via nonsense-mediated mRNA decay in response to environmental stress. We previously reported that activating transcription factor 5 (ATF5) mRNA increases in response to amino acid limitation, and that this increase is dependent on mRNA stabilization. The ATF5 gene allows transcription of mRNAs with two alternative 5'-UTRs, 5'-UTRα and 5'-UTRβ, derived from exon 1α and exon 1β. 5'-UTRα contains the upstream open reading frames uORF1 and uORF2. Phosphorylation of eukaryotic initiation factor 2α during the integrated stress response had been previously shown to lead to bypassing of uORF2 translation and production of ATF5 protein. Translation of uORF2 is expected to result in translational termination at a position 125 nucleotides upstream of the exon junction, and this fits the criterion of a nonsense-mediated decay target mRNA. We investigated the potential role of 5'-UTRα in the control of mRNA stabilization, and found that 5'-UTRα reduced the stability of ATF5 mRNA. 5'-UTRα-regulated destabilization of mRNA was suppressed by knockdown of the nonsense-mediated decay factors Upf1 and Upf2. Mutation of the downstream AUG (uAUG2) rendered mRNA refractory to Upf1 and Upf2 knockdown. Moreover, 5'-UTRα-regulated down-regulation was hindered by amino acid limitation and tunicamycin treatment, and stress-induced phosphorylation of eukaryotic initiation factor 2α was involved in stabilization of ATF5 mRNA. These studies show that ATF5 mRNA is a naturally occurring normal mRNA target of nonsense-mediated decay, and provide evidence for linkage between stress-regulated translational regulation and the mRNA decay pathway. This linkage constitutes a mechanism that regulates expression of stress response genes. 23871190 Synchronous bilateral tonsillar carcinomas associated with human papillomavirus. Although the incidence of human papillomavirus (HPV)-positive oropharyngeal carcinoma is increasing, only a limited number of synchronous bilateral HPV-positive tonsillar carcinomas have been reported to date. Here, we describe an additional case of 61-year-old female. Pathological analysis proved squamous cell carcinoma in biopsy specimens from bilateral tonsillar lesions and a fine needle aspirate from an enlarged cervical node. Polymerase chain reaction (PCR) and direct sequencing showed HPV-16 DNA in all of the biopsy specimens and fine needle aspirate with completely concordant sequences. Bilateral tonsillar lesions were immunohistochemically positive for p16. Taken together with radiological findings, she was diagnosed to have bilateral tonsillar carcinomas (cT1N2bM0 on the right side and cT2N0M0 on the left side). We administered concurrent chemoradiotherapy to treat these synchronous lesions, and the restaging workup resulted in overall complete response. No recurrent and/or metastatic disease has been evident 20 months after the restaging. It seems reasonable to include bilateral tonsils as a therapeutic target in the treatment of HPV-positive unknown primary carcinoma. 23964962 Merozoite surface protein-3 alpha as a genetic marker for epidemiologic studies in Plasmodium vivax: a cautionary note. Plasmodium vivax is the most widespread of the human malaria parasites in terms of geography, and is thought to present unique challenges to local efforts aimed at control and elimination. Parasite molecular markers can provide much needed data on P. vivax populations, but few such markers have been critically evaluated. One marker that has seen extensive use is the gene encoding merozoite surface protein 3-alpha (MSP-3α), a blood-stage antigen known to be highly variable among P. vivax isolates. Here, a sample of complete msp-3α gene sequences is analysed in order to assess its utility as a molecular marker for epidemiologic investigations. Amplification, cloning and sequencing of additional P. vivax isolates from different geographic locations, including a set of Venezuelan field isolates (n = 10), yielded a sample of 48 complete msp-3α coding sequences. Characterization of standard population genetic measures of diversity, phylogenetic analysis, and tests for recombination were performed. This allowed comparisons to patterns inferred from the in silico simulation of a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) protocol used widely. The larger sample of MSP-3α diversity revealed incongruence between the observed levels of nucleotide polymorphism, which were high in all populations, and the pattern of PCR-RFLP haplotype diversity. Indeed, PCR-RFLP haplotypes were not informative of a population's genetic diversity and identical haplotypes could be produced from analogous bands in the commonly used protocol. Evidence of frequent and variable insertion-deletion mutations and recurrent recombination between MSP-3α haplotypes complicated the inference of genetic diversity patterns and reduced the phylogenetic signal. The genetic diversity of P. vivax msp-3α involves intragenic recombination events. Whereas the high genetic diversity of msp-3α makes it a promising marker for some epidemiological applications, the ability of msp-3α PCR-RFLP analysis to accurately track parasites is limited. Local studies of the circulating alleles are needed before implementing PCR-RFLP approaches. Furthermore, evidence from the global sample analysed here suggests such msp-3α PCR-RFLP methods are not suitable for broad geographic studies or tracking parasite populations for an extended period of time. 23381692 Clopidogrel, CYP2C19, and a Black Box. It has been presumed that CYP2C19 has a major role in the metabolism of clopidogrel. This presumption has been based on in vitro drug metabolism studies using microsomes from baculovirus infected insect cells (BD-Supersomes™). If clopidogrel were primarily a CYP2C19 substrate, a drug/drug interaction with CYP2C19 inhibitors, such as proton pump inhibitors (PPIs), for example, omeprazole and lansoprazole would be anticipated. Several ex vivo studies, using ADP stimulated platelet aggregation, suggested that there was such an interaction. The data from these studies served as a basis for FDA to provide a "Black Box" warning for the clopidogrel label in March of 2010. However, a prospective clinical study, COGENT, and several large meta-analyses have failed to demonstrate a negative effect on major adverse cardiovascular events (MACE), with concomitant administration of clopidogrel and PPIs. The in vitro work using "Supersomes" was revisited. In vitro metabolism using hepatosomes, which resemble the native cytochrome P-450 enzyme expression, has confirmed the earlier work that clopidogrel is primarily a CYP3A substrate. This result correlates better with clinical findings. The absence of an increase in MACE by concomitant administration of PPIs, which are CYP2C19 inhibitors, to a regimen including clopidogrel, is therefore not surprising. A hypothesis is offered to explain why subjects, who carry two reduced function alleles of CYP2C19, may have more reactive platelets. 23955948 Comparing salinity tolerance in embryonic and larval development of two species of water strider, Aquarius paludum and Gerris latiabdominis (Hemiptera: Gerridae). Water strider Aquarius paludum (Fabricius) is a cosmopolitan species colonizes mainly freshwater but occasionally brackish habitats throughout the Palearctic and Oriental regions. Water strider Gerris latiabdominis (Miyamoto) is a common species in Japan lives in temporary habitats as freshwater paddy fields. These two species often occur syntopically. We investigated differences in the developmental response to brackish water during embryonic and larval stages between the two species. Eggs were exposed to 0-1.8% NaCl solutions within 24 h of oviposition. Larvae of G. latiabdominis were exposed to salinities of 0, 0.5%, and 0.9% from the first instar until adult emergence. Limits of NaCl concentration for hatching were 1.3% and 1.0% for A. paludum and G. latiabdominis, respectively. The hatching rate of G. latiabdominis was lower than that of A. paludum at salinities ≥0.9%. The period of embryonic development of G. latiabdominis was more prolonged than that of A. paludum at a given salinity. Although the salinity tolerance of G. latiabdominis was lower than that of A. paludum, our results suggest G. latiabdominis has the physiological capacity to expand into brackish waters. High and low salinity tolerances of A. paludum and G. latiabdominis, respectively, reflect the relatively wide range of habitat salinities utilized by A. paludum and the relatively restricted habitats preferred by G. latiabdominis. The high salinity tolerance of A. paludum could be an important factor contributing to their cosmopolitan distribution because high tolerance to salinity means the possibility of them to be dispersed via ocean or sea to other continents and islands. 23897913 Essential contractual language for medical necessity in children. The previous policy statement from the American Academy of Pediatrics, "Model Language for Medical Necessity in Children," was published in July 2005. Since that time, there have been new and emerging delivery and payment models. The relationship established between health care providers and health plans should promote arrangements that are beneficial to all who are affected by these contractual arrangements. Pediatricians play an important role in ensuring that the needs of children are addressed in these emerging systems. It is important to recognize that health care plans designed for adults may not meet the needs of children. Language in health care contracts should reflect the health care needs of children and families. Informed pediatricians can make a difference in the care of children and influence the role of primary care physicians in the new paradigms. This policy highlights many of the important elements pediatricians should assess as providers develop a role in emerging care models. 23501052 The role of sleep and sleep deprivation in consolidating fear memories. Sleep, in particular REM sleep, has been shown to improve the consolidation of emotional memories. Here, we investigated the role of sleep and sleep deprivation on the consolidation of fear memories and underlying neuronal mechanisms. We employed a Pavlovian fear conditioning paradigm either followed by a night of polysomnographically monitored sleep, or wakefulness in forty healthy participants. Recall of learned fear was better after sleep, as indicated by stronger explicitly perceived anxiety and autonomous nervous responses. These effects were positively correlated with the preceding time spent in REM sleep and paralleled by activation of the basolateral amygdala. These findings suggest REM sleep-associated consolidation of fear memory in the human amygdala. In view of the critical participation of fear learning mechanisms in the etiology of anxiety and post-traumatic stress disorder, deprivation of REM sleep after exposure to distressing events is an interesting target for further investigation. 23688377 Percutaneous suprapubic stone extraction for posterior urethral stones in children: efficacy and safety. To evaluate the safety and efficacy of percutaneous suprapubic stone extraction (PSPSE) for pediatric posterior urethral stones. Between July 2007 and June 2010, 54 boys presenting with acute urinary retention due to posterior urethral stones underwent PSPSE. Patients were a mean age of 66.4 months (range, 8-180 months). The stone size was 0.7-1.9 cm. Patients were placed under general anesthesia, and a 7F urethroscope was used to pushback the stone to the bladder. A 3-mm suprapubic puncture with a scalpel was performed, followed by insertion of a straight narrow hemostat through the puncture aided with cystoscopic guidance. The stone was grasped with the hemostat in its narrowest diameter and was extracted percutaneously or crushed if friable. The suprapubic puncture was closed with a single 4-0 Vicryl (Ethicon) suture. Intact stone retrieval was achieved in 45 patients, and the stone was crushed into minute fragments in 9 patients. Intraperitoneal extravasation developed in 1 patient that required open surgical intervention. Mean operative time was 22 minutes. Patients were monitored for up to 17 months, with complete resolution of symptoms and stone clearance. PSPSE provides a minimally invasive approach for the extraction of urethral and bladder stones in the pediatric population. The use of a straight hemostat for suprapubic stone extraction or crushing is a good alternative to suprapubic tract dilation, with minimal morbidity. 23563807 Application of aptamers for targeted therapeutics. Aptamers are short, single-stranded oligonucleotides that are isolated through a process termed systematic evolution of ligands by exponential enrichment. With the advent of cell-based selection technology, aptamers can be selected to bind protein targets that are expressed on the cell surface. These aptamers demonstrate excellent specificity and high affinity toward their target proteins and are often internalized upon binding to their targets. This has opened up the possibility of using aptamers for cell-specific targeted drug delivery. In this review, we will discuss cell-surface protein targets, the aptamers that bind them, and their applications for targeted therapeutics. 23255217 Identification of MDP (muramyl dipeptide)-binding key domains in NOD2 (nucleotide-binding and oligomerization domain-2) receptor of Labeo rohita. In lower eukaryotes-like fish, innate immunity contributed by various pattern recognition receptor (PRR) plays an essential role in protection against diseases. Nucleotide-binding and oligomerization domain (NOD)-2 is a cytoplasmic PRR that recognizes MDP (muramyl dipeptide) of the Gram positive and Gram negative bacteria as ligand and activates signalling to induce innate immunity. Hypothesizing a similar NOD2 signalling pathway of higher eukaryotes, the peripheral blood leucocytes (PBLs) of rohu (Labeo rohita) was stimulated with MDP. The data of quantitative real-time PCR (qRT-PCR) revealed MDP-mediated inductive expression of NOD2 and its down-stream molecule RICK/RIP2 (receptor-interacting serine-threonine protein kinase-2). This observation suggested the existence of MDP-binding sites in rohu NOD2 (rNOD2). To investigate it, 3D model of ligand-binding leucine-rich repeat (LRR) region of rNOD2 (rNOD2-LRR) was constructed following ab initio and threading approaches in I-TASSER web server. Structural refinement of the model was performed by energy minimization, and MD (molecular dynamics) simulation was performed in GROMACS (Groningen Machine for Chemical Simulations). The refined model of rNOD2-LRR was validated through SAVES, ProSA, ProQ, WHAT IF and MolProbity servers, and molecular docking with MDP was carried out in GOLD 4.1. The result of docking identified LRR3-7 comprising Lys820, Phe821, Asn822, Arg847, Gly849, Trp877, Trp901 and Trp931 as MDP-binding critical amino acids in rNOD2. This is the first study in fish to provide an insight into the 3D structure of NOD2-LRR region and its important motifs that are expected to be engaged in MDP binding and innate immunity. 23344113 Bioactivity and applications of sulphated polysaccharides from marine microalgae. Marine microalgae have been used for a long time as food for humans, such as Arthrospira (formerly, Spirulina), and for animals in aquaculture. The biomass of these microalgae and the compounds they produce have been shown to possess several biological applications with numerous health benefits. The present review puts up-to-date the research on the biological activities and applications of polysaccharides, active biocompounds synthesized by marine unicellular algae, which are, most of the times, released into the surrounding medium (exo- or extracellular polysaccharides, EPS). It goes through the most studied activities of sulphated polysaccharides (sPS) or their derivatives, but also highlights lesser known applications as hypolipidaemic or hypoglycaemic, or as biolubricant agents and drag-reducers. Therefore, the great potentials of sPS from marine microalgae to be used as nutraceuticals, therapeutic agents, cosmetics, or in other areas, such as engineering, are approached in this review. 23786488 Chenopodolin: A Phytotoxic Unrearranged ent-Pimaradiene Diterpene Produced by Phoma chenopodicola, a Fungal Pathogen for Chenopodium album Biocontrol. A new phytotoxic unrearranged ent-pimaradiene diterpene, named chenopodolin, was isolated from the liquid culture of Phoma chenopodicola, a fungal pathogen proposed for the biological control of Chenopodium album, a common worldwide weed of arable crops such as sugar beet and maize. The structure of chenopodolin was established by spectroscopic, X-ray, and chemical methods as (1S,2S,3S,4S,5S,9R,10S,12S,13S)-1,12-acetoxy-2,3-hydroxy-6-oxopimara-7(8),15-dien-18-oic acid 2,18-lactone. At a concentration of 2 mg/mL, the toxin caused necrotic lesions on Mercurialis annua, Cirsium arvense, and Setaria viride. Five derivatives were prepared by chemical modification of chenopodolin functionalities, and some structure-activity relationships are discussed. 23902243 Personalized therapy for breast cancer: a dream or a reality? Breast cancer oncology represents one of the disciplines where personalized cancer medicine has been most actively pursued. The class-discovery studies conceptually advanced the field, underlining the molecular heterogeneity governing this common disease. The advent of high-throughput molecular profiling technologies holds great promise for the advance of all aspects of personalized cancer medicine, namely accurate prognostication, prediction of response to common systemic therapies and individualized monitoring of the disease. Moreover, an ever-expanding arsenal of targeted therapeutic compounds under clinical development, coupled with emerging powerful tools for comprehensive molecular and functional characterization, pose significant promise for improved clinical outcomes for breast cancer patients. Interrogation of the germline genetic variation offers further promise towards tailoring of breast cancer management. Well-conducted prospective validation studies are needed if breast cancer personalized therapy is to transform from a dream into a reality. 23909690 Effects of Bound Phosphate on the Bioreduction of Lepidocrocite (γ-FeOOH) and Maghemite (γ-Fe2O3) and Formation of Secondary Minerals. Natural Fe(III) oxides typically contain a range of trace elements including P. Although solution phase and adsorbed P (as phosphate) have been shown to impact the bioreduction of Fe(III) oxides and the formation of "biogenic" secondary minerals, little is known about the potential effects of occluded/incorporated phosphate. We have examined the bioreduction of Fe(III) oxides (lepidocrocite (γ-FeOOH) and maghemite (γ-Fe2O3)) containing 0-3 mass% P as "bound" (a term we use to include both adsorbed and occluded/incorporated) phosphate. Kinetic dissolution studies showed congruent release of Fe and P, suggesting that the phosphate in these materials was incorporated within the particles; however, 53% or 86% of the total phosphate associated with the lepidocrocites containing 0.7 or 3 mass% P, respectively, was extracted with 0.1 M NaOH and can be considered to be adsorbed, both to exterior surfaces and within micropores. In the absence of phosphate, lepidocrocite was rapidly reduced to magnetite by Shewanella putrefaciens CN32, and over time the magnetite was partially transformed to ferrous hydroxy carbonate (FHC). The presence of 0.2-0.7 mass% P significantly inhibited the initial reduction of lepidocrocite but ultimately resulted in greater Fe(II) production and the formation of carbonate green rust. The bioreduction of maghemite with and without bound phosphate resulted in solid-state conversion to magnetite, with subsequent formation of FHC. We also examined the potential redox cycling of green rust under alternating Fe(III)-reducing and oxic conditions. Oxidation of biogenic green rust by O2 resulted in conversion to ferric green rust, which was readily reduced back to green rust by S. putrefaciens CN32. These results indicate the potential for cycling of green rust between reduced and oxidized forms under redox dynamics similar to those encountered in environments that alternate between iron-reducing and oxic conditions, and they are consistent with the identification of green rust in soils/sediments with seasonal redox cycling. 23015691 Quantitative analysis of the interaction of constitutive androstane receptor with chemicals and steroid receptor coactivator 1 using surface plasmon resonance biosensor systems: a case study of the Baikal seal (Pusa sibirica) and the mouse. The constitutive androstane receptor (CAR) not only displays a high basal transcriptional activity but also acts as a ligand-dependent transcriptional factor. It is known that CAR exhibits different ligand profiles across species. However, the mechanisms underlying CAR activation by chemicals and the species-specific responses are not fully understood. The objectives of this study are to establish a high-throughput tool to screen CAR ligands and to clarify how CAR proteins from the Baikal seal (bsCAR) and the mouse (mCAR) interact with chemicals and steroid receptor coactivator 1 (SRC1). We developed the surface plasmon resonance (SPR) system to assess quantitatively the interaction of CAR with potential ligands and SRC1. The ligand-binding domain (LBD) of bsCAR and mCAR was synthesized in a wheat germ cell-free system. The purified CAR LBD was then immobilized on the sensor chip for the SPR assay, and the kinetics of direct interaction of CARs with ligand candidates was measured. Androstanol and androstenol, estrone, 17β-estradiol, TCPOBOP, and CITCO showed compound-specific but similar affinities for both CARs. The CAR-SRC1 interaction was ligand dependent but exhibited a different ligand profile between the seal and the mouse. The results of SRC1 interaction assay accounted for those of our previous in vitro CAR-mediated transactivation assay. In silico analyses also supported the results of CAR-SRC1 interaction; there is little structural difference in the ligand-binding pocket of bsCAR and mCAR, but there is a distinct discrimination in the helix 11 and 12 of these receptors, suggesting that the interaction of ligand-bound CAR and SRC1 is critical for determining species-specific and ligand-dependent transactivation over the basal activity. The SPR assays demonstrated a potential as a high-throughput screening tool of CAR ligands. 23968095 Anharmonic theoretical simulations of infrared spectra of halogenated organic compounds. The recent implementation of the computation of infrared (IR) intensities beyond the double-harmonic approximation [J. Bloino and V. Barone, J. Chem. Phys. 136, 124108 (2012)] paved the route to routine calculations of infrared spectra for a wide set of molecular systems. Halogenated organic compounds represent an interesting class of molecules, from both an atmospheric and computational point of view, due to the peculiar chemical features related to the halogen atoms. In this work, we simulate the IR spectra of eight halogenated molecules (CH2F2, CHBrF2, CH2DBr, CF3Br, CH2CHF, CF2CFCl, cis-CHFCHBr, cis-CHFCHI), using two common hybrid and double-hybrid density functionals in conjunction with both double- and triple-ζ quality basis sets (SNSD and cc-pVTZ) as well as employing the coupled-cluster theory with basis sets of at least triple-ζ quality. Finally, we compare our results with available experimental spectra, with the aim of checking the accuracy and the performances of the computational approaches. 23687076 Mortality of congenital osteochondrodysplasias: a nationwide registry-based study. Osteochondrodysplasias are a heterogeneous group of more than 200 entities, characterized by abnormalities of cartilage, bone growth, and skeletal development. The aim of this study was to assess temporal and spatial changes in overall mortality due to these disorders in Spain, using data from a nationwide registry. Annual deaths showing osteochondrodysplasias as the underlying cause of death were selected using the International Classification of Diseases-9th revision (ICD-9) codes for the period 1981 through 1998, and ICD-10 codes for the period 1999 through 2008. Age-adjusted mortality rates were calculated by sex, and geographic analysis was performed by municipality. A total of 679 deaths were recorded (53% men). Age-adjusted mortality rates went from 0.09 (0.06, 0.12) per 100,000 population in 1981 to 0.05 (0.03, 0.08) per 100,000 population in 2008. A changing trend in the age-standardized mortality rate was in evidence, with an annual increase of 2.4% (-0.4, 5.2) from 1981 to 1994, and an annual decrease of -7.3% (-10.9, -3.5) from 1995 onwards. Geographic analysis showed some places situated in the west and south of Spain with greater risk of mortality. There is a need to identify risk factors and to increase overall knowledge about the life expectancy and epidemiology of osteochondrodysplasias. 23856807 Accumulation of trace metals in two commercially important shrimp species from camamu bay, northeastern Brazil. Camamu Bay is the second largest estuary in Bahia state, northeastern Brazil, being recognized by its high diversity and economical relevance for fisheries and tourism. To evaluate the impacts of environmental disturbances in Camamu Bay, trace metals (Cr, Mn, Fe, Co, Ni, Cu, and Pb) were quantified in two widespread and commercially exploited shrimp species (Farfantepenaeus paulensis and Xiphopenaeus kroyeri). High concentrations of all metals but Pb were observed in both species by ICPOES. The concentration values for Cr, Co, and Mn were invariably higher than the accepted limits for human consumption in Brazil. Inter and intraspecific variation in metal levels might be related to biological particularities and body size. The accentuated contamination by trace metals in both species validated them as efficient bioindicators of environmental quality. Thus, effective planning, monitoring and regulatory policies should be adopted to inspect and remediate the metal contamination in natural resources from Camamu Bay. 23737247 Anatomical characterization of athetotic and spastic cerebral palsy using an atlas-based analysis. To analyze diffusion tensor imaging (DTI) in two types of cerebral palsy (CP): the athetotic-type and the spastic-type, using an atlas-based anatomical analysis of the entire brain, and to investigate whether these images have unique anatomical characteristics that can support functional diagnoses. We retrospectively analyzed the DTI of seven children with athetotic-type, 11 children with spastic-type, and 20 healthy control children, all age-matched. The severity of motor dysfunction was evaluated with the Gross Motor Function Classification System (GMFCS). The images were normalized using a linear transformation, followed by large deformation diffeomorphic metric mapping. For 205 parcellated brain areas, the volume, fractional anisotropy, and mean diffusivity were measured. Principal component analysis (PCA) was performed for the Z-scores of these parameters. The GMFCS scores in athetotic-type were significantly higher than those in spastic-type (P < 0.001). PCA extracted anatomical components that comprised the two types of CP, as well as the severity of motor dysfunction. In the athetotic group, the abnormalities were more severe than in the spastic group. In the spastic group, significant changes were concentrated in the lateral ventricle and periventricular structures. Our results quantitatively delineated anatomical characteristics that reflected the functional findings in two types of CP. J. Magn. Reson. Imaging 2013;38:288-298. © 2013 Wiley Periodicals, Inc. 23247074 Phase separation as a key to a thermoelectric high efficiency. This work elucidates the possible reasons for the outstanding, but never reproduced thermoelectric properties of the doped Ti(0.5)Zr(0.25)Hf(0.25)NiSn Heusler compounds. The structural investigations done via synchrotron X-ray diffraction measurements and scanning electron microscope measurements, which clearly show that the microstructure consists of three temperature stable C1(b) phases with possible semi-coherent interfaces, are presented. The exceptional thermoelectric properties are due to this intrinsic phase separation. It is possible to reproduce the high Figure of Merit values with ZT = 1.2 at 830 K. Furthermore, the influence of doping different elements on the Sn position in this Heusler material system is investigated. 23909813 Dietary sorbitol and mannitol: food content and distinct absorption patterns between healthy individuals and patients with irritable bowel syndrome. Sorbitol and mannitol are naturally-occurring polyol isomers. Although poor absorption and induction of gastrointestinal symptoms by sorbitol are known, the properties of mannitol are poorly described. We aimed to expand data on food composition of these polyols, and to compare their absorptive capacities and symptom induction in patients with irritable bowel syndrome (IBS) and healthy individuals. Food samples were analysed for sorbitol and mannitol content. The degree of absorption measured by breath hydrogen production and gastrointestinal symptoms (visual analogue scales) was evaluated in a randomised, double-blinded, placebo-controlled study in 21 healthy and 20 IBS subjects after challenges with 10 g of sorbitol, mannitol or glucose. Certain fruits and sugar-free gum contained sorbitol, whereas mannitol content was higher in certain vegetables. Similar proportions of patients with IBS (40%) and healthy subjects (33%) completely absorbed sorbitol, although more so with IBS absorbed mannitol (80% versus 43%; P = 0.02). Breath hydrogen production was similar in both groups after lactulose but was reduced in patients with IBS after both polyols. No difference in mean (SEM) hydrogen production was found in healthy controls after sorbitol [area-under-the-curve: 2766 (591) ppm 4 h(-1) ] or mannitol [2062 (468) ppm 4 h(-1) ] but, in patients with IBS, this was greater after sorbitol [1136 (204) ppm 4 h(-1) ] than mannitol [404 (154) ppm 4 h(-1) ; P = 0.002]. Overall gastrointestinal symptoms increased significantly after both polyols in patients with IBS only, although they were independent of malabsorption of either of the polyols. Increased and discordant absorption of mannitol and sorbitol occurs in patients with IBS compared to that in healthy controls. Polyols induced gastrointestinal symptoms in patients with IBS independently of their absorptive patterns, suggesting that the dietary restriction of polyols may be efficacious. 23687071 A Versatile Approach towards the Compaction, Decompaction, and Immobilization of DNA at Interfaces by Using Cyclodextrins. We investigate the temperature dependence of interactions of β-cyclodextrin (CD)/hexadecyltrimethylammonium bromide (CTAB) self-assemblies with DNA during the decompaction of DNA/CTAB complexes. By combining direct imaging techniques with density and sound-velocity measurements, we can explain the decompaction process and suggest a suitable model. The DNA-decompaction process by using CDs is accompanied by interactions with surfaces, such as glass or mica. The mechanism of β-CD/CTAB self-assembly is elucidated and the immobilization of DNA onto negatively charged surfaces is explained. Differences between the fractal dimensions of DNA that is adsorbed onto the surfaces are related to strong and weak binding, which permit the partial relaxation of DNA on the surfaces. The β-CD/CTAB self-assembled monolayers are demonstrated to be a facile and efficient route for surface functionalization, which allows for the immobilization of biomacromolecules in close proximity without any intermediate binding or deprotection steps. Moreover, this route is expected to show several advantages that might contribute to improving the performance of future biosensors as gentle immobilization-limiting alteration of the protein structure, oriented immobilization, thereby allowing homogeneous accessibility, reversible immobilization, thereby allowing reutilizations, and high compatibility with various types of biomacromolecules. 23959851 Nanotechnology-Based Drug Delivery Systems for Targeting, Imaging and Diagnosis of Neurodegenerative Diseases. Neurodegenerative disorders are becoming prevalent with the increasing age of the general population. A number of difficulties have emerged for the potential treatment of neurodegenerative diseases, as these disorders may be multi systemic in nature. Due to limitations regarding the blood brain barrier (BBB) structure, efflux pumps and metabolic enzyme expression, conventional drug delivery systems do not provide efficient therapy for neurodegenerative disorders. Nanotechnology can offer impressive improvement of the neurodegenerative disease treatment by using bio-engineered systems interacting with biological systems at a molecular level. This review focuses on the nano-enabled system applications for the treatment and diagnosis of neurodegenerative diseases, in particular Alzheimer's, Parkinson's and Prion diseases. 23820578 Cysteamine-Modified Silver Nanoparticle Aggregates for Quantitative SERS Sensing of Pentachlorophenol with a Portable Raman Spectrometer. Cysteamine-modified silver nanoparticle aggregates has been fabricated for pentachlorophenol (PCP) sensing by surface-enhanced Raman spectroscopy (SERS) using a portable Raman spectrometer. The cysteamine monolayers could preconcentrate PCP close to the substrate surface through the electrostatic interaction, which makes the SERS detection of PCP possible. Moreover, the Raman bands of cysteamine could be used as the internal spectral reference in the quantitative analysis. Qualitative detection of PCP was carried out by SERS without any sample pretreatment. Quantitative analysis of PCP was further realized based on the prepared substrate, as the log-log plot of normalized SERS intensity of PCP versus its concentrations exhibits a good linear relationship. The SERS signals collected on 20 randomly selected points show that the relative standard deviation of the normalized Raman intensity is 5.8%, which indicates the substrate had good uniformity. The PCP sensor also shows good long-term stability in the analyte solution. The substrate was cyclic immersed into PCP and methanol solution; after several cycles, the sensor still had good adsorption to PCP, which revealed the sensor has good reusability. Coupling with a portable Raman spectrometer, the cysteamine-modified silver nanoparticle aggregates have the potential to be used for in situ and routine SERS analysis of PCP in environmental samples. 23883478 The optimal use of cardiac imaging in the quantification of carcinoid heart disease. Carcinoid heart disease is a rare cause of right-sided valvular dysfunction, primarily mediated by serotonin. It is an important complication in patients with carcinoid syndrome and occurs in 20-50% of such patients. Echocardiography is the main technique used for the assessment of carcinoid heart disease, but other imaging modalities are also important, particularly in the quantification of the severity of the disease. We sought to review the role of cardiac imaging in the assessment of carcinoid heart disease. 23853025 Bilateral radix entomolaris with primary and permanent mandibular first molars. Dental practitioners should be aware of the morphological dental anomalies like additional roots; their location, incidence and associated unusual root canal morphology. They should also carefully interpret the intraoral radiographs so that such anomalies do not go unnoticed. 23740830 Multivariate t linear mixed models for irregularly observed multiple repeated measures with missing outcomes. Missing outcomes or irregularly timed multivariate longitudinal data frequently occur in clinical trials or biomedical studies. The multivariate t linear mixed model (MtLMM) has been shown to be a robust approach to modeling multioutcome continuous repeated measures in the presence of outliers or heavy-tailed noises. This paper presents a framework for fitting the MtLMM with an arbitrary missing data pattern embodied within multiple outcome variables recorded at irregular occasions. To address the serial correlation among the within-subject errors, a damped exponential correlation structure is considered in the model. Under the missing at random mechanism, an efficient alternating expectation-conditional maximization (AECM) algorithm is used to carry out estimation of parameters and imputation of missing values. The techniques for the estimation of random effects and the prediction of future responses are also investigated. Applications to an HIV-AIDS study and a pregnancy study involving analysis of multivariate longitudinal data with missing outcomes as well as a simulation study have highlighted the superiority of MtLMMs on the provision of more adequate estimation, imputation and prediction performances. 22902273 Nanomaterial scaffolds for stem cell proliferation and differentiation in tissue engineering. Tissue engineering is a clinically driven field and has emerged as a potential alternative to organ transplantation. The cornerstone of successful tissue engineering rests upon two essential elements: cells and scaffolds. Recently, it was found that stem cells have unique capabilities of self-renewal and multilineage differentiation to serve as a versatile cell source, while nanomaterials have lately emerged as promising candidates in producing scaffolds able to better mimic the nanostructure in natural extracellular matrix and to efficiently replace defective tissues. This article, therefore, reviews the key developments in tissue engineering, where the combination of stem cells and nanomaterial scaffolds has been utilized over the past several years. We consider the high potential, as well as the main issues related to the application of stem cells and nanomaterial scaffolds for a range of tissues including bone, cartilage, nerve, liver, eye etc. Promising in vitro results such as efficient attachment, proliferation and differentiation of stem cells have been compiled in a series of examples involving different nanomaterials. Furthermore, the merits of the marriage of stem cells and nanomaterial scaffolds are also demonstrated in vivo, providing early successes to support subsequent clinical investigations. This progress simultaneously drives mechanistic research into the mechanotransduction process responsible for the observations in order to optimize the process further. Current understanding is chiefly reported to involve the interaction of stem cells and the anchoring nanomaterial scaffolds by activating various signaling pathways. Substrate surface characteristics and scaffold bulk properties are also reported to influence not only short term stem cell adhesion, spreading and proliferation, but also longer term lineage differentiation, functionalization and viability. It is expected that the combination of stem cells and nanomaterials will develop into an important tool in tissue engineering for the innovative treatment of many diseases. 23845145 Risk factors for serious adverse effects of thiopurines in patients with Crohn's disease. Purpose: Thiopurines are effective in attaining and maintaining remission in patients with inflammatory bowel diseases (IBD). The major drawback of these drugs are their serious adverse effects (SAE), highlighting the importance of preemptive identification of patients at risk. We aimed to examine whether gene polymorphisms in GSTM1, GSTT1 and TPMT, combined with various clinical parameters, can predict thiopurine induced SAE. Methods: A retrospective cohort of 176 Crohn's Disease (CD) patients treated with thiopurines (131 with 6MP and 45 with azathioprine) was genotyped for common polymorphisms in GSTM1, GSTT1 and TPMT. Clinical data including SAE, age, ethnicity, gender and smoking status were extracted from patient charts. SAEs evaluated were myelosuppression, hepatotoxicity and pancreatitis. Associations between demographic, clinical, and genetic variables and thiopurine induced SAE were assessed. Results: Twenty-four patients (14%) developed SAE, revealing a significant association between thiopurine induced SAE and GSTM1-null genotype (P=0.05), older age (P=0.016) and active smoking status (P=0.043) and SAE. On multi-variant analysis, past or current smokers were at increased risk for developing thiopurine related SAE (OR 2.915, CI 95%: 1.199- 7.084), specifically pancreatitis (p<0.001). No association was found between TPMT or GSTT1 polymorphisms and the development of SAE. Conclusions: Active smoking and GSTM1-null genotype appear to be risk factors for thiopurine induced SAEs (i.e. myelosuppression, hepatotoxicity and pancreatitis) in patients with CD. Corroboration of these associations in larger cohorts is warranted. 23897111 Modeling and Regression Analysis of Semiochemical Dose-Response Curves of Insect Antennal Reception and Behavior. Dose-response curves of the effects of semiochemicals on neurophysiology and behavior are reported in many articles in insect chemical ecology. Most curves are shown in figures representing points connected by straight lines, in which the x-axis has order of magnitude increases in dosage vs. responses on the y-axis. The lack of regression curves indicates that the nature of the dose-response relationship is not well understood. Thus, a computer model was developed to simulate a flux of various numbers of pheromone molecules (10(3) to 5 × 10(6)) passing by 10(4) receptors distributed among 10(6) positions along an insect antenna. Each receptor was depolarized by at least one strike by a molecule, and subsequent strikes had no additional effect. The simulations showed that with an increase in pheromone release rate, the antennal response would increase in a convex fashion and not in a logarithmic relation as suggested previously. Non-linear regression showed that a family of kinetic formation functions fit the simulated data nearly perfectly (R (2) >0.999). This is reasonable because olfactory receptors have proteins that bind to the pheromone molecule and are expected to exhibit enzyme kinetics. Over 90 dose-response relationships reported in the literature of electroantennographic and behavioral bioassays in the laboratory and field were analyzed by the logarithmic and kinetic formation functions. This analysis showed that in 95 % of the cases, the kinetic functions explained the relationships better than the logarithmic (mean of about 20 % better). The kinetic curves become sigmoid when graphed on a log scale on the x-axis. Dose-catch relationships in the field are similar to dose-EAR (effective attraction radius, in which a spherical radius indicates the trapping effect of a lure) and the circular EARc in two dimensions used in mass trapping models. The use of kinetic formation functions for dose-response curves of attractants, and kinetic decay curves for inhibitors, will allow more accurate predictions of insect catch in monitoring and control programs. 23905962 Enhancing pressure ulcer prevention using wound dressings: what are the modes of action? Recent clinical research has generated interest in the use of sacral wound dressings as preventive devices for patients at risk of ulceration. This study was conducted to identify the modes of action through which dressings can add to pressure ulcer prevention, for example, shear and friction force redistribution and pressure distribution. Bench testing was performed using nine commercially available dressings. The use of dressings can reduce the amplitude of shear stress and friction reaching the skin of patients at risk. They can also effectively redirect these forces to wider areas which minimises the mechanical loads upon skeletal prominences. Dressings can redistribute pressure based upon their effective Poisson ratio and larger deflection areas, providing greater load redistribution. 23274715 Multi-walled carbon nanotube increases the excitability of hippocampal CA1 neurons through inhibition of potassium channels in rat's brain slices. This study was to investigate the neurotoxicity of multi-walled carbon nanotube (MWCNT) by measuring neuronal excitability in rat hippocampal neurons and exploring the underlying mechanism. Whole cell patch-clamp technique was used. Action potential properties and the pattern of repetitive firing rate were assessed. Our data showed that spike half-width and repetitive firing rate were significantly increased in a concentration-dependent manner. Furthermore, voltage-activated potassium currents were recorded. It was found that MWCNT produced a concentration-dependent inhibition in amplitudes of I(A) and I(K). In addition, MWCNT had effect on the activation kinetics of I(A) and I(K) with V(h) being shifted to the negative potential at high concentration, while I(A) inactivation curve was considerably shifted to the hyperpolarize potential with V(h) being increased. However, no effect was found on the recovery from inactivation of I(A). The results suggest that MWCNT increases the excitability of hippocampal CA1 neurons by inhibiting voltage-gated potassium current. 23968783 Ex vivo absorption of promestriene from oil-in-water emulsion into infant foreskin. Hypospadias is a birth defect in which the urinary tract opening is not at the tip of the penis. Hypospadias surgery is frequently complicated by healing deficiencies. Topical treatments with oestrogens were reported to improve healing. In the present study, ex vivo percutaneous absorption of promestriene, a synthetic oestrogen resulting of the double esterification of estradiol was conducted as a pre-requisite for further clinical trial in infants. Penetration of promestriene into infant foreskin treated with commercial oil in water emulsion (10μg/mg) for 24h was characterized showing controlled release properties enabling epidermal concentration more than six times higher than dermal concentration 4.13±2.46mgg(-1) versus 0.62±0.84mgg(-1), respectively). Furthermore, apparent promestriene fluxes into and through the skin (i.e., 1.5μg.cm-2.h-1 and<0.89μg.cm-2.h-1, respectively) were calculated from (i) drug amount retained into epidermis and dermis, or (ii) the limit of detection into the receptor fluid. In conclusion, less than 2% of initial dose were absorbed within 24h which compared well with others steroids applied topically in colloidal systems. 23874317 Imagined motor action and eye movements in schizophrenia. Visual exploration and planning of actions are reported to be abnormal in schizophrenia. Most of the studies monitoring eye movements in patients with schizophrenia have been performed under free-viewing condition. The present study was designed to assess whether mentally performing an action modulates the visuomotor behavior in patients with schizophrenia and in healthy controls. Visual scan paths were monitored in eighteen patients with schizophrenia and in eighteen healthy controls. Participants performed two tasks in which they were asked either to (1) look at a scene on a computer screen (free viewing), or (2) picture themselves making a sandwich in front of a computer screen (active viewing). The scenes contained both task-relevant and task-irrelevant objects. Temporal and spatial characteristics of scan paths were compared for each group and each task. The results indicate that patients with schizophrenia exhibited longer fixation durations, and fewer fixations, than healthy controls in the free viewing condition. The patients' visual exploration improved in the active viewing condition. However, patients looked less at task-relevant objects and looked more at distractors than controls in the active viewing condition in which they were asked to picture themselves making a sandwich in moving their eyes to task-relevant objects on an image. These results are consistent with the literature on deficits in motor imagery in patients with schizophrenia and it extends the impairment to visual exploration in an action imagery task. 23436220 Effects of oral deoxynivalenol exposure on immune-related parameters in lymphoid organs and serum of mice vaccinated with porcine parvovirus vaccine. Mice were exposed to deoxynivalenol (DON) via drinking water at a concentration of 2 mg/L for 36 days. On day 8 of treatment, inactivated porcine parvovirus vaccine (PPV) was injected intraperitoneally. The relative and absolute weight of the spleen was significantly decreased in the DON-treated group (DON). Antibody titers to parvovirus in serum were 47.9 ±â€‰2.4 in the vaccination group (Vac), but 15.2 ±â€‰6.5 in the group treated with DON and vaccine (DON + Vac). The IgA and IgG was not different in the DON, Vac an,d DON + Vac groups. IgM was significantly lower only in the DON + Vac group. However IgE was significantly increased in the Vac and DON + Vac group, but no change was observed between the Vac and DON + Vac groups. The concentrations of IL-2, IL-4, GM-CSF, MCP-1 and Rantes in serum, and IL-1α in mesenteric lymph node and MIP-1β in spleen were significantly increased by DON treatment compared to control. The concentrations of IL-2, IL-5, IL-6, IL-9, IL-12, IL-13 and Rantes in thymus, of IL-2 in spleen, and of IL-1α, IL-1β, IL-3, IL-5, IL-10, IL-17, G-CSF, GM-CSF and MCP-1 in mesenteric lymph nodes were significantly decreased in mice compared to those in the Vac group, while concentrations of IL-1α, IL-2, IL-9, IL-13,G-CSF, GM-CSF, IFN-γ, MCP-1, MIP-1α and TNF-α were significantly increased in serum compared to the Vac group. In conclusion, the results presented here indicate that exposure to DON at 2.0 mg/L via drinking water can disrupt the immune response in vaccinated mice by modulating cytokines and chemokines involved in their immune response to infectious disease. 23871878 Effects of food-deprivation and refeeding on the regulation and sources of blood glucose appearance in European seabass (Dicentrarchus labrax L.). Sources of blood glucose in European seabass (initial weight 218.0±43.0g; mean±S.D., n=18) were quantified by supplementing seawater with deuterated water (5%-(2)H2O) for 72h and analyzing blood glucose (2)H-enrichments by (2)H NMR. Three different nutritional states were studied: continuously fed, 21-day of fast and 21-day fast followed by 3days of refeeding. Plasma glucose levels (mM) were 10.7±6.3 (fed), 4.8±1.2 (fasted), and 9.3±1.4 (refed) (means±S.D., n=6), showing poor glycemic control. For all conditions, (2)H-enrichment of glucose position 5 was equivalent to that of position 2 indicating that blood glucose appearance from endogenous glucose 6-phosphate (G6P) was derived by gluconeogenesis. G6P-derived glucose accounted for 65±7% and 44±10% of blood glucose appearance in fed and refed fish, respectively, with the unlabeled fraction assumed to be derived from dietary carbohydrate (35±7% and 56±10%, respectively). For 21-day fasted fish, blood glucose appearance also had significant contributions from unlabeled glucose (52±16%) despite the unavailability of dietary carbohydrates. To assess the role of hepatic enzymes in glycemic control, activity and mRNA levels of hepatic glucokinase (GK) and glucose 6-phosphatase (G6Pase) were assessed. Both G6Pase activity and expression declined with fasting indicating the absence of a classical counter-regulatory stimulation of hepatic glucose production in response to declining glucose levels. GK activities were basal during fed and fasted conditions, but were strongly stimulated by refeeding. Overall, hepatic G6Pase and GK showed limited capacity in regulating glucose levels between feeding and fasting states. 23898190 SIRT2 directs the replication stress response through CDK9 deacetylation. Sirtuin 2 (SIRT2) is a sirtuin family deacetylase that directs acetylome signaling, protects genome integrity, and is a murine tumor suppressor. We show that SIRT2 directs replication stress responses by regulating the activity of cyclin-dependent kinase 9 (CDK9), a protein required for recovery from replication arrest. SIRT2 deficiency results in replication stress sensitivity, impairment in recovery from replication arrest, spontaneous accumulation of replication protein A to foci and chromatin, and a G2/M checkpoint deficit. SIRT2 interacts with and deacetylates CDK9 at lysine 48 in response to replication stress in a manner that is partially dependent on ataxia telangiectasia and Rad3 related (ATR) but not cyclin T or K, thereby stimulating CDK9 kinase activity and promoting recovery from replication arrest. Moreover, wild-type, but not acetylated CDK9, alleviates the replication stress response impairment of SIRT2 deficiency. Collectively, our results define a function for SIRT2 in regulating checkpoint pathways that respond to replication stress through deacetylation of CDK9, providing insight into how SIRT2 maintains genome integrity and a unique mechanism by which SIRT2 may function, at least in part, as a tumor suppressor protein. 23558202 Cyclohexanone derivatives with cytotoxicity from the fungus Penicillium commune. Four new cyclohexanone derivatives (2-5) and one known analog, (-)-Palitantin (1) were isolated from the EtOAc extract of Penicillium commune, a fungal strain of low-temperature habitats. The structures of 2-5 were determined on the basis of extensive spectroscopic analysis. Furthermore, the absolute configuration of 2 was assigned by electronic circular dichroism (ECD) calculations, whereas that 3-5 were deduced via the CD data. Cytotoxicities of 2-5 against five human carcinoma cell lines (Hela, A549, MCF7, HCT116, T24) were evaluated. 23965393 Effect of graded levels of fiber from alfalfa meal on intestinal nutrient and energy flow and hindgut fermentation in growing pigs. The objective of this experiment was to determine the effects of fiber level from alfalfa meal and collection period on the intestinal nutrient and energy flow and hindgut fermentation in growing pigs. Twenty-four pigs (initial BW = 21.4 ± 1.5 kg) were prepared by T-cannula insertion into the distal ileum and allotted to 4 treatments. The pigs were provided a corn-soybean meal control diet or a diet in which corn and soybean meal were partly replaced by 5, 10, or 20% of alfalfa meal to give the graded levels of dietary fiber during two 10-d collection periods. The BW of pigs at the start of period 1 and 2 were 32.2 ± 2.4 and 37.7 ± 4.2 kg, respectively. The final BW at the end of period 2 was 46.8 ± 4.0 kg. The apparent ileal digestibility (AID) and apparent total tract digestibility (ATTD) of nutrients and energy were measured. The VFA concentration was also determined in the ileal and fecal samples. Nutrient digestibility was not affected by inclusion of 5% alfalfa meal in the diet. The AID, ATTD, and hindgut fermentation of DM, carbohydrates (CHO), and GE decreased (linear, P < 0.05) as the level of alfalfa meal in the diet increased. The intestinal flow of DM, CHO, ADF, and GE increased (linear, P < 0.05) by increasing the level of dietary alfalfa. The pH in the ileal digesta and the concentration of acetate, propionate, and total VFA in the feces increased (linear, P < 0.01) as the level of alfalfa meal in the diet increased. From experiment period 1 to 2, the ATTD and hindgut fermentation of CHO decreased (P < 0.01), whereas the concentrations of propionate, valerate, and total VFA in ileal samples increased (P < 0.05). A multiple linear regression analysis, taking into account both the SDF and IDF intake, explained the variation (P < 0.01) in the total tract flow of NDF (93%), ADF (84%), GE (73%), DM (71%), and CHO (62%). In conclusion, the diet containing 5% of alfalfa meal did not affect nutrient and energy digestion. The intestinal flow of CHO decreased over the course of the 10-d collection period. The VFA concentration increased with fiber level and 10-d exposure to the experimental diets. Soluble and insoluble fibers from alfalfa meal have differential roles in nutrient digestion, which may help explain the variation observed in the intestinal flow of nutrients. 23672485 Two-photon optical interrogation of individual dendritic spines with caged dopamine. We introduce a novel caged dopamine compound (RuBi-Dopa) based on ruthenium photochemistry. RuBi-Dopa has a high uncaging efficiency and can be released with visible (blue-green) and IR light in a two-photon regime. We combine two-photon photorelease of RuBi-Dopa with two-photon calcium imaging for an optical imaging and manipulation of dendritic spines in living brain slices, demonstrating that spines can express functional dopamine receptors. This novel compound allows mapping of functional dopamine receptors in living brain tissue with exquisite spatial resolution. 23359217 Changing concepts and findings on autism. New research findings provide major challenges regarding our understanding of the concept of autism. These are critically discussed in relation to research relevant to classification, genetics, environmental risk factors, gene-environment interplay, animal models, biomarkers, clinical features, neuropathology, pharmacotherapy, behavioral treatments, and functioning in adult life. It is concluded that, although there have been major research advances; there is a need for a reconceptualization and an avoidance of claims that go beyond the evidence. 23623600 Structural integrity of the substantia nigra and subthalamic nucleus predicts flexibility of instrumental learning in older-age individuals. Flexible instrumental learning is required to harness the appropriate behaviors to obtain rewards and to avoid punishments. The precise contribution of dopaminergic midbrain regions (substantia nigra/ventral tegmental area [SN/VTA]) to this form of behavioral adaptation remains unclear. Normal aging is associated with a variable loss of dopamine neurons in the SN/VTA. We therefore tested the relationship between flexible instrumental learning and midbrain structural integrity. We compared task performance on a probabilistic monetary go/no-go task, involving trial and error learning of: "go to win," "no-go to win," "go to avoid losing," and "no-go to avoid losing" in 42 healthy older adults to previous behavioral data from 47 younger adults. Quantitative structural magnetization transfer images were obtained to index regional structural integrity. On average, both some younger and some older participants demonstrated a behavioral asymmetry whereby they were better at learning to act for reward ("go to win" > "no-go to win"), but better at learning not to act to avoid punishment ("no-go to avoid losing" > "go to avoid losing"). Older, but not younger, participants with greater structural integrity of the SN/VTA and the adjacent subthalamic nucleus could overcome this asymmetry. We show that interindividual variability among healthy older adults of the structural integrity within the SN/VTA and subthalamic nucleus relates to effective acquisition of competing instrumental responses. 23710884 Evaluation of warfarin resistance using transcription activator-like effector nucleases-mediated vitamin K epoxide reductase knockout HEK293 cells. Single nucleotide polymorphisms in the vitamin K epoxide reductase (VKOR) gene have been successfully used for warfarin dosage prediction. However, warfarin resistance studies of naturally occurring VKOR mutants do not correlate with their clinical phenotype. This discrepancy presumably arises because the in vitro VKOR activity assay is performed under artificial conditions using the non-physiological reductant dithiothreitol. The aim of this study is to establish an in vivo VKOR activity assay in mammalian cells (HEK293) where VKOR functions in its native milieu without interference from endogenous enzymes. Endogenous VKOR activity in HEK293 cells was knocked out by transcription activator-like effector nucleases (TALENs)-mediated genome editing. Knockout of VKOR in HEK293 cells significantly decreased vitamin K-dependent carboxylation with vitamin K epoxide (KO) as substrate. However, the paralog of VKOR, VKORC1L1, also exhibits substantial ability to convert KO to vitamin K for carboxylation. Using both VKOR and VKORC1L1 knockout cells, we examined the enzymatic activity and warfarin resistance of 10 naturally occurring VKOR mutants that were reported previously to have no activity in an in vitro assay. All 10 mutants are fully active; five have increased warfarin resistance, with the order being W59R>L128R≈W59L>N77S≈S52L. Except for the L128R mutant, this order is consistent with the clinical anticoagulant dosages. The other five VKOR mutants do not change VKOR's warfarin sensitivity, suggesting that factors other than VKOR play important roles. In addition, we confirmed that the conserved loop cysteines in VKOR are not required for active site regeneration after each cycle of oxidation. 23448271 The surface area of the hand and the palm for estimating percentage of total body surface area: results of a meta-analysis. The estimation of body surface area involvement is an important tool. Hand surface area (HSA) or palm surface area (PSA) is commonly used for the estimate, with an assumption that HSA represents 1% of the total body surface area (TBSA). To establish (i) the most accurate values for mean HSA% and PSA% of TBSA, and (ii) the variability of these with patient variables. The PubMed, Embase and Cochrane databases were searched and 14 eligible studies were identified. Weighted means of HSA% and PSA% were produced. The meta-analysis examined systematic variation associated with sex, age (for children), body mass index (BMI) and ethnic group using random-effects models. HSA% is 13% lower than the accepted 1% value for all adults (P = 0·004). PSA% is not significantly different from the accepted 0·5% value (P = 0·82). Men have a significantly higher HSA% than women (P < 0·0001). Children have a significantly higher HSA% than adults (P < 0·0001). HSA% falls with increasing BMI in adults (P < 0·0001). A comparison of European, Chinese and Indian subcontinent ethnic groups showed that each group was different from the others (P < 0·05). The use of HSA equating to 1% TBSA results in an overestimate for adults (particularly women) and an underestimate for children. PSA equating to 0·5% TBSA appears to be suitable for adults. Patient variables including sex and BMI result in variation of HSA as a percentage of TBSA. The heterogeneity of the included studies and the lack of data for children are the major limitations of this study. 23867657 Ways to improve the patient-physician relationship. This article revises the main conclusions from recent reviews and research, about the different dimensions that shape the patient-physician relationship, delineating specific areas of intervention that would reinforce the quality of this interaction. The selected articles reflect the permanent interest that exists about this topic. Within the most promissory findings significant associations were found from statistical as well as clinical standpoints. These associated verbal and non-verbal communication skills, as well as the empathizing ability of the physician, with clinical results of the patients, were measured with subjective parameters (e.g. patient satisfaction) and especially objective ones (e.g. physiological markers). Nevertheless, the results are still not robust and cannot be translatable. The implications of these studies are at a conceptual and instrumental level. A better precision of the dimensions and variables that define the patient-physician relationship will permit the design of educational strategies and training that will empower the physician for an interaction with his patients of greater technical and relational efficiency. 23872457 Early chest tube removal after video-assisted thoracic surgery lobectomy with serous fluid production up to 500 ml/day. In fast-track pulmonary resections, we removed chest tubes after video-assisted thoracic surgery (VATS) lobectomy with serous fluid production up to 500 ml/day. Subsequently, we evaluated the frequency of recurrent pleural effusions requiring reintervention. Data from 622 consecutive patients undergoing VATS lobectomy from January 2009 to December 2011 were registered prospectively in an institutional database. Data included age, gender, lobe(s) resected, bleeding and duration of surgery. Follow-up was 30 days from discharge. All complications requiring pleurocentesis or reinsertion of a chest tube, and all readmissions were registered. Twenty-three patients were excluded due to missing data, in-hospital mortality and loss to follow-up, leaving 599 for final analysis. Our primary outcome was the number of patients requiring reintervention due to recurrent pleural effusion. Secondary outcomes included time of chest tube removal and time to discharge. The incidence of recurrent pleural effusions requiring reintervention was compared between three groups according to the postoperative day (POD) of chest tube removal (Day 0-1, 2-3 and ≥4, respectively) using Fisher's exact test. Pleural effusion after chest tube removal required reintervention in 17 patients (2.8%). Of these, 7 needed readmission. Median time from surgery to chest tube removal was 2 days, and median time from surgery to discharge was 4 days. No statistically significant association was found between the incidence of reinterventions due to recurrent pleural effusion and the POD of chest tube removal (P = 0.50). The median time from chest tube removal to discharge was 1 day in all groups. Of the patients who needed reintervention, none had complications regarding this, except one who developed pneumothorax after pleurocentesis. Our findings suggest that chest tube removal after VATS lobectomy is safe despite volumes of serous fluid production up to 500 ml/day. The proportion of patients who developed pleural effusion necessitating reintervention was low (2.8%), and a complication of the reintervention was seen in only 1 patient. 23789789 Assessing the Performance of MM/PBSA and MM/GBSA Methods. 3. The Impact of Force Fields and Ligand Charge Models. Here, we systematically investigated how the force fields and the partial charge models for ligands affect the ranking performance of the binding free energies predicted by the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) approaches. A total of 46 small molecules targeted to five different protein receptors were employed to test the following issues: (1) the impact of five AMBER force fields (ff99, ff99SB, ff99SB-ILDN, ff03, and ff12SB) on the performance of MM/GBSA, (2) the influence of the time scale of molecular dynamics (MD) simulations on the performance of MM/GBSA with different force fields, (3) the impact of five AMBER force fields on the performance of MM/PBSA, and (4) the impact of four different charge models (RESP, ESP, AM1-BCC, and Gasteiger) for small molecules on the performance of MM/PBSA or MM/GBSA. Based on our simulation results, the following important conclusions can be obtained: (1) for short time-scale MD simulations (1 ns or less), the ff03 force field gives the best predictions by both MM/GBSA and MM/PBSA; (2) for middle time-scale MD simulations (2-4 ns), MM/GBSA based on the ff99 force field yields the best predictions, while MM/PBSA based on the ff99SB force field does the best; however, longer MD simulations, for example, 5 ns or more, may not be quite necessary; (3) for most cases, MM/PBSA with the Tan's parameters shows better ranking capability than MM/GBSA (GB(OBC1)); (4) the RESP charges show the best performance for both MM/PBSA and MM/GBSA, and the AM1-BCC and ESP charges can also give fairly satisfactory predictions. Our results provide useful guidance for the practical applications of the MM/GBSA and MM/PBSA approaches. 23935564 5-HT3 and 5-HT4 antagonists inhibit peristaltic contractions in guinea-pig distal colon by mechanisms independent of endogenous 5-HT. Recent studies have shown that endogenous serotonin is not required for colonic peristalsis in vitro, nor gastrointestinal (GI) transit in vivo. However, antagonists of 5-Hydroxytryptamine (5-HT) receptors can inhibit peristalsis and GI-transit in mammals, including humans. This raises the question of how these antagonists inhibit GI-motility and transit, if depletion of endogenous 5-HT does not cause any significant inhibitory changes to either GI-motility or transit? We investigated the mechanism by which 5-HT3 and 5-HT4 antagonists inhibit distension-evoked peristaltic contractions in guinea-pig distal colon. In control animals, repetitive peristaltic contractions of the circular muscle were evoked in response to fixed fecal pellet distension. Distension-evoked peristaltic contractions were unaffected in animals with mucosa and submucosal plexus removed, that were also treated with reserpine (to deplete neuronal 5-HT). In control animals, peristaltic contractions were blocked temporarily by ondansetron (1-10 μM) and SDZ-205-557 (1-10 μM) in many animals. Interestingly, after this temporary blockade, and whilst in the continued presence of these antagonists, peristaltic contractions recovered, with characteristics no different from controls. Surprisingly, similar effects were seen in mucosa-free preparations, which had no detectable 5-HT, as detected by mass spectrometry. In summary, distension-evoked peristaltic reflex contractions of the circular muscle layer of the guinea-pig colon can be inhibited temporarily, or permanently, in the same preparation by selective 5-HT3 and 5-HT4 antagonists, depending on the concentration of the antagonists applied. These effects also occur in preparations that lack any detectable 5-HT. We suggest caution should be exercised when interpreting the effects of 5-HT3 and 5-HT4 antagonists; and the role of endogenous 5-HT, in the generation of distension-evoked colonic peristalsis. 23921600 The SafeBoosC Phase II Randomised Clinical Trial: A Treatment Guideline for Targeted Near-Infrared-Derived Cerebral Tissue Oxygenation versus Standard Treatment in Extremely Preterm Infants. Near-infrared spectroscopy-derived regional tissue oxygen saturation of haemoglobin (rStO2) reflects venous oxygen saturation. If cerebral metabolism is stable, rStO2 can be used as an estimate of cerebral oxygen delivery. The SafeBoosC phase II randomised clinical trial hypothesises that the burden of hypo- and hyperoxia can be reduced by the combined use of close monitoring of the cerebral rStO2 and a treatment guideline to correct deviations in rStO2 outside a predefined target range. Aims: To describe the rationale for and content of this treatment guideline. Methods: Review of the literature and assessment of the quality of evidence and the grade of recommendation for each of the interventions. Results and Conclusions: A clinical intervention algorithm based on the main determinants of cerebral perfusion-oxygenation changes during the first hours after birth was generated. The treatment guideline is presented to assist neonatologists in making decisions in relation to cerebral oximetry readings in preterm infants within the SafeBoosC phase II randomised clinical trial. The evidence grades were relatively low and the guideline cannot be recommended outside a research setting. © 2013 S. Karger AG, Basel. 23958107 Multiple benign symmetric lipomatosis - a differential diagnosis of obesity. Benign symmetrical lipomatosis (BSL), or Madelung's disease, is a rare disease characterized by the progressive growth of diffuse, painless, non-enveloped symmetric lipomas. The etiology of this disease remains unknown, although it was associated in the medical literature with alcohol and nicotine abuse, metabolic disorders and a number of malignancies. It is assumed that there is a genetic predisposition for this affliction. The management in such cases is surgical removal of the lipomas, most times in several sessions, but this is often followed by relapse. However, surgical removal of the lipomas can provide satisfactory patient functionality and cosmetic results. The differential diagnosis is made with morbid obesity, Cushing syndrome, angiolipomatosis, encapsulated lipomas, neurofibromatosis, myxoid liposarcoma, lymphoma, salivary gland disease, Frölich and lipomatosis syndrome in patients infected with HIV. The current paper reports the case of a 55 year-old man, who presented with several large lipomatous masses, arranged symmetrically on the front and back of the trunk, and several smaller lipomas in the upper and lower limbs. Treatment consisted of resection of these lipomas in several sessions, without recurrence at one year after the last operation. 23764435 Educational agenda for diagnostic error reduction. Diagnostic errors are a major patient safety concern. Although the majority of diagnostic errors are partially attributable to cognitive mistakes, the most effective means of improving clinician cognition in order to achieve gains in diagnostic reliability are unclear. We propose a tripartite educational agenda for improving diagnostic performance among students, residents and practising physicians. This agenda includes strengthening the metacognitive abilities of clinicians, fostering intuitive reasoning and increasing awareness of the role of systems in the diagnostic process. The evidence supporting initiatives in each of these realms is reviewed and a course of future implementation and study is proposed. The barriers to designing and implementing this agenda are substantial and include limited evidence supporting these initiatives and the challenges of changing the practice patterns of practising physicians. Implementation will need to be accompanied by rigorous evaluation. 23420692 Co-delivery of 10-Hydroxycamptothecin with Doxorubicin Conjugated Prodrugs for Enhanced Anticancer Efficacy. Well-defined amphiphilic linear-dendritic prodrugs (MPEG-b-PAMAM-DOX) are synthesized by conjugating doxorubicin (DOX), to MPEG-b-PAMAM through the acid-labile hydrazone bond. The amphiphilic prodrugs form self-assembled nanoparticles in deionized water and encapsulate the hydrophobic anticancer drug 10-hydroxycamptothecin (HCPT) with a high drug loading efficiency. Studies on drug release and cellular uptake of the co-delivery system reveal that both drugs are released in a pH-dependent manner and effectively taken up by MCF-7 cells. In vitro methyl thiazolyl tetrazolium (MTT) assays and drug-induced apoptosis tests demonstrate the HCPT-loaded nanoparticles suppress cancer cell growth more efficiently than the MPEG-b-PAMAM-DOX prodrugs, free HCPT, and physical mixtures of MPEG-b-PAMAM-DOX and HCPT at equivalent DOX or HCPT doses. 23468252 miRNA-374 regulates dexamethasone-induced differentiation of primary cultures of porcine adipocytes. To investigate the effect of glucocorticoid on adipocytes metabolism and miRNAs that may be involved in adipocyte differentiation, primary porcine preadipocytes were treated with 10-6 M dexamethasone and RU486 (a glucocorticoid receptor antagonist) for 48 h. PPAR-γ (peroxisome proliferators-activated receptor-γ), and C/EBP-β (CCTTA enhancer binding protein-β) gene and protein expression were measured. The expressions of miRNAs predicted to directly target C/EBP-β were determined, and the functions of the potential miRNAs were verified. The results showed that the triglyceride content in cultured adipocytes increased significantly after 10-6 M dexamethasone treatment for 48 h, whereas the cell viability did not differ among the four groups (Control: 10-6 M dexamethasone; 10-6 M RU486: 10-6 M dexamethasone+10-6 M RU486) (p>0.05). Cells treated with dexamethasone for 48 h significantly upregulated perilipin and PPAR-γ gene expression, and PPAR-γ protein expression was also significantly increased. However, C/EBP-β mRNA and protein expression levels were significantly decreased. Both miR-374a and miR-374b, targeting the C/EBP-β 3'-UTR (3'-untranslated region), were significantly increased. Dual luciferase activity assay results indicated that miR-374a/b was directly recognised and bound to the 3'-UTR of C/EBP-β and thereby suppressed C/EBP-β gene expression. The present study showed that 10-6 M dexamethasone promotes lipid accumulation in primary cultures of porcine preadipocytes. PPAR-γ and C/EBP-β protein abundance showed differences after 48 h dexamethasone treatment; miR-374a/b may be involved in regulating of C/EBP-β expression. These results provide new targets for further regulation of porcine lipid metabolism. 23925795 In situ alcoholysis of triacylglycerols by application of switchable-polarity solvents. A new derivatization procedure for the gas-chromatographic analysis of vegetable oils. We describe a new use of switchable-polarity solvents for the simultaneous derivatization and extraction of triacylglycerols from vegetable oils before gas-chromatographic analysis. Different equimolecular mixtures of the commercially available amidine 1,8-diazabicyclo[5.4.0]undec-7-ene and n-alkyl alcohols were tested. Triolein was used as a model compound. Very good results were achieved by using butanol (recovery of butyl oleate was 89 ±â€‰4 %). The procedure was applied for the characterization of the fatty acid profile of different vegetable oils. No statistically significant differences from the results obtained with the application of two traditional methods were evidenced. Moreover, the use of switchable-polarity solvents showed many advantages: owing to the basicity of the amidines, no catalyst was required; the transterification reaction was conducted under mild conditions, one step and in situ; no particular matrix interferences were evidenced; the solvent was recovered. 23701399 The imaging Maastricht Acute Stress Test (iMAST): a neuroimaging compatible psychophysiological stressor. Several protocols have been developed for inducing acute stress in laboratory settings. Still, effectively eliciting stress in a neuroimaging environment remains challenging. Here, we describe the evaluation of a combined physical and psychosocial stress protocol (n = 42). The imaging Maastricht Acute Stress Test (iMAST) consists of a 5-min preparation phase and a 10-min acute stress phase, with alternating trials of cold pressor stress generated through an advanced thermal stimulator and mental arithmetic challenges along with social-evaluative pressure (i.e., negative feedback). Results demonstrate that participants displayed meaningful subjective stress responses, as well as significant increases in salivary alpha-amylase and cortisol levels. Our data show that the iMAST may prove to be a potent alternative to existing imaging stress paradigms to explore poststress neuronal changes and brain determinants of resilience. 23332751 Sequence-specific transcription factor NF-Y displays histone-like DNA binding and H2B-like ubiquitination. The sequence-specific transcription factor NF-Y binds the CCAAT box, one of the sequence elements most frequently found in eukaryotic promoters. NF-Y is composed of the NF-YA and NF-YB/NF-YC subunits, the latter two hosting histone-fold domains (HFDs). The crystal structure of NF-Y bound to a 25 bp CCAAT oligonucleotide shows that the HFD dimer binds to the DNA sugar-phosphate backbone, mimicking the nucleosome H2A/H2B-DNA assembly. NF-YA both binds to NF-YB/NF-YC and inserts an α helix deeply into the DNA minor groove, providing sequence-specific contacts to the CCAAT box. Structural considerations and mutational data indicate that NF-YB ubiquitination at Lys138 precedes and is equivalent to H2B Lys120 monoubiquitination, important in transcriptional activation. Thus, NF-Y is a sequence-specific transcription factor with nucleosome-like properties of nonspecific DNA binding and helps establish permissive chromatin modifications at CCAAT promoters. Our findings suggest that other HFD-containing proteins may function in similar ways. 23676315 Improvement in Myocardial Function by Terminalia arjuna in Streptozotocin-Induced Diabetic Rats: Possible Mechanisms. Vascular complications are a leading cause of mortality and morbidity in diabetic patients. Herbal drugs are increasingly being used in the treatment of cardiovascular disorders. The present study was designed to examine the therapeutic potential of Terminalia arjuna bark extract in improving myocardial function in streptozotocin (STZ)-induced diabetic rats. After 8 weeks of STZ administration, rats showed a decline in left ventricular pressure (LVP), maximal rate of rise and fall in LVP (LV [dP/dt] max and LV [dP/dt] min), cardiac contractility index (LV [dP/dt] max/LVP), and rise in LV end-diastolic pressure. Altered lipid profile, oxidative stress, and increased levels of endothelin 1 (ET-1), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6) along with histological changes in heart and pancreas were observed in diabetic rats. T arjuna significantly attenuated cardiac dysfunction and myocardial injury in diabetic rats. It also reduced oxidative stress, ET-1, and inflammatory cytokine levels. The decreased body weight, heart rate blood pressure, and raised blood sugar in diabetic rats did not improve after T arjuna therapy. Results suggest that T arjuna bark extract improves the altered myocardial function in diabetic rats possibly through maintaining endogenous antioxidant enzyme activities, decreasing ET-1 and cytokine levels. 23824199 Interventional nephrology: Physical examination as a tool for surveillance for the hemodialysis arteriovenous access. The prospective recognition of stenosis affecting dialysis vascular access and its prospective treatment is important in the management of the hemodialysis patient. Surveillance by physical examination is easily learned, easily performed, quickly done, and economical. In addition, it has a level of accuracy and reliability equivalent to other approaches that require special instrumentation. Physical examination should be part of any education to all hemodialysis care givers. This review presents the basic principles of physical examination of the hemodialysis vascular access and discusses the evidence behind its value. 23904476 Electronic excitations and metallization of dense solid hydrogen. Theoretical calculations and an assessment of recent experimental results for dense solid hydrogen lead to a unique scenario for the metallization of hydrogen under pressure. The existence of layered structures based on graphene sheets gives rise to an electronic structure related to unique features found in graphene that are well studied in the carbon phase. The honeycombed layered structure for hydrogen at high density, first predicted in molecular calculations, produces a complex optical response. The metallization of hydrogen is very different from that originally proposed via a phase transition to a close-packed monoatomic structure, and different from simple metallization recently used to interpret recent experimental data. These different mechanisms for metallization have very different experimental signatures. We show that the shift of the main visible absorption edge does not constrain the point of band gap closure, in contrast with recent claims. This conclusion is confirmed by measured optical spectra, including spectra obtained to low photon energies in the infrared region for phases III and IV of hydrogen. 23694750 Isolation of endophytic bacteria producing the anti-cancer alkaloid camptothecine from Miquelia dentata Bedd. (Icacinaceae). Camptothecine (CPT), a quinoline alkaloid, is a potent inhibitor of eukaryotic topoisomerase I. Because of this activity, several semi-synthetic derivatives of CPT are in clinical use against ovarian and small lung cancers. Together with its derivatives, CPT is the third largest anti-cancer drug in the world market. CPT is produced by several plant species belonging to the Asterid clade. In the recent past, several studies have reported the production of CPT by endophytic fungal associates of some of these plant species. In this paper, we report the production of CPT by endophytic bacteria isolated from Miquelia dentata Bedd. (Icacinaceae). Besides CPT, the bacteria also produced 9-methoxy CPT (9-MeO-CPT), in culture, independent of the host tissue. The chemical nature of CPT and 9-MeO-CPT was determined by LC-MS and ESI-MS/MS analysis, and was shown to be similar to that produced by the host tissue. One of the bacterial isolates examined, showed indications of attenuation of CPT production through sub-culture. This is the first report of production of CPT by endophytic bacteria. The identity of the bacteria was ascertained by Gram staining and 16s rRNA sequencing. We discuss the possible mechanisms that might be involved in the synthesis of CPT by endophytic bacteria. 23563362 Prolonged Administration of Pyridostigmine Impairs Neuromuscular Function with and without Down-regulation of Acetylcholine Receptors. The acetylcholinesterase inhibitor, pyridostigmine, is prophylactically administered to mitigate the toxic effects of nerve gas poisoning. The authors tested the hypothesis that prolonged pyridostigmine administration can lead to neuromuscular dysfunction and even down-regulation of acetylcholine receptors. Pyridostigmine (5 or 25 mg·kg·day) or saline was continuously administered via osmotic pumps to rats, and infused for either 14 or 28 days until the day of neuromuscular assessment (at day 14 or 28), or discontinued 24 h before neuromuscular assessment. Neurotransmission and muscle function were examined by single-twitch, train-of-four stimulation and 100-Hz tetanic stimulation. Sensitivity to atracurium and acetylcholine receptor number (quantitated by I-α-bungarotoxin) provided additional measures of neuromuscular integrity. Specific tetanic tensions (Newton [N]/muscle weight [g]) were significantly (P < 0.05) decreased at 14 (10.3 N/g) and 28 (11.1 N/g) days of 25 mg·kg·day pyridostigmine compared with controls (13.1-13.6 N/g). Decreased effective dose (0.81-1.05 vs. 0.16-0.45 mg/kg; P < 0.05) and decreased plasma concentration (3.02-3.27 vs. 0.45-1.37 μg/ml; P < 0.05) of atracurium for 50% paralysis (controls vs. 25 mg·kg·day pyridostigmine, respectively), irrespective of discontinuation of pyridostigmine, confirmed the pyridostigmine-induced altered neurotransmission. Pyridostigmine (25 mg·kg·day) down-regulated acetylcholine receptors at 28 days. Prolonged administration of pyridostigmine (25 mg·kg·day) leads to neuromuscular impairment, which can persist even when pyridostigmine is discontinued 24 h before assessment of neuromuscular function. Pyridostigmine has the potential to down-regulate acetylcholine receptors, but induces neuromuscular dysfunction even in the absence of receptor changes. 23454828 Which metabolites circulate? Characterization of the circulating metabolites for a new chemical entity in humans is essential for safety assessment, an understanding of their contributions to pharmacologic activities, and their potential involvement in drug-drug interactions. This review examines the abundance of metabolites relative to the total parent drug [metabolite-to-parent (M/P) ratio] from 125 drugs in relation to their structural and physicochemical characteristics, lipoidal permeability, protein binding, and fractional formation from parent (fm). Our analysis suggests that fm is the major determinant of total drug M/P ratio for amine, alcohol, N- and S-oxide, and carboxylic acid metabolites. Passage from the hepatocyte to systemic circulation does not appear to be limiting owing to the vast majority of metabolites formed being relatively lipid permeable. In some cases, active transport plays an important role in this process (e.g., carboxylic acid metabolites). Differences in total parent drug clearance and metabolite clearance are attenuated by the reduction in lipophilicity introduced by the metabolic step and resultant compensatory changes in unbound clearance and protein binding. A small subclass of these drugs (e.g., terfenadine) is unintentional prodrugs with very high parent drug clearance, resulting in very high M/P ratios. In contrast, arenol metabolites show a more complex relationship with fm due largely to the new metabolic routes (conjugation) available to the metabolite compared with the parent drug molecule. For these metabolites, a more thorough understanding of the elimination clearance of the metabolite is critical to discern the likelihood of whether the phenol will constitute a major circulating metabolite. 23884575 Quinuclidine compounds differently act as agonists of Kenyon cell nicotinic acetylcholine receptors and induced distinct effect on insect ganglionic depolarizations. We have recently demonstrated that a new quinuclidine benzamide compound named LMA10203 acted as an agonist of insect nicotinic acetylcholine receptors. Its specific pharmacological profile on cockroach dorsal unpaired median neurons (DUM) helped to identify alpha-bungarotoxin-insensitive nAChR2 receptors. In the present study, we tested its effect on cockroach Kenyon cells. We found that it induced an inward current demonstrating that it bounds to nicotinic acetylcholine receptors expressed on Kenyon cells. Interestingly, LMA10203-induced currents were completely blocked by the nicotinic antagonist α-bungarotoxin. We suggested that LMA10203 effect occurred through the activation of α-bungarotoxin-sensitive receptors and did not involve α-bungarotoxin-insensitive nAChR2, previously identified in DUM neurons. In addition, we have synthesized two new compounds, LMA10210 and LMA10211, and compared their effects on Kenyon cells. These compounds were members of the 3-quinuclidinyl benzamide or benzoate families. Interestingly, 1 mM LMA10210 was not able to induce an inward current on Kenyon cells compared to LMA10211. Similarly, we did not find any significant effect of LMA10210 on cockroach ganglionic depolarization, whereas these three compounds were able to induce an effect on the central nervous system of the third instar M. domestica larvae. Our data suggested that these three compounds could bind to distinct cockroach nicotinic acetylcholine receptors. 23227928 Predicting dislocations and grain boundaries in two-dimensional metal-disulfides from the first principles. Guided by the principles of dislocation theory, we use the first-principles calculations to determine the structure and properties of dislocations and grain boundaries (GB) in single-layer transition metal disulfides MS(2) (M = Mo or W). In sharp contrast to other two-dimensional materials (truly planar graphene and h-BN), here the edge dislocations extend in third dimension, forming concave dreidel-shaped polyhedra. They include different number of homoelemental bonds and, by reacting with vacancies, interstitials, and atom substitutions, yield families of the derivative cores for each Burgers vector. The overall structures of GB are controlled by both local-chemical and far-field mechanical energies and display different combinations of dislocation cores. Further, we find two distinct electronic behaviors of GB. Typically, their localized deep-level states act as sinks for carriers but at large 60°-tilt the GB become metallic. The analysis shows how the versatile GB in MS(2) (if carefully engineered) should enable new developments for electronic and opto-electronic applications. 23286196 Discovery of 5-benzyl-3-phenyl-4,5-dihydroisoxazoles and 5-benzyl-3-phenyl-1,4,2-dioxazoles as potent firefly luciferase inhibitors. Luciferase reporter assays are commonly used in high-throughput screening methods. Here, we report new firefly luciferase (FLuc) inhibitors based on 5-benzyl-3-phenyl-4,5-dihydroisoxazoles and 5-benzyl-3-phenyl-1,4,2-dioxazoles, which showed up as "false positives" in a luciferase reporter gene-based assay for nuclear receptor antagonists. The inhibition was shown to be noncompetitive for both natural enzyme substrates (d-luciferin and ATP) and selective to FLuc and proven to arise from a direct interaction between the enzyme and the inhibitor. Of the 63 evaluated compounds, 28 showed significantly better inhibition potency than the well-known inhibitor resveratrol (IC(50) = 59 nM), with five compounds having distinctly subnanomolar IC(50) values. The most efficient compounds inhibited the luminescence at concentrations lower than (1)/(100) in comparison to resveratrol (lowest IC(50) = 0.26 nM) and can thus be considered to belong to the most potent FLuc inhibitors reported thus far. Overall, the novel inhibitors form a unique molecular library for structure-activity relationship (SAR) analyses. 23743595 Intrinsic loss due to unstable modes in graphene. The mechanism of dissipation operative at the nanoscale remains poorly understood for most cases. In this work, using molecular dynamics simulations, we show that the unstable out-of-plane mode leads to the absorption of energy from the in-plane motion in graphene. The in-plane vibration modulates the potential energy profile for the out-of-plane modes. For the fundamental out-of-plane mode in the loading direction, the minimum of the potential energy shifts because of in-plane compressive strain. The structure takes a finite amount of time to relax to the new potential energy configuration. A hysteresis in the out-of-plane dynamics is observed when the time period of in-plane excitation becomes comparable to the time required for this relaxation. Increasing the stiffness of the out-of-plane modes by giving an initial tensile strain leads to a considerable decrease in dissipation rate. 23942341 Detection and differentiation of field and vaccine strains of canine distemper virus using reverse transcription followed by nested real time PCR (RT-nqPCR) and RFLP analysis. Canine distemper virus (CDV) is the cause of a severe and highly contagious disease in dogs. Practical diagnosis of canine distemper based on clinical signs and laboratory tests are required to confirm CDV infection. The present study aimed to develop a molecular assay to detect and differentiate field and vaccine CDV strains. Reverse transcription followed by nested real time polymerase chain reaction (RT-nqPCR) was developed, which exhibited analytical specificity (all the samples from healthy dogs and other canine infectious agents were not incorrectly detected) and sensitivity (all replicates of a vaccine strain were positive up to the 3125-fold dilution - 10(0.7) TCID50). RT-nqPCR was validated for CDV detection on different clinical samples (blood, urine, rectal and conjunctival swabs) of 103 animals suspected to have distemper. A total of 53 animals were found to be positive based on RT-nqPCR in at least one clinical sample. Blood resulted in more positive samples (50 out of 53, 94.3%), followed by urine (44/53, 83.0%), rectal (38/53, 71%) and conjunctival (27/53, 50.9%) swabs. A commercial immunochromatography (IC) assay had detected CDV in only 30 conjunctival samples of these positive dogs. Nucleoprotein (NC) gene sequencing of 25 samples demonstrated that 23 of them were closer to other Brazilian field strains and the remaining two to vaccine strains. A single nucleotide sequences difference, which creates an Msp I restriction enzyme digestion, was used to differentiate between field and vaccine CDV strains by restriction fragment length polymorphism (RFLP) analysis. The complete assay was more sensitive than was IC for the detection of CDV. Blood was the more frequently positive specimen and the addition of a restriction enzyme step allowed the differentiation of vaccine and Brazilian field strains. 23250002 Assessing the temporal relationship between cognition and gait: slow gait predicts cognitive decline in the mayo clinic study of aging. The association between gait speed and cognition has been reported; however, there is limited knowledge about the temporal associations between gait slowing and cognitive decline among cognitively normal individuals. The Mayo Clinic Study of Aging is a population-based study of Olmsted County, Minnesota, United States, residents aged 70-89 years. This analysis included 1,478 cognitively normal participants who were evaluated every 15 months with a nurse visit, neurologic evaluation, and neuropsychological testing. The neuropsychological battery used nine tests to compute domain-specific (memory, language, executive function, and visuospatial skills) and global cognitive z-scores. Timed gait speed (m/s) was assessed over 25 feet (7.6 meters) at a usual pace. Using mixed models, we examined baseline gait speed (continuous and in quartiles) as a predictor of cognitive decline and baseline cognition as a predictor of gait speed changes controlling for demographics and medical conditions. Cross-sectionally, faster gait speed was associated with better performance in memory, executive function, and global cognition. Both cognitive scores and gait speed declined over time. A faster gait speed at baseline was associated with less cognitive decline across all domain-specific and global scores. These results were slightly attenuated after excluding persons with incident mild cognitive impairment or dementia. By contrast, baseline cognition was not associated with changes in gait speed. Our study suggests that slow gait precedes cognitive decline. Gait speed may be useful as a reliable, easily attainable, and noninvasive risk factor for cognitive decline. 23871922 Pretreatment of sugarcane bagasse with liquid hot water and aqueous ammonia. Low water consumption operation (LWCO) can reduce the usage of water and energy input for the liquid hot water (LHW) pretreatment of sugarcane bagasse (SB) but causes great negative effects on the saccharification rate of xylose and enzymatic digestibility (ED) of cellulose. Therefore, a combined pretreatment with LHW and aqueous ammonia (LHWAA) was developed. ED of glucan and xylan is enhanced greatly resulted from the removal of hemicellulose and lignin after the LHWAA pretreatment. However, the intriguing results of low lignin removal and ED value were observed at the high reaction temperature of 180°C for the second step pretreatment of AA. It was proposed that lignin or pseudo-lignin droplet redeposited on the surface of residual solids might play a crucial role in determining the ED, so it is indispensable to make the enzyme access to the cellulose by the step of post-treatment with ultrasonic washing or hot washing. Coupled with the process of post-treatment and enzymatic hydrolysis, a high hemicellulose derived sugars recovery of 75.5% and glucose recovery of 87% was obtained for LHWAA pretreatment. 23954720 Protective effects of diphenyl diselenide in a mouse model of brain toxicity. Interest in organoselenide chemistry and biochemistry has increased in the past three decades, mainly due to their chemical and biological activities. Here, we investigated the protective effect of the organic selenium compound diphenyl diselenide (PhSe)2 (5μmol/kg), in a mouse model of methylmercury (MeHg)-induced brain toxicity. Our group has previously demonstrated that the oral and repeated administration (21days) of MeHg (40mg/L) induced MeHg brain accumulation at toxic concentrations, and a pattern of severe cortical and cerebellar biochemical and behavioral. In order to assess neurotoxicity, the neurochemical parameters, namely, mitochondrial complexes I, II, II-III and IV, glutathione peroxidase (GPx) and glutathione reductase (GR) activities, the content of thiobarbituric acid-reactive substances (TBA-RS), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and brain-derived neurotrophic factor (BDNF), as well as, metal deposition were investigated in mouse cerebral cortex. Cortical neurotoxicity induced by brain MeHg deposition was characterized by the reduction of complexes I, II, and IV activities, reduction of GPx and increased GR activities, increased TBA-RS and 8-OHdG content, and reduced BDNF levels. The daily treatment with (PhSe)2 was able to counteract the inhibitory effect of MeHg on mitochondrial activities, the increased oxidative stress parameters, TBA-RS and 8-OHdG levels, and the reduction of BDNF content. The observed protective (PhSe)2 effect could be linked to its antioxidant properties and/or its ability to reduce MeHg deposition in brain, which was here histochemically corroborated. Altogether, these data indicate that (PhSe)2 could be consider as a neuroprotectant compound to be tested under neurotoxicity. 23219498 Effects of lack of pulsatility on pulmonary endothelial function in the Fontan circulation. Continuous flow in the Fontan circulation results in impairment of pulmonary artery endothelial function, increased pulmonary arterial resistance, and, potentially, late failure of Fontan circulation. We investigated the mechanisms of vascular remodeling and altered vascular reactivity associated with chronic privation of pulsatility on pulmonary vasculature. A total of 30 pigs were evenly distributed in 3 groups: 10 underwent a sham procedure (group I) and 20 underwent a cavopulmonary shunt between the superior vena cava and right pulmonary artery-10 with complete ligation of the proximal right pulmonary artery (group II, nonpulsatile) and 10 with partial ligation (group III, micropulsatile). At 3 months postoperatively, the in vivo hemodynamics, in vitro vasomotricity (concentration response curves on pulmonary artery isolated rings), and endothelial nitric oxide synthase protein level were assessed. A comparison between group and between the right and left lung in each group was performed. Group II developed right pulmonary hypertension and increased right pulmonary resistance. Endothelial function was altered in group II, as reflected by a decrease in the vasodilation response to acetylcholine and ionophoric calcium but preservation of the nonendothelial-dependent response to sodium nitroprusside. Group III micropulsatility attenuated pulmonary hypertension but did not prevent impairment of the endothelial-dependant relaxation response. Right lung Western blotting revealed decreased endothelial nitric oxide synthase in group II (0.941 ± 0.149 vs sham 1.536 ± 0.222, P = .045) that was preserved in group III (1.275 ± 0.236, P = .39). In a chronic model of unilateral cavopulmonary shunt, pulsatility loss resulted in an altered endothelial-dependant vasorelaxation response of the pulmonary arteries. Micropulsatility limited the effects of pulsatility loss. These results are of importance for potential therapies against pulmonary hypertension in the nonpulsatile Fontan circulation, by retaining accessory pulmonary flow or pharmaceutical modulation of nonendothelial-dependant pulmonary vasorelaxation. 23926636 Genetically Engineered Mouse Models Reveal the Importance of Proteases as Osteoarthritis Drug Targets. More than two decades of research has revealed a combination of proteases that determine cartilage degradation in osteoarthritis. These include metalloproteinases, which degrade the major macromolecules in cartilage, aggrecan and type II collagen, serine proteases, and cysteine proteases, for example cathepsin K. This review summarizes the function of proteases in osteoarthritis progression, as revealed by studies of genetically engineered mouse models. A brief overview of the biochemical characteristics and features of several important proteases is provided, with the objective of increasing understanding of their function. Published data reveal at least three enzymes to be major targets for osteoarthritis drug development: ADAMTS-5, MMP-13, and cathepsin K. In surgical models of osteoarthritis, mice lacking these enzymes are protected from cartilage damage and, to varying degrees, from bone changes. In-vivo studies targeting these proteases with selective small-molecule inhibitors have been performed for a variety of animal models. Mouse models will provide opportunities for future tests of the therapeutic effect of protease inhibitors, both on progression of structural damage to the joint and on associated pain. 23828322 Radically resected pituitary adenomas: prognostic role of Ki 67 labeling index in a monocentric retrospective series and literature review. Ki-67 Labeling Index is an immunocytochemical marker of cell proliferation. The correlation of Ki-67 expression with pituitary adenomas recurrence has been investigated and is highly debated. Aim of this study was to evaluate whether Ki-67 correlates with recurrence even in patients with an apparently completely removed pituitary adenoma. We retrospectively reviewed the database of the Hypothalamic-Pituitary Disease Unit at the Catholic University of Rome, collected between 2003 and 2011. Inclusion criteria were: patients who underwent surgery at the Department of Neurosurgery with an apparently complete removal of a pituitary adenoma; Ki-67 histological evaluation by the same operator and values of <3 %. All patients underwent endocrine evaluation of the hypothalamic-pituitary function, ophthalmologic and neuro-radiological examinations, during the preoperative period and follow-up. Out of 490 patients recorded on the database of the Hypothalamic-Pituitary Disease Unit at the Catholic University of Rome, 191 cases met the inclusion criteria. Recurrence was observed in 49 cases (25.7 % of the patients who had undergone radical excision). Optional cut-off value was identified at Ki-67 values of 1.50 %. This was associated with worse disease-free survival time, even after correction for age at treatment, gender, positivity to p53, functional classification and Knosp grading. Ki-67 labeling index may be useful in postoperative management, even in patients who underwent radical PA removal. We suggest a Ki-67 cut-off value of 1.5 % to plan an adequate clinical follow-up. 23849987 Combination of low-dose mycophenolate mofetil with cyclosporine and methotrexate as GVHD prophylaxis in unrelated donor allogeneic stem cell transplantation. We report the results of HLA-matched unrelated donor allogeneic stem cell transplantation with new GVHD prophylaxis regimen consisted of cyclosporine, methotrexate and low-dose mycophenolate mofetil in 139 patients with hematologic malignancies. The incidence of grades II-IV and III-IV acute GVHD were 43.0% and 17.3%, respectively. The incidence of chronic GVHD was 42.1%, with 16.5% extensive grade. The cumulative incidence of transplant-related mortality at 100 days and 3 years were 7.9% and 29.7%, respectively. Three-year overall survival, disease-free survival and relapse incidence were 58.7%, 55.3% and 19.6%, respectively. These results suggest the new regime may be effective for the prophylaxis of acute and chronic GVHD in unrelated donor transplantation. 23159708 Implementation and evaluation of an optical fiber system as novel process monitoring tool during lyophilization. Lyophilization is an important and well-established pharmaceutical drying process. Product temperature is the most critical process parameter during lyophilization as it impacts both product quality and process efficiency. Traditionally, thermocouples (TCs) or resistance temperature detectors (RTDs) and recently, manometric temperatures measurements (MTMs) have been used to monitor the product temperature. But, all of these techniques have several drawbacks. The objective of this study was the implementation and evaluation of an optical fiber system as novel process monitoring tool during lyophilization. Therefore, temperature profiles of mannitol, sucrose, or trehalose were recorded with various prototypes of the optical fiber sensors (OFSs) and compared to data obtained with conventional TCs or Pirani/capacitance manometry with respect to the endpoint of primary drying. The OFS allowed easy handling and easy center bottom positioning. Data obtained with the OFS in contact with product were in good agreement with data obtained via TCs or Pirani/capacitance manometry. The OFSs showed significantly higher sensitivity, faster response, and better resolution compared to TCs. This allowed for the detection of additional excipient crystallization events. It was found that force effects on unshielded sensors enabled to detect glass transitions. Three-dimensional temperature profiles were obtained with an OFS helix configuration. The possible integration of a glass fiber with several OFSs in series into the shelf surface enables non-invasive, automatic loading compatible monitoring of the drying process. In conclusion, these advantages turn the novel optical fiber systems into a highly attractive process monitoring tool during lyophilization. 23345044 Two novel mutations in CYP11B1 and modeling the consequent alterations of the translated protein in classic congenital adrenal hyperplasia patients. Mutations in the 11β-hydroxylase (CYP11B1) gene are the second leading cause of congenital adrenal hyperplasia (CAH), an autosomal recessive disorder characterized by adrenal insufficiency, virilization of female external genitalia, and hypertension with or without hypokalemic alkalosis. Molecular analysis of CYP11B1 gene in CAH patients with 11β-hydroxylase deficiency was performed in this study. Cycle sequencing of 9 exons in CYP11B1 was performed in 5 unrelated families with 11β-hydroxylase deficient children. Three-dimensional models for the normal and mutant proteins and their affinity to their known substrates were examined. Analysis of the CYP11B1 gene revealed two novel mutations, a small insertion in exon 7 (InsAG393) and a small deletion in exon 2 (DelG766), and three previously known missense mutations (T318M, Q356X, and R427H). According to docking results, the affinity of the protein to its substrates is highly reduced by these novel mutations. DelG766 has more negative impact on the protein in comparison to InsAG393. The novel mutations, InsAG393 and DelG766, change the folding of the protein and disrupt the enzyme's active site as it was measured in the protein modeling and substrate binding analysis. Molecular modeling and sequence conservation were predictive of clinical severity of the disease and correlated with the clinical diagnosis of the patients. 23843540 Taste familiarity is inversely correlated with arc/arg3.1 hemispheric lateralization. Biochemical, electrophysiological, and imaging studies suggest that the anterior part of the insular cortex (IC) serves as primary taste cortex, whereas fMRI studies in human propose that the anterior IC is also involved in processing of general novelty or saliency information. Here, we compared activity regulated cytoskeleton associated protein (Arc)/Arg3.1 protein levels in the rat IC following administration of familiar versus novel tastes. Surprisingly, there was no correlation between novel taste and Arc/Arg3.1 levels when measured as the sum of both left and right insular cortices. However, when left and right IC were examined separately, Arc/Arg3.1 level was lateralized following novel taste learning. Moreover, Arc/Arg3.1 lateralization was inversely correlated with taste familiarity, whereas the high lateralization of Arc/Arg3.1 expression observed following novel taste learning is reduced proportionally to the increment in taste familiarity. In addition, unilateral inhibition of protein synthesis in the IC had asymmetrical effect on memory, inducing strong memory impairment similarly to bilateral inhibition or memory preservation, indicating that hemispheric lateralization is central for processing taste saliency information. These results provide indications, at the gene level of expression, for the role of IC lateralization in processing novel taste information and for the asymmetrical contribution of protein synthesis in each hemisphere during memory consolidation. 23356789 A new iridoid glycoside and potential MRB inhibitory activity of isolated compounds from the rhizomes of Cyperus rotundus L. A new iridoid glycoside, rotunduside (1), along with four known iridoid glycosides, 10-O-p-hydroxybenzoyltheviridoside (2), 10-O-vanilloyltheviridoside (3), 6″-O-(trans-p-coumaroyl)-procumbide (4) and loganic acid (5), was isolated from the rhizomes of Cyperus rotundus L. Their chemical structures were elucidated on the basis of UV, IR, MS and NMR spectroscopic analyses. In addition, the macrophages respiratory burst (MRB) inhibitory activity of the isolated compounds was reported. Compound 2 exhibited considerable MRB inhibitory activity in the test with IC(50) value of ∼37 μM. 22983144 Enhancement of social novelty discrimination by positive allosteric modulators at metabotropic glutamate 5 receptors: adolescent administration prevents adult-onset deficits induced by neonatal treatment with phencyclidine. Metabotropic glutamate-5 receptors (mGluR5), which physically and functionally interact with N-methyl-D-Aspartate (NMDA) receptors, likewise control cognitive processes and have been proposed as targets for novel classes of antipsychotic agent. Since social cognition is impaired in schizophrenia and disrupted by NMDA receptor antagonists like dizocilpine, we evaluated its potential modulation by mGluR5. Acute administration (0.63-40 mg/kg) of the mGluR5 positive allosteric modulators (PAMs), 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and ADX47273, reversed a delay-induced impairment in social novelty discrimination (SND) in adult rats. The action of CDPPB was blocked by the mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (2.5-10 mg/kg), and was also expressed upon microinjection into frontal cortex (0.63-10 μg/side), but not striatum. Supporting an interrelationship between mGluR5 and NMDA receptors, enhancement of SND by CDPPB was blocked by dizocilpine (0.08 mg/kg) while, reciprocally, dizocilpine-induced impairment in SND was attenuated by CDPPB (10 mg/kg). The SND deficit elicited by post-natal administration of phencyclidine (10 mg/kg, days 7-11) was reversed by CDPPB or ADX47273 in adults at week 8. This phencyclidine-induced impairment in cognition emerged in adult rats from week 7 on, and chronic, pre-symptomatic treatment of adolescent rats with CDPPB over weeks 5-6 (10 mg/kg per day) prevented the appearance of SND deficits in adults until at least week 13. In conclusion, as evaluated by a SND procedure, mGluR5 PAMs promote social cognition via actions expressed in interaction with NMDA receptors and exerted in frontal cortex. MGluR5 PAMs not only reverse but also (when given during adolescence) prevent the emergence of cognitive impairment associated with a developmental model of schizophrenia. 23866805 Minimally Invasive and Conventional Aortic Valve Replacement: A Propensity Score Analysis. The study aimed to compare the short-term results of aortic valve replacement through minimally invasive and sternotomy approaches. This is a retrospective, observational, cohort study of prospectively collected data on 709 patients undergoing isolated primary aortic valve replacement between 2004 and 2011. Of these, 338 were performed through either right anterior minithoracotomy or upper ministernotomy. With propensity score matching, 182 patients (minimally invasive group) were compared with 182 patients in conventional sternotomy (control group). After propensity matching, the 2 groups were comparable in terms of preoperative characteristics. Cardiopulmonary bypass time (117.5 vs 104.1 min, p < 0.0001) and aortic cross-clamping time (83.8 vs 71.3 min, p < 0.0001) were longer in the minimally invasive group, with no difference in length of stay (median 6 vs 5 days, p = 0.43), but shorter assisted ventilation time (median 8 vs 7 hours, p = 0.022). Overall in-hospital mortality was identical between the groups (1.64 vs 1.64%, p = 1.0). No difference in the incidence of major and minor postoperative complications and related morbidity was observed. Minimally invasive aortic valve replacement was associated with a lower incidence of new onset postoperative atrial fibrillation (21% vs 31%, p = 0.04). Reduction of the complication rate was observed. Median transfusion pack per patient was higher in the control group (2 vs 1 units, p = 0.04). Our experience shows that mini-access isolated aortic valve surgery is a reproducible, safe, and effective procedure and reduces assisted ventilation duration, the need for blood product transfusion, and incidence of post-surgery atrial fibrillation. 23869054 Legislative epidemics: the role of model law in the transnational trend to criminalise HIV transmission. HIV-related state laws are being created transnationally though the use of omnibus model laws. In 2004, the US Agency for International Development (USAID) funded the creation of one such guidance text known as the USAID/Action for West Africa Region Model Law, or N'Djamena Model Law, which led to the rapid spread of HIV/AIDS laws, including the criminalisation of HIV transmission, across much of West and Central Africa (2005-2010). In this article, I explicate how an epidemic of highly problematic legislation spread across the region as a result of a text-mediated work process enabled through model laws. I theorise the textual genre of model laws arguing that these texts are best understood as 'preoperative documents' which, when activated, can lead to swift legislative reform in and beyond the field of HIV/AIDS governance. The legislative process being investigated was made visible through participant observation, archival research, textual analysis and informant interviews with national and international stakeholders (n=32). This involved ethnographic research in Canada, the USA, Switzerland, Austria, South Africa and Senegal (2010-2011). The untold policy processes and narratives explored in this article make evident how the work of contesting problematic HIV/AIDS model laws and newly drafted state laws involves both creating new texts and contesting the legitimacy and efficacy of others. 23948981 Clinical and biomechanical performance of patients with failed rotator cuff repair. The purpose of the study was clinical and advanced biomechanical evaluation of shoulder function with respect to rotator cuff (RC) integrity following repair. This was a retrospective study of 111 cases with solid single row rotator cuff repair and a minimal one-year follow-up. The RC repair was performed as an open procedure in 42 patients, arthroscopically assisted in 34 and fully arthroscopic in 48 cases. Evaluation protocol included ultrasound evaluation of the RC integrity, clinical evaluation using shoulder scores and advanced biomechanical evaluation (isometric and the isokinetic strength testing). Ultrasound evaluation revealed complete retear in 16 %, partial retear in 10 % and intact repair in 74 % of the cases. Isometric testing of flexion and abduction had shown that shoulders with complete retear were weaker by 45 % compared to those with full tendon healing. Isokinetic testing revealed 29-43 % deficits in peak external rotation torque comparing complete retear vs. normal healing. Patients' ability to generate shoulder power and withstand a load proved to be lower in circumstances of a complete lack of healing (40-43 % and 34-55 %, respectively). Partial retears did not have a negative impact on the biomechanical properties of shoulders. Surprisingly, there were no significant differences in the shoulder scores related to the quality of healing. In terms of patient satisfaction the results were good and the patients declared themselves better in all cases, no matter what quality of healing had been recorded ultimately. According to the results of this research rotator cuff integrity after open or arthroscopic repair does not seem to affect clinical scores. Recurrent tears may result in lower muscle performance in terms of active motion, strength and endurance. Advanced shoulder testing may be essential in assessing the patients' ability to return to sports or heavy labour. 23742889 The complete mitochondrial genome of Sasakia funebris (Leech) (Lepidoptera: Nymphalidae) and comparison with other Apaturinae insects. Sasakia funebris, a member of the lepidopteran family, Nymphalidae (superfamily Papilionoidea) is a rare species and is found only in some areas of South China. In this study, the 15,233bp long complete mitochondrial genome of S. funebris was determined, and harbors the gene arrangement identical to all other sequenced lepidopteran insects. The nucleotide composition of the genome is highly A+T biased, accounting for 81.2%. All protein-coding genes (PCGs) start with typical ATN codons, except for COI which begins with the CGA codon. All tRNAs have a typical clover-leaf secondary structure, except for tRNA(Ser(AGN)), the dihydrouridine (DHU) arm of which forms a simple loop. The S. funebris A+T-rich region of 370bp contains several features common to the Lepidoptera insects, including the motif ATAGA followed by a 19bp poly-T stretch, and two tandem repeats consisting of 18bp repeat units and 14bp repeat units. The phylogenetic analyses of Apaturinae based on mitogenome sequences showed: (S. funebris+Sasakia charonda)+(Apatura metis+Apatura ilia). This result is consistent with the morphological classification. 23737633 Using a physics experiment in a lecture setting to engage biology students with the concepts of Poiseuille's law. Biology students enrolled in a typical undergraduate physiology course encounter Poiseuille's law, a physics equation that describes the properties governing the flow of blood through the circulation. According to the equation, a small change in vessel radius has an exponential effect on resistance, resulting in a larger than expected change in blood flow. To help engage students in this important concept, we performed a physics experiment as a lecture demonstration to mimic the original research by the 19th-century French scientist. We tested its impact as a research project and found that students who viewed the demonstration reacted very positively and showed an immediate increase in test performance, while the control group was able to independently "catch up" at the fourth week posttest. We further examined whether students' math skills mapped to learning gains. The students with lower math scores who viewed the demonstration had slightly more improvement in test performance than those students who did not view the demonstration. Our data suggest that watching a lecture demonstration may be of even greater benefit to biology students with lower math achievement. 23600917 Executive functions in girls with and without childhood ADHD: developmental trajectories and associations with symptom change. We prospectively followed an ethnically and socioeconomically diverse sample of girls with attention-deficit/hyperactivity disorder (ADHD) (n = 140) and a matched comparison sample (n = 88) from childhood through young adulthood to evaluate developmental trajectories of executive functions (EF) and associations between EF trajectories and dimensional measures of ADHD symptoms. We hypothesized that (a) EF trajectories would be similar in girls both with and without childhood ADHD, with the ADHD group showing greater impairment across time; and (b) changes in EF abilities would predict changes in ADHD symptoms across time, consistent with the theory that ADHD symptom reductions partially result from prefrontally mediated EF development. Latent growth curve models were used to evaluate development of sustained attention, response inhibition, working memory, and global EF abilities, and associations between EF trajectories and ADHD symptom trajectories. Girls with childhood-diagnosed ADHD showed greater improvement across development on measures of sustained attention and global EF, but similar rates of improvement on measures of working memory and response inhibition. Changes in the global EF measure predicted changes in both inattentive and hyperactive-impulsive symptoms across time, whereas changes in response inhibition predicted changes in hyperactive-impulsive symptoms; associations between changes in other EF variables and symptoms were not significant. Findings suggest variability in patterns of EF improvement over time in females with ADHD histories and indicate that EF development may play a role in symptom change. 23210506 Oral leukoplakia in a South African sample: a clinicopathological study. This study analysed differences in clinicopathological features of oral leukoplakia in different racial groups in the greater Johannesburg area of South Africa, with emphasis on the black population. The retrospective review included cases diagnosed clinically as oral leukoplakia and histologically as hyperkeratosis without dysplasia, hyperkeratosis with mild, moderate or severe dysplasia, and carcinoma in situ from 1990 to 2010. Age, gender, ethnicity, clinical appearance, site of lesion and tobacco smoking habit were recorded. Fourteen per cent of oral leukoplakia occurred in black South Africans compared with 80% in white South Africans. In contrast to whites, blacks were diagnosed with oral leukoplakia at a younger age; there were more men affected than women; and the proportion of idiopathic leukoplakia was greater. There were significantly more blacks (23%) than whites (13%) with non-homogenous leukoplakia and significantly more whites (51%) than blacks (23%) with dysplastic oral leukoplakia. This study suggests that oral leukoplakia, especially non-homogenous and idiopathic forms affects South African blacks less frequently than white South Africans; and in the former, it occurs more in men and at a younger age. These findings may provide some guidance in establishing screening policies for oral cancer, particularly suited for blacks. 23657286 Zingerone enhances glutamatergic spontaneous excitatory transmission by activating TRPA1 but not TRPV1 channels in the adult rat substantia gelatinosa. Transient receptor potential (TRP) channels are thought to play a role in regulating nociceptive transmission to spinal substantia gelatinosa (SG) neurons. It remains to be unveiled whether the TRP channels in the central nervous system are different in property from those involved in receiving nociceptive stimuli in the peripheral nervous system. We examined the effect of the vanilloid compound zingerone, which activates TRPV1 channels in the cell body of a primary afferent neuron, on glutamatergic excitatory transmission in the SG neurons of adult rat spinal cord slices by using the whole cell patch-clamp technique. Bath-applied zingerone reversibly and concentration-dependently increased spontaneous excitatory postsynaptic current (EPSC) frequency. This effect was accompanied by an inward current at -70 mV that was resistant to glutamate receptor antagonists. These zingerone effects were repeated and persisted in Na(+)-channel blocker tetrodotoxin-, La(3+)-, or IP3-induced Ca(2+)-release inhibitor 2-aminoethoxydiphenyl borate-containing or Ca(2+)-free Krebs solution. Zingerone activity was resistant to the selective TRPV1 antagonist capsazepine but sensitive to the nonselective TRP antagonist ruthenium red, the TRPA1 antagonist HC-030031, and the Ca(2+)-induced Ca(2+)-release inhibitor dantrolene. TRPA1 agonist allyl isothiocyanate but not capsaicin inhibited the facilitatory effect of zingerone. On the other hand, zingerone reduced monosynaptically evoked EPSC amplitudes, as did TRPA1 agonists. Like allyl isothiocyanate, zingerone enhanced GABAergic spontaneous inhibitory transmission in a manner sensitive to tetrodotoxin. We conclude that zingerone presynaptically facilitates spontaneous excitatory transmission, probably through Ca(2+)-induced Ca(2+)-release mechanisms, and produces a membrane depolarization in SG neurons by activating TRPA1 but not TRPV1 channels. 23666809 Minimally invasive pulmonary surgery for lung cancer, up to date. Recently, the minimally invasive surgical approach is an important issue in the pulmonary surgery. In this review, we present the current fashion of video-assisted thoracic surgery (VATS) and new approach including robotic lobectomy. There is no clear definition or standard for this surgical procedure regarding VATS lobectomy. Therefore, no randomized controlled trial of VATS and conventional lobectomy can be set up. Although the definition of VATS lobectomy is not straightforward, VATS lobectomy showed the technical feasibility of conventional lobectomy in mortality and postoperative complication as well as lymph node dissection. VATS procedure for advanced lung cancer is unclear whether such observations can be developed into a standardized approach. There are no reports to evaluate the advantages of robotic lobectomy in terms of treatment outcomes for lung cancer compared with VATS lobectomy. However, we believe that robotic lobectomy has clear potential to improve the quality of minimally invasive surgery. 23703530 Distinct and additive effects of sodium bicarbonate and continuous mild heat stress on fiber type shift via calcineurin/NFAT pathway in human skeletal myoblasts. Ingestion of sodium bicarbonate (NaHCO3) is known to enhance athletic performance, probably via increased extracellular buffering capacity. At present, little is known about the direct effects of NaHCO3 on myogenesis, especially in vitro. Here, we examined the effects of NaHCO3 and the combined effects of NaHCO3 and continuous mild heat stress (CMHS) at 39°C on the differentiation of human skeletal muscle myoblasts (HSMMs). Levels of myosin heavy chain (MyHC) type I mRNA increased with increasing NaHCO3 concentrations; in contrast, those of MyHC IIx decreased. The NaHCO3-induced fast-to-slow shift was additively enhanced by CMHS. Likewise, intracellular calcium levels and expression of three factors, nuclear factor of activated T cells c2 (NFATc2), NFATc4, and peroxisome-proliferator-activated receptor-γ coactivator-1α, were upregulated with increasing NaHCO3 concentrations; moreover, these effects of NaHCO3 were additively enhanced by CMHS. Overexpression experiments and small interfering RNA-mediated knockdown experiments confirmed that NFATc2 and NFATc4 were involved in MyHC I regulation. The present study provided evidence that NaHCO3 and CMHS distinctly and additively induced a fast-to-slow fiber type shift through changes in intracellular calcium levels and the modulation of calcium signaling. 23770419 Hypoxia reduces endothelial Ang1-induced Tie2 activity in a Tie1-dependent manner. Despite the altered expression of Tie receptors and angiopoietin ligands during hypoxic conditions, the effect of hypoxia on Tie-mediated endothelial responses has not been elucidated. In this study, we found that hypoxia increased Tie receptor expression but attenuated angiopoietin-1 (Ang1)-induced Tie2 activity, including Tie2 phosphorylation, Tie2 downstream signaling activation, and endothelial cell tube formation. However, Ang1 binding to endothelial cells was increased during hypoxic conditions. We demonstrated that Tie1 suppression restored the Tie2 activity and that Tie1-mediated Tie2 suppression was independent of tyrosine phosphatase activity. These results suggest that under hypoxic conditions, Tie1 is critical for reducing Ang1-induced Tie2 activity and angiogenesis. 23381506 The challenging image-guided abdominal mass biopsy: established and emerging techniques 'if you can see it, you can biopsy it'. Image-guided percutaneous biopsy of abdominal masses is among the most commonly performed procedures in interventional radiology. While most abdominal masses are readily amenable to percutaneous biopsy, some may be technically challenging for a number of reasons. Low lesion conspicuity, small size, overlying or intervening structures, motion, such as that due to respiration, are some of the factors that can influence the ability and ultimately the success of an abdominal biopsy. Various techniques or technologies, such as choice of imaging modality, use of intravenous contrast and anatomic landmarks, patient positioning, organ displacement or trans-organ approach, angling CT gantry, triangulation method, real-time guidance with CT fluoroscopy or ultrasound, sedation or breath-hold, pre-procedural image fusion, electromagnetic tracking, and others, when used singularly or in combination, can overcome these challenges to facilitate needle placement in abdominal masses that otherwise would be considered not amenable to percutaneous biopsy. Familiarity and awareness of these techniques allows the interventional radiologist to expand the use of percutaneous biopsy in clinical practice, and help choose the most appropriate technique for a particular patient. 23806135 Prevalence of Drug Resistance Mutations and HIV Type 1 Subtypes in an HIV Type 1-Infected Cohort in Rural Tanzania. Abstract The development of resistance mutations in drug-targeted HIV-1 genes compromises the success of antiretroviral therapy (ART) programs. Genotyping of these mutations enables adjusted therapeutic decisions both at the individual and population level. We investigated over time the prevalence of HIV-1 primary drug resistance mutations in treatment-naive patients and described the HIV-1 subtype distribution in a cohort in rural Tanzania at the beginning of the ART rollout in 2005-2007 and later in 2009. Viral RNA was analyzed in 387 baseline plasma samples from treatment-naive patients over a period of 5 years. The reverse transcriptase (RT) and protease genes were reversely transcribed, polymerase chain reaction (PCR) amplified, and directly sequenced to identify HIV-1 subtypes and single nucleotide polymorphisms associated with drug resistance (DR-SNPs). The prevalence of major DR-SNPs in 2005-2007 in the RT gene was determined: K103N (5.0%), Y181C (2.5%), M184V (2.5%), and G190A (1.7%), and M41L, K65KR, K70KR, and L74LV (0.8%). In samples from 2009 only K103N (3.3%), M184V, and T215FY (0.8%) were detected. Initial frequencies of subtypes C, A, D, and recombinants were 43%, 32%, 18%, and 7%, respectively. Later similar frequencies were found except for the recombinants, which were found twice as often (15%), highlighting the subtype diversity and a relatively stable subtype frequency in the area. DR-SNPs were found at initiation of the cohort despite very low previous ART use in the area. Statistically, frequencies of major mutations did not change significantly over the studied 5-year interval. These mutations could reflect primary resistances and may indicate a possible risk for treatment failure. 23621417 Safety and tolerability of paricalcitol in patients with chronic kidney disease. Introduction: Secondary hyperparathyroidism (SHPT) is a complication of chronic kidney disease (CKD). Beyond skeletal complications, uncontrolled SHPT is associated with cardiovascular mortality. Vitamin D receptor activators (VDRAs) are a mainstay of therapy for SHPT; however, use is limited by hypercalcemia, though less so with calcitriol analogs such as paricalcitol and there is emerging experience with oral formulations for non-SHPT indications. The role of VDRAs in the treatment of SHPT becomes a complex question as alternative strategies have developed. Areas covered: This review summarizes trials that established the safety and efficacy of paricalcitol for SHPT. Comparative experience with paricalcitol as against other VDRAs will be reviewed as will the experience with paricalcitol in non-dialysis CKD and comparative experience with non-VDRA-based therapy. Expert opinion: VDRA therapy is considered first-line therapy for treatment of SHPT. Paricalcitol has demonstrated superiority to calcitriol with respect to parathyroid hormone suppression and calcium-phosphorus balance. Oral formulations of paricalcitol appear to be similarly effective for SHPT. While there is evidence to suggest adjunctive antiproteinuria benefit with the use of VDRAs, efficacy of these agents to slow the progression of CKD or to reduce cardiovascular risk has not yet been demonstrated. 23871391 Toxicity of indoxyl derivative accumulation in bacteria and its use as a new counterselection principle. In this work we describe the conditional toxic effect of the expression of enzymes that cleave 5-bromo-4-chloro-3-indolyl (BCI) substrates and its use as a new counterselection principle useful for the generation of clean and unmarked mutations in the genomes of bacteria. The application of this principle was demonstrated in the thermophile Thermus thermophilus HB27 and in a mesophile for which currently no counterselection markers are available, Micrococcus luteus ATCC 27141. For T. thermophilus, the indigogenic substrate BCI-β-glucoside was used in combination with the T. thermophilus β-glucosidase gene (bgl). For M. luteus, a combination of BCI-β-galactoside and the E. coli lacZ gene was implemented. We observed a strong growth-inhibiting effect when the strains were grown on agar plates containing the appropriate BCI substrates, the inhibition being proportional to the substrate concentration and the level of bgl/lacZ expression. The growth inhibition apparently depends on intracellular BCI substrate cleavage and accumulation of toxic indoxyl precipitates. The bgl and lacZ genes were used as counterselection markers for the rapid generation of scar-less chromosomal deletions in T. thermophilus HB27 (both in a Δbgl and in a wild type background) and in M. luteus ATCC 27141. In addition to Thermus and Micrococcus, sensitivity to BCI substrate cleavage was observed for other Gram-negative and Gram-positive species belonging to various bacterial phyla, including representatives of the genera Staphylococcus, Bacillus, Corynebacterium, Rhodococcus, Paracoccus and Xanthomonas. Thus, the toxicity of indoxyl derivative accumulation upon BCI substrate cleavage can be used for selection purposes in a broad range of microorganisms. 23900391 Expeditious organic-free assembly: morphologically controlled synthesis of iron oxides using microwaves. A microwave hydrothermal method is developed for the synthesis of iron oxides, α-Fe2O3, β-FeOOH, and the junction of α-Fe2O3-β-FeOOH. This method is absolutely organic-free, and various structures could be obtained simply by changing the use of the iron source and NaOH. The as-prepared sea urchin-like β-FeOOH exhibits excellent catalytic performance for the degradation of methylene blue (MB) in the presence of H2O2. 23824630 Morbidity after thyroid surgery: Patient perspective. To evaluate patient perception of morbidity after thyroid surgery. Survey of consecutive patients (case series). A standardized questionnaire was mailed to 312 patients who underwent thyroid surgery during a 3-year period (January 2008 to December 2010). Replies were received from 202 (64%) patients (56 male, 166 female; age, 55 ± 16 years) at 6 to 39 months (median, 23 months) after lobectomy (n = 119) or total thyroidectomy (n = 76) for benign (n = 160) or malignant (n = 42) conditions. Subjective voice assessment using a visual analogue scale was normal in 111 patients, deteriorated in 80 patients, and improved in 21 patients. Voice handicap index scores were normal in 126 (62%) patients and increased in 76 (38%) patients to a median of 17 (range, 11-29). Voice-related quality of life was excellent in 107 (53%) patients, fair to good in 66 patients, and poor to fair in 29 patients. Subjective assessment of swallowing was reported as normal in 84 patients, moderately affected in 56 patients (score, 11-15) and severely affected in 62 patients (score, 16-40; median, 23). Calcium supplements prescribed routinely after bilateral surgery were interrupted within 2 to 4 weeks in 56 patients and within 3 to 6 months in 18 patients. None of the respondents had persistent hypoparathyroidism. Appearance of the scar assessed using the Manchester score ranged from 5 to 16 (median, 7). Asked whether they would consider robotic thyroid surgery to avoid a cervical scar, only 38 patients said they were definitely interested. A large proportion of patients report persistent moderate voice and swallowing problems after thyroid surgery. These findings are similar to a recent international multicenter survey of more than 2,000 patients with thyroid cancer. Hypocalcemia and cosmetic outcome raised no significant concerns. 4. Laryngoscope, 2012. 23800407 Participation after multidisciplinary rehabilitation for moderate to severe traumatic brain injury in adults. The article by Brasure et al represents a systematic review of the literature on effectiveness of multidisciplinary rehabilitation for traumatic brain injury using rigorous methodology and focusing on participation as an outcome. The review assumes that rehabilitation "seeks to restore an individual's functioning and participation to preinjury levels" and that participation is a preferentially valued outcome. Each of these assumptions can be challenged on clinical and/or methodologic grounds. For example, holistic neuropsychologic rehabilitation seeks to promote changes in a patient's social identity as much as their social participation. Participation may not be directly related to changes in patients' activity limitations or well-being, and will not be the appropriate outcome for all studies of treatment effectiveness. The emphasis on methodologic rigor needs to be balanced by the search for relevance and reliance on the best available evidence to guide clinical practice. 23608948 Mechanistic insights into RNase L through use of an MDMX-derived multi-functional protein domain. RNase L is part of the innate immune response to viral infection. It is activated by a small oligonucleotide (2-5A) whose synthesis is initiated as part of the interferon response. Binding of 2-5A to the N-terminal regulatory region, the ANK domain, of RNase L activates its ribonuclease activity and results in cleavage of RNA in the cell, which ultimately leads to apoptosis of the infected cell. The mechanism by which 2-5A activates the ribonuclease activity of RNase L is currently unclear but 2-5A has been shown to induce dimerization of RNase L. To investigate the importance of dimerization of RNase L, we developed a 15kDa dimerization-inducing protein domain that was fused to the N-terminus of RNase L. From these studies we provide direct evidence that dimerization of RNase L occurs at physiologically relevant protein concentrations and correlates with activation of ribonuclease activity. We also show that the binding of 2-5A to RNase L promotes dimerization of the ANK domain and suggest how this could transmit a signal to the rest of the protein to activate ribonuclease activity. Finally, we show that the dimerization-inducing domain can be used as a general fusion partner to aid in protein expression and purification. 23891614 The effect of regions flanking target site on siRNA potency. For a successful RNA interference (RNAi) experiment, selecting the small interference RNA (siRNA) candidates which maximize the knock down effect of the given gene is the critical step. Although various computational approaches have been attempted, the design of efficient siRNA candidates is far from satisfactory yet. In this study, we proposed a novel feature selection algorithm of combined random forest and support vector machine to predict active siRNAs. Using a publically available dataset, we demonstrated that the predictive accuracy would be markedly improved when the context sequence features outside the target site were included. The Pearson correlation coefficient for regression is as high as 0.721, compared to 0.671, 0.668, 0.680, and 0.645, for Biopredsi, i-score, ThermoComposition21 and DSIR, respectively. It revealed that siRNA-target interaction requires appropriate sequence context not only in the target site but also in a broad region flanking the target site. 23834470 Mesenchymal stem cells in acute lung injury: are they ready for translational medicine? Acute lung injury (ALI) is a severe clinical condition responsible for high mortality and the development of multiple organ dysfunctions, because of the lack of specific and effective therapies for ALI. Increasing evidence from pre-clinical studies supports preventive and therapeutic effects of mesenchymal stem cells (MSCs, also called mesenchymal stromal cells) in ALI/ARDS (acute respiratory distress syndrome). Therapeutic effects of MSCs were noticed in various delivery approaches (systemic, local, or other locations), multiple origins (bone marrow or other tissues), or different schedules of administrations (before or after the challenges). MSCs could reduce the over-production of inflammatory mediators, leucocyte infiltration, tissue injury and pulmonary failure, and produce a number of benefit factors through interaction with other cells in the process of lung tissue repair. Thus, it is necessary to establish guidelines, standard operating procedures and evaluation criteria for translating MSC-based therapies into clinical application for patients with ALI. 23759101 The role of the DNA-binding One Zinc Finger (DOF) transcription factor family in plants. The DOF (DNA-binding One Zinc Finger) family of transcription factors is involved in many fundamental processes in higher plants, including responses to light and phytohormones as well as roles in seed maturation and germination. DOF transcription factor genes are restricted in their distribution to plants, where they are in many copies in both gymnosperms and angiosperms and also present in lower plants such as the moss Physcomitrella patens and in the alga Chlamydomonas reinhardtii which possesses a single DOF gene. DOF transcription factors bind to their promoter targets at the consensus sequence AAAG. This binding depends upon the presence of the highly conserved DOF domain in the protein. Depending on the target gene, DOF factor binding may activate or repress transcription. DOF factors are expressed in most if not all tissues of higher plants, but frequently appear to be functionally redundant. Recent next-generation sequencing data provide a more comprehensive survey of the distribution of DOF sequence classes among plant species and within tissue types, and clues as to the evolution of functions assumed by this transcription factor family. DOFs do not appear to be implicated in the initial differentiation of the plant body plan into organs via the resolution of meristematic zones, in contrast to MADS-box and homeobox transcription factors, which are found in other non-plant eukaryotes, and this may reflect a more recent evolutionary origin. 23374537 Epigenetic mechanisms of drug addiction. Epigenetic regulation can mediate long-lasting changes in gene expression, which makes it an attractive mechanism for the stable behavioral abnormalities that characterize drug addiction. Recent research has unveiled numerous types of epigenetic modifications within the brain's reward circuitry in animal models of drug addiction. In this review, we summarize the latest advances in the field, focusing on histone modifications, DNA methylation, and noncoding RNAs. We also highlight several areas for future research. Unraveling the highly complex epigenetic mechanisms of addiction is adding to our understanding of this syndrome and has the potential to trigger novel approaches for better diagnosis and therapy. 23720755 Prefoldin protects neuronal cells from polyglutamine toxicity by preventing aggregation formation. Huntington disease is caused by cell death after the expansion of polyglutamine (polyQ) tracts longer than ∼40 repeats encoded by exon 1 of the huntingtin (HTT) gene. Prefoldin is a molecular chaperone composed of six subunits, PFD1-6, and prevents misfolding of newly synthesized nascent polypeptides. In this study, we found that knockdown of PFD2 and PFD5 disrupted prefoldin formation in HTT-expressing cells, resulting in accumulation of aggregates of a pathogenic form of HTT and in induction of cell death. Dead cells, however, did not contain inclusions of HTT, and analysis by a fluorescence correlation spectroscopy indicated that knockdown of PFD2 and PFD5 also increased the size of soluble oligomers of pathogenic HTT in cells. In vitro single molecule observation demonstrated that prefoldin suppressed HTT aggregation at the small oligomer (dimer to tetramer) stage. These results indicate that prefoldin inhibits elongation of large oligomers of pathogenic Htt, thereby inhibiting subsequent inclusion formation, and suggest that soluble oligomers of polyQ-expanded HTT are more toxic than are inclusion to cells. 23063845 Giant cell tumor of bone: a basic science perspective. Comprehending the pathogenesis of giant cell tumor of bone (GCT) is of critical importance for developing novel targeted treatments for this locally-aggressive primary bone tumor. GCT is characterized by the presence of large multinucleated osteoclast-like giant cells distributed amongst mononuclear spindle-like stromal cells and other monocytes. The giant cells are principally responsible for the extensive bone resorption by the tumor. However, the spindle-like stromal cells chiefly direct the pathology of the tumor by recruiting monocytes and promoting their fusion into giant cells. The stromal cells also enhance the resorptive ability of the giant cells. This review encompasses many of the attributes of GCT, including the process of giant cell formation and the mechanisms of bone resorption. The significance of the receptor activator of nuclear factor-κB ligand (RANKL) in the development of GCT and the importance of proteases, including numerous matrix metalloproteinases, are highlighted. The mesenchymal lineage of the stromal cells and the origin of the hematopoietic monocytes are also discussed. Several aspects of GCT that require further understanding, including the etiology of the tumor, the mechanisms of metastases, and the development of an appropriate animal model, are also considered. By exploring the current status of GCT research, this review accentuates the significant progress made in understanding the biology of the tumor, and discusses important areas for future investigation. 23842652 Single-cell genomics reveals complex carbohydrate degradation patterns in poribacterial symbionts of marine sponges. Many marine sponges are hosts to dense and phylogenetically diverse microbial communities that are located in the extracellular matrix of the animal. The candidate phylum Poribacteria is a predominant member of the sponge microbiome and its representatives are nearly exclusively found in sponges. Here we used single-cell genomics to obtain comprehensive insights into the metabolic potential of individual poribacterial cells representing three distinct phylogenetic groups within Poribacteria. Genome sizes were up to 5.4 Mbp and genome coverage was as high as 98.5%. Common features of the poribacterial genomes indicated that heterotrophy is likely to be of importance for this bacterial candidate phylum. Carbohydrate-active enzyme database screening and further detailed analysis of carbohydrate metabolism suggested the ability to degrade diverse carbohydrate sources likely originating from seawater and from the host itself. The presence of uronic acid degradation pathways as well as several specific sulfatases provides strong support that Poribacteria degrade glycosaminoglycan chains of proteoglycans, which are important components of the sponge host matrix. Dominant glycoside hydrolase families further suggest degradation of other glycoproteins in the host matrix. We therefore propose that Poribacteria are well adapted to an existence in the sponge extracellular matrix. Poribacteria may be viewed as efficient scavengers and recyclers of a particular suite of carbon compounds that are unique to sponges as microbial ecosystems.The ISME Journal advance online publication, 11 July 2013; doi:10.1038/ismej.2013.111. 23194554 Structural analysis of linear mixed-linkage glucooligosaccharides by tandem mass spectrometry. Dextrans and glucooligosaccharides (GLOS) are produced by lactic acid bacteria (LAB) during sourdough fermentation. The dextrans can act as hydrocolloids in sourdough bread, while the GLOS may have antistaling and prebiotic properties, depending on their structure. Development of high-throughput methods for screening the structural properties of dextrans and GLOS produced by different LAB in varying fermentation conditions is therefore of interest. In this study we explored the possibility of using electrospray ionisation tandem mass spectroscopy (ESI-MS/MS) to unequivocally determine the structures of underivatised GLOS. The emphasis was on linear mixed linked model GLOS, especially those containing (1→3) linkages that are common in dextrans. After evaluation of the model GLOS, the ESI-MS/MS method was used to determine the linkage positions of two mixed-linked tetrasaccharides obtained by hydrolysis of Weissella confusa and Leuconostoc citreum dextrans. In positive mode, only the reducing end linkage could be determined because isomeric fragment ions, present in subsequent MS(n) cycles, hindered assignment of the remaining linkages. By contrast, it was possible to unambiguously assign all the linkages in each GLOS using the negative mode spectra. The present study thus shows that negative mode is the preferred method for ESI-MS/MS structural analysis of underivatised GLOS. In combination with liquid chromatography this method will enable rapid profiling of the structural variation of dextrans and prebiotic GLOS. 23657154 Long chain fatty acids and gene expression in inflammation and immunity. The purpose of this review is to discuss recent studies reporting on the influence of fatty acids on gene expression in relation to inflammation and immune responses. Saturated fatty acids promote, whereas several n-3 fatty acids, in particular eicosapentaenoic and docosahexaenoic acids, some isomers of conjugated linoleic acid, and punicic acid suppress, expression of inflammatory genes. The most common targets of fatty acids are genes encoding cytokines, chemokines, cyclooxygenase, nitric oxide synthase, and matrix metalloproteinases. The anti-inflammatory actions of fatty acids often involve inhibition of activation of nuclear factor-κB and activation of peroxisome proliferator-activated receptors α and γ. Common upstream events include actions on Toll-like receptors and via G-protein coupled receptors. Fatty acids can influence expression of genes involved in immune and inflammatory cell development and differentiation. Recent studies using genome-wide analyses demonstrate that dietary fatty acids can alter expression of a large number (many hundreds) of genes in human peripheral blood mononuclear cells. A wide range of fatty acids alter expression of genes involved in development, differentiation, and function of cells involved in inflammation and immunity. 23947684 Accuracy of endoscopic diagnosis of Helicobacter pylori infection according to level of endoscopic experience and the effect of training. Accurate prediction of Helicobacter pylori infection status on endoscopic images can contribute to early detection of gastric cancer, especially in Asia. We identified the diagnostic yield of endoscopy for H. pylori infection at various endoscopist career levels and the effect of two years of training on diagnostic yield. A total of 77 consecutive patients who underwent endoscopy were analyzed. H. pylori infection status was determined by histology, serology, and the urea breast test and categorized as H. pylori-uninfected, -infected, or -eradicated. Distinctive endoscopic findings were judged by six physicians at different career levels: beginner (<500 endoscopies), intermediate (1500-5000), and advanced (>5000). Diagnostic yield and inter- and intra-observer agreement on H. pylori infection status were evaluated. Values were compared between the two beginners after two years of training. The kappa (K) statistic was used to calculate agreement. For all physicians, the diagnostic yield was 88.9% for H. pylori-uninfected, 62.1% for H. pylori-infected, and 55.8% for H. pylori-eradicated. Intra-observer agreement for H. pylori infection status was good (K > 0.6) for all physicians, while inter-observer agreement was lower (K = 0.46) for beginners than for intermediate and advanced (K > 0.6). For all physicians, good inter-observer agreement in endoscopic findings was seen for atrophic change (K = 0.69), regular arrangement of collecting venules (K = 0.63), and hemorrhage (K = 0.62). For beginners, the diagnostic yield of H. pylori-infected/eradicated status and inter-observer agreement of endoscopic findings were improved after two years of training. The diagnostic yield of endoscopic diagnosis was high for H. pylori-uninfected cases, but was low for H. pylori-eradicated cases. In beginners, daily training on endoscopic findings improved the low diagnostic yield. 23636130 Worldwide need for a comprehensive database of stability data for pharmaceuticals stored in uncontrolled environments. Developing a database to compile all known, relevant information on the stability of pharmaceuticals in tropical environments would vastly increase access to this information, improving safety and reducing cost. Many studies have examined the stability of pharmaceuticals stored under conditions that exceed manufacturer specifications, but this information is published across so many journals and Websites that it can be virtually inaccessible to clinics or suppliers needing to make pharmaceutical inventory management decisions. We have made progress toward the completion of a database of this nature, but resources and abilities of international public health organizations will be needed to bring the database fully to fruition. 23352144 Biofilm inhibitors that target amyloid proteins. Bacteria establish stable communities, known as biofilms, that are resistant to antimicrobials. Biofilm robustness is due to the presence of an extracellular matrix, which for several species-among them Bacillus subtilis-includes amyloid-like protein fibers. In this work, we show that B. subtilis biofilms can be a simple and reliable tool for screening of molecules with antiamyloid activity. We identified two molecules, AA-861 and parthenolide, which efficiently inhibited biofilms by preventing the formation of amyloid-like fibers. Parthenolide also disrupted pre-established biofilms. These molecules also impeded the formation of biofilms of other bacterial species that secrete amyloid proteins, such as Bacillus cereus and Escherichia coli. Furthermore, the identified molecules decreased the conversion of the yeast protein New1 to the prion state in a heterologous host, indicating the broad range of activity of the molecules. 23850236 Baicalein and hydroxypropyl-γ-cyclodextrin complex in poloxamer thermal sensitive hydrogel for vaginal administration. The present study aimed to prepare a chemically and physically stable formulation of baicalein (Ba) in an in situ thermally sensitive hydrogel for vaginal administration. An inclusion complex of Ba and hydroxypropyl-γ-cyclodextrin (HP-γ-CD) was first developed to increase the stability and solubility of Ba in an aqueous solution. The formation of the Ba-HP-γ-CD complex was characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray powder diffractometry (XRPD). Poloxamers 407, 188 (P407, P188), sodium alginate (SA), hydroxypropylmethylcellulose (HPMC), and benzalkonium bromide were mixed to obtain a hydrogel with an appropriate gelation temperature for vaginal use. Among the formulations examined, P407/Ba-HP-γ-CD/HPMC/P188/benzalkonium bromide (18/0.96/0.5/4.0/0.02%) represented the appropriate gelation temperature and acceptable drug release rate at the administration site. Release of Ba-HP-γ-CD from the poloxamer hydrogel followed Peppas equation, which suggests that it occurred through coupled corrosion-diffusion mechanism, and the corrosion-release curve showed that corrosion was the primary mode of release. In animal study, treatment by using Ba-HP-γ-CD thermosensitive hydrogel could produce a restoration of damaged tissues. Thermosensitive hydrogel formulation of the Ba-HP-γ-CD complex appears to be a promising treatment for cervicitis. 23188828 Phosphorylation of ribosomal protein S3 and antiapoptotic TRAF2 protein mediates radioresistance in non-small cell lung cancer cells. Radioresistance is considered as a main factor restricting efficacy of radiotherapy. However, the exact molecular mechanism of radioresistance has not been explained yet. In this study, to elucidate radioresistance mechanism in lung cancer, we compared radiation responses in two types of non-small cell lung cancer (NSCLC) cells with different radiosensitivity and identified key molecules conferring radioresistance. In radioresistant NSCLC cells, ionizing radiation (IR) led to casein kinase 2α (CK2α)- and PKC-mediated phosphorylation of rpS3 and TRAF2, respectively, which induced dissociation of rpS3-TRAF2 complex and NF-κB activation, resulting in significant up-regulation of prosurvival genes (cIAP1, cIAP2, and survivin). Also, dissociated phospho-rpS3 translocated into nucleus and bound with NF-κB complex (p65 and p50), contributing to p65 DNA binding property and specificity. However, in radiosensitive NSCLC cells, IR-mediated rpS3 phosphorylation was not detected due to the absence of CK2α overexpression. Consequently, IR-induced rpS3-TRAF2 complex dissociation, NF-κB activation, and prosurvival gene expression were not presented. Taken together, our findings revealed a novel radioresistance mechanism through functional orchestration of rpS3, TRAF2, and NF-κB in NSCLC cells. Moreover, we provided the first evidence for the function of rpS3 as a new TRAF2-binding protein and demonstrated that phosphorylation of both rpS3 and TRAF2 is a key control point of radioresistance in NSCLC cells. These results suggest that regulation of rpS3 and TRAF2 in combination with radiotherapy could have high pharmacological therapeutic potency for radioresistance of NSCLC. 23919419 Healthcare system effects of pay-for-performance for smoking status documentation. Objectives: To evaluate the impact on smoking status documentation of a payer-sponsored pay-for-performance (P4P) incentive that targeted a minority of an integrated healthcare delivery system's patients. Study Design: Three commercial insurers simultaneously adopted P4P incentives to document smoking status of their members with 3 chronic diseases. The healthcare system responded by adding a smoking status reminder to all patients' electronic health records (EHRs). We measured change in smoking status documentation before (2008-2009) and after (2010-2011) P4P implementation by patient P4P eligibility. Methods: The P4P-eligible patients were compared primarily with a subset of non-P4P-eligible patients who resembled P4P-eligible patients and also with all non-P4P-eligible patients. Multivariate models adjusted for patient and provider characteristics and accounted for provider-level clustering and preimplementation trends. Results: Documentation increased from 48% of 207,471 patients before P4P to 71% of 227,574 patients after P4P. Improvement from 56% to 83% occurred among P4P-eligible patients (adjusted odds ratio [AOR], 3.6; 95% confidence interval [CI], 2.9-4.5) and from 56% to 80% among the comparable subset of non-P4P-eligible patients (AOR, 3.0; 95% CI, 2.3-3.9). The difference in improvement between groups was significant (AOR, 1.3; 95% CI, 1.1-1.4; P = .009). Conclusions: A P4P incentive targeting a minority of a healthcare system's patients stimulated adoption of a systemwide EHR reminder and improved smoking status documentation overall. Combining a P4P incentive with an EHR reminder might help healthcare systems improve treatment delivery for smokers and meet "meaningful use" standards for EHRs. 23852673 A review of integrating electroactive polymers as responsive systems for specialized drug delivery applications. Electroactive polymers (EAPs) are promising candidate materials for the design of drug delivery technologies, especially in conditions where an "on-off" drug release mechanism is required. To achieve this, EAPs such as polyaniline, polypyrrole, polythiophene, ethylene vinyl acetate, and polyethylene may be blended into responsive hydrogels in conjunction with the desired drug to obtain a patient-controlled drug release system. The "on-off" drug release mechanism can be achieved through the environmental-responsive nature of the interpenetrating hydrogel-EAP complex via (i) charged ions initiated diffusion of drug molecules; (ii) conformational changes that occur during redox switching of EAPs; or (iii) electroerosion. These release mechanisms are not exhaustive and new release mechanisms are still under investigation. Therefore, this review seeks to provide a concise incursion and critical overview of EAPs and responsive hydrogels as a strategy for advanced drug delivery, for example, controlled release of neurotransmitters, sulfosalicyclic acid from cross-linked hydrogel, and vaccine delivery. The review further discusses techniques such as linear sweep voltammetry, cyclic voltammetry, impedance spectroscopy, and chronoamperometry for the determination of the redox capability of EAPs. The future implications of the hydrogel-EAP composites include, but not limited to, application toward biosensors, DNA hybridizations, microsurgical tools, and miniature bioreactors and may be utilized to their full potential in the form of injectable devices as nanorobots or nanobiosensors. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013. 23827789 Characterization of porcine P58(IPK) gene and its up-regulation after H1N1 or H3N2 influenza virus infection. The 58-kDa inhibitor of the interferon-induced double-stranded RNA-activated protein kinase (P58(IPK)) is a cellular protein that is activated during influenza virus infection. Although the function of human P58(IPK) has been studied for a long time, porcine P58(IPK) (pP58(IPK)) has little been studied except for its cloning. In this study, we aimed to investigate the characteristics of the pP58(IPK) gene, determine its subcellular localization, and find its expression change during H1N1 or H3N2 infection. First, the sequence and structure of pP58(IPK) were analyzed. Second, pP58(IPK) gene was cloned into pEGFP-N1 and pEGFP-C1 vectors, respectively, which were transfected into cells to determine its subcellular localization. Third, Lung tissues of piglets from H1N1 infected, H3N2 infected and control groups were analyzed using histopathology, real-time PCR, and immunohistochemistry. The sequence and structure of pP58(IPK) was highly similar to the counterpart of human. pP58(IPK) protein distributed only in the cytoplasm. Lung tissues of piglets infected by H1N1 or H3N2 appeared obvious pathological changes, and the expression of pP58(IPK) in both mRNA and protein level was up-regulated by approximate 1.5-fold in piglets infected by H1N1 or H3N2 comparing with control piglets. We analyzed the characteristics of the pP58(IPK) gene, constructed a phylogenetic tree, determined its subcellular localization, and investigated its expression changes during H1N1 or H3N2 infection. The fundamental data accumulated in this study provides a potential medical model for investigating the function of P58(IPK) during influenza A viruses infection. 23747811 Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV 3CL protease inhibitors: Structure-activity relationship study. This work describes the design, synthesis, and evaluation of low-molecular weight peptidic SARS-CoV 3CL protease inhibitors. The inhibitors were designed based on the potent tripeptidic Z-Val-Leu-Ala(pyrrolidone-3-yl)-2-benzothiazole (8; Ki = 4.1 nM), in which the P3 valine unit was substituted with a variety of distinct moieties. The resulting series of dipeptide-type inhibitors displayed moderate to good inhibitory activities against 3CL(pro). In particular, compounds 26m and 26n exhibited good inhibitory activities with Ki values of 0.39 and 0.33 Î¼M, respectively. These low-molecular weight compounds are attractive leads for the further development of potent peptidomimetic inhibitors with pharmaceutical profiles. Docking studies were performed to model the binding interaction of the compound 26m with the SARS-CoV 3CL protease. The preliminary SAR study of the peptidomimetic compounds with potent inhibitory activities revealed several structural features that boosted the inhibitory activity: (i) a benzothiazole warhead at the S1' position, (ii) a γ-lactam unit at the S1-position, (iii) an appropriately hydrophobic leucine moiety at the S2-position, and (iv) a hydrogen bond between the N-arylglycine unit and a backbone hydrogen bond donor at the S3-position. 23909851 Issues related to development of new antiseizure treatments. This report represents a summary of the discussions led by the antiseizure treatment working group of the International League Against Epilepsy (ILAE)/American Epilepsy Society (AES) Working Groups joint meeting in London (London Meeting). We review here what is currently known about the pharmacologic characteristics of current models of refractory seizures, both for adult and pediatric epilepsy. In addition, we address how the National Institute of Neurological Disorders and Stroke (NINDS)-funded Anticonvulsant Screening Program (ASP) is evolving to incorporate appropriate animal models in the search for molecules that might be sufficiently novel to warrant further pharmacologic development. We also briefly address what we believe is necessary, going forward, to achieve the goal of stopping seizures in all patients, with a call to arms for funding agencies, the pharmaceutical industry, and basic researchers. 23535522 Novel suture technique for hemostatic aortic anastomosis: backstitch. Postoperative anastomotic suture line complications, such as hemorrhage and pseudoaneurysm, are often encountered in thoracic aortic surgery. To minimize these complications different anastomotic techniques have been developed. We hereby describe a new distal anastomotic technique, which involves positioning the graft inside the aorta at the distal end, reinforcing the suture line with an externally placed Teflon felt strip, and finishing the anastomosis with a circumferential and continued suture technique called "backstitch." 23125004 Trajectories of psychological distress after colorectal cancer. Heightened psychological distress after cancer is common but likely highly heterogeneous. This raises potential challenges in how and when to target services; however, data describing longitudinal patterns of distress are limited. This study describes the long term psychological outcomes for colorectal cancer (CRC) survivors and trajectories of adjustment over time. A prospective survey of a population-based sample of 1966 CRC survivors assessed sociodemographic variables, perceived social support and psychological distress, including distress subtypes of anxiety, depression and somatization, at six time points from 5 months to 5 years post-diagnosis. Over the 5-year trajectory, the prevalence of high overall distress ranged between 44% and 32% but was greater for men compared with women (p < 0.001). Four distress trajectory styles within clusters were identified for overall distress and for each distress subtype with a constant low distress group providing the basis for comparison. Higher distress trajectories varied for overall distress and distress subtypes but were generally differentiated by gender, younger age, lower education, poor socioeconomic advantage, late disease stage and poor social support. For global distress, by comparison with women, men with CRC are vulnerable to distress, with men who are younger and with low education and poor social support being a priority for targeted intervention. While distress screening early in the cancer experience will identify those with a constant high distress trajectory, others with late emerging distress or caseness may be missed. On this basis, distress screening through the illness trajectory into long term survivorship seems warranted. Copyright © 2012 John Wiley & Sons, Ltd. 23528295 Synthesis of indolyl-3-acetonitrile derivatives and their inhibitory effects on nitric oxide and PGE2 productions in LPS-induced RAW 264.7 cells. Arvelexin is one of major constituents of Brassica rapa that exerts anti-inflammatory activities. Several indolyl-3-acetonitrile derivatives were synthesized as arvelexin analogs and evaluated for their abilities to inhibit NO and PGE2 productions in LPS-induced RAW 264.7 cells. Of the indolyl-3-acetonitriles synthesized, compound 2k, which possesses a hydroxyl group at C-7 position of the indole ring and an N-methyl substituent, more potently inhibited NO and PGE2 productions and was less cytotoxic than arvelexin on macrophage cells. 23688771 Hypertension, obesity, and coronary artery disease in the survivors of congenital heart disease. Obesity, hypertension, and coronary artery disease are prevalent in the general population and well recognized as contributors to cardiac morbidity and mortality. With surgical and medical advances, there is a growing and aging population with congenital heart disease who are also at risk of developing these comorbidities. In addition, some congenital cardiac lesions predispose patients to conditions such as hypertension or coronary artery disease. The effect of these comorbidities on the structurally abnormal heart is not well understood, but might be very important, especially in those with residual abnormalities. Thus, in addition to surveillance for and treatment of late complications it is important for the congenital cardiologist to consider and aggressively manage acquired comorbidities. In this review we explore the prevalence of hypertension, obesity, and coronary artery disease, discuss congenital lesions that predispose to these conditions and review management strategies for this unique population. 23850759 ER stress-induced cell death mechanisms. The endoplasmic-reticulum (ER) stress response constitutes a cellular process that is triggered by a variety of conditions that disturb folding of proteins in the ER. Eukaryotic cells have developed an evolutionarily conserved adaptive mechanism, the unfolded protein response (UPR), which aims to clear unfolded proteins and restore ER homeostasis. In cases where ER stress cannot be reversed, cellular functions deteriorate, often leading to cell death. Accumulating evidence implicates ER stress-induced cellular dysfunction and cell death as major contributors to many diseases, making modulators of ER stress pathways potentially attractive targets for therapeutics discovery. Here, we summarize recent advances in understanding the diversity of molecular mechanisms that govern ER stress signaling in health and disease. This article is part of a Special Issue entitled: Cell Death Pathways. 23296101 Lack of transient receptor potential melastatin 8 activation by phthalate esters that enhance contact hypersensitivity in mice. We studied the involvement of sensory neurons in skin sensitization to allergens using a mouse model in which the T-helper type 2 response is essential. Skin sensitization to fluorescein isothiocyanate (FITC) has been shown to be enhanced by several phthalate esters, including dibutyl phthalate (DBP). For different types of phthalate esters, we found a correlation between the ability of transient receptor potential (TRP) A1 activation and that of enhancing skin sensitization. A TRPA1-specific antagonist, HC-030031, was shown to suppress skin sensitization in the presence of DBP. However, since phthalate esters also activate TRPV1, phthalate esters could activate other types of TRP channels non-selectively. Furthermore, sensitization to FITC is also enhanced by menthol, which activates TRPA1 and TRPM8. Here we established an in vitro system for measuring TRPM8 activation. The selectivity for TRPM8 was established by the fact that two TRPM8 agonists (menthol and icilin) induced calcium mobilization, whereas agonists of TRPA1 and TRPV1 did not. We demonstrated that phthalate esters do not activate TRPM8. TRPA1-antagonist HC-030031 did not inhibit TRPM8 activation induced by menthol or icilin. These results show that phthalate esters activate TRPA1 and TRPV1 with selectivity. TRPM8 activation is not likely to be involved in the sensitization to FITC. 23969345 CT and MRI of Pediatric Skull Lesions with Fluid-Fluid Levels. SUMMARY:Fluid-fluid levels can occur whenever different fluid densities are contained within a cystic or compartmentalized lesion, usually related to the evolution of hematoma or necrosis. Review of the literature demonstrated that throughout the skeletal system, the most common etiology for fluid-fluid levels is aneurysmal bone cyst, but there are no dedicated studies of the pediatric calvaria, to our knowledge. In this report, we present clinicopathologic characteristics and CT and MR imaging of 11 patients with pediatric skull mass lesions demonstrating fluid-fluid levels. MR imaging demonstrated more fluid-fluid levels compared with CT in all cases. The etiologies of skull lesions with fluid-fluid levels were Langerhans cell histiocytosis in 4 (36.6%), aneurysmal bone cysts in 3 (27.2%), cephalohematoma in 3 (27.2%), and metastatic neuroblastoma in 1 (9%). Radiologists should be aware of the other etiologies of calvarial lesions with fluid-fluid levels in the pediatric skull. 23643618 Nanoneedle insertion into the cell nucleus does not induce double-strand breaks in chromosomal DNA. An atomic force microscope probe can be formed into an ultra-sharp cylindrical shape (a nanoneedle) using micro-fabrication techniques such as focused ion beam etching. This nanoneedle can be effectively inserted through the plasma membrane of a living cell to not only access the cytosol, but also to penetrate through the nuclear membrane. This technique shows great potential as a tool for performing intranuclear measurements and manipulations. Repeated insertions of a nanoneedle into a live cell were previously shown not to affect cell viability. However, the effect of nanoneedle insertion on the nucleus and nuclear components is still unknown. DNA is the most crucial component of the nucleus for proper cell function and may be physically damaged by a nanoneedle. To investigate the integrity of DNA following nanoneedle insertion, the occurrence of DNA double-strand breaks (DSBs) was assessed. The results showed that there was no chromosomal DNA damage due to nanoneedle insertion into the nucleus, as indicated by the expression level of γ-H2AX, a molecular marker of DSBs. 23736951 Intravenous infusion of phage-displayed antibody library in human cancer patients: enrichment and cancer-specificity of tumor-homing phage-antibodies. Phage display is a powerful method for target discovery and selection of ligands for cancer treatment and diagnosis. Our goal was to select tumor-binding antibodies in cancer patients. Eligibility criteria included absence of preexisting anti-phage-antibodies and a Stage IV cancer status. All patients were intravenously administered 1 Ã— 10(11) TUs/kg of an scFv library 1 to 4 h before surgical resection of their tumors. No significant adverse events related to the phage library infusion were observed. Phage were successfully recovered from all tumors. Individual clones from each patient were assessed for binding to the tumor from which clones were recovered. Multiple tumor-binding phage-antibodies were identified. Soluble scFv antibodies were produced from the phage clones showing higher tumor binding. The tumor-homing phage-antibodies and derived soluble scFvs were found to bind varying numbers (0-5) of 8 tested normal human tissues (breast, cervix, colon, kidney, liver, spleen, skin, and uterus). The clones that showed high tumor-specificity were found to bind corresponding tumors from other patients also. Clone enrichment was observed based on tumor binding and DNA sequence data. Clone sequences of multiple variable regions showed significant matches to certain cancer-related antibodies. One of the clones (07-2,355) that was found to share a 12-amino-acid-long motif with a reported IL-17A antibody was further studied for competitive binding for possible antigen target identification. We conclude that these outcomes support the safety and utility of phage display library panning in cancer patients for ligand selection and target discovery for cancer treatment and diagnosis. 23937455 Molecular imprinted magnetic nanoparticles for controlled delivery of mitomycin C. Controlled drug delivery system is a technique which has considerable recent potential in the fields of pharmacy and medicine. Mitomycin C is commonly used drug in the treatment of superficial bladder and breast cancers. In the present study, mitomycin C-imprinted magnetic poly(hydroxyethyl methacrylate)-based nanoparticles (MIMNs) were prepared using surfactant free emulsion polymerization for controlled delivery of mitomycin C. The MIMNs were characterized by fourier transform infrared spectroscopy, scanning electron microscopy, atomic force microscopy, electron spin resonance, and elemental analysis. The average particle diameter of MIMNs was about 200 nm. 23859980 Antipsychotic Polypharmacy in a Treatment-Refractory Schizophrenia Population Receiving Adjunctive Treatment With Electroconvulsive Therapy. Antipsychotic polypharmacy (APP) is frequent, but its pattern is unknown in treatment-refractory schizophrenia-spectrum patients receiving electroconvulsive therapy (ECT). We performed a retrospective chart review of ECT-treated inpatients hospitalized at 2 Danish University hospitals from 2003 to 2008, focusing on APP patterns in patients with schizophrenia-spectrum disorders (n = 79, 13.2%). In addition to univariate analyses, a multivariate logistic regression analysis was performed to identify independent predictors of APP. Of 79 antipsychotic-treated patients (aged 48.6 ± 14.2 years; illness duration, 18.3 ± 10.6 years) ultimately treated with ECT, 86.1% received 2 or more psychotropic medications, including mood stabilizers (19.0%), antidepressants (32.9%), and APP (72.2%; 2 antipsychotics = 41.8%, 3 = 21.5%, 4-5 = 7.6%). Most patients received first-generation antipsychotic (FGA) + second-generation antipsychotic (SGA) (48.1%), followed by SGA + SGA (24.1%), SGA monotherapy (22.8%), and FGA monotherapy (5.1%). Individual antipsychotics included olanzapine (44.3%), risperidone (26.6%), clozapine (26.6%), quetiapine (22.1%), ziprasidone (13.9%), aripiprazole (10.1%), and sertindole (3.8%). Antipsychotic polypharmacy was associated with a greater number of FGAs (0.8 ± 0.7 vs 0.1 ± 0.4, P < 0.0001) and SGAs (1.7 ± 0.8 vs 0.8 ± 0.4, P < 0.0001), zuclopenthixol use (31.6% vs 0%, P = 0.0019), olanzapine use (52.6% vs 22.7%, P = 0.017), less serotonin-noradrenaline reuptake inhibitor use (3.5% vs 18.2%, P = 0.027), and a trend toward more good to excellent ECT response (86.0% vs 68.2%, P = 0.071). In the logistic regression analysis, APP was independently associated with a higher number of FGAs (P = 0.0002) and olanzapine use (P = 0.0098) (r = 0.314, P < 0.0001). Only 22.6% of this treatment-refractory population received clozapine, yet 72.4% received APP. Following the results from our study as well as the general level of evidence, patients with refractory schizophrenia-spectrum disorder should receive clozapine or ECT before being tried on APP. 23865694 Retinoic acid-producing, ex vivo-generated human tolerogenic dendritic cells induce the proliferation of immunosuppressive B-lymphocytes. While much is known about tolerogenic dendritic cell effects on Foxp3+ T-regulatory cells, virtually nothing is known about their effects on another arm of immunoregulation that is mediated by a subpopulation of immunosuppressive B-cells. These cells suppress rheumatoid arthritis, lupus and inflammatory bowel disease in mice, and functional defects have been reported in human lupus. We show that co-stimulation-impaired tolerogenic dendritic cells that prevent and reverse type 1 diabetes mellitus induce the proliferation of human immunosuppressive B-cells in vitro. We also show that the suppressive properties of these B-cells concentrate inside the CD19+ CD24+ B-cell population and more specifically inside the CD19+ CD24+ CD38+ B-regulatory cell population. We discovered that B-cell conversion into suppressive cells in vitro is partially-dependent on dendritic cell production of retinoic acid and also that CD19+ CD24+ CD38+ B-regulatory cells express retinoic acid receptors. Taken together, our data suggest a model whereby part of the immunosuppressive properties of human tolerogenic dendritic cells could be mediated by retinoic acid which, in addition to its known role in favoring T-cell differentiation to Foxp3+ T-regulatory cells, acts to convert B-cells into immunosuppressive cells. 23349488 The type 2 diabetes associated gene Ide is required for insulin secretion and suppression of α-synuclein levels in β-cells. Genome wide association studies have identified several type 2 diabetes (T2D) risk loci linked to impaired β-cell function. The identity and function of the causal genes in these susceptibility loci remain, however, elusive. The HHEX/IDE T2D locus is associated with decreased insulin secretion in response to oral glucose stimulation in humans. Here we have assessed β-cell function in Ide knock-out (KO) mice. We find that glucose stimulated insulin secretion (GSIS) is decreased in Ide KO mice due to impaired replenishment of the releasable pool of granules and that the Ide gene is haploinsufficient. We also show that autophagic flux and microtubule content is reduced in β-cells of Ide KO mice. One important cellular role for IDE involves the neutralization of amyloidogenic proteins and we find that α-synuclein and IDE levels are inversely correlated in β-cells of Ide KO mice and T2D patients. Moreover, we provide evidence that both gain- and loss-of-function of α-synuclein in β-cells in vivo not only impair GSIS but also autophagy. Together, these data identify the Ide gene as a regulator of GSIS, suggest a molecular mechanism for β-cell degeneration as a consequence of Ide deficiency, and additionally corroborates and extends a previously established important role for α-synuclein in β-cell function. 23934172 Rapid detection of bacteria in urine samples by the "three-plug-injection" method using capillary electrophoresis. This study explored a method that can rapidly detect bacteria in urine samples for the auxiliary determination of urinary tract infections (UTIs). Urine samples from patients with UTIs (230 cases) were obtained using aseptic technique. The urine biochemical assay was then carried out using an automated urine analyzer for all the urine samples. Bacterial species were identified by a combination of bacterial culture technique, morphological observation and the BACT-IST microbial identification/susceptibility analysis system. The most common seven species of bacteria in the study included Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter cloacae, Enterococcus faecalis, Staphylococcus aureus and Staphylococcus epidermidis. Bacterial samples were suspended in sample buffer solutions and separated by the "three-plug-injection" method using capillary electrophoresis (CE). Each species of bacteria appeared as a bacterial peak. The mixture of the seven species also provided only one peak. Further analysis showed that the concentration limit for the "three-plug-injection" method is 10(6) colony forming units (CFU)/mL, and there is a good linear relationship between the peak height and bacterial concentration (R(2)=0.99). The effect of urine composition on CE results was also investigated. The results showed that urine composition, i.e., proteins, white blood cells (WBCs) and red blood cells (RBCs), affected the peak retention time but could not affect the separation of bacteria. The results demonstrated that the bacteria in urine samples can be detected within 10min by the "three-plug-injection" method using CE. The "three-plug-injection" method is therefore suitable for the rapid detection of organisms in clinical urine samples from UTIs. 23224858 Percutaneous nephrolithotomy in adult patients with spina bifida, severe spinal deformity and large renal stones. To present our experience in patients with spina bifida with severe spinal abnormality undergoing percutaneous nephrolithotomy (PCNL) for large stone burden. A retrospective review identified five spina bifida patients with abnormal spinal curvature who had a PCNL for large kidney stones. The mean age was 28 years. In two patients, stones were on the concave side of the scoliotic spine further limiting percutaneous access. Mean stone burden was 940 mm2. All patients were paraplegic, three patients had symptomatic stone disease. We performed initial percutaneous renal access in radiology department and staged nephrolithotomy in operating room. Tract dilatation was accomplished using Amplatz dilators and a 24 Ch or 26 Ch nephroscope was used. Fragmentation and stone removal were accomplished in all patients using pneumatic and or ultrasound lithotripter and a retrieval grasper. No anaesthetic complications were recorded. One patient required multiple percutaneous tracts, four had single tract to access stones. Three patients were stone free after PCNL. One required second PCNL through the same tract and another patient had multiple adjunctive ESWL. All five patients were stone clear after the final procedure. Two patients required blood transfusion. No patient had major complication or admission to intensive care unit. Percutaneous nephrolithotomy in patients with spina bifida is challenging but safe. Detailed pre-operative anaesthetic assessment and precise uroradiological evaluation of renal anatomy is essential. Second-look PCNL and additional ESWL/URS treatment may be required to completely clear stones. 22549476 Gene Finding in Primary Open-angle Glaucoma. There is extensive evidence that there is a genetic component to developing primary open-angle glaucoma (POAG). Unraveling this genetic component might clarify the pathophysiology of the disease and greatly assist in treatment and prevention of visual loss of many thousands of individuals. Linkage and association studies have helped identify loci and genes involved. The vast majority of the known heritable component of POAG, however, remains to be elucidated. Future studies should further investigate the identified loci and their role across different populations; assess genetic interactions and genotype-phenotype correlations; and aim at identifying new POAG genes by modern sequencing techniques. 23850478 Basic rules for polarised cell growth. Growth by cell elongation is a morphological process that transcends taxonomic kingdoms. Examples of this polarised growth form include hyphal tip growth in actinobacteria and filamentous fungi and pollen tube development. The biological processes required to produce polarisation in each of these examples are very different. However, commonality of the polarised growth habit suggests that certain "basic physical rules" of development are being followed. In this paper we are concerned with trying to further elucidate some of these basic rules. To this end, we focus on a simple and hence ubiquitous description of the polarised cell, its geometry, and using a mathematical model investigate how geometry and the deposition of new wall material could be related. We show that this simple model predicts both cell geometry and the location of maximal wall-deposition in a range of examples. 22926046 Proteomic allergen-peptide/protein interaction assay for the identification of human skin sensitizers. Modification of proteins by skin sensitizers is a pivotal step in T cell mediated allergic contact dermatitis (ACD). In this process small reactive chemicals interact covalently or non-covalently with cellular or extracellular skin self-proteins or self-peptides to become recognized by the human immune system. Aiming to develop a novel non-animal in vitro test system for predicting sensitization potential of small reactive chemicals in human skin the allergen-peptide/protein interaction assay (APIA) has been developed. By applying modern proteomic technologies together with a target peptide containing all amino acids, the assay permits the profiling of all amino acid specific allergen-peptide interactions. Moreover, potentially crucial allergen-specific Cys-modifications are qualitatively monitored by mass spectrometry and confirmed by a dual peptide approach. Assay conditions chosen mimic the distinct human epidermal reactivity compartments of the skin surface (pH 5.5), stratum basale (pH 6.8), and typical physiological conditions (pH 7.4). An extreme as well as a moderate human contact sensitizer produced Cys-specific mass shifts, whereas a skin irritant did not. Our data indicate that MALDI-MS based and skin-related in vitro technology platforms - like the APIA - are promising tools in developing alternative non-animal allergen assays. This will assist in chemical classification and next generation risk assessment strategies, including REACH and experimental immunotoxicology. 23870256 Analysis of the kinetics and bistability of ubiquinol:cytochrome C oxidoreductase. Ubiquinol:cytochrome c oxidoreductase, bc1 complex, is the enzyme in the respiratory chain of mitochondria responsible for the transfer reducing potential from ubiquinol to cytochrome c coupled to the movement of charge against the electrostatic potential across the mitochondrial inner membrane. The complex is also implicated in the generation of reactive oxygen species under certain conditions and is thus a contributor to cellular oxidative stress. Here, a biophysically detailed, thermodynamically consistent model of the bc1 complex for mammalian mitochondria is developed. The model incorporates the major redox centers near the Qo- and Qi-site of the enzyme, includes the pH-dependent redox reactions, accounts for the effect of the proton-motive force of the reaction rate, and simulates superoxide production at the Qo-site. The model consists of six distinct states characterized by the mobile electron distribution in the enzyme. Within each state, substates that correspond to various electron localizations exist in a rapid equilibrium distribution. The steady-state equation for the six-state system is parameterized using five independent data sets and validated in comparison to additional experimental data. Model analysis suggests that the pH-dependence on turnover is primarily due to the pKa values of cytochrome bH and Rieske iron sulfur protein. A previously proposed kinetic scheme at the Qi-site where ubiquinone binds to only the reduced enzyme and ubiquinol binds to only the oxidized enzyme is shown to be thermodynamically infeasible. Moreover, the model is able to reproduce the bistability phenomenon where at a given overall flux through the enzyme, different rates of superoxide production are attained when the enzyme is differentially reduced. 23861850 Nonlinear Distribution Pattern of Hibernating Bats in Caves along an Elevational Gradient in Mountain (Carpathians, Southern Poland). Thermal gradients along changes in elevation in mountainous environments are reflected by different biotas. Although there have been studies of elevation variation in bat assemblages in summer, winter changes in the same gradients remain unknown. The objective of this study was to document changes in the species composition of bats hibernating in caves along a temperate elevational gradient. We studied 70 caves between from 300 m to 1,930 m altitude along a slope of the Carpathian Mountains in southern Poland. We recorded changes in bats, including species richness, abundance, altitudinal distribution and dominance during consecutive winters between 2003 and 2009. Similarity of dominance of faunal structure was assessed by using the Bray-Curtis similarity index. We used the generalised additive model and rarefaction to study the variation in species richness, and generalized additive mixed models to examine the effect of abiotic factors on the qualitative and quantitative structure of bat assemblages. During 351 surveys we recorded 13,856 hibernating bats from 15 species. Species richness peaked around mid-elevation (1,100-1,400 m a.s.l.) with richness declining at both higher and lower elevations. Based on the results of a cluster analysis, we could distinguish among four altitudinal zones that differed in species richness and dominance structure. This is the first study documenting changes in species richness and variation of structure of bats hibernating in caves along an elevational gradient. The most surprising and key finding is the fact that changes in the structure of assemblages of hibernating bats along the altitudinal gradient occurred in jumps, forming zones similar to those observed in the vegetation zones. Moreover, species richness and dominance structure of assemblages of hibernating bats in the mountains depended not only on location above sea level, but also on local geomorphologic conditions which strongly affected the microclimate of the caves. 23937857 Idiopathic pulmonary fibrosis: the need for early diagnosis. Idiopathic pulmonary fibrosis (IPF), a chronic fibrosing lung disease of a progressive nature and unknown etiology, has the largest epidemiological impact and the worst prognosis among the idiopathic interstitial pneumonias (IIP). Despite the progress in pathogenetic knowledge, many aspects are still dubious, in particular the biomolecular mechanisms activated in the early stages of the disease. Early diagnosis is desirable not only to better define aspects of the natural history of the disease, but also to customize treatment protocols. An early diagnosis of IPF should necessarily be based on the ability to highlight a number of features drawn not only from a careful composition of specific anamnestic data with clinical, functional and radiological parameters, but also from biological markers that, in a proper context, can provide guidance and confirm a clinical-anamnestic suspicion. The identification of specific biomarkers for IPF is a modern and attractive look for the potential clinical implications in terms of diagnosis, prediction of disease progression and prognosis. Biomolecular investigations on IPF were performed selectively on tissue samples, bronchoalveolar lavage (BAL), or blood: nowadays the "multi-omic" approach may allow studying individual constitutional profiles resorting to a series of biomolecular disciplines, the so-called "omics", which focuses on responses of the entire genomic complex, in line with the current trend to quantitatively analyze the interactions of all components of a biological system. Such refined investigations are an essential base for research now, but they might become a routine in the near future, allowing a more precise classification of patients suffering from a disease of unclear taxonomy. 23962398 Anti-Leishmania antibodies in blood donors from the Midwest region of Brazil. The aim of the study was to detect asymptomatic infection by Leishmania sp. in blood donors. Serum samples (430) were tested by Immunofluorescent Antibody Test, and an interview with the blood donors was carried out. Antibodies were detected in 15.6% of samples. The variables associated with the infection were: origin of the donor, presence of builds, parks or squares, sick dog in the neighborhood, and neighboring with leishmaniasis. It was observed association between origin of donors and the presence of sick dog. It is important a careful screening of donors, due to the risk of infection through blood transfusion. 23620211 Dabigatran for the Prevention of Stroke and Systemic Embolism in Atrial Fibrillation: A NICE Single Technology Appraisal. The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of dabigatran etexilate (Boehringer Ingelheim Ltd, UK) to submit evidence for the clinical and cost-effectiveness of this drug for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) as part of the NICE single technology appraisal process. The Centre for Reviews and Dissemination and the Centre for Health Economics at the University of York were commissioned to act as the evidence review group (ERG). This article presents a summary of the manufacturer's submission, the ERG report and the subsequent development of NICE guidance for the use of dabigatran within the UK National Health Service. Dabigatran was granted marketing authorisation by the European Medicines Agency for a sequential dosing regimen (DBG sequential), in which patients under 80 years are treated with dabigatran 150 mg twice daily (DBG150) and patients 80 years and over are given dabigatran 110 mg twice daily (DBG110). NICE decisions are bound by the marketing authorisation; therefore, the decision problem faced by the committee was whether the DBG sequential regimen was effective and cost-effective compared with warfarin or aspirin for patients with non-valvular AF and one or more risk factors. The RE-LY trial, a large multi-centre non-inferiority randomised clinical trial, was the primary source of clinical evidence. DBG150 was shown to be non-inferior, and subsequently superior to warfarin, for the primary outcome of all stroke/systemic embolism. DBG110 was found to be non-inferior to warfarin. Results were presented for a post hoc subgroup analysis for patients under and over 80 years of age, where DBG110 showed a statistically significant reduction of haemorrhagic stroke and intracranial haemorrhage in comparison to warfarin in patients over 80 years of age. This post hoc subgroup analysis by age was the basis for the licensed DBG sequential regimen. The economic evaluation compared the costs and outcomes of DBG110, DBG150 and DBG sequential against warfarin, aspirin, and aspirin plus clopidogrel. Across the three dosing regimens, dabigatran was associated with greater costs and better health outcomes than warfarin; however, DBG150 offered the most benefits and dominated DBG110 and DBG sequential (i.e. less costly and more effective). The cost-effectiveness of DBG150 was less favourable for patients well controlled on warfarin. In the first appraisal meeting, the committee issued a 'minded no' decision until additional analyses on the licensed DBG sequential regimen were presented by the manufacturer. These additional analyses indicated that the incremental cost-effectiveness ratio (ICER) of the DBG sequential regimen compared with warfarin ranged from £8,388 to £18,987 per quality-adjusted life year (QALY) gained depending on the level of monitoring costs assumed for warfarin. Patients on warfarin would need to be within therapeutic range 83-85 % of the time for the ICER to exceed £30,000 per additional QALY. Following consideration of the additional evidence and the responses from a large number of consultees and commentators, the committee recommended dabigatran as DBG sequential as an option for the prevention of stroke and systemic embolism in people with non-valvular AF with one or more risk factors for ischaemic stroke. 23881756 Predictors of outcome after alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy. Special interest for the septal coronary anatomy. Alcohol septal ablation (ASA) provides symptomatic relief in most but not all patients with hypertrophic obstructive cardiomyopathy (HOCM). Therefore we investigated predictors of outcome after ASA. Clinical, echocardiographic, angiographic and procedural characteristics were analysed in 113 consecutive patients. Successful ASA was defined as NYHA ≤ 2 with improvement of at least 1 class combined with a resting gradient < 30 mmHg and provoked gradient < 50 mmHg at 4-month follow-up. In 37 patients ASA was not successful. In multivariate analysis, baseline gradient (OR 1.06 (1.01-1.11) per 5 mmHg, p = 0.024) and distance to the ablated septal branch (OR 1.09 (1.03-1.16) per mm, p = 0.004) were predictors of unsuccessful outcome. The combined presence of a non-ablated septal branch and a distance ≥ 19 mm to the ablated branch was a predictor of unsuccessful outcome (OR 5.88 (2.06-16.7), p < 0.001). Baseline gradient and a greater distance from the origin of the left anterior descending artery to the ablated septal branch combined with a non-ablated proximal septal branch are associated with an unsuccessful outcome after ASA. 23828660 Hacking cell differentiation: transcriptional rerouting in reprogramming, lineage infidelity and metaplasia. Initiating neoplastic cell transformation events are of paramount importance for the comprehension of regeneration and vanguard oncogenic processes but are difficult to characterize and frequently clinically overlooked. In epithelia, pre-neoplastic transformation stages are often distinguished by the appearance of phenotypic features of another differentiated tissue, termed metaplasia. In haemato/lymphopoietic malignancies, cell lineage ambiguity is increasingly recorded. Both, metaplasia and biphenotypic leukaemia/lymphoma represent examples of dysregulated cell differentiation that reflect a history of trans-differentiation and/or epigenetic reprogramming. Here we compare the similarity between molecular events of experimental cell trans-differentiation as an emerging therapeutic concept, with lineage confusion, as in metaplasia and dysplasia forecasting tumour development. 23517746 Medical Expulsive Therapy versus Early Endoscopic Stone Removal for Acute Renal Colic: An Instrumental Variable Analysis. The use of medical expulsive therapy to hasten stone passage potentially decreases expenditures around episodes of renal colic. However, these efficiency gains may be mitigated if patients treated with medical expulsive therapy have frequent health care encounters due to pain while waiting for the stones to pass. Using claims data (2002 to 2006) we identified adult men with acute renal colic. We compared 6-week payments as well as frequency of hospitalization and emergency department revisits associated with an initial course of medical expulsive therapy with those for early endoscopic stone removal. To account for unmeasured confounding we performed an instrumental variable analysis, exploiting variation in recommended treatments based on the day of the week that a patient's first emergency department visit occurred. Overall 1,835 and 4,397 men underwent medical expulsive therapy or early endoscopic stone removal, respectively. Although minimal differences existed between men with respect to the day of the week of emergency department presentation, weekend encounters were strongly associated with receiving medical expulsive therapy (p <0.001). Two-stage least squares regression revealed 6-week payments to be tenfold lower for men on medical expulsive therapy who were candidates for either treatment (p <0.001). While there was no difference in frequency of hospitalization, these men were more likely to have a repeat emergency department visit compared to those who underwent endoscopic stone removal (68.8% vs 39.6%, respectively, p = 0.025). Findings on medical expulsive therapy are mixed, with lower 6-week payments but more frequent repeat emergency department visits. These data inform patients who are candidates for medical expulsive therapy or endoscopic stone removal when making decisions about their care. 23574816 Clinically significant differences exist between curves in operative idiopathic early-onset scoliosis and adolescent idiopathic scoliosis. Retrospective analysis. To determine if statistically significant differences exist between operative idiopathic early-onset scoliosis (IEOS) and adolescent idiopathic scoliosis (AIS) in primary curve characteristics, stable vertebra, kyphosis, or lumbar deformity and, if so, to identify the clinical significance of these differences. To our knowledge, no study has statistically compared radiographical measures of operative IEOS and AIS. We identified operative patients (60, IEOS; 1537, AIS) in 2 multicenter databases and measured preoperative radiographical parameters of interest. The measurements were compared using the Student t test and other appropriate statistical methods (significance, P= 0.05). The IEOS and AIS groups were significantly different in primary curve magnitude (70°± 20°vs. 54°± 13°, respectively; P< 0.001), stable vertebra location (L3.0 ± 1.4 vs. L2.1 ± 2.2, respectively; P= 0.001), and T2 to T12 kyphosis (40°± 15°vs. 31°± 13°, respectively; P< 0.001). Distribution of major curve apex was unimodal centered close to the thoracolumbar junction in IEOS versus bimodal in AIS. Primary curve type was thoracic in 83% and 79% and thoracolumbar/lumbar in 17% and 21% of patients with IEOS and AIS, respectively. When the overall cohorts were separated into curve types and these subsets were compared, statistically significant differences were found between IEOS and AIS in thoracic primary curves (apex, magnitude, direction, proximal and distal Cobb vertebrae, and lumbar deformity) and thoracolumbar/lumbar primary curves (magnitude). Significant radiographical differences exist between operative IEOS and AIS curves. IEOS curves are greater in magnitude, more kyphotic, less well compensated, and have a more caudal apex and stable vertebra. These findings suggest that younger patients may require more distal instrumentation and that proximal fixation techniques should consider the additional pullout forces created by the greater kyphosis.Level of Evidence: 3. 23871561 In-vial dual extraction liquid chromatography coupled to mass spectrometry applied to streptozotocin-treated diabetic rats. Tips and pitfalls of the method. The aim of metabolomics studies is the comprehensive and quantitative analysis of all metabolites in a cell, tissue or organism. This approach requires sample preparation methods to be fast, reproducible and able to extract a wide range of analytes with different polarities, as well as analytical platforms able to detect the extracted metabolites. Recently, we have developed a one-step extraction method consisting of a lipophilic and hydrophilic layer within a single vial insert, in-vial dual extraction (IVDE). In order to check possible application of this method to real biological case, analysis of plasma samples obtained from three streptozotocin-induced diabetic and three control rats was performed. Analytical validity of the method was proved by the calculation (in quality control samples) of relative standard deviation (RSD) for detected metabolites. The percentage of metabolites with RSD<30% was 93% for Fatty acyls, 80% for Glycerolipids, 93% for Glycerophospholipids, 68% for Sterol lipids, and 91% for Sphingolipids. IVDE allowed for selection of more than 600 different features discriminating two studied groups. For around 40% of these masses putative identification was possible. Adequate, with several considerations described within this paper, application of IVDE method enables wide metabolite coverage from a single 20μL plasma aliquot. Within the features putatively identified, glycerolipids and glycerophospholipids arose as the most important groups of compounds discriminating diabetic rats from controls. All discriminating metabolites give an idea of the large metabolic differences that can be present in non-controlled type 1 diabetes. 23787704 Supramolecular attachment of metalloporphyrins to graphene oxide and its pyridine-containing derivative. Functionalized with porphyrins: The interactions of metalloporphyrins with graphene oxide and pyridine-substituted graphene oxide have been probed. The interactions elucidated offer unprecedented tools in the quest for functional nanostructured materials. 23430405 Identification of regulatory relationships in Parkinson's disease. Parkinson's disease is a complex chronic neurodegenerative disease common in elderly people and greatly affects the quality of their life. However, the pathogenesis of Parkinson's disease is still incompletely understood to date. The purpose of this present study is to explore the pathogenesis of Parkinson's disease using a computational bioinformatics analysis of gene expression. We downloaded gene expression profiles on Parkinson's disease from the Gene Expression Omnibus database and predicted the miRNAs and transcription factors of differentially expressed genes in Parkinson's disease. A total of 11 genes associated with Parkinson's disease initiation were identified, including junction plakoglobin (JUP). Besides, we identified a new transcription factor, N-Myc down-regulated gene 1 (NDRG1), which is regulated by miRNA-133 in Parkinson's disease. Furthermore, we proposed a hypothesis that there may be two kinds of regulatory relationships among miRNA-133, NDRG1, and JUP: direct regulatory relationship and indirect relationship. The results presented in this work confirmed the role of miRNA-133 in Parkinson's disease and substantiated our understanding of miRNA-related neurodegenerative states in general. 23564221 Transjugular intrahepatic portosystemic shunt induced short- and long-term cerebral blood flow variations in cirrhotic patients: an arterial spin labeling MRI study. Short- and long-term effects of transjugular intrahepatic portosystemic shunt (TIPS) on cerebral blood flow (CBF) in patients with cirrhosis are still unclear. The purpose of this longitudinal study was to explore CBF alteration patterns in cirrhotic patients after TIPS. Thirteen cirrhotic patients (7 male, 6 female, mean age 50.0 ±â€‰9.3 years) underwent arterial-spin labeling (ASL) MRI 1-9 days (median 1 days) before TIPS. Follow-up MR examinations were performed about 1 week (median 6 days), 3 months (n = 6), 6-9 months (n = 5) and 12-18 months (n = 5) after TIPS. CBF, ammonia level, Child-Pugh score, number connection test type A (NCT-A) and digit symbol test (DST) scores were converted into relative values by dividing by his/her pre-TIPS values, and then, compared via one-way analysis of variance (ANOVA). Correlations between the pre- and post-TIPS changes of relative CBF (rCBF) and the changes of relative ammonia (rAmmonia), Child-Pugh (rChild-Pugh), and NCT-A/DST (rNCT-A/rDST) scores were calculated by crossing subjects. Compared with the pre-TIPS level, the global rCBF slightly increased by 10.9 % about 1 week later, then rapidly decreased by 14.2 % 3 months later, and flatly decreased by 17.2 % in 6-9 months and 18.0 % in 12-18 months following TIPS. The changes of 3-month rDST score were slightly correlated with 3-month rCBF rather than 1-week rCBF, (P < 0.1, FDR-corrected) No difference was found between the pre- and post-TIPS rAmmonia levels, rChild-Pugh and rNCT-A/rDST scores (Post-hoc P > 0.05). CBF measured at different time points after TIPS insertion showed different patterns, indicating varying longitudinal effects of TIPS on CBF. A sharp decline of rCBF was found in the 1 week to 3 months period after insertion, indicating that high event rate of hepatic encephalopathy might relate with the unadaptable CBF in patients undergoing TIPS insertion. 23911653 Comparison of cells free in coelomic and water-vascular system of sea cucumber, Apostichopus japonicus. The sea cucumber, Apostichopus japonicus possesses a variety of cells populating in both the coelomic (cells in the coelomic are called coelomocytes) and water-vascular system. In this study, we compared cells in these two systems of A. japonicus on total cell number, cell types and surface antigens through monoclonal antibodies against coelomocytes. The results demonstrated that the cell types observed in coelomic also could be found in water-vascular system, but the total cell number and percentages of each type were different. The total number of coelomocytes was 2-3 times of that in water-vascular system. Lymphoid cells were numerically dominant in coelomic system, while spherulocytes with pseudopods in water-vascular system. Results of indirect immunofluorescence assay technique showed that both coelomocytes and cells in water-vascular system could be recognized by the corresponding MAbs, and the distribution of its positive signals was not different. In conclusion, cell types and surface antigens in coelomic and water-vascular system were same, but the total cell number and percentages of each type were different. And further researches are needed on whether there are differences in functions of the different composition. 23958790 Artesunate inhibits the growth of gastric cancer cells through the mechanism of promoting oncosis both in vitro and in vivo. This study aims to investigate the significance and mechanism of artesunate involved in suppressing the proliferation of gastric cancer in vitro and in vivo. In the in-vitro experiments, artesunate inhibited the growth of gastric cancer cell lines (SGC-7901, BGC-823, and AGS) with concentration-dependent activity, with no significant effect on GES-1 cells. BGC-823 cells treated with artesunate showed the typical morphologic features of oncosis rather than apoptosis. Meanwhile, we observed calcium overload, downregulation of vascular endothelial growth factor expression, and upregulation of calpain-2 expression in the artesunate-treated BGC-823 cells. In addition, the in-vivo study showed that artesunate produced a dose-dependent tumor regression in nude mice. The antitumor activity of 240 mg/kg artesunate was similar to that of 10 mg/kg docetaxel. Furthermore, compared with the control group, no significant difference was observed in the body weight of artesunate-treated nude mice other than docetaxel-treated nude mice. These observations show that artesunate has concentration-dependent inhibitory activities against gastric cancer in vitro and in vivo by promoting cell oncosis through an impact of calcium, vascular endothelial growth factor, and calpain-2 expression. 23889202 Brain responses to audiovisual speech mismatch in infants are associated with individual differences in looking behaviour. Research on audiovisual speech integration has reported high levels of individual variability, especially among young infants. In the present study we tested the hypothesis that this variability results from individual differences in the maturation of audiovisual speech processing during infancy. A developmental shift in selective attention to audiovisual speech has been demonstrated between 6 and 9 months with an increase in the time spent looking to articulating mouths as compared to eyes (Lewkowicz & Hansen-Tift. (2012) Proc. Natl Acad. Sci. USA, 109, 1431-1436; Tomalski et al. (2012) Eur. J. Dev. Psychol., 1-14). In the present study we tested whether these changes in behavioural maturational level are associated with differences in brain responses to audiovisual speech across this age range. We measured high-density event-related potentials (ERPs) in response to videos of audiovisually matching and mismatched syllables /ba/ and /ga/, and subsequently examined visual scanning of the same stimuli with eye-tracking. There were no clear age-specific changes in ERPs, but the amplitude of audiovisual mismatch response (AVMMR) to the combination of visual /ba/ and auditory /ga/ was strongly negatively associated with looking time to the mouth in the same condition. These results have significant implications for our understanding of individual differences in neural signatures of audiovisual speech processing in infants, suggesting that they are not strictly related to chronological age but instead associated with the maturation of looking behaviour, and develop at individual rates in the second half of the first year of life. 23902945 Mutations in eIF4ENIF1 Are Associated With Primary Ovarian Insufficiency. Context:Primary ovarian insufficiency (POI), or premature ovarian failure, results from ovarian follicle depletion with a consequent elevation of FSH levels before age 40 years. We identified a family in which 9 women in 3 consecutive generations developed menopause at approximately age 30 years. We hypothesized a genetic cause with a dominant mode of inheritance.Design:This was a family-based genetic study and a replicate group of women with POI.Setting:The study was conducted at an academic medical center.Patients:Seven affected women and an obligate carrier and 7 unaffected family members were genotyped. The genes of interest were also sequenced in 38 unrelated women with POI.Intervention:The DNA from 7 family members was subjected to whole-exome sequencing. The genotypes of interest were confirmed and genotypes of additional family members and unrelated women with POI were determined using Sanger sequencing.Main Outcome Measure:A high-impact, deleterious variant that segregated appropriately with POI in the family was measured.Results:A heterozygous stop codon (Ser429X) was identified in the eukaryotic translation initiation factor 4E nuclear import factor 1 (eIF4ENIF1) in the proband and all affected women but not in the unaffected family members. The chance that such a high-impact, deleterious variant would segregate appropriately among the affected and unaffected relatives by chance is very low (P < .05). There were no additional mutations identified in eIF4ENIF1 or eIF4E in 38 unrelated women with POI.Conclusion:Data demonstrate a new gene associated with dominantly inherited POI. These results highlight the importance of translation initiation factors and their regulators in ovarian function. 23919754 Myxoinflammatory Fibroblastic Sarcoma in Children and Adolescents: Clinicopathologic Aspects of a Rare Neoplasm. Abstract Abstract Myxoinflammatory fibroblastic sarcoma (MIFS), originally described as a low-grade malignant soft tissue tumor in adults, has recently been reported in children and in non-acral sites. This report describes the clinicopathologic features of a series of five MIFS in children and adolescents, ranging in age from 5 to 17 years (mean 13 years), including three males and two females. These tumors presented as small, superficial, slowly growing soft tissues masses of the scalp, neck, middle finger, forearm, and thigh. Histologically, the tumors were composed of spindled and plump polygonal cells with prominent nuclear pleomorphism, nuclear pseudoinclusions, large eosinophilic nucleoli, myxoid foci intermingled with spindled foci, and an accompanying inflammatory infiltrate of lymphocytes, plasma cells, and variable neutrophils. Immunohistochemical analysis revealed variable reactivity for CD34 and smooth muscle actin in the tumor cells. Genetic analysis in three cases showed no rearrangements of TGFBR3 or MGEA5. Followup in four cases revealed no recurrence or metastasis. These five cases of childhood and adolescent MIFS demonstrate an expanded age range and topographic distribution and a favorable outcome. The differential diagnosis and importance of recognizing this rare neoplasm in young patients are discussed. Key Words: acral myxoinflammatory fibroblastic sarcoma, fibroma, fibromatosis, inflammatory myxohyaline tumor, myxoinflammatory fibroblastic sarcoma, myxoma. 23370524 Chemo-responsive, self-oscillating gels that undergo biomimetic communication. Species ranging from single-cell organisms to social insects can undergo auto-chemotaxis, where the entities move towards a chemo-attractant that they themselves emit. Polymer gels undergoing the self-oscillating Belousov-Zhabotinsky (BZ) reaction exhibit autonomous, periodic pulsations, which produce chemical species collectively referred to as the activator. The diffusion of this activator into the surrounding solution affects the dynamic behavior of neighboring BZ gels and hence, the BZ gels not only emit, but also respond to self-generated chemical gradients. This review describes recent experimental and computational studies that reveal how this biomimetic behavior effectively allows neighboring BZ gels to undergo cooperative, self-propelled motion. These distinctive properties of the BZ gels provide a route for creating reconfigurable materials that autonomously communicate with neighboring units and thereby actively participate in constructing the desired structures. 23219467 The discovery, engineering and characterisation of a highly potent anti-human IL-13 fab fragment designed for administration by inhalation. We describe the discovery, engineering and characterisation of a highly potent anti-human interleukin (IL)-13 Fab fragment designed for administration by inhalation. The lead candidate molecule was generated via a novel antibody discovery process, and the selected IgG variable region genes were successfully humanised and reformatted as a human IgG γ1 Fab fragment. Evaluation of the biophysical properties of a selection of humanised Fab fragments in a number of assays allowed us to select the molecule with the optimal stability profile. The resulting lead candidate, CA652.g2 Fab, was shown to have comparable activity to the parental IgG molecule in a range of in vitro assays and was highly stable. Following nebulisation using a mesh nebuliser, CA652.g2 Fab retained full binding affinity, functional neutralisation potency and structural integrity. Epitope mapping using solution nuclear magnetic resonance confirmed that the antibody bound to the region of human IL-13 implicated in the interaction with IL-13Rα1 and IL-13Rα2. The work described here resulted in the discovery and design of CA652.g2 human γ1 Fab, a highly stable and potent anti-IL-13 molecule suitable for delivery via inhalation. 23754504 Clinical significance of IgA anti-cardiolipin and IgA anti-β2glycoprotein I antibodies. IgA antiphospholipid antibodies (aPL) are not currently recognized as formal laboratory criteria for the Antiphospholipid Syndrome (APS). This is mainly due to methodological issues (different study designs, use of various non-standardized IgA assays). However, there are experimental data showing the pathogenic role of IgA anti-cardiolipin antibodies (aCL) and IgA anti-β2glycoprotein I antibodies (anti-β2GPI). Isolated IgA aCL are not very common, therefore their testing could be useful in the case of strong suspicion of APS but negative results for other aPL tests. IgA anti-β2GPI seem to be the most prevalent isotype in patients with Systemic Lupus Erythematosus (SLE), with a significant association with thrombotic events. Such a clinical relevance has been recently recognized by the inclusion of these autoantibodies among the aPL tests in the novel SLICC classification criteria for SLE. Emerging interest has been raised by IgA anti-β2GPI against domain 4/5 as a novel subgroup of clinically relevant aPL. 23303738 2-Carbaborane-3-phenyl-1H-indoles--synthesis via McMurry reaction and cyclooxygenase (COX) inhibition activity. Cyclooxygenase-2 (COX-2) inhibitors have been the focus of medicinal chemistry efforts for years, and many compounds that exhibit high selectivity and affinity have been developed. As carbaboranes represent interesting pharmacophores as phenyl mimetics in drug development, this paper presents the synthesis of carbaboranyl derivatives of COX-2-selective 2,3-disubstituted indoles. Despite the lability of carbaboranes under reducing conditions, 2-carbaborane-3-phenyl-1H-indoles could be synthesized by McMurry cyclization of the corresponding amides. Whereas the meta-carbaboranyl-substituted derivatives lacked COX inhibitory activity, an ortho-carbaboranyl analogue was active, but showed a selectivity shift toward COX-1. 23887929 An Empirical Typology of Social Networks and Its Association With Physical and Mental Health: A Study With Older Korean Immigrants. Objectives.In the context of social convoy theory, the purposes of the study were (a) to identify an empirical typology of the social networks evident in older Korean immigrants and (b) to examine its association with self-rated health and depressive symptoms.Method.The sample consisted of 1,092 community-dwelling older Korean immigrants in Florida and New York. Latent class analyses were conducted to identify the optimal social network typology based on 8 indicators of interpersonal relationships and activities. Bivariate and multivariate analyses were conducted to examine how the identified social network typology was associated with self-rating of health and depressive symptoms. Results from the latent class analysis identified 6 clusters as being most optimal, and they were named diverse, unmarried/diverse, married/coresidence, family focused, unmarried/restricted, and restricted. Memberships in the clusters of diverse and married/coresidence were significantly associated with more favorable ratings of health and lower levels of depressive symptoms.Discussion.Notably, no distinct network solely composed of friends was identified in the present sample of older immigrants; this may reflect the disruptions in social convoys caused by immigration. The findings of this study promote our understanding of the unique patterns of social connectedness in older immigrants. 23925585 Microfluidic barcode assay for antibody-based confirmatory diagnostics. Confirmatory diagnostics offer high clinical sensitivity and specificity typically by assaying multiple disease biomarkers. Employed in clinical laboratory settings, such assays confirm a positive screening diagnostic result. These important multiplexed confirmatory assays require hours to complete. To address this performance gap, we introduce a simple 'single inlet, single outlet' microchannel architecture with multiplexed analyte detection capability. A streptavidin-functionalized, channel-filling polyacrylamide gel in a straight glass microchannel operates as a 3D scaffold for a purely electrophoretic yet heterogeneous immunoassay. Biotin and biotinylated capture reagents are patterned in discrete regions along the axis of the microchannel resulting in a barcode-like pattern of reagents and spacers. To characterize barcode fabrication, an empirical study of patterning behaviour was conducted across a range of electromigration and binding reaction timescales. We apply the heterogeneous barcode immunoassay to detection of human antibodies against hepatitis C virus and human immunodeficiency virus antigens. Serum was electrophoresed through the barcode patterned gel, allowing capture of antibody targets. We assess assay performance across a range of Damkohler numbers. Compared to clinical immunoblots that require 4-10 h long sample incubation steps with concomitant 8-20 h total assay durations; directed electromigration and reaction in the microfluidic barcode assay leads to a 10 min sample incubation step and a 30 min total assay duration. Further, the barcode assay reports clinically relevant sensitivity (25 ng ml(-1) in 2% human sera) comparable to standard HCV confirmatory diagnostics. Given the low voltage, low power and automated operation, we see the streamlined microfluidic barcode assay as a step towards rapid confirmatory diagnostics for a low-resource clinical laboratory setting. 23928719 Interaction of free-living marine nematodes in the artificial mangrove environment (southeast coast of India). Free-living marine nematode diversity was analyzed between Avicennia marina and Rhizophora mucronata mangrove covers of the Vellar Estuary (southeast coast of India). A total of 4,976 specimens of free-living marine nematodes were collected in 56 species. Comparatively, a higher species richness was obtained for A. marina (52 species) than for R. mucronata (44 species), whereas 40 species commonly existed in both mangrove covers. A higher density of nematodes was found in sediments of sandy nature, whereas there was lower total organic carbon compared to silt/clay composition; epigrowth feeders were dominant over the other feeding groups based on organic enrichment in surface sediments. Principal component analysis clearly explained the relationship between the environmental parameters of various months. Higher R values of analysis of similarities revealed significant differences in nematode assemblages between months, and it was quite evident by non-metric multidimensional scaling. Diversity indices showed higher values in the dry months. RELATE analysis explained serial changes in nematode species composition between months, and a relationship between biotic and abiotic variables was clarified using the BIO-ENV procedure. Viscosia spp., Metachromadora spp., Theristus spp., and Sphaerolaimus spp. were candidate species of A. marina leaf interaction by observation. 23811818 Step by step: A proof of concept study of C-Mill gait adaptability training in the chronic phase after stroke. Objective: To evaluate the concept of C-Mill gait adaptability training. Design: Pre- and post-intervention assessments. Subjects: Sixteen community-dwelling persons in the chronic phase after stroke (mean age 54.8 years). Methods: Participants received 10 sessions (1 h per session, for 5-6 weeks) of gait adaptability training on an instrumented treadmill augmented with visual targets and obstacles (C-Mill). Pre- and post-intervention assessments included: (i) clinical assessments of balance and gait: 10-m walking test, Timed Up-and-Go test, Berg Balance Scale, obstacle sub-task of the Emory Functional Ambulation Profile, and the Trunk Impairment Scale; (ii) physical activity level, assessed with a pedometer; (iii) success rate of accurate step adjustments towards a displacing target, assessed with an instrumented Target-Stepping Task; (iv) participant's experience with the training. Results: All clinical assessments improved significantly after training (all p < 0.05), except for the Trunk Impairment Scale (p = 0.584). Physical activity increased by 19.6% (p < 0.05). Improvements in Target-Stepping Task success rates depended on the specific testing condition (time × body support × step direction, χ2(1) = 3.884, p < 0.05). All participants appreciated the training. Conclusion: The concept of C-Mill gait adaptability training in the chronic phase after stroke is promising and warrants future research involving a randomized controlled trial. 23876476 Maternal Prepregnancy Body Mass Index and Their Children's Blood Pressure and Resting Cardiac Autonomic Balance at Age 5 to 6 Years. Adverse intrauterine conditions can program hypertension. Because one of the underlying mechanisms is thought to be cardiac autonomic balance, we investigated the association between prepregnancy body mass index (BMI) and blood pressure and indicators of the autonomic balance in the child at age 5 to 6 years. Also investigated was whether these associations were mediated by standardized birth weight and child BMI. Pregnant women (n=3074) participating in the Amsterdam Born Children and their Development study completed a questionnaire at gestational week 14. At age 5 to 6 years, offspring's sympathetic drive (pre-ejection period), parasympathetic drive (respiratory sinus arrhythmia), and heart rate were measured by electrocardiography and impedance cardiography at rest. Blood pressure was assessed simultaneously. After adjusting for possible maternal/offspring confounders, prepregnancy BMI was positively linearly associated with diastolic blood pressure (β=0.11 mm Hg; 95% confidence interval, 0.05-0.17), systolic blood pressure (β=0.14 mm Hg; 95% confidence interval, 0.07-0.21), but not with heart rate, sympathetic or parasympathetic drive. After adding birth weight and child BMI to the model, the independent effect size of prepregnancy body mass index on systolic blood pressure (β=0.07 mm Hg; 95% confidence interval, 0.00-0.14) and diastolic blood pressure (β=0.07 mm Hg; 95% confidence interval, 0.01-0.13) decreased by ≈50%. Birth weight did not mediate these relationships, but was independently and negatively associated with blood pressure. Child BMI was positively associated with blood pressure and partly mediated the association between prepregnancy BMI and blood pressure. In conclusion, higher prepregnancy BMI is associated with higher blood pressure in the child (aged 5-6 years) but does not seem to be attributable to early alterations in resting cardiac autonomic balance. Child BMI, but not birth weight, mediated the association between prepregnancy BMI and blood pressure. 23214931 Foams stabilized by multilamellar polyglycerol ester self-assemblies. The importance of surfactant self-assemblies in foam stabilization is well-known. The aim of the current study was to investigate the self-assemblies of the nonionic surfactant polyglycerol ester (PGE) in bulk solutions, at the interface and within foams, using a combined approach of small-angle neutron scattering, neutron reflectivity, and electron microscopy. PGE bulk solutions contain vesicles as well as open lamellar structures. Upon heating of the solutions the lamellar spacing increases, with significant differences in the presence of NaCl or CaCl(2) as compared to the standard solution. The adsorption of the multilamellar structures present in the bulk solutions lead to a multilayered film at the air-water interface. The ordering within this film was increased as a result of a 20% area compression mimicking a coalescence event. Finally, PGE foams were shown to be stabilized not only by strong interfacial films but also by agglomerated self-assemblies within the interstitial areas of the foams. 23953624 A HER2-targeted RNA aptamer molecule labeled with (99m)Tc for single-photon imaging in malignant tumors. A modified RNA aptamer with HER2-specific binding was conjugated to hynic and labeled with (99m)Tc, for potential use as a radiopharmaceutical for diagnostic imaging of ovarian cancer cells (SKOV-3) with high HER2 expression. The aptamer was radiolabeled with (99m)Tc by using hynic as the chelator and tricine as the co-ligand. Stability testing of the radioconjugated aptamer was performed via ITLC and SDS-PAGE in normal saline and serum. The aptamer-radionuclide conjugate was evaluated for cellular HER2-specific binding, saturation affinity, and cellular internalization in SKOV-3 and MCF-7 cells, and its biodistribution properties were assessed in normal and SKOV-3 tumor-bearing mice. Radiolabeling of the aptamer was achieved with high yield and radiochemical purity, and the (99m)Tc-hynic-RNA aptamer was highly stable in normal saline and serum. Cellular experiments showed specific binding of the aptamer to the HER2 receptor with a dissociation constant of 27nM. Rapid blood clearance was observed after injection of the (99m)Tc-hynic-RNA aptamer, and the main excretion route was via the hepatobilary system. While the radioconjugated aptamer bound specifically to the HER2 receptor on cells in vitro, it did not show any significant tumor-to-blood or tumor-to-muscle ratios in mice. Modifications to radiolabeled aptamer will require improving its pharmacokinetic properties and tumor uptake in vivo. 23588559 Low allopurinol doses are sufficient to optimize azathioprine therapy in inflammatory bowel disease patients with inadequate thiopurine metabolite concentrations. PURPOSE: Recent studies in patients with inflammatory bowel diseases (IBD) on thiopurine therapy suggest that too low 6-thioguanine nucleotide concentrations (6-TGN) and too high methylmercaptopurine nucleotide concentrations (MMPN) can be reversed by a combination therapy of allopurinol and low-dose thiopurines. To date, however, optimal dosing has not been established. The aim of this study was to evaluate the minimal allopurinol doses necessary to achieve adequate 6-TGN concentrations in combination with low-dose azathioprine. METHODS: A stepwise dose-escalation of allopurinol was performed in 11 azathioprine-pretreated IBD patients with inadequately low 6-TGN concentrations (<235 pmol/8 × 10(8) erythrocytes) and/or elevated MMPN concentrations (>5,000 pmol/8 × 10(8) erythrocytes) and/or elevated liver enzymes (alanine aminotransferase and/or aspartate aminotransferase levels one- to threefold the upper limit of normal). Six patients were recruited into an open study, and five were treated in the context of an individualized therapeutic approach. Adverse effects, azathioprine metabolites, liver enzymes and whole blood counts were monitored two to three times per month. RESULTS: Adequate 6-TGN concentrations were achieved with a combination of 25 mg allopurinol and 50 mg azathioprine in one patient and with 50 mg allopurinol and 50 mg azathioprine in nine patients. Median 6-TGN concentrations (range) were 336 (290-488) pmol/8 × 10(8) erythrocytes after an 8-week-long intake of the final dose combination. One patient dropped out due to nausea after the first intake. MMPN concentrations and liver enzymes normalized immediately in all affected patients. All patients finishing the dose-escalation regimen tolerated the treatment without toxicity. CONCLUSIONS: Combination therapy with only 50 mg allopurinol and 50 mg azathioprine daily is sufficient, efficacious and safe in most IBD patients with inadequate thiopurine metabolite concentrations to optimize azathioprine-based IBD therapy. 23100159 Enhanced carcinogenicity by coexposure to arsenic and iron and a novel remediation system for the elements in well drinking water. Various carcinomas including skin cancer are explosively increasing in arsenicosis patients who drink arsenic-polluted well water, especially in Bangladesh. Although well drinking water in the cancer-prone areas contains various elements, very little is known about the effects of elements except arsenic on carcinogenicity. In order to clarify the carcinogenic effects of coexposure to arsenic and iron, anchorage-independent growth and invasion in human untransformed HaCaT and transformed A431 keratinocytes were examined. Since the mean ratio of arsenic and iron in well water was 1:10 in cancer-prone areas of Bangladesh, effects of 1 μM arsenic and 10 μM iron were investigated. Iron synergistically promoted arsenic-mediated anchorage-independent growth in untransformed and transformed keratinocytes. Iron additionally increased invasion in both types of keratinocytes. Activities of c-SRC and ERK that regulate anchorage-independent growth and invasion were synergistically enhanced in both types of keratinocytes. Our results suggest that iron promotes arsenic-mediated transformation of untransformed keratinocytes and progression of transformed keratinocytes. We then developed a low-cost and high-performance adsorbent composed of a hydrotalcite-like compound for arsenic and iron. The adsorbent rapidly reduced concentrations of both elements from well drinking water in cancer-prone areas of Bangladesh to levels less than those in WHO health-based guidelines for drinking water. Thus, we not only demonstrated for the first time increased carcinogenicity by coexposure to arsenic and iron but also proposed a novel remediation system for well drinking water. 23872802 Femoral Lengthening Over a Pediatric Femoral Nail: Results and Complications. Limb lengthening by callotasis as described by Ilizarov has become the standard method of lower extremity lengthening. Lengthening over an intramedullary nail to allow early removal of the external fixator has also become common in adults but few studies have addressed the efficacy in children. A retrospective review of 37 consecutive children who had undergone femoral lengthening with external fixator over an intramedullary nail was performed. Charts were reviewed for demographics, surgical details, and complications. Radiographs were examined to determine magnitude of lengthening and to calculate lengthening index. The average age of the 37 patients was 11.6 years (range, 8.1 to 17.0). The amount of lengthening averaged 7.0 cm (range, 3.0 to 11.4 cm), which represented a mean 20.4% increase in length. The mean time in the fixator was 81 days. The lengthening index was 1.21 days/mm. Thirteen patients developed major complications (37.8%) including 4 limbs that failed to lengthen initially, 3 fractures (1 before fixator removal and 3 after fixator removal), 2 nail failures, 4 deep infections, and 2 joint subluxations requiring operative care. The 3 fractures after fixator removal were treated with exchange nailing as were the 2 intramedullary nail failures. Four patients (10.8%) developed deep infections requiring irrigation, debridement, and IV antibiotics. One patient developed a late hip subluxation, which was treated with a shelf osteotomy but resulted in pain and limitation of motion. One patient developed knee subluxation during lengthening requiring operative intervention. The technique was successful in obtaining a good result with a functional lengthened femur without unresolved problems in 94% of the patients despite a significant rate of major complications, particularly in those with a congenital etiology. Only 2 of the 37 patients ultimately had results that were ultimately compromised by complications. Femoral lengthening over an intramedullary nail with the aid of an external fixator has shown to be an effective method for correcting limb length discrepancy. The technique has a high complication rate similar to other methods of lengthening. Level IV-Case Series. 23932373 Analysis of the unsaponifiable fraction of lipids belonging to various milk-types by using comprehensive two-dimensional gas chromatography with dual mass spectrometry/flame ionization detection and with the support of high resolution time-of-flight mass spectrometry for structural elucidation. The present investigation is focused on the use of a comprehensive two-dimensional GC (GC×GC) method, with dual mass spectrometry/flame ionization detection (MS/FID), for the qualitative and quantitative analysis of the unsaponifiable fraction of milk lipids (cow butter, buffalo, ewe, and goat milks). The structure of many constituents (particularly sterols) was confirmed by using GC-high resolution time-of-flight MS. The GC×GC column set used consisted of a low-polarity first dimension, and a medium-polarity secondary one, both characterized by a high thermal stability. The use of dual detection enabled the attainment of both mass spectral information and relative % FID data. The complexity of the fingerprint, generated by the unsaponifiable fraction, justified the employment of the two-dimensional GC technology. However, it was two other GC×GC characteristics that contributed most to the attainment of promising results, namely sensitivity enhancement and the formation of group-type patterns. Because many milk lipid constituents were not contained in the MS databases employed, exact mass information proved to be valuable for identification purposes. 23832418 The Wilms' tumor suppressor WT1 enhances CD95L expression and promotes activation-induced cell death in leukemic T cells. The role of Wilms' tumor suppressor 1 (WT1) in leukemogenesis has been investigated mostly in acute (AML) and chronic (CML) myeloid leukemias. So far, its oncogenic role has been controversially discussed because both overexpression and inactivating mutations are found. A recent study on primary samples from patients with acute T-cell leukemia (T-ALL) revealed that most of them do not express WT1 proteins although they express WT1 mRNA. In our study, we investigated WT-1 expression in ten T-ALL cell lines established from leukemia/lymphoma patients. We show that consistent with the finding in primary T-ALL cells, most of the leukemic T-cell lines tested do not overexpress WT1 proteins. We found that leukemic T-cells overexpressing WT1 protein produce higher levels of CD95L and show elevated CD95L-mediated activation-induced cell death (AICD) compared to cells lacking or expressing low levels of WT1. Ectopic expression of WT1 in the WT1-nonexpressing leukemic T-cell line increases CD95L expression and elevates activation-induced apoptosis, whereas silencing WT1 expression in the WT1-overexpressing leukemic T-cell line by siRNA confers reduced CD95L expression and reduction in AICD. Chromatin immunoprecipitation and luciferase-promoter reporter analysis demonstrate that WT1 binds to and enhances CD95L promoter activity through the Egr-binding sites. Our study provides a new role of WT1 in regulation of CD95L-mediated cell death. 23872035 An easily accessible web-based minimization random allocation system for clinical trials. Minimization as an adaptive allocation technique has been recommended in the literature for use in randomized clinical trials. However, it remains uncommonly used due in part to a lack of easily accessible implementation tools. To provide clinical trialists with a robust, flexible, and readily accessible tool for implementing covariate-adaptive biased-coin randomization. We developed a Web-based random allocation system, MinimRan, that applies Pocock-Simon (for trials with 2 or more arms) and 2-way (currently limited to 2-arm trials) minimization methods for trials using only categorical prognostic factors or the symmetric Kullback-Leibler divergence minimization method for trials (currently limited to 2-arm trials) using continuous prognostic factors with or without categorical factors, in covariate-adaptive biased-coin randomization. In this paper, we describe the system's essential statistical and computer programming features and provide as an example the randomization results generated by it in a recently completed trial. The system can be used in single- and double-blind trials as well as single-center and multicenter trials. We expect the system to facilitate the translation of the 3 validated random allocation methods into broad, efficient clinical research practice. 23640687 Drug-Induced Macular Edema. Macular edema constitutes a serious pathologic entity of ophthalmology resulting in vision loss with a remarkable impact on the quality of life of patients. It is the final common pathway of various systemic diseases and underlying intraocular conditions, with diabetes mellitus being the most frequent cause. Other causes include venous occlusive disease, intraocular surgery, and inflammatory conditions of the posterior segment of the eye. Macular edema is a recognized side effect of various systemic and local medications and requires special consideration among ophthalmologists and other clinicians. Recently, antidiabetic thiazolidinediones have been implicated in the development of macular edema, and a review of the English literature revealed that other systemically administered drugs like fingolimod, recently approved for relapsing forms of multiple sclerosis, the anticancer agents tamoxifen and the taxanes, as well as niacin and interferons have been reported to cause macular edema. Ophthalmologic pharmaceutical agents, like prostaglandin analogs, epinephrine, timolol, and ophthalmic preparation preservatives have also been reported to cause macular edema as an adverse event. The purpose of this article is to provide a short, balanced overview of the available evidence in this regard. The available data and the possible pathophysiologic mechanisms leading to the development of macular edema are discussed. Possible therapeutic strategies for drug-induced macular edema are also proposed. 23912530 Androgen therapy in women: for whom and when. Androgens play a primary role in female physiopathology. The age-related reduction in the production of ovarian and adrenal androgens may significantly affect women's health. The decline of circulating androgens results from a combination of two events: reduced ovarian production and aged-related decline in adrenal androgen synthesis. The relative androgen deficiency in pre- and postmenopausal women may induce impairment of sexual function, libido, well-being, energy and may contribute to reduced cognitive functions. Whether androgen deficiency also affects cardiovascular or bone biology in women during reproductive aging is still controversial. Both in the central nervous system and peripheral tissues, there are multiple ways whereby androgens target their specific actions through a particular tropism of the brain areas that are involved in sexual function, behavior and cognition. Among circulating available androgens that are involved in several domains of sexual response, adrenal androgens seem to be related to some sexual symptoms as well as diminished cognitive function in postmenopausal women. The possibilities of treating low sexual desire/hypoactive sexual desire disorder are multifaceted and should include the combination of both pharmacological treatments able to maximize biological signals that drive the sexual response as well as individualized psychosocial therapies to overcome personal and relational difficulties. Transdermal testosterone has been proved to be effective but the use of additional treatment like oral or vaginal dehydroepiandrosterone is still controversial, despite many evidences support it. The decision to treat premenopausal or postmenopausal women with signs/symptoms of androgen insufficiency is mainly based on the clinical judgment, together with estrogens co-administration and following informed consent related to the unknown long-term risks. 23052546 Development of the serotonergic cells in murine raphe nuclei and their relations with rhombomeric domains. The raphe nuclei represent the origin of central serotonergic projections. The literature distinguishes seven nuclei grouped into rostral and caudal clusters relative to the pons. The boundaries of these nuclei have not been defined precisely enough, particularly with regard to developmental units, notably hindbrain rhombomeres. We hold that a developmental point of view considering rhombomeres may explain observed differences in connectivity and function. There are twelve rhombomeres characterized by particular genetic profiles, and each develops between one and four distinct serotonergic populations. We have studied the distribution of the conventional seven raphe nuclei among these twelve units. To this aim, we correlated 5-HT-immunoreacted neurons with rhombomeric boundary landmarks in sagittal mouse brain sections at different developmental stages. Furthermore, we performed a partial genoarchitectonic analysis of the developing raphe nuclei, mapping all known serotonergic differentiation markers, and compared these results, jointly with others found in the literature, with our map of serotonin-containing populations, in order to examine regional variations in correspondence. Examples of regionally selective gene patterns were identified. As a result, we produced a rhombomeric classification of some 45 serotonergic populations, and suggested a corresponding modified terminology. Only a minor rostral part of the dorsal raphe nucleus lies in the midbrain. Some serotonergic neurons were found in rhombomere 4, contrary to the conventional assumption that it lacks such neurons. We expect that our reclassification of raphe nuclei may be useful for causal analysis of their differential molecular specification, as well as for studies of differential connectivity and function. 23946604 Appropriate treatment of acute sigmoid volvulus in the emergency setting. To investigate an appropriate strategy for the treatment of patients with acute sigmoid volvulus in the emergency setting. A retrospective review of 28 patients with acute sigmoid volvulus treated in the Department of Colorectal Surgery, Changhai Hospital, Shanghai from January 2001 to July 2012 was performed. Following the diagnosis of acute sigmoid volvulus, an initial colonoscopic approach was adopted if there was no evidence of diffuse peritonitis. Of the 28 patients with acute sigmoid volvulus, 19 (67.9%) were male and 9 (32.1%) were female. Their mean age was 63.1 ± 22.9 years (range, 21-93 years). Six (21.4%) patients had a history of abdominal surgery, and 17 (60.7%) patients had a history of constipation. Abdominal radiography or computed tomography was performed in all patients. Colonoscopic detorsion was performed in all 28 patients with a success rate of 92.8% (26/28). Emergency surgery was required in the other two patients. Of the 26 successfully treated patients, seven (26.9%) had recurrent volvulus. Colonoscopy is the primary emergency treatment of choice in uncomplicated acute sigmoid volvulus. Emergency surgery is only for patients in whom nonoperative treatment is unsuccessful, or in those with peritonitis. 23401373 Modulation of photophysics and pKa shift of the anti-cancer drug camptothecin in the nanocavities of supramolecular hosts. This article reports the pK(a) shift of an anti-cancer drug, 20(S)-camptothecin (CPT), upon encapsulation into the nanocavity of a cucurbit[7]uril (CB7) macrocycle. Steady-state, time-resolved fluorescence and electrospray ionisation mass spectrometry (ESI-MS) studies provide evidence for the formation of both 1:1 and 2:1 (CB7⋅CPT) stoichiometries. Astonishingly, we have found that protonation of CPT takes place at a higher concentration of macrocycle (≥50 μM) when the 2:1 stoichiometric complex develops. However, we did not find any proof for protonation of CPT when it is encased by a β-cyclodextrin cavity, which has a cavity size almost the same as that of CB7. Hence, we conclude that electron-rich carbonyl portals of CB7 have an important role in protonation of the drug in the 2:1 inclusion complex. Docking and semi-empirical quantum chemical calculations have been employed to gain an insight into the molecular picture of orientation of CPT in the inclusion complexes. It is clearly seen from the optimised structure of the 2:1 (CB7⋅CPT) inclusion complex that the quinoline nitrogen of CPT does not reside within either of the CB7 cavities, rather it is almost sandwiched between two CB7 rings, and therefore, it experiences huge electron density exerted by both carbonyl portals of the macrocycles. As a result, the pK(a) of CPT shifts from 1.2 to 6.2. Finally, controlled release of the drug has been achieved through the introduction of NaCl, which is rich in cells, as an external stimulus. We hope this recognition-mediated binding and release mechanism can be useful for activation of the drug and controlled release of the drug in therapeutic uses. 23153671 An antioxidant regenerating system for continuous quenching of free radicals in chronic wounds. A novel antioxidant regenerating system consisting of cellobiose dehydrogenase (CDH), cellobiose, and phenolic antioxidants with potential application for continuous quenching of free radical species in chronic wounds was developed. This antioxidant regenerating system, continuously quenched in situ produced ·NO, O(2)(·-) and OH· radicals and the produced oxidized phenolic antioxidants were regenerated back to their original parent compounds by CDH using cellobiose as electron donor. This system therefore prevented the accumulation of oxidized phenolic antioxidants. Interestingly, this study also challenges the relevance of using total antioxidant capacities values of plant crude extracts obtained using biologically none relevant radical species like (2,2-diphenyl-1-picrylhydrazyl (DPPH)), Trolox Equivalent Antioxidant Capacity (TEAC), etc. when applied as medicinal remedies. This is because methoxylated phenolic antioxidants like sinapic acid, ferulic acid; 2,6-dimethoxyphenol readily donate their electrons to these radicals (DPPH, TEAC, etc.), thereby greatly influencing the total antioxidant values although this study showed that they are not at all effective in quenching O(2)(·-) radicals and again are not the most effective quenchers of NO and OH radicals as demonstrated during this study. 23852609 Stratified meta-analysis of intermittent pneumatic compression of the lower limbs to prevent venous thromboembolism in hospitalized patients. Optimal thromboprophylaxis for patients at risk of bleeding remains uncertain. This meta-analysis assessed whether intermittent pneumatic compression (IPC) of the lower limbs was effective in reducing venous thromboembolism and whether combining pharmacological thromboprophylaxis with IPC would enhance its effectiveness. Two reviewers searched MEDLINE, EMBASE, and the Cochrane controlled trial register (1966-February 2013) for randomized, controlled trials and assessed the outcomes and quality of the trials independently. Trials comparing IPC with pharmacological thromboprophylaxis, thromboembolic deterrent stockings, no prophylaxis, and a combination of IPC and pharmacological thromboprophylaxis were considered. Trials that used IPC <24 hours or compared different types of IPC were excluded. A total of 16 164 hospitalized patients from 70 trials met the inclusion criteria and were subjected to meta-analysis. IPC was more effective than no IPC prophylaxis in reducing deep vein thrombosis (7.3% versus 16.7%; absolute risk reduction, 9.4%; 95% confidence interval [CI], 7.9-10.9; relative risk, 0.43; 95% CI, 0.36-0.52; P<0.01; I(2)=34%) and pulmonary embolism (1.2% versus 2.8%; absolute risk reduction, 1.6%; 95% CI, 0.9-2.3; relative risk, 0.48; 95% CI, 0.33-0.69; P<0.01; I(2)=0%). IPC was also more effective than thromboembolic deterrent stockings in reducing deep vein thrombosis and appeared to be as effective as pharmacological thromboprophylaxis but with a reduced risk of bleeding (relative risk, 0.41; 95% CI, 0.25-0.65; P<0.01; I(2)=0%). Adding pharmacological thromboprophylaxis to IPC further reduced the risk of deep vein thrombosis (relative risk, 0.54; 95% CI, 0.32-0.91; P=0.02; I(2)=0%) compared with IPC alone. IPC was effective in reducing venous thromboembolism, and combining pharmacological thromboprophylaxis with IPC was more effective than using IPC alone. 23632168 Decisive role of Reelin signaling during early stages of Alzheimer's disease. Alzheimer's disease (AD) is one of the largest unmet medical concerns of our society. Around 25 million patients worldwide together with their families are still waiting for an effective treatment. We have recently initiated a re-evaluation of our knowledge of the molecular and cellular mechanisms underlying sporadic AD. Based on the existing literature, we have proposed a mechanistic explanation of how the late-onset form of the disease may evolve on the cellular level. Here, we expand this hypothesis by addressing the pathophysiological changes underlying the early and almost invariant appearance of the neurofibrillary tangles, the only reliable correlate of the cognitive status, in distinct brain areas and their consistent "spread" along interconnected neurons as the disease advances. In this review we present and discuss novel evidence that the extracellular signaling protein Reelin, expressed along the olfactory and limbic pathways in the adult brain, might hold a key to understand the earliest steps of the disease, highlighting the olfactory pathway as the brain's Achilles heel involved in the initiation of the pathophysiological characteristic of late-onset AD. 23617834 MicroRNA-32 (miR-32) regulates phosphatase and tensin homologue (PTEN) expression and promotes growth, migration, and invasion in colorectal carcinoma cells. BACKGROUND: Colorectal carcinoma (CRC) is one of the leading causes of cancer-related mortality worldwide. MicroRNAs (miRNAs, miRs) play important roles in carcinogenesis. MiR-32 has been shown to be upregulated in CRC. In this study, we identified the potential effects of miR-32 on some important biological properties of CRC cells, and clarified the regulation of PTEN by miR-32. METHODS: The effect of miR-32 on PTEN expression was assessed in CRC cell lines with miR-32 mimics/inhibitor to increase/decrease miR-32 expression. Furthermore, the roles of miR-32 in regulating CRC cells biological properties were analyzed with miR-32 mimics/inhibitor-transfected cells. The 3[prime]-untranslated region (3[prime]-UTR) of PTEN combined with miR-32 was verified by dual-luciferase reporter assay. RESULTS: Gain-of-function and loss-of-function studies showed that overexpression of miR-32 promoted SW480 cell proliferation, migration, and invasion, reduced apoptosis, and resulted in downregulation of PTEN at a posttranscriptional level. However, miR-32 knock-down inhibited these processes in HCT-116 cells and enhanced the expression of PTEN protein. In addition, we further identified PTEN as the functional downstream target of miR-32 by directly targeting the 3[prime]-UTR of PTEN. CONCLUSIONS: Our results demonstrated that miR-32 was involved in tumorigenesis of CRC at least in part by suppression of PTEN. 23828484 CT-guided radiofrequency ablation following high-dose chemotherapy of a liver-metastasizing pancreatoblastoma with tumor thrombus in the portal vein. Pancreatoblastoma is a rare neoplasm encountered most commonly in infants and young children. Unresectable or metastatic tumors have a poor prognosis despite adjuvant chemotherapy or radiotherapy. We report the successful use of CT-guided radiofrequency ablation subsequent to intensive chemotherapy in an 8-year-old girl with liver-metastasizing pancreatoblastoma and with right and segment 4 portal vein tumor thrombosis. She has been in remission for 3 years. 23765177 Cause-Specific Mortality and 30-year Relative Survival of Crohn's Disease and Ulcerative Colitis. Data from the northern hemisphere suggest that patients with ulcerative colitis (UC) have similar survival to the general population, whereas mortality in Crohn's disease (CD) is increased by up to 50%. There is a paucity of data from the southern hemisphere, especially in Australia. A prevalence cohort (1977-1992) of patients with inflammatory bowel disease (IBD) diagnosed after 1970 was studied. Survival status data and causes of death up to December 2010 were extracted from the National Death Index. Relative survival analysis was carried out separately for men and women. Of 816 cases (384 men, 432 women; 373 CD, 401 UC, 42 indeterminate colitis), 211 (25.9%) had died by December 2010. Median follow-up was 22.2 years. Relative survival of all patients with IBD was not significantly different from the general population at 10, 20, and 30 years of follow-up. Separate analyses of survival in CD and UC also showed no differences from the general population. There was no difference in survival between patients diagnosed earlier (1971-1979) or later (1980-1992). At least 17% of the deaths were caused by IBD. Fatal cholangiocarcinomas were more common in IBD (P < 0.001), and fatal colorectal cancers more common in UC (P = 0.047). In Australia, IBD patient survival is similar to the general population. In contrast to data from Europe and North America, survival in CD is not diminished in Australia. IBD caused direct mortality in 17%, especially as biliary and colorectal cancers are significant causes of death. 23934686 Platelet-derived growth factor B induces senescence and transformation in normal human fibroblasts. Normal cells enter a senescent state upon aberrant oncogenic signals and this response inhibits tumor initiation and progression. It is now well admitted that intracellular and membrane localized oncogenes can illicit oncogene induced senescence. However, the effect of mitogenic growth factor on cellular senescence is so far largely unknown. Here we show that normal human dermal fibroblasts display a complex response to Platelet derived growth factor B (PDGFB) expression. Indeed, PDGFB expression induces, in the same cell population, both senescence and cellular transformation. Remarkably both populations are sustained with passages suggesting that transformed cells eventually enter a senescent state. This senescence state is p53 dependent as inhibiting the p53 pathway blocks the ability of PDGFB to induce senescence and results in strong cellular transformation increase upon PDGFB expression. The relevance of these observations is supported by the fact that human dermatofibrosarcoma protuberans, skin tumors arising from constitutive PDGFB production with little aggressiveness, also display some senescence hallmarks. Together these data support the view that PDGFB, a mitogenic growth factor, has a limited ability to induce senescence. We propose that this low level of senescence might decrease the transforming ability of this factor without totally abolishing it. 22546614 Metabotropic glutamate 7 (mGlu7) receptor: a target for medication development for the treatment of cocaine dependence. Brain glutamate has been shown to play an important role in reinstatement to drug seeking, a behavior considered to be of relevance to relapse to drug taking in humans. Therefore, glutamate receptors, in particular metabotropic glutamate (mGlu) receptors, have become important targets for medication development for the treatment of drug dependence. In this review article, we focus on the mGlu7 receptor subtype, and discuss recent findings with AMN082, a selective mGlu7 receptor allosteric agonist, in animal models with relevance to drug dependence. Systemic or local administration of AMN082 into the nucleus accumbens (NAc), a critical brain region involved in reward and drug dependence processes, inhibited the reinforcing and motivational effects of cocaine, heroin and ethanol, as assessed by the intravenous drug self-administration procedure. In addition, AMN082 inhibited the reward-enhancing effects induced by cocaine, as assessed in the intracranial self-stimulation procedure, and cocaine- or cue-induced reinstatement of drug-seeking behavior. In vivo microdialysis studies indicated that systemic or intra-NAc administration of AMN082 significantly decreased extracellular γ-aminobutyric acid (GABA) and elevated extracellular glutamate, but had no effect on extracellular dopamine in the NAc, suggesting that a non-dopaminergic mechanism underlies the effects of AMN082 on the actions of cocaine. Further, data indicated that AMN082-induced changes in glutamate were the net effect of two actions: one is the direct inhibition of glutamate release by activation of mGlu7 receptors on glutamatergic neurons; another is the indirect increases of glutamate release mediated by decreases in GABA transmission. These increases in extracellular glutamate functionally antagonized cocaine-induced inhibition of NAc-ventral pallidum GABAergic neurotransmission, and therefore, the rewarding effects of cocaine. In addition, elevated extracellular glutamate activated presynaptic mGlu2/3 autoreceptors which in turn inhibited cocaine priming- or cue-induced enhancement of glutamate release and reinstatement of drug-seeking behavior. Taken together, these findings suggest that the mGlu7 receptor is an important target for medication development for the treatment of drug dependence. AMN082 or other mGlu7 receptor allosteric agonists may have potential as novel pharmacotherapies for cocaine addiction. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23624193 Nuclear DNA content variation and evolution in liverworts. Across embryophytes there is a significant range in DNA content, both in regards to genome size (total DNA in an unreduced chromosome complement) and degree of endoreduplication (when DNA replication not followed by division resulting in various ploidy levels within the same individual). However, there is little information available on DNA content evolution in liverworts, the likely sister group to all other living plants. This study seeks to detect a phylogenetic structure in the variation in genome size and degree of endopolyploidy within liverworts. Furthermore, we test the hypothesis that shifts in breeding systems and genome size are correlated, as polyploidy is suggested to be a possible mechanism for the evolution of monoecy in liverworts and could therefore be associated with larger genome sizes. Genome size was determined for 67 liverwort species from 33 families using flow cytometry. Estimates for 48 species and 16 families are new to science. A phylogeny was reconstructed using the plastid gene rbcL. Over all taxa analyzed, there was a considerable range in genome size estimates with 1C-values from 0.27 pg (Jungermannia rubra) to 20.46 pg (Phyllothallia fuegiana). Large genome sizes were also found in the Haplomitriopsida. None of the liverwort species showed evidence of endopolyploidy. Although some taxa may be polyploids, a correlation between shifts in genome size and breeding system is lacking. Importantly, genome size variation in liverworts exhibits strong phylogenetic signal (Pagel's λ=0.99955). 23634844 Reversible Sliding in Networks of Nanowires. This work demonstrates that metal nanowires in a percolating network can reversibly slide across one another. Reversible sliding allows networks of metal nanowires to maintain electrical contact while being stretched to strains greater than the fracture strain for individual nanowires. This phenomenon was demonstrated by using networks of nanowires as compliant electrodes for a dielectric elastomer actuator. Reversible nanowire sliding enabled actuation to a maximum area strain of 200%, and repetitive cycling of the actuator to an area strain of 25% over 150 times. During actuation, the transmittance of the network increased 4.5 times, from 13% to 58%. Compared to carbon-based compliant electrodes, networks of metal nanowires can actuate across a broader range of optical transmittance. The widely tunable transmittance of nanowire-based actuators allows for their use as a light valve. 23832127 Enhanced catalytic activity in strained chemically exfoliated WS2 nanosheets for hydrogen evolution. Efficient evolution of hydrogen through electrocatalysis at low overpotentials holds tremendous promise for clean energy. Hydrogen evolution can be easily achieved by electrolysis at large potentials that can be lowered with expensive platinum-based catalysts. Replacement of Pt with inexpensive, earth-abundant electrocatalysts would be significantly beneficial for clean and efficient hydrogen evolution. To this end, promising results have been reported using 2H (trigonal prismatic) XS2 (where X  =  Mo or W) nanoparticles with a high concentration of metallic edges. The key challenges for XS2 are increasing the number and catalytic activity of active sites. Here we report monolayered nanosheets of chemically exfoliated WS2 as efficient catalysts for hydrogen evolution with very low overpotentials. Analyses indicate that the enhanced electrocatalytic activity of WS2 is associated with the high concentration of the strained metallic 1T (octahedral) phase in the as-exfoliated nanosheets. Our results suggest that chemically exfoliated WS2 nanosheets are interesting catalysts for hydrogen evolution. 23811115 Detection of sentinel lymph node metastases in cervical cancer: Assessment of KRT19 mRNA in the one-step nucleic acid amplification (OSNA) method. The purpose of this study was to examine the utility of the one-step nucleic acid amplification (OSNA) assay using cytokeratin (CK) 19 (KRT19) messenger RNA (mRNA) for the detection of sentinel lymph node (SLN) metastases in cervical cancer patients. To determine a cutoff value, KRT19 mRNA was assessed by OSNA assay using 239 lymph nodes (LNs) (217 histopathologically negative LNs and 22 positive LNs). A cutoff value was determined by statistical analysis of the copy numbers obtained by OSNA assay. Subsequently, performance evaluation of the OSNA assay (applying the cutoff value above) on 130 SLNs (32 patients) was used to investigate (through concordance) whether the OSNA assay exhibited diagnostic performance equivalent to the two-mm interval histopathological examination. Two hundred fifty copies/μL of KRT19 mRNA in the OSNA assay appeared to be an optimal cutoff value. In performance evaluation of the OSNA assay, we identified five positive SLNs and 125 negative SLNs by OSNA assay using KRT19 mRNA, exhibiting 96.2% agreement with two-mm interval histopathological examination. Our results indicated that the KRT19 mRNA OSNA assay can detect LN metastases as accurately as two-mm interval histopathological examination and thus may be an effective additional or alternative method for a rapid intra-operative examination of SLNs in cervical cancer. 23744068 Differential Contribution of Insulin and Amino Acids to the mTORC1-Autophagy Pathway in the Liver and Muscle. Autophagy is a highly inducible intracellular degradation process. It is generally induced by nutrient starvation and suppressed by food intake. Mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1) is considered to be the major regulator of autophagy, but the precise mechanism of in vivo regulation remains to be fully characterized. Here, we examined the autophagy-suppressive effect of glucose, insulin, and amino acids in the liver and muscle in mice starved for 1 day. Refeeding after starvation with a standard mouse chow rapidly suppressed autophagy in both tissues, and this suppression was inhibited by rapamycin administration almost completely in the liver and partially in muscle, confirming that mTORC1 is indeed a crucial regulator in vivo. As glucose administration showed no major suppressive effect on autophagy, we examined the role of insulin and amino acids using hyperinsulinemic-euglycemic clamp and intravenous amino acid infusion techniques. Insulin administration showed a clear effect on the mTORC1-autophagy pathway in muscle, but had only a very weak effect in the liver. By contrast, amino acids were able to regulate the mTORC1-autophagy pathway in the liver, but less effectively in muscle. These results suggest that autophagy is differentially regulated by insulin and amino acids in a tissue-dependent manner. 23204147 The Frequency of Adjusted Renal Dosing of Tenofovir DF and Its Effects on Patient Outcomes. Tenofovir disoproxil fumarate (TDF), a nucleotide reverse transcriptase inhibitor used in the treatment of human immunodeficiency virus (HIV) and hepatitis B, is renally eliminated and has been associated with renal toxicities. Dose adjustments are recommended for patients with creatinine clearance (CrCL) <50 mL/min. We retrospectively determined the frequency in which HIV clinic providers adjusted TDF doses in patients with CrCL <50 mL/min over a 2-year period and compared clinical outcomes in patients who had TDF dose adjustments based on CrCL <50 mL/min versus those who did not. Thirty-nine patients with CrCL <50 mL/min were identified. Dose-adjusted patients (N = 9) continued their TDF-based antiretroviral regimens for 21 months longer following the first CrCL < 50 mL/min (P = .0193) and had gains in CD4 cell counts over 12 months (P = .0009). There were no statistically significant differences in CrCL or percentage of patients with detectable HIV-1 RNA at 6 and 12 months following first CrCL <50 mL/min in those who did versus did not have a TDF dose adjustment. In summary, HIV providers often failed to dose-adjust TDF in patients with CrCL <50 mL/min, but dose-adjusted patients appeared to stay on their TDF-based regimens longer and have greater gains in CD4 cells. Larger, prospective studies are needed to validate these results. 23946420 Near-unity nuclear polarization with an open-source 129Xe hyperpolarizer for NMR and MRI. The exquisite NMR spectral sensitivity and negligible reactivity of hyperpolarized xenon-129 (HP(129)Xe) make it attractive for a number of magnetic resonance applications; moreover, HP(129)Xe embodies an alternative to rare and nonrenewable (3)He. However, the ability to reliably and inexpensively produce large quantities of HP(129)Xe with sufficiently high (129)Xe nuclear spin polarization (PXe) remains a significant challenge-particularly at high Xe densities. We present results from our "open-source" large-scale (∼1 L/h) (129)Xe polarizer for clinical, preclinical, and materials NMR and MRI research. Automated and composed mostly of off-the-shelf components, this "hyperpolarizer" is designed to be readily implementable in other laboratories. The device runs with high resonant photon flux (up to 200 W at the Rb D1 line) in the xenon-rich regime (up to 1,800 torr Xe in 500 cc) in either single-batch or stopped-flow mode, negating in part the usual requirement of Xe cryocollection. Excellent agreement is observed among four independent methods used to measure spin polarization. In-cell PXe values of ∼90%, ∼57%, ∼50%, and ∼30% have been measured for Xe loadings of ∼300, ∼500, ∼760, and ∼1,570 torr, respectively. PXe values of ∼41% and ∼28% (with ∼760 and ∼1,545 torr Xe loadings) have been measured after transfer to Tedlar bags and transport to a clinical 3 T scanner for MR imaging, including demonstration of lung MRI with a healthy human subject. Long "in-bag" (129)Xe polarization decay times have been measured (T1 ∼38 min and ∼5.9 h at ∼1.5 mT and 3 T, respectively)-more than sufficient for a variety of applications. 22887720 Microindentation for in vivo measurement of bone tissue material properties in atypical femoral fracture patients and controls. Atypical femoral fractures (AFF) associated with long-term bisphosphonates (LTB) are a growing concern. Their etiology is unknown, but bone material properties might be deteriorated. In an AFF series, we analyzed the bone material properties by microindentation. Four groups of patients were included: 6 AFF, 38 typical osteoporotic fractures, 6 LTB, and 20 controls without fracture. Neither typical osteoporotic fractures nor controls have received any antiosteoporotic medication. A general laboratory workup, bone densitometry by dual-energy X-ray absorptiometry (DXA), and microindentation testing at the tibia were done in all patients. Total indentation distance (Total ID), indentation distance increase (IDI), and creep indentation distance (Creep ID) were measured (microns). Age-adjusted analysis of covariance (ANCOVA) was used for comparisons. Controls were significantly younger than fracture groups. Bisphosphonate exposure was on average 5.5 years (range 5 to 12 years) for the AFF and 5.4 years (range 5 to 8 years) for the LTB groups. Total ID (microns) showed better material properties (lower Total ID) for controls 36 (± 6; mean ± SD) than for AFF 46 (± 4) and for typical femoral fractures 47 (± 13), respectively. Patients on LTB showed values between controls and fractures, 38 (± 4), although not significantly different from any of the other three groups. IDI values showed a similar pattern 13 (± 2), 16 (± 6), 19 (± 3), and 18 (± 5). After adjusting by age, significant differences were seen between controls and typical (p < 0.001) and atypical fractures (p = 0.03) for Total ID and for IDI (p < 0.001 and p < 0.05, respectively). There were no differences in Creep ID between groups. Our data suggest that patients with AFF have a deep deterioration in bone material properties at a tissue level similar to that for the osteoporotic fracture group. The LTB group shows levels that are in between controls and both type of fractures, although not statistically different. These results suggest that bisphosphonate therapy probably does not put the majority of patients at risk for AFF. 23851283 In vivo mapping of RNA-RNA interactions in Staphylococcus aureus using the endoribonuclease III. Ribonucleases play key roles in gene regulation and in the expression of virulence factors in Staphylococcus aureus. Among these enzymes, the double-strand specific endoribonuclease III (RNase III) is a key mediator of mRNA processing and degradation. Recently, we have defined, direct target sites for RNase III processing on a genome-wide scale in S. aureus. Our approach is based on deep sequencing of cDNA libraries obtained from RNAs isolated by in vivo co-immunoprecipitation with wild-type RNase III and two cleavage-defective mutants. The use of such catalytically inactivated enzymes, which still retain their RNA binding capacity, allows the identification of novel RNA substrates of RNase III. In this report, we will summarize the diversity of RNase III functions, discuss the advantages and the limitations of the approach, and how this strategy identifies novel mRNA targets of small non-coding RNAs in S. aureus. 23842143 Molecular identification of Mycobacterium avium subspecies paratuberculosis in oral biopsies of Crohn's disease patients. Oral lesions may be found in patients with Crohn's disease (CD), in a percentage up to 20%. The aim of this study was to investigate a possible relationship between Mycobacterium avium subsp. paratuberculosis (MAP) and oral lesions in CD patients. 23 oral biopsies were examined performing IS900 Nested PCR; 9 of them were positive: 8 from CD patients and 1 from a control. Our purpose is to go on with this study, amplifying the number of subjects examined and testing subjects with oral lesions related to diseases other than CD to verify the specific association between MAP and oral lesions in CD patients. 23635031 Carbon Dioxide Clathrate Hydrates: Selective Role of Intermolecular Interactions and Action of the SDS Catalyst. The ability of a single sodium dodecyl sulfate (SDS) molecule to promote the formation of CO2 clathrate hydrates in water (as it does for methane) has been investigated at the microscopic level. For this purpose, the components of the related force field were carefully formulated and assembled following the procedure previously adopted for methane. The properties of the whole system (as well as those of its components) were analyzed by carrying out extended molecular dynamics calculations. Contrary to what happens for methane, the calculations singled out the propensity of CO2 (pure) water clusters to form clathrate hydrate-like structures and the disappearance of such propensity when a single SDS molecule is added to the clusters. This feature was found to be due to the strong interaction of carbon dioxide with the additive that makes the SDS molecule lose its shape together with its ability to drive water molecules to form a suitable cage. 23952189 Combination use of atomoxetine hydrochloride and olanzapine in the treatment of attention-deficit/hyperactivity disorder with comorbid disruptive behavior disorder in children and adolescents 10-18 years of age. Abstract Objective: The aim of this study was to assess the use of atomoxetine and olanzapine in combination to treat attention-deficit/hyperactivity disorder (ADHD) and comorbid disruptive behaviors in children and adolescents 10-18 years of age. Methods: Eleven subjects ages 10-18 received open-label atomoxetine and olanzapine for a 10 week treatment period. Patients were assessed at baseline, 2 weeks, 4 weeks, 6 weeks, and 10 weeks (posttreatment). ADHD improvement was measured through the ADHD Rating Scale (ADHD-RS) (Investigator and Parent ratings). Aggression was measured through the Modified Overt Aggression Scale (MOAS). Results: The combined use of atomoxetine and olanzapine resulted in statistically significant improvement in ADHD symptoms and overt aggression from baseline to posttreatment. As evidenced by a 33% reduction in symptoms on the ADHD-RS-I and the MOAS, 73% of patients were considered responders to ADHD treatment, whereas 55% responded to treatment for aggression. Both medications were generally well tolerated. Olanzapine treatment was associated with significant weight gain. Patients gained, on average, 3.9 kg. throughout the treatment period. Conclusions: These data provide initial evidence that combination use of atomoxetine and olanzapine for the treatment of ADHD and comorbid disruptive behaviors was effective in reducing ADHD symptoms and aggressive behavior in a 10 week treatment period. 23821160 Expression of orphan nuclear receptor NR4A2 in gastric cancer cells confers chemoresistance and predicts an unfavorable postoperative survival of gastric cancer patients with chemotherapy. NR4A2, an orphan nuclear receptor essential in the generation of dopaminergic neurons, has been recently linked to inflammation and cancer. This study sought to identify the role of NR4A2 on chemoresistance and postoperative prognosis of gastric cancer (GC). NR4A2 was transfected into GC cells to investigate its effects on chemoresistance to 5-fluorouracil and the tumorigenicity in nude mice. This study also investigated prostaglandin E2 (PGE2 )-induced NR4A2 expression and its effect on chemoresistance. Surgical specimens from patients with stage I through III GC were examined immunohistochemically for NR4A2 expression. Median follow-up time was 76 months for 245 patients. Ectopic expression of NR4A2 significantly increased the chemoresistance and attenuated 5-fluorouracil-induced apoptosis. Transient treatment of GC cells with PGE2 significantly upregulated NR4A2 expression via the protein kinase A pathway and increased the chemoresistance. Ectopic expression of NR4A2 significantly increased the tumorigenicity. In clinical samples, NR4A2 was preferentially expressed in lymphocytes and epithelial cytoplasm in adjacent mucosa. High expression of NR4A2 (immunoreactive score ≥ 3) in cancer cells significantly predicted an unfavorable postoperative disease-specific survival of patients with stage I to III GC (P = .011), especially for those who received 5-fluorouracil-based chemotherapy (P = .016). This effect was not found in those without the chemotherapy. In multivariate Cox analyses, age, TNM (tumor/node/metastasis) stage, and high NR4A2 expression significantly predicted an unfavorable postoperative survival. High NR4A2 expression in GC cells confers chemoresistance, attenuates 5-fluorouracil-induced apoptosis, and predicts an unfavorable survival, especially for those who received chemotherapy. NR4A2 might serve as a prognostic and predictive factor and therapeutic target for patients with GC. Cancer 2013. © 2013 American Cancer Society. 23874714 Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assembly. To find histone deacetylase 3 (HDAC3)-selective inhibitors, a series of 504 candidates was assembled using "click chemistry", by reacting nine alkynes bearing a zinc-binding group with 56 azide building blocks in the presence of Cu(I) catalyst. Screening of the 504-member triazole library against HDAC3 and other HDAC isozymes led to the identification of potent and selective HDAC3 inhibitors T247 and T326. These compounds showed potent HDAC3 inhibition with submicromolar IC50s, whereas they did not strongly inhibit other isozymes. Compounds T247 and T326 also induced a dose-dependent selective increase of NF-κB acetylation in human colon cancer HCT116 cells, indicating selective inhibition of HDAC3 in the cells. In addition, these HDAC3-selective inhibitors induced growth inhibition of cancer cells, and activated HIV gene expression in latent HIV-infected cells. These findings indicate that HDAC3-selective inhibitors are promising candidates for anticancer drugs and antiviral agents. This work also suggests the usefulness of the click chemistry approach to find isozyme-selective HDAC inhibitors. 23252795 Adverse events associated with mTOR inhibitors. INTRODUCTION: The mTOR (mechanistic target of rapamycin, formerly known as mammalian target of rapamycin) kinase is centrally involved in the regulation of cell growth and metabolism in response to intra- and extracellular energetic stimuli and growth factors. The importance of mTOR in health and diseases has fueled the development of molecules that inhibit mTOR signaling, including rapalogs (sirolimus, temsirolimus, everolimus and deforolimus), which complex with FK506-binding protein 12 (FK-BP12) to inhibit mTOR complex 1 (MTORC1) activity in an allosteric manner, or the more recent ATP-competitive mTOR inhibitors (mTORi), which target the catalytic site of the enzyme. However, clinical development of these mTORi has revealed that these drugs produced numerous side effects that could be serious and/or debilitating. Despite pharmacological efforts to develop drugs with an improved safety profile, these side effects are often unpredictable and may frequently preclude the efficiency of mTORi. AREAS COVERED: The objective of this review is to perform a comprehensive survey of the safety profiles of various rapalog-based therapies from the available clinical literature. The authors will discuss the potential mechanisms of these therapies, taking into account the knowledge of the biological pathways regulated by mTOR. EXPERT OPINION: A better prevention and management of mTORi-related side effects requires the identification of alterations in related biological pathways that will help to delineate therapeutic targets. 23945071 Human motion classification based on a textile integrated and wearable sensor array. A system for classification of motion patterns is presented based on a non-contact magnetic induction monitoring device. This device is textile integrated, wearable, and able to measure pulse and respiratory activity. The proposed classifiers are a neural network, support vector machine, and a decision tree algorithm generated by bootstrap aggregating. Their performance is compared using a data set comprising five different types of motion patterns. In addition, the dependence of the misclassification error on the input sample length is investigated. The features used for classification were based on information derived by discrete wavelet transform and on lower and higher order statistical measures. With the presented magnetic induction device, all tested classifiers were able to classify the defined motion pattern with an accuracy of over 93%. The proposed bootstrap aggregating decision tree algorithm produces the best classification performance (accuracy of 96%). The support vector machine classifier shows the least dependence on the sample length. 23063655 Regulation of Ca(V)2 calcium channels by G protein coupled receptors. Voltage gated calcium channels (Ca²⁺ channels) are key mediators of depolarization induced calcium influx into excitable cells, and thereby play pivotal roles in a wide array of physiological responses. This review focuses on the inhibition of Ca(V)2 (N- and P/Q-type) Ca²⁺-channels by G protein coupled receptors (GPCRs), which exerts important autocrine/paracrine control over synaptic transmission and neuroendocrine secretion. Voltage-dependent inhibition is the most widespread mechanism, and involves direct binding of the G protein βγ dimer (Gβγ) to the α1 subunit of Ca(V)2 channels. GPCRs can also recruit several other distinct mechanisms including phosphorylation, lipid signaling pathways, and channel trafficking that result in voltage-independent inhibition. Current knowledge of Gβγ-mediated inhibition is reviewed, including the molecular interactions involved, determinants of voltage-dependence, and crosstalk with other cell signaling pathways. A summary of recent developments in understanding the voltage-independent mechanisms prominent in sympathetic and sensory neurons is also included. This article is part of a Special Issue entitled: Calcium channels. 22349829 TGF-β1-dependent L1CAM expression has an essential role in macrophage-induced apoptosis resistance and cell migration of human intestinal epithelial cells. Patients with chronic inflammatory bowel disease (IBD) have an increased risk to develop colorectal cancer (CRC) particularly after long duration of the disease. Chronic inflammation of the intestinal mucosa is characterized by a marked enrichment of immune cells such as macrophages as well as by high expression of cytokines and growth factors including transforming growth factor-beta 1 (TGF-β1). The adhesion molecule L1CAM mediates chemoresistance and migration of tumor cells and is elevated in CRC tissues being associated with metastatic spread and poor prognosis for the patients. In this study, we examine the role of TGF-β1-induced L1CAM expression and macrophages in malignant transformation of intestinal epithelial cells. We demonstrate that TGF-β1 stimulation leads to a Slug-dependent upregulation of L1CAM expression already in the colonic intestinal epithelial cell line NCM460 thereby enhancing cell motility and apoptosis resistance. Accordingly, NCM460 cells acquired a migratory and apoptosis-resistant phenotype if transfected with L1CAM. Immunohistochemistry of colonic biopsies revealed considerable L1CAM expression in intestinal epithelial cells in tissues from IBD patients but not in normal colonic tissues. Moreover, L1CAM expression increased with duration of disease being associated with the presence of CD33+ macrophages. Coculture with macrophages generated from monocyte colony-stimulating factor (MCSF)-treated monocytes led to the upregulation of Slug and L1CAM in NCM460 cells thereby elevating cell motility and apoptosis resistance. Pharmacological inhibition of TGF-β1 signalling abolished expression of Slug and L1CAM in cocultured NCM460 cells resulting in decreased cell migration and apoptosis resistance. In conclusion, these data provide new insights into the mechanisms by which IBD promotes malignant transformation of intestinal epithelial cells and underscore the role of L1CAM and macrophages in this scenario. 23746363 Formation of perfluorinated surfactants from precursors by indigenous microorganisms in groundwater. The formation of perfluorinated surfactants (PFSs) from their precursors in waters is of concern. In this study, the formation of PFSs through biodegradation of precursors was measured in incubation tests. Indigenous microorganisms in groundwater were able to biodegrade perfluorooctane sulfonamide (FOSA) to yield perfluorooctane sulfonate (PFOS). The addition of nutrients and soil promoted the formation. A 42-d incubation test using sources of groundwater recharge showed that PFOS, perfluorooctanoate, and perfluorononanoate were significantly and remarkably (⩾1.5×) formed from precursors in street runoff through biodegradation, but not in rainwater or wastewater effluent. Significant formation of PFSs from precursors in street runoff was observed. 23467071 Corticosterone responses and personality in birds: Individual variation and the ability to cope with environmental changes due to climate change. Birds can respond to an internal or external stimulus with activation of the HPA axis and secretion of corticosterone. There is considerable individual variation in corticosterone responses, and individual responses can be very different from the mean response for a group of birds. Corticosterone responses and behavioural responses to environmental stimuli are determined by individual characteristics called personality. It is proposed that birds with low corticosterone responses and proactive personalities are likely to be more successful (have greater fitness) in constant or predictable conditions, whilst birds with reactive personalities and high corticosterone responses will be more successful in changing or unpredictable conditions. The relationship between corticosterone responses and fitness thus depends on the prevailing environmental conditions, so birds with either low or high corticosterone responses can have the greatest fitness and be most successful, but in different situations. It is also proposed that birds with reactive personalities and high corticosterone responses will be better able to cope with environmental changes due to climate change than birds with proactive personalities and relatively low corticosterone responses. Phenotypic plasticity in corticosterone responses can be quantified using a reaction norm approach, and reaction norms can be used to determine the degree of plasticity in corticosterone responses of individual birds, and mean levels of plasticity in responses of species of birds. Individual corticosterone responses and personality, and reaction norms for corticosterone responses, can in future be used to predict the ability of birds to cope with environmental changes due to climate change. 23902302 Efficacy and safety using autotransfusion system with postoperative shed blood following total knee arthroplasty in haemophilia. The purpose of this study was to evaluate the efficacy and safety of postoperative wound drain salvage and autotransfusion system in haemophilic patients undergoing elective total knee arthroplasty (TKA). No literature exists on reinfusing drained blood in patient with haemophilia undergoing TKA. Eighty-eight knees of 66 patients received cemented TKA due to end-stage haemophilic arthropathy (group I; with autotransfusion in 59 knees, group II; without autotransfusion in 29 knees). In group I, the postoperative shed blood was transfused within 6 h after surgery. The amount of blood drainage and reinfused blood, rate and amount of allogenic transfusion, postoperative change of haemoglobin level, prothrombin time (PT) and activated partial thromboplastin time were analysed. The mean postoperative blood drainage was 932 ± 479 mL in group I and 830 ± 492 mL in group II (P > 0.05). The mean volume of blood reinfused was 530 ± 265 mL in group I. Allogenic transfusion was needed in six knees (10.2%) of group I and eight knees (27.6%) of group II (P = 0.036). The mean volume of allogenic transfusion was 480 ± 49 mL in group I and 1041 ± 691 mL in group II (P > 0.05). Changes of all the laboratory results before and after TKA showed no statistically significant difference except PT was prolonged in group I (P = 0.008) at postoperative day 1. Moreover, there was no significant complication related to either reinfusion or allogenic transfusion in both groups. This study showed that reinfusion of drained blood is a simple, safe and efficacious method in patients with haemophilia undergoing TKA. 23880525 Emotional communication in medical consultations with native and non-native patients applying two different methodological approaches. To explore the potential agreement between two different methods to investigate emotional communication of native and non-native patients in medical consultations. The data consisted of 12 videotaped hospital consultations with six native and six non-native patients. The consultations were coded according to coding rules of the Verona Coding definitions of Emotional Sequences (VR-CoDES) and afterwards analyzed by discourse analysis (DA) by two co-workers who were blind to the results from VR-CoDES. The agreement between VR-CoDES and DA was high in consultations with many cues and concerns, both with native and non-native patients. In consultations with no (or one cue) according to VR-CoDES criteria the DA still indicated the presence of emotionally salient expressions and themes. In some consultations cues to underlying emotions are communicated so vaguely or veiled by language barriers that standard VR-CoDES coding may miss subtle cues. Many of these sub-threshold cues could potentially be coded as cues according to VR-CoDES main coding categories, if criteria for coding vague or ambiguous cues had been better specified. Combining different analytical frameworks on the same dataset provide us new insights on emotional communication. 23421631 Potential of nanocrystalline cellulose-fibrin nanocomposites for artificial vascular graft applications. The potential of synthesizing new nanocomposites from nanocrystalline cellulose (NCC) and fibrin for small-diameter replacement vascular graft (SDRVG) application was demonstrated. Periodate oxidation of NCC can augment reactive carbonyl groups on NCC and facilitate its cross-linking with fibrin. NCC-fibrin nanocomposites were synthesized, composed of homogeneously dispersed oxidized NCC (ONCC) in a fibrin matrix, with fibrin providing elasticity and ONCC providing strength. The maximum strength and elongation of the nanocomposites were determined by Atomic Force Microscopy (AFM) and compared with a native blood vessel. The manipulation of degree of oxidation of NCC and the NCC-to-fibrin ratio resulted in the variation of strength and elongation of the nanocomposites, indicating that the nanocomposites can be tailored to conform to the diverse mechanical properties of native blood vessels. A mechanistic understanding of the molecular interactions of ONCC and fibrin was illustrated. This study established fundamental information to utilizing NCC for SDRVG applications. 23879836 Transplanted Induced Pluripotent Stem Cells Mitigate Oxidative Stress and Improve Cardiac Function through the Akt Cell Survival Pathway in Diabetic Cardiomyopathy. Recent evidence suggests transplanted stem cells improve left ventricular function in diabetic induced cardiomyopathy (DICM). However, little is known about the mechanisms by which induced pluripotent stem (iPS) cells or factors released from these cells inhibit adverse cardiac remodeling in DICM. The present study was designed to determine molecular mediators and pathways regulated by transplanted iPS cells and their conditioned media (CM) in DICM. Animals were divided into four experimental groups such as control, streptozotocin (STZ), STZ+iPS-CM, and STZ+iPS cells. Experimental diabetes was induced in C57BL/6 mice by intraperitoneal STZ injections (100 mg/kg body weight for 2 consecutive days). Following STZ injections, iPS cells or CM was given intravenously for 3 consecutive days. Animals were humanely killed, and hearts were harvested at D14. Animals transplanted with iPS cells or CM demonstrated a significant reduction in apoptosis, mediated by Akt upregulation and ERK1/2 downregulation, and inhibition of interstitial fibrosis via MMP-9 suppression compared with the STZ group. Oxidative stress was significantly hindered in iPS cell and CM groups as evidenced by diminished pro-oxidant expression and enhanced antioxidant (catalase and MnSOD) concentration. Echocardiography data suggest a significant improvement in cardiac function in cells and CM groups in comparison to STZ. In conclusion, our data strongly suggest that iPS cells and CM attenuate oxidative stress and associated apoptosis and fibrosis. Moreover, we also suggest that increased antioxidant levels, decreased adverse cardiac remodeling, and improved cardiac function is mediated by iPS CM and cells in DICM through multiple autocrine and paracrine mechanisms. 23322473 Arsenic present in the soil-vine-wine chain in vineyards situated in an old mining area in Trentino, Italy. The present study follows arsenic (As) transfer through the chain of soil-vine-leaves-grapes-wine to assess the possible risk of arsenic intake related to consuming grapes and wines produced in 10 vineyards located in a mining area rich in this element. The results are compared with date from 18 uncontaminated areas. In the soil, the content of As extracted with acqua regia and that extracted with ammonium acetate, were analyzed. Leaves and berries were analyzed after washing with acidified aqueous solution and acid mineralization in a closed vessel, whereas wines were simply diluted before analysis. All analyses were performed using an inductively coupled plasma mass-spectrometer. The aqua regia extractable As concentration in soil ranged from 3.7 to 283 mg/kg, whereas available As varied from 18 to 639 µg/kg, and As total concentration ranged from 16.3 to 579 µg/kg dry weight in leaves and from <0.1 to 36.8 µg/kg dry weight in grapes. Arsenic levels in wines were always below 1.62 µg/L, with higher concentration in red wines than in white wines. Significant and positive correlations between the As concentrations in soils, leaves, and berries are highlighted, with the samples collected near the mining area having significantly higher values. Nevertheless, As levels in wines were always well below the limit (200 µg/L) suggested by the International Organization of Vine and Wine. 23857007 Resolvin D1 reduces deterioration of tight junction proteins by upregulating HO-1 in LPS-induced mice. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is characterized by increased pulmonary permeability with high mortality. Resolvin D1 (RvD1), which has potent anti-inflammatory and pro-resolving activity, can attenuate pulmonary edema in the animal model of ALI. However, the mechanism underlying the protection of RvD1 on pulmonary edema is still unknown. Here we explore the effects and mechanism of RvD1 on the disruption of tight junction protein that results in the permeability edema in a model of lipopolysaccharide (LPS)-induced ALI. The severity of pulmonary edema was assessed by wet-to-dry rate and Evans blue infiltration; expressions of tight junction (TJ) proteins occludin and zona occludin-1 (ZO-1) were examined by immunofluorescence staining and western blot; mRNA in lung tissue was studied by real time-PCR; the TUNEL kit was performed for the detection of apoptosis of pulmonary barrier. Twenty-four hours after LPS inhalation by mice, wet-to-dry rate and Evans blue infiltration indicated that pretreatment with RvD1 relieved the pulmonary edema and pulmonary capillary permeability. Moreover, RvD1 attenuated the LPS-induced deterioration of TJ protein ZO-1 and occludin significantly. And we found that RvD1 increased heme oxygenase-1 (HO-1) expression contributed to the protection on the deterioration of TJs. In addition, we found that RvD1 could reduce pulmonary cellular apoptosis in LPS-induced mice. In conclusion, RvD1 possesses the ability that relieves the pulmonary edema and restores pulmonary capillary permeability and reduces disruption of TJs in LPS-induced ALI of mice, at least in part, by upregulating HO-1 expression.Laboratory Investigation advance online publication, 15 July 2013; doi:10.1038/labinvest.2013.80. 23955075 Salivary Cortisol and Cold Pain Sensitivity in Female Twins. There is a dearth of knowledge about the link between cortisol and pain sensitivity. We examined the association of salivary cortisol with indices of cold pain sensitivity in 198 female twins and explored the role of familial confounding. Three-day saliva samples were collected for cortisol levels and a cold pressor test was used to collect pain ratings and time to threshold and tolerance. Linear regression modeling with generalized estimating equations examined the overall and within-pair associations. Lower diurnal variation of cortisol was associated with higher pain ratings at threshold (p = 0.02) and tolerance (p < 0.01). The relationship of diurnal variation with pain ratings at threshold and tolerance was minimally influenced by familial factors (i.e., genetics and common environment). Understanding the genetic and non-genetic mechanisms underlying the link between HPA axis dysregulation and pain sensitivity may help to prevent chronic pain development and maintenance. 22497568 Improving oral absorption via drug-loaded nanocarriers: absorption mechanisms, intestinal models and rational fabrication. Although it is acknowledged that the main impediment of orally administered therapeutic agents is their extensive and changeable pre-systemic metabolism, low absorption and instability in harsh environment of the gastrointestinal (GI) tract are also main influential factors, resulting into inadequate and erratic drug bioavailability. To overcome these shortcomings, nanotechnology has offered new promising strategies to prevent and treat a wide variety of diseases by employing different oral drug-carrier structures capable to enhance therapeutic effects and minimize the toxicity of healthy organs or cells. This review, in general, elucidates some considerable features of in vitro oral drug delivery in three different parts. The first one summarizes the main challenges for oral drug delivery and available absorption mechanisms. The second part embodies an in-depth discussion on the role of the intestinal absorption models used to predict permeability, cellular uptake or even toxicity of nanoparticles, resulting into the design of nanocarriers with optimum efficacy for oral delivery. The third section of the literature is devoted, more particularly, to nanocarriers developed for oral absorption in the past few years, including the behavior of nanovehicles upon oral administration with respect to membrane permeability, retention properties and stability, as well as methods which may lengthen residence time in the GI environment or improve drug absorption. 23850841 Network-based target ranking for polypharmacological therapies. With the growing understanding of complex diseases, the focus of drug discovery has shifted from the well-accepted "one target, one drug" model, to a new "multi-target, multi-drug" model, aimed at systemically modulating multiple targets. In this context, polypharmacology has emerged as a new paradigm to overcome the recent decline in productivity of pharmaceutical research. However, finding methods to evaluate multicomponent therapeutics and ranking synergistic agent combinations is still a demanding task. At the same time, the data gathered on complex diseases has been progressively collected in public data and knowledge repositories, such as protein-protein interaction (PPI) databases. The PPI networks are increasingly used as universal platforms for data integration and analysis. A novel computational network-based approach for feasible and efficient identification of multicomponent synergistic agents is proposed in this paper. Given a complex disease, the method exploits the topological features of the related PPI network to identify possible combinations of hit targets. The best ranked combinations are subsequently computed on the basis of a synergistic score. We illustrate the potential of the method through a study on Type 2 Diabetes Mellitus. The results highlight its ability to retrieve novel target candidates, which role is also confirmed by the analysis of the related literature. 23857127 Studies toward the First Stereoselective Total Synthesis of (±)-Quinolizidine 195C and Other Transformations. Starting from a thio-substituted 4-quinolizidinone, a series of C-6 alkylated derivatives with a trans C-6, C-9a relationship was synthesized. Further transformations led to the first stereoselective total synthesis of the structure proposed for (±)-quinolizidine 195C, the major alkaloid isolated from the skin extracts of the Madagascan frog Mantella betsileo. Since the spectral data of the synthetic and natural products differed significantly, the true structure of (±)-quinolizidine 195C remains uncertain. 23827378 Early communication in preterm infants following intervention in the NICU. Despite ongoing improvements in clinical care, preterm infants experience a variety of stressors in the first weeks of life, including necessary medical procedures, which may affect development. Some stress-reduction programmes based in the Neonatal Intensive Care Unit (NICU) have reported a positive impact on development. In particular, trials of the Mother-Infant Transaction Program (MITP) have shown positive short and longer term effects, and are based on training parents to recognise and minimise stress responses in preterm infants. To evaluate the impact on early developmental milestones of an enhanced MITP (PremieStart) delivered over an extended period in the NICU. This was a parallel 2-group randomised controlled trial involving 109 women with 123 infants born at <30weeks gestation assessed initially at term-equivalent age and then at 6months' corrected-age. Intervention mothers were more sensitive in providing infant care, stressed their infants less, showed greater awareness of, and responded more appropriately to, negative infant cues (p<0.05 in each case). Intervention infants displayed significantly lower stress when being bathed by mothers at term-equivalent age (p<0.05). At 6months corrected-age, intervention infants showed higher mean scores on the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist. The strongest effects appeared in Symbolic behaviour (p=0.05) and this was reflected in the Total score (p<0.05). As significant cognitive and language deficits are reported in longitudinal studies of preterm children, an intervention that improves early infant communication abilities is promising, especially since previous research suggests that the strongest benefits may emerge at later ages. 23943256 The 3.5-year survival rates of primary molars treated according to three treatment protocols: a controlled clinical trial. This study aimed to test the hypothesis that there is no difference in the survival rates of molars treated according to the conventional restorative treatment (CRT) using amalgam, atraumatic restorative treatment (ART) using high-viscosity glass ionomer, and ultraconservative treatment (UCT) protocol after 3.5 years. Cavitated primary molars were treated according to CRT, ART, and UCT (small cavities were restored with ART and medium/large cavities were daily cleaned with toothpaste/toothbrush under supervision). Molar extractions resulting from toothache, sepsis, or pulp exposure were failures. The Kaplan-Meier method was used to estimate the survival curves. The numbers of treated teeth, among the 302 6-7-year-old children, were 341 (CRT), 244 (ART), and 281 (for UCT group: 109 small ART, 166 open cavities, and 6 combinations). Protocol groups were similar at baseline regarding gender and mean decayed missing filled tooth score, but not regarding age and type of surface. The numbers of molars extracted were 22 (CRT), 16 (ART), and 26 (UCT). Fistulae were most often recorded. After 3.5 years, the cumulative survival rate ±â€‰standard error for all molars treated was 90.9 ±â€‰2.0 % with CRT, 90.4 ±â€‰2.4 % with ART, and 88.6 ±â€‰1.9 % with UCT (p = 0.13). Only a type of surface effect was observed over the 3.5-year period: survival rates for molars were higher for single- than for multiple-surface cavities. There was no difference in the cumulative survival rates of primary molars treated according to the CRT, ART, and UCT protocols over a 3.5-year period. Keeping cavities in primary molars biofilm-free might be another treatment option alongside restoring such cavities through conventional and ART protocols. 23752975 Role of macrophage-derived hypoxia-inducible factor (HIF)-1α as a mediator of vascular remodelling. Excessive vascular remodelling leads to progression of a wide range of vasculopathies, and the immune response to intimal injuries is crucial in this process. This vascular remodelling occurs in the hypoxic microenvironment and is closely related to the immune system. Macrophages play a key role in immunological-cell-mediated arterial remodelling. In this study, we clarified the role of macrophage-derived hypoxia-inducible factor (HIF-1α) in vascular remodelling. Wire-induced femoral arterial injury was inflicted in mice lacking the macrophage-specific HIF-1α gene and in their wild-type counterparts. The mutant mice showed both suppressed wire-induced neointimal thickening and decreased infiltration of inflammatory cells in the adventitia, compared with wild-type mice. Studies to clarify the mechanism of restrained vascular remodelling in the mutant mice revealed decreased production of pro-inflammatory cytokines by the activated macrophages and suppressed macrophage migration activity in the mutant mice. Gene expressions of the HIF-1α-deficient macrophages positively correlated with the phenotypic profile of M2 macrophages and negatively correlated with that of M1 macrophages. Our results show that HIF-1α in macrophages plays a crucial role in promoting vascular inflammation and remodelling. As decreasing HIF-1α activity in macrophages may prevent the progression of vascular remodelling, HIF-1α may be a possible therapeutic target in vascular diseases. 23490311 Pediatric diabetic ketoacidosis, fluid therapy, and cerebral injury: the design of a factorial randomized controlled trial. Treatment protocols for pediatric diabetic ketoacidosis (DKA) vary considerably among centers in the USA and worldwide. The optimal protocol for intravenous (IV) fluid administration is an area of particular controversy, mainly in regard to possible associations between rates of IV fluid infusion and the development of cerebral edema (CE), the most common and the most feared complication of DKA in children. Theoretical concerns about associations between osmotic fluid shifts and CE have prompted recommendations for conservative fluid infusion during DKA. However, recent data suggest that cerebral hypoperfusion may play a role in cerebral injury associated with DKA. Currently, there are no existing data from prospective clinical trials to determine the optimal fluid treatment protocol for pediatric DKA. The Pediatric Emergency Care Applied Research Network FLUID (FLuid therapies Under Investigation in DKA) study is the first prospective randomized trial to evaluate fluid regimens for pediatric DKA. This 13-center nationwide factorial design study will evaluate the effects of rehydration rate and fluid sodium content on neurological status during DKA treatment, the frequency of clinically overt CE and long-term neurocognitive outcomes following DKA. 23872592 Secondhand smoke exposure and intermittent claudication: a Scotland-wide study of 4231 non-smokers. Active smoking is an important risk factor for peripheral arterial disease. In contrast, published evidence on the association with secondhand smoke (SHS) is very limited. The aim of this study was to examine the association between SHS exposure and intermittent claudication (IC) among middle aged non-smokers. Multivariate logistic regression analyses were used to adjust for potential confounders. The Scottish Health Survey, a pan-Scotland, representative survey of the general population. We conducted a cross-sectional study using the Scottish Health Surveys undertaken between 1998 and 2010. Inclusion was restricted to participants aged >45 years. Of the 4231 confirmed non-smokers (self-reported non-smokers with salivary cotinine concentrations <15 ng/mL), 134 (3.2%) had IC based on the Edinburgh Claudication Questionnaire. There was evidence of a dose relationship, whereby the risk of IC increased with increasing cotinine concentration. Following adjustment for potential confounders, participants with a cotinine concentration ≥2.7 ng/mL were still significantly more likely to have IC (OR 1.76, 95% CI 1.04 to 3.00; p=0.036) compared with those with a cotinine concentration <0.7 ng/mL. Among non-smokers, 5.6% (95% CI -0.8% to 11.7%) of cases of IC were attributable to cotinine concentrations ≥2.7 ng/mL and a further 3.6% (95% CI -6.6% to 12.8%) to cotinine concentrations of 0.7-2.6 ng/mL. As with coronary heart disease and stroke, SHS exposure was independently associated with IC. Our findings add to the published evidence in support of protecting the general public from SHS exposure. 23815596 Vitamin D supplementation and risk of respiratory tract infections: A meta-analysis of randomized controlled trials. Abstract Background: It is well-documented that serum levels of 25-hydroxyvitamin D (25-OHD) are inversely associated with the risk of respiratory tract infections (RTIs). However, whether or not vitamin D supplementation prevents RTIs remains inconclusive. The aim of this study was to evaluate the role of vitamin D supplementation in preventing RTIs in healthy populations by performing a meta-analysis of randomized controlled trials (RCTs). Methods: RCTs regarding the association between vitamin D supplementation and the risk of RTIs were identified by searching PubMed, Embase, and Cochrane databases through January 2013. Reference lists of retrieved articles were also reviewed. Either a fixed-effects or, in the presence of heterogeneity, a random-effects model was used to calculate the pooled preventive effects. Results: Seven RCTs involving 4827 participants were included in this meta-analysis. The pooled relative risk (RR) for subjects administered with vitamin D compared with control groups was 0.98 (95% confidence interval 0.93-1.03, p = 0.45). Meta-regression analyses showed almost no impact on the RR of age, vitamin D dosing regimen, and length of follow-up. Omission of any single trial had little impact on the pooled risk estimates. No evidence of publication bias was observed. Conclusions: Our findings do not support the routine use of vitamin D supplementation for RTI prevention in healthy populations. Larger studies are needed to investigate the effects of vitamin D supplementation on RTI prevention in various populations and to further clarify the influences of age, vitamin D dosing regimen, baseline levels of vitamin D, and study length. 23529860 Synthesis, antimicrobial evaluation and molecular modelling of novel sulfonamides carrying a biologically active quinazoline nucleus. A novel series of quinazolines 5-10, triazoloquinazolines 11-17 and triazinoquinazoline 19 bearing a biologically active sulfonamide moiety were synthesized, utilizing methyl 2-isothiocyanato benzoate 2. Some of the newly synthesized compounds revealed promising bacterial growth inhibition, compared with the ampicillin, as the reference drug. A LigandScout approach-generated pharmacophore model for the Staph aureus bacteria growth inhibition was done. The degree of fitting of the test set compounds (3, 4, 6, 8, 11, 17) to the generated hypothetical model revealed a qualitative measure of the more or less microbial inhibition of Staphylococcus aureus. Compounds (7, 8, 10, 12, 15, 17 and 22), which revealed significant activity, are able to effectively satisfy the proposed pharmacophore geometry, using the energy accessible conformers (E conf < 20 kcal/mol). 23666897 Solvent-assisted directed self-assembly of spherical microdomain block copolymers to high areal density arrays. The fabrication process for 5 Tb/in(2) bit patterns using solvent-assisted directed self-assembly is investigated. The N-methyl-2-pyrrolidone solvent vapor-annealing method was used to achieve good long-range lateral ordering of low-molecular-weight polystyrene-block-polydimethylsiloxane with a lattice spacing of 11 nm on flat Si substrates, PS modified substrates and lithographically patterned substrates, respectively. 23302712 Comparative toxicity of eight metals on freshwater fish. Two freshwater fish, Rasbora sumatrana (Cyprinidae) and Poecilia reticulata (guppy; Poeciliidae), were exposed to a range of eight heavy metals (copper (Cu), cadmium (Cd), zinc (Zn), lead (Pb), nickel (Ni), iron (Fe), aluminium (Al), and manganese (Mn)) at varied concentrations for 96 h in the laboratory. Mortality was assessed and median lethal concentrations (LC(50)) were calculated. It was observed that the LC(50) values increased with a decrease in mean exposure times, for all metals and for both fish types. The 96-h LC(50) values for Cu, Cd, Zn, Pb, Ni, Fe, Al, and Mn were 0.006, 0.10, 0.46, 0.63, 0.83, 1.71, 1.53, and 5.71 mg/L for R. sumatrana and 0.038, 0.17, 1.06, 1.99, 15.62, 1.46, 6.76, and 23.91 mg/L for P. reticulata, respectively. The metal toxicity trend for R. sumatrana and P. reticulata from most to least toxic was Cu > Cd > Zn > Pb > Ni > Al > Fe > Mn and Cu > Cd > Zn > Fe > Pb > Al > Ni > Mn, respectively. Results indicated that Cu was the most toxic metal on both fish, and R. sumatrana was more sensitive than P. reticulata to all the eight metals. 23856805 Predictive factors of diagnostic accuracy of CT-guided transthoracic fine-needle aspiration for solid noncalcified, subsolid and mixed pulmonary nodules. The aim of this study was to analyse factors predicting the diagnostic accuracy of computed tomography (CT)-guided transthoracic fine-needle aspiration (TTFNA) for solid noncalcified, subsolid and mixed pulmonary nodules, with particular attention to those responsible for false negative results with a view to suggesting a method for their correction. From January 2007 to March 2010, we retrospectively reviewed the CT images of 198 patients of both sexes (124 males and 74 females; mean age, 70 years; range age, 44-90) used for the guidance of TTFNA of pulmonary nodules. Aspects considered were: lesion size and density, distance from the pleura, and lesion site. Multiplanar reformatted images (MPR) were retrospectively obtained in the sagittal and axial oblique planes relative to needle orientation. The overall diagnostic accuracy of TTFNA CTguided biopsy was 86% for nodules between 0.7 and 3 cm, 83.3% for those between 0.7 and 1.5 cm, and 92% for those between 2 and 3 cm. Accuracy was 95.1% for solid pulmonary nodules, 84.6% for mixed nodules, and 66.6% for subsolid nodules. The diagnostic accuracy of CT-guided TTFNA in relation to the distance between the nodule and the pleural plane was 95.6% for lesions adhering to the pleura and 83.5% for central ones. The diagnostic accuracy was 84.2% for the pulmonary upper lobe nodules, 85.3% for the lower lobe and 90.9% for those in the lingula and middle lobe. In 75% of false negative and inadequate/insufficient cases the needle was found to lie outside the lesion, after reconstruction of the needle path by MPR. The positive predictive factors of CT-guided TTFNA are related to the nodule size, density and distance from the pleural plane. The most common negative predictive factor of CT-guided TTFNA is the wrong position of the needle tip, as observed in the sagittal and axial oblique sections of the MPR reconstructions. The diagnostic accuracy of CT-guided TTFNA can therefore be improved by using the MPR technique to plan the needle path during the FNA procedure. 23886912 Pyocalycosis: A Report of Two Cases of Complicated Hydrocalycosis. Hydrocalycosis is defined as cystic dilatation of a major calyx with a demonstrable connection to the renal pelvis and an epithelial lining of the cyst wall. Although this condition has long been known, there are no sufficient data concerning this pathology in the literature. In this study, we present two complicated hydrocalycosis - 'pyocalycosis' - and discussed the therapeutic approaches. © 2013 S. Karger AG, Basel. 23906627 Hematological improvement during iron-chelation therapy in myelodysplastic syndromes: The experience of the "Rete Ematologica Lombarda" To analyze the unpredicted event of hematological improvement (HI) during iron-chelation therapy (ICT), we reviewed a series of 53 myelodysplastic patients with transfusion dependency in a retrospective study involving 8 centers afferent to the "Rete Ematologica Lombarda". According to the IWG response criteria published in the year 2000, we observed erythroid responses in 19 patients (35.1%), 5 major (9.2%) and 14 minor (25.9%). In the assessable patients, platelet response was 8/13 (61%) and neutrophil response was 13/17 (76.4%). Only in patients with erythroid improvement, multilineage responses were observed. Apparently, patients with greater erythropoiesis dysfunction may take more advantage. 23867873 Analysis of volatile organic compounds of bacterial origin in chronic gastrointestinal diseases. The aim of this study was to determine whether volatile organic compounds (VOCs) present in the headspace of feces could be used to diagnose or distinguish between chronic diseases of the gastrointestinal tract and apparently healthy volunteers. A total of 87 people were recruited, divided between 4 categories: healthy volunteers (n = 19), Crohn's disease (n = 22), ulcerative colitis (n = 20), and irritable bowel syndrome (n = 26). They each supplied fecal samples before, and except for the healthy volunteers, after treatment. Fecal samples were incubated in a sample bag with added purified air at 40°C and headspace samples were taken and concentrated on thermal sorption tubes. Gas chromatography-mass spectrometry then desorbed and analyzed these. The concentrations of a selection of high-abundance compounds were determined and assessed for differences in concentration between the groups. Crohn's disease samples showed significant elevations in the concentrations of ester and alcohol derivates of short-chain fatty acids and indole compared with the other groups; indole and phenol were elevated in ulcerative colitis and irritable bowel syndrome but not at a statistically significant level. After treatment, the levels of many of the VOCs were significantly reduced and were more similar to those concentrations in healthy controls. The abundance of a number of VOCs in feces differs markedly between Crohn's disease and other gastrointestinal conditions. Following treatment, the VOC profile is altered to more closely resemble that of healthy volunteers. 23404171 Extended Right Hepatectomy in a Liver with a Non-bifurcating Portal Vein: the Hanging Maneuver Protects the Portal System in the Presence of Anomalies. Variations in portal vein anatomy occur in 20-35 % of individuals. A non-bifurcating portal vein (PV) was suspected on preoperative imaging in a patient with a large right lobe hepatocellular carcinoma. The single PV curved within the liver parenchyma from right to left supplying second-order branches along its course. Utilizing the hanging maneuver, an extended right hemihepatectomy was safely performed. This approach allowed for preservation of the main PV and its left-sided branches while easily identifying the second-order right branches for ligation. Knowledge of portal vein variations and identification preoperatively by cross-sectional imaging are critical. The hanging maneuver aids in the preservation of the main portal vein and its left-sided branches during right hemihepatectomy in the presence of portal vein anomalies, and this technique can be used to improve safety in hepatobiliary surgery. 23751120 Copper chaperone Atox1 interacts with the metal-binding domain of Wilson's disease protein in cisplatin detoxification. Human copper transporters ATP7B (Wilson's disease protein) and ATP7A (Menkes' disease protein) have been implicated in tumour resistance to cisplatin, a widely used anticancer drug. Cisplatin binds to the copper-binding sites in the N-terminal domain of ATP7B, and this binding may be an essential step of cisplatin detoxification involving copper ATPases. In the present study, we demonstrate that cisplatin and a related platinum drug carboplatin produce the same adduct following reaction with MBD2 [metal-binding domain (repeat) 2], where platinum is bound to the side chains of the cysteine residues in the CxxC copper-binding motif. This suggests the same mechanism for detoxification of both drugs by ATP7B. Platinum can also be transferred to MBD2 from copper chaperone Atox1, which was shown previously to bind cisplatin. Binding of the free cisplatin and reaction with the cisplatin-loaded Atox1 produce the same protein-bound platinum intermediate. Transfer of platinum along the copper-transport pathways in the cell may serve as a mechanism of drug delivery to its target in the cell nucleus, and explain tumour-cell resistance to cisplatin associated with the overexpression of copper transporters ATP7B and ATP7A. 22488710 Pre-existing fas ligand (FasL) in cancer cells elicits tumor-specific protective immunity, but delayed induction of FasL expression after inoculation facilitates tumor formation. Overexpression of Fas ligand (FasL) in cancer cells elicits potential antitumor effects via recruitment of neutrophils. Conversely, FasL-expressing tumors may counterattack tumor-infiltrating lymphocytes by delivering apoptotic death signals via Fas/FasL interactions, which may lead to tumor escape. In order to distinguish the role of FasL in antitumor activity and tumor progression, Lewis lung carcinoma cells (LLC-1) were used to establish the cell line LLC-FasL, in which FasL expression was repressed by doxycycline (Dox) treatment and induced in the absence of Dox. LLC-FasL cells promote tumor regression when expressing FasL, whereas tumor outgrowth is observed by depletion of FasL expression. To investigate whether initial expression of FasL during tumor formation is critical for FasL-mediated tumor regression, Dox-treated LLC-FasL cells were inoculated into Dox-treated mice, but Dox treatment was stopped 5 days after inoculation. When low cell numbers were inoculated, we observed 80% survival and no tumor formation, whereas no mice survived inoculation with high cell numbers, despite the delayed induction of FasL by Dox withdrawal. The inoculation of a high density of cells may establish a favorable tumor microenvironment before the expression of FasL. Our findings demonstrate that FasL may elicit antitumor activity when it is initially present on injected cancer cells and thus can act prior to tumor microenvironment formation. Furthermore, a well-established tumor microenvironment abrogates FasL-mediated antitumor activity. © 2012 Wiley Periodicals, Inc. 23831183 The effect of sugar solution type, sugar concentration and viscosity on the imbibition and energy intake rate of bumblebees. Nectar is an essential resource for bumblebees and many other flower-visiting insects. The main constituents of nectar are sugars, which vary in both composition and concentration between plant species. We assessed the influence of sugar concentration, sugar solution viscosity and sugar solution composition on the imbibition and energy intake rate of bumblebees, Bombus impatiens Cresson (Hymenoptera: Apidae). To do this, we measured their rate of solution intake for 49 different sugar solution treatments, which varied in both sugar composition and concentration. In general, the imbibition rates of bumblebees were found to increase with increasing sugar concentration, probably due to their preference for high sugar concentrations, up to a concentration of 27% (w/w), at which point solutions reached a threshold viscosity of approximately 1.5-1.6mPa.s. Above this threshold, the increasing viscosity of the solutions physically inhibited the imbibition rates of bees, and imbibition rate began to decrease as the concentration increased. Nevertheless, bumblebee energy intake rate increased with increasing concentration up to about 42-56%. Although we found that sugar solution composition had an impact on both imbibition and energy intake rate, its effect was not as straightforward as that of sugar concentration and viscosity. 23590223 Ticagrelor: positive, negative and misunderstood properties as a new antiplatelet agent. Dual antiplatelet therapy is essential for the management of acute coronary syndrome. In particular, combination therapy using aspirin with a platelet ADP (i.e. P2Y12 ) receptor inhibitor, such as clopidogrel, prasugrel or, more recently, ticagrelor, has been recommended for patients with acute coronary syndrome. Pharmacological agents that reversibly inhibit platelet aggregation without metabolic activation in the liver are believed to reduce cardiovascular mortality compared with the current drug of choice for antiplatelet therapy, namely clopidogrel. These findings are based on a multicentre, double-blind, double-dummy, randomized controlled trial. Numerous factors are postulated to contribute to the improved survival of patients who take ticagrelor compared with those taking clopidogrel, including the risk of myocardial infarction, heart failure, arrhythmia and bleeding. In addition, clopidogrel may lead to a much higher incidence of infection. Although ticagrelor has recently been approved for use in the US and exhibits superiority over other antiplatelet agents, certain concerns remain regarding its use, including lung injury and dyspnoea, thus raising the issue of its true superiority over clopidogrel or prasugrel. Recent studies into ticagrelor report conflicting data, with certain aspects of its mechanisms of action still not fully understood. Ticagrelor has beneficial effects following its clinical application, such as achieving overall higher reductions in mortality compared with the use of clopidogrel and prasugrel. Harmful effects associated with the use of ticagrelor include a higher incidence of dyspnoea and major bleeding compared with clopidogrel. 23561590 Two-year follow-up of outcomes of second-generation everolimus-eluting stents versus first-generation drug-eluting stents for stenosis of saphenous vein grafts used as aortocoronary conduits. Second-generation everolimus-eluting stents (EESs) have demonstrated superiority in efficacy and safety compared with first-generation drug-eluting stents (DESs) in the treatment of native coronary artery lesions. The present study evaluated and compared the safety and efficacy of EESs and first-generation DESs in saphenous vein graft lesions. The EES group consisted of 88 patients with 96 lesions, and the first-generation DES group consisted of 243 patients with 317 lesions (sirolimus-eluting stents, n = 212; paclitaxel-eluting stents, n = 105). The end points included target lesion revascularization, target vessel revascularization, major adverse cardiovascular events (composite of all-cause death, myocardial infarction, and target vessel revascularization), and definite stent thrombosis at 2 years. The groups had similar baseline characteristics and graft ages (128.1 ± 77.5 vs 132.4 ± 90.8 months, p = 0.686). The EES group had more type C lesions and less embolic protection device use. The peak postprocedure values of creatinine kinase-MB and troponin I were similar between the 2 groups. Overall, major adverse cardiovascular events occurred in 18.2% of EES patients and 35.0% of first-generation DES patients (p = 0.003), mainly driven by a lower target vessel revascularization rate (6.8% vs 24.5%, p <0.001). The target lesion revascularization rate was lower in the EES group (1.1% vs 11.6%, p = 0.005). Stent thrombosis was low and similar between the 2 groups (0% vs 0.8%, p = 1.000). On multivariate analysis, the type of DES implanted and graft age were the only independent predictors of major adverse cardiovascular events. In conclusion, the superiority of EESs compared with first-generation DESs shown in native artery lesions has been extended to saphenous vein graft lesions and should be considered as the DES of choice for this lesion type. 23846601 Acute complications of patients with pelvic fractures after pelvic angiographic embolization. Hemodynamically unstable patients with a pelvic fracture and arterial pelvic bleeding frequently are treated with pelvic angiographic embolization (PAE). PAE is reported to be a safe and effective method of controlling hemorrhage. However, the loss of blood supply and subsequent ischemia from embolization may lead to adverse consequences. We sought to determine (1) the frequency and types of complications observed after PAE; (2) the mortality after PAE; and (3) the clinical factors associated with complications and mortality after PAE. We conducted a retrospective case series descriptive study at a Level I trauma center. Using our institution's trauma registry, we isolated patients with pelvic fractures treated with PAE admitted between June 1999 and December 2007. Complications attributed to PAE occurring in the initial hospital stay were recorded. We identified 98 patients with pelvic fractures treated by PAE with an average hospital stay of 25.3 days. The complication rate was 11% and included six patients with gluteal muscle necrosis (6%), five with surgical wound breakdown (5%), four deep infections (4%), one superficial infection, two patients with of impotence (2%), and one with bladder necrosis. The mortality rate in the PAE group reached 20%. Bilateral embolization was performed in 100% of the patients with complications. Nonselective embolization was performed in 81% of patients with complications. All of the patients with gluteal necrosis had bilateral nonselective embolization. Bilateral or nonselective PAE is associated with significant complications during the initial hospital stay. The value of PAE should be weighed against its possible adverse consequences. Selective unilateral arterial embolization should be considered whenever possible. Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. 23356933 Mucinous Cystadenoma in the Lung of a Captive-born Moustached Tamarin (Saguinus mystax). A 2-year-old, captive-born, male moustached tamarin was subjected to necropsy examination after a fatal head trauma. A solitary, circumscribed, subpleural mass (0.6 cm diameter) was found in the right caudal lung lobe. The mass was diagnosed as a mucinous cystadenoma. Histochemical and immunohistochemical tests were performed to further characterize the tumour. Surfactant proteins A, B, C and D were not found in the neoplastic cells, suggesting that the tumour arose from a non-surfactant-producing alveolar lining cell. Pulmonary mucinous cystadenomas are uncommon benign tumours in man and have not been reported previously in animals. 23887230 Physical Exercise Induces Specific Adaptations Resulting in Reduced Organ Injury and Mortality During Severe Polymicrobial Sepsis. High physical activity levels are associated with wide-ranging health benefits, disease prevention, and longevity. In the present study, we examined the impact of regular physical exercise on the severity of organ injury and survival probability, as well as characteristics of the systemic immune and metabolic response during severe polymicrobial sepsis. Animal study. University laboratory. Male C57BL/6N mice. Mice were trained for 6 weeks by treadmill and voluntary wheel running or housed normally. Polymicrobial sepsis in mice was induced by injection of fecal slurry. Subsequently, mice were randomized into the following groups: healthy controls, 6 hours postsepsis, and 24 hours postsepsis. Blood and organ samples were collected and investigated by measuring clinical chemistry variables, cytokines, plasma metabolites, and bacterial clearance. Organ morphology and damage were characterized by histological staining. Physical exercise improved survival and the ability of bacterial clearance in blood and organs. The release of pro- and anti-inflammatory cytokines, including interleukin-6 and interleukin-10, was diminished in trained compared to untrained mice during sepsis. The sepsis-associated acute kidney tubular damage was less pronounced in pretrained animals. By metabolic profiling and regression analysis, we detected lysophosphatidylcholine 14:0, tryptophan, as well as pimelylcarnitine linked with levels of neutrophil gelatinase-associated lipocalin representing acute tubular injury (corrected R = 0.910; p < 0.001). We identified plasma lysophosphatidylcholine 16:0, lysophosphatidylcholine 17:0, and lysophosphatidylcholine 18:0 as significant metabolites discriminating between trained and untrained mice during sepsis. Regular physical exercise reduces sepsis-associated acute kidney injury and death. As a specific mechanism of exercise-induced adaptation, we identified various lysophosphatidylcholines that might function as surrogate for improved outcome in sepsis. 23561721 Management of gunshot wounds to the hand: a literature review. Hand trauma resulting from firearms is becoming more common in civilian life. In the past, as in wartime, infection was a main source of concern following firearm-related hand injuries, whereas in current civilian life with modern medical care, infection rates are actually low for such injuries. As infection is now of lesser concern, the focus should shift to improve functional outcomes. This review summarizes available literature regarding the management of gunshot wounds to the hand, with particular focus on functional outcomes. In conducting this review, we found that there is not comprehensive information regarding management of gunshot wounds to the hand, and literature discussing functional recovery of the hand is limited. Given the current evidence related to management of gunshot wounds to the hand, we believe that early debridement, antibiotic treatment, reconstruction, and rehabilitation offer patients the best chance for full functional recovery. 23564400 Clinical measures of disease in adult non-CF bronchiectasis correlate with airway microbiota composition. Despite the potentially important roles for infection in adult non-cystic fibrosis (CF) bronchiectasis disease progression, the bacterial species present in the lower airways of these patients is poorly characterised. To provide a comprehensive cross-sectional analysis of bacterial content of lower airway samples from patients with non-CF bronchiectasis using culture-independent microbiology. Paired induced sputum and bronchoalveolar lavage samples, obtained from 41 adult patients with non-CF bronchiectasis, were analysed by 16S ribosomal RNA gene pyrosequencing. Assessment of species distribution and dispersal allowed 'core' and 'satellite' bacterial populations to be defined for this patient group. Microbiota characteristics correlated with clinical markers of disease. 140 bacterial species were identified, including those associated with respiratory tract infections and opportunistic infections more generally. A group of core species, consisting of species detected frequently and in high abundance, was defined. Core species included those currently associated with infection in bronchiectasis, such as Pseudomonas aeruginosa, Haemophilus influenzae and Streptococcus pneumoniae, and many species that would be unlikely to be reported through standard diagnostic surveillance. These included members of the genera Veillonella, Prevotella and Neisseria. The comparative contribution of core and satellite groups suggested a low level of random species acquisition. Bacterial diversity was significantly positively correlated with forced expiratory volume in 1 s (FEV1) and bacterial community composition similarity correlated significantly with FEV1, neutrophil count and Leicester cough score. Characteristics of the lower airways microbiota of adult patients with non-CF bronchiectasis correlate significantly with clinical markers of disease severity. 23370290 L-type voltage-dependent calcium channel is involved in the snake venom group IA secretory phospholipase A2-induced neuronal apoptosis. Snake venom group IA secretory phospholipase A2 (sPLA2-IA) is known as a neurotoxin. Snake venom sPLA2s are neurotoxic in vivo and in vitro, causing synergistic neurotoxicity to cortical cultures when applied with toxic concentrations of glutamate. However, it has not yet been cleared sufficiently how sPLA2-IA exerts neurotoxicity. Here, we found sPLA2-IA induced neuronal cell death in a concentration-dependent manner. This death was a delayed response requiring a latent time for 6h. sPLA2-IA-induced neuronal cell death was accompanied with apoptotic blebbing, condensed chromatin, and fragmented DNA, exhibiting apoptotic features. NMDA receptor blockers suppressed the neurotoxicity of sPLA2-IA, but an AMPA receptor blocker did not. Interestingly, L-type voltage-dependent Ca(2+) channel (L-VDCC) blocker significantly protected neurons from the sPLA2-IA-induced apoptosis. On the other hand, neither N-VDCC blockers nor P/Q-VDCC blocker did. In conclusion, we demonstrated that sPLA2-IA induced neuronal cell death via apoptosis. Furthermore, the present study suggests that not only NMDA receptor but also L-VDCC contributed to the neurotoxicity of snake venom sPLA2-IA. 23788260 Classification of skin moles from optical spectropolarimetric images: a pilot study. A new skin-imaging method, which was developed recently, gives an informative image data about skin moles by collecting scattered polarized light reflected from their tissue area at different wavelengths and polarizations. This method is called as optical rotational spectropolarimetric imaging (ORSI), which scans the polarization states by continuously rotating a linearly polarized light incident on the lesion and collecting the reflected sequence of images. A novel method to distinguish cancerous from benign moles by analyzing the images obtained using this imaging system is proposed. The proposed method performs an automatic examination of the polarized images according to characteristics such as their cross-image local contrasts, large-scale homogeneity, border disorder, and asymmetry. The pilot study was conducted with 10 subjects, in which two ORSI image sequences at two different wavelengths were taken for each subject. Results show good separation between cancerous and benign moles and between benign moles with high dysplasia. 23418211 Lifetime physical activity and the risk of amyotrophic lateral sclerosis. It has been hypothesised that physical activity is a risk factor for developing amyotrophic lateral sclerosis (ALS), fuelled by observations that professional soccer players and Gulf War veterans are at increased risk. In a population based study, we determined the relation between physical activity and risk of sporadic ALS, using an objective approach for assessing physical activity. 636 sporadic ALS patients and 2166 controls, both population based, completed a semistructured questionnaire on lifetime history of occupations, sports and hobbies. To objectively compare the energy cost of a lifetime history of occupational and leisure time physical activities and to reduce recall bias, metabolic equivalent scores were assigned to each activity based on the Compendium of Physical Activities. ALS patients had significantly higher levels of leisure time physical activity compared with controls (OR 1.08, 95% CI 1.02 to 1.14, p=0.008). No significant difference was found between patients and controls in the level of vigorous physical activities, including marathons and triathlons, or in occupational activity. Cumulative measures of physical activity in quartiles did not show a dose-response relationship. An increased risk of ALS with higher levels of leisure time physical activity was found in the present study. The lack of association with occupational physical activity and the absence of a dose-response relationship strengthen the hypothesis that not increased physical activity per se but rather a genetic profile or lifestyle promoting physical fitness increases ALS susceptibility. 23887959 Reference ranges and distribution of placental volume by 3-dimensional virtual organ computer-aided analysis between 11 weeks and 13 weeks 6 days. Objectives- The purpose of this study was to determine the feasibility, reproducibility, and distribution of placental volume measurements according to the crown-rump length between 11 weeks and 13 weeks 6 days. Methods- Images were acquired in 128 pregnancies followed in Burgundy during first-trimester screening sonography using an abdominal 3-dimensional transducer. The placental volume was then calculated by the virtual organ computer-aided analysis method with a rotation angle of 30° by a single operator. Results- Placental volumes ranged from 33.3 to 107.6 cm(3) with a mean ± SD of 62.3 ± 14.8 cm(3); the 5th and 10th percentiles were 38.0 and 44.20 cm(3), respectively, whereas the 90th and 95th percentiles were 80.25 and 86.68 cm(3). An exponential relationship was found between placental volume and crown-rump length: ln placental volume = 0.018 × crown-rump length + 2.93425; ln SD = 0.15; r(2) = 0.58. Finally, the mean placental quotient, defined as the ratio of placental volume to crown-rump length, was 1 ± 0.1 cm(3)/mm; the respective percentile values were 0.74, 0.81, 1.18, and 1.29 cm(3)/mm. No associations were found between parity or smoking and the placental quotient or between obesity and the placental quotient. Intraobserver reproducibility was good, with a mean difference of 0.2 cm(3). Conclusions- Measurement of placental volume between 11 weeks and 13 weeks 6 days is reliable and reproducible and correlates strongly with crown-rump length. 23794369 Nanosegregation and neighbor-cation control of photoluminescence in carbidonitridosilicate phosphors. Blue, green, and yellow phosphors are obtained in the Sr1-x Y0.98+x Ce0.02 Si4 N7-x Cx system (x=0→1). Decreases in thermal quenching barrier height with x result from a dominant neighboring-cation effect, through which the replacement of Sr(2+) by Y(3+) reduces the covalency of CeN bonding. Green emission is observed from a cation-segregated nanostructure of SrYSi4 N7 and Y2 Si4 N6 C domains in x=0.2-0.6 samples. 23920342 Nitrosyl-cobinamide (NO-Cbi), a new nitric oxide donor, improves wound healing through cGMP/cGMP-dependent protein kinase. Nitric oxide (NO) donors have been shown to improve wound healing, but the mechanism is not well defined. Here we show that the novel NO donor nitrosyl-cobinamide (NO-Cbi) improved in vitro wound healing in several cell types, including an established line of lung epithelial cells and primary human lung fibroblasts. On a molar basis, NO-Cbi was more effective than two other NO donors, with the effective NO-Cbi concentration ranging from 3 to 10μM, depending on the cell type. Improved wound healing was secondary to increased cell migration and not cell proliferation. The wound healing effect of NO-Cbi was mediated by cGMP, mainly through cGMP-dependent protein kinase type I (PKGI), as determined using pharmacological inhibitors and activators, and siRNAs targeting PKG type I and II. Moreover, we found that Src and ERK were two downstream mediators of NO-Cbi's effect. We conclude that NO-Cbi is a potent inducer of cell migration and wound closure, acting via cGMP, PKG, Src, and extracellular signal regulated kinase (ERK). 23340918 Serum 25-hydroxyvitamin D, parathyroid hormone, and their association with metabolic syndrome in Chinese. Increasing evidence suggests that 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) levels are associated with metabolic syndrome (MetS). In 2010, we explored the association of serum 25(OH)D and PTH levels with MetS in 1,390 Chinese participants, aged 20-83 years. Anthropometric phenotypes, blood pressure, and the incidence of MetS were evaluated. In addition, serum lipids, 25(OH)D, and PTH were measured. The median concentration of 25(OH)D and PTH were 55.3 nmol/l and 2.8 pmol/l, respectively. The prevalence of vitamin D deficiency (<50 nmol/l) was 39.9 %, with 34.5 % in men and 47.8 % in women. After accounting for confounding factors and serum PTH, a 10 nmol/l higher serum 25(OH)D level was associated with a 10 % lower risk of MetS (OR = 0.90, 95 % CI 0.84-0.96, P = 0.0007). Furthermore, participants with vitamin D sufficiency had a 35 % lower risk of MetS than those with vitamin D deficiency (OR = 0.65, 95 % CI 0.51-0.84, P = 0.0009). PTH was not associated with the risk of MetS after adjustment for confounding factors. These results were confirmed in both men and women. Thus in this cohort of Chinese individuals, vitamin D deficiency is common and optimal vitamin D level is inversely associated with MetS, independent of several confounders and PTH level. The clinical significance of these findings warrants further study. 23958600 The Gordian Knot of dysbiosis, obesity and NAFLD. The development of obesity and NAFLD is known to be determined by host genetics, diet and lack of exercise. In addition, the gut microbiota has been identified to influence the development of both obesity and NAFLD. Evidence for the role of the gut microbiota has been shown by preclinical studies of transfer of gut microbiota from lean and obese individuals, with the recipient developing the metabolic features of the donor. Many bidirectional interactions of the gut microbiota, including with food, bile and the intestinal epithelium, have been identified. These interactions might contribute to the distinct steps in the progression from lean to obese states, and to steatosis, steatohepatitis and eventually fibrosis. The predominant steps are efficient caloric extraction from the diet, intestinal epithelial damage and greater entry of bacterial components into the portal circulation. These steps result in activation of the innate immune system, liver inflammation and fibrosis. Fortunately, therapeutic interventions might not require a full understanding of these complex interactions. Although antibiotics are too unselective in their action, probiotics have shown efficacy in reversing obesity and NASH in experimental systems, and are under investigation in humans. 23794397 Impact of social discrimination, job concerns, and social support on filipino immigrant worker mental health and substance use. The personal and social impact of mental health problems and substance use on workforce participation is costly. Social determinants of health contribute significantly to health disparities beyond effects associated with work. Guided by a theory-driven model, we identified pathways by which social determinants shape immigrant worker health. Associations between known social determinants of mental health problems and substance use (social discrimination, job and employment concerns, and social support) were examined using structural equation modeling in a sample of 1,397 immigrants from the Filipino American Community Epidemiological Study. Social discrimination and low social support were associated with mental health problems and substance use (P < 0.05). Job and employment concerns were associated with mental health problems, but not substance use. The integration of social factors into occupational health research is needed, along with prevention efforts designed for foreign-born ethnic minority workers. Am. J. Ind. Med. 56:1082-1094, 2013. © 2013 Wiley Periodicals, Inc. 23901808 Susceptibility of Human Liver Cells to Porcine Endogenous Retrovirus. The risk of porcine endogenous retrovirus infection is a major barrier for pig-to-human xenotransplant. Porcine endogenous retrovirus, present in porcine cells, can infect many human and nonhuman primate cells in vitro, but there is no evidence available about in vitro infection of human liver cells. We investigated the susceptibility of different human liver cells to porcine endogenous retrovirus. The supernatant from a porcine kidney cell line was added to human liver cells, including a normal hepatocyte cell line (HL-7702 cells), primary hepatocytes (Phh cells), and a liver stellate cell line (Lx-2 cells), and to human embryonic kidney cells as a reference control. Expression of the porcine endogenous retrovirus antigen p15E in the human cells was evaluated with polymerase chain reaction, reverse transcription-polymerase chain reaction, and Western blot. The porcine endogenous retrovirus antigen p15E was not expressed in any human liver cells (HL-7702, Phh, or Lx-2 cells) that had been exposed to supernatants from porcine kidney cell lines. Porcine endogenous retrovirus-specific fragments were amplified in human kidney cells. Human liver cells tested were not susceptible to infection by porcine endogenous retrovirus. Therefore, not all human cells are susceptible to porcine endogenous retrovirus. 23959553 Blood Pressure Rhythmicity and Visceral Fat in Children With Hypertension. Primary hypertension is associated with disturbed activity of the sympathetic nervous system and altered blood pressure rhythmicity. We analyzed changes in cardiovascular rhythmicity and its relation with target organ damage during 12 months of antihypertensive treatment in 50 boys with hypertension (median, 15.0 years). The following parameters were obtained before and after 12 months of antihypertensive treatment: 24-hour ambulatory blood pressure, left ventricular mass, carotid intima-media thickness, and MRI for visceral and subcutaneous adipose tissue. Amplitudes and acrophases of mean arterial pressure and heart rate rhythms were obtained for 24-, 12-, and 8-hour periods. After 1 year of treatment, 68% of patients were normotensive, and left ventricular mass and carotid intima-media thickness decreased in 60% and 62% of patients, respectively. Blood pressure and heart rate rhythmicity patterns did not change. Changes in blood pressure amplitude correlated with the decrease of waist circumference (P=0.035). Moreover, the decrease of visceral fat correlated with the decrease of 24-hour mean arterial pressure and heart rate acrophases (both P<0.05). There were no differences in changes of blood pressure and heart rate rhythms between patients who achieved or did not achieve normotension and regression of left ventricular mass and carotid intima-media thickness. It was concluded that abnormal cardiovascular rhythmicity persists in children with primary hypertension despite effective antihypertensive treatment, which suggests that it may be the primary abnormality. The correlation between changes in cardiovascular rhythmicity and visceral obesity may indicate that the visceral fat plays an important role in the sympathetic activity of adolescents with hypertension. 23940377 Ba2+- and Bupivacaine-Sensitive Background K+ Conductances Mediate Rapid EPSP Attenuation in Oligodendrocyte Precursor Cells. Glutamatergic transmission onto oligodendrocyte precursor cells (OPCs) may regulate OPC proliferation, migration and differentiation. Dendritic integration of excitatory postsynaptic potentials (EPSPs) is critical for neuronal functions, and mechanisms regulating dendritic propagation and summation of EPSPs are well understood. However, little is known about EPSP attenuation and integration in OPCs. We developed realistic OPC models for synaptic integration, based on passive membrane responses of OPCs obtained by simultaneous dual whole-cell patch-pipette recordings. Compared with neurons, OPCs have a very low value of membrane resistivity, which is largely mediated by Ba(2+)- and bupivacaine-sensitive background K(+) conductances. The very low membrane resistivity not only leads to rapid EPSP attenuation along OPC processes but also sharpens EPSPs and narrows the temporal window for EPSP summation. Thus, background K(+) conductances regulate synaptic responses and integration in OPCs, thereby affecting activity-dependent neuronal control of OPC development and function. 23579289 MicroRNA-214 suppresses osteogenic differentiation of C2C12 myoblast cells by targeting Osterix. Osterix (Osx) is an osteoblast-specific transcription factor that is essential for osteoblast differentiation and bone formation. Osx-null mice, which exhibit a complete absence of bone formation and arrested osteoblast differentiation, die immediately after birth. However, our understanding of the regulatory mechanism of Osx expression remains poor. MicroRNAs (miRNAs) are a class of small non-coding RNAs that play pivotal roles in diverse biological processes, including the development, differentiation, proliferation, survival, and oncogenesis of cells and organisms. In this study, we aimed to investigate the impact of miRNAs on Osx expression. Bioinformatic analyses predicted that miR-214 would be a potential regulator of Osx. The direct binding of miR-214 to the Osx 3' untranslated region (3' UTR) was demonstrated by a luciferase reporter assay using a construct containing the Osx 3' UTR. Deletion mutant construction revealed that the Osx 3' UTR contained two miR-214 binding sites. MiR-214 expression was inversely correlated with Osx expression in Saos-2 and U2OS cells. The forced expression of miR-214 in Saos-2 cells led to a reduction in the level of Osx protein. Moreover, the role of miR-214 in the osteogenic differentiation of C2C12 cells was investigated. We found that the osteogenic differentiation of C2C12 cells was enhanced by the downregulation of miR-214 expression, as measured by increased alkaline phosphatase activity and matrix mineralization. Taken together, these results indicate that miR-214 is a novel regulator of Osx, and that it plays an important role in the osteogenic differentiation of C2C12 cells as a suppressor. 23876673 The impact of the availability of prevention studies on the desire to undergo predictive testing in persons at risk for autosomal dominant Alzheimer's disease. Persons at risk for autosomal dominant neurodegenerative diseases provide the opportunity to efficiently test preventive interventions. Only a minority of such persons, however, choose to undergo revealing genetic testing, presenting a challenge to enrollment. Thirty-four preclinical Latinos (n=26) and non-Latinos at risk for familial Alzheimer's disease (FAD) unaware of their genetic status were administered a questionnaire exploring their interest in undergoing revealing genetic testing at baseline and in the context of eligibility for four prevention trials of increasing invasiveness. Forty-four percent of subjects expressed a baseline interest in undergoing revealing testing which increased to 85% in order to be eligible for a study of an oral drug "felt to be very safe." If there were a 50% chance of receiving placebo, this number dropped to 62% (p=0.02). Among those not interested in a study involving a 50% chance of receiving placebo, a range of 5% to 40% chance of receiving placebo was given as acceptable. For more invasive studies, living in the United States (as opposed to Mexico) positively influenced the likelihood of participating. Our data suggest that clinical trial designs in which persons must confront their genetic status prior to enrollment are feasible. Study designs to minimize the likelihood of being placed on placebo or provide the eventual administration of the drug through open-label extensions should be considered. 23482393 Characterization of the 5-hydroxymethylcytosine-specific DNA restriction endonucleases. In T4 bacteriophage, 5-hydroxymethylcytosine (5hmC) is incorporated into DNA during replication. In response, bacteria may have developed modification-dependent type IV restriction enzymes to defend the cell from T4-like infection. PvuRts1I was the first identified restriction enzyme to exhibit specificity toward hmC over 5-methylcytosine (5mC) and cytosine. By using PvuRts1I as the original member, we identified and characterized a number of homologous proteins. Most enzymes exhibited similar cutting properties to PvuRts1I, creating a double-stranded cleavage on the 3' side of the modified cytosine. In addition, for efficient cutting, the enzymes require two cytosines 21-22-nt apart and on opposite strands where one cytosine must be modified. Interestingly, the specificity determination unveiled a new layer of complexity where the enzymes not only have specificity for 5-β-glucosylated hmC (5βghmC) but also 5-α-glucosylated hmC (5αghmC). In some cases, the enzymes are inhibited by 5βghmC, whereas in others they are inhibited by 5αghmC. These observations indicate that the position of the sugar ring relative to the base is a determining factor in the substrate specificity of the PvuRts1I homologues. Lastly, we envision that the unique properties of select PvuRts1I homologues will permit their use as an additive or alternative tool to map the hydroxymethylome. 23962520 Autophosphorylation of gatekeeper tyrosine by symbiosis receptor kinase. Plant receptor-like kinases (RLKs) share their evolutionary origin with animal interleukin-1 receptor-associated kinase (IRAK)/Pelle family of soluble kinases and are distinguished by having tyrosine as 'gatekeeper'. This position is adjacent to the hinge region and is hidden in a hydrophobic pocket of the catalytic cleft of protein kinases and is therefore least probable to be a target for any modification. This communication illustrates the accessibility of the gatekeeper site (Y670) towards both autophosphorylation and dephosphorylation in the recombinant cytoplasmic domain of symbiosis receptor kinase from Arachis hypogaea (AhSYMRK). Autophosphorylation on gatekeeper tyrosine was detected prior to extraction but never under in vitro conditions. We hypothesize gatekeeper phosphorylation to be associated with synthesis/maturation of AhSYMRK and this phenomenon may be prevalent among RLKs. 23825405 Role of nociceptor αCaMKII in transition from acute to chronic pain (hyperalgesic priming) in male and female rats. We have previously shown that activation of protein kinase Cε (PKCε) in male rats induces a chronic, long-lasting change in nociceptors such that a subsequent exposure to proinflammatory mediators produces markedly prolonged mechanical hyperalgesia. This neuroplastic change, hyperalgesic priming, is dependent on activation of cytoplasmic polyadenylation element-binding protein (CPEB), downstream of PKCε, and consequent translation of mRNAs in the peripheral terminal of the nociceptor. Since α calmodulin-dependent protein kinase II (αCaMKII), a molecule implicated in neuroplasticity, is a target of CPEB and can also affect CPEB function, we investigated its role in the transition from acute to chronic pain. Priming induced by direct activation of PKCε can be prevented by inhibition of αCaMKII. In addition, direct activation of αCaMKII induces priming, which was not prevented by pretreatment with PKCε antisense, suggesting that αCaMKII is downstream of PKCε in the induction of priming. Activation of ryanodine receptors (RyRs), which can lead to activation of αCaMKII, also induced priming, in a calcium- and αCaMKII-dependent manner. Similarly, inhibition of the RyR and a calcium buffer prevented induction of priming by PKCε. Unlike activation of PKCε, ryanodine and αCaMKII induced priming in female as well as male rats. Our results demonstrate a contribution of αCaMKII to induction of hyperalgesic priming, a phenomenon implicated in the transition from acute to chronic pain. 23911104 An LRRTM4-HSPG Complex Mediates Excitatory Synapse Development on Dentate Gyrus Granule Cells. Selective synapse development determines how complex neuronal networks in the brain are formed. Complexes of postsynaptic neuroligins and LRRTMs with presynaptic neurexins contribute widely to excitatory synapse development, and mutations in these gene families increase the risk of developing psychiatric disorders. We find that LRRTM4 has distinct presynaptic binding partners, heparan sulfate proteoglycans (HSPGs). HSPGs are required to mediate the synaptogenic activity of LRRTM4. LRRTM4 shows highly selective expression in the brain. Within the hippocampus, we detected LRRTM4 specifically at excitatory postsynaptic sites on dentate gyrus granule cells. LRRTM4(-/-) dentate gyrus granule cells, but not CA1 pyramidal cells, exhibit reductions in excitatory synapse density and function. Furthermore, LRRTM4(-/-) dentate gyrus granule cells show impaired activity-regulated AMPA receptor trafficking. These results identifying cell-type-specific functions and multiple presynaptic binding partners for different LRRTM family members reveal an unexpected complexity in the design and function of synapse-organizing proteins. 23841501 Urinary metabolic biomarkers link oxidative stress indicators associated with general arsenic exposure to male infertility in a han chinese population. To investigate the hypothesis that general environmental arsenic (As) exposure can impair male fertility, we designed a case-control study examining possible correlations between the concentrations of different As species in urine [controls (n = 151) vs cases (n = 140)], urinary metabolic biomarkers [controls (n = 158) vs cases (n = 135)], and infertility characterized by poor semen quality. Regional participants were recruited sequentially from the affiliated hospitals of Nanjing Medical University. Elevated inorganic arsenate (Asi(V)) exposure was associated with infertility: in comparison with the first quartile, subjects with Asi(V) levels above the median were more likely to exhibit male idiopathic infertility with increasing adjusted odds ratios (AOR) of 4.9 [95% confidence interval (CI), 1.8-13.6] and 13.6 (95% CI, 4.8-38.6) at the third and fourth quartiles (P = 0.000 for trend), respectively. Other As species did not exhibit a significant dose-dependent correlation with infertility risk. Levels of urinary biomarkers correlated with both male infertility and Asi(V) concentrations [controls (n = 145) vs cases (n = 123)]; the latter correlation was independent of disease. These included acylcarnitines, aspartic acid, and hydroxyestrone, which were negatively associated with infertility, and uridine and methylxanthine, which were positively associated. In conclusion, for the first time we show that elevated urinary concentrations of Asi(V) from general As exposure are significantly associated with male infertility, and As species may exert toxicity via oxidative stress and sexual hormone disrupting mechanisms, as indicated by related biomarkers. 23962736 Object-based encoding in visual working memory: A life span study. Recent studies on development of visual working memory (VWM) predominantly focus on VWM capacity and spatial-based information filtering in VWM. Here we explored another new aspect of VWM development: object-based encoding (OBE), which refers to the fact that even if one feature dimension is required to be selected into VWM, the other irrelevant dimensions are also extracted. We explored the OBE in children, young adults, and old adults, by probing an "irrelevant-change distracting effect" in which a change of stored irrelevant feature dramatically affects the performance of task-relevant features in a change-detection task. Participants were required to remember two or four simple colored shapes, while color was used as the relevant dimension. We found that changes to irrelevant shapes led to a significant distracting effect across the three age groups in both load conditions; however, children showed a greater degree of OBE than did young and old adults. These results suggest that OBE exists in VWM over the life span (6-67 years), yet continues to develop along with VWM. 23802669 Modulation of inflammation and oxidative stress in canine chondrocytes. To determine whether oxidative stress could be induced in canine chondrocytes in vitro. Chondrocytes obtained from healthy adult mixed-breed dogs. Harvested chondrocytes were maintained at 37°C with 5% CO2 for 24 hours. To assess induction of oxidative stress, 2 stimuli were used: hydrogen peroxide and a combination of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). To determine the effect of hydrogen peroxide, a set of chondrocyte-seeded plates was incubated with control medium alone or hydrogen peroxide (100, 200, or 300μM) for 24 hours. For inhibition of oxidative stress, cells were incubated for 24 hours with N-acetylcysteine (NAC; 10mM) before exposure to hydrogen peroxide. Another set of chondrocyte-seeded plates was incubated with control medium alone or with IL-1β (10 ng/mL) and TNF-α (1 ng/mL) for 24 hours. Supernatants were obtained for measurement of prostaglandin E2 production, and cell lysates were used for measurement of superoxide dismutase (SOD) activity and reduced-glutathione (GSH) concentration. Chondrocytes responded to the oxidative stressor hydrogen peroxide with a decrease in SOD activity and GSH concentration. Exposure to the antioxidant NAC caused an increase in SOD activity in hydrogen peroxide-stressed chondrocytes to a degree comparable with that in chondrocytes not exposed to hydrogen peroxide. Similarly, NAC exposure induced significant increases in GSH concentration. Activation with IL-1β and TNF-α also led to a decrease in SOD activity and increase in prostaglandin E2 production. Canine chondrocytes responded to the oxidative stress caused by exposure to hydrogen peroxide and cytokines. Exposure to oxidative stress inducers could result in perturbation of chondrocyte and cartilage homeostasis and could contribute to the pathophysiology of osteoarthritis. Use of antioxidants, on the other hand, may be helpful in the treatment of arthritic dogs. 23708616 Silver deposited polystyrene (PS) microspheres for surface-enhanced Raman spectroscopic-encoding and rapid label-free detection of melamine in milk powder. Silver nanoparticles coated amino modified polystyrene microspheres (PS-NH2/Ag NPs) with extremely high surface enhanced Raman scattering (SERS) activity and uniform surface morphology were created by precise controlling of deposition time. Nanojets that were formed underneath the individual microspheres could be used for nondestructive analysis of species adsorbed on the smooth gold or glass surface. A 10 fold enhancement of SERS was observed between PS-NH2/Ag NPs and gold surface compared to glass surface due to more effective coupling of surface plasmonic resonance. These microsphere SERS substrates could detect 2-Mercaptopyridine down to 10(-9)M. Four different thiol compounds have been successfully utilized as tags to prepare SERS encoded PS-NH2/Ag NPs microspheres. Furthermore, the potential application of these SERS substrate for rapid detection of melamine in milk powder was explored. A linear relationship was observed between SERS intensity and logarithm of melamine concentrations with the limit of detection (LOD) of 1.9 × 10(-8)mol/L. The promising advantages of easy sample pretreatment, low protein background interference, short detection time and low cost makes the PS-NH2/Ag NPs substrate a potential detection tool in the field of food safety. 23677059 Newborn screening for Fabry disease in Japan: prevalence and genotypes of Fabry disease in a pilot study. Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A (GLA) activity. Enzyme replacement therapy (ERT) for FD is available, and newborn mass screening for FD is being implemented. Here, we undertook a pilot study of newborn mass screening for FD in Japan. GLA activity in dried blood spots was measured using a fluorescence assay and confirmed by measurement of GLA activity in white blood cells (WBCs) in infants with abnormally low GLA activity. This was followed up by genetic testing. A total of 21 170 neonates were enrolled in the study. Of these, seven (five boys, two girls) had low GLA activities, which were verified by the WBC GLA activity assay. Thus, the initial fluorescence assay was suitable for newborn mass screening for FD. Pathogenic mutations of the GLA gene, that is, V199M and IVS4+919G>A, were found in two boys and one boy, respectively. Functional mutations, E66Q and c.-10C>T: g.1170C>T, were found in two boys and one girl, respectively. The prevalence of test-positive newborns was 1/3024, while that of those with a pathogenic mutation was 1/7057. The numbers are higher than those previously anticipated. Standardized management for FD found during newborn mass screening, including an ERT regimen, remains to be established. 23959740 Postoperative arrhythmia in patients with bidirectional cavopulmonary anastomosis. Bidirectional cavopulmonary anastomosis (BDCPA) is part of the staged Fontan palliation for congenital heart defects with single-ventricle morphology. The aim of this study was to describe incidence and characteristics of early postoperative arrhythmias in patients undergoing BDCPA. Retrospective analysis of 60 patients undergoing BDCPA at the age of <12 months from 2001 to 2008 at a single centre. Arrhythmias were subclassified in sinus bradycardia, premature atrial/ventricular contraction, supraventricular tachycardia and atrioventricular block. The groups were compared according to age at operation and diagnosis. Postoperative follow-up data were included until Fontan completion. Postoperative arrhythmia was observed in 20 patients: 12 temporary and 8 persisting until hospital discharge. Sinus bradycardia is a common postoperative arrhythmia and occurred in 16 patients (9 transient, 7 persistent until hospital discharge). One patient undergoing BDCPA and a Damus-Kaye-Stansel procedure had a persisting first-degree atrioventricular block. The occurrence of a postoperative arrhythmia was independent of age and diagnostic group (hypoplastic left heart vs non-hypoplasic left heart). After hospital discharge, five of the eight arrhythmia resolved spontaneously resulting in 2 patients with sinus bradycardia and 1 patient with a first-degree AV block immediately before the Fontan completion was undertaken. Postoperative arrhythmias in patients with BDCPA occur early after surgery and are temporary. Severe and life-threatening arrhythmias are rare although the interventions are complex and the patients very young. The most common arrhythmia is sinus bradycardia. 23909913 Vaccination with recombinant modified vaccinia virus Ankara prevents the onset of intestinal allergy in mice. Modified vaccinia virus Ankara (MVA)-encoding antigens are considered as safe vaccine candidates for various infectious diseases in humans. Here, we investigated the immune-modulating properties of MVA-encoding ovalbumin (MVA-OVA) on the allergen-specific immune response. The immune-modulating properties of MVA-OVA were investigated using GM-CSF-differentiated BMDCs from C57BL/6 mice. OVA expression upon MVA-OVA infection of BMDCs was monitored. Activation and maturation markers on viable MVA-OVA-infected mDCs were analyzed by flow cytometry. Secretion of INF-γ, IL-2, and IL-10 was determined in a co-culture of BMDCs infected with wtMVA or MVA-OVA and OVA-specific OT-I CD8(+)  and OT-II CD4(+ ) T cells. BALB/c mice were vaccinated with wtMVA, MVA-OVA, or PBS, sensitized to OVA/alum and challenged with a diet containing chicken egg white. OVA-specific IgE, IgG1, and IgG2a and cytokine secretion from mesenteric lymph node (MLN) cells were analyzed. Body weight, body temperature, food uptake, intestinal inflammation, and health condition of mice were monitored. Infection with wtMVA and MVA-OVA induced comparable activation of mDCs. MVA-OVA-infected BMDCs expressed OVA and induced enhanced IFN-γ and IL-2 secretion from OVA-specific CD8(+ ) T cells in comparison with OVA, wtMVA, or OVA plus wtMVA. Prophylactic vaccination with MVA-OVA significantly repressed OVA-specific IgE, whereas OVA-specific IgG2a was induced. MVA-OVA vaccination suppressed TH 2 cytokine production in MLN cells and prevented the onset of allergic symptoms and inflammation in a mouse model of OVA-induced intestinal allergy. Modified vaccinia virus Ankara-ovalbumin (MVA-OVA) vaccination induces a strong OVA-specific TH 1- immune response, likely mediated by the induction of IFN-γ and IgG2a. Finally, MVA-based vaccines need to be evaluated for their therapeutic potential in established allergy models. 23600789 Three new triterpene glycosides from Ilex asprella. Three new sulfated triterpene glycosides, asprellanosides C-E (1-3), were isolated from the roots of Ilex asprella. Their structures were elucidated as 3β-[(2-O-sulfo-β-d-xylopyranosyl)oxy]urs-12,19(29)-diene-28-oic acid 28-β-d-glucopyranoside (1), 3β-[(2-O-sulfo-β-d-xylopyranosyl)oxy]urs-12,19-diene-28-oic acid 28-β-d-glucopyranoside (2), and 3β-[(2-O-sulfo-β-d-xylopyranosyl)oxy]urs-12,19-diene-28-oic acid (3) on the basis of the spectral and chemical methods. 23892436 The multi zinc-finger protein Trps1 acts as a regulator of histone deacetylation during mitosis. TRPS1, the gene mutated in human "Tricho-Rhino-Phalangeal syndrome," encodes a multi zinc-finger nuclear regulator of chondrocyte proliferation and differentiation. Here, we have identified a new function of Trps1 in controlling mitotic progression in chondrocytes. Loss of Trps1 in mice leads to an increased proportion of cells arrested in mitosis and, subsequently, to chromosome segregation defects. Searching for the molecular basis of the defect, we found that Trps1 acts as regulator of histone deacetylation. Trps1 interacts with two histone deacetylases, Hdac1 and Hdac4, thereby increasing their activity. Loss of Trps1 results in histone H3 hyperacetylation, which is maintained during mitosis. Consequently, chromatin condensation and binding of HP1 is impaired, and Trps1-deficient chondrocytes accumulate in prometaphase. Overexpression of Hdac4 rescues the mitotic defect of Trps1-deficient chondrocytes, identifying Trps1 as an important regulator of chromatin deacetylation during mitosis in chondrocytes. Our data provide the first evidence that the control of mitosis can be linked to the regulation of chondrocyte differentiation by epigenetic consequences of altered Hdac activity. 23329465 Nonalcoholic fatty liver disease: current issues and novel treatment approaches. Nonalcoholic fatty liver disease (NAFLD) is considered the most common liver disorder in the Western world. It is commonly associated with insulin resistance, obesity, dyslipidaemia, type 2 diabetes mellitus (T2DM) and cardiovascular disease. Nonalcoholic steatohepatitis (NASH) is characterized by steatosis with necroinflammation and eventual fibrosis, which can lead to end-stage liver disease and hepatocellular carcinoma. Its pathogenesis is complex, and involves a state of 'lipotoxicity' in which insulin resistance, with increased free fatty acid release from adipose tissue to the liver, play a key role in the onset of a 'lipotoxic liver disease' and its progression to NASH. The diagnosis of NASH is challenging, as most affected patients are symptom free and the role of routine screening is not clearly established. A complete medical history is important to rule out other causes of fatty liver disease (alcohol abuse, medications, other). Plasma aminotransferase levels and liver ultrasound are helpful in the diagnosis of NAFLD/NASH, but a liver biopsy is often required for a definitive diagnosis. However, there is an active search for plasma biomarkers and imaging techniques that may non-invasively aid in the diagnosis. The treatment of NASH requires a multifaceted approach. The goal is to reverse obesity-associated lipotoxicity and insulin resistance via lifestyle intervention. Although there is no pharmacological agent approved for the treatment of NAFLD, vitamin E (in patients without T2DM) and the thiazolidinedione pioglitazone (in patients with and without T2DM) have shown the most consistent results in randomized controlled trials. This review concentrates on our current understanding of the disease, with a focus on the existing therapeutic approaches and potential future pharmacological developments for NAFLD and NASH. 23830640 The differences between ICL repair during and outside of S phase. DNA interstrand crosslinks (ICLs) are complex lesions that block essential DNA transactions including DNA replication, recombination, and RNA transcription. Naturally occurring ICLs are rare, yet these lesions are the major cause of toxicity following treatment with several classes of crosslinking cancer chemotherapeutic drugs. ICLs are repaired during and outside of S phase by pathways with overlapping as well as distinct features. Here, we discuss some recent insights into the mechanisms of replication-dependent and replication-independent repair of ICLs with special emphasis on the differences between these repair pathways. 23874794 Mitochondrial Acclimation Capacities to Ocean Warming and Acidification Are Limited in the Antarctic Nototheniid Fish, Notothenia rossii and Lepidonotothen squamifrons. Antarctic notothenioid fish are characterized by their evolutionary adaptation to the cold, thermostable Southern Ocean, which is associated with unique physiological adaptations to withstand the cold and reduce energetic requirements but also entails limited compensation capacities to environmental change. This study compares the capacities of mitochondrial acclimation to ocean warming and acidification between the Antarctic nototheniid Notothenia rossii and the sub-Antarctic Lepidonotothen squamifrons, which share a similar ecology, but different habitat temperatures. After acclimation of L. squamifrons to 9°C and N. rossii to 7°C (normocapnic/hypercapnic, 0.2 kPa CO2/2000 ppm CO2) for 4-6 weeks, we compared the capacities of their mitochondrial respiratory complexes I (CI) and II (CII), their P/O ratios (phosphorylation efficiency), proton leak capacities and mitochondrial membrane fatty acid compositions. Our results reveal reduced CII respiration rates in warm-acclimated L. squamifrons and cold hypercapnia-acclimated N. rossii. Generally, L. squamifrons displayed a greater ability to increase CI contribution during acute warming and after warm-acclimation than N. rossii. Membrane unsaturation was not altered by warm or hypercapnia-acclimation in both species, but membrane fatty acids of warm-acclimated L. squamifrons were less saturated than in warm normocapnia-/hypercapnia-acclimated N. rossii. Proton leak capacities were not affected by warm or hypercapnia-acclimation of N. rossii. We conclude that an acclimatory response of mitochondrial capacities may include higher thermal plasticity of CI supported by enhanced utilization of anaplerotic substrates (via oxidative decarboxylation reactions) feeding into the citrate cycle. L. squamifrons possesses higher relative CI plasticities than N. rossii, which may facilitate the usage of energy efficient NADH-related substrates under conditions of elevated energy demand, possibly induced by ocean warming and acidification. The observed adjustments of electron transport system complexes with a higher flux through CI under warming and acidification suggest a metabolic acclimation potential of the sub-Antarctic L. squamifrons, but only limited acclimation capacities for N. rossii. 23861963 The Effect of Illumination and Time of Day on Movements of Bobcats (Lynx rufus). Understanding behavioral changes of prey and predators based on lunar illumination provides insight into important life history, behavioral ecology, and survival information. The objectives of this research were to determine if bobcat movement rates differed by period of day (dark, moon, crepuscular, day), lunar illumination (<10%, 10 - <50%, 50 - <90%, >90%), and moon phase (new, full). Bobcats had high movement rates during crepuscular and day periods and low movement rates during dark periods with highest nighttime rates at 10-<50% lunar illumination. Bobcats had highest movement rates during daytime when nighttime illumination was low (new moon) and higher movement rates during nighttime when lunar illumination was high (full moon). The behaviors we observed are consistent with prey availability being affected by light level and by limited vision by bobcats during darkness. 23962075 Two new ursolic acid saponins from Morina nepalensis var. alba Hand-Mazz. A saponin-enriched fraction was prepared from the EtOH extract of the whole plant of Morina nepalensis var. alba Hand-Mazz. It showed α-glucosidase inhibitory activity, from which two new triterpene saponins (1 and 2), along with one known saponin (3), were isolated. The structures of the new saponins were identified by spectroscopic analysis, including extensive 1D and 2D NMR techniques and hydrolysis followed by chromatographic analysis. The three saponins were assayed for α-glucosidase inhibitory activities. 23453261 Is the HCV-HIV co-infection prevalence amongst injecting drug users a marker for the level of sexual and injection related HIV transmission? Amongst injecting drug users (IDUs), HIV is transmitted sexually and parenterally, but HCV is transmitted primarily parenterally. We assess and model the antibody prevalence of HCV amongst HIV-infected IDUs (denoted as HCV-HIV co-infection prevalence) and consider whether it proxies the degree of sexual HIV transmission amongst IDUs. HIV, HCV and HCV-HIV co-infection prevalence data amongst IDU was reviewed. An HIV/HCV transmission model was adapted. Multivariate model uncertainty analyses determined whether the model's ability to replicate observed data trends required the inclusion of sexual HIV transmission. The correlation between the model's HCV-HIV co-infection prevalence and estimated proportion of HIV infections due to injecting was evaluated. The median HCV-HIV co-infection prevalence (prevalence of HCV amongst HIV-infected IDUs) was 90% across 195 estimates from 43 countries. High HCV-HIV co-infection prevalences (>80%) occur in most (75%) settings, but can be lower in settings with low HIV prevalence (<10%) or high HIV/HCV prevalence ratios (HIV prevalence divided by HCV prevalence>0.75). The model without sexual HIV transmission reproduced some data trends but could not reproduce any epidemics with high HIV/HCV prevalence ratios (>0.85) or low HCV-HIV co-infection prevalence (<60%) when HIV prevalence>10%. The model with sexual HIV transmission reproduced data trends more closely. The proportion of HIV infections due to injecting correlated with HCV-HIV co-infection prevalence; suggesting that up to 80/60/<20% of HIV infections could be sexually transmitted in settings with HCV-HIV co-infection prevalence between 50-60/70-80/>90%. Substantial sexual HIV transmission may occur in many IDU populations; HCV-HIV co-infection prevalence could signify its importance. 23826857 Discovery of a statistically significant and interpretable relationship between redox reactivity and lethality of drugs. A statistically significant and interpretable relationship between electrophilicity as a redox reactivity indicator and LD50 as a lethality indicator of drugs was discovered, and this relationship could be interpreted by the action of the cytochrome P450. The drugs chosen in this study was Topoisomerase II inhibitor anticancer drugs, and the electrophilicity of drugs was obtained by quantum chemical calculation. Since the P450 detoxification mechanism is the catalytic oxidation of drug molecules, it may infer that the drug molecules being easily oxidized (low electrophilicity) will be weak in lethality in general. In addition, this relationship revealed two structural scaffolds for the anthracycline-based topoisomerase II inhibitors, and their lethality mechanisms are not totally the same. Such relationship can assist in designing new drugs that candidates possessing low electrophilicity are recommended for lowering of lethality, and moieties providing a large inductive effect can reduce the electrophilicity of the anthracycline-based topoisomerase II inhibitors. 23702103 Explaining long-term outcomes among drug dependent mothers treated in women-only versus mixed-gender programs. Specialized substance abuse treatment for parenting women is thought to improve outcomes, but long-term impacts and how they occur are poorly understood. Utilizing a sample of 789 California mothers followed for 10 years after admission to women-only (WO) or mixed-gender (MG) drug treatment, we examine the relationship between WO treatment and outcomes and whether it is mediated by post-treatment exposures to criminal justice and health services systems. At follow-up, 48% of mothers had a successful outcome (i.e., no use of illicit drugs, not involved with the criminal justice system, alive). Controlling for patient characteristics, WO (vs. MG) treatment increased the odds of successful outcome by 44%. In the structural equation model WO treatment was associated with fewer post-treatment arrests, which was associated with better outcomes. Women-only substance abuse treatment has long-term benefits for drug-dependent mothers, a relationship that may be partially explained by post-treatment exposure to the criminal justice system. Findings underscore additional leverage points for relapse prevention and recovery-supportive efforts for drug-dependent mothers. 23698460 Prognostic significance of left ventricular dyssynchrony by phase analysis of gated SPECT in medically treated patients with dilated cardiomyopathy. The study aimed to investigate the value of clinical variables and rest gated single-photon emission computed tomography (SPECT) in predicting cardiac deaths in medically treated dilated cardiomyopathy (DCM) patients. This is a retrospective study. Fifty-six consecutive hospitalized DCM patients who underwent rest gated SPECT myocardial perfusion imaging were initially recruited. Patients were further excluded for receiving heart transplantation, cardiac resynchronization treatment, and noncardiac death during follow-up. The remaining 48 medically treated DCM patients were selected into the final analysis. Phase analysis of gated SPECT was conducted to identify left ventricular (LV) dyssynchrony. Cardiac death during follow-up was considered as the only endpoint. Univariate and multivariate Cox proportional hazards regression analysis were performed to identify the independent predictors of cardiac death. Kaplan-Meier cumulative survival analysis with stratification was performed, and survival curves were compared by log-rank test. The mean age was 47.5 ± 15.8 years (range, 15-76 yrs) and 85.4% were men. The mean LV ejection fraction was 22.2 ± 7.7%. During the follow-up period (22.7 ± 5.1 mos), 12 (25.0%) cardiac deaths occurred. Compared to survivors, patients with cardiac death had lower body mass index (BMI, P = 0.010), higher percent of prolonged QRS duration (QRSD, P = 0.043), and severe LV dyssynchrony (P = 0.002). Multivariate Cox analysis demonstrated that severe LV dyssynchrony [hazard ratio = 9.607, 95% confidential interval (95% CI) 2.064-44.713, P = 0.004] and BMI (hazard ratio = 0.851, 95% CI 0.732-0.989, P = 0.036) were predictive of cardiac death. Left ventricular dyssynchrony assessed by phase analysis of gated SPECT and BMI are predictive of cardiac death in medically treated DCM patients. 23838981 Hyperventilation as a strategy for improved repeated sprint performance. Repeated high intensity sprints incur substantial anaerobic metabolic challenges and create an acidic muscle milieu that is unfavorable for subsequent performance. Hyperventilation, resulting in respiratory alkalosis, acts as a compensatory mechanism for metabolic acidosis. This study tested the hypothesis that hyperventilation performed during recovery intervals would attenuate performance decrement in repeated sprint pedaling. Thirteen male university athletes performed ten sets of 10 s maximal pedaling on a cycle ergometer with a 60 s recovery between sets under control (spontaneous breathing) and hyperventilation conditions in a crossover, counter-balanced manner. Pedaling load (kp) was set at 0.075 × body mass. Peak and mean power outputs were documented for each set to compare performance decrements over 10 sets between conditions. Hyperventilation (60 breaths/min and PETCO2 maintained at 20-25 mmHg) was performed 30 s before each sprint set. This intervention successfully increased blood pH by 0.03-0.07 but lowered PCO2 by 1.2-8.4 mmHg throughout exercise (P < 0.001). The peak and mean power outputs, and blood [La] accumulation were not significantly different between the conditions. However, a significant condition × time interaction existed for peak power (P = 0.035) and mean power (P = 0.023), demonstrating an attenuation in power decrement in later sprint sets with hyperventilation. In conclusion, hyperventilation implemented during recovery intervals of repeated sprint pedaling attenuated performance decrements in later exercise bouts that was associated with substantial metabolic acidosis. The practical implication is that hyperventilation may have a strategic role for enhancing training effectiveness and may give an edge in performance outcomes. 23644076 Microglia during development and aging. Microglia are critical nervous system-specific cells influencing brain development, maintenance of the neural environment, response to injury, and repair. They contribute to neuronal proliferation and differentiation, pruning of dying neurons, synaptic remodeling and clearance of debris and aberrant proteins. Colonization of the brain occurs during gestation with an expansion following birth with localization stimulated by programmed neuronal death, synaptic pruning, and axonal degeneration. Changes in microglia phenotype relate to cellular processes including specific neurotransmitter, pattern recognition, or immune-related receptor activation. Upon activation, microglia cells have the capacity to release a number of substances, e.g., cytokines, chemokines, nitric oxide, and reactive oxygen species, which could be detrimental or beneficial to the surrounding cells. With aging, microglia shift their morphology and may display diminished capacity for normal functions related to migration, clearance, and the ability to shift from a pro-inflammatory to an anti-inflammatory state to regulate injury and repair. This shift in microglia potentially contributes to increased susceptibility and neurodegeneration as a function of age. In the current review, information is provided on the colonization of the brain by microglia, the expression of various pattern recognition receptors to regulate migration and phagocytosis, and the shift in related functions that occur in normal aging. 23954946 Behavioural therapy for smoking cessation: The effectiveness of different intervention types for disadvantaged and affluent smokers. Disadvantaged smokers are less likely to be successful when trying to stop smoking than more affluent smokers. In the UK, NHS Stop Smoking Services (SSS) provide a range of pharmacotherapy and behavioural support, delivered by advisors with a range of backgrounds. Whether the types of support provided and who provides it influence differences in quit rates amongst low SES smokers compared with high SES smokers has not previously been examined. 202,084 records of smokers in England who attended a NHS Stop Smoking Service between July 2010 and June 2011 were acquired. Smokers were followed-up by services at four weeks post quit date. Multilevel logistic regression models of CO validated quits were employed. Disadvantage was explored through the National Statistics Socio-Economic Classification (NS-SEC) and by eligibility for free prescriptions, an indicator of low income amongst adults aged between 19 and 59 in England. Affluent smokers were more likely to quit than disadvantaged smokers (OR 1.38 (1.35 to 1.42) for clients who paid for prescriptions compared to those eligible for free prescriptions). 80% of service clients received one-to-one counselling but open group forms of behavioural therapy were more successful (main effect OR 1.26 (1.12 to 1.41)) except amongst some of the most disadvantaged clients (long-term unemployed and prisoners). Closed groups were little deployed and they were not significantly more successful than one-to-one behavioural therapy after controls. Who delivered treatment did make a difference for some clients, with all but the most affluent less likely to be successful if they had been treated by a nurse compared with other types of advisers, including smoking cessation specialists (main effect OR 0.73 (0.65 to 0.83)). This study provides further evidence that disadvantaged smokers find quitting more difficult even when they have attended a smoking cessation programme. The findings suggest that open groups should be promoted, although they may not be as effective as other forms of behavioural therapy for the long-term unemployed or prisoners. Further research is required to explore why most groups of smokers who attended services staffed by nurses were less likely to quit than those who received treatment from other types of advisors. 23772774 Medical alternatives to oocyte donation in women with premature ovarian failure: a systematic review. Oocyte donation can satisfy the desire to have children in women with premature ovarian failure (POF) but little progress has been made to improve reproduction using the patients' own gametes. The aim of this study was to assess the effectiveness of alternative treatments to oocyte donation in patients with POF. A systematic search of MEDLINE, EMBASE and Cochrane databases from January 1988 to January 2012 using descriptors related to POF, ovulation induction, and pregnancy was made. Randomized clinical trials of women with POF undergoing various treatments to achieve ovulation induction, often compared with alternative treatment and placebo groups, were only selected. Outcomes of interest were those related to pregnancy (biochemical and live birth). Twelve trials were included and analysed for methodology, inclusion and exclusion criteria, number of patients included, characteristics and type of intervention, and results in terms of ovulation rate, pregnancy rate and ongoing pregnancy rate. The large methodological variability among studies prevented to combined data for a meta-analysis. None of the studies showed statistically significant differences between the study groups. The lack of case-control studies with a placebo group makes it impossible to establish differences between a treatment and no treatment. 23617393 Insulin receptor substrate-2 is expressed in kidney epithelium and up-regulated in diabetic nephropathy. Diabetic nephropathy (DN) is a progressive fibrotic condition that may lead to end-stage renal disease and kidney failure. Transforming growth factor-β1 and bone morphogenetic protein-7 (BMP7) have been shown to induce DN-like changes in the kidney and protect the kidney from such changes, respectively. Recent data identified insulin action at the level of the nephron as a crucial factor in the development and progression of DN. Insulin requires a family of insulin receptor substrate (IRS) proteins for its physiological effects, and many reports have highlighted the role of insulin and IRS proteins in kidney physiology and disease. Here, we observed IRS2 expression predominantly in the developing and adult kidney epithelium in mouse and human. BMP7 treatment of human kidney proximal tubule epithelial cells (HK-2 cells) increases IRS2 transcription. In addition, BMP7 treatment of HK-2 cells induces an electrophoretic shift in IRS2 migration on SDS/PAGE, and increased association with phosphatidylinositol-3-kinase, probably due to increased tyrosine/serine phosphorylation. In a cohort of DN patients with a range of chronic kidney disease severity, IRS2 mRNA levels were elevated approximately ninefold, with the majority of IRS2 staining evident in the kidney tubules in DN patients. These data show that IRS2 is expressed in the kidney epithelium and may play a role in the downstream protective events triggered by BMP7 in the kidney. The specific up-regulation of IRS2 in the kidney tubules of DN patients also indicates a novel role for IRS2 as a marker and/or mediator of human DN progression. 23872897 Comparative quantification of oxygen release by wetland plants: electrode technique and oxygen consumption model. Understanding oxygen release by plants is important to the design of constructed wetlands for wastewater treatment. Lab-scale systems planted with Phragmites australis were studied to evaluate the amount of oxygen release by plants using electrode techniques and oxygen consumption model. Oxygen release rate (0.14 g O2/m(2)/day) measured using electrode techniques was much lower than that (3.94-25.20 gO2/m(2)/day) calculated using the oxygen consumption model. The results revealed that oxygen release by plants was significantly influenced by the oxygen demand for the degradation of pollutants, and the oxygen release rate increased with the rising of the concentration of degradable materials in the solution. The summary of the methods in qualifying oxygen release by wetland plants demonstrated that variations existed among different measuring methods and even in the same measuring approach. The results would be helpful for understanding the contribution of plants in constructed wetlands toward actual wastewater treatment. 23522700 Superior mesenteric artery pseudoaneurysm after blunt abdominal trauma. True aneurysms and pseudoaneurysms of the visceral arteries are uncommon. Visceral artery aneurysms (VAAs) represent 0.1-0.2% of all vascular aneurysms and were also found in 0.1% of autopsies. VAAs most commonly affect the splenic (60%), hepatic (20%), and superior mesenteric (9%) arteries. Mesenteric injury caused by blunt abdominal trauma is relatively rare. A 30-year-old man arrived at our trauma hospital and was found to have a traumatic pseudoaneurysm of the superior mesenteric artery (SMA) after a motor vehicle collision. To date, only 10 visceral arterial pseudoaneurysms have been reported in the literature. We present an 11th case of a pseudoaneurysm involving the SMA after blunt abdominal trauma. 23759586 Attenuation of dexamethasone-induced cell death in multiple myeloma is mediated by miR-125b expression. Dexamethasone is a key front-line chemotherapeutic for B-cell malignant multiple myeloma (MM). Dexamethasone modulates MM cell survival signaling but fails to induce marked cytotoxicity when used as a monotherapy. We demonstrate here the mechanism behind this insufficient responsiveness of MM cells toward dexamethasone, revealing in MM a dramatic anti-apoptotic role for microRNA (miRNA)-125b in the insensitivity toward dexamethasone-induced apoptosis. MM cells responding to dexamethasone exhibited enhanced expression of oncogenic miR-125b. Dexamethasone also induced expression of miR-34a, which acts to suppress SIRT1 deacetylase, and thus allows maintained acetylation and inactivation of p53. p53 mRNA is also suppressed by miR-125b targeting. Reporter assays showed that both these dexamethasone-induced miRNAs act downstream of their target genes to prevent p53 tumor suppressor actions and, ultimately, resist cytotoxic responses in MM. Use of antisense miR-125b transcripts enhanced expression of pro-apoptotic p53, repressed expression of anti-apoptotic SIRT1 and, importantly, significantly enhanced dexamethasone-induced cell death responses in MM. Pharmacological manipulations showed that the key regulation enabling complete dexamethasone sensitivity in MM cells lies with miR-125b. In summary, dexamethasone-induced miR-125b induces cell death resistance mechanisms in MM cells via the p53/miR-34a/SIRT1 signaling network and provides these cells with an enhanced level of resistance to cytotoxic chemotherapeutics. Clearly, such anti-apoptotic mechanisms will need to be overcome to more effectively treat nascent, refractory and relapsed MM patients. These mechanisms provide insight into the role of miRNA regulation of apoptosis and their promotion of MM cell proliferative mechanisms. 23816404 Properdin in complement activation and tissue injury. The plasma protein properdin is the only known positive regulator of complement activation. Although regarded as an initiator of the alternative pathway of complement activation at the time of its discovery more than a half century ago, the role and mechanism of action of properdin in the complement cascade has undergone significant conceptual evolution since then. Despite the long history of research on properdin, however, new insight and unexpected findings on the role of properdin in complement activation, pathogen infection and host tissue injury are still being revealed by ongoing investigations. In this article, we provide a brief review on recent studies that shed new light on properdin biology, focusing on the following three topics: (1) its role as a pattern recognition molecule to direct and trigger complement activation, (2) its context-dependent requirement in complement activation on foreign and host cell surfaces, and (3) its involvement in alternative pathway complement-mediated immune disorders and considerations of properdin as a potential therapeutic target in human diseases. 23891701 Chalcone derivatives from the fern Cyclosorus parasiticus and their anti-proliferative activity. Three new chalcone derivatives, named parasiticins A-C (1-3), were isolated from the leaves of Cyclosorus parasiticus, together with four known chalcones, 5,7-dihydroxy-4-phenyl-8-(3-phenyl-trans-acryloyl)-3,4-dihydro-1-benzopyran-2-one (4), 2'-hydroxy-4',6'-dimethoxychalcone (5), 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (6), 2',4'-dihydroxy-6'-methoxy-3'-methylchalcone (7). The chemical structures of the new isolated compounds were elucidated unambiguously by spectroscopic data analysis. The cytotoxic activities of compounds 1-7 were evaluated against six human cancer cell lines in vitro. Compounds 3 and 6 exhibited substantial cytotoxicity against all six cell lines, especially toward HepG2 with the IC50 values of 1.60 and 2.82μM, respectively. Furthermore, we demonstrated that compounds 3 and 6 could induce apoptosis in the HepG2 cell line, which may contribute significantly to their cytotoxicity. 23598424 FTIR spectral signature of anticancer drug effects on PC-3 cancer cells: is there any influence of the cell cycle? FTIR spectroscopy was recently demonstrated to be a useful tool to obtain a unique fingerprint of several anticancer drugs. While cell responses to anticancer drugs are related to their "mode of action", it is obvious that some of the drugs used in the previous studies affect the cell cycle. For example, antimicrotubules disable the mitotic apparatus by disrupting the formation or the depolymerisation of microtubules. Cells are thus mostly blocked in the G2/M phase. On the other hand, it has been suggested that the changes observed in the cell spectra due to treatments could be related to the cell cycle. The aim of the present study is to examine this hypothesis and to investigate whether spectral variations induced by a treatment reflect the cell cycle behaviour or the metabolic perturbations induced by the drug. To answer this question, a method was developed that allows an unambiguous identification of the cell cycle phase for each individual cell. This method is based on the superimposition of three types of images: visible, infrared and propidium iodide fluorescence images. Propidium iodide intercalates the bases of the DNA. As the DNA amount in a cell is correlated with the cell cycle phase, the exact phase of each individual cell could be identified. On IR images, mean spectra corresponding to single cells were calculated and associated with the cycle stage defined using fluorescence images. Statistical analyses were applied on these IR spectra, first in order to compare spectra of cells from different stages of the cycle and second, to investigate to what extent the modifications related to the cell cycle contribute to the spectral variations due to paclitaxel treatment. Results demonstrate that the FTIR cell cycle signature is very small with respect to the changes induced by paclitaxel. 23951132 Osterix-cre labeled progenitor cells contribute to the formation and maintenance of the bone marrow stroma. We have carried out fate mapping studies using Osterix-EGFPCre and Osterix-CreERt animal models and found Cre reporter expression in many different cell types that make up the bone marrow stroma. Constitutive fate mapping resulted in the labeling of different cellular components located throughout the bone marrow, whereas temporal fate mapping at E14.5 resulted in the labeling of cells within a region of the bone marrow. The identity of cell types marked by constitutive and temporal fate mapping included osteoblasts, adipocytes, vascular smooth muscle, perineural, and stromal cells. Prolonged tracing of embryonic precursors labeled at E14.5dpc revealed the continued existence of their progeny up to 10 months of age, suggesting that fate mapped, labeled embryonic precursors gave rise to long lived bone marrow progenitor cells. To provide further evidence for the marking of bone marrow progenitors, bone marrow cultures derived from Osterix-EGFPCre/Ai9 mice showed that stromal cells retained Cre reporter expression and yielded a FACS sorted population that was able to differentiate into osteoblasts, adipocytes, and chondrocytes in vitro and into osteoblasts, adipocytes, and perivascular stromal cells after transplantation. Collectively, our studies reveal the developmental process by which Osterix-Cre labeled embryonic progenitors give rise to adult bone marrow progenitors which establish and maintain the bone marrow stroma. 23918493 In the safety net: a tale of ticking clocks and tricky diagnoses. In a time-crunched clinic, a physician and her resident battle the clock to uncover a potentially fatal diagnosis. 23772071 Pilus Gene Pool Variation and the Virulence of Corynebacterium diphtheriae Clinical Isolates during Infection of a Nematode. Toxigenic Corynebacterium diphtheriae strains cause diphtheria in humans. The toxigenic C. diphtheriae isolate NCTC13129 produces three distinct heterotrimeric pili that contain SpaA, SpaD, and SpaH, making up the shaft structure. The SpaA pili are known to mediate bacterial adherence to pharyngeal epithelial cells. However, to date little is known about the expression of different pili in various clinical isolates and their importance in bacterial pathogenesis. Here, we characterized a large collection of C. diphtheriae clinical isolates for their pilin gene pool by PCR and for the expression of the respective pilins by immunoblotting with antibodies against Spa pilins. Consistent with the role of a virulence factor, the SpaA-type pili were found to be prevalent among the isolates, and most significantly, corynebacterial adherence to pharyngeal epithelial cells was strictly correlated with isolates that were positive for the SpaA pili. By comparison, the isolates were heterogeneous for the presence of SpaD- and SpaH-type pili. Importantly, using Caenorhabditis elegans as a model host for infection, we show here that strain NCTC13129 rapidly killed the nematodes, the phenotype similar to isolates that were positive for toxin and all pilus types. In contrast, isogenic mutants of NCTC13129 lacking SpaA-type pili or devoid of toxin and SpaA pili exhibited delayed killing of nematodes with similar kinetics. Consistently, nontoxigenic or toxigenic isolates that lack one, two, or all three pilus types were also attenuated in virulence. This work signifies the important role of pili in corynebacterial pathogenesis and provides a simple host model to identify additional virulence factors. 22983867 Swim training of monosodium L-glutamate-obese mice improves the impaired insulin receptor tyrosine phosphorylation in pancreatic islets. The goal of the present study was to investigate changes on glucose homoeostasis and of the insulin receptor (IR) and insulin receptor substrate-1 (IRS-1) signalling in pancreatic islets from MSG-obese mice submitted to or not submitted to swim training. Swim training of 90-day-old MSG mice was used to evaluate whether signalling pathways of the IR and IRS-1 in islets are involved with the insulin resistance and glucose intolerance observed in this obese animal model. The results showed that IR tyrosine phosphorylation (pIR) was reduced by 42 % in MSG-obese mice (MSG, 6.7 ± 0.2 arbitrary units (a.u.); control, 11.5 ± 0.4 a.u.); on the other hand, exercise training increased pIR by 76 % in MSG mice without affecting control mice (MSG, 11.8 ± 0.3; control, 12.8 ± 0.2 a.u.). Although the treatment with MSG increased IRS-1 tyrosine phosphorylation (pIRS-1) by 96 % (MSG, 17.02 ± 0.6; control, 8.7 ± 0.2 a.u.), exercise training also increased it in both groups (control, 13.6 ± 0.1; MSG, 22.2 ± 1.1 a.u.). Current research shows that the practice of swim training increases the tyrosine phosphorylation of IRS-1 which can modulate the effect caused by obesity in insulin receptors. 23843577 No impact of obesity susceptibility loci on weight regain after a lifestyle intervention in overweight children. Abstract Objective: An obesity risk allele at the NEGR1 locus was shown to be associated with weight regain after a lifestyle intervention in obese adults. Independent confirmation and studies in children are lacking. Therefore, we analyzed the impact of this and 11 additional obesity susceptibility loci on weight regain after a lifestyle intervention in overweight children. Design and Methods: We longitudinally analyzed the changes in weight status as body mass index standard deviation score (BMI-SDS) in 282 overweight children (10.6±2.5 years, 47% male, BMI 27.1±3.9 kg/m2) both at the end of a 1-year lifestyle intervention and at 1 year after the end of intervention. We genotyped obesity risk single nucleotide polymorphisms (SNPs) derived from genome-wide association studies in or in proximity to the following genes: NEGR1, TNKS, SDCCAG8, FTO, MC4R, TMEM18, PTER, MTCH2, SH2B1, MAF, NPC1, and KCTD15. Results: The children reduced their BMI-SDS (-0.28±0.35; p<0.001) during intervention and increased their BMI-SDS between the end of intervention and 1 year later (+0.05±0.36; p=0.027). None of the SNPs including NEGR1 was related significantly to weight regain. Conclusions: We found no evidence for effects of any of the GWAS-based obesity marker alleles on weight regain in the course of 1 year after an intervention. 23846401 (DNS)C: a fluorescent, environmentally sensitive cytidine derivative for the direct detection of GGG triad sequences. With the goal of developing a fluorescent nucleoside sensitive to its environment, in this study we synthesized , a novel modified 2'-deoxycytidine bearing a 5-(dimethylamino)naphthalene-1-sulfonyl (dansyl) moiety at the N4 position, and tested its properties in monomeric and oligomeric states. undergoes intramolecular photoinduced electron transfer between its dansyl and cytosine units, resulting in remarkable changes in fluorescence that depend on the choice of solvent. In addition, the fluorescence behavior and thermal stability of oligonucleotides containing are dependent on the nature of the flanking and neighboring bases. Notably, exhibits fluorescence enhancement only in fully matched duplex DNA containing a GGG triad sequence. The environmental sensitivity of can be exploited as a fluorescence tool for monitoring the interactions of DNA with other biomolecules, including DNA, RNA, and proteins. 23840035 Pediatric oncology providers perceptions of barriers and facilitators to early integration of pediatric palliative care. Pediatric patients experience significant symptoms during cancer treatment. Symptom management is frequently inadequate. We studied perceptions of pediatric oncology care providers regarding early integration of palliative care (PC) for pediatric patients to identify barriers and facilitators that might assist in understanding how care could be improved. Pediatric oncology providers were recruited to participate in four focus groups. A proposal for early integration of a pediatric palliative care team (PPCT) was presented and followed by a facilitated discussion. Data were analytically categorized into themes by three independent coders using constant comparative analysis and crystallization techniques. A consensus approach was used to indentify final themes. Barriers to the proposed care model of early integration of a PPCT included provider role, conflicting philosophy, patient readiness, and emotional influence and were more prevalent in the physician participants compared to nurse practitioner, nursing, and social work participants. Facilitators included patient eligibility, improved patient care, education, and evidence-based medicine. Though all participants were invested in providing optimal patient care, physician participants believed the current standard of care model is meeting the needs of patients and family, while the nurse practitioner, nursing, and social work participants working on the same healthcare team believed the proposed care model would improve the overall care of children diagnosed with cancer. Differing perceptions among healthcare providers regarding the care of children with cancer suggest that team functioning could be improved. Avenues for pilot testing early integration of PC could provide useful information for a next study. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc. 23945574 Treatment of Fast Breathing in Neonates and Young Infants With Oral Amoxicillin Compared With Penicillin-Gentamicin Combination: Study Protocol for a Randomized, Open-label Equivalence Trial. The World Health Organization recommends hospitalization and injectable antibiotic treatment for young infants (0-59 days old), who present with signs of possible serious bacterial infection. Fast breathing alone is not associated with a high mortality risk for young infants and has been treated with oral antibiotics in some settings. This trial was designed to examine the safety and efficacy of oral amoxicillin for young infants with fast breathing compared with that of an injectable penicillin-gentamicin combination. The study is currently being conducted in the Democratic Republic of Congo, Kenya and Nigeria. This is a randomized, open-label equivalence trial. All births in the community are visited at home by trained community health workers to identify sick infants who are then referred to a trial study nurse for assessment. The primary outcome is treatment failure by day 8 after enrollment, defined as clinical deterioration, development of a serious adverse event including death, persistence of fast breathing by day 4 or recurrence up to day 8. Secondary outcomes include adherence to study therapy, relapse, death between days 9 and 15 and adverse effects associated with the study drugs. Study outcomes are assessed on days 4, 8, 11 and 15 after randomization by an independent outcome assessor who is blinded to the treatment being given. The results of this study will help inform the development of policies for the treatment of fast breathing among neonates and young infants in resource-limited settings. 23396578 Synthesis, structural characterization and catalytic evaluation of the ring-opening polymerization of discrete five-coordinate alkyl aluminium complexes. Five-coordinate alkyl aluminium complexes [AlR(κ(2)-pbpam)2] (R = Me 1, Et 2), [AlR(κ(2)-sbpam)2] (R = Me 3, Et 4) and [AlR{κ(2)-(S)-mbpam}2] (R = Me 5, Et 6), -pbpam [pbpam = N-phenyl-2,2-bis(3,5-dimethylpyrazol-1-yl)acetamidate], sbpam [sbpam = N-sec-butyl-2,2-bis(3,5-dimethylpyrazol-1-yl)acetamidate] and (S)-mbpam [(S)-mbpam = (S)-(-)-N-α-methylbenzyl-2,2-bis(3,5-dimethylpyrazol-1-yl)acetamidate] were obtained by an alkane elimination route involving the reaction of the previously reported acetamide heteroscorpionate precursors with 0.5 equiv. of the corresponding AlR3. In the solid state, complexes 1-6 adopt a distorted trigonal bipyramidal structure with the heteroscorpionate ligands arranged in a κ(2)-NO coordination mode. The molecular structures of 1-6 in solution were studied by VT NMR spectroscopy and a fluxional exchange between coordinated and noncoordinated pyrazole rings was observed. This process led to interconversion between the different isomers. Compounds 4 and 6 were used as precursors for the synthesis of the aryloxide aluminium compounds [Al(OR)(κ(2)-sbpam)2] (7) and [Al(OR){κ(2)-(S)-mbpam}2] (8) (R = 2,6-Me2C6H3O) by reaction with the corresponding 2,6-dimethylphenol. The structures of the complexes were determined by spectroscopic methods, and the X-ray crystal structures of 2, 6 and 7 were also established. Five-coordinate compounds 1-8 were evaluated as initiators in the ring-opening polymerization of rac-lactide. Compound 5 was also evaluated in the presence of a co-initiator. Finally, a study of the block and random copolymerization of ε-caprolactone and L-lactide was carried out. 23178381 Aspidin PB, a phloroglucinol derivative, induces apoptosis in human hepatocarcinoma HepG2 cells by modulating PI3K/Akt/GSK3β pathway. Aspidin PB, a phloroglucinol derivative isolated from Dryopteris fragrans (L.) Schott, has been previously reported to exert high biological activities. In the present study, we analyzed the apoptotic mechanisms of aspidin PB on human hepatoma cell line, HepG2. Initially, aspidin PB was shown to inhibit the growth of HepG2 cells in a time and dose-dependent manner. After treatment with aspidin PB for 72 h, 48 h and 24 h using MTT assay, the IC(50) values were 10.59 μM, 20.86 μM and 46.59 μM, respectively. Aspidin PB was capable to induce apoptosis, as measured by mitochondrial membrane potential (ΔΨm), acridine orange (AO) staining and propidium iodide (PI)/annexin V-FITC double staining. To further explore the signaling pathway of aspidin PB-mediated apoptosis, we examined PI3K/Akt related proteins. Western blot analysis revealed that aspidin PB inhibited PI3K expression, phosphorylation of Ser473 Akt and Ser9 GSK3β followed by up-regulation of nonsteroidal anti-inflammatory drugs activated gene-1 (NAG-1) expression. Similarly, the effects of aspidin PB on PI3K, Akt, GSK3β, NAG-1 expression were abolished by treatment with the PI3K inhibitor, wortmannin. Taken together, our data suggested that the PI3K/Akt/GSK3β signal pathway may represent one of the major mechanisms of the effects of aspidin PB on human hepatocarcinoma cells. 23960202 Effects of Core Auditory Cortex Deactivation on Neuronal Response to Simple and Complex Acoustic Signals in the Contralateral Anterior Auditory Field. Interhemispheric communication has been implicated in various functions of sensory signal processing and perception. Despite ample evidence demonstrating this phenomenon in the visual and somatosensory systems, to date, limited functional assessment of transcallosal transmission during periods of acoustic signal exposure has hindered our understanding of the role of interhemispheric connections between auditory cortical fields. Consequently, the present investigation examines the impact of core auditory cortical field deactivation on response properties of contralateral anterior auditory field (AAF) neurons in the felis catus. Single-unit responses to simple and complex acoustic signals were measured across AAF before, during, and after individual and combined cooling deactivation of contralateral primary auditory cortex (A1) and AAF neurons. Data analyses revealed that on average: 1) interhemispheric projections from core auditory areas to contralateral AAF neurons are predominantly excitatory, 2) changes in response strength vary based on acoustic features, 3) A1 and AAF projections can modulate AAF activity differently, 4) decreases in response strength are not specific to particular cortical laminae, and 5) contralateral inputs modulate AAF neuronal response thresholds. Collectively, these observations demonstrate that A1 and AAF neurons predominantly modulate AAF response properties via excitatory projections. 22892665 Show me your license, please: deregulation of centriole duplication mechanisms that promote amplification. Centrosomes are organelles involved in generating and organizing the interphase microtubule cytoskeleton, mitotic spindles and cilia. At the centrosome core are a pair of centrioles, structures that act as the duplicating elements of this organelle. Centrioles function to recruit and organize pericentriolar material which nucleates microtubules. While centrioles are relatively simple in construction, the mechanics of centriole biogenesis remain an important yet poorly understood process. More mysterious still are the regulatory mechanisms that oversee centriole assembly. The fidelity of centriole duplication is critical as defects in either the assembly or number of centrioles promote aneuploidy, primary microcephaly, birth defects, ciliopathies and tumorigenesis. In addition, some pathogens employ mechanisms to promote centriole overduplication to the detriment of the host cell. This review summarizes our current understanding of this important topic, highlighting the need for further study if new therapeutics are to be developed to treat diseases arising from defects of centrosome duplication. 23902569 Submucosal tumors: Comprehensive guide for the diagnosis and therapy of gastrointestinal submucosal tumors. Small submucosal tumors (SMT) without symptoms are frequently found by endoscopic and radiological examinations. To find proper diagnostic measures and therapeutic indications for histologically undiagnosed SMT, we reviewed published articles in PubMed between 1990 and March 2013 using the key words 'submucosal tumor' and the name of a specific disease. SMT is observed in a wide range of gastrointestinal (GI) diseases and conditions, including compression by extra-GI organs and lesions, congenital tumors, inflammation, and benign as well as malignant neoplastic lesions. In the diagnosis of diseases and decision-making for therapy, endoscopic ultrasonography (EUS) and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) may play a key role. Symptomatic SMT and SMT histologically diagnosed as malignant or potentially malignant tumors such as gastrointestinal stromal tumor (GIST) should be treated by surgery. SMT >5 cm, SMT increasing in size and those with'high-risk features' including irregular border, heterogeneous internal echo such as anechoic area, and heterogeneous enhancement by contrast media may also be removed by surgery. Laparoscopic approach is feasible for gastric GIST <5 cm and this is considered less invasive than the open approach. Emerging techniques using flexible endoscopes appear less invasive, but require further evidence and are still under clinical study. Correct diagnosis of SMT is challenging; however, EUS and EUS-FNA are useful in the histological diagnosis and clinical decision-making. In the future, minimally invasive approaches may be a mainstream of surgical treatment for small SMT. 23289665 On the azo/hydrazo equilibrium in Sudan I azo dye derivatives. In this study, Raman, infrared, UV/vis, NMR, and single crystal X-ray diffraction spectroscopies are used to elucidate the tautomeric equilibrium of azo dyes derived from 1-phenyl-azo-2-naphthol (Sudan I). A new crystallographic structure is described for Sudan I, revealing the presence of intramolecular hydrogen bonds and supramolecular interactions, such as the unconventional C-H···O hydrogen bond type, π-stacking, and charge-dipole interactions. All of these weak intermolecular interactions play a role in the stability of the crystalline structure. Theoretical calculations are also reported for geometries, energy, and spectroscopic properties. The predicted spectra are in accordance with the experiments carried out in the solid state and in solution of dichloromethane, carbon tetrachloride, and chloroform, suggesting the hydrazo form as the preferable tautomer in gas and condensate phases for Sudan I and its derivatives. 23745584 ERK signaling pathway regulates embryonic survival and eye development in goldfish, Carassius auratus. The extracellular signal-regulated kinase (ERK) is one of the three major types of mitogen-activated protein kinases. Previous studies showed that ERKs mediate various signaling pathways for cell proliferation, differentiation, survival and transformation in mammals. In the present study, we use goldfish as a model system and demonstrate that ERK kinases play important roles in promoting embryonic survival and regulate development of eye and trunk in vertebrates. ERKs are highly expressed in multiple tissues including lens epithelial cells, lens fiber cells, retina, brain, muscle and heart of adult goldfish. Injection of the dominant negative ERK mutant (DNM-ERK) into the fertilized eggs of goldfish significantly inhibited ERK activity at blastula stage, and completely blocked ERK activity at gastrula and later stages. As a result, the blastula cells were induced into apoptosis, and majority of the injected embryos were lethal at embryonic stages. At the molecular level, inhibition of ERK activity by DNM-ERKs suppressed phosphorylation of Bad at Ser-112 to promote apoptosis. Similar results were observed when MEK activity was inhibited by U0126 treatment. The survived embryos display significant abnormality in the phenotypes of both eye and trunk. Associated with the abnormality in the eye development, phosphorylation in Pax-6 and expression of HSF4 were significantly decreased and expression of the β-crystallin gene was also downregulated. These results provide novel information regarding the roles of ERKs in regulating vertebrate development. 23567949 Thiazolidin-4-one and thiazinan-4-one derivatives analogous to rosiglitazone as potential antihyperglycemic and antidyslipidemic agents. A number of thiazolidin-4-one and thiazinan-4-one derivatives were prepared by three component condensation in one pot reaction method. These compounds were evaluated for anti-hyperglycemic activity by in vitro and in vivo assay systems. The compounds with thiazolidin-4-one and thiazinan-4-one moieties exhibited significant anti-hyperglycemic activity. A few compounds (3a, 3b, 4a and 4b) have exhibited both anti-hyperglycemic and anti-dyslipidemic activities. Among them the thiazinan-4-one derivative 4a showed maximal (45%) improvement in oral glucose tolerance test in db/db mice at 30 mg/kg oral dose. 23834479 Comparative cost analysis of management of secondary hyperparathyroidism with paricalcitol or cinacalcet with low-dose vitamin D in hemodialysis patients. Abstract Objective: The objective of this analysis was to compare costs of paricalcitol or cinacalcet plus low dose vitamin D, and of phosphate binders, in patients in the IMPACT SHPT study; and to extrapolate those to estimate expected annual maintenance costs. Methods: IMPACT SHPT was a 28-week, randomized, open-label trial. Subjects from 12 countries received intravenous (IV) or oral paricalcitol, or oral cinacalcet plus fixed IV doxercalciferol or oral alfacalcidol. The primary end-point was the proportion of subjects who achieved a mean intact parathyroid hormone (iPTH) value of 150-300 pg/mL during weeks 21-28 (evaluation period). This study compares the costs of study drugs and phosphate binders among participants during the study and annualized. This analysis includes only those subjects that reached the evaluation period (134 in each group). Results: The mean total drug costs over the study period were €2606 (SD = €2000) in the paricalcitol group and €3034 (SD = €3006) in the cinacalcet group (difference €428, p = 0.1712). The estimated annualized costs were €5387 (SD = €4139) in the paricalcitol group and €6870 (SD = €6256) in the cinacalcet group (difference €1492, p = 0.0395). In addition, a significantly greater proportion (p = 0.010) of subjects in the paricalcitol arm (56.0%) achieved an iPTH of 150-300 pg/mL during the evaluation period compared to the cinacalcet arm (38.2%). Limitations: This was a secondary analysis of the IMPACT SHPT study which was not designed or powered for costs as an outcome. The dosing of study drugs and phosphate binders in the IMPACT study may not reflect actual practice, and patients were followed for 28 weeks, while the treatment of SHPT is long-term. Conclusion: Patients with SHPT requiring hemodialysis who were treated with a paricalcitol-based regimen for iPTH control had lower estimated annual drug costs compared to those treated with cinacalcet plus low-dose vitamin D. 23554095 Expression, purification and proteomic analysis of recombinant histone H4 acetylated at lysine 16. Many histone covalent modifications have been identified and shown to play key regulatory roles in eukaryotic transcription, DNA damage repair, and replication. In vitro experiments designed to understand the mechanistic role of individual modifications require the availability of substantial quantities of pure histones, homogeneously modified at specific residues. We have applied the amber stop codon/suppressor tRNA strategy to the production of histone H4 acetylated at lysine 16, a particularly important isoform of this histone. Our success relies on adapting the H4 DNA sequence to the codon preference of E. coli and on preventing the premature decay of the H4 mRNA. These modifications to the original procedure render it easily applicable to the generation of any covalently modified histone H4 isoform. 23607964 Synthesis and antiprogestational properties of novel 17-fluorinated steroids. Progesterone receptor (PR) plays a key role in reproductive functions, and compounds that inhibit progesterone action (antiprogestins) have potential use in the treatment of estrogen- and progesterone-dependent diseases, including uterine leiomyomas and breast cancer. In the present study, we chemically synthesized novel 17-fluorinated steroids and evaluated the cytotoxicity profiles of these compounds in T47D breast cancer cells compared to the activity of known antiprogestins, including ZK230 211, RU-486, CDB2914, CDB4124 and ORG33628. We analyzed in vitro receptor-binding assays and PR-transactivation assays to establish the antiprogestational activity of these molecules. The representative antiprogestin EC304 was found to inhibit in vitro tumorigenicity in a dose-dependent fashion in T47D cells by a colony formation assay at 1 and 10nM concentrations. The potent in vivo antiprogestational activity of EC304 was also demonstrated in an antinidation assay for the interruption of early pregnancy in rats. The strong antiprogestational activity and absence of antiglucocorticoid activity in EC compounds may demonstrate their utility in the treatment of leiomyoma, endometriosis and breast cancer. 23880567 The role of the dorsal dentate gyrus in object and object-context recognition. The aim of this study was to determine the role of the dorsal dentate gyrus (dDG) in object recognition memory using a black box and object-context recognition memory using a clear box with available cues that define a spatial context. Based on a 10min retention interval between the study phase and the test phase, the results indicated that dDG lesioned rats are impaired when compared to controls in the object-context recognition test in the clear box. However, there were no reliable differences between the dDG lesioned rats and the control group for the object recognition test in the black box. Even though the dDG lesioned rats were more active in object exploration, the habituation gradients did not differ. These results suggest that the dentate gyrus lesioned rats are clearly impaired when there is an important contribution of context. Furthermore, based on a 24h retention interval in the black box the dDG lesioned rats were impaired compared to controls. 23891187 Selective orexin receptor antagonists. The orexin, or hypocretin, neuropeptides (orexin-A and orexin-B) are produced on neurons in the hypothalamus which project to key areas of the brain that control sleep-wake states, modulation of food intake, panic, anxiety, emotion, reward and addictive behaviors. These neuropeptides exert their effects on a pair of G-protein coupled receptors termed the orexin-1 (OX1) and orexin-2 (OX2) receptors. Emerging biology suggests the involvement of these receptors in psychiatric disorders as they are thought to play a key role in the regulation of multiple systems. This review is intended to highlight key selective OX1 or OX2 small-molecule antagonists. 23964248 Cognitive impairment in bipolar disorder and schizophrenia: a systematic review. Aims: Previous comparisons of cognitive decline among patients with bipolar disorder (BD) and schizophrenia (SZ) have found somehow quite similar profiles of deficits, but results have varied between studies. Therefore an extensive and thoughtful systematic review of the matter is warranted. Methods: Studies were found through systematic search (PubMed) following PRISMA guidelines. To be included, studies must have assessed the following cognitive functions: executive functions, memory, IQ, attention-concentration, and perceptuomotor function. In order to make comparison between the two entities, studies should include BD patients with operationally defined euthymia, schizophrenic patients in remission, and third group of healthy control patients. Comparisons were made after controlling for years of schooling and residual affective symptoms. Results: We found that overall both SZ and BD patients present deficits on all neurocognitive measures compared to healthy controls. In particular, SZ patients show more severe and pervasive cognitive deficits while BD patients present a milder and more confined impairment. In addition, evidence from the literature suggests that SZ and BD patients share a similar cognitive impairment profile with different degrees of deficits. Therefore, the difference between the two groups seems to be more quantitative (degree of deficit) rather than qualitative (profile), supporting a dimensional approach to the two clinical entities. Limitations of the present review includes the impossibility to control for effects of medication, varying time required for assessment across studies, illness diagnosis reliability, and course severity. Conclusion: Patients with BD might exhibit a cognitive impairment that could be similar to SZ in terms of their profile, although patients with SZ may have more severe and widespread impairments. 23864624 The homologous tripartite viral RNA polymerase of A/swine/Korea/CT1204/2009(H1N2) influenza virus synergistically drives efficient replication and promotes respiratory-droplet transmission in ferrets. We previously reported that A/swine/Korea/1204/2009(H1N2) virus was virulent and transmissible in ferrets in which the respiratory droplet'transmissible virus (CT-Sw/1204) had acquired simultaneous HAD225G and NAS315N mutations. Incorporating these mutations into the non-pathogenic A/swine/Korea/1130/2009(H1N2, Sw/1130) virus consequently altered pathogenicity and growth in animal models but could not establish efficient transmission or remarkable disease. We, therefore, exploited various reassortants of these two viruses to better understand and identify other viral factors responsible for pathogenicity, transmissibility, or both. We found that possession of the CT-Sw/1204 tripartite viral polymerase enhanced replicative ability and pathogenicity in mice more significantly than did individual expression of polymerase subunit proteins. In ferrets, homologous expression of viral RNA polymerase complex genes in the context of the mutant Sw/1130 carrying the HA225G and NA315N modifications induced optimal replication in the upper nasal and lower respiratory tracts and also promoted efficient aerosol transmission to respiratory droplet'contact ferrets. These data show that the synergistic function of the tripartite polymerase gene complex of CT-Sw/1204 is critically important for virulence and transmission independent of the surface glycoproteins. Sequence comparison results reveal putative differences that are likely to be responsible for variation in disease. Our findings may help elucidate previously undefined viral factors that could expand the host range and disease severity induced by triple-reassortant swine viruses, including the A(H1N1)pdm09 virus, and therefore further justify the ongoing development of novel antiviral drugs targeting the viral polymerase complex subunits. 23726015 Spatial modelling of Bacillus anthracis ecological niche in Zimbabwe. Anthrax continues to cause significant mortalities in livestock, wildlife and humans worldwide. In Zimbabwe, anthrax outbreaks have been reported almost annually over the past four decades. In this study we tested whether anthrax outbreak data and a set of environmental variables can be used to predict the ecological niche for Bacillus anthracis using maximum entropy modelling for species geographical distribution (Maxent). Confirmed geo-referenced anthrax outbreaks data for the period 1995-2010 were used as presence locations and a set of environmental parameters; precipitation, temperature, vegetation biomass, soil type and terrain as predictor variables. Results showed that the environmental variables can adequately predict the ecological niche of B. anthracis (AUC for test data=0.717, p<0.001), with soil type as the most important predictor followed by variance of vegetation biomass and maximum temperature. These results imply that the model we tested may be used by animal health authorities in devising better control strategies for anthrax. 23891186 Anticonvulsant properties of histamine H3 receptor ligands belonging to N-substituted carbamates of imidazopropanol. Ligands targeting central histamine H3 receptors (H3Rs) for epilepsy might be a promising therapeutic approach. Therefore, the previously described and structurally strongly related imidazole-based derivatives belonging to carbamate class with high H3R in vitro affinity, in-vivo antagonist potency, and H3R selectivity profile were investigated on their anticonvulsant activity in maximal electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled seizure models in Wistar rats. The effects of systemic injection of H3R ligands 1-13 on MES-induced and PTZ-kindled seizures were screened and evaluated against the reference antiepileptic drug (AED) Phenytoin (PHT) and the standard histamine H3R inverse agonist/antagonist Thioperamide (THP) to determine their potential as new antiepileptic drugs. Following administration of the H3R ligands 1-13 (5, 10 and 15mg/kg, ip) there was a significant dose dependent reduction in MES-induced seizure duration. The protective action observed for the pentenyl carbamate derivative 4, the most protective H3R ligand among 1-13, was significantly higher (P <0.05) than that of standard H3R antagonist THP, and was reversed when rats were pretreated with the selective H3R agonist R-(α)-methyl-histamine (RAMH) (10mg/kg), or with the CNS penetrant H1R antagonist Pyrilamine (PYR) (10mg/kg). In addition, subeffective dose of H3R ligand 4 (5mg/kg, ip) significantly potentiated the protective action in rats pretreated with PHT (5mg/kg, ip), a dose without appreciable protective effect when given alone. In contrast, pretreatment with H3R ligand 4 (10mg/kg ip) failed to modify PTZ-kindled convulsion, whereas the reference drug PHT was found to fully protect PTZ-induced seizure. These results indicate that some of the investigated imidazole-based H3R ligands 1-13 may be of future therapeutic value in epilepsy. 23908605 Spatial distribution of D1R- and D2R-expressing medium-sized spiny neurons differs along the rostro-caudal axis of the mouse dorsal striatum. The striatum projection neurons are striatonigral and striatopallidal medium-sized spiny neurons (MSNs) that preferentially express D1 (D1R) and D2 (D2R) dopamine receptors, respectively. It is generally assumed that these neurons are physically intermingled, without cytoarchitectural organization although this has not been tested. To address this question we used BAC transgenic mice expressing enhanced green fluorescence (EGFP) under the control of Drd1a or Drd2 promoter and spatial point pattern statistics. We demonstrate that D1R- and D2R-expressing MSNs are randomly distributed in most of the dorsal striatum, whereas a specific region in the caudal striatum, adjacent to the GPe, lacks neurons expressing markers for indirect pathway neurons. This area comprises almost exclusively D1R-expressing MSNs. These neurons receive excitatory inputs from the primary auditory cortex and the medial geniculate thalamic nucleus and a rich dopamine innervation. This area contains cholinergic and GABAergic interneurons but apparently no D2R/A2aR modulation because no fluorescence was detected in the neuropil of Drd2-EGFP or Drd2-Cre, and Adora-Cre BAC transgenic mice crossed with reporter mice. This striatal area that expresses calbindin D28k, VGluT1 and 2, is poor in μ opiate receptors and preproenkephalin. Altogether, the differences observed in D1R-MSNs, D2R-MSNs, and interneurons densities, as well as the anatomical segregation of D1R- and D2R/A2aR-expressing MSNs suggest that there are regional differences in the organization of the striatum. 23826712 Vascular perfusion of the dorsal and palmar condyles of the equine third metacarpal bone. Palmar osteochondral disease (POD) is an overload arthrosis that commonly affects fetlock joints of racing Thoroughbreds (TB), but the etiopathogenesis of the disease has not been well defined. The aim of this study was to compare India ink perfusion in the dorsal and palmar condyles of the third metacarpal bone (MC3) in both passively flexed and maximally extended fetlock joints from paired equine cadaver limbs. Descriptive cadaver study comparing perfusion of condyles of MC3 in paired cadaver limbs in flexion (control group) and maximal extension (intervention group). Pairs of forelimbs were acquired from 5 TB horses euthanised for reasons unrelated to lameness. Limb pairs were perfused intra-arterially with India ink and then randomly assigned to passive flexion or maximal extension of the fetlock joint. Limbs were sectioned sagittally in 3 mm sections through the fetlock, and 12 sections per limb were processed using a modified tissue-clearing technique. Sections were subsequently digitally imaged, and bone perfusion evaluated with image analysis software. Greater perfusion of the dorsal condyle compared to palmar condyle was observed in 78% of sections from limbs in passive flexion, and 92% of maximally extended sections. Perfusion to the palmar aspect of the condyle was significantly decreased (P<0.0001) when the limbs were placed in maximal extension compared to passive flexion. The palmar condyle of MC3 had less perfusion than the dorsal condyle when the fetlock joint was in passive flexion and this difference was exacerbated by maximal extension. Based on the anatomical location of POD lesions, perfusion differences between the dorsal and palmar condyles of MC3 may be associated with development of these lesions. 23870177 Associations between social support and stroke survivors' health-related quality of life-A systematic review. Social support to stroke survivors has been recognized as an important determinant of their health-related quality of life (HRQoL), but this relationship is not clarified to date. More insight in the relationships between various types (i.e. emotional, instrumental, or informational support) and sources (i.e. partner, children) of social support and HRQoL might target post-stroke educational and counseling interventions to strengthen patient's social networks and supportive relationships. Systematic review. 11 original articles could be included. Most of these articles studied the overall perceived social support without further specification of type or source. They show a positive relation between perceived social support and stroke survivors' HRQoL. Relations between perceived social support and HRQoL seems to be more often significant and were stronger than relationships between specific social support types or sources and HRQoL. Due to the small number of studies and the heterogeneity in methods of assessing social support, a clear statement about the specific influence of social support source or type could not be made. Attention should be paid to promoting social support on the short and long term. Further research is needed to clarify the influence of social support type and source. 23746584 Liver fat content and lipid metabolism in dairy cows during early lactation and during a mid-lactation feed restriction. During the transition period, the lipid metabolism of dairy cows is markedly affected by energy status. Fatty liver is one of the main health disorders after parturition. The aim of this study was to evaluate the effects of a negative energy balance (NEB) at 2 stages in lactation [NEB at the onset of lactation postpartum (p.p.) and a deliberately induced NEB by feed restriction near 100 d in milk] on liver triglyceride content and parameters of lipid metabolism in plasma and liver based on mRNA abundance of associated genes. Fifty multiparous dairy cows were studied from wk 3 antepartum to approximately wk 17 p.p. in 2 periods. According to their energy balance in period 1 (parturition to wk 12 p.p.), cows were allocated to a control (CON; n=25) or a restriction group (RES; 70% of energy requirements; n=25) for 3 wk in mid lactation starting at around 100 d in milk (period 2). Liver triglyceride (TG) content, plasma nonesterified fatty acids (NEFA), and β-hydroxybutyrate were highest in wk 1 p.p. and decreased thereafter. During period 2, feed restriction did not affect liver TG and β-hydroxybutyrate concentration, whereas NEFA concentration was increased in RES cows as compared with CON cows. Hepatic mRNA abundances of tumor necrosis factor α, ATP citrate lyase, mitochondrial glycerol-3-phosphate acyltransferase, and glycerol-3-phosphate dehydrogenase 2 were not altered by lactational and energy status during both experimental periods. The expression of fatty acid synthase was higher in period 2 compared with period 1, but did not differ between RES and CON groups. The mRNA abundance of acetyl-coenzyme A-carboxylase showed a tendency toward higher expression during period 2 compared with period 1. The solute carrier family 27 (fatty acid transporter), member 1 (SLC27A1) was upregulated in wk 1 p.p. and also during feed restriction in RES cows. In conclusion, the present study shows that a NEB has different effects on hepatic lipid metabolism and TG concentration in the liver of dairy cows at early and later lactation. Therefore, the homeorhetic adaptations during the periparturient period trigger excessive responses in metabolism, whereas during the homeostatic control of endocrine and metabolic systems after established lactation, as during the period of feed restriction in the present study, organs are well adapted to metabolic and environmental changes. 23896420 Inactivated vaccine against viral hemorrhagic septicemia (VHS) emulsified with squalene and aluminum hydroxide adjuvant provides long term protection in olive flounder (Paralichthys olivaceus). Viral hemorrhagic septicemia (VHS) in olive flounder (Paralichthys olivaceus) remains an unsolved health problem in Korean aquaculture. Vaccination plays a significant role in modern aquaculture, and the duration of protection provided is of vital importance. Here, we have demonstrated the efficacy, duration of protection and safety of an inactivated vaccine emulsified with squalene (5%) and aluminum hydroxide (0.5%). The inactivated VHS vaccine provided a moderate protection of 37% and 47% relative percent survival (RPS) at 4 and 10 weeks post vaccination (wpv). Addition of squalene and aluminum hydroxide into inactivated VHS vaccine clearly enhanced the level of protection showing 58% and 83% RPS at 4 and 10wpv, respectively, indicating the need for adjuvants to enhance the efficacy. The vaccinated fish showed significant protection at 3, 6, 12, 18, 24, and 40wpv (except week 57) than non-vaccinated fish to an intraperitoneal challenge of 10(7.1)TCID50/fish at 15°C, with RPS of 60%, 64%, 71%, 55%, 52% and 50% (45% at 57 week), respectively, covering the duration of natural outbreak. Fish challenged at 18wpv at 6°C showed 56% RPS and protection at a low temperature. The antibody titer was high at 3wpv with an OD of 1.08±0.13, but decreased gradually and was undetectable by 24wpv. The vaccine formulation was safe without injection site reactions, adhesions, or pigmentation observed at 6, 12, 18, or 24wpv. Inflammatory reactions were observed in the spleen intestine at 6 and 12wpv but were similar as control by 24wpv. These results confirm that this vaccine is efficient and safe for olive flounder and could offer an appropriate strategy to prevent VHS without causing side effects. 23889607 Genetic diversity of antigens Rv2945c and Rv0309 in Mycobacterium tuberculosis strains may reflect ongoing immune evasion. Host immune pressure and associated immune evasion of pathogenic bacteria are key features of host-pathogen co-evolution. A previous study showed that human T-cell epitopes of Mycobacterium tuberculosis are evolutionarily hyperconserved and thus it was deduced that M. tuberculosis lacks antigenic variation and immune evasion. Here, we selected 173 clinical M. tuberculosis complex (MTBC) isolates from China, amplified the genes encoding Rv2945c and Rv0309, and compared the sequences. The results showed that genetic diversity existed in these two genes among the MTBC strains and two single nucleotide polymorphisms (SNPs) presented higher polymorphisms. Antigen Rv2945c harbored a higher number of amino acid substitutions of its T-cell epitopes, which may reflect ongoing immune evasion. In addition, the high dN/dS value of Rv0309 suggested antigen Rv0309 might be involved in diversifying selection to evade host immunity. Finally, a small group of strains were identified based on the genetic diversity of these two genes, which might indicate that they interact differently with human T cells compared with other strains. 23925263 Reactions of Cp2M (M = Ni, V) with dilithium diamido-aryl reagents; retention and oxidation of the transition metal ions. The reactions of dilithium 1,2-diamidobenzene, [1,2-(HN)2C6H4]Li2 ()Li2, and dilithium 1,8-diamidonaphthalene, [1,8-(NH)2C10H6]Li2 ()Li2, with Cp2Ni and Cp2V have been used to obtain the new complexes ()2Ni{Li(THF)2}2 (), ()3V{Li(THF)2}3 () and ()6Ni6·{[()3()3Ni6Li(THF)](2-)·2[Li(THF)4](+)} (), in which retention or oxidation of the initial metal(ii) centre is observed. Whereas and contain one transition metal ion within ion-paired structures, has a complicated co-crystalline composition which contains octahedral Ni6-cages constructed from six square-planar (16e) Ni(II) centres. 23831461 Function of seipin: New insights from Bscl2/seipin knockout mouse models. Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterized by near absence of adipose tissue and severe insulin resistance. Since the discovery of the gene in 2001, several cellular studies intended to unravel the biological function of seipin and revealed that seipin-deficiency alters adipocyte differentiation and lipid droplet morphology. However, the exact function of the protein remains unclear and the pathophysiology of BSCL in patients carrying BSCL2/seipin mutations is poorly understood. A major breakthrough in the field of seipin came recently, with the demonstration by three independent groups that Bscl2-deficient mice (Bscl2(-/-)) developed severe lipodystrophy with only residual white and brown fat pads, validating a critical role for seipin in adipose tissue homeostasis. Using in vivo, ex vivo and in vitro methods, these studies demonstrate that seipin plays a key role in adipogenesis, lipid droplet homeostasis and cellular triglyceride lipolysis. In addition to adipose tissue impairment, Bscl2(-/-) mice are diabetic and display severe hepatic steatosis. Treatment with thiazolidinediones (TZD) in Bscl2(-/-) mice increases adipose tissue mass and partially rescues the metabolic complications associated with BSCL, highlighting that lipoatrophy is the major cause of the BSCL phenotype. Except an unexpected hypotriglyceridemia, Bscl2(-/-) mice phenotype represents an almost perfect picture of the human disease. This review analyses how these studies using Bscl2(-/-) mice brought new insights into seipin function and the mechanisms involved in the pathophysiology of BSCL. We also analyse some of the human data in the light of the mouse phenotyping and discuss the validity of Bscl2(-)(/)(-) mice model to test pharmaceutical approaches for treating BSCL and its associated metabolic complications. 23968813 Ancylostoma ceylanicum, a re-emerging but neglected parasitic zoonosis. Although Ancylostoma ceylanicum is known to be an endemic and widely distributed hookworm of dogs and cats in Asia, its contribution to human morbidity as a potentially zoonotic hookworm remains largely unexplored. Since its discovery by Lane (1913) as a 'new parasite' of humans a century ago, the hookworm has been regarded as a 'rare' and 'abnormal' parasite and largely overlooked in surveys of human parasites. Recent molecular-based surveys in Asia, however, have demonstrated that A.ceylanicum is the second most common hookworm species infecting humans, comprising between 6% and 23% of total patent hookworm infections. In experimentally induced infections, A.ceylanicum mimics the clinical picture produced by the anthroponotic hookworms of 'ground itch' and moderate to severe abdominal pain in the acute phase. Natural infections with A.ceylanicum in humans have been reported in almost all geographical areas in which the hookworm is known to be endemic in dogs and cats, however for the majority of reports, no clinical data are available. Much like the anthroponotic hookworm species, patent A.ceylanicum adults can isolate within the jejunum to produce chronic infections that on occasion, may occur in high enough burdens to produce anaemia. In addition, the hookworm can act much like Ancylostoma caninum and be found lower in the gastrointestinal tract leading to abdominal distension and pain, diarrhoea and occult blood in the faeces accompanied by peripheral eosinophilia. Whether A.ceylanicum is capable of producing both classical hookworm disease and evoking morbidity through an uncontrolled allergic response in some individuals remains unascertained. Future investigations combining the use of molecular diagnostic tools with clinical and pathological data will shed further light on its role as a human pathogen. The control of this zoonosis necessitates an integrated and inter-sectorial "One Health" approach be adopted in communities where large numbers of dogs share a close relationship with humans. 23887880 Retrospective study of pregnant women placed under expectant management for persistent hemorrhage. To examine the clinicopathological characteristics of pregnant women who presented with intermittent hemorrhage occurring throughout pregnancy until delivery. A total of 24 women with intermittent hemorrhage occurring throughout pregnancy were categorized into two groups, a group with persistent subchorionic hematoma (PSH) and another with chronic abruption (CA), and the pregnancy outcomes were compared between the two groups. The data were expressed as medians (range). There were 18 women in the PSH group and 6 women in the CA group. The median gestational age at delivery was 27.9 (22.1-33.4) weeks in the PSH group and 32.9 (24.3-33.1) weeks in the CA group, revealing a significantly earlier gestational age at delivery in the former group (p = 0.014). The percentage of the women developing acute abruption tended to be higher in the CA group [66.7 % (4/6)] than in the PSH group [26.3 % (5/18)]. Small for gestational age (SGA) infants and neonatal chronic lung disease were seen at high incidences, but only in the PSH group [21.1 % (4/18) and 42.1 % (8/18), respectively]. PSH was associated with earlier gestational age at delivery, a higher incidence of SGA infants, and poorer pregnancy outcomes than CA. 23456415 Systemic lupus erythematosus (SLE) at the Kenyatta National Hospital. Systemic lupus erythematosus (SLE) is a complex disease with varied clinical presentation and autoantibody production. It has previously been reported as rare in Black Africans. We established a Rheumatology clinic at the Kenyatta National Hospital in April 2010, and a 1 year audit of this clinic was carried out in September 2011. This is a report of this audit of patients who met the American College of Rheumatology (ACR) criteria for SLE. Thirteen patients met the ACR criteria; their mean age was 34 years, and they were all female. The commonest manifestations were malar rash and arthritis in 69.2 %. Antinuclear antibody was present in 79.6 %, and anti-dsDNA was present in 38.5 %. None of them had human immunodeficiency virus infection; 30 % had other comorbidities (hypertension, diabetes, and renal failure). Thirty percent also had an infection during this period. All these 13 were on prednisolone and 92 % of them were on hydroxychloroquine. There was no reported death during the study period. This confirms the presence of SLE in patients in Kenya who meet the ACR criteria. 23916586 Cytotoxicity of bovine α-lactalbumin: Oleic acid complexes correlates with the disruption of lipid membranes. HAMLET/BAMLET (Human/Bovine α-Lactalbumin Made Lethal to Tumors) is a tumoricidal substance composed of partially unfolded human/bovine α-lactalbumin (HLA/BLA) and several oleic acid (OA) molecules. The HAMLET mechanism of interaction involves an insufficiently understood effect on the membrane or its embedded components. We examined the effect of BLAOA (bovine α-lactalbumin complexed with oleic acid, a HAMLET-like substance) and its individual components on cells and artificial lipid membranes using viability staining and metabolic dyes, fluorescence spectroscopy, leakage integrity assays and microscopy. Our results show a dose-dependency of OA used to prepare BLAOA on its ability to induce tumor cell death, and a correlation between leakage and cell death. BLAOA incorporates into the membrane, tightens the lipid packing and lowers their solvent accessibility. Fluorescence imaging reveals that giant unilamellar vesicles (GUVs) develop blebs and eventually collapse upon exposure to BLAOA, indicating that the lipid packing reorganization can translate into observable morphological effects. These effects are observed to be local in GUVs, and a tightly packed and solvent-shielded lipid environment is associated with leakage and GUV disruption. Furthermore, the effects of BLAOA on membrane are pH dependent, with an optimum of activity on artificial membranes near neutral pHs. While BLA alone is effective at membrane disruption at acidic pHs, OA is ineffective in a pH range of 4.5 to 9.1. Taken together, this supports a model where the lipid, fatty acid and protein components enhance each other's ability to affect the overall integrity of the membrane. 23942563 The Extra Burden of Infliximab Infusions in Inflammatory Bowel Disease. Infliximab (IFX) infusions require repeated hospitalizations. The median duration of each hospitalization stay, including time for infusion and the cost for the health care system, are unknown. We assessed the extra burden of IFX infusions in inflammatory bowel disease (IBD). This was a prospective cross-sectional study enrolling all consecutive patients with IBD treated with IFX at the Nancy IBD Unit (January to March 2012). Four parameters were assessed: median travel duration, median time that patients stayed at the IBD unit, reimbursement for transport by the health care system, and impact of IFX infusions on their work. Among 137 IBD patients, 48.9% were women, 74.5% had Crohn's disease, and the median age was 35 (range, 18-65) years. The median travel duration backward and forward from home to the Nancy IBD unit was 2 (range, 0.5-4) hours. The patients stayed at the IBD unit for a median period of 4.5 (range, 2.8-6.7) hours. For 63.5% of the patients (87/137), transport was reimbursed by the health care system. Of the patients receiving IFX infusions, 10.9% (15/137) were unemployed, 24.8% (34/137) had the agreement of their employer to spend 1 day at the hospital for their IFX infusion, 27.0% (36/137) asked specifically a vacation for the IFX infusion, and 13.9% (19/137) were in sick leave. The patients spend a median of 6.5 hours outside their home for each IFX infusion, and they often take a day of vacation or rest. This represents an extra burden for IFX-treated patients and for the health care system. 23474985 Continuous evolution of avian infectious bronchitis virus resulting in different variants co-circulating in southern China. Sixty field strains of avian infectious bronchitis virus (IBV) were isolated from chicken flocks in different regions of Guangxi from 1985 to 2012. Phylogenetic analysis of S1 subunit glycoprotein genes revealed that field isolates from 2009-2011 mostly belonged to the LX4 type, while those from 1985-2008 belonged to the HN08 type, and a few others belonged to the 4/91 type, the TW type and the Mass type. In addition, it is noteworthy that no obvious regional differences were found among these 60 strains isolated from six regions in Guangxi, while there was a high degree of sequence identity among the isolates in the same period of time. 23895724 Ulnar Neuropathy at the Elbow: An Evidence-based Algorithm. Ulnar neuropathy at the elbow is the second most common compression neuropathy of the upper extremity and poses a challenge for treating physicians. Lack of a standardized grading system, outcome measures, or surgical indications can make treatment decisions difficult to justify. Conclusions drawn from the available literature include similar rates of good to excellent outcomes for in situ decompression; transposition in the subcutaneous, submuscular, or intramuscular planes; and endoscopic decompression. Outcomes for revision surgery are generally less favorable. Development of standardized outcomes measures will be important in improving the quality and comparability of the literature on this subject. 23904174 Late-emigrating trunk neural crest cells in turtle embryos generate an osteogenic ectomesenchyme in the plastron. The turtle plastron is composed of a keratinized epidermis overlying nine dermal bones. Its developmental origin has been controversial; recent evidence suggests that the plastral bones derive from trunk neural crest cells (NCCs). This study extends the observations that there is a turtle-specific, second wave of NCC delamination and migration, after the original NCCs have reached their destination and differentiated. This second wave was confirmed by immunohistochemistry in whole mounts and serial sections, by injecting DiI into the lumen of the neural tube and tracing labeled cells into the plastron, and by isolating neural tubes from older turtle embryos and observing delaminating NCCs. This later migration gives rise to a plastral ectomesenchyme that expresses NCC markers and can be induced to initiate bone formation. The NCCs of this second migration have properties similar to those of the earlier NCCs, but also express markers characteristic of cranial NCCs. The majority of the cells of the plastron mesenchyme express neural crest markers, and have osteogenic differentiation capabilities that are similar or identical to craniofacial ectomesenchyme. Our evidence supports the contention that turtle plastron bones are derived from a late emigrating population of cells derived from the trunk neural crest. Developmental Dynamics, 2013. © 2013 Wiley Periodicals, Inc. 23924381 Diazo Compounds as Electrophiles To React with 1,4-Dilithio-1,3-dienes: Efficient Synthesis of 1-Imino-pyrrole Derivatives. 1-Imino-pyrrole and indole derivatives were synthesized in high yields from the reaction of diaryl diazomethanes with 1,4-dilithio-1,3-dienes. Diaryl diazomethanes reacted as electrophiles in this reaction. An unprecedented Zn-complex was formed via transmetalation of the above reaction intermediate with ZnCl2 and was structurally characterized. The trans-μ2-η(1):η(1) coordination mode in the solid state for this azaallylzinc compound was observed. 23764385 A longitudinal study of fronto-limbic brain structures in patients with bipolar I disorder during lithium treatment. In order to assess the association between therapeutic response to lithium treatment and fronto-limbic brain structures' volumes in bipolar I patients (BPI) 24 BPI and 11 healthy comparisons underwent MRI scans at baseline and 4 weeks later. The BPIs received lithium during the 4 week period with a goal of achieving therapeutic blood levels of >0.5mEq/L (mean level 0.67mEq/L). Mood symptoms were rated with the Hamilton Depression and the Young Mania Rating Scales at baseline and after 4 weeks, and response was defined as >50% decrease on either scale. Hippocampus, amygdala, prefrontal (PFC), dorsolateral prefrontal (DLPFC), and anterior cingulate cortex (ACC) volumes were obtained by Freesurfer image analysis suite. According to baseline symptoms and treatment response, patients were assigned to three groups: euthymics (n=6), responders (n=12) and non-responders (n=6). Taken over both time periods, non-responders had smaller right amygdala than healthy comparisons and euthymic BPI (p=0.035 and p=0.003, respectively). When baseline and after treatment volumes were compared, there was a significant enlargement in left PFC and left DLPFC in BPI who responded to treatment (p=0.002 and p=0.006, respectively). Left hippocampus and right ACC volumes decreased in non-responders (p=0.02 and p=0.0001, respectively). According to the findings decreased left hippocampus and right ACC volumes may be markers of non-response to lithium amongst BPI. Smaller right amygdala may reflect symptomatic remission and be a marker of treatment non-response. Increases in left PFC and left DLPFC as a result of lithium treatment may relate to lithium's neurotrophic effects. 23951339 Genetic characterization of the gypsy moth from china (lepidoptera, lymantriidae) using inter simple sequence repeats markers. This study provides the first genetic characterization of the gypsy moth from China (Lymantriadispar), one of the most recognized pests of forests and ornamental trees in the world. We assessed genetic diversity and structure in eight geographic populations of gypsy moths from China using five polymorphic Inter simple sequence repeat markers, which produced reproducible banding patterns. We observed 102 polymorphic loci across the 176 individuals sampled. Overall genetic diversity (Nei's, H) was 0.2357, while the mean genetic diversity within geographic populations was 0.1845 ± 0.0150. The observed genetic distance among the eight populations ranged from 0.0432 to 0.1034. Clustering analysis (using an unweighted pair-group method with arithmetic mean and multidimensional scaling), revealed strong concordance between the strength of genetic relationships among populations and their geographic proximity. Analysis of molecular variance demonstrated that 25.43% of the total variability (F ST = 0.2543, P < 0.001) was attributable to variation among geographic populations. The results of our analyses investigating the degree of polymorphism, genetic diversity (Nei's and Shannon) and genetic structure, suggest that individuals from Hebei may be better able to adapt to different environments and to disperse to new habitats. This study provides crucial genetic information needed to assess the distribution and population dynamics of this important pest species of global concern. 23719554 Impact of continuing folic acid after the first trimester of pregnancy: findings of a randomized trial of Folic Acid Supplementation in the Second and Third Trimesters. Supplementation with folic acid (FA) is recommended worldwide before and during early pregnancy because of its proven effect in preventing neural tube defects, but the role of FA after the 12th gestational week (GW) is much less clear. We investigated maternal folate and homocysteine responses and related effects in the newborn that resulted from continued FA supplementation after the first trimester of pregnancy. Pregnant women, aged 18-35 y, who were attending an antenatal clinic in Northern Ireland with singleton uncomplicated pregnancies and reported taking FA supplements in the first trimester, were randomly assigned at the start of trimester 2 to receive 400 μg FA/d or a placebo capsule. A total of 119 women (60 women in the placebo group; 59 women in the treatment group) completed the trial. From GWs 14-36, mean (±SD) serum folate decreased (from 45.7 ± 21.3 to 19.5 ± 16.5 nmol/L; P < 0.001) in unsupplemented women, whereas plasma homocysteine increased (6.6 ± 2.3 to 7.6 ± 2.3 μmol/L; P < 0.001). However, FA supplementation prevented these changes and resulted in a significant increase in red blood cell folate concentrations from 1203 ± 639 to 1746 ± 683 nmol/L (P < 0.001; GWs 14-36). Cord blood folate was significantly higher in the FA group than in the placebo group (red blood cell concentrations of 1993 ± 862 and 1418 ± 557 nmol/L, respectively; P = 0.001). Continued supplementation with 400 μg FA/d in trimesters 2 and 3 of pregnancy can increase maternal and cord blood folate status and prevent the increase in homocysteine concentration that otherwise occurs in late pregnancy. Whether these effects have benefits for pregnancy outcomes or early childhood requires additional study. 23239824 Aging-Induced Dysregulation of Dicer1-Dependent MicroRNA Expression Impairs Angiogenic Capacity of Rat Cerebromicrovascular Endothelial Cells. Age-related impairment of angiogenesis is likely to play a central role in cerebromicrovascular rarefaction and development of vascular cognitive impairment, but the underlying mechanisms remain elusive. To test the hypothesis that dysregulation of Dicer1 (ribonuclease III, a key enzyme of the microRNA [miRNA] machinery) impairs endothelial angiogenic capacity in aging, primary cerebromicrovascular endothelial cells (CMVECs) were isolated from young (3 months old) and aged (24 months old) Fischer 344 × Brown Norway rats. We found an age-related downregulation of Dicer1 expression both in CMVECs and in small cerebral vessels isolated from aged rats. In aged CMVECs, Dicer1 expression was increased by treatment with polyethylene glycol-catalase. Compared with young cells, aged CMVECs exhibited altered miRNA expression profile, which was associated with impaired proliferation, adhesion to vitronectin, collagen and fibronectin, cellular migration (measured by a wound-healing assay using electric cell-substrate impedance sensing technology), and impaired ability to form capillary-like structures. Overexpression of Dicer1 in aged CMVECs partially restored miRNA expression profile and significantly improved angiogenic processes. In young CMVECs, downregulation of Dicer1 (siRNA) resulted in altered miRNA expression profile associated with impaired proliferation, adhesion, migration, and tube formation, mimicking the aging phenotype. Collectively, we found that Dicer1 is essential for normal endothelial angiogenic processes, suggesting that age-related dysregulation of Dicer1-dependent miRNA expression may be a potential mechanism underlying impaired angiogenesis and cerebromicrovascular rarefaction in aging. 23835477 An ABA-mimicking ligand that reduces water loss and promotes drought resistance in plants. Abscisic acid (ABA) is the most important hormone for plants to resist drought and other abiotic stresses. ABA binds directly to the PYR/PYL family of ABA receptors, resulting in inhibition of type 2C phosphatases (PP2C) and activation of downstream ABA signaling. It is envisioned that intervention of ABA signaling by small molecules could help plants to overcome abiotic stresses such as drought, cold and soil salinity. However, chemical instability and rapid catabolism by plant enzymes limit the practical application of ABA itself. Here we report the identification of a small molecule ABA mimic (AM1) that acts as a potent activator of multiple members of the family of ABA receptors. In Arabidopsis, AM1 activates a gene network that is highly similar to that induced by ABA. Treatments with AM1 inhibit seed germination, prevent leaf water loss, and promote drought resistance. We solved the crystal structure of AM1 in complex with the PYL2 ABA receptor and the HAB1 PP2C, which revealed that AM1 mediates a gate-latch-lock interacting network, a structural feature that is conserved in the ABA-bound receptor/PP2C complex. Together, these results demonstrate that a single small molecule ABA mimic can activate multiple ABA receptors and protect plants from water loss and drought stress. Moreover, the AM1 complex crystal structure provides a structural basis for designing the next generation of ABA-mimicking small molecules. 23933275 Identification of a PTC-containing DlRan transcript and its differential expression during somatic embryogenesis in Dimocarpus longan. RAN (Ras-related nuclear protein) plays crucial roles in multiple cellular processes in yeast, animals and plants. Here we present a DlRan gene and its alternative splicing transcripts containing premature terminator codons (PTCs), identified from embryogenic cultures in longan. Multiple alignment and splicing pattern analyses indicated that DlRan-1 transcript harboring PTC was the consequence of alternative splicing. The accumulation of DlRan PTC-containing transcripts increased significantly when the embryogenic calli were treated with the translation inhibitor, cycloheximide, indicating that DlRan-1 may be targeted by NMD. The analysis of expression profiles of DlRan transcripts revealed that differential expression levels of the alternative spliced DlRan transcripts occurred during the development of embryogenic callus, globular-shaped embryos, and cotyledon-shaped embryos, respectively, in the longan somatic embryogenesis, and were in consistent with the embryo development in corresponding wild-type transcripts. The present work offers evidence to speculate that the alternatively spliced PTC-containing transcripts can be functional and may shed light on expression regulation of DlRan during development of the longan somatic embryos. 23948275 Optimization of pullulanase production in Escherichia coli by regulation of process conditions and supplement with natural osmolytes. In this study, the effects of temperature, IPTG (Isopropyl β-d-1-thiogalactopyranoside) concentration, and osmolytes (proline, K-glutamate, and betaine) on cell growth and soluble pullulanase productivity of recombinant Escherichia coli were investigated. The yield of soluble pullulanase was found to be enhanced with decrease in cultivation temperature, lower IPTG concentration, and betaine supplementation in a shake flask. In addition, a modified two-stage feeding strategy was proposed and applied in a 3-L fermentor supplied with 20mM betaine, which achieved a dry cell weight of 59.3gL(-1). Through this cultivation approach at 25°C, the total soluble activity of pullulanase reached 963.9UmL(-1), which was 8.3-fold higher than that observed without addition of betaine at 30°C (115.8UmL(-1)). The higher expression of soluble pullulanase in a scalable semisynthetic medium showed the potential of the proposed process for the industrial production of soluble enzyme. 23370213 Mechanisms of the placebo response. The concept of placebo response has evolved in the past few years from the clinical trial setting and medical practice to a psychobiological model that gives us important information on how the patient's brain is modified by the psychosocial context around the therapy. In this review, some examples will be given where physiological or pathological conditions are altered following the administration of an inert substance along with verbal instructions tailored to induce expectation of a change, and explanations will be presented with details on neurotransmitter changes and neural pathways activated. Although nothing is known about the biological underpinnings of the placebo response in the respiratory system, this review may help extending the neurobiological investigation of placebos from conditions such as pain and Parkinson's disease to respiratory disorders and symptoms such as cough. 23223424 Trends in the first decade of 21st century healthcare utilisation in a rheumatoid arthritis cohort compared with the general population. To study 21st century trends in healthcare utilisation by patients with rheumatoid arthritis (RA) compared with the general population. Observational cohort study. Using Swedish healthcare register data, we identified 3977 Region Skåne residents (mean age in 2001, 62.7 years; 73% women) presenting with RA (International Classification of Diseases-10 codes M05 or M06) in 1998-2001. We randomly sampled two referents from the general population per RA patient matched for age, sex and area of residence. We calculated the year 2001-2010 trends for the annual ratio (RA cohort/referents) of the mean number of hospitalisations and outpatient clinic visits. By the end of the 10-year period, 62% of patients and 74% of referents were still alive and resident in the region. From 2001 to 2010, the ratio (RA cohort/referents) of the mean number of hospitalisations for men and women decreased by 27% (p=0.01) and 28% (p=0.004), respectively. The corresponding decrease was 29% (p=0.005) and 16% (p=0.004) for outpatient physician care, 34% (p=0.009) and 18% (p=0.01) for nurse visits, and 34% (p=0.01) and 28% (p=0.004) for physiotherapy. The absolute reduction in number of hospitalisations was from an annual mean of 0.79 to 0.69 in male patients and from 0.71 to 0.59 in female patients. The corresponding annual mean number of consultations in outpatient physician care by male and female RA patients changed from 9.2 to 7.7 and from 9.9 to 8.7, respectively. During the first decade of the 21st century, coinciding with increasing use of earlier and more active RA treatment including biological treatment, overall inpatient and outpatient healthcare utilisation by a cohort of patients with RA decreased relative to the general population. 23950960 Species-Specific and Cross-Reactive IgG1 Antibody Binding to Viral Capsid Protein 1 (VP1) Antigens of Human Rhinovirus Species A, B and C. Human rhinoviruses (HRV) are associated with upper and lower respiratory illnesses, including severe infections causing hospitalization in both children and adults. Although the clinical significance of HRV infections is now well established, no detailed investigation of the immune response against HRV has been performed. The purpose of this study was to assess the IgG1 antibody response to the three known HRV species, HRV-A, -B and -C in healthy subjects. Recombinant polypeptides of viral capsid protein 1 (VP1) from two genotypes of HRV-A, -B and -C were expressed as glutathione S-transferase (GST) fusion proteins and purified by affinity and then size exclusion chromatography. The presence of secondary structures similar to the natural antigens was verified by circular dichroism analysis. Total and species-specific IgG1 measurements were quantitated by immunoassays and immunoabsorption using sera from 63 healthy adults. Most adult sera reacted with the HRV VP1 antigens, at high titres. As expected, strong cross-reactivity between HRV genotypes of the same species was found. A high degree of cross-reactivity between different HRV species was also evident, particularly between HRV-A and HRV-C. Immunoabsorption studies revealed HRV-C specific titres were markedly and significantly lower than the HRV-A and HRV-B specific titres (P<0.0001). A truncated construct of HRV-C VP1 showed greater specificity in detecting anti-HRV-C antibodies. High titres of IgG1 antibody were bound by the VP1 capsid proteins of HRV-A, -B and -C, but for the majority of people, a large proportion of the antibody to HRV-C was cross-reactive, especially to HRV-A. The improved specificity found for the truncated HRV-C VP1 indicates species-specific and cross-reactive regions could be defined. 23928106 Alteration of cardiac glucose metabolism in association to low birth weight: Experimental evidence in lambs with left ventricular hypertrophy. Intrauterine growth restriction that results in low birth weight (LBW) has been linked to the onset of pathological cardiac hypertrophy. An altered transition from a fetal to an adult energy metabolism phenotype, with increased reliance on glucose rather than fatty acids for energy production, could help explain this connection. We have therefore investigated cardiac metabolism in relation to left ventricular hypertrophy in LBW lambs, at 21days after birth. The expression of regulatory molecules involved in cardiac glucose and fatty acid metabolism was measured using real-time PCR and Western blotting. A section of the left ventricle was fixed for Periodic Acid Schiff staining to determine tissue glycogen content. There was increased abundance of insulin signalling pathway proteins (phospho-insulin receptor, insulin receptor and phospho-Akt) and the glucose transporter (GLUT)-1, but no change in GLUT-4 or glycogen content in the heart of LBW compared to ABW lambs. There was, however, increased abundance of cardiac pyruvate dehydrogenase kinase 4 (PDK-4) in LBW compared to ABW lambs. There were no significant changes in the mRNA expression of components of the peroxisome proliferator activated receptor regulatory complex or proteins involved in fatty acid metabolism. We concluded that LBW induced left ventricular hypertrophy was associated with increased GLUT-1 and PDK-4, suggesting increased glucose uptake, but decreased efficacy for the conversion of glucose to ATP. A reduced capacity for energy conversion could have significant implications for vulnerability to cardiovascular disease in adults who are born LBW. 23737480 Incidence and outcomes of patients with late recurrence of Wilms' tumor. Most relapses from Wilms' tumor occur within 2 years from diagnosis. This study aims to describe the incidence and outcome of patients who experienced a late recurrence (LR) more than 5 years after diagnosis across several clinical trials, and to develop evidence-based recommendations for follow-up surveillance. Available records on children with Wilms' tumor enrolled onto 10 national or international cooperative clinical trials were reviewed to identify patients who experienced a LR. Seventy of 13,330 (0.5%) patients with Wilms' tumor experienced a LR. No gender bias was observed. Median time elapsing between initial Wilms' tumor diagnosis and first recurrence was 13.2 years (range: 5.1-17.3 years). Initial tumor stage was: stage I (15); stage II (19); stage III (14); stage IV (8); bilateral disease stage V (14). The most frequent sites of relapse were-abdomen: 21, lungs: 20, and contralateral kidney: 15. Thirty-five children died of disease progression. Recurrence in the contralateral kidney was associated with a better outcome (13/15 patients alive), while initial tumor stage did not seem to influence the post-recurrence outcome. Therapies administered at recurrence varied between centers, preventing any conclusion about the best salvage treatment. LR of Wilms' tumor is rare and associated with similar outcome to those experiencing earlier recurrence. The low rate of LR does not justify prolonged monitoring. Further study of the biology of these tumors may give us some insights in regards to mechanisms on tumor cell dormancy or cancer stem cell maintenance. Pediatr Blood Cancer 2013;60:1612-1615. © 2013 Wiley Periodicals, Inc. 23725342 Synthesis of Redox-Active Molecules and Their Signaling Functions During the Expression of Plant Disease Resistance. Abstract Significance: Activation of immune responses in plants is associated with a parallel burst of both reactive oxygen intermediates (ROIs) and nitric oxide (NO). The mechanisms by which these small redox-active molecules are synthesized and their signaling functions are critical for plants to defend themselves against pathogen infection. Recent Advances: The synthesis of apoplastic ROIs by plants after pathogen recognition has long been attributed to membrane-bound NAPDH oxidases. However, the emerging data suggest a role for other enzymes in various subcellular locations in ROI production after defense activation. It is becoming widely appreciated that NO exerts its biochemical function through the S-nitrosylation of reactive cysteine thiols on target proteins, constituting a key post-translational modification. Recent evidence suggests that S-nitrosylation of specific defense-related proteins regulates their activity. Critical Issues: The source(s) of NO production after pathogen recognition remain(s) poorly understood. Some NO synthesis can be attributed to the activity of nitrate reductase but to date, no nitric oxide synthase (NOS) has been identified in higher plants. However, the signaling functions of S-nitrosylation are becoming more apparent and thus dissecting the molecular machinery underpinning this redox-based modification is vital to further our understanding of plant disease resistance. Future Directions: In addition to identifying new contributors to the oxidative burst, the discovery of an NOS in higher plants would significantly move the field forward. Since S-nitrosylation has now been confirmed to play various roles in immune signaling, this redox-based modification is a potential target to exploit for improving disease resistance in crop species. Antioxid. Redox Signal. 00, 000-000. 23034406 Tyrosine kinase inhibitor induced pancreatitis. Sorafenib and sunitinib are oral tyrosine kinase inhibitors, commonly used in the treatment of metastatic renal cell carcinoma. Known adverse events associated with tyrosine kinase inhibitors include hypertension and palmarplantar erythrodysesthesia. We report two cases of acute pancreatitis associated with tyrosine kinase inhibitors. 23545481 In vitro intestinal and hepatic metabolism of Di(2-ethylhexyl) phthalate (DEHP) in human and rat. Species and organ differences in the intrinsic clearance and the enzymes involved in the metabolism of DEHP were examined in subcellular fractions of the intestine and liver as well as by recombinant cytochrome P450 (CYP) isoforms of human and rat. Estimated clearance (CLint) of DEHP via esterase-mediated pathway in human intestine was 2.4-fold greater than that in human liver while its value in rat intestine was 1.7-fold less than that in rat liver. Ranks of CLint for CYP-mediated oxidation/dealkylation of MEHP were human liver>rat liver>human intestine>rat intestine. Estimates of CLint for the production of mono(2-ethyl-5-hydroxyhexyl) phthalate and mono(2-ethyl-5-oxohexyl) phthalate by human CYP2C9(*)1 were 4.2- and 2.6-fold greater than those by rat CYP2C6, respectively. Total CLint via hCYP2C9(*)3-mediated oxidation was 1.9- and 2.6-fold less than those by hCYP2C9(*)2 and 2C9(*)1, respectively. Estimated CLint for phthalic acid production by hCYP3A4 was 24.5μLnmolCYP(-1)min(-1) while it was continuously produced by rCYP2C6 and 3A2 via passive mechanism. These species/organ differences in major metabolic pathway and CYP isoforms should be considered for appraisal of the potential adverse health effects of DEHP. 23404178 Genetic basis of woven nest size in subsocial spider mites. The variation in nest size of social spider mites of the genus Stigmaeopsis is assumed to correspond to their anti-predator strategy and to be a key aspect of their social organization and speciation. It is known that the length of the dorsal setae (sc1, 2nd propodosomal setae) correlates with the nest size. We conducted interspecies cross experiments to determine the heredity of sc1 length and nest size using two closely related species that build different sized nests, Stigmaeopsis saharai Saito et Mori and Stigmaeopsis takahashii Saito et Mori. A cross between a S. saharai female and a S. takahashii male produced several viable F1 females. We measured sc1 length and the nest size of the F1 females and then compared these values with those of their parent species. The sc1 length of F1 females and the nest size constructed by these mites were intermediate with respect to the values of the two parent species. Therefore, the length of the sc1 and nest size are heritable. This result sheds light on the importance of considering the genetic basis for the variations in social organization. 23314104 Singular phase nano-optics in plasmonic metamaterials for label-free single-molecule detection. The non-trivial behaviour of phase is crucial for many important physical phenomena, such as, for example, the Aharonov-Bohm effect and the Berry phase. By manipulating the phase of light one can create 'twisted' photons, vortex knots and dislocations which has led to the emergence of the field of singular optics relying on abrupt phase changes. Here we demonstrate the feasibility of singular visible-light nano-optics which exploits the benefits of both plasmonic field enhancement and the peculiarities of the phase of light. We show that properly designed plasmonic metamaterials exhibit topologically protected zero reflection yielding to sharp phase changes nearby, which can be employed to radically improve the sensitivity of detectors based on plasmon resonances. By using reversible hydrogenation of graphene and binding of streptavidin-biotin, we demonstrate an areal mass sensitivity at a level of fg mm(-2) and detection of individual biomolecules, respectively. Our proof-of-concept results offer a route towards simple and scalable single-molecule label-free biosensing technologies. 23579775 Evaluation of an automated chemiluminescent immunoassay kit for antinuclear antibodies in autoimmune diseases. The identification of antinuclear antibodies (ANA) is an essential step in the diagnosis of different autoimmune diseases. The gold standard method for their detection is immunofluorescence assay. However, this is a subjective and laborious method, thus a need for simplified objective methods has aroused. In the current work, we evaluated such automated method, the LIAISON(®) (DiaSorin, Italy) for the detection of ANA. A total of 242 sera were analyzed including 67 from healthy subjects, 107 from primary biliary cirrhosis (PBC) patients, 20 from scleroderma patients and 48 from patients with Sjögren's syndrome. All sera were analyzed using the automated chemiluminescent immunoassays, LIAISON(®) for the presence of ANA (kit No. 310300). Positive samples were further analyzed for the presence of antidouble-stranded DNA (dsDNA) and autoantibodies to 6 extractable nuclear antigens (ENA) of the LIAISON(®) (kits No. 310330 and 310331). Negative samples were further analyzed by Blueblot ANA assay (D-TEK, Belgium) or BlueDot Liver (D-TEK, Belgium) as appropriate. The LIAISON(®) specificity for ANA screening was 97%. ANA positivity was determined in 80% of all patients. The sensitivity was 95.5% in scleroderma, 83% in PBC and 72.9% in Sjogren's syndrome. ENA was positive in all ANA-positive scleroderma and Sjögren's sera and in 27% of ANA-positive PBC sera. Among scleroderma or Sjögren patients that were ANA negative, 4 samples were positive for anti-SSA and 2 for RNP-68 utilizing Blueblot assays. M2 protein was found in 1 out of the ANA-negative PBC patients. The LIAISON(®) ANA screen is specific and sensitive for the evaluation of ANA in patients with primary biliary cirrhosis, scleroderma and Sjögren's syndrome. 23711610 Development of loop-mediated isothermal amplification (LAMP) for detection of Theileria equi. Several approaches have been developed for diagnosis of Theileria equi infection in horses and donkeys but all of them have limitations in practice. Due to numerous strengths including easy operation, cheapness and high sensitivity and specificity, LAMP has been already extensively used for surveillance of a number of diseases. We here set up a LAMP assay based on 18S rRNA gene for T. equi diagnosis. The approach was specific enough to differentiate T. equi from other evolutionary-related protozoa. Moreover, it was sensitive enough that LAMP was capable of detecting as much low as 10 copy target gene and 1 pg/μl blood genomic DNA. It was further demonstrated that LAMP was much more sensitive than canonical blood smear and comparable to PCR using test and field samples. The present results support an idea that LAMP developed in this study is reliable, reproducible and highly sensitive and specific, being a potential to be globally used for surveillance of T. equi infection in the field. 23836193 Chemical composition and antioxidant activity of a Lebanese plant Euphorbia macroclada schyzoceras. To determine the chemical composition, total phenolic and total flavonoid contents of the crude extracts from leaves and stems of a Lebanese plant Euphorbia macroclada schyzoceras (E. macroclada), and to evaluate their antioxidant potential using DPPH, H2O2, and chelating of ferrous ions tests. Quantification of the total phenolic and total flavonoid contents of the crude extracts from leaves and stems and the antioxidant activities were evaluated using spectrophotometric analyses. The chemical composition has been estimated using different techniques such as IR, LC/MS and NMR. Ethanolic extract from leaves of E. macroclada was better than aqueous extract and showed higher content in total phenolic and total flavonoid than found in the stems. On the other hand, using DPPH and H2O2 tests, this extract from leaves showed higher antioxidant capacity than aqueous extract. However, using the chelating of ferrous ions test, the antioxidant activity of the aqueous extract of both stems and leaves was stronger than that of ethanolic once. The chemical composition of the whole plant showed the presence of some aromatic compounds and fatty acids. Both ethanolic and water extracts from both parts of this plant are effective and have good antioxidant power. So, this plant can be used in the prevention of a number of diseases related to oxidative stress. 23427167 Physical Properties and Erosion Behavior of Poly(trimethylene carbonate-co-ε-caprolactone) Networks. Form-stable resorbable networks are prepared by gamma irradiating trimethylene carbonate (TMC)- and ε-caprolactone (CL)-based (co)polymer films. To evaluate their suitability for biomedical applications, their physical properties and erosion behavior are investigated. Homopolymer and copolymer networks that are amorphous at room temperature are flexible and rubbery with elastic moduli ranging from 1.8 ± 0.3 to 5.2 ± 0.4 MPa and permanent set values as low as 0.9% strain. The elastic moduli of the semicrystalline networks are higher and range from 61 ± 3 to 484 ± 34 MPa. The erosion behavior of (co)polymer networks is investigated in vitro using macrophage cultures, and in vivo by subcutaneous implantation in rats. In macrophage cultures, as well as upon implantation, a surface erosion process is observed for the amorphous (co)polymer networks, while an abrupt decrease in the rate and a change in the nature of the erosion process are observed with increasing crystallinity. These resorbable and form-stable networks with tuneable properties may find application in a broad range of biomedical applications. 23832184 A holistic approach combining factor analysis, positive matrix factorization, and chemical mass balance applied to receptor modeling. Rapid urbanization and population growth resulted in severe deterioration of air quality in most of the major cities in India. Therefore, it is essential to ascertain the contribution of various sources of air pollution to enable us to determine effective control policies. The present work focuses on the holistic approach of combining factor analysis (FA), positive matrix factorization (PMF), and chemical mass balance (CMB) for receptor modeling in order to identify the sources and their contributions in air quality studies. Insight from the emission inventory was used to remove subjectivity in source identification. Each approach has its own limitations. Factor analysis can identify qualitatively a minimal set of important factors which can account for the variations in the measured data. This step uses information from emission inventory to qualitatively match source profiles with factor loadings. This signifies the identification of dominant sources through factors. PMF gives source profiles and source contributions from the entire receptor data matrix. The data from FA is applied for rank reduction in PMF. Whenever multiple solutions exist, emission inventory identifies source profiles uniquely, so that they have a physical relevance. CMB identifies the source contributions obtained from FA and PMF. The novel approach proposed here overcomes the limitations of the individual methods in a synergistic way. The adopted methodology is found valid for a synthetic data and also the data of field study. 23850777 Beauvericin-induced cytotoxicity via ROS production and mitochondrial damage in Caco-2 cells. The cytotoxicity of beauvericin (BEA) on human colon adenocarcinoma (Caco-2) cells was studied as a function of time. Moreover, the oxidative damage and cell death endpoints were monitored after 24, 48 and 72h. After BEA exposure, the IC50 values ranged from 1.9±0.7 to 20.6±6.9μM. A decrease in reduced glutathione (GSH; 31%) levels, as well as an increase in oxidized glutathione (GSSG, 20%) was observed. In the presence of BEA, reactive oxygen species (ROS) level was highly increased at an early stage with the highest production of 2.0-fold higher than the control that was observed at 120min. BEA induced cell death by mitochondria-dependent apoptotic process with loss of the mitochondrial membrane potential (ΔΨm; 9% compared to the control), increase in LPO level (from 120% to 207% compared to the control) and reduced G0/G1 phase, with an arrest in G2/M, in a dose and time-dependent manner. Cell proliferation, apoptosis and ΔΨm determined, were in a dose- time-dependent manner. Moreover, DNA damage was observed after 12.0μM concentration. This study demonstrated that oxidative stress is one of the mechanism involved in BEA toxicity, moreover apoptosis induction and loss of ΔΨm contribute to its cytotoxicity in Caco-2 cells. 23853138 Brain arteriovenous malformations and seizures: an Italian study. To evaluate seizures as first clinical manifestation of brain arteriovenous malformations (AVMs), in relation to angioarchitectural features of these vascular anomalies. We performed a prospective observational study, collecting records of patients with AVMs consecutively admitted to the Neurological and Neurosurgery Units of Perugia University and to the Neurosurgery Unit of Terni Hospital, during a 10-year period (1 January 2002 to 1 June 2012). Two groups of patients, with or without seizures as AVM first presentation, were analysed to identify differences in demographic and angiographic features. A multivariate logistic regression model was also developed. We examined 101 patients with AVMs, 55 male and 46 female. Seizures were the initial clinical manifestation in 31 (30.7%) patients. We found a significant difference (p<0.05) between two groups of patients, with or without seizures as AVM first presentation concerning location, side, topography and venous drainage. A multivariate logistic regression model showed that clinical presentation with seizures was correlated with a location in the temporal and frontal lobes, and with a superficial topography. The strongest association (OR 3.48; 95% CI 1.77 to 6.85) was observed between seizures and AVM location in the temporal lobe. Vascular remodelling and haemodynamic changes of AVMs might create conditions for epileptogenesis. However, here we show that malformations with specific angiographic characteristics are more likely to be associated with seizures as first clinical presentation. Location is the most important feature related to epilepsy and in particular the temporal lobe might play a crucial role in the occurrence of seizure. 23884381 Pinched-flow hydrodynamic stretching of single-cells. Reorganization of cytoskeletal networks, condensation and decondensation of chromatin, and other whole cell structural changes often accompany changes in cell state and can reflect underlying disease processes. As such, the observable mechanical properties, or mechanophenotype, which is closely linked to intracellular architecture, can be a useful label-free biomarker of disease. In order to make use of this biomarker, a tool to measure cell mechanical properties should accurately characterize clinical specimens that consist of heterogeneous cell populations or contain small diseased subpopulations. Because of the heterogeneity and potential for rare populations in clinical samples, single-cell, high-throughput assays are ideally suited. Hydrodynamic stretching has recently emerged as a powerful method for carrying out mechanical phenotyping. Importantly, this method operates independently of molecular probes, reducing cost and sample preparation time, and yields information-rich signatures of cell populations through significant image analysis automation, promoting more widespread adoption. In this work, we present an alternative mode of hydrodynamic stretching where inertially-focused cells are squeezed in flow by perpendicular high-speed pinch flows that are extracted from the single inputted cell suspension. The pinched-flow stretching method reveals expected differences in cell deformability in two model systems. Furthermore, hydraulic circuit design is used to tune stretching forces and carry out multiple stretching modes (pinched-flow and extensional) in the same microfluidic channel with a single fluid input. The ability to create a self-sheathing flow from a single input solution should have general utility for other cytometry systems and the pinched-flow design enables an order of magnitude higher throughput (65 000 cells s(-1)) compared to our previously reported deformability cytometry method, which will be especially useful for identification of rare cell populations in clinical body fluids in the future. 23810120 General intellectual functioning as a buffer against theory-of-mind deficits in individuals at ultra-high risk for psychosis. The influence of neurocognition, including general intelligence, on theory of mind (ToM) among patients with schizophrenia spectrum disorder is controversial. The purpose of the present study was to identify the influences of the non-ToM cognition and general intelligence on ToM performance in individuals at ultra-high risk (UHR) for psychosis. Fifty-five UHR subjects and 58 healthy controls (HCs) completed neurocognitive, verbal, and nonverbal ToM tasks. UHR individuals showed poorer performance in the two verbal ToM tasks, the false-belief task and the strange-story tasks. Moreover, the UHR subjects displayed poorer recall on the interference list of the verbal learning test. Linear regression analysis revealed that neurocognitive functioning, including executive functioning, working memory, and general intelligence, accounted for significant amounts of the variance in the results for UHR individuals: 20.4% in the false-belief task, 44.0% in the strange-story task, and 49.0% in the nonverbal cartoon task. Neurocognition, including general intelligence, was not a significant contributor to performance on ToM tasks in HCs. ToM deficits were not noted in UHR individuals with above-average IQ scores (≥110) compared with UHR subjects with IQ scores less than 110, who displayed significant differences on all ToM tasks compared with HCs. The present results suggest that ToM deficits in UHR individuals are complex and may be influenced by non-ToM cognition. Our findings are discussed in relation to the role of neurocognitive abilities in ToM-related impairments in UHR individuals. 23558103 The importance of integration and top-down salience when listening to complex multi-part musical stimuli. In listening to multi-part music, auditory streams can be attended to either selectively or globally. More specifically, musicians rely on prioritized integrative attention which incorporates both stream segregation and integration to assess the relationship between concurrent parts. In this fMRI study, we used a piano duet to investigate which factors of a leader-follower relationship between parts grab the listener's attention and influence the perception of multi-part music. The factors considered included the structural relationship between melody and accompaniment as well as the temporal relationship (asynchronies) between parts. The structural relationship was manipulated by cueing subjects to the part of the duet that had to be prioritized. The temporal relationship was investigated by synthetically shifting the onset times of melody and accompaniment to either a consistent melody or accompaniment lead. The relative importance of these relationship factors for segregation and integration as attentional mechanisms was of interest. Participants were required to listen to the cued part and then globally assess if the prioritized stream was leading or following compared to the second stream. Results show that the melody is judged as more leading when it is globally temporally ahead whereas the accompaniment is not judged as leading when it is ahead. This bias may be a result of the interaction of salience of both leader-follower relationship factors. Interestingly, the corresponding interaction effect in the fMRI-data yields an inverse bias for melody in a fronto-parietal attention network. Corresponding parameter estimates within the dlPFC and right IPS show higher neural activity for attending to melody when listening to a performance without a temporal leader, pointing to an interaction of salience of both factors in listening to music. Both frontal and parietal activation implicate segregation and integration mechanisms and a top-down influence of salience on attention and the perception of leader-follower relations in music. 23708469 C.L.I.P.--continuous live imaging platform for direct observation of C. elegans physiological processes. Direct observation of developmental and physiological changes in certain model organisms over time has been technically challenging. In the model organism Caenorhabditis elegans, these studies require frequent or continuous imaging at physiologically benign conditions. However, standard methods use anaesthetics, glue, or microbeads, which prevent animals from feeding during the experiment. Thus, the animals' normal physiological function may be affected over time. Here we present a platform designed for dynamic studies of C. elegans. The system is capable of immobilizing only the animals' bodies under benign conditions and without physical deformation. Simultaneously, the animals' heads remain free to move and feed for the duration of the experiment. This allows for high-resolution and high-magnification fluorescent imaging of immobilized and feeding animals. The system is very easy to fabricate, set up, and operate, and should be widely applicable to many problems in developmental and physiological studies. 23158218 Developmental associations between traits of autism spectrum disorder and attention deficit hyperactivity disorder: a genetically informative, longitudinal twin study. Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), and associated subclinical traits, regularly co-occur with one another. However, the aetiology of their co-occurrence remains poorly understood. This paper provides the first genetically informative, longitudinal analysis of the interaction between traits of ASD and ADHD, and explores their genetic and environmental overlap. Method Parents of approximately 5000 twin pairs completed questionnaires assessing traits of ASD and ADHD when twins were aged 8 and 12 years. Cross-lagged longitudinal modelling explored their developmental association, enabling a consideration of phenotypic-driven processes. Overlapping aetiological influences on traits at age 12 years were explored using bivariate twin modelling. Traits of ADHD at age 8 years were more strongly predictive of traits of ASD at 12 years than traits of ASD at 8 years were of traits of ADHD at 12 years. Analysis of traits by subscales assessing specific symptom domains suggested that communication difficulties were most strongly associated with traits of ADHD. Bivariate modelling suggested moderate genetic overlap on traits in males (genetic correlation = 0.41), and a modest degree of overlap in females (genetic correlation = 0.23) at age 12 years. Traits of ADHD at age 8 years significantly influence traits of ASD at age 12 years, after controlling for their initial relationship at age 8 years. In particular, early ADHD traits influenced later communication difficulties. These findings demonstrate the dynamic nature of co-occurring traits across development. In addition, these findings add to a growing body of literature suggesting that traits of ASD and ADHD may arise via similar aetiological processes. 23371806 Oroxylin A improves attention deficit hyperactivity disorder-like behaviors in the spontaneously hypertensive rat and inhibits reuptake of dopamine in vitro. In previous studies we have demonstrated that the γ-aminobutryic acid-A (GABA-A) receptor antagonist oroxylin A has an awakening effect and it also represses ADHD-like behaviors (hyperactivity, impulsivity and inattention) in the spontaneously hypertensive rat (SHR) model of attention-deficit hyperactivity disorder (ADHD). We hypothesized that the effects of oroxylin A were exerted via the GABA-A receptor given the important role of the GABAergic system in ADHD. However, it is possible that aside from the GABAergic system, oroxylin A may influence other systems especially those implicated in ADHD (e.g. DAergic, etc.). To test this hypothesis, we evaluated the effects of GABA agonist, or dopamine (DA) antagonist in oroxylin A-induced alleviation of ADHD-like behaviors in SHR. SHR showed inattention and impulsivity as measured by the Y-maze and the electro-foot shock aversive water drinking tests, respectively. Oroxylin A significantly improved these behaviors, furthermore, its effect on SHR impulsivity was attenuated by haloperidol, a DA antagonist, but not by baicalein, an agonist of the GABA-A receptor. In vitro studies showed that oroxylin A inhibited DA uptake similar to methylphenidate, a dopamine transporter blocker, but did not influence norepinephrine uptake unlike atomoxetine, a selective NE reuptake inhibitor. Collectively, the present findings suggest that oroxylin A improves ADHD-like behaviors in SHR via enhancement of DA neurotransmission and not modulation of GABA pathway as previously reported. Importantly, the present study indicates the potential therapeutic value of oroxylin A in the treatment of ADHD. 23625175 The Value of Expression of M2-PK and VEGF in Patients with Advanced Gastric Cancer. Glycolytic pyruvate kinase isoenzyme type M2 (M2-PK) plays a key role in tumor metabolism and energy production. Vascular endothelial growth factor (VEGF) is critical in regulating angiogenesis which is an essential process required for tumor growth and metastasis. These two genes may function in accordance with tumor development. The purpose of this study was to investigate the relationship between the expression of M2-PK and VEGF, and their association with clinicopathological features in patients with advanced gastric cancer. Expression of M2-PK and VEGF were examined in 142 cases of paraffin-embedded tissue blocks from patients with advanced gastric cancer. M2-PK expression was found to strongly correlate with that of VEGF (r = 0.718). In addition, expression of M2-PK and VEGF correlates with tumor size (p = 0.0001, and p = 0.0017, respectively), depth of invasion (p = 0.0024, and p = 0.0261, respectively), and lymph node metastasis (p = 0.036, and p = 0.028, respectively). The high expression levels of M2-PK and VEGF may indicate poor prognosis in patients with advanced gastric cancer. 23585555 Relationship between serum thyrotropin levels and intrarenal hemodynamic parameters in euthyroid subjects. OBJECTIVE: Low thyroid function may be associated with a reduced glomerular filtration rate (GFR) calculated on the basis of creatinine metabolism. Thyroid hormone directly affects serum creatinine in muscle and low thyroid function might exert a similar direct effect in the kidney. The goal of the study was to evaluate this possibility by assessment of the inulin-based GFR and to examine the mechanism underlying the reduction of GFR. PATIENTS AND METHODS: Renal and glomerular hemodynamics were assessed by simultaneous measurements of plasma clearance of para-aminohippurate (CPAH) and inulin (Cin) in 26 patients with serum creatinine <1.00 mg/dl and without thyroid disease. All subjects were normotensive with or without antihypertensive treatment and were kept in a sodium-replete state. Renal and glomerular hemodynamics were calculated using Gomez`s formulae. RESULTS: Serum thyroid stimulating hormone (TSH), including within the normal range (0.69-4.30 μIU/ml), was positively correlated with vascular resistance at the afferent arteriole (Ra) (r = 0.609, p = 0.0010), but not at the efferent arteriole (Re). Serum TSH was significantly and negatively correlated with renal plasma flow (RPF), renal blood flow (RBF), and glomerular filtration rate (GFR) (r = -0.456, p = 0.0192; r = -0.438, p = 0.0252; r = -0.505, p = 0.0086, respectively). In multiple regression analysis, serum TSH was significantly positively associated with Ra after adjustment for age and mean blood pressure. CONCLUSIONS: These findings suggest that low thyroid function, even within the normal range, is associated with reduced RPF, RBF and GFR, which might be caused by a preferential increase of Ra. 23687342 Atypical presentation of verrucous carcinoma: a case study and review of the literature. Verrucous carcinoma is a slow-growing lesion that is most often found on the weight-bearing surface of the foot and should be considered in the differential diagnosis for chronic nonhealing wounds in the diabetic neuropathic population. Accurate diagnosis may be difficult initially and often requires repeat histopathologic evaluation by an experienced pathologist. Verrucous carcinoma can invade deeper tissues; however, extension to bone is a rare occurrence. The authors present a case report of an atypical verrucous carcinoma on the dorsal aspect of the foot and a review of the literature. Studies suggest that multiple therapies exist and recurrence does occur; however, this is less likely with wide excision and more so with Mohs' surgery. With a high clinical suspicion and thorough histopathologic exam, bone involvement and amputation may be avoided. Levels of Evidence: Therapeutic, Level IV. 23822191 Congenital nystagmus in two infants born from mothers exposed to methadone during pregnancy. Methadone is commonly prescribed as a substitute for illicit opioids. Use of methadone during pregnancy is associated with neonatal abstinence syndrome (NAS), reduced head circumference as well as a slight increase in neonatal mortality and morbidity. Less is known about the effects of methadone on the visual system.Cases: We report two Italian cases of nystagmus in infants born from mothers exposed to methadone during pregnancy. Ophthalmic or central disorders were excluded as a cause of nystagmus in both infants. The first case was followed at 3, 6 and 12 months while the second one was evaluated at 5 and 8 months. Both infants had normal neurological and cognitive development. Their first evaluation revealed different characteristics but both showed progressive improvement in ocular disorder, persistence of pendular horizontal nystagmus and nearly normal visual acuity. This report, the first description of Italian cases of nystagmus related to use of methadone during pregnancy, underlies the importance of a careful investigation of drug use in pregnancy in cases of unexplained congenital nystagmus. 23563092 The PML isoform IV is a negative regulator of nuclear EGFR's transcriptional activity in lung cancer. Epidermal growth factor receptor (EGFR) is a membrane-bound receptor tyrosine kinase, which can transduce intracellular signals responsible for cell proliferation. It is frequently overexpressed and/or constitutively activated in non-small cell lung cancer and thus is considered as a major cause of this disease. Recently, EGFR has been found in the nucleus where the nuclear EGFR (nEGFR) can function as a transcription factor activating the transcription of genes such as cyclin D1 gene (CCND1), which is essential for cell proliferation. Nevertheless, how nEGFR's transcriptional activity is regulated remains unclear. Promyelocytic leukemia protein (PML) is a tumor suppressor, which is lost in various cancers including lung cancer. However, the role of PML in the suppression of lung cancer growth is still unclear. When we investigated the role of PML in the regulation of lung cancer cell growth, we found that PML isoform IV (PMLIV) preferentially represses the growth of lung cancer cells bearing constitutively active EGFR. Besides, when growing in the EGFR activating conditions, the growth of EGFR wild-type bearing A549 cells has been repressed by PMLIV overexpression. We also found that PMLIV can interact physically with nEGFR and represses the transcription of nEGFR target genes. We showed that PMLIV is recruited by nEGFR to the target promoters and reduces the promoter histone acetylation level via HDAC1. Together, our results suggest that PMLIV interacts with nEGFR upon EGFR activation and represses the transcription of nEGFR target genes such as CCND1 and thus leading to inhibition of the lung cancer cell growth. 23874497 Bayesian Mixture Models for Assessment of Gene Differential Behaviour and Prediction of pCR through the Integration of Copy Number and Gene Expression Data. We consider modeling jointly microarray RNA expression and DNA copy number data. We propose Bayesian mixture models that define latent Gaussian probit scores for the DNA and RNA, and integrate between the two platforms via a regression of the RNA probit scores on the DNA probit scores. Such a regression conveniently allows us to include additional sample specific covariates such as biological conditions and clinical outcomes. The two developed methods are aimed respectively to make inference on differential behaviour of genes in patients showing different subtypes of breast cancer and to predict the pathological complete response (pCR) of patients borrowing strength across the genomic platforms. Posterior inference is carried out via MCMC simulations. We demonstrate the proposed methodology using a published data set consisting of 121 breast cancer patients. 23843149 Kinase in Motion: Insights into the Dynamic Nature of p38α by High-Pressure NMR Spectroscopic Studies. Protein kinases are highly dynamic and complex molecules. Here we present high-pressure and relaxation studies of the activated p38α mitogen-activated protein kinase (MAPK). p38α plays a central role in inflammatory diseases such as rheumatoid arthritis and is therefore a highly attractive pharmaceutical target. The combination of high pressure and NMR spectroscopy allowed for a detailed per-residue based assessment of the structural plasticity of p38α and the accessibility of low-lying excited-energy conformations throughout the kinase structure. Such information is uniquely accessible through the combination of liquid-state NMR and high pressure and is of considerable value for the drug discovery process. The interactions of p38α and DFG-in and DFG-out ligands were studied under the application of high pressure, and we demonstrate how we can alter kinase dynamics by pressure in a similar way to what has previously only been observed by ligand binding. Pressure is shown to be a mild and efficient tool for manipulation of intermediate-timescale dynamics. 23639451 Fusidic acid and rifampicin co-loaded PLGA nanofibers for the prevention of orthopedic implant associated infections. Implant-associated infections following invasive orthopedic surgery are a major clinical problem, and are one of the primary causes of joint failure following total joint arthroplasty. Current strategies using perioperative antibiotics have been met with little clinical success and have resulted in various systemic toxicities and the promotion of antibiotic resistant microorganisms. Here we report the development of a biodegradable localized delivery system using poly(D,L-lactic acid-co-glycolic acid) (PLGA) for the combinatorial release of fusidic acid (FA) (or its sodium salt; SF) and rifampicin (RIF) using electrospinning. The drug-loaded formulations showed good antibiotic encapsulation (~75%-100%), and a biphasic drug release profile. All dual-loaded formulations showed direct antimicrobial activity in vitro against Staphylococcus epidermidis, and two strains of methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, lead formulations containing 10% (w/w) FA/SF and 5% (w/w) RIF were able to prevent the adherence of MRSA to a titanium implant in an in vivo rodent model of subcutaneous implant-associated infection. 23872615 Detection of antibody to Purpureocillium lilacinum by immunofluorescent assay and flow cytometry in serum of infected C57BL/6 mice. Purpureocillium lilacinum is an emerging pathogenic fungus that can cause different clinical manifestations ranging from cutaneous and sub-cutaneous infections to severe oculomycosis. In this study, using both conventional indirect immunofluorescence and non-conventional flow cytometry approaches, IgG antibodies were readily detected in both C57BL/6 immunocompetent and immunosuppressed mice after i.v. infection with P. lilacinum. The humoral immune response was specific, since virtually no antibodies were detected in the serum of control mice. Flow cytometry assays also showed both quantitative and qualitative differences in total IgG and its isotypes in sera of immunocompetent and immunosupressed infected mice. Although a good starting point, it is clear that the effectiveness of serological assays for P. lilacinum hyalohyphomycosis identification in clinical studies still requires further standardization. Upon further validation in humans, these techniques have the potential to be suitable to detect P. lilacinum infection in patients, thereby avoiding current laborious and time-consuming culture techniques. 23951047 Glycemic Index, Glycemic Load and Mammographic Breast Density: The EPIC Florence Longitudinal Study. A few studies have evaluated the association between diet and mammographic breast density (MBD) and results are inconsistent. MBD, a well-recognized risk factor for breast cancer, has been proposed as a marker of cumulative exposure to hormones and growth factors. Diets with a high glycemic index (GI) or glycemic load (GL) may increase breast cancer risk, via an effect on the insulin-like growth factor axis. We have investigated the association between carbohydrate intake, GI, GL and MBD in a prospective study. We identified a large series of women, in the frame of the EPIC-Florence cohort, with a mammogram taken five years after enrolment, when detailed information on dietary and lifestyle habits and anthropometric measurements had been collected. Mammograms have been retrieved (1,668, 83%) and MBD assessed according to Wolfe's classification. We compared women with high MBD (P2+DY Wolfe's categories) with those with low MBD (N1+P1) through logistic models adjusted for age, education, body mass index, menopause, number of children, breast feeding, physical activity, non-alcohol energy, fibers, saturated fat and alcohol. A direct association between GL and high MBD emerged in the highest quintile of intake in comparison with the lowest quintile (OR = 1.73, 95%CI 1.13-2.67, p for trend = 0.048) while no association with glycemic index was evident. These results were confirmed after exclusion of women reporting to be on a diet or affected with diabetes, and when Hormone Replacement Therapy at the date of mammographic examination used to assess MBD was considered. The effect was particularly evident among leaner women, although no interaction was found. A positive association was suggested for increasing simple sugar and total carbohydrates intakes limited to the highest quintiles. In this Italian population we observed an association between glycemic load, total and rapidly absorbed carbohydrates and high MBD. These novel results warrant further investigations. 23774791 Codelivery of VEGF siRNA and Gemcitabine Monophosphate in a Single Nanoparticle Formulation for Effective Treatment of NSCLC. There is an urgent need for new therapeutics for the treatment of aggressive and metastatic refractory human non-small-cell lung cancer (NSCLC). Antiangiogenesis therapy and chemotherapy are the two major treatment options. Unfortunately, both types of therapies when used individually have their disadvantages. Integrating antiangiogenesis therapy with chemotherapy is expected to target the tumor's vascular endothelial cells and the tumor cells simultaneously. In this study, we coformulated Vascular endothelial growth factor (VEGF) siRNA targeting VEGFs and gemcitabine monophosphate (GMP) into a single cell-specific, targeted lipid/calcium/phosphate (LCP) nanoparticle formulation. Antitumor effect of the combination therapy using LCP loaded with both VEGF siRNA and GMP was evaluated in both subcutaneous and orthotopic xenograft models of NSCLC with systemic administration. The improved therapeutic response, as compared with either VEGF siRNA or GMP therapy alone, was supported by the observation of 30-40% induction of tumor cell apoptosis, eightfold reduction of tumor cell proliferation and significant decrease of tumor microvessel density (MVD). The combination therapy led to dramatic inhibition of tumor growth, with little in vivo toxicity. In addition, the current studies demonstrated the possibility of incorporating multiple nucleic acid molecules and phosphorylated small-molecule drugs, targeting to different pathways, into a single nanoparticle formulation for profound therapeutic effect. 23917124 System-dependent regulations of colour-pattern development: a mutagenesis study of the pale grass blue butterfly. Developmental studies on wing colour patterns have been performed in nymphalid butterflies, but efficient genetic manipulations, including mutagenesis, have not been well established. Here, we have performed mutagenesis experiments in a lycaenid butterfly, the pale grass blue Zizeeria maha, to produce colour-pattern mutants. We fed the P-generation larvae an artificial diet containing the mutagen ethyl methane sulfonate (EMS), and the F1- and F2-generation adults showed various aberrant colour patterns: dorsoventral transformation, anterioposterior background colouration gap, weak contrast, disarrangement of spots, reduction of the size of spots, loss of spots, fusion of spots, and ectopic spots. Among them, the disarrangement, reduction, and loss of spots were likely produced by the coordinated changes of many spots of a single wing around the discal spot in a system-dependent manner, demonstrating the existence of the central symmetry system. The present study revealed multiple genetic regulations for system-dependent and wing-wide colour-pattern determination in lycaenid butterflies. 23886375 Strengthening the health workforce and rolling out universal health coverage: the need for policy analysis. This article opens a debate about how to think about moving forward with the emerging twin movements of human resources for health (HRH) and universal health coverage (UHC). There is sufficient evidence to warrant these movements, but actors and the policy process significantly affect which policies are adopted and how they are implemented. How exactly this occurs in low- and middle-income countries (LMICs) is not very well understood. Furthermore, it is not clear whether actors will mobilize for or against the emergent HRH and UHC agendas. Policy analysis should help illuminate potential strategies to account for multiple interests and divergent values in volatile stakeholder environments. We argue that not only should the movement for UHC be paired with current efforts to address the human resources crisis, but also, for both to succeed, we need to know more about how health policy works in LMICs. 23886663 LRRK2 secretion in exosomes is regulated by 14-3-3. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset Parkinson's disease (PD). Emerging evidence suggests a role for LRRK2 in the endocytic pathway. Here, we show that LRRK2 is released in extracellular microvesicles (i.e. exosomes) from cells that natively express LRRK2. LRRK2 localizes to collecting duct epithelial cells in the kidney that actively secrete exosomes into urine. Purified urinary exosomes contain LRRK2 protein that is both dimerized and phosphorylated. We provide a quantitative proteomic profile of 1673 proteins in urinary exosomes and find that known LRRK2 interactors including 14-3-3 are some of the most abundant exosome proteins. Disruption of the 14-3-3 LRRK2 interaction with a 14-3-3 inhibitor or through acute LRRK2 kinase inhibition potently blocks LRRK2 release in exosomes, but familial mutations in LRRK2 had no effect on secretion. LRRK2 levels were overall comparable but highly variable in urinary exosomes derived from PD cases and age-matched controls, although very high LRRK2 levels were detected in some PD affected cases. We further characterized LRRK2 exosome release in neurons and macrophages in culture, and found that LRRK2-positive exosomes circulate in cerebral spinal fluid (CSF). Together, these results define a pathway for LRRK2 extracellular release, clarify one function of the LRRK2 14-3-3 interaction and provide a foundation for utilization of LRRK2 as a biomarker in clinical trials. 23674604 Pharmacology of AMG 416 (Velcalcetide), a Novel Peptide Agonist of the Calcium-Sensing Receptor, for the Treatment of Secondary Hyperparathyroidism in Hemodialysis Patients. A novel peptide, AMG 416 (formerly KAI-4169, and with a United States Adopted Name: velcalcetide), has been identified that acts as an agonist of the calcium-sensing receptor (CaSR). This article summarizes the in vitro and in vivo characterization of AMG 416 activity and the potential clinical utility of this novel compound. AMG 416 activates the human CaSR in vitro, acting by a mechanism distinct from that of cinacalcet, the only approved calcimimetic, since it can activate the CaSR both in the presence or the absence of physiologic levels of extracellular calcium. Administration of AMG 416 in vivo into either normal or renally compromised rats results in dose-dependent reductions in parathyroid hormone (PTH) levels and corresponding decreases in serum calcium, regardless of the baseline level of PTH. Treatment of 5/6 nephrectomized rats with AMG 416 resulted in dramatic improvements in their metabolic profile, including lower PTH and serum creatinine levels, reduced amounts of vascular calcification, attenuated parathyroid hyperplasia, and greater expression of the parathyroid gland regulators CaSR, vitamin D receptor, and FGF23 receptor compared with vehicle-treated animals. No drug accumulation was observed under this dosing regimen, and the terminal half-life of AMG 416 was estimated to be 2-4.5 hours. As a long-acting CaSR agonist, AMG 416 is an innovative new therapy for the treatment of hemodialysis patients with secondary hyperparathyroidism. 23782355 Monitoring contact sensitization to p-phenylenediamine (PPD) by patch testing with PPD 0.3% in petrolatum. Being a contact allergen of general relevance, p-phenylenediamine (PPD) is patch tested in the baseline series. However, PPD 1% in petrolatum may actively sensitize. Patch testing with PPD at 0.35% pet. proved to be safe, as far as active sensitization is concerned. To determine whether PPD 0.3% pet. reliably detects PPD sensitization. Patch testing with PPD 0.3% pet. and 1% pet. synchronously was performed in consecutive patients in a multicentre study within the Information Network of Departments of Dermatology. Altogether, 2042 patients were patch tested. PPD 1% pet. yielded 6.0% positive reactions (n = 123), and PPD 0.3% pet. yielded 4.7% (n = 95). The synchronous reproducibility of PPD reactions was similar as known from parallel patch tests with identical PPD concentrations. The diagnostic properties of PPD 0.3% pet. expressed as reaction index and positivity ratio were good. Of the 123 patients reacting to PPD 1% pet., 32 (26%) had no positive reaction to PPD 0.3% pet. In 22 of these 32 patients (69%), no clinical relevance could be found. As patch testing with PPD 0.3% pet. is reliable according to our results, we recommend replacing PPD 1% pet. in the baseline series with PPD 0.3% pet. 23891418 EUS-guided pancreatic duct intervention: outcomes of a single tertiary-care referral center experience. EUS can provide access to the main pancreatic duct (MPD) for therapeutic intervention. The long-term clinical success of EUS-guided MPD interventions is unknown. To determine technical and clinical success rates, predictors of success, and long-term outcomes of EUS-guided MPD intervention. Retrospective, single-center study. Tertiary-care referral center. Forty-five patients. EUS-guided MPD stent retrieval or placement. Technical and clinical success rates, adverse events, and long-term clinical outcomes. Among the 45 patients, 37 had undergone failed ERCP, and 29 had surgically altered anatomy. Median follow-up after initial EUS-guided intervention was 23 months. Two patients underwent EUS for stent removal, and EUS-guided MPD stent placement was attempted in 43 patients. Technical success was achieved in 32 of 43 patients (74%) with antegrade (n = 18) or retrograde (n = 14) stent insertion. Serious adverse events occurred in 3 patients (6%). Patients underwent a median of 2 (range 1-6) follow-up procedures for revision or removal of stents, without adverse events. Complete symptom resolution occurred in 24 of 29 patients (83%) while stents were in place, including all 6 with nondilated ducts. Stents were removed in 23 patients, who were then followed for an additional median of 32 months; 4 patients had recurrent symptoms. Among the 11 failed cases, most had persistent symptoms or required surgery. Retrospective study design, individualized patient management. EUS-guided MPD intervention is feasible and safe, with long-term clinical success in the majority of patients. EUS provides important treatment options, particularly in patients who would otherwise undergo surgery. 23946406 Early experience shapes amygdala sensitivity to race: an international adoption design. In the current study, we investigated how complete infant deprivation to out-group race impacts behavioral and neural sensitivity to race. Although monkey models have successfully achieved complete face deprivation in early life, this is typically impossible in human studies. We overcame this barrier by examining youths with exclusively homogenous racial experience in early postnatal development. These were youths raised in orphanage care in either East Asia or Eastern Europe as infants and later adopted by American families. The use of international adoption bolsters confidence of infant exposure to race (e.g., to solely Asian faces or European faces). Participants completed an emotional matching task during functional MRI. Our findings show that deprivation to other-race faces in infancy disrupts recognition of emotion and results in heightened amygdala response to out-group faces. Greater early deprivation (i.e., later age of adoption) is associated with greater biases to race. These data demonstrate how early social deprivation to race shapes amygdala function later in life and provides support that early postnatal development may represent a sensitive period for race perception. 23500099 Immunocytochemical identification of electroneutral Na⁺-coupled HCO₃⁻ transporters in freshly dissociated mouse medullary raphé neurons. The medullary raphé (MR) of the medulla oblongata contains chemosensitive neurons that respond to increases in arterial [CO₂], by altering firing rate, with increases being associated with serotonergic (5-hydroxytryptamine [5HT]) neurons and decreases, with GABAergic neurons. Both types of neurons contribute to increased alveolar ventilation. Decreases in intracellular pH are thought to link the rise in [CO₂] to increased ventilation. Because electroneutral Na(+)-coupled HCO₃(-) transporters (nNCBTs), which help protect cells from intracellular acidosis, are expressed robustly in the neurons of the central nervous system, a key question is whether these transporters are present in chemosensitive neurons. Therefore, we used an immunocytochemistry approach to identify neurons (using a microtubule associated protein-2 monoclonal antibody) and specifically 5HT neurons (TPH monoclonal antibody) or GABAergic neurons (GAD2 monoclonal antibody) in freshly dissociated cells from the mouse MR. We also co-labeled with polyclonal antibodies against the three nNCBTs: NBCn1, NDCBE, and NBCn2. We exploited ePet-EYFP (enhanced yellow fluorescent protein) mice (with EYFP-labeled 5HT neurons) as well as mice genetically deficient in each of the three nNCBTs. Quantitative image analysis distinguished positively stained cells from background signals. We found that >80% of GAD2(+) cells also were positive for NDCBE, and >90% of the TPH(+) and GAD2(+) cells were positive for the other nNCBTs. Assuming that the transporters are independently distributed among neurons, we can conclude that virtually all chemosensitive MR neurons contain at least one nNCBT. 23763919 Upfront autologous stem cell transplantation for untreated high-risk diffuse large B-cell lymphoma in patients up to 60 years of age. Although rituximab added to CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) is the standard chemotherapy for untreated DLBCL, its therapeutic effect is limited in younger patients with high-intermediate risk or high-risk disease according to the age-adjusted international prognostic index. In fact, the efficacy and safety of HDT plus rituximab followed by ASCT for such patients remain unclear. We retrospectively investigated the safety and effectiveness of HDT/ASCT in patients with untreated DLBCL. Twenty-two patients, aged 60 years and younger, with untreated DLBCL (classified as high-intermediate [n = 14 (64%)] or high [n = 8 (32%)] risk) underwent upfront HDT/ASCT between January 2004 and December 2008, achieving either a complete response (CR; n = 15 (68%)) or a partial response (PR; n = 7 (32%)). The 5-year overall survival rate was 81.0% and the progression-free survival rate was 73.0%, with no significant difference between risk groups based on the international prognostic index. The most common nonhematologic toxicity was febrile neutropenia [n = 9 (41%)]. The cause of all 3 fatalities was exacerbation of the underlying disease, and no treatment-related mortality was observed. No variables with a significant influence on overall survival were identified, but a correlation of the treatment response before transplanation with progression-free survival was suggested (CR vs. PR: 92% vs. 30%, P = .002). These results suggest that adding rituximab to upfront HDT/ASCT is feasible and can improve the outcome in untreated patients with poor-prognosis DLBCL. In the future, upfront HDT/ASCT should be more extensively evaluated in clinical trials. 23846776 Concomitant Oral and Intravenous Pharmacokinetics of Dabrafenib, a BRAF Inhibitor, in Patients with BRAF V600 Mutation-Positive Solid Tumors. Dabrafenib is an orally bioavailable, potent, and selective inhibitor of human wild-type BRAF and CRAF kinases as well as mutant forms of BRAF kinase. The aim of this phase 1, single-center, open-label study in four patients with BRAF mutation-positive solid tumors was to determine the absolute bioavailability of a 150 mg oral dose of dabrafenib. A microtracer study approach, in which a 50 µg radiolabeled intravenous (IV) microdose of dabrafenib was given concomitantly with a 150 mg oral dose, was used to simultaneously recover IV and oral pharmacokinetic parameters. The least squares mean (90% CI) absolute bioavailability of dabrafenib (HPMC capsules) was 94.5% (81.3%, 109.7%). Median Tmax after oral administration was 2.0 hours and the geometric mean terminal half-life was 4.8 hours. The geometric mean clearance and volume of distribution after IV administration were 12.0 L/h and 45.5 L, respectively. Human clearance and volume of distribution at steady state were in agreement with predictions made using allometric scaling of pharmacokinetic parameters from four preclinical species. In conclusion, dabrafenib absolute bioavailability was high, whereas first-pass metabolism was low. Furthermore, the microtracer approach provided an innovative and efficient method for assessing the absolute bioavailability of dabrafenib in patients with advanced cancer. 23940085 Different circadian expression of major matrix-related genes in various types of cartilage: modulation by light-dark conditions. We screened circadian-regulated genes in rat cartilage by using a DNA microarray analysis. In rib growth-plate cartilage, numerous genes showed statistically significant circadian mRNA expression under both 12:12 h light-dark and constant darkness conditions. Type II collagen and aggrecan genes-along with several genes essential for post-translational modifications of collagen and aggrecan, including prolyl 4-hydroxylase 1, lysyl oxidase, lysyl oxidase-like 2 and 3'-phosphoadenosine 5'-phosphosulphate synthase 2-showed the same circadian phase. In addition, the mRNA level of SOX9, a master transcription factor for the synthesis of type II collagen and aggrecan, has a similar phase of circadian rhythms. The circadian expression of the matrix-related genes may be critical in the development and the growth of various cartilages, because similar circadian expression of the matrix-related genes was observed in hip joint cartilage. However, the circadian phase of the major matrix-related genes in the rib permanent cartilage was almost the converse of that in the rib growth-plate cartilage under light-dark conditions. We also found that half of the oscillating genes had conserved clock-regulatory elements, indicating contribution of the elements to the clock outputs. These findings suggest that the synthesis of the cartilage matrix macromolecules is controlled by cell-autonomous clocks depending upon the in vivo location of cartilage. 23769321 In vitro evaluation of biomimetic nanocomposite scaffold using endometrial stem cell derived osteoblast-like cells. Current study encourages the differentiation of human endometrial stem cells into osteoblast-like cells using osteogenic media for potential bone tissue engineering purposes. A biomimetic nanocomposite scaffolds based on GEL/calcium phosphate were fabricated and behavior of differentiated osteoblast cells was evaluated after seeding on this scaffold. Prepared scaffolds were assessed in terms of attachment, alkaline phosphatase activity, gene expression and proliferation of osteoblast cells. The matrix mineralization was approved by alizarin red and the treated cultures with osteogenic media and BMP2 were positive for osteopontin and osteocalcin antibodies. RT-PCR confirmed presence of osteopontin, osteonectin and alkaline phosphatase mRNA after differentiation in EnSCs-derived osteoblast-like cells. Also, it has been shown that the biomimetic nanocomposites possess appropriate chemical and physical properties to support the attachment and proliferation of differentiated osteoblast cells. 23895332 Self-construction of supramolecular polyrotaxane films by an electrotriggered morphogen-driven process. The design of films using a one-pot process has recently attracted increasing interest in the field of polymer thin film formation. Herein we describe the preparation of one-pot supramolecular polyrotaxane (PRX) films using the morphogen-driven self-construction process. This one-pot buildup strategy where the film growth is triggered by the electrochemical formation and diffusion of a catalyst in close vicinity of the substrate has recently been introduced by our group. A one-pot mixture was used that contained (i) poly(acrylic acid) (PAA) functionalized by azide groups grafted on the polymer chain through oligo(ethylene glycol) (EG) arms, leading to PAA-EG13-N3, (ii) cyclodextrins (α and β CD), as macrocycles that can be threaded along EG arms, (iii) alkyne-functionalized stoppers (ferrocene or adamantane), to cap the PRX assembly by click chemistry, and (iv) copper sulfate. The one-pot mixture solution was brought into contact with a gold electrode. Cu(I), the morphogen, was generated electrochemically from Cu(II) at the electrode/one-pot solution interface. This electrotriggered click reaction leads to the capping of polypseudorotaxane yielding to PRXs. The PRXs can self-assemble through lateral supramolecular interactions to form aggregates and ensure the cohesion of the film. The film buildup was investigated using different types of CD and alkyne functionalized stoppers. Supramolecular PRX aggregates were characterized by X-ray diffraction measurements. The film topographies were imaged by atomic force microscopy. The influence of the concentration in CD and the presence of a competitor were studied as well. The stability of the resulting film was tested in contact with 8 M urea and during the electrochemical oxidation of ferrocene. 23547780 Key targets and relevant inhibitors for the drug discovery of tuberculosis. Tuberculosis (TB) is an infectious disease caused by the pathogen Mycobacterium tuberculosis (M. tuberculosis), killing about two million people worldwide each year. An increase in the prevalence of drug-resistant strains of M. tuberculosis in the past decades has renewed focus on the development of new drugs that can treat both drug-sensitive and resistant TB infections. M. tuberculosis evades the host immune system and drug regimes by entering dormant phase within macrophage. As a consequence, there is a pressing need for new vaccines and antimicrobials to treat persistent infections. As clinically used antibiotics target very few essential functions of mycobacterium, it is rational that identification of new targets that are essential for bacterial growth and survival can serve as starting point for designing of novel drugs to cure both drug-sensitive and resistant TB infections. With the development of molecular biology and structural biology and the availability of the genome sequence of M. tuberculosis, some success has been achieved in the identification of new targets in M. tuberculosis and their relevant inhibitors. This review summarizes about ninety important targets that participate in a range of diverse physiological processes in M. tuberculosis and seven new drugs currently in clinical phase 2 or 3 trials. In addition, promising inhibitors with novel mechanisms of action and clinical vaccine candidates are highlighted. 23793080 Inhibition of Listeria monocytogenes and Escherichia coli O157:H7 in liquid broth medium and during processing of fermented sausage using autochthonous starter cultures. The antimicrobial effect of two autochthonous starter cultures of Lactobacillus sakei was evaluated in vitro (in liquid broth medium) and in situ assays. The inactivation of foodborne pathogens Listeria monocytogenes (serotype 4ab No 10) and Escherichia coli O157:H7 ATCC 43888 was investigated during the production of fermented sausage according to a typical Greek recipe using L. sakei strains as starter cultures. The inactivation kinetics were modeled using GInaFiT, a freeware tool to assess microbial survival curves. By the end of the ripening period, the inhibition of L. monocytogenes was significant in treatments with L. sakei 8416 and L. sakei 4413 compared to the control treatment. A 2.2-log reduction of the population of E. coli O157:H7 resulted from the autochthonous starter culture L. sakei 4413 during sausage processing. The use of the autochthonous starter cultures constitutes an additional improvement to the microbial safety by reducing foodborne pathogens. 23588839 Comparison of in vitro and in vivo biological effects of trabectedin, lurbinectedin (PM01183) and Zalypsis® (PM00104). This study: (i) investigated the in vitro cytotoxicity and mode of action of lurbinectedin (PM01183) and Zalypsis® (PM00104) compared with trabectedin in cell lines deficient in specific mechanisms of repair, (ii) evaluated their in vivo antitumor activity against a series of murine tumors and human xenografts. The antiproliferative activity, the DNA damage and the cell cycle perturbations induced by the three compounds on tumor lines were very similar. Nucleotide Excision Repair (NER) deficient cells were approximately fourfold more resistant to trabectedin, lurbinectedin and Zalypsis®. Cells deficient in non-homologous end joining (NHEJ), MRN complex and translesion synthesis (TLS) were slightly more sensitive to the three compounds (approximately fivefold) while cells deficient in homologous recombination (HR) were markedly more sensitive (150-200-fold). All three compounds showed a good antitumor activity in several in vivo models. Lurbinectedin and trabectedin had a similar pattern of antitumor activity in murine tumors and in xenografts, whereas Zalypsis® appeared to have a distinct spectrum of activity. The fact that no relationship whatsoever was found between the in vitro cytotoxic potency and the in vivo antitumor activity, suggests that in addition to direct cytotoxic mechanisms other host-mediated effects are involved in the in vivo pharmacological effects. 23966876 Masculinization of gene expression is associated with exaggeration of male sexual dimorphism. Gene expression differences between the sexes account for the majority of sexually dimorphic phenotypes, and the study of sex-biased gene expression is important for understanding the genetic basis of complex sexual dimorphisms. However, it has been difficult to test the nature of this relationship due to the fact that sexual dimorphism has traditionally been conceptualized as a dichotomy between males and females, rather than an axis with individuals distributed at intermediate points. The wild turkey (Meleagris gallopavo) exhibits just this sort of continuum, with dominant and subordinate males forming a gradient in male secondary sexual characteristics. This makes it possible for the first time to test the correlation between sex-biased gene expression and sexually dimorphic phenotypes, a relationship crucial to molecular studies of sexual selection and sexual conflict. Here, we show that subordinate male transcriptomes show striking multiple concordances with their relative phenotypic sexual dimorphism. Subordinate males were clearly male rather than intersex, and when compared to dominant males, their transcriptomes were simultaneously demasculinized for male-biased genes and feminized for female-biased genes across the majority of the transcriptome. These results provide the first evidence linking sexually dimorphic transcription and sexually dimorphic phenotypes. More importantly, they indicate that evolutionary changes in sexual dimorphism can be achieved by varying the magnitude of sex-bias in expression across a large proportion of the coding content of a genome. 23891307 Infectivity of a genotype 4 hepatitis E virus cDNA clone by intrahepatic inoculation of laboratory rats. A cDNA clone of a genotype 4 swine hepatitis E virus (HEV) strain (SAAS-FX17), identified in Shanghai, has been constructed. Capped RNA transcripts were prepared in vitro and shown to be replication-competent in Huh7 cells. Sprague-Dawley (SD) rats administered the RNA transcripts by intrahepatic inoculation developed active infections as evidenced by fecal virus shedding and sero-conversion to anti-HEV. The former was first detected between 23 and 30 days post-inoculation (dpi) and persisted until 45dpi. Sera of rats inoculated with RNA transcripts became anti-HEV positive between 30 and 40dpi, and reverted to anti-HEV negative at 52dpi. Our data indicate for the first time that intrahepatic inoculation of rats with RNA transcripts of an HEV cDNA clone may serve as an alternative animal model for HEV research. 23735825 (+)-Altholactone exhibits broad spectrum immune modulating activity by inhibiting the activation of pro-inflammatory cytokines in RAW 264.7 cell lines. An evaluation of Indonesian plants to identify compounds with immune modulating activity revealed that the methanolic extract of an Alphonsea javanica Scheff specimen possessed selective anti-inflammatory activity in a nuclear factor-kappa B (NF-κB) luciferase and MTT assay using transfected macrophage immune (Raw264.7) cells. A high-throughput LC/MS-ELSD based library approach of the extract in combination with the NF-κB and MTT assays revealed the styryl lactone (+)-altholactone (2) was responsible for the activity. Compound 2, its acetylated derivate (+)-3-O-acetylaltholactone (3), and the major compound of this class, (+)-goniothalmin (1), were further evaluated to determine their anti-inflammatory potential in the NF-κB assay. Concentration-response studies of 1-3 indicated that only 2 possessed NF-κB based anti-inflammatory activity. Compound 2 reduced the LPS-induced NO production, phosphorylation of IκBα, and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) using Western blot analysis. Further studies using qPCR indicated 2 reduced the expression of eight pro-inflammatory cytokines/enzymes (0.8-5.0μM) which included: COX-2, iNOS, IP-10, IL-1β, MCP-1, GCS-F, IL-6 and IFN-β. These results indicated that 2 displays broad spectrum immune modulating activity by functioning as an anti-inflammatory agent against LPS-induced NF-κB signaling. Conversely the selective cytotoxicity and in vivo anti-tumor and anti-inflammatory activity previously reported for 1 do not appear to arise from a mechanism that is linked to the NF-κB immune mediated pathway. 23835890 Bone density and alendronate effects in Duchenne muscular dystrophy patients. Introduction: Patients with DMD have low bone mineral density (BMD) and are at high risk for fractures. We examined changes in BMD and the effects of alendronate in DMD patients treated at our institution in the last decade. Methods: Retrospective cohort study of 39 DMD patients. Results: Patients had screening dual energy x-ray absorptiometry (DXA) at an average age of 12 years. The vast majority had low Z-scores at the total hip and lumbar spine. Patients treated with glucocorticoids had a significantly lower Z-score at the spine than those not treated with glucocorticoids. Z-scores at the hip trended down without alendronate (P= 0.07) and trended up with alendronate (P= 0.4). Discussion: By age 12 years, most patients with DMD had low Z-scores. They may have benefitted from earlier screening. Z-score at the hip trended downward without alendronate and trended upward (stabilized) with alendronate, but these trends were not statistically significant. © 2013 Wiley Periodicals, Inc. 23722549 PML-RARα and Its Phosphorylation Regulate PML Oligomerization and HIPK2 Stability. The PML gene is frequently fused to the retinoic acid receptor α (RARα) gene in acute promyelocytic leukemia (APL), generating a characteristic PML-RARα oncogenic chimera. PML-RARα disrupts the discrete nuclear speckles termed nuclear bodies, which are formed in PML, suggesting that nuclear body disruption is involved in leukemogenesis. Nuclear body formation that relies upon PML oligomerization and its stabilization of the hypoxia-inducible protein kinase (HIPK)-2 is disrupted by expression of the PML-RARα chimera. Here, we report that disruption of nuclear bodies is also mediated by PML-RARα inhibition of PML oligomerization. PKA-mediated phosphorylation of PML-RARα blocked its ability to inhibit PML oligomerization and destabilize HIPK2. Our results establish that both PML oligomerization and HIPK2 stabilization at nuclear bodies are important for APL cell differentiation, offering insights into the basis for the most common prodifferentiation therapies of APL used clinically. Cancer Res; 73(14); 4278-88. ©2013 AACR. 23865826 Comparison of T2 and T2*-weighted MR molecular imaging of a mouse model of glioma. Standard MRI has been used for high-grade gliomas detection, albeit with limited success as it does not provide sufficient specificity and sensitivity to detect complex tumor structure. Therefore targeted contrast agents based on iron oxide, that shorten mostly T2 relaxation time, have been recently applied. However pulse sequences for molecular imaging in animal models of gliomas have not been yet fully studied. The aim of this study was therefore to compare contrast-to-noise ratio (CNR) and explain its origin using spin-echo (SE), gradient echo (GE), GE with flow compensation (GEFC) as well as susceptibility weighted imaging (SWI) in T2 and T2* contrast-enhanced molecular MRI of glioma. A mouse model was used. U87MGdEGFRvIII cells (U87MG), derived from a human tumor, were injected intracerebrally. A 9.4 T MRI system was used and MR imaging was performed on the 10 day after the inoculation of the tumor. The CNR was measured prior, 20 min, 2 hrs and 24 hrs post intravenous tail administration of glioma targeted paramagnetic nanoparticles (NPs) using SE, SWI, GE and GEFC pulse sequences. The results showed significant differences in CNR among all pulse sequences prior injection. GEFC provided higher CNR post contrast agent injection when compared to GE and SE. Post injection CNR was the highest with SWI and significantly different from any other pulse sequence. Molecular MR imaging using targeted contrast agents can enhance the detection of glioma cells at 9.4 T if the optimal pulse sequence is used. Hence, the use of flow compensated pulse sequences, beside SWI, should to be considered in the molecular imaging studies. 23804552 Nitrogen deposition, plant carbon allocation, and soil microbes: Changing interactions due to enrichment. • Premise of the study: Nitrogen (N) inputs to the terrestrial environment have doubled worldwide during the past century. N negatively impacts plant diversity, but it is unknown why some species are more susceptible than others. While it is often assumed that competition drives species decline, N enrichment also strongly affects soil microbial communities. Can these changes affect plant-microbe interactions in ways that differentially influence success of plant species? Furthermore, can altered plant-microbe interactions lead to carbon (C) limitation in plants? • Methods: We focused on a species that increases (Deschampsia cespitosa) and one that decreases (Geum rossii) in abundance in N-fertilized plots in alpine tundra. We measured soil microbes using phospholipid fatty acids, and C limitation and transfer using a (13)C tracer experiment, C:N ratios, nonstructural carbohydrates, and leaf preformation. • Key results: While N profoundly influenced microbial communities, this change occurred similarly in association with both plant species. N addition did not alter total C allocation to microbes in either species, but it changed patterns of microbial C acquisition more in Geum, specifically in gram-negative bacteria. Geum showed evidence of C limitation: it allocated less C to storage organs, had lower C:N and carbohydrate stores, and fewer preformed leaves in N plots. • Conclusions: Carbon limitation may explain why some species decline with N enrichment, and the decline may be due to physiological responses of plants to N rather than to altered plant-microbe interactions. Global change will alter many processes important in structuring plant communities; noncompetitive mechanisms of species decline may be more widespread than previously thought. 22512587 A review on the development in the field of NIDDM based thiazolidinedione PPARγ agonists. Peroxisome Proliferator Activated Receptors gamma (PPARγ) are a class of ligand activated transcription factors with a prominent role in the regulation of metabolic processes. The present work aims towards examining the functional and structural features that facilitate the binding of small molecules based on Thiazolidinedione pharmacophore to PPARs. The intent of this article is to review all the reported thiazolidinediones and associated groups of PPARγ ligands. 23708821 Adherence to imatinib therapy in gastrointestinal stromal tumors and chronic myeloid leukemia. The number of anticancer drugs available in oral formulation has risen sharply in the past few years and this is expected to continue to increase over the next several decades. For patients, the convenience of self-administration constitutes a major benefit associated with oral therapy. For clinicians, however, the transition from parenteral to oral therapy has resulted in concerns about adherence to therapy, its monitoring, and its effects on clinical outcomes. Several studies have demonstrated that imatinib is effective at improving overall survival and/or recurrence-free survival in patients with gastrointestinal stromal tumors and chronic myeloid leukemia (primary and metastatic disease). Despite the survival benefit and the favorable toxicity profile of imatinib, however, adherence to imatinib remains poor. Herein, we review the evidence showing the effects of nonadherence on patient outcomes as well as data indicating that adherence to imatinib (and oral anticancer therapy in general) is suboptimal. We also highlight factors that may contribute to nonadherence and suggest key steps that can be implemented by the multidisciplinary medical team to overcome the daily challenges of adherence. Improving adherence to imatinib depends on open communication and comprehensive patient education. All of this is essential to maximize benefits from therapy and improve clinical outcomes for our patients. 23879730 Accurate single nucleotide variant detection in viral populations by combining probabilistic clustering with a statistical test of strand bias. Deep sequencing is a powerful tool for assessing viral genetic diversity. Such experiments harness the high coverage afforded by next generation sequencing protocols by treating sequencing reads as a population sample. Distinguishing true single nucleotide variants (SNVs) from sequencing errors remains challenging, however. Current protocols are characterised by high false positive rates, with results requiring time consuming manual checking. By statistical modelling, we show that if multiple variant sites are considered at once, SNVs can be called reliably from high coverage viral deep sequencing data at frequencies lower than the error rate of the sequencing technology, and that SNV calling accuracy increases as true sequence diversity within a read length increases. We demonstrate these findings on two control data sets, showing that SNV detection is more reliable on a high diversity human immunodeficiency virus sample as compared to a moderate diversity sample of hepatitis C virus. Finally, we show that in situations where probabilistic clustering retains false positive SNVs (for instance due to insufficient sample diversity or systematic errors), applying a strand bias test based on a beta-binomial model of forward read distribution can improve precision, with negligible cost to true positive recall. By combining probabilistic clustering (implemented in the program ShoRAH) with a statistical test of strand bias, SNVs may be called from deeply sequenced viral populations with high accuracy. 23062658 Medium to long-term results of the UNIX uncemented unicompartmental knee replacement. We report the first non-designer study of the Unix uncemented unicompartmental knee prosthesis. Eighty-five consecutive UKRs were carried out with sixty-five available for follow-up. Oxford Knee Scores, WOMAC questionnaire and radiological assessment were completed. The mean Oxford Knee Score was thirty-eight and WOMAC Score was twenty. Overall Kaplan Meier survival estimate is 76% (95% confidence interval 60%-97%) at 12years and 88% (95% confidence interval 76-100%) with aseptic loosening as the endpoint. Radiographic assessment showed lysis in the tibia in 6% of patients with no lysis evident around the central fin. Survivorship is comparable to other published series of UKRs. We suggest the central fin design is key to dissipating large forces throughout the proximal tibia, resulting in low levels of tibial loosening. Level of evidence IV. 23681802 Matrix metalloproteinases in cancer: their value as diagnostic and prognostic markers and therapeutic targets. Biomarkers are used as tools in cancer diagnostics and in treatment stratification. In most cancers, there are increased levels of one or several members of the matrix metalloproteinases (MMPs). This is a family of proteolytic enzymes that are involved in many phases of cancer progression, including angiogenesis, invasiveness, and metastasis. It has therefore been expected that MMPs could serve as both diagnostic and prognostic markers in cancer patients, but despite a huge number of studies, it has been difficult to establish MMPs as cancer biomarkers. In the present paper, we assess some of the challenges associated with MMP research as well as putative reasons for the conflicting data on the value of these enzymes as diagnostic and prognostic markers in cancer patients. We also review the prognostic value of a number of MMPs in patients with lung, colorectal, breast, and prostate cancers. The review also discusses MMPs as potential target molecules for therapeutic agents and new strategies for development of such drugs. 23903161 Soliton self-frequency shift controlled by a weak seed laser in tellurite photonic crystal fibers. We report the first demonstration of soliton self-frequency shift (SSFS) controlled by a weak continuous-wave (CW) laser, from a tellurite photonic crystal fiber pumped by a 1560 nm femtosecond fiber laser. The control of SSFS is performed by the cross-gain modulation of the 1560 nm femtosecond laser. By varying the input power of the weak CW laser (1560 nm) from 0 to 1.17 mW, the soliton generated in the tellurite photonic crystal fiber blue shifts from 1935 to 1591 nm. The dependence of the soliton wavelength on the operation wavelength of the weak CW laser is also measured. The results show the CW laser with a wavelength tunable range of 1530-1592 nm can be used to control the SSFS generation. 23883831 Recovery Room Radiographs Not Found to Have Incremental Utility Above: Intraoperative Images after Lumbar Fusion Procedures. Retrospective case series.OBJECTIVE: To characterize the clinical utility of imaging in the recovery room after lumbar fusion procedures.SUMMARY OF BACKGROUND DATA: Two sets of images are commonly obtained at the end of lumbar fusion procedures: intraoperative fluoroscopic images near the time of wound closure and plain film images after the procedure in the recovery room. The latter may have low clinical utility.METHODS: We identified a consecutive series of lumbar fusion procedures. A panel of three reviewers assessed intraoperative and recovery room series both for radiographic adequacy and for issues with the surgical construct.RESULTS: 190 cases were reviewed, of which 92 were posterolateral lumbar fusions, 42 were anterior lumbar interbody fusions (ALIFs), 24 were transforaminal lumbar interbody fusions (TLIFs), and 32 were anterior-posterior fusions. All intraoperative series were adequate, while only 90% of recovery room series were adequate. Recovery room series had visible issues with construct placement in 4 cases. In each of these cases, however, the issue was also clearly visible on the intraoperative series, was found to be acceptable clinically, and did not alter management in any way.CONCLUSION: This study demonstrates that recovery room images are inferior to intraoperative images and offer little or no incremental clinical utility for detecting issues with surgical constructs after lumbar fusion procedures. In settings where it is still performed, recovery room imaging might be discontinued to realize savings in cost, radiation exposure, and time. 23843428 Sniffer Patch Laser Uncaging REsponse (SPLURgE): an assay of regional differences in allosteric receptor modulation and neurotransmitter clearance. Allosteric modulators exert actions on neurotransmitter receptors by positively or negatively altering the effective response of these receptors to their respective neurotransmitter. γ-aminobutyric acid (GABA) type-A ionotropic receptors (GABAARs) are major targets for allosteric modulators such as benzodiazepines, neurosteroids, and barbiturates. Analysis of substances that produce similar effects has been hampered by the lack of techniques to assess the localization and function of such agents in brain slices. Here we describe measurement of the Sniffer Patch Laser Uncaging REsponse (SPLURgE), which combines the sniffer patch recording configuration with laser photolysis of caged GABA. This methodology enables the detection of allosteric GABAAR modulators endogenously present in discrete areas of the brain slice, and allows for the application of exogenous GABA with spatiotemporal control without altering the release and localization of endogenous modulators within the slice. Here we demonstrate the development and use of this technique for the measurement of allosteric modulation in different areas of the thalamus. Application of this technique will be useful in determining whether a lack of modulatory effect on a particular category of neurons or receptors is due to insensitivity to allosteric modulation or a lack of local release of endogenous ligand. We also demonstrate that this technique can be used to investigate GABA diffusion and uptake. This method thus provides a biosensor assay for rapid detection of endogenous GABAAR modulators, and has the potential to aid studies of allosteric modulators that exert effects on other classes of neurotransmitter receptors, such as glutamate, acetylcholine, or glycine receptors. 23763768 Revolution rather than rotation of AAA+ hexameric phi29 nanomotor for viral dsDNA packaging without coiling. It has long been believed that the DNA-packaging motor of dsDNA viruses utilizes a rotation mechanism. Here we report a revolution rather than rotation mechanism for the bacteriophage phi29 DNA packaging motor. The phi29 motor contains six copies of the ATPase (Schwartz et al., this issue); ATP binding to one ATPase subunit stimulates the ATPase to adopt a conformation with a high affinity for dsDNA. ATP hydrolysis induces a new conformation with a lower affinity, thus transferring the dsDNA to an adjacent subunit by a power stroke. DNA revolves unidirectionally along the hexameric channel wall of the ATPase, but neither the dsDNA nor the ATPase itself rotates along its own axis. One ATP is hydrolyzed in each transitional step, and six ATPs are consumed for one helical turn of 360°. Transition of the same dsDNA chain along the channel wall, but at a location 60° different from the last contact, urges dsDNA to move forward 1.75 base pairs each step (10.5bp per turn/6ATP=1.75bp per ATP). Each connector subunit tilts with a left-handed orientation at a 30° angle in relation to its vertical axis that runs anti-parallel to the right-handed dsDNA helix, facilitating the one-way traffic of dsDNA. The connector channel has been shown to cause four steps of transition due to four positively charged lysine rings that make direct contact with the negatively charged DNA phosphate backbone. Translocation of dsDNA into the procapsid by revolution avoids the difficulties during rotation that are associated with DNA supercoiling. Since the revolution mechanism can apply to any stoichiometry, this motor mechanism might reconcile the stoichiometry discrepancy in many phage systems where the ATPase has been found as a tetramer, hexamer, or nonamer. 23122093 Antiproliferative and immunoactivatory ability of an enzymatic extract from rice bran. The validation of natural products as source of functional foods or nutraceuticals has become an important issue in current health research. Thus, the present work has tested on MOLT-4 cells (human T cell acute lymphoblastic leukemic) the antiproliferative effect of a water-soluble enzymatic extract from rice bran (EERB). Present work shows that EERB induces cellular death in MOLT-4 cells in a dose-dependent way (0-10mg/mL) but not in non-tumoral lymphocytes. Flow cytometric analysis of MOLT-4 cells treated with EERB showed the presence of death cells by apoptosis rather than necrosis. Additionally, EERB also exerts an immunoactivatory effect on N13 microglia cells, by inducing TNF-alpha (tumour necrosis factor-α) expression, which plays a key role in the innate immune response to infection. Accordingly, we can propose EERB as a useful natural standardized extract with antiproliferative and immunoactivatory ability that would be beneficial to apply in the functional food field. 23474029 Robust PEGylated hyaluronic acid nanoparticles as the carrier of doxorubicin: Mineralization and its effect on tumor targetability in vivo. The in vivo stability and tumor targetability of self-assembled polymeric nanoparticles are crucial for effective drug delivery. In this study, to develop biostable nanoparticles with high tumor targetability, poly(ethylene glycol)-conjugated hyaluronic acid nanoparticles (PEG-HANPs) were mineralized through controlled deposition of inorganic calcium and phosphate ions on the nanoparticular shell via a sequential addition method. The resulting nanoparticles (M-PEG-HANPs) had a smaller size (153.7±4.5nm) than bare PEG-HANPs (265.1±9.5nm), implying that mineralization allows the formation of compact nanoparticles. Interestingly, when the mineralized nanoparticles were exposed to acidic buffer conditions (40%) LVEF (P interaction not significant). The overall benefits of dabigatran for stroke/SE prevention, and major and intracranial bleeding, relative to warfarin in the RE-LY trial were consistent in patients with and without HF. 23319394 The novel phosphoinositide 3-kinase-mammalian target of rapamycin inhibitor, BEZ235, circumvents erlotinib resistance of epidermal growth factor receptor mutant lung cancer cells triggered by hepatocyte growth factor. Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, is a critical problem in the management of patients with EGFR mutant lung cancer. Several mechanisms have been reported involved in this acquired resistance, including hepatocyte growth factor (HGF) activation of an alternative pathway. PI3K and mTOR are downstream molecules of receptor tyrosine kinases, such as EGFR and Met, and are thought to be ideal targets for controlling various tumor types. We assessed whether BEZ235, a dual inhibitor of PI3K and mTOR, could overcome the EGFR-TKI resistance induced by HGF in an EGFR mutant lung cancer model. Exogenous and endogenous HGF triggered resistance to erlotinib in the PC-9 and HCC827, EGFR mutant lung cancer cell lines. BEZ235 alone inhibited the viability of PC-9 and HCC827 cells in vitro, irrespective of the presence or the absence of HGF. Using a xenograft model of severe combined immunodeficient mice with HGF-gene-transfected PC-9 cells (PC-9/HGF), we found that BEZ235 inhibited tumor growth, whereas erlotinib did not. BEZ235 monotherapy also inhibited the phosphorylation of Akt and p70S6K/S6RP, downstream molecules of PI3K and mTOR, respectively, as well as suppressing tumor-cell proliferation and angiogenesis of PC-9/HGF tumors. These results suggest that BEZ235, even as monotherapy, may be useful in managing HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer. 23915006 Expression of VEGF-D in epithelial ovarian cancer and its relationship to lymphatic metastasis. To investigate the contribution of vascular endothelial growth factor (VEGF)-D to tumor progression, tumor lymphangiogenesis and lymphatic metastasis in epithelial ovarian cancer. The expression profiles of VEGF-D in 18 benign, 14 borderline and 87 malignant epithelial ovarian cancers were examined using immunohistochemical (IHC) staining. Lymphatic vessels were identified using IHC staining on lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), which is a lymph-specific receptor for hyaluronan in identifying lymphatic vessels. The potential correlation among VEGF-D, lymphatic vessel density (LVD) and clinico-pathological factors of the epithelial ovarian cancer was also analyzed. Positive IHC staining of VEGF-D was observed in 17% of benign, 21% of borderline and 80% of malignant epithelial ovarian tumors specimens. In the epithelial ovarian cancer specimens, the LVD was 3.41 ± 2.37 in the VEGF-D negative (17 patients), 5.42 ± 3.49 in the weak (26 patients), 7.22 ± 2.36 in the moderate (27 patients) and 7.35 ± 4.06 in the strong (17 patients) groups, respectively. Additionally, the expression of VEGF-D was positively correlated with LVD (r = 0.415, P < 0.001). The expression level of VEGF-D was significantly higher in lymph node-positive epithelial ovarian cancer than in lymph node-negative patients (P = 0.009, P < 0.05). The expression of VEGF-D was significantly correlated with lymph node metastasis, International Federation of Gynecology and Obstetrics stage and tumor histological differentiation, but not with the patients' age or histology type. VEGF-D may play an important role in the process of lymphatic metastasis of epithelial ovarian cancer. 23932656 Activation of protein kinase C delta reduces hepatocellular damage in ischemic preconditioned rat liver. Liver ischemic preconditioning (IPC), pre-exposure of the liver to transient ischemia, has been applied as a useful surgical method to prevent liver ischemia and reperfusion (I/R) injury. Although activation of protein kinase C (PKC), especially novel PKCs, has been known as central signaling responsible for the liver protection of IPC, determination of the involved isozyme in strong protection afforded by IPC has not been elucidated. Rats were subjected to 90 min of partial liver ischemia followed by 3, 6, and 24 h of reperfusion. IPC was induced by 10 min of ischemia after 10 min of reperfusion before sustained ischemia. Rottlerin, a PKC-δ selective inhibitor; PKC-εV1-2 peptide, a selective PKC-ε inhibitor; and 3,7-dimethyl-1-[2-propargyl] xanthine, an adenosine A2 receptor antagonist, were intravenously injected before IPC. N-acetyl-L-cysteine, a strong antioxidant, and Nω-nitro-L-arginine methyl ester, a nonselective nitric oxide synthase inhibitor, were injected intraperitoneally before IPC. IPC resulted in strong protection against liver I/R injury as evidenced by biochemical and histologic analyses. Inhibition of PKC-δ strongly attenuated the IPC-induced liver protection, whereas PKC-ε inhibition did not exert any effect on IPC-induced protection. Although inhibition of reactive oxygen species, adenosine, and nitric oxide attenuated the beneficial effects of IPC, inhibition of adenosine only attenuated PKC-δ and -ε translocation. Our findings suggest that IPC protects against I/R-induced hepatic injury through activation of PKC-δ. 23689993 Cryptanalysis and improvement of 'a privacy enhanced scheme for telecare medical information systems'. To ensure reliable telecare services some user authentication schemes for telecare medical information system (TMIS) have been presented in literature. These schemes are proposed with intent to regulate only authorized access to medical services so that medical information can be protected from misuse. Very recently Jiang et al. proposed a user authentication scheme for TMIS which they claimed to provide enhanced privacy. They made use of symmetric encryption/decryption with cipher block chaining mode (CBC) to achieve the claimed user privacy. Their scheme provides features like user anonymity and user un-traceability unlike its preceding schemes on which it is built. Unluckily, authors overlook some important aspects in designing their scheme due to which it falls short to resist user impersonation attack, guessing attacks and denial of service attack. Besides, its password change phase is not secure; air message confidentiality is at risk and also has some other drawbacks. Therefore, we propose an improved scheme free from problems observed in Jiang et al.'s scheme and more suitable for TMIS. 23272784 Nanoscale stabilization of new phases in the PbTe-Sb2Te3 system: Pb(m)Sb(2n)Te(m+3n) nanocrystals. A series of novel rock-salt-type Pb(m)Sb(2n)Te(m+3n) nanocrystals (m = 2, 3, 4, 6, 8, and 10; n = 1 and 2) were successfully prepared using a colloidal synthesis route. These materials are stable only on the nanoscale and have no bulk analogues. Elemental compositions were determined using scanning transmission electron microscopy/energy-dispersive X-ray spectroscopy (STEM/EDS) and inductively coupled plasma atomic emission spectroscopy (ICP-AES). The nanocrystals exhibit well-defined band energies in the mid-IR region that are nearly independent of their atomic compositions. Pb(m)Sb(2n)Te(m+3n) nanocrystals behave as metastable homogeneous solid solutions at room temperature and tend to phase separate into the respective binary PbTe + Sb(2)Te(3) at 300 °C. Furthermore, pair distribution function (PDF) analysis suggests that the local structure of these Pb(m)Sb(2n)Te(m+3n) nanocrystals is distorted with respect to the rock-salt structure. 23818580 Inverse modulation of plant immune and brassinosteroid signaling pathways by the receptor-like cytoplasmic kinase BIK1. Maintaining active growth and effective immune responses is often costly for a living organism to survive. Fine-tuning the shared cross-regulators is crucial for metazoans and plants to make a trade-off between growth and immunity. The Arabidopsis regulatory receptor-like kinase BAK1 complexes with the receptor kinases FLS2 in bacterial flagellin-triggered immunity and BRI1 in brassinosteroid (BR)-mediated growth. BR homeostasis and signaling unidirectionally modulate FLS2-mediated immune responses at multiple levels. We have shown previously that BIK1, a receptor-like cytoplasmic kinase, is directly phosphorylated by BAK1 and associates with FLS2/BAK1 complex in transducing flagellin signaling. In contrast to its positive role in plant immunity, we report here that BIK1 acts as a negative regulator in BR signaling. The bik1 mutant displays various BR hypersensitive phenotypes accompanied with increased accumulation of de-phosphorylated BES1 proteins and transcriptional regulation of BZR1 and BES1 target genes. BIK1 associates with BRI1, and is released from BRI1 receptor upon BR treatment, which is reminiscent of FLS2-BIK1 complex dynamics in flagellin signaling. The ligand-induced release of BIK1 from receptor complexes is associated with BIK1 phosphorylation. However, in contrast to BAK1-dependent FLS2-BIK1 dissociation, BAK1 is dispensable for BRI1-BIK1 dissociation. Unlike FLS2 signaling which depends on BAK1 to phosphorylate BIK1, BRI1 directly phosphorylates BIK1 to transduce BR signaling. Thus, BIK1 relays the signaling in plant immunity and BR-mediated growth via distinct phosphorylation by BAK1 and BRI1, respectively. Our studies indicate that BIK1 mediates inverse functions in plant immunity and development via dynamic association with specific receptor complexes and differential phosphorylation events. 23665358 Breaking the symmetry: Immune enhancement increases persistence of dengue viruses in the presence of asymmetric transmission rates. The dengue viruses exist as four antigenically distinct serotypes. These four serotypes co-circulate and interact with each other through multiple immune-mediated mechanisms. Though the majority of previous efforts to understand the transmission dynamics of dengue have assumed identical characteristics for these four serotypes, empirical data suggests that they differ from one another in important ways. Here, we examine dynamics and persistence in models that do not assume symmetry between the dengue viruses. We find that for serotype transmission rates that are only slightly asymmetric, increased transmissibility of secondary infections through immune enhancement increases the persistence of all dengue viruses in opposition to findings in symmetric models. We identify an optimal magnitude of immune enhancement that maximizes the probability of persistence of all four serotypes. In contrast to other pathogen systems where heterogeneity between serotypes in transmissibility facilitates competitive exclusion (Bremmermann and Thieme, 1989), here we find that in the presence of Antibody Dependent Enhancement (ADE) heterogeneity can increase the persistence of multiple serotypes of dengue. 23266449 A self-assembled nanocarrier loading teniposide improves the oral delivery and drug concentration in tumor. We attempted to improve the oral delivery of lipophilic teniposide to achieve higher drug concentration in tumor by self-assembled nanocarrier for further oral chemotherapy. The teniposide loaded self-assembled nanocarrier (TSN) was spherical nanometric particles with narrow size distribution. The intestinal absorption of teniposide from TSN was obviously improved 4.09- and 6.35-fold in duodenum and jejunum at 0.5h after oral administration, then significantly decreased with the prolongation of time. The cellular uptake of TSN in Caco-2 cell monolayer was significantly enhanced over 3 folds and increased with incubation time. Moreover, TSN could be internalized into Caco-2 cell monolayer through clathrin-mediated endocytosis pathway, and then mainly transported into the systemic circulation via portal vein and intestinal lymphatic pathway. The pharmacokinetic results indicated that the AUC(0-t) value of TSN in rats was significantly improved 5.41-fold than that of teniposide solution, moreover, the teniposide concentration in tumor from TSN was obviously improved over 7-fold in tumor bearing mice. The captured image indicated that the oral administered TSN could specifically accumulate in tumor in the xenograft model. Therefore, the self-assembled nanocarrier was promising to enhance the oral delivery of lipophilic teniposide and its concentration in tumor for oral chemotherapy. 23939139 Squaramide-catalysed enantioselective Michael addition of pyrazolin-5-ones to nitroalkenes. An efficient chiral squaramide-catalysed enantioselective Michael addition of pyrazolin-5-ones to nitroalkenes has been developed. This reaction afforded the chiral pyrazol-3-ol derivatives in high to excellent yields (up to >99%) with high enantioselectivities (up to 94% ee) for most substrates under very low catalyst loading (0.25 mol%). This catalytic asymmetric reaction provides valuable and easy access to chiral pyrazol-3-ol derivatives, which possess potential pharmaceutical activity. 23592595 An in Vivo Tagging Method Reveals that Ras Undergoes Sustained Activation upon Transglutaminase-Mediated Protein Serotonylation. Don't interrupt! Protein serotonylation has been implicated in living cells, yet its role remains poorly defined because of the lack of characterization tools. We synthesized a serotonin derivative to enable selective tagging of serotonylation and to investigate its effect on Ras; the latter displayed undisrupted interaction with Raf-1 at the Ras binding domain. 23754270 Antiangiogenic effects of oxymatrine on pancreatic cancer by inhibition of the NF-κB-mediated VEGF signaling pathway. Oxymatrine, the main alkaloid component in the traditional Chinese herbal medicine Sophora japonica (Sophora flavescens Ait), has been reported to have antitumor properties. However, the mechanisms of action in human pancreatic cancer are not well established to date. In the present study, we investigated the antiangiogenic effects of oxymatrine on human pancreatic cancer as well as the possible mechanisms involved. The results of the cell viability assay showed that treatment of PANC-1 pancreatic cancer cells with oxymatrine resulted in cell growth inhibition in a dose- and time-dependent manner. To investigate the possible mechanisms involved in these events, we performed western blotting and reverse transcription-polymerase chain reaction (RT-PCR) analysis. The results revealed that oxymatrine decreased the expression of angiogenesis-associated factors, including nuclear factor κB (NF-κB) and vascular endothelial growth factor (VEGF). Finally, the antiproliferative and antiangiogenic effects of oxymatrine on human pancreatic cancer were further confirmed in pancreatic cancer xenograft tumors in nude mice. In conclusion, our studies for the first time suggest that oxymatrine has potential antitumor effects on pancreatic cancer via suppression of angiogenesis, probably through regulation of the expression of the NF-κB-mediated VEGF signaling pathway. 23740555 A bipodal dicyano anchor unit for single-molecule spintronic devices. The conductance through single 7,7,8,8-tetracyanoquinodimethane (TCNQ) connected to gold electrodes is studied with the nonequilibrium Green's function method combined with density functional theory. The aim of the study is to derive the effect of a dicyano anchor group, C(CN)2 , on energy level alignment between the electrode Fermi level and a molecular energy level. The strong electron-withdrawing nature of the dicyano anchor group lowers the LUMO level of TCNQ, resulting in an extremely small energy barrier for electron injection. At zero bias, electron transfer from electrodes easily occurs and, as a consequence, the anion radical state of TCNQ with a magnetic moment is formed. The unpaired electron in the TCNQ anion radical causes an exchange splitting between the spin-α and spin-β transmission spectra, allowing the single TCNQ junction to act as a spin-filtering device. 23857302 Flow velocities of Alaskan glaciers. Our poor understanding of tidewater glacier dynamics remains the primary source of uncertainty in sea level rise projections. On the ice sheets, mass lost from tidewater calving exceeds the amount lost from surface melting. In Alaska, the magnitude of calving mass loss remains unconstrained, yet immense calving losses have been observed. With 20% of the global new-water sea level rise coming from Alaska, partitioning of mass loss sources in Alaska is needed to improve sea level rise projections. Here we present the first regionally comprehensive map of glacier flow velocities in Central Alaska. These data reveal that the majority of the regional downstream flux is constrained to only a few coastal glaciers. We find regional calving losses are 17.1 Gt a(-1), which is equivalent to 36% of the total annual mass change throughout Central Alaska. 22899104 Motion corrected compressed sensing for free-breathing dynamic cardiac MRI. Compressed sensing (CS) has been demonstrated to accelerate MRI acquisitions by reconstructing sparse images of good quality from highly undersampled data. Motion during MR scans can cause inconsistencies in k-space data, resulting in strong motion artifacts in the reconstructed images. For CS to be useful in these applications, motion correction techniques need to be combined with the undersampled reconstruction. Recently, joint motion correction and CS approaches have been proposed to partially correct for effects of motion. However, the main limitation of these approaches is that they can only correct for affine deformations. In this work, we propose a novel motion corrected CS framework for free-breathing dynamic cardiac MRI that incorporates a general motion correction formulation directly into the CS reconstruction. This framework can correct for arbitrary affine or nonrigid motion in the CS reconstructed cardiac images, while simultaneously benefiting from highly accelerated MR acquisition. The application of this approach is demonstrated both in simulations and in vivo data for 2D respiratory self-gated free-breathing cardiac CINE MRI, using a golden angle radial acquisition. Results show that this approach allows for the reconstruction of respiratory motion corrected cardiac CINE images with similar quality to breath-held acquisitions. Magn Reson Med 70:504-516, 2013. © 2012 Wiley Periodicals, Inc. 23904823 The German quality indicators in intensive care medicine 2013--second edition. Quality indicators are key elements of quality management. The quality indicators for intensive care medicine of the German Interdisciplinary Society of Intensive Care Medicine (DIVI) from the year 2010 were recently evaluated when their validity time expired after two years. Overall one indicator was replaced and further three were in part changed. The former indicator I "elevation of head of bed" was replaced by the indicator "Daily multi-professional ward rounds with the documentation of daily therapy goals" and added to the indicator IV "Weaning and other measures to prevent ventilator associated pneumonias (short: Weaning/VAP Bundle)" (VAP = ventilator-associated pneumonia) which aims at the reduction of VAP incidence. The indicator VIII "Documentation of structured relative-/next-of-kin communication" was refined. The indicator X "Direction of the ICU by a specially trained certified intensivist with no other clinical duties in a department" was also updated according to recent study results. These updated quality indicators are part of the Peer Review in intensive care medicine. The next update of the quality indicators is due in 2016. Abstract available from the publisher. 23281812 Tetrahydropyrroloquinolinone type dual inhibitors of aromatase/aldosterone synthase as a novel strategy for breast cancer patients with elevated cardiovascular risks. The application of aromatase inhibitors to postmenopausal breast cancer patients increases the risk of cardiovascular diseases (CVD), which is believed to be caused by the abnormally high concentrations of aldosterone as a consequence of the estrogen deficiency. Dual inhibitors of aromatase (CYP19) and aldosterone synthase (CYP11B2) are therefore proposed as a novel strategy for the adjuvant therapy to reduce the CVD risk for these patients. By combining decisive structural features of CYP11B2 and CYP19 inhibitors into a common template, a series of pyridinylmethyl substituted 1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-ones were designed and synthesized. Interestingly, the substituents on the methylene bridge showed strong influences on the inhibitory activities leading to opposite effects, that is, a given substituent showed an increase in inhibition of one enzyme, while it led to a decrease for the other enzyme. The compromise of this conflict led to compounds 3j, 3k, 3n, and 3p as potent and selective dual inhibitors of CYP19 and CYP11B2, especially compound 3p, which exhibited IC(50) values of 32 and 41 nM for CYP19 and CYP11B2, respectively, and a high selectivity toward CYP17 and CYP11B1. This compound is considered as a candidate for further evaluation in vivo. 23931325 Mechanism of How Salt-Gradient-Induced Charges Affect the Translocation of DNA Molecules through a Nanopore. Experiments using nanopores demonstrated that a salt gradient enhances the capture rate of DNA and reduces its translocation speed. These two effects can help to enable electrical DNA sequencing with nanopores. Here, we provide a quantitative theoretical evaluation that shows the positive net charges, which accumulate around the pore entrance due to the salt gradient, are responsible for the two observed effects: they reinforce the electric capture field, resulting in promoted molecule capture rate; and they induce cationic electroosmotic flow through the nanopore, thus significantly retarding the motion of the anionic DNA through the nanopore. Our multiphysical simulation results show that, during the polymer trapping stage, the former effect plays the major role, thus resulting in promoted DNA capture rate, while during the nanopore-penetrating stage the latter effect dominates and consequently reduces the DNA translocation speed significantly. Quantitative agreement with experimental results has been reached by further taking nanopore wall surface charges into account. 23906554 Addictive behaviors related to opioid use for chronic pain: A population-based study. The growing body of research showing increased opioid use in patients with chronic pain coupled with concerns regarding addiction encouraged the development of this population-based study. The goal of the study was to investigate the co-occurrence of indicators of addictive behaviors in patients with chronic non-cancer pain in long-term opioid treatment. The study combined data from the individual-based Danish Health Survey in 2010 and the official Danish health and socio-economic, individual-based registers. From a simple random sample of 25,000 adults (16 years or older) living in Denmark, 13,281 individuals were analyzed through multiple logistic regression analyses to assess the association between chronic pain (lasting ⩾6 months), opioid use, health behavior, and body mass index. Six potential addictive behaviors were identified: daily smoking; high alcohol intake; illicit drug use in the past year; obesity; long-term use of benzodiazepines; and long-term use of benzodiazepine-related drugs. At least 2 of the 6 addictive behaviors were observed in 22.6% of the long-term opioid users with chronic pain compared with 11.5% of the non-opioid users with chronic pain and 8.9% of the individuals without chronic pain. Thus, a strong association was demonstrated between long-term opioid use and the clustering of addictive behaviors. An intricate relationship between chronic pain, opioid use, and addictive behaviors was observed in this study, which deserves both clinical attention and further research. 23488628 CD133/CD140a-Based Isolation of Distinct Human Multipotent Neural Progenitor Cells and Oligodendrocyte Progenitor Cells. The mechanisms underlying the specification of oligodendrocyte fate from multipotent neural progenitor cells (NPCs) in developing human brain are unknown. In this study, we sought to identify antigens sufficient to distinguish NPCs free from oligodendrocyte progenitor cells (OPCs). We investigated the potential overlap of NPC and OPC antigens using multicolor fluorescence-activated cell sorting (FACS) for CD133/PROM1, A2B5, and CD140a/PDGFαR antigens. Surprisingly, we found that CD133, but not A2B5, was capable of enriching for OLIG2 expression, Sox10 enhancer activity, and oligodendrocyte potential. As a subpopulation of CD133-positive cells expressed CD140a, we asked whether CD133 enriched bone fide NPCs regardless of CD140a expression. We found that CD133(+)CD140a(-) cells were highly enriched for neurosphere initiating cells and were multipotent. Importantly, when analyzed immediately following isolation, CD133(+)CD140a(-) NPCs lacked the capacity to generate oligodendrocytes. In contrast, CD133(+)CD140a(+) cells were OLIG2-expressing OPCs capable of oligodendrocyte differentiation, but formed neurospheres with lower efficiency and were largely restricted to glial fate. Gene expression analysis further confirmed the stem cell nature of CD133(+)CD140a(-) cells. As human CD133(+) cells comprised both NPCs and OPCs, CD133 expression alone cannot be considered a specific marker of the stem cell phenotype, but rather comprises a heterogeneous mix of glial restricted as well as multipotent neural precursors. In contrast, CD133/CD140a-based FACS permits the separation of defined progenitor populations and the study of neural stem and oligodendrocyte fate specification in the human brain. 23438131 Effects of Right Ventricular Nonapical Pacing on Cardiac Function: A Meta-analysis of Randomized Controlled Trials. A meta-analysis of randomized controlled trials (RCTs) was conducted to compare the effects of right ventricular nonapical (RVNA) and right ventricular apical (RVA) pacing on cardiac function. A systematic literature search was performed using MEDLINE, EMBASE, and the Cochrane Library to identify RCTs comparing RVNA pacing with RVA pacing with follow-up ≥2 months. Twenty RCTs involving 1,114 patients were included. Compared with RVA pacing, RVNA (mainly right ventricular septum [RVS]) pacing exhibited not only excellent pacing threshold and R-wave amplitude but also higher impedance. RVNA pacing showed a significant increase in left ventricular ejection fraction (LVEF) at the end of follow-up (weighted mean difference = 3.58, 95% confidence interval = 1.80-5.35), and the effects were observed in the following subgroups: 6-month follow-up, ≤12-month follow-up, >12-month follow-up, baseline LVEF ≤45%, and baseline LVEF >45%. RVS and RVA pacing significantly differed in improving LVEF (weighted mean difference = 4.82, 95% confidence interval = 2.78-6.87). In addition, RVNA pacing resulted in a narrower QRS duration, a smaller left ventricular end-systolic volume, and a lower New York Heart Association functional class. This meta-analysis found that RVNA (mainly RVS) pacing exhibited satisfactory long-term lead performance compared with RVA pacing and demonstrated beneficial effects in improving LVEF after the 6-month follow-up. Furthermore, it proved superior to RVA pacing in terms of interventricular synchrony and cardiac function. 23850716 Truncated recombinant non-structural protein 2C-based indirect ELISA for FMD sero-surveillance. Foot-and-mouth disease (FMD) is a transboundary animal disease caused by foot-and-mouth disease virus. In India, systematic preventive vaccination using inactivated trivalent (O, A and Asia 1) vaccine is the strategy being adopted to control FMD. The use of non-structural protein (NSP)-contaminated inactivated vaccine raises concerns over differentiation of infected and vaccinated animals (DIVA) by NSP based immunoassays. However, 2C being a membrane associated protein usually remain absent in vaccine formulations and thus, anti-2C response is one of the most reliable indicator of the FMDV infection. In this study, 34 amino acids from N-terminus of 2C protein were removed to eliminate membrane-binding amphipathic helicase activity for the expression of recombinant protein in soluble form. Truncated 2C (2Ct) was utilized for development of an indirect ELISA (I-ELISA) for bovine and the developed 2Ct I-ELISA was validated using a panel constituting of serum of naïve, vaccinated and infected animals. The assay was compared with the in-house r3AB3 I-ELISA and the overall concordance was 85.31%. The diagnostic sensitivity and specificity of the 2Ct I-ELISA were 92.9% and 94.0%, respectively. The apparent prevalence of anti-2C antibodies for random bovine samples tested by the developed assay was 23.7%. The developed ELISA will help in augmenting the sensitivity of detection if used in combination with r3AB3 I-ELISA for sero-surveillance. 23707539 Electrophysiological correlates of melodic processing in congenital amusia. Music listening involves using previously internalized regularities to process incoming musical structures. A condition known as congenital amusia is characterized by musical difficulties, notably in the detection of gross musical violations. However, there has been increasing evidence that individuals with the disorder show preserved musical ability when probed using implicit methods. To further characterize the degree to which amusic individuals show evidence of latent sensitivity to musical structure, particularly in the context of stimuli that are ecologically valid, electrophysiological recordings were taken from a sample of amusic and control participants as they listened to real melodies. To encourage them to pay attention to the music, participants were asked to detect occasional notes in a different timbre. Using a computational model of auditory expectation to identify points of varying levels of expectedness in these melodies (in units of information content (IC), a measure which has an inverse relationship with probability), ERP analysis investigated the extent to which the amusic brain differs from that of controls when processing notes of high IC (low probability) as compared to low IC ones (high probability). The data revealed a novel effect that was highly comparable in both groups: Notes with high IC reliably elicited a delayed P2 component relative to notes with low IC, suggesting that amusic individuals, like controls, found these notes more difficult to evaluate. However, notes with high IC were also characterized by an early frontal negativity in controls that was attenuated in amusic individuals. A correlation of this early negative effect with the ability to make accurate note expectedness judgments (previous data collected from a subset of the current sample) was shown to be present in typical individuals but compromised in individuals with amusia: a finding in line with evidence of a close relationship between the amplitude of such a response and explicit knowledge of musical deviance. 23474317 Effects of perinatal exposure to waterborne fluoxetine on memory processing in the cuttlefish Sepia officinalis. Recent ecotoxicological studies highlight the increasing presence of pharmaceuticals discharged in the aquatic environment. Amongst them is the antidepressant fluoxetine (FLX), a selective serotonin reuptake inhibitor, primarily indicated for treatment of depression. The effect of chronic exposure to FLX on memory processing in 1-month-old cuttlefish Sepia officinalis was evaluated. Three groups of new-borns were reared in different conditions: one control group (no FLX) and two groups exposed to environmental concentrations of FLX (1 and 100ng/L) from 15 days pre-hatching to 1 month post-hatching. Acquisition and retention performances were assessed using the 'prawn-in-the-tube' procedure. Perinatal exposure to fluoxetine led to significant changes in memory processing of the animals. The lowest observed effect concentration of this antidepressant on learning and retention was 1ng/L which is under the range of environmental contamination. Cuttlefish exposed at low FLX concentration had impaired acquisition capabilities and animals exposed at high FLX concentration displayed a deficit of memory retention compared to the control group that had nonimpaired initial acquisition and retention performances. The results subsequently suggested that FLX-induced changes in cognitive capacities could potentially lead to inappropriate predatory behaviors in the natural environment. The study provides the basis for future studies on how pharmaceutical contaminants disrupt cognition in ecologically and economically relevant marine invertebrates. 23536275 Dissolved heavy metals in the Tigris River (Turkey): spatial and temporal variations. Multivariate statistical techniques, such as analysis of variance, cluster analysis (CA), correlation analysis, principal component analysis (PCA), and factor analysis (FA), were applied to determine the spatial and temporal variations of dissolved heavy metals in the Tigris River at 7 different sites spread over the river stretch of about 500 km during the period of February 2008 to January 2009. The results indicated that Fe, Cr, and Ni were the most abundant elements in the river water, whereas Cd and As were the less abundant. Cu, Fe, Ni, and Zn showed significant spatial variations, reflecting the influence of anthropogenic activities. The lowest total concentration of heavy metals was found at site 2 downstream of the Dicle Dam due to clean water from the dam. The concentrations of most metals were found lower when compared with results of previous studies due to reduction of the activity of the copper mine plant and the construction of two dams on the river. The lowest total concentrations were determined in February due to high precipitation and snow melts. Hierarchical agglomerative CA classified all the sampling sites into three main groups of spatial similarities. Clusters 1 (Maden and Bismil), 2 (Cizre), and 3 (EÄŸil, Diyarbakır, Batman, and Hasankeyf) corresponded to moderate polluted and relatively low polluted regions, respectively. PCA/FA, CA, and correlation analysis suggest that Cu, Ni, and Zn are controlled by anthropogenic sources. 23845820 Unequal access to vaccines in the WHO European Region during the A(H1N1) influenza pandemic in 2009. In a severe pandemic, rapid production and deployment of vaccines will potentially be critical in mitigating the impact on populations and essential services. We compared access to vaccines and timing of delivery relative to identification of A(H1N1)pdm09 and the geographic progression of the pandemic in the WHO European Region in order to identify gaps in provision. Information on vaccine procurement and donations was collected through a web-based survey conducted in all 53 member states of the Region. Among the 51 countries responding to the survey, the majority (84%) implemented vaccination campaigns against A(H1N1)pdm09. However, time of vaccine receipt and number of doses varied substantially across the region, with delayed access in many countries especially in those in the lowest income range. Improving access to influenza vaccines in low resource countries and solving issues of product liability should help reduce inequalities and operational challenges arising during a future public health crisis. 23672318 Comparison of percutaneous nephrolithotomy under spinal versus general anesthesia: a randomized clinical trial. Abstract Purpose: To evaluate the safety and efficacy of spinal anesthesia compared with general anesthesia in patients who underwent percutaneous nephrolithotomy (PCNL). Patients and Methods: One hundred patients with American Society of Anesthesiologists (ASA) score <3 were randomly divided into two groups according to the type of anesthesia. Spinal anesthesia was performed using an injection of 0.25 mg/kg bupivacaine 0.5% in the intrathecal space; no opium (fentanyl) agent was used. All procedures were performed with the patient in the prone position. Stone access was made by using fluoroscopic guidance, and the tract was dilated using a single-stage technique. All patients received a solution including 1 mg/kg morphine in every 100 mL physiologic saline through the volumetric pump during the 3-hour post-PCNL period in the recovery room. Afterward, morphine (0.05 mg/kg) was injected only according to the verbal rating scale greater than 3 after discharge from the recovery room until 24 hours after surgery. Results: The two groups were matched by mean age, distribution of stone location, and stone burden. Mean operative time, hospital stay, stone-free rate and mean hemoglobin drop were comparable between the two groups. The rate of complications according to the Clavien grading system was nearly similar in both groups. Mean analgesic requirement during 24 hours after PCNL was 6.8 mg in the spinal group and 13.2 mg in the general group (P<0.001). Conclusion: It seems that using spinal anesthesia by intrathecal injection of local anesthetic solutions vs general anesthesia has comparable surgical outcomes and reduces the requirement for analgesia after PCNL in the early postoperative period. 23807653 Small doses from artificial UV sources elucidate the photo-production of vitamin D. To clarify the relation between UV exposure and vitamin D status, 201 volunteers wore personal electronic UV dosimeters during daylight hours, to record their UV exposure over a 10 week period when ambient UV levels were significantly less than the summer maxima. Blood samples to determine serum 25-hydroxyvitamin D3 [25(OH)D3] levels were taken at the end of week 4 and week 8. Participants were then given a single full-body exposure of approximately 2 SED from one of four artificial UV sources with different spectral outputs and a further blood sample taken at study completion, nominally week 10. The artificial UV exposure reversed the mean seasonal decline in 25(OH)D3. Increases in 25(OH)D3 from week 8 to week 10 were related to total UV exposure, including the ambient sun exposures. These exposures were weighted by the erythemal action spectrum and separately for three different action spectra for pre-vitamin D production. For the erythema weighting function, 25(OH)D3 increased 1.78 ± 0.25 nmol per litre per SED, a value consistent with other studies. Any differences due to age, BMI, gender, and skin reflectance were not statistically significant. Ethnicity differences were the only significant factor, with Asians producing the least vitamin D, and Maori the most. There was no statistically significant improvement in consistency between sources for any of the three pre-vitamin weightings compared with that for erythema. Further work is needed to verify which vitamin D action spectrum is most appropriate. Nevertheless, these small doses of UV from artificial sources were helpful in quantifying the relationship between UV exposure and vitamin D status among the New Zealand population. 23770748 Predictors of long-term outcomes in symptomatic hypertrophic obstructive cardiomyopathy patients undergoing surgical relief of left ventricular outflow tract obstruction. We report the predictors of long-term outcomes of symptomatic hypertrophic cardiomyopathy patients undergoing surgical relief of left ventricular outflow tract obstruction. We studied 699 consecutive patients who have hypertrophic cardiomyopathy with severe symptomatic left ventricular outflow tract obstruction (47±11 years, 63% male) intractable to maximal medical therapy, who were referred to a tertiary hospital between January 1997 and December 2007 for the surgical relief of left ventricular outflow tract obstruction. We excluded patients <18 years of age, those with an ejection fraction <50%, those with hypertensive heart disease of the elderly, and those with more than mild aortic or mitral stenosis. Clinical, echocardiographic, and Holter data were recorded. A composite end point of death, appropriate internal cardioverter defibrillator discharges, resuscitated from sudden death, documented stroke, and admission for congestive heart failure was recorded. During a mean follow-up of 6.2±3 years, 86 patients (12%) met the composite end point with 30-day, 1-year, and 2-year event rates of 0.7%, 2.8%, and 4.7%, respectively. The hard event rate (death, defibrillator discharge, and resuscitated from sudden death) at 30 days, 1 year, and 2 years was 0%, 1.5%, and 3%, respectively. Stepwise multivariable analysis identified residual postoperative atrial fibrillation (hazard ratio, 2.12; confidence interval, 1.37-3.34; P=0.001) and increasing age (hazard ratio, 1.49; confidence interval, 1.22-1.82; P=0.001) as independent predictors of long-term composite outcomes. Symptomatic adult hypertrophic cardiomyopathy patients undergoing surgery for the relief of left ventricular outflow tract obstruction have low event rates during long-term follow-up; worse outcomes are predicted by increasing age and the presence of residual atrial fibrillation during follow-up. 23475553 Semi-continuous in situ magnetic separation for enhanced extracellular protease production-modeling and experimental validation. In modern biotechnology proteases play a major role as detergent ingredients. Especially the production of extracellular protease by Bacillus species facilitates downstream processing because the protease can be directly harvested from the biosuspension. In situ magnetic separation (ISMS) constitutes an excellent adsorptive method for efficient extracellular protease removal during cultivation. In this work, the impact of semi-continuous ISMS on the overall protease yield has been investigated. Results reveal significant removal of the protease from Bacillus licheniformis cultivations. Bacitracin-functionalized magnetic particles were successfully applied, regenerated and reused up to 30 times. Immediate reproduction of the protease after ISMS proved the biocompatibility of this integrated approach. Six subsequent ISMS steps significantly increased the overall protease yield up to 98% because proteolytic degradation and potential inhibition of the protease in the medium could be minimized. Furthermore, integration of semi-continuous ISMS increased the overall process efficiency due to reduction of the medium consumption. Process simulation revealed a deeper insight into protease production, and was used to optimize ISMS steps to obtain the maximum overall protease yield. 23594958 Expansion of CD27(high) plasmablasts in transverse myelitis patients that utilize VH4 and JH6 genes and undergo extensive somatic hypermutation. Patients with the autoimmune disease multiple sclerosis (MS) typically present with the clinically isolated syndromes (CIS) transverse myelitis (TM) or optic neuritis (ON). B-cell disturbances have been well documented in patients with MS and CIS patients with ON, but not in CIS patients with TM, despite the fact that these patients have the worst clinical outcome of all CIS types. The goal of this study was to characterize the B-cell populations and immunoglobulin genetics in TM patients. We found a unique expansion of CD27(high) plasmablasts in both the cerebrospinal fluid and periphery of TM patients that is not present in ON patients. Additionally, plasmablasts from TM patients show evidence for positive selection with increased somatic hypermutation accumulation in VH4(+) B cells and receptor editing that is not observed in ON patients. These characteristics unique to TM patients may impact disease severity and progression. 23462569 NMR-based metabonomic in hippocampus, nucleus accumbens and prefrontal cortex of methamphetamine-sensitized rats. (1)H NMR spectroscopy was applied to investigate the changes of cerebral metabolites in brain hippocampus, nucleus accumbens (NAC) and prefrontal cortex (PFC) of the rats subjected to subcutaneous twice-daily injections of 2.5mg/kg methamphetamine (MAP) for 7 days. The results indicated that MAP exposure induced significant behavioral sensitization and altered cerebral metabolites in rats. The neurotransmitters glutamate, glutamine and GABA significantly decreased in hippocampus, NAC and PFC. Specifically, increased succinic acid semialdehyde, a metabolism product of GABA, was observed in hippocampus. Additionally, decreased serotonin was observed in both NAC and PFC, whereas decreased dopamine was only observed in NAC after repeated MAP treatment. Glutathione obviously decreased in above brain regions, whereas acetylcysteine declined in hippocampus and NAC, and taurine declined in NAC and PFC. Homocysteic acid was elevated in hippocampus and NAC by repeated MAP administration. Membrane ingredients like phosphocholine elevated in response to MAP administration in NAC and PFC. N-Acetyl-aspartate, a marker of neuronal viability, decreased in the three regions; however, myo-inositol, a glial cell marker, increased in hippocampus and PFC. Tricarboxylic acid cycle intermediate products, such as α-ketoglutarate, succinate, citrate and the methionine significantly decreased in above three brain regions after MAP administration; however, ADP decreased in hippocampus. These results indicate that repeated MAP treatment causes neurotransmitters disturbance, imbalance between oxidative stress and antioxidants, and gliosis in hippocampus, NAC and PFC. Profound metabolic changes detected across brain regions provide the first evidence of metabonomic changes in MAP-induced sensitized rats. 23740381 Robotic-assisted laparoscopic reconstructive surgery in the lower urinary tract. Open surgery has long been the most common surgical approach for the correction of congenital anomalies of the lower urinary tract in children. With the continued development of minimally invasive surgery in adult urology, including endoscopic, conventional, and robot-assisted laparoscopic approaches, the indications for minimally invasive surgery have similarly expanded in the pediatric population. The most commonly performed robotic procedure in children has been pyeloplasty for ureteropelvic junction obstruction; the use of robotics in complex reconstructive surgery in the lower urinary tract has also been acceptable. In this review, we summarize recent viewpoints regarding robotic-assisted laparoscopic reconstructive surgeries in the lower urinary tract, such as ureteral reimplantation, appendicovesicostomy, and augmentation enterocystoplasty in the pediatric population, and critically summarize the current knowledge on outcomes in the literature. We also discuss our technique and the outcomes of robotic ureteral reimplantation. This review demonstrates that robotic-assisted laparoscopic reconstructive surgeries in the lower urinary tract are technically feasible and may achieve outcomes that are equalto those of open surgery, with reduced morbidity. 23922807 Circulating miRNA Biomarkers for Alzheimer's Disease. A minimally invasive diagnostic assay for early detection of Alzheimer's disease (AD) is required to select optimal patient groups in clinical trials, monitor disease progression and response to treatment, and to better plan patient clinical care. Blood is an attractive source for biomarkers due to minimal discomfort to the patient, encouraging greater compliance in clinical trials and frequent testing. MiRNAs belong to the class of non-coding regulatory RNA molecules of ∼22 nt length and are now recognized to regulate ∼60% of all known genes through post-transcriptional gene silencing (RNAi). They have potential as useful biomarkers for clinical use because of their stability and ease of detection in many tissues, especially blood. Circulating profiles of miRNAs have been shown to discriminate different tumor types, indicate staging and progression of the disease and to be useful as prognostic markers. Recently their role in neurodegenerative diseases, both as diagnostic biomarkers as well as explaining basic disease etiology has come into focus. Here we report the discovery and validation of a unique circulating 7-miRNA signature (hsa-let-7d-5p, hsa-let-7g-5p, hsa-miR-15b-5p, hsa-miR-142-3p, hsa-miR-191-5p, hsa-miR-301a-3p and hsa-miR-545-3p) in plasma, which could distinguish AD patients from normal controls (NC) with >95% accuracy (AUC of 0.953). There was a >2 fold difference for all signature miRNAs between the AD and NC samples, with p-values<0.05. Pathway analysis, taking into account enriched target mRNAs for these signature miRNAs was also carried out, suggesting that the disturbance of multiple enzymatic pathways including lipid metabolism could play a role in AD etiology. 23773042 Do we become a different person when hitting the road? Personality development of sojourners. International mobility is a prevalent life event that particularly affects university students. The aim of this longitudinal study was twofold: First, we examined the impact of international mobility on personality (Big Five) change, separating self-selection effects from socialization processes. Second, we extended prior analyses on the association between life events and personality development by investigating the mechanisms that account for socialization processes. In particular, we assessed whether individual differences in the fluctuation of support relationships serve as an explanatory link. We used a prospective control group design with 3 measurement occasions. A sample of university students, containing both short-term (i.e., 1 semester) and long-term (i.e., 1 academic year) sojourners (N = 527) along with control students (N = 607), was tracked over the course of an academic year. Multivariate latent models revealed 3 main findings: First, initial (pre-departure) levels of Extraversion and Conscientiousness predicted short-term sojourning, and Extraversion and Openness predicted long-term sojourning. Second, both forms of sojourning were associated with increases in Openness and Agreeableness and a decrease in Neuroticism above and beyond the observed self-selection. Third, the acquisition of new international support relationships largely accounted for the sojourn effects on personality change. These findings help to fill the missing link between life events and personality development by establishing social relationship fluctuation as an important mediating mechanism. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23855810 Splanchnic vein thrombosis in myeloproliferative neoplasms. Splanchnic vein thrombosis (SVT) is one of the most important complications of myeloproliferative neoplasms (MPN). Although MPN are common causes of SVT, the pathophysiological mechanisms underlying this predisposition, their epidemiology and natural history are not fully understood. Studies have concentrated on the generalized prothrombotic environment generated by MPN and their relationship with abnormal blood counts, thereby furthering our knowledge of arterial and venous thrombosis in this population. In contrast, there are few studies that have specifically addressed SVT in the context of MPN. Recent research has demonstrated in patients with MPN the existence of factors increasing the risk of SVT such as the presence of the JAK2 V617F mutation and its 46/1 haplotype. Features unique to the circulating blood cells, splanchnic vasculature and surrounding micro-environment in patients with MPN have been described. There are also abnormalities in local haemodynamics, haemostatic molecules, the spleen, and splanchnic endothelial and endothelial progenitor cells. This review considers these important advances and discusses the contribution of individual anomalies that lead to the development of SVT in both the pre-neoplastic and overt stage of MPN. Clinical issues relating to epidemiology, recurrence and survival in these patients have also been reviewed and their results discussed. 23829892 Negligible Nuclear FOXP3 Expression in Breast Cancer Epithelial Cells Compared With FOXP3-Positive T Cells. The presence of forkhead box protein 3 (FOXP3) in breast cancer cells is a matter of debate. We systematically analyzed expression of FOXP3 in 1574 breast carcinomas. For nuclear FOXP3 detection in epithelial breast cancer cells, tissue microarray technology was used. In addition, cultured breast cancer cell lines (ZR75-1, MCF7-WH, BT20, T47D, and SKBR3) were tested for FOXP3 expression using real-time polymerase chain reaction and flow cytometry for messenger RNA (mRNA) and protein quantification. We could neither detect any significant levels of mRNA or protein expression of FOXP3 in human breast cancer cell lines, nor in breast cancer specimens. Weak nuclear staining for FOXP3 was detectable in 16 of 1574 breast cancer cases (1%) and was only seen in a small proportion of malignant cells. There was no difference in survival between patients with FOXP3-positive or -negative tumors. FOXP3 does most likely not play a significant role in breast cancer biology, because it is only scarcely expressed in a very small proportion of breast cancer samples. 23474483 Moderate GLUT4 overexpression improves insulin sensitivity and fasting triglyceridemia in high-fat diet-fed transgenic mice. The GLUT4 facilitative glucose transporter mediates insulin-dependent glucose uptake. We tested the hypothesis that moderate overexpression of human GLUT4 in mice, under the regulation of the human GLUT4 promoter, can prevent the hyperinsulinemia that results from obesity. Transgenic mice engineered to express the human GLUT4 gene and promoter (hGLUT4 TG) and their nontransgenic counterparts (NT) were fed either a control diet (CD) or a high-fat diet (HFD) for up to 10 weeks. Homeostasis model assessment of insulin resistance scores revealed that hGLUT4 TG mice fed an HFD remained highly insulin sensitive. The presence of the GLUT4 transgene did not completely prevent the metabolic adaptations to HFD. For example, HFD resulted in loss of dynamic regulation of the expression of several metabolic genes in the livers of fasted and refed NT and hGLUT4 TG mice. The hGLUT4 TG mice fed a CD showed no feeding-dependent regulation of SREBP-1c and fatty acid synthase (FAS) mRNA expression in the transition from the fasted to the fed state. Similarly, HFD altered the response of SREBP-1c and FAS mRNA expression to feeding in both strains. These changes in hepatic gene expression were accompanied by increased nuclear phospho-CREB in refed mice. Taken together, a moderate increase in expression of GLUT4 is a good target for treatment of insulin resistance. 23027684 Anti-inflammatory Effects of the Zingiber officinale roscoe Constituent 12-Dehydrogingerdione in Lipopolysaccharide-stimulated Raw 264.7 Cells. Ginger has long been used worldwide as a spice, seasoning, and wine and is also used as a traditional medicine. There have been no previous studies of the potential beneficial effects of the ginger constituent 12-dehydrogingerdione (12-DHGD). We investigated the anti-inflammatory effect of 12-DHGD on lipopolysaccharide (LPS)-stimulated Raw 264.7 cells. The cytotoxicity of 12-DHGD was measured using the MTT assay, and production of prostaglandin E2 (PGE2 ) and the inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α was measured by ELISA. Production of nitric oxide (NO) was measured using Griess reagent and expression of cyclooxygenase-2 (COX-2) and inducible NO (iNOS) enzymes was assessed by reverse transcriptase-polymerase chain reaction. Treatment of Raw 264.7 cells with 12-DHGD significantly inhibited LPS-stimulated production of NO (at 12-DHGD concentrations of 150 and 200 ng/ml), IL-6 (at 50, 100, 150, and 200 ng/ml), and PGE2 (at 200 ng/ml). Consistent with the effects on NO and PGE2 production, 12-DHGD treatment also inhibited the LPS-stimulated increase in iNOS and COX-2 mRNA levels. However, 12-DHGD did not affect production of IL-1β or TNF-α in response to LPS. 12-DHGD, a constituent of ginger, is a potent inhibitor of proinflammatory mediator production in Raw 264.7 macrophage cells. Copyright © 2012 John Wiley & Sons, Ltd. 23726345 Design, synthesis and biological evaluation of novel aminothiazoles as antiviral compounds acting against human rhinovirus. We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure-activity relationships. A comprehensive investigational library was designed and performed allowing the identification of potent compounds with lower molecular weight and improved ADME profile. 31d-1, 31d-2, 31f showed good exposures in CD-1 mice. The mechanism of action was discovered to be a host target: the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIß). The identification of the pan-HRV active compound 31f combined with a structurally distinct literature compound T-00127-HEV1 allowed the assessment of target related tolerability of inhibiting this kinase for a short period of time in order to prevent HRV replication. 23906865 Gray colored glasses: Is major depression partially a sensory perceptual disorder? Major depression is a neuropsychiatric disorder that can involve profound dysregulation of mood. While depression is associated with additional abnormalities besides reduced mood, such as cognitive dysfunction, it is not well established that sensory perception is also altered in this disorder (aside from in psychotic depression). Recent studies have shown that visual processing, in as early a stage as the retina, is impaired in depression. This paper examines the hypothesis that major depression can involve alterations in sensory perception. A Pubmed literature search investigated several lines of evidence: innervation of sensory cortex by serotonin and norepinephrine; antidepressant drugs and depression itself affecting processing of facial expressions of emotion; electroencephalography (EEG) studies of depressed persons and antidepressant drugs; involvement of the serotonergic 5HT2A receptor in both depression and hallucinogenic drug action; psychotic depression involving sensory distortions; dopamine possibly playing a role in depression; and the antidepressant effect of blocking the NMDA receptor with ketamine. Data from each of these lines of evidence support the hypothesis that major depression can involve sensory perceptual alterations. Loss of interest in one's daily activities and inability to experience pleasure, also known as anhedonia, in major depression may in part be mediated by sensory abnormalities, whereby normal sensory perceptions are no longer present to activate reward circuitry. The data supporting the hypothesis tend to be associative, so further confirmation of the hypothesis awaits additional controlled experiments. 23688586 Depletion of PHF14, a novel histone-binding protein gene, causes neonatal lethality in mice due to respiratory failure. The plant homeodomain (PHD) finger is identified in many chromatin-binding proteins, and functions as a 'reader' that recognizes specific epigenetic marks on histone tails, bridging transcription factors and their associated complexes to chromatin, and regulating gene expression. PHD finger-containing proteins perform many biological functions and are involved in many human diseases including cancer. PHF14 is predicted to code for a protein with multiple PHD fingers. However, its function is unidentified. The aim of this study is to characterize PHF14 and investigate its biological significance by employing multiple approaches including mouse gene-targeting knockout, and molecular cloning and characterization. Three transcripts of PHF14 in human cell lines were identified by reverse transcriptase polymerase chain reaction. Two isoforms of PHF14 (PHF14α and PHF14β) were cloned in this study. It was found that PHF14 was ubiquitously expressed in mouse tissues and human cell lines. PHF14α, the major isoform of PHF14, was localized in the nucleus and also bound to chromatin during cell division. Interestingly, co-immunoprecipitation results suggested that PHF14α bound to histones via its PHD fingers. Strikingly, gene-targeting knockout of PHF14 in mice resulted in a neonatal lethality due to respiratory failure. Pathological analysis revealed severe disorders of tissue and cell structures in multiple organs, particularly in the lungs. These results indicated that PHF14 might be an epigenetic regulator and play an important role in the development of multiple organs in mouse. 23887200 Recent advances in computational predictions of NMR parameters for the structure elucidation of carbohydrates: methods and limitations. All living systems are comprised of four fundamental classes of macromolecules - nucleic acids, proteins, lipids, and carbohydrates (glycans). Glycans play a unique role of joining three principal hierarchical levels of the living world: (1) the molecular level (pathogenic agents and vaccine recognition by the immune system, metabolic pathways involving saccharides that provide cells with energy, and energy accumulation via photosynthesis); (2) the nanoscale level (cell membrane mechanics, structural support of biomolecules, and the glycosylation of macromolecules); (3) the microscale and macroscale levels (polymeric materials, such as cellulose, starch, glycogen, and biomass). NMR spectroscopy is the most powerful research approach for getting insight into the solution structure and function of carbohydrates at all hierarchical levels, from monosaccharides to oligo- and polysaccharides. Recent progress in computational procedures has opened up novel opportunities to reveal the structural information available in the NMR spectra of saccharides and to advance our understanding of the corresponding biochemical processes. The ability to predict the molecular geometry and NMR parameters is crucial for the elucidation of carbohydrate structures. In the present paper, we review the major NMR spectrum simulation techniques with regard to chemical shifts, coupling constants, relaxation rates and nuclear Overhauser effect prediction applied to the three levels of glycomics. Outstanding development in the related fields of genomics and proteomics has clearly shown that it is the advancement of research tools (automated spectrum analysis, structure elucidation, synthesis, sequencing and amplification) that drives the large challenges in modern science. Combining NMR spectroscopy and the computational analysis of structural information encoded in the NMR spectra reveals a way to the automated elucidation of the structure of carbohydrates. 23083216 Pregnancy outcome following use of levodopa, pramipexole, ropinirole, and rotigotine for restless legs syndrome during pregnancy: a case series. Restless legs syndrome (RLS) is related to parity, and its symptoms may worsen during pregnancy. Treatment with levodopa or dopamine agonists is the first-line therapy for RLS; however, there are limited data on treatment in pregnancy. We therefore assessed the safety of levodopa, pramipexole, rotigotine, and ropinirole in pregnancy. Prospective documentation of pregnancies exposed to levodopa, pramipexole, rotigotine, and ropinirole between 1998 and 2011 was evaluated as to their outcome (teratogenicity or fetotoxicity) by the Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy. We were able to complete 59 pregnancy outcomes exposed to RLS pharmacotherapy. For specific treatments, the numbers of exposed pregnancies/live born children/spontaneous abortions/induced abortions/malformations were as follows: levodopa only: 38/29 (one pair of twins)/3/7/3; pramipexole only: 12/9/3/0/0; rotigotine only: 2/2/0/0/0; ropinirole only: 3/2/0/1/0; levodopa combined with pramipexole: 3/3/0/0/0; levodopa combined with ropinirole: 1/1/0/0/0. No major birth defects were found with any RLS treatment, and three infants exposed to levodopa had minor anomalies. In our small prospective case series, there was no increased risk above baseline for major malformations or other adverse outcomes for levodopa and pramipexole. If necessary, levodopa treatment may be considered as an alternative to cabergoline, for which safety has been well documented in pregnancy. 23774435 In Vitro and In Vivo Studies of the Antiparasitic Activity of Sterol 14α-Demethylase (CYP51) Inhibitor VNI against Drug-Resistant Strains of Trypanosoma cruzi. Chagas disease affects more than 10 million people worldwide, and yet, as it has historically been known as a disease of the poor, it remains highly neglected. Two currently available drugs exhibit severe toxicity and low effectiveness, especially in the chronic phase, while new drug discovery has been halted for years as a result of a lack of interest from pharmaceutical companies. Although attempts to repurpose the antifungal drugs posaconazole and ravuconazole (inhibitors of fungal sterol 14α-demethylase [CYP51]) are finally in progress, development of cheaper and more efficient, preferably Trypanosoma cruzi-specific, chemotherapies would be highly advantageous. We have recently reported that the experimental T. cruzi CYP51 inhibitor VNI cures with 100% survival and 100% parasitological clearance both acute and chronic murine infections with the Tulahuen strain of T. cruzi. In this work, we further explored the potential of VNI by assaying nitro-derivative-resistant T. cruzi strains, Y and Colombiana, in highly stringent protocols of acute infection. The data show high antiparasitic efficacy of VNI and its derivative (VNI/VNF) against both forms of T. cruzi that are relevant for mammalian host infection (bloodstream and amastigotes), with the in vivo potency, at 25 mg/kg twice a day (b.i.d.), similar to that of benznidazole (100 mg/kg/day). Transmission electron microscopy and reverse mutation tests were performed to explore cellular ultrastructural and mutagenic aspects of VNI, respectively. No mutagenic potential could be seen by the Ames test at up to 3.5 μM, and the main ultrastructural damage induced by VNI in T. cruzi was related to Golgi apparatus and endoplasmic reticulum organization, with membrane blebs presenting an autophagic phenotype. Thus, these preliminary studies confirm VNI as a very promising trypanocidal drug candidate for Chagas disease therapy. 23836447 Humic acid induces the endothelial nitric oxide synthase phosphorylation at Ser1177 and Thr495 Via Hsp90α and Hsp90β upregulation in human umbilical vein endothelial cells. Humic acid (HA) has been implicated as a contributory factor for blackfoot disease, which is an endemic peripheral vascular disease. We investigated the effect of HA on the regulation of endothelial nitric oxide (NO) synthase (eNOS) in human umbilical vein endothelial cells (HUVECs) to evaluate the involvement of eNOS and related factors in peripheral vascular impairment with HA exposure. Treatment of HUVECs with HA induced upregulation of eNOS. This result coincides with those of previous studies. Furthermore this is the first study to report that HA induces upregulation of heat shock protein (Hsp)90α, Hsp90β, eNOS phosphorylation at Ser1177, and eNOS phosphorylation at Thr495, as compared to that in the control. In contrast, treatment with BAPTA, an intracellular Ca(2+) chelator, inhibited upregulation of these proteins induced by HA. This study demonstrates that HA treatment leads to increases in both Hsp90α and Hsp90β proteins and indicates that Hsp90α leads to eNOS phosphorylation at Ser1177 and that Hsp90β leads to eNOS phosphorylation at Thr495, respectively. Upregulation of eNOS, Hsp90α, and Hsp90β in HUVECs is regulated by intracellular Ca(2+) accumulation induced by HA. These results suggest that upregulation of eNOS phosphorylation at Ser1177 and eNOS phosphorylation at Thr495 produce NO and superoxide anions, respectively, resulting in generation of peroxynitrite, which causes impairment of vascular endothelial cells. © 2013 Wiley Periodicals, Inc. Environ Toxicol, 2013. 23894476 Proline Dehydrogenase Regulates Redox State and Respiratory Metabolism in Trypanosoma cruzi. Over the past three decades, L-proline has become recognized as an important metabolite for trypanosomatids. It is involved in a number of key processes, including energy metabolism, resistance to oxidative and nutritional stress and osmoregulation. In addition, this amino acid supports critical parasite life cycle processes by acting as an energy source, thus enabling host-cell invasion by the parasite and subsequent parasite differentiation. In this paper, we demonstrate that L-proline is oxidized to Δ(1)-pyrroline-5-carboxylate (P5C) by the enzyme proline dehydrogenase (TcPRODH, E.C. 1.5.99.8) localized in Trypanosoma cruzi mitochondria. When expressed in its active form in Escherichia coli, TcPRODH exhibits a Km of 16.58±1.69 µM and a Vmax of 66±2 nmol/min mg. Furthermore, we demonstrate that TcPRODH is a FAD-dependent dimeric state protein. TcPRODH mRNA and protein expression are strongly upregulated in the intracellular epimastigote, a stage which requires an external supply of proline. In addition, when Saccharomyces cerevisiae null mutants for this gene (PUT1) were complemented with the TcPRODH gene, diminished free intracellular proline levels and an enhanced sensitivity to oxidative stress in comparison to the null mutant were observed, supporting the hypothesis that free proline accumulation constitutes a defense against oxidative imbalance. Finally, we show that proline oxidation increases cytochrome c oxidase activity in mitochondrial vesicles. Overall, these results demonstrate that TcPRODH is involved in proline-dependant cytoprotection during periods of oxidative imbalance and also shed light on the participation of proline in energy metabolism, which drives critical processes of the T. cruzi life cycle. 23386387 Structural and Optoelectronic Characterization of RF Sputtered ZnSnN2. ZnSnN2 , a new earth-abundant semiconductor, is synthesized and characterized for use as a photovoltaic absorber material. Results confirm the predicted orthorhombic Pna21 crystal structure in RF sputtered thin films. Additionally, optical measurements reveal a direct bandgap of about 2 eV, which is larger than our calculated bandgap of 1.42 eV due to the Burstein-Moss effect. 23721814 Transgenic expression of the FTDP-17 tauV337M mutation in brain dissociates components of executive function in mice. Frontotemporal lobe dementia (FTD) is a heterogeneous range of disorders, a subset of which arise from fully penetrant, autosomal dominant point mutations in the gene coding for the microtubule associated protein tau. These genetic tauopathies are associated with complex behavioural/cognitive disturbances, including compromised executive function. In the present study, we modelled the effects of the FTD with Parkinsonism linked to chromosome 17 (FTDP-17) tauV337M mutation (known as the Seattle Family A mutation) expressed in mice on executive processes using a novel murine analogue of the Stroop task. Employing biconditional discrimination procedures, Experiment 1 showed that normal mice, but not mice with excitotoxic lesions of the medial prefrontal cortex, were able to use context cues to resolve response conflict generated by incongruent stimulus compounds. In contrast to predictions, response conflict resolution was not disrupted by the tauV337M mutation (Experiment 2). However, while context appropriate actions were goal-directed in wild-type mice, performance of tauV337M mice was not goal-directed (Experiment 3). The results indicate that the tauV337M mutation in mice disrupts, selectively, a subset of processes related to executive function. 22431436 Francesco Parona (1842-1908) and his contributions to our understanding of surgery through anatomy. Much of the life of Francesco Parona and many of his contributions to medicine are unknown outside of Europe. Parona made novel contributions to many surgical techniques and medical treatments and was an active member of society and the Italian political regime. Parona's name lives on eponymously by his "space" in the forearm. This paper will discuss the personal life and medical contributions of Francesco Parona. 23900293 Ethical implications of Italian legislation on 'epilepsy and driving' The laws concerning driving licences and epilepsy in different countries are very diverse with regard to the criteria for issuance or renewal of licences, and also the methods of evaluating fitness. In 2011, a law was issued in Italy implementing the European directives on driving licences, including provisions for mandatory notification that a driver is epileptic. This was established regardless of the European rules that require compulsory notification only of patients. The Federation of Italian Boards of Physicians has made recommendations against mandated physician reporting, resulting in a current confusion between legal and ethical recommendations to medical doctors. The mandatory notification enacted by Italian law raises ethical concerns about disparities in access to care and possible violations of the right to confidentiality of patient information. Moreover, the law discussed here fails to emphasise the importance of physicians ensuring compliance by the patient, by sharing the correct information about the risks associated with illegal driving and by obtaining information from the patient through regular check-ups. An urgent revision of the law is required to implement the duty of the physician to provide information and to ensure that the rule about mandatory notification should be erased in favour of optional self-reporting by epileptics as the preferred way to notify the licensing authority. The implementation of these measures could correct the dichotomy between the law and the ethical recommendations for medical doctors and protect the rights of people with epilepsy as well as those of any other patients whose pathology or impairment could imply a risk to the community. 23844089 Differential Expression of Three Members of the Multidomain Adhesion CCp Family in Babesia bigemina, Babesia bovis and Theileria equi. Members of the CCp protein family have been previously described to be expressed on gametocytes of apicomplexan Plasmodium parasites. Knocking out Plasmodium CCp genes blocks the development of the parasite in the mosquito vector, making the CCp proteins potential targets for the development of a transmission-blocking vaccine. Apicomplexans Babesia bovis and Babesia bigemina are the causative agents of bovine babesiosis, and apicomplexan Theileria equi causes equine piroplasmosis. Bovine babesiosis and equine piroplasmosis are the most economically important parasite diseases that affect worldwide cattle and equine industries, respectively. The recent sequencing of the B. bovis and T. equi genomes has provided the opportunity to identify novel genes involved in parasite biology. Here we characterize three members of the CCp family, named CCp1, CCp2 and CCp3, in B. bigemina, B. bovis and T. equi. Using B. bigemina as an in vitro model, expression of all three CCp genes and proteins was demonstrated in temperature-induced sexual stages. Transcripts for all three CCp genes were found in vivo in blood stages of T. equi, and transcripts for CCp3 were detected in vivo in blood stages of B. bovis. However, no protein expression was detected in T. equi blood stages or B. bovis blood stages or B. bovis tick stages. Collectively, the data demonstrated a differential pattern of expression of three orthologous genes of the multidomain adhesion CCp family by B. bigemina, B. bovis and T. equi. The novel CCp members represent potential targets for innovative approaches to control bovine babesiosis and equine piroplasmosis. 23907211 Fabrication of a protease sensor for caspase-3 activity detection based on surface plasmon resonance. Diagnosis of apoptosis is essential to the early detection of therapy efficiency and the evaluation of disease progression. Caspase-3 is supposed to be closely related to cellular apoptosis. We describe here a label-free surface plasmon resonance (SPR) detection of apoptosis based on caspase-3 activity assay through enzyme digestion. An artificial peptide sequence was designed as a substrate of caspase-3 and immobilized on a gold disk through covalent binding. The 4Lys part at the end of the pentadecyl-peptide was designed to form a unique peptide array through electrostatic repulsion. The immobilization of the peptide on the gold surface was carefully characterized by SPR and atomic force microscopy. The catalytic conditions of caspase-3 were optimized with electrochemical impedance spectroscopy. The detection limit of caspase-3 was found at a concentration of 1 pg mL(-1). The activity of caspase-3 in apoptotic cells could also be measured sensitively by the one-step and intuitional SPR response decrease. The fabricated simple and convenient caspase-3 sensor is proposed for application in clinical analysis. 23827804 Cornmeal and starch influence the dynamic of fumonisin B, A and C production and masking in Fusarium verticillioides and F. proliferatum. Fusarium verticillioides and F. proliferatum can infect maize ears and produce fumonisins. The fumonisin B (FB) series is the most prolifically produced, followed by fumonisin C (FC), A (FA) and P (FP); moreover hidden forms of fumonisins have been detected in maize and derivatives. There is a lack of information about which maize component may affect fumonisin pattern production. Therefore, in this work we studied the role of cornmeal and corn starch, as the sole source of nutrition, in the production dynamic of all fumonisin series, hidden forms included, in different strains of F. verticillioides and F. proliferatum incubated at 25°C for 7-45days. Both Fusarium species produced high amounts of FB, following the chemotype FB1>FB2>FB3; FC and FA were produced in lesser amounts, showing the chemotypes: FA2+FA3>FA1 and FC1>FC2+FC3>FC4, respectively; while no FP were detected. F. verticillioides was more prolific than F. proliferatum in fumonisin production (ten times more on average) in all the tested conditions. Fumonisin production was higher in cornmeal than in starch based medium in both Fusarium species; FA and FC were detected only in the former medium. An important role of amylopectin as an inducing factor for fumonisin biosynthesis was suggested, as were acid pH conditions. Fumonisin hidden forms may occur in cornmeal medium, whereas they were never found at significant levels in corn starch medium. 23817032 The long-term effects of postoperative complications. This review examines the long-term influence of postoperative complications on survival. Although it is intuitive that complications after surgery worsen short-term outcomes, it is not clear to what extent and why a longer-term relationship may exist. Most studies have focused on outcomes after cancer surgery. Despite mixed results in smaller cohorts, large multicentre analyses consistently identify an association between postoperative complications and long-term mortality. In part, this phenomenon may be due to unmeasured confounding factors or insufficient separation of short and long-term consequences. Nevertheless, functional and biological imprints established during postoperative complications are likely to be relevant, and are the subject of ongoing research. Patients that develop postoperative complications and survive the immediate risk period, demonstrate worsened long-term mortality. The field of perioperative medicine is increasingly mandated to identify vulnerable individuals, develop and implement strategies to prevent and treat complications, and provide better care pathways after hospital discharge. 23750707 Ion Pairing with Bile Salts Modulates Intestinal Permeability and Contributes to Food-Drug Interaction of BCS Class III Compound Trospium Chloride. In the current study the involvement of ion pair formation between bile salts and trospium chloride (TC), a positively charged Biopharmaceutical Classification System (BCS) class III substance, showing a decrease in bioavailability upon coadministration with food (negative food effect) was investigated. Isothermal titration calorimetry provided evidence of a reaction between TC and bile acids. An effect of ion pair formation on the apparent partition coefficient (APC) was examined using (3)H-trospium. The addition of bovine bile and bile extract porcine led to a significant increase of the APC. In vitro permeability studies of trospium were performed across Caco-2-monolayers and excised segments of rat jejunum in a modified Ussing chamber. The addition of bile acids led to an increase of trospium permeation across Caco-2-monolayers and rat excised segments by approximately a factor of 1.5. The addition of glycochenodeoxycholate (GCDC) was less effective than taurodeoxycholate (TDOC). In the presence of an olive oil emulsion, a complete extinction of the permeation increasing effects of bile salts was observed. Thus, although there are more bile acids in the intestine in the fed state compared to the fasted state, these are not able to form ion pairs with trospium in fed state, because they are involved in the emulsification of dietary fats. In conclusion, the formation of ion pairs between trospium and bile acids can partially explain its negative food effect. Our results are presumably transferable to other organic cations showing a negative food effect. 23945514 Cavernous Sinus Thrombosis as a Result of a Fungal Infection: A Case Report. Cavernous sinus thrombosis (CST) is a rare disease with the potential for significant morbidity and even death. Rapid diagnosis and aggressive medical and surgical management are imperative for patients with CST. The cause may be aseptic or infectious. When the cause is infectious in nature, it is most commonly from a bacterial origin. However, we present the case of a 57-year-old man with a fungally related CST that ultimately led to his death. 23904141 Emergency ultrasound-based algorithms for diagnosing blunt abdominal trauma. Ultrasonography is regarded as the tool of choice for early diagnostic investigations in patients with suspected blunt abdominal trauma. Although its sensitivity is too low for definite exclusion of abdominal organ injury, proponents of ultrasound argue that ultrasound-based clinical pathways enhance the speed of primary trauma assessment, reduce the number of computed tomography scans and cut costs. To assess the effects of trauma algorithms that include ultrasound examinations in patients with suspected blunt abdominal trauma. We searched the Cochrane Injuries Group's Specialised Register, CENTRAL (The Cochrane Library), MEDLINE (OvidSP), EMBASE (OvidSP), CINAHL (EBSCO), publishers' databases, controlled trials registers and the Internet. Bibliographies of identified articles and conference abstracts were searched for further elligible studies. Trial authors were contacted for further information and individual patient data. The searches were updated in February 2013. Studies: randomised controlled trials (RCTs) and quasi-randomised trials (qRCTs). Participants: patients with blunt torso, abdominal or multiple trauma undergoing diagnostic investigations for abdominal organ injury. Interventions: diagnostic algorithms comprising emergency ultrasonography (US). Controls: diagnostic algorithms without ultrasound examinations (for example, primary computed tomography [CT] or diagnostic peritoneal lavage [DPL]). Outcome measures: mortality, use of CT and DPL, cost-effectiveness, laparotomy and negative laparotomy rates, delayed diagnoses, and quality of life. Two authors independently selected trials for inclusion, assessed methodological quality and extracted data. Where possible, data were pooled and relative risks (RRs), risk differences (RDs) and weighted mean differences, each with 95% confidence intervals (CIs), were calculated by fixed- or random-effects modelling, as appropriate. We identified four studies meeting our inclusion criteria. Overall, trials were of moderate methodological quality. Few trial authors responded to our written inquiries seeking to resolve controversial issues and to obtain individual patient data. We pooled mortality data from three trials involving 1254 patients; relative risk in favour of the US arm was 1.00 (95% CI 0.50 to 2.00). US-based pathways significantly reduced the number of CT scans (random-effects RD -0.52, 95% CI -0.83 to -0.21), but the meaning of this result is unclear. Given the low sensitivity of ultrasound, the reduction in CT scans may either translate to a number needed to treat or number needed to harm of two. There is currently insufficient evidence from RCTs to justify promotion of ultrasound-based clinical pathways in diagnosing patients with suspected blunt abdominal trauma. 23938212 Unusual presentation of alveolar echinococcosis as prostatic and paraprostatic cysts in a dog. Alveolar echinococcosis (AE) is caused by the larval stage (metacestode) of Echinococcus multilocularis. The domestic dog can act as a definitive host and harbor adult cestodes in its small intestine or become an aberrant intermediate host carrying larval stages that may cause severe lesions in the liver, lungs and other organs with clinical signs similar to AE in humans. A case of canine AE, affecting the liver and prostate with development of multilocular hydatid paraprostatic cysts and possible lung involvement is described in an 8-year-old neutered male Labrador retriever dog.The dog presented with progressive weight loss, acute constipation, stranguria and a suspected soft tissue mass in the sublumbar region. Further evaluation included computed tomography of the thorax and abdomen, which revealed cystic changes in the prostate, a paraprostatic cyst, as well as lesions in the liver and lungs. Cytological examination of fine-needle aspirates of the liver, prostate and paraprostatic cyst revealed parasitic hyaline membranes typical of an Echinococcus infection and the presence of E. multilocularis-DNA was confirmed by PCR. The dog was treated with albendazole and debulking surgery was considered in case there was a good response to antiparasitic treatment. Constipation and stranguria resolved completely. Six months after the definitive diagnosis, the dog was euthanized due to treatment-resistant ascites and acute anorexia and lethargy. To the authors' knowledge, this is the first publication of an E. multilocularis infection in a dog causing prostatic and paraprostatic cysts. Although rare, E. multilocularis infection should be considered as an extended differential diagnosis in dogs presenting with prostatic and paraprostatic disease, especially in areas where E. multilocularis is endemic. 23836742 Reforming medicare through 'version 2.0' of accountable care. Medicare needs fundamental reform to achieve fiscal sustainability, improve value and quality, and preserve beneficiaries' access to physicians. Physician fees will fall by one-quarter in 2014 under current law, and the dire federal budget outlook virtually precludes increasing Medicare spending. There is a growing consensus among policy makers that reforming fee-for-service payment, which has long served as the backbone of Medicare, is unavoidable. Accountable care organizations (ACOs) provide a new payment alternative but currently have limited tools to control cost growth or engage and reward beneficiaries and providers. To fundamentally reform Medicare, this article proposes an enhanced version of ACOs that would eliminate the scheduled physician fee cuts, allow fees to increase with inflation, and enhance ACOs' ability to manage care. In exchange, the proposal would require modest reductions in overall Medicare spending and require ACOs to accept increased accountability and financial risk. It would cause per beneficiary Medicare spending by 2023 to fall 4.2 percent below current Congressional Budget Office projections and help the program achieve fiscal sustainability. 23097498 Positive selection within a diatom species acts on putative protein interactions and transcriptional regulation. Diatoms are the most species-rich group of microalgae, and their contribution to marine primary production is important on a global scale. Diatoms can form dense blooms through rapid asexual reproduction; mutations acquired and propagated during blooms likely provide the genetic, and thus phenotypic, variability upon which natural selection may act. Positive selection was tested using genome and transcriptome-wide pair-wise comparisons of homologs in three genera of diatoms (Pseudo-nitzschia, Ditylum, and Thalassiosira) that represent decreasing phylogenetic distances. The signal of positive selection was greatest between two strains of Thalassiosira pseudonana. Further testing among seven strains of T. pseudonana yielded 809 candidate genes of positive selection, which are 7% of the protein-coding genes. Orphan genes and genes encoding protein-binding domains and transcriptional regulators were enriched within the set of positively selected genes relative to the genome as a whole. Positively selected genes were linked to the potential selective pressures of nutrient limitation and sea surface temperature based on analysis of gene expression profiles and identification of positively selected genes in subsets of strains from locations with similar environmental conditions. The identification of positively selected genes presents an opportunity to test new hypotheses in natural populations and the laboratory that integrate selected genotypes in T. pseudonana with their associated phenotypes and selective forces. 23925953 Development of a Human Antibody Tolerant Mouse Model to Assess the Immunogenicity Risk Due to Aggregated Biotherapeutics. We describe a novel human immunoglobulin G2 (IgG2 )-tolerant and immune-competent heterozygous mouse model (Xeno-het) developed by crossbreeding a human Ig-tolerized XenoMouse® with a C57BL/6J wild-type mouse. The Xeno-het mouse expresses both mouse and human immunoglobulin G (IgG) genes, resulting in B-cells expressing human and mouse IgG, and secretion of human and mouse Ig into serum. This model was utilized to evaluate the immunogenicity risk of aggregated and chemically modified human antibodies. The mice were tested for their ability to break tolerance to self-tolerant monomeric antibodies. Aggregates made by mechanical stirring elicited an anti-drug antibody (ADA) response, but did not induce a robust and long-term memory B and T-cell response. Chemically modified antibodies made by oxidation were only weak and transient inducers of an immune response, as measured by a lack of both an ADA response and a B-cell antigen-specific response. Aggregate size was an important characteristic, as specific-sized protein-coated beads were able to elicit an immune response. We propose the use of this model to identify risk factors such as aggregation during manufacturing at early development for an increased potential immunogenicity risk. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci. 23771984 Extraintestinal Clostridium difficile Infections. Background. Clostridium difficile causes diarrhea that ranges from a benign, self-limiting antibiotic use-associated disease to a life-threatening pseudomembranous colitis. Clostridium difficile has rarely been isolated in extraintestinal infections. Our objective was to characterize clinical features and risk factors of these infections. Methods. Extraintestinal C. difficile infections (CDIs) were searched for in an electronic database of all C. difficile-positive isolates found during a 10-year period. The medical records were reviewed retrospectively. Disease severity and comorbidities of the patients were evaluated using Horn disease severity and Charlson comorbidity indexes. Results. Extraintestinal CDI was found in 31 patients who comprised 0.17% of all CDIs. Two patients had bacteremic infections, 4 had abdominal infections without any prior surgery, 7 had abdominal infections after surgery, 4 had perianal abscesses, 13 had wound infections, and 1 had C. difficile in a urinary catheter. In most cases (85%), C. difficile was isolated together with other microbes. Most (81%) patients developed the infection when hospitalized and many had severe comorbidities. Sixteen (52%) had diarrhea. The 1-year mortality rate was 36% and it correlated with the severity of underlying diseases. Conclusions. Extraintestinal CDIs occur mainly in hospitalized patients with significant comorbidities. Extraintestinal CDIs in the abdominal area may result from either intestinal perforation after infection or after intestinal surgery. Wound infections may result from colonization by feces. Clostridium difficile may reach distant sites via bacteremia. Mortality in extraintestinal CDIs is associated with the severity of underlying diseases. 23583510 Novel racemic tetrahydrocurcuminoid dihydropyrimidinone analogues as potent acetylcholinesterase inhibitors. The synthesis of racemic tetrahydrocurcumin- (THC-), tetrahydrodemethoxycurcumin- (THDC-) and tetrahydrobisdemethoxycurcumin- (THBDC-) dihydropyrimidinone (DHPM) analogues was achieved by utilizing the multi-component Biginelli reaction in the presence of copper sulphate as a catalyst. The evaluation of acetylcholinesterase inhibitors for Alzheimer's disease of these compounds showed that they exhibited higher inhibitory activity than their parent analogues. THBDC-DHPM demonstrated the most potent inhibitory activity with an IC50 value of 1.34±0.03μM which was more active than the approved drug galanthamine (IC50=1.45±0.04μM). 23137527 Shift work and cancer risk: potential mechanistic roles of circadian disruption, light at night, and sleep deprivation. Shift work that includes a nighttime rotation has become an unavoidable attribute of today's 24-h society. The related disruption of the human circadian time organization leads in the short-term to an array of jet-lag-like symptoms, and in the long-run it may contribute to weight gain/obesity, metabolic syndrome/type II diabetes, and cardiovascular disease. Epidemiologic studies also suggest increased cancer risk, especially for breast cancer, in night and rotating female shift workers. If confirmed in more controlled and detailed studies, the carcinogenic effect of night and shift work will constitute additional serious medical, economic, and social problems for a substantial proportion of the working population. Here, we examine the possible multiple and interconnected cancer-promoting mechanisms as a consequence of shift work, i.e., repeated disruption of the circadian system, pineal hormone melatonin suppression by exposure to light at night, sleep-deprivation-caused impairment of the immune system, plus metabolic changes favoring obesity and generation of proinflammatory reactive oxygen species. 23585516 Impact of maternal use of asthma-controller therapy on perinatal outcomes. Asthma during pregnancy usually requires treatment with controller medications about which more safety information is needed. The objectives are to assess the impact of the use of long-acting β2-agonists (LABAs) and the dose of inhaled corticosteroids (ICSs) during pregnancy on the prevalence of low birth weight (LBW), preterm birth (PB) and small for gestational age (SGA). A cohort of women with asthma giving birth from 1998 to 2008 was constructed from Québec (Canada) administrative databases. LBW was defined as weight <2500 g, PB as delivery before 37 weeks' gestation and SGA as a birth weight below the 10th percentile. The impact of the use of LABAs and the dose of ICSs during pregnancy on the outcomes was determined with generalised-estimating-equation models. The cohort included 7376 pregnancies: 8.8% exposed to LABAs and 56.9% exposed to ICSs. All LABA users also received ICSs. The prevalence of LBW, PB and SGA was 7.7%, 9.5% and 13.5%, respectively. LABA use was not found to be associated with increased prevalence of LBW (OR 0.81; 95% CI 0.58 to 1.12), PB (OR 0.84; 95% CI 0.61 to 1.15) or SGA (OR 0.92; 95% CI 0.70 to 1.20). Mean ICSs doses >125 μg/day (fluticasone-equivalent) were associated with a non-significant trend of increased LBW, PB and SGA. Despite the possibility of residual confounding due to uncontrolled or more severe asthma or smoking status, the use of LABA and low to moderate doses of ICSs were not associated with increased prevalence of perinatal outcomes. Additional research on higher ICSs doses is required to better evaluate their safety during pregnancy. 23044430 Mitochondrial function in cardiac hypertrophy. Cardiac hypertrophic program is a chronic, complex process, and occurs in response to long-term increases of hemodynamic load related to a variety of pathophysiological conditions. Mitochondria, known as "the cellular power plants", occupy about one-third of cardiomyocyte volume and supply roughly 90% of the adenosine triphosphate (ATP). Impairment of energy metabolism has been regarded as one of the main pathogenesis of cardiac hypertrophy. Thus, we summarize here the molecular events of mitochondrial adaptations, including the mitochondrial genesis, ATP generation, ROS signaling and Ca(2+) homeostasis in cardiac hypertrophy, expecting that this effort will shed new light on understanding the maladaptive cardiac remodeling. 23840027 Cingulate area 32 homologies in mouse, rat, macaque and human: Cytoarchitecture and receptor architecture. Homologizing between human and non-human area 32 has been impaired since Brodmann said he could not homologize with certainty human area 32 to a specific cortical domain in other species. Human area 32 has four divisions, however, and two can be structurally homologized to non-human species with cytoarchitecture and receptor architecture: pregenual (p32) and subgenual (s32) in human and macaque monkey and areas d32 and v32 in rat and mouse. Cytoarchitecture showed that areas d32/p32 have a dysgranular layer IV in all species and areas v32/s32 have large and dense neurons in layer V, while a layer IV is not present in area v32. Areas v32/s32 have the largest neurons in layer Va. Features unique to human include large layer IIIc pyramids in both divisions, sparse layer Vb in area p32, and elongated neurons in layer VI, while area s32 has the largest layer Va neurons. Receptor fingerprints of both subdivisions of area 32 differed between species in size and shape, although AMPA/GABAA and NMDA/GABAA ratios were comparable between humans, monkeys and rats and were significantly lower than in mice. Layers I-III of primate and rodent area 32 subdivisions share more similarities in their receptor densities than layers IV-VI. Monkey and human subdivisions of area 32 are more similar to each other than to rat and mouse subdivisions. In combination with intracingulate connections, the location, cytoarchitecture and ligand binding studies demonstrate critical homologies among the four species. J. Comp. Neurol., 2013. © 2013 Wiley Periodicals, Inc. 23660682 Investigation of APOE isoforms and the association between APOE E3 and E4 with migraine in the Australian Caucasian population. Migraine is a debilitating neurovascular disease that is associated with pulsating head pain accompanied by nausea, vomiting, photophobia, phonophobia and sometimes visual sensory disturbances. Because of its role in nitric oxide regulation and interleukin release, apolipoprotein E (APOE) has been suggested to play a role in the migraine pathogenesis pathway. This study evaluated the potential role of three APOE variants in an Australian population and the role that they may play in susceptibility to migraine. The study found no significant association between the tested variants and migraine for any of the APOE variants investigated. 23909957 Study of the Transition Metal Ordering in Layered NaxNix/2Mn1-x/2O2 (2/3 ≤ x ≤ 1) and Consequences of Na/Li Exchange. A series of layered oxides within the NaxNiix/2Mn1-x/2O2 (2/3 ≤ x ≤ 1) system were synthesized by classical solid-state methodologies. A study of their long and short-range structure was undertaken by combining X-ray diffraction and NMR spectroscopy. A transition from P2 to O3 stacking was observed at x > 0.8 when samples were made at 900 °C, which was accompanied by disordering of ions in the transition metal layer. The magnetic properties of the materials were consistent with this picture of ordering, with all samples showing antiferromagnetic character. At x = 2/3, competition between a P2 and a P3 structure, with different degrees of transition metal ordering, was found depending on the synthesis temperature. Na/Li exchange led to structures with octahedral or tetrahedral coordination of the alkali metal, and Li/Ni crystallographic exchange in the resulting O3 phases. The transition from alkali metal prismatic coordination to octahedral/tetrahedral coordination involves [TMO6]∞ layer shearing that induces some structural disorder through the formation of stacking faults. 23714007 Saccharomyces cerevisiae deletion strains with complex DNA content profiles. To identify Saccharomyces cerevisiae genes required for the proper timing of cell cycle transitions, we previously reported a systematic examination of the DNA content of homozygous diploid deletion strains. However, deletion strains with complex DNA content profiles were not examined in that study. Here, we report S. cerevisiae genes that when deleted give rise to DNA content profiles consistent with roles of the corresponding gene products during DNA replication. We also identified a set of genes whose deletion leads to increased DNA content, consistent with defects in mitosis, cytokinesis, or cell separation. Finally, we examined known interactions between the gene products of each group, placing these gene products in functional networks. Taken together, the data we present further validate the roles of the corresponding gene products in these processes, facilitating efforts to delineate gene function critical for genome replication, maintenance, and segregation. 23841819 Recent mechanistic insights on glycoconjugate vaccines and future perspectives. Vaccination is a key strategy for the control of various infectious diseases. Many pathogens, such as Streptococcus pneumoniae , Haemophilus influenzae type b (Hib), and Neisseria meningitidis produce on their surfaces dense and complex glycan structures, which represent an optimal target for eliciting carbohydrate specific antibodies able to confer protection against those bacteria. Glycoconjugates represent nowadays an important class of efficacious and safe commercial vaccines. It has been known for a long time that covalent linkage of poorly immunogenic carbohydrates to protein is fundamental to provide T cell epitopes for eliciting a memory response of the immune system against the saccharide. However, while the traditional mechanism of action of glycoconjugates has considered peptides generated from the carrier protein to be responsible of T cell help recruitment, only recently evidence of the active involvement of the carbohydrate part in determining the T cell help has been shown. In addition, zwitterionic polysaccharides have been proven to activate the adaptive immune system without further conjugation to protein. Progress in this interface area between chemistry and biology, in combination with novel synthetic and biosynthetic methods for the preparation of glycoconjugates, is opening new perspectives to clarify their mechanism of action and give new insights for the design of improved carbohydrate-based vaccines. 23932940 Plasmodium falciparum rhoptry neck protein 5 peptides bind to human red blood cells and inhibit parasite invasion. Plasmodium falciparum malaria parasite invasion of erythrocytes is an essential step in host infection and the proteins involved in such invasion are the main target in developing an antimalarial vaccine. Secretory organelle-derived proteins (micronemal AMA1 protein and the RON2, 4, and 5 rhoptry neck proteins) have been recently described as components of moving junction complex formation allowing merozoites to move into a newly created parasitophorous vacuole. This study led to identifying RON5 regions involved in binding to human erythrocytes by using a highly robust, sensitive and specific receptor-ligand interaction assay; it is further shown that the RON5 protein remains highly conserved throughout different parasite strains. It is shown that the binding peptide-erythrocyte interaction is saturable and sensitive to chymotrypsin and trypsin. Invasion inhibition assays using erythrocyte binding peptides showed that the RON5-erythrocyte interaction could be critical for merozoite invasion of erythrocytes. This work provides evidence (for the first time) suggesting a fundamental role for RON5 in erythrocyte invasion. 23897807 Regulation of the Src Kinase-Associated Phosphoprotein 55 Homologue by the protein tyrosine phosphatase PTP-PEST in the control of cell motility. PTP-PEST is a cytosolic ubiquitous protein tyrosine phosphatase (PTP) that contains, in addition to its catalytic domain, several protein-protein interaction domains that allow it to interface with several signaling pathways. Among others, PTP-PEST is a key regulator of cellular motility and cytoskeleton dynamics. The complexity of the PTP-PEST interactome underscores the necessity to identify its interacting partners and physiological substrates in order to further understand its role in focal adhesion complex turnover and actin organization. Using a modified yeast substrate trapping two-hybrid system, we identified a cytosolic adaptor protein named Src Kinase Associated Phosphoprotein 55 Homologue (SKAP-Hom) as a novel substrate of PTP-PEST. In order to confirm PTP-PEST interaction with SKAP-Hom, in vitro pull down assays were performed demonstrating that the PTP catalytic domain and Proline-rich 1 (P1) domain are respectively binding to the SKAP-Hom Y260 and Y297 residues and its SH3 domain. Subsequently, we generated and rescued SKAP-Hom deficient mouse embryonic fibroblasts (MEFs) with WT SKAP-Hom, SKAP-Hom tyrosine mutants (Y260F, Y260F/Y297F), or SKAP-Hom SH3 domain mutant (W335K). Given the role of PTP-PEST, wound-healing and trans-well migration assays were performed using the generated lines. Indeed, SKAP-Hom deficient MEFs showed a defect in migration compared to WT-rescued MEFs. Interestingly, the SH3 domain mutant-rescued MEFs showed an enhanced cell migration corresponding potentially with higher tyrosine phosphorylation levels of SKAP-Hom. These findings suggest a novel role of SKAP-Hom and its phosphorylation in the regulation of cellular motility. Moreover, these results open new avenues by which PTP-PEST regulates cellular migration, a hallmark of metastasis. 23001607 Non-coding RNAs and EZH2 interactions in cancer: long and short tales from the transcriptome. A large amount of data indicates that non-coding RNAs represent more than the "dark matter" of the genome. Both microRNAs and long non-coding RNAs are involved in several fundamental biologic processes, and their deregulation may lead in oncogenesis. Interacting with the Polycomb-repressive complex 2 subunit EZH2, they could affect the expression of protein-coding genes and form feedback networks and autoregulatory loops. They can also form networks with upstream and downstream important factors, in which EZH2 represent the stabilizing factor of the pathway. As such non-coding RNAs affect the epigenetic modifications leading to malignant transformation. 22688440 Palliative treatment of colorectal cancer in Germany: cost of care and quality of life. To estimate the costs of palliative care for colorectal cancer (CRC) from the perspective of German statutory health insurance and to measure the patients' quality of life (QoL) for a 2-year time period. A prospective observational multicentre study was carried out to estimate the direct costs of care over a 2-year period. Case report forms, medical records, and claims data were all applied to document medical and resource usage data in real-world settings. QoL was measured by using the Short Form-12 Health Survey. In total 101 patients (mean age 67.09 ± 11.13 years, 68 % male) from 12 different settings were included. The mean costs per patient during the 1st and 2nd years were calculated to be 42,361€ and 32,023€, respectively. Highest mean costs were calculated for the second quarter, which reached an amount of 12,900€ (95 % CI: 11,127€-14,673€). Mean physical summary scores and mean mental summary scores were 41.8 and 49.7, respectively. This is the first study assessing the costs of palliative care and the quality of life of patients with CRC in real-world health-care delivery in Germany. It could be shown that CRC treatment represents an enormous economic burden to the German health-care system. Increased efforts in promoting effective and efficient treatment options, or performance-based medication reimbursement schemes, might be helpful in reducing the costs. 23945237 Differentiation and functional regulation of human fetal NK cells. The human fetal immune system is naturally exposed to maternal allogeneic cells, maternal antibodies, and pathogens. As such, it is faced with a considerable challenge with respect to the balance between immune reactivity and tolerance. Here, we show that fetal natural killer (NK) cells differentiate early in utero and are highly responsive to cytokines and antibody-mediated stimulation but respond poorly to HLA class I-negative target cells. Strikingly, expression of killer-cell immunoglobulin-like receptors (KIRs) did not educate fetal NK cells but rendered them hyporesponsive to target cells lacking HLA class I. In addition, fetal NK cells were highly susceptible to TGF-β-mediated suppression, and blocking of TGF-β signaling enhanced fetal NK cell responses to target cells. Our data demonstrate that KIR-mediated hyporesponsiveness and TGF-β-mediated suppression are major factors determining human fetal NK cell hyporesponsiveness to HLA class I-negative target cells and provide a potential mechanism for fetal-maternal tolerance in utero. Finally, our results provide a basis for understanding the role of fetal NK cells in pregnancy complications in which NK cells could be involved, for example, during in utero infections and anti-RhD-induced fetal anemia. 23554460 Aerobic interval training attenuates remodelling and mitochondrial dysfunction in the post-infarction failing rat heart. Following a large myocardial infarction (MI), remaining viable muscle often undergoes pathological remodelling and progresses towards chronic heart failure. Mitochondria may also be affected by this process and, due to their functional importance, likely contribute to the progression of the disease. Aerobic interval training (AIT) has been shown effective in diminishing pathological myocardial transformation, but the effects of AIT on mitochondrial function in hearts undergoing remodelling are not known. Adult female Sprague-Dawley rats were randomized to either 8 weeks of aerobic interval treadmill running (5 days/week), which started 4 weeks after left coronary artery ligation (MI-Trained), or a sedentary group (MI-Sedentary). Echocardiography was performed before and after the 8-week period, at which point the left ventricles (LVs) were also harvested. Twelve weeks after surgery, MI-Sedentary rats had significantly lower LV fractional shortening compared with MI-Trained rats. Complex I-dependent respiration assessed in isolated LV mitochondria was decreased by ∼37% in MI-Sedentary and 17% in MI-Trained animals (group differences P < 0.05), compared with sham-operated animals. This was paralleled with diminished ATP production and increased degree of protein oxidation in MI-Sedentary rats. The enzymatic activity of complex I was also decreased to a greater extent in MI-Sedentary than in MI-Trained animals, with no evidence of its reduced expression. When complex II substrate was used, no differences among the three groups were observed. Exercise reduces LV contractile deterioration in post-infarction heart failure and alleviates the extent of mitochondrial dysfunction, which is paralleled with preserved complex I activity. 23889588 Age, renal dysfunction, cardiovascular disease, and antihyperglycemic treatment in type 2 diabetes mellitus: findings from the renal insufficiency and cardiovascular events italian multicenter study. To assess the distribution of antihyperglycemic treatments according to age and renal function and its relationship with cardiovascular disease in type 2 diabetes mellitus (T2DM). Cross-sectional analysis. Nineteen hospital-based diabetes mellitus clinics in 2007 and 2008. Fifteen thousand seven hundred thirty-three individuals with T2DM from the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study. Current antihyperglycemic treatments were recorded. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Albuminuria was measured using immunonephelometry or immunoturbidimetry. Prevalence of major acute cardiovascular events was calculated according to age quartiles, treatments, and categories of eGFR (1 = â‰¥90; 2 = 60-89; 3 = 30-59; and 4 = <30 mL/min per 1.73 m(2) ). Across age quartiles, eGFR declined progressively at a time-linear rate, with an acceleration in older adults, whereas albuminuria increased; age and eGFR were associated with cardiovascular events independently of other confounders. With increasing age, percentage of participants using lifestyle treatments for their T2DM and taking metformin or glitazones fell; percentage taking sulphonylureas and repaglinide rose, and percentage taking insulin remained stable. In eGFR categories 3 and 4, use of metformin was 41.4% and 14.5%, respectively, and that of sulphonylureas was 34.2% and 18.1%, respectively. Inappropriate prescription of these agents, especially sulphonylureas, increased with age. Metformin was independently associated with lower prevalence of cardiovascular disease for any age quartile and eGFR category than all other treatments. In real-life conditions, use of agents that are not recommended in elderly adults with diabetes mellitus with moderate to severe renal impairment is frequent, but metformin is associated with lower cardiovascular event rates even in these individuals. 23842589 Nonconvulsive Electrographic Seizures Are Common in Children With Abusive Head Trauma. To determine the prevalence of nonconvulsive seizures in children with abusive head trauma. Retrospective study of children with abusive head trauma undergoing clinically indicated continuous electroencephalographic monitoring. PICU of a tertiary care hospital. Children less than or equal to 2 years old with evidence of abusive head trauma determined by neuroimaging, physical examination, and determination of abuse by the Child Protection Team. None. Thirty-two children with abusive head trauma were identified with a median age of 4 months (interquartile range 3, 5.5 months). Twenty-one of 32 children (66%) underwent electroencephalographic monitoring. Those monitored were more likely to have a lower admission Glasgow Coma Scale (8 vs 15, p = 0.05) and be intubated (16 vs 2, p= 0.002). Electrographic seizures occurred in 12 of 21 children (57%) and constituted electrographic status epilepticus in 8 of 12 children (67%). Electrographic seizures were entirely nonconvulsive in 8 of 12 children (67%). Electroencephalographic background category (discontinuous and slow-disorganized) (p=0.02) and neuroimaging evidence of ischemia were associated with the presence of electrographic seizures (p = 0.05). Subjects who had electrographic seizures were no more likely to have clinical seizures at admission (67% electrographic seizures vs 33% none, p = 0.6), parenchymal imaging abnormalities (61% electrographic seizures vs 39% none, p = 0.40), or extra-axial imaging abnormalities (56% electrographic seizures vs 44% none, p = 0.72). Four of 21 (19%) children died prior to discharge; none had electrographic seizures, but all had attenuated-featureless electroencephalographic backgrounds. Follow-up outcome data were available for 16 of 17 survivors at a median duration of 9.5 months following PICU admission, and the presence of electrographic seizures or electrographic status epilepticus was not associated with the Glasgow Outcome Scale score (p = 0.10). Electrographic seizures and electrographic status epilepticus are common in children with abusive head trauma. Most seizures have no clinical correlate. Further study is needed to determine whether seizure identification and management improves outcome. 23303916 An evolutionarily conserved signaling mechanism mediates far-red light responses in land plants. Phytochromes are plant photoreceptors important for development and adaptation to the environment. Phytochrome A (PHYA) is essential for the far-red (FR) high-irradiance responses (HIRs), which are of particular ecological relevance as they enable plants to establish under shade conditions. PHYA and HIRs have been considered unique to seed plants because the divergence of seed plants and cryptogams (e.g., ferns and mosses) preceded the evolution of PHYA. Seed plant phytochromes translocate into the nucleus and regulate gene expression. By contrast, there has been little evidence of a nuclear localization and function of cryptogam phytochromes. Here, we identified responses to FR light in cryptogams, which are highly reminiscent of PHYA signaling in seed plants. In the moss Physcomitrella patens and the fern Adiantum capillus-veneris, phytochromes accumulate in the nucleus in response to light. Although P. patens phytochromes evolved independently of PHYA, we have found that one clade of P. patens phytochromes exhibits the molecular properties of PHYA. We suggest that HIR-like responses had evolved in the last common ancestor of modern seed plants and cryptogams and that HIR signaling is more ancient than PHYA. Thus, other phytochromes in seed plants may have lost the capacity to mediate HIRs during evolution, rather than that PHYA acquired it. 23842440 Assessment of phytochemicals, antimicrobial and cytotoxic activities of extract and fractions from Fagonia olivieri (Zygophyllaceae). In Pakistan Fagonia olivieri (Zygophyllaceae) is commonly used in the indigenous system of medicine for treatment of conditions like diabetes, cancer, fever, asthma, toothache, stomach troubles and kidney disorders. This study evaluated the crude methanol extract of F. olivieri (FOM) and its derived fractions for their antimicrobial and cytotoxic activities as well as the classes of phytochemical. Dried powder of whole plant of F. olivieri was extracted with methanol (FOM) and the resultant was fractionated to give n-hexane fraction (FOH), chloroform fraction (FOC), ethyl acetate fraction (FOE), n-butanol fraction (FOB) and residual aqueous fraction (FOA). Methanol extract and its derived fractions were subjected to phytochemical screening using standard procedures. Also the extract and fractions were assayed for antibacterial, antifungal and cytotoxic activities using agar well diffusion technique, agar tube dilution method and brine shrimps lethality test, respectively. The results obtained for phytochemical analysis indicate the presence of saponins and alkaloids in all the tested extract and fractions while anthraquinones were not detected. The results showed that all the bacterial strains tested in this study were susceptible to at least one of the fractions tested. However, FOE and FOB were the best antibacterial fractions and showed antibacterial activity against maximum number of bacterial strains. The results showed that Escherichia coli was the most sensitive bacterium while Bordetella bronchiseptica and Enterobacter aerogenes were less susceptible against various fractions. Maximum percent inhibition for growth was recorded for the fungus Aspergillus flavus with FOE whereas growth of Aspergillus fumigatus and Fusarium solani was inhibited by FOM and its all derived fractions. Minimum LC50 (24.07 mg/L) for brine shrimp assay was recorded for FOE followed by LC50 of FOC (26.1 mg/L) and FOB (30.05 mg/L) whereas maximum LC50 was exhibited by FOH (1533 mg/L). These results indicated the use of F. olivieri to treat infections with emphasis to isolate and characterize the active principle responsible for antibacterial, antifungal and cytotoxic activities and its exploitation as therapeutic agent. 23746141 Tuning the band gap of graphene nanoribbons synthesized from molecular precursors. A prerequisite for future graphene nanoribbon (GNR) applications is the ability to fine-tune the electronic band gap of GNRs. Such control requires the development of fabrication tools capable of precisely controlling width and edge geometry of GNRs at the atomic scale. Here we report a technique for modifying GNR band gaps via covalent self-assembly of a new species of molecular precursors that yields n = 13 armchair GNRs, a wider GNR than those previously synthesized using bottom-up molecular techniques. Scanning tunneling microscopy and spectroscopy reveal that these n = 13 armchair GNRs have a band gap of 1.4 eV, 1.2 eV smaller than the gap determined previously for n = 7 armchair GNRs. Furthermore, we observe a localized electronic state near the end of n = 13 armchair GNRs that is associated with hydrogen-terminated sp(2)-hybridized carbon atoms at the zigzag termini. 23589406 Protective effects of caffeic acid phenethyl ester on dose-dependent intoxication of rats with paraquat. PURPOSE: Paraquat (PQ; 1,1'dimethyl-bipyridilium 4,4'-dichloride), which is used extensively throughout the world, is highly toxic to humans. We aimed to investigate the protective effects of different doses of caffeic acid phenethyl ester (CAPE) on PQ-intoxicated rats.Materials and methods:A total of 80 rats were divided into the following eight groups, comprising 10 rats in each group: group 1: control; group 2: administered with CAPE (10 µmol/kg); group 3: administered with 15 mg/kg PQ (PQ15 group); group 4: administered with 30 mg/kg PQ (PQ30 group); group 5: administered with 45 mg/kg PQ (PQ45 group); group 6: administered with 15 mg/kg PQ + CAPE; group 7: administered with 30 mg/kg PQ + CAPE and group 8: administered with 45 mg/kg PQ + CAPE. Both PQ and CAPE were injected intraperitoneally. Pancreatic tissue was examined with both haematoxylin and eosin and immunochemical staining. RESULTS: The ratio of the immunohistochemical staining area to the total pancreatic area of the β cells revealed that statistically significant differences were observed only between the PQ and PQ + CAPE groups (p < 0.05). Discussion:The evaluation of the data suggests that CAPE can be used to prevent acute effects of PQ intoxication. 23937487 Real-time characterisation of Cannabinoid Receptor 1 (CB1 ) allosteric modulators reveals novel mechanism of action. The cannabinoid receptor type 1 (CB1 ) has an allosteric binding site. The drugs ORG27569 and PSNCBAM-1 have been extensively characterised with regard to their effects on signalling of the orthosteric ligand CP55,940 and studies have suggested that these allosteric modulators increase binding affinity but act as non-competitive antagonists in functional assays. To gain a deeper understanding of allosteric modulation of CB1 , we examined real-time signalling and trafficking responses of the receptor in the presence of allosteric modulators. Studies of CB1 signalling were carried out in HEK 293 and AtT20 cells expressing HA-tagged human and rat CB1 . We measured real-time accumulation of cAMP, activation and desensitization of potassium channel-mediated cellular hyperpolarisation and CB1 internalisation. ORG27569 and PSNCBAM-1 produce a complex, concentration and time-dependent modulation of agonist-mediated regulation of cAMP levels, as well as an increased rate of desensitisation of CB1 -mediated cellular hyperpolarisation and a delay in agonist-induced receptor internalisation. Contrary to previous studies characterising allosteric modulators at CB1, this study suggests that the mechanism of action is not non-competitive antagonism of signalling, but rather that enhanced binding results in an increased rate of receptor desensitisation and delayed internalisation which results in time dependent modulation of cAMP signalling. The observed effect of the allosteric modulators is therefore dependent on the time frame over which the signalling response occurs. This finding may have important consequences for the potential therapeutic application of these compounds. 23903803 Pitfalls and Recommendations in Cases of Laser Removal of Decorative Tattoos With Pigmented Lesions: Case Report and Review of the Literature. IMPORTANCE Pigmented lesions in decorative tattoos cause diagnostic difficulties at a clinical and dermoscopic level. In cases of laser removal of tattoos, hidden suspicious nevi may be revealed gradually. OBSERVATIONS We describe the first case of a malignant melanoma that developed on a preexisting nevus within a tattoo during and between the phases of laser removal. The patient refused to undergo excision of the nevus until we made excision conditional for continued laser treatment. CONCLUSIONS AND RELEVANCE The English literature reports 16 cases of malignant melanoma developing in tattoos. Correlation between the placement of tattoos and the development of malignant melanoma remains unclear. Our case emphasizes the diagnostic problems of pigmented lesions within tattoos. For safety reasons, tattoos should never be placed on pigmented lesions; if they are, the tattoos should not undergo laser treatment. We suggest an excision before starting laser tattoo removal. Dermoscopic assessments on a regular basis during the period of tattoo removal are recommended. 23859878 A comparative study: In vitro effects of EPA and DHA on immune functions of head-kidney macrophages isolated from large yellow croaker (Larmichthys crocea). Comparative effects of different concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on immune responses of head-kidney macrophages isolated from large yellow croaker were studied in vitro. After exposing to serum-free medium for 1 day, cultured cells were incubated in medium supplemented with graded levels of EPA or DHA (0, 5, 25, 100, 200 and 1000 Î¼M, respectively) in the form of fatty acid bovine serum albumin (FA-BSA) complex for 12 h, 24 h and 36 h, respectively. Control samples were incubated in the absence of EPA or DHA (2% bovine serum albumin, BSA). Following stimulation, cell viability, lipid peroxidation, secretary phopholipase A2 (sPLA2) and prostaglandin E2 (PGE2) production as well as some immune parameters including phagocytosis, respiratory burst activity and interleukin 1β (IL-1β) production were determined. Results showed that EPA and DHA affected cell viability in dose-dependent and time-dependent manners. In particular, cell viability was significantly decreased after 24 h and 36 h incubation with 1000 Î¼M EPA or DHA (P < 0.05). Higher levels of EPA (200 and 1000 Î¼M) caused a significant increase in the production of malondialdehyde (MDA) (P < 0.05), while DHA did not significantly affect the MDA production. EPA significantly increased the intracellular superoxide anion synthesis which, on the contrary, was significantly reduced by DHA. Phagocytosis percentage (PP) values were significantly higher in treatments with 5 Î¼M DHA (P < 0.05), but significantly decreased by 200 and 1000 Î¼M EPA and DHA compared to the control group (P < 0.05). Decreased PGE2 production was produced by cells treated with relatively low doses of EPA or DHA. When high levels of stimulants (1000 Î¼M EPA or DHA) were used, PGE2 levels were elevated and reached a significant level (P < 0.05). Both EPA and DHA significantly inhibited the production of sPLA2, where DHA exerted the more potent inhibitory effects than EPA. No pronounced effect was observed on IL-1β production among all the treatments, and IL-1β level in cell culture supernatant was fairly low (only approximately 6 pg/ml). Those findings suggested that EPA and DHA could influence the immunity and physiological conditions of macrophages from head kidney of large yellow croaker in vitro. 23625207 The role of home blood pressure telemonitoring in managing hypertensive populations. Hypertension is a common chronic disease affecting nearly one-third of the United States population. Many interventions have been designed to help patients manage their hypertension. With the evolving climate of healthcare, rapidly developing technology, and emphasis on delivering patient-centered care, home-based blood pressure telemonitoring is a promising tool to help patients achieve optimal blood pressure (BP) control. Home-based blood pressure telemonitoring is associated with reductions in blood pressure values and increased patient satisfaction. However, additional research is needed to understand cost-effectiveness and long-term clinical outcomes of home-based BP monitoring. We review key interventional trials involving home based BP monitoring, with special emphasis placed on studies involving additionally behavioral modification and/or medication management. Furthermore, we discuss the role of home-based blood pressure telemonitoring within the context of the patient-centered medical home and the evolving role of technology. 23968867 Effects of sustained swimming on the red and white muscle transcriptome of rainbow trout (Oncorhynchus mykiss) fed a carbohydrate-rich diet. Training at sustainable swimming speeds can produce changes in fish skeletal muscle that are important for aquaculture due to their growth-potentiating effects. Such changes may be even more relevant when fish are fed diets containing an increasing proportion of carbohydrates as an energy source. We evaluated the effects of moderate-intensity sustained swimming on the transcriptomic response of red and white muscle in rainbow trout fed a carbohydrate-rich diet using microarray and qPCR. Analysis of the red and white muscle transcriptome in resting or swimming (1.3 body lengths/s) for 30days revealed significant changes in the expression of a large number of genes (395 and 597, respectively), with a total of 218 differentially expressed genes (DEGs) common for both muscles. A large number of the genes involved in glucose use and energy generation, contraction, development, synthesis and catabolism of proteins were up-regulated in red and white muscle. Additionally, DEGs in both muscles were involved in processes of defense response and apoptosis. Skeletal muscle contraction activates a transcriptional program required for the successful adaptation of both muscles to the changing demands imposed by swimming conditions. Future studies should further clarify the mechanisms involved in the adaptation of both tissues to exercise and assess possible benefits of such conditions for cultured fish. 23792436 Cardiolipin deficiency affects respiratory chain function and organization in an induced pluripotent stem cell model of Barth syndrome. Barth syndrome (BTHS) patients carrying mutations in tafazzin (TAZ1), which is involved in the final maturation of cardiolipin, present with dilated cardiomyopathy, skeletal myopathy, growth retardation and neutropenia. To study how mitochondrial function is impaired in BTHS patients, we generated induced pluripotent stem cells (iPSCs) to develop a novel and relevant human model system for BTHS. BTHS-iPSCs generated from dermal fibroblasts of three patients with different mutations in TAZ1 expressed pluripotency markers, and were able to differentiate into cells derived from all three germ layers both in vitro and in vivo. We used these cells to study the impact of tafazzin deficiency on mitochondrial oxidative phosphorylation. We found an impaired remodeling of cardiolipin, a dramatic decrease in basal oxygen consumption rate and in the maximal respiratory capacity in BTHS-iPSCs. Simultaneous measurement of extra-cellular acidification rate allowed us a thorough assessment of the metabolic deficiency in BTHS patients. Blue native gel analyses revealed that decreased respiration coincided with dramatic structural changes in respiratory chain supercomplexes leading to a massive increase in generation of reactive oxygen species. Our data demonstrate that BTHS-iPSCs are capable of modeling BTHS by recapitulating the disease phenotype and thus are important tools for studying the disease mechanism. 23401094 Design of a Highly Efficient O2 Cathode Based on Bilirubin Oxidase from Magnaporthe oryzae. Fungi for the better: The so far highest known current density (1.37 mA cm(-2) ) for the enzymatic O2 reduction under physiological conditions is reported. This is achieved by the design of a new redox polymer with an increased catalytic site density and by using a new bilirubin oxidase (BOD) from Magnaporthe oryzae. 23580334 Revisiting a role for a mammary tumor retrovirus in human breast cancer. There remains great controversy as to whether mouse mammary tumor virus (MMTV), the etiological agent of mammary cancer in mice, or a closely related human retrovirus, plays a role in the development of breast cancer in humans. On one hand, retroviruses such as human T-cell lymphotropic virus and human immunodeficiency virus (HIV) are known causative agents of cancer (in the case of HIV, albeit, indirectly), but attempts to associate other retroviruses with human cancers have been difficult. A recent, high profile, example has been the postulated involvement of another mouse virus, xenotropic murine leukemia virus-related virus, in human prostate cancer, which is now thought to be due to contamination. Here, we review some of the more recent evidence for and against the involvement of MMTV in human breast cancer and suggest future studies that may allow a definitive answer to this conundrum. 23853312 Association of epigenetic alterations in the human C7orf24 gene with the aberrant gene expression in malignant cells. Human chromosome 7 open reading frame 24 (C7orf24)/γ-glutamyl cyclotransferase has been suggested to be a potential diagnostic marker for several cancers, including carcinomas in the bladder urothelium, breast and endometrial epithelium. We here investigated the epigenetic regulation of the human C7orf24 promoter in normal diploid ARPE-19 and IMR-90 cells and in the MCF-7 and HeLa cancer cell lines to understand the transcriptional basis for the malignant-associated high expression of C7orf24. Chromatin immunoprecipitation analysis revealed that histone modifications associated with active chromatin were enriched in the proximal region but not in the distal region of the C7orf24 promoter in HeLa and MCF-7 cells. In contrast, elevated levels of histone modifications leading to transcriptional repression and accumulation of heterochromatin proteins in the C7orf24 promoter were observed in the ARPE-19 and IMR-90 cells, compared to the levels in HeLa and MCF-7 cancer cells. In parallel, the CpG island of the C7orf24 promoter was methylated to a greater extent in the normal cells than in the cancer cells. These results suggest that the transcriptional silencing of the C7orf24 gene in the non-malignant cells is elicited through heterochromatin formation in its promoter region; aberrant expression of C7orf24 associated with malignant alterations results from changes in chromatin dynamics. 23945473 Genotoxicity biomarkers associated with exposure to traffic and near-road atmospheres: a review. Diesel and gasoline emissions, which are the primary components of traffic exhaust, are known or possible human carcinogens, respectively, and working or living near high-traffic roads is associated with various health effects, including cancer. To help understand the mechanistic basis for this observation, the present article reviews 63 studies on genotoxicity biomarkers in traffic-exposed subjects, with office workers being the typical control subjects. The six primary biomarkers used in these studies were the traditional cytogenetic end points, chromosome aberrations (CAs), micronucleus (MN) and sister chromatid exchange, and the standard molecular end points for DNA damage, (32)P-postlabeling, the comet assay and urinary 8-hydroxydeoxyguanosine. These six assays accounted for 74 of the 87 biomarker assessments reported in the studies; all six effectively distinguished traffic-exposed from control populations, giving an average 89% positive results among exposed versus control subjects. In addition, three genomic biomarkers effectively distinguished between the exposed and control populations; these assays measured changes in gene expression, leukocyte telomere length and DNA methylation. Nearly half of all of the studies included exposure assessments involving blood (primarily protein adducts), urine (primarily 1-hydroxypyrene) or air (primarily polycyclic aromatic hydrocarbons); these assays distinguished the exposed from the control subjects for the vast majority of the studies. All but three of the 63 reports were environmental studies that investigated 18 general exposure categories, such as traffic police and automobile/bus mechanics. The studies were performed in 20 countries; however, nearly all of the environmental studies were performed in Europe and Asia, with only one each from Africa, North America and South America. Given that several of the biomarkers are associated with increased cancer risk, including CAs, MNs and altered telomere length, the data reviewed here provide strong mechanistic support for the ability of chronic exposure to traffic exhaust to increase cancer risk. 23582343 An optimal combination for EVAR: low profile endograft body and continuous spiral stent limbs. to evaluate the outcomes of EVAR performed with a new generation of bifurcated endografts and limbs. prospectively collected data from fifty consecutive patients with abdominal aortic aneurysms (AAA) treated at our institution with a Low Profile Zenith(®) bifurcated body/Zenith(®) Spiral-Z legs combo were analysed. AngioCT scans and Ultrasound exams were performed prior to discharge. Ultrasound examination was repeated 6 months after the procedure to assess endograft patency and to depict endoleaks Median age was 70.6 years [50-88] and median ASA score was 3 [2-4]. Median aortic diameter was 56 mm [49-81]. Of the 100 external iliac access vessels, 14 had a diameter of 6 mm or lower. All endografts were successfully implanted. Post-operative Ultrasound examination and angioCT scan depicted both 1 type Ia, and 10 and 19 type 2 endoleaks respectively. An asymptomatic thrombosis of the left external iliac artery distal to the endograft limb was also depicted. 30-day mortality rate was 0%. Two patients died respectively three and four months after EVAR. Both deaths were not aneurysm related. All patients underwent an ultrasound exam 6-12 months after EVAR. All endografts main bodies and limbs were patent. Five endoleaks were depicted, all were type II endoleaks (the early type Ia endoleak had sealed spontaneously; it was confirmed by an angioCT scan). One patient presented a significant stenosis of the left iliac limb at the level of a narrow and calcified aortic bifurcation. It was successfully treated by bilateral iliac angioplasty and kissing balloon stenting. EVAR performed with the Zenith LP main body in combination with Spiral-Z Iliac Legs is safe and effective. No limb occlusions were diagnosed at the 6 month follow up even in challenging iliac anatomies usually considered as contra indications for EVAR. Our first results are most satisfying and calling to be completed by a longer follow up. 23928455 Josef Jadassohn-An Appreciation on the Occasion of His 150th Birthday. : Josef Jadassohn was a pioneering dermatologist who influenced the development of his specialty in many ways. He introduced the patch test for detection of hypersensitivity reactions, gave original descriptions of several entities, such as nevus sebaceous, granulosis rubra nasi, and pachyonychia congenita, and edited the Handbuch der Haut- und Geschlechtskrankheiten, the most comprehensive textbook of dermatology ever published. Moreover, Jadassohn left a phalanx of distinguished students, including Felix Lewandowsky, Wilhelm Lutz, Max Jessner, Hans Biberstein, Hermann Pinkus, and Marion B. Sulzberger. 23759678 RXRγ gene variants are associated with HIV lipodystrophy. HIV lipodystrophy (HIVLD), associated with combination antiretroviral therapy (cART), leads to metabolic and cardiovascular diseases. Nuclear receptors play a central role in lipid homoeostasis and drug disposition; their genetic variants may predispose an individual to the development of HIVLD. DNA samples obtained from cART-treated HIV-positive patients with (HIVLD+; 124) and without (HIVLD-; 56) HIVLD were genotyped for 77 single nucleotide polymorphisms in nine nuclear receptor genes. Statistical analysis was carried out using Haploview software and by logistic regression. Three single nucleotide polymorphisms in RXRγ (rs2134095, rs113471, rs2194899) and its haplotypes (HIVLD+, 54%; HIVLD-, 40.6%; P=0.02) showed significant association with HIVLD. Multivariate analysis identified time since diagnosis (P=0.001) and carriage of the RXRγ haplotype (P=0.02) to be independently associated with HIVLD. Genetic variation in RXRγ, a common binding partner of nuclear receptors that modulate lipid homoeostasis and drug disposition, may contribute to the development of HIVLD in cART-treated HIV patients. These results need replication in other cohorts. 23930616 An uncommon cause of gross hematuria: two cases of ureteroarterial fistula. Ureteroarterial fistula (UAF) is a rare but potentially fatal cause of hematuria seen in patients with prolonged ureteral stenting in the setting of surgery or abdominal radiation. It presents as episodic, transfusion-dependent hematuria with formation of clots. There is no current consensus for the optimal way to diagnose or treat UAF. We report two cases of UAF that required repeated studies and provocative testing to confirm the diagnosis. Both were successfully managed by endovascular stenting. Clinicians must recognize the diagnostic difficulties involved and maintain a high index of suspicion for UAF in stented patients with intermittent, severe hematuria. 23892226 Estimation of PFOS emission from domestic sources in the eastern coastal region of China. Perfluorooctane sulfonate (PFOS) and related chemicals (collectively "PFOS equivalents") have been released to the environment through widespread consumer use and disposal of PFOS-containing products like carpet, leather, textiles, paper, food containers, household cleansers, etc. Accordingly, in addition to PFOS-related industries, domestic activities may also considerably contribute to the PFOS emissions in the eastern coastal region of China, which has been characterized by high industrial input. In the present study, domestic emissions of PFOS equivalents derived from municipal wastewater treatment plants were estimated at the county level, using a regression model of domestic emission density with population density and per capita disposable income as independent variables. The total emission load of PFOS equivalents from domestic sources in the eastern coastal region of China was 381kg in 2010, and large cities were prominent as the emission centers. The domestic emission density averaged 0.37g/km(2)·a for the entire study area. Generally, the Beijing-Tianjin area, Pearl River Delta and Yangtze River Delta, as the most populous and economically developed areas in China, showed significantly higher emission density. Geographical variations within individual provinces were noteworthy. The average per capita discharge load of PFOS equivalents arising from domestic activities was 1.91μg/day per capita in the eastern coastal region of China, which is consistent with previous estimates in Korea, but lower than those calculated for developed countries. In comparison, the spatial distributions of provincial PFOS emissions from domestic and industrial sources were similar to each other; however, the latter was much larger for all the provinces. 23870159 The new St Jude Trifecta versus Carpentier-Edwards Perimount Magna and Magna Ease aortic bioprosthesis: Is there a hemodynamic superiority? The Trifecta valve (St Jude Medical, St Paul, Minn) is a new bioprosthetic heart valve designed for supra-annular aortic valve replacement. We compared the hemodynamic performance of the Trifecta against the Perimount-Magna and Magna-Ease valve prostheses (Edwards Lifesciences, Irvine, Calif) in a nonrandomized, observational, single-center study. A total of 346 consecutive patients with aortic valve disease underwent aortic valve replacement between January 2003 and November 2011, with implantation of the Trifecta (group 1, n = 121), the Perimount-Magna (group 2, n = 126), or the Magna Ease bioprosthesis (group 3, n = 99). Clinical and hemodynamic data were prospectively recorded and compared. Hemodynamic performance was evaluated by transthoracic echocardiography, including mean pressure gradient (MPG) and aortic valve area (AVA) at baseline, discharge, and 6-month follow-up. A multivariate model of covariance analysis was constructed to further compare the primary study end points of MPG and AVA at 6-month follow-up. For all valve sizes, unadjusted MPGs did not differ (P = .08), but AVAs differed (P < .001) between groups at 6-month follow-up. After final adjustment by a multivariate model of covariance analysis, neither the MPGs (P = .16) nor the AVAs (P = .92) at 6 months postoperatively were influenced by the type of prosthesis used. The present observational study is the first to compare the new Trifecta valve with well-established supra-annular aortic valve bioprostheses from a hemodynamic perspective. Although mean pressure gradients and aortic valve areas seem to be advantageous at 6-month follow-up with the new Trifecta valve, after multivariate covariance analysis, no influence of prosthesis type on mean pressure gradient or aortic valve area could be demonstrated. 23887039 Prevention of cholestasis in the murine rotavirus-induced biliary atresia model using passive immunization and nonreplicating virus-like particles. Biliary atresia (BA) is a neonatal cholangiopathy of unknown etiology that results in obliteration of bile ducts and is the primary indication for liver transplant in children. A murine model of BA, which involves infecting newborn mice with rhesus rotavirus (RRV) and leads to development of an obstructive cholangiopathy, has provided a model to assess measures to prevent and treat BA. We used this mouse model of RRV-induced BA to determine if passive immunization of pups using maternal immunization [injection of dams with non-replicating rotavirus (RV) virus-like particles (VLPs) or live RRV] or injection of pups with RV immune serum would protect these RRV-infected neonates from developing BA (measured using cholestasis). Parenteral immunization of mouse dams with two formulations of VLPs (containing viral proteins 2/6 or 2/6/7) resulted in a significant increase in serum RV antibody, and pups born to these immunized dams were protected from developing cholestasis following neonatal infection with RRV. Serum RV-specific antibody with titers of≥400-800 in dams significantly protected pups from developing cholestasis, and a significant trend of increasing protection with high titers was observed (p<0.0001). Cholestatic pups had lower levels of RV serum antibody and higher serum (p<0.01) and liver (p<0.05) RV antigen compared to healthy pups. Passive transfer of low-titer (1600; p<0.05) or high-titer (25,600; p<0.01) RV immune serum to neonatal pups prior to RRV infection also protected them from developing cholestasis. Together, these findings indicate that passively acquired, neutralizing or non-neutralizing RV serum antibody attenuates viral replication and protects pups against disease in the RRV BA model. Early reduction of viral load by clearance with RV-specific antibody is likely a critical determinant of disease in this model. 23772616 HIV-associated chronic immune activation. Systemic chronic immune activation is considered today as the driving force of CD4(+) T-cell depletion and acquired immunodeficiency syndrome (AIDS). A residual chronic immune activation persists even in HIV-infected patients in which viral replication is successfully inhibited by anti-retroviral therapy, with the extent of this residual immune activation being associated with CD4(+) T-cell loss. Unfortunately, the causal link between chronic immune activation and CD4(+) T-cell loss has not been formally established. This article provides first a brief historical overview on how the perception of the causative role of immune activation has changed over the years and lists the different kinds of immune activation characteristic of human immunodeficiency virus (HIV) infection. The mechanisms proposed to explain the chronic immune activation are multiple and are enumerated here, as well as the mechanisms proposed on how chronic immune activation could lead to AIDS. In addition, we summarize the lessons learned from natural hosts that know how to 'show AIDS the door', and discuss how these studies informed the design of novel immune modulatory interventions that are currently being tested. Finally, we review the current approaches aimed at targeting chronic immune activation and evoke future perspectives. 23707213 The effects of Rhizoma Zingiberis on pharmacokinetics of six Aconitum alkaloids in herb couple of Radix Aconiti Lateralis-Rhizoma Zingiberis. Radix Aconiti Lateralis (Fuzi in Chinese, derived from the lateral roots of Aconitum Carmichaeli Debx.) is widely used for the treatment of heart failure, internal cold, arthralgia, diarrhea and edema for thousands of years. It was usually prescribed in combination with Rhizoma Zingiberis (Ganjiang in Chinese, derived from the dry rhizome of Zingiber officinale Rosc.) to decrease toxicity and increase efficacy. In order to investigate the influence of Rhizoma Zingiberis on pharmacokinetics of six Aconitum alkaloids, i.e. aconitine (AC), hypaconitine (HA), mesaconitine (MA), benzoylaconine (BAC), benzoylhypaconine (BHA) and benzoylmesaconine (BMA), in Fuzi-Ganjiang herb couple, the comparative pharmacokinetics of six Aconitum alkaloids after oral administration of Fuzi and Fuzi-Ganjiang aqueous extract was carried out. A sensitive, specific and rapid LC-MS/MS method was developed to determine the six analytes in plasma. Then the rats were randomly divided into two groups and orally administered with Fuzi and Fuzi-Ganjiang aqueous extract. At designated time points after oral administration, the concentrations of the six Aconitum alkaloids in rat plasma were determined, and main pharmacokinetic parameters were investigated using 3P97 (Practical Pharmacokinetics Program Version 1.0). Comparing with Fuzi group, both T1/2 and AUC0-t of AC and HA decreased (P<0.05), while T1/2, AUC0-t and Cmax of BAC, BHA increased (P<0.05) in Fuzi-Ganjiang group, which indicated that Ganjiang could promote the elimination of AC and HA and enhance the absorption of BAC, BHA and BMA. The differences of pharmacokinetics of Aconitum alkaloids in rat plasma could support those of pharmacologics and toxicity in previous reports between Fuzi and Fuzi-Ganjiang herb couple. The results might be helpful in explaining the mechanism of combination of Fuzi-Ganjiang to decrease toxicity and increase efficacy. 23942896 Immunolocalization and distribution of functional temperature-sensitive TRP channels in salivary glands. Transient receptor potential (TRP) cation channels are unique cellular sensors involved in multiple cellular functions. Their role in salivary secretion remains to be elucidated. The expression and localization of temperature-sensitive TRP channels in salivary (submandibular, sublingual and parotid) glands were analyzed by immunohistochemistry and quantitative real-time reverse transcription plus the polymerase chain reaction (RT-PCR). The effects of various TRP channel agonists on carbachol (CCh)-induced salivary secretion in the submandibular gland and on the intracellular Ca(2+) concentration ([Ca(2+)]i) in a submandibular epithelial cell line were also investigated. Immunohistochemistry revealed the expression of TRP-melastatin subfamily member 8 (TRPM8) and TRP-ankyrin subfamily member 1 (TRPA1) in myoepithelial, acinar and ductal cells in the sublingual, submandibular and parotid glands. In addition, TRP-vanilloid subfamily member 1 (TRPV1), TRPV3 and TRPV4 were also expressed in myoepithelial, acinar and ductal cells in all three types of gland. Quantitative real-time RT-PCR results demonstrated the mRNA expression of TRPV1, TRPV3, TRPV4, TRPM8 and TRPA1 in acinar and ductal cells in these salivary glands. Perfusion of the entire submandibular gland with the TRPV1 agonist capsaicin (1 Î¼M) via the submandibular artery significantly increased CCh-induced salivation, whereas perfusion with TRPM8 and TRPA1 agonists (0.5 Î¼M WS12 and 100 Î¼M allyl isothiocyanate) decreased it. Application of agonists for each of the thermosensitive TRP channels increased [Ca(2+)]i in a submandibular epithelial cell line. These results indicate that temperature-sensitive TRP channels are localized and distributed in acinar, ductal and myoepithelial cells in salivary glands and that they play a functional role in the regulation and/or modulation of salivary secretion. 23632960 Molecular subtypes of breast cancer: metabolic correlation with (18)F-FDG PET/CT. To determine whether the metabolic features of breast tumours differ among molecular subtypes. This prospective study included 168 women diagnosed with locally advanced breast cancer. PET/CT was requested in the initial staging before neoadjuvant treatment (multicentre study, FISCAM grant). All patients underwent an (18)F-FDG PET/CT scan with a dual time-point acquisition. Both examinations (PET-1 and PET-2) were evaluated qualitatively and semiquantitatively with calculation of SUVmax (SUV-1 and SUV-2, respectively), and the percentage variation in the SUVs and retention indexes (RI) between PET-1 and PET-2 in the breast tumour were calculated. Biological prognostic parameters, including the steroid receptor status, HER-2 expression, proliferation rate (Ki-67) and grading, were determined from primary tumour tissue. Tumour subtypes were classified following the recommendations of the 12th International Breast Conference, by immunohistochemical surrogates as luminal A, luminal B-HER2(-), luminal B-HER2(+), HER2(+) or basal. Metabolic semiquantitative parameters and molecular subtypes were correlated. Of the 168 tumours, 151 were classified: 16 were luminal A, 53 were luminal B-HER2(-), 29 were luminal B-HER2(+), 18 were HER2(+) and 35 were basal. There were significant differences between SUV-1 and SUV-2 and the different subtypes, with higher SUVs in HER2(+) and basal tumours. No significant differences were found with respect to RI. Semiquantitative metabolic parameters showed statistically significant differences among the molecular subtypes of the tumours evaluated. Therefore, there seems to be a relationship between molecular and glycolytic phenotypes. 23897220 Altered gastric vagal mechanosensitivity in diet-induced obesity persists on return to normal chow and is accompanied by increased food intake. Background and aims:Gastric vagal afferents convey satiety signals in response to mechanical stimuli. The sensitivity of these afferents is decreased in diet-induced obesity. Leptin, secreted from gastric epithelial cells, potentiates the response of vagal afferents to mechanical stimuli in lean mice, but has an inhibitory effect in high-fat diet (HFD)-induced obese mice. We sought to determine whether changes in vagal afferent function and response to leptin in obesity were reversible by returning obese mice consuming a HFD to standard laboratory chow diet (SLD).Methods:Eight-week-old female C57BL/6 mice were either fed a SLD (N=20) or HFD (N=20) for 24 weeks. A third group was fed a HFD for 12 weeks and then a SLD for a further 12 weeks (RFD, N=18). An in vitro gastro-oesophageal vagal afferent preparation was used to determine the mechanosensitivity of gastric vagal afferents and the modulatory effect of leptin (0.1-10 nM) was examined. Retrograde tracing and quantitative RT-PCR were used to determine the expression of leptin receptor (LepR) messenger RNA (mRNA) in whole nodose and specific cell bodies traced from the stomach.Results:After 24 weeks, both the HFD and RFD mice had increased body weight, gonadal fat mass, plasma leptin, plasma insulin and daily energy consumption compared with the SLD mice. The HFD and RFD mice had reduced tension receptor mechanosensitivity and leptin further inhibited responses to tension in HFD, RFD but not SLD mice. Mucosal receptors from both the SLD and RFD mice were potentiated by leptin, an effect not seen in HFD mice. LepR expression was unchanged in the whole nodose, but was reduced in the mucosal afferents of the HFD and RFD mice.Conclusion:Disruption of gastric vagal afferent function by HFD-induced obesity is only partially reversible by dietary change, which provides a potential mechanism preventing maintenance of weight loss.International Journal of Obesity advance online publication, 27 August 2013; doi:10.1038/ijo.2013.138. 23639026 Expanding functions of intracellular resident mono-ADP-ribosylation in cell physiology. Poly-ADP-ribosylation functions in diverse signaling pathways, such as Wnt signaling and DNA damage repair, where its role is relatively well characterized. Contrarily, mono-ADP-ribosylation by for example ARTD10/PARP10 is much less understood. Recent developments hint at the involvement of mono-ADP-ribosylation in transcriptional regulation, the unfolded protein response, DNA repair, insulin secretion and immunity. Additionally, macrodomain-containing hydrolases, MacroD1, MacroD2 and C6orf130/TARG1, have been identified that make mono-ADP-ribosylation reversible. Complicating further progress is the lack of tools such as mono-ADP-ribose-specific antibodies. The currently known functions of mono-ADP-ribosylation are summarized here, as well as the available tools such as mass spectrometry to study this modification in vitro and in cells. 23934949 Joint segmentation and named entity recognition using dual decomposition in Chinese discharge summaries. In this paper, we focus on three aspects: (1) to annotate a set of standard corpus in Chinese discharge summaries; (2) to perform word segmentation and named entity recognition in the above corpus; (3) to build a joint model that performs word segmentation and named entity recognition. Two independent systems of word segmentation and named entity recognition were built based on conditional random field models. In the field of natural language processing, while most approaches use a single model to predict outputs, many works have proved that performance of many tasks can be improved by exploiting combined techniques. Therefore, in this paper, we proposed a joint model using dual decomposition to perform both the two tasks in order to exploit correlations between the two tasks. Three sets of features were designed to demonstrate the advantage of the joint model we proposed, compared with independent models, incremental models and a joint model trained on combined labels. Micro-averaged precision (P), recall (R), and F-measure (F) were used to evaluate results. The gold standard corpus is created using 336 Chinese discharge summaries of 71 355 words. The framework using dual decomposition achieved 0.2% improvement for segmentation and 1% improvement for recognition, compared with each of the two tasks alone. The joint model is efficient and effective in both segmentation and recognition compared with the two individual tasks. The model achieved encouraging results, demonstrating the feasibility of the two tasks. 23515915 Diversity of Archaea in Brazilian savanna soils. Although the richness of Bacteria and Fungi in Cerrado' soils has been reported, here we report, for the first time, the archaeal community in Cerrado's soils. DNA extracted from soil of two distinct vegetation types, a dense subtype of sensu strict (cerrado denso) and riverbank forest (mata de galeria), was used to amplify Archaea-specific 16S rRNA gene. All of the fragments sequenced were classified as Archaea into the phylum Thaumarchaeota, predominantly affiliated to groups I.1b and I.1c. Sequences affiliated to the group I.1a were found only in the soil from riverbank forest. Soils from 'cerrado denso' had greater Archaea richness than those from 'mata de galeria' based on the richness indexes and on the rarefaction curve. β-Diversity analysis showed significant differences between the sequences from the two soil areas studied because of their different thaumarchaeal group composition. These results provide information about the third domain of life from Cerrado soils. 23787063 A phase II clinical trial of the Vascular Disrupting Agent BNC105P as second line chemotherapy for advanced Malignant Pleural Mesothelioma. BNC105P is a tubulin polymerisation inhibitor that selectively disrupts tumour vasculature and suppresses cancer cell proliferation. This agent has exhibited preclinical and phase I activity in Malignant Pleural Mesothelioma (MPM). This phase II, single arm trial investigated the efficacy and safety of BNC105P as second line therapy in MPM. Participants had progressive MPM after first line pemetrexed/platinum chemotherapy, ECOG PS 0-1, adequate organ function, and measurable disease. BNC105P 16mg/m(2) was administered intravenously on day 1 and 8 every 21 days until progression or undue toxicity. The primary endpoint was centrally reviewed objective response rate (RR). Tumour response was assessed every two cycles using modified RECIST. 30 patients were enrolled in 10 months, predominantly male (90%), ECOG PS 1 (77%), epithelioid histology (67%), and non-metastatic disease (67%). All patients received at least one dose of study drug, with a median of 2 cycles. No significant haematologic, biochemical, or cardiac adverse events (AEs) were observed. Grade 3 or 4 AEs occurred in 10 patients (33%). There were 2 deaths on study: 1 cardiorespiratory, the other to pneumonia. We observed 1 partial response (3%); 13 patients had stable disease (43%). Median progression free survival was 1.5 months (95% CI 1.4-2.4); median overall survival was 8.2 months (95% CI 3.8-11.9). BNC105P was safe and tolerable. The sole response was insufficient to warrant further research as a single agent. 23893312 The motor neuron response to SMN1 deficiency in spinal muscular atrophy. Objective: To measure and analyze motor unit number estimation (MUNE) values longitudinally in spinal muscular atrophy (SMA). Methods: Sixty-two children with SMA types 2 and 3 were observed prospectively for up to 42 months. Longitudinal electrophysiological data were collected, including compound motor action potential (CMAP), single motor unit action potential (SMUP), and MUNE. Results: Significant motor neuron loss and compensatory collateral reinnervation were noted at baseline. Over time, there was a significant mean increase in MUNE (4.92 units/year, P = 0.009), a mean decrease in SMUP amplitude (-6.32 μV/year, P = 0.10) and stable CMAP amplitude. Discussion: The unexpected longitudinal results differ from findings in amyotrophic lateral sclerosis, perhaps indicating that compensatory processes in SMA involve new motor unit development. A better understanding of the mechanisms of motor unit decline and compensation in SMA is important for assessing novel therapeutic strategies and for providing key insights into disease pathophysiology. © 2013 Wiley Periodicals, Inc. 23947877 The nature of free O-H stretching in water adsorbed on carbon nanosystems. Motivated by the existence of several recent works claiming for unusual hydrogen bonds in water adsorbed or confined in carbon nanostructures, we have analyzed the nature of a sharp O-H stretching at 3700 cm(-1) in H2O∕graphene recorded in vibrational measurements. The interpretation of such mode is rather controversial. On the basis of a careful inspection of our spectroscopic data and of literature, we suggest that the interpretation of this feature as a fingerprint of surface hydrophobicity, electronic effects or disorder is astray. Instead, it merely arises from interface effects. 22689059 Cooperation between p53 and the telomere-protecting shelterin component Pot1a in endometrial carcinogenesis. Type II endometrial cancer (EMCA) represents only 10% of all EMCAs, but accounts for 40% of EMCA-related mortality. Previous studies of human tumors have shown an association between Type II tumors and damaged telomeres. We hypothesized that the lack of murine Type II EMCA models is due to the extremely long telomeres in laboratory mouse strains. We previously showed that telomerase-null mice with critically short telomeres developed endometrial lesions histologically resembling endometrial intraepithelial carcinoma (EIC), the accepted precursor for Type II EMCA. However, these mice did not develop invasive endometrial adenocarcinoma, and instead succumbed prematurely to multi-organ failure. Here, we modeled critical telomere attrition by conditionally inactivating Pot1a, a component of the shelterin complex that stabilizes telomeres, within endometrial epithelium. Inactivation of Pot1a by itself did not stimulate endometrial carcinogenesis, and did not result in detectable DNA damage or apoptosis in endometrium. However, simultaneous inactivation of Pot1a and p53 resulted in EIC-like lesions by 9 months indistinguishable from those seen in late generation telomerase-null mice. These lesions progressed to invasive endometrial adenocarcinomas as early as 9 months of age with metastatic disease in 100% of the animals by 15 months. These tumors were poorly differentiated endometrial adenocarcinomas with prominent nuclear atypia, resembling human Type II cancers. Furthermore, these tumors were aneuploid with double-stranded DNA breaks and end-to-end telomere fusions and most were tetraploid or near-tetraploid. These studies lend further support to the hypothesis that telomeric instability has a critical role in Type II endometrial carcinogenesis and provides an intriguing in-vivo correlate to recent studies implicating telomere-dependent tetraploidization as an important mechanism in carcinogenesis. 23934274 Adherence and Weight Loss Outcomes in Bariatric Surgery: Does Cognitive Function Play a Role? Although bariatric surgery is the most effective intervention for severe obesity, a significant minority of participants fail to achieve or maintain optimal weight loss at extended follow-up. Accumulating evidence suggests that adherence to prescribed postoperative recommendations, including attendance at follow-up appointments and dietary and physical activity, is related to improved weight loss outcomes. However, adherence to these guidelines presents a significant challenge for many patients, potentially due in part to deficits in cognitive function. In this paper, we briefly examine current literature of adherence on postoperative weight loss outcomes, and review emerging evidence that the cognitive dysfunction present in a subset of obese individuals is related to weight loss outcomes following bariatric procedures. We then extend these findings, positing a role for cognitive function in moderating the relationship between adherence and postoperative outcomes. 23607682 Social reward: interactions with social status, social communication, aggression, and associated neural activation in the ventral tegmental area. Nearly all species engage in a variety of intraspecific social interactions, and there is evidence that these interactions are rewarding. Less is known, however, about the factors that influence social reward. Using the conditioned place preference paradigm, we tested whether social interactions are rewarding for male Syrian hamsters. We also tested whether social stimuli increase neural activation in the ventral tegmental area (VTA), a component of the mesolimbic reward system, and how individual differences in social behavior and experience influence neural activation. In the present study, we found that hamsters developed a conditioned place preference for social interactions, but the effects were significantly stronger in dominant animals compared with subordinates. The number of Fos-immunoreactive cells in the VTA was significantly higher in hamsters that had engaged in a direct social encounter compared with hamsters exposed to a caged stimulus hamster or controls. Interestingly, socially experienced males had more Fos-immunoreactive cells in the VTA than socially naive males after exposure to a social stimulus. Surprisingly, the amount of Fos immunoreactivity in the VTA induced by a social stimulus was correlated with the amount of aggressive/dominance behaviors that had been observed during interactions that had occurred 2 months earlier. Our results indicate that social interactions between males are rewarding, and that social dominance increases the reward value. Social interactions stimulate the mesolimbic reward system, and social experience enhances its response to novel social stimuli and may produce long-term changes in the neural mechanisms that mediate the maintenance of dominance over long periods of time. 23649499 Cosmetic rhinoseptoplasty in acute nasal bone fracture. Objective Traditionally, rhinoseptoplasty for nasal bone fracture is only considered after an unsatisfactory outcome from initial closed reduction. However, better surgical outcomes may be achieved if rhinoseptoplasty is performed at the same time as the nasal bone fracture reduction. This study investigated the surgical outcomes of patients who underwent rhinoseptoplasty concomitantly with nasal bone fracture reduction according to their computed tomography image-based nasal bone fracture classifications. Study Design Case series with chart review. Setting Academic tertiary care medical center. Subjects and Methods Fifty-six patients who underwent rhinoseptoplasty concomitantly with nasal bone fracture reduction were enrolled in this study. Nasal bone fractures were classified into 6 types by computed tomography scans. Two independent facial plastic surgeons evaluated the outcomes 6 months postoperatively using a visual analog scale. The nasal tip projection and rotation were measured using the pre- and postoperative profile views. Results The satisfaction scores of type I, IIo, and IIIo fractures without septal fracture were significantly higher than those of type II, III, and IV fractures with septal fractures. Among the patients, 82.1% underwent lower vault surgery. The nasal tip projection and rotation were increased after surgery in patients without septal fractures, whereas the tip rotation was elevated but the projection was unchanged postoperatively in patients with septal fractures. Conclusion Rhinoseptoplasty for acute nasal bone fractures can be performed at the same time as nasal bone fracture reduction. However, nasal bone fracture with septal fracture should be managed carefully. 22693339 Multivariate activation and connectivity patterns discriminate speech intelligibility in Wernicke's, Broca's, and Geschwind's areas. The brain network underlying speech comprehension is usually described as encompassing fronto-temporal-parietal regions while neuroimaging studies of speech intelligibility have focused on a more spatially restricted network dominated by the superior temporal cortex. Here we use functional magnetic resonance imaging with a novel whole-brain multivariate pattern analysis (MVPA) to more fully characterize neural responses and connectivity to intelligible speech. Consistent with previous univariate findings, intelligible speech elicited greater activity in bilateral superior temporal cortex relative to unintelligible speech. However, MVPA identified a more extensive network that discriminated between intelligible and unintelligible speech, including left-hemisphere middle temporal gyrus, angular gyrus, inferior temporal cortex, and inferior frontal gyrus pars triangularis. These fronto-temporal-parietal areas also showed greater functional connectivity during intelligible, compared with unintelligible, speech. Our results suggest that speech intelligibly is encoded by distinct fine-grained spatial representations and within-task connectivity, rather than differential engagement or disengagement of brain regions, and they provide a more complete view of the brain network serving speech comprehension. Our findings bridge a divide between neural models of speech comprehension and the neuroimaging literature on speech intelligibility, and suggest that speech intelligibility relies on differential multivariate response and connectivity patterns in Wernicke's, Broca's, and Geschwind's areas. 23588006 Cholesterol-mediated membrane surface area dynamics in neuroendocrine cells. How cholesterol, a key membrane constituent, affects membrane surface area dynamics in secretory cells is unclear. Using methyl-β-cyclodextrin (MβCD) to deplete cholesterol, we imaged melanotrophs from male Wistar rats in real-time and monitored membrane capacitance (Cm), fluctuations of which reflect exocytosis and endocytosis. Treatment with MβCD reduced cellular cholesterol and caused a dose-dependent attenuation of the Ca(2+)-evoked increase in Cm (IC50=5.3mM) vs. untreated cells. Cytosol dialysis of MβCD enhanced the attenuation of Cm increase (IC50=3.3mM), suggesting cholesterol depletion at intracellular membrane sites was involved in attenuating exocytosis. Acute extracellular application of MβCD resulted in an immediate Cm decline, which correlated well with the cellular surface area decrease, indicating the involvement of cholesterol in the regulation of membrane surface area dynamics. This decline in Cm was three-fold slower than MβCD-mediated fluorescent cholesterol decay, implying that exocytosis is the likely physiological means for plasma membrane cholesterol replenishment. MβCD had no effect on the specific Cm and the blockade of endocytosis by Dyngo 4a, confirmed by inhibition of dextran uptake, also had no effect on the time-course of MβCD-induced Cm decline. Thus acute exposure to MβCD evokes a Cm decline linked to the removal of membrane cholesterol, which cannot be compensated for by exocytosis. We propose that the primary contribution of cholesterol to surface area dynamics is via its role in regulated exocytosis. 23895933 FOXO/Fringe is necessary for maintenance of the germline stem cell niche in response to insulin insufficiency. The stem cell niche houses and regulates stem cells by providing both physical contact and local factors that regulate stem cell identity. The stem cell niche also plays a role in integrating niche-local and systemic signals, thereby ensuring that the balance of stem cells meets the needs of the organism. However, it is not clear how these signals are merged within the niche. Nutrient-sensing insulin/FOXO signaling has been previously shown to directly control Notch activation in the Drosophila female germline stem cell (GSC) niche, which maintains the niche and GSC identity. Here, we demonstrate that FOXO directly activates transcription of fringe, a gene encoding a glycosyltransferase that modulates Notch glycosylation. Fringe facilitates Notch inactivation in the GSC niche when insulin signaling is low. We also show that the Notch ligand predominantly involved is GSC niche-derived Delta. These results reveal that FOXO-mediated regulation of fringe links the insulin and Notch signaling pathways in the GSC niche in response to nutrition, and emphasize that stem cells are regulated by complex interactions between niche-local and systemic signals. 23856418 Hypoxia preconditioned bone marrow mesenchymal stem cells promote liver regeneration in a rat massive hepatectomy model. Bone marrow mesenchymal stem cells (BMMSCs) have been reported to facilitate liver regeneration after toxic injuries. However, the effect of BMMSCs on liver regeneration after massive hepatectomy is barely studied. Here we explored whether infusion of BMMSCs promotes liver regeneration in a rat massive hepatectomy model. Hypoxia preconditioning was achieved by culturing BMMSCs under a hypoxia environment. Then 85% hepatectomy was performed and hypoxia or normoxia preconditioned BMMSCs were infused into the portal vein. A group of rats received vascular endothelial growth factor (VEGF) neutralizing antibody perioperatively, and underwent 85% hepatectomy and a subsequent infusion of hypoxia preconditioned BMMSCs to verify the role of VEGF in the effects of BMMSCs on liver regeneration. Liver samples were collected and liver regeneration was evaluated postoperatively. Hypoxia preconditioning enhanced the expression of VEGF in BMMSCs in vitro. Infusion of BMMSCs promoted proliferation of hepatocytes, reflected by elevated cyclin D1 expression and proliferating cell nuclear antigen-positive hepatocytes. However, BMMSC infusion did not improve the serum albumin level, liver weight/body weight ratio, and survival after operation. Infusion of hypoxia preconditioned BMMSCs significantly elevated cyclin D1, proliferating cell nuclear antigen-positive hepatocytes, liver weight/body weight ratio, and survival compared with normoxia preconditioned BMMSCs, accompanied by an increased serum albumin level. The level of VEGF in liver homogenate was much higher in hypoxia preconditioned BMMSC-treated animals than in other groups. In addition, the perioperative injection of VEGF neutralizing antibody significantly blocked the therapeutic effects of hypoxia preconditioned BMMSCs on liver injury and regeneration in this model. Hypoxia preconditioned BMMSCs enhanced liver regeneration after massive hepatectomy in rats, possibly by upregulating the level of VEGF. 23937726 Alternative sigma factor RpoN and its modulation protein YhbH are indispensable for Erwinia amylovora virulence. In Erwinia amylovora, ECF (extracytoplasmic functions) alternative sigma factor HrpL regulates the transcription of hrp (hypersensitive response and pathogenicity)-type III secretion system (T3SS) genes by binding to a consensus sequence known as the hrp box in hrp gene promoters. In turn, the expression of hrpL has been proposed to be positively controlled by alternative sigma factor 54 (σ(54) ) (RpoN) and HrpS, a member of the σ(54) enhancer-binding proteins (EBPs). However, the function of RpoN has not been characterized genetically in E. amylovora. In this study, we investigated the role of RpoN, a nitrogen limitation sigma factor, and its modulation protein YhbH, a novel ribosome-associated protein, in E. amylovora virulence. Our results showed that mutations in hrpS, hrpL, rpoN and yhbH, but not yfiA and rmf3, resulted in a nonpathogenic phenotype on immature pear fruits and apple shoots. Consistently, the expression of T3SS genes, including hrpL, dspE, hrpN and hrpA, was barely detected in hrpS, hrpL, rpoN and yhbH mutants. These mutants were also not capable of eliciting a hypersensitive response (HR) on tobacco; however, the overexpression of hrpL using an inducible promoter rescued the HR-eliciting abilities of these mutants. These results suggest that a sigma factor cascade exists in the regulatory networks of E. amylovora and regulates important virulence factors. On the basis of this study and previously reported data, a model is proposed for the regulation of T3SS in E. amylovora. 23931691 BOD biosensor based on the yeast Debaryomyces hansenii immobilized in poly(vinyl alcohol) modified by N-vinylpyrrolidone. An amperometric biosensor for assessing the biochemical oxygen demand (BOD) was formed by immobilizing Debaryomyces hansenii VKM Y-2482 yeast cells in poly(vinyl alcohol) modified by N-vinylpyrrolidone. Modification provided for a high sensitivity and stability of the bioreceptor. A high oxidative activity of the receptor element and the absence of any toxic effect of assayed compounds were shown for 34 substrates (alcohols, carbohydrates, carboxylic acids, amino acids, nitrophenols and surfactants) that may occur in wastewaters. Estimates of the measurement range and region of the linear dependence of signals on the BOD level, pH and temperature sensitivities, dependences of signals on concentrations of salts, stability, Michaelis kinetic constants and assay rates were obtained. The BOD values determined by the biosensor in assayed wastewater samples were shown to have a high correlation with those obtained by the standard dilution method. 23839064 IKKβ in intestinal epithelial cells regulates allergen-specific IgA and allergic inflammation at distant mucosal sites. Regulation of allergic responses by intestinal epithelial cells (IECs) remains poorly understood. Using a model of oral allergen sensitization in the presence of cholera toxin as adjuvant and mice with cell-specific deletion of inhibitor-κB kinase (IKKβ) in IECs (IKKβ(ΔIEC)), we addressed the contribution of IECs to allergic sensitization to ingested antigens and allergic manifestations at distant mucosal site of the airways. Cholera toxin induced higher pro-inflammatory responses and altered the profile of the gut microbiota in IKKβ(ΔIEC) mice. Antigen-specific immunoglobulin E (IgE) responses were unaltered in IKKβ(ΔIEC) mice, but their IgA antibodies (Abs), T helper type 1 (Th1) and Th17 responses were enhanced. Upon nasal antigen challenge, these mice developed lower levels of allergic lung inflammation, which correlated with higher levels of IgA Abs in the airways. The IKKβ(ΔIEC) mice also recruited a higher number of gut-sensitized T cells in the airways after nasal antigen challenge and developed airway hyper-responsiveness, which were suppressed by treatment with anti-interleukin-17A. Fecal microbiota transplant during allergic sensitization reduced Th17 responses in IKKβ(ΔIEC) mice, but did not affect IgA Ab responses. In summary, we show that IKKβ in IECs shapes the gut microbiota and immune responses to ingested antigens and influences allergic responses in the airways via regulation of IgA Ab responses.Mucosal Immunology advance online publication 10 July 2013. doi:10.1038/mi.2013.43. 23916552 An observational study of patient selection criteria for post-cardiac arrest therapeutic hypothermia. To date, there is no comprehensive assessment of how therapeutic hypothermia and post-arrest care are being implemented clinically. At this stage in the translation of post-arrest science to clinical practice, this analysis is overdue. This study examines the first step of post-arrest care - the selection of patients for TH and post-arrest care. We conducted a systematic review to search for all publicly available TH and post-arrest protocols. Observational data was reported and no statistical inferences were made. Notable variation was observed in the following selection criteria: total ischemic time and hemodynamic requirements. Additionally, only some of the criteria were evidence based. This study demonstrates the wide range and variety of patient selection criteria that are being used for implementation of post-cardiac arrest care. The consequences of this selection criteria variability are currently unmeasured and likely underestimated. Variability is likely to breed inefficiency. Some patients who could benefit do not get treated. Other patients get cooled, yet will never regain consciousness. This variability may be important when considering inter-hospital variation in post-arrest care and outcomes. 23932978 A novel core-satellite CdTe/Silica/Au NCs hybrid sphere as dual-emission ratiometric fluorescent probe for Cu(2+) Herein, we synthesized a novel core-satellite CdTe/Silica/Au NCs hybrid sphere by covalently linking the separately synthesized highly fluorescent bovine serum albumin (BSA) stabilized gold nanoclusters (Au@BSA NCs) to the surface of the amino functionalized CdTe@SiO2 spheres by using the EDC chemistry. Numerous "satellites" of Au NCs were linked on the surface of the CdTe@SiO2 by the way of amide bonding. The synthesized dual-emission hybrid spheres were further characterized by the transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS), UV-vis absorption spectroscopy, Fourier transform infrared (FTIR) spectroscopy, photoluminescence (PL), etc. Finally, the CdTe/Silica/Au NCs hybrid spheres were developed as ratiometric fluorescence probe for the determination of Cu(2+) with high sensitivity and selectivity. The fluorescence intensity ratio (F545nm/F655nm) of the probe against the concentration of Cu(2+) showed a good linear relationship from 6.0×10(-7)molL(-1) to 100.0×10(-7)molL(-1). It showed an excellent reproducibility (0.67% relative standard deviation for 10 replicate measurements of Cu(2+) at 40.0×10(-7)molL(-1)) and low detection limit (4.1×10(-7)molL(-1)). Furthermore, the ratiometric fluorescent probe was successfully applied in the determination of Cu(2+) in vegetable samples with satisfactory results. 23934649 Serum concentrations of perfluorinated alkyl acids and their associations with diet and personal characteristics among Swedish adults. In this study, food is suggested as a major source of human exposure to perfluorinated alkyl acids (PFAA). We investigated relations between serum levels of PFAA in adults and diet/lifestyle factors nationwide in Sweden. In 2010-2011, adults (18-80 years, N = 270) recorded their diet for 4 days and answered a food frequency questionnaire. PFAA were measured in blood serum as well as v-3 fatty acids in plasma phospholipids as a biomarker for fish consumption. Higher levels of PFAA were associated with male sex, increased age, and higher education. Women reporting full breastfeeding for ≥12 months had 32-44% lower levels of perfluorooctane sulfonate, perfluorooctanoic acid, and perfluorohexane sulfonate than women who never nursed their infants full-time. Serum perfluorooctane sulfonate, perfluorononanoic acid, perfluorodecanoic acid, and perfluoroundecanoic acid were positively related to n-3 fatty acids in plasma (partial r = 0.19-0.34, p ≤ 0.05). The relatively strong correlations between biomarkers of fish consumption and certain PFAA suggest that PFAA exposure should be taken into account in health risk and benefit assessment of fish consumption. Breastfeeding appears to be a major source of elimination of certain PFAA among women, and consequently PFAA exposure of nursed infants could be significant. 23574434 Bapineuzumab and solanezumab for Alzheimer's disease: is the 'amyloid cascade hypothesis' still alive? The 'amyloid cascade hypothesis' remains the leading hypothesis to explain the pathophysiology of Alzheimer's disease (AD). Immunotherapeutic agents have been developed to remove the neurotoxic amyloid β42 protein and prevent the hypothesized amyloid β42-induced neurotoxicity and neurodegeneration. The most notable of these immunotherapies are bapineuzumab and solanezumab. This article briefly reviews the experimental agents in development for treatment of AD and then discusses the results of bapineuzumab and solanezumab in AD patients, as reported in preclinical studies, clinical trials and press releases. Phase III trials showed that bapineuzumab failed to improve cognitive and functional performances in AD patients, and was associated with a high incidence of amyloid-related imaging abnormalities (ARIA). Solanezumab's two Phase III trials in AD patients failed to meet endpoints when analyzed independently. However, analysis of pooled data from both trials showed a significant reduction in cognitive decline in mild AD patients. The improvement was associated with an increase in plasma amyloid-β (Aβ) levels and a low incidence of ARIA in solanezumab-treated patients. The marginal benefits of solanezumab are encouraging to support continued evaluation in future studies, and offer small support in favor of the ongoing viability of the 'amyloid cascade hypothesis' of AD. 23662777 Exploring neural cell dynamics with digital holographic microscopy. In this review, we summarize how the new concept of digital optics applied to the field of holographic microscopy has allowed the development of a reliable and flexible digital holographic quantitative phase microscopy (DH-QPM) technique at the nanoscale particularly suitable for cell imaging. Particular emphasis is placed on the original biological information provided by the quantitative phase signal. We present the most relevant DH-QPM applications in the field of cell biology, including automated cell counts, recognition, classification, three-dimensional tracking, discrimination between physiological and pathophysiological states, and the study of cell membrane fluctuations at the nanoscale. In the last part, original results show how DH-QPM can address two important issues in the field of neurobiology, namely, multiple-site optical recording of neuronal activity and noninvasive visualization of dendritic spine dynamics resulting from a full digital holographic microscopy tomographic approach. 23950017 5q31.3 Microdeletion syndrome: Clinical and molecular characterization of two further cases. The 5q31.3 microdeletion syndrome has recently emerged as a distinct clinical entity, and we report two new patients with de novo deletions of this region, bringing the total to seven. Similarly to previously reported cases, the phenotype of our patients is characterized by marked hypotonia, apnea, developmental delay, and feeding difficulties. Both patients had abnormal movements which did not correlate with epileptiform activity on electroencephalogram (EEG). Developmental brain changes on neuroimaging consisted of abnormalities predominantly affecting the white matter and frontal lobes. The 5q31.3 deleted regions overlap those of previously reported cases, and allow further refinement of the shortest region of overlap to 101 kb, including only three genes. Of these, the purine-rich element binding protein A (PURA) gene has an established role in brain development, and we propose that haploinsufficiency for this gene is primarily responsible for the neurodevelopmental features observed. © 2013 Wiley Periodicals, Inc. 23830989 Biomarkers for methotrexate-induced liver injury: Urinary protein profiling of psoriasis patients. Hepatic fibrosis is an adverse drug reaction of methotrexate (MTX) seen after long-term use in psoriasis patients. Currently, patients are monitored for MTX-induced hepatic fibrosis by performing liver biopsy, which is risky and burdensome for the patient, or by measuring plasma procollagen type III aminopeptide (PIIINP), which is not conclusive. The objective of this study was to identify novel predictive and preferably non-invasive biomarkers to monitor psoriasis patients for MTX-induced hepatic fibrosis. Urine samples were collected from 60 psoriasis patients treated with MTX and divided into two categories: low cumulative dose (<1500mg MTX) and high cumulative dose (>1500mg). Urinary proteins were profiled using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and identified using electrospray ionization LTQ. In urine of psoriasis patients with high cumulative MTX dose multiple proteins were identified that are associated with hepatic fibrosis, such as N-cadherin, inter-alpha-trypsin inhibitor heavy chain H4, haptoglobin and serotransferrin. These proteins may be candidate urinary biomarkers to monitor MTX-induced hepatic fibrosis. In conclusion, urinary proteome analysis identified a profile of potentially predictive biomarkers for MTX-induced hepatic fibrosis in psoriasis patients with high cumulative dose of MTX. 23722716 The description of Mediorhynchus africanus n. sp. (Acanthocephala: Gigantorhynchidae) from galliform birds in Africa. Mediorhynchus africanus n. sp. is described from specimens collected from the helmeted guinea fowls, Numida meliagris Linn. 1758 in Kruger National Park and elsewhere in subSaharan Africa from the same and other galliform birds. These specimens were previously assigned to Mediorhynchus gallinarum Bhaleroa (Proc Zool Soc Lond Ser B Syst Morph 107:199-203, 1937) described from chickens, Gallus gallus L. in India and subsequently reported from other Asian countries. The identification of the African forms as M. gallinarum was based on similarities in the structure and measurements of the proboscis, proboscis armature and receptacle, lemnisci, and reproductive organs. A detailed study of specimens from South Africa and descriptions reported from elsewhere in Africa revealed marked differences that clearly distinguish the African material as new species. The African specimens are pseudo-segmented and flattened, the proboscis has two prominent apical pores, sensory pits are prevalent throughout the trunk, the posterior end of the female is broad with dorso-terminal dome-like extension opposite the subterminal gonopore, and the eggs are large. The Asian specimens from Indonesia and elsewhere are cylindrical and non-segmented, the proboscis lacks prominent apical pores, sensory pits are rare on the trunk, the posterior end of the female is pointed with a terminal gonopore, and the eggs are markedly smaller. We used DNA sequence from one mitochondrial gene (cytochrome oxidase subunit I) and one nuclear gene (18S ribosomal RNA) to infer the phylogenetic relationships of M. africanus and M. gallinarum and selected Acanthocephala. Medioryhnchus is monophyletic and M. africanus and M. gallinarum are allopatric sister species (9.7 % sequence divergence). All findings indicate that M. africanus should be ranked as a separate species. 23845595 Comparative effects of sodium channel blockers in short term rat whole embryo culture. This study was undertaken to examine the effect on the rat embryonic heart of two experimental drugs (AZA and AZB) which are known to block the sodium channel Nav1.5, the hERG potassium channel and the l-type calcium channel. The sodium channel blockers bupivacaine, lidocaine, and the l-type calcium channel blocker nifedipine were used as reference substances. The experimental model was the gestational day (GD) 13 rat embryo cultured in vitro. In this model the embryonic heart activity can be directly observed, recorded and analyzed using computer assisted image analysis as it responds to the addition of test drugs. The effect on the heart was studied for a range of concentrations and for a duration up to 3h. The results showed that AZA and AZB caused a concentration-dependent bradycardia of the embryonic heart and at high concentrations heart block. These effects were reversible on washout. In terms of potency to cause bradycardia the compounds were ranked AZB>bupivacaine>AZA>lidocaine>nifedipine. Comparison with results from previous studies with more specific ion channel blockers suggests that the primary effect of AZA and AZB was sodium channel blockage. The study shows that the short-term rat whole embryo culture (WEC) is a suitable system to detect substances hazardous to the embryonic heart. 23911337 Estrogen-, androgen- and aryl hydrocarbon receptor mediated activities in passive and composite samples from municipal waste and surface waters. Passive and composite sampling in combination with in vitro bioassays and identification and quantification of individual chemicals were applied to characterize pollution by compounds with several specific modes of action in urban area in the basin of two rivers, with 400,000 inhabitants and a variety of industrial activities. Two types of passive samplers, semipermeable membrane devices (SPMD) for hydrophobic contaminants and polar organic chemical integrative samplers (POCIS) for polar compounds such as pesticides and pharmaceuticals, were used to sample wastewater treatment plant (WWTP) influent and effluent as well as rivers upstream and downstream of the urban complex and the WWTP. Compounds with endocrine disruptive potency were detected in river water and WWTP influent and effluent. Year-round, monthly assessment of waste waters by bioassays documented estrogenic, androgenic and dioxin-like potency as well as cytotoxicity in influent waters of the WWTP and allowed characterization of seasonal variability of these biological potentials in waste waters. The WWTP effectively removed cytotoxic compounds, xenoestrogens and xenoandrogens. There was significant variability in treatment efficiency of dioxin-like potency. The study indicates that the WWTP, despite its up-to-date technology, can contribute endocrine disrupting compounds to the river. Riverine samples exhibited dioxin-like, antiestrogenic and antiandrogenic potencies. The study design enabled characterization of effects of the urban complex and the WWTP on the river. Concentrations of PAHs and contaminants and specific biological potencies sampled by POCIS decreased as a function of distance from the city. 23816941 18F-Fluoride PET/CT Scan for Quantification of Bone Metabolism in the Inner Ear in Patients With Otosclerosis-A Pilot Study. In otosclerosis, CT of the temporal bone is used to confirm the diagnosis. Whereas CT is a static diagnostic tool displaying the demineralization caused by otosclerosis, imaging of bone metabolism by F-fluoride PET may provide quantitative information. This could be useful for prognosis and stratification of patients. The aim of this study was to assess F-fluoride activity in patients with otosclerosis and to evaluate its use as a complementary diagnostic tool. All patients with otosclerosis underwent a PET/CT scan. Audiometric data were collected. The severity of otosclerosis was assessed using a recognized radiological classification. The control group consisted of patients who had undergone F-fluoride PET/CT scan for orthopedic purpose. Regions of interest were drawn on PET scans which corresponded to standardized anatomical sites as defined on CT, to measure bone metabolism using standardized uptake values (SUVmax and SUVmean). Group 1 consisted of 11 otosclerosis patients (16 eligible temporal bones) and group 2 consisted of 5 control patients (10 temporal bones). On PET scan, visual assessment of temporal bones with otosclerosis showed increased metabolic activity in the otic capsule in 11/16 cases. The SUVmax in the entire otic capsule was significantly higher in otosclerosis patients compared to control subjects. Significant differences in SUVmean were found between otosclerosis and control subjects in the fenestral and saccule area. Moreover, metabolic activity in these regions significantly correlated with hearing loss and CT classification. F-Fluoride PET scanning using SUV measurements has the potential to be a diagnostic tool in otosclerosis. 23878070 Dynamic contrast enhanced MRI parameters and tumor cellularity in a rat model of cerebral glioma at 7 T. To test the hypothesis that a noninvasive dynamic contrast enhanced MRI (DCE-MRI) derived interstitial volume fraction (ve ) and/or distribution volume (VD ) were correlated with tumor cellularity in cerebral tumor. T1 -weighted DCE-MRI studies were performed in 18 athymic rats implanted with U251 xenografts. After DCE-MRI, sectioned brain tissues were stained with Hematoxylin and Eosin for cell counting. Using a Standard Model analysis and Logan graphical plot, DCE-MRI image sets during and after the injection of a gadolinium contrast agent were used to estimate the parameters plasma volume (vp ), forward transfer constant (K(trans) ), ve , and VD . Parameter values in regions where the standard model was selected as the best model were: (mean ± S.D.): vp = (0.81 ± 0.40)%, K(trans) = (2.09 ± 0.65) × 10(-2) min(-1) , ve = (6.65 ± 1.86)%, and VD = (7.21 ± 1.98)%. The Logan-estimated VD was strongly correlated with the standard model's vp + ve (r = 0.91, P < 0.001). The parameters, ve and/or VD , were significantly correlated with tumor cellularity (r ≥ -0.75, P < 0.001 for both). These data suggest that tumor cellularity can be estimated noninvasively by DCE-MRI, thus supporting its utility in assessing tumor pathophysiology. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc. 23746860 The promotion of bone healing by progranulin, a downstream molecule of BMP-2, through interacting with TNF/TNFR signaling. Endochondral ossification plays a key role in the bone healing process, which requires normal cartilage callus formation. Progranulin (PGRN) growth factor is known to enhance chondrocyte differentiation and endochondral ossification during development, yet whether PGRN also plays a role in bone regeneration remains unknown. In this study we established surgically-induced bone defect and ectopic bone formation models based on genetically-modified mice. Thereafter, the bone healing process of those mice was analyzed through radiological assays including X-ray and micro CT, and morphological analysis including histology and immunohistochemistry. PGRN deficiency delayed bone healing, while recombinant PGRN enhanced bone regeneration. Moreover, PGRN was required for BMP-2 induction of osteoblastogenesis and ectopic bone formation. Furthermore, the role of PGRN in bone repair was mediated, at least in part, through interacting with TNF-α signaling pathway. PGRN-mediated bone formation depends on TNFR2 but not TNFR1, as PGRN promoted bone regeneration in deficiency of TNFR1 but lost such effect in TNFR2 deficient mice. PGRN blocked TNF-α-induced inflammatory osteoclastogenesis and protected BMP-2-mediated ectopic bone formation in TNF-α transgenic mice. Collectively, PGRN acts as a critical mediator of the bone healing process by constituting an interplay network with BMP-2 and TNF-α signaling, and this represents a potential molecular target for treatment of fractures, especially under inflammatory conditions. 23911745 Molecular mechanisms of homeostatic synaptic downscaling. Homeostatic synaptic downscaling is a negative feedback response to chronic elevated network activity to reduce the firing rate of neurons. This form of synaptic plasticity decreases the strength of individual synapses to the same proportion, or in a multiplicative manner. Because of this, synaptic downscaling has been hypothesized to counter the potential run-away excitation due to Hebbian type of long term potentiation (LTP), while preserving relative synaptic weight encoded in individual synapses and thus memory information. In this article, we will review the current knowledge on the signaling and molecular mechanisms of synaptic downscaling. Specifically, we focus on three general areas. First the functional roles of several immediate early genes such as Plk2, Homer1a, Arc and Narp are discussed. Secondly, we examine the current knowledge on the regulation of synaptic protein levels by ubiquitination and transcriptional repression in synaptic downscaling. Thirdly, we review the dynamics of signaling molecules such as kinases and phosphatases critical for synaptic downscaling, and their regulation of synaptic scaffolding proteins. Finally we briefly discuss the heterogeneity of homeostatic synaptic downscaling mechanisms. This article is part of a Special Issue entitled 'Homeostatic Plasticity'. 23624301 Micrometastasis in gastric cancer. Circulating tumor cells (CTCs) are a crucial contributor and indicator for cancer metastasis. The presence of CTCs and other two forms of occult disease including circulating tumor microembolus (CTMs) as well as disseminated tumor cells (DTCs) as a sign for micrometastasis has been associated with adverse survival of both localized and metastatic cancers. However, their assignments in micrometastasis are still not well understood. This mini-review is aimed to provide an overview of the biological features and the clinical impact of CTCs, DTCs and CTM in gastric cancer (GC), and to summarize the technical limitations of detection methods in addition to the significance of distinct migration modes in epithelial-mesenchymal transition (EMT) and gastric micrometastasis. Although there are controversies over current CTC identification strategies, both single and collective migration modes as indispensable parts of micrometastasis are influential participants in GC progression, diagnosis and prognosis. CTCs, CTM and DTCs are not separated forms of the occult disease; however available techniques fail to detect all subsets of them. Therefore, micrometastatic detection should be combined with conventional pathological examinations in order to make more accurate predictions of tumor outcomes. Novel markers further defining the features of CTC subsets are warranted. 23688774 The benefit of pretreatment esophageal screening with image-enhanced endoscopy on the survival of patients with hypopharyngeal cancer. Synchronous esophageal cancers can suppress the survival of patients with hypopharyngeal cancers. Esophageal screening with the image-enhanced endoscopy may identify more synchronous cancers while there is no evidence to support its benefit on survival. A total of 281 and 320 patients were diagnosed with hypopharyngeal cancer before and after the policy of routine esophageal screening. Primary outcome measures were overall survival. Among those who received screening, 49 patients (49/180, 27.2%) had synchronous esophageal cancers; treatment planning was changed in 42 (23.3%). Before and after the policy, percentages of stage I-II synchronous cancers were 20% (3/15) and 53.1% (26/49), respectively. Adjunctive therapies for synchronous cancers have led to a better survival after the policy than before (P=0.002). The Cox regression model quantified a survival benefit of 29% (95% CI: 11-43%) when adjusting for TNM stage of hypopharyngeal cancer. In post-policy period, the survival was better for those who chose screening than those who did not (HR: 0.57, 95% CI: 0.41-0.79). Among those without screening, there was no difference between the pre- and post-policy periods (HR: 0.96, 95% CI: 0.74-1.26). Patients with hypopharyngeal cancers may benefit from the esophageal screening with image-enhanced endoscopy through the better detection of early-stage synchronous cancers. 23676770 What is a factorial trial? Randomized controlled trials (RCTs), typically, randomize participants to one of two intervention groups. It has been shown, however, that about 25% of RCTs published in the scientific literature randomize participants to three or more treatment groups. These studies are called 'multi-arm' trials: there may be, for instance, two or more experimental intervention groups with a common control group, or two control intervention groups such as a placebo group and a standard treatment group. A special case of multi-arm studies are factorial trials, which address two or more intervention comparisons carried out simultaneously, using four or more intervention groups. 23792473 Posture affects emotional responses: A Head Down Bed Rest and ERP study. Body posture, mainly represented by horizontal bed rest, has been found to be associated with cortical inhibition, altered perceptual and cognitive processing. In the present research, the influence of Head Down Bed Rest (HDBR) - a condition also termed simulated microgravity - on emotional responses has been studied. Twenty-two male subjects were randomly assigned to either Sitting Control or HDBR group. After 3-h, subjects attended to a passive viewing emotional task in which 75 IAPS slides, divided into 25 pleasant, 25 neutral and 25 unpleasant, were presented in random order for 6s each, while EEG was recorded from F7, F8 and Pz locations. Results showed in Sitting Controls the expected greater P300 and Late Positive Potential (LPP) to pleasant and unpleasant compared with neutral slides, an effect which indicates greater processing of emotional arousing stimuli. The HDBR group showed smaller non-significant differences among all emotional conditions in both ERP components. Arousal and valence subjective evaluations, typically less sensitive to experimental manipulation, did not differentiate groups. The observed ability of HDBR to inhibit cortical emotional responses raises an important issue on the risk that astronauts underestimate a dangerous/threatening situation or that long-term bedridden inpatients develop depressive symptoms. 23860847 Foldamers of β-peptides: conformational preference of peptides formed by rigid building blocks. The first MI-IR spectra of a triamide nanosystem. To determine local chirality driven conformational preferences of small aminocyclobutane-1-carboxylic acid derivatives, X-(ACBA) n -Y, their matrix-isolation IR spectra were recorded and analyzed. For the very first time model systems of this kind were deposited in a frozen (~10 K) noble gas matrix to reduce line width and thus, the recorded sharp vibrational lines were analyzed in details. For cis-(S,R)-1 monomer two "zigzag" conformers composed of either a six or an eight-membered H-bonded pseudo ring was identified. For trans-(S,S)-2 stereoisomer a zigzag of an eight-membered pseudo ring and a helical building unit were determined. Both findings are fully consistent with our computational results, even though the relative conformational ratios were found to vary with respect to measurements. For the dimers (S,R,S,S)-3 and (S,S,S,R)-4 as many as four different cis,trans and three different trans,cis conformers were localized in their matrix-isolation IR (MI-IR) spectra. These foldamers not only agree with the previous computational and NMR results, but also unambiguously show for the first time the presence of a structure made of a cis,trans conformer which links a "zigzag" and a helical foldamer via a bifurcated H-bond. The present work underlines the importance of MI-IR spectroscopy, applied for the first time for triamides to analyze the conformational pool of small biomolecules. We have shown that the local chirality of a β-amino acid can fully control its backbone folding preferences. Unlike proteogenic α-peptides, β- and especially (ACBA) n type oligopeptides could thus be used to rationally design and influence foldamer's structural preferences. 23914738 Knowledge, attitude and practice towards voluntary counseling and testing among university students in North West Ethiopia: a cross sectional study. Voluntary counseling and testing (VCT) is one among different approaches which have been implemented as an attempt to slow the spread of HIV infection and minimize its impact at the individual, family and society level. VCT is perceived to be an effective strategy in risk reduction among sexually active young people like tertiary level students. Ethiopia as a country with high burden of HIV started responding to the epidemic by preparing and updating guidelines on VCT. The objective of this study was to assess the level of knowledge, attitude and practice of Voluntary Counseling and Testing (VCT) for HIV among university students in North West Ethiopia. A cross sectional study was conducted from February to May 2010 using a stratified sampling method to enroll students from different faculties into the study. A total of 330 university students filled in a self-administered questionnaire with response rate of 97.3%. Main outcome measures included level of knowledge, attitude and practice of VCT for HIV. A chi-square test was used to determine an association between a number of independent factors and dependant variables.Result: About 66.1% of the study participants were males with a mean age of 20 years. Majority (75.6%) of the respondents were Orthodox with 63% reported living in urban areas before joining the university. From the study participants 86.3% were knowledgeable on VCT, 73.3% had positive attitude towards VCT for HIV and 61.8% had had VCT for HIV in the past. Previous residence before joining the university, level of education, sex and religion were among the sociodemographic variables that showed statistically significant association with the one or more of the outcome variables. Fear of positive results, stigma and discrimination following the positive results were reported as main barriers for VCT uptake. The findings reveal important barriers for VCT uptake and suggest strategies to reduce stigma and discrimination. 23578259 Tuning the Electrical and Optical Properties of Graphene by Ozone Treatment for Patterning Monolithic Transparent Electrodes. Tunable electrical and optical properties of graphene are vital to promote its use as film electrodes in a variety of devices. We developed an etching-free ozone treatment method to continuously tune the electrical resistance and optical transmittance of graphene films by simply varying the time and temperature of graphene exposure to ozone. Initially, ozone exposure dramatically decreases the electrical resistance of graphene films by p-doping, but this is followed by increases in the resistance and optical transmittance as a result of surface oxidation. The rate of resistance increase can be significantly increased by raising the treatment temperature. The ozone-oxidized graphene is not removed but is gradually transformed to graphene oxide (GO). On the basis of such effects of ozone treatment, we demonstrate a well-defined graphene pattern by using ozone photolithography, in which the ozone-treated graphene electrodes are monolithic but separated by insulating GO regions. Such a monolithic graphene pattern shows low optical contrast, a clean and more hydrophilic surface, indicating the promising use of ozone treatment to achieve high-performance graphene-based optoelectronic devices. 22962847 Work engagement supports nurse workforce stability and quality of care: nursing team-level analysis in psychiatric hospitals. Burnout and work engagement are two sides of one coin, two opposite poles related not only to how workers personally experience their jobs but also to how they experience their jobs within the context of work teams/groups. Engaged workers have a lot of energy, are very enthusiastic about their jobs and are absorbed by their work. Nurses' job performance in hospitals, including psychiatric hospitals, is dependent upon their relationships with physicians and other healthcare workers and their superiors, how they are involved in the decisions about their work and whether or not they are provided with the right resources and adequate support. When nursing teams are able to perform well, nurses tend to be more engaged and satisfied with their jobs and are more willing to stay in their positions. Engaged nursing teams report better quality of patient care in psychiatric hospitals. Research in healthcare settings reveals important links between work environment factors, burnout and organizational outcomes. Recently, research focuses on work engagement, the opposite (positive) pole from burnout. The current study investigated the relationship of nurse practice environment aspects and work engagement (vigour, dedication and absorption) to job outcomes and nurse-reported quality of care variables within teams using a multilevel design in psychiatric inpatient settings. Validated survey instruments were used in a cross-sectional design. Team-level analyses were performed with staff members (n = 357) from 32 clinical units in two psychiatric hospitals in Belgium. Favourable nurse practice environment aspects were associated with work engagement dimensions, and in turn work engagement was associated with job satisfaction, intention to stay in the profession and favourable nurse-reported quality of care variables. The strongest multivariate models suggested that dedication predicted positive job outcomes whereas nurse management predicted perceptions of quality of care. In addition, reports of quality of care by the interdisciplinary team were predicted by dedication, absorption, nurse-physician relations and nurse management. The study findings suggest that differences in vigour, dedication and absorption across teams associated with practice environment characteristics impact nurse job satisfaction, intention to stay and perceptions of quality of care. 23848295 Unexpected MH deaths without exposure to inhalation anesthetics in pediatric patients. Children, later found to have ryanodine receptor type one variants (RYR1), died without exposure to inhalation anesthetics. Family members with the same RYR1 variants had contracture tests consistent with susceptibility to malignant hyperthermia or in vitro testing showed increased sensitivity to RYR1 agonist. 23892468 Rheumatoid forefoot deformity: pathophysiology, evaluation and operative treatment options. Despite recent advances in pharmacological management of rheumatoid arthritis, forefoot deformity, with its symptoms, remains a common problem, often requiring operative treatment. Typical deformities in these patients comprise hallux valgus and deformity of the lesser metatarsophalangeal (MTP) joints and toes. With regard to the lesser rays the standard operative procedure, advocated for the disabling forefoot pain in these patients, remains metatarsal head resection. It should be considered that with increasing success of pharmacological treatment the degree of forefoot deformity in these patients is becoming less and that resection of the lesser MTP joints is becoming more and more superfluous. This supports a trend towards metatarsal head-preserving surgery. The optimal treatment of the hallux deformity remains unclear. Fusion of the first MTP joint is, generally, recommended. This article will discuss the current surgical options in rheumatoid forefoot pathology. 23903760 Chemopreventive effect of zingerone against colon carcinogenesis induced by 1,2-dimethylhydrazine in rats. Zingerone [4-(4-hydroxy-3-methoxyphenyl)-2-butane], one of the active phenolic components isolated from Zingiber officinale, has antioxidant and anticarcinogenic properties. In our study, we have evaluated the effect of different doses of zingerone on lipid peroxidation (thiobarbituric acid-reactive substances, lipid hydroxyl radical and conjugated dienes), tissue enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase), and nonenzymatic antioxidants (reduced glutathione, vitamin E, vitamin C), and also the formation of aberrant crypt foci (ACF) in male albino Wistar rats with colon cancer induced using 1,2-dimethylhydrazine (DMH). The rats were divided into six groups. Group 1 served as a control group and received a modified pellet diet; the rats in group 2 received a modified pellet diet along with zingerone (40 mg/kg b.w., orally every day); groups 3-6 were administered DMH (20 mg/kg b.w., subcutaneously) once a week for the first 4 weeks; and groups 4-6 received zingerone at three different doses of 10, 20 and 40 mg/kg b.w., respectively, every day for 16 weeks. Increased tumour incidence and ACF formation were accompanied by a decrease in the tissue lipid peroxidation, enzymatic and nonenzymatic antioxidant activities observed in the colon of DMH-treated rats. Supplementation with zingerone in DMH-treated rats led to a significant decrease in the tumour incidence and ACF formation with simultaneous modulation in the level of tissue lipid peroxidation and antioxidant status. Thus, in conclusion, we can suggest that zingerone effectively inhibits DMH-induced colon carcinogenesis in male Wistar rats. 23962537 Immunogenicity and safety of HCV E1E2 peptide vaccine in chronically HCV-infected patients who did not respond to interferon based therapy. Antibody mediated neutralization and specific cell mediated immunity are necessary to combat HCV infection. Viral load reduction following administration of non adjuvanted envelope peptide vaccine was investigated in chronic HCV-infected patients who did not respond to interferon and ribavirin (IFN+RBV) treatment. The roles of humoral and cellular arms in viral load decline were examined and tolerability was evaluated. In an open-label study, patients with mild CHC (genotype 4a) were enrolled in 2 groups of 14 patients each; they received subcutaneous injections of Cenv3 at 648μg×3 monthly doses (group I) and 324μg×6 biweekly doses (group II). Vaccine sera were examined for specific antibody titers against vaccine epitopes by ELISA, HCV RNA levels by real-time PCR and specific CD4(+)/CD8(+) T lymphocytes by enzyme-linked immunospot assay (ELIspot). Safety of Cenv3 vaccination was tested on bases of changes in liver functions, kidney function and blood cell counts. Cenv3 induced significant in antibody mediated viral neutralization and cellular responses with remarkable decline of HCV RNA in about two thirds of patients under study. The product is safe and tolerable with slight improvement in liver functions and platelet counts. Although, humoral and cellular arms of the immune system are usually impaired in CHC, the selected envelope epitopes were able to induce responses sufficient to reduce significantly viral RNA concentrations in chronic HCV-infected patients shown to be non responders to standard of care treatment. The observed immunogenicity and tolerability of Cenv3 paves the road for further studies toward development of a prophylactic vaccine against HCV. The clinical trial was registered in the ClinicalTrials.gov; under the identifier no.: NCT01718834. 23884047 Applying Quality Function Deployment Model in Burn Unit Service Improvement. Quality function deployment (QFD) is one of the most effective quality design tools. This study applies QFD technique to improve the quality of the burn unit services in Ghotbedin Hospital in Shiraz, Iran. First, the patients' expectations of burn unit services and their priorities were determined through Delphi method. Thereafter, burn unit service specifications were determined through Delphi method. Further, the relationships between the patients' expectations and service specifications and also the relationships between service specifications were determined through an expert group's opinion. Last, the final importance scores of service specifications were calculated through simple additive weighting method. The findings show that burn unit patients have 40 expectations in six different areas. These expectations are in 16 priority levels. Burn units also have 45 service specifications in six different areas. There are four-level relationships between the patients' expectations and service specifications and four-level relationships between service specifications. The most important burn unit service specifications have been identified in this study. The QFD model developed in the study can be a general guideline for QFD planners and executives. 23926267 Arctigenin Effectively Ameliorates Memory Impairment in Alzheimer's Disease Model Mice Targeting Both β-Amyloid Production and Clearance. Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The β-amyloid (Aβ)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aβ production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aβ production by suppressing β-site amyloid precursor protein cleavage enzyme 1 expression and promote Aβ clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aβ formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery. 23716129 MicroRNAs as Biomarkers for Ischemic Heart Disease. MicroRNAs (miRs) are short, noncoding RNAs that function as posttranscriptional inhibitors of mRNA translation to protein. They are essential for normal development and homeostasis. Dysregulated expression patterns both cause and result from disease states. Generally studied as intracellular mediators, miRs can be isolated from body fluids and exhibit remarkable stability to degradation. These features, in combination with their tissue specificity, make miRs attractive candidates as blood-derived biomarkers for coronary artery disease (CAD), the most frequent cause of death worldwide. The use of miRs as biomarkers in both symptomatic and asymptomatic CAD and the influence of conventional cardiovascular risk factors and CAD treatment on their circulating levels are the topics of this review. To conclude, it highlights the remaining hurdles to tackle before this promising application of miRs can enter into routine clinical practice. 23871327 Ultrasound of the Inferior Vena Cava Does Not Predict Hemodynamic Response to Early Hemorrhage. Ultrasonographic evaluation of the inferior vena cava (IVC) provides information on central hemodynamics and predicts fluid responsiveness during positive pressure ventilation. In spontaneously breathing patients, the correlations between IVC dynamics and the hemodynamic response to volume shifts remain to be described. We aimed to describe the correlation between IVC dynamics and the changes in cardiac output (CO) caused by controlled hemorrhage. Healthy donors from the blood bank were eligible for inclusion. Measurements of the IVC and CO were performed before and immediately after blood donation using ultrasound methods. A control group served to evaluate the effect of resting. Thirty-seven participants completed the study. IVC collapsibility index (IVC-CI) and IVC end expiratory diameter (IVCe) both changed significantly after blood donation (p < 0.001). The baseline IVC-CI and IVCe did not correlate with the change in CO (p-values ≥ 0.40). The alterations in IVC-CI and IVCe induced by blood donation also did not correlate with the change in CO (p ≥ 0.71). The sensitivities of IVC-CI or IVCe, defined as an increase in IVC-CI and a decrease in IVCe, for picking up any decrease in CO were 81.3% and 84.4%, respectively. In the control group, no effect was seen between measurements. IVC-CI and IVCe did not correlate with the magnitude of hemodynamic response to early hemorrhage. The sensitivity of serial IVC measurements was approximately 80% for detecting early blood loss. 23875929 Hidden consequences of olfactory dysfunction: a patient report series. The negative consequences of olfactory dysfunction for the quality of life are not widely appreciated and the condition is therefore often ignored or trivialized. 1,000 patients with olfactory dysfunction participated in an online study by submitting accounts of their subjective experiences of how they have been affected by their condition. In addition, they were given the chance to answer 43 specific questions about the consequences of their olfactory dysfunction. Although there are less practical problems associated with impaired or distorted odor perception than with impairments in visual or auditory perception, many affected individuals report experiencing olfactory dysfunction as a debilitating condition. Smell loss-induced social isolation and smell loss-induced anhedonia can severely affect quality of life. Olfactory dysfunction is a serious condition for those affected by it and it deserves more attention from doctors who treat affected patients as well as from scientist who research treatment options. 23523985 Mental imagery, emotion and psychopathology across child and adolescent development. Mental imagery-based interventions are receiving increasing interest for the treatment of psychological disorders in adults. This is based on evidence that mental imagery potently influences the experience of emotion in non-clinical samples, and that a number of psychological disorders are marked by syndrome-specific, distressing abnormalities in mental imagery. During childhood and adolescence, neurocognitive development impacting mental imagery processes may moderate its relationship with clinically-relevant emotional symptoms at a number of potential loci. Crucially, these changes could impact vulnerability to distressing mental imagery and the efficacy of mental imagery-based clinical interventions. This review synthesises evidence pertaining to developmental changes in the role and content of mental imagery, and in the cognitive sub-processes required to generate and sustain mental images. Subsequently, we discuss implications for understanding the developmental relationship between mental imagery, emotion and psychopathology. Translational cognitive neuroscience research investigating the content, emotional impact and neurocognitive substrates of mental imagery across development may reveal insights into trajectories of vulnerability to symptoms of a number of psychological disorders. If proper consideration is given to developmental factors, techniques based on mental imagery may be valuable as part of a treatment armoury for child and adolescent clinical populations and those at risk of emotional disorders. 23939896 In Vitro Characterization of GSK5852, a Novel HCV Polymerase Inhibitor. GSK5852 is an HCV NS5B polymerase inhibitor with EC50 values in the low nanomolar range in the genotype 1 and 2 subgenomic replicon system as well as the infectious HCV cell-culture system. We have characterized the antiviral activity of GSK5852 using chimeric replicon systems with NS5B genes from additional genotypes as well as NS5B sequences from clinical isolates of patients infected with HCV of genotypes 1a and 1b. The inhibitory activity of GSK5852 remained unchanged on these intergenotypic and intragenotypic replicon systems. GSK5852 furthermore displays an excellent resistance profile and shows less than a five-fold potency loss across clinically important NS5B resistance mutations P495L, M423T, C316Y or Y448H. Testing of a diverse mutant panel also revealed a lack of cross resistance against known resistance mutations in other viral proteins. Data from both newer 454 and traditional population sequencing showed a pattern of mutations arising in the NS5B RNA dependent RNA polymerase in replicon cells exposed to GSK5852. GSK5852 was more potent than HCV-796, an earlier inhibitor in this class, and showed greater reductions in HCV RNA during long term treatment of replicons. GSK5852 is similar to HCV-796 in its activity against multiple genotypes but its superior resistance profile suggests that it could be an attractive component of an all oral regimen for treating HCV. 23125075 Engaging consumers in medicaid nursing home reimbursement policy: lessons from new york and Minnesota. Purpose of the Study: This study draws lessons for successful consumer engagement in Medicaid nursing home (NH) reimbursement policy from New York and Minnesota. In these two states, resident advocates have influenced reimbursement policy to better encourage access, care quality, and quality of life. Twenty-four semi-structured interviews were conducted, including consumer advocates, state agency officials, legislators/legislative staff, and NH industry representatives. Transcripts were coded to identify recurring themes and patterns in responses. Related documents were reviewed as well. Findings: Interviewees report that consumer advocates should participate in NH reimbursement policy making to provide a unique perspective distinct from other stakeholder groups. Skills necessary for successful participation include developing, demonstrating, and sharing expertise to gain credibility as a legitimate actor. Effective strategies include participating on state workgroups and taskforces and developing and accessing relationships with key legislative and executive branch officials. A division of labor may be useful with those consumer advocates possessing expertise in NH reimbursement policy partnering with other organizations with the experience and resources necessary to marshal grassroots support. State and federal reimbursement reform provide opportunities for consumer advocacy influence during the design and implementation process. The experience of consumer groups in New York and Minnesota provide lessons for advocates looking to influence these and other reimbursement initiatives. 23915740 Tailoring adjuvant treatments for the individual patient with luminal breast cancer. Estrogen Receptor-positive/HER-2 negative breast cancers represent a heterogeneous group of tumors. Luminal A and B tumor subtypes can be identified through immunohistochemical assessment of estrogen and progesterone receptor, Ki-67 and HER-2 status. Patients with high levels of expression of steroid hormone receptors and low proliferation (Luminal A) are commonly cured with endocrine therapy alone. Patients with doubtful endocrine responsiveness or with high proliferation index (Luminal B/Her-negative) require the addition of chemotherapy to the best endocrine therapy. Controversies still exist on the identification of those patients who do not benefit from chemotherapy. Tailored adjuvant treatments should be considered in the therapeutic algorithm of patients with luminal tumors. 23463238 Novel insights into the biology of interleukin-32. Interleukin (IL)-32 is known as a proinflammatory cytokine that is likely involved in several diseases, including infections, chronic inflammation, and cancer. Since the first report in 2005, IL-32 has been the subject of numerous studies to unravel the biological function of this molecule. For example, silencing of endogenous IL-32 in primary or cell lines of human origin consistently suppressed responses to Toll-like receptors. The protein folding structure of the six isoforms of IL-32 does not resemble that of any classical cytokine and as of this writing, a specific IL-32 receptor has not been identified. Instead, we propose a mechanism by which exposure to extracellular IL-32 or overexpression of the molecule results in binding to intracellular partners that influences functions such as gene expression, cell death, or survival. As such, this review offers insights into the role of IL-32 in several diseases, host defense, inflammation, immune function, and cancer. Finally, possibilities to target IL-32 in several diseases are proposed. 23568605 Linezolid versus vancomycin or teicoplanin for nosocomial pneumonia: meta-analysis of randomised controlled trials. Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of nosocomial pneumonia. Compared with glycopeptide antibiotics, linezolid achieves higher lung epithelial lining fluid concentrations, which may have an advantage in treating nosocomial pneumonia patients. The objective of this study was to evaluate the efficacy and safety of linezolid versus vancomycin or teicoplanin for the treatment of nosocomial pneumonia. Data were obtained from the Cochrane Central Register of Controlled Trials and the EMBASE and MEDLINE databases. Randomised controlled studies involving the use of linezolid versus vancomycin or teicoplanin in nosocomial pneumonia patients were included in the study. Twelve linezolid trials were included. There was no statistically significant difference between the two groups in the treatment of nosocomial pneumonia regarding the clinical cure rate [relative risk (RR) = 1.08, 95 % confidence interval (CI) = 1.00-1.17, p = 0.06]. Linezolid was associated with better microbiological eradication rate in nosocomial pneumonia patients compared with glycopeptide antibiotics (RR = 1.16, 95 % CI = 1.03-1.31, p = 0.01). There were no differences in the all-cause mortality (RR = 0.95, 95 % CI = 0.83-1.09, p = 0.46) between the two groups. However, the risks of rash (RR = 0.41, 95 % CI = 0.24-0.71, p = 0.001) and renal dysfunction (RR = 0.41, 95 % CI = 0.27-0.64, p < 0.0001) were higher with glycopeptide antibiotics. Although linezolid was more effective in eradicating microbiology than glycopeptide antibiotics for nosocomial pneumonia patients, it did not demonstrate superiority in clinical cure. The incidences of renal dysfunction and rash are higher in the glycopeptide antibiotics group. 23673242 Solvent modulated photophysics of 9-methyl anthroate: exploring the effect of polarity and hydrogen bonding on the emissive state. Photophysical properties of an anthracene derivative 9-methyl anthroate (9-MA) have been investigated using absorption and emission spectroscopy, in combination with quantum chemical calculations. Solvatochromic effects on the Stokes shifted emission band clearly demonstrate the highly polar character of the excited state, which is also supported by the enhancement of dipole moment of the molecule upon photoexcitation. The emission band has been found to be dependent on polarity and hydrogen-bonding ability of the solvents. Multiple linear regression analysis method has been utilized to rationalize the effect of hydrogen bonding interaction on the emissive state, which was further confirmed by the analysis of the non-radiative decay constants and urea induced H-bonding disruption study. The experimental results correlate well with theoretical predictions obtained via density functional theory (DFT). 23246619 Development and evaluation of colloidal modified nanolipid carrier: Application to topical delivery of tacrolimus, Part II -In vivo assessment, drug targeting, efficacy, and safety in treatment for atopic dermatitis. In atopic dermatitis (AD), topical anti-inflammatory therapy with skin barrier restoration to prevent repeated inflammatory episodes leads to long-term therapeutic success. Tacrolimus, although effective against AD, is a challenging molecule due to low solubility, low-penetration, poor-bioavailability, and toxicity. Part I of this paper, reported novel modified nanolipid carrier system for topical delivery of tacrolimus (T-MNLC), offering great opportunity to load low-solubility drug with improved entrapment efficiency, enhanced stability and improved skin deposition. Present investigation focused on restoration of skin barrier, site-specific delivery, therapeutic effectiveness, and safety of novel T-MNLC. T-MNLC greatly enhanced occlusive properties, skin hydration potential and reduced transepidermal water loss. This might help to reduce the number of flares and better control the disease. Cutaneous uptake and drug deposition in albino rats by HPLC and confocal laser scanning microscopy revealed prominently elevated drug levels in all skin strata with T-MNLC as compared to reference. T-MNLC demonstrated efficient suppression of inflammatory responses in BALB/c mice model of AD. Safety assessment by acute and repeated-dose dermal toxicity demonstrated mild keratosis and collagenous mass infiltration at the treatment area with repeated application of reference. Interestingly, T-MNLC showed no evident toxicity exhibiting safe drug delivery. Thus, novel T-MNLC would be a safe, effective, and esthetically appealing alternative to conventional vehicles for treatment for AD. 23770106 Periodic and chaotic dynamics in a map-based model of tumor-immune interaction. Clinicians and oncologists believe that tumor growth has unpredictable dynamics. For this reason they encounter many difficulties in the treatment of cancer. Mathematical modeling is a great tool to improve our better understanding of the complicated biological system of tumor growth. Also, it can help to identify states of the disease and as a result help to predict later behaviors of the tumor. Having an insight into the future behaviors of the tumor can be very useful for the oncologists and clinicians to decide on the treatment method and dosage of the administered drug. This paper suggests that a suitable model for the tumor growth system should be a discrete model capable of exhibiting periodic and complex chaotic dynamics. This is the key feature of the proposed model. The model is validated here through experimental data and its potential dynamics are analyzed. The model can explain many biologically observed tumor states and dynamics, such as exponential growth, and periodic and chaotic behaviors in the steady states. The model shows that even an avascular tumor could become invasive under certain conditions. 23482378 Antihypertensive actions of moderate hyperbilirubinemia: role of superoxide inhibition. Moderate (approximately 2-fold) increases in plasma unconjugated bilirubin levels are able to attenuate the development of angiotensin II (Ang II)-dependent hypertension. To determine the specific role of decreases in superoxide production to the blood pressure-lowering effects of moderate hyperbilirubinemia (MHyB), we performed this study, in which the Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin was given to Ang II-infused mice in the presence and absence of moderate hyperbilirubinemia. Apocynin (14mM) was administered in the drinking water prior to treatment with UDP-glucuronosyltransferase 1A1 antisense morpholino (16 μg/kg), which was administered by intravenous injection every third day. Treatments were started before the implantation of Ang II-containing minipumps (1μg/kg/min) and continued throughout the protocol. Ang II infusion increased blood pressure to 145±2mm Hg. Apocynin treatment alone reduced blood pressure to 135±5mm Hg, whereas MHyB alone decreased blood pressure to 118±5mm Hg in Ang II-infused mice. Prior inhibition of NADPH oxidase with apocynin did not result in a further decrease in blood pressure in MHyB mice, which averaged 117±3mm Hg (n = 6 mice per group). In aortic preparations, apocynin treatment decreased Ang II-mediated superoxide production from 2433±120 relative light units (RLU)/min/mg to 1851±126 RLU/min/mg (n = 4 mice per group), which was similar to levels observed in MHyB mice alone (1473±132 RLU/min/mg) or in combination with apocynin (1503±115 RLU/min/mg). Our results indicate that MHyB lowers blood pressure by a mechanism that is partially dependent on the inhibition of superoxide production. 23161352 The role of microbial communities in parturition: is there evidence of association with preterm birth and perinatal morbidity and mortality? In 2005, the World Health Organization estimated that 9.6% or 12.9 million births worldwide were born preterm at <37 weeks of gestation and were accompanied by a mortality rate as high as 42% (http://www.who.int/bulletin/volumes/88/1/08-062554). Significant data suggesting that intrauterine infection is an important modifier for the risk of preterm birth have emerged over the past four decades. However, causative microbial culprits have yet to be identified, and interventional trials with antimicrobials have uniformly failed to demonstrate a significant benefit. To the contrary, treatment for clinically asymptomatic, commonly associated polymicrobial communities (i.e., bacterial vaginosis) has resulted in an increase in the rate of preterm birth. This article discusses the importance of vaginal microbiome and the variance in its composition during normal pregnancy. We will expand this discussion to include possible mechanisms that might trigger preterm birth in at-risk subjects. Finally, we will review why preterm birth may be an ideal forum with which to apply our rapidly expanding metagenomic sequencing and analytic pipelines to discern the role of host and microbe in the relative continuum of health and disease. 23883541 Vitamin D supplementation restores suppressed synaptic plasticity in Alzheimer's disease. Hippocampus, an appropriate area of brain for assessment of long-term potentiation (LTP), has been found to be susceptible to neural damages caused by Alzheimer's disease. Evidence indicates that vitamin D supports nerve transmission and synaptic plasticity. Vitamin D receptors are expressed in the hippocampus. The present study evaluates occurrence of LTP in the control (CON) group fed with normal regimen and, three groups of Aβ-treated rats taking normal (ALZ), vitamin D-free (ALZ - D), or 1,25(OH)2D3 supplemented (ALZ + D) food regimens. In in vivo experiments pre- and post-tetanus field extracellular postsynaptic potentials (fEPSPs) were recorded in the CA3-CA1 pathway. We found that the amplitude of baseline fEPSPs was significantly lower in the ALZ group compared with the CON one; lack of vitamin D further declined the amplitude of responses in the ALZ - D animals. While the tetanic stimulation elicited a considerable LTP in the CON rats it was failed to induce LTP in the ALZ animals. Furthermore, the tetanus considerably depressed the amplitude of recordings in the ALZ - D group. 1,25(OH)2D3 supplementation restored post-tetanus potentiation of fEPSPs amplitude in the ALZ + D groups. The present findings signify the crucial role of vitamin D on the basic synaptic transmission and synaptic plasticity. 23215155 Super-resolution mapping of reactive sites on titania-based nanoparticles with water-soluble fluorogenic probes. Interfacial charge transfer at the heterogeneous surface of semiconductor nanoparticles is a fundamental process that is relevant to many important applications, such as photocatalysis, solar cells, and sensors. In this study, we developed new water-soluble fluorogenic probes for interfacial electron transfer reactions on semiconductor nanoparticles. The synthesized boron-dipyrromethene-based fluorescence dyes have one or two sulfonate groups, which confer solubility in aqueous media, and a dinitrophenyl group as a redox reaction site. These probes produce the corresponding fluorescent products via multiple interfacial electron transfer processes, allowing us to investigate the photoinduced redox reactions over individual pristine and Au-nanoparticle-deposited TiO(2) nanoparticles at the single-particle, single-molecule levels. The minimum probe concentration to detect single-product molecules on a single TiO(2) nanoparticle was found to be in the nanomolar range (<10 nM) in acidic solution. Furthermore, super-resolution mapping of the reaction sites revealed that visible-light-induced reduction reactions preferentially occurred on the TiO(2) surface within a distance of a few tens of nanometers around the deposited Au nanoparticles. This result was qualitatively interpreted on the basis of plasmon-induced electron and/or energy transfer mechanisms. Overall, this study provides a great deal of valuable information related to solar-energy-conversion processes that is impossible or difficult to obtain from ensemble-averaged experiments. 23957795 A review of treatment and management modalities for premenstrual dysphoric disorder. Premenstrual dysphoric disorder (PMDD) affects 5 to 8 percent of women and can significantly decrease their quality of life. Symptoms generally present during the late luteal phase of the menstrual cycle and can affect women emotionally, behaviorally, cognitively and physiologically. This article reviews the clinical literature on PMDD and the evidence behind various methods of symptom management. Evidence suggests that a holistic approach, including lifestyle modifications, pharmacotherapy and cognitive behavioral therapy, is most beneficial for symptom reduction and improvement in daily functioning and quality of life. 23907061 Wogonin induced G1 cell cycle arrest by regulating Wnt/β-catenin signaling pathway and inactivating CDK8 in human colorectal cancer carcinoma cells. Wogonin, a naturally occurring mono-flavonoid, has been reported to have tumor therapeutic potential and good selectivity both in vitro and in vivo. Herein, we investigated the anti-proliferation effects and associated mechanisms of wogonin in human colorectal cancer in vitro. The flow-cytometric analysis showed that wogonin induced a G1 phase cell cycle arrest in HCT116 cells in a concentration- and time-dependent manner. Meanwhile, the cell cycle-related proteins, such as cyclin A, E, D1, and CDK2, 4 were down-regulated in wogonin-induced G1 cell cycle arrest. Furthermore, we showed that the anti-proliferation and G1 arrest effect of wogonin on HCT116 cells was associated with deregulation of Wnt/β-catenin signaling pathway. Wogonin-treated cells showed decreased intracellular levels of Wnt proteins, and activated degradation complex to phosphorylated and targeted β-catenin for proteasomal degradation. Wogonin inhibited β-catenin-mediated transcription by interfering in the transcriptional activity of TCF/Lef, and repressing the kinase activity of CDK8 which has been considered as an oncogene involving in the development of colorectal cancers. Moreover, CDK8 siRNA-transfected HCT116 cells showed similar results to wogonin treated cells. Thus, our data suggested that wogonin induced anti-proliferation and G1 arrest via Wnt/β-catenin signaling pathway and it can be developed as a therapeutic agent against human colorectal cancer. 23874379 Re-Annotation of Protein-Coding Genes in the Genome of Saccharomyces cerevisiae Based on Support Vector Machines. The annotation of the well-studied organism, Saccharomyces cerevisiae, has been improving over the past decade while there are unresolved debates over the amount of biologically significant open reading frames (ORFs) in yeast genome. We revisited the total count of protein-coding genes in S. cerevisiae S288c genome using a theoretical approach by combining the Support Vector Machine (SVM) method with six widely used measurements of sequence statistical features. The accuracy of our method is over 99.5% in 10-fold cross-validation. Based on the annotation data in Saccharomyces Genome Database (SGD), we studied the coding capacity of all 1744 ORFs which lack experimental results and suggested that the overall number of chromosomal ORFs encoding proteins in yeast should be 6091 by removing 488 spurious ORFs. The importance of the present work lies in at least two aspects. First, cross-validation and retrospective examination showed the fidelity of our method in recognizing ORFs that likely encode proteins. Second, we have provided a web service that can be accessed at http://cobi.uestc.edu.cn/services/yeast/, which enables the prediction of protein-coding ORFs of the genus Saccharomyces with a high accuracy. 23711840 High coral cover and subsequent high fish richness on mature breakwaters in Taiwan. Breakwaters are widely used in coastal development. Breakwaters can alter habitats by undermining shallow coastal ecosystems, especially coral reefs. However, recent studies indicate that mature breakwaters can have well-developed corals and coral-associated fishes. Breakwaters with colonized corals may act as surrogates of natural coral reefs against the global coral crisis. Here, we examined the composition of corals, fishes, and benthic biota/abiota between natural reefs and mature breakwaters to evaluate the possibility of breakwaters supplementing natural reefs. We found equal or higher coral cover, fish abundance, and species richness on breakwaters. Conversely, differential coral growth forms and fish assemblages on mature breakwaters suggested the irreplaceability of natural reefs. Corals and coral reef fishes on mature man-made structures, however, may improve the resistance and resilience of coral reefs. Conclusively, despite high coral cover on mature man-made structures appropriate management (e.g., marine reserves) is still necessary to sustain the coral reefs. 23395825 Elevation of 4-hydroxynonenal and malondialdehyde modified protein levels in cerebral cortex with cognitive dysfunction in rats exposed to 1-bromopropane. 1-Bromopropane (1-BP), an alternative to ozone-depleting solvents (ODS), exhibits central nervous system (CNS) toxicity in animals and humans. This study was designed to relate CNS damage by Morris water maze (MWM) test and oxidative stress to 1-BP exposure in the rat. Male Wistar rats were randomly divided into 4 groups (n=10), and treated with 0, 200, 400 and 800mg/kgbw 1-BP for consecutive 12 days, respectively. From day 8 to day 12 of the experiment, MWM test was employed to assess the cognitive function of rats. The cerebral cortex of rats was obtained immediately following the 24h after MWM test conclusion. Glutathione (GSH), oxidized glutathione (GSSG) and total thiol (total-SH) content, GSH reductase (GR) and GSH peroxidase (GSH-Px) activities, malondialdehyde (MDA) level, as well as 4-hydroxynonenal (4-HNE) and MDA modified proteins in homogenates of cerebral cortex were measured. The obtained results showed that 1-BP led to cognitive dysfunction of rats, which was evidenced by delayed escape latency time and swimming distances in MWM performance. GSH and total-SH content, GSH/GSSG ratio, GR activity significantly decreased in cerebral cortex of rats, coupling with the increase of MDA level. 4-HNE and MDA modified protein levels obviously elevated after 1-BP exposure. GSH-Px activities in cerebral cortex of rats also increased. These data suggested that 1-BP resulted in enhanced lipid peroxidation of brain, which might play an important role in CNS damage induced by 1-BP. 23860346 Covert dyskinesia associated with aripiprazole: a case report and review of the literature. The atypical antipsychotic agents are felt by many to have a lower risk of inducing the development of dyskinetic movements than the conventional antipsychotic agents agents such as haloperidol and fluphenazine. However, that does not mean that treatment with the atypical antipsychotic agents carries no risk of developing dyskinesias. To the contrary, all of the atypical antipsychotic agents, including aripiprazole, have been associated with the induction of dyskinetic movements. We will present the case of a patient who developed a covert dyskinesia that manifested shortly after the discontinuation of aripiprazole. We will review the use of aripiprazole and the adverse effects most commonly associated with its use. We will also discuss the risk factors associated with the development of tardive dyskinesia and review the different clinical variations (withdrawal dyskinesia, covert dyskinesia, tardive diskinesia) of medication-induced dyskinesias. 23891602 Major trauma registry of Navarre (Spain): the accuracy of different survival prediction models. To determine which factors predict death among trauma patients who are alive on arrival at hospital. Design prospective cohort study method. Data were collected on 378 trauma patients who were initially delivered by the emergency medical services of Navarre (Spain) with multiple injuries with a new injury severity score of 15 or more in 2011-2012. These data related to age, gender, presence of premorbid conditions, abbreviated injury score, injury severity score, new injury severity score (NISS), revised trauma score (RTS), and prehospital and hospital response times. Bivariate analysis was used to show the association between each variable and time until death. Mortality prediction was modeled using logistic regression analysis. The variables related to the end result were the age of the patient, associated comorbidity, NISS, and hospital RTS. Two models were formulated: in one, the variables used were quantitative, while in the other model these variables were converted into dichotomous qualitative variables. The predictive capability of the two models was compared with the trauma and injury severity score using the area under the curve. The predictive capacities of the three models had areas under the curve of 0.93, 0.88, and 0.87. The response times of the Navarre emergency services system, measured as the sum of the time taken to reach the hospital (median time of 65 min), formulate computed tomography (46 min), and perform crucial surgery (115 min), when required, were not taken into account. Age, premorbid conditions, hospital RTS, and NISS are significant predictors of death after trauma. The time intervals between the accident and arrival at the hospital, arrival at the hospital and the first computed tomography scan or the first crucial emergency intervention, do not appear to affect the risk of death. 23907441 Anaplastic Oligodendroglioma: A New Treatment Paradigm and Current Controversies. Anaplastic oligodendroglial tumors have gained increasing interest with the emerging role of molecular markers and systemic chemotherapy during the past years. The long-term results of two landmark trials, RTOG 9402 and EORTC 26961, have resulted in a reconsideration of the appropriate therapeutic approaches for patients with these tumors. Both trials indicate that patients whose tumors harbor a 1p/19q co-deletion benefit particularly from the addition of procarbazine/lomustine (CCNU)/vincristine (PCV) chemotherapy to radiation therapy (RT). The median survival of patients with co-deleted tumors treated within the RTOG trial with PCV before irradiation was 14.7 years compared with 7.3 years of patients who received RT alone. Median overall survival has not been reached in the RT plus PCV arm of the EORTC trial, but a similar difference can be anticipated after a follow-up of more than 12 years. In contrast, no such benefit was observed for patients with tumors lacking 1p/19q co-deletion. Outside clinical trials, patients with anaplastic oligodendroglial tumors, and 1p/19q co-deletion therefore should be offered a combined treatment modality regimen, including radio- and chemotherapy. PCV, however, is associated with significant hematological toxicity and also nonhematological side effects, which probably translate into reduced quality of life for long-term survivors. Therefore, it might be warranted to replace PCV by temozolomide, which displays a more favorable side effect profile. Data from the NOA-04 study suggest that PCV and temozolomide have similar effects. However, long-term data on the benefit from temozolomide are lacking, making a definite answer on the equivalence of temozolomide and PCV in anaplastic oligodendroglioma (AO) impossible. The current evidence precludes RT alone for AO patients. Neither the RTOG nor the EORTC trial defined the role of chemotherapy alone. A comparison of combined modality treatment with chemotherapy alone followed by RT at progression is pending. Long-term follow-up of NOA-04 patients and results from future trials may help to clarify these questions. With more and more AO patients living 10 years or more, particular attention must be paid to late side effects, such as neurotoxicity, and careful monitoring is required for all treated patients. 23939489 Dependence of All-Cause Standardized In-Hospital Mortality on Sepsis Mortality Between 2005 and 2010. Sepsis is the 11th leading cause of death in the United States. The authors evaluated the dependence of all-cause in-hospital mortality on sepsis mortality. A retrospective observational cohort design and All Patient Refined Diagnosis Related Groups were used to evaluate 150 410 patients (>17 years of age) over 6 years. The hospital standardized mortality ratio (HSMR) decreased from 0.80 ± 0.04 to 0.65 ± 0.04 (observed/expected [O/E]). The HSMR was correlated with the standardized sepsis mortality ratio (SSMR), accounting for 61% of the variation (P < .0001). The mortality rate for sepsis declined from 14.54 ± 1.60% to 8.57 ± 1.88% (P < .002), and the SSMR decreased from 0.82 ± 0.09 to 0.48 ± 0.07 (O/E; P < .002). The months of sepsis mortality matched the months of hospital mortality for the lowest of each (odds ratio = 0.30, 95% confidence interval = 0.14-0.65; P < .003) and the highest of each (odds ratio = 1.47, 95% confidence interval = 1.18-1.84; P < .0007). Monitoring monthly mortality of sepsis can provide insight for timely intervention into variation of total in-hospital mortality. 23929566 Alfred owre: revisiting the thought of a distinguished, though controversial, early twentieth-century dental educator. Many in dental education are unfamiliar with the professional life and thought of Dr. Alfred Owre, a distinguished though controversial dental educator in the early twentieth century. Owre served as dean of dentistry at both the University of Minnesota, 1905-27, and Columbia University, 1927-33. He was also a member of the Carnegie Foundation's commission that developed the report Dental Education in the United States and Canada, written by Dr. William J. Gies. Owre was a controversial leader due to his creative and original ideas that challenged dental education and the profession. His assessment and critique of the problems of dental education in his era can readily be applied to contemporary dental education and the profession, just as his vision for transformative change resonates with ideas that continue to be advocated by some individuals today. This article also documents his tumultuous relationship with Gies. 23896607 Charge-ordering transition in (TMTTF)2X explored via dilatometry. Charge-ordering phenomena have been highly topical over the past few years. A phase transition towards a charge-ordered state has been observed experimentally in several classes of materials. Among them, many studies have been devoted to the family of quasi-one-dimensional organic charge-transfer salts (TMTTF)2X, where (TMTTF) stands for tetramethyltetrathiafulvalene and X for a monovalent anion (X = PF6, AsF6 and SbF6). However, the relationship between the electron localization phenomena and the role of the lattice distortion in stabilizing the charge-ordering pattern is poorly documented in the literature. Here we present a brief overview of selected literature results, with emphasis placed on recent thermal expansion experiments probing the charge-ordering transition of these salts. 23428986 Poly-(ethylene glycol) modified gelatin nanoparticles for sustained delivery of the anti-inflammatory drug Ibuprofen-Sodium: An in vitro and in vivo analysis. The limited bioavailability and rapid clearance of the anti-inflammatory drug Ibuprofen Sodium (IbS) necessitates repeated drug administration. To address this, injectable IbS loaded PEGylated gelatin nanoparticles (PIG NPs) of size ~200nm and entrapment efficiency ~70%, providing sustained release in vitro were prepared by a modified two-step desolvation process. The developed nanomedicine, containing a range of IbS concentrations up to 1mg/mL proved to be non-toxic, hemocompatible and non-immunogenic, when tested through various in vitro assays and was reaffirmed by in vivo cytokine analysis. HPLC analysis of intravenously administered PIG NPs showed a sustained release of IbS for ~4days with improved bioavailability and pharmacokinetics when compared to bare IbS and IbS-loaded non-PEGylated GNPs. Histological analysis of liver and kidney revealed tissue integrity as in the control, indicating biocompatibility of PIG NPs. The results demonstrate improved plasma half-life of IbS when encapsulated within nanogelatin, thereby aiding reduction in its frequency of administration. In this preclinical study, improved plasma half-life of ibuprofen sodium was demonstrated when encapsulated within PEGylated gelatin nanoparticles of ~200 nm size, expected to lead to reduced frequency of administration in future clinical applications. 23891066 Patient Engagement and Reported Outcomes in Surgical Recovery: Effectiveness of an e-Health Platform. Electronic health information platforms have the potential to support standardized care delivery models, engage patients, and deliver patient self-assessment tools. We tested whether an e-health platform could support the delivery and acquisition of patient-reported outcomes (PROs) during hospitalization after cardiac surgery. Secondarily, we tested if patient reported data were predictive of resource use (length of stay) or outcomes (discharge disposition). Subjects were 149 cardiac surgical patients, over age 50 years, undergoing routine surgery, with an expected length of stay of 5 to 7 days. While hospitalized, patients were provided with iPads (Apple), which delivered a personalized care plan. That plan included daily patient "To Do" lists with self-assessment modules that included recovery-related patient reported outcomes. Those included an early screen for discharge planning (ESDP) as well as daily pain and mobility self-assessments using the visual analog pain scale and the I-MOVE mobility scale. We measured completion rates for the self assessments, determined length of stay (short, intermediate, or long) and discharge disposition (home independently or other), and evaluated whether patient self-assessments were predictive of these outcomes. Patients completed 98% of the 1,418 self-assessments that were delivered. The ESDP and mobility self-assessments were predictive of length of hospital stay (p = 0.004 and p = 0.012, respectively) and of discharge disposition (p < 0.0001 and p < 0.007, respectively). Lower ESDP scores and higher I-MOVE scores were predictive of shorter lengths of stay and a higher likelihood of discharge to home independently. Our trial demonstrated that an e-health platform, combined with mobile computing, can effectively deliver customized care plans with which patients can interact. Furthermore, patient self-reported data are predictive of length of stay and discharge disposition. 23917913 Modification of Antimicrobial Prophylaxis Based on Rectal Culture Results to Prevent Fluoroquinolone-Resistant Escherichia coli Infections after Prostate Biopsy. For patients undergoing transrectal ultrasound-guided biopsy of the prostate (TRUBP), use of rectal screening culture results to guide antimicrobial prophylaxis was effective for prevention of fluoroquinolone-resistant Escherichia coli infections. In practice, elimination of infections after TRUBP required the rectal screening protocol and addition of gentamicin for patients missing prior screening. 23541568 Genetic deletion of the long isoform of the von Hippel-Lindau tumour suppressor gene product alters microtubule dynamics. The von Hippel-Lindau tumour suppressor protein (pVHL) controls distinct cellular responses ranging from targeting hypoxia inducible factor α (HIFα) subunits for degradation and promotion of chromosomal stability to the regulation of microtubule dynamics. pVHL is produced in mammalian cells as a long and a short isoform, derived from alternate translational initiation sites in a single Vhl mRNA. However, it is unclear whether these isoforms have different cell biological activities that may represent different tumour suppressor activities of pVHL. Through a knock-in strategy to mutate the first translational initiation site from methionine to leucine (M1L) we have genetically deleted the pVHL long protein isoform in mice, allowing dissection of isoform-specific functions of pVHL. Vhl(M1L/M1L) mice exhibit no obvious phenotypic abnormalities. While numerous pVHL-mediated activities, including degradation of HIFα transcription factors, are unaffected, microtubule dynamics are altered in primary cells derived from Vhl(M1L/M1L) mice to an extent similar to that seen following complete loss of pVHL function. We conclude that the microtubule-regulating function and the HIFα-regulating function of pVHL are separable activities mediated by different protein isoforms. 23804390 Epidemiological and Microbiological Characteristics of an Outbreak Caused by OXA-48-Producing Enterobacteriaceae in a Neonatal Intensive Care Unit in Jerusalem, Israel. This study describes the course of an OXA-48-producing Enterobacteriaceae (OPE) outbreak that started in March 2012 in a neonatal intensive care unit (NICU) in Jerusalem, Israel. During the peak of the outbreak (January to August 2012), there were 49 patients who had proven or suspected acquisition of OPE in the NICU, including 16 with invasive infections, out of a total of 156 patients who were hospitalized during that period. Three children hospitalized in the pediatric ICU were identified as carriers of OPE. Three patients with a previous stay in the affected NICU were identified as OPE carriers upon admission to another hospital. The Ministry of Health was notified and then intervened in July 2012. Intervention included cohorting colonized patients, conducting frequent rectal-culture surveillance, and improving the implementation of infection control practices. As a result, the incidence of OPE acquisition declined to 5 cases in the first 4 months, followed by no new cases in the next 3 months. Thirty-one patient-unique isolates were available for analysis: 29 Klebsiella pneumoniae isolates, all belonging to a single clone (sequence type 39 [ST39]), and 2 isolates from Enterobacter cloacae. All isolates possessed the blaOXA-48 and blaCTX-M-14 genes, which are located on the same plasmid. This plasmid, similar to the global blaOXA-48-harboring vector, has now acquired blaCTX-M-14, leading to resistance to all β-lactam agents. 23957391 Barley malt wort fermentation by exopolysaccharide forming Weissella cibaria MG1 for the production of a novel beverage. The growing interest of governments and industry in developing healthy and natural alternative foods and beverages which will fulfil the consumer drive towards a healthy lifestyle and clean-label, natural diet has led to an increase into traditional lactic acid bacteria fermentation research. In particular, this research aims to address the organoleptic modulation of beverages using in situ produced bacterial polysaccharides. Weisella cibaria MG1 is capable of producing exopolysaccharides (dextran) and oligosaccharides (glucooligosaccharides) during sucrose-supplemented barley malt derived wort fermentation. Up to 36.4 g l(-1) of dextran was produced in an optimised system which improved the rheological profile of the resulting fermentate. Additionally, small amounts of organic acids were formed and ethanol remanied below 0.5% (v/v), the threshold volume for a potential health claim designation. The results suggest that the cereal fermentate produced by W. cibaria MG1 could be potentially used for the production of a range of novel, nutritious and functional beverages. Using conventional raw materials and traditional processes, novel LAB-fermented beverages can be produced representing an innovative mechanism towards fulfilling the aim to decrease government and personal costs as well as potentially ameliorating consumer lifestyle regarding dietary-related disease. This article is protected by copyright. All rights reserved. 23714137 Venom proteomic characterization and relative antivenom neutralization of two medically important Pakistani elapid snakes (Bungarus sindanus and Naja naja). Intra- and interspecific variation in venom composition has been shown to have a major effect upon the efficacy of antivenoms. Due to the absence of domestically produced antivenoms, Pakistan is wholly reliant upon antivenoms produced in other countries, such as India. However, the efficacy of these antivenoms in neutralising the venoms of Pakistani snakes has not been ascertained. This is symptomatic of the general state of toxicological research in this country, which has a myriad of highly toxic and medically important venomous animals. Thus, there is a dire need for knowledge regarding the fundamental proteomics of these venoms and applied knowledge of the relative efficacy of foreign antivenoms. Here we present the results of our proteomic research on two medically important snakes of Pakistan: Bungarus sindanus and Naja naja. Indian Polyvalent Antivenom (Bharat Serums and Vaccines Ltd), which is currently marketed for use in Pakistan, was completely ineffective against either Pakistani species. In addition to the expected pre- and post-synaptic neurotoxic activity, the venom of the Pakistan population of N. naja was shown to be quite divergent from other populations of this species in being potently myotoxic. These results highlight the importance of studying divergent species and isolated populations, where the same data not only elucidates clinical problems in need of immediate attention, but also uncovers sources for novel toxins with potentially useful activities. Pakistan Bungarus sindanus and Naja naja venoms are differentially complex. Naja naja is potently myotoxic. Neither venom is neutralized by Indian antivenom. These results have direct implications for the treatment of envenomed patients in Pakistan. The unusually myotoxic effects of Naja naja demonstrates the value of studying remote populations for biodiscovery. 23445346 Single-molecule spectroscopy on RC-LH1 complexes of Rhodopseudomonas acidophila strain 10050. We have revisited the RC-LH1 complex from Rhodopseudomonas (Rps.) acidophila for single-molecule spectroscopy. For the current study the pigment-protein complexes were stabilized in the detergent buffer solution using a relatively mild detergent (dodecyl-β-D-maltoside (DDM) instead of lauryldimethylamine N-oxide (LDAO)). This leads to a significant reduction of the fraction of broken/dissociated RC-LH1 complexes with respect to previous studies and has allowed us to investigate a sufficiently large sample of individual RC-LH1 complexes. For most of the complexes the fluorescence-excitation spectra exhibit a narrow spectral feature at the red end of the spectrum. Analysis of the statistics of the spectral properties yields a close resemblance with the results obtained on RC-LH1 complexes from Rps. palustris for which a low-resolution X-ray structure is available. Based on this comparison we come to the conclusion that for both species the RC-LH1 complex can be described by the same structural model, that is, an overall elliptical assembly of pigments that features a gap. 23875966 Low rates of child testing for HIV persist in a high-risk area of East Africa. Children in low- and middle-income countries (LMIC) are the least touched by recent successes in the diagnosis and treatment of HIV/AIDS globally. Early treatment is essential for a child's longer and higher quality of life; however, by 2011, only a small proportion of HIV-seropositive children in LMIC countries were receiving treatment, in part because of persisting low rates of diagnosis. This study of the prevalence and characteristics of children tested for HIV was embedded in the Coping with HIV/AIDS in Tanzania (CHAT) study in which HIV-seropositive and HIV-seronegative adults, and adults with unknown HIV status were asked about HIV testing for their children. Data were gathered from November 2009 to August 2010 during the scale-up of Prevention of Mother To Child Transmission and Early Infant Diagnosis programs in the region. Reports on 1776 children indicate that 31.7% of all children were reported to have been tested, including only 42.9% of children with an HIV-seropositive caregiver. In general, children more likely to be HIV tested were biological children of study participants, younger, of widowed adults, living in urban areas, and of HIV-seropositive parents/caregivers. Children belonging to the two indigenous tribes, Chagga and Pare, were more likely to be tested than those from other tribes. Rates of testing among children less than two years old were low, even for the HIV-seropositive caregiver group. The persistence of low testing rates is discussed in terms of the accessibility and acceptability of child testing in resource poor settings. 23538867 Astaxanthin Suppresses MPP+-Induced Oxidative Damage in PC12 Cells through a Sp1/NR1 Signaling Pathway. Objective: To investigate astaxanthin (ATX) neuroprotection, and its mechanism, on a 1-methyl-4-phenyl-pyridine ion (MPP+)-induced cell model of Parkinson's disease. Methods: Mature, differentiated PC12 cells treated with MPP+ were used as an in vitro cell model. The MTT assay was used to investigate cell viability after ATX treatment, and western blot analysis was used to observe Sp1 (activated transcription factor 1) and NR1 (NMDA receptor subunit 1) protein expression, real-time PCR was used to monitor Sp1 and NR1 mRNA, and cell immunofluorescence was used to determine the location of Sp1 and NR1 protein and the nuclear translocation of Sp1. Results: PC12 cell viability was significantly reduced by MPP+ treatment. The expression of Sp1 and NR1 mRNA and protein were increased compared with the control (p < 0.01). Following co-treatment with ATX and MPP+, cell viability was significantly increased, and Sp1 and NR1 mRNA and protein were decreased, compared with the MPP+ groups (p < 0.01). In addition, mithracycin A protected PC12 cells from oxidative stress caused by MPP+ by specifically inhibiting the expression of Sp1. Moreover, cell immunofluorescence revealed that ATX could suppress Sp1 nuclear transfer. Conclusion: ATX inhibited oxidative stress induced by MPP+ in PC12 cells, via the SP1/NR1 signaling pathway. 23939398 Heat shock protein-27 attenuates foam cell formation and atherogenesis by down-regulating scavenger receptor-A expression via NF-κB signaling. Previously, we showed an inverse correlation between HSP27 serum levels and experimental atherogenesis in ApoE(-/-) mice that over-express HSP27 and speculated that the apparent binding of HSP27 to scavenger receptor-A (SR-A) was of mechanistic importance in attenuating foam cell formation. However, the nature and importance of the interplay between HSP27 and SR-A in atheroprotection remained unclear. Treatment of THP-1 macrophages with recombinant HSP27 (rHSP27) inhibited acLDL binding (-34%; p<0.005) and uptake (-38%, p<0.05). rHSP27 reduced SR-A mRNA (-39%, p=0.02), total protein (-56%, p=0.01) and cell surface (-53%, p<0.001) expression. The reduction in SR-A expression by rHSP27 was associated with a 4-fold increase in nuclear factor-kappa B (NF-κB) signaling (p<0.001 versus control), while an inhibitor of NF-κB signaling, BAY11-7082, attenuated the negative effects of rHSP27 on both SR-A expression and lipid uptake. To determine if SR-A is required for HSP27 mediated atheroprotection in vivo, ApoE(-/-) and ApoE(-/-) SR-A(-/-) mice fed with a high fat diet were treated for 3weeks with rHSP25. Compared to controls, rHSP25 therapy reduced aortic en face and aortic sinus atherosclerotic lesion size in ApoE(-/-) mice by 39% and 36% (p<0.05), respectively, but not in ApoE(-/-)SR-A(-/-) mice. In conclusion, rHSP27 diminishes SR-A expression, resulting in attenuated foam cell formation in vitro. Regulation of SR-A by HSP27 may involve the participation of NF-κB signaling. Lastly, SR-A is required for HSP27-mediated atheroprotection in vivo. 23874817 NGF-Induced Cell Differentiation and Gene Activation Is Mediated by Integrative Nuclear FGFR1 Signaling (INFS). Nerve growth factor (NGF) is the founding member of the polypeptide neurotrophin family responsible for neuronal differentiation. To determine whether the effects of NGF rely upon novel Integrative Nuclear FGF Receptor-1 (FGFR1) Signaling (INFS) we utilized the PC12 clonal cell line, a long-standing benchmark model of sympathetic neuronal differentiation. We demonstrate that NGF increases expression of the fgfr1 gene and promotes trafficking of FGFR1 protein from cytoplasm to nucleus by inhibiting FGFR1 nuclear export. Nuclear-targeted dominant negative FGFR1 antagonizes NGF-induced neurite outgrowth, doublecortin (dcx) expression and activation of the tyrosine hydroxylase (th) gene promoter, while active constitutive nuclear FGFR1 mimics the effects of NGF. NGF increases the expression of dcx, th, βIII tubulin, nurr1 and nur77, fgfr1and fibroblast growth factor-2 (fgf-2) genes, while enhancing binding of FGFR1and Nur77/Nurr1 to those genes. NGF activates transcription from isolated NurRE and NBRE motifs. Nuclear FGFR1 transduces NGF activation of the Nur dimer and raises basal activity of the Nur monomer. Cooperation of nuclear FGFR1 with Nur77/Nurr1 in NGF signaling expands the integrative functions of INFS to include NGF, the first discovered pluripotent neurotrophic factor. 23918768 One-stage repair in complex multisegmental thoracic aneurysmal disease: results of a multicentre study. Patients with thoracic aneurysmal disease involving the arch and the descending or thoracoabdominal aorta may require more than one surgical intervention. The results of one-stage repair using a hybrid stent-graft in the frozen elephant trunk manner are presented. Between January 2005 and March 2012, 113 (age 67 ± 10 years) of 358 registered patients in the International E-Vita Open® Registry were operated on for combined arch and descending and thoracoabdominal aortic aneurysm. Thirty-one (27%) patients had a previous cardiothoracic, abdominal aortic surgery or endovascular repair. The E-Vita Open® hybrid stent-graft was used in all cases. Postoperatively and during the follow-up (100%), aortic image examinations were performed. Combined arch replacement and antegrade stent-grafting distally (graft diameter 34 ± 4 mm) were performed under selective cerebral perfusion (72 ± 27 min) and hypothermic visceral ischaemia (65 ± 27 min). Postoperatively, aneurysm exclusion was completely and partially achieved in 80% and 20%, respectively. In-hospital mortality and survival rate after 5 years were 12% (13 of 113) and 78%, respectively. Latest aortic imaging demonstrated 93% complete aneurysm exclusion. Freedom from secondary endovascular intervention and open surgery were 88 and 90%, respectively. In multisegmental thoracic aneurysmal disease, combined arch replacement with distal repair by a hybrid stent-graft enables one-stage treatment with acceptable mortality. Aneurysm exclusion by the stent-graft seems to be primarily curative and allows easier access for distal open or endovascular reintervention. 23826718 Interaction of antioxidants and exercise on insulin sensitivity in healthy and prediabetic rats. Meal-induced insulin sensitization (MIS) describes the augmented postprandial response to insulin through action of the hepatic insulin sensitizing substance (HISS). HISS-action is impaired in insulin resistance associated with aging and type 2 diabetes, but could be preserved by the antioxidant cocktail SAMEC, along with voluntary exercise. In this study, we tested whether antioxidant supplementation during voluntary training would interact with the effects of exercise on HISS-mediated glucose uptake in healthy and prediabetic rats. The 7-day voluntary running-wheel training was used as an exercise intervention. SAMEC supplementation was provided only during the 7-day training session. The rapid insulin sensitivity test (RIST) was conducted to determine insulin- and HISS-dependent glucose uptake in 14-week-old healthy rats, and sucrose-induced insulin-resistant rats, with or without exercise in the presence or absence of SAMEC supplementation. The postprandial insulin sensitivity was increased by exercise, primarily through enhancement of the HISS-dependent glucose uptake, which remained unaffected by SAMEC. SAMEC supplementation did not either harm or add benefit to the positive effects of exercise on insulin sensitivity in healthy or prediabetic rats. While SAMEC alone was a demonstrated preventive against the progressive loss of HISS action in previous studies, short-term supplementation in this study did not reverse the established disease state. 23772701 Central nervous system involvement with multiple myeloma: long term survival can be achieved with radiation, intrathecal chemotherapy, and immunomodulatory agents. Involvement of the central nervous system (CNS) in multiple myeloma (MM) is a rare complication, with reported survival of <6 months. This report describes 37 MM patients with leptomeningeal and/or parenchymal brain involvement treated at our institution and identifies factors associated with long-term survival. From January 1999 to December 2010, 37 patients with CNS MM were evaluated at our institution. Clinical characteristics, treatment and survival were retrospectively collected. CNS disease was present at MM diagnosis in 24% and at relapse in 76%. Plasma cell leukemia (40%) and skull plasmacytomas (65%) were common, suggesting haematological and contiguous spread. Intrathecal (IT) chemotherapy was used in 81%, cranial and/or spinal irradiation in 78%, and various systemic therapies [immunomodulatory agents (IMiDs) (51%), cisplatin-based (DPACE; cisplatin, doxorubicin, cyclophosphamide, etoposide) (27%), bortezomib (19%), alkylators (11%), dexamethasone alone (8%), auto-transplant (5%)]. Median survival from CNS disease was only 4·6 months [95% confidence interval (CI): 2·8-6·7]; however, nine patients had prolonged survival (median: 17·1 months, 95% CI: 13·2-67·4). In general, these long-term survivors were treated with radiotherapy, multi-dosing IT chemotherapy, and IMiD-containing therapy. CNS MM is a highly aggressive disease but in our experience, long-term survival can be achieved with the combination of multi-dosing IT chemotherapy, radiation and IMiD-based therapy. 23686408 Communication between community and hospital pharmacists: impact on medication reconciliation at admission. Objective To evaluate the non-intentional prescription discrepancies between home medication and hospital medication for in-patients, their potential clinical impact and the impact of pharmaceutical communication between community pharmacists (CP) and hospital clinical pharmacists (HCP) to prevent them. Setting Prospective study of 278 in-patient's files hospitalized in orthopaedic surgery + units. Methods After reconciliation by the HCP including patient interviews, GP prescription reviews and CP drug delivery analyses, we analysed patient files (prescription and patient chart) and we compared the administered drugs (home medication) to those that the patient should have received. We tracked the pharmaceutical intervention, the physician acceptance and the identified and avoided errors. The clinical impact of each discrepancy was evaluated by a team composed of a physician and a clinical pharmacist. Main outcome measure Frequency of intentional and non-intentional discrepancy (NID), evaluation of NID clinical impact and rate of NID identified and corrected by the reconciliation procedure. Results 278 consecutive patients were included in the study. 1,532 prescription lines were analysed and 471 discrepancies were observed [IC95 % = (28.43; 33.00)]. Nonintentional discrepancies (NID) affected 9.2 % of prescription lines [IC95 % = (7.7; 10.6)] and 34.2 % of patients [IC95 % = (31.3; 37.1)]. Fifty-one patients (18.3 %) had at least one NID classified as potentially harmful. Sixty-nine percent of errors at admission were identified by the reconciliation procedure including data exchanges with CP. Conclusion This study demonstrates the importance of drug reconciliation at patient's admission by the HCP supported by communication with the CP. 23644204 Enmein-type diterpenoid analogs from natural kaurene-type oridonin: Synthesis and their antitumor biological evaluation. A series of enmein-type diterpenoid analogs (11-20) derived from natural kaurene-type diterpenoid oridonin were synthesized and biologically evaluated. All target compounds showed improved anti-proliferative activities against four human cancer cell lines compared with natural oridonin and parent compound 10. Some compounds were more potent than positive control Taxol. Furthermore, mechanistic investigation showed that the representative compound 17 affected cell cycle and induced apoptosis at low micro-molar level in human hepatoma Bel-7402 cells, via an oxidative stress triggered mitochondria-related caspase-dependent pathway. 23073474 Engineered peptides for the development of actively tumor targeted liposomal carriers of doxorubicin. Chemotherapy is still the treatment of choice for many types of cancer; but its effectiveness is hampered by dose limiting toxicity. Properly designed delivery systems can overcome this shortcoming by reducing the non-specific distribution and toxicity of chemotherapeutics in healthy organs and at the same time increasing drug concentrations at tumor tissue. In this study, we developed stealth liposomal formulations of doxorubicin (DOX) having a novel stable engineered peptide ligand, namely p18-4, that binds specifically to breast cancer cell line MDA-MB-435 on its surface. The coupling of p18-4 to liposomes was carried out through conventional, post insertion and post conjugation techniques and prepared liposomes were characterized for their size and level of peptide modification. The p18-4 decorated liposomal DOX formulations were then evaluated for their cellular uptake as well as cytotoxicity against the human breast cancer MDA-MB-435 cells. In this context, the effect of coupling technique on the uptake and cytotoxicity of p18-4 liposomal DOX in MDA-MB-435 cells was evaluated. The conventional and post conjugation methods of peptide incorporation were found to be more reliable for the preparation of p18-4 decorated liposomes for active DOX targeting to MDA-MB-435 cells. p18-4 decoration of liposomes by these methods did not have a notable effect on the size of prepared liposomes and DOX release, but increased the uptake and cytotoxicity of encapsulated DOX in MDA-MB-435 cells. The results show a potential for p18-4 decorated liposomes prepared by conventional and post conjugation method for tumor targeted delivery of DOX in breast tumor models. 23712291 Multiplexed electrokinetic sample fractionation, preconcentration and elution for proteomics. Both 6 and 8-channel integrated microfluidic sample pretreatment devices capable of performing "in space" sample fractionation, collection, preconcentration and elution of captured analytes via sheath flow assisted electrokinetic pumping are described. Coatings and monolithic polymer beds were developed for the glass devices to provide cationic surface charge and anodal electroosmotic flow for delivery to an electrospray emitter tip. A mixed cationic ([2-(methacryloyloxy)ethyl] trimethylammonium chloride) (META) and hydrophobic butyl methacrylate-based monolithic porous polymer, photopolymerized in the 6- or 8-fractionation channels, was used to capture and preconcentrate samples. A 0.45 wt% META loaded bed generated comparable anodic electroosmotic flow to the cationic polymer PolyE-323 coated channel segments in the device. The balanced electroosmotic flow allowed stable electrokinetic sheath flow to prevent cross contamination of separated protein fractions, while reducing protein/peptide adsorption on the channel walls. Sequential elution of analytes trapped in the SPE beds revealed that the monolithic columns could be efficiently used to provide sheath flow during elution of analytes, as demonstrated for neutral carboxy SNARF (residual signal, 0.08% RSD, n = 40) and charged fluorescein (residual signal, 2.5% n = 40). Elution from monolithic columns showed reproducible performance with peak area reproducibility of ~8% (n = 6 columns) in a single sequential elution and the run-to-run reproducibility was 2.4-6.7% RSD (n = 4) for elution from the same bed. The demonstrated ability of this device design and operation to elute from multiple fractionation beds into a single exit channel for sample analysis by fluorescence or electrospray mass spectrometry is a crucial component of an integrated fractionation and assay system for proteomics. 23606437 MRI confirms loss of blood-brain barrier integrity in a mouse model of disseminated candidiasis. Disseminated candidiasis primarily targets the kidneys and brain in mice and humans. Damage to these critical organs leads to the high mortality associated with such infections, and invasion across the blood-brain barrier can result in fungal meningoencephalitis. Candida albicans can penetrate a brain endothelial cell barrier in vitro through transcellular migration, but this mechanism has not been confirmed in vivo. MRI using the extracellular vascular contrast agent gadolinium diethylenetriaminepentaacetic acid demonstrated that integrity of the blood-brain barrier is lost during C. albicans invasion. Intravital two-photon laser scanning microscopy was used to provide the first real-time demonstration of C. albicans colonizing the living brain, where both yeast and filamentous forms of the pathogen were found. Furthermore, we adapted a previously described method utilizing MRI to monitor inflammatory cell recruitment into infected tissues in mice. Macrophages and other phagocytes were visualized in kidney and brain by the administration of ultrasmall iron oxide particles. In addition to obtaining new insights into the passage of C. albicans across the brain microvasculature, these imaging methods provide useful tools to study further the pathogenesis of C. albicans infections, to define the roles of Candida virulence genes in kidney versus brain infection and to assess new therapeutic measures for drug development. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. 23780988 Immunotherapy of autologous tumor lysate-loaded dendritic cell vaccines by a closed-flow electroporation system for solid tumors. Dendritic cell (DC)-based vaccines with the use of various antigen loading methods have been developed for cancer immunotherapy. Electroporation (EP) of a whole tumor cell lysate into DCs was previously found to be more potent for eliciting antigen-specific CD8 + T-cells compared to co-incubation of tumor cell lysates with DCs in vitro. In the present report, we studied the feasibility, safety and antitumor effect in the clinical use of an EP-DC vaccine for the immunotherapy of various types of human solid tumors. We successfully prepared an autologous tumor lysate-loaded EP-DC vaccine with high cell viability by the closed-flow electroporation system. In the phase I clinical trial, mild adverse events associated with the EP-DC vaccine were found during the treatment of advanced or recurrent cancer, or during the adjuvant therapy of some types of cancer; no autoimmune responses were observed after treatment with the autologous tumor lysate-loaded EP-DC vaccines. For the antitumor effect of the EP-DC vaccine against the 41 various types of solid tumor, the overall response rate [complete remission (CR) + partial response (PR)] was 4.9% (2/41) and the clinical benefit rate [CR+ PR + long stable disease (SD)] was 31.7% (13/41). Furthermore, the delayed-type hypersensitivity (DTH) reactivity was positive in most cases of long SD and the positive rate of DTH was 91.7% (11/12) for the patients with clinical benefit. In conclusion, the safety and feasibility of the EP-DC vaccine with autologous tumor lysates were confirmed, and it was found that the antitumor effect might be associated with the immunological response induced by the EP-DC vaccine for cancer immunotherapy. 23815241 Vitamin B12-induced acneiform eruption. Abstract Drug-induced acne is a specific subset of acne that usually has some specific features, namely monomorphic pattern, unusual location of the lesions beyond the seborrheic areas, uncommon age of onset, a resistance to conventional acne treatment. Several drugs have been associated with the development of eruptions that may simulate acne vulgaris. However, so far, there are a few cases of vitamin B12-induced acne. We report a case of acneiform eruption induced by vitamin B12 injection in a 37-year-old female patient. 23220748 Ticlopidine, a cholestatic liver injury-inducible drug, causes dysfunction of bile formation via diminished biliary secretion of phospholipids: involvement of biliary-excreted glutathione-conjugated ticlopidine metabolites. The antiplatelet drug, ticlopidine (TIC), reportedly causes cholestatic liver injuries. The present study analyzed the effect of TIC on bile formation, revealing that the biliary secretion of phospholipids was significantly decreased in TIC-administered Sprague Dawley (SD) rats. However, the effect of TIC on biliary phospholipids was not observed in SD rats pretreated with diethylaminoethyl diphenylpropylacetate that inhibits cytochrome P450s (P450), or in Eisai hyperbilirubinemic rats (EHBR) lacking functional multidrug resistance-associated protein 2 (MRP2/ABCC2). These results suggest that glutathione-conjugated TIC metabolites (TIC-SGs), which were formed in the liver after P450s-mediated metabolism and were excreted extensively into bile by MRP2, mediated the observed alterations of the bile composition. Administration of TIC caused significant liver injuries in SD rats, with decreased biliary phospholipids, but not in EHBR, consistent with the in vitro observation that phospholipid-bile acid-mixed micelles moderated the cytotoxic effects of bile acids. Further analyses revealed that TIC-SGs did not directly inhibit multidrug resistance 3 P-glycoprotein (MDR3/ABCB4)-mediated phosphatidylcholine efflux in vitro. Because the diminished biliary secretion of phospholipids with TIC administration was restored by taurocholate infusion in SD rats, the decreased biliary concentration of bile acids, due to the stimulation of bile acid-independent bile flow driven by TIC-SGs, might have indirectly attenuated phospholipid secretion. In conclusion, extensive biliary excretion of TIC-SGs decreased the biliary secretion of phospholipids, which might have increased the risk of TIC-induced cholestatic liver injury. 23916149 Investigation of acyclic uridine amide and 5'-amido nucleoside analogues as potential inhibitors of the Plasmodium falciparum dUTPase. Previously we have shown that trityl and diphenyl deoxyuridine derivatives and their acyclic analogues can inhibit Plasmodium falciparum dUTPase (PfdUTPase). We report the synthesis of conformationally restrained amide derivatives as inhibitors PfdUTPase, including both acyclic and cyclic examples. Activity was dependent on the orientation and location of the amide constraining group. In the case of the acyclic series, we were able to obtain amide-constrained analogues which showed similar or greater potency than the unconstrained analogues. Unfortunately these compounds showed lower selectivity in cellular assays. 23840927 The genome sequence of the colonial chordate, Botryllus schlosseri. Botryllus schlosseri is a colonial urochordate that follows the chordate plan of development following sexual reproduction, but invokes a stem cell-mediated budding program during subsequent rounds of asexual reproduction. As urochordates are considered to be the closest living invertebrate relatives of vertebrates, they are ideal subjects for whole genome sequence analyses. Using a novel method for high-throughput sequencing of eukaryotic genomes, we sequenced and assembled 580 Mbp of the B. schlosseri genome. The genome assembly is comprised of nearly 14,000 intron-containing predicted genes, and 13,500 intron-less predicted genes, 40% of which could be confidently parceled into 13 (of 16 haploid) chromosomes. A comparison of homologous genes between B. schlosseri and other diverse taxonomic groups revealed genomic events underlying the evolution of vertebrates and lymphoid-mediated immunity. The B. schlosseri genome is a community resource for studying alternative modes of reproduction, natural transplantation reactions, and stem cell-mediated regeneration. DOI:http://dx.doi.org/10.7554/eLife.00569.001. 23964745 The relationship between children kidney diseases and adult ESRD-an epidemiological investigation of 700 cases. Abstract Background: We planned an epidemic investigation of 700 cases who suffered from chronic renal failure (CRF) to search for the evidence to demonstrate the relationship between children kidney diseases and adult CRF. Methods: Seven hundred patients from four hospitals in Chengdu, China, were investigated face-to-face to complete a questionnaire referring to the information of diagnoses, treatment, history and so on. These enumeration count data were analyzed by statistical description. Results: In 700 patients, there were 402 male and 298 female including 21 children and 679 adults. In the disease spectrum, the unclear accounted for 36.3% of totality. Chronic glomerulonephritis made the top proportion (14.4%) in primary kidney diseases. Diabetic nephropathy (15.3%), hypertensive nephropathy (10.1%), and gouty nephropathy (6%) made the primary proportion in secondary kidney diseases. In 21 children, chronic glomerulonephritis had the highest proportion of 52.4%, followed by nephrotic syndrome (19%), Henoch-Schönlein purpura (9.5%), and urinary tract obstruction (4.8%). Thirty-eight cases developed into kidney diseases during childhood including 21 children mentioned above, in which 17 cases presented CRF in the adult stage. The primary renal diseases are chronic glomerulonephritis (60.5%), purpura nephritis (18.4%), nephrotic syndrome (10.5%), urinary tract obstruction (2.6%), and the unclear (7.9%). Conclusion: The survey showed that there were a high proportion of patients whose causes were unknown, to which attention should be paid. Chronic glomerulonephritis remained the main cause of CRF no matter whether in children or in adults. Purpura during childhood, used to be thought as self-limited, might eventually develop into CRF in adulthood, which caught our eyes. 23933179 Development of numerical estimation in Chinese preschool children. Although much is known about the development of mental representations of numbers, it is not clear how early children begin to represent numbers on a linear scale. The current study aimed to examine the development of numerical estimation of Chinese preschoolers. In total, 160 children of three age groups (51 3- and 4-year-olds, 50 5-year-olds, and 59 6-year-olds) were administered the numerical estimation task on three types of number lines (Arabic numbers, dots, and objects). All three age groups took the test on the 0-10 number lines, and the oldest group also took it on the 0-100 and 0-1000 Arabic number lines. Results showed that (a) linear representation of numbers increased with age, (b) representation of numbers was consistent across the three types of tasks, (c) Chinese participants generally showed earlier onset of various landmarks of attaining linear representations (e.g., linearity of various number ranges, accuracy, intercepts) than did their Western counterparts, as reported in previous studies, and (d) the estimates of older Chinese preschoolers on the 0-100 and 0-1000 symbolic number lines fitted the two-linear and linear models better than alternative models such as the one-cycle, two-cycle, and logarithmic models. These results extend the small but accumulating literature on the earlier development of number cognition among Chinese preschoolers compared with their Western counterparts, suggesting the importance of cultural factors in the development of early number cognition. 23897187 Thirty years in a peritoneal dialysis unit: long-term survival. Introduction: Peritoneal dialysis (PD) is an established renal replacement therapy technique which thanks to the technological and clinical advances has improved its survival rates in recent years. Objectives: The aim of this study was to evaluate patient and technique survival in PD over 30 years, according to the different decades in order to consolidate its usefulness in healthcare. Method: Retrospective cohort study including all patients in the PD programme of the Hospital Universitario La Paz (Madrid), from 1980 to 2010. Demographic and clinical variables were collected from medical records. Results: A total of 667 patients were included, 54.4% male, with a mean age of 51.47 years and a median follow-up period of 23.1 months. There was a progressive increase in PD incident patients, especially in automated PD (APD). Patient survival at 5 years was 54%, with a median of 64.66 months, increasing significantly in the last decade (P=.000). Age, comorbidity, male sex, chronic ambulatory PD (CAPD) and diabetes were predictors of patient survival. Technique survival at 5 years was 64.2% with a median of 82 months. The success of the technique was greater in younger patients on APD and with lower comorbidity. Conclusions: Over 30 years, we found an increase in incident patients. Age, comorbidity and diabetes still continue to be the main determining factors for survival. 23567962 Preparation and antimalarial activity of semisynthetic lycorenine derivatives. A set of twenty one lycorenine derivatives has been prepared from the alkaloid hippeastrine (1). The modifications performed on hippeastrine included some functional group transformations, structural simplification and preparation of dimers. All alkaloids were tested as potential antimalarial agents, being the hippeastrine dimers the most active compounds. 23123425 Dietary quercetin ameliorates nonalcoholic steatohepatitis induced by a high-fat diet in gerbils. Dietary quercetin is highly abundant in edible plants, which possesses a wide range of pharmacological properties. This study was to investigate hepatoprotective effects of quercetin in the nonalcoholic steatohepatitis (NASH) gerbils induced by a high-fat diet (HFD), and to evaluate its regulatory mechanism on hepatic inflammatory response. The gerbils were fed with HFD for 28 days to induce NASH. From 15th day to 28th day, the treated drugs were given daily to each animal, respectively. The lipid profiles and biochemical markers were determined at the end of the experiment. The expressions of Sirt1, NF-κB p65 and iNOS were detected by immunohistochemistry and Western blot analysis. The results showed that oral administration of quercetin at doses of 30-60 mg/kg to hyperlipidemia rats for 14 days were highly effective in decreasing the levels of serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). It could decrease lipid accumulation in the hepatocytes, and reduce serum levels of pro-inflammatory cytokines TNF-α and IL-6 via regulating the expressions of Sirt1, NF-κB p65 and iNOS. Thus, dietary quercetin had significant therapeutic benefits and could be explored as a potential promising candidate for the prevention of NASH. 23774723 Predictors of quality of life in Turkish adult primary care patients. This study determines perceived self-efficacy, personal characteristics and quality of life among Turkish adult primary care patients. The research used descriptive cross-sectional design. The sample group had moderate perceived self-efficacy and was mostly satisfied with quality of life. These findings help health professionals to improve quality of life in healthy adults. 23567391 Symptoms of depression in survivors of severe sepsis: a prospective cohort study of older americans. To examine if incident severe sepsis is associated with increased risk of subsequent depressive symptoms and to assess which patient characteristics are associated with increased risk of depressive symptoms. Prospective longitudinal cohort study. Population-based cohort of older U.S. adults interviewed as part of the Health and Retirement Study (1998-2006). A total of 439 patients who survived 471 hospitalizations for severe sepsis and completed at least one follow-up interview. Depressive symptoms were assessed with a modified version of the Center for Epidemiologic Studies Depression Scale. Severe sepsis was identified using a validated algorithm in Medicare claims. The point prevalence of substantial depressive symptoms was 28% at a median of 1.2 years before sepsis, and remained 28% at a median of 0.9 years after sepsis. Neither incident severe sepsis (relative risk [RR]: 1.00; 95% confidence interval [CI]: 0.73, 1.34) nor severe sepsis-related clinical characteristics were significantly associated with subsequent depressive symptoms. These results were robust to potential threats from missing data or alternative outcome definitions. After adjustment, presepsis substantial depressive symptoms (RR: 2.20; 95% CI: 1.66, 2.90) and worse postsepsis functional impairment (RR: 1.08 per new limitation; 95% CI: 1.03, 1.13) were independently associated with substantial depressive symptoms after sepsis. The prevalence of substantial depressive symptoms in severe sepsis survivors is high but is not increased relative to their presepsis levels. Identifying this large subset of severe sepsis survivors at increased risk for major depression, and beginning interventions before hospital discharge, may improve outcomes. 23900947 Linkage between community diversity of sulfate-reducing microorganisms and methylmercury concentration in paddy soil. Sulfate-reducing microorganisms (SRM) have been thought to play a key role in mercury (Hg) methylation in anoxic environments. The current study examined the linkage between SRM abundance and diversity and contents of methylmercury (MeHg) in paddy soils collected from a historical Hg mining area in China. Soil profile samples were collected from four sites over a distance gradient downstream the Hg mining operation. Results showed that MeHg content in the soil of each site significantly decreased with the extending distance away from Hg mine. Soil MeHg content was correlated positively with abundance of SRM and the contents of organic matter (OM), NH4 (+), SO4 (2-), and Hg. The abundances of SRM based on dissimilatory (bi) sulfite reductase (dsrAB) gene at 0-40 cm depths were higher than those at 40-80 cm depth at all sites. The SRM community composition varied in the soils of different sampling sites following terminal restriction fragment length polymorphism (T-RFLP) and phylogenetic analyses, which appeared to be correlated with contents of MeHg, OM, NH4 (+), and SO4 (2-) through canonical correspondence analysis. The dominant groups of SRM in the soils examined belonged to Deltaproteobacteria and some unknown SRM clusters that could have potential for Hg methylation. These results advance our understanding of the relationship between SRM and methylmercury concentration in paddy soil. 23397135 Glaucoma: an extension of various chronic neurodegenerative disorders. The eyes are the window of the brain; various pathologies of the eyes can be explained on the basis of neurological disorders and vice versa. Today, our only approach for the management of glaucoma is intraocular pressure (IOP) reduction, whether by pharmacological or surgical methods. Available methods may effectively control IOP but fall short of stopping the progression of glaucoma. IOP is just one of the risk factors our therapy addresses, so we need to work towards shifting our approach towards addressing other factors involved in the etiopathogenesis of the disease. Pathogenesis of glaucoma at molecular level can be compared with that of common neurodegenerative diseases like Alzheimer's and Parkinsonism. Targets for therapeutic intervention in chronic neurodegenerative diseases and glaucoma include apoptosis, axonal transport, free radical damage, role of polyunsaturated fatty acids, chaperones, gene regulation, etc. p38MAPK is a common pathway involved in all the neurodegenerative disease and glaucoma as well, and more research in this direction can be really beneficial for the development of novel diagnostic and therapeutic measures. 23436747 A novel graphene oxide-based surface plasmon resonance biosensor for immunoassay. Graphene oxide (GO) is used as a support for binding with proteins. A GO-based wavelength modulation surface plasmon resonance biosensor shows high sensitivity and selectivity for detection of human immunoglobulin G (IgG). When IgG is coupled with gold nanorods (AuNRs), the size increase results in a refractive index change. 22595503 CAD: how it works, how to use it, performance. Computer-aided diagnosis (CAD) systems are software algorithms designed to assist radiologists (or other practitioners) in solving a diagnostic problem by using a visual prompt (or "CAD mark") to direct the observer towards potential pathology. CT colonography is a recent arrival to CAD, but could represent one of its most fruitful applications in the future. In contrast to other organs, where a variety of different pathologies are equally represented, significant colorectal pathologies other than polyps and cancer are relatively uncommon. As we shall see, this simplifies the diagnostic task for artificial intelligence developers and also for radiologists who, ultimately, must make the final decision. This review aims to present the current state-of-the-art for CAD applied to CT colonography. A brief overview of the technical essentials and of the diagnostic performance of CAD in isolation, is followed by an explanation of how CAD is used in day-to-day practice. The last section will deal with the most controversial issues affecting CAD performance in clinical practice, with a focus on the interaction between human and artificial intelligence. 23832310 Comparison of the safety and effectiveness of endoscopic biliary decompression by nasobiliary catheter and plastic stent placement in acute obstructive cholangitis. Endoscopic retrograde biliary drainage (ERBD) using a plastic stent is suggested to be as effective as endoscopic nasobiliary drainage (ENBD) with a nasobiliary catheter for temporary biliary drainage in acute obstructive cholangitis. However, there are few studies that have compared the two methods. We therefore compared the safety and effectiveness of endoscopic biliary decompression by nasobiliary catheter versus plastic stent placement in these patients. A total of 94 screened patients with acute obstructive cholangitis were randomised to undergo emergency endoscopic biliary drainage with ENBD (n = 47) or ERBD (n = 47). Clinical outcomes and adverse events were compared. Patient backgrounds were similar in the two groups. Endoscopic biliary drainage was successfully achieved in all patients. Eleven patients underwent unscheduled endoscopic retrograde cholangiopancreatography (ERCP) to replace the nasobiliary catheter, 10 due to a catheter (1 in the ENBD group) or stent (9 in the ERBD group) blockage and 1 due to catheter migration. Clinical manifestations were similar, however, there was a significantly lower patient discomfort score in the ERBD group (p <0.05). The mean serum gamma-glutamyltransferase and total bilirubin concentrations after ERCP were significantly higher in the ERBD than ENBD group (p <0.001). Complication rates were similar in the ENBD and ERBD groups. However, the incidence rate of blockage in ERBD was statistically higher than ENBD (p = 0.015). Endoscopic biliary decompression is an effective treatment for patients with acute obstructive cholangitis. In contrast to other studies, we found an increased rate of blockage in the ERBD group and a greater decrease in liver enzyme levels in the ENBD group. 23841793 Dacryocystocele: a rare cause of neonatal respiratory distress. Abstract Dacryocystocele consist in congenital dilatation of the tear duct. It is a benign anomaly with a good prognosis that is caused by blockage of the nasolacrimal drainage system. Classically it appears as a bluish mass in the region of the inner edge of the eye and, less frequently, as respiratory distress in the neonatal period. We report a case of a newborn with episodic cyanosis and difficult feeding secondary to dacryocystocele. 23484638 Bacterial biofilms and chronic rhinosinusitis. Chronic rhinosinusitis (CRS) is a highly prevalent disease in the adult and pediatric population. It causes significant burden and the management is considered one of the most costly public health conditions. Comorbidities include asthma, aspirin sensitivity, and nasal polyposis. Staphylococcus aureus biofilms and exotoxins that act as superantigens have been implicated to play an important pathological role in the incidence, maintenance, and ongoing burden of CRS. A better understanding of the interplay between bacterial factors, host factors, and the environment will facilitate better management of this disease. This literature review focuses on these factors and highlights current research in this field. 23834152 Regulating miRNA by Natural Agents as a New Strategy for Cancer Treatment. MicroRNAs (miRNAs) are small single-strand non-coding endogenous RNAs that regulate gene expression by multiple mechanisms. Recent evidence suggests that miRNAs are critically involved in the pathogenesis, evolution, and progression of cancer. The miRNAs are also crucial for the regulation of cancer stem cells (CSCs). In addition, miRNAs are known to control the processes of Epithelial-to-Mesenchymal Transition (EMT) of cancer cells. This evidence suggests that miRNAs could serve as targets in cancer treatment, and as such manipulating miRNAs could be useful for the killing CSCs or reversal of EMT phenotype of cancer cells. Hence, targeting miRNAs, which are deregulated in cancer, could be a promising strategy for cancer therapy. Recently, the regulation of miRNAs by natural, nontoxic chemopreventive agents including curcumin, resveratrol, isoflavones, (-)-epigallocatechin-3-gallate (EGCG), lycopene, 3,3'- diindolylmethane (DIM), and indole-3-carbinol (I3C) has been described. Therefore, natural agents could inhibit cancer progression, increase drug sensitivity, reverse EMT, and prevent metastasis though modulation of miRNAs, which will provide a newer therapeutic approach for cancer treatment especially when combined with conventional therapeutics. 23684707 Cyathostoma (Cyathostoma) phenisci Baudet, 1937 (Nematoda: Syngamidae), a parasite of respiratory tract of African penguin Spheniscus demersus: Morphological and molecular characterisation with some ecological and veterinary notes. Here we provide a morphological and molecular analysis of the taxonomic status of Cyathostoma (Cyathostoma) phenisci Baudet, 1937, a rare nematode parasite of African penguin Spheniscus demersus. Taxonomical evaluation is supplemented wi th ecological and epidemiological analysis of the nematode's occurrence in the African penguin's population. Tracheae and air sacs of 13 among the 94 necropsied birds (overall prevalence 13.8%) contained a total of 33 nematode specimens (20 females, 13 males). The highest prevalence was observed in juveniles (6 infected, 25%) and "blues" (6 infected, 14.3%), followed by nestlings (1 infected, 7.7%); no nematodes were found in adults. Our morphological and morphometric analysis shows that C. phenisci is closely related to another species, Cyathostoma (Cyathostoma) verrucosum (Hovorka & Macko, 1959). The doubtful status of the latter species was confirmed by molecular data: comparison of ITS2 sequence of C. phenisci with previously deposited sequences of C. verrucosum showed 96.3% similarity in this region. On this basis, we recognized Cyathostoma (Cyathostoma) verrucosum (Hovorka & Macko, 1959) as a synonym of Cyathostoma (Cyathostoma) phenisci Baudet, 1937. 23718715 Angiotensin II type 1 receptor blockade restores angiotensin-(1-7)-induced coronary vasodilation in hypertrophic rat hearts. The aim of the present study was to investigate the coronary effects of Ang-(1-7) [angiotensin-(1-7)] in hypertrophic rat hearts. Heart hypertrophy was induced by abdominal aorta CoA (coarctation). Ang-(1-7) and AVE 0991, a non-peptide Mas-receptor agonist, at picomolar concentration, induced a significant vasodilation in hearts from sham-operated rats. These effects were blocked by the Mas receptor antagonist A-779. Pre-treatment with L-NAME (NG-nitro-L-arginine methyl ester) or ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinozalin-1-one) [NOS (NO synthase) and soluble guanylate cyclase inhibitors respectively] also abolished the effect of Ang-(1-7) in control hearts. The coronary vasodilation produced by Ang-(1-7) and AVE 0991 was completely blunted in hypertrophic hearts. Chronic oral administration of losartan in CoA rats restored the coronary vasodilation effect of Ang-(1-7). This effect was blocked by A-779 and AT2 receptor (angiotensin II type 2 receptor) antagonist PD123319. Acute pre-incubation with losartan also restored the Ang-(1-7)-induced, but not BK (bradykinin)-induced, coronary vasodilation in hypertrophic hearts. This effect was inhibited by A-779, PD123319 and L-NAME. Chronic treatment with losartan did not change the protein expression of Mas and AT2 receptor and ACE (angiotensin-converting enzyme) and ACE2 in coronary arteries from CoA rats, but induced a slight increase in AT2 receptor in aorta of these animals. Ang-(1-7)-induced relaxation in aortas from sham-operated rats was absent in aortas from CoA rats. In vitro pre-treatment with losartan restored the Ang-(1-7)-induced relaxation in aortic rings of CoA rats, which was blocked by the Mas antagonist A-779 and L-NAME. These data demonstrate that Mas is strongly involved in coronary vasodilation and that AT1 receptor (angiotensin II type 1 receptor) blockade potentiates the vasodilatory effects of Ang-(1-7) in the coronary beds of pressure-overloaded rat hearts through NO-related AT2- and Mas-receptor-dependent mechanisms. These data suggest the association of Ang-(1-7) and AT1 receptor antagonists as a potential therapeutic avenue for coronary artery diseases. 23789791 Impact of extended maceration and regulated deficit irrigation (RDI) in Cabernet Sauvignon wines: characterization of proanthocyanidin distribution, anthocyanin extraction, and chromatic properties. The impact of extended maceration (EM) was studied in Cabernet Sauvignon grapes sourced from a vineyard subjected to four regulated deficit irrigation (RDI) treatments: (I) 100% replenishment of crop evapotranspiration (100% ETc), (II) 70% ETc, (III) 25% ETc until véraison, followed by 100% ETc until harvest, and IV) 25% ETc. Each vineyard replicate was made into wine with two replicates designated as controls (10-day skin contact) and two as extended maceration (EM, 30-day skin contact). The mean degree of polymerization (mDP), size distribution, concentration, and composition of wine proanthocyanidins (PAs) and monomeric flavan-3-ols of 90 fractions were characterized by preparative and analytical HPLC techniques. The maceration length imparted a larger effect on most chemical parameters. The RDI treatment had no effect on the extraction patterns of anthocyanins, PAs, and/or on the origin of the PAs extracted into the wines. Conversely, EM led to anthocyanin losses and increased PA extraction during maceration, with ~73% of seed-derived PAs. Accordingly, the concentration of monomeric flavan-3-ols, oligomeric (2 ≤ mDP < 5) and polymeric PAs (mDP ≥ 5) was higher in EM wines. The size distribution of the wines' PAs revealed two major peaks as a function of concentration at mDP 2 (22-27% of total PAs mass) and at mDP 6-7 (12-17% of total PAs mass) and was found to follow a non-normal Rayleigh-type distribution. 23682700 Vertical transmission of rift valley Fever virus without detectable maternal viremia. Abstract Rift Valley fever virus (RVFV) is a zoonotic bunyavirus that causes abortions in domesticated ruminants. Sheep breeds exotic to endemic areas are reportedly the most susceptible to RVFV infection. Within the scope of a risk assessment program of The Netherlands, we investigated the susceptibility of a native breed of gestating sheep to RVFV infection. Ewes were infected experimentally during the first, second, or third trimester of gestation. Mortality was high among ewes that developed viremia. Four of 11 inoculated ewes, however, did not develop detectable viremia nor clinical signs and did not seroconvert for immunoglobulin G (IgG) or IgM antibodies. Surprisingly, these ewes were found to contain viral RNA in maternal and fetal organs, and the presence of live virus in fetal organs was demonstrated by virus isolation. We demonstrate that RVFV can be transmitted vertically in the absence of detectable maternal viremia. 23799926 Cylindrical rotating triboelectric nanogenerator. We demonstrate a cylindrical rotating triboelectric nanogenerator (TENG) based on sliding electrification for harvesting mechanical energy from rotational motion. The rotating TENG is based on a core-shell structure that is made of distinctly different triboelectric materials with alternative strip structures on the surface. The charge transfer is strengthened with the formation of polymer nanoparticles on surfaces. During coaxial rotation, a contact-induced electrification and the relative sliding between the contact surfaces of the core and the shell result in an "in-plane" lateral polarization, which drives the flow of electrons in the external load. A power density of 36.9 W/m(2) (short-circuit current of 90 μA and open-circuit voltage of 410 V) has been achieved by a rotating TENG with 8 strip units at a linear rotational velocity of 1.33 m/s (a rotation rate of 1000 r/min). The output can be further enhanced by integrating more strip units and/or applying larger linear rotational velocity. This rotating TENG can be used as a direct power source to drive small electronics, such as LED bulbs. This study proves the possibility to harvest mechanical energy by TENGs from rotational motion, demonstrating its potential for harvesting the flow energy of air or water for applications such as self-powered environmental sensors and wildlife tracking devices. 23471851 Soluble soy protein peptic hydrolysate stimulates adipocyte differentiation in 3T3-L1 cells. The molecular mechanisms underlying the potential health benefit effects of soybean proteins on obesity-associated metabolic disorders have not been fully clarified. In this study, we investigated the effects of soluble soybean protein peptic hydrolysate (SPH) on adipocyte differentiation by using 3T3-L1 murine preadipocytes. The addition of SPH increased lipid accumulation during adipocyte differentiation. SPH increased the mRNA expression levels of an adipogenic marker gene and decreased that of a preadipocyte marker gene, suggesting that SPH promotes adipocyte differentiation. SPH induced antidiabetic and antiatherogenic adiponectin mRNA expression and secretion. Moreover, SPH increased the mRNA expression levels of insulin-responsive glucose transporter 4 and insulin-stimulated glucose uptake. The expression levels of peroxisome proliferator-activated receptor γ (PPARγ), a key regulator of adipocyte differentiation, during adipocyte differentiation were up-regulated in 3T3-L1 cells treated with SPH, and lipid accumulation during adipocyte differentiation induced by SPH was inhibited in the presence of a PPARγ antagonist. However, SPH did not exhibit PPARγ ligand activity. These findings indicate that SPH stimulates adipocyte differentiation, at least in part, via the up-regulation of PPARγ expression levels. These effects of SPH might be important for the health benefit effects of soybean proteins on obesity-associated metabolic disorders. 23798359 Gaze avoidance in social anxiety disorder. The relationship between gaze avoidance and social anxiety has been examined previously using eye-tracking and static social images. Overall, findings to date highlight increased gaze avoidance as a behavioral marker of social anxiety. The purpose of the present study was to better elucidate the relationship between gaze avoidance and social anxiety disorder (SAD) symptoms via covert eye tracking of gaze tendencies in response to a dynamic computerized social interaction simulation. On the basis of the bivalent fear of evaluation (BFOE) model of social anxiety,([1]) it was expected that participants with SAD, compared to nonsocially anxious control (NSAC) participants, would exhibit gaze avoidance in response to both positive and negative social feedback. Participants with SAD (n = 20), and a sample of demographically equivalent NSAC (n = 19), were administered clinical diagnostic interviews and a computerized social simulation task. The simulation task consisted of viewing 26 dynamic videos (13 positive and 13 negative), each 12 s in duration. All participants were covertly eye tracked during the simulation. SAD participants exhibited greater global gaze avoidance in response to both the positive and negative video clips in comparison to the controls. Moreover, the SAD group exhibited equivalent gaze avoidance in response to stimuli of both emotional valences. These results provide additional support for gaze avoidance as a behavioral marker of SAD, as well as additional support for the BFOE model. Implications for the assessment of SAD are discussed. 23970866 K(+) channels and cell cycle progression in tumor cells. K(+) ions play a major role in many cellular processes. The deregulation of K(+) signaling is associated with a variety of diseases such as hypertension, atherosclerosis, or diabetes. K(+) ions are important for setting the membrane potential, the driving force for Ca(2+) influx, and regulate volume of growing cells. Moreover, it is increasingly recognized that K(+) channels control cell proliferation through a novel signaling mechanisms triggered and modulated independently of ion fluxes. In cancer, aberrant expression, regulation and/or sublocalization of K(+) channels can alter the downstream signals that converge on the cell cycle machinery. Various K(+) channels are involved in cell cycle progression and are needed only at particular stages of the cell cycle. Consistent with this idea, the expression of Eag1 and HERG channels fluctuate along the cell cycle. Despite of acquired knowledge, our understanding of K(+) channels functioning in cancer cells requires further studies. These include identifying the molecular mechanisms controlling the cell cycle machinery. By understanding how K(+) channels regulate cell cycle progression in cancer cells, we will gain insights into how cancer cells subvert the need for K(+) signal and its downstream targets to proliferate. 23904188 A truncated Flt1 isoform that activates Src and promotes invasion in breast cancer cells is upregulated by Notch-1 and Notch-3 and downregulated by miR-200c and retinoic acid. We have previously reported that the major isoform of Flt1/VEGFR-1 expressed in MDA-MB-231 breast cancer cells was a truncated intracellular isoform transcribed from intron 21 (i21 Flt1). This isoform upregulated the active form of Src and increased breast cancer cell invasiveness. Since expression of the transmembrane and soluble Flt1 isoforms of HUVEC is activated by Notch signaling, we wondered whether the expression of the intracellular isoform i21 Flt1 was also dependent on Notch activation. We report here that the expression of i21 Flt1 in HUVEC and MDA-MB-231 cells is downregulated by the γ-secretase inhibitor DAPT. In addition, treatment of MDA-MB-231 cells with siRNA specific for Notch-1 and Notch-3 downregulates the expression of i21 Flt1. In agreement with these findings, HUVEC and MDA-MB-231 breast cancer cells, cultured on dishes coated with recombinant human Dll4 extracellular domain, express higher levels of i21 Flt1. In cancer cells, Flt1 is a target of the micro RNA family miR-200. In MDA-MB-231 breast cancer cells, the truncated intracellular isoform i21 Flt1 is also negatively regulated by miR-200c. Retinoic acid interferes i21 Flt1 expression by downregulating Notch-3 and upregulating miR-200 expression. Treatment of MDA-MB-231 breast cancer cells with both a γ-secretase inhibitor and retinoic acid suppresses the expression of i21 Flt1, providing a new mechanism to explain the effectiveness of this therapeutic approach. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc. 23454835 Alternariol induces abnormal nuclear morphology and cell cycle arrest in murine RAW 264.7 macrophages. The mycotoxin alternariol (AOH), a frequent contaminant in fruit and cereal products, is known to induce DNA damage with subsequent cell cycle arrest. Here we elucidated the effects of AOH on stages of cell cycle progression using the RAW 264.7 macrophage model. AOH resulted in an accumulation of cells in the G2/M-phase (4N). Most cells exhibited a large G2 nucleus whereas numbers of true mitotic cells were reduced relative to control. Both cyclin B1 and p-cdc2 levels increased, while cyclin B1 remained in the cytoplasm; suggesting arrest in the G2/M transition point. Remarkably, after exposure to AOH for 24h, most of the cells exhibited abnormally shaped nuclei, as evidenced by partly divided nuclei, nuclear blebs, polyploidy and micronuclei (MN). AOH treatment also induced abnormal Aurora B bridges, suggesting that cytokinesis was interfered within cells undergoing karyokinesis. A minor part of the resultant G1 tetraploid (4N) cells re-entered the S-phase and progressed to 8N cells. 23899865 Pulmonary toxicity of carbon nanotubes and asbestos - Similarities and differences. Carbon nanotubes are a valuable industrial product but there is potential for human pulmonary exposure during production and their fibrous shape raises the possibility that they may have effects like asbestos, which caused a worldwide pandemic of disease in the20th century that continues into present. CNT may exist as fibres or as more compact particles and the asbestos-type hazard only pertains to the fibrous forms of CNT. Exposure to asbestos causes asbestosis, bronchogenic carcinoma, mesothelioma, pleural fibrosis and pleural plaques indicating that both the lungs and the pleura are targets. The fibre pathogenicity paradigm was developed in the 1970s-80s and has a robust structure/toxicity relationship that enables the prediction of the pathogenicity of fibres depending on their length, thickness and biopersistence. Fibres that are sufficiently long and biopersistent and that deposit in the lungs can cause oxidative stress and inflammation. They may also translocate to the pleura where they can be retained depending on their length, and where they cause inflammation and oxidative stress in the pleural tissues. These pathobiological processes culminate in pathologic change - fibroplasia and neoplasia in the lungs and the pleura. There may also be direct genotoxic effects of fibres on epithelial cells and mesothelium, contributing to neoplasia. CNT show some of the properties of asbestos and other types of fibre in producing these types of effects and more research is needed. In terms of the molecular pathways involved in the interaction of long biopersistent fibres with target tissue the events leading to mesothelioma have been a particular area of interest. A variety of kinase pathways important in proliferation are activated by asbestos leading to pre-malignant states and investigations are under way to determine whether fibrous CNT also affects these molecular pathways. Current research suggests that fibrous CNT can elicit effects similar to asbestos but more research is needed to determine whether they, or other nanofibres, can cause fibrosis and cancer in the long term. 23420142 Relationship between body colour, feeding, and reproductive arrest under short-day development in Tetranychus pueraricola (Acari: Tetranychidae). In Tetranychus spider mites (Acari: Tetranychidae), diapausing females have a conspicuous orange body colour, which is used as an indicator of diapause induction in many laboratory studies. However, to which extent body colour reflects reproductive activity is scarcely investigated. In this study, we investigated the relationship between body colour, reproductive arrest, and food intake in the inbred strain of T. pueraricola individually reared at 20 °C with a 10:14 h light: dark photoperiod. Our results showed that (1) body colour is a good indicator of reproductive arrest 11 days after adult emergence but does not completely reflect reproductive status at an earlier age; (2) even orange females intermittently feed, and the arrest of feeding comes after the change in body colour; and (3) reproducing females have a higher risk of death than non-reproducing females. These results suggest that measurement of diapause incidence by body colour alone may miss the variation in reproductive status in early adult life. 23347171 Three-dimensional echocardiography in the evaluation of global and regional function in patients with recent myocardial infarction: a comparison with magnetic resonance imaging. We aimed to compare three-dimensional (3D) and two-dimensional (2D) echocardiography in the evaluation of patients with recent myocardial infarction (MI), using late-enhancement magnetic resonance imaging (LE-MRI) as a reference method. Echocardiography and LE-MRI were performed approximately 1 month after first-time MI in 58 patients. Echocardiography was also performed on 35 healthy controls. Left ventricular (LV) ejection fraction by 3D echocardiography (3D-LVEF), 3D wall-motion score (WMS), 2D-WMS, 3D speckle tracking-based longitudinal, circumferential, transmural and area strain, and 2D speckle tracking-based longitudinal strain (LS) were measured. The global correlations to infarct size by LE-MRI were significantly higher (P < 0.03) for 3D-WMS and 2D-WMS compared with 3D-LVEF and the 4 different measurements of 3D strain, and 2D global longitudinal strain (GLS) was more closely correlated to LE-MRI than 3D GLS (P < 0.03). The segmental correlations to infarct size by LE-MRI were also significantly higher (P < 0.04) for 3D-WMS, 2D-WMS, and 2D LS compared with the other indices. Three-dimensional WMS showed a sensitivity of 76% and a specificity of 72% for identification of LV infarct size >12%, and a sensitivity of 73% and a specificity of 95% for identification of segments with transmural infarct extension. Three-dimensional WMS and 2D gray-scale echocardiography showed the strongest correlations to LE-MRI. The tested 3D strain method suffers from low temporal and spatial resolution in 3D acquisitions and added diagnostic value could not be proven. 23578638 Characterization of Hatay honeys according to their multi-element analysis using ICP-OES combined with chemometrics. Chemical characterisation has been carried out on 45 honey samples collected from Hatay region of Turkey. The concentrations of 17 elements were determined by inductively coupled plasma optical emission spectrometry (ICP-OES). Ca, K, Mg and Na were the most abundant elements, with mean contents of 219.38, 446.93, 49.06 and 95.91mgkg(-1) respectively. The trace element mean contents ranged between 0.03 and 15.07mgkg(-1). Chemometric methods such as principal component analysis (PCA) and cluster analysis (CA) techniques were applied to classify honey according to mineral content. The first most important principal component (PC) was strongly associated with the value of Al, B, Cd and Co. CA showed eight clusters corresponding to the eight botanical origins of honey. PCA explained 75.69% of the variance with the first six PC variables. Chemometric analysis of the analytical data allowed the accurate classification of the honey samples according to origin. 23806604 Can temperate insects take the heat? A case study of the physiological and behavioural responses in a common ant, Iridomyrmex purpureus (Formicidae), with potential climate change. Insects in temperate regions are predicted to be at low risk of climate change relative to tropical species. However, these assumptions have generally been poorly examined in all regions, and such forecasting fails to account for microclimatic variation and behavioural optimisation. Here, we test how a population of the dominant ant species, Iridomyrmex purpureus, from temperate Australia responds to thermal stress. We show that ants regularly forage for short periods (minutes) at soil temperatures well above their upper thermal limits (upper lethal temperature=45.8±1.3°C; CTmax=46.1°C) determined over slightly longer periods (hours) and do not show any signs of a classic thermal performance curve in voluntary locomotion across soil surface temperatures of 18.6-57°C (equating to a body temperature of 24.5-43.1°C). Although ants were present all year round, and dynamically altered several aspects of their thermal biology to cope with low temperatures and seasonal variation, temperature-dependence of running speed remained invariant and ants were unable to elevate high temperature tolerance using plastic responses. Measurements of microclimate temperature were higher than ant body temperatures during the hottest part of the day, but exhibited a stronger relationship with each other than air temperatures from the closest weather station. Generally close associations of ant activity and performance with microclimatic conditions, possibly to maximise foraging times, suggest I. purpureus displays highly opportunistic thermal responses and readily adjusts behaviour to cope with high trail temperatures. Increasing frequency or duration of high temperatures is therefore likely to result in an immediate reduction in foraging efficiency. In summary, these results suggest that (1) soil-dwelling temperate insect populations may be at higher risks of thermal stress with increased frequency or duration of high temperatures resulting from climate change than previously thought, however, behavioural cues may be able to compensate to some extent; and (2) indices of climate change-related thermal stress, warming tolerance and thermal safety margin, are strongly influenced by the scale of climate metrics employed. 23834434 Morphometric analysis of osteonal architecture in bones from healthy young human male subjects using scanning electron microscopy. The shape and structure of bones is a topic that has been studied for a long time by morphologists and biologists with the goal of explaining the laws governing their development, aging and pathology. The osteonal architecture of tibial and femoral mid-diaphyses was examined morphometrically with scanning electron microscopy in four healthy young male subjects. In transverse sections of the mid-diaphysis, the total area of the anterior, posterior, lateral and medial cortex sectors was measured and analysed for osteonal parameters including osteon number and density, osteon total and bone area and vascular space area. Osteons were grouped into four classes including cutting heads (A), transversely cut osteons (B), longitudinally cut osteons (C) and sealed osteons (D). The morphometric parameters were compared between the inner (endosteal) and outer (periosteal) half of the cortex. Of 5927 examined osteons, 24.4% cutting heads, 71.1% transversely cut osteons, 2.3% longitudinally cut osteons and 2.2% sealed osteons were found. The interosteonic bone (measured as the area in a lamellar system that has lost contact with its own central canal) corresponded to 51.2% of the endosteal and 52.4% of the periosteal half-cortex. The mean number of class A cutting heads and class B osteons was significantly higher in the periosteal than in the endosteal half-cortex (P < 0.001 and P < 0.05, respectively), whereas there was no significant difference in density. The mean osteon total area, osteon bone area and vascular space area of both classes A and B were significantly higher (P < 0.001 for all three parameters) in the endosteal than in the periosteal half-cortex. The significant differences between the two layers of the cortex suggest that the osteoclast activity is distributed throughout the whole cortical thickness, with more numerous excavations in the external layer, but larger resorption lacunae closer to the marrow canal. A randomly selected population of 109 intact class B osteons was examined at higher magnification (350×) to count osteocyte lacuna and to analyse their relationship with osteon size parameters. The distribution frequency of the mean number of osteocyte lacunae increased with the increment in the sub-classes of osteon bone area, whereas the density did not show significant differences. The number of osteocyte lacunae had a direct correlation with the osteon bone area and the mean osteon wall thickness, as well as the mean number of lamellae. The osteocyte lacunae density showed an inverse relationship. These data suggest a biological regulation of osteoblast activity with a limit to the volume of matrix produced by each cell and proportionality with the number of available cells in the space of the cutting cone (total osteon area). The collected data can be useful as a set of control parameters in healthy human bone for studies on bone aging and metabolic bone diseases. 23768314 Investigation into the performance of different models for predicting stutter. In this paper we have examined five possible models for the behaviour of the stutter ratio, SR. These were two log-normal models, two gamma models, and a two-component normal mixture model. A two-component normal mixture model was chosen with different behaviours of variance; at each locus SR was described with two distributions, both with the same mean. The distributions have difference variances: one for the majority of the observations and a second for the less well-behaved ones. We apply each model to a set of known single source Identifiler™, NGM SElect™ and PowerPlex(®) 21 DNA profiles to show the applicability of our findings to different data sets. SR determined from the single source profiles were compared to the calculated SR after application of the models. The model performance was tested by calculating the log-likelihoods and comparing the difference in Akaike information criterion (AIC). The two-component normal mixture model systematically outperformed all others, despite the increase in the number of parameters. This model, as well as performing well statistically, has intuitive appeal for forensic biologists and could be implemented in an expert system with a continuous method for DNA interpretation. 23842603 Predictors of quality of life outcomes in chronic rhinosinusitis after sinus surgery. The predictive value of olfaction for quality of life (QoL) recovery after endoscopic sinus surgery (ESS) in chronic rhinosinusitis (CRS) is still underestimated. The aim of this study was to explore the proportion of patients suffering from CRS who experience clinically significant QoL improvement after ESS and identify pre-operative clinical phenotypes that best predict surgical outcomes for QoL, focusing mainly on the role of patients' olfaction. One hundred eleven patients following ESS for CRS and 48 healthy subjects were studied. Olfactory function was expressed by the combined "Threshold Discrimination Identification" score using "Sniffin' sticks" test pre-treatment and 12 months after treatment. All subjects completed validated, widely used QoL questionnaires, specific for olfaction (Questionnaire of Olfactory Deficits: QOD), for assessing psychology (Beck Depression Inventory: BDI) and for general health (Short Form-36: SF-36). Statistically significant improvement of olfactory function by 41.8 % and of all QoL questionnaires scores (all p < 0.001) was observed on the 12-month follow-up examination. Clinically significant improvement for QoL was measured in a proportion of 56.8 % of patients on QOD, 64.9 % on SF-36 and 49.5 % on BDI scales results. Although olfactory dysfunction, nasal polyps, female gender, high socio-economic status and non-smoking habits were significantly associated with better QoL results, multivariate logistic regression analysis revealed that only olfactory dysfunction and nasal polyps were independent predictors significantly associated with higher likelihood of clinically significant improvement in all QoL questionnaire results. Olfactory dysfunction and nasal polyps were independent pre-operative predictors for surgical outcomes with regard to QoL results. 23736097 Neurotoxicity of dibutyl phthalate in brain development following perinatal exposure: A study in rats. Dibutyl-phthalate (DBP) is a ubiquitous environmental contaminant. However, its neurotoxic effects on neonatal, immature or mature brains remain unclear. Here, we aimed to investigate the neurotoxicity of perinatal exposure of DBP on rodent offspring animals. Pregnant rats received intragastric DBP (500mg/kg body weight) daily from gestational day (GD) 6 to postnatal day (PND) 21. Animals in the control group received the same volume of edible corn oil. Brain sections or tissues from offspring rats on PND5, PND21 and PND60 were collected for analysis. Histological examination demonstrated that perinatal exposure of DBP resulted in hippocampal neuron loss and structural alternation in neonatal and immature offspring rats (PND5 and PND21), while no significant change was found in mature rats (PND60). DBP exposure induced cell apoptosis in hippocampal neurons of these neonatal and immature animals, as evidenced by the increased number of TUNEL-positive and Annexin V-propidium iodide (PI) positive cells and up-regulated caspase-3 activity. Moreover, DBP exposure decreased the expression of synaptophysin in the hippocampus and reduced both the slope and amplitude of field excitatory postsynaptic potentials (fEPSPs). DBP also impaired the spatial learning and memory of offspring rats. However, no significant difference in the susceptibility to DBP-induced neurotoxicity was found between male and female offspring rats. Our findings indicated that perinatal exposure of DBP could induce neurotoxicity in neonatal and immature offspring animals, but had no influence on mature animals after DBP withdrawal. These results may provide basic experimental evidence for better understanding the neurotoxic effects of DBP on neonatal, immature and mature brains. 23903794 THE ROLES OF GENETIC FACTORS IN UVEITIS AND THEIR CLINICAL SIGNIFICANCE. Uveitis is a diverse group of intraocular inflammatory disease and is a significant cause of visual loss worldwide. Recent studies have identified various endogenous immune mechanisms and genetic factors that are involved in the pathogenesis of uveitis. This review provides an overview on the role of genetics in the development and clinical course of uveitis. PUBMED was used for literature search, and articles published from 1970 to 2012 that evaluated the genetic associations and mechanisms involved in the development and clinical features of uveitis were included. Studies have demonstrated associations between various genetic factors and the development and clinical course of intraocular inflammatory conditions. Genes involved included genes expressing interleukins, chemokines, chemokine receptors, and tumor necrosis factor and genes involved in complement system, oxidation, and other intracellular molecular pathways. Multiple genetic factors play important roles in the pathogenesis of uveitis and may influence the clinical course of uveitis. Further studies to investigate the genetic mechanisms of uveitis might identify additional genetic associations and might have the potential for identifying novel therapeutic targets in the treatment of intraocular inflammation. 23562823 Genome-wide association study in a Chinese population with diabetic retinopathy. Diabetic retinopathy (DR) is a leading cause of preventable blindness in adults. To identify genetic contributions in DR, we studied 2071 type 2 diabetics. We first conducted a genome-wide association study of 1007 individuals, comparing 570 subjects with ≥8 years duration without DR (controls) with 437 PDR (cases) in the Chinese discovery cohort. Cases and controls were similar for HbA1c, diabetes duration and body mass index. Association analysis with imputed data identified three novel loci: TBC1D4-COMMD6-UCHL3 (rs9565164, P = 1.3 × 10(-7)), LRP2-BBS5 (rs1399634, P = 2.0 × 10(-6)) and ARL4C-SH3BP4 (rs2380261, P = 2.1 × 10(-6)). Analysis of an independent cohort of 585 Hispanics diabetics with or without DR though did not confirm these signals. These genes are still of particular interest because they are involved in insulin regulation, inflammation, lipid signaling and apoptosis pathways, all of which are possibly involved with DR. Our finding nominates possible novel loci as potential DR susceptibility genes in the Chinese that are independent of the level of HbA1c and duration of diabetes and may provide insight into the pathophysiology of DR. 23903665 Purification of DNA eluates from the ProbeTec GC Q(x) assay on BD Viper™ XTR allows for further analysis and confirmation of gonorrhea. Low positive predictive values of Neisseria gonorrhoeae nucleic acid amplification tests in low-prevalence populations are a major challenge for accurate diagnostics. It is therefore necessary to verify all positive N. gonorrhoeae results with a different assay and target gene, preferably using the same sample. The BD ProbeTec™ Q(x) Collection Kit for Endocervical or Lesion Specimens, which is recommended for BD Viper™ XTR, is incompatible with other commercial platforms. Therefore, a confirmatory PCR has not been available for samples received on this transport medium. To be able to verify results from these samples with another assay, our objective was to establish a procedure for using the DNA eluates from BD Viper™ XTR for further analysis. DNA eluates from BD Viper™ XTR were collected and analyzed in two in-house confirmatory real-time PCRs targeting the porA pseudogene and the opa multicopy gene. BD Viper™ XTR DNA eluates were analyzed directly and also after purification with the nucleic acid extraction system NucliSENS® easyMag®. Purification of BD Viper™ XTR DNA eluates with the nucleic acid extraction system NucliSENS® easyMag® provided a sensitivity of the in-house PCR comparable to BD Viper™. With the inclusion of two target genes in the confirmatory PCR, specific and reliable verification of results were obtained. This study presents a simple, inexpensive procedure which allows for rapid verification of gonorrhea from samples received on the BD ProbeTec™ Q(x) Collection Kit for Endocervical or Lesion Specimens. 23879859 Tunable heparan sulfate mimetics for modulating chemokine activity. Heparan sulfate (HS) glycosaminoglycans participate in critical biological processes by modulating the activity of a diverse set of protein binding partners. Such proteins include all known members of the chemokine superfamily, which are thought to guide the migration of immune cells through their interactions with HS. Here, we describe an expedient, divergent synthesis to prepare defined HS glycomimetics that recapitulate the overall structure and activity of HS glycosaminoglycans. Our approach uses a core disaccharide precursor to produce a variety of differentially sulfated glycopolymers. We demonstrate that a specific trisulfated mimetic antagonizes the chemotactic activity of the proinflammatory chemokine RANTES with potency similar to that of heparin, without inhibiting serine proteases in the blood coagulation cascade. Our work provides a general strategy for modulating chemokine activity and dissecting the pleiotropic functions of HS/heparin through the presentation of defined sulfation motifs within polymeric scaffolds. 23965411 A Hybrid Atomistic Electrodynamics-Quantum Mechanical Approach for Simulating Surface-Enhanced Raman Scattering. Surface-enhanced Raman scattering (SERS) is a technique that has broad implications for biological and chemical sensing applications by providing the ability to simultaneously detect and identify a single molecule. The Raman scattering of molecules adsorbed on metal nanoparticles can be enhanced by many orders of magnitude. These enhancements stem from a twofold mechanism: an electromagnetic mechanism (EM), which is due to the enhanced local field near the metal surface, and a chemical mechanism (CM), which is due to the adsorbate specific interactions between the metal surface and the molecules. The local field near the metal surface can be significantly enhanced due to the plasmon excitation, and therefore chemists generally accept that the EM provides the majority of the enhancements. While classical electrodynamics simulations can accurately simulate the local electric field around metal nanoparticles, they offer few insights into the spectral changes that occur in SERS. First-principles simulations can directly predict the Raman spectrum but are limited to small metal clusters and therefore are often used for understanding the CM. Thus, there is a need for developing new methods that bridge the electrodynamics simulations of the metal nanoparticle and the first-principles simulations of the molecule to facilitate direct simulations of SERS spectra. In this Account, we discuss our recent work on developing a hybrid atomistic electrodynamics-quantum mechanical approach to simulate SERS. This hybrid method is called the discrete interaction model/quantum mechanics (DIM/QM) method and consists of an atomistic electrodynamics model of the metal nanoparticle and a time-dependent density functional theory (TDDFT) description of the molecule. In contrast to most previous work, the DIM/QM method enables us to retain a detailed atomistic structure of the nanoparticle and provides a natural bridge between the electronic structure methods and the macroscopic electrodynamics description. Using the DIM/QM method, we have examined in detail the importance of the local environment on molecular excitation energies, enhanced molecular absorption, and SERS. Our results show that the molecular properties are strongly dependent not only on the distance of the molecule from the metal nanoparticle but also on its orientation relative to the nanoparticle and the specific local environment. Using DIM/QM to simulate SERS, we show that there is a significant dependence on the adsorption site. Furthermore, we present a detailed comparison between enhancements obtained from DIM/QM simulations and those from classical electrodynamics simulations of the local field. While we find qualitative agreement, there are significant differences due to the neglect of specific molecule-metal interactions in the classical electrodynamics simulations. Our results highlight the importance of explicitly considering the specific local environment in simulations of molecule-plasmon coupling. 23531112 Aromatherapy and the central nerve system (CNS): therapeutic mechanism and its associated genes. Molecular medical research on aromatherapy has been steadily increasing for use as an adjuvant therapy in managing psychiatric disorders and to examine its therapeutic mechanisms. Most studies, as well as clinically applied experience, have indicated that various essential oils, such as lavender, lemon and bergamot can help to relieve stress, anxiety, depression and other mood disorders. Most notably, inhalation of essential oils can communicate signals to the olfactory system and stimulate the brain to exert neurotransmitters (e.g. serotonin and dopamine) thereby further regulating mood. However, little research has been done on the molecular mechanisms underlying these effects, thus their mechanism of action remains ambiguous. Several hypotheses have been proposed regarding the therapeutic mechanism of depression. These have mainly centered on possible deficiencies in monoamines, neurotrophins, the neuroendocrine system, c-AMP, cation channels as well as neuroimmune interactions and epigenetics, however the precise mechanism or mechanisms related to depression have yet to be elucidated. In the current study, the effectiveness of aromatherapy for alleviating psychiatric disorders was examined using data collected from previously published studies and our unpublished data. A possible signaling pathway from olfactory system to the central nerve system and the associated key molecular elements of aromatherapy are also proposed. 23952853 Bronchoscopic findings and bleeding control predict survival in patients with solid malignancies presenting with mild hemoptysis. Background: Regardless of its volume, hemoptysis is a concerning symptom. Mild hemoptysis and its significance in patients with solid malignancies has not been studied. Methods: We conducted a retrospective chart review of patients with solid malignancies who presented for evaluation of mild hemoptysis. In this population, we studied the impact of bronchoscopic findings and endobronchial therapies on overall survival and bleeding recurrence. Patients were categorized into four groups on the basis of the presence or absence of active bleeding and endobronchial disease at the time of initial bronchoscopy: active bleeding with endobronchial lesion (AB/EBL), active bleeding without endobronchial lesion (AB/no-EBL), absence of active bleeding but with endobronchial lesion (no-AB/EBL), and absence of active bleeding and endobronchial lesion (no-AB/no-EBL). Measurements and Main Results: Ninety-five of the 112 patients with solid malignancies and mild hemoptysis underwent bronchoscopies. There was a significantly lower median survival time for patients with bronchoscopic findings of active bleeding and endobronchial lesion compared with patients with no active bleeding and/or no endobronchial lesion (3.48 mo; 95% confidence interval [CI], 2.14-6.05). On a multivariate analysis, factors independently associated with improved survival were higher hemoglobin values (hazard ratio [HR], 0.78; 95% CI, 0.67-0.91) and cessation of hemoptysis without recurrence at 48 hours (HR, 0.43; 95% CI, 0.22-0.84). Variables independently associated with worse survival were disease stage (HR, 10.8; 95% CI, 2.53-46.08) and AB/EBL (HR, 3.20; 95% CI, 1.74-5.89). Conclusions: In patients with solid malignancies presenting with mild hemoptysis, bronchoscopic findings of AB/EBL are associated with decreased survival. Hemoptysis control without recurrence at 48 hours after endobronchial intervention may improve survival. 23944826 Back pain. During a placement at an orthopaedic outpatients department, I cared for patients experiencing back pain, and associated disorders of the spine and musculoskeletal system. 23714138 Dynamic mechanical thermal analysis of composite resins with CQ and PPD as photo-initiators photoactivated by QTH and LED units. The aim of this study was to evaluate the thermal and mechanical properties of the composite resins containing the photo-initiators camphorquinone (CQ) and/or phenyl-propanodione (PPD) when photoactivated with halogen lamp (XL2500/3M-ESPE), monowave (UltraBlueIS/DMC) and polywave (UltraLume5/Ultradent) LED units. A blend of BisGMA, UDMA, BisEMA and TEGDMA was prepared with the same wt% of photo-initiators CQ and/or PPD and 65wt% of silaneted filler particles. Compression strength (CS), diametral tensile strength (DTS) and diametral modulus (DM) were tested. Thermogravimetric analysis (TGA) was made and the lost residual monomer were verified. Dynamic mechanical thermal analysis (DMTA) was used for to analyze the glass transition temperature (Tg) and the storage modulus in 37°C. Degree of conversion (DC) was accomplished in the same samples of DMA using middle-infrared spectroscopy (mid-IR). CQ, CQ/PPD and PPD obtained the same results for all mechanical properties (CS, DTS and DM), lost residual monomer and storage modulus in 37°C, regardless LCU used. The results of Tg showed that the combination PPD-UltraLume5 produced the highest values. DC showed that the combination CQ-UltraLume5 resulted in the highest values and PPD-XL2500 in the lowest DC values. The study shows that PPD is not only effective photosensitizers, but also photocrosslinking agents for dental composite resins with a similar efficiency to CQ. 23937638 Demyelination Initiated by Oligodendrocyte Apoptosis through Enhancing Endoplasmic Reticulum-Mitochondria Interactions and Id2 Expression after Compressed Spinal Cord Injury in Rats. Demyelination is one of the most important pathological factors of spinal cord injury. Oligodendrocyte apoptosis is involved in triggering demyelination. However, fewer reports on pathological changes and mechanism of demyelination have been presented from compressed spinal cord injury (CSCI). The relative effect of oligodendrocyte apoptosis on CSCI-induced demyelination and the mechanism of apoptosis remain unclear. In this study, a custom-designed model of CSCI was used to determine whether or not demyelination and oligodendrocyte apoptosis occur after CSCI. The pathological changes in axonal myelinated fibers were investigated by osmic acid staining and transmission electron microscopy. Myelin basic protein (MBP), which is used in myelin formation in the central nervous system, was detected by immunofluorescence and Western blot assays. Oligodendrocyte apoptosis was revealed by in situ terminal-deoxytransferase-mediated dUTP nick-end labeling. To analyze the mechanism of oligodendrocyte apoptosis, we detected caspase-12 [a representative of endoplasmic reticulum (ER) stress], cytochrome c (an apoptotic factor and hallmark of mitochondria), and inhibitor of DNA binding 2 (Id2, an oligodendrocyte lineage gene) by immunofluorescence and Western blot assays. The custom-designed model of CSCI was successfully established. The rats were spastic, paralyzed, and incontinent. The Basso, Beattie, and Bresnahan (BBB) locomotor rating scale scores were decreased as time passed. The compressed spinal cord slices were ischemic. Myelin sheaths became swollen and degenerative; these sheaths were broken down as time passed after CSCI. MBP expression was downregulated after CSCI and consistent with the degree of demyelination. Oligodendrocyte apoptosis occurred at 1 day after CSCI and increased as caspase-12 expression was enhanced and cytochrome c was released. Id2 was distributed widely in the white matter. Id2 expression increased with time after CSCI. Demyelination occurred after CSCI and might be partly caused by oligodendrocyte apoptosis, which was positively correlated with ER-mitochondria interactions and enhanced Id2 expression after CSCI in rats. 23549730 Distribution of MICB diversity in the Zhejiang Han population: PCR sequence-based typing for exons 2-6 and identification of five novel MICB alleles. The polymorphism of major histocompatibility complex class I chain-related gene B (MICB) and variations in MICB alleles in a variety of populations have been characterized using several genotyping approaches. In the present study, a novel polymerase chain reaction sequence-based typing (PCR-SBT) method was established for the genotyping of MICB exons 2-6, and the allelic frequency of MICB in the Zhejiang Han population was investigated. Among 400 unrelated healthy Han individuals from Zhejiang Province, China, a total of 20 MICB alleles were identified, of which MICB*005:02:01, MICB*002:01:01, and MICB*004:01:01 were the most predominant alleles, with frequencies of 0.57375, 0.1225, and 0.08375, respectively. Nine MICB alleles were detected on only one occasion, giving a frequency of 0.00125. Of the 118 distinct MICB ∼ HLA-B haplotypes identified, 42 showed significant linkage disequilibrium (P < 0.05). Haplotypes MICB*005:02:01 ∼ B*46:01, MICB*005:02:01 ∼ B*40:01, and MICB*008 ∼ B*58:01 were the most common haplotypes, with frequencies of 0.0978, 0.0761, and 0.0616, respectively. Five novel alleles, MICB*005:07, MICB*005:08, MICB*027, MICB*028, and MICB*029 were identified. Compared with the MICB*005:02:01 sequence, a G > A substitution was observed at nucleotide position 210 in MICB*005:07, and a 1,134 T > C substitution in MICB*005:08 and an 862 G > A substitution in MICB*027 were detected. In addition, it appears that MICB*028 probably arose from MICB*004:01:01 with an A to G substitution at position 1,147 in exon 6. MICB*029 had a G > T transversion at nucleotide position 730 in exon 4, compared with that of MICB*002:01:01. On the basis of the new PCR-SBT assay, these observed results demonstrated MICB allelic variations in the Zhejiang Han population. 23629517 COMPLETE ARTIFICIAL SALIVA ALTERS EXPRESSION OF PROINFLAMMATORY CYTOKINES IN HUMAN DERMAL FIBROBLASTS. Complete artificial saliva (CAS) is a saliva substitute often used as a vehicle for test articles, including smokeless tobacco products. In the course of a study employing normal adult human dermal fibroblasts (HDFa) as a model in vitro, we discovered that CAS as a vehicle introduced a significant change in the expression of proinflammatory cytokines. To determine the effects of CAS on gene expression, real-time quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) gene array analysis was used. Results indicate that robust changes in the expression of the proinflammatory cytokine interleukin 8 (IL8) and the vascular cell adhesion molecule 1 (VCAM1) occur within 5 hours of exposure to CAS. To determine whether CAS also alters cytokine release into the culture media, cytometric bead array (CBA) assays for human inflammatory cytokines were performed. Analysis shows that CAS induced the release of IL8 and interleukin 6 (IL6). This study focused on determining which components in CAS were responsible for the proinflammatory response in HDFa. The following components were investigated: α-amylase, lysozyme, acid phosphatase, and urea. Results demonstrated that enzymatically active α-amylase induced gene expression for proinflammatory cytokines IL8, IL6, tumor necrosis factor-α (TNFα), and interleukin 1α (IL1α), and for VCAM1. Therefore, it is important to carefully evaluate the "vehicle effects" of CAS and its components in in vitro toxicology research. 23778650 Noninvasive Prognostication of Polyomavirus BK Virus-Associated Nephropathy. BK virus-associated nephropathy (BKVN) is associated with an increased risk of graft failure. Levels of mRNAs encoding proteins implicated in inflammation and fibrosis were measured in urine collected at the time of biopsy diagnosis of BKVN in 29 kidney graft recipients and analyzed for prognosticating graft failure using logistic regression. Ten of 29 BKVN patients had graft failure within 36 months of BKVN diagnosis and the remaining 19 patients did not. Serum creatinine level, BKVN biopsy stage, and urinary cell levels of mRNA for plasminogen activator inhibitor (PAI)-1, vimentin, tissue inhibitor of metalloproteinase-1, fibronectin, granzyme B, or perforin were associated with graft failure. A combination of PAI-1 mRNA level, BKVN biopsy stage, and creatinine level (P=0.0015, by logistic regression) and a combination of PAI-1 mRNA and creatinine levels (P=0.001) were the best-fitting models for prognosticating graft failure, and PAI-1 mRNA level was the only independent predictor (odds ratio, 2.8; 95% confidence interval [CI], 1.1-6.8; P=0.03) by multivariable analysis. The area under the curve for the combination of PAI-1 mRNA, biopsy, and creatinine was 0.92 (95% CI, 0.80-1.0; P<0.001) by receiver operating characteristic curve analysis, and the area under the curve was 0.92 (95% CI, 0.80-1.0; P<0.001) for the combination of PAI-1 mRNA and creatinine. Graft outcome was correctly predicted in 27 of 29 BKVN patients by either model. Urinary cell level of PAI-1 mRNA, measured at the time of BKVN diagnosis, is an independent prognosticator of graft failure and a prediction model of serum creatinine and PAI-1 mRNA is as accurate as the model that includes the biopsy result. 23414804 Ester hydrolysis by a histidine-containing cavitein. We have used a template-assembled synthetic protein (TASP) to investigate catalytic function in ester hydrolysis. A histidine-containing cavitein has been found to catalyze ester hydrolysis with a rate increase of 18 times that of background. 23861246 Mer receptor tyrosine kinase is a therapeutic target in pre-B cell acute lymphoblastic leukemia. Acute lymphoblastic leukemia (ALL) is currently treated with an intense regimen of chemotherapy yielding cure rates near 85%. However, alterations to treatment strategies using available drugs are unlikely to provide significant improvement in survival or decrease therapy-associated toxicities. Here, we report ectopic expression of the Mer receptor tyrosine kinase in pre-B cell ALL (B-ALL) cell lines and pediatric patient samples. Inhibition of Mer in B-ALL cell lines decreased activation of AKT and MAPKs, and led to transcriptional changes including a decrease in the anti-apoptotic PRKCB gene and increase in pro-apoptotic BAX and BBC3 genes. Further, Mer inhibition promoted chemosensitization, decreased colony forming potential in clonogenic assays, and delayed disease onset in a mouse xenograft model of leukemia. Our results identify Mer as a potential therapeutic target in B-ALL and suggest that inhibitors of Mer may potentiate lymphoblast killing when used in combination with chemotherapy. This strategy could reduce minimal residual disease and/or allow for chemotherapy dose reduction, thereby leading to improved event-free survival and reduced therapy-associated toxicity for patients with B-ALL. Additionally, Mer is aberrantly expressed in numerous other malignancies suggesting that this approach may have broad applications. 23921507 The Obesity Paradox in Patients With Acute Coronary Syndrome: Results From the Gulf RACE-2 Study. We investigated the association between in-hospital and peri-hospital mortality and body mass index (BMI)/waist circumference (WC) in a prospective acute coronary syndrome (ACS) registry in the Arabian Gulf. No significant associations with in-hospital mortality were found. Normal BMI had highest peri-hospital mortality, notably those with high WC. In logistic regression of mortality on obesity measures and potential confounders, the effects of obesity measures were no longer significant. In-hospital death increased by 5% with age and decreased by 42% in males. Mortality increased 3.7-fold with ST-elevation myocardial infarction (STEMI) and 3.0-fold with heart failure (HF) but decreased by 33% with dyslipidemia. Peri-hospital death increased by 4% with age and decreased by 30% in males. Mortality increased 2.8-fold with STEMI and 2.4-fold with HF. In- and peri-hospital mortality in ACS is significantly associated with age, gender, STEMI, HF, and dyslipidemia but not obesity measures. 23906422 Identification of novel HDAC inhibitors through cell based screening and their evaluation as potential anticancer agents. A series of benzimidazole based HDAC inhibitors have been rationally designed, synthesized and screened. The SAR of this new chemotype is described. The lead compound, 11e, showed strong activity in several cellular assays and demonstrated in vivo efficacy in mouse xenograft pancreatic cancer models. 23942268 Chronic ketamine administration impairs mitochondrial complex I in the rat liver. Ketamine can induce hepatotoxicity which has been suggested to be dependent on mitochondrial impairment. This study investigated the long-term effects of chronic low-dose ketamine on liver mitochondrial function, oxidative stress parameters, liver histology and glycogen content. Adult rats were administered with saline or ketamine (5 or 10mg/kg) twice a day for a fourteen-day period in order to mimic chronic treatments. Effects between groups were compared ten days after the treatment had ended. Liver mitochondrial function was monitored in isolated mitochondrial extracts through evaluation of respiration parameters and activity of respiratory complexes, as well as oxidative stress, through lipid peroxidation, protein oxidation and superoxide dismutase activity. The hepatic histology and liver glycogen content were also evaluated. Ketamine groups showed a decreased evolution in body weight gains during the treatment period. Ketamine had no effect either on serum liver enzymes or on the oxidative stress parameters of liver mitochondria. Ketamine decreased the hepatic glycogen content, inhibited mitochondrial complex I and oxygen consumption when glutamate-malate substrate was used. These findings reflect a long-term mitochondrial bioenergetic deterioration induced by ketamine, which may explain the increased susceptibility of some patients to its prolonged or repeated use. 23712212 The Ilizarov paradigm: thirty years with the Ilizarov method, current concerns and future research. The Ilizarov method of bone lengthening, reconstruction and osteosynthesis has developed immensely since its introduction by G.A. Ilizarov in the Soviet Union in the 1960s and in the Western countries in the early 1980s. It has become an integral part of the arsenal used by the orthopaedic community worldwide. The evolutionary development of the method and its current role has considerably improved the quality of life for millions of people around the whole world. Despite the great versatility of its possible applications for bone injuries and diseases, the Ilizarov method could not and cannot be the alternative to a range of other methods that are applied for some specific bone conditions, but rather is a method of choice. Its combination with the current methods of internal fixation or the means of internal fixation that use the biological principles that were laid down by G.A. Ilizarov have demonstrated the importance of tension stress, blood supply, functional loading, and fragment control during bone treatment. The objective of this study was to present an overview of the current state and concerns in the application of the Ilizarov method and define the prospective research trends aimed at regeneration stimulation, better control of treatment, infection barriers and patient comfort. 23777369 Differences between diabetes patients who are interested or not in the use of a patient web portal. Abstract Objective: A patient Web portal allows patients to access their personal health record through the Internet. It may improve diabetes outcomes, but the adoption is unsatisfactory. We examined the differences between patients with and without a login in order to optimize its use. Patients and Methods: A survey was conducted among patients from 62 general practices and one outpatient clinic that all use a diabetes Web portal. Between November 2011 and March 2012 questionnaires were sent to 1,500 patients with and 3,000 patients without a login. Patient groups were stratified according to type of diabetes. Demographic and diabetes-related variables were analyzed with multivariable regression analysis. Results: The total response rate was 67%. Fewer than 50% of the patients did request a login. Among 128 patients with type 1 diabetes mellitus, those with a login (89.8%) were younger and more frequently treated by an internist. In 1,262 patients with type 2 diabetes mellitus, fewer patients had a log-in (41.0%), and the likelihood of having a login was independently associated with younger age, male gender, higher educational level, treatment by an internist, longer duration of diabetes, and polypharmacy (all P<0.001). Conclusions: Patients with type 1 diabetes request a login more frequently than patients with type 2 diabetes, and patients with a login are strikingly different than patients without. The healthcare provider seems to play an important role in patients' Web utilization. Simply promoting use of electronic healthcare methods does not make sense. It is important to address disparities between patient groups to optimize the use of a Web portal. 23935092 Epicardial wave mapping in human long-lasting persistent atrial fibrillation: transient rotational circuits, complex wavefronts, and disorganized activity. To characterize the nature of atrial fibrillation (AF) activation in human persistent AF (PerAF) using modern tools including activation, directionality analyses, complex-fractionated electrogram, and spectral information. The mechanism of PerAF in humans is uncertain. High-density epicardial mapping (128 electrodes/6.75 cm(2)) of the posterior LA wall (PLAW), LA and RA appendage (LAA, RAA), and RSPV-LA junction was performed in 18 patients with PerAF undergoing open heart surgery. Continuous 10 s recordings were analysed offline. Activation patterns were characterized into four subtypes (i) wavefronts (broad or multiple), (ii) rotational circuits (≥2 rotations of 360°), (iii) focal sources with centrifugal activation of the entire mapping area, or (iv) disorganized activity [isolated chaotic activation(s) that propagate ≤3 bipoles or activation(s) that occur as isolated beats dissociated from the activation of adjacent bipole sites].Activation at a total of 36 regions were analysed (14 PLAW, 3 RSPV-LA, 12 LAA, and 7 RAA) creating a database of 2904 activation patterns. In the majority of maps, activation patterns were highly heterogeneous with multiple unstable activation patterns transitioning from one to another during each recording. A mean of 3.8 ± 1.6 activation subtypes was seen per map. The most common patterns seen were multiple wavefronts (56.2 ± 32%) and disorganized activity (24.2 ± 30.3%). Only 2 of 36 maps (5.5%) showed a single stable activation pattern throughout the 10-s period. These were stable planar wavefronts. Three transient rotational circuits were observed. Two of the transient circuits were located in the posterior left atrium, while the third was located on the anterior surface of the LAA. Focal activations accounted for 11.3 ± 14.2% of activations and were all short-lived (≤2 beats), with no site demonstrating sustained focal activity. Human long-lasting PerAF is characterized by heterogeneous and unstable patterns of activation including wavefronts, transient rotational circuits, and disorganized activity. 23587766 Gluteus medius: an intramuscular EMG investigation of anterior, middle and posterior segments during gait. Previous electromyographic (EMG) studies of gluteus medius (GMed) have not accurately quantified the function of the three proposed structurally and functionally unique segments (anterior, middle and posterior). Therefore this study used anatomically verified locations for intramuscular electrode recordings in three segments of GMed to determine whether the segments are functionally independent. Bipolar fine wire electrodes were inserted into each segment of GMed in 15 healthy individuals. Participants completed a series of four walking trials, followed by maximum voluntary isometric contractions (MVICs) in five different positions. Temporal and amplitude variables for each segment were compared across the gait cycle using ANOVA. The relative contributions of each segment to the MVIC trials were compared with non-parametric tests. All segments showed a biphasic response during the stance phase of gait. There were no differences in amplitude variables (% MVIC) between segments, but the anterior segment had a later peak during both the first and second bursts.For the MVIC trials, there were significant differences in amplitude between segments in four of the five test positions. These data indicate that GMed is composed of three functionally independent segments. This study contributes to the theoretical understanding of the role of GMed. 23801774 Ovarian Carcinoma: Quantitative Biexponential MR Imaging Relaxometry Reveals the Dynamic Recruitment of Ferritin-expressing Fibroblasts to the Angiogenic Rim of Tumors. Purpose: To quantitatively monitor the dynamic perivascular recruitment of ferritin heavy chain (FHC)-overexpressing fibroblasts to ovarian carcinoma xenografts by using R2 mapping and biexponential magnetic resonance (MR) relaxometry. Materials and Methods: In vivo studies of female mice were approved by the institutional animal care and use committee. In vitro analysis included MR-based R2 relaxation measurements of monkey kidney cell line (CV1) fibroblasts that overexpress FHC, followed by inductively coupled plasma mass spectrometry to assess cellular iron content. For in vivo analysis, CV1-FHC fibroblasts were either mixed with fluorescent human ovarian carcinoma cells before subcutaneous implantation (coinjection) or injected intraperitoneally 4 days after the cancer cells were injected (remote recruitment). Dynamic changes in tumor R2 were used to derive CV1-FHC cell fraction in both models. In coinjection tumors, dynamic contrast material-enhanced MR imaging was used to measure tumor fractional blood volume. Whole-body fluorescence imaging and immunohistochemical staining were performed to validate MR results. One-way repeated measures analysis of variance was used to assess MR and fluorescence imaging results and tumor volume, and one-way analysis of variance was used to assess spectrometric results, fractional blood volume, and immunohistochemical evaluation. Results: CV1-FHC fibroblasts (vs CV1 fibroblasts) showed enhanced iron uptake (1.8 mmol ± 0.5 × 10(-8) vs 0.9 mmol ± 0.5 × 10(-8); P < .05), retention (1.6 mmol ± 0.5 × 10(-8) vs 0.5 mmol ± 0.5 × 10(-8), P < .05), and cell density-dependent R2 contrast. R2 mapping in vivo revealed preferential recruitment of CV1-FHC cells to the tumor rim in both models. Measurement of fractional blood volume was similar in all tumors (2.6 AU ± 0.5 × 10(-3) for CV1, 2.3 AU ± 0.3 × 10(-3) for CV1-FHC, 2.9 ± 0.3 × 10(-3) for CV1-FHC-ferric citrate). Dynamic changes in CV1-FHC cell fraction determined at MR relaxometry in both models were confirmed at immunohistochemical analysis. Conclusion: FHC overexpression, when combined with R2 mapping and MR relaxometry, enabled in vivo detection of the dynamic recruitment of exogenously administered fibroblasts to the vasculature of solid tumors. © RSNA, 2013 Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122053/-/DC1. 22833355 CINtec® PLUS dual immunostain: a triage tool for cervical pap smears with atypical squamous cells of undetermined significance and low grade squamous intraepithelial lesion. ASC and LSIL comprise the majority of abnormal Pap smears. Currently, high-risk human papillomavirus testing is utilized to triage women with ASC for colposcopy; however, no cost effective triage method is available for LSIL. p16 and Ki-67 have each been shown to be good biomarkers for high grade cervical intraepithelial neoplasia (HG CIN).We evaluated the role of the CINtec® PLUS p16/Ki-67 dual immunostain as a marker for underlying (U) or subsequent (S) HG CIN. One hundred and eighty eight cervical SurePath Pap smears with histological and/or cytological follow-up were retrieved from our departmental files. The Pap stained slides were destained and then immunostained utilizing the CINtec® PLUS dual staining reagent kit. Results of the dual stain were correlated with follow-up diagnoses. Sensitivity, specificity, and positive and negative predictive values of CINtec® PLUS for U or S HG CIN were compared with those of HR HPV testing and with p16 and Ki-67 immunostaining alone. The sensitivity of CINtec® PLUS for U or S HG CIN was 91% in the ASC group and 100% in the LSIL group, while the corresponding specificities were 61 and 43%, respectively. The sensitivity and specificity of CINtec® PLUS for U or S HG CIN in both groups combined were 97 and 53%, respectively. CINtec® PLUS was more specific than HR HPV testing and Ki-67 and p16 immunostains alone in detecting an U or S HG CIN. CINtec® PLUS is a helpful adjunct in identifying U or S HG CIN when applied to SurePath Pap smears with ASC or LSIL. 23335626 Comparative toxicological study of the novel protein phosphatase inhibitor 19-Epi-okadaic acid in primary cultures of rat cerebellar cells. Okadaic acid (OKA) and analogues are frequent contaminants of coastal waters and seafood. Structure analysis of the isolated OKA analogue 19-epi-OKA showed important conformation differences expected to result in lower protein phosphatase (PP) inhibitory potencies than OKA. However, 19-epi-OKA and OKA inhibitory activities versus PP2A were unexpectedly found to be virtually equipotent. To investigate the toxicological relevance of these findings, we tested the effects of 19-epi-OKA on cultured cerebellar cells and compared them with those of OKA and its isomer dinophysistoxin-2. 19-epi-OKA caused degeneration of neurites and neuronal death with much lower potency than its congeners. The concentration of 19-epi-OKA that reduced after 24h the maximum neuronal survival (EC5024) by 50% was ~300nM compared with ~2nM and ~8nM for OKA and dinophysistoxin-2, respectively. Exposure to 19-epi-OKA resulted also in less toxicity for cultured glial cells (EC5024,19-epi-OKA ~ 600nM; EC5024,OKA ~ 20nM). 19-epi-OKA induced apoptotic condensation and fragmentation of chromatin, activation of caspases, and activation of ERK1/2 MAP kinases, features previously reported for OKA and dinophysistoxin-2. Also, differential sensitivity to 19-epi-OKA was observed between neuronal and glial cells, a specific characteristic shared by OKA and dinophysistoxin-2 but not by other toxins. Our results are consistent with 19-epi-OKA being included among the group of toxins of OKA and derivatives and support the suitability of cellular bioassays for the detection of these compounds. 23832681 Surveillance Imaging in Pediatric Hodgkin Lymphoma. Children with Hodgkin Lymphoma (HL) routinely undergo surveillance computed tomography (CT) imaging for up to 5 years post-therapy (Rx), resulting in increased cost and radiation exposure without clear benefit. A number of recent studies have demonstrated that routine surveillance imaging, by CT, positron emission tomography (PET)/CT, as well as other imaging techniques, may be over-utilized for routine surveillance of patients with Hodgkin Lymphoma, and-in addition to contributing to increased cost and radiation exposure-show no clear survival benefit. The purpose of this review is to summarize recent data evaluating routine surveillance imaging and its role in detecting disease relapse in patients with Hodgkin Lymphoma. 23946164 A novel porous bioceramics scaffold by accumulating hydroxyapatite spherulites for large bone tissue engineering in vivo. II: Construct Large volume of bone grafts. In vivo engineering of bone autografts using bioceramic scaffolds with appropriate porous structures is a potential approach to prepare autologous bone grafts for the repair of critical-sized bone defects. This study investigated the evolutionary process of osteogenesis, angiogenesis, and compressive strength of bioceramic scaffolds implanted in two non-osseous sites of dogs: the abdominal cavity and the dorsal muscle. Hydroxyapatite (HA) sphere-accumulated scaffolds (HASA) with controlled porous structures were prepared and placed in the two sites for up to 6 months. Analyses of retrieved scaffolds found that osteogenesis and angiogenesis were faster in scaffolds implanted in dorsal muscles compared with those placed in abdominal cavities. The abdominal cavity, however, can accommodate larger bone grafts with designed shape. Analyses of scaffolds implanted in abdominal cavities (an environment of a low mesenchymal stem cell density) further demonstrated that angiogenesis play critical roles during osteogenesis in the scaffolds, presumably by supplying progenitor cells and/or mesenchymal stem cells as seed cells. This study also examined the relationship between the volume of bone grafts and the physiological environment of in vivo bioreactor. These results provide basic information for the selection of appropriate implanting sites and culture time required to engineer autologous bone grafts for the clinical bone defect repair. Based on these positive results, a pilot study has applied the grafts constructed in canine abdominal cavity to repair segmental bone defect in load-bearing sites (limbs). 23790997 Conscious consideration of herd immunity in influenza vaccination decisions. Influenza vaccination decisions may be influenced by perceived risk reduction related to herd immunity. This paper examines how free-riding (i.e., foregoing vaccination because of reduced risk perceptions related to herd immunity) or protective benefits to the community affect vaccination decisions. A survey of a nationally representative panel of U.S. adults (N=442 respondents; data collected and analyzed during 2012) asked about how respondents made vaccination decisions, including whether and how vaccination among the members of respondents' social networks influenced their own vaccination decisions. Most individuals (61%) reported that vaccination in the social network would not influence their decision. Among those perceiving being influenced by vaccination in their social network, most stated that an increase in network vaccination coverage would make them more likely to get vaccinated, rather than less. Overall, only 6% (28 of 442) gave a response consistent with the reduced-risk logic of herd immunity, which was more common among those stating that they would be less likely to get vaccinated (emphasizing free-riding) than among those more likely to get vaccinated (emphasizing social protection; 33% vs 11%, two-sided, p=0.0005). The reduced-risk logic of herd immunity, and more specifically free-riding, is consciously considered by relatively few individuals. Far more common are social influences bolstering personal vaccination, such as peer pressure and social learning (6% vs 11%, two-sided, p=0.015). Interventionists may be more successful by capitalizing on existing social-influence considerations than by trying to combat the conscious lure of free-riding. 23792380 Oxidation of nonylphenol and octylphenol by manganese dioxide: kinetics and pathways. Due to their potent estrogenicity and ubiquitous occurrence, non-ionic surfactant metabolites nonylphenol (NP) and octylphenol (OP) are of significant concern. Abiotic chemical oxidation by naturally abundant metal oxides may be an important route of their environmental attenuation, but is poorly understood. We investigated the reaction kinetics and pathways of NP and OP with MnO2. At pH 5.5 and 100 mg/L δ-MnO2, 92, 84 and 76% of 4-n-NP, 4-tert-OP and technical nonylphenol (tNP) was transformed in 90 min, respectively. A further experiment using a Mn-containing soil and Mn-removed soil confirmed that soil MnO2 caused NP removal. Multiple reaction products, including hydroquinone, hydroxylated products, dimers and trimers were identified through fragmentation analysis by GC-MS/MS and UPLC-MS/MS, allowing the construction of tentative pathways. This study suggested that abiotic oxidation by MnO2 may contribute to the dissipation of tNP, 4-n-NP, 4-tert-OP and their analogues in the natural environment. 23706780 Heterogeneity in clinical characteristics and co-morbidities in dyspneic individuals with COPD GOLD D: Findings of the DICES trial. Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous respiratory disease with important extra-pulmonary features and comorbidities. The aim of this study was to assess clinical heterogeneity in a well-defined subgroup of individuals with COPD GOLD D, including possible gender differences. Pulmonary function, arterial blood gases, exercise performance, quadriceps muscle function, problematic activities of daily life, dyspnea, health status and comorbidities have been assessed in 117 individuals with a MRC dyspnea grade 4/5 and COPD GOLD D entering pulmonary rehabilitation. A broad range of values were found for diffusion capacity, exercise capacity, quadriceps muscle function and health status. Indeed, the high coefficients of variation were found for these outcomes. Problematic activities of daily life as well as objectified comorbidities also varied to a great extent. Moreover, significant gender differences were found for exercise performance, lower-limb muscle function and various comorbidities. The current findings emphasize that COPD is a heterogeneous disease whose clinical presentation varies significantly, even in individuals with very severe COPD with the same degree of dyspnea and all classified as GOLD D. Trial registration: NTR2322. 23567395 Measures of Anticholinergic Drug Exposure, Serum Anticholinergic Activity, and All-cause Postdischarge Mortality in Older Hospitalized Patients with Hip Fractures. To assess possible associations between anticholinergic drug exposure and serum anticholinergic activity (SAA) and their capacities to predict all-cause mortality in older hospitalized patients. Academic medical center. Data on clinical characteristics, full medication exposure, SAA, and 4 anticholinergic drug scoring systems (ADSSs: Anticholinergic Risk Scale [ARS], Anticholinergic Drug Scale, Anticholinergic Burden scale, and anticholinergic component of the Drug Burden Index) were collected in 71 older hospitalized patients (age 84 ± 6 years) awaiting surgical repair after hip fractures. The median (range) SAA was 2.8 (1.1-4.9) pmol/mL. Age (ρ = 0.25, p = 0.03), Katz Index of Independence in Activities of Daily Living score (ρ = 0.39, p = 0.001), in-hospital delirium (ρ = 0.29, p = 0.01), preadmission cognitive impairment (ρ = 0.31, p = 0.01), and the number of nonanticholinergic drugs (n-NA, ρ = -0.27, p = 0.02) were associated with SAA. No significant associations were detected between ADSSs and SAA. Cognitive impairment (β = 2.1, 95% confidence interval [CI]: 0.7 to 2.5, p = 0.005) and n-NA (β = -0.3, 95% CI: -0.5 to -0.03, p = 0.03) were independently associated with SAA. Cognitive impairment (hazard ratio [HR]: 6.7, 95% CI: 1.1 to 40.3, p = 0.04) and higher ARS scores (HR: 2.2, 95% CI: 1.2 to 3.7, p = 0.006) independently predicted 3-month mortality whereas in-hospital delirium (HR: 3.6, 95% CI: 1.3 to 10.3, p = 0.02), living at home (HR: 0.2, 95% CI: 0.0 to 0.9, p = 0.03), and length of hospital stay (HR: 1.1, 95% CI: 1.0 to 1.2, p = 0.004) independently predicted 1-year mortality after adjustment for age, gender, and Charlson comorbidity index. Cognitive impairment and n-NA, but not ADSSs, are independently associated with SAA in older hospitalized patients. The ARS score, together with cognitive impairment, in-hospital delirium, place of residence, and length of hospital stay, predicts all-cause mortality in this group. 23210778 Colchicine semisynthetics: chemotherapeutics for cancer? Nitrogen-containing bioactive alkaloids of plant origin play a significant role in human health and medicine. Several semisynthetic antimitotic alkaloids are successful in anticancer drug development. Gloriosa superba biosynthesizes substantial quantities of colchicine, a bioactive molecule for gout treatment. Colchicine also has antimitotic activity, preventing growth of cancer cells by interacting with microtubules, which could lead to the design of better cancer therapeutics. Further, several colchicine semisynthetics are less toxic than colchicine. Research is being conducted on effective, less toxic colchicine semisynthetic formulations with potential drug delivery strategies directly targeting multiple solid cancers. This article reviews the dynamic state of anticancer drug development from colchicine semisynthetics and natural colchicine production and briefly discusses colchicine biosynthesis. 23893694 Preparation and characterization of a novel dual-retention mechanism mixed-mode stationary phase with PEG 400 and succinic anhydride as ligand for protein separation in WCX and HIC modes. A novel dual-retention mechanism mixed-mode stationary phase based on silica gel functionalized with PEG 400 and succinic anhydride as the ligand was prepared and characterized by infrared spectra and elemental analysis. Because of the ligand containing PEG 400 and carboxyl function groups, it displayed hydrophobic interaction chromatography (HIC) characteristic in a high-salt-concentration mobile phase, and weak cation exchange chromatography (WCX) characteristic in a low-salt-concentration mobile phase. As a result, it can be employed to separate proteins with both WCX and HIC modes. The resolution and selectivity of the stationary phase was evaluated under both HIC and WCX modes with protein standards, and its performance was comparable to that of conventional ion-exchange chromatography and HIC columns. The results indicated that the novel dual-retention mechanism column, in many cases, could replace two individual WCX and HIC columns as a '2D column'. In addition, the mixed retention mechanism of proteins on this '2D column' was investigated with stoichiometric displacement theory for retention of solute in liquid chromatography in detail in order to understand why the dual-retention mechanism column has high resolution and selectivity for protein separation under WCX and HIC modes, respectively. Based on this '2D column', a new 2DLC technology with a single column was developed. It is very important in proteome research and recombinant protein drug production to save column expense and simplify the processes in biotechnology. Copyright © 2013 John Wiley & Sons, Ltd. 23784973 Waldenström macroglobulinemia: 2013 update on diagnosis, risk stratification, and management. Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, and lymphadenopathy. The presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. Age, hemoglobin level, platelet count, β2 microglobulin, and monoclonal IgM concentrations are characteristics required for prognosis. Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-based therapy is used in virtually all US patients with WM and can be combined with alkylating agent or purine nucleoside analog (or both). The preferred Mayo Clinic nonstudy therapeutic induction is rituximab, cyclophosphamide, and dexamethasone. Future stem cell transplantation should be considered in induction therapy selection. Bortezomib, thalidomide, everolimus, lenalidomide, and bendamustine have all been shown to have activity in WM. Given WM's natural history, reduction of complications will be a priority for future treatment trials. Am. J. Hematol. 88:703-711, 2013. © 2013 Wiley Periodicals, Inc. 23939063 Regularization functional semi-automated incorporation of anatomical prior information in image-guided fluorescence tomography. The use of anatomical priors in fluorescence tomography is known to improve image quality and accuracy significantly. However, the use of prior information is often implemented by incorporating user segmented structural images into the optical reconstruction algorithm, a process requiring significant time and expertise. We propose an automated implementation which encodes the gray-scale prior image directly into the regularization term, eliminating the need for direct prior image segmentation, which is extendable to any spatially defined prior data. The proposed method is supported by in vivo studies. 23146663 P2Y purinergic receptors: new targets for analgesic and antimigraine drugs. Millions of individuals worldwide suffer from acute and, more severely, chronic pain conditions (e.g., neuropathic pain, and migraine). The latter bear tremendous personal, familial, and social costs, since sufferers and their relatives undergo a complete turnaround of their lives with the search of relief from pain becoming their pivotal thought. Sadly, to date no effective pharmacological approaches are available which can alleviate chronic pain significantly or in the long run in all patients. The current central strategy for the development of new and effective painkillers lies in the hypothesis that cellular and/or molecular players in nociception must exists that are not targeted by "classical" analgesics, and therefore researchers have put tremendous efforts into the in-depth analysis of the pathways leading to pain development and maintenance over time. In this complex scenario, two outsiders are now taking the center stage: glial cells in sensory ganglia and in the central nervous system, thanks to their ability to communicate with neurons and to modulate their firing, and the purinergic system. Extracellular purine and pyrimidine nucleotides are involved in the physiology of virtually every body district, and their extracellular concentrations massively increase under pathological situations, suggesting that they might represent potential targets for the modulation of disease-associated symptoms, like pain. Here, we provide an overview of the present knowledge of the role of nucleotides in nociception, with a particular emphasis on G protein-coupled P2Y receptors and their involvement in the communication between first- and second-order neurons in sensory nerve pathways and surrounding glial cells. 23946426 Extensive diversity in circadian regulation of plasma lipids and evidence for different circadian metabolic phenotypes in humans. The circadian system regulates daily rhythms in lipid metabolism and adipose tissue function. Although disruption of circadian clock function is associated with negative cardiometabolic end points, very little is known about interindividual variation in circadian-regulated metabolic pathways. Here, we used targeted lipidomics-based approaches to profile the time course of 263 lipids in blood plasma in 20 healthy individuals. Over a span of 28 h, blood was collected every 4 h and plasma lipids were analyzed by HPLC/MS. Across subjects, about 13% of lipid metabolites showed circadian variation. Rhythmicity spanned all metabolite classes examined, suggesting widespread circadian control of lipid-mediated energy storage, transport, and signaling. Intersubject agreement for lipids identified as rhythmic was only about 20%, however, and the timing of lipid rhythms ranged up to 12 h apart between individuals. Healthy subjects therefore showed substantial variation in the timing and strength of rhythms across different lipid species. Strong interindividual differences were also observed for rhythms of blood glucose and insulin, but not cortisol. Using consensus clustering with iterative feature selection, subjects clustered into different groups based on strength of rhythmicity for a subset of triglycerides and phosphatidylcholines, suggesting that there are different circadian metabolic phenotypes in the general population. These results have potential implications for lipid metabolism disorders linked to circadian clock disruption. 23935910 Targeting Imperfect Vaccines against Drug-Resistance Determinants: A Strategy for Countering the Rise of Drug Resistance. The growing prevalence of antimicrobial resistance in major pathogens is outpacing discovery of new antimicrobial classes. Vaccines mitigate the effect of antimicrobial resistance by reducing the need for treatment, but vaccines for many drug-resistant pathogens remain undiscovered or have limited efficacy, in part because some vaccines selectively favor pathogen strains that escape vaccine-induced immunity. A strain with even a modest advantage in vaccinated hosts can have high fitness in a population with high vaccine coverage, which can offset a strong selection pressure such as antimicrobial use that occurs in a small fraction of hosts. We propose a strategy to target vaccines against drug-resistant pathogens, by using resistance-conferring proteins as antigens in multicomponent vaccines. Resistance determinants may be weakly immunogenic, offering only modest specific protection against resistant strains. Therefore, we assess here how varying the specific efficacy of the vaccine against resistant strains would affect the proportion of drug-resistant vs. -sensitive strains population-wide for three pathogens - Streptococcus pneumoniae, Staphylococcus aureus, and influenza virus - in which drug resistance is a problem. Notably, if such vaccines confer even slightly higher protection (additional efficacy between 1% and 8%) against resistant variants than sensitive ones, they may be an effective tool in controlling the rise of resistant strains, given current levels of use for many antimicrobial agents. We show that the population-wide impact of such vaccines depends on the additional effect on resistant strains and on the overall effect (against all strains). Resistance-conferring accessory gene products or resistant alleles of essential genes could be valuable as components of vaccines even if their specific protective effect is weak. 23904274 UK stance on adult growth hormone replacement; the Economist versus the Endocrinologist. In the UK through the use of a forced economic model, endocrinologists are in the curious position of offering GH replacement to some patients with severe GHD but withholding it from other patients with even more severe GHD.This approach is counter-intuitive to endocrine practice in treating endocrine deficiency states. For all other endocrine deficiencies, one would opt for treating those with the most severe biochemical evidence of deficiency first.If this endocrine approach was applied to adult GH replacement in an era of rationing, one would start with the GHD patients with a pathologically low IGF-I level. Given that the prevalence of subnormal IGF-I levels in a GHD population is age-dependent, this would result in GH replacement being offered to more young AOGHD and COGHD adults, and less often to middle-aged and elderly AOGHD adults. This in itself has the added advantage that the skeletal benefits appear greater in the former cohort of patients. 23836591 Validation of an algorithm to identify antiretroviral-naïve status at time of entry into a large, observational cohort of HIV-infected patients. Large, observational HIV cohorts play an important role in answering questions which are difficult to study in randomized trials; however, they often lack detailed information regarding previous antiretroviral treatment (ART). Knowledge of ART treatment history is important when ascertaining the long-term impact of medications, co-morbidities, or adverse reactions on HIV outcomes. We performed a retrospective study to validate a prediction algorithm for identifying ART-naïve patients using the Veterans Aging Cohort Study's Virtual Cohort-an observational cohort of 40 594 HIV-infected veterans nationwide. Medical records for 3070 HIV-infected patients were reviewed to determine history of combination ART treatment. An algorithm using Virtual Cohort laboratory data was used to predict ART treatment status and compared to medical record review. Among 3070 patients' medical records reviewed, 1223 were eligible for analysis. Of these, 990 (81%) were ART naïve at cohort entry based on medical record review. The prediction algorithm's sensitivity was 86%, specificity 47%, positive predictive value (PPV) 87%, and negative predictive value 45%, using a viral load threshold of <400 copies/ml. Sensitivity analysis revealed that PPV would be maximized by increasing the viral load threshold, whereas sensitivity would be maximized by lowering the viral load threshold. A prediction algorithm using available laboratory data can be used to accurately identify ART-naïve patients in large, observational HIV cohorts. Use of this algorithm will allow investigators to accurately limit analyses to ART-naïve patients when studying the contribution of ART to outcomes and adverse events. Copyright © 2013 John Wiley & Sons, Ltd. 23664529 Possible roles of barrier-to-autointegration factor 1 in regulation of keratinocyte differentiation and proliferation. Barrier-to-autointegration factor 1 (BANF1) is an essential component of the nuclear lamina. Recent studies have clarified that BANF1 is a causative molecule of Nestor-Guillermo progeria syndrome. Despite recent progress in studies on BANF1, the role of BANF1 in keratinocytes has not been addressed at all. This study aims to determine the localization of BANF1 in psoriatic epidermal keratinocytes as well as in normal keratinocytes and to clarify its possible function in those keratinocytes. Immunohistochemistry of BANF1 was performed on 10 cases of psoriasis and 10 healthy control individuals. Expression of molecules associated with inflammation of the skin by HSC-1, a human skin squamous cell carcinoma cell line, stimulated by TPA and treated with siRNA to BANF1 were analyzed with quantitative PCR and Western blot. Strong nuclear-dominant immunostaining of BANF1 was seen in the epidermal keratinocytes of psoriatic lesions, although in the normal epidermis, all the KCs in the upper epidermis showed cytoplasmic-dominant staining of BANF1. By BANF1 knockdown in TPA-stimulated HSC-1 cells, the mRNA levels of S100A9 were significantly elevated compared with those of control HSC-1 cells treated with siRNA to CD4. The protein expression level of S100A9 and phosphorylated c-Jun was elevated by BANF1 knockdown. BANF1 is translocated onto the nuclear envelope in the psoriatic epidermal keratinocytes, suggesting that BANF1 is associated with upregulated proliferation of keratinocytes in psoriatic lesions. Activation of BANF1 possibly suppresses S100A9 expression and inactivates c-Jun, resulting in suppression of cutaneous inflammation. 23937954 Screening for developmental delay among children attending a rural community welfare clinic in Ghana. Periodic screening for developmental delays (DD) could avert the incidence of disability among children. However, such routine programme is yet to take off in rural welfare clinics in Ghana. Mothers of under-5 children who were attending rural child welfare clinic participated in this study. The socio-demographic data of the mothers and their children were recorded. The children were screened to assess their gross motor skills, fine motor skills, communication skills, and problem solving/cognition and social/personal interaction using Ages and Stages Questionnaire. Score below the threshold points on a developmental domain defines DD for a child. Data analysis involved percentages and frequency while Chi-square was performed to determine the associations between the selected socio-demographic risk factors and DD. Alpha value was set at p < 0.05. Three hundren and thirty (330) children were screened and majority 60(18%), were found within the age range 3 months 1 day to 5 months 0 day. 251(76%) had normal weight (2.5 kg-3.5) while 26(7.6%) were underweight (<2.5 kg). Generally, 147(44.6%) of the children had DD in the different domains of the questionnaires. 41(12.4%) had DD in social/personal interaction while 19(5.8%) were delayed in the communication domain. Birth weight and duration of gestation were significantly associated with communication domain while the level of education of the mothers and duration of gestation were significantly associated with gross motor domain. An appreciable proportion of the children were found to experience developmental delays and the most prevalent occurence was in personal/social interaction. Birth weight, gestational age and maternal educational level provide insight into a link with communication and gross motor skills. 23819769 Association of arterial blood pressure and CPR quality in a child using three different compression techniques. A case report. A 2-year-old boy found in cardiac arrest secondary to drowning received standard CPR for 35 minutes and was transported to a tertiary hospital for rewarming from hypothermia. Chest compressions in hospital were started using two-thumb encircling hands technique. Subsequently two-thumbs direct sternal compression technique and after sternal force/depth sensor placement, chest compression with classic one-hand technique were done. By using CPR recording/feedback defibrillator, quantitative CPR quality data and invasive arterial pressures were available for analyses for 5 hours and 35 minutes. 316 compressions with the two-thumb encircling hands technique provided a mean (SD) systolic arterial pressure (SAP) of 24 (4) mmHg, mean arterial pressure (MAP) 18 (3) and diastolic arterial pressure (DAP) of 15 (3) mmHg. ~6000 compressions with the two thumbs direct compression technique created a mean SAP of 45 (7) mmHg, MAP 35 (4) mmHg and DAP of 30 (3) mmHg. ~20,000 compressions with the sternal accelerometer in place produced SAP 50 (10) mmHg, MAP 32 (5) mmHg and DAP 24 (4) mmHg. Restoration of spontaneous circulation (ROSC) was achieved at the point when the child achieved normothermia by using peritoneal dialysis. Unfortunately, the child died ten hours after ROSC without any signs of neurological recovery. This case demonstrates improved hemodynamic parameters with classic one-handed technique with real-time quantitative quality of CPR feedback compared to either the two-thumbs encircling hands or two-thumbs direct sternal compression techniques. We speculate that the improved arterial pressures were related to improved chest compression depth when a real-time CPR recording/feedback device was deployed. 23302586 Discovering some novel 7-chloroquinolines carrying a biologically active benzenesulfonamide moiety as a new class of anticancer agents. Based on the reported anticancer activity of quinolines, a new series of 7-chloroquinoline derivatives bearing the biologically active benzenesulfonamide moiety 2-17 and 19-25 were synthesized starting with 4,7-dichloroquinolne 1. Compound 17 was the most active compound with IC(50) value 64.41, 75.05 and 30.71 µM compared with Doxorubicin as reference drug with IC(50) values 82.53, 88.32 and 73.72 µM on breast cancer cells, skin cancer cells and neuroblastoma, respectively. All the synthesized compounds were evaluated for their in vitro anticancer activity on breast cancer cells, skin cancer cells and neuroblastoma cells. Most of the synthesized compounds showed moderate activity. In order to suggest the mechanism of action for their cytotoxic activity, molecular docking for all synthesized compounds was done on the active site of phosphoinositide kinase (PI3K) and good results were obtained. 23736828 Benzyne cycloaddition onto carbon nanohorns. A facile approach for the covalent functionalization of carbon nanohorns (CNHs) based on the benzyne cycloaddition reaction is presented. The benzynes were in situ generated from either anthranilic acid by decomposition of the internal benzenediazonium-2-carboxylate or from 2-(trimethylsilyl)-phenyl triflate by fluoride ion attack at the silicon atom followed by displacement of the trimethylsilyl group under mild conditions. Moreover, the functionalization reaction was tested and performed under conventional conditions as well as under microwave irradiation. Modified CNHs possessing fused rings onto their graphitic skeleton were fully characterized by means of complementary spectroscopic techniques, thermogravimetric analysis, electron microscopy and light scattering. Moreover, Sonogashira coupling with propargyl alcohol followed by condensation with thioctic acid, to the iodo-modified CNHs obtained from the cycloaddition reaction of 2-amino-5-iodobenzoic acid with CNHs, resulted in the preparation of a new CNH-based material in which endocyclic disulfides are extended from the fused rings onto CNHs. The latter moieties were used to immobilize gold nanoparticles, furnishing the CNH-Au(nano) hybrid material, in which the former were identified with the aid of UV-Vis and EDX spectroscopy. 23842893 Fluorescence Characteristics of Bisphenol A in Room Temperature Ionic Liquids. Room temperature ionic liquids (RTILs) are emerging as a new class of 'green' solvents for use in a wide range of chemical processes. RTILs can sensitize or quench fluorescence of organic chemicals and their interactions still remain unclear, especially for weakly fluorescent chemicals. Herein, we report the effects of six RTILs on the fluorescence behavior of bisphenol A (BPA). The fluorescence intensities (FIs) of BPA in a RTIL-acetonitrile system were significantly quenched compared to acetonitrile. The quenching effect was stronger for [CnMIM]BF4 than [CnMIM]PF6. A decreasing trend of fluorescence lifetime (FL) of BPA was observed for [C6MIM]PF6 (4.26 to 3.86 ns) and [C14MIM]PF6 (4.15 to 3.78 ns) with increasing RTIL concentrations in the range of 1-10 mM. The quenching mode was consistent with a static quenching mechanism based on the consistency of FL and FI results. The emission bands of BPA and RTILs did not interfere with each other when RTILs were used as the solvent. The investigated RTILs enhanced the FIs of strongly fluorescing chemicals (12.0 ~ 19.0-fold for norfloxacin and 6.1 ~ 8.5-fold for dansyl chloride), but quenched those of weakly fluorescing chemicals (BPA). These results demonstrate that RTILs have different fluorescent effects on organic chemicals with different fluorophores. The interactions between RTILs and BPA result from many factors in addition to viscosity, such as solvent electrostatic dielectric constant, refractive index, density, polarization and molecular interaction. These results provide a theoretical foundation for application of RTILs in the analysis of weakly fluorescing chemical. 23286528 Unique Properties of Ceria Nanoparticles Supported on Metals: Novel Inverse Ceria/Copper Catalysts for CO Oxidation and the Water-Gas Shift Reaction. Oxides play a central role in important industrial processes, includingapplications such as the production of renewable energy, remediation of environmental pollutants, and the synthesis of fine chemicals. They were originally used as catalyst supports and were thought to be chemically inert, but now they are used to build catalysts tailored toward improved selectivity and activity in chemical reactions. Many studies have compared the morphological, electronic, and chemical properties of oxide materials with those of unoxidized metals. Researchers know much less about the properties of oxides at the nanoscale, which display distinct behavior from their bulk counterparts. More is known about metal nanoparticles. Inverse-model catalysts, composed of oxide nanoparticles supported on metal or oxide substrates instead of the reverse (oxides supporting metal nanoparticles), are excellent tools for systematically testing the properties of novel catalytic oxide materials. Inverse models are prepared in situ and can be studied with a variety of surface science tools (e.g. scanning tunneling microscopy, X-ray photoemission spectroscopy, ultraviolet photoemission spectroscopy, low-energy electron microscopy) and theoretical tools (e.g. density functional theory). Meanwhile, their catalytic activity can be tested simultaneously in a reactor. This approach makes it possible to identify specific functions or structures that affect catalyst performance or reaction selectivity. Insights gained from these tests help to tailor powder systems, with the primary objective of rational design (experimental and theoretical) of catalysts for specific chemical reactions. This Account describes the properties of inverse catalysts composed of CeOx nanoparticles supported on Cu(111) or CuOx/Cu(111) as determined through the methods described above. Ceria is an important material for redox chemistry because of its interchangeable oxidation states (Ce(4+) and Ce(3+)). Cu(111), meanwhile, is a standard catalyst for reactions such as CO oxidation and the water-gas shift (WGS). This metal serves as an ideal replacement for other noble metals that are neither abundant nor cost effective. To prepare the inverse system we deposited nanoparticles (2-20 nm) of cerium oxide onto the Cu(111) surface. During this process, the Cu(111) surface grows an oxide layer that is characteristic of Cu2O (Cu(1+)). This oxide can influence the growth of ceria nanoparticles. Evidence suggests triangular-shaped CeO2(111) grows on Cu2O(111) surfaces while rectangular CeO2(100) grows on Cu4O3(111) surfaces. We used the CeOx/Cu2O/Cu(111) inverse system to study two catalytic processes: the WGS (CO + H2O → CO2 + H2) and CO oxidation (2CO + O2 → 2CO2). We discovered that the addition of small amounts of ceria nanoparticles can activate the Cu(111) surface and achieve remarkable enhancement of catalytic activity in the investigated reactions. In the case of the WGS, the CeOx nanoparticle facilitated this process by acting at the interface with Cu to dissociate water. In the CO oxidation case, an enhancement in the dissociation of O2 by the nanoparticles was a key factor. The strong interaction between CeOx nanoparticles and Cu(111) when preoxidized and reduced in CO resulted in a massive surface reconstruction of the copper substrate with the introduction of microterraces that covered 25-35% of the surface. This constitutes a new mechanism for surface reconstruction not observed before. These microterraces helped to facilitate a further enhancement of activity towards the WGS by opening an additional channel for the dissociation of water. In summary, inverse catalysts of CeOx/Cu(111) and CeO2/Cu2O/Cu(111) demonstrate the versatility of a model system to obtain insightful knowledge of catalytic processes. These systems will continue to offer a unique opportunity to probe key catalytic components and elucidate the relationship between structure and reactivity of novel materials and reactions in the future. 23703823 Chronic low level trimethyltin exposure and the risk of developing nephrolithiasis. Nephrolithiasis (kidney stones) is a common disease with the prevalence that is increasing globally. We previously found that trimethyltin (TMT), a by-product of plastic stabilisers, can inhibit the H(+)/K(+) ATPase activity in renal intercalated cells and alter urinary pH, which is a known risk factor for nephrolithiasis. In this study, we conducted a cross-sectional analysis to evaluate the impact of chronic low level occupational TMT exposure on nephrolithiasis. This study included 216 healthy workers with TMT exposure and 119 workers as controls with no TMT exposure. All study participants were administered a questionnaire and underwent a routine clinical examination including an ultrasonographic screening for kidney stones. Exposures were assessed by measuring TMT concentrations in personal air samples, blood and urine. Logistic regression analysis was used to estimate the ORs and 95% CIs for the risk of kidney stones. TMT exposed workers had a higher prevalence of kidney stones (18.06%) in comparison with control workers (5.88%). High TMT concentrations in personal air samples, blood and urines were positively associated with increased prevalence of kidney stones in workers exposed to TMT compared with controls workers (p-trend values=0.005, 0.008 and 0.002, respectively). The length of employment in plants with elevated TMT levels (duration of the exposure) was significantly associated with the increased prevalence of kidney stones (p trend=0.001). The ORs were 2.66 for <3 years, 3.73 for 3-<10 years and 7.89 for 10+ years of employment compared with control workers. To our knowledge, this is the first report to demonstrate that occupational exposure to TMT is a potential risk factor for nephrolithiasis. 23916469 The atypical lipopolysaccharide ofFrancisella. Bacterial lipopolysaccharides (LPSs) are ubiquitous molecules that are prominent components of the outer membranes of most gram-negative bacteria. Genetic and structural characterizations of Francisella LPS have revealed substantial differences when compared to more commonly studied LPSs of the Enterobacteriaceae. This review discusses both the general characteristics and the unusual features of Francisella LPS. 23161584 Application of multiple geochemical markers to investigate organic pollution in a dynamic coastal zone. Multiple geochemical markers, including aliphatic hydrocarbons (n-alkanes), linear alkylbenzenes (LABs), and polycyclic aromatic hydrocarbons (PAHs), were employed to relate sediment organic chemical pollution in the coastal zone off South China to socioeconomic development there. Concentrations of Σn-C(15-35) (n-alkanes with 15-35 carbon atoms), ΣLAB (sum of C(10) to C(13) LABs), and Σ(26) PAH (sum of 26 PAH compounds) ranged from 110 to 3,160, 11 to 160, and 26 to 600 ng/g, with medians of 730, 40, and 230 ng/g, respectively. Natural hydrocarbons were mainly derived from terrestrial higher plant waxes, and in minor amounts from aquatic plankton and bacteria. Compositions of LABs indicated that considerable amounts of poorly treated wastewater had been directly discharged or transported to the eastern and western coastal areas of Guangdong Province. In addition, anthropogenic hydrocarbons were derived largely from vehicular emissions and combustion of domestic coal and biomass and to a lesser extent from oil spills. Eastern and western coastal sediments contained higher levels of LABs but lower levels of PAHs than those of the Pearl River Estuary, a coastal area of the Pearl River Delta. This spatial pattern of organic pollution was consistent with chemical use patterns. The eastern and western regions of Guangdong Province are economically less developed than the Pearl River Delta region, where more domestic wastewater treatment plants have been built. However, greater amounts of energy are consumed in the latter region to produce more combustion-derived PAH contamination. 23959311 Oral DAV131, a Charcoal-based Adsorbent, Inhibits Intestinal Colonization by Beta-lactam Resistant Klebsiella pneumoniae in Cefotaxime-Treated Mice. Antibiotics excreted into the intestinal tract, such as broad spectrum cephalosporins, disrupt the indigenous microflora, affect colonization resistance (CR), and promote intestinal colonization by resistant bacteria. We tested whether oral DAV131, a charcoal-based adsorbent, would prevent colonization by a cefotaxime (CTX) resistant Klebsiella pneumoniae strain (PUG-2) in CTX treated mice.Mice received CTX, saline, CTX and DAV131, or saline and DAV131 for 3 days before oral challenge with 10(6) CFU of PUG-2. Fecal CTX concentrations and counts of PUG-2 were assayed. Fecal CTX disappeared when DAV131 was given concomitantly to CTX (p<0.05), and area under the curve of PUG-2 fecal density was significantly reduced (p<0.01). In conclusion, reducing intestinal antibiotic exposure with DAV131 may reduce colonization by resistant strains during treatments compare with CTX only treatment. This might open new possibilities for decreasing the impact of antibiotics on the intestinal microbiota during treatments. 23895132 The anti-inflammatory effect of kaempferol on early atherosclerosis in high cholesterol fed rabbits. Atherosclerosis has been widely accepted as an inflammatory disease of vascular, adhesion molecules play an important role in the early progression of it. The aim of the present study was to evaluate the effect of kaempferol on the inflammatory molecules such as E-selectin (E-sel), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesionmolecule-1 (VCAM-1) and monocyte chemotactic protein-1 (MCP-1) in high cholesterol induced atherosclerosis rabbit models. Thirty male New Zealand white (NZW) rabbits were randomly divided into five groups, control group, model group, fenofibrate (12 mg/kg) group and kaempferol groups (150 mg/kg and 30 mg/kg). The rabbits were fed with a normal diet or a high cholesterol diet for 10 weeks. Levels of blood lipids, serum tumour-necrosis factor-alpha (TNF-α) and serum interleukin-1beta (IL-1β) were detected at the end of the sixth and tenth week. Malonaldehyde (MDA) level and superoxide dismutase (SOD) activity in serum were also determined. Lesion areas of the aorta were measured with morphometry analysis after ten weeks. Gene expression of E-sel, ICAM-1, VCAM-1 and MCP-1 in aortas was determined by RT-PCR (reverse transcription-polymerase chain reaction). Immunohistochemical staining was employed to measure protein expression of E-sel, ICAM-1, VCAM-1 and MCP-1. Model rabbits fed with ten weeks of high-cholesterol diet developed significant progression of atherosclerosis. Compared with the control, levels of blood lipids, TNF-α, IL-1β and MDA increased markedly in serum of model rabbits, while SOD levels decreased. Gene and protein expressions of E-sel, ICAM-1, VCAM-1 and MCP-1 in atherosclerotic aortas increased remarkably in model group. However, comparing to the model rabbits, levels of TNF-α, IL-1β and MDA decreased significantly and serum SOD activity increased, gene and protein expressions of E-sel, ICAM-1, VCAM-1 and MCP-1 in aortas decreased significantly with the treatment of kaempferol. Kaempferol shows anti-atherosclerotic effect by modulating the gene and protein expression of inflammatory molecules. 23846496 Acat1 gene ablation in mice increases hematopoietic progenitor cell proliferation in bone marrow and causes leukocytosis. To investigate the role of acyl-CoA:cholesterol acyltransferase 1 (ACAT1) in hematopoiesis. ACAT1 converts cellular cholesterol to cholesteryl esters for storage in multiple cell types and is a potential drug target for human diseases. In mouse models for atherosclerosis, global Acat1 knockout causes increased lesion size; bone marrow transplantation experiments suggest that the increased lesion size might be caused by ACAT1 deficiency in macrophages. However, bone marrow contains hematopoietic stem cells that give rise to cells in myeloid and lymphoid lineages; these cell types affect atherosclerosis at various stages. Here, we test the hypothesis that global Acat1(-/-) may affect hematopoiesis, rather than affecting macrophage function only, and show that Acat1(-/-) mice contain significantly higher numbers of myeloid cells and other cells than wild-type mice. Detailed analysis of bone marrow cells demonstrated that Acat1(-/-) causes a higher proportion of the stem cell-enriched Lin(-)Sca-1(+)c-Kit(+) population to proliferate, resulting in higher numbers of myeloid progenitor cells. In addition, we show that Acat1(-/-) causes higher monocytosis in Apoe(-/-) mouse during atherosclerosis development. ACAT1 plays important roles in hematopoiesis in normal mouse and in Apoe(-/-) mouse during atherosclerosis development. 23788734 Bright hot impacts by erupted fragments falling back on the Sun: a template for stellar accretion. Impacts of falling fragments observed after the eruption of a filament in a solar flare on 7 June 2011 are similar to those inferred for accretion flows on young stellar objects. As imaged in the ultraviolet (UV)-extreme UV range by the Atmospheric Imaging Assembly onboard the Solar Dynamics Observatory, many impacts of dark, dense matter display uncommonly intense, compact brightenings. High-resolution hydrodynamic simulations show that such bright spots, with plasma temperatures increasing from ~10(4) to ~10(6) kelvin, occur when high-density plasma (>10(10) particles per cubic centimeter) hits the solar surface at several hundred kilometers per second, producing high-energy emission as in stellar accretion. The high-energy emission comes from the original fragment material and is heavily absorbed by optically thick plasma, possibly explaining the lower mass accretion rates inferred from x-rays relative to UV-optical-near infrared observations of young stars. 23871926 Microwave pyrolysis of microalgae for high syngas production. The microwave induced pyrolysis of the microalgae Scenedesmus almeriensis and its extraction residue was carried out at 400 and 800°C. The results show that it is possible to obtain a gas fraction with a high content (c.a. 50vol.%) in H2 from both materials, regardless of the pyrolysis temperature. Furthermore, an outstanding syngas production and high gas yields were achieved. The maximum syngas concentration obtained was c.a. 94vol.%, in the case of the pyrolysis of the residue at 800°C, indicating that the production of CO2 and light hydrocarbons was minimized. The same experiments were carried out in a conventional electric furnace in order to compare the products and yields obtained. It was found that microwave induced pyrolysis gives rise not only to higher gas yields but also to greater syngas and H2 production. 23927246 The tensor hypercontracted parametric reduced density matrix algorithm: Coupled-cluster accuracy with O(r(4)) scaling. Tensor hypercontraction is a method that allows the representation of a high-rank tensor as a product of lower-rank tensors. In this paper, we show how tensor hypercontraction can be applied to both the electron repulsion integral tensor and the two-particle excitation amplitudes used in the parametric 2-electron reduced density matrix (p2RDM) algorithm. Because only O(r) auxiliary functions are needed in both of these approximations, our overall algorithm can be shown to scale as O(r(4)), where r is the number of single-particle basis functions. We apply our algorithm to several small molecules, hydrogen chains, and alkanes to demonstrate its low formal scaling and practical utility. Provided we use enough auxiliary functions, we obtain accuracy similar to that of the standard p2RDM algorithm, somewhere between that of CCSD and CCSD(T). 23664977 Alternative splicing generates a truncated isoform of human TNFRSF11A (RANK) with an altered capacity to activate NF-κB. Alternative splicing (AS) is a major post-transcriptional modification taking place in all cells. Many members of the TNF receptor superfamily modulate their function through protein isoforms produced by alternative splicing. TNFRSF11A (RANK) gene, through alternative splicing produces multiple isoforms truncated in their intracellular domain, with distinct functions. Here, we report the identification and characterization of a novel human TNFRSF11A (RANK) variant from human normal brain, named RANK-e5a (TNFRSF11A_e5a). The novel variant lacks 42 nucleotides from exon 5, giving rise to a novel shorter form of exon 5, named exon 5a. The incorporation of the novel exon 5a in RANK mRNA does not affect the open reading frame, producing a truncation of thirteen amino acids of the third and fourth TNFR motifs of the extracellular part of the receptor. By western blot analysis and immunofluorescence staining we were able to further characterize the RANK-e5a isoform at the protein level. In addition, we performed an ELISA assay to characterize RANK/RANKL and RANK-e5a/RANKL binding capacities, and we identified a reduced affinity of RANK-e5a to bind RANKL. Finally, when RANK-e5a is stimulated by RANK ligand, its capability to activate NF-κB is reduced compared to the wild type RANK receptor. Overall, our data provide a novel regulatory mechanism for the RANK/RANKL system, at the RANK receptor level. 23844833 Determining Equilibrium Fluctuations Using Temperature-Dependent 2D-IR. We demonstrate the capability of temperature-dependent 2D-IR to characterize sources of vibrational population transfer. In a model system of iron diene tricarbonyl "piano stool" complexes, this approach reveals symmetry breaking associated with equilibrium fluctuations and differentiates these from fluxional rearrangement. Tricarbonyl(1,3-butadiene)iron and tricarbonyl(1,5-cyclooctadiene)iron are shown to undergo intramolecular vibrational redistribution (IVR) coupled to the wagging motion of their carbonyl ligands. In the case of both molecules, these equilibrium fluctuations are distinguished from chemical exchange behaviors by their temperature dependence and arguments of molecular symmetry. 23462698 Alcohol cirrhosis alters nuclear receptor and drug transporter expression in human liver. Unsafe use of alcohol results in approximately 2.5 million deaths worldwide, with cirrhosis contributing to 16.6% of reported deaths. Serum insulin levels are often elevated in alcoholism and may result in diabetes, which is why alcoholic liver disease and diabetes often are present together. Because there is a sizable population with these diseases alone or in combination, the purpose of this study was to determine whether transporter expression in human liver is affected by alcoholic cirrhosis, diabetes, and alcoholic cirrhosis coexisting with diabetes. Transporters aid in hepatobiliary excretion of many drugs and toxic chemicals and can be determinants of drug-induced liver injury. Drug transporter expression and transcription factor-relative mRNA and protein expression in normal, diabetic, cirrhotic, and cirrhosis with diabetes human livers were quantified. Cirrhosis significantly increased ABCC4, 5, ABCG2, and solute carrier organic anion (SLCO) 2B1 mRNA expression and decreased SLCO1B3 mRNA expression in the liver. ABCC1, 3-5, and ABCG2 protein expression was also upregulated by alcoholic cirrhosis. ABCC3-5 and ABCG2 protein expression was also upregulated in diabetic cirrhosis. Cirrhosis increased nuclear factor E2-related factor 2 mRNA expression, whereas it decreased pregnane-X-receptor and farnesoid-X-receptor mRNA expression in comparison with normal livers. Hierarchical cluster analysis indicated that expressions of ABCC2, 3, and 6; SLCO1B1 and 1B3; and ABCC4 and 5 were more closely related in the livers from this cohort. Overall, alcoholic cirrhosis altered transporter expression in human liver. 23927012 Combination of Multistep IMAC Enrichment with High-pH Reverse Phase Separation for In-Depth Phosphoproteomic Profiling. Typical mass spectrometric phosphoproteome studies are complicated by the need for large amounts of starting material and extensive sample preparation to ensure sufficient phosphopeptide identifications. In this paper, we present a novel strategy to perform optimized multistep IMAC enrichment from whole cell lysates followed by high-pH reverse phase fractionation (multi-IMAC-HLB; HLB means hydrophilic-lipophilic-balanced reversed-phase cartridge). The peptide-to-IMAC ratio was optimized to maximize IMAC performance, while multistep IMAC enrichment enabled improved phosphopeptide acquisition. The addition of the HLB step further fractionates the IMAC enriched phosphopeptides while desalting the samples, which dramatically reduces the sample manipulation time and sample loss compared to other popular strategies. We compared the phosphopeptide identification results of the multi-IMAC-HLB method with 3 mg of starting material to the well-established SCX-IMAC method with 15 mg of starting material. We identified 8969 unique phosphopeptides with the multi-IMAC-HLB method, compared to 5519 unique phosphopeptides identified with the SCX-IMAC method, an increase of 62.5%. The increase in the numbers of identified phosphopeptides is due to the increase in the ratio of identified phosphopeptides out of all detected peptides, 70.5% with multi-IMAC-HLB method compared to 32.3% with the SCX-IMAC method. Multi-IMAC-HLB is a robust and efficient method for in-depth phosphoproteomic research. 23822867 The cilium in lights: new views of an ancient organelle. Nearly all cells have cilia, microtubule based projections from the apical cell surface, and nearly all cells use them in essential and unique ways. How mammalian cilia function in vivo as mechanosensors, signal transducers, or in fluid propulsion has been difficult to study due to lack of tools for live imaging of cilia. A new transgenic mouse that enables tissue-specific GFP labeling of cilia creates new opportunities for using live imaging to understand cilium function and to better characterize the many genetic models of ciliopathies. See research article: http://www.ciliajournal.com/content/2/1/8. 23223523 SERS performance of gold nanotubes obtained by sputtering onto polycarbonate track-etched membranes. Surface-enhanced Raman scattering (SERS) is a powerful and versatile tool for studying molecules on metallic surfaces with great impact on areas such as electrochemistry, catalysis and related subjects. The search for new SERS-active substrates with high performance, namely high enhancement factors and reproducibility, is currently the main focus of several research groups. Here is shown an alternative easy and inexpensive synthetic approach to a SERS-substrate comprised of gold nanotubes obtained by the sputtering onto polycarbonate track-etched membranes used as template. Its SERS performance was evaluated by mapping (10 × 10) μm(2) areas and resulted in average enhancement factors that span from 2.3 × 10(3) to 1.2 × 10(5) with a maximum enhancement factor of 2.5 × 10(5). The enhancement depended strongly on the template pore diameter, with the best performance obtained when membranes with pore diameters of 400 nm were used as template. Further analysis showed that the larger enhancements came from coalesced gold nanotubes and detection of the dye rhodamine 6G at concentrations as low as 0.1 nM was possible. These results put this substrate as a valuable and easy-to-fabricate tool for studying and detecting molecules on surfaces. The proposed methodology could be easily adapted to other metals, such as silver and copper. 23879651 A strategy for multimodal deformable image registration to integrate PET/MR into radiotherapy treatment planning. Background. Combined positron emission tomography (PET)/magnetic resonance imaging (MRI) is highly promising for biologically individualized radiotherapy (RT). Hence, the purpose of this work was to develop an accurate and robust registration strategy to integrate combined PET/MR data into RT treatment planning. Material and methods. Eight patient datasets consisting of an FDG PET/computed tomography (CT) and a subsequently acquired PET/MR of the head and neck (HN) region were available. Registration strategies were developed based on CT and MR data only, whereas the PET components were fused with the resulting deformation field. Following a rigid registration, deformable registration was performed with a transform parametrized by B-splines. Three different optimization metrics were investigated: global mutual information (GMI), GMI combined with a bending energy penalty (BEP) for regularization (GMI+ BEP) and localized mutual information with BEP (LMI+ BEP). Different quantitative registration quality measures were developed, including volumetric overlap and mean distance measures for structures segmented on CT and MR as well as anatomical landmark distances. Moreover, the local registration quality in the tumor region was assessed by the normalized cross correlation (NCC) of the two PET datasets. Results. LMI+ BEP yielded the most robust and accurate registration results. For GMI, GMI+ BEP and LMI+ BEP, mean landmark distances (standard deviations) were 23.9 mm (15.5 mm), 4.8 mm (4.0 mm) and 3.0 mm (1.0 mm), and mean NCC values (standard deviations) were 0.29 (0.29), 0.84 (0.14) and 0.88 (0.06), respectively. Conclusion. Accurate and robust multimodal deformable image registration of CT and MR in the HN region can be performed using a B-spline parametrized transform and LMI+ BEP as optimization metric. With this strategy, biologically individualized RT based on combined PET/MRI in terms of dose painting is possible. 23583216 Maternal soluble fms-like tyrosine kinase-1, placental growth factor, plasminogen activator inhibitor-2, and folate concentrations and early fetal size: the Generation R study. Fetal growth is dependent on adequate development of the placenta. Impaired angiogenesis and vasculogenesis in early pregnancy compromises placental and embryonic development. The proteins soluble fms-like tyrosine kinase (sFlt)-1, placental growth factor (PlGF), and plasminogen activator inhibitor (PAI)-2, and the B vitamin folate are determinants of placental development. This study aims to identify associations between these maternal biomarkers and early fetal size. From a prospective birth cohort study in The Netherlands, 1491 pregnant women were selected for this study. At a mean gestational age (GA) of 12.4 weeks (SD 0.8) maternal venous blood samples were obtained to determine the concentrations of sFlt-1, PlGF, PAI-2, and folate. Early fetal size was assessed with measurement of the crown-to-rump length (CRL) at a mean of 12.4 weeks' GA (SD 0.8). Analyses were performed using multivariable linear regression analyses with the biomarkers (continuous, quintiles) as regressors and CRL as main outcome measure. Linear trend analysis showed positive associations between maternal sFlt-1 (P < .001), PlGF (P = .042), PAI-2 (P < .001), and folate (P = .039) and CRL. These associations were independent of GA, maternal age, height, body mass index, ethnicity, fetal sex, parity, educational level, smoking, and folic acid supplement use (folate not adjusted). sFlt-1, PlGF, PAI-2, and folate are positively associated with first-trimester fetal size. 23945990 The interactions of nitrogen dioxide with graphene-stabilized Rh clusters: a DFT study. We study the interactions of NO2 gas molecules with Rh nanoparticles supported on graphene, using first-principles molecular dynamics in the Car-Parrinello scheme. The stability, morphology, adsorption energies of various models of Rhx nanoparticles (x = 1, 3, 10, 20) supported on graphene, and the binding of NO2 molecules to the Rh clusters, together with its effect on the graphene properties, are reported. Metastable flat structures anchored to the substrate that can bind NO2 to Rh via both N and O atoms are identified, with adsorption energies in the range 60-70 kcal per mole per molecule. 23474766 Volumetric evaluation of dual-energy perfusion CT by the presence of intrapulmonary clots using a 64-slice dual-source CT. Dual-energy perfusion CT (DEpCT) directly represents the iodine distribution in lung parenchyma and low perfusion areas caused by intrapulmonary clots (IPCs) are visualized as low attenuation areas. To evaluate if volumetric evaluation of DEpCT can be used as a predictor of right heart strain by the presence of IPCs. One hundred and ninety-six patients suspected of having acute pulmonary embolism (PE) underwent DEpCT using a 64-slice dual-source CT. DEpCT images were three-dimensionally reconstructed with four threshold ranges: 1-120 HU (V120), 1-15 HU (V15), 1-10 HU (V10), and 1-5 HU (V5). Each relative ratio per V120 was expressed as the %V15, %V10, and %V5. Volumetric data-sets were compared with D-dimer, pulmonary arterial (PA) pressure, right ventricular (RV) diameter, RV/left ventricular (RV/LV) diameter ratio, PA diameter, and PA/aorta (PA/Ao) diameter ratio. The areas under the ROC curves (AUCs) were examined for their relationship to the presence of IPCs. This study was approved by the local ethics committee. PA pressure and D-dimer were significantly higher in the patients who had IPCs. In the patients with IPCs, V15, V10, V5, %V15, %V10, and %V5 were also significantly higher than those without IPC (P ≤ 0.001). %V5 had a better correlation with D-dimer (r = 0.30, P < 0.001) and RV/LV diameter ratio (r = 0.27, P < 0.001), and showed a higher AUC (0.73) than the other CT measurements. The volumetric evaluation by DEpCT had a correlation with D-dimer and RV/LV diameter ratio, and the relative ratio of volumetric CT measurements with a lower attenuation threshold might be recommended for the analysis of acute PE. 23941286 Engagement with the criminal justice system among opioid dependent people: Retrospective cohort study. Studies of offending among people who use drugs typically focus upon small and potentially unrepresentative samples. We examined an entire population of opioid dependent clients' contact with the criminal justice system to develop more accurate population-wide measures of offending among opioid-dependent people in Australia. Retrospective data linkage study. All entrants to opioid substitution therapy (OST) for opioid dependence in New South Wales, Australia, between 1985 and 2010, with data on court appearances from 1 December 1993 to 31 March 2011. All 48, 069 individuals who received OST between 1985-2010. Person years (PY) of observation and charge rates for major crime categories estimated by sex, age, and time. 638,545 charges were laid against cohort members between 1993 and 2011. Eight in ten males (79.7%) and 67.9% of females had at least one charge; rates were 94.15 per 100PY (95% CI 93.89-94.41) among males, and 53.19 per 100PY (95% CI 52.91-53.46) among females, and highest at 15-19 years (175.74/100PY males (95% CI 174.45-177.03), 75.60/100PY females (95% CI 74.46-76.76)) and 20-24 years (144.61/100PY males (95% CI 143.70-145.53), 84.50/100PY females (95% CI 83.53-85.48)). The most frequent charges were theft (24.5% of charges), traffic/vehicle (16.3%), offences against justice (10.5%), illicit drug (10.0%), intentional injury(9.9%) and public order offences (8.9%). Overall, 20.8% of the cohort accounted for 67.4% of charges. The most frequently appearing 5.6% of the cohort accounted for 24.3% of costs ($75.5M). Among opioid dependent people in Australia, a minority account for the majority of the criminal justice contact and levels of offending are not consistent over time, sex or age. 23376161 Catalpol suppresses advanced glycation end-products-induced inflammatory responses through inhibition of reactive oxygen species in human monocytic THP-1 cells. Advanced glycation end-products (AGEs) play a pivotal role in the development of diabetic complications by inducing inflammation. We previously reported that the fresh roots of Rehmannia glutinosa Libosch., which have been used for the treatment of diabetes in traditional Korean medicine, also have the potential to suppress AGE-mediated inflammatory response in THP-1 cells. In the present study, we isolated catalpol from R. glutinosa, and examined whether it has anti-inflammatory effects on AGE-stimulated THP-1 cells. Catalpol reduced the expression of pro-inflammatory mediates, such as monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), inducible NO synthase (iNOS), and receptor for AGE (RAGE). Promoter and electromobility shift assays showed that transcriptional activation of NF-κB was significantly reduced by catalpol treatment, while AP-1 was not. Catalpol also suppressed AGE-induced phosphorylation of mitogen activated protein (MAP) kinases, degradation of IκBα and the nuclear localization of NF-κB. Moreover, the production of intracellular reactive oxygen species (ROS) elicited by AGE was also suppressed by catalpol treatment, through dual action of reducing ROS itself and inhibiting NADPH oxidase activity. Our findings indicate that catalpol suppresses AGE-mediated inflammation by inhibiting ROS production and NF-κB activity. We suggest that catalpol, a major constituent of the fresh roots of R. glutinosa, contributes to the prevention of AGE-mediated diabetic complications. 23000916 Pharmacological targeting of endoplasmic reticulum stress signaling in cancer. The endoplasmic reticulum (ER) stress response constitutes a cellular process that can be triggered by a great variety of conditions that cause imbalances in intracellular homeostasis and threaten proper cell functioning. In response, the ER stress response activates an adaptive effort aimed at neutralizing these threats and reestablishing homeostasis. However, if these countermeasures are unsuccessful and severe imbalances persist, the ER stress response may abandon its pro-survival efforts and instead may initiate a pro-apoptotic program to eliminate the faulty cell for the benefit of the organism as a whole. Because vigorous growth of malignant tumors may create stressful conditions, such as hypoglycemia, hypoxia, or accumulation of misfolded proteins during revved up protein synthesis, the adaptive, pro-survival components of the ER stress response system (e.g., GRP78/BiP) are frequently found chronically activated in tumor cells. This differential to non-stressed normal cells has been proposed to represent an Achilles' heel of tumor cells that may be exploitable by therapeutic intervention. In this model, the goal would be to further aggravate the pre-existing stress conditions in tumor cells with appropriate pharmacological agents, so that the already engaged pro-survival mechanism would be overwhelmed and the ER stress response forced to switch to its pro-apoptotic mode (e.g., CHOP/GADD153). This review will discuss the principle of pharmacological ER stress aggravation, and will present preclinical models with promise for cancer therapeutic applications. 23580240 Concurrent inhibition of PI3K and mTORC1/mTORC2 overcomes resistance to rapamycin induced apoptosis by down-regulation of Mcl-1 in mantle cell lymphoma. Mantle cell lymphoma (MCL) is an aggressive form of Non-Hodgkin-lymphoma (NHL) with an ongoing need for novel treatments. Apart from the translocation t(11:14), which facilitates constitutive transcription of cyclin D1, additional aberrations are frequently observed in MCL, including a recurrent dysregulation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. mTOR, a key component of this pathway, is pivotal for the assembly of mTOR complex (mTORC) 1 and 2. Temsirolimus, an analog of the mTOR inhibitor rapamycin, is approved for the treatment of relapsed MCL. Response rates, however, are low and response durations are short. We demonstrate that inhibition of mTORC1 by rapamycin or blocking of mTORC1 and mTORC2 in conjunction with PI3K by NVP-BEZ235 reduces proliferation of MCL cell lines to a similar extent. However, only NVP-BEZ235 is able to sufficiently inhibit the downstream pathway of mTOR and to mediate cell death through activation of the intrinsic apoptosis pathway. Further analysis demonstrated that the anti-apoptotic Bcl-2 family member Mcl-1 plays a central role in regulation of MCL survival. While Mcl-1 protein levels remained unchanged after coculture with rapamycin, they were down-regulated in NVP-BEZ235 treated cells. Furthermore, inhibition of Mcl-1 by the BH3-only mimetic obatoclax or down-regulation of constitutive Mcl-1, but not of Bcl-2 or Bcl-xL , by siRNA facilitated cell death of MCL cells and enhanced NVP-BEZ235's capacity to induce cell death. Our findings may help to lay the foundation for further improvements in the treatment of MCL. 23908481 Estimation of the association between antibody titers and protection against confirmed influenza virus infection in children. Antibody titers measured by hemagglutination inhibition (HAI) correlate with protection against influenza virus infection, and are used to specify criteria for vaccine licensure. In a randomized controlled trial of seasonal influenza vaccination in 773 children 6-17y, we estimated that HAI titers of 1:40 against A(H1N1)pdm09 and B(Victoria-lineage) were associated with 48% (95% confidence interval, CI: 30%-62%) and 55% (95%CI: 32%-70%) protection against PCR-confirmed infection with each strain. Our analysis accounted for waning in antibody titers over time, and could be particularly useful in settings where influenza activity is delayed or prolonged relative to measurement of antibody titers. 23929934 Decreased cord-blood phospholipids in young age at onset type 1 diabetes. Children developing type 1 diabetes may have risk markers already in their umbilical cord blood. It is hypothesized that the risk for type 1 diabetes at an early age may be increased by a pathogenic pregnancy and be reflected in altered cord-blood composition. In this study metabolomics was used to test if the cord-blood lipidome was affected in children diagnosed with type 1 diabetes before eight years of age. The present case-control study of 76 index children diagnosed with type 1 diabetes before eight years of age and 76 healthy controls matched for HLA risk, gender and date of birth as well as mother's age and gestational age revealed that cord-blood phosphatidylcholines and phosphatidylethanolamines were significantly decreased in children diagnosed with type 1 diabetes before four years of age. Reduced levels of triglycerides correlated to gestational age in both index and control children and to age at diagnosis only in the index children. Finally, gestational infection during the first trimester was associated with lower cord blood total lysophosphatidylcholines in both index and control children. In conclusion, metabolomics of umbilical cord blood may identify children at increased risk for type 1 diabetes. Low phospholipid levels at birth may represent key mediators of the immune system and contribute in early induction of islet autoimmunity. 23678030 Role of vasopressin in maintenance of potassium homeostasis in severe hemorrhage. Uncontrolled elevation in plasma potassium within minutes of rapid blood volume loss is associated with mortality and distinguishes nonsurvivors of severe hemorrhage from survivors. In a pig model of severe hemorrhage, we discovered that along with a sharp increase in plasma potassium coincident with a shut down of urine flow, nonsurvivors also had an insufficient vasopressin response to hemorrhage. In contrast, survivors did have elevated vasopressin levels in response to hemorrhage and maintained plasma potassium within normal limits. While it has been demonstrated for some time that vasopressin can influence secretion of potassium in the distal nephron, the magnitude of this effect and conditions under which this contributes to physiological modulation of potassium excretion has yet to be defined. In this review, we assess the evidence that would suggest that vasopressin plays a key role in modulating potassium excretion and is important in the regulation of potassium homeostasis during hemorrhage. 23711969 Acute compartment syndrome of the thigh secondary to isolated common femoral vessel injury: an unusual etiology. We report a case of acute compartment syndrome of the thigh secondary to common femoral vessel injury. The lesion was associated with common femoral artery dissection and common femoral vein rupture. Emergency surgical treatment consisted of resection-anastomosis of the arterial dissection, vein ligature, and fasciotomies. The patient is symptom-free after 15 months of follow-up. Isolated vascular injury is an unusual cause of acute compartment syndrome of the thigh. This case serves to increase awareness that isolated vascular injury, without femoral fracture or multiple injury, can result in thigh compartment syndrome. Early recognition and treatment of vascular involvement contributes to better functional outcome of this rare condition, but treatment modalities remain subject to discussion. 23537890 The involvement of heme oxygenase 1 but not nitric oxide synthase 2 in a hepatoprotective action of quercetin in lipopolysaccharide-induced hepatotoxicity of d-galactosamine sensitized rats. The objective of this study was to evaluate potential hepatoprotective capabilities of quercetin in relation to its modulation of the HO-1 and NOS-2 activities in an experimental model of fulminant liver failure. Liver insult was induced by in vivo administration of d-galactosamine (d-GalN, 400mg/kg, i.p.) and lipopolysaccharide (LPS, 10μg/kg, i.p.). The effects of quercetin (50mg/kg, i.p) on d-GalN toxicity was evaluated by standard biochemical, RT-PCR and Western blot methods. Administration of d-GalN/LPS combination resulted in significantly higher plasma levels of aminotransferases, as well as increased mRNA and protein expressions of both HO-1 and NOS-2 enzymes. Quercetin exhibited cytoprotective effects on the liver, as evidenced by decreased aminotransferase plasma levels. Additionally, quercetin treatment in d-GalN/LPS treated rats significantly increased HO-1 mRNA and its protein expressions. On the contrary, quercetin did not exhibit any significant effects on the levels of nitrites, and NOS-2 mRNA and protein expressions in d-GalN/LPS treated rats. Quercetin when given alone did not have any significant changes on liver enzymes nor HO-1 and NOS-2 mRNA and protein expressions. It can be concluded that the quercetin's induction of HO-1 and its byproducts, without concomitant NOS-2 activity reduction, is among mechanisms contributing to the hepatoprotective effect in d-GalN/LPS hepatotoxicity. 23270994 The vasorelaxant effects of 1-nitro-2-phenylethane involve stimulation of the soluble guanylate cyclase-cGMP pathway. 1-Nitro-2-phenylethane is the first organic NO₂-containing molecule isolated from plants. It possesses interesting hypotensive, bradycardic, and vasodilator properties, but the mode by which it induces vasorelaxation is still unknown. The underlying mechanism involved in the vasodilator effect of 1-nitro-2-phenylethane was investigated in rat aorta. The vasorelaxant effects of 1-nitro-2-phenylethane did not depend on endothelial layer integrity, and the effects were refractory to L-N(G)-nitroarginine methyl ester (L-NAME)-induced nitric oxide synthase inhibition. Vasorelaxation was similarly resistant to treatment with indomethacin, cis-N-(2-phenylcyclopentyl)-azacyclotridec-1-en-2-amine hydrochloride (MDL-12330A), and KT5720, indicating that neither prostaglandin release nor adenylyl cyclase activation is involved. Conversely, methylene blue- and ODQ-induced guanylate cyclase inhibition reduced the vasorelaxation induced by 1-nitro-2-phenylethane. The pharmacological blockade of K(+) channels with tetraethylammonium, glybenclamide, and 4-aminopyridine also blunted vasorelaxation induced by 1-nitro-2-phenylethane. The effects of 1-nitro-2-phenylethane were reversed by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and comparable to the effects induced by sodium nitroprusside. In silico analysis using an Ns H-NOX subunit of guanylate cyclase revealed a pocket on the macromolecule surface where 1-nitro-2-phenylethane preferentially docked. In vitro, 1-nitro-2-phenylethane increased cyclic guanosine 3',5'-monophosphate (cGMP) levels in rat aortic rings, an effect also reversed by ODQ. In conclusion, 1-nitro-2-phenylethane produces vasodilator effects by stimulating the soluble guanylate cyclase-cGMP pathway. 23765384 Stress echocardiography and major cardiac events in patients with normal exercise test. Exercise test (ET) is the preferred initial noninvasive test for the diagnosis and risk stratification of coronary artery disease (CAD), however, its lower sensitivity may fail to identify patients at greater risk of adverse events. To assess the value of stress echocardiography (SE) for predicting all-cause mortality and major cardiac events (MACE) in patients with intermediate pretest probability of CAD and a normal ET. 397 patients with intermediate CAD pretest probability , estimated by the Morise score, and normal ET who underwent SE were studied. The patients were divided into two groups according to the absence (G1) or presence (G2) of myocardial ischemia on SE .End points evaluated were all-cause mortality and MACE, defined as cardiac death and nonfatal acute myocardial infarction (AMI). G1 group was comprised of 329 (82.8%) patients. The mean age of the patients was 57.37 ± 11 years and 44.1% were male. During a mean follow-up of 75.94 ± 17.24 months, 13 patients died, three of them due to cardiac causes, and 13 patients suffered nonfatal AMI. Myocardial ischemia remained an independent predictor of MACE (HR 2.49; [CI] 95% 1.74-3.58). The independent predictors for all-cause mortality were male gender (HR 9.83; [CI] 95% 2.15-44.97) and age over 60 years (HR 4.57; [CI] 95% 1.39-15.23). Positive SE for myocardial ischemia is a predictor of MACE in the studied sample, which helps to identify a subgroup of patients at higher risk of events despite having normal ET. 23934772 Exhaustive comparison and classification of ligand-binding surfaces in proteins. Many proteins function by interacting with other small molecules (ligands). Identification of ligand-binding sites (LBS) in proteins can therefore help to infer their molecular functions. A comprehensive comparison among local structures of LBSs was previously performed, in order to understand their relationships and to classify their structural motifs. However, similar exhaustive comparison among local surfaces of LBSs (patches) has never been performed, due to computational complexity. To enhance our understanding of LBSs, it is worth performing such comparisons among patches and classifying them based on similarities of their surface configurations and electrostatic potentials. In this study, we first developed a rapid method to compare two patches than reported methods. We then clustered patches corresponding to the same PDB chemical component identifier for a ligand, and selected a representative patch from each cluster. We subsequently exhaustively compared the representative patches and clustered them using similarity score, PatSim. Finally, the resultant PatSim scores were compared with similarities of atomic structures of the LBSs and those of the ligand-binding protein sequences and functions. Consequently, we classified the patches into approximately 2,000 well-characterized clusters. We found that about 63% of these clusters are used in identical protein folds, although about 25% of the clusters are conserved in distantly related proteins and even in proteins with cross-fold similarity. Furthermore, we showed that patches with higher PatSim score have potential to be involved in similar biological processes. Statement for a broader audience For better understanding of biochemical functions of proteins based on their three-dimensional structures, an exhaustive comparison among surfaces of small-molecule binding sites of all proteins submitted in Protein Data Bank was performed, and approximately 2,000 well-characterized local surfaces were identified from their similarities. Consequently, although 63% of them correlate with their evolutionary-related families and protein folds, about 25% are distantly related or even have different folds. 23949825 Frailty and intellectual disability: A different operationalization? Frailty is increasingly being recognized as a relevant health measure in older populations, associated with an increased risk of adverse health outcomes and care dependency. Because it is generally perceived that people with intellectual disabilities are "old" from age 50 onwards, frailty research in this group might lead to an understanding of factors, contributing to this perception. The development since the 1990s of conceptual and operational definitions of frailty has resulted in different approaches: biological (phenotype), multidimensional, and non-specific deficit accumulation. All approaches consider disability a consequence rather than a cause of frailty. This may be different for long-disabled populations, which would have consequences for validity of frailty measures. First research shows that the different approaches are applicable to study populations with intellectual disabilities as well. Frailty as defined by both the phenotypic and deficit accumulation approach appears to develop considerably earlier and is more severe in people with intellectual disabilities than in the general older population, supporting the notion of early aging. Before any clinical implications can be outlined, health outcomes (validity), causes, and prevention of frailty should be investigated. © 2013 Wiley Periodicals, Inc. Dev Disabil Res Rev 2013;18:17-21. 23604706 Skeletal muscle oxygen uptake in obese patients: functional evaluation by knee-extension exercise. We hypothesized, in a group of obese women (OB), a more significant impairment of aerobic metabolism during knee extension (KE) exercise vs. that described during cycle ergometer exercise, lending support to the role of skeletal muscles in limiting exercise tolerance in OB. Eleven OB (age 29.5 ± 5.5 years, body mass index 43.2 ± 5.4 kg m(-2)) and 10 non-obese controls (CTRL) women were tested. Fat-free mass of a lower-limb (FFMLL) was assessed by a densitometer. Heart rate (HR) and pulmonary O2 uptake ([Formula: see text]O2) were determined during incremental exercise tests to voluntary exhaustion carried out on a custom-built KE ergometer and on a cycle ergometer (CE). FFMLL and maximal isometric force of KE muscles were higher in OB vs. CTRL (+42.4 and +46.2 %, respectively). Peak work rate was significantly lower in OB (-18.4 %) vs. CTRL in CE, but not in KE. Expressed in mL min(-1), peak [Formula: see text]O2 was not different in OB vs. CTRL in CE and in KE. After it was divided per unit of FFM involved in the exercises, peak [Formula: see text]O2 was significantly lower in OB vs. CTRL, both for CE (-19 %) and KE (-33 %). Expressed per unit of exercising muscle mass, peak oxidative function is impaired in OB. The impairment is more pronounced after limitations related to cardiovascular O2 delivery are reduced. In OB muscle hypertrophy and the increased muscle force allow to preserve exercise tolerance during aerobic exercises carried out by relatively small muscle masses. 23810043 Phenotypic diversity in white adults with moderate to severe Class III malocclusion. Class III malocclusion is characterized by a composite of dentoskeletal patterns that lead to the forward positioning of the mandibular teeth in relation to the maxillary teeth and a concave profile. Environmental and genetic factors are associated with this condition, which affects 1% of the population in the United States and imposes significant esthetic and functional burdens on affected persons. The purpose of this study was to capture the phenotypic variation in a large sample of white adults with Class III malocclusion using multivariate reduction methods. Sixty-three lateral cephalometric variables were measured from the pretreatment records of 292 white subjects with Class II malocclusion (126 male, 166 female; ages, 16-57 years). Principal component analysis and cluster analysis were used to capture the phenotypic variation and identify the most homogeneous groups of subjects to reduce genetic heterogeneity. Principal component analysis resulted in 6 principal components that accounted for 81.2% of the variation. The first 3 components represented variation in mandibular horizontal and vertical positions, maxillary horizontal position, and mandibular incisor angulation. The cluster model identified 5 distinct subphenotypes of Class III malocclusion. A spectrum of phenotypic definitions was obtained replicating results of previous studies and supporting the validity of these phenotypic measures in future research of the genetic and environmental etiologies of Class III malocclusion. 23473970 Engineering of transcriptional regulators enhances microbial stress tolerance. Both prokaryotes and eukaryotes have pyramid-shaped hierarchical regulatory networks that control gene transcription, enabling the cell to respond to natural environmental changes. In recent years, manipulation and engineering of transcriptional regulatory proteins and networks have been used to elicit microbial tolerance to industrially relevant stresses. We review the current research on the engineering of regulators that include specific, "middle level", and global regulators, and native, artificial, and exogenous regulators. With an increasing number of transcriptional regulators identified and characterized, this methodology should prove promising for the improvement of microbial stress tolerance. 23912379 Self-organized colloidal quantum dots and metal nanoparticles for plasmon-enhanced intermediate-band solar cells. A colloidal deposition technique is presented to construct long-range ordered hybrid arrays of self-assembled quantum dots and metal nanoparticles. Quantum dots are promising for novel opto-electronic devices but, in most cases, their optical transitions of interest lack sufficient light absorption to provide a significant impact in their implementation. A potential solution is to couple the dots with localized plasmons in metal nanoparticles. The extreme confinement of light in the near-field produced by the nanoparticles can potentially boost the absorption in the quantum dots by up to two orders of magnitude.In this work, light extinction measurements are employed to probe the plasmon resonance of spherical gold nanoparticles in lead sulfide colloidal quantum dots and amorphous silicon thin-films. Mie theory computations are used to analyze the experimental results and determine the absorption enhancement that can be generated by the highly intense near-field produced in the vicinity of the gold nanoparticles at their surface plasmon resonance.The results presented here are of interest for the development of plasmon-enhanced colloidal nanostructured photovoltaic materials, such as colloidal quantum dot intermediate-band solar cells. 23810460 Electroacupuncture at acupoints could predict the outcome of anterior nucleus thalamus high-frequency electrical stimulation in medically refractory epilepsy. Preliminary reports have demonstrated that anterior nucleus thalamus high-frequency electrical stimulation (ANT-HFS) is an effective treatment for patients who suffer from medically refractory epilepsy. However, its extensive application has been hampered by the high cost and the unpredictable outcome before the operation. Just like ANT-HFS in the brain, electroacupuncture (EA) at acupoints with electrical stimulation is also efficient in treating medically refractory epilepsy. Although the therapeutic mechanisms involve different activated positions, the neurotransmitters generated by the electrical stimulation are similar. It has been demonstrated that both ANT-HFS and EA at acupoints are related to an imbalance between the excitatory [glutamate (Glu), aspartate (Asp)] and inhibitory [GABA, glycine (Gly) and taurine (Tau)] neuronal transmitters. We, therefore, hypothesize that outcome of EA at acupoints can predict the therapeutic effect of ANT-HFS. 23887253 Bandgap opening by patterning graphene. Owing to its remarkable electronic and transport properties, graphene has great potential of replacing silicon for next-generation electronics and optoelectronics; but its zero bandgap associated with Dirac fermions prevents such applications. Among numerous attempts to create semiconducting graphene, periodic patterning using defects, passivation, doping, nanoscale perforation, etc., is particularly promising and has been realized experimentally. However, despite extensive theoretical investigations, the precise role of periodic modulations on electronic structures of graphene remains elusive. Here we employ both the tight-binding modeling and first-principles electronic structure calculations to show that the appearance of bandgap in patterned graphene has a geometric symmetry origin. Thus the analytic rule of gap-opening by patterning graphene is derived, which indicates that if a modified graphene is a semiconductor, its two corresponding carbon nanotubes, whose chiral vectors equal graphene's supercell lattice vectors, are both semimetals. 23889376 Faithful solid state optical memory with dynamically decoupled spin wave storage. We report a high fidelity optical memory in which dynamical decoupling is used to extend the storage time. This is demonstrated in a rare-earth doped crystal in which optical coherences were transferred to nuclear spin coherences and then protected against environmental noise by dynamical decoupling, leading to storage times of up to 4.2 ms. An interference experiment shows that relative phases of input pulses are preserved through the whole storage and retrieval process with a visibility ≈1, demonstrating the usefulness of dynamical decoupling for extending the storage time of quantum memories. We also show that dynamical decoupling sequences insensitive to initial spin coherence increase retrieval efficiency. 23638710 De novo hepatitis B virus infection from anti-HBc-positive donors in pediatric living donor liver transplantation. The aim of this study was to analyze the incidence and risk factors of de novo hepatitis B virus (HBV) infection from hepatitis B core antibody (anti-HBc)-positive donors in pediatric living donor liver transplantation (LDLT). We retrospectively analyzed 46 recipients without pre-liver transplantation (LT) HBV infection evidence who underwent LDLT from October 2006 to May 2011 in our center. HBV markers, including hepatitis B surface antigen (HBsAg) and antibody (anti-HBs), anti-HBc, hepatitis B e antigen (HBeAg) and antibody (anti-HBe) were determined in both donors and recipients before LT and in recipients after LT. HBV DNA titer was measured if the recipients were strongly suspected of de novo HBV infection. Without prophylaxis, de novo HBV infection occurred in 11 of 46 recipients (23.9%) 6-36 months after LT. All 11 patients received grafts from anti-HBc-positive donors. The donors' baseline status and the characteristics of recipients at the time of transplantation were not associated with the acquisition of de novo hepatitis B infection. The overall 2-year survival rate of patients from anti-HBc-positive donors was 84.2%. Two de novo HBV-infected patients who had YMDD mutation were given adefovir combined with lamivudine, and their liver function gradually improved during the follow-up period. Anti-HBc-positive donors can significantly increase the incidence of de novo HBV infection in HBsAg-negative recipients. Administration with adefovir in patients who are resistant to lamivudine seems to be an effective and safe way for de novo HBV infection. 23952136 Analysis of risk factors for chronic subdural haematoma recurrence after burr hole surgery: Optimal management of patients on antiplatelet therapy. Objective. Not much is known about surgical management of patients with chronic subdural haematoma (CSDH) treated with antiplatelet or anticoagulant therapy. The aims of this study were to review the surgical outcomes of patients with CSDH and assess the risks of antiplatelet in their surgical management. Methods. We retrospectively analysed 448 consecutive patients with CSDH treated by one burr hole surgery at our institution. Among them, 58 patients had been on antiplatelet therapy. We discontinued the antiplatelet agents before surgery for all 58 patients. For 51 of these 58 patients (87.9%), early surgery was performed within 0-2 days from admission. We analysed the association between recurrence and patient characteristics, including history of antiplatelet or anticoagulant therapy; age (< 70 years or ≥ 70 years); side; history of angiotensin receptor II blocker, angiotensin converting enzyme blocker, or statin therapy; and previous medical history of head trauma, infarction, hypertension, diabetes mellitus, haemodialysis, seizure, cancer, or liver cirrhosis. Results. Recurrence occurred in 40 patients (8.9%), which was one of the lowest rates in the literature. Univariate analysis showed that only the presence of bilateral haematomas was associated with increased recurrence rate while antiplatelet or anticoagulant therapy did not significantly increase recurrence risk. Also, the recurrence rate from early surgery (0-2 days from drug cessation) for patients on antiplatelet therapy was not significantly higher than that from elective surgery (5 days or more after drug cessation). However, multivariate analysis revealed that previous history of cerebral infarction was an independent risk factor for CSDH recurrence. Conclusions. Our overall data support the safety of early surgery for patients on the preoperative antiplatelet therapy without drug cessation or platelet infusion. Patients with a previous history of infarction may need to be closely followed regardless of antiplatelet or anticoagulant therapy. 23952452 Capillary force on a micrometric sphere trapped at a fluid interface exhibiting arbitrary curvature gradients. We report theoretical predictions and measurements of the capillary force acting on a spherical colloid smaller than the capillary length that is placed on a curved fluid interface of arbitrary shape. By coupling direct imaging and interferometry, we are able to measure the in situ colloid contact angle and to correlate its position with respect to the interface curvature. Extremely tiny capillary forces down to femtonewtons can be measured with this method. Measurements agree well with a theory relating the capillary force to the gradient of Gaussian curvature and to the mean curvature of the interface prior to colloidal deposition. Numerical calculations corroborate these results. 23832190 Changing trend of Epstein-Barr virus association in Hodgkin lymphoma in the Republic of Korea. Hodgkin lymphoma (HL) in resource-poor population shows an early childhood peak with predominance of mixed cellularity (MCHL) and high Epstein-Barr virus (EBV) association, whereas HL in resource-rich population has a peak in ages 15-29 years with the predominance of nodular sclerosis (NSHL) and low EBV association. We examined the changing trend of HL in association with EBV in Korea in 385 cases of HL (1980-2011). Data from 1980-1995 and 1996-2011 were compared. Age distribution showed a marked decrease in children (age < 15 years) (21.0 % to 8.6 %, p = 0.004) and sharp increase in young adults (ages 15-29 years) and ages 30-59 years. Male predominance decreased from 3.04 to 1.57. Predominant subtype changed from MCHL to NSHL; MCHL fell from 53.3 % to 26.4 % (p < 0.001), and NSHL rose from 24.8 % to 58.2 % (p < 0.001). EBV-positive HL decreased from 66.7 % to 38.2 %. However, in young adult females, EBV positive cases increased, contributing to the peak in this age group. Epidemiology of HL in Korea is rapidly changing into a Western pattern concurrent with the socioeconomic changes. Analysis of the cases stratified by EBV status and sex identified a smaller hidden peak in the young adult age, which confirms the four disease hypothesis proposed by Jarrett. We propose EBV testing as an essential component in epidemiologic study of Hodgkin lymphoma. 23937444 Non-removal of an abnormally invasive placenta at cesarean section with postoperative uterine artery embolization. To evaluate the outcome of three different modes of management of abnormally invasive placenta over a six year period. Retrospective cohort study. Tertiary hospital in Hong Kong. In 39 757 deliveries, 25 cases of abnormally invasive placenta were identified at cesarean section. Identification of cases by hospital database and review of medical records. Blood loss, blood transfusion requirement, operative time, duration of hospital stay, secondary postpartum hemorrhage and endometritis. Six women were managed by leaving the placenta in-situ and by post-operative uterine artery embolization. Ten women were managed by an extirpative approach and nine cases with direct cesarean hysterectomy. The success rate of non-removal of the placenta with uterine artery embolization was 4/6 (67%). The intra-operative blood loss,blood transfusion requirements and operation times were the lowest in the group with non-removal of the placenta, although a higher secondary complication rate and a longer hospital stay followed. Non-removal of an abnormally invasive placenta at cesarean section and prophylactic postoperative uterine artery embolization is an alternative to elective cesarean hysterectomy. This article is protected by copyright. All rights reserved. 23553995 Statistical reporting deficiencies in environmental toxicology. Null hypothesis significance testing is one of the most widely used forms of statistical testing in environmental toxicology. In this short communication, the authors show that the reporting of statistical information when using null hypothesis significance testing is frequently inadequate in environmental toxicology research. The authors demonstrate this by analyzing the statistical information reported for papers employing t tests or analyses of variance in the Environmental Toxicology section of Environmental Toxicology and Chemistry in 2010, which comprised 68% of papers published by this journal in that year. Of these papers, 60% fail to report exact p values, 85% fail to provide degrees of freedom, and 90% fail to report critical effect sizes. Statistical power was reported in only <2% of the published papers. The insufficient provision of statistical information makes interpretation of study results by reviewers and readers difficult. Consistently reporting exact p values with degrees of freedom, considering and explicitly stating biologically relevant critical effect sizes, and reporting statistical power associated with nonsignificant results would be easy to implement and would promote scientific progress in environmental toxicology through increased statistical transparency. Environ Toxicol Chem 2013;32:1737-1739. © 2013 SETAC. 23786499 Herbarium specimens reveal the footprint of climate change on flowering trends across north-central North America. Shifting flowering phenology with rising temperatures is occurring worldwide, but the rarity of co-occurring long-term observational and temperature records has hindered the evaluation of phenological responsiveness in many species and across large spatial scales. We used herbarium specimens combined with historic temperature data to examine the impact of climate change on flowering trends in 141 species collected across 116,000 km(2) in north-central North America. On average, date of maximum flowering advanced 2.4 days °C(-1) , although species-specific responses varied from - 13.5 to + 7.3 days °C(-1) . Plant functional types exhibited distinct patterns of phenological responsiveness with significant differences between native and introduced species, among flowering seasons, and between wind- and biotically pollinated species. This study is the first to assess large-scale patterns of phenological responsiveness with broad species representation and is an important step towards understanding current and future impacts of climate change on species performance and biodiversity. 23829670 Estimates and determinants of economic impacts from influenza-like illnesses caused by respiratory viruses in Australian children attending childcare: a cohort study. Influenza and other respiratory infections cause excess winter morbidity in children. This study assessed the economic impact of influenza-like illness (ILI) on families with children attending childcare using a societal perspective. We conducted a prospective cohort study in 90 childcare centres and one general practitioner clinic in Sydney, Australia, during 2010. Healthy children aged ≥6 months to <3 years were enrolled. Economic impacts of ILI (temperature ≥37·8°C or parental report of fever, plus ≥1 respiratory symptoms) were collected at 2 and 4 weeks after ILI onset by telephone interview. Parent-collected respiratory specimens were tested for respiratory viruses using real-time PCR (RT-PCR). Costs associated with healthcare visits, medication usage, carer time lost (work or recreation) and home care and/or additional childcare were collected. Influenza-like illness costs were described and further analysed using a Tobit model. Zero-inflated Poisson regression was employed to compare the numbers of healthcare visits for each ILI. Of 381 children enrolled and analysed, 105 developed 124 ILIs. Specimens were available for 117 ILIs: five were positive by RT-PCR for A(H1N1)pdm09, 39 for adenovirus, 39 for rhinovirus, 15 for a coronavirus and 27 for a polyomavirus. The mean cost of all ILIs was AU$626 (95% confidence interval: AU$484-768) per ILI with no significant differences observed between viruses. Carers lost on average 13 hours of work and 3 hours of leisure time per ILI. Independent drivers of ILI costs were having both parents in employed work and longer duration of ILI. In multivariate analyses, four variables were significantly associated with an increased number of healthcare visits per ILI: non-Caucasian child, living in a detached house, both parents in employed work and having an ILI with one or more viruses identified. For families with a child attending childcare, ILIs cause a substantial economic burden. An ILI in a child with working parents and/or with longer duration appears to cost more in monetary terms. Healthcare visits were increased if the child was non-Caucasian, lived in a detached house, had working parents or had a virus-positive ILI. Our findings on the estimates and determinants of economic impacts from respiratory virus infection highlight the importance and feasibility of an interdisciplinary (epidemiology/health economics) approach to such research. 23900285 An ER-peroxisome tether exerts peroxisome population control in yeast. Eukaryotic cells compartmentalize biochemical reactions into membrane-enclosed organelles that must be faithfully propagated from one cell generation to the next. Transport and retention processes balance the partitioning of organelles between mother and daughter cells. Here we report the identification of an ER-peroxisome tether that links peroxisomes to the ER and ensures peroxisome population control in the yeast Saccharomyces cerevisiae. The tether consists of the peroxisome biogenic protein, Pex3p, and the peroxisome inheritance factor, Inp1p. Inp1p bridges the two compartments by acting as a molecular hinge between ER-bound Pex3p and peroxisomal Pex3p. Asymmetric peroxisome division leads to the formation of Inp1p-containing anchored peroxisomes and Inp1p-deficient mobile peroxisomes that segregate to the bud. While peroxisomes in mother cells are not released from tethering, de novo formation of tethers in the bud assists in the directionality of peroxisome transfer. Peroxisomes are thus stably maintained over generations of cells through their continued interaction with tethers. 23510897 Adverse outcomes in older adults attending emergency department: systematic review and meta-analysis of the Triage Risk Stratification Tool. The objective of this study was to assess the predictive ability of the Triage Risk Stratification Tool (TRST) in identifying older adults at risk of adverse outcomes [return to emergency department (ED), hospitalization, or a composite outcome] within 30 and 120 days following discharge from ED. A systematic search was conducted to identify studies validating the TRST in older adults aged at least 65 years discharged from ED. The methodological quality of selected studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. A score of at least 2 was used to identify high-risk patients. A bivariate random effects model was applied to generate pooled estimates of sensitivity and specificity. The discriminative ability of the tool was assessed using the c statistic. Heterogeneity was assessed graphically and statistically using the variance of the logit-transformed sensitivity and specificity. Six studies (3233 patients) were included. With a cutoff of at least 2, the pooled sensitivity of the TRST for a composite outcome at 30 days was 0.58 (95% confidence interval 0.52-0.65), the specificity was 0.61 (95% confidence interval 0.58-0.64). Similar values were obtained for the composite outcome at 120 days and the individual outcomes at both timepoints. The c statistic was consistently low across the outcomes and timepoints. There was little heterogeneity across studies. In conclusion, the TRST is limited in its ability to discriminate between older adults with or without an adverse outcome following discharge from ED. The low levels of heterogeneity gives us confidence that the pooled estimates reflect the predictive ability of the TRST in clinical practice. 23571773 Pharmacovigilance Using Clinical Notes. With increasing adoption of electronic health records (EHRs), there is an opportunity to use the free-text portion of EHRs for pharmacovigilance. We present novel methods that annotate the unstructured clinical notes and transform them into a deidentified patient-feature matrix encoded using medical terminologies. We demonstrate the use of the resulting high-throughput data for detecting drug-adverse event associations and adverse events associated with drug-drug interactions. We show that these methods flag adverse events early (in most cases before an official alert), allow filtering of spurious signals by adjusting for potential confounding, and compile prevalence information. We argue that analyzing large volumes of free-text clinical notes enables drug safety surveillance using a yet untapped data source. Such data mining can be used for hypothesis generation and for rapid analysis of suspected adverse event risk.Clinical Pharmacology & Therapeutics (2013); advance online publication 10 April 2013. doi:10.1038/clpt.2013.47. 23887890 Gamma-secretase inhibition attenuates oxaliplatin-induced apoptosis through increased Mcl-1 and/or Bcl-xL in human colon cancer cells. The Notch signaling pathway plays a significant role in differentiation, proliferation, apoptosis, and stem cell processes. It is essential for maintenance of the normal colon crypt and has been implicated in colorectal cancer oncogenesis. Downregulation of the Notch pathway through gamma-secretase inhibitors (GSIs) has been shown to induce apoptosis and enhance response to chemotherapy in a variety of malignancies. In this study, we analyzed the effect of MRK-003 (Merck), a potent inhibitor of gamma-secretase, on oxaliplatin-induced apoptosis in colon cancer. Unexpectedly, gamma-secretase inhibition reduced oxaliplatin-induced apoptosis while GSI treatment alone was shown to have no effect on growth or apoptosis. We determined that the underlying mechanism of action involved an increase in protein levels of the anti-apoptotic Bcl-2 family members Mcl-1 and/or Bcl-xL which resulted in reduced Bax and Bak activation. Blocking of Mcl-1 and/or Bcl-xL through siRNA or the small molecule inhibitor obatoclax restored the apoptotic potential of cells treated with both oxaliplatin and MRK-003. Moreover, obatoclax synergized with MRK-003 alone to induce apoptosis. Our findings warrant caution when treating colon cancer with the combination of GSIs and chemotherapy, whereas other drug combinations, such as GSIs plus obatoclax, should be explored. 22963374 A new flavonoid and other polar compounds from Galeopsis angustifolia Ehrh. ex Hoffm. The analysis of the polar fraction of Galeopsis angustifolia Ehrh. ex Hoffm. indicates that the main components are iridoids and flavonoids. Six compounds were identified: a new flavonoid, 3'-hydroxy-isoscutellarein 7-O-[6'″acetyl-β-D-glucopyranosyl-(1 → 2)-β-D-glucopyranoside]; three iridoid glucosides: harpagide, acetyl harpagide and for the first time in this species, 8-epi-loganin; two known acetylated flavonoid glycosides: 3'-hydroxy-4'-O-methylisoscutellarein 7-O-[6'″acetyl-β-D-allopyranosyl-(1 → 2)-6″-acetyl-β-D-glucopyranoside], 3'-hydroxy-4'-O-methylisoscutellarein 7-O-[6'″acetyl-β-D-allopyranosyl-(1 → 2)-β-D-glucopyranoside]. Both flavonoids and iridoids are present in high amount; respectively, 16.7% and 4.5% of the crude extract. 23842787 Implementation of a novel otolaryngology clinic for indigent patients. This study was designed to describe the implementation, utilization, and outcomes of an otolaryngology clinic for indigent patients employing a novel design. Pilot study. A tertiary-care academic otolaryngology department partnered with a nonprofit outpatient clinic for indigent patients in order to provide free subspecialty consultation services. A novel format was utilized in which the department provided on-site, scheduled outpatient multidisciplinary consultation on weekends, staffed by volunteer health care providers and ancillary staff. A review of the program was conducted using prospectively collected data. Clinic design, staffing, utilization, and feasibility were described, along with demographic and clinical data for all patients participating in the clinic from October 2010 through January 2012. Five clinics were held over 15 months, totaling 74 patient visits, with positive feedback regarding accessibility and quality of services provided. A total of 60 procedures were performed, including audiograms, endoscopies, otologic procedures, biopsies and/or excisions. The estimated value of medical services that were provided was $37,302. Four potentially life-threatening conditions were newly diagnosed. Twenty patients received conclusive evaluation and treatment at the time of their first visit. Eighteen patients required further subspecialty treatment and/or surgery that could not be provided in the outpatient setting, and were referred appropriately. The partnership between an academic otolaryngology department and a nonprofit clinic provided free on-site consultation for indigent patients. Such an arrangement is feasible, well utilized, and successful in delivering comprehensive specialized services to indigent patients who lack traditional access to medical care. 23696212 Biomechanical comparison of anatomic single- and double-bundle anterior cruciate ligament reconstructions: an in vitro study. Arthroscopic identification of the anteromedial (AM) and posterolateral (PL) bundle locations of the anterior cruciate ligament (ACL) has facilitated an improved quantitative description of ACL anatomy. Few studies have directly compared the biomechanical laxity of anatomic single-bundle (SB) versus anatomic double-bundle (DB) ACL reconstruction techniques based on precise anatomic descriptions. Anatomic tunnel positioning for SB and DB reconstructions would produce comparable anterior-posterior and rotatory knee laxity. Controlled laboratory study. Nine matched pairs of cadaveric knees were evaluated for the kinematics of intact, ACL-deficient, and either anatomic SB or anatomic DB ACL-reconstructed knees. Reconstruction tunnels were placed either centrally in the ACL footprint or within the AM and PL footprints. A 6 degrees of freedom robotic system was used to assess knee laxity with an 88-N anterior tibial load and a simulated pivot-shift test of combined 10-N · m valgus and 5-N · m internal tibial torques. Rotational motion was measured with internal and external torques of 5 N · m along with varus and valgus torques of 10 N · m. One-sample and 2-sample independent t tests were used to compare between groups (P < .05). No significant differences were found between anatomic SB and DB reconstruction groups during anterior tibial loading. Anterior tibial translations during simulated pivot shift had no significant differences between anatomic reconstruction groups. Tibial rotation for internal/external and varus/valgus torques showed no significant differences between anatomic reconstructions, with the exception of small (<3°) but statistically significant differences in internal rotation at 20° and 30° of flexion. Despite the similar behavior between the 2 anatomic reconstruction groups, neither technique was able to reproduce the intact state during an anterior tibial load. No significant differences in anterior translation were found between the anatomic SB and anatomic DB ACL reconstructions for simulated pivot shift or anterior tibial loading. Although significant differences between reconstructions were observed for internal rotation, the small magnitude of these differences (<3°) may not have clinical significance. 23801331 Polysialic Acid on Neuropilin-2 Is Exclusively Synthesized by the Polysialyltransferase ST8SiaIV and Attached to Mucin-type O-Glycans Located between the b2 and c Domain. Neuropilin-2 (NRP2) is well known as a co-receptor for class 3 semaphorins and vascular endothelial growth factors, involved in axon guidance and angiogenesis. Moreover, NRP2 was shown to promote chemotactic migration of human monocyte-derived dendritic cells (DCs) toward the chemokine CCL21, a function that relies on the presence of polysialic acid (polySia). In vertebrates, this posttranslational modification is predominantly found on the neural cell adhesion molecule (NCAM), where it is synthesized on N-glycans by either of the two polysialyltransferases, ST8SiaII or ST8SiaIV. In contrast to NCAM, little is known on the biosynthesis of polySia on NRP2. Here we identified the polySia attachment sites and demonstrate that NRP2 is recognized only by ST8SiaIV. Although polySia-NRP2 was found on bone marrow-derived DCs from wild-type and St8sia2(-/-) mice, polySia was completely lost in DCs from St8sia4(-/-) mice despite normal NRP2 expression. In COS-7 cells, co-expression of NRP2 with ST8SiaIV but not ST8SiaII resulted in the formation of polySia-NRP2, highlighting distinct acceptor specificities of the two polysialyltransferases. Notably, ST8SiaIV synthesized polySia selectively on a NRP2 glycoform that was characterized by the presence of sialylated core 1 and core 2 O-glycans. Based on a comprehensive site-directed mutagenesis study, we localized the polySia attachment sites to an O-glycan cluster located in the linker region between b2 and c domain. Combined alanine exchange of Thr-607, -613, -614, -615, -619, and -624 efficiently blocked polysialylation. Restoration of single sites only partially rescued polysialylation, suggesting that within this cluster, polySia is attached to more than one site. 23336063 Gobichelin A and B: Mixed-Ligand Siderophores Discovered Using Proteomics. "Omic" strategies have been increasingly applied to natural product discovery processes, with (meta-)genome sequencing and mining implemented in many laboratories to date. Using the proteomics-based discovery platform called PrISM (Proteomic Investigation of Secondary Metabolism), we discovered two new siderophores gobichelin A and B from Streptomyces sp. NRRL F-4415, a strain without a sequenced genome. Using the proteomics information as a guide, the 37 kb gene cluster responsible for production of gobichelins was sequenced and its 20 open reading frames interpreted into a biosynthetic scheme. This led to the targeted detection and structure elucidation of the new compounds produced by nonribosomal peptide (NRP) synthesis. 23931600 Patterning and Impregnation of Superhydrophobic Surfaces Using Aqueous Solutions. We report a solvent-assisted approach to the patterning and impregnation of porous superhydrophobic coatings that permits the use of entirely aqueous solutions. This approach permits immobilization of proteins and enzymes, creating opportunities to decorate superhydrophobic surfaces with hydrophilic domains and channels that can capture aliquots of aqueous media, guide and mix aqueous solutions, and chemically process streams of organic molecules. Because this approach does not require destruction of non-wetting features, it can also be used to transfer highly water-soluble polymers and small molecules without compromising superhydrophobicity, providing methods for post-fabrication loading of water-soluble agents into protective non-wetting coatings that are difficult to achieve using other approaches. 23863702 State-specific healthy life expectancy at age 65 years - United States, 2007-2009. Healthy life expectancy (HLE) is a population health measure that combines mortality data with morbidity or health status data to estimate expected years of life in good health for persons at a given age. HLE accounts for quantity and quality of life and can be used to describe and monitor the health status of populations. HLE estimates for countries have been used for predicting future health service needs, evaluating health programs, and identifying trends and inequalities, but to date, few studies have reported HLE at the state level for the United States. To determine state-level estimates, CDC used data from the National Vital Statistics Systems (NVSS), U.S. Census Bureau, and Behavioral Risk Factor Surveillance System (BRFSS) to calculate HLEs for persons aged 65 years, by sex and race, for each of the 50 states and the District of Columbia (DC). Those calculations indicate that, during 2007-2009, females had a greater HLE than males at age 65 years in every state and DC. HLE was greater for whites than for blacks in all states from which sufficient data were available and DC, except in Nevada and New Mexico. These results can be used as a baseline for states to monitor changes in the HLE of persons aged 65 years as they age and identify health disparities among subpopulations. 23397236 Both young and older adults discount suggestions from older adults on a social memory test. In the present study, we examined the impacts of participant age and confederate age on social memory processes. During a collaborative recall phase, young and older adult participants were exposed to the erroneous memory reports of a young or an older adult confederate. On a subsequent individual recall test, young and older adult participants were equally likely to incorporate the confederates' erroneous suggestions into their memory reports, suggesting that participant age had a minimal effect on social memory processes. However, confederate age did have a marked effect: Young adult participants were less likely to incorporate misleading suggestions from older adult confederates and less likely to report "remembering" items suggested by older adult confederates. Critically, older adult participants were also less likely to incorporate misleading information from fellow older adult confederates. Both young and older adult participants discounted older adult confederates' contributions to a memory test. 23535287 Cajaninstilbene acid (CSA) exerts cytoprotective effects against oxidative stress through the Nrf2-dependent antioxidant pathway. Cajaninstilbene acid (CSA), an active compound separated from pigeon pea leaves, possesses the highly efficient antioxidant activities. Transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important regulator of cellular oxidative stress. This study examined the role of Nrf2 in CSA-mediated antioxidant effects on human hepatocarcinoma (HepG2) cell line. The generation of reactive oxygen species (ROS) upon H2O2 and CSA treatment was lower than that of H2O2 alone. CSA activated Nrf2 as evaluated by Western blotting. A luciferase reporter assay also demonstrated that CSA-activated signaling resulted in the increased transcriptional activity of Nrf2 through binding to the antioxidant response element (ARE) enhancer sequence. Our study indicated that treatment of HepG2 cells with CSA induces Nrf2-dependent ARE activity and gene expression of heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutamate-cysteine ligase modifier subunits by activation of PI3K/AKT, ERK and JNK signaling pathways. Inhibition of Nrf2 by siRNA reduced CSA-induced upregulation of these Nrf2-related enzymes. These results suggest that the Nrf2/ARE pathway plays an important role in the regulation of CSA-mediated antioxidant effects in HepG2 cells. 23893561 Modelling and control of a five-degrees-of-freedom pneumatically actuated magnetic resonance-compatible robot. Magnetic resonance imaging (MRI) combined with robotic assistance has the potential to improve on clinical outcomes of biopsy and local treatment of prostate cancer. This paper introduces a pneumatically actuated surgical robotic system for prostatic interventions under MRI guidance. A mechanical dynamics model was established using the Lagrange method and simulated using MATLAB software. A pneumatic actuator model was built through the use of system identification, and stability analysis was proposed based on the Nyquist criterion. In addition, a proportional-integral-derivative controller was implemented on the robot for accurate position control. Simulation results showed that the steady-state error of a step response was 0.3 mm and the tracking error of a 1.0 Hz sinusoidal response was 1.5 mm. Experimental results showed that the insertion precision was 0.72 mm in the general laboratory environment. The results demonstrated that the robotic system with the designed controller was effective in both position control and trajectory tracking. Copyright © 2013 John Wiley & Sons, Ltd. 23927390 Using the Optimality Index-US to Teach Midwifery Students to Recognize and Implement Evidence-Based Practices That Promote Optimal Outcomes in Perinatal Health. Perinatal optimality means achieving maximal perinatal outcomes with minimal interventions considering women's past and present histories. The Optimality Index-US (OI-US) is a research tool designed to measure potential associations between evidence-based perinatal care processes and outcomes in aggregate groups of women against an optimal standard. This article describes how the Shenandoah University Nurse-Midwifery Program uses the OI-US to teach students to recognize evidence-based care, reflect on the influences that care processes may have on outcomes, and consider the value of measuring the relationship between interventions and outcomes. Case studies and individual presentations apply the optimality concept by illustrating different care processes, identifying evidence-based care, and evaluating management through the optimality lens. A pilot study was performed in which a 10-question interview was administered to 9 midwifery students before graduation. Two research questions were addressed: "Is the OI-US an effective teaching tool?" and "How can the program improve this strategy?" Narrative analysis was used to interpret students' understandings of the tool, how it affected their clinical learning, and its potential to use in future practices. Four themes were identified: 1) students felt the OI-US gave them a foundation to assess their management and the confidence to plan future management, 2) students used the OI-US as a teaching tool to help women prevent nonoptimal events from occurring, 3) students thought the OI-US would be feasible to use in their future practices, and 4) lack of accessibility to a printed version of the tool while providing care was an obstacle for efficient use. Students suggested increasing the tool's accessibility and using it in other learning activities. The use of the OI-US should be explored further to teach evidence-based care, to generate reflection concerning potential associations between perinatal care processes and outcomes, and to challenge students to question non-evidence-based practices. 23873328 Development of the metabolic syndrome and electrocardiographic features of left ventricular hypertrophy in middle-aged working subjects. Background and aims. The metabolic syndrome (MS) leads to excess cardiovascular disease, including heart failure. Left ventricular hypertrophy (LVH) is common in MS patients, but it is unknown whether onsets of the MS and LVH coincide. Herein, we tested the association between development of the MS and of electrocardiographic LVH in a cohort of middle-aged individuals. Methods. We included 303 working subjects (mean age 43.0±6.2; 41% males), followed-up for 4.3±0.8 years. ATP-III MS components were determined. Electrocardiographic LVH features were assessed by the Sokolow and Cornell voltage indexes and the Rohmilt-Estes score. Results. At baseline, the Cornell index was significantly higher in subjects with (n=55; 18.2%) than in those without MS (12.8±6.4 vs 10.9±5.4 mm; p=0.023), while the Sokolow index and Rohmilt- Estes score were not different. At follow-up, individuals who developed (n=51) compared to those who did not develop MS showed a significant increase in Cornell voltage index (1.0±0.6 vs - 0.55±0.3 mm; p=0.035) and in Rohmilt-Estes score (0.17±0.17 vs -0.08±0.04; p=0.028). The change in Cornell index over time was directly correlated with change in the number of MS components (r=0.133; p=0.02) and HOMA-IR (r=0.117; p=0.046). The association between MS onset and increase in Cornell index / Rohmilt-Estes score was independent from confounders. Conclusions. In a young population of working subjects, the development of MS is associated with worsening features of LVH. Early LVH electrocardiographic screening in young subjects who develop the MS should be considered and performed using the Cornell voltage index. 23313085 Vinclozolin--no transgenerational inheritance of anti-androgenic effects after maternal exposure during organogenesis via the intraperitoneal route. The goal of this study was to examine the potential transgenerational inheritance of anti-androgenic effects induced by Vinclozolin administered intraperitoneally to pregnant Wistar rats (Crl:WI[Han]). Dams were dosed with Vinclozolin at 0, 4 or 100mg/kg bw/d on gestation days 6-15. Male offspring of F1-F3 generations were bred with untreated females to yield F2-F4 offspring. No evident anti-androgenic effects were observed at 4mg/kg bw/d, but a case of hypospadias as well as delayed sexual maturation in F1 male offspring was observed as a sign of anti-androgenicity at 100mg/kg bw/d. However, F1-F3 males developed normally to sexual maturity and were able to mate and to generate healthy progeny. Sperm count, morphology and motility were not affected in F1-F4 generation male offspring. In conclusion, transgenerational inheritance of Vinclozolin's anti-androgenic effects was not evident in outbred Wistar rats. 23820554 The saccus vasculosus of fish is a sensor of seasonal changes in day length. The pars tuberalis of the pituitary gland is the regulatory hub for seasonal reproduction in birds and mammals. Although fish also exhibit robust seasonal responses, they do not possess an anatomically distinct pars tuberalis. Here we report that the saccus vasculosus of fish is a seasonal sensor. We observe expression of key genes regulating seasonal reproduction and rhodopsin family genes in the saccus vasculosus of masu salmon. Immunohistochemical studies demonstrate that all of these genes are expressed in the coronet cells of the saccus vasculosus, suggesting the existence of a photoperiodic signalling pathway from light input to neuroendocrine output. In addition, isolated saccus vasculosus has the capacity to respond to photoperiodic signals, and its removal abolishes photoperiodic response of the gonad. Although the physiological role of the saccus vasculosus has been a mystery for several centuries, our findings indicate that the saccus vasculosus acts as a sensor of seasonal changes in day length in fish. 23823129 Measles outbreak spreading from the community to an anthroposophic school, Berlin, 2011. SUMMARY Between April and July 2011 there was an outbreak of measles virus, genotype D4, in Berlin, Germany. We identified 73 case-patients from the community and among students of an anthroposophic school, who participated in a 4-day school trip, as well as their family and friends. Overall, 27% were aged ⩾20 years, 57% were female and 15% were hospitalized. Of 39 community case-patients, 38% were aged ⩾20 years, 67% were female and 63% required hospitalization. Unvaccinated students returning from the school trip were excluded from school, limiting transmission. Within the group of 55 school-trip participants, including 20 measles case-patients, a measles vaccine effectiveness of 97·1% (95% confidence interval 83·4-100) for two doses was estimated using exact Poisson regression. Our findings support school exclusions and the recommendation of one-dose catch-up vaccination for everyone born after 1970 with incomplete or unknown vaccination status, in addition to the two-dose routine childhood immunization recommendation. 23871670 Innate Immune-Directed NF-κB Signaling Requires Site-Specific NEMO Ubiquitination. While the I kappa kinase (IKK) scaffolding protein NF-κB essential modulator (NEMO) binds to polyubiquitin chains to transmit inflammatory signals, NEMO itself is also ubiquitinated in response to a variety of inflammatory agonists. Although there have been hints that polyubiquitination of NEMO is essential for avoiding inflammatory disorders, the in vivo physiologic role of NEMO ubiquitination is unknown. In this work, we knock in a NEMO allele in which two major inflammatory agonist-induced ubiquitination sites cannot be ubiquitinated. We show that mice with a nonubiquitinatable NEMO allele display embryonic lethality. Heterozygous females develop inflammatory skin lesions, decreased B cell numbers, and hypercellular spleens. Embryonic lethality can be complemented by mating onto a TNFR1(-/-) background, at the cost of severe steatohepatitis and early mortality, and we also show that NEMO ubiquitination is required for optimal innate immune signaling responses. These findings suggest that NEMO ubiquitination is crucial for NF-κB activity in response to innate immune agonists. 23913712 Nuclear quantum effect and temperature dependency on the hydrogen-bonded structure of base pairs. The structure of Watson-Crick-type adenine-thymine and guanine-cytosine pairs has been studied by hybrid Monte Carlo (HMC) and path integral hybrid Monte Carlo (PIHMC) simulations with the use of semiempirical PM6-DH+ method in the gas phase. We elucidated the nuclear quantum effect and temperature dependency on the hydrogen-bonded moiety of base pairs. It was shown that the contribution of nuclear quantum effect on the hydrogen-bonded structure is significant not only at low temperature 150 K but also at temperature as high as 450 K. The relative position of hydrogen-bonded proton between two heavy atoms and the nuclear quantum nature of the proton are also shown. Furthermore, we have applied principal component analysis to HMC and PIHMC simulations to analyze the nuclear quantum effect on intermolecular motions. We found that the ratio of Buckle mode (lowest vibrational mode from normal mode analysis) decreases due to the nuclear quantum effect, whereas that of Propeller mode (second lowest vibrational mode) increases. In addition, nonplanar structures of base pairs were found to become stable due to the nuclear quantum effect from two-dimensional free energy landscape along Buckle and Propeller modes. © 2013 Wiley Periodicals, Inc. 22521497 The effect of the internet on teen and young adult tobacco use: a literature review. Research has shown that a positive association exists between exposure to smoking imagery, such as that found in movies and print advertising, and the subsequent uptake of cigarette smoking. Children appear to be especially vulnerable to advertising messaging and other positive portrayals of smoking, given that most adult smokers develop the habit before age 18 years. Although many traditional types of media have been studied, the current generation of youth is growing up as digital natives, with young people increasingly using the Internet for entertainment and to obtain information. Currently the Internet is an essentially unregulated marketplace of ideas and images. However, the effect of the Internet on teen smoking initiation has received little attention in studies. In this literature review, we summarize and critique the existing work, identify current knowledge gaps, and offer suggestions to health care providers about how to address this issue. 23931732 Vesicular trafficking and stress response coupled to PI3K inhibition by LY294002 as revealed by proteomic and cell biological analysis. LY294002 is a synthetic quercetin-like compound which, unlike wortmannin, is an inhibitor of phosphatidylinositol 3-kinase (PI3K). It inhibits endocytosis and vacuolar transport. We report here on the proteome-wide effects of LY294002 on Arabidopsis roots focusing on proteins involved in vesicular trafficking and stress response. At the subcellular level, LY294002 caused swelling and clustering of late endosomes leading to inhibition of vacuolar transport. At the proteome level, this compound caused changes in abundances of proteins categorized to 10 functional classes. Among proteins involved in vesicular trafficking, a small GTPase ARFA1f was more abundant, indicating its possible contribution to the aggregation and fusion of late endosomes triggered by LY294002. Our study provides new information on storage proteins and vacuolar hydrolases in vegetative tissues treated by LY294002. Vacuolar hydrolases were downregulated while storage proteins were more abundant, suggesting that storage proteins were protected from degradation in swollen multivesicular bodies upon LY294002 treatment. Upregulation of 2S albumin was validated by immunoblotting and immunolabelling analyses. Our study also pointed to the control of antioxidant enzyme machinery by PI3K because LY294002 downregulated two isozymes of superoxide dismutase. This most likely occurred via PI3K-mediated downregulation of protein AtDJ1A. Finally, we discuss specificity differences of LY294002 and wortmannin against PI3K which are reflected at the proteome level. Compared to wortmannin, LY294002 showed more narrow and perhaps also more specific effects on proteins as suggested by gene ontology functional annotation. 23265503 The influence of pectolytic enzyme addition and prefermentative mash heating during the winemaking process on the phenolic composition of Okuzgozu red wine. The effects of pectolytic enzyme addition and mash heating prior to fermentation on the phenolic component of Okuzgozu red wine during the winemaking and ageing processes were investigated. In general, the highest concentration of total phenolics was found in the mash-heated wines, whereas the total flavan-3-ol and total anthocyanin contents in all of the wines, decreased notably during the winemaking and ageing processes. As determined by HPLC, hydroxycinnamic acids were the major phenolic acids in the red wines. After 6 months in the bottle, the enzyme-treated wines had lower phenolic acid concentrations than had the control and mash-heated wines, but no significant (p<0.05) differences were found in the concentration of total phenolic acids between the control and mash-heated wines. All of the phenolic acid levels decreased with the winemaking and ageing processes whereas only gallic acid increased. The wines treated by the pectolytic enzyme addition had a lower monomeric flavan-3-ol content than had the other wines, and the amount of monomeric anthocyanins extracted did not increase with the addition of enzymes. 23587692 Subregions of the human superior frontal gyrus and their connections. The superior frontal gyrus (SFG) is located at the superior part of the prefrontal cortex and is involved in a variety of functions, suggesting the existence of functional subregions. However, parcellation schemes of the human SFG and the connection patterns of each subregion remain unclear. We firstly parcellated the human SFG into the anteromedial (SFGam), dorsolateral (SFGdl), and posterior (SFGp) subregions based on diffusion tensor tractography. The SFGam was anatomically connected with the anterior and mid-cingulate cortices, which are critical nodes of the cognitive control network and the default mode network (DMN). The SFGdl was connected with the middle and inferior frontal gyri, which are involved in the cognitive execution network. The SFGp was connected with the precentral gyrus, caudate, thalamus, and frontal operculum, which are nodes of the motor control network. Resting-state functional connectivity analysis further revealed that the SFGam was mainly correlated with the cognitive control network and the DMN; the SFGdl was correlated with the cognitive execution network and the DMN; and the SFGp was correlated with the sensorimotor-related brain regions. The SFGam and SFGdl were further parcellated into three and two subclusters that are well corresponding to Brodmann areas. These findings suggest that the human SFG consists of multiple dissociable subregions that have distinct connection patterns and that these subregions are involved in different functional networks and serve different functions. These results may improve our understanding on the functional complexity of the SFG and provide us an approach to investigate the SFG at the subregional level. 23355347 Gas Dielectric Transistor of CuPc Single Crystalline Nanowire for SO2 Detection Down to Sub-ppm Levels at Room Temperature. A room-temperature highly-sensitive SO2 sensor with fast response and complete recovery is constructed based on gas dielectric field-effect transistor (FET) of CuPc single crystalline nanowire. The exposed conductive channel by gas dielectric is responsible for the high sensitivity to SO2 and the adsorption of the SO2 molecules dramatically enhances the field-effect mobility. These results not only open up new opportunities to develop new SO2 sensors, but also provide an efficient way to improve the performance of organic FETs. 23895071 HeartWare miniaturized intrapericardial ventricular assist device: advantages and adverse events in comparison to contemporary devices. Increasing incidence of end-stage heart failure and limited availability of donor organs have led to longer waiting times for cardiac transplantation and subsequently increasing mortality. Ventricular assist device therapy is fast becoming an accepted alternative treatment to treat end-stage heart failure and is being implemented as a bridge to decision, bridge to myocardial recovery, bridge to heart transplantation or as a destination therapy. LVADs not only enable hemodynamic stabilization and recovery of secondary organ failure in severely ill patients, but have also been shown to reduce pulmonary vascular resistance in nontransplantable candidates. Technology of ventricular assist devices has evolved over several decades of time and generations of devices. The HVAD(®) Pump (HeartWare International, Inc., MA, USA) is a third-generation, miniaturized, continuous-flow ventricular assist device. Due to its miniaturized housing and intrapericardial placing, it can be used proficiently to support the right ventricle and has also demonstrated great utility in minimally invasive and off-pump implantation, exchange and explantation. It is favored for similar reasons in adolescents and in heart failure due to complex congenital heart disease. The purpose of this article is to review the clinical use of HeartWare(®) Ventricular Assist System (HeartWare System; HeartWare International, Inc.) with different strategies pertaining to its advantages and adverse events in comparison with contemporary devices. 22944068 Suppression of collagen Q expression in the extrajunctional regions of rat fast muscles is encoded in their stem cells (satellite cells). In rat fast muscles, collagen Q (ColQ) expression is restricted to the neuromuscular junctions. In contrast, it is high also extrajunctionally in the slow soleus muscles. Fast muscles activated by chronic low-frequency electrical stimulation, similar to neural activation of the soleus muscles, did not increase their extrajunctional expression of ColQ. We assumed that the myogenic stem cells (satellite cells) in fast and slow muscles were intrinsically different in regard to the capacity that they convey to their respective muscle fibers to increase the extrajunctional ColQ expression upon innervation. ColQ mRNA levels were determined by quantitative real-time PCR. Extensive neural suppression of the extrajunctional ColQ expression in regenerating fast muscles during maturation is a very slow process requiring 30-60days. If the immature regenerating fast EDL muscles were indirectly or directly electrically stimulated immediately after innervation by chronic low-frequency impulse pattern for 8days, no significant increase of the extrajunctional ColQ mRNA levels was observed in stimulated regenerates in comparison to non-stimulated ones. In contrast, the extrajunctional ColQ mRNA levels in the regenerates of the soleus muscles, trans-innervated by the EDL nerve at the time of muscle injury, increased 4- to 5-fold after 8days of the same chronic low-frequency electrical stimulation in comparison to those in the stimulated EDL regenerates. Since both fast and slow muscles completely regenerated only from their own myogenic stem cells and were innervated by the same nerve and later activated by the same tonic pattern of impulses, these results demonstrated that the mechanism causing incapacity of regenerating fast muscles to increase their extrajunctional ColQ expression upon tonic activation is encoded in their satellite cells, which in this respect differ from those in the slow muscles. 23624932 Regulation of cerebral cortex size and folding by expansion of basal progenitors. Size and folding of the cerebral cortex increased massively during mammalian evolution leading to the current diversity of brain morphologies. Various subtypes of neural stem and progenitor cells have been proposed to contribute differently in regulating thickness or folding of the cerebral cortex during development, but their specific roles have not been demonstrated. We report that the controlled expansion of unipotent basal progenitors in mouse embryos led to megalencephaly, with increased surface area of the cerebral cortex, but not to cortical folding. In contrast, expansion of multipotent basal progenitors in the naturally gyrencephalic ferret was sufficient to drive the formation of additional folds and fissures. In both models, changes occurred while preserving a structurally normal, six-layered cortex. Our results are the first experimental demonstration of specific and distinct roles for basal progenitor subtypes in regulating cerebral cortex size and folding during development underlying the superior intellectual capability acquired by higher mammals during evolution. 23965052 Vending machines 'need to stock healthier choices'. The RCN has echoed a cancer prevention charity's concerns that hospitals in England should offer healthier food in vending machines for staff and patients. 23122109 Resveratrols in Vitis berry skins and leaves: their extraction and analysis by HPLC. An orthogonal L(36) (6)(5) test design was applied to select the optimum conditions for extracting resveratrols from grape berry skins and leaves. Solvent choice was the most important factor in the extraction of resveratrols, and mixed methanol and ethyl acetate [50:50 (v/v)] had much higher extraction efficiency than the other five solvents tested. For extracting resveratrols, 1g of berry skins or leaf tissue extracted in 10 mL methanol and ethyl acetate [50:50 (v/v)] for 24h at 25°C in darkness was the optimized extraction condition. The optimized analytical method for HPLC was a multi-step gradient elution using acetonitrile and water. The optimized method was used to determine resveratrols among three different cultivars. The cultivar 'Zhi 168' had the highest total resveratrols in berry skins while 'Saint-Emilion' had the lowest resveratrols. The resveratrol content of 'Beta' was between that of 'Zhi 168' and 'Saint-Emilion'. 23892203 Conservation strategy for Pelargonium sidoides DC: Phenolic profile and pharmacological activity of acclimatized plants derived from tissue culture. Pelargonium sidoides DC (Geraniaceae), a popular medicinal plant used in folk medicine in the treatment of respiratory-related infections has gained international prominence due to its usage in several herbal formulations. This has led to high demand and the subsequent decimation of wild populations. Using plant tissue culture techniques, Pelargonium sidoides plants were cloned in vitro, acclimatized under greenhouse conditions and evaluated for their phytochemical content and pharmacological activity. Phenolic content in extracts of in vitro-derived, greenhouse-acclimatized and wild Pelargonium sidoides plants were analyzed using UPLC-MS/MS. The oxygen radical absorbance capacity (ORAC), 2,2-diphenyl-1-picryl hydrazyl (DPPH) radical scavenging activity and minimum inhibitory concentration (MIC) of the extracts against bacterial and fungal strains were evaluated. Similarities in phenolic profiles were identified confirming the chemical signatures that characterize Pelargonium sidoides plants. Extracts of greenhouse-acclimatized and wild plants exhibited comparable antimicrobial and antioxidant properties. Overall, the study highlights the potential of integrating plant tissue culture technologies in conservation strategies of medicinal plants. In particular, the results strongly suggest the feasibility of both large-scale cultivation and plant part substitution as alternative solutions to the current destructive overharvesting practices of wild Pelargonium sidoides populations. 23708632 A multi-purpose flow manifold for the spectrophotometric determination of sulphide, sulphite and ethanol involving gas diffusion: application to wine and molasses analysis. A simple and rugged flow set up was designed for spectrophotometric determination of sulphide, sulphite and ethanol aiming at quality assessment of wines, control of industrial fermentation, and selection of yeast strain. The different assays involved gas diffusion through a Teflon planar membrane and were carried out after minor modifications in the manifold, namely reagent composition and total flow rate. Main figures of merit: linear analytical curves=0.50-6.0 mg L(-1)S(2-), 2.5-20.0 mg L(-1) SO3(-) and 5.0-25.0% (v/v) of ethanol; detection limits (3σ)=0.035 mg L(-1)S(2-), 0.2 mg L(-1) SO3(-) and 0.18% (v/v) of ethanol; peak height r.s.d.=2.18% for 4.03 mg L(-1)S(2-) spiked molasses, 2.21% for a 9.82 mg L(-1) SO3(-) wine and 2.07% for a typical wine (12.53% v/v of ethanol), sampling rate=15, 57 and 29 h(-1), reagent consumptions=1.9 µmol of N,N-dimethyl-p-phenylenediamine, 1.68 µg of Malachite green and 0.68 mmol Cr(VI) per determination, respectively. 23887658 Long Non-Coding RNAs in Haematological Malignancies. Long non-coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides in length. LncRNAs are as diverse as mRNAs and they normally share the same biosynthetic machinery based on RNA polymerase II, splicing and polyadenylation. However, lncRNAs have low coding potential. Compared to mRNAs, lncRNAs are preferentially nuclear, more tissue specific and expressed at lower levels. Most of the lncRNAs described to date modulate the expression of specific genes by guiding chromatin remodelling factors; inducing chromosomal loopings; affecting transcription, splicing, translation or mRNA stability; or serving as scaffolds for the organization of cellular structures. They can function in cis, cotranscriptionally, or in trans, acting as decoys, scaffolds or guides. These functions seem essential to allow cell differentiation and growth. In fact, many lncRNAs have been shown to exert oncogenic or tumor suppressor properties in several cancers including haematological malignancies. In this review, we summarize what is known about lncRNAs, the mechanisms for their regulation in cancer and their role in leukemogenesis, lymphomagenesis and hematopoiesis. Furthermore, we discuss the potential of lncRNAs in diagnosis, prognosis and therapy in cancer, with special attention to haematological malignancies. 23597309 CH-01 is a hypoxia-activated prodrug that sensitizes cells to hypoxia/reoxygenation through inhibition of Chk1 and Aurora A. The increased resistance of hypoxic cells to all forms of cancer therapy presents a major barrier to the successful treatment of most solid tumors. Inhibition of the essential kinase, Checkpoint kinase 1 (Chk1) has been described as a promising cancer therapy for tumors with high levels of hypoxia-induced replication stress. However, as inhibition of Chk1 affects normal replication and induces DNA damage, these agents also have the potential to induce genomic instability and contribute to tumorigenesis. To overcome this problem, we have developed a bioreductive prodrug, which functions as a Chk1/Aurora A inhibitor specifically in hypoxic conditions. To achieve this activity, a key functionality on the Chk1 inhibitor (CH-01) is masked by a bioreductive group, rendering the compound inactive as a Chk1/Aurora A inhibitor. Reduction of the bioreductive group nitro moiety, under hypoxic conditions, reveals an electron-donating substituent that leads to fragmentation of the molecule, affording the active inhibitor. Most importantly, we show a significant loss of viability in cancer cell lines exposed to hypoxia in the presence of CH-01. This novel approach targets the most aggressive and therapy-resistant tumor fraction while protecting normal tissue from therapy-induced genomic instability. 23761423 Association of risk variants for type 2 diabetes and hyperglycemia with gestational diabetes. The aim of this study was to investigate the association of risk variants for type 2 diabetes (T2D) and hyperglycemia with gestational diabetes (GDM). Five hundred and thirty-three Finnish women who were diagnosed with GDM and 407 controls with normal glucose tolerance during the pregnancy were genotyped for 69 single-nucleotide polymorphisms (SNPs) which have been previously verified as susceptibility risk variants for T2D and hyperglycemia. All participants underwent an oral glucose tolerance test at the follow-up study after the index pregnancy. Risk variants rs10830963 and rs1387153 of MTNR1B were significantly associated with GDM (odds ratio (OR)=1.62 (95% CI 1.34-1.96), P=4.5×10(-7) and 1.38 (1.14-1.66), P=7.6×10(-4) respectively). Both SNPs of MTNR1B were also significantly associated with elevated fasting glucose level and reduced insulin secretion at follow-up. Additionally, risk variants rs9939609 of FTO, rs2796441 of TLE1, rs560887 of G6PC2, rs780094 of GCKR, rs7903146 of TCF7L2 and rs11708067 of ADCY5 showed nominally significant associations with GDM (OR range from 1.25 to 1.30). Our study suggests that GDM and T2D share a similar genetic background. Our findings also provide further evidence that risk variants of MTNR1B are associated with GDM by increasing fasting plasma glucose and decreasing insulin secretion. 23871531 Breast phyllodes tumor: A review of literature and a single center retrospective series analysis. Complete surgical resection is the standard treatment for localized breast phyllodes tumors. Post-surgical treatments are still a matter of debate. We carried out an overview of the literature to investigate the clinical outcome of patients with phyllodes tumor. A retrospective analysis of mono-institutional series has been included as well. We reviewed all the retrospective series reported from 1951 until April 2012. We analyzed cases treated at our institution from 1999 to 2010. Eighty-three articles (5530 patients; 1956 malignant tumors) were reviewed. Local recurrences were independent of histology. Distant recurrences were more frequent in the malignant tumors (22%). A total of 172 phyllodes tumors were included in the retrospective analysis. Prognosis of phyllodes tumors is excellent. There are no convincing data to recommend any adjuvant treatment after surgery. Molecular characterization may well provide new clues to permit identification of active treatments for the rare poor prognosis cases. 23751955 Outcomes of allogeneic hematopoietic cell transplantation in patients with dyskeratosis congenita. We describe outcomes after allogeneic transplantation in 34 patients with dyskeratosis congenita who underwent transplantation between 1981 and 2009. The median age at transplantation was 13 years (range, 2 to 35). Approximately 50% of transplantations were from related donors. Bone marrow was the predominant source of stem cells (24 of 34). The day-28 probability of neutrophil recovery was 73% and the day-100 platelet recovery was 72%. The day-100 probability of grade II to IV acute GVHD and the 3-year probability of chronic graft-versus-host disease were 24% and 37%, respectively. The 10-year probability of survival was 30%; 14 patients were alive at last follow-up. Ten deaths occurred within 4 months from transplantation because of graft failure (n = 6) or other transplantation-related complications; 9 of these patients had undergone transplantation from mismatched related or from unrelated donors. Another 10 deaths occurred after 4 months; 6 of them occurred more than 5 years after transplantation, and 4 of these were attributed to pulmonary failure. Transplantation regimen intensity and transplantations from mismatched related or unrelated donors were associated with early mortality. Transplantation of grafts from HLA-matched siblings with cyclophosphamide-containing nonradiation regimens was associated with early low toxicity. Late mortality was attributed mainly to pulmonary complications and likely related to the underlying disease. 23962450 Urban-rural differences in adolescent eating behaviour: a multilevel cross-sectional study of 15-year-olds in Scotland. Improving the diet of the Scottish population has been a government focus in recent years. Population health is known to vary between geographies; therefore alongside trends and socio-economic inequalities in eating behaviour, geographic differences should also be monitored. Eating behaviour data from the 2010 Scotland Health Behaviour in School-aged Children survey were modelled using multilevel linear and logistic modelling. Data were collected in schools across urban and rural Scotland. Schoolchildren aged 15 years. Adolescents living in remote rural Scotland had the highest consumption frequency of vegetables (on average consumed on 6·68 d/week) and the lowest consumption frequency of sweets and crisps (on 4·27 and 3·02 d/week, respectively). However, it was not in the major four cities of Scotland (Glasgow, Edinburgh, Dundee and Aberdeen) but in the geography described by the classification 'other urban' areas (large towns of between 10 000 and 125 000 residents) that adolescents had the poorest diet. Deprivation and rurality were independently associated with food consumption for all but fruit consumption. Sharing a family meal, dieting behaviour, food poverty and breakfast consumption did not differ by rurality. Variance at the school level was significant for fruit and vegetable consumption frequencies and for irregular breakfast consumption, regardless of rurality. Young people from rural areas have a healthier diet than those living in urban areas. The eating behaviours examined did not explain these differences. Future research should investigate why urban-rural differences exist for consumption frequencies of 'healthy' and 'unhealthy' foods. 23187687 Effects of bidentate coordination on the molecular properties rapta-C based complex using theoretical approach. In this work several quantum properties including the NEDA and QTAIM are computed on three models of rapta-C complexes using DFT with hybrid functional and basis set with ECP and without ECP. Several interesting correlations within the observed properties and also with the reported experimental behaviors of these complexes including their biological activities are presented. The study shows that the stability of the two complexes with bidentate ligands is associated with their high hydrogen bonding stability and existence of stronger non-covalent metal-ligand bonds. The energy decomposition analysis indicated that inter-atomic interactions in the three forms of rapta-C complexes and their stability are governed by the charge transfer term with significant contributions from polarization and electrostatic terms. The higher stability of complex 1 and 2 over 3 comes from the lower exchange repulsion and higher polarization contributions to their stability which agrees perfectly with the experimental observation. Our results provide insight into the nature of intramolecular forces that influence the structural stability of the three complexes. 23866920 A feasibility study of brief group-based acceptance and commitment therapy for chronic pain in general practice: recruitment, attendance, and patient views. Acceptance and commitment therapy (ACT), a form of cognitive-behavioral therapy, may help meet a need for accessible and cost-effective treatments for chronic pain. ACT has a growing evidence base, but has not yet been tested within general practice settings. Aim The purpose of the present study was to examine the feasibility of conducting a full-scale randomized controlled trial of ACT in general practice. A total of 481 potential participants with chronic pain identified from general practice in southwest England were invited into a treatment trial. Subsequently, 102 (21.2%) of those invited were screened, and 73 (71.6%) of those screened were allocated to ACT plus usual care or usual care alone. The ACT treatment included four, four-hour group-based sessions over two weeks. Twenty-six (70.3%) of the patients allocated to ACT attended three or four sessions. Those who received ACT rated it as credible in a short survey, with Mdn rating 7.0 on a 0-10 scale, across five credibility items. During a post-treatment interview considering 12 aspects of the study from invitation to treatment termination, a median of 79.2% of participants rated the aspects 'acceptable.' Qualitative data from the interviews showed a mixed picture of patient experiences, revealing possible tensions between patients' wishes to avoid discomfort and confusion, and treatment methods that explicitly ask patients to, in essence, 'live with' some discomfort and confusion. These data suggest that further study of ACT, as a treatment for chronic pain, is feasible in general practice and it may be possible to further optimize the treatment experience. 23836505 Antagonistic Effects of Anti-EMMPRIN Antibody When Combined with Chemotherapy Against Hypovascular Pancreatic Cancers. To examine the antagonistic effects of anti-extracellular matrix metalloprotease inducer (anti-EMMPRIN) antibody when combined with chemotherapy using a hypovascular pancreatic tumor model. Severely compromised immunodeficient mice bearing orthotopic MIA PaCa-2 tumors were used (five to six animals per group). Dynamic contrast-enhanced magnetic resonance imaging was used to examine the relationship between tumor vascularity and size. Therapy was initiated when tumors were hypovascular. Treatments included: (1) gemcitabine alone, (2) anti-EMMPRIN antibody alone, and (3) combination, each for 2 weeks. Additionally, another treatment arm included β-lapachone, an NAD(P)H/quinone 1 (NQO1) bioactivated agent. (18)F-fluoro-D-glucose-positron emission tomography/computed tomography imaging was used weekly to monitor therapeutic effects. Gemcitabine or anti-EMMPRIN monotherapy significantly delayed tumor growth, but the combination therapy showed an antagonistic effect. Similarly, tumor growth was significantly suppressed by β-lapachone alone, and additive effects were noted when combined with gemcitabine, but the therapeutic efficacy was reduced when anti-EMMPRIN antibody was added. Anti-EMMPRIN antibody with chemotherapy in hypovascular tumors results in antagonistic effects. 23767666 Randomized controlled trials in endourology: a quality assessment. Abstract Purpose: To analyze the quality of studies reporting randomized clinical trials (RCTs) in the field of endourology. Materials and Methods: RCTs published in the Journal of Endourology from 1993 until 2011 were identified. The Jadad scale, van Tulder scale, and Cochrane Collaboration Risk of Bias Tool (CCRBT) were used to assess the quality of the studies. The review period was divided into early (1993-1999), mid (2000-2005), and late (2006-2011) terms. Studies were categorized by country of origin, subject matter, single- vs multicenter setting, Institutional Review Board (IRB) approval and funding support, and blinding vs nonblinding. Results: In total, 3339 articles had been published during the defined review period, of which 165 articles were reporting a RCT. There was a significant increase in the number of RCTs published over time, with 18 (2.81%), 43 (4.88%), and 104 (5.72%) studies identified in the early, mid, and late term, respectively (P=0.009). Nevertheless, there was no difference in terms of quality of reporting, as assessed with the Jadad scale, van Tulder scale, or CCRBT, between the three study terms. On the other hand, significant differences were found in both the number of high qualitative RCTs that used blinding methodology and those that had IRB review, when comparing the early, mid, and late terms. Conclusion: There has been a growing number of Journal of Endourology publications reporting on RTC over the last two decades. The quality of reporting for these studies remains suboptimal, however. Researchers should focus on a more appropriate description of key features of any given RCT, such as randomization and allocation methods, as well as disclosure of IRB review and financial support. 23950844 Correction: Involvement of Dynamin-Related Protein 1 in Free Fatty Acid-Induced INS-1-Derived Cell Apoptosis. [This corrects the article on p. e49258 in vol. 7.]. 23890226 pH1N1 - a comparative analysis of public health responses in Ontario to the influenza outbreak, public health and primary care: lessons learned and policy suggestions. Ontario's 36 Public Health Units (PHUs) were responsible for implementing the H1N1 Pandemic Influenza Plans (PIPs) to address the first pandemic influenza virus in over 40 years. It was the first under conditions which permitted mass immunization. This is therefore the first opportunity to learn and document what worked well, and did not work well, in Ontario's response to pH1N1, and to make recommendations based on experience. Our objectives were to: describe the PIP models, obtain perceptions on outcomes, lessons learned and to solicit policy suggestions for improvement. We conducted a 3-phase comparative analysis study comprised of semi-structured key informant interviews with local Medical Officers of Health (n = 29 of 36), and Primary Care Physicians (n = 20) and in Phase 3 with provincial Chief-Medical Officers of Health (n = 6) and a provincial Medical Organization. Phase 2 data came from a Pan-Ontario symposium (n = 44) comprised leaders representing: Public Health, Primary Care, Provincial and Federal Government. PIPs varied resulting in diverse experiences and lessons learned. This was in part due to different PHU characteristics that included: degree of planning, PHU and Primary Care capacity, population, geographic and relationships with Primary Care. Main lessons learned were: 1) Planning should be more comprehensive and operationalized at all levels. 2) Improve national and provincial communication strategies and eliminate contradictory messages from different sources. 3) An integrated community-wide response may be the best approach to decrease the impact of a pandemic. 4) The best Mass Immunization models can be quickly implemented and have high immunization rates. They should be flexible and allow for incremental responses that are based upon: i) pandemic severity, ii) local health system, population and geographic characteristics, iii) immunization objectives, and iv) vaccine supply. "We were very lucky that pH1N1 was not more severe." Consensus existed for more detailed planning and the inclusion of multiple health system and community stakeholders. PIPs should be flexible, allow for incremental responses and have important decisions (E.g., under which conditions Public Health, Primary Care, Pharmacists or others act as vaccine delivery agents.) made prior to a crisis. 23945536 Varela-Mato, V.; Cancela, J.M.; Ayan, C.; Molina, A.; Martín, V. Lifestyle and Health among Spanish University Students: Differences by Gender and Academic Discipline. Int. J. Environ. Res. Public Health 2012, 9, 2728-2741. The authors wish to make the following correction to this paper [1]. In the article it is mentioned that "the study obtained the approval of the university's Students Vice-Chancellery and the government bodies of the involved academic centers and also by the Ethics Committee of the University of Vigo." However, it should read: "The study obtained the approval of the university's Students Vice-Chancellery and the government bodies of the involved academic centers" only. 22659409 Attenuation of methamphetamine seeking by the mGluR2/3 agonist LY379268 in rats with histories of restricted and escalated self-administration. Recent findings implicate group II metabotropic glutamate receptors (mGluR(2/3)) in the reinforcing effects of psychostimulants and have identified these receptors as potential treatment targets for drug addiction. Here, we investigated the effects of mGluR(2/3) stimulation on cue- and drug-primed reinstatement in rats with different histories of methamphetamine (METH) self-administration training, under two conditions: 16 daily sessions of short access (90 min/day, ShA), or 8 daily sessions of short access followed by 8 sessions of long access (6 h/day, LgA). Following self-administration and subsequent extinction training, rats were pretreated with the selective mGluR(2/3) agonist LY379268 (variable dose, 0-3 mg/kg), exposed to METH-paired cues or a priming injection of METH (1 mg/kg), and tested for reinstatement of METH-seeking behavior. LgA rats self-administered greater amounts of METH during the second half of training, but when pretreated with vehicle, ShA and LgA rats showed cue- and drug-primed reinstatement at equivalent response rates. However, LgA rats demonstrated greater sensitivity to mGluR(2/3) stimulation with attenuated responding during cue-induced reinstatement after 0.3 mg/kg and higher doses of LY379268, whereas ShA rats decreased cue-induced reinstatement behavior following 1.0 mg/kg and 3.0 mg/kg LY379268. Additionally, both LgA and ShA rats exhibited decreased METH-primed reinstatement behavior following 0.3 mg/kg and higher doses of LY379268. A separate group of control rats was trained to self-administer sucrose pellets, and demonstrated attenuated cue-induced sucrose-seeking behavior following 1.0 and 3.0 mg/kg LY379268. Together, the results indicate that LY379268 has differential attenuating effects on cue-induced reinstatement behavior in rats with different histories of METH intake. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23850680 Purification and characterization of two polyhydroxyalcanoates from Bacillus cereus. This work aimed to study the potential of 155 strains of Bacillus sp., isolated from a collection of Tunisian microorganisms, for polyhydroxyalcanoates production. The strains were submitted to a battery of standard tests commonly used for determining bioplastic properties. The findings revealed that two of the isolates, namely Bacillus US 163 and US 177, provided red excitations at a wavelength of approximately 543nm. The polyhydroxyalcanoates produced by the two strains were purified. Gas chromatography-mass spectroscopy (GC-MS), Fourier transformed infrared spectroscopy (FTIR), and gel permeation chromatography (GPC) were used to characterize the two biopolymers. Bacillus US 163 was noted to produce a poly methyl-3-hydroxy tetradecanoic acid (P-3HTD) with an average molecular weight of 455kDa, a completely amorphous homopolymer without crystallinity. The US 177 strain produced a homopolymer of methyl-3-hydroxy octadecanoic acid (P3-HOD) with an average molecular weight of 555kDa. Exhibiting the highest performance, US 163 and US 177 were submitted to 16S rRNA gene sequencing, and the results revealed that they belonged to the Bacillus cereus species. Overall, the findings indicated that the Bacilli from petroleum soil have a number of promising properties that make them promising candidates for bioplastic production. 23919278 β-blockers: a new role in cancer chemotherapy? β-blockers are a class of drugs that are widely used in treating cardiac, respiratory and other ailments. They act by blocking β-adrenergic receptor-mediated signaling. Studies in various cancers have shown that patients taking a β-blocker have higher survival and lower recurrence and metastasis rates. This is supported by several preclinical and in vitro studies showing that adrenergic activation modulates apoptosis, promotes angiogenesis and other cancer hallmarks, and these effects can be abrogated by β-blockers. These studies provide a rationale for the use of β-blockers as adjuvants with cancer chemotherapy. However, all published studies so far are retrospective and most do not take into account the specific β-blocker used or address which is most likely to benefit cancer patients. The published epidemiological studies are correlative and have not examined the adrenergic receptor status of the tumors. Knowledge of the β-adrenergic receptor status of tumor cells is essential in choosing the best β-blocker for adjuvant therapy. A comprehensive, prospective study is necessary to definitively prove the utility of using β-blockers with chemotherapy and to identify the specific β-blocker most likely to benefit patients with cancer. 23443935 The simultaneous occurrence of human norovirus and hepatitis E virus in a Norway rat (Rattus norvegicus). Wild rats can be reservoirs and vectors for several human pathogens. An initial RT-PCR screening of the intestinal contents of Norway rats trapped in the sewer system of Copenhagen, Denmark, for caliciviruses revealed the presence of a human norovirus in one of 11 rodents. Subsequent phylogenetic analysis of the ~4.0-kb 3'-terminus of the norovirus genome resulted in the identification of a recombinant GI.b/GI.6 strain. The simultaneous detection of hepatitis E virus-like particles in the feces of this rat by transmission electron microscopy was confirmed by RT-PCR and sequence determination, resulting in the identification of a novel rat hepatitis E virus. 23832701 Nox2 and Nox4 Influence Neonatal C-kit+ Cardiac Precursor Cell Status and Differentiation. Redox status has emerged as critical in modulating stemness and lineage commitment in several precursor cell types. However, a role for redox genes, specifically NADPH oxidases (Nox), in cardiac precursor cells (CPCs) has not been established. We tested whether CPCs marked by type III receptor tyrosine kinase c-kit (c-kit(+)) exhibit a unique NADPH oxidase signature that confers precursor status, and that alterations in this profile are functionally linked to changes in lineage specification. Dihydroethidium (DHE) microfluorography indicated reduced basal ROS formation within early postnatal c-kit(+) CPCs. Real-time quantitative PCR revealed downregulation of ROS generator Nox2 and its subunit p67(phox) in c-kit(+) CPCs under basal conditions, but upregulation of Nox2 and Nox4 over the course of differentiation. Adenoviral silencing of Nox2 and Nox4 increased expression of CPC markers, c-kit and Flk-1, and blunted smooth and cardiac muscle differentiation, respectively, while overexpression of Nox2 and Nox4 significantly reduced c-kit expression. These changes were accompanied by altered expression of transcription factors regulating cardiac lineage commitment, Gata6 and Gata4, and cytokine, TGF-β1. Similar to other precursor cell types, RT(2)Profiler PCR Arrays revealed that c-kit(+) CPCs also exhibit enhanced antioxidant capacity at the mRNA level. In conclusion, we report that c-kit(+) CPCs demonstrate reduced Nox2 expression and ROS levels, and that increases in Nox2 and Nox4 influence their differentiation into mature cells. We speculate that ROS generators Nox2 and Nox4, along with the antioxidant genes identified by PCR Arrays, may be novel targets in CPCs which could prove useful in cell-based therapy of the heart. 23809095 Prehospital neurologic deterioration is independent predictor of outcome in traumatic brain injury: analysis from National Trauma Data Bank. The prevalence and impact of prehospital neurologic deterioration (PhND) in patients with traumatic brain injury (TBI) have not been investigated. We aimed to determine the prevalence of PhND during emergency medical service (EMS) transportation among patients with TBI and its impact on patient's outcome. We used the National Trauma Data Bank, using data files from 2009 to 2010 to identify patients with TBI through International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. The initial Glasgow Coma Scale (GCS) score ascertained at the scene by EMS was compared with the subsequent GCS score evaluation in the emergency department (ED) to identify neurologic deterioration (defined as a decrease in GCS of ≥2 points). Patients' demographics, initial injury severity score (ISS), admission GCS score, and hospital outcome were compared between patients with PhND and patients without neurologic deterioration. A total of 257 127 patients with TBI were identified. Among patients with TBI, 22 254 patients had PhND, which comprised 9% of all patients with TBI. The mean of GCS score decrease during EMS transport was 5 points (±3). Patients without PhND tended to have higher GCS recorded by EMS (median, 15 vs 12; P < .0001). Patients with TBI who had PhND had significantly higher hospital length of stay and intensive care unit days after adjusting for baseline characteristics and EMS GCS score, EMS transport time, type of injury, presence of intracranial hemorrhages, and ED ISS (P < .0001). These patients had higher rate of in-hospital mortality after adjusting for the same variables (odds ratio, 2.30; 95% confidence interval, 2.18-2.41). Prehospital neurologic deterioration occurs in 9% of patients with TBI. It is more prevalent in men and associated with lower EMS GCS level and higher ED ISS. Prehospital neurologic deterioration is an independent predictor of worse hospital outcome and higher resource use in patients with TBI. 23917126 PTSD symptoms, disclosure, and relationship distress: Explorations of mediation and associations over time. Emotional numbing symptoms of posttraumatic stress disorder (PTSD) are negatively associated with relationship satisfaction in combat veterans and their romantic partners. Many speculate that one mechanism of this association may be decreased disclosure by veterans, but previous studies lacked appropriate data to test this hypothesis. In a sample of 224 OIF/OEF-era National Guard service members (SMs) and 214 of their romantic partners, we measured SMs' PTSD symptoms. Four to six months later, we assessed both partners' reports of SMs' emotional disclosure and both partners' relationship satisfaction (83 SMs and 91 partners completed Time 2). In a path analysis, SMs' emotional numbing was negatively associated with their later relationship satisfaction. Furthermore, SMs' emotional numbing was negatively associated with both partners' reports of SMs' emotional disclosure. Finally, SMs' emotional numbing exerted significant or nearly significant indirect effects on both partners' relationship satisfaction via decreased emotional disclosure. The findings demonstrated the importance of accounting for both partners' perceptions when studying couple functioning in the context of PTSD or treating PTSD via conjoint intervention. 23165215 Local structure and dynamics of benzene confined in the IRMOF-1 nanocavity as studied by molecular dynamics simulation. The local structure and dynamic behaviour of a benzene molecular assembly confined within the nano-cavities of a zinc-based metal-organic framework, [Zn(4)O(CO(2)C(6)H(4)CO(2))(3)](n) (IRMOF-1), were investigated by means of molecular dynamics (MD) simulations. The local structure of the confined benzene molecules was evaluated using radial distribution functions. The sites for adsorption of benzene in IRMOF-1 were well defined by the simulation. The diffusion coefficients at ambient temperature suggested that the mobility of the confined benzene was high, comparable to the bulk fluid. Decreasing the temperature gave rise to the aggregation of benzene in the IRMOF-1 frameworks. Molecular aggregation was attributed to the localization of benzene in the large and the small cavities of IRMOF-1, respectively. Both the translational diffusion coefficient and the trajectory of benzene provided evidence that the localization of benzene in the large and the small cavities takes place at ca. 200 K. Furthermore, at high benzene loading, the migration of benzene in the small cavities was prevented (frozen) below 135 K. Thus, the translational degree of freedom of the benzene molecules changed drastically, depending on the temperature. 23886915 Coronary atheroma volume and cardiovascular events during maximally intensive statin therapy. The impact of baseline coronary plaque burden on the clinical outcome in patients receiving aggressive low-density lipoprotein cholesterol (LDL-C) lowering therapy to levels <70 mg/dL is unknown. We assessed the prognostic significance of baseline coronary plaque burden following high-intensity statin therapy. SATURN used serial intravascular ultrasound (IVUS) to measure coronary atheroma volume in 1039 patients before and after 24 months of treatment with rosuvastatin 40 mg or atorvastatin 80 mg. This post hoc analysis compared the relationship between baseline percent atheroma volume (PAV) and major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, coronary revascularization, hospitalization for unstable angina) in patients with baseline PAV less than (n = 519) or greater than (n = 520) the median. Patients with a higher baseline PAV had a similar LDL-C compared with those with a lower baseline PAV at baseline (119.0 ± 29 vs. 121.0 ± 27 mg/dL, P = 0.09) and at follow-up (65.3 ± 23 vs. 65.8 ± 22 mg/dL, P = 0.47). In multivariable analysis, each standard deviation increase in baseline PAV was associated with a 28% increase in MACE [HR 1.28 (1.05, 1.57), P = 0.01]. Those with the highest quartile of baseline PAV (>41.8%) had a 2-year cumulative MACE rate of 12%, which was significantly higher (log-rank P = 0.001) than MACE rates of all lower PAV quartiles (MACE: quartile 3, 2, and 1 were 5.7, 7.9, and 5.1%, respectively). LDL-C levels at baseline [HR 0.96 (0.79, 1.18), P = 0.73] and on-treatment [HR 1.19 (0.83, 1.73), P = 0.35] were not associated with MACE. Following 2 years of high-intensity statin therapy, a baseline coronary atheroma volume predicted MACE, despite the achievement of very low on-treatment LDL-C levels. 23660997 Cumulative Incidence and Risk Factors for Hospitalization and Surgery in a Population-based Cohort of Ulcerative Colitis. We sought to identify clinical and demographic features influencing hospitalization and colectomy in a population-based inception cohort of ulcerative colitis. Between 1970 and 2004, a total of 369 patients (58.5% males) from Olmsted County, MN, were followed from diagnosis for 5401 person-years. The cumulative probability of hospitalization and colectomy were estimated using the Kaplan-Meier method. Cox proportional hazards regression was used to identify factors associated with hospitalization and colectomy. The cumulative probability of first hospitalization was 29.4% at 5 years (95% confidence interval [CI], 24.5%-34.1%), 38.7% at 10 years (33.1%-43.8%), 49.2% at 20 years (42.7%-55.2%), and 52.3% at 30 years (45.1%-59.7%). The incidence rate of hospitalizations decreased over the last 4 decades, although cumulative probability of first hospitalization increased with successive decades of diagnosis. Early need for corticosteroids (hazard ratio [HR], 1.8; 95% CI, 1.1%-2.7%) and early need for hospitalization (HR, 1.5; 95% CI, 1.02-2.4) were independent predictors of hospitalization after 90 days of illness. The cumulative probability of colectomy from the time of diagnosis was 13.1% at 5 years (95% CI, 9.4%-16.6%), 18.9% at 10 years (95% CI, 14.4%-23.2%), and 25.4% at 20 years (95% CI, 19.8%-30.8%). Male gender (HR, 2.1; 95% CI, 1.3-3.5), diagnosis in the 1990s (HR, 2.0; 95% CI, 1.01-4.0), and diagnosis in 2000 to 2004 (HR, 3.7; 95% CI, 1.7-8.2) were significantly associated with colectomy risk. Colectomy rates were comparable to reports from northern Europe. The numbers of hospitalizations show a decreasing trend. Male gender and being diagnosed in the 2000 to 2004 period predicted colectomy while extensive colitis predicted future hospitalizations. 23306025 The role of individual gastric emptying of pellets in the prediction of diclofenac in vivo dissolution. The objective of the present study was to check for the possibility to successfully predict individual in vivo dissolution/absorption profiles resulting from fasted administration of a diclofenac extended release pellet formulation. For this purpose dissolution profiles were generated with different dissolution setups using a set of media reflecting pH-conditions in the different segments of the gastrointestinal tract. Since gastric emptying of pellets seemed to be a critical factor for in vivo drug release, a set of different gastric residence times was screened in in vitro studies. Subsequently, in vitro release profiles were first directly compared with the individual in vivo absorption profiles and in a second step a mathematical model, which had been developed in a previous study, was applied to calculate predicted individual in vivo release profiles based on in vitro release profiles and individual gastric emptying. The comparison of predicted individual in vivo release profiles and individual in vivo absorption profiles showed a high degree of similarity, thus confirming the suitability of a set of different gastric residence times used in in vitro drug release testing. Additionally, obtained results indicated that a substantial part of variability of diclofenac absorption profiles can be explained by the variability of pellet gastric emptying kinetics. 23884645 Stability of Genomic Imprinting and Gestational-Age Dynamic Methylation in Complicated Pregnancies Conceived Following Assisted Reproductive Technologies. For the past three decades, assisted reproductive technologies (ART) have revolutionised infertility treatments. The use of ART is thought to be safe. However, early investigations suggested that children born as a result of ART had higher risk of diseases with epigenetic aetiologies including imprinting disorders caused by a lack of maternal methylation at imprinting control elements. In addition, large epidemiology studies have highlighted an increased risk of obstetric complications, including severe intrauterine growth restriction (IUGR) in babies conceived using ART. It is plausible that the increased frequency of IUGR may be due to abnormal imprinting, since these transcripts are key for normal fetal growth and development. To address this, we have collected a large cohort of placenta and cord blood samples from ART conceptions and compared the imprinting status with appropriate non-ART population. Using a custom DNA methylation array that simultaneously quantifies 25 imprinted differentially methylated regions we observed similar epigenetic profiles between groups. A multiplex Sequenom iPLEX allelic expression assay revealed monoallelic expression for 11 imprinted transcripts in our placenta cohort. We also observe appropriate gestational age-dependent methylation dynamics at retrotransposable elements and promoters associated with growth genes in ART placental biopsies. This study confirms that children conceived by ART do not show variability in imprinted regulation and that loss-of-imprinting is not commonly associated with non-syndromic IUGR or prematurity. 23679925 A2A adenosine receptors are up-regulated in lymphocytes from amyotrophic lateral sclerosis patients. Abstract Adenosine, a purine nucleoside interacting with A1, A2A, A2B and A3 adenosine receptors (ARs), is a potent endogenous modulator of inflammatory and neuronal processes involved in the pathophysiology of several neurodegenerative diseases. In the present study, ARs were investigated in lymphocytes from patients with amyotrophic lateral sclerosis (ALS) and compared with age-matched healthy subjects. In ALS patients A2AARs were analysed by using RT-PCR, Western blotting and saturation binding experiments. The effect of A2AAR stimulation on cyclic AMP levels was evaluated in lymphocytes from ALS patients and healthy subjects. An up-regulation of A2AARs was observed in ALS patients with respect to healthy subjects while A1, A2B and A3AR affinity and density did not change. In ALS patients, the A2AAR density values correlated with the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. Furthermore, the stimulation of A2AARs mediated a significant increase in cyclic AMP levels in lymphocytes from ALS patients, with a higher potency than in lymphocytes from healthy subjects. In conclusion, the positive correlation between A2AAR density and ALSFRS-R scores could indicate a possible protective effect of this receptor subtype, representing an interesting starting point for the study of alternative therapeutic approaches for ALS based on A2AAR modulation. 23873838 Downregulation of cytochrome P450scc as an initial adverse effect of adult exposure to diethylstilbestrol on testicular steroidogenesis. Reproductive toxicities and endocrine disruptions caused by chemicals in adult males are still poorly understood. It is our objectives to understand further details of the initial adverse effects leading severe testicular toxicities of a pharmaceutical endocrine disruptor, diethylstilbestrol (DES). Downregulations of both testicular regulatory proteins, such as the steroidogenic acute regulatory protein (StAR) and the peripheral benzodiazepine receptor (PBR), which play important roles in the transport of cholesterol into the mitochondria, and cytochrome P450 mediating the cholesterol side chain cleavage reaction (P450scc), were observed in the rat orally administered DES (340 μg/kg/2 days) for 2 weeks. We found that after only 1 week treatment with DES, the blood and testicular testosterone (TS) levels were drastically decreased without abnormalities of the StAR and PBR; however, the protein and mRNA levels of P450scc were diminished. Decrease in the conversion rate of cholesterol to pregnenolone was delayed in the in vitro assay using the testicular mitochondrial fraction from the rat treated with DES for 1 week. When the precursors in TS biosynthesis containing the testis were identified and determined by liquid chromatography-mass spectrometry analysis, decreased levels of all precursors except cholesterol were observed. In conclusion, suppressed cytochrome P450scc expression in adult male rat was identified as an initial target of DES in testicular steroidogenesis disorder leading reproductive toxicities. © 2013 Wiley Periodicals, Inc. Environ Toxicol, 2013. 23258195 Heterogeneous oxidation of a phosphocholine on synthetic sea salt by ozone at room temperature. The ozonolysis of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) adsorbed on salt mixtures as models for sea-salt particles was studied in real time using diffuse reflection infrared Fourier transform spectrometry (DRIFTS) at room temperature with and without added water vapor. The salt substrates were a mixture of MgCl(2)·6H(2)O with NaCl or a commercially available synthetic sea salt. Ozone concentrations ranged from (0.25 to 3.9) × 10(13) molecules cm(-3) (0.1-1.6 ppm). The major products identified by FTIR and confirmed using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry were the secondary ozonide (SOZ) and a phospholipid aldehyde and carboxylic acid formed by scission of the double bond. The reaction probabilities for the two substrates were similar, γ = (6-7) × 10(-7), with an estimated overall uncertainty of a factor of two. The presence of water vapor decreased the yield of SOZ relative to the products formed by C[double bond, length as m-dash]C scission, but also increased the availability of the double bond for reaction, particularly on the less hygroscopic commercial sea-salt substrate. Thus, water not only affects the mechanisms and products, but also the structure of the phospholipid on the salt in a manner that affects its reactivity. The results of these studies suggest that the reactivity and products of oxidation of unsaturated phospholipids on sea-salt particles in air will be very sensitive to the nature and phase of the substrate, the amount of water present, and whether there is phase separation between the organics and the inorganic salt mixture. 23940251 Badger - an accessible genome exploration environment. High quality draft genomes are now easy to generate, as sequencing and assembly costs have dropped dramatically. However, building a user friendly, searchable website and database for a newly annotated genome is not straightforward. Here we present Badger, a lightweight and easy-to-install genome exploration environment designed for next generation, non-model organism genomes. Badger is released under the GPL and is available at http://badger.bio.ed.ac.uk/. We show two working examples: (1) a test dataset included with the source code and (2) a collection of four filarial nematode genomes. mark.blaxter@ed.ac.uk. 23572428 Statins and autoimmunity. Statins have immunomodulatory effects. Hence, they could be advantageous for different reasons. First, statins can serve as adjunct therapy in autoimmune diseases. Second, they may play a role in the prevention of accelerated atherosclerosis in the same population. In this review, we discuss the mechanisms of immune regulation by statins and review the literature for their benefit in many autoimmune diseases. In these studies, statins lead to an improvement in the disease activity scores in rheumatoid arthritis patients; a reduction in prothrombotic factors in anti-phospholipid syndrome patients; changes in vasculature, proteinuria, and cardiac events in systemic lupus erythematosus patients; changes in vasculature and proteinuria in patients with vasculitis; disease activity scores in ankylosing spondylitis; and finally vascular changes in patients with systemic sclerosis. Hence, these studies suggest that statins could be used as adjuncts to standard therapy due to their anti-inflammatory, immunomodulatory, and anti-thrombogenic effects. More evidence-based research is required to determine whether statin regimens will become the standard of care in patients with autoimmune diseases. 23771746 Effects of piperine and deoxyschizandrin on synchronized Ca(2+) oscillations in cultured hippocampal neuronal cells. It has been reported that piperine (PIP) and deoxyschizandrin (DS) can modulate synchronized Ca(2+) oscillations in cultured hippocampal neuronal networks. We investigated the modulation effects of four different combinations of piperine and deoxyschizandrin on synchronized Ca(2+) oscillations in cultured hippocampal neuronal networks. The results showed that all four combinations (PIP:DS 4.9:1.9, 2.45:2.85, 7.35:0.95, and 2.45:0.95 mg/L) inhibit Ca(2+) oscillation intensity to a similar extent. However, the first three combinations had strong inhibitory effects on the frequency of Ca(2+) oscillations whereas the last combination (2.45:0.95 mg/L) only slightly enhanced the frequency of Ca(2+) oscillations. We propose an improved Chay's model to explain the mechanism of the effects of piperine and deoxyschizandrin on synchronized Ca(2+) oscillations in cultured hippocampal neuronal cells. We concluded that deoxyschizandrin modulated synchronized Ca(2+) oscillations in cultured hippocampal neuronal networks bidirectionally and the effect depended on concentration. Deoxyschizandrin reduced voltage-gated sodium channel conductance and ATP-sensitive potassium channel conductance, and affected the rate of exchange of intracellular calcium and the pump activity of Ca(2+)-ATPase in the endoplasmic reticulum (ER). Piperine reduced the activity of calcium release in the ER, and reduced the pump activity of calcium in the cytomembrane or enhanced the pump activity of Ca(2+)-ATPase in the ER. 23862956 Initial reduction of the NiO(100) surface in hydrogen. The reduction of NiO in hydrogen, a reaction with many industrial applications, has not received sufficient attention from theoretical standpoint because the complexity of the material properties and the process present considerable computational challenges. We report here the results of a systematic study on the hydrogen reduction of an ideal NiO(100) surface that produces a water molecule and an NiO(100) surface with an oxygen vacancy, using the Hubbard U corrected density functional theory method, with some of the key results verified by the hybrid density functional method. The major findings are: (1) the O vacancy in the NiO(100) surface slab is stabilized in the subsurface layer, although the vacancy is likely to remain on the outermost surface layer because the barrier for O vacancy migration from the surface to the second layer is as high as 3.02 eV; (2) regarding the energetics of hydrogen interaction with the ideal NiO(100) surface, water formation, and concomitant reduction of NiO is favored at higher H coverage even though surface hydrogenation is energetically more favorable than water formation at lower H coverage; (3) kinetically, the pull-off of the surface oxygen atom and simultaneous activation of the nearby Ni atoms play key roles in hydrogen reduction of NiO(100); and (4) a dual role of hydrogen is revealed as both a reactant and a mediator, which reduces the maximum kinetic barrier from 2.41 eV to 1.86 eV. 23925744 Incidence of displacement after nondisplaced distal radial fractures in adults. It is standard practice to closely monitor distal radial fractures treated nonoperatively to ensure that there is no fracture displacement. Patients are often asked to initially return weekly for radiographs. To our knowledge, nondisplaced distal radial fractures in adults have not been specifically evaluated to determine if this level of vigilance is required. If this subset of fractures is unlikely to displace, the cost, radiation exposure, and inconvenience of weekly office visits could be spared. Using our billing database, we identified 642 closed distal radial fractures among the patients who presented to our institution during the four-year period from the beginning of 2006 to the end of 2009. Radiographs of the injuries were reviewed to identify fractures for which radiographic measurements were within predefined radiographic norms. Only those fractures that were believed to be nondisplaced by all reviewers were classified as nondisplaced for the purposes of this study. Radiographic measurements were made at the time of injury and at the time of fracture union to evaluate for displacement over time. The total number of clinic visits and radiographs that were received were calculated from the longitudinal medical record for each patient. Eighty-two fractures were identified as nondisplaced. None displaced or required operative intervention. The largest measured difference from injury to fracture union for radial inclination was 3.6° (average 0.8°); for radial height, 2.1 mm (average 0.5 mm); and for palmar tilt, 3.1° (average 1.0°). These numbers are all within the error of measurement. Nondisplaced distal radial fractures in adults appear to be inherently stable, and it may be appropriate to treat this subset of distal radial fractures with cast immobilization (when swelling allows) and a single follow-up visit with radiographs to document union at the time of cast removal. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. 23774997 Orthogonally protected D-galactosamine thioglycoside building blocks via highly regioselective, double serial and double parallel inversions of β-D-thiomannoside. An efficient route for the synthesis of orthogonally protected D-galactosamine thioglycosides via one-pot double serial and double parallel displacements of the D-mannosyl-2,4-bis-trifluoromethanesulfonates by azide and nitrite ions is described. These building blocks were utilized to synthesize the rare disaccharide moiety of the zwitterionic polysaccharide of Bacteroides fragilis and the selectively protected Tn antigen. 23215584 An ultrastrong nanofibrillar biomaterial: the strength of single cellulose nanofibrils revealed via sonication-induced fragmentation. We report the mechanical strength of native cellulose nanofibrils. Native cellulose nanofibrils, purified from wood and sea tunicate, were fully dispersed in water via a topochemical modification of cellulose nanofibrils using 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO) as a catalyst. The strength of individual nanofibrils was estimated based on a model for the sonication-induced fragmentation of filamentous nanostructures. The resulting strength parameters were then analyzed based on fracture statistics. The mean strength of the wood cellulose nanofibrils ranged from 1.6 to 3 GPa, depending on the method used to measure the nanofibril width. The highly crystalline, thick tunicate cellulose nanofibrils exhibited higher mean strength of 3-6 GPa. The strength values estimated for the cellulose nanofibrils in the present study are comparable with those of commercially available multiwalled carbon nanotubes. 23416145 Collaborative virtual organisation and infrastructure for drug discovery. A virtual organisation approach was applied to collaborative drug discovery integrating experimental and computational design approaches. Scientists Against Malaria was formed with the goal of designing novel antimalarial drug candidates. The collaboration of nine founding partners carried out computational and laboratory work that produced significant volumes of data and metadata, the interpretation for the analysis of which, as well as the related decision making, was challenging. During the first phase the partners developed this 'green-field' project from initiation through to target selection and modelling, computational screening, biological materials and assay preparation, culminating in the completion of initial experimental testing. A support infrastructure involving a semantic collaborative laboratory framework, interoperating with a cloud of web services through an ontology describing the virtual and experimental screening data, was designed and tested. 23943620 Activation of PKC-MAPK signaling in response to inositol starvation triggers Sir2p-dependent telomeric silencing in yeast. Depriving wild type yeast of inositol, an essential precursor for many vital signaling molecules in eukaryotic cells, activates a number of stress response pathways, including Protein Kinase C (PKC) signaling. We now report that activation of PKC signaling by inositol deprivation or by blocking complex sphingolipid synthesis with aureobasidin A results in increased Sir2p dependent telomeric silencing in wild type yeast. Telomeric silencing is dependent on Slt2p, which is the terminal MAPK of the PKC signaling pathway. In addition, consistent with the idea that Sir2p enzymatic activity and its function in silencing depend on an adequate supply of NAD(+); we found that inositol depletion induces the expression of the BNA2 gene, which is involved in the de novo pathway for NAD(+) synthesis. In the bna2Δ; and npt1Δ; mutants, defective in NAD(+) synthesis via the de novo and salvage pathways respectively, silencing is greatly reduced. Surprisingly, however, when nicotinic acid is omitted from the medium, a condition associated with low cellular NAD(+) levels, wild type cells exhibit increased telomeric silencing in the absence of inositol and/or at 37C. The increase in telomeric silencing in response to the absence of inositol in wild type cells is correlated to chronological life span extension. We conclude that increased Sir2p-dependent silencing in wild type cells in response to inositol deprivation is stress induced and dependent on an active PKC signaling pathway, as well as both pathways for endogenous synthesis of NAD(+), but is not correlated to the absolute level of cellular NAD(+). 23940785 Pomalidomide Shows Significant Therapeutic Activity against CNS Lymphoma with a Major Impact on the Tumor Microenvironment in Murine Models. Primary CNS lymphoma carries a poor prognosis. Novel therapeutic agents are urgently needed. Pomalidomide (POM) is a novel immunomodulatory drug with anti-lymphoma activity. CNS pharmacokinetic analysis was performed in rats to assess the CNS penetration of POM. Preclinical evaluation of POM was performed in two murine models to assess its therapeutic activity against CNS lymphoma. The impact of POM on the CNS lymphoma immune microenvironment was evaluated by immunohistochemistry and immunofluorescence. In vitro cell culture experiments were carried out to further investigate the impact of POM on the biology of macrophages. POM crosses the blood brain barrier with CNS penetration of ~ 39%. Preclinical evaluations showed that it had significant therapeutic activity against CNS lymphoma with significant reduction in tumor growth rate and prolongation of survival, that it had a major impact on the tumor microenvironment with an increase in macrophages and natural killer cells, and that it decreased M2-polarized tumor-associated macrophages and increased M1-polarized macrophages when macrophages were evaluated based on polarization status. In vitro studies using various macrophage models showed that POM converted the polarization status of IL4-stimulated macrophages from M2 to M1, that M2 to M1 conversion by POM in the polarization status of lymphoma-associated macrophages is dependent on the presence of NK cells, that POM induced M2 to M1 conversion in the polarization of macrophages by inactivating STAT6 signaling and activating STAT1 signaling, and that POM functionally increased the phagocytic activity of macrophages. Based on our findings, POM is a promising therapeutic agent for CNS lymphoma with excellent CNS penetration, significant preclinical therapeutic activity, and a major impact on the tumor microenvironment. It can induce significant biological changes in tumor-associated macrophages, which likely play a major role in its therapeutic activity against CNS lymphoma. POM should be further evaluated in clinical trials. 23870021 Definitive treatment of vein of Galen aneurysmal malformation with stereotactic radiosurgery. Vein of Galen aneurysmal malformations (VGAMs) are uncommon congenital malformations arising from fistulous communication with the median vein of the prosencephalon, a primitive precursor of midline cerebral venous structures. Angiographic embolization is the primary modality for treatment given historically poor microsurgical outcomes. Only a few reports of treatment by Gamma Knife radiosurgery (GKRS) exist in the literature, and the results are variable. The authors present 2 cases of VGAM in which GKRS provided definitive treatment with good outcome: one case involving antenatal presentation of a high-output, mural-type VGAM with complex clinical course refractory to multiple embolic procedures, and the other a choroidal-type VGAM presenting with hemorrhage in an adult and without a feasible embolic approach. With discussion of these cases and review of the literature, the authors advocate inclusion of GKRS as a therapeutic option for treatment of these complex lesions. 23638449 A prospective study of the onset of PTSD symptoms in the first month after trauma exposure. The course of posttraumatic stress disorder (PTSD) symptoms in the month after trauma exposure has not been determined adequately. Symptom group C (avoidance/numbing) has been identified retrospectively as a marker for PTSD, but prospective studies are needed to determine whether these symptoms can provide substantially earlier identification of those who will have PTSD 1 month after trauma exposure. We evaluated 42 patients hospitalized for traumatic injuries over the first post-injury month to track development of posttraumatic symptoms. Symptoms emerged rapidly, with group B (intrusion) and group D (hyperarousal) symptoms occurring earlier than group C symptoms. At 1 week, group C criteria accurately predicted who would develop PTSD by 1 month, and by 2 weeks, group C criteria also predicted who would not develop PTSD by 1 month. The findings, if replicated, may permit earlier identification of PTSD and more timely, appropriate treatment. 23623931 The effect of a retrieval cue on the return of spider fear. Exposure therapy is often used as treatment for anxiety disorders. However, a change in context after exposure can result in fear renewal. This renewal can be attenuated by using retrieval cues stemming from the exposure context. The present study investigated the effect of such a cue in spider-fearful persons. Thirty-three participants underwent an in vivo exposure session while wearing a bracelet (retrieval cue). After exposure, half of the participants continued to wear the bracelet at home until follow-up (cue groups); the other half handed over the bracelet after exposure (no cue groups). Half of the participants in each group received the follow-up in the exposure context (AAcue and AAnocue); for the other half follow-up was conducted in a novel environment (ABcue and ABnocue). A switch in context at follow-up resulted in more self-reported anxiety and arousal compared to no switch. However, the retrieval cue did not attenuate this renewed responding. The number of participant per condition was limited, which might have obscured possible retrieval cue effects due to a lack of power. Additionally, information about the retrieval cue was provided after exposure, which might have weakened the association between the cue and exposure therapy. Furthermore, no autonomic measures were incorporated, restricting the effect to self-report measures. For future studies we would recommend to explicitly link the retrieval cue before onset of the exposure session and to incorporate autonomic measures. Our findings indicate that a switch in context resulted in more self-reported anxiety and arousal, but that a cue stemming from the exposure context did not attenuate this renewal. 23859799 Proximal inhibition of p38 MAPK stress signaling prevents distal axonopathy. The p38 mitogen-activated protein kinase (MAPK) isoforms are phosphorylated by a variety of stress stimuli in neurodegenerative disease and act as upstream activators of myriad pathogenic processes. Thus, p38 MAPK inhibitors are of growing interest as possible therapeutic interventions. Axonal dysfunction is an early component of most neurodegenerative disorders, including the most prevalent optic neuropathy, glaucoma. Sensitivity to intraocular pressure at an early stage disrupts anterograde transport along retinal ganglion cell (RGC) axons to projection targets in the brain with subsequent degeneration of the axons themselves; RGC body loss is much later. Here we show that elevated ocular pressure in rats increases p38 MAPK activation in retina, especially in RGC bodies. Topical eye-drop application of a potent and selective inhibitor of the p38 MAPK catalytic domain (Ro3206145) prevented both the degradation of anterograde transport to the brain and degeneration of axons in the optic nerve. Ro3206145 reduced in the retina phosphorylation of tau and heat-shock protein 27, both down-stream targets of p38 MAPK activation implicated in glaucoma, as well as expression of two inflammatory responses. We also observed increased p38 MAPK activation in mouse models. Thus, inhibition of p38 MAPK signaling in the retina may represent a therapeutic target for preventing early pathogenesis in optic neuropathies. 23847044 THE EFFECT OF DIABETES COMPLICATIONS ON HEALTH-RELATED QUALITY OF LIFE: THE IMPORTANCE OF LONGITUDINAL DATA TO ADDRESS PATIENT HETEROGENEITY. We estimate the impact of six diabetes-related complications (myocardial infarction, ischaemic heart disease, stroke, heart failure, amputation and visual acuity) on quality of life, using seven rounds of EQ-5D questionnaires administered between 1997 and 2007 in the UK Prospective Diabetes Study. The use of cross-sectional data to make such estimates is widespread in the literature, being less expensive and easier to collect than repeated-measures data. However, analysis of this dataset suggests that cross-sectional analysis could produce biased estimates of the effect of complications on QoL. Using fixed effects estimators, we show that variation in the quality of life between patients is strongly influenced by time-invariant patient characteristics. Our results highlight the importance of studying quality-of-life changes over time to distinguish between time-invariant determinants of QoL and the effect on QoL of specific events such as diabetes complications. Copyright © 2013 John Wiley & Sons, Ltd. 23640103 Modelling the Cost Effectiveness of Disease-Modifying Treatments for Multiple Sclerosis : Issues to Consider. Several cost-effectiveness models of disease-modifying treatments (DMTs) for multiple sclerosis (MS) have been developed for different populations and different countries. Vast differences in the approaches and discrepancies in the results give rise to heated discussions and limit the use of these models. Our main objective is to discuss the methodological challenges in modelling the cost effectiveness of treatments for MS. We conducted a review of published models to describe the approaches taken to date, to identify the key parameters that influence the cost effectiveness of DMTs, and to point out major areas of weakness and uncertainty. Thirty-six published models and analyses were identified. The greatest source of uncertainty is the absence of head-to-head randomized clinical trials. Modellers have used various techniques to compensate, including utilizing extension trials. The use of large observational cohorts in recent studies aids in identifying population-based, 'real-world' treatment effects. Major drivers of results include the time horizon modelled and DMT acquisition costs. Model endpoints must target either policy makers (using cost-utility analysis) or clinicians (conducting cost-effectiveness analyses). Lastly, the cost effectiveness of DMTs outside North America and Europe is currently unknown, with the lack of country-specific data as the major limiting factor. We suggest that limited data should not preclude analyses, as models may be built and updated in the future as data become available. Disclosure of modelling methods and assumptions could improve the transferability and applicability of models designed to reflect different healthcare systems. 23942621 Interaction between polygenic risk for cigarette use and environmental exposures in the Detroit neighborhood health study. Cigarette smoking is influenced both by genetic and environmental factors. Until this year, all large-scale gene identification studies on smoking were conducted in populations of European ancestry. Consequently, the genetic architecture of smoking is not well described in other populations. Further, despite a rich epidemiologic literature focused on the social determinants of smoking, few studies have examined the moderation of genetic influences (for example, gene-environment interactions) on smoking in African Americans. In the Detroit Neighborhood Health Study (DNHS), a sample of randomly selected majority African American residents of Detroit, we constructed a genetic risk score (GRS), in which we combined top (P-value <5 × 10(-7)) genetic variants from a recent meta-analysis conducted in a large sample of African Americans. Using regression (effective n=399), we first tested for association between the GRS and cigarettes per day, attempting to replicate the findings from the meta-analysis. Second, we examined interactions with three social contexts that may moderate the genetic association with smoking: traumatic events, neighborhood social cohesion and neighborhood physical disorder. Among individuals who had ever smoked cigarettes, the GRS significantly predicted the number of cigarettes smoked per day and accounted for ∼3% of the overall variance in the trait. Significant interactions were observed between the GRS and number of traumatic events experienced, as well as between the GRS and average neighborhood social cohesion; the association between genetic risk and smoking was greater among individuals who had experienced an increased number of traumatic events in their lifetimes, and diminished among individuals who lived in a neighborhood characterized by greater social cohesion. This study provides support for the utility of the GRS as an alternative approach to replication of common polygenic variation, and in gene-environment interaction, for smoking behaviors. In addition, this study indicates that environmental determinants have the potential to both exacerbate (traumatic events) and diminish (neighborhood social cohesion) genetic influences on smoking behaviors. 23856979 Usefulness of Thiopurine Metabolites in Predicting Azathioprine Resistance in Pediatric IBD Patients. Few data on azathioprine (AZA) therapy for inflammatory bowel disease (IBD) exist for children. We evaluated whether the 6-thioguanine nucleotides (6-TGN) level predicts AZA refractoriness in children with IBD and whether children benefit an AZA dose escalation. Seventy-eight children with IBD initially treated with an AZA dose of 1.5-2.5 mg/kg/day were retrospectively included. The dose was adjusted based on the clinical status. The receiver operating characteristic curve and logistic regression were used to determine predictors for AZA resistance. Initially, 18 of 40 (45%) patients receiving a dose of <2 mg/kg/day and 11 of 38 (28.9%) patients receiving a dose of 2-2.5 mg/kg/day achieved remission. The 6-TGN level above 250 pmol/8.10(8) RBCs was associated with a higher remission rate, though non-significant. Among 35 patients with a dose escalation due to treatment failure, 12 (34.3%) achieved remission (the median 6-TGN level increased from 260 to 394 pmol/8.10(8) RBCs [P = .002]), 23 (67.6%) were AZA refractory. A 6-TGN level above 405 pmol/8.10(8) RBCs was the only predictor for AZA resistance (sensitivity 78.3%, specificity 75%, OR 10.8 [95% CI: 2.1-55.7, P = .004]). Serial metabolite monitoring is useful to identify children with IBD resistant to AZA. Children who cannot achieve remission despite a 6-TGN level above 405 pmol/8.10(8) RBCs should receive alternative therapies than dose increase. 23727182 Protective effects of aqueous extract from Acanthopanax senticosus against corticosterone-induced neurotoxicity in PC12 cells. Acanthopanax senticosus, classified into the family of Araliaceae, has been known for thousands of years as a remedy and is used to treat various diseases in traditional Chinese medicine system including hypertension, ischemic heart disease and hepatitis. This study aimed to examine the protective effects of aqueous extract from Acanthopanax senticosus (ASE) on corticosterone-induced neurotoxicity and its possible mechanisms, using PC12 cells as a suitable in vitro model of depression. In this paper, PC12 cells were treated with 200μM of corticosterone in the absence or presence of ASE in varying concentrations for 24h. Then, cell viability was measured by MTT assay. The release amount of lactate dehydrogenase (LDH) was quantified using LDH assay kit. Apoptosis of PC12 cells was measured by Annexin V-FITC and PI labeling. The intracellular Ca(2+) content was tested by fluorescent labeling. The mRNA level of brain-derived neurotrophic factor (BDNF) was examined by real-time RT-PCR, and the expression of cAMP response element binding protein (CREB) was determined by western blotting. The results showed that treatment with 200μM of corticosterone could induce cytotoxicity in PC12 cells. However, different concentrations of ASE (50, 100, 200, and 400μg/mL) significantly increased the cell viability, decreased the LDH release, suppressed the apoptosis of PC12 cells, attenuated the intracellular Ca(2+) overloading, up-regulated the BDNF mRNA level and CREB protein expression compared with the corresponding corticosterone-treated group. The present results suggest that ASE exerts a neuroprotective effect on corticosterone-induced neurotoxicity in PC12 cells, which may be one of the acting mechanisms that accounts for the in vivo antidepressant activity of ASE. 23752613 Neutrophil recruitment to the lung in both C5a- and CXCL1-induced alveolitis is impaired in vitamin D-binding protein-deficient mice. Knowledge of how neutrophils respond to chemotactic signals in a complex inflammatory environment is not completely understood. Moreover, even less is known about factors in physiological fluids that regulate the activity of chemoattractants. The vitamin D-binding protein (DBP) has been shown to significantly enhance chemotaxis to complement activation peptide C5a using purified proteins in vitro, and by ex vivo depletion of DBP in physiological fluids, but this function has not been determined in vivo. DBP null ((-/-)) mice were used to investigate how a systemic absence of this plasma protein affects leukocyte recruitment in alveolitis models of lung inflammation. DBP(-/-) mice had significantly reduced (~50%) neutrophil recruitment to the lungs compared with their wild-type DBP(+/+) counterparts in three different alveolitis models, two acute and one chronic. The histology of DBP(-/-) mouse lungs also showed significantly less injury than wild-type animals. The chemotactic cofactor function of DBP appears to be selective for neutrophil recruitment, but, in contrast to previous in vitro results, in vivo DBP can enhance the activity of other chemoattractants, including CXCL1. The reduced neutrophil response in DBP(-/-) mice could be rescued to wild-type levels by administering exogenous DBP. Finally, in inflammatory fluids, DBP binds to G-actin released from damaged cells, and this complex may be the active chemotactic cofactor. To our knowledge, results show for the first time that DBP is a significant chemotactic cofactor in vivo and not specific for C5a, suggesting that this ubiquitous plasma protein may have a more significant role in neutrophil recruitment than previously recognized. 23898216 Cathepsin B activity has a crucial role in the developmental competence of bovine cumulus-oocyte complexes exposed to heat shock during in vitro maturation. Cathepsin B was found to be correlated inversely with the quality of bovine oocytes and embryos. The aims of this study were to evaluate i) the relationship between heat shock during in vitro maturation (IVM) of bovine cumulus-oocyte complexes (COCs) and cathepsin B activity in relation to apoptosis and ii) the effect of supplementation of cathepsin B inhibitor (E-64) during IVM of heat-shocked COCs on embryonic development. After IVM at 38.5 °C for 22 h (control group) or at 38.5 °C for 5 h followed by 41 °C for 17 h (heat shock group) either with or without 1 μM E-64, activities and protein expression of cathepsin B and caspase 3 were evaluated as well as TUNEL staining. After IVF, developmental rate, total cell number, and the percentage of apoptotic cells in blastocysts were evaluated on day 8 (day 0, IVF day). Heat-shocked IVM COCs showed significantly high activities and expressions of both cathepsin B, and caspase 3 accompanied by a significant increase in number of TUNEL-positive cells. Addition of E-64 significantly decreased the activities of cathepsin B and caspase 3, and TUNEL-positive cells in heat-shocked IVM COCs. Moreover, addition of 1 μM E-64 during IVM under heat shock conditions significantly improved both developmental competence and quality of the produced embryos. These results indicate that heat shock induction of cathepsin B is associated with apoptosis of COCs, and inhibition of cathepsin B activity can improve the developmental competence of heat-shocked COCs during IVM. 23915592 Mechanical Circulatory Support and Heart Transplantation: Donor and Recipient Factors Influencing Graft Survival. Mechanical circulatory support is an accepted strategy to bridge patients to heart transplantation (HTx). Among mechanical circulatory support patients who go on to HTx, factors associated with improved graft survival have not been fully elucidated. Using the Scientific Registry for Transplant Recipients, we identified adults who were treated with a left ventricular assist device (LVAD) or total artificial heart (TAH) before HTx. Kaplan-Meier and multivariate Cox regression models were used to identify patient, donor, and device characteristics associated with graft survival. Between January 1997 and February 2012, 2,785 adults underwent HTx. Before HTx, 2,674 patients were treated with a LVAD (HeartMate XVE, 724; HeartMate II, 1,882; HeartWare, 68), and 111 were treated with a TAH. Follow-up averaged 25 ± 24 months. Gender mismatch occurred in 23%. Graft survival did not differ between LVAD groups (all p > 0.168), but TAH was associated with reduced graft survival compared with LVADs (p < 0.001). After controlling for device type (LVAD vs TAH), lower recipient pulmonary vascular resistance, shorter ischemic time, younger donor age, donor-to-recipient gender match, and higher donor-to-recipient body mass index ratio were independent predictors of longer graft survival (all p < 0.05). TAH was associated with reduced graft survival after transplant, and survival did not differ between the LVAD device groups. Additional variables that were independently associated with graft survival were donor age, recipient peripheral vascular resistance, ischemic time, gender match, and donor-to-recipient body mass index ratio. Recognition of these factors may inform decisions regarding device support and donor suitability. 23347889 The development and preliminary validation of the Taiwanese Manual Ability Measure for Burns. To develop and validate the Taiwanese Manual Ability Measure for Burns (T-MAM for Burns), a task-oriented functional evaluation tool to assess self-reported manual ability in burn patients. A longitudinal study. A sample of 45 burn patients from burn rehabilitation centers with varying degrees of hand involvement. The preliminary testing version was formed by adding burn specific items to the Taiwanese version of the Manual Ability Measure. A field test was then conducted for item reduction and psychometric properties testing. Out of 55 initial items, 20 were selected into the final version of the T-MAM for Burns. Psychometric analyses indicated that it was reliable (test-retest ICC=.99), with adequate concurrent validity with various other hand function tests (r=-.79 with the short form Disabilities of the Arm, Shoulder, and Hand, or, the QuickDASH) and discriminative validity (significant difference (t=2.99, P=.005) between groups with unilateral vs. bilateral hand burns), and responsive (ES=.24 and .44 at one- and 3-month evaluations). This study shows that the T-MAM for Burns has great potential to be a functional outcome measure for burn rehabilitation. Additional research with a larger sample should be conducted to further confirm its validity and reliability. 23648277 Impaired language function in generalized epilepsy: inadequate suppression of the default mode network. We aimed to study the effect of a potential default mode network (DMN) dysfunction on language performance in epilepsy. Language dysfunction in focal epilepsy has previously been connected to brain damage in language-associated cortical areas. In this work, we studied generalized epilepsy (GE) without focal brain damage to see if the language function was impaired. We used functional magnetic resonance imaging (fMRI) to investigate if the DMN was involved. Eleven persons with GE and 28 healthy controls were examined with fMRI during a sentence-reading task. We demonstrated impaired language function, reduced suppression of DMN, and, specifically, an inadequate suppression of activation in the left anterior temporal lobe and the posterior cingulate cortex, as well as an aberrant activation in the right hippocampal formation. Our results highlight the presence of language decline in people with epilepsy of not only focal but also generalized origin. 23833193 Piceatannol Enhances Cisplatin Sensitivity in Ovarian Cancer via Modulation of p53, X-linked Inhibitor of Apoptosis Protein (XIAP), and Mitochondrial Fission. Resistance to cisplatin (CDDP) in ovarian cancer (OVCA) arises from the dysregulation of tumor suppressors and survival signals. During genotoxic challenge, these factors can be influenced by secondary agents that facilitate the induction of apoptosis. Piceatannol is a natural metabolite of the stilbene resveratrol found in grapes and is converted from its parent compound by the enzyme CYP1BA1 p450. It has been hypothesized to exert specific effects against various cellular targets; however, its ability to influence CDDP resistance in cancer cells has not been investigated to date. Here, we show that piceatannol is a potent enhancer of CDDP sensitivity in OVCA, and this effect is achieved through the modulation of several major determinants of chemoresistance. Piceatannol enhances p53-mediated expression of the pro-apoptotic protein NOXA, increases XIAP degradation via the ubiquitin-proteasome pathway, and enhances caspase-3 activation. This response is associated with an increase in Drp1-dependent mitochondrial fission, leading to more effective induction of apoptosis. In vivo studies using a mouse model of OVCA reveal that a number of these changes occur in association with a greater overall reduction in tumor weight when mice are treated with both piceatannol and CDDP, in comparison to treatment with either agent alone. Taken together, these findings demonstrate the potential application of piceatannol to enhance CDDP sensitivity in OVCA, and it acts on p53, XIAP, and mitochondrial fission. 23620344 Chloroplast-targeted expression of the codon-optimized truncated cry1Ah gene in transgenic tobacco confers a high level of protection against insects. The study of insect-resistant transgenic tobacco provides a good foundation for the further application of the cry1Ah gene in other important crops. To improve transgene expression levels and insect resistance, the coding sequence of the novel Bacillus thuringiensis insecticidal gene cry1Ah (truncated cry1Ah) was modified according to the codon bias of the plant by increasing its GC content from the original 37 % to 48, 55, and 63 % (designated m1-cry1Ah, m2-cry1Ah, and m3-cry1Ah, respectively). In addition, the m3-cry1Ah gene was linked with a transit peptide sequence for chloroplast-targeted expression (designated ctp-m3-cry1Ah). Four plant expression vectors were constructed harboring m1-cry1Ah, m2-cry1Ah, m3-cry1Ah, or ctp-m3-cry1Ah. A total of 23 transgenic tobacco lines were produced with the four constructs by Agrobacterium tumefaciens-mediated transformation. PCR, Southern hybridization, quantitative RT-PCR and ELISA indicated that the cry1Ah gene was not only integrated into the tobacco genome, but was also successfully expressed at the mRNA and protein levels. The Cry1Ah protein level in ctp-m3-cry1Ah plants reached 4.42 Î¼g/g fresh weight, which was a 2- to 10-fold increase over the levels observed in m1-cry1Ah, m2-cry1Ah, and m3-cry1Ah plants and resulted in the highest resistance to Helicoverpa armigera based on bioassays. Our results demonstrated that combining the codon optimization of cry1Ah gene with the targeting of Cry1Ah protein to the chloroplasts conferred a high level of protection against insects. The results of our experiments in tobacco, an important model system, provide a good foundation for enhancing the insecticidal efficacy of staple crops. 23529106 Intuitive Tactile Zooming for Graphics Accessed by Individuals Who are Blind and Visually Impaired. One possibility of providing access to visual graphics for those who are visually impaired is to present them tactually: unfortunately, details easily available to vision need to be magnified to be accessible through touch. For this, we propose an "intuitive" zooming algorithm to solve potential problems with directly applying visual zooming techniques to haptic displays that sense the current location of a user on a virtual diagram with a position sensor and, then, provide the appropriate local information either through force or tactile feedback. Our technique works by determining and then traversing the levels of an object tree hierarchy of a diagram. In this manner, the zoom steps adjust to the content to be viewed, avoid clipping and do not zoom when no object is present. The algorithm was tested using a small, "mouse-like" display with tactile feedback on pictures representing houses in a community and boats on a lake. We asked the users to answer questions related to details in the pictures. Comparing our technique to linear and logarithmic step zooming, we found a significant increase in the correctness of the responses (odds ratios of 2.64:1 and 2.31:1, respectively) and usability (differences of 36% and 19%, respectively) using our "intuitive" zooming technique. 23677517 CD161 expression characterizes a subpopulation of human regulatory T cells that produces IL-17 in a STAT3-dependent manner. Treg cells are critical for the prevention of autoimmune diseases and are thus prime candidates for cell-based clinical therapy. However, human Treg cells are "plastic", and are able to produce IL-17 under inflammatory conditions. Here, we identify and characterize the human Treg subpopulation that can be induced to produce IL-17 and identify its mechanisms. We confirm that a subpopulation of human Treg cells produces IL-17 in vitro when activated in the presence of IL-1β, but not IL-6. "IL-17 potential" is restricted to population III (CD4(+) CD25(hi) CD127(lo) CD45RA(-) ) Treg cells expressing the natural killer cell marker CD161. We show that these cells are functionally as suppressive and have similar phenotypic/molecular characteristics to other subpopulations of Treg cells and retain their suppressive function following IL-17 induction. Importantly, we find that IL-17 production is STAT3 dependent, with Treg cells from patients with STAT3 mutations unable to make IL-17. Finally, we show that CD161(+) population III Treg cells accumulate in inflamed joints of patients with inflammatory arthritis and are the predominant IL-17-producing Treg-cell population at these sites. As IL-17 production from this Treg-cell subpopulation is not accompanied by a loss of regulatory function, in the context of cell therapy, exclusion of these cells from the cell product may not be necessary. 23859257 Restoring the Salivary Cortisol Awakening Response Through Nasal Continuous Positive Airway Pressure Therapy in Obstructive Sleep Apnea. Partial and largely conflicting data are currently available on the interplay between obstructive sleep apnea (OSA) and hypothalamus-pituitary-adrenal axis (HPA) activity in adult obese men. This study was performed to evaluate the daily trajectories of salivary cortisol, specifically with respect to the salivary cortisol awakening response (CAR), a common method used to assess HPA axis activity. The main findings of this study were that adult male obese subjects who were newly diagnosed with severe OSA showed the following: (1) a flattening of the CAR; (2) levels of cortisol at awakening that were lower than those of the controls; and (3) maintenance of the physiological circadian activity of the HPA axis, with the highest hormone concentrations produced in the morning and the lowest in the evening. This study was also designed to investigate the effects of 3 and 6 mos of treatment with continuous airways positive pressure (CPAP). CPAP use resulted in a significant recovery of the sleep patterns disrupted by OSA; moreover, mild neuropsychological signs of depression and anxiety in severe OSA patients were concomitantly progressively improved by CPAP treatment. Furthermore, this study reports that 3 and 6 mos of CPAP therapy restored the presence of CAR and was able to significantly reduce the difference in the morning cortisol levels between the OSA and control groups. In conclusion, we report here that compared with obese nonapneic matched controls, OSA patients present a dysregulation of HPA axis activity, as shown by the flattening of the diurnal pattern of cortisol production in response to repeated challenge due to hypoxia and sleep fragmentation. This dysregulation was especially detectable in the first hour after awakening and restored after 3 and 6 mos of treatment with CPAP. 22940902 The impact of bystanding to workplace bullying on symptoms of depression among women and men in industry in Sweden: an empirical and theoretical longitudinal study. Prospective studies on bystanding to workplace bullying and the health outcomes are scarce. To investigate the work environmental risk factors of depressive symptoms among bystanders to bullying in both women and men in four large industrial organizations in Sweden. The number of respondents at four large industrial enterprises with more than one year at the workplace at T1: n = 2,563 (Women: n = 342; Men: n = 2,227). Bystanders to bullying at T1: n = 305 (Women: n = 30; Men: n = 275). The total number of those with symptoms of depression at T2: Women: n = 30; Men: n = 161. Two thousand one hundred and seventy-seven employees answered the questionnaire on T1 and T2 with an 18-month interval. "To have depressive symptoms" was defined as not having depressive symptoms at T1 but having depressive symptoms at T2. The number of men who were bystanders to bullying was larger compared to women. However, the proportion of women who were bystanders to bullying and developed depressive symptoms 18 months later was higher in comparison with men (33.3 and 16.4 %, respectively). Further, "Being a bystander to bullying" 1.69 (1.13-2.53), "Rumors of changes in the workplace" 1.53 (1.10-2.14), "Reduced role clarity" 2.30 (1.21-4.32), "Lack of appreciation of being in the group" 1.76 (1.22-2.53) increased the risk of future symptoms of depression. "Job Strain" was not an adjusted risk factor for depression. Our results support previous findings that bystanding to workplace bullying is related to future depressive symptoms. 23728800 Morphogenetic analysis of peri-implantation development. Background:Although successful implantation is required for development in placental mammals, the molecular and morphogenetic events that define peri-implantation remain largely unexplored. Results: Here we present detailed morphological and immunohistochemical analysis of mouse embryos between embryonic day 3.75 and 5.25 of gestation, during the implantation process in vivo. We examined expression patterns of key transcription factors (Sox2, Oct4, Nanog, Cdx2, Gata6, Sox17, and Yy1) during pre- and postimplantation development. Additionally, we examined morphogenetic changes through analysis of ZO-1, Laminin, and E-Cadherin localization. The results presented reveal novel changes in gene expression and morphogenetic events during peri-implantation in utero. Here we show: (1) molecular and morphological changes in primitive endoderm cells as they transition from a salt and pepper distribution to a sheet covering the inner cell mass; (2) tissue-specific GATA6 levels; and (3) a striking pattern of SOX17 that is suggestive of a functional role either directing or permitting implantation at specific sites in the uterine epithelium. Conclusions: A growing number of knockout mice display peri-implantation lethality, and the data presented herein identify key morphogenetic landmarks that can be used to characterize mutant phenotypes, as well as further our basic understanding of peri-implantation development. Developmental Dynamics 242:1110-1120, 2013. © 2013 Wiley Periodicals, Inc. 23879649 Dose/volume-based evaluation of the accuracy of deformable image registration for the rectum and bladder. Background and purpose. Deformable image registration (DIR) is a key component of image-guided and adaptive strategies in radiotherapy. DIR based on image intensities alone is promising for online applications, but is challenged in regions with low intensity gradients. In this study we have investigated the performance of intensity- based DIR applied to contour propagation of the rectum and bladder, focusing on the consequences in terms of dose/volume parameters. Material and methods. The rectum and bladder volumes were delineated in the planning computed tomography (pCT) scan and in 8-9 repeat CTs (Vmanual) for nine prostate cancer patients. The volumes from the pCT were propagated onto the repeat CTs using intensity-based DIR (Vprop). Dose/volume parameters for Vmanual and Vprop were derived by dose re-calculations following rigid registration on prostate fiducials. Linear regression was used to identify qualitative and quantitative volumetric measures of the DIR performance being associated with the differences in dose/volume parameters. Results. The median differences in dose/volume parameters assessed for Vprop and Vmanual were modest, but individual differences ˜ 7 Gy were seen. The observed differences in dose/volume parameters showed strong correlations to the measures of the DIR performance as well as with the volume variations, most pronounced for the rectum (R(2) = 0.63-0.85; p ≤ 0.05). Conclusion. Limitations in the intensity-based DIR algorithm resulted in large individual differences in dose/volume parameters between propagated and manually segmented volumes, which were correlated with volumetric measures of the DIR performance. 23847120 Rivastigmine is associated with restoration of left frontal brain activity in Parkinson's disease. The objective of this study was to investigate how acetylcholinesterase inhibitor (ChEI) treatment affects brain function in Parkinson's disease (PD). Twelve patients with PD and either dementia or mild cognitive impairment underwent task-free functional magnetic resonance imaging before and after 3 months of ChEI treatment and were compared with 15 age- and sex-matched neurologically healthy controls. Regional spontaneous brain activity was measured using the fractional amplitude of low-frequency fluctuations. At baseline, patients showed reduced spontaneous brain activity in regions important for motor control (eg, caudate, supplementary motor area, precentral gyrus, thalamus), attention and executive functions (eg, lateral prefrontal cortex), and episodic memory (eg, precuneus, angular gyrus, hippocampus). After treatment, the patients showed a similar but less extensive pattern of reduced spontaneous brain activity relative to controls. Spontaneous brain activity deficits in the left premotor cortex, inferior frontal gyrus, and supplementary motor area were restored such that the activity was increased posttreatment compared with baseline and was no longer different from controls. Treatment-related increases in left premotor and inferior frontal cortex spontaneous brain activity correlated with parallel reaction time improvement on a test of controlled attention. PD patients with cognitive impairment show numerous regions of decreased spontaneous brain function compared with controls, and rivastigmine is associated with performance-related normalization in the left frontal cortex function. © 2013 Movement Disorder Society. 23881525 High carbonate level of apatite in kidney stones implies infection, but is it predictive? The presence of infectious microorganisms in urinary stones is commonly inferred from stone composition, especially by the presence of struvite in a stone. The presence of highly carbonated apatite has also been proposed as a marker of the presence of bacteria within a stone. We retrospectively studied 368 patients who had undergone percutaneous nephrolithotomy (PCNL), and who also had culture results for both stone and urine. Urine culture showed no association with stone mineral content, but stone culture was more often positive in struvite-containing stones (73 % positive) and majority apatite stones (65 %) than in other stone types (54 %, lower than the others, P < 0.02). In 51 patients in whom the carbonate content of apatite could be measured, carbonate in the apatite was weakly predictive of positive stone culture with an optimal cutoff value of 13.5 % carbonate (sensitivity 0.61, specificity 0.80). In positive cultures of stones (all mineral types combined), organisms that characteristically produce urease were present in 71 % of the cases, with no difference in this proportion among different types of stone. In summary, the type of mineral in the stone was predictive of positive stone culture, but this correlation is imperfect, as over half of non-struvite, non-apatite stones were found to harbor culturable organisms. We conclude that mineral type is an inadequate predictor of whether a stone contains infectious organisms, and that stone culture is more likely to provide information useful to the management of patients undergoing PCNL. 23747555 Inferring wavelength dependence of AOD and Ångström exponent over a sub-tropical station in South Africa using AERONET data: Influence of meteorology, long-range transport and curvature effect. Aerosol optical properties over a southern sub-tropical site Skukuza, South Africa were studied to determine the variability of the aerosol characteristics using CIMEL Sunphotometer data as part of the AErosol RObotic NETwork (AERONET) from December 2005 to November 2006. Aerosol optical depth (AOD), Ångström exponent (α), and columnar water vapor (CWV) data were collected, analyzed, and compiled. Participating in this network provided a unique opportunity for understanding the sources of aerosols affecting the atmosphere of South Africa (SA) and the regional radiation budget. The meteorological patterns significantly (p<0.05) influenced the amount and size distribution of the aerosols. Results showed that seasonal variation of AOD at 500nm (AOD500) over the observation site were characterized by low values (0.10-0.13) in autumn, moderate values (0.14-0.16) in summer and winter seasons, and high to very high values (0.18-0.40) during the spring, with an overall mean value of 0.18±0.12. Ångström exponent α440-870, varied from 0.5 to 2.89, with significant (p<0.0001) seasonal variability. CWV showed a strong annual cycle with maximum values in the summer and autumn seasons. The relationship between AOD, Ångström exponent (α), and CWV showed a strong dependence (p<0.0001) of α on AOD and CWV, while there was no significant correlation between AOD and CWV. Investigation of the adequacy of the simple use of the spectral AOD and Ångström exponent data was used in deriving the curvature (a2) showed to obtain information for determining the aerosol-particle size. The negative a2 values are characterized by aerosol-size dominated by fine-mode (0.1-1μm), while the positive curvatures indicate abundance of coarse particles (>1μm). Trajectory cluster analyses revealed that the air masses during the autumn and winter seasons have longer advection pathways, passing over the ocean and continent. This is reflected in the aerosol properties that are derived from the ocean, desert, and anthropogenic activities that include biomass burning and industrial pollution. 22985061 Telomerase activity and telomere length distribution in vascular endothelial cells in a short-term culture under the presence of hydrogen peroxide. The aim of this study was to assess the biological effects of oxidative stress on human vascular endothelial cells. The telomeric changes and the alterations of the expression of telomere-associated proteins in human umbilical venous endothelial cells (HUVEC) cultured in the presence of hydrogen peroxide (H2 O2 ) were analyzed. During the culture, the cell growth rate decreased, whereas the telomerase activity of the surviving cells increased. As the H2 O2 level increased, long telomeres decreased proportionally, thus resulting in a telomere length distribution that was rich in short telomeres. These observations suggested that H2 O2 -affected endothelial cells bear telomeric features similar to those of aged cells. In contrast, the expression of telomere-associated proteins, TRF1 and TRF2, showed different changes. TRF1 increased in relation to H2 O2 concentration, whereas TRF2 showed no significant change. The surviving cells exposed to H2 O2 showed a H2 O2 -dose dependent increase in telomerase activity, whereas the telomere protein and RNA components were only elevated in low concentrations of H2 O2 . The increase in telomerase activity and TRF1 protein expression of vascular endothelial cell might show an aspect of cellular protective reaction against oxygen stress. 23751068 Resveratrol prevents development of eosinophilic rhinosinusitis with nasal polyps in a mouse model. Since the recent establishment of a murine model of eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP), both the development of new drugs for treatment or prevention of eosinophilic CRSwNP and elucidation of their pathogenesis have been feasible. We investigated the therapeutic effects of resveratrol on CRSwNP and its mechanism of action using a murine model. After induction of eosinophilic CRSwNP, the therapeutic effects of resveratrol were tested and compared with those of triamcinolone acetonide. Histopathologic changes were evaluated using hematoxylin and eosin for overall inflammation, Sirius red for eosinophils, and Masson's trichrome stain for collagen. The expression levels of the interleukin (IL)-4, IL-5, prostaglandin D synthase, and leukotriene C4 synthase genes were assessed by quantitative real-time PCR. Cyclooxygense-2 and 5-lipoxygense levels were evaluated by immunohistochemical staining and Western blot analysis. The degree of eosinophilic infiltration and subepithelial fibrosis was significantly decreased by administration of high-dose resveratrol, the potency of which was similar to that of triamcinolone acetonide. The expression levels of the IL-4, IL-5, prostaglandin D synthase, and leukotriene C4 synthase genes were significantly decreased by administration of low- or high-dose resveratrol. The production of 5-lipoxygenase was strongly inhibited by high-dose resveratrol. Resveratrol may be useful for the prevention of eosinophilic CRSwNP. A key mechanism of its action is believed to be its anti-inflammatory effect, particularly on eosinophils, by inhibiting the lipoxygenase pathway. 23772653 Accurate Models for P-gp Drug Recognition Induced from a Cancer Cell Line Cytotoxicity Screen. P-glycoprotein (P-gp, MDR1) is a promiscuous drug efflux pump of substantial pharmacological importance. Taking advantage of large-scale cytotoxicity screening data involving 60 cancer cell lines, we correlated the differential biological activities of ∼13 000 compounds against cellular P-gp levels. We created a large set of 934 high-confidence P-gp substrates or nonsubstrates by enforcing agreement with an orthogonal criterion involving P-gp overexpressing ADR-RES cells. A support vector machine (SVM) was 86.7% accurate in discriminating P-gp substrates on independent test data, exceeding previous models. Two molecular features had an overarching influence: nearly all P-gp substrates were large (>35 atoms including H) and dense (specific volume of <7.3 Å(3)/atom) molecules. Seven other descriptors and 24 molecular fragments ("effluxophores") were found enriched in the (non)substrates and incorporated into interpretable rule-based models. Biological experiments on an independent P-gp overexpressing cell line, the vincristine-resistant VK2, allowed us to reclassify six compounds previously annotated as substrates, validating our method's predictive ability. Models are freely available at http://pgp.biozyne.com . 23207892 The acute effect of different half squat set configurations on jump potentiation. Boullosa, DA, Abreu, L, Beltrame, LGN, and Behm, DG. The acute effect of different half squat set configurations on jump potentiation. J Strength Cond Res 27(8): 2059-2066, 2013-The aim of this study was to evaluate the acute effect of a half squat exercise performed with different set configurations on jump potentiation. Twelve resistance-trained men were evaluated on 3 occasions separated by 48-96 hours. First, they performed a 5 repetitions maximum (5RM) test. Subsequently, they performed in a randomized order 2 sessions: one session with 5RM until failure and the other with the same workload but with 30-second rest intervals between repetitions (i.e., cluster set [CS]). Countermovement jump performance was examined during the second and third sessions for jump height and force-time parameters using a force platform at the following time intervals: before and at 1, 3, 6, 9, and 12 minutes. Separate comparisons for each variable at the different time intervals were analyzed using analysis of variance, effect size, and qualitative inferences. The majority of the parameters improved independently of the time they occurred, except for peak force and vertical stiffness after a set until failure. For peak power, it appears that the cluster treatment resulted in superior potentiation at 1 minute, whereas the 5RM treatment resulted in greater potentiation at 9 minutes. Effect size analysis and qualitative outcomes revealed an improvement in vertical stiffness and a lowering in the depth of the countermovement in CS. There were significant correlations between participants' 5RM relative performance and various force-time parameters only in CS. It appears that a CS induces greater peak power than a 5RM set at 1 minute, although the reverse occurs at 9 minutes. Delayed potentiation associated with the 5RM may be attributed to greater fatigue versus the CS approach. Therefore, it follows that the optimal method for inducing peak power potentiation is dependent on the available time between heavy half squat exercise and the subsequent jump performance. 23860614 Transcatheter Closure of Patent Ductus Arteriosus and Atrial Septal Defect Without On-Site Surgical Backup: A Two-Year Experience in an African Community. Congenital heart disease contributes significantly to the health burden of children in Nigeria. Interventions for congenital heart disease have been available in the developed world since the first report on device closure of patent ductus arteriosus (PDA) in 1967 by Porstmann. However, this did not start in Nigeria until October 2010. This study aimed to document the profiles of the patients who had undergone interventions for congenital heart diseases since the availability of the procedure, the challenges encountered, and the prospects associated with the interventions at the study site. All the patients referred to undergo interventions for congenital heart disease at the study center between October 2010 and 2012 were studied. The profile of the patient, including diagnosis at referral, indication for interventions, and interventions performed, were documented. The patients ranged in age from 3 to 62 years (mean age, 13.54 ± 17.7 years), and the male-to-female ratio was 1:3. The diagnosis at referral included PDA in 10 (83 %) of the 12 patients and secundum atrial septal defect in 2 patients (17 %). They all had transcatheter closure of the defects. Interventional procedures for congenital heart diseases currently are available locally, but the high degree of manpower training required, the cost, and the local availability of consumables are major factors limiting their use. Regional and international collaboration could be mutually beneficial. 23771063 DagSolid: a new Geant4 solid class for fast simulation in polygon-mesh geometry. Even though a computer-aided design (CAD)-based geometry can be directly implemented in Geant4 as polygon-mesh using the G4TessellatedSolid class, the computation speed becomes very slow, especially when the geometry is composed of a large number of facets. To address this problem, in the present study, a new Geant4 solid class, named DagSolid, was developed based on the direct accelerated geometry for the Monte Carlo (DAGMC) library which provides the ray-tracing acceleration algorithm functions. To develop the DagSolid class, the new solid class was derived from the G4VSolid class, and its ray-tracing functions were linked to the corresponding functions of the DAGMC library. The results of this study show that the use of the DagSolid class drastically improves the computation speed. The improvement was more significant when there were more facets, meaning that the DagSolid class can be used more effectively for complicated geometries with many facets than for simple geometries. The maximum difference of computation speed was 1562 and 680 times for Geantino and ChargedGeantino, respectively. For real particles (gammas, electrons, neutrons, and protons), the difference of computation speed was less significant, but still was within the range of 53-685 times depending on the type of beam particles simulated. 23864227 Identification of Fatigue Biomarkers in Treated and Treatment-Naive HIV Patients: Preliminary Results. Objective assessment in human immunodeficiency virus (HIV)-related fatigue has been elusive because the biological mechanisms are not well characterized. We tried to identify low-abundance plasma proteins that correlate with self-reported fatigue intensity in people living with HIV. We used plasma samples from 32 patients with HIV with varying degrees of fatigue who were either treated with nucleoside reverse transcriptase inhibitors or treatment naïve. The plasma samples were enriched for low-abundance proteins and trypsinized. The peptides were analyzed using shotgun proteomics. Five targets correlated with severity of fatigue: apolipoprotein A-1 (ApoA1), apolipoprotein B (ApoB), histine-rich glycoprotein, alpha-1 B glycoprotein, and orosomucoid 2. These targets were selected based on total abundance and spectral count differences, and ApoA1 and ApoB were analyzed via Western blots to verify the mass spectrometry results. ApoA1 levels were higher in untreated patients, while ApoB results suggested a possible positive trend in treated patients. Further analysis is needed to identify additional low-abundance proteins and confirm already-identified proteins as potential fatigue biomarkers. 23623578 Dilemmas and diagnostic difficulties in meningioma. This article will review the uncommon locations and morphological features of meningiomas, which are important to recognize in order to avoid misdiagnosis. Uncommon locations will be demonstrated at the cerebellopontine angle, pineal, optic, intraventricular, and intradiploic regions. Unusual imaging features including cysts, metaplastic changes, and peritumoural oedema will also be discussed. 23873992 Sex differences in neonatal mortality in Sarlahi, Nepal: the role of biology and environment. Studies in South Asia have documented increased risk of neonatal mortality among girls, despite evidence of a biological survival advantage. Associations between gender preference and mortality are cited as reasons for excess mortality among girls. This has not, however, been tested in statistical models. A secondary analysis of data from a population-based randomised controlled trial of newborn infection prevention conducted in rural southern Nepal was used to estimate sex differences in early and late neonatal mortality, with girls as the reference group. The analysis investigated which underlying biological factors (immutable factors specific to the newborn or his/her mother) and environmental factors (mutable external factors) might explain observed sex differences in mortality. Neonatal mortality was comparable by sex (Ref=girls; OR 1.06, 95% CI 0.92 to 1.22). When stratified by neonatal period, boys were at 20% (OR 1.20, 95% CI 1.02% to 1.42%) greater risk of early and girls at 43% (OR 0.70, 95% CI 0.51% to 0.94%) greater risk of late neonatal mortality. Biological factors, primarily respiratory depression and unconsciousness at birth, explained excess early neonatal mortality among boys. Increased late neonatal mortality among girls was explained by a three-way environmental interaction between ethnicity, sex and prior sibling composition (categorised as primiparous newborns, infants born to families with prior living boys or boys and girls, and infants born to families with only prior living girls). Risk of neonatal mortality inverted between the early and late neonatal periods. Excess risk of early neonatal death among boys was consistent with biological expectations. Excess risk for late neonatal death among girls was not explained by overarching gender preference or preferential care-seeking for boys as hypothesised, but was driven by increased risk among Madeshi girls born to families with only prior girls. 23343773 Is myofascial pain in temporomandibular disorder patients a manifestation of delayed-onset muscle soreness? In a study to the possible role of overuse of the jaw muscles in the pathogenesis of jaw muscle pain, we used a protocol involving concentric and eccentric muscle contractions to provoke a state of delayed-onset muscle soreness (DOMS) in the jaw muscles of healthy individuals. We tested whether the accompanying signs and symptoms would yield the temporary diagnosis of myofascial pain according to the research diagnostic criteria for temporomandibular disorders (RDC/TMD) in these individuals. Forty persons (mean age±SD=27.7±7.5 y) performed six, 5-minute bouts of eccentric and concentric jaw muscle contractions. Before and immediately after the exercise, and 24 hours, 48 hours, and 1 week later, self-reported muscle fatigue and pain, pain-free maximum mouth opening, pressure-pain thresholds, and the number of painful jaw muscle palpation sites were recorded. Significant signs and symptoms of DOMS in the jaw muscles were found, which all had resolved after 1 week. In 31 (77.5%) of the participants, these signs and symptoms also gave rise to a temporary diagnosis of myofascial pain according to the RDC/TMD. The results of this study demonstrate that an experimental protocol involving concentric and eccentric muscle contractions can provoke DOMS in the jaw muscles and the temporary diagnosis of myofascial pain according to the RDC/TMD. The results observed strengthen the supposition that the myofascial pain in TMD patients may be a manifestation of DOMS in the jaw muscles. 23936400 Plant species composition alters the sign and strength of an emergent multi-predator effect by modifying predator foraging behaviour. The prediction of pest-control functioning by multi-predator communities is hindered by the non-additive nature of species functioning. Such non-additivity, commonly termed an emergent multi-predator effect, is known to be affected by elements of the ecological context, such as the structure and composition of vegetation, in addition to the traits of the predators themselves. Here we report mesocosm experiments designed to test the influence of plant density and species composition (wheat monoculture or wheat and faba bean polyculture) on the emergence of multi-predator effects between Adalia bipunctata and Chrysoperla carnea, in their suppression of populations of the aphid Metopolophium dirhodum. The mesocosm experiments were followed by a series of behavioural observations designed to identify how interactions among predators are modified by plant species composition and whether these effects are consistent with the observed influence of plant species composition on aphid population suppression. Although plant density was shown to have no influence on the multi-predator effect on aphid population growth, plant composition had a marked effect. In wheat monoculture, Adalia and Chrysoperla mixed treatments caused greater suppression of M. dirhodum populations than expected. However this positive emergent effect was reversed to a negative multi-predator effect in wheat and faba bean polyculture. The behavioural observations revealed that although dominant individuals did not respond to the presence of faba bean plants, the behaviour of sub-dominants was affected markedly, consistent with their foraging for extra-floral nectar produced by the faba bean. This interaction between plant composition and predator community composition on the foraging behaviour of sub-dominants is thought to underlie the observed effect of plant composition on the multi-predator effect. Thus, the emergence of multi-predator effects is shown to be strongly influenced by plant species composition, mediated, in this case, by the provision of extra-floral nectar by one of the plant species. 23398503 Lessons in microcapsule assembly from imaging delivery of a bioluminescent enzyme. Layer-by-layer assembled microcapsules have potential applications as delivery and biosensing systems, which make them attractive tools for use in various aspects of nanomedicine. We examined the effect of microcapsule location on activity of the bioluminescent enzyme luciferase in both intact capsules and following cell uptake. In intact capsules, the rate of reaction of luciferase was greatest for luciferase in the outer layer and least in the core. Following cell uptake, luciferase in the outer layer was rapidly reactive, and a similar rate of reaction and activity was observed for luciferase placed in capsule interior (core). By contrast, there was minimal activity detected when microcapsules with luciferase sandwiched between polyelectrolytes in a middle layer were delivered to cells. This study informs us of the availability of bioactive molecules located in different positions within microcapsules and will enable better microcapsule construction in line with the intended application, particularly delivery of functional proteins to cells. 23087260 Extracellular loop II modulates GTP sensitivity of the prostaglandin EP3 receptor. Unlike the majority of G protein-coupled receptors, the prostaglandin E(2) (PGE(2)) E-prostanoid 3 (EP3) receptor binds agonist with high affinity that is insensitive to the presence of guanosine 5[prime]-O-(3-thio)triphosphate (GTPγS). We report the identification of mutations that confer GTPγS sensitivity to agonist binding. Seven point mutations were introduced into the conserved motif in the second extracellular loop (ECII) of EP3, resulting in acquisition of GTP-sensitive agonist binding. One receptor mutation W203A was studied in detail. Loss of agonist binding was observed on intact human embryonic kidney 293 cells expressing the W203A receptor, conditions where high GTP levels are present; however, high affinity binding [(3)H]PGE(2) was observed in broken cell preparations washed free of GTP. The [(3)H]PGE(2) binding of W203A in broken cell membrane fractions was inhibited by addition of GTPγS (IC(50) 21 ± 1.8 nM). Taken together, these results suggest that the wild-type EP3 receptor displays unusual characteristics of the complex coupled equilibria between agonist-receptor and receptor-G protein interaction. Moreover, mutation of ECII can alter this coupled equilibrium from GTP-insensitive agonist binding to more conventional GTP-sensitive binding. This suggests that for the mutant receptors, ECII plays a critical role in linking the agonist bound receptor conformation to the G protein nucleotide bound state. 23902263 The immunity regulator BAK1 contributes to resistance against diverse RNA viruses. The plant's innate immune system detects potential biotic threats through recognition of microbe-associated molecular patterns (MAMPs), or danger-associated molecular patterns (DAMPs), by pattern recognition receptors (PRRs). A central regulator of pattern-triggered immunity (PTI) is the BRI1 associated kinase 1 (BAK1) which undergoes complex formation with PRRs upon ligand binding. Although viral patterns inducing PTI are well known from animal systems, nothing similar has been reported for plants. Antiviral defense in plants is rather thought to be mediated by posttranscriptional gene silencing of viral RNA, or through effector-triggered immunity, i.e. recognition of virus-specific "effectors" by resistance proteins. Nevertheless, infection by compatible viruses can also lead to the induction of defense gene expression, indicating that plants may also recognize viruses through PTI. Here we show that PTI, or at least the presence of the regulator BAK1, is important for antiviral defense of Arabidopsis plants. Arabidopsis bak1 mutants show increased susceptibility to three different RNA viruses during compatible interactions. Furthermore, crude viral extracts, but not purified virions, induce several PTI marker responses in a BAK1-dependent manner. Overall, we conclude that BAK1-dependent PTI contributes to antiviral resistance in plants. 23862675 Systems biology characterization of engineered tissues. Tissue engineering and molecular systems biology are inherently interdisciplinary fields that have been developed independently so far. In this review, we first provide a brief introduction to tissue engineering and to molecular systems biology. Next, we highlight some prominent applications of systems biology techniques in tissue engineering. Finally, we outline research directions that can successfully blend these two fields. Through these examples, we propose that experimental and computational advances in molecular systems biology can lead to predictive models of bioengineered tissues that enhance our understanding of bioengineered systems. In turn, the unique challenges posed by tissue engineering will usher in new experimental techniques and computational advances in systems biology. 23970074 Fast evolutionary genetic differentiation during experimental colonizations. Founder effects during colonization of a novel environment are expected to change the genetic composition of populations, leading to differentiation between the colonizer population and its source population. Another expected outcome is differentiation among populations derived from repeated independent colonizations starting from the same source. We have previously detected significant founder effects affecting rate of laboratory adaptation among Drosophila subobscura laboratory populations derived from the wild. We also showed that during the first generations in the laboratory, considerable genetic differentiation occurs between foundations. The present study deepens that analysis, taking into account the natural sampling hierarchy of six foundations, derived from different locations, different years and from two samples in one of the years. We show that striking stochastic effects occur in the first two generations of laboratory culture, effects that produce immediate differentiation between foundations, independent of the source of origin and despite similarity among all founders. This divergence is probably due to powerful genetic sampling effects during the first few generations of culture in the novel laboratory environment, as a result of a significant drop in Ne. Changes in demography as well as high variance in reproductive success in the novel environment may contribute to the low values of Ne. This study shows that estimates of genetic differentiation between natural populations may be accurate when based on the initial samples collected in the wild, though considerable genetic differentiation may occur in the very first generations of evolution in a new, confined environment. Rapid and significant evolutionary changes can thus occur during the early generations of a founding event, both in the wild and under domestication, effects of interest for both scientific and conservation purposes. 23604718 Sparstolonin B suppresses lipopolysaccharide-induced inflammation in human umbilical vein endothelial cells. Sparstolonin B (SsnB) is an isocoumarin compound isolated from the tubers of both Sparganium stoloniferum and Scirpus yagara. We previously demonstrated that SsnB blocked the Toll-like receptor (TLR) 2- and TLR4-triggered inflammatory signaling in macrophages by inhibiting the recruitment of MyD88 to the TIR domains of TLR2 and TLR4. The present study was designed to examine the effects of SsnB on vascular inflammatory responses in human umbilical vein endothelial cells (HUVECs) challenged by lipopolysaccharide (LPS, a TLR4 ligand). We found that SsnB dose-dependently attenuated the LPS-induced expression of interleukin (IL)-1β and monocyte chemoattractant protein 1 both at the transcription and translation levels in HUVEC. LPS-induced endothelial cell adhesion molecules, intercellular adhesion molecular-1 and vascular cell adhesion molecule-1 expressions were also reduced by treatment with SsnB. In addition, co-incubation with SsnB attenuated THP-1 monocyte adhesion to LPS-activated HUVECs. Furthermore, SsnB efficiently suppressed LPS-induced phosphorylation of extracellular -signal-regulated kinase (Erk1/2) and Akt in HUVECs. These findings show that SsnB can suppress endothelial cell inflammation, suggesting that SsnB might be suitable for development as a therapeutic agent for inflammatory cardiovascular disease. 23935906 Pro-inflammatory flagellin proteins of prevalent motile commensal bacteria are variably abundant in the intestinal microbiome of elderly humans. Some Eubacterium and Roseburia species are among the most prevalent motile bacteria present in the intestinal microbiota of healthy adults. These flagellate species contribute "cell motility" category genes to the intestinal microbiome and flagellin proteins to the intestinal proteome. We reviewed and revised the annotation of motility genes in the genomes of six Eubacterium and Roseburia species that occur in the human intestinal microbiota and examined their respective locus organization by comparative genomics. Motility gene order was generally conserved across these loci. Five of these species harbored multiple genes for predicted flagellins. Flagellin proteins were isolated from R. inulinivorans strain A2-194 and from E. rectale strains A1-86 and M104/1. The amino-termini sequences of the R. inulinivorans and E. rectale A1-86 proteins were almost identical. These protein preparations stimulated secretion of interleukin-8 (IL-8) from human intestinal epithelial cell lines, suggesting that these flagellins were pro-inflammatory. Flagellins from the other four species were predicted to be pro-inflammatory on the basis of alignment to the consensus sequence of pro-inflammatory flagellins from the β- and γ- proteobacteria. Many fliC genes were deduced to be under the control of σ(28). The relative abundance of the target Eubacterium and Roseburia species varied across shotgun metagenomes from 27 elderly individuals. Genes involved in the flagellum biogenesis pathways of these species were variably abundant in these metagenomes, suggesting that the current depth of coverage used for metagenomic sequencing (3.13-4.79 Gb total sequence in our study) insufficiently captures the functional diversity of genomes present at low (≤1%) relative abundance. E. rectale and R. inulinivorans thus appear to synthesize complex flagella composed of flagellin proteins that stimulate IL-8 production. A greater depth of sequencing, improved evenness of sequencing and improved metagenome assembly from short reads will be required to facilitate in silico analyses of complete complex biochemical pathways for low-abundance target species from shotgun metagenomes. 23751295 Association between executive/attentional functions and caries in children with cerebral palsy. The aim of the present study was to evaluate the existence of an association between attention/executive functions and the development of dental caries in individuals with cerebral palsy (CP). Seventy-six children with CP were selected from a physical rehabilitation center and a school serving children with disabilities. The control group was made up of 89 children without neurological impairment. Socioeconomic status, presence of teeth with cavities due to caries, degree of motor impairment and intellectual, executive and attentional functions were assessed. Mean age of participants was 8.9 years (SD=3.56). The CP group had a significantly lower performance (p<0.05, Mann-Whitney test) on the intelligence, attentional function and executive function tests in comparison to the control group. Controlling for the clinical diagnosis (CP or control group), motor impairment and intellectual function, the significant explanatory variables for the presence of teeth with cavities were performance on the Complex Rey figure test (OR=0.941) and the Digit Span subtest of the Wechsler Intelligence Scale for Children in backward order (OR=0.581). After controlling for intellectual function, clinical diagnosis and motor impairment, deficits in executive and attentional functions increased the odds of developing dental caries in children with cerebral palsy. 23967240 Mesenchymal stromal (stem) cell therapy fails to improve outcomes in experimental severe influenza. Severe influenza remains a major public health threat and is responsible for thousands of deaths annually. Increasing antiviral resistance and limited effectiveness of current therapies highlight the need for new approaches to influenza treatment. Extensive pre-clinical data have shown that mesenchymal stromal (stem) cell (MSC) therapy can induce anti-inflammatory effects and enhance repair of the injured lung. We hypothesized that MSC therapy would improve survival, dampen lung inflammation and decrease acute lung injury (ALI) in a murine model of severe influenza. C57Bl/6 mice were infected with influenza A/PuertoRico/8/34 (mouse-adapted H1N1) or influenza A/Mexico/4108/2009 (swine-origin pandemic H1N1) and administered human or mouse MSCs via the tail vein, either pre- or post- infection. MSC efficacy was evaluated as both an independent and adjunctive treatment strategy in combination with the antiviral agent, oseltamivir. Weight loss and survival were monitored. Inflammatory cells, cytokine/chemokines (IFN-γ, CXCL10, CCL2 and CCL5) and markers of ALI (total protein and IgM), were measured in bronchoalveolar lavage fluid and lung parenchyma. Administration of murine MSCs or human MSCs in a prophylactic or therapeutic regimen failed to improve survival, decrease pulmonary inflammation/inflammatory cell counts or prevent ALI in influenza virus-infected mice. MSCs administered in combination with oseltamivir also failed to improve outcomes. Despite similarities in the clinical presentation and pathobiology of ALI and severe influenza, our findings suggest that MSC therapy may not be effective for prevention and/or treatment of acute severe influenza. 23883116 Regimen-Specific Effects of RNA-Modified Chimeric Antigen Receptor T Cells in Mice with Advanced Leukemia. Abstract Cytotoxic T lymphocytes modified with chimeric antigen receptors (CARs) for adoptive immunotherapy of hematologic malignancies have demonstrated activity in early phase clinical trials. While T cells bearing stably expressed CARs are efficacious and have potential long-term persistence, temporary expression of a CAR via RNA electroporation is also potentially efficacious in preclinical models. Temporary CAR expression using RNA presents a method of testing CARs clinically with additional safety where there may be concerns about possible chronic "on-target, off-tumor" toxic effects, as the degradation of RNA ensures complete removal of the CAR over time without relying on suicide induction systems. CD19-directed RNA CAR T cells were tested in vivo for efficacy and comparison to lentiviral vector (LV)-generated stable CAR T cells. We tested the hypothesis that multiple infusions of RNA CAR T cells preceded by lymphodepleting chemotherapy could mediate improved survival and sustained antitumor responses in a robust leukemia xenograft model. The saturation strategy using rationally designed multiple infusions of RNA CARs based on multiple model iterations approached the efficacy of a stable LV expression method. Two-color imaging revealed that relapse was a locoregional phenomenon in both the temporary and the stable expression models. In marked contrast to stably expressed CARs with retroviral or LV technology, the efficacy of RNA CARs appears independent of the costimulatory signaling endodomains likely because they more influence proliferation and persistence rather than short-term efficacy. The efficacy of the RNA CAR infusions may approach that of stably expressed CARs, offer theoretically safer initial clinical testing in addition to suicide systems, and allow for rapid and effective iterative preclinical modeling for the testing of new targets. 23942428 Kinetic and mechanistic investigation of the substitution reactions of four and five co-ordinated rhodium stibine complexes with a bulky phosphite. The substitution reaction of trans-[Rh(Cl)(CO)(SbPh3)2] () with tris(2,4-di-tert-butylphenyl)phosphite (2,4-TBPP) to form trans-[Rh(Cl)(CO)(2,4-TBPP)2] () in two consecutive steps has been investigated by UV-vis stopped-flow spectrophotometry. The experiments were performed in dichloromethane and in ethyl acetate, at 298 K and 268 K respectively for the first reaction step, and for the second reaction step over a temperature range from 278 to 313 K in both solvents. The first step is very fast (up to 1630 s(-1)) and on the limit of what is observable with the stopped-flow technique. Introduction of the five-coordinate complex trans-[Rh(Cl)(CO)(SbPh3)3] () in equilibrium with (), by adding an excess SbPh3, led to a significant decrease in overall reaction rate for the formation of the intermediate trans-[Rh(Cl)(CO)(SbPh3)2(2,4-TBPP)] (). Activation parameters for the second substitution reaction, in which is converted to , has been determined as ΔH(‡) = 22.85 ± 0.17 and 28.38 ± 0.10 kJ mol(-1) and ΔS(‡) = -144.7 ± 0.6 and -100.9 ± 0.4 J mol(-1) K(-1) for CH2Cl2 and EtOAc respectively, supporting an associative pathway. A strongly coordinating solvent promotes both reactions. In all reaction steps a strong tendency for stibines to promote 5-coordinated, fairly stable intermediates is manifested. 23969510 Control of the spatial arrangements of supramolecular networks based on saddle-distorted porphyrins by intermolecular hydrogen bonding. Supramolecular integration of a saddle-distorted zinc(ii) porphyrin complex, which has hydroxyl groups at the para-position of the four meso-aryl groups, has been demonstrated on the basis of hydrogen bonding among the peripheral hydroxyl groups. The hydrogen-bonding patterns were controlled by the recrystallization solvents and additives, and particularly, addition of a bifunctional ligand such as 4,4'-bipyridine (bpy). The coordination of bpy to form dinuclear Zn(II)-porphyrin complexes causes a conformational difference: the dimeric complex with four hydroxyl groups is in an eclipsed form, however, a derivative without hydroxyl groups is in a staggered form due to the presence or absence of the intermolecular hydrogen bonding. In addition, the dimerization by the bpy coordination resulted in the expansion of the intermolecular space formed in the porphyrin networks, suggesting the potential to be applied for inclusion of guest molecules. 23896119 Testicular Inflammation as a New Manifestation of IgG4-associated Disease. IgG4-related disease has properties of a systemic disorder but simultaneously is associated with a growing list of organ-specific manifestations including autoimmune pancreatitis, IgG4-associated cholangitis, IgG4-related kidney disease, and IgG4-associated prostatitis. In this study, we present, to the best of our knowledge, the first case of a patient with multiorgan IgG4-related disease who lost his testes because of IgG4-related testicular inflammation. We postulate that IgG4-related disease in the urogenital tract is not restricted to IgG4-related kidney disease and prostatitis, but that this rare disorder may also affect the testis. 23122087 HPLC confirmatory method development for the determination of seven quinolones in salmon tissue (Salmo salar L.) validated according to the European Union Decision 2002/657/EC. A confirmatory high pressure liquid chromatographic method for the determination of seven quinolone antibiotics in tissue of Atlantic salmon (Salmo salar L.) was developed. Ciprofloxacin (CIP), danofloxacin (DAN), enrofloxacin (ENR), sarafloxacin (SAR), oxolinic acid (OXO), nalidixic acid (NAL) and flumequine (FLU) were separated on a Perfectsil ODS-2 120 (250 mm × 4 mm, 5 μm) column by gradient elution with a mobile phase consisting of 0.1% trifluoroacetic acid (pH=1), acetonitrile and methanol at 25°C within 22 min. Analytes were monitored at 255 nm (for the determination of OXO, NAL and FLU) and 275 nm (for CIP, DAN, ENR and SAR) by means of photodiode array detector. Examined quinolones were isolated from salmon tissue by extraction with citrate buffer solution (pH=4.7) and purified by solid phase extraction using Oasis HLB (200mg/6 mL) cartridges. The developed method was fully validated in terms of selectivity, linearity, accuracy, precision, stability and sensitivity according to the European Union Decision 2002/657/EC. The accuracy of the method was additionally proved by its application to certified reference material of salmon tissue (BCR® 725). 23435735 Auditory cortex is implicated in tinnitus distress: a voxel-based morphometry study. Neuroimaging studies of tinnitus suggest the involvement of wide-spread neural networks for perceptual, attentional, memory, and emotional processes encompassing auditory, frontal, parietal, and limbic areas. Despite sparse findings for tinnitus duration and laterality, tinnitus distress has been shown to be related to changes in non-auditory cortical areas. The aim of this study was to correlate tinnitus characteristics with grey matter volume in two large samples of tinnitus patients. High-resolution brain images were obtained using a 1.5 T magnetic resonance imaging scanner and analysed by means of voxel-based morphometry. In sample one (n = 257), tinnitus distress correlated negatively with grey matter volume in bilateral auditory areas including the Heschl's gyrus and insula, that is, the higher the tinnitus distress the lower the grey matter volume. The effects of this correlation were small, but stable after correction for potential confounders such as age, gender, and audiometric parameters. This negative correlation was replicated in a second independent sample (n = 78). Our results support the notion that the role of the auditory cortex in tinnitus is not restricted to perceptual aspects. The distress observed was dependent on grey matter alterations in the auditory cortex, which could reflect reverberations between perceptual and distress networks. 23635857 Descemet membrane endothelial keratoplasty: learning curve of a single surgeon. To evaluate the learning curve of standardized "no-touch" Descemet membrane endothelial keratoplasty (DMEK) of a single surgeon in a clinic without an in-house eye bank facility. For 25 eyes of 22 patients, Descemet graft preparation and DMEK surgery were performed according to the protocols of the Netherlands Institute for Innovative Ocular Surgery with minor modifications. Best spectacle-corrected visual acuity, subjective refraction, Scheimpflug tomography, and endothelial cell density of the donor tissue were documented before and at 1, 3, and 6 months after the surgery; intraoperative and postoperative complications were recorded. No donor tissue was lost owing to preparation failure of the Descemet graft allowing all surgeries to be completed as planned. At 6 months after the surgery, 83% of eyes reached ≥ 20/40 (≥ 0.5), 48% ≥ 20/28 (≥ 0.8), and 30% (7/23) ≥ 20/20 (≥ 1.0) (n = 23). The mean change in both spherical equivalent and refractive cylinder in the same interval was minimal (0.03 diopter). Mean donor endothelial cell density decreased from 2444 cells per square millimeter (± 198 cells/mm2) before the surgery to 1331 cells per square millimeter (± 491 cells/mm2) at 6 months after the surgery. Partial graft detachment requiring rebubbling occurred in 9 cases (36%). One eye developed primary graft failure. This case series shows that DMEK by a beginning surgeon can achieve good results without preparing the graft in an eye bank. Use of backup tissue can be avoided by strictly adhering to the Netherlands Institute for Innovative Ocular Surgery techniques and by harvesting the graft the day before surgery to avoid last-minute cancellation. 23969082 A case of pseudogout of the temporomandibular joint with giant cell reparative granuloma of the temporal bone. Pseudogout, also known as calcium pyrophosphate dihydrate deposition disease (CPPD) with giant cell reparative granuloma (GCRG) of the temporal bone is a rare disease, which is very easy to misdiagnose. When two diseases occur simultaneously, the pathological tissue of diseases is closely associated, which complicates clinical representation and causes enormous difficulty in diagnosis and treatment. We report a case of CPPD of the temporomandibular joint accompanied by surrounding GCRG of temporal bone in a 62-year-old male. 23912556 Scores on the Safe Functional Motion test predict incident vertebral compression fracture. The Safe Functional Motion test (SFM) was developed to document movement strategies used to perform everyday activities that may increase the risk for osteoporotic fracture. After adjusting for variables known to predict vertebral compression fracture (VCF), baseline score on the SFM was a significant independent predictor of incident VCF at 1- and 3-year follow-ups. Functional movements may contribute to risk for VCF. We hypothesize that scores on the SFM, a performance-based test of physical function, are associated with incident VCF. An osteoporosis clinic database was queried for men and women ≥50 years with an initial SFM and corresponding data for prevalent VCF, history of injurious falls, femoral neck bone mineral density (fnBMD), osteoporosis medication use, and incident morphometric VCF at 1-year (n = 878) and 3-year follow-ups (n = 503). Multiple logistic regressions, adjusted for gender, age, injurious fall(s), fnBMD, prevalent VCF at baseline, and osteoporosis medication use, were used to determine whether SFM score was associated with incident VCF at follow-up visits. Baseline SFM score was a significant independent predictor of incident VCF at 1-year follow-up (adjusted odds ratio (95 % confidence intervals (CI)) = 0.818 (0.707, 0.948); p < 0.008) and 3-year follow-up (adjusted odds ratio (95 % CI) = 0.728 (0.628, 0.844); p < 0.0001). Baseline fnBMD and osteoporosis medication use were significant predictors at 1-year (p = 0.05 and  < 0.0001, respectively) and 3-year (p < 0.01 and 0.001, respectively) follow-ups. At 3-year follow-up, gender and prevalent VCF were also significant predictors (p = 0.003 and 0.007, respectively). For every 10-point increase in SFM score, the odds of future VCF decreases by 18 % at 1 year and 27 % at 3 years after adjusting for known covariates. The SFM may aid in the identification of modifiable functional risk factors for VCF. 23884082 Coenurus cerebralis Cysts in the Left Lateral Cerebral Ventricle of a Ewe. A three-and-a-half year-old female Rahmani ewe was presented suffering from nervous symptoms. Grossly, a large cyst measuring 7 × 4 cm and weighing 145 g occupied the dilated left lateral ventricle. The overlying cerebral tissue was thin, atrophied and congested. It tore easily, and the cyst was evacuated spontaneously. Microscopically, liquefactive necrosis surrounded by aggregations of macrophages, eosinophils, lymphocytes, fibroblasts and giant cells was predominantly observed. Hyperplasia and severe necrosis of the ependymal cell lining of the lateral ventricle were observed. Extensive subependymal inflammatory cell infiltrations, accompanied by neovascularization and fibroblastic proliferation, were seen. Based on the gross and histopathological lesions and cyst morphology and location, the cyst was diagnosed as Coenurus cerebralis. This report describes a rare case of coenurus cyst in the left lateral cerebral ventricle of a ewe and the associated lesion. 23934400 NtERF32: a non-NIC2 locus AP2/ERF transcription factor required in jasmonate-inducible nicotine biosynthesis in tobacco. Nicotine biosynthesis in tobacco (Nicotiana tabacum L.) is highly regulated by jasmonic acid (JA). Two nuclear loci, A and B (renamed NIC1 and NIC2) have been identified that mediate JA-inducible nicotine formation and total alkaloid accumulation. NIC2 was recently shown to be a cluster of seven genes encoding Apetala2/Ethylene-Response Factor (AP2/ERF)-domain transcription factors (TFs) in Group IX of the tobacco AP2/ERF family. Here we report the characterization of several NtERF TF genes that are not within the NIC2 locus, but required for methyl JA (MeJA)-induced nicotine biosynthesis. Expression of NtERF1, NtERF32, and NtERF121 is rapidly induced (<30 min) by MeJA treatment. All three of these TFs specifically bind the GCC box-like element of the GAG motif required for MeJA-induced transcription of NtPMT1a, a gene encoding putrescine N-methyltransferase, the first committed step in the synthesis of the nicotine pyrrolidine ring. Ectopic overexpression of NtERF32 increases expression of NtPMT1a in vivo and elevates total alkaloid contents, whereas RNAi-mediated knockdown of NtERF32 reduces the mRNA levels of multiple genes in the nicotine biosynthetic pathway including NtPMT1a and quinolinate phosphoribosyltransferase (NtQPT2), and lowers nicotine and total alkaloid levels. We conclude that NtERF32 and related ERF genes are important non-NIC2 locus associated transcriptional regulators of nicotine and total alkaloid formation. 23943070 Cellularized Microcarriers as Adhesive Building Blocks for Fabrication of Tubular Tissue Constructs. To meet demands of vascular reconstruction, there is a need for prosthetic alternatives to natural blood vessels. Here we explored a new conduit fabrication approach. Macroporous, gelatin microcarriers laden with human umbilical vein endothelial cells and aortic smooth muscle cells were dispensed into tubular agarose molds and found to adhere to form living tubular tissues. The ability of cellularized microcarriers to adhere to one another involved cellular and extracellular matrix bridging that included the formation of epithelium-like cell layers lining the lumenal and ablumenal surfaces of the constructs and the deposition of collagen and elastin fibers. The tubular tissues behaved as elastic solids, with a uniaxial mechanical response that is qualitatively similar to that of native vascular tissues and consistent with their elastin and collagen composition. Linearized measures of the mechanical response of the fabricated tubular tissues at both low and high strains were observed to increase with duration of static culture, with no significant loss of stiffness following decellularization. The findings highlight the utility of cellularized macroporous gelatin microcarriers as self-adhering building blocks for the fabrication of living tubular structures. 23771009 Interocular evaluation of axial length and retinal thickness in people with myopic anisometropia. To investigate the changes in axial length and retinal thickness and their relationships with myopia in highly myopic anisometropia. A total of 87 Chinese subjects (25.28±11.98 years, mean±SD) were divided into two groups: anisometropia (n=38) and nonanisometropia (n=49). All eyes were measured for axial length, refractive status, and macular thickness (optical coherence tomography). Ocular biometric results were compared between eyes of subgroups. Linear correlation between refractive error and other biometric results was performed. In the anisometropic group, the inner ring macula and part of the outer ring macula (nasal and inferior quadrants) in the higher myopic eyes were significantly thinner than in the fellow eyes (P≤0.007), but the foveal thickness (minimum and average) was similar (P≥0.050) between the two eyes. However, the minimum and average foveal thicknesses were found to be significantly thicker in the highly myopic eyes than those in the emmetropic to moderate myopic eyes (P≤0.016) in the nonanisometropic group. Among the eyes ranging from emmetropia to high myopia, the refractive error was negatively correlated to the axial length of the eye (P<0.001) and the thinning of inner ring macula is consistent with the increase in both myopia and axial length. There was a negative correlation in refractive error and axial length but no correlation in parafoveal thickness between eyes of the same subjects (P<0.001) in the anisometropic group. In people with myopic anisometropia, the higher myopic eye has a longer axial length but a thinner parafoveal region than its fellow eye. The axial growth in the development of high myopia seems to be centrally regulated; however, the changes in parafoveal thickness are likely manipulated by local mechanisms within the eye. 23583415 Robotic single-site hysterectomy (RSS-H) vs. laparoendoscopic single-site hysterectomy (LESS-H) in early endometrial cancer: a double-institution case-control study. To report our experience with single-site robotic platform for IS3000 "Da Vinci" Si Surgical System to perform robotic single site hysterectomy (RSS-H), and to compare peri-operative results with a historical series of laparoendoscopic single site hysterectomies (LESS-H). This is a retrospective case-control study, performed at the Gynecologic Oncologic Unit, National Cancer Institute "Regina Elena", Rome, and at the Gynecologic Oncologic Unit, Catholic University of the Sacred Heart, Rome, Italy between December 2011 and January 2013. 19 women underwent RSS-H (cases) and 38 patients were submitted to LESS-H (controls) for early endometrial cancer. Pre-surgical procedures (port placement and docking) required a median time of 8 min in the RSS-H group and a median time of 2 min in the LESS-H group (p=0.0001). The median estimated blood loss was 75 ml in the cases and 30 ml in the controls (p=0.005). The median operative time, calculated from the beginning of intraperitoneal procedures to the skin closure, was 90 min in the cases and 107 ml in the controls (p=ns). The median time to discharge from the hospital was postoperative day two for both techniques. The few differences we registered do not seem clinically relevant, thus making the two procedures comparable. 23197648 Bisphenol A inhibits voltage-activated Ca(2+) channels in vitro: mechanisms and structural requirements. Bisphenol A (BPA), a high volume production chemical compound attracts growing attention as a health-relevant xenobiotic in humans. It can directly bind to hormone receptors, enzymes, and ion channels to become biologically active. In this study we show that BPA acts as a potent blocker of voltage-activated Ca(2+) channels. We determined the mechanisms of block and the structural elements of BPA essential for its action. Macroscopic Ba(2+) / Ca(2+) currents through native L-, N-, P/Q-, T-type Ca(2+) channels in rat endocrine GH(3) cells, mouse dorsal root ganglion neurons or cardiac myocytes, and recombinant human R-type Ca(2+) channels expressed in human embryonic kidney (HEK) 293 cells were rapidly and reversibly inhibited by BPA with similar potency (EC(50) values: 26-35 μM). Pharmacological and biophysical analysis of R-type Ca(2+) channels revealed that BPA interacts with the extracellular part of the channel protein. Its action does not require intracellular signaling pathways, is neither voltage- nor use-dependent, and does not affect channel gating. This indicates that BPA interacts with the channel in its resting state by directly binding to an external site outside the pore-forming region. Structure-effect analyses of various phenolic and bisphenolic compounds revealed that 1) a double-alkylated (R-C(CH(3))(2)-R, R-C(CH(3))(CH(2)CH(3))-R), or double-trifluoromethylated sp(3)-hybridized carbon atom between the two aromatic rings and 2) the two aromatic moieties in angulated orientation are optimal for BPA's effectiveness. Since BPA highly pollutes the environment and is incorporated into the human organism, our data may provide a basis for future studies relevant for human health and development. 23898311 Effects of short-term inpatient treatment on sensitivity to a size contrast illusion in first-episode psychosis and multiple-episode schizophrenia. Introduction: In the Ebbinghaus illusion, a shape appears larger than its actual size when surrounded by small shapes and smaller than its actual size when surrounded by large shapes. Resistance to this visual illusion has been previously reported in schizophrenia, and linked to disorganized symptoms and poorer prognosis in cross-sectional studies. It is unclear, however, when in the course of illness this resistance first emerges or how it varies longitudinally with illness phase. Method: We addressed these issues by having first-episode psychosis patients, multiple-episode schizophrenia patients and healthy controls complete a psychophysical task at two different time points, corresponding to hospital admission and discharge for patients. The task required judging the relative size of two circular targets centered on either side of the screen. Targets were presented without context (baseline), or were surrounded by shapes that made the size judgment harder or easier (misleading and helpful contexts, respectively). Context sensitivity was operationalized as the amount of improvement relative to baseline in the helpful condition minus the amount of decrement relative to baseline in the misleading condition. Results: At hospital admission, context sensitivity was lower in the multiple-episode group than in the other groups, and was marginally less in the first episode than in the control group. In addition, schizophrenia patients were significantly more and less accurate than the other groups in the misleading and helpful conditions, respectively. At discharge, all groups exhibited similar context sensitivity. In general, poorer context sensitivity was related to higher levels of disorganized symptoms, and lower level of depression, excitement, and positive symptoms. Discussion: Resistance to the Ebbinghaus illusion, as a characteristic of the acute phase of illness in schizophrenia, increases in magnitude after the first episode of psychosis. This suggests that visual context processing is a state-marker in schizophrenia and a biomarker of relapse and recovery. 23895800 In planta induced changes in the native plasmid profile of Pseudomonas syringae pathover phaseolicola strain 1302A. Pseudomonas syringae pv. phaseolicola (Pph) strain 1302A, a causative agent of halo blight in the common bean Phaseolus vulgaris, contains four native plasmids designated pAV505 (150kb), pAV506 (50kb), pAV507 (47kb) and pAV508 (42kb). Pph 1302A also contains a 106kb genomic island PPHGI-1 which shares features with integrative and conjugative elements (ICElands) and carries the effector gene avrPphB (hopAR1) which triggers a defensive response in bean cultivars carrying the matching R3 resistance gene. It has been shown that when Pph 1302A is sequentially inoculated (passaged) through resistant bean cultivar Tendergreen (TG) in which the hypersensitive response (HR) is generated, the three largest plasmids are lost and an extra ∼100kb plasmid is gained, which tests confirmed to be the 106kb circular form of PPHGI-1. The aim of the current study was to determine if upon further passaging through bean plants, the plasmid profile of Pph 1302A would alter again and if the missing plasmids had been integrated into the chromosome. Pph 1302A-P6, the strain with the altered plasmid profile was passaged twice through TG and of the four re-isolated strains examined all displayed the plasmid profile associated with wildtype Pph 1302A, that is, all four native plasmids had reappeared and the PPHGI-1 plasmid was absent. This demonstrated that the plasmid composition of Pph 1302A-P6 could indeed change on further exposure to the plant environment and also that the seemingly missing native plasmids were still present within the genome, lending evidence to the theory that they had integrated into the chromosome. Furthermore two of these re-isolated strains had lost PPHGI-1 entirely, meaning they no longer triggered a HR on TG and instead generated a disease response. This study clearly demonstrates the plasticity of the bacterial genome and the extent it can be influenced by the plant environment and conditions generated during the HR. 23462336 The role of impulsivity in relapse vulnerability. Drug dependence in humans is often accompanied by behavioral disturbances such as maladaptive levels of impulsivity. In turn, there is accumulating evidence from preclinical laboratory animal and clinical studies indicating that impulsive behavior might be causally linked to several distinct processes in drug addiction, including the onset, maintenance and relapsing nature of drug use. This leads to the question as to whether pharmacological or behavioral approaches aimed at ameliorating impulsivity might prove effective therapeutic interventions in human drug dependence. This paper reviews evidence for an important role of impulsivity as a determinant of drug dependence with a particular focus on relapse vulnerability and addresses the implications of these findings for the clinical management of relapse prevention. 23157678 Understanding respiratory syncytial virus infection to improve treatment and immunity. Despite significant research since it was discovered more than 50 years ago, respiratory syncytial virus (RSV) continues to be the leading agent causing infant hospitalization and respiratory distress worldwide. Although RSV normally does not cause mortality, this virus is recognized as a major public health and economic burden around the globe. RSV can modulate host immunity leading to an inflammatory response that produces lung damage and virus dissemination in the host airways. Remarkably, infection with the virus elicits poor immunity that in most cases fails to protect against subsequent exposures. Here, we review advances made on the understanding of the lifecycle of the virus, some of the molecular mechanisms it has evolved to cause pathology and ineffective immunity during infection. Hopefully, ongoing research will contribute to developing new drugs and candidate vaccines that will decrease the health burden caused by this virus. 23570983 Just getting into cells is not enough: mechanisms underlying 4-(N)-stearoyl gemcitabine solid lipid nanoparticle's ability to overcome gemcitabine resistance caused by RRM1 overexpression. Gemcitabine is a deoxycytidine analog that is widely used in the chemotherapy of many solid tumors. However, acquired tumor cell resistance often limits its use. Previously, we discovered that 4-(N)-stearoyl gemcitabine solid lipid nanoparticles (4-(N)-GemC18-SLNs) can overcome multiple acquired gemcitabine resistance mechanisms, including RRM1 overexpression. The present study was designed to elucidate the mechanisms underlying the 4-(N)-GemC18-SLNs' ability to overcome gemcitabine resistance. The 4-(N)-GemC18 in the 4-(N)-GemC18-SLNs entered tumor cells due to clathrin-mediated endocytosis of the 4-(N)-GemC18-SLNs into the lysosomes of the cells, whereas the 4-(N)-GemC18 alone in solution entered cells by diffusion. We substantiated that it is the way the 4-(N)-GemC18-SLNs deliver the 4-(N)-GemC18 into tumor cells that allows the gemcitabine hydrolyzed from the 4-(N)-GemC18 to be more efficiently converted into its active metabolite, gemcitabine triphosphate (dFdCTP), and thus more potent against gemcitabine-resistant tumor cells than 4-(N)-GemC18 or gemcitabine alone. Moreover, we also showed that the RRM1-overexpressing tumor cells were also cross-resistant to cytarabine, another nucleoside analog commonly used in cancer therapy, and 4-(N)-stearoyl cytarabine carried by solid lipid nanoparticles can also overcome the resistance. Therefore, formulating the long-chain fatty acid amide derivatives of nucleoside analogs into solid lipid nanoparticles may represent a platform technology to increase the antitumor activity of the nucleoside analogs and to overcome tumor cell resistance to them. 23581511 Stratum corneum evaluation methods: overview. The stratum corneum serves as a main barrier for the skin, minimizing water loss and regulating absorption of substances. Because of its surface location, it is readily available for analysis. Consequently, many techniques are amenable to investigating its content and function. Here, we review the methods employed to evaluate the stratum corneum and its function. We reviewed Pubmed and Embase search results for 'stratum corneum, 'method,' methods,' 'technique,' and 'evaluation' and extracted pertinent articles that discussed ways to examine the stratum corneum and its constituents. Traditional and novel methods vary by accuracy, ease of use, time requirements, cost, invasiveness, and equipment requirements. The methods reviewed all contribute to our current picture of the stratum corneum. Tape stripping continues to be the most widely used, but variations in the use of the corneocytes obtained further contribute to the diversity in evaluation methods. 23870029 Chlamydia screening in pregnancy in Australia: Integration of national guidelines into clinical practice and policy. Chlamydia trachomatis is the most common reportable infection in Australia. Since 2006, the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) have recommended chlamydia screening in pregnant women aged <25 years. To assess clinical uptake and policy integration of the 2006 RANZCOG recommendation on chlamydia testing in pregnant women aged <25 years. A mixed method approach was used involving a literature review, a survey of obstetricians and gynaecologists, and survey of hospital managers from April 2010 to May 2010. Of the 1644 participating RANZCOG Fellows, Trainees, and Diplomates, 21.2% reported universal screening for pregnant women <25 years (25% of primary care clinicians, 23% of those working in the public hospital sector, 16% of those working in both public and private hospitals, and 13% of those in private hospitals or private practice). There was a strong association between members who agreed with the guideline and offering universal screening to pregnant women aged <25 years (adjusted odds ratio = 17.1, 95% CI: 6.0-49.2, P < 0.01). Of the 143 participating hospital managers who completed the hospital policy questionnaire; 20% reported that their hospital had a formal screening guideline. There were two national and four state/local policy documents recommending chlamydia screening in pregnancy. This study shows low uptake of chlamydia screening of young pregnant women by RANZCOG Fellows, Trainees, and Diplomates involved in antenatal care and highlights the need for national clinical leadership regarding screening for chlamydia among pregnant women aged <25 years. 23657802 Method for simultaneous analysis of nine second-line anti-tuberculosis drugs using UPLC-MS/MS. Therapeutic drug monitoring (TDM) of anti-tuberculosis (TB) drugs is beneficial for patients responding slowly to treatment and those with multidrug-resistant TB. We used ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to develop a rapid method for simultaneously measuring the blood concentrations of nine second-line anti-TB drugs: streptomycin, kanamycin, clarithromycin, cycloserine, moxifloxacin, levofloxacin, para-aminosalicylic acid, prothionamide and linezolid. Serum samples were extracted with acidified methanol and neutralized with NaOH. A Waters Acquity HSS T3 column and gradients of ammonium formate and acetonitrile in 0.1% formic acid were used for UPLC separation. Drug concentrations were determined by multiple reaction monitoring in positive ion mode, and assay performance was evaluated. We applied this method to TDM, analysing random serum samples from 85 patients treated with second-line drugs. Sample preparation using acidified methanol extraction followed by neutralization yielded good recovery and ionization efficiency, with chromatographic separation achieved within 3 min per sample. Within-run and between-run precisions were 1.7%-7.5% and 1.7%-12.4%, respectively, at concentrations representing low and high levels for the nine drugs. Lower limits of detection and quantification were 0.025-0.5 and 0.25-5.0 μg/mL, respectively. Linearity was acceptable at five concentrations for each drug. No ion suppression was observed at the retention time for most compounds, except for streptomycin, kanamycin and cycloserine, which were eluted close to the void volume of the column. In a limited pilot study, all quantifiable human samples had values within the validated assay ranges. The performance of our MS/MS detection technique was generally acceptable. The method provided rapid, sensitive and reproducible quantification of nine second-line anti-TB drugs and should facilitate drug monitoring during treatment. 23800726 Aromatic interactions in asymmetric catalysis: control of enantioselectivity in Diels-Alder reactions catalysed by camphor-derived hydrazides. Density functional theory calculations (M06-2X//B3LYP) have been performed to determine the factors responsible for enantioselectivity in Diels-Alder reactions catalysed by two series of camphor-derived amines. Hydrazides and sulfonylhydrazides catalyze the reaction of cyclopentadiene with cinnamaldehyde to give the same enantiomer of cycloadduct. The calculations reveal that the two classes of catalysts control enantioselectivity by opposite mechanisms. Hydrazides favour addition to the bottom face of a trans iminium cation, while sulfonylhydrazides favour addition to the top face of a cis iminium ion. In the transition state for cycloadditions catalysed by , a stabilising CH-π interaction between the diene and a benzyl substituent α to the iminium nitrogen accelerates the reaction and enhances the enantioselectivity. The facial selectivity can be reinforced by appending onto the benzyl side-arm an α-methyl group that sterically hinders addition to the top face. 23886650 Evaluation of novel lipid based formulation of β-Artemether and Lumefantrine in murine malaria model. The present investigation aims at formulating lipid based drug delivery system of β-Artemether and Lumefantrine and comparative pharmacological evaluation with innovator formulation. Commercial modified oil and indigenous natural fatty acids comprised the oily phase in developing lipidic formulation of β-Artemether and Lumefantrine. The developed system was characterized for mean globule size, stability by freeze thaw cycles, and birefringence. Developed formulation and innovator formulation were compared for their in vivo anti-malarial activity at different dose levels in male Swiss mice, infected with lethal ANKA strain of Plasmodium berghei. The percent parasitemia, activity against time and animal survival period were examined. On fourth day of antimalarial studies, at normal and ½ dose levels, formulations revealed zero percent parasitemia while control showed 33.92±6.00% parasitemia. At 1/10 dose level, developed and innovator formulations revealed zero percent parasitemia upto 11th day, however, three mice from innovator formulation demonstrated recrudescence after 12th day. Both the formulations at normal dose and ½ dose levels showed 100% activity and survival whereas at 1/10 dose level, innovator formulation showed, 62.5% survival. The developed lipidic system of β-Artemether and Lumefantrine exhibited excellent antimalarial activity with 100% survival. 23676674 Variation and genetic control of protein abundance in humans. Gene expression differs among individuals and populations and is thought to be a major determinant of phenotypic variation. Although variation and genetic loci responsible for RNA expression levels have been analysed extensively in human populations, our knowledge is limited regarding the differences in human protein abundance and the genetic basis for this difference. Variation in messenger RNA expression is not a perfect surrogate for protein expression because the latter is influenced by an array of post-transcriptional regulatory mechanisms, and, empirically, the correlation between protein and mRNA levels is generally modest. Here we used isobaric tag-based quantitative mass spectrometry to determine relative protein levels of 5,953 genes in lymphoblastoid cell lines from 95 diverse individuals genotyped in the HapMap Project. We found that protein levels are heritable molecular phenotypes that exhibit considerable variation between individuals, populations and sexes. Levels of specific sets of proteins involved in the same biological process covary among individuals, indicating that these processes are tightly regulated at the protein level. We identified cis-pQTLs (protein quantitative trait loci), including variants not detected by previous transcriptome studies. This study demonstrates the feasibility of high-throughput human proteome quantification that, when integrated with DNA variation and transcriptome information, adds a new dimension to the characterization of gene expression regulation. 23930979 Visualization of Phase Evolution in Model Organic Photovoltaic Structures via Energy-Filtered Transmission Electron Microscopy. The morphology of the active layer in an organic photovoltaic bulk-heterojunction device is controlled by the extent and nature of phase separation during processing. We have studied the effects of fullerene crystallinity during heat treatment in model structures consisting of a layer of poly(3-hexylthiophene) (P3HT) sandwiched between two layers of [6,6]-phenyl-C61-butyric acid methyl ester (PCBM). Utilizing a combination of focused ion-beam milling and energy-filtered transmission electron microscopy, we monitored the local changes in phase distribution as a function of annealing time at 140 °C. In both cases, dissolution of PCBM within the surrounding P3HT was directly visualized and quantitatively described. In the absence of crystalline PCBM, the overall phase distribution remained stable after intermediate annealing times up to 60 s, whereas microscale PCBM aggregates were observed after annealing for 300 s. Aggregate growth proceeded vertically from the substrate interface via uptake of PCBM from the surrounding region, resulting in a large PCBM-depleted region in their vicinity. When precrystallized PCBM was present, amorphous PCBM was observed to segregate from the intermediate P3HT layer and ripen the crystalline PCBM underneath, owing to the far lower solubility of crystalline PCBM within P3HT. This process occurred rapidly, with segregation already evident after annealing for 10 s and with uptake of nearly all of the amorphous PCBM by the crystalline layer after 60 s. No microscale aggregates were observed in the precrystallized system, even after annealing for 300 s. 23864786 Effect of amitriptyline on gastrointestinal function and brain-gut peptides: A double-blind trial. To study the effects of low-dose amitriptyline (AMT) on gastrointestinal function and brain-gut peptides in healthy Chinese volunteers. This was a double-blind, randomised, placebo-controlled, two-period cross-over trial. Twenty-eight healthy volunteers were randomised and administered 1-wk treatments of AMT (12.5 mg tid) or placebo. Before and during the final two days of treatment, gastric emptying, proximal gastric accommodation and visceral sensitivity were measured by drinking-ultrasonography test; the orocecal transit time (OCTT) was measured by lactulose hydrogen breath test, and fasting blood was collected. Plasma levels of ghrelin, motilin and neuropeptide Y (NPY) were measured by enzyme-linked immunosorbent assay kits. AMT slowed the OCTT (109.2 ± 29.68 min vs 96.61 ± 23.9 min, P = 0.004) but did not affect liquid gastric emptying and had no effect on proximal gastric accommodation. AMT resulted in decreases in the visual analogue scale (VAS) for difficulty in drinking 600 and 800 mL of water (3.57 ± 0.94 vs 2.98 ± 0.85, 5.57 ± 0.82 vs 4.57 ± 0.98, P < 0.01 for both), although it had no significant effect on the VAS for difficulty in drinking 200 mL and 400 mL of water. AMT significantly increased the plasma ghrelin level (442.87 ± 176.79 pg/mL vs 526.87 ± 158.44 pg/mL, P = 0.04) and the neuropeptide-Y level (890.15 ± 131.46 pg/mL vs 965.64 ± 165.63 pg/mL, P = 0.03), whereas it had no effect on the MTL level. Low-dose AMT could slow OCTT, make the stomach less sensitive and increase the plasma levels of ghrelin and NPY. Thus, we recommend the use of low-dose AMT for functional gastrointestinal disorders. 23966595 European birds adjust their flight initiation distance to road speed limits. Behavioural responses can help species persist in habitats modified by humans. Roads and traffic greatly affect animals' mortality not only through habitat structure modifications but also through direct mortality owing to collisions. Although species are known to differ in their sensitivity to the risk of collision, whether individuals can change their behaviour in response to this is still unknown. Here, we tested whether common European birds changed their flight initiation distances (FIDs) in response to vehicles according to road speed limit (a known factor affecting killing rates on roads) and vehicle speed. We found that FID increased with speed limit, although vehicle speed had no effect. This suggests that birds adjust their flight distance to speed limit, which may reduce collision risks and decrease mortality maximizing the time allocated to foraging behaviours. Mobility and territory size are likely to affect an individuals' ability to respond adaptively to local speed limits. 23834399 Immunohistochemical localization of translationally controlled tumor protein in the mouse digestive system. Translationally controlled tumor protein (TCTP) is a housekeeping protein, highly conserved among various species. It plays a major role in cell differentiation, growth, proliferation, apoptosis and carcinogenesis. Studies reported so far on TCTP expression in different digestive organs have not led to any understanding of the role of TCTP in digestion, so we localized TCTP in organs of the mouse digestive system employing immunohistochemical techniques. Translationally controlled tumor protein was found expressed in all organs studied: tongue, salivary glands, esophagus, stomach, small and large intestines, liver and pancreas. The expression of TCTP was found to be predominant in epithelia and neurons of myenteric nerve ganglia; high in serous glands (parotid, submandibular, gastric, intestinal crypts, pancreatic acini) and in neurons of myenteric nerve ganglia, and moderate to low in epithelia. In epithelia, expression of TCTP varied depending on its type and location. In enteric neurons, TCTP was predominantly expressed in the processes. Translationally controlled tumor protein expression in the liver followed porto-central gradient with higher expression in pericentral hepatocytes. In the pancreas, TCTP was expressed in both acini and islet cells. Our finding of nearly universal localization and expression of TCTP in mouse digestive organs points to the hitherto unrecognized functional importance of TCTP in the digestive system and suggests the need for further studies of the possible role of TCTP in the proliferation, secretion, absorption and neural regulation of the digestive process and its importance in the physiology and pathology of digestive process. 23953271 Pharmacological treatment and demographic characteristics of pediatric patients with Attention Deficit Hyperactivity Disorder, Sweden. The aim of this study was to describe the pediatric population with ADHD and their pharmacological treatment. Using the Swedish National Patient Register and the Prescribed Drug Register we identified individuals below 19 years of age who were diagnosed or medically treated for ADHD for the first time 2006-2007. The unique patient identifiers were used to link information from the two registers to describe demographic characteristics, hospital care and drug treatments. Logistic regression model estimated the association between age, sex, frequency of hospitalization, diagnosis or treatment for other mental disorders and risk of gap in the treatment. Totally the study included 7931 patients of whom 74% were males. The mean age at first diagnosis was 12 years. Some 84% were medically treated for ADHD and approximately 90% received methylphenidate as the first substance. Combination therapy was rare and the most common combination was methylphenidate and atomoxetine. More than 55% of the patients, which could be followed up for two years after start of treatment, had at least one treatment gap of six months. Older age at diagnosis, lower number of hospitalizations and comorbidity with other mental disorders increased risks of gaps in medication. Approximately one fifth of the patients recorded in the National Patient Register as diagnosed with ADHD did not receive pharmacological treatment. Medication adherence seems to be low, when measured as gaps in treatment. 23413273 Integration of analytical instruments with computer scripting. Automation of laboratory routines aided by computer software enables high productivity and is the norm nowadays. However, the integration of different instruments made by different suppliers is still difficult, because to accomplish it, the user must have knowledge of electronics and/or low-level programming. An alternative approach is to control different instruments without an electronic connection between them, relying only on their software interface on a computer. This can be achieved through scripting, which is the emulation of user operations (mouse clicks and keyboard inputs) on the computer. The main advantages of this approach are its simplicity, which enables people with minimal knowledge of computer programming to employ it, and its universality, which enables the integration of instruments made by different suppliers, meaning that the user is totally free to choose the devices to be integrated. Therefore, scripting can be a useful, accessible, and economic solution for laboratory automation. 23926441 Second generation drug-eluting stents: a review of the everolimus-eluting platform. Everolimus-eluting stents (EES) represent the next generation of drug-eluting stents (DES). Important design modifications include thin strut stent backbones, less inflammatory and more biocompatible polymers, and lower drug dosing. The cobalt chromium EES fluoropolymer XIENCE V stent has been the most extensively studied of such stents. In animal models, this stent demonstrated minimal vessel inflammation, a biologically active endothelium with strut coverage similar to a bare metal stent, and inhibition of intimal hyperplasia comparable to that seen with sirolimus-eluting stents. The SPIRIT family of clinical trials demonstrated low rates of late loss, and clinical restenosis, as well as low rates of very late stent thrombosis. These excellent clinical outcomes addressed limitations of the 1st generation DES, and substantiated widespread clinical use of the EES platform. 22634361 Anxiolytic- but not antidepressant-like activity of Lu AF21934, a novel, selective positive allosteric modulator of the mGlu₄ receptor. Previous studies demonstrated that the Group III mGlu receptor-selective orthosteric agonist, LSP1-2111 produced anxiolytic- but not antidepressant-like effects upon peripheral administration. Herein, we report the pharmacological actions of Lu AF21934, a novel, selective, and brain-penetrant positive allosteric modulator (PAM) of the mGlu(4) receptor in the stress-induced hyperthermia (SIH), four-plate, marble-burying and Vogel's conflict tests. In all models, except Vogel's conflict test, a dose-dependent anxiolytic-like effect was seen. The anti-hyperthermic effect of Lu AF21934 (5 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (10 mg/kg) and was not serotonin-dependent, as it persisted in serotonin-deficient mice and upon blockade of either 5-HT(1A) receptors by WAY100635, or 5-HT(2A/2C) receptors by ritanserin. These results suggest that the GABAergic system, but not the serotonergic system, is involved in the mechanism of the anxiolytic-like phenotype of Lu AF21934 in rodents. Lu AF21934 did not produce antidepressant-like effects in the tail suspension test (TST) in mice; however, it decreased the basal locomotor activity of mice that were not habituated to activity cages. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23918744 OPTIMISING RADIOGRAPHIC BITEWING EXAMINATION TO ADULT AND JUVENILE PATIENTS THROUGH THE USE OF ANTHROPOMORPHIC PHANTOMS. Four anthropomorphic phantoms (an adult male, an adult female, a 10-y-old child and a 5-y-old child) were exposed to bitewing radiographs at film and digital settings using both rectangular and round collimation. Optically stimulated dosemeters were used. For children, average organ doses were <40 µGy and the organs with the highest doses were the salivary glands, parotid, oral mucosa, skin and extrathoracic airway. For adults, average organ doses were <200 µGy. Highest adult doses were to the salivary glands, oral mucosa and skin. Effective doses ranged from 1.5 to 1.8 µSv for children and from 2.6 to 3.6 µSv for adults when optimised technique factors were employed, including digital receptors, rectangular collimation, size-appropriate exposure times and proper clinical judgment. Optimised doses were a fraction of the natural daily background exposure. Therefore, predictions of hypothetical cancer incidence or detriment in patient populations exposed to such low doses are highly speculative and should be discouraged. 23893399 Assessment of Sedative Effects of Passiflora edulis f. flavicarpa and Passiflora alata Extracts in Mice, Measured by Telemetry. Several Passiflora species have been used widely as a folk medicine due to their sedative and anxiolytic activities. In Brazil, a number of native plants of the genus Passiflora exist, but only Passiflora edulis f. flavicarpa (PE) and Passiflora alata (PA) are of commercial value. Thus, the aim of the present study was to investigate the sedative effects of aqueous extracts obtained from the pericarp as well as from the leaves of PE and PA in mice using radiotelemetry. Aqueous extracts from PE and PA were tested for effects on locomotion over 180 min in 300 mg/kg, 600 mg/kg and 1200 mg/kg, in male C57BL/6J mice after oral administration. For validation of the telemetry system, caffeine (negative control) and midazolam (positive control) were used. All tested extracts decreased locomotor activity in a dose-dependent manner in comparison to the control group. The two lower concentrations of each extract showed the highest decrease in locomotion after 24 min, while 1200 mg/kg had a significant sedative effect already after 18 min. Interestingly, aqueous extracts of PA were more active in comparison to aqueous extracts of PE and the pericarp extracts of both plants showed more pronounced effects on locomotor activity if compared to leaf extracts. In conclusion, the present study represents an innovative, objective approach to measure sedative effects of plant extracts with minimized handling-related stress and remote data collection. Copyright © 2013 John Wiley & Sons, Ltd. 23885099 Effect of siRNA Against β-NGF on Nerve Fibers of a Rat Model With Endometriosis. Objective:This study examines whether silencing specific β-nerve growth factor small interfering RNA (β-NGF siRNA) can affect the growth of ectopic endometriotic implants, generalized hyperalgesia, and nerve fiber density in endometriosis.Methods:Four specific β-NGF siRNAs were detected by Western blot analysis, and the most efficient specific siRNA was transferred into rats with surgically induced endometriosis through gene transfer. The length × width × height of each ectopic transplant that survived from 2 groups were measured at pre-and postbombardment after 2 weeks. The transplants were collected 2 weeks after bombardment. Warm-water tail flick test was performed before the rats were sacrificed. The specimens were sectioned and stained immunohistochemically with antibodies against the types of nerve fibers to compare the presence of different nerve fibers in the treatment and control groups. The serums and supernatants of the peritoneal washings in the treatment and control groups were collected for enzyme-linked immunosorbent assay (ELISA) analysis. The extra rats were successfully induced with endometriosis and through gene transfer as described above. The spherical volumes of the transplants and tail flick latency post-bombardment after 4, 6, 8, and 10 weeks were measured.Results:The spherical volumes in the treatment group were much smaller than those in the control group, and tail flick latency significantly increased in the treatment group postbombardment after 2 weeks. The ELISA analysis showed that the concentrations of β-NGF in the serums and supernatants of the peritoneal fluid decreased in the treatment group unlike in the control group. Less sympathetic and sensory innervation was observed in the treatment group postbombardment after 2 weeks. The outcomes of the spherical volumes of the transplants and tail flick latency postbombardment after 4, 6, 8, and 10 weeks showed that the sizes of the transplants did not return to their previous size and that the treatment had some effects on generalized hyperalgesia.Conclusion:Specific siRNA-mediated silencing of the β-NGF gene expression after gene transfer suppressed the growth of ectopic endometriotic implants resulted in a significant improvement in generalized hyperalgesia as well as reduced sympathetic and sensory nerve fiber density in the treatment group. 23936203 Targeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells. Multiple myeloma is a hematological cancer that is considered incurable despite advances in treatment strategy during the last decade. Therapies targeting single pathways are unlikely to succeed due to the heterogeneous nature of the malignancy. Proliferating cell nuclear antigen (PCNA) is a multifunctional protein essential for DNA replication and repair that is often overexpressed in cancer cells. Many proteins involved in the cellular stress response interact with PCNA through the five amino acid sequence AlkB homologue 2 PCNA-interacting motif (APIM). Thus inhibiting PCNA's protein interactions may be a good strategy to target multiple pathways simultaneously. We initially found that overexpression of peptides containing the APIM sequence increases the sensitivity of cancer cells to contemporary therapeutics. Here we have designed a cell-penetrating APIM-containing peptide, ATX-101, that targets PCNA and show that it has anti-myeloma activity. We found that ATX-101 induced apoptosis in multiple myeloma cell lines and primary cancer cells, while bone marrow stromal cells and primary healthy lymphocytes were much less sensitive. ATX-101-induced apoptosis was caspase-dependent and cell cycle phase-independent. ATX-101 also increased multiple myeloma cells' sensitivity against melphalan, a DNA damaging agent commonly used for treatment of multiple myeloma. In a xenograft mouse model, ATX-101 was well tolerated and increased the anti-tumor activity of melphalan. Therefore, targeting PCNA by ATX-101 may be a novel strategy in multiple myeloma treatment. 23929560 The Latent Symptom Structure of the Beck Depression Inventory: Second Edition in Latina Pregnant Women. Pregnancy represents a unique period of time when women are at an increased risk of developing depression. Although the Beck Depression Inventory-Second Edition (BDI-II) is one of the most widely used self-report measures of depression symptomology, its psychometric properties and underlying factor structures have not been determined for antenatal women and among Latinas. The current study evaluated the latent symptom structure of the BDI-II in a community-based sample of Latina pregnant women (N = 217) identified to be at high risk for depression. Exploratory factor analyses were used to identify underlying salient individual item loadings for two- and three-factor models. Confirmatory factor analyses then examined several different indices to determine the best model fit. Examination of exploratory and confirmatory factor analyses supports a three-factor oblique structure of the BDI-II composed of Cognitive-Affective, Somatic, and Pregnancy Symptoms. The three-factor model provides clinicians with the ability to target specific constellations of depressive symptoms instead of relying on the BDI-II total score that represents the overall severity of depression in this population. 23589419 Ecosystem services and the protection, restoration, and management of ecosystems exposed to chemical stressors. Ecosystem services-the benefits people obtain from ecosystem structures and processes-are essential for human survival and well-being. Chemicals are also an essential component of modern life; however, they may cause adverse ecological effects and reduce ecosystem service provision. Environmental policy makers are increasingly adopting the ecosystem services concept, but applying this approach to the protection, restoration, and management of ecosystems requires the development of new understanding, tools, and frameworks. There is an urgent need to understand and predict the effect of single and multiple stressors on ecosystem service delivery across different spatial scales (local to global), to develop indicators that can be used to quantify and map services and identify synergies and trade-offs between them, to establish protection goals and restoration targets defined in terms of the types and levels of service delivery required, and to develop approaches for the assessment and management of chemical risk to ecosystem services that consider the whole life cycle of products and processes. These are major research challenges for the environmental science community in general and for ecotoxicologists and risk assessors in particular. Environ. Toxicol. Chem. 2013;32:974-983. © 2013 SETAC. 23614725 Oxidative damage and genotoxic effect in mice caused by sub-chronic exposure to low-dose volatile organic compounds. Abstract Volatile organic compounds (VOCs) are widely used as constituents of household chemicals. Although adverse health effects have been reported, long-term exposure to low-level VOCs mixture has not been studied. Especially, there is a lack of substantial information on the sensitive biomarkers and carcinogenic markers. In the present study, we examined oxidative stress and genotoxic effects of sub-chronic low-dose VOCs mixture (formaldehyde, benzene, toluene and xylene). Male Kunming mice were exposed to 0 (control) and three different doses of VOCs mixture (group 1S, 5S and 10S) for 90 d (2 h/d). Group 1S is 0.10, 0.11, 0.20 and 0.20 mg/m(3), group 5S is 0.50, 0.55, 1.00 and 1.00 mg/m(3), group 10S is 1.00, 1.10, 2.00 and 2.00 mg/m(3), which, respectively, corresponded to 1, 5 and 10 times of indoor air quality standard (IAQS) in China. One day following VOCs exposure, oxidative stress markers in lung, 8-hydroxy-2'-deoxyguanosine in bronchoalveolar lavage fluid and genotoxicity (DNA damage) in liver were examined. Results showed that exposure to VOCs (IAQS dose) resulted in oxidative damages of lung, which were supported by the significant changes on reactive oxygen species, reduced glutathione (GSH), GSH S-transferase, total antioxidative capacity, malondialdehyde, protein carbonyl and nitric oxide (NO). Moreover, oxidative stress markers in group 5S and 10S (except NO) in lung were affected significantly. In addition, VOCs exposure also induced significantly DNA damage in liver. Our study suggested long-term VOCs inhalation at low levels caused oxidative stress and genotoxicity response in mice. Since effects were seen at the current IAQS level, further studies below this level are necessary. 23936217 Aberrant expression and secretion of heat shock protein 90 in patients with bullous pemphigoid. The cell stress chaperone heat shock protein 90 (Hsp90) has been implicated in inflammatory responses and its inhibition has proven successful in different mouse models of autoimmune diseases, including epidermolysis bullosa acquisita. Here, we investigated expression levels and secretory responses of Hsp90 in patients with bullous pemphigoid (BP), the most common subepidermal autoimmune blistering skin disease. In comparison to healthy controls, the following observations were made: (i) Hsp90 was highly expressed in the skin of BP patients, whereas its serum levels were decreased and inversely associated with IgG autoantibody levels against the NC16A immunodominant region of the BP180 autoantigen, (ii) in contrast, neither aberrant levels of circulating Hsp90 nor any correlation of this protein with serum autoantibodies was found in a control cohort of autoimmune bullous disease patients with pemphigus vulgaris, (iii) Hsp90 was highly expressed in and restrictedly released from peripheral blood mononuclear cells of BP patients, and (iv) Hsp90 was potently induced in and restrictedly secreted from human keratinocyte (HaCaT) cells by BP serum and isolated anti-BP180 NC16A IgG autoantibodies, respectively. Our results reveal an upregulated Hsp90 expression at the site of inflammation and an autoantibody-mediated dysregulation of the intracellular and extracellular distribution of this chaperone in BP patients. These findings suggest that Hsp90 may play a pathophysiological role and represent a novel potential treatment target in BP. 23949899 Efficacy and Safety of Mildronate for Acute Ischemic Stroke: A Randomized, Double-Blind, Active-Controlled Phase II Multicenter Trial. Mildronate, an inhibitor of carnitine-dependent metabolism, is considered to be an anti-ischemic drug. This study is designed to evaluate the efficacy and safety of mildronate injection in treating acute ischemic stroke. We performed a randomized, double-blind, multicenter clinical study of mildronate injection for treating acute cerebral infarction. 113 patients in the experimental group received mildronate injection, and 114 patients in the active-control group received cinepazide injection. In addition, both groups were given aspirin as a basic treatment. Modified Rankin Scale (mRS) score was performed at 2 weeks and 3 months after treatment. National Institutes of Health Stroke Scale (NIHSS) score and Barthel Index (BI) score were performed at 2 weeks after treatment, and then vital signs and adverse events were evaluated. A total of 227 patients were randomized to treatment (n = 113, mildronate; n = 114, active-control). After 3 months, there was no significant difference for the primary endpoint between groups categorized in terms of mRS scores of 0-1 and 0-2 (p = 0.52 and p = 0.07, respectively). There were also no significant differences for the secondary endpoint between groups categorized in terms of NIHSS scores of >5 and >8 (p = 0.98 and p = 0.97, respectively) or BI scores of >75 and >95 (p = 0.49 and p = 0.47, respectively) at 15 days. The incidence of serious adverse events was similar between the two groups. Mildronate injection is as effective and safe as cinepazide injection in treating acute cerebral infarction. 23616110 Menopausal symptoms, sexual function, depression, and quality of life in Korean patients with breast cancer receiving chemotherapy. The purpose of this study was to study the relationships among menopausal symptoms, sexual function, depression, and quality of life in women with breast cancer undergoing chemotherapy. Two hundred women participated in this cross-sectional study. Data were collected with the Menopause Rating Scale (MRS), Female Sexual Function Index (FSFI), Beck Depression Inventory II (BDI-II), and the Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B). Data were analyzed using descriptive statistics, t-tests, ANOVA, Scheffe's test, and Pearson product moment correlations using SPSS v. 20. Participants had alterations in menopausal symptoms and sexual function, and were depressed with a decreased quality of life. These factors are known to influence satisfaction with family support (p < 0.05) and sexual relationships (p < 0.05). Nurses should provide education to women with breast cancer on their sexual issues and encourage them to attend family support programs. They should also encourage family members to be proactive in addressing menopausal and depressive symptoms in these women with a goal to enhance their sexual functioning and quality of life. 23849657 Cognitive, personality, and social factors associated with adolescents' online personal information disclosure. The current study aims to understand the factors that influence adolescents' disclosure of personally identifiable information (PII) on social networking sites (SNSs). A survey was conducted among 780 adolescent participants (between 13 and 18) who were Facebook users. Structural equation modeling was used for analyzing the data and obtaining an overarching model that include cognitive, personality, and social factors that influence adolescents' PII disclosure. Results showed privacy concern as the cognitive factor reduces adolescents' PII disclosure and it serves as a potential mediator for personality and social factors. Amongst personality factors, narcissism was found to directly increase PII disclosure, and social anxiety indirectly decreases PII disclosure by increasing privacy concern. Amongst social factors, active parental mediation decreases PII disclosure directly and indirectly by increasing privacy concern. Restrictive parental mediation decreases PII disclosure only indirectly by increasing privacy concern. Implications of the findings to parents, educators, and policy makers were discussed. 23684007 How to establish causality in epilepsy surgery. Focality in electro-clinical or neuroimaging data often motivates epileptologists to consider epilepsy surgery in patients with medically-uncontrolled seizures, while not all focal findings are causally associated with the generation of epileptic seizures. With the help of Hill's criteria, we have discussed how to establish causality in the context of the presurgical evaluation of epilepsy. The strengths of EEG include the ability to determine the temporal relationship between cerebral activities and clinical events; thus, scalp video-EEG is necessary in the evaluation of the majority of surgical candidates. The presence of associated ictal discharges can confirm the epileptic nature of a particular spell and whether an observed neuroimaging abnormality is causally associated with the epileptic seizure. Conversely, one should be aware that scalp EEG has a limited spatial resolution and sometimes exhibits propagated epileptiform discharges more predominantly than in situ discharges generated at the seizure-onset zone. Intraoperative or extraoperative electrocorticography (ECoG) is utilized when noninvasive presurgical evaluation, including anatomical and functional neuroimaging, fails to determine the margin between the presumed epileptogenic zone and eloquent cortex. Retrospective as well as prospective studies have reported that complete resection of the seizure-onset zone on ECoG was associated with a better seizure outcome, but not all patients became seizure-free following such resective surgery. Some retrospective studies suggested that resection of sites showing high-frequency oscillations (HFOs) at >80Hz on interictal or ictal ECoG was associated with a better seizure outcome. Others reported that functionally-important areas may generate HFOs of a physiological nature during rest as well as sensorimotor and cognitive tasks. Resection of sites showing task-related augmentation of HFOs has been reported to indeed result in functional loss following surgery. Thus, some but not all sites showing interictal HFOs are causally associated with seizure generation. Furthermore, evidence suggests that some task-related HFOs can be transiently suppressed by the prior occurrence of interictal spikes. The significance of interictal HFOs should be assessed by taking into account the eloquent cortex, seizure-onset zone, and cortical lesions. Video-EEG and ECoG generally provide useful but still limited information to establish causality in presurgical evaluation. A comprehensive assessment of data derived from multiple modalities is ultimately required for successful management. 23480174 MD simulations of the formation of stable clusters in mixtures of alkaline salts and imidazolium-based ionic liquids. Structural and dynamical properties of room-temperature ionic liquids containing the cation 1-butyl-3-methylimidazolium ([BMIM](+)) and three different anions (hexafluorophosphate, [PF6](-), tetrafluoroborate, [BF4](-), and bis(trifluoromethylsulfonyl)imide, [NTf2](-)) doped with several molar fractions of lithium salts with a common anion at 298.15 K and 1 atm were investigated by means of molecular dynamics simulations. The effect of the size of the salt cation was also analyzed by comparing these results with those for mixtures of [BMIM][PF6] with NaPF6. Lithium/sodium solvation and ionic mobilities were analyzed via the study of radial distribution functions, coordination numbers, cage autocorrelation functions, mean-square displacements (including the analysis of both ballistic and diffusive regimes), self-diffusion coefficients of all the ionic species, velocity and current autocorrelation functions, and ionic conductivity in all the ionic liquid/salt systems. We found that lithium and sodium cations are strongly coordinated in two different positions with the anion present in the mixture. Moreover, [Li](+) and [Na](+) cations were found to form bonded-like, long-lived aggregates with the anions in their first solvation shell, which act as very stable kinetic entities within which a marked rattling motion of salt ions takes place. With very long MD simulation runs, this phenomenon is proved to be on the basis of the decrease of self-diffusion coefficients and ionic conductivities previously reported in experimental and computational results. 23672244 4E-BP1 regulates the differentiation of white adipose tissue. 4E Binding protein 1 (4E-BP1) suppresses translation initiation. The absence of 4E-BP1 drastically reduces the amount of adipose tissue in mice. To address the role of 4E-BP1 in adipocyte differentiation, we characterized 4E-BP1(-/-) mice in this study. The lack of 4E-BP1 decreased the amount of white adipose tissue and increased the amount of brown adipose tissue. In 4E-BP1(-/-) MEF cells, PPARγ coactivator 1 alpha (PGC-1α) expression increased and exogenous 4E-BP1 expression suppressed PGC-1α expression. The level of 4E-BP1 expression was higher in white adipocytes than in brown adipocytes and showed significantly greater up-regulation in white adipocytes than in brown adipocytes during preadipocyte differentiation into mature adipocytes. The amount of PGC-1α was consistently higher in HB cells (a brown preadipocyte cell line) than in HW cells (a white preadipocyte cell line) during differentiation. Moreover, the ectopic over-expression of 4E-BP1 suppressed PGC-1α expression in white adipocytes, but not in brown adipocytes. Thus, the results of our study indicate that 4E-BP1 may suppress brown adipocyte differentiation and PGC-1α expression in white adipose tissues. 23157468 Legitimacy in legacy: a discussion paper of historical scholarship published in the Journal of Advanced Nursing, 1976-2011. This paper presents a discussion of historical scholarship published in the Journal of Advanced Nursing. The Journal of Advanced Nursing provides a forum for disseminating high-quality research and scholarship. For over 35 years, scholars have used the Journal of Advanced Nursing to disseminate research into aspects of nursing, including nursing history. The data source was Wiley Online electronic database for the Journal of Advanced Nursing for the period 1976-December 2011. Relative to other academic concerns, nursing history represents a topic of limited concern to nursing scholars, as evidenced in published scholarship in the Journal of Advanced Nursing. The trends in historical scholarship in the journal have been on disciplinary development, the place and context of practice, and gendered relationships. While these are legitimate academic concerns, they suggest a lack of attention to clinical practice in historical research, that which confers social legitimacy on the discipline. Nursing derives its social legitimacy, in part, through its history, including reliable accounts of the legacy of nursing work in the development of healthcare systems. Disciplinary development in nursing is advanced by giving greater prominence to nursing history in nursing scholarship, including the history of nursing practice Relative to other academic concerns, nursing scholarship affords little prominence to the topic of nursing history and less still to the history of practice, as evidenced in the outputs of one of nursing's major organs of scholarship. Not to assign due importance to the history of nursing and its practice demonstrates nursing's lack of disciplinary maturity. 23909276 Enucleation versus Evisceration in Ocular Trauma: A Retrospective Review and Study of Current Literature. Abstract Purpose: To compare variables and outcomes from ocular trauma leading to either enucleation or evisceration to better inform surgical decision making. Design: Retrospective chart review. Methods: We reviewed 441 patients between 2001 and 2012 presenting with ocular trauma to a Level 1 trauma center in Queens, New York; of these, there were 16 enucleations and 6 eviscerations. Retrospective chart review noted age, gender, mechanism of injury, initial and final visual acuity, time to surgery, length of follow-up, pain, degree of motility, and complications. A review of literature in the context of our study was performed. Results: 20 patients were male and 2 patients were female; average age was 44 (SD: 20.0, range 18-91). 9/16 patients were enucleated to prevent sympathetic ophthalmia, whereas only 1/5 patient was eviscerated for this indication (p = 0.1619). No cases of sympathetic ophthalmia were reported over an average follow-up of 316 days. Average length of follow-up varied significantly between the two groups, with an average of 370.4 days (SD: 566.9, range 0-1870) for enucleated eyes and 172.7 days (SD: 146.3, range 0-422) for eviscerated eyes (p = 0.42). Medpor implants were preferred in eviscerations (5/6 eviscerations), whereas hydroxyapatite implants were preferred in enucleations (10/16 enucleations, p = 0.04). Conclusions: Surgical decision-making in ocular trauma is largely based on surgeon preference and experience, with minimal evidence in the literature to support either enucleation or evisceration. We recommend evisceration over enucleation in cases of reliable patient follow-up due to the low incidence of sympathetic ophthalmia. 23110439 Highly predictive ligand-based pharmacophore and homology models of ABHD6. α/β-Hydrolase domain-containing 6 (ABHD6) represents a potentially attractive therapeutic target for indirectly potentiating 2-arachidonoylglycerol signaling; however, the enzyme is currently largely uncharacterized. Here, we describe a five element, ligand-based pharmacophore model along with a refined homology model of ABHD6. Following a virtual screen of a modest database, both the pharmacophore and homology models were found to be highly predictive, preferentially identifying ABHD6 inhibitors over drug-like non-inhibitors. The models yield insight into the features required for optimal ligand binding to ABHD6 and the atomic structure of the binding site. In combination, the two models should be very helpful not only in high-throughput virtual screening, but also in lead optimization, and will facilitate the development of novel, selective ABHD6 inhibitors as potential drugs. 23860828 Photosynthetic electron transport and specific photoprotective responses in wheat leaves under drought stress. The photosynthetic responses of wheat (Triticum aestivum L.) leaves to different levels of drought stress were analyzed in potted plants cultivated in growth chamber under moderate light. Low-to-medium drought stress was induced by limiting irrigation, maintaining 20 % of soil water holding capacity for 14 days followed by 3 days without water supply to induce severe stress. Measurements of CO2 exchange and photosystem II (PSII) yield (by chlorophyll fluorescence) were followed by simultaneous measurements of yield of PSI (by P700 absorbance changes) and that of PSII. Drought stress gradually decreased PSII electron transport, but the capacity for nonphotochemical quenching increased more slowly until there was a large decrease in leaf relative water content (where the photosynthetic rate had decreased by half or more). We identified a substantial part of PSII electron transport, which was not used by carbon assimilation or by photorespiration, which clearly indicates activities of alternative electron sinks. Decreasing the fraction of light absorbed by PSII and increasing the fraction absorbed by PSI with increasing drought stress (rather than assuming equal absorption by the two photosystems) support a proposed function of PSI cyclic electron flow to generate a proton-motive force to activate nonphotochemical dissipation of energy, and it is consistent with the observed accumulation of oxidized P700 which causes a decrease in PSI electron acceptors. Our results support the roles of alternative electron sinks (either from PSII or PSI) and cyclic electron flow in photoprotection of PSII and PSI in drought stress conditions. In future studies on plant stress, analyses of the partitioning of absorbed energy between photosystems are needed for interpreting flux through linear electron flow, PSI cyclic electron flow, along with alternative electron sinks. 23466538 Preparation of ZnFe2O4 nanoparticles in the template of silk-fibroin peptide and their neuro-cytocompability in PC12 cells. There is an urgency to prepare non-neurotoxic nanoparticles (NPs) as MRI contrast agent. We prepared ZnFe2O4 NPs with monocrystal structure in the template of silk-fibroin (SF) peptide at room temperature. Analyses of their crystallite size and NPs diameter after the growth of 1 d and 8 d indicated that SF peptide could promote nucleation, growth and dispersion of NPs. Results of EDS, Raman and TG proved that there was 4 wt% of the chemical composition of SF in as-prepared NPs. A possible growth mechanism of ZnFe2O4 NPs in the template of SF is proposed. The saturation magnetizations of NPs with SF (SF-NPs) were about 15 and 30 emu/g for 1 and 8 d, respectively. SF-NPs obviously promoted the viability of PC12 cells at NPs concentration of 0.0625 mg/mL in 2 d and 5 d of co-culture. Analysis of neurite length indicated no significant decreases of the experimental groups at different SF-NPs concentrations (from 0.0625 to 0.5 mg/mL) after 5 d cell co-culture, because SF peptide coating could slow the release of iron/zinc ions from NPs. Furthermore, SF-NPs did not destroy the organelles, karyotheca and the neurite using the observation in the cell ultrathin sections. Based on their good magnetic property and neuro-cytocompatibility, the potential application of ZnFe2O4 NPs with SF as MRI contrast agents would be envisioned. 23530595 Bioinspired Water-Enhanced Mechanical Gradient Nanocomposite Films That Mimic the Architecture and Properties of the Squid Beak. Inspired by the water-enhanced mechanical gradient character of the squid beak, we herein report a nanocomposite that mimics both the architecture and properties of this interesting natural material. Similar to the squid beak, we have developed nanocomposites where the degree of cross-linking is controlled along the length of the film. In this study, we utilized tunicate cellulose nanocrystals as the nanofiller that are functionalized with allyl moieties. Using photoinduced thiol-ene chemistry, we have been able to cross-link the CNC nanofiller. In the dry state where strong CNC interactions can occur, only a small mechanical contrast is observed between the cross-linked and uncross-linked samples. However, when the films are exposed to water, which "switches off" the noncovalent CNC interactions, a significant mechanical contrast is observed between the same films. For example, at 20 wt % CNC (in the dry film), an increase in wet modulus from 60 to 300 MPa (∼500% increase) is observed after photoirradiation. Furthermore, we show that the wet modulus can be controlled by altering the UV exposure time which allows access to mechanical gradient films. 23860951 The protective effect of coffee consumption on cutaneous melanoma risk and the role of GSTM1 and GSTT1 polymorphisms. The authors examined the association between coffee consumption and cutaneous melanoma and the implication of GSTM1 and GSTT1 polymorphisms. A hospital-based case-control study was conducted in the inpatient wards of IDI-San Carlo Rome, Italy, including 304 incident cases of cutaneous melanoma and 305 controls. Information on socio-demographic characteristics, medical history, smoking, sun exposure, pigmentary characteristics and diet was collected for all subjects. Within the study, individual patterns at two polymorphic genes (GSTM1 and GSTT1) belonging to glutathione S-transferases family were investigated in 188 cases of cutaneous melanoma and 152 controls. Logistic regression was the method used to estimate odds ratio and 95 % confidence intervals. High frequency of coffee drinking (>once daily), compared with low-frequency consumption of coffee (≤7 times weekly) was associated with a protective effect for cutaneous melanoma (OR 0.46; 95 % CI 0.31-0.68) after adjusting for sex, age, education, hair colour, common nevi, skin phototype, and sunburn episodes in childhood. When stratified by GSTM1 and GSTT1 genotype, the protective effect of coffee was extremely high for subjects with both GSTM1 and GSTT1 null polymorphisms (OR 0.01; 95 % CI 0.0003-0.54). Our results show a protective effect of coffee consumption for cutaneous melanoma, in particular for those with homozygous deletion for GSTM1 and GSTT1. 23561200 Fatty acid profiling of the seed oils of some varieties of field peas (Pisum sativum) by RP-LC/ESI-MS/MS: Towards the development of an oilseed pea. Reversed-phase liquid chromatography coupled to negative-ion electrospray tandem mass spectrometry (RP-LC/ESI-MS/MS) was used to study the fatty acid profile from the oil of harvested field pea (Pisum sativum) varieties as part of a research project to develop this legume as a commercial oilseed for Canada. The seed oils from pea samples contained palmitic and stearic acids as major saturated fatty acids. Oleic, linoleic and linolenic acids were the major unsaturated fatty acids found. Small percentages of other long chain fatty acids were also detected. This profile suggests that the species of field pea investigated might have the potential to be used as raw materials to develop a future new oilseed crop for the food industry. Fatty acid extracts did not require further manipulation before final analysis by RP-LC/ESI-MS/MS, indicating the utility and relative simplicity of this technique for future screening studies. 23872269 A new accurate assay for Coxsackievirus A 16 by fluorescence detection of isothermal RNA amplification. Coxsackievirus A 16 (CA16) is one of the most common causes of hand, foot, and mouth disease (HFMD) worldwide. Without a vaccine or antiviral drug early, rapid, and accurate detection is critical for preventing and controlling HFMD. A simultaneous amplification and testing (SAT) assay was developed for detecting CA16 based on isothermal RNA amplification with fluorescence using standard, real-time PCR equipment. Primers and probes were designed to target the VP1 region of CA16. Virus strains and clinical specimens were used to evaluate the diagnostic performance characteristics of the assay. The assay detected as few as 10 copies of CA16 RNA transcripts. Using real-time PCR plus sequencing as the reference standard, the sensitivity and specificity of the SAT-CA16 assay were 100% and 99.2%, respectively. These findings indicate that SAT-CA16 is a rapid and reliable method for detecting CA16. 23959795 Treg Vaccination in Autoimmune Type 1 Diabetes. Foxp3(+) regulatory T (Treg) cells are critical contributors to the establishment and maintenance of immunological self-tolerance. Autoimmune type 1 diabetes (T1D) is characterized by the loss of self-tolerance to the insulin-producing β cells in the pancreas and the destruction of β cells, resulting in the development of chronic hyperglycemia at diagnosis. The application of strong-agonistic T-cell receptor ligands provided under subimmunogenic conditions functions as a critical means for the efficient de novo conversion of naive CD4(+) T cells into Foxp3(+) Treg cells. The specific induction of Treg cells upon supply of strong-agonistic variants of certain self-antigens could therefore function as a critical instrument in order to achieve safe and specific prevention of autoimmunity such as T1D via the restoration of self-tolerance. Such immunotherapeutic strategies are being developed, and in the case of T1D aim to restrict autoimmunity and β-cell destruction. In this review, we discuss the requirements and opportunities for Treg-based tolerance approaches with the goal of interfering with autoimmune T1D. 23918928 Furin is the primary in vivo convertase of angiopoietin-like 3 and endothelial lipase in hepatocytes. The proprotein convertases (PCs) furin, PC5/6, and PACE4 exhibit unique and/or complementary functions. Their knockout (KO) in mice resulted in strong and specific phenotypes demonstrating that, in vivo, these PCs are unique and essential during development. However, they also exhibit redundant functions. Liver angiopoietin-like 3 (ANGPTL3) inhibits lipolysis by binding to lipoprotein lipases. It is found in the plasma as full length and truncated forms. The latter is more active and generated by cleavage at a furin-like site. Endothelial lipase (EL) binds heparin sulfate proteoglycans on cell surfaces and catalyzes the hydrolysis of HDL phospholipids. EL activity is regulated by two endogenous inhibitors, ANGPTL3 and ANGPTL4, and by PCs that inactivate EL through cleavage releasing the N-terminal catalytic and C-terminal lipid-binding domains. Herein, because furin and PC5/6 complete KOs are lethal, we used mice lacking furin or PC5/6 specifically in hepatocytes (hKO) or mice completely lacking PACE4. In primary hepatocytes, ANGPTL3 was processed into ANGPTL3 intracellularly by furin only, and extracellularly mainly by PACE4. In vivo, the absence of furin in hepatocytes reduced by ~50% the circulating levels of cleaved ANGPTL3, while the lack of PACE4 had only a minor effect. Analysis of the EL processing in primary hepatocytes and in vivo revealed that it is essentially cleaved by furin. However, the lack of furin or PC5/6 in hepatocytes and complete PACE4 KO did not appreciably modify plasma HDL levels or EL activity. Thus, inhibition of furin in liver would not be expected to modify the plasma lipid profiles. 23523830 Quercetin and epigallocatechin-3-gallate effect on the anisotropy of model membranes with cholesterol. Cell membrane fluidity, which can be altered by oxidative stress, plays an important role in the cell physiology. Flavonoids are among the most studied food substances that prevent and/or reduce oxidative stress, but their action mechanisms are far from being understood. We performed a study on the effect of quercetin and epigallocatechin-3-gallate on 2-Dimyristoyl-sn-glycero-3-phosphocholine small unilamellar vesicles (SUVs) with different amounts of cholesterol, using Laurdan as a fluorescent probe, to put into evidence the perturbations of the phospholipid membrane fluidity and local lipid order in an attempt to decipher the action mechanism of the flavonoids at the cell membrane level. Results indicate that polyphenols modulate the transition from the gel phase to the liquid crystalline phase of SUVs in all studied membranes. SUVs with cholesterol have by themselves higher phase transition temperature and the presence of polyphenols stabilizes further the membrane. Quercetin has a dose-dependent effect on the fluidity and local order of the lipid membranes, whilst epigallocatechin-3-gallate action is not dose-dependent, the differences being attributable to the hydrophobic/hydrophilic character of the substances. The findings are discussed within the frame of earlier reports on the effect of polyphenols on artificial membranes. 23747309 Alternative splicing variants of proinsulin mRNA and the effects of excess proinsulin on cardiac morphogenesis. Alternative forms of proinsulin mRNA with differential translational capacities and unknown significance are expressed in several developing tissues and in the adult pancreas. In the chick embryo developing heart, we observed low expression of the translationally active transcript of embryonic proinsulin (Pro1B), and predominant expression of the intron 1-unspliced variant, translationally inactive. In the embryonic mouse heart, intron 1-unspliced isoform appeared after E12.5. This tight regulation is required for normal development, since overexpression of Pro1B resulted in abnormal cardiac morphogenesis in 40% of chick embryos, and was accompanied by changes in gene expression of Amhc1and Vmhc1. 23906268 One-stage arthroscopic repair of rotator cuff tears with shoulder stiffness. The purpose of this study is to describe a 1-stage treatment with concomitant arthroscopic capsular release and rotator cuff repair and present clinical outcomes with a minimum follow-up of 2 years. Arthroscopic rotator cuff repair was performed in 211 consecutive patients. Forty-three patients had severe concomitant shoulder stiffness at the time of the repair. In the stiffness group, 1-stage arthroscopic capsular release and rotator cuff repair were performed. Preoperative mean passive forward flexion was 124°, whereas external rotation at the side was 309°. All patients were evaluated at a minimum 2-year follow-up, which included a visual analog scale score for pain, tests of muscle power and range of motion, the Constant score, and the modified American Shoulder and Elbow Surgeons shoulder evaluation form and modified University of California, Los Angeles scores. The mean visual analog scale score during motion at the last follow-up was 1.5 in the stiffness group and 1.3 in the non-stiffness group. In the stiffness group, forward flexion was 175° whereas external rotation at the side was 60° postoperatively; shoulder motion improved (P < .001) and was comparable with that of the contralateral side. Other functional outcome instruments showed no statistical difference between the 2 groups. In this study, 1-stage treatment of patients with rotator cuff tears and shoulder stiffness was performed by arthroscopic capsular release and cuff repair, and overall satisfactory results were achieved in selected patients. The results of the stiffness group in this study were statistically the same as those in the non-stiffness group. Level III, retrospective comparative study. 23926347 Emergence of a C-terminal seven amino acid elongation of NS1 around 1950 conferred a minor growth advantage to former seasonal influenza A viruses. Influenza A viruses circulating in humans from ∼1950 to ∼1987 featured a non-structural (NS1) protein with a C-terminal extension of seven amino acids. The biological significance of this NS1 elongation remained elusive. We observed that replication kinetics of wild-type A/Hong Kong/01/68 (H3N2) and a mutant encoding a truncated NS1 were indistinguishable in most experimental systems. However, wild-type virus out-competed the mutant during mixed infections, suggesting that the NS1 extension conferred minor growth advantages. 23629011 Climate change air toxic co-reduction in the context of macroeconomic modelling. This paper examines the health implications of global PM reduction accompanying greenhouse gas emissions reductions in the 180 national economies of the global macroeconomy. A human health effects module based on empirical data on GHG emissions, PM emissions, background PM concentrations, source apportionment and human health risk coefficients is used to estimate reductions in morbidity and mortality from PM exposures globally as co-reduction of GHG reductions. These results are compared against the "fuzzy bright line" that often underlies regulatory decisions for environmental toxics, and demonstrate that the risk reduction through PM reduction would usually be considered justified in traditional risk-based decisions for environmental toxics. It is shown that this risk reduction can be on the order of more than 4 × 10(-3) excess lifetime mortality risk, with global annual cost savings of slightly more than $10B, when uniform GHG reduction measures across all sectors of the economy form the basis for climate policy ($2.2B if only Annex I nations reduce). Consideration of co-reduction of PM-10 within a climate policy framework harmonized with other environmental policies can therefore be an effective driver of climate policy. An error analysis comparing results of the current model against those of significantly more spatially resolved models at city and national scales indicates errors caused by the low spatial resolution of the global model used here may be on the order of a factor of 2. 23681472 Coffee consumption and the risk of overall and fatal prostate cancer in the NIH-AARP Diet and Health Study. Evidence on the association between coffee consumption and prostate cancer risk is inconsistent; furthermore, few studies have examined the relationship between coffee consumption and fatal prostate cancer. The aim of this study was to investigate whether coffee intake is associated with the risk of overall and fatal prostate cancer. We conducted a prospective analysis among 288,391 men in the National Institutes of Health AARP Diet and Health Study who were between 50 and 71 years old at baseline in 1995-1996. Coffee consumption was assessed at baseline. Cox proportional hazards models were used to calculate the age- and multivariable-adjusted hazard ratios (HR)s and 95 % confidence intervals (CIs). Over 11 years of follow-up, 23,335 cases of prostate cancer were ascertained, including 2,927 advanced and 917 fatal cases. Coffee consumption was not significantly associated with prostate cancer risk. The multivariable-adjusted HRs (95 % CI), comparing those who drank six or more cups per day to nondrinker, were as follows: 0.94 (0.86-1.02), p trend = 0.08 for overall prostate cancer, 1.13 (0.91-1.40), p trend = 0.62 for advanced prostate cancer, and 0.79 (0.53-1.17), p trend = 0.20 for fatal prostate cancer. The findings remained nonsignificant when we stratified by prostate-specific antigen testing history or restricted to nonsmokers. We found no statistically significant association between coffee consumption and the risk of overall, advanced, or fatal prostate cancer in this cohort, though a modest reduction in risk could not be excluded. 23514045 Anticonvulsant/antiepileptic carbonic anhydrase inhibitors: a patent review. Introduction: An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. The International League Against Epilepsy classifies seizures in two broad categories: partial (localized to one cerebral hemisphere) and generalized (localized to both cerebral hemispheres). One indirect pathway for the treatment of epilepsy includes the inhibition of carbonic anhydrase (CA), thereby increasing CO2 levels in the brain. Areas covered: Carbonic anhydrases (EC 4.2.1.1) are ubiquitous metalloenzymes that catalyze the reversible hydration/dehydration of CO2/HCO3 (-), respectively. CA inhibitors (CAIs) such as acetazolamide, methazolamide, topiramate, zonisamide, and sulthiame can reduce seizures through perturbation of the CO2 equilibrium and/or the inhibition of ion channels. This review focuses on the mechanism of epilepsy, CA catalysis, and recent developments in the treatment of epilepsy using CAIs. Expert opinion: Based on the observed active-site binding interactions of CAIs in crystal structures and their respective inhibition constants, structure-activity relationships can be mapped. Various CAIs along with novel techniques to administer them have been patented in the last four years. However, epilepsy continues to be a path less traveled when it comes to CAIs. A major area of research must focus toward the design of isoform-specific inhibitors using analogs of existing CAIs. 23894530 Mitochondrial autophagy involving renal injury and aging is modulated by caloric intake in aged rat kidneys. A high-calorie (HC) diet induces renal injury and promotes aging, and calorie restriction (CR) may ameliorate these responses. However, the effects of long-term HC and CR on renal damage and aging have been not fully determined. Autophagy plays a crucial role in removing protein aggregates and damaged organelles to maintain intracellular homeostasis and function. The role of autophagy in HC-induced renal damage is unknown. We evaluated the expression of LC3/Atg8 as a marker of the autophagosome; p62/SQSTM1; polyubiquitin aggregates as markers of autophagy flux; Ambra1, PINK1, Parkin and Bnip3 as markers of mitophagy; 8-hydroxydeoxyguanosine (8-OHdG) as a marker of DNA oxidative damage; and p16 as a marker of organ aging by western blot and immunohistochemical staining in the kidneys of 24-month-old Fischer 344 rats. We also observed mitochondrial structure and autolysosomes by transmission electron microscopy. Expression of the autophagosome formation marker LC3/Atg8 and markers of mitochondrial autophagy (mitophagy) were markedly decreased in the kidneys of the HC group, and markedly increased in CR kidneys. p62/SQSTM1 and polyubiquitin aggregates increased in HC kidneys, and decreased in CR kidneys. Transmission electron microscopy demonstrated that HC kidneys showed severe abnormal mitochondrial morphology with fewer autolysosomes, while CR kidneys exhibited normal mitochondrial morphology with numerous autolysosomes. The level of 8-hydroxydeoxyguanosine was increased in HC kidneys and decreased in CR kidneys. Markers of aging, such as p16 and senescence-associated-galactosidase, were increased significantly in the HC group and decreased significantly in the CR group. The study firstly suggests that HC diet inhibits renal autophagy and aggravates renal oxidative damage and aging, while CR enhances renal autophagy and ameliorates oxidative damage and aging in the kidneys. 23891792 Pyruvate minimizes rtPA toxicity from in vitro oxygen-glucose deprivation and reoxygenation. Clinical application of recombinant tissue plasminogen activator (rtPA) for stroke is limited by hemorrhagic transformation, which narrows rtPA's therapeutic window. In addition, mounting evidence indicates that rtPA is potentially neurotoxic if it traverses a compromised blood brain barrier. Here, we demonstrated that pyruvate protects cultured HT22 neuronal and primary microvascular endothelial cells co-cultured with primary astrocytes from oxygen glucose deprivation (OGD)/reoxygenation stress and rtPA cytotoxicity. After 3 or 6h OGD, cells were reoxygenated with 11mmol/L glucose±pyruvate (8mmol/L) and/or rtPA (10µg/ml). Measured variables included cellular viability (calcein AM and annexin-V/propidium iodide), reactive oxygen species (ROS; mitosox red and 2',7'-dichlorofluorescein diacetate), NADPH, NADP(+) and ATP contents (spectrophotometry), matrix metalloproteinase-2 (MMP2) activities (gelatin zymography), and cellular contents of MMP2, tissue inhibitor of metalloproteinase-2 (TIMP2), and phosphor-activation of anti-apoptotic p70s6 kinase, Akt and Erk (immunoblot). Pyruvate prevented the loss of HT22 cells after 3h OGD±rtPA. After 6h OGD, rtPA sharply lowered cell viability; pyruvate dampened this effect. Three hours OGD and 4h reoxygenation with rtPA increased ROS formation by about 50%. Pyruvate prevented this ROS formation and doubled cellular NADPH/NADP(+) ratio and ATP content. In endothelial cell monolayers, 3h OGD and 24h reoxygenation increased FITC-dextran leakage, indicating disruption of intercellular junctions. Although rtPA exacerbated this effect, pyruvate prevented it while sharply lowering MMP2/TIMP2 ratio and increasing phosphorylation of p70s6 kinase, Akt and Erk. Pyruvate protects neuronal cells and microvascular endothelium from hypoxia-reoxygenation and cytotoxic action of rtPA while reducing ROS and activating anti-apoptotic signaling. These results support the proposed use of pyruvate as an adjuvant to dampen the side effects of rtPA treatment, thereby extending rtPA's therapeutic window. 23884341 XAFS in dilute magnetic semiconductors. X-Ray absorption fine structure (XAFS) spectroscopy has experienced a rapid development in the last four decades and has proved to be a powerful structure characterization technique in the study of local environments in condensed matter. In this article, we first introduce the XAFS basic principles including theory, data analysis and experiment in some detail. Then we attempt to make a review on the applications of XAFS to the study of atomic and electronic structure in dilute magnetic semiconductor (DMS) systems. The power of XAFS in characterizing this interesting material system, such as determining the occupation sites and distribution of the dopants, detecting the presence of metal clusters or secondary phases, as well as identifying the defect types and dopant valence, will be illuminated by selected examples. This review should be of interest both to newcomers in the DMS field and to an interdisciplinary community of researchers working in synthesis, characterization and utilization of DMS materials. 23238093 The Effects of Eccentric Exercise on Muscle Function and Proprioception of Individuals Being Overweight and Underweight. Paschalis, V, Nikolaidis, MG, Theodorou, AA, Deli, CK, Raso, V, Jamurtas, AZ, Giakas, G, and Koutedakis, Y. The effects of eccentric exercise on muscle function and proprioception of individuals being overweight and underweight. J Strength Cond Res 27(9): 2542-2551, 2013-The aim of this study was to estimate the effect of being overweight or underweight on proprioception at rest and after muscle damaging eccentric exercise. Twelve lean, 12 overweight, and 8 underweight female participants performed an eccentric exercise session using the knee extensor muscles of the dominant leg. Muscle damage indices and proprioception were assessed up to 3 days postexercise. The results indicated that proprioception at baseline of the lean individuals was superior to that of the other 2 groups. The overweight individuals exhibited a smaller knee joint reaction angle to release than did the lean group, whereas the underweight individuals exhibited a larger reaction angle to release than did the lean group. After eccentric exercise, proprioception was affected more in the overweight and the underweight groups than in the lean group. The greater exercise-induced muscle damage appeared in the overweight group, and the deficient muscle mass of the underweight participants could explain in part the greater disturbances that appeared in proprioception in these 2 groups than for the lean counterparts. In conclusion, deviating from the normal body mass is associated with significant disturbances in the proprioception of the legs at rest and after participation in activities involving eccentric actions. 23893913 Determination of telaprevir in plasma of HCV-infected patients by HPLC-UV. Telaprevir is a direct acting antiviral agent, used with pegylated interferon and ribavirin for the management of chronic hepatitis C virus (HCV) genotype 1 infection, in patients not responding to therapy with pegylated interferon and ribavirin only. Although 75% of patients achieve a sustained virological response after treatment with telaprevir, adverse drug-drug interactions and undesirable events often occur. Therefore, telaprevir monitoring is pivotal to improve the management of HCV infection. Here, the first High-Performance Liquid Chromatography-Ultraviolet (HPLC-UV) method to quantify telaprevir in human plasma of HCV-genotype 1-infected patients is reported. The volume of the plasma sample was 700 μL. This method involved automated solid-phase extraction with Oasis HLB Cartridge 1 cc (divinylbenzene and N-vinylpyrrolidone). The extracted samples were reconstituted with 150 μL of 60/40 water/acetonitrile. Thirty microliters of these samples was injected into a HPLC-UV system, and the analytes were eluted on a X Terra(®) RP18 column (250 mm × 4.6 mm i.d.) with a particle size of 5 μm. The mobile phase (ammonium acetate buffer, 150 mM, pH 8.0, and methanol:acetonitrile 50:50) was delivered at 1.0 mL/min with linear gradient elution. The total run time for a single analysis was 16 min; telaprevir was detected by UV at 276 and 286 nm. The calibration curve was linear from 312.5 to 20,000 ng/mL (r(2) > 0.996). The absolute recovery of telaprevir ranged between 89 and 93% at concentrations of quality control samples of 800, 4,000, 8,000, and 16,000 ng/mL. Both precision and accuracy were always <15%. The HPLC-UV method reported here: (i) has been validated, (ii) is currently applied to monitor telaprevir in plasma of HCV-infected patients, and (iii) appears useful in a routine laboratory. © 2013 IUBMB Life, 65(9):800-805, 2013. 23541276 Diffusion-weighted MR imaging of mucin-rich mucinous tubular and spindle cell carcinoma of the kidney: a case report. Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare indolent subtype of renal cell carcinoma, which has variable magnetic resonance (MR) imaging features due to histomorphologic diversity. Diffusion-weighted MR imaging has shown its ability to differentiate benign and malignant renal neoplasms in some recent studies and can be a useful adjunct to routine MR sequences in ambiguous cases. We present a histopathology proven case of MTSCC highlighting the role of diffusion-weighted imaging in guiding the surgical management. 23554062 Incomplete cre-mediated excision leads to phenotypic differences between Stra8-iCre; Mov10l1(lox/lox) and Stra8-iCre; Mov10l1(lox/Δ) mice. In the Cre-loxp system, expression level and activity of Cre recombinase in a Cre deleter line are critical because these determine not only the cell specificity of gene knockout (KO), but also the efficiency of Cre-mediated excision in a specific cell lineage. Although the spatiotemporal expression pattern of a Cre transgene is usually defined upon the generation of the mouse line, the Cre excision efficiency in a specific targeted cell lineage is rarely evaluated and often assumed to be 100%. Incomplete excision can lead to highly variable phenotypes owing to mosaicism (i.e., coexistence of cells with the flox or the recombined flox allele) and this problem has long been overlooked. Here, we report that Stra8-codon-improved Cre recombinase (iCre), a transgenic allele expressing iCre under the control of the male germ cell-specific Stra8 promoter, could efficiently delete one Mov10l1 flox allele in spermatogenic cells, whereas the excision was incomplete when two Mov10l1 flox alleles were present. The incomplete Cre-mediated excision led to a testicular phenotype that was much less severe than that in the true conditional KO (inactivation, 100%) mice. Our findings suggest that it is essential to determine the efficiency of Cre excision when Cre-loxp system is used for deleting genes in a specific cell lineage and the Cre; gene(lox) (/) (Δ) genotype should be used to evaluate phenotypes instead of Cre; gene(lox/lox) owing to the fact that the latter usually bears incomplete deletion of the flox allele(s). genesis 51:481-490. © 2013 Wiley Periodicals, Inc. 23702411 Rapid changes in brain structure predict improvements induced by perceptual learning. Practice-dependent changes in brain structure can occur in task relevant brain regions as a result of extensive training in complex motor tasks and long-term cognitive training but little is known about the impact of visual perceptual learning on brain structure. Here we studied the effect of five days of visual perceptual learning in a motion-color conjunction search task using anatomical MRI. We found rapid changes in gray matter volume in the right posterior superior temporal sulcus, an area sensitive to coherently moving stimuli, that predicted the degree to which an individual's performance improved with training. Furthermore, behavioral improvements were also predicted by volumetric changes in an extended white matter region underlying the visual cortex. These findings point towards quick and efficient plastic neural mechanisms that enable the visual brain to deal effectively with changing environmental demands. 23894544 Pollination Services Provided by Bees in Pumpkin Fields Supplemented with Either Apis mellifera or Bombus impatiens or Not Supplemented. Pollinators provide an important service in many crops. Managed honey bees (Apis mellifera L.) are used to supplement pollination services provided by wild bees with the assumption that they will enhance pollination, fruit set and crop yield beyond the levels provided by the wild bees. Recent declines in managed honey bee populations have stimulated interest in finding alternative managed pollinators to service crops. In the eastern U.S., managed hives of the native common eastern bumble bee (Bombus impatiens Cresson) may be an excellent choice. To examine this issue, a comprehensive 2-yr study was conducted to compare fruit yield and bee visits to flowers in pumpkin (Cucurbita pepo L.) fields that were either supplemented with A. mellifera hives, B. impatiens hives or were not supplemented. We compared pumpkin yield, A. mellifera flower visitation frequency and B. impatiens flower visitation frequency between treatments. Results indicated that supplementing pumpkin fields with either A. mellifera or B. impatiens hives did not increase their visitation to pumpkin flowers or fruit yield compared with those that were not supplemented. Next, the relationship between frequency of pumpkin flower visitation by the most prominent bee species (Peponapis pruinosa (Say), B. impatiens and A. mellifera) and fruit yield was determined across all pumpkin fields sampled. Fruit yield increased as the frequency of flower visits by A. mellifera and B. impatiens increased in 2011 and 2012, respectively. These results suggest that supplementation with managed bees may not improve pumpkin production and that A. mellifera and B. impatiens are important pollinators of pumpkin in our system. 23851429 Animal models and cell lines of pancreatic neuronimal models and cell lines of pancreatic neuroendocrine tumors. Pancreatic neuroendocrine tumors (PNETs), also known as islet cell tumors, are mostly indolent neoplasms that probably arise from a network of endocrine cells that includes islet cells and pluripotent precursors in the pancreatic ductal epithelium. The incidence and prevalence of PNETs continue to rise in recent years because of more sensitive detection. The molecular pathogenesis, early detection, molecular predictors of tumor behavior, and targeted drug therapy of PNETs are not well understood and require additional basic and translational research. The rarity and indolent nature of these tumors, difficulty of access to appropriate patient tissue samples, and varying histopathology and secreted hormones pose particular challenges to PNET researchers. Animal models and cell lines are indispensable tools for investigating the pathogenesis, pathophysiology, mechanisms for tumor invasion and metastasis, and therapeutics of PNETs. This review summarizes currently available animal models and cell lines of PNETs, which have provided valuable insights into the pathogenesis and natural history of human PNETs. In the future, animal models and cell lines of PNETs should also be used to study early tumor detection and molecular predictors of tumor behavior and to test the responses to, and mechanisms for, novel targeted drug therapies. 23946045 Management of neonatal jaundice varies by practitioner type. To survey current practices among different types of medical practitioners in Ontario to assess if national guidelines for screening and management of neonatal hyperbilirubinemia were being followed. An anonymized, cross-sectional survey distributed by mail and e-mail. Ontario. From each group (general practitioners, family medicine practitioners, and pediatricians), 500 participants were randomly selected, and all 390 registered midwives were selected. Compliance with national guidelines for screening, postdischarge follow-up, and management of newborns with hyperbilirubinemia. Of the 1890 potential respondents, 321 (17%) completed the survey. Only 41% of family physicians reported using national guidelines, compared with 75% and 69% of pediatricians and midwives, respectively (P < .001). Bilirubin was routinely measured for all newborns before discharge by 42% of family physicians, 63% of pediatricians, and 22% of midwives (P < .001). Newborn follow-up was completed within 72 hours after discharge by 60% of family physicians, 89% of pediatricians, and 100% of midwives. Management of neonatal hyperbilirubinemia differed significantly (P < .001), with 91% of family physicians, 99% of pediatricians, and 79% of midwives correctly managing a case scenario according to the guidelines. The management of jaundice varied considerably among the different practitioner types, with pediatricians both most aware of the guidelines and most likely to follow them. Increased knowledge translation efforts are required to promote adherence to the jaundice management guidelines across all practitioner types, but particularly among family physicians. 23859436 Different Oligomeric Properties and Stability of Highly Homologous A1 and Proto-Oncogenic A2 Variants of Mammalian Translation Elongation Factor eEF1. Translation elongation factor 1A (eEF1A) directs aminoacyl-tRNA to the A site of 80S ribosomes. In addition, more than 97% homologous variants of eEF1A, A1 and A2, whose expression in different tissues is mutually exclusive, may fulfill a number of independent moonlighting functions in the cell; for instance, the unusual appearance of A2 in an A1-expressing tissue was recently linked to the induction of carcinogenesis. The structural background explaining the different functional performance of the highly homologous proteins is unclear. Here, the main difference in the structural properties of these proteins was revealed to be the improved ability of A1 to self-associate, as demonstrated by synchrotron small-angle X-ray scattering (SAXS) and analytical ultracentrifugation. Besides, the SAXS measurements at different urea concentrations revealed the low resistance of the A1 protein to urea. Titration of the proteins by hydrophobic dye 8-anilino-1-naphthalenesulfonate showed that the A1 isoform is more hydrophobic than A2. As the different association properties, lipophilicity, and stability of the highly similar eEF1A variants did not influence considerably their translation functions, at least in vitro, we suggest this difference may indicate a structural background for isoform-specific moonlighting roles. 23926417 Identification of differentially evolved genes: an alternative approach to detection of accelerated molecular evolution from genome-wide comparative data. One of the most important measures for detecting molecular adaptations between species/lineages at the gene level is the comparison of relative fixation rates of synonymous (dS) and non-synonymous (dN) mutations. This study shows that the branch model is sensitive to tree topology and proposes an alternative approach, devogs, which does not require phylogenetic topology for analysis. We compared devogs with a branch model method using virtual data and a varying ω ratio, in which parameters were obtained from real data. The positive predictive value, sensitivity, and specificity of the branch model were affected by the phylogenic tree topology. Devogs showed greater positive predictive value, whereas the branch model method had greater sensitivity. In a working example using devogs, a group of human RNA polymerase II-related genes, which are important in mediating alternative splicing, were significantly accelerated compared to four other mammals. 23965164 Pharmacological therapies to enhance motor recovery and walking after stroke: emerging strategies. Stroke is the most common serious neurological disorder. To date, the focus for research and trials has been on prevention and acute care. Many patients are left with serious neurological impairments and limitations in activity and participation after stroke. Recent preliminary research and trials suggest that the brain is 'plastic' and that the natural history of stroke recovery can be improved by physical therapy and pharmacotherapy. Motor weakness and the ability to walk have been the primary targets for testing interventions that may improve recovery after stroke. Physical therapeutic interventions enhance recovery after stroke; however, the timing, duration and type of intervention require clarification and further trials. Pharmacotherapy, in particular with dopaminergic and selective serotonin-reuptake inhibitors, shows promise in enhancing motor recovery after stroke; however, further large-scale trials are required. 23623323 The effect of liposomal size on the targeted delivery of doxorubicin to Integrin αvβ3-expressing tumor endothelial cells. Size of the liposomes (LPs) specially governs its biodistribution. In this study, LPs were developed with controlled sizes, where variation in LP size dictates the ligand-receptor interaction, cellular internalization and its distribution within the tumor microenvironment. The therapeutic efficacies of doxorubicin (DOX)-loaded RGD modified small size (~100 nm in diameter, dnm) and large size (~300 dnm) PEGylated LPs (RGD-PEG-LPs) were compared to that of Doxil (a clinically used DOX-loaded PEG-LP, ~100 dnm) in DOX resistant OSRC-2 (Renal cell carcinoma, RCC) tumor xenografts. Doxil, which accumulated in tumor tissue via the enhanced permeability and retention (EPR) effect, failed to suppress tumor growth. Small size RGD-PEG-LP, that targets the tumor endothelial cells (TECs) and extravasates to tumor cells, failed to provide anti-tumor effect. Large size RGD-PEG-LP preferentially targets the TECs via minimization of the EPR effect, and significantly reduced the tumor growth, which was exerted through its strong anti-angiogenic activity on the tumor vasculature rather than having a direct effect on DOX resistant RCC. The prepared large size RGD-PEG-LP that targets the TECs via interacting with Integrin αvβ3, is a potentially effective and alternate therapeutic strategy for the treatment of DOX resistant tumor cells by utilizing DOX, in cases where Doxil is ineffective. 23963443 Epinephrine electro-oxidation highlights fast electrochemistry at the graphite basal surface. Macroscale and nanoscale measurements of epinephrine electro-oxidation at graphite electrodes, with different step edge densities, demonstrate unequivocally that the reaction occurs readily at the basal surface, and that step edges are not required for molecular electrocatalysis, in contrast to the current literature model. 23419484 Integrating clinical pharmacology concepts in individualized therapy with tyrosine kinase inhibitors. Tyrosine kinases have emerged as important tumor targets for the design of potent and selective inhibitors. Eighteen of these tyrosine kinase inhibitors (TKIs) have already been approved for the treatment of diseases that were previously essentially resistant to standard chemotherapy. Major efforts are ongoing that focus on the development of companion diagnostics for investigational and approved TKIs, as well as on integrating clinical pharmacology principles in clinical practice to decrease toxicity and improve efficacy. 23943271 Understanding primate communities: Recent developments and future directions. In 1999, the edited volume Primate Communities presented several studies that examined broad-scale patterns of primate diversity.(1) Similar studies were being conducted on nonprimate taxa; advances in data availability and statistical approaches were allowing scientists to investigate a variety of new questions and to reexamine classical questions in novel ways. While such studies on nonprimate taxa have continued at a steady pace, they have only crept forward for primate species (Fig. ). In the intervening time, the field of macroecology (Box 1) rapidly developed and has resulted in several books and the establishment of new research institutes. We suggest that examining primate communities, especially in a macroecological context, is an important line of research for our field to embrace and an area where biological anthropologists can provide major contributions. We review the current state of research, describe new datasets and research tools, and suggest future research directions. 23855014 Therapeutic clowning in paediatric practice. Over the past 30 years, there has been much research into the health benefits of humour and laughter. Although often viewed very positively, rigorous evaluation of the therapeutic effect of clowning is complex. Clowning is a multi-modal intervention, which may have an impact on medical conditions, procedures, family functioning and health care teams. Clowns help children to adapt to their hospital surroundings and can distract from, and demystify, painful or frightening procedures through 'doses of fun' to complement traditional clinical interventions. This paper provides a review of the paediatric literature and reveals studies looking at the effect of clown interventions on various practical procedures and individual medical conditions, and the effects of clowning within clinical teams. 23950668 Anagnorisma chamrani sp. n. (Lepidoptera, Noctuidae) from Iran. A new Anagnorisma species, Anagnorisma chamrani sp. n., is described from Binaloud Mountains of Khorasan-e-Razavi province in north-eastern Iran, and compared with its sister species, Anagnorisma eucratides (Boursin, 1960). The adults, and male and female genitalia of both species are illustrated in 11 figures. The genus Anagnorisma is recorded for the first time for the fauna of Iran. 23810663 Biomechanics of the heel-raise test performed on an incline in two knee flexion positions. Although single-legged heel-raise cycles are often performed on an incline in different knee flexion positions to discriminate the relative contribution of the triceps surae muscles, detailed kinematic and kinetic analyses of this procedure are not available. Our study characterizes and compares the biomechanics and clinical outcomes of single-legged heel-raise cycles performed to volitional exhaustion on an incline with the knee straight (0°) and bent (45°), considering the effect of sex and age. Fifty-six male and female volunteers, with equal numbers of younger (20 to 40years of age) and older (40 to 60years of age) individuals, completed a maximal number of heel-raise cycles on an incline at both nominal knee angles. Kinematic and kinetic data were acquired during testing using a 3D motion capturing system and multi-axial force plate. The impact of fatigue on performance was quantified using changes in maximal voluntary isometric contraction force and biomechanical performance of cycles. Overall, participants completed three more cycles and maintained better biomechanical performance with 45° than 0° of knee flexion. More precisely, the decreases in maximal heel-raise heights, plantar-flexion angles at maximal height and ranges of ankle motion per cycle were all smaller with the knee bent. However, several outcomes indicated similar plantar-flexion fatigue at both knee angles. Males demonstrated a more rapid decline in peak ground reaction forces during testing; but otherwise, neither sex nor age significantly impacted outcomes. It is concluded that the differences discerned here in the biomechanics of single-legged heel-raise cycles performed at 0° and 45° of knee flexion to volitional exhaustion on an incline may be too small to identify in clinical settings or reflect substantial alterations in the relative contribution of the triceps surae muscles. 23825347 History of the meat animal evaluation contest: A pedagogical stimulant. A century ago students were exposed to livestock judging and meat judging, though each was taught as an independent entity. Fifty years ago universities started combining subjects involving the evaluation process, whether characteristics involved traits of the live animal or those related to meat value. Universities developed a meat animal evaluation contest (MAEC) that included breeding livestock, market livestock, and meat products. Using production records, students culled, ranked, priced, and answered questions about breeding and market cattle, swine, and sheep. For market livestock, ranks and values were scored on carcass data after the livestock were harvested. Students graded, ranked, answered questions, and priced meat products. A communications component involved students being given a problem to be discussed as a group presentation. In 1964, the first MAEC was conducted at Rath Packing Co., Waterloo, IA, and included 40 students. In 1967, the contest was held at The Farmbest Co. and IBP of Denison, IA, and included 87 students. In 1968, the MAEC moved to the Knights of Ak-Sar-Ben, Omaha, NE, and by 1988, 187 students (22 universities) competed. In 1995, the MAEC moved to the United Stockyards Co., St. Joseph, MO. Starting in 2004, it moved to various universities (South Dakota State University, Oklahoma State University, University of Nebraska, and Texas Tech University). The MAEC has stimulated students to better learn and understand the details of meat animal evaluation and has encouraged the development of evaluation courses as well as satellite and symposia programs. To date, over 6,000 students representing 40 universities have participated. 23052036 Endocrine disruptors fludioxonil and fenhexamid stimulate miR-21 expression in breast cancer cells. Fenhexamid and fludioxonil are antifungal agents used in agricultural applications, which are present at measurable amounts in fruits and vegetables. Fenhexamid and fludioxonil showed endocrine disruptor activity as antiandrogens in an androgen receptor reporter assay in engineered human breast cancer cells. Little is known about how environmental chemicals regulate microRNA (miRNA) expression. This study examined the effect of fenhexamid and fludioxonil on the expression of the oncomiR miR-21 in MCF-7, T47D, and MDA-MB-231 human breast cancer cells and downstream targets of miR-21 in MCF-7 cells. Fenhexamid and fludioxonil stimulated miR-21 expression in a concentration-dependent manner and reduced the expression of miR-21 target Pdcd4 protein. Antisense to miR-21 blocked the increase in Pdcd4 protein by fenhexamid and fludioxonil. Fenhexamid and fludioxonil reduced miR-125b and miR-181a, demonstrating specificity of miRNA regulation. Induction of miR-21 was inhibited by the estrogen receptor antagonist fulvestrant, by androgen receptor antagonist bicalutamide, by actinomycin D and cycloheximide, and by inhibitors of the mitogen-activated protein kinases and phosphoinositide 3-kinase pathways. Fenhexamid activation was inhibited by the arylhydrocarbon receptor antagonist α-napthoflavone. Fenhexamid and fludioxonil did not affect dihydrotestosterone-induced miR-21 expression. Fludioxonil, but not fenhexamid, inhibited MCF-7 cell viability, and both inhibited estradiol-induced cell proliferation and reduced cell motility. Together these data indicate that fenhexamid and fludioxonil use similar and distinct mechanisms to increase miR-21 expression with downstream antiestrogenic activity. 23712256 VEGF-A165 Potently Induces Human Blood-Nerve Barrier Endothelial Cell Proliferation, Angiogenesis, and Wound Healing In Vitro. Several mitogens such as vascular endothelial growth factor (VEGF) have been implicated in mammalian vascular proliferation and repair. However, the molecular mediators of human blood-nerve barrier (BNB) development and specialization are unknown. Primary human endoneurial endothelial cells (pHEndECs) were expanded in vitro and specific mitogen receptors detected by western blot. pHEndECs were cultured with basal medium containing different mitogen concentrations with or without heparin. Non-radioactive cell proliferation, Matrigel(â„¢)-induced angiogenesis and sterile micropipette injury wound healing assays were performed. Proliferation rates, number and total length of induced microvessels, and rate of endothelial cell monolayer wound healing were determined and compared to basal conditions. VEGF-A165 in the presence of heparin, was the most potent inducer of pHEndEC proliferation, angiogenesis, and wound healing in vitro. 1.31 nM VEGF-A165 induced ~110 % increase in cell proliferation relative to basal conditions (∼51 % without heparin). 2.62 pM VEGF-A165 induced a three-fold increase in mean number of microvessels and 3.9-fold increase in total capillary length/field relative to basal conditions. In addition, 0.26 nM VEGF-A165 induced ∼1.3-fold increased average rate of endothelial wound healing 4-18 h after endothelial monolayer injury, mediated by increased cell migration. VEGF-A165 was the only mitogen capable of complete wound closure, occurring within 30 h following injury via increased cell proliferation. This study demonstrates that VEGF-A165, in the presence of heparin, is a potent inducer of pHEndEC proliferation, angiogenesis, and wound healing in vitro. VEGF-A165 may be an important mitogen necessary for human BNB development and recovery in response to peripheral nerve injury. 23893332 The effect of aliskiren on urinary cytokine/chemokine responses to clamped hyperglycaemia in type 1 diabetes. Acute clamped hyperglycaemia activates the renin-angiotensin-aldosterone system (RAAS) and increases the urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus. Our objective was to determine whether blockade of the RAAS would blunt the effect of acute hyperglycaemia on urinary cytokine/chemokine excretion, thereby giving insights into potentially protective effects of these agents prior to the onset of clinical nephropathy. Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances) and urinary cytokines/chemokines were measured after 6 h of clamped euglycaemia (4-6 mmol/l) and hyperglycaemia (9-11 mmol/l) on two consecutive days in patients with type 1 diabetes mellitus (n = 27) without overt nephropathy. Measurements were repeated after treatment with aliskiren (300 mg daily) for 30 days. Before aliskiren, clamped hyperglycaemia increased filtration fraction (from 0.188 ± 0.007 to 0.206 ± 0.007, p = 0.003) and urinary fibroblast growth factor-2 (FGF2), IFN-α2 and macrophage-derived chemokine (MDC) (p < 0.005). After aliskiren, the filtration fraction response to hyperglycaemia was abolished, resulting in a lower filtration fraction after aliskiren under clamped hyperglycaemic conditions (p = 0.004), and none of the biomarkers increased in response to hyperglycaemia. Aliskiren therapy also reduced levels of urinary eotaxin, FGF2, IFN-α2, IL-2 and MDC during clamped hyperglycaemia (p < 0.005). The increased urinary excretion of inflammatory cytokines/chemokines in response to acute hyperglycaemia is blunted by RAAS blockade in humans with uncomplicated type 1 diabetes mellitus. 23371369 Hippocampal volume reduction in elderly patients at risk for postoperative cognitive dysfunction. Postoperative cognitive dysfunction (POCD) is a formidable public health issue, which would not only affect the quality of life among elderly patients but also lead to pulmonary infection and increased mortality. While, there is a lack of an effective indicator in predicting POCD. As one pivotal part of the limbic system in brain, hippocampus is associated with cognitive function. Hippocampal atrophy could indicate the degree of changes in cognitive function. Forty-one ASA II or III patients (23 male, 18 female) aged ≥65 years undergoing open gastrointestinal tract surgery were enrolled in this study. MRI was performed to measure the volume of hippocampal formation before surgery and the results were standardized according to individual intracranial volume. All patients underwent a battery of neuropsychological tests including sensitive tests on the Wechsler adult memory scale and Wechsler adult intelligence scale, trail making test and the grooved pegboard test. We used the Z score to identify POCD as recommended by ISPOCD. All patients were then divided into POCD group and non-POCD group according to the results of the neuropsychological tests. The results of the tests were correlated with the volume of hippocampal formation measured by MRI. The value of MRI measurement of hippocampal volume in predicting POCD was analyzed. Multivariate linear correlation analyses of compositive Z score using potential contributing factors such as age, duration of anesthesia, education and hippocampal volume was carried out. Thirty-six patients completed the whole battery of neuropsychological tests after surgery. Thirteen of the 36 patients were found to have POCD (36 %) on the postoperative 4th day. The hippocampal volume was significantly smaller in POCD group (4.75 ± 0.23) than in non-POCD group (5.06 ± 0.31). Hippocampal volume had great influence on Z score, and had negative correlation with Z score. The MRI measurement of hippocampal volume is suggested to be valuable as a predictor of POCD in the elderly. 23942267 Sodium butyrate inhibits interferon-gamma induced indoleamine 2,3-dioxygenase expression via STAT1 in nasopharyngeal carcinoma cells. Indoleamine 2,3-dioxygenase (IDO) inhibits T-cell proliferation by catalyzing the conversion of l-tryptophan to l-kynurenine. IDO-induced immune tolerance weakens the clinical outcomes of immunotherapies. Sodium butyrate (NaB), one of the histone deacetylase inhibitors (HDACIs), has potential anti-tumor effects. Our previous studies revealed that NaB could inhibit IFN-γ induced IDO expression in nasopharyngeal carcinoma cells, CNE2. In the present study, we aim to investigate to the mechanism of NaB interfering with the interferon-gamma (IFN-γ)-mediated IDO expression signaling transduction. IDO expression and STAT1 phosphorylation in CNE2 cells were analyzed by western blotting and STAT1 acetylation was evaluated by immunoprecipitation. STAT1 nuclear translocation and NF-κB activity were detected by transient transfection and reporter gene assay. We found that NaB inhibited IFN-γ-induced IDO expression in CNE2 cells via decreasing phosphorylation and nuclear translocation of STAT1, but not via down-regulation of IFN-γ-receptor (IFNGR). Immunoprecipitation assays revealed that NaB increased STAT1 acetylation. Furthermore, NaB elevated the activity of NF-κB in CNE2 cells, and blocking the NF-κB activity had no effect on the IFN-γ-induced IDO expression. These results suggest that NaB inhibited IFN-γ-induced IDO expression via STAT1 increased acetylation, decreased phosphorylation, and reduced nuclear translocation. These provided new evidence for the anti-tumor action of NaB and potential drug targets to reduce the IDO-induced immune tolerance. 23523989 A novel microhabitat for parasitic copepods: a new genus of Ergasilidae (Copepoda: Cyclopoida) from the urinary bladder of a freshwater fish. An endoparasitic copepod is reported from the urinary bladder of a fish for the first time. Endoparasitic copepods on fish hosts are extremely rare and the impact of colonization of this novel microhabitat on the biology of the parasite is discussed. This curious association was reported from two different host families of Neotropical freshwater fishes, Erythrinidae and Cichlidae, collected from the Cristalino River, a tributary of the Araguaia River, in Brazil. The copepod is fully described using light and scanning electron microscopy. Urogasilus brasiliensis n. g., n. sp. represents a new genus and species of the family Ergasilidae and can be distinguished from other genera by its unique tagmosis, in which the fourth and fifth pedigerous somites and the genital double-somite are all fused to form an elongate trunk. The anal somite is the only free abdominal somite present. The pattern of leg segmentation is also unique, with legs 1 to 3 each having a 2-segmented endopod and leg 4 reduced to a single seta. The discovery of ovigerous female ergasilids in the urinary bladder of a fish is novel and this discovery represents a good model for further studies on the adaptations to an endoparasitic lifestyle. 23202888 Hierarchical assembly of ultrathin hexagonal SnS2 nanosheets onto electrospun TiO2 nanofibers: enhanced photocatalytic activity based on photoinduced interfacial charge transfer. Well-designed hierarchical nanostructures with one dimensional (1D) TiO(2) nanofibers (120-350 nm in diameter and several micrometers in length) and ultrathin hexagonal SnS(2) nanosheets (40-70 nm in lateral size and 4-8 nm in thickness) were successfully synthesized by combining the electrospinning technique (for TiO(2) nanofibers) and a hydrothermal growth method (for SnS(2) nanosheets). The single-crystalline SnS(2) nanosheets with a 2D layered structure were uniformly grown onto the electrospun TiO(2) nanofibers consisted of either anatase (A) phase or anatase-rutile (AR) mixed phase TiO(2) nanoparticles. The definite heterojunction interface between SnS(2) nanosheets and TiO(2) (A or R) nanoparticles were investigated by high resolution transmission electron microscopy (HRTEM) and X-ray photoelectron spectroscopy (XPS). Moreover, the as-prepared SnS(2)/TiO(2) hierarchical nanostructures as nanoheterojunction photocatalysts exhibited excellent UV and visible light photocatalytic activities for the degradation of organic dyes (rhodamine B and methyl orange) and phenols (4-nitrophenol), remarkably superior to the TiO(2) nanofibers and the SnS(2) nanosheets, mainly owing to the photoinduced interfacial charge transfer based on the photosynergistic effect of the SnS(2)/TiO(2) heterojunction. Significantly, the SnS(2)/TiO(2) (AR) hierarchical nanostructures as the tricomponent heterojunction system possessed stronger photocatalytic activity than the bicomponent heterojunction system of SnS(2)/TiO(2) (A) hierarchical nanostructures or TiO(2) (AR) nanofibers, which was discussed in terms of the three-way photosynergistic effect between SnS(2), TiO(2) (A) and TiO(2) (R) component in the SnS(2)/TiO(2) (AR) heterojunction resulting in the high separation efficiency of photoinduced electron-hole pairs, as evidenced by photoluminescence (PL) and surface photovoltage spectra (SPS). 23932309 Vocal Economy in Vocally Trained Actresses and Untrained Female Subjects. Vocally trained actresses are expected to have more vocal economy than nonactresses. Therefore, we hypothesize that there will be differences in the electroglottogram-based voice economy parameter quasi-output cost ratio (QOCR) between actresses and nonactresses. This difference should remain across different levels of intensity. A total of 30 actresses and 30 nonactresses were recruited for this study. Participants from both groups were required to sustain the vowels /a/, /i/, and /u/, in habitual, moderate, and high intensity levels. Acoustic variables such as sound pressure level (SPL), fundamental frequency (F0), and glottal contact quotient (CQ) were obtained. The QOCR was then calculated. There were no significant differences among the groups for QOCR. Positive correlations were observed for QOCR versus SPL and QOCR versus F0 in all intensity levels. Negative correlation was found between QOCR and CQ in all intensity levels. Considering the differences among intensity levels, from habitual to moderate and from moderate to loud, only the CQ did not differ significantly. The QOCR, SPL, and F0 presented significant differences throughout the different intensity levels. The QOCR did not reflect the level of vocal training when comparing trained and nontrained female subjects in the present study. Both groups demonstrated more vocal economy in moderate and high intensity levels owing to more voice output without an increase in glottal adduction. 23953412 Sorafenib sensitizes head and neck squamous cell carcinoma cells to ionizing radiation. There is a great need to improve the outcome of locoregionally advanced squamous cell carcinomas of the head and neck (HNSCC). Standard treatment includes a combination of surgery, radio- and chemotherapy. The addition of molecular targeting agents to conventional treatment may improve outcomes. In this study the Raf inhibitor sorafenib was used to increase the radiosensitivity of HNSCC cell lines. In a panel of six cell lines (A549, FaDu, UTSCC 60A, UTSCC 42A, UTSCC 42B, UTSCC 29) radiosensitivity was measured by colony formation assay and apoptosis and cell cycle analysis were performed by flow cytometry. DNA repair was analyzed by 53BP1 immunohistochemistry. Sorafenib added prior to irradiation resulted in an increased cellular radiosensitivity (DEF0.5=1.11-1.84). Radiosensitization was not caused by an enhanced rate of apoptosis or cell cycle effects. In contrast, sorafenib was shown for the first time to block the repair of DNA double-strand breaks (DSB). Our data suggest that sorafenib may be used to overcome the radioresistance of HNSCC through the inhibition of DSB repair. 23939948 SWCNT/Graphite Nanoplatelet Hybrid Thin Films for Self-Temperature-Compensated, Highly Sensitive and Extensible Piezoresistive Sensors. Highly sensitive single-wall carbon nanotube/graphite nanoplatelet (SWCNT/GNP) hybrid thin-film sensors are developed, which possess the unique capability for self-temperature compensation. This unique property in combination with their high gauge sensitivity and large reversible extensibility promises the SWCNT/GNP hybrid thin film piezoresistive sensors for a wide range applications, such as in man-machine interaction and body monitoring. 23723258 Floral ontogeny and gene protein localization rules out euanthial interpretation of reproductive units in Lepironia (Cyperaceae, Mapanioideae, Chrysitricheae). In the sedge subfamily Mapanioideae there are considerable discrepancies between the standard trimerous monocot floral architecture expected and the complex floral and inflorescence morphologies seen. Decades of debate about whether the basic reproductive units are single flowers or pseudanthia have not resolved the question. This paper evaluates current knowledge about Mapaniid reproductive structures and presents an ontogenetic study of the Mapaniid genus Lepironia with the first floral protein expression maps for the family, localizing the products of the APETALA1/FRUITFULL-like (AP1/FUL) MADS-box genes with the aim of shedding light on this conundrum. A range of reproductive developmental stages, from spikelet primordia through to infructescence material, were processed for anatomical and immunohistochemical analyses. The basic reproductive unit is subtended by a bract and possesses two prophyll-like structures, the first organs to be initiated on the primordium, which grow rapidly, enclosing two whorls of initiating leaf-like structures with intervening stamens and a central gynoecium, formed from an annular primordium. The subtending bract and prophyll-like structures possess very different morphologies from that of the internal leaf-like structures and do not show AP1/FUL-like protein localization, which is otherwise strongly localized in the internal leaf-like structures, stamens and gynoecia. Results support the synanthial hypothesis as the evolutionary origin of the reproductive unit. Thus, the basic reproductive unit in Lepironia is an extremely condensed pseudanthium, of staminate flowers surrounding a central terminal pistillate female flower. Early in development the reproductive unit becomes enclosed by a split-prophyll, with the whole structure subtended by a bract. 23912655 Transient hemiparesis due to a ruptured cerebral aneurysm in the prehospital setting. A 67-year-old woman developed a sudden onset headache and left hemiparesis. Emergency medical technicians found that she was conscious, but had left hemiparesis. On arrival, she had an isolated headache without any neurological deficits, however, suddenly became comatose during a head CT examination, which demonstrated a subarachnoid haemorrhage. The head CT angiography on the second day revealed a cerebral aneurysm at the right middle cerebral artery, which was clipped on the same day. The patient demonstrated left haemiplegia and total aphasia after the operation, however, the neurological deficit gradually subsided and discharged on foot in 4 months without any deficits. Some patients with a subarachnoid haemorrhage may demonstrate transient neurological deficits, like those occurring during an ischaemic stroke, so emergency medical technicians and physicians should pay attention to treat such patients gently to avoid the re-rupture of a cerebral aneurysm, especially if the patient has headache symptoms. 23411225 Effects of sodium caseinate concentration and storage conditions on the oxidative stability of oil-in-water emulsions. The oxidative stability of various oils (sunflower, camelina and fish) and 20% oil-in-water (O/W) emulsions, were examined. The mean particle size decreased from 1179 to 325 nm as sodium caseinate (emulsifier) concentration was increased from 0.25% to 3% in O/W emulsions (P<0.05). Increasing the microfluidisation pressure from 21 to 138 MPa, resulted in a particle size decrease from 289 to 194 nm (P<0.05). Emulsified oils had lower detectable lipid hydroperoxide and p-Anisidine values than their corresponding bulk oils (P<0.05). The lipid hydroperoxide and p-Anisidine values of emulsions generally decreased as sodium caseinate concentration increased, and similarly decreased as microfluidisation pressure increased (P<0.05). Increasing storage temperature of the emulsions from 5 to 60°C, resulted in lower detectable lipid oxidation products during storage (P<0.05). 23454145 Relative expression of cholesterol transport-related proteins and inflammation markers through the induction of 7-ketosterol-mediated stress in Caco-2 cells. Human diets contain sterol oxidation products that can induce cytotoxic effects, mainly caused by cholesterol oxides. However, phytosterol oxides effects have been less extensively investigated. This study evaluates the production of inflammatory biomarkers (IL-1β, IL-8, IL-10, TNFα) and the influence of gene expression transporters and enzymes related to cholesterol absorption and metabolism (NPC1L1, ABCG5/8, HMGCoA, ACAT) produced by 7-ketosterols (stigmasterol/cholesterol) in Caco-2 cells. These effects were linked to intracellular signaling pathways by using several inhibitors. Results showed 7-ketostigmasterol to have a greater proinflammatory potential than 7-ketocholesterol. In non-pre-treated cells, only efflux transporters were down-regulated by 7-ketosterols, showing a greater influence upon ABCG5 expression. Cell-pre-incubation with bradykinin induced changes in ABCG expression levels after 7-ketostigmasterol-incubation; however, the energetic metabolism inhibition reduced NPC1L1 expression only in 7-ketocholesterol-incubated cells. In non-pre-treated cells, HMG-CoA was up-regulated by both 7-ketosterols. However, exposure to inhibitors down-regulated the expression levels, mainly in 7-ketocholesterol-incubated cells. While ACAT expression values in non-pre-treated cells were unchanged, exposure to inhibitors caused down-regulation of mRNA levels. These results suggest that internalization and excretion of 7-ketostigmasterol is probably influenced by [Ca]i, which also could mediate HMGCoA activity in POPs metabolism. However, energetic metabolism and reducing equivalents exert different influences upon the 7-ketosterol internalization. 23847304 Segmentation by depth does not always facilitate visual search. In visual search, target detection times are relatively insensitive to set size when targets and distractors differ on a single feature dimension. Search can be confined to only those elements sharing a single feature, such as color (Egeth, Virzi, & Garbart, 1984). These findings have been taken as evidence that elementary feature dimensions support a parallel segmentation of a scene into discrete sets of items. Here we explored if relative depth (signaled by binocular disparity) could support a similar parallel segmentation by examining the effects of distributing distracting elements across two depth planes. Three important empirical findings emerged. First, when the target was a feature singleton on the target depth plane, but a conjunction search among distractors on the nontarget plane, search efficiency increased compared to a single depth plane. Second, benefits of segmentation in depth were only observed when the target depth plane was known in advance. Third, no benefit of segmentation in depth was observed when both planes required a conjunction search, even with prior knowledge of the target depth plane. Overall, the benefit of distributing the elements of a search set across two depth planes was observed only when the two planes differed both in binocular disparity and in the elementary feature composition of individual elements. We conclude that segmentation of the search array into two depth planes can facilitate visual search, but unlike color or other elementary properties, does not provide an automatic, preattentive segmentation. 23715658 Analysis of Nontypeable Haemophilus influenzae Phase-Variable Genes During Experimental Human Nasopharyngeal Colonization. Background. Studies of nontypeable Haemophilus influenzae (NTHi) have demonstrated that a number of genes associated with infectivity have long repeat regions associated with phase variation in expression of the respective gene. The purpose of this study was to determine the genes that underwent phase variation during a 6-day period of experimental human nasopharyngeal colonization. Methods. Strain NTHi 2019Str(R)1 was used to colonize the nasopharynx of human subjects in a study of experimental colonization. Thirteen phase-variable genes were analyzed in NTHi 2019Str(R)1. Samples of NTHi 2019Str(R)1 were cultured from subjects during the 6-day colonization period. We used capillary electrophoresis and Roche 454 pyrosequencing to determine the number of repeats in each gene from each sample. Results. A significant number of samples switched licA and igaB from phase off in the inoculated strain to phase on during the 4-day period of observation. lex2A also showed variability as compared to baseline, but the differences were not significant. The remaining genes showed no evidence of phase variation. Conclusions. Our studies suggest that the phase-on genotypes of licA and igaB are important for early human nasopharynx colonization. lex2A showed a trend from phase off to phase on, suggesting a potentially important role in the colonization process. 23876128 'Safe enough in here?': patients' expectations and experiences of feeling safe in an acute psychiatric inpatient ward. To understand the experience of being a patient on an acute psychiatric inpatient ward. Acute psychiatric inpatient care is an integral part of the mental health system. A key driver for admission to acute wards is risk. Previous research indicates that people do not always feel safe when in an acute ward. Understanding the patient experience of safety can influence nursing practice, as well as policy and service development. A qualitative approach was used. Patient experience was conceptualised as represented through narrative as data. Sociolinguistic theories linking narrative structure with meaning informed the development of the analytic framework. Thirteen patients with a variety of diagnoses were recruited from an acute ward. Unstructured interviews were carried out in participants' homes two and six weeks postdischarge. Holistic analysis of each individual's data set was undertaken. Themes running across these holistic analyses were then identified and developed. Participant narratives were focused around themes of help, safety and power. This study presents findings relating to the experience of safety. Participants expected to be safe from themselves and from others. Initially, they experienced a sense of safety from the outside world. Lack of knowledge of their fellow patients made them feel vulnerable. Participants expected the nurses to keep them safe, and felt safer when there were male nurses present. Participants talk about safety in terms of psychological and physical safety. A key issue was the perception of threat from other patients, highlighting the need to consider patient safety as more than physical safety. Nurses need to be sensitive to the possibility that patients feel unsafe in the absence of obvious threat. Institutional structures that challenge patients' sense of safety must be examined. 23808513 Asialoglycoprotein receptor scintigraphy with 99mTc-galactosyl human serum albumin (99mTc-GSA) as an early predictor of survival in acute liver failure. This study evaluated the usefulness of asialoglycoprotein receptor scintigraphy with 99mTc-galactosyl human serum albumin (99mTc-GSA scintigraphy) as an early predictor for prognosis of acute liver failure. Forty-eight patients with acute liver failure and without a past history of chronic liver disease were enrolled. Patients were divided into survival and non-survival groups by 28-day mortality. 99mTc-GSA scintigraphy to detect uptake ratio of the heart at 15 minutes to that at three minutes (HH15) and uptake ratio of the liver at 15 minutes to the liver plus the heart at 15 minutes (LHL15), and measurements of serum total bilirubin, hepatocyte growth factor and prothrombin time were performed immediately after the diagnosis of acute liver failure. Areas under the receiver operating characteristic curves were used to compare the prognostic ability of total bilirubin, hepatocyte growth factor, prothrombin time, HH15 ratio, LHL15 ratio and the model for end-stage liver disease score. Clinical characteristics of patients in the survival group (n=20) and in the non-survival group (n=28) were not significantly different. HH15 and LHL15 uptake ratios in the survival group were 0.670 and 0.875, and they were significantly lower and higher than those in the non-survival group, respectively. All patients with LHL15 <0.760 died, and the area under the receiver operating characteristic curve for LHL15 were significantly larger than the areas under the receiver operating characteristic curves of serum variables and model for end-stage liver disease score. In summary, in patients with acute liver failure without chronic liver disease, HH15 and LHL15 of 99mTc-GSA scintigraphy are more useful variables in predicting prognosis than serum variables and model for end-stage liver disease score. 23889596 Presenting the improved possibility for staying well might be better than talking about change in risk: Use of the Non-Occurrence Probability Increase (NOPI). Abstract Objective. Talking about risk with patients is problematic since the individual's risk is not addressed and is usually very low. This study aimed to see how fact presentation influenced the decision-making process for general practitioners concerning treatment for the prevention of cardiovascular disease. Rather than looking at the risk of becoming ill, often presented as high figures of relative risk reduction (RRR), it could be useful to present the probability of staying well, i.e. from the concept of non-occurrence probability (NOP) and non-occurrence probability increase (NOPI) - simply a single measure of change in NOP. Design. General practitioners (GPs) had personal response keypads to answer two questions, presented differently, concerning whether they would allow themselves to be treated or not be treated for the risk of cardiovascular death. Setting and subjects. Five audiences consisting of general practitioners attending lectures. Results. When the question was presented as RRR, 68% and 86%, respectively, of the physicians responded that they would take the decision to treat. When presented as the concept of NOPI the figures were reduced to 18% and 16%, respectively (p < 10-6). Implications. Developing tools to explain treatment effect is crucial to enhancing health care quality. Since NOPI is one potential way of presenting prevention of risk we encourage future research to evaluate the NOPI concept compared with RRR and absolute risk reduction (ARR). 23796992 Deficits in physical function among young childhood cancer survivors. PURPOSE Childhood cancer survivors (CCSs) are at risk for physical disability. The aim of this investigation was to characterize and compare physical performance among CCSs and a group of siblings age < 18 years and determine if diagnosis, treatment, and physical activity levels were associated with lower performance scores. METHODS CCSs ≥ 5 years from diagnosis and a sibling comparison group were recruited and evaluated for strength, mobility, and fitness. Physical performance measures were compared in regression models between survivors and siblings by diagnosis and among survivors by treatment exposures and physical activity levels. Results CCSs (n = 183; mean age ± standard deviation [SD], 13.5 ± 2.5 years; 53% male) scored lower than siblings (n = 147; mean age ± SD, 13.4 ± 2.4 years; 50% male) on lower-extremity strength testing, the timed up-and-go (TUG) test, and the 6-minute walk (6MW) test, despite reporting similar levels and types of habitual physical activity. The lowest scores were prevalent among survivors of CNS tumors and bone and soft tissue sarcomas on strength testing (score ± SD: CNS tumors, 76.5 ± 4.7; sarcoma 67.1 ± 7.2 v siblings, 87.3 ± 2.4 Newton-meters quadricep strength at 90° per second; P = .04 and .01, respectively) and among CNS tumor survivors on the TUG (score ± SD: 5.1 ± 0.1 v siblings, 4.4 ± 0.1 seconds; P < .001) and 6MW tests (score ± SD: 533.3 ± 15.6 v siblings, 594.1 ± 8.3 m; P < .001). CONCLUSION CCSs may have underlying physiologic deficits that interfere with function that cannot be completely overcome by participation in regular physical activity. These survivors may need referral for specialized exercise interventions in addition to usual counseling to remain physically active. 23715810 Neurological morbidity of surgical resection of pediatric cerebellar astrocytomas. Review of children with low-grade cerebellar astrocytoma (LGCA) prior to 1992 showed a 98 % rate of gross total resection (GTR) but a concerning incidence of permanent neurological dysfunction. The purpose of this study was to determine the rate of GTR of LGCA since 1992 and frequency of neurologic injury. Retrospective review of children with LGCA was performed. CT/MR scans were rereviewed to assess extent of resection. Primary outcomes included incidence of GTR and incidence of permanent new neurological deficits. Other outcomes included late effects severity score (LESS), Bloom score for functional status, and educational assessment. Of 50 LGCA, GTR was achieved in 38 (76 %) compared to 43 of 44 (98 %) prior to 1992 (p < 0.004). Permanent new neurologic deficits from surgery occurred in 16 % compared to 18 % in the prior era (p = 0.61). For 35 patients operated on by the 2 surgeons in the prior study, 74 % had GTR, with permanent neurological deficits in 8.6 %. At latest follow-up, all patients were alive, 16 % with residual tumor. LESS was two or less (mild or no deficit) in 94 %. Bloom score was one or two (no or mild disability) in 90 %. Eighty-six percent attended normal school. Less aggressive resection of LGCA in children may reduce postoperative neurologic deficits in the hands of the same surgeons as in the prior study but not overall at our institution. The good long-term outcomes suggest that it may be appropriate to do incomplete resection rather than risk additional neurological deficit. 23838126 Neurobiology and clinical implications of lucid dreaming. Several lines of evidence converge to the idea that rapid eye movement sleep (REMS) is a good model to foster our understanding of psychosis. Both REMS and psychosis course with internally generated perceptions and lack of rational judgment, which is attributed to a hyperlimbic activity along with hypofrontality. Interestingly, some individuals can become aware of dreaming during REMS, a particular experience known as lucid dreaming (LD), whose neurobiological basis is still controversial. Since the frontal lobe plays a role in self-consciousness, working memory and attention, here we hypothesize that LD is associated with increased frontal activity during REMS. A possible way to test this hypothesis is to check whether transcranial magnetic or electric stimulation of the frontal region during REMS triggers LD. We further suggest that psychosis and LD are opposite phenomena: LD as a physiological awakening while dreaming due to frontal activity, and psychosis as a pathological intrusion of dream features during wake state due to hypofrontality. We further suggest that LD research may have three main clinical implications. First, LD could be important to the study of consciousness, including its pathologies and other altered states. Second, LD could be used as a therapy for recurrent nightmares, a common symptom of depression and post-traumatic stress disorder. Finally, LD may allow for motor imagery during dreaming with possible improvement of physical rehabilitation. In all, we believe that LD research may clarify multiple aspects of brain functioning in its physiological, altered and pathological states. 23465511 Polymer analysis by supercritical fluid chromatography. Synthetic polymers always have distributions of the degrees of polymerization. Supercritical fluid chromatography (SFC) is almost only one technique to be able to separate pure polymer that has exactly unique degree of polymerization. For typical examples of SFC separation of polymers, four kinds of polymers: polystyrene, poly(ethylene glycol), some nonionic surfactants, and polyprenol are described about the conditions of SFC. Separated pure polymers which have no molecular weight distribution, are called uniform polymer. Uniform polymers are really useful to calibrate or validate various detectors. Here, the applications of calibrating ultraviolet detector, evaporative light scattering detector, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry are summarized. These detectors have strong molecular weight dependence of their sensitivity coefficient, in contrast to the good linearity of sample concentration. 23459442 COMT Val158Met modulates subjective responses to intravenous nicotine and cognitive performance in abstinent smokers. The catechol-O-methyltransferase (COMT) Val158Met polymorphism may be a risk factor for nicotine addiction. This study examined the influence of the COMT Val158Met polymorphism on subjective, physiological and cognitive effects of intravenous (IV) nicotine use in African Americans (AAs; n=56) and European Americans (EAs; n=68) smokers. Overnight abstinent smokers received saline followed by 0.5 and 1.0 mg per 70 kg doses of nicotine, administered 30 min apart. Smokers with valine (Val)/Val genotype, compared with methionine (Met) carriers, had greater negative subjective effects from IV nicotine and had more severe withdrawal severity following overnight abstinence from smoking. Women with Val/Val genotype reported greater difficulty concentrating and irritability than men with Val/Val or Met carrier genotypes. The Val/Val genotype was associated with better performance on the math task and in AA smokers it was associated with greater systolic blood pressure. These results support the rationale of pharmacologically inhibiting COMT to aid with smoking cessation among Val/Val genotype smokers.The Pharmacogenomics Journal advance online publication, 5 March 2013; doi:10.1038/tpj.2013.1. 23695435 Colonization of Madagascar periwinkle (Catharanthus roseus), by endophytes encoding gfp marker. This study reports the introduction of gfp marker in two endophytic bacterial strains (Pantoea agglomerans C33.1, isolated from cocoa, and Enterobacter cloacae PR2/7, isolated from citrus) to monitor the colonization in Madagascar perinwinkle (Catharanthus roseus). Stability of the plasmid encoding gfp was confirmed in vitro for at least 72 h of bacterial growth and after the colonization of tissues, under non-selective conditions. The colonization was observed using fluorescence microscopy and enumeration of culturable endophytes in inoculated perinwinkle plants that grew for 10 and 20 days. Gfp-expressing strains were re-isolated from the inner tissues of surface-sterilized roots and stems of inoculated plants, and the survival of the P. agglomerans C33:1gfp in plants 20 days after inoculation, even in the absence of selective pressure, suggests that is good colonizer. These results indicated that both gfp-tagged strains, especially P. agglomerans C33.1, may be useful tools to deliver enzymes or other proteins in plant. 23896170 Exploration of hydrophobic modification degree of chitosan-based nanocomplexes on the oral delivery of enoxaparin. The objective of this paper is to elucidate the influence of lipophilic modification degree of chitosan on the peroral absorption of enoxaparin. A series of novel chitosan grafted glyceryl monostearate (GM) copolymers with different GM substitution degree were synthesized and the successful synthesis was confirmed by (1)H NMR, FTIR and X-ray diffraction. Enoxaparin loaded nanocomplexes with different carriers were prepared by self-assembly process. Influence of GM substitution degree and chitosan molecular weight in the copolymer on the properties of the nanocomplexes was investigated. Morphology of the nanocomplexes was observed by atomic force microscopy. Mucoadhesive properties of the nanocomplexes were characterized using mucin particle method. Initially, mucoadhesion of the nanocomplexes increased with the increase of GM substitution degree and it started to decrease when the substitution degree was up to 18.6%. A good linear relationship between GM substitution degree and in vivo absorption of enoxaparin in fasted rats was established in the substitution degree range of 0-11.1%. In agreement with mucoadhesion data, further increasing GM substitution degree to 18.6% caused a decrease in oral absorption. In conclusion, oral bioavailability of enoxaparin can be enhanced by structure modification of the carriers and the bioavailability is hydrophobic modification degree dependent. 22799538 β-Orcinol-type depsides from the lichen Thamnolia vermicularis. A phytochemical investigation of a herb tea made from Thamnolia vermicularis led to the isolation of three new β-orcinol-type depsides (1, 2 and 3), along with seven known compounds hypothamnolic acid (4), 3'-methylevenic acid (5), baeomycesic acid (6), squamatic acid (7), methyl 3'-methyllecanorate (8), barbatinic acid (9) and atranorin (10). The structures of the new compounds were determined on the basis of spectroscopic evidence, including 1-D and 2-D NMR and ESI-MS techniques. 23932105 Piggyback multifocal IOLs for a hyperopic-presbyopic surprise after cataract surgery in high myopic patients. To demonstrate the utility of piggyback multifocal intraocular lenses (IOLs) for a hyperopic-presbyopic surprise after cataract surgery in highly myopic patients. Case report. A 43-year-old woman with high myopia presented with dense subcapsular cataracts. The IOL power calculated with the Haigis formula gave a lens of -7D for emmetropia in the right eye. The refractive result was a spherical equivalent refractive error of +2.25. To overcome refractive surprise, a refractive multifocal +3D Sulcoflex 653F with an additional 3.5D for near vision was implanted, achieving a best-corrected visual acuity of 20/40. The lens offered her good intermediate vision for computer work. With a Sulcoflex IOL, it is possible to achieve good near-intermediate visual acuity and spectacle independence, especially in highly myopic eyes with good near visual acuity. In addition, the implantation of these IOLs might correct residual refractive errors following previous implantation of a monofocal IOL. 23868102 Cost Effectiveness of Denosumab versus Oral Bisphosphonates for Postmenopausal Osteoporosis in the US. In the US, 26 % of women aged ≥65 years, and over 50 % of women aged ≥85 years are affected with postmenopausal osteoporosis (PMO). Each year, the total direct health care costs are estimated to be $US12-18 billion. The cost effectiveness of denosumab versus oral bisphosphonates in postmenopausal osteoporotic women from a US third-party payer perspective was evaluated. A lifetime cohort Markov model was developed with seven health states: 'well', hip fracture, vertebral fracture, 'other' osteoporotic fracture, post-hip fracture, post-vertebral fracture, and dead. During each cycle, patients could have a fracture, remain healthy, remain in a post-fracture state or die. Relative fracture risk reductions, background fracture risks, mortality rates, treatment-specific persistence rate, utilities, and medical and drug costs were derived using published sources. Expected costs and quality-adjusted life years (QALYs) were estimated for generic alendronate, denosumab, branded risedronate, and branded ibandronate in the overall PMO population and high-risk subgroups: (a) ≥2 of the following risks: >70 years of age, bone mineral density (BMD) T score less than or equal to -3.0, and prevalent vertebral fracture; and (b) ≥75 years of age. Costs and QALYs were discounted at 3 % annually, and all costs were inflated to 2012 US dollars. Sensitivity analyses were conducted by varying parameters e.g., efficacies of interventions, costs, utilities, and the medication persistence ratio. In the overall PMO population, total lifetime costs for alendronate, denosumab, risedronate, and ibandronate were $US64,400, $US67,400, $US67,600 and $US69,200, respectively. Total QALYs were 8.2804, 8.3155, 8.2735 and 8.2691, respectively. The incremental cost-effectiveness ratio (ICER) for denosumab versus generic alendronate was $US85,100/QALY. Risedronate and ibandronate were dominated by denosumab. In the high-risk subgroup (a), total costs for alendronate, denosumab, risedronate and ibandronate were $US70,400, $US70,800, $US74,000 and $US76,900, respectively. Total QALYs were 7.2006, 7.2497, 7.1969 and 7.1841, respectively. Denosumab had an ICER of $US7,900/QALY versus generic alendronate and dominated all other strategies. Denosumab dominated all strategies in women aged ≥75 years. Base-case results between denosumab and generic alendronate were most sensitive to the relative risk of hip fracture for both drugs and the cost of denosumab. In each PMO population examined, denosumab represented good value for money compared with branded bisphosphonates. Furthermore, denosumab was either cost effective or dominant compared with generic alendronate in the high-risk subgroups. 23920024 Persons with multiple disabilities increase adaptive responding and control inadequate posture or behavior through programs based on microswitch-cluster technology. Study I used typical microswitch-cluster programs to promote adaptive responding (i.e., object manipulation) and reduce inappropriate head or head-trunk forward leaning with a boy and a woman with multiple disabilities. Optic, tilt, and vibration microswitches were used to record their adaptive responses while optic and tilt microswitches monitored their posture. The study included an ABB(1)AB(1) sequence, in which A represented baseline phases, B represented an intervention phase in which adaptive responses were always followed by preferred stimulation, and B(1) represented intervention phases in which the adaptive responses led to preferred stimulation only if the inappropriate posture was absent. Study II assessed a non-typical, new microswitch-cluster program to promote two adaptive responses (i.e., mouth cleaning to reduce drooling effects and object assembling) with a man with multiple disabilities. Initially, the man received preferred stimulation for each cleaning response. Then, he received stimulation only if mouth cleaning was preceded by object assembling. The results of Study I showed that both participants had large increases in adaptive responding and a drastic reduction in inappropriate posture during the B(1) phases and a 2-week post-intervention check. The results of Study II showed that the man learned to control drooling effects through mouth cleaning and used object assembling to extend constructive engagement and interspace cleaning responses functionally. The practical implications of the findings are discussed. 23937800 Rectal endoscopy findings following stereotactic body radiation therapy for clinically localized prostate cancer. Treating prostate cancer with SBRT could potentially minimize radiation proctitis by reducing high-dose rectal irradiation. In addition, it offers the potential radiobiologic benefits of hypofractionation. This study reports the endoscopic changes and the associated clinical rectal toxicity in these patients. We reviewed the records of patients treated from 2008--2011 for localized prostate cancer who had rectal endoscopy following SBRT. SBRT was delivered either as primary treatment in 5 fractions of 7--7.25 Gy, or as an initial boost in 3 fractions of 6.5 Gy followed by conventionally fractionated radiotherapy to 45--50.4 Gy. Endoscopic changes were graded using the Vienna Rectoscopy Score (VRS). Rectal toxicity was graded via CTCAEv.4. Rectal quality of life (QOL) was assessed via the bowel domain of the EPIC-26 questionnaire. Fifty-one patients with a median 23 months follow-up were analyzed. Thirty-five patients completed SBRT monotherapy and 16 patients received SBRT as a boost to conventionally fractionated IMRT. The median interval from SBRT to rectal endoscopy was 13 months. Endoscopy revealed VRS Grade 1--2 telangiectasias for 10 patients and VRS Grade 1--2 mucosal edema for 12 patients. No rectal ulcerations, strictures or necrosis were observed. Grade 1--2 late rectal bleeding occurred in 10 patients. There were no CTCAEv.4 Grade >=3 toxicities. Mean EPIC bowel scores decreased from a baseline value of 96.9 to 82.3 at 1-month, but subsequently increased to 91.0 at 24 months. In this cohort that is skewed towards patients with rectal complaints, the rate and severity of endoscopic changes following SBRT is low. Rectal toxicity and QOL were comparable to patients treated with other radiation modalities. Prospective trials examining the endoscopic outcomes following SBRT for prostate cancer are needed for confirmation of the findings of this study.Trial registration: The Georgetown Institutional Review Board has approved this retrospective study (IRB 2009--510). 23962076 Inequalities in multimorbidity in South Africa. Very little is known about socioeconomic related inequalities in multimorbidity, especially in developing countries. Traditionally, studies on health inequalities have mainly focused on a single disease condition or different conditions in isolation. This paper examines socioeconomic inequality in multimorbidity in illness and disability in South Africa between 2005 and 2008. Data were drawn from the 2005, 2006, 2007, and 2008 rounds of the nationally representative annual South African General Household Surveys (GHS). Indirectly standardised concentration indices were used to assess socioeconomic inequality. A proxy index of socioeconomic status was constructed, for each year, using a selected set of variables that are available in all the GHS rounds. Multimorbidity in illness and disability were constructed using data on nine illnesses and six disabilities contained in the GHS. Multimorbidity affects a substantial number of South Africans. Most often, based on the nine illness conditions and six disability conditions considered, multimorbidity in illness and multimorbidity in disability are each found to involve only two conditions. In 2008 in South Africa, the multimorbidity that affected the greatest number of individuals (0.6% of the population) combined high blood pressure (BP) with at least one other illness. The combination of sexually transmitted diseases (STDs) and other condition or conditions is the least reported (i.e. 0.02% of the population). Between 2005 and 2008, multimorbidity in illness and disability is more prevalent among the poor; in disabilities this is yet more consistent. The concentration index of multiple illnesses in 2005 and 2008 are -0.0009 and -0.0006 respectively. The corresponding values for multiple disabilities are -0.0006 and -0.0006 respectively. While there is a dearth of information on the socioeconomic distribution of multimorbidity in many developing countries, this paper has shown that its distribution in South Africa indicates that the poor bear a greater burden of multimorbidity. This is more so for disability than for illness. This paper argues that, given the high burden and skewed socioeconomic distribution of multimorbidity, there is a need to design policies to address this situation. Further, there is a need to design surveys that specifically assess multimorbidity. 22970858 Genetic toxicology of thallium: a review. This review summarizes the current knowledge about the general toxicity of thallium (Tl) and its environmental sources, with special emphasis placed on its potential mutagenic, genotoxic, and cytotoxic effects on both eukaryotic and prokaryotic cells. Tl is a nonessential heavy metal that poses environmental and occupational threats as well as therapeutic hazards because of its use in medicine. It is found in two oxidation states, thallous (Tl(+)) and thallic (Tl(3+)), both of which are considered highly toxic to human beings and domestic and wild organisms. Many Tl compounds are colorless, odorless and tasteless, and these characteristics, combined with the high toxicity of TI compounds, have led to their use as poisons. Because of its similarity to potassium ions (K(+)), plants and mammals readily absorb Tl(+) through the skin and digestive and respiratory systems. In mammals, it can cross the placental, hematoencephalic, and gonadal barriers. Inside cells, Tl can accumulate and interfere with the metabolism of potassium and other metal cations, mimicking or inhibiting their action. The effects of Tl on genetic material have not yet been thoroughly explored, and few existing studies have focused exclusively on Tl(+). Both in vivo and in vitro studies indicate that Tl compounds can have a weak mutagenic effect, but no definitive effect on the induction of primary DNA damage or chromosomal damage has been shown. These studies have demonstrated that Tl compounds are highly toxic and lead to changes in cell-cycle progression. 23876285 Suprasellar and sellar paraganglioma presenting as a nonfunctioning pituitary macroadenoma. It is extremely rare for paragangliomas to be present in the brain. We present a 44-year-old man with a suprasellar-sellar paraganglioma encasing the internal carotid arteries. We review all such tumors reported in the literature and conclude that paraganglioma should be kept in the differential diagnosis of unusual suprasellar-sellar lesions. 23826593 Fatty liver disease--a practical guide for GPs. Non-alcoholic fatty liver disease (NAFLD), encompassing both simple steatosis and non-alcoholic steato-hepatitis (NASH), is the most common cause of liver disease in Australia. Non-alcoholic fatty liver disease needs to be considered in the context of the metabolic syndrome, as cardiovascular disease will account for much of the mortality associated with NAFLD. To provide an approach to the identification of NAFLD in general practice, the distinction between simple steatosis and NASH, and the management of these two conditions. Non-alcoholic steato-hepatitis is more common in the presence of diabetes, obesity, older age and increased inflammation, and is more likely to progress to cirrhosis. Cirrhosis may be complicated by hepatocellular carcinoma or liver failure. Hepatocellular carcinoma has also been described in NASH without cirrhosis. Assessment and treatment of features of the metabolic syndrome may reduce associated cardiovascular mortality. Numerous agents have been evaluated, but weight loss remains the only effective treatment for NAFLD. 23353655 Sonhafouonic acid, a new cytotoxic and antifungal hopene-triterpenoid from Zehneria scabra camerunensis. A new hopene-type triterpenoid, namely sonhafouonic acid 1a was isolated from Zehneria scabra camerunensis, together with eight known compounds. The structure of 1a was established by extensive NMR and high resolution MS techniques and confirmed by single-crystal X-ray crystallographic analysis. Compound 1a exhibited inhibitory activity against mycelial growth of two peronosporomycete phytopathogens Pythium ultimum and Aphanomyces cochliodes and cytotoxicity towards brine shrimp larvae (Artemia salina) at 10 μg/mL. 23455323 Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor. Approximately 50% of melanomas depend on mutant B-RAF for proliferation, metastasis and survival. The inhibition of oncogenic B-RAF with highly targeted compounds has produced remarkable albeit short-lived clinical responses in B-RAF mutant melanoma patients. Reactivation of signaling downstream of B-RAF is frequently associated with acquired resistance to B-RAF inhibitors, and the identification of B-RAF targets may provide new strategies for managing melanoma. Oncogenic B-RAF(V600E) is known to promote the stabilizing phosphorylation of the anti-apoptotic protein Mcl-1, implicated in melanoma survival and chemoresistance. We now show that B-RAF(V600E) signaling also induces the transcription of Mcl-1 in melanocytes and melanoma. We demonstrate that activation of STAT3 serine-727 and tyrosine-705 phosphorylations is promoted by B-RAF(V600E) activity and that the Mcl-1 promoter is dependent on a STAT consensus-site for B-RAF-mediated activation. Consequently, suppression of STAT3 activity disrupted B-RAF(V600E)-mediated induction of Mcl-1 and reduced melanoma cell survival. We propose that STAT3 has a central role in the survival and contributes to chemoresistance of B-RAF(V600E) melanoma.Oncogene advance online publication, 4 March 2013; doi:10.1038/onc.2013.45. 23870017 Proximal subcutaneous migration of the distal end of a ventriculoperitoneal shunt presenting with recurrent cerebrospinal fluid galactorrhea. The authors report an unusual case of recurrent proximal migration of the distal end of a ventriculoperitoneal shunt catheter presenting as CSF galactorrhea. The authors review the pertinent literature and discuss the possible causes as well as techniques to prevent a similar occurrence. 23869090 Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts. To assess the associations between both uric acid levels and hyperuricaemia, with ischaemic heart disease and blood pressure, and to explore the potentially confounding role of body mass index. Mendelian randomisation analysis, using variation at specific genes (SLC2A9 (rs7442295) as an instrument for uric acid; and FTO (rs9939609), MC4R (rs17782313), and TMEM18 (rs6548238) for body mass index). Two large, prospective cohort studies in Denmark. We measured levels of uric acid and related covariables in 58 072 participants from the Copenhagen General Population Study and 10 602 from the Copenhagen City Heart Study, comprising 4890 and 2282 cases of ischaemic heart disease, respectively. Blood pressure and prospectively assessed ischaemic heart disease. Estimates confirmed known observational associations between plasma uric acid and hyperuricaemia with risk of ischaemic heart disease and diastolic and systolic blood pressure. However, when using genotypic instruments for uric acid and hyperuricaemia, we saw no evidence for causal associations between uric acid, ischaemic heart disease, and blood pressure. We used genetic instruments to investigate body mass index as a potentially confounding factor in observational associations, and saw a causal effect on uric acid levels. Every four unit increase of body mass index saw a rise in uric acid of 0.03 mmol/L (95% confidence interval 0.02 to 0.04), and an increase in risk of hyperuricaemia of 7.5% (3.9% to 11.1%). By contrast with observational findings, there is no strong evidence for causal associations between uric acid and ischaemic heart disease or blood pressure. However, evidence supports a causal effect between body mass index and uric acid level and hyperuricaemia. This finding strongly suggests body mass index as a confounder in observational associations, and suggests a role for elevated body mass index or obesity in the development of uric acid related conditions. 23777255 A click chemistry approach to 5,5'-disubstituted-3,3'-bisisoxazoles from dichloroglyoxime and alkynes: luminescent organometallic iridium and rhenium bisisoxazole complexes. 5,5'-Disubstituted-3,3'-bisisoxazoles are prepared in one step by the dropwise addition of aqueous potassium hydrogen carbonate to a mixture of dichloroglyoxime and terminal alkynes. The reaction exhibits a striking preference for the 5,5'-disubstituted 3,3'-bisisoxazole over the 4,5'-regioisomer. Organometallic iridium and rhenium bisisoxazole complexes are luminescent with emission wavelengths varying depending upon the identity of the 5,5'-substituent (phenyl, butyl). 23963426 Committee opinion no. 574: marriage equality for same-sex couples. : Same-sex couples encounter barriers to health care that include concerns about confidentiality and disclosure, stigma and discriminatory attitudes and treatment, limited access to health care and health insurance, and often a limited understanding of their health risks. Same-sex couples and their families are adversely affected by the lack of legal recognition of their relationships, a problem with major implications for the health of same-sex couples and their families. Tangible harm has come from the lack of financial and health care protections granted to legal spouses, and children are harmed by the lack of protections afforded to families in which partners are married. However, the recent Supreme Court ruling, The United States v Windsor, which afforded equal treatment for legally married same-sex couples will provide many important health and financial benefits. Evidence suggests that marriage confers health benefits to individuals and families, yet a sizable proportion of individuals do not experience these health benefits because of their sexual orientation. Additional data suggest that same-sex couples who live in states with bans on same-sex unions experience adverse health outcomes. Civil marriage is currently available to same-sex couples in only thirteen states and the District of Columbia and honored by one state. The American College of Obstetricians and Gynecologists endorses marriage equality for same-sex couples and equal treatment for these couples and their families and applauds the Supreme Court's decision as an important step in improving access to benefits received by legally married same-sex couples. However, additional efforts are necessary to ensure that same-sex couples in every state can receive these same benefits. 23848994 Syntheses, Structures, and Nonlinear Optical Properties of Quaternary Chalcogenides: Pb4Ga4GeQ12 (Q = S, Se). Two noncentrosymmetric isostructural compounds Pb4Ga4GeQ12 (Q = S, Se) with their own structure type have been synthesized by solid-state reactions at high temperature. They crystallize in the tetragonal space group P4̅21c (No. 114) with a = 12.673(2) Å and c = 6.128(2) Å, and a = 13.064(7) Å and c = 6.310(5) Å, respectively, and Z = 2. The major structure motif features a three-dimensional framework constructed by chains of GaQ4 tetrahedra that are interconnected by separated GeQ4 tetrahedra at regular intervals. Interestingly, such a [Ga4GeQ12](8-) framework is flexible to allow the addition of Ag(+) or Li(+) to occupy the embedded A- or B-type of vacancies to generate the previously reported [AgGa5Q12](7-) or [LiGa5Q12](7-) interstitial compounds without symmetry breaking. The title compounds (Q = S, Se) have optical band gaps of 2.35 and 1.91 eV, respectively, and wide IR transparent regions of 0.80-22.5 and 0.75-22.5 μm, respectively. Significantly, the powder Pb4Ga4GeSe12 sample exhibits a strong second-harmonic-generation (SHG) response that is ∼2 times that of the benchmark AgGaS2 at a laser radiation of 2.05 μm with a non phase-matchable behavior. The calculated d36 coefficient agrees well with the experimental observation. The density functional theory (DFT) calculations suggest that the SHG response originates from the electronic transitions from Se 4p states to Pb 6p, Ga 4p, and Ge 4p states. 23800513 Ailing bones and failing kidneys: a case of chronic cadmium toxicity. Heavy metal toxicity is often caused by occupational exposure. Chronic cadmium toxicity is a significant health concern among workers engaged in zinc smelting, battery production and silver jewellery industries, particularly in developing countries. We report the case of a 48-year-old man who presented with severe osteoporosis, impaired renal function and acquired Fanconi syndrome. He was finally diagnosed with chronic cadmium toxicity resulting from long-term occupational exposure. Cadmium has a long biological half-life and there is no effective treatment for people who are exposed to it. Therefore, an early diagnosis and prevention of further exposure are important. 23237013 Estimating the heritability of reporting stressful life events captured by common genetic variants. Although usually thought of as external environmental stressors, a significant heritable component has been reported for measures of stressful life events (SLEs) in twin studies. Method We examined the variance in SLEs captured by common genetic variants from a genome-wide association study (GWAS) of 2578 individuals. Genome-wide complex trait analysis (GCTA) was used to estimate the phenotypic variance tagged by single nucleotide polymorphisms (SNPs). We also performed a GWAS on the number of SLEs, and looked at correlations between siblings. A significant proportion of variance in SLEs was captured by SNPs (30%, p = 0.04). When events were divided into those considered to be dependent or independent, an equal amount of variance was explained for both. This 'heritability' was in part confounded by personality measures of neuroticism and psychoticism. A GWAS for the total number of SLEs revealed one SNP that reached genome-wide significance (p = 4 Ã— 10-8), although this association was not replicated in separate samples. Using available sibling data for 744 individuals, we also found a significant positive correlation of R 2 = 0.08 in SLEs (p = 0.03). These results provide independent validation from molecular data for the heritability of reporting environmental measures, and show that this heritability is in part due to both common variants and the confounding effect of personality. 23561168 Cultivar variations in antioxidant and antihyperlipidemic properties of pomelo pulp (Citrus grandis [L.] Osbeck) in Thailand. Pomelo (Citrus grandis L. Osbeck) is a native fruit of great economic importance in Southeast Asia. To provide experimental evidence for the antioxidant and antihyperlipidemic properties of pomelo, 6 cultivars, including Kao-Yai (KY), Thong-dee (TD), Kao-Tangkwa (KT), Kao-Numpueng (KN), Ta-Koi (TK), and Tubtim Siam (TS) were evaluated. KY had the highest phenolic content, and the strongest 1,1-diphenyl-2-pireyhydrazyl radical scavenging capacity and hydroxyl radical scavenging activity. From the high-performance liquid chromatography analysis, naringin and naringenin were the major flavonoids in the KT and TK cultivars. Six pomelo cultivars had antihyperlipidemic activities including the inhibition of pancreatic lipase and cholesterol esterase, as well as cholesterol micelle formation and bile acid binding. Hierarchical clustering analysis showed that the 6 cultivars were separated into 2 classifications. In addition, the total phenolics of the pomelo cultivars were significantly correlated with ferric reducing antioxidant power and Trolox equivalent antioxidant capacity. The results suggest that pomelo provides significant health benefits and may be used for developing functional foods. 23845745 A systematic review of diffusion weighted MRI studies of white matter microstructure in adolescent substance users. Recent studies using diffusion weighted magnetic resonance imaging (DW-MRI) have provided evidence of abnormal white matter microstructure in adults with substance use disorders (SUDs). While there is a growing body of research using DW-MRI to examine the impact of heavy substance use during adolescence, this literature has not been systematically reviewed. Online databases were searched for DW-MRI studies of adolescent substance users, and 10 studies fulfilled the inclusion and exclusion criteria. We identified consistent evidence for abnormal white matter microstructure in neocortical association pathways as well as in projection and thalamic pathways. Dose-dependent relationships between DW-MRI measures and patterns of substance use were also observed. The consistency of these findings with DW-MRI research in adults suggests that white matter microstructure is impacted in the early stages of heavy substance use. However, given the largely cross-sectional nature of the available data, important questions remain regarding the extent to which white matter abnormalities are a consequence of adolescent exposure to alcohol and other drugs of abuse or reflect pre-existing differences that increase risk for SUDs. 23885867 Multiple Mechanisms Contribute to Centriole Separation in C. elegans. Centrosome function in cell division requires their duplication, once, and only once, per cell cycle. Underlying centrosome duplication are alternating cycles of centriole assembly and separation [1]. Work in vertebrates has implicated the cysteine protease separase in anaphase-coupled centriole separation (or disengagement) and identified this as a key step in licensing another round of assembly [2]. Current models have separase cleaving a physical link between centrioles, potentially cohesin [3, 4], that prevents reinitiation of centriole assembly unless disengaged. Here, we examine separase function in the C. elegans early embryo. We find that depletion impairs separation and consequently duplication of sperm-derived centrioles at the meiosis-mitosis transition. However, subsequent cycles proceed normally. Whereas mitotic centrioles separate in the context of cortical forces acting on a disassembling pericentriolar material, sperm centrioles are not associated with significant pericentriolar material or subject to strong forces. Increasing centrosomal microtubule nucleation restores sperm centriole separation and duplication in separase-depleted embryos, while forced pericentriolar material disassembly drives premature separation in mitosis. These results emphasize the critical role of cytoskeletal forces and the pericentriolar material in centriole separation. Separase contributes to separation where forces are limited, offering a potential explanation for results obtained in different experimental models [5-7]. 23784880 Doping of organic semiconductors: impact of dopant strength and electronic coupling. Molecular doping: The standard model for molecular p-doping of organic semiconductors (OSCs) assumes integer charge transfer between OSC and dopant. This is in contrast to an alternative model based on intermolecular complex formation instead. By systematically varying the acceptor strength it was possible to discriminate the two models. The latter is clearly favored, suggesting strategies for the chemical design of more efficient molecular dopants. 23841577 Detection of Anti-HLA Antibodies in Maternal Blood in the Second Trimester to Identify Patients at Risk of Antibody-Mediated Maternal Anti-Fetal Rejection and Spontaneous Preterm Delivery. Maternal anti-fetal rejection is a mechanism of disease in spontaneous preterm labor. The objective of this study was to determine whether the presence of human leukocyte antigen (HLA) panel-reactive antibodies (PRA) during the second trimester increases the risk of spontaneous preterm delivery. This longitudinal case-control study included pregnant women with spontaneous preterm deliveries (n = 310) and control patients with normal term pregnancies (n = 620), matched for maternal age and gravidity. Maternal plasma samples obtained at 14-16, 16-20, 20-24, and 24-28 weeks of gestation were analyzed for HLA class I and class II PRA positivity using flow cytometry. The fetal HLA genotype and maternal HLA alloantibody epitope were determined for a subset of patients with positive HLA PRA. (i) Patients with spontaneous preterm delivery were more likely to exhibit HLA class I (adjusted OR = 2.54, P < 0.0001) and class II (adjusted OR = 1.98, P = 0.002) PRA positivity than those delivering at term; (ii) HLA class I PRA positivity for patients with spontaneous preterm delivery between 28 and 34 weeks (adjusted OR = 2.88; P = 0.001) and after 34 weeks of gestation (adjusted OR = 2.53; P < 0.0001) was higher than for those delivering at term; (iii) HLA class II PRA positivity for patients with spontaneous preterm delivery after 34 weeks of gestation was higher than for those delivering at term (adjusted OR = 2.04; P = 0.002); (iv) multiparous women were at a higher risk for HLA class I PRA positivity than nulliparous women (adjusted OR = 0.097, P < 0.0001 for nulliparity); (v) nulliparous women had a higher rate of HLA class I PRA positivity with advancing gestational age (P = 0.001); and (vi) 78% of women whose fetuses were genotyped had alloantibodies specific against fetal HLA class I antigens. Pregnant women with positive HLA class I or class II PRA during the second trimester are at an increased risk of spontaneous preterm delivery due to antibody-mediated maternal anti-fetal rejection. 23252711 Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity. Cyclin-dependent kinase 9/cyclin T, the protein kinase heterodimer that constitutes positive transcription elongation factor b, is a well-validated target for treatment of several diseases, including cancer and cardiac hypertrophy. In order to aid inhibitor design and rationalize the basis for CDK9 selectivity, we have studied the CDK-binding properties of six different members of a 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series that bind to both CDK9/cyclin T and CDK2/cyclin A. We find that for a given CDK, the melting temperature of a CDK/cyclin/inhibitor complex correlates well with inhibitor potency, suggesting that differential scanning fluorimetry (DSF) is a useful orthogonal measure of inhibitory activity for this series. We have used DSF to demonstrate that the binding of these compounds is independent of the presence or absence of the C-terminal tail region of CDK9, unlike the binding of the CDK9-selective inhibitor 5,6-dichlorobenzimidazone-1-β-d-ribofuranoside (DRB). Finally, on the basis of 11 cocrystal structures bound to CDK9/cyclin T or CDK2/cyclin A, we conclude that selective inhibition of CDK9/cyclin T by members of the 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series results from the relative malleability of the CDK9 active site rather than from the formation of specific polar contacts. 23274539 α-Terpineol induces fatty liver in mice mediated by the AMP-activated kinase and sterol response element binding protein pathway. The use of herbal medicines in disease prevention and treatment is growing rapidly worldwide, without careful consideration of safety issues. α-Terpineol is a monoterpene alcoholic component of Melaleuca alternifolia, Salvia officinalis and Carthamus tinctorius that is used widely as a flavor and essential oil in food. The present study showed that α-terpineol induces fatty liver via the AMP-activated protein kinase (AMPK)-mTOR-sterol regulatory element-binding protein-1 (SREBP-1) pathway. α-Terpineol-treated hepatocytes had significantly increased neutral lipid accumulation. α-Terpineol suppressed AMPK phosphorylation, and increased p70S6 kinase (p70S6K) phosphorylation and SREBP-1 activation. It also increased luciferase activity in cells transfected with LXRE-tk-Luc and SRE-tk-Luc. Inhibition of mTOR signaling by co-treatment with rapamycin or co-transfection with dominant negative p70S6K blocked completely the effects of α-terpineol. α-Terpineol oral administration to mice for 2weeks led to decreased AMPK phosphorylation and increased SREBP-1 activation in the liver, followed by hepatic lipid accumulation. Conversely, rapamycin co-treatment reversed α-terpineol-induced SREBP-1 activation and fatty liver in mice. These data provide evidence that α-terpineol causes fatty liver, an effect mediated by the AMPK/mTOR/SREBP-1 pathway. 23959766 Extending JAGS: A tutorial on adding custom distributions to JAGS (with a diffusion model example). We demonstrate how to add a custom distribution into the general-purpose, open-source, cross-platform graphical modeling package JAGS ("Just Another Gibbs Sampler"). JAGS is intended to be modular and extensible, and modules written in the way laid out here can be loaded at runtime as needed and do not interfere with regular JAGS functionality when not loaded. Writing custom extensions requires knowledge of C++, but installing a new module can be highly automatic, depending on the operating system. As a basic example, we implement a Bernoulli distribution in JAGS. We further present our implementation of the Wiener diffusion first-passage time distribution, which is freely available at https://sourceforge.net/projects/jags-wiener/ . 23952242 The Synthesis of Indoline and Benzofuran Scaffolds Using a Suzuki-Miyaura Coupling/Oxidative Cyclization Strategy. The generation of indolines and benzofurans from the combination of Suzuki-Miyaura coupling reactions with oxidative cyclizations is described. 23332355 Sustained impairment of α2A-adrenergic autoreceptor signaling mediates neurochemical and behavioral sensitization to amphetamine. In rodents, drugs of abuse induce locomotor hyperactivity, and repeating injections enhance this response. This effect, called behavioral sensitization, persists months after the last administration. It has been shown that behavioral sensitization to amphetamine develops parallel to an increased release of norepinephrine (NE) in the prefrontal cortex (PFC). Rats and mice were repeatedly treated with amphetamine (1 or 2 mg/kg intraperitoneally, respectively) to obtain sensitized animals. The NE release in the PFC was measured by microdialysis in freely moving mice (n = 55). Activity of locus coeruleus (LC) noradrenergic neurons was determined in anaesthetized rats (n = 15) by in vivo extracellular electrophysiology. The α2A-adrenergic autoreceptor (α2A-AR) expression was assessed by autoradiography on brain slices, and Gαi proteins expression was measured by western blot analysis of LC punches. In sensitized rats LC neurons had a higher spontaneous firing rate, and clonidine-an α2A-adrenergic agonist-inhibited LC neuronal firing less efficiently than in control animals. Clonidine also induced lower levels of NE release in the PFC of sensitized mice. This desensitization was maintained by a lower density of Gαi1 and Gαi2 proteins in the LC of sensitized mice rather than weaker α2A-AR expression. Behavioral sensitization was facilitated by α2A-AR antagonist, efaroxan, during amphetamine injections and abolished by clonidine treatment. Our data indicate that noradrenergic inhibitory feedback is impaired for at least 1 month in rats and mice repeatedly treated with amphetamine. This work highlights the key role of noradrenergic autoreceptor signaling in the persistent modifications induced by repeated amphetamine administration. 23691916 Vegetation limits the impact of a warm climate on boreal wildfires. Strategic introduction of less flammable broadleaf vegetation into landscapes was suggested as a management strategy for decreasing the risk of boreal wildfires projected under climatic change. However, the realization and strength of this offsetting effect in an actual environment remain to be demonstrated. Here we combined paleoecological data, global climate models and wildfire modelling to assess regional fire frequency (RegFF, i.e. the number of fires through time) in boreal forests as it relates to tree species composition and climate over millennial time-scales. Lacustrine charcoals from northern landscapes of eastern boreal Canada indicate that RegFF during the mid-Holocene (6000-3000 yr ago) was significantly higher than pre-industrial RegFF (ad c. 1750). In southern landscapes, RegFF was not significantly higher than the pre-industrial RegFF in spite of the declining drought severity. The modelling experiment indicates that the high fire risk brought about by a warmer and drier climate in the south during the mid-Holocene was offset by a higher broadleaf component. Our data highlight an important function for broadleaf vegetation in determining boreal RegFF in a warmer climate. We estimate that its feedback may be large enough to offset the projected climate change impacts on drought conditions. 23890029 A 2-year-old girl with co-inherited cystic fibrosis and sickle cell-β+ thalassemia presenting with recurrent vaso-occlusive events during cystic fibrosis pulmonary exacerbations: a case report. This is the first published report of a young girl with co-inherited sickle cell-β+ thalassemia and cystic fibrosis. Although a small subset of patients with co-inherited cystic fibrosis and other hemoglobinopathies have been reported, this patient developed early hematologic and pulmonary complications that were more severe than the previous cases. To assess pulmonary co-morbidities, we used infant pulmonary function testing through the raised volume rapid thoracoabdominal compression technique as both an established study of early cystic fibrosis and also as a newer study of mechanism for early sickle cell lung disease. This further serves as the first report of the raised volume rapid thoracoabdominal compression technique to determine raised volume forced expiratory flows and fractional lung volumes in a patient with a hemoglobinopathy. A 2-year-old African-American girl with co-inherited cystic fibrosis and sickle cell-β+ thalassemia developed severe hematologic complications (recurrent vaso-occlusive events, hepatic sequestration, and acute chest syndrome) during periods of cystic fibrosis pulmonary exacerbations and weight loss. Because cystic fibrosis and sickle cell-β+ thalassemia both confer distinct patterns of pulmonary disease, infant pulmonary function testing with the raised volume rapid thoracoabdominal compression technique was used to define respiratory pathophysiology and guide treatment options. Infant pulmonary function testing data demonstrated moderate-to-severe lower airways obstruction, moderate air trapping, and no evidence of restrictive lung disease. Infant pulmonary function testing with the raised volume rapid thoracoabdominal compression technique guided therapy in this patient with cystic fibrosis and sickle cell-β+ thalassemia. Although this is an original case report on a unique patient, this case highlights the need to evaluate early respiratory pathophysiology in a broader population of young patients with hemoglobinopathies and screen those at risk for early pulmonary co-morbidities. 23895695 Prenatal and childhood antecedents of suicide: 50-year follow-up of the 1958 British Birth Cohort Study. We aimed to elucidate early antecedents of suicide including possible mediation by early child development. Method Using the 1958 birth cohort, based on British births in March 1958, individuals were followed up to adulthood. We used data collected at birth and at age 7 years from various informants. Suicides occurring up to 31 May 2009 were identified from linked national death certificates. Multivariable Cox proportional hazard models were used to investigate risk factors. Altogether 12399 participants (n = 44 suicides) had complete data. The strongest prenatal risk factors for suicide were: birth order, with risk increasing in later-born children [p trend = 0.063, adjusted hazard ratio (HR)], e.g. for fourth- or later-born children [HR = 2.27, 95% confidence interval (CI) 0.90-5.75]; young maternal age (HR = 1.18, 95% CI 0.34-4.13 for ⩽19 years and HR = 0.41, 95% CI 0.19-0.91 for >29 years, p trend = 0.034); and low (<2.5 kg) birth weight (HR = 2.48, 95% CI 1.03-5.95). The strongest risk factors at 7 years were externalizing problems in males (HR = 2.96, 95% CI 1.03-8.47, p trend = 0.050) and number of emotional adversities (i.e. parental death, neglected appearance, domestic tension, institutional care, contact with social services, parental divorce/separation and bullying) for which there was a graded association with risk of suicide (p trend = 0.033); the highest (HR = 3.12, 95% CI 1.01-9.62) was for persons with three or more adversities. Risk factors recorded at birth and at 7 years may influence an individual's long-term risk of suicide, suggesting that trajectories leading to suicide have roots in early life. Some factors are amenable to intervention, but for others a better understanding of causal mechanisms may provide new insights for intervention to reduce suicide risk. 23881745 Cover image, volume 34, issue 23. The picture shows the density of the binding 6s orbital combination for the most stable predicted planar D2h Au10 cluster, presented by Daniel A. Götz, Rolf Schäfer, and Peter Schwerdtfeger on page 1975. The bonding molecular orbital lies deep within the 5d space of gold due to relativistic effects stabilizing planar structures. The isomeric three-dimensional C2v structure lies close by in energy, making a prediction for the most stable geometric structure very difficult for quantum chemical methods. 23702791 Impact of the moon on cerebral aneurysm rupture. Several external and internal risk factors for cerebral aneurysm rupture have been identified to date. Recently, it has been reported that moon phases correlate with the incidence of aneurysmal subarachnoid hemorrhage (SAH), however, another author found no such association. Therefore, the present study investigates the influence of the lunar cycle on the incidence of aneurysmal rupture, the initial clinical presentation, and the amount of subarachnoid blood. Lunar phase and the particular day of the lunar cycle were correlated to the date of aneurysm rupture, aneurysm location, initial clinical presentation, and amount of subarachnoid blood assessed from CT scans of all patients treated for basal SAH in our department from 2003 to 2010. We found no correlation between incidence of aneurysmal SAH, location of the aneurysm, initial clinical presentation, or amount of subarachnoid blood and the lunar cycle. The moon influences neither the incidence of aneurysmal SAH nor the grade of initial neurological deterioration or amount of subarachnoid blood. 23829999 What happens to depressed adolescents? A follow-up study into early adulthood. This study describes the mental illness and psychosocial outcomes of adolescents who experienced a depressive disorder and identifies predictors of full remission and recurrence. 140 adolescents with major depressive disorder, dysthymic disorder, or depressive disorder NOS were offered psychosocial and/or antidepressant treatment across two clinical trials. Three to nine years later (mean 5.7 years), 111 adolescents and young adults completed self-, parent- and clinician-reported measures of psychopathology and psychosocial functioning in a naturalistic follow-up study. The Structured Clinical Interview for DSM-IV Axis 1 Disorders was used to determine the presence or absence of depressive disorder as well as other Axis 1 Disorders. By the follow-up assessment, most adolescents made a full remission from their index depressive disorder (92.6%). Recurrence of depressive disorder (52.4%) during the follow-up period was common, as was the experience of other disorders including anxiety, substance abuse and eating disorders. Time to full remission and recurrence did not vary between baseline types of depressive disorder. Self-reported depressive symptoms and anxiety disorder were associated with failure to achieve full remission while socio-economic status, self-reported self-efficacy and depressive symptoms were associated with recurrence of depressive disorder. Due to different treatment starting times, the length of the follow up period varied by up to 5.2 years. Adolescents who experience depressive disorder are at high risk of ongoing mental illness and psychosocial impairment. Predictors of the course of depressive disorder may be of use in determining which adolescents may require more intensive intervention. 23842938 The impact of electronic health records on people with diabetes in three different emergency departments. To evaluate if electronic health records (EHR) with prior clinical information have observable effects for patients with diabetes presenting to emergency departments (ED), we examined measures of quality and resource utilization. Retrospective observational studies of patients in three ED (A=5510; B=4393; C=3324) were conducted comparing patients with prior information in the EHR to those without such information. Differences with respect to hospitalization, mortality, length of stay (LOS), and numbers of ED orders for tests, procedures and medications were examined after adjusting for age, gender, race, marital status, comorbidities and for acuity level within each ED. There were 7% fewer laboratory test orders at one ED and 3% fewer at another; fewer diagnostic procedures were performed at two of the sites. At one site 36% fewer medications were ordered. The odds of being hospitalized were lower for EHR patients at one site and hospital LOS was shorter at two of the sites. EHR patient ED LOS was 18% longer at one site. There was no demonstrable impact of an EHR on mortality. Results varied in magnitude and direction by site. The pattern of significant results varied by ED but tended to reveal reduced utilization and better outcomes for patients although EHR patients' ED LOS was longer at one site. The presence of prior information in an EHR may be a valuable adjunct in the care of diabetes patients in ED settings but the pattern of impact may vary from ED to ED. 23863700 The integration of the detection of systemic sclerosis-associated antibodies in a routine laboratory setting: comparison of different strategies. Abstract Background: Detection of systemic sclerosis-associated autoantibodies (SSc-Ab) is mostly restricted to anti-centromere and anti-topoisomerase-I. However, anti-RNA-polymerase-III and anti-PM/Scl are also important diagnostic markers for the disease supporting their incorporation in the laboratory repertoire. The aim of this study was to compare different testing strategies integrating the identification of these extra SSc-Ab in a routine testing algorithm. Methods: Sera from 144 consecutive SSc-patients and 265 controls were screened for antinuclear antibodies (ANA) by indirect immunofluorescence (ANA IIF) and tested for anti-extractable nuclear antigen (ENA) using five different assays that differ in their ability to detect SSc-Ab [two screening enzyme immunossays (EIA) with antigen mixtures, one multi-parameter line-immunoassay and two EIA with individual antigens]. Results: The application of SSc-Ab testing in cascade with the routine ANA/anti-ENA tests improved diagnostic performance characteristics. Besides the type of algorithm, also the number of antigens included in the screening EIA as well as the expected patient/control ratio, influenced the average expected costs and the number of additional SSc-Ab tests to be performed. In laboratories with an expected patient/control ratio of 0.002, cascade testing was most exploited by the use of a screening EIA that included all SSc-Ab as a secondary test after ANA IIF. Conclusions: Restriction of the performance of additional SSc-Ab assays based on the results of prior ANA/anti-ENA tests is a cost-effective strategy allowing optimized use of laboratory resources with minimal loss in diagnostic capacity. 23884319 Menthol Cigarette and Marijuana Use Among Adolescents. Menthol cigarette and marijuana use among adolescents is high; however, little is known about dual use in this age. Thus, we examined these rates among 2 samples of adolescents in Connecticut. Study 1 examined a school-wide survey assessing variables related to cigarettes and marijuana among high school students (N = 837 [13% smokers]) and Study 2 examined these factors using baseline data of high school-aged, treatment-seeking, daily cigarette smokers prior to quitting (N = 132). In Study 1, lifetime marijuana use among all adolescents was 33% and past 30-day marijuana use was 21%. Among cigarette smokers, 55% reported smoking menthol cigarettes, 84% reported lifetime marijuana use, and 66% reported past 30-day marijuana use. Multivariate-adjusted logistic regression models indicated that cigarette smokers, when compared with nonsmokers, had greater rates of lifetime (odds ratio [OR] = 10.91) and past 30-day marijuana use (OR = 10.44). Among smokers, use of menthol cigarettes, when compared with use of nonmenthol cigarettes, was associated with greater lifetime (OR = 5.05) but not past 30-day marijuana use. In Study 2 with daily smokers, 59% of adolescents reported use of menthol cigarettes and 66% reported past 30-day marijuana use. Compared with nonmenthol cigarette smokers, menthol cigarette smokers were more likely to report past 30-day marijuana use (OR = 2.44). Cigarette smoking is associated with marijuana use, and among smokers, menthol cigarette smoking further increased the odds of marijuana use. More research on the dual use of marijuana and tobacco is needed to inform prevention and treatment of substance use. 23859343 Erythropoietin in Friedreich ataxia. In Friedreich ataxia (FRDA), several candidate substances including erythropoietin (EPO) focus on increase in the amount of frataxin and aim to counteract the consequences of frataxin deficiency. Evidence for recombinant human erythropoietin (rHuEPO) in FRDA is based on in vitro studies using mouse neuronal cell lines, human fibroblasts, cardiomyocytes, and primary lymphocytes from FRDA patients or control subjects which showed a dose-dependent increase of frataxin after incubation with different erythropoietins. The mechanism by which EPO induces frataxin increase remains to be elucidated, but may involve post-transcriptional and/or post-translational modifications of frataxin or alterations in frataxin half-life and metabolism. In vivo data on rHuEPO's ability to increase frataxin in FRDA patients is contradictory as studies on the effect of EPO derivatives in FRDA differ in treatment regimen, sample size, and duration. Open-label studies indicate for sustained frataxin increase, decrease of oxidative stress, and clinical improvement in FRDA patients after administration of rHuEPO. Two randomized controlled studies found acceptable safety and tolerability of EPO derivatives in FRDA. Secondary outcome measures, however, such as frataxin up-regulation and clinical efficacy were not met. This review will focus on (i) pre-clinical work on erythropoietins in FRDA and (ii) clinical studies in FRDA patients exposed to erythropoietins. 23963051 Skin discolouration with acute onset parkinsonism secondary to systemic zirconium intoxication. A 72-year-old woman presented with suspected parkinsonism and discolouration of the skin especially on sun-exposed areas. Thorough investigation revealed systemic zirconium intoxication due to intake of metallic colloids as a home remedy as a cause of the skin colour change. There may be an association between skin discolouration and her parkinsonism. This is unique in that various clinical manifestations developed following systemic ingestion of zirconium and this should serve as a warning on the risk of taking illicit dietary supplements. 23517464 Ultrafast Spectroscopy of Quantum Confined States in a Single CdSe Nanowire. We measure for the first time transient absorption spectra of individual CdSe nanowires with about 10 nm diameter. Confinement of the carrier wave functions leads to discrete states which can be described by a six-band effective mass model. Combining transient absorption and luminescence spectroscopy allows us to track the excitation dynamics in the visible and near-infrared spectral range. About 10% of all absorbed photons lead to an excitation of the lowest energy state. Of these excitations, less than 1% lead to a photon in the optical far-field. Almost all emission is reabsorbed by other parts of the nanowire. These findings might explain the low overall quantum efficiency of CdSe nanowires. 23957776 Enlarging head size as the only presentation of Salmonella Typhimurium brain abscess in an infant: a short report. The authors describe a 5-month-old male harbouring a giant Salmonella Typhimurium cerebral abscess who presented with progressively enlarging head size, without any features of septicemia. The report details the radiological findings, differential diagnoses and management problems regarding the index case. 23499825 Steroidal glycosides from the bulbs of Fritillaria meleagris and their cytotoxic activities. Steroidal glycosides (1-18), including 10 new compounds (1-10), were isolated from the bulbs of Fritillaria meleagris (Liliaceae). The structures of the new compounds were determined by two-dimensional (2D) NMR analysis, and by hydrolytic cleavage followed by spectroscopic and chromatographic analysis. The isolated compounds and their aglycones were evaluated for cytotoxic activity against HL-60 human promyelocytic leukemia cells and A549 human lung adenocarcinoma cells. Morphological observation and flow cytometry analysis showed that 5β-spirostanol glycoside (2) and a cholestane derivative (17a) induced apoptotic cell death in HL-60 cells through different mechanisms of action. Furthermore, the (22R)-spirosolanol glycoside (11) selectively induced apoptosis in A549 cells without affecting the caspase-3 activity level. 23747944 Visuospatial working memory in specific language impairment: A meta-analysis. We conducted a meta-analysis of the data from studies comparing visuospatial working memory (WM) in children with specific language impairment (SLI) and typically developing (TD) children. The effect sizes of 21 studies (including 32 visuospatial storage tasks and 9 visuospatial central executive (CE) tasks) were identified via computerized database searches and the reference sections of the identified studies. Meta-analyses and moderator analyses were conducted to examine the magnitude of the differences in visuospatial storage and CE, and their relation to the inclusion criteria used for SLI and the age of the children. The results showed significant effect sizes for visuospatial storage (d=0.49) and visuospatial CE (d=0.63), indicating deficits in both components of visuospatial WM in children with SLI. The moderator analyses showed that greater impairment in visuospatial storage was associated with more pervasive language impairment, whereas age was not significant associated with visuospatial WM. The finding of deficits in visuospatial WM suggests domain-general impairments in children with SLI. It raises questions about the language-specificity of a diagnosis of SLI. Careful attention should thus be paid to both verbal and visuospatial WM in clinical practice, and especially in those children with pervasive language impairments. 23881064 Benefits of small volume and small syringe for bone marrow aspirations of mesenchymal stem cells. Aspirating bone marrow from the iliac crest using small volumes of 1-4 ml with a 10-ml syringe has been historically proposed for harvesting adult mesenchymal stem cells and described as a standard technique to avoid blood dilution. The disadvantage of repeated small aspirations is that there is a significantly increased time to harvest the bone marrow. However, it is not known if a large volume syringe can improve the rate of bone marrow aspiration without increasing blood dilution, thus reducing the quality of the aspirate. We compared the concentrations of mesenchymal stem cells obtained under normal conditions with two different size syringes. Thirty adults (16 men and 14 women with a mean age of 49 ±â€‰14 years) underwent surgery with aspiration of bone marrow from their iliac crest. Bilateral aspirates were obtained from the iliac crest of the same patients with a 10-ml syringe and a 50-ml syringe. Cell analysis determined the frequencies of mesenchymal stem cells (as determined by the number of colonies) from each size of syringe. The cell count, progenitor cell concentration (colonies/ml marrow) and progenitor cell frequency (per million nucleated cells) were calculated. All bone marrow aspirates were harvested by the same surgeon. Aspirates of bone marrow demonstrated greater concentrations of mesenchymal stem cells with a 10-ml syringe compared with matched controls using a 50-ml syringe. Progenitor cell concentrations were on average 300 % higher using a 10-ml syringe than matched controls using a 50-ml syringe (p < 0.01). In normal human donors, bone marrow aspiration from 30 patients demonstrated a reduced mesenchymal stem cell number in aspirates obtained using a larger volume syringe (50 ml) as compared with a smaller volume syringe (10 ml). 23901233 Surgical management of patients with bowel obstructions secondary to gastric cancer. To assess whole-body fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in the management of small bowel obstructions (SBOs) secondary to gastric cancer and its role in treatment strategies. The medical records of all of the patients who were admitted for an intestinal obstruction after curative resection for gastric cancer were retrospectively reviewed. PET/CT was performed before a clinical treatment strategy was established for each patient. The patients were divided into 2 groups: patients with no evidence of a tumor recurrence and patients with evidence of a tumor recurrence. Tumor recurrences included a local recurrence, peritoneal carcinomatosis or distant metastases. The primary endpoint was the 1-year survival rate, and other variables included patient demographics, the length of hospital stay, complications, and mortality. The median time between a diagnosis of gastric cancer and the detection of a SBO was 1.4 years. Overall, 31 of 65 patients (47.7%) had evidence of a tumor recurrence on the PET/CT scan, which was the only factor that was associated with poor survival. Open and close surgery was the main type of surgical procedure reported for the patients with tumor recurrences. R0 resections were performed in 2 patients, including 1 who underwent combined adjacent organ resection. In the group with no evidence of a tumor recurrence on PET/CT, bowel resections were performed in 7 patients, adhesiolysis was performed in 7 patients, and a bypass was performed in 1 patient. The 1-year survival curves according to PET/CT evidence of a tumor recurrence vs no PET/CT evidence of a tumor recurrence were significantly different, and the 1-year survival rates were 8.8% vs 93.5%, respectively. There were no significant differences (P = 0.71) in the 1-year survival rates based on surgical vs nonsurgical management (0% with nonoperative treatment vs 20% after exploratory laparotomy). (18)F-FDG PET/CT can be used to identify the causes of bowel obstructions in patients with a history of gastric cancer, and this method is useful for planning the surgical management of these patients. 23161427 Ilexpublesnins C-M, eleven new triterpene saponins from the roots of Ilex pubescens. Eleven new triterpene saponins, ilexpublesnins C-M (1-11), along with ten known analogues were isolated from the roots of Ilex pubescens. Their structures were elucidated on the basis of extensive spectroscopic analysis, including 1D and 2D NMR experiments. Compounds 1, 2, 10, and 11 contain a 24-aldehyde, which is rare for triterpene saponins from Ilex. These compounds were evaluated in vitro for their cytotoxic effects on human cancer cell lines HepG2, HLE, BEL7402, BEL7403, BEL7405, MCF-7, and HeLa. Among them, only compounds 6 and 19 showed cytotoxicity against the MCF-7 cell line [inhibition (%): 33.14 and 34.03, respectively]. 23701701 Trans-1-amino-3-(18)F-fluorocyclobutanecarboxylic acid (anti-(18)F-FACBC) is a feasible alternative to (11)C-methyl-L-methionine and magnetic resonance imaging for monitoring treatment response in gliomas. Amino acid PET tracers are promising for visualizing gliomas and evaluating radiochemotherapeutic effects. We compared the glioma detection and early response assessment utility between trans-1-amino-3-fluoro-1-(14)C-cyclobutanecarboxylic acid (anti-(14)C-FACBC) and (3)H-methyl-l-methionine ((3)H-Met) by simultaneously analyzing their uptake by rat gliomas treated with and without temozolomide (TMZ) in vitro and in vivo. C6 rat gliomas were incubated with low-dose TMZ to induce chemoresistance. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay demonstrated a significantly greater surviving fraction in the TMZ-resistant subline (C6R) than in drug-naive cells (C6). The anti-(14)C-FACBC and (3)H-Met uptakes were quantified using a triple-label accumulation assay to examine the relationship between tracer uptake and proliferation ((3)H-thymidine (TdR) accumulation rate) in tumor cells. C6 and C6R cells were inoculated into the right and left basal ganglia, respectively, of rats. Efficacy of TMZ against the orthotopic gliomas was analyzed by MRI, Evans blue extravasation, anti-(14)C-FACBC and (3)H-Met autoradiography, and MIB-5 proliferation index. The (3)H-TdR accumulation rate and amino acid tracer (anti-(14)C-FACBC and (3)H-Met) uptake significantly decreased 48 and 72h, respectively, after TMZ treatment in C6 but not C6R cells. Anti-(14)C-FACBC uptake correlated significantly with (3)H-Met uptake and the (3)H-TdR accumulation rate. In the intracerebral glioma model, anti-(14)C-FACBC and (3)H-Met autoradiography clearly delineated the tumor extent, which spread well beyond the high-T2-intensity and enhancing lesions visible on MRI and Evans blue extravasation. TMZ significantly decreased anti-(14)C-FACBC and (3)H-Met uptake and the MIB-5 index of C6 but not C6R tumors. TMZ inhibited tracer uptake and tumor proliferation before morphological changes on MRI. Anti-(14)C-FACBC, like (3)H-Met, was more sensitive than post-contrast T1-weighted MRI for detecting tumor extent and early tumor response to TMZ treatment. Anti-(18)F-FACBC should be a sensitive and precise imaging biomarker for tumor extent visualization and response assessment in glioma patients. 23692773 Micronutrients in Italian ham: a survey of traditional products. The study provides original analytical data on the micronutrient profile of some traditional Italian hams, representative of the major ham categories produced in Italy: 4 dry-cured hams (Modena, Nazionale, Parma, San Daniele), 3 cooked hams (Cotto, Scelto, Alta Qualità), 1 smoked ham (Speck). Data on macronutrients (protein, lipid, moisture), energy, trace elements (Fe, Zn, Cu, Mn, Se), B vitamins (B1, B2, PP, B6, B12) and vitamin E level in the 80 Italian hams sampled are reported. Smoked and dry-cured ham were the richest sources of Fe, Zn and Se and, among vitamins, dry-cured ham had the highest level of B2, PP, B6 and B12; cooked ham provided the lowest energy intake. The contribution of ham to micronutrients recommended dietary allowances was estimated: a ham portion (50g) was a good source especially of Zn and Se providing over 12% of RDA of both; among B vitamins, dry-cured ham greatly contributed to B1 and B6 vitamins RDA (both over 30%). 22473026 Impact of Altitude on Predicting Midterm Outcome in Patients With ST Elevation Myocardial Infarction. This study investigated the effects of altitude on occurrence of mid-term negative events among patients presenting with ST elevation myocardial infarction (STEMI). This study enrolled 492 patients with STEMI. 119 of those patients were living at an intermediate altitude (1960 m, Group I) and 373 were living at sea level (0 m, Group II). There was no significant difference between the different altitude groups in terms of the incidence of cardiac death, urgent target vessel revascularization (TVR), stroke/transient ischemic attack (TIA) and composite endpoints. However, Group I had a significantly higher reinfarction incidence when compared with the Group II. Independent predictors of 6-month composite endpoints were history of statin use, presentation with acute stent thrombosis, peak CK-MB level, success of procedure, Killip classification, and left ventricular ejection fraction. In conclusion, altitude status and altitude-related hematologic changes had no influence over the mid-term outcomes in STEMI patients treated with percutaneous intervention. 23942969 Pilot Study of Doppler optical coherence tomography of retinal blood flow following laser photocoagulation in poorly controlled diabetic patients. Purpose: To investigate the effect of panretinal photocoagulation (PRP) on retinal blood flow and shear rate using Doppler Fourier-domain optical coherence tomography (FD-OCT) in poorly controlled diabetics with proliferative diabetic retinopathy (PDR). Methods: Prospective interventional pilot study in patients with a new clinical diagnosis of PDR. Retinal blood flow and vessel diameter was measured using Doppler FD-OCT according to a previously described method, immediately before PRP treatment and 7-8 weeks after the last PRP session. Results:10 patients with poorly controlled PDR (mean hemoglobin A1c= 9.2 +/-2.0%) and 10 control subjects were included in the study. PDR patients had significantly lower blood flow (~25%) than control subjects both at baseline (p=0.01) and after PRP (p=0.003). Compared to controls, venous and arterial velocities were significantly decreased in diabetics at baseline (~27%; p<0.001, and 0.017 respectively) as well as after PRP (p<0.001 and 0.006 respectively). Compared to controls, venous and arterial shear rates were significantly reduced in diabetics at baseline (~27%; p=0.002, 0.03) and after PRP (p=0.002, 0.03). PRP in this group of PDR patients did not have a statistically significant effect on retinal blood flow or vessel parameters, though there was a trend for decreased arterial diameter (p=0.09). Conclusions: This is the first study to use Doppler FD-OCT to quantify functional changes in retinal vascular parameters in poorly controlled PDR patients. Compared to controls, blood flow parameters were decreased at baseline, but did not decrease further following PRP, with important implications related to diabetes control, endothelial function and therapeutic response. 23958612 Preliminary study: taiwanese mothers' experiences of children with sensory processing disorder. Different cultural backgrounds and parental experiences influence parenting styles and approaches to raising children with disabilities. Family-centered care should consider parental, especially main caregivers, experiences with their disabled children. In Taiwan, in most of homes, mothers are the main caregivers. The purpose of this study was to explore Taiwanese mothers' experiences with their children who have sensory processing disorder. This study used a qualitative ethnographic design and semistructured interview format. Transcripts were analyzed and synthesized into themes. Three mothers were interviewed. The following three themes emerged: (a) relationships within the shared worlds of disability and culture, (b) daily life challenges and expectations, and (c) opportunity to receive professional services. These Taiwanese mothers expressed that they experienced stress from being blamed for insufficient skills and from the shame of their children's disabilities that reflected lack of teacher, friend, and other family members' understanding of the cause of their children's inappropriate behaviors. Their children experienced difficulties performing daily activities, which resulted in stresses on both the mother and her child. The interviewed mothers needed to receive timely, long-term services from healthcare professionals. However, hospitals are inadequately staffed with occupational therapists, which delays care for children with special needs. Taiwanese mothers experience stresses from themselves, their child, and others. Healthcare professionals should apply a family-centered service approach to fulfill the needs of mothers and their disabled children. Moreover, healthcare professionals should promote greater awareness of sensory processing disorder symptoms and interventions to increase public awareness and acceptance of these children. 23958741 The Course of Disability Before and After a Serious Fall Injury. IMPORTANCE Although a serious fall injury is often a devastating event, little is known about the course of disability (ie, functional trajectories) before a serious fall injury or the relationship between these trajectories and those that follow the fall. OBJECTIVES To identify distinct sets of functional trajectories in the year immediately before and after a serious fall injury, to evaluate the relationship between the prefall and postfall trajectories, and to determine whether these results differed based on the type of injury. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study conducted in greater New Haven, Connecticut, from March 16, 1998, to June 30, 2012, in 754 community-living persons aged 70 years or older who were initially nondisabled in their basic activities of daily living. Of the 130 participants who subsequently sustained a serious fall injury, 62 had a hip fracture and 68 had another fall-related injury leading to hospitalization. MAIN OUTCOMES AND MEASURES Functional trajectories, based on 13 basic, instrumental, and mobility activities assessed during monthly interviews, were identified in the year before and the year after the serious fall injury. RESULTS Before the fall, 5 distinct trajectories were identified: no disability in 16 participants (12.3%), mild disability in 34 (26.2%), moderate disability in 34 (26.2%), progressive disability in 23 (17.7%), and severe disability in 23 (17.7%). After the fall, 4 distinct trajectories were identified: rapid recovery in 12 participants (9.2%), gradual recovery in 35 (26.9%), little recovery in 26 (20.0%), and no recovery in 57 (43.8%). For both hip fractures and other serious fall injuries, the probabilities of the postfall trajectories were greatly influenced by the prefall trajectories, such that rapid recovery was observed only among persons who had no disability or mild disability, and a substantive recovery, defined as rapid or gradual, was highly unlikely among those who had progressive or severe disability. The postfall trajectories were consistently worse for hip fractures than for the other serious injuries. CONCLUSIONS AND RELEVANCE The functional trajectories before and after a serious fall injury are quite varied but highly interconnected, suggesting that the likelihood of recovery is greatly constrained by the prefall trajectory. 23859724 Does it matter if teachers and schools match the student? Racial and ethnic disparities in problem behaviors. Black youth often lag behind their non-Hispanic white peers in educational outcomes, including teacher-evaluated school performance. Using data from four waves of the Early Childhood Longitudinal Study-Kindergarten Cohort, the analyses presented here identify the extent to which children receive different evaluations from their teachers depending on the racial/ethnic match of teachers and students. This study is distinct from previous work because we examine the assessment of an individual child by multiple teachers. The results indicate that Black children receive worse assessments of their externalizing behaviors (e.g. arguing in class and disrupting instruction) when they have a non-Hispanic white teacher than when they have a Black teacher. Further, these results exist net of school context and the teacher's own ratings of the behavior of the class overall. 23866381 Final priority; National Institute on Disability and Rehabilitation Research--Rehabilitation Research and Training Centers. Final priority. The Assistant Secretary for Special Education and Rehabilitative Services announces a priority for the Disability and Rehabilitation Research Projects and Centers Program administered by the National Institute on Disability and Rehabilitation Research (NIDRR). Specifically, we announce a priority for a Rehabilitation Research and Training Center (RRTC) on Community Living Policy. The Assistant Secretary may use this priority for competitions in fiscal year (FY) 2013 and later years. We take this action to focus research attention on areas of national need. We intend this priority to improve outcomes among individuals with disabilities. 23778782 Effect of whole and ground Salba seeds (Salvia Hispanica L.) on postprandial glycemia in healthy volunteers: a randomized controlled, dose-response trial. Incorporation of seeds into food products may attenuate postprandial glycemia. Whether these should be consumed as whole or in ground form is not known. Using an acute, randomized controlled crossover design, the glycemic response of 13 healthy participants (6M:7F; 25.4±2.6 kg/m(2)) was studied on nine separate occasions. Test meals consisted of 7, 15 or 24 g of whole or ground Salba baked into white bread, and three control breads matched for energy, and macronutrient profile. Capillary blood samples were collected at fasting and over 2 h post consumption. A significant effect of dose (P=0.04), but no effect of form (P=0.74) or dose-form interaction (P=0.98) was found. No adverse events were reported. This study demonstrates that both ground and whole Salba are equally effective in attenuating blood glucose levels in a dose-dependent manner when incorporated into bread. Flexibility in the use of either the ground or whole seed may increase the ease of incorporation and acceptability as a dietary supplement. 23888871 How to Teach Medication Management: A Review of Novel Educational Materials in Geriatrics. Medication management is an important component of medical education, particularly in the field of geriatrics. The Association of American Medical Colleges has put forth 26 minimum geriatrics competencies under eight domains for graduating medical students; medication management is one of these domains. The Portal of Geriatric Online education (www.POGOe.org) is an online public repository of geriatrics educational materials and modules developed by geriatrics educators and academicians in the United States, freely available for use by educators and learners in the field. The three POGOe materials presented in this review showcase pearls of medication management for medical and other professional students in novel learning formats that can be administered without major prior preparation. The review compares and contrasts the three materials in descriptive and tabular formats to enable its appropriate use by educators in promoting self-learning or group learning among their learners. 23660729 A new severity of illness scale using a subset of Acute Physiology And Chronic Health Evaluation data elements shows comparable predictive accuracy. Severity of illness scores have gained considerable interest for their use in predicting outcomes such as mortality and length of stay. The most sophisticated scoring systems require the collection of numerous physiologic measurements, making their use in real-time difficult. A severity of illness score based on a few parameters that can be captured electronically would be of great benefit. Using a machine-learning technique known as particle swarm optimization, we attempted to reduce the number of physiologic parameters collected in the Acute Physiology, Age, and Chronic Health Evaluation IV system without losing predictive accuracy. Retrospective cohort study of ICU admissions from 2007 to 2011. Eighty-six ICUs at 49 U.S. hospitals where an Acute Physiology, Age, and Chronic Health Evaluation IV system had been installed. 81,087 admissions, of which 72,474 did not have any missing values. None. Machine-learning algorithms were used to come up with the minimal set of variables that were capable of yielding an accurate severity of illness score: the Oxford Acute Severity of Illness Score. Predictive models of ICU mortality using Oxford Acute Severity of Illness Score were developed on admissions during 2007-2009 and validated on admissions during 2010-2011. The most parsimonious Oxford Acute Severity of Illness Score consisted of seven physiologic measurements, elective surgery, age, and prior length of stay. Predictive models of ICU mortality using Oxford Acute Severity of Illness Score achieved an area under the receiver operating characteristic curve of 0.88 and calibrated well. A reduced severity of illness score had discrimination and calibration equivalent to more complex existing models. This was accomplished in large part using machine-learning algorithms, which can effectively account for the nonlinear associations between physiologic parameters and outcome. 23732256 A Prospective Evaluation of Real-Time PCR Assays for the Detection of Orientia tsutsugamushi and Rickettsia spp. for Early Diagnosis of Rickettsial Infections during the Acute Phase of Undifferentiated Febrile Illness. Abstract. One hundred and eighty febrile patients were analyzed in a prospective evaluation of Orientia tsutsugamushi and Rickettsia spp. real-time polymerase chain reaction (PCR) assays for early diagnosis of rickettsial infections. By paired serology, 3.9% (7 of 180) and 6.1% (11 of 180) of patients were confirmed to have acute scrub or murine typhus, respectively. The PCR assays for the detection of O. tsutsugamushi and Rickettsia spp. had high specificity (99.4% [95% confidence interval (CI): 96.8-100] and 100% [95% CI: 97.8-100], respectively). The PCR results were also compared with immunoglobulin M (IgM) immunofluorescence assay (IFA) on acute sera. For O. tsutsugamushi, PCR sensitivity was twice that of acute specimen IgM IFA (28.6% versus 14.3%; McNemar's P = 0.3). For Rickettsia spp., PCR was four times as sensitive as acute specimen IgM IFA (36.4% versus 9.1%; P = 0.08), although this was not statistically significant. Whole blood and buffy coat, but not serum, were acceptable specimens for these PCRs. Further evaluation of these assays in a larger prospective study is warranted. 23279319 Serum RANTES level influences the response to pegylated interferon and ribavirin therapy in chronic hepatitis C. Prediction of treatment responses to pegylated interferon (PEG IFN) plus ribavirin (RBV) therapy is uncertain for genotype 1b chronic hepatitis C. In this study, 96 patients were investigated for the correlation between 36 pretreatment serum chemokine/cytokine levels and PEG IFN/RBV treatment efficacy by a sandwich enzyme-linked immunoassay (ELISA) and a bead array. First, chemokines/cytokines were measured semiquantitatively by sandwich ELISA in 31 randomly-selected patients and the serum regulated on activation normal T-cell expressed and secreted (RANTES) level was found to be significantly higher in the sustained virological response (SVR) group than the non-SVR group (P = 0.048). Precise RANTES measurement in all 96 patients using a bead array confirmed this correlation (P = 0.002). However, the genetic RANTES haplotype was not significantly related to the serum level. The serum RANTES level was extracted by multivariate analysis (odds ratio = 4.09, 95% confidence interval = 1.02-16.5, P = 0.048) as an independent variable contributing to SVR. The serum RANTES level is an important determinant influencing the virological response to PEG IFN/RBV therapy in chronic hepatitis C. 23683094 Development and application of active films for food packaging using antibacterial peptide of Bacillus licheniformis Me1. An attempt was made to evaluate the effectiveness of partially purified antibacterial peptide (ppABP) produced by Bacillus licheniformis Me1 for food preservation by means of active packaging. The active packaging films containing ppABP were developed using two different packing materials [low-density polyethylene (LDPE) and cellulose films] by two different methods: soaking and spread coating. The activated films showed antibacterial activity against pathogens. The release study of ppABP from coated film showed that the LDPE films liberated ppABP as soon as it comes in contact with water, while gradual release of coated ppABP was observed in case of cellulose films. The activated films showed residual activity in different simulating conditions, such as pH of food and storage temperatures. The activated films demonstrated its biopreservative efficacy in controlling the growth of pathogens in cheese and paneer. The ppABP-activated films were found to be effective for biopreservation. The ppABP from active films got diffused into the food matrix and reduced the growth rate and maximum growth population of the target micro-organism. Both types of ppABP-activated films can be used as a packaging material to control spoilage and pathogenic organisms in food, thereby extending the shelf life of foods. 23912789 Impaired heart rate variability in patients with mitral annular calcification: an observational study. The aim of the present study was to study time indices of heart rate variability (HRV) in patients with mitral annular calcification (MAC). A cross-sectional observational study was performed. Fifty patients with echocardiographic evidence of MAC and 50 age- and gender-matched control subjects without echocardiographic evidence of MAC were included. All the study participants underwent 2-dimensional echocardiographic examinations and 24-hour Holter monitoring for HRV analysis. Student-t, Mann-Whitney U and Chi-square tests were used for statistical analysis. Hypertension and coronary artery disease were more common in the MAC group than in the control group. All HRV parameters including mean RR interval, SDNN, SDANN, SDNN index, pNN50 and RMSSD were reduced in the MAC group when compared with the control group (p<0.05 for all). In hypertensive subgroup, all HRV parameters except mean RR interval were diminished in patients with MAC when compared with those without MAC (p<0.05 for all). In non-hypertensive subgroup, all HRV parameters were also diminished in patients with MAC when compared with those without MAC. In the subgroup of patients with coronary artery disease, patients had lower HRV parameters except mean RR interval, pNN50 and RMSSD in comparison to those without MAC (p<0.05 for all). In the subgroup of patients without coronary artery disease, all HRV parameters were depressed in patients with MAC in comparison to those without MAC (p<0.05 for all). Our findings indicate that MAC was associated with reduced heart rate variability which possibly reflects decreased parasympathetic tone with a predominant activity of the sympathetic tone. 23942574 Precision phenotyping of biomass accumulation in triticale reveals temporal genetic patterns of regulation. To extend agricultural productivity by knowledge-based breeding and tailor varieties adapted to specific environmental conditions, it is imperative to improve our ability to assess the dynamic changes of the phenome of crops under field conditions. To this end, we have developed a precision phenotyping platform that combines various sensors for a non-invasive, high-throughput and high-dimensional phenotyping of small grain cereals. This platform yielded high prediction accuracies and heritabilities for biomass of triticale. Genetic variation for biomass accumulation was dissected with 647 doubled haploid lines derived from four families. Employing a genome-wide association mapping approach, two major quantitative trait loci (QTL) for biomass were identified and the genetic architecture of biomass accumulation was found to be characterized by dynamic temporal patterns. Our findings highlight the potential of precision phenotyping to assess the dynamic genetics of complex traits, especially those not amenable to traditional phenotyping. 22935616 Noncanonical control of C. elegans germline apoptosis by the insulin/IGF-1 and Ras/MAPK signaling pathways. The insulin/IGF-1 pathway controls a number of physiological processes in the nematode worm Caenorhabditis elegans, including development, aging and stress response. We previously found that the Akt/PKB ortholog AKT-1 dampens the apoptotic response to genotoxic stress in the germline by negatively regulating the p53-like transcription factor CEP-1. Here, we report unexpected rearrangements to the insulin/IGF-1 pathway, whereby the insulin-like receptor DAF-2 and 3-phosphoinositide-dependent protein kinase PDK-1 oppose AKT-1 to promote DNA damage-induced apoptosis. While DNA damage does not affect phosphorylation at the PDK-1 site Thr350/Thr308 of AKT-1, it increased phosphorylation at Ser517/Ser473. Although ablation of daf-2 or pdk-1 completely suppressed akt-1-dependent apoptosis, the transcriptional activation of CEP-1 was unaffected, suggesting that daf-2 and pdk-1 act independently or downstream of cep-1 and akt-1. Ablation of the akt-1 paralog akt-2 or the downstream target of the insulin/IGF-1 pathway daf-16 (a FOXO transcription factor) restored sensitivity to damage-induced apoptosis in daf-2 and pdk-1 mutants. In addition, daf-2 and pdk-1 mutants have reduced levels of phospho-MPK-1/ERK in their germ cells, indicating that the insulin/IGF-1 pathway promotes Ras signaling in the germline. Ablation of the Ras effector gla-3, a negative regulator of mpk-1, restored sensitivity to apoptosis in daf-2 mutants, suggesting that gla-3 acts downstream of daf-2. In addition, the hypersensitivity of let-60/Ras gain-of-function mutants to damage-induced apoptosis was suppressed to wild-type levels by ablation of daf-2. Thus, insulin/IGF-1 signaling selectively engages AKT-2/DAF-16 to promote DNA damage-induced germ cell apoptosis downstream of CEP-1 through the Ras pathway. 23578923 Irisin levels correlate with energy expenditure in a subgroup of humans with energy expenditure greater than predicted by fat free mass. OBJECTIVE: Obesity is a result of chronic overconsumption of calories relative to the amount of energy expended. While fat free mass can account for ~80% of the variance in energy expenditure, there is still considerable variability in energy requirements between individuals that cannot be explained. We hypothesized that responsiveness to the recently discovered myokine, irisin, which has been touted to increase energy expenditure via activation of brown adipocytes in rodents and possibly humans, may explain some of the variability in energy expenditure. MATERIALS/METHODS: Post-menopausal women (n=17) spent 24-h in a whole room indirect calorimeter. During the study day, subjects remained sedentary and consumed meals tailored to their energy requirements. Plasma irisin, leptin and adiponectin were measured in samples taken from each subject. RESULTS: Our results suggest that in general, irisin levels do not correlate with 24-h energy expenditure, however, for a subpopulation irisin levels and energy expenditure are highly correlative. CONCLUSION: Irisin may help explain some of the observed variability in individual energy requirements that cannot be accounted for by fat free mass. Therefore, interventions designed to increase irisin action may prove to be promising avenues for the treatment of obesity. 23085432 Deriving an explicit hepatic clearance equation accounting for plasma protein binding and hepatocellular uptake. High throughput in vitro biochemical and cell-based assays have the promise to provide more mechanism-based assessments of the adverse effects of large numbers of chemicals. One of the most challenging hurdles for interpreting in vitro toxicity findings is the need for reverse dosimetry tools that estimate the exposures that will give concentrations in vivo similar to the active concentrations in vitro. Recent experience using IVIVE approaches to estimate in vivo pharmacokinetics (Wetmore et al., 2012) identified the need to develop a hepatic clearance equation that explicitly accounted for a broader set of protein binding and membrane transport processes and did not depend on a well-mixed description of the liver compartment. Here we derive an explicit steady-state hepatic clearance equation that includes these factors. In addition to the derivation, we provide simple computer code to calculate steady-state extraction for any combination of blood flow, membrane transport processes and plasma protein-chemical binding rates. This expanded equation provides a tool to estimate hepatic clearance for a more diverse array of compounds. 23739032 Hemoglobin and red blood cells catalyze atom transfer radical polymerization. Hemoglobin (Hb) is a promiscuous protein that not only transports oxygen, but also catalyzes several biotransformations. A novel in vitro catalytic activity of Hb is described. Bovine Hb and human erythrocytes were found to display ATRPase activity, i.e., they catalyzed the polymerization of vinyl monomers under conditions typical for atom transfer radical polymerization (ATRP). N-isopropylacrylamide (NIPAAm), poly(ethylene glycol) methyl ether acrylate (PEGA), and poly(ethylene glycol) methyl ether methacrylate (PEGMA) were polymerized using organobromine initiators and the reducing agent ascorbic acid in acidic aqueous solution. In order to avoid chain transfer from polymer radicals to Hb's cysteine residues, the accessible cysteines were blocked by a reaction with a maleimide. The formation of polymers with bromine chain ends, relatively low polydispersity indices (PDI), first order kinetics and an increase in the molecular weight of poly(PEGA) and poly(PEGMA) upon conversion indicate that control of the polymerization by Hb occurred via reversible atom transfer between the protein and the growing polymer chain. For poly(PEGA) and poly(PEGMA), the reactions proceeded with a good to moderate degree of control. Sodium dodecyl sulfate (SDS) gel electrophoresis, circular dichroism spectroscopy, and time-resolved ultraviolet-visible (UV-vis) spectroscopy revealed that the protein was stable during polymerization, and only underwent minor conformational changes. As Hb and erythrocytes are readily available, environmentally friendly, and nontoxic, their ATRPase activity is a useful tool for synthetic polymer chemistry. Moreover, this novel activity enhances the understanding of Hb's redox chemistry in the presence of organobromine compounds. 23804118 Treatment of Western Australia's mentally ill during the early colonial period, 1826-1865. This paper describes the early settlement of Western Australia and colonial strategies implemented to manage the mentally ill. Western Australian Colonial treatment of the mentally ill began in 1829 with the first mentally ill patient, Dr Nicholas Were Langley. Building commenced to house the mentally ill with the use of a prison, 'The Round House', and later the temporary shelter 'Scott's Warehouse'. Both convicts and the mentally ill were initially housed together, but evidence exists of attempts to provide therapeutic diversions at Scott's Warehouse. 23891697 A predictive model of neurodegeneration in idiopathic REM-sleep behavior disorder. To investigate whether Parkinson's disease (PD) and dementia are competing risks in subjects with idiopathic rapid-eye-movement sleep behavior disorder (RBD). The number of incidental PD cases observed in 11 longitudinal RBD studies was compared with the corresponding expected number as estimated by a simple mathematical model based on population parameters for PD age-of-onset. The expected number of incidental PD cases exceeded observed PD cases (p-value < 0.001) but was in agreement with the sum of observed PD cases and observed mild cognitive impairment/dementia cases (p-value = 0.34). Sensitivity analyses confirmed the results. In the RBD population, PD and dementia cases are competing risks, suggesting that alpha-synuclein pathology occurs simultaneously in substantia nigra and neocortex. This observation has implications for the design and analysis of trials of neuroprotection. 23959103 Matrix-derived combination effect and risk assessment of estragole from basil-containing plant food supplements (PFS). Basil-containing plant food supplements (PFS) can contain estragole which can be metabolised into a genotoxic and carcinogenic 1'-sulfoxymetabolite. This study describes the inhibition of sulfotransferase (SULT)-mediated bioactivation of estragole by compounds present in basil-containing PFS. Results reveal that PFS consisting of powdered basil material contain other compounds with considerable in vitro SULT-inhibiting activity, whereas the presence of such compounds in PFS consisting of basil essential oil was limited. The inhibitor in powdered basil PFS was identified as nevadensin. Physiologically based kinetic (PBK) modeling was performed to elucidate if the observed inhibitory effects can occur in vivo. Subsequently, risk assessment was performed using the Margin of Exposure (MOE) approach. Results suggest that the consequences of the in vivo matrix-derived combination effect are significant when estragole would be tested in rodent bioassays with nevadensin at ratios detected in PFS, thereby increasing MOE values. However, matrix-derived combination effects may be limited at lower dose levels, indicating that the importance of matrix-derived combination effects for risk assessment of individual compounds should be done on a case-by-case basis considering dose-dependent effects. Furthermore, this study illustrates how PBK modeling can be used in risk assessment of PFS, contributing to further reduction in the use of experimental animals. 23788687 Effects of RANK-Ligand Antibody (Denosumab) Treatment on Bone Turnover Markers in a Girl With Juvenile Paget's Disease. Context: Juvenile Paget's disease (JPD) is an extremely rare, yet painful and debilitating bone disease with onset occurring during early childhood. JPD can be caused by loss of function of osteoprotegerin, resulting in subsequent stimulation of osteoclasts via the receptor activator of nuclear factor-κB (RANK) pathway. Increased bone turnover and lack of bone modeling lead to severe deformities, frequent fractures, short stature, and loss of hearing. Setting: The treatment for JPD is challenging and has previously been based on administration of either calcitonin or bisphosphonates. However, with the development of denosumab, a receptor activator of nuclear factor-κB-ligand (RANKL) antibody, a treatment targeting the pathophysiology of JPD may be available. We report the effects of denosumab treatment on an 8-year-old girl with a severe form of JPD. Patient: Before starting the denosumab treatment regimen, the patient had been treated for 3.5 years with iv pamidronate. Intervention and Outcome: The administration of denosumab resulted in improved disease control compared with bisphosphonate, as assessed by monitoring markers of bone turnover. Alkaline phosphatase levels dropped within the normal range and remained at normal levels for 5 months after the final dose of denosumab. Additionally, bone pain was more efficiently controlled with denosumab. However, concomitant with the first injection, severe hypocalcemia developed, for which the patient was hospitalized and iv calcium supplementation was required for 13 days. Conclusions: Denosumab appears to be significantly effective for osteoclast inhibition for the treatment of JPD. However, in our patient, denosumab administration was associated with severe hypocalcemia, indicating that close monitoring of calcium levels is required during treatment. 23457090 Robust Synthesis of Gold Cubic Nanoframes through a Combination of Galvanic Replacement, Gold Deposition, and Silver Dealloying. A facile, robust approach to the synthesis of Au cubic nanoframes is described. The synthesis involves three major steps: 1) preparation of Au-Ag alloyed nanocages using a galvanic replacement reaction between Ag nanocubes and HAuCl4 ; 2) deposition of thin layers of pure Au onto the surfaces of the nanocages by reducing HAuCl4 with ascorbic acid, and; 3) formation of Au cubic nanoframes through a dealloying process with HAuCl4 . The key to the formation of Au cubic nanoframes is to coat the surfaces of the Au-Ag nanocages with sufficiently thick layers of Au before they are dealloyed. The Au layer could prevent the skeleton of a nanocage from being fragmented during the dealloying step. The as-prepared Au cubic nanoframes exhibit tunable localized surface plasmon resonance peaks in the near-infrared region, but with much lower Ag content as compared with the initial Au-Ag nanocages. 23913272 Vesicular and non-vesicular transport feed distinct glycosylation pathways in the Golgi. Newly synthesized proteins and lipids are transported across the Golgi complex via different mechanisms whose respective roles are not completely clear. We previously identified a non-vesicular intra-Golgi transport pathway for glucosylceramide (GlcCer)-the common precursor of the different series of glycosphingolipids-that is operated by the cytosolic GlcCer-transfer protein FAPP2 (also known as PLEKHA8) (ref. 1). However, the molecular determinants of the FAPP2-mediated transfer of GlcCer from the cis-Golgi to the trans-Golgi network, as well as the physiological relevance of maintaining two parallel transport pathways of GlcCer-vesicular and non-vesicular-through the Golgi, remain poorly defined. Here, using mouse and cell models, we clarify the molecular mechanisms underlying the intra-Golgi vectorial transfer of GlcCer by FAPP2 and show that GlcCer is channelled by vesicular and non-vesicular transport to two topologically distinct glycosylation tracks in the Golgi cisternae and the trans-Golgi network, respectively. Our results indicate that the transport modality across the Golgi complex is a key determinant for the glycosylation pattern of a cargo and establish a new paradigm for the branching of the glycosphingolipid synthetic pathway. 23261673 Qalibra: a general model for food risk-benefit assessment that quantifies variability and uncertainty. The EU project BRAFO proposed a framework for risk-benefit assessment of foods, or changes in diet, that present both potential risks and potential benefits to consumers (Hoekstra et al., 2012a). In higher tiers of the BRAFO framework, risks and benefits are integrated quantitatively to estimate net health impact measured in DALYs or QALYs (disability- or quality-adjusted life years). This paper describes a general model that was developed by a second EU project, Qalibra, to assist users in conducting these assessments. Its flexible design makes it applicable to a wide range of dietary questions involving different nutrients, contaminants and health effects. Account can be taken of variation between consumers in their diets and also other characteristics relevant to the estimation of risk and benefit, such as body weight, gender and age. Uncertainty in any input parameter may be quantified probabilistically, using probability distributions, or deterministically by repeating the assessment with alternative assumptions. Uncertainties that are not quantified should be evaluated qualitatively. Outputs produced by the model are illustrated using results from a simple assessment of fish consumption. More detailed case studies on oily fish and phytosterols are presented in companion papers. The model can be accessed as web-based software at www.qalibra.eu. 23814013 Mitotane reduces human and mouse ACTH-secreting pituitary cell viability and function. Medical therapy for Cushing's disease (CD) is currently based on agents mainly targeting adrenocortical function. Lately, pituitary-directed drugs have been developed, with limited efficacy. Mitotane, a potent adrenolytic drug, has been recently investigated for the treatment of CD, but the direct pituitary effects have not been clarified so far. The aim of our study was to investigate whether mitotane may affect corticotroph function and cell survival in the mouse pituitary cell line AtT20/D16v-F2 and in the primary cultures of human ACTH-secreting pituitary adenomas, as an in vitro model of pituitary corticotrophs. We found that in the AtT20/D16v-F2 cell line and in primary cultures, mitotane reduces cell viability by inducing caspase-mediated apoptosis and reduces ACTH secretion. In the AtT20/D16v-F2 cell line, mitotane reduces Pomc expression and blocks the stimulatory effects of corticotropin-releasing hormone on cell viability, ACTH secretion, and Pomc expression. These effects were apparent at mitotane doses greater than those usually necessary for reducing cortisol secretion in Cushing's syndrome, but still in the therapeutic window for adrenocortical carcinoma treatment. In conclusion, our results demonstrate that mitotane affects cell viability and function of human and mouse ACTH-secreting pituitary adenoma cells. These data indicate that mitotane could have direct pituitary effects on corticotroph cells. 23918583 IgG4-Related Sclerosing Disease Involving the Superior Vena Cava and the Atrial Septum of the Heart. A 55-year-old woman presented with frequent episodes of syncope due to sinus pauses. During ambulatory Holter monitoring, atrial fibrillation and first-degree atrioventricular nodal block were observed. Magnetic resonance imaging and CT scans showed a tumor-like mass from the superior vena cava to the right atrial septum. Open chest cardiac biopsy was performed. The tumor was composed of proliferating IgG4-positive plasma cells and lymphocytes with surrounding sclerosis. The patient was diagnosed with IgG4-related sclerosing disease. Because of frequent sinus pauses and syncope, a permanent pacemaker was implanted. The cardiac mass was inoperable, but it did not progress during the one-year follow-up. 23928001 Long-term treatment with fasudil improves bleomycin-induced pulmonary fibrosis and pulmonary hypertension via inhibition of Smad2/3 phosphorylation. Pulmonary hypertension (PH) associated with pulmonary fibrosis (PF) considerably worsens prognosis of interstitial lung diseases (ILD). RhoA/Rho-kinases (ROCK) pathway is implicated in high pulmonary vascular tone and pulmonary fibrosis but the effect of ROCK inhibitors on PH associated with PF is not known. We therefore aimed to determine whether long-term treatment with fasudil, a selective ROCK inhibitor, could attenuate PF and PH induced by bleomycin in mice. Male C57BL/6 mice received a single dose of intratracheal bleomycin (3.3 U/kg) to induce PF. Treatment with fasudil (30 mg kg(-1) day(-1)) was given intraperitoneally for 7, 14 or 21 days until mice underwent hemodynamic measurements. Right ventricular systolic pressure (RVSP) and RV/(LV + S) ratio were assessed. Lung inflammatory cells profiles, including macrophages, neutrophils, lymphocytes B and lymphocytes T were assessed by immunohistochemistry. Lung fibrosis was evaluated by histological and biochemical methods. Pulmonary arteriole muscularization and medial wall thickness (MWT) were evaluated by immunohistochemical staining for α-SMA. Bleomycin induced severe PF and PH in mice, associated with an increased RhoA/ROCK activity in the lung. Fasudil reduced lung inflammation and lung collagen content, and attenuated the increased RVSP, RV hypertrophy, and pulmonary vascular remodeling in bleomycin-intoxicated mice. Fasudil inhibited the increased activity of RhoA/ROCK pathway, and partly altered bleomycin-associated activation of TGF-β1/Smad pathway, via inhibition of Smad2/3 phosphorylation. The efficacy of long-term treatment with fasudil suggests that the blockade of RhoA/ROCK pathway may be a promising therapy for patients with ILD-associated PH. 23858017 Cortical lesion load correlates with diffuse injury of multiple sclerosis normal appearing white matter. Degeneration of central nervous system normal appearing white matter (NAWM) underlies disability and progression in multiple sclerosis (MS). Axon loss typifies NAWM degeneration. The objective of this paper is to assess correlation between cortical lesion load and magnetisation transfer ratio (MTR) of the NAWM in MS. This was in order to test the hypothesis that cortical lesions cause NAWM degeneration. Nineteen patients with MS underwent 7 Tesla magnetisation-prepared-rapid-acquisition-gradient-echo (MPRAGE), and magnetisation transfer ratio (MTR) brain magnetic resonance imaging (MRI). Cortical lesions were identified using MPRAGE and MTR images of cortical ribbons. White matter lesions (WMLs) were segmented using MPRAGE images. WML maps were subtracted from white matter volumes to produce NAWM masks. Pearson correlation was calculated for NAWM MTR vs cortical lesion load, and WML volumes. Cortical lesion volumes and counts all had significant correlation with NAWM mean MTR. The strongest correlation was with cortical lesion volumes obtained using MTR images (r = -0.6874, p = 0.0006). WML volume had no significant correlation with NAWM mean MTR (r = -0.08706, p = 0.3615). Our findings are consistent with the hypothesis that cortical lesions cause NAWM degeneration. This implicates cortical lesions in the pathogenesis of NAWM axon loss, which underpins long-term disability and progression in MS. 23880053 Changes in Fetal Left and Right Ventricular Strain Mechanics during Normal Pregnancy. The aim of this study was to detect normal changes in fetal two-dimensional speckle-tracking echocardiography-derived values for global and regional longitudinal left and right ventricular strain, strain rate, and time to peak (T2P) global strain during pregnancy. Forty-four healthy fetuses were examined prospectively during the second-trimester and third-trimester ultrasound examinations (20-24 and 30-34 weeks, respectively). Clips with high frame rates (mean, 120 frames/sec) of two-dimensional (B-mode) grayscale images of apical or basal four-chamber views of both ventricles were used for offline analyses of global and regional walls and segments (basal, mid, and apical) of myocardial strain and strain rate as well as T2P global strain in the longitudinal direction. There were statistically significant decreases in global and regional strain of the right ventricle between the second and third trimesters. No statistically significant changes were observed in global and regional strain of the left ventricle. Global and regional strain rates of both ventricles decreased in a similar way during pregnancy. The mean T2P longitudinal left ventricular global strain (adjusted for heart rate) increased mildly during fetal life. Whereas T2P longitudinal strain of the left ventricle at 20 to 24 weeks was statistically significantly shorter than that of the right ventricle, no difference in T2P longitudinal strain was found at 30 to 34 weeks of gestation between both ventricles. The establishment of these changes between the second-trimester and third-trimester two-dimensional speckle-tracking echocardiography-derived reference values is a mandatory prerequisite for its use in evaluating (pathologic) changes in both ventricular functions during pregnancy. 23850438 High local genetic diversity of canine parvovirus from Ecuador. Canine parvovirus (CPV) comprises three antigenic variants (2a, 2b, and 2c) that are distributed globally with different frequencies and levels of genetic variability. CPVs from central Ecuador were herein analyzed to characterize the strains and to provide new insights into local viral diversity, evolution, and pathogenicity. Variant prevalence was analyzed by PCR and partial sequencing for 53 CPV-positive samples collected during 2011 and 2012. The full-length VP2 gene was sequenced in 24 selected strains and a maximum-likelihood phylogenetic tree was constructed using both Ecuadorian and worldwide strains. Ecuadorian CPVs have a remarkable genetic diversity that includes the circulation of all three variants and the existence of different evolutionary groups or lineages. CPV-2c was the most prevalent variant (54.7%), confirming the spread of this variant in America. Ecuadorian CPV-2c strains clustered in two lineages, which represent the first evidence of polyphyletic CPV-2c circulating in South America. CPV-2a strains constituted 41.5% of the samples and clustered in a single lineage. The two detected CPV-2b strains (3.8%) were clearly polyphyletic and appeared related to Ecuadorian CPV-2a or foreign CPV-2b strains. Besides the substitution at residue 426 that is used to identify the variants, two amino acid changes occurred in Ecuadorian strains: Val139Iso and Thr440Ser. Ser(440) occurred in a biologically relevant domain of VP2 and is here described for the first time in CPV. The associations of Ecuadorian CPV-2c and CPV-2a with clinical symptoms indicate that dull mentation, hemorrhagic gastroenteritis and hypothermia occurred more frequently in infection with CPV-2c than with CPV-2a. 23892560 Luminescent metal-organic framework-functionalized graphene oxide nanocomposites and the reversible detection of high explosives. Achieving both high specificity and sensitivity are essential for gas phase chemical detection systems. Recent implementation of Metal-Organic Frameworks (MOFs) have shown great success in separation and storage systems for specific gas molecules. By implementing a MOF structure comprised of Zn(2+) coordinated trans-stilbene derivatives, a gas responsive material has been created which exhibits a high photoluminescence quantum yield, offering new opportunities for chemical sensors. Here, we reveal a nanocomposite material, assembled from azobenzene functionalized graphene oxide and stilbene-MOF, that is capable of luminescent quenching by explosive gases. This unique system displays selectivity to dinitrotoluene (71% quenching) over trinitrotoluene (20% quenching) with sub ppm sensitivity and response times of less than a minute. We show that this implementation of a graphene-based MOF composite provides a unique strategy in the development of molecularly well-defined materials having rapid, reversible, and gas selective fluorescent quenching capabilities. This opens the way for new advances in the assembly of low density frameworks using isomerization suppressed materials. 23722553 Evaluation of LDH-A and Glutaminase Inhibition In Vivo by Hyperpolarized 13C-Pyruvate Magnetic Resonance Spectroscopy of Tumors. Hyperpolarized (13)C magnetic resonance spectroscopy provides a unique opportunity to detect real-time metabolic fluxes as a means to measure metabolic treatment responses in vivo. Here, we show that pharmacologic inhibition of lactate dehydrogenase-A suppressed the conversion of hyperpolarized (13)C-pyruvate to lactate in murine xenografts of P493 human lymphoma. In contrast, a glutaminase inhibitor reduced conversion of (13)C-pyruvate to alanine without affecting conversion of pyruvate to lactate. These results illustrate the ability to monitor biomarkers for responses to antimetabolic therapy in real-time, paving the way for clinical development of imaging biomarkers to monitor metabolic pharmacodynamics. Cancer Res; 73(14); 4190-5. ©2013 AACR. 23861763 Is granger causality a viable technique for analyzing FMRI data? Multivariate neural data provide the basis for assessing interactions in brain networks. Among myriad connectivity measures, Granger causality (GC) has proven to be statistically intuitive, easy to implement, and generate meaningful results. Although its application to functional MRI (fMRI) data is increasing, several factors have been identified that appear to hinder its neural interpretability: (a) latency differences in hemodynamic response function (HRF) across different brain regions, (b) low-sampling rates, and (c) noise. Recognizing that in basic and clinical neuroscience, it is often the change of a dependent variable (e.g., GC) between experimental conditions and between normal and pathology that is of interest, we address the question of whether there exist systematic relationships between GC at the fMRI level and that at the neural level. Simulated neural signals were convolved with a canonical HRF, down-sampled, and noise-added to generate simulated fMRI data. As the coupling parameters in the model were varied, fMRI GC and neural GC were calculated, and their relationship examined. Three main results were found: (1) GC following HRF convolution is a monotonically increasing function of neural GC; (2) this monotonicity can be reliably detected as a positive correlation when realistic fMRI temporal resolution and noise level were used; and (3) although the detectability of monotonicity declined due to the presence of HRF latency differences, substantial recovery of detectability occurred after correcting for latency differences. These results suggest that Granger causality is a viable technique for analyzing fMRI data when the questions are appropriately formulated. 23157384 Different fates of Alzheimer's disease amyloid-β fibrils remodeled by biocompatible small molecules. Amyloid fibrils implicated in numerous human diseases are thermodynamically very stable. Stringent conditions that would not be possible in a physiological environment are often required to disrupt the stable fibrils. Recently, there is increasing evidence that small molecules can remodel amyloid fibrils in a physiologically relevant manner. In order to investigate possible fibril remodeling mechanisms using this approach, we performed comparative studies on the structural features of the different amyloid-β (Aβ) aggregates remodeled from Aβ fibrils by three biocompatible small molecules: methylene blue; brilliant blue G; and erythrosine B. Combined with circular dichroism (CD), immuno-blotting, transmission electron microscopy (TEM), and atomic force microscopy (AFM) results, it was found that brilliant blue G- and erythrosine B-treatment generate fragmented Aβ fibrils and protofibrils, respectively. In contrast, incubation of the Aβ fibrils with methylene blue perturbs fibrillar structure, leading to amorphous Aβ aggregates. Our findings provide insights on the molecular mechanism of amyloid fibril formation and remodeling and also illustrate the possibility of controlled changes in biomolecule nanostructures. 23940677 Efficiency of household reactive case detection for malaria in rural southern zambia: simulations based on cross-sectional surveys from two epidemiological settings. Case detection and treatment are critical to malaria control and elimination as infected individuals who do not seek medical care can serve as persistent reservoirs for transmission. Household malaria surveys were conducted in two study areas within Southern Province, Zambia in 2007 and 2008. Cross-sectional surveys were conducted approximately five times throughout the year in each of the two study areas. During study visits, adults and caretakers of children were administered a questionnaire and a blood sample was obtained for a rapid diagnostic test (RDT) for malaria. These data were used to estimate the proportions of individuals with malaria potentially identified through passive case detection at health care facilities and those potentially identified through reactive case finding. Simulations were performed to extrapolate data from sampled to non-sampled households. Radii of increasing size surrounding households with an index case were examined to determine the proportion of households with an infected individual that would be identified through reactive case detection. In the 2007 high transmission setting, with a parasite prevalence of 23%, screening neighboring households within 500 meters of an index case could have identified 89% of all households with an RDT positive resident and 90% of all RDT positive individuals. In the 2008 low transmission setting, with a parasite prevalence of 8%, screening neighboring households within 500 meters of a household with an index case could have identified 77% of all households with an RDT positive resident and 76% of all RDT positive individuals. Testing and treating individuals residing within a defined radius from an index case has the potential to be an effective strategy to identify and treat a large proportion of infected individuals who do not seek medical care, although the efficiency of this strategy is likely to decrease with declining parasite prevalence. 23938867 Molecular evolution and patterns of duplication in the SEP/AGL6-like lineage of the Zingiberales: a proposed mechanism for floral diversification. The diversity of floral forms in the plant order Zingiberales has evolved through alterations in floral organ morphology. One striking alteration is the shift from fertile, filamentous stamens to sterile, laminar ("petaloid") organs in the stamen whorls, attributed to specific pollination syndromes. Here we examine the role of the SEPALLATA (SEP) genes, known to be important in regulatory networks underlying floral development and organ identity, in the evolution of development of the diverse floral organs phenotypes in the Zingiberales. Phylogenetic analyses show that the SEP-like genes have undergone several duplication events giving rise to multiple copies. Selection tests on the SEP-like genes indicate that the two copies of SEP3 have mostly evolved under balancing selection, probably due to strong functional restrictions as a result of their critical role in floral organ specification. In contrast, the two LOFSEP copies have undergone differential positive selection, indicating neofunctionalization. RT-PCR, gene expression from RNA-seq data and in situ hybridization analyses show that the recovered genes have differential expression patterns across the various whorls and organ types found in the Zingiberales. Our data also suggest that AGL6, sister to the SEP-like genes, may play an important role in stamen morphology in the Zingiberales. Thus, the SEP-like genes are likely to be involved in some of the unique morphogenetic patterns of floral organ development found among this diverse order of tropical monocots. This work contributes to a growing body of knowledge focused on understanding the role of gene duplications and the evolution of entire gene networks in the evolution of flower development. 23918178 Facets of Small RNA-Mediated Regulation in Legionella pneumophila. Legionella pneumophila is a water-borne pathogen that causes a severe lung infection in humans. It is able to replicate inside amoeba in the water environment, and inside lung macrophages in humans. Efficient regulation of gene expression is critical for responding to the conditions that L. pneumophila encounters and for intracellular multiplication in host cells. In the last two decades, many reports have contributed to our understanding of the critical importance of small regulatory RNAs (sRNAs) in the regulatory network of bacterial species. This report presents the current state of knowledge about the sRNAs expressed by L. pneumophila and discusses a few regulatory pathways in which sRNAs should be involved in this pathogen. 23873447 C-H functionalization: thoroughly tuning ligands at a metal ion, a chemist can greatly enhance catalyst's activity and selectivity. This brief essay consists of a few "exciting stories" devoted to relations within a metal-complex catalyst between a metal ion and a coordinated ligand. When, as in the case of a human couple, the rapport of the partners is cordial and a love cements these relations, a chemist finds an ideal married couple, in other words he obtains a catalyst of choice which allows him to functionalize C-H bonds very efficiently and selectively. Examples of such lucky marriages in the catalytic world of ions and ligands are discussed here. Activity of the catalyst is characterized by turnover number (TON) or turnover frequency (TOF) as well as by yield of a target product. Introducing a chelating N,N- or N,O-ligand to the catalyst molecule (this can be an iron or manganese derivative) sharply enhances its activity. However, the activity of vanadium derivatives (with additionally added to the solution pyrazinecarboxylic acid, PCA) as well as of various osmium complexes does not dramatically depend on the nature of ligands surrounding metal ions. Complexes of these metals are very efficient catalysts in oxidations with H2O2. Osmium derivatives are record-holders exhibiting extremely high TONs whereas vanadium complexes are on the second position. Finally, elegant examples of alkane functionalization on the ions of non-transition metals (aluminium, gallium etc.) are described when one ligand within the metal complex (namely, hydroperoxyl ligand HOO(-)) helps other ligand of this complex (H2O2 molecule coordinated to the metal) to disintegrate into two species, generating very reactive hydroxyl radical. Hydrogen peroxide molecule, even ligated to the metal ion, is perfectly stable without the assistance of the neighboring HOO(-) ligand. This ligand can be easily oxidized donating an electron to its partner ligand (H2O2). In an analogous case, when the central ion in the catalyst is a transition metal, this ion changing its oxidation state can donate an electron to the coordinated H2O2 fragment. This provokes the O-O bond rupture in the hydrogen peroxide molecule as is assumed for the role of Fe(2+) ions in the Fenton system. 23949103 Family structure, marital discord and offspring's psychopathology in early adulthood: a prospective study. With marital breakdown and discord relatively common, we examined whether family structure and the quality of marital relationship have a long-term impact on offspring's psychopathology in early adulthood. This study aimed to examine the association of family structure and marital discord in the family with a wide range of offspring's mental health and problem behaviours at 21 years. Data were from the Mater-University of Queensland Study of Pregnancy, a population based birth cohort study, which commenced in Brisbane, Australia in 1981. Mothers and children were followed up at birth, 6 months and 5, 14 and 21 years after the initial interview. Marital status and marital quality were assessed at the 14 year follow-up. Young Adult Self-Report sub-scales of mental health and problem behaviours were measured at the 21-year follow-up. Type of family structure and the quality of marital relationship (at the 14-year follow-up) predicted offspring's psychopathology at 21 years. When a selected group of confounding factors were included in the multivariate analyses, children who lived with a step-father, un-partnered mother, or in families where parents had conflict in marital relationship reported higher symptoms of psychopathology at 21 years. The association between marital problems and young adult psychopathology does not appear to be confounded by a wide range of confounding variables. Further research is needed to explore the mechanism of these associations to develop preventive programmes. 23580745 Effects of Early, Late, and Long-term Nonselective β-Blockade on Left Ventricular Remodeling, Function, and Survival in Chronic Organic Mitral Regurgitation. Background- Mitral regurgitation (MR) produces sympathetic nervous system activation which is detrimental in other causes of heart failure. However, whether β-blockade is beneficial in MR has not been determined. Methods and Results- Eighty-seven rats with significant organic MR were randomized to the β-blockade group (n=43) or the control group (n=44). Carvedilol was started in week 2 post MR induction and given for 23 to 35 weeks in the β-blockade group. Echocardiography was performed at baseline and at weeks 2, 6, 12, 24, 30, and 36 after MR induction. After 23 weeks of β-blockade, heart rates were significantly reduced by carvedilol (308±25 versus 351±31 beats per minute; P<0.001). Left ventricular end-diastolic (2.2±0.7 versus 1.59±0.6 mL; P<0.001), end-systolic volumes (0.72±0.42 versus 0.40±0.19 mL; P<0.001), and mass index (2.40±0.55 versus 2.06±0.62 g/kg; P<0.001) were significantly higher, and left ventricular fraction shortening (33±7% versus 38±7%; P<0.001) and ejection fraction (69±11% versus 75±7%; P<0.001) were significantly lower in the β-blockade group than in the control group. Systolic blood pressure was lower in the β-blockade group than in the control group (114±10 versus 93±12 mm Hg; P<0.005). Survival probability was significantly lower in the early β-blockade group than in the control group (88% versus 96%; P=0.03). Conclusions- Early and long-term nonselective β-blockade was associated with adverse left ventricular remodeling, systolic dysfunction, and a reduction in survival in the experimental rat model of organic MR. 23597652 Susceptibility and intra-species transmission of the H9N2 G1 prototype lineage virus in Japanese quail and turkeys. Avian influenza viruses of the H9N2 subtype have circulated in the poultry population in Asia, Far and Middle East since the mid-1990 s. One of the most widespread lineages established in poultry is the G1 lineage. This lineage has undergone further evolution and reassortment since its first detection in 1997 and G1-like H9N2 viruses still circulate. In this study we have investigated the susceptibility of quail and turkeys to the H9N2 G1-lineage prototype strain (A/quail/Hong Kong/G1/97). Contact transmission experiments were carried out in both avian species. Animals were infected oro-nasally with increasing doses of the virus (10(3)-10(6) EID 50/0.1 ml) and sentinel birds were introduced 4 days post infection (pi) in each experimental group. Quail were more susceptible than turkeys, as they were readily infected with lower challenge doses. Interestingly, infection of turkeys was associated with worse clinical condition. Transmission was detected in both species. Quail infected with a dose less than or equal to 10(4) EID50 transmitted the virus to the sentinels without showing any signs of disease. These findings reinforce the hypothesis that quail may ensure the perpetuation of H9N2 viruses in poultry, acting as a silent reservoir. 23835560 The natural history of a newly developed flexion contracture following primary total knee arthroplasty. We investigated the incidence, natural history, and functional consequences of a newly developed flexion contracture after total knee arthroplasty (TKA). Forty patients with full knee extension preoperatively who developed a postoperative flexion contracture were match-paired 1:2 with 80 patients who had full extension. The incidence of a newly developed flexion contracture, ROM, and Knee Society scores (KSS) at six weeks, four months, and one year were analysed. The incidence of a new flexion contracture at six weeks was 14 %, but diminished to 5 % and 0.3 % at four months and one year, respectively. One year after surgery, there was no difference in the KSS (p = 0.5). This study showed that the majority of patients who developed a new flexion contracture after TKA have full knee extension one year postoperatively. Moreover, knee extension and KSS at one year are equivalent to those patients who did not developed a flexion contracture. 23405969 Assessment of left ventricular size and function during cardiac surgery. An intraoperative evaluation of six two-dimensional echocardiographic methods with real time three-dimensional echocardiography as a reference. Transesophageal echocardiography is recommended to monitor left ventricular (LV) size and function in various operations. Generally, two-dimensional (2D) methods are applied intraoperatively. The aim of this study was to compare the accuracy and feasibility of 6 commonly used 2D methods to assess LV function during surgery. LV function in 120 consecutive patients was evaluated. Real time three-dimensional transesophageal echocardiograpy (3DTEE) served as reference. End-diastolic and end-systolic volumes and ejection fraction (EF) were analyzed with Simpson's method of discs (monoplane [MP] and biplane [BP]), eyeball method, Teichholz' method, and speckle tracking (ST) methods. Furthermore, fractional area change (FAC) and peak systolic pressure rise (dP/dt) were determined. Each 2D method was evaluated regarding correlation and agreement with 3DE, intra- and interobserver variability and the time required for evaluation. Simpson BP showed the strongest correlation and best agreement with 3DE for EF (limits of agreement 3.7 ± 11.6%) and volumes. Simpson MP showed similar agreement with 3DE compared to ST (2.8 ± 14.5% vs. 2.0 ± 15.3% and 3.8 ± 14.4% vs. 1.9 ± 15.6%, respectively). Both the eyeball method and Teichholz' method showed wide limits of agreement (-1.5 ± 18.2% and 5.2 ± 22.1%, respectively). DP/dt did not correlate with 3DE. FAC and ST FAC showed similar agreement. Application of 3DE (429 ± 108 seconds) took the longest time, and the eyeball method took the shortest time (8 ± 5 seconds) for analysis. Simpson BP is the most accurate intraoperative 2D method to evaluate LV function, followed by long-axis MP evaluations. Short-axis views were less accurate but may be suited for monitoring. We do not recommend using dP/dt. 23436240 Simultaneous determination of eleven major components in Fugan Fang using high-performance liquid chromatography coupled with mass spectrometry. Fugan fang (FGF) is a traditional Chinese medicine (TCM) prescription that has been used in treating hepatic illnesses for many years. In this study, an analytical method is developed for the quantitative analysis of the major components of FGF. This method is based on high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS) on a reverse-phase C18 column. Results show that 0.01% acetic acid and acetonitrile is the optimum mobile phase in gradient elution. All compounds showed good linearity (r(2) ≥ 0.9948). Recoveries measured at three concentration levels varied from 83.5 to 104.8%. The method was validated with respect to precision, repeatability and accuracy and was successfully applied in the quantification of the 11 components of FGF products. The validated HPLC-MS method provides a basis for assessing the quality of TCM prescriptions containing many bioactive components. 23300053 Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C. Earlier studies have suggested neurocognitive impairment in patients with chronic hepatitis C virus (HCV) infection even before liver cirrhosis has developed. Since these deficits might be reversible after successful antiviral therapy, we analyzed the long-term course of neurocognitive parameters in HCV patients with and without successful virus elimination by an interferon-based antiviral treatment. In a multicenter study including 168 HCV patients receiving antiviral therapy (peginterferon alpha-2b and ribavirin) we performed a long-term follow-up of neurocognitive performance before and after treatment. Neurocognitive function was psychometrically assessed using the computer-aided TAP (Test Battery of Attentional Performance). When tested at least 12 months after termination of antiviral treatment, patients with sustained virologic response (SVR) had improved significantly as compared to their pretreatment performance in three of five TAP subtasks (vigilance, P < 0.001; shared attention: optical task, P < 0.001; working memory, P < 0.001). Patients who failed to eradicate the virus, however, showed no significant long-term changes in neurocognitive performance in all five subtasks assessed (0.194 < P < 0.804). In the posttreatment evaluation, neurocognitive function was significantly better in responders to the antiviral therapy as compared to nonresponders. Conclusion: Successful eradication of HCV leads to a significant improvement of relevant aspects of attentional and neurocognitive performance, indicating that the neurocognitive impairment caused by chronic HCV infection is potentially reversible. This therefore suggests an added therapeutic benefit of antiviral treatment in HCV infection. Improvement of neurocognitive function may be an additional treatment indication in patients with HCV. (HEPATOLOGY 2013;58:497-504). 23859071 Investigation of PNPLA3 and IL28B Genotypes on Diabetes and Obesity After Liver Transplantation: Insight Into Mechanisms of Disease. To identify genetic risks for obesity and diabetes postliver transplantation (LT), LT recipients underwent genotyping for IL28B rs12979860 (n = 295) and PNPLA3 rs738409 (n = 205) polymorphism in both donors and recipients. The development of obesity and diabetes/impaired fasting glucose (IFG) was determined 1-5 years post-LT. Recipient PNPLA-3 genotype was independently associated with obesity (BMI > 30) at 3 years posttransplant (genotype CC 33.7%, CG 48.3% and GG 82.4%, p = 0.002), with an odds ratio (OR 2.54, CI 1.38-4.66, p = 0.003), associated with the G allele. Diabetes/IFG diagnosed within 5 years posttransplant associated with PNPLA-3 non-CC genotype (HR 1.59, 1.12-2.26, p = 0.010), but not IL28B TT genotype (HR 1.46, 0.94-2.27, p = 0.092). No genotype variable was independently predictive of diabetes/IFG. The combination of PNPLA-3 non-CC and IL28B TT genotype was associated with increased risk of diabetes/IFG compared to PNPLA-3 CC, IL28B non-TT (HR 2.64, CI 1.30-5.39, p = 0.008). Donor genotypes were not associated with any of the outcomes analyzed. In conclusion, PNPLA-3 non-CC genotype is associated with posttransplant obesity but not independently with diabetes/IFG. The lack of donor related risk suggests a peripheral rather than central mechanism of insulin resistance in liver transplant recipients. 23291713 Autophagy inhibition for chemosensitization and radiosensitization in cancer: do the preclinical data support this therapeutic strategy? Recognition of the cytoprotective functions of autophagy that occur in tumor cells exposed to various forms of chemotherapy or radiation has generated intense interest in the possibility that pharmacological interference with autophagy could provide a clinical strategy for overcoming therapeutic resistance. Multiple clinical trials are currently in progress to evaluate the antimalarial agent chloroquine (generally in its clinical formulation as hydroxychloroquine) and its impact on various forms of cancer therapy. In this commentary/review, we focus on the relatively limited number of studies in the literature where chloroquine has been tested in combination with chemotherapy or radiation in experimental tumor-bearing animal models. We also present recent data from our own laboratories, in cell culture experiments as well as in vivo studies, which demonstrate that neither chloroquine nor silencing of an autophagy regulatory gene was effective in conferring radiation sensitivity in an experimental model of breast cancer. The capacity for sensitization by chloroquine appears to be quite wide-ranging, with dramatic effects for some drugs/tumor models and modest or minimal effects in others. One possible caveat is that, with only a few exceptions, experiments have generally been performed in xenograft models, thereby eliminating the involvement of the immune system, which might ultimately be proven to play a central role in determining the effectiveness of autophagy inhibition in chemosensitization or radiosensitization. Nevertheless, a careful review of the current literature suggests that caution is likely to be warranted in translating preclinical findings relating to autophagy inhibition as an adjunctive therapeutic strategy. 23234644 Novobiocin analogues with second-generation noviose surrogates. Hsp90 is a promising therapeutic target for the treatment of cancer. Novobiocin is the first Hsp90 C-terminal inhibitor ever identified and recent structure-activity relationship studies on the noviose sugar identified several commercially available amines as suitable surrogates. In an effort to further understand this region of the molecule, analogues containing various N'-amino substituents were prepared and evaluated against two breast cancer cell lines for determination of their efficacy. Compound 37j manifested the most potent anti-proliferative activity from these studies and induced Hsp90-dependent client protein degradation at mid nano-molar concentrations. 23937307 Structural Coupling of Extrinsic Proteins with the Oxygen-Evolving Center in Red Algal Photosystem II As Revealed by Light-Induced FTIR Difference Spectroscopy. Effects of binding of extrinsic proteins (PsbO, PsbQ', PsbV, and PsbU) on the structure of the oxygen-evolving center (OEC) in photosystem II core complexes from a red alga, Cyanidium caldarium, were studied using Fourier transform infrared (FTIR) spectroscopy. S2-minus-S1 FTIR difference spectra showed that the protein conformations of the OEC, revealed by the changes in amide I and II bands, were significantly altered upon depletion of all the extrinsic proteins, but mostly recovered when PsbV was rebound with the support of other extrinsic proteins. The recovery of protein conformations correlated well with O2 evolution activity. This PsbV function of retaining a proper OEC conformation in red algae resembles that of PsbP in higher plants reported previously. 23912911 Continuous Moniezia benedeni Infection in Confined Cattle Possibly Maintained by an Intermediate Host on the Farm. Infection with Moniezia benedeni is sometimes found in confined cattle in Japan. Between October 2011 and January 2013, we monitored the fecal egg prevalence at a confined cattle farm in Miyazaki prefecture where continuous M. benedeni infection has been recognized for years to evaluate the possible infection routes. Fecal egg prevalence changed seasonally with the highest in October 2011 (27.3%: 9/33). This was followed by a gradual decrease until July 2012 (9.4%: 3/32) and then an increase between August to December 2012 when new egg-excreting cases were observed. The pattern of seasonal changes was similar to that reported previously for cattle kept in a barn with an outside playing yard. Although M. benedeni-infected mites were not found, we constantly detected an oribatid mite, Oribatula sakamorii Aoki, 1970, in the litter of cattle bedding from May to October 2012. This species belongs to a genus which has been reported to be a suitable intermediate host for M. benedeni, suggesting that M. benedeni infection may have been autonomously maintained at the farm via oribatid mites living in the cowshed. When infected cattle were treated with praziquantel, it was found that a single oral inoculation with a dose of 5 mg/kg was effective for deworming. 23939555 The prognostic impact of tumor-associated macrophages and intra-tumoral apoptosis in non-small cell lung cancer. Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80% of all lung malignancies. Tumor-associated macrophages (TAM) are abundant components of NSCLC. Although under certain conditions TAM can kill tumor cells, they can also act as tumor promoters secreting a variety of factors that directly stimulate tumor invasion and metastasis. TAM presents two distinct phenotypes: the classically activated (or M1) phenotype, which is highly pro-inflammatory (phagocytic and cytotoxic), and the alternatively activated (or M2) phenotype, which has anti-inflammatory and pro-tumoral properties. The polarization status of TAM depends on stimulating factors from the tumor microenvironment, and some in vitro evidence implies that the phagocytosis of apoptotic bodies derived from tumoral cells is a key factor in M1/M2 modulation, raising the question of whether the evaluation of the apoptotic index (AI) and macrophage polarization have a prognostic role in NSCLC patient survival. The present article systematically reviewed the published series of clinical data that correlated the AI and/or macrophage densities and polarization status (M1/M2) with the outcome of non-small cell lung cancer patients. Even though an overwhelming body of clinical data support that TAM's density, micro-anatomical localization, phenotype and intra-tumoral AI are independent predictors of survival time, no study to date has been conducted to evaluate the impact of these parameters altogether in NSCLC patient outcome. Joint analysis of these biologic factors in future studies might reveal their prognostic value in the management of NSCLC cases. 23404155 Morbidity and mortality after laparoscopic gastrectomy for advanced gastric cancer: results of a phase II clinical trial. Very few reports are available on laparoscopic gastrectomy (LG) for advanced gastric cancer (AGC) patients. We therefore conducted a prospective phase II clinical trial to address the feasibility of LG in AGC. Morbidity and mortality were evaluated. The eligibility criteria were as follows: 20-80 years of age, cT2N0-cT4aN2, American Society of Anesthesiologists score of 3 or less, and no other malignancy. A total of 204 patients were enrolled onto this study. Of these, 16 were excluded because far-advanced stages of disease were identified after laparoscopic exploration, and 31 were excluded because early gastric cancer was diagnosed postoperatively. All patients underwent a D2 lymphadenectomy. Morbidity was stratified according to the Clavien-Dindo classification. Conversion to open surgery occurred in 11 patients (7.0 %). The mean hospital stay was 6.3 days for distal gastrectomy and 8.5 days for total gastrectomy. The mean number of collected lymph nodes was 52.7 for distal gastrectomy and 63.8 for total gastrectomy. The rates of local and systemic complications of grade II or more were 8.3 and 3.2 %. One patient died of operative complications. In multivariate analysis, old age (>70 years) was an independent risk factor for complications, and old age and Billroth I anastomosis were predictable risk factors for local complications. LG with D2 lymphadenectomy was safe and technically feasible for the treatment of AGC, with acceptable rate of morbidity and mortality. ClinicalTrial.gov Registration: NCT01441336. 23836245 Perioperative Morbidity and Mortality of Same-day Bilateral TKAs: Incidence and Risk Factors. Controversy persists regarding the safety of same-day bilateral TKAs, and indications for same-day versus staged bilateral surgery need to be clarified. We compared the (1) 30-day mortality, (2) rates of in-hospital complications, (3) in-hospital charges, and (4) risk factors for complications among patients undergoing same-day and staged bilateral TKAs at two separate admissions within 1 year either less than 3 months apart (staged 0-3) or more than 3 months apart (staged 3-12) at an institution where same-day bilateral TKAs were discouraged in patients with more severe medical comorbidities. We analyzed institutional data from 3960 same-day, 172 staged 0-3, and 1533 staged 3-12 bilateral TKAs performed between 1998 and 2011. Patient demographics, comorbidities, and 30-day mortality were tabulated. Same-day patients were younger and healthier. Outcomes of interest included complications, blood transfusions, transfer to rehabilitation, and in-hospital charges. Regression models were conducted to identify independent risk factors for major morbidity or mortality. There were no differences in 30-day mortality among groups. The same-day group experienced more acute postoperative anemia, blood transfusions, and transfers to rehabilitation, but otherwise had complications comparable to those of the staged groups. In-hospital charges were lower in the same-day group. Congestive heart failure and pulmonary hypertension were the most significant factors associated with morbidity and mortality in the same-day group. In a high-volume subspecialty setting in which patients undergoing same-day bilateral TKAs were generally much healthier and younger, we found that same-day bilateral TKAs appeared to be safe. Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. 23825359 β-Adrenergic Regulation of the L-type Ca2+ Channel Does Not Require Phosphorylation of α1C Ser1700. Rationale: Sympathetic nervous system triggered activation of protein kinase A (PKA), which phosphorylates several targets within cardiomyocytes, augments inotropy, chronotropy and lusitopy. An important target of β-adrenergic stimulation is the sarcolemmal L-type Ca(2+) channel, CaV1.2, which plays a key role in cardiac excitation-contraction coupling. The molecular mechanisms of β-adrenergic regulation of CaV1.2 in cardiomyocytes, however, are incompletely known. Recently, it has been postulated that proteolytic cleavage at Ala(1800) and PKA phosphorylation of Ser(1700) are required for β-adrenergic modulation of CaV1.2. Objective: To assess the role of Ala(1800) in the cleavage of α1C and the role of Ser(1700) and Thr(1704) in mediating the adrenergic regulation of CaV1.2 in the heart. Methods and Results: Using a transgenic approach that enables selective and inducible expression in mice of FLAG-epitope tagged, dihydropyridine-resistant CaV1.2 channels harboring mutations at key regulatory sites, we show that adrenergic regulation of CaV1.2 current and fractional shortening of cardiomyocytes do not require phosphorylation of either Ser(1700) or Thr(1704) of the α1C subunit. The presence of Ala(1800) and the (1798)NNAN(1801) motif in α1C are not required for proteolytic cleavage of the α1C C-terminus, and deletion of these residues did not perturb adrenergic-modulation of CaV1.2 current. Conclusions: These results show that PKA phosphorylation of α1C Ser(1700) does not have a major role in the sympathetic stimulation of Ca(2+) current and contraction in the adult murine heart. Moreover, this new transgenic approach enables functional and reproducible screening of α1C mutants in freshly isolated adult cardiomyocytes in a reliable, timely and cost-effective manner. 23934879 Nematicidal metabolites from roots of Stellera chamaejasme against Bursaphelenchus xylophilus and Bursaphelenchus mucronatus. Bursaphelenchus xylophilus, the causal agent of pine wilt disease, severely damages pine forests, and Bursaphelenchus mucronatus, a species related to B. xylophilus, is weakly pathogenic. Because the use of synthetic pesticides to control pine wilt disease has raised concerns for human and environmental health, a search for useful botanically based compounds is needed. The ethyl acetate layer from an ethanol extract of Stellera chamaejasme L. roots showed significant nematicidal activity against B. xylophilus and B. mucronatus, with LC50 values of 169.7 and 37.7 µg mL(-1) , respectively, at 72 h. Further purification of the active layer yielded eight effective nematicidal compounds, which were identified by mass and nuclear magnetic resonance spectral data. Among the eight bioactive compounds, chamaejasmenin C induced the highest mortality against B. xylophilus with a LC50 value of 2.7 μM at 72 h, and chamaechromone exhibited strong nematicidal activity against B. mucronatus with a LC50 value of 0.003 μM at 72 h. The nematicidal metabolites from S. chamaejasme roots could be used as lead compounds for developing botanically based nematicides for the management of pine wilt disease. 23145496 Aetiology and outcome of open and closed globe eye injuries in children. This paper reports on the aetiology and outcome of childhood open and closed globe eye injuries presenting to the Children's Hospital at Westmead, Sydney, Australia from January 2000 to December 2008. Hospital-based retrospective study. Two hundred three cases of childhood eye injuries identified in a nine-year period, comprising 81 open globe and 122 closed globe injuries. Hospital records were examined for demographic data and injuries were classified into open globe and closed globe, based on the Ocular Trauma Classification. Parameters affecting the final visual outcome such as type of injury, zone of injury, initial visual acuity, wound length (only in open globe injuries) and lens injury were assessed. Most of the eye injuries resulted from the child poking itself or being poked accidentally (26%), with the home being the most common place of injury. A favourable visual outcome was noted with closed globe injuries as compared with open globe injuries (P < 0.01). Parameters that indicated a poor visual outcome included globe ruptures, zone 3 injuries, poor initial visual acuity, wound length >10 mm and lens trauma. Final visual acuity of 6/12 or better was observed in 68% of injured eyes. This study demonstrated improved visual outcomes when compared with previous studies. However, many unsalvageable childhood eye injuries with little useful vision were evident, and most disconcerting is that the majority of childhood eye injuries in this study were preventable. 23868685 Effect of Short-term Maximal Voluntary Co-contraction Training on Neuromuscular Function. The present study aimed to examine the effect of short-term training utilizing voluntary co-contraction with maximal efforts. 23 healthy young men (training group: TG, n=13; control group: CG, n=10) participated in this study. TG conducted a 4-week training program (3 days/week), which consisted of 4s simultaneous maximal voluntary contractions of elbow flexors and extensors at 90°of the elbow joint, followed by 4s muscle relaxation (10 repetitions/set, 5 sets/day). Before and after the intervention, maximal voluntary isometric and isokinetic torques and the muscle thicknesses of the elbow flexors and extensors were determined. The electromyograms (EMGs) of the 2 muscle groups during isometric maximal voluntary contraction (MVC) were also recorded. After the intervention, CG did not show any significant changes in all measured variables. In TG, significant increases were found in the agonist EMG activities during MVC, and maximal isometric and isokinetic torques of the elbow flexors and extensors, without significant changes in the muscle thicknesses and involuntary coactivation levels during MVC. The current results indicate that the training mode with maximal voluntary co-contraction is effective for improving the force-generating capabilities of the exercising muscles, without any increases in the level of involuntary coactivation during MVC. 23473900 Penile measurements in tanzanian males: guiding circumcision device design and supply forecasting. Voluntary medical male circumcision decreases the risk in males of HIV infection through heterosexual intercourse by about 60% in clinical trials and 73% at post-trial followup. In 2007 WHO and the Joint United Nations Programme on HIV/AIDS (UNAIDS) recommended that countries with a low circumcision rate and high HIV prevalence expand voluntary medical male circumcision programs as part of a national HIV prevention strategy. Devices for adult/adolescent male circumcision could accelerate the pace of scaling up voluntary medical male circumcision. Detailed penile measurements of African males are required for device development and supply size forecasting. Consenting males undergoing voluntary medical male circumcision at 3 health facilities in the Iringa region, Tanzania, underwent measurement of the penile glans, shaft and foreskin. Age, Tanner stage, height and weight were recorded. Measurements were analyzed by age categories. Correlations of penile parameters with height, weight and body mass index were calculated. In 253 Tanzanian males 10 to 47 years old mean ± SD penile length in adults was 11.5 ± 1.6 cm, mean shaft circumference was 8.7 ± 0.9 cm and mean glans circumference was 8.8 ± 0.9 cm. As expected, given the variability of puberty, measurements in younger males varied significantly. Glans circumference highly correlated with height (r = 0.80) and weight (r = 0.81, each p <0.001). Stretched foreskin diameter moderately correlated with height (r = 0.68) and weight (r = 0.71, each p <0.001). Our descriptive study provides penile measurements of males who sought voluntary medical male circumcision services in Iringa, Tanzania. To our knowledge this is the first study in a sub-Saharan African population that provides sufficiently detailed glans and foreskin dimensions to inform voluntary medical male circumcision device development and size forecasting. 23829881 The Effect of Freezing on Reactions with Environmental Impact. The knowledge that the freezing process can accelerate certain chemical reactions has been available since the 1960s, particularly in relation to the food industry. However, investigations into such effects on environmentally relevant reactions have only been carried out since the late 1980s. Some 20 years later, the field has matured and scientists have conducted research into various important processes such as the oxidation of nitrite ions to nitrates, sulfites to sulfates, and elemental mercury to inorganic mercury. Field observations mainly carried out in the polar regions have driven this work. For example, researchers have found that both ozone and mercury are removed from the troposphere completely (and almost instantaneously) at the time of Arctic polar sunrise. The monitoring activities suggested that both the phenomena were caused by involvement of bromine (and possibly iodine) chemistry. Scientists investigating the production of interhalide products (bromine and iodine producing interhalides) in frozen aqueous solutions have found that these reactions result in both rate accelerations and unexpected products. Furthermore, these scientists did this research with environmentally relevant concentrations of reagents, thereby suggesting that these reactions could occur in the polar regions. The conversion of elemental mercury to more oxidized forms has also shown that the acceleration of reactions can occur when environmentally relevant concentrations of Hg(0) and oxidants are frozen together in aqueous solutions. These observations, coupled with previous investigations into the effect of freezing on environmental reactions, lead us to conclude that this type of chemistry could potentially play a significant role in the chemical processing of a wide variety of inorganic components in polar regions. More recently, researchers have recognized the implications of these complementary field and laboratory findings toward human health and climate change. In this Account, we focus on the chemical and physical mechanisms that may promote novel chemistry and rate accelerations when water-ice is present. Future prospects will likely concentrate, once again, on the low-temperature chemistry of organic compounds, such as the humic acids, which are known cryospheric contaminants. Furthermore, data on the kinetics and thermodynamics of all types of reaction promoted by the freezing process would provide much assistance in determining their implications to environmental computer models. 23265461 Apoptosis during postmortem conditioning and its relationship to duck meat quality. The aim of this work was to examine the relationship of skeletal muscle apoptosis and postmortem development of meat quality. Colour, cooking loss, myofibril fragmentation index (MFI) and shear force of duck breast and thigh meat postmortem were measured, and changes of positive nuclei were assessed with Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphophate nick end-labelling method (TUNEL). Correlation analysis revealed that apoptosis were positively correlated with colour (L(*), a(*) and b(*)), cooking loss and MFI (P<0.05), while it is negatively correlated with shear force (P<0.05). Our results indicate the growing level of duck skeletal muscle cell apoptosis was associated with the postmortem development of meat quality traits such as meat colour, water holding capacity and tenderness. 23696547 Cannabis, ischemic stroke, and transient ischemic attack: a case-control study. There is a temporal relationship between cannabis use and stroke in case series and population-based studies. Consecutive stroke patients, aged 18 to 55 years, who had urine screens for cannabis were compared with a cohort of control patients admitted to hospital without cardiovascular or neurological diagnoses. One hundred sixty of 218 (73%) ischemic stroke/transient ischemic attack patients had urine drug screens (100 men; mean [SD] age, 44.8 [8.7] years). Twenty-five (15.6%) patients had positive cannabis drug screens. These patients were more likely to be men (84% versus 59%; χ(2): P=0.016) and tobacco smokers (88% versus 28%; χ(2): P<0.001). Control urine samples were obtained from 160 patients matched for age, sex, and ethnicity. Thirteen (8.1%) control participants tested positive for cannabis. In a logistic regression analysis adjusted for age, sex, and ethnicity, cannabis use was associated with increased risk of ischemic stroke/transient ischemic attack (odds ratio, 2.30; 95% confidence interval, 1.08-5.08). However after adjusting for tobacco use, an association independent of tobacco could not be confirmed (odds ratio, 1.59; 95% confidence interval, 0.71-3.70). This study provides evidence of an association between a cannabis lifestyle that includes tobacco and ischemic stroke. Further research is required to clarify whether there is an association between cannabis and stroke independent of tobacco. http://www.anzctr.org.au. Unique identifier: ACTRN12610000198022. 23934396 Automated quantitative analysis of lipid accumulation and hydrolysis in living macrophages with label-free imaging. The accumulation of lipids in macrophages is a key factor that promotes the formation of atherosclerotic lesions. Several methods such as biochemical assays and neutral lipid staining have been used for the detection of lipids in cells. However, a method for real-time quantitative assessment of the lipid content in living macrophages has yet to be shown, particularly for its kinetic process with drugs, due to the lack of suitable tools for non-invasive chemical detection. Here we demonstrate label-free real-time monitoring of lipid droplets (LDs) in living macrophages by using coherent anti-Stokes Raman scattering (CARS) microscopy. In addition, we have established an automated image analysis method based on maximum entropy thresholding (MET) to quantify the cellular lipid content. The result of CARS image analysis shows a good correlation (R (2) > 0.9) with the measurement of biochemical assay. Using this method, we monitored the processes of lipid accumulation and hydrolysis in macrophages. We further characterized the effect of a lipid hydrolysis inhibitor (diethylumbelliferyl phosphate, DEUP) and determined the kinetic parameters such as the inhibition constant, K i. Our work demonstrates that the automated quantitative analysis method is useful for the studies of cellular lipid metabolism and has potential for preclinical high-throughput screening of therapeutic agents related to atherosclerosis and lipid-associated disorders. 23954742 MiR-106b induces mitochondrial dysfunction and insulin resistance in C2C12 myotubes by targeting mitofusin-2. MicroRNA-106b (miR-106b) is reported to correlate closely with skeletal muscle insulin resistance and type 2 diabetes. The aim of this study was to identify an mRNA targeted by miR-106b which regulates skeletal muscle insulin sensitivity. MiR-106b was found to target the 3' untranslated region (3' UTR) of mitofusin-2 (Mfn2) through miR-106b binding sites and to downregulate Mfn2 protein abundance at the post-transcriptional level by luciferase activity assay combined with mutational analysis and immunoblotting. Overexpression of miR-106b resulted in mitochondrial dysfunction and insulin resistance in C2C12 myotubes. MiR-106b was increased in insulin-resistant cultured C2C12 myotubes induced by TNF-α, and accompanied by increasing Mfn2 level, miR-106b loss of function improved mitochondrial function and insulin sensitivity impaired by TNF-α in C2C12 myotubes. In addition, both overexpression and downregulation of miR-106b upregulated peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and estrogen-related receptor (ERR)-α expression. MiR-106b targeted Mfn2 and regulated skeletal muscle mitochondrial function and insulin sensitivity. Therefor, Inhibition of miR-106b may be a potential new strategy for treating insulin resistance and type 2 diabetes. 23936047 When women deliver with no one present in Nigeria: who, what, where and so what? With the current maternal mortality ratio (MMR) of 630/100,000 live births, Nigeria ranks among the nations with the highest mortality rates in the world. The use of skilled assistants during delivery has been identified a key predictor in the reduction of mortality rates in the world over. Not only are Nigerian women predominantly using unskilled attendants, one in five births are delivered with No One Present (NOP). We assessed who, what, where and the so what of this practice using 2008 Nigeria DHS (NDHS) data. The study revealed that the prevalence of NOP is highest in the northern part of Nigeria with 94% of all observed cases. Socio-demographic factors, including, women's age at birth, birth order, being Muslim, and region of residence, were positively associated with NOP deliveries. Mother's education, higher wealth quintiles, urban residence, decision-making autonomy, and a supportive environment for women's social and economic security were inversely associated with NOP deliveries. Women's autonomy and social standing were critical to choosing to deliver with skilled attendance, which were further amplified by economic prosperity. Women's' economic wellbeing is entwined with their feelings of independence and freedom. Programs that seek to improve the autonomy of women and their strategic participation in sound health seeking decisions will, most likely, yield better results with improvements in women's education, income, jobs, and property ownership. As a short term measure, the use of conditional cash transfer, proven to work in several countries, including 18 in sub-Saharan Africa, is recommended. Its use has the potential to reduce household budget constraint by lowering cost-related barriers associated with women's ability to demand and use life-saving services. Given the preponderance of NOP in the Northern region, the study suggests that interventions to eradicate NOP deliveries must initially focus this region as priority. 23884926 Fascin regulates the migration of subventricular zone-derived neuroblasts in the postnatal brain. After birth, stem cells in the subventricular zone (SVZ) generate neuroblasts that migrate along the rostral migratory stream (RMS) to become interneurons in the olfactory bulb (OB). This migration is a fundamental event controlling the proper integration of new neurons in a pre-existing synaptic network. Many regulators of neuroblast migration have been identified; however, still very little is known about the intracellular molecular mechanisms controlling this process. Here, we show that the actin-bundling protein fascin is highly upregulated in mouse SVZ-derived migratory neuroblasts. Fascin-1ko mice display an abnormal RMS and a smaller OB. Bromodeoxyuridine labeling experiments show that lack of fascin significantly impairs neuroblast migration, but does not appear to affect cell proliferation. Moreover, fascin depletion substantially alters the polarized morphology of rat neuroblasts. Protein kinase C (PKC)-dependent phosphorylation of fascin on Ser39 regulates its actin-bundling activity. In vivo postnatal electroporation of phosphomimetic (S39D) or nonphosphorylatable (S39A) fascin variants followed by time-lapse imaging of brain slices demonstrates that the phospho-dependent modulation of fascin activity ensures efficient neuroblast migration. Finally, fluorescence lifetime imaging microscopy studies in rat neuroblasts reveal that the interaction between fascin and PKC can be modulated by cannabinoid signaling, which controls neuroblast migration in vivo. We conclude that fascin, whose upregulation appears to mark the transition to the migratory neuroblast stage, is a crucial regulator of neuroblast motility. We propose that a tightly regulated phospho/dephospho-fascin cycle modulated by extracellular signals is required for the polarized morphology and migration in neuroblasts, thus contributing to efficient neurogenesis. 23583314 Happy eating: the underestimated role of overeating in a positive mood. Emotional eaters are often presumed to eat in response to negative emotions, while positive emotions have been largely neglected. The current study induced a positive, negative, or neutral mood in a student sample and subsequently measured food intake. In addition, the relation between caloric intake and mood improvement was assessed. It was expected that emotional eaters would consume more food than non-emotional eaters in the emotional conditions, and also more than in the neutral condition. Moderated regression analyses indeed showed a significant increase in food intake for emotional eaters in the positive compared to the neutral condition, and a trend towards higher food consumption than non-emotional eaters. No effects were found in the negative condition. With regard to mood changes during food intake, Pearson correlations demonstrated an association between amount of calories consumed and mood improvement after 5min of food consumption. However, there was no evidence for differences between emotional and non-emotional eaters. The current findings underline the importance of positive emotions in emotional eating, and provide new insights on the relationship between eating and mood melioration. 23856921 Combined Hemorrhage/Trauma Models in Pigs - Current State and Future Perspectives. The majority of injury combinations in multiply injured patients entail the chest, abdomen and extremities. Numerous pig models focus on the investigation of posttraumatic pathophysiology, organ performance monitoring and on potential treatment options. Depending on the experimental question, previous authors have included isolated insults (controlled or uncontrolled hemorrhage, chest trauma) or a combination of these injuries (hemorrhage with abdominal trauma, chest trauma, traumatic brain injury and/or long bone fractures).Combined trauma models in pigs can provide a high level of clinical relevance, when they are properly designed and mimicking the clinical situation. However, most of these models focus on the first hours after trauma, to assess the acute sequel of traumatic hemorrhage. However, hemorrhagic shock and the associated mass transfusion are also major causes for organ failure and mortality in the later clinical course. Thus, most models lack information on the pathomechanisms during the late posttraumatic phase. Studying new therapies only during the early phase is also not reflective of the clinical situation. Therefore, a longer observation period is required to study the effects of therapeutic approaches during intensive care treatment when using animal models. These long-term studies of combined trauma models will allow the development of valuable therapeutic approaches relevant for the later posttraumatic course. This review summarizes the existing porcine models and outlines the need for long term models in order to provide real effective novel therapeutics for multiple injured patients to improve organ function and clinical outcome. 23702710 CYCLONE-A Utility for De Novo Sequencing of Microbial Cyclic Peptides. We have developed a de novo sequencing software tool (CYCLONE) and applied it for determination of cyclic peptides. The program uses a non-redundant database of 312 nonribosomal building blocks identified to date in bacteria and fungi (more than 230 additional residues in the database list were isobaric). The software was used to fully characterize the tandem mass spectrum of several cyclic peptides and provide sequence tags. The general strategy of the script was based on fragment ion pre-characterization to accomplish unambiguous b-ion series assignments. Showcase examples were a cyclic tetradepsipeptide beauverolide, a cyclic hexadepsipeptide roseotoxin A, a lasso-like hexapeptide pseudacyclin A, and a cyclic undecapeptide cyclosporin A. The extent of ion scrambling in smaller peptides was as low as 5 % of total ion current; this demonstrated the feasibility of CYCLONE de novo sequencing. The robustness of the script was also tested against database sets of various sizes and isotope-containing data. It can be downloaded from the http://ms.biomed.cas.cz/MSTools/ website. Figure á…Ÿ 23525091 Production of soluble eukaryotic recombinant proteins in E. coli is favoured in early log-phase cultures induced at low temperature. Producing recombinant plant proteins expressed in Escherichia coli produce in high yields and in a soluble and functional form can be difficult. Under overexpression conditions, proteins frequently accumulate as insoluble aggregates (inclusion bodies) within the producing bacteria. We evaluated how the initial culture density, temperature and duration of the expression stage affect the production of some eukaryotic enzymes in E. coli. A high yield of active soluble proteins was obtained by combining early-log phase cultures and low temperatures for protein induction. When IPTG was added at OD600 = 0.1 and cultures were maintained at 4°C for 48-72 h, the soluble protein yield was 3 fold higher than that obtained in the mid-log phase (OD600 = 0.6). Besides, the target protein expression increased and the endogenous bacterial proteins reduced, thus making the protein purification process easier and more efficient. The protocol can be widely applied to proteins with a heterologous expression which was limited by loss of activity at high temperatures or by low soluble recombinant protein yield. 23766478 Impairment of intrinsically photosensitive retinal ganglion cells associated with late stages of retinal degeneration. To evaluate quantitative and qualitative age-related changes in intrinsically photosensitive melanopsin-containing retinal ganglion cells (ipRGCs) in transgenic P23H rats, an animal model of autosomal dominant retinitis pigmentosa (RP) was examined. ipRGC density, morphology, and integrity were characterized by immunohistochemistry in retinas extracted from P23H and Sprague-Dawley (SD) rats aged 4, 12, and 18 months. Differences between SD and P23H rats throughout the experimental stages, as well as the interactions among them, were morphologically evaluated. In rat retinas, we have identified ipRGCs with dendrites stratifying in either the outer margin (M1) or inner side (M2) of the inner plexiform layer, and in both the outer and inner plexuses (M3). A small group of M1 cells had their somas located in the inner nuclear layer (M1d). In SD rats, ipRGCs showed no significant changes associated with age, in terms of either mean cell density or the morphologic parameters analyzed. However, the mean density of ipRGCs in P23H rats fell by approximately 67% between 4 and 18 months of age. Moreover, ipRGCs in these animals showed a progressive age-dependent decrease in the dendritic area, the number of branch points and terminal neurite tips per cell, and the Sholl area. In the P23H rat model of retinitis pigmentosa, density, wholeness, and dendritic arborization of melanopsin-containing ganglion cells decrease in advanced stages of the degenerative disease. 23925651 The associations between QCT-based vertebral bone measurements and prevalent vertebral fractures depend on the spinal locations of both bone measurement and fracture. We examined how spinal location affects the relationships between quantitative computed tomography (QCT)-based bone measurements and prevalent vertebral fractures. Upper spine (T4-T10) fractures appear to be more strongly related to bone measures than lower spine (T11-L4) fractures, while lower spine measurements are at least as strongly related to fractures as upper spine measurements. Vertebral fracture (VF), a common injury in older adults, is most prevalent in the mid-thoracic (T7-T8) and thoracolumbar (T12-L1) areas of the spine. However, measurements of bone mineral density (BMD) are typically made in the lumbar spine. It is not clear how the associations between bone measurements and VFs are affected by the spinal locations of both bone measurements and VF. A community-based case-control study includes 40 cases with moderate or severe prevalent VF and 80 age- and sex-matched controls. Measures of vertebral BMD, strength (estimated by finite element analysis), and factor of risk (load:strength ratio) were determined based on QCT scans at the L3 and T10 vertebrae. Associations were determined between bone measures and prevalent VF occurring at any location, in the upper spine (T4-T10), or in the lower spine (T11-L4). Prevalent VF at any location was significantly associated with bone measures, with odds ratios (ORs) generally higher for measurements made at L3 (ORs = 1.9-3.9) than at T10 (ORs = 1.5-2.4). Upper spine fracture was associated with these measures at both T10 and L3 (ORs = 1.9-8.2), while lower spine fracture was less strongly associated (ORs = 1.0-2.4) and only reached significance for volumetric BMD measures at L3. Closer proximity between the locations of bone measures and prevalent VF does not strengthen associations between bone measures and fracture. Furthermore, VF etiology may vary by region, with VFs in the upper spine more strongly related to skeletal fragility. 23891330 Prevalence of Dry Eye Disease and its Risk Factors in Visual Display Terminal Users: The Osaka Study. To investigate tear function and prevalence of dry eye disease (DED) in visual display terminal (VDT) users. Cross-sectional study. Six hundred and seventy-two young and middle-aged Japanese office workers who used VDT completed questionnaires and underwent dry eye testing. We estimated the prevalence of DED using logistic regression analysis to examine associations between DED and possible risk factors. The ocular surface feature, prevalence of DED, and risk factors were evaluated. Of the 672 workers, 561 (83.5%, mean age: 43.3 ± 9.1 years) completed the questionnaire. The percentage of women with a composite outcome of definite DED or probable DED was 76.5%, which was higher than that among men (60.2%; odds ratio [OR] = 2.00; 95% confidence interval [CI], 1.29-3.10, P = .002). Workers over 30 years of age had a higher risk of DED (OR = 2.22; 95% CI, 1.06-4.66), as did workers using a VDT >8 hours per day (OR = 1.94; 95% CI, 1.22-3.09). Average Schirmer value was 18.7 ± 11.7 mm and tear break-up time (TBUT) was 4.0 ± 2.5 seconds (78.6% of study participants had TBUT ≤5 seconds). DED is prevalent among young to middle-aged Japanese VDT users. Ophthalmic findings revealed short TBUT and corneal staining accompanied by normal Schirmer test values. Increased risk for DED was noted for women aged over 30 years and prolonged VDT use. Measures to modify the adverse impact of VDT use on the ocular surface may provide a positive impact on public health and quality of life for office workers using VDTs. 23897903 Improving Gait and Balance in Patients With Leukoaraiosis Using Transcranial Direct Current Stimulation and Physical Training: An Exploratory Study. . Leukoaraiosis describes ischemic white matter lesions, a leading cause of gait disturbance in the elderly. . Our aim was to improve gait and balance in patients with leukoaraiosis by combining a single session of transcranial direct current stimulation (tDCS) and physical training (PT). . We delivered anodal tDCS over midline motor and premotor areas in 9 patients with leukoaraiosis. Patients underwent gait and balance training during tDCS stimulation (real/sham). This was repeated 1 week later with the stimulation crossed-over (sham/real) in a double-blind design. Assessments included gait velocity, stride length, stride length variability (primary gait outcomes), and a quantitative retropulsion test (primary balance outcome). . Combining tDCS and PT improved gait velocity, stride length, stride length variability, and balance (all at P ≤ .05). Overall, training without tDCS showed no significant effects. . Combined anodal tDCS and PT improves gait and balance in this patient group, suggesting that tDCS could be an effective adjunct to PT in patients with leukoaraiosis, for whom no treatment is currently available. 23857515 Anticancer effects of marine carotenoids, fucoxanthin and its deacetylated product, fucoxanthinol, on osteosarcoma. Survival of osteosarcoma patients hinges on prevention or treatment of recurrent and metastatic lesions. Therefore, novel chemotherapeutics for more effective treatment and prevention of this disease are required. Carotenoids are natural pigments and exhibit various biological functions. We evaluated the anti-osteosarcoma properties of several carotenoids. Among carotenoids, fucoxanthin and its metabolite fucoxanthinol, inhibited the cell viability of osteosarcoma cell lines. Fucoxanthinol induced G1 cell cycle arrest by reducing the expression of cyclin-dependent kinase 4, cyclin-dependent kinase 6 and cyclin E and apoptosis by reducing the expression of survivin, XIAP, Bcl-2 and Bcl-xL. Apoptosis was associated with activation of caspases-3, -8 and -9. In addition, fucoxanthinol inhibited the phosphorylation of phosphoinositide-dependent kinase 1 and Akt and the downstream glycogen synthase kinase 3β, resulting in downregulation of β-catenin. Fucoxanthinol inhibited the cell migration and invasion of osteosarcoma cells. It also reduced matrix metalloproteinase-1 expression and the activator protein-1 signal. Treatment of mice inoculated with osteosarcoma cells with fucoxanthin inhibited the development of osteosarcoma in mice. Fucoxanthin and fucoxanthinol inhibit cell growth, migration and invasion and induce apoptosis of osteosarcoma cells at least in part by inhibiting Akt and activator protein-1 pathways. Our findings provide a rationale for clinical evaluation of these novel agents in osteosarcoma. 23718960 Initiating policy, systems, and environmental changes for childhood obesity prevention by engaging six faith-based organizations. Little is known about how to engage faith-organizations, especially churches, when using policy, systems, and environmental (PSE) change approaches for prevention. This article documents the PSE changes implemented by engaging 6 faith organizations, with an estimated reach of 3500 members, for 18 months. Timeline (n = 6), focus group (n = 6), report (n = 18), and observational meeting (n = 16) and event (n = 5) summaries were analyzed using content analysis. Early changes were usually environmental changes. Mid and later changes focused on policy and systems change. Churches structured for process and outcome accountability and person-centered accountability can accomplish PSE changes. 23579167 Sclerostin: how human mutations have helped reveal a new target for the treatment of osteoporosis. In the 1990s there was a tremendous mood of optimism among pharmaceutical scientists that identification of disease-associated variations in the human genome would result in a surge of new drug targets (the 'gene-to-drug' mantra). To date the expected deluge of new drugs has not arrived. However, a small number of drugs arising directly from the study of rare human disorders showing Mendelian inheritance are now entering late stage clinical trials. Here we describe the advantages of this approach and discuss the background and early clinical trial findings with antibodies directed at a target identified in this way. 23801576 Relaxin treatment reverses insulin resistance in mice fed a high-fat diet. The endogenous hormone relaxin increases vascular reactivity and angiogenesis. We demonstrate that acute relaxin infusion in lean C57BL/6J mice enhances skeletal muscle perfusion and augments muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. However, an acute effect was absent in mice fed a high-fat (HF) diet for 13 weeks. In contrast, mice fed an HF diet for 13 weeks and continuously treated with relaxin for the final 3 weeks of the diet exhibited decreased fasting blood glucose. Insulin-stimulated whole-body glucose disappearance and percent suppression of hepatic glucose production are corrected by chronic relaxin. The increase in peripheral glucose utilization is a result of augmented in vivo skeletal muscle glucose uptake. Relaxin intervention improves endothelial-dependent vascular reactivity and induces a two-fold proliferation in skeletal muscle capillarity. The metabolic effects of the treatment are not attributed to changes in myocellular insulin signaling. Relaxin intervention reverses the accumulation of collagen III in the liver and collagen III and collagen IV in the heart; this is induced by HF feeding. These studies show the potential of relaxin in the treatment of diet-induced insulin resistance and vascular dysfunction. Relaxin provides a novel therapeutic approach targeting the extramyocellular barriers to insulin action, which are critical to the pathogenesis of insulin resistance. 23944795 New study method reveals reasons for link between gallstones and high BMI. Observational studies have suggested a link between elevated body mass index (BMI) and gallstones, but whether this reflects a causal effect has been unclear. 23778966 Arabidopsis MSI1 connects LHP1 to PRC2 complexes. Polycomb group (PcG) proteins form essential epigenetic memory systems for controlling gene expression during development in plants and animals. However, the mechanism of plant PcG protein functions remains poorly understood. Here, we probed the composition and function of plant Polycomb repressive complex 2 (PRC2). This work established the fact that all known plant PRC2 complexes contain MSI1, a homologue of Drosophila p55. While p55 is not essential for the in vitro enzymatic activity of PRC2, plant MSI1 was required for the functions of the EMBRYONIC FLOWER and the VERNALIZATION PRC2 complexes including trimethylation of histone H3 Lys27 (H3K27) at the target chromatin, as well as gene repression and establishment of competence to flower. We found that MSI1 serves to link PRC2 to LIKE HETEROCHROMATIN PROTEIN 1 (LHP1), a protein that binds H3K27me3 in vitro and in vivo and is required for a functional plant PcG system. The LHP1-MSI1 interaction forms a positive feedback loop to recruit PRC2 to chromatin that carries H3K27me3. Consequently, this can provide a mechanism for the faithful inheritance of local epigenetic information through replication. 23512075 Apogeotropic variant of lateral semicircular canal benign paroxysmal positional vertigo: is there a correlation between clinical findings, underlying pathophysiologic mechanisms and the effectiveness of repositioning maneuvers? The apogeotropic variant of horizontal semicircular canal (h-SCC) benign paroxysmal positional vertigo (BPPV) is attributed to canalithiasis of the anterior arm or cupulolithiasis. This study is an attempt to distinguish the most effective maneuvers for each case, by investigating any correlation, between the clinical findings or the treatment options and the possible location of the displaced debris. A review of the literature (1990-2012) was conducted via the PubMed database with the search terms "apogeotropic nystagmus and benign paroxysmal positional vertigo." Articles on central nervous system lesions were excluded. The studies included in the analysis provided detailed diagnostic and therapeutic protocols, supported by the resolution of the signs and symptoms through repositioning maneuvers. Descriptive statistics were used to summarize the findings. Intergroup and intragroup comparisons were performed through Pearson's χ or Fischer's exact test. Protocols vary considerably among studies. Nystagmus from seated to supine position is the best studied secondary clinical sign and possibly a clinical indication of cupulolithiasis. In patients with symmetrical responses in the head yaw test, no significant differences can be detected in the occurrence of secondary signs of lateralization compared to patients with asymmetrical responses. The Gufoni maneuver seems to be effective in all pathophysiologic types of apogeotropic h-SCC BPPV. The Barbeque and Vannucchi-Asprella maneuvers mainly target at lithiasis of the anterior ampullary arm. The results of this analysis may imply that different clinical subgroups of h-SCC BPPV may regard to different pathophysiologic and therapeutical mechanisms. 23864581 Effects of Metformin Dose on Cancer Risk Reduction in Patients with Type 2 Diabetes Mellitus: A 6-Year Follow-up Study. To explore the effects of metformin dose on cancer risk reduction in patients with type 2 diabetes. Population-based cohort study. National Health Insurance program Longitudinal Health Insurance Database. A total of 65,754 age- and gender-matched patients without diabetes and no previous cancer diagnosis were extracted from the database. We compared cancer risk among the subjects who had no diabetes, had type 2 diabetes but were not on diabetes drugs, used metformin only, used antidiabetic drugs other than metformin, or used metformin in combination with other antidiabetic drugs. Our results revealed dose-dependent effects of metformin on cancer risk and cancer onset times. A significant decrease in cancer risk was found in the monotherapy group who received more than 360 defined daily doses (DDDs) of metformin (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.24-0.66). The greatest decrease in cancer risk was observed in patients who took more than 1080 DDDs (HR 0.27, 95% CI 0.09-0.84). Significantly greater dose-dependent effects were seen in patients who used metformin in combination with other antidiabetic drugs. The magnitude of cancer risk reduction and prolonged cancer onset times produced by metformin in patients with type 2 diabetes depended on the dose of metformin, regardless of whether metformin was used alone or combined with other antidiabetic drugs. 23844224 Aging and curvature discrimination from static and dynamic touch. Two experiments evaluated the ability of 30 older and younger adults to discriminate the curvature of simple object surfaces from static and dynamic touch. The ages of the older adults ranged from 66 to 85 years, while those of the younger adults ranged from 20 to 29 years. For each participant in both experiments, the minimum curvature magnitude needed to reliably discriminate between convex and concave surfaces was determined. In Experiment 1, participants used static touch to make their judgments of curvature, while dynamic touch was used in Experiment 2. When static touch was used to discriminate curvature, a large effect of age occurred (the thresholds were 0.67 & 1.11/m for the younger and older participants, respectively). However, when participants used dynamic touch, there was no significant difference between the ability of younger and older participants to discriminate curvature (the thresholds were 0.58 & 0.59/m for the younger and older participants, respectively). The results of the current study demonstrate that while older adults can accurately discriminate surface curvature from dynamic touch, they possess significant impairments for static touch. 23795975 Clinically relevant reductions in HbA1c without hypoglycaemia: results across four studies of saxagliptin. In four 24-week controlled studies, the antihyperglycaemic efficacy of saxagliptin was demonstrated in patients with type 2 diabetes mellitus as add-on therapy to glyburide, a thiazolidinedione, or metformin, and when used in initial combination with metformin vs. metformin monotherapy in drug-naive patients. Data from these studies were analysed to compare the proportions of patients who achieved specific reductions from baseline in glycated haemoglobin [HbA1c ; reductions of ≥ 0.5% and ≥ 0.7% in all studies (prespecified); reductions ≥ 1.0% in the add-on studies and ≥ 1.0% to ≥ 2.5% in the initial combination study (post hoc)] for saxagliptin vs. comparator at week 24. We report overall rates of glycaemic response defined by these reductions in HbA1c and rates of response without experiencing hypoglycaemia. Large glycaemic response rates were higher with saxagliptin 2.5 and 5 mg/day than with comparator (HbA1c  â‰¥ 1.0%, 31.7-50.3% vs. 10.3-20.0%) as add-on therapy and higher with saxagliptin 5 mg/day as initial combination with metformin than with metformin monotherapy (HbA1c  â‰¥ 2.0%, 68.3% vs. 49.8%) in drug-naive patients. Addition of saxagliptin was associated with a low incidence of hypoglycaemia; overall response rates and response rates excluding patients who experienced hypoglycaemia were similar. Analysis of several demographic and baseline clinical variables revealed no consistent correlations with response to saxagliptin. Whether receiving saxagliptin as an add-on therapy to glyburide, a thiazolidinedione, or metformin or in initial combination with metformin, a greater percentage of patients achieve clinically relevant large reductions in HbA1c vs. comparator, with a low incidence of hypoglycaemia. 23017415 Amino acid composition, antinutrients and allergens in the peanut protein fraction obtained by an aqueous enzymatic process. Enzyme-assisted aqueous extraction (EAE) of peanut kernel was used to extract oil and protein. The aqueous fraction (AF) obtained by EAE had a better essential amino acid profile than the residues obtained by solvent extraction (Rs) and cold pressing (Rc). No major difference in the trypsin inhibitor activity among AF, Rs and Rc was observed; however, the trypsin inhibitor activity was drastically reduced in the residue obtained after EAE. AF was subjected to MALDI-TOF/MS, revealing it to be rich in peptides (107) with molecular masses from m/z 700 to 2369Da. AF had an extremely low phytate content and was rich in peptides, which could be used as a food supplement. ESI-MS/MS data were used for the identification of major peanut allergens, viz., Ara h1, h3, h6-8. Their allergenic potential needs to be established. 23861532 Undifferentiated spondyloarthritis vs ankylosing spondylitis and psoriatic arthritis: a real-life prospective cohort study of clinical presentation and response to treatment. Objective. SpA is a phenotypically heterogeneous disease, with AS and PsA as its best studied subtypes. This study aimed to investigate whether, despite a different phenotypic presentation, patients with undifferentiated SpA (uSpA) have similar disease activity and response to treatment to those with AS and PsA.Methods. 175 patients presenting at a dedicated SpA outpatient clinic were recruited in a real-life prospective cohort with follow-up every 3 months. Clinical characteristics, disease activity at presentation and response to treatment of uSpA were compared with AS and PsA.Results. Twenty-three per cent (n = 40) of the patients were classified as uSpA. These patients were younger and tended to have a shorter disease duration than AS and PsA patients. uSpA patients exhibited a mixed axial (inflammatory back pain in 87.5%) and peripheral (peripheral arthritis in 62.5%) phenotype, with almost half of the patients having low-grade sacroiliitis on conventional X-ray. The overall disease activity in uSpA was similar to AS and higher than in PsA, also when analysing only anti-TNF naive patients. Initiation of TNF blockade significantly decreased disease activity in uSpA, with a similar amplitude to that in AS and PsA.Conclusion. uSpA is a frequent, severe and anti-TNF-responsive phenotypic subtype of SpA. In agreement with the new ASAS classification criteria for axial and peripheral SpA and emerging data on TNF blockade in non-radiographic axial SpA and peripheral uSpA, these data emphasize the need for early diagnosis and optimal treatment of not only AS and PsA but also other SpA subforms. 23488912 Columnar Cell Variant of Papillary Thyroid Carcinoma: A Study of Ten Cases with Emphasis On CDX-2 Expression. Background: Columnar cell variant is a recognized rare variant of papillary thyroid carcinoma associated with an uncertain clinical course. This variant has two sub variants, and one is regarded as a more aggressive form in comparison to the more common classical and follicular variants. These tumors have morphological resemblance with endometrial or colonic adenocarcinoma. CDX2, a transcription factor of the caudal homeobox family, plays a key role in intestinal development and differentiation and it is widely used as a marker to detect adenocarcinoma of intestinal and colonic origin. CDX2 has been rarely reported in papillary thyroid carcinoma. Methods: We studied ten cases of columnar cell variant of papillary thyroid carcinoma. The histological, architectural, and cytological features fulfilled the diagnostic criteria of the columnar cell variant of papillary thyroid carcinoma as defined by the current WHO classification. Ten patients (6M : 4F) ranging from 32 to 90 years of age (mean 58.3 years) presented with tumors classified as indolent (4 cases) or aggressive (6 cases); 3 with BRAFV600E mutation. All cases were -Catenin negative. The Ki-67 proliferative index was up to 50%. All cases were TTF-1 positive. Using paraffin embedded blocks, immunohistochemistry for CDX2 was performed to evaluate the reactivity of this antibody to this variant of papillary thyroid carcinoma. Results: Nuclear positivity for CDX2 was detected in one out of the ten cases studied (10%); the other nine cases did not express CDX2. Conclusion: Only one of our cases showed nuclear positivity for CDX2, therefore our study failed to confirm this as a marker for columnar cell variant of papillary thyroid carcinoma. The absence of CDX2 in the majority of the cases does not support the theory of CDX2 playing a role in the intestinal phenotype of these tumors. KEYWORDS: Papillary Thyroid Carcinoma, CDX-2, Columnar Cell, Immunohistochemistry. 23960167 The 26-Week Tg.Rash2 Mice Carcinogenicity Studies: Microscopic Examination of Only Select Tissues in Low- and Mid-dose Groups. A typical 26-week Tg.rasH2 mouse carcinogenicity study usually has 4 dose groups, composed of 25 mice/sex, which include 1 control and 3 test article-treated groups. In every study, there is a protocol required full tissue list of 49 tissues which is examined microscopically in all animals of these 4 dose groups. Based on retrospective analysis of the historical control data collected from studies conducted in Tg.rasH2 mice from 2004 to 2012, we propose that a full tissue list be examined as usual in the control and high-dose groups; however, in the low- and mid-dose groups, only select tissues should be examined. The select tissue list is generated after analyzing common tumors, uncommon tumors seen grossly, uncommon tumors not seen grossly, organ weight variations with accountable microscopic lesions, and target organs identified in the high-dose groups. The proposed changes to the International Conference on Harmonization S1 guidance may lead to an increased need for 26-week Tg.rasH2 mice studies. The time savings resulting from processing and evaluating a select tissue list rather than a full tissue list from low- and mid-dose groups of Tg.rasH2 mouse studies will further accelerate early completion of these studies without compromising the quality and integrity. 23547843 Cytotoxicity and Modulation of Cancer-Related Signaling by (Z)- and (E)-3,4,3',5'-Tetramethoxystilbene Isolated from Eugenia rigida. Bioassay-guided fractionation of the leaves of Eugenia rigida yielded three stilbenes, (Z)-3,4,3',5'-tetramethoxystilbene (1), (E)-3,4,3',5'-tetramethoxystilbene (2), and (E)-3,5,4'-trimethoxystilbene (3). Their structures were determined using 1D- and 2D-NMR spectroscopy and HRESIMS. The sterically hindered Z-stereoisomer 1, a new natural product, was prepared by time-dependent photoisomerization of the E-isomer (2) under UV irradiation at λ254 nm, while 2,3,5,7-tetramethoxyphenanthrene (5) was identified at λ365 nm by UHPLC/APCI-MS and NMR spectroscopy. Compounds 1-3 were tested against a panel of luciferase reporter gene assays that assess the activity of many cancer-related signaling pathways, and the Z-isomer (1) was found to be more potent than the E-isomer (2) in inhibiting the activation of Stat3, Smad3/4, myc, Ets, Notch, and Wnt signaling, with IC50 values between 40 and 80 μM. However, both compounds showed similar inhibition against Ap-1 and NF-κB signaling. In addition, 1 demonstrated cytotoxic activity toward human leukemia cells, solid tumor cells of epidermal, breast, and cervical carcinomas, and skin melanoma, with IC50 values between 3.6 and 4.3 μM, while 2 was weakly active against leukemia, cervical carcinoma, and skin melanoma cells. Interestingly, 2 showed antioxidant activity by inhibition of ROS generation to 50% at 33.3 μM in PMA-induced HL-60 cells, while 1 was inactive at 100 μM (vs Trolox 1.4 μM). 23688651 Comparative effectiveness of nonpurpuragenic 595-nm pulsed dye laser and microsecond 1064-nm neodymium:yttrium-aluminum-garnet laser for treatment of diffuse facial erythema: A double-blind randomized controlled trial. Facial erythema is a common symptom that responds to vascular laser treatment, but there are few comparative studies. We sought to compare the effectiveness of microsecond 1064-nm neodymium:yttrium-aluminum-garnet (Nd:YAG) laser with nonpurpuragenic 595-nm pulsed dye laser (PDL) for diffuse facial erythema. This was a split-face, double-blind randomized controlled trial. Bilateral cheeks received 4 treatments each at one month intervals with PDL or Nd:YAG. Spectrophotometer measurements, digital photographs, pain scores, and patient preferences were recorded. Sixteen patients enrolled and 2 dropped out. Fourteen patients, all skin types I to III, 57% women, mean age 42 years, completed the study and were analyzed. Spectrophotometer readings changed after both PDL (8.9%) and Nd:YAG (2.5%), but varied by treatment type, with PDL reducing facial redness 6.4% more from baseline than Nd:YAG (P = .0199; 95% confidence interval -11.6 to -1.2). Pain varied (P = .0028), with Nd:YAG associated with less pain, at 3.07, than PDL at 3.87. Subjects rated redness as improved by 52% as a result of PDL, and 34% as a result of Nd:YAG (P = .031; 95% confidence interval -34.6 to -1.94). No serious adverse events were observed. Lasers settings are not standardized across devices. Facial erythema is safely and effectively treated with PDL and Nd:YAG. Nonpupuragenic PDL may be more effective for lighter-skinned patients, but microsecond Nd:YAG may be less painful. 23394441 Glargine safety, diabetes and cancer. INTRODUCTION: In 2009, several epidemiological studies suggested a higher frequency of malignancy in insulin glargine -treated patients. A number of follow-up epidemiological population studies as well as two randomized, controlled clinical studies, one a 5000-patient retinopathy study and the other a 12,000-patient cardiovascular outcomes trial (ORIGIN), found no higher frequency of malignancy in glargine-treated patients. AREAS COVERED: We reviewed the existing literature as well as U.S. FDA records to investigate the association of cancer, diabetes, and insulin. There is a 20 - 40% higher incidence of malignancy in type 2 diabetes patients. Certain cancers are more common, including hepatocellular and pancreatic carcinoma, colorectal cancer, renal cancer, and breast and endometrial cancer, and non-Hodgkin's lymphoma. There are numerous inter-related factors which may promote both diabetes and malignancy, including dietary patterns, obesity, insulin resistance, and alcoholism. Patients who receive insulin treatment are typically older and "sicker" than those who receive oral agents. EXPERT OPINION: It is very difficult to prove causal associations between diabetes and cancer due to the host of confounding factors. The hypothesis that hyperinsulinemia and IGF-1 receptor activation promote cancer is strong, but confounded by the association of hyperinsulinemia with obesity, which separately promotes malignancy. Although statistical techniques to adjust for confounding variables can improve epidemiological comparisons, the lesson of the glargine cancer controversy is that controlled clinical trials are the only means to definitely prove hypotheses. 23722460 Characteristics of respiratory distress syndrome in infants of different gestational ages. The purpose of this study was to compare the risk factors, clinical characteristics, and complications of respiratory distress syndrome (RDS) in infants delivered very preterm, late preterm, and term in order to help optimize the management of RDS in neonates. A retrospective study was conducted on neonates admitted to the NICU between January 2006 and December 2010. The enrolled infants with RDS were categorized as very preterm (<32(0/7) weeks gestation), moderately preterm (32(0/7)-33(6/7) weeks), late preterm (34(0/7)-36(6/7) weeks), and term (37(0/7)-42(0/7) weeks). The rates, potential risk factors, clinical characteristics, and complications of RDS of these four groups were comparatively analyzed. There was an increasing trend in incidence of RDS among the NICU admissions annually. Caesarean section without labor was significantly associated with RDS in term and late preterm infants (P < 0.001). Rates of requirements for ventilator and pulmonary surfactant were similar in very preterm and term infants but significantly lower in late preterm infants (P < 0.001). The oxygenation index value was not substantially lower in late preterm and term infants compared to very preterm infants, and the arterial oxygenation efficiency was improved slowly (P < 0.001). Incidence of pneumonia and occurrence of pneumothorax were significantly higher in term infants (P < 0.001). Term infants with RDS showed an association of RDS with caesarean section without labor and lung infection. These infants also showed slower improvement of oxygenation after surfactant administration and mechanical ventilation, and they experienced a high rate of pneumothorax complication, which was also noticed in late preterm neonates. 23420586 Collapsin response mediator protein 4 affects the number of tyrosine hydroxylase-immunoreactive neurons in the sexually dimorphic nucleus in female mice. In the sexually dimorphic anteroventral periventricular nucleus (AVPV) of the hypothalamus, females have a greater number of tyrosine hydroxylase-immunoreactive (TH-ir) and kisspeptin-immunoreactive (kisspeptin-ir) neurons than males. In this study, we used proteomics analysis and gene-deficient mice to identify proteins that regulate the number of TH-ir and kisspeptin-ir neurons in the AVPV. Analysis of protein expressions in the rat AVPV on postnatal day 1 (PD1; the early phase of sex differentiation) using two-dimensional fluorescence difference gel electrophoresis followed by MALDI-TOF-MS identified collapsin response mediator protein 4 (CRMP4) as a protein exhibiting sexually dimorphic expression. Interestingly, this sexually differential expressions of CRMP4 protein and mRNA in the AVPV was not detected on PD6. Prenatal testosterone exposure canceled the sexual difference in the expression of Crmp4 mRNA in the rat AVPV. Next, we used CRMP4-knockout (CRMP4-KO) mice to determine the in vivo function of CRMP4 in the AVPV. Crmp4 knockout did not change the number of kisspeptin-ir neurons in the adult AVPV in either sex. However, the number of TH-ir neurons was increased in the AVPV of adult female CRMP4-KO mice as compared with the adult female wild-type mice. During development, no significant difference in the number of TH-ir neurons was detected between sexes or genotypes on embryonic day 15, but a female-specific increase in TH-ir neurons was observed in CRMP4-KO mice on PD1, when the sex difference was not yet apparent in wild-type mice. These results indicate that CRMP4 regulates the number of TH-ir cell number in the female AVPV. 23843136 Arthroscopically assisted stabilization of acute high-grade acromioclavicular joint separations in a coracoclavicular Double-TightRope technique: V-shaped versus parallel drill hole orientation. The arthroscopically assisted Double-TightRope technique has recently been reported to yield good to excellent clinical results in the treatment of acute, high-grade acromioclavicular dislocation. However, the orientation of the transclavicular-transcoracoidal drill holes remains a matter of debate. A V-shaped drill hole orientation leads to better clinical and radiologic results and provides a higher vertical and horizontal stability compared to parallel drill hole placement. This was a cohort study; level of evidence, 2b. Two groups of patients with acute high-grade acromioclavicular joint instability (Rockwood type V) were included in this prospective, non-randomized cohort study. 15 patients (1 female/14 male) with a mean age of 37.7 (18-66) years were treated with a Double-TightRope technique using a V-shaped orientation of the drill holes (group 1). 13 patients (1 female/12 male) with a mean age of 40.9 (21-59) years were treated with a Double-TightRope technique with a parallel drill hole placement (group 2). After 2 years, the final evaluation consisted of a complete physical examination of both shoulders, evaluation of the Subjective Shoulder Value (SSV), Constant Score (CS), Taft Score (TF) and Acromioclavicular Joint Instability Score (ACJI) as well as a radiologic examination including bilateral anteroposterior stress views and bilateral Alexander views. After a mean follow-up of 2 years, all patients were free of shoulder pain at rest and during daily activities. Range of motion did not differ significantly between both groups (p > 0.05). Patients in group 1 reached on average 92.4 points in the CS, 96.2 % in the SSV, 10.5 points in the TF and 75.9 points in the ACJI. Patients in group 2 scored 90.5 points in the CS, 93.9 % in the SSV, 10.5 points in the TF and 84.5 points in the ACJI (p > 0.05). Radiographically, the coracoclavicular distance was found to be 13.9 mm (group 1) and 13.4 mm (group 2) on the affected side and 9.3 mm (group 1) and 9.4 mm (group 2) on the contralateral side. The distance of neither the affected side nor the contralateral side differed significantly between both groups (p > 0.05). In group 1, eight patients (53 %) and in group 2 four patients (31 %) revealed signs of dynamic posterior instability (p > 0.05). Clavicular drill hole enlargement was found to be equally distributed in group 1, whereas group 2 displayed a cone-shaped form. The Double-TightRope technique yields good to excellent clinical results in both V-shaped and parallel drill hole placement. Partial recurrent vertical and horizontal instability represents a problem in both techniques. So far, no significant differences regarding clinical or radiologic results have been found. Long-term results are needed to reveal possible advantages in terms of clinical and radiologic acromioclavicular stability. 23625908 1,1-Diphenyl,2-picrylhydrazyl free radical scavenging, bactericidal, fungicidal and leishmanicidal properties of Teucrium stocksianum. In the present study, we evaluated the pharmacological and toxicological effects of Teucrium stocksianum. The crude extract of T. stocksianum (Ts.Cr) and its subsequent organic fractions: n-hexane (Ts.Hex), chloroform (Ts.CHCl3) and ethyl acetate (Ts.EtAc) exhibited 1,1-diphenyl,2-picrylhydrazyl free radical scavenging activity with different potencies. Ts.EtAc was found to be most potent. Ts.Cr, Ts.Hex, Ts.CHCl3 and Ts.EtAc showed significant bactericidal activity against Escherichia coli, Staphylococcus aureus, Salmonella typhi, Shigella flexneri and Bacillus subtilis at their extent. Ts.Cr, Ts.Hex, Ts.CHCl3 and Ts.EtAc displayed fungicidal action against Aspergillus niger, Aspergillus flavus, Aspergillus fumigatus and Fusarium solani at various minimum inhibitory concentrations. Ts.Cr and Ts.EtAc exhibited marked inhibition of Leishmania tropica growth, observed after 48 and 96 hrs of treatment. These data indicate that the T. stocksianum methanolic extract and its resultant fractions possess antioxidant, antibacterial, antifungal and antileishmanial activities. Thus, the present research unearths the scientific base for T. stocksianum medicinal application as antioxidant and antimicrobial agents. 23938141 PET and PET-CT imaging findings of peritoneal and omental involvement in patients with lymphoma. A retrospective institutional-review-board-approved study was performed evaluating positron emission tomography (PET)-computed tomography (CT) imaging findings of peritoneal and omental involvement of lymphoma. Twelve patients were identified with a wide spectrum of imaging findings on PET-CT including but not limited to peritoneal thickening, ascites, and serosal involvement. Lymphoma is among the rare causes of malignant peritoneal or omental involvement. The most common manifestations of peritoneal lymphomatosis are peritoneal 2-[fluorine 18] fluoro-2-deoxy-d-glucose uptake with corresponding peritoneal thickening and nonobstructive serosal masses on CT. 23435613 Allelic imbalance in sporadic parathyroid carcinoma and evidence for its de novo origins. Parathyroid cancer is a rare, clinically aggressive cause of primary hyperparathyroidism, and whether these malignancies generally evolve from pre-existing benign adenomas or arise de novo is unclear. Furthermore, while inactivation of the CDC73 (HRPT2) tumor suppressor gene, encoding parafibromin, is a major contributor, other genes essential to parathyroid carcinogenesis remain unknown. We sought to identify genomic regions potentially harboring such oncogenes or tumor suppressor genes, and to gain insight into the origins and molecular relationship of malignant versus benign parathyroid tumors. We performed genome-wide copy-number and loss of heterozygosity analysis using Affymetrix 50K SNP mapping arrays and/or comparative genomic hybridization on 16 primary parathyroid carcinomas, local recurrences or distant metastases, and matched normal controls, from 10 individuals. Recurrent regions of allelic loss were observed on chromosomes 1p, 3, and 13q suggesting that key parathyroid tumor suppressor genes are located in these chromosomal locations. Recurrent allelic gains were seen on chromosomes 1q and 16, suggesting the presence of parathyroid oncogenes on these chromosomes. Importantly, the most common alteration in benign parathyroid adenomas, loss of 11q, was not found as a recurrent change in the malignant parathyroid tissues. Molecular allelotyping using highly polymorphic microsatellite markers provided further confirmation that the prevalence of 11q loss is markedly and significantly lower in carcinomas as compared with adenomas. Our observations provide molecular support for the concept that sporadic parathyroid cancer usually arises de novo, rather than evolving from a pre-existing typical benign adenoma. Furthermore, these results help direct future investigation to ultimately determine which of the candidate genes in these chromosomal locations make significant contributions to the molecular pathogenesis of parathyroid cancer. 23891161 Systematic screening for undernutrition in hospitals: Predictive factors for success. Since 2007, systematic screening for undernutrition has become a performance indicator (PI) for hospitals within the National Benchmarks on Quality of Care of the Dutch Health Care Inspectorate (HCI). Its introduction was guided by a national implementation program. The aim of this study was to evaluate the screening results from 2007 to 2010 and to identify predictive factors for achieved screening results. All 97 Dutch hospitals were obliged to report screening results to the HCI. An additional questionnaire was developed to determine hospital characteristics, including hospital type, size, participation in implementation program, screening tool used, use of electronic records, presence of hospital-wide or ward task forces, and protocol-defined referral. Multivariate linear regression analysis was used to identify predictive factors for the obtained screening results in 2010. The mean screening percentage increased from 51 ± 28% in 2007 (n = 75 hospitals, n = 340,000 patients) to 72 ± 17% in 2010 (n = 97; n = 1,050,000) (p < 0.01). Eighty-one hospitals returned the questionnaire. A higher screening percentage was associated with more clinical admissions (highest vs. lowest tertile: β = 14.0, 95% CI 3.9-20.5; p < 0.01; middle vs. lowest: β = 7.3, -0.8 to 15.6; p = 0.05), presence of protocol-defined referral to a dietician (β = 10.5, 2.9-18.0; p < 0.01), and use of the SNAQ screening tool (vs. MUST: β = 9.1, 1.7-16.6; p = 0.02). Screening percentages have increased significantly since the introduction of the PI. Screening was more frequent in hospitals which have more patient admissions, protocol-defined referral to a dietician, and who use the SNAQ screening tool. This information may assist in improving Dutch screening rates and in implementation in other countries. 23919863 Cervical cancer screening among Michigan women: 'The Special Cancer Behavioral Risk Factor Survey', 2004-2008. The burden of cervical cancer remains greater among minority women. The purpose of this study was to evaluate racial/ethnic disparities in cervical cancer screening among minority women in Michigan. Data from 8,023 women (≥ 40 years) surveyed in the 2004-2008 Michigan Special Cancer Behavioral Risk Factor Survey were used to assess racial/ethnic differences in cervical cancer screening, knowledge and beliefs. Unexpectedly, African-American and Hispanic women reported being screened for cervical cancer at rates similar to, or higher than, Whites. Women demonstrated limited knowledge of cervical cancer risk factors and its signs/symptoms. Most minority women were more likely than Whites to believe in the importance of cervical screening, with Hispanic women more likely to support HPV vaccination. Differential utilisation of screening does not explain the disproportionately high rates of cervical cancer among minorities. Future research should examine disparities in the follow-up of abnormal cervical results and receipt of treatment. 23820387 Synthesis and the 5-HT6 receptor antagonistic effect of 3-arylsulfonylamino-5,6-dihydro-6-substituted pyrazolo[3,4]pyridinones for neuropathic pain treatment. A novel series of 3-arylsulfonylamino-5,6-dihydro-6-substituted-1H-pyrazolo[3,4-c]pyridine-7-ones was designed and synthesized as 5-HT6 ligands. Among the derivatives synthesized, the lead compound, 12b, having piperidine functionality at the 6-position and (1-naphthyl)sulfonamino at the 3-position of the core structure showed the most potent 5-HT6 inhibitory activity in vitro, good stability without CYP liability, and good neuropathic pain alleviation activity in a rat animal model. 23561640 Alcohol use increases diagnostic testing, procedures, charges, and the risk of hospital admission: a population-based study of injured patients in the emergency department. Alcohol use may alter mental status and vital signs in injured patients, leading to increased testing during emergency department (ED) evaluation. We hypothesized that alcohol use increases the hospital charges when caring for these injured patients. The National Hospital Ambulatory Medical Care Survey collects weighted population-based estimates of ED use. We analyzed injury-related visits of adult patients, and resource use and admission rates were compared by the presence of alcohol. Alcohol was involved in 6.0% of injury-related ED visits. Alcohol-present patients arrived by ambulance more frequently (45% vs 21%, P < .001), had a 26% longer ED stay (211 vs 167 minutes, P < .001), and underwent more diagnostic testing. They were twice as likely to be admitted (14.0% vs 6.5%, P < .001). Additional ED charges were over $217 million. Patients with alcohol-related injuries use significantly more resources, with a significant added financial burden. Insurance companies in many states can deny coverage for injuries caused by alcohol use, shifting these expenses to trauma centers. 22692947 Infertility insurance mandates and multiple births. In 2002, 15.4% of women of childbearing age in the USA reported struggles with infertility. Over the past 3 decades, drugs and assisted reproductive technologies have been developed to treat infertility, but treatment is costly. Since 1985, several states have adopted insurance mandates that require providers to cover or offer infertility treatments. In this paper, I examine the impact of strong mandate-to-cover laws on multiple births, which are associated with infertility treatment use. I also investigate whether the laws had heterogeneous treatment effects. Using birth certificate data from 1980-2002, I show that the laws had a small and statistically insignificant impact on multiple birth rates. However, I find that there were over 5300 mandate-induced triplet and higher-order births over the period, for which the delivery costs alone are estimated to be over $900 million. Increases in multiple birth rates are only observed for women over 30 and are greater for women who are married, white, or have a college degree. This is consistent with previous work, which finds that the mandates did not reduce disparities in treatment use. 23962667 The effect of exercise interventions on cognitive outcome in Alzheimer's disease: a systematic review. ABSTRACT Background: Non-pharmacological interventions may have a role in both the prevention and slowing down of disease progression in Alzheimer's disease (AD). The role of exercise in disease prevention, for example, has been extensively evaluated in large epidemiological studies. Much less is known about the potential benefit of exercise in patients already diagnosed with AD. It was therefore the aim of this systematic review to assess the effectiveness of exercise in attenuating cognitive decline within AD. Method: A systematic review was conducted statistically accompanied by a meta-analysis. Publications between January 1991 and October 2012 were identified by searching the electronic databases PubMed, Science Direct, Web of Knowledge, and PsychINFO. Selected studies required AD patients to take part in an exercise-based randomized controlled trial (RCT) and have a cognitive outcome measure. Results: Six RCTs were identified that exclusively considered the effect of exercise in AD patients. Exercise generally had a positive effect on rate of cognitive decline in AD. A meta-analysis found that exercise interventions have a positive effect on global cognitive function, 0.75 (95% CI = 0.32-1.17). Conclusions: From the six studies reviewed, the evidence suggests that exercise can have a positive effect on rate of cognitive decline in AD. However, the variation between study designs makes conclusions regarding the optimum intervention on cognitive outcome in AD difficult. Well-designed and powered RCTs are still needed to ascertain the efficacy of exercise in slowing down cognitive impairment in AD patients. However, a positive initial indication for exercise efficacy justifies such efforts. 23649536 Estrogen receptor alpha: Molecular mechanisms and emerging insights. Estrogen receptor alpha (ERα) is a cellular receptor for the female sex hormone estrogen and other natural and synthetic ligands and play critical roles in normal development and physiology and in the etiology and treatment of endocrine-related diseases. ERα is a member of the nuclear receptor superfamily of transcription factors and regulates target gene expression in a ligand-dependent manner. It has also been shown to interact with G-protein coupled receptors and associated signaling molecules in the cytoplasm. Transcriptionally, ERα either binds DNA directly through conserved estrogen response element sequence motifs or indirectly by tethering to other interacting transcription factors and nucleate transcriptional regulatory complexes which include an array of co-regulator proteins. Genome-scale studies of ERα transcriptional activity and localization have revealed mechanistic complexity and insights including novel interactions with several transcription factors, including FOXA1, AP-2g, GATA3, and RUNX1, which function as pioneering, collaborative, or tethering factors. The major challenge and exciting prospect moving forward is the comprehensive definition and integration of ERα complexes and mechanisms and their tissue-specific roles in normal physiology and in human diseases. J. Cell. Biochem. 114: 2203-2208, 2013. © 2013 Wiley Periodicals, Inc. 23932506 Wild daffodils of the section Ganymedes from the Iberian Peninsula as a source of mesembrane alkaloids. The aim of this work was to perform a detailed study of the alkaloid content of Narcissus triandrus, as well as a complete analysis of the alkaloid profile of 18 wild populations, comprising all the taxa of the section Ganymedes. Through the application of a combination of spectroscopic and chromatographic methods, the isolation and structural elucidation of 3 compounds are reported for the first time from a natural source (2-oxomesembrenone, 7,7a-dehydromesembrenone and 2-oxoepimesembranol), together with the identification of 5 major common mesembrane alkaloids. Additionally, the GC-MS analysis of the alkaloid profile demonstrated the regular presence of mesembranes in all the studied plants, showing mesembrenone as the predominant compound without any typical Amaryllidaceae alkaloid being detected. 23875791 Carbohydrate use and reduction in number of balance beam falls: implications for mental and physical fatigue. Artistic Gymnastics is a sport where athletes are frequently fatigued. One element that might influence this aspect is carbohydrate, an important energy substrate for the muscles and the CNS. Our goal was to investigate the influence of fatigue over artistic gymnastics athlete's performance and the effects of a carbohydrate supplementation on their performance. We evaluated 15 athletes divided in 2 groups (control and fatigue) from 12 to 14 years old in two different experimental days. On the first day (water day), they did 5 sets of exercises on the balance beam (experimental protocol) ingesting only water, CG (control group) warmed up before the experimental protocol and FG (fatigue group) did a fatigue circuit, warm up exercises and then the experimental protocol. On the second day (carbohydrate day), we used the same protocol but CG ingested a sugar free flavored juice and FG ingested a 20% concentration maltodextrin solution before the protocol on the balance beam. We observed a greater number of falls from the balance beam from the FG on the first day (5.40 +/- 1.14 FG vs 3.33 +/- 1.37 CG; p = 0.024) and a decrease in the number of falls on the second day (2.29 +/- 1.25 FG water day vs 5.40 +/- 1.14 FG carbohydrate day; p = 0.0013). Carbohydrate solution was able to supply muscle demands and improve the athlete's focus showed by the reduced number of falls. 23298863 Pharmacokinetic and pharmacodynamic modeling of hedgehog inhibitor TAK-441 for the inhibition of Gli1 messenger RNA expression and antitumor efficacy in xenografted tumor model mice. 6-Ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide (TAK-441) is a potent, selective hedgehog signaling pathway inhibitor that binds to Smo and is being developed for the treatment of cancer. The objectives of these studies were to explore the possibility of establishing of a link between the pharmacokinetics of TAK-441 and the responses of Gli1 mRNA in tumor-associated stromal or skin cells and the antitumor effect of hedgehog inhibition. To this end, we built pharmacokinetic and pharmacodynamic models that describe the relationship of the concentrations of TAK-441 plasma to the responses of Gli1 mRNA in the tumor (target) and skin (surrogate) and to tumor growth inhibition in mice bearing xenografts of human pancreatic tumors (PAN-04). The responses of Gli1 mRNA and tumor growth were described by an indirect response model and an exponential tumor growth model, respectively. The IC50 values for Gli1 mRNA inhibition in the tumor and skin by TAK-441 were estimated to be 0.0457 and 0.113 μg/ml, respectively. The IC90 value for tumor growth inhibition was estimated to be 0.68 μg/ml. These results suggest that a >83% inhibition of Gli1 mRNA expression in the skin or a >94% inhibition of Gli1 mRNA expression in the tumor would be required to sufficiently inhibit (>90%) hedgehog-related tumor growth in the xenografted model mice. We conclude that Gli1 mRNA expression in the tumor and skin could be a useful biomarker for predicting the antitumor effect of hedgehog inhibitors. 23705900 Engineering Functional Epithelium for Regenerative Medicine and In Vitro Organ Models: A Review. Recent advances in the fields of microfabrication, biomaterials, and tissue engineering have provided new opportunities for developing biomimetic and functional tissues with potential applications in disease modeling, drug discovery, and replacing damaged tissues. An intact epithelium plays an indispensable role in the functionality of several organs such as the trachea, esophagus, and cornea. Furthermore, the integrity of the epithelial barrier and its degree of differentiation would define the level of success in tissue engineering of other organs such as the bladder and the skin. In this review, we focus on the challenges and requirements associated with engineering of epithelial layers in different tissues. Functional epithelial layers can be achieved by methods such as cell sheets, cell homing, and in situ epithelialization. However, for organs composed of several tissues, other important factors such as (1) in vivo epithelial cell migration, (2) multicell-type differentiation within the epithelium, and (3) epithelial cell interactions with the underlying mesenchymal cells should also be considered. Recent successful clinical trials in tissue engineering of the trachea have highlighted the importance of a functional epithelium for long-term success and survival of tissue replacements. Hence, using the trachea as a model tissue in clinical use, we describe the optimal structure of an artificial epithelium as well as challenges of obtaining a fully functional epithelium in macroscale. One of the possible remedies to address such challenges is the use of bottom-up fabrication methods to obtain a functional epithelium. Modular approaches for the generation of functional epithelial layers are reviewed and other emerging applications of microscale epithelial tissue models for studying epithelial/mesenchymal interactions in healthy and diseased (e.g., cancer) tissues are described. These models can elucidate the epithelial/mesenchymal tissue interactions at the microscale and provide the necessary tools for the next generation of multicellular engineered tissues and organ-on-a-chip systems. 23919844 Enhanced recovery programmes: Do these have a role in gynaecology? Enhanced recovery (ER) has become increasingly ubiquitous in most surgical specialities and its use is gathering pace. It has been proven to be a safe and effective means of managing patients perioperatively, while also improving patient outcomes, and its use in gynaecology has recently been supported by the Royal College of Obstetricians and Gynaecologists (RCOG). ER is gaining popularity, despite being a diversion from the traditional surgical approach, demanding an orchestration of primary, secondary, social and auxillary care teams to work effectively. ER has been heralded as improving clinical outcomes and patient satisfaction, while simultaneously allowing increased patient turnover. This has potentially massive impacts on service provision within the NHS and is likely to become a proof of concept that the NHS can adapt. ER can be championed as a flexible and contemporary healthcare model, which can be improved as patients' needs and NHS resources change. 23796039 First Fabrication of Electrowetting Display by Using Pigment-in-Oil Driving Pixels. We report the first fabrication of pigment particle-based electrowetting display (EWD) by using the requisite poly(isobutylene)-imide (PIB-imide) for effectively dispersing insoluble colorant in decane/water system. The series of PIB-imide dispersants were prepared from the amidation/imidation of PIB-succinic anhydride with different hydrophobic lengths and a suitable amine. The structurally tailored dispersants by adopting the highly hydrophobic PIB tails allows the formation of homogeneous dispersion of nanosized pigment particles in decane and clearly separated from water. The pigment dispersion at particle size of ca. 100 nm and a low viscosity of 2-3 cps was obtained and fabricated into an EWD device which was operated at a driving voltage of 15-20 V in achieving a maximum aperture ratio of 80%. With the advantage of both fast response time and vivid color, the pigment-based EWD, as shown in the video, stands out as a promising new option for future transparent display and serves as a critical foundation for the next-generation advanced display applications. 23754307 Identification of cyclopropaneoctanoic Acid 2-hexyl in human adipose tissue and serum. Fatty acids containing a cyclopropane ring in their structure (cyclopropane FA) have been found in a wide variety of bacteria, a number of protozoa, and Myriapoda. Little is known about cyclopropane FA in mammal, especially in human tissues. The present study deals with the identification of cyclopropane FA in adipose tissue and serum of humans and rats. Fatty acids extracted from the adipose tissue and serum obtained from obese women during bariatric surgery were methylated and analyzed on GC-MS. We have identified: cyclopropaneoctanoic acid 2-hexyl, cyclopropaneoctanoic acid 2-octyl, cyclopropanenonanoic acid, and 2-[[2-[(2-ethylcyclopropyl)methyl]cyclopropyl]methyl] acid in human adipose tissue. We confirmed the presence of cyclopropaneoctanoic acid 2-hexyl by derivatization of FA extracted from human adipose tissue to picolinyl esters. Cyclopropaneoctanoic acid 2-hexyl was the main cyclopropane FA (approximately 0.4 % of total fatty acids in human adipose tissue, and about 0.2 % of total fatty acids in the serum). In adipose tissue cyclopropaneoctanoic acid 2-hexyl was found mainly in triacylglycerols, whereas in serum in phospholipids and triacylglycerols. The cyclopropaneoctanoic acid 2-hexyl has also been found in serum, and adipose tissue of rats in amounts comparable to humans. The content of cyclopropaneoctanoic acid 2-hexyl decreased in adipose tissue of rats maintained on a restricted diet for 1 month. In conclusion, we demonstrated that cyclopropaneoctanoic acid 2-hexyl is present in human adipose tissue and serum. Adipose tissue cyclopropaneoctanoic acid 2-hexyl is stored mainly in triacylglycerols and the storage of this cyclopropane FA is affected by food restriction. 23901845 Gaze, goals and growing up: Effects on imitative grasping. Developmental differences in the use of social-attention cues to imitation were examined among children aged 3 and 6 years old (n = 58) and adults (n = 29). In each of 20 trials, participants watched a model grasp two objects simultaneously and move them together. On every trial, the model directed her gaze towards only one of the objects. Some object pairs were related and had a clear functional relationship (e.g., flower, vase), while others were functionally unrelated (e.g., cardboard square, ladybug). Owing to attentional effects of eye gaze, it was expected that all participants would more faithfully imitate the grasp on the gazed-at object than the object not gazed-at. Children were expected to imitate less faithfully on trials with functionally related objects than those without, due to goal-hierarchy effects. Results support effects of eye gaze on imitation of grasping. Children's grasping accuracy on functionally related and functionally unrelated trials was similar, but they were more likely to only use one hand on trials where the object pairs were functionally related than unrelated. Implications for theories of imitation are discussed. 23965950 Genetic and Environmental Influences on the Familial Transmission of Externalizing Disorders in Adoptive and Twin Offspring. IMPORTANCE Twin-family studies have shown that parent-child resemblance on substance use disorders and antisocial behavior can be accounted for by the transmission of a general liability to a spectrum of externalizing disorders. Most studies, however, include only biological parents and offspring, which confound genetic and environmental transmission effects. OBJECTIVE To examine the familial transmission of externalizing disorders among both adoptive (genetically unrelated) and biological relatives to better distinguish genetic and environmental mechanisms of transmission. DESIGN Family study design wherein each family included the mother, father, and 2 offspring, including monozygotic twin, dizygotic twin, nontwin biological, and adoptive offspring. Structural equation modeling was used to estimate familial transmission effects and their genetic and environmental influences. SETTING Participants were recruited from the community and assessed at a university laboratory. PARTICIPANTS A total of 1590 families with biological offspring and 409 families with adoptive offspring. Offspring participants were young adults (mean age, 26.2 years). MAIN OUTCOMES AND MEASURES Symptom counts of conduct disorder, adult antisocial behavior, and alcohol, nicotine, and drug dependence. RESULTS There was a medium effect for the transmission of the general externalizing liability for biological parents (r = 0.27-0.30) but not for adoptive parents (r = 0.03-0.07). In contrast, adoptive siblings exhibited significant similarity on the general externalizing liability (r = 0.21). Biometric analyses revealed that the general externalizing liability was highly heritable (a2 = 0.61) but also exhibited significant shared environmental influences (c2 = 0.20). CONCLUSIONS AND RELEVANCE Parent-child resemblance for substance use disorders and antisocial behavior is primarily due to the genetic transmission of a general liability to a spectrum of externalizing disorders. Including adoptive siblings revealed a greater role of shared environmental influences on the general externalizing liability than previously detected in twin studies and indicates that sibling rather than parent-child similarity indexes important environmental risk factors for externalizing disorders. 23967103 Renal Expression of FGF23 in Progressive Renal Disease of Diabetes and the Effect of Ace Inhibitor. Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone mainly produced by bone that acts in the kidney through FGF receptors and Klotho. Here we investigated whether the kidney was an additional source of FGF23 during renal disease using a model of type 2 diabetic nephropathy. Renal expression of FGF23 and Klotho was assessed in Zucker diabetic fatty (ZDF) and control lean rats at 2, 4, 6, 8 months of age. To evaluate whether the renoprotective effect of angiotensin converting enzyme (ACE) inhibitor in this model was associated with changes in FGF23 and Klotho, ZDF rats received ramipril from 4, when proteinuric, to 8 months of age. FGF23 mRNA was not detectable in the kidney of lean rats, nor of ZDF rats at 2 months of age. FGF23 became measurable in the kidney of diabetic rats at 4 months and significantly increased thereafter. FGF23 protein localized in proximal and distal tubules. Renal Klotho mRNA and protein decreased during time in ZDF rats. As renal disease progressed, serum phosphate levels increased in parallel with decline of fractional phosphorus excretion. Ramipril limited proteinuria and renal injury, attenuated renal FGF23 upregulation and ameliorated Klotho expression. Ramipril normalized serum phosphate levels and tended to increase fractional phosphorus excretion. These data indicate that during progressive renal disease the kidney is a site of FGF23 production which is limited by ACE inhibition. Interfering pharmacologically with the delicate balance of FGF23 and phosphorus in diabetes may have implications in clinics. 23811604 Effect of IL-10 on LOX-1 expression, signalling and functional activity: An atheroprotective response. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) has gained attention for its pro-inflammatory potential in atherogenesis. This study evaluates LOX-1 receptor modulation in the presence of an atheroprotective cytokine, interleukin-10 (IL-10). Both oxidized low-density lipoprotein (oxLDL) and IL-10 stimulated LOX-1 cell surface expression on THP-1 macrophages. However, our study demonstrates differential roles of oxLDL and IL-10 on LOX-1 functionality. Seemingly, oxLDL-induced LOX-1 promoted pro-inflammatory signalling by increasing intracellular NO, a substrate for pro-inflammatory peroxynitrite. In contrast, IL-10-induced LOX-1 facilitated scavenging of extracellular oxLDL without any effect on pro-inflammatory signalling. The atheroprotective effects of IL-10 were demonstrated by both facilitation of cellular oxLDL uptake and expression of LOXIN, an atheroprotective haplotype of the LOX-1 gene. Thus, increased expression of IL-10 may help to attenuate the risk of atherosclerosis developed by pro-inflammatory signal(s) generated through the interaction of oxLDL with its cognate receptor LOX-1 on macrophages. 23640495 Thin-capped atheromata with reduced collagen content in pigs develop in coronary arterial regions exposed to persistently low endothelial shear stress. The mechanisms promoting the focal formation of rupture-prone coronary plaques in vivo remain incompletely understood. This study tested the hypothesis that coronary regions exposed to low endothelial shear stress (ESS) favor subsequent development of collagen-poor, thin-capped plaques. Coronary angiography and 3-vessel intravascular ultrasound were serially performed at 5 consecutive time points in vivo in 5 diabetic, hypercholesterolemic pigs. ESS was calculated along the course of each artery with computational fluid dynamics at all 5 time points. At follow-up, 184 arterial segments with previously identified in vivo ESS underwent histopathologic analysis. Compared with other plaque types, eccentric thin-capped atheromata developed more in segments that experienced lower ESS during their evolution. Compared with lesions with higher preceding ESS, segments persistently exposed to low ESS (<1.2 Pa) exhibited reduced intimal smooth muscle cell content; marked intimal smooth muscle cell phenotypic modulation; attenuated procollagen-I gene expression; increased gene and protein expression of the interstitial collagenases matrix-metalloproteinase-1, -8, -13, and -14; increased collagenolytic activity; reduced collagen content; and marked thinning of the fibrous cap. Eccentric thin-capped atheromata, lesions particularly prone to rupture, form more frequently in coronary regions exposed to low ESS throughout their evolution. By promoting an imbalance of attenuated synthesis and augmented collagen breakdown, low ESS favors the focal evolution of early lesions toward plaques with reduced collagen content and thin fibrous caps-2 critical determinants of coronary plaque vulnerability. 23919216 Emerging causes of iron deficiency anemia refractory to oral iron supplementation. While oral iron supplementation is commonly used throughout many clinical setting, treatment with intravenous (IV) iron has historically been reserved for specific settings, such as chronic kidney disease, gynecologic issues, and anemia associated with cancer and its treatments. However, the use of IV iron has begun to gain popularity in the treatment of iron deficiency anemia (IDA) associated with two conditions that are being seen more frequently than in years past: patients who are status post gastric bypass procedure and those with inflammatory bowel disease (IBD). The Roux-en-Y procedure involves connecting a gastric pouch to the jejunum, creating a blind loop consisting of distal stomach, duodenum, and proximal jejunum that connects to the Roux limb to form a common tract. IDA occurs in 6%-50% of patients who have undergone a gastric bypass, the etiology being multifactorial. The proximal gastric pouch, the primary site of gastric acid secretion, is bypassed, resulting in a decreased ability to metabolize molecular iron. Once metabolized, most iron is absorbed in the duodenum, which is entirely bypassed. After undergoing bypass procedures, most patients significantly limit their intake of red meat, another factor contributing to post-bypass IDA. Chronic anemia occurs in approximately 1/3 of patients who suffer from IBD, and almost half of all IBD patients are iron deficient. IBD leads to IDA through multiple mechanisms, including chronic intestinal blood loss, decreased absorption capabilities of the duodenum secondary to inflammation, and an inability of many IBD patients to tolerate the side effects of oral ferrous sulfate. In this study, we reviewed the charts of all patients who received IV iron at Sylvester Comprehensive Cancer Center/University of Miami Hospital Clinic from January 2007 to May 2012. The most common indications for IV iron were for issues related to cancer and its treatment (21.9%), IBD (20.1%), and gastric bypass (15.0%). Of the 262 patients who received IV iron, 230 received iron sucrose and 36 received iron dextran. While doses of 100, 200, 300, and 400 mg of iron sucrose were given, 100 and 200 mg were by far the most common dosages used, 122 and 120 times, respectively. The number of dosages of iron sucrose given ranged from 1 to 46, with a mean of 5.5 and a median of 4 doses. The average dose of iron dextran given was 870.5 mg, with 1000 mg being the most common dosage used. Most patients (22 of 36) who received iron dextran only received one dose. While patients with traditional indications for IV iron, such as gynecologic issues and kidney disease, still were represented in this study, we expect to see a continued increase in physicians using IV iron for emerging gastrointestinal indications, especially considering the increased safety of new low-molecular formulations. 23728429 Application' and validation of autochthonous lactic acid bacteria starter cultures for controlled leek fermentations and their influence on the antioxidant properties of leek. Leek (Allium ampeloprasum var. porrum) is one of Belgium's most important outdoor vegetables, mainly cultivated for its white shaft. Fermentation of leek offers opportunities in view of biomass valorization and product diversification. This study deals with the implementation and validation of starter cultures to perform controlled leek fermentations and to ensure a high quality of the end-products. Therefore, a thorough study of the fermentation microbiology and the influence of three starter culture strains (Lactobacillus plantarum IMDO 788, Lactobacillus sakei IMDO 1358, and Leuconostoc mesenteroides IMDO 1347) on the metabolite kinetics of leek fermentation and antioxidant properties of leek was performed. Overall, the application of lactic acid bacteria starter cultures resulted in a fast prevalence of the species involved, coupled to an accelerated acidification. Of the three starter cultures tested, the mixed starter culture of L. plantarum IMDO 788 and L. mesenteroides IMDO 1347 was most promising, as its application resulted in fermented leek of good microbiological quality and in a more extensive carbohydrate consumption, whereby diverse end-metabolites were produced. However, high residual fructose concentrations allowed yeast outgrowth, resulting in increased ethanol and glycerol concentrations, and indicated the lack of a prevailing strictly heterofermentative LAB species. The antioxidant capacity of fermented leek samples, as measured with the oxygen radical absorbance capacity assay, increased when starter cultures were used, whereas with regard to 2,2-diphenyl-1-picrylhydrazyl free radical scavenging activity, only leek fermented with L. sakei IMDO 1358 scored higher than spontaneously fermented leek. The total phenolic content was not influenced by the use of starter cultures, while the S-alk(en)yl-L-cysteine sulfoxides content decreased strongly. A preliminary sensory analysis revealed that the spontaneously fermented leek and the one obtained with the mixed starter culture were preferred by consumers, emphasizing again the importance of microbial successions in vegetable fermentations. 23701299 Recent developments in the discovery of novel antipsychotic agents modualating dopamine and serotonin receptors. Currently, schizophrenia, as a serious psychiatric disorder, continues affecting the quality of life in the psychotics. This disease is often debilitating and chronic, showing broad symptoms at one end by hallucinations, delusions, thought disorder and the other end by affective flattening, catatonia, social isolation. In order to combat this disease, many antipsychotic drugs have been developed and introduced into clinical practice in the past half century. However, only a small minority of them can treat effectively schizophrenia without side effects. In view of this situation, high attention has been given to the exploration of desired antipsychotic agents influential especially through the modulation of dopamine and serotonin receptors with substantial strides made in recent years, leading to the discovery of many novel chemical entities with intriguing profiles. In this review, we summarize novel structural antipsychotics in development and discuss the future direction of ideal antipsychotic drug candiates. In particular, the promising atypical antipsychotic profiles of new molecules and the inspirations for their design are highlighted. 23872211 Dispersive liquid-liquid microextraction followed by high-performance liquid chromatography-ultraviolet detection to determination of opium alkaloids in human plasma. A novel, simple, rapid and sensitive dispersive liquid-liquid microextraction method based on the solidification of floating organic drop (DLLME-SFO) combined with high-performance liquid chromatography-ultraviolet detection (HPLC-UV) was used to determine opium alkaloids in human plasma. During the extraction procedure, plasma protein was precipitated by using a mixture of zinc sulfate solution and acetonitrile. Some effective parameters on extraction were studied and optimized. Under the optimum conditions (extraction solvent: 30.0μl 1-undecanol; disperser solvent: 470μl acetone; pH: 9; salt addition: 1%(w/v) NaCl and extraction time: 0.5min), calibration curves are linear in the range of 1.5-1000μgl(-1) and limit of detections (LODs) are in the range of 0.5-5μgl(-1). The relative standard deviations (RSDs) for 100μgl(-1) of morphine and codeine, 10.0μgl(-1) of papaverine and 20.0μgl(-1) of noscapine in diluted human plasma are in the range of 4.3-7.4% (n=5). Finally, the method was successfully applied in the determination of opium alkaloids in the actual human plasma samples. The relative recoveries of plasma samples spiked with alkaloids are 88-110.5%. The obtained results show that DLLME-SFO combined with HPLC-UV is a fast and simple method for the determination of opium alkaloids in human plasma. 23859226 Floor of mouth masses in children: Proposal of a new algorithm. Many surgical techniques have been described to manage floor of mouth masses, but few studies have described the approach to these masses in children. This case series summarizes a single institution's experience with pediatric floor of mouth masses. We performed a retrospective chart review of all children who presented at our tertiary care facility with FOM masses between 2007 and 2012. Charts were reviewed for clinical presentation, preoperative, intraoperative and postoperative management. Thirteen cases were retrieved: 6 dermoid cysts, 4 ranulas, 1 lymphatic malformation, 1 imperforate submandibular duct, and 1 enlarged salivary gland. In 10 of 13 patients, clinical diagnosis was consistent with postoperative diagnosis. Imaging was consistent with postoperative diagnosis in 8 of 9 cases. Ten of 13 masses were managed transorally; 7 were excised, 2 were marsupialized and 1 was managed with submandibular duct dilation. Three masses with a larger submental component, 2 dermoids and 1 ranula, were removed transcervically. Most patients undergoing transoral excision underwent nasotracheal intubation; patients who underwent marsupialization underwent orotracheal intubation. There were no recurrences, complications or postoperative infections. An additional surgical procedure was necessary in one patient. Our cohort displays a common distribution of lesion types when compared to the literature. Low recurrence and infection rates are observed when oral masses are removed transorally, and masses with a larger cervical component are removed transcervically. More complex masses may warrant additional surgical procedures. 23471121 Neurotrophin 3 genotype and emotional adverse effects of osmotic-release oral system methylphenidate (OROS-MPH) in children with attention-deficit/ hyperactivity disorder. Neurotrophin 3 (NTF3) has been studied in relation to the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) and mood disorders as well as psychostimulant action. We hypothesized that the risk of an emotional side effect to methylphenidate (MPH) treatment may be associated with NTF3 genotypes. Ninety-six medication-naïve children with ADHD (mean age 8.70, standard deviation 1.41 years, 79 males) were genotyped and treated with MPH. At baseline, which was prior to MPH treatment, and after two weeks of medication, investigators asked children and their parents or caregivers about adverse events using a symptom rating scale. ADHD subjects with the A/A genotype at the NTF3 rs6332 polymorphism showed the highest 'Emotionality' and 'Over-focus/euphoria' factor scores, followed by those with the G/A genotype and those with the G/G genotype (p=0.042 and p=0.045, respectively). ADHD subjects with the A/A genotype at the NTF3 rs6332 polymorphism showed the highest 'Proneness to crying' and 'Nail biting' item scores, followed by those with the G/A genotype and those with the G/G genotype (p=0.047 and p=0.017, respectively). These data provide preliminary evidence that genetic variation in the NTF3 gene is related to susceptibility to emotional side effects in response to MPH treatment in Korean children with ADHD. 23896712 Immunohistochemical Expression of Cyclin D1, p16Ink4a, p21WAF1, and Ki-67 Correlates With the Severity of Cervical Neoplasia. High-risk human papillomaviruses are closely associated with cervical cancer and its precursor lesions through interactions between the E6 and E7 oncoproteins and the cell-cycle regulatory proteins, such as p53 and pRb, respectively. As other molecules involved in the cell-cycle control seem to be important for human papillomavirus (HPV)-mediated cervical carcinogenesis, we have analyzed the expression of p53, p21, p16, cyclin D1, and Ki-67 and the presence of HPV (HPV pool and HPV-16) by immunohistochemical studies using tissue microarray in low squamous intraepithelial lesions (n=50), high squamous intraepithelial lesions (n=98), and cervical carcinoma (n=18). We have found a significant increase in the expression of p16 and p21 (P<0.001) from low- to high-grade lesions and cancer. In contrast, cyclin D1 expression showed a significant decrease in more severe lesions (P<0.001). p16, Ki-67, p21, and p53 positivity increased with the cell-layer level and the lesion severity, with stronger correlations being observed for p16 and Ki-67. High positivity for HPV pool (96.3%) and HPV-16 (77.5%) immunostaining was detected in all cases, with an association between p16 and cyclin D1 expression and HPV-16 infection. Our tissue microarray results corroborate the usefulness of the immunohistochemical assessment of cell-cycle biomarkers in distinguishing different groups of precursor lesions of the cervix and cervical carcinoma. 23949792 Treatment of anthracycline extravasations using dexrazoxane. Extravasation of cytotoxic agents is a true medical emergency. Dexrazoxane is the only licensed drug for the treatment of anthracycline extravasations. Dexrazoxane proved to be effective and moderately well tolerated. However, alternative approaches for the management of anthracycline extravasations are available such as topical DMSO and cooling. There appears to be general agreement about dexrazoxane usefulness when extravasations involve large volumes of anthracycline and/or central venous access device. Nevertheless, the non-invasive combination of DMSO and cooling is the most commonly described therapy, particularly in small anthracycline extravasations. Further research is still needed to establish unequivocal situations where dexrazoxane must be initiated. 23895432 Predictive toxicology of cobalt ferrite nanoparticles: comparative in-vitro study of different cellular models using methods of knowledge discovery from data. Cobalt-ferrite nanoparticles (Co-Fe NPs) are attractive for nanotechnology-based therapies. Thus, exploring their effect on viability of seven different cell lines representing different organs of the human body is highly important. The toxicological effects of Co-Fe NPs were studied by in-vitro exposure of A549 and NCIH441 cell-lines (lung), precision-cut lung slices from rat, HepG2 cell-line (liver), MDCK cell-line (kidney), Caco-2 TC7 cell-line (intestine), TK6 (lymphoblasts) and primary mouse dendritic-cells. Toxicity was examined following exposure to Co-Fe NPs in the concentration range of 0.05 -1.2 mM for 24 and 72 h, using Alamar blue, MTT and neutral red assays. Changes in oxidative stress were determined by a dichlorodihydrofluorescein diacetate based assay. Data analysis and predictive modeling of the obtained data sets were executed by employing methods of Knowledge Discovery from Data with emphasis on a decision tree model (J48). Different dose-response curves of cell viability were obtained for each of the seven cell lines upon exposure to Co-Fe NPs. Increase of oxidative stress was induced by Co-Fe NPs and found to be dependent on the cell type. A high linear correlation (R2=0.97) was found between the toxicity of Co-Fe NPs and the extent of ROS generation following their exposure to Co-Fe NPs. The algorithm we applied to model the observed toxicity belongs to a type of supervised classifier. The decision tree model yielded the following order with decrease of the ranking parameter: NP concentrations (as the most influencing parameter), cell type (possessing the following hierarchy of cell sensitivity towards viability decrease: TK6 > Lung slices > NCIH441 > Caco-2 = MDCK > A549 > HepG2 = Dendritic) and time of exposure, where the highest-ranking parameter (NP concentration) provides the highest information gain with respect to toxicity. The validity of the chosen decision tree model J48 was established by yielding a higher accuracy than that of the well-known "naive bayes" classifier. The observed correlation between the oxidative stress, caused by the presence of the Co-Fe NPs, with the hierarchy of sensitivity of the different cell types towards toxicity, suggests that oxidative stress is one possible mechanism for the toxicity of Co-Fe NPs. 23925486 Light-inducible activation of target mRNA translation in mammalian cells. A genetically encoded optogenetic system was constructed that activates mRNA translation in mammalian cells in response to light. Blue light induces the reconstitution of an RNA binding domain and a translation initiation domain, thereby activating target mRNA translation downstream of the binding sites. 23315988 Acute toxicity of zinc oxide nanoparticles to the rat olfactory system after intranasal instillation. With the increased applications of zinc oxide (ZnO) nanoparticles (NPs), the toxicity of ZnO NPs arouses great concerns from the nano community and the general public. In this study, we report the toxicity of ZnO NPs (30 nm) to the rat olfactory system after intranasal instillation revealed by non-invasive magnetic resonance imaging (MRI). MRI scans were performed on a 4.7-T scanner at 1, 2, 3 and 7 days post-exposure, and the histological changes of the rat olfactory epithelium were evaluated. The influences of chemical component and dispersant of the NPs were also investigated. In addition, an olfactory behavior test was performed. The MRI and histological results indicated that ZnO NPs induced significant damages to the olfactory epithelium, including disruption of the olfactory epithelial structures and inflammation. The destruction of mitochondria in epithelial cells was observed under transmission electron microscopy (TEM), suggesting that the possible toxicological mechanism might involve cellular energy metabolic dysfunction. Further, the lesion of the olfactory epithelium disturbed sniffing behaviors of the treated animals. The results suggest that MRI is potentially useful as a screening tool to assess the consequence of occupational exposure of ZnO NPs. Caution should therefore be taken during the use and disposal of ZnO NPs to prevent the unintended public health impacts. Copyright © 2012 John Wiley & Sons, Ltd. 23860290 Body composition among female NCAA Division I athletes across the competitive season and over a multi-year time frame. Body composition can affect athletic performance. Numerous studies have documented changes in body composition in female collegiate athletes from pre- to post-season; however, longitudinal studies examining changes across years are scarce. Therefore, the primary purpose of this study was to assess longitudinal body composition changes among female collegiate athletes across three years. Two hundred and twelve female athletes from basketball (BB; n=38), soccer (SOC; n=47), swimming (SW; n=52), track (sprinters and jumpers; TR; n=49), and volleyball (VB; n=26) with an initial mean age of 19.2±1.2 yrs, height of 172.4±8.9 cm, and total mass of 66.9±9.0 kg had body composition assessments using DXA pre- and post-season over three years. A restricted maximum-likelihood linear mixed model regression analysis examined body composition differences by sport, and year. Changes (p <0.05) over three years included the following: Lean mass increased in VB from year 1 to 2 (0.7 kg), year 2 to 3 (1.1 kg) and year 1 to 3 (1.8 kg) and in SW from year 1 to 3 (0.6 kg); and %BF increased in BB from year 1 to 3 (1.7%). There were no changes in SOC or TR. These results indicate that during their college careers, female collegiate athletes can be expected to maintain their %BF and athletes in sports like SW and VB can anticipate an increase in lean mass, but the increases may be less than many athletes, coaches and trainers envision. 23500489 On the origin of the selectivity of plasmidic H-NS towards horizontally acquired DNA: linking H-NS oligomerization and cooperative DNA binding. The nucleoid-associated protein H-NS is a global modulator of the expression of genes associated with adaptation to environmental changes. A variant of H-NS expressed in the R27 plasmid was previously shown to selectively modulate the expression of horizontally acquired genes, with minimal effects on core genes that are repressed by the chromosomal form of H-NS. Both H-NS proteins are formed by an oligomerization domain and a DNA-binding domain, which are connected by a linker that is highly flexible in the absence of DNA. We studied DNA binding by means of oligomer-forming chimeric proteins in which domains of the chromosomal and plasmidic variants are exchanged, as well as in monomeric truncated forms containing the DNA-binding domain and variable portions of the linker. Point mutations in the linker were also examined in full-length and truncated H-NS constructs. These experiments show that the linker region contributes to DNA binding affinity and that it is a main component of the distinct DNA binding properties of chromosomal and plasmidic H-NS. We propose that interactions between the linker and DNA limit the flexibility of the connection between H-NS oligomerization and DNA binding and provide an allosteric indirect readout mechanism to detect long-range distortions of DNA, thus enabling discrimination between core and horizontally acquired DNA. 23873781 Heptacene: Increased Persistence of a 4n+2 π-Electron Polycyclic Aromatic Hydrocarbon by Oxidation to the 4n π-Electron Dication. An unexpectedly stable Dication: Heptacene (a 4n+2 π-electron compound) is so highly reactive that it cannot be isolated. Its dication (a 4n π-electron compound) can be obtained from heptacene dimers/oligomers in sulfuric acid at room temperature and can be kept for more than one year in the absence of oxygen. (See picture for the UV/Vis-NIR spectra of the dications of tetracene to heptacene.). 23821035 Dpp signaling inhibits proliferation in the Drosophila wing by Omb-dependent regional control of bantam. The control of organ growth is a fundamental aspect of animal development but remains poorly understood. The morphogen Dpp has long been considered as a general promoter of cell proliferation during Drosophila wing development. It is an ongoing debate whether the Dpp gradient is required for the uniform cell proliferation observed in the wing imaginal disc. Here, we investigated how the Dpp signaling pathway regulates proliferation during wing development. By systematic manipulation of Dpp signaling we observed that it controls proliferation in a region-specific manner: Dpp, via omb, promoted proliferation in the lateral and repressed proliferation in the medial wing disc. Omb controlled the regional proliferation rate by oppositely regulating transcription of the microRNA gene bantam in medial versus lateral wing disc. However, neither the Dpp nor Omb gradient was essential for uniform proliferation along the anteroposterior axis. 23526480 Brief migraine episodes in children and adolescents-a modification to International Headache Society pediatric migraine (without aura) diagnostic criteria. The international Headache Society (I H S) diagnostic criteria (International classification of headache disorders edition 2- ICHD 2) for headache in children and adults improved the accuracy of migraine diagnoses. However many short duration headaches in children, receive an atypical migraine diagnosis. This study is to diagnose children and adolescents who presented with such atypical migraines of less than one hour duration. 1402 children and adolescents aged 5 to 15 years who presented with recurrent brief activity affected head pain, were studied. Known and common migraine triggers and family history of migraine were recorded in all. All the children studied had moderate to severe headache lasting 5 to 45 minutes which forced them motionless during the attacks (thus fulfilling 2 diagnostic pain features). At least one of the ICHD2 pediatric migraine diagnostic symptoms (nausea / vomiting / photophobia / phonophobia) were present in all. Two additional features were diagnostic of brief migraines in all of them- one of the parents or siblings was a migrainer and one of the common migraine triggers as a precipitating factor. This study concludes that if duration of head pain is less than one hour ,two additional features to be included to diagnose definitive migraine in children and adolescents - one migraine parent or sibling and one of the migraine triggers precipitating the head pain. 23918719 Rates and energetics of intramolecular electron transfer processes in conjugated metallofullerenes. In this paper, we report on the design, redox potentials, excited state energies and radical ion pair state energies in electron donor-acceptor conjugates comprising the electron-donating π-extended tetrathiafulvalene and several electron-accepting fullerenes. To this end, we contrast an empty fullerene, that is, C₆₀, with two endohedral metallofullerenes, that is, open-shell La@C₈₂ and closed-shell La₂@C₈₀, in terms of charge separation and charge recombination dynamics. 23642537 Biologic properties of surgical scaffold materials derived from dermal ECM. Surgical scaffold materials manufactured from donor human or animal tissue are increasingly being used to promote soft tissue repair and regeneration. The clinical product consists of the residual extracellular matrix remaining after a rigorous decellularization process. Optimally, the material provides both structural support during the repair period and cell guidance cues for effective incorporation into the regenerating tissue. Surgical scaffold materials are available from several companies and are unique products manufactured by proprietary methodology. A significant need exists for a more thorough understanding of scaffold properties that impact the early steps of host cell recruitment and infiltration. In this study, a panel of in vitro assays was used to make direct comparisons of several similar, commercially-available materials: Alloderm, Medeor Matrix, Permacol, and Strattice. Differences in the materials were detected for both cell signaling and scaffold architecture-dependent cell invasion. Material-conditioned media studies found Medeor Matrix to have the greatest positive effect upon cell proliferation and induction of migration. Strattice provided the greatest chemotaxis signaling and best suppressed apoptotic induction. Among assays measuring structure-dependent properties, Medeor Matrix was superior for cell attachment, followed by Permacol. Only Alloderm and Medeor Matrix supported chemotaxis-driven cell invasion beyond the most superficial zone. Medeor Matrix was the only material in the chorioallantoic membrane assay to support substantial cell invasion. These results indicate that both biologic and structural properties need to be carefully assessed in the considerable ongoing efforts to develop new uses and products in this important class of biomaterials. 23553340 Development and Regulation of Biosimilars: Current Status and Future Challenges. Biologic medicinal products developed via rDNA technology as recombinant protein-based medicines that have been in clinical use since the early 1980s as original biopharmaceuticals have greatly contributed to the therapy of severe metabolic and degenerative diseases. The recent expiration of the data protection or patents for most of them created opportunities for the development of copy versions of original biopharmaceuticals with similar biologic activity (termed biosimilars). Production of these new products is expected to meet worldwide demand, promote market competition, maintain the incentives for innovation, and sustain the healthcare systems. The licencing of these products, however, relies on the experience gained with the original biopharmaceuticals. Critical issues related to this class of medicinal products include their terminology (to avoid confusion with generics and non-innovator copy versions that have not been tested according to the biosimilar guidelines), manufacturing, and regulation. The European Union (EU) has been the first to establish a regulatory framework for marketing authorization application (MAA) and has named these products biosimilars, a term also recently adopted by the US FDA. Unlike the conventional, more common small molecular weight human medicines and chemical generics, protein-based medicines exhibit higher molecular weight, complexity in structure and function that can be affected by changes in the manufacturing process. Therefore, biosimilars represent a relatively heterogeneous class of medicinal products that make their regulation quite challenging. According to the current understanding in the EU, a biosimilar is a copy version of an already authorized biopharmaceutical (or reference product) with similar biologic activity, physicochemical characteristics, efficacy, and safety, based on a full comparability exercise at quality, preclinical and clinical level to ensure similar efficacy and safety. Guidance has been provided through several Committee for Medicinal Products for Human Use (CHMP) guidelines as well as individual scientific advice requested from the European Medicines Agency (EMA) by various companies for the development and regulation of biosimilars. This review is mainly focused on the current status of regulation of biosimilars in the EU as well as on future challenges lying ahead for the improvement of the requirements needed for the marketing authorization of biosimilars. Emphasis is given on the quality requirements concerning these medicinal products (biologics). 23867913 Conventional versus frozen elephant trunk surgery for extensive disease of the thoracic aorta. To compare early and mid-term outcomes after repair of extensive aneurysm of the thoracic aorta using the conventional elephant trunk or frozen elephant trunk (FET) procedures. Fifty-seven patients with extensive thoracic aneurysmal disease were treated using elephant trunk (n = 36) or FET (n = 21) procedures. Patients with aortic dissection, descending thoracic aorta (DTA) diameter less than 40 mm, and thoracoabdominal aneurysms were excluded from the analysis, as were those who did not undergo antegrade selective cerebral perfusion during circulatory arrest. Short-term and mid-term outcomes were compared according to elephant trunk/FET surgical management. Preoperative and intraoperative variables were similar in the two groups, except for a higher incidence of female sex, coronary artery disease and associated procedures in elephant trunk patients. Hospital mortality (elephant trunk: 13.9% versus FET: 4.8%; P = 0.2), permanent neurologic dysfunction (elephant trunk: 5.7% versus FET: 9.5%; P = 0.4) and paraplegia (elephant trunk: 2.9% versus FET: 4.8%; P = 0.6) rates were similar in the two groups. Follow-up was 100% complete. In the elephant trunk group, 68.4% of patients did not undergo a second-stage procedure during follow-up for a variety of reasons. Of these patients, the DTA diameter was greater than 51 mm in 72.2% and two (6.7%) died due to aortic rupture while awaiting stage-two intervention. Endovascular second-stage procedures were successfully performed in all FET patients with residual DTA aneurysmal disease (n = 3), whereas nine of 11 elephant trunk patients who returned for second-stage procedures required conventional surgical replacement through a lateral thoracotomy. Kaplan-Meier estimate of 4-year survival was 75.8 ± 7.6 and 72.8 ± 10.6 in elephant trunk and FET patients, respectively (log-rank P = 0.8). In patients with extensive aneurysmal disease of thoracic aorta, elephant trunk and FET procedures seem to be associated with similar satisfactory early and mid-term outcomes. The FET approach leads to single-stage treatment of all aortic disease in most patients, and facilitates endovascular second-stage treatment in patients with residual DTA disease. The elephant trunk staged-approach appears to leave a considerable percentage of patients at risk for adverse aortic events. 22498818 Resource provision and environmental change for the prevention of skin cancer: systematic review of qualitative evidence from high-income countries. This paper presents the findings of a systematic review of qualitative studies from high-income (OECD) countries relating to sun protection and skin cancer, with a focus on barriers and facilitators for the following interventions: resource provision; environmental change; and multi-component interventions. Twenty-three study reports were included in the review. Data were analysed using a thematic analysis methodology with the Health Belief Model as a framework. The risk and potential severity of skin cancer are not seen as important concerns, and tanning which is not deliberate is seen as less dangerous. There are a number of social and practical barriers to the use of sun protection resources, including cost, inconvenience and social norms. There are important differences between age groups and between men and women in attitudes. 23357567 Formation of mainstream cigarette smoke constituents prioritized by the World Health Organization--yield patterns observed in market surveys, clustering and inverse correlations. The WHO TobReg proposed mandating ceilings on selected smoke constituents determined from the market-specific median of nicotine-normalized yield distributions. Data validating this regulatory concept were obtained from essentially single-blend surveys. This process is strongly impacted by inverse correlations among yields. In the present study, 18 priority WHO smoke constituent yields (nicotine-normalized) were determined (using two smoking regimens) from 262 commercial brands including American, Virginia and local blends from 13 countries. Principal Component Analysis was used to identify yields patterns, clustering of blend types and the inverse correlations causing these clusters. Three principal components explain about 75% of total data variability. PC1 was sensitive to the relative levels of gas- and particle-phase compounds. PC2 and PC3 cluster American- and Virginia-blends, revealing inverse correlations: Nitrogen oxides and amino- or nitroso-aromatic compounds inversely correlate to either formaldehyde and acrolein, or benzo(a)pyrene and di-hydroxybenzenes. These results can be explained by reviewing the processes determining each components smoke delivery. Regulatory initiatives simultaneously targeting selected smoke constituents in markets with mixed blend styles will be strongly impacted by the inverse correlations described. It is difficult to predict the ultimate impact of such regulations on public health, considering the complex chemistry of cigarette smoke formation. 23827713 Acute methylone intoxication in an accidental drowning - A case report. A 19-year-old woman who was known to use illicit drugs (ecstasy and marijuana) was found floating in the ocean 100 yards from the beach. When last seen the previous evening, she had said to a friend that she was going to "get in the water." Reports to police indicated that she "may have been on ecstasy." There were no notes of a suicidal nature, illicit drugs, drug paraphernalia, tobacco cigarettes, or alcoholic beverages at the scene. Autopsy findings were consistent with drowning. Postmortem blood initially screened positive for methamphetamine and cannabinoids by ELISA and was subsequently confirmed for methylone by a specific GC-MS SIM analysis following solid-phase extraction. Concentrations found in the peripheral blood, central blood, vitreous, liver and gastric contents were measured at 3.4mg/L 3.4mg/L, 4.3mg/L, 11mg/kg, and 1.7mg, respectively. No other amphetamine-like compound (including ecstasy) was detected. These results are discussed in relation to previous cases of toxicity, and the lack of potential for substantial methylone postmortem redistribution. 23891437 Motion predicted online dynamic MRI reconstruction from partially sampled k-space data. In this work we address the problem of reconstructing dynamic MRI sequences in an online fashion, i.e. reconstructing the current frame given that the previous frames have been already reconstructed. The reconstruction consists of a prediction and a correction step. The prediction step is based on an Auto-Regressive AR(1) model. Assuming that the prediction is good, the difference between the predicted frame and the actual frame (to be reconstructed) will be sparse. In the correction step, the difference between the predicted frame and the actual frame is estimated from partially sampled K-space data via a sparsity promoting least squares minimization problem. We have compared the proposed method with state-of-the-art methods in online dynamic MRI reconstruction. The experiments have been carried out on 2D and 3D Dynamic Contrast Enhanced (DCE) MRI datasets. Results show that our method yields the least reconstruction error. 23887192 Glioma Spheroids Obtained Via Ultrasonic Aspiration are Viable and Express Stem Cell Markers: A New Tissue Resource for Glioma Research. Ultrasonic aspirators allow safe, rapid and accurate removal of brain tumors. However, the tissue fragments removed are used surprisingly little in research. To investigate whether such tissue fragments could be cultured as organotypic multicellular spheroids since access to biopsy tissue is often limited. Tissue fragments obtained by ultrasonic aspiration from 10 glioblastomas and tumor biopsy tissue from seven of these tumors were cultured in serum-containing and serum-free medium. Upon culturing, the fragments formed spheroids, which were prepared for histology. Two glioblastoma cell lines from ultrasonic fragments and biopsy tissue were established as well. Hematoxylin eosin staining showed viable glioma spheroids obtained from both ultrasonic and biopsy tissue in both types of medium. EGFR and PTEN/chromosome 10 status were found to be preserved in most spheroids (7-8 out of 10 tumors) together with the level of GFAP, VWF and Ki-67. The level of stem cell markers CD133, Bmi-1, nestin and Sox2 was preserved as well. The ultrasonic spheroids had higher levels of GFAP and VWF and a lower level of Bmi-1, nestin, Sox2 and Olig2 compared to that found in conventional biopsy spheroids. For both types of spheroids, the stem cell medium seemed to favor expression of stem cell markers. The established cell lines were both capable of spheroid formation at clonal density and tumor formation in vivo. Viable organotypic and proliferating spheroids were easily obtained from ultrasonic tissue fragments. The preservation of markers and establishment of cell lines with tumor initiating cell properties suggest ultrasonic spheroids as a new tissue resource for glioma research. 23859627 Symmetry breaking and hole localization in multiple core electron ionization. Motivated by recent opportunitites to study hollow molecules with multiple core holes offered by X-ray free electron lasers, we revisit the core-hole localization and symmetry breaking problem, now studying ionization of more than one core electron. It is shown, using a N2 molecule with one, two, three, and four core holes, for example, that in a multiconfigurational determination of the core ionization potentials employing a molecular point group with broken inversion symmetry, one particular configuration is sufficient to account for the symmetry breaking relaxation energy in an independent particle approximation in the case of one or three holes, whereas the choice of point group symmetry is unessential for two and four holes. The relaxation energy follows a quadratic dependence on the number of holes in both representations. 23459167 Differential phosphoproteome of the striatum from pleiotrophin knockout and midkine knockout mice treated with amphetamine: Correlations with amphetamine-induced neurotoxicity. The neurotrophic factors pleiotrophin (PTN) and midkine (MK) have been shown to modulate amphetamine-induced neurotoxicity. Accordingly, PTN-/- and MK-/- mice show an increased vulnerability to amphetamine-induced neurotoxic effects. In an effort to uncover new pharmacological targets to prevent amphetamine neurotoxic effects, we have now used a proteomic approach to study protein phosphorylation, in which we combined phosphoprotein enrichment, by immobilized metal affinity chromatography (IMAC), with two-dimensional gel electrophoresis and mass spectrometry, in order to identify the phosphoproteins regulated in the striatum of PTN-/-, MK-/- and wild type (WT) mice treated with amphetamine. We identified 13 differentially expressed phosphoproteins that are judged to be relevant in the neuroprotective roles of PTN and MK against amphetamine-induced neurotoxicity. It is very interesting to note that 4 of these phosphoproteins, annexin A7 (ANXA7), COP9 signalosome subunit 5 (COPS5), aldehyde dehydrogenase family 1 member A1 (ALDH1A1) and creatine kinase U-type (CKMT1), are known to be involved in Parkinson's disease, a result of significant importance since PTN and MK have been also demonstrated to limit Parkinson's disease (PD) progress and have been suggested to be among the important genetic factors possibly preventing the development of PD in methamphetamine abusers. The data identify phosphoproteins differentially regulated by amphetamine treatment and/or the presence of endogenous PTN/MK which may be relevant mediators of PTN/MK neuroprotective effects against amphetamine-induced neurotoxicity. The data support further studies to validate the phosphoproteins here identified as possible new pharmacological targets to prevent amphetamine neurotoxic effects. 23846378 Patient satisfaction following endoscopic endonasal dacryocystorhinostomy: a quality of life study. PurposeTo assess the subjective success and quality of life of adult patients post endoscopic endonasal dacryocystorhinostomy (EE-DCR) for acquired nasolacrimal duct obstruction.DesignRetrospective, questionnaire study performed at least 6 months post EE-DCR.ParticipantsHundred and ten of the 282 consecutive patients who underwent EE-DCR.MethodsA standardised questionnaire (Glasgow Benefit Inventory, GBI) was used to analyse the quality of life. The questionnaire examines four parameters, providing total, subscale, social, and physical scores.Main outcome measuresWe aimed to assess patient experience following EE-DCR surgery. Total GBI scores range from -100 to +100, the former reflecting maximal negative benefit and corresponding to subjective worsening of tearing and impact on quality of life. Any positive score reflects a satisfactory surgical outcome and +100 represents maximal positive benefit. A score of zero is no perceived benefit.ResultsThe average age was 62 years, 63% were female. In three of the parameters measured, there was a subjective improvement post surgery: subscale score 22.16 (95% CI: 15.23-29.09), total score 15.04 (95% CI: 9.74-20.35), and social support score 4.67 (95% CI: 0.93-8.42). Physical health scored -4.47 (95% CI: -10.25 to 1.32). Secondary analyses demonstrate no statistical significance with respect to outcome whether a trainee or consultant performed the procedure. Younger patients (under split median of 63.5) had a better total score 19.04 (95% CI: 11.35-27.74) than those older than 63.5 years (11.04, 95% CI: 3.61-18.47).DiscussionThis study shows that EE-DCR gave patients improvement in quality of life, proven by a validated questionnaire. The mean total score of 15.04 found in our study compares with the 18.7 recorded by Feretis et al in 2009. Results were irrespective of the grade of surgeon, similar to the findings of Fayers et al for functional successes.ConclusionThis study supports the use of EE-DCR for the improvement of quality of life in adult patients.Eye advance online publication, 12 July 2013; doi:10.1038/eye.2013.96. 23571833 Blood oxygen level-dependent magnetic resonance imaging of the kidneys: influence of spatial resolution on the apparent r2* transverse relaxation rate of renal tissue. The aim of this study was to quantify the influence of image resolution on the apparent transverse relaxivity (R2*) of the magnetic resonance (MR) signal in human renal tissue in vivo and in phantom measurements. This prospective study included 17 healthy volunteers (age, 32 ± 8 years, 6 women). Parametrical R2* maps were computed via monoexponential fitting of multiecho 2-dimensional fast-field echo data measured at 1.5 T (repetition time [TR], 150 milliseconds; flip angle [FA], 40°; minimum echo time [TE], 4.6 milliseconds; ΔTE, 5 milliseconds; 16 echoes) and at 3 T (TR, 140 milliseconds; FA, 70°; minimum TE, 2 milliseconds; ΔTE, 5 milliseconds; 16 echoes) with varying nominal volumes of the encoded voxels (from 5.76 to 36.0 mm). For each voxel size, mean R2* values were computed in regions of interest drawn in the left and right renal parenchyma. For data acquired using minimum voxel size, the mean R2* values were computed over the cortex and medulla separately. The squared 2-norm of the residuals was computed to evaluate the goodness of the pixel-wise exponential fits. Six multiecho MR images of a water phantom were acquired using a 2-dimensional fast-field echo sequence (FA, 50°; TR, 108 milliseconds; TE, 4 milliseconds; ΔTE, 20 milliseconds) at 3 T after shim adjustment and in the presence of a uniform background gradient of 40 μT/m. The nominal voxel size was varied in a range between 2 and 12.5 mm. Mean R2* values of 13.04 ± 0.71 s (right renal cortex) and 16.47 ± 1.92 s (right renal medulla) were computed at 1.5 T. At 3 T, the R2* of the right medulla was 28.27 ± 1.52 s and the cortical R2* was 19.22 ± 2.32 s. Comparable relaxivity values were found over the left kidney at both field strengths. Increasing R2* values were observed for increasing voxel volume in both the water phantom and renal tissue data. At a constant slice thickness of 4 mm, the decrease in the in-plane resolution from 1.2 × 1.2 mm to 3.0 × 3.0 mm led to a maximum increase of the renal R2* of 15% at 1.5 T and of 12% at 3 T. Increasing the slice thickness from 3 to 8 mm at a constant in-plane resolution of 1.5 × 1.5 mm resulted in a maximum increase of the renal R2* of 30% at 1.5 T and of 26% at 3 T. On the other hand, increasing the voxel size improved the goodness of the fit implied by the smaller residuals. The phantom experiments and in vivo acquisitions of healthy renal tissue documented a significant dependence of the apparent R2* relaxation rate on the spatial resolution of the MR imaging data. In clinical practice, the voxel volume for the quantification of renal R2* should be optimized in a compromise between minimizing the effects of macroscopic field inhomogeneity and maintaining a sufficiently high signal-to-noise ratio and goodness of fit. When comparing quantitative R2* among different publications, the influence of the spatial resolution should be taken into account. 23866680 Spontaneous tumour shrinkage in 1261 observed patients with sporadic vestibular schwannoma. Objective: To determine the rate of spontaneous tumour shrinkage in a group of patients with sporadic vestibular schwannoma managed with a 'wait and scan' approach. Patients: All patients with a unilateral cerebello-pontine angle tumour resembling a vestibular schwannoma were registered prospectively in a national database in Denmark. Patients registered with tumour shrinkage were identified and all computed tomography and magnetic resonance imaging scans retrieved, re-evaluated and related to the clinical data. Results: Of 1261 observed patients, 48 displayed spontaneous shrinkage (3.81 per cent). Mean absolute shrinkage was 6.25 mm, equivalent to 52.1 per cent. Absolute shrinkage correlated with tumour size and follow-up period, whereas relative shrinkage was significantly greater for tumours which were purely intrameatal at diagnosis. There was no correlation between age and the degree of shrinkage. Conclusion: Four per cent of sporadic vestibular schwannomas shrink spontaneously. These findings substantiate the 'wait and scan' strategy for tumours with a largest extrameatal diameter of up to 20 mm. 23881805 New flexible endoscopic full-thickness suturing device: a triple-arm-bar suturing system. Background and study aim: A reliable full-thickness suturing device is necessary for pure natural orifice transluminal endoscopic surgery (NOTES). The present study focused on assessing the reliability of a new suturing device. Methods: A total of 60 single sutures were tested to close 5-cm incisions in 8-cm square pieces of resected swine stomach. Each incision was sutured by an over-the-scope clip (OTSC; n = 20), a single hand-sewn stitch (n = 20), or a single triple-arm-bar suturing system (TBSS) stitch. The maximum pulling force durability (MPD) of each suture was tested. To assess the reliability of the TBSS for endoscopic full-thickness resection (EFTR), 60 EFTRs of 50 mm diameter were performed on excised swine stomachs. After EFTR, full-thickness sutures were made using 3-stitch OTSCs (n = 20), 10-stitch hand-sewn sutures (n = 20), or 10-stitch TBSS sutures (n = 20). Outcomes were the MPD test for both single stitch and multiple stitch applications and the suturing time for single-stitch sutures.Results: In the single-stitch MPD tests, there were significant differences between OTSCs and hand-sewn sutures (P = 0.0002) and between OTSCs and TBSS sutures (P = 0.0001), but no significant difference between hand-sewn and TBSS sutures. The multiple-stitch sutures revealed significant differences between OTSCs and hand-sewn sutures (P = 0.0039), and between OTSCs and TBSS sutures (P = 0.013). There was no significant difference between hand-sewn and TBSS sutures. There were significant differences in suture times between OTSC, hand-sewn sutures, and TBSS sutures (P < 0.05). Conclusions: Both single-stitch and multiple-stitch sutures using TBSS have similar strength to hand-sewn sutures. TBSS is a reliable suturing device. 23895739 Inflammatory stress response in A549 cells as a result of exposure to coal: Evidence for the role of pyrite in coal workers' pneumoconiosis pathogenesis. On the basis of a recent epidemiological study it is hypothesized that pyrite content in coal is an important factor in coal workers' pneumoconiosis (CWP) pathogenesis. While the role of pyrite in pathogenesis remains to be resolved, the ability of the mineral to generate reactive oxygen species (ROS) through various mechanisms is likely a contributing factor. The aim of this study was to elucidate the importance of the pyrite content of coal in generating an inflammatory stress response (ISR), which is defined as the upregulation of ROS normalized by cell viability. The ISR of A549 human lung epithelial cells in the presence of natural coal samples with variable pyrite contents was measured. Normalized to surface area, five particle loadings for each coal reference standard were analyzed systematically for a total of 24h. The ISR generated by coals containing 0.00, 0.01, and 0.49wt.% pyritic sulfur is comparable to,though less than, the ISR generated by inert glass beads (299% of the control). The coals containing 0.52 and 1.15wt.% pyritic sulfur generated the greatest ISR (798% and 1426% of the control, respectively). While ISR does not increase proportionally to pyrite content in coal, the two coals with the highest pyritic sulfur and available iron contents generate the greatest ISR. Therefore, the present study indicates that coals with elevated pyrite contents are likely to induce a significant health burden by stimulating inflammation within the lungs, and may contribute to the development of CWP. 23962458 Prevalence and incidence rates of psoriatic arthritis in central Norway: data from the Nord-Trondelag Health Study (HUNT). A wide range in the prevalence (<0.01-0.25%) and incidence (0.5-23.1/100 000) of psoriatic arthritis (PsA) is reported. The main objective of this study was to examine the prevalence and incidence of PsA in central Norway. The patients were recruited from the Nord-Trøndelag Health Study 3, a population study carried out in 2006-2008. All 94 194 inhabitants aged >20 years were invited and 50 806 (54%) responded. The study consisted of a questionnaire (Q1) and a brief medical examination. Q1 included questions if the persons suffered from psoriasis, rheumatoid arthritis (RA) or ankylosing spondylitis (AS). Patients with self-reported psoriasis further answered a specific questionnaire on psoriasis including a questionnaire concerning PsA. In order to identify patients with PsA we used the following criteria: Persons reporting they had or may have PsA; persons answering that they had psoriasis and RA; and persons answering that they had psoriasis and AS. Using this approach, 1278 patients were identified. Hospital files were evaluated by a rheumatologist according to a predefined protocol to verify the diagnosis of PsA. 338 patients, 144 men and 194 women, were verified to have PsA. The prevalence of PsA was 6.7 (95% CI 5.9 to 7.4) per 1000 inhabitants >20 years with no significant difference between men and women. In the 9-year period of 2000-2008, a total of 188 patients were diagnosed with PsA, which give an incidence rate of 41.3/100 000 (35.8-47.6). The prevalence of PsA in central Norway appears to be higher than previously reported. The reason for this is unknown and may include environmental factors, life style factors and genetic differences. 23888931 Massive Enhancement of Photoluminescence through Nanofilm Dewetting. Due to the rather low efficiencies of conjugated polymers in solid films, their successful applications are scarce. However, recently several experiments indicated that a proper control of molecular conformations and stresses acting on the polymers may provide constructive ways to boost efficiency. Here, we report an amazingly large enhancement of photoluminescence as a consequence of strong shear forces acting on the polymer chains during nanofilm dewetting. Such sheared chains exhibited an emission probability many times higher than the nonsheared chains within a nondewetted film. This increase in emission probability was accompanied by the emergence of an additional blue-shifted emission peak, suggesting reductions in conjugation length induced by the dewetting-driven mass redistribution. Intriguingly, exciton quenching on narrow-band-gap substrates was also reduced, indicating suppression of vibronic interactions of excitons. Dewetting and related shearing processes resulting in enhanced photoluminescence efficiency are compatible with existing fabrication methods of polymer-based diodes and solar cells. 23807276 Endothelial activation biomarkers increase after HIV-1 acquisition: plasma vascular cell adhesion molecule-1 predicts disease progression. We aimed to determine whether endothelial activation biomarkers increase after HIV-1 acquisition, and whether biomarker levels measured in chronic infection would predict disease progression and death in HIV-1 seroconverters. HIV-1-seronegative Kenyan women were monitored monthly for seroconversion, and followed prospectively after HIV-1 acquisition. Plasma levels of angiopoietin-1 and angiopoietin-2 (ANG-1, ANG-2) and soluble vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin were tested in stored samples from pre-infection, acute infection, and two chronic infection time points. We used nonparametric tests to compare biomarkers before and after HIV-1 acquisition, and Cox proportional-hazards regression to analyze associations with disease progression (CD4 < 200 cells/μl, stage IV disease, or antiretroviral therapy initiation) or death. Soluble ICAM-1 and VCAM-1 were elevated relative to baseline in all postinfection periods assessed (P < 0.0001). Soluble E-selectin and the ANG-2:ANG-1 ratio increased in acute infection (P = 0.0001), and ANG-1 decreased in chronic infection (P = 0.0004). Among 228 participants followed over 1028 person-years, 115 experienced disease progression or death. Plasma VCAM-1 levels measured during chronic infection were independently associated with time to HIV progression or death (adjusted hazard ratio 5.36, 95% confidence interval 1.99-14.44 per log10 increase), after adjustment for set point plasma viral load, age at infection, and soluble ICAM-1 levels. HIV-1 acquisition was associated with endothelial activation, with sustained elevations of soluble ICAM-1 and VCAM-1 postinfection. Soluble VCAM-1 may be an informative biomarker for predicting the risk of HIV-1 disease progression, morbidity, and mortality. 23942450 Mechanisms and mechanics of cell competition in epithelia. When fast-growing cells are confronted with slow-growing cells in a mosaic tissue, the slow-growing cells are often progressively eliminated by apoptosis through a process known as cell competition. The underlying signalling pathways remain unknown, but recent findings have shown that cell crowding within an epithelium leads to the eviction of cells from the epithelial sheet. This suggests that mechanical forces could contribute to cell elimination during cell competition. 22924841 A novel surgical-prosthetic approach for soft tissue dehiscence coverage around single implant. The aim of the study was to evaluate soft-tissue coverage and patient aesthetic satisfaction of a novel surgical-prosthetic approach to soft tissue dehiscence (STD) around single endosseous implant. Twenty patients with buccal soft tissues dehiscence around single implants in the aesthetic area were consecutively enrolled. Treatment consisted in: removal of the implant supported crown, reduction in the implant abutment, coronally advanced flap in combination with connective tissue graft (CTG) and final restoration. The unrestored contralateral tooth normally positioned without recession defect was used as a reference. The soft tissue coverage and patient satisfaction were evaluated 1 year after the final restoration. One-year mean STD coverage was 96.3%, and complete coverage was achieved in 75% of the treated sites. The increase (1.54 ± 0.21 mm) in buccal soft tissue thickness (STT) at 1 year was significantly correlated with CTG thickness at time of the surgery. The mean difference between graft thickness and STT increase was 0.09 ± 0.14 mm, corresponding to the 5.8% of the original graft thickness. The aesthetic analysis showed a significant improvement between the baseline (median, 3.8; 95% CI, 2-4) and the 1-year (median, 8.0; 95% CI, 8-10) visual analogue scale (VAS) scores. The results from the present study demonstrated that the proposed bilaminar technique was effective in the coverage of buccal STD around single dental implant and the suggested prosthetic-surgical approach was aesthetically successful. 23918690 Liver Glucagon Receptors (GluR): Effect of Exercise and Fasting on Binding Characteristics, GluR-mRNA, and GluR Protein Content in Rats. The purpose of the study was to investigate the effects of acute exercise and fasting on glucagon receptor (GluR) binding characteristics, GluR-mRNA, and protein content in rat liver. Liver homogenates were prepared and plasma membranes were purified by aqueous 2-phase affinity partitioning in rats fed at rest (control) and after 180 min of swimming exercise and 24 h of fasting (7 rats/group). Saturation curve of plasma membranes incubated with [125I]-glucagon showed significant higher GluR density following exercise and fasting than in the control group (8.19±0.29 and 8.01±0.65 vs. 3.09±0.12 pmol/mg of proteins, respectively). When compared to control rats, GluR Kd was also higher following exercise and fasting (0.46±0.05 and 0.56±0.13 vs. 0.33±0.05 nM, respectively; significantly different for fasting only). Expression of GluR-mRNA and protein content were both significantly higher (~100% and ~90%, respectively) following the 24-h fast than in the control rats, but not following exercise. These results, in line with the literature showing an increased sensitivity of the liver to glucagon following exercise and fasting, indicate that an increased density of GluR on plasma membranes can be obtained by 2 complementary mechanisms: externalization of pre-existing GluR from intracellular pools operative in response to the prolonged exercise, and de novo synthesis of GluR operative only in response to fasting. The reduction in plasma insulin concentration and/or depletion of liver glycogen stores, which results from both prolonged exercise and fasting, could be involved in the control of these mechanisms. 22411354 Mental workload as a key factor in clinical decision making. The decision making process is central to the practice of a clinician and has traditionally been described in terms of the hypothetico-deductive model. More recently, models adapted from cognitive psychology, such as the dual process and script theories have proved useful in explaining patterns of practice not consistent with purely cognitive based practice. The purpose of this paper is to introduce the concept of mental workload as a key determinant of the type of cognitive processing used by clinicians. Published research appears to be consistent with 'schemata' based cognition as the principle mode of working for those engaged in complex tasks under time pressure. Although conscious processing of factual data is also used, it may be the primary mode of cognition only in situations where time pressure is not a factor. Further research on the decision making process should be based on outcomes which are not dependant on conscious recall of past actions or events and include a measure of mental workload. This further appears to support the concept of the patient, within the clinical environment, as the most effective learning resource. 23695533 Gambling problems in young people: experience from the Asian region. To introduce the existing research conducted into gambling problems among young people in the Asian region. The prevalence rates of gambling-related problems of young people ranged from 32 to 60% for participation, from 1.5 to 5.0% for problem gambling and from 0.07 to 2.66% for pathological gambling in Asia; social gambling and lottery were the most popular gambling types. Psychiatric comorbidity is common among pathological gamblers, but the causal mechanisms are unclear. The psychological theories on youth gambling in Asia included diathesis, motivation, stress, coping, cognitive and positive youth development. The Positive Adolescent Training through Holistic Social Programmers has been developed; this aims to intervene and help those young people experiencing gambling problems in Hong Kong. Published gambling studies on young people in Asia are limited and have different definitions, research tools and diagnostic criteria. Therefore, the results vary and are incomparable. More work needs to be done in the near future, on comorbidity mechanisms, the neuropsychological and neurobiological mechanisms of youth gambling and, importantly, an increase in early intervention programmes. 23430683 Functional genomics of Staphylococcus aureus. Staphylococcus aureus remains a major opportunistic human pathogen, and while in many individuals it is associated with asymptomatic colonization, it is also capable of causing a range of clinical syndromes from minor skin infections to life-threatening septicemia. Staphylococcus aureus has also demonstrated a remarkable capacity to acquire antimicrobial resistance. Recent technological advances in genomics have led to an avalanche of studies providing deep insights into how S. aureus is evolving globally and within the human host. However, there are still significant experimental barriers in using these insights to try and better understand the biology of S. aureus. Here, we summarize recent advances in the understanding of S. aureus through the use of genomic approaches, and contemplate what the near future holds for truly functional genomics that will allow us to better understand the biology of this pathogen. 23919838 C-reactive protein and incident diabetes in patients with arterial disease. Systemic low-grade inflammation, as measured by high-sensitive C-reactive protein (hsCRP), may contribute to the risk of type 2 diabetes in patients with manifest arterial disease. Cohort study in 4072 patients with manifest arterial disease without diabetes. The relation between quartiles of hsCRP and type 2 diabetes was assessed with Cox regression analyses, taking age, smoking and blood pressure-lowering medication and lipid-lowering medication into account. Insulin resistance was estimated with homeostasis model of insulin resistance (HOMA-IR). In exploratory models, adjustments were performed for body mass index (BMI) and visceral and subcutaneous adipose tissue thickness. During a median follow-up of 5·0 (IQR 2·5-8·2) years, 288 subjects developed diabetes. High hsCRP was independently associated with incident diabetes (Q4 vs. Q1 males: HR 1·62; 95% CI 1·06-2·48; females: HR 3·12; 95% CI 1·57-6·21). HOMA-IR at baseline is related to hsCRP plasma levels (Q4 vs. Q1: males: β 0·27; 95% CI 0·19-0·36; females: β 0·35; 95% CI 0·22-0·48). The risk of diabetes associated with hsCRP was abolished in males (Q4 vs. 1 HR 1·23; 95% CI 0·80-1·88) and attenuated in females (Q4 vs. 1 HR 2·32; 95% CI 1·14-4·75) after adding BMI to the model, but not modified by statin use (P for interaction: 0·61). Patients with manifest arterial disease with high hsCRP plasma levels are at increased risk to develop type 2 diabetes and are more insulin resistant as compared to those with low hsCRP levels. This increase in risk is more pronounced in females than in males and is not modified by statin use. 23742795 Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus. Quantitative sensory testing (QST) is a psychophysical method used to quantify somatosensory function in response to controlled stimuli in healthy subjects and patients. Although QST shares similarities with the quantitative assessment of hearing or vision, which is extensively used in clinical practice and research, it has not gained a large acceptance among clinicians for many reasons, and in significant part because of the lack of information about standards for performing QST, its potential utility, and interpretation of results. A consensus meeting was convened by the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain (NeuPSIG) to formulate recommendations for conducting QST in clinical practice and research. Research studies have confirmed the utility of QST for the assessment and monitoring of somatosensory deficits, particularly in diabetic and small fiber neuropathies; the assessment of evoked pains (mechanical and thermal allodynia or hyperalgesia); and the diagnosis of sensory neuropathies. Promising applications include the assessment of evoked pains in large-scale clinical trials and the study of conditioned pain modulation. In clinical practice, we recommend the use QST for screening for small and large fiber neuropathies; monitoring of somatosensory deficits; and monitoring of evoked pains, allodynia, and hyperalgesia. QST is not recommended as a stand-alone test for the diagnosis of neuropathic pain. For the conduct of QST in healthy subjects and in patients, we recommend use of predefined standardized stimuli and instructions, validated algorithms of testing, and reference values corrected for anatomical site, age, and gender. Interpretation of results should always take into account the clinical context, and patients with language and cognitive difficulties, anxiety, or litigation should not be considered eligible for QST. When appropriate standards, as discussed here, are applied, QST can provide important and unique information about the functional status of somatosensory system, which would be complementary to already existing clinical methods. 23930714 Evaluation of Coptidis Rhizoma-Euodiae Fructus couple and Zuojin products based on HPLC fingerprint chromatogram and simultaneous determination of main bioactive constituents. Abstract Context: Coptidis Rhizoma-Euodiae Fructus couple (CEC) is a classic traditional Chinese medicine preparation consisting of Coptidis Rhizoma and Euodiae Fructus at the ratio of 6:1, and used to treat gastro-intestinal disorders. Alkaloids are the main bioactive component. This research provides comprehensive analysis information for the quality control of CEC. Objective: To develop a high-performance liquid chromatography-diode array detection fingerprint for chemical composition characteristics of CEC and its products. Materials and methods: The samples were separated with a Gemini C18 column by using gradient elution with water-formic acid (100:0.03) and acetonitrile as mobile phase. Flow rate was 1.0 mL/min and detection wavelength was 250 nm. Similarity analysis and principal component analysis (PCA) were employed to evaluate quality consistencies of analytes. Mean chromatograms and correlation coefficients of analytes were calculated by the software "Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine". Results: Fingerprint chromatogram comparison determined 20 representative general fingerprint peaks, and the fingerprint chromatogram resemblances are all better than 0.988. Consistent results were obtained to show that CEC and its related samples could be successfully divided into three groups. Contribution plots generated by PCA were performed to interpret differences among the sample groups while peaks which significantly contributed to classification were identified. Seven bioactive constituents in the samples were verified by quantitative analysis. Discussion and conclusion: The chromatographic fingerprint with similarity evaluation and PCA assay combined with quantification of seven compounds could be utilized as a quality control method for the herbal couple. 23639506 Immune circuits in asthma. Asthma is an inflammatory disorder of the conducting airways that has traditionally been classified according to severity. While this has been helpful in guiding treatment with drugs that are currently available such as β2-adrenoceptor agonists and corticosteroids, it takes little account of disease heterogeneity and causal pathways. This review draws attention to subphenotypes of asthma involving different mechanisms and moves the focus away from the adaptive immune response more towards innate immune mechanisms. This mandates a new view of the disease in which causal pathways linked to biomarkers are found and treatments targeted to these pathways as described in a more personalised approach to medicine. 23554450 A Thyroxine Absorption Test Followed by Weekly Thyroxine Administration: A Method to Assess Non-Adherence to Treatment. OBJECTIVE: For patients, who remain hypothyroid despite the administration of what would seem adequate doses of levothyroxine, the underlying cause can be difficult to determine. The possibility of a biological cause should first be explored; however, in the majority of cases poor adherence to medication is likely to be the main cause of treatment failure. When non-adherence is suspected but not volunteered, options to confirm the suspicion are limited. In this study we identified patients for whom known drug and pathological causes of levothyroxine malabsorption were excluded and despite often high doses of levothyroxine, the patients remained hypothyroid. DESIGN: Using a weight-determined oral levothyroxine bolus administration, absorption was initially assessed in twenty-three patients. In nearly all patients this was shown to be maximal at 120mins post ingestion. This was then followed by the continued administration of a weekly thyroxine bolus for a four-week period after which TSH and free T4 levels were recorded. RESULTS: All patients showed a rise in free T4 at 120mins following the administration of the levothyroxine bolus, with a mean increase of 54± 3% from baseline. Following the treatment period, using an equivalent weekly levothyroxine dose which was significantly less than that of the daily dose taken by the patients before the test, the TSH reduced from baseline in ~75% of cases. CONCLUSION: Using this combination of tests allows significant malabsorptive problems to be first identified, then potential non-adherence to be demonstrated. A management plan can then be implemented to increase adherence, aiming to improve treatment outcomes. 23932934 ActiGraph GT3X+ cut-points for identifying sedentary behaviour in older adults in free-living environments. To determine the ActiGraph GT3X+ cut-points with the highest accuracy for estimating time spent in sedentary behaviour in older adults in free-living environments. ActivPAL(3)™ was used as the reference standard. Cross-sectional study. 37 participants (13 males and 24 females, 73.5±7.3 years old) wore an ActiGraph GT3X+ and an ActivPAL(3)™ for 7 consecutive days. For ActivPAL(3)™, variables were created based on posture. For ActiGraph GT3X+, sedentary behaviour was defined as (1) vector magnitude and (2) vertical axis counts for 1-s, 15-s and 1-min epochs, with cut-points for 1-s epochs of <1 to <10counts, for 15-s epochs of <1 to <100counts and for 1-min epochs of <1 to <400counts. For each of the ActiGraph GT3X+ cut-points, area under the receiver operating characteristic curve (area under the curve), sensitivity, specificity, and percentage correctly classified were calculated. Bias and 95% limits of agreement were calculated using the Bland-Altman method. The highest areas under the curve were obtained for the vector magnitude cut-points: <1count/s, <70counts/15-s, and <200counts/min; and for the vertical axis cut-points: <1count/s, <10counts/15-s and <25counts/min. Mean biases ranged from -4.29 to 124.28min/day. The 95% limits of agreement for these cut-points were ±2h suggesting great inter-individual variation. The results suggest that cut-points are dependent on unit of analyses (i.e. epoch length and axes); cut-points for a given epoch length and axis cannot simply be extrapolated to other epoch lengths. Limitations regarding inter-individual variability and misclassification of standing activity as sitting/lying must be considered. 23376091 Arsenic induced neuronal apoptosis in guinea pigs is Ca2+ dependent and abrogated by chelation therapy: role of voltage gated calcium channels. Arsenic contaminated drinking water has affected more than 200 million people globally. Chronic arsenicism has also been associated with numerous neurological diseases. One of the prime mechanisms postulated for arsenic toxicity is reactive oxygen species (ROS) mediated oxidative stress. In this study, we explored the kinetic relationship of ROS with calcium and attempted to dissect the calcium ion channels responsible for calcium imbalance after arsenic exposure. We also explored if mono- or combinational chelation therapy prevents arsenic-induced (25ppm in drinking water for 4 months) neuronal apoptosis in a guinea pig animal model. Results indicate that chronic arsenic exposure caused a significant increase in ROS followed by NO and calcium influx. This calcium influx is mainly dependent on L-type voltage gated channels that disrupt mitochondrial membrane potential, increase bax/bcl2 levels and caspase 3 activity leading to apoptosis. Interestingly, blocking of ROS could completely reduce calcium influx whereas calcium blockage partially reduced ROS increase. While in general mono- and combinational chelation therapies were effective in reversing arsenic induced alteration, combinational therapy of DMSA and MiADMSA was most effective. Our results provide evidence for the role of L-type calcium channels in regulating arsenic-induced calcium influx and DMSA+MiADMSA combinational therapy may be a better protocol than monotherapy in mitigating chronic arsenicosis. 23306542 Mesenchymal stem cells and idiopathic pulmonary fibrosis. Potential for clinical testing. Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating, and fatal lung disease characterized by interstitial fibrosis with decreasing lung volumes and hypoxemic respiratory failure. The prognosis for patients with IPF is poor and the quest to find effective therapies has been unsuccessful. Despite several clinical trials over the past decade, there are no U.S. Food and Drug Administration-approved treatments for patients with IPF and thus no standard of care. In terms of pathogenesis, IPF is characterized by alveolar epithelial cell injury and activation with interstitial inflammation, fibroblast proliferation with extracellular matrix collagen deposition, and loss of lung function. Because mesenchymal stem cells (MSCs) home to sites of injury, inhibit inflammation, and contribute to epithelial tissue repair, their use has been suggested as a therapy for the treatment of IPF. MSCs have potential as a novel therapeutic agent in multiple diseases and they have been safely administered in a number of clinical trials. Some, but not all, preclinical studies in animal models of lung fibrosis suggest that MSCs might be effective in the treatment of IPF. Given the safety and ease of MSC administration in other patient populations, the results in preclinical animal models of IPF, and the major need for novel therapeutic options in this devastating disease, we propose that carefully designed clinical trials of MSCs for the treatment of patients with IPF are appropriate. Establishing safety in the setting of IPF is the first priority in early clinical trials followed by clinical and biological measures of efficacy. 23889414 Universal damping behavior of dipole oscillations of one-dimensional ultracold gases induced by quantum phase slips. We study superflow decay via quantum phase slips in trapped one-dimensional (1D) quantum gases through dipole oscillations induced by sudden displacement of the trapping potential. We find the relation between the damping rate of the dipole oscillation G and the phase-slip nucleation rate Γ as G∝Γ/v, where v is the flow velocity. This relation allows us to show that damping of 1D Bose gases in optical lattices, which has been extensively studied in experiment, is due to quantum phase slips. It is also found that the damping rate versus the flow velocity obeys the scaling formula for an impurity potential even in the absence of an explicit impurity. We suggest that the damping rate at a finite temperature exhibits a universal crossover behavior upon changing the flow velocity. 23259935 Tailorable cell culture platforms from enzymatically cross-linked multifunctional poly(ethylene glycol)-based hydrogels. As stem-cell-based therapies rapidly advance toward clinical applications, there is a need for cheap, easily manufactured, injectable gels that can be tailored to carry stem cells and impart function to such cells. Herein we describe a process for making hydrogels composed of hydroxyphenyl propionic acid (HPA) conjugated, branched poly(ethylene glycol) (PEG) via an enzyme mediated, oxidative cross-linking method. Functionalization of the branched PEG with HPA at varying degrees of substitution was confirmed via attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and (1)H NMR. The versatility of this hydrogel system was exemplified through variations in the degree of HPA substitution, polymer concentration, and the concentration of cross-linking reagents (horseradish peroxidase and H(2)O(2)), which resulted in a range of mechanical properties and gelation kinetics for these gels. Cross-linking of the PEG-HPA conjugate with a recombinantly produced Fibronectin fragment (Type III domains 7-10) encouraged attachment and spreading of human mesenchymal stem cells (hMSCs) when assessed in both two-dimensional and three-dimensional formats. Interestingly, when encapsulated in both nonfunctionalized and functionalized cross-linked PEG-HPA gels, MSCs showed good viability over all time periods assessed. With tunable gelation kinetics and mechanical properties, these hydrogels provide a flexible in vitro cell culture platform that will likely have significant utility in tissue engineering as an injectable delivery platform for cells to sites of tissue damage. 23911352 Uncontrolled epilepsy is not necessarily the same as drug-resistant epilepsy: Differences between populations with newly diagnosed epilepsy and chronic epilepsy. A proportion of patients with seemingly "uncontrolled" epilepsy could still control their epilepsy with further pharmacological manipulations. It is possible that their epilepsy might not be truly "drug-resistant". We audited the patients with "uncontrolled epilepsy" using the recent ILAE definition of drug-resistant epilepsy. Patients with newly diagnosed epilepsy at Glasgow and patients with chronic epilepsy treated in Hong Kong were independently assessed at their last clinic visit. If the patient was not seizure-free, the epilepsy was considered "uncontrolled". In this latter situation, if the patient had adequate trials of two or more tolerated, appropriately chosen, and appropriately used AED schedules, the epilepsy was classified as "drug-resistant" in accordance with the ILAE definition. If not, the outcome was classified as "undefined", and the reason(s) for this was documented. In the newly diagnosed cohort with uncontrolled epilepsy (n=311), outcome was "undefined" in 175 (56%). The most common reasons were trying just one AED usually at the patient's behest (n=68; 39%); intermittent compliance (60; 34%); adverse effects at low dosage (51; 29%); inadequate dosing (49; 28%); social issues such as imprisonment, alcohol, and recreational drug use (34; 19%); psychiatric problems affecting documentation, attendance, etc. (32; 18%); patient choice accepting less than optimal control (14; 8%); and seizure freedom of less than 12months (12.7%). In the chronic cohort of 194 patients with uncontrolled epilepsy, drug responsiveness was "undefined" in just 79 (41%). The most common reasons were inadequate use of the AED(s) (35; 44%), followed by a lack of information on treatment response in the medical records (18; 23%) and failure of only one adequately used AED (11; 14%). Uncontrolled epilepsy is not necessarily the same as drug-resistant epilepsy. Efforts should be made to understand why a patient is not seizure-free so that appropriate adjustment in AED regimen can be taken to enable the patient to attain long-term seizure freedom. 23277103 Effects of glyphosate-based herbicides on embryo-larval development and metamorphosis in the Pacific oyster, Crassostrea gigas. Pesticides may be involved in oyster summer mortality events, not necessarily as a single causative agent but as an additional stressor. In this context, the present study aimed to assess the toxicity of glyphosate, its by-product, aminomethylphosphonic acid (AMPA) and two commercial formulations, Roundup Express(®) (R(EX)) and Roundup Allées et Terrasses(®) (R(AT)), containing glyphosate as the active ingredient, on the early life stages of the Pacific oyster, Crassostrea gigas. The embryotoxicity of these chemicals were quantified by considering both the rates of abnormalities and the arrested development or types of abnormalities in D-shaped larvae after 48 h exposure. The success of metamorphosis was examined in pediveliger larvae exposed for 24 h. Experiments involving both endpoints included range finding experiments for herbicide concentrations ranging from 0.1 to 100,000 μg L(-1). This range was then narrowed down in order to determine precise EC(50) values. Actual concentrations of the herbicide were determined at the beginning and after 48 h (embryotoxicity) and 24 h (metamorphosis) to evaluate the potential temporal variation in the concentrations. During embryo-larval development, no mortalities were recorded at any of the concentrations of glyphosate and AMPA, whereas no embryos or D-shaped larvae could be observed after exposure to 10,000 μg L(-1) of R(EX) or R(AT). Compared with the controls, no effects on embryo-larval development were recorded between 0.1 and 1000 μg L(-1), regardless of the chemical tested. Above a threshold, which varied according to the chemical used, the gradient of herbicide concentrations correlated with a gradient of severity of abnormality ranging from normal larvae to arrested development (an "old embryo" stage). The EC(50) values were 28,315 and 40,617 μg L(-1) for glyphosate and its metabolite, respectively, but much lowered values of 1133 and 1675 μg L(-1) for R(EX) and R(AT), respectively. Metamorphosis tests also revealed a significant difference between molecules, as the EC(50) values exceeded 100,000 μg L(-1) for glyphosate and AMPA but were as low as 6366 and 6060 μg L(-1) for the commercial formulations, which appeared relatively more toxic. Overall, the embryo-larval development of C. gigas was more sensitive to glyphosate-based herbicides compared to various endpoints studied in regulatory model organisms, and embryos and D-shaped larvae were more sensitive compared to pediveliger larvae. 23711782 Incorporation of biphasic calcium phosphate microparticles in injectable thermoresponsive hydrogel modulates bone cell proliferation and differentiation. To provide osteoblast cells with a three-dimensional environment closer to bone matrix, an engineered construct mimicking bone components have been designed and evaluated. A biocompatible injectable thermo-responsive hydrogel, hyaluronic acid-g-chitosan-g-poly (N-isopropylacrylamide) (HA-CPN), was used as a biomimetic organic gel matrix while embedded biphasic calcium phosphate (BCP) ceramic micoparticles were used to replace mineralized matrix. The physicochemical properties of HA-CPN/BCP hydrogel composite were characterized by X-ray diffraction, thermogravimeric analysis, differential scanning calorimetric, and Fourier transform infrared spectroscopy. Human fetal osteoblast cells were cultured in vitro in HA-CPN and HA-CPN/BCP scaffold to study cell viability, proliferation, gene expression, and maintenance of their osteoblastic differential potentials. Overall, HA-CPN/BCP can serve as a better injectable carrier for bone cells than HA-CPN with enhanced proliferation rate and alkaline phosphatase activity from biochemical assays, improved calcium deposition and mineralization of extracellular matrix by histological examinations, and elevated gene expression of all essential osteoblastic genes from quantitative real-time PCR, to provide a cell/scaffold construct with higher mechanical strength and elasticity. From in vivo nude mice subcutaneous implantation experiments, the injected cell mass can form ectopic bone tissue in HA-CPN/BCP hydrogel composite. 23918905 Paget Cells on Endometrial and Endocervical Curettings in a Patient With Recurrent Vulvar Paget's Disease. Introduction. Paget's disease of the vulva is a rare malignancy primarily affecting Caucasian women in their seventh to eighth decades. Most patients experience an indolent disease course and undergo surgical excision for disease control. Although progression to invasive adenocarcinoma is rare, recurrence is common because of the difficulty of achieving negative surgical margins. Case presentation. We report a case of a 73-year-old woman with a long-standing history of recurrent vulvar Paget's disease who presented with postmenopausal bleeding. Workup revealed extensive endocervical involvement by Paget's disease, resulting in Paget cells on endocervical curettage, as well as endometrial curettage (because of cervical contamination). Conclusion. Extensive endocervical involvement by vulvar Paget's disease can occur despite multiple reexcisions and topical therapy. The presence of Paget cells on endometrial and endocervical curettings, particularly in patients without visible vulvar or cervical lesions, should raise suspicion of endocervical involvement and prompt further evaluation of disease extension. 23726776 Interpersonal problems and impacts: Further evidence for the role of interpersonal functioning in treatment outcome in major depressive disorder. Empirical research has converged to support the concurrent association between social difficulties and psychiatric symptoms; yet, longitudinal associations between interpersonal problems and treatment outcome require clarification. The current investigation evaluated the influence of interpersonal problems assessed prior to treatment on interpersonal impacts assessed during treatment as well as on treatment outcome in outpatients with major depressive disorder (MDD). 125 participants with a primary diagnosis of MDD were randomized to receive cognitive behavioural therapy or interpersonal therapy. Participants completed the Beck Depression Inventory-II, Hamilton Depression Rating Scale, and Inventory of Interpersonal Problems Circumplex before and after treatment. Therapists completed the Impact Message Inventory during and after treatment. Interpersonal distress improved over the course of treatment; all other interpersonal changes were non-significant when distress was taken into account. Pre-treatment rigidity and agentic problems predicted less reduction in depressive symptoms, whereas agentic and communal impacts upon therapists during treatment predicted greater symptom change. Overall interpersonal distress was only indirectly associated with treatment response later in treatment, through its association with agentic style. Results did not differ across therapy type, and were replicated across self-report and interviewer-rated measures of depression severity. Limitations include the brief duration of treatment, lack of medication arm, and potentially restricted generalizability of patients in a randomized control trial to those in routine practice. Interpersonal style demonstrated a trait-like stability over treatment, and appears to fluctuate due to co-occurring distress. Yet, specific interpersonal styles were negative prognostic indicators, even within therapy specifically targeting interpersonal functioning. 23171604 Effect of dibutyryl cyclic adenosine monophosphate on reactive oxygen species and glutathione of porcine oocytes, apoptosis of cumulus cells, and embryonic development. The present study was conducted to investigate the effect of dibutyryl cyclic adenosine monophosphate (dbcAMP) supplemented into porcine maturation medium on reactive oxygen species (ROS) and glutathione (GSH) levels of oocytes, and apoptosis of cumulus cells (CC). In addition, the effect of dbcAMP on embryonic development following in vitro fertilization (IVF) or parthenogenetic activation (PA) was determined. Cumulus-oocyte complexes (COCs) were cultured in 0 mM (control), 0.5 mM, 1 mM, 5 mM, or 10 mM dbcAMP-supplemented medium for 22 h, then for another 22 h without dbcAMP. GSH and ROS levels of oocytes were assessed at 44 h of culture by dichlorohydrofluorescein diacetate or 4-chloromethyl-6,8-difluoro-7-hydroxycoumarin staining, respectively. Additionally, COCs were cultured in 0.5 mM or 1 mM dbcAMP and then fertilized in vitro or activated parthenogenetically. Embryonic development and blastocyst cell numbers and apoptosis levels on day 8 of culture were investigated. CC apoptosis at 44 h of culture and blastocyst apoptosis were assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. GSH levels in the 0.5 mM dbcAMP and control groups were increased (P < 0.05), while levels of oocyte ROS and CC apoptosis in the control, 0.5 mM, and 1 mM dbcAMP groups were significantly lower than the levels in other groups. Cleavage and blastocyst rates, cell numbers, and apoptosis levels were not significantly different in embryos derived by either IVF or PA among the groups, with the exception of significantly increased apoptotic levels in IVF blastocysts produced from oocytes treated with 1 mM dbcAMP. In conclusion, dbcAMP treatment during in vitro maturation (IVM) did not improve embryonic development under our study's parameters compared with control conditions, although 0.5 mM dbcAMP showed significantly higher GSH levels and lower blastocyst apoptotic levels compared with 1 mM dbcAMP. 23865985 Extensive hybridization and associated geographic trends between two rockfishes Sebastes vulpes and S. zonatus (Teleostei: Scorpaeniformes: Sebastidae). Interspecific hybridization is an important evolutionary process, which has significant influence on the diversity within and between participating taxa. Although interspecific hybridization in terrestrial and freshwater organisms has been subjected to many detailed studies, studies in marine realm have been limited in terms of both numbers and detail. In this study, the potential for interspecific hybridization between two rockfishes, Sebastes vulpes and S. zonatus, occurring in the western North Pacific, was assessed on the basis of 177 specimens collected from three sampling localities within the main geographic distribution of both species, and analysed using a combination of amplified fragment length polymorphisms (AFLP), mitochondrial DNA (mtDNA) markers and morphometric characters. Bayesian-based individual genetic assignment based on 364 AFLP loci detected a total of 63 (35.6%) hybrid specimens in the data set, the presence of interspecific hybrids also being rigorously supported by mtDNA analysis using partial sequences from the control region and morphological analysis based on 31 morphometric characters. Hybrids from all three localities were found, showing a common pattern of biased introgression across the localities whereby hybrids were more closely related to S. zonatus than to S. vulpes. Apart from this common pattern, rates of hybridization varied considerably among the localities, being greater in the northern localities. Variations in the local rates of hybridization were associated with variations in habitat segregation and thermal regime, implying that vertical water temperature regimes determined the extent of habitat segregation of the two species and, accordingly, the opportunity for hybridization. 23922423 Behavioural profile of zonisamide in adult patients with epilepsy and neuropsychiatric comorbidity. Zonisamide is a newer antiepileptic drug indicated as adjunctive therapy in the treatment of adult patients with partial-onset seizures, with or without secondary generalization. Following isolated reports of zonisamide-induced mania, other behavioural adverse effects, including psychosis and suicidal ideation have been associated with its use, and it was suggested that past psychiatric history is among the factors associated with discontinuation of zonisamide therapy in patients with epilepsy. We therefore set out to assess the tolerability profile of zonisamide in this particular group of patients with epilepsy, who are at risk of developing adverse reactions to zonisamide. This study investigated the prevalence and characteristics of adverse effects resulting from the use of zonisamide in a retrospective chart review of patients with epilepsy and co-morbid cognitive and/or behavioural problems, recruited from the specialist neuropsychiatry clinic at the National Centre for Mental Health, BSMHFT and University of Birmingham. We identified 12 eligible patients (3 males, mean age 36 years, range 16-59 years). All patients had a clinical diagnosis of treatment-refractory epilepsy (9=temporal lobe epilepsy), supported by neurophysiological and neuroimaging findings, and had concomitant and/or previous antiepileptic medications (11=levetiracetam, 8=carbamazepine, 6=lamotrigine, 6=valproate). In our neuropsychiatric sample, 6 patients had a previous diagnosis of depression, 2 anxiety disorders, 2 learning disability, 2 neurodevelopmental disorders (Tourette syndrome and autism) and 1 psychosis. Co-morbid non-epileptic attack disorder was documented in 4 patients. In the majority of cases, zonisamide (mean maintenance dose=212.5mg daily, range 50-500 mg daily) was well tolerated and behavioural adverse effects were not severe. Three patients (25.0%) discontinued zonisamide over the observation period (mean duration 15 months, range 1-48 months). The main reasons for discontinuation were lack of efficacy on seizure control (two cases) and emerging depression as an adverse effect (one case). This preliminary observation of relatively low discontinuation rate of zonisamide in a selected population of patients with epilepsy and neuropsychiatric comorbidity prompts further research to establish whether this medication is a safe treatment option for vulnerable patients with treatment-refractory epilepsy. 23780762 Novel GM animal technologies and their governance. Scientific advances in methods of producing genetically modified (GM) animals continue, yet few such animals have reached commercial production. Existing regulations designed for early techniques of genetic modification pose formidable barriers to commercial applications. Radically improved techniques for producing GM animals invite a re-examination of current regulatory regimes. We critically examine current GM animal regulations, with a particular focus on the European Union, through a framework that recognises the importance of interactions among regulatory regimes, innovation outcomes and industry sectors. The current focus on the regulation of risk is necessary but is unable to discriminate among applications and tends to close down broad areas of application rather than facilitate innovation and positive industry interactions. Furthermore, the fields of innovative animal biosciences appear to lack networks of organisations with co-ordinated future oriented actions. Such networks could drive coherent programmes of innovation towards particular visions and contribute actively to the development of regulatory systems for GM animals. The analysis presented makes the case for regulatory consideration of each animal bioscience related innovation on the basis of the nature of the product itself and not the process by which it was developed. 23947568 A Comparative Kirkwood-Buff Study of Aqueous Methanol Solutions Modeled by the CHARMM Additive and Drude Polarizable Force Fields. A comparative study on aqueous methanol solutions modeled by the CHARMM additive and Drude polarizable force fields was carried out by employing Kirkwood-Buff analysis. It was shown that both models reproduced the experimental Kirkwood-Buff integrals and excess coordination numbers adequately well over the entire concentration range. The Drude model showed significant improvement over the additive model in solution densities, partial molar volumes, excess molar volumes, concentration-dependent diffusion constants, and dielectric constants. However, the additive model performed somewhat better than the Drude model in reproducing the activity derivative, excess molar Gibbs energy and excess molar enthalpy of mixing. This is due to the additive model achieving a better balance among solute-solute, solute-solvent, and solvent-solvent interactions, indicating the potential for improvements in the Drude polarizable alcohol model. 23872979 Dry-gel conversion synthesis of Cr-MIL-101 aided by grinding: high surface area and high yield synthesis with minimum purification. A dry gel conversion synthesis aided by fine-grinding of the synthesis precursors produces a MIL-101 product with a high surface area greater than 4100 m(2) g(-1) and a product yield approaching 90% in a very reproducible manner after only simple water washing. 23863032 Identification of Inhibitors of the Antibiotic-Resistance Target New Delhi Metallo-β-lactamase 1 by both Nanoelectrospray Ionization Mass Spectrometry and Ultrafiltration Liquid Chromatography/Mass Spectrometry Approaches. Mass spectrometry-based platforms have gained increasing success in discovery of ligands bound to therapeutic targets as drug candidates. We established both a nanoelectrospray ionization mass spectrometry (nanoESI-MS) assay and an ultrafiltration liquid chromatography/mass spectrometry (LC/MS) assay to identify new ligands for New Delhi metallo-β-lactamase 1 (NDM-1), responsible for worldwide antibiotic resistance. To alleviate nonspecific binding of hydrophobic compounds and eliminate false positives typically encountered in the indirect LC/MS-based assay, we introduced a blocking protein in the control, which remarkably enhances the selectivity and accuracy of the indirect approach. Side-by-side comparison of the two MS-based approaches for the first time further reveals unique advantages of the indirect approach, including better reproducibility and tolerance of interference. Moreover, the success of fishing out a potent ligand from a mixture of small-molecule fragments demonstrates great potential of the indirect LC/MS-based approach for constructing a robust screening platform against combinatorial libraries or natural product extracts. More importantly, by combining the results of MS-based analyses, enzymatic activity assay, competition experiments, and structural simulation, we discovered a new compound as a promising drug candidate targeting NDM-1. 23891817 Retinal ganglion cells: Energetics, compartmentation, axonal transport, cytoskeletons and vulnerability. Retinal ganglion cells (RGCs) are specialized projection neurons that relay an immense amount of visual information from the retina to the brain. RGC signal inputs are collected by dendrites and output is distributed from the cell body via very thin (0.5-1 Î¼m) and long (∼50 mm) axons. The RGC cell body is larger than other retinal neurons, but is still only a very small fraction (one ten thousandths) of the length and total surface area of the axon. The total distance traversed by RGCs extends from the retina, starting from synapses with bipolar and amacrine cells, to the brain, to synapses with neurons in the lateral geniculate nucleus. This review will focus on the energy demands of RGCs and the relevant tissues that surround them. RGC survival and function unexceptionally depends upon free energy, predominantly adenosine triphosphate (ATP). RGC energy metabolism is vastly different when compared to that of the photoreceptors. Each subcellular component of the RGC is remarkably different in terms of structure, function and extracellular environment. The energy demands and distribution of each component are also distinct as evidenced by the uneven distribution of mitochondria and ATP within the RGC - signifying the presence of intracellular energy gradients. In this review we will describe RGCs as having four subcellular components, (1) Dendrites, (2) Cell body, (3) Non-myelinated axon, including intraocular and optic nerve head portions, and (4) Myelinated axon, including the intra-orbital and intracranial portions. We will also describe how RGCs integrate information from each subcellular component in order achieve intracellular homeostatic stability as well as respond to perturbations in the extracellular environment. The possible cellular mechanisms such as axonal transport and axonal cytoskeleton proteins that are involved in maintaining RGC energy homeostasis during normal and disease conditions will also be discussed in depth. The emphasis of this review will be on energetic mechanisms within RGC components that have the most relevance to clinical ophthalmology. 23543917 RNA blood levels of osteopontin splice variants are cancer markers. Despite a sizeable and continuously growing literature on osteopontin and cancer the molecule has not yet found entry into clinical diagnostics. Our identification of spliced variants that are more specific for cancer than the full-length transcript has opened new possibilities for reaching this goal. Here we have developed a real-time RT-PCR blood test and evaluated it in a pilot study of breast, lung, pancreatic, gynecologic, and other cancers, compared to non-cancer controls. Osteopontin-b was increased in lung cancers and pancreatic cancers. When applying a cutoff of 2 standard deviations above normal, elevation in osteopontin-b transcripts detected over 40% of lung cancers. Osteopontin-c was increased in gynecologic and pancreatic cancers. Elevation in osteopontin-c of 2 standard deviations above the normal mean value also detected a fraction of breast cancers and lung cancers, suggesting heterogeneity within those types of tumors. Specifically, breast carcinomas were associated with significantly higher levels of osteopontin-c mRNA in the blood than carcinomas in situ. In lung cancer patients, the osteopontin-c blood RNA levels had an increasing trend with tumor grade. Osteopontin-b and -c in the blood are biomarkers for distinct cancers. Our investigations may have bearing on cancer screening and diagnosis. 23947348 Natural killer cells: multifaceted players with key roles in hepatitis C immunity. Natural killer cells (NKs) are involved in every stage of hepatitis C viral (HCV) infection, from protection against HCV acquisition and resolution in the acute phase to treatment-induced clearance. In addition to their direct antiviral actions, NKs are involved in the induction and priming of appropriate downstream T-cell responses. In the setting of chronic HCV, overall NK cell levels are decreased, subset distribution is altered, and changes in NK receptor (NKR) expression have been demonstrated, although the contribution of individual NKRs to viral clearance or persistence remains to be clarified. Enhanced NK cell cytotoxicity accompanied by insufficient interferon-γ production may promote liver damage in the setting of chronic infection. Treatment-induced clearance is associated with activation of NK cells, and it will be of interest to monitor NK cell responses to triple therapy. Activated NK cells also have anti-fibrotic properties, and the same hepatic NK cell populations that are actively involved in control of HCV may also be involved in control of HCV-associated liver damage. We still have much to learn, in particular: how do liver-derived NKs influence the outcome of HCV infection? Do NK receptors recognize HCV-specific components? And, are HCV-specific memory NK populations generated? 23299396 Investigating the speed-accuracy trade-off: Better use deadlines or response signals? Deadlines (DLs) and response signals (RSs) are two well-established techniques for investigating speed-accuracy trade-offs (SATs). Methodological differences imply, however, that corresponding data do not necessarily reflect equivalent processes. Specifically, the DL procedure grants knowledge about trial-specific time demands and requires responses before a prespecified period has elapsed. In contrast, RS intervals often vary unpredictably between trials, and responses must be given after an explicit signal. Here, we investigated the effects of these differences in a flanker task. While all conditions yielded robust SAT functions, a right-shift of the curves pointed to reduced performance in RS conditions (Experiment 1, blocked; Experiments 2 and 3, randomized), as compared with DL conditions (Experiments 1-3, blocked), indicating that the detection of the RS imposes additional task demands. Moreover, the flanker effect vanished at long intervals in RS settings, suggesting that stimulus-related effects are absorbed in a slack when decisions are completed prior to the signal. In turn, effects of a flat (Experiment 2) versus a performance-contingent payment (Experiment 3) indicated that susceptibility to response strategies is higher in the DL than in the RS method. Finally, the RS procedure led to a broad range of slow responses and high accuracies, whereas DL conditions resulted in smaller variations in the upper data range (Experiments 1 and 2); with performance-contingent payment (Experiment 3), though, data ranges became similar. Together, the results uncover characteristic procedure-related effects and should help in selection of the appropriate technique. 23894278 The role of gender in scholarly authorship. Gender disparities appear to be decreasing in academia according to a number of metrics, such as grant funding, hiring, acceptance at scholarly journals, and productivity, and it might be tempting to think that gender inequity will soon be a problem of the past. However, a large-scale analysis based on over eight million papers across the natural sciences, social sciences, and humanities reveals a number of understated and persistent ways in which gender inequities remain. For instance, even where raw publication counts seem to be equal between genders, close inspection reveals that, in certain fields, men predominate in the prestigious first and last author positions. Moreover, women are significantly underrepresented as authors of single-authored papers. Academics should be aware of the subtle ways that gender disparities can occur in scholarly authorship. 23806189 Relationship between previous history of Streptococcus uberis infection and response to a challenge model. Streptococcus uberis is the most common cause of clinical mastitis at calving in pasture-based dairy cows. Results of experimental inoculations were compared with cows' previous history of infection to help define a model for susceptibility to Str. uberis mastitis. Cows used had either no apparent history of intramammary infection (IMI) by Str. uberis or other major mastitis pathogens throughout their productive lifetime ('apparently uninfected'; AUI), or had a confirmed history of Str. uberis IMI ('historically infected'; HI). Cows were exposed to Str. uberis in sequential steps: dipping of the teat end (DIP; n=53 cows); a teat canal inoculation (TCI; n=33 cows); and, finally, intramammary inoculation challenge (IC; n=7 cows). Only cows that remained free of infection at each step progressed to the next phase. Infection rates were similar between AUI or HI cows following the DIP (9 and 17% respectively), or the TCI (75 and 68% respectively). Physical and biochemical traits of cows were examined. Analysis of traits prior to inoculations implied that HI cows produced more milk fat, while AUI cows tended to have longer teat canals. Analysis of traits for cows that became infected following DIP, implied that there was a positive association with milk fat production and negative association with somatic cell count (SCC), while there was a positive association with the duration of p.m. milking, and negative association with SCC in those cows that became infected following TCI. Only AUI cows became infected following the IC inoculation. Similarity in response to experimental inoculation between the two groups suggests that the current dip or teat canal inoculation (using a 3-mm depth of inoculation) models are not good predictors of natural resistance to Str. uberis. However, a population of cows was identified that remained uninfected after DIP, TCI and IC, and may comprise a resistant phenotype. 23756194 Screening for Fabry disease in patients undergoing dialysis for chronic renal failure in Turkey: Identification of new case with novel mutation. Chronic renal failure (CRF) is a serious complication of Fabry disease (FD). The aims of the present study were to determine the prevalence of unrecognized FD in Turkish hemodialysis population and to investigate the molecular background. Primarily, α-galactosidase A (α-Gal A) activity was investigated on DBS in 1136 patients of both sexes who underwent dialysis for CRF in Turkey. The disease was confirmed by analyzing enzyme activity in leukocyte and GLA gene sequencing in all patients in whom α-Gal A level was 40% of normal or less. Mean age of the patients (44.5% female, 52.5% male) was 56.46±15.85years. Enzyme activity was found low with DBS method in 12 patients (four males, eight females). Two men, but no women, were diagnosed with FD by enzymatic and molecular analysis. In consequence of genetic analysis of a case, a new mutation [hemizygote c.638C>T (p.P214S) missense mutation in exon 5] was identified, which was not described in literature. Family screening of cases identified six additional cases. As a result of this initial screening study performed on hemodialysis patients for the first time with DBS method in Turkey, the prevalence of FD was detected as 0.17%. Although the prevalence seems to be low, screening studies are of great importance for detecting hidden cases as well as for identifying other effected family members. 23908377 The role of cyclase-associated protein in regulating actin filament dynamics - more than a monomer-sequestration factor. Dynamic reorganization of the actin cytoskeleton is fundamental to a number of cell biological events. A variety of actin-regulatory proteins modulate polymerization and depolymerization of actin and contribute to actin cytoskeletal reorganization. Cyclase-associated protein (CAP) is a conserved actin-monomer-binding protein that has been studied for over 20 years. Early studies have shown that CAP sequesters actin monomers; recent studies, however, have revealed more active roles of CAP in actin filament dynamics. CAP enhances the recharging of actin monomers with ATP antagonistically to ADF/cofilin, and also promotes the severing of actin filaments in cooperation with ADF/cofilin. Self-oligomerization and binding to other proteins regulate activities and localization of CAP. CAP has crucial roles in cell signaling, development, vesicle trafficking, cell migration and muscle sarcomere assembly. This Commentary discusses the recent advances in our understanding of the functions of CAP and its implications as an important regulator of actin cytoskeletal dynamics, which are involved in various cellular activities. 23108216 Promoting effect of polysaccharide isolated from Mori fructus on dendritic cell maturation. Maturation of dendritic cells (DCs) is usually attenuated in the tumor microenvironment, which is an important immunological problem in DC-based immunotherapy of cancer. In this study, we report the effect of a Mori fructus polysaccharide (MFP) on DC maturation. MFP was treated to DCs generated from mouse BM cells. MFP induced phenotypic maturation of DCs, as proven by the increased expression of CD40, CD80/86, and MHC-I/II molecules. MFP induced functional maturation of DCs, in that MFP increased the expression of IL-12, IL-1β, TNF-α, and IFN-β, decreased antigen capture capacity, and enhanced allogenic T cell stimulation. MFP efficiently induced maturation of DCs from C3H/HeN mice having normal toll-like receptor4 (TLR4), but not DCs from C3H/HeJ mice having mutated TLR4, suggesting that TLR4 might be one of the membrane receptors of MFP. As a mechanism of action, MFP increased phosphorylation of mitogen-activated protein kinase (MAPKs), and nuclear translocation of NF-κB p65 subunit, which were important signal molecules downstream from TLR4. These data suggest that MFP induces DC maturation through TLR4 and MFP can be used as an adjuvant in DC-based cancer immunotherapy. 23892532 Seven years of objective and subjective outcomes of transobturator (TVT-O) vaginal tape: Why do tapes fail? This study reports long-term outcomes of the transvaginal tension-free vaginal tape-obturator (TVT-O) procedure for treating stress urinary incontinence (SUI), including possible risk factors for failure. This was a retrospective study of women who underwent TVT-O with or without concomitant prolapse surgery. Procedures were performed at a tertiary referral urogynecology unit. Participants presented with SUI and had urodynamic stress incontinence (USI). Women with a history of previous anti-incontinence procedures, radical pelvic surgery, and detrusor overactivity (DO) were excluded. Objective cure was defined as absence of urine leakage during a cough stress test (CST). Subjective outcome was based on the International Consultation on Incontinence Questionnaire for Evaluating Female Lower Urinary Tract Symptoms (ICIQ-FLUTS). Quality of life was assessed using the King's Health Questionnaire (KHQ). Univariate and multivariate analyses were used to identify risk factors for subjective failure. One hundred twenty-four consecutive women were assessed, with a median follow-up of 90.3 (range 80-103) months. Overall objective and subjective cure rates were 81.5 % (101/124) and 83.5 % (103/124), respectively. A significant improvement was observed in all KHQ domains. Concomitant vaginal hysterectomy [odds ratio (OR) = 2.98, 95 % confidence interval (CI) 1.10-8.05, p = 0.03] and increasing point C (OR = 1.17, 95 % CI 1.05-1.30, p = 0.006] were associated with a higher risk for subjective failure. De novo urgency rate was 7 %. The TVT-O procedure provides high objective and subjective long-term efficacy, a clinically meaningful improvement in patient quality of life, and an excellent safety profile. Concomitant vaginal hysterectomy and apical compartment prolapse were associated with a higher risk for objective and subjective failure. 23870005 Pseudomonas aeruginosa bacteremia in patients with liver cirrhosis: a comparison with bacteremia caused by Enterobacteriaceae. This study was performed to detect risk factors for Pseudomonas aeruginosa bacteremia in patients with liver cirrhosis. A retrospective case-control study was designed to identify risk factors for P. aeruginosa bacteremia in cirrhotic patients. The cases were cirrhotic patients with P. aeruginosa bacteremia and the controls were cirrhotic patients with Enterobacteriaceae bacteremia. Sixty-one cases and the same number of controls were enrolled. In a multivariate analysis, younger age {adjusted odds ratio (aOR) per one year: 0.96, 95% confidence interval: 0.93 - 0.99}, nosocomial acquisition (aOR 3.87, 95% confidence interval: 1.50 - 9.94), preexisting biliary disease (aOR 4.79, 95% confidence interval: 1.92 - 10.47), and recent exposure to immunosuppressive agent (aOR 3.10, 95% confidence interval: 1.23 - 7.82) were associated with P. aeruginosa bacteremia. In the case group the frequency of appropriate initial antibiotic regimens was considerably lower than in the control group: 29.5% vs. 65.6% (P <0.01). However, thirty day mortality did not differ significantly between cases and controls (19.7% vs. 24.6%). Nosocomial acquisition, preexisting biliary disease, and recent use of immunosuppressive agents are strong predictive factors for P. aeruginosa bacteremia in cirrhotic patients. 23664449 Favorable prognosis of operable non-small cell lung cancer (NSCLC) patients harboring an increased expression of tumor endothelial markers (TEMs). Genome analyses of endothelial cells identified genes specifically expressed by tumor endothelial cells, called tumor endothelial markers (TEMs). Currently there are no data available concerning the role of TEMs in non-small cell lung cancer (NSCLC). Therefore, the aim of this study was to investigate the role of TEMs in NSCLC in vitro and in vivo. First we evaluated the expression of various TEMs (Robo4, Clec14 and ECSCR) by qRT-PCR and Western blot analyses in three NSCLC cell lines (A549, Calu1, Colo699) and compared them to human umbilical vein endothelial cells (HUVECs), endothelial colony forming cells (ECFCs) and human bronchial epithelial cells (HBEpCs). Next the expression of TEMs was measured in resected tumor tissue of NSCLC patients (n = 63) by qRT-PCR and compared to adjacent non-cancerous lung tissue (n = 52). Further, immunohistochemical analysis of Robo4 expression in tumor tissue (n = 33) and adjacent non-cancerous tissue (n = 27) was performed. We found that NSCLC cell lines and HBEpC did not express TEMs on the mRNA level compared to HUVECs (p = 0.001). In the contrary, a significant up-regulation of Robo4 and Clec14 was found in tumor samples (Robo4 p = 0.03, Clec14 p = 0.002). Both facts clearly indicate that these proteins are allocated to the tumor stromal department. Correlation with clinical data showed that increased TEM expression correlated with prolonged overall survival of operated NSCLC patients (Robo4 high 120.5 vs. Robo4 low 47.6 months, Clec14 high 108.1 vs. Clec14 low 54.5 months and ECSCR high 120.5 vs. ECSCR low 42.2 months). In summary, we found that TEMs are overexpressed in NSCLC stromal tissue and that an increased TEM expression correlated with an increased overall survival in early stage NSCLC. 22885522 The development and application of small molecule modulators of SF3b as therapeutic agents for cancer. The identification of potent spliceosome modulators that demonstrate antitumor activity indicates that this complex may be a target for drug development. Several natural products have been demonstrated to bind to the SF3b1 subunit of this macromolecule and these agents modulate alternative RNA splicing. In this article we describe their biological properties, discuss the validity of the spliceosome as a therapeutic target, and propose that alteration of alternative splicing represents a viable approach for inducing tumor-selective cytotoxicity. 23554391 Experimental and theoretical investigation of multistage extraction of 1,3-propanediol using the extraction system phosphate/1-butyl-3-methylimidazolium trifluoromethanesulfonate/water. The separation of 1,3-propanediol from fermentation broth is a challenging and energy-demanding step using conventional unit operations. One alternative process is the use of an aqueous two-phase system incorporating ionic liquids to use synergy effects of both technologies. Within this manuscript, the technical feasibility of the extraction of 1,3-propanediol using the aqueous two-phase system phosphate (salt)/1-butyl-3-methylimidazolium trifluoromethanesulfonate (ionic liquid)/water in a continuously operated process in pilot-scale is presented. The extraction was performed in a multistage mixer-settler unit and successfully modeled with an equilibrium-stage model and correlations to describe the liquid-liquid equilibrium of the salt/ionic liquid/water two-phase system. The developed and validated model was used for a further investigation of the influence of different process parameters in the determined operating window. Theses parameters include the number of stages, the phase ratio, the pH, and the mass fraction of the involved components. The results prove that the phosphate and 1-butyl-3-methylimidazolium trifluoromethanesulfonate mass fraction, the phase ratio, and the number of stages have a considerable influence on the recovery of 1,3-propanediol, whereas the pH value has only a smaller impact. Those results can be used for optimization of the system as well as for targeting future research within this area. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 29:933-942, 2013. 23092949 The pyridyl group in ligand design for selective metal ion complexation and sensing. Factors in polypyridyl ligands that control their thermodynamic metal ion selectivity in aqueous solution, and their use in selective fluorescent sensing, are examined. Preorganization of polypyridyl ligands ranging from bidentate to tetradentate by bridging benzo groups, as are present in 1,10-phenanthroline (phen) compared to 2,2'-bipyridyl (bpy), is discussed. The role of solvation is considered in relation to the relative affinity of ligands containing pyridyl groups for divalent and trivalent metal ions in aqueous solution. The effects of steric clashes between H atoms on polypyridyl ligands in decreasing complex stability are evaluated, as well as the effect of chelate ring size on metal ion selectivity. Phen ligands with other donor groups present at the 2 and 9 positions, such as alcohols, amides, carboxylates, and oximes are discussed. The design of pyridyl-based ligands for the separation of Am(III) from lanthanide(III) ions is considered, as well as ligands for the removal of metal ions such as Cu(II) or Zn(II) in neurological diseases such as Alzheimer's. The design of pyridyl-based fluorescent sensors for selective sensing of metal ions is examined in terms of the role of spin-orbit coupling constants (ζ), paramagnetism, and steric effects in the development of selective fluorescent sensors that operate via chelation enhanced fluorescence (CHEF). It is concluded that for lighter metal ions with smaller ζ values such as Zn(II) and Ca(II), and to a lesser extent Cd(II), that the CHEF effect can be achieved with pyridyl-containing fluorophores that coordinate directly to the metal ion. The way in which steric effects can be used to decrease the CHEF effect in Zn(II) relative to Cd(II) to enable selective sensing of the latter is analyzed. For heavier metal ions such as Hg(II) and Pb(II), because of their large ζ values which quench fluorescence, it is concluded that the fluorophore should be tethered to the metal-binding part of the sensor, and prevented from binding to the metal ion by steric and electronic factors. How Hg(II) can quench the CHEF effect by π-contact with fluorophores such as the anthracenyl group, which at first sight might not seem able to bond with metal ions, is examined. 23930702 The validity of clinic-based samples in approximating out-of-care HIV-infected populations. Tremendous strides have been made in the diagnosis and treatment of human immunodeficiency virus (HIV); perhaps now the largest barrier to controlling HIV is retaining those diagnosed in care. Data on out-of-care populations are needed to develop effective retention methods, yet obtaining these remains methodologically challenging due to inherent difficulties in sampling. The purpose of this study was to evaluate whether individuals identified by two sampling methods commonly used to approximate out-of-care populations were significantly different from a sample of newly identified out-of-care persons. We compared medical records of 345 out-of-care persons identified by a novel population-based health information exchange who had not received CD4 or viral load monitoring in >1 year with: medical records from a randomly selected, time-matched sample of 488 HIV-infected persons with at least one HIV care visit in the past 5 years, and interviews with 382 participants from a time-matched clinic-based convenience sample. Newly identified out-of-care persons were significantly different from both proxies with respect to demographic, clinical, and utilization characteristics, suggesting that samples of in-care proxy persons are inadequate to describe those not engaged in care. Novel approaches to sampling out-of care populations are urgently needed in order to better understand these populations and ways to improve retention and slow the HIV/AIDS epidemic. 23868609 Advanced nuclear analytical and related techniques for the growing challenges in nanotoxicology. Manufactured nanomaterials with novel physicochemical properties are an important basis for nanosciences and related technologies. Nanotoxicology, aiming to understand the principles of interactions at the nano-bio interface and the relationship between the physicochemical properties of nanomaterials and their toxicological profiles, has become a new frontier in nanoscience. Nearly one decade of nanotoxicology research has shown that the interactions between nanomaterials and proteins, cells, animals, humans and the environment as well as the underlying mechanisms of toxicity for nanomaterials are remarkably complicated, requiring dedicated analytical methodology and tools. Because of their advantages of absolute quantification, high sensitivity, excellent accuracy and precision, low matrix effects and non-destructiveness, nuclear analytical techniques have been playing important roles in the study of nanotoxicology. A systematic summary and comprehensive review of the advanced nuclear analytical and related techniques in nanotoxicology is greatly needed. In this review article, we present a comprehensive overview of nuclear analytical techniques applied to the physicochemical characterization of nanomaterials, structural analysis of bio-nano interactions, visualization of nanomaterials in vitro, quantification of bio-distribution, bio-accumulation, and transformation of nanomaterials in vivo. As important complementary tools, optical imaging technologies are also highlighted. Future directions regarding advanced nuclear analytical approaches for nanotoxicology are also discussed. The rapid development of advanced light source-based techniques will enable new high-throughput screening techniques and provide high sensitivity with low detection limits, which are required for the distribution, imaging, and structural analysis of nanomaterials, and the molecular information of biomarkers for all aspects of nanotoxicology. 23929738 Common chromosome fragile sites in human and murine epithelial cells and FHIT/FRA3B loss-induced global genome instability. Chromosomal positions of common fragile sites differ in lymphoblasts and fibroblasts, with positions dependent on the epigenetically determined density of replication origins at these loci. Because rearrangement of fragile loci and associated loss of fragile gene products are hallmarks of cancers, we aimed to map common fragile sites in epithelial cells, from which most cancers derive. Among the five most frequently activated sites in human epithelial cells were chromosome bands 2q33 and Xq22.1, which are not among top fragile sites identified in lymphoblasts or fibroblasts. FRA16D at 16q23 was among the top three fragile sites in the human epithelial cells examined, as it is in lymphoblasts and fibroblasts, while FRA3B at 3p14.2, the top fragile locus in lymphoblasts, was not fragile in most epithelial cell lines tested. Epithelial cells exhibited varying hierarchies of fragile sites; some frequent epithelial cell fragile sites are apparently not frequently altered in epithelial cancers and sites that are frequently deleted in epithelial cancers are not necessarily among the most fragile. Since we have reported that loss of expression of the FRA3B-encoded FHIT protein causes increased replication stress-induced DNA damage, we also examined the effect of FHIT-deficiency on markers of genome instability in epithelial cells. FHIT-deficient cells exhibited increases in fragile breaks and in γH2AX and 53BP1 foci in G1 phase cells, confirming in epithelial cells that the FHIT gene and encompassing FRA3B, is a "caretaker gene" necessary for maintenance of genome stability. © 2013 Wiley Periodicals, Inc. 23685208 Experimental investigations of weak definite and weak indefinite noun phrases. Definite noun phrases typically refer to entities that are uniquely identifiable in the speaker and addressee's common ground. Some definite noun phrases (e.g., the hospital in Mary had to go the hospital and John did too) seem to violate this uniqueness constraint. We report six experiments that were motivated by the hypothesis that these "weak definite" interpretations arise in "incorporated" constructions. Experiments 1-3 compared nouns that seem to allow for a weak definite interpretation (e.g., hospital, bank, bus, radio) with those that do not (e.g., farm, concert, car, book). Experiments 1 and 2 used an instruction-following task and picture-judgment task, respectively, to demonstrate that a weak definite need not uniquely refer. In Experiment 3 participants imagined scenarios described by sentences such as The Federal Express driver had to go to the hospital/farm. Scenarios following weak definite noun phrases were more likely to include conventional activities associated with the object, whereas following regular nouns, participants were more likely to imagine scenarios that included typical activities associated with the subject; similar effects were observed with weak indefinites. Experiment 4 found that object-related activities were reduced when the same subject and object were used with a verb that does not license weak definite interpretations. In Experiment 5, a science fiction story introduced an artificial lexicon for novel concepts. Novel nouns that shared conceptual properties with English weak definite nouns were more likely to allow weak reference in a judgment task. Experiment 6 demonstrated that familiarity for definite articles and anti-familiarity for indefinite articles applies to the activity associated with the noun, consistent with predictions made by the incorporation analysis. 23668532 Asymptomatic brucellosis infection in humans: implications for diagnosis and prevention. Human brucellosis is mainly caused by contact with Brucella-infected animals and their secretions and carcasses. Individuals who are continuously in contact with animals are considered to be at a high risk but only some show symptoms and are diagnosed as cases of brucellosis. Here, we showed that asymptomatic brucellosis infections occur among humans. Asymptomatic infections mainly result from less frequent contact with Brucella and/or contact with low-virulence Brucella. In our study, patients with asymptomatic infection had low antibody titres and different contact patterns. Awareness of asymptomatic infection is important for early diagnosis of brucellosis and prevention of chronic infection. 23832714 Four-year paracorporeal left ventricular assist device (LVAD) support for heart failure after Rastelli operation. It is well known that heart failure can occur after a conventional Rastelli operation (using an anatomical right ventricle as a systemic ventricle) in patients with congenitally corrected transposition of the great arteries (CCTGA). At present, heart transplantation (HTx) is the only definitive therapy known to save such patients. The left ventricular assist device (LVAD) has been employed for patients presenting with acute deterioration of chronic heart failure as a bridge to transplantation when early HTx is not feasible. LVAD implantation in postoperative cases and/or in patients with dextrocardia is often difficult because of the complex anatomy. We report the case of a 26-year-old male patient with CCTGA who presented with heart failure after a conventional Rastelli operation and in whom paracorporeal LVAD implantation was undertaken for the management of right (systemic) ventricular failure. The patient recovered from the heart failure and remained on the HTx list for approximately 4 years with LVAD support. 23769874 Elevated cytokine responses to Vibrio harveyi infection in the Japanese pufferfish (Takifugu rubripes) treated with Lactobacillus paracasei spp. paracasei (06TCa22) isolated from the Mongolian dairy product. With the aim of evaluating the effect of a Mongolian dairy product derived Lactobacillus paracasei spp. paracasei (strain 06TCa22) (Lpp) on the cytokine-mediated immune responses to Vibrio harveyi infection, we examined 16 cytokine expressions in the Japanese pufferfish, Takifugu rubripes. Fish were orally treated with the heat-killed Lpp at 1 mg g(-1) body weight d(-1) for 3 days. At 24 h posttreatment, fish were infected by an intramuscular injection of 0.1 mL V. harveyi bacterial suspension (10(8) cfu mL(-1)). Additionally, superoxide anion production (SAP) and phagocytic activity (PA) of head kidney cells were assessed during 120 h postinfection period. Significant up-regulation of pro-inflammatory (IL-1β, IL-6, IL-17A/F-3, TNF-α and TNF-N), cell-mediated immune inducing (IL-12p35, IL-12p40 and IL-18), antiviral/intra-cellular pathogen killing (I-IFN-1 and IFN-γ), anti-inflammatory (IL-10) and lymphocyte agonistic (IL-2, IL-7, IL-15, IL-21 and TGF-β1) cytokines was observed in the treated fish compared to control ones during the pathogen infection. Furthermore, significantly increased SAP and PA (P < 0.01; 0.05) were recorded in the treated fish compared to untreated fish. These results suggest the beneficial role of Lpp in enhancement of cytokine-mediated immunity in the Japanese pufferfish against V. harveyi infection and application of this product as a potential fish immunostimulant. 23954783 The Tetraspanin CD9 Affords High-Purity Capture of All Murine Hematopoietic Stem Cells. Prospective isolation is critical for understanding the cellular and molecular aspects of stem cell heterogeneity. Here, we identify the cell surface antigen CD9 as a positive marker that provides a simple alternative for hematopoietic stem cell isolation at high purity. Crucially, CD9 affords the capture of all hematopoietic stem cells in murine bone marrow in the absence of contaminating populations that lack authentic stem cell function. Using CD9 as a tool to subdivide hematopoietic stem-cell-containing populations, we provide evidence for heterogeneity at the cellular, functional, and molecular levels. 23666534 A case of spontaneous systemic immunity to melanoma associated with cure after amputation for extensive regional recurrence. Survival after amputation for melanoma is short; however, rare long-term survivors are reported. The mechanism for durable systemic tumor control in patients with regional failure is not known. To explore whether systemic tumor immunity may be implicated, tumor and circulating immune responses were examined in a patient who survived disease-free 14 years after hip disarticulation. A 71-year-old female with extensive regional metastases of melanoma in the left lower extremity underwent amputation for palliative reasons. Tumor was collected at surgery, and blood was collected during follow-up. Tumor sections were evaluated for lymphocytic infiltration and NY-ESO-1 expression by immunohistochemistry. Cellular immune responses to defined tumor antigens were evaluated by ELISPOT assay, and antibody responses to a panel of tumor antigens were assayed by ELISA. The patient's tumor had minimal lymphocytic infiltrate (immunotype A). NY-ESO-1 was strongly expressed by the melanoma cells. Circulating T-cell responses to NY-ESO-1 peptides were observed 6 and 12 years postoperatively, and antibodies to NY-ESO-1 were detected 2-6 years after surgery. The patient described in this report experienced relentless regional tumor progression, with intravascular metastases, and then 14-year systemic disease-free survival after palliative resection, without evidence of melanoma recurrence before death from other causes. Her immune response to NY-ESO-1 likely failed to control established regional metastases because T cells were unable to infiltrate them. It is possible, however, that among other factors, the host immune response may have contributed to systemic protection. 23958544 Expression of Gastrin-releasing Peptide Receptor in Epidermoid Carcinoma of the Anal Canal. Gastrin-releasing peptide is a neuroendocrine homolog of bombesin that demonstrated important growth-stimulatory effects in various types of cancer. High levels of expression of gastrin-releasing peptide receptors (GRPR) has been found in different malignancies, and the studies exploring the therapeutic use of GRPR antagonists have shown promising results. Our aim was to determine the GRPR expression in epidermoid carcinoma of the anal canal and discuss its potential clinical applications. We performed immunohistochemical analysis for GRPR on formalin-fixed and paraffin-embedded tumor samples obtained from 35 patients with anal cancer. As a control group, we analyzed 24 samples of nonmalignant anal tissues (hemorrhoidectomy specimens). GRPR expression was evaluated using a semiquantitative approach according to the intensity and distribution of staining. All analyzed tissues, except 1 control sample, showed positive GRPR immunoexpression. GRPR was strongly expressed in 54% of cancer specimens as compared with only 12% of the control specimens (P<0.003). In tumors, the receptor showed a diffuse and homogenous pattern of distribution within the specimens. In contrast, control specimens showed a focal pattern of staining restricted to the basal half of the epithelium. In conclusion, we demonstrated that GRPR is highly expressed in epidermoid carcinoma of the anal canal, suggesting this receptor might have a role in anal carcinogenesis. Our results provide a basis for exploiting GRPR as a target for diagnostic and therapeutic purposes in the anal cancer. 23757093 Influence of the delocalization error and applicability of optimal functional tuning in density functional calculations of nonlinear optical properties of organic donor-acceptor chromophores. Nonempirically tuned hybrid density functionals with range-separated exchange are applied to calculations of the first hyperpolarizability (β∥ ) and charge-transfer (CT) excitations of linear "push-pull" donor-acceptor-substituted organic molecules with extended π-conjugated bridges. An unphysical delocalization with increasing chain length in density functional calculations can be reduced significantly by enforcing an asymptotically correct exchange-correlation potential adjusted to give frontier orbital energies representing ionization potentials. The delocalization error for a number of donor-acceptor systems is quantified by calculations with fractional electron numbers and from orbital localizations. Optimally tuned hybrid variants of the PBE functional incorporating range-separated exchange can produce similar magnitudes for β∥ as Møller-Plesset second-order perturbation (MP2) correlated calculations. Improvements are also found for CT excitation energies, with results similar to an approximate coupled-cluster model (CC2). 23877070 Characterization of metabolites of 20(S)-protopanaxadiol in rats using ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry. In this study, ultra-performance liquid chromatography (UPLC)/quadrupole-time-of-flight mass spectrometry (QTOF-MS) was applied to the rapid analysis of 20(S)-protopanaxadiol (PPD) metabolites in rats after oral administration, enabling the structural characterization of 23 metabolites in plasma, bile, urine, and feces. 16 of these, including M1-M5, M9, and M11-M15, have not been previously reported. The results also indicated that demethylation, dehydration, dehydrogenation, oxidation, deoxidation, and glucuronidation were the major metabolic reactions of PPD in vivo. This study provides important information about the metabolism of PPD which will be helpful for fully understanding its mechanism of action. Furthermore, structural modification of PPD in vivo may aid in obtaining new chemical derivatives for pharmacological screening. 23926593 Two 2D metal-calixarene aggregates incorporating pre-designed coordination nanocages. Two 2D metal-calixarene aggregates were designed and assembled by M4-TC4A (M = Fe, Co; TC4A = p-tert-butylthiacalix[4]arene) SBUs and {MCl2} units with isonicotinic acid molecules, which presents a possible way to build the extended metal-calixarene assemblies incorporating pre-designed nanocages using multifunctional linkers. 23265449 Vicilin and the basic subunit of legumin are putative chickpea allergens. IgE-mediated reactions to food allergens constitute a major health problem in industrialized countries. Chickpea is consumed in Mediterranean countries, and reportedly associated with IgE-mediated hypersensitivity reactions. However, the nature of allergic reactions to chickpea has not been characterized. A serum pool from paediatric patients allergic to chickpeas was used to detect IgE-binding proteins from chickpea seeds by immunoassay and immunoblot inhibition assay. Protein samples enriched in chickpea legumin and vicilin were obtained by anion exchange chromatography, and were identified by mass spectrometric analysis. IgE-immunoassays of globulin fractions from chickpeas revealed that vicilin (50 kDa) and the basic subunit of legumin (20 kDa) were bound by IgE from patient sera. Pea and lentil protein extracts strongly inhibited the IgE binding to chickpea globulin. We speculate that vicilin and the basic subunit of legumin are major chickpea allergens. Also, the globulin fraction of chickpea likely cross-reacts with the allergenic proteins of pea and lentil. 23839383 116 Mechanical vs Chemical Prophylaxis for Deep Venous Thrombosis in Patients Undergoing Lumbar Spinal Fusion: Comparative Effectiveness and Cost-Benefit. Venous thromboembolism is a common preventable cause of morbidity after surgery with an incidence ranging from 0.3-31% in elective spinal surgery. Therefore, patients undergoing surgery receive routine prophylaxis for DVT. Recently, the added utility of chemical DVT prophylaxis in addition to mechanical DVT prophylaxis has been questioned. We set out to determine comparative effectiveness and cost-benefit of mechanical vs chemical DVT prophylaxis in patients undergoing elective lumbar spinal fusion. All patients undergoing lumbar spinal fusion (1-3 levels) for degenerative spine disease over a 2-year period were enrolled into our prospective registry. During the first year, all patients received mechanical and chemical prophylaxis (subcutaneous heparin twice a day) for DVT [chemical prophylaxis group]. During the second year, patients only received mechanical prophylaxis for DVT [mechanical prophylaxis group]. At the end of this 2-year period, we evaluated whether this categorical switch influenced the incidence of DVT and the cost-benefit associated with it. A total of 355 patients (208 in chemical group and 147 in mechanical group) were included in the study. There were no significant differences in the baseline characteristics and treatment variables of the 2 groups (P > .05). The categorical switch from chemical to mechanical DVT prophylaxis did not change the incidence of DVT after lumbar fusion surgery in chemical vs mechanical prophylaxis group ([1 (0.48%) vs 1 (0.68%); P = .80] in mechanical prophylaxis group). Incidence of bleeding complications like epidural hematoma was 0.96% in chemical group vs 0.68% in mechanical group. Converting from chemical to mechanical prophylaxis resulted in $20,937 savings without a rise in peri-operative thromboembolism. In our experience, mechanical and chemical DVT prophylaxis had equivalent effectiveness in preventing peri-operative DVT after elective lumbar spinal fusion. Use of mechanical vs chemical DVT prophylaxis can lead to cost savings of up to $20,937 per 150 patients treated per year. 23864417 Pharmacokinetic Analysis of Piperacillin Administered with Tazobactam in Critically Ill, Morbidly Obese Surgical Patients. To evaluate the steady-state pharmacokinetic and pharmacodynamic parameters of piperacillin in morbidly obese, surgical intensive care patients. Open-label single-center prospective study. Level I trauma center and university-affiliated teaching institution. Nine morbidly obese (body mass index [BMI] 40.0 kg/m(2) or higher) hospitalized patients admitted to the trauma and surgical intensive care service who were treated with piperacillin-tazobactam between December 15, 2010, and April 18, 2012. Patients received intravenous piperacillin-tazobactam 4.5 g every 6 hours, administered as a 30-minute infusion. Patients' blood samples were collected after the administration of the fourth, fifth, or sixth dose (i.e., at steady state). Serum piperacillin concentrations were determined by using a validated high-performance liquid chromatography assay; these concentrations were used to estimate pharmacokinetic parameters, and 5000-patient Monte Carlo simulations were performed. The probability of target attainment for 50% or higher of the dosing interval during which free (unbound) drug concentrations exceeded the minimum inhibitory concentration (%fT > MIC) of likely pathogens was calculated for piperacillin at various MICs. Patient demographic and clinical characteristics included a mean ± SD total body weight of 164 ± 50 kg, BMI of 57 ± 15.3 kg/m(2) , and age 57 ± 11 years, and a median Acute Physiology and Chronic Health Evaluation II score of 22 (interquartile range 21-26). Compared with values previously reported in other populations, the volume of distribution was increased in the study patients, and total system clearance was decreased. The net result was a mean ± SD half-life of 3.7 ± 1.2 hours compared with ~1 hour reported in other populations. This contributed to an extended %fT > MIC for likely pathogens. Results from all nine patients showed %fT > MIC of 100% at the susceptibility breakpoint MIC of 16 mg/L and 85% or higher at an MIC of 32 mg/L. The pharmacokinetics of piperacillin is altered in morbidly obese, surgical intensive care patients. The use of standard-dosage piperacillin-tazobactam 4.5 g intravenously every 6 hours was shown to be an appropriate dosage for this study population. 22930682 Variations in the nature of behavioral experience can differentially alter the consequences of developmental exposures to lead, prenatal stress, and the combination. Behavioral experience (BE) can critically influence later behavior and brain function, but the central nervous system (CNS) consequences of most developmental neurotoxicants are examined in the absence of any such context. We previously demonstrated marked differences in neurotransmitter changes produced by developmental lead (Pb) exposure ± prenatal stress (PS) depending upon whether or not rats had been given BE (Cory-Slechta, D. A., Virgolini, M. B., Rossi-George, A., Weston, D., and Thiruchelvam, M. (2009). The current study examined the hypothesis that the nature of the BE itself would be a critical determinant of outcome in mice that had been continually exposed to 0 or 100 ppm Pb acetate in drinking water alone or in combination with prenatal restraint stress. Half of the offspring in each of the four resulting groups/gender were exposed to positively reinforced (food-rewarded Fixed Interval schedule-controlled behavior) or negatively reinforced (inescapable forced swim) BE. Brain monoamines and amino acids differed significantly in relation to BE, even in control animals, as did the trajectory of effects of Pb ± PS, particularly in frontal cortex, hippocampus (both genders), and midbrain (males). In males, Pb ± PS-related changes in neurotransmitters correlated with behavioral performance. These findings suggest that CNS consequences of developmental toxicants studied in the absence of a broader spectrum of BEs may not necessarily be predictive of human outcomes. Evaluating the role of specific BEs as a modulator of neurodevelopmental insults offers the opportunity to determine what specific BEs may ameliorate the associated impacts and can assist in establishing underlying neurobiological mechanisms. 23761083 Disruption of cell-cell junctions and induction of pathological cytokines in the retinal pigment epithelium of light-exposed mice. To elucidate the influences of light exposure on the retinal pigment epithelium (RPE) in vivo that may be involved in the pathogenesis of AMD. Six- to 7-week-old BALB/c mice were exposed to light at 2000 lux for 3 hours. Flat-mount RPE samples were immunostained with anti-ZO-1 antibody for evaluating tight junction, anti-N-cadherin, and anti-β-catenin antibodies for adherens junction, and stained with phalloidin for actin cytoskeleton. The reactive oxygen species (ROS) level was measured using DCFH-DA; Rho-associated coiled-coil forming kinase (ROCK) activity was by ELISA. Cytokine expression was analyzed by real-time RT-PCR and/or ELISA in the RPE-choroid, and macrophage recruitment was by real-time RT-PCR and immunohistochemistry. Either an antioxidant, N-Acetyl-L-cysteine (NAC), or a ROCK inhibitor, Y-27632, were administered to analyze the roles of ROS and ROCK activation, respectively. Light exposure disrupted staining patterns of tight junctions, adherens junctions, and actin cytoskeleton in the RPE, where ROS was elevated. However, NAC treatment avoided the RPE changes, reducing ROS. ROCK activity increased after light exposure was suppressed by NAC, and the structural disruptions were suppressed by Y-27632. The levels of MCP-1, CCL11, and IL-6 increased after light exposure were suppressed by NAC. Light-induced MCP-1 and IL-6 were suppressed by Y-27632. Macrophage recruitment after light exposure was also suppressed either by NAC or Y-27632. Light exposure induced ROS and Rho/ROCK activation, which caused disruption of cell-cell junctions (tight junctions and adherens junctions) and actin cytoskeleton, the RPE's barrier structure, and induced AMD-associated pathological changes in the RPE-choroid. 23866760 Can informal social distancing interventions minimize demand for antiviral treatment during a severe pandemic? In the case of a pandemic, individuals may alter their behaviour. A dynamic model incorporating social distancing can provide a mechanism to consider complex scenarios to support decisions regarding antiviral stockpile size while considering uncertainty around behavioural interventions. We have examined the impact of social distancing measures on the demand for limited healthcare resources such as antiviral drugs from a central stockpile during a severe pandemic. We used an existing age-structured model for pandemic influenza in Canada and biologically plausible scenarios for severe influenza transmission within the population. We incorporated data from published reports regarding stated intentions to change behaviour during a pandemic as well as the magnitude and duration of time that individuals expected to maintain the behavioural change. We ran simulations for all combinations of parameter values to identify the projected antiviral requirements in each scenario. With 12 weeks of distancing, the effect is relatively small for the lowest R0 of 1.6 with a projected stockpile to treat 25.6% being required (IQR = 21.7 -- 28.7%) unless the proportion of people involved (81%) and magnitude of the behaviour change is large (69% reduction in contacts). If 24 weeks of distancing occurs, with only a low to moderate reduction in contacts (38% or less), it is not possible to bring treatment requirements below 20% regardless of what proportion of the population engages in distancing measures when transmissibility is high (R0 = 2.0; stockpile size = 31%, IQR = 29.2 -- 33.5%). Our results demonstrate that the magnitude and duration of social distancing behaviours during a severe pandemic have an impact on the need for antiviral drugs. However, significant investments over a long period of time (>16 weeks) are required to decrease the need for antiviral treatment to below 10% of the total population for a highly transmissible viral strain (R0 > 1.8). Encouraging individuals to adopt behaviours that decrease their daily contact rate can help to control the spread of the virus until a vaccine becomes available however; relying on these measures to justify stockpiling fewer courses of treatment will not be sufficient in the case of a severe pandemic. 23215455 Syphilis-related perceptions not associated with risk behaviors among men who have sex with men having regular male sex partner(s) in Nanjing, China. The prevalence of HIV among men who sex with men (MSM)has been increasing sharply in China. The prevalence of unprotected anal intercourse (UAI)among them is very high, especially when male regular sex partners are involved. Many MSM having regular sex partners are engaged in multiple sex partnerships, which often involved UAI. This study interviewed 168 MSM in Nanjing, China, having had anal intercourse with at least one male regular sex partner in the last six months. Amongst the participants, 52.4% reported having had UAI with male regular sex partners whilst 50.0% reported multiple male sex partnerships in the last six months. Multivariate analysis showed that monthly personal income higher than 2000 RMB (multivariate OR = 0.49, 95% CI: 0.26-0.96), HIV antibody testing in the last year (multivariate OR = 0.19, 95% CI: 0.06-0.60), sexual position being both insertive and receptive during anal sex with male sex partners in general (multivariate OR = 0.43, 95% CI: 0.18-0.99; reference group: with receptive position only) were associated with lower likelihoods of UAI. Syphilis-related perceptions, including knowledge, cognitions (perceived susceptibility, perceived severity, self-efficacy in avoiding syphilis infection and perceived infectivity and perceived syphilis-related norms among MSM in general)were not associated with risk behaviors (UAI and multiple male sex partnerships). Our sampled MSM are exposed to very high risk of HIV/STD transmission. We found no association between syphilis-related perceptions and the two types of risk behaviors. Future studies are warranted to understand such associations in the context of sexual intercourse with nonregular sex partners among MSM. 23888335 Analysis of histomorphology in malignant hyperthermia-susceptible patients. Malignant hyperthermia (MH) is a potentially lethal disorder of skeletal muscle triggered by anesthetic agents. A histomorphological examination of diseased muscle may provide insight into MH pathophysiology, but it is not a routine part of standard-of-care practice for the identification of MH-susceptibility. In this study, we investigated muscle histomorphology in a large cohort of MH-susceptible (MHS) patients and examined its relationship to genotype and phenotype. All consenting patients who were identified as MHS based on a caffeine-halothane contracture test (CHCT) performed during 1992-2011 were retrospectively identified and recruited for this study. Results of the histomorphological examination, which is a routine part of our centre-specific practice, were reviewed. Patient demographics, MH proband status, histological features, CHCTs, and genetic results for MH-causative mutations were summarized. Seven of the 399 patients classified as MHS had histological characteristics consistent with central core disease, and one patient was a carrier of Duchenne's muscular dystrophy. Eighty-six (22%) patients had histological abnormalities, and five (6%) of these had evidence of "frank" myopathy. No histologic abnormalities were consistent among the MHS patients; however, a higher proportion of MH probands had abnormal histomorphology compared with the general MHS population, and patients with evidence of "frank" myopathy showed similarities in clinical history, biochemistry, CHCT, and genetic testing. Despite the inability of the histomorphological examination to identify consistent features in MHS patients, histology may serve as a potential adjunct to CHCT and aid in the identification of other myopathies. Nevertheless, the specifics of its utility ought to be assessed in other studies and by way of formal cost-effectiveness analysis. 23949896 Novel truncating thyroglobulin gene mutations associated with congenital hypothyroidism. Mutations in the thyroglobulin (TG) gene have been reported to cause congenital hypothyroidism (CH) and we have been investigating the genetic architecture of CH in a large cohort of consanguineous/multi-case families. Our aim in this study was to determine the genetic basis of CH in four affected individuals coming from two separate consanguineous families. Since CH is usually inherited in autosomal recessive manner in consanguineous/multi-case families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the TG gene. First we investigated the potential genetic linkage of families to any known CH locus using microsatellite markers and then determined the pathogenic mutations in linked-genes by Sanger sequencing. Both families showed potential linkage to TG locus and we detected two previously unreported nonsense TG mutations (p.Q630X and p.W637X) that segregated with the disease status in both families. This study highlights the importance of molecular genetic studies in the definitive diagnosis and classification of CH, and also adds up to the limited number of nonsense TG mutations in the literature. It also suggests a new clinical testing strategy using next-generation sequencing in all primary CH cases. 23824187 Cap Snatching in Yeast L-BC Double-stranded RNA Totivirus. Yeast L-A double-stranded RNA virus furnishes its transcript with a 5' cap structure by a novel cap-snatching mechanism in which m(7)Gp from a host mRNA cap structure is transferred to the 5'-diphosphate terminus of the viral transcript. His-154 of the coat protein Gag forms an m(7)Gp adduct, and the H154R mutation abolishes both m(7)Gp adduct formation and cap snatching. Here we show that L-BC, another totivirus closely related to L-A, also synthesizes 5'-diphosphorylated transcripts and transfers m(7)Gp from mRNA to the 5' termini of the transcripts. L-BC Gag also covalently binds to the cap structure and the mutation H156R, which corresponds to H154R of L-A Gag, abolishes cap adduct formation. Cap snatching of the L-BC virus is very similar to that of L-A; N7 methylation of the mRNA cap is essential for cap donor activity, and only 5'-diphosphorylated RNA is used as cap acceptor. L-BC cap snatching is also activated by viral transcription. Furthermore, both viruses require Mg(2+) and Mn(2+) for cap snatching. These cations are not only required for transcription activation but also directly involved in the cap transfer process. These findings support our previous proposal that the cap-snatching mechanism of the L-A virus is shared by fungal totiviruses closely related to L-A. Interestingly, L-A and L-BC viruses accept either viral transcript as cap acceptor in vitro. Because L-A and L-BC viruses cohabit in many yeast strains, it raises the possibility that their cohabitation in the same host may be beneficial for their mutual cap acquisition. 23904281 Gamma knife surgery for patients with volumetric classification of nonfunctioning pituitary adenomas: a systematic review and meta-analysis. To scrutinize the literature in order to analyze the efficacy and safety of Gamma knife surgery (GKS) for nonfunctioning pituitary adenomas (NFPAs) with volumetric classification. Electronic databases including MedLine, PubMed and Cochrane Central were searched. The literature relating to patients with NFPAs treated with GKS was collected. Eligible studies reported on the rate of tumor control (RTC), the rate of radiosurgery-induced optic neuropathy injury (RRIONI), the rate of radiosurgery-induced endocrinological deficits (RRIED), and other parameters. 17 studies met the criteria. According to the tumor volume, NFPAs were divided into three groups: the RTC of group I(93 patients) with tumor volumes less than 2 ml was 99%(95% CI:96-100%), the RRIONI was 1%(95% CI:0-4%), the RRIED was 1%(95% CI:0-4%). The RTC of group (301 patients) with volumes from 2 to 4 ml was 96%(95% CI:92-99%), the RRIONI was 0 (95% CI:0-2%) and RRIED was 7%(95% CI:2-14%). The RTC of group (531 patients) with volumes larger than 4 ml was 91%(95% CI:89-94%), the RRIONI was 2%(95% CI:0-5%) and the RRIED was 22%(95%CI:14-31%). There were significant differences in the RTC and in the RRIED among three groups (P<0.001), which showed that there were higher RRIED and lower RTC with the increase of tumor volume. NFPAs, according to the tumor volume classification, need stratification for GKS treatment. GKS is the optimal choice for group II NFPAs. Patients with residual tumor volume less then 4ml will benefit most from GKS treatment. 23933236 Elongate microparticles for enhanced drug delivery to ex vivo and in vivo pig skin. The delivery of therapeutics and cosmaceuticals into and/or through the skin is hindered by epidermal barriers. To overcome the skin's barriers we have developed a novel cutaneous delivery method using high aspect ratio elongate microparticles (EMPs). Using ex vivo and in vivo pig skin we assess the penetration and delivery characteristics of the elongate microparticles. With reflectance confocal microscopy we observed that the elongate microparticles successfully penetrated the epidermis and upper dermis. Delivery was then assessed using two different length populations of EMPs, comparing their delivery profile to topical alone using sodium fluorescein and confocal microscopy. We observed a relatively uniform and continuous delivery profile in the EMP treated area within the upper layers of the skin - up to seven times greater than topical alone. Finally, we delivered two therapeutically relevant compounds (Vitamins A and B3), showing enhanced delivery using the EMPs. To our knowledge this is the first report using high aspect ratio elongate microparticles in this manner for enhanced topical delivery to the skin. 23809452 Age-related differences in radiographic parameters for femoroacetabular impingement in hip arthroplasty patients. To compare the prevalence of femoroacetabular impingement (FAI) radiographic findings between patients aged younger than 50 years and those aged 50 years or older who underwent total hip arthroplasty. Total hip arthroplasty patients aged younger than 50 years and those aged 50 years or older were identified retrospectively from a facility medical record database. Fifty patients from each group were randomly selected, and preoperative radiographs were collected. Dysplastic, inflammatory, post-traumatic, and osteonecrosis patients were excluded. Radiographs were evaluated for FAI-specific findings. Intraobserver and interobserver reliability was evaluated with κ statistics for categorical variables and intraclass correlation coefficients for continuous variables. An independent t test was used to compare continuous variables, χ(2) analysis was used for discrete variables, and a z ratio was used to analyze proportions. The mean age between the subgroups of patients aged younger than 50 years and those aged 50 years or older (43 years and 68 years, respectively) was significantly different (P < .05). Findings in the subgroup aged younger than 50 years included significantly more men (P < .001), decreased lateral joint space with maintained medial joint space (P < .05), significantly greater alpha angle on both the anteroposterior view and the frog-leg lateral view (P < .05), significantly higher Tönnis and Sharp angles (P < .01), and significantly lower center-edge angle (P < .001). This retrospective case series shows an increased prevalence of FAI findings (specifically cam pathology) in a patient population aged younger than 50 years undergoing total hip arthroplasty when compared with a cohort aged 50 years or older. Level III, retrospective comparative study. 23471580 The value of 18F-FDG PET/CT in diagnosing infectious endocarditis. Early detection of infectious endocarditis is challenging. For diagnosing infectious endocarditis, the revised Duke criteria are the gold standard. Evidence of endocardial involvement on echocardiography is a major criterion, but sensitivity and specificity of echocardiography are not optimal. Here we investigated the utility of (18)F-fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (PET/CT) to diagnose infectious endocarditis in patients with gram-positive bacteraemia. Seventy-two patients with gram-positive bacteraemia were prospectively included. Patients with a positive blood culture growing Staphylococcus aureus, Streptococcus species or Enterococcus species were eligible when a risk factor for developing metastatic infectious foci was present. Infectious endocarditis was defined according to the revised Duke criteria. All patients underwent (18)F-FDG PET/CT and echocardiography. (18)F-FDG uptake in or around the heart valves was evaluated independently by two nuclear medicine physicians. Sensitivity for diagnosing infectious endocarditis with (18)F-FDG PET/CT was 39% and specificity was 93%. The positive predictive value was 64% and negative predictive value was 82%. The mortality rate in patients without infectious endocarditis and without increased (18)F-FDG uptake in or around the heart valves was 18%, and in patients without infectious endocarditis but with high (18)F-FDG uptake in or around the heart valves the mortality rate was 50% (p = 0.181). (18)F-FDG PET/CT is currently not sufficiently adequate for the diagnosis of infectious endocarditis because of its low sensitivity. Improvements such as patient preparation with low carbohydrate-fat allowed diet and technical advances in the newest PET/CT scanners may increase sensitivity in future studies. 23965406 Brachial plexus injury associated with extracorporeal membrane oxygenation. Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary support system. We present 2 patients of ECMO-related brachial plexus injury. Patients were selected from a registry of 154 patients treated with ECMO from January 2002 to September 2011. Five patients had unilateral arm weakness after the initiation of ECMO therapy. There was no neurological examination or electrophysiological testing data available for 3 patients. Diagnosis of brachial plexus injury was confirmed in 2 patients, one based on neurological examination and one based on electrophysiological testing. Axillary artery cannulation resulting in hematoma formation was identified as a probable risk factor for brachial plexus injury in our 2 patients. 23946483 PKA-dependent phosphorylation of Rap1 regulates its membrane localization and cell migration. The small G protein Rap1 can mediate inside-out-signaling by recruiting effectors to the plasma membrane that signal to pathways involved in cell adhesion and cell migration. This action relies on the membrane association of Rap1, which is dictated by post-translational prenylation as well as by a stretch of basic residues within its carboxy-terminus. One feature of this stretch of acidic residues is that it lies adjacent to a functional phosphorylation site for the cAMP-dependent protein kinase PKA. This phosphorylation has two effects on Rap1 action. One, it decreases the level of Rap1 activity as measured by GTP-loading and the coupling of Rap1 to RapL, a Rap1 effector that couples Rap1 GTP-loading to integrin activation. Two, it destabilizes the membrane localization of Rap1, promoting its translocation into the cytoplasm. These two actions, decreased GTP-loading and decreased membrane localization, are related, as the translocation of Rap1-GTP into the cytoplasm is associated with its increased GTP hydrolysis and inactivation. The consequences of this phosphorylation in Rap1-dependent cell adhesion and cell migration were also examined. Active Rap1 mutants that lack this phosphorylation site had a minimal effect on cell adhesion but strongly reduced cell migration, when compared to an active Rap1 mutant that retained the phosphorylation site. This suggests that optimal cell migration is associated with cycles of Rap1 activation, membrane egress and inactivation, and requires the regulated phosphorylation of Rap1 by PKA. 23838571 Development of Potent Fluorescent Polyamine Toxins and Application in Labeling of Ionotropic Glutamate Receptors in Hippocampal Neurons. The natural product argiotoxin-636 (ArgTX-636) found in the venom of the Argiope lobata spider is a potent open-channel blocker of ionotropic glutamate (iGlu) receptors, and recently, two analogues, ArgTX-75 and ArgTX-48, were identified with increased potency and selectivity for iGlu receptor subtypes. Here, we have exploited these analogues as templates in the development of fluorescent iGlu receptor ligands to be employed as unique tools for dynamic studies. Eighteen fluorescent analogues were designed and synthesized, and subsequently pharmacologically evaluated at three iGlu receptor subtypes, which resulted in the discovery of highly potent fluorescent iGlu receptor antagonists with IC50 values as low as 11 nM. The most promising ligands were further characterized showing retention of their mechanism of action, as open-channel blockers of iGlu receptors, as well as preservation of the photophysical properties of the incorporated fluorophores. Finally, we demonstrate the applicability of the developed probes for imaging of iGlu receptors in hippocampal neurons. 23231808 Acetazolamide impairs fear memory consolidation in rodents. Acetazolamide (AZ) is an carbonic anhydrase inhibitor, which has been used in the treatment of seizures, mountain sickness and glaucoma. Memory impairment by AZ has been reported in patient interviews; however, the related mechanism is unclear. We applied two fear conditioning paradigms, shuttle avoidance and passive avoidance, in both rats and mice to investigate this clinical anecdote. Adult Wistar rats receiving AZ 1 h before the shuttle avoidance test showed decreased avoidance rates, especially at high dosage. Adult ICR mice receiving AZ both before and after acquisition trials showed the decreased step-through latencies during the passive avoidance test. This impairment of fear memory was corroborated with decreased LTP by AZ in the amygdala. AZ only inhibited fear conditioning-induced ERK phosphorylation and had no effect on Akt phosphorylation. In conclusion, our study confirmed the adverse cognitive effect of AZ in animal and electrophysiological studies. In clinical practice, clinicians should be aware of this side effect in patients taking AZ. In addition, this inhibition of fear memory by AZ could potentially be applied to patients with posttraumatic stress disorder. 23894352 Hepatic Cannabinoid Receptor Type 1 Mediates Alcohol-Induced Regulation of Bile Acid Enzyme Genes Expression Via CREBH. Bile acids concentration in liver is tightly regulated to prevent cell damage. Previous studies have demonstrated that deregulation of bile acid homeostasis can lead to cholestatic liver disease. Recently, we have shown that ER-bound transcription factor Crebh is a downstream effector of hepatic Cb1r signaling pathway. In this study, we have investigated the effect of alcohol exposure on hepatic bile acid homeostasis and elucidated the mediatory roles of Cb1r and Crebh in this process. We found that alcohol exposure or Cb1r-agonist 2-AG treatment increases hepatic bile acid synthesis and serum ALT, AST levels in vivo alongwith significant increase in Crebh gene expression and activation. Alcohol exposure activated Cb1r, Crebh, and perturbed bile acid homeostasis. Overexpression of Crebh increased the expression of key bile acid synthesis enzyme genes via direct binding of Crebh to their promoters, whereas Cb1r knockout and Crebh-knockdown mice were protected against alcohol-induced perturbation of bile acid homeostasis. Interestingly, insulin treatment protected against Cb1r-mediated Crebh-induced disruption of bile acid homeostasis. Furthermore, Crebh expression and activation was found to be markedly increased in insulin resistance conditions and Crebh knockdown in diabetic mice model (db/db) significantly reversed alcohol-induced disruption of bile acid homeostasis. Overall, our study demonstrates a novel regulatory mechanism of hepatic bile acid metabolism by alcohol via Cb1r-mediated activation of Crebh, and suggests that targeting Crebh can be of therapeutic potential in ameliorating alcohol-induced perturbation of bile acid homeostasis. 23351274 Chlamydia trachomatis infection prevents front-rear polarity of migrating HeLa cells. Chlamydiae are obligate intracellular bacterial pathogens that cause trachoma, sexually transmitted diseases and respiratory infections in humans. Fragmentation of the host cell Golgi apparatus (GA) is essential for chlamydial development, whereas the consequences for host cell functions, including cell migration are not well understood. We could show that Chlamydia trachomatis-infected cells display decelerated migration and fail to repopulate monolayer scratch wounds. Furthermore, infected cells lost the ability to reorient the fragmented GA or the microtubule organization centre (MTOC) after a migratory stimulus. Silencing of golgin-84 phenocopied this defect in the absence of the infection. Interestingly, GA stabilization via knockdown of Rab6A and Rab11A improved its reorientation in infected cells and it was fully rescued after inhibition of Golgi fragmentation with WEHD-fmk. These results show that C. trachomatis infection perturbs host cell migration on multiple levels, including the alignment of GA and MTOC. 23701263 Coaxial InxGa1-xN/GaN Multiple Quantum Well Nanowire Arrays on Si(111) Substrate for High-Performance Light-Emitting Diodes. We report the growth of high-quality nonpolar (m-plane) and semipolar (r-plane) multiple quantum well (MQW) nanowires (NWs) for high internal quantum efficiency light emitting diodes (LEDs) without polarization. Highly aligned and uniform InxGa1-xN/GaN MQW layers are grown coaxially on the {1-100} sidewalls of hexagonal c-axis n-GaN NWs on Si(111) substrates by a pulsed flow metal-organic chemical vapor deposition (MOCVD) technique. The photoluminescence (PL) measurements reveal that the wavelength and intensity of an MQW structure with various pairs (2-20) are very stable and possess composition-dependent emission ranging from 369 to 600 nm. The cathodoluminescence (CL) spectrum of individual InxGa1-xN/GaN MQW NW is dominated by band-edge emission at 369 and 440 nm with a relatively homogeneous profile of parallel alignment. High-resolution transmission electron microscopy (HR-TEM) studies of coaxial InxGa1-xN/GaN MQW NWs measured along the ⟨0001⟩ and ⟨2-1-10⟩ zone axes reveal that the grown NWs are uniform with six nonpolar m-plane facets without any dislocations and stacking faults. The p-GaN/InxGa1-xN/GaN MQW/n-GaN NW coaxial LEDs show a current rectification with a sharp onset voltage at 2.65 V in the forward bias. The linear enhancement of power output could be attributed to the elimination of piezoelectric fields in the InxGa1-xN/GaN MQW active region. The superior performance of coaxial NW LEDs is observed in comparison with that of thin film LEDs. Overall, the feasibility of obtaining low defect and strain free m-plane coaxial NWs using pulsed MOCVD can be utilized for the realization of high-power LEDs without an efficiency droop. These kinds of coaxial NWs are viable high surface area MQW structures which can be used to enhance the efficiency of LEDs. 22795086 Cardioembolic Stroke is Frequent in Late Recurrence After Transient Ischemic Attack. Transient ischemic attack (TIA) is often followed by a stroke episode. Differences between early and late recurrent stroke, however, have not been elucidated. We enrolled 133 consecutive patients with acute ischemic stroke who presented to our hospital and had previously been diagnosed with TIA. They were divided into 5 groups according to the interval between TIA and subsequent stroke: <48 hours (group 1); 48 hours to 1 week (group 2); 1 week to 1 month (group 3); 1 month to 3 months (group 4); and >3 months (group 5). Patients who underwent recurrent stroke within and after 1 week subsequent to TIA (the early and late recurrence groups, respectively) were compared with regard to clinical findings. Of the 133 patients, 46 (34.6%) were in group 1, 29 (21.8%) in group 2, 23 (17.3%) in group 3, 18 (13.5%) in group 4, and 17 (12.8%) in group 5. Most of the noncardioembolic strokes were observed shortly after TIA, while the percentage of cardioembolic stroke remained high even after long post-TIA periods. The prevalence of atrial fibrillation (AF) was higher in the late recurrence group than in the early recurrence group (41.4% v 24.0%, P = .033). Among 42 patients with AF, 12 (28.6%) were newly diagnosed at the time of stroke. The frequency of cardioembolic stroke did not decline as time after TIA passed. More than one quarter of AF patients had been asymptomatic before stroke, suggesting the need for repeated examinations to detect AF in patients with TIA of unknown etiology. 23916992 Encapsulated islets for diabetes therapy: History, current progress, and critical issues requiring solution. Insulin therapy became a reality in 1921 dramatically saving lives of people with diabetes, but not protecting them from long-term complications. Clinically successful free islet implants began in 1989 but require life long immunosuppression. Several encapsulated islet approaches have been ongoing for over 30years without defining a clinically relevant product. Macro-devices encapsulating islet mass in a single device have shown long-term success in large animals but human trials have been limited by critical challenges. Micro-capsules using alginate or similar hydrogels encapsulate individual islets with many hundreds of promising rodent results published, but a low incidence of successful translation to large animal and human results. Reduction of encapsulated islet mass for clinical transplantation is in progress. This review covers the status of both early and current studies including the presentation of corporate efforts involved. It concludes by defining the critical items requiring solution to enable a successful clinical diabetes therapy. 23689756 Process and reactor design for biophotolytic hydrogen production. The green alga Chlamydomonas reinhardtii has the ability to produce molecular hydrogen (H2), a clean and renewable fuel, through the biophotolysis of water under sulphur-deprived anaerobic conditions. The aim of this study was to advance the development of a practical and scalable biophotolytic H2 production process. Experiments were carried out using a purpose-built flat-plate photobioreactor, designed to facilitate green algal H2 production at the laboratory scale and equipped with a membrane-inlet mass spectrometry system to accurately measure H2 production rates in real time. The nutrient control method of sulphur deprivation was used to achieve spontaneous H2 production following algal growth. Sulphur dilution and sulphur feed techniques were used to extend algal lifetime in order to increase the duration of H2 production. The sulphur dilution technique proved effective at encouraging cyclic H2 production, resulting in alternating Chlamydomonas reinhardtii recovery and H2 production stages. The sulphur feed technique enabled photobioreactor operation in chemostat mode, resulting in a small improvement in H2 production duration. A conceptual design for a large-scale photobioreactor was proposed based on these experimental results. This photobioreactor has the capacity to enable continuous and economical H2 and biomass production using green algae. The success of these complementary approaches demonstrate that engineering advances can lead to improvements in the scalability and affordability of biophotolytic H2 production, giving increased confidence that H2 can fulfil its potential as a sustainable fuel of the future. 23446434 Artificial leaf structures as a UV detector formed by the self-assembly of ZnO nanoparticles. Artificial leaf structures have been fabricated by the self-assembly of ZnO nanoparticles. A hydrothermal method was used to synthesize the nanoparticles. The self-assembly patterns showed asymmetric dendritic morphologies, larger surface-to-volume ratios, a broad absorption band and high resistance. A non-equilibrium two-stage-formation process included diffusion limited aggregation, and the phase-field model was introduced to explain the formation mechanism of the pattern. A high-performance ultraviolet detector was fabricated on the artificial leaf structures, which showed that the current under the irradiation of a UV lamp (1.21 mW cm(-2)) was about 10(4) times greater than in the dark. The various and functional properties of the pattern show us the vast prospects of potential applications for light harvesting systems and other optical-electric devices. 23747949 Immunogenicity of decellularized porcine liver for bioengineered hepatic tissue. Liver disease affects millions of patients each year. The field of regenerative medicine promises alternative therapeutic approaches, including the potential to bioengineer replacement hepatic tissue. One approach combines cells with acellular scaffolds derived from animal tissue. The goal of this study was to scale up our rodent liver decellularization method to livers of a clinically relevant size. Porcine livers were cannulated via the hepatic artery, then perfused with PBS, followed by successive Triton X-100 and SDS solutions in saline buffer. After several days of rinsing, decellularized liver samples were histologically analyzed. In addition, biopsy specimens of decellularized scaffolds were seeded with hepatoblastoma cells for cytotoxicity testing or implanted s.c. into rodents to investigate scaffold immunogenicity. Histological staining confirmed cellular clearance from pig livers, with removal of nuclei and cytoskeletal components and widespread preservation of structural extracellular molecules. Scanning electron microscopy confirmed preservation of an intact liver capsule, a porous acellular lattice structure with intact vessels and striated basement membrane. Liver scaffolds supported cells over 21 days, and no increased immune response was seen with either allogeneic (rat-into-rat) or xenogeneic (pig-into-rat) transplants over 28 days, compared with sham-operated on controls. These studies demonstrate that successful decellularization of the porcine liver could be achieved with protocols developed for rat livers, yielding nonimmunogenic scaffolds for future hepatic bioengineering studies. 23810676 Oxazolopyridines and thiazolopyridines as monoamine oxidase B inhibitors for the treatment of Parkinson's disease. In Parkinson's disease, the motor impairments are mainly caused by the death of dopaminergic neurons. Among the enzymes which are involved in the biosynthesis and catabolism of dopamine, monoamine oxidase B (MAO-B) has been a therapeutic target of Parkinson's disease. However, due to the undesirable adverse effects, development of alternative MAO-B inhibitors with greater optimal therapeutic potential towards Parkinson's disease is urgently required. In this study, we designed and synthesized the oxazolopyridine and thiazolopyridine derivatives, and biologically evaluated their inhibitory activities against MAO-B. Structure-activity relationship study revealed that the piperidino group was the best choice for the R(1) amino substituent to the oxazolopyridine core structure and the activities of the oxazolopyridines with various phenyl rings were between 267.1 and 889.5nM in IC50 values. Interestingly, by replacement of the core structure from oxazolopyrine to thiazolopyridine, the activities were significantly improved and the compound 1n with the thiazolopyridine core structure showed the most potent activity with the IC50 value of 26.5nM. Molecular docking study showed that van der Waals interaction in the human MAO-B active site could explain the enhanced inhibitory activities of thiazolopyridine derivatives. 23639190 Mikania laevigata: Chemical characterization and selective cytotoxic activity of extracts on tumor cell lines. Cancer is the second major cause of mortality worldwide, losing only to cardiovascular disease. Nowadays, around 50% of antineoplastic drugs were discovered and isolated by indications of plants in folk medicine. In Brazilian flora there are many species of plants which have great therapeutic importance, highlighting the Mikania laevigata (Asteraceae) that has been used for their valuable properties, especially in the respiratory tract. In the present study, the compounds of M. laevigata extracts were characterized by High Resolution Mass Spectrometry (HRMS) and Gas Chromatography with Mass analysis (GC/MS-EI). Therefore, the presence of some compounds with promising biological properties as antitumor activity was detected. Coumarin (1,2-benzopyrone) was previously reported as responsible for some biological activities of this plant species. Here, the extracts were evaluated by their cytotoxic activity against tumor (Hep-2, HeLa) and non tumor (MRC-5) cell lines, presenting significant inhibitory activity of cell growth in all extracts analyzed, chloroform, ethyl acetate, hexane, ethanol, which is related to its chemical composition. From the four different extracts here tested, two of them, hexane and ethanol, presented a clear selectivity against both tumor cells lines investigated. This can be explained by variances and increase of phenolic compounds in the ethanol fraction and an association of molecules with coumarin found in the hexane fraction. 23692368 Nanomechanics of molecules and living cells with scanning ion conductance microscopy. Hydrodynamic flow through a nanopipet in a scanning ion conductance microscope (SICM) can exert localized forces on a sample surface. These forces can be used for trapping of molecules in lipid bilayers and for mapping the mechanical properties of living cells. 23818572 Common gene pathways and families altered by DNA methylation in breast and prostate cancers. Epigenetic modifications, such as DNA methylation, are widely studied in cancer as they are stable and easy to measure genome wide. DNA methylation changes have been used to differentiate benign from malignant tissue and to predict tumor recurrence or patient outcome. Multiple genome wide DNA methylation studies in breast and prostate cancers have identified genes that are differentially methylated in malignant tissue compared with non-malignant tissue or in association with hormone receptor status or tumor recurrence. Although this has identified potential biomarkers for diagnosis and prognosis, what is highlighted by reviewing these studies is the similarities between breast and prostate cancers. In particular, the gene families/pathways targeted by DNA methylation in breast and prostate cancers have significant overlap and include homeobox genes, zinc finger transcription factors, S100 calcium binding proteins, and potassium voltage-gated family members. Many of the gene pathways targeted by aberrant methylation in breast and prostate cancers are not targeted in other cancers, suggesting that some of these targets may be specific to hormonal cancers. Genome wide DNA methylation profiles in breast and prostate cancers will not only define more specific and sensitive biomarkers for cancer diagnosis and prognosis but also identify novel therapeutic targets, which may be direct targets of agents that reverse DNA methylation or which may target novel gene families that are themselves DNA methylation targets. 23677979 FOXC1 is enriched in the mammary luminal progenitor population, but is not necessary for mouse mammary ductal morphogenesis. Expression of FOXC1, a forkhead box transcription factor, correlates with the human basal-like breast cancer (BLBC) subtype, and functional analyses have revealed its importance for in vitro invasiveness of BLBC cells. Women diagnosed with this breast tumor subtype have a poorer outcome because of the lack of targeted therapies; thus, continued investigation of factors driving these tumors is critical to uncover novel therapeutic targets. Several processes that dictate normal mammary morphogenesis parallel cancer progression, and enforced expression of FOXC1 can induce a progenitor state in more-differentiated mammary epithelial cells. Consequently, evaluating how FOXC1 functions in the normal gland is critical to further understand BLBC biology. Although FOXC1 is well known to control normal development of a number of tissues, its role in the mammary gland has not yet been investigated. Herein, we describe FOXC1 expression patterning in the normal breast, where it is localized to the basal/myoepithelium, suggesting that FOXC1 would be required for normal development. However, mammary glands lacking Foxc1 have no overt defect in ductal outgrowth, alveologenesis, or lineage specification. Of significant interest, we found that expression of FOXC1 is enriched in the normal luminal progenitor population, which is the postulated cell of origin of BLBC. These results indicate that FOXC1 is unnecessary for mammary morphogenesis and that its role in BLBC likely involves processes that are unrelated to cell lineage specification. 23928496 Effects of aging and divided attention on episodic feeling-of-knowing accuracy. This research investigated the effect of aging on episodic feeling-of-knowing (FOK) using a divided attention (DA) paradigm in order to examine whether DA in younger adults mimics the effects of aging when decreasing either memory encoding or monitoring processes. To that end, four groups of participants were tested on the FOK task: young adults (control group), young adults under DA at encoding, young adults under DA when making FOK judgments, and older adults. Our results showed that DA at encoding in young adults mimicked the effect of aging on memory performance, and also on FOK magnitude and accuracy, supporting the memory-constraint hypothesis (Hertzog et al., 2010). However, our results do not completely contradict the monitoring-deficit hypothesis, as DA during FOK judgments also affected FOK accuracy, but to a lesser extent than the aging effect or DA during encoding. We suggest that the age-related FOK deficit may be due to a lower level of deep encoding, leading to difficulty retrieving target-related contextual details enabling accurate prediction of subsequent recognition. 23843523 Two projection streams from macaque v1 to the pale cytochrome oxidase stripes of v2. In the primate visual cortex, areas V1 and V2 distribute information they receive from the retina to virtually all extrastriate cortex, parsing this information into dorsal and ventral streams. Therefore, understanding the connectivity between V1 and V2 is crucial to understand visual cortical processing. Cytochrome oxidase staining in V2 reveals a repeating pattern of pale-thick-pale-thin stripes. V1 sends parallel output pathways to distinct V2 stripes. Previous models proposed either three or two parallel V1-to-V2 pathways in macaque, but both models viewed the two pale stripes within a single stripe cycle as a single compartment. However, recent studies have suggested that the two pale stripes may be functionally distinct, and in marmosets they also differ anatomically in the laminar origin of projections they receive from V1. Here we have asked whether the two pale stripes are also anatomically distinct in macaque. We made small retrograde tracer injections in different pale stripe types. We found that while both pale stripes receive a predominant V1 input from layers 2/3, only one set of pale stripes (pale lateral) receives significant projections from layer 4B, while the other set (pale medial) receives few or no layer 4B projections. Moreover, different tracer injections in nearby pale stripe types revealed that 97-99% of layer 2/3 cells only project to a single pale stripe type. These results demonstrate that in macaque, the two pale stripes are anatomically distinct compartments, and support the notion of two distinct projection streams from V1 to the two pale stripes of V2. 23926208 Elevated Remnant Cholesterol Causes Both Low-Grade Inflammation and Ischemic Heart Disease, While Elevated Low-Density Lipoprotein Cholesterol Causes Ischemic Heart Disease without Inflammation. Elevated nonfasting remnant cholesterol and low-density lipoprotein(LDL) cholesterol are causally associated with ischemic heart disease(IHD), but whether elevated nonfasting remnant cholesterol and LDL cholesterol both cause low-grade inflammation is presently unknown. We studied 60,608 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease study, of which 10,668 had IHD diagnosed between 1977 and 2011. We genotyped for variants affecting levels of 1) nonfasting remnant cholesterol, 2) LDL cholesterol, 3) C-reactive protein by CRP alleles, and 4) C-reactive protein by interleukin 6 receptor alleles. Using a multi-directional Mendelian randomization design, we investigated possible causal associations between the lipoproteins and C-reactive protein, and between the lipoproteins and IHD. A 1mmol/L(39mg/dL) higher level of nonfasting remnant cholesterol was associated observationally with a 37%(95%CI:35-39%) higher C-reactive protein level, and causally with a 28%(10-48%) higher level. For LDL cholesterol, a 1mmol/L(39mg/dL) higher level was associated observationally with a 7%(6-7%) higher C-reactive protein level, but we found no causal association. Likewise, higher levels of C-reactive protein did not associate causally with elevated nonfasting remnant cholesterol or LDL cholesterol. Finally, the causal risk ratio for IHD for a 1mmol/L(39mg/dL) higher level was 3.3(95%CI: 2.1-5.2) for nonfasting remnant cholesterol and 1.8(1.5-2.2) for LDL cholesterol. The causal associations for remnant cholesterol were present even in those without diabetes mellitus and obesity. Elevated nonfasting remnant cholesterol is causally associated with low-grade inflammation and with IHD, while elevated LDL cholesterol associated causally with IHD without inflammation. 23163402 Integrated onshore-offshore investigation of a mediterranean layered coastal aquifer. Most of the Mediterranean coastal porous aquifers are intensively exploited. Because of climatic and anthropogenic effects, understanding the physical and geological controls on groundwater distribution and flow dynamics in such aquifers is crucial. This study presents the results of a structural investigation of a system located along the coastline of the Gulf of Lions (NW Mediterranean). A key aspect of this study relies on an onshore-offshore integrated approach combining outcrops, seismic profiles, and borehole data analysis. This multidisciplinary approach provides constraints on pore-fluid salinity distribution and stratigraphic organization, which are crucial in assessing the modes of groundwater/seawater exchanges. Onshore, Lower Pliocene deposits dip gently seaward. They are unconformably overlain by Holocene clays in the lagoons. Offshore the Pliocene deposits either outcrop at the seabed or are buried below nonconsolidated sands infilling paleo-valleys. Beneath the lido, the groundwater salinity distribution consists of salty pore water, overlying fresher pore water. Active circulation of groundwater masses is inferred from the geophysical results. In particular, offshore outcrops and paleo-valleys may play an important role in salt water intrusion. 23953650 Tailor-made polyfluoroacrylate and its block copolymer by RAFT polymerization in miniemulsion; improved hydrophobicity in the core-shell block copolymer. Controlled/living radical polymerization (CRP) of a fluoroacrylate was successfully carried out in miniemulsion by Reversible Addition Fragmentation chain Transfer (RAFT) process. In this case, 2,2,3,3,4,4,4-heptafluorobutyl acrylate (HFBA) was polymerized using 2-cyanopropyl dodecyl trithiocarbonate (CPDTC) as RAFT agent, Triton X-405 and sodium dodecyl sulfonate (SDS) as surfactant, and potassium persulphate (KPS) or 2,2'-azobis isobutyronitrile (AIBN) as initiator. Being compatible with hydrophobic fluoroacrylate, this RAFT agent offered very high conversion and good control over the molecular weight of the polymer. The miniemulsion was stable without any costabilizer. The long chain dodecyl group (-C12H25) (Z-group in the RAFT agent) had beneficial effect in stabilizing the miniemulsion. When 2-cyano 2-propyl benzodithioate (CPBD) (Z=-C6H5) was used as RAFT agent, the conversion was less and particle size distribution was very broad. Block copolymerization with butyl acrylate (BA) using PHFBA as macro-RAFT agent showed core-shell morphology with the aggregation of PHFBA segment in the shell. GPC as well as DSC analysis confirmed the formation of block copolymer. The core-shell morphology was confirmed by TEM analysis. The block copolymers (PHFBA-b-PBA) showed significantly higher water contact angle (WCA) showing much better hydrophobicity compared to PHFBA alone. 23959002 Profile of HIV-infected patients receiving second-line antiretroviral therapy in a resource-limited setting in Nigeria. Second-line antiretroviral therapy (ART) accounts for less than 5% of total ART in resource-limited settings. We described the baseline characteristics, reasons for switch and treatment outcomes of Nigerian patients receiving second-line ART. In this retrospective cohort study we recorded the baseline characteristics of HIV-infected adults whose treatment regimen was switched from a non-nucleoside reverse transcriptase inhibitor, a first-line agent, to a protease inhibitor-based second-line regimen. The duration of follow-up was 12 months. Of 4229 patients who started first-line therapy, 186 (4.4%) were switched to second-line therapy after a mean duration of 16.6 ± 7.6 months. Their mean age was 41.8 ± 9.6 years and 59.1% were women. The median (range) viral load and CD4 cell counts at switch were 4.7 (4.1-6.3) log10 copies/ml and 71 (6-610) cells/µl, respectively. The predominant reason for switch was virological failure (79.0%). Only 55.4% and 36.6% of patients had CD4 cell count and viral load at 12 months. About 82%, 79% and 82% of patients with available data achieved virological suppression at 3 months, 6 months and 12 months respectively (p = 0.81). The proportion of patients who achieved ≥50% rise in CD4 cell count increased from 55.8% at 3 months to 78.6% at 12 months (p = 0.0002). The rate of switch to second-line therapy was low but there were good treatment outcomes among patients with available data. Attrition rate was high. Regular viral load monitoring, improved availability/affordability of second-line regimens and retention in care should become priorities in resource-limited settings. 23470073 The role of endothelin system in cardiovascular disease and the potential therapeutic perspectives of its inhibition. Since its identification in 1988 and the recognition of its primary role as a potent vasoconstrictor, endothelin has been extensively studied and is now considered as a ubiquitous protein, involved in important aspects of human homeostasis as well as in several pathophysiological pathways, mostly associated with cardiovascular disease. From an evolutionary point of view, endothelin consists a primitive molecule with the rare characteristic of being exactly the same in all mammals, thus permitting scientists to perform experiments in animals and doing predictions for humans. The understanding of its contribution to the genesis, evolution and maintenance of disease through activation of special receptor subtypes has led to the development of both selective and unselective receptor antagonists. Despite the disappointing results of these antagonists in the field of heart failure, almost from the initial animal trials of bosentan, a dual endothelin receptor antagonist, in pulmonary arterial hypertension, it has been demonstrated that the drug leads at least to hemodynamic and clinical improvement of the patients, thus receiving official approval for the management of this rare but eventually lethal disease. Resistant hypertension is another area where endothelin receptor blockers might potentially play a role, while the pathophysiological role of endothelin in atherosclerotic coronary artery disease is well-established and the relative research goes on. The main goal of this review is to describe the endothelin system and mostly to enlighten its role in pathophysiologic pathways, as well to state the relative research in the various fields of cardiovascular disease and also highlight its prognostic significance wherever there exists one. 23954916 Bone morphogenetic protein signaling in nephron progenitor cells. Bone morphogenetic protein (BMP) signaling plays an essential role in many aspects of kidney development, and is a major determinant of outcome in kidney injury. BMP treatment is also an essential component of protocols for differentiation of nephron progenitors from pluripotent stem cells. This review discusses the role of BMP signaling to nephron progenitor cells in each of these contexts. 23436267 Inhibitory effect of ketoconazole on the pharmacokinetics of a multireceptor tyrosine kinase inhibitor BMS-690514 in healthy participants: assessing the mechanism of the interaction with physiologically-based pharmacokinetic simulations. BMS-690514, a selective inhibitor of the ErbB and vascular endothelial growth factor receptors, has shown antitumor activity in early clinical development. The compound is metabolized by multiple enzymes, with CYP3A4 responsible for the largest fraction (34%) of metabolism. It is also a substrate of P-glycoprotein (P-gp) in vitro. To assess the effect of ketoconazole on BMS-690514 pharmacokinetics, 17 healthy volunteers received 200 mg BMS-690514 alone followed by 100 mg BMS-690514 with ketoconazole (400 mg once daily for 4 days). The AUC(∞) of 100 mg BMS-690514 concomitantly administered with ketoconazole was similar to that of 200 mg BMS-690514 alone. The dose-normalized C(max) and AUC(∞) of BMS-690514 from the 100-mg BMS-690514/400-mg ketoconazole treatment increased by 55% and 127%, respectively, relative to those from 200 mg BMS-690514 alone. Prediction of the drug-drug interaction (DDI) using a population-based simulator (Simcyp) indicated that, in addition to CYP3A4 inhibition, the inhibition of P-gp by ketoconazole in the intestine, liver, and kidneys must be invoked to fully account for the DDI observed. This finding suggests that the inhibition of P-gp by ketoconazole, along with its effect on CYP3A4, needs to be considered when designing a DDI study of ketoconazole with a victim drug that is a dual substrate. 23948586 Regulation of Cardiac L-Type Ca2+ Channel CaV1.2 Via the β-Adrenergic-cAMP-Protein Kinase A Pathway: Old Dogmas, Advances, and New Uncertainties. In the heart, adrenergic stimulation activates the β-adrenergic receptors coupled to the heterotrimeric stimulatory Gs protein, followed by subsequent activation of adenylyl cyclase, elevation of cyclic AMP levels, and protein kinase A (PKA) activation. One of the main targets for PKA modulation is the cardiac L-type Ca(2+) channel (CaV1.2) located in the plasma membrane and along the T-tubules, which mediates Ca(2+) entry into cardiomyocytes. β-Adrenergic receptor activation increases the Ca(2+) current via CaV1.2 channels and is responsible for the positive ionotropic effect of adrenergic stimulation. Despite decades of research, the molecular mechanism underlying this modulation has not been fully resolved. On the contrary, initial reports of identification of key components in this modulation were later refuted using advanced model systems, especially transgenic animals. Some of the cardinal debated issues include details of specific subunits and residues in CaV1.2 phosphorylated by PKA, the nature, extent, and role of post-translational processing of CaV1.2, and the role of auxiliary proteins (such as A kinase anchoring proteins) involved in PKA regulation. In addition, the previously proposed crucial role of PKA in modulation of unstimulated Ca(2+) current in the absence of β-adrenergic receptor stimulation and in voltage-dependent facilitation of CaV1.2 remains uncertain. Full reconstitution of the β-adrenergic receptor signaling pathway in heterologous expression systems remains an unmet challenge. This review summarizes the past and new findings, the mechanisms proposed and later proven, rejected or disputed, and emphasizes the essential issues that remain unresolved. 23922269 RHD3 family of dynamin-like GTPases mediates homotypic endoplasmic reticulum fusion and is essential for Arabidopsis development. In all eukaryotic cells, the endoplasmic reticulum (ER) forms a tubular network, whose generation requires fusion of ER membranes. In Arabidopsis thaliana, the membrane-bound GTPase RHD3 (ROOT HAIR DEDECTIVE 3) is a potential candidate to mediate ER fusion. In addition, Arabidopsis has two tissue-specific isoforms of RHD3, namely RHD3-like (RL) proteins, and their function is not clear. Here, we show that a null allele of RHD3, rhd3-8, causes growth defects and shortened root hairs. A point mutant, rhd3-1, exhibits a more severe growth phenotype than the null mutant, likely because it exerts a dominant-negative effect on the RL proteins. Genetic analysis reveals that the double deletion of RHD3 and RL1 is lethal and the rhd3 rl2 plants produce no viable pollens, suggesting that the RL proteins are redundant to RHD3. RHD3 family proteins can replace Sey1p, the homolog of RHD3 in yeast, in the maintenance of ER morphology, and they are able to fuse membranes both in vivo and in vitro. Our results suggest that RHD3 proteins mediate ER fusion and are essential for plant development, and the formation of the tubular ER network is of general physiological significance. 23686911 Descriptive epidemiology of idiopathic clubfoot. Clubfoot is a common structural malformation, occurring in approximately 1/1,000 live births. Previous studies of sociodemographic and pregnancy-related risk factors have been inconsistent, with the exception of the strong male preponderance and association with primiparity. Hypotheses for clubfoot pathogenesis include fetal constraint, Mendelian-inheritance, and vascular disruption, but its etiology remains elusive. We conducted a population-based case-control study of clubfoot in North Carolina, Massachusetts, and New York from 2007 to 2011. Mothers of 677 clubfoot cases and 2,037 non-malformed controls were interviewed within 1 year of delivery about socio-demographic and reproductive factors. Cases and controls were compared for child's sex, maternal age, education, cohabitation status, race/ethnicity, state, gravidity, parity, body mass index (BMI), and these pregnancy-related conditions: oligohydramnios, breech delivery, bicornuate uterus, plural birth, early amniocentesis (<16 weeks), chorionic villous sampling (CVS), and plural gestation with fetal loss. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for state. Cases were more likely to be male (OR: 2.7; 2.2-3.3) and born to primiparous mothers (1.4; 1.2-1.7) and mothers with BMI ≥30 kg/m(2) (1.4; 1.1-1.8). These associations were greatest in isolated and bilateral cases. ORs for the pregnancy-related conditions ranged from 1.3 (breech delivery) to 5.6 (early amniocentesis). Positive associations with high BMI were confined to cases with a marker of fetal constraint (oligohydramnios, breech delivery, bicornuate uterus, plural birth), inheritance (family history in 1st degree relative), or vascular disruption (early amniocentesis, CVS, plural gestation with fetal loss). Pathogenetic factors associated with obesity may be in the causal pathway for clubfoot. 23671163 Heterogeneous responses of nucleus incertus neurons to corticotrophin-releasing factor and coherent activity with hippocampal theta rhythm in the rat. Abstract  The nucleus incertus (NI) of the rat hindbrain is a putative node in the ascending control of the septohippocampal system and hippocampal theta rhythm and is stress and arousal responsive. NI contains GABA neurons that express multiple neuropeptides, including relaxin-3 (RLN3) and neuropeptide receptors, including corticotrophin-releasing factor receptor-1 (CRF-R1), but the precise anatomical and physiological characteristics of NI neurons are unclear. Therefore, we examined the firing properties of NI neurons and their responses to CRF, the correlation of these responses with occurrence of relaxin-3, and NI neuron morphology in the rat. Most NI neurons excited by intracerebroventricular CRF infusion were RLN3-positive (9 of 10), whereas all inhibited cells were RLN3-negative (8 of 8). The spontaneous firing of RLN3 (n = 6) but not non-RLN3 neurons (n = 6) was strongly modulated and phase-locked with the initial ascending phase of hippocampal theta oscillations. In brain slices, the majority of recorded NI neurons (15 of 19) displayed excitatory responses to CRF, which uniformly increased action potential frequency and membrane potential depolarization in the presence of tetrodotoxin, indicating a direct, postsynaptic action of CRF on NI neurons. This excitation was associated with reduction in the slow component of afterhyperpolarization and a strong depolarization. Quantitative analysis in naïve rats of validated CRF-R1, RLN3 and neuronal nuclear antigen (NeuN) immunoreactivity revealed 52% of NI neurons as CRF-R1 positive, of which 53% were RLN3 positive, while 48% of NI neurons lacked CRF-R1 and RLN3. All RLN3 neurons expressed CRF-R1. CRF neurons that projected to the NI were identified in lateral preoptic hypothalamus, but not in paraventricular hypothalamus, bed nucleus of stria terminalis or central amygdala. Our findings suggest NI is an important site for CRF modulation of hippocampal theta rhythm via effects on GABA/RLN3 transmission. 23797040 Quantification of a pegylated interferon-alpha2a product by a customised and validated reverse phase-high performance liquid chromatography method. There is increasing development of pegylated proteins as clinical products for therapeutic interventions in human disease. Quantification of such products relies on appropriately calibrated traditional methods, including reverse phase-high performance liquid chromatography (RP-HPLC). However, currently available pharmacopoeia calibrants, e.g., chemical reference substances (CRS), are highly purified non-pegylated proteins of known concentration. These are uncertain to be suitable for calibration purposes where the precise quantification of the mass of pegylated proteins, often heterogeneous with respect to polyethylene glycol (PEG) chain size, structure, attachment sites and isomer numbers and proportions, is required. In this study, a customised RP-HPLC method was developed and validated for the analysis of a pegylated IFN-α2a product having a linear 20kDa PEG chain (PEG20-IFN-α2a; Reiferon Retard(®)). Since the PEG20 moiety generated no signal at the detection wavelength of 210nm, the concentration of the base IFN-α2a molecules in PEG-IFN-α2a could be determined. By calculating the UV absorbance at 210nm of peak areas in their respective chromatographic profiles, a high correlation (r(2)≥0.995) of PEG20-IFN-α2a concentrations with equal concentrations of the CRS of IFN-α2a, or of a well-characterised PEG20-IFN-α2a internal reference substance (IRS) was found. This finding confirmed the suitability of this CRS as a primary calibrant for mass determinations of PEG20-IFN-α2a by the customised RP-HPLC method. Application of this method to the quantitative analysis of 10 batches of Reiferon Retard(®) yielded accurate and consistent results, indicating its utility for mass determinations of current and future Reiferon Retard(®) batches. 23900502 Elevated expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in primary sclerosing cholangitis: Ιmplications for cholangiocarcinogenesis. Cholangiocarcinoma (CCA) occurs frequently in primary sclerosing cholangitis (PSC). Cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) induced by inflammation are believed to mediate prostaglandin E2 (PGE2) production thereby promoting carcinogenesis. Their expression in PSC-associated CCA tissues and non-neoplastic bile duct epithelial cells (BDECs) in PSC was investigated. COX-2 and mPGES-1 levels in 15 PSC patients (7 with CCA) were scored using immunohistochemical staining. The results were compared with those obtained in CCA tissues and non-neoplastic BDECs (controls) of 15 sporadic CCA patients. Non-neoplastic BDECs from large and small bile ducts were investigated separately. The mRNA expression levels of COX-2 and mPGES-1 in CCA tissues were analyzed by quantitative polymerase chain reaction. Ki-67 immunostaining was performed to evaluate cell proliferation. COX-2 was strongly expressed in PSC-associated CCA tissues and non-neoplastic BDECs in PSC. This expression was significantly upregulated in both compared with sporadic CCA tissues and non-neoplastic BDECs in sporadic CCA (both P<0.01). mPGES-1 was expressed at moderate to strong levels in PSC. Compared with controls, the expression was significantly higher in non-neoplastic small BDECs (P<0.01). COX-2 mRNA levels were significantly higher in PSC-associated tissues than in sporadic CCA tissues (P<0.01). Conversely, no differences were observed in mPGES-1 mRNA levels. Ki-67 labeling indices were higher in PSC-associated CCA tissues and non-neoplastic BDECs in PSC than in controls. In conclusion, COX-2 and mPGES-1 were highly expressed in PSC-associated CCA tissues and non-neoplastic BDECs in PSC, suggesting the involvement of COX-2 and mPGES-1 in cholangiocarcinogenesis. 23960130 Salmonella penetration through eggshells of chickens of different genetic backgrounds. Eggs have been identified as a source of salmonellosis, making the transmission of Salmonella to eggs of great concern to the poultry industry. The goal of this experiment was to determine the ability of Salmonella to penetrate the eggshell of 5 different breeds of noncommercial chicken, Barred Plymouth Rock, White Leghorn, Brown Leghorn, Fayoumi, and Light Sussex, and 1 commercial Lohmann LSL-Lite. Egg weight, breaking force, shell weight, and shell thickness measurements were taken for 30 eggs per breed. A 1 cm in diameter hole was cut out from the narrow end of 30 additional eggs per breed. The shells were filled with plate count agar containing tetracycline and 0.1% 2,3,5-triphenyl terazolium chloride and sealed with paraffin wax. Agar-filled eggs were submerged for 1 min in an overnight culture of tetracycline-resistant Salmonella Heidelberg and incubated at 37°C for 40 h. Eggs were candled and visual colonies were counted and reported as cfu per egg and cfu per gram of shell. The SAS mixed model was used to evaluate differences between breeds for egg quality characteristics and the number of cfu per egg and per gram of shell. Commercial layers (62.6 g) and Barred Plymouth Rock (61.5 g) produced the largest eggs, whereas Fayoumi (47.1 g) produced the smallest (P < 0.05). Force to break the shell was lowest (P < 0.05) for Barred Plymouth Rock (3.6 kg) and greatest for the commercial (4.4 kg), White Leghorn (4.4 kg), and Fayoumi (4.2 kg). Bacteria penetrating the shell was lowest (P < 0.05) for Barred Plymouth Rock (10.7 cfu/g) and highest for Light Sussex (27.7 cfu/g) and Brown Leghorn (27.2 cfu/g), with other breeds intermediate. These results indicate that there are breed-specific influences on the ability of an egg to resist Salmonella, which cannot be explained by shell quality measurements. Further investigations are warranted to determine the contributing factors to shell penetration by bacteria. This study highlights the value in maintaining heritage chicken breeds as a genetic resource for the future. 23839341 Pirfenidone Attenuates Cardiac Fibrosis in a Mouse Model of TAC-Induced Left Ventricular Remodeling by Suppressing NLRP3 Inflammasome Formation. Objectives: Left ventricular remodeling is a frequent complication of hypertension with no therapeutic treatment available for the subsequent onset of myocardial fibrosis. Pirfenidone is an antifibrotic small-molecular-size drug with anti-inflammatory properties that is used as a treatment for fibrotic diseases, but its effects on hypertension-induced myocardial fibrosis are unknown. Therefore, we tested whether pirfenidone could ameliorate hypertension-induced left ventricular remodeling and whether hypertension-induced NLRP3 (Nod-like receptor pyrin domain containing 3), a critical protein in NLRP3 inflammasome formation, is involved in the therapeutic mechanism. Methods: A TAC-induced mouse model of hypertension and left ventricular hypertrophy was treated with pirfenidone, and survival, collagen deposition by histopathologic examination, heart function by echocardiography, concentrations of fibrosis-related inflammatory cytokines TGF-β1, IL-1β in heart homogenate and in vitro cell cultures by ELISA, levels of ROS and inflammatory cells by flow cytometry, and levels of NLRP3 by Western blotting and immunohistochemistry were measured. Results: Pirfenidone increased the survival rate and attenuated myocardial fibrosis and inflammatory mediators in the TAC-induced hypertension-complicated left ventricular remodeling mouse model. The inhibition of NLRP3 expression by pirfenidone attenuated the expression of IL-1β and IL-1β-induced inflammatory and profibrotic responses. Conclusions: Pirfenidone may be useful in the treatment of hypertension-induced myocardial fibrosis by inhibiting NLRP3-induced inflammation and fibrosis. 23939143 Role of drug-independent stress factors in liver injury associated with diclofenac intake. Although a basic understanding of the chemical and biological events leading to idiosyncratic drug toxicity is still lacking, it appears that drug-independent risk factors that increase reactive metabolite formation or alter cellular stress and immune response may be critical determinants in the response to an otherwise non-toxic drug. Thus, we were interested to determine the impact of various drug-independent stress factors - lipopolysaccharide (LPS), poly I:C (PIC) or glutathione depletion via buthionine sulfoximine (BSO) - on the toxicity of diclofenac (Dcl), a model drug associated with rare but significant cases of serious hepatotoxicity, and to understand if enhanced toxicity occurs through alterations of drug metabolism and/or modulation of stress response pathways. Co-treatment of rats repeatedly given therapeutic doses of Dcl for 7 days with a single dose of LPS 2h before the last Dcl dose resulted in severe liver toxicity. Neither LPS nor diclofenac alone or in combination with PIC or BSO had such an effect. While it is thought that bioactivation to reactive Dcl acyl glucuronides (AG) and subsequent protein adduct formation contribute to Dcl induced liver injury, LC-MS/MS analyses did not reveal increased formation of 4'- and 5-hydroxy-Dcl, Dcl-AG or Dcl-AG dependent protein adducts in animals treated with LPS/Dcl. Hepatic gene expression analysis suggested enhanced activation of NFκB and MAPK pathways and up-regulation of co-stimulatory molecules (IL-1β, TNF-α, CINC-1) by LPS/Dcl and PIC/Dcl, while protective factors (HSPs, SOD2) were down-regulated. LPS/Dcl led to extensive release of pro-inflammatory cytokines (IL-1β, IL-6, IFN-γ, TNF-α) and factors thought to constitute danger signals (HMGB1, CINC-1) into plasma. Taken together, our results show that Dcl enhanced the inflammatory response induced by LPS - and to a lesser extent by PIC - through up-regulation of pro-inflammatory molecules and down-regulation of protective factors. This suggests sensitization of cells to cellular stress mediated by non-drug-related risk factors by therapeutic doses of Dcl, rather than potentiation of Dcl toxicity by the stress factors. 22899728 Effect of copper overload on the survival of HepG2 and A-549 human-derived cells. We investigated the effect of copper (Cu) overload (20-160 µM/24 h) in two cell lines of human hepatic (HepG2) and pulmonary (A-549) origin by determining lipid and protein damage and the response of the antioxidant defence system. A-549 cells were more sensitive to Cu overload than HepG2 cells. A marked increase was observed in both the cell lines in the nitrate plus nitrite concentration, protein carbonyls and thiobarbituric acid reactive substances (TBARS). The TBARS increase was consistent with an increment in saturated fatty acids at the expense of polyunsaturated acids in a Cu concentration-dependent fashion. Antioxidant enzymes were stimulated by Cu overload. Superoxide dismutase activity increased significantly in both the cell lines, with greater increases in HepG2 than in A-549 cells. A marked increase in ceruloplasmin and metallothionein content in both the cell types was also observed. Dose-dependent decreases in α-tocopherol and ferric reducing ability were observed. Total glutathione content was lower in A-549 cells and higher in HepG2. Calpain and caspase-3 were differentially activated in a dose-dependent manner under copper-induced reactive oxygen species production. We conclude that Cu exposure of human lung- and liver-derived cells should be considered a reliable experimental system for detailed study of mechanism/mechanisms by which Cu overload exerts its deleterious effects. 23864439 Epigenetics Primer: Why the Clinician Should Care About Epigenetics. Epigenetics describes heritable alterations of gene expression that do not involve DNA sequence variation and are changeable throughout an organism's lifetime. Not only can epigenetic status influence drug response, but it can also be modulated by drugs. In this review, the three major epigenetic mechanisms are described: covalent DNA modification, histone protein modification, and regulation by noncoding RNA. Further, this review describes how drug therapy can influence, and be influenced by, these mechanisms. Drugs with epigenetic mechanisms are already in use, with many more likely to be approved within the next few years. As the understanding of epigenetic processes improves, so will the ability to use these data in the clinic to improve patient care. 23821032 Tubulogenesis. Metazoans require epithelial and endothelial tubes to transport liquids and gasses throughout their bodies. Although biological tubes may look relatively similar at first glance, there are multiple and distinct mechanisms by which tubes form and even more regulatory events driving the cell shape changes that produce tubes of specific dimensions. An overview of the current understanding of the molecular processes and physical forces involved in tubulogenesis is presented in this review and the accompanying poster. 23272907 Inhibition of mTOR Signaling by Quercetin in Cancer Treatment and Prevention. Quercetin is an abundant micronutrient in our daily diet. Several beneficial health effects are associated with the dietary uptake of this bioflavonoid, including alleviating effects on chronic inflammation and atherosclerosis. A variety of in vitro data indicate a possible use of quercetin for cancer treatment purposes through its interaction with multiple cancer-related pathways. Among these, recent data reveal that quercetin can inhibit mTOR activity in cancer cells. Inhibition of the mTOR signaling pathway by quercetin has directly been described and can further be deduced from its interference with PI3K-dependent Akt stimulation, AMP-dependent protein kinase activation and hamartin upregulation. The ability of quercetin to interfere with both mTOR activity and activation of the PI3K/Akt signaling pathway gives quercetin the advantage to function as a dual-specific mTOR/PI3K inhibitor. The mTOR complex, often hyperactivated in cancer, is a crucial regulator of homeostasis controlling essential pathways leading to cell growth, protein biosynthesis and autophagy. The ability of quercetin to inhibit mTOR activity by multiple pathways makes this otherwise safe bioflavonoid an interesting tool for the treatment of cancers and other diseases associated with mTOR deregulation. 23658124 Two lanthanide(III)-copper(II) organic frameworks based on {OLn6 } clusters that exhibited a large magnetocaloric effect and slow relaxation of the magnetization. Two new 3D lanthanide(III)-copper(II) organic frameworks based on unusual {OLn6} clusters have been successfully synthesized and fully characterized. Crystallographic studies showed that the {OLn6} clusters acted as 12-connected nodes that were linked together by [CuL2] (H2L = 3-hydroxypyrazine-2-carboxylic acid) moieties to construct an interesting 4,12-c net with the point symbol {4(36).6(30)}{4(4).6(2)}3. Magnetic studies revealed that these two isostructural heterometallic frameworks exhibited different magnetic properties, depending on the different anisotropies of the lanthanide spin carriers: Gd-Cu showed a large magnetocaloric effect, with an entropy change (-ΔS(m)) of 35.76 J  kg(-1)  K(-1), which is one of the largest values in high-dimensional complexes, whilst Dy-Cu exhibited slow relaxation of the magnetization at low temperatures. 23376427 The gradient function as an exploratory goodness-of-fit assessment of the random-effects distribution in mixed models. Inference in mixed models is often based on the marginal distribution obtained from integrating out random effects over a pre-specified, often parametric, distribution. In this paper, we present the so-called gradient function as a simple graphical exploratory diagnostic tool to assess whether the assumed random-effects distribution produces an adequate fit to the data, in terms of marginal likelihood. The method does not require any calculations in addition to the computations needed to fit the model, and can be applied to a wide range of mixed models (linear, generalized linear, non-linear), with univariate as well as multivariate random effects, as long as the distribution for the outcomes conditional on the random effects is correctly specified. In case of model misspecification, the gradient function gives an important, albeit informal, indication on how the model can be improved in terms of random-effects distribution. The diagnostic value of the gradient function is extensively illustrated using some simulated examples, as well as in the analysis of a real longitudinal study with binary outcome values. 23884818 Comparative antioxidant activity of cultivated and wild Vaccinium species investigated by EPR, human neutrophil burst and COMET assay. The Vaccinium (V.) spp. berries are considered a source of antioxidants, mainly belonging to polyphenols, specifically flavonoids and anthocyanins. Wild genotypes generally contain more antioxidants than cultivated counterparts. So, seven different antioxidants assays on extracts from cultivated and wild Vaccinium berries were performed, to evaluate their difference in terms of bioactivity on oxidative protection and minimum dosage to have a significant action. Four cell-free antioxidant assays (ABTS radical scavenging and electronic paramagnetic resonance using Fremy's salt, superoxide anion and hydroxyl radical), and three assays on human cells (two luminol amplified chemiluminescence, LACL, one on DNA damage, COMET) were used to measure the effects of cultivated blueberry (V. corymbosum) and wild bilberry (V. myrtillus) on the differently induced oxidative stress. Concentrations vs activity patterns were obtained by successive dilutions of extracts in order to identify both EC50 and minimum significant activity (MSA). All the assays (except for the hydroxyl radical scavenging) showed a good relationship mainly with anthocyanin and polyphenol content and the significant greater activity of wild Vaccinium extracts. In fact, LACL data gave an EC50 of 11.8 and an MSA of 5.2 g were calculated as fresh weight dosage in cultivated berries, compared with lower doses in wild berries, EC50 of 5.7 g and MSA of 3.4 g. Wild Vaccinium extracts averaged 3.04 and 2.40 fold more activity than cultivated extracts by EC50 and MSA, respectively. COMET assay confirmed the stronger action on DNA protection in wild samples. 23881512 Density effect on great tit (Parus major) clutch size intensifies in a polluted environment. Long-term data on a great tit (Parus major) population breeding in a metal-polluted zone around a copper-nickel smelter indicate that, against expectations, the clutch size of this species is decreasing even though metal emissions in the area have decreased considerably over the past two decades. Here, we document long-term population-level changes in the clutch size of P. major and explore if changes in population density, population numbers of competing species, timing of breeding, breeding habitat, or female age distribution can explain decreasing clutch sizes. Clutch size of P. major decreased by one egg in the polluted zone during the past 21 years, while there was no significant change in clutch size in the unpolluted reference zone over this time period. Density of P. major nests was similar in both environments but increased threefold during the study period in both areas (from 0.8 to 2.4 nest/ha). In the polluted zone, clutch size has decreased as a response to a considerable increase in population density, while a corresponding density change in the unpolluted zone did not have such an effect. The other factors studied did not explain the clutch size trend. Fledgling numbers in the polluted environment have been relatively low since the beginning of the study period, and they do not show a corresponding decrease to that noted for the clutch size over the same time period. Our study shows that responses of commonly measured life-history parameters to anthropogenic pollution depend on the structure of the breeding population. Interactions between pollution and intrinsic population characters should therefore be taken into account in environmental studies. 23067059 A hybrid method employing breakdown anodization and electrophoretic deposition for superhydrophilic surfaces. A fabrication method is developed for superhydrophilic surfaces with high capillary pressure and fast spreading speed. The fabrication method consists of electrophoretic deposition (EPD) and breakdown anodization (BDA). Nanopores and micropores were produced on titanium plates by EPD and BDA, respectively. In EPD, TiO(2) nanoparticles were used to enhance the surface energy and create nanoporous structures, while BDA was employed to produce microporous structures. Capillary rise measurements (CRM) were utilized to characterize superhydrophilic surfaces in terms of capillary pressure and spreading speed. From CRM, it was revealed that microporous structures play a dominant role in determining transport properties, and nanoporous structures affect local wettability without significantly reducing spreading speed. By combining BDA and EPD into a hybrid method, dual-scale (nano and micro) porous structures were produced on titanium plates. The methods presented offer the potential to vary the transport characteristics of superhydrophilic surfaces by altering the nanoscale and microscale features independently. As an example, surfaces with unconventional capillary flows were produced by the hybrid method. This method provides additional opportunities to investigate wetting phenomena while offering a potentially low cost process for industrial applications. 23523226 A comparative study of 1% silver sulphadiazine (Flammazine(®)) versus an enzyme alginogel (Flaminal(®)) in the treatment of partial thickness burns. In the conservative treatment of burns, rapid wound healing is desirable to obtain good a esthetic and functional results. The aim of this study was to compare the efficacy of 1% Silversulfadiazine (SSD/Flammazine(®)) and an enzyme alginogel (Flaminal(®) or Flaminal(®) Forte) on the healing of superficial and intermediate partial thickness burns. In this retrospective cohort study comparable burn wounds treated with Flaminal(®) or with 1% SSD were included. Outcome parameters included: length of hospital stay, bacterial burden and time to wound closure. Significance was tested using SPSS package. 44 wounds in the Flaminal(®) group, and 39 wounds in the 1% SSD group were included. Wounds treated with Flaminal(®) showed a significantly higher bacterial load (p=0.024) and contained significantly more bacterial species (p=0.010) but showed a significantly shorter healing time of 17 vs. 24 days (p<0.0001). A significantly shorter healing time was demonstrated in partial thickness burn wounds treated with Flaminal(®) versus 1% SSD, which may lead to a shorter length of hospital stay and better scar quality. The possibility of accurate burn depth assessment and the results in this study corroborate the change in treatment protocol made in the year 2000 when we switched from 1% SSD to Flaminal(®). 23832642 Taurine drinking attenuates the burden of intestinal adult worms and muscle larvae in mice with Trichinella spiralis infection. The parasitic nematode Trichinella spiralis can cause trichinellosis, which leads to pathological processes in the intestine and muscle. The intestinal invasion determines the development, subsequent course, and consequences of the disease. Gastrointestinal nematode infection, including with T. spiralis, is accompanied by a rapid and reversible expansion of mucosal mast cell and goblet cell in the intestinal epithelium, which play important roles in the host immune response to parasite and worm expulsion from the intestine. Taurine and its derivatives have anti-infection and anti-inflammatory properties. We investigated whether taurine supplementation in mice could influence the development and pathological processes of infection with T. spiralis. Supplementing 1 % taurine in drinking water in mice infected with T. spiralis could alleviate the burden of intestinal adult worms on days 7 and 10 postinfection (all p < 0.01) and the formation of infective muscle larvae in striated muscle during T. spiralis infection (p < 0.01). As compared with T. spiralis infection alone, taurine treatment increased the number of goblet cells on days 7, 10, and 15 (p < 0.01 and p < 0.05) and alleviated intestinal mucosal mast cell hyperplasia on days 10 and 15 (all p < 0.01). So taurine supplementation in drinking water increased infection-induced intestinal goblet cell hyperplasia and ameliorated mucosal mastocytosis. Thus, taurine can ameliorate the pathological processes of trichinellosis and may be of great value for the treatment and prevention of infection with T. spiralis and other gastrointestinal nematodes. 23621612 Endosomal trafficking of the receptor tyrosine kinase MuSK proceeds via clathrin-dependent pathways, Arf6 and actin. Muscle-specific kinase (MuSK), a receptor tyrosine kinase, is the key player during the formation of the neuromuscular junction. Signal transduction events downstream of MuSK activation induce both pre- and postsynaptic differentiation, which, most prominently, includes the clustering of acetylcholine receptors at synaptic sites. More recently, regulated MuSK endocytosis and degradation have been implicated as crucial events for MuSK signalling activity, implicating a cross-talk between signalling and endocytosis. In the present study, we use a live imaging approach to study MuSK endocytosis. We find that MuSK is internalized via a clathrin-, dynamin-dependent pathway. MuSK is transported to Rab7-positive endosomes for degradation and recycled via Rab4- and Rab11-positive vesicles. MuSK activation by Dok7 mildly affects the localization of MuSK on the cell surface but has no effect on the rate of MuSK internalization. Interestingly, MuSK colocalizes with actin and Arf6 at the cell surface and during endosomal trafficking. Disruption of the actin cytoskeleton or the proper function of Arf6 concentrates MuSK in cell protrusions. Moreover, inhibition of Arf6 or cytoskeletal rearrangements impairs acetylcholine receptor clustering and phosphorylation. These results suggest that MuSK uses both classical and nonclassical endosomal pathways that involve a variety of different components of the endosomal machinery. 23911769 Implicit learning of geometric eigenfaces. The human visual system can implicitly extract a prototype of encountered visual objects (Posner & Keele, 1968). While learning a prototype provides an efficient way of encoding objects at the category level, discrimination among individual objects requires encoding of variations among them as well. Here we show that in addition to the prototype, human adults also implicitly learn the feature correlations that capture the most significant geometric variations among faces. After studying a group of synthetic faces, observers mistook as seen previously unseen faces representing the first two principal components (eigenfaces, Turk & Pentland, 1991) of the studied faces at significantly higher rates than the correct recognition of the faces actually studied. Implicit learning of the most significant eigenfaces provides an optimal way for encoding variations among faces. The data thus extend the types of summary statistics that can be implicitly extracted by the visual system to include several principal components. 23684960 Regional variations in MR relaxation of hip joint cartilage in subjects with and without femoralacetabular impingement. The objective of this study was to analyze regional variations of magnetic resonance (MR) relaxation times (T1ρ and T2) in hip joint cartilage of healthy volunteers and subjects with femoral acetabular impingement (FAI). Morphological and quantitative images of the hip joints of 12 healthy volunteers and 9 FAI patients were obtained using a 3T MR scanner. Both femoral and acetabular cartilage layers in each joint were semi-automatically segmented on sagittal 3D high-resolution spoiled gradient echo (SPGR) images. These segmented regions of interest (ROIs) were automatically divided radially into twelve equal sub-regions (30(0) intervals) based on the fitted center of the femur head. The mean value of T1ρ/T2 was calculated in each sub-region after superimposing the divided cartilage contours on the MR relaxation (T1ρ/T2) maps to quantify the relaxation times. T1ρ and T2 relaxation times of the femoral cartilage were significantly higher in FAI subjects compared to healthy controls (39.9±3.3msec in FAI vs. 35.4±2.3msec in controls for T1ρ (P=0.0020); 33.9±3.1msec in FAI vs. 31.1±1.7msec in controls for T2 (P=0.0160)). Sub-regional analysis showed significantly different T1ρ and T2 relaxation times in the anterior-superior region (R9) of the hip joint cartilage between subjects with FAI and healthy subjects, suggesting possible regional differences in cartilage matrix composition between these two groups. Receiver operating characteristic (ROC) analysis showed that sub-regional analysis in femoral cartilage was more sensitive in discriminating FAI joint cartilage from that of healthy joints than global analysis of the whole region (T1ρ: area under the curve (AUC)=0.981, P=0.0001 for R9 sub-region; AUC=0.901, P=0.002 for whole region; T2: AUC=0.976, P=0.0005 for R9 sub-region; AUC=0.808, P=0.0124 for whole region). The results of this study demonstrated regional variations in hip cartilage composition using MR relaxation times (T1ρ and T2) and suggested that analysis based on local regions was more sensitive than global measures in subjects with and without FAI. 23899628 A logically derived diet to stop MS relapses. This brief document outlines reasons for expecting that diets which cause gout should help prevent multiple sclerosis relapses. 23948462 The Efficacy of Induction Chemotherapy with Docetaxel, Cisplatin and 5-fluorouracil Combined with Cisplatin Concurrent Chemoradiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma: A Matched Pair Analysis. The role of induction chemotherapy (ICT) for head and neck squamous cell carcinoma (HNSCC) is controversial. The aim of the study was to assess the benefit of ICT with docetaxel, cisplatin and 5-fluorouracil (5-FU) (TPF) when combined with concurrent cisplatin chemoradiotherapy (CRT) for HNSCC. Patients with HNSCC treated between January 2005 and December 2010 with radical intent with either TPF or cisplatin and 5-FU (PF) ICT and documented intention to proceed with concurrent cisplatin CRT were identified retrospectively. The use and choice of ICT regimen was at the clinician's discretion. In total, 68 patients treated with TPF were identified and were matched for T and N stage and tumour site to 68 patients treated with PF. A survival analysis was carried out using Kaplan-Meier and the Cox proportional hazards model. The median follow-up was 29.9 versus 36.3 months for the TPF and PF groups, respectively. Three year locoregional relapse-free survival (RFS), distant RFS, RFS, cancer-specific survival and overall survival rates for the TPF and PF groups were 84.2, 91.6, 82.6, 81.3 and 74.9% versus 73.7, 84.9, 71.9, 72.1 and 62.9%, respectively. On multivariate analysis, treatment with TPF predicted for improved locoregional RFS (P = 0.03) and overall survival (P = 0.05). The addition of docetaxel to a cisplatin doublet ICT regimen before concurrent CRT may improve disease control for locally advanced HNSCC. 23949929 MRI diffusion-weighted imaging (DWI) in pediatric small bowel Crohn disease: correlation with MRI findings of active bowel wall inflammation. Restricted diffusion on diffusion-weighted imaging (DWI) sequences during magnetic resonance enterography (MRE) has been shown in segments of bowel affected by Crohn disease. However, the exact meaning of this finding, particularly within the pediatric Crohn disease population, is poorly understood. The purpose of this study was to determine the significance of bowel wall restricted diffusion in children with small bowel Crohn disease by correlating apparent diffusion coefficient (ADC) values with other MRI markers of disease activity. A retrospective review of pediatric patients (≤ 18 years of age) with Crohn disease terminal ileitis who underwent MRE with DWI at our institution between May 1, 2009 and May 31, 2011 was undertaken. All of the children had either biopsy-proven Crohn disease terminal ileitis or clinically diagnosed Crohn disease, including terminal ileal involvement by imaging. The mean minimum ADC value within the wall of the terminal ileum was determined for each examination. ADC values were tested for correlation/association with other MRI findings to determine whether a relationship exists between bowel wall restricted diffusion and disease activity. Forty-six MRE examinations with DWI in children with terminal ileitis were identified (23 girls and 23 boys; mean age, 14.3 years). There was significant negative correlation or association between bowel wall minimum ADC value and established MRI markers of disease activity, including degree of bowel wall thickening (R = (-)0.43; P = 0.003), striated pattern of arterial enhancement (P = 0.01), degree of arterial enhancement (P = 0.01), degree of delayed enhancement (P = 0.045), amount of mesenteric inflammatory changes (P < 0.0001) and presence of a stricture (P = 0.02). ADC values were not significantly associated with bowel wall T2-weighted signal intensity, length of disease involvement or mesenteric fibrofatty proliferation. Increasing bowel wall restricted diffusion (lower ADC values) is associated with multiple MRI findings that are traditionally associated with active inflammation in pediatric small bowel Crohn disease. 23907830 Effects of administration of subtoxic doses of acetaminophen on liver and blood levels of insulin-like growth factor-1 in rats. Acetaminophen (APAP) is widely used in the treatment of pain. Toxic doses of APAP cause acute liver failure, but therapeutic doses are believed to be safe. The purpose of this study is to investigate the effects of administration of subtoxic doses of APAP on liver and blood levels of insulin-like growth factor-1 (IGF-1) in rats. Low dose (100 mg/kg) and high dose (250 mg/kg) of APAP were intraperitoneally injected into Wistar albino rats. Following administration of therapeutic doses of APAP, there were no significant changes in serum transaminases and liver glutathione levels. Both doses of APAP induced a decrease in liver and blood levels of IGF-1 when compared with the controls. There was no significant difference in liver IGF-1 levels between the high-dose and low-dose APAP groups; however, there was a significant difference in blood IGF-1 levels between both the groups. The histological examination showed that low dose of APAP induced mild degree of structural change, while high dose of APAP induced severe structural damage. In conclusion, these results suggest that blood IGF-1 levels may have a value in predicting hepatic damage resulting from therapeutic doses of APAP. 23922863 Drawing to remember: external support of older adults' eyewitness performance. Although healthy aging is accompanied by a general decline in memory functioning, environmental support at retrieval can improve older adults' (+65 years) episodic remembering. Despite those over the age of 65years representing a growing proportion of the population, few environmental retrieval support methods have been empirically evaluated for use with older witnesses and victims of crime. Here, the efficacy of a novel retrieval technique, the Sketch Mental Reinstatement of Context, is compared with a standard Mental Reinstatement of Context and a no support control (Control). Fifty-one participants witnessed an unexpected live event, and 48 hours later were interviewed using one of three aforementioned techniques. In line with predictions emanating from cognitive theories of aging and the environmental support hypothesis, participants in the Sketch Mental Reinstatement of Context condition recalled significantly more correct information and fewer inaccurate items. The Sketch Mental Reinstatement of Context technique appears to scaffold memory retrieval in an age-appropriate manner during a post-event interview, possibly by encouraging more effortful retrieval and reducing dual-task load. As such, this procedure offers an effective alternative to current approaches, adding to the toolbox of techniques available to forensic and other interviewers. 23937826 Fibrous tumours of the ovary: Aetiologies and MRI features. The ovaries can be affected by a vast variety of tumours, which may be benign or malignant, solid or cystic. Although ultrasonography is often the first examination performed in the evaluation of gynaecological conditions, magnetic resonance imaging is nowadays the most accurate imaging technique in the characterization of ovarian masses. Once the ovarian origin of a pelvic mass has been determined, the detection of any fibrous component within the lesion significantly reduces the spectrum of aetiologies that should be considered. Fibrotic tissue usually displays marked low-signal intensity on T2-weighted sequences at MRI, and enhancement is mostly moderate after intravenous administration of gadolinium chelates. This review aims to provide the main diagnoses to consider at MRI whenever an ovarian tumour, both purely solid or solid and cystic, contains a fibrous component, even if minimally abundant. The corresponding key imaging features are provided. 23752816 Synthesis, structures and luminescent properties of a series of novel Sr(II)-Ln(III) (Ln = Eu, Gd, Tb) coordination polymers. Eight novel Sr(II)-Ln(III) heteronuclear coordination polymers based on pyridine-2,6-dicarboxylic acid (H2pda) and imidazole (im) ligands, namely, [LnSr(pda)3(H2O)5]·Him·H2O (Ln = Eu (1), Gd (2), Tb (3)), [Ln2Sr(pda)6(H2O)5]·4Him·C2H5OH·nH2O (Ln = Eu (4), n = 5; Gd (5), n = 4), [LnSr(pda)3(H2O)4]·Him·3H2O (Ln = Gd (6), Tb (7)), and [GdSr(pda)3(H2O)5]·Him·C2H5OH·3H2O (8), have been prepared by employing different amounts of imidazole. X-ray crystal structure analysis reveals that these compounds exhibit a rich structural chemistry. Complexes 1-3 possess 2-D frameworks. Complexes 4-5, 6-7, and 8 exhibit three types of 1-D chain structure. The structures of the complexes could be rationally tuned via adding different amounts of imidazole. The luminescent properties of these complexes have been investigated. The results show that Eu(III) and Tb(III) complexes exhibit intense red and green luminescence emission which are characteristics of Tb(III) and Eu(III), respectively. Solid-state quantum yield and the lifetime of these complexes are also reported. 23924085 Brain-derived neurotrophic factor (Val66Met) polymorphism and olfactory ability in young adults. Brain- derived neurotrophic factor (BDNF) is linked to neurodegenerative diseases (e.g. Alzheimer disease and Parkinson disease) which are often characterized by olfactory impairment. A specific single nucleotide polymorphism of the BDNF gene, the Val66Met, modulates intracellular trafficking and activity-dependent secretion of BDNF protein. The aim of this study was to investigate a possible association between brain- derived neurotrophic factor Val66Met polymorphism and olfactory function, a well-known biomarker for neurodegeneration, in healthy young adults. A total of 101 subjects (45 males, age 38.7 +/- 9.4 years) were assessed using the Sniffin' Sticks Extended Test, a highly reliable commercial olfactory test composed of three sub-parts, calculating olfactory threshold (sensitivity), odor discrimination and odor identification. The Val66Met polymorphism was determined by polymerase chain reaction -restriction fragment length polymorphism (PCR-RFLP) analysis. An impaired function in Met carriers was found, especially when compared to subjects with Val/Val genotype, in the threshold (5.5 +/- 2.0 vs 6.5 +/- 1.8, p = 0.009), discrimination (10.3+/- 2.5 vs 11.9 +/- 2.2, p = 0.002), and identification task (13.3 +/- 1.6 vs 14.1 +/- 1.3, p = 0.007), as well as in the overall TDI Score (29.1 +/- 4.5 vs 32.6 +/- 3.9, p < 0.001). These findings appear to have implications for the evaluation of olfactory function and the relation of its impairment to cognitive decline and neurodegenerative disease. 23920281 A Rare Case of Pediatric Colloid Cysts in Bilateral Ventricles. Colloid cysts often arise in the third ventricle. It is quite rare for colloid cysts to arise from lateral ventricles. We describe a case of a patient with colloid cysts in the bilateral ventricles. The patient eventually underwent a surgical operation to alleviate the symptoms. Colloid cysts have the potential to be misdiagnosed in the clinical practice; therefore, magnetic resonance imaging and magnetic resonance spectroscopy would be effective for differential diagnosis. 23838471 Peripheral blood lymphocyte subsets in Fasciola hepatica infected and immunised goats. The proportions of CD4(+), CD8(+) and WC1+ T lymphocytes from peripheral blood using flow cytometry were investigated in goats infected with Fasciola hepatica and previously immunised with recombinant Cathepsin-L1 (rCL1) and Glutathione-S-transferase sigma class (GST). The immunisation trial did not induce protective responses, and no significant differences were recorded between immunised and non-immunised groups. However, there was a significant decrease in the proportion of CD4(+) T lymphocytes in the infected groups both at 5 weeks post-infection (wpi), coinciding with the migratory stage of the infection, and at 12wpi in the biliary stage of the infection. The proportional decrease in this circulating population may be related to the recruitment of CD4(+) T cells in liver and hepatic lymph nodes and also to the immunomodulatory effect of the parasite through the interaction of F. hepatica excretory-secretory products (FhESP) with this cell population. To date, this is the first report about the effect of F. hepatica infection in peripheral lymphocyte subsets in goats. 23887908 Draft Genome Sequence of Gluconobacter frateurii NBRC 103465, a Glyceric Acid-Producing Strain. Gluconobacter frateurii strain NBRC 103465 can efficiently produce glyceric acid (GA) from raw glycerol feedstock derived from biodiesel fuel production processes. Here, we report the 3.4-Mb draft genome sequence of G. frateurii NBRC 103465. The draft genome sequence can be applied to examine the enzymes and electron transport system involved in GA production. 23503457 Enteropathogenic Escherichia coli-induced macrophage inhibitory cytokine 1 mediates cancer cell survival: an in vitro implication of infection-linked tumor dissemination. Mucosally adherent Escherichia coli is frequently observed in intestinal surface of patients with colorectal cancer, but rarely in healthy control. Particularly, enteropathogenic Escherichia coli (EPEC) is known to be closely associated with colorectal carcinogenesis in human. In this study, one consequence of EPEC infection in human intestinal cancer cells was induction of macrophage inhibitory cytokine 1 (MIC-1), which is a multifunctional cytokine with biological activities involved in cancer cell growth, differentiation and migration. The present investigation assessed the involvement of MIC-1 protein in EPEC infection-mediated cancer cell survival. The challenge with EPEC induced cancer cell detachment via cytoskeleton rearrangement, which was positively associated with induced MIC-1 expression. Moreover, MIC-1 also mediated RhoA GTPase-linked survival of the detached cancer cells. Blocking of MIC-1 or RhoA activity increased cellular apoptosis of the detached cancer cells. In terms of signaling pathway, MIC-1 triggered transforming growth factorβ-activated kinase 1 (TAK1), which enhanced expression of RhoA GTPase. We conclude that EPEC enhances MIC-1 gene expression in the human intestinal cancer cells, which can be associated with enhanced tumor cell resistance to anchorage-dependent tumor cell death via enhanced TAK1 and RhoA GTPase.Oncogene advance online publication, 18 March 2013; doi:10.1038/onc.2012.508. 23897720 Comparison of a new ELISA-based with the flow cytometric assay for vasodilator-associated stimulated phosphoprotein (VASP) phosphorylation to assess P2Y12 -inhibition after ticagrelor intake. Ticagrelor is a P2Y12 receptor antagonist, with superior effects but also ensuing enhanced bleeding risk as compared to clopidogrel. Determination of platelet inhibition may be useful to confirm efficient platelet inhibition on an individual patient level and to identify patients at risk for bleeding. The vasodilator-associated stimulated phosphoprotein (VASP) phosphorylation assay specifically measures platelet P2Y12 inhibition, but has so far required individual sample processing. A new ELISA-based VASP assay has been developed which allows batch analysis after initial platelet activation. Due to the reversible binding of ticagrelor it is unclear if the ELISA and flow cytometric assays provide comparable results; several washing steps of the ELISA may potentially result in false low results through dilution. We hypothesized that the conventional and new methods may be comparable when ticagrelor is used. We pair-wise compared the platelet reactivity index (PRI) between assays in a prospective clinical trial. Six healthy volunteers received a single 180 mg loading dose of ticagrelor. PRI-values of the two methods correlated well (r=0.97, p<0.001). Ticagrelor rapidly decreased PRI values on average after 50 minutes, but nadir levels 2-6 hours after ticagrelor intake were 15% higher when PRI% was measured with the flow cytometric method. Bland-Altman analysis showed that the flow cytometric assay measured markedly higher PRI levels than the new ELISA-based technique (mean difference 13%). The new ELISA-based VASP assay offers an alternative to the currently used flow cytometric method, but measures lower PRI levels, particularly when PRI falls below 20% after ticagrelor intake. © 2013 Clinical Cytometry Society. 23740248 SLLISWD Sequence in the 10FNIII Domain Initiates Fibronectin Fibrillogenesis. Fibronectin (FN) assembly into extracellular matrix is tightly regulated and essential to embryogenesis and wound healing. FN fibrillogenesis is initiated by cytoskeleton-derived tensional forces transmitted across transmembrane integrins onto RGD binding sequences within the tenth FN type III (10FNIII) domains. These forces unfold 10FNIII to expose cryptic FN assembly sites; however, a specific sequence has not been identified in 10FNIII. Our past steered molecular dynamics simulations modeling 10FNIII unfolding by force at its RGD loop predicted a mechanical intermediate with a solvent-exposed N terminus spanning the A and B β-strands. Here, we experimentally confirm that the predicted 23-residue cryptic peptide 1 (CP1) initiates FN multimerization, which is mediated by interactions with 10FNIII that expose hydrophobic surfaces that support 8-anilino-1-napthalenesulfonic acid binding. Localization of multimerization activity to the C terminus led to the discovery of a minimal 7-amino acid "multimerization sequence" (SLLISWD), which induces polymerization of FN and the clotting protein fibrinogen in addition to enhancing FN fibrillogenesis in fibroblasts. A point mutation at Trp-6 that reduces exposure of hydrophobic sites for 8-anilino-1-napthalenesulfonic acid binding and β-structure formation inhibits FN multimerization and prevents physiological cell-based FN assembly in culture. We propose a model for cell-mediated fibrillogenesis whereby cell traction force initiates a cascade of intermolecular exchange starting with the unfolding of 10FNIII to expose the multimerization sequence, which interacts with strand B of another 10FNIII domain via a Trp-mediated β-strand exchange to stabilize a partially unfolded intermediate that propagates FN self-assembly. 23749307 Prognostic factors for teenage and adult patients with high-grade osteosarcoma: an analysis of 240 patients. The aim of this retrospective, multicenter study was to evaluate clinicopathological characteristics, prognostic factors and treatment outcomes of teenage and adult patients with high-grade osteosarcoma. A total of 240 osteosarcoma patients who were diagnosed and treated from March 1995 to September 2011 were analyzed. Median age was 20 years (range 13-74 years), and 153 patients (63.8%) were male. Primary tumor localization was extremity in 204 patients (85.4 %), trunk in 21 patients (8.8%) and head and neck region in 14 patients (5.9%). According to American Joint Committee on Cancer staging system, 186 patients (77.5%) were stage II, 3 (1.3%) were stage III and 48 (20.0%) were stage IV. Median overall survival (OS) was 55 months (95 % CI 36.8-73.1 months). OS after 2, 5 and 10 years were 67, 49 and 42%, respectively. Univariable analysis for OS showed that male gender (p = 0.032), high baseline lactate dehydrogenase (LDH) level (p < 0.001), high baseline serum alkaline phosphatase level (p = 0.002), telangiectatic subtype (p = 0.023), presence of metastasis at diagnosis (p < 0.001), presence of tumor positive margins after primary surgery (p = 0.015), poor pathological response to preoperative chemotherapy (p = 0.006) and presence of recurrent disease during follow-up period (p < 0.001) were significantly associated with poor survival. Patients who received postoperative methotrexate plus doxorubicin plus cisplatin (M + A + P) combination regimen (p = 0.019), underwent surgery for recurrent disease (p < 0.001) and received chemotherapy for recurrent disease (p < 0.001) had longer OS. In multivariable analysis for OS, only high LDH level (p = 0.002) and the presence of metastasis at diagnosis (p = 0.011) were associated with poor OS, whereas the patients who received chemotherapy for recurrent disease had a longer OS (p = 0.009). 23866017 Comparably high retention and low relapse rates in different subpopulations of bipolar patients in a German non-interventional study. Although a range of pharmacotherapeutical options are available for the treatment of bipolar disorder, patient non-adherence to prescribed treatment regimens and early treatment discontinuation remain among the primary obstacles to effective treatment. Therefore, this observational study assessed time on mood stabilizing medication and retention rates in patients with bipolar disorder (BD). In an 18-month, prospective, multicenter, non-interventional study conducted in Germany 761 outpatients (>=18 years) with BD and on maintenance therapy were documented. For analysis, patients were stratified by baseline medication: monotherapy olanzapine (OM, N = 186), lithium (LM, N = 152), anticonvulsants (N = 216), other mood stabilizing medication (OMS, N = 44); combination therapy olanzapine/lithium (N = 47), olanzapine/anticonvulsant (N = 68), other combinations (OC, N = 48). Continuation on medication was assessed as retention rates with 95% confidence intervals. Time to discontinuation and relapse-free time were calculated by Kaplan-Meier analysis. A relapse was defined as increase to CGI-BP >3, worsening of CGI-BP by >=2 points, hospitalization or death related to BD. A Cox regression was calculated for the discontinuation of mood stabilizing therapy (reference: OM). Logistic regression models with stepwise forward selection were used to explore possible predictors of maintenance of treatment and relapse. After 540 days (18 months), the overall retention rate of baseline medication was 87.7%, without notable differences between the cohorts. The overall mean time on mood stabilizing treatment was 444.7 days, with a range of 377.5 (OMS) to 481 (LM) by cohort. 74.0% of all patients were without relapse, with rates between the cohorts ranging from 58.4% (OC) to 80.2% (LM). Retention rates exceeded controlled trial results in all treatment cohorts, in addition to other explanations possibly reflecting that the physicians were expertly adapting treatment regimens to the individual patient's disease characteristics and special needs. 23962793 Novel male exposure reduces uterine e-cadherin, increases uterine luminal area, and diminishes progesterone levels while disrupting blastocyst implantation in inseminated mice. Exposure to novel male mice disrupts blastocyst implantation in inseminated female mice, and evidence increasingly implicates the female's absorption of male urinary estrogens. We observed implantation sites in male-exposed and isolated control female mice during gestation days (GD) 2-8, observing a significant reduction in male-exposed females compared to controls, particularly on GD 6 and 8. We also measured transitions in uterine luminal area and e-cadherin expression, as these processes are modulated by estrogens. Luminal area was greater in male-exposed females than in controls during the post-implantation period (GD 5-7). E-cadherin levels were suppressed by male exposure, particularly during GD 4-7. Serum progesterone levels were also reduced in male-exposed females. The effects of male exposure on uterine closure and e-cadherin levels are consistent with established effects of estrogens, and suggest a possible mechanism that could contribute to implantation failure. This article is part of a Special Issue entitled 'Pregnancy and Steroids'. 23958565 TGF-β Signaling Promotes Pulmonary Hypertension Caused by Schistosoma Mansoni. The pathogenic mechanisms underlying pulmonary arterial hypertension (PAH) due to schistosomiasis, one of the most common causes of pulmonary hypertension (PH) worldwide, remains unknown. We hypothesized that TGF-β signaling as a consequence of Th2 inflammation is critical for the pathogenesis of this disease. Mice sensitized and subsequently challenged with S. mansoni eggs developed PH associated with an increase in right ventricular systolic pressure (RVSP), thickening of the pulmonary artery media, and right ventricular hypertrophy. Rho-kinase dependent vasoconstriction accounted for about 60% of the increase in RVSP. The pulmonary vascular remodeling and PH were dependent on increased TGF-β signaling, as pharmacological blockade of the TGF-β ligand and receptor, and mice lacking Smad3 were significantly protected from Schistosoma-induced PH. Blockade of TGF-β signaling also led to a decrease in IL4 and IL13 concentrations, which drive the Th2 responses characteristic of schistosomiasis lung pathology. Lungs of patients with schistosomiasis-associated PAH have evidence of TGF-β signaling in their remodeled pulmonary arteries. Experimental S. mansoni-induced pulmonary vascular disease relies on canonical TGF-β signaling. 23685933 Cognitive outcomes of patients undergoing therapeutic hypothermia after cardiac arrest. We aimed to study the long-term cognitive abilities of patients surviving out-of-hospital cardiac arrest who were treated with therapeutic hypothermia (TH). We prospectively identified and examined consecutive survivors of out-of-hospital cardiac arrest who underwent TH at our institution from June 2006 to May 2011. The results of brain imaging, serum neuron-specific enolase (NSE) measurements, and EEGs were recorded. We assessed cognitive domains using the modified Telephone Interview for Cognitive Status. An education-adjusted score of ≥ 32 was considered normal. Of 133 total patients, 77 (58%) were alive at a median follow-up of 20 months (interquartile range 14-24 months). We interviewed 56 patients (73% of those alive). Median age was 67 years (range 24-88 years). Fifty-one patients (91%) were living independently. Modified Telephone Interview for Cognitive Status scores ranged from 16 to 41. Thirty-three (60%) were considered cognitively normal and 22 (40%) were cognitively impaired. The time to assessment did not differ among the cognitive outcomes (p = 0.557). The median duration of coma was 2 days, possibly indicating that patients with severe anoxic injury were not included. Eighteen patients were not working at the time of their cardiac arrest (17 were retired and 1 was unemployed). Of the 38 patients who were working up to the time of the cardiac arrest, 30 (79%) returned to work. Cognitive outcome was not associated with age, time to return of spontaneous circulation, brain atrophy, or leukoaraiosis. The majority of surviving patients who underwent TH after cardiac arrest in this series had preserved cognitive function and were able to return to work. 23124811 Subsyndromal delirium in older people: a systematic review of frequency, risk factors, course and outcomes. To determine the frequency, risk factors, course and outcomes of subsyndromal delirium (SSD) in older people by systematically reviewing evidence on these topics. Subsyndromal delirium was defined as the presence of one or more symptoms of delirium, not meeting criteria for delirium and not progressing to delirium. MEDLINE, EMBASE, PsycINFO and the Web of Science were searched for potentially relevant articles published from 1996 to June 2011. The bibliographies of relevant articles were searched for additional references. Twelve studies met the inclusion criteria. The validity of included studies was assessed according to Evidence-Based Medicine criteria. Information about the study population and methods, age, gender, proportion with dementia, diagnostic criteria, period and frequency of observation, and the topics above was systematically abstracted, tabulated and synthesized using standard meta-analysis techniques. The combined prevalence of SSD was 23% (95% CI, 9-42%); the combined incidence was 13% (95% CI, 6-23%). Risk factors were similar to those for delirium. Episodes lasted up to 133 days and were often recurrent. Outcomes were poor and often intermediate between those of older people with or without delirium. Of note, there was significant unexplained heterogeneity in the results of studies of prevalence, incidence and some risk factors. SSD in older people may be a frequent and clinically important condition that falls on a continuum between no symptoms and full delirium. Because of significant unexplained heterogeneity in the results of studies of SSD, however, the results of this review must be interpreted cautiously. Further research is necessary. Copyright © 2012 John Wiley & Sons, Ltd. 23763875 Career prospects for graduating nuclear medicine residents: survey of nuclear medicine program directors. There has been much consternation in the nuclear medicine (NM) community in recent years regarding the difficulty many NM graduates experience in securing initial employment. A survey designed to determine the extent and root causes behind the paucity of career opportunities was sent to all 2010-2011 NM residency program directors. The results of that survey and its implications for NM trainees and the profession are presented and discussed in this article. 23499211 Motor control during sleep and wakefulness: clarifying controversies and resolving paradoxes. Data accumulated during the last 40 years, since the discovery that there is a loss of muscle tone during REM sleep, have delineated many of the neurotransmitter systems, synaptic mechanisms and neuronal circuitries involved in the control of somatic motoneurons during sleep and waking states. Nevertheless, there are still a number of extant controversies as well as paradoxical and conflicting data. For example, the paradoxical modulation of motor activity that occurs in individuals with cataplexy during wakefulness compared to REM sleep is unresolved as are the mechanisms that are responsible for the control of hypoglossal motoneurons during normal states and those that are operative during sleep disorders such as obstructive sleep apnea. In addition, the circuitry whereby the hypocretinergic system promotes motor activation during wakefulness, and motor inhibition during REM sleep, has yet to be clarified. The use of new techniques, such those involving optogenetics and nanoparticles, will help to clarify the preceding issues and provide as a foundation for addressing a number of current critical unanswered questions such as those dealing with the differential control of motor activity in newborns and the aged. The resulting data will strengthen the foundation for the development of efficacious therapeutics to treat disorders of motor control that occur during sleep as well as wakefulness. 23860264 Factors Associated With Remaining in a Skilled Nursing Facility for Over 90 Days from Admission: Residents' Participation in Therapy and Desire to Return to the Community. To identify the factors associated with stay in a skilled nursing facility (SNF) among new enrollees who did not fully participate in therapy sessions. Data (n = 36,133) were obtained from the Minimum Data Set version 2.0 in the state of Michigan in 2009. Study participants were new SNF enrollees (n = 699) who did not fully participate in therapy sessions despite their desire to return to the community. Multivariate logistic regressions were performed to identify factors contributing to remaining in a nursing home for 91 days or longer. New SNF enrollees were more likely to remain in nursing home when they were depressed (odds ratio [OR] = 1.41; 95% confidence interval [CI], 1.09-2.08; P = .01), experiencing delirium (OR = 3.20; 95% CI, 1.48-5.92; P < .001), were not in pain (OR = 0.83; 95% CI, 0.60-0.95; P = .03), or in less complex care (OR = 0.57; 95% CI, 0.44-0.81; P < .01). A higher number of new SNF enrollees than previously reported were likely to stay in nursing homes (28.0%). Depression and delirium were associated with stay in an SNF, while pain and higher complexity of care were associated with returning to the community. 23912151 Uncovering a key to the process of metastasis in human cancers: a review of critical regulators of anoikis. Anoikis ('homelessness' in Greek) is a form of apoptosis following the detachment of cells from the appropriate extracellular matrix (Chiarugi and Giannoni in Biochem Pharmacol 76:1352-1364, 2008). Resistance to anoikis is a critical mediator of metastasis in cancer by enabling cancer cells to survive during invasion and transport in the blood and lymph. Numerous regulators and mechanisms of anoikis in human cancer have been proposed to date. Consequently, the identification of key regulators of anoikis that can be targeted to at least partially restore anoikis sensitivity in cancer cells is important in the development of therapies to treat metastatic cancer. A literature search focusing on the regulators of anoikis in human cancer was performed on the Medline, Embase and Scopus databases. Mcl-1, Cav-1, Bcl-xL, cFLIP, 14-3-3ζ and Bit1 appear to regulate anoikis in human cancer by participating in the intrinsic apoptotic pathway, extrinsic apoptotic pathway or caspase-independent pathways. Mcl-1, Cav-1, Bcl-xL, cFLIP and 14-3-3ζ are suppressors of anoikis, and their upregulation confers anoikis resistance to cancer cells. Bit1 is a promoter of anoikis and is downregulated to confer anoikis resistance in metastatic cancer. Anoikis is a complex process involving the crosstalk between different signalling pathways. The dysregulated expression of key regulators of anoikis that participate in these signalling pathways promotes anoikis resistance in human cancer. These regulators of anoikis might therefore be the targets for developing therapies to overcome anoikis resistance in metastatic cancer. 23764399 Cell Cycle and Apoptosis Regulatory Protein (CARP)-1 is Expressed inOsteoblasts and Regulated by PTH. Bone mass is dependent on osteoblast proliferation, differentiation and life-span of osteoblasts. Parathyroid hormone (PTH) controls osteoblast cell cycle regulatory proteins and suppresses mature osteoblasts apoptosis. Intermittent administration of PTH increases bone mass but the mechanism of action are complex and incompletely understood. Cell Cycle and Apoptosis Regulatory Protein (CARP)-1 (aka CCAR1) is a novel transducer of signaling by diverse agents including cell growth and differentiation factors. To gain further insight into the molecular mechanism, we investigated involvement of CARP-1 in PTH signaling in osteoblasts. Immunostaining studies revealed presence of CARP-1 in osteoblasts and osteocytes, while a minimal to absent levels were noted in the chondrocytes of femora from 10 to 12-week old mice. Treatment of 7-day differentiated MC3T3-E1 clone-4 (MC-4) mouse osteoblastic cells and primary calvarial osteoblasts with PTH for 30min to 5h followed by Western blot analysis showed 2- to 3-fold down-regulation of CARP-1 protein expression in a dose- and time-dependent manner compared to the respective vehicle treated control cells. H-89, a Protein Kinase A (PKA) inhibitor, suppressed PTH action on CARP-1 protein expression indicating PKA-dependent mechanism. PMA, a Protein Kinase C (PKC) agonist, mimicked PTH action, and the PKC inhibitor, GF109203X, partially blocked PTH-dependent downregulation of CARP-1, implying involvement of PKC. U0126, a Mitogen-Activated Protein Kinase (MAPK) Kinase (MEK) inhibitor, failed to interfere with CARP-1 suppression by PTH. In contrast, SB203580, p38 inhibitor, attenuated PTH down-regulation of CARP-1 suggesting that PTH utilized an Extracellular Signal Regulated Kinase (ERK)-independent but p38 dependent pathway to regulate CARP-1 protein expression in osteoblasts. Immunofluorescence staining of differentiated osteoblasts further revealed nuclear to cytoplasmic translocation of CARP-1 protein following PTH treatment. Collectively, our studies identified CARP-1 for the first time in osteoblasts and suggest its potential role in PTH signaling and bone anabolic action. 22859661 Combined effects of treatment with vitamin C, vitamin E and selenium on the skin of diabetic rats. The aim of this study was to investigate the effects of vitamin C, vitamin E and selenium (Se) on the skin tissue of streptozotocin-induced diabetic rats. Swiss albino rats were divided into four groups: control, control + antioxidants, diabetic, diabetic + antioxidants groups. Diabetes was induced by intraperitoneal injection of 65 mg/kg streptozotocin. Vitamin C (250 mg/kg), vitamin E (250 mg/kg) and Se (0.2 mg/kg) were given by gavage technique to rats of one diabetic and one control group for 30 days. In the diabetic group, the levels of serum urea and creatinine, skin lipid peroxidation and nonenzymatic glycosylation levels increased, but skin glutathione levels decreased. Treatment with vitamin C, vitamin E and Se reversed these effects. The present study showed that vitamin C, vitamin E and Se exerted antioxidant effects and consequently may prevent skin damage caused by streptozotocin-induced diabetes. 22986338 Juvenile hormone levels reflect social opportunities in the facultatively eusocial sweat bee Megalopta genalis (Hymenoptera: Halictidae). The evolution of eusociality is hypothesized to have involved de-coupling parental care from reproduction mediated by changes in endocrine regulation. While data for obligately eusocial insects are consistent with this hypothesis, we lack information from species representative of the transition from solitary reproduction to eusociality. Here we report the first evidence for a link between endocrine processes and social behavior in a facultatively eusocial bee, Megalopta genalis (Halictidae). Using females that varied in social, reproductive, and ecological context, we measured juvenile hormone (JH), a major regulator of colony caste dynamics in other eusocial species. JH was low at adult emergence, but elevated after 10 days in all nesting females. Females reared in cages with ad lib nutrition, however, did not elevate JH levels after 10 days. All reproductive females had significantly more JH than all age-matched non-reproductive females, suggesting a gonadotropic function. Among females in established nests, JH was higher in queens than workers and solitary reproductives, suggesting a role for JH in social dominance. A lack of significant differences in JH between solitary reproductives and non-reproductive workers suggests that JH content reflects more than reproductive status. Our data support the hypothesis that endocrine modifications are involved in the evolutionary decoupling of reproductive and somatic effort in social insects. These are the first measurements of JH in a solitary-nesting hymenopteran, and the first to compare eusocial and solitary nesting individuals of the same species. 23947357 Myeloid-derived suppressor cells: the dark knight or the joker in viral infections? Myeloid derived suppressor cells (MDSCs) are immature cells of myeloid origin, frequently found in tumor microenvironments and in the blood of cancer patients. In recent years, MDSCs have also been found in non-cancer settings, including a number of viral infections. The evasion of host immunity employed by viruses to establish viral persistence strikingly parallels mechanisms of tumor escape, prompting investigations into the generation and function of MDSCs in chronic viral infections. Importantly, analogous to the tumor microenvironment, MDSCs effectively suppress antiviral host immunity by limiting the function of several immune cells including T cells, natural killer cells, and antigen-presenting cells. In this article, we review studies on the mechanisms of MDSC generation, accumulation, and survival in an effort to understand their emergent importance in viral infections. We include a growing list of viral infections in which MDSCs have been reported. Finally, we discuss how MDSCs might play a role in establishing chronic viral infections and identify potential therapeutics that target MDSCs. 23947881 Interfacial behavior of simple inorganic salts at the air-water interface investigated with a polarizable model with electrostatic damping. New molecular models that incorporated polarizable interactions with electrostatic damping were developed to better understand the interfacial properties of aqueous electrolyte systems. The models were parameterized to give free energies of aqueous solvation and the change in activity with respect to concentration in agreement with experiment. Specifically, we investigated NaCl, NaBr, and NaI systems, finding anion propensity for the air-water interface was reduced in comparison with previously developed polarizable models. This coincided with a more negative surface excess than that given by previously developed polarizable models. Furthermore, we investigated the interfacial properties of SrCl2 aqueous systems, finding that strontium had a moderate enhancement in interfacial density in comparison with bulk, while still having a fairly large negative surface excess, in agreement with experimental results. 23714711 Application of the video head impulse test to detect vertical semicircular canal dysfunction. The video head impulse test (vHIT) is a useful clinical tool to detect semicircular canal dysfunction. However, so far, vHIT has been limited to measurement of the function of the horizontal semicircular canals. The goal of this study was to determine if vHIT can detect vertical semicircular canal dysfunction. Horizontal and vertical eye movements were recorded in response to abrupt, passive, unpredictable head turns (head impulses) in the planes of the vertical semicircular canals by high-speed video (250-Hz sampling rate) together with measures of the head movement. Head impulses were delivered diagonally in the plane of the vertical semicircular canals, whereas gaze was directed along the same plane. Patients with known vestibular loss as shown by previous scleral search coil recording were tested to identify if the vHIT testing could detect the loss. The results of patients with unilateral, bilateral, and individual semicircular canal dysfunction were compared with the results of a healthy control subject. The patient with bilateral vestibular loss had no compensatory slow eye movements in any direction. The patient with unilateral vestibular loss showed reduced response for head impulses activating the canals in their affected right ear (right anterior, right posterior, and right horizontal head impulses). The patient with isolated canal loss showed reduced response for head impulses activating the affected right posterior canal. vHIT detects peripheral deficits of both vertical and horizontal semicircular canal function and is a new tool for measuring dysfunction of individual semicircular canals in vestibular patients. 23877710 Lower serum albumin level is associated with higher fractional excretion of creatinine. Creatinine clearance (Ccr) overestimates glomerular filtration rate (GFR) due to the tubular secretion of creatinine. It is known that fractional excretion of creatinine (FE-Cr) increases with decreasing GFR. Association of serum albumin level with the tubular secretion of creatinine was also reported previously. Alteration of FE-Cr may affect the performance of GFR estimating equations based on serum creatinine. Therefore, we analyzed the factors influencing FE-Cr and compared the performance of GFR equations in subjects stratified by serum albumin levels. Seven hundred and fifty-seven Japanese subjects were included. GFR was measured by inulin renal clearance. GFR and Ccr were measured simultaneously. FE-Cr was calculated as the ratio of Ccr to GFR. Multivariate analysis was performed to evaluate the factors influencing FE-Cr. Age, gender, GFR, body mass index (BMI), body weight, height and serum albumin level were analyzed as the parameters. Estimated GFR was calculated by Japanese GFR equations based on serum creatinine (Eq-cr), serum cystatin C (Eq-cys) and 5 variables including serum albumin (Eq-5var). FE-Cr in subjects with serum albumin <3.0, 3.0-3.9 and ≥4.0 g/dl were 1.63 ± 0.48, 1.53 ± 0.55, and 1.40 ± 0.36, respectively. FE-Cr in subjects with serum albumin <3.0 or 3.0-3.9 g/dl were significantly higher than the value in subjects with serum albumin ≥4.0 g/dl. Multivariate analysis showed that GFR (p < 0.0001) and serum albumin level (p = 0.004) were independent parameters affecting FE-Cr. Biases of Eq-cr, Eq-cys and Eq-5var in subjects with serum albumin <3.0 g/dl were -9.5 ± 17.5, -0.7 ± 17.1 and -0.6 ± 14.8 ml/min/1.73 m(2), respectively. Eq-cr significantly overestimated GFR compared with Eq-cys or Eq-5var. Biases in subjects with serum albumin ≥4.0 g/dl were 6.4 ± 18.8, 2.0 ± 18.1 and 3.0 ± 18.3 ml/min/1.73 m(2), respectively. Eq-cr significantly underestimated GFR compared with Eq-cys or Eq-5var. GFR and serum albumin level were independent parameters affecting FE-Cr. Alteration of FE-Cr according to the serum albumin levels may be one of the reasons of the bias of GFR equation based on serum creatinine. 23849983 The importance of the pose in three-dimensional imaging of the ptotic breast. 3D imaging of the breast has recently emerged as a new method for objective breast assessment. However in the ptotic breast shape, which is seen in the majority of cases, the sub-mammary fold remains obscured when the breast is captured in an upright body posture. A self-designed positioning frame for 3D breast capture was utilized as a safe positioning aide. Six volunteers stood on an adjustable standing step, leaning with the hips against a soft-coated hip roll while stretching forward with the upper body extending to a nearly horizontal position and reaching with the arms forward resting on arm pads. 3D breast capture was conducted simultaneously with eight digital cameras that were positioned to capture the right, left, anterior and inferior views of the breast. Capture was repeated three times at different time intervals. The reproducibility of the pose, captures and 3D measurements were investigated. The custom-made positioning frame allowed the complete capture of the breast, even in the ptotic shapes. The investigation of the reproducibility revealed a 6.25% standard deviation of the pose; this being the variable with the smallest variation compared with the variations obtained for reproducibility of captures and 3D measurements. The difference between the first and second pose was not significant at 95% CI (-77.3; 11.9), p = 0.119. The presented system used a self-designed positioning frame, by which the complete capture of the ptotic breast in near horizontal upper body posture was achieved. Reproducibility of the pose for 3D capture was satisfactory. 23153635 Implementing a Virtual Exchange Project for student nurses in Queensland and Nottingham. This paper discusses the design and initial progress made with a virtual learning environment to help student nurses develop an understanding of cultural awareness and globalization. Using a Web-based application the Virtual Exchange Project was designed to facilitate study-elsewhere experiences located in the student's own setting. Promotion of the United Nations' Millennium Development goals provided an opportunity for student nurses to explore changes in global health and disease patterns, nursing education and systems of nurse regulation in the United Kingdom and Australia. A pedagogical framework created for this activity acknowledges the social and academic identities that learners often use, when working together in a virtual environment. The architecture of the Virtual Exchange supports local conversations about nurse education and health and social issues across hemispheres. 23966797 Procalcitonin as a useful marker to decide upon intervention for urinary tract infection. Because the use of procalcitonin has been advocated as a marker of bacterial infection, this study was carried out to determine the usefulness of serum PCT as an early marker to decide upon intervention for urinary tract infection. The subjects were 68 patients with urinary tract infection (UTI) in whom we measured serum procalcitonin concentration at the start of treatment. There were 47 patients with nonobstructed UTI and 21 with obstructed UTI. All patients with obstructed UTI were subjected to intervention. There were significant differences in procalcitonin, white blood cells, and creatinine levels between patients with nonobstructed and obstructed UTI (P < 0.05). Although this retrospective study comprised a small number of patients, we found that procalcitonin was a useful marker to decide upon urinary intervention. 23900885 Downregulation of miR-181b in mouse brain following ischemic stroke induces neuroprotection against ischemic injury through targeting heat shock protein A5 and ubiquitin carboxyl-terminal hydrolase isozyme L1. Understanding the molecular mechanism of cerebral hypoxic preconditioning (HPC)-induced endogenous neuroprotection may provide potential therapeutic targets for ischemic stroke. By using bioinformatics analysis, we found that miR-181b, one of 19 differentially expressed miRNAs, may target aconitate hydratase (ACO2), heat shock protein A5 (HSPA5), and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) among 26 changed protein kinase C isoform-specific interacting proteins in HPC mouse brain. In this study, the role of miR-181b in oxygen-glucose deprivation (OGD)-induced N2A cell ischemic injury in vitro and mouse middle cerebral artery occlusion (MCAO)-induced cerebral ischemic injury in vivo, and its regulation of ACO2, HSPA5, and UCHL1 were further determined. We found that miR-181b expression levels significantly decreased in mouse brain following MCAO and in OGD-treated N2A cells. Up- and downregulation of miR-181b by transfection of pre- or anti-miR-181b could negatively regulate HSPA5 and UCHL1 (but not ACO2) protein levels as well as N2A cell death and programmed cell death in OGD-treated N2A cells. By using a T7 promoter-driven control dual luciferase assay, we confirmed that miR-181b could bind to the 3'-untranslated rergions of HSPA5 and UCHL1 mRNAs and repress their translations. miR-181b antagomir reduced caspase-3 cleavage and neural cell loss in cerebral ischemic cortex and improved neurological deficit of mice after MCAO. In addition, HSPA5 and UCHL1 short interfering RNAs (siRNAs) blocked anti-miR-181b-mediated neuroprotection against OGD-induced N2A cell injury in vitro. These results suggest that the downregulated miR-181b induces neuroprotection against ischemic injury through negatively regulating HSPA5 and UCHL1 protein levels, providing a potential therapeutic target for ischemic stroke. © 2013 Wiley Periodicals, Inc. 23958215 Advances in skin cancer early detection and diagnosis. To provide an overview of 1) traditional methods of skin cancer early detection, 2) current technologies for skin cancer detection, and 3) evolving practice models of early detection. Peer-reviewed databased articles and reviews, scholarly texts, and Web-based resources. Early detection of skin cancer through established methods or newer technologies is critical for reducing both skin cancer mortality and the overall skin cancer burden. A basic knowledge of recommended skin examination guidelines and risk factors for skin cancer, traditional methods to further examine lesions that are suspicious for skin cancer and evolving detection technologies can guide patient education and skin inspection decisions. 23721798 Novel aspects of understanding molecular working mechanisms of salivary glands of worker honeybees (Apis mellifera) investigated by proteomics and phosphoproteomics. Honeybee salivary glands (SGs) are important exocrine glands. However, the molecular basis of how SGs fulfill their biological duty is still elusive. Proteomics and phosphoproteomics of cephalic SG (HSG) and thoracic SG (TSG) were compared between normal and single-cohort honeybee colonies. Of 113 and 64 differentially regulated proteins and phosphoproteins, 86 and 33 were identified, respectively. The SGs require a wide spectrum of proteins to support their multifaceted functions and ensure normal social management of the colony. Changes of protein expression and phosphoproteins are key role players. The HSG triggers labor transition from in-hive work to foraging activities via the regulation of juvenile hormone and ethyl oleate levels. The stronger expression of proteins involved in carbohydrate and energy metabolism, protein folding, protein metabolism, cellular homeostasis and cytoskeleton in TSG, supports the gland to efficiently enhance honey processing by synthesis and secretion of saliva into nectar. The age structure of the colony is vital for increased production efficiency. This data reveals the molecular underpinning of SGs to accomplish their biological missions and provides new knowledge for the beekeeping industry for enhancing the management and production efficiency of the colony and honey quality through manipulation of potential target proteins. This study comprehensively analyses the characteristic of the proteome and phosphoproteome of honeybee salivary glands (SGs) between normal and single-cohort honeybee colonies. The SGs need a wide spectrum of proteins to support their multifaceted functions and ensure normal social management of the colony. The cephalic SG triggers labor transition from in-hive work to foraging behavior via the regulation of juvenile hormone and ethyl oleate titer. The thoracic SG stronger expressed of proteins related to carbohydrate and energy metabolism, protein folding, protein metabolism, cellular homeostasis and cytoskeleton to support the gland to efficiently enhance honey processing by synthesis and secretion of saliva into nectar. This data reveals the molecular underpinning of SGs to accomplish their biological missions and provides new knowledge for the beekeeping industry for enhancing the maintenance and production efficiency of the colony and honey quality through manipulation of potential target proteins. 23698116 Chronic effects of dietary vitamin D deficiency without increased calcium supplementation on the progression of experimental polycystic kidney disease. Increasing evidence indicates that vitamin D deficiency exacerbates chronic kidney injury, but its effects on renal enlargement in polycystic kidney disease (PKD) are not known. In this study, male Lewis polycystic kidney disease (LPK) rats received a normal diet (ND; AIN-93G) supplemented with or without cholecalciferol (vitamin D-deficient diet, VDD; both 0.5% calcium), commenced at either postnatal week 3 (until weeks 10-20; study 1) or from week 10 (until week 20; study 2). Levels of 25-hydroxy vitamin D were reduced in groups receiving the VDD (12 ± 1 nmol/l vs. 116 ± 5 in ND; P < 0.001). In study 1, food intake and weight gain increased by ∼25% in LPK rats receiving the VDD ad libitum, and at week 20 this was associated with a mild reduction in the corrected serum calcium (SCa(2+), 7.4%) and TKW:BW ratio (8.8%), and exacerbation of proteinuria (87%) and hypertension (19%; all P < 0.05 vs. ND). When LPK rats were pair-fed for weeks 3-10, there was a further reduction in the SCa(2+) (25%) and TKW:BW ratio (22%) in the VDD group (P < 0.05 vs. ND). In study 2, the VDD did not alter food intake and body weight, reduced SCa(2+) (7.7%), worsened proteinuria (41.9%), interstitial monocyte accumulation (26.4%), renal dysfunction (21.4%), and cardiac enlargement (13.2%, all P < 0.05), but there was a trend for a reduction in the TKW:BW ratio (13%, P = 0.09). These data suggest that chronic vitamin D deficiency has adverse long-term actions on proteinuria, interstitial inflammation, renal function, and cardiovascular disease in PKD, and these negate its mild inhibitory effect on kidney enlargement. 23146756 Toxicity of the synthetic polymeric 3-alkylpyridinium salt (APS3) is due to specific block of nicotinic acetylcholine receptors. The in vivo and in vitro toxic effects of the synthetic polymeric 3-alkylpyridinium salt (APS3), from the Mediterranean marine sponge Reniera sarai, were evaluated on mammals, with emphasis to determine its mode of action. The median lethal doses of APS3 were 7.25 and higher that 20mg/kg in mouse and rat, respectively. Intravenous administration of 7.25 and 20mg/kg APS3 to rat caused a significant fall followed by an increase in mean arterial blood pressure accompanied by tachycardia. In addition, cumulative doses of APS3 (up to 60 mg/kg) inhibited rat nerve-evoked skeletal muscle contraction in vivo, with a median inhibitory dose (ID(50)) of 37.25mg/kg. When administrated locally by intramuscular injection to mouse, APS3 decreased the compound muscle action potential recorded in response to in vivo nerve stimulation, with an ID(50) of 0.5mg/kg. In vitro experiments confirmed the inhibitory effect of APS3 on mouse hemidiaphragm nerve-evoked muscle contraction with a median inhibitory concentration (IC(50)) of 20.3 μM, without affecting directly elicited muscle contraction. The compound inhibited also miniature endplate potentials and nerve-evoked endplate potentials with an IC(50) of 7.28 μM in mouse hemidiaphragm. Finally, APS3 efficiently blocked acetylcholine-activated membrane inward currents flowing through Torpedo nicotinic acetylcholine receptors (nAChRs) incorporated to Xenopus oocytes, with an IC(50) of 0.19 μM. In conclusion, our results strongly suggest that APS3 blocks muscle-type nAChRs, and show for the first time that in vivo toxicity of APS3 is likely to occur through an antagonist action of the compound on these receptors. 23474485 Histidine augments the suppression of hepatic glucose production by central insulin action. Glucose intolerance in type 2 diabetes is related to enhanced hepatic glucose production (HGP) due to the increased expression of hepatic gluconeogenic enzymes. Previously, we revealed that hepatic STAT3 decreases the expression of hepatic gluconeogenic enzymes and suppresses HGP. Here, we show that increased plasma histidine results in hepatic STAT3 activation. Intravenous and intracerebroventricular (ICV) administration of histidine-activated hepatic STAT3 reduced G6Pase protein and mRNA levels and augmented HGP suppression by insulin. This suppression of hepatic gluconeogenesis by histidine was abolished by hepatic STAT3 deficiency or hepatic Kupffer cell depletion. Inhibition of HGP by histidine was also blocked by ICV administration of a histamine H1 receptor antagonist. Therefore, histidine activates hepatic STAT3 and suppresses HGP via central histamine action. Hepatic STAT3 phosphorylation after histidine ICV administration was attenuated in histamine H1 receptor knockout (Hrh1KO) mice but not in neuron-specific insulin receptor knockout (NIRKO) mice. Conversely, hepatic STAT3 phosphorylation after insulin ICV administration was attenuated in NIRKO but not in Hrh1KO mice. These findings suggest that central histidine action is independent of central insulin action, while both have additive effects on HGP suppression. Our results indicate that central histidine/histamine-mediated suppression of HGP is a potential target for the treatment of type 2 diabetes. 23613208 In vitro effects of pollutants from particulate and volatile fractions of air samples-day and night variability. Chemicals in air were characterized for potential interference with signaling of estrogen, androgen, and arylhydrocarbon (AhR) receptors, which are known to play an important role in endocrine-disruptive changes in vivo. Previously, effects of this type have been studied mainly in particulate matter in the ambient air from various localities. In this study, both volatile and particulate fractions of air from three sites in Banja Luka region (Bosnia and Herzegovina) were investigated to describe the distribution of endocrine-disrupting contaminants on a small spatial scale. Circadian variability of air pollution was investigated by collecting samples during both day and night. Air samples collected from urban localities at night were more potent in producing the AhR-mediated effects than those collected during daytime. This trend was not observed at the reference rural location. None of the samples showed significant estrogenic or androgenic activity. On the other hand, anti-androgenicity was detected in both particulate and vapor phases, while anti-estrogenicity was detected only in the particulate fraction of air from all localities. The AhR-mediated potencies of samples were associated primarily with non-persistent compounds. Based on the concentrations of 28 individual compounds, PAHs accounted for approximately 30 % of the AhR-mediated potency determined by the bioassay. The results show that there can be a significant difference between levels of bioactive compounds in air between daytime and nighttime. 23930675 Effects of polymorphisms in ABCG2, SLCO1B1, SLC10A1 and CYP2C9/19 on plasma concentrations of rosuvastatin and lipid response in Chinese patients. Aim: This study examined whether the ABCG2 421C>A polymorphism and variants in other genes potentially related to the pharmacokinetics of rosuvastatin influenced the plasma concentration of rosuvastatin in Chinese patients with hypercholesterolemia. Patients & methods: Overnight fasting blood samples were collected from 291 patients who had received a rosuvastatin 10 mg night-time dose for at least 4 weeks. Plasma concentrations of rosuvastatin and N-desmethyl rosuvastatin were quantified using liquid chromatography tandem mass spectrometry. Results: In subjects with the ABCG2 421AA genotype (n = 39), the mean plasma concentrations of rosuvastatin and its metabolite were 63 and 41% greater than the values in those with the 421CA genotype (n = 108) and 120 and 99% greater than in those with the 421CC genotype (n = 129). The plasma concentrations of rosuvastatin were associated (r = -0.194; p = 0.001) with the percentage reduction in low-density lipoprotein cholesterol with rosuvastatin, but the association was not significant after adjusting for the ABCG2 421C>A polymorphism. The SLCO1B1 521T>C polymorphism was associated with increased plasma concentrations of rosuvastatin and impaired N-demethylation of rosuvastatin, but had no impact on its lipid-lowering effect. Polymorphisms in CYP2C9, CYP2C19 and SLC10A1 had minimal effects. Conclusion: These findings suggest that the increased plasma concentrations of rosuvastatin in Chinese patients are associated with increased lipid-lowering effects and lower doses of rosuvastatin should be effective in subjects with the ABCG2 421C>A variant. Original submitted 18 April 2013; Revision submitted 17 June 2013. 23836142 Determining the subcellular location of new proteins from microscope images using local features. Evaluation of previous systems for automated determination of subcellular location from microscope images has been done using datasets in which each location class consisted of multiple images of the same representative protein. Here, we frame a more challenging and useful problem where previously unseen proteins are to be classified. Using CD-tagging, we generated two new image datasets for evaluation of this problem, which contain several different proteins for each location class. Evaluation of previous methods on these new datasets showed that it is much harder to train a classifier that generalizes across different proteins than one that simply recognizes a protein it was trained on. We therefore developed and evaluated additional approaches, incorporating novel modifications of local features techniques. These extended the notion of local features to exploit both the protein image and any reference markers that were imaged in parallel. With these, we obtained a large accuracy improvement in our new datasets over existing methods. Additionally, these features help achieve classification improvements for other previously studied datasets. The datasets are available for download at http://murphylab.web.cmu.edu/data/. The software was written in Python and C++ and is available under an open-source license at http://murphylab.web.cmu.edu/software/. The code is split into a library, which can be easily reused for other data and a small driver script for reproducing all results presented here. A step-by-step tutorial on applying the methods to new datasets is also available at that address. murphy@cmu.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. 23727404 The selective μ opioid receptor antagonist β-funaltrexamine attenuates methamphetamine-induced stereotypical biting in mice. We investigated whether pretreatment with opioid receptor antagonists affected methamphetamine (METH)-induced stereotypy in mice. Pretreatment of male ICR mice with naloxone, a relatively non-selective opioid receptor antagonist, significantly attenuated the total incidence of METH-induced stereotypical behavior compared with saline vehicle-pretreated subjects. Furthermore, the distribution of METH-induced stereotypical behavior was affected by naloxone administration. Thus, METH-induced stereotypical sniffing and persistent locomotion were significantly increased by naloxone treatment while stereotypical biting was reduced. One way to interpret this pattern of effects is that pretreatment with naloxone appeared to produce a shift in the dose-response curve for METH. Thus, while the more intense forms of oral-facial stereotypies were reduced, increased persistent locomotion was observed in mice given naloxone followed by METH. The selective μ opioid receptor antagonist β-funaltrexamine, but not nor-binaltorphimine (a κ-selective antagonist) nor naltrindole (a δ-selective antagonist), mimicked the effect of naloxone. These observations suggest that opioid receptor antagonists may attenuate METH-induced stereotypical biting in mice via μ opioid receptors, and suggest that antagonism of this system may be a potential therapeutic approach to reducing some deleterious effects of METH use and perhaps in the treatment of some forms of self-injurious behavior. 23933586 Inhibition of Src activation with cardiotoxin III blocks migration and invasion of MDA-MB-231 cells. Cardiotoxin III (CTX III), a basic polypeptide isolated from Naja naja atra venom, has been demonstrated to display anticancer activity. Breast cancer is a highly malignant carcinoma and most deaths of breast cancer are caused by metastasis. In this study, we show that CTX III blocks migration and invasion of MDA-MB-231 breast cancer cells without affecting apoptosis or cell cycle arrest. CTX III caused significant block of Src kinase activity in MDA-MB-231 cells. Moreover, CTX III treatment was correlated with reduced phosphorylation of FAK at Tyr576, 861 and 925 sites, p130(Cas) at Tyr410, and paxillin at Tyr118. CTX III also suppressed the activation of extracellular signal-regulated kinase1/2 and phosphatidylinositol 3-kinase/Akt. Consistent with inhibition of these signaling pathways and invasion, CTX III inhibited the expression of matrix metalloproteinase-9. In addition, Src specific inhibitor PP2 caused a significant decrease in the phosphorylation of FAK, p130(Cas), paxillin, PI3K/Akt, and ERK1/2. Taken together, CTX III significantly inhibited phosphorylation of Src and downstream molecules as well as cell migration and invasion. Our findings provide evidences that CTX III inhibits Src-mediated signaling pathways involved in controlling MDA-MB-231 cell migration and invasion, suggesting that it has therapeutic potential in breast cancer treatment. 23406025 In vitro polyphenolics erythrocyte model and in vivo chicken embryo model revealed gallic acid to be a potential hemorrhage inducer: physicochemical action mechanisms. The in vivo chicken embryo model (CEM) demonstrated that gallic acid (GA) induced dysvascularization and hypoxia. Inflammatory edema, Zenker's necrosis, hemolysis, and liposis of cervical muscles were the common symptoms. Levels of the gene hif-1α, HIF-1α, TNF-α, IL-6, and NFκB in cervical muscles were all significantly upregulated, while the vascular endothelial growth factor (VEGF) was downregulated in a dose-responsive manner. Consequently, the cervical muscle inflammation and hemolysis could have been stimulated en route to the tissue TNF-α-canonical and the atypical pathways. We hypothesized that GA could deplete the dissolved oxygen (DO) at the expense of semiquinone and quinone formation, favoring the reactive oxygen species (ROS) production to induce RBC disruption and Fe(2+) ion release. To explore this, the in vitro polyphenolics-erythrocyte model (PEM) was established. PEM revealed that the DO was rapidly depleted, leading to the release of a huge amount of Fe (II) ions and hydrogen peroxide (HPO) in a two-phase kinetic pattern. The kinetic coefficients for Fe (II) ion release ranged from 0.347 h(-1) to 0.774 h(-1); and those for Fe (III) ion production were from 6.66 × 10(-3) h(-1) to 8.93 × 10(-3) h(-1). For phase I HPO production, they ranged from 0.236 h(-1) to 0.774 h(-1) and for phase II HPO production from 0.764 h(-1) to 2.560 h(-1) at GA within 6 μM to 14 μM. Thus, evidence obtained from PEM could strongly support the phenomena of CEM. To conclude, GA tends to elicit hypoxia-related inflammation and hemolysis in chicken cervical muscles through its extremely high prooxidant activity. 23883683 Pupillary reflex measurement predict insufficient analgesia before endotracheal suctioning in critically ill patients. This study aimed to evaluate the pupillary dilatation reflex (PDR) during a tetanic stimulation to predict insufficient analgesia before nociceptive stimulations in intensive care unit (ICU). In this prospective non-interventional study in a surgical ICU of a university hospital, PDR was assessed during a tetanic stimulation (10, 20 or 40 mA) immediately before 40 endotracheal suctions (ES) in 34 deeply sedated patients. An insufficient analgesia during ES was defined by an increase >= 1 point on the Behavioral Pain Scale (BPS). 27 (68%) patients had insufficient analgesia. PDR with 10 mA, 20 mA and 40 mA were higher in patients with insufficient analgesia (P< 0.01). The threshold values of the pupil diameter variation during a 10, 20 and 40 mAtetanic stimulation to predict an insufficient analgesia during an ES were 1, 5 and 13% respectively. The areas (95% [confidence interval] CI) under the receiver-operating curve were 0.70 (0.54 - 0.85), 0.78 (0.61 - 0.91) and 0.85 (0.721 - 0.954) with 10, 20 and 40 mAtetanic stimulations respectively. A sensitivity analysis using the Richmond Agitation Sedation Scale (RASS) confirmed the results. The 40 mA stimulation was poorly tolerated. In deeply sedated mechanically ventilated patients, a pupil diameter variation >= 5% during a 20 mAtetanic stimulation was highly predictable of insufficient analgesia during ES. A 40 mAtetanic stimulation is painful and should not be used. 23339884 Sonochemical effects on free phenolic acids under ultrasound treatment in a model system. Sonochemical effects on seven free phenolic acids under ultrasound treatment in a model system have been investigated. The degradation products have also been tentatively identified by FTIR and HPLC-UV-ESIMS. Five phenolic acids (protocatechuic acid, p-hydroxybenzoic acid, vanillic acid, p-coumaric acid, and ferulic acid) proved to be stable, while two others (caffeic acid and sinapic acid) were degraded under ultrasound treatment. The nature of the solvent and the temperature has been identified as important factors in determining the degradation reaction. Liquid height, ultrasonic intensity, and duty cycle of the ultrasound exposure affected only the degradation rate and did not change the nature of the degradation. The degradation rates of caffeic acid and sinapic acid decreased with increasing temperature. The degradation kinetics of these two acids under ultrasound conformed to zeroth-order reactions at -5 to 25 °C. Both decomposition and polymerization reactions occurred when caffeic acid and sinapic acid were subjected to ultrasound. Degradation products, such as the corresponding decarboxylation products and their dimers, have been tentatively identified. 23908576 Caruncular abscess due to actinomycosis. The authors report a caruncular abscess caused by actinomycosis. A 47-year-old woman was admitted with persistent purulent discharge from the caruncle of the left eye for a duration of six months. Excisional drainage was performed, and 'sulfur granules' were observed, consistent with actinomyces infection. Intraoperative lacrimal probing and irrigation were performed to confirm that the abscess and canaliculus were not connected. Oral and topical antibiotics were administered postoperatively; the lesion resolved with no evidence of recurrence, and the symptom improved. 23707917 2,5,6-Trisubstituted imidazo[2,1-b][1,3,4]thiadiazoles: Search for antihyperlipidemic agents. A novel series of 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]thiadiazoles 4(a-d) and 7(a-i) were rationally designed through QSAR based pharmacophore approach and synthesized from 5-(1,3-benzodioxol-5-yl)-[1,3,4]thiadiazol-2-amine (1). The structures of these compounds were established by IR, (1)H NMR, (13)C NMR, HRMS technique. All the compounds were evaluated for their in vitro antihyperlipidemic activity using trition induced hyperlipidemic model. The newly synthesized title compound 7d, 7e and 7h showed a significant decrease in the serum, TCH, TG LDL and VLDL values along with an increase in serum HDL levels as compared to standard drug Fenofibrate. The treated groups also showed significant decrease in the atherogenic index, LDL:HDL risk ratios and the level of SGOT, SGPT and ALP activities compared to cholesterol induced hyperlipidemic control group. 23812606 Intravital multiphoton microscopy can model uptake and excretion of fluorescein in hepatic ischemia-reperfusion injury. The liver is important in the biotransformation of various drugs, where hepatic transporters facilitate uptake and excretion. Ischemia-reperfusion (I/R) injury is a common occurrence in liver surgery, and the developing oxidative stress can lead to graft failure. We used intravital multiphoton tomography, with fluorescence lifetime imaging, to characterize metabolic damage associated with hepatic I/R injury and to model the distribution of fluorescein as a measure of liver function. In addition to measuring a significant increase in serum alanine transaminase levels, characteristic of hepatic I/R injury, a decrease in the averaged weighted lifetime of reduced nicotinamide adenine dinucleotide phosphate was observed, which can be attributed to a changed metabolic redox state of the hepatocytes. I/R injury was associated with delayed uptake and excretion of fluorescein and elevated area-under-the-curve within the hepatocytes compared to sham (i.e., untreated control) as visualized and modeled using images recorded by intravital multiphoton tomography. High-performance liquid chromatography analysis showed no differences in plasma or bile concentrations of fluorescein. Finally, altered fluorescein distribution was associated with acute changes in the expression of liver transport proteins. In summary, multiphoton intravital imaging is an effective approach to measure liver function and is more sensitive in contrasting the impact of I/R injury than measuring plasma and bile concentrations of fluorescein. 23893844 Diagnostic Accuracy and Cost-Effectiveness of a Pocket-Sized Transthoracic Echocardiographic Imaging Device. The recently introduced pocket-sized portable transthoracic echocardiography (pTTE) is accurate for measurement of cardiac chamber size and function as well as for assessment of valvular regurgitation. This study aimed to compare the diagnostic accuracy of the pocket-sized pTTE with the standard TTE (sTTE) and assess its cost-effectiveness. The use of pocket-sized pTTE, as an initial screening tool, may be feasible, accurate and cost-effective in the diagnostic strategy of cardiac abnormalities. The study subjects were 200 patients scheduled for sTTE and an electrocardiogram (ECG). Each patient underwent pTTE examination with the Vscan (GE Medical Systems, Milwaukee, WI) immediately after sTTE. The findings of pTTE and the ECG were compared with the results of sTTE. Cost-effectiveness was calculated. There was a strong agreement in the detection of abnormal findings between pTTE and sTTE (agreement = 90%), whereas the agreement between the ECG and sTTE was 65%. When pTTE or the ECG was used as an initial screening tool prior to sTTE, similar cost reduction was obtained (approximately 30%) by reducing the number of referrals for sTTE. However, the negative predictive value of a diagnostic strategy with pTTE (92%) was superior to that with an ECG (67%). This study demonstrates that the pocket-sized pTTE provides accurate detection of cardiac structural and functional abnormalities beyond the ECG. In addition, the use of pTTE as an initial screening tool prior to sTTE is cost-effective, suggesting that the pocket-sized pTTE is poised to alter the current diagnostic strategy in clinical practice. 23411298 Cyto-genotoxic and oxidative effects of a continuous UV-C treatment of liquid egg products. UV-C treatment of food is a promising non-thermal processing technology to improve food safety and preservation. Most of the chemical constituents of food absorb UV-C light that can lead to chemical modifications and quality changes. This work investigated the effects of UV-C treatment of liquid egg products on lipid, protein oxidations and potential cyto- and genotoxic effects on intestinal epithelial cells in vitro. Egg preparations (egg white, yolk, liquid whole egg) were treated with UV-C (254 nm, volumetric doses between 0 and 115,619 J L(-1)) using a commercial UV-C processing unit equipped with a Dean Flow reactor. UV-C treatment at high doses (from 32,181 J L(-1), about 2 times higher than that needed to inactivate 5 log of relevant microorganisms) showed an increased lipid oxidation in egg yolk and slight effects in liquid whole eggs; this was confirmed by slightly but not statistically significant increased peroxide values. UV-C induced also slight protein damage, characterised by the total sulfhydryl group reduction. These UV-C-induced oxidative modifications in egg preparations however did not cause any increase in the cyto- or genotoxic (DNA strand breaks) effects in intestinal Caco-2 cells. 23818422 Nitroxyl radicals for studying electron transfer. Electron-transfer (ET) rates are measured by use of time-resolved EPR spectroscopy, involving photooxidation of nitroxyl radicals by a ruthenium bipyridyl complex. This permits acquisition of the fundamental characteristics of ET in solution. The method was used on two spin-labeled derivatives of bacteriorhodopsin, and is applicable to proteins, nucleic acids, and biological membranes. 23907493 Multiple Resistance Mechanisms Acting in Unison in an Escherichia coli Clinical Isolate. The emergence of multiple-resistant isolates poses a serious problem in the hospital environment making it important to evaluate the responsible factors. This work ascertains the mechanisms responsible for the development of resistance in enterobacterial clinical isolates. The major resistance mechanisms have been explored. The presence of target mutations, drug hydrolyzing enzymes, active efflux pump, and drug-resistance genes were elucidated experimentally employing standard methods. One of the clinical isolates was resistant to five classes of structurally unrelated antibiotics and showed involvement of multiple resistance mechanisms. Here, we report the simultaneous presence of multiple drug-resistance mechanisms in an Escherichia coli clinical isolate. 23960171 Seroprevalence study of Equine rhinitis B virus (ERBV) in Australian weanling horses using serotype-specific ERBV enzyme-linked immunosorbent assays. Respiratory infections are a major burden in the performance horse industry. Equine rhinitis B virus (ERBV) has been isolated from horses displaying clinical respiratory disease, and ERBV-neutralizing antibodies have been detected in 50-80% of horses in reported surveys. Current ERBV isolation and detection methods may underestimate the number of ERBV-positive animals and do not identify multiple serotype infections. The aim of the current study was to develop a serotyping ERBV antibody-detection enzyme-linked immunosorbent assay (ELISA) and examine the seroprevalence of ERBV in a group of Australian weanling horses. ELISAs with high sensitivity and specificity were developed. The seroprevalence of ERBV in the weanling horses was high (74-86%); ERBV-3 antibodies were most prevalent (58-62%) and ERBV-2 antibodies were least prevalent (10-16%). Many horses were seropositive to 2 or more serotypes. All 3 serotypes of ERBV were detected, and concurrent positivity to multiple serotypes was common. 23834234 Single-agent lenalidomide is active in patients with relapsed or refractory aggressive non-Hodgkin lymphoma who received prior stem cell transplantation. Patients with aggressive non-Hodgkin lymphoma (NHL) who relapse after autologous stem cell transplantation (ASCT) have a poor prognosis. Additional therapy is often poorly tolerated, and new treatment modalities are needed. This efficacy and safety study was a retrospective analysis of two phase II trials (NHL-002 and NHL-003) that studied single-agent lenalidomide in patients with relapsed/refractory aggressive NHL with prior (n = 87) compared with no prior ASCT (n = 179). The overall response rate in the ASCT group was 39% [14% complete response (CR)], including 29% in patients with diffuse large B-cell lymphoma, 63% in mantle cell lymphoma, and 60% in transformed lymphoma. The timing of transplant relative to receiving lenalidomide had no effect on outcomes. Median progression-free survival for the ASCT group was 3·7 months (16·9 months for patients in CR; 7·3 months for partial responders) at a median 12·5-month follow-up. Median response duration was 7·9 months. Regardless of prior ASCT, lenalidomide monotherapy was efficacious in heavily pretreated patients with aggressive, relapsed/refractory NHL, with a safety profile that was consistent with prior studies of single-agent lenalidomide. 23861862 Differences in aqueous concentrations of cytokines in macular edema secondary to branch and central retinal vein occlusion. This study investigates the differential aqueous concentrations of interleukin 6, 8, 1β (IL-6, IL-8, IL-1β, respectively), serum amyloid A (SAA), transforming growth factor (TGF)-β, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) in eyes with macular edema as a result of a branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). Significantly higher concentrations of IL-6, IL-8, IL-1β, TGF-β, bFGF, SAA, and VEGF were found in the aqueous humor of CRVO and BRVO patients than in the aqueous humor of control patients. A significant correlation was observed between the concentration of bFGF and the inner central macular thickness (CMT) of BRVO patients (r = 0.688; P = 0.02). A significant correlation was observed between the concentration of SAA and both the full and outer CMT of the ischemic group (r = 0.545 and 0.683, respectively; P = 0.04 and 0.01, respectively). In the non-ischemic group, the level of IL-6 was significantly associated with inner CMT (r = 0.560; P = 0.03). The full and outer CMT was significantly reduced in CRVO patients when compared with BRVO patients (P = 0.02 and 0.02, respectively) after injection of intravitreal bevacizumab (IVB) at 4 weeks. Serum amyloid A as a major protein involved in the acute and chronic stages of inflammation, and IL-6 and bFGF were significantly associated with the extent of macular edema in patients with RVO. Besides VEGF, other inflammatory cytokines and angiogenesic factors may be associated with RVO. This finding may have implications for the medical treatment of RVO. 23890057 A comparison of the reparative and angiogenic properties of mesenchymal stem cells derived from the bone marrow of BALB/c and C57/BL6 mice in a model of limb ischemia. BALB/c mice and C57/BL6 mice have different abilities to recover from ischemia. C57/BL6 mice display increased vessel collateralization and vascular endothelial growth factor expression with a consequent rapid recovery from ischemia compared with BALB/c mice. Mesenchymal stem cells (MSCs) are one of the main cell types that contribute to the recovery from ischemia because, among their biological activities, they produce several proangiogenic paracrine factors and differentiate into endothelial cells. The objective of this study was to evaluate whether the MSCs of these two mouse strains have different inductive capacities for recovering ischemic limbs. MSCs from these two strains were obtained from the bone marrow, purified and characterized before being used for in vivo experiments. Limb ischemia was surgically induced in BALB/c mice, and MSCs were injected on the fifth day. The evolution of limb necrosis was evaluated over the subsequent month. Muscle strength was assessed on the 30th day after the injection, and then the animals were sacrificed to determine the muscle mass and perform histological analyses to detect cellular infiltration, capillary and microvessel densities, fibrosis, necrosis and tissue regeneration. The MSCs from both strains promoted high level of angiogenesis similarly, resulting in good recovery from ischemia. However, BALB/c MSCs promoted more muscle regeneration (57%) than C57/BL6 MSCs (44%), which was reflected in the increased muscle strength (0.79 N versus 0.45 N). The different genetic background of MSCs from BALB/c mice and C57/BL6 mice was not a relevant factor in promoting angiogenesis of limb ischemia, because both cells showed a similar angiogenic activity. These cells also showed a potential myogenic effect, but the stronger effect promoted by BALB/c MSCs indicates that the different genetic background of MSCs was more relevant in myogenesis than angiogesis. 23479280 Theoretical study of the thermodynamic and burning properties of oxygen-rich hydrazine derivatives-green and powerful oxidants for energetic materials. A series of no-chlorine and oxygen-rich hydrazine derivatives (hydrazine modified with -NO2 and NO3 (-) groups) was designed and optimized to obtain molecular geometries and electronic structures at density functional theory-B3PW91/6-311++G(3df,3pd) level. Some important properties such as bond dissociation enthalpy, density, natural bond orbitals, thermodynamic parameters, molecular orbital energy and burning rate were then calculated. The simulation results revealed that these compounds exhibit excellent performance, with significant superiority over traditional oxidants found in propellants. 23908571 Clinical Outcomes of Double Staining and Additional ILM Peeling during ERM Surgery. To assess the clinical outcomes in idiopathic epiretinal membrane (ERM) patients after vitrectomy and ERM removal with or without additional indocyanine green (ICG)-assisted internal limiting membrane (ILM) peeling. The medical records of 43 patients with an idiopathic ERM that underwent vitrectomy and ERM removal between July 2007 and April 2010 were reviewed. The patients were divided into two groups: triamcinolone-assisted simple ERM peeling only (group A, n = 23) and triamcinolone-assisted ERM peeling followed by ICG staining and peeling of the remaining internal ILM (group B, n = 20). No difference was found between the two groups in terms of visual acuity, macular thickness, P1 amplitude or implicit time on multifocal-electroretinogram (mfERG) at six and 12 months postoperatively. In group B, ICG staining after ERM peeling demonstrated that the ILM had been removed together with the ERM in 12 eyes (60%), and all 12 eyes showed punctate retinal hemorrhages during ERM peeling. There was no recurrence of an ERM in either group. Additional procedures involving ICG staining and ILM peeling during ERM surgery do not appear to have an additive effect on the clinical outcomes in terms of visual acuity, retinal function based on mfERG, or recurrence rate. 23756568 Required characteristics of Paenibacillus polymyxa JB-0501 as potential probiotic. The ability of Paenibacillus polymyxa to inhibit the growth of Escherichia coli generic ATCC 25922 (Escherichia coli ATCC 25922) and to adhere to monolayers of the enterocyte-like human cell line Caco-2 was evaluated. P. polymyxa JB-0501 (P. polymyxa JB-0501), found in a livestock feed probiotic supplement, was compared to P. polymyxa reference strain ATCC 43685 and ATCC 7070 (P. polymyxa ATCC) in terms of carbohydrate utilization and resistance to lysozyme, acid, bile salts, and hydrogen peroxide. JB-0501 grew at pH 4.5 and at H2O2 concentrations less than 7.3 Î¼g/ml and presented a higher affinity to hexadecane and decane. Bile salts at 0.2 % inhibited the growth of all three strains. P. polymyxa JB-0501 and P. polymyxa ATCC 43865 adhered to Caco-2 cell monolayers. The percentage of cells that adhered ranged from about 0.35 to 6.5 % and was partially proportional to the number applied. Contact time (from 15 min to 1 h) had little impact on adhesion. P. polymyxa JB-0501 inhibited the growth of E. coli ATCC 25922, as proven by the diffusion tests in agar. Taken together, these results suggested that P. polymyxa JB-0501 has the potential probiotic properties to justify its consideration as a livestock feed supplement. 23837461 A randomized phase III trial of adjunctive zonisamide in pediatric patients with partial epilepsy. To assess the efficacy and safety/tolerability of adjunctive zonisamide treatment in pediatric patients with partial epilepsy. In this phase III, double-blind, randomized, placebo-controlled, multicenter trial, 207 patients (age 6-17 years) with partial epilepsy, receiving one or two antiepileptic drugs, were randomized to receive adjunctive zonisamide or placebo. Zonisamide was initiated at 1 mg/kg/day, titrated to a target dose of 8 mg/kg/day over 8 weeks (one down-titration permitted), and maintained for 12 weeks. The primary efficacy end point was the proportion of responders (≥50% seizure frequency reduction from baseline) during the 12-week maintenance period. Safety/tolerability assessments included the incidence of treatment-emergent adverse events (TEAEs). In total, 93 (86.9%) of 107 patients randomized to zonisamide and 90 (90.0%) of 100 patients randomized to placebo completed the trial. Responder rates were 50% for zonisamide versus 31% for placebo (p = 0.0044; intention-to-treat population, last observation carried forward). The overall incidence of TEAEs was similar for zonisamide (55.1%) versus placebo (50.0%), with low rates of serious TEAEs with zonisamide and placebo (3.7% vs. 2.0%) and TEAEs leading to withdrawal (0.9% vs. 3.0%). TEAEs reported more frequently with zonisamide versus placebo were decreased appetite (6.5% vs. 4.0%), decreased weight (4.7% vs. 3.0%), somnolence (4.7% vs. 2.0%), vomiting (3.7% vs. 2.0%), and diarrhea (3.7% vs. 1.0%). Adjunctive zonisamide treatment was shown to be effective and well tolerated in pediatric patients with partial epilepsy. No new or unexpected safety findings emerged. 23810547 Assessment of stability of surface anchors for antibacterial coatings and immobilized growth factors on titanium. Titanium (Ti) has been functionalized with biomolecules for biomedical purposes. However, there is very limited information on the stability of such functionalities. Ti surface functionalized with carboxymethyl chitosan (CMCS) and bone morphogenetic protein 2 (BMP-2) has been reported to inhibit bacterial colonization while at the same time enhances osteoblast functions. In this work, three types of anchoring molecules, (3-aminopropyl) triethoxysilane (Silane), dopamine (DA), and polydopamine (PDA), were used for immobilizing the CMCS on Ti. The CMCS-modified surfaces were subjected to 70% ethanol treatment, autoclaving, and prolonged immersion in phosphate buffered saline (PBS). After the treatment procedures, the ability of the CMCS-modified substrates to inhibit colonization by Staphylococcus epidermidis (S. epidermidis) was assessed to evaluate the stability of the immobilized CMCS. The bacterial adhesion assays showed that the CMCS-DA- and CMCS-PDA-modified Ti remained stable after 70% ethanol treatment, autoclaving, and prolonged immersion in PBS, whereas the CMCS-Silane-modified Ti was less stable after autoclaving and prolonged immersion in PBS. The CMCS-DA- and CMCS-PDA-modified Ti substrates were functionalized with BMP-2 and used to support osteoblast growth. Evaluation of alkaline phosphatase (ALP) activity and calcium deposition from osteoblasts cultured on these substrates, which have been treated with 70% ethanol, or subjected to autoclaving, and prolonged immersion in PBS indicated that the immobilized BMP-2 on these surfaces retained its bioactivity. 23916810 Phosphodiesterase 5 inhibitor acts as a potent agent sensitizing acute myeloid leukemia cells to 67-kDa laminin receptor-dependent apoptosis. (-)-Epigallocatechin-3-O-gallate (EGCG), a polyphenol in green tea, induces apoptosis in acute myeloid leukemia (AML) cells without affecting normal cells. In this study, we observed that cGMP acts as a cell death mediator of the EGCG-induced anti-AML effect through acid sphingomyelinase activation. EGCG activated the Akt/eNOS axis, a well-known mechanism in vascular cGMP upregulation. We also observed that a major cGMP negative regulator, phosphodiesterase 5, was overexpressed in AML cells, and PDE5 inhibitor, an anti-erectile dysfunction drug, synergistically enhanced the anti-AML effect of EGCG. This combination regimen killed AML cells via overexpressed 67-kDa laminin receptors. 23495085 (1) H and (13) C NMR analysis of 2-acetamido-3-mercapto-3-methyl-N-aryl-butanamides and 2-acetamido-3-methyl-3-nitrososulfanyl-N-aryl-butanamide derivatives. The complete assignment of the (1) H and (13) C NMR spectra of various 2-acetamido-3-mercapto-3-methyl-N-aryl-butanamides and 2-acetamide-3-methyl-3-nitrososulfanyl-N-aryl-butanamides with p-methoxy, o-chloro and m-chloro substituents is reported. Copyright © 2013 John Wiley & Sons, Ltd. 23600946 Drug-induced hypo- and hyperprolactinemia: mechanisms, clinical and therapeutic consequences. Introduction: The altered profiles of prolactin secretion in the anterior hypophysis, generated by pathological, pharmacological or toxicological causes, have special consequences on multiple functions in both genders. Areas covered: This selective review presents the main mechanisms controlling prolactin secretion, focusing on the interplay of various neurotransmitters or xenobiotics, but also on the role of psychic or posttraumatic stress. A detailed analysis of several pharmacotherapeutic groups with hyperprolactinemic effects emphasize on the relevance of the pharmacokinetic/pharmacodynamic mechanisms and the clinical significance of the long term administration. Expert opinion: Accurate monitoring and evaluation of the hyperprolactinemia induced by xenobiotics is strongly recommended. The typical antipsychotics and some of the atypical agents (amisulpride, risperidone, paliperidone), as well as some antidepressants, antihypertensives and prokinetics, are the most important groups inducing hyperprolactinemia. The hyperprolactinemic effects are correlated with their affinity for dopamine D2 receptors, their blood-brain barrier penetration and, implicitly, the requested dose for adequate occupancy of cerebral D2 receptors. Consequently, integration of available pharmacokinetic and pharmacodynamic data supports the idea of therapeutic switch to non-hyperprolactinemic agents (especially aripiprazole) or their association, for an optimal management of antipsychotic-induced hyperprolactinemia. Possible alternative strategies for counteracting the xenobiotics-induced hyperprolactinemia are also mentioned. 23909920 Hyperplex-MRM: A Hybrid Multiple Reaction Monitoring Method Using mTRAQ/iTRAQ Labeling for Multiplex Absolute Quantification of Human Colorectal Cancer Biomarker. Novel biomarker verification assays are urgently required to improve the efficiency of biomarker development. Benefitting from lower development costs, multiple reaction monitoring (MRM) has been used for biomarker verification as an alternative to immunoassay. However, in general MRM analysis, only one sample can be quantified in a single experiment, which restricts its application. Here, a Hyperplex-MRM quantification approach, which combined mTRAQ for absolute quantification and iTRAQ for relative quantification, was developed to increase the throughput of biomarker verification. In this strategy, equal amounts of internal standard peptides were labeled with mTRAQ reagents Δ0 and Δ8, respectively, as double references, while 4-plex iTRAQ reagents were used to label four different samples as an alternative to mTRAQ Δ4. From the MRM trace and MS/MS spectrum, total amounts and relative ratios of target proteins/peptides of four samples could be acquired simultaneously. Accordingly, absolute amounts of target proteins/peptides in four different samples could be achieved in a single run. In addition, double references were used to increase the reliability of the quantification results. Using this approach, three biomarker candidates, ademosylhomocysteinase (AHCY), cathepsin D (CTSD), and lysozyme C (LYZ), were successfully quantified in colorectal cancer (CRC) tissue specimens of different stages with high accuracy, sensitivity, and reproducibility. To summarize, we demonstrated a promising quantification method for high-throughput verification of biomarker candidates. 23867962 Brain wave maturation and neurodevelopmental outcome in extremely low gestational age neonates. Objective:Infants born at extremely low gestational ages are at high risk for developmental impairments. Early predictors of these impairments are useful for both clinicians and researchers. Our objective was to assess the correlation between the rate of brain wave maturation as measured by serial amplitude-integrated electroencephalograms (aEEGs) and scores on standardized measures of infant development in extremely low gestational age neonates.Study Design:This was a prospective observational study of 65 infants born before 28 weeks' gestational age who were assessed with an aEEG monthly between 28 and 36 weeks' postmenstrual age and with the Bayley Scales of Infant and Toddler Development-III at 18 to 22 months adjusted age. We analyzed the correlation between the rate of brain wave maturation on aEEG and Bayley Scales of Infant and Toddler Development-III Cognitive and Motor Scales.Result:The mean rate of brain wave maturation was 0.83 (±0.36) points per week. Brain wave maturation was not correlated with either the Cognitive or Motor Scale (adjusted regression coefficients for Cognitive and Motor Scales were 1.61 (s.e.: 4.20; P=0.70) and 2.39 (s.e.: 4.62; P=0.61), respectively.Conclusion:Among extremely preterm infants, the rate of maturational changes in brain wave characteristics between 28 and 36 weeks' postmenstrual age is not predictive of developmental abilities at 18 to 22 months adjusted age.Journal of Perinatology advance online publication, 18 July 2013; doi:10.1038/jp.2013.79. 23877683 Head-to-head comparison of inhibitory and cidal activities of fluconazole, itraconazole, voriconazole, posaconazole and isavuconazole against clinical isolates of Trichosporon asahii determined by three methods: MIC, minimum fungicidal concentration and time-kill curves. Treatment of disseminated Trichosporon infections still remains difficult. Amphotericin B frequently displays inadequate fungicidal activity and echinocandins have no meaningful antifungal effect against this genus. Triazoles are currently the drugs of choice for treatment of Trichosporon infections. This study evaluates the inhibitory and fungicidal activities of five triazoles against 90 clinical isolates of Trichosporon asahii. MICs (μg/ml) were determined by the CLSI M27-A3 microdilution method at 24 and 48h using two endpoints, MIC-2 and MIC-0 (lowest concentration that inhibited ∼50 and 100% of growth, respectively). Minimum fungicidal concentrations (MFC, μg/ml) were determined by seeding 100 μl of all clear MIC wells (using an inoculum of 10(4) CFU/ml) onto Sabouraud dextrose agar. Time-killing curves were assayed against 4 clinical T. asahii isolates and T. asahii ATCC 201110 strain. MIC-2/MIC-0/MFC (μg/ml) values that inhibited 90% of isolates at 48h were respectively: 8/32/64 for fluconazole, 1/2/8 (itraconazole), 0.12/0.5/2 (voriconazole), 0.5/2/4 (posaconazole), and 0.25/1/4 (isavuconazole). MIC-0 endpoints yielded more consistent MIC results which remained mostly unchanged when extending the incubation to 48h (98-100% agreement with 24h values) and are easier to interpret. By time-kill experiments, none of the drugs reached the fungicidal endpoint (99.9% killing), killing activity being shown but at concentrations not reached in serum. Statistical analysis reveals that killing rates are dose- and antifungal-dependent. The lowest concentration at which killing activity begins was for voriconazole and the highest for fluconazole. These results suggest that azoles display fungistatic activity and lack fungicidal effect against T. asahii. By rank order, the most active triazole is voriconazole followed by itraconazole ∼ posaconazole ∼ isavuconazole > fluconazole. 23601401 Effect of different maize meal diets on growth and vitamin A: Case-study on chickens. South Africa embarked on mandatory vitamin and mineral fortification of wheat flour and maize meal in 2003 as part of a multi-faceted approach to alleviate malnutrition. However, it was reported, in 2008, that vitamin A deficiency increased despite the mandatory fortification programme. This motivates an investigation into the absorption of vitamin A as fortificant in the maize meal. Relative absorption, in chickens as the biological model, was determined by evaluating growth and vitamin A status. The weight, cumulative feed intake and liver retinol stores of chickens on different diets were measured over a 6week period. The fortified white maize meal diet was able to maintain the vitamin A status of the chickens. Poor absorption of the fortificant vitamin A is therefore not a constraint in combating vitamin A deficiency. It is in therefore also important to focus on the level of fortification delivered when consumed as a traditional prepared dish. In the traditional diet, maize porridge is often consumed with only a relish. The total fat content of the traditional meal is very low, lacking absorption enhancers. 23911918 Emissions from a generator fueled by blends of diesel, biodiesel, acetone, and isopropyl alcohol: Analyses of emitted PM, particulate carbon, and PAHs. Biodiesel is one of alternative energies that have been extensively discussed and studied. This research investigates the characteristics of particulate matter (PM), particulate carbon, and polycyclic aromatic hydrocarbons (PAHs) emitted from a generator fueled by waste-edible-oil-biodiesel with acetone and isopropyl alcohol (IPA) addition. The tested biodieselhols consisted of pure diesel oil (D100) with 1-3vol.% pure acetone (denoted as A), 1-70vol.% waste-edible-oil-biodiesel (denoted as W), and 1vol.% pure isopropyl alcohol (the stabilizer, denoted as P). The results show that in comparison to W1D99, W3D97, W5D95, W10D90, and W20D80, the use of biodieselhols achieved additional reduction of PM and particulate organic carbon (OC) emission, and such reduction increased as the addition percentage of pure acetone increased. Regardless of the percentages of added waste-edible-oil-biodiesel, acetone, and isopropyl alcohol, the use of biodieselhol in place of D100 could reduce the emissions of Total-PAHs (by 6.13-42.5% (average=24.1%)) and Total-BaPeq (by 16.6-74.8% (average=53.2%)) from the diesel engine generator. Accordingly, the W/D blended fuels (W<20vol.%) containing acetone (1-3vol.%) and isopropyl alcohol (1vol.%) are a potential alternative fuel for diesel engine generators because they substantially reduce emissions of PM, particulate OC, Total-PAHs, and Total-BaPeq. 23313353 Comparison of complex versus simple activity of daily living staging: validation of simple stages. To compare activities of daily living (ADL) staging based on 2-level responses to ADL difficulty questions (simple ADL stages) with ADL staging based on 4-level ADL question responses (complex ADL stages). Analysis of the Second Longitudinal Study of Aging, a prospective cohort study, using descriptive statistics and logistic regression. Participants' homes. Community-dwelling persons (N=9447) aged ≥70 years in 1994. Not applicable. (1) Agreement and face validity: baseline simple ADL stage; (2) construct validity: baseline health, difficulty, and need characteristics; (3) prognostic comparison (determined at the Wave 2 interview): primary-nursing home use and/or death; secondary-death. The systems showed good agreement (κ=.75). The simple ADL stages stratified people into distinct groups and reflected the expected stepwise increases from stage 0 to stage IV in health and need characteristics, such as the prevalence of home-related challenges (2.9%-84.5%) and perceived need for home modifications (2.1%-33.6%). In comparing the prognostic ability using the primary outcome, the complex system model demonstrated slightly increased discrimination between milder stages and a slightly higher C statistic (.666 vs .664). Although complex staging appears slightly better at classifying people into distinct prognostic strata with respect to nursing home use and/or death at Wave 2, simple ADL stages demonstrate strong, clinically relevant associations with health and need characteristics. 23720794 Use of Vitek 2 Antimicrobial Susceptibility Profile To Identify mecC in Methicillin-Resistant Staphylococcus aureus. The emergence of mecC methicillin-resistant Staphylococcus aureus (MRSA) poses a diagnostic challenge for clinical microbiology laboratories. Using the Vitek 2 system, we tested a panel of 896 Staphylococcus aureus isolates and found that an oxacillin-sensitive/cefoxitin-resistant profile had a sensitivity of 88.7% and a specificity of 99.5% for the identification of mecC MRSA isolates. The presence of the mecC gene, determined by bacterial whole-genome sequencing, was used as the gold standard. This profile could provide a zero-cost screening method for identification of mecC-positive MRSA strains. 23841752 Ameliorative effect of naringenin on hyperglycemia-mediated inflammation in hepatic and pancreatic tissues of Wistar rats with streptozotocin- nicotinamide-induced experimental diabetes mellitus. In diabetes mellitus (DM), sustained hyperglycemia results in the generation of reactive oxygen species, ultimately leading to increased oxidative stress and inflammation in vital tissues. In the present study, possible ameliorative effects of naringenin on hyperglycemia-mediated inflammation in experimental streptozocin (STZ)-nicotinamide-induced DM were sought. DM was induced experimentally in overnight-fasted Wistar rats (150-180 g) by intra-peritoneal injection of STZ (50 mg/kg.b.w) and of nicotinamide (110 mg/kg.b.w); control rats (n = 6) received only vehicle (0.5 ml of 0.1 M of cold citrate buffer; pH 4.5). One group of diabetic rats (n = 6) was left untreated while another group of diabetic rats (n = 6) received naringenin (50 mg/kg b.w./day) orally for 21 days. At this time, hemotological indices (erythrocyte sedimentation rate [ESR], total white blood cell [WBC] count, differential WBC percentage, and platelet count) were measured. Significant alterations in expression of gene and protein biomarkers of inflammation in hepatic and pancreatic tissues were determined by measuring mRNA levels and the level of protein expressed, respectively, as was the total nitric oxide level in these tissues. Diabetic rats showed significantly higher mean ESR values, total WBC counts, differential WBC percentages, and platelet counts than those in control rats; similarly, mean mRNA levels of C-reactive protein, pro-inflammatory cytokine, nuclear factor-κB and inducible nitric oxide synthase genes and mean intensities of expression of the corresponding proteins in the hepatic and pancreatic tissue samples from diabetic rats significantly exceeded those in control rats. However, in diabetic rats treated with naringenin, the values of hematological, mRNA transcript and protein indices of inflammation were all lower than those in diabetic rats. These results suggest that naringenin possibly alleviates hyperglycemia-mediated inflammation in experimental STZ-nicotinamide-induced DM in Wistar rats. 23898245 General developmental health in the VPA-rat model of autism. Autism is a neurodevelopmental condition diagnosed by impaired social interaction, abnormal communication and, stereotyped behaviors. While post-mortem and imaging studies have provided good insights into the neurobiological symptomology of autism, animal models can be used to study the neuroanatomical, neurophysiological and molecular mediators in more detail and in a more controlled environment. The valproic acid (VPA) rat model is an environmentally triggered model with strong construct and clinical validity. It is based on VPA teratogenicity in humans, where mothers who are medicated with VPA during early pregnancy show an increased risk for giving birth to an autistic child. In rats, early embryonic exposure, around the time of neural tube closure, leads to autism-like anatomical and behavioral abnormalities in the offspring. Considering the increasing use of the VPA rat model, we present our observations of the general health of Wistar dams treated with a single intraperitoneal injection of 500 or, 600 mg/kg VPA on embryonic day E12.5, as well as their male and female offspring, in comparison to saline-exposed controls. We report increased rates of complete fetal reabsorption after both VPA doses. VPA 500 mg/kg showed no effect on dam body weight during pregnancy or, on litter size. Offspring exposed to VPA 500 mg/kg showed smaller brain mass on postnatal days 1 (P1) and 14 (P14), in addition to abnormal nest seeking behavior at P10 in the olfactory discrimination test, relative to controls. We also report increased rates of physical malformations in the offspring, rare occurrences of chromodacryorrhea and, developmentally similar body mass gain. Further documentation of developmental health may guide sub-grouping of individuals in a way to better predict core symptom severity. 23963781 Protein domain definition should allow for conditional disorder. Proteins are often classified in a binary fashion as either structured or disordered. However this approach has several deficits. Firstly, protein folding is always conditional on the physiochemical environment. A protein which is structured in some circumstances will be disordered in others. Secondly, it hides a fundamental asymmetry in behavior. While all structured proteins can be unfolded through a change in environment, not all disordered proteins have the capacity for folding. Failure to accommodate these complexities confuses the definition of both protein structural domains and intrinsically disordered regions. We illustrate these points with an experimental study of a family of small binding domains, drawn from the RNA polymerase of mumps virus and its closest relatives. Assessed at face value the domains fall on a structural continuum, with folded, partially folded, and near unstructured members. Yet the disorder present in the family is conditional, and these closely related polypeptides can access the same folded state under appropriate conditions. Any heuristic definition of the protein domain emphasizing conformational stability divides this domain family in two, in a way that makes no biological sense. Structural domains would be better defined by their ability to adopt a specific tertiary structure: a structure that may or may not be realized, dependent on the circumstances. This explicitly allows for the conditional nature of protein folding, and more clearly demarcates structural domains from intrinsically disordered regions that may function without folding. 23445562 Achievement of pregnancies in women with primary ovarian insufficiency using close monitoring of follicle development: case reports. Women with primary ovarian insufficiency (POI)/premature ovarian failure exhibit hypergonadotropic hypogonadism due to follicle dysfunction and depletion before the age of 40 years. Because ovulation is extremely rare and thought to be unpredictable in women with POI and because no ovulation induction regimens have been shown to be efficacious, oocyte donation is the only evidence-based treatment for women with POI with desired fertility. Oocyte donation is, however, extremely limited in several countries including Japan. Here, we report four women with POI who achieved pregnancies resulting from timed intercourse or intrauterine insemination in combination with cyclic estrogen/progesterone therapy and close monitoring of follicle development. These four patients were diagnosed with POI at the mean age of 27.5 ± 8.5 (mean ± SD; range, 19-35), subjected to follicle monitoring at the mean age of 29.8 ± 5.7 (23-35), and conceived at the mean age of 34.5 ± 3.9 (29-38). The interval between the initiation of follicle monitoring and pregnancy was 4.8 ± 2.8 (2-8) years. In one of the patients, her most recent ovulation occurred after a three-year interval. All four patients had uncomplicated pregnancies with term deliveries. In the event that oocyte donation and adoption are not available and/or various treatments with intensive ovulation induction have been unsuccessful, close and continuous monitoring of follicle growth to identify very rare ovulatory events might be considered for patients with POI and desired fertility. 23876194 What is the association between quality of treatment for depression and patient outcomes? A cohort study of adults consulting in primary care. The association between adequate treatment for a Major Depressive Episode (MDE) and improvements in depressive symptoms is not well established in naturalistic practice conditions. The main objective of this study was to examine the association between receiving at least one minimally adequate treatment for MDE (i.e. according to clinical guidelines) in the previous 12 months and evolution of depressive symptoms at 6- and 12-months. Associations with receiving pharmacotherapy and/or psychotherapy and the role of severity of depression were examined. This cohort study included 908 adults meeting criteria for previous-year MDE and consulting at one of 65 primary care clinics in Quebec, Canada. Multilevel analyses were performed. Results show that (i) receiving at least one minimally adequate treatment for depression was associated with greater improvements in depression symptoms at 6 and at 12 months; (ii) adequate pharmacotherapy and adequate psychotherapy were both associated with greater improvements in depression symptoms, and (iii) the association between adequate treatment and improvement in depression symptoms varied as a function of severity of symptoms at the time of inclusion in the cohort with worse symptoms at the time of inclusion being associated with greater reductions at 6 and 12 months. Measures are self-reported. Participants were recruited at different stages over the course of their MDE. This study shows that adequate treatment for depression is associated with improvements in depressive symptoms in naturalistic primary care practice conditions, but that those with more severe depressive symptoms are more likely to receive adequate treatment and improve across time. 23957368 Delicate Refinement of Surface Nanotopography by Adjusting TiO2 Coating Chemical Composition for Enhanced Interfacial Biocompatibility. Surface topography and chemistry have significant influences on the biological performance of biomedical implants. Our aim is to produce an implant surface with favorable biological properties by dual modification of surface chemistry and topography in one single simple process. In this study, because of its chemical stability, excellent corrosion resistance, and biocompatibility, titanium oxide (TiO2) was chosen to coat the biomedical Ti alloy implants. Biocompatible elements (niobium (Nb) and silicon (Si)) were introduced into TiO2 matrix to change the surface chemical composition and tailor the thermophysical properties, which in turn leads to the generation of topographical features under specific thermal history of plasma spraying. Results demonstrated that introduction of Nb2O5 resulted in the formation of Ti0.95Nb0.95O4 solid solution and led to the generation of nanoplate network structures on the composite coating surface. By contrast, the addition of SiO2 resulted in a hairy nanostructure and coexistence of rutile and quartz phases in the coating. Additionally, the introduction of Nb2O5 enhanced the corrosion resistance of TiO2 coating, whereas SiO2 did not exert much effect on the corrosion behaviors. Compared to the TiO2 coating, TiO2 coating doped with Nb2O5 enhanced primary human osteoblast adhesion and promoted cell proliferation, whereas TiO2 coatings with SiO2 were inferior in their bioactivity, compared to TiO2 coatings. Our results suggest that the incorporation of Nb2O5 can enhance the biological performance of TiO2 coatings by changing the surface chemical composition and nanotopgraphy, suggesting its potential use in modification of biomedical TiO2 coatings in orthopedic applications. 23812966 Histone H1.0-a potential molecular marker with prognostic value for patients with malignant gliomas. Histones are proteins closely associated with the DNA molecules and serve as a structural scaffold for the organization of chromatin. They play an important role in the regulation of gene expression by changing the level of DNA compaction. The special subtype of the linker histone family-H1 zero (H1.0) is generally expressed in non-dividing, terminally differentiated cells. The aim of our study is to investigate the correlation between the quantities of histone H1.0 in human gliomas, the histopathological grade and the overall survival. Twenty-nine (N = 29) patients with intraaxial lesions underwent a microsurgical tumor resection. Tumor samples were snap-frozen in liquid nitrogen immediately after resection. Following a specific protocol, linker histones were extracted from the tumor specimens and the quantities of histone H1.0 were assessed. All patients were followed up prospectively. Of the 29 patients in our study (M:F = 17:12), five had a grade II astrocytoma, seven had a grade III, and 17 had a grade IV, according to the World Health Organization (WHO) classification. At the end of the study, three patients were still alive. The mean quantities of H1.0 were: 23.3 for grade II tumors, 13.9 for grade III and 11.3 for grade IV tumors. The statistical analysis demonstrated that the histological grade, age and Karnofsky performance status (KPS) remain among the most reliable predictive factors for the survival of patients with gliomas. Grade III-IV gliomas had significantly less histone H1.0 than grade II gliomas. Conformably, in a multivariate Cox regression analysis, H1.0 made a small but significant contribution (p < 0.05) to survival rates. Our study confirmed that histone H1.0 is a potential biological marker with prognostic value for the survival of patients with gliomas. The quantities of histone H1.0 are correlated to the histopathological grade of the tumor. The more aggressive and malignant gliomas tend to have lower quantities of histone H1.0. 23778747 Impact of Dietary and Exercise Interventions on Weight Change and Metabolic Outcomes in Obese Children and Adolescents: A Systematic Review and Meta-analysis of Randomized Trials. IMPORTANCE Diet and exercise represent the mainstays of obesity treatment. No systematic review has been conducted comparing the effect of dietary and exercise intervention in reducing metabolic risks in overweight children. OBJECTIVE To compare the effects of diet-only intervention with those of diet plus exercise or exercise only on weight loss and metabolic risk reduction in overweight children. EVIDENCE REVIEW English-language articles from 1975 to 2010 available from 7 databases were reviewed. One person searched the databases. Two independent reviewers assessed abstracts and articles against the following eligibility criteria: randomized controlled trials conducted in overweight and obese children aged 18 years or younger, comparing dietary intervention with a diet plus exercise program or an exercise-only program. Study quality was critically appraised by 2 reviewers using established criteria. The main outcome measures were body mass index, body fat percentage, lean body mass, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, fasting glucose, and fasting insulin. FINDINGS Fifteen studies were identified and included. Based on the small number of short-term trials currently available, both diet-only and diet plus exercise interventions resulted in weight loss and metabolic profile improvement. However, the addition of exercise to dietary intervention led to greater improvements in levels of high-density lipoprotein cholesterol (3.86 mg/dL [to convert to millimoles per liter, multiply by 0.0259]; 95% CI, 2.70 to 4.63), fasting glucose (-2.16 mg/dL [to convert to millimoles per liter, multiply by 0.0555]; 95% CI, -3.78 to -0.72), and fasting insulin (-2.75 μIU/mL [to convert to picomoles per liter, multiply by 6.945]; 95% CI, -4.50 to -1.00) over 6 months. The diet-only intervention caused greater reductions in levels of triglycerides (at the end of active intervention) and low-density lipoprotein cholesterol (at subsequent follow-up). CONCLUSIONS AND RELEVANCE This review provides insights into the impact of dietary and exercise interventions on metabolic risk reduction in the pediatric population. However, further studies are required to confirm the evidence with rigorous design, appropriate sample size, longer duration of follow-up, and better strategies to improve compliance and achieve long-term sustainability. 23046090 Erasing the engram: The unlearning of procedural skills. Huge amounts of money are spent every year on unlearning programs-in drug-treatment facilities, prisons, psychotherapy clinics, and schools. Yet almost all of these programs fail, since recidivism rates are high in each of these fields. Progress on this problem requires a better understanding of the mechanisms that make unlearning so difficult. Much cognitive neuroscience evidence suggests that an important component of these mechanisms also dictates success on categorization tasks that recruit procedural learning and depend on synaptic plasticity within the striatum. A biologically detailed computational model of this striatal-dependent learning is described (based on Ashby & Crossley, 2011). The model assumes that a key component of striatal-dependent learning is provided by interneurons in the striatum called the tonically active neurons (TANs), which act as a gate for the learning and expression of striatal-dependent behaviors. In their tonically active state, the TANs prevent the expression of any striatal-dependent behavior. However, they learn to pause in rewarding environments and thereby permit the learning and expression of striatal-dependent behaviors. The model predicts that when rewards are no longer contingent on behavior, the TANs cease to pause, which protects striatal learning from decay and prevents unlearning. In addition, the model predicts that when rewards are partially contingent on behavior, the TANs remain partially paused, leaving the striatum available for unlearning. The results from 3 human behavioral studies support the model predictions and suggest a novel unlearning protocol that shows promising initial signs of success. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23349490 Enhanced NFκB Activity Impairs Vascular Function through PARP-1, SP-1 and COX2-Dependent Mechanisms in Type 2 Diabetes. Type 2 diabetes (T2D) is associated with vascular dysfunction. We hypothesized that increased nuclear factor kappa B (NFκB) signaling contributes to vascular dysfunction in T2D. We have treated type 2 diabetic (db(-)/db(-)) and control (db(-)/db(+)) mice with two NFκB inhibitors (DHMEQ, 6mg/kg, twice a week and IKK-NBD peptide, 500 μg/kg/day) for four weeks. Pressure-induced myogenic tone (MT) was significantly potentiated, while endothelium dependent relaxation (EDR) was impaired in small coronary arterioles (CA) and mesenteric resistance artery (MRA) from diabetic mice compared to control. Interestingly, diabetic mice treated with NFκB inhibitors significantly reduced MT potentiation and improved EDR. Importantly, vascular function was also rescued in db(-)/db(-p50NFκB-/-) and db(-)/db(-PARP-1-/-) double knockout mice compared to db(-)/db(-) mice. Additionally, the acute in vitro down regulation of NFκB-p65 using p65NFκB shRNA lentivirus in arteries from db(-)/db(-) mice also improved vascular function. The NFκB inhibition did not affect blood glucose level and body weight. The RNA levels for Sp-1 and eNOS phosphorylation were decreased, while p65NFκB phosphorylation, cleaved PARP-1 and COX-2 expression were increased in arteries from diabetic mice, which were restored after NFκB inhibition and in db(-)/db(-p50NFκB-/-) and db(-)/db(-PARP-1-/-) mice.In the present study, we provided evidence that enhanced NFκB activity impairs vascular function by PARP-1, Sp-1 and COX-2-dependent mechanisms in male type 2 diabetic mice. Therefore, NFκB could be a potential target to overcome diabetes-induced vascular dysfunction. 23746357 A Three-Loci Variable Number of Tandem Repeats Analysis for Molecular Subtyping of Vibrio cholerae O1 and O139. Abstract Rapid and easy-to-use molecular subtyping methods are being explored and used for the surveillance of bacterial diseases, including multiple-loci variable number of tandem repeats (VNTR) analysis (MLVA). In this study, we assessed different VNTR combinations for the subtyping of Vibrio cholerae serogroups O1 and O139 with strain panels selected from a long-term nationwide cholera survey. By only using three highly variable loci (VC0147, VCA0171, and VCA0283), we acquired a high discriminatory power, which equals that found after using a combination of all nine loci and that of a pulsed-field gel electrophoresis analysis. Evaluation using the outbreak strains showed a good clustering of the three-loci MLVA (VC0147, VCA0171, and VCA0283). In addition, a six-loci MLVA (VC0147, VC0437, VC1457, VC1650, VCA0171, and VCA0283) protocol allowed for the clustering of O1/O139 V. cholerae strains, which have different serogroups/biotypes and toxigenic/nontoxigenic characteristics. Here, we propose that the three-loci MLVA can be utilized as a molecular subtyping protocol in cholera epidemiological investigations, and the six-loci MLVA can be used in phylogenetic and population structure analyses of V. cholerae O1/O139. 23954054 The perspective of psychosocial support a decade after bam earthquake: achievements and challenges. The 2003 Bam earthquake was one of the most catastrophic disasters to have struck Iran. This article summarizes the short-term and long-term psychological, social, and economic impacts of the Bam earthquake on survivors across a decade since its occurrence. Identification and definition of capability as well as recognizing the nature and extent of personal and social capabilities in a community are priceless in preventing disasters and reducing their consequent destruction. 23623932 Distinct physiological role of amidino-TAPA-sensitive and DAMGO-insensitive μ-opioid receptor splice variants in the mouse spinal cord. The physiological role of the distinct splice variants for cloned mouse μ-opioid receptor (mMOR-1), mMOR-1J, mMOR-1K and mMOR-1L, which are sensitive to N(α)-amidino-Tyr-D-Arg-Phe-β-Ala (amidino-TAPA) and insensitive to [D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO), was described in the mouse spinal cord. The antinociception induced by intrathecally (i.t.) injected amidino-TAPA was attenuated by i.t. pretreatment with antisera against the endogenous opioid peptides dynorphin A, dynorphin B, α-neo-endorphin, or [Leu(5)]enkephalin in naïve mice. However, in mice whose spinal mMOR-1J had been knocked-down using the antisense oligodeoxynucleotide (ODN) for exon-12 of mMOR-1 gene, the inhibiting effect of antiserum against dynorphin A on amidino-TAPA-induced antinociception was eliminated. In contrast, the inhibiting effect of antisera against dynorphin B or α-neo-endorphin on amidino-TAPA-induced antinociception was eliminated in mice whose spinal mMOR-1K had been knocked-down using the antisense ODN for exon-13 of mMOR-1 gene. Moreover, the inhibiting effect of antisera against dynorphin A or [Leu(5)]enkephalin on amidino-TAPA-induced antinociception was eliminated in mice whose spinal mMOR-1L had been knocked-down using the antisense ODN for exon-14 of mMOR-1 gene. The present results suggest that the distinct antinociceptive profile of amidino-TAPA, that is the release of endogenous κ- and δ-opioid peptides in spinal cord, is mediated through the activation of mMOR-1J, mMOR-1K or mMOR-1L, which contain the sequence encoded by exon-12, exon-13 or exon-14 of mMOR-1 gene, respectively. 23890682 Insulin resistance and fasting plasma glucose in first degree relatives of patients with type 1 diabetes. We analyzed the relationship between fasting plasma glucose (FPG), the presence of autoantibodies, first phase of insulin secretion and insulin resistance in the first degree relatives of patients with type 1 diabetes. The group studied consisted of 90 healthy relatives, divided into two groups: "high-normal" FPG group (≥88mg/dl) and "low-normal" FPG group (<88/mg/dl). All subjects underwent an intravenous glucose tolerance test, and the 1st phase insulin response (FPIR) and FPIR-to-HOMA-IR-ratio were calculated. Additionally, islet autoantibodies (GADA, IAA and IA-2A) were determined by radioimmunoassays. The subjects with "high-normal" FPG were older (p=0.0009), had higher BMI (p<0.0001) and lower HOMA%B (p=0.0004), FPIR (p=0.006) and FPIR-to-HOMA-IR-ratio (p=0.004) in comparison with the "low-normal" FPG group. Autoantibodies were present in 40.9% and in 21.7% of the subjects with "high-normal" and "low-normal" FPG, respectively. In the "high-normal" FPG group, FPG correlated positively with GADA (r=0.31, p=0.04), and HOMA-IR (r=0.19, p=0.02), and negatively with HOMA%B (r=-0.36, p=0.001), whereas FPIR correlated positively with HOMA%B (r=0.55, p=0.0001) and BMI (r=0.30, p=0.04). After an adjustment for BMI, the difference in FPIR between the "high-normal" and "low-normal" FPG groups remained significant (p=0.025), whereas the difference in FPIR-to-HOMA-IR-ratio became insignificant. Our results suggest that taking into account the impact of age and BMI on insulin sensitivity, it would be expected that the relatives of patients with type 1 diabetes with "high-normal" glucose levels would become gradually unable to compensate for increasing insulin resistance. 23956876 Motor Skill Training Promotes Sensorimotor Recovery and Increases Microtubule-Associated Protein-2 (MAP-2) Immunoreactivity in the Motor Cortex after Intracerebral Hemorrhage in the Rat. Motor skill learning may induce behavioral and neurophysiological adaptations after intracerebral hemorrhage (ICH). Learning a new motor skill is associated with dendritic reorganization and requires protein synthesis and expression of MAP-2. The purpose of this study was to evaluate motor performance and expression of MAP-2 in the motor cortex of rats submitted to intracerebral hemorrhage model (ICH) and skill task training (SK) or unskilled training (US) during 4 weeks. The Staircase test was used for behavioral evaluation, and relative optical densities and morphometrical analysis were used to estimate MAP-2 immunoreactivity and parameters of brain tissue in both motor cortices. Results show that skill task training performed with the impaired forelimb was able to increase MAP-2 immunoreactivity in the motor cortex either in sham or in ICH groups in both cortices: ipsilesional [F (5,35) = 14.25 (P < 0.01)] and contralesional hemispheres [F (5,35) = 9.70 (P < 0.01)]. ICH alone also increased MAP-2 immunoreactivity despite the absence of functional gains. Behavioral evaluation revealed that ICH-SK group performed better than ICH and ICH-US animals in the Staircase test. Data suggest that motor skill training induces plastic modifications in both motor cortices, either in physiological or pathological conditions and that skill motor training produces higher brain plasticity and positive functional outcomes than unskilled training after experimental intracerebral hemorrhage. 23949048 Percutaneous endoscopic gastrostomy tube placement in left versus right middle cerebral artery stroke: Effects of laterality. Prolonged dysphagia after middle cerebral artery (MCA) territory strokes may require percutaneous endoscopic gastrostomy (PEG) tube feeding. We examined the predictors of PEG placement among patients with MCA stroke. It was hypothesized that stroke laterality was a predictor. A retrospective cohort study of existing data from Hartford Hospital Stroke Database was done. A total of 157 patients with acute ischemic MCA stroke were included. Patients were divided into the "PEG" group (n = 24) and "no PEG" group (n = 133). Existing demographic, clinical and swallowing data were compared between the 2 groups. Demographic data were similar between the groups. The "PEG" group had a higher admission National Institute of Health Stroke Scale (NIHSS) score, higher proportion of patients who had thrombolytic administration, in- hospital aspiration pneumonia and inability to be assessed on first swallow evaluation. Multivariate analysis revealed that all, except thrombolytic administration may predict PEG placement. Admission NIHSS score, in-hospital aspiration pneumonia and inability to undergo first swallow evaluation may predict PEG placement in patients with acute MCA stroke. Stroke laterality was not associated. This knowledge facilitates early identification of patients that may require PEG tube placement for early nutrition provision and discharge to rehabilitation. 23941241 Fluorescent Dye Cocktail for Multiplex Drug-Site Mapping on Human Serum Albumin. Elucidating how molecules bind to HSA is fundamental for predicting drug incompatibilities. Through combinatorial screening, we identified a novel fluorescent dye (BD140) with turn-on fluorescence emission and specific binding at HSA drug site 2. We further combined it with dansylamide to develop a fluorescent dye cocktail for high-throughput mapping of the interaction between therapeutics at HSA drug-binding sites. 23665062 A review of contemporary options for medical management of hemangiomas, other vascular tumors, and vascular malformations. Vascular anomalies include vascular tumors and vascular malformations. With growing pharmacologic options and parallels to cancer treatment and biology, the hematologist-oncologist has assumed a more prominent role in clinical care and research relating to these diagnoses. This also is a growing area for targeted therapies and drug repositioning. We performed a review of contemporary options for medical management of these lesions. PubMed was searched for "vascular anomaly", "hemangioma", "vascular malformation", "arteriovenous malformation", "capillary malformation", "cerebral cavernous malformation", "lymphatic malformation", and "venous malformation", each with "drug treatment" as a modifier. Manuscripts were reviewed to verify diagnoses, indications for treatment, dose-schedules, evidence of effectiveness, toxicities, and mechanisms of action. ClinicalTrials.gov also was reviewed for relevant trials. More than 20 agents were identified which have been used to treat vascular anomalies. Rigorous studies are lacking for many of these. The rarity of these tumors has limited development of medical approaches to treatment. Cooperative group trials will be needed to prove the effectiveness of drugs which have shown promise in cases and small series. The observant clinician remains a powerful tool for identifying potential new treatments for vascular tumors and malformations. 23893668 Characterization of the myometrial transcriptome in women with an arrest of dilatation during labor. Abstract Objective: The molecular basis of failure to progress in labor is poorly understood. This study was undertaken to characterize the myometrial transcriptome of patients with an arrest of dilatation (AODIL). Study design: Human myometrium was prospectively collected from women in the following groups: (1) spontaneous term labor (TL; n=29) and (2) arrest of dilatation (AODIL; n=14). Gene expression was characterized using Illumina® HumanHT-12 microarrays. A moderated Student's t-test and false discovery rate adjustment were used for analysis. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) of selected genes was performed in an independent sample set. Pathway analysis was performed on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database using Pathway Analysis with Down-weighting of Overlapping Genes (PADOG). The MetaCore knowledge base was also searched for pathway analysis. Results: (1) Forty-two differentially expressed genes were identified in women with an AODIL; (2) gene ontology analysis indicated enrichment of biological processes, which included regulation of angiogenesis, response to hypoxia, inflammatory response, and chemokine-mediated signaling pathway. Enriched molecular functions included transcription repressor activity, heat shock protein (Hsp) 90 binding, and nitric oxide synthase (NOS) activity; (3) MetaCore analysis identified immune response chemokine (C-C motif) ligand 2 (CCL2) signaling, muscle contraction regulation of endothelial nitric oxide synthase (eNOS) activity in endothelial cells, and triiodothyronine and thyroxine signaling as significantly overrepresented (false discovery rate <0.05); (4) qRT-PCR confirmed the overexpression of Nitric oxide synthase 3 (NOS3); hypoxic ischemic factor 1A (HIF1A); Chemokine (C-C motif) ligand 2 (CCL2); angiopoietin-like 4 (ANGPTL4); ADAM metallopeptidase with thrombospondin type 1, motif 9 (ADAMTS9); G protein-coupled receptor 4 (GPR4); metallothionein 1A (MT1A); MT2A; and selectin E (SELE) in an AODIL. Conclusion: The myometrium of women with AODIL has a stereotypic transcriptome profile. This disorder has been associated with a pattern of gene expression involved in muscle contraction, an inflammatory response, and hypoxia. This is the first comprehensive and unbiased examination of the molecular basis of an AODIL. 23884315 Propionibacterium acnes Induces IL-1β Secretion via the NLRP3 Inflammasome in Human Monocytes. Propionibacterium acnes induction of inflammatory responses is a major etiological factor contributing to the pathogenesis of acne vulgaris. In particular, the IL-1 family of cytokines has a critical role in both initiation of acne lesions and in the inflammatory response in acne. In this study, we demonstrated that human monocytes respond to P. acnes and secrete mature IL-1β partially via the NLRP3-mediated pathway. When monocytes were stimulated with live P. acnes, caspase-1 and caspase-5 gene expression was upregulated; however, IL-1β secretion required only caspase-1 activity. P. acnes induced key inflammasome genes including NLRP1 and NLPR3. Moreover, silencing of NLRP3, but not NLRP1, expression by small interfering RNA attenuated P. acnes-induced IL-1β secretion. The mechanism of P. acnes-induced NLRP3 activation and subsequent IL-1β secretion was found to involve potassium efflux. Finally, in acne lesions, mature caspase-1 and NLRP3 were detected around the pilosebaceous follicles and colocalized with tissue macrophages. Taken together, our results indicate that P. acnes triggers a key inflammatory mediator, IL-1β, via NLRP3 and caspase-1 activation, suggesting a role for inflammasome-mediated inflammation in acne pathogenesis.Journal of Investigative Dermatology advance online publication, 15 August 2013; doi:10.1038/jid.2013.309. 23720058 Which Patient is Most Likely to Benefit From Dronedarone? Analysis From the Magdeburg Dronedarone Registry (MADRE Study). Based on an analysis of the Magdeburg Dronedarone Registry data we sought to determine which patients could benefit from dronedarone therapy regarding rhythm control. The study included 191 patients (85 women) aged 63 ± 10 years with a history of paroxysmal or persistent AF and a follow-up of 14 ± 5 months. The total AF recurrence rate was 67% and lone AF was significantly more often associated with AF recurrences than non-lone AF (84% vs. 62%, P = .01). Arterial hypertension, treated coronary artery disease, and diabetes mellitus were not significantly related to AF recurrences (64%, 67%, 58% resp. P = .3). Response rate to dronedarone in patients with slightly increased left atrial size was significantly greater than in patients with normal or markedly increased left atrial size (47%, 16%, 27% resp., P = .001). The rate of adverse effects was 32% in the study sample, and was significantly lower in patients with lone AF as compared to those with non-lone AF (11% vs. 37%, P = .002). The body mass index was a predictor neither of response rate nor adverse effects. The results suggest that dronedarone is more effective in patients with non-lone AF and slightly increased left atrial size. 23860340 GET-SERF, a new gradient encoded SERF experiment for the trivial edition of (1)H-(19)F couplings. A new spatially encoded heteronuclear (1)H-(19)F selective refocusing NMR experiment (GET-SERF) is proposed. This sequence allows editing in one single 2D experiment all couplings between a selected fluorine site and all the proton nuclei of the molecule. Its efficiency is illustrated in the case of diflunisal, a difluorinated anti-inflammatory drug, in isotropic and anisotropic media. 23111828 Griseofulvin inhibits the growth of adrenocortical cancer cells in vitro. Supernumerary centrosomes and aneuploidy are associated with a malignant phenotype of tumor cells. Centrosomal clustering is a mechanism used by cancer cells with supernumerary centrosomes to solve the threatening problem of multipolar spindles. Griseofulvin is an antifungal substance that interferes with the microtubule apparatus and inhibits centrosomal clustering. It has also been demonstrated that griseofulvin inhibits the growth of tumor cells in vitro and in vivo. However, it is not yet known whether treatment with griseofulvin inhibits growth of adrenocortical tumor cells. We studied the viability and antiproliferative effects of griseofulvin on cultured NCI-H295R adrenocortical carcinoma cells using Wst-1-, BrdUrd-, and [3H]-thymidine assays. For the detection of apoptosis we used a caspase 3/7 cleavage assay and light microscopy techniques. We observed that incubation with griseofulvin for 24-48 h leads to a decrease in the viability and proliferation of NCI-H295R cells in a dose-dependent manner. Significant effects could be observed after incubation with griseofulvin as measured by Wst-1-, BrdUrd-, and [3H]dT- uptake assays. Apoptosis of NCI-H295R cells was increased in a dose-dependent manner up to 4.5-fold after incubation with griseofulvin 40 μM for 24 h as shown by caspase 3/7 cleavage assay and light microscopy. With regard to new treatment strategies for adrenocortical cancer, griseofulvin, and possibly other agents, which interfere with the microtubule apparatus and inhibit centrosomal clustering, may turn out to be interesting targets for further research. 23953200 Raman spectroscopy and partial least squares analysis in discrimination of peripheral cells affected by Huntington's disease. Huntington's disease (HD) is a neurodegenerative disorder caused by trinucleotide CAG (Cytosine-Adenine-Guanine) expansion on the Huntingtin gene (HTT) encoding for the Huntingtin protein (Htt). The protein has been linked in peripheral fibroblasts with dysregulation of cellular components which are part of lipid rafts in plasma membrane sub-domains. Therefore the analysis of the plasma membrane might be a useful diagnostic biomarker for the detection of the presence and possible onset of HD in readily accessible peripheral cells. Here Raman spectroscopy has been used with a chemometric approach in the form of Partial Least Square (PLS) for an initial corroboration that the plasma membrane is indeed a sub-cellular biomarker discriminator for HD identification. Observations were made in the spectral regions from 400 to 1800cm(-1) and 2700 to 3200cm(-1) with the former region displaying the most significant differences and peak displacement between plasma membranes extracted from HD and control fibroblast cells. The major differences in plasma membrane composition reside in sub-cellular elements putatively associated to cholesterol, phospholipids (mainly phophatidylinositol) as well as proteins containing tyrosine. These findings are indicative of the plasma membrane as an amenable biomarker for HD for further in vitro research with possible applications in vivo models. 23643335 The protective effects of parent-college student communication on dietary and physical activity behaviors. Recent studies suggest that parents maintain influence as their adolescents transition into college. Advances in communication technology make frequent communication between parents and college students easy and affordable. This study examines the protective effect of parent-college student communication on student eating and physical activity behaviors. Participants were 746 first-year, first-time, full-time students at a large university in the United States who completed a baseline and 14 daily web-based surveys. On days when students communicated with their parents for 30 minutes or more, they consumed fruits and vegetables, an additional 14%, more times and were 50% more likely to engage in 30 minutes or more of physical activity, consistent with a protective within-person effect. Encouraging parents to communicate with their college-aged children could improve these students' daily eating and physical activity behaviors and should be explored as a relatively easy and affordable component of a student preventive intervention. 23921620 Averted HIV infections due to expanded antiretroviral treatment eligibility offsets risk of transmitted drug resistance: a modeling study. Earlier antiretroviral therapy initiation can reduce the incidence of HIV-1. This benefit can be offset by increased transmitted drug resistance (TDR). We compared the preventive benefits of reducing incident infections with the potential TDR increase in East Africa. A mathematical model was constructed to represent Kampala, Uganda, and Mombasa, Kenya. We predicted the effect of initiating treatment at different immunological thresholds (<350, <500 CD4 cells/μl) on infections averted and mutation-specific TDR prevalence over 10 years compared to initiating treatment at CD4 below 200 cells/μl. When initiating treatment at CD4 below 350 cells/μl, we predict 18 [interquartile range (IQR) 11-31] and 46 (IQR 30-83) infections averted for each additional case of TDR in Kampala and Mombasa, respectively, and 22 (IQR 17-35) and 32 (IQR 21-57) infections averted when initiating at below 500. TDR is predicted to increase most strongly when initiating treatment at CD4 below 500 cells/μl, from 8.3% (IQR 7.7-9.0%) and 12.3% (IQR 11.7-13.1%) in 2012 to 19.0% (IQR 16.5-21.8%) and 19.2% (IQR 17.1-21.5%) in 10 years in Kampala and Mombasa, respectively. The TDR epidemic at all immunological thresholds was comprised mainly of resistance to non-nucleoside reverse transcriptase inhibitors. When 80-100% of individuals with virological failure are timely switched to second-line therapy, TDR is predicted to decline irrespective of treatment initiation threshold. Averted HIV infections due to the expansion of antiretroviral treatment eligibility offset the risk of transmitted drug resistance, as defined by more infections averted than TDR gained. The effectiveness of first-line non-nucleoside reverse transcriptase inhibitor-based therapy can be preserved by improving switching practices to second-line therapy. 23950662 Maternal mortality in rural South Africa: the impact of case definition on levels and trends. Uncertainty in the levels of global maternal mortality reflects data deficiencies, as well as differences in methods and definitions. This study presents levels and trends in maternal mortality in Agincourt, a rural subdistrict of South Africa, under long-term health and sociodemographic surveillance. All deaths of women aged 15 years-49 years occurring in the study area between 1992 and 2010 were investigated, and causes of death were assessed by verbal autopsy. Two case definitions were used: "obstetrical" (direct) causes, defined as deaths caused by conditions listed under O00-O95 in International Classification of Diseases-10; and "pregnancy-related deaths", defined as any death occurring during the maternal risk period (pregnancy, delivery, 6 weeks postpartum), irrespective of cause. The case definition had a major impact on levels and trends in maternal mortality. The obstetric mortality ratio averaged 185 per 100,000 live births over the period (60 deaths), whereas the pregnancy-related mortality ratio averaged 423 per 100,000 live births (137 deaths). Results from both calculations increased over the period, with a peak around 2006, followed by a decline coincident with the national roll-out of Prevention of Mother-to-Child Transmission of HIV and antiretroviral treatment programs. Mortality increase from direct causes was mainly due to hypertension or sepsis. Mortality increase from other causes was primarily due to the rise in deaths from HIV/AIDS and pulmonary tuberculosis. These trends underline the major fluctuations induced by emerging infectious diseases in South Africa, a country undergoing rapid and complex health transitions. Findings also pose questions about the most appropriate case definition for maternal mortality and emphasize the need for a consistent definition in order to better monitor and compare trends over time and across settings. 23485591 Research on cholinesterases in the Soviet Union and Russia: A historical perspective. Research on cholinesterases and effects of their inhibition in the USSR and Russia since 1930-1940s till present is exposed in historical aspects. The first physiological and toxicological effects of cholinesterase inhibition were reported by Alexander Ginetsinsky during World War II, when academic institutions were evacuated from Leningrad to Kazan. The main scientific schools that initiated research on chemistry, enzymology and physiology of cholinesterases and their inhibitors were leaded by Alexandr and Boris Arbuzovs, Victor Rozengart, Viktor Yakovlev, Michael Michelson, Martin Kabachnik, Mikhail Voronkov, Ivan Knunyants, Alexandr Bretskin and others. They investigated the main physiological effects of cholinesterase inhibitors, and analyzed the catalytic mechanisms of cholinesterases and related enzymes. Their contributions are landmarks in the history of cholinesterase research. At the present time revival of research on cholinesterases in different universities and institutes is vivid, in particular at the Moscow State University, research institutes of Russian Academy of Sciences and Kazan Scientific Center. 23970396 Extramural extension as indicator for postoperative adjuvant chemotherapy in Stage IIA (pT3N0) colon cancer. The usefulness of adjuvant chemotherapy (CMT) in patients with Stage IIA colon cancer remains unclear. The present study aimed to investigate extramural extension as an indicator for adjuvant CMT. Data were reviewed from 202 consecutive patients with Stage IIA colon cancer that underwent curative surgery between 1995 and 2007. The distance of the extramural extension (DEE) was measured histologically. The optimal prognostic cut-off point of the DEE for oncologic outcomes was statistically determined. The eligible surviving patients had been followed for a median period of 75 months (range: 2-210 months). Patients were subdivided into two groups according to the optimal cut-off point; DEE ≤5 mm (pT3a) and DEE >5 mm (pT3b). The pT3b was the most powerful independent risk factor for postoperative recurrence (P = 0.0324, HR: 3.04, 95% CI: 1.098-8.408), and was significantly correlated with distant metastasis (P = 0.0161 HR: 5.19, 95% CI: 1.765-15.239). The recurrence-free and cancer-specific 5-year survival rates in patients with pT3b were significantly lower than in patients with pT3a (81.5% vs. 95.4%, P = 0.0003 and 85.9% vs. 97.4%, P = 0.0007, respectively). pT3b could be an important risk factor for distant metastasis in Stage IIA colon cancer. Postoperative adjuvant CMT may be indicated for patients with pT3b. J. Surg. Oncol. © 2013 The Authors. Journal of Surgical Oncology Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. 22997242 Human gastric TFF2 peptide contains an N-linked fucosylated N,N'-diacetyllactosediamine (LacdiNAc) oligosaccharide. In the human stomach, the peptide trefoil factor family 2 (TFF2) is secreted together with the mucin MUC6 by mucous neck cells (MNCs) and antral gland cells. TFF2 is strongly associated with the gastric mucus and promotes gastric restitution. Here, TFF2 was purified from the human corpus and antrum, respectively, by size-exclusion chromatography, and the N-linked glycan structure at N-15 of the mature peptide was determined. As a hallmark, the unusual monofucosylated N,N'-diacetylhexosediamine (tentatively assigned as GalNAcβ1 → 4GlcNAc, LacdiNAc) modification was detected as the terminal structure of a bi-antennary complex type N-glycan exhibiting also core fucosylation. Replicate analyses did not show microheterogeneities in the fraction of peptide-N-glycosidase F cleaved and permethylated N-glycans when analyzed by matrix-assisted laser desorption ionization (MALDI) mass spectrometry (MS). On the glycopeptide level, a minor glycan microheterogeneity was evident in liquid chromatography-electrospray ionization (ESI)-MS, demonstrating the presence of underfucosylated species. The tryptic TFF2 N-glycopeptide p34-39 (LSPHNR N-glycosylated with Fuc3Hex3HexNAc6) was identified by both ESI-tandem mass spectrometry and MALDI-post-source decay analysis. Lectin analyses with the Wisteria floribunda agglutinin indicated the potential presence of LacdiNAc terminating glycans and revealed minor differences between TFF2 from fundic units, i.e. MNCs, and antral units, i.e. antral gland cells. Strikingly, on the level of the primary structure, there was no indication that the formation of the proposed LacdiNAc structure is cis-controlled by a peptidic determinant related to the published sequences. 23946828 Lanostane- and cycloartane-type triterpenoids from Abies balsamea oleoresin. Phytochemical analysis of A. balsamea oleoresin led to the isolation of three new 3,4-seco-lanostane triterpenoids 1-3, one new cycloartane triterpenoid 4 along with fourteen known terpenoids. Structure determinations were based on extensive 1D/2D NMR, IR and MS spectroscopic analyses, and comparison with literature data. The isolated compounds were evaluated in vitro for their cytotoxicity against human cell lines (A549, DLD-1, WS1) and their antibacterial activity against E. coli and S. aureus. Abiesonic acid (6) exhibited weak cytotoxic activity against A549 (IC50 = 22 µM) while compounds 1 and 4 were weakly active against S. aureus (MIC = 25 µM). 23254628 Impact of Voxel Size Variation on CBCT-Based Diagnostic Outcome in Dentistry: a Systematic Review. The objective of this study was to make a systematic review on the impact of voxel size in cone beam computed tomography (CBCT)-based image acquisition, retrieving evidence regarding the diagnostic outcome of those images. The MEDLINE bibliographic database was searched from 1950 to June 2012 for reports comparing diverse CBCT voxel sizes. The search strategy was limited to English-language publications using the following combined terms in the search strategy: (voxel or FOV or field of view or resolution) and (CBCT or cone beam CT). The results from the review identified 20 publications that qualitatively or quantitatively assessed the influence of voxel size on CBCT-based diagnostic outcome, and in which the methodology/results comprised at least one of the expected parameters (image acquisition, reconstruction protocols, type of diagnostic task, and presence of a gold standard). The diagnostic task assessed in the studies was diverse, including the detection of root fractures, the detection of caries lesions, and accuracy of 3D surface reconstruction and of bony measurements, among others. From the studies assessed, it is clear that no general protocol can be yet defined for CBCT examination of specific diagnostic tasks in dentistry. Rationale in this direction is an important step to define the utility of CBCT imaging. 23953349 Prevalence and co-occurrence of parentally reported possible asthma and allergic manifestations in pre-school children. The aim of this study was to make an in-depth analysis of the prevalence and co-occurrence in pre-school children of possible asthma and atopic manifestations. In Sweden 74%-84% of preschool children, depending on age, attend municipality organised day-care centres. Parents of 5,886 children 1--6 years of age, sampled from day-care centres in 62 municipalities all over Sweden, responded to a postal questionnaire regarding symptoms indicating prevalent possible asthma, allergic rhinitis, eczema, and food, furred pet and pollen allergy and other data in their children. Possible asthma was defined as any of the four criteria wheezing four times or more during the last year, physician diagnosis and current wheezing, ever had asthma and current wheezing, and current use of inhalation steroids, all based on questionnaire responses. The overall prevalence of possible asthma was 8.9%, of eczema 21.7%, of rhinitis 8.1%, and of food allergy 6.6%. There was a highly significant co-occurrence between possible asthma and all atopic manifestations, 35.7% having any of the manifestations. Presence of pet allergy was the manifestation showing the closest co-occurrence with presence of possible asthma, presence of pollen allergy with presence of rhinitis, and presence of food allergy with presence of eczema. Assessed from plots of age-specific prevalence of possible asthma, rhinitis, eczema and food allergy, the prevalence of all manifestations increased from one to three years of age and then decreased, except for rhinitis where the prevalence increased until six years of age, indicating no specific ordered sequence. Parentally reported possible asthma, eczema and food allergy had a curvilinear prevalence course across age with a maximum at age 3, while rhinitis prevalence increased consistently with age. Co-occurrence between possible asthma and atopic manifestations was common, and some combinations were more common than others, but there was no evidence of a specific ordered onset sequence. 23527941 Examining the relationship between alcohol-energy drink risk profiles and high-risk drinking behaviors. The mixing of alcohol and energy drinks (AMEDs) is a trend among college students associated with higher rates of heavy episodic drinking and negative alcohol-related consequences. The goals of this study were to take a person-centered approach to identify distinct risk profiles of college students based on AMED-specific constructs (expectancies, attitudes, and norms) and examine longitudinal associations between AMED use, drinking, and consequences. A random sample of incoming freshmen (n = 387, 59% female) completed measures of AMED use, AMED-specific expectancies, attitudes, and normative beliefs, and drinking quantity and alcohol-related consequences. Data were collected at 2 occasions: spring semester of freshmen year and fall semester of sophomore year. Latent profile analysis identified 4 subgroups of individuals: occasional AMED, anti-AMED, pro-AMED, and strong peer influence. Individuals in the pro-AMED group reported the most AMED use, drinking, and consequences. There was a unique association between profile membership and AMED use, even after controlling for drinking. Findings highlighted the importance of AMED-specific expectancies, attitudes, and norms. The unique association between AMED risk profiles and AMED use suggests AMED use is a distinct behavior that could be targeted by AMED-specific messages included in existing brief interventions for alcohol use. 23934785 Possible s(±)-wave pairing evidenced by midgap surface bound states in Fe-pnictide superconductors. A phenomenological theory of tunneling spectroscopy for Fe-pnictide superconductors is developed by taking into consideration asymmetric interface scattering between particle and holes. It is shown that, consistent with anti-phase s(±)-wave pairing, appreciable zero-energy surface bound states exist on the [100] surface of Fe-pnictide superconductors. However, in contrast to the [110] bound states in d-wave cuprate superconductors, these bound states arise as a result of non-conservation of momentum perpendicular to the interface for tunneling electrons and the s(±) pairing, and hence they can only exist in a small window (∼ ± 6(∘)) in the orientation of edges near the [100] direction. Our results explain why a zero-bias conductance peak is often observed in tunneling spectroscopy and why, when it disappears, two coherent peaks show up. These results provide unambiguous signals to test for possible s(±)-wave pairing in Fe-pnictide superconductors. 23428656 Cocaine-induced adaptations in D1 and D2 accumbens projection neurons (a dichotomy not necessarily synonymous with direct and indirect pathways). Cocaine exposure causes enduring neuroadaptations in ventral striatum, or nucleus accumbens (NAc), an area critically involved in reward learning and relapse of drug seeking. Medium spiny neurons (MSNs) in striatum are dichotomous in their expression of either D1 or D2 dopamine receptors, along with other receptors and neuropeptides. In dorsal striatum, these two subpopulations show non-overlapping innervation of distinct terminal fields via the direct or indirect pathways. However, NAc D1-MSNs and D2-MSNs are not fully segregated in this manner, with both cell types innervating ventral pallidum. Recent studies show that D1-MSNs and D2-MSNs play opposing roles in cocaine-associated behaviors. Further, cocaine induces differential adaptations in these two subpopulations in NAc, including changes to synaptic plasticity, glutamatergic signaling, and spine morphology. 23924333 The wish for annihilation in 'love-death' as collapse of the need for recognition, in Wagner's Tristan und Isolde. Wagner's Tristan und Isolde holds a central position in Western music and culture. It is shown to demonstrate consequences of interruption of developmental processes involving the need for recognition of subjectivity, resulting in the collapse of this need into the wish for annihilation of self and other through 'love-death' [Liebestod]. A close reading of the musical language of the opera reveals how this interruption is demonstrated, and the consequent location of identity outside of language, particularly suitable for expression in music. Isolde's dynamics are presented as distinct from that of Tristan, and in contrast to other interpretations of Tristan and Isolde's love as an attack on the Oedipal order, or as a regressive wish for pre-Oedipal union. Isolde's Act I narrative locates the origin of her desire in the protagonists' mutual gaze at a traumatic moment. In this moment powerful and contrasting emotions converge, evoking thwarted developmental needs, and arousing the fantasy of redemption in love-death. By removing the magical elements, Wagner enables a deeper understanding of the characters' positions in relation to each other, each with his or her own needs for recognition and traumatic experiences. These positions invite mutual identifications resulting in rising tension between affirmation of identity and annihilation, with actual death as the only possible psychic solution. The dynamics described in the opera demonstrate the function of music and opera in conveying meaning which is not verbally expressible. 23180678 Enantioanalysis of pipecolic acid with stochastic and potentiometric microsensors. Stochastic and potentiometric microsensors based on porphyrins and polymeric surfactants such as polysodium N-undecanoyl-L-leucylvanilate and polysodium N-undecanoyl-L-vanilate were developed for enantioselective assay of pipecolic acid. The matrices used for the design of the stochastic sensors were diamond paste and graphite paste, while the matrix used for the design of potentiometric sensors was carbon paste. The response characteristics of the microsensors were determined for the enantiomers of pipecolic acid. The response characteristics, selectivity, and enantioselectivity studies proved that the proposed microsensors can be used for clinical enantioanalysis of pipecolic acid in biological fluids, e.g., urine and whole blood. 23647397 Prostacyclin and its analogues in pulmonary artery hypertension: a meta-analysis. Abstract Objective: Individual studies examining the effects of prostacyclin and its analogues on pulmonary artery hypertension (PAH) have reported controversial results. This study aims to evaluate the efficacy of these agents for PAH by a meta-analysis based on randomized controlled trials (RCTs). Research design and methods: We systematically searched Pubmed, MEDLINE, EMBASE, ISI Web of Science, and the Cochrane Library through April 2012. All published RCTs reporting the effects of treatment with prostacyclin or its analogues in PAH were included. Summary statistics were calculated using a random effects model. Results: A total of 14 RCTs with 1606 participants were analyzed. Overall, prostacyclin and its analogues increased 6-minute walk distance (6-MWD) (weighted mean differences [WMD] = 18.78 meters, 95% confidence interval [CI]: 11.21 to 26.35; p < 0.01) and improved NYHA functional class status (odds ratios [OR] = 3.98, 95% CI: 1.70 to 9.34; p = 0.001) compared with the control. Moreover, these agents led to statistically significant reductions in mean pulmonary artery pressure (mPAP) (WMD = -4.63 mmHg, 95% CI: -6.81 to -2.44; p < 0.01) and pulmonary vascular resistance (PVR) (standardized mean difference [SMD] = -0.69, 95% CI: -0.96 to -0.43; p < 0.01). Notably, there were distinct effects on these endpoints observed in pooled subgroup analyses based on agent class (all p for interaction < 0.01). In addition, PAH-specific therapy appeared to have superiority over the control in reducing the incidence of all-cause death (OR = 0.49, 95% CI: 0.26 to 0.94; p = 0.03). However, there existed a substantial publication bias, which appeared to markedly impact the overall result of 6-MWD. Conclusions: PAH-specific treatment with prostacyclin and its analogues significantly improved exercise capacity, cardiopulmonary hemodynamics, and lowered all-cause mortality in patients with PAH. 23960209 A Segregated Neural Pathway for Prefrontal Top-Down Control of Tactile Discrimination. It has proven difficult to separate functional areas in the prefrontal cortex (PFC), an area implicated in attention, memory, and distraction handling. Here, we assessed in healthy human subjects whether PFC subareas have different roles in top-down regulation of sensory functions by determining how the neural links between the PFC and the primary somatosensory cortex (S1) modulate tactile perceptions. Anatomical connections between the S1 representation area of the cutaneous test site and the PFC were determined using probabilistic tractography. Single-pulse navigated transcranial magnetic stimulation of the middle frontal gyrus-S1 link, but not that of the superior frontal gyrus-S1 link, impaired the ability to discriminate between single and twin tactile pulses. The impairment occurred within a restricted time window and skin area. The spatially and temporally organized top-down control of tactile discrimination through a segregated PFC-S1 pathway suggests functional specialization of PFC subareas in fine-tuned regulation of information processing. 23909956 Slow Relaxation of the Magnetization of an Mn(III) Single Ion. A Mn(III)-salen-type complex with a diamagnetic [Co(III)(CN)6](3-) moiety, [Mn(III)(5-TMAM(R)-salmen)(H2O)Co(III)(CN)6]·7H2O·MeCN [1; 5-TMAM(R)-salmen = (R)-N,N'-(1-methylethylene)bis(5-trimethylammoniomethylsalicylideneiminate], was prepared. From direct-current magnetic susceptibilities, magnetization, and high-field and multifrequency electronic spin resonance measurements on powdered samples, 1 has a significant uniaxial anisotropy. Frequency-dependent alternating-current susceptibility signals were clearly observed, indicating slow magnetic relaxation. Thus, complex 1 behaves as a single-ion magnet. 23786914 Analysis of miR-137 expression and rs1625579 in dorsolateral prefrontal cortex. MicroRNAs (miRNAs) are small non-coding RNAs that act as potent regulators of gene expression. A recent GWAS reported the rs1625579 SNP, located downstream of miR-137, as the strongest new association with schizophrenia [Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA, et al. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011;43:969-76.]. Prior to this GWAS finding, a schizophrenia imaging-genetic study found miR-137 target genes significantly enriched for association with activation in the dorsolateral prefrontal cortex (DLPFC) [Potkin SG, Macciardi F, Guffanti G, Fallon JH, Wang Q, Turner JA, et al. Identifying gene regulatory networks in schizophrenia. Neuroimage 2010;53:839-47.]. We investigated the expression levels of miR-137 and three candidate target genes (ZNF804A, CACNA1C, TCF4) in the DLPFC of postmortem brain tissue from 2 independent cohorts: (1) 26 subjects (10 control (CTR), 7 schizophrenia (SZ), 9 bipolar disorder (BD)) collected at the UCI brain bank; and (2) 99 subjects (33 CTR, 35 SZ, 31 BD) obtained from the Stanley Medical Research Institute (SMRI). MiR-137 expression in the DLPFC did not differ between diagnoses. We also explored the relationship between rs1625579 genotypes and miR-137 expression. Significantly lower miR-137 expression levels were observed in the homozygous TT subjects compared to TG and GG subjects in the control group (30% decrease, p-value = 0.03). Moreover, reduced miR-137 levels in TT subjects corresponded to increased levels of the miR-137 target gene TCF4. The miR-137 expression pattern in 9 brain regions was significant for regional effect (ANOVA p-value = 1.83E-12), with amygdala and hippocampus having the highest miR-137 expression level. In conclusion, decreased miR-137 expression is associated with the SZ risk allele of rs1625579, and potential regulation of TCF4, another SZ candidate gene. This study offers additional support for involvement of miR-137 and downstream targets as mechanisms of risk for psychiatric disorders. 23237479 Effects of transcranial direct current stimulation (tDCS) on executive functions: influence of COMT Val/Met polymorphism. Transcranial direct current stimulation (tDCS) is a frequently used technique to investigate healthy and impaired neuronal functions. Its modulatory effect on executive functions is of particular interest for understanding the mechanisms underlying integration of cognition and behavior. The key role of prefrontal dopamine function for executive functions suggest that differences of the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene would interact with tDCS interventions in this domain. In this study, we hypothesized that the COMT Met allele homozygosity, associated with higher levels of prefrontal dopamine, would influence the effect of tDCS on higher-level executive functions. Forty-six healthy subjects participated in a double-blind sham-controlled crossover study and underwent COMT genotyping. Anodal tDCS (20 min, 1 mA) to the left dorsolateral prefrontal cortex (dlPFC) or sham stimulation was applied during the performance of a parametric Go/No-Go (PGNG) test measuring sustained attention, response inhibition and cognitive flexibility as measured by set-shifting. In COMT Met/Met allele carrier anodal tDCS of the dlPFC was associated with a deterioration of set-shifting ability, which is assessed by the most challenging level of the PGNG. Without regard to the carrier status of the COMT Val158Met polymorphism no effects of anodal tDCS on executive functions could be determined. In line with the model of non-linear effects of l-dopa on cortical plasticity high dopaminergic prefrontal activity mediated by COMT Val158Met polymorphism predicts a detrimental effect of anodal tDCS on cognitive flexibility. Therefore, we suggest that the individual genetic profile may modulate behavioral effect of tDCS. More precise application of brain stimulation techniques according to the individual genetic patterns may support the development of personalized treatment approaches. 23904457 Comparing the role of antibodies to nontyphoidal Salmonella in high- and low-income countries and implications for vaccine development. The article by Trebicka et al. (1) in the current issue of Clinical and Vaccine Immunology on antibodies to Salmonella among adults and children in the US, is paradoxically important for our understanding of immunity to nontyphoidal Salmonella (NTS) globally, and the development of a much-needed vaccine for Africa.… 23349208 Evaluation of suppressive and pro-resolving effects of EPA and DHA in human primary monocytes and T-helper cells. Despite their beneficial anti-inflammatory properties, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may increase the infection risk at high doses, likely by generating an immune-depressed state. To assess the contribution of different immune cell populations to the immunomodulatory fatty acid effect, we comparatively investigated several aspects of inflammation in human T-helper (Th) cells and monocytes. Both fatty acids, but DHA to a lesser extent compared with EPA, selectively and dose-dependently reduced the percentage of cytokine-expressing Th cells in a peroxisome proliferator-activated receptor (PPAR)γ-dependent fashion, whereas the expression of the cell surface marker CD69 was unaltered on activated T cells. In monocytes, both EPA and DHA increased interleukin (IL)-10 without affecting tumor necrosis factor (TNF)-α and IL-6. Cellular incorporation of EPA and DHA occurred mainly at the expense of arachidonic acid. Concomitantly, thromboxane B (TXB)2 and leukotriene B (LTB)4 in supernatants decreased, while levels of TXB3 and LTB5 increased. This increase was independent of activation and in accordance with cyclooxygenase expression patterns in monocytes. Moreover, EPA and DHA gave rise to a variety of mono- and trihydroxy derivatives of highly anti-inflammatory potential, such as resolvins and their precursors. Our results suggest that EPA and DHA do not generally affect immune cell functions in an inhibitory manner but rather promote pro-resolving responses. 23888281 Assessment of genetic diversity and distribution of endophytic fungal communities of Alternaria solani isolates associated with the dominant Karanja plants in Sanganer Region of Rajasthan. Higher plants are ubiquitously colonized with fungal endophytes that often lack readily detectable structures. Current study examines the distribution of endophytic fungal communities within Karanja plants and diversity of novel fungal endophyte Alternaria solani isolates collected from different locations of Sanganer region of Rajasthan. Results confirmed that A. solani is a major fungal endophyte consortium associated with Karanja plants. PCR Amplified fragments using random amplified polymorphic DNA (RAPD) primers were subjected to unweighted pair group method analysis (UPGMA), which clearly distinguished twelve ecologically diverse A. solani isolates. A total of 58 RAPD loci were amplified, out of which 35 (60.34%) were polymorphic and 23 were monomorphic (39.66%) in nature. These polymorphic loci were identified with an average of 2.92 bands per primer. The efficacy of RAPD markers proved as an efficient marker system with respect to detection of polymorphism and number of loci scored and can be used for the identification of a particular isolates, thereby defining core collections and strengthening their exploitation in acquiring novel products produced by them. 23792621 Size-resolved aerosol trace elements at a rural mountainous site in Northern China: Importance of regional transport. This paper presents an intensive field measurement campaign carried out at the rural mountainous site of Xinglong (960ma.s.l.) in Northern China during Sep. 3-20 2008. Size-segregated samples were collected daily and analyzed for 25 trace elements (TEs). The majority of the TEs showed comparable concentrations in fine (<2.1μm) and coarse particles (2.1-9μm). In addition, elements like K, Mn, Cu, Se, Mo, Ag, Cd, Tl and Pb were accumulated in fine mode whereas Al, Co and Sb were concentrated in a coarse mode. For most of the TEs, their enrichment factor (EF) increased with decreasing particle size from large (>9μm) to coarse, and to fine, signifying influences by anthropogenic emissions. The observed concentrations of heavy metals in fine particles, with EF values higher than 100, were significantly higher than the historical data recorded in the 1980s and 1990s, reflecting the increasing emissions in the target area. One pronounced event occurred on Sep. 14 when all of the TEs showed a peak, which was associated with regional emissions from both southeast (SE) and southwest (SW) indicated by backward trajectory analysis. This is further supported by the measurements in upwind sites where the concentrations of TEs were several times higher than those in Xinglong, suggesting potential source regions. Episodes of heavy metals were generally characterized by significant enhancements of fine mode and air mass trajectories from SE or SW alone. Taking this finding and factor analysis results together, the metallic episodes were attributable to the long-range transport of regional plumes from coal consumption and nonferrous metal smelting. With the rapid urbanization and industrialization in Northern China, the increasing emissions of TEs will place a great strain on human health and the environment in the downwind regions, thus long-term and multi-site observation with high time resolution are necessary. 23334090 Self-assembly of double helical nanostructures inside carbon nanotubes. We use molecular dynamics (MD) simulations to show that a DNA-like double helix of two poly(acetylene) (PA) chains can form inside single-walled carbon nanotubes (SWNTs). The computational results indicate that SWNTs can activate and guide the self-assembly of polymer chains, allowing them to adopt a helical configuration in a SWNT through the combined action of the van der Waals potential well and the π-π stacking interaction between the polymer and the inner surface of SWNTs. Meanwhile both the SWNT size and polymer chain stiffness determine the outcome of the nanostructure. Furthermore, we also found that water clusters encourage the self-assembly of PA helical structures in the tube. This molecular model may lead to a better understanding of the formation of a double helix biological molecule inside SWNTs. Alternatively, it could form the basis of a novel nanoscale material by utilizing the 'empty' spaces of SWNTs. 23726926 Tissue properties of the human vertebral body sub-structures evaluated by means of microindentation. The better understanding of vertebral mechanical properties can help to improve the diagnosis of vertebral fractures. As the bone mechanical competence depends not only from bone mineral density (BMD) but also from bone quality, the goal of the present study was to investigate the anisotropic indentation moduli of the different sub-structures of the healthy human vertebral body and spondylophytes by means of microindentation. Six human vertebral bodies and five osteophytes (spondylophytes) were collected and prepared for microindentation test. In particular, indentations were performed on bone structural units of the cortical shell (along axial, circumferential and radial directions), of the endplates (along the anterio-posterior and lateral directions), of the trabecular bone (along the axial and transverse directions) and of the spondylophytes (along the axial direction). A total of 3164 indentations down to a maximum depth of 2.5 µm were performed and the indentation modulus was computed for each measurement. The cortical shell showed an orthotropic behavior (indentation modulus, Ei, higher if measured along the axial direction, 14.6±2.8 GPa, compared to the circumferential one, 12.3±3.5 GPa, and radial one, 8.3±3.1 GPa). Moreover, the cortical endplates (similar Ei along the antero-posterior, 13.0±2.9 GPa, and along the lateral, 12.0±3.0 GPa, directions) and the trabecular bone (Ei= 13.7±3.4 GPa along the axial direction versus Ei=10.9±3.7 GPa along the transverse one) showed transversal isotropy behavior. Furthermore, the spondylophytes showed the lower mechanical properties measured along the axial direction (Ei=10.5±3.3 GPa). The original results presented in this study improve our understanding of vertebral biomechanics and can be helpful to define the material properties of the vertebral substructures in computational models such as FE analysis. 23969421 Indirect effect of financial strain on daily cortisol output through daily negative to positive affect index in the Coronary Artery Risk Development in Young Adults Study. Daily affect is important to health and has been linked to cortisol. The combination of high negative affect and low positive affect may have a bigger impact on increasing HPA axis activity than either positive or negative affect alone. Financial strain may both dampen positive affect as well as increase negative affect, and thus provides an excellent context for understanding the associations between daily affect and cortisol. Using random effects mixed modeling with maximum likelihood estimation, we examined the relationship between self-reported financial strain and estimated mean daily cortisol level (latent cortisol variable), based on six salivary cortisol assessments throughout the day, and whether this relationship was mediated by greater daily negative to positive affect index measured concurrently in a sample of 776 Coronary Artery Risk Development in Young Adults (CARDIA) Study participants. The analysis revealed that while no total direct effect existed for financial strain on cortisol, there was a significant indirect effect of high negative affect to low positive affect, linking financial strain to elevated cortisol. In this sample, the effects of financial strain on cortisol through either positive affect or negative affect alone were not significant. A combined affect index may be a more sensitive and powerful measure than either negative or positive affect alone, tapping the burden of chronic financial strain, and its effects on biology. 23968310 Modular Design of Redox-Responsive Stabilizers for Nanocrystals. Many potent drugs are difficult to administer intravenously due to poor aqueous solubility. A common approach for addressing this issue is to process them into colloidal dispersions known as "nanocrystals" (NCs). However, NCs possess high-energy surfaces that must be stabilized with surfactants to prevent aggregation. An optimal surfactant should have high affinity for the nanocrystal's surface to stabilize it, but may also include a trigger mechanism that could offer the possibility of altering size distribution and uptake of the NC. This study presents a modular and systematic strategy for optimizing the affinity of polymeric stabilizers for drug nanocrystals both before and after oxidation (i.e., the selected trigger), thus allowing for the optimal responsiveness for a given application to be identified. A library of 10 redox-responsive polymer stabilizers was prepared by postpolymerization modification, using the thiol-yne reaction, of two parent block copolymers. The stabilizing potential of these polymers for paclitaxel NCs is presented as well as the influence of oxidation on size and dissolution following exposure to reactive oxygen species (ROS), which are strongly associated with chronic inflammation and cancer. Owing to the versatility of postpolymerization modification, this contribution provides general tools for preparing triggered-sheddable stabilizing coatings for nanoparticles. 23880270 Role of the Extracellular Signal-regulated Kinase 1/2 Pathway in Driving Tricalcium Silicate-induced Proliferation and Biomineralization of Human Dental Pulp Cells In Vitro. The aim of this study was to investigate the role of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in regulating tricalcium silicate (C3S)-driven proliferation and biomineralization of human dental pulp cells (hDPCs) in vitro. Human DPCs were cultured in C3S-containing medium and compared with untreated controls. Cell viability was measured by the methyl-thiazol-tetrazolium assay. Biomineralization was assessed by staining calcium deposits on the extracellular matrix with von Kossa and alizarin red S stains. Phosphorylated ERK1/2 was evaluated by immunoblotting. The ERK1/2 inhibitor U0126 was used to assess the role of this pathway on stage of the cell cycle and mineralization-dependent gene expressions of hDPCs by using flow cytometry and real-time polymerase chain reaction, respectively. Data were analyzed by analysis of variance followed by the Student-Newman-Keuls post hoc test, with significance set at P < .05. The viability and biomineralization of hDPCs were promoted by C3S extracts (P < .05). Phosphorylated ERK1/2 strongly appeared after hDPCs were cultured in the C3S extracts for 30 minutes. Moreover, inhibition of the ERK1/2 pathway in C3S-treated hDPCs decreased proliferation and the expression of mineralization-dependent genes, including collagen type I, dentin sialophosphoprotein, osteopontin, and osteocalcin (P < .05). C3S stimulated the proliferation and biomineralization of hDPCs in vitro, with the ERK1/2 pathway playing a key role in the regulation of these effects. 23706552 Use of Testosterone Replacement Therapy in the United States and Its Effect on Subsequent Prostate Cancer Outcomes. To assess utilization trends and determine the effect of testosterone replacement therapy on outcomes in men who subsequently developed prostate cancer. We used linked Surveillance, Epidemiology, and End Results-Medicare data to identify 149,354 men diagnosed with prostate cancer from 1992 to 2007. Of those, 2,237 men (1.5%) underwent testosterone replacement therapy before their prostate cancer diagnosis. Propensity scoring methods were used to assess cancer-specific outcomes of testosterone replacement vs no replacement therapy. Testosterone replacement was associated with older age at cancer diagnosis, nonwhite race, and higher comorbidity (P <.001). No testosterone vs testosterone before the prostate cancer diagnosis was associated with higher grade (34% vs 30%, P <.0001) and more T4 (6.5% vs 4.3%, P <.0001) tumors. Mortality was decreased in men with â‰¥2 prostate-specific antigen (PSA) tests in the year before their cancer diagnosis. No significant difference was found between groups in overall survival, cancer-specific survival, or use of salvage androgen-deprivation therapy after initial treatment. Through our observational study design, we show that testosterone use was low throughout the study period. Testosterone use was not associated with aggressive prostate cancer and did not affect overall or disease-specific mortality. Although our findings support growing evidence that testosterone replacement is safe with respect to prostate cancer, confirmatory prospective studies are needed. 23952969 Tailoring Directional Scattering through Magnetic and Electric Resonances in Subwavelength Silicon Nanodisks. Interference of optically induced electric and magnetic modes in high-index all-dielectric nanoparticles offers unique opportunities for tailoring directional scattering and engineering the flow of light. In this article we demonstrate theoretically and experimentally that the interference of electric and magnetic optically induced modes in individual subwavelength silicon nanodisks can lead to the suppression of resonant backscattering and to enhanced resonant forward scattering of light. To this end we spectrally tune the nanodisk's fundamental electric and magnetic resonances with respect to each other by a variation of the nanodisk aspect ratio. This ability to tune two modes of different character within the same nanoparticle provides direct control over their interference, and, in consequence, allows for engineering the particle's resonant and off-resonant scattering patterns. Most importantly, measured and numerically calculated transmittance spectra reveal that backward scattering can be suppressed and forward scattering can be enhanced at resonance for the particular case of overlapping electric and magnetic resonances. Our experimental results are in good agreement with calculations based on the discrete dipole approach as well as finite-integral frequency-domain simulations. Furthermore, we show useful applications of silicon nanodisks with tailored resonances as optical nanoantennas with strong unidirectional emission from a dipole source. 23907997 Catalytic 1,4-Selective Hydrosilylation of Pyridines and Benzannulated Congeners. Radically different! The hydrosilylation of pyridines and quinolines is strictly 1,4-selective and likely involves an ionic one-step rather than the established radical two-step hydride transfer from a ruthenium(II) hydride complex onto the respective pyridinium and quinolinium ion intermediates (see scheme; Ar(F) =3,5-(CF3 )2 C6 H3 ). Even 4-substituted substrates react highly regioselectively. Isoquinolines yield the 1,2-reduced heterocycles. 23968773 Analysis of protein expression in zebrafish during gonad differentiation by targeted proteomics. The molecular mechanisms governing sex determination and differentiation in the zebrafish (Danio rerio) are not fully understood. To gain more insights into the function of specific genes in these complex processes, the expression of multiple candidates needs to be assessed, preferably on the protein level. Here, we developed a targeted proteomics method based on selected reaction monitoring (SRM) to study the candidate sex-related proteins in zebrafish which were selected based on a global proteomics analysis of adult gonads and representational difference analysis of male and female DNA, as well as on published information on zebrafish and other vertebrates. We employed the developed SRM protocols to acquire time-resolved protein expression profiles during the gonad differentiation period in vas::EGFP transgenic zebrafish. Evidence on protein expression was obtained for the first time for several candidate genes previously studied only on the mRNA level or suggested by bioinformatic predictions. Tuba1b (tubulin, alpha 1b), initially included in the study as one of the potential housekeeping proteins, was found to be preferentially expressed in the adult testis with nearly absent expression in the ovary. The revealed changes in protein expression patterns associated with gonad differentiation suggest that several of the examined proteins, especially Ilf2 and Ilf3 (interleukin enhancer-binding factors 2 and 3), Raldh3 (retinaldehyde dehydrogenase type 3), Zgc:195027 (low density lipoprotein-related receptor protein 3) and Sept5a (septin 5a), may play a specific role in the sexual differentiation in zebrafish. 23856201 Effect of systematic downsizing rigid ring annuloplasty in patients with moderate ischemic mitral regurgitation. Functional ischemic mitral regurgitation (FIMR) increases mortality independently of the baseline characteristics and ventricular function. The effect of treating FIMR with annuloplasty is unclear when mitral regurgitation is moderate. Myocardial revascularization alone has been shown to improve mitral valve function. We randomized 31 patients with moderate (grade 2-4) FIMR to receive either coronary artery bypass grafting (CABG) alone or CABG plus downsizing mitral ring annuloplasty. The patients were followed up for clinical outcomes and echocardiographic assessment of mitral valve function and left ventricular dimensions at 3 and 12 months. Clinical improvement was assessed using the Minnesota quality-of-life questionnaire, 6-minute walk test, and brain natriuretic peptide levels. The clinical course was similar in the 2 groups of patients during the study period. FIMR was perfectly corrected intraoperatively in the ring group. Echocardiographic follow-up at 3 months showed no difference in the FIMR grade between the 2 groups (66% less than grade 2 in the CABG alone and 86% in the CABG plus ring group; P = .316). The improvement in the CABG alone group was even more marked at 12 months (85% less than grade 2 in the CABG group and 85% in the CABG plus ring group). The left ventricular ejection fraction was significantly better at 3 months in the CABG alone group, although at 12 months, the left ventricular ejection fraction in the 2 groups had improved similarly. Although initially effective at reducing moderate FIMR, the addition of a ring did not change the clinical course after CABG surgery. At 12 months, no echocardiographic difference was found in terms of residual mitral regurgitation, left ventricular dimensions and function, or clinical outcomes. 23629699 Identification of PTC725, an orally bioavailable small molecule that selectively targets the hepatitis C Virus NS4B protein. While new direct-acting antiviral agents for the treatment of chronic hepatitis C virus (HCV) infection have been approved, there is a continued need for novel antiviral agents that act on new targets and can be used in combination with current therapies to enhance efficacy and to restrict the emergence of drug-resistant viral variants. To this end, we have identified a novel class of small molecules, exemplified by PTC725, that target the nonstructural protein 4B (NS4B). PTC725 inhibited HCV 1b (Con1) replicons with a 50% effective concentration (EC50) of 1.7 nM and an EC90 of 9.6 nM and demonstrated a >1,000-fold selectivity window with respect to cytotoxicity. The compounds were fully active against HCV replicon mutants that are resistant to inhibitors of NS3 protease and NS5B polymerase. Replicons selected for resistance to PTC725 harbored amino acid substitutions F98L/C and V105M in NS4B. Anti-replicon activity of PTC725 was additive to synergistic in combination with alpha interferon or with inhibitors of HCV protease and polymerase. Immunofluorescence microscopy demonstrated that neither the HCV inhibitors nor the F98C substitution altered the subcellular localization of NS4B or NS5A in replicon cells. Oral dosing of PTC725 showed a favorable pharmacokinetic profile with high liver and plasma exposure in mice and rats. Modeling of dosing regimens in humans indicates that a once-per-day or twice-per-day oral dosing regimen is feasible. Overall, the preclinical data support the development of PTC725 for use in the treatment of chronic HCV infection. 23217846 Common mental disorder diagnosis and need for treatment are not the same: findings from a population-based longitudinal survey. Controversy exists regarding whether people in the community who meet criteria for a non-psychotic mental disorder diagnosis are necessarily in need of treatment. Some have argued that these individuals require treatment and that policy makers need to develop outreach programs for them, whereas others have argued that the current epidemiologic studies may be diagnosing symptoms of distress that in many cases are self-limiting and likely to remit without treatment. All prior studies that have addressed this issue have been cross-sectional. We examined the longitudinal outcomes of individuals with depressive, anxiety and substance use (DAS) disorder(s) who had not previously received any treatment. Method Data came from a nationally representative US sample. A total of 34 653 non-institutionalized adults (age ≥20 years) were interviewed at two time points, 3 years apart. DAS disorders, mental health service use and quality of life (QoL) were assessed at both time points. Individuals with a DAS disorder who had not previously received any treatment were significantly more likely than those who had been previously treated to have remission of their index disorder(s) without subsequent treatment, to be free of co-morbid disorder(s) and not to have attempted suicide during the 3-year follow-up period (50.7% v. 33.0% respectively, p < 0.05). At wave 2, multiple linear regression demonstrated that people with a remission of their baseline DAS disorder(s) had levels of functioning similar to those without a DAS disorder. Individuals with an untreated DAS disorder at baseline have a substantial likelihood of remission without any subsequent intervention. 23899604 Increased activation of the epidermal growth factor receptor in transgenic mice overexpressing epigen causes peripheral neuropathy. In the mammalian nervous system, axons are commonly surrounded by myelin, a lipid-rich sheath that is essential for precise and rapid conduction of nerve impulses. In the peripheral nervous system (PNS), myelin sheaths are formed by Schwann cells which wrap around individual axons. While the tyrosine kinase receptors ERBB2 and ERBB3 are established mediators of peripheral myelination, less is known about the functions of the related epidermal growth factor receptor (EGFR) in the regulation of PNS myelination. Here, we report a peripheral neurodegenerative disease caused by increased EGFR activation. Specifically, we characterize a symmetric and distally pronounced, late-onset muscular atrophy in transgenic mice overexpressing the EGFR ligand epigen. Histological examination revealed a demyelinating neuropathy and axon degeneration, and molecular analysis of signaling pathways showed reduced protein kinase B (PKB, AKT) activation in the nerves of Epigen-tg mice, indicating that the muscular phenotype is secondary to PNS demyelination and axon degeneration. Crossing of Epigen-tg mice into an EGFR-deficient background revealed the pathology to be completely EGFR-dependent. This mouse line provides a new model for studying molecular events associated with early stages of peripheral neuropathies, an essential prerequisite for the development of successful therapeutic interventions. 23922227 Cost-effectiveness of hematopoietic stem cell mobilization strategies including plerixafor in multiple myeloma and lymphoma patients. Peripheral blood stem cells (PBSCs) are preferred source of hematopoietic stem cells for autologous transplantation. Mobilization of PBSCs using chemotherapy and/or granulocyte colony-stimulating factor (G-CSF) however fails in around 20%. Combining G-CSF with plerixafor increases the mobilizations success. We compared cost-effectiveness of following schemes: the use of plerixafor "on demand" (POD) during the first mobilization in all patients with inadequate response, the remobilization with plerixafor following failure of the first standard mobilization (SSP), and the standard (re)mobilization scheme without plerixafor (SSNP). Decision tree models populated with data from a first-of-a-kind patient registry in six Czech centers (n = 93) were built to compare clinical benefits and direct costs from the payer's perspective. The success rates and costs for POD, SSP and SSNP mobilizations were; 94.9%, $7,197; 94.7%, $8,049; 84.7%, $5,991, respectively. The direct cost per successfully treated patient was $7,586, $8,501, and $7,077, respectively. The cost of re-mobilization of a poor mobilizer was $5,808 with G-CSF only and $16,755 if plerixafor was added. The total cost of plerixafor "on-demand" in the sub-cohort of poor mobilizers was $17,120. Generally, plerixafor improves the mobilization success by 10% and allows an additional patient to be successfully mobilized for incremental $11,803. Plerixafor is better and cheaper if used "on demand" than within a subsequent remobilization. J. Clin. Apheresis, 2013. © 2013 Wiley Periodicals, Inc. 23780721 Nickel-Mediated Radioiodination of Aryl and Heteroaryl Bromides: Rapid Synthesis of Tracers for SPECT Imaging. Rapid and efficient radioiodination of aryl and heteroaryl bromides has been achieved using a nickel(0)-mediated halogen-exchange reaction. This transformation gives direct access to [(123) I]- and [(125) I]-imaging agents for single photon emission computed tomography (SPECT), such as 5-[(123) I]-A85380 (see scheme, Boc=tert-butyloxycarbonyl, cod=1,5-cyclooctadiene, TFA=trifluoroacetic acid). 23832043 Three new olanzapine structures: the acetic acid monosolvate, and the propan-2-ol and propan-2-one hemisolvate monohydrates. The crystal structures of three new solvates of olanzapine [systematic name: 2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine], namely olanzapine acetic acid monosolvate, C17H20N4S·C2H4O2, (I), olanzapine propan-2-ol hemisolvate monohydrate, C17H20N4S·0.5C3H8O·H2O, (II), and olanzapine propan-2-one hemisolvate monohydrate, C17H20N4S·0.5C3H6O·H2O, (III), are presented and compared with other known olanzapine forms. There is a fairly close resemblance of the molecular conformation for all studied analogues. The crystal structures are built up through olanzapine dimers, which are characterized via C-H...π interactions between the aliphatic fragment (1-methylpiperazin-4-yl) and the aromatic fragment (benzene system). All solvent (guest) molecules participate in hydrogen-bonding networks. The crystal packing is sustained via intermolecular Nhost-H...Oguest, Oguest-H...Nhost, Oguest-H...Oguest and Chost-H...Oguest hydrogen bonds. It should be noted that the solvent propan-2-ol in (II) and propan-2-one in (III) show orientational disorder. The propan-2-ol molecule lies close to a twofold axis, while the propan-2-one molecule resides strictly on a twofold axis through the carbonyl C atom. In both cases, the water molecules present positional disorder of the H atoms. 23350801 Development of an improved three-dimensional in vitro intestinal mucosa model for drug absorption evaluation. Human epithelial cell culture models of monolayer Caco-2 cells have been widely employed to assess the absorption of drug molecules across intestinal mucosa. However, cautions should be taken when interpreting the conclusions from those models due to their undesirable phenotype and functionality when compared with the native intestinal tissue. In the present study, an improved, more physiologically relevant three-dimensional (3D) culture model of the intestinal mucosa was developed to study drug absorption, in which a coculture of epithelial cells, including Caco-2 cells and HT29-methotrexate cells, was indirectly seeded on a Transwell filter insert with collagen gel and stromal cells (fibroblasts and immunocytes) incorporation. This setting-up provided a compatible environment to improve the phenotype and functionality of the epithelial cells. Compared with the monolayer culture of Caco-2 cells, the reconstructed 3D model displayed more physiologically relevant characteristics evidenced by its decreased TEER value and mucus-like layer formation. A decreased expression of P-gp and an increased expression of BCRP were also observed in the current 3D culture model, leading to a changed secretory permeability of their substrates. More importantly, an improved correlation (R(2)=0.843) was obtained between the absorptive permeability across the 3D coculture model and the human absorption fraction especially for those model compounds with moderate or high permeability. Thus, this engineered 3D coculture model presents a unique, improved opportunity to evaluate drug permeability in vitro. 23221832 Quantitative Description of the Lie-to-Sit-to-Stand-to-Walk Transfer by a Single Body-Fixed Sensor. Sufficient capacity and quality of performance of complex movement patterns during daily activity, such as standing up from a bed, is a prerequisite for independent living and also may be an indicator of fall risk. Until now, the transfer from lying-to-sit-to-stand-to-walk (LSSW) was investigated by functional testing, subjective rating or for activity classification of subtasks. The aim of this study was to use a single body-fixed inertial sensor to describe the complex movement of the LSSW transfer. Fifteen older patients of a geriatric rehabilitation clinic (median age 81 years) and ten young, healthy persons (median age 37 years) were instructed to stand up from bed in a continuous movement and to start walking. Data acquisition was performed using an inertial measurement unit worn on the lower back. Parameters extracted from the sensor outputs were able to correctly classify the subjects into a correct group with sensitivity and specificity between 90% and 100%. ICCs 3,1 of the descriptive parameters ranged between 0.85 and 0.95 in the cohort of older patients. The different strategies adopted to transfer from lying to standing up were estimated through an extended Kalman filter. The results obtained in this study suggest the usability of the instrumented LSSW test in clinical settings. 23690235 Prognostic value of survivin expression in breast cancer patients: a meta-analysis. The prognostic role of survivin expression in breast cancer patients has been widely reported. However, controversy still remains. Thus, a meta-analysis was conducted to obtain a more precise estimation of the relationship between survivin expression and overall survival (OS) in breast cancer patients. Relevant articles were selected for further assessment by online search in PubMed, EMBASE, and China National Knowledge Infrastructure. Pooled hazard ratios (HR) with 95 % confidence interval (95 % CI) were used to estimate the strength of the association between survivin expression and OS in breast cancer patients. Funnel plots of Begger's and Egger's linear regression test were used to evaluate the publication bias. Heterogeneity and sensitivity analysis were also assessed. Fifteen studies were included in the final analysis with the total number of 2,202 patients. There was a significant association between positive survivin expression and a poor OS consequence in patients with breast cancer (pooled HR 1.80, 95 % CI 1.55-2.09). No significant heterogeneity was observed among all the eligible studies (x (2) = 21.87, p = 0.081, I (2) = 36.0 %). Publication bias was absent. Sensitivity analysis revealed that the results of this meta-analysis were robust. Our results suggested that high survivin expression had an unfavorable prognostic role for patients with breast cancer. 23881854 Enhancing the Deperoxidation Activity of Cobalt(II)Acetylacetonate by the Addition of Octanoic Acid. The homolytic scission of peroxides with catalytic amounts of cobalt(II) complexes is used in several industrial oxidation processes. In this contribution, we report that addition of small amounts of octanoic acid significantly enhances the catalytic deperoxidation activity of the cobalt(II)acetylacetonate complex. We attribute this to the stabilization of the CoOOR bond upon coordination of octanoic acid, preventing the unimolecular scission. As such, the cobalt peroxo intermediate is forced to enter an alternative catalytic cycle which causes its rapid conversion to the highly reactive cobalt hydroxy. This shift in catalytic cycle results in a higher pre-exponential rate factor, over-compensating the higher barrier of the new rate-determining step. 23604005 Strain-induced Dirac cone-like electronic structures and semiconductor-semimetal transition in graphdiyne. By means of first-principles calculations combined with the tight-binding approximation, the strain-induced semiconductor-semimetal transition in graphdiyne is discovered. It is shown that the band gap of graphdiyne increases from 0.47 eV to 1.39 eV with increasing the biaxial tensile strain, while the band gap decreases from 0.47 eV to nearly zero with increasing the uniaxial tensile strain, and Dirac cone-like electronic structures are observed. The uniaxial strain-induced changes of the electronic structures of graphdiyne come from the breaking of geometrical symmetry that lifts the degeneracy of energy bands. The properties of graphdiyne under strains are found to differ remarkably from that of graphene. 23957046 A Cohort Study of Caries Incidence and Baseline Socioeconomic, Clinical and Demographic Variables: A Kaplan-Meier Survival Analysis. Purpose: To determine the incidence of dental caries and evaluate the influence of socioeconomic, clinical and demographic variables on the time for disease to appear in the permanent teeth after 3 years of follow-up. Materials and Methods: The random sample of this cohort study consisted of 427 5-year-old preschool children attending 22 public preschools in Piracicaba, SP, Brazil. Dental caries was measured using the dmf/DMF indices. The Kaplan- Meier survival analysis method was used to study the isolated effect of socioeconomic, clinical and demographic variables on caries incidence after 3 years. A Cox proportional hazards regression model was built to test the influence of the variables collected at baseline on time to develop DMFT increment. Results: Survival analysis showed that children without past caries experience in primary teeth at baseline remained caries free in permanent teeth for a longer period than children with past caries experience at baseline. The variables monthly family income, parents' educational level, number of people living in the household, home ownership and car ownership were not significant. Conclusion: Children who presented past caries experience in primary teeth at baseline are at greater risk of developing DMFT increment than children who have no past caries experience at baseline. 23861485 Cardiac Insulin Resistance and Decreased Mitochondrial Energy Production Precede the Development of Systolic Heart Failure Following Pressure Overload Hypertrophy. -Cardiac hypertrophy is accompanied by significant alterations in energy metabolism. Whether these changes in energy metabolism precede and/or contribute to the development of heart failure in the hypertrophied heart is not clear. -Mice were subjected to cardiac hypertrophy secondary to pressure-overload as a result of an abdominal aortic constriction (AAC). The rates of energy substrate metabolism were assessed in isolated working hearts obtained 1-, 2-, and 3-wks following AAC. Mice subjected to AAC demonstrated a progressive development of cardiac hypertrophy. In vivo assessment of cardiac function (via echocardiography) demonstrated diastolic dysfunction by 2-wk (20% increase in E/E'), and systolic dysfunction by 3-wk (16% decrease in %EF). Marked cardiac insulin-resistance by 2-wk post-AAC was evidenced by a significant decrease in insulin-stimulated rates of glycolysis and glucose oxidation, and plasma membrane translocation of glucose transporter 4 (GLUT4). Overall ATP production rates were decreased at 2- and 3-wk post-AAC (by 37% and 47%, respectively), due to a reduction in mitochondrial oxidation of glucose, lactate, and fatty acids that was not accompanied by an increase in myocardial glycolysis rates. Reduced mitochondrial complex V activity was evident at 3-wk post AAC, concomitant with a reduction in the ratio of phosphocreatine (PCr) to ATP. -The development of cardiac insulin-resistance and decreased mitochondrial oxidative metabolism are early metabolic changes in the development of cardiac hypertrophy, which create an energy deficit that may contribute to the progression from hypertrophy to heart failure. 23904262 IDH1 mutation is associated with improved overall survival in patients with glioblastoma: a meta-analysis. Previous studies proposed that isocitrate dehydrogenase 1 (IDH1) mutation was associated with improved survival in patients with glioblastoma, but those studies reported varying estimates and yielded inconclusive results. The purpose of the present study was to determine the effect of IDH1 mutation on the prognosis of patients with glioblastoma by performing a meta-analysis. Pubmed and Embase databases were searched for eligible studies. Studies reporting overall survival by IDH1 mutation in patients with glioblastoma were considered potentially eligible for the meta-analysis. For the quantitative aggregation of the survival results, the IDH mutation effect was measured by the pooled hazard ratio (HR) with its 95 % confidence interval (95%CI). Nine studies with a total of 1,669 patients with glioblastoma were finally included into this meta-analysis. Overall, the IDH1 mutation was associated with improved survival in patients with glioblastoma (random effects model HR = 0.45, 95%CI 0.29-0.69, P < 0.001). Sensitivity analysis further showed that the pooled estimates were stable in this meta-analysis. Therefore, the findings from this meta-analysis suggest that IDH1 mutation is associated with improved overall survival in patients with glioblastoma. 23725227 Ethical Considerations in Determining Standard of Prevention Packages for HIV Prevention Trials: Examining PrEP. The successful demonstration that antiretroviral (ARV) drugs can be used in diverse ways to reduce HIV acquisition or transmission risks - either taken as pre-exposure prophylaxis (PrEP) by those who are uninfected or as early treatment for prevention (T4P) by those living with HIV - expands the armamentarium of existing HIV prevention tools. These findings have implications for the design of future HIV prevention research trials. With the advent of multiple effective HIV prevention tools, discussions about the ethics and the feasibility of future HIV prevention trial designs have intensified. This article outlines arguments concerning the inclusion of newly established ARV-based HIV prevention interventions as standard of prevention in HIV prevention trials from multiple perspectives. Ultimately, there is a clear need to incorporate stakeholders in a robust discussion to determine the appropriate trial design for each study population. 23397572 Lithium/sulfur batteries with high specific energy: old challenges and new opportunities. In this review, we begin with a brief discussion of the operating principles and scientific/technical challenges faced by the development of lithium/sulfur cells. We then introduce some recent progress in exploring cathodes, anodes, and electrolytes for lithium/sulfur cells. In particular, several effective strategies used to enhance energy/power density, obtain good efficiencies, and prolong cycle life will be highlighted. We also discuss recent advancements in techniques for investigating electrode reactions in real time and monitoring structural/morphological changes of electrode materials under cell operating conditions to gain a better understanding of the mechanistic details of electrode processes. Finally, the opportunities and perspective for future research directions will be discussed. 23551461 Using genomic data to revisit an early example of reproductive character displacement in Haitian Anolis lizards. The pattern of reproductive character displacement (RCD)-in which traits associated with reproductive isolation are more different where two species occur together than where they occur in isolation-is frequently attributed to reinforcement, a process during which natural selection acting against maladaptive mating events leads to enhanced prezygotic isolation between species or incipient species. One of the first studies of RCD to include molecular genetic data was described 40 years ago in a complex of Haitian trunk anole lizards using a small number of allozyme loci. In this example, Anolis caudalis appears to experience divergence in the color and pattern of an extensible throat fan, or dewlap, in areas of contact with closely related species at the northern and southern limits of its range. However, this case study has been largely overlooked for decades; meanwhile, explanations for geographic variation in dewlap color and pattern have focused primarily on adaptation to local signalling environments. We reinvestigate this example using amplified fragment length polymorphism (AFLP) genome scans, mtDNA sequence data, information on dewlap phenotypes and GIS data on environmental variation to test the hypothesis of RCD generated by reinforcement in Haitian trunk anoles. Together, our phenotypic and genetic results are consistent with RCD at the southern and northern limits of the range of A. caudalis. We evaluate the evidence for reinforcement as the explanation for RCD in Haitian trunk anoles, consider alternative explanations and provide suggestions for future work on the relationship between dewlap variation and speciation in Haitian trunk anoles. 23927129 High stimulus variability in nonnative speech learning supports formation of abstract categories: Evidence from Japanese geminates. This study reports effects of a high-variability training procedure on nonnative learning of a Japanese geminate-singleton fricative contrast. Thirty native speakers of Dutch took part in a 5-day training procedure in which they identified geminate and singleton variants of the Japanese fricative /s/. Participants were trained with either many repetitions of a limited set of words recorded by a single speaker (low-variability training) or with fewer repetitions of a more variable set of words recorded by multiple speakers (high-variability training). Both types of training enhanced identification of speech but not of nonspeech materials, indicating that learning was domain specific. High-variability training led to superior performance in identification but not in discrimination tests, and supported better generalization of learning as shown by transfer from the trained fricatives to the identification of untrained stops and affricates. Variability thus helps nonnative listeners to form abstract categories rather than to enhance early acoustic analysis. 23943598 Sugar-Modified Foldamers as Conformationally Defined and Biologically Distinct Glycopeptide Mimics. To fold or not to fold? It is shown that attached sugars play a defining role in the conformations adopted by a pair of novel SAA-derived foldamers in water and that these differences are reflected in the contrasting interactions of these glycofoldamers with various biological targets. C green, O red, N blue, H gray; green oval=mannose. 23850441 An attenuated EIAV strain and its molecular clone strain differentially induce the expression of Toll-like receptors and type-I interferons in equine monocyte-derived macrophages. Activations of endosomal TLRs include TLR3, TLR7/8, and TLR9 stimulates the production of cytokines, such as type I interferons (IFNs), and therefore involves in virus-host interactions. In the present study, two equine anemia virus (EIAV) strains EIAVFDDV13 and EIAVFDDV3-8, which showed different induction on protective immunity, were compared regarding their ability to regulate the expression of endosomal TLRs, as well as type I IFNs, after infection of equine monocyte-derived macrophages (eMDMs). Our results showed that EIAVFDDV13 dramatically up-regulated the expression of TLR3 and IFNβ and less robustly up-regulated the expression of TRL9 and IFNα1, whereas EIAVFDDV3-8 induced significantly lower expression of type I IFN mRNA and protein and more strongly down-regulated the expression of TLR7 and TLR8. In addition, no significant differences in cell apoptosis were observed between these two strains. Given that the genomic variation of EIAVFDDV13 is considerably higher than that of molecular clone EIAVFDDV3-8, our results suggest that stronger TLR3 activation and increased INFβ production induced by the multi-species strain are associated with an effective vaccine-elicited protective immune response. 23824727 Red blood cell MUFAs and risk of coronary artery disease in the Physicians' Health Study. Previous studies have reported beneficial effects of a Mediterranean diet rich in monounsaturated fatty acids (MUFAs) on coronary artery disease (CAD) risk. However, these findings remain inconsistent because some experimental studies have suggested atherogenic and lipotoxicity effects of long-chain and very-long-chain MUFAs on cardiomyocytes. We examined whether red blood cell (RBC) long-chain and very-long-chain MUFAs are associated with risk of CAD in the Physicians' Health Study. The ancillary study used a prospective nested case-control design to select 1000 cases of incident CAD and 1000 control subjects matched for age, year of birth, and time of blood collection. RBC MUFAs were measured by using gas chromatography, and CAD was validated by an endpoint committee. Conditional logistic regression was used to estimate RRs. The mean (±SD) age was 68.7 ± 8.7 y. In a multivariable model that was controlled for matching factors and established CAD risk factors and RBC saturated and omega-3 (n-3) fatty acids, ORs for CAD associated with each SD increase of 20:1n-9 and log 22:1n-9 were 0.89 (95% CI: 0.80, 1.00; P = 0.0441) and 0.83 (95% CI: 0.72, 0.95; P = 0.0086). However, only the 22:1n-9-CAD relation remained statistically significant after Bonferroni correction (P < 0.0125). RBC cis 18:1n-9 and 24:1n-9 were not associated with CAD risk. Our data suggest an inverse association of RBC 22:1n-9 but not 20:1n-9, 18:1n-9, or 24:1n-9 with CAD risk after Bonferroni correction in the Physicians' Health Study. 23935961 High-sensitivity C-reactive protein and risk of sepsis. Conventional C-reactive protein assays have been used to detect or guide the treatment of acute sepsis. The objective of this study was to determine the association between elevated baseline high-sensitivity C-reactive protein (hsCRP) and the risk of future sepsis events. We studied data from 30,239 community dwelling, black and white individuals, age ≥45 years old enrolled in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Baseline hsCRP and participant characteristics were determined at the start of the study. We identified sepsis events through review of hospital records. Elevated hsCRP was defined as values >3.0 mg/L. Using Cox regression, we determined the association between elevated hsCRP and first sepsis event, adjusting for sociodemographic factors (age, sex, race, region, education, income), health behaviors (tobacco and alcohol use), chronic medical conditions (coronary artery disease, diabetes, dyslipidemia, hypertension, chronic kidney disease, chronic lung disease) and statin use. Over the mean observation time of 5.7 years (IQR 4.5-7.1), 974 individuals experienced a sepsis event, and 11,447 (37.9%) had elevated baseline hsCRP (>3.0 mg/L). Elevated baseline hsCRP was independently associated with subsequent sepsis (adjusted HR 1.56; 95% CI 1.36-1.79), adjusted for sociodemographics, health behaviors, chronic medical conditions and statin use. Elevated baseline hsCRP was associated with increased risk of future sepsis events. hsCRP may help to identify individuals at increased risk for sepsis. 23777373 Potential anti-angiogenic sulfates of andrographolide. A new regioisomer of andrographolide, 17-hydro-9-dehydro-andrographolide (1), and five new sulfates of andrographolide (2-6) were isolated from Xiyanping, a China licensed anti-inflammatory drug derived from andrographolide through sulfation reaction. Their chemical structures were elucidated by spectroscopic and chemical methods. The inhibition effects of these compounds on angiogenesis were evaluated by rat aortic ring assay. Compounds 1 and 3 exhibited strong inhibitory activities on vascular endothelial cell tube formation in rat aorta ring at the concentration of 1 Î¼M. Compounds 4 and 5 showed moderate suppression on angiogenesis at 10 Î¼M. 22209525 Computerized tomography in pediatric oncology. Computerized tomography (CT) is an extremely powerful imaging modality, which provides extremely valuable information for the diagnosis, staging, and management of pediatric solid tumors. In recent years, the concern of potential risks associated with ionizing radiation from diagnostic imaging - especially from CT - has greatly increased. In children with cancer the radiation burden from CT studies can easily accumulate because of repeated studies for disease staging, assessment of response to therapy, and follow up. The purpose of this article is to review the role of CT and its imaging key points for diagnosis, staging and planning surgical excision of common extracranial pediatric tumors, according to protocol specific imaging guidelines. The issue of the radiation burden from CT in children with cancer, and criteria of good practice to reduce it, will also be discussed. 23750461 Emotional congruence with children and sexual offending against children: A meta-analytic review. Objective: Emotional congruence with children is an exaggerated affective and cognitive affiliation with children that is posited to be involved in the initiation and maintenance of sexual offending against children. The current meta-analysis examined the relationship between emotional congruence with children and sexual offending against children, sexual recidivism, and change following sexual offender treatment. Method: A systematic literature review of online academic databases, conference proceedings, governmental agency websites, and article, book chapter, and book reference lists was performed. Thirty studies on emotional congruence with children in sexual offenders against children (SOC) were included in a random-effects meta-analysis. Results: Extrafamilial SOC-especially those with male victims-evidenced higher emotional congruence with children than most non-SOC comparison groups and intrafamilial SOC. In contrast, intrafamilial SOC evidenced less emotional congruence with children than many of the non-SOC comparison groups. Higher levels of emotional congruence with children were associated with moderately higher rates of sexual recidivism. The association between emotional congruence with children and sexual recidivism was significantly stronger in extrafamilial SOC samples (d = 0.58, 95% CI [0.31, 0.85]) compared with intrafamilial SOC samples (d = -0.15, 95% CI [-0.58, 0.27]). Similarly, emotional congruence with children showed a significant reduction from pre- to posttreatment for extrafamilial SOC (d = 0.41, 95% CI [0.33, 0.85]), but not for intrafamilial SOC (d = 0.06, 95% CI [-0.10, 0.22]). Conclusions: Emotional congruence with children is a characteristic of extrafamilial SOC, is moderately predictive of sexual recidivism, and is potentially amenable through treatment efforts. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23643448 Enhancing skills of critical reflection to evidence learning in professional practice. Professional organisations and regulatory bodies are making critical reflection a mandatory component of professional practice. Reflection is a vital part of learning from experience and is central to developing and maintaining competency across a practitioner's lifetime. This paper will discuss key educational theories to illustrate why reflection is important. Kolb's and Gibbs' reflective cycles are used to structure the process of critical reflection. Elements of the educational tradition of Bildung are discussed and integrated to enrich the understanding of self and to facilitate the reader's ability to enhance their professional practice. 23278641 Bone marrow mast cell burden and serum tryptase level as markers of response in patients with systemic mastocytosis. Abstract Two important response criteria in systemic mastocytosis (SM) are the elimination or reduction in percentage of bone marrow mast cells (MCs) and the reduction of serum tryptase levels. We investigated the accuracy of a single time point reduction of bone marrow MCs and serum tryptase level as response criteria in 50 patients with SM with available serial assessments. Bone marrow MC percentage varied significantly, with an average coefficient of variation (CV) of 65% (range, 6-173%) and 44% of patients having a CV higher than the average. The average CV for serum tryptase level was 19% (range, 0-96%), with 36% of patients having a CV higher than average. These wide variations in bone marrow MC burden and serum tryptase level were independent of the administration of SM-directed therapy, type of therapy or disease subtype. Furthermore, the achievement of a single time point therapy-induced bone marrow complete response (no histological evidence of malignant bone marrow MCs) did not correlate with tryptase level or symptomatic improvement. In conclusion, the value of single measurements of bone marrow MC percentage and serum tryptase level as response criteria in SM is not supported by clinical data. Incorporation of an assessment of the degree in reduction of MCs and tryptase, and assessment of response durability, would make response criteria more clinically meaningful. 23791213 Parenchymal volume preservation and ischemia during partial nephrectomy: functional and volumetric analysis. To determine the relative effect of type and duration of ischemia and parenchymal volume preservation on renal function after partial nephrectomy (PN). Ninety-two patients with localized renal tumors (2007-2012) managed with PN at our center with necessary studies for analysis were included. This comprised 37 patients with a solitary kidney and 55 with a contralateral kidney. Thirty-five patients were managed with hypothermia and 57 with limited warm ischemia. Volumetric computed tomography was used to measure the volume of functional parenchyma before and after PN in the operated and contralateral kidneys. Glomerular filtration rate (GFR) was determined by the modification of diet in renal disease 2 equation, along with renal scan data for patients with a contralateral kidney. Regression analysis assessed the relationships between %GFR preserved in the operated kidney and potential predictive factors. All postoperative analyses were performed 4-12 months after surgery. Median age was 61 years, median tumor size 3.5 cm, and median RENAL nephrometry score 8. Median cold ischemia time was 28 minutes and median warm ischemia time 21 minutes. Median %GFR preserved in the operated kidney was 79%. Median %parenchymal volume saved was 83%. Function in the contralateral kidney only increased marginally (median increase 6%). On regression analysis, %GFR preserved associated most strongly with %parenchymal volume saved (P <.0001), but also with lower RENAL scores (P = .0457) and the use of hypothermia (P = .0209). In contrast, ischemia time did not correlate with %GFR preserved (P = .5051). Ultimate function after PN primarily correlated with parenchymal volume preservation, whereas ischemia played a secondary role. Thus, maximal parenchymal preservation with a precise PN should be a priority during PN. 23957497 Life cycle evolution: was the eumetazoan ancestor a holopelagic, planktotrophic gastraea? Two theories for the origin of animal life cycles with planktotrophic larvae are now discussed seriously: The terminal addition theory proposes a holopelagic, planktotrophic gastraea as the ancestor of the eumetazoans with addition of benthic adult stages and retention of the planktotrophic stages as larvae, i.e. the ancestral life cycles were indirect. The intercalation theory now proposes a benthic, deposit-feeding gastraea as the bilaterian ancestor with a direct development, and with planktotrophic larvae evolving independently in numerous lineages through specializations of juveniles. Information from the fossil record, from mapping of developmental types onto known phylogenies, from occurrence of apical organs, and from genetics gives no direct information about the ancestral eumetazoan life cycle; however, there are plenty of examples of evolution from an indirect development to direct development, and no unequivocal example of evolution in the opposite direction. Analyses of scenarios for the two types of evolution are highly informative. The evolution of the indirect spiralian life cycle with a trochophora larva from a planktotrophic gastraea is explained by the trochophora theory as a continuous series of ancestors, where each evolutionary step had an adaptational advantage. The loss of ciliated larvae in the ecdysozoans is associated with the loss of outer ciliated epithelia. A scenario for the intercalation theory shows the origin of the planktotrophic larvae of the spiralians through a series of specializations of the general ciliation of the juvenile. The early steps associated with the enhancement of swimming seem probable, but the following steps which should lead to the complicated downstream-collecting ciliary system are without any advantage, or even seem disadvantageous, until the whole structure is functional. None of the theories account for the origin of the ancestral deuterostome (ambulacrarian) life cycle. All the available information is strongly in favor of multiple evolution of non-planktotrophic development, and only the terminal addition theory is in accordance with the Darwinian theory by explaining the evolution through continuous series of adaptational changes. This implies that the ancestor of the eumetazoans was a holopelagic, planktotrophic gastraea, and that the adult stages of cnidarians (sessile) and bilaterians (creeping) were later additions to the life cycle. It further implies that the various larval types are of considerable phylogenetic value. 23657596 Exploring the dermal "template effect" and its structure. Scar formation is the problem for clinic surgery. Recent studies showed that the scar formation was closely related to the dermal defect. Three-dimensional (3-d) structures of dermal tissues act as a template to modulate cell functions that are essential the regeneration of skin structure and function. The dermal tissue's integrity and continuity is a prerequisite for repair to take place. Loss of the dermal tissue integrity and continuity due to trauma leads to a lack of the template effect, which may be one important mechanism that hinders the recovery of cell function, resulting in scar formation. These studies give us two questions: what is the three-dimensional (3-d) structure of the dermal tissue? How do the tissues form? Up to now, it is well known that the molecular structure of collagen, the micro-structure of microfibril, however, the mesoscopic structure of dermal tissues is still unclear. Our recently rudimentary studies showed the problem might be resolved by phase-contrast micro-tomography with synchrotron radiation, which is likely to open new avenues for further investigations on wound regeneration and skin tissue engineering. 23628199 The generation of desired functional groups on poly(4-vinyl pyridine) particles by post-modification technique for antimicrobial and environmental applications. Poly(4-vinyl pyridine) (p(4-VP)) particles were synthesized by a simple micro-emulsion polymerization technique using sodium dodecyl sulfate (SDS) as surfactant. The prepared p(4-VP) particles were then treated various modifying agents with different functional groups. The modifying agents used in the modification of p(4-VP) particles are N-alkyl quaternizing agents such as 2-bromo ethanol (-OH), 4-bromo butyronitrile (-CN), and 2-bromoethylamine hydrobromide (-NH2). The functional groups on the modified p(4-VP) particles were confirmed by FT-IR spectrometry and zeta potential measurements. The size of p(4-VP) and modified p(4-VP) particles is between 300 and 700 nm, and the zeta potentials of modified p(4-VP) particles were varied between 2 and 45 mV. Moreover, a second post-modification was carried out on 4-bromo butyronitrile modified p(4-VP) particles by amidoximation. The modified p(4-VP) particles were also tested for their antimicrobial effects against various bacteria such as Staphylococcus aureus, Bacillus subtilis, and Escherichia coli. It was found that p(4-VP) do not posses antimicrobial properties, whereas the modified forms especially p(4-VP)(+) and p(4-VP)(+)-NH3(+) showed highly bactericidal characteristics. Due to the positive charge by means of new functional groups generated on p(4-VP)-based particles by modification, the absorption of oppositely charged reagents such as fluorescein sodium salt (FSS) was increased drastically. For example, the absorption capacity of unmodified p(4-VP) was increased to 93.3, 93.5, and 93.6 form 37.6 mg for p(4-VP)(+), p(4-VP)(+)-NH2, p(4-VP)(+)-NH3(+), respectively. Moreover, upon modification, except Cu(II), Co(II) and Ni(II) absorption capacities were increased from about 15.9, and 22.1 mg to 21.1 and 39,1 mg per gram particles. 23818591 Family-based training program improves brain function, cognition, and behavior in lower socioeconomic status preschoolers. Using information from research on the neuroplasticity of selective attention and on the central role of successful parenting in child development, we developed and rigorously assessed a family-based training program designed to improve brain systems for selective attention in preschool children. One hundred forty-one lower socioeconomic status preschoolers enrolled in a Head Start program were randomly assigned to the training program, Head Start alone, or an active control group. Electrophysiological measures of children's brain functions supporting selective attention, standardized measures of cognition, and parent-reported child behaviors all favored children in the treatment program relative to both control groups. Positive changes were also observed in the parents themselves. Effect sizes ranged from one-quarter to half of a standard deviation. These results lend impetus to the further development and broader implementation of evidence-based education programs that target at-risk families. 23870877 Ester synthesis and hydrolysis in an aqueous environment, and strain specific changes during malolactic fermentation in wine with Oenococcus oeni. Previous work has shown that Oenococcus oeni produces esterases that are capable of hydrolysing artificial substrates. Using SPME-GCMS, this study provides evidence that purified O. oeni esterases have the ability to both synthesise and hydrolyse esters. Two purified esterases (EstA2 and EstB28) synthesised ethyl butanoate and ethyl hexanoate to varying degrees. Both purified esterases hydrolysed ethyl butanoate, ethyl hexanoate and ethyl octanoate. Once this dual activity was confirmed, malolactic fermentation (MLF) trials were conducted in wine with O. oeni strains that had been previously observed to have either high or low esterase activity against artificial substrates. Strain specific differences were observed and strains with low esterase hydrolysis activity against artificial substrates had a higher level of total esters measured after MLF. The results demonstrate the impact that O. oeni has on wine aroma and relates this to the ester hydrolysis and synthesis abilities of O. oeni strains. 23611334 SAKE: a new quantification tool for positron emission tomography studies. In dynamic positron emission tomography (PET) studies, spectral analysis (SA) refers to a data-driven quantification method, based on a single-input single-output model for which the transfer function is described by a sum of exponential terms. SA allows to quantify numerosities, amplitudes and eigenvalues of the transfer function allowing, in this way, to separate kinetic components of the tissue tracer activity with minimal model assumptions. The SA model can be solved with a linear estimator alone or with numerical filters, resulting in different types of SA approaches. Once estimated the number, amplitudes and eigenvalues of the transfer function, one can distinguish the presence in the system of irreversible and/or reversible components as well as derive parameters of physiological significance. These characteristics make it an appealing alternative method to compartmental models which are widely used for the quantitative analysis of dynamic studies acquired with PET. However, despite its applicability to a large number of PET tracers, its implementation is not straightforward and its utilization in the nuclear medicine community has been limited especially by the lack of an user-friendly software application. In this paper we proposed SAKE, a computer program for the quantitative analysis of PET data through the main SA methods. SAKE offers a unified pipeline of analysis usable also by people with limited computer knowledge but with high interest in SA. 23186244 Ion pair dynamics: solvolyses of chiral 1,3-diarylallyl carboxylates as a case study. Chiral ion pairs play a key role in modern enantioselective synthesis, though little is known about their properties. We have now used the special features of unsymmetrically substituted allyl derivatives to obtain unprecedented insight into ion pair dynamics. By employing chiral high-performance liquid chromatography, it was possible to follow the time-dependent concentrations of all four isomeric esters (two regioisomeric pairs of enantiomers) and all four isomeric alcohols generated during the hydrolysis of enantiopure 1-(4-chlorophenyl)-3-phenylallyl and 3-(4-chlorophenyl)-1-phenylallyl 4-nitrobenzoates. Combination of these results with the directly measured rate constant for the reaction of the laser-flash photolytically generated 1-(4-chlorophenyl)-3-phenylallyl cation with water provided a complete mechanistic scheme for allyl carboxylate solvolysis. It is demonstrated that solvolysis and internal return can be explained by the same intermediates. The correlation equation log k = s(N)(N + E) was used to elucidate the variable importance of external and internal return in the solvolysis reactions. This information will be crucial for the interpretation of the ultrafast dynamics of ion pairs generated by femtosecond laser pulses. 23740385 An ultrasensitive, non-enzymatic glucose assay via gold nanorod-assisted generation of silver nanoparticles. This report demonstrates a colorimetric, non-enzymatic glucose assay with a low detection limit of 0.07 μM based on negatively charged gold nanorod-enhanced redox reaction. This glucose assay could generate silver nanoparticles as the readout that can be visualized by the naked eye, and only 4 femtomoles of nanorods are needed for glucose determination in one human plasma sample. 23970395 Malformations, genetic abnormalities, and wilms tumor. Wilms Tumor (WT) can occur in association with tumor predisposition syndromes and/or with clinical malformations. These associations have not been fully characterized at a clinical and molecular genetic level. This study aims to describe clinical malformations, genetic abnormalities, and tumor predisposition syndromes in patients with WT and to propose guidelines regarding indications for clinical and molecular genetic explorations. This retrospective study analyzed clinical abnormalities and predisposition syndromes among 295 patients treated for WT between 1986 and 2009 in a single pediatric oncological center. Clinically identified malformations and predisposition syndromes were observed in 52/295 patients (17.6%). Genetically proven tumor predisposition syndromes (n = 14) frequently observed were syndromes associated with alterations of the chromosome WT1 region such as WAGR (n = 6) and Denys-Drash syndromes (n = 3), syndromes associated with alterations of the WT2 region (Beckwith-Wiedeman syndrome, n = 3), and Fanconi anemia (n = 2). Hemihypertrophy and genito-urinary malformations (n = 12 and n = 16, respectively) were the most frequently identified malformations. Other different syndromes or malformations (n = 10) were less frequent. Median age of WT diagnosis was significantly earlier for children with malformations than those without (27 months vs. 37 months, P = 0.0009). There was no significant difference in terms of 5-year EFS and OS between WT patients without or with malformations. The frequency of malformations observed in patients with WT underline the need of genetic counseling and molecular genetic explorations for a better follow-up of these patients, with a frequently good outcome. A decisional tree, based on clinical observations of patients with WT, is proposed to guide clinicians for further molecular genetic explorations. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc. 23523964 Differential effects of acute and chronic zinc (Zn) exposure on hepatic lipid deposition and metabolism in yellow catfish Pelteobagrus fulvidraco. The present study is conducted to determine the potential mechanisms of Zn on hepatic lipid deposition and metabolism for yellow catfish Pelteobagrus fulvidraco with 8-week chronic exposure to low Zn levels (Zn levels: 0.05, 0.35 and 0.86mg/l Zn, respectively) and 96-h acute exposure to a high Zn level (Zn level: 4.71mg/l Zn, respectively). For that purpose, hepatic lipid deposition and Zn accumulation, hepatic carnitine palmitoyltransferase I (CPT I) and lipoprotein lipase (LPL) activities, and the hepatic mRNA expression of ten genes involved in lipid metabolism are determined. Chronic (8 weeks) exposure to low Zn levels apparently increases hepatic lipid content, hepatosomatic index (HSI) (P<0.05) and LPL activity, and reduces hepatic CPT I activity. In contrast, the acute (96h) exposure to high Zn level reduces hepatic lipid content, HSI and LPL activity, and increases CPT I activity. The change of mRNA levels of genes related to lipid metabolism is Zn concentration-dependent. Pearson correlations among mRNA expression levels, lipid content, CPT I and LPL activities in liver are also observed in yellow catfish with the 8-week chronic Zn exposure. For the first time, our study demonstrates the effect of waterborne Zn exposure on lipid metabolism at the molecular levels in fish, which may contribute to understanding the mechanism of Zn-induced hepatic toxicity in fish. 23504216 The effect of chronic seaweed subsidies on herbivory: plant-mediated fertilization pathway overshadows lizard-mediated predator pathways. Flows of energy and materials link ecosystems worldwide and have important consequences for the structure of ecological communities. While these resource subsidies typically enter recipient food webs through multiple channels, most previous studies focussed on a single pathway of resource input. We used path analysis to evaluate multiple pathways connecting chronic marine resource inputs (in the form of seaweed deposits) and herbivory in a shoreline terrestrial ecosystem. We found statistical support for a fertilization effect (seaweed increased foliar nitrogen content, leading to greater herbivory) and a lizard numerical response effect (seaweed increased lizard densities, leading to reduced herbivory), but not for a lizard diet-shift effect (seaweed increased the proportion of marine-derived prey in lizard diets, but lizard diet was not strongly associated with herbivory). Greater seaweed abundance was associated with greater herbivory, and the fertilization effect was larger than the combined lizard effects. Thus, the bottom-up, plant-mediated effect of fertilization on herbivory overshadowed the top-down effects of lizard predators. These results, from unmanipulated shoreline plots with persistent differences in chronic seaweed deposition, differ from those of a previous experimental study of the short-term effects of a pulse of seaweed deposition: while the increase in herbivory in response to chronic seaweed deposition was due to the fertilization effect, the short-term increase in herbivory in response to a pulse of seaweed deposition was due to the lizard diet-shift effect. This contrast highlights the importance of the temporal pattern of resource inputs in determining the mechanism of community response to resource subsidies. 23880411 Two polyoxometalate-based coordination polymers constructed from Mn(II)-4,4'-bipyridine-N,N'-dioxide building blocks and Keggin-type clusters: Syntheses, crystal structures and spectral properties. Two polyoxometalate-based coordination polymers {[Mn2(dpdo)4(H2O)6](GeMo12O40)(H2O)4}n (1) and {[Mn2(dpdo)4(H2O)6](GeW12O40)(H2O)3}n (2) (dpdo=4,4'-bipyridine-N,N'-dioxide) have been synthesized and characterized by IR, elemental analysis, XRPD, TG technique and X-ray crystallography. The polymers 1 and 2 are basically isostructural and feature a 3D supramolecular framework decorated with Keggin-type polyanion clusters based on one-dimension polymeric chains, which formed through the coordination interaction of Mn(II) and dpdo. The luminescent properties of the polymers were investigated in the solid state at room temperature. 22278137 Mucopolysaccharidosis: cardiologic features and effects of enzyme-replacement therapy in 24 children with MPS I, II and VI. We determined the cardiologic features of children with MPS I, II and VI, and evaluated the effect of enzyme-replacement therapy (ERT) on cardiac disease. Twenty-four children aged 1-18 years with MPS I, II or VI were prospectively evaluated with echocardiogram and electrocardiogram from the start of enzyme-replacement therapy up to 6 years of treatment. At start of therapy, 66% had abnormal cardiac geometric features. Left-ventricular mass index (LVMI) was increased in half of the patients, due mainly to concentric hypertrophy in MPS I and II and to eccentric hypertrophy in MPS VI. Regurgitation was most severe in a subgroup of young MPS VI patients (<5 years) at the mitral valve. At baseline, all patients had abnormal valves. The ECG showed no clear rhythm or conduction abnormalities; neither, in most patients, did it reflect the hypertrophy. After ERT, the LVMI Z-score normalized in 70% of the patients who had a Z-score > 2. LVMI Z-scores decreased significantly in patients with MPS I and MPS II (p = 0.04 and p = 0.032). Despite ERT, valve regurgitation increased in 60% of the patients. We conclude that all our MPS patients have cardiac abnormalities. The most severe cardiac disease was observed in a subgroup of young MPS VI patients. While ERT had an effect on LVMI and IVSd, it apparently had little or none on valve regurgitation. 23624115 Anthelmintic activity of Arisaema franchetianum and Arisaema lobatum essential oils against Haemonchus contortus. ETHNOPHARMACOLOGICAL RELEVANCE: Arisaema franchetianum and Arisaema lobatum are two perennial plants native to China. Arisaema franchetianum is universally used to promote the subsidence of induration and swelling, quicken blood and relieve pains, and kill intestinal parasites in humans and animals. Arisaema lobatum is used to treat malaria, intestinal parasites, and snake and insect bites in humans and animals. The aim of this study was to determine the composition of the essential oils from Arisaema franchetianum and Arisaema lobatum and evaluate the anthelmintic effect against Haemonchus contortus. MATERIALS AND METHODS: Two oils were investigated by GC and GC-MS. The anthelmintic bioassay tests of Arisaema franchetianum and Arisaema lobatum essential oil, linalool and carvacrol were performed using egg hatch assay (EHA), larval development assay (LDA) and larval migration inhibition assay (LMIA). RESULTS: Fifty six components representing 96.88% of the Arisaema franchetianum oil and 64 components representing 96.88% of the Arisaema lobatum oil were identified. Carvacrol and linalool were found to be the major constituents of two oils. In the EHA, greater than 99% inhibition were observed with Arisaema franchetianum oil at 10mg/mL (CE50 1.63mg/mL) and Arisaema lobatum oil at 5 and 10mg/mL (CE50 0.48mg/mL). In the LDA, both oils induced complete inhibition at 10mg/mL, with the CE50 being 1.10mg/mL for Arisaema franchetianum oil and 0.73mg/mL for Arisaema lobatum oil. In the LMIA, the Arisaema franchetianum oil and Arisaema lobatum oil at best inhibited 74.1% and 95.6% of larval migration at 10mg/mL, respectively. Carvacrol exhibited similar activity to Arisaema lobatum essential oil and linalool did not show high activity in every assay. CONCLUSIONS: These data show for the first time that the essential oils obtained from Arisaema franchetianum or Arisaema lobatum had promising anthelmintic activity against Haemonchus contortus. Arisaema plant may offer an alternative source for the control of gastrointestinal nematodes of sheep and goats. 23673553 Rapid assessment of homogeneity and stability of amorphous solid dispersions by atomic force microscopy--from bench to batch. To verify the robustness and fundamental value of Atomic Force Microscopy (AFM) and AFM-based assays to rapidly examine the molecular homogeneity and physical stability of amorphous solid dispersions on Hot-Melt-Extrudates. Amorphous solid dispersions were prepared with a Hot-Melt Extruder (HME) and profiled by Raman Microscopy and AFM following a sequential analytical routine (Multi-Scale-Imaging-of-Miscibiliy (MIMix)). Extrudates were analyzed before and after incubation at elevated temperature and humidity. The data were compared with published results as collected on miniaturized melt models. The value of molecular phase separation rates for long term stability prediction was assessed. Data recorded on the extrudates are consistent with those published, and they can be compared side by side. Such direct data comparisons allow the identification of possible sources of extrudate heterogeneities. The surface roughness analysis of fracture-exposed interfaces is a novel quantitative way to trace on the nanometer scale the efficiencies of differently conducted HME-processes. Molecular phase separation rates are shown to be relevant for long term stability predictions. The AFM-based assessment of API:excipient combinations is a robust method to rapidly identify miscible and stable solid dispersions in a routine manner. It provides a novel analytical tool for the optimization of HME processes. 23454417 Protein nitration promotes inducible nitric oxide synthase transcription mediated by NF-κB in high glucose-stimulated human lens epithelial cells. Although an important event in hyperglycaemia-induced oxidative stress is the nuclear factor-kappa b (NF-κB)-activated inducible nitric oxide synthase (iNOS) expression, the underlying mechanism is not fully characterized. Peroxynitrite, formed from NO and superoxide, can induce multiple proteins nitration, even including NF-κB and iNOS, to alter their functions. In this study, we found high glucose caused conspicuous nitration of nuclear NF-κB p65 and its co-activator p300 in human lens epithelial cells. The nitration of NF-κB and p300 promoted their co-localization and binding to ensure the activation of the iNOS gene transcription. Moreover, nearly all predicted NF-κB binding sites in the human iNOS gene promoter were responsive to high glucose stimulation, might for a synergistic role. While, only the NF-κB binding site -5212 showed significant alterations by high glucose and peroxynitrite stimulations, indicating it a more important role in the protein nitration promoted iNOS gene transcription. Our results demonstrated that protein nitration can promote the NF-κB-activated iNOS gene transcription in human lens epithelial cells by high glucose stimulation. 23904473 A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study). This study compared the efficacy and safety of subcutaneous (SC) versus intravenous (IV) formulations of tocilizumab in patients with rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs (DMARD). Patients (n=1262) were randomly assigned to receive tocilizumab-SC 162 mg weekly+placebo-IV every 4 weeks or tocilizumab-IV 8 mg/kg every 4 weeks+placebo-SC weekly in combination with traditional DMARD. The primary outcome was to demonstrate the non-inferiority of tocilizumab-SC to tocilizumab-IV with regard to the proportion of patients in each group achieving an American College of Rheumatology (ACR) 20 response at week 24 using a 12% non-inferiority margin (NIM). Secondary outcomes were disease activity score using 28 joints (DAS28), ACR responses, health assessment questionnaire scores and safety assessments. At week 24, 69.4% (95% CI 65.5 to 73.2) of tocilizumab-SC-treated patients versus 73.4% (95% CI 69.6 to 77.1) of tocilizumab-IV-treated patients achieved an ACR20 response (weighted difference between groups -4.0%, 95% CI -9.2 to 1.2); the 12% NIM was met. ACR50/70 responses, DAS28 and physical function improvements were comparable between the tocilizumab-SC and tocilizumab-IV groups. The safety profiles of tocilizumab-SC and tocilizumab-IV were similar, and the most common adverse event was infection. Injection-site reactions (ISR) occurred more frequently in the tocilizumab-SC group than in the tocilizumab-IV (placebo-SC) group. No anaphylaxis was reported over the 24 weeks. Tocilizumab-SC 162 mg weekly demonstrated comparable efficacy to tocilizumab-IV 8 mg/kg. The safety profile of tocilizumab-SC is consistent with the known and well-established safety profile of tocilizumab-IV, with the exception of a higher incidence of ISR, which were more common with tocilizumab-SC administration. 23611883 Learning to smell: repeated exposure increases sensitivity to androstenone, a major component of boar taint. This study aimed to assess whether repeated exposure affects subjects' ability to detect androstenone. Olfactory acuity of 77 female and 44 male subjects (age 37.5 ± 11.7 years) was assessed three times during six weeks. Replicate triangle tests using various dilutions of androstenone (0.5, 5.0, and 50.0 μg/g) on filter paper smell strips were applied. Subjects were either assigned to a test group (TRAIN) using androstenone for daily training, or to a control group (CONTR) using a placebo. For the low, the intermediate, and the high level of androstenone presented, detection rate increased from 14.1 to 30.6%, 40.5 to 62.8%, and 65.3 to 78.5% respectively within 6 weeks from the initial assessment. Results suggest that mere exposure during repeated olfactory testing increased subjects' ability to correctly discriminate androstenone. The olfactory improvement was, however, more pronounced in the TRAIN group. Androstenone detection appears to be associated with its individual appreciation. 23181669 Brewster angle microscopy of Langmuir films of athabasca bitumens, n-C5 asphaltenes, and SAGD bitumen during pressure-area hysteresis. Bitumen films formed on water surfaces have negative consequences, both environmental and economic. CanmetENERGY has placed considerable research emphasis on understanding the structures of the bitumen films on water as a necessary step before optimization of bitumen extraction. The detailed structures of the adsorbed molecules and, especially, the role of asphaltene molecules at the interfaces are still under scrutiny and debate. In the present study, we compared bitumen and asphaltene films as they were compressed and expanded under various surface pressures in order to achieve a clearer understanding of bitumen film structures. We used a customized NIMA Langmuir trough interfaced to a Brewster angle microscope (BAM) and CCD camera (Nanofilm_ep3BAM, Accurion, previously Nanofilm Gmbh) to study images of bitumen films at the air/water interface. The bitumen film appeared uniform with high reflectivity at a surface pressure of 18 mN·m(-1) and exhibited a coarse pebblelike interface with reduced reflectivity in the liquid condensed (LC) phase at higher pressures (18-35 mN·m(-1)). During the first cycle of compression asphaltene films showed well-defined phase transitions and a uniformly smooth interface in the LC phase between 9 and 35 mN·m(-1). However, folding or buckling occurred at surface pressures from 35 to 44 mN·m(-1). On expansion, asphaltene films appeared to break into islands. The hysteresis of the pressure-area isotherm was much larger for asphaltenes than for bitumen. In both compression and expansion cycles, BAM images for bitumen films appeared to be more reproducible than those of the asphaltene films at the same surface pressures. Films for low-°API SAGD bitumen were almost identical to those for surface-mined bitumen. Films formed from partially deasphalted surface-mined bitumens showed higher compressibility and lower rigidity than the original bitumen. The BAM images illustrated significant differences between the partially deasphalted and original bitumen films. Other components in bitumen also played important roles in determining the interfacial properties of bitumen films. 23266383 Clinical characteristics of norovirus-associated deaths: a systematic literature review. Although deaths are often reported in the context of norovirus outbreaks, clinical and epidemiologic characteristics of the decedents prior to death are not well established. Through a literature review of published reports of deaths associated with norovirus infection, we identified and summarized 158 norovirus-associated deaths in 12 countries from 1988 to 2011. 23731774 Crosstalk between B16 melanoma cells and B-1 lymphocytes induces global changes in tumor cell gene expression. The analysis of gene expression patterns in cancers has improved the understanding of the mechanisms underlying the process of metastatic progression. However, the acquisition of invasive behavior in melanoma is poorly understood. In melanoma, components of the immune system can contribute to tumor progression, and inflammatory cells can influence almost all aspects of cancer progression, including metastasis. Recent studies have attributed an important role to B-1 cells, a subset of B lymphocytes, in melanoma progression. In vitro interactions between B16 melanoma cells and B-1 lymphocytes lead to increased B16 cell metastatic potential, but the molecular changes induced by B-1 lymphocytes on B16 cells have not yet been elucidated. In this study, we used a microarray approach to assess the gene expression profile of B16 melanoma cells following contact with B-1 lymphocytes (B16B1). The microarray analysis identified upregulation in genes involved with metastatic progression, such as ctss, ccl5, cxcl2 and stat3. RT-qPCR confirmed this increase in mRNA expression in B16B1 samples. As previous studies have indicated that the ERK1/2 MAPK cascade is activated in melanoma cells following contact with B-1 lymphocytes, RT-qPCR was performed with RNA from melanoma cells before and after contacting B-1 cells and untreated or treated with ERK phosphorylation inhibitors. The results showed that the expression of stat3, ctss and cxcl2 increased in B16B1 but decreased following ERK1/2 MAPK inhibition. Ccl5 gene expression increased after contacting B-1 cells and was maintained at the same level following inhibitor treatment. Stat3 was verified and validated at the protein level by Western blot analysis. STAT3 expression was also significantly increased in B16B1, suggesting that this pathway can also contribute to the increased metastatic phenotype observed in our model. These results indicated that B-1 cells induce important global gene expression changes in B16 melanoma cells. We also evaluated the relationship of some of the genes identified as differentially expressed and the ERK1/2 MAPK cascade. This work may have important implications for understanding the role of B-1 lymphocytes and the ERK/MAPK cascade in the metastatic process. 23010392 Changes in trace elements during lactation in a marine top predator, the grey seal. Lactation in pinnipeds represents the most significant cost to mothers during the reproductive cycle. Dynamics of trace elements and their mobilization associated with energy reserves during such an intense physiological process remains poorly understood in marine mammals. The changes in tissue concentrations of 11 elements (Ca, Cd, Cr, Cu, Fe, Hg, Ni, Pb, Se, V, and Zn) were investigated in a longitudinal study during the lactation period and during the post-weaning fast period. Blood, milk, blubber, and hair samples were collected sequentially from 21 mother-pup pairs of grey seals (Halichoerus grypus) from the Isle of May in Scotland. Maternal transfer through the milk was observed for all trace elements, except for Cd. As an indicator of the placental transfer, levels in pup lanugo (natal coat) revealed also the existence of maternal transfer and accumulation of all assayed trace elements during the foetal development. The placental and mammary barriers against non-essential metal transfer to offspring appear to be absent or weak in grey seals. Examining the contamination levels showed that this grey seal population seems more highly exposed to Pb than other phocid populations (2.2 mg/kg dw of grey seal hair). In contrast, blood and hair levels reflected a lower Hg exposure in grey seals from the Isle of May than in harbour seals from the southeastern North Sea. This study also showed that trace element concentrations in blood and blubber could change rapidly over the lactation period. Such physiological processes must be considered carefully during biomonitoring of trace elements, and potential impacts that rapid fluctuations in concentrations can exert on seal health should be further investigated. 23512195 Association between linear measurements of corpus callosum and gait in the elderly. Segmentation and diffusion-tensor-imaging of the corpus callosum (CC) have been linked to gait impairment. However, such measurements are impracticable in clinical routine. The purpose of this study was to evaluate the association between simple linear measurements of CC thickness with gait. Two hundred and seventy-two community-dwelling subjects underwent neurological assessment and brain MRI. Mid-sagittal reformats of T1-weighted images were used to determine CC thickness. The association of measurements with clinical evaluation of gait was assessed by multivariate regression, controlling for numerous clinical and imaging confounders. Differences in CC thickness were, moreover, compared between subgroups with no, moderate or severe impairment of gait. In univariate analyses, thickness of the genu and body of CC but not the splenium were associated with postural stability (P < 0.01). Multivariate regression revealed thickness of CC genu as the only imaging variable independently associated with gait (P = 0.01). Genu thickness was significantly different between subjects with high and low (P = 0.0003) or high and moderate (P = 0.001) risk of fall. Atrophy of the CC genu is an imaging marker of gait impairment in the elderly suggesting higher risk of fall. Simple linear measurements of CC can help in MRI evaluation of patients with gait impairment. • Regional atrophy of the corpus callosum reflects disruption of gait regulation • Genu thickness on cranial MRI is an independent marker of gait impairment • Findings help in the MRI evaluation of patients with gait impairment. 23736038 Silica-supported Ti chloride tetrahydrofuranates, precursors of Ziegler-Natta catalysts. The structural and electronic properties of silica-supported titanium chloride tetrahydrofuranates samples, obtained by impregnating a polymer-grade dehydroxylated silica with TiCl4(thf)2 and TiCl3(thf)3 complexes, precursors of Ziegler-Natta catalysts, are investigated by means of FT-IR, XAS, XES and diffuse reflectance UV-Vis spectroscopy, coupled with DFT calculations. The properties of the two silica-supported samples are very similar, irrespective of the starting precursor. In both cases, most of the chlorine ligands originally surrounding the Ti sites are substituted by oxygen ligands upon grafting on silica. As a consequence, the electronic properties of silica-supported Ti sites are largely different from those of the corresponding precursors, and in both cases most of the grafted Ti sites have a formal oxidation state of +4. The whole set of experimental data provide evidence that mono-nuclear Ti species are mainly present at the silica surface. 23350872 Termini of bottom-up fabricated graphene nanoribbons. Atomically precise graphene nanoribbons (GNRs) can be obtained via thermally induced polymerization of suitable precursor molecules on a metal surface. This communication discusses the atomic structure found at the termini of armchair GNRs obtained via this bottom-up approach. The short zigzag edge at the termini of the GNRs under study gives rise to a localized midgap state with a characteristic signature in scanning tunneling microscopy (STM). By combining STM experiments with large-scale density functional theory calculations, we demonstrate that the termini are passivated by hydrogen. Our results suggest that the length of nanoribbons grown by this protocol may be limited by hydrogen passivation during the polymerization step. 22438199 Brain activity during sympathetic response in anticipation and experience of pain. Pain is a multidimensional phenomenon with sensory, affective, and autonomic components. Here, we used parametric functional magnetic resonance imaging (fMRI) to correlate regional brain activity with autonomic responses to (i) painful stimuli and to (ii) anticipation of pain. The autonomic parameters used for correlation were (i) skin blood flow (SBF) and (ii) skin conductance response (SCR). During (i) experience of pain and (ii) anticipation of pain, activity in the insular cortex, anterior cingulate cortex (ACC), prefrontal cortex (PFC), posterior parietal cortex (PPC), secondary somatosensory cortex (S2), thalamus, and midbrain correlated with sympathetic outflow. A conjunction analysis revealed a common central sympathetic network for (i) pain experience and (ii) pain anticipation with similar correlations between brain activity and sympathetic parameters in the anterior insula, prefrontal cortex, thalamus, midbrain, and temporoparietal junction. Therefore, we here describe shared central neural networks involved in the central autonomic processing of the experience and anticipation of pain. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc. 23329466 Ranolazine: a review of its use as add-on therapy in patients with chronic stable angina pectoris. Extended-release ranolazine (ranolazine ER) [Ranexa(®)] is an antianginal agent that achieves its effects via a novel mechanism of action (inhibition of the late phase of the inward sodium current), without affecting heart rate or blood pressure (BP). This article reviews the efficacy, safety and tolerability of ranolazine ER as add-on therapy in patients with chronic stable angina pectoris, as well as summarizing its pharmacological properties and its use in non-ST-elevation acute coronary syndromes. In the CARISA and ERICA trials, add-on therapy with ranolazine ER improved exercise tolerance and/or reduced angina frequency and nitroglycerin use in patients with chronic stable angina; benefits were seen across a variety of patient subgroups. Although results of the MERLIN-TIMI 36 trial do not support the use of ranolazine ER in the acute management of non-ST-elevation acute coronary syndromes, they do support its use as an antianginal therapy. Ranolazine ER was generally well tolerated, with the most commonly reported adverse events including dizziness, nausea, asthenia and constipation. Despite being associated with modest increases in the corrected QT interval, ranolazine ER demonstrated antiarrhythmic effects in the MERLIN-TIMI 36 trial. In conclusion, ranolazine ER provides an important option for use as add-on therapy to reduce symptoms in patients with chronic stable angina. 23659920 Can concreteness training buffer against the negative effects of rumination on PTSD? An experimental analogue study. Trauma-related rumination has been found to be an important maintaining factor for PTSD. On the background of the processing mode account of ruminative thinking, this study tested whether the relationship between rumination and analogue PTSD symptoms can be modified by training participants in a concrete mode of processing. Healthy participants were trained in either an abstract or a concrete style of processing. Afterwards, they watched a stressful film. The interactive effect of training condition and trait rumination on intrusive memories of the film was examined. Following abstract training, a positive relationship between trait rumination and intrusive memories of the film emerged. As hypothesized, this relationship disappeared following concrete training. include the lack of a no-training control group and the analogue paradigm used. The study provides preliminary evidence that the relationship between trait rumination and analogue PTSD symptoms can be modified. If replicated in future studies, it may be promising to examine the value of concreteness training for prevention and/or treatment of PTSD. 22864678 Culture of human bone marrow-derived mesenchymal stem cells on of poly(L-lactic acid) scaffolds: potential application for the tissue engineering of cartilage. Due to the attractive properties of poly(L-lactic acid) (PLLA) for tissue engineering, the aim was to determine the growth and differentiation capacity of mesenchymal stromal cells (MSCs) in PLLA scaffolds and their potential use in the treatment of cartilage diseases. MSCs were cultured in PLLA films and thin porous membranes to study adherence and proliferation. Permeability and porosity were determined for the different scaffolds employed. The optimal conditions for cell seeding were first determined, as well as cell density and distribution inside the PLLA. Scaffolds were then maintained in expansion or chondrogenic differentiation media for 21 days. Apoptosis, proliferation and chondrogenic differentiation was assessed after 21 days in culture by immunohistochemistry. Mechanical characteristics of scaffolds were determined before and after cell seeding. MSCs uniformly adhered to PLLA films as well as to porous membranes. Proliferation was detected only in monolayers of pure PLLA, but was no longer detected after 10 days. Mechanical characterization of PLLA scaffolds showed differences in the apparent compression elastic modulus for the two sizes used. After determining high efficiencies of seeding, the production of extracellular matrix (ECM) was determined and contained aggrecan and collagens type I and X. ECM produced by the cells induced a twofold increase in the apparent elastic modulus of the composite. Biocompatible PLLA scaffolds have been developed that can be efficiently loaded with MSCs. The scaffold supports chondrogenic differentiation and ECM deposition that improves the mechanics of the scaffold. Although this improvement does not met the expectations of a hyaline-like cartilage ECM, in part due to the lack of a mechanical stimulation, their potential use in the treatment of cartilage pathologies encourages to improve the mechanical component. 23632760 The Impact of the Body Mass Index on Outcome After Subarachnoid Hemorrhage: Is There an Obesity Paradox in SAH? A Retrospective Analysis. Obesity is a risk factor for cardiovascular disease and associated with a poor outcome, especially for intensive care patients. However, recent studies have described favorable outcomes of obese patients after stroke, a phenomenon called the "obesity paradox." To assess the impact of the body mass index (BMI) on outcome after subarachnoid hemorrhage (SAH). We analyzed the data for 741 SAH patients. A BMI greater than 25 kg/m was considered overweight and greater than 30 kg/m obese. The outcome according to the Glasgow Outcome Scale at discharge and after 6 months was assessed using logistic regression analysis. According to the BMI, 268 patients (36.2%) were overweight and 113 (15.2%) were obese. A favorable outcome (Glasgow Outcome Scale score >3) was achieved in 53.0% of overweight patients. In contrast, 61.4% of the 360 patients with a normal BMI had a favorable outcome (P = .021). However, in the multivariate analysis, only age (odds ratio [OR]: 1.051, 95% confidence interval [CI]: 1.04-1.07, P < .001), World Federation of Neurological Surgeons grade (OR: 2.095, 95% CI: 1.87-2.35, P < .001), occurrence of vasospasm (OR: 2.90, 95% CI: 1.94-4.34, P < .001), and aneurysm size larger than 12 mm (OR: 2.215, 95% CI: 1.20-4.10, P = .011) were independent predictors of outcome after 6 months. Of the 321 poor grade patients (World Federation of Neurological Surgeons score >3), 171 (53.3%) were overweight. Of these, 21.6% attained a favorable outcome compared with 35.3% of normal-weight patients (P = .006). Although many physicians anticipate a worse outcome for obese patients, in our study, the BMI was not an independent predictor of outcome. Based on the BMI, obesity seems to be negligible for outcome after SAH compared with the impact of SAH itself, the patient's age, occurrence of vasospasm, or aneurysm size. CI, confidence intervalCVS, cerebral vasospasmGOS, Glasgow Outcome ScaleSAH, subarachnoid hemorrhageWFNS, World Federation of Neurological SurgeonsWHO, World Health Organization. 23794215 Reversible dihydrogen activation in cationic rare-Earth-metal polyhydride complexes. In or out? A quadruply hydride-bridged dilutetium complex releases dihydrogen under CH bond activation of one of the methyl groups of the ligand. The resulting trihydrido complex readily takes up dihydrogen. 23360454 Differential expression of natural killer cell activating receptors in blood versus bone marrow in patients with monoclonal gammopathy. In monoclonal gammopathies (MG) and multiple myeloma (MM), normal natural cytotoxicity receptors (NCR) expression (NCR1/NKp46, NCR2/NKp44, NCR3/NKp30) is observed in natural killer (NK) cells. Nonetheless, except in plasma cell leukemia, few tumor plasmocytes are present in PB, while NK studies have been performed on peripheral blood (PB). For this reason we focused our attention on NK from bone marrow (BM). Our study demonstrates that the down-regulation of NCR3/NKp30 is only detectable in NK from BM but not in PB, and shows a drastic decrease of both NKG2D and CD244/2B4/p38 expression in NK from BM in comparison with PB. In conclusion, our data more precisely describe the mechanism of immune escape of MG/MM from innate immunity since we show a drastic down regulation of 3 major activating NK receptors (NCR3/NKp30, NKG2D and CD244/2B4/p38) at the site of tumor, i.e BM, that was undetectable in PB. Further studies regarding immune regulatory drugs in MG/MM will imperiously require the assessment of immune cell status not only in PB but also in BM to obtain more relevant data regarding anti-tumor efficacy. 23602123 Development of a novel reverse transcriptase polymerase chain reaction to determine the Gram reaction and viability of bacteria in clinical specimens. To develop a novel RNA based assay to determine the Gram reaction and viability of bacteria in clinical specimens. Reverse transcriptase PCR (RT-PCR) targeting 16SrRNA region was optimized using Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853 by using two novel sets of primers. Sixty clinical specimens consisting of 31 intraocular specimens (19 vitreous fluids and 12 aqueous humor), 11 peripheral blood specimens and 18 other clinical specimens were subjected to standard microbiological culture and RT-PCR to determine the Gram reaction and viability of bacteria. The amplified products were subjected to DNA sequencing to identify the bacterium. The sensitivity of RT-PCR was 0.4fg and the primers amplified bacterial cDNA. RT-PCR detected the presence of bacteria in 60 clinical specimens indicating the presence of viable bacteria. Concordant results were obtained with both primer sets. Seventy five bacterium comprising 52 single (69.3%) and 23 mixed bacteria (30.6%), both Gram positive and Gram negative were detected. These results correlated with the bacterial identity by PCR based DNA sequencing. RT-PCR is a reliable tool to identify the presence of viable bacteria and to precisely determine Gram reaction. 23379830 Thiamine and Fatigue in Inflammatory Bowel Diseases: An Open-label Pilot Study. Abstract Objectives: To demonstrate that fatigue and other disorders related to ulcerative colitis and Crohn's disease are the manifestation of an intracellular mild thiamine deficiency and not due to malabsorbtion, augmented requirements, or nutritional factors, and that this dysfunction is curable with high doses of thiamine administered orally or parenterally. Design: In this pilot study, we treated fatigue in eight patients with ulcerative colitis and four patients affected by Crohn's disease from January to April 2011. The patients were recruited through general practitioners' surveys and among personnel and affiliated personnel of the clinic Villa Immacolata. Fatigue was measured using the chronic fatigue syndrome scale, and the determination of thiamine and thiamine pyrophosphate levels in the blood was carried out through blood tests. The levels of thiamine and thiamine pyrophosphate in the blood were normal. All patients were assigned to receive high doses of thiamine orally. Depending upon the body weight of each patient, dosage ranged from 600 mg/day (60 kg) to 1,500 mg/day (90 kg). The chronic fatigue syndrome scale as well as thiamine and thiamine pyrophosphate levels in the blood were measured 20 days after the beginning of the therapy. Results: Ten patients out of twelve showed complete regression of fatigue, while the remaining two patients showed nearly complete regression of fatigue compared to the chronic fatigue syndrome scale scores before therapy. Conclusions: The absence of blood thiamine deficiency and the efficacy of high-dose thiamine in our patients suggest that fatigue is the manifestation of a thiamine deficiency, likely due to a dysfunction of the active transport of thiamine inside the cells, or due to structural enzymatic abnormalities. The administration of large quantities of thiamine increases the concentration in the blood to levels in which the passive transport restores the normal glucose metabolism in all cells and leads to a complete regression of fatigue. 23580394 Optoelectronic Processes in Squaraine Dye-Doped OLEDs for Emission in the Near-Infrared. A novel all-organic host-guest system for emission in the NIR is introduced and investigated with respect to its opto-electronic processes. The good agreement between theoretical and experimental results highlights the model character of this system and its potential for electroluminescent application. Comparative measurements provide access to the recombination mechanisms on molecular length scale and show that the emission behavior of the device under operation is controlled by charge carrier dynamics. 23734008 Endothelial dysfunction in small arteries of essential hypertensive patients: role of cyclooxygenase-2 in oxidative stress generation. Essential hypertensive patients show a reduced nitric oxide availability secondary to oxidative stress generation in peripheral microcirculation. Cyclooxygenase (COX) contributes to reduce nitric oxide availability. We assessed the possible vascular sources of oxidative stress, including COX-1, COX-2, and nicotinamide adenine dinucleotide phosphate oxidase, as determinants of endothelial dysfunction in small arteries isolated from essential hypertensive patients or normotensive controls. Small arteries were dissected after subcutaneous fat biopsies and evaluated on a pressurized micromyograph. Endothelium-dependent vasodilation was assessed by acetylcholine, repeated under NG-nitro-l-arginine methyl ester, SC-560 (COX-1 inhibitor), DuP-697 (COX-2 inhibitor), ascorbic acid, or the nicotinamide adenine dinucleotide phosphate oxidase inhibitors apocynin or diphenylene iodonium. Vascular oxidative stress generation (fluorescent dihydroethidium), COX-1 and COX-2 expression (Western blot), and localization (immunohistochemistry) were also assessed. In controls, response to acetylcholine was blunted by NG-nitro-l-arginine methyl ester (P<0.001) and unmodified by SC-560, DuP-697, or ascorbic acid. In hypertensive patients, relaxation to acetylcholine was blunted, resistant to NG-nitro-l-arginine methyl ester or SC-560, and enhanced (P<0.01) by DuP-697, apocynin, or diphenylene iodonium (P<0.05). Furthermore, in hypertensive patients, response to acetylcholine was normalized by ascorbic acid or apocynin+DuP-697. Intravascular oxidative stress generation was enhanced in hypertensive patients, decreased (P<0.01) by DuP-697, partly attenuated by apocynin or diphenylene iodonium, and prevented by ascorbic acid. Enhanced COX-2 expression and localization in the vascular media of hypertensive patients were also detected. In small resistance arteries of essential hypertensive patients, COX-2 is overexpressed and reduces nitric oxide availability. COX-2 represents a major source of oxidative stress generation, whereas nicotinamide adenine dinucleotide phosphate oxidase plays a minor, but significant, role in promoting superoxide generation. 23960213 Time- but Not Sleep-Dependent Consolidation of tDCS-Enhanced Visuomotor Skills. Consolidation of motor skills after training can occur in a time- or sleep-dependent fashion. Recent studies revealed time-dependent consolidation as a common feature of visuomotor tasks. We have previously shown that anodal transcranial direct current stimulation (tDCS) in combination with repeated motor training benefits consolidation by the induction of offline skill gains in a complex visuomotor task, preventing the regular occurrence of skill loss between days. Here, we asked 2 questions: What is the time course of consolidation between days for this task and do exogenously induced offline gains develop as a function of time or overnight sleep? We found that both the development of offline skill loss in sham-stimulated subjects and offline skill gains induced by anodal tDCS critically depend on the passage of time after training, but not on overnight sleep. These findings support the view that tDCS interacts directly with the physiological consolidation process. However, in a control experiment, anodal tDCS applied after the training did not induce skill gains, implying that coapplication of tDCS and training is required to induce offline skill gains, pointing to the initiation of consolidation already during training. 23958403 LuxS contributes to virulence in avian pathogenic Escherichia coli O78:K80:H9. Avian pathogenic Escherichia coli (APEC) cause avian colibacillosis, a poultry disease characterized by multiple organ infections resulting in significant economic loss in the poultry industry. Several virulence factors are important for disease manifestation in APEC of which, role of quorum sensing has not been investigated. Quorum sensing is a population dependent cell-cell signaling system which modulates numerous physiological processes such as biofilm formation and virulence in multiple species. LuxS, a well-known controller in the QS, plays a role in regulating virulence in various bacterial species. Here we investigated the role of LuxS in regulating virulence in APEC O78:K80:H9. Mutation of luxS resulted in a significant reduction of virulence in APEC O78:K80:H9, evidenced by both in vivo and in vitro assays such as decreased invasion of internal organs in chicken embryo, reduced lethality in chicken embryo lethality assay, and altered lipopolysaccharide (LPS) profile. In addition, the abilities of the knockout strain to survive in chicken macrophage cell lines and to invade in chicken embryo fibroblast cells were significantly diminished. Further, structure and expression level of the LPS profile was significantly altered in the knockout strain, which may be one of the contributing factors for the persistence and virulence of APEC. Complementation of luxS gene in trans restored the virulence of the knockout strain to the level of wild-type bacteria. Taken together, these results show that LuxS contributes to the virulence in APEC O78:K80:H9 strain and partly explain the role played by LuxS in the pathogenesis of APEC strains. 23919680 Dramatic Inundation Changes of China's Two Largest Freshwater Lakes Linked to the Three Gorges Dam. Ever since its planning in the 1990s, the Three Gorges Dam (TGD) caused endless debate in China on its potential impacts on the environment and humans. However, to date, synoptic assessment of environmental changes and their potential linkage with the TGD is still lacking. Here, we combine remote sensing, meteorological, and hydrological observations to investigate the potential influence of the TGD on the downstream freshwater lakes. A 10 year Moderate Resolution Imaging Spectroradiometer (MODIS) time series from 2000 to 2009 revealed significantly decreasing trends (3.3 and 3.6%/year) in the inundation areas of the two largest freshwater lakes of China (Poyang Lake and Dongting Lake) downstream of the TGD since its impoundment in 2003, after which both relative humidity and surface runoff coefficient of the lakes' drainages also dropped dramatically. These environmental changes appear to be linked to the TGD. 23831350 Differential regulation of SC1/PRDM4 and PRMT5 mediated protein arginine methylation by the nerve growth factor and the epidermal growth factor in PC12 cells. During neuronal development, the neuroepithelial stem cells (NSCs) initially undergo proliferative divisions, later switching to neurogenic ones whereby one NSC and a post-mitotic neuron are generated. We recently showed that a member of the PRDM family of transcriptional regulators, PRDM4/SC1, recruits a type II protein arginine methyltransferase, PRMT5, to maintain the "stem-like" cellular state of the embryonic mouse cortical NSCs. However, little is known about the regulation of activity of this complex under proliferation- or differentiation-inducing growth conditions. In the present work I investigate the regulation of SC1/PRMT5-mediated methylation activity in PC12 cells treated with EGF or NGF. I present evidence that NGF down-regulates SC1/PRMT5 methyltransferase (MTase) activity and that the reduction in SC1/PRMT5 MTase activity occurs mainly in the nucleus. I suggest that high levels of SC1/PRMT5 activity are associated with the proliferative state of the cells. 23130662 Glycolytic enzymes PGK1 and PKM2 as novel transcriptional targets of PPARγ in breast cancer pathophysiology. Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor and plays important roles in breast cancer cell proliferation. The complexity of the underlying biochemical and molecular mechanisms of breast cancer and the involvement of PPARγ in breast cancer pathophysiology are unclear. In this study, we carried out prediction of the peroxisome proliferator response element (PPRE) motifs in 2332 genes reported to be involved in breast cancer in literature. A total of 178 genes were found to have PPRE (DR1/DR2) and/or PPAR-associated conserved motif (PACM) motifs. We further constructed protein-protein interaction network, disease gene network and gene ontology (GO) analyses to identify novel key genes for experimental validation. We identified two genes in the glycolytic pathway (phosphoglycerate kinase 1 (PGK1) and pyruvate kinase M2 (PKM2)) at the ATP production steps and experimentally validated their repression by PPARγ in two breast cancer cell lines MDA-MB-231 and MCF-7. Further analysis suggested that this repression leads to decrease in ATP levels and apoptosis. These investigations will help us in understanding the molecular mechanisms by which PPARγ regulates the cellular energy pathway and the use of its ligands in human breast cancer therapeutics. 23333573 Composition and anti-oxidant, anti-cancer and anti-inflammatory activities of Artemisia herba-alba, Ruta chalpensis L. and Peganum harmala L. In this study, biological activities of methanolic extracts from Artemisia herba-alba, Ruta chalpensis L. and Peganum harmala L. plants, collected in Centre of Tunisia, were investigated. Results showed an important phenolic composition of Artemisia herba-alba (123.95±4.3g GAE/kg of dry mass). The extract of this plant showed, using different antioxidant assays (DPPH, ABTS and AAPH/linoleic acid methods) and an IFN-γ/LPS induced RAW 264.7 murine macrophages' assay, the highest antioxidant (IC50 (DPPH assay) 20.64±0.84mg/L) and anti-inflammatory (72% inhibition at 150mg/L) activities, respectively. Excepting Peganum harmala L. extract, the two other extracts showed a high anticancer activity against several cell lines (human bladder carcinoma RT112, human laryngeal carcinoma Hep2 and human myelogenous leukemia K562), for A. herba-laba IC50=81.59±4.4, 59.05±3.66 and 90.96mg/L respectively, but not on normal peripheral blood mononuclear cells. All these biological activities are well correlated with the phenolic contents of these extracts. These findings demonstrate the remarkable potential of these plants as valuable source of antioxidants with exhibit original and interesting anti-inflammatory and anticancer capacities. 23959673 Exchange protein activated by cAMP (Epac) induces vascular relaxation by activating Ca2+-sensitive K+ channels in rat mesenteric artery. Vasodilator-induced elevation of intracellular cyclic AMP (cAMP) is a central mechanism governing arterial relaxation but is incompletely understood due to the diversity of cAMP effectors. Here we investigate the role of the novel cAMP effector exchange protein directly activated by cAMP (Epac) in mediating vasorelaxation in rat mesenteric arteries. In myography experiments, the Epac-selective cAMP analogue 8-pCPT-2'-O-Me-cAMP-AM (5μM, subsequently referred to as 8-pCPT-AM) elicited a 77.6 ± 7.1% relaxation of phenylephrine-contracted arteries over a 5 minute period (mean ± SEM; n=6). 8-pCPT-AM induced only a 16.7 ± 2.4% relaxation in arteries pre-contracted with high extracellular K(+) over the same time period (n=10), suggesting that some of Epac's relaxant effect relies upon vascular cell hyperpolarization. This involves Ca(2+)-sensitive, large-conductance K(+) (BKCa) channel opening since iberiotoxin (100nM) significantly reduced the ability of 8-pCPT-AM to reverse phenylephrine-induced contraction (arteries relaxed by only 35.0 ± 8.5% over a 5 minute exposure to 8-pCPT-AM, n=5; p<0.05). 8-pCPT-AM increased Ca(2+) spark frequency in Fluo-4-AM-loaded mesenteric myocytes from 0.045 + 0.008 to 0.103 + 0.022 sparks/s/μm (p<0.05) and reversibly increased both the frequency (0.94 ± 0.25 to 2.30 ± 0.72s-1) and amplitude (23.9 ± 3.3 to 35.8 ± 7.7pA) of spontaneous transient outward currents (STOCs) recorded in isolated mesenteric myocytes (n=7; p<0.05). 8-pCPT-AM-activated STOCs were sensitive to iberiotoxin (100nM) and to ryanodine (30μM). Current clamp recordings of isolated myocytes showed a 7.9 ± 1.0mV (n=10) hyperpolarization in response to 8-pCPT-AM that was sensitive to iberiotoxin (n=5). Endothelial disruption suppressed 8-pCPT-AM-mediated relaxation in phenylephrine-contracted arteries (24.8 ± 4.9% relaxation after 5 minutes exposure, n=5; p<0.05), as did apamin and TRAM-34, blockers of Ca(2+)-sensitive, small- and intermediate-conductance K(+) (SKCa and IKCa) channels, respectively, and N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS). In Fluo-4-AM-loaded mesenteric endothelial cells, 8-pCPT-AM induced a sustained increase in global Ca(2+). Our data suggest that Epac hyperpolarizes smooth muscle by 1) increasing localized Ca(2+) release from ryanodine receptors (Ca(2+) sparks) to activate BKCa channels, and 2) endothelial-dependent mechanisms involving the activation of SKCa/IKCa channels and NOS. Epac-mediated smooth muscle hyperpolarization will limit Ca(2+) entry via voltage-sensitive Ca(2+) channels and represents a novel mechanism of arterial relaxation. 23047026 Cholinesterases in development: AChE as a firewall to inhibit cell proliferation and support differentiation. Acetylcholinesterase (AChE) is a most remarkable protein, not only because it is one of the fastest enzymes in nature, but also since it appears in many molecular forms and is regulated by elaborate genetic networks. AChE is expressed in many tissues during development and in mature organisms, as well as in healthy and diseased states. In search for alternative, "non-classical" functions of cholinesterases (ChEs), AChE could either work within the frame of classic cholinergic systems, but in non-neural tissues ("non-synaptic function"), or act non-enzymatically. Here, we review briefly some of the major ideas and advances of this field, and report on some recent progress from our own experimental work, e.g. that (i) non-neural ChEs have pronounced, predominantly enzymatic effects on early embryonic (limb) development in chick and mouse, that (ii) retinal R28 cells of the rat overexpressing synaptic AChE present a significantly decreased cell proliferation, and that (iii) in developing chick retina ACh-synthesizing and ACh-degrading cells originate from the same postmitotic precursor cells, which later form two locally opposing cell populations. We suggest that such distinct distributions of ChAT(+) vs. AChE(+) cells in the inner half retina provide graded distributions of ACh, which can direct cell differentiation and network formation. Thus, as corroborated by works from many labs, AChE can be considered a highly co-opting protein, which can combine enzymatic and non-enzymatic functions within one molecule. 23892090 576kb deletion in 1p36.33-p36.32 containing SKI is associated with limb malformation, congenital heart disease and epilepsy. 1p36 deletion (monosomy 1p36) is one of the most common terminal deletions observed in humans, characterized by special facial features, mental retardation, heart defects, development delay and epilepsy. Previously, we reported molecular findings in patients with limb, congenital heart disease (CHD) and other malformations with SNP-array. In a syndromic patient of the same cohort, we detected a small deletion of 1p36.33-p36.32 containing SKI (Sloan-Kettering Institute protooncoprotein). Recently, dominant mutations in SKI were identified to be correlated with Shprintzen-Goldberg syndrome. Retrospective examination revealed this patient with limb malformations, CHD, epilepsy and mild development delay. Together with previous reports, our study suggests that the 1p36.33-1p36.32 deletion encompassing SKI may represents a previous undescribed microdeletion disorder. 23821679 Microfluidic Platforms for Single-Cell Protein Analysis. Elucidation of the heterogeneity of cells is a challenging task due to the lack of efficient analytical tools to make measurements with single-cell resolution. Microfluidics has emerged as a powerful platform for single-cell analysis with the ability to manipulate small volume and integrate multiple sample preparation steps into one device. In this review, we discuss the differentiating advantages of microfluidic platforms that have been demonstrated for single-cell protein analysis. 23842624 Downregulation of microRNA-100 correlates with tumor progression and poor prognosis in hepatocellular carcinoma. Increasing evidence suggests that dysregulation of microRNAs is correlated with malignant transformation and tumor development. miR-100, a potential tumor suppressor, is downregulated by many human cancers. However, the expression and functions of miR-100 in hepatocellular carcinoma (HCC) are still unclear. The aim of this study was to detect the expression of miR-100 in HCC tissues and investigate its clinicopathological and prognostic significance. Also, the effects of miR-100 on growth and apoptosis of HCC cells and its potential molecular mechanisms were analyzed. Results showed that the expression level of miR-100 in HCC tissues was significantly lower than that in matched non-cancerous liver tissues. Also, low-miR-100 expression was observed to be significantly correlated with higher tumor grade, higher incidence of lymph node metastasis, advanced TNM stage and higher incidence of tumor recurrence in HCC patients. Multivariate survival analyses suggested that low-miR-100 expression was an independent prognostic factor for HCC patients (HR = 1.66, 95 % CI 1.32-2.82, P = 0.019). In addition, we found that upregulation of miR-100 could inhibit growth and increase apoptosis of HCC cells by downregulating polo-like kinase 1 (plk1). In HCC tissues, miR-100 expression was inversely correlated with the expression of plk1 protein (r = -0.418; P = 0.029). Therefore, downregulation of miR-100 was correlated with progressive pathological feature and poor prognosis in HCC patients, and miR-100 could function as a tumor suppressor by targeting plk1. miR-100 may serve as a prognostic marker and molecular therapeutic target in HCC. 23778973 Comparative analysis of the revenues of pylorus-preserving pancreatic head resections and laparoscopic cholecystectomies as prototypic surgical procedures in the German health-care system. Although centralization of complex surgical procedures such as pancreaticoduodenectomies is associated with a reduction in morbidity and mortality rates, it is unclear whether such surgeries are adequately represented in the German disease-related group (DRG) system. Out of all patients who underwent pancreatic resections (n = 450) at our institution between January 2008 and November 2011, 76 patients who underwent a pylorus-preserving pancreatic head resection due to pancreatic head adenocarcinoma were selected for analysis. The revenues generated by these surgical procedures were compared with those of 144 patients who had undergone elective laparoscopic cholecystectomies for symptomatic gallstone disease between January 2009 and September 2010 in our hospital. In patients undergoing pylorus-preserving pancreaticoduodenectomy, revenues per case were 1,585.55 Euros, with an average length of hospital stay (ALOS) of 19.9 days (range 7-55 days) and an average postoperative hospital stay of 16 days; however, if the ALOS was exceeded, expenditures increasingly exceeded returns. Analysis of the cohort of patients with pylorus-preserving pancreaticoduodenectomies demonstrated average revenues per day of 79.27 Euros. In contrast, for laparoscopic cholecystectomy, which was treated with high surgical standardization and stringent case management, the ALOS was only 2.8 days, producing average revenues of 288.80 Euros per day and total revenues of 817.53 Euros per case. At university hospitals, cost-effective realization of major pancreatic surgery is difficult, while highly standardized surgeries such as laparoscopic cholecystectomies can be performed at a favorable balance. This may be due to, firstly, an underrepresentation of university hospitals in the German DRG calculation basis and, secondly, to a relatively long preoperative hospital stay as a result of extensive diagnostic measures. We consider this kind of preoperative assessment paramount for an academic pancreatic center and thus argue for an increased reimbursement for these procedures. 23442415 Adipokines and insulin resistance, predictors of response to therapy in Egyptian patients with chronic hepatitis C virus genotype 4. Hepatitis C virus (HCV) infection has major health impact worldwide and is a significant cause of chronic liver disease. In Egypt, HCV is highly endemic (up to 15% of the population); 91% of the patients are infected with genotype 4. Searching for new predictors of response to therapy is mandatory to decrease the cost and the adverse effects of current therapy. The aim of this study was to clarify the usefulness of serum leptin, adiponectin, and insulin resistance (IR) as predictors of response to treatment in hepatitis C virus genotype 4 (HCVG4). One hundred patients with chronic HCVG4 who were candidates for treatment with pegylated interferon α and ribavirin were included in the study. Age, sex, and BMI were determined, and quantitative HCV PCR, assessment of serum leptin, adiponectin, IR, and pretreatment liver profile, and liver biopsy were performed. The male to female ratio was 68/32; the mean age of the patients was 40.9 ± 7.8 years and BMI was 28.3 ± 10 kg/m. Sustained virological response (SVR) was achieved by 56% of the patients. On performing logistic regression, BMI [odds ratio (OR) 6.5; P=0.004], serum leptin (OR 27.8; P ≤ 0.001), aspartate aminotransferase (OR 1.06; P ≤ 0.001), IR (OR 1.15; P ≤ 0.001), histological activity index (OR 1.77; P=0.006), and fibrosis (OR 2.93; P=0.001) were found to be independent negative predictors of SVR, whereas serum adiponectin (OR 0.74; P ≤ 0.001) was found to be an independent positive predictor of SVR. Pretreatment adiponectin (cutoff 13.75; sensitivity 92.86%; specificity 86.86%) shows area under the curve of 0.879 (95% confidence interval 0.802-0.956; P<0.001) and insignificant area under the curve for leptin or IR. BMI, pretreatment high leptin levels, and IR are negative predictors for SVR and pretreatment low adiponectin levels are an independent positive predictor for SVR in HCVG4. 23438238 G16R single nucleotide polymorphism but not haplotypes of the β(2)-adrenergic receptor gene alters cardiac output in humans. Variation in genes encoding the β(2)-adrenergic receptor (ADRB2) and angiotensin-converting enzyme (ACE) may influence Q (cardiac output). The 46G>A (G16R) SNP (single nucleotide polymorphism) has been associated with β(2)-mediated vasodilation, but the effect of ADRB2 haplotypes on Q has not been studied. Five SNPs within ADRB2 (46G>A, 79C>G, 491C>T, 523C>A and 1053G>C by a pairwise tagging principle) and the I/D (insertion/deletion) polymorphism in ACE were genotyped in 143 subjects. Cardiovascular variables were evaluated by the Model flow method at rest and during incremental cycling exercise. Only the G16R polymorphism was associated with Q. In carriers of the Arg(16) allele, Q(rest) (resting Q) was 0.4 [95% CI (confidence interval), 0.0-0.7] l/min lower than in G16G homozygotes (P=0.048). During exercise, the increase in Q was by 4.7 (95% CI, 4.3-5.2) l/min per litre increase in pulmonary Vo(2) (oxygen uptake) in G16G subjects, but the increase was 0.5 (0.0-0.9) l/min lower in Arg16 carriers (P=0.035). A similar effect size was observed for the Arg16 haplotypes ACCCG and ACCCC. No interaction was found between ADRB2 and ACE polymorphisms. During exercise, the increase in Q was 0.5 (CI, 0.0 -1.0) l/min greater in ACE I/I carriers compared with I/D and D/D subjects (P=0.054). In conclusion, the ADRB2 Arg16 allele in humans is associated with a lower Q both at rest and during exercise, overriding the effects of haplotypes. 23266021 Salivary alpha-amylase and cortisol responsiveness following electrical stimulation stress in obsessive-compulsive disorder patients. Salivary α-amylase (sAA) serves as a marker of sympathoadrenal medullary system (SAM) activity. Salivary AA has not been extensively studied in obsessive-compulsive disorder (OCD) patients. In the current study, 45 OCD patients and 75 healthy volunteers were assessed with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Profile of Mood State (POMS), and the State-Trait Anxiety Inventory (STAI). Measures of heart rate variability (HRV), sAA, and salivary cortisol were also obtained following the application of electrical stimulation stress. The Y-BOCS and POMS Tension-Anxiety, Depression-Dejection, Anger-Hostility, Fatigue, and Confusion scores were significantly increased in patients with OCD compared with healthy controls. In contrast, Vigor scores were significantly decreased in patients with OCD relative to scores in healthy controls. There was no difference in HRV between the patients and the controls. Salivary AA levels in female and male OCD patients were significantly elevated relative to controls both before and after electrical stimulation. In contrast, there were no differences in salivary cortisol levels between OCD patients and controls. The elevated secretion of sAA before and after stimulation may suggest an increased responsiveness to novel and uncontrollable situations in patients with OCD. An increase in sAA might be a characteristic change of OCD. 23934539 A History of Prior Preeclampsia As a Risk Factor for Preterm Birth. Objective The objectives of this study are to evaluate the frequency and type of preterm birth (PTB) in women with prior preeclampsia and to compare neonatal outcomes between spontaneous PTB (SPTB) and medically indicated PTB (IPTB) groups.Study Design A secondary analysis of data in women with prior preeclampsia enrolled in a multicenter randomized trial for preeclampsia prevention. Delivery indications were categorized as SPTB and IPTB. Primary outcomes were rates of SPTB and IPTB by gestational age (GA). The rates of composite respiratory morbidity and neonatal intensive care unit (NICU) admission were compared between the PTB groups.Results Of the 606 pregnancies studied, 142 (23%) pregnancies were delivered at < 37 weeks: 67 (47%) pregnancies were caused by SPTB and 75 (53%) pregnancies were caused by IPTB. Of those who delivered preterm, 89 (63%) were in the late preterm period. The overall rate of the composite neonatal morbidity was 23%. The rates of composite neonatal morbidity, NICU admission, and perinatal death were not different between the groups. The frequency of small for gestational age (SGA) infants was higher in the IPTB group as compared with the SPTB group (21.3 vs. 1.4%, p = 0.01).Conclusion Women with prior preeclampsia are at high risk for PTB (SPTB and IPTB), particularly late PTB, as well as increased risk for SGA. 23566384 Anaphylaxis knowledge and practice preferences of pediatric emergency medicine physicians: a national survey. To assess the knowledge and practice preferences of anaphylaxis in pediatric emergency medicine (PEM) physicians by practice setting, and to identify factors associated with intramuscular (IM) epinephrine administration and admission of patients with anaphylaxis. The cohort was a cross-sectional convenience sample; potential participants were recruited using contact information obtained from the American Board of Pediatrics and American Board of Medical Specialties membership databases and were asked to complete a 12 item survey. Board-certified PEM physicians were categorized by practice setting: university hospital, non-university hospital with a residency training program, or community hospital with no residency training program. Management practices based on practice setting are presented as proportions. Multivariate logistic regression identified factors associated with IM epinephrine administration and admission of patients with anaphylaxis for observation. Of the 1114 PEM physicians solicited, 620 (56%) completed the survey. The majority (93.5%) correctly identified epinephrine as the treatment of choice for anaphylaxis, yet only 66.9% used the IM route of administration, and only 37.4% admitted affected patients for observation. Factors associated with the use of IM epinephrine included the presence of a residency program at the site of care (OR, 2.28, 95% CI, 1.3-4.04) and higher volume of anaphylaxis cases (OR, 1.21; 95% CI, 1.06-1.38). Increasing anaphylaxis case volume was associated with decreased likelihood of admission of patients with anaphylaxis (OR, 0.81; 95% CI, 0.72-0.92). Even though the majority of PEM physicians correctly report using epinephrine in pediatric anaphylaxis, not all use the preferred administration route, and many discharge patients home after an abbreviated period. 23868507 The Use of Polyurethane as an Elastomer in Thermoplastic Microfluidic Devices and the Study of its Creep Properties. We report using polyurethane (PU) as an elastomer in microvalves integrated with thermoplastic microfluidic devices. Elastomer-based microvalves have been used in a number of applications and the elastomer often used is polydimethylsiloxane (PDMS). Although it is a convenient material for prototyping, PDMS has been recognized to possess shortcomings such as solvent incompatibility and unfavorable manufacturability. We investigated the use of PU as an elastomer to address the challenges. A reliable method was developed to bond hydride materials such as PU and cyclic olefin copolymer (COC). The film thickness from 3.5 to 24.5 μm was studied to identify an appropriate thickness of PU films for desirable elasticity in microvalves. We integrated PU with thermally actuated, elastomer-based microvalves in thermoplastic devices. Valve actuations were demonstrated, and the relationship between the valve actuation time and heater power was studied. We compared PU with PDMS in terms of their microvalve performance. Valves with PDMS failed to function after 2 weeks since the thermal-sensitive solution evaporated through porous PDMS membrane, whereas the same valve with PU functioned properly after 8 months. In addition, we evaluated the creep and creep recovery of PU, which is a common phenomenon of viscoelastic materials and is related to the long-term elastic property of PU after prolonged use. This article is protected by copyright. All rights reserved. 23611526 Spontaneous partition of carbon nanotubes in polymer-modified aqueous phases. The distribution of nanoparticles in different aqueous environments is a fundamental problem underlying a number of processes, ranging from biomedical applications of nanoparticles to their effects on the environment, health, and safety. Here, we study distribution of carbon nanotubes (CNTs) in two immiscible aqueous phases formed by the addition of polyethylene glycol (PEG) and dextran. This well-defined model system exhibits a strikingly robust phenomenon: CNTs spontaneously partition between the PEG- and the dextran-rich phases according to nanotube's diameter and metallicity. Thermodynamic analysis suggests that this chirality-dependent partition is determined by nanotube's intrinsic hydrophobicity and reveals two distinct regimes in hydrophobicity-chirality relation: a small diameter (<1 nm) regime, where curvature effect makes larger diameter tubes more hydrophobic than small diameter ones, and a large diameter (>1.2 nm) regime, where nanotube's polarizability renders semiconducting tubes more hydrophobic than metallic ones. These findings reveal a general rule governing CNT behaviors in aqueous phase and provide an extremely simple way to achieve spatial separation of CNTs by their electronic structures. 23871073 Use of allyl isothiocyanate and carbon nanotubes in an antimicrobial film to package shredded, cooked chicken meat. We developed antimicrobial packaging incorporated with allyl isothiocyanate (AIT) and carbon nanotube (CNT), and this packaging was used for shredded cooked chicken meat inoculated with Salmonella Choleraesuis. The following parameters were analysed during the 40days of storage: microbial counts, colour characteristics and changes in the oxidation of the meat as well as changes in the mechanical properties of the film, the structure of the antimicrobial film and the diffusion of the antimicrobial agent into the food. The incorporation of AIT into the films increased the elongation at the break (E) value of the films and decreased the tensile strength (TS) value of the films. The CNT was important to retain the AIT which is a volatile substance in the film. The diffusion of the AIT from the film into the chicken reduced the microbial contamination, controlled oxidation and reduced the colour changes. Thus, these packages were effective for the 40days of storage. 23965617 Tapetum and middle layer control male fertility in Actinidia deliciosa. Background and AimsDioecism characterizes many crop species of economic value, including kiwifruit (Actinidia deliciosa). Kiwifruit male sterility occurs at the microspore stage. The cell walls of the microspores and the pollen of the male-sterile and male-fertile flowers, respectively, differ in glucose and galactose levels. In numerous plants, pollen formation involves normal functioning and degeneration timing of the tapetum, with calcium and carbohydrates provided by the tapetum essential for male fertility. The aim of this study was to determine whether the anther wall controls male fertility in kiwifruit, providing calcium and carbohydrates to the microspores.MethodsThe events occurring in the anther wall and microspores of male-fertile and male-sterile anthers were investigated by analyses of light microscopy, epifluorescence, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL assay) and transmission electron microscopy coupled with electron spectroscopy. The possibility that male sterility was related to anther tissue malfunctioning with regard to calcium/glucose/galactose provision to the microspores was also investigated by in vitro anther culture.Key ResultsBoth tapetum and the middle layer showed secretory activity and both degenerated by programmed cell death (PCD), but PCD was later in male-sterile than in male-fertile anthers. Calcium accumulated in cell walls of the middle layer and tapetum and in the exine of microspores and pollen, reaching higher levels in anther wall tissues and dead microspores of male-sterile anthers. A specific supply of glucose and calcium induced normal pollen formation in in vitro-cultured anthers of the male-sterile genotype.ConclusionsThe results show that male sterility in kiwifruit is induced by anther wall tissues through prolonged secretory activity caused by a delay in PCD, in the middle layer in particular. In vitro culture results support the sporophytic control of male fertility in kiwifruit and open the way to applications to overcome dioecism and optimize kiwifruit production. 23883423 Human papillomavirus genotypes distribution in 175 invasive cervical cancer cases from Brazil. Invasive cervical cancer is the second most common malignant tumor affecting Brazilian women. Knowledge on Human Papillomavirus (HPV) genotypes in invasive cervical cancer cases is crucial to guide the introduction and further evaluate the impact of new preventive strategies based on HPV. We aimed to provide updated comprehensive data about the HPV types' distribution in patients with invasive cervical cancer. Fresh tumor tissue samples of histologically confirmed invasive cervical cancer were collected from 175 women attending two cancer reference hospitals from São Paulo State: ICESP and Hospital de Câncer de Barretos. HPV detection and genotyping were performed by the Linear Array HPV Genotyping Test (Roche Molecular Diagnostics, Pleasanton,USA). 170 out of 172 valid samples (99%) were HPV DNA positive. The most frequent types were HPV16 (77.6%), HPV18 (12.3%), HPV31 (8.8%), HPV33 (7.1%) and HPV35 (5.9%). Most infections (75%) were caused by individual HPV types. Women with adenocarcinoma were not younger than those with squamous cell carcinoma, as well, as women infected with HPV33 were older than those infected by other HPV types. Some differences between results obtained in the two hospitals were observed: higher overall prevalence of HPV16, absence of single infection by HPV31 and HPV45 was verified in HC-Barretos in comparison to ICESP patients. To our knowledge, this is one of the largest studies made with fresh tumor tissues of invasive cervical cancer cases in Brazil. This study depicted a distinct HPV genotype distribution between two centers that may reflect the local epidemiology of HPV transmission among these populations. Due to the impact of these findings on cervical cancer preventive strategies, extension of this investigation to routine screening populations is warranted. 23753114 GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients. Does a GnRH agonist (GnRHa) trigger followed by a bolus of 1.500 IU hCG in a group of patients at risk of ovarian hyperstimulation syndrome (OHSS) reduce the OHSS incidence compared with hCG trigger? A GnRHa trigger followed by early luteal hCG support with one bolus of 1.500 IU hCG appears to reduce OHSS in patients at risk of OHSS; however, in a low-risk group a second bolus of 1.500 IU hCG induced two cases of late onset OHSS. A GnRHa trigger is an alternative to hCG in GnRH antagonist co-treated cycles. Two RCTs were performed in four Danish IVF units. A total of 446 patients were assessed for eligibility and 390 patients were enrolled in the study from January 2009 until December 2011. The primary outcome of the study was OHSS incidence in the group at risk of OHSS. Patients received a fixed dose of recombinant human FSH for the first 4 days. On the day of triggering, patients were assessed for their risk of OHSS based on the total number of follicles ≥11 mm diameter, and were classified as being at risk of OHSS when the total number of follicles ≥11 mm was between 15 and 25 and at low risk of OHSS when the total number of follicles ≥11 mm was ≤14. Two separate randomization lists were used for each of the OHSS risk groups. Women at risk of OHSS were allocated (RCT 1) to either: Group A (n = 60), ovulation triggering with a bolus of 0.5 mg buserelin (GnRHa) s.c. followed by a single bolus of 1.500 IU hCG s.c. after the oocyte retrieval-or: Group B (n = 58): 5.000 IU hCG. Similarly, women at low risk of OHSS were allocated (RCT 2) to receive either: Group C (n = 125), a bolus of 0.5 mg buserelin s.c., followed by a bolus of 1.500 IU hCG s.c. after oocyte retrieval and a second bolus of 1.500 IU hCG on the day of oocyte retrieval +5-or: Group D (n = 141), 5.000 IU hCG. Groups C and D were included in order to obtain preliminary data. In women at risk of OHSS (RCT 1) (15-25 follicles) no OHSS case was seen in Group A (GnRHa trigger and one bolus of 1.500 IU hCG), whereas two cases of moderate late-onset OHSS occurred in group B (3.4%), (P = 0.24). In contrast, in women at a low risk of OHSS (RCT 2) (≤14 follicles) two cases of late-onset OHSS occurred in Group C (GnRHa trigger and two boluses of 1.500 IU hCG), whereas no OHSS case was encountered in Group D (P = 0.22). Although the first RCT was powered to include 168 patients at risk of OHSS (15-25 follicles ≥11 mm) randomized to either GnRHa trigger or hCG trigger, the trial was prematurely discontinued when a total of 118 patients at risk of OHSS were randomized. In addition the second RCT in the OHSS low-risk group was designed as a feasibility study to assess the incidence of OHSS after GnRHa trigger and dual hCG administration versus 5.000 IU hCG. No power calculation was performed for this trial. In addition, there was a lack of blinding in the RCTs. Although a non-significant result, one bolus of 1.500 IU hCG after GnRHa trigger tended to reduce the OHSS rate in patients with 15-25 follicles ≥11 mm as well as secure the ongoing pregnancy rate. In contrast, in patients at low risk of OHSS the administration of two boluses of 1.500 IU hCG after GnRHa trigger should be avoided as it may induce OHSS. The study was supported by a research grant by MSD, Denmark. No conflict of interest was declared. Project number: VN-20060036MCH. NCT00627406. 23027610 Chemical differences between voided and bladder urine in the aye-aye (Daubentonia madagascariensis): implications for olfactory communication studies. Urine serves a communicative function in many mammalian species. In some species, the signaling function of urine can be enhanced by the addition of chemical compounds from glands along the distal portion of the urogenital tract. Although urine marking is the main mode of chemical communication in many primate species, there has been no study of the contribution of urogenital secretions to the chemical complexity of primate urine. Here, we compared the chemical composition of bladder urine versus voided urine in the aye-aye, Daubentonia madagascariensis, a strepsirrhine primate that relies on urine in intraspecific communication. Both types of urine, collected from each of 11 aye-ayes representing both sexes of varying adult ages, underwent headspace analysis via gas chromatography and mass spectrometry. Although the average number of compounds was similar in bladder and voided urine, 17% of the compounds detected occurred exclusively in voided urine (but only in a subset of individuals). An overall measure of chemical complexity (using a nonmetric multidimensional scaling analysis) showed that both types of urine were chemically different at the individual level. There was no apparent sex or age differences in the chemical components found in aye-aye urine. Nonetheless, the individual dissimilarities between bladder urine and voided urine indicate chemical contributions from structures along the urogenital tract and offer further support for the relevance of urinary communication in the aye-aye. 23707164 A brief history of the global effort to develop a preventive HIV vaccine. Soon after HIV was discovered as the cause of AIDS in 1983-1984, there was an expectation that a preventive vaccine would be rapidly developed. In trying to achieve that goal, three successive scientific paradigms have been explored: induction of neutralizing antibodies, induction of cell mediated immunity, and exploration of combination approaches and novel concepts. Although major progress has been made in understanding the scientific basis for HIV vaccine development, efficacy trials have been critical in moving the field forward. In 2009, the field was reinvigorated with the modest results obtained from the RV144 trial conducted in Thailand. Here, we review those vaccine development efforts, with an emphasis on events that occurred during the earlier years. The goal is to provide younger generations of scientists with information and inspiration to continue the search for an HIV vaccine. 23728992 Sun protection training based on a theater play for preschoolers: an effective method for imparting knowledge on sun protection? Sun protection in childhood is important to reduce the risk of developing skin cancer later in life. The "Periods-of-Life-Program" for primary prevention of skin cancer introduces a combination of individual and environmental interventions for the preschool period. Within this pilot study, an intervention group received cognitive-behavioral and environmental interventions. A control group had solely received the environmental intervention, and a wait-control group received no intervention. Nursery school children (n = 80, 3 to 6 years of age) of four nursery schools were randomly assigned to these groups on school level. The ability of the cognitive-behavioral intervention (a theater play) to enhance sun protection knowledge was examined. The theater play improved knowledge over all age groups (p < .05 η(2) = .06). Age-specific analyses showed better results for children aged 5 to 6 (p < .05 η(2) = .20) compared to children aged 3 to 4 years (p = .17 η(2) = .04). In combining cognitive-behavioral and environmental interventions, the "Periods-of-Life-Program" is a promising strategy for primary prevention of skin cancer. 23924427 Percutaneous suprapubic tube bladder drainage after robot-assisted radical prostatectomy: a step-by-step guide. To describe our technique of maintaining bladder drainage after robot-assisted radical prostatectomy (RARP) using a percutaneous suprapubic tube (PST) in place of a urethral catheter. A watertight anastomosis permits placement of the PST. Contraindications include morbid obesity, concomitant inguinal hernia mesh repair, anticoagulation therapy, limited hand dexterity in the patient, bladder neck reconstruction and extensive adhesiolysis at RARP. The necessary equipment includes a 14-F PST balloon catheter set, a three-way connector, a connecting tube, a suture passer, 1/0 polypropylene sutures on a CT1 needle, a sterile plastic button, adhesive and steri-strips. The important steps for PST placement are: Step 1: robot-assisted placement of a bladder wall anchor suture; Step 2: transferring the bladder wall suture to anterior abdominal skin; Step 3: guided placement of the PST under robotic vision; Step 4: securing the PST within the bladder and abdominal wall; Step 5. postoperative care: clamping the PST on postoperative day 5, recording each void and post-void residual urine volumes in a patient diary, removal of the PST on postoperative day 7 after 48 h of voiding with residual urine <100 mL per void. We provide a concise step-by-step guide for placement of a PST during RARP as well as important management aspects for the successful adoption of this technique. 23859648 What Evidence Supports Special Processing for Faces? A Cautionary Tale for fMRI Interpretation. We trained a neurocomputational model on six categories of the photographic images used in previous fMRI studies of object and face processing. Multivariate pattern analyses of the activations elicited in the object-encoding layer of the model yielded results consistent with two previous, contradictory fMRI studies. Findings from one of the studies [Haxby, J. V., Gobbini, M. I., Furey, M. L., Ishai, A., Schouten, J. L., & Pietrini, P. Distributed and overlapping representations of faces and objects in ventral temporal cortex. Science, 293, 2425-2430, 2001] were interpreted as evidence for the object-form topography model. Findings from the other study [Spiridon, M., & Kanwisher, N. How distributed is visual category information in human occipito-temporal cortex? An fMRI study. Neuron, 35, 1157-1165, 2002] were interpreted as evidence for neural processing mechanisms in the fusiform face area that are specialized for faces. Because the model contains no special processing mechanism or specialized architecture for faces and yet it can reproduce the fMRI findings used to support the claim that there are specialized face-processing neurons, we argue that these fMRI results do not actually support that claim. Results from our neurocomputational model therefore constitute a cautionary tale for the interpretation of fMRI data. 23500732 N-hydroxypropyltrimethylammonium polydimethylaminoethylmethacrylate sub-microparticles for oral delivery of insulin--an in vitro evaluation. The present study describes the synthesis and in vitro evaluation of quaternised polydimethylaminoethylmethacrylate for oral delivery of insulin. Quaternisation of the polymer was carried out by conjugating N-hyroxypropyltrimethylammonium chloride to aminoterminated polydimethylaminoethylmethacrylate. Quaternised particles were characterised by particle size, zeta potential measurements, nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), differential scanning calorimetry (DSC) and atomic force microscopy (AFM). In addition, in vitro insulin release experiments, cytotoxic evaluation on L929 & Caco-2 cells, mucoadhesion, enzymatic degradation and tight junction visualisation studies were also performed to evaluate the potential of this matrix for oral delivery of insulin. Results suggest that the quaternised particles exhibited positive zeta potential with a particle size of 513.6±17 nm. Dose-dependent cytotoxic evaluation of quaternised particles on L929 & Caco-2 cells confirmed the nontoxic nature of the matrix. Quaternised particles were more mucoadhesive compared to parent polymer. Adhesive behaviour of mucin with quaternised particles were confirmed by DSC. Moreover these particles exhibited calcium chelating ability and displayed significant inhibitory effect towards trypsin and chymotrypsin. These particles also helped in the opening of tight junctions by disruption of actin filaments and binding to Zona Occludens (ZO-1) proteins. Preliminary studies suggest that the quaternised particles can act as suitable candidates for oral delivery of insulin. 23934511 Recent Advances in Treatment of Primary Central Nervous System Lymphoma. Therapeutic options are limited in primary central nervous system lymphoma (PCNSL) with no uniform consensus on optimal management and few published, randomized trials. High-dose methotrexate in combination with other chemotherapeutic agents forms the mainstay of treatment. There hasn't been much progress beyond high-dose methotrexate in this disease, and although results from trials using high-dose chemotherapy and autologous stem-cell transplant seem promising, these need to be further validated. Moreover, the role of whole brain radiation in the upfront setting remains to be determined. However, international efforts in this direction are underway, with ongoing randomized trials in newly diagnosed PCNSL, more research on the molecular pathogenesis and biomarkers, and the use of novel agents in salvage therapy. There also is emphasis on quality of life parameters and neurocognitive status. Future treatment options should optimize high-efficacy rates while minimizing the risk of neurotoxicity. 23891968 Comparison between oral and intra-articular antinociceptive effect of dexketoprofen and tramadol combination in monosodium iodoacetate-induced osteoarthritis in rats. Dexketoprofen and tramadol, alone or in combination, were evaluated after oral or intra-articular administration on knee osteoarthritis nociception induced by intra-articular (i.ar.) monosodium iodoacetate (MIA, 1mg/25µl) in the rat right knee while the left knee received saline (25µl). Seven days after MIA treatment, dexketoprofen, tramadol, their combination or the vehicle were administered. Nociception was evaluated as alteration in hind limb weight distribution with Incapacitance tester at different time-points after drug administration. Oral dexketoprofen (0.1-1mg/kg) or tramadol (0.5-5mg/kg) induced maximal antinociception at 1 and 5mg/kg, respectively. Their combination dose-dependently increased the intensity and duration of antinociception, that was additive and lasted up to 3 days. Also the intra-articular administration of dexketoprofen or tramadol (10-100µg/25µl) inhibited MIA-induced nociception, and the combination of the lower doses (10µg/25µl) produced a long lasting more than additive antinociceptive effect indicating a synergistic interaction between the two drugs. This effect was significantly reduced by naloxone (10μg/25μl, i.ar.) co-administered with both compounds. The intra-articular administration of both drugs at 10µg/25µl in the contralateral control knee joint provoked a marked synergistic antinociceptive effect indicating significant systemic diffusion through synovial membrane. The oral or intra-articular combination of dexketoprofen and tramadol produced additive or synergistic antinociceptive effects, respectively, in the model of MIA-induced osteoarthritis in rats, that might allow to obtain therapeutic advantages with lower side effects. 23773327 Development of an in vitro index to characterize fertilizing capacity of boar ejaculates. The aim of this research was the selection of spermatozoa parameters related to boar fertility performance and their combination into an in vitro index. A first set (data set 1) of 36 Pietrain boars with 138 ejaculates from two seasons with 5083 single-sire inseminations from 34 farms was used to determine correlations between in vitro sperm quality parameters and fertility performance. 2970 ejaculates representing a second set (data set 2) served calculation of seasonal and age effects on semen quality. Morphological spermatozoa parameters were estimated manually with a phase contrast microscope on the day of semen collection, whereas mitochondrial activity and viability were analyzed by double-staining with rhodamine123/propidium iodide on day 2 of semen storage using flow cytometry. Sperm motility was tested on day 7 by thermoresistance (TRT) after 30min (TRT1) and 300min (TRT2) incubation at 38̊C using computer-assisted semen analysis (CASA). Correlations revealed four independent sperm quality parameters qualifying as relevant predictors of boar fertility: (i) percentage of spermatozoa with proximal cytoplasmic droplets, (ii) percentage of spermatozoa with active mitochondria, (iii) beat cross frequency of progressively motile spermatozoa in TRT1, and (iv) oscillation measure of the actual path of progressively motile spermatozoa in TRT2. There were no significant effects of sperm concentration, ejaculate volume, and total number of sperm cells per ejaculate on litter size (LS) and on pregnancy rate (PR). Our findings suggest the usefulness of sperm quality parameters based on adjusted range of methods and enable the construction of an in vitro index as a means to predicting boar fertility. 23821229 Comparison of the Sex-Specific Associations Between Systolic Blood Pressure and the Risk of Cardiovascular Disease: A Systematic Review and Meta-analysis of 124 Cohort Studies, Including 1.2 Million Individuals. Conflicting results have been reported on whether the association between increments in systolic blood pressure (SBP) and cardiovascular disease differs between men and women. We performed a systematic review with meta-analysis to compare reliably sex-specific associations between SBP and cardiovascular risk. PubMed MEDLINE was systematically searched for prospective population-based cohort studies published between January 1, 1966, and March 31, 2012. Studies were selected if they presented sex-specific estimates, with associated variability, of the relative risk for either ischemic heart disease or stroke according to SBP. The data were pooled using random effects models with inverse variance weighting, and estimates of the ratio of the relative risks per 10 mm Hg increment in SBP, comparing women with men, were derived. Data from 124 prospective cohort studies, including information on 1197 472 individuals (44% women) and 26 176 stroke and 24 434 ischemic heart disease events, were included. Overall, there was no evidence to suggest a sex difference in the relationship between SBP and either the risk of stroke (pooled ratio of relative risks, 0.98 [95% confidence interval, 0.96; 1.01]; P=0.13) or ischemic heart disease (pooled ratio of relative risks, 1.00 [95% confidence interval, 0.97; 1.04]; P=0.85). Elevated levels of SBP are a major risk factor for stroke and ischemic heart diseases in both women and men. This study unequivocally demonstrates the broadly similar impact of SBP increments on cardiovascular outcomes in both sexes. 23652820 Transcriptome profiling reveals differential transcript abundance in response to chilling stress in Populus simonii. We report global gene expression patterns of poplar in response to chilling stress. A total of 1,085 significantly differentially expressed genes, involved in photosynthesis, signal transduction, and regulation of transcription, were identified. To understand the gene network underlying the response to chilling stress in the poplar, Populus simonii, we determined the genome transcript expression profile using an Affymetrix GeneChip with 56,000 genes. Our results revealed 11,626 cold-responsive genes, with 5,267 upregulated and 6,359 downregulated. In terms of biological processes, gene ontology (GO) analysis indicated that cold-induced genes were enriched in response to temperature stimulus, reactive oxygen species, and hormone stimulus. GO terms including cellular nitrogen compound metabolic processes, photosynthesis, and generation of precursor metabolites and energy were enriched in the cold-repressed genes. The functional annotation of differentially expressed genes revealed genes involved in photosynthesis, calcium/calmodulin-mediated signal transduction, abscisic acid (ABA) homeostasis and transport, and antioxidant defense systems. Gene expression analysis showed that the majority of genes involved in photosynthesis were repressed, but the THF1 gene was induced, suggesting that it may play an important role in the production of vesicles for leaf development under low-temperature conditions. Several genes involved in calcium/calmodulin-mediated signal transduction, ABA homeostasis and transport, and antioxidant defense systems were significantly induced under chilling stress, suggesting that they may act as positive regulators in the enhanced low-temperature tolerance of poplar. Several transcription factors had divergent expression patterns, suggesting they have variable functional responses to abiotic stress. This profile of global gene expression patterns during chilling stress will be valuable for future studies on the molecular mechanisms of chilling tolerance in woody plants. 23850361 Laparoscopically Assisted Vaginal Radical Hysterectomy: Systematic Review of the Literature. Laparoscopically assisted vaginal radical vaginal hysterectomy (LAVRH), a minimally invasive technique that seems to be an attractive alternative to traditional surgery, remains unexplored in the treatment of cervical cancer. We searched Medline (1966-2013) and Scopus (2004-2013) search engines, as well as reference lists from all included studies. Ten studies were retrieved; including 6 retrospective cohort studies, 2 prospective cohort studies, 1 retrospective randomized trial, and a phase II randomized control trial. LAVRH provided equal recurrence-free rates when performed in patients with tumors not exceeding 2 cm in greatest diameter. Its main advantages seem to be less intraoperative blood loss and more radical pelvic lymphadenectomy. The primary disadvantages of the technique are a higher rate of disease-positive surgical margins, resulting in the need for adjuvant therapy, and the slow learning curve required for a surgeon to gain expertise. With use in minimally invasive surgery of newer techniques such as total laparoscopic radical hysterectomy and robotic-assisted radical hysterectomy, and possible future adoption of more conservative techniques such as cervical conization with pelvic lymphadenectomy, the question remains as to whether LAVRH will be adopted by the surgical community or lost to oblivion. 23685189 Oral L-citrulline administration improves memory deficits following transient brain ischemia through cerebrovascular protection. L-citrulline (L-Cit) is known to increase nitric oxide (NO) production via the increase of L-arginine (L-Arg) concentration in the blood and improve endothelial dysfunction in cardiovascular diseases. However, little is known about the effects of L-Cit on cerebrovascular dysfunction. Here we showed that oral L-Cit administration prevents cerebrovascular injury following cerebral ischemia using a 20-min bilateral common carotid artery occlusion (BCCAO) mouse model. After BCCAO ischemia, mice were treated with L-Cit (50, 75, or 100 mg/kg p.o.) for 10 days once a day. L-Cit administration not only prevented neuronal cell death but also prevented capillary loss in the hippocampal region following brain ischemia. The cerebrovascular protective effect of L-Cit was associated with the restoration of endothelial nitric oxide synthase (eNOS) expression in the hippocampus. In addition, we devised a novel protocol to analyze NOx(-) (NO(2-) and NO(3-)) productions following L-Arg infusion using in vivo microdialysis and revealed that decreased L-Arg-induced NOx(-) levels were improved in the hippocampus of BCCAO mice following repeated L-Cit administration. Finally, memory deficits following brain ischemia were improved by oral administration of L-Cit. In summary, L-Cit is a potential therapeutic agent that protects cerebrovascular injury and in turn prevents neuronal cell death. Thereby, oral L-Cit administration improves cognitive deficits following brain ischemia. 23946132 Serum albumin-protamine conjugate for biocompatible platform for targeted delivery of therapeutic macromolecules. A well-defined, one-to-one conjugate between human serum albumin (HSA) and protamine was synthesized and characterized as a biocompatible carrier for macromolecules. In circulation, the conjugate will camouflage drug molecules upon complex formation, while liberating free drug at the desired location using a triggering mechanism. The N-terminus of protamine was thiolated and conjugated with the unpaired Cysteine-34 of HSA, and was purified by ion-exchange chromatography. The molecular weight of the conjugate was 70.8 kDa, confirming one-to-one conjugation between HSA (66.6 KDa) and protamine (4200 Da). Superimposed fluorescence spectra of native HSA and HSA-protamine conjugate indicated no conformational change around the Trp-214. The conjugate had marked reduction in hemolytic and cytotoxic properties compared to protamine. When therapeutic potential was tested using tissue plasminogen activator (tPA) as a model drug, HSA-protamine conjugate suppressed the enzymatic activity by 65%, which was fully recovered by a triggering agent, heparin. The construct showed binding characteristics with activated platelets upon conjugation with a targeting peptide, demonstrating flexibility to introduce suitable homing moiety on the surface. The camouflaged construct retained triggered release property in human plasma condition. Overall, the conjugate has a good potential to serve as a biocompatible platform for macromolecular drugs. 23900970 Nebulised hypertonic saline solution for acute bronchiolitis in infants. Airway oedema and mucus plugging are the predominant pathological features in infants with acute viral bronchiolitis. Nebulised hypertonic saline solution may reduce these pathological changes and decrease airway obstruction. To assess the effects of nebulised hypertonic (≥ 3%) saline solution in infants with acute viral bronchiolitis. We searched CENTRAL 2013, Issue 4, OLDMEDLINE (1951 to 1965), MEDLINE (1966 to April week 4, 2013), EMBASE (1974 to May 2013), LILACS (1985 to May 2013) and Web of Science (1955 to May 2013). Randomised controlled trials (RCTs) and quasi-RCTs using nebulised hypertonic saline alone or in conjunction with bronchodilators as an active intervention and nebulised 0.9% saline as a comparator in infants up to 24 months of age with acute bronchiolitis. Two review authors independently performed study selection, data extraction and assessment of risk of bias in included studies. We conducted meta-analyses using the Cochrane statistical package RevMan 5.2. We used the random-effects model for meta-analyses. We used mean difference (MD) and risk ratio (RR) as effect size metrics. We included 11 trials involving 1090 infants with mild to moderate acute viral bronchiolitis (500 inpatients, five trials; 65 outpatients, one trial; and 525 emergency department patients, four trials). All but one of the included trials were of high quality with a low risk of bias. A total of 560 patients received hypertonic saline (3% saline n = 503; 5% saline n = 57). Patients treated with nebulised 3% saline had a significantly shorter mean length of hospital stay compared to those treated with nebulised 0.9% saline (MD -1.15 days, 95% confidence interval (CI) -1.49 to -0.82, P < 0.00001). The hypertonic saline group also had a significantly lower post-inhalation clinical score than the 0.9% saline group in the first three days of treatment (day 1: MD -0.88, 95% CI -1.36 to -0.39, P = 0.0004; day 2: MD -1.32, 95% CI -2.00 to -0.64, P = 0.001; day 3: MD -1.51, 95% CI -1.88 to -1.14, P < 0.00001). The effects of improving clinical score were observed in both outpatients and inpatients. Four emergency department-based trials did not show any significant short-term effects (30 to 120 minutes) of up to three doses of nebulised 3% saline in improving clinical score and oxygen saturation. No significant adverse events related to hypertonic saline inhalation were reported. Current evidence suggests nebulised 3% saline may significantly reduce the length of hospital stay among infants hospitalised with non-severe acute viral bronchiolitis and improve the clinical severity score in both outpatient and inpatient populations. 23825127 GHRH Receptor-Targeted Botulinum Neurotoxin Selectively Inhibits Pulsatile GH Secretion in Male Rats. Botulinum neurotoxin is a potent inhibitor of acetylcholine secretion and acts by cleaving members of the soluble N-ethylmaleimide-sensitive factor-attachment protein receptor family, which are critical to exocytotic vesicular secretion. However, the potential of botulinum neurotoxin for treating secretory disease is limited both by its neural selectivity and the necessity for direct injection into the relevant target tissue. To circumvent these limitations, a technology platform called targeted secretion inhibitors (TSIs) is being developed. TSIs are derived from botulinum neurotoxin but are retargeted to specific cell types to inhibit aberrant secretion. A TSI called qGHRH-LHN/D, with a GHRH receptor targeting domain and designed to specifically inhibit pituitary somatotroph GH release through cleavage of the N-ethylmaleimide-sensitive factor-attachment protein receptor protein, vesicle-associated membrane protein (VAMP), has recently been described. Here we show this TSI activates GHRH receptors in primary cultured rat pituicytes is internalized into these cells, depletes VAMP-3, and inhibits phorbol-12-myristate-13-acetate-induced GH secretion. In vivo studies show that this TSI, but not one with an inactive catalytic unit, produces a dose-dependent inhibition of pulsatile GH secretion, thus confirming its mechanism of action through VAMP cleavage. Selectivity of action has been shown by the lack of effect of this TSI in vivo on secretion from thyrotrophs, corticotrophs, and gonadotrophs. In the absence of suitable in vivo models, these data provide proof of concept for the use of somatotroph-targeted TSIs in the treatment of acromegaly and moreover raise the potential that TSIs could be used to target other diseases characterized by hypersecretion. 23884291 Integrated approach to treatment-resistant atrial fibrillation: additional value of acupuncture. A 62-year-old patient with chronic bronchitis had treatment-resistant atrial fibrillation. Electrical cardioversion was performed, but sinus rhythm (SR) lasted only for some minutes. Administration of amiodarone was withheld in favour of a course of acupuncture treatment in order to increase the success rate of a second attempt of electrical cardioversion. After two acupuncture treatments, spontaneous conversion to SR occurred. Relapses into atrial fibrillation in the following five winters, associated with attacks of bronchitis, also responded to acupuncture. The mechanisms of action of the acupuncture treatment and the value of this integrated approach to treatment are discussed. 23721916 Synthesis and preliminary biological evaluation of a compound library of triazolylcyclitols. A small library of compounds was prepared by a combination of toluene dioxygenase (TDO)-catalyzed enzymatic dihydroxylation and copper(I)-catalyzed Hüisgen cycloaddition. Some compounds were obtained by coupling an alkyne and a conduritol derivative, while more complex structures were obtained by a double Hüisgen reaction of a dialkyne and two molecules of the cyclitol. The compounds were fully characterized and subjected to preliminary biological screening. 23901249 Astaxanthin protects ARPE-19 cells from oxidative stress via upregulation of Nrf2-regulated phase II enzymes through activation of PI3K/Akt. Oxidative stress on retinal pigment epithelial (RPE) cells is thought to play a crucial role in the development and progression of age-related macular degeneration. Astaxanthin (AST) is a carotenoid that shows significant antioxidant properties. This study was designed to investigate the protective effect of AST on ARPE-19 cells against oxidative stress and the possible underlying mechanism. ARPE-19 cells exposed to different doses of H2O2 were incubated with various concentrations of AST and cell viability subsequently detected with the (4-[3-[4-iodophenyl]-2-4(4-nitrophenyl)-2H-5- tetrazolio-1,3-benzene disulfonate]; WST-1) assay. The apoptosis rate and intracellular levels of reactive oxygen species (ROS) were measured with flow cytometry. NAD(P)H quinine oxidoreductase 1 (NQO1), hemeoxygenase-1 (HO-1), glutamate-cysteine ligase modifier subunit (GCLM), and glutamate-cysteine ligase catalytic subunit (GCLC) expression were examined with real-time PCR and western blotting. The nuclear localization of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein and the expression levels of cleaved caspase-3 and protein kinase B proteins were evaluated with western blotting. AST clearly reduced H2O2-induced cell viability loss, cell apoptosis, and intracellular generation of ROS. Furthermore, treatment with AST activated the Nrf2-ARE pathway by inducing Nrf2 nuclear localization. Consequently, Phase II enzymes NQO1, HO-1, GCLM, and GCLC mRNA and proteins were increased. AST inhibited expression of H2O2-induced cleaved caspase-3 protein. Activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway was involved in the protective effect of AST on the ARPE-19 cells. AST protected ARPE-19 cells against H2O2-induced oxidative stress via Nrf2-mediated upregulation of the expression of Phase II enzymes involving the PI3K/Akt pathway. 23379370 Lessons Learned in Empirical Scoring with smina from the CSAR 2011 Benchmarking Exercise. We describe a general methodology for designing an empirical scoring function and provide smina, a version of AutoDock Vina specially optimized to support high-throughput scoring and user-specified custom scoring functions. Using our general method, the unique capabilities of smina, a set of default interaction terms from AutoDock Vina, and the CSAR (Community Structure-Activity Resource) 2010 data set, we created a custom scoring function and evaluated it in the context of the CSAR 2011 benchmarking exercise. We find that our custom scoring function does a better job sampling low RMSD poses when crossdocking compared to the default AutoDock Vina scoring function. The design and application of our method and scoring function reveal several insights into possible improvements and the remaining challenges when scoring and ranking putative ligands. 23582447 Novel imino sugar α-glucosidase inhibitors as antiviral compounds. Deoxynojirimycin (DNJ) based imino sugars display antiviral activity in the tissue culture surrogate model of Hepatitis C (HCV), bovine viral diarrhoea virus (BVDV), mediated by inhibition of ER α-glucosidases. Here, the antiviral activities of neoglycoconjugates derived from deoxynojirimycin, and a novel compound derived from deoxygalactonojirimycin, by click chemistry with functionalised adamantanes are presented. Their antiviral potency, in terms of both viral infectivity and virion secretion, with respect to their effect on α-glucosidase inhibition, are reported. The distinct correlation between the ability of long alkyl chain derivatives to inhibit ER α-glucosidases and their anti-viral effect is demonstrated. Increasing alkyl linker length between DNJ and triazole groups increases α-glucosidase inhibition and reduces the production of viral progeny RNA and the maturation of the envelope polypeptide. Disruption to viral glycoprotein processing, with increased glucosylation on BVDV E2 species, is representative of α-glucosidase inhibition, whilst derivatives with longer alkyl linkers also show a further decrease in infectivity of secreted virions, an effect proposed to be distinct from α-glucosidase inhibition. 23207893 Short-term Effects of Proprioceptive Training With Unstable Platform on Athletes' Stabilometry. Romero-Franco, N, Martínez-López, EJ, Lomas-Vega, R, Hita-Contreras, F, Osuna-Pérez, MC, and Martínez-Amat, A. Short-term effects of proprioceptive training with unstable platform on athletes' stabilometry. J Strength Cond Res 27(8): 2189-2197, 2013-The purpose of this study was to determine the short-term stabilometric effects of proprioceptive training in athletes by using a BOSU ball and a Swiss ball as unstable platforms. Thirty-seven athletes from a variety of disciplines were divided into a control group (n = 17) and an experimental group (n = 20). Both performed a warm-up, and in addition, the experimental group carried out a proprioceptive exercise session after the warm-up. Proprioceptive exercise session consisted of six 25-minute exercise sessions with the BOSU ball and the Swiss ball as unstable platforms. Bipedal stabilometry was assessed before the training session (M0), immediately after training (M1), 30 minutes later (M2), 1 hour after training (M3), 6 hours after training (M4), and 24 hours after training (M5). Analysis of variance (α = 0.05) revealed significant differences immediately after training (M1) in speed (p = 0.022) and length covered by the center of pressure (p = 0.021) in the experimental group. These differences were even more acute 6 hours later (M4; p = 0.021). In fact, the same group exhibited significant differences in mediolateral position after 30 minutes (M2; p = 0.001) compared with the baseline measure and the control group. Apart from these, no other significant differences were found. A proprioceptive exercise session using a BOSU ball and a Swiss ball as unstable platforms induced short-term negative effects on the stabilometry of athletes. Likewise, an immediate trend to improvement was apparent in the stabilometry of the control group after the warm-up. 23922833 Electroconvulsive therapy induces neurogenesis in frontal rat brain areas. Electroconvulsive therapy (ECT) is an effective therapy for several psychiatric disorders, including severe major depression, mania and certain forms of schizophrenia. It had been proposed that ECT acts by modulating local plasticity via the stimulation of neurogenesis. In fact, among antidepressant therapies, ECT is the most robust enhancer of neurogenesis in the hippocampus of rodents and non-human primates. The existence of ECT-triggered neurogenesis in other brain areas, particularly in those adjacent to the other main locus of neurogenesis, the subventricular zone (SVZ), had so far remained unknown. Here we show that ECT also strongly enhances neurogenesis in frontal brain areas, especially in the rostro-medial striatum, generating specific, small-size calretinin-positive interneurons. We provide here the first evidence that ECT stimulates neurogenesis in areas outside the hippocampus. Our data may open research possibilities that focus on the plastic changes induced by ECT in frontal limbic circuitry. 23958024 Resistance of the constitutive microflora of biofilms formed on whey reverse-osmosis membranes to individual cleaning steps of a typical clean-in-place protocol. This experiment evaluates the effectiveness of individual steps of a clean-in-place protocol against the biofilm constitutive microflora isolated from the biofilms developed on whey reverse-osmosis membranes, aged 2 to 14 mo, under industrial processing conditions. The isolates used for the in vitro resistance studies included species of Bacillus, Enterococcus, Streptococcus, Staphylococcus, Micrococcus, Aeromonas, Corynebacterium, Pseudomonas, Klebsiella, and Escherichia. The 6 cleaning steps (alkali, surfactant, acid, enzyme, a second surfactant, and sanitizer treatment) revealed resistance of isolates in both planktonic and biofilm-embedded cell states. The most effective step was the acid treatment, which resulted in 4.54 to 7.90 and 2.09 to 5.02 log reductions of the planktonic and biofilm-embedded cells, respectively. Although the sanitizer step causing a reduction of 4.91 to 8.33 log in the case of planktonic cells, it was less effective against the biofilm-embedded cells, resulting in a reduction of 0.59 to 1.64 log. Bacillus spp. showed the highest resistance in both planktonic, as well as embedded cell states. 23924525 The Late Effects of Anticancer Therapy after Childhood Wilm's Tumor: The Role of Diastolic Function and Ambulatory Blood Pressure Monitoring. Wilms' tumor, or nephroblastoma, is the most common primary malignant renal tumor of childhood. The excellent outcome now expected for most children with this tumor is attributed to the combination of effective adjuvant chemotherapy, improved surgical and anesthetic techniques and also the radiosensitivity of the tumor. The numerous organ systems are subject to the late effects of anticancer therapy. The aim of this study was to investigate the blood pressure profile and ambulatory blood pressure monitoring, and also cardiac diastolic functions and pulmonary venous flow in 25 children with unilateral Wilms' tumor in remission. The patient group consists of 25 patients who successfully completed anticancer treatment for unilateral Wilms' tumor. Thirty-three age-, weight- and height-matched healthy children were considered as a control group for an echocardiographic study. Also, 20 age-, weight- and height-matched healthy children were considered as a control group for the ambulatory blood pressure monitoring study. In our study, 24 h, daytime and night-time systolic blood pressure and night-time diastolic blood pressure measurements were found to be significantly increased in the patient group compared with healthy children. We detected diastolic filling pattern abnormalities. We also found increase in pulmonary venous flow (systolic and diastolic) in Wilms' tumor group. We suggest the regular follow-up of survivors of Wilms' tumor for care and prevention of cardiovascular diseases. 23408151 One novel susceptibility locus associate with systemic lupus erythematosus in Chinese Han population. The aim of the study is to explore additional susceptibility factors for systemic lupus erythematosus (SLE) in Chinese Hans. Based on our previous GWAS of SLE, we performed a multistage replication study involving 3,152 cases and 7,050 controls from China to identify additional susceptibility loci for SLE by using the Sequenom MassArray system. All Chinese Han samples used in this study were obtained from doctors through collaboration with multiple hospitals in two geographic regions (central and southern China). Single-marker association analyses were performed using logistic regression with gender as a covariate in each case-control cohort. The joint analysis of all combined samples was performed using logistic regression with gender and sample cohorts as covariates. The significant association evidence for rs906868 (OR = 1.14, 95 % CI 1.08-1.20, P combined = 7.71 Ã— 10(-10)) and rs7579944 (OR = 1.13, 95 % CI 1.07-1.19, P combined = 5.55 Ã— 10(-9)) was observed, which located at 2p23.1. In this region, limb bud and heart development homolog (LBH) was the only gene indicated, suggesting LBH might be a susceptibility gene for SLE, although its function was still unknown. The results indicated that the SNP rs7579944, rs906868 at 2p23.1 showed significant association with SLE. The genes LBH which located in this loci might be the predisposing genes of SLE. 23418678 Simultaneous determination of evodiamine and evodine in Beagle dog plasma using liquid chromatography tandem mass spectrometry. A sensitive, rapid, and specific liquid chromatography/tandem mass spectrometry assay has been established and validated for the quantitation of evodiamine and evodine in Beagle dog plasma. Plasma samples of 0.2 ml were processed by liquid-liquid extraction with n-hexane/ethyl acetate (2:1, v/v). Chromatographic separations were done on a Symmetry C(18) column (100 mm × 4.6 mm, ID, 5 μm) at 35°C with a linear gradient of methanol and 20 mM ammonium formate containing 0.2% formic acid. Evodiamine, evodine, and glibenclamide [internal standard (IS)] were ionized with an electrospray ionization source operated in positive ion mode. The MS/MS transitions were m/z 304.1 → 161.1 for evodiamine, m/z 471.2 → 425.1 for evodine, and m/z 494.1 → 369.1 for IS. Calibration curves were linear over the concentration range of 0.1-100 ng/ml for evodiamine and 0.5-500 ng/ml for evodine. The mean extraction recoveries were 88.10 ± 3.21% for evodiamine and 81.24 ± 4.07% for evodine. The intra- and inter-day precisions were less than 11.10% and 12.81%, and the accuracy was within ± 11.76% for both analytes. Evodiamine and evodine were stable during storage and analytical periods. The validated method has been successfully applied to a pharmacokinetic study of evodiamine and evodine in beagle dogs after oral administration. 23822890 Comparison of dilatation & curettage and endometrial aspiration biopsy accuracy in patients treated with high-dose oral progestin plus levonorgestrel intrauterine system for early-stage endometrial cancer. To compare the diagnostic accuracy of dilatation & curettage (D&C) vs. endometrial aspiration biopsy in follow-up evaluation of patients treated with high-dose oral progestin plus levonorgestrel intrauterine system (LNG-IUS) for early-stage endometrial cancer (EC). A prospective observational study was conducted with 11 patients with FIGO grade 1 or 2, clinical stage IA endometrioid adenocarcinoma. Patients were aged up to 40years wishing to preserve fertility treated with high-dose oral progestin plus LNG-IUS. Treatment response assessment was done at three month intervals. Endometrial tissues were obtained via endometrial aspiration biopsy with LNG-IUS in place and D&C after removal of LNG-IUS. We identified 28 cases; the histologic results were compared. Kappa statistics were used to assess the agreement of two methods. Diagnostic concordance between examinations was assessed for 9 out of 28 cases examined (32.1%). These consisted of three cases with both examination results of normal, 3 cases with endometrioid adenocarcinoma, 1 case with complex endometrial hyperplasia, 2 cases with material insufficient for diagnosis. Endometrioid adenocarcinoma on D&C was diagnosed in 9 out of 28 cases, but from endometrial aspiration biopsy, only 3 of these 9 cases were diagnosed with endometrioid adenocarcinoma, giving the diagnostic concordance at 33% (kappa value=0.27). From endometrial aspiration biopsy, 17 out of 28 cases (60.7%) had material insufficiency for diagnosis. In patients treated with high-dose oral progestin plus LNG-IUS for early-stage EC, endometrial aspiration biopsy with LNG-IUS in place may be not reliable as a follow-up evaluation method. 23948577 Antioxidant capacity and DNA-interaction studies of zinc complexes with a non-steroidal anti-inflammatory drug, mefenamic acid. Zinc(II) complexes of a non-steroidal anti-inflammatory drug, mefenamic acid(=Hmef) in the absence or presence of the nitrogen donor heterocyclic ligands 2,2'-bipyridine(=bipy), 2,2'-bipyridylamine(=bipyam), 2,2'-dipyridylketone oxime(=Hpko) or 1,10-phenanthroline(=phen) have been synthesized and characterized. The crystal structures of [Zn(mef-O,O')2(bipy)], 2, [Zn(mef-O)2(Hpko-N,N')2]·EtOH, 4 and [Zn(mef-O)(mef-O,O')(phen)(H2O)], 5, have been determined by X-ray crystallography showing distinct binding modes of mefenamato carboxylato group, bidentate in 2, monodentate in 4 or both in 5. Interaction studies of the complexes with calf-thymus DNA (CT DNA) have shown that complexes can bind to CT DNA with [Zn(mef-O)2(Hpko)2] exhibiting the highest binding constant to CT DNA (Kb=1.93(±0.04)×10(7)M(-1)). The complexes can bind to CT DNA via intercalation as concluded by DNA solution viscosity measurements. Competitive studies with ethidium bromide (EB) have shown that the complexes can displace the DNA-bound EB. The complexes exhibit good binding affinity to serum albumin proteins with [Zn(mef-O)2(H2O)4], 1 exhibiting the highest quenching ability (kq=1.46×10(15)M(-1)s(-1) for human and 5.55×10(15)M(-1)s(-1) for bovine serum albumin). All compounds have been tested for their antioxidant and free radical scavenging activity as well as for their in vitro inhibitory activity against soybean lipoxygenase. The scavenging activity is low to moderate against 1,1-diphenyl-picrylhydrazyl (DPPH) radicals and high against hydroxyl and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS(+)) radicals, with [Zn(mef-O)2(H2O)4], 1 (ABTS%, 0.1mM: 94.75(±1.06)%; OH%, 0.1mM: 96.69(±0.27)%; LOX: IC50=27.34(±0.90)μM) exhibiting the highest scavenging activity of the ABTS radical cation among the complexes. Additionally, the complexes exhibit higher scavenging and LOX inhibitory activity than free mefenamic acid (ABTS%, 0.1mM: 66.32(±0.38)%; OH%,0.1mM: 92.51(±0.44)%; LOX: IC50=48.52(±0.88)μM). 23919677 Calpain cleavage and inactivation of the sodium calcium exchanger-3 occurs downstream of Aβ in Alzheimer's disease. Alzheimer's disease (AD) is a neurodegenerative disorder characterized by pathological deposits of β-amyloid (Aβ) in senile plaques, intracellular neurofibrillary tangles (NFTs) comprising hyperphosphorylated aggregated tau, synaptic dysfunction and neuronal death. Substantial evidence indicates that disrupted neuronal calcium homeostasis is an early event in AD that could mediate synaptic dysfunction and neuronal toxicity. Sodium calcium exchangers (NCXs) play important roles in regulating intracellular calcium and accumulating data suggests that reduced NCX function, following aberrant proteolytic cleavage of these exchangers, may contribute to neurodegeneration. Here we show that elevated calpain, but not caspase-3, activity is a prominent feature of AD brain. In addition, we observe increased calpain-mediated cleavage of NCX3, but not a related family member NCX1, in AD brain relative to unaffected tissue and that from other neurodegenerative conditions. Moreover, the extent of NCX3 proteolysis correlated significantly with amounts of Aβ1-42. We also show that exposure of primary cortical neurons to oligomeric Aβ1-42 results in calpain-dependent cleavage of NCX3 and we demonstrate that loss of NCX3 function is associated with Aβ toxicity. Our findings suggest that Aβ mediates calpain cleavage of NCX3 in AD brain, and therefore that reduced NCX3 activity could contribute to the sustained increases in intraneuronal calcium concentrations that are associated with synaptic and neuronal dysfunction in AD. This article is protected by copyright. All rights reserved. 23850307 Patient expectations before arthroscopic shoulder surgery: correlation with patients' reasons for seeking treatment. Elevated expectations before orthopaedic procedures appear to correlate with inferior preoperative subjective measures. The purpose of this study was to evaluate preoperative patient expectations before arthroscopic shoulder surgery and to correlate them with preoperative subjective measures and patients' reasons for seeking treatment. We prospectively collected and retrospectively analyzed data from patients before elective arthroscopic shoulder surgery for a wide range of pathologic processes. Preoperative subjective data included QuickDASH scores, pain and functional components of the American Shoulder and Elbow Surgeons (ASES) score, and mental and physical components of the SF-12 score. Expectations data were collected and grouped on the basis of the reasons for seeking of medical treatment and ranked according to their relative importance. The study included 313 shoulders. There were 205 men and 108 women with a mean age at surgery of 48.7 years (range, 18-78 years). Overall, the most important expectations were for the "shoulder to be back to the way it was before the problem started" and to continue participation in sporting activities. Patients who presented with the "shoulder coming out" had fewer important expectations than did those who presented for other reasons. Those patients who indicated a desire to continue participation in sports had significantly less pain (improved ASES pain scores) compared with the rest of the population. Although return to sport was the most important expectation overall, the importance of other expectations varied by patients' reasons for seeking treatment. The current questionnaire may have limited use in patients with shoulder instability. 23750004 Septin rings act as a template for myosin higher-order structures and inhibit redundant polarity establishment. The mechanisms of the coordinated assembly and disassembly of the septin/myosin ring is central for the understanding of polar growth and cytokinesis in yeast and other organisms. The septin- and myosin-binding protein Bni5p provides a dual function during the formation and disassembly of septin/myosin rings. Early in the cell cycle, Bni5p captures Myo1p at the incipient bud site and actively transforms it into higher-order structures. Additionally, Bni5p stabilizes the septin/myosin ring and is released from the septins shortly before the onset of cytokinesis. If this Bni5p dissociation from the septins is artificially prevented, ring disassembly is impaired and the untimely appearance of septin/myosin ring is induced. The prematurely formed septin/myosin rings delay the establishment of a new polarity axis and the progression into a new cell cycle. This observation suggests a negative feedback between septin/myosin ring formation and polarity establishment that might help to guarantee the singular assembly of this structure and the synchronization of its formation with the cell cycle. 23778529 Biological evidence for a causal role of HPV16 in a small fraction of laryngeal squamous cell carcinoma. Background:Human papillomavirus (HPV) is a causal factor in virtually all cervical and a subset of oropharyngeal squamous cell carcinoma (OP-SCC), whereas its role in laryngeal squamous cell carcinoma (L-SCC) is unclear.Methods:Formalin-fixed paraffin-embedded (N=154) and deep-frozen tissues (N=55) of 102 L-SCC patients were analysed for the presence of 51 mucosal HPV types. HPV DNA-positive (HPV DNA+) cases were analysed for E6*I mRNA transcripts of all high risk (HR)/probably/possibly (p)HR-HPV identified, and for HPV type 16 (HPV16) viral load. Expression of p16(INK4a), pRb, cyclin D1 and p53 was analysed by immunohistochemistry.Results:Ninety-two patients were valid in DNA analysis, of which 32 (35%) had at least one HPV DNA+ sample. Among the 29 single infections, 22 (76%) were HPV16, 2 (7%) HPV56 and 1 each (4%) HPV45, HPV53, HPV70, HPV11 and HPV42. Three cases harboured HPV16 with HPV33 (twice) or HPV45. Only 32% of HPV DNA+ findings were reproducible. Among HPV16 DNA+ L-SCC, 2 out of 23 (9%) had high viral loads, 5 out of 25 (21%) expressed E6*I mRNA and 3 out of 21 (14%) showed high p16(INK4a) and low pRb expression (all three HPV16 RNA-positive), immunohistochemical marker combination not identified in any other HPV DNA+ or HPV DNA-negative (HPV DNA-) L-SCC, respectively.Conclusion:HPV type 16 has a causative role in a small subgroup of L-SCC (<5% in this German hospital series). 23772669 Prognostic significance of immunohistochemical expression of the angiogenic molecules vascular endothelial growth factor-A, vascular endothelial growth factor receptor-1 and vascular endothelial growth factor receptor-2 in patients with classical Hodgkin lymphoma. Angiogenesis leads to new blood vessel formation and is implicated in both physiological and pathological situations. The vascular endothelial growth factor (VEGF) family is the major mediator of this process. The aim of our study was to evaluate the expression of VEGF-A, vascular endothelial growth factor receptor-1 (VEGFR-1) and VEGFR-2 and their correlation with clinicopathological parameters and prognosis in patients with classical Hodgkin lymphoma (cHL), since the role of angiogenesis in this tumor still remains unclear. The immunohistochemical expression of VEGF-A, VEGFR-1 and VEGFR-2 was examined in 194 patients with cHL. The neoplastic Hodgkin Reed-Sternberg (HRS) cells expressed VEGF-A, VEGFR-1 and VEGFR-2 in 90.3%, 97.2% and 94.1% of cases, respectively. Only the expression of VEGFR-2 was positively correlated with serum albumin levels ≥ 4 g/dL. No correlation with patient outcome was observed. All three molecules were statistically correlated with ramifications of blood vessels. Summarizing, our results are not sufficient to consider VEGF-A and/or VEGF receptors as prognosticators in cHL. 23884733 Effects of isotonic and isometric exercises with mist sauna bathing on cardiovascular, thermoregulatory, and metabolic functions. To clarify the effects of isometric and isotonic exercise during mist sauna bathing on the cardiovascular function, thermoregulatory function, and metabolism, six healthy young men (22 ±â€‰1 years old, height 173 ±â€‰4 cm, weight 65.0 ±â€‰5.0 kg) were exposed to a mist sauna for 10 min at a temperature of 40 °C, and relative humidity of 100 % while performing or not performing ∼30 W of isometric or isotonic exercise. The effect of the exercise was assessed by measuring tympanic temperature, heart rate, systolic and diastolic blood pressure, chest sweat rate, chest skin blood flow, and plasma catecholamine and cortisol, glucose, lactate, and free fatty acid levels. Repeated measures ANOVA showed no significant differences in blood pressure, skin blood flow, sweat rate, and total amount of sweating. Tympanic temperature increased more during isotonic exercise, and heart rate increase was more marked during isotonic exercise. The changes in lactate indicated that fatigue was not very great during isometric exercise. The glucose level indicated greater energy expenditure during isometric exercise. The free fatty acid and catecholamine levels indicated that isometric exercise did not result in very great energy expenditure and stress, respectively. The results for isotonic exercise of a decrease in lactate level and an increase in plasma free fatty acid level indicated that fatigue and energy expenditure were rather large while the perceived stress was comparatively low. We concluded that isotonic exercise may be a more desirable form of exercise during mist sauna bathing given the changes in glucose and free fatty acid levels. 23336064 Mechanistic insight into inhibition of two-component system signaling. Two-component signal transduction systems (TCSs) are commonly used by bacteria to couple environmental stimuli to adaptive responses. Targeting the highly conserved kinase domain in these systems represents a promising strategy for the design of a broad-spectrum antibiotic; however, development of such compounds has been marred by an incomplete understanding of the conserved binding features within the active site that could be exploited in molecule design. Consequently, a large percentage of the available TCS inhibitors demonstrate poor target specificity and act via multiple mechanisms, with aggregation of the kinase being the most notable. In order to elucidate the mode of action of some of these compounds, molecular modeling was employed to dock a suite of molecules into the ATP-binding domain of several histidine kinases. This effort revealed a key structural feature of the domain that is likely interacting with several known inhibitors and is also highly conserved. Furthermore, generation of several simplified scaffolds derived from a reported inhibitor and characterization of these compounds using activity assays, protein aggregation studies and saturation transfer differential (STD) NMR suggests that targeting of this protein feature may provide a basis for the design of ATP-competitive compounds. 23358949 Magnetic fluid hyperthermia modeling based on phantom measurements and realistic breast model. Magnetic fluid hyperthermia (MFH) is a minimally invasive procedure that destroys cancer cells. It is based on a superparamagnetic heat phenomenon and consists in feeding a ferrofluid into a tumor, and then applying an external electromagnetic field, which leads to apoptosis. The strength of the magnetic field, optimal dose of the ferrofluid, the volume of the tumor and the safety standards have to be taken into consideration when MFH treatment is planned. In this study, we have presented the novel complementary investigation based both on the experiments and numerical methodology connected with female breast cancer. We have conducted experiments on simplified female breast phantoms with numerical analysis and then we transferred the results on an anatomically-like breast model. 23512597 Modest fructose beverage intake causes liver injury and fat accumulation in marginal copper deficient rats. Dietary fructose and copper interaction may play an important role in the pathogenesis of nonalcoholic fatty liver disease. In this study, whether or not modest fructose consumption (3% fructose, w/v) (which is more closely related to the American lifestyle with regard to sugar beverage consumption) affects copper status, and causes liver injury and fat accumulation in marginal copper deficient rats was investigated. Male weanling Sprague-Dawley rats were fed either an adequate copper (6ppm) or a marginally copper deficient (1.6ppm) diet for 4 weeks. Deionized water or deionized water containing 3% fructose (w/v) was given ad lib. Modest fructose consumption further impaired copper status in the marginal copper deficient rats and increased hepatic iron accumulation. Liver injury and fat accumulation were significantly induced in the marginal copper deficient rats exposed to fructose. Our data suggest that modest fructose consumption can impair copper status and lead to hepatic iron overload, which in turn, may lead to liver injury and fatty liver in marginal copper deficient rats. This study provides important information on dietary fructose and copper interaction, suggesting that dietary fructose-induced low copper availability might be an important mechanism underlying fructose-induced fatty liver. 23587649 Acute and chronic interference with BDNF/TrkB-signaling impair LTP selectively at mossy fiber synapses in the CA3 region of mouse hippocampus. Brain-derived neurotrophic factor (BDNF) signaling via TrkB crucially regulates synaptic plasticity in the brain. Although BDNF is abundant at hippocampal mossy fiber (MF) synapses, which critically contribute to hippocampus dependent memory, its role in MF synaptic plasticity (long-term potentiation, LTP) remained largely unclear. Using field potential recordings in CA3 of adult heterozygous BDNF knockout (ko, BDNF+/-) mice we observed impaired (∼50%) NMDAR-independent MF-LTP. In contrast to MF synapses, LTP at neighboring associative/commissural (A/C) fiber synapses remained unaffected. To exclude that impaired MF-LTP in BDNF+/- mice was due to developmental changes in response to chronically reduced BDNF levels, and to prove the importance of acute availability of BDNF in MF-LTP, we also tested effects of acute interference with BDNF/TrkB signaling. Inhibition of TrkB tyrosine kinase signaling with k252a, or with the selective BDNF scavenger TrkB-Fc, both inhibited MF-LTP to the same extent as observed in BDNF+/- mice. Basal synaptic transmission, short-term plasticity, and synaptic fatigue during LTP induction were not significantly altered by treatment with k252a or TrkB-Fc, or by chronic BDNF reduction in BDNF+/- mice. Since the acute interference with BDNF-signaling did not completely block MF-LTP, our results provide evidence that an additional mechanism besides BDNF induced TrkB signaling contributes to this type of LTP. Our results prove for the first time a mechanistic action of acute BDNF/TrkB signaling in presynaptic expression of MF-LTP in adult hippocampus. 23416643 Diagnostic accuracy of renal pelvic dilatation for detecting surgically managed ureteropelvic junction obstruction. In this study we evaluate the diagnostic accuracy of renal pelvic dilatation for detecting infants with prenatal hydronephrosis who will need surgical intervention for ureteropelvic junction obstruction during followup. Between 1999 and 2010, 371 newborns diagnosed with isolated prenatal hydronephrosis were prospectively followed. The main event of interest was the need for pyeloplasty. Diagnostic odds ratio, sensitivity, specificity and diagnostic accuracy (assessed by AUC) of fetal renal pelvic dilatation and postnatal renal pelvic dilatation were evaluated. A total of 312 patients were included in the analysis and 25 (7.5%) infants underwent pyeloplasty. The diagnostic performance for detecting the need for pyeloplasty was excellent for all ultrasonography measurements. The AUC was 0.96 (95% CI 0.92-0.98) for fetal renal pelvic dilatation, 0.97 (95% CI 0.95-0.98) for postnatal renal pelvic dilatation and 0.95 (95% CI 0.92-0.97) for the Society for Fetal Urology grading system. A cutoff of 18 mm for fetal renal pelvic dilatation and a cutoff of 16 mm for postnatal renal pelvic dilatation had the best diagnostic odds ratio to identify infants who needed pyeloplasty. Considering a diagnosis to be positive only if fetal renal pelvic dilatation was greater than 18 mm and postnatal dilatation was greater than 16 mm, sensitivity was 100% and specificity was 86% (95% CI 80.7-89.9). Our findings suggest that the combination of fetal and postnatal renal pelvic dilatation is able to increase the diagnostic accuracy for detecting infants who need a more comprehensive postnatal investigation for upper urinary tract obstruction. 23876098 Efficacy and safety of rituximab plus low-dose oral fludarabine and cyclophosphamide as first-line treatment of Elderly patients with indolent Non hodgkin lymphomas. ABSTRACT Indolent non-Hodgkin lymphomas (iNHL) are B-cell neoplasms for which no consensus is available about optimal first line therapy. Chemoimmunotherapy with fludarabine, cyclophospamide and rituximab is very effective but may give severe hematological and non-hematological toxicity at standard doses, especially in elderly patients. In this phase II study 25 untreated elderly iNHL patients received rituximab (375mg/m(2)) plus low-dose oral fludarabine (25mg/m(2) for 4 consecutive days) and cyclophosphamide (150mg/m(2) for 4 consecutive days), for 4 monthly cycles. Twenty-three patients were responsive (92%), 12 patients achieved complete remission (48%). Twenty-one patients (84%) were alive, median follow-up was 30 months, median event free survival (EFS) was not reached. Patients which we previously treated with chemotherapy alone had a shorter EFS (median 20 months). Compliance was good with mild toxicity. This regimen is effective for elderly iNHL patients; the addition of rituximab results in long EFS without affecting toxicity. 23924799 From Bretonneau to therapeutic antibodies, from specificity to specific remedies, Saint-Cyr-Sur-Loire, France, November 19, 2012. Held on November 19, 2012 in Saint-Cyr-sur-Loire, France, the symposium "From Bretonneau to therapeutic antibodies, from specificity to specific remedies" focused on the historical development of antibodies as therapeutics, with an emphasis on the seminal work of the French physician Pierre-Fidèle Bretonneau (1778-1862). The morning session was devoted to discussion of the evolution of the concept of specificity in medicine, which started with an epistemological definition. The contributions of Bretonneau to the emergence of the concept of specificity, notably with his studies on diphtheria, and the subsequent development of antidiphtheric serotherapy in Europe during the period 1894-1898 were then presented in detail. The afternoon session began with a presentation on the role of French physiologists during the years 1860-1890 in establishing the basic concepts of specific immunity and the principles of serotherapy. The history of antivenom serotherapy, particularly its discovery by Césaire Phisalix, and the development of antilymphocyte globulins as successful transplantation drugs were then discussed. The symposium ended with the inauguration of a stele representing Bretonneau, who lived in Saint-Cyr-sur-Loire and died 150 y ago. 23199991 Sitosterol as an antioxidant in frying oils. The antioxidative effect of sitosterol at 1, 2 and 5% levels, in triolein, refined canola, high oleic sunflower and flaxseed oils, continuously heated for a period of up to 72 h at frying temperature of 180 °C, was studied. High Pressure Size Exclusion Chromatography (HPSEC) was used to monitor changes in peak areas of triacylglycerol (TG) polymer, monomer and ester hydrolysis products. The presence of enhanced levels of sitosterol was found to significantly decrease TG polymer formation in triolein and the vegetable oil samples after heating at 180 °C for a period of 72 h. A corresponding increase in the level of intact TG monomer and the extent of TG ester hydrolysis was observed in all samples with enhanced levels of sitosterol. Conversion of sterol to steradiene, by the 1, 2 elimination of water, may be responsible for the antioxidative effect of sitosterol at frying temperatures. 23939979 Characterisation of messenger RNAs termini in Schmallenberg virus and related Simbuviruses. Schmallenberg virus (SBV) is an emerging arbovirus infecting ruminants in Europe. SBV belongs to the Bunyaviridae family within the Simbu serogroup. Its genome comprises three segments, small (S), medium (M) and large (L) that altogether encode six proteins and contain non-translated regions (NTR). NTRs are involved in initiation and termination of the transcription and in genome packaging. This study explored 3' mRNA termini of SBV and related Simbuviruses. In addition 5' termini of SBV mRNA were characterised. For the three SBV segments, cap-snatching was found to initiate mRNA transcription both in vivo and in vitro. Presence of extraneous nucleotides between host RNA leaders and the viral termini fits with the previously described prime-and-realign theory. At the 3' termini, common features were identified for SBV and related Simbuviruses. However, different patterns were observed for the three segments termini of a same virus. 23678032 Estradiol modulates recovery of REM sleep in a time-of-day-dependent manner. Ovarian hormones are thought to modulate sleep and fluctuations in the hormonal milieu are coincident with sleep complaints in women. In female rats, estradiol increases waking and suppresses sleep. In this study, we asked whether this effect is mediated via circadian or homeostatic regulatory mechanisms. Ovariectomized female rats received daily injections of estradiol benzoate (EB) or sesame oil that mimicked the rapid increase and subsequent decline of circulating estradiol at proestrus. In one experiment, animals were sleep deprived for 6 h starting at lights-on, so that recovery began in the mid-light phase; in the second experiment, animals were sleep deprived starting in the mid-light phase, so that recovery began at lights-off. EB suppressed baseline rapid eye movement (REM) and non-REM (NREM) sleep and increased waking in the dark phase. In both experiments, EB enhanced REM recovery in the light phase while suppressing it in the dark compared with oil; this effect was most pronounced in the first 6 h of recovery. By contrast, NREM recovery was largely unaffected by EB. In summary, EB enhanced waking and suppressed sleep, particularly REM sleep, in the dark under baseline and recovery conditions. These strong temporally dependent effects suggest that EB consolidates circadian sleep-wake rhythms in female rats. 23519095 Is Tako-tsubo syndrome in the postpartum period a clinical entity different from peripartum cardiomyopathy? To conduct a systematic review of case reports about Tako-tsubo syndrome (TTS) after delivery in order to assess whether TTS in the postpartum period is a peculiar entity or only a variant form of peripartum cardiomyopathy. We performed a systematic literature search on the occurrence of TTS after Cesarean section or spontaneous delivery using the scientific literature databases Medline, EMBASE and the Cochrane library. We selected 14 case reports in English. Primary/elective cesarean section or spontaneous delivery; absence of preexisting cardiovascular disease or fetal malformations; identification of diagnostic criteria for TTS; onset of TTS symptoms after delivery were the inclusion criteria. Fifteen cases were selected. Cesarean section 24 h before the onset of TTS was reported in 13. All patients presented dyspnea or chest pain. The majority had mild troponin elevation, non-ST-segment elevation. Apical ballooning was observed in 60% of cases, midventricular ballooning in 33%, basal ballooning in 7%. Although 13 patients experienced acute cardiac complications (pulmonary edema, cardiogenic shock, cardiac arrest), in all left ventricular systolic function normalized within 13.43 ± 10.96 days. Women in the postpartum period, notably after Cesarean delivery, may represent another new vulnerable group at increased risk for TTS. TTS in the postpartum period should be considered a clinical entity different from peripartum cardiomyopathy with specific clinical, therapeutic and prognostic implications. 23623784 Comparison of facial morphologies between adult Chinese and Houstonian Caucasian populations using three-dimensional imaging. The objective of this study was to compare the facial morphologies of an adult Chinese population to a Houstonian white population. Three-dimensional (3D) images were acquired via a commercially available stereophotogrammetric camera system, 3dMDface™. Using the system, 100 subjects from a Houstonian population and 71 subjects from a Chinese population were photographed. A complex mathematical algorithm was performed to generate a composite facial average (one for males and one for females) for each subgroup. The computer-generated facial averages were then superimposed based on a previously validated superimposition method. The facial averages were evaluated for differences. Distinct facial differences were evident between the subgroups evaluated. These areas included the nasal tip, the peri-orbital area, the malar process, the labial region, the forehead, and the chin. Overall, the mean facial difference between the Chinese and Houstonian female averages was 2.73±2.20mm, while the difference between the Chinese and Houstonian males was 2.83±2.20mm. The percent similarity for the female population pairings and male population pairings were 10.45% and 12.13%, respectively. The average adult Chinese and Houstonian faces possess distinct differences. Different populations and ethnicities have different facial features and averages that should be considered in the planning of treatment. 23783098 Increased skeletal muscle volume in women with familial partial lipodystrophy, dunnigan variety. Introduction: Familial partial lipodystrophy, Dunnigan variety (FPLD), an autosomal dominant disorder caused by LMNA mutations, is characterized by fat loss from the extremities. However, it is unclear whether these patients appear muscular because of a lack of subcutaneous fat or have an actual increase in muscle mass. Therefore, we compared muscle mass and volume of selected muscles in women with FPLD and control subjects using dual-emission x-ray absorptiometry (DXA) and magnetic resonance imaging (MRI). Methods: Whole-body axial MRI and DXA scans were obtained on 39 women, aged 18 to 65 years, with FPLD and 17 healthy women matched for body mass index and age (group 1). Volumes of muscles in both the thighs, calves, and psoas were calculated from MRI scans and muscle mass in extremities were calculated from DXA. In addition, abdominal MRI and DXA scans were analyzed from 129 healthy, frequency-matched women (group 2). Comparisons between women with FPLD and control subjects were made using ANOVA, adjusting for height, body mass index, and age. Results: Patients with FPLD, compared with control subjects had significantly greater volumes of the thigh muscles, (6358 ± 1491 vs 5198 ± 716 mL, P = .002), calf muscles (3133 ± 713 vs 2397 ± 335 mL; P < .001), and psoas muscles (210 ± 51 vs 175 ± 34 [group 1] and 165 ± 38 mL [group 2], P < .001). Patients with FPLD also had significantly increased arm and leg muscle masses when measured by DXA (P < .001). Insulin sensitivity, assessed by insulin tolerance tests, was negatively correlated to the calf muscle volume. Conclusions: Female patients with FPLD have increased skeletal muscle volume and mass compared with those of normal women. 23861818 Killer Immunoglobulin-Like Receptor (KIR) Centromeric-AA Haplotype Is Associated with Ethnicity and Tuberculosis Disease in a Canadian First Nations Cohort. Killer immunoglobulin-like receptors (KIR) on natural killer (NK) cells interact with other immune cells to monitor the immune system and combat infectious diseases, such as tuberculosis (TB). The balance of activating and inhibiting KIR interactions helps determine the NK cell response. In order to examine the enrichment or depletion of KIRs as well as to explore the association between TB status and inhibitory/stimulatory KIR haplotypes, we performed KIR genotyping on samples from 93 Canadian First Nations (Dene, Cree, and Ojibwa) individuals from Manitoba with active, latent, or no TB infection, and 75 uninfected Caucasian controls. There were significant differences in KIR genes between Caucasians and First Nations samples and also between the First Nations ethnocultural groups (Dene, Cree, and Ojibwa). When analyzing ethnicity and tuberculosis status in the study population, it appears that the KIR profile and centromeric haplotype are more predictive than the presence or absence of individual genes. Specifically, the decreased presence of haplotype B centromeric genes and increased presence of centromeric-AA haplotypes in First Nations may contribute to an inhibitory immune profile, explaining the high rates of TB in this population. 22439883 Essential oils composition of Periploca laevigata Aiton subsp. angustifolia (Labill.) Markgraf (Apocynaceae-Periplocoideae). The essential oil of roots, branches, leaves, flowers and fruits of Periploca laevigata Aiton subsp. angustifolia (Apocynaceae) from Lampedusa Island has been obtained by hydrodistillation and its composition analysed. The analyses allowed the identification and quantification of 86 volatile compounds. Branches showed the higher diversity with 57 compounds followed by fruits with 33, roots with 23, flowers with 16 and leaves with six compounds, respectively. In the matrices examined three constituents, heneicosane, docosane and tricosane are in common, although with different percentages. At least the most abundant compounds found in the matrices have been reported to have several biological activities. 2-Hydroxy-4-methoxybenzaldehyde identified in the roots as the most abundant component (70.7%) and present with 8.3% in the branches is a potent tyrosinase inhibitor present in several African medicinal plants, and thus being used as an ingredient in cosmetic and other medicinal products, primarily in relation to hyperpigmentation. Among the compounds identified, several play a role as semiochemicals for many animals, and 28 allomones, 43 pheromones, 21 kairomones have been identified. P. laevigata subsp. angustifolia in Lampedusa Island is host to a community of visitors, and the possible ecological role of the volatiles found is briefly discussed. 23954205 Reduced intra-erythrocytic growth of glycerol kinase knockout Plasmodium falciparum parasites during in vitro blood stage development. Malaria is a devastating disease and Plasmodium falciparum is the most lethal parasite infecting humans. Understanding the biology of this parasite is vital in identifying potential novel drug targets. During every 48-hour intra-erythrocytic asexual replication cycle, a single parasite can produce up to 32 progeny. This extensive proliferation implies that parasites require substantial amounts of lipid precursors for membrane biogenesis. Glycerol kinase is a highly conserved enzyme that functions at the interface of lipid synthesis and carbohydrate metabolism. P. falciparum glycerol kinase catalyzes the ATP-dependent phosphorylation of glycerol to glycerol-3-phosphate, a major phospholipid precursor. The P. falciparum glycerol kinase gene was disrupted using double crossover homologous DNA recombination to generate a knockout parasite line. Southern hybridization and mRNA analysis were used to verify gene disruption. Parasite growth rates were monitored by flow cytometry. Radiolabelling studies were used to assess incorporation of glycerol into parasite phospholipids. Disruption of the P. falciparum glycerol kinase gene produced viable parasites, but their growth was significantly reduced to 56.5±1.8% when compared to wild type parasites. (14)C-glycerol incorporation into the major phospholipids of the parasite membrane, phosphatidylcholine and phosphatidylethanolamine, was 48.4±10.8% and 53.1±5.7% relative to an equivalent number of wild type parasites. P. falciparum glycerol kinase is required for optimal intra-erythrocytic asexual parasite development. Exogenous glycerol may be used as an alternative carbon source for P. falciparum phospholipid biogenesis, despite the lack of glycerol kinase to generate glycerol-3-phosphate. These studies provide new insight into glycerolipid metabolism in P. falciparum. 23840285 Primary non-Hodgkin's lymphoma of bone: poly-ostotic versus mono-ostotic subtypes. Primary non-Hodgkin's lymphoma of bone (PNHLB) accounts for less than 5% of all primary bone tumours and less than 1% of all non-Hodgkin's lymphoma. Due to its rarity, only a few retrospective studies have been published describing the prognosis and its treatment. We report our experience of 20 cases of PNHLB with their clinicopathologic correlation that were treated at our centre over a period of ten years. There were 16 cases of the mono-ostotic subtype and four cases of poly-ostotic subtype. All of these had a histological diagnosis of diffuse large B-cell lymphoma. The age of presentation was fifth to sixth decade. The mono-ostotic subtype commonly presented with the involvement of femur or humerus, while the poly-ostotic subtype commonly had paraparesis due to vertebral involvement. Cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-based chemotherapy was given to all patients, but definitive radiotherapy was used only in the mono-ostotic subtype. At median follow-up of 38 months (range 5-96 months), event-free survival was 81% and 25% with mono-ostotic and poly-ostotic subtypes, respectively. Thus poly-ostotic PNHLB is a distinctive entity with a poor prognosis, and larger studies are needed for better management of this subtype. 23639549 From genetics of inflammatory bowel disease towards mechanistic insights. Advancements in human genetics now poise the field to illuminate the pathophysiology of complex genetic disease. In particular, genome-wide association studies (GWAS) have generated insights into the mechanisms driving inflammatory bowel disease (IBD) and implicated genes shared by multiple autoimmune and autoinflammatory diseases. Thus, emerging evidence suggests a central role for the mucosal immune system in mediating immune homeostasis and highlights the complexity of genetic and environmental interactions that collectively modulate the risk of disease. Nevertheless, the challenge remains to determine how genetic variation can precipitate and sustain the inappropriate inflammatory response to commensals that is observed in IBD. Here, we highlight recent advancements in immunogenetics and provide a forward-looking view of the innovations that will deliver mechanistic insights from human genetics. 23949663 Potential role of viruses in white plague coral disease. White plague (WP)-like diseases of tropical corals are implicated in reef decline worldwide, although their etiological cause is generally unknown. Studies thus far have focused on bacterial or eukaryotic pathogens as the source of these diseases; no studies have examined the role of viruses. Using a combination of transmission electron microscopy (TEM) and 454 pyrosequencing, we compared 24 viral metagenomes generated from Montastraea annularis corals showing signs of WP-like disease and/or bleaching, control conspecific corals, and adjacent seawater. TEM was used for visual inspection of diseased coral tissue. No bacteria were visually identified within diseased coral tissues, but viral particles and sequence similarities to eukaryotic circular Rep-encoding single-stranded DNA viruses and their associated satellites (SCSDVs) were abundant in WP diseased tissues. In contrast, sequence similarities to SCSDVs were not found in any healthy coral tissues, suggesting SCSDVs might have a role in WP disease. Furthermore, Herpesviridae gene signatures dominated healthy tissues, corroborating reports that herpes-like viruses infect all corals. Nucleocytoplasmic large DNA virus (NCLDV) sequences, similar to those recently identified in cultures of Symbiodinium (the algal symbionts of corals), were most common in bleached corals. This finding further implicates that these NCLDV viruses may have a role in bleaching, as suggested in previous studies. This study determined that a specific group of viruses is associated with diseased Caribbean corals and highlights the potential for viral disease in regional coral reef decline. 23761630 The neutral, hydrophobic isoleucine at position I521 in the extracellular S4 domain of hERG contributes to channel gating equilibrium. The human ether-a-go-go related (hERG) potassium channel has unusual functional characteristics in that the rates of channel activation and deactivation are much slower than inactivation, which is attributed to specific structural elements within the NH2 terminus and the S1-S4 voltage-sensing domains (VSD). Although the charged residues in the VSD have been extensively modified and mutated as a result, the role and importance of specific hydrophobic residues in the S4 has been much less explored in studies of hERG gating. We found that charged, but not neutral or hydrophobic, amino acid substitution of isoleucine 521 at the outer end of the S4 transmembrane domain resulted in channels activating at much more negative voltages associated with a marked hyperpolarization of the conductance-voltage (G-V) relationship. The contributions of different physicochemical properties to this effect were probed by chemical modification of channels substituted with cysteine at position I521. When positively charged reagents including tetramethyl-rhodamine-5-maleimide (TMRM), 1-(2-maleimidylethyl)-4-[5-(4-methoxyphenyl)oxazol-2-yl] pyridinium methane-sulfonate (PyMPO), [2-(trimethylammonium)ethyl] methanethiosulfonate chloride (MTSET), and 2-aminoethyl methanethiosulfonate hydrobromide (MTSEA) were bound to the cysteine, I521C channels activated at more negative membrane potentials. To examine the contributions to hERG gating of other residues at the outer end of S4 (520-528), we performed a cysteine scan combined with MTSET modification. Only L520C, along with I521C, shows a substantial hyperpolarizing shift of the G-V relationship upon MTSET modification. The data indicate that the neutral, hydrophobic residue I521 at the extracellular end of S4 is critical for stabilizing the closed conformation of the hERG channel relative to the open state and by comparison with Shaker supports the alignment of hERG I521 with Shaker L361. 23253102 A cold responsive galactinol synthase gene from Medicago falcata (MfGolS1) is induced by myo-inositol and confers multiple tolerances to abiotic stresses. Galactinol synthase (GolS, EC 2.4.1.123) catalyzes formation of galactinol and the subsequent synthesis of raffinose family oligosaccharides. The relationship of GolS to drought and salt tolerance has been well documented, however, little information is available about the role of GolS gene in cold tolerance. A coding sequence of MfGolS1 cDNA was cloned from Medicago sativa spp falcata (i.e. M. falcata), a species that exhibits greater cold tolerance than alfalfa (M. sativa). MfGolS1 transcript was not detected in untreated vegetative tissues using RNA blot hybridization; however, it was greatly induced in leaves, but not in stem and petiole, after cold treatment. Higher levels of MfGolS1 transcript were induced and maintained in M. falcata than in M. sativa during cold acclimation. Accordingly, more sugars including sucrose, galactinol, raffinose and stachyose were accumulated in M. falcata than in M. sativa. The data indicated that MfGolS1 transcript and its resultant sugar accumulation were associated with the differential cold tolerance between M. falcata and M. sativa. MfGolS1 transcript was weakly induced by dehydration and salt stresses, but not responsive to abscisic acid. MfGolS1 could be induced by myo-inositol, which is proposed to participate in cold-induced MfGolS1 expression. Overexpression of MfGolS1 in tobacco resulted in elevated tolerance to freezing and chilling in transgenic plants as a result of enhanced levels of galactinol, raffinose and stachyose. Tolerance to drought and salt stresses was also increased in the transgenic tobacco plants. It is suggested that MfGolS1 plays an important role in plant tolerance to abiotic stresses. 23947922 Correlation of Wnt5a expression with histopathological grade/stage in urothelial carcinoma of the bladder. Bladder cancer, including urothelial carcinoma (UC), is the most common malignancy of the urinary tract and the fourth most frequent cancer overall in men. Wnt5a, a member of theWnt family of proteins, has been shown to have contradictory roles in the pathogenesis of many cancers, acting either as tumor suppressor or tumor promoter. The objective of this study was to investigate the expression and role of Wnt5a in the pathogenesis of UC and suggest possible clinical applications for diagnosis, prognosis and treatment. We characterized the expression of Wnt5a in 33 human UC samples using immunohistochemistry. The samples were obtained via transurethral resection, immediately fixed in formalin and then embedded in paraffin. The correlation between Wnt5a immunoreactivity, histological grade, and pathological stage of the tumor was analyzed. The expression of Wnt5a mRNA as well as the effect of Wnt5a on cell migration was also evaluated in two UC cell lines, T24 and J82, and a normal urothelial cell line. Our immunohistochemical results revealed that Wnt5a staining intensity correlated positively with the histological grade and pathological stage of the UC. Wnt5a mRNA expression differed widely in the three urothelial cell lines, with high levels in one carcinoma cell line and low levels in the other cell line in comparison to the normal urothelial cell line. Migration increased in both UC cell lines in response to Wnt5a treatment. Our results show that the Wnt5a pathway may play a role in the pathogenesis of UC and suggest that Wnt5a may serve as an additional, complementary diagnostic/prognostic markerfor UC.Virtual slidehttp://www.diagnosticpathology.diagnomx.eu/vs/1952312091979566. 22982445 Leukotriene D4 induces cognitive impairment through enhancement of CysLT₁ R-mediated amyloid-β generation in mice. Amyloid plaques in the extracellular parenchyma mainly consist of amyloid-β peptides (Aβ), one of the pathological hallmarks in Alzheimer's disease (AD). In the present study, we examined neuroinflammation, amyloidogenesis, and memory performance following intracerebral infusions of leukotriene D4 (LTD4) in mice. The results demonstrated that intracerebral infusions of LTD4 (1 ng/mouse) produced memory impairment as determined by Morris water maze test and Y-maze test in mice, and caused the accumulation of Aβ1-40 and Aβ1-42 in the hippocampus and cortex through increased activity of β- and γ-secretases accompanied with increased expression of amyloid precursor protein (APP). LTD4 also induced expression of cysteinyl leukotriene receptor 1 (CysLT(1)R) and NF-κB p65 in the hippocampus and cortex. Pretreatment with pranlukast (1.5 ng/mouse, intracerebroventricularly), a CysLT(1)R antagonist, blocked LTD4-induced amyloidogenesis, memory deficits. Pranlukast (0.6 μM) also prevented LTD4 (20 nM)-induced amyloidogenesis in the cultured neurons in vitro. Moreover, LTD4-induced increases in CysLT(1)R and NF-κB p65 in the brain were also attenuated by pranlukast. These results suggest that LTD4 increases Aβ peptide burden via activation of CysLT(1)R, which further affects APP levels and activity of β- and γ-secretases via the NF-κB pathway. Our findings identify CysLT(1)R signaling as a novel proinflammatory and proamyloidogenic pathway, and suggest a rationale for development of therapeutics targeting the CysLT(1)R in neuroinflammatory diseases such as AD. 23479446 Notch receptors in human choroid plexus tumors. Notch signaling plays a role in development and formation of the normal choroid plexus (nCP), and in formation of various tumors in humans. Activation of Notch3 has been reported to promote tumor growth in invasive gliomas and to initiate formation of choroid plexus tumors (CPT) in mice. We investigated the expression of all currently known Notch receptors (Notch 1-4) in 55 samples of nCP and 88 CPT, including 61 choroid plexus papillomas (CPP), 22 atypical CPP and 5 choroid plexus carcinomas by immunohistochemistry. Notch expression was semiquantitatively evaluated separately for membranous/cytoplasmic and for nuclear staining. In addition, we examined Her2 expression (EGFR2, Her2/neu, ErbB2, CD340) because of its functional link to Notch signaling. All samples were negative for Notch3. Membranous/cytoplasmic expression of Notch1 (p⟨0.0001) and Notch4 (p=0.046) was significantly higher, whereas Notch2 expression was significantly lower (p⟨0.0001) in nCP compared to CPT. Nuclear expression of Notch1, -2 and -4 was significantly higher in CPT compared to nCP (p⟨0.0001 each). Expression of Notch2 and Notch4 showed a shift from a prevailing membranous/cytoplasmic expression in nCP to a predominant nuclear expression in CPT. Her2 was weakly expressed in 42/84 CPT but only in 2/53 nCP (p=0.0001) and positively correlated with nuclear expression of Notch1, -2 and 4 in CPT. In summary, a shift between membranous/cytoplasmic (non-canonical signaling pathway) and nuclear expression (canonical signaling pathway) of Notch1, -2 and -4 and upregulation of Her2 indicate neoplastic transformation in human CP and may reveal new therapeutic approaches. 23767048 Nano-particle modified stationary phases for high-performance liquid chromatography. This review covers the latest developments and applications of nano-materials in stationary phase development for various modes of high-performance liquid chromatography. Specific attention is placed upon the development of new composite phases, including the synthetic and immobilisation strategies used, to produce either encapsulated nano-particles, or surface attached nano-particles, layers, coatings and other structures. The resultant chromatographic applications, where applicable, are discussed with comment upon enhanced selectivity and/or efficiency of the nano-particle modified phases, where such effects have been identified. In the main this review covers developments over the past five years and is structured according to the nature of the nano-particles themselves, including carbonaceous, metallic, inorganic, and organopolymer based materials. 23959108 Amyotrophic Lateral Sclerosis and Spinocerebellar Ataxia Type 2 in a Family With Full CAG Repeat Expansions of ATXN2. IMPORTANCE A family with coexistence of spinocerebellar ataxia type 2 and amyotrophic lateral sclerosis (ALS) is described. OBSERVATIONS Intermediate or full CAG repeat expansions of ATXN2 are associated with ALS. However, no coexistence of spinocerebellar ataxia type 2 and ALS in a family has been reported in the literature. We describe a 47-year-old woman with an 11-year history of ataxia and her paternal uncle with ALS who were evaluated at Columbia University Medical Center since July 2006. Both our patient with ataxia and her uncle with ALS have full pathological CAG repeat expansions of ATXN2. CONCLUSIONS AND RELEVANCE The diverse clinical phenotypes of ATXN2 CAG expansions and their coexistence in a single family are highlighted. A clinician should consider the diagnosis of spinocerebellar ataxia type 2 when encountering a patient with ataxia and a family history of ALS. 23291326 Chemical composition and anticancer activity of essential oils of Mediterranean sage (Salvia officinalis L.) grown in different environmental conditions. Salvia officinalis L. can be found worldwide and its leaves are commonly used as ingredient in food industry. Sage essential oil is applied in the treatment of a range of diseases and has been shown to possess different biological activities. The objectives of our research were to study the effects of environment on crop, chemical composition and anticancer activity on S. officinalis essential oil. Sage was cultivated at eighteen experimental sites in south-central Italy (Molise) in different growing environments. The essential oils (S1-S18), extracted by hydrodistillation, were analyzed by GC and CG/MS. Results show that the main components were α-thujone, camphor, borneol, γ-muurolene and sclareol for all the samples, but the percentages of these compounds varied depending on environmental factors such as altitude, water availability and pedo-climatic conditions. The growth-inhibitory and proapoptotic effects of the eighteen sage essential oils were evaluated in three human melanoma cell lines, A375, M14, and A2058. 23946588 Acoustic radiation force impulse of the liver. Acoustic radiation force impulse (ARFI) imaging is a new and promising ultrasound-based diagnostic technique that, evaluating the wave propagation speed, allows the assessment of the tissue stiffness. ARFI is implemented in the ultrasound scanner. By short-duration acoustic radiation forces (less than 1 ms), localized displacements are generated in a selected region of interest not requiring any external compression so reducing the operator dependency. The generated wave scan provides qualitative or quantitative (wave velocity values) responses. Several non-invasive methods for assessing the staging of fibrosis are used, in order to avoid liver biopsy. Liver function tests and transient elastography are non-invasive, sensitive and accurate tools for the assessment of liver fibrosis and for the discrimination between cirrhotic and non-cirrhotic liver. Many published studies analyse ARFI performance and feasibility in studying diffuse liver diseases and compare them to other diagnostic imaging modalities such as conventional ultrasonography and transient elastography. Solid focal liver lesions, both benign and malignant, are common findings during abdominal examinations. The accurate characterization and differential diagnosis are important aims of all the imaging modalities available today. Only few papers describe the application of ARFI technology in the study of solid focal liver lesions, with different results. In the present study, the existing literature, to the best of our knowledge, about ARFI application on diffuse and focal liver pathology has been evaluated and results and statistical analyses have been compared, bringing to the conclusion that ARFI can be used in the study of the liver with similar accuracy as transient elastography in diagnosing significant fibrosis or cirrhosis and has got some advantages in respect to transient elastography since it does not require separate equipment, better displays anatomical structures and measurements can be successfully carried out almost in every patient. 23612559 To call or not to call--that is the question (while driving). We studied whether decisions to engage in cell phone conversation while driving and the consequences of such decisions are related to the driver's age, to the road conditions (demands of the driving task), and to the driver's role in initiating the phone call (i.e. the driver as caller vs. as receiver). Two experiments were performed in a driving simulator in which driver age, road conditions and phone conversation, as a secondary task, were manipulated. Engagement in cell phone conversations, performance in the driving and the conversation tasks, and subjective effort assessment were recorded. In general, drivers were more willing to accept incoming calls than to initiate calls. In addition, older and younger drivers were more susceptible to the deleterious effects of phone conversations while driving than middle aged/experienced drivers. While older drivers were aware of this susceptibility by showing sensitivity to road conditions before deciding whether to engage in a call or not, young drivers showed no such sensitivity. The results can guide the development of young driver training programs and point at the need to develop context-aware management systems of in-vehicle cell phone conversations. 23850131 The effect of waiting time on pain intensity after elective surgical lumbar discectomy. Waitlists are commonly used in Canada to manage access to surgical procedures such as elective surgical lumbar discectomy (ESLD). The timing of enrollment onto the waitlist is important as this is a proxy measure for the concordance of preferences for surgery between a patient and surgeon. After enrollment, the waiting time to actual surgery extends the duration of preoperative symptoms, which possibly affects the outcome of ESLD. Waiting time also specifically reflects the delay in service delivery imposed by the limited capacity of the health-care system. To determine if a system-imposed delay in treatment, that is, longer waiting time, for ESLD is associated with a higher odds of experiencing residual postoperative pain. Ambidirectional cohort study with 2-year retrospective and 3-year prospective components, conducted at a major tertiary care center serving a metropolitan area in Canada. Patients aged 16 years or older with sciatica because of herniated lumbar disc, confirmed on advanced imaging, were recruited at the time of waitlist enrollment for ESLD. Patients with significant comorbidity or emergency indications for surgery were excluded. Of 391 participants, 291 had complete follow-up information at 6 months postoperatively. Intensity of the predominant symptom (worse of either back or leg pain) was assessed on the 11-point numerical rating scale at waitlist enrollment and 6 months postoperatively. Pain scores were highly skewed and therefore categorized into four ordinal levels defined by quartiles. For the primary analysis, time to surgery from waitlist enrollment was dichotomized based on a predetermined clinically meaningful cut-point of 12 weeks. Ordinal logistic regression was used to compare the odds of experiencing higher pain intensity between wait groups. Control of confounders was achieved using both propensity scores and conventional multivariable modeling. In unadjusted analyses, long-wait patients were 80% more likely than short-wait patients to experience higher ordinal pain intensity at 6 months; unadjusted proportional odds ratio (POR)=1.8 (95% confidence interval [CI], 1.2-2.8). The association held after controlling for all imbalances in measured confounders, with long-wait patients still being 70% more likely to report worse pain; adjusted POR=1.7 (95% CI, 1.0-2.8). A waiting time of 12 weeks or more after waitlist enrollment for ESLD is associated with a modest likelihood of experiencing worse pain at 6 months postoperatively. This result was not because of differences in measured confounders. Future studies are encouraged to identify other, as-of-yet unmeasured, variables that might be associated with both longer waiting times and worse outcomes among ESLD patients. Until then, in jurisdictions where highly constrained access to ESLD is managed through waitlists, the expected waiting time for the operation could be an informative deciding criterion for patients with otherwise unresolved preferences for operative treatment. 23708796 Distinct mechanisms of transcriptional pausing orchestrated by GAGA factor and M1BP, a novel transcription factor. Thousands of genes in Drosophila have Pol II paused in the promoter proximal region. Almost half of these genes are associated with either GAGA factor (GAF) or a newly discovered factor we call M1BP. Although both factors dictate the association of Pol II at their target promoters, they are nearly mutually exclusive on the genome and mediate different mechanisms of regulation. High-resolution mapping of Pol II using permanganate-ChIP-seq indicates that pausing on M1BP genes is transient and could involve the +1 nucleosome. In contrast, pausing on GAF genes is much stronger and largely independent of nucleosomes. Distinct regulatory mechanisms are reflected by transcriptional plasticity: M1BP genes are constitutively expressed throughout development while GAF genes exhibit much greater developmental specificity. M1BP binds a core promoter element called Motif 1. Motif 1 potentially directs a distinct transcriptional mechanism from the canonical TATA box, which does not correlate with paused Pol II on the genomic scale. In contrast to M1BP and GAF genes, a significant portion of TATA box genes appear to be controlled at preinitiation complex formation. 23929278 Case-control study of lifetime alcohol consumption and endometrial cancer risk. Alcohol consumption is hypothesized to increase the risk of endometrial cancer by increasing circulating estrogen levels. This study sought to investigate the association between lifetime alcohol consumption and endometrial cancer risk. We recruited 514 incident endometrial cancer cases and 962 frequency age-matched controls in this population-based case-control study in Alberta, Canada, from 2002 to 2006. Participants completed in-person interviews querying lifetime alcohol consumption and other relevant health and lifestyle factors. Participants reported the usual number of drinks of beer, wine, and liquor consumed; this information was compiled for each drinking pattern reported over the lifetime to estimate average lifetime exposure to alcohol. Lifetime average alcohol consumption was relatively low (median intake: 3.9 g/day for cases, 4.9 g/day for controls). Compared with lifetime abstainers, women consuming >2.68 and ≤8.04 g/day alcohol and >8.04 g/day alcohol on average over the lifetime showed 38 and 35 % lower risks of endometrial cancer, respectively (p trend = 0.023). In addition, average lifetime consumption of all types of alcohol was associated with decreased risks. There was no evidence for effect modification by body mass index, physical activity, menopausal status, and hormone replacement therapy use combined and effects did not differ by type of endometrial cancer (type I or II). This study provides epidemiologic evidence for an inverse association between relatively modest lifetime average alcohol consumption (approximately 1/4 to 1/2 drink/day) and endometrial cancer risk. The direction of this relation is consistent with previous studies that examined similar levels of alcohol intake. 23732260 HEARTSTRING enabled no-touch proximal anastomosis for off-pump coronary artery bypass grafting: current evidence and technique. Surgical revascularization remains the standard of care for many patients. Off-pump coronary artery bypass grafting (OPCAB) without cardiopulmonary bypass (CPB) has evolved during the past 20 years, and as such can significantly reduce the occurrence of neurological complications. While avoiding the aortic cross-clamping required in conventional on-pump techniques, OPCAB results in a lower incidence of stroke. However, clamp-related risk of stroke remains if partial or side-biting clamps are applied for proximal anastomoses. Others and we have demonstrated that no-touch 'anaortic' approaches avoiding any clamping during off-pump procedures via complete in situ grafting result in significantly reduced stroke rates when compared with partial clamping. Therefore, OPCAB in situ grafting has been proposed as the 'standard of care' to reduce neurological complications. However, this technique may not be applicable to for every patient as the use of free grafts (arterial or venous) requiring proximal anastomosis is often still necessary to achieve complete revascularization. In these situations, proximal anastomosis can be performed without a partial clamp by using the HEARTSTRING device, and over the last few years, considerable evidence has arisen supporting the impact of HEARTSTRING-enabled anastomosis to significantly minimize atheroembolism and neurological complications when compared with partial- or side-bite clamping. This paper provides a systematic overview and technical information about the combination of OPCAB and clampless strategies using the HEARTSTRING for proximal anastomosis to reduce stroke to levels reported for percutaneous coronary intervention. 23673875 Correlation between pathology and neuromelanin MR imaging in Parkinson's disease and dementia with Lewy bodies. Direct correlation between neuropathological findings and postmortem neuromelanin MR imaging (NmMRI) was performed in the substantia nigra pars compacta (SNc) to clarify the pathological background of the signal changes in normal, Parkinson's disease (PD), and dementia with Lewy bodies (DLB) cases. NmMRI of 10 % formalin-fixed autopsied midbrains was performed in three cases (normal control, DLB, and PD) with a 3T imaging system, using a 3D gradient echo T1-weighted sequence with a magnetization transfer contrast pulse. Neuropathological examinations of the midbrains were performed, and the density of neuromelanin-positive neurons (number per square millimeter) was determined. The extent of iron deposition in the midbrain was also evaluated using ferritin immunohistochemistry. Furthermore, we directly correlated the contrast signal ratio in the SNc and the density of neuromelanin-containing neurons. Diffuse hyperintense areas in the SNc reflected well-preserved neuromelanin-containing neurons in the normal control case, whereas an iso-intense area in the SNc showed severe loss of neuromelanin-containing neurons in the DLB and PD cases. Increased signal intensity in the SNc was apparently not influenced by iron deposition. Furthermore, a significant positive correlation between signal intensity and the density of neuromelanin-containing neurons was seen in the SNc. Based on the direct correlation between postportem NmMRI and neuropathological findings, signal intensity in the SNc is closely related to the quantity of neuromelanin-containing neurons but is not influenced by iron deposition. 23934601 Cancer risk and genotype-phenotype correlations in PTEN hamartoma tumor syndrome. Patients with germline PTEN mutations are at high risk of developing benign and malignant tumours. We aimed to evaluate the cumulative risk of several types of cancer and of dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease, LDD). In addition, genotype-phenotype correlations in PTEN hamartoma tumour syndrome (PHTS) were assessed. Data on patients with PTEN mutations were collected from clinical genetic centres in Western Europe, Australia, and the USA. The cumulative risk of developing cancers of the breast, thyroid, endometrium, skin, kidneys, colorectum, and lungs, and also LDD was calculated by Kaplan-Meier methods. Associations between mutations and cancer were assessed by Chi square means. A total of 180 germline PTEN mutation carriers, 81 males (45 %), from nine countries were included. The cumulative risk of developing any cancer and/or LDD at age 60 was 56 % for males and 87 % for females (p = 0.001). Females had significant higher risks of developing breast cancer, thyroid cancer, and LDD than males. The only genotype-phenotype correlation identified was a lower frequency of thyroid cancer in patients with missense mutations (p = 0.014). In conclusion, PHTS patients, particularly females, have a substantial risk of developing one or more tumours from a broad tumour spectrum. Major genotype-phenotype associations could not be identified. 23337692 Development and psychometric testing of the Antenatal Care Scale within the context of the Theory of Planned Behaviour. to develop an instrument based on the Theory of Planned Behaviour (TPB) to determine the attitudes and intentions of women towards receiving antenatal care. this methodological study was carried out at health centres in Isparta, Turkey. 266 pregnant women who were able to communicate, did not have a systemic disease, and who volunteered to participate were included in this study. They were chosen by a random sampling method. A Likert-type scale composed of six subfactors and 26 items was used. Cronbach's α for the Antenatal Care Scale (ANCS) was 0.96, and values for the six subfactors were between 0.88 and 0.94. the ANCS was found to be a valid and reliable instrument to determine the attitudes and intentions of women towards receiving antenatal care. 23375250 Circulating tumor cells in colorectal cancer patients. The availability of sensitive methods has allowed the detailed study of circulating tumor cells only recently. Evolving evidence support the prognostic and predictive role of these cells in patients affected by several solid tumors, including colorectal cancer. Ongoing studies are aimed at confirming that the molecular characterization of circulating tumor cells in peripheral blood and in bone marrow of patients is a powerful tool to improve the patient risk-stratification, to monitor activity of the drugs, to develop more appropriate targeted therapies and tailored treatments. In parallel, results from these correlative studies promise to gain a better biological understanding of the metastatic process. The clinical utility of the detection of circulating tumor cells in patients affected by colorectal cancer is still hampered by a number of specific hurdles. Improvement in sensitivity and specificity of the available methods of detection, standardization of these methods and functional characterization of circulating tumor cells in well designed and statistically well powered studies are the key steps to reach these ambitious objectives in colorectal cancer patients as well. 23562495 TRP and ASIC channels mediate the antinociceptive effect of citronellyl acetate. Background Citronellyl acetate (CAT), a monoterpene product of the secondary metabolism of plants, has been shown in the literature to possess several different biological activities. However, no antinociceptive abilities have yet been discussed. Here, we used acute pain animal models to describe the antinociceptive action of CAT. Methods The acetic acid-induced writhing test and the paw-licking test, in which paw licking was induced by glutamate and formalin, were performed to evaluate the antinociceptive action of CAT and to determine the involvement of PKC, PKA, TRPV1, TRPA1, TRPM8 and ASIC in its antinociceptive mechanism. To do so, we induced paw-linking using agonists. Results CAT was administered intragastrically (25, 50, 75, 100 and 200mg/kg), and the two higher doses caused antinociceptive effects in the acetic acid model; the highest dose reduced pain for 4h after it was administered (200mg/kg). In the formalin test, two doses of CAT promoted antinociception in both the early and later phases of the test. The glutamate test showed that its receptors are involved in the antinociceptive mechanism of CAT. Pretreatment with CAT did not alter locomotor activity or motor coordination. In an investigation into the participation of TRP channels and ASICs in CAT's antinociceptive mechanism, we used capsaicin (2.2μg/paw), cinnamaldehyde (10mmol/paw), menthol (1.2mmol/paw) and acidified saline (2% acetic acid, pH 1.98). The results showed that TRPV1, TRPM8 and ASIC, but not TRPA1, are involved in the antinociceptive mechanism. Finally, the involvement of PKC and PKA was also studied, and we showed that both play a role in the antinociceptive mechanism of CAT. Conclusion The results of this work contribute information regarding the antinociceptive properties of CAT on acute pain and show that, at least in part, TRPV1, TRPM8, ASIC, glutamate receptors, PKC and PKA participate in CAT's antinociceptive mechanism. 23821235 Hypersalinity Toxicity Thresholds for Nine California Ocean Plan Toxicity Test Protocols. Currently, several desalination facilities have been proposed to operate or are actually operating in California. These facilities' use of reverse osmosis (RO) may discharge hypersaline reject brine into the marine environment. The risks, if any, this brine would pose to coastal receiving waters are unknown. To test the toxicity of hypersaline brine in the absence of any additional toxic constituents, we prepared brine and tested it with the seven toxicity test organisms listed in the 2009 California Ocean Plan. The most sensitive protocols were the marine larval development tests, whereas the most tolerant to increased salinities were the euryhaline topsmelt, mysid shrimp, and giant kelp tests. Reject brines from the Monterey Bay Aquarium's RO desalination facility were also tested with three species. The effects of the aquarium's brine effluent on topsmelt, mussels, and giant kelp were consistent with those observed in the salinity tolerance experiments. This information will be used by regulators to establish receiving water limitations for hypersaline discharges. 23419055 Synthesis and characterization of hybrid hyaluronic Acid-gelatin hydrogels. Biomimetic hybrid hydrogels have generated broad interest in tissue engineering and regenerative medicine. Hyaluronic acid (HA) and gelatin (hydrolyzed collagen) are naturally derived polymers and biodegradable under physiological conditions. Moreover, collagen and HA are major components of the extracellular matrix (ECM) in most of the tissues (e.g., cardiovascular, cartilage, neural). When used as a hybrid material, HA-gelatin hydrogels may enable mimicking the ECM of native tissues. Although HA-gelatin hybrid hydrogels are promising biomimetic substrates, their material properties have not been thoroughly characterized in the literature. Herein, we generated hybrid hydrogels with tunable physical and biological properties by using different concentrations of HA and gelatin. The physical properties of the fabricated hydrogels including swelling ratio, degradation, and mechanical properties were investigated. In addition, in vitro cellular responses in both two and three-dimensional culture conditions were assessed. It was found that the addition of gelatin methacrylate (GelMA) into HA methacrylate (HAMA) promoted cell spreading in the hybrid hydogels. Moreover, the hybrid hydrogels showed significantly improved mechanical properties compared to their single component analogs. The HAMA-GelMA hydrogels exhibited remarkable tunability behavior and may be useful for cardiovascular tissue engineering applications. 22903307 Asthma in Children in Relation to Pre-term Birth and Fetal Growth Restriction. To assess the impact of parental asthma on risk of pre-term birth (PTB) and intrauterine growth restriction, and their subsequent association with childhood asthma. Three sequential cross-sectional surveys were conducted in 1993 (3,746), 1998 (1,964) and 2006 (1,074) in the same 15 schools among 5-11 year old children in Merseyside using the same respiratory health questionnaire completed by parents (sample size in brackets). Between 1993 and 2006, prevalence of PTB varied between 12.4 and 15.2 %, and of small for gestational age (SGA or growth restricted) babies between 2.1 and 4.6 %, and maternal asthma prevalence between 8.1 and 13.4 %. For the combined surveys mothers with asthma were more likely to have a PTB than non-asthmatic mothers (OR 1.39, 95 % CI 1.10-1.95, p < 0.001), and in the 2006 survey were more likely to have an SGA baby. 40.9 % of PTBs of asthmatic mothers developed doctor diagnosed asthma compared to 34.3 % for term babies (adjusted OR 1.65, 1.34-2.04, p < 0.001). The corresponding estimates for the symptom triad of cough, wheeze and breathlessness were 19.4 and 17.6 % (adjusted OR 1.78, 0.79-3.98). Conversely SGA babies were less likely to develop doctor diagnosed asthma (adjusted OR 0.49, 0.27-0.90, p < 0.021), or the symptom triad of cough, wheeze and breathlessness (adjusted OR 0.22, 0.05-0.97, p < 0.043), whether or not the mother was asthmatic. Maternal asthma is an independent risk factor for PTB which predisposes to childhood asthma. Intrauterine growth restriction was protective against childhood asthma. 23689939 Colonization of the Mouse Upper Gastrointestinal Tract by Lactobacillus murinus: A Histological, Immunocytochemical, and Ultrastructural Study. Lactobacillus is normally present in animals and humans colonizing several epithelia, mainly those belonging to the upper gastrointestinal tract. Most of the information about the distribution of Lactobacillus in mice has been obtained by bacterial culture and characterization, and only few reports have described the direct presence of these bacteria in tissues, especially in the gastric mucosa. In this study, we have characterized and evaluated the location and detailed relationship between Lactobacillus and epithelia using a combination of histological, molecular, immunocytochemical and ultrastructural methods. Normal Balb/c mice were sacrificed to study esophagus and stomach. Partial 16S rRNA gene sequencing, Gram, and P.A. Schiff staining allowed us to demonstrate that Lactobacillus murinus isolated from each animal colonize not only the epithelium of the forestomach but also that belonging to the distal esophagus. The pattern of colonization was linear over the keratinized epithelium, and also in a vertical way of focal bacterial aggregates. This was confirmed by transmission electron microscopy, and the nature of bacteria was further assessed by immunocytochemistry. Our results indicate that L. murinus can colonize the stomach and the esophagus epithelia in a biofilm-like manner, possibly acting as a defense barrier against colonization by other bacteria. 23958409 Non-invasive positive pressure ventilation in children. Non-invasive positive pressure ventilation is increasingly used in children both in acute and in chronic setting. Clinical data supporting safety, efficacy and limitations in children are growing. Technical problems related to the ventilators performance and interfaces selection have not been fully resolved, especially for younger children. Non-invasive ventilation can be applied at home. Its use at home requires appropriate diagnostic procedures, accurate titration of the ventilators, cooperative and educated families and careful, well-organized follow-up programs. 23880353 Contribution of Seasonality in Transmission of Mycobacterium tuberculosis to Seasonality in Tuberculosis Disease: A Simulation Study. A seasonal rise in tuberculosis (TB) notifications has been confirmed in several studies. Here, we examined one hypothesis for its cause: increased transmission of TB during wintertime due to crowding. Seasonality analysis was performed on actual and simulated notifications of clustered TB cases, which are considered to be representative of recent transmission, diagnosed from 1993 to 2004 in the Netherlands (n = 4,746). To test the hypothesis of winter crowding, notifications were simulated by adding patient delay and incubation period to an infection date randomly taken to be in winter in 80% of cases. The incubation periods were derived from frequency distributions for different TB disease localizations drawn from the literature. Seasonality analysis was performed using autocorrelation function plots and spectral analysis. Actual notifications showed strong seasonality in clustered TB and clustered extrapulmonary TB cases but not in clustered pulmonary TB cases. Analysis of simulated notifications revealed barely significant seasonality only in extrapulmonary TB cases. Our results suggest that increased transmission of TB during wintertime is unlikely to be the only cause of the seasonal peak in TB notifications. A factor closer to the notification date probably contributes to the seasonality observed in TB notifications. 22292803 Prevalence of enamel defects in permanent teeth of patients with complete cleft lip and palate. Objective : To evaluate the prevalence, types, location, and characteristics of enamel defects in anterior permanent teeth of patients with complete unilateral and bilateral cleft lip and palate, as well as the relation with the cleft. Setting : Hospital for Rehabilitation of Craniofacial Anomalies, Bauru, São Paulo, Brazil. Participants : Eighty patients of both genders, 12 years and older, with unilateral or bilateral cleft lip and palate. Methods : A single examiner carried out clinical examination under artificial light with a dental probe and mirror after drying teeth according to the modified DDE index. Results : Seventy-four of 80 patients presented with at least one tooth affected by enamel defects: 165 of 325 evaluated teeth (50.8%) presented enamel defects, with hypoplasia being the most prevalent (50.7%), followed by diffuse opacity (23.1%) and demarcated opacity (18.4%). The most affected tooth was 21 (36.5%), followed by 11 (34%), located at the middle (40%) and incisal (33%) thirds. Most defects occur at the buccal surface (47.7%), followed by the distal (22.7%), the mesial (19%), and the palatal (10.6%) surfaces. A significant relationship was found between the cleft side and enamel defects. Conclusion : Upper anterior teeth of patients with complete cleft lip and palate present a high prevalence of enamel defects; the highest percentage on the cleft side suggests that the cleft does influence the occurrence of enamel defects in permanent teeth. 23561205 Curcumin inhibits invasion and metastasis in K1 papillary thyroid cancer cells. Curcumin, the active constituent of dietary spice turmeric, possesses a strong potential for cancer prevention and treatment. However, there is no study to address the effects of curcumin on invasion and metastasis of thyroid cancers. Thyroid cancer is the most common malignancy of endocrine organs, and its incidence rates have steadily increased over recent decades. Although most indolent tumours can be effectively managed, metastatic tumours at distant secondary sites behave aggressively and currently there is no effective form of treatment. Here, for the first time it has been reported that curcumin inhibit multiple metastasis steps of K1 papillary thyroid cancer cells. Curcumin dose-dependently suppressed viability of K1 cells as well as its cell attachment, spreading, migration and invasion abilities. Moreover, curcumin could also down-regulate the expression and activity of matrix metalloproteinase-9 (MMP-9). The findings showed that curcumin might be an effective tumouristatic agent for the treatment of aggressive papillary thyroid carcinomas. 23857022 Avian Hosts of West Nile Virus in Arizona. West Nile virus (WNV) causes sporadic outbreaks of human encephalitis in Phoenix, Arizona. To identify amplifying hosts of WNV in the Phoenix area, we blood-sampled resident birds and measured antibody prevalence following an outbreak in the East Valley of metropolitan Phoenix during summer, 2010. House sparrow (Passer domesticus), house finch (Haemorhous mexicanus), great-tailed grackle (Quiscalus mexicanus), and mourning dove (Zenaida macroura) accounted for most WNV infections among locally resident birds. These species roost communally after early summer breeding. In September 2010, Culex vector-avian host contact was 3-fold greater at communal bird roosts compared with control sites, as determined by densities of resting mosquitoes with previous vertebrate contact (i.e., blood-engorged or gravid mosquitoes). Because of the low competence of mourning doves, these were considered weak amplifiers but potentially effective free-ranging sentinels. Highly competent sparrows, finches, and grackles were predicted to be key amplifying hosts for WNV in suburban Phoenix. 23373650 Bioactive natural products from the antarctic and arctic organisms. Polar regions are remote and challenging areas on the earth. In view of the unique environment and the severe competition in polar regions, it's considered that the ecological system might be the producer of new compounds with diversity biological activities. This review is an attempt to consolidate the studies about 97 natural products isolated from Antarctic and Arctic organisms including microbes, algae, sponges, bryozoans, and tunicates and so on published in the recent years. The emphasis is mainly about the new compounds, source organisms and biological activities, which signifies the immense competence of Antarctic and Arctic organisms as bioactive natural products producers. 23832631 Screening of different computational models for the preparation of sol-gel imprinted materials. Different computational models were used and screened to find a rational way in selecting the appropriate functional silane monomer for the best molecular imprinted xerogel (MIX) formulation. Several functional silane monomers were used and allowed to react with a template model, tetracycline (TC). The resulting template-monomer complex molecules were first optimized and their interaction energies (IEs) were calculated using different computational methods such as semi-empirical methods, ab-initio methods, density functional theory (DFT) methods and solvent model method. The formulations used for calculation were also prepared and their performance in binding with TC was determined using tritium labeled sample. Results showed that the rankings of the different formulations varied with the different computational methods. However, rankings of the IEs of the xerogels are similar to that of the imprinting factor (IF) when HF and B3LYP at SV(P) and SVP basis set levels were used. The best imprinted xerogel, allyltriethoxysilane (AtEOS) ranked first in ten out of the 26 computational models that were screened and at all computational methods at tetramer system. 23878221 Inflammatory monocytes are potent antitumor effectors controlled by regulatory CD4+ T cells. The present study evaluates the impact of immune cell populations on metastatic development in a model of spontaneous melanoma [mice expressing the human RET oncogene under the control of the metallothionein promoter (MT/ret mice)]. In this model, cancer cells disseminate early but remain dormant for several weeks. Then, MT/ret mice develop cutaneous metastases and, finally, distant metastases. A total of 35% of MT/ret mice develop a vitiligo, a skin depigmentation attributable to the lysis of normal melanocytes, associated with a delay in tumor progression. Here, we find that regulatory CD4(+) T cells accumulate in the skin, the spleen, and tumor-draining lymph nodes of MT/ret mice not developing vitiligo. Regulatory T-cell depletion and IL-10 neutralization led to increased occurrence of vitiligo that correlated with a decreased incidence of melanoma metastases. In contrast, inflammatory monocytes/dendritic cells accumulate in the skin of MT/ret mice with active vitiligo. Moreover, they inhibit tumor cell proliferation in vitro through a reactive oxygen species-dependent mechanism, and both their depletion and reactive oxygen species neutralization in vivo increased tumor cell dissemination. Altogether, our data suggest that regulatory CD4(+) T cells favor tumor progression, in part, by inhibiting recruitment and/or differentiation of inflammatory monocytes in the skin. 23801764 Diversification through multitrait evolution in a coevolving interaction. Mutualisms between species are interactions in which reciprocal exploitation results in outcomes that are mutually beneficial. This reciprocal exploitation is evident in the more than a thousand plant species that are pollinated exclusively by insects specialized to lay their eggs in the flowers they pollinate. By pollinating each flower in which she lays eggs, an insect guarantees that her larval offspring have developing seeds on which to feed, whereas the plant gains a specialized pollinator at the cost of some seeds. These mutualisms are often reciprocally obligate, potentially driving not only ongoing coadaptation but also diversification. The lack of known intermediate stages in most of these mutualisms, however, makes it difficult to understand whether these interactions could have begun to diversify even before they became reciprocally obligate. Experimental studies of the incompletely obligate interactions between woodland star (Lithophragma; Saxifragaceae) plants and their pollinating floral parasites in the moth genus Greya (Prodoxidae) show that, as these lineages have diversified, the moths and plants have evolved in ways that maintain effective oviposition and pollination. Experimental assessment of pollination in divergent species and quantitative evaluation of time-lapse photographic sequences of pollination viewed on surgically manipulated flowers show that various combinations of traits are possible for maintaining the mutualism. The results suggest that at least some forms of mutualism can persist and even diversify when the interaction is not reciprocally obligate. 23754337 Investigation of the effect of the uneven distribution of CYP3A4 and P-glycoprotein in the intestine on the barrier function against xenobiotics: A simulation study. CYP3A4 and P-glycoprotein (P-gp) have similar substrate specificities and work together to form an intestinal absorption barrier against xenobiotics. Previous reports have indicated that CYP3A4 expression decreases gradually, whereas P-gp expression increases, from the upper to lower small intestine. The physiological rationale for this uneven distribution of CYP3A4 and P-gp as a barrier against xenobiotics has not been determined. To clarify the effect of these distribution patterns on barrier function, we constructed a mathematical model that included passive membrane permeation, P-gp-mediated apical efflux, and CYP3A4-mediated metabolism, and we simulated the effects of these distribution patterns on the fraction absorbed of co-substrates without changing their overall activities. The simulation showed that the physiological distribution patterns of both CYP3A4 and P-gp result in the lowest fraction absorbed, but not for drugs with low CYP3A4 and high P-gp-mediated clearances. These results suggest that the distribution pattern of CYP3A4 is especially important for the barrier function. On the other hand, physiological distribution pattern of P-gp exerts the maximum barrier function for dual good substrates for P-gp and CYP3A4, but even distribution of P-gp mostly suppresses the intestinal absorption of good P-gp, but poor CYP3A4 substrates. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3196-3204, 2013. 23934379 Photon activation therapy: a Monte Carlo study on dose enhancement by various sources and activation media. In the present study, a number of brachytherapy sources and activation media were simulated using MCNPX code and the results were analyzed based on the dose enhancement factor values. Furthermore, two new brachytherapy sources ((131)Cs and a hypothetical (170)Tm) were evaluated for their application in photon activation therapy (PAT). (125)I, (103)Pd, (131)Cs and hypothetical (170)Tm brachytherapy sources were simulated in water and their dose rate constant and the radial dose functions were compared with previously published data. The sources were then simulated in a soft tissue phantom which was composed of Ag, I, Pt or Au as activation media uniformly distributed in the tumour volume. These simulations were performed using the MCNPX code, and dose enhancement factor (DEF) was obtained for 7, 18 and 30 mg/ml concentrations of the activation media. Each source, activation medium and concentration was evaluated separately in a separate simulation. The calculated dose rate constant and radial dose functions were in agreement with the published data for the aforementioned sources. The maximum DEF was found to be 5.58 for a combination of the (170)Tm source with 30 mg/ml concentration of I. The DEFs for (131)Cs and (170)Tm sources for all the four activation media were higher than those for other sources and activation media. From this point of view, these two sources can be more useful in photon activation therapy with photon emitter sources. Furthermore, (131)Cs and (170)Tm brachytherapy sources can be proposed as new options for use in the field of PAT. 23404833 Implication of high-body-fat percentage on cardiometabolic risk in middle-aged, healthy, normal-weight adults. This study investigated the number of Korean adults who had a normal body mass index (BMI) but high body-fat percentage (BF%) and determined their increased risk factors for cardiovascular diseases, including high blood pressure, hyperglycemia, and dyslipidemia. This cross-sectional study was based on 12,386 subjects (6,534 men and 5,852 women), with a normal BMI, between 30 and 49 years of age. Subjects were categorized into two groups by BF% (normal BF% group, BF% <25 for men, and BF% <30 for women; high BF(%) group, BF% ≥25 for men, and BF% ≥30 for women). The proportion of subjects with a normal BMI and high BF% was 12.7% (n = 1,572; 291 [4.5%] men and 1,281 [21.9%] women). Subjects with a high BF% had a significantly higher prevalence of high blood pressure (men only), hyperglycemia, and dyslipidemia. Multiple logistic regression analyses revealed that subjects with a normal BMI and high BF% had a 1.63 (adjusted odds ratio, 95% confidence interval: 1.21-2.19) in men and 1.56 (adjusted odds ratio, 95% confidence interval: 1.36-1.80) in women increased risk of one or more cardiovascular risk factors compared to subjects in the normal BMI and normal BF% group, even after adjusting for abdominal obesity. High BF% is associated with a high cardiometabolic risks, regardless of abdominal obesity, in normal-weight Korean adults. Thus, follow-up screening of those with a high BF% may be necessary to detect and prevent cardiometabolic diseases, particularly for women with a normal BMI. 23708454 Electrospun Fe2O3-Al2O3 nanocomposite fibers as efficient adsorbent for removal of heavy metal ions from aqueous solution. In this study, Iron oxide-alumina mixed nanocomposite fiber was prepared by electrospinning method and its performance was evaluated as a heavy metal ion adsorbent. Here boehmite nanoparticle was synthesized by sol-gel method and was impregnated in PVP-iron acetylacetonate solution in a ratio of 1:1:2. These boehmite impregnated polymer solution was electrospun to form nanocomposite polymer fiber. The electrospun nanofiber was sintered at 1000°C for converting it to pure oxide form for further application as adsorbent. Iron oxide-alumina mixed nanocomposite fiber was characterized by UV-vis-DRS, IR, SEM-EDX, TEM, BET and TGA-DTA analytical techniques. Batch adsorption experiments were carried out to study the sorption behavior of Cu(2+), Pb(2+), Ni(2+) and Hg(2+) ions as a function of initial concentration, contact time and pH. The removal percentage was in the order of Cu(2+)TT/GG>AA mutations comprised 70% of all dinucleotide substitutions and were more common in tumors arising in SSD skin (P = 0.0008) and in BRAF/NRAS WT tumors (P = 0.0007). Targetable and potentially targetable mutations in WT tumors, including NF1, KIT, and NOTCH1, were spread over various signaling pathways.CONCLUSION: Melanomas arising in SSD skin have higher mutation loads and contain a spectrum of molecular subtypes compared with BRAF- and NRAS-mutant tumors indicating multigene screening approaches and combination therapies may be required for management of these patients. Clin Cancer Res; 19(17); 1-10. ©2013 AACR. 23892160 Kinetic modeling on CO2 capture using basic oxygen furnace slag coupled with cold-rolling wastewater in a rotating packed bed. In this study, direct and indirect carbonation of basic oxygen furnace slag (BOFS) coupled with cold-rolling wastewater (CRW) was carried out via a rotating packed bed (RPB). The solid products were qualitatively characterized by scanning electron microscopy (SEM) and X-ray diffraction (XRD) and quantitatively analyzed with thermogravimetric analysis (TGA). The leachate was analyzed with inductively coupled plasma-optical emission spectroscopy (ICP-OES). The results indicate that the maximum achievable carbonation conversion (MACC) of BOFS was 90.7%, corresponding to a capture capacity of 0.277g CO2/g of BOFS, by direct carbonation with CRW under a rotation speed of 750rpm at 30°C for 20min. In addition, CO2 mass balance among the gas, liquid, and solid phases within an RPB was well-developed, with an error less than 10%, to confirm the actual CO2 capture capacity of BOFS with precision and accuracy. Furthermore, a reaction kinetic model based on mass balance was established to determine the reaction rate constant for various liquid agents (CRW and pure water). It was concluded that co-utilization of alkaline wastes including BOFS and CRW via the RPB is a novel approach for both enhancing CO2 capture capacity and reducing the environmental impacts of alkaline wastes. 23842856 CYP2D6 genotype in relation to tamoxifen efficacy in a Dutch cohort of the tamoxifen exemestane adjuvant multinational (TEAM) trial. The clinical importance of CYP2D6 genotype as predictor of tamoxifen efficacy is still unclear. Recent genotyping studies on CYP2D6 using DNA derived from tumor blocks have been criticized because loss of heterozygosity (LOH) in tumors may lead to false genotype assignment. Postmenopausal early breast cancer patients who were randomized to receive tamoxifen, followed by exemestane in a large randomized controlled trial were genotyped for five CYP2D6 alleles. CYP2D6 genotypes and phenotypes were related to disease-free survival during tamoxifen use (DFS-t) in 731 patients. By analyzing microsatellites flanking the CYP2D6 gene, patients whose genotyping results were potentially affected by LOH were excluded. In addition, exploratory analyses on 24 genetic variants of other metabolic enzymes and the estrogen receptor were performed. For the CYP2D6 analysis, only 2.3 % of the samples were excluded, because influence of LOH could not be ruled out. No association was found between the CYP2D6 genotype or predicted phenotype and DFS-t (poor vs. extensive metabolizers: unadjusted hazard ratio 1.33, 95 % CI 0.52-3.43; P = 0.55). DFS-t was associated with UGT2B15*2 (Vt/Vt + Wt/Vt vs. Wt/Wt: adjusted hazard ratio 0.47, 95 % CI 0.25-0.89; P = 0.019) and the estrogen receptor-1 polymorphism ESR1 PvuII (gene-dose effect: adjusted hazard ratio 1.63, 95 % CI 1.04-2.54; P = 0.033). In postmenopausal early breast cancer patients treated with adjuvant tamoxifen followed by exemestane neither CYP2D6 genotype nor phenotype did affect DFS-t. This is in accordance with two recent studies in the BIG1-98 and ATAC trials. Our study is the first CYP2D6 association study using DNA from paraffin-embedded tumor tissue in which potentially false interpretation of genotyping results because of LOH was excluded. Polymorphisms in the estrogen receptor-1 and UGT2B15 may be associated with tamoxifen efficacy, but these findings need replication. 23658108 Transcriptome analysis of injured human meniscus reveals a distinct phenotype of meniscus degeneration with aging. Meniscus tears are associated with a heightened risk of osteoarthritis. This study aimed to advance our understanding of the metabolic state of injured human meniscus at the time of arthroscopic partial meniscectomy through transcriptome-wide analysis of gene expression in relation to the patient's age and degree of cartilage chondrosis. The degree of chondrosis of knee cartilage was recorded at the time of meniscectomy in symptomatic patients without radiographic osteoarthritis. RNA preparations from resected menisci (n = 12) were subjected to transcriptome-wide microarray and QuantiGene Plex analyses. Variations in the relative changes in gene expression with age and chondrosis were analyzed, and integrated biologic processes were investigated computationally. We identified a set of genes in torn menisci that were differentially expressed with age and chondrosis. There were 866 genes that were differentially regulated (≥1.5-fold difference and P < 0.05) with age and 49 with chondrosis. In older patients, genes associated with cartilage and skeletal development and extracellular matrix synthesis were repressed, while those involved in immune response, inflammation, cell cycle, and cellular proliferation were stimulated. With chondrosis, genes representing cell catabolism (cAMP catabolic process) and tissue and endothelial cell development were repressed, and those involved in T cell differentiation and apoptosis were elevated. Differences in age-related gene expression suggest that in older adults, meniscal cells might dedifferentiate and initiate a proliferative phenotype. Conversely, meniscal cells in younger patients appear to respond to injury, but they maintain the differentiated phenotype. Definitive molecular signatures identified in damaged meniscus could be segregated largely with age and, to a lesser extent, with chondrosis. 23721810 Preparation of a dibenzylated 1,4-diazacyclohexane-derived strong anion-exchange stationary phase. This paper reports the preparation of a novel, silica-based, strong anion-exchange stationary phase from a 1,4-diazacyclohexane derivative. To prepare the difunctional strong anion-exchange stationary phase, activated silica beads were first bonded with 3-chloropropyltriethoxysilane and then reacted with 1-methylpiperazine followed by benzyl chloride. The silica beads, the strong anion-exchange stationary phase and its precusors were instrumentally characterized. Aromatic acids were separated with non-aqueous anion-exchange chromatography. After elution with eluant prepared in mixed solvents of water and methanol, the resulting 1,4-diazacyclohexane-derived, difunctional, strong anion-exchange stationary phase exhibited good separation and selectivity for the aromatic acids investigated. The effects of eluant pH, eluant ion concentration and solvent composites on the separations were investigated. Organic acids with different substituents were eluted in order of decreasing dissociation coefficients, with no observable peak shape differences. 23914349 Additive Influence of Extracellular pH, Oxygen Tension, and Pressure on Invasiveness and Survival of Human Osteosarcoma Cells. Background/Purpose: The effects of chemical and physical interactions in the microenvironment of solid tumors have not been fully elucidated. We hypothesized that acidosis, hypoxia, and elevated interstitial fluid pressure (eIFP) have additive effects on tumor cell biology and lead to more aggressive behavior during tumor progression. We investigated this phenomenon using three human osteosarcoma (OS) cell lines and a novel in vitro cell culture apparatus. Materials and Methods: U2OS, SaOS, and MG63 cell lines were cultured in media adjusted to various pH levels, oxygen tension (hypoxia 2% O2, normoxia 20% O2), and hydrostatic gage pressure (0 or 50 mmHg). Growth rate, apoptosis, cell cycle parameters, and expression of mRNA for proteins associated with invasiveness and tumor microenvironment (CA IX, VEGF-A, HIF-1A, MMP-9, and TIMP-2) were analyzed. Levels of CA IX, HIF-1α, and MMP-9 were measured using immunofluorescence. The effect of pH on invasiveness was evaluated in a Matrigel chamber assay. Results: Within the acidic-hypoxic-pressurized conditions that simulate the microenvironment at a tumor's center, invasive genes were upregulated, but the cell cycle was downregulated. The combined influence of acidosis, hypoxia, and IFP promoted invasiveness and angiogenesis to a greater extent than did pH, pO2, or eIFP individually. Significant cell death after brief exposure to acidic conditions occurred in each cell line during acclimation to acidic media, while prolonged exposure to acidic media resulted in reduced cell death. Furthermore, 48-h exposure to acidic conditions promoted tumor invasiveness in the Matrigel assay. Conclusion: Our findings demonstrate that tumor microenvironmental parameters - particularly pH, pO2, and eIFP - additively influence tumor proliferation, invasion, metabolism, and viability to enhance cell survival and must be controlled in OS research. 23902524 Evaluation of accelerated collagen cross-linking for the treatment of melting keratitis in eight dogs. Melting keratitis is serious condition presenting a high risk of permanent blindness and is caused by infectious or noninfectious factors. In humans, the clinical efficacy of collagen cross-linking (CXL) has been described in the treatment of refractory infectious keratitis by arresting keratomalacia. The aim of this study was to evaluate the efficacy of accelerated CXL for the treatment of melting keratitis in dogs. Eight dogs were treated for unilateral melting keratitis by accelerated CXL. Corneas were irradiated by UVA (370 nm) at 30 mW/cm² irradiance for 3 min after soaking by 0.1% riboflavin in 20% dextran for 30 min. Follow-up was conducted 3, 7, 14, and 30 days after treatment. Pain improvement was observed for all cases within 3 days after treatment. Epithelial healing was observed within 15 days for all cases. Disappearance of cellular infiltration was observed for all cases at day 7. The corneal vascularization disappeared for 4 of 8 dogs and was reduced for 4 of 8 dogs within 1 month. At 1 month, all cases presented a variable degree of corneal scarring, but all eyes had visual function. No recurrent infection was observed. The main observation of this study is that all the cases have presented with the same clinical result regardless of the presence and the sensitivity of the infectious agents and regardless of the duration of the condition prior to CXL treatment. Accelerated CXL appears to be a valuable option for the treatment of melting keratitis. 23872366 Multiple large foreign protein expression by a single recombinant baculovirus: A system for production of multivalent vaccines. Baculovirus expression system offers the advantage of expression of several large proteins simultaneously by a single recombinant virus. To date, expression of multiple large (>100kDa) proteins has been hampered by the need to generate large constructs and repeat use of homologous sequence and promoter. The development of multi-loci baculovirus expression system overcomes these issues by enabling the recombination of large foreign sequences into different regions of the genome. In this paper, we have examined the co-expression of African horse sickness virus (AHSV) VP2 proteins from multiple serotypes in a single recombinant baculovirus. To this end, recombinant baculoviruses expressing multiple AHSV VP2 proteins were generated and it was found that up to six different AHSV serotypes (serotype 1, 3, 4, 5, 7 and 8) VP2 proteins (∼120kDa) could be expressed simultaneously from different loci of baculovirus genome. The expression of VP2 of one serotype was not significantly hindered by the presence of other serotypes, although there were slight differences in expression level between different serotypes. The expression of VP2 of further serotypes from additional loci resulted in a lesser expression level of VP2 proteins. Based on these findings, three additional recombinant baculoviruses encompassing all nine AHSV serotypes were constructed (serotypes 1, 7, 8 or serotypes 2, 4, 5 or serotypes 3, 6, 9) and each of the triple recombinant viruses exhibited similar expression level of each VP2. This system allows for the expression of a number of large proteins that has the potential to be exploited for multivalent vaccines production. 23712657 DeMix: deconvolution for mixed cancer transcriptomes using raw measured data. Tissue samples of tumor cells mixed with stromal cells cause underdetection of gene expression signatures associated with cancer prognosis or response to treatment. In silico dissection of mixed cell samples is essential for analyzing expression data generated in cancer studies. Currently, a systematic approach is lacking to address three challenges in computational deconvolution: (i) violation of linear addition of expression levels from multiple tissues when log-transformed microarray data are used; (ii) estimation of both tumor proportion and tumor-specific expression, when neither is known a priori; and (iii) estimation of expression profiles for individual patients. We have developed a statistical method for deconvolving mixed cancer transcriptomes, DeMix, which addresses the aforementioned issues in array-based expression data. We demonstrate the performance of our model in synthetic and real, publicly available, datasets. DeMix can be applied to ongoing biomarker-based clinical studies and to the vast expression datasets previously generated from mixed tumor and stromal cell samples. All codes are written in C and integrated into an R function, which is available at http://odin.mdacc.tmc.edu/∼wwang7/DeMix.html. wwang7@mdanderson.org Supplementary data are available at Bioinformatics online. 23846994 Clinical evaluation for lower abdominal aorta balloon occluding in the pelvic and sacral tumor resection. To investigate the values of clinical application of lower abdominal aorta balloon occluding in the pelvic and sacral tumor resection. From January 2004 to January 2010, 137 patients were diagnosed as sacral or pelvic tumors and underwent surgery in our institution. Forty-five patients underwent resection combined with lower abdominal aorta balloon occluding to control hemorrhage (balloon occluding group), the remaining 92 patients underwent conventional resection (conventional therapy group). We compared operative time, intraoperative hemorrhage, the amount of blood transfusion, postoperative complications, mean hospital stay as well as rates of tumor recurrence or metastasis at 3 years. En-bloc resection was performed in 93.3% (42/45) patients in balloon occluding group while the conventional therapy group was 78.2% (79/92). The balloon occluding group showed significantly shorter mean operating time, lower blood loss, lower blood transfusion, and lower postoperative drainage volume than did the conventional therapy group. The two treatment groups showed no significant difference in mean hospital stay, frequency of postoperative complications or rates of tumor recurrence or metastasis at 3 years. The application of lower abdominal aorta balloon occluding to control hemorrhage during the surgery contributes to a more clear operation field, less operation time as well as less blood loss and blood transfusion. Moderate prolong of the occluding duration can improve the safety of the surgery and contribute to more radical resection of the tumor without increase of the risks for complications. J. Surg. Oncol. 2013; 108:148-151. © 2013 Wiley Periodicals, Inc. 23936306 Oro-Gustatory Perception of Dietary Lipids and Calcium Signaling in Taste Bud Cells Are Altered in Nutritionally Obesity-Prone Psammomys obesus. Since the increasing prevalence of obesity is one of the major health problems of the modern era, understanding the mechanisms of oro-gustatory detection of dietary fat is critical for the prevention and treatment of obesity. We have conducted the present study on Psammomys obesus, the rodent desert gerbil which is a unique polygenic natural animal model of obesity. Our results show that obese animals exhibit a strong preference for lipid solutions in a two-bottle test. Interestingly, the expression of CD36, a lipido-receptor, in taste buds cells (TBC), isolated from circumvallate papillae, was decreased at mRNA level, but remained unaltered at protein level, in obese animals. We further studied the effects of linoleic acid (LA), a long-chain fatty acid, on the increases in free intracellular calcium (Ca(2+)) concentrations, [Ca(2+)]i, in the TBC of P. obesus. LA induced increases in [Ca(2+)]i, largely via CD36, from intracellular pool, followed by the opening of store-operated Ca(2+) (SOC) channels in the TBC of these animals. The action of this fatty acid on the increases in [Ca(2+)]i was higher in obese animals than that in controls. However, the release of Ca(2+) from intracellular stores, studied also by employing thapsigargin, was lower in TBC of obese animals than control rodents. In this study, we show, for the first time, that increased lipid intake and altered Ca(2+) signaling in TBC are associated with obesity in Psammomys obesus. 23554455 Public accessibility of biomedical articles from PubMed Central reduces journal readership--retrospective cohort analysis. Does PubMed Central--a government-run digital archive of biomedical articles--compete with scientific society journals? A longitudinal, retrospective cohort analysis of 13,223 articles (5999 treatment, 7224 control) published in 14 society-run biomedical research journals in nutrition, experimental biology, physiology, and radiology between February 2008 and January 2011 reveals a 21.4% reduction in full-text hypertext markup language (HTML) article downloads and a 13.8% reduction in portable document format (PDF) article downloads from the journals' websites when U.S. National Institutes of Health-sponsored articles (treatment) become freely available from the PubMed Central repository. In addition, the effect of PubMed Central on reducing PDF article downloads is increasing over time, growing at a rate of 1.6% per year. There was no longitudinal effect for full-text HTML downloads. While PubMed Central may be providing complementary access to readers traditionally underserved by scientific journals, the loss of article readership from the journal website may weaken the ability of the journal to build communities of interest around research papers, impede the communication of news and events to scientific society members and journal readers, and reduce the perceived value of the journal to institutional subscribers. 23961798 Motives for self-harm: views of nurses in a secure unit. Self-harm is a widespread behaviour among people with mental health problems. Although guidance on how to manage self-harm is offered, it is still a behaviour that is misunderstood by many nurses. Such misunderstanding is generally attributed to the perceived motives for self-harm and lack of specialized education to manage the behaviour. As a consequence, the care provided is usually inadequate and inappropriate. Yet, research concerning nurses' reasons of users' self-harming behaviours is limited. This paper reports on a study that explores nurses' explanations of the motives for self-harm in a secure adolescent unit in England. The study utilized a phenomenological methodology with semi-structured individual interviews (n = 25). The data were analysed thematically using interpretative phenomenological analysis. The findings indicate that the behaviour of self-harm has multiple motives. Examples of these include affect regulation, coping with distress, averting death, regaining control and attention seeking. Self-harm is a complex behaviour commonly experienced in secure environments. Nurses assume that users who self-harm are motivated by a desire to seek attention and manipulate others. Users may find these beliefs humiliating. Such feelings may increase users' risks for further self-harm. Most adolescents who self-harm experience unbearable emotions because of their past sexual abusive encounters. They self-harm to regulate these emotions. These affect regulatory functions may act as reinforcers of self-harming behaviours. Improved understanding of self-harm and its motives may result in improved nurse-user relationships and thus safer and more effective care provision. 23942417 Systematic Investigation of Organic Photovoltaic Cell Charge Injection/Performance Modulation by Dipolar Organosilane Interfacial Layers. With the goal of investigating and enhancing anode performance in bulk-heterojunction (BHJ) organic photovoltaic (OPV) cells, the glass/tin-doped indium oxide (ITO) anodes are modified with a series of robust silane-tethered bis(fluoroaryl)amines to form self-assembled interfacial layers (IFLs). The modified ITO anodes are characterized by contact angle measurements, X-ray reflectivity, ultraviolet photoelectron spectroscopy, X-ray photoelectron spectroscopy, grazing incidence X-ray diffraction, atomic force microscopy, and cyclic voltammetry. These techniques reveal the presence of hydrophobic amorphous monolayers of 6.68 to 9.76 Å thickness, and modified anode work functions ranging from 4.66 to 5.27 eV. Two series of Glass/ITO/IFL/Active Layer/LiF/Al BHJ OPVs are fabricated with the active layer = poly(3-hexylthiophene):phenyl-C71-butyric acid methyl ester (P3HT:PC71BM) or poly[[4,8-bis[(2-ethylhexyl)oxy]benzo[1,2-b:4,5-b']dithiophene-2,6-diyl][3-fluoro-2-[(2-ethylhexyl)-carbonyl]thi-eno[3,4-b]thiophenediyl]]:phenyl-C71-butyric acid methyl ester (PTB7:PC71BM). OPV analysis under AM 1.5G conditions reveals significant performance enhancement versus unmodified glass/ITO anodes. Strong positive correlations between the electrochemically-derived heterogeneous electron transport rate constants (ks) and the device open circuit voltage (Voc), short circuit current (Jsc), hence OPV power conversion efficiency (PCE), are observed for these modified anodes. Furthermore, the strong functional dependence of the device response on ks increases as greater densities of charge carriers are generated in the BHJ OPV active layer, and is attributable to enhanced anode carrier extraction in the case of high-ks IFLs. 23862588 Protective effects of equol and their polyphenolic isomers against dermal aging: Microarray/protein evidence with clinical implications and unique delivery into human skin. Abstract Context: Equol is a polyphenolic/isoflavonoid molecule that can be expressed as isomers. However, the characteristics of the equol isomers on dermal gene/protein expression and human skin percutaneous absorption remain unknown. Objective: Perform a comprehensive investigation on equol as: R-equol, racemic equol or S-equol to determine their differential expression of skin-related genes, quantify collagen expression and determine percutaneous absorption in human skin. Methods: Quantified: (i) gene expression/mRNA levels via gene array technology using human skin equivalents with equol exposure at 1.2% in qPCR experiments, (ii) in vitro collagen expression in human fibroblasts, and (iii) percutaneous absorption by Franz cell techniques. Results: In the qPCR studies, only three genes displayed the greatest significant expression by S-equol, whereas 16 genes displayed the greatest significant levels (either stimulation or inhibition) by R-equol and/or racemic equol, such as extracellular matrix proteins (i.e., collagen and elastin), nerve growth factor, aging genes [FOS, 100 A8 and A9 calcium-binding proteins, 5α-reductase type 1, and matrix metalloproteinases (1, 3, and 9)], and inflammatory genes (e.g., interleukin-1 alpha, interleukin-6, and cyclooxygenase-1). Collagen type I expression in fibroblasts was greater with racemic versus S-equol treatment at 1 and 10 nM. Percutaneous absorption demonstrated high sequestering in keratinocytes with subsequent accumulation/release over time. Discussion and conclusion: Overall, these results illustrate the significant differences in mirror-image molecules or isomers of equol where R-equol and/or racemic equol are better molecules for skin gene expression compared to S-equol and the percutaneous absorption of equol represents a unique epidermal reservoir delivery mechanism. 23917816 Case-control study of arsenic in drinking water and lung cancer in california and nevada. Millions of people are exposed to arsenic in drinking water, which at high concentrations is known to cause lung cancer in humans. At lower concentrations, the risks are unknown. We enrolled 196 lung cancer cases and 359 controls matched on age and gender from western Nevada and Kings County, California in 2002-2005. After adjusting for age, sex, education, smoking and occupational exposures, odds ratios for arsenic concentrations ≥85 µg/L (median = 110 µg/L, mean = 173 µg/L, maximum = 1,460 µg/L) more than 40 years before enrollment were 1.39 (95% CI = 0.55-3.53) in all subjects and 1.61 (95% CI = 0.59-4.38) in smokers. Although odds ratios were greater than 1.0, these increases may have been due to chance given the small number of subjects exposed more than 40 years before enrollment. This study, designed before research in Chile suggested arsenic-related cancer latencies of 40 years or more, illustrates the enormous sample sizes needed to identify arsenic-related health effects in low-exposure countries with mobile populations like the U.S. Nonetheless, our findings suggest that concentrations near 100 µg/L are not associated with markedly high relative risks. 23877127 Investigation of tree spectral reflectance characteristics using a mobile terrestrial line spectrometer and laser scanner. In mobile terrestrial hyperspectral imaging, individual trees often present large variations in spectral reflectance that may impact the relevant applications, but the related studies have been seldom reported. To fill this gap, this study was dedicated to investigating the spectral reflectance characteristics of individual trees with a Sensei mobile mapping system, which comprises a Specim line spectrometer and an Ibeo Lux laser scanner. The addition of the latter unit facilitates recording the structural characteristics of the target trees synchronously, and this is beneficial for revealing the characteristics of the spatial distributions of tree spectral reflectance with variations at different levels. Then, the parts of trees with relatively low-level variations can be extracted. At the same time, since it is difficult to manipulate the whole spectrum, the traditional concept of vegetation indices (VI) based on some particular spectral bands was taken into account here. Whether the assumed VIs capable of behaving consistently for the whole crown of each tree was also checked. The specific analyses were deployed based on four deciduous tree species and six kinds of VIs. The test showed that with the help of the laser scanner data, the parts of individual trees with relatively low-level variations can be located. Based on these parts, the relatively stable spectral reflectance characteristics for different tree species can be learnt. 23740985 Pyrrolidine Dithiocarbamate Inhibits Herpes Simplex Virus 1 and 2 Replication, and Its Activity May Be Mediated through Dysregulation of the Ubiquitin-Proteasome System. Pyrrolidine dithiocarbamate (PDTC) is widely used as an antioxidant or an NF-κB inhibitor. It has been reported to inhibit the replication of human rhinoviruses, poliovirus, coxsackievirus, and influenza virus. In this paper, we report that PDTC could inhibit the replication of herpes simplex virus 1 and 2 (HSV-1 and HSV-2). PDTC suppressed the expression of HSV-1 and HSV-2 viral immediate early (IE) and late (membrane protein gD) genes and the production of viral progeny. This antiviral property was mediated by the dithiocarbamate moiety of PDTC and required the presence of Zn(2+). Although PDTC could potently block reactive oxygen species (ROS) generation, it was found that this property did not contribute to its anti-HSV activity. PDTC showed no activity in disrupting the mitogen-activated protein kinase (MAPK) pathway activation induced by viral infection that was vital for the virus's propagation. We found that PDTC modulated cellular ubiquitination and, furthermore, influenced HSV-2-induced IκB-α degradation to inhibit NF-κB activation and enhanced PML stability in the nucleus, resulting in the inhibition of viral gene expression. These results suggested that the antiviral activity of PDTC might be mediated by its dysregulation of the cellular ubiquitin-proteasome system (UPS). 23936371 The PI3K/Akt/mTOR Pathway Is Implicated in the Premature Senescence of Primary Human Endothelial Cells Exposed to Chronic Radiation. The etiology of radiation-induced cardiovascular disease (CVD) after chronic exposure to low doses of ionizing radiation is only marginally understood. We have previously shown that a chronic low-dose rate exposure (4.1 mGy/h) causes human umbilical vein endothelial cells (HUVECs) to prematurely senesce. We now show that a dose rate of 2.4 mGy/h is also able to trigger premature senescence in HUVECs, primarily indicated by a loss of growth potential and the appearance of the senescence-associated markers ß-galactosidase (SA-ß-gal) and p21. In contrast, a lower dose rate of 1.4 mGy/h was not sufficient to inhibit cellular growth or increase SA-ß-gal-staining despite an increased expression of p21. We used reverse phase protein arrays and triplex Isotope Coded Protein Labeling with LC-ESI-MS/MS to study the proteomic changes associated with chronic radiation-induced senescence. Both technologies identified inactivation of the PI3K/Akt/mTOR pathway accompanying premature senescence. In addition, expression of proteins involved in cytoskeletal structure and EIF2 signaling was reduced. Age-related diseases such as CVD have been previously associated with increased endothelial cell senescence. We postulate that a similar endothelial aging may contribute to the increased rate of CVD seen in populations chronically exposed to low-dose-rate radiation. 23894473 Alignment of Synaptic Vesicle Macromolecules with the Macromolecules in Active Zone Material that Direct Vesicle Docking. Synaptic vesicles dock at active zones on the presynaptic plasma membrane of a neuron's axon terminals as a precondition for fusing with the membrane and releasing their neurotransmitter to mediate synaptic impulse transmission. Typically, docked vesicles are next to aggregates of plasma membrane-bound macromolecules called active zone material (AZM). Electron tomography on tissue sections from fixed and stained axon terminals of active and resting frog neuromuscular junctions has led to the conclusion that undocked vesicles are directed to and held at the docking sites by the successive formation of stable connections between vesicle membrane proteins and proteins in different classes of AZM macromolecules. Using the same nanometer scale 3D imaging technology on appropriately stained frog neuromuscular junctions, we found that ∼10% of a vesicle's luminal volume is occupied by a radial assembly of elongate macromolecules attached by narrow projections, nubs, to the vesicle membrane at ∼25 sites. The assembly's chiral, bilateral shape is nearly the same vesicle to vesicle, and nubs, at their sites of connection to the vesicle membrane, are linked to macromolecules that span the membrane. For docked vesicles, the orientation of the assembly's shape relative to the AZM and the presynaptic membrane is the same vesicle to vesicle, whereas for undocked vesicles it is not. The connection sites of most nubs on the membrane of docked vesicles are paired with the connection sites of the different classes of AZM macromolecules that regulate docking, and the membrane spanning macromolecules linked to these nubs are also attached to the AZM macromolecules. We conclude that the luminal assembly of macromolecules anchors in a particular arrangement vesicle membrane macromolecules, which contain the proteins that connect the vesicles to AZM macromolecules during docking. Undocked vesicles must move in a way that aligns this arrangement with the AZM macromolecules for docking to proceed. 23844246 Chemical communication of antibiotic resistance by a highly resistant subpopulation of bacterial cells. The overall antibiotic resistance of a bacterial population results from the combination of a wide range of susceptibilities displayed by subsets of bacterial cells. Bacterial heteroresistance to antibiotics has been documented for several opportunistic Gram-negative bacteria, but the mechanism of heteroresistance is unclear. We use Burkholderia cenocepacia as a model opportunistic bacterium to investigate the implications of heterogeneity in the response to the antimicrobial peptide polymyxin B (PmB) and also other bactericidal antibiotics. Here, we report that B. cenocepacia is heteroresistant to PmB. Population analysis profiling also identified B. cenocepacia subpopulations arising from a seemingly homogenous culture that are resistant to higher levels of polymyxin B than the rest of the cells in the culture, and can protect the more sensitive cells from killing, as well as sensitive bacteria from other species, such as Pseudomonas aeruginosa and Escherichia coli. Communication of resistance depended on upregulation of putrescine synthesis and YceI, a widely conserved low-molecular weight secreted protein. Deletion of genes for the synthesis of putrescine and YceI abrogate protection, while pharmacologic inhibition of putrescine synthesis reduced resistance to polymyxin B. Polyamines and YceI were also required for heteroresistance of B. cenocepacia to various bactericidal antibiotics. We propose that putrescine and YceI resemble "danger" infochemicals whose increased production by a bacterial subpopulation, becoming more resistant to bactericidal antibiotics, communicates higher level of resistance to more sensitive members of the population of the same or different species. 23935479 Full design automation of multi-state RNA devices to program gene expression using energy-based optimization. Small RNAs (sRNAs) can operate as regulatory agents to control protein expression by interaction with the 5' untranslated region of the mRNA. We have developed a physicochemical framework, relying on base pair interaction energies, to design multi-state sRNA devices by solving an optimization problem with an objective function accounting for the stability of the transition and final intermolecular states. Contrary to the analysis of the reaction kinetics of an ensemble of sRNAs, we solve the inverse problem of finding sequences satisfying targeted reactions. We show here that our objective function correlates well with measured riboregulatory activity of a set of mutants. This has enabled the application of the methodology for an extended design of RNA devices with specified behavior, assuming different molecular interaction models based on Watson-Crick interaction. We designed several YES, NOT, AND, and OR logic gates, including the design of combinatorial riboregulators. In sum, our de novo approach provides a new paradigm in synthetic biology to design molecular interaction mechanisms facilitating future high-throughput functional sRNA design. 23936516 Crucial Role of Perilipin-3 (TIP47) in Formation of Lipid Droplets and PGE2 Production in HL-60-Derived Neutrophils. Cytosolic lipid droplets (LDs), which are now recognized as multifunctional organelles, accumulate in leukocytes under various inflammatory conditions. However, little is known about the characteristic features of LDs in neutrophils. In this study, we show that perilipin-3 (PLIN3; formerly called TIP47) is involved in LD formation and the inflammatory response in HL-60-derived neutrophils. HL-60, a promyelocytic cell line, was differentiated into neutrophils via treatment with all-trans retinoic acid. After differentiation, cells were stimulated with Porphyromonas gingivalis lipopolysaccharide (P.g-LPS), a major pathogen in adult periodontitis. When HL-60-derived neutrophils were stimulated with P.g-LPS, LDs increased in both number and size. In the differentiated cells, PLIN3 was induced while PLIN1, PLIN2 and PLIN5 were not detected. PGE2 production and the PLIN3 protein level were increased by the P.g-LPS treatment of the cells in a dose-dependent manner. When PLIN3 was down-regulated with siRNA treatment, LDs essentially disappeared and the level of PGE2 secreted in the cell culture medium decreased by 65%. In addition, the suppression of PLIN3 repressed the PGE2 producing enzymes; i.e., microsomal PGE synthase-1, -2 and cyclooxygenase-2. These findings indicate that PLIN3 has a pivotal role in LD-biogenesis in HL-60-derived neutrophils, and that PLIN3 is associated with the synthesis and secretion of PGE2. 23664086 A psychological pathway from insomnia to depression among older adults. Higher levels of insomnia predict greater depression severity among older adults; however, the psychological mechanisms underlying this relationship are unclear. This study tested a path model that explored whether dysfunctional beliefs about sleep and hopelessness mediated the relationship from insomnia to depression. It was hypothesized that insomnia would predict depression, both directly and indirectly, via dysfunctional beliefs about sleep and hopelessness. A community sample of 218 independent-living Australian older adults aged from 65 to 96 years completed a self-report questionnaire package. From the initial 218 participants, 171 completed a measure of depression three months later. Path analysis demonstrated that maladaptive sleep beliefs and hopelessness partly explained how insomnia influenced depression, irrespective of the presence of obstructive sleep apnea and/or restless legs syndrome. An older adult's beliefs about sleep and sense of hopelessness were important psychological factors that helped explain how insomnia related to depression. 23677577 C-reactive protein, lipid-soluble micronutrients, and survival in colorectal cancer patients. Identification of biomarkers associated with survival in patients with cancer is important for elucidating the underlying mechanisms of cancer progression and identifying possible interventions to reduce cancer morbidity and mortality. Using stored patient plasma samples from a multiethnic population-based case-control study of invasive colorectal cancer, we measured posttreatment blood levels of C-reactive protein (CRP) and lipid-soluble micronutrients. Patients (n = 368) were followed after phlebotomy (mean of 8 years), during which time 47% died (25% colorectal cancer specific). HRs were estimated by Cox proportional hazards regression with adjustment for stage, age at diagnosis, ethnicity, sex, smoking status, and month of blood draw. A positive association with overall risk of death was observed for CRP [HR for highest vs. lowest quintile: 1.80; 95% confidence interval (CI), 1.07-3.04; Ptrend = 0.01], whereas inverse associations were generally observed for retinol and carotenoids (HRs for overall risk of death for the highest quintile ranging from 0.5-0.8); these associations were significant for retinol (Ptrend = 0.0002), α-carotene (Ptrend = 0.02), and total carotenoids (Ptrend = 0.02) and were generally consistent across subgroups (sex, ethnicity, cancer anatomical subtype, and stage). HRs for retinol and carotenoids were attenuated somewhat after adjustment for CRP. Similar trends for CRP were observed for colorectal cancer-specific deaths (HR for highest vs. lowest tertile: 2.06; 95% CI, 1.18-3.61; Ptrend = 0.01) as for deaths from all other causes (Pheterogeneity = 0.78). These observations are consistent with a direct relationship between circulating CRP and overall survival among patients with colorectal cancer. These results, if reproduced, suggest that reduction of inflammation should be explored as a potential complementary treatment strategy. 23927895 Iron acquisition in the human fungal pathogen Cryptococcus neoformans. Iron sequestration by the vertebrate host is considered an efficient defense mechanism against pathogenic microbes. However, this mechanism, so called nutritional immunity, is often overcome by the iron acquisition systems that have evolved in microbial pathogens. Numerous studies have been carried out to identify the key components of these systems and to understand their underlying mechanisms, including recent investigations in the basidiomycete fungal pathogen Cryptococcus neoformans. Iron acquisition is essential for the survival and pathogenesis of this fungus within vertebrate hosts. Growing evidence suggests that the fungus is able to utilize several different iron sources available in the host, and that the intracellular or extracellular localization of the pathogen influences its iron acquisition strategy. Herein, we review current findings on the components and regulatory elements of the iron acquisition systems in C. neoformans. 23747173 Endogenous cannabinoids in amygdala and hippocampus in post-mortem brains of Cloninger type 1 and 2 alcoholics. Accumulating evidence continues to link certain aspects of the endogenous cannabinoid (EC) system with alcohol dependence, negative-reinforcement learning, and the modulation of stress responses. Specific alterations in brain regions that are related to stress and negative-reinforcement learning have been reported to exist in Cloninger type 1 and type 2 alcoholics. To study possible differences in profiles of EC systems between Cloninger type 1 (n = 9) and type 2 (n = 8) alcoholics and non-alcoholic control subjects (n = 10), we analyzed post-mortem amygdala and hippocampus brain samples for several ECs by quantitative liquid chromatography with triple quadrupole mass-spectrometric detection. A significant difference was found between these 3 groups in terms of EC profiles in the amygdala (p = 0.037). In particular, this difference was prominent for variations in docosahexaenoylethanolamide levels, which were significantly higher in type 1 alcoholics (p = 0.022) when compared to controls. There was also a large negative correlation between anandamide concentration and mGlu1/5 receptor density in the hippocampi of Cloninger type 1 alcoholics (R = -0.88, p = 0.002), which was not seen in Cloninger type 2 alcoholics or in controls. Although preliminary, and from relatively small diagnostic groups, these results suggest that the EC system profile may be altered in the hippocampus and amygdala of Cloninger type 1 alcoholics. 23639909 Exposure to food contaminants during pregnancy. During pregnancy, the fetus is exposed to contaminants from its mother's diet. This work provides an assessment of the dietary exposure of pregnant women to inorganic contaminants (aluminum, mercury, lead, inorganic arsenic, cobalt), polychlorodibenzodioxins, polychlorodibenzofurans, dioxin-like and non-dioxin-like polychlorobiphenyls (DL-PCBs, NDL-PCBs), polybromodiphenyl ethers (PBDEs), perfluoroalkyl acids, mycotoxins (zearalenone, patulin, trichothecenes), and heat-generated compounds (acrylamide and polycyclic aromatic hydrocarbons). Consumption data of 2002 pregnant women aged 18 to 45 from the EDEN cohort study were combined with contamination data from the second French total diet study to assess the exposure before pregnancy (n=1861) and during the third trimester of pregnancy (n=1775). Exposure was also assessed considering the season during which the third trimester of pregnancy occurred. Significant changes in consumptions during pregnancy and between seasons were associated with differences in exposures for some substances. Some contaminant exposures appeared to be of health concern. Margins of exposure to acrylamide (635 to 1094 for mean), inorganic arsenic, lead, and BDE-99 (≤100) were too low to exclude all risks. For NDL-PCBs, T-2 and HT-2 toxins, and deoxynivalenol, significant exceedings of toxicological reference values were found before pregnancy, but there was no significant exceeding in the third trimester. 23957045 Caries Risk Assessment in Preschool Children in Saudi Arabia. Purpose: Caries is a prevalent condition in Saudi Arabia. At present, knowledge regarding caries risk factors in Saudi Arabia is limited. The present study aimed to identify characteristic features of Saudi preschoolers at high risk for caries, using the American Academy of Pediatric Dentistry caries risk assessment tool (CAT ) and to report the most significant caries risk predictors. Materials and Methods: A sample of 407 children aged 4 and 5 years was selected randomly from private and public nursery schools. Their parents answered a questionnaire prepared using the CAT . Each child was examined for the presence of caries and his/her oral hygiene status. Results: According to the CAT , almost all children (89%) were considered to be at high risk. Caries was significantly more prevalent among children attending public than private schools. All CAT variables were significantly related to the presence of caries except general health condition and water fluoridation. Logistic regression analysis showed previous caries experience, enamel demineralisation, and socio-economic status to be the most significant caries risk factors. Conclusion: Most of the Saudi children are considered to be at high risk for caries. Previous caries experience, enamel demineralisation and socioeconomic status are the most significant caries risk predictors. These groups should be targeted for inclusion in caries prevention programmes. 23765131 Preparation of superhydrophobic, long-neck vase-like polymer surfaces. Polymer surfaces comprising nanopillars with various geometries were prepared by nanoimprinting the surface using anodic aluminium oxide templates. In particular, a simple fabrication method for long-neck vase-like stepped nanopillars was established, and the surface showed considerable enhancement in the water contact angle, for example from 95.7° to 150.6° for the polystyrene surface. This enhanced hydrophobicity could be explained by the desirable reduction in the area of the solid-liquid interface and reduced sticking between the nanopillars. 23862631 Modeling clinical endpoints as a function of time of switch to second-line ART with incomplete data on switching times. Modeling clinical endpoints as a function of change in antiretroviral therapy (ART) attempts to answer one simple but very challenging question: was the change in ART beneficial or not? We conceive a similar scientific question of interest in the current manuscript except that we are interested in modeling the time of ART regimen change rather than a comparison of two or more ART regimens. The answer to this scientific riddle is unknown and has been difficult to address clinically. Naturally, ART regimen change is left to a participant and his or her provider and so the date of change depends on participant characteristics. There exists a vast literature on how to address potential confounding and those techniques are vital to the success of the method here. A more substantial challenge is devising a systematic modeling strategy to overcome the missing time of regimen change for those participants who do not switch to second-line ART within the study period even after failing the initial ART. In this article, we adopt and apply a statistical method that was originally proposed for modeling infusion trial data, where infusion length may be informatively censored, and argue that the same strategy may be employed here. Our application of this method to therapeutic HIV/AIDS studies is new and interesting. Using data from the AIDS Clinical Trials Group (ACTG) Study A5095, we model immunological endpoints as a polynomial function of a participant's switching time to second-line ART for 182 participants who already failed the initial ART. In our analysis, we find that participants who switch early have somewhat better sustained suppression of HIV-1 RNA after virological failure than those who switch later. However, we also found that participants who switched very late, possibly censored due to the end of the study, had good HIV-1 RNA suppression, on average. We believe our scientific conclusions contribute to the relevant HIV literature and hope that the basic modeling strategy outlined here would be useful to others contemplating similar analyses with partially missing treatment length data. 23839368 101 Clinical Course After Percutaneous Epidural Neuroplasty According to the Type of Single Level Herniated Lumbar Disc With 12 Months Follow-up. The clinical course after percutaneous epidural neuroplasty (PEN) among the different types of HLD is not well documented. The purpose of this study is to determine whether treatment outcome is affected by the type of HLD and to evaluate effectiveness of PEN in single level HLD. A consecutive series of 430 patients who underwent PEN for single level HLD were included in this study. Preoperatively, all patients were categorized into bulging (B), protrusion (P), extrusion (E) and sequestration (S) with Pfirrmann grade (G0 to G3). Visual analog scale (VAS) score, SF-12 and Odom's criteria were measured in preoperative and scheduled postoperative follow-up period (1, 3, 6 and 12 months). There was no significant difference in treatment outcomes according to the type of HLD (P > .05) except more decreased in VAS (leg) in E and S groups than in B and P groups (0 < .05). Subsequent surgery was considered in 59 patients (13.7%), and the operation was more frequently observed in E and S than B and P and in G1 to G3 than G0. Mean back pain and leg pain VAS of total follow-up patients were decreased respectively, from 6.90 and 4.23 in preoperative to 2.25 and 1.45 in 1 month, to 2.61 and 1.68 in 3 months, to 2.28 and 1.48 in 6 months, and to 2.88 and 1.48 in 12 months after PEN (P < .001). More than 70% of all patients with PEN showed good and excellent Odom's criteria during 12 months follow-up, and more than 70% of patients with E and S type of HLD didn't need surgical treatment. The efficacy of PEN was not differently affected by the different type of HLD. PEN is a safe and effective treatment for back and leg pain due to single level HLD in 12 months follow-up study. 23475194 Exploring clinical determinants and anxiety symptom domains among Asian breast cancer patients. Psychological distress, such as anxiety, is commonly experienced by breast cancer patients. This study was designed to evaluate the presentation of anxiety symptom domains among Asian breast cancer patients and to identify clinical factors that were associated with occurrence of anxiety. An observational study was conducted between August 2009 and January 2012. Breast cancer patients (stages I to III) with different chemotherapy treatment status completed the Beck Anxiety Inventory (BAI) to evaluate the prevalence and severity of their anxiety symptoms. Demographical and clinical data were collected. Multiple linear regression was conducted to delineate clinical factors associated with anxiety. A total of 319 patients were recruited (age: 51 ± 9 years; 80.9 % Chinese; 69.6 % stage I/II). The median BAI total score was 8 (IQR, 4-14). Anxiety severities varied greatly across patients with different chemotherapy treatment status: patients who were receiving concurrent chemotherapy at the point of assessment (n = 161) experienced more severe anxiety symptoms, as compared to pre-chemotherapy receiving (n = 78) patients and post-chemotherapy (n = 88) patients (29.8 % vs. 9.0 % vs. 20 %, respectively; p = 0.021). Regression model identified fatigue (p < 0.001) and the concurrent receipt of chemotherapy (p < 0.001) as the strongest factors associated with anxiety. Concomitant neuropsychiatric medicines (antidepressants, anxiolytics, and hypnotics) were moderately associated with anxiety occurrence. This is the largest series to date to evaluate anxiety symptom domains among Asian breast cancer patients. Results suggest that toxicities of chemotherapy may have contributed to the presentation of anxiety symptoms. 23770359 Fibromodulin promoted in vitro and in vivo angiogenesis. Fibromodulin (FMOD) is an extracellular matrix (ECM) small leucine-rich proteoglycan (SLRP) that plays an important role in cell fate determination. Previous studies revealed that not only is FMOD critical in fetal-type scarless wound healing, but it also promotes adult wound closure and reduces scar formation. In addition, FMOD-deficient mice exhibit significantly reduced blood vessel regeneration in granulation tissues during wound healing. In this study, we investigated the effects of FMOD on angiogenesis, which is an important event in wound healing as well as embryonic development and tumorigenesis. We found that FMOD accelerated human umbilical vein endothelial HUVEC-CS cell adhesion, spreading, actin stress fiber formation, and eventually tube-like structure (TLS) network establishment in vitro. On a molecular level, by increasing expression of collagen I and III, angiopoietin (Ang)-2, and vascular endothelial growth factor (VEGF), as well as reducing the ratio of Ang-1/Ang-2, FMOD provided a favorable network to mobilize quiescent endothelial cells to an angiogenic phenotype. Moreover, we also confirmed that FMOD enhanced angiogenesis in vivo by using an in ovo chick embryo chorioallantoic membrane (CAM) assay. Therefore, our data demonstrate that FMOD is a pro-angiogenic and suggest a potential therapeutic role of FMOD in the treatment of conditions related to impaired angiogenesis. 23831369 The compact conformation of the Plasmodium knowlesi myosin tail interacting protein MTIP in complex with the C-terminal helix of myosin A. The myosin motor of the malaria parasite's invasion machinery moves over actin fibers while it is making critical contacts with the myosin-tail interacting protein (MTIP). Previously, in a "compact" Plasmodium falciparum MTIP•MyoA complex, MTIP domains 2 (D2) and 3 (D3) make contacts with the MyoA helix, and the central helix is kinked, but in an "extended" Plasmodium knowlesi MTIP•MyoA complex only D3 interacts with the MyoA helix, and the central helix is fully extended. Here we report the crystal structure of the compact P. knowlesi MTIP•MyoA complex. It appears that, depending on the pH, P. knowlesi MTIP can adopt either the compact or the extended conformation to interact with MyoA. Only at pH values above ∼7.0, can key hydrogen bonds can be formed by the imidazole group of MyoA His810 with an aspartate carboxylate from the hinge of MTIP and a lysine amino group of MyoA simultaneously. 23925556 Proteomic Analysis of Sarcoplasmic Peptides of Two Related Fish Species for Food Authentication. Detection of species-specific sarcoplasmic peptides can be used as proteomic markers for fish food authentication and identification of species of origin in processed products. In the present study, proteomics technology was employed for differential characterization of sarcoplasmic peptides of two closely related fish species, Sperata seenghala and Sperata aor. Species-specific peptides were searched in white muscle extracts of the two species for identification of unique peptides that might aid in differentiation of the species, under two-dimensional gel electrophoresis platform. A total of 19 proteins were identified by combined matrix-assisted laser desorption ionization time-of-flight mass spectrometry and liquid chromatography-tandem mass spectrometry, of which nine and two proteins were found to be unique to S. seenghala and S. aor, respectively. One of the proteins, triosephosphate isomerase (TPI) was found to have three isoforms, out of which two were specific to S. aor, and one was specific to S. seenghala. All the three isoforms of TPI were present in the mixed samples of raw protein extracts of S. seenghala and S. aor, an observation that can be exploited to differentiate between the species and detection of deceptive practices of fraudulent substitution of commercially valuable fish species with inferior ones and differential characterization between closely related fish species. 23597713 Effect of surfactants on preformed fibrils of human serum albumin. The central reason behind pathogenesis of various neurological disorders is usually attributed to the accumulation of aggregated proteins particularly in fibrillar morphology in vivo. One of the plausible remedial treatments for such disorders may be to identify molecules which are capable of either preventing formation of fibrils or disintegrating formed fibrils. The effect of cationic surfactants cetyl trimethylammonium bromide (CTAB), dodecyl trimethylammonium bromide (DTAB) and the anionic surfactant sodium dodecyl sulfate (SDS) in vitro toward mature HSA fibrils has been investigated. The process has been monitored using ThT fluorescence, FTIR, circular dichroism, fluorescence microscopy and HRTEM. It was observed that the micelles of cationic surfactants were able to effectively disrupt the HSA fibrils, among which CTAB was found to be the most potent. 23774192 Ag-decorated TiO2 nanograss for 3D SERS-active substrate with visible light self-cleaning and reactivation. The production of SERS-active substrates which are uniform, sensitive, reproducibile and durable still remains an important issue. Here, we report a strategy for the fabrication of a large-area Ag-decorated TiO2 nanograss SERS-active substrate by a simple solvothermal approach combined with Ag evaporation. The nanograss consists of dense rutile TiO2 nanorods of about 5 nm in diameter and the decorated Ag nanoparticles are an average of 8 nm in diameter. The Ag protrusions and gaps between them contribute to three dimensional SERS "hot spots" which can be modulated by simply controlling the Ag evaporating parameters. The Ag-decorated TiO2 substrate is highly efficient in detecting rhodamine 6G (R6G) and 4-aminothiophenol (4-ATP) molecules and has good homogeneity. An obvious red shift and even high enhancement of b2 vibration mode were observed in detecting 4-ATP due to the effective charge transfer from the Ag atoms to sulfur atoms. The Ag-decorated TiO2 substrate can be easily self-cleaned and reactivated by visible light irradiation without obvious degeneration of SERS signals. Our results demonstrate that the Ag-decorated TiO2 substrate with high and homogeneous SERS activity has potential feasibility as a sensitive SERS probe. 23450766 Precarious employment, psychosocial working conditions, and health: Cross-sectional associations in a population-based sample of working Australians. Precarious employment has been associated with poor health, but the potential mechanisms are unclear. We examined the relationships between precarious employment and health, and investigated psychosocial working conditions as potential mediators. A cross-sectional population-based survey was conducted in South Australia in 2009 (N = 1,016 employed). SF-12 measures of mental and physical health were modeled using logistic regression in relation to employment arrangement, controlling for socio-demographics, years in job and psychosocial working conditions. There was no association between casual full-time or part-time employment and poor mental health in multivariate analyses. Conversely, there was a significant association between casual full-time employment and poor physical health (compared to permanent full-time workers, OR = 3.14, 95% CI 1.26-7.85). The association with physical health was unaffected by adjustment for psychosocial working conditions. Casual full-time employment was strongly associated with poor physical health but not with poor mental health. This association was not mediated by the psychosocial working conditions measured in this study, but may be related to other (unmeasured) working conditions. Am. J. Ind. Med. 56:838-844, 2013. © 2013 Wiley Periodicals, Inc. 23647919 Sequences of multiple bacterial genomes and a Chlamydia trachomatis genotype from direct sequencing of DNA derived from a vaginal swab diagnostic specimen. Ultra-deep Illumina sequencing was performed on whole genome amplified DNA derived from a Chlamydia trachomatis-positive vaginal swab. Alignment of reads with reference genomes allowed robust SNP identification from the C. trachomatis chromosome and plasmid. This revealed that the C. trachomatis in the specimen was very closely related to the sequenced urogenital, serovar F, clade T1 isolate F-SW4. In addition, high genome-wide coverage was obtained for Prevotella melaninogenica, Gardnerella vaginalis, Clostridiales genomosp. BVAB3 and Mycoplasma hominis. This illustrates the potential of metagenome data to provide high resolution bacterial typing data from multiple taxa in a diagnostic specimen. 23821604 The role of carbon dioxide as an orientation cue for western corn rootworm larvae within the maize root system: implications for an attract-and-kill approach. Western corn rootworm larvae use CO2 to locate maize roots. However, the importance of CO2 as a specific orientation cue close to maize roots has not been investigated unequivocally. This study aimed at elucidating the effect of CO2 -emitting capsules in combination with a soil insecticide (Tefluthrin = attract and kill) within the root system. We hypothesized that the capsules would result in aggregation of the larvae at the soil insecticide, thus increasing its efficacy. A nondestructive observation device was used to study larval distribution and behaviour. Spatial analysis of distance indices (SADIE) revealed aggregation of the larvae around the capsules in an attract-and-kill treatment after 4 h, which was not found with the conventional treatment without the capsules. However, larval mortality did not differ between treatments. CO2 is a weak attractant for western corn rootworm larvae within the root system. Consequently, an attract-and-kill strategy based on a CO2 product will not contribute to better control compared with conventional Tefluthrin applications. Host-specific compounds, combined with a CO2 source, should be used to target more larvae, making attract and kill a feasible management option against this pest. © 2013 Society of Chemical Industry. 23312371 Discomfort during lateral acceleration: influence of seat cushion and backrest. Lateral acceleration causes discomfort but how the discomfort depends on the frequency of acceleration or characteristics of seating is poorly understood. Using magnitude estimation, twelve male subjects rated the discomfort caused by lateral oscillation at eight frequencies (0.2-1.0 Hz) across four seating conditions (a rigid seat and a train seat, both with and without backrests). Discomfort increased with increasing frequency of lateral acceleration in a similar manner for all four seating conditions. However, at all frequencies and with both seats there was less discomfort when sitting with backrest support than without. Least discomfort occurred on the train seat with backrest and greatest discomfort on the rigid seat without backrest. Current standards predict an additive effect of backrest on vibration discomfort, but the findings show that low frequency lateral acceleration can cause less discomfort when sitting with a backrest than when sitting on the same seat without a backrest. 23883860 The spread of attention across features of a surface. Contrasting theories of visual attention have emphasized selection by spatial location, individual features and whole objects. We used functional magnetic resonance imaging to ask whether and how attention to one feature of an object spreads to other features of the same object. Subjects viewed two spatially superimposed surfaces of random dots that were segregated by distinct color-motion conjunctions. The color and direction of motion of each surface changed smoothly and in a cyclical fashion. Subjects were required to track one feature (e.g., color) of one of the two surfaces and detect brief moments when the attended feature diverged from its smooth trajectory. To tease apart the effect of attention to individual features on the hemodynamic response, we used a frequency-tagging scheme. In this scheme, the stimulus features (color and direction of motion) are modulated periodically at distinct frequencies so that the contribution of each feature to the hemodynamics can be inferred from the harmonic response at the corresponding frequency. We found that attention to one feature (e.g., color) of one surface not only increased the response modulation to the attended feature but also to the other feature (e.g., motion) of the same surface. This attentional modulation was evident in multiple visual areas and was present as early as V1. The spread of attention to the behaviorally irrelevant features of a surface suggests that attention may automatically select all features of a single object. Thus, object-based attention may be supported by an enhancement of feature-specific sensory signals in the visual cortex. 23749633 T cell activation threshold regulated by E3 ubiquitin ligase Cbl-b determines fate of inducible regulatory T cells. E3 ubiquitin ligase Casitas-B-lineage lymphoma protein-b (Cbl-b) is critical for establishing the threshold for T cell activation and is essential for induction of T cell anergy. Recent studies suggest that Cbl-b is involved in the development of CD4(+)CD25(+) inducible regulatory T cells (iTregs). In this study, we report that the optimal induction of Foxp3 by naive CD4(+)CD25(-) T cells requires suboptimal TCR triggering. In the absence of Cbl-b, the TCR strength for optimal Foxp3 induction is downregulated in vitro. Using TCR-transgenic Rag(-/-) mice in combination with Cbl-b deficiency, we show that in vivo iTreg development is also controlled by Cbl-b via tuning the TCR strength. Furthermore, we show that Akt-2 but not Akt-1 regulates Foxp3 expression downstream of Cbl-b. Therefore, we demonstrate that Cbl-b regulates the fate of iTregs via controlling the threshold for T cell activation. 23852325 Effects of aging on force coordination in bimanual task performance. We investigated within- and between-hands grip-load force coordination in both healthy young and older adult participants during bimanual tasks involving realistic actions. Age-related changes in manual behaviors such as grip force production and safety margins were expected in older adults. Within-hand grip-load coordination was expected to decrease with aging during the performance of dynamic actions, but not static actions. The effects of task and hand dominance on task performance were also evaluated. Grip force production increased with age; however, changes in fingertip frictional properties with aging increased the risk of object slip. Indices of within-hand grip-load coordination did not alter with age, but such indices were affected by task goals. The action of connecting two independent objects, particularly with rotational action, was associated with declines in all indices of within- and between-hands force coordination, independent of age. Evidence of task-specific differences in within-hand grip-load coordination in the current data set suggests that individual hand specification emerges and persists with age in everyday bimanual prehension tasks, independent of the action role assigned to the dominant and non-dominant hands. 23954172 Accumulation of C-terminal fragments of transactive response DNA-binding protein 43 leads to synaptic loss and cognitive deficits in human TDP-43 transgenic mice. Accumulation of the transactive response DNA-binding protein 43 (TDP-43) is a major hallmark of several neurodegenerative disorders, collectively known as TDP-43 proteinopathies. The most common TDP-43 proteinopathies, frontotemporal lobar degeneration with TDP-43-positive inclusions, and amyotrophic lateral sclerosis, share overlapping neuropathological and clinical phenotypes. The development and detailed analysis of animal models of TDP-43 proteinopathies are critical for understanding the pathogenesis of these disorders. Transgenic mice overexpressing mutant human TDP-43 (herein referred to as hTDP-43) are characterized by neurodegeneration and reduced life span. However, little is known about the behavioral phenotype of these mice. Here we report the novel finding that hTDP-43 mice develop deficits in cognition, motor performance, and coordination. We show that these behavioral deficits are associated with the accumulation of nuclear and cytosolic TDP-43 C-terminal fragments, a decrease in endogenous TDP-43 levels, and synaptic loss. Our findings provide critical insights into disease pathology, and will help guide future preclinical studies aimed at testing the effects of potential therapeutic agents on the onset and progression of TDP-43 proteinopathies. 23872275 Therapeutic enhancement of vascular-targeted photodynamic therapy by inhibiting proteasomal function. Vascular-targeted photodynamic therapy (vPDT) is a novel vascular targeting modality based on site-directed delivery of a photosensitizer to tumor vasculature, which induces reactive oxygen species (ROS)-mediated vascular effects upon light activation. To enhance the therapeutic outcome of vPDT, we combined proteasomal inhibitor bortezomib and vPDT using photosensitizer verteporfin in the present study. We found that bortezomib in combination with verteporfin-PDT induced more accumulation of ubiquitinated proteins and apoptosis in endothelial cells than each individual treatment. The combination therapy also enhanced vPDT-induced inhibition in tumor growth. These results indicate that bortezomib can be used together with verteporfin-PDT for enhanced treatment outcome. 23345579 Mass spectrometry method to identify aging pathways of Sp- and Rp-tabun adducts on human butyrylcholinesterase based on the acid labile P-N bond. The phosphoramidate nerve agent tabun inhibits butyrylcholinesterase (BChE) and acetylcholinesterase by making a covalent bond on the active site serine. The adduct loses an alkyl group in a process called aging. The mechanism of aging of the tabun adduct is controversial. Some studies claim that aging proceeds through deamination, whereas crystal structure studies show aging by O-dealkylation. Our goal was to develop a method that clearly distinguishes between deamination and O-dealkylation. We began by studying the tetraisopropyl pyrophosphoramide adduct of BChE because this adduct has two P-N bonds. Mass spectra showed that the P-N bonds were stable during trypsin digestion at pH 8 but were cleaved during pepsin digestion at pH 2. The P-N bond in tabun was also acid labile, whereas the P-O bond was stable. A scheme to distinguish aging by deamination from aging by O-dealkylation was based on the acid labile P-N bond. BChE was inhibited with Sp- and Rp-tabun thiocholine nerve agent model compounds to make adducts identical to those of tabun with known stereochemistry. After aging and digestion with pepsin at pH 2, peptide FGES198AGAAS from Sp-tabun thiocholine had a mass of 902.2 m/z in negative mode, indicating that it had aged by deamination, whereas peptide FGES198AGAAS from Rp-tabun thiocholine had a mass of 874.2 m/z in negative mode, indicating that it had aged by O-dealkylation. BChE inhibited by authentic, racemic tabun yielded both 902.2 and 874.2 m/z peptides, indicating that both stereoisomers reacted with BChE and aged either by deamination or dealkylation. 23164602 A new ganoderic acid from Ganoderma lucidum mycelia and its stability. A new ganoderic acid (GA), 3α,22β-diacetoxy-7α-hydroxyl-5α-lanost-8,24E-dien-26-oic acid (1), together with four known compounds GA-Mk (2), -Mc (3), -S (4) and -Mf (5), was isolated and characterized from Ganoderma lucidum mycelia. The structure of compound 1 was elucidated on the basis of interpretation of extensive spectroscopic data (HRMS, IR, UV, 1D and 2D NMR). Due to its apparent degradation during preparation procedures, the stability of compound 1 was assessed in several solvents in a short-term study that demonstrated the optimal stability in aproptic environment. A possible mechanism of acid-catalyzed degradation of compound 1 in methanol was proposed, consisting of a fast protonation, followed by a committed step of hydroxyl group removal. In addition, all isolated compounds were tested in vitro for their cytotoxic activities against 95D and HeLa tumor cell lines, with IC(50) values ranging from14.7 to 38.5μM. The results may improve the understanding of chemical stability of GAs and provide valuable information on their separation, analysis and application. 22975750 Involvement in activities and wandering in nursing home residents with cognitive impairment. Analysis of a relationship between wandering and involvement in meaningful activities in nursing home residents with cognitive impairment. Cross-sectional analysis of the Minimum Data Set information. The analyses were conducted on 8 nursing homes in the Netherlands. The participants were residents aged 65 years and above with an evidence of cognitive impairment. Items in the Minimum Data Set related to wandering behavior, involvement in activities, presence of psychotic symptoms, and treatment with antipsychotics. Ambulatory residents who exhibited wandering were divided into: those whose behavior was easily altered [modifiable wandering (MW)] and those whose wandering behavior was not easily altered by the staff [nonmodifiable wandering (NMW)]. The duration of time for which they had opportunity to be involved in meaningful activities was estimated from involvement in activities of nonambulatory residents. The prevalence of wandering increased with severity of cognitive impairment. MW was present in 3.5% of total residents (8.5% of ambulatory), whereas NMW was present in 11.2% of the total ambulatory and nonambulatory residents (26.6% of ambulatory). The risk of NMW was increased with resistiveness to care and decreased with antipsychotic use. Individuals with NMW were less involved in activities. NMW was more prevalent in facilities in which residents were involved in activities for a shorter duration. Involvement of residents in meaningful activities should be tested for reducing the incidence of problematic wandering and for decrease in usage of antipsychotic medications. 23369672 Current and future approaches to the therapy of human rabies. Human rabies has traditionally been considered a uniformly fatal disease. However, recent decades have seen several instances in which individuals have developed clinical signs of rabies, but survived, usually with permanent neurologic sequelae. Most of these patients had received prophylactic rabies vaccine before the onset of illness. The best outcomes have been seen in patients infected with bat viruses, which appear to be less virulent for humans than strains associated with other rabies vectors. In 2003, an article by rabies experts suggested that survival might be improved through a combination of vaccine, anti-rabies immunoglobulin, antiviral drugs and the anesthetic ketamine, which had shown benefit in an animal model. One year later, a girl in Milwaukee who developed rabies after bat exposure was treated with some of these measures, plus a drug-induced (therapeutic) coma, and survived her illness with mild neurologic sequelae. Although the positive outcome in this case has been attributed to the treatment regimen, it more likely reflects the patient's own brisk immune response, as anti-rabies virus antibodies were detected at the time of hospital admission, even though she had not been vaccinated. This conclusion is supported by the failure of the "Milwaukee Protocol" to prevent death in numerous subsequent cases. Use of this protocol should therefore be discontinued. Future research should focus on the use of animal models to improve understanding of the pathogenesis of rabies and for the development of new therapeutic approaches. 23023768 Electrical detection of spin precession in freely suspended graphene spin valves on cross-linked poly(methyl methacrylate). Spin injection and detection is achieved in freely suspended graphene using cobalt electrodes and a nonlocal spin-valve geometry. The devices are fabricated with a single electron-beam-resist poly(methyl methacrylate) process that minimizes both the fabrication steps and the number of (aggressive) chemicals used, greatly reducing contamination and increasing the yield of high-quality, mechanically stable devices. As-grown devices can present mobilities exceeding 10(4) cm(2) V(-1) s(-1) at room temperature and, because the contacts deposited on graphene are only exposed to acetone and isopropanol, the method is compatible with almost any contacting material. Spin accumulation and spin precession are studied in these nonlocal spin valves. Fitting of Hanle spin precession data in bilayer and multilayer graphene yields a spin relaxation time of ∼125-250 ps and a spin diffusion length of 1.7-1.9 μm at room temperature. 23829624 Are monoclonal antibodies a safe treatment for cancer during pregnancy? Monoclonal antibodies (mAbs) are the cornerstone of the treatment of several types of tumors, but their use in pregnant women is not clearly defined. Here, we report and analyze all available data on mAb treatment in pregnant cancer patients. A literature search was performed from 2000 until January 2013 and all articles addressing safety of mAbs during pregnancy were reviewed. We found very few data on the use of bevacizumab in pregnant women. However, owing to its antiangiogenic effects and possible consequences on fetal development, it should be avoided during pregnancy. Trastuzumab administration has been associated with an elevated incidence of oligohydramnios and poor neonatal outcomes, particularly when prescribed after the first trimester for repeated infusions, and therefore it is not recommended. Rituximab does not seem to be teratogenic, but a transient prolonged neutropenia in the newborns was reported, without major infectious consequences in most cases. Few data are available about other mAbs, and hence their use during pregnancy remains discouraged. 23954093 Analysis of Inpatient Use of Fresh Frozen Plasma and Other Therapies and Associated Outcomes in Patients with Major Bleeds from Vitamin K Antagonism. We conducted an observational study of outcomes and costs associated with fresh frozen plasma (FFP) use in patients receiving warfarin with intracerebral, gastrointestinal, or musculoskeletal bleeding. Patients who had at least 1 International Classification of Diseases, Ninth Revision code indicative of anticoagulation history, received ≥1 unit FFP, and had patient costs >$0 were identified from a database of >600 US hospitals. The main outcome was transfusion of additional blood products (eg, cryoprecipitate, red blood cells, or platelets) or vitamin K. Further outcomes included administration of other bleeding-related therapies (eg, recombinant activated factor VII, albumin, or crystalloids), incidence of fluid overload, days in the intensive care unit, discharge status, and total hospital costs. The most frequently administered products were vitamin K and red blood cells, given to 55.6% to 61.0% and 19.2% to 29.3% of patients, respectively. The number of FFP units transfused correlated highly with fluid overload (r > 0.91) and was associated with inpatient mortality, nonhome discharge, and intensive care unit admittance. For both inpatient mortality and nonhome discharge, the odds ratio was significant when ≥4 units FFP were transfused (P < 0.05). A dose of >2 units FFP was associated with an increased probability of an intensive care unit stay (P < 0.05). Total costs were greater among patients receiving >2 units FFP compared with patients who received 1 unit FFP (P < 0.001), with a substantial increase in costs incurred when ≥4 units FFP were transfused. In patients with warfarin-related bleeding, inpatient mortality, nonhome discharge, intensive care unit admission, and hospital costs were associated with the number of units of FFP transfused. 23855618 Mechanisms and Rescue Strategies of Calcineurin Inhibitor Mediated Tolerance Abrogation Induced by Anti-CD4 mAb Treatment. To ensure safety tolerance induction protocols are accompanied by conventional immunosuppressive drugs (IS). But IS such as calcineurin inhibitors (CNI), for example, cyclosporin A (CsA), can interfere with tolerance induction. We investigated the effect of an additional transient CsA treatment on anti-CD4mAb-induced tolerance induction upon rat kidney transplantation. Additional CsA treatment induced deteriorated graft function, resulting in chronic rejection characterized by glomerulosclerosis, interstitial fibrosis, tubular atrophy and vascular changes. Microarray analysis revealed enhanced intragraft expression of the B cell attracting chemokine CXCL13 early during CsA treatment. Increase in CXCL13 expression is accompanied by enhanced B cell infiltration with local and systemic IgG production and C3d deposition as early as 5 days upon CsA withdrawal. Adding different CNIs to cultures of primary mesangial cells isolated from glomeruli resulted in a concentration-dependent increase in CXCL13 transcription. CsA in synergy with TNF-α can enhance the B cell attracting and activating potential of mesangial cells. Transient B cell depletion or transfer of splenocytes from tolerant recipients 3 weeks after transplantation could rescue tolerance induction and did inhibit intragraft B cell accumulation, alloantibody production and ameliorate chronic rejection. 23860420 Carbon materials as new nanovehicles in hot-melt drug deposition. The application of commercially available carbon materials (nanotubes and porous carbons) for the preparation of drug delivery systems is studied. We used two types of carbon nanotubes (CNT) and two activated carbons as potential materials in so-called hot-melt drug deposition (HMDD). The materials were first studied using Raman spectroscopy. Paracetamol was chosen as a model drug. The performed thermal analysis, kinetics, and adsorption-desorption studies revealed that nanoaggregates are formed between carbon nanotubes. In contrast, in pores of activated carbon we do not observe this process and the drug adsorption phenomenon mechanism is simply the filling of small pores. The formation of nanoaggregates was confirmed by the results of GCMC (grand canonical Monte Carlo) simulations and the study of the surface area on nitrogen adsorption-desorption isotherms. The application of carbon nanotubes in HMDD offers the possibility of controlling the rate of drug delivery. Performed MTT tests of nanotubes and drug-loaded nanotubes show that the observed decrease in cell viability number is caused by the influence of the cytostatic properties of nanotubes-they inhibit the proliferation of cells. The carbon nanotubes studied in this paper are essentially nontoxic. 23601385 Assessing caffeine intake in the United Kingdom diet. Caffeine occurs naturally in the leaves and seeds of many plants and is artificially added to some beverages. Consumption of caffeine has been linked to both positive and adverse health outcomes. We incorporated estimates of caffeine content (mg/100g or ml) of foods and drinks, taken from the published literature, to provide a preliminary estimate of caffeine intake for the UK population, based on data collected in the National Diet and Nutrition Survey 2008-10. Among consumers mean total caffeine intakes of adult men 19+ y were significantly greater than intakes by boys 4-10y and 11-18y (p<0.05), with the same age-related differences seen for females. 4.1% of men 19+ y and 3.8% of women 19+ y had caffeine intakes in excess of 300mg/d. The addition of caffeine to UK food composition databases will allow more detailed study of the health effects of caffeine consumption. 23916924 Long Term Cardiovascular Risk in Women Prescribed Fertility Therapy. We investigated whether fertility therapy might contribute to subsequent cardiovascular disease. Fertility medications are used for one percent of births yet may also lead to endothelial injury with long-term adverse consequence for the mother. We performed a population-based cohort analysis of women who gave birth in Ontario, Canada between July 1, 1993 and March 31, 2010, distinguishing those who did and did not receive fertility therapy in the two years prior to delivery. Cox proportional models were derived to estimate hazard ratios (HR) with and without adjustment for baseline characteristics. The primary outcome was a composite cardiovascular endpoint of death, non-fatal coronary ischemia, stroke, transient ischemic attack, thromboembolism or heart failure. Among 1,186,753 women who delivered during the study period, 6,979 gave birth following fertility therapy. After 9.7 years of median follow-up, women who delivered following fertility therapy had fewer cardiovascular events than controls (103 vs. 117 events per 100,000 person-years), equivalent to an unadjusted HR 0.96 (95% confidence interval [CI], 0.72-1.29, p=0.79) and an adjusted HR 0.55 (95% CI, 0.41-0.74, p<0.0001). An apparent relative lower risk was observed across all age and income groups. Women who received fertility therapy also had lower risk-adjusted all-cause mortality, thromboembolic events, subsequent depression, alcoholism, and self-harm (p<0.01 for each). Successful fertility therapy was not associated with an increased risk of cardiovascular disease later in life. 23662794 Impact of non-cardiovascular surgery on reactive hyperaemia and arterial endothelial function. Vascular reactivity is a surrogate marker for atherosclerosis and is predictive of cardiovascular outcome. Non-cardiovascular surgery is associated with perioperative cardiovascular complications in high-risk patients. To evaluate the impact of non-cardiovascular surgery on reactive hyperaemia and arterial endothelial function and to investigate the relationships between endothelial dysfunction and invasive (laparotomy) or minimally invasive (laparoscopic) surgery, we prospectively evaluated 106 patients undergoing abdominal surgery under general anaesthesia (71 laparotomy, 35 laparoscopy). Measurements of blood pressure, heart rate and pain (on a visual analogue scale (VAS)) were undertaken. Brachial endothelium-dependent flow-mediated dilation (FMD), endothelium-independent dilation, nitroglycerin (NTG)-induced dilation and reactive hyperaemia were measured with high-resolution B-mode ultrasound on preoperative Day 1 (baseline), as well as 2 h and 1 and 7 days postoperatively. Blood pressure and heart rate were significantly higher 2 h postoperatively. Pain, as measured on the VAS, was higher (P < 0.01) and reactive hyperaemia and FMD were significantly lower (P < 0.001) at 2 h and 1 day postoperatively compared with values at baseline and on postoperative Day 7. By postoperative Day 7, FMD had recovered to baseline levels. Patients undergoing laparoscopic surgery had less FMD reduction on Days 1 and 7 (7.5 ± 1.5% and 7.9 ± 1.5%, respectively) compared with those undergoing laparotomy (6.4 ± 1.6% (P = 0.001) and 7.0 ± 1.6% (P = 0.006), respectively), consistent with potential cardiovascular benefit. Responses to NTG were stable throughout. Backward multivariate linear regression analysis indicated that FMD was independently related to age and VAS (model R = 0.486; F = 6.4; P < 0.001). Reactive hyperaemia and arterial endothelial function are significantly reduced in the early postoperative period, particularly after laparotomy compared with laparoscopy, which may be related to postoperative cardiovascular events. 23964415 Eyes-on training and radiological expertise: an examination of expertise development and its effects on visual working memory. Our aim was to examine the specificity of the effects of acquiring expertise on visual working memory (VWM) and the degree to which higher levels of experience within the domain of expertise are associated with more efficient use of VWM. Previous research is inconsistent on whether expertise effects are specific to the area of expertise or generalize to other tasks that also involve the same cognitive processes. It is also unclear whether more training and/or experience will lead to continued improvement on domain-relevant tasks or whether a plateau could be reached. In Experiment I, veterinary medicine students completed a one-shot visual change detection task. In Experiment 2, veterinarians completed a flicker change detection task. Both experiments involved stimuli specific to the domain of radiology and general stimuli. In Experiment I, veterinary medicine students who had completed an "eyes-on" radiological training demonstrated a domain-specific effect in which performance was better on the domain-specific stimuli than on the domain-general stimuli. In Experiment 2, veterinarians again showed a domain-specific effect, but performance was unrelated to the amount of experience veterinarians had accumulated. The effect of experience is domain specific and occurs during the first few years of training, after which a plateau is reached. VWM training in one domain may not lead to improved performance on other VWM tasks. In acquiring expertise, eyes-on training is important initially, but continued experience may not be associated with further improvements in the efficiency of VWM. 23493572 Hypothalamic Ceramide levels regulated by CPT1C mediate the orexigenic effect of Ghrelin. Recent data suggest that ghrelin exerts its orexigenic action through regulation of hypothalamic AMP-activated protein kinase pathway, leading to a decline in malonyl-CoA levels and desinhibition of carnitine palmitoyltransferase 1A (CPT1A), which increases mitochondrial fatty acid oxidation and ultimately enhances the expression of the orexigenic neuropeptides agouti-related protein (AgRP) and neuropeptide Y (NPY). However, it is unclear whether the brain-specific isoform CPT1C, which is located in the endoplasmic reticulum of neurons, may play a role in this action. Here, we demonstrate that the orexigenic action of ghrelin is totally blunted in CPT1C knockout (KO) mice, despite having the canonical ghrelin signaling pathway activated. We also demonstrate that ghrelin elicits a marked upregulation of hypothalamic C18:0 ceramide levels mediated by CPT1C. Notably, central inhibition of ceramide synthesis with myriocin negated the orexigenic action of ghrelin and normalized the levels of AgRP and NPY, as well as their key transcription factors phosphorylated cAMP-response element-binding protein and forkhead box O1. Finally, central treatment with ceramide induced food intake and orexigenic neuropeptides expression in CPT1C KO mice. Overall, these data indicate that, in addition to formerly reported mechanisms, ghrelin also induces food intake through regulation of hypothalamic CPT1C and ceramide metabolism, a finding of potential importance for the understanding and treatment of obesity. 23874743 Characterization of vascular disease risk in postmenopausal women and its association with cognitive performance. While global measures of cardiovascular (CV) risk are used to guide prevention and treatment decisions, these estimates fail to account for the considerable interindividual variability in pre-clinical risk status. This study investigated heterogeneity in CV risk factor profiles and its association with demographic, genetic, and cognitive variables. A latent profile analysis was applied to data from 727 recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Women were cognitively healthy, within three years of their last menstrual period, and free of current or past CV disease. Education level, apolipoprotein E ε4 allele (APOE4), ethnicity, and age were modeled as predictors of latent class membership. The association between class membership, characterizing CV risk profiles, and performance on five cognitive factors was examined. A supervised random forest algorithm with a 10-fold cross-validation estimator was used to test accuracy of CV risk classification. The best-fitting model generated two distinct phenotypic classes of CV risk 62% of women were "low-risk" and 38% "high-risk". Women classified as low-risk outperformed high-risk women on language and mental flexibility tasks (p = 0.008) and a global measure of cognition (p = 0.029). Women with a college degree or above were more likely to be in the low-risk class (OR = 1.595, p = 0.044). Older age and a Hispanic ethnicity increased the probability of being at high-risk (OR = 1.140, p = 0.002; OR = 2.622, p = 0.012; respectively). The prevalence rate of APOE-ε4 was higher in the high-risk class compared with rates in the low-risk class. Among recently menopausal women, significant heterogeneity in CV risk is associated with education level, age, ethnicity, and genetic indicators. The model-based latent classes were also associated with cognitive function. These differences may point to phenotypes for CV disease risk. Evaluating the evolution of phenotypes could in turn clarify preclinical disease, and screening and preventive strategies. ClinicalTrials.gov NCT00154180. 23871821 Getting to the guts of the matter: The status and potential of 'omics' research of parasitic protists of the human gastrointestinal system. Parasitic protists are a major cause of diarrhoeal illnesses in humans globally. Collectively, enteric pathogens exceed all other forms of infectious disease, in terms of their estimated global prevalence and socioeconomic impact. They have a disproportionately high impact on children in impoverished communities, leading to acute (diarrhoea, vomiting, dehydration and death) and chronic disease (malabsorption, malnutrition, physical and cognitive stunting and predisposition to chronic, non-communicable disease) consequences. However, historically, investment in research and disease control measures has been disproportionately poor, leading to their current classification as neglected pathogens. A sound understanding of their biology is essential in underpinning detection, treatment and control efforts. One major tool in rapidly improving our knowledge of these parasites is the use of biological systems, including 'omic' technologies. In recent years, these tools have shown significant success when applied to enteric protists. This review summarises much of this knowledge and highlights the significant remaining knowledge gaps. A major focus of the present review was to provide a perspective on a way forward to address these gaps using advanced biotechnologies. 23769819 Lung function after allogeneic hematopoietic stem cell transplantation in children: a longitudinal study in a population-based cohort. Reduction in pulmonary function (PF) has been reported in up to 85% of pediatric patients during the first year after hematopoietic stem cell transplantation (HSCT). Our understanding of the etiology for this decrease in lung function is, however, sparse. The aim of this study was to describe PF during follow-up in a population-based pediatric HSCT cohort and to investigate factors in the transplantation process associated with PF decline. A retrospective, population-based, single-center study of HSCT patients spanning 2 decades was performed. Longitudinal changes in PF over time and associations to transplantation-related factors were investigated using a mixed linear model. One hundred thirty patients were included in the longitudinal analysis and observed for a median (range) of 3.3 (.2 to 16.8) years, during which 1084 PF tests were performed. Sixty-two percent of the patients experienced a decline in lung function of more than 10% during the first 3 to 9 months after HSCT. The decline in forced expiratory volume in 1 second, forced expiratory volume in 1 second/forced vital capacity and diffusion capacity of the lung for carbon monoxide were strongly associated with acute graft-versus-host disease (GvHD). Other factors associated with PF decline were malignant diagnosis, busulfan-based conditioning, patient and donor age, female donor to male recipient, as well as chronic GvHD. Mild to moderate decline in PF is frequent and appears associated with acute GvHD and other parameters that are risk factors for chronic GvHD in children. This indicates that alloreactivity is central in pathogenesis of the decrease in PF that follows HSCT in children. 23788379 Dynamic control of dendrimer-fullerene association by axial coordination to the core. The effect of axial coordination of pyridine derivatives to the core porphyrin on the fullerene encapsulation of the 4th generation carbazole-phenylazomethine dendrimer (ZnPG2-2) was investigated. The axial coordination of large (bulky) pyridine derivatives affects the cavity in an allosteric manner, and the size-selectivity of the fullerene association could be controlled. 23871396 A case of CRB1-negative Coats-like retinitis pigmentosa. Retinitis pigmentosa is a heterogeneous group of ocular diseases that causes progressive degeneration of the photoreceptor cells mainly affecting the rods of the peripheral retina. The association between retinitis pigmentosa and exudative retinopathy was first described in 1956 and has been called "Coats-like retinitis pigmentosa." Mutations in the Crumbs homolog 1 (CRB1) gene have been reported as a risk factor for developing Coats-like changes in patients with autosomal recessive retinitis pigmentosa. We report the case of a 15-year-old girl affected by CRB1 gene-negative retinitis pigmentosa and Coats-like exudative vasculopathy who was successfully treated with laser photocoagulation. 23398239 Temporal effects of ethanol consumption on energy homeostasis, hepatic steatosis, and insulin sensitivity in mice. Alcoholic liver disease (ALD) progresses from steatosis to inflammation, fibrosis, and cirrhosis. Although ALD has been associated with insulin resistance, it is unclear whether insulin resistance coincides with the development of steatosis. We studied the temporal relationship of steatosis and glucose homeostasis in mice fed a Lieber-DeCarli liquid control or ethanol (EtOH) diet for 2, 4, or 8 weeks. We studied the effects of alcohol consumption on energy balance, body composition, and hepatic lipids. Glucose tolerance test was performed, and insulin sensitivity was evaluated with hyperinsulinemic-euglycemic clamp. EtOH-fed mice developed hepatic steatosis over time as compared with control-fed mice despite similar energy intake and expenditure, and gain in body weight and fat. EtOH-fed mice developed glucose intolerance as early as 2 weeks, while insulin resistance developed at 4 weeks. A hyperinsulinemic clamp study at 8 weeks revealed both hepatic and peripheral insulin resistance in EtOH-fed mice. Insulin resistance was associated with hepatic steatosis, increased ceramide levels, and Perilipin 2 expression. Chronic EtOH consumption leads to the development of hepatic steatosis, impaired glucose tolerance, and insulin resistance. These changes are independent of energy intake or expenditure, weight, whole body fat content, and inflammation. A better understanding of the processes linking EtOH-induced steatosis and abnormal glucose homeostasis may lead to novel therapies targeting the progression of ALD. 23936564 Immunological Profile of HTLV-1-Infected Patients Associated with Infectious or Autoimmune Dermatological Disorders. In the present study, the frequency, the activation and the cytokine and chemokine profile of HTLV-1 carriers with or without dermatological lesions were thoroughly described and compared. The results indicated that HTLV-1-infected patients with dermatological lesions have distinct frequency and activation status when compared to asymptomatic carriers. Alterations in the CD4(+)HLA-DR(+), CD8(+) T cell, macrophage-like and NKT subsets as well as in the serum chemokines CCL5, CXCL8, CXCL9 and CXCL10 were observed in the HTLV-1-infected group with skin lesions. Additionally, HTLV-1 carriers with dermatological skin lesions showed more frequently high proviral load as compared to asymptomatic carriers. The elevated proviral load in HTLV-1 patients with infectious skin lesions correlated significantly with TNF-α/IL-10 ratio, while the same significant correlation was found for the IL-12/IL-10 ratio and the high proviral load in HTLV-1-infected patients with autoimmune skin lesions. All in all, these results suggest a distinct and unique immunological profile in the peripheral blood of HTLV-1-infected patients with skin disorders, and the different nature of skin lesion observed in these patients may be an outcome of a distinct unbalance of the systemic inflammatory response upon HTLV-1 infection. 23475571 Segregated flux balance analysis constrained by population structure/function data: the case of PHA production by mixed microbial cultures. In this study we developed a segregated flux balance analysis (FBA) method to calculate metabolic flux distributions of the individual populations present in a mixed microbial culture (MMC). Population specific flux data constraints were derived from the raw data typically obtained by the fluorescence in situ hybridization (FISH) and microautoradiography (MAR)-FISH techniques. This method was applied to study the metabolic heterogeneity of a MMC that produces polyhydroxyalkanoates (PHA) from fermented sugar cane molasses. Three populations were identified by FISH, namely Paracoccus sp., Thauera sp., and Azoarcus sp. The segregated FBA method predicts a flux distribution for each of the identified populations. The method is shown to predict with high accuracy the average PHA storage flux and the respective monomeric composition for 16 independent experiments. Moreover, flux predictions by segregated FBA were slightly better than those obtained by nonsegregated FBA, and also highly concordant with metabolic flux analysis (MFA) estimated fluxes. The segregated FBA method can be of high value to assess metabolic heterogeneity in MMC systems and to derive more efficient eco-engineering strategies. For the case of PHA-producing MMC considered in this work, it becomes apparent that the PHA average monomeric composition might be controlled not only by the volatile fatty acids (VFA) feeding profile but also by the population composition present in the MMC. 23163429 A question of time: the land snail Murella muralis (Gastropoda: Pulmonata) reveals constraints on past ecological speciation. The lively debate about speciation currently focuses on the relative importance of factors driving population differentiation. While many studies are increasingly producing results on the importance of selection, little is known about the interaction between drift and selection. Moreover, there is still little knowledge on the spatial-temporal scales at which speciation occurs, that is, arrangement of habitat patches, abruptness of habitat transitions, climate and habitat changes interacting with selective forces. To investigate these questions, we quantified variation on a fine geographical scale analysing morphological (shell) and genetic data sets coupled with environmental data in the land snail Murella muralis, endemic to the Mediterranean island of Sicily. Analysis of a fragment of the mitochondrial DNA cytochrome oxidase I gene (COI) and eight nuclear microsatellite loci showed that genetic variation is highly structured at a very fine spatial scale by local palaeogeographical events and historical population dynamics. Molecular clock estimates, calibrated here specifically for Tyrrhenian land snails, provided a framework of palaeogeographical events responsible for the observed geographical variations and migration routes. Finally, we showed for the first time well-documented lines of evidence of selection in the past, which explains divergence of land snail shell shapes. We suggest that time and palaeogeographical history acted as constraints in the progress along the ecological speciation continuum. Our study shows that testing for correlation among palaeogeography, morphology and genetic data on a fine geographical scale provides information fundamental for a detailed understanding of ecological speciation processes. 23855010 Retaining ligaments of the face: review of anatomy and clinical applications. The retaining ligaments of the face are important in understanding concepts of facial aging and rejuvenation. They are located in constant anatomic locations where they separate facial spaces and compartments. Their superficial extensions form subcutaneous septa that separate facial fat compartments. Their main significance relates to their surgical release in order to achieve the desired aesthetic outcome. Furthermore, they have a sentinel role in their anatomic relationship to facial nerve branches. When performing facial aesthetic surgery, plastic surgeons should select a plane of dissection, release the appropriate ligaments depending on the desired aesthetic goals, and avoid nerve injury by using the ligaments as anatomic landmarks. Descriptions of the retaining ligaments are variable in the literature; due to different interpretations of anatomy, several classifications, locations, and nomenclature systems have been proposed. This article will review and clarify the anatomy of the retaining ligaments of the face, including the cheek, mandible, temporal, and periorbital areas. 23129252 Developmental disorders and altered gene expression in the tropical clawed frog (Silurana tropicalis) exposed to 17α-ethinylestradiol. Several endocrine-disrupting chemicals with estrogenic activity can affect sexual development and reproduction in aquatic wildlife. The occurrence of oocytes in the testis (testis-ova) is one reproductive disorder and can be used as a valid endpoint when studying disruptive effects of estrogenic chemicals. To elucidate the molecular basis of testis-ova induction, we conducted gene expression analysis in the gonads of Silurana tropicalis exposed to 0, 3, 10 and 30 ng l(-1) 17α-ethinylestradiol (EE2) from 2 days after fertilization to the juvenile stage (14 weeks after fertilization). The frequencies of testis-ova induction or male to female sex-reversal of the gonads increased in an EE2 dose-dependent manner. Microarray analysis showed that expressions of a large number of genes were significantly changed by EE2 exposure. Genes including egg envelope composition (zp4, zpax, zpc, zp3.2 and egg cortical granule lectin), 42S particle genes (42Sp50, 42Sp43 and 42Sp48) and regulation of female germ cells (figla) are associated with the testis-ova and sex-reversal situation in the gonads. Of those, expression of zpc and 42Sp50 genes is associated with testis-ova. Thus, we propose that these genes are useful biomarkers for toxicological research in amphibians developmentally exposed to estrogenic chemicals. Copyright © 2012 John Wiley & Sons, Ltd. 23820610 Alcohol-induced metabolomic differences in humans. Alcohol consumption is one of the world's major risk factors for disease development. But underlying mechanisms by which moderate-to-heavy alcohol intake causes damage are poorly understood and biomarkers are sub-optimal. Here, we investigated metabolite concentration differences in relation to alcohol intake in 2090 individuals of the KORA F4 and replicated results in 261 KORA F3 and up to 629 females of the TwinsUK adult bioresource. Using logistic regression analysis adjusted for age, body mass index, smoking, high-density lipoproteins and triglycerides, we identified 40/18 significant metabolites in males/females with P-values <3.8E-04 (Bonferroni corrected) that differed in concentrations between moderate-to-heavy drinkers (MHD) and light drinkers (LD) in the KORA F4 study. We further identified specific profiles of the 10/5 metabolites in males/females that clearly separated LD from MHD in the KORA F4 cohort. For those metabolites, the respective area under the receiver operating characteristic curves were 0.812/0.679, respectively, thus providing moderate-to-high sensitivity and specificity for the discrimination of LD to MHD. A number of alcohol-related metabolites could be replicated in the KORA F3 and TwinsUK studies. Our data suggests that metabolomic profiles based on diacylphosphatidylcholines, lysophosphatidylcholines, ether lipids and sphingolipids form a new class of biomarkers for excess alcohol intake and have potential for future epidemiological and clinical studies. 23279849 Morin inhibits STAT3 tyrosine 705 phosphorylation in tumor cells through activation of protein tyrosine phosphatase SHP1. The major goal of cancer drug discovery is to find an agent that is safe and affordable, yet effective against cancer. Here we show that morin (3,5,7,2',4'-pentahydroxyflavone) has potential against cancer cells through suppression of the signal transducer and activator of transcription 3 (STAT3) pathway, which is closely linked to the transformation, survival, proliferation, and metastasis of cancer. We found that morin completely suppressed inducible and constitutively activated STAT3 and blocked the nuclear translocation of STAT3 and its DNA binding in multiple myeloma and head and neck squamous carcinoma cells. Morin inhibited activated Src, JAK-1, and JAK-2, all of which are linked to STAT3 activation, while up-regulating a protein inhibitor of activated STAT3, PIAS3. Pervanadate reversed the effects of morin on STAT3 phosphorylation, indicating the role of a protein tyrosine phosphatase. Furthermore, morin induced SHP1 expression at both the mRNA and protein levels, and silencing of SHP1 abrogated the effect of morin on STAT3 phosphorylation, indicating that morin mediates its effects on STAT3 through SHP1. Suppression of STAT3 correlated with the down-regulation of various gene products linked to tumor survival, proliferation, and angiogenesis and led to sensitization of tumor cells to thalidomide and bortezomib. Comparing the activities of morin with those of four structurally related flavonols demonstrated the importance of hydroxyl groups in the B ring in inhibiting STAT3 activation. These findings suggest that morin suppresses the STAT3 pathway, leading to the down-regulation of STAT3-dependent gene expression and chemosensitization of tumor cells. 23832258 Quantitative measurement of m-RNA levels to assess expression of cyclooxygenase-II, inducible nitric oxide synthase and 12-lipoxygenase genes in middle ear cholesteatoma. To assess expression of three main inflammatory genes, COX-II, ALOX-12 and i-NOS, quantitatively at transcriptional level in cholesteatoma matrix tissue. Ten patients who have chronic otitis media with primary acquired cholesteatoma were included in this study. Tissue samples obtained from cholesteatoma matrix and external ear canal skin (control tissue). Expression of the targeted genes (COX-II, i-NOS and LOX-12) was assessed using real-time quantitative polymerase chain reaction (RT-PCR) technique. The amount of COX2 mRNA was significantly higher in cholesteatoma matrix at transcriptional level (p = 0.038). There was no statistically significant difference regarding expression of iNOS and LOX12 mRNA levels (p > 0.05). There is a significant overexpression of the mRNA of COX-II in cholesteatoma matrix, which indicates a difference between the normal skin and cholesteatoma matrix at molecular level. COX-II gene overexpression seems to be associated with pathogenesis of cholesteatoma. This molecular change is similar to the molecular abnormalities observed in some benign and malignant neoplasms. Invasive and locally destructive nature of cholesteatoma may be due to COX-II overexpression. Absence of an increase in the gene expressions of i-NOS and LOX-12 in cholesteatoma matrix suggests that these mediators may not be related with the pathogenesis and evolution of cholesteatoma. 23689011 Swine, human or avian influenza viruses differentially activates porcine dendritic cells cytokine profile. Swine influenza virus (SwIV) is considered a zoonosis and the fact that swine may act as an intermediate reservoir for avian influenza virus, potentially infectious for humans, highlights its relevance and the need to understand the interaction of different influenza viruses with the porcine immune system. Thus, in vitro porcine bone marrow-derived dendritic cell (poBMDCs) were infected with a circulating SwIV A/Swine/Spain/SF32071/2007(H3N2), 2009 human pandemic influenza virus A/Catalonia/63/2009(H1N1), low pathogenic avian influenza virus (LPAIV) A/Anas plathyrhynchos/Spain/1877/2009(aH7N2) or high pathogenic avian influenza virus (HPAIV) A/Chicken/Italy/5093/1999(aH7N1). Swine influenza virus H3N2 infection induced an increase of SLA-I and CD80/86 at 16 and 24h post infection (hpi), whereas the other viruses did not. All viruses induced gene expression of NF-κB, TGF-β, IFN-β and IL-10 at the mRNA level in swine poBMDCs to different extents and in a time-dependent manner. All viruses induced the secretion of IL-12 mostly at 24hpi whereas IL-18 was detected at all tested times. Only swH3N2 induced IFN-α in a time-dependent manner. Swine H3N2, aH7N2 and aH7N1 induced secretion of TNF-α also in a time-dependent manner. Inhibition of NF-κB resulted in a decrease of IFN-α and IL-12 secretion by swH3N2-infected poBMDC at 24hpi, suggesting a role of this transcription factor in the synthesis of these cytokines. Altogether, these data might help in understanding the relationship between influenza viruses and porcine dendritic cells in the innate immune response in swine controlled through soluble mediators and transcription factors. 23892246 Exploitation of genetic interaction network topology for the prediction of epistatic behavior. Genetic interaction (GI) detection impacts the understanding of human disease and the ability to design personalized treatment. The mapping of every GI in most organisms is far from complete due to the combinatorial amount of gene deletions and knockdowns required. Computational techniques to predict new interactions based only on network topology have been developed in network science but never applied to GI networks. We show that topological prediction of GIs is possible with high precision and propose a graph dissimilarity index that is able to provide robust prediction in both dense and sparse networks. Computational prediction of GIs is a strong tool to aid high-throughput GI determination. The dissimilarity index we propose in this article is able to attain precise predictions that reduce the universe of candidate GIs to test in the lab. 23955712 Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB1 receptors (CB1Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB1R signaling in beta cells, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB1R-deficient (Cnr1(-/-)) or Nlrp3(-/-) mice, with the endocannabinoid anandamide. Peripheral CB1R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB1R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB1R as a therapeutic target in T2DM. 23773394 Dosimetric impact of the interplay effect during stereotactic lung radiation therapy delivery using flattening filter-free beams and volumetric modulated arc therapy. We investigated the dosimetric impact of the interplay effect during RapidArc stereotactic body radiation therapy for lung tumors using flattening filter-free (FFF) beams with different dose rates. Seven tumors with motion ≤20 mm, treated with 10-MV FFF RapidArc, were analyzed. A programmable phantom with sinusoidal longitudinal motion (30-mm diameter "tumor" insert; period = 5 s; individualized amplitude from planning 4-dimensional computed tomography) was used for dynamic dose measurements. Measurements were made with GafChromic EBT III films. Plans delivered the prescribed dose to 95% of the planning target volume, created by a 5-mm expansion of the internal target volume. They comprised 2 arcs and maximum dose rates of 400 and 2400 MU/min. For 2400 MU/min plans, measurements were repeated at 3 different initial breathing phases to model interplay over 2 to 3 fractions. For 3 cases, 2 extra plans were created using 1 full rotational arc (with contralateral lung avoidance sector) and 1 partial arc of 224° to 244°. Dynamic and convolved static measurements were compared by use of gamma analysis of 3% dose difference and 1 mm distance-to-agreement. For 2-arc 2400 MU/min plans, maximum dose deviation of 9.4% was found in a single arc; 7.4% for 2 arcs (single fraction) and <5% and 3% when measurements made at 2 and 3 different initial breathing phases were combined, simulating 2 or 3 fractions. For all 7 cases, >99% of the area within the region of interest passed the gamma criteria when all 3 measurements with different initial phases were combined. Single-fraction single-arc plans showed higher dose deviations, which diminished when dose distributions were summed over 2 fractions. All 400 MU/min plans showed good agreement in a single fraction measurement. Under phantom conditions, single-arc and single-fraction 2400 MU/min FFF RapidArc lung stereotactic body radiation therapy is susceptible to interplay. Two arcs and ≥2 fractions reduced the effect to a level that appeared unlikely to be clinically significant. 23465613 Chemical ligation of oligodeoxynucleotides by X-irradiation and its application to regulation of G-quadruplex formation. We demonstrated radiolytic ligation of oligodeoxynucleotides (ODNs) possessing disulfide bond and its application to regulation of DNA quadruplex formation. G-rich hexamer ODNs had poor ability to form quadruplex, while X-irradiation of the ODNs induced interstrand exchange reaction at disulfide bond to form ligated 12 mer ODNs, leading to the ready formation of quadruplex due to the entropic effect. Since complexation of the ligated ODNs with hemin in the presence of K(+) showed strong soret band absorption and also catalyzed the H(2)O(2)-mediated oxidation of luminol, it appears that the quadruplex formed from ligated ODNs showed a function similar to native DNA quadruplex. 23918285 Is the short messaging service feasible to improve adherence to tuberculosis care? A cross-sectional study. The short messaging service (SMS) is supposed to improve adherence of TB patients to regular treatment. A cross-sectional study using survey questionnaires and in-depth interviews was performed with pulmonary TB patients to identify the feasibility of SMS reminders and determinants of mobile phone utilization. The rates of mobile ownership and messages usage were 91.1% and 80.4% respectively, and 81% held favorable opinion on SMS reminders. Gender, age, education level and income profile were likely to be influencing factors. The SMS reminder system was feasible to initiate given high access to mobile phones and positive views. Features of service users should be considered when implementing SMS interventions. 23639198 Effects of Trypanosoma brucei infection and diminazene aceturate therapy on testicular morphology and function of Nigerian local dogs. The effects of Trypanosoma brucei infection on testicular morphology and function and the changes associated with treatment of infected dogs with diminazene aceturate were studied using fifteen Nigerian adult male dogs. The dogs were randomly assigned into three groups A, B and C consisting of five dogs each. Groups A and B were infected with 1×10(6) trypanosomes and group C was the uninfected control. Following infection, parasitaemia levels were monitored daily whereas the rectal temperature, body weight, packed cell volume, scrotal circumference and serum testosterone levels were monitored weekly. At parasitaemia peak, dogs in group A were orchidectomised while dogs in group B were treated with 7.0mg/kg body weight of diminazene aceturate (DA). Dogs in groups B and C were later orchidectomised on day 73 of the experiment. The harvested testes and epididymides were weighed and the epididymal sperm reserves of all the dogs determined. Also the sperm quality (mass activity, sperm motility and sperm morphology) were determined. The testes were sectioned after processing and studied histomorphologically. Acute trypanosomosis was observed following infection. The low serum testosterone levels observed from day 14 post infection (pi) gradually improved following treatment. Testicular weight, epididymal weight and sperm quality were significantly low (p<0.05) in the infected dogs when compared to the control group but gradually improved following treatment. Histomorphological studies revealed testicular degeneration characterized by depopulation of seminiferous tubules and depletion of spermatogenic cells in dogs of group A whereas the tissue sections of the testes of dogs in group B were similar to those of the control group. It was therefore concluded that infection of dogs with T. brucei adversely affected testicular morphology and function. Treatment with diminazene aceturate reversed the reproductive abnormalities caused by the parasite. 23411309 In vitro antioxidant properties of crude extracts and compounds from brown algae. Research on the bioactives from seaweeds has increased in recent years. Antioxidant activity is one of the most studied, due to the interest of these compounds both as preservatives and protectors against oxidation in food and cosmetics and also due to their health implications, mainly in relation to their potential as functional ingredients. Brown algae present higher antioxidant potential in comparison with red and green families and contain compounds not found in terrestrial sources. In vitro antioxidant chemical methods, used as a first approach to evaluate potential agents to protect from lipid oxidation in foods, confirmed that the brown algae crude extracts, fractions and pure components are comparatively similar or superior to synthetic antioxidants. Particular emphasis on the fucoidan and phlorotannin polymeric fractions is given, considering variations associated with the species, collection area, season, and extraction and purification technologies. 23454002 High rates of pregnancy loss by subordinates leads to high reproductive skew in wild golden lion tamarins (Leontopithecus rosalia). Across taxa, cooperative breeding has been associated with high reproductive skew. Cooperatively breeding golden lion tamarins (Leontopithecus rosalia) were long thought to have a monogynous mating system in which reproduction was limited to a single dominant female. Subordinates with few reproductive opportunities delayed dispersal and remained in the natal group to provide alloparental care to siblings, thus allowing dominant reproductive females to meet the energetic needs associated with high rates of reproduction and successful infant rearing. The goal of this study was to re-assess monogyny in wild golden lion tamarin groups based upon pregnancy diagnoses that used non-invasive enzyme immunoassay for progesterone and cortisol, combined with weekly data on individual weight gain, bi-annual physical examinations noting pregnancy and lactation status and daily behavioral observations. We established quantitative and qualitative criteria to detect and determine the timing of pregnancies that did not result in the birth of infants. Pregnancy polygyny occurred in 83% of golden lion tamarin groups studied. The loss of 64% of subordinate pregnancies compared to only 15% by dominant females limited reproductive success mainly to dominant females, thus maintaining high reproductive skew in female golden lion tamarins. Pregnancy loss by subordinate adults did not appear to result from dominant interference in subordinate hormonal mechanisms, but more likely resulted from subordinate abandonment of newborn infants to mitigate dominant aggression. 23612745 Occurrence and significance of odontoid lateral mass interspace asymmetry in trauma patients. The odontoid lateral mass interspace (OLMI) is the space between the lateral aspect of the dens axis and the medial circumference of the massa lateralis atlantis. The position of OLMI asymmetry as a normal variant or pathologic finding is an area of debate and clinical interest in trauma patients. We designed this prospective study to lay a framework for proposing strategies for the appropriate use of OLMI. A total of 301 adult patients admitted for trauma were included. Computed tomography (CT) and magnetic resonance imaging (MRI) of the cervical spine were performed and examined for the presence OLMI asymmetry and bony/ligamentous lesions of the occipitoatlantoaxial complex. Head rotation is linked to the occurrence of OLMI asymmetry. Reliable OLMI asymmetry evaluation is limited by observer agreement under a threshold value of 1.0 mm. In all, 86 patients (28.6 %) were found to have OLMI asymmetry on CT after trauma. Among these patients, 17.4 % had a bony/ligamentous lesion of the occipitoatlantoaxial complex. Among the patients without OLMI asymmetry, 8.8 % were found to have such lesions. OLMI asymmetry should only be investigated by CT scans of the head in optimal position and with the threshold value of 1.0 mm. OLMI asymmetry should not be used alone as a sign of a cervical spine lesion. MRI should be performed if: (1) the physician has a high degree of suspicion of a cervical spine lesion; (2) OLMI asymmetry was demonstrated on a technically adequate CT scan; (3) clinical symptoms persist in patients with OLMI asymmetry when no acute MRI was performed. 23535235 Fabrication and characterization of monodisperse PLGA-alginate core-shell microspheres with monodisperse size and homogeneous shells for controlled drug release. Monodisperse PLGA-alginate core-shell microspheres with controlled size and homogeneous shells were first fabricated using capillary microfluidic devices for the purpose of controlling drug release kinetics. Sizes of PLGA cores were readily controlled by the geometries of microfluidic devices and the fluid flow rates. PLGA microspheres with sizes ranging from 15 to 50μm were fabricated to investigate the influence of the core size on the release kinetics. Rifampicin was loaded into both monodisperse PLGA microspheres and PLGA-alginate core-shell microspheres as a model drug for the release kinetics studies. The in vitro release of rifampicin showed that the PLGA core of all sizes exhibited sigmoid release patterns, although smaller PLGA cores had a higher release rate and a shorter lag phase. The shell could modulate the drug release kinetics as a buffer layer and a near-zero-order release pattern was observed when the drug release rate of the PLGA core was high enough. The biocompatibility of PLGA-alginate core-shell microspheres was assessed by MTT assay on L929 mouse fibroblasts cell line and no obvious cytotoxicity was found. This technique provides a convenient method to control the drug release kinetics of the PLGA microsphere by delicately controlling the microstructures. The obtained monodisperse PLGA-alginate core-shell microspheres with monodisperse size and homogeneous shells could be a promising device for controlled drug release. 23282091 Treatment and prevention of various therapeutic conditions using OX receptor antagonistic activity (WO2012081692). Application WO2012081692 from Taisho Pharmaceutical Co. Ltd. claims pyrazole-based antagonists of the orexin-1 and orexin-2 receptors. Utility in a number of therapeutic areas is claimed, including the treatment of sleep disorders; the most likely use of the claimed compounds. Data from in vitro functional assays are presented, with the claimed compounds typically being dual orexin receptor antagonists (DORAs) or having moderate selectivity for orexin-1. Structurally, the claimed compounds represent a variation on established DORA SAR themes and translate features of clinical compounds into a pyrazole-based scaffold. Example 52, the most potent molecule in the application, has similar molecular weight and lipophilicity to suvorexant, the most advanced DORA, with broadly comparable potency in functional assays. 23758330 Everolimus leads to a lower risk of BKV viremia than mycophenolic acid in de novo renal transplantation patients: a single-center experience. There are limited published data concerning the effects of different immunosuppressive regimens on the development of polyomavirus (BKV) viremia. We examined the risk of developing BKV viremia in kidney transplant recipients receiving everolimus (EVR) or mycophenolic acid (MPA) as maintenance therapy. We observationally analyzed 296 patients who underwent renal transplantation at our center between 2005 and 2010: 58 were treated with EVR and low-dose cyclosporine (LD-CyA) (group 1) and 238 with MPA and standard-dose CyA (group 2). All of the patients received induction therapy with basiliximab and maintenance steroids. BKV viremia (a whole-blood viral load of >850 copies/mL) was measured by means of real-time polymerase chain reaction at least once a month during a 12-month follow-up period. BKV viremia was detected in 57 patients (19%), five (9%) in group 1 and 52 (22%) in group 2. Kaplan-Meier analyses showed that freedom from BKV viremia was significantly more frequent in group 1. The mean time of onset of BKV viremia was about four months after transplantation in both groups. The median viral load was greater in group 2 (12.5 ± 6.1 vs. 2.5 ± 1.8 Ã— 10(4)  copies/mL; p = 0.01). After the onset of BKV viremia, graft function significantly declined in group 2: 11 patients developed polyomavirus-associated nephropathy (PVAN) and four presumptive PVAN; nine experienced an acute rejection after the discontinuation of MPA, and 11 (21%) lost their graft. There was no graft loss in group 1. These findings suggest that in comparison with MPA and Cya, an EVR and LD-CyA regimen lowers the risk of BKV viremia after kidney transplantation and favorably alters outcomes. 23588003 Molecular cloning and immunogenicity evaluation of rotavirus structural proteins as candidate vaccine. The middle capsid protein of rotavirus, VP6, constitutes approximately 51% of the virion by weight. The high degree of identity (>87-99%) in the primary amino acid sequences of VP6 proteins from mammalian rotaviruses suggests VP6-based vaccines could potentially provide heterotypic protection. For this reason, significant effort has been directed toward producing recombinant rotavirus VP6 vaccines. We have cloned and expressed 155bp of the VP6 most frequent in Egyptian rotavirus sewage isolates, encoding the VP6 protein in the pET30b vector having an apparent molecular mass of 12.5kDa. The recombinant VP6 expressed by the transformants was detected by SDS-PAGE analysis. Rabbits immunized with the recombinant rotavirus expressed VP6 elicited VP6-specific IgG antibodies that provided significant reductions in the infectious units of the Egyptian rotavirus sewage isolate and human reference rotavirus Wa strain in vitro assay. 23787809 Enhanced mechanical strength and electrical conductivity of carbon-nanotube/TiC hybrid fibers. We report the synthesis of carbon nanotube/TiC hybrid fibers using a polymer-assisted chemical solution approach. Ti metal ions are bound to aqueous polyethyleneimine (PEI) to form precursor solution. Amphiphilic PEI with Ti easily permeates the CNT fibers. Upon annealing in a controlled atmosphere, a homogeneous TiC network is formed in the CNT fibers. The obtained CNT/TiC hybrid fibers show prominent enhancement in mechanical strength and electrical conductivity. The tensile strength and conductivity of CNT/TiC fibers can be improved to 0.67 GPa and 1650 S cm(-1) at room temperature, respectively. More importantly, a tensile modulus as high as 420 GPa has been achieved for the CNT/TiC fibers. Analysis shows that the cross-linking matrix of hard TiC plays a significant role in the improvement of mechanical strength. Furthermore, the electrons are transported in the CNT/TiC fiber by a three dimensional hopping mechanism. 23504510 Testicular function and fertility in men with Klinefelter syndrome: a review. Klinefelter syndrome, 47,XXY (KS), is the most frequent sex chromosome aberration in males, affecting 1 in 660 newborn boys. The syndrome is characterized by testicular destruction with extensive fibrosis and hyalinization of the seminiferous tubules resulting in small testes, hypergonadotropic hypogonadism, and azoospermia in the majority of cases. Until recently, infertility was considered an untreatable condition in KS. However, with the development of new advanced assisted reproductive techniques such as testicular sperm extraction (TESE) combined with ICSI it seems that KS patients should no longer be labelled as infertile. Especially, microdissection (micro)-TESE has proved to be an advantageous procedure for the identification of testicular spermatozoa in KS. The aim of this review was to describe current knowledge on the testicular changes occurring in KS, the associated changes in reproductive hormones and spermatogenesis, and the existing possibilities of biological fatherhood in 47,XXY patients. 23927993 t(11;14) multiple myeloma: A subtype associated with distinct immunological features, immunophenotypic characteristics but divergent outcome. t(11;14)(q13;q32) is the most common chromosome translocation in multiple myeloma (MM), but a consensus of clinicopathological features and impact on survival is yet to be reached. We analyzed a cohort of 350 patients with various plasma cell malignancies, including newly diagnosed MM (NDMM, n=253), relapsed/refractory MM (RRMM, n=77), as well as primary and secondary plasma cell leukemia (PCL, n=10 and n=10, respectively). Results: A remarkably higher frequency of t(11;14) was observed in the PCL than in the NDMM. A high incidence of t(11;14) was detected in the IgD, IgM, and nonsecretory MM. The t(11;14) MM group was associated with a significantly higher positive rate of B-lineage associated antigens CD20 and CD79a as well as the lack of CD56 expression. t(11;14) was less likely to be accompanied by 13q14 deletion than 13q14 deletion frequency in non-t(11;14) population (p=0.026), and fewer patients displaying t(11;14) were identified as belonging to the high-risk cytogenetic group due to the extremely low incidence of t(4;14) and t(14;16). As a whole, patients exhibiting t(11;14) had a comparable outcome with the control cohort in NDMM, but CD20 was able to identify two subsets of the disease with dissimilar outcomes. Among patients receiving bortezomib-based treatment, patients harboring t(11;14) without CD20 expression had a significantly shortened PFS (11.0 versus 43.0 months, p=0.005) and OS (16.5 versus 54.0 months, p=0.016) compared with patients displaying t(11;14) with CD20. Our findings suggest that although the t(11;14) plasma cell disorder displayed distinct biological, clinical and laboratory features, it was a heterogeneous disease with divergent outcome. 23250712 Potential factors correlating to the PMDA's decision to waive Japanese Phase 2 and 3 studies for oncology drugs New Drug Application in Japan. Current status of oncology drugs approved in Japan without supporting Japanese Phase 2 and 3 clinical trial (J-P2/3) data and potential factors correlating to the decision of Japanese health agency Pharmaceuticals and Medical Devices Agency (PMDA) to waive J-P2/3 data were investigated. Approximately 15 % of 61 investigated recently-approved oncology drugs were granted a J-P2/3 waiver. Drugs that were designated as Fast Track in the United States tended to be granted a J-P2/3 waiver. The orphan drug designation in Japan was also suggested to be correlated with the decision of J-P2/3 waiver, even though the trend was not significant. Specific factors related to the clinical importance, such as the designation of US Fast Track status, may have a correlation with the likelihood of J-P2/3 waiver, suggesting that the clinical importance of the drug is common in both countries. If the key criteria used to determine the waiving of Japanese clinical trial data were clearly disclosed by the regulatory agency, the development of some clinically important oncology drugs could be further expedited. 23936132 Oxidized Phospholipids Induce Ceramide Accumulation in RAW 264.7 Macrophages: Role of Ceramide Synthases. Oxidized phospholipids (OxPLs), including 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) and 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphocholine (POVPC) are among several biologically active derivatives that are generated during oxidation of low-density lipoproteins (LDLs). These OxPLs are factors contributing to pro-atherogenic effects of oxidized LDLs (OxLDLs), including inflammation, proliferation and death of vascular cells. OxLDL also elicits formation of the lipid messenger ceramide (Cer) which plays a pivotal role in apoptotic signaling pathways. Here we report that both PGPC and POVPC are cytotoxic to cultured macrophages and induce apoptosis in these cells which is associated with increased cellular ceramide levels after several hours. In addition, exposure of RAW 264.7 cells to POVPC and PGPC under the same conditions resulted in a significant increase in ceramide synthase activity, whereas, acid or neutral sphingomyelinase activities were not affected. PGPC is not only more toxic than POVPC, but also a more potent inducer of ceramide formation by activating a limited subset of CerS isoforms. The stimulated CerS activities are in line with the C16-, C22-, and C24:0-Cer species that are generated under the influence of the OxPL. Fumonisin B1, a specific inhibitor of CerS, suppressed OxPL-induced ceramide generation, demonstrating that OxPL-induced CerS activity in macrophages is responsible for the accumulation of ceramide. OxLDL elicits the same cellular ceramide and CerS effects. Thus, it is concluded that PGPC and POVPC are active components that contribute to the capacity of this lipoprotein to elevate ceramide levels in macrophages. 23911278 Brainstem arteriovenous malformation presenting with dyspraxic handwriting in a young girl. We report the case of a 11-year-old girl who developed an isolated hand-writing disorder with dysgraphia at the beginning of the school year in the sixth grade. A brain magnetic resonance angiography showed a round arteriovenous malformation sited in the left side of the midbrain extending to the ipsilateral medio-basal thalamus. Child neurologists should never neglect a thorough neurological evaluation in case of isolated worsening of handwriting, to rule out possible underlying organic causes. 23703796 MicroRNAs support the monophyly of enteropneust hemichordates. Understanding the evolutionary history of deuterostomes requires elucidating the phylogenetic interrelationships amongst the constituent taxa. Although the monophyly and interrelationships among the three principal groups-the chordates, the echinoderms, and the hemichordates-are well established, as are the internal relationships among the echinoderm and chordate taxa, the interrelationships among the principal groups of hemichordates-the harrimaniid enteropneusts, the ptychoderid enteropneusts, and the pterobranchs-remain unresolved. Depending on the study some find enteropneusts paraphyletic with pterobranchs (e.g., Cephalodiscus) more closely related to the harrimaniid enteropneusts (e.g., Saccoglossus) than either are to the ptychoderid enteropneusts (e.g., Ptychodera), whereas other studies support a monophyletic Enteropneusta. To try and resolve between these two competing hypotheses, we turned to microRNAs, small ∼22 nt non-coding RNA genes that have been shown to shed insight into particularly difficult phylogenetic questions. Using deep sequencing we characterized the small RNA repertoires of two hemichordate species, Cephalodiscus hodgsoni and Ptychodera flava, and the crinoid echinoderm Antedon mediterranea, and combined our results with the described complements of the hemichordate Saccoglossus kowalevskii, the sea urchin Strongylocentrotus purpuratus, and the starfish Patiria miniata. Our data unambiguously support the monophyly of Enteropneusts as S. kowalevskii shares 12 miRNA sequences with P. flava that are not present in the C. hodgsoni or A. mediterranea libraries, and have never been reported from another metazoan taxon. Thus, these data resolve the phylogenetic position of pterobranchs, ultimately allowing for a better understanding of body plan evolution throughout the deuterostomes. J. Exp. Zool. (Mol. Dev. Evol.) 320B: 368-374, 2013. © 2013 Wiley Periodicals, Inc. 23744591 Parathyroidectomy eliminates arrhythmic risk in primary hyperparathyroidism, as evaluated by exercise test. To investigate whether parathyroidectomy (PTx) reverses risk factors for arrhythmias related to the QT dynamic changes evaluated during bicycle ergometry exercise test (ET). Twenty-four postmenopausal women with primary hyperparathyroidism (PHPT) (mean age 60.08.4 years) and 30 sex- and age-matched controls underwent ET, echocardiography, and biochemical evaluation. The following stages were considered during ET: rest, peak exercise, and recovery. The patients were randomized to two groups: 12 underwent PTx (group A) and 12 were followed-up conservatively (group B). After 6 months, the patients were studied again. Groups A and B showed no differences in mean baseline biochemical values, echocardiographic parameters, and QTC interval. PHPT patients showed an increased occurrence of ventricular premature beats (VPBS) during ET compared with controls (37.0 vs 6.6%, P=0.03). Serum calcium level was a predictor of VPBS (P=0.05). Mean value of QTC was in the normal range at baseline (Group A: 401±16.9; group B: 402.25±13.5 ms) but significantly lower than controls (417.8±25.1 ms, P<0.01). A negative correlation was found between QTc and calcium values (P=0.03). Physiological reduction of QTc interval from rest to peak exercise was not observed in PHPT patients before surgery. After PTx, group A had a significant reduction in VPBs compared with baseline (at baseline, 5 of 12 vs none of 12 patients after PTx, P=0.03) and a restored normal QT adaptation during ET. Group B showed no significant changes after a 6-month period. PTx reduces the occurrence of VPBs and restored the QTc adaptation during ET. 23794105 Drug library screening against metronidazole-sensitive and metronidazole-resistant Trichomonas vaginalis isolates. Metronidazole and tinidazole are effective treatments for most patients with trichomoniasis but not for individuals who are infected with very resistant strains of Trichomonas vaginalis or persons with hypersensitivity to the 5-nitroimidazole drugs. Thus, there is a need for additional oral therapies to treat trichomoniasis. We screened the US Drug Collection Library against metronidazole-susceptible and resistant strains of T vaginalis. Activity was measured by incubating parasites and drugs for 48 h in the presence of tritiated thymidine. Growth inhibition was determined by the reduction of incorporated radioactivity by compounds at 20 μM in comparison to media control. Drugs that showed good initial activity were further tested to calculate IC50 values. Drugs with the most promise were tested together with metronidazole to see if there was any combinatorial effect. Of the 1040 drugs in the library, 83 (8%) reduced growth of a metronidazole-susceptible T vaginalis strain by at least 20%. Of these, IC50 values were calculated for 27 compounds and 8 drugs were evaluated in combination with metronidazole. Disulfiram and nithiamide were non-5-nitroimidazole drugs that showed the best activity against parasites when used alone. Albendazole and coenzyme B12 were the most promising compounds to boost the efficacy of metronidazole. No one drug was as effective as any of the 5-nitroimidazole compounds. However, disulfiram and nithiamide may be useful to treat individuals with hypersensitivity to 5-nitroimidazole drugs and albendazole and coenzyme B12 may be helpful in combination with metronidazole or tinidazole for treatment of persons with highly resistant T vaginalis infections. 23886743 Intramedullary Spinal Cord Metastases: Visibility on PET and Correlation with MRI Features. BACKGROUND AND PURPOSE:Studies systematically evaluating the detection of intramedullary spinal cord metastasis with PET are lacking. Our purpose was to evaluate the visibility of intramedullary spinal cord metastasis on PET in a single institutional series and to correlate PET and MR imaging features.MATERIALS AND METHODS:Patients were included if pretreatment MR imaging identifying an intramedullary spinal cord metastasis and an [(18)F] FDG-PET examination near the time of MR imaging were available. PET examinations were retrospectively reviewed, with reviewers blinded and then unblinded to the PET report and MR imaging findings. PET intramedullary spinal cord metastasis features were compared with and correlated with previously analyzed MR imaging lesion characteristics. Original clinical PET reports were reviewed.RESULTS:The final study sample was 10 PET examinations in 10 patients with 13 intramedullary spinal cord metastases. In 7 (70%) patients, retrospective blinded review demonstrated convincing evidence of 10 (77%) intramedullary spinal cord metastases. Three MR imaging features correlated with intramedullary spinal cord metastases being visible on PET compared with those nonvisible, respectively: larger lesion enhancement size: mean size: 32.1 mm versus 6.0 mm (P = .038); larger longitudinal extent of T2 signal abnormality: mean 5.6 versus 1.0 segments (P = .0081); and larger ratio of extent of T2 signal abnormality to contrast enhancement: 3.8 versus 1.0 (P = .0069). Intramedullary spinal cord metastasis was confidently reported clinically in 2 (20%) patients, accounting for 5 (38%) intramedullary spinal cord metastases.CONCLUSIONS:Most intramedullary spinal cord metastases can be detected on PET when performed near the time of pretreatment MR imaging. However, intramedullary spinal cord metastases may not be clinically reported on PET. Larger lesions with more edema are more likely to be visible. The spinal cord should be specifically and carefully assessed on PET for evidence of intramedullary spinal cord metastases to provide timely diagnosis. 23827799 Detectability of simulated pulmonary nodules on chest radiographs: Comparison between irradiation side sampling indirect flat-panel detector and computed radiography. To compare the detectability of simulated pulmonary nodules on chest radiographs between an irradiation side sampling indirect flat-panel detector (ISS-FPD) and computed radiography (CR). This study was an observer performance study. Simulated pulmonary nodules of 8mm in diameter were superimposed on an anthropomorphic chest phantom. Chest radiographs were acquired under 2 exposure levels (4 and 3.2mAs) with the ISS-FPD and the CR. Six thoracic radiologists evaluated all 40 images (10 patterns×2 different exposure doses×2 different systems) for the presence or absence of a lesion over each of 12 defined areas on a 3-megapixel monochrome liquid-crystal display. Receiver operating characteristic (ROC) curves were obtained for observation in predefined 480 areas. A jackknife method was used for statistical analysis. Differences with a P value of <0.05 were considered significant. The analysis of the observer detection of simulated pulmonary nodules showed larger areas under the ROC curve (AUC) by the ISS-FPD than by the CR. There was a statistically significant difference between the two systems at 3.2mAs (P=0.0330). The ISS-FPD was superior to the CR for the detection of simulated pulmonary nodules at 3.2mAs. 23827315 Role of cysteine-protease CGHC motifs of ER-60, a protein disulfide isomerase, in hepatic apolipoprotein B100 degradation. Apolipoprotein B100 (apoB), the structural component of very low density lipoproteins (VLDL), is susceptible to misfolding and subsequent degradation by several intracellular pathways. ER-60, which has been implicated in apoB degradation, is a protein disulfide isomerase (PDI) that forms or rearranges disulfide bonds in substrate proteins and also possesses cysteine protease activity. To determine which ER-60 function is important for apoB degradation, adenoviruses encoding wild-type human ER-60 or a mutant form of human ER-60 (C60A, C409A) that lacked cysteine protease activity were overexpressed in HepG2 cells. Overexpression of wild-type ER-60 in HepG2 cells promoted apoB degradation and impaired apoB secretion, but mutant ER-60 overexpression did not. In McArdle RH-7777 cells, VLDL secretion was markedly inhibited following overexpression of wild-type but not mutant ER-60, an effect that could be blocked by oleate treatment. Mutant ER-60 was not trapped on apoB as it was with the control substrate tapasin, suggesting that ER-60's role in apoB degradation is likely unrelated to its protein disulfide isomerase activity. Thus, ER-60 may participate in apoB degradation by acting as a cysteine protease. We postulate that apoB cleavage by ER-60 within the ER lumen could facilitate proteasomal degradation of the C-terminus of translocationally-arrested apoB. 23867651 Berberine's effect on periodontal tissue degradation by matrix metalloproteinases: an in vitro and in vivo experiment. Periodontal disease involves tissue destruction caused by interactions among bacterial antigens and inflammatory mediators including matrix metalloproteinases (MMPs). Berberine, an isoquinoline alkaloid isolated from medicinal herbs, can inhibit the degradative action of extracellular MMPs. The effect of berberine on the periodontal expression of MMPs was examined in vitro and in vivo. Gelatinolytic activity of pro-MMP-2, MMP-2, and MMP-9 in the human gingival fibroblast and/or U-937 was compared after treatment with Porphyromonas gingivalis lipopolysaccharide (P.g. LPS) in four medias containing 0, 1, 10 and 100μM of berberine each. Twelve animals were divided into three groups for the study: (A) non-ligation, (B) ligation, and (C) ligation-plus-berberine (75mg/kg berberine by gastric lavage daily); and the effect of berberine on periodontal destruction was evaluated in the ligature-induced periodontitis in rats for 8 days by micro computerized tomography (micro-CT), histology and immunohistochemistry (IHC). An enhancing effect of P.g. LPS on MMP activities was identified, with a greater effect on fibroblasts/U937 co-culture than on either culture alone. When berberine was added to the LPS-treated cultures, the activities of MMPs were significantly reduced in dose-dependent manner. In the animals, the trends of the following parameters were compared. 1. Micro-CT distances between cemento-enamel junction (CEJ) and dental alveolar bone crest: B>C>A. 2. Histometrically measured crest bone levels: B>C>A. 3. Amount of collagen deposited in tissue areas: A>C>B. 4. Attachment loss: B>C≈A. 5. Connective tissue (CT) attachment: B>either A or C. 6. Expression of cells stained positive for MMP-2 and -9 by IHC: B>C>A. In conclusion, berberine demonstrated in vitro an inhibitory effect on P.g. LPS-enhanced MMP activities of HGF and U937 macrophages, reducing in vivo gingival tissue degradation in periodontitic rats. We thus propose that berberine may slow periodontal degradation through the regulation of MMPs in periodontitis induced by bacterial plaque. 23850693 Kinetic characterization of ebselen, chelerythrine and apomorphine as glutaminase inhibitors. Glutaminase catalyzes the hydrolysis of glutamine to glutamate and plays a central role in the proliferation of neoplastic cells via glutaminolysis, as well as in the generation of excitotoxic glutamate in central nervous system disorders such as HIV-associated dementia (HAD) and multiple sclerosis. Both glutaminase siRNA and glutaminase inhibition have been shown to be effective in in vitro models of cancer and HAD, suggesting a potential role for small molecule glutaminase inhibitors. However, there are no potent, selective inhibitors of glutaminase currently available. The two prototypical glutaminase inhibitors, BPTES and DON, are either insoluble or non-specific. In a search for more drug-like glutaminase inhibitors, we conducted a screen of 1280 in vivo active drugs (Library of Pharmacologically Active Compounds (LOPAC(1280))) and identified ebselen, chelerythrine and (R)-apomorphine. The newly identified inhibitors exhibited 10 to 1500-fold greater affinities than DON and BPTES and over 100-fold increased efficiency of inhibition. Although non-selective, it is noteworthy that the affinity of ebselen for glutaminase is more potent than any other activity yet described. It is possible that the previously reported biological activity seen with these compounds is due, in part, to glutaminase inhibition. Ebselen, chelerythrine and apomorphine complement the armamentarium of compounds to explore the role of glutaminase in disease. 23852613 Super-hydrated zeolites: pressure-induced hydration in natrolites. High-pressure synchrotron X-ray powder diffraction studies of a series of alkali-metal-exchanged natrolites, A16 Al16 Si24 O80 ⋅n H2 O (A=Li, K, Na, Rb, and Cs and n=14, 16, 22, 24, 32), in the presence of water, reveal structural changes that far exceed what can be achieved by varying temperature and chemical composition. The degree of volume expansion caused by pressure-induced hydration (PIH) is inversely proportional to the non-framework cation radius. The expansion of the unit-cell volume through PIH is as large as 20.6 % in Li-natrolite at 1.0 GPa and decreases to 6.7, 3.8, and 0.3 % in Na-, K-, and Rb-natrolites, respectively. On the other hand, the onset pressure of PIH appears to increase with non-framework cation radius up to 2.0 GPa in Rb-natrolite. In Cs-natrolite, no PIH is observed but a new phase forms at 0.3 GPa with a 4.8 % contracted unit cell and different cation-water configuration in the pores. In K-natrolite, the elliptical channel undergoes a unique overturn upon the formation of super-hydrated natrolite K16 Al16 Si24 O80 ⋅32 H2 O at 1.0 GPa, a species that reverts back above 2.5 GPa as the potassium ions interchange their locations with those of water and migrate from the hinge to the center of the pores. Super-hydrated zeolites are new materials that offer numerous opportunities to expand and modify known chemical and physical properties by reversibly changing the composition and structure using pressure in the presence of water. 23752084 Ras, Raf, and MAP kinase in melanoma. A growing understanding of the biology and molecular mechanisms of melanoma has led to the identification of a number of driver mutations for this aggressive tumor. The most common mutations affect signaling of the Ras/Raf/MAPK (mitogen-activated protein kinase) pathway. This review will focus on mutations in genes encoding proteins that play a role in the MAPK pathway and that have been implicated in melanoma biology, such as BRAF, NRAS, and MEK (MAPK kinase), and detail the current understanding of their role in melanoma progression from a molecular biology perspective. Furthermore, this review will also consider some additional mutations in genes such as KIT, GNAQ, and GNA11, which can be seen in certain subtypes of melanoma and whose gene products interact with the MAPK pathway. In addition, the association of these molecular changes with clinical and classical histopathologic characteristics of melanoma will be outlined and their role in diagnosis of melanocytic lesions discussed. Finally, a basic overview of the current targeted therapy landscape, as far as relevant to the pathologist, will be provided. 23962144 Education is associated with lower levels of abdominal obesity in women with a non-agricultural occupation: an interaction study using China's four provinces survey. The prevalence of obesity is increasing rapidly in low- and middle-income countries (LMICs) as their populations become exposed to obesogenic environments. The transition from an agrarian to an industrial and service-based economy results in important lifestyle changes. Yet different socioeconomic groups may experience and respond to these changes differently. Investigating the socioeconomic distribution of obesity in LMICs is key to understanding the causes of obesity but the field is limited by the scarcity of data and a uni-dimensional approach to socioeconomic status (SES). This study splits socioeconomic status into two dimensions to investigate how educated women may have lower levels of obesity in a context where labour market opportunities have shifted away from agriculture to other forms of employment. The Four Provinces Study in China 2008/09 is a household-based community survey of 4,314 people aged >=60 years (2,465 women). It was used to investigate an interaction between education (none/any) and occupation (agricultural/non-agricultural) on high-risk central obesity defined as a waist circumference >=80 cm. An interaction term between education and occupation was incorporated in a multivariate logistic regression model, and the estimates adjusted for age, parity, urban/rural residence and health behaviours (smoking, alcohol, meat and fruit & vegetable consumption). Complete case analyses were undertaken and results confirmed using multiple imputation to impute missing data. An interaction between occupation and education was present (P = 0.02). In the group with no education, the odds of central obesity in the sedentary occupation group were more than double those of the agricultural occupation group even after taking age group and parity into account (OR; 95%CI: 2.21; 1.52, 3.21), while in the group with any education there was no evidence of such a relationship (OR; 95%CI: 1.25; 0.92, 1.70). Health behaviours appeared to account for some of the association. These findings suggest that education may have a protective role in women against the higher odds of obesity associated with occupational shifts in middle-income countries, and that investment in women's education may present an important long term investment in obesity prevention. Further research could elucidate the mechanisms behind this association. 23926324 Peripheral tissue homing receptors enable T cell entry into lymph nodes and affect the anatomical distribution of memory cells. Peripheral tissue homing receptors enable T cells to access inflamed nonlymphoid tissues. In this study, we show that two such molecules, E-selectin ligand and α4β1 integrin, enable activated and memory T cells to enter lymph nodes (LN) as well. This affects the quantitative and qualitative distribution of these cells among regional LN beds. CD8 memory T cells in LN that express these molecules were mostly CD62L(lo) and would normally be classified as effector memory cells. However, similar to central memory cells, they expanded upon Ag re-encounter. This led to differences in the magnitude of the recall response that depended on the route of immunization. These novel cells share properties of both central and effector memory cells and reside in LN based on previously undescribed mechanisms of entry. 23769451 Serum levels of chemokine (C-X-C motif) ligand 9 (CXCL9) are associated with tumor progression and treatment outcome in patients with oral cavity squamous cell carcinoma. The aim of this cohort study was to examine the role of chemokine (C-X-C motif) ligand 9 (CXCL9) on oral cavity squamous cell carcinoma (OSCC). Sera from 181 OSCC patients, 231 healthy individuals, and 50 OSCC tumor samples were enrolled. CXCL9 expression in tissue samples was analyzed by quantitative real-time PCR and immunohistochemistry. CXCL9 serum concentrations were measured by enzyme-linked immunosorbent assay. Effects of CXCL9 on OSCC cell function were investigated by cell proliferation assays, trans-well migration/invasion assays, and RNA interference. CXCL9 expression was significantly higher than for normal epithelium in the tissue samples. CXCL9 serum concentrations were also significantly higher in OSCC patients compared to those in healthy individuals. Serum CXCL9 levels were significantly higher in OSCC patients with higher pT status, pathological overall stages, tumor depths, and positive bone invasion (P=0.033, 0.004, 0.041, and 0.002, respectively). Moreover, OSCC patients with higher CXCL9 levels (>209pg/mL, median level) before treatment had worse prognoses for overall survival and disease-specific survival (P=0.0006 and 0.0009, respectively). Multivariate logistic regression analyses also indicated that higher CXCL9 serum levels were an independent prognostic factor for overall survival and disease-free survival (P=0.003 and 0.004, respectively). The in vitro suppression of CXCL9 expression in SCC25 cells using specific interfering RNAs attenuated cell proliferation, migration and invasiveness. Our study demonstrated that CXCL9 is associated with tumor burden and aggressiveness of OSCC tumors and serum level of this ligand may be useful as a prognostic indicator. 23969239 Loss of corticostriatal and thalamostriatal synaptic terminals precedes striatal projection neuron pathology in heterozygous Q140 Huntington's disease mice. Motor slowing, forebrain white matter loss, and striatal shrinkage have been reported in premanifest Huntington's disease (HD) prior to overt striatal neuron loss. We carried out detailed LM and EM studies in a genetically precise HD mimic, heterozygous Q140 HD knock-in mice, to examine the possibility that loss of corticostriatal and thalamostriatal terminals prior to striatal neuron loss underlies these premanifest HD abnormalities. In our studies, we used VGLUT1 and VGLUT2 immunolabeling to detect corticostriatal and thalamostriatal (respectively) terminals in dorsolateral (motor) striatum over the first year of life, prior to striatal projection neuron pathology. VGLUT1+ axospinous corticostriatal terminals represented about 55% of all excitatory terminals in striatum, and VGLUT2+ axospinous thalamostriatal terminals represented about 35%, with VGLUT1+ and VGLUT2+ axodendritic terminals accounting for the remainder. In Q140 mice, a significant 40% shortfall in VGLUT2+ axodendritic thalamostriatal terminals and a 20% shortfall in axospinous thalamostriatal terminals were already observed at 1month of age, but VGLUT1+ terminals were normal in abundance. The 20% deficiency in VGLUT2+ thalamostriatal axospinous terminals persisted at 4 and 12months in Q140 mice, and an additional 30% loss of VGLUT1+ corticostriatal terminals was observed at 12months. The early and persistent deficiency in thalamostriatal axospinous terminals in Q140 mice may reflect a development defect, and the impoverishment of this excitatory drive to striatum may help explain early motor defects in Q140 mice and in premanifest HD. The loss of corticostriatal terminals at 1year in Q140 mice is consistent with prior evidence from other mouse models of corticostriatal disconnection early during progression, and can explain both the measurable bradykinesia and striatal white matter loss in late premanifest HD. 23955315 Coherent manipulation of spin qubits based on polyoxometalates: the case of the single ion magnet [GdW30P5O110](14-) Polyoxometalate single ion magnet [GdW30P5O110](14-) () has been studied by generalized Rabi oscillation experiments. It was possible to increase the number of coherent rotations tenfold through matching the Rabi frequency with the frequency of the proton. Achieving high coherence with polyoxometalate chemistry, we show its excellent potential not only for the storage of quantum information but even for the realization of quantum algorithms. 23601400 Capacity building in food composition for Africa. Capacity building in food and nutrition involves more than formal training and individual development. Such a process is long term and continues, requiring lasting mentorship, coaching and leadership development, including individual commitment to continued self-development. It expands to include the development of knowledge and skills of an individual within his/her organizational or institutional arrangements, and requires buy-in and support from his/her institution or organization, as well as other funding bodies involved in agriculture and health. It needs to be supported by government and be part of the regional and international agenda for agriculture and health. Under the auspices of International Network of Food Data Systems (INFOODS), an African Network of Food Data Systems (AFROFOODS) was established in September 1994, and a number of training courses, educational and scientific publications, posters, presentations and visits were hosted, organized and delivered with the aim to build enthusiasm, long term commitment and capacity in food composition within the AFROFOODS region. Formal training and human resource development were the major focus to take food composition forward in Africa. Significant progress was made in food composition activities, but constraints including lack of organizational and institutional commitment and financial support are straining the pace of progress. 22227884 Optimizing the order of operations for movement scrubbing: Comment on Power et al. A recent study by Power and colleagues shows that BOLD artifacts induced by head movement can substantially alter patterns of resting-state functional connectivity and proposes a novel procedure for reducing these artifacts by deleting (or "scrubbing") movement-contaminated volumes. The authors acknowledge that this work is descriptive and not prescriptive, and note that future studies may refine the proposed scrubbing method. Nevertheless, it is worth pointing out that this method can be improved substantially by a single transposition in the order of operations. Temporal filtering is known to introduce ringing artifacts that emanate from sharp transitions in signal intensity. The method proposed in the target article applies temporal filtering before deleting contaminated volumes-in effect, spreading movement-related artifacts backwards and forwards in time, but deleting only the originally contaminated data. Using simulated data, we show that deleting and replacing contaminated volumes before temporal filtering removes a greater proportion of artifactual signal while retaining a greater proportion of the original data. 23504250 Metal content in caviar of wild Persian sturgeon from the southern Caspian Sea. Caviar (fish roe of sturgeon) may contain high levels of contaminants. An inductively coupled plasma-optical emission spectrometer and a direct mercury analyzer were used to assess the contents of four heavy metals (Hg, Se, Sn, and Ba) in caviar of wild Persian sturgeon sea foods. The levels of Hg ranged from 1.39 to 1.50 Î¼g g(-1), Se from 0.90 to 1.10 Î¼g g(-1), Sn from 0.23 to 0.33, and Ba from 0.71 to 1.17 Î¼g g(-1). Evaluation of these levels showed that except for Hg, the average concentrations of other metals are significantly lower than adverse level for the human consumption when compared with Food and Agricultural Organization of the United Nations and World Health Organization permissible limits. Therefore, their contribution to the total body burden of these heavy metals can be considered as negligibly small given that caviar is a luxury product. 23659736 Glucocorticoid synthesis-related genes: HSD11B1 and HSD11B2 in hypertensive disorders in pregnancy. To determine whether polymorphisms of the maternal glucocorticoid-related genes (HSD11B1 and HSD11B2) are associated with pregnancy-induced hypertension (PIH) in a haplotype-based case-control study. A total of 166 PIH patients and 222 age-matched controls were genotyped, with two single-nucleotide polymorphisms (SNPs) for the HSD11B1 gene (rs2235543 and rs846910) and three SNPs for the HSD11B2 gene (rs12920590, rs45483293 and rs3743729) used as genetic markers. After separation into preeclampsia (PE) and gestational hypertension (GH) subgroups, PIH patients were assessed. Significant differences were noted between PE and control groups (p = 0.022, p = 0.034, respectively) for the frequency of genotypes and alleles for rs846910 of HSD11B1. The frequency of the AA genotype of rs846910 was significantly higher in PIH and PE groups compared to controls. Logistic regression analyses showed that this genotype was a risk factor for PIH and PE (adjusted OR 2.9, 95% CI 1.3-6.5 and adjusted OR 3.2, 95% CI 1.4-7.4, respectively). The frequency of the T-A haplotype established by rs2235543-rs846910 was also significantly higher in PIH and PE groups (p = 0.045, p = 0.042, respectively). rs846910 in the HSD11B1 gene could be a marker for hypertensive disorders during pregnancy. The T-A haplotype constructed by rs2235543-rs846910 was also a useful susceptibility marker for PIH and PE. 23771128 Role of navigated total knee arthroplasty for acute tibial fractures in the elderly. The role of total knee arthroplasty (TKA) in acute tibial fractures with existing comminution/bone loss, osteoporosis or preexistent arthritis has been described in the literature. Many of these procedures necessitate the use of stems to off-load the component and augments/wedges to avoid overresection and hence restore the joint line. Conventional methods may not be consistently accurate in restoring the desired alignment within 3° of the anatomical axis in this complex scenario. Computer-assisted TKA has been demonstrated to reproducibly and accurately restore the mechanical axis and joint line in primary TKA. Literature review has sparse data on use of navigation in acute TKA. 9 cases of acute tibial fractures (6 tibial plateau and 3 diaphyseal) were treated by navigated primary knee arthroplasty and followed up over 26-month duration. All fractures healed without notable complications. Mean range of movement was 114°. Mean Knee Society score was 84. Out of 9 cases 5 were graded as excellent, 3 good and 1 fair. All knees were corrected to within a mean of 1.7° of the calculated mechanical axis. Total knee arthroplasty should be considered a treatment option for acute upper tibial fractures in the elderly with coexistent knee arthritis and poor bone stock. Computer-assisted navigation aids in restoration of mechanical axis and component positioning. 23661613 Immunohistochemical expression of ERG in the molecular epidemiology of fatal prostate cancer study. Gene fusions between the ERG transcription factor and the androgen-regulated gene TMPRSS2 occur in a subset of prostate cancers and contribute to transformation of prostatic epithelial cells. Prior reports have used fluorescence in situ hybridization (FISH) or quantitative PCR (QPCR) to determine the presence of TMPRSS2-ERG fusions or ERG expression, respectively. Recently, several groups have reported on immunohistochemistry (IHC) to measure ERG expression, which is much more readily performed in clinical practice. However, the prior studies examining ERG expression by IHC had small sample sizes or they failed to clarify the association of ERG protein expression with important clinico-pathological features or prostate cancer-specific mortality. Methods: To address these deficits, we evaluated ERG expression by IHC in 208 radical prostatectomy samples from the Kaiser Permanente Molecular Epidemiology of Fatal Prostate Cancer (MEFPC) study, a case-control study of prostate cancer-specific mortality. Nuclear ERG expression was seen in neoplastic prostate epithelia in 49 of the samples (23.7%). ERG expression in tumor cells was associated with higher tumor stage (OR = 2.0, 95% confidence interval 1.0-4.0, P value = 0.04). ERG immunoreactivity was positively associated with prostate cancer-specific mortality, although the confidence interval was wide (OR = 1.9, 95% confidence interval 0.88-4.0, P value = 0.10). Our results demonstrate that ERG protein expression is readily quantifiable with an existing commercial antibody. Evaluating ERG protein expression may improve our ability to identify the subset of more aggressive, invasive prostate cancers. Prostate 73: 1371-1377, 2013. © 2013 Wiley Periodicals, Inc. 23621667 Dietary and plant polyphenols exert neuroprotective effects and improve cognitive function in cerebral ischemia. Cerebral ischemia is caused by an interruption of blood flow to the brain which generally leads to irreversible brain damage. Ischemic injury is associated with vascular leakage, inflammation, tissue injury, and cell death. Cellular changes associated with ischemia include impairment of metabolism, energy failure, free radical production, excitotoxicity, altered calcium homeostasis, and activation of proteases all of which affect brain functioning and also contribute to longterm disabilities including cognitive decline. Inflammation, mitochondrial dysfunction, increased oxidative/nitrosative stress, and intracellular calcium overload contribute to brain injury including cell death and brain edema. However, there is a paucity of agents that can effectively reduce cerebral damage and hence considerable attention has focused on developing newer agents with more efficacy and fewer side-effects. Polyphenols are natural compounds with variable phenolic structures and are rich in vegetables, fruits, grains, bark, roots, tea, and wine. Most polyphenols have antioxidant, anti-inflammatory, and anti-apoptotic properties and their protective effects on mitochondrial functioning, glutamate uptake, and regulating intracellular calcium levels in ischemic injury in vitro have been demonstrated. This review will assess the current status of the potential effects of polyphenols in reducing cerebral injury and improving cognitive function in ischemia in animal and human studies. In addition, the review will also examine available patents in nutrition and agriculture that relates to cerebral ischemic injury with an emphasis on plant polyphenols. 23891910 A sensory-enhanced context allows renewal of an extinguished fear response in the infant rat. Studies of extinction in preweanling rats have failed to find ABA-renewal in a fear conditioning paradigm. This result supports the hypothesis postulating ontogenetic qualitative differences in experimental extinction. A similar result in adult rats led to the conclusion that ABA-renewal requires contexts A and B to differ in several types of features, including odor cues. Recently we reported experimental evidence of the renewal of an extinguished taste aversion response in infant rats employing contexts which differ in their odor content. The present study examines the possibility of renewing an extinguished fear response in infant rats when contexts A and B do not include (Experiment 1) or include (Experiment 2) an explicit odor. Results showed absence of renewal when using standard contexts (without explicit odors, Experiment 1). However, when contexts A and B varied also in their odor content, the ABA-renewal procedure was effective in reinstating the extinguished CR (Experiment 2). Thus, it can be concluded that the sensory content of the context determines the observation of renewal in the infant rat, a result that is coherent with previous observations in the adult rat. As a whole, these results challenge our understanding of extinction as a learning process that is qualitatively different in preweanling rats than in later stages of ontogeny. 23749343 Incidence of postoperative anterior cruciate ligament reconstruction infections: graft choice makes a difference. Infections after anterior cruciate ligament reconstruction (ACLR) can be devastating. Hamstring tendon autografts may be more susceptible to infections than other graft types. To determine the incidence of surgical site infections (SSIs) in a large sample of patients who underwent ACLR and to evaluate the risk of superficial and deep SSIs associated with grafts used for ACLR. Cohort study; Level of evidence, 2. All primary ACLRs performed between February 2005 and September 2010 registered in the Kaiser Permanente ACLR registry were included in the study. The graft types evaluated included the bone-patellar tendon-bone (BPTB) autograft, hamstring tendon autograft, and allograft (all types). The main end point of the study, SSIs (deep and superficial), was prospectively ascertained using an electronic screening algorithm and adjudicated by the principal investigator. Descriptive statistics were used to describe the cohort, and logistic regression models were used to evaluate the likelihood of an infection. There were 10,626 cases that fit the study criteria. The overall cohort was 64% male, mean age was 29 ± 11 years, and mean body mass index (BMI) was 27 ± 5 kg/m(2). The overall incidence of SSIs was 0.48% (n = 51), with 17 (0.16%) superficial infections and 34 (0.32%) deep infections. Hamstring tendon autografts (n = 20; 0.61%) had the highest incidence of deep SSIs of the graft types (BPTB autograft, n = 2 [0.07%]; allograft, n = 12 [0.27%]; P < .001). After adjusting for age, sex, and BMI, the likelihood of a patient with a hamstring autograft having a deep SSI was 8.24 times higher (95% CI, 1.91-35.55; P = .005) than someone receiving a BPTB autograft. The risk of infections in allografts was not statistically significantly higher than BPTB autografts. The overall SSI rate after ACLR was 0.48%. Deep SSIs were identified in 0.32% of the ACLR cases and superficial SSIs in 0.16%. An 8.2-times higher risk of SSIs was observed in hamstring tendon autografts compared with BPTB autografts. No difference in SSI incidence was identified between allografts and BPTB autografts. Surgeons should bear in mind that although the overall infection rates after ACLR are low, there is an increased risk of deep infections with hamstring tendon autografts. 23893664 Alteration of circulating miRNAs in SSc: miR-30b regulates the expression of PDGF receptor β Objective. Although several miRNAs have been shown to regulate autoimmune pathogenesis by affecting lymphocyte function, the roles of miRNAs in the pathogenesis of SSc remain unclear. Therefore the purpose of this study was to identify miRNAs that play a role in the pathogenesis of SSc by quantitative PCR screening of serum miRNAs.Methods. Ninety-five miRNAs that were predicted to target SSc-related genes [IL-4, TGF-β, CTGF, PDGF-B, PDGF receptor (PDGFR) α/β and COL1A2) by in silico analyses were selected. The expression of these miRNAs in sera of SSc patients and healthy controls was measured by quantitative PCR. Involvement of miR-30b, which was most strongly down-regulated in SSc patients, in the regulation of PDGFR-β expression was examined by transfection experiments and 3'-untranslated region (3'-UTR) target luciferase assays. The expression of miR-30b in skin was evaluated in a bleomycin-induced dermal fibrosis model in mice and in SSc patients.Results. Nineteen of 95 miRNAs were significantly decreased in the sera of SSc patients. Among them, miR-30b was most strongly down-regulated in SSc patients (P = 0.00006) and the levels of miR-30b were inversely correlated with modified Rodnan skin scores. Transfection of a miR-30b mimic repressed PDGFR-β expression in dermal fibroblasts and the activity of a luciferase reporter containing 3'-UTR of PDGFR-β. Moreover, the expression of miR-30b was down-regulated in bleomycin-treated sclerotic skin and in affected skin in SSc patients.Conclusion. Down-regulation of miR-30b might be involved in the pathogenesis of SSc. 23942421 The first synthesis of natural disulfide bruguiesulfurol and biological evaluation of its derivatives as a novel scaffold for PTP1B inhibitors. Bruguiesulfurol (1), a cyclic 4-hydroxy-dithiosulfonate isolated from mangrove plant Bruguiera gymnorrhiza, was concisely synthesized for the first time in four steps, and a series of its synthetic derivatives were evaluated for in vitro inhibitory effects on PTP1B and related PTPs. Some derivatives were found to have improved pharmacological profile compared with hit 1. Among them, 5a showed the potent selectivity towards PTP1B over other PTPs, including TCPTP, and 7j exhibited the strongest PTP1B inhibitory activity with an IC50 value of 4.54μM. 23922483 Bleeding Dieulafoy's-like lesions of the gut identified by capsule endoscopy. Dieulafoy's-like lesions (DLs-like) represent a cause of obscure gastrointestinal bleeding, enteroscopy being the main diagnostic and therapeutic procedure. Frequently, more than one enteroscopy is needed to identify the bleeding vessel. In our practice, video capsule endoscopy (VCE) identified and guided therapy in four cases of DLs-like; three of them were localized on the small bowel. We report, for the first time, a diagnosis of colonic DL-like performed by colon capsule endoscopy. Two patients presented with severe cardiovascular disorders, being hemodynamically unstable during VCE examination. Based on the VCE findings, only one invasive therapeutic procedure per patient was necessary to achieve hemostasis. VCE and enteroscopy may be regarded as complementary procedures in patients with gut DLs-like. 23313623 OAT1 and OAT3: targets of drug-drug interaction between entecavir and JBP485. Entecavir and JBP485 (a dipeptide) exhibit the antihepatitis activities and it is possible for the two drugs to be coadministered in the treatment of hepatitis. We aimed to elucidate whether entecavir was a substrate of OAT1, OAT3, OCT, and PEPT1 and to investigate the targets of drug-drug interactions between entecavir and JBP485. Plasma and urine concentrations of entecavir following intravenous and oral administration in vivo, uptake of entecavir in kidney slices and transfected cells in vitro, were determined by LC-MS/MS. Following intravenous co-administration of entecavir and JBP485 in rats, entecavir AUC increased 1.93-fold, t1/2β was prolonged 2.08-fold, CLP decreased 49%, CLR decreased 73%, and accumulated urinary excretion decreased 54%. However, following oral co-administration, the entecavir Tmax and Cmax were not affected; the degree of change in other pharmacokinetic parameters (AUC, t1/2β, CLP, and accumulated urinary excretion) was similar to that of intravenous administration. The uptake of entecavir was nearly identical in hPEPT1- as in vector-HELA cells. In rat kidney slices, uptake of entecavir was markedly inhibited by p-aminohippurate, benzylpenicillin, JBP485, and tetraethyl ammonium. In hOAT1- and hOAT3-HEK293 cells, uptake of entecavir was significantly higher compared to vector-HEK293 cells and was markedly inhibited by p-aminohippurate, benzylpenicillin, and JBP485. Km and Vmax values of entecavir were 250 μM and 0.83 nmol/mg protein/30s (OAT1) and 23 μM and 1.1 nmol/mg protein/30 s (OAT3), respectively. Entecavir is the substrate of OAT1, OAT3, and OCT. Moreover, OAT1 and OAT3 are the targets of DDI between entecavir and JBP485. 23932895 Ectoparasites and anti-Leishmania antibodies: Association in an observational case-control study of dogs from a Brazilian endemic area. It has been proposed that the transmission of canine visceral leishmaniasis might involve the participation of mechanical vectors, including ticks of the family Ixodidae, in particular the brown dog tick Rhipicephalus sanguineus, and the cat flea Ctenocephalides felis felis. Here, the association between the infestation by R. sanguineus and C. felis felis and the occurrence of anti-Leishmania antibodies was evaluated in an observational case-control study of dogs living in a Brazilian endemic area for canine visceral leishmaniasis. Blood samples were taken once every three months for one year from 96 initially seronegative domestic dogs, and submitted to indirect immunofluorescence antibody assay. All dogs were evaluated for the presence of ticks and fleas, and the results were expressed qualitatively as infested or non-infested, irrespective of the intensity of infestation. At the end of follow-up, twenty dogs had turned seropositive, while 68 remained seronegative and 8 were excluded because of incomplete data. All the dogs were asymptomatic. The odds of infection was significantly greater (OR=3.54, CI95%=1.10-12.53) for dogs infested by C. felis felis compared to their non-infested counterparts. In contrast, the odds of infection showed no significance difference between non-infested and R. sanguineus-infested groups of dogs (OR=0.31, CI95%=0.03-1.52). This study provides further evidence for the potential role of C. felis felis in mechanically transmitting Leishmania among the canine population. 23316943 One-pot synthesis of tin-embedded carbon/silica nanocomposites for anode materials in lithium-ion batteries. We report a facile "one-pot" method for the synthesis of Sn-embedded carbon-silica (CS) mesostructured (nanostructured) composites through the selective interaction of resol (carbon precursor), tetraethylorthosilicate (TEOS), and tributylphenyltin (Sn precursor) with an amphiphilic diblock copolymer, poly(ethylene oxide-b-styrene), PEO-b-PS. A unique morphology transition from Sn nanowires to spherical Sn nanoparticles embedded in CS framework has been obtained. Metallic Sn species are homogeneously embedded in a rigid CS framework and are effectively confined within the nanostructures. The resulting composites are used as anode materials for lithium-ion batteries and exhibit high specific capacities (600 mA h g⁻¹ at a current density of 45 mA g⁻¹, and 440 mA h g⁻¹ at a current density of 300 mA g⁻¹) and an excellent cyclability of over 100 cycles with high Coulombic efficiency. Most of all, the novel method developed in this work for synthesizing functional hybrid materials can be extended to the preparation of various functional nanocomposites owing to its versatility and facileness. 23265459 Antioxidant and immunomodulatory activity of selenium exopolysaccharide produced by Lactococcus lactis subsp. lactis. Exopolysaccharide (EPS) was isolated and purified from Lactococcus lactis subsp. Lactis culture broth. Selenium chloride oxide (SeCl(2)O) was added to the EPS to synthesize selenium-exopolysaccharide (Se-EPS). The in vitro and in vivo antioxidant and in vivo immunomodulatory activity of EPS and Se-EPS were compared. EPS and Se-EPS scavenged superoxide anions and hydroxyl radicals. They also increased catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, while decreasing malondialdehyde (MDA) levels in serum and in the livers of mice. Se-EPS showed stronger in vitro and in vivo antioxidant activity than were shown by EPS. The in vivo immunoenhancement activity of EPS and Se-EPS induced by cyclophosphamide (CY) treatment in immunosuppressed mice was researched. EPS and Se-EPS treatments increased macrophage phagocytosis, spleen and thymus indices and haemolytic complement activity (HC(50)). Se-EPS showed stronger immunomodulatory activity than did EPS. 23891716 Role of fibroblast growth factor 8 in neurite outgrowth from spiral ganglion neurons in vitro. Many neurons degenerate after injuries resulting from overstimulation, drugs, genetic mutations, and aging. Although several growth factors and neurotrophins delay degeneration and promote regrowth of neural processes, the role of fibroblast growth factor 8 (FGF8) in mammalian spiral ganglion neurons (SGN) neurite outgrowth has not been examined. This study develops and uses SGN cell cultures suitable for experimental analysis, it investigates whether FGF8a and FGF8b isoforms affect the neurite outgrowth from SGN cultured in vitro. We found that both FGF8a and FGF8b promoted the outgrowth of neurites from cultured SGN. This response is mediated by FGF receptors and involves the activation of IκBα-mediated NFκB signaling pathway. These findings suggest that, besides its morphogenetic role during development, FGF8 may have trophic functions in the adult which are relevant to regeneration. 23897622 Design, synthesis and characterisation of cyclic analogues of the iron regulatory peptide hormone hepcidin. The peptide hormone hepcidin is a key regulator of iron homeostasis in vertebrates. Hepcidin acts by binding to ferroportin, the sole known iron exporter, causing it to be internalised and thus trapping iron within the cell. Dysregulation of hepcidin concentrations is associated with a range of iron-related diseases and hepcidin-based therapeutics could be developed as candidate treatments for these diseases. However peptide-based drugs, despite their many advantages, are often limited by their susceptibility to degradation within the body. Here we describe the design, synthesis and characterisation of a series of backbone cyclised hepcidin analogues as an approach to produce stable hepcidin-based leads. The cyclic peptides were shown by NMR to be structurally analogous to native hepcidin. Comparison of the stability of hepcidin with one of the cyclic analogues in human serum revealed that 77% of the cyclic peptide but only 18% of linear hepcidin remained after 24 hours. The cyclic peptides were tested for their ability to induce internalisation of GFP-ferroportin in vitro but were all found to be inactive. This study demonstrates that backbone cyclisation of disulfide-rich peptides is a suitable approach for increasing stability. However, careful consideration of a number of factors, including location of important residues and their bioactive conformation, is required to generate biologically active lead molecules. © 2013 Wiley Periodicals, Inc. Biopolymers, 2013. 23896552 Antifungal effect and pore-forming action of lactoferricin B like peptide derived from centipede Scolopendra subspinipes mutilans. The centipede Scolopendra subspinipes mutilans has been a medically important arthropod species by using it as a traditional medicine for the treatment of various diseases. In this study, we derived a novel lactoferricin B like peptide (LBLP) from the whole bodies of adult centipedes, S. s. mutilans, and investigated the antifungal effect of LBLP. LBLP exerted an antifungal and fungicidal activity without hemolysis. To investigate the antifungal mechanism of LBLP, a membrane study with propidium iodide was first conducted against Candida albicans. The result showed that LBLP caused fungal membrane permeabilization. The assays of the three dimensional flow cytometric contour plot and membrane potential further showed cell shrinkage and membrane depolarization by the membrane damage. Finally, we confirmed the membrane-active mechanism of LBLP by synthesizing model membranes, calcein and FITC-dextran loaded large unilamellar vesicles. These results showed that the antifungal effect of LBLP on membrane was due to the formation of pores with radii between 0.74nm and 1.4nm. In conclusion, this study suggests that LBLP exerts a potent antifungal activity by pore formation in the membrane, eventually leading to fungal cell death. 23900898 Cardiac Regeneration and Cellular Therapy: Is there a Benefit of Exercise? Cardiovascular diseases (CVD) are a global epidemic in developed countries. Cumulative evidence suggests that myocyte formation is preserved during postnatal life, in adulthood or senescence, suggesting the existence of a growth reserve of the heart throughout lifespan. Several medical therapeutic approaches to CVD have considerably improved the clinical outcome for patients. Intense interest has been focused on regenerative medicine as an emerging strategy for CVD. Cellular therapeutic approaches have been proposed for enhancing survival and propagation of stem cells in myocardium, leading to cardiac cellular repair. Strong epidemiological and clinical data exists concerning the impact of regular physical exercise on cardiovascular health. Several mechanisms of acute and chronic exercise-induced cardiovascular adaptations to exercise have been presented, considering primary and secondary prevention of CVD. In this context, exercise-related improvements in the function and regeneration of the cardiovascular system may be associated with the exercise-induced activation, mobilization, differentiation, and homing of stem and progenitor cells. In this review several topics will be addressed concerning the relation between exercise, recruitment and biological activity of blood-circulating progenitor cells and resident cardiac stem cells. We hypothesize that exercise-induced stem cell activation may enhance overall heart function and improve the efficacy of cardiac cellular therapeutic protocols. 23435714 The architecture of Norway spruce ectomycorrhizae: three-dimensional models of cortical cells, fungal biomass, and interface for potential nutrient exchange. Gathering realistic data on actual fungal biomass in ectomycorrhized fine root systems is still a matter of concern. Thus far, observations on architecture of ectomycorrhizae (ECMs) have been limited to analyses of two-dimensional (2-D) images of tissue sections. This unavoidably causes stereometrical problems that lead to inadequate assumptions about actual size of cells and their arrangement within ECM's functional compartments. Based on extensive morphological investigations of field samples, we modeled the architectural components of an average-sized Norway spruce ECM. In addition to our comprehensive and detailed quantitative data on cell sizes, we studied actual shape and size, in vivo arrangement, and potential nutrient exchange area of plant cortical cells (CCs) using computer-aided three-dimensional (3-D) reconstructions based on semithin serial sections. We extrapolated a factual fungal biomass in ECMs (Hartig net (HN) included) of 1.71 t ha(-1) FW (0.36 t ha(-1) DW) for the top 5 cm of soil for an autochthonous, montane, optimum Norway spruce stand in the Tyrolean Alps. The corresponding potential nutrient exchange area in ECMs including main axes of ECM systems, which is defined as the sum of interfaces between plant CCs and the HN, amounts to at least 3.2 × 10(5) m(2) ha(-1). This is the first study that determines the contribution of the HN to the total fungal biomass in ECMs as well as the quantification of its contact area. Our results may stimulate future research on fungal below-ground processes and their impact on the global carbon cycle. 23968564 Refactoring the Silent Spectinabilin Gene Cluster Using a Plug-and-Play Scaffold. Natural products (secondary metabolites) are a rich source of compounds with important biological activities. Eliciting pathway expression is always challenging but extremely important in natural product discovery because an individual pathway is tightly controlled through a unique regulation mechanism and hence often remains silent under the routine culturing conditions. To overcome the drawbacks of the traditional approaches that lack general applicability, we developed a simple synthetic biology approach that decouples pathway expression from complex native regulations. Briefly, the entire silent biosynthetic pathway is refactored using a plug-and-play scaffold and a set of heterologous promoters that are functional in a heterologous host under the target culturing condition. Using this strategy, we successfully awakened the silent spectinabilin pathway from Streptomyces orinoci. This strategy bypasses the traditional laborious processes to elicit pathway expression and represents a new platform for discovering novel natural products. 23906862 Hansen solubility parameter analysis on the dispersion of zirconia nanocrystals. Nanoparticle dispersible in a broad range of solvents is desirable when preparing an organic/inorganic nanocomposite. In this report, the dispersion behavior of carboxylate-grafted zirconia nanoparticle in 25 solvents covering a wide range of polarity was analyzed based on their Hansen solubility parameters (HSP). Particles grafted with alkyl-chain longer than four carbons could only be dispersed in non-polar solvents, while that grafted with acetic acid was dispersible in polar ones. However, particle modified with methacrylic acid (MA) was compatible with both types of solvents, which was rather unexpected. Further NMR analysis showed that the carboxylate-grafted samples contained a trace amount of triethanolamine (TEA) due to the particular ZrO2 synthesis process employed. The combination of the hydrophilic TEA ligand with the short hydrophobic tail of methacrylate broadened the range of compatible solvents from benzene to methanol. Such an extended solvent compatibility was observed previously only for nanoparticles covered with large polymer surfactants having both hydrophilic and hydrophobic groups. Achieving this with two small molecules having separate functional groups is crucial when one needs to maximize the inorganic content in a composite. 23231492 Tilting the balance between canonical and noncanonical conformations for the H1 hypervariable loop of a llama VHH through point mutations. Nanobodies are single-domain antibodies found in camelids. These are the smallest naturally occurring binding domains and derive functionality via three hypervariable loops (H1-H3) that form the binding surface. They are excellent candidates for antibody engineering because of their favorable characteristics like small size, high solubility, and stability. To rationally engineer antibodies with affinity for a specific target, the hypervariable loops can be tailored to obtain the desired binding surface. As a first step toward such a goal, we consider the design of loops with a desired conformation. In this study, we focus on the H1 loop of the anti-hCG llama nanobody that exhibits a noncanonical conformation. We aim to "tilt" the stability of the H1 loop structure from a noncanonical conformation to a (humanized) type 1 canonical conformation by studying the effect of selected mutations to the amino acid sequence of the H1, H2, and proximal residues. We use all-atomistic, explicit-solvent, biased molecular dynamic simulations to simulate the wild-type and mutant loops in a prefolded framework. We thus find mutants with increasing propensity to form a stable type 1 canonical conformation of the H1 loop. Free energy landscapes reveal the existence of conformational isomers of the canonical conformation that may play a role in binding different antigenic surfaces. We also elucidate the approximate mechanism and kinetics of transitions between such conformational isomers by using a Markovian model. We find that a particular three-point mutant has the strongest thermodynamic propensity to form the H1 type 1 canonical structure but also to exhibit transitions between conformational isomers, while a different, more rigid three-point mutant has the strongest propensity to be kinetically trapped in such a canonical structure. 23066988 Metformin directly inhibits ghrelin secretion through AMP-activated protein kinase in rat primary gastric cells. The antidiabetic drug Metformin causes weight loss in both diabetic and non-diabetic individuals. Metformin treatment is also associated with lower circulating levels of the orexigenic hormone ghrelin. To test whether Metformin directly affects ghrelin cells, rat primary stomach cells were treated with Metformin and the levels of ghrelin secretion, proghrelin gene expression and activation of adenosine monophosphate-activated protein kinase (AMPK) were examined. Metformin significantly reduced ghrelin secretion and proghrelin mRNA production and both these effects were blocked by co-incubation with the AMPK inhibitor compound C. Furthermore, the AMPK activator 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) significantly inhibited ghrelin secretion. Additionally, ghrelin cells were shown to express AMPK. Finally, Metformin treatment caused a significant increase in the level of phosphorylated (active) AMPK. Our results show that Metformin directly inhibits stomach ghrelin production and secretion through AMPK. This reduction in ghrelin secretion may be one of the key components in Metformin's mechanism of weight loss. 23900045 Remodeling of small intramyocardial coronary arteries distal to total occlusions after myocardial infarction in pigs. The present study was designed to investigate whether microvascular remodeling could occur in hibernating myocardium and infarction regions distal to a total occluded coronary artery after acute myocardial infarction. Copper stents were implanted in the left descending coronary arteries of 64 pigs to induce anterior wall myocardial infarction. The pigs were assigned randomly to group A (n=8; killed at 1 week), group B (n=8; killed at 2 weeks), group C (n=16; killed at 4 weeks), group D (n=16; killed at 3 months), and group E (n=16; killed at 6 months). The control group included six pigs that were subjected to the same procedures but without implantation of copper stents. The wall area (WA) and lumen area (LA) of small intramyocardial coronary arteries (SIMCA) distal to occlusions were measured and the ratios of WA/LA and LA/total vessel area (%L) were calculated. The composition of the arterial wall was determined by Masson's trichrome stain, transmission electron microscope. A significant increase in WA/LA and decrease %L in SIMCA were observed in group B (P<0.05), group C (P<0.01), group D (P<0.01), and group E (P<0.01) compared with the control. There was increased area of collagen fiber in the thickened arterial wall in group C (P<0.05), group D (P<0.01), and group E (P<0.01) compared with the control group, group A, and group B. A significantly increased ratio of the synthetic phenotype vascular smooth muscle cells were found in group B (P<0.05), group C (P<0.01), group D (P<0.01), and group E (P<0.01) compared with the control group. Several weeks after occlusion of epicardial coronary, the SIMCAs distal to occlusion developed remodeling, with an increase in wall thickness and a decrease in lumen size. These structural changes may restrict blood flow to ischemic or hibernating myocardium after revascularization. 23904524 Metformin inhibits growth of eutopic stromal cells from adenomyotic endometrium via AMPK activation and subsequent inhibition of AKT phosphorylation: a possible role in the treatment of adenomyosis. Adenomyosis is a finding that is associated with dysmenorrhea and heavy menstrual bleeding, associated with PI3K/AKT signaling overactivity. To investigate the effect of metformin on the growth of eutopic endometrial stromal cells (ESCs) from patients with adenomyosis and to explore the involvement of AMP-activated protein kinase (AMPK) and PI3K/AKT pathways. Primary cultures of human ESCs were derived from normal endometrium (normal endometrial stromal cells (N-ESCs)) and adenomyotic eutopic endometrium (adenomyotic endometrial stroma cells (A-ESCs)). Expression of AMPK was determined using immunocytochemistry and western blot analysis. 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assays were used to determine the effects of metformin and compound C on ESCs and also to detect growth and proliferation of ESCs. AMPK and PI3K/AKT signaling was determined by western blotting. A-ECSs exhibited greater AMPK expression than N-ESCs. Metformin inhibited proliferation of ESCs in a concentration-dependent manner. The IC50 was 2.45 mmol/l for A-ESCs and 7.87 mmol/l for N-ESCs. Metformin increased AMPK activation levels (p-AMPK/AMPK) by 2.0±0.3-fold in A-ESCs, 2.3-fold in A-ESCs from the secretory phase, and 1.6-fold in the proliferation phase. The average reduction ratio of 17β-estradiol on A-ESCs was 2.1±0.8-fold in proliferative phase and 2.5±0.5-fold in secretory phase relative to the equivalent groups not treated with 17β-estradiol. The inhibitory effects of metformin on AKT activation (p-AKT/AKT) were more pronounced in A-ESCs from the secretory phase (3.2-fold inhibition vs control) than in those from the proliferation phase (2.3-fold inhibition vs control). Compound C, a selective AMPK inhibitor, abolished the effects of metformin on cell growth and PI3K/AKT signaling. Metformin inhibits cell growth via AMPK activation and subsequent inhibition of PI3K/AKT signaling in A-ESCs, particularly during the secretory phase, suggesting a greater effect of metformin on A-ESCs from secretory phase. 23778295 Association between clinical signs assessed by manual segmental examination and findings of the lumbar facet joints on magnetic resonance scans in subjects with and without current low back pain: A prospective, single-blind study. The relevance of magnetic resonance imaging (MRI) findings such as facet joint (FJ) effusion and edema in low back pain (LBP) is still unknown. Therefore, we prospectively evaluated the presence of these MRI findings in the lumbar spine (Th12-S1) and their association with pain evoked by manual segmental FJ provocation tests (spinal percussion, springing, and segmental rotation tests) in 75 subjects with current LBP (⩾30days in the past 3months) compared with 75 sex- and age-matched control subjects. FJs were considered painful, if ⩾1 provocation test triggered LBP. FJs were classified as true positives, if the same FJ was painful and showed effusion and/or edema. FJs with effusion and/or edema and painful FJs were present significantly more frequently in subjects with LBP, but these conditions were also common in control subjects (27% vs 21% and 50% vs 12%, respectively). Effusion and/or edema were present in 65 subjects with LBP (87%) and in 56 control subjects (75%, not significant); painful FJs were present in 68 (91%) and 29 (39%) (P<0.01) LBP and control subjects, respectively. True-positive findings occurred in 16% of LBP FJs and in 2% of control FJs (P<0.01); 46 LBP subjects (61%) and 9 control subjects (12%, P<0.01) had true-positive findings. Pain on provocation and FJ effusion and/or edema were significantly correlated only in patients with LBP. In conclusion, only true-positive findings (ie, concurrent effusion and/or edema and positive provocation test results in the same FJ) discriminate well enough between control subjects and subjects with current LBP, whereas neither effusion and/or edema nor FJ provocations tests alone are suitable to detect suspected FJ arthropathy. 23613149 Dietary Flaxseed Oil Supplementation Mitigates the Effect of Lead on the Enzymes of Carbohydrate Metabolism, Brush Border Membrane, and Oxidative Stress in Rat Kidney Tissues. Lead is a heavy metal widely distributed in the environment. Lead is a ubiquitous environmental toxin that is capable of causing numerous acute and chronic illnesses. Human and animal exposure demonstrates that lead is nephrotoxic. However, attempts to reduce lead-induced nephrotoxicity were not found suitable for clinical use. Recently, flaxseed oil (FXO), a rich source of ω-3 fatty acids and lignans, has been shown to prevent/reduce the progression of certain types of cardiovascular and renal disorders. In view of this, the present study investigates the protective effect of FXO on lead acetate (PbAc)-induced renal damage. Rats were pre-fed normal diet and the diet rich in FXO for 14 days, and then, four doses of lead acetate (25 mg/kg body weight) were administered intraperitoneally while still on diet. Various serum parameters, enzymes of carbohydrate metabolism, brush border membrane (BBM), and oxidative stress were analyzed in rat kidney. PbAc nephrotoxicity was characterized by increased serum creatinine and blood urea nitrogen. PbAc increased the activities of lactate dehydrogenase and NADP-malic enzyme, whereas it decreased malate and glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, fructose-1, 6-bisphosphatase, and BBM enzyme activities. PbAc caused oxidant/antioxidant imbalances as reflected by increased lipid peroxidation and decreased activities of superoxide dismutase, glutathione peroxidase, and catalase. In contrast, FXO alone enhanced the enzyme activities of carbohydrate metabolism, BBM, and antioxidant defense system. FXO feeding to PbAc-treated rats markedly enhanced resistance to PbAc-elicited deleterious effects. In conclusion, dietary FXO supplementation ameliorated PbAc-induced specific metabolic alterations and oxidative damage by empowering antioxidant defense mechanism and improving BBM integrity and energy metabolism. 23892274 Pharmacokinetic interactions between 20(S)-ginsenoside Rh2 and the HIV protease inhibitor ritonavir in vitro and in vivo. Aim:20(S)-Ginsenoside Rh2 (Rh2) has shown potent inhibition on P-glycoprotein (P-gp), while most HIV protease inhibitors are both substrates and inhibitors of P-gp and CYP3A4. The aim of this study was to investigate the potential pharmacokinetic interactions between Rh2 and the HIV protease inhibitor ritonavir.Methods:The effects of Rh2 on the cellular accumulation and transepithelial transport of ritonavir were studied in Caco-2 and MDCK-MDR1 cells. Male rats were administered Rh2 (25 or 60 mg/kg, po) or Rh2 (5 mg/kg, iv), followed by ritonavir (25 mg/kg, po). The P-gp inhibitors verapamil (20 mg/kg, po) or GF120918 (5 mg/kg, po) were used as positive controls. The concentrations of ritonavir in plasma, bile, urine, feces and tissue homogenates were analyzed using LC-MS.Results:Rh2 (10 μmol/L) significantly increased the accumulation and inhibited the efflux of ritonavir in Caco-2 and MDCK-MDR1 cells, as verapamil did. But Rh2 did not significantly alter ritonavir accumulation or transport in MDCK-WT cells. Intravenous Rh2 significantly increased the plasma exposure of ritonavir while reducing its excretion in the bile, and oral verapamil or GF120918 also increased plasma exposure of ritonavir but without changing its excretion in the bile. Interestingly, oral Rh2 at both doses did not significantly change the plasma profile of ritonavir. Moreover, oral Rh2 (25 mg/kg) significantly elevated the ritonavir concentration in the hepatic portal vein, and markedly increased its urinary excretion and tissue distribution, which might counteract the elevated absorption of ritonavir.Conclusion:Rh2 inhibits the efflux of ritonavir through P-gp in vitro. The effects of Rh2 on ritonavir exposure in vivo depend on the administration route of Rh2: intravenous, but not oral, administration of Rh2 significantly increased the plasma exposure of ritonavir. 23585146 Validity and Responsiveness of VELO: A Velopharyngeal Insufficiency Quality of Life Measure. Objective Test the Velopharyngeal Insufficiency (VPI) Effects on Life Outcomes (VELO) instrument for validity, reliability, and responsiveness. Study Design Observational cohort. Setting Academic tertiary medical center. Subjects Children with VPI (n = 59) and their parents (n = 84) were prospectively enrolled from a pediatric VPI clinic. Methods Pediatric speech language pathologists diagnosed VPI using perceptual speech analysis and rated VPI severity and speech intelligibility deficit (each as minimal, mild, moderate, or severe). All parents and youth 8+ years old (n = 24) completed the VELO instrument and other quality-of-life questionnaires at baseline; the first 40 subjects completed the VELO instrument again 2 weeks later. Treatments included Furlow palatoplasty (n = 20), sphincter pharyngoplasty (n = 14), or an obturator (n = 2), and 29 of 36 (81%) subjects completed the questionnaires 3 months posttreatment. VELO was tested with correlations for criterion validity against VPI severity, construct validity against speech intelligibility and velopharyngeal gap size, and concurrent validity against other quality-of-life measures (r > .40 demonstrating validity); for test-retest reliability using intraclass correlation (>.6 demonstrating reliability); and for responsiveness with the 3-month posttreatment measure using the paired t test. Results Parental responses are reported; youth responses showed similar results. The VELO instrument did not meet criterion validity (r = -.18, P = .10), or functional construct validity (r = -.37, P = .001), but did meet anatomic construct and concurrent validity (each r > .50, P < .01). VELO scores demonstrated excellent test-retest reliability (r = .85, P < .001) and responsiveness (baseline 54 ± 14 to posttreatment 70 ± 18, P < .001). Conclusion VELO provides a VPI-specific quality-of-life instrument that demonstrates concurrent validity, test-retest reliability, and responsiveness to change in quality of life with treatment. 23924949 Interleukin-6 and obesity: the crosstalk between intestine, pancreas and liver. The concept of IL-6 as a deleterious interleukin was challenged by its anti-inflammatory actions. The beneficial health effects of exercise and the crosstalk between insulin-sensitive tissues and insulin-producing cells are mediated by IL-6. IL-6 displays pleiotropic functions in a tissue-specific and physiological context-dependent manner. There is evidence suggesting that IL-6 worsens insulin resistance in the liver and adipose tissue, while improving insulin sensitivity in the muscle. The effects of this cytokine are influenced by its acute or chronical presence, the latter being associated with insulin resistance. IL-6 has anti-inflammatory effects and a compensatory role in obesity by increasing islet GLP-1 production. The therapeutic approach of blocking IL-6 signal can be diabetogenic. 23850397 Preparation, characterization, and transport of dexamethasone-loaded polymeric nanoparticles across a human placental in vitro model. The purpose of this study was to prepare dexamethasone-loaded polymeric nanoparticles and evaluate their potential for transport across human placenta. Statistical modeling and factorial design was applied to investigate the influence of process parameters on the following nanoparticle characteristics: particle size, polydispersity index, zeta potential, and drug encapsulation efficiency. Dexamethasone and nanoparticle transport was subsequently investigated using the BeWo b30 cell line, an in vitro model of human placental trophoblast cells, which represent the rate-limiting barrier for maternal-fetal transfer. Encapsulation efficiency and drug transport were determined using a validated high performance liquid chromatography method. Nanoparticle morphology and drug encapsulation were further characterized by cryo-transmission electron microscopy and X-ray diffraction, respectively. Nanoparticles prepared from poly(lactic-co-glycolic acid) were spherical, with particle sizes ranging from 140 to 298nm, and encapsulation efficiency ranging from 52 to 89%. Nanoencapsulation enhanced the apparent permeability of dexamethasone from the maternal compartment to the fetal compartment more than 10-fold in this model. Particle size was shown to be inversely correlated with drug and nanoparticle permeability, as confirmed with fluorescently labeled nanoparticles. These results highlight the feasibility of designing nanoparticles capable of delivering medication to the fetus, in particular, potential dexamethasone therapy for the prenatal treatment of congenital adrenal hyperplasia. 23819728 Effects of respiratory and non-respiratory factors on disability among older adults with airway obstruction: The Cardiovascular Health Study. Abstract Background: High rates of disability associated with chronic airway obstruction may be caused by impaired pulmonary function, pulmonary symptoms, other chronic diseases, or systemic inflammation. Methods: We analyzed data from the Cardiovascular Health Study, a longitudinal cohort of 5888 older adults. Categories of lung function (normal; restricted; borderline, mild-moderate, and severe obstruction) were delineated by baseline spirometry (without bronchodilator). Disability-free years were calculated as total years alive and without self-report of difficulty performing &γτ;1 Instrumental Activities of Daily Living over 6 years of follow-up. Using linear regression, we compared disability-free years by lung disease category, adjusting for demographic factors, body mass index, smoking, cognition, and other chronic co-morbidities. Among participants with airflow obstruction, we examined the association of respiratory factors (FEV1 and dyspnea) and non-respiratory factors (ischemic heart disease, congestive heart failure, diabetes, muscle weakness, osteoporosis, depression and cognitive impairment) on disability-free years. Results: The average disability free years were 4.0 out of a possible 6 years. Severe obstruction was associated with 1 fewer disability-free year compared to normal spirometry in the adjusted model. For the 1,048 participants with airway obstruction, both respiratory factors (FEV1 and dyspnea) and non-respiratory factors (heart disease, coronary artery disease, diabetes, depression, osteoporosis, cognitive function, and weakness) were associated with decreased disability-free years. Conclusions: Severe obstruction is associated with greater disability compared to patients with normal spirometery. Both respiratory and non-respiratory factors contribute to disability in older adults with abnormal spirometry. 23897873 Primary progressive aphasia and the language network: The 2013 H. Houston Merritt Lecture. Review of clinical and biological features of primary progressive aphasia (PPA). The PPA syndrome arises when language-dominant (usually left) hemisphere becomes the principal target of neurodegeneration. Depending on the distribution of neuronal loss within the language network, agrammatic (PPA-G), logopenic (PPA-L), and semantic (PPA-S) subtypes are identified. The most common underlying neuropathology is frontotemporal degeneration with tauopathy in PPA-G, frontotemporal degeneration with TDP-43 proteinopathy in PPA-S, and Alzheimer pathology in PPA-L. When Alzheimer pathology is detected, the neurofibrillary tangles show lower entorhinal-to-neocortical ratios and greater leftward asymmetry in PPA than in the typical amnestic dementia of Alzheimer disease. The ε4 allele of APOE, a major risk factor for Alzheimer pathology in amnestic dementias, is not a risk factor for Alzheimer pathology in PPA. These observations indicate that Alzheimer disease has biological variants with distinct patterns of lesion distribution and perhaps also molecular background. The selective vulnerability of the language network in PPA is likely to reflect complex interactions between factors that determine the type of histopathology, on one hand, and those that influence the resilience of the language network, on the other. A history of learning disability, including dyslexia, is emerging as one of the potential factors in this second group of determinants. Patient care in PPA should be individualized so that speech therapy can address the specific type of language impairment while pharmacologic therapy is directed to the underlying disease process. 23904623 Antisense Reduction of Tau in Adult Mice Protects against Seizures. Tau, a microtubule-associated protein, is implicated in the pathogenesis of Alzheimer's Disease (AD) in regard to both neurofibrillary tangle formation and neuronal network hyperexcitability. The genetic ablation of tau substantially reduces hyperexcitability in AD mouse lines, induced seizure models, and genetic in vivo models of epilepsy. These data demonstrate that tau is an important regulator of network excitability. However, developmental compensation in the genetic tau knock-out line may account for the protective effect against seizures. To test the efficacy of a tau reducing therapy for disorders with a detrimental hyperexcitability profile in adult animals, we identified antisense oligonucleotides that selectively decrease endogenous tau expression throughout the entire mouse CNS-brain and spinal cord tissue, interstitial fluid, and CSF-while having no effect on baseline motor or cognitive behavior. In two chemically induced seizure models, mice with reduced tau protein had less severe seizures than control mice. Total tau protein levels and seizure severity were highly correlated, such that those mice with the most severe seizures also had the highest levels of tau. Our results demonstrate that endogenous tau is integral for regulating neuronal hyperexcitability in adult animals and suggest that an antisense oligonucleotide reduction of tau could benefit those with epilepsy and perhaps other disorders associated with tau-mediated neuronal hyperexcitability. 23856882 Moral Distress and its Interconnection with Moral Sensitivity and Moral Resilience: Viewed from the Philosophy of Viktor E. Frankl. The interconnection between moral distress, moral sensitivity, and moral resilience was explored by constructing two hypothetical scenarios based on a recent Swedish newspaper report. In the first scenario, a 77-year-old man, rational and awake, was coded as "do not resuscitate" (DNR) against his daughter's wishes. The patient died in the presence of nurses who were not permitted to resuscitate him. The second scenario concerned a 41-year-old man, who had been in a coma for three weeks. He was also coded as "do not resuscitate" and, when he stopped breathing, was resuscitated by his father. The nurses persuaded the physician on call to resume life support treatment and the patient recovered. These scenarios were analyzed using Viktor Frankl's existential philosophy, resulting in a conceivable theoretical connection between moral distress, moral sensitivity, and moral resilience. To substantiate our conclusion, we encourage further empirical research. 23313807 Evaluation of cage leaving behaviour in rats as a free choice paradigm. Introduction: The free exploratory paradigm is regarded as a reliable test for trait anxiety in mice but it may also be useful in rats. Previously, we showed that rat strains differ in their free exploration of novel areas, i.e. the surroundings of their familiar home cage when the lid was removed. Aim: Therefore, the purpose of the present study was to further examine strain, sex, and age differences in animals from different breeders in combination with pharmacological treatment designed to modify anxiety. Methods: In the present study free exploratory behaviour test was evaluated in Sprague Dawley and Wistar rats from different breeders. We assessed seasonal variation, habituation to the test, and the impact of gender and age on exploration. Furthermore, we monitored exploration following intraperitoneal diazepam, 8-OH-DPAT and caffeine administration. Parameters measured were latency to start exploring the outside of the cage, the percentage of rats that explored the outside, as well as the number of visits. Results: There was no seasonal variability in free exploratory behaviour. However, strains and sexes differed in the test results, though age-related differences had less impact. Diazepam (2mg/kg) and 8-OH-DPAT (30, 100 and 300μg/kg) decreased neophobia while caffeine (50mg/kg) increased the latency to explore the outside the next day. Discussion: The free exploratory behaviour test can be used as a simple and complementary test to study trait anxiety-related behaviour in rats. 23933877 In vitro efficacy of synthetic skin repellent IR3535 on head lice (Pediculus capitis). In in vitro tests, skin repellent IR3535, applied in the form of the Diffusil(®) H Prevental product in an aerosol bomb (active compound 20 %), killed 100 % of head lice (females and males) and nymphs 2 and 3, when directly sprayed at a dose of 0.94 mg of the active compound per square centimeter. Crawling lice exposed for 1 min on the filter paper impregnated by the same concentration showed no effort to suck blood 30 min after exposition. Twenty hours later, their mortality rate was 11 %. After the lice had been exposed for approximately 1 min (until they actively left the area) on 5 cm round areas of skin of test persons treated with the repellent at a mean total dose of 23.3 mg of active compound, they showed no effort to suck blood on the clean skin of other test person either immediately after exposure or 30 min later. Their mortality after 20 h ranged from 59 to 16 %, depending on the time elapsed from skin treatment (10 min to 27 h). 23462938 Measuring the efficiencies of visiting nurse service agencies using data envelopment analysis. This study develops a measure of the efficiency of visiting nurse (VN) agencies in Japan, examining the issues related to the measurement of efficiency, and identifying the characteristics that influence efficiency. We have employed a data envelopment analysis to measure the efficiency of 108 VN agencies, using the numbers of 5 types of staff as the input variables and the numbers of 3 types of visits as the output variables. The median efficiency scores of the VN agencies were found to be 0.80 and 1.00 according to the constant returns to scale (CRS) and variable returns to scale (VRS) models, respectively, and the median scale efficiency score was 0.95. This study supports using both the CRS and VRS models to measure the scale efficiency of VN service agencies. We also found that relatively efficient VN agencies filled at least 30 % of staff positions with experienced workers, and so concluded that this characteristic has a direct influence on the length of visits. 23067575 Genetic approaches in Drosophila for the study neurodevelopmental disorders. The fruit fly Drosophila melanogaster is one of the premier genetic model organisms used in biomedical research today owing to the extraordinary power of its genetic tool-kit. Made famous by numerous seminal discoveries of basic developmental mechanisms and behavioral genetics, the power of fruit fly genetics is becoming increasingly applied to questions directly relevant to human health. In this review we discuss how Drosophila research is applied to address major questions in neurodevelopmental disorders. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. 23969101 A Novel Liposomal Formulation of FTY720 (Fingolimod) for Promising Enhanced Targeted Delivery. We describe here development and characterization of the physicochemical and pharmacokinetic properties a novel liposomal formulation for FTY720 delivery, LP-FTY720. The mean diameter of LP-FTY720 was ~157 nm, and the FTY720 entrapment efficiency was ~85%. The liposomal formulation protected FTY720 from degradation in aqueous buffer and showed toxicity in CLL patient B cells comparable to that of free FTY720. Following intravenous injection in ICR mice, LP-FTY720 had an increased elimination phase half-life (~ 28 vs. ~ 19 hr) and decreased clearance (235 vs. 778 mL/hr/kg) compared to the free drug. Antibodies against CD19, CD20 and CD37 were incorporated into LP-FTY720, which provided targeted delivery to CLL patient B cells and thus achieved higher killing efficacy. The novel liposomal carrier of FTY720 demonstrated improved pharmacokinetic properties, comparable activity, and a potential platform for targeted delivery to CLL by overcoming the limited application of free FTY720 to B malignancy treatment. 23969402 Attitudes About Palliative Care: A Comparison of Pediatric Critical Care and Oncology Providers. IntroductionPediatric critical care and oncology providers care for patients who have life-threatening or serious illness, yet they receive little palliative care education.ObjectiveCompare oncology and critical care providers' attitudes regarding palliative care.MethodsAn electronic survey assessed respondents' opinions of whether, when, and why palliative care should be utilized.ResultsResponse rate was 49%. Critical care physicians were more likely to incorporate palliative care for psychosocial support; oncologists for symptom control. Those with palliative care education were more likely to involve in palliative care, did so earlier and for reasons other than end-of-life planning.ConclusionsOncology and critical care providers utilized palliative care for different reasons. 23374329 Challenges of providing maintenance hemodialysis in a resource poor country: Experience from a single teaching hospital in Lagos, Southwest Nigeria. Providing maintenance hemodialysis is associated with high costs and poor outcomes. In Nigeria, more than 90% of the population lives below the poverty line, and patients with end-stage renal disease (ESRD) pay out-of-pocket for maintenance hemodialysis. To highlight the challenges of providing maintenance hemodialysis for patients with ESRD in Nigeria, we reviewed records of all patients who joined the maintenance hemodialysis program of our dialysis unit over a 21-month period. Information regarding frequency of hemodialysis, types of vascular access for dialysis, mode of anemia treatment and frequency of blood transfusion received were retrieved. One hundred and twenty patients joined the maintenance hemodialysis program of our unit during the period under review. Seventy-two (60%) were males and the mean age of the study population was 47 + 14 years. The mean hemoglobin concentration at commencement of dialysis was 7.3 g/dL + 1.6 g/dL. The initial vascular access was femoral vein cannulation in all the patients. A total of 73.5% of the patients required blood transfusion at some point with 33% receiving five or more pints of blood. Only 3.3% of the patients had thrice weekly dialysis, 21.7% dialyzed twice weekly, 23.3% once weekly, 16.7% once in two weeks, 2.5% once in three weeks and 11.7% once monthly. At the time of review, 8.3% of the patients had died while 38.3% were lost to follow-up. Majority of patients with ESRD on maintenance hemodialysis in our unit were poorly prepared for dialysis, were under-dialyzed, and were frequently transfused with blood with resultant poor outcomes. 23849679 4D-networking by mitotic phosphatases. Faithful progression through mitosis is critically dependent on the timely phosphorylation and dephosphorylation of a host of proteins. The involved protein kinases and phosphatases are embedded in interconnected feedback and feedforward circuits that ensure swift and robust phase transitions. Here we review recent evidence showing that protein phosphatases are modulators of the mitotic entry but also organize the mitotic exit through an orderly dephosphorylation of their substrates. In addition, phosphatases spatiotemporally restrict the phosphorylation of key regulatory proteins and oppose kinases to control highly dynamic mitotic processes, including chromosome congression and checkpoint signaling. In accordance with their important role as nodes in phosphorylation networks, mitotic protein phosphatases are tightly regulated in four dimensions. 23256725 The effects of kisspeptin in human reproductive function - therapeutic implications. Kisspeptin is a 54-amino acid peptide which is encoded by the KiSS-1 gene and activates the G protein-coupled receptor GPR54. Evidence suggests that this system is a key regulator of mammalian and human reproduction. Animal studies have shown that GPR54-deficient mice have abnormal sexual development. Central and peripheral administration of kisspeptin stimulates the hypothalamic-pituitary-gonadal (HPG) axis whilst pre-administration of a gonadotrophin releasing hormone (GnRH) antagonist abolishes this effect. In humans, inactivating GPR54 mutations cause normosmic hypogonadotrophic hypogonadism whilst activation of GPR54 signalling is associated with premature puberty. In healthy human volunteers, the acute intravenous administration of kisspeptin potently increases plasma luteinising hormone (LH) levels and significantly increases plasma follicle stimulating hormone (FSH) and testosterone without side effects in both males and in females particularly in the preovulatatory phase of the menstrual cycle. In infertility due to hypothalamic amenorrhoea acute administration of kisspeptin results in stimulation of reproductive hormones. The kisspeptin/GPR54 system therefore appears to play an important role in the regulation of reproduction in humans. Hence kisspeptin has potential as a novel tool for the manipulation of the HPG axis and treatment of infertility in humans. This review discusses the evidence highlighting kisspeptin's key role in human reproduction. 23566542 Relation of aspirin response to age in patients with stable coronary artery disease. Recent studies have suggested that clopidogrel response may vary significantly with age. Limited data are available exploring the age dependency of ex vivo aspirin response in young and old patients with stable coronary artery disease. Patients with stable coronary artery disease (n = 583) who had been treated with aspirin 75 to 325 mg/day for ≥1 week were recruited from a general cardiology practice. The study cohort was divided into 2 groups: patients aged <75 years (n = 438) and patients aged ≥75 years (n = 145). Aspirin response was determined using the VerifyNow Aspirin Test, and resistance was defined as ≥500 or 550 aspirin reaction units (ARU). The independent predictive value of age on VerifyNow score (as a continuous function) was determined using multivariate linear regression, adjusted for gender, body mass index, and diabetes mellitus. Younger and older patients had similar baseline clinical profiles, including relative doses of aspirin therapy. The mean VerifyNow Aspirin Test score was significantly higher in patients aged ≥75 years: 450 ± 54 versus 434 ± 53 ARU (p = 0.0007). After accounting for the primary covariates, age remained a predictor of VerifyNow score (p = 0.007). Aspirin resistance on the basis of the 500-ARU cutoff was higher in older patients (19% vs 11%, p = 0.009), but there was no difference when the 550-ARU cutoff was used (7% vs 5%, p = 0.40). In conclusion, aspirin response differs significantly by age in patients with stable CAD. 23874581 Mesothelin Virus-Like Particle Immunization Controls Pancreatic Cancer Growth through CD8(+) T Cell Induction and Reduction in the Frequency of CD4(+)foxp3(+)ICOS(-) Regulatory T Cells. Our previous study has shown that mesothelin (MSLN) is a potential immunotherapeutic target for pancreatic cancer. Here, we further studied the immunogenicity of chimeric murine MSLN-virus-like particles (mMSLN-VLPs), their ability to break tolerance to mMSLN, a self-antigen, and deciphered the mechanism of immune responses elicited by mMSLN-VLP immunization using a pancreatic cancer (PC) mouse model. In addition to what we have found with xenogeneic human MSLN-VLP (hMSLN-VLP), mMSLN-VLP immunization was able to break the tolerance to intrinsic MSLN and mount mMSLN-specific, cytotoxic CD8(+) T cells which led to a significant reduction in tumor volume and prolonged survival in an orthotopic PC mouse model. Furthermore, CD4(+)foxp3(+) regulatory T cells (Tregs) were progressively decreased in both spleen and tumor tissues following mMSLN-VLP immunization and this was at least partly due to elevated levels of IL-6 production from activated plasmocytoid dendritic cell (pDC)-like cells following mMSLN-VLP immunization. Moreover, mMSLN-VLP treatment mainly reduced the frequency of the CD4(+)foxp3(+)ICOS(-) Treg subset. However, mMSLN-VLP induced IL-6 production also increased ICOSL expression on pDC-like cells which supported the proliferation of immunosuppressive CD4(+)foxp3(+)ICOS(+) Treg cells. This study reveals that mMSLN-VLP immunization is capable of controlling PC progression by effectively mounting an immune response against mMSLN, a tumor self-antigen, and altering the immunosuppressive tumor microenvironment via activation of pDCs-like cells and reduction in the frequency of CD4(+)foxp3(+)ICOS(-) Treg cells. However, combination therapies will likely need to be used in order to target residual CD4(+)foxp3(+)ICOS(+) Treg cells. 23423714 Metabolic dephenylation of the rubber antioxidant N-phenyl-2-naphthylamine to carcinogenic 2-naphthylamine in rats. N-Phenyl-2-naphthylamine (P2NA) was widely used as oxidation inhibitor, particularly in rubber manufacturing. Technical-grade P2NA was contaminated with carcinogenic 2-naphthylamine (2NA), and bladder cancer risk in exposed workers was attributed to this impurity. Investigations in humans and mammalian species revealed that small amounts of 2NA are excreted into urine after exposure to P2NA. However, since 2NA per se is not carcinogenic and main downstream metabolites of 2NA have not been found in urine so far, it remained uncertain if 2NA derived from P2NA dephenylation is further activated to carcinogenic downstream metabolites. An experimental animal study was therefore designed to indicate if, and if yes to which extent, 2NA from P2NA dephenylation is accessible to the metabolic pathway that is held responsible for the carcinogenicity of 2NA. Groups of 5 male and female CD rats were dosed with P2NA (2-550 mg/kg b.w.) and 2NA (0.075-75 mg/kg b.w.); 2NA-haemoglobin adducts and urinary 2NA excretion were determined applying GC-MS/MS. 2NA haemoglobin adducts originated dose-dependently after 2NA and P2NA dosing. To induce identical adduct concentrations, an approximately 100-200-fold higher dose of P2NA was necessary compared to 2NA. Since haemoglobin adducts are formed by the same pathway (N-hydroxylation) as the ultimate carcinogens from 2NA, the comparison of adduct concentrations after 2NA and P2NA dosage permits a quantitative estimate of the carcinogenicity of P2NA. The results show that 2NA derived from dephenylation of P2NA enters the carcinogenic downstream pathway of 2NA in rats. Hence, the bladder cancer risk after human exposures to P2NA must be re-evaluated. 23934157 Estrogen Aggravates Iodoacetate-induced Temporomandibular Joint Osteoarthritis. Temporomandibular joint osteoarthritis (TMJOA) is clinically characterized by female preponderance, with a female-to-male ratio of more than 2:1; however, the underlying mechanism remains obscure. We examined the effects of estrogen on TMJOA induced by monosodium iodoacetate. Female rats were randomly and equally divided into 5 groups: control, sham-ovariectomized, and ovariectomized rats treated, respectively, with 17β-estradiol (E2) at doses of 0 μg, 20 μg, and 80 μg/day until the end of the experiment. After induction of TMJOA, TMJs were evaluated by histopathology and microCT, and the expression of Fas, FasL, caspase 3, and caspase 8 was evaluated by real-time polymerase chain-reaction or immunohistochemistry. Another 5 groups of female rats were used to evaluate the effect of estrogen receptor antagonist ICI 182780 on E2 effects on TMJOA, when injected intraperitoneally into the control, sham-ovariectomized, and 80-μg-E2-treated groups. We found that E2 potentiated cartilage degradation and subchondral bone erosion in iodoacetate-induced TMJOA. E2 also potentiated mRNA expression of Fas, FasL, caspase 3, and caspase 8 in the condylar cartilage. Moreover, the estrogen receptor antagonist partially blocked E2 effects on TMJOA. These findings suggest that E2 could aggravate TMJOA, which may be an important mechanism underlying the sexual dimorphism of TMJOA. 23855642 Strongyloidiasis complicating immunosuppression for pemphigus vulgaris. A 35 year old woman who was born in Bangladesh developed oral erosions and painful cutaneous blisters. There was no other past medical history of note and she was not taking any medication.On examination she had oral and widespread cutaneous erosions and flaccid bullae affecting the skin. Nikolsky's sign was negative. A clinical diagnosis of pemphigus vulgaris (PV) was made and she was commenced on oral prednisolone 60mg daily, lansoprazole and alendronic acid. This article is protected by copyright. All rights reserved. 23843988 Paleoecological and taphonomic implications of insect-damaged pleistocene vertebrate remains from rancho la brea, southern california. The La Brea Tar Pits, the world's richest and most important Late Pleistocene fossil locality, offers unsurpassed insights into southern California's past environments. Recent studies at Rancho La Brea document that insects serve as sensitive and valuable paleoecological and taphonomic indicators. Of the thousands of fossil bird and mammal bones recovered from the Tar Pits, insect trace damage is thus far almost exclusively confined to the foot bones of large herbivores, especially bison, camel, and horse species. Our laboratory experiments with dermestid and tenebrionid beetles establish that the larvae of both consume bone, producing different characteristic feeding traces and providing the first documentation that tenebrionids consume bone. The presence of carcass-exploiting insects in the Rancho La Brea biota provides insight into the taphonomy of the asphaltic bone masses and the environmental conditions under which they accumulated. The succession of dermestids, tenebrionids, and indeterminate traces on many of the foot elements, combined with the climate restrictions and life cycles of these insects, indicate that carcasses could remain unsubmerged for at least 17-20 weeks, thus providing the most reliable estimate to date. Attribution of these traces also suggests that the asphaltic fossils only accumulated during warmer intervals of the Late Pleistocene. Forensic studies need to reevaluate the role of tenebrionids in carcass decomposition and other additional insects that modify bone. 23672960 Organohalogenated contaminants in domestic cats' plasma in relation to spontaneous acromegaly and type 2 diabetes mellitus: a clue for endocrine disruption in humans? It was recently hypothesized that pets may serve as sentinels to explore human exposure to organohalogenated chemicals (OHCs) via indoor environments and adverse health effects. The current study investigates OHCs contamination in domestic cats suffering from diabetes mellitus (DM), particularly DM induced by acromegaly and a form of DM akin to human type 2 DM (T2DM). Plasma from three groups of domestic cats was analyzed: acromegaly induced DM, T2DM and age matched control cats without DM. Analytes targeted included organochlorine pesticides, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs), together with their hydroxylated (HO-) metabolites. Similar PCB profiles were measured in cat plasma compared to humans, while the PBDE profile (dominated by BDE-99 (48%-55%) and BDE-47 (19%-25%)), the PCB and PBDE metabolite profiles were different in cat plasma than found in humans. Significantly higher OHC concentrations were recorded in plasma of acromegalic cats compared to the other two groups. Group differences in the PCBs/HO-PCBs ratios suggest that acromegalic cats have a lower capacity to metabolize persistent OHCs, like PCBs, than diabetic cats or cats without an endocrinopathy. As pituitary tumorigenesis in animals can be induced by estrogens, and PCBs may act as xenoestrogens, further investigation into whether there could be a causative link with the induction of feline acromegaly is warranted. Interestingly, BDE-47/BDE-99 ratios in cats were similar to the ratios in house dust. The results of this study suggest that domestic cats may represent a good model to assess human exposure to chemicals present in indoor dust. 23888433 Guidelines for elderly patients with multimorbidity: how to cope with a dark night without fear. The epidemiological transition has produced a society with a growing number of the elderly affected by multiple chronic diseases which often requires polypharmacy. Despite being the main users of medications, the elderly are largely underrepresented in clinical trials, especially if they have multimorbidity. It follows that the results of these trials are not applicable in the real world and potentially harmful. In order to breach the wall of this complexity, several suggestions have been put forward, from new clinical trial methodology, simulation models, and the use of patient-centered as opposed to disease-centered indicators. It is likely that comparative effectiveness research will accelerate the shift toward a focus on "universal" outcomes on which all diseases exert an effect. I believe that there is no "one-size-fits-all" solution in this area, but two ideas come to my mind. Why do we not invest more in educating our future geriatricians? And why do we not invest in public awareness campaigns? 23701251 A phase II open-label study of the intravenous administration of homoharringtonine in the treatment of myelodysplastic syndrome. Homoharringtonine is an alkaloid inhibitor of protein synthesis with activity in myeloid malignancies. We report a phase II pilot study of homoharringtonine in myelodysplastic syndrome (MDS). Induction consisted of homoharringtonine at 2.5 mg/m(2) via continuous infusion for 7 days. Maintenance was given every 4 weeks. Nine patients were enrolled: five with refractory anaemia with excess blasts, two with refractory anaemia with excess blasts in transformation, one each with refractory anaemia and chronic myelomonocytic leukaemia respectively. Median age was 70 years (55-84) and 6 (66%) were male. Per International Prognostic Scoring System (IPSS) two patients were intermediate-1, five intermediate-2 and two high-risk. Median chemotherapy courses were one (1-3). One patient (11%) responded with complete haematological and cytogenetic remission after one course. Eight patients did not respond (four had stable disease, two progressed to acute leukaemia and two died during induction - from aspergillus pneumonia and intracerebral haemorrhage respectively). Grade 3/4 myelosuppression seen in 56% (5/9). Serious non-haematological toxicities included one case of grade 4 left bundle branch heart block and one grade 3 nephrotoxicity. Median time between courses was 42 days (35-72 days). In conclusion homoharringtonine might have clinical activity in some patients with MDS. 23631750 Multicenter implementation of a severe sepsis and septic shock treatment bundle. Severe sepsis and septic shock are leading causes of intensive care unit (ICU) admission, morbidity, and mortality. The effect of compliance with sepsis management guidelines on outcomes is unclear. To assess the effect on mortality of compliance with a severe sepsis and septic shock management bundle. Observational study of a severe sepsis and septic shock bundle as part of a quality improvement project in 18 ICUs in 11 hospitals in Utah and Idaho. Among 4,329 adult subjects with severe sepsis or septic shock admitted to study ICUs from the emergency department between January 2004 and December 2010, hospital mortality was 12.1%, declining from 21.2% in 2004 to 8.7% in 2010. All-or-none total bundle compliance increased from 4.9-73.4% simultaneously. Mortality declined from 21.7% in 2004 to 9.7% in 2010 among subjects noncompliant with one or more bundle element. Regression models adjusting for age, severity of illness, and comorbidities identified an association between mortality and compliance with each of inotropes and red cell transfusions, glucocorticoids, and lung-protective ventilation. Compliance with early resuscitation elements during the first 3 hours after emergency department admission caused ineligibility, through lower subsequent severity of illness, for these later bundle elements. Total severe sepsis and septic shock bundle compliances increased substantially and were associated with a marked reduction in hospital mortality after adjustment for age, severity of illness, and comorbidities in a multicenter ICU cohort. Early resuscitation bundle element compliance predicted ineligibility for subsequent bundle elements. 23883676 Sex differences in angiotensin II- and aldosterone-induced hypertension: the central protective effects of estrogen. Premenopausal women have lower blood pressure and a reduced incidence of cardiovascular disease compared to age-matched men. Similar sex differences have been seen across species and in multiple animal models of hypertension. While important progress over the last decade has been made in elucidating some of the mechanisms underlying these differences, there are still significant gaps in our knowledge. Understanding the cellular and molecular mechanisms responsible for sex differences in hypertension will be important for developing sex specific therapies targeted toward the prevention and treatment of hypertension. Female sex hormones, especially estrogen, have been demonstrated to modulate the renin-angiotensin-aldosterone system (RAAS) and to have beneficial effects on cardiovascular function through actions not only on the kidney, heart and vasculature, but also on the central nervous system (CNS). This review primarily focuses on the central regulatory actions of estrogen on brain nuclei involved in blood pressure regulation and the interactions between estrogen and the RAAS in the CNS by which estrogen plays an important protective role against the development of hypertension. 23892208 A deficiency in CCR2+ monocytes: the hidden side of Alzheimer's disease. Alzheimer's disease (AD) is a neurodegenerative disorder characterized by intracellular neurofibrillary tangle formation and extracellular amyloid-β (Aβ) deposition. To date, microglia seem to act as double-edged swords, being either beneficial (e.g. clearance of Aβ) or detrimental (e.g. secretion of neurotoxic factors) in AD. Following a rather intense debate on the question, a consensus has emerged that microglia can renew themselves via proliferation of already differentiated microglia as well as via the de novo recruitment of monocytes of mouse models of AD. However, recent advances suggest distinct function for resident and bone marrow-derived microglia (BMDM), and have emphasized the neuroprotective functions of BMDM. BMDM is the only subset of cells that restrict cerebral amyloidosis in the AD brain, which has been recently attributed to CCR2(+) monocytes. Moreover, an impaired recruitment of CCR2(+) monocytes has been reported in AD patients, as seen from the CCR2(+) monocytopenia found in the bloodstream and BM. The present review summarizes the current knowledge on the roles and dysfunctions of CCR2(+) monocytes in AD and their potential as key therapeutic targets. 23892635 List-mode reconstruction for the Biograph mCT with physics modeling and event-by-event motion correction. Whole-body PET/CT scanners are important clinical and research tools to study tracer distribution throughout the body. In whole-body studies, respiratory motion results in image artifacts. We have previously demonstrated for brain imaging that, when provided with accurate motion data, event-by-event correction has better accuracy than frame-based methods. Therefore, the goal of this work was to develop a list-mode reconstruction with novel physics modeling for the Siemens Biograph mCT with event-by-event motion correction, based on the MOLAR platform (Motion-compensation OSEM List-mode Algorithm for Resolution-Recovery Reconstruction). Application of MOLAR for the mCT required two algorithmic developments. First, in routine studies, the mCT collects list-mode data in 32 bit packets, where averaging of lines-of-response (LORs) by axial span and angular mashing reduced the number of LORs so that 32 bits are sufficient to address all sinogram bins. This degrades spatial resolution. In this work, we proposed a probabilistic LOR (pLOR) position technique that addresses axial and transaxial LOR grouping in 32 bit data. Second, two simplified approaches for 3D time-of-flight (TOF) scatter estimation were developed to accelerate the computationally intensive calculation without compromising accuracy. The proposed list-mode reconstruction algorithm was compared to the manufacturer's point spread function + TOF (PSF+TOF) algorithm. Phantom, animal, and human studies demonstrated that MOLAR with pLOR gives slightly faster contrast recovery than the PSF+TOF algorithm that uses the average 32 bit LOR sinogram positioning. Moving phantom and a whole-body human study suggested that event-by-event motion correction reduces image blurring caused by respiratory motion. We conclude that list-mode reconstruction with pLOR positioning provides a platform to generate high quality images for the mCT, and to recover fine structures in whole-body PET scans through event-by-event motion correction. 23371970 Fast-twitch glycolytic skeletal muscle is predisposed to age-induced impairments in mitochondrial function. The etiology of mammalian senescence is suggested to involve the progressive impairment of mitochondrial function; however, direct observations of age-induced alterations in actual respiratory chain function are lacking. Accordingly, we assessed mitochondrial function via high-resolution respirometry and mitochondrial protein expression in soleus, quadricep, and lateral gastrocnemius skeletal muscles, which represent type 1 slow-twitch oxidative muscle (soleus) and type 2 fast-twitch glycolytic muscle (quadricep and gastrocnemius), respectively, in young (10-12 weeks) and mature (74-76 weeks) mice. Electron transport through mitochondrial complexes I and III increases with age in quadricep and gastrocnemius, which is not observed in soleus. Mitochondrial coupling efficiency during respiration through complex I also deteriorates with age in gastrocnemius and shows a tendency (p = .085) to worsen in quadricep. These data demonstrate actual alterations in electron transport function that occurs with age and are dependent on skeletal muscle type. 23651231 N-acetylcysteine Versus Placebo for Treating Nail Biting, a Double Blind Randomized Placebo Controlled Clinical Trial. Nail biting is a common behavioral problem. While there are established behavioral interventions for management, they are of modest efficacy, and there is minimal evidence for effective pharmacotherapy. This study investigated the role of N-acetylcysteine (NAC) a potent glutathione and glutamate modulator for the treatment of pathological nail biting in children and adolescents. This pilot randomized, double-blind, placebo-controlled clinical trial of NAC (800mg/day) or placebo enrolled 42 children and adolescents with chronic nail biting. Nail length was the objective outcome. Evaluations were carried out three times; before treatment, one month after enrollment in the study, and two months after enrollment. The duration (chronicity) of nail biting in the NAC and placebo groups was 3.63(2.45) and 5.09(3.74) years (P=0.14). The mean nail length gradually increased in both the NAC and placebo groups during this trial. There was a statistically significant difference between the two groups regarding increased nail length after the first month of trial [(5.21(5.75) and 1.18(3.02) millimeters], however no difference after two months was observed. Two patients in the NAC group discontinued medication due to adverse events. One patient experienced headache, agitation, and social withdrawal, and another patient expressed severe aggression after taking medication and was withdrawn from the study. This study supports the hypothesis that NAC decreases nail biting behavior in children and adolescents over the short term. NAC is relatively well tolerated and severe adverse effects are rare. However, there was a high rate of dropout. Further studies with longer durations that build on these preliminary data are recommended. This study is registered at the Iranian Registry of Clinical Trials (Irct registration number: IRCT201103023930N3). 23434636 Advances in the discovery of kinesin spindle protein (Eg5) inhibitors as antitumor agents. Cancer is considered as one of the most serious health problems. Despite the presence of many effective chemotherapeutic agents, their severe side effects together with the appearance of mutant tumors limit the use of these drugs and increase the need for new anticancer agents. Eg5 represents an attractive target for medicinal chemists since Eg5 is overexpressed in many proliferative tissues while almost no Eg5 is detected in nonproliferative tissues. Many Eg5 inhibitors displayed potent anticancer activity against some of the mutant tumors with limited side effects. The present review provides an overview about the progress in the discovery of Eg5 inhibitors especially from 2009 to 2012 as well as the clinical trials conducted on some of these inhibitors. 23767893 Management of simultaneous traumatic brain injury and aortic injury. Object Simultaneous traumatic brain injury (TBI) and aortic injury has been considered unsurvivable for many years because treatments such as sedation and blood pressure goals conflict for these 2 conditions. Additionally, surgical interventions for aortic injury often require full anticoagulation, which is contraindicated in patients with TBI. For these reasons, and due to the relative rarity of aortic injury/TBI, little data are available to guide treating physicians. Methods A retrospective review was performed on all simultaneous TBI and aortic injury cases from 2000 to 2012 at a university-affiliated, Level I trauma center. Patient demographics, imaging studies, interventions, and outcomes were analyzed. Traumatic brain injury/aortic injury cases treated with endovascular stenting were specifically studied to determine trends in procedure timing, use of anticoagulation, and neurological outcome. Results Thirty-three patients with concurrent TBI and aortic injury were identified over a 12-year period. The median patient age was 44 years (range 16-86 years) and the overall mortality rate after imaging diagnosis was 46%. All surviving patients were awake and neurologically functional at discharge, and 83% were discharged home or to rehabilitation facilities. Patients who died had a higher Injury Severity Scale score (p = 0.006). Severe TBI (p = 0.045) or hemodynamic instability (p = 0.015) upon arrival to the hospital was also correlated with increased mortality rates. Thirty-three percent of aortic injury/TBI patients (n = 11) underwent endovascular stenting, and 7 of these patients received intravenous anticoagulation therapy at the time of surgery. Six of these 7 anticoagulation-treated patients experienced no significant progression on postoperative brain CT, whereas 1 patient died of hemodynamic instability prior to undergoing further imaging. Conclusions Simultaneous TBI and aortic injury is a rare condition with a historically poor prognosis. However, these results suggest that many patients can survive with a good quality of life. Technological advances such as endovascular aortic stenting may improve patient outcome, and anticoagulation is not absolutely contraindicated after TBI. 23247176 Halogen-bonding-triggered supramolecular gel formation. Supramolecular gels are topical soft materials involving the reversible formation of fibrous aggregates using non-covalent interactions. There is significant interest in controlling the properties of such materials by the formation of multicomponent systems, which exhibit non-additive properties emerging from interaction of the components. The use of hydrogen bonding to assemble supramolecular gels in organic solvents is well established. In contrast, the use of halogen bonding to trigger supramolecular gel formation in a two-component gel ('co-gel') is essentially unexplored, and forms the basis for this study. Here, we show that halogen bonding between a pyridyl substituent in a bis(pyridyl urea) and 1,4-diiodotetrafluorobenzene brings about gelation, even in polar media such as aqueous methanol and aqueous dimethylsulfoxide. This demonstrates that halogen bonding is sufficiently strong to interfere with competing gel-inhibitory interactions and create a 'tipping point' in gel assembly. Using this concept, we have prepared a halogen bond donor bis(urea) gelator that forms co-gels with halogen bond acceptors. 23796259 A multi-country study of the "intrapartum stillbirth and early neonatal death indicator" in hospitals in low-resource settings. To determine the feasibility of introducing a simple indicator of quality of obstetric and neonatal care and to determine the proportion of potentially avoidable perinatal deaths in hospitals in low-income countries. Between September 1, 2011, and February 29, 2012, data were collected from consecutive women who were admitted to the labor ward of 1 of 6 hospitals in 4 low-income countries. Fetal heart tones on admission were monitored, and demographic and birth data were recorded. Data were obtained for 3555 women and 3593 neonates (including twins). The doptone was used on 97% of women admitted. The overall perinatal mortality rate was 34 deaths per 1000 deliveries. Of the perinatal deaths, 40%-45% occurred in the hospital and were potentially preventable by better hospital care. The results demonstrated that it is possible to accurately determine fetal viability on admission via a doptone. Implementation of doptone use, coupled with a concise data record, might form the basis of a low-cost and sustainable program to monitor and evaluate efforts to improve quality of care and ultimately might help to reduce the in-hospital component of perinatal mortality in low-income countries. 23660273 Analysis of the effect of various decalcification agents on the quantity and quality of nucleic acid (DNA and RNA) recovered from bone biopsies. Molecular studies are part of standard care for cancer patients. Bone, a common and sometimes sole site of metastasis, requires decalcification for morphological examination. Many commonly used decalcification agents contain strong acids that degrade nucleic acids. The paradigm shift in oncology, with biomarker targeted therapy and gene expression profiling analysis, requires sufficient nucleic acid recovery from bone biopsy specimens. We systematically studied the effects of a spectrum of decalcification agents on the quantity and quality of RNA and DNA recovered from bone biopsies. Multiple bone biopsies of similar size and cellularity were fixed in 10% neutral-buffered formalin, randomized to various decalcification agents for 2 hours then processed, and embedded. Tissue lysates were obtained from unstained sections and nucleic acid isolated. DNA and RNA were quantified. Assessment of DNA and RNA integrity was accomplished by comparison of the average cycle threshold by polymerase chain reaction of selected housekeeping genes for each agent. Results were then analyzed by 2-sample t test. There was a significant decrease in both DNA and RNA yield and integrity with strong acids (hydrochloric, nitric) vs 14% EDTA and formic acid. DNA yield was (mean nanograms) 6.15 vs 68.68 (P < .001) and RNA was (mean nanograms) 121.53 vs 288.89 (P = .003), respectively. DNA integrity (mean cycle threshold) was 35.79 vs 30.16 (P < .001), and RNA was 33.03 vs 26.5 (P < .001), respectively. Decalcification of bone biopsies with EDTA or formic acid agents was associated with a significant improvement in recovered nucleic acid quantity and quality. 23932951 Current strategies for inhibiting FGFR activities in clinical applications: opportunities, challenges and toxicological considerations. Aberrations in fibroblast growth factor receptor (FGFR) signaling are instrumental to the pathophysiology of several malignancies and disorders. Hence, FGFR inhibitors are explored in therapeutics with early candidates developed as competitors for the ATP-binding pocket in the kinase domain. More recent programs yielded compounds of diverse scaffolds with alternative binding modes. Concurrently, monoclonal antibodies and peptide-based agents provide independent options for clinical development. Notwithstanding this rapid progress, we contemplate the toxicological impact of FGFR inhibition based on the defined role of FGFR family members in physiology and homeostasis. The high homology among FGFR1-4 and also with other kinase subfamilies creates an additional challenge in developing selective inhibitors. It orchestrates an ongoing conundrum of moderating a balance between synergism through multitargeting kinase inhibition and minimizing off-target toxicities. 23921654 Brief report: a comparison of clinical and research practices in measuring cerebral perfusion pressure: a literature review and practitioner survey. Our objective was to determine whether there is variability in the foundational literature and across centers in how mean arterial blood pressure is measured to calculate cerebral perfusion pressure. We reviewed foundational literature and sent an e-mail survey to members of the Neurocritical Care Society. Of 32 articles reporting cerebral perfusion pressure data, the reference point for mean arterial blood pressure was identified in 16: 10 heart and 6 midbrain. The overall survey response rate was 14.3%. Responses from 31 of 34 (91%) United Council for Neurologic Subspecialties fellowship-accredited Neurointensive Care Units indicated the reference point was most often the heart (74%), followed by the midbrain (16%). Conflicting answers were received from 10%. There is substantive heterogeneity in both research reports and clinical practice in how mean arterial blood pressure is measured to determine cerebral perfusion pressure. 23937407 Polyelectrolyte Interlayer for Ultra-Sensitive Organic Transistor Humidity Sensors. We demonstrate low-voltage, flexible, transparent pentacene humidity sensors with ultrahigh sensitivity, good reliability, and fast response/recovery behavior. The excellent performances of these devices are derived from an inserted polyelectrolyte (poly[2-(methacryloyloxy)ethyltrimethylammonium chloride-co-3-(trimethoxysilyl)propyl methacrylate] (poly(METAC-co-TSPM)) interlayer, which releases free Cl(-) ions in the electrolyte dielectric layer under humid conditions and boosts the electrical current in the transistor channel. This has led to extreme device sensitivity, such that electrical signal variations exceeding 7 orders of magnitude have been achieved in response to a 15% change in the relative humidity level. The new sensors exhibit a fast responsivity and a stable performance toward changes in humidity levels. Furthermore, the humidity sensors, mounted on flexible substrates, provided low voltage (<5 V) operation while preserving the unique ultrasensitivity and fast responsivity of these devices. We believe that the strategy of utilizing the enhanced ion motion in an inserted polyelectrolyte layer of an OFET structure can potentially improve sensor technologies beyond humidity-responsive systems. 23698595 Neurodegenerative disorders and metabolic disease. Most genetic causes of neurodegenerative disorders in childhood are due to neurometabolic disease. There are over 200 disorders, including aminoacidopathies, creatine disorders, mitochondrial cytopathies, peroxisomal disorders and lysosomal storage disorders. However, diagnosis can pose a challenge to the clinician when patients present with non-specific problems like epilepsy, developmental delay, autism, dystonia and ataxia. The variety of specialist tests involved can also be daunting. This review aims to give a practical approach to the investigation and diagnosis of neurometabolic disease from the neonatal period to late childhood while prioritising disorders where there are therapeutic options. In particular, patients who have a complex clinical picture of several neurological and non-neurological features should be investigated. 23939069 Experimental demonstration and observation of a plasmon wave occuring at a GaAs-Au-GaN interface. Integration of surface plasmon structures using semiconductor materials is limited due to the difficulties encountered in maintaining the resonance conditions upon packaging. We propose here a technology process allowing us to bond two semiconductors, such as gallium nitride (GaN) and gallium arsenide (GaAs), through a thin metal layer. This solution allows the excitation of a surface plasmon wave in an integrated classical Kretschmann configuration. The Letter presents various metal bonding conditions employed for Au deposited on both GaN/sapphire and GaAs substrates aiming at semiconductor-metal-semiconductor interfaces transparent at telecom wavelengths. The process conditions for the bondings are optimized using Ti/Au (3  nm/30  nm) layers on each of the wafers to be bonded under an applied pressure of 500 mbar at a low temperature of 250°C. 23896690 Keys and seats: Spatial response coding underlying the joint spatial compatibility effect. Spatial compatibility effects (SCEs) are typically observed when participants have to execute spatially defined responses to nonspatial stimulus features (e.g., the color red or green) that randomly appear to the left and the right. Whereas a spatial correspondence of stimulus and response features facilitates response execution, a noncorrespondence impairs task performance. Interestingly, the SCE is drastically reduced when a single participant responds to one stimulus feature (e.g., green) by operating only one response key (individual go/no-go task), whereas a full-blown SCE is observed when the task is distributed between two participants (joint go/no-go task). This joint SCE (a.k.a. the social Simon effect) has previously been explained by action/task co-representation, whereas alternative accounts ascribe joint SCEs to spatial components inherent in joint go/no-go tasks that allow participants to code their responses spatially. Although increasing evidence supports the idea that spatial rather than social aspects are responsible for joint SCEs emerging, it is still unclear to which component(s) the spatial coding refers to: the spatial orientation of response keys, the spatial orientation of responding agents, or both. By varying the spatial orientation of the responding agents (Exp. 1) and of the response keys (Exp. 2), independent of the spatial orientation of the stimuli, in the present study we found joint SCEs only when both the seating and the response key alignment matched the stimulus alignment. These results provide evidence that spatial response coding refers not only to the response key arrangement, but also to the-often neglected-spatial orientation of the responding agents. 23902422 Safety and efficacy of a genetic vaccine targeting telomerase plus chemotherapy for the therapy of canine B-cell lymphoma. Abstract Client-owned pet dogs represent exceptional translational models for advancement of cancer research because they reflect the complex heterogeneity observed in human cancer. We have recently shown that a genetic vaccine targeting dog telomerase reverse transcriptase (dTERT) and based on adenovirus DNA electro-gene-transfer (Ad/DNA-EGT) technology can induce strong cell-mediated immune responses against this tumor antigen and increase overall survival of dogs affected by B-cell lymphosarcoma (LSA) in comparison with historical controls when combined with a cyclophosphamide, vincristine, and prednisone (COP) chemotherapy regimen. Here, we have conducted a double-arm clinical trial with an extended number of LSA patients, measured the antigen-specific immune response, and evaluated potential toxic effects of the immunotherapy along with a follow-up of patients survival for 3.5 years. The immune response was measured by enzyme-linked immunospot assay. The expression of dTERT was quantified by quantitative polymerase chain reaction. Changes in hematological parameters, local/systemic toxicity or organic dysfunction and fever were monitored over time during the treatment. dTERT-specific cell-mediated immune responses were induced in almost all treated animals. No adverse effects were observed in any dog patient that underwent treatment. The overall survival time of vaccine/COP-treated dogs was significantly increased over the COP-only cohort (>76.1 vs. 29.3 weeks, respectively, p<0.0001). There was a significant association between dTERT expression levels in LSA cells and overall survival among vaccinated patients. In conclusion, Ad/DNA-EGT-based cancer vaccine against dTERT in combination with COP chemotherapy is safe and significantly prolongs the survival of LSA canine patients. These data confirm the therapeutic efficacy of dTERT vaccine and support the evaluation of this approach for other cancer types as well as the translation of this approach to human clinical trials. 23845170 Evaluation of ovarian function in 35-40-year-old women with polycystic ovary syndrome. To assess gonadotrophin secretion, ovarian steroid production and ovarian reserve in PCOS women during the onset of reproductive decline, in order to characterize their ovarian function at this age. Forty PCOS patients and 35 healthy women (35-40 years of age) were included. Clinical history, anthropometry, transvaginal ultrasound and a leuprolide acetate test (10μg/kg s.c.) were performed. Gonadotrophins, steroid hormones, SHBG, inhibin B and AMH were determined. Basal and peak LH levels were similar in both groups. Basal and peak FSH levels were significantly higher in the control group. Androgens, peak oestradiol, ovarian volume, antral follicle count and AMH levels were significantly higher in PCOS patients. These observations suggest that during late reproductive age, gonadotrophin secretion in women with PCOS is clearly different from that observed in control women and may also differ from that of younger PCOS patients. New features like normal LH and lower FSH levels associated with a higher ovarian reserve may give a different reproductive profile to these women. 23624207 Augmented sensitivity to methotrexate by curcumin induced overexpression of folate receptor in KG-1 cells. Folate receptors are targets of various strategies aimed at efficient delivery of anti-cancer drugs. Folate receptors also play a role in the uptake of antifolate drugs which are used for therapeutic intervention in leukemia. Therefore, it is important to identify compounds which regulate expression of folate receptors in leukemic cells. The present study examined if curcumin could modulate the uptake and cytotoxicity of the antifolate drug methotrexate, in KG-1 leukemic cells. This is the first report to show that curcumin (10-50 Î¼M) causes a significant, dose-dependent, 2-3 fold increase in uptake of radiolabelled folic acid and methotrexate into KG-1 cells both at 24 h and 48 h of treatment. Interestingly, pre-treatment of KG-1 leukemic cells with curcumin (10 Î¼M and 25 Î¼M) also caused a statistically significant enhancement in the cytotoxicity of methotrexate. We performed Real Time Quantitative RT-PCR to confirm the upregulation of FRβ mRNA in curcumin treated cells. Immunocytochemistry and Western blotting showed that curcumin caused increased expression of folate receptor βin KG-1 cells. Our data show that the mechanism of curcumin action involves up-regulation of folate receptor β mRNA and protein in KG-1 cells. Therefore, combination of non-toxic concentrations of curcumin and methotrexate, may be a viable strategy for therapeutic intervention for leukemias using a folate receptor-targeted drug delivery system. 23870248 Assessment of plaque evolution in coronary bifurcations located beyond everolimus eluting scaffolds: serial intravascular ultrasound virtual histology study. To evaluate the atherosclerotic evolution in coronary bifurcations located proximally and distally to a bioresorbable scaffold. Thirty bifurcations located >5 mm beyond the scaffolded segment, being investigated with serial intravascular ultrasound virtual histology (IVUS-VH) examinations, at baseline and 2-years, in patients enrolled in the ABSORB cohort B1 study were included in this analysis. In each bifurcation, the frames portraying the proximal rim, in-bifurcation, and distal rim of the ostium of the side branch were analyzed. The geometric parameters and plaque types were evaluated at baseline and 2-years follow-up. There were no significant differences in the geometrical parameters such as lumen, vessel and plaque areas as well as in the composition of the atheroma between baseline and 2-years follow-up.When we separately examined the bifurcations located proximally and distally to the scaffolded segment, no changes were found at the distal bifurcations, while at the proximal bifurcations there was a statistical significant decrease in the plaque burden (36.67 ± 13.33% at baseline vs. 35.06 ± 13.20% at 2 years follow-up, p = 0.04).Ten necrotic core rich plaques were found at baseline, of which 2 regressed to either fibrotic plaque or to intimal thickening at 2 years follow-up. The other 8 did not change. Disease progression was noted in 3 plaques (1 adaptive intimal thickening, 1 fibrotic and 1 fibrocalcific plaque) that evolved to necrotic rich plaques. Plaque regression was noted at the bifurcations located proximally to the bioresorbable scaffold but not at these located distally. Additional studies are required to confirm this finding and examine further the effect of drug elution on atherosclerotic evolution. 23869191 Dracorhodin Perchlorate Induced Human Breast Cancer MCF-7 Apoptosis through Mitochondrial Pathways. Objective: Dracorhodin perchlorate (DP) was a synthetic analogue of the antimicrobial anthocyanin red pigment dracorhodin. It was reported that DP could induce apoptosis in human prostate cancer, human gastric tumor cells and human melanoma, but the cytotoxic effect of DP on human breast cancer was not investigated. This study would investigate whether DP was a candidate chemical of anti-human breast cancer. Methods: The MTT assay reflected the number of viable cells through measuring the activity of cellular enzymes. Phase contrast microscopy visualized cell morphology. Fluorescence microscopy detected nuclear fragmentation after Hoechst 33258 staining. Flowcytometric analysis of Annexin V-PI staining and Rodamine 123 staining was used to detect cell apoptosis and mitochondrial membrane potential (MMP). Real time PCR detected mRNA level. Western blot examined protein expression. Results: DP dose and time-dependently inhibited the growth of MCF-7 cells. DP inhibited MCF-7 cell growth through apoptosis. DP regulated the expression of Bcl-2 and Bax, which were mitochondrial pathway proteins, to decrease MMP, and DP promoted the transcription of Bax and inhibited Bcl-2. Apoptosis-inducing factor (AIF) and cytochrome c which localized in mitochondrial in physiological condition were released into cytoplasm when MMP was decreased. DP activated caspase-9, which was the downstream of mitochondrial pathway. Therefore DP decreased MMP to release AIF and cytochrome c into cytoplasm, further activating caspase 9, lastly led to apoptosis. Conclusion: Therefore DP was a candidate for anti-breast cancer, DP induced apoptosis of MCF-7 through mitochondrial pathway. 23855793 Medication Counselling: Physicians' Perspective. Medication reviews have the potential to lower the incidence of prescribing errors. To benefit from a medication review, the prescriber must adhere to medication counselling. Adherence rates vary from 39 to 100%. The aim of this study was to examine counselling-naive hospital physicians' perspectives and demands to medication counselling as well as study factors that might increase adherence to the counselling. The study was conducted as a questionnaire survey among physicians at Aarhus University Hospital, Denmark. The questionnaire was developed based on focus group interviews and literature search, and was pilot-tested among 30 physicians before being sent to 669 physicians. The questionnaire consisted of 35 items divided into four categories: attitudes (19 items), behaviours (3 items), assessment (8 items) and demographics (5 items). The response rate was 60% (400/669). Respondents were employed at psychiatric, medical or surgical departments. Eighty-five per cent of respondents agreed that patients would benefit of an extra medication review, and 72% agreed that there was a need for external medication counselling. The most important factor that could increase adherence was the clinical relevance of the counselling as 78% rated it of major importance. The most favoured method for receiving counselling was via the electronic patient record. 23796077 Two new acridone alkaloids from the branch of Atalantia buxifolia and their biological activity. Two new acridone alkaloids, 3-methoxy-1,4,5-trihydroxy-10-methylacridone (1) and 2,3-dimethoxy-1,4,5-trihydroxy-10-methylacridone (2), were isolated from the ethanol extract of the branch of Atalantia buxifolia. Their structures were elucidated by spectroscopic methods including 1D and 2D NMR. Compounds 1 and 2 exhibited significant antibacterial activity against Staphylococcus aureus and weak inhibitory effect on acetylcholinesterase. 23958282 A place for play? The influence of the home physical environment on children's physical activity and sedentary behaviour. The home environment is an important influence on the sedentary behaviour and physical activity of children, who have limited independent mobility and spend much of their time at home. This article reviews the current evidence regarding the influence of the home physical environment on the sedentary behaviour and physical activity of children aged 8-14 years. A literature search of peer reviewed articles published between 2005 and 2011 resulted in 38 observational studies (21 with activity outcomes, 23 with sedentary outcomes) and 11 experimental studies included in the review. The most commonly investigated behavioural outcomes were television watching and moderate to vigorous physical activity. Media equipment in the home and to a lesser extent the bedroom were positively associated with children's sedentary behaviour. Physical activity equipment and the house and yard were not associated with physical activity, although environmental measures were exclusively self-reported. On the other hand, physical activity equipment was inversely associated with sedentary behaviours in half of studies. Observational studies that investigated the influence of the physical and social environment within the home space, found that the social environment, particularly the role of parents, was important. Experimental studies that changed the home physical environment by introducing a television limiting device successfully decreased television viewing, whereas the influence of introducing an active video game on activity outcomes was inconsistent. Results highlight that the home environment is an important influence on children's sedentary behaviour and physical activity, about which much is still unknown. While changing or controlling the home physical environment shows promise for reducing screen based sedentary behaviour, further interventions are needed to understand the broader impact of these changes. Future studies should prioritise investigating the influence of the home physical environment, and its interaction with the social environment, on objectively measured sedentary time and home context specific behaviours, ideally including technologies that allow objective measures of the home space. 23909550 Positive predictive factors and subgroup analysis of clinically relevant improvement after anterior cervical decompression and fusion for cervical disc disease: a 10- to 13-year follow-up of a prospective randomized study. Object The main purpose of this 10- to 13-year follow-up of a prospective randomized study was to identify preoperative factors that predicted good long-term outcome after anterior cervical decompression and fusion (ACDF) with the Cloward procedure or the cervical intervertebral fusion cage. A second purpose was to investigate subgroup differences at the 10-year follow-up between patients with and without clinically relevant improvement (CRI) and between men and women. Methods To evaluate clinically meaningful outcomes, good outcome was defined as CRI in neck-related pain intensity (≥ 30-mm improvement on a visual analog scale), and CRI in neck-specific disability (≥ 20% improvement in the neck disability index [NDI]) from preoperative measurements to the 10-year follow-up. A total of 73 patients (77% of the original study sample) completed questionnaires at least 10 years after ACDF. Results High preoperative neck-related pain intensity and preoperative nonsmoking status were predictors of CRI in neck-related pain intensity, and male sex was a predictor of CRI in neck-specific disability; however, no additional predictive factors were identified for good outcome after ACDF. The surgical procedure, number of operated levels, and radiological factors such as healing status did not influence the prediction models. Individuals without CRI in neck-specific disability (75%) and pain intensity (43%) reported a worse outcome for several psychosocial outcome variables compared with those with CRI. At the 10-year follow-up, women reported significantly greater neck- and arm-related pain intensity than men, and women also reported more disability and worse psychosocial status. Women reported CRI on the NDI less frequently than men (p = 0.01). Conclusions Preoperative predictive factors of good outcome 10-13 years after ACDF included initial high neck-related pain intensity, nonsmoking status at the time of surgery, and male sex. There were greater improvements in pain intensity than in neck-specific disability, and the latter showed a greater association with psychosocial factors. These results suggest the need for multimodal postoperative rehabilitation for patients who do not have a satisfactory outcome after ACDF. 23856117 Characterization of FlipIDAM as a SERT-selective SPECT imaging agent. Biological evaluation of ([(125)I]4), a new single-photon emission computed tomography (SPECT) radioligand for imaging the serotonin transporter (SERT) which displayed improved in vivo kinetics for mapping SERT binding sites in the brain. In vitro binding studies of [(125)I]4 were performed with membrane homogenates of LLC-PK1 cells stably transfected and overexpressing one of the monoamine transporter (SERT, DAT or NET) and rat cortical homogenates. Biodistribution and ex vivo autoradiography studies were carried out in rats. In vivo competition experiments were evaluated to determine the SERT selectivity of [(125)I]4 vs. ([(125)I]1). In vitro binding studies of 4 showed excellent binding affinity (Ki,SERT=0.90±0.05nM) and excellent selectivity over the other monoamine transporters (100 fold and >4000 fold for NET and DAT respectively). Scatchard analysis of saturation binding of [(125)I]4 to rat cortical homogenates gave a Kd value of 0.5±0.09nM and a Bmax value of 801.4±58.08fmol/mg protein. The biodistribution study showed rapid high brain uptake (3.09±0.11% dose/organ at 2min) and a good target to non-target ratio (hypothalamus to cerebellum) at 30min (2.62) compared to [(125)I]1 (2.19). Ex vivo autoradiography showed that FlipIDAM localizes in accordance with SERT distribution patterns in the brain. In vivo and ex vivo competition experiments with specific and non-specific SERT compounds also showed that [(125)I]4 binds specifically to SERT rich regions. The biological evaluation of [(125)I]4 demonstrates that [(123)I]4 would be a good candidate for SPECT imaging of SERT. 23760597 Luminescence phenomena of biodegradable photoluminescent poly(diol citrates). The possible origin of luminescent properties of biodegradable photoluminescent polyesters (BPLPs) has been revealed by isolation and identification of luminescent agent from the hydrolyzate of BPLP. Elemental analysis, ESI-MS, (1)H, (13)C, 2D HSQC and COSY NMR spectra confirmed the chemical structure as 5-oxo-2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine-3,7-dicarboxylic acid (TPA). 23832567 Transcatheter left ventricular outflow tract stent placement in a low birth weight child with hypoplastic left ventricle, mitral atresia, transposition of the great arteries, ventricular septal defect and severe pulmonary stenosis. A baby boy, the first of triplets born at 33 weeks gestation weighing 1.88 kg, presented with neonatal cyanosis and was diagnosed with mitral atresia, hypoplastic left ventricle, ventricular septal defect, d-transposition of the great arteries, severe pulmonary stenosis, and hypoplastic branch pulmonary arteries. He was treated with prostaglandin until seven weeks of age. The patent ductus arteriosus was curly Q and not suitable for stent placement. Cardiac catheterization was undertaken and using an antegrade approach, a Multi-Link Ultra stent was implanted across the left ventricular outflow tract (LVOT) and inflated to 5 mm to improve antegrade pulmonary blood flow. This allowed reasonable pulmonary arterial growth to allow the patient undergo bidirectional Glenn shunt at five months of age. This first report of LVOT stenting in this setting may provide an alternative to placement of a systemic to pulmonary arterial shunt when ductal stenting is not possible. © 2013 Wiley Periodicals, Inc. 23832831 Bare histidine-serine models: implication and impact of hydrogen bonding on nucleophilicity. A new family of 2-hydroxyalk(en/yn)ylimidazoles has been evaluated as serine-histidine bare dyad models for the ring-opening reaction of L-lacOCA, a cyclic O-carboxyanhydride. These models were selected to unravel the implication of intramolecular hydrogen bonding and to substantiate its influence on the nucleophilicity of the alcohol moiety, as it is suspected to occur in enzyme active sites. Although designed to exclusively facilitate the preliminary step of proton transfer during the studied ring-opening reaction, these minimalistic models depicted a measureable increase in reactivity relative to the isolated fragments. A couple of reliable experimental and theoretical methods have been developed to readily monitor the strength of the intramolecular hydrogen bond in dilute solution. Results show that the folded conformers are the most nucleophilic species because of the intramolecular hydrogen bond. 23561290 Virus-like particles: promising platforms with characteristics of DIVA for veterinary vaccine design. In general, it is difficult to differentiate infected from vaccinated animals through vaccination with conventional vaccines, thereby impeding the serological surveillance of animal diseases. DIVA (differentiating infected from vaccinated animals) vaccine, originally known as marker vaccine, usually based on the absence of at least one immunogenic protein in the vaccine strain, allows DIVA in conjunction with a diagnostic test that detects antibodies against the antigens lacking in the vaccine strain. Virus-like particles (VLPs), composed of one or more structural proteins but no genomes of native viruses, mimic the organization and conformation of authentic virions but have no ability to self-replicate in cells, potentially yielding safer vaccine candidates. Since VLPs containing either monovalent or multivalent antigen can be produced in compliance with the requirements for serological surveillance, the use of VLP-based vaccines plays a promising role in DIVA vaccination strategies against animal diseases. Here, we critically reviewed VLPs and companion diagnostics with properties of DIVA for veterinary vaccine design, and three different VLPs as promising platforms for DIVA vaccination strategies in animals. 23872099 Prospective and retrospective time perception are related to mental time travel: Evidence from Alzheimer's disease. Unlike prospective time perception paradigms, in which participants are aware that they have to estimate forthcoming time, little is known about retrospective time perception in normal aging and Alzheimer's disease (AD). Our paper addresses this shortcoming by comparing prospective and retrospective time estimation in younger adults, older adults, and AD patients. In four prospective tasks (lasting 30s, 60s, 90s, or 120s) participants were asked to read a series of numbers and to provide a verbal estimation of the reading time. In four other retrospective tasks, they were not informed about time judgment until they were asked to provide a verbal estimation of four elapsed time intervals (lasting 30s, 60s, 90s, or 120s). AD participants gave shorter verbal time estimations than older adults and younger participants did, suggesting that time is perceived to pass quickly in these patients. For all participants, the duration of the retrospective tasks was underestimated as compared to the prospective tasks and both estimations were shorter than the real time interval. Prospective time estimation was further correlated with mental time travel, as measured with the Remember/Know paradigm. Mental time travel was even higher correlated with retrospective time estimation. Our findings shed light on the relationship between time perception and the ability to mentally project oneself into time, two skills contributing to human memory functioning. Finally, time perception deficits, as observed in AD patients, can be interpreted in terms of dramatic changes occurring in frontal lobes and hippocampus. 23955346 Transgenic Expression and Functional Characterization of Human Platelet Derived Growth Factor BB (hPDGF-BB) in Tobacco (Nicotiana tabacum L.). Recombinant human platelet derived growth factor BB (rhPDGF-BB) is clinically approved for treating diabetic neuropathic ulcers. Plant-based expression systems offer less expensive ways of producing recombinant drugs, which do not require purification for clinical use. From this perspective, rhPDGF-BB is an ideal candidate for expression in plants as it can be applied topically. Here, we report a proof of concept study, in which rhPDGF-BB was expressed in tobacco plants, and its biological activity was tested in vitro. The mature human platelet derived growth factor BB (hPDGF-BB) gene was codon-optimized for tobacco and fused with ER targeting and retention signals, 5' and 3' UTRs of arc5-1 gene along with CaMV 35S promoter, and then, transferred by Agrobacterium-mediated transformation. Gene and protein expression of hPDGF-BB were confirmed by PCR and immunoblot studies. Bioactivity of hPDGF-BB expressed protein was determined by in vitro assays such as proliferation and migration in NIH3T3 cells. Our data reveals that total soluble proteins containing hPDGF-BB from transgenic plants showed a 4.5-fold increase in fibroblast proliferation compared to non-transgenic plants. Furthermore, plant-made rhPDGF-BB induced chemotaxis of treated cells and promoted wound healing in vitro. These results clearly demonstrate that functionally active rhPDGF-BB protein can be produced in plants and might have therapeutic benefits. 23754470 Dose-dependent alterations in gene expression and testosterone production in fetal rat testis after exposure to di-n-hexyl phthalate. In utero exposure to the phthalate ester plasticizer di-n-hexyl phthalate (DnHP) is known to affect the development of the male reproductive system and induce alterations in androgen-dependent tissues of male rat offspring. Male reproductive malformations produced by several phthalates have been causally linked to decreased testosterone production during the gestational period. This study was designed to evaluate the dose-response relationship for the effects of DnHP on the synthesis and production of testosterone in the fetal rat testis. Pregnant Sprague-Dawley rats were administered the vehicle (olive oil) and either DnHP (5 to 625 mg kg(-1) per day) or diethylhexyl phthalate (DEHP) (50 or 625 mg kg(-1) per day), by gavage, from gestation day (GD) 12 to19. Fetal testes were assessed on GD 19. DnHP reduced ex vivo testosterone production and down-regulated the expression of several genes required for cholesterol transport and steroid synthesis (i.e. SR-B1, StAR, P450scc, 3βHSD and P450c17). These inhibitions were dose dependent. A no-effect level was established at 5 mg kg(-1) per day and a lowest-effect level at 20 mg kg(-1) per day. mRNA levels of SR-B1, StAR, P450scc and 3βHSD were not similarly decreased in the adrenals. In conclusion, DnHP shares the same mode of action as DEHP in disrupting fetal testicular androgen synthesis. Alterations in testosterone production and in key steroidogenic gene expressions were apparent at lower doses than those causing postnatal reproductive malformations after gestational exposure during the critical period of male sexual differentiation. This suggests that they can be considered early biomarkers of DnHP-induced fetal testicular effects in rats. Copyright © 2013 John Wiley & Sons, Ltd. 23443810 Effect of miR-21 on Renal Fibrosis by Regulating MMP-9 and TIMP1 in kk-ay Diabetic Nephropathy Mice. MicroRNAs (miRs) play important roles in initiation and progression of many pathologic processes. However, the roles of miRs in diabetic nephropathy remain unclear. This study was to determine whether miR-21 was involved in diabetic nephropathy and to explore the relationship between miR-21 and MMP9/TIMP1 expression in diabetic nephropathy. In situ hybridization studies showed that miR-21 was primarily localized and distributed in cortical glomerular and renal tubular cells in diabetic kk-ay kidney. Real-time quantitative RT-PCR demonstrated that the expression of miR-21 was significantly increased in kk-ay mice, compared with control C57BL mice. Interestingly, miR-21 expression positively correlated with urine albumin creatine ratio (ACR), TIMP1, collagen IV (ColIV), and fibronectin (FN); while negatively correlated with creatine clearance ratio (Ccr) and MMP-9 protein. Importantly, antagomir-21 not only ameliorated Ccr and ACR but also decreased TIMP1, ColIV, and FN proteins. In conclusion, our data demonstrate that miR-21 contributes to renal fibrosis by mediating MMP9/TIMP1 and that inhibition of miR-21 may be a novel target for diabetic nephropathy. 23924988 Management of Congenital Nasolacrimal Duct Obstruction-Latin American Study. To survey the management of congenital nasolacrimal duct obstruction, in particular, the timing of intervention and the use of massage, probing, nasolacrimal intubation, nasal endoscopy, and dacryocystorhinostomy. This was an exploratory study that used an electronic questionnaire, which was sent via Internet to the members of Ojoplast, a social network composed of ophthalmologists from several Latin American countries. The responses were analyzed using adherence and the chi-square test. Seventy-two completed questionnaires were received. Approximately 64% of survey participants indicated that they use massage as the initial treatment for congenital nasolacrimal duct obstruction until 1 year of age and lacrimal probing (70.8%) for patients >1 year of age. Early probing used by 58.3% of the patients for a dilated lacrimal sac, and 66.7% reported that lacrimal system probing in conjunction with irrigation is effective. If the probing is not effective, 65.3% indicated that they repeat the procedure a second time. If the patient does not respond to massage or probing, 69.4% perform lacrimal system intubation. Sixty-two percent of the respondents indicated that they perform dacryocystorhinostomy for cases in which probing or intubation is not effective. The members of Ojoplast adopt massage as the initial treatment for congenital nasolacrimal duct obstruction for patients <1 year of age. Probing is performed on patients >1 year of age, and early probing is used only for cases of dilated lacrimal sac. When massage and probing are not effective, intubation is performed, and if intubation is unsuccessful, dacryocystorhinostomy is performed, in which the external approach to dacryocystorhinostomy is used most often. 23698311 The Autographa californica Multiple Nucleopolyhedrovirus ORF78 Is Essential for Budded Virus Production and General Occlusion Body Formation. ORF78 (ac78) of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is a baculovirus core gene of unknown function. To determine the role of ac78 in the baculovirus life cycle, an AcMNPV mutant with ac78 deleted, Ac78KO, was constructed. Quantitative PCR analysis revealed that ac78 is a late gene in the viral life cycle. After transfection into Spodoptera frugiperda cells, Ac78KO produced a single-cell infection phenotype, indicating that no infectious budded viruses (BVs) were produced. The defect in BV production was also confirmed by both viral titration and Western blotting. However, viral DNA replication was unaffected, and occlusion bodies were formed. An analysis of BVs and occlusion-derived viruses (ODVs) revealed that AC78 is associated with both forms of the virions and is an envelope structural protein. Electron microscopy revealed that AC78 also plays an important role in the embedding of ODV into the occlusion body. The results of this study demonstrate that AC78 is a late virion-associated protein and is essential for the viral life cycle. 22711683 Impact of intraoral stent on the side effects of radiotherapy for oral cancer. The intraoral stent is a mouth-opening device which may be used during head and neck cancer radiotherapy with the intention of preventing unnecessary irradiation in normal adjacent tissue. The use of this device during intensity-modulated radiation therapy (IMRT) has not been reported in the literature. A 30-year-old woman with squamous cell carcinoma of the tongue was submitted to a CT for IMRT treatment planning with and without the use of the intraoral stent. Dosimetric analysis showed that the irradiation dose to the maxilla, both parotid glands, and left submandibular gland decreased with the use of this device. This article shows that intraoral stents seem to be useful in decreasing the radiation dose to healthy structures, especially in bone structures and salivary glands during radiotherapy, and emphasizes the importance of a multidisciplinary team during oncological therapy. 23965590 The CUSUM Analysis of the Learning Curve for Endoscopic Thyroidectomy by the Breast Approach. Objectives. To evaluate the learning curve for endoscopic thyroidectomy by the breast approach (ETBBA) based on the cumulative summation (CUSUM) technique. Methods. The study included 110 consecutive patients who underwent ETBBA by a single surgeon between January 2009 and May 2012 at the Xiangya Hospital of Central South University, Changsha, China. The learning curve was evaluated using the CUSUM technique. The patients were chronologically arranged into 3 phases by the CUSUM analysis for operative time. Demographic data and operative parameters were also analyzed. Results. The mean operative time (OT) was 125.3 minutes. The conversion rate for technical difficulties and the definitive complication rate were 6.4% and 10%, respectively. The learning curve was analyzed mainly by OT using the CUSUM technique. There was a significant improvement in the average OT (P < .05) after the first 27 patients and again after the first 67 patients (P < .05). A downward trend in OT was found up to the last patient. There were similarities in gender, tumor size, extent of surgery, blood loss, histology, hospital stay, conversion rate, and complications among the 3 phases. Comparison of 2 neighboring phases also showed no significant differences in age. Conclusions. ETBBA performed by surgeons has a remarkable learning curve. There were 27 cases in the early stage of the learning curve, whereas mastery level could be achieved with 67 cases. 23517282 Prospective multicentre study of the effect of voluntary plasmapheresis on plasma cholesterol levels in donors. LDL apheresis is used to treat patients with familial hypercholesterolaemia, and low-volume plasmapheresis for plasma donation may similarly lower cholesterol levels in some donors. This study was designed to assess the effect of plasmapheresis on total, LDL and HDL cholesterol levels in a plasma donor population. This was a prospective, unblinded longitudinal cohort study in which a blood sample was obtained for analysis before each donation. Data from 663 donors were analysed using a multivariable repeated measures regression model with a general estimating equations approach with changes in cholesterol as the primary outcome measure. The model predicted a significant decrease in total and LDL cholesterol for both genders and all baseline cholesterol levels (P < 0·01). The greatest total cholesterol decreases (women, -46·8 mg/dL; men, -32·2 mg/dL) were associated with high baseline levels and 2-4 days between donations. Small but statistically significant increases (P â‰¤ 0·01) in HDL cholesterol were predicted for donors with low baseline levels. These results suggest that, in donors with elevated baseline cholesterol levels, total and LDL cholesterol levels may decrease during routine voluntary plasmapheresis. 23636518 Laparoscopic repair of a lumbar hernia: report of a case and extensive review of the literature. Lumbar hernias are a protrusion of intra-abdominal contents through a weakness or rupture in the posterior abdominal wall. They are considered to be a rare entity with approximately 300 cases reported in the literature since it was first described by Barbette in 1672. Petit described the inferior lumbar triangle in 1783 and Grynfeltt described the superior lumbar triangle in 1866; both are anatomical boundaries where 95 % of lumbar hernias occur, whereas the other 5 % are considered to be diffuse. Twenty percent of lumbar hernias are congenital and the other 80 % are acquired; the acquired lumbar hernias can be further classified into either primary (spontaneous) or secondary. The typical presentation of lumbar hernias is a patient with a protruding semispherical bulge in the back with a slow growth. However, they may present with an incarcerated or strangulated bowel, so it is recommended that all lumbar hernias must be repaired as soon as they are diagnosed. The "gold standard" for diagnosing a lumbar hernia is a CT scan, because it is able to delineate muscular and fascial layers, detect a defect in one or more of these layers, evaluate the presence of herniated contents, differentiate muscle atrophy from a real hernia, and serve as a useful tool in the differential diagnosis, such as tumors. Recent studies have demonstrated the advantages of a laparoscopic repair instead of the classic open approach as the ideal treatment option for lumbar hernias. We report a case of a spontaneous lumbar hernia initially diagnosed as a lipoma and corrected with the open approach, but after relapsing 2 years later it was corrected using a laparoscopic approach. It is followed by an extensive review of lumbar hernias literature regarding history, anatomy, and surgical techniques. 22914250 Clinical outcomes of aortic root replacement after previous aortic root replacement. The study objective was to examine the short- and long-term outcomes of reoperative aortic root replacement after a previous aortic root replacement. From September 1985 to February 2011, 84 consecutive patients underwent reoperative aortic root replacement. The patients' mean age was 46 ± 15 years (range, 19-80 years), and 86% were men. The main indication for reoperation was failed biological or bioprosthetic aortic valve and prosthetic valve endocarditis. Cox proportional hazard regression modeling was performed to identify risk factors that adversely affected overall survival. The operative mortality was 6% (5 patients). Perioperative morbidity included myocardial infarction in 2 patients, low cardiac output syndrome in 7 patients, sepsis in 3 patients, pulmonary complications in 7 patients, renal failure in 3 patients, reoperation for bleeding or tamponade in 5 patients, superficial sternal wound infections in 3 patients, permanent transvenous pacemaker in 8 patients, and stroke in 1 patient. Kaplan-Meier estimates for survival at 5, 10, and 12 years were 82.5% ± 4.7%, 72.5% ± 6.4%, and 65.0% ± 7.6%, respectively; the freedom from reoperation was 100%, 92.3% ± 5.2%, 92.3% ± 5.2%, respectively; and valve-related mortality was 93.1% ± 3.4%, 90.8% ± 4.0%, and 86.2% ± 5.8%, respectively. During the follow-up, valve-related deaths occurred in 7 patients. Age by increments of 5 years (hazard ratio, 1.205; 95% confidence interval, 1.036-1.401) and prosthetic valve endocarditis (hazard ratio, 2.662; 95% confidence interval, 1.054-6.724) were independent risk factors for mortality. Aortic root replacement after a previous aortic root replacement is associated with a relatively low operative mortality and perioperative morbidity, but long-term survival is suboptimal. Increasing age and prosthetic valve endocarditis adversely affect survival. 23937921 Mortality After Septic Versus Aseptic Revision Total Hip Arthroplasty: A Matched-Cohort Study. Mortality rates after revision total hip arthroplasty (THA) for periprosthetic sepsis were investigated in 93 patients and compared to 93 patients, matched for age, gender, year of surgery, who underwent revision for aseptic failures. The mortality rate was 33% (31/93) in the septic group and 22% (20/93) in the aseptic group at 5 and 6year follow-up, respectively (P=0.10). Patients in the septic group died on average 6years earlier (74 versus 80yrs; P<0.05) than those in the aseptic group. Charlson Comorbidity Index (CCI) was an independent predictor of mortality among the both groups (P<0.05), while age (P<0.01) was a predictor of mortality only in the aseptic group. While revision THA for sepsis alone did not predict increased mortality, a 33% mortality rate at five years in patients with an average age of 66years and earlier death by 6years compared to aseptic revisions is alarming. 23932524 One-step breast reconstruction with polyurethane-covered implants after skin-sparing mastectomy. Skin-sparing mastectomy (SSM) and immediate one-step breast reconstruction with implants has become an increasingly popular, effective treatment for selected patients with breast carcinoma. However, it is associated with high complication rates. Breast augmentation with polyurethane-covered implants (PCIs) has consistently had optimal short-term and long-term results with low rates of capsular contracture. The aim of this study was to evaluate the clinical and aesthetic outcomes of immediate one-step breast reconstruction with PCI after SSM in early breast cancer patients at a single institution. We reviewed the records of 221 consecutive breast cancer patients who underwent one-stage immediate reconstruction with PCI after SSM from 1995 through 2005. Patient and tumour characteristics, type of reconstruction, postoperative complications, aesthetic results and recurrence rate were analysed. The mean age of the patients was 52 ± 11 years (range, 30-76; standard deviation (SD), 11). The American Joint Committee on Cancer (AJCC) pathologic stages were 0 (10%), I (63.3%) and II (26.7%). Thirty-nine (17.65%; confidence interval (CI) = 13.04-23.1) of the 221 patients had complications; seven had prosthesis extrusion requiring an implant (five due to skin necrosis, one due to infection and one due to late haematoma). In six of these seven cases, the procedure was indicated for local recurrence after conservative breast surgery with adjunctive radiation therapy (rescue procedure). Thirty-two (14.4%) patients had minor complications: 12 had cutaneous rash, four had malpositioned implants and 16 had inadequate implant projection. At long-term follow-up, four (1.8%) patients had developed grade IV capsular contracture associated with postoperative radiation therapy. At a median follow-up of 98 months (range, 36-156), 14 (6.3%) patients had tumour recurrence and 12.2% had distant metastasis. Nineteen patients had died of cancer, and 192 (86.8%) remained disease free. One-stage immediate breast reconstruction with PCI after SSM appears to be oncologically safe and provides a high level of patient satisfaction. 23966584 Risk-Taking Behavior: Dopamine D2/D3 Receptors, Feedback, and Frontolimbic Activity. Decision-making involves frontolimbic and dopaminergic brain regions, but how prior choice outcomes, dopamine neurotransmission, and frontostriatal activity are integrated to affect choices is unclear. We tested 60 healthy volunteers using the Balloon Analogue Risk Task (BART) during functional magnetic resonance imaging. In the BART, participants can pump virtual balloons to increase potential monetary reward or cash out to receive accumulated reward; each pump presents greater risk and potential reward (represented by the pump number). In a separate session, we measured striatal D2/D3 dopamine receptor binding potential (BPND) with positron emission tomography in 13 of the participants. Losses were followed by fewer risky choices than wins; and during risk-taking after loss, amygdala and hippocampal activation exhibited greater modulation by pump number than after a cash-out event. Striatal D2/D3 BPND was positively related to the modulation of ventral striatal activation when participants decided to cash out and negatively to the number of pumps in the subsequent trial; but negatively related to the modulation of prefrontal cortical activation by pump number when participants took risk, and to overall earnings. These findings provide in vivo evidence for a potential mechanism by which dopaminergic neurotransmission may modulate risk-taking behavior through an interactive system of frontal and striatal activity. 23835212 Sickness absence due to otoaudiological diagnoses; a descriptive nationwide study. Hearing difficulties constitute a large public health problem. Knowledge about their consequences in terms of sickness absence due to otoaudiological diagnoses is very scarce. The aim of this study was to gain such knowledge. Both individuals with sick leave due to otoaudiological diagnoses and sick-leave spells due to these diagnoses were examined, in a nationwide setting. Through Swedish nationwide registers we identified all 4768 individuals, aged 16--64 years and living in Sweden who were sickness absent due to otoaudiological diagnoses (ICD10; H60-H95) in 2005. We described the demographic characteristics of these individuals, as well as aspects regarding prevalence and duration of such sick-leave spells, in general and in four specific diagnosis groups; otological, hearing, vertigo, and tinnitus. Sick leave due to otoaudiological diagnoses was more common among women in all diagnosis groups except with tinnitus. Individuals with a hearing or tinnitus sick-leave diagnosis had a higher educational level and were hospitalized fewer days compared to those sickness absent due to vertigo or otological diagnoses. Particularly, sick-leave spells due to hearing or tinnitus diagnoses tended to be long, in many cases lasting the entire year. The majority of the individuals only had one sick-leave spell in 2005. Although the actual number of individuals with a sick-leave spell due to specific otoaudiological diagnosis might not be considered high, the high prevalence of long sick-leave spells due to particularly hearing and tinnitus diagnoses indicates the importance of preventive and rehabilitative actions. 23597916 Study designs for identifying risk compensation behavior among users of biomedical HIV prevention technologies: Balancing methodological rigor and research ethics. The growing evidence base for biomedical HIV prevention interventions - such as oral pre-exposure prophylaxis, microbicides, male circumcision, treatment as prevention, and eventually prevention vaccines - has given rise to concerns about the ways in which users of these biomedical products may adjust their HIV risk behaviors based on the perception that they are prevented from infection. Known as risk compensation, this behavioral adjustment draws on the theory of "risk homeostasis," which has previously been applied to phenomena as diverse as Lyme disease vaccination, insurance mandates, and automobile safety. Little rigorous evidence exists to answer risk compensation concerns in the biomedical HIV prevention literature, in part because the field has not systematically evaluated the study designs available for testing these behaviors. The goals of this Commentary are to explain the origins of risk compensation behavior in risk homeostasis theory, to reframe risk compensation as a testable response to the perception of reduced risk, and to assess the methodological rigor and ethical justification of study designs aiming to isolate risk compensation responses. Although the most rigorous methodological designs for assessing risk compensation behavior may be unavailable due to ethical flaws, several strategies can help investigators identify potential risk compensation behavior during Phase II, Phase III, and Phase IV testing of new technologies. Where concerns arise regarding risk compensation behavior, empirical evidence about the incidence, types, and extent of these behavioral changes can illuminate opportunities to better support the users of new HIV prevention strategies. This Commentary concludes by suggesting a new way to conceptualize risk compensation behavior in the HIV prevention context. 23863091 Functional results after orthotopic bladder substitution: A prospective multicentre study comparing four types of neobladder. Abstract Objective. The aim of this study was to evaluate enterocystometry, voiding pattern and urine leakage of four types of orthotopic bladder substitute. Material and methods. At eight urological departments, 78 consecutive men were studied: 66 with an ileal neobladder [30 Studer pouches (S), 24 Hautmann pouches (H) and 12 T-pouches (T)] and 12 with a right colonic [Goldwasser type (G)] neobladder. Enterocystometry, determination of residual urine, micturition protocol and 24 h pad weight test were performed 6 and 12 months postoperatively. Results. Colonic neobladders had higher pouch pressure at first desire, normal desire and strong desire than ileal neobladders (except at first and normal desire at 12 months) (p < 0.02) and contraction was present more often at both 6 and 12 months (p < 0.01 and p < 0.01). Compliance was good in all types of pouch. Intermittent self-catheterization was more common in H patients at 6 months (p = 0.033). All patients with colonic neobladders used pads during the day and night. In patients with ileal pouches 32% used pads during the day and 70% during the night at 12 months. Urine leakage was higher in patients with colonic bladders at 6 and 12 months during the day (mean/median of 98/31 ml and 82/16 ml versus 10/0 ml and 4/0 ml, p < 0.001). T-pouches had excellent day-time continence, but nocturnal leakage was high. Conclusions. The Hautmann pouch and the Studer pouch behaved similarly at enterocystometry and clinically, and continence was good in the majority of patients. The low number of patients with the other two types of pouch precludes definitive statements. 23411295 Prediction of fatty acid composition in Camellia oleifera oil by near infrared transmittance spectroscopy (NITS). Under the serious circumstances of Camellia oleifera adulteration, the accurate examination for quality trait of C. oleifera oil is extremely urgent. For rapid determination of FA composition in C. oleifera oil, the feasibility of NITS was first studied. The quantitative models for FA were built based on PLS regression. NITS spectra is able to accurately predict for oleic, linoleic, and palmitic acids (R(cv)>0.844, R(2)>0.886). R(cv) are 0.91987, 0.95755, and 0.84447, and R(2) are 0.9424, 0.9682, 0.8862 for NITS models of oleic, linoleic, and palmitic acids, respectively. But models for stearic and unsaturated acids are less accurate, with values of R(cv) from 0.67440 to 0.69114, and R(2) from 0.6834 to 0.7587. These results indicate that NITS will have potential to be used in predicting FA composition of C. oleifera oil. 23413841 Determination of fetal body volume measurement at term with magnetic resonance imaging: effect of various factors. Abstract Purpose: To evaluate various factors that potentially influence the fetal body volume (FBV) measurement using magnetic resonance imaging (MRI) and to analyze whether the technique of measurement could be simplified. Materials and methods: In 20 singleton pregnancies scheduled for a planned delivery, FBV measurements were performed by two independent operators on sagittal, axial and coronal planes and with various slice thickness and intersection gap, totalizing 100 examinations. MR estimation of fetal weight (MR-EFW) was calculated based on the equation developed by Baker. The relative error of MR-EFW was calculated in function of birth weight (BW). Regression analysis was used to investigate the effect on the relative error of MR-EFW of different variables but also to investigate the effect on the measurement time of the FBV of various factors. Results: The mean relative error of MR-EFW was 1.96% and was significantly associated only with patient's BMI but not with the type of MR sequence used or other variables. Type of MR sequence used and BW were significantly associated with the measurement time of FBV. Conclusion: Using MRI, the time for FBV measurement can be significantly reduced using thicker slices or intersection gap, with similar accuracy. 23692465 Functional analysis and transcriptional regulation of two orthologs of ARO10, encoding broad-substrate-specificity 2-oxo-acid decarboxylases, in the brewing yeast Saccharomyces pastorianus CBS1483. The hybrid genomes of Saccharomyces pastorianus consist of subgenomes similar to those of S. cerevisiae and S. eubayanus, and impact of the genome structure on flavour production and its regulation is poorly understood. This study focuses on ARO10, a 2-oxo-acid decarboxylase involved in production of higher alcohols. In S. pastorianus CBS1483, four ARO10 copies were identified, three resembled S. cerevisiae ARO10 and one S. eubayanus ARO10. Substrate specificities of lager strain (Lg)ScAro10 and LgSeubAro10 were compared by individually expressing them in a pdc1Δ-pdc5Δ-pdc6Δ-aro10Δ-thi3Δ S. cerevisiae strain. Both isoenzymes catalysed decarboxylation of the 2-oxo-acids derived from branched-chain, sulphur-containing amino acids and preferably phenylpyruvate. Expression of both alleles was induced by phenylalanine, however in contrast to the S. cerevisiae strain, the two genes were not induced by leucine. Additionally, LgSeubARO10 showed higher basal expression levels during growth with ammonia. ARO80, which encodes ARO10 transcriptional activator, is located on CHRIV and counts three Sc-like and one Seub-like copies. Deletion of LgSeubARO80 did not affect LgSeubARO10 phenylalanine induction, revealing 'trans' regulation across the subgenomes. ARO10 transcript levels showed a poor correlation with decarboxylase activities. These results provide insights into flavour formation in S. pastorianus and illustrate the complexity of functional characterization in aneuploid strains. 22976785 The role of residues T248, Y249 and T422 in the function of human pregnane X receptor. The pregnane X receptor (PXR) is a key xenobiotic receptor that regulates the expression of numerous drug-metabolizing enzymes. Some posttranslational mechanisms modulate its transcriptional activity. Although several kinases have been shown to directly phosphorylate this receptor, little is known about phosphorylation sites of PXR. In the present work, we examined T248, Y249 and T422 putative phosphorylation sites determined based on in silico consensus kinase site prediction analysis. T248 and T422 residues are critical for the interaction of the PXR ligand-binding domain and the activation function-2 (AF2) domain. Site-directed mutagenesis analysis was performed to generate phospho-deficient and phospho-mimetic mutants. We examined transactivation activity of the PXR mutants in gene reporter assays, formation of PXRmutant/RXRα heterodimer, binding of PXR mutants to the CYP3A4 gene response element DR3 and CYP3A4 expression in HepG2 cells after expression of the mutants. We found that T248D mutant activated CYP3A4 transactivation constitutively regardless of the presence or absence of a ligand. Contrary, T248V mutant exhibited low basal and ligand-inducible transactivation capacity as compared to wild-type PXR. Dose-response analysis revealed reduced ligand-dependent transactivation potency of PXR Y249D mutant. Transactivation of the CYP3A4 promoter was abolished with T422A/D mutants. All PXR mutants formed heterodimer with RXRα at a similar level to that observed with wild-type PXR. The ability to bind to DNA in vitro was substantially decreased in case of T248D, T422D and T248V mutants. Our data thus indicate that phosphorylation of T248, Y249 and T422 residues may be critical for the both basal and ligand-activated function of PXR. 23562492 Comparison between piezoelectric material properties obtained by using low-voltage magnitude frequency sweeping and high-level short impulse signals. Determination of electromechanical piezoceramic material parameters is usually done by fitting the measured input electrical impedance of the piezoceramic sample to the theoretical modelling equation for the input electrical impedance of the unloaded free piezoceramic resonator. The input electrical impedance of the sample is usually measured by using low voltage or current magnitude frequency sweeping signals. In this work, the complex material parameters of piezoceramic samples are determined in the real operating conditions by using the high voltage short impulse excitation signals. The input electrical impedance determined in the impulse mode around thickness extensional vibration mode (TE) and calculated piezoceramic parameters (clamped dielectric permittivity, electromechanical coupling factor, elastic stiffness and piezoelectric constant) are compared to the results obtained by using the low voltage magnitude frequency sweeping signals. When impulse excitation is used, the series resonance frequency is decreased and the input electrical impedance magnitude at series resonance is increased, which means that overall losses included in the piezoceramic parameters are increased. The complex material parameters obtained from the input electrical impedances determined by using the low voltage magnitude sweeping signal and high level short impulse signals are included in the KLM theoretical model describing the piezoceramic sample behaviour around TE mode. Better agreement between measured and theoretically determined current magnitude response around TE mode has been obtained, in the KLM model, when piezoceramic parameters determined by using the impulse signal excitations are included in the modelling. The physical reason for increase of the losses in piezoceramic material could lie in the fact that the ferroelectric domains in the piezoceramic respond harder on very short impulse excitation signals than on continuous frequency sweeping signals which are usually used in determination of piezoelectric material parameters. 23794269 Duplication of AKT3 as a cause of macrocephaly in duplication 1q43q44. Somatic and germline duplications of AKT3 and activating mutations of this gene have been reported in individuals with megalencephaly and hemimegalencephaly. We report on a patient with macrocephaly and a 3 Mb duplication on 1q43q44 that includes AKT3. This duplication was detected by array comparative genomic hybridization. The patient presented with moderate developmental delays in gross motor movements and speech. She also had macrocephaly, frontal bossing, hypertelorism, wide nasal bridge, small alae nares, short philtrum, prominent upper lip, and low-set, protruding ears. The 3 Mb duplicated region contained 15 genes including AKT3. The observation of megalencephaly in a child with 1q43q44 duplication provides further evidence of involvement of AKT3 dosage imbalances in brain growth disturbance. © 2013 Wiley Periodicals, Inc. 23946490 Class I Lysine Deacetylases Facilitate Glucocorticoid-Induced Transcription. Nuclear receptors use lysine acetyltransferases (KATs) and lysine deacetylases (KDACs) in regulating transcription through histone acetylation. KATs interact with steroid receptors upon binding of an agonist and are recruited to target genes. KDACs have been shown to interact with steroid receptors upon binding to an antagonist. We have shown previously that KDAC inhibitors (KDACi) potently repress the mouse mammary tumor virus promoter through transcriptional mechanisms and impair the ability of the GR to activate it, suggesting that KDACs can play a positive role in GR transactivation. In the current study we have extended this analysis to the entire GR transcriptome and find that the KDACi, valproic acid (VPA), impairs the ability of agonist-bound GR to activate about 50% of its target genes. This inhibition is largely due to impaired transcription rather than defective GR processing and was also observed using a structurally-distinct KDACi. Depletion of KDAC1 expression mimicked the effects of KDACi in over half of the genes found to be impaired in GR transactivation. Simultaneous depletion of KDACs 1 and 2 caused full or partial impairment of several more GR target genes. Altogether we find that Class I KDAC activity facilitates GR-mediated activation at a sizable fraction of GR-activated target genes and that KDAC1 alone or in coordination with KDAC2 is required for efficient GR transactivation at many of these target genes. Finally, our work demonstrates that KDACi exposure has a significant impact on GR signaling and thus has ramifications for the clinical use of these drugs. 23567044 Real-time imaging and kinetics measurements of focused ultrasound-induced extravasation in skeletal muscle using SPECT/CT. Drugs need to overcome several biological barriers such as the endothelium and cellular membranes in order to reach their target. Promising new therapeutics, many of which are charged and macromolecular, are not able to passively extravasate, let alone cross cell membranes, and stay mainly in the blood pool upon intravenous injection until clearance. Using focused ultrasound (fUS) in combination with circulating microbubbles (MBs) leads to temporary localized tissue permeabilization allowing extravasation of (macro) molecules from the vascular system. Thus, fUS is a promising approach for localized drug delivery. However, little is known about the permeabilization kinetics in skeletal muscle. In this study, we used single photon emission computed tomography (SPECT) to characterize the kinetics of extravasation of (111)In-labeled bovine serum albumin (BSA), a model macromolecular drug, in muscle treated with fUS and MBs. The same fUS protocol was applied to 6 groups of mice with different times, ∆t, between fUS application and BSA injection (∆t=-10, 2.5, 10, 30, 60, 90min) followed by SPECT imaging. For ∆t≤30min we observed an exponential accumulation of activity in an area of the treated muscle which extended to a volume larger than the fUS pattern with highest accumulation for short waiting times ∆t. The extent of extravasation decreased exponentially with increasing ∆t, with a calculated half-life of ca. 21min, defining the time window of extravasation. The same treatment without MBs did not induce extravasation of BSA thus supporting MBs and drug co-injection strategies. These results provide essential information for the development of fUS based strategies for localized drug delivery. 23200736 Tigecycline prevents LPS-induced release of pro-inflammatory and apoptotic mediators in neuronal cells. Pro-inflammatory and pro-apoptotic mediators have been involved in the pathogenesis of neurodegenerative diseases. Tigecycline (Tig), a glycylcycline antibiotic and an analog of Minocycline, is shown to exert anti-inflammatory effects that are distinct from its anti-microbial activity. Its neuroprotective mechanism is unknown. In this study, we investigated the direct protective mechanisms of tigecycline against lipopolysaccharide (LPS)-induced Rat pheochromocytoma (PC12) cells. The results showed that tigecycline significantly attenuated the expression and the release of nuclear factor-kappa beta (NF-κB), tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β), as well as nitric oxide (NO) levels in LPS-induced PC12 cells. In addition, tigecycline dose-dependently decreased cytochrome c release and caspase-3 activity. This later finding corroborated the results of decreased pro-apoptotic Bad, and increased anti-apoptotic Bcl-2 protein expression thus, confirming a neuroprotective effect of the drug in differentiated PC12 cells induced with LPS. The findings of our study suggest new targets for tigecycline and support the potential for tigecycline to be investigated as a therapeutic agent for neurodegenerative disorders. 23904763 Impact of the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology clinical practice guidelines for EGFR and ALK testing in lung cancer in Canada. This paper summarizes the practical impact of the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology lung cancer biomarkers guidelines on the lung cancer approach in Canada, providing possible practical solutions for other similar health care systems in which scientific reality needs to be constantly balanced against economic reality. 23950983 Direct detection of alternative open reading frames translation products in human significantly expands the proteome. A fully mature mRNA is usually associated to a reference open reading frame encoding a single protein. Yet, mature mRNAs contain unconventional alternative open reading frames (AltORFs) located in untranslated regions (UTRs) or overlapping the reference ORFs (RefORFs) in non-canonical +2 and +3 reading frames. Although recent ribosome profiling and footprinting approaches have suggested the significant use of unconventional translation initiation sites in mammals, direct evidence of large-scale alternative protein expression at the proteome level is still lacking. To determine the contribution of alternative proteins to the human proteome, we generated a database of predicted human AltORFs revealing a new proteome mainly composed of small proteins with a median length of 57 amino acids, compared to 344 amino acids for the reference proteome. We experimentally detected a total of 1,259 alternative proteins by mass spectrometry analyses of human cell lines, tissues and fluids. In plasma and serum, alternative proteins represent up to 55% of the proteome and may be a potential unsuspected new source for biomarkers. We observed constitutive co-expression of RefORFs and AltORFs from endogenous genes and from transfected cDNAs, including tumor suppressor p53, and provide evidence that out-of-frame clones representing AltORFs are mistakenly rejected as false positive in cDNAs screening assays. Functional importance of alternative proteins is strongly supported by significant evolutionary conservation in vertebrates, invertebrates, and yeast. Our results imply that coding of multiple proteins in a single gene by the use of AltORFs may be a common feature in eukaryotes, and confirm that translation of unconventional ORFs generates an as yet unexplored proteome. 23504639 Legal psychoactive substances as risk factors for sleep-related bruxism: a nationwide finnish twin cohort study. Different psychoactive factors including alcohol, coffee and tobacco, are considered as risk factors for bruxism. Often, heavy drinking and generous intake of coffee are correlated with smoking. Interactions between these agents may confound studies. The aim was to investigate the possible independent effects of drinking alcohol and coffee consumption on the occurrence of bruxism. Data derived from the Finnish Twin Cohort study consisting of 12,502 twin individuals (45.6% men, 54.4% women, mean age 44 years) born during the 1930-1957. The twins responded to a questionnaire sent in 1990 (response rate of 77%) consisting of 103 multiple-choice questions, seven dealing with tobacco use, four on alcohol use, one about coffee consumption and two with bruxism. Increasing alcohol intake raised the risk for weekly bruxism even when adjusted for smoking status [heavy drinking odds ratio (OR) 1.9; 95% CI 1.23-2.84, binge drinking OR 1.6; 95% CI 1.28-2.12, and passing-out due to excessive alcohol intoxication at least twice within the previous year OR 1.5; 95% CI 1.09-2.18]. The situation was similar to that for coffee consumption of more than eight cups per day (OR 1.4; 95% CI 1.01-1.98). Interaction analyses for 'smoking with risk factors' revealed no statistically significant interactions. Current smoking was an independent risk factor for bruxism in all models (OR 2.3-2.7). Given the observed associations between alcohol drinking, binge drinking, passing-out due to excessive alcohol intake and coffee consumption, the results support our hypothesis of an independent association of both alcohol use, and coffee consumption with bruxism. 23965253 Small molecule inhibitors of WNT/beta-catenin signaling block IL1beta/TNFalpha induced cartilage degradation. Introduction In this study, we tested the ability of small molecule inhibitors of WNT/beta-catenin signaling to block IL1beta/TNFalpha induced cartilage degradation. Pro-inflammatory cytokines like IL1beta and TNFalpha are potent inducers of cartilage degradation by up-regulating MMP expression and activity. Since WNT/beta-catenin signaling was found to be involved in IL1beta/TNFalpha induced upregulation of MMP activity, we hypothesized that inhibition of WNT/beta-catenin signaling might block IL1beta/TNFalpha induced cartilage degradation. We tested the effect of small molecules that block the interaction between beta-catenin and TCF/LEF transcription factors on IL1beta/TNFalpha induced cartilage degradation in mouse fetal metatarsals. Methods We used mouse fetal metatarsals treated with IL1beta and TNFalpha as an ex vivo model for cytokine induced cartilage degradation. Metatarsals were treated with IL1beta and TNFalpha in combination with small molecules PKF115-584, PKF118-310 and CGP049090 at different concentrations and harvested for histology and gene expression analysis. Results We found that IL1beta/TNFalpha induced cartilage degradation in mouse fetal metatarsals was blocked by inhibiting WNT/beta-catenin signaling using small molecules PKF115-584 and partially using CGP049090, dose-dependently. In addition, we found that PKF115-584 blocked IL1beta and TNFalpha induced MMP mRNA expression, but did not reverse the inhibitory effect of IL1beta on the expression of cartilage anabolic genes. Conclusion In this study, we showed that inhibition of WNT/beta-catenin signaling by small molecules can effectively prevent IL1beta/TNFalpha induced cartilage degradation, by blocking MMP expression and activity. Furthermore, we elucidate the involvement of WNT/beta-catenin signaling in IL1beta/TNFalpha induced cartilage degradation. 23805995 Xanthone Glycoside Constituents of Swertia kouitchensis with α-Glucosidase Inhibitory Activity. Ten new xanthone glycosides, kouitchensides A-J (1-10), and 11 known analogues were isolated from an n-butanol fraction of Swertia kouitchensis. The structures of these glycosides were determined on the basis of extensive spectroscopic data interpretation and comparison with data reported in the literature. In an in vitro test, compounds 2, 4, 5, 6, 11, 12, and 13 (IC50 values in the range 126 to 451 μM) displayed more potent inhibitory effects against α-glucosidase activity than the positive control, acarbose (IC50 value of 627 μM). 23876407 Universal approximation by radial basis function networks of Delsarte translates. We prove that, under certain mild conditions on the kernel function (or activation function), the family of radial basis function neural networks obtained by replacing the usual translation with the Delsarte one, and taking the same smoothing factor in all kernel nodes, has the universal approximation property. 23347049 Catalytic DNAs that harness violet light to repair thymine dimers in a DNA substrate. UV1C is an in vitro selected catalytic DNA that shows efficient photolyase activity, using light of <310 nm wavelength to photo-reactivate CPD thymine dimers within a substrate DNA. We show here that a minimal mutational strategy of substituting a guanine analogue, 6MI, for single guanine residues within UV1C extends the DNAzyme's activity into the violet region of the spectrum. These 6MI point mutant DNAzymes fall into three distinct functional classes, which photo-reactivate the thymine dimer along different pathways. Cumulatively, they reveal the modus operandi of the original UV1C DNAzyme to be a surprisingly versatile one. The interchangeable properties of no less than six of the G→6MI point mutants highlight UV1C's built-in functional flexibility, which may serve as a starting point for the creation of efficient, visible light-harnessing, photolyase DNAzymes for either the prophylaxis or therapy of UV damage to human skin. 23820459 Apparent lisinopril overdose requiring hemodialysis. A case of apparent overdose of angiotensin-converting-enzyme inhibitors requiring hemodialysis is reported. A 51-year-old white man (weight, 85 kg; height, 178 cm; body mass index, 28) with a history of hypertension, low back pain, and anxiety apparently took 27 lisinopril 10-mg tablets (3.18 mg/kg body weight) over a period of 3 or fewer days. The friend who brought him to the emergency department reported that the patient was hard to rouse and was speaking incoherently on the day of admission. Over the previous few days, the patient reportedly had visual hallucinations, incoherence, and inarticulate speech. Laboratory tests, electrocardiography, and computed tomography were performed. The patient was judged to have high-anion-gap metabolic acidosis, acute kidney injury, severe hyperkalemia, and rhabdomyolysis. He was given three doses of albuterol via a nebulizer, three doses of calcium gluconate 1 g i.v., two doses of sodium bicarbonate 100 meq i.v., two doses of sodium polystyrene sulfonate 30 g orally, three doses of insulin 10 units i.v., and three doses of dextrose 25 g (as 50% dextrose injection) i.v. He then underwent emergent hemodialysis and was admitted to the intensive care unit. The patient's confusion abated, kidney function improved, and acid-base and electrolyte imbalances resolved. The patient was discharged after 15 days. A man who had evidently taken an overdose of lisinopril had multiorgan dysfunction in the absence of hypotension. The abnormalities resolved after he was treated for acidosis and hyperkalemia and received hemodialysis to remove the lisinopril. 23622547 Internally heated membrane interfaced to a gas chromatography flame ionization detector. Volatile Organic Compounds (VOCs) mixtures in aqueous solutions have been investigated using a simple and efficient all-in-one on-line sampling, isolation, enrichment and pre-concentration internally heated membrane connected to a gas chromatography flame ionization detector (GC-FID). In our previous study with the internally heated membrane, no GC column was used in the instrument. In this new study, we introduce a GC column in the instrument design and this makes it possible for mixtures to be investigated. This new experimental design enabled high resolution separation of analyte mixtures capable of being adsorbed, diffused, and desorbed from the device for detection with an FID. With the new design we present data from investigation of competitive adsorption effects on the membrane. The data showed that analyte adsorption and diffusion onto the membrane can be affected when mixtures of analytes are introduced. The application of multiple linear regressions approach to the data enabled us to correct for the problem of competitive adsorption. Analyte adsorption and diffusion was affected by the diffusion coefficients of the analytes; the higher the diffusion coefficient the better the extraction from the membrane. Increasing the sampling time from 1 to 4 min increases the response by 77%. The sampling time responses were linear up to 4 min sampling time. Above 4 min sampling time, the data deviate from linearity. The effect of adding salt to standards has no effect on analyte absorption onto the membrane. The detection limits for key VOCs studied with an internal standard calibration ranged from 0.2 to 194 ng cm(-3). 23402278 Thiolates chemically induce redox activation of BTZ043 and related potent nitroaromatic anti-tuberculosis agents. The development of multidrug resistant (MDR) and extensively drug resistant (XDR) forms of tuberculosis (TB) has stimulated research efforts globally to expand the new drug pipeline. Nitroaromatic compounds, including 1,3-benzothiazin-4-ones (BTZs) and related agents, are a promising new class for the treatment of TB. Research has shown that the nitroso intermediates of BTZs that are generated in vivo cause suicide inhibition of decaprenylphosphoryl-β-D-ribose 2' oxidase (DprE1), which is responsible for cell wall arabinogalactan biosynthesis. We have designed and synthesized novel anti-TB agents inspired from BTZs and other nitroaromatic compounds. Computational studies indicated that the unsubstituted aromatic carbons of BTZ043 and related nitroaromatic compounds are the most electron-deficient and might be prone to nucleophilic attack. Our chemical studies on BTZ043 and the additional nitroaromatic compounds synthesized by us and others confirmed the postulated reactivity. The results indicate that nucleophiles such as thiolates, cyanide, and hydride induce nonenzymatic reduction of the nitro groups present in these compounds to the corresponding nitroso intermediates by addition at the unsubstituted electron-deficient aromatic carbon present in these compounds. Furthermore, we demonstrate here that these compounds are good candidates for the classical von Richter reaction. These chemical studies offer an alternate hypothesis for the mechanism of action of nitroaromatic anti-TB agents, in that the cysteine thiol(ate) or a hydride source at the active site of DprE1 may trigger the reduction of the nitro groups in a manner similar to the von Richter reaction to the nitroso intermediates, to initiate the inhibition of DprE1. 23201002 Oligochitosan polyplexes as carriers for retinal gene delivery. Non-viral gene therapy represents a promising approach for the treatment of retinal diseases. However, the lack of an efficient carrier hampers the implementation of this therapy. In this study, we evaluated low molecular weight ultrapure oligochitosans for the delivery of the pCMS-EGFP plasmid into the rat retina cells after subretinal and intravitreal administrations. Polyplexes were technologically characterized. Resulting polyplexes based on ultrapure oligochitosans were slightly spherical, protected the plasmid against enzymatic digestion, and their charge and size values ranged from 8 to 14 millivolts and from 150 to 69 nm respectively depending on the N/P ratio. In HEK-293 cultured cells, transfection efficiency significantly increased from 12% to 30% when pH decreased from 7.4 to 7.1 (data normalized to Lipofectamine™ 2000). However, no significant transfection was detected in ARPE-19 cultured cells. Subretinal administrations transfected mainly the pigmented cells of the retinal pigment epithelium and the light sensitive photoreceptor cells, whereas intravitreal injections transfected cells in the ganglion cell layer, blood vessels in the inner layers of the retina and photoreceptors. These results support the potential use of oligochitosans for delivering genetic material into retinal cells in vivo. 23562611 Crystallization of poly(ethylene oxide) with acetaminophen - A study on solubility, spherulitic growth, and morphology. A simple, sensitive, efficient, and novel method analyzing the number of spherulitic nuclei was proposed to estimate the solubility of a model drug acetaminophen (APAP) in poly(ethylene oxide) (PEO). At high crystallization temperature (323K), 10% APAP-PEO had the same low number of spherulitic nuclei as pure PEO, indicating that APAP and PEO were fully miscible. At low crystallization temperature (303K), the number of nuclei for 10% APAP-PEO was significantly higher, suggesting that APAP was oversaturated and therefore recrystallized and acted as a nucleating agent. Based on the results obtained, the solubility of APAP in PEO is possibly between the concentration of 0.1% and 1% at 303K. The spherulitic growth rate G of PEO was found to decrease with increasing APAP concentration, suggesting that APAP is most likely functioning as a chemical defect and is either rejected from or included in the PEO crystals during chain folding. APAP could possibly locate in the inter-spherulitic, inter-fibrillar, inter-lamellar, or intra-lamellar regions of PEO. At 323K, the morphology of 10% APAP-PEO is more dendritic than spherulitic with large unfilled space in between dendrites and spherulites, which is a sign of one or the combination of the four modes of segregation. An extensive spherulitic nucleation and growth kinetics study using the classical theoretical relationships, for example, the Hoffman-Lauritzen (HL) and Avrami theories, was conducted. Both microscopic and differential scanning calorimetric (DSC) analysis yielded similar values for the nucleation constant Kg as well as the fold surface free energy σe and work of chain folding q. The values of σe and q increased with APAP concentration, indicating that the chain folding of PEO was hindered by APAP. 23859336 Effect of dietary caloric restriction on the nociceptive threshold of rats that underwent aerobic and resistance exercise training. The purpose of this study was to evaluate the effect that exercise and caloric restriction have on the nociceptive threshold of rats. Male Wistar rats were divided into two groups: one group that was fed ad libitum (FED) and another group that was subjected to dietary caloric restriction (CR). The CR group received 50% of the food the FED group received, for 4 weeks. Both groups were submitted to aerobic (AE) and resistance (RE) exercise training protocols performed in a rodent treadmill and in a weight-lifting exercise model, respectively. Mechanical and thermal nociceptive thresholds were measured by tail-flick and paw-withdrawal tests, respectively. Both exercise protocols produced antinociception, but there was no difference found between the FED and CR groups after either 1 or 4 weeks. Additionally, although dietary caloric restriction alone did not result in antinociception, it did increase the running time of animals during aerobic exercise and increased the load lifted in resistance exercise after 4 weeks. These results indicate that caloric restriction for 1 or 4 weeks did not alter the nociceptive threshold, but could play an important role in improvement of physical performance. 23759469 Lower docosahexaenoic acid concentrations in the postmortem prefrontal cortex of adult depressed suicide victims compared with controls without cardiovascular disease. A growing body of evidence suggests that deficits in long-chain omega-3 (LCn-3) fatty acids may contribute to major depressive disorder (MDD) and principal causes of excess mortality including suicide and cardiovascular disease. In the present study we compared concentrations of docosahexaenoic acid (DHA, 22:6n-3), the principal LCn-3 fatty acid in brain, in the postmortem prefrontal cortex (BA10) of adult depressed suicide victims and controls with and/or without cardiovascular disease. DHA concentrations (μmol/g) in the prefrontal cortex (PFC, BA10) of adult male and female suicide victims (n = 20) and controls with (n = 8) or without (n = 12) cardiovascular disease were determined by gas chromatography. There was a non-significant trend for lower DHA concentrations in suicide victims compared with all controls (-10%, p = 0.06, d = 0.5). Significantly lower DHA concentrations were observed in suicide victims compared with controls without cardiovascular disease (-14%, p = 0.03, d = 0.7) but not controls with cardiovascular disease (-4%, p = 0.71, d = 0.1). There was a non-significant trend for lower DHA concentrations in controls with cardiovascular disease compared with controls without cardiovascular disease (-11%, p = 0.1, d = 0.6). Adult depressed suicide victims exhibit lower postmortem PFC DHA concentrations compared with controls without cardiovascular disease. These data add to a growing body of evidence implicating DHA deficits in the pathophysiology of MDD, suicide, and cardiovascular disease. 23851398 The effect of rituximab on vaccine responses in patients with immune thrombocytopenia. B-cell depletion therapy may impair vaccine responses and increase infection risk in patients with immune thrombocytopenia (ITP). Capitalizing on a multicenter randomized placebo-controlled trial, we investigated the effects of rituximab on the antibody and cellular responses to Streptococcus pneumoniae polysaccharide vaccine and Haemophilus influenzae type b (Hib) conjugate vaccine in ITP patients. Of 60 patients in the main trial, 24 patients received both vaccines 6 months after rituximab (n=17) or placebo (n=7). Among 20 evaluable patients, 3/14 (21%) in the rituximab group and 4/6 (67%) in the placebo group achieved a 4-fold increase in anti-pneumococcal antibodies (p=0.12). For anti-Hib antibodies, 4/14 (29%) and 5/6 (83%), respectively, achieved a 4-fold increase (p<0.05). Fewer patients in the rituximab group demonstrated functional Hib killing (2/14 [14%] versus 5/6 [83%], p<0.05). Three of 14 rituximab-treated patients failed to respond to vaccines by any criteria. After vaccinations, pre-plasma cell blasts and interferon-γ secreting T-cells were reduced in rituximab-treated patients. We found that antibody responses were impaired for at least 6 months after rituximab. Cellular immunity was reduced in parallel with the depleted B-cell pool. These findings have implications for the timing of vaccinations and the mechanism of infection after rituximab in patients with ITP. 23956496 A Passive Radio-Frequency Identification (RFID) Gas Sensor With Self-Correction Against Fluctuations of Ambient Temperature. Uncontrolled fluctuations of ambient temperature in the field typically greatly reduce accuracy of gas sensors. In this study, we developed an approach for the self-correction against fluctuations of ambient temperature of individual gas and vapor sensors. The main innovation of our work is in the temperature correction which is accomplished without the need for a separate uncoated reference sensor or a separate temperature sensor. Our sensors are resonant inductor-capacitor-resistor (LCR) transducers coated with sensing materials and operated as multivariable passive (battery-free) radio-frequency identification (RFID) sensors. Using our developed approach, we performed quantitation of an exemplary vapor over the temperature range from 25 to 40 °C. This technical solution will be attractive in numerous applications where temperature stabilization of a gas sensor or addition of auxiliary temperature or uncoated reference sensors is prohibitive. 23711626 Luminal Cysteine-Proteases Degrade Colonic Tight Junction Structure and Are Responsible for Abdominal Pain in Constipation-Predominant IBS. Luminal serine-proteases lead to increased colonic paracellular permeability and visceral hypersensitivity in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). Other proteases, namely cysteine-proteases (CPs), increase airway permeability by digesting epithelial tight junction proteins. In this study, we focused on constipation-predominant IBS (IBS-C) and we aimed to (i) evaluate CP levels in two cohorts of IBS patients, (ii) test if IBS-C fecal supernatant (FSN) affects permeability, and visceral sensitivity after repeated administrations in mice, and (iii) evaluate occludin expression in IBS-C colonic biopsies. Fecal CP activity was determined using selective substrate and inhibitor (E64). The effect of papain, as positive control, and IBS-C FSN administrations were evaluated on colonic paracellular permeability and mucosal occludin levels in mice and T84 monolayers. Occludin protein levels were evaluated in IBS-C colonic biopsies. Sensitivity to colorectal distension (CRD) was measured after repeated administrations of IBS-C FSN. We found in a subset of IBS-C patients an enhanced fecal CP activity, in comparison with healthy controls and IBS-D patients. CP activity levels positively correlated with disease severity and abdominal pain scoring. This association was confirmed by receiver operating characteristic curve analysis. In mice, repeated application of IBS-C FSN into colon triggered increased permeability, linked to the enzymatic degradation of occludin, and was associated with enhanced visceral sensitivity to CRD. Finally, occludin levels were found decreased in colonic biopsies from IBS-C patients, and IBS-C FSNs were able to degrade recombinant human occludin in vitro. All these effects were abolished by preincubation of IBS-C FSN with a CP inhibitor, E64. These data suggest that luminal CPs may represent a new factor contributing to the genesis of symptoms in IBS. 23816361 Combined toxicity of pesticide mixtures on green algae and photobacteria. Different organisms have diverse responses to the same chemicals or mixtures. In this paper, we selected the green algae Chlorella pyrenoidosa (C. pyrenoidosa) and photobacteria Vibrio qinghaiensis sp.-Q67 (V. qinghaiensis) as target organisms and determined the toxicities of six pesticides, including three herbicides (simetryn, bromacil and hexazinone), two fungicides (dodine and metalaxyl) and one insecticide (propoxur), and their mixtures by using the microplate toxicity analysis. The toxicities of three herbicides to C. pyrenoidosa are much higher than those to V. qinghaiensis, and the toxicities of metalaxyl and propoxur to V. qinghaiensis are higher than those to C. pyrenoidosa, while the toxicity of dodine to C. pyrenoidosa is similar to those to V. qinghaiensis. Using the concentration addition as an additive reference model, the binary pesticide mixtures exhibited different toxicity interactions, i.e., displayed antagonism to C. pyrenoidosa but synergism to V. qinghaiensis. However, the toxicities of the multi-component mixtures of more than two components are additive and can be predicted by the concentration addition model. 23918736 Hypermetabolism in 18F-FDG PET Predicts Favorable Outcome Following Decompressive Surgery in Patients with Degenerative Cervical Myelopathy. The aim of this study was to prospectively assess the regional changes of glucose metabolism of the cervical spinal cord in patients with degenerative cervical spine stenosis and symptomatic cervical myelopathy after decompressive surgery using (18)F-FDG PET. Twenty patients with symptomatic degenerative monosegmental cervical stenosis with neuroradiologic signs of spinal cord compression underwent decompressive surgery. The clinical course using a functional status score (Japanese Orthopedic Association [JOA] score), (18)F-FDG uptake, and MR imaging were assessed before and at follow-up 12 mo after surgery. Pre- and postoperative changes of (18)F-FDG PET were correlated to the patients' clinical outcome. Ten patients demonstrated preoperatively a focally increased (18)F-FDG uptake at the level of the stenosis. At follow-up, the uptake declined significantly (P = 0.008), and a significant improvement of JOA scores (P < 0.001) could be observed. The remaining 10 patients were characterized preoperatively by an inconspicuous glucose uptake at the level of cord compression in combination with a poststenotic decrease of (18)F-FDG uptake. At follow-up, both JOA scores and (18)F-FDG uptake changed insignificantly. Focal glucose hypermetabolism at the level of cervical spinal cord compression may predict an improved outcome after surgical decompression. Thus, this finding on (18)F-FDG PET suggests a functional damage in a reversible phase of cervical myelopathy. 23849377 Clinical and radiological aspects of rhinoliths: report of five cases. Rhinoliths are calcified masses in the nasal cavity caused by the deposition of nasal, lacrimal, and inflammatory mineral salts by accretion around an endogenous or exogenous nidus. Rhinoliths can be seen as incidental findings on panoramic radiography, although they typically appear blurred due to remaining outside the focus. Therefore, rhinoliths may be difficult to recognize; this difficulty can lead to misdiagnosis. Computed tomography (CT)/cone beam CT (CBCT) scans are generally necessary to define the precise location and to make a differential diagnosis. This article describes radiologic features of five cases of rhinoliths that were detected incidentally on panoramic radiographs. CT or CBCT images were obtained before removing the rhinoliths. 23948575 The relation between Internet and social media use and the demographic and clinical parameters, quality of life, depression, cognitive function and sleep quality in hemodialysis patients: Social media and hemodialysis. There are very few studies in the literature investigating the Internet use in hemodialysis (HD) patients. However, no study examined the relationship between Internet and social media use and quality of life, depression, cognitive function and sleep problems in HD patients. The study is cross-sectional in design. All patients underwent history taking; physical examination; laboratory analysis and quality of life (by a short form of the Medical Outcomes Study), depression (by the Beck Depression Inventory), cognitive function (by the Standardized Mini Mental State Examination) and sleep problems (by the Pittsburgh Sleep Quality Index) evaluation. In total, 134 HD patients (male/female: 73/61, age: 53.0±13.4 years) were included. Patients with mail, Facebook and Twitter accounts were younger, were less depressive, had better quality of life, had higher cognitive function and were more educated compared to patients who did not have these accounts. Patients with Internet-based research about their disease were less depressive, had better quality of life and sleep quality, had higher cognitive function and were more educated compared to patients who did not have Internet-based research. Internet and social media use was closely related with quality of life, depression, cognitive function and education in HD patients. Studies are needed on whether Internet use under the supervision of health care professionals will improve clinical outcomes, adherence, quality of life, depression and decision making in HD patients. 23500377 Detection and discrimination of recombinant plasmid encoding hepatitis C virus core/E1 gene based on PNA and double-stranded DNA hybridization. Development of an electrochemical DNA biosensor for direct detection and discrimination of double-stranded plasmid (ds-Pl) without the need for denaturation of the target plasmid sample using a peptide nucleic acid (PNA) oligomer as the probe is described. This goal was achieved by modification of gold electrode with 6-mercapto-1-hexanol following monolayer self-assembly of cysteine conjugated 20-mer PNA oligomer probe, complementary to the HCV core/E1 region, which binds to ds-Pl and forms PNA/ds-Pl structure. The significant variation in differential pulse voltammetric response of methylene blue on the probe modified electrode upon contacting with complementary double-strand plasmid to form PNA/ds-Pl triplex structure is the principle of target plasmid detection. The results indicated that the reduction peak current was linear with the concentration of complementary strand in the range of 10-300 pg/μl with a detection limit of 9.5 pg/μl. 23503460 The regulatory roles of phosphatases in cancer. The relevance of potentially reversible post-translational modifications required for controlling cellular processes in cancer is one of the most thriving arenas of cellular and molecular biology. Any alteration in the balanced equilibrium between kinases and phosphatases may result in development and progression of various diseases, including different types of cancer, though phosphatases are relatively under-studied. Loss of phosphatases such as PTEN (phosphatase and tensin homologue deleted on chromosome 10), a known tumour suppressor, across tumour types lends credence to the development of phosphatidylinositol 3--kinase inhibitors alongside the use of phosphatase expression as a biomarker, though phase 3 trial data are lacking. In this review, we give an updated report on phosphatase dysregulation linked to organ-specific malignancies.Oncogene advance online publication, 18 March 2013; doi:10.1038/onc.2013.80. 23524312 Accumulation of phenolic compounds in in vitro cultures and wild plants of Lavandula viridis L'Hér and their antioxidant and anti-cholinesterase potential. In this study, we evaluated the phenolic profile, antioxidant and anti-cholinesterase potential of different extracts from wild plants and in vitro cultures of Lavandula viridis L'Hér. The HPLC-DAD analysis allowed the identification and quantification of 3-O-caffeoylquinic, 4-O-caffeoylquinic, 5-O-caffeoylquinic and rosmarinic acids, and luteolin and pinocembrin. Water/ethanol extract from in vitro cultures contained the highest amount of the identified phenolic compounds (51652.92mg/kg). To investigate the antioxidant activity we used Trolox equivalent antioxidant capacity, oxygen radical absorbance capacity, Fe(2+) chelation activity and the inhibition of Fe(2+)-induced lipid peroxidation in mouse brain homogenates (in vitro). Overall, all the extracts from both wild plants and in vitro cultures exhibited ability to scavenge free radicals, to chelate Fe(2+) and to protect against lipid peroxidation. In addition, the extracts from L. viridis were active in inhibiting both acetylcholinesterase and butyrylcholinesterase (Ellman's method). Our findings suggest that L. viridis in vitro cultures represent a promising alternative for the production of active metabolites with antioxidant and anti-cholinesterase activity. 23563602 How to differentiate benign from malignant myometrial tumours using MR imaging. To retrospectively evaluate the ability of magnetic resonance imaging (MRI) to differentiate malignant from benign myometrial tumours. Fifty-one women underwent MRI before surgery for evaluation of a solitary myometrial tumour. At histopathology, there were 25 uncertain or malignant mesenchymal tumours and 26 benign leiomyomas. Conventional morphological MRI criteria were recorded in addition to b 1,000 signal intensity and apparent diffusion coefficient (ADC). Odds ratios (OR) were calculated for each criterion. A multivariate analysis was performed to construct an interpretation model. The significant criteria for prediction of malignancy were high b 1,000 signal intensity (OR = +∞), intermediate T2-weighted signal intensity (OR = +∞), mean ADC (OR = 25.1), patient age (OR = 20.1), intra-tumoral haemorrhage (OR = 21.35), endometrial thickening (OR = 11), T2-weighted signal heterogeneity (OR = 10.2), menopausal status (OR = 9.7), heterogeneous enhancement (OR = 8) and non-myometrial origin on MRI (OR = 4.9). In the recursive partitioning model, using b 1,000 signal intensity, T2 signal intensity, mean ADC, and patient age, the model correctly classified benign and malignant tumours in 47 of the 51 cases (92.4 %). We have developed an interpretation model usable in routine practice for myometrial tumours discovered at MRI including T2 signal, b 1,000 signal and ADC measurement. • MRI is widely used to differentiate benign from malignant myometrial tumours. • By combining T2-weighted, b 1,000 and ADC features, MRI is 92.4 % accurate. • DWI may limit misdiagnoses of uterine sarcoma as benign leiomyoma. • Patient age is important when considering a solitary myometrial tumour. 23950664 Rapid recovery following fulminant meningococcemia complicated by myocarditis in a 15-year-old Nepalese girl: a case report. Fulminant meningococcemia is a relatively rare life-threatening disease caused by Neisseria meningitidis. The clinical presentation is varied, but, when associated with myocarditis, it carries a particularly poor prognosis. We report a case of a patient with fulminant meningococcemia who subsequently developed severe myocardial dysfunction and successfully recovered within a period of 14 days of hospitalization. A 15-year-old girl presented with headache, fever, body ache, and diarrhea for 1 day, and ecchymotic rash over her body for 4 hours. Blood cultures confirmed infection with N. meningitidis. After 6 days in the hospital, the patient developed anasarca, elevated jugular venous pressure, and shock. The patient was managed with intravenous ceftriaxone and captopril. Over the next 3 days the patient rapidly improved and started walking. Meningococcemia complicated by myocarditis has an extremely poor prognosis with high mortality. Our case suggests that recovery from a severe myocardial dysfunction can occur rapidly within a few days. Prompt recognition and management in this case might have contributed to the patient's rapid recovery from myocarditis. 23896240 Current Outcome of Esophagectomy in the Very Elderly: Experience of a German High-volume Center. Operative management of esophageal carcinoma in the very elderly is still controversially discussed. It is not yet decided whether the risk warrants the procedure. The aim of this study is to analyze the outcome of esophagectomy for esophageal cancer in the very elderly. Factors influencing the clinical course and determining the outcome are identified. A retrospective study 292 consecutive cases of esophagectomy for nonmetastatic esophageal cancer at a German tertiary referral hospital between 2004 and 2011 were reviewed. Two age groups (75 years or older and younger than 75 years) were formed. The mean age was 63 years. Altogether 45 patients were 75 years or older. There were no significant differences in American Society of Anesthesiologists score, operative procedure, or in the frequency of anastomotic leakage between the age groups. However, very elderly patients with anastomotic leak had an eight times higher risk for fatal outcome than the very elderly without leak (odds ratio [OR], 8.54; 95% confidence interval [CI], 1.0 to 112.18; P = 0.025). Moreover, the odds for postoperative death were five times higher in very elderly patients with leak than in younger patients sustaining anastomotic leakage (OR, 5.67; 95% CI, 0.67 to 73.83; P = 0.046). In general, the very elderly had a three times higher risk for a fatal outcome (OR, 3.30; 95% CI, 1.37 to 7.86; P = 0.008). In-hospital mortality of the very elderly was 11 out of 45 compared with 8 per cent (20 of 247) in the younger group. Fatal outcome was more often caused by medical (seven) than by surgical complications (four cases). The remaining 34 patients recovered well. Very elderly patients undergoing esophagectomy have no elevated risk for occurrence of surgical complications, whereas the mortality of these complications is much higher. Improved outcome is achievable by timely management of postoperative surgical as well as medical complications. Notwithstanding the increased mortality, esophagectomy should be considered in thoroughly selected very elderly patients with curable esophageal carcinoma. 23800683 Enhancement of anaerobic ammonium oxidation in lake sediment by applying drinking water treatment residuals. In this study, the effect of drinking water treatment residuals (WTRs), non-hazardous byproducts from drinking water treatment plants, on anaerobic ammonium oxidation (anammox) in lake sediments were investigated, qualitatively and quantitatively based on enrichment tests. The results suggested that after the enrichment, anammox were strengthened significantly in enriched sediments with no WTRs (ESNW) and with WTRs (ESW). Comparatively, anammox bacteria in ESW were more aggregated than ESNW. The activity (9.2nmolg(-1)h(-1)) and abundance (9.8×10(7)copiesg(-1)) of anammox bacteria in ESW were also higher than ESNW (6.1nmolg(-1)h(-1)and 8.9×10(7)copiesg(-1)). Further analysis suggested that after enrichment, anammox bacteria in sediments were phylogenetically more distant from Candidatus Kuenenia; anammox bacteria in ESW were closely related to Candidatus Brocadia. Overall, WTRs promoted aggregation, strengthened activity and increased abundance of anammox bacteria in lake sediments. Therefore, WTRs can enhance anammox in lake sediments. 23925246 A directional tuning map of Drosophila elementary motion detectors. The extraction of directional motion information from changing retinal images is one of the earliest and most important processing steps in any visual system. In the fly optic lobe, two parallel processing streams have been anatomically described, leading from two first-order interneurons, L1 and L2, via T4 and T5 cells onto large, wide-field motion-sensitive interneurons of the lobula plate. Therefore, T4 and T5 cells are thought to have a pivotal role in motion processing; however, owing to their small size, it is difficult to obtain electrical recordings of T4 and T5 cells, leaving their visual response properties largely unknown. We circumvent this problem by means of optical recording from these cells in Drosophila, using the genetically encoded calcium indicator GCaMP5 (ref. 2). Here we find that specific subpopulations of T4 and T5 cells are directionally tuned to one of the four cardinal directions; that is, front-to-back, back-to-front, upwards and downwards. Depending on their preferred direction, T4 and T5 cells terminate in specific sublayers of the lobula plate. T4 and T5 functionally segregate with respect to contrast polarity: whereas T4 cells selectively respond to moving brightness increments (ON edges), T5 cells only respond to moving brightness decrements (OFF edges). When the output from T4 or T5 cells is blocked, the responses of postsynaptic lobula plate neurons to moving ON (T4 block) or OFF edges (T5 block) are selectively compromised. The same effects are seen in turning responses of tethered walking flies. Thus, starting with L1 and L2, the visual input is split into separate ON and OFF pathways, and motion along all four cardinal directions is computed separately within each pathway. The output of these eight different motion detectors is then sorted such that ON (T4) and OFF (T5) motion detectors with the same directional tuning converge in the same layer of the lobula plate, jointly providing the input to downstream circuits and motion-driven behaviours. 23918472 Biochemical and morphological characterization of A2BP1 in neuronal tissue. A2BP1 is considered to regulate alternative splicing of important neuronal transcripts and has been implicated in a variety of neurological and developmental disorders. A2BP1 was found in neuronal cells and was analyzed biochemically and morphologically. In this study, we prepared a specific antibody against A2BP1, anti-A2BP1, and carried out protein expression and localization analyses of A2BP1 in rat and mouse tissues. By Western blotting, A2BP1 showed tissue-dependent expression profiles and was expressed in a developmental-stage-dependent manner in the brain. A2BP1 was detected at high levels in neocortex and cerebellum in the rat brain. Immunohistochemical analyses demonstrated that A2BP1 was highly expressed in differentiated neurons but not in mitotically active progenitor cells in the cerebral cortex during developmental stages. In cortical neurons, A2BP1 had accumulated mainly in the nucleus and diffusely distributed in the cell body and dendrites. In differentiated primary cultured rat hippocampal neurons, although A2BP1 was enriched in the nucleus and diffusely distributed in the cytoplasm, it was found in a punctate distribution adjacent to synapses. The results suggest that in neuronal tissues A2BP1 plays important roles, which are regulated in a spatiotemporal manner. © 2013 Wiley Periodicals, Inc. 23830053 Community-acquired pneumonia at the Hospital de Clínicas de Porto Alegre: evaluation of a care protocol. To assess the adequacy of medical prescriptions for community-acquired pneumonia at the emergency department of the Hospital de Clínicas de Porto Alegre, we conducted a prospective cohort study, from January through April 2011. All patients with suspected pneumonia were selected from the first prescription of antimicrobials held in the emergency room. Patients with a description of pneumonia, community-acquired pneumonia, respiratory infection, or other issues related to community-acquired pneumonia were selected for review. Two-hundred and fifteen patients were studied. Adherence to the hospital care protocol was: 11.2% for the initial recommended tests (chest X-ray and collection of sputum sample), 34.4% for blood cultures, and 92.1% for the antimicrobial choice. Sixty percent of the prescriptions consisted of a combination of drugs, and the association of beta-lactam and macrolide was the most common. The Hospital Infection Control Committee evaluated patients' prescriptions within a median time of 23.5h (IQR 25-75%, 8-24). Negative evaluations accounted for 10% of prescriptions (n=59). Fourteen percent of the patients died during hospitalization. In the multivariate analysis, Pneumonia Severity Index Score and use of ampicillin+sulbactam alone were independently related to in-hospital mortality. There was a high adherence to the hospital's CAP protocol, in relation to antimicrobial choice. Severity score and use of ampicillin+sulbactam alone were independently associated to in-hospital death. 23673310 Endolysosome involvement in HIV-1 transactivator protein-induced neuronal amyloid beta production. The increased life expectancy of people living with HIV-1/AIDS is accompanied by increased prevalence of HIV-1-associated neurocognitive disorder. As well, these individuals are increasingly experiencing Alzheimer's disease (AD)-like neurocognitive problems and neuropathological features such as increased deposition of amyloid beta (Aβ) protein. Findings that Aβ production occurs largely in endolysosomes, that HIV-1 transactivator protein (Tat) disrupts endolysosome function-an early pathological feature of AD-and that HIV-1 Tat can increase Aβ levels prompted us to test the hypothesis that endolysosome dysfunction is associated with HIV-1 Tat-induced increases in neuronal Aβ generation. Using primary cultured rat hippocampal neurons, we found that treatment with HIV-1 Tat caused such morphological changes as enlargement of endolysosomes identified with LysoTracker dye and such functional changes as elevated endolysosome pH measured ratiometrically with LysoSensor dye. The HIV-1 Tat-induced changes in endolysosome function preceded temporally HIV-1 Tat-induced increases in Aβ generation measured using enzyme-linked immunosorbent assay. In addition, we demonstrated that HIV-1 Tat increased endolysosome accumulation of Aβ precursor protein and Aβ identified using immunostaining with 4G8 antibodies. Furthermore, we demonstrated that treatment of neurons with HIV-1 Tat increased endolysosome accumulation of beta amyloid-converting enzyme, the rate-limiting enzymatic step for Aβ production, and enhanced beta amyloid-converting enzyme activity. Together, our findings suggest that HIV-1 Tat increases neuronal Aβ generation and thereby contributes to the development of AD-like pathology in HIV-1-infected individuals by disturbing endolysosome structure and function. 23957557 Role of exercise-induced reactive oxygen species in the modulation of Heat Shock Protein response. Abstract The multiple roles that have been associated with heat shock proteins (HSPs), inside and outside cells are remarkable. HSPs have been found to play a fundamental role in multiple stress conditions and to offer protection from subsequent insults. Exercise, because of the physiological stresses associated with it, is one of the main stimuli associated with a robust increase of different HSPs in several tissues. Given the combination of physiological stresses induced by exercise, and the 'cross-talk' that occurs between signalling pathways in different tissues, it is likely that exercise induces the HSP expression through a combination of 'stressors', among which reactive oxygene species (ROS) could play a major role. Indeed, although an imbalance between ROS production and antioxidant levels results in oxidative stress, causing damage to lipids, proteins and nucleic acids with a possible activation of the programmed cell death pathway, at moderate concentrations ROS play an important role as regulatory mediators in signaling processes. Many of the ROS-mediated responses actually protect the cells against oxidative stress and re-establish redox homeostasis. The aim of this review is to provides a critical update on the role of exercise-induced ROS in the modulation of the heat shock protein's response, focusing on experimental results from animal and human studies where the link between redox homeostasis and HSPs expression in different tissues has been addressed. 23381939 Ultralow reflection from a-Si nanograss/Si nanofrustum double layers. A double-layer nanostructure comprising amorphous Si nanograss on top of Si nanofrustums (NFs) with a total height of 680 nm exhibits ultralow reflection. Almost near-unity absorption and near-zero reflectance result in this layered nanostructure, over a broad range of wavelengths and a wide range of angles of incidence, due to the low packing density of a-Si and the smooth transition of the refractive index from the air to the Si substrate across both the nanograss and NF layers. 23953861 An integrative review: Application of self-efficacy instruments for walking in populations with peripheral arterial disease. The study objective was to identify which self-efficacy measurement instruments are being used for walking in patients with peripheral arterial disease (PAD), the psychometrics of these instruments, and recommendations for use in research on patients with PAD. PAD is a common problem for individuals with similar risk factors as cardiovascular disease (CVD). Experts recommend a supervised walking program with incremental increases in speed and distance as an initial treatment for patients with intermittent claudication. Because patients may experience pain while walking, there is a tendency to be nonadherent with exercise therapy, and many limit or avoid walking all together, resulting in a sedentary lifestyle. Self-efficacy plays a role in determining a person's confidence in his or her ability to participate in an exercise program. Data sources for this study were PubMed, Cumulative Index of Nursing and Allied Health Literature, PsycINFO, and the Cochrane database. The integrative review method described by Wittemore and Knafl was used for this review (Wittemore R, Knafl K. The integrative review: updated methodology. J Adv Nurs 2005;52:546-53.). Publications were retrieved electronically and reviewed for inclusion on the basis of studies that measured self-efficacy for walking in populations with PAD, peripheral vascular disease, and CVD. The analysis consisted of 9 publications. Only 2 studies were specific to the population with PAD. The remaining studies addressed self-efficacy issues in CVD or congestive heart failure. The analysis identified 4 instruments based on Bandura's Social Cognitive Theory that were used to assess self-efficacy: (1) the Self-Efficacy Expectation Scale, (2) the Self-Efficacy for Managing Chronic Disease Scale, (3) the Performance-Based Efficacy Scale, and (4) the Barriers Self-Efficacy Scale. The Self-Efficacy Expectation Scale was most frequently used in these studies. The use of the Self-Efficacy Expectation Scale instruments for walking in patients with PAD is limited because reliability and validity have been demonstrated in an older, mostly white population with CVD and congestive heart failure. Instruments that encompass the key constructs of self-efficacy, including physical, personal, and environmental aspects, would allow full evaluation with identification of potential explanations for success or failure for the chosen outcome. This should be taken into consideration in future studies when using instruments of self-efficacy. 23821695 Cost-Effectiveness of Using 2 vs 3 Primary Doses of 13-Valent Pneumococcal Conjugate Vaccine. Although effective in preventing pneumococcal disease, 13-valent pneumococcal conjugate vaccine (PCV13) is the most expensive vaccine on the routinely recommended pediatric schedule in the United States. We examined the cost-effectiveness of switching from 4 total doses to 3 total doses by removing the third dose in the primary series in the United States. We used a probabilistic model following a single birth cohort of 4.3 million to calculate societal cost savings and increased disease burden from removing the 6-month dose of PCV13. Based on modified estimates of 7-valent pneumococcal conjugate vaccine from randomized trials and observational studies, we assumed that vaccine effectiveness under the 2 schedules is identical for the first 6 months of life and largely similar after administration of the 12- to 15-month booster dose. Removing the third dose of PCV13 would annually save $500 million (in 2011$) but would also result in an estimated 2.5 additional deaths among inpatients with pneumonia or invasive pneumococcal disease. Such dose removal would also result in 261 000 estimated otitis media and 12 000 estimated pneumonia cases annually. These additional illnesses could be prevented through modest increases in coverage. Overall, societal savings per additional life-year lost would be ∼$6 million. When nonfatal outcomes are also considered, savings would range from $143 000 to $4 million per additional quality adjusted life-year lost, depending on the assumptions used for otitis media. Sizable societal cost savings and a moderate pneumococcal disease increase could be expected from removing the PCV13 primary series' third dose. 23641780 Design, synthesis, and biological evaluation of pyridoquinazoline derivatives as potent epidermal growth factor receptor inhibitors. Abstract Pyridoquinazolines have been synthesized, characterized, and tested for their in vitro epidermal growth factor receptor (EGFR) tyrosine kinase inhibitory activity. The compounds were prepared from alkylideno/arylideno-bis-ureas. Their structures were elucidated on the basis of elemental analyses and spectral studies (infrared, nuclear magnetic resonance [1H NMR], fourier transform infrared spectroscopy [FTIR], and electron ionization mass spectrometry [EI-MS]). Three of the new compounds had IC50 values in the range of 4.5-11.0 nM. The cellular EGFR internalization response of selected compounds was evaluated using HeLa cells. Three halogenated derivatives had a pronounced effect in inhibiting EGFR internalization. 23764763 Bioactivity and cytotoxicity of glass and glass-ceramics based on the 3CaO·P2O 5-SiO 2-MgO system. The mechanical strength of bioactive glasses can be improved by controlled crystallization, turning its use as bulk bone implants viable. However, crystallization may affect the bioactivity of the material. The aim of this study was to develop glass-ceramics of the nominal composition (wt%) 52.75(3CaO·P2O5)-30SiO2-17.25MgO, with different crystallized fractions and to evaluate their in vitro cytotoxicity and bioactivity. Specimens were heat-treated at 700, 775 and 975 °C, for 4 h. The major crystalline phase identified was whitlockite, an Mg-substituted tricalcium phosphate. The evaluation of the cytotoxicity was carried out by the neutral red uptake methodology. Ionic exchanges with the simulated body fluid SBF-K9 acellular solution during the in vitro bioactivity tests highlight the differences in terms of chemical reactivity between the glass and the glass-ceramics. The effect of crystallinity on the rates of hydroxycarbonate apatite (HCA) formation was followed by Fourier transformed infrared spectroscopy. Although all glass-ceramics can be considered bioactive, the glass-ceramic heat-treated at 775 °C (V775-4) presented the most interesting result, because the onset for HCA formation is at about 24 h and after 7 days the HCA layer dominates completely the spectrum. This occurs probably due to the presence of the whitlockite phase (3(Ca,Mg)O·P2O5). All samples were considered not cytotoxic. 23903092 Pharmacological interventions to modulate attentional bias in addiction. Attentional bias in substance-dependent patients is the tendency to automatically direct attention to substance-related cues in the environment. Preclinical models suggest that attentional bias emerges as a consequence of dopaminergic activity evoked by substance-related cues. The aim of the current review is to describe pharmacological mechanisms underlying attentional bias in humans and to critically review empirical studies that aimed to modulate attentional bias in substance-dependent patients by using pharmacological agents. The findings of the reviewed studies suggest that attentional bias and related brain activation may be modulated by dopamine. All of the reviewed studies investigated acute effects of pharmacological agents, while measurements of chronic pharmacological treatments on attentional bias and clinically relevant measures such as relapse are yet lacking. Therefore, the current findings should be interpreted as a proof of principle concerning the role of dopamine in attentional bias. At the moment, there is too little evidence for clinical applications. While the literature search was not limited to dopamine, there is a lack of studies investigating the role of non-dopaminergic neurotransmitter systems in substance-related attentional bias. A focus on neurotransmitter systems such as acetylcholine and noradrenaline could provide new insights regarding the pharmacology of substance-related attentional bias. 23943839 Nicotine Dependence and Biochemical Exposure Measures in the Second Trimester of Pregnancy. The Heaviness of Smoking Index (HSI) is validated to measure nicotine dependence in nonpregnant smokers, and in these smokers, mean salivary and serum cotinine levels are related by a ratio of 1.25. However, as nicotine metabolism increases during gestation, these findings may differ in pregnancy. We investigated the validity of HSI in pregnancy by comparing this with 3 biochemical measures; and in a search for a less-invasive cotinine measure in pregnancy, we also explored the relationship between mean blood and salivary cotinine levels. Cross-sectional analyses using baseline data from the Smoking, Nicotine, and Pregnancy Trial. Participants were 16-46 years old, 12-24 weeks gestation, smoked more than 5 cigarettes per day and had exhaled carbon monoxide (CO) readings of at least 8 ppm. Linear regression was used to examine correlations between HSI and blood cotinine, and salivary cotinine and exhaled CO. Correlation between blood and salivary cotinine was investigated using linear regression through the origin. HSI scores were associated with blood cotinine (R (2) = 0.20, n = 662, p < .001), salivary cotinine (R (2) = 0.11, n = 967, p < .001), and exhaled CO (R (2) = 0.13, n = 1,050, p < .001). Salivary and blood cotinine levels, taken simultaneously, were highly correlated (R (2) = 0.91, n = 628, p < .001) and the saliva:blood level ratio was 1.01 (95% CI 0.99-1.04). Correlations between HSI and biochemical measures in pregnancy were comparable with those obtained outside pregnancy, suggesting that HSI has similar validity in pregnant smokers. Salivary and blood cotinine levels are roughly equivalent in pregnant smokers. 23666340 A universally applicable and rapid method for measuring the growth of streptomyces and other filamentous microorganisms by methylene blue adsorption-desorption. Quantitative assessment of growth of filamentous microorganisms, such as streptomycetes, is generally restricted to determination of dry weight. Here, we describe a straightforward methylene blue-based sorption assay to monitor microbial growth quantitatively, simply, and rapidly. The assay is equally applicable to unicellular and filamentous bacterial and eukaryotic microorganisms. 23352610 The Polycystic Ovary Syndrome and recent human evolution. The Polycystic Ovary Syndrome (PCOS) is a complex endocrine disorder characterised both by reproductive and metabolic disturbance, and is the most common cause globally of ovarian infertility. It is also a familial polygenic condition, linked genetically to both Type 2 diabetes and the metabolic syndrome. The striking evolutionary paradox of this prominent genetically-based condition, which impairs fertility, is that not only should it have diminished in prevalence, but it should have done so rapidly - unless there has been some form of balancing selection. The emerging discipline of evolutionary medicine can provide important insights into the causes and patterns of occurrence of common diseases such as PCOS. In this paper we review the impacts of PCOS on infertility, fecundability and lifetime reproductive success and then critically appraise published hypotheses about the evolutionary origins of PCOS and related conditions. 23869988 Anti-programmed cell death-1 antibody as a new serological marker for type 1 autoimmune hepatitis. Recently, the association of the dysfunction of programmed cell death (PD)-1 expressed on activated lymphocytes with the pathogenesis of autoimmune hepatitis (AIH) has been speculated. This study aimed to investigate the association of serum anti-PD-1 antibodies with clinical characteristics of type 1 AIH. Serum samples before the initiation of prednisolone treatment were obtained from 52 type 1 AIH patients, 24 patients with drug-induced liver injury (DILI), 30 patients with acute viral hepatitis (AVH), 11 patients with primary sclerosing cholangitis (PSC), and 62 healthy volunteers. Titers of serum anti-PD-1 antibodies were measured by indirect enzyme-linked immunosorbent assay. The cut-off level was represented by a mean absorbance + 2 standard deviations in healthy volunteers. Prevalence of serum anti-PD-1 antibodies was 63% in type 1 AIH patients, 8% in DILI patients, 13% in AVH patients, 18% in PSC patients, and 3% in healthy volunteers. In type 1 AIH patients, titers of serum anti-PD-1 antibodies were correlated with serum levels of bilirubin (r = 0.31, P = 0.030) and alanine aminotransferase (r = 0.31, P = 0.027) but not serum immunoglobulin G levels. Positivity for serum ani-PD-1 antibodies was associated with the later normalization of serum alanine aminotransferase levels after the initiation of prednisolone and the disease relapse. Serum anti-PD-1 antibodies would be useful for the discrimination of type 1 AIH from DILI, AVH and PSC as an auxiliary diagnostic marker. Furthermore, anti-PD-1 antibodies may be associated with clinical characteristics of type 1 AIH. 23918323 Corrosive Substance Ingestion in Children. To evaluate children who ingested corrosive substances, in terms of demographic features, nature of ingested substances, clinical findings, management and complications. A total of 1709 cases aged between 0 and 16 y who ingested corrosive substance were analyzed retrospectively by evaluating the medical records of the patients. The mean age of the cases was 35.23 ±â€‰30.65 mo and male:female ratio was 1.45. Forty one percent of corrosive substances causing intoxication contained NaOH. Thirty percent of the families consisted of 5 or more members. Fourteen percent of the mothers were illiterate. Stricture formation was observed in 29 (1.69 %) of the cases during follow-up. In 79.31 % of those cases alkaline substance ingestion was responsible for stricture development. It was found that stricture formation occurred more frequently among cases who were older than 5 y of age and this finding was statistically significant (p = 0.001). The cases older than 5 y of age with the diagnosis of grade 2b esophagitis must be followed up closely for the stricture formation. In order to protect children from corrosive ingestion, importance must be given to preventive measures such as education of families, keeping and storing these agents out of the reach of children and providing safety caps for these products. 23669351 Enhanced optineurin E50K-TBK1 interaction evokes protein insolubility and initiates familial primary open-angle glaucoma. Glaucoma is the leading cause for blindness affecting 60 million people worldwide. The optineurin (OPTN) E50K mutation was first identified in familial primary open-angle glaucoma (POAG), the onset of which is not associated with intraocular pressure (IOP) elevation, and is classified as normal-tension glaucoma (NTG). Optineurin (OPTN) is a multifunctional protein and its mutations are associated with neurodegenerative diseases such as POAG and amyotrophic lateral sclerosis (ALS). We have previously described an E50K mutation-carrying transgenic (E50K(-tg)) mouse that exhibited glaucomatous phenotypes of decreased retinal ganglion cells (RGCs) and surrounding cell death at normal IOP. Further phenotypic analysis of these mice revealed persistent reactive gliosis and E50K mutant protein deposits in the outer plexiform layer (OPL). Over-expression of E50K in HEK293 cells indicated accumulation of insoluble OPTN in the endoplasmic reticulum (ER). This phenomenon was consistent with the results seen in neurons derived from induced pluripotent stem cells (iPSCs) from E50K mutation-carrying NTG patients. The E50K mutant strongly interacted with TANK-binding kinase 1 (TBK1), which prohibited the proper oligomerization and solubility of OPTN, both of which are important for OPTN intracellular transition. Treatment with a TBK1 inhibitor, BX795, abrogated the aberrant insolubility of the E50K mutant. Here, we delineated the intracellular dynamics of the endogenous E50K mutant protein for the first time and demonstrated how this mutation causes OPTN insolubility, in association with TBK1, to evoke POAG. 23967417 Helicobacter pylori incidence and re-infection in the Aklavik H. pylori Project. The Aklavik H. pylori Project (AHPP) (www.canhelpworkinggroup.ca) is a community-driven project examining Helicobacter pylori infection and its influence on health in a diverse Aboriginal community in the Northwest Territories. Initial research revealed that 58% of 333 participants who underwent a urea breath test (UBT) between 2007 and 2010 were H. pylori-positive. From 2008 to 2010, we offered treatment to H. pylori-positive participants and 113 consented to this treatment. We estimated H. pylori incidence in AHPP participants who initially tested negative and the re-infection frequency in initially positive participants who were successfully treated to clear the infection. Participants who were initially H. pylori-negative or negative after treatment during 2008-2010 were eligible for inclusion. From November 2011 to June 2012, participants were offered a UBT and the samples were analyzed using infrared spectroscopy (IRIS). Participants with a positive test result were classified as new cases for estimating incidence among participants testing negative at baseline and re-infection among those successfully treated for H. pylori infection. Among 38 initially negative participants, follow-up UBT showed that 33 remained negative, 3 were positive, and 2 had uncertain status. The estimated incidence proportion during the follow-up period was 8.3% (95% CI: 1.8-22.0%). Among 43 participants with a negative post-treatment UBT, 41 remained negative and 2 were positive. The estimated re-infection proportion during the follow-up period was 4.7% (95% CI: 0.6-16.0%). The frequency of new cases was similar in males and females. Aboriginal participants had a combined re-infection/incidence rate of 2.4% per year (95% CI: 0.8-5.9% per year). All 9 non-Aboriginal participants remained free from infection throughout the study period, as did all 23 participants aged 55 years and above. The AHPP has substantially reduced the burden of infection in Aklavik since 2008. Continued monitoring, treatment, community engagement and knowledge translation activities are needed to ensure a lasting benefit of the project. 23386483 Identification and characterization of bacterial diterpene cyclases that synthesize the cembrane skeleton. Digging up skeletons: We report the identification and the functional characterization of two terpene cyclases (DtcycA and DtcycB) that were mined from the genome of Streptomyces sp. SANK 60404. DtcycA and DtcycB are novel bacterial diterpene cyclases for the synthesis of the cembrane skeleton. 23968312 Evaluation of the acceptability of Peer Physical Examination (PPE) in medical and osteopathic students: a cross sectional survey. Peer physical examination (PPE) is a method of training in medical and osteopathic curricula. The aim of this study was to compare the acceptability of PPE in two classes of medical and osteopathic students after their first experience, to obtain comparative information useful for an understanding of the different professional approaches. The leading hypothesis was that osteopathic students enter the curriculum with a more positive attitude to bodily contact.As a secondary aim, this study validated the new version of a questionnaire to assess the acceptability of PPE. A new version of a previously validated questionnaire and an instrument from the literature (the Examining Fellow Student [EFS] questionnaire) were used for a cross-sectional survey in a class of 129 3rd year medical students and in two parallel classes of 1st year osteopathic students (total of 112 students). The mean score of the new questionnaire was significantly higher for the osteopathic students than for the medical students (53.4 +/- 6.3 vs.43.4 +/- 8.9; p < 0.01). The only independent variables that were significantly predictive of the score in a linear regression analysis were gender and the condition of medical or osteopathic student. The EFS mean score also showed a significant difference between the osteopathic and medical students (30.76 +/- 2.9 vs. 27.85 +/- 4.3; p < 0.01).Factor analysis of the new questionnaire identified three factors (appropriateness and usefulness, sexual implications and passive role) accounting for 62.8% of the variance. Criterion validity was assessed by correlation with the EFS (Pearson's r coefficient = 0.61). Reliability was expressed in terms of Cronbach's alpha coefficient, which equals 0.86. These quantitative results are consistent with previous qualitative research on the process of embodiment both in medicine and osteopathy. The new questionnaire proved to be valid and reliable. The objective assessment of the acceptability of PPE is a way to determine differences in students' attitudes towards contact with the body and can be used for counselling students regarding career choice. This study can also highlight differences between students from different professions and serve as a basis for reflection for improved mutual interprofessional understanding and future interprofessional education. 23157638 A general approach for combining voxel-based meta-analyses conducted in different neuroimaging modalities. Meta-analyses are useful to summarize the exponential amount of inconsistent and conflicting neuroimaging data. However, they are usually separately conducted for each different neuroimaging modality, preventing the multimodal integration of different imaging findings in a given neuropsychiatric disorder. Here, we describe an innovative method to meta-analytically combine the results of different imaging modalities, such as structural and functional paradigms. The method accounts for the presence of noise in the estimation of the p-values, and can be easily applied to any meta-analytical software. We hope that with this advanced imaging tool, researchers will be able to provide more complete multimodal pictures of the brain regions affected in different neuropsychiatric disorders. 23722681 A differential mobility spectrometry/mass spectrometry platform for the rapid detection and quantitation of DNA adduct dG-ABP. There is continued interest in exploring new analytical technologies for the detection and quantitation of DNA adducts, biomarkers which provide direct evidence of exposure and genetic damage in cells. With the goal of reducing clean-up steps and improving sample throughput, a Differential Mobility Spectrometry/Mass Spectrometry (DMS/MS) platform has been introduced for adduct analysis. A DMS/MS platform has been utilized for the analysis of dG-ABP, the deoxyguanosine adduct of the bladder carcinogen 4-aminobiphenyl (4-ABP). After optimization of the DMS parameters, each sample was analyzed in just 30 s following a simple protein precipitation step of the digested DNA. A detection limit of one modification in 10^6 nucleosides has been achieved using only 2 µg of DNA. A brief comparison (quantitative and qualitative) with liquid chromatography/mass spectrometry is also presented highlighting the advantages of using the DMS/MS method as a high-throughput platform. The data presented demonstrate the successful application of a DMS/MS/MS platform for the rapid quantitation of DNA adducts using, as a model analyte, the deoxyguanosine adduct of the bladder carcinogen 4-aminobiphenyl. 23830816 Protective activity of Cynara scolymus L. leaf extract against chemically induced complex genomic alterations in CHO cells. Cynara scolymus L., popularly known as artichoke, has been widely used in traditional medicine as an herbal medicament for therapeutic purposes. The study aimed at assessing the protective activity of Cynara scolymus leaf extract (LE) against DNA lesions induced by the alkylating agent ethylmethnesulphonate (EMS) in Chinese hamster ovary cells (CHO). The ability of C. scolymus L. LE to modulate the mutagenicity of EMS was examined using the cytokinesis block micronucleus (CBMN) cytome assay in three antigenotoxic protocols, pre- post- and simultaneous treatments. In the pre-treatment, C. scolymus L. LE reduced the frequencies of MNi and NBUDs induced by EMS in the lower concentration. In contrast, at the highest concentration (5mg/ml) artichoke enhanced the frequency of MNi, potentiating EMS genotoxicity. In the simultaneous treatment only the induction of MNi was repressed by the exposure of cells to C. scolymus L. LE. No modification in genotoxicity was observed in LE post-treatment. The results obtained in this study suggest that lower concentrations of artichoke prevent chemically induced genomic damage in mammalian cells. In this context, the protective activity of C. scolymus L. could be associated to its constitutive antioxidants compounds. 23666100 Increased bacterial putrescine has no impact on gut morphology and physiology in gnotobiotic adolescent mice. Gut bacteria influence host anatomy and physiology. It has been proposed that bacterial metabolites including polyamines are responsible for intestinal maturation and mucosal growth. We have hypothesised that bacterially produced polyamines act as trophic factors and thereby influence large intestinal crypt depth and thickness of the different gut layers. For that purpose, germ-free mice were associated with two different microbial consortia. One group was colonised with a simplified human microbiota (SIHUMI). The second group was associated with SIHUMI + Fusobacterium varium (SIHUMI + Fv), which is known to produce high amounts of polyamines. Polyamine concentrations were measured by HPLC and morphological parameters were determined microscopically. Germ-free and conventional mice served as controls. The caecal putrescine concentration of the SIHUMI + Fv was 61.8 μM (47.6-75.5 μM), whereas that of conventional and SIHUMI mice was 28.8 μM (1.3-41.7 μM) and 24.5 μM (16.8-29.1 μM), respectively. The caecal putrescine concentration of germ-free mice was only 0.6 μM (0-1.0 μM). Caecal crypt depth and thickness of the different caecal layers revealed no significant differences between SIHUMI and SIHUMI + Fv mice. However, the crypt depth in the caeca of conventional, SIHUMI and SIHUMI + Fv mice was increased by 48.6% (P<0.001), 39.7% (P<0.001) and 28.5% (P<0.05), respectively, compared to germ-free mice. These findings indicate that increased intestinal putrescine concentrations do not influence gut morphology in our gnotobiotic adolescent mice. 23947911 Isolated complete caudate lobectomy for hepatic tumor of the anterior transhepatic approach: surgical approaches and perioperative outcomes. How to resect the caudate lobe safely is a major challenge to current liver surgery which requires further study. Nine cases (6 hepatic cell carcinoma, 2 cavernous hemangioma and 1 intrahepatic cholangiocacinoma) were performed using the anterior transhepatic approach in the isolated complete caudate lobe resection. During the operation, we used the following techniques: the intraoperative routine use of Peng's multifunction operative dissector (PMOD), inflow and outflow of hepatic blood control, low central venous pressure and selective use of liver hanging maneuver. There were no perioperative deaths observed after the operation. The median operating time was 230 +/- 43.6 minutes, the median intraoperative blood loss was 606.6 +/- 266.3 ml and the median length of postoperative hospital stay was 12.6 +/- 2.9 days. The incidence of complications was 22.22 % (2/9). PMOD and "curettage and aspiration" technique can be of great help of in the dissection of vessels and parenchyma, clearly making caudate lobe resection safer, easier and faster. 23899540 Chromoendoscopy versus Narrow Band Imaging for Colonic Surveillance in Inflammatory Bowel Disease. Mucosal dye spraying (chromoendoscopy [CE]) has been shown in controlled studies to enhance lesion detection in colitis surveillance. Narrow band imaging (NBI) potentially offers a more convenient mode of highlighting mucosal lesions. The primary objectives of this study were to compare CE and NBI in colitis surveillance with respect to lesion detection. A secondary objective was to assess the accuracy of the mucosal pit pattern (Kudo classification) with NBI in predicting mucosal histology. Patients with colitis of 8 years or greater disease duration underwent screening colonoscopy with NBI, followed immediately by CE by 2 endoscopists blinded to each other's results. All lesions were biopsied to confirm histology. Diagnostic yield of each modality for dysplastic lesions. Accuracy of Kudo classification by NBI for neoplasia. Forty-four participants were enrolled. One hundred forty-four colonic lesions were identified in total. Overall, CE identified more lesions than NBI (131 versus 102, P < 0.001); however, most were nondysplastic. CE detected 23 neoplastic (dysplastic or indefinite for dysplasia) lesions in 11 patients and NBI 20 lesions in 10 patients, P = 0.180. Kudo assessment by NBI had low sensitivity for dysplasia (42%) and modest accuracy (74%) for dysplasia. NBI detected fewer lesions than CE in chronic colitis; however, most were not dysplastic. There was a nonsignificant trend in favor of CE for detection of dysplasia. At present, NBI cannot be recommended as an alternative to CE for dysplasia surveillance in colitis. 23045305 Social-cognitive determinants of exercise behaviour among adolescents with mild congenital heart disease. Background: Nowadays, most adolescents with mild congenital heart disease (CHD) undergo medical or surgical correction in early childhood for their congenital anomalies. There is a need to examine the determinants of exercise behaviour among adolescents (CHD) who are able to exercise. Aims: The aims of this study were to examine determinants of exercise among adolescents with mild CHD, including personal beliefs about exercise, interpersonal influences on exercise, and availability of physical environments for exercise, based on social-cognitive theory. Method: A repeated-measures study was conducted at three medical centres in Taiwan. All participants, 126 adolescents with CHD aged 12 to 18 years, had a cardiologist's recommendation of exercise with no limits or limits only on vigorous exercise. Self-administered questionnaires were completed during a summer vacation and again in the fall semester of school along with a 7-day exercise log. The data were analysed using structured equation modelling. Results: The effect of interpersonal influences on total exercise and moderate-to-vigorous exercise was mediated by personal exercise beliefs. Peer influences had significant effects on moderate-to-vigorous exercise through the mediator of perceived exercise self-efficacy. There was no significant difference in the determinants of exercise behaviour during two periods. Personal exercise beliefs, particularly perceived exercise self-efficacy, played the most important role in determining the performance of moderate-to-vigorous exercise. Conclusions: The social-cognitive determinants may serve as a clinical reference for promoting exercise among adolescents with mild CHD. 23500387 Curcumin attenuates allergic airway inflammation by regulation of CD4(+)CD25(+) regulatory T cells (Tregs)/Th17 balance in ovalbumin-sensitized mice. The present study aimed to determine the protective effects and the underlying mechanisms of curcumin on ovalbumin (OVA)-induced allergic inflammation in a mouse model of allergic asthma. Asthma mice model was established by ovalbumin. A total of 60 mice were randomly assigned to six experimental groups: control, model, dexamethasone (2mg/kg), and curcumin (50mg/kg, 100mg/kg, 200mg/kg). Airway resistance (Raw) was measured by the forced oscillation technique, differential cell count in BAL fluid (BALF) was measured by Wright-Giemsa staining, histological assessment was measured by hematoxylin and eosin (HE) staining, BALF levels of Treg/Th17 cytokines were measured by enzyme-linked immunosorbent assay, Treg cells and Th17 cells were evaluated by flow cytometry (FCM). Our study demonstrated that curcumin inhibited OVA-induced increases in eosinophil count; interleukin (IL)-17A level were recovered in bronchoalveolar lavage fluid increased IL-10 level in bronchoalveolar lavage fluid. Histological studies demonstrated that curcumin substantially inhibited OVA-induced eosinophilia in lung tissue. Flow cytometry (FCM) studies demonstrated that curcumin remarkably inhibited Th17 cells and significantly increased Treg cells. The results in vivo show ovalbumin-induced significantly broke Treg/Th17 balance; curcumin treatments markedly attenuated the inflammatory in asthma model by regulating Treg/Th17 balance. Our findings support the possible use of curcumin as a therapeutic drug for patients with allergic asthma. 23044709 Overexpression of H1 calponin in osteoblast lineage cells leads to a decrease in bone mass by disrupting osteoblast function and promoting osteoclast formation. H1 calponin (CNN1) is known as a smooth muscle-specific, actin-binding protein which regulates smooth muscle contractive activity. Although previous studies have shown that CNN1 has effect on bone, the mechanism is not well defined. To investigate the role of CNN1 in maintaining bone homeostasis, we generated transgenic mice overexpressing Cnn1 under the control of the osteoblast-specific 3.6-kb Col1a1 promoter. Col1a1-Cnn1 transgenic mice showed delayed bone formation at embryonic stage and decreased bone mass at adult stage. Morphology analyses showed reduced trabecular number, thickness and defects in bone formation. The proliferation and migration of osteoblasts were decreased in Col1a1-Cnn1 mice due to alterations in cytoskeleton. The early osteoblast differentiation of Col1a1-Cnn1 mice was increased, but the late stage differentiation and mineralization of osteoblasts derived from Col1a1-Cnn1 mice were significantly decreased. In addition to impaired bone formation, the decreased bone mass was also associated with enhanced osteoclastogenesis. Tartrate-resistant acid phosphatase (TRAP) staining revealed increased osteoclast numbers in tibias of 2-month-old Col1a1-Cnn1 mice, and increased numbers of osteoclasts co-cultured with Col1a1-Cnn1 osteoblasts. The ratio of RANKL to OPG was significantly increased in Col1a1-Cnn1 osteoblasts. These findings reveal a novel function of CNN1 in maintaining bone homeostasis by coupling bone formation to bone resorption. 23868086 Inflammatory mediators in saliva associated with arterial stiffness and subclinical atherosclerosis. Whereas circulating levels of C-reactive protein (CRP) have been associated with, for example, arterial stiffness, subclinical atherosclerosis and metabolic syndrome, other inflammatory biomarkers with potential interest for these conditions may not be measurable systemically. The predictive value of salivary biomarkers in these contexts has remained largely unexplored. The aim of the present study was to establish the association of different salivary biomarkers of inflammation with subclinical cardiovascular disease. Two hundred and fifty-nine individuals were included in the study. Saliva and plasma samples were collected, and each individual underwent carotid ultrasound and measures of pulse wave velocity and blood pressure. Medical history of previous cardiovascular disease, current medications and smoking were collected by questionnaire. Salivary levels of CRP, leukotriene B4 (LTB4), prostaglandin E2 (PGE2), matrix metalloproteinase 9 (MMP-9), creatinine and lysozyme were measured. Salivary levels of CRP were significantly correlated with plasma levels (r = 0.73, P < 0.0001). In an age-adjusted and sex-adjusted analysis, salivary CRP was significantly and positively correlated with mean arterial blood pressure, pulse pressure, pulse wave velocity, BMI, metabolic syndrome, waist-to-hip ratio and intima-media thickness. Increasing age and sex-adjusted salivary CRP tertiles were in addition associated with carotid plaques. In a multivariate analysis, CRP and MMP-9 were associated with intima-media thickness, LTB4 and PGE2 with arterial stiffness, and lysozyme with hypertension. Saliva may represent an alternative mean for evaluation of cardiovascular risk. 23466543 Controlled lateral packing of insulin monolayers influences neuron polarization in solid-supported cultures. Neurons are highly polarized cells, composed of one axon and several branching dendrites. One important issue in neurobiology is to understand the molecular factors that determine the neuron to develop polarized structures. A particularly early event, in neurons still lacking a discernible axon, is the segregation of IGF-1 (Insulin like Growth Factor-1) receptors in one neurite. This receptor can be activated by insulin in bulk, but, it is not known if changes of insulin organization as a monomolecular film may affect neuron polarization. To this end, in this work we developed solid-supported Langmuir-Blodgett films of insulin with different surface packing density. Hyppocampal pyramidal neurons, in early stage of differentiation, were cultured onto those substrates and polarization was studied after 24 h by confocal microscopy. Also we used surface reflection interference contrast microscopy and confocal microscopy to study attachment patterns and morphology of growth cones. We observed that insulin films packed at 14 mN/m induced polarization in a similar manner to high insulin concentration in bulk, but insulin packed at 44 mN/m did not induce polarization. Our results provide novel evidence that the neuron polarization through IGF-1 receptor activation can be selectively modulated by the lateral packing of insulin organized as a monomolecular surface for cell growth. 23918245 Guidelines on processing and reporting of prostate biopsies: the 2013 update of the pathology committee of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The histopathological examination of a prostate biopsy is the basis of prostate cancer diagnostics. Prostate cancer grade and extent of cancer in the diagnostic biopsy are important determinants of patient management. Quality of the prostate biopsy and its processing may influence the outcome of the histopathological evaluation. Further, an unambiguous and concise pathology reporting is essential for an appropriate clinical decision process. Since our initial report in 2003, there have been several practice changes, including the increased uptake of follow-up biopsies of patients who are under active surveillance, increasingly taken under guidance of MRI, or who underwent a prostate-sparing therapy. Therefore, we investigated the literature on the current pathology practices and recommendations with regard to prostate biopsy processing and reporting, both at initial diagnosis and in the context of follow-up biopsies in order to update our guidelines on the optimal processing and reporting of prostate biopsies. 23161751 Do Subtoxic levels of chlorate influence the desiccation tolerance of Egeria densa? Among the different factors hypothesized to be responsible for the virtual disappearance of Egeria densa, once a dominant aquatic macrophyte in a southern Chile wetland ecosystem, are the negative effects of certain chemical compounds (mainly chlorate) and harsh environmental conditions (desiccation caused by prolonged atmospheric exposure). The authors performed an integrated experiment in which E. densa plants were first exposed for four weeks inside a mesocosm system to levels of chlorate that existed in the wetland at the time of the plant's demise and then exposed to desiccation conditions that also resembled those that the system had experienced. Hence, the authors tested the hypothesis that E. densa plants exposed to sublethal levels of chlorate are more susceptible to the deleterious effect of desiccation compared with plants that had not been exposed to chlorate. This hypothesis was tested by means of quantifying physiologically related parameters in plants right after the four weeks under water and then after the desiccation period of 6 h. Their results rejected this hypothesis, because all plants, regardless of their history, are equally affected by desiccation. 23849788 Host cell tropism mediated by Australian bat lyssavirus envelope glycoproteins. Australian bat lyssavirus (ABLV) is a rhabdovirus of the lyssavirus genus capable of causing fatal rabies-like encephalitis in humans. There are two variants of ABLV, one circulating in pteropid fruit bats and another in insectivorous bats. Three fatal human cases of ABLV infection have been reported with the third case in 2013. Importantly, two equine cases also arose in 2013; the first occurrence of ABLV in a species other than bats or humans. We examined the host cell entry of ABLV, characterizing its tropism and exploring its cross-species transmission potential using maxGFP-encoding recombinant vesicular stomatitis viruses that express ABLV G glycoproteins. Results indicate that the ABLV receptor(s) is conserved but not ubiquitous among mammalian cell lines and that the two ABLV variants can utilize alternate receptors for entry. Proposed rabies virus receptors were not sufficient to permit ABLV entry into resistant cells, suggesting that ABLV utilizes an unknown alternative receptor(s). 23749209 XIAP inhibits autophagy via XIAP-Mdm2-p53 signalling. The primary role of autophagy is adaption to starvation. However, increasing evidence suggests that autophagy inhibition also plays an important role in tumorigenesis. Upregulation of X-linked inhibitor of apoptosis (XIAP) has been associated to a variety of human cancers, yet the underlying mechanisms remain obscure. Here, we report that XIAP suppresses autophagy by exerting a previously unidentified ubiquitin E3 ligase activity towards Mdm2, which is a negative regulator of p53. XIAP controls serum starvation-induced autophagy downstream of the PI3K/Akt pathway. In mouse models, inhibition of autophagy by XIAP promotes tumorigenecity of HCT116 cells. XIAP-mediated autophagy inhibition is also largely validated in clinical tumour samples. These findings reveal a novel XIAP-Mdm2-p53 pathway that mediates the inhibition of autophagy, by which XIAP may contribute to tumorigenesis. 23963891 Yeast Two-Hybrid Analysis of PriB-Interacting Proteins in Replication Restart Primosome: A Proposed PriB-SSB Interaction Model. PriB is one of the components of the replication restart primosome. The activity mediated by the primosomal proteins, including PriB, is required for reinitiating chromosomal DNA replication in bacteria after DNA damage. As such, the study of the interactions between PriB and members in the primosome is essential to better understand their mechanism of action. In this study, we investigated PriB-interacting proteins in the primosome through the yeast two-hybrid system. Yeast two-hybrid analysis using two strains, Y187 and AH109, revealed that PriB interacts with PriA, DnaT, SSB, and itself and does not interact with DnaA, DnaB, DnaC, or DnaG. In addition, mutational analysis showed that PriB may bind to SSB via K82, K84, and K89 in the L45 loop. Based on these preliminary data, we proposed a PriB-SSB interaction model. Further work can focus on determination of how PriB binds to the PriA-SSB complex in replication restart. 23908642 Emotional expression in music: contribution, linearity, and additivity of primary musical cues. The aim of this study is to manipulate musical cues systematically to determine the aspects of music that contribute to emotional expression, and whether these cues operate in additive or interactive fashion, and whether the cue levels can be characterized as linear or non-linear. An optimized factorial design was used with six primary musical cues (mode, tempo, dynamics, articulation, timbre, and register) across four different music examples. Listeners rated 200 musical examples according to four perceived emotional characters (happy, sad, peaceful, and scary). The results exhibited robust effects for all cues and the ranked importance of these was established by multiple regression. The most important cue was mode followed by tempo, register, dynamics, articulation, and timbre, although the ranking varied across the emotions. The second main result suggested that most cue levels contributed to the emotions in a linear fashion, explaining 77-89% of variance in ratings. Quadratic encoding of cues did lead to minor but significant increases of the models (0-8%). Finally, the interactions between the cues were non-existent suggesting that the cues operate mostly in an additive fashion, corroborating recent findings on emotional expression in music (Juslin and Lindström, 2010). 23968764 Transapical Aortic Valve Replacement for Severe Aortic Stenosis: Results From the Nonrandomized Continued Access Cohort of the PARTNER Trial. Transapical (TA) aortic valve replacement was an integral part of the Placement of Transcatheter Aortic Valves (PARTNER) trial. Enrollment during the randomized trial included 104 transapical (premarket approval TA [PMA-TA]) and 92 surgical aortic valve replacements (SAVR) within the TA cohort. On completion of the trial, enrollment continued in a nonrandomized continued access (NRCA) program. We compared the outcomes of NRCA-TA procedures with those of PMA-TA and SAVR. In 22 centers, 975 patients underwent TA aortic valve replacement as part of the NRCA registry. Inclusion and exclusion criteria were unchanged from the previously reported PARTNER trial. All patients were followed up for at least 1 year. Thirty-day or in-hospital mortality was 8.8% for the NRCA-TA cohort, compared with 10.6% and 12.0% for the PMA-TA and SAVR patients, respectively (p = 0.54). One-year mortality in the NRCA-TA cohort was 22.1%, not significantly lower than the mortality in PMA-TA and SAVR patients at 29.0% and 25.3%, respectively (p = 0.27). Thirty-day or in-hospital stroke was 2.2% among NRCA-TA patients in contrast to the 6.7% stroke rate observed in the PMA-TA group and 5.4% in SAVR patients (p = 0.008). Lower rates of neurologic adverse events in the NRCA-TA group persisted at 1 year compared with the PMA-TA and SAVR patients. Among the 975 patients in the NRCA-TA cohort, rates of major outcomes including death and stroke compared favorably with outcomes of PMA-TA and SAVR patients enrolled in the PARTNER trial. This trend toward improved outcomes may be attributed to improved patient selection, individual centers surmounting the procedural learning curve, and refinements in surgical technique. 23871872 Electroactive species-doped poly(3,4-ethylenedioxythiophene) films: Enhanced sensitivity for electrochemical simultaneous determination of vitamins B2, B6 and C. Herein, functionalized PEDOT films were prepared by incorporation of two electroactive species, ferrocenecarboxylic acid (Fc(-)) and ferricyanide (Fe(CN)6(4-)) as doping anions during the electropolymerization of PEDOT at glassy carbon electrodes (GCEs) from aqueous solution. The electrochemically synthesized electroactive species-doped PEDOT films have been carefully characterized by scanning electron microscopy (SEM), FTIR and UV/Vis spectra and various electrochemical techniques. Such nanostructured films combined the advantages of PEDOT (high conductivity and stability) together with electroactive species (good electrochemical activity) and were applied as electrochemical sensors for simultaneous determination of vitamin B2 (VB2), vitamin B6 (VB6) and vitamin C (VC). The results showed that the oxidation peak currents of vitamins obtained at the GCEs modified with electroactive species-doped PEDOT films were much higher than those at the ClO4(-)-doped PEDOT films and bare GCEs. The experiment results also illustrated that the sensors possessed high selectivity with no interference from other potential competing species. Moreover, the proposed sensors were successfully employed for the determination of vitamins in orange juice samples with satisfactory results. 23594999 Aberrant free radical biology is a unifying theme in the etiology and pathogenesis of major human diseases. The seemingly disparate areas of oxygen toxicity, radiation exposure, and aging are now recognized to share a common feature-the aberrant production and/or removal of biologically derived free radicals and other reactive oxygen and nitrogen species (ROS/RNS). Advances in our understanding of the effects of free radicals in biology and medicine have been, and continue to be, actively translated into clinically tractable diagnostic and therapeutic applications. This issue is dedicated to recent advances, both basic discoveries and clinical applications, in the field of free radicals in biology and medicine. As more is understood about the proximal biological targets of aberrantly produced or removed reactive species, their sensors, and effectors of compensatory response, a great deal more will be learned about the commonalities in mechanisms underlying seemingly disparate disease states. Together with this deeper understanding, opportunities will arise to devise rational therapeutic interventions to decrease the incidence and severity of these diseases and positively impact the human healthspan. 23855836 1-Substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones Endowed with Dual DNA-PK/PI3-K Inhibitory Activity. Analogues of (dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (NU7441), a potent inhibitor of DNA-dependent protein kinase (DNA-PK; IC50 = 42 ± 2 nM), have been synthesized in which water-solubilizing groups [NHCO(CH2)nNR(1)R(2), where n = 1 or 2 and the moiety R(1)R(2)N was derived from a library of primary and secondary amines, e.g., morpholine] were placed at the 1-position. Several of the newly synthesized compounds exhibited high potency against DNA-PK and potentiated the cytotoxicity of ionizing radiation (IR) in vitro 10-fold or more (e.g., 2-(4-ethylpiperazin-1-yl)-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thio-phen-1-yl)acetamide, 39; DNA-PK IC50 = 5.0 ± 1 nM, IR dose modification ratio = 13). Furthermore, 39 was shown to potentiate not only IR in vitro but also DNA-inducing cytotoxic anticancer agents, both in vitro and in vivo. Counter-screening against other members of the phosphatidylinositol 3-kinase (PI-3K) related kinase (PIKK) family unexpectedly revealed that some of the compounds were potent mixed DNA-PK and PI-3K inhibitors. 23402300 A low-overpotential potassium-oxygen battery based on potassium superoxide. Li-O(2) battery is regarded as one of the most promising energy storage systems for future applications. However, its energy efficiency is greatly undermined by the large overpotentials of the discharge (formation of Li(2)O(2)) and charge (oxidation of Li(2)O(2)) reactions. The parasitic reactions of electrolyte and carbon electrode induced by the high charging potential cause the decay of capacity and limit the battery life. Here, a K-O(2) battery is report that uses K(+) ions to capture O(2)(-) to form the thermodynamically stable KO(2) product. This allows for the battery to operate through the one-electron redox process of O(2)/O(2)(-). Our studies confirm the formation and removal of KO(2) in the battery cycle test. Furthermore, without the use of catalysts, the battery shows a low discharge/charge potential gap of less than 50 mV at a modest current density, which is the lowest one that has ever been reported in metal-oxygen batteries. 23937757 Mechanical axis of the lower extremity determined by a new digital photographic method. Assessment of the mechanical axis is routine during the examination of patients with lower extremity pain. Long-leg radiographic examination is the gold standard for exact measurement, but it is associated with a significant radiation dose. An alternative method to examine the mechanical axis has been warranted. This article validates a newly developed computerized photograph method to calculate the mechanical axis using a digital photograph. The location of the center of the femoral head was calculated using ink marks on both superior iliac spines. Twenty-five patients (10 women and 15 men) had both legs examined using the photographic method and long-leg radiography examination. The digital photograph method was found to be highly reliable. The interobserver absolute mean difference was 0.99°±0.85°, and the intraobserver absolute mean difference (day-to-day variation) was 1.04°±0.81°. The mechanical axis determined by the 2 methods was highly correlated (R=0.943). The long-leg radiography method was within an average of ±1.88° of the photographic method, with a 95% probability. The photographic method appears to be an effective alternative to conventional long-leg radiography. The photographic method seems convenient in the routine examination of patients with leg pain and children with suspected axial deformity and for follow-up after treatment for malalignment. Calculation coefficients for children and a possible racial difference remain to be studied. 23967823 The prevalence of depression and anxiety among Chinese adults with cancer: a systematic review and meta-analysis. A lot of empirical studies have been conducted to evaluate the prevalence of depression and anxiety among Chinese adults with cancer. We aimed to conduct a meta-analysis in order to evaluate the prevalence and odds ratios of depression and anxiety in Chinese adults with cancer compared with those without. The three most comprehensive computerized Chinese academic databases-CNKI, Wangfang and Vip databases-were systematically screened through September 2012. PubMed and Web of Science (SCIE) were also searched from their inception until September 2012 without language restrictions, and an internet search was also used. Case--control studies assessing the prevalence of depression and anxiety among Chinese adults with cancer were analyzed. Study selection and appraisal were conducted independently by three authors. The non-weighted prevalence, pooled random-effects estimates of odds ratio (OR) and 95% confidence intervals (CI) were all calculated. Seventeen eligible studies with a total of 3497 subjects were included. The prevalence of depression and anxiety were significantly higher in adults with cancer compared with those without (Depression: 54.90% vs. 17.50%, OR = 7.85, 95%CI = 5.56-11.07, P = 0.000; Anxiety: 49.69% vs. 18.37%, OR = 6.46, 95%CI = 4.36-9.55, P = 0.000), the same situation was also observed in subgroup of control groups, assessment methods and cancer types. Although no difference of depression was observed in studies utilizing clinical diagnosis compared with self-report, the OR of anxiety in adults with cancer compared with those without was higher in studies utilizing clinical diagnosis (OR = 8.42, 95%CI = 4.83-14.70) than self-reports (OR = 5.83, 95%CI = 3.64-9.34). The ORs of depression and anxiety in cancer patients compared with disease group (Depression: OR = 6.03, 95%CI = 4.23-8.61; Anxiety: OR = 4.40, 95%CI = 3.05-6.36) were lower than in those compared with normal group (Depression: OR = 13.58, 95%CI = 6.26-29.46; Anxiety: OR = 15.47, 95%CI = 10.00-23.95). We identified high prevalence rates of depression and anxiety among Chinese adults with cancer. The findings support that the prevalence of depression and anxiety among adults with cancer should receive more attention in Chinese medical settings. 23865564 Development and validity of a questionnaire to test the knowledge of primary care personnel regarding nutrition in obese adolescents. In light of its epidemic proportions in developed and developing countries, obesity is considered a serious public health issue. In order to increase knowledge concerning the ability of health care professionals in caring for obese adolescents and adopt more efficient preventive and control measures, a questionnaire was developed and validated to assess non-dietitian health professionals regarding their Knowledge of Nutrition in Obese Adolescents (KNOA). The development and evaluation of a questionnaire to assess the knowledge of primary care practitioners with respect to nutrition in obese adolescents was carried out in five phases, as follows: 1) definition of study dimensions 2) development of 42 questions and preliminary evaluation of the questionnaire by a panel of experts; 3) characterization and selection of primary care practitioners (35 dietitians and 265 non-dietitians) and measurement of questionnaire criteria by contrasting the responses of dietitians and non-dietitians; 4) reliability assessment by question exclusion based on item difficulty (too easy and too difficult for non-dietitian practitioners), item discrimination, internal consistency and reproducibility index determination; and 5) scoring the completed questionnaires. Dietitians obtained higher scores than non-dietitians (Mann-Whitney U test, P < 0.05), confirming the validity of the questionnaire criteria. Items were discriminated by correlating the score for each item with the total score, using a minimum of 0.2 as a correlation coefficient cutoff value. Item difficulty was controlled by excluding questions answered correctly by more than 90% of the non-dietitian subjects (too easy) or by less than 10% of them (too difficult). The final questionnaire contained 26 of the original 42 questions, increasing Cronbach's α value from 0.788 to 0.807. Test-retest agreement between respondents was classified as good to very good (Kappa test, >0.60). The KNOA questionnaire developed for primary care practitioners is a valid, consistent and suitable instrument that can be applied over time, making it a promising tool for developing and guiding public health policies. 23969810 What is new in preterm birth prevention?: important recent articles. This month, we focus on current research in preterm birth prevention. Dr. Andrews discusses recent publications, and each is concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. 22931535 Adhesion of osteoblasts to a vertically aligned TiO2 nanotube surface. The adhesion of cells to vertically aligned TiO2 nanotubes is reviewed. The attraction between a negatively charged nanotube surface and a negatively charged osteoblast is facilitated by charged protein-mediators like proteins with a quadrupolar internal charge distribution, fibronectin and vitronectin. It is shown that adhesion and spreading of osteoblasts on vertically aligned TiO2 nanotube surfaces depend on the diameter of the nanotubes. Apparently, a small diameter nanotube surface has on average more sharp convex edges per unit area than a large one, leading to stronger binding affinity on its surface. 23137955 Polydatin ameliorates renal injury by attenuating oxidative stress-related inflammatory responses in fructose-induced urate nephropathic mice. A series of studies have recently demonstrated that the oxidative stress, nuclear factor-kappa B (NF-κB) activation and the subsequent coordinated inflammatory responses played an important role in the pathogenesis of urate nephropathy (UN). Polydatin has been suggested to have the properties of anti-oxidative, anti-inflammatory and nephroprotective effects. However, the possible protective and beneficial effects of polydatin on UN are not fully elucidated. Therefore, we investigated the potential beneficial effects and possible mechanisms of polydatin on UN. In this study, polydatin showed inhibitory activities on xanthine oxidase to repress the level of serum uric acid in vivo and in vitro. Further investigations revealed that polydatin displayed little toxic effects and significantly ameliorated the renal function in fructose-induced UN mice. The nephroprotective activities of polydatin was not only due to the effects on remarkably attenuating the oxidative stress induced by uric acid, but also on markedly suppressing the oxidative stress-related inflammatory cascade, including decreasing the expressions of NF-κB p65, COX-2 and iNOS proteins and inhibiting the productions of TNF-α, PGE(2) and IL-1β. These findings elucidated that polydatin exhibited prominent nephroprotective activities and low toxic effects. 23601082 The potential of sarcospan in adhesion complex replacement therapeutics for the treatment of muscular dystrophy. Three adhesion complexes span the sarcolemma and facilitate critical connections between the extracellular matrix and the actin cytoskeleton: the dystrophin- and utrophin-glycoprotein complexes and α7β1 integrin. Loss of individual protein components results in a loss of the entire protein complex and muscular dystrophy. Muscular dystrophy is a progressive, lethal wasting disease characterized by repetitive cycles of myofiber degeneration and regeneration. Protein replacement therapy offers a promising approach for the treatment of muscular dystrophy. Recently, we demonstrated that sarcospan facilitates protein-protein interactions amongst the adhesion complexes and is an important therapeutic target. Here, we review current protein replacement strategies, discuss the potential benefits of sarcospan expression, and identify important experiments that must be addressed for sarcospan to move to the clinic. This article is protected by copyright. All rights reserved. 23934336 The renin-angiotensin system meets the hallmarks of cancer. The hallmarks of cancer are described as the distinctive and complementary capacities that cells must acquire during the multistep development of becoming a cancer cell that allow them to survive, proliferate and disseminate. The renin-angiotensin system (RAS) was first discovered and extensively studied in the physiological regulation of systemic arterial pressure. RAS signalling increases cell proliferation in malignancy by directly affecting tumour and stromal cells and by indirectly modulating the growth of vascular cells during angiogenesis. We aim to describe and give a general view of how the RAS is involved in several hallmarks of cancer and how this could open a window to several interesting treatments. 23815549 Prediction of the origin of French Legionella pneumophila strains using a mixed-genome microarray. Legionella is a water and soil bacterium that can infect humans, causing a pneumonia known as Legionnaires' disease. The pneumonia is almost exclusively caused by the species L. pneumophila, of which serogroup 1 is responsible for 90% of patients. Within serogroup 1, large differences in prevalence in clinical isolates have been described. A recent study, using a Dutch Legionella strain collection, identified five virulence associated markers. In our study, we verify whether these five Dutch markers can predict the patient or environmental origin of a French Legionella strain collection. In addition, we identify new potential virulence markers and verify whether these can predict better. A total of 219 French patient isolates and environmental strains were compared using a mixed-genome micro-array. The micro-array data were analysed to identify predictive markers, using a Random Forest algorithm combined with a logistic regression model. The sequences of the identified markers were compared with eleven known Legionella genomes, using BlastN and BlastX; the functionality for each of the predictive markers was checked in the literature. The five Dutch markers insufficiently predicted the patient or environmental origin of the French Legionella strains. Subsequent analyses identified four predictive markers for the French collection that were used for the logistic regression model. This model showed a negative predictive value of 91%. Three of the French markers differed from the Dutch markers, one showed considerable overlap and was found in one of the Legionella genomes (Lorraine strain). This marker encodes for a structural toxin protein RtxA, described for L. pneumophila as a factor involved in virulence and entry in both human cells and amoebae. The combination of a mixed-genome micro-array and statistical analysis using a Random Forest algorithm has identified virulence markers in a consistent way. The Lorraine strain and related Dutch and French Legionella strains contain a marker that encodes a RtxA protein which probably is involved in the increased prevalence in clinical isolates. The current set of predictive markers is insufficient to justify its use as a reliable test in the public health field in France. Our results suggest that genetic differences in Legionella strains exist between geographically distinct entities. It may be necessary to develop region-specific mixed-genome microarrays that are constantly adapted and updated. 23473805 Lipid raft modulation by Rp1 reverses multidrug resistance via inactivating MDR-1 and Src inhibition. Multidrug resistance (MDR) is a major obstacle to effective cancer therapy. The membrane transporter MDR-1 (P-gp, ABCB1), a member of the ATP-binding cassette (ABC) transporter family, effluxes anti-cancer drugs from cancer cells. Increased activity of MDR-1 is known to be the main mechanism for multidrug resistance. MDR-1 is known to be localized in the cholesterol- and sphingolipid-enriched plasma membrane microdomains, known as lipid rafts. Disruption of lipid rafts by cholesterol depletion alters lipid raft functions, indicating that cholesterol is critical for raft function. Because ginsenosides are structurally similar to cholesterol, in this study, we investigated the effect of Rp1, a novel ginsenoside derivative, on drug resistance using drug-sensitive OVCAR-8 and drug-resistant NCI/ADR-RES and DXR cells. Rp1 treatment resulted in an accumulation of doxorubicin or rhodamine 123 by decreasing MDR-1 activity in doxorubicin-resistant cells. Rp1 synergistically induced cell death with actinomycin D in DXR cells. Rp1 appeared to redistribute lipid rafts and MDR-1 protein. Moreover, Rp1 reversed resistance to actinomycin D by decreasing MDR-1 protein levels and Src phosphorylation with modulation of lipid rafts. Addition of cholesterol attenuated Rp1-induced raft aggregation and MDR-1 redistribution. Rp1 and actinomycin D reduced Src activity, and overexpression of active Src decreased the synergistic effect of Rp1 with actinomycin D. Rp1-induced drug sensitization was also observed with several anti-cancer drugs, including doxorubicin. These data suggest that lipid raft-modulating agents can be used to inhibit MDR-1 activity and thus overcome drug resistance. 23355494 Relation between respiratory function tests and life habits of the university students. Among the university students especially in adolescence period, smoking habits and unhealthy lifestyles are major problems in social life. In this study, it is intended to reveal smoking habits and lifestyles of the students from Suleyman Demirel University and to determine the effects of smoking and lifestyles on pulmonary functions. Materials and methods: Participants were 94 university students who were getting formal education in the Suleyman Demirel University central campus. Data were analysed by analysis of variance and chi-square tests. For all analysis, p value of <0.05 was considered significant. Results: Students' mean age was 19.9 ± 0.9 years, and of all the students 74 (78.7%) were undergraduate students; remaining 20 (21.3%) were graduate students. Of all the students, 27 (28.7%), which comprised the largest group of the students, were living in state dormitory. Body mass index (BMI) was examined for the study group; according to BMI, body weight was generally within normal limits but 17.39% of girls' were found to be underweight. Conclusions: Respiratory parameters can be affected by many factors. Smoking habit of university students can be prevented, and it is an important point that they have a healthy lifestyle both for their own health and for future generations. 23863825 Dairy products, dietary calcium and bone health: possibility of prevention of osteoporosis in women: the Polish experience. The objective of the study was to analyze the consumption of dairy products and dietary calcium by women in the context of bone mineral density and to assess opportunities to prevent osteoporosis in a dietary manner. The study was carried out with 712 Polish women. In 170 women aged 32 to 59 bone mineral density (BMD) was measured. The data on the consumption of dairy products and dietary calcium and some other osteoporosis risk factors was collected from 712 women. The average calcium intake from a diet was 507 mg/day. Only 2% of the women met Polish calcium intake recommendations. During adulthood, dairy product consumption or dietary calcium intake did not differ significantly between women with low BMD (below -1 SD) and women with regular BMD (≥-1 SD) (47.4 vs. 44.3 servings/week and 459 vs. 510 mg/day, respectively, p > 0.05). The odds ratios adjusted for age, menstruation and BMI in women with upper BMD tercile in comparison to the reference group (bottom tercile) was 2.73 (95% CI: 1.14, 6.55; p < 0.05) for the daily consumption of dairy products during the pre-school period and 2.40 (95% CI: 1.01, 5.70; p < 0.05) for the daily consumption of dairy products during the school period. Two clusters of women were established. In the S1 cluster, low BMD (below -1 SD) was associated with older age (≥ 50 years), lack of menstrual cycle. In the S2 cluster, regular BMD (≥-1 SD) was related to younger aged women (<50 years), presence of menstrual cycle, consumption of higher level of dairy products (≥28 servings/week) during adulthood and daily intake of dairy products during childhood and adolescence. The results indicate that good bone health to the larg e extent depended upon the combined impact of dietary factors and some non-modifiable risk factors of osteoporosis such as age and the presence of menstruation. Consumption of dairy products in childhood and adolescence may improve bone mineral density and reduce the risk of osteoporosis in adult women. 23881656 Diet or exercise, or both, for weight reduction in women after childbirth. Weight retention after pregnancy may contribute to obesity. It is known that diet and exercise are recommended components of any weight loss programme in the general population. However, strategies to achieve healthy body weight among postpartum women have not been adequately evaluated. The objectives of this review were to evaluate the effect of diet, exercise or both for weight reduction in women after childbirth, and to assess the impact of these interventions on maternal body composition, cardiorespiratory fitness, breastfeeding performance and other child and maternal outcomes. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2012) and LILACS (31 January 2012). We scanned secondary references and contacted experts in the field. We updated the search of the Cochrane Pregnancy and Childbirth Group's Trials Register on 30 April 2013 and added the results to the awaiting classification section of the review. All published and unpublished randomised controlled trials (RCTs) and quasi-randomised trials of diet or exercise or both, among women during the postpartum period. Both review authors independently assessed trial quality and extracted data. Results are presented using risk ratio (RR) for categorical data and mean difference (MD) for continuous data. Data were analysed with a fixed-effect model. A random-effects model was used in the presence of heterogeneity. Fourteen trials were included, but only 12 trials involving 910 women contributed data to outcome analysis. Women who exercised did not lose significantly more weight than women in the usual care group (two trials; n = 53; MD -0.10 kg; 95% confidence interval (CI) -1.90 to 1.71). Women who took part in a diet (one trial; n = 45; MD -1.70 kg; 95% CI -2.08 to -1.32), or diet plus exercise programme (seven trials; n = 573; MD -1.93 kg; 95% CI -2.96 to -0.89; random-effects, T² = 1.09, I² = 71%), lost significantly more weight than women in the usual care group. There was no difference in the magnitude of weight loss between diet alone and diet plus exercise group (one trial; n = 43; MD 0.30 kg; 95% CI -0.06 to 0.66). The interventions seemed not to affect breastfeeding performance adversely. Evidence from this review suggests that both diet and exercise together and diet alone help women to lose weight after childbirth. Nevertheless, it may be preferable to lose weight through a combination of diet and exercise as this improves maternal cardiorespiratory fitness and preserves fat-free mass, while diet alone reduces fat-free mass. This needs confirmation in large trials of high methodological quality. For women who are breastfeeding, more evidence is required to confirm whether diet or exercise, or both, is not detrimental for either mother or baby. 23863094 Heat shock proteins can be targets of regulatory T cells for therapeutic intervention in rheumatoid arthritis. Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by excessive immune responses resulting in inflammation of the joints. Although current therapies can be successful in dampening inflammation, a long-lived state of tolerance is seldom achieved. Therefore, novel therapies are needed that restore and maintain tolerance in patients with RA. Targeting regulatory T cells (Tregs) is a successful strategy to achieve tolerance, as was shown in studies performed in animal models and in human clinical trials. The antigen-specificity of Tregs is crucial for their effectiveness and allows for very specific targeting of these cells. However, which antigen is suitable for autoimmune diseases such as RA, for which the autoantigens are largely unknown? Heat shock proteins (HSPs) are ubiquitously expressed and can be up-regulated during inflammation. Additionally, HSPs, or HSP-derived peptides are immunogenic and can be recognised by a variety of immune cells, including Tregs. Therefore, this review highlights the potential of HSP-specific Tregs to control inflammatory immune responses. Targeting HSP-specific Tregs in RA can be achieved via the administration of HSPs (derived peptides), thereby controlling inflammatory responses. This makes HSPs attractive candidates for therapeutic intervention in chronic autoimmune diseases, with the ultimate goal of inducing long-lasting tolerance. 23454653 In chemico evaluation of prohapten skin sensitizers: behavior of 2-methoxy-4-(¹³C)methylphenol in the peroxidase peptide reactivity assay (PPRA) as an alternative to animal testing. In chemico methods, based on the assessment of a hapten's reactivity toward peptides, have been proposed as alternative methods for the assessment of the skin sensitizing potential of chemicals. However, even with these approaches showing promise, a major drawback is the activation of prohaptens, i.e. molecules needing a metabolic activation to become reactive and therefore sensitizing. Recently, it has been proposed to couple an enzymatic activation step based on horseradish peroxidase (HRP)/hydrogen peroxide to such peptide reactivity assays. To evaluate this approach, the behavior of 2-methoxy-4-methylphenol (2M4MP), reported as a moderate sensitizer according to the Local Lymph Node Assay (LLNA), has been investigated in this assay. To follow the reaction with the peptides and characterize more easily intermediates and adducts, the molecule was first (13)C isotopically substituted at the most probable reactive position. When 2M4MP was incubated with HRP/H2O2 in a mixture PBS (pH 7.4, 0.1M)/acetonitrile 2:1, two main products were formed deriving from the formation of a quinone methide 2M4MQ subsequently trapped by either H2O2 or H2O to form a benzylic hydroperoxide or alcohol, respectively. When nucleophiles such as GSH or a peptide containing a cysteine residue (Pep-Cys) were present in the reaction medium, the quinone methide 2M4MQ was trapped by the more nucleophilic thiol function to form thio-adducts. No modifications of 2M4MP were observed when the same reactions were carried out without HRP confirming that the activation of the molecule was enzyme related. Amino nucleophiles were shown to be far less reactive towards the quinone methide 2M4MQ with only tiny formation of adducts with lysine or arginine side chains. In addition we demonstrated that the same enzymatic activation could also take place in a microemulsion based on sodium dodecyl sulfate/tert-butanol/chloroform/buffer. 23370570 Ocular vestibular evoked myogenic potential to air conducted sound stimulation and video head impulse test in acute vestibular neuritis. Air-conducted (ACS) cervical VEMP (cVEMP) reflect both saccular and inferior vestibular nerve function. Ocular VEMP (oVEMP) to air and bone-conducted vibration (BCV) are critically discussed, whether they reflect predominantly utricular and superior vestibular nerve function. The video head impulse test (vHIT) accurately detects changes in the high frequency range (5-7 Hz) of the vestibular ocular reflex (VOR) in all 3 planes and can be used to assess semicircular canals (SCC) impairment. To evaluate oVEMP and cVEMP in response to 500 Hz ACS stimulation and to compare these with vHIT results in acute unilateral vestibular neuritis (VN) to classify the probable involvement of SCC and otolith organs. Patients with VN were studied. ACS oVEMP and ACS cVEMP (100 dB nHL 500 Hz tone burst stimulation) were recorded. The vHIT for the 3 SCC were performed simultaneously. ACS oVEMP and ACS cVEMP in combination with vHIT allows the differentiation of 4 types of VN: entire VN (EVN), superior VN (SVN), inferior VN (IVN), and ampullary VN (AVN). Lesions of EVN, SVN, and IVN may be either complete or partial. ACS oVEMP and ACS cVEMP to 500 Hz stimulation together with the vHIT allows a better differentiation of receptor involvement in VN. Results suggest a different origin of AC oVEMP and AC cVEMP to 500 Hz in complete SVN and IVN. Partial SVN and IVN may indicate a role of saccular fibers in oVEMP. 23849714 Impact of self-reported juvenile abuse on treatment outcome in patients with major depressive disorder. We assessed the impact of juvenile abuse (emotional, physical, or sexual) on response to treatment in adults with major depressive disorder (MDD) suboptimally responsive to antidepressant therapy. A post hoc analysis explored the relationship between self-reported history of juvenile abuse and response to risperidone or placebo augmentation during a 6-week double-blind study period in patients with MDD suboptimally responsive to a previous adequate trial of antidepressant monotherapy. Overall, only one clinical measure showed a small, but statistically significant difference in outcome between patients with abuse versus without abuse (HRSD-17). In patients reporting abuse (n=141), improvement with risperidone versus placebo augmentation was greater on several measures: HRSD-17 total and 2 subscale scores, responder rates, Q-LES-Q, and PaRTS-D. In patients without abuse (n=127), only two measures showed significant improvement: HRSD-17 subscale and PaRTS-D. Responder rates (HRSD-17) were: 40.9% (risperidone) versus 23.1% (placebo; p=0.01; odds ratio=2.7) in those with abuse, and 41.0% versus 34.4% (p=0.39; odds ratio=1.4) in those without. Adverse events rates were: 37.0% (risperidone) and 54.4% (placebo) in patients with abuse, and 56.3% and 55.6% in those without. Analysis not preplanned. Validated questionnaire not used to determine abuse status. Self-reported juvenile abuse history may impact response to risperidone augmentation therapy in adults with MDD suboptimally responsive to antidepressants. Abuse status may reduce placebo response and reporting of adverse events. 23955313 Gray-matter macrostructure in cognitively healthy older persons: associations with age and cognition. A deeper understanding of brain macrostructure and its associations with cognition in persons who are considered cognitively healthy is critical to the early detection of persons at risk of developing dementia. Few studies have examined the associations of all three gray-matter macrostructural brain indices (volume, thickness, surface area) with age and cognition, in the same persons who are over the age of 65 and do not have cognitive impairment. We performed automated morphometric reconstruction of total gray matter, cortical gray matter, subcortical gray matter and 84 individual regions in 186 persons (60 % over the age of 80) without cognitive impairment. Morphometric measures were scaled and expressed as difference per decade of age and an adjusted score was created to identify those regions in which there was greater atrophy per decade of age compared to cortical or subcortical brain averages. The results showed that there is substantial total volume loss and cortical thinning in cognitively healthy older persons. Thinning was more widespread than volume loss, but volume loss, particularly in temporoparietal and hippocampal regions, was more strongly associated with cognition. 23700213 Development of UV-Excitable Red and Near-Infrared Fluorescent Labels and Their Application for Simultaneous Multicolor Bioimaging by Single-Wavelength Excitation. We report a new type of UV-excitable red/NIR-emissive fluorescent dyads (PKF series). Conjugation of a pyrene and a novel bright red/near-infrared (NIR) fluorophore resulted in large quasi-Stokes shift while retaining intense fluorescence emission and sharp spectral bands. Labeling of PKF dyads to biomolecules was performed by means of introduction of a succinimidyl ester. Simultaneous Ca(2+)/albumin dual-color intracellular imaging by PKF in combination with fura-2 (UV-excitable/VIS-emissive Ca(2+) indicator) reveals its usefulness as a new bioimaging tool. 23875507 Revisiting gainsharing. Gainsharing initiatives stalled in the past due to legal concerns, but they are enjoying a renaissance as part of broader initiatives, such as accountable care organizations and bundled payments. In the past, with so much of the focus on the legal aspects of gainsharing, the potential of gainsharing to preserve physician choice, reduce costs, and maintain or improve quality may have been underestimated. A gradual gainsharing rollout tailored to the needs of various clinical areas can boost an organization's prospects for success. 23817973 Phase II clinical study of modified FOLFOX7 (intermittent oxaliplatin administration) plus bevacizumab in patients with unresectable metastatic colorectal cancer-CRAFT study. Purpose Continuous treatment with FOLFOX therapy is associated with peripheral nerve toxicity, and to improve this inconvenient side effect various methods of administration are being investigated. A regimen of intermittent oxaliplatin administration by continuous infusion therapy, i.e., modified FOLFOX7 (mFOLFOX7) + bevacizumab, was designed with the goal of alleviating severe peripheral nerve disorders and hematological toxicity. A phase II clinical study was conducted to evaluate the efficacy and safety of this regimen. Methods Previously untreated patients were assigned to mFOLFOX7 (oxaliplatin 85 mg/m(2), levofolinate [l-LV] 200 mg/m(2), 5-fluorouracil [5-FU] 2400 mg/m(2)) + bevacizumab (5 mg/kg) administered every 2 weeks for 8 cycles, maintenance without oxaliplatin for 8 cycles, and reintroduction of mFOLFOX7 + bevacizumab for 8 cycles or until disease progression. Progression free survival (PFS) following the first dose (PFS 1) and following reintroduction of oxaliplatin (PFS 2) were used as indices for assessing the efficacy of intermittent administration. Results Fifty-two patients were enrolled, with median age of 64 years (range, 36-74). Median PFS 1 was 11.8 months (95 % confidence interval [CI], 9.5 to 13.7), median time to treatment failure was 10.3 months (95 % CI, 5.6 to 12.1), percentage of patients with neutropenia of grade 3 or higher was 7.8 %, and percentage with peripheral nerve disorders was 3.9 %. Response rate was 50 %, and 84.4 % of patients who started modified simplified LV5FU2 + bevacizumab were reintroduced to oxaliplatin. Conclusion By excluding 5-FU bolus administration and administering bevacizumab continuously the mFOLFOX7 + bevacizumab regimen with preplanned withdrawal of oxaliplatin showed high tolerability and prevented severe peripheral neuropathy and neutropenia without reducing efficacy. 23231502 Peptidyl-prolyl cis/trans-isomerase A1 (Pin1) is a target for modification by lipid electrophiles. Oxidation of membrane phospholipids is associated with inflammation, neurodegenerative disease, and cancer. Oxyradical damage to phospholipids results in the production of reactive aldehydes that adduct proteins and modulate their function. 4-Hydroxynonenal (HNE), a common product of oxidative damage to lipids, adducts proteins at exposed Cys, His, or Lys residues. Here, we demonstrate that peptidyl-prolyl cis/trans-isomerase A1 (Pin1), an enzyme that catalyzes the conversion of the peptide bond of pSer/pThr-Pro moieties in signaling proteins from cis to trans, is highly susceptible to HNE modification. Incubation of purified Pin1 with HNE followed by MALDI-TOF/TOF mass spectrometry resulted in detection of Michael adducts at the active site residues His-157 and Cys-113. Time and concentration dependencies indicate that Cys-113 is the primary site of HNE modification. Pin1 was adducted in MDA-MB-231 breast cancer cells treated with 8-alkynyl-HNE as judged by click chemistry conjugation with biotin followed by streptavidin-based pulldown and Western blotting with anti-Pin1 antibody. Furthermore, orbitrap MS data support the adduction of Cys-113 in the Pin1 active site upon HNE treatment of MDA-MB-231 cells. siRNA knockdown of Pin1 in MDA-MB-231 cells partially protected the cells from HNE-induced toxicity. Recent studies indicate that Pin1 is an important molecular target for the chemopreventive effects of green tea polyphenols. The present study establishes that it is also a target for electrophilic modification by products of lipid peroxidation. 23899550 Inherited and Acquired Thrombophilias. Thrombophilias represent an evolving story that continues to stir controversy for care providers and obstetrical patients. The predominant thrombophilic mutations include the factor V Leiden mutation, prothrombin gene mutation G20210A, methylene tetrahydrafolate reductase C667T, and deficiencies of the natural anticoagulants proteins C and S, and antithrombin. Prospective cohort studies have provided an accurate assessment of the risk of placenta-mediated complications posed by common inherited thrombophilic conditions. Acquired thrombophilic conditions consist of the antiphospholipid antibody syndrome (APAS) and hyperhomocysteinemia. Well-conducted, placebo-controlled, randomized trials have demonstrated no benefit of anticoagulation in women with recurrent pregnancy loss and inherited thrombophilia. The routine use of anticoagulation to prevent other placenta-mediated complications in the setting of inherited thrombophilia should be considered experimental until the results of adequate clinical trials are available. Heparin anticoagulation and antiplatelet therapies are the cornerstone of treatment of APAS in pregnancy. 23963471 High-rate repetitive transcranial magnetic stimulation in migraine prophylaxis: a randomized, placebo-controlled study. Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for pain but there is no class 1 study on its role in migraine prophylaxis. In this study we report the efficacy and safety of high-rate rTMS in migraine prophylaxis. Adult migraine patients having >4 attacks/month were randomized to high-rate rTMS or sham stimulation. Stimulation in the form of 10 Hz rTMS, 600 pulses in 10 trains were delivered to the hot spot of the right abductor digiti minimi in 412 s. Three sessions were delivered on alternate days. The outcome was defined at 1 month. The primary outcome measures were reduction in headache frequency and severity >50 % as assessed by the Visual Analogue Scale (VAS). The secondary outcome measures were functional disability, rescue medication and adverse events. Fifty patients each were randomized to rTMS or sham stimulation. The baseline characteristics of rTMS and sham stimulation groups were similar. At 1 month, headache frequency (78.7 vs. 33.3 %; P = 0.0001) and VAS score (76.6 vs. 27.1 %; P = 0.0001) improved significantly in the patients receiving rTMS compared to those in the sham stimulation group. Functional disability also improved significantly in rTMS group (P = 0.0001). Only one patient following rTMS developed transient drowsiness and was withdrawn from the study. This study provides evidence of the efficacy and safety of 10 Hz rTMS in migraine prophylaxis. 23638657 Genetic engineering of Lactobacillus diolivorans. In this study, we developed a toolbox for genetic manipulation of Lactobacillus diolivorans, a promising production organism for 1,3-propanediol from glycerol. Two major findings play a key role for successful transformation of this organism: (1) the absence of a native plasmid, because a native plasmid is a major obstacle for transformation of L. diolivorans, and (2) the absence of DNA methylation. A suitable expression plasmid, pSHM, for homologous and heterologous protein expression in L. diolivorans was constructed. This plasmid is based on the replication origin repA of L. diolivorans. The native glyceraldehyde-3-phosphate dehydrogenase promoter is used for constitutive expression of the genes of interest. Functional expression of genes in L. diolivorans was shown with two examples: production of green fluorescent protein resulted in a 40- to 60-fold higher fluorescence of the obtained clones compared with the wild-type strain. Finally, the homologous overexpression of a putatively NADPH-dependent 1,3-propanediol oxidoreductase improved 1,3-propanediol production by 20% in batch cultures. 23400933 Ultrastructural and Functional Alterations of EC Coupling Elements in mdx Cardiomyocytes: An Analysis from Membrane Surface to Depth. A dilated cardiomyopathy (DCM) is associated with Duchenne muscular dystrophy (DMD). The loss of dystrophin leads to membrane instability and calcium dysregulation in skeletal muscle but effects of such a loss are not elucidated at cardiomyocytes level. We sought to examine whether membrane and transverse tubules damages occur in ventricular myocytes from mdx mouse model of DMD and how they impact the function of single excitation-contraction coupling elements. Scanning ion conductance microscopy (SICM) was used to characterize the integrity loss of living mdx cardiomyocytes surface. 2D Fourier transform analysis of labeled internal networks (transverse tubules, alpha-actinin, dihydropyridine receptors, ryanodine receptors) was performed to evaluate internal alterations. During calcium measurements, "smart microperfusions" of depolarizing solutions were applied through SICM nanopipette, stimulating single tubules elements. These approaches revealed structural membrane surface (39 % decrease for Z-groove ratio) and transverse tubules disorganization (21 % transverse tubules ratio decrease) in mdx as compared to control. These disruptions were associated with functional alterations (sixfold increase of calcium signal duration and twofold increase of sparks frequency). In DCM associated with DMD, myocytes display evident membrane alterations at the surface level but also in the cell depth with a disruption of transverse tubules network as observed in other cases of heart failure. These ultrastructural changes are associated with changes in the function of some coupling elements. Thus, these profound disruptions may play a role in calcium dysregulation through excitation-contraction coupling elements perturbation and suggest a transverse tubules stabilizing role for dystrophin. 23257353 Nursing Accounting Competencies Related to HIV in a Papua New Guinea Context. Nursing administration is an important part of the campaign to eliminate HIV across Papua New Guinea (PNG). This paper considers the critical importance of developing nursing leadership in effective accounting competencies in relation to HIV projects in PNG. The results of the study's textual analysis of audit reports of the Auditor General of PNG revealed a failure on the part of PNG's main health agencies involved with its national HIV program to provide competent financial reporting. In light of these results, this study shows how improving accounting and other financial competencies among nursing leaders would benefit the implementation of the PNG HIV national strategy. The findings of this study have implications not only for the internal control of HIV nursing competencies but also for nursing leadership related to HIV issues in a developing-country context. 23521217 Re-expression of microRNA-150 induces EBV-positive Burkitt lymphoma differentiation by modulating c-Myb in vitro. Burkitt lymphoma (BL) is a highly aggressive B-cell lymphoma that includes two forms of BL differing in Epstein-Barr virus (EBV) infection status, EBV-positive and EBV-negative. Although many efforts, such as high-intensity, short-duration combination chemotherapy, have been devoted to improving therapy for this rapidly proliferating neoplasm, there are still significant treatment-associated toxicities. Therefore, there remains a need for novel effective therapeutic strategies. MicroRNAs play a role in "fine tuning" the physiological and pathological differentiation process, by which cells can rapidly regulate dynamic events such as cell-lineage decisions and morphogenesis. This unique miRNA feature shifts the traditional one drug target paradigm to a novel one drug multiple targets paradigm. Here, we found that BL cell lines showed an extremely low expression of microRNA-150 (miR-150), and then restored miR-150 expression at physiologic levels in BL cell lines Daudi, Raji, BJAB, and Ramos. The results showed that re-expression of miR-150 reduced proliferation of Daudi and Raji cells. Furthermore, Daudi and Raji, both of which are of EBV-positive germinal center B-cell origin, transduced with miR-150 can be rescued to differentiate toward B-cell terminal stage. However, no significant changes were observed in BJAB or Ramos cells, which are of EBV-negative germinal center B-cell origin. Of note, re-expression of miR-150 also resulted in decreasing c-Myb protein levels. Additionally, c-Myb knockdown in Daudi and Raji cell lines recapitulated the partial characteristics similar to that caused by re-expression of miR-150. Taken together, our findings show that miR-150 can induce EBV-positive BL differentiation by targeting c-Myb. 23934328 Receptor Trafficking and the Regulation of Synaptic Plasticity by SUMO. Timely and efficient information transfer at synapses is fundamental to brain function. Synapses are highly dynamic structures that exhibit long-lasting activity-dependent alterations to their structure and transmission efficiency, a phenomenon termed synaptic plasticity. These changes, which occur through alterations in presynaptic release or in the trafficking of postsynaptic receptor proteins, underpin the formation and stabilisation of neural circuits during brain development, and encode, process and store information essential for learning, memory and cognition. In recent years, it has emerged that the ubiquitin-like posttranslational modification SUMOylation is an important mediator of several aspects of neuronal and synaptic function. Through orchestrating synapse formation, presynaptic release and the trafficking of postsynaptic receptor proteins during forms of synaptic plasticity such as long-term potentiation, long-term depression and homeostatic scaling, SUMOylation is being increasingly appreciated to play a central role in neurotransmission. In this review, we outline key discoveries in this relatively new field, provide an update on recent progress regarding the targets and consequences of protein SUMOylation in synaptic function and plasticity, and highlight key outstanding questions regarding the roles of protein SUMOylation in the brain. 23932981 Anti-viral immune responses in a primitive lung: Characterization and expression analysis of interferon-inducible immunoproteasome subunits LMP2, LMP7 and MECL-1 in a sarcopterygian fish, the Nigerian spotted lungfish (Protopterus dolloi). Lungfishes (Dipnoi) represent the closest ancestor of tetrapods. Dipnoi have dual breathing modes extracting oxygen from water and air. The primitive lungs of lungfishes are exposed to external antigens including viruses. To date, the immune response of lungfishes against viruses has not been investigated. During viral immune responses, cell exposure to type I interferon induces the replacement of the constitutive proteasome with LMP2, LMP7 and MECL-1 beta subunits forming the immunoproteasome and enhancing antigen presentation to MHC class I molecules. In order to study the immune defense system of the lungfish lung, we have characterized for the first time the three immunoproteasome subunits in the sarcopterygian fish, the Nigerian spotted lungfish (Protopterus dolloi). LMP2, LMP7 and MECL-1 were identified in P. dolloi and their sequences encoded predicted proteins of 216, 275 and 278 amino acids, respectively. The mRNA of these three genes was expressed in multiple tissues, including the lung, with the highest abundance observed in kidney and post-pyloric spleen. In vitro stimulation of lungfish lung and kidney primary cell cultures with PolyI:C for 4 and 12h resulted in increased LMP2, LMP7 and MECL-1 expression in both tissues. These results suggest a central role of these genes in the activation of an antiviral immune response in lungfish. Importantly, they indicate that the primitive lung of the common ancestor of all tetrapods is capable of inducing the expression of these genes in response to viral stimulation. 23594238 Efficient electroporation of liposomes doped with pore stabilizing nisin. Abstract Context: Liposomes have a long history as passive and active drug carriers. Recently, a few methods have been realized to control the release from liposomes, including heating, ultrasound and laser. Objective: We report on a new approach to drive release from liposomes using electric fields. Materials and methods: Liposomes were manufactured containing a high concentration of (quenched) 5-6 carboxyfluorescein dye. Nisin, a well-known amphiphilic peptide lantibiotic that works by stabilizing pores formed in cell membranes, was mixed in solution inside or outside the liposomes. The liposomes were then electroporated using a range of voltages, and assayed for increases in fluorescence due to release of dye. Release was measured against positive and negative controls, with positive control release driven by a strong detergent. Results: Our results demonstrate that the addition of nisin significantly reduces the electric field required to release the contents of liposomes, from 2000 V/m to approximately 200 V/m. This result proves that, in principle, electroporation (EP) of liposomes doped with small amounts of amphiphilic pore stabilizing peptides may be a practical means to drive release of liposomal contents in vivo. Conclusion: Drug delivery from liposomes doped with amphiphilic peptides using EP is feasible. This technique could be developed into a potent adjuvant to tumor ablation using irreversible EP. 23402856 Combined effects of organochlorine pesticides heptachlor and hexachlorobenzene on the promotion stage of hepatocarcinogenesis in rats. We aimed to investigate the combined effect of organochlorine pesticides heptachlor (HEP) and hexachlorobenzene (HCB) by using a medium-term rat liver bioassay. Male F344 rats were initially administered diethylnitrosamine (DEN, 200mg/kgi.p.); after a 2-week non-dosing period, they were given diets containing HEP (5 or 25ppm), HCB (70 or 350ppm), or their mixtures (5 and 70ppm or 25 and 350ppm) for 6weeks. All rats were subjected to partial hepatectomy at week 3 and killed at week 8. We observed additive or synergistic effects of HEP and HCB in groups treated with mixtures of these pesticides. Number and area of preneoplastic foci positive for glutathione S-transferase placental form (GST-P) were consistently higher in these groups than the sum of individual values in the groups treated with HEP or HCB alone. Consistent with these findings, HEP and HCB had additive or synergistic effects on cell proliferation induction within the preneoplastic foci and cytochrome P450 (CYP) 2B1 and 3A1 induction, which may lead to more efficient metabolic activation of HEP and HCB. On the basis of these findings, we conclude that HEP and HCB have additive and synergistic effects on the development of GST-P-positive foci and that higher risks are associated with a combination of residual organochlorine pesticides in foods than with individual residual organochlorine pesticides. 23965412 The effect of low dose lipopolysaccharide on thyroid hormone-regulated actin cytoskeleton modulation and type 2 iodothyronine deiodinase activity in astrocytes. Systemic infection/inflammation can severely interfere with brain development. Lipopolysaccharide (LPS) is a major cell wall component of gram-negative bacteria and commonly used to model the response by infections. Since perinatal exposure to LPS shows neurodevelopmental defects partly similar to those seen in perinatal hypothyroidism, we examined the effect of LPS on thyroxin (T4)-mediated signalings in astrocytes. Initially, C6 rat glioma-derived clonal cells were used, whose biological nature is similar to that of astrocytes. To measure the effects of LPS and T4, actin polymerization and D2 activity assays were carried out. LPS treatment (10 ng/mL) markedly induced actin depolymerization, whereas 10 nM T4 promoted actin polymerization. Furthermore, T4 partly rescued LPS-induced actin depolymerization. LPS treatment (10 ng/mL) increased D2 activity, whereas T4 (10 nM) suppressed this activity. T4 restored LPS-increased D2 activity at 10 nM. LPS-induced actin depolymerization and D2 activity were blocked by p38 MAP kinase inhibitor. Such effects were not seen in T4-mediated changes. Furthermore, similar results were found in the cerebellar primary astrocyte. These results indicate that, although LPS affects T4-regulated cellular events such as actin polymerization and D2 activity, which may induce neurodevelopmental defects similar to those in perinatal hypothyroidism, LPS signaling pathways are independent of T4 signaling pathways. 23384347 The transferrin receptor-1 membrane stub undergoes intramembrane proteolysis by signal peptide peptidase-like 2b. The successive events of shedding and regulated intramembrane proteolysis are known to comprise a fundamental biological process of type I and II membrane proteins (e.g. amyloid precursor protein, Notch receptor and pro-tumor necrosis factor-α). Some of the resulting fragments were shown to be involved in important intra- and extracellular signalling events. Although shedding of the human transferrin receptor-1 (TfR1) has been known for > 30 years and soluble TfR1 is an accepted diagnostic marker, the fate of the remaining N-terminal fragment (NTF) remains unknown. In the present study, we demonstrate for the first time that TfR1-NTF is subject to regulated intramembrane proteolysis and, using MALDI-TOF-TOF-MS, we have identified the cleavage site as being located C-terminal from Gly-84. We showed that the resulting C-terminal peptide is extracellularly released after regulated intramembrane proteolysis and it was detected as a monomer with an internal disulfide bridge. We further identified signal peptide peptidase-like 2a and mainly signal peptide peptidase-like 2b as being responsible for the intramembrane proteolysis of TfR1-NTF. 23946081 Clinical implications of a feeling of incomplete emptying with little post-void residue in men with lower urinary tract symptoms. It remains unclear why patients suffer from a feeling of incomplete emptying despite no or little post-void residual (PVR). Accordingly, we evaluated the clinical implications thereof in men with lower urinary tract symptoms (LUTS). Records were obtained from a prospectively maintained database for 905 first-visit men with LUTS. Patients with comorbidities that may affect voiding function and with PVR > 20 ml were excluded. Finally, 421 patients were eligible for the study. By International Prostate Symptom Score (IPSS), a score for evaluating a feeling of incomplete emptying, 106 patients (25.2%) were characterized as experiencing no symptoms (score 0, 1), 201 (47.7%) as mild to moderate symptoms (score 2, 3), and 114 (27.1%) as severe symptoms (score 4, 5). The severity of a feeling of incomplete emptying was significantly associated with total IPSS and with subscores for both voiding and storage symptoms (P < 0.001). Comparing patients with severe symptoms (severe group, N = 114) with a propensity score-matched control group, adjusting for age, PVR, and maximum flow rate, total IPSS was significantly different between the two groups (23.04 ± 5.68 vs. 13.21 ± 5.48, respectively; P < 0.001). The subscores for both voiding and storage symptoms were also significantly worse in the severe group. The quality of life score was 4.51 ± 0.80 in the severe group and 3.53 ± 1.05 in control group (P < 0.001). A feeling of incomplete emptying despite little PVR was frequently observed and, notably, this was significantly associated with worsening of both voiding and storage symptoms, even after adjusting for relevant variables. Neurourol. Urodynam. 9999:XX-XX, 2013. © 2013 Wiley Periodicals, Inc. 23957425 The Clinicopathologic Significance of Endothelial Tubuloreticular Inclusions in Glomerular Diseases. Abstract Background: The presence of tubuloreticular inclusions (TRIs) in endothelial cells (ECs) always evokes suspicion of an association with underlying viral infections or autoimmune diseases. However, other underlying diseases can be associated with TRI expression. Since identification of the underlying disease is of primary consideration for management of glomerulonephritis (GN), it is important to clarify the clinical significance of TRI expression. Methods: The authors studied 104 renal biopsy cases having TRI. They investigated their clinicopathological profiles and focused on potential connections with underlying diseases. Results: Among 104 renal biopsy cases, 62 cases (59.6%) were associated with lupus nephritis (LN) and 20 cases (19.2%) were associated with a viral infection (hepatitis B virus (13), hepatits C virus (4), and human immunodeficiency virus (3)). Other underlying disease groups included membranous GN (MGN) (7), IgA nephropathy (7), Henoch-Schoenlein purpura (HSP) nephritis (2), and others (6). The incidence of TRIs in both LN and viral infections was significantly higher than for other diseases (p < 0.0001). Among 7 MGN cases, 2 cases were diabetes, 1 case was associated with lung cancer, another case with antineutrophilic cytoplasmic antibody (ANCA), and the others showed no evidence of systemic disease. On immunofluorescence (IF) study, 2 MGN cases, 2 IgA nephropathy cases, and 1 HSP nephritis case showed C1q deposition, with no evidence of SLE. Conclusions: TRIs were identified in MGN and other glomerular diseases, including IgA nephropathy and HSP nephritis. However, a diagnosis of LN should be considered because TRIs associated with a full-house IF pattern are usually found in LN. 23959560 Increased Renal Epithelial Na Channel Expression and Activity Correlate With Elevation of Blood Pressure in Spontaneously Hypertensive Rats. Elevation of blood pressure with age is one of the hallmarks of hypertension in both males and females. This study examined transcriptomic profiles in the kidney of 12-, 40-, and 80-week-old spontaneously hypertensive rats and 4 recombinant inbred strains in search for functional genetic elements supporting temporal dynamics of blood pressure elevation. We found that both in males and females of spontaneously hypertensive rats and hypertensive recombinant inbred strains age-dependent blood pressure increment was accompanied by 50% heightened expression of epithelial sodium channel β- and γ-subunits. Epithelial sodium channel subunit expression correlated positively with blood pressure but correlated negatively with renin expression. Increased epithelial sodium channel activity was observed in cultured epithelial cells isolated from the kidney medulla of 80-week-old spontaneously hypertensive rats but not in age-matched normotensive Wistar Kyoto. This difference remained evident after 24-hour treatment with aldosterone. (22)Na uptake in the perfused kidney medulla was increased whereas the urinary Na/K ratio was decreased in old spontaneously hypertensive rats compared with normotensive controls. The difference was eliminated by the administration of epithelial sodium channel inhibitor benzamil. Observations in recombinant inbred strains representing various mixtures of parental hypertensive and normotensive genomes suggest that Scnn1g and Scnn1b genes themselves are not implicated in heightened expression and that the increased expression is neither secondary nor required for a partial elevation of blood pressure in contrast to spontaneously hypertensive rats. We suggest that spontaneously hypertensive rats display an intact negative feed-back between renin-angiotensin-system and epithelial Na channel activity whose upregulated expression is supported by a yet unknown mechanism. 23842559 Reoperation for Refractory Epilepsy in Childhood: A Second Chance for Selected Patients. Reoperations account for >10% in pediatric epilepsy surgery cohorts and they are especially relevant in young children with catastrophic epilepsy. To determine surgical outcomes and their predictive factors in reoperations for refractory epilepsy in childhood. We retrospectively analyzed presurgical findings, resections and outcomes of 23 consecutive children that underwent reoperations from 2000-2011. Etiology included cortical dysplasia with/without glioneuronal tumor in 19 patients (83%), sole glioneuronal tumor in 2, and tuberous sclerosis and Rasmussen's encephalitis in one each. Reasons for failure of initial surgery were functional considerations in 8 (35%), incorrect delineation of the epileptogenic zone in 8 (35%), and resection not performed as initially planned in 7 (30%) cases. Final procedures included 8 (35%) intralobar, 8 (35%) multilobar resections and 7 (30%) hemispherotomies. Following reoperations, 14 (61%) patients were seizure-free, 6 (26%) showed significant or worthwhile improvement, and 3 (13%) failed to respond to surgery. Six of 8 patients that underwent the first resection before the age of 3 years, 6 of 8 whose first resection was limited by functional considerations, and all 7 with hemispherotomy as the final resection achieved seizure freedom after reoperation. Reoperation is particularly beneficial for selected children with refractory epilepsy associated with cortical dysplasia that failed to respond to an initial limited and/or early resection but achieved seizure freedom after extensive procedures. When indicated, reoperation should be performed at the youngest possible age to profit from higher functional plasticity in compensating for neurologic deficit. 23916568 Spontaneous self-assembly of DNA fragments into nucleus-like structures from yolk granules of fertilized chicken eggs: Antoine Béchamp meets Bong Han Kim via Olga Lepeshinskaya. We found evidence that spontaneous self-assembly of DNA molecules from yolk granules occurred during the very early stage of egg fertilization. In order to find solid evidence for self-assembly of DNA molecules, we collected many available data in different stages of fertilized eggs, making a data table. At first by using acridine orange vital staining to demonstrate DNA, we noticed that some yolk granules emitted DNA signals that gradually increased with increasing incubation time from very small sizes to much larger nucleus-like structures. For convincing evidence, we also used another vital dye, Hoechst 33258 DNA-specific dye, to trace the changes in the yolk granules. The patterns of the DNA signals from yolk granules stained with Hoechst 33258 were the same as those from the yolk granules stained with acridine orange. A partial phase contrast microscopic image of the changes in the yolk granules showed some liquid-like material around the granules before the formation of the nucleus-like structures. Concomitant use of fluorescence and partial phase contrast microscopy suggested that these liquid-like materials may have been released from yolk granules in which spontaneous self-assembly of DNA molecules had occurred. Finally, in order to verify whether the DNA signals came from real DNA molecules or not, by using deoxyribonuclease I (DNAse), we confirmed that the nucleus-like structures were really assembled DNA molecules. Thus, in this article, we report evidence for the self-assembly of DNA molecules toward cell-like structures and discuss our findings, comparing them with those in the works of other pioneers, especially Antoine Béchamp, Olga Lepeshinskaya and Bong Han Kim, who insisted on the existence of a mitosis-free alternative pathway for generating new cells. 23969936 Characterization and clinical relevance of ALDHbright populations in prostate cancer. High aldehyde dehydrogenase (ALDH) has been suggested to selectively mark cells with high tumorigenic potential in established prostate cancer (PCa) cell lines. However, the existence of cells with high ALDH activity (ALDHbright) in primary PCa specimens has not been demonstrated so far. We investigated the presence, phenotype, and clinical significance of ALDHbright populations in clinical PCa specimens. We used Aldefluor™ technology and FACS staining to identify and characterize ALDHbright populations in cells freshly isolated from clinical PCa specimens. Expression of genes encoding ALDH specific isoforms was evaluated by quantitative real-time PCR in normal prostate, benign prostatic hyperplasia (BPH) and PCa tissues. ALDH1A1 specific expression and prognostic significance was assessed by staining two tissue microarrays that included over 500 samples of BPH, prostatic intraepithelial neoplasia (PIN), and multi-stage PCa. ALDHbright cells were detectable in freshly excised PCa specimens (n= 39), and were mainly included within the EpCAM(+) and Trop2(+) cell populations. Although several ALDH isoforms were expressed to high extents in PCa, only ALDH1A1 gene expression significantly correlated with ALDH activity (p<0.01), and was increased in cancers with high Gleason scores (p=0.03). Most importantly, ALDH1A1 protein was expressed significantly more frequently and at higher levels in advanced-stage as compared to low-stage PCa and BPH. Notably, ALDH1A1 positivity was associated with poor survival (p=0.02) in hormone-naive patients. Our data indicate that ALDH contributes to the identification of subsets of PCa cells of potentially high clinical relevance. 23919806 Upregulation of Ying Yang 1 (YY1) suppresses esophageal squamous cell carcinoma development through heme oxygenase-1. Esophageal squamous cell carcinoma (ESCC) is one of the deadliest malignancies worldwide. Ying Yang 1 (YY1), a ubiquitously expressed GLI-Krüppel zinc finger transcription factor, plays a regulatory role in a variety of fundamental biological processes, such as embryonic development, growth, apoptosis, differentiation and oncogenic transformation. The purpose of this study was to investigate the expression of YY1 in normal and cancerous esophageal tissues and its function in ESCC development. We found that the expression of YY1 mRNA was significantly increased in the tumor tissues, compared with the para-tissues or normal esophageal tissues. The increased expression of YY1 in tumor samples was further confirmed by immunohistochemistry. Furthermore, the overexpression of YY1 conferred radioresistance to the ESCC TE-1 cells and resulted in markedly reduced cell proliferation. Accordingly, the small interfering RNA-mediated silencing of YY1 expression in TE-1 cells resulted in increased proliferation by enhancing the binding of P21 to Cyclin D1 and CDK4, a protein complex known to mediate cell cycle progression. Moreover, besides P21, heme oxygenase-1 (HO-1) was identified as a YY1 downstream effector, as YY1 stimulated HO-1 expression in esophageal cancer cells. YY1 mediated biological function through transcription of HO-1. Forced expression of HO-1 could moderately suppress proliferation of TE-1 cells. The expression of YY1 significantly correlated with that of HO-1 in ESCC tissues. Taken together, we demonstrated overexpression of YY1 in esophageal carcinoma and identified HO-1 as its target. This article is protected by copyright. All rights reserved. 23906754 Ochratoxin A in raw materials and cooked meat products made from OTA-treated pigs. The aim of this study was to determine ochratoxin A (OTA) concentrations in the raw materials and cooked meat products made from pigs sub-chronically exposed to OTA. The treated animal group (n=5) was administered with 300μg OTA/kg of feed for 30days, whereas the control group (n=5) was left untreated. OTA concentrations were quantified using immunoassay (ELISA) and high performance liquid chromatography with fluorescence detection (HPLC-FD). OTA concentration was the highest in the kidney, followed by the lungs, liver, blood, spleen, heart, and adipose tissue. As for the final meat products, the highest average OTA concentration was detected in black pudding sausages (14.02±2.75μg/kg), then in liver sausages (13.77±3.92μg/kg), while the lowest was found in pâté (9.33±2.66μg/kg). The results pointed out that a sub-chronic pig exposure leads to the accumulation of OTA in raw materials and consequently in meat products, whose level of contamination is directly dependent on OTA contents in raw materials used for their production. 23526159 Engineered resistance in potato against potato leafroll virus, potato virus A and potato virus Y. Transgenic potato plants of Solanum tuberosum cultivar Vales Sovereign were generated that expressed fused, tandem, 200 bp segments derived from the capsid protein coding sequences of potato virus Y (PVY strain O) and potato leafroll virus (PLRV), as well as the cylindrical inclusion body coding sequences of potato virus A (PVA), as inverted repeat double-stranded RNAs, separated by an intron. The orientation of the expressed double-stranded RNAs was either sense-intron-antisense or antisense-intron-sense RNAs, and the double-stranded RNAs were processed into small RNAs. Four lines of such transgenic potato plants were assessed for resistance to infection by PVY-O, PLRV, or PVA, all transmitted by a natural vector, the green-peach aphid, Myzus persicae. Resistance was assessed by the absence of detectable virus accumulation in the foliage. All four transgenic potato lines tested showed 100 % resistance to infection by either PVY-O or PVA, but variable resistance to infection by PLRV, ranging from 72 to 96 % in different lines. This was regardless of the orientation of the viral inserts in the construct used to generate the transgenic plants and the gene copy number of the transgene. This demonstrates the potential for using tandem, fused viral segments and the inverted-repeat expression system to achieve multiple virus resistance to viruses transmitted by aphids in potato. 23966586 Mechanical performance of spider orb webs is tuned for high-speed prey. Spiders in the Orbiculariae spin orb webs that dissipate the mechanical energy of their flying prey, bringing the insects to rest and retaining them long enough for the spider to attack and subdue their meals. Small prey are easily stopped by webs but provide little energetic gain. While larger prey offer substantial nourishment, they are also challenging to capture and can damage the web if they escape. We therefore hypothesized that spider orb webs exhibit properties that improve their probability of stopping larger insects while minimizing damage when the mechanical energy of those prey exceeds the web's capacity. Large insects are typically both heavier and faster flying than smaller prey, but speed plays a disproportionate role in determining total kinetic energy, so we predicted that orb webs may dissipate energy more effectively under faster impacts, independent of kinetic energy per se. We used high-speed video to visualize the impact of wooden pellets fired into orb webs to simulate prey strikes and tested how capture probability varied as a function of pellet size and speed. Capture probability was virtually nil above speeds of ~3 m s(-1). However, successful captures do not directly measure the maximum possible energy dissipation by orb webs because these events include lower-energy impacts that may not significantly challenge orb web performance. Therefore, we also compared the total kinetic energy removed from projectiles that escaped orb webs by breaking through the silk, asking whether more energy was removed at faster speeds. Over a range of speeds relevant to insect flight, the amount of energy absorbed by orb webs increases with the speed of prey (i.e. the rates at which webs are stretched). Orb webs therefore respond to faster - and hence higher kinetic energy - prey with better performance, suggesting adaptation to capture larger and faster flying insect prey. This speed-dependent toughness of a complex structure suggests the utility of the intrinsic toughness of spider silk and/or features of the macro-design of webs for high-velocity industrial or military applications, such as ballistic energy absorption. 23816043 Antiproliferative activity on human prostate carcinoma cell lines of new peptidomimetics containing the spiroazepinoindolinone scaffold. Peptidomimetics containing the spiroazepinoindolinone scaffold were designed and synthesized in order to ascertain their antiproliferative activity on the DU-145 human prostatic carcinoma cell line. Ethyl 2'-oxa-1,2,3,5,6,7-hexahydrospiro[4H-azepine-4,3'-3H-indole]-1'-carboxylate scaffold was functionalized at nitrogen azepino ring with Aib-(l/d)Trp-OH dipeptides. Combining the different stereochemistries of the scaffold and the tryptophan, diastereoisomeric peptidomimetics were prepared and tested. Their biological activity was evaluated by proliferation studies proving that the isomer containing S spiroazepino-indolinone scaffold and l tryptophan is the most active compound. Docking studies confirmed that the active peptidomimetic could bind the GHSR-1a receptor with docking scores comparable with those of well-known agonists even though with a somewhat different binding mode. 23597444 Toxicity study of isolated polypeptide from wool hydrolysate. The cytotoxicity of wool polypeptide has been evaluated by both cell and animal models. Wool was dissolved in sodium hydroxide solution, the pH value of the solution was adjusted to 5.55 and the precipitate was harvested as wool polypeptide. The spray-dried polypeptide was collected as powders and characterized by SEM, FTIR and TG-DSC. The cell culturing results showed that wool polypeptide had no obvious negative effect on cell viability in vitro. Both acute oral toxicity and subacute 30-day oral toxicology studies showed that wool polypeptide had no influence on body weight, feed consumption, blood chemistry, and hematology at any dose levels. There were no treatment related findings on gross or detailed necroscopy, organ weights, organ/body weight ratios and histology. Our study indicated the absence of toxicity in wool polypeptide and supported its safe use as a food ingredient or drug carrier. 23758802 Thermally Induced Superhydrophilicity in TiO2 Films Prepared by Supersonic Aerosol Deposition. Superhydrophilic and superhydrophobic surfaces enable self-cleaning phenomena, either forming a continuous water film or forming droplets that roll off the surface, respectively. TiO2 films are well-known for their extreme hydrophilicity and photocatalytic characteristics. Here, we describe nanostructured TiO2 thin films prepared by supersonic aerosol deposition, including a thorough study of the effects of the annealing temperature on the crystal structure, surface morphology, surface roughness, and wetting properties. Powder X-ray diffraction showed that supersonic deposition resulted in fragmentation and amorphization of the micrometer-size anatase (60%)-rutile (40%) precursor powder and that, upon annealing, a substantial fraction of the film (∼30%) crystallized in the highly hydrophilic but metastable brookite phase. The film morphology was also somewhat modified after annealing. Scanning electron microscopy and atomic force microscopy revealed rough granular films with high surface roughness. The as-deposited TiO2 films were moderately hydrophilic with a water contact angle (θ) of ∼45°, whereas TiO2 films annealed at 500 °C became superhydrophilic (θ ∼ 0°) without UV illumination. This thermally induced superhydrophilicity of the TiO2 films can be explained on the basis of the combined effects of the change in the crystal structure, surface microstructure, and surface roughness. Supersonic aerosol deposition followed by annealing is uniquely able to produce these nanostructured films containing a mixture of all three TiO2 phases (anatase, rutile, and brookite) and exhibiting superhydrophilicity without UV illumination. 23866982 Suppression of atrogin-1 and MuRF1 prevents dexamethasone-induced atrophy of cultured myotubes. The mechanistic role of the ubiquitin ligases atrogin-1 and MuRF1 in glucocorticoid-induced muscle wasting is not fully understood. Here, we tested the hypothesis that glucocorticoid-induced muscle atrophy is at least in part linked to atrogin-1 and MuRF1 expression and that the ubiquitin ligases are regulated by compensatory mechanisms. The expression of atrogin-1 and MuRF1 was suppressed individually or in combination in cultured L6 myotubes by using siRNA technique. Myotubes were treated with dexamethasone followed by determination of mRNA and protein levels for atrogin-1 and MuRF1, protein synthesis and degradation rates, and myotube morphology. Suppression of atrogin-1 resulted in increased expression of MuRF1 and vice versa, suggesting that the ubiquitin ligases are regulated by compensatory mechanisms. Simultaneous suppression of atrogin-1 and MuRF1 resulted in myotube hypertrophy, mainly reflecting stimulated protein synthesis, and prevented dexamethasone-induced myotube atrophy, mainly reflecting inhibited protein degradation. The results provide evidence for a link between upregulated atrogin-1 and MuRF1 expression and glucocorticoid-induced muscle atrophy. The study also suggests that atrogin-1 and MuRF1 levels are regulated by compensatory mechanisms and that inhibition of both ubiquitin ligases may be needed to prevent glucocorticoid-induced muscle proteolysis and atrophy. 23902229 Standardising dialysate potassium does not increase patient risk. Rapid intradialytic potassium shifts during haemodialysis have been associated with increased mortality and morbidity. Standardising dialysate potassium to 2 mmol/l may decrease the potassium shift. To examine the effect of standardising dialysate potassium to 2 mmol/l for all chronic dialysis treatments. Pre- and post-intervention comparison of monthly serum potassium. Ninety-seven individuals, of whom 56 patients could be matched across both data collection periods. Serum potassium data were categorised based on a target range 3.5-6.0 mmol/l. Overall pre- and post-intervention mean scores were compared using a paired samples t-test. Data for patients routinely prescribed dialysate potassium 1 mmol/l pre-intervention (n = 6) underwent paired samples t-test to compare their mean serum potassium pre- and post-intervention. There was no statistically significant change in serum potassium post-intervention. The majority of patients remained within the target range, including the subset of patients who had a history of high serum potassium during the pre-intervention period. A standard potassium dialysate of 2 mmol/l may reduce intradialytic serum potassium shifts and may assist in standardising safer work practices. 23836070 Suppressive effects of adaptive servo-ventilation on ventricular premature complexes with attenuation of sympathetic nervous activity in heart failure patients with sleep-disordered breathing. Ventricular arrhythmias play a critical role in chronic heart failure (CHF) and are associated with adverse clinical outcomes. Sleep-disordered breathing (SDB) is associated with arrhythmias and/or a poor prognosis in CHF. Adaptive servo-ventilation (ASV) is a ventilatory support system designed to normalize ventilation in CHF patients with SDB. However, the effects of ASV on ventricular arrhythmias and sympathetic nervous activity are still unclear. Nineteen CHF patients with SDB were examined. We performed simultaneous overnight polysomnography and 24-h Holter ECG monitoring, and measured levels of daily urinary catecholamines for two consecutive days (baseline and on ASV). ASV significantly improved the apnea-hypopnea index (p < 0.01), arousal index (p < 0.01), and mean SpO2 (p < 0.01), and decreased daily urinary catecholamines (0.466-0.353 mg/day, p = 0.016) compared to baseline. Furthermore, power in the low to high frequency range as a marker of sympathetic nervous activity decreased across a 24-h period (24-h period: 2.8-1.9, p = 0.017; during daytime: 3.7-2.3, p = 0.013; and during sleep time: 1.5-1.3, p = 0.026). Importantly, ASV significantly decreased ventricular premature complexes not only during sleep time but also across a 24-h period (40.5-21.9 beats/h, p = 0.013). The short-term use of ASV reduced ventricular arrhythmias with the attenuation of sympathetic nervous activity, as demonstrated by urinary catecholamines and heart rate variability. ASV may have anti-sympathetic nervous and anti-arrhythmic effects for CHF with SDB. 23964924 Targeting MnSOD in Basal Breast Carcinoma using Agonists of PPARγ: a new strategy for enhancing chemosensitivity. Aim: Whereas earlier reports highlighted a tumor suppressor role for MnSOD, recent evidence indicates increased expression in a variety of human cancers including aggressive breast carcinoma. In the present report, we hypothesized that MnSOD expression is significantly amplified in the aggressive breast carcinoma basal subtype and targeting MnSOD could be an attractive strategy for enhancing chemosensitivity of this highly aggressive breast cancer subtype. Results: Using MDA-MB-231 and BT549 as a model of basal breast cancer cell lines we show that knockdown of MnSOD decreased the colony forming ability and sensitized the cells to drug-induced apoptosis, while drug resistance was associated with increased MnSOD expression. In an attempt to develop a clinically relevant approach to downregulate MnSOD expression in patient with basal breast carcinoma, we employed activation of the peroxisome proliferator-activated receptor gamma (PPARγ) to repress MnSOD expression, PPARγ activation significantly reduced MnSOD expression, increased chemosensitivity and inhibited tumor growth. Moreover, as a proof-of-concept for the clinical use of PPAR agonists to decrease MnSOD expression, biopsies derived from breast cancer patients who had received synthetic PPARγ ligands as anti-diabetic therapy had significantly reduced MnSOD expressions. Finally, we provide evidence to implicate peroxynitrite as the mechanism involved in the increased sensitivity to chemotherapy induced by MnSOD repression. Innovation and Conclusion: These data provide evidence to link increased MnSOD expression with the aggressive basal breast cancer, and underscore the judicious use of PPARγ ligands for specifically downregulating MnSOD to increase the chemosensitivity of this subtype of breast carcinoma. 23463253 A method for non-invasive full-field imaging and quantification of chemical species. We present a novel method for full-field scalar visualization and quantification of species concentration fields. We term this method species-altered fluorescence imaging (SAFI). The method employs electrically neutral fluorescent dyes whose quantum yields are selectively quenched or enhanced by species of interest. SAFI enables simultaneous imaging of material interfaces and provides non-invasive, scalar-field quantitation of two-dimensional species concentration fields. We describe criteria for choosing SAFI dyes and tabulate 35 promising SAFI dyes and their relevant properties. Next, we describe species concentration quantification with SAFI via Stern-Volmer quenching and discuss the sensitivity and resolution of our method. We demonstrate this method with two dyes, 6-methoxy-N-(3-sulfopropyl)quinolinium (SPQ) and 10-(3-sulfopropyl)acridinium betaine (SAB). We demonstrate our method in full-field visualization of several challenging electrokinetic flows: isotachophoresis (ITP) in both cationic and anionic modes, and in a convective electrokinetic instability (EKI) flow. Through these experiments we collectively quantify ion concentration shock velocities, simultaneously measure concentrations of five species, and quantify the development of an unsteady, chaotic, 2D flow. 23622702 Stent versus off-pump coronary bypass grafting in the second-generation drug-eluting stent era. Second-generation drug-eluting stents (DESs) are known to have better safety and clinical outcomes compared with the first-generation DESs. We compared the clinical results of off-pump coronary artery bypass grafting (OPCAB) with percutaneous coronary intervention (PCI) using second-generation DESs. The study enrolled 1,821 patients with triple-vessel or left main coronary disease, or both, who underwent OPCAB or PCI with second-generation DESs from 2008 to 2011. Major adverse cardiac and cerebrovascular events (MACCEs), including death, myocardial infarction, stroke, and target vessel revascularization, were retrospectively compared between the two groups in a real-world and in a matched population (n = 1,294). Follow-up duration was 23.0 ± 13.0 months (range, 0 to 56 months). The postprocedural mortality rate was comparable between the two groups (p = 0.384). The overall rate of MAACEs was 7.3% in the PCI group and 3.8% in the OPCAB group (p = 0.001). The 3-year rate of freedom from MACCEs was 88.4% ± 1.5% in the PCI group and 94.9% ± 1.0% in the OPCAB group (p < 0.001). In a matched population comparison, the 3-year rate of freedom from a MACCE was 87.5% ± 2.0% in the PCI group and 95.3% ± 1.2% in the OPCAB group (p = 0.001). The determining factors were nonfatal myocardial infarction and target vessel revascularization. The OPCAB group showed a superior rate of freedom from MACCEs in the triple-vessel (p = 0.008) and left main subset analysis (p = 0.001). The OPCAB showed superior outcomes in triple-vessel or left main disease, or both, compared with PCI in the second-generation DES era after 23 months of follow-up. Nonfatal myocardial infarction and target vessel revascularization were the determining factors. Longer follow-up with randomization will clarify our results. 23844998 Effect of 36 CYP2C9 variants found in the Chinese population on losartan metabolism in vitro. Abstract 1.  CYP2C9 is an important member of the cytochrome P450 enzyme superfamily, with 57 CYP2C9 allelic variants being previously reported. Among these variants, we recently identified 21 novel alleles (*36-*56) in the Han Chinese population. The aim of this study was to assess the catalytic activities of 36 CYP2C9 variants found in the Chinese population toward losartan in vitro. 2.  Insect microsomes expressing the 36 CYP2C9 variants were incubated with 0.5-25 μM losartan for 30 min at 37 °C. Next, the products were extracted, and signal detection was performed using high-performance liquid chromatography. 3.  Compared with wild-type CYP2C9.1, the intrinsic clearance (Vmax/Km) values of all variants except for CYP2C9.56 were significantly altered. One variant exhibited markedly increased values (>250%), whereas 33 variants exhibited significantly decreased values (from 20 to 96%) due to increased Km and/or decreased Vmax values. 4.  These findings suggest that more attention should be paid to subjects carrying these infrequent CYP2C9 alleles when administering losartan in the clinic. 23782277 Co-catalyzed cross-coupling of alkyl halides with tertiary alkyl Grignard reagents using a 1,3-butadiene additive. The cobalt-catalyzed cross-coupling of alkyl (pseudo)halides with alkyl Grignard reagents in the presence of 1,3-butadiene as a ligand precursor and LiI is described. Sterically congested quaternary carbon centers could be constructed by using tertiary alkyl Grignard reagents. This reaction proceeds via an ionic mechanism with inversion of stereochemistry at the reacting site of the alkyl halide and is compatible with various functional groups. The use of both 1,3-butadiene and LiI was essential for achieving high yields and high selectivities. 23682593 The influence of the frequency of functional markers on repetitive imitation of syntactic constructions in children with specific language impairment, from their own language productions. Several studies provide considerable insight into the role that frequency plays in language development. However, no study has investigated the direct relationship between frequency and grammatical acquisition in children with specific language impairment (SLI). In this study, we focus specifically on the influence of the frequency of functional words on the ability of children with SLI to produce grammatical constructions based on the children's own previous production but containing previously unused functional words. To test our hypothesis, the children were administered an imitative repetition task, tailored to their current level of language development. Results showed that children with SLI performed more poorly than language-matched children with typical language development. The difference between the two groups was more marked when the previously unused functional words were infrequent rather than frequent. Consequently, it would seem that the token frequency of functional words influences grammatical acquisition in children with SLI. The results and their implications for linguistic theories are discussed. 23874828 Successful Human Infection with P. falciparum Using Three Aseptic Anopheles stephensi Mosquitoes: A New Model for Controlled Human Malaria Infection. Controlled human malaria infection (CHMI) is a powerful method for assessing the efficacy of anti-malaria vaccines and drugs targeting pre-erythrocytic and erythrocytic stages of the parasite. CHMI has heretofore required the bites of 5 Plasmodium falciparum (Pf) sporozoite (SPZ)-infected mosquitoes to reliably induce Pf malaria. We reported that CHMI using the bites of 3 PfSPZ-infected mosquitoes reared aseptically in compliance with current good manufacturing practices (cGMP) was successful in 6 participants. Here, we report results from a subsequent CHMI study using 3 PfSPZ-infected mosquitoes reared aseptically to validate the initial clinical trial. We also compare results of safety, tolerability, and transmission dynamics in participants undergoing CHMI using 3 PfSPZ-infected mosquitoes reared aseptically to published studies of CHMI using 5 mosquitoes. Nineteen adults aged 18-40 years were bitten by 3 Anopheles stephensi mosquitoes infected with the chloroquine-sensitive NF54 strain of Pf. All 19 participants developed malaria (100%); 12 of 19 (63%) on Day 11. The mean pre-patent period was 258.3 hours (range 210.5-333.8). The geometric mean parasitemia at first diagnosis by microscopy was 9.5 parasites/µL (range 2-44). Quantitative polymerase chain reaction (qPCR) detected parasites an average of 79.8 hours (range 43.8-116.7) before microscopy. The mosquitoes had a geometric mean of 37,894 PfSPZ/mosquito (range 3,500-152,200). Exposure to the bites of 3 aseptically-raised, PfSPZ-infected mosquitoes is a safe, effective procedure for CHMI in malaria-naïve adults. The aseptic model should be considered as a new standard for CHMI trials in non-endemic areas. Microscopy is the gold standard used for the diagnosis of Pf malaria after CHMI, but qPCR identifies parasites earlier. If qPCR continues to be shown to be highly specific, and can be made to be practical, rapid, and standardized, it should be considered as an alternative for diagnosis. ClinicalTrials.gov NCT00744133 NCT00744133. 23810263 Factors associated with rapid failure in a Treatment Alternatives for Safer Communities (TASC) program. Identify factors associated with early treatment failure in a Treatment Alternatives for Safer Communities (TASC) program, a case management criminal justice diversion program for individuals under community corrections supervision. Demographics, medication history, substance dependence, and criminal history variables for 21,419 individuals were used as predictor variables for successful treatment outcome in a Cox Proportional Hazards Survival analysis which was used to assess the relationship between predictor variables and the length of time before treatment failure. Early treatment failure was associated with a number of factors linked to social stability, including: being divorced separated or widowed, being less educated, being without insurance or on government insurance, and being unemployed. Regarding addiction and criminal history, being dependent on cocaine or opioids and being under supervision for person, property, or court offenses were risk factors. Being male and being a member of a racial minority were also risk factors for early treatment failure. Meeting criteria for sedative/hypnotic dependence and being under legal supervision for a substance offense were associated with a longer duration of time to treatment failure. Social stability, addiction history, and current criminal charges all appear to influence performance in TASC. Individuals with multiple risk factors may benefit from referral to a higher level of care upon admittance to TASC. 23809456 Deep vein thrombosis after arthroscopic anterior cruciate ligament reconstruction: a prospective cohort study of 100 patients. To establish the incidence of venous thromboembolic complications as detected by bilateral complete compression ultrasonography (CCUS) after arthroscopic anterior cruciate ligament (ACL) reconstruction without thromboprophylaxis. We performed a prospective cohort study to establish the incidence of venous thromboembolic complications after arthroscopic ACL reconstruction, as detected by bilateral CCUS at 14 days (range, 11 to 17 days) postoperatively. One hundred consecutive patients underwent bilateral extended ultrasonography. One hundred predominantly European patients with a mean age of 30 ± 10 years and mean body mass index of 25 ± 4 underwent ACL reconstruction with a mean operative duration of 68 ± 23 minutes and a tourniquet time of 76 ± 23 minutes. In 84% of patients an autologous hamstring graft was used, in 14% a bone-patellar tendon-bone graft was used, and 2 patients received an allograft. Of 100 patients, 9 (incidence, 9%; 95% confidence interval, 4.2 to 16.4) showed asymptomatic proximal or distal deep vein thrombosis on CCUS, of whom 4 (incidence, 4%; 95% confidence interval, 1.1 to 9.9) were symptomatic. A nonfatal pulmonary embolus developed in 1 patient during the 8-week follow-up period. This study shows that the incidence of venous thromboembolism after arthroscopic ACL reconstruction is relatively high; a 9% incidence of asymptomatic proximal or distal deep vein thrombosis was found, whereas 4% of patients were symptomatic. Further research is recommended to assess the need for thromboprophylaxis in patients undergoing ACL reconstruction, especially when risk factors are present. Level IV, case series. 23066093 The biarylpyrazole compound AM251 alters mitochondrial physiology via proteolytic degradation of ERRα. The orphan nuclear receptor estrogen-related receptor alpha (ERRα) directs the transcription of nuclear genes involved in energy homeostasis control and the regulation of mitochondrial mass and function. A crucial role for controlling ERRα-mediated target gene expression has been ascribed to the biarylpyrazole compound 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251) through direct binding to and destabilization of ERRα protein. Here, we provide evidence that structurally related AM251 analogs also have negative impacts on ERRα protein levels in a cell-type-dependent manner while having no deleterious actions on ERRγ. We show that these off-target cellular effects of AM251 are mediated by proteasomal degradation of nuclear ERRα. Cell treatment with the nuclear export inhibitor leptomycin B did not prevent AM251-induced destabilization of ERRα protein, whereas proteasome inhibition with MG132 stabilized and maintained its DNA-binding function, indicative of ERRα being a target of nuclear proteasomal complexes. NativePAGE analysis revealed that ERRα formed a ∼220-kDa multiprotein nuclear complex that was devoid of ERRγ and the coregulator peroxisome proliferator-activated receptor γ coactivator-1. AM251 induced SUMO-2,3 incorporation in ERRα in conjunction with increased protein kinase C activity, whose activation by phorbol ester also promoted ERRα protein loss. Down-regulation of ERRα by AM251 or small interfering RNA led to increased mitochondria biogenesis while negatively impacting mitochondrial membrane potential. These results reveal a novel molecular mechanism by which AM251 and related compounds alter mitochondrial physiology through destabilization of ERRα. 23742057 Generation and functional analysis of human TNF-α/iNOS-producing dendritic cells (Tip-DC). A unique type of CD11c(pos) dendritic cells (DC) is abundant in inflamed tissue, for example, in chronic inflammatory skin diseases. Due to their remarkable production of tumor necrosis factor (TNF)-α and inducible NO synthase (iNOS), these cells have been referred to as TNF and iNOS-producing DC (Tip-DC). While Tip-DC have been mainly characterized in murine models of infection, functional data about their human counterpart are lacking. We sought to generate human Tip-DC in vitro und thus provide a new model for the investigation of their phenotype and function. We generated human Tip-DC from monocytic precursor cells of healthy individuals, atopic and psoriatic patients using human serum. Resting and stimulated cells were analyzed by flow cytometry, real-time PCR, and by ELISA. INOS activity was measured by fluorometric detection of NO. Tip-DC closely resembled their in vivo counterparts by expressing CD11c, CD86, and CD40 while lacking CD1a, CD1c, or CD207/Langerin. Bacterial stimulation of Tip-DC from healthy donors, atopic dermatitis, or psoriasis patients resulted in a similar increase in iNOS activity and TNF-α production. In kinetic experiments, TNF-α, a putative activator of Tip-DC, could not induce NOS2. Upon bacterial stimulation, TNFA, IL6, IL12B, and IL23A mRNA appeared in a first wave, while IL12A and NOS2 mRNA were up-regulated later on but not blocked by anti-TNF-α agents, implying a biphasic pro-inflammatory response. We developed a new model for the study of human Tip-DC and provide the first evidence of their pro-inflammatory capacity. 23566936 Detection of Neorickettsia risticii from various freshwater snail species collected from a district irrigation canal in Nevada County, California. This study investigated the role of a district irrigation canal in Nevada County, California, USA, as the point source of infection for Neorickettsia risticii, causative agent of equine neorickettsiosis (EN). A total of 568 freshwater snails comprising Juga spp., Planorbella subcrenata (Carpenter, 1857) (Rough Rams-horn), Physella virgata (Gould, 1855) (Protean Physa) and feces from three horses with EN were collected and tested for N. risticii by real-time PCR. A total of four freshwater snails tested PCR positive for N. risticii. Phylogenetic analysis showed 99.8-100% homology between the different snail and horse N. risticii isolates. This study represents the first report of infection with N. risticii in Planorbella subcrenata and suggests that the irrigation canal was the aquatic environment responsible for the spread of N. risticii. 23804653 Specialized sorting of GLUT4 and its recruitment to the cell surface are independently regulated by distinct Rabs. Adipocyte glucose uptake in response to insulin is essential for physiological glucose homeostasis: stimulation of adipocytes with insulin results in insertion of the glucose transporter GLUT4 into the plasma membrane and subsequent glucose uptake. Here we establish that RAB10 and RAB14 are key regulators of GLUT4 trafficking that function at independent, sequential steps of GLUT4 translocation. RAB14 functions upstream of RAB10 in the sorting of GLUT4 to the specialized transport vesicles that ferry GLUT4 to the plasma membrane. RAB10 and its GTPase-activating protein (GAP) AS160 comprise the principal signaling module downstream of insulin receptor activation that regulates the accumulation of GLUT4 transport vesicles at the plasma membrane. Although both RAB10 and RAB14 are regulated by the GAP activity of AS160 in vitro, only RAB10 is under the control of AS160 in vivo. Insulin regulation of the pool of RAB10 required for GLUT4 translocation occurs through regulation of AS160, since activation of RAB10 by DENND4C, its GTP exchange factor, does not require insulin stimulation. 23871639 The interplay between regulatory and effector T cells in autoimmune hepatitis: Implications for innovative treatment strategies. Autoimmune hepatitis is an immuno-mediated inflammatory liver disorder of unknown etiology and is characterized by hypergammaglobulinaemia, circulating autoantibodies and interface hepatitis. The disease may often present as an acute icteric hepatitis, or run an insidious and progressive course, and in most of the cases it is expected to evolve toward liver cirrhosis and end-stage liver failure, without prompt and appropriate treatment with steroids and other immunosuppressive drugs. Nonetheless, several patients are non-responsive or become non-tolerant to conventional therapy with prednisone/prednisolone with or without azathioprine. Recent findings highlight the role of the interplay between CD4+CD25+ regulatory T cells and Th17 cells in the pathogenesis of autoimmune hepatitis. A numerical and functional imbalance between regulatory and effector cells in favor of the latter appears to be pivotal in the progression of the disease. In addition, the intra-hepatic microenvironment of autoimmune hepatitis is particularly rich in pro-inflammatory cytokines such as IL-6, IL-17, IL-23, IL-1β which play a crucial role in perpetuating and expanding effector cells and subsequent liver damage, whereas regulatory T cells are greatly disadvantaged and inhibited in such polarized habitat. Novel therapeutic interventions should aim at modulating the intra-hepatic pro-inflammatory milieu while favoring the expansion of regulatory T cells. Liver autoantigen-specific regulatory T cells generated and expanded in vitro from patients' own cells might offer a potentially curative approach to autoimmune hepatitis by inhibiting effector cells of the same specificity without inducing pan-immunosuppression. 23954705 MALDI-MS tissue imaging identification of biliverdin reductase B overexpression in prostate cancer. New biomarkers are needed to improve the specificity of prostate cancer detection and characterisation of individual tumors. In a proteomics profiling approach using MALDI-MS tissue imaging on frozen tissue sections, we identified discriminating masses. Imaging analysis of cancer, non-malignant benign epithelium and stromal areas of 15 prostatectomy specimens in a test and 10 in a validation set identified characteristic m/z peaks for each tissue type, e.g. m/z 10775 for benign epithelial, m/z 6284 and m/z 6657.5 for cancer and m/z 4965 for stromal tissue. A 10-fold cross-validation analysis showed highest discriminatory ability to separate tissue types for m/z 6284 and m/z 6657.5, both overexpressed in cancer, and a multicomponent mass peak cluster at m/z 10775-10797.4 overexpressed in benign epithelial tissue. ROC AUC values for these three masses ranged from 0.85 to 0.95 in the discrimination of malignant and non-malignant tissue. To identify the underlying proteins, prostate whole tissue extract was separated by nano-HPLC and subjected to MALDI TOF/TOF analysis. Proteins in fractions containing discriminatory m/z masses were identified by MS/MS analysis and candidate marker proteins subsequently validated by immunohistochemistry (IHC). Biliverdin reductase B (BLVRB) turned out to be overexpressed in PCa tissue. In this study on cryosections of radical prostatectomies of prostate cancer patients, we performed a MALDI-MS tissue imaging analysis and a consecutive protein identification of significant m/z masses by nano-HPLC, MALDI TOF/TOF and MS/MS analysis. We identified BLVRB as a potential biomarker in the discrimination of PCa and benign tissue, also suggesting BVR as a feasible therapeutic target. 23703212 CLIP-based prediction of mammalian microRNA binding sites. Prediction and validation of microRNA (miRNA) targets are essential for understanding functions of miRNAs in gene regulation. Crosslinking immunoprecipitation (CLIP) allows direct identification of a huge number of Argonaute-bound target sequences that contain miRNA binding sites. By analysing data from CLIP studies, we identified a comprehensive list of sequence, thermodynamic and target structure features that are essential for target binding by miRNAs in the 3' untranslated region (3' UTR), coding sequence (CDS) region and 5' untranslated region (5' UTR) of target messenger RNA (mRNA). The total energy of miRNA:target hybridization, a measure of target structural accessibility, is the only essential feature common for both seed and seedless sites in all three target regions. Furthermore, evolutionary conservation is an important discriminating feature for both seed and seedless sites. These features enabled us to develop novel statistical models for the predictions of both seed sites and broad classes of seedless sites. Through both intra-dataset validation and inter-dataset validation, our approach showed major improvements over established algorithms for predicting seed sites and a class of seedless sites. Furthermore, we observed good performance from cross-species validation, suggesting that our prediction framework can be valuable for broad application to other mammalian species and beyond. Transcriptome-wide binding site predictions enabled by our approach will greatly complement the available CLIP data, which only cover small fractions of transcriptomes and known miRNAs due to non-detectable levels of expression. Software and database tools based on the prediction models have been developed and are available through Sfold web server at http://sfold.wadsworth.org. 23945270 Cytotoxicity of Brazilian plant extracts against oral microorganisms of interest to dentistry. With the emergence of strains resistant to conventional antibiotics, it is important to carry studies using alternative methods to control these microorganisms causing important infections, such as the use of products of plant origin that has demonstrated effective antimicrobial activity besides biocompatibility. Therefore, this study aimed to evaluate the antimicrobial activity of plant extracts of Equisetum arvense L., Glycyrrhiza glabra L., Punica granatum L. and Stryphnodendron barbatimam Mart. against Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus mutans, Candida albicans, Candida tropicalis, and Candida glabrata, and to analyze the cytotoxicity of these extracts in cultured murine macrophages (RAW 264.7). Antimicrobial activity of plant extracts was evaluated by microdilution method based on Clinical and Laboratory Standards Institute (CLSI), M7-A6 and M27-A2 standards. The cytotoxicity of concentrations that eliminated the microorganisms was evaluated by MTT colorimetric method and by quantification of proinflammatory cytokines (IL-1β and TNF-α) using ELISA. In determining the minimum microbicidal concentration, E. arvense L., P. granatum L., and S. barbatimam Mart. extracts at a concentration of 50 mg/mL and G. glabra L. extract at a concentration of 100 mg/mL, were effective against all microorganisms tested. Regarding cell viability, values were 48% for E. arvense L., 76% for P. granatum L, 86% for S. barbatimam Mart. and 79% for G. glabra L. at the same concentrations. About cytokine production after stimulation with the most effective concentrations of the extracts, there was a significant increase of IL-1β in macrophage cultures treated with S. barbatimam Mart. (3.98 pg/mL) and P. granatum L. (7.72 pg/mL) compared to control (2.20 pg/mL) and a significant decrease of TNF-α was observed in cultures treated with G. glabra L. (4.92 pg/mL), S. barbatimam Mart. (0.85 pg/mL), E. arvense L. (0.83 pg/mL), and P. granatum L. (0.00 pg/mL) when compared to control (41.96 pg/mL). All plant extracts were effective against the microorganisms tested. The G. glabra L. extract exhibited least cytotoxicity and the E. arvense L. extract was the most cytotoxic. 23732327 Quaternized N-substituted carboxymethyl chitosan derivatives as antimicrobial agents. Introduction of quaternary ammonium moieties into N-substituted carboxymethyl chitosan (N-substituted CMCh) derivatives enhances their biological activity. Several derivatives of CMCh having a variety of N-aryl substituents bearing either electron-donating or electron withdrawing groups have been synthesized by the reaction between amino group of CMCh with various aromatic aldehydes under acidic conditions, followed by reduction of the produced Schiff base derivatives with sodium cyanoborohydride. Each of the reduced derivatives was further quaternized using N-(3-chloro-2-hydroxy-propyl)trimethylammonium chloride (Quat-188). The resulting quaternized materials were characterized by FTIR and (1)H NMR spectroscopy. Their antibacterial activities against Streptococcus pneumoniae (S. pneumonia, RCMB 010010), Bacillis subtilis (B. subtilis, RCMB 010067), as Gram positive bacteria and against Escherichia coli (E. coli, RCMB 010052) as Gram negative bacteria and their antifungal activities against Aspergillus fumigatus (A. fumigates, RCMB 02568), Geotricum candidum (G. candidum, RCMB 05097), and Candida albicans (C. albicans, RCMB 05031) were examined using agar disk diffusion method. The results indicated that all the quaternized derivatives showed better antimicrobial activities than that of CMCh. These derivatives are highly potent against Gram positive bacteria compared to Gram negative bacteria. This is illustrated for example as the values of minimum inhibitory concentration (MIC) of Q4NO2-BzCMCh against B. subtilis and S. pneumonia were 6.25 and 12.5μg/mL, respectively corresponded to 20.0μg/mL against E. coli. The antimicrobial activity of quaternized N-aryl CMCh derivatives affected by not only the nature of the microorganisms but also by the nature, position and number of the substituent groups on the phenyl ring. Thus while the derivatives with groups of electron withdrawing nature show higher inhibition zone diameter and lower MIC values relative to that of those having electron-donating nature, the non-substituted derivative lies between these two extremes. Antibacterial activities of Q4NO2-BzCMCh, Q3Cl-BzCMCh and Q3Br-BzCMCh against E. coli are nearly equivalent to that of the standard drug Gentamycin. Q3Br-BzCMCh emerged almost equivalent antibacterial activity to Ampicillin against S. pneumonia. 23900459 Nonvolatile multilevel data storage memory device from controlled ambipolar charge trapping mechanism. The capability of storing multi-bit information is one of the most important challenges in memory technologies. An ambipolar polymer which intrinsically has the ability to transport electrons and holes as a semiconducting layer provides an opportunity for the charge trapping layer to trap both electrons and holes efficiently. Here, we achieved large memory window and distinct multilevel data storage by utilizing the phenomena of ambipolar charge trapping mechanism. As fabricated flexible memory devices display five well-defined data levels with good endurance and retention properties showing potential application in printed electronics. 23803415 Garcinol, a polyisoprenylated benzophenone modulates multiple proinflammatory signaling cascades leading to the suppression of growth and survival of head and neck carcinoma. Constitutive activation of proinflammatory transcription factors such as STAT3 and NF-κB plays a pivotal role in the proliferation and survival of squamous cell carcinoma of the head and neck (HNSCC). Thus, the agents that can modulate deregulated STAT3 and NF-κB activation have a great potential both for the prevention and treatment of HNSCC. In the present report, we investigated the potential effects of garcinol, an active component of Garcinia indica on various inflammatory mediators involved in HNSCC progression using cell lines and xenograft mouse model. We found that garcinol inhibited constitutively activated STAT3 in HNSCC cells in a time- and dose-dependent manner, which correlated with the suppression of the upstream kinases (c-Src, JAK1, and JAK2) in HNSCC cells. Also, we noticed that the generation of reactive oxygen species is involved in STAT3 inhibitory effect of garcinol. Furthermore, garcinol exhibited an inhibitory effect on the constitutive NF-κB activation, mediated through the suppression of TGF-β-activated kinase 1 (TAK1) and inhibitor of IκB kinase (IKK) activation in HNSCC cells. Garcinol also downregulated the expression of various gene products involved in proliferation, survival, and angiogenesis that led to the reduction of cell viability and induction of apoptosis in HNSCC cells. When administered intraperitoneally, garcinol inhibited the growth of human HNSCC xenograft tumors in male athymic nu/nu mice. Overall, our results suggest for the first time that garcinol mediates its antitumor effects in HNSCC cells and mouse model through the suppression of multiple proinflammatory cascades. Cancer Prev Res; 6(8); 843-54. ©2013 AACR. 23802221 A novel ionic liquid-metal complex electrolyte for a remarkable increase in the efficiency of dye-sensitized solar cells. A novel ionic liquid-metal complex (ILMC) electrolyte was developed for dye-sensitized solar cells (DSCs). A high efficiency of nearly 7% was achieved, which was 69.2% higher compared with an ionic liquid (IL) electrolyte without a metal center. The high conductivity, inhibited electron recombination and longer electron lifetime contribute to the superior performance of the ILMC electrolyte. 23597129 MePR: A Novel Human Mesenchymal Progenitor Model with Characteristics of Pluripotency. Human embryo stem cells or adult tissues are excellent models for discovery and characterization of differentiation processes. The aims of regenerative medicine are to define the molecular and physiological mechanisms that govern stem cells and differentiation. Human mesenchymal stem cells (hMSCs) are multipotent adult stem cells that are able to differentiate into a variety of cell types under controlled conditions both in vivo and in vitro, and they have the remarkable ability of self-renewal. hMSCs derived from amniotic fluid and characterized by the expression of Oct-4 and Nanog, typical markers of pluripotent cells, represent an excellent model for studies on stemness. Unfortunately, the limited amount of cells available from each donation and, above all, the limited number of replications do not allow for detailed studies. Here, we report on the immortalization and characterization of novel mesenchymal progenitor (MePR) cell lines from amniotic fluid-derived hMSCs, whose biological properties are similar to primary amniocytes. Our data indicate that MePR cells display the multipotency potential and differentiation rates of hMSCs, thus representing a useful model to study both mechanisms of differentiation and pharmacological approaches to induce selective differentiation. In particular, MePR-2B cells, which carry a bona fide normal karyotype, might be used in basic stem cell research, leading to the development of new approaches for stem cell therapy and tissue engineering. 23664336 Understanding colloidal FeSx formation from iron phosphate precipitation sludge for optimal phosphorus recovery. The use of sulfide to form iron sulfide precipitates is an attractive option for separation and recovery of phosphorus and ferric iron from ferric phosphate sludge generated in wastewater treatment. The key factors affecting the simultaneous generation and separation of iron sulfide precipitates and phosphate solution from ferric phosphate sludge have so far not been thoroughly investigated. This study therefore focuses on the recovery of phosphorus from synthetic sludge by controlled sulfide addition under different operating conditions. The factors that affect the phosphorus recovery, as well as the optimal process conditions to achieve an effective solid-liquid separation, were investigated. The separation of the FeSx particles is a significant challenge due to the colloidal nature of the particles formed. Faster separation and higher phosphorus recovery was achieved when operating at pH 4 with dosing times of at least 1h. At this pH, phosphorus recovery of 70±6% was reached at the stoichiometric S/Fe molar ratio of 1.5, increasing to over 90% recovery at a S/Fe molar ratio of 2.5. Zeta potential results confirmed the colloidal nature of the iron sulfide precipitate, with the isoelectric point around pH 4, explaining the fast separation of the FeSx particles at this pH. 23598058 An examination of associations between the inability to taste phenylthiocarbamide (PTC) and clinical characteristics and trait markers in first-episode, nonaffective psychotic disorders. Research findings are mixed as to whether or not the inability to taste phenylthiocarbamide (PTC) might represent an endophenotypic trait marker for schizophrenia. We hypothesized associations between PTC-tasting status and select clinical characteristics and trait markers in patients with psychotic disorders that, if present, would provide support for the inability to taste PTC as a trait marker. In a first-episode psychosis sample (n=93), we measured PTC tasting, family history of psychosis, age at onset of prodrome and psychosis, severity of positive and negative symptoms, global impairment in functioning, neurological soft signs, and four neurocognitive domains (verbal learning/memory, visual learning/memory, verbal working memory, and spatial working memory). Associations between PTC-non-tasting and clinical/neurocognitive variables were examined with χ(2) tests and independent samples t tests. Among participants, 67.7% tasted PTC in comparison to a strip of control paper, and 25.8% were non-tasters. Tasters and non-tasters did not show statistically significant differences with respect to family history, age at onset, severity of symptoms, neurological soft signs, or the four neurocognitive domains. In conjunction with other findings, it is unlikely that PTC-non-tasting is a trait marker of schizophrenia, though a conclusive study is warranted. 23529672 Diagnostic performance of (99m)Tc-MIBI scan in predicting the malignancy of thyroid nodules: a meta-analysis. Several studies have investigated the diagnostic performance of (99m)Tc-MIBI scan in the evaluation of thyroid nodules suspicious for malignancy with conflicting results. The aim of our study is to meta-analyze published data on this topic. A comprehensive literature search of studies published through December 2012 regarding the diagnostic performance of (99m)Tc-MIBI scan in the evaluation of thyroid nodules suspicious for malignancy was carried out. Pooled sensitivity and specificity of (99m)Tc-MIBI scan on a per lesion-based analysis and the area under the ROC curve were calculated. Pathological reports of thyroid nodules were considered as reference standard. Twenty-one studies were included in the meta-analysis. Pooled sensitivity and specificity of (99m)Tc-MIBI scan in detecting malignant thyroid nodules were 85.1 % [95 % confidence interval (95 % CI): 81.1-88.5 %] and 45.7 % (95 % CI: 42.7-48.7 %), respectively, on a per lesion-based analysis, irrespective of eventual results of previous technetium pertechnetate ((99m)TcO4) or iodine-123 ((123)I) scan. The area under the ROC curve was 0.78. A sub-analysis restricted to data on hypofunctioning nodules on (99m)TcO4 or (123)I scans was performed: pooled sensitivity and specificity of (99m)Tc-MIBI scan in these nodules were 82.1 % (95 % CI: 77.2-86.3 %) and 62.8 % (95 % CI: 58.9-66.7 %), respectively, on a per lesion-based analysis. The area under the ROC curve was 0.81. (99m)Tc-MIBI scan is a sensitive diagnostic tool in predicting the malignancy of thyroid nodules. Therefore, this imaging method could be helpful in patients with thyroid nodules in which malignancy is suspected on the basis of conventional diagnostic techniques. Higher specificity can be reached when hypofunctioning thyroid nodules are considered. 23767822 Rapid Identification and Differentiation of Non-O157 Shiga Toxin-Producing Escherichia coli Using Polymerase Chain Reaction Coupled to Electrospray Ionization Mass Spectrometry. Abstract A polymerase chain reaction (PCR)-mass spectroscopy assay was developed to identify non-O157 Shiga toxin-producing Escherichia coli (STEC) with Plex-ID biosensor system, a platform identifying short PCR amplicons by specific base compositions. This assay simultaneously amplifies five fragments of two housekeeping genes, two subunits of stx2 gene, and four other virulence genes of STEC. A total of 164 well-characterized STEC isolates were examined with the assay to build a DNA base composition database. Another panel of 108 diverse STEC isolates was tested with the established database to evaluate the assay's identification capability. Among the 108 isolates, the assay specificity was 100% for three (stx1, eae, and aggA) out of five tested virulence genes, but 99% for stx2 and 96% for hlyA, respectively. Main stx1/stx2 subtypes and multiple alleles of stx1/stx2 could be differentiated. The assay successfully identified several clinically significant serotypes, including O91:H14, O103:H25, O145:H28/NM, O113:H21, and O104:H4. Meanwhile, it was able to group isolates with different levels of pathogenic potential. The results suggest that this high-throughput method may be useful in clinical and regulatory laboratories for STEC identification, particularly strains with increased pathogenic potential. 23809284 Implementing patient education in the CKD clinic. The passage of the Medicare Improvements for Patients and Providers Act (MIPPA) encouraged education for Stage 4 CKD patients by reimbursing qualified providers for formal instruction. This marked the first time Medicare reimbursed for kidney disease education. Although the law lays out specific requirements, it leaves much of the structure and content of the instruction up to the providers. The CKD clinic staffed by advanced practitioners (physician assistants, nurse practitioners, and/or clinical nurse specialists) provides a natural fit for patient education. Educated patients choose home modalities more frequently; more often start dialysis with a permanent vascular access; and generally score higher on tests measuring mood, mobility, and anxiety. However, sufficient research into the effects of CKD patient education is lacking. 23748359 Inducible knock out of pregnancy-associated plasma protein-a gene expression in the adult mouse: effect on vascular injury response. Pregnancy-associated plasma protein-A (PAPP-A) enhances local IGF signaling through its ability to proteolyze inhibitory IGF binding proteins. In vivo, PAPP-A (like IGF) appears to exhibit antagonistic pleiotropy; ie, it has beneficial effects early in life but detrimental effects later in life. Accordingly, PAPP-A knockout (KO) mice are born as proportional dwarfs and have diminished reproductive vigor and reduced peak bone mass acquisition at puberty. On the other hand, PAPP-A KO mice live approximately 30% longer than their wild-type littermates, with decreased incidence and severity of age-related diseases and resistance to adverse responses of vascular injury. To be able to distinguish the impact of PAPP-A deficiency in the adult from that in early life, we developed a mouse model suitable for inducible Cre recombinase-mediated excision of the PAPP-A gene. In this study, we characterize the conditional PAPP-A KO mouse model for efficacy of tamoxifen-induced floxed PAPP-A excision in various tissues of adult mice and demonstrate a significant (P = .0001) reduction of neointimal formation in these mice after unilateral carotid artery ligation. 23535954 Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. This phase I/II study in patients with metastatic castration-resistant prostate cancer (mCRPC) explored ipilimumab as monotherapy and in combination with radiotherapy, based on the preclinical evidence of synergistic antitumor activity between anti-CTLA-4 antibody and radiotherapy. In dose escalation, 33 patients (≥6/cohort) received ipilimumab every 3 weeks × 4 doses at 3, 5, or 10 mg/kg or at 3 or 10 mg/kg + radiotherapy (8 Gy/lesion). The 10-mg/kg cohorts were expanded to 50 patients (ipilimumab monotherapy, 16; ipilimumab + radiotherapy, 34). Evaluations included adverse events (AEs), prostate-specific antigen (PSA) decline, and tumor response. Common immune-related AEs (irAEs) among the 50 patients receiving 10 mg/kg ± radiotherapy were diarrhea (54%), colitis (22%), rash (32%), and pruritus (20%); grade 3/4 irAEs included colitis (16%) and hepatitis (10%). One treatment-related death (5 mg/kg group) occurred. Among patients receiving 10 mg/kg ± radiotherapy, eight had PSA declines of ≥50% (duration: 3-13+ months), one had complete response (duration: 11.3+ months), and six had stable disease (duration: 2.8-6.1 months). In mCRPC patients, ipilimumab 10 mg/kg ± radiotherapy suggested clinical antitumor activity with disease control and manageable AEs. Two phase III trials in mCRPC patients evaluating ipilimumab 10 mg/kg ± radiotherapy are ongoing. ClinicalTrials.gov identifier: NCT00323882. 23765764 Utility of the Pentax-AWS in performing tracheal intubation while wearing chemical, biological, radiation and nuclear personal protective equipment: a randomised crossover trial using a manikin. Following a chemical, biological, radiation and nuclear (CBRN) incident, prompt establishment of an advanced airway is required for patients with respiratory failure within the warm zone, while wearing personal protective equipment (PPE). Previous studies reported that intubation attempts were prolonged, and incidence of esophageal intubation was increased with conventional Macintosh laryngoscope (McL), while wearing CBRN-PPE. Pentax-AWS (AWS), a recently introduced portable video laryngoscope, was compared with the McL to test its utility for tracheal intubation while wearing CBRN-PPE. 31 participants performed unsuited and suited intubations on an advanced life support simulator. The sequence of intubating devices and PPE wearing were randomised. Time to complete tracheal intubation (primary end point), time to see the vocal cords, overall success rate, percentage of glottic opening, dental compression and ease of intubation were measured. Suited intubations required significantly longer time to complete intubation than unsuited intubations, in both McL and AWS (22.2 vs 26.4 s, 14.2 vs 18.2 s, respectively). However, suited AWS intubations required shorter time to complete tracheal intubation than unsuited McL intubations (18.2 vs 22.2 s). In secondary outcomes, moreover, suited intubations using the AWS compared favourably with unsuited intubations using the McL. Although the CBRN-PPE adversely affected time required to complete tracheal intubation with the AWS, suited intubations using the AWS were even superior to unsuited intubations using the McL. The AWS should be a promising device to perform tracheal intubation while wearing the CBRN-PPE. 23916903 Emergency stabilization of the pelvic ring: Clinical comparison between three different techniques. Emergency devices for pelvic ring stabilization include circumferential sheets, pelvic binders, and c-clamps. Our knowledge of the outcome of these techniques is currently based on limited information. Using the dataset of the German Pelvic Trauma Registry, demographic and injury-associated characteristics as well as the outcome of pelvic fracture patients after sheet, binder, and c-clamp treatment was compared. Outcome parameters included transfusion requirement of packed red blood cells, length of hospital stay, mortality, and incidence of lethal pelvic bleeding. Two hundred seven of 6137 (3.4%) patients documented in the German Pelvic Trauma Registry between April 30th 2004 and January 19th 2012 were treated by sheets, binders, or c-clamps. In most cases, c-clamps (69%) were used, followed by sheets (16%), and binders (15%). The median age was significantly lower in patients treated with binders than in patients treated with sheets or c-clamps (26 vs. 47 vs. 42years, p=0.01). Sheet wrapping was associated with a significantly higher incidence of lethal pelvic bleeding compared to binder or c-clamp stabilization (23% vs. 4% vs. 8%). No significant differences between the study groups were found in sex, fracture type, blood haemoglobin concentration, arterial blood pressure, Injury Severity Score, the incidence of additional pelvic packing and arterial embolization, need of red blood cell transfusion, length of hospitalisation, and mortality. The data suggest that emergency stabilization of the pelvic ring by binders and c-clamps is associated with a lower incidence of lethal pelvic bleeding compared to sheet wrapping. Level III. 23815562 Evaluation of safety and efficacy of a fixed olmesartan/amlodipine combination therapy compared to single monotherapies. Background: Hypertension is known to be one of the main risk factors for cardiovascular disease. Objectives: To evaluate the safety and efficacy of a fixed olmesartan/amlodipine (Olme/Amlo) combination in improving blood pressure control, lipid profile, insulin sensitivity and some inflammatory and insulin resistance markers. Two hundred and seventy-six hypertensive patients were randomly assigned to olmesartan 20 mg, amlodipine 10 mg or a single pill containing an Olme/Amlo combination 20/5 mg for 12 months. We evaluated after 6 and 12 months: body weight, body mass index (BMI), systolic and diastolic blood pressure (SBP and DBP, respectively), fasting plasma glucose (FPG), fasting plasma insulin (FPI), lipid profile, vaspin, visfatin, interleukins 8 and 10 (IL-8 and IL-10, respectively). Patients also underwent an euglycemic, hyperinsulinemic clamp. Results: Olme/Amlo combination was more effective in decreasing SBP, and DPB compared to single monotherapies after 12 months. Olme/Amlo combination, but not amlodipine, decreased FPG after 12 months. FPI and HOMA index were decreased, and M value increased by Olme/Amlo combination compared to olmesartan monotherapy, and to amlodipine monotherapy. Olme/Amlo significantly decreased IL-8 and IL-10 better than each monotherapy. Conclusions: Olme/Amlo single pill combination can be a safe and effective option to reduce blood pressure, improve insulin sensitivity and decrease inflammatory markers. 22940854 In silico structural and functional analysis of the human TOPK protein by structure modeling and molecular dynamics studies. Over expression of T-lymphokine-activated killer cell-originated protein kinase (TOPK) has been associated with leukemia, myeloma tumors and various other cancers. The function and regulatory mechanism of TOPK in tumor cells remains unclear. Structural studies that could reveal the regulatory mechanism have been a challenge because of the unavailabity of TOPK's crystal structure. Hence, in this study, the 3D structure of TOPK protein has been constructed by using multiple templates. The quality and reliability of the generated model was checked and the molecular dynamics method was utilized to refine the model. APBS method was employed to know the electrostatic potential surface of the modeled protein and it was found that the optimum pH for protein stability is 3.4 which will further help in mechanistic hypothesis of TOPK protein. Active site of TOPK was identified from available literature and HTVS was employed to identify the lead molecules. The expected binding modes of protein-ligand complexes were reproduced in the MD simulation which indicates that the complex is relatively stable. The pharmacokinetic properties of the lead molecules are also under acceptable range. TOPK act as a substrate for CDK1 and the protein-protein docking and dynamics studies were carried out to analyze the effect of Thr9Ala mutation of TOPK in the two protein complex formation. It shows that the wild type complex is more stable when compared with the mutant type. Such structural information at atomic level not only exhibits the action modes of TOPK inhibitors but also furnishes a novel starting point for structure based drug design of TOPK inhibitors. 23893949 Messenger RNA-based vaccines: progress, challenges, applications. Twenty years after the demonstration that messenger RNA (mRNA) was expressed and immunogenic upon direct injection in mice, the first successful proof-of-concept of specific protection against viral infection in small and large animals was reported. These data indicate wider applicability to infectious disease and should encourage continued translation of mRNA-based prophylactic vaccines into human clinical trials. At the conceptual level, mRNA-based vaccines-more than other genetic vectors-combine the simplicity, safety, and focused immunogenicity of subunit vaccines with favorable immunological properties of live viral vaccines: (1) mRNA vaccines are molecularly defined and carry no excess information. In the environment and upon physical contact, RNA is rapidly degraded by ubiquitous RNases and cannot persist. These characteristics also guarantee tight control over their immunogenic profile (including avoidance of vector-specific immune responses that could interfere with repeated administration), pharmacokinetics, and dosing. (2) mRNA vaccines are synthetically produced by an enzymatic process, just requiring information about the nucleic acid sequence of the desired antigen. This greatly reduces general complications associated with biological vaccine production, such as handling of infectious agents, genetic variability, environmental risks, or restrictions to vaccine distribution. (3) RNA can be tailored to provide potent adjuvant stimuli to the innate immune system by direct activation of RNA-specific receptors; this may reduce the need for additional adjuvants. The formation of native antigen in situ affords great versatility, including intracellular localization, membrane association, posttranslational modification, supra-molecular assembly, or targeted structural optimization of delivered antigen. Messenger RNA vaccines induce balanced immune responses including B cells, helper T cells, and cytotoxic T lymphocytes, rendering them an extremely adaptable platform. This article surveys the design, mode of action, and capabilities of state-of-the-art mRNA vaccines, focusing on the paradigm of influenza prophylaxis. For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article. 23838503 Delayed diagnosis of oral squamous cell carcinoma following dental treatment. Oral squamous cell carcinoma (SCC) can present with a wide range of clinical appearances. Consequently, an oral SCC, particularly in its early stage, may not be considered suspicious by a clinician, thereby delaying diagnosis. Delayed diagnosis of an oral SCC could result in more advanced disease at the time of treatment, leading to more extensive and costly treatment, greater morbidity and poorer survival. The aim of this study was to identify cases of oral SCC treated at Southern Heath (Melbourne, Australia) with a history of prediagnosis dental treatment, and to determine the delay between dental treat- ment and appropriate surgical assessment of the oral SCC. Patients were identified from the head and neck tumour database at Southern Health who met the inclusion crite- ria and relevant data were recorded. Twelve patients met the inclusion criteria and 83% of cases involved the mandible. Dental extraction was the most common prediagnosis treatment performed (75%). The average delay from dental treatment to surgical assessment was just over eight weeks and all patients were found to have stage IV disease. Most patients had received extensive surgical resections (83%), neck dissections (75%) and adjunctive therapy (83%). Oral SCC can sometimes be difficult to diagnose, which can result in more extensive treatment and greater morbidity. Health professionals and patients need to be aware that non-healing oral lesions, even after dental treatment such as a dental extraction, need to be considered as suspicious and an appropriate surgical referral should be made. 23837798 Borrelia burgdorferi sensu lato prevalence in tick populations in Estonia. Estonia is located in a unique area of co-distribution of Ixodes ricinus and I. persulcatus, which are the main tick vectors of Borrelia burgdorferi sensu lato. In the last decade, the incidence rate of Lyme borreliosis in Estonia has increased dramatically up to 115.4 per 100,000 in 2012. Here we present the first survey of the presence, the prevalence and genetic characteristics of B. burgdorferi s.l. complex spirochetes in the tick population in Estonia. During the years 2006-2009, 2833 unfed Ixodes ricinus and I. persulcatus were collected from 43 sites in 7 counties in mainland Estonia as well as in 10 sites on the Saaremaa Island. DNA samples from ticks were analyzed individually using nested PCR of the ribosomal 5S-23S spacer region followed by bidirectional sequencing. The overall estimated prevalence of B. burgdorferi s.l was 9.7% and varied from 4.9% to 24.2% on the mainland and to 10.7% in Saaremaa Island. Ixodes persulcatus ticks showed significantly higher prevalence rates compared to that in I. ricinus-16.3% and 8.2%, respectively. The most prevalent genospecies was B. afzelii which was detected in 53.5% of Borrelia-positive ticks, followed by B. garinii and B. valaisiana with 26.2% and 5.5%, respectively. Also, B. bavariensis and B. burgdorferi s.s. DNA in single I. ricinus ticks were detected. Borrelia afzelii, B. garinii and B. valaisiana were detected in both tick species. Two genetic subgroups of B. garinii (NT29 and 20047) and two genetic subgroups of B. afzelii (NT28 and VS461) were found to be circulating in all studied regions as well as in both tick species, except B. garinii subgroup NT29, which was found only in I. persulcatus ticks. In the current study we detected the circulation of five B. burgdorferi s.l. genospecies and estimated the prevalence in ticks in different regions of Estonia. Detection and genetic characterization of Borrelia genospecies, especially those of public health importance, in the natural foci may help assessing high risk areas of human exposure to B. burgdorferi s.l. 23583743 Monitoring brain activation changes in the early postoperative period after radical prostatectomy using fMRI. Urinary incontinence is a major concern following radical prostatectomy. The etiology is multifactorial involving intrinsic sphincter deficiency and/or detrusor hyperactivity and/or decreased bladder compliance. Recent studies employing functional imaging methodology nicely demonstrated the reference regions of the micturition circuit. Based on these landmarks this work complements this field of research by studying patients with bladder dysfunction. Our aim was to evaluate, whether iatrogenic impairment of the pelvic floor muscles after retropubic radical prostatectomy (RRP) causes detectable changes in fMRI in the early postoperative period. fMRI was performed at 3T in 22 patients before and after RRP with urge to void due to a filled bladder. In a non-voiding model they were instructed to contract or to relax the pelvic floor muscles repetitively. As previously reported in healthy men, contraction and relaxation of pelvic floor muscles induced strong activations in the brainstem and more rostral areas in our group of patients before and after RRP. In general, all of them had stronger activations during contraction than during relaxation in all regions before and after the operation. Even though there was no difference in the activation level when relaxing the pelvic floor before and after the operation, we found stronger activation during contraction when comparing the preoperative with the postoperative level in some of the regions. The results suggest that the same cortical and subcortical networks can be demonstrated for micturition control in patients with prostate cancer as in healthy subjects. However, impaired pelvic floor muscle function after RRP seems to induce different activation intensities. 23852863 Structure of Microcin B-Like Compounds Produced by Pseudomonas syringae and Species Specificity of Their Antibacterial Action. Escherichia coli microcin B (Ec-McB) is a posttranslationally modified antibacterial peptide containing multiple oxazole and thiazole heterocycles and targeting the DNA gyrase. We have found operons homologous to the Ec-McB biosynthesis-immunity operon mcb in recently sequenced genomes of several pathovars of the plant pathogen Pseudomonas syringae, and we produced two variants of P. syringae microcin B (Ps-McB) in E. coli by heterologous expression. Like Ec-McB, both versions of Ps-McB target the DNA gyrase, but unlike Ec-McB, they are active against various species of the Pseudomonas genus, including human pathogen P. aeruginosa. Through analysis of Ec-McB/Ps-McB chimeras, we demonstrate that three centrally located unmodified amino acids of Ps-McB are sufficient to determine activity against Pseudomonas, likely by allowing specific recognition by a transport system that remains to be identified. The results open the way for construction of McB-based antibacterial molecules with extended spectra of biological activity. 23885078 Hsp70-Dependent Antiviral Immunity against Cytopathic Neuronal Infection by Vesicular Stomatitis Virus. The major inducible 70 kDa heat shock protein (hsp70) protects against measles virus (MeV) neurovirulence in the mouse that is caused by a cell-associated non-cytolytic neuronal infection. Protection is type I interferon (IFN) dependent, and we have established a novel axis of antiviral immunity in which hsp70 is released from virus-infected neurons to induce IFN-β in macrophages. The present work used vesicular stomatitis virus (VSV) to establish the relevance of hsp70-dependent antiviral immunity to fulminant cytopathic neuronal infections. In vitro, hsp70 that was constitutively expressed in mouse neuronal cells caused a modest increase in VSV replication. Infection induced an early extracellular release of hsp70 from viable cells, and the release was progressive, increasing with virus-induced apoptosis and cell lysis. The impact of this VSV-hsp70 interaction on neurovirulence was established in weanling male hsp70 transgenic and non-transgenic mice. Constitutive expression of hsp70 in neurons of transgenic mice enhanced viral clearance from brain, reduced mortality, and was correlated to enhanced expression of type I IFN mRNA. Non-transgenic mice were also protected against neurovirulence and expressed increased type I IFN mRNA in brain when hsp70 was expressed by a recombinant VSV (rVSV-hsp70), indicating that hsp70 in the virus infected cell is sufficient for host protection. In vitro data confirmed extracellular release of hsp70 from cells infected with VSV-hsp70, and also showed that viral replication is not enhanced when hsp70 is expressed in this manner, suggesting that hsp70-mediated protection in vivo is not dependent on stimulatory effects of hsp70 on virus gene expression. 23847314 Association Study in a South Indian Population Supports rs1015213 as a Risk Factor for Primary Angle Closure. Three loci defined by single nucleotide polymorphisms (SNPs) rs11024102 in PLEKHA7, rs3753841 in COL11A1, and rs1015213 between the PCMTD1 and ST18 genes, recently have been associated with primary angle closure glaucoma (PACG). We explored the genetic association of these SNPs with subtypes of primary angle closure in a South Indian population. The study included three case definitions: primary angle closure/primary angle closure glaucoma (PAC/PACG, N = 180); primary angle closure suspect (PACS, N = 171), and a combined any-angle closure group. Controls consisted of 411 individuals from South India. Genotyping for all three SNPs was performed using the TaqMan allelic discrimination assay. Genetic association was estimated using a χ(2) test statistics and logistic regression. Among the three studied SNPs, significant genetic association was identified for rs1015213 in the PAC/PACG (P = 0.002) and any-angle closure (P = 0.003) analyses. However, no significant genetic association was seen when in PACS subjects (P = 0.052). SNPs rs3753841 and rs11024102 showed no evidence of genetic association with angle-closure phenotypes (P > 0.05) in South Indian participants. In our study, rs1015213 (located in the intergenic region between PCMTD1 and ST18) was associated significantly with PAC/PACG, confirming prior reports of an association between this region and angle closure glaucoma. Further work with a larger sample size is necessary to confirm the importance of COL11A1 and PLEKHA7 in the pathogenesis of glaucoma. 23432429 Binding of Diverse Environmental Chemicals with Human Cytochromes P450 2A13, 2A6, and 1B1 and Enzyme Inhibition. A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with P450 2A13 than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for P450 2A13. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with P450 2A13. Coumarin 7-hydroxylation, catalyzed by P450 2A13, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of P450 2A13, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of P450 2A13. The metabolism of chemicals by P450 2A13 during the assays explained why some of the chemicals that bound well were poor inhibitors of P450 2A13. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of P450 2A13 with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that P450 2A13, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest. 23872412 Pathogenesis of diabetic neuropathy: Focus on neurovascular mechanisms. Neuropathies of the peripheral and autonomic nervous systems affect up to half of all people with diabetes, and are major risk factors for foot ulceration and amputation. The aetiology is multifactorial: metabolic changes in diabetes may directly affect neural tissue, but importantly, neurodegenerative changes are precipitated by compromised nerve vascular supply. Experiments in animal models of diabetic neuropathy suggest that similar metabolic sequelae affect neurons and vasa nervorum endothelium. These include elevated polyol pathway activity, oxidative stress, the formation of advanced glycation and lipoxidation end products, and various pro-inflammatory changes such as elevated protein kinase C, nuclear factor κB and p38 mitogen activated protein kinase signalling. These mechanisms do not work in isolation but strongly interact in a mutually facilitatory fashion. Nitrosative stress and the induction of the enzyme poly (ADP-ribose) polymerase form one important link between physiological stressors such as reactive oxygen species and the pro-inflammatory mechanisms. Recently, evidence points to endoplasmic stress and the unfolded protein response as forming another crucial link. This review focuses on the aetiopathogenesis of neurovascular changes in diabetic neuropathy, elucidated in animal studies, and on putative therapeutic targets the majority of which have yet to be tested for efficacy in clinical trials. 23897433 Molecular characterisation of two homoeologous elicitor-responsive lipin genes in cotton. The identification and molecular characterisation of two lipin-like gene copies (GhLIPN) in cotton, Gossypium hirsutum, an allotetraploid derived from two progenitor diploid Gossypium species, is described. Sequence analyses of the GhLIPN copies, designated GhLIPN-1 and -2, revealed that they contain 11 exons, separated by ten introns. They each have a 2,643 bp open reading frame that encodes 880 aa proteins, and share a 97.7 and 95.5 % sequence similarity at the translated nucleotide and amino acid level, respectively. The GhLIPN genes have a distinct domain architecture consisting of an archetypical N-terminal lipin domain, followed by a haloacid dehalogenase (HAD) domain towards the C-terminus. A Southern blot did not distinguish between the two gene copies, which suggests that they may be homoeologs rather than paralogs. GhLIPN-2 is more similar to a homoeologous sequence from G. raimondii, representing the ancestral D-genome, compared to GhLIPN-1 that matches G. herbaceum and that represents the A-genome. Our data indicate that GhLIPN-1 and GhLIPN-2 are homoeologs that derive from the A- and the D-diploid genomes, respectively. The promoter sequences of GhLIPN-1 and -2 differ by 56 %, as a result of multiple indels. In silico analysis of the promoter regions revealed that both genes contain numerous putative defence-related and elicitor-responsive cis-elements that support a role for GhLIPN in defence responses. Relative quantification real-time PCR confirmed the up-regulation in response to a cell-wall-derived V. dahliae elicitor, which supported the association of GhLIPN with defence signalling. The results add a new dimension to the proposed roles of lipins in plants by suggesting that lipins may have a role in defence signalling. 23795558 Preparation of anti-Vicinal Amino Alcohols: Asymmetric Synthesis of d-erythro-Sphinganine, (+)-Spisulosine, and d-ribo-Phytosphingosine. Two variations of the Overman rearrangement have been developed for the highly selective synthesis of anti-vicinal amino alcohol natural products. A MOM ether-directed palladium(II)-catalyzed rearrangement of an allylic trichloroacetimidate was used as the key step for the preparation of the protein kinase C inhibitor d-erythro-sphinganine and the antitumor agent (+)-spisulosine, whereas the Overman rearrangement of chiral allylic trichloroacetimidates generated by the asymmetric reduction of an α,β-unsaturated methyl ketone allowed rapid access both to d-ribo-phytosphingosine and l-arabino-phytosphingosine. 23908236 Two dimensions of value: dopamine neurons represent reward but not aversiveness. Whereas reward (appetitiveness) and aversiveness (punishment) have been distinguished as two discrete dimensions within psychology and behavior, physiological and computational models of their neural representation have treated them as opposite sides of a single continuous dimension of "value." Here, I show that although dopamine neurons of the primate ventral midbrain are activated by evidence for reward and suppressed by evidence against reward, they are insensitive to aversiveness. This indicates that reward and aversiveness are represented independently as two dimensions, even by neurons that are closely related to motor function. Because theory and experiment support the existence of opponent neural representations for value, the present results imply four types of value-sensitive neurons corresponding to reward-ON (dopamine), reward-OFF, aversive-ON, and aversive-OFF. 23955382 A Comparison of Retinyl Palmitate and Red Palm Oil β-Carotene as Strategies to Address Vitamin A Deficiency. Vitamin A deficiency continues to be an international public health problem with several important health consequences including blindness and overall increased rates of morbidity and mortality. To address this widespread issue, a series of strategies have been put into place from dietary diversification to supplementation and fortification programs. Retinyl palmitate has been used successfully for decades as a supplement as well as a way to fortify numerous foods, including vegetable oil, rice, monosodium glutamate, cereal flours and sugar. Recently, there has been rising interest in using a natural source of carotenoids, β-carotene from red palm oil (RPO), for fortification. Although RPO interventions have also been shown to effectively prevent Vitamin A deficiency, there are numerous challenges in using beta-carotene from RPO as a fortification technique. β-Carotene can induce significant changes in appearance and taste of the fortified product. Moreover, costs of fortifying with beta-carotene are higher than with retinyl palmitate. Therefore, RPO should only be used as a source of Vitamin A if it is produced and used in its crude form and regularly consumed without frying. Furthermore, refined RPO should be fortified with retinyl palmitate, not β-carotene, to ensure that there is adequate Vitamin A content. 23578654 Hemocyanin-derived phenoloxidase activity: A contributing factor to hyperpigmentation in Nephrops norvegicus. The phenomenon of hyperpigmentation (melanosis) in shellfish has long been attributed to phenoloxidase enzymes. Over the last number of years, the oxygen carrier hemocyanin, has demonstrated several immune- and physiological functionalities, most notably, inducible phenoloxidase activity. In this study, hemocyanin purified from the hemolymph of Nephrops norvegicus displays diphenoloxidase activity in the presence of a number of elicitors and retains structural and functional integrity throughout the process of freeze-thawing (at -25°C). Conversely, cellular phenoloxidase activity (present in cell-lysates), demonstrates >98% reduction in activity after freeze-thawing. We present evidence that hemocyanin may act as a causative agent of hyperpigmentation in N. norvegicus. The inhibition of hemocyanin-derived phenoloxidase activity is discussed, and for the first time, the biophysical interactions of shellfish hemocyanin with known phenoloxidase inhibitors are presented. 23044046 Angiogenesis is required for stress fracture healing in rats. Although angiogenesis and osteogenesis are critically linked, the importance of angiogenesis for stress fracture healing is unknown. In this study, mechanical loading was used to create a non-displaced stress fracture in the adult rat forelimb. Fumagillin, an anti-angiogenic agent, was used as the water soluble analogue TNP-470 (25mg/kg) as well as incorporated into lipid-encapsulated α(v)β(3) integrin targeted nanoparticles (0.25mg/kg). In the first experiment, TNP-470 was administered daily for 5 days following mechanical loading, and changes in gene expression, vascularity, and woven bone formation were quantified. Although no changes in vascularity were detected 3 days after loading, treatment-related downregulation of angiogenic (Pecam1) and osteogenic (Bsp, Osx) genes was observed at this early time point. On day 7, microCT imaging of loaded limbs revealed diminished woven bone formation in treated limbs compared to vehicle treated limbs. In the second experiment, α(v)β(3) integrin targeted fumagillin nanoparticles were administered as before, albeit with a 100-fold lower dose, and changes in vascularity and woven bone formation were determined. There were no treatment-related changes in vessel count or volume 3 days after loading, although fewer angiogenic (CD105 positive) blood vessels were present in treated limbs compared to vehicle treated limbs. This result manifested on day 7 as a reduction in total vascularity, as measured by histology (vessel count) and microCT (vessel volume). Similar to the first experiment, treated limbs had diminished woven bone formation on day 7 compared to vehicle treated limbs. These results indicate that angiogenesis is required for stress fracture healing, and may have implications for inducing rapid repair of stress fractures. 23708372 XRD and FTIR studies the effect of heat treatment and doping the transition metal oxide on LiNbO3 and LiNb3O8 nano-crystallite phases in lithium borate glass system. Glasses of various compositions in the system 90 Li2B4O710 Nb2O5 mixed with T.M ions (where T.M is the transition metal) were prepared by quenching technique. Heat-treatment of the parent glasses was performed at 540, 570 and 620°C, for 5 and 16h. The glass structure evolution during the controlled crystallization was examined by XRD and FT-IR spectroscopy analysis. The crystalline phases present in the glass ceramics were identified via X-ray diffraction as a function of heat treatment. The FT-IR data propose for these glasses and heat-treated glass network structures mainly built by: di-, tri-, tetra-, penta-and ortho-borate groups. It was found that the quantitative evolution of these various borate species in the glass structures is influenced by the transition metal. A detailed discussion relating to the N4 evolution with the T.M content was made. 23931472 Impact of thiazolidinediones on macular thickness and volume in diabetic eyes. To assess the impact of thiazolidinedione (TZDs) use on macular thickness and volume in patients with diabetes with no macular edema and no diabetic retinopathy (DR) or mild nonproliferative diabetic retinopathy (NPDR). Cross-sectional prospective pilot study. One hundred twenty patients (60 in each group) were enrolled, but 108 completed the study (59 in the TZD group and 49 in the non-TZD group). Patients with type II diabetes mellitus were categorized into 2 groups depending on TZD intake. Those with no prior history of treatment for DR were considered for the study. Patients in both groups had assessment of visual acuity and dilated fundus examination. Only patients with no evidence of macular edema and no DR or mild-NPDR were included. Spectral-domain ocular coherence tomography (SD-OCT) was used for measurement of central retinal thickness (CRT) and macular volume. Main outcome measure was difference in mean macular volume and central thickness between the TZD and the non-TZD groups. Baseline demographics and characteristics were well matched between both groups. There was no significant difference in mean CRT of both groups (p = 0.13), but macular volume was significantly lower in the TZD group (p = 0.038). Patients with no macular edema and no DR or mild NPDR on TZDs did not show evidence of fluid retention in the macula on SD-OCT. Larger studies are needed to confirm these results. 23948080 Response of miRNAs and their targets to salt and drought stresses in cotton (Gossypium hirsutum L.). MicroRNAs (miRNAs) are an important gene regulator, controlling almost all biological and metabolic processes, in both plants and animals. In this study, we investigated the effect of drought and salinity stress on the expression of miRNAs and their targets in cotton (Gossypium hirsutum L.). Our results show that the expression change of miRNAs and their targets were dose-dependent and tissue-dependent under salinity and drought conditions. The expression of miRNAs in leaf was down-regulated under higher salinity stress while shows variable patterns in other conditions. The highest fold-changes of miRNAs were miR398 in roots with 28.9 fold down-regulation under 0.25% NaCl treatment and miR395 in leaves with 7.6 fold down-regulation under 1% PEG treatment. The highest up-regulation of miRNA targets was AST in roots with 4.7 fold-change under 2.5% PEG and the gene with highest down-regulation was CUC1 in leaves with 25.6 fold-change under 0.25% NaCl treatment. Among seven miRNA-target pairs we studied, five pairs, miR156-SPL2, miR162-DCL1, miR159-TCP3, miR395-APS1 and miR396-GRF1, show significant regulation relationship in roots and leaves under salinity stress concentration. 23860335 Maternal prepregnancy weight status and associations with children's development and disabilities at kindergarten. Objective:Obesity is prevalent among women of reproductive age, and developmental disabilities in children continue to increase. We examined associations between mother's prepregnancy body mass index (BMI) and physical and developmental disabilities, and objective measures of reading and math skills and fine and gross motor function in children.Methods:We used the Early Childhood Longitudinal Study-Birth Cohort (ECLS-B; n=5200), a cohort of children born in 2001 and followed until kindergarten. Children were classified according to maternal prepregnancy BMI (in kg per m(2)): underweight (BMI <18.5), normal weight (BMI 18.5-24.9), overweight (BMI 25.0-29.9), obese class I (BMI 30.0-34.9) and obese class II/III (BMI 35.0). Parent reports of doctor-diagnosed disabilities were collected up to kindergarten and classified as learning and behavioral or physical. Children's reading and math and fine and gross motor function were assessed at kindergarten according to standardized tests. Linear and modified logistic regression models were adjusted for maternal sociodemographic variables, family enrichment variables, and children's sex, age and year of kindergarten entry. Additional adjustment for current child BMI was performed in separate models. All data are weighted to be nationally representative of the children born in 2001.Results:Compared with children of normal-weight mothers, children born to obese class II/III mothers had an increased risk of learning or behavioral (risk ratio 1.67; 95% confidence interval 1.27, 2.21)), but not physical disabilities (risk ratio 0.57; 95% confidence interval 0.27, 1.22). Gross (P<0.001), but not fine (P=0.06) motor function was significantly associated with maternal BMI, but gross motor function was attenuated after adjustment for current child BMI (P=0.05). Children's reading scores (P=0.01) but not math scores (P=0.11) were significantly associated with maternal BMI.Conclusions:In this nationally representative US cohort, children born to severely obese mothers had an increased risk for diagnosed learning and behavioral but not physical disabilities by kindergarten.International Journal of Obesity advance online publication, 6 August 2013; doi:10.1038/ijo.2013.128. 23617563 Physiotherapeutic approach in early and late post-menopausal Brazilian women. Abstract To evaluate changes in joints after physiotherapy in post-menopausal women, specifically to identify clinical responses to the measurements of flexibility, functional capacity and joint pain in early and late post-menopausal women at a multi-disciplinary health education programme. A total of 69 women participated in the Integral Program for the Attention to Climacteric Women at the Department of Gynecology - Federal University of Sao Paulo and were sorted into two groups of early (n = 32) and late (n = 37) post-menopause. The average age of menopause was 47.9 ± 5.6 years. The Blatt Kupperman Menopausal Index scores for the early (baseline = 12.8 ± 6.1) and late (baseline = 14.1 ± 7.7) post-menopausal groups after the programme were 8.4 ± 7.1 and 9.4 ± 8.1, respectively. Both groups presented improvements regarding functional capacity (p < 0.01) and complaints of pain (p < 0.001) after the intervention. The group of early post-menopausal women had better flexibility for hip flexion (p < 0.001), and the late post-menopausal group showed greater improvement in shoulder flexion (p < 0.001), extension (p < 0.001) and elbow flexion (p < 0.001). After multi-disciplinary approach, both early and late post-menopausal groups experienced decrease in intensity of climacteric symptoms, reduction in pain intensity and improvement in functional capacity, but the flexibility was different between both the groups. 23402799 Scrub typhus complicated by acute respiratory distress syndrome and acute liver failure: a case report from Northeast India. Acute respiratory distress syndrome (ARDS) is a serious complication of scrub typhus. Only a few cases of scrub typhus complicated by ARDS have been discussed in the literature to date. Herein we report the case of a patient who presented with scrub typhus complicated by ARDS and acute liver failure (ALF) and who was successfully treated in our institute. Due to the non-specificity and diversity of the initial presenting symptoms, a lack of awareness about the disease amongst physicians, and the lack of accessibility to facilities for serodiagnosis in developing countries, there is a chance of misdiagnosis during the early stage. At the same time, early diagnosis and prompt treatment are crucial to prevent life-threatening complications. Our patient was initially misdiagnosed with a common cold and then malaria. By the time a correct diagnosis was made, complications had already developed. To the best of our knowledge, this is the first case of scrub typhus complicated by ARDS and ALF to be reported from the northeastern region of India. 23391838 Secondary degeneration detected by combining voxel-based morphometry and tract-based spatial statistics in subcortical strokes with different outcomes in hand function. Secondary degeneration of the pyramidal tract after focal motor pathway stroke has been observed by diffusion tensor imaging. However, the relationships between outcomes in hand function and secondary degeneration in widespread regions are not well understood. For the first time, we investigated the differences of secondary degeneration across the whole brain between subgroups of patients with stroke. We selected 23 patients who had a subcortical stroke in the left motor pathway and displayed only motor deficits. The patients were divided into 2 subgroups: CPH (11 patients) and PPH (12 patients). Twelve healthy controls matched for age and handedness were also recruited. We used both optimized VBM and TBSS to explore differences of FA across the whole brain between CPH and PPH. Furthermore, ROI analysis was carried out in the identified regions detected by VBM analysis to further quantify the degree of secondary degeneration in the CPH and PPH and compare these with healthy controls. Compared with PPH, FA was significantly decreased in the CPH in widespread regions of the motor system remote from the primary lesion, including the ipsilesional brain stem, medial frontal gyrus, precentral gyrus, superior temporal gyrus, supplementary motor area, and contralesional postcentral gyrus. In addition, FA within these identified regions correlated with Fugl-Meyer Assessment scores (hand+wrist). This study suggests a potential biomarker for outcome differences in hand function after subcortical stroke. 23211937 l-DOPA modifies the antidepressant-like effects of reboxetine and fluoxetine in rats. Nowadays the most widely used antidepressants are selective serotonin reuptake inhibitors (SSRI) or noradrenaline reuptake inhibitors (NRI), however, these take four to eight weeks to exert their effects and each drug is efficacious only in 60-70% of patients. In an attempt to improve the efficacy of antidepressants, new drugs that also modify dopamine levels are being developed. The aim of this study was to investigate the impact of l-DOPA administration on the effect elicited by antidepressants on serotonergic and noradrenergic neurotransmission. To this end, single-unit extracellular recordings of the noradrenergic nucleus, locus coeruleus (LC), and the serotonergic nucleus, dorsal raphe (DRN) combined with behavioural approaches were performed. l-DOPA did not modify the basal neuronal activity in either the LC or the DRN or induce any change in the modified forced swimming test. However, l-DOPA enhanced the neuronal response to reboxetine in the LC and increased its antidepressant-like effects but counteracted the effect of fluoxetine on neurons in the LC and decreased its antidepressant-like effect. The sensitivity of neurons in the DRN to reboxetine and fluoxetine was not altered by the administration of l-DOPA. Taken together, these results indicate that l-DOPA modifies the effect of SSRI and NRI antidepressants in opposing ways. 23211523 β-catenin regulates GnRH-induced FSHβ gene expression. The regulation of gonadotropin synthesis by GnRH plays an essential role in the neuroendocrine control of reproduction. The known signaling mechanisms involved in gonadotropin synthesis have been expanding. For example, involvement of β-catenin in LHβ induction by GnRH has been discovered. We examined the role of β-catenin in FSHβ gene expression in LβT2 gonadotrope cells. GnRH caused a sustained increase in nuclear β-catenin levels, which was significantly reduced by c-Jun N-terminal kinase (JNK) inhibition. Small interfering RNA-mediated knockdown of β-catenin mRNA demonstrated that induction of FSHβ mRNA by GnRH depended on β-catenin and that regulation of FSHβ by β-catenin occurred independently of the JNK-c-jun pathway. β-Catenin depletion had no impact on FSHβ mRNA stability. In LβT2 cells transfected with FSHβ promoter luciferase fusion constructs, GnRH responsiveness was conferred by the proximal promoter (-944/-1) and was markedly decreased by β-catenin knockdown. However, none of the T-cell factor/lymphoid enhancer factor binding sites in that region were required for promoter activation by GnRH. Chromatin immunoprecipitation further corroborated the absence of direct interaction between β-catenin and the 1.8-kb FSHβ promoter. To elucidate the mechanism for the β-catenin effect, we analyzed approximately 1 billion reads of next-generation RNA sequencing β-catenin knockdown assays and selected the nuclear cofactor breast cancer metastasis-suppressor 1-like (Brms1L) as one candidate for further study. Subsequent experiments confirmed that Brms1L mRNA expression was decreased by β-catenin knockdown as well as by JNK inhibition. Furthermore, knockdown of Brms1L significantly attenuated GnRH-induced FSHβ expression. Thus, our findings indicate that the expression of Brms1L depends on β-catenin activity and contributes to FSHβ induction by GnRH. 23859976 Absorption in Self-Selected Activities Is Associated With Lower Ambulatory Blood Pressure but Not for High Trait Ruminators. A range of nonpharmacological interventions (e.g., meditation) have positive effects on blood pressure (BP) but tend to have poor adherence. These interventions may lower BP partly by absorbing and directing attention away from one's negative thoughts. We hypothesized that recurring self-selected activities (SSAs) that are attentionally absorbing may similarly lower BP. We examined the effect of reported engagement in SSAs during the previous month prior to participation on ambulatory BP (ABP) and whether those prone to rumination were less likely to show these effects. Participants (n = 38) reported engagement in SSAs and how absorbing they were, responded to trait rumination and perceived stress questionnaires, wore an ABP monitor for 24 hours, and at each ABP measurement answered electronic diary questions assessing activity levels, affect, social interactions, and caffeine and tobacco use. Regression analyses tested whether the reported absorption of SSAs, trait rumination, and their interaction predicted daytime and nighttime systolic and diastolic ABP. Greater absorption predicted lower daytime and nighttime ABP (bs = -18.83 to -8.79; Ps < .05), but this relationship was moderated by trait rumination (bs = 3.72 to 9.97; Ps < .05). Follow-up analyses revealed that absorption was unrelated to ABP for those with high trait rumination but that more absorption predicted lower ABP for those less prone to rumination. Our results suggest that regular engagement in absorbing SSAs is related to lower ABP. These findings have implications for the development of nonpharmacological interventions and suggest SSAs may serve as an adjuvant intervention strategy to lower BP. 23964275 Antigen and transforming growth factor Beta receptors contribute to long term functional and phenotypic heterogeneity of memory CD8 T cells. Pathogen-specific CD8 T cells provide a mechanism for selectively eliminating host cells that are harboring intracellular pathogens. The pathogens are killed when lytic molecules are injected into the cytoplasm of the infected cells and begin an apoptotic cascade. Activated CD8 T cells also release large quantities of pro-inflammatory cytokines that stimulate other immune cells in the local vicinity. As the alveoli are extraordinarily sensitive to cytokine induced damage, multiple layers of immune regulation limit the activities of immune cells that enter the lungs. These mechanisms include receptor-mediated signaling pathways in CD8 T cells that respond to peptide antigens and transforming growth factor β. Both pathways influence the functional and phenotypic properties of long-lived CD8 T cells populations in peripheral and lymphoid tissues. 23855984 Insights into TREM2 biology by network analysis of human brain gene expression data. Rare variants in TREM2 cause susceptibility to late-onset Alzheimer's disease. Here we use microarray-based expression data generated from 101 neuropathologically normal individuals and covering 10 brain regions, including the hippocampus, to understand TREM2 biology in human brain. Using network analysis, we detect a highly preserved TREM2-containing module in human brain, show that it relates to microglia, and demonstrate that TREM2 is a hub gene in 5 brain regions, including the hippocampus, suggesting that it can drive module function. Using enrichment analysis we show significant overrepresentation of genes implicated in the adaptive and innate immune system. Inspection of genes with the highest connectivity to TREM2 suggests that it plays a key role in mediating changes in the microglial cytoskeleton necessary not only for phagocytosis, but also migration. Most importantly, we show that the TREM2-containing module is significantly enriched for genes genetically implicated in Alzheimer's disease, multiple sclerosis, and motor neuron disease, implying that these diseases share common pathways centered on microglia and that among the genes identified are possible new disease-relevant genes. 23938054 Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice. In autosomal recessive early-onset Parkinsonism (PARK2), the pathogenetic process from the loss of function of a ubiquitin ligase parkin to the death of dopamine neurons remains unclear. A dominant hypothesis attributes the neurotoxicity to accumulated substrates that are exempt from parkin-mediated degradation. Parkin substrates include two septins; SEPT4/CDCrel-2 which coaggregates with α-synuclein as Lewy bodies in Parkinson's disease, and its closest homolog SEPT5/CDCrel-1/PNUTL1 whose overload with viral vector can rapidly eliminate dopamine neurons in rats. However, chronic effects of pan-neural overload of septins have never been examined in mammals. To address this, we established a line of transgenic mice that express the largest gene product SEPT454kDa via the prion promoter in the entire brain. Histological examination and biochemical quantification of SEPT4-associated proteins including α-synuclein and the dopamine transporter in the nigrostriatal dopamine neurons found no significant difference between Sept4Tg/+ and wild-type littermates. Thus, the hypothetical pathogenicity by the chronic overload of SEPT4 alone, if any, is insufficient to trigger neurodegenerative process in the mouse brain. Intriguingly, however, a systematic battery of behavioral tests revealed unexpected abnormalities in Sept4Tg/+ mice that include consistent attenuation of voluntary activities in distinct behavioral paradigms and altered social behaviors. Together, these data indicate that septin dysregulations commonly found in postmortem human brains with Parkinson's disease, schizophrenia and bipolar disorders may be responsible for a subset of behavioral abnormalities in the patients. 23891102 Phase II trial of proton beam accelerated partial breast irradiation in breast cancer. Here, we report the results of our phase II, prospective study of proton beam accelerated partial breast irradiation (PB-APBI) in patients with breast cancer after breast conserving surgery (BCS). Thirty patients diagnosed with breast cancer were treated with PB-APBI using a single-field proton beam or two fields after BCS. The treatment dose was 30 cobalt gray equivalent (CGE) in six CGE fractions delivered once daily over five consecutive working days. All patients completed PB-APBI. The median follow-up time was 59months (range: 43-70months). Of the 30 patients, none had ipsilateral breast recurrence or regional or distant metastasis, and all were alive at the last follow-up. Physician-evaluated toxicities were mild to moderate, except in one patient who had severe wet desquamation at 2months that was not observed beyond 6months. Qualitative physician cosmetic assessments of good or excellent were noted in 83% and 80% of the patients at the end of PB-APBI and at 2months, respectively, and decreased to 69% at 3years. A good or excellent cosmetic outcome was noted in all patients treated with a two-field proton beam at any follow-up time point except for one. For all patients, the mean percentage breast retraction assessment (pBRA) value increased significantly during the follow-up period (p=0.02); however, it did not increase in patients treated with two-field PB-APBI (p=0.3). PB-APBI consisting of 30 CGE in six CGE fractions once daily for five consecutive days can be delivered with excellent disease control and tolerable skin toxicity to properly selected patients with early-stage breast cancer. Multiple-field PB-APBI may achieve a high rate of good-to-excellent cosmetic outcomes. Additional clinical trials with larger patient groups are needed. 23666204 Prediagnostic body weight and survival in high grade glioma. Greater adiposity has been linked to an increased risk and/or poorer survival in a variety of cancers. We examined whether prediagnostic body weight 1-5 years prior to diagnosis is associated with survival in patients with high grade glioma. The analysis was based on a series of patients with high-grade glioma (N = 853) enrolled in a US-based multicenter case-control study. Subjects reported height and weight 1-5 years prior to interview and at age 21. BMI was categorized according to WHO criteria as underweight (BMI <18.5 kg/m(2)), normal weight (BMI 18.5-24.9 kg/m(2)), overweight (BMI 25-29.9 kg/m(2)) and obese (BMI ≥30 kg/m(2)). Proportional hazards regression was used to estimate hazard ratios (HR) and 95 % confidence intervals (CIs) for glioma-related death according to body mass index (BMI, kg/m(2)). Overall survival was reduced among patients underweight (median survival: 12.0 months) or obese (median: 13.6 months) when compared to patients of normal weight (median: 17.5 months) prior to glioma diagnosis (p = 0.004). In a multivariate model controlling for other prognostic factors, an excess mortality was observed in patients reporting obese body weights 1-5 years prior to study interview when compared to patients with a normal BMI (HR = 1.32; 95 % CI 1.04-1.68). Consistent patterns of association with excess body weight were observed in men and women, and all findings were similar regardless of treatment for glioma. A lower than optimal body weight was associated with a nonsignificant excess mortality in multivariate analysis. Premorbid obesity was significantly associated with a poor patient outcome independent of treatment and established prognostic factors. Excess body weight may be an adverse prognostic factor in glioma, a relationship observed across a spectrum of cancer types. The current findings linking prediagnostic body weight with mortality in high-grade glioma warrant further research. 23657140 Blood volume determination, a nuclear medicine test in evolution. The method for determining blood volume has evolved substantially since first attempts were made in the latter part of the nineteenth century with the exsanguination of animals. The now accepted methods are based on indicator dilution methodologies. First attempts utilized inert dyes such as Evans Blue and Cardiogreen. These were found to be impractical due, primarily, to their rapid clearance from the blood. For many years, the most accepted method for blood volume determination was the dual isotope technique. This procedure utilizes chromium 51 or 99mTc to label autologous red cells and radioiodine 125 or 131 to label human serum albumin (HSA). Plasma and red cell volumes are measured separately and the results "combined". The procedure requires on-site labeling of autologous red cells and HSA, and meticulous preparation of standards and doses. The complexity of this method leads to performance times of 6 to 8 hours. An FDA-approved single isotope method is now employed in over 60 major institutions. HSA is labeled with radioiodine 131 at an FDA radiopharmaceutical facility, and test doses and standards are provided to laboratories in kit form. The red cell volume is derived by a calculation utilizing the measured plasma volume and the value for the average whole-body hematocrit. All calculations are carried out by a dedicated microprocessor, and a final report is generated and printed. The results are compared with predicted normal values for male and female patients based on percentage deviation from normal weight. Preliminary results are available in 30 minutes and complete calculations in 90 minutes. 23959425 Crkl Efficiently Mediates Cell Proliferation, Migration, and Invasion Induced by TGF-β Pathway in Glioblastoma. Crk-like (CrkL) is an adapter protein that has crucial roles in cell proliferation, adhesion, and migration. However, the expression pattern and potential mechanism of CrkL protein in glioblastoma multiforme (GBM) have not been fully elucidated. To determine roles of CrkL in cell signaling, proliferation, and migration, small interfering RNAs and plasmids transfection were used to suppress or overexpress CrkL in U87 and U251; soft-agar assay and wound-healing assay were used to observe cell invasiveness, migration, and proliferation. Erk1/2, Smad2, and matrix metalloproteinase 9 (MMP9) were also analyzed by western blot. CrkL was expressed in U87 and U251 cell lines and can be activated by transforming growth factor-beta 1 (TGF-β1) in vitro; CrkL knockdown significantly suppressed the expression of phosph-ERK1/2 and MMP9 but enhanced phosph-Smad2 expression compared with control (p < 0.001). Overexpression of CrkL against control upregulated phosph-ERK1/2 and MMP9 and, at the same time, downregulated phosph-Smad2 (p < 0.01). On the other hand, CrkL knockdown could significantly affect U87 and U251 invasiveness (p < 0.01) and wound closure (p < 0.01) using soft-agar assay and wound-healing assay. These studies suggest that CrkL efficiently mediates cell proliferation, migration, and invasion induced by TGF-β pathway in glioblastoma. Furthermore, CrkL can be used as a potential and efficient therapeutic target of GBM and may also mediate other signaling pathway. 23216071 Autophagy and Bcl-2/BNIP3 death regulatory pathway in non-small cell lung carcinomas. We recently showed that non-small cell lung carcinomas (NSCLCs) are of dismal prognosis when encompassing accelerated autophagic activity. The regulation of this abnormally functioning degradation system and its association with hypoxia and apoptosis in lung carcinoma patients is unexplored. In this study we used 115 NSCLC tissues to examine the immunohistochemical expression of four distinct molecules - the major regulator of autophagy Beclin 1, the anti-apoptotic and anti-autophagic protein Bcl-2, the pro-apoptotic and pro-autophagic protein BNIP3, and a marker of hypoxia and glucolysis, the glucose transporter Glut 1. Most cases showed reduced reactivity for Beclin 1 (62%) and Bcl-2 (82%) proteins, almost half of our sample revealed strong BNIP3 expression (57%), whereas most of the carcinomas strongly expressed Glut 1 antigen (71%). Beclin 1 expression showed no association with survival. Bcl-2 positivity was a marker of good prognosis (p = 0.04), whereas BNIP3 (p = 0.0004) and Glut 1 (p = 0.03) expression correlated with poor outcome in Stage I disease. Autophagic status was negatively associated with Bcl-2 (p = 0.0006), but positively with Glut 1 expression (p = 0.001). In conclusion, the accelerated autophagic status in NSCLC is unrelated to Beclin 1 and BNIP3 expression, but does show significant association with Bcl-2 reactivity. Furthermore, we showed important correlations between glucolysis and autophagy, guiding new pathways in future lung carcinoma research. 23892623 Bioethanol Production from Ipomoea Carnea Biomass Using a Potential Hybrid Yeast Strain. The paper deals with the exploitation of Ipomoea carnea as a feedstock for the production of bioethanol. Dilute acid pretreatment under optimum conditions (3 %H2SO4, 120 °C for 45 min) produced 17.68 g L(-1) sugars along with 1.02 g L(-1) phenolics and 1.13 g L(-1) furans. A combination of overliming and activated charcoal adsorption facilitated the removal of 91.9 % furans and 94.7 % phenolics from acid hydrolysate. The pretreated biomass was further treated with a mixture of sodium sulphite and sodium chlorite and, a maximum lignin removal of 81.6 % was achieved. The enzymatic saccharification of delignified biomass resulted in 79.4 % saccharification with a corresponding sugar yield of 753.21 mg g(-1). Equal volume of enzymatic hydrolysate and acid hydrolysate were mixed and used for fermentation with a hybrid yeast strain RPRT90. Fermentation of mixed detoxified hydrolysate at 30 °C for 28 h produced ethanol with a yield of 0.461 g g(-1). A comparable ethanol yield (0.414 g g(-1)) was achieved using a mixture of enzymatic hydrolysate and undetoxified acid hydrolysate. Thus, I. carnea biomass has been demonstrated to be a potential feedstock for bioethanol production, and the use of hybrid yeast may pave the way to produce bioethanol from this biomass. 23625987 Genetic testing in children with surfactant dysfunction. To present the UK experience in genetic diagnoses of surfactant protein dysfunction disorders and develop a referral algorithm for neonates and children with persistent respiratory problems. Between 2006 and 2011, 427 cases were referred for surfactant mutation analyses to the North East Thames Regional Molecular Genetics Laboratory at Great Ormond Street Hospital, London. The results were reviewed and referring physicians of mutation positive cases contacted to complete a questionnaire providing clinical, radiological, histological and outcome information. 25 new cases were found to have genetic mutations for surfactant dysfunction disorders (7.5%), with six resulting in surfactant protein B dysfunction, seven surfactant protein C dysfunction and 12 ATP-binding cassette subfamily A member 3 (ABCA3) dysfunction. The referrals were from 15 different paediatric centres. In addition, three affected surfactant protein B (SFTPB) cases were prenatal diagnoses, following the birth of previously affected children. The majority of the confirmed cases (23 of 25) were born after 37 weeks gestation. All children with SFTPB dysfunction and the majority of ABCA3 patients presented with respiratory distress at birth. All SFTPB cases died from intractable respiratory failure. The outcome for ABCA3 mutations was variable with seven survivors. The clinical and radiological presentation of surfactant protein C (SFTPC) patients suggested mainly interstitial lung process with the majority surviving on medication. Surfactant mutation analysis is now well established in the UK and allows better genetic diagnosis and counselling. The rarity of the condition makes it difficult to develop a validated algorithm for genetic evaluation with a need for international networking. Referrals need to be rationalised for the service to be time and cost effective. 23891787 The impact of a population-level school food and nutrition policy on dietary intake and body weights of Canadian children. The objective of this study is to assess population-level trends in children's dietary intake and weight status before and after the implementation of a provincial school nutrition policy in the province of Nova Scotia, Canada. Self-reported dietary behavior and nutrient intake and measured body mass index were collected as part of a population-level study with grade 5 students in 2003 (n=5215) and 2011 (5508), prior to and following implementation of the policy. We applied random effects regression methods to assess the effect of the policy on dietary and health outcomes. In 2011, students reported consuming more milk products, while there was no difference in mean consumption of vegetables and fruits in adjusted models. Adjusted regression analysis revealed a statistically significant decrease in sugar-sweetened beverage consumption. Despite significant temporal decreases in dietary energy intake and increases in diet quality, prevalence rates of overweight and obesity continued to increase. This population-level intervention research suggests a positive influence of school nutrition policies on diet quality, energy intake and healthy beverage consumption, and that more action beyond schools is needed to curb the increases in the prevalence of childhood obesity. 23906276 Treatment of large cystic medial osteochondral lesions of the talus with autologous osteoperiosteal cylinder grafts. To investigate the clinical, radiologic, and second-look arthroscopic outcomes of autologous iliac crest osteoperiosteal cylinder graft transplantation for medial osteochondral lesions of the talus (OLTs) with large subchondral cysts. Between January 2008 and December 2010, 17 consecutive cases of medial OLT with a subchondral cyst larger than 10 mm in diameter received transplantation of autologous osteoperiosteal cylinder graft, which was harvested from the ipsilateral iliac crest. The visual analog scale score for pain during daily activities, American Orthopaedic Foot & Ankle Society hindfoot and ankle scores, and subjective satisfaction survey rating were obtained. Plain radiographs and magnetic resonance imaging of the ankle were obtained before and after surgery. In 13 cases second-look arthroscopy was performed 12 months postoperatively and the cartilage repair was assessed with the criteria of the International Cartilage Repair Society. Sixteen patients were available for follow-up at a mean of 32.6 months (range, 24 to 48 months). The mean visual analog scale score decreased from 5.51 ± 0.83 preoperatively to 0.98 ± 0.98 at the latest follow-up, and the median American Orthopaedic Foot & Ankle Society score improved from 75 preoperatively to 90 at the latest follow-up. Seven patients resumed sporting activities. Overall, 7 patients rated the result as excellent, 8 as good, and 1 as fair. The radiolucent area of the cysts disappeared on the plain radiographs in all cases. The mean Magnetic Resonance Observation of Cartilage Repair Tissue score was 60 ± 9.4 points, whereas subchondral bone edema persisted on the postoperative magnetic resonance images in 16 cases. The mean International Cartilage Repair Society arthroscopic score for cartilage repair at second-look arthroscopy was 9 ± 1.4 points. Autologous iliac crest osteoperiosteal cylinder graft transplantation with supplemental bone grafting is a simple, safe, and effective procedure for treatment of large cystic medial OLT. It can successfully fill the subchondral cyst and repair the cartilage defect. Level IV, therapeutic case series. 23946011 Quantum dot approaches for target-based drug screening and multiplexed active biosensing. Biomolecule detection using quantum dots (Qdots), nanometer-sized semiconductor crystals, effectively addresses the limitations associated with conventional optical and biochemical techniques, as Qdots offer several key advantages over traditional fluorophores. In this minireview, we discuss the role of Qdots as a central nanoscaffold for the polyvalent assembly of multifunctional biomolecular probes and describe recent advances in Qdot-based biorecognition. Specifically, we focus on Qdot applications in target-based, drug screening assays and real-time active biosensing of cellular processes. 23962523 Sudden unexpected death in epilepsy (SUDEP): Development of a safety checklist. The incidence of sudden death appears to be 20 times higher in patients with epilepsy compared with the general population. Epilepsy-related death, particularly sudden unexpected death in epilepsy (SUDEP), is still underestimated by healthcare professionals and this may reflect the mistaken belief that epilepsy is a benign condition. The risk of death associated with epilepsy appeared rarely to have been discussed with patients or their families. It appears the decision to discuss SUDEP and also to peg SUDEP risk is arbitrary and clinical. Unfortunately there is no structured evidenced mechanism at present to represent person centered risk of SUDEP and there is currently no easy manner or template to have this discussion with the family and the patient. We conducted a detailed literature review in Medline, Embase and Psychinfo databases to extract the common risk factors as evidenced from literature till date. Research into risk factors has identified a number of risk factors for SUDEP, some of which are potentially modifiable. Based on the literature review, we believe that the ascertained risk factors could be employed in clinical practice as a checklist to reduce an individual patient's risk of SUDEP. The SUDEP safety checklist may be of practical use in reducing risks in some individuals and is definitely of use in helping communication. An evidence based checklist identifying the major risk factors can help both clinicians and patients to focus on minimizing certain risk factors and promote safety by focusing on the modifiable factors and guide treatment. It can be a tool to open a person centered discussion with patients and to outline how individual behaviors could impact on risk. 23947658 Arylations of Substituted Enamides by Aryl Iodides: Regio- and Stereoselective Synthesis of (Z)-β-Amido-β-Arylacrylates. Arylations of substituted enamides by aryl iodides were achieved for the first time via an unusual PdCl2(COD)/Ag3PO4 catalytic system. A broad range of (Z)-β-amido-β-arylacrylates were prepared regio- and stereoselectively in a highly efficient manner. 23688141 Resveratrol and analogues: a review of antioxidant activity and applications to human health. Resveratrol has been extensively researched for its powerful antioxidant capacity and other biological effects. The number of patents involving this compound has been growing in recent years. However, the biggest problem associated with this molecule, a limited bioavailability due to its fast metabolism in the liver, has led to obtaining its analogues or derivatives. In this work, we selected patents which describe the application of the antioxidant activity of resveratrol and its analogues as food for the human segment. 23866785 A new type of protein chip to detect hepatocellular carcinoma-related autoimmune antibodies in the sera of hepatitis C virus-positive patients. We report here a new type of protein chip to detect antibodies in sera. This chip method was used to a prototype created to detect hepatocellular carcinoma (HCC) -related autoantibodies in the sera of hepatitis C virus (HCV) infected individuals. Five cysteine-tagged (Cys-tag) and green fluorescent protein (GFP)-fused recombinant heat shock protein 70 (HSP70), superoxide dismutase 2 (SOD2), and peroxiredoxin 6 (PRDX6), were spotted and immobilized on maleimide-incorporated diamond-like carbon (DLC) substrates. The antibodies in diluted sera were trapped by these proteins at each spot on the chip, and visualized by a fluorescence-conjugated anti-human IgG. The total immobilized protein level of each spot was detected with anti-GFP mouse IgG and a fluorescence-conjugated secondary anti-mouse IgG. The ratio between the two fluorescence intensities was used to quantify autoantibody levels in each serum sample. Heat treatment of the chip in a solution of denaturing and reducing agents, before serum-incubation, improved autoantibody detection. We tested serum samples from healthy individuals and HCC patients using the chips. The HSP70 autoantibodies were found at high levels in sera from HCV-positive HCC patients, but not in HCV-negative sera. This protein chip system may have useful properties to capture a specific set of antibodies for predicting the onset of particular cancers such as HCC in HCV-infected individuals. 23744301 Solution phase van der Waals epitaxy of ZnO wire arrays. As an incommensurate epitaxy, van der Waals epitaxy allows defect-free crystals to grow on substrates even with a large lattice mismatch. Furthermore, van der Waals epitaxy is proposed as a universal platform where heteroepitaxy can be achieved irrespective of the nature of the overlayer material and the method of crystallization. Here we demonstrate van der Waals epitaxy in solution phase synthesis for seedless and catalyst-free growth of ZnO wire arrays on phlogopite mica at low temperature. A unique incommensurate interface is observed even with the incomplete initial wetting of ZnO onto the substrate. Interestingly, the imperfect contacting layer does not affect the crystalline and optical properties of other parts of the wires. In addition, we present patterned growth of a well-ordered array with hexagonal facets and in-plane alignment. We expect our seedless and catalyst-free solution phase van der Waals epitaxy synthesis to be widely applicable in other materials and structures. 23917147 Application of a molecular based approach for the early detection of short term 3-chloroaniline shock loads on activated sludge bacterial community and functionality. Microbial processes are central elements in wastewater treatment plants (WWTPs) to mineralize the organic matter, to degrade pollutants and to decrease the amount of suspended solids. This activity can be disrupted by organic and inorganic pollutants present in wastewater streams. Hence, it is of primary importance to investigate and monitor the structure and functionality of the sludge-resident microbial communities. We simulated a 3-chloroaniline (3-CA) shock load in 3-CA adapted and non-adapted semi-continuous activated-sludge (SCAS) reactors to selectively stress the Ammonia Oxidizing Bacteria (AOB). Recently developed setting-independent theoretical interpretation of molecular DNA and RNA fingerprinting patterns were used to evaluate the responses of the microbial populations. Ammonium accumulation in treated reactors upon 3-CA addition confirmed the disruption of the functionality under stress conditions. Molecular analyses coupled to their interpretation highlighted that shock loaded reactors clustered separately from non-treated ones, especially when AOBs community was specifically targeted. Furthermore, the interpretation of RNA-based analyses, as compared to DNA-based ones, allowed to more promptly depicting shifts in a stressed community. We showed that the use of RNA-based molecular tools in combination with a new set of parameters is a powerful tool to link functional failures with microbial structure modifications in WWTPs, providing a potential tool for a rational optimization of the processes (Microbial Resource Management - MRM). 23752513 Complete Sequences of Two Plasmids in a blaNDM-1-Positive Klebsiella oxytoca Isolate from Taiwan. Genetic determinants of a blaNDM-1-positive, multidrug-resistant bacterial isolate that caused active infection was investigated by DNA sequencing. Two plasmids, pKOX_NDM1 and pKOX-R1, were identified for the Klebsiella oxytoca strain E718. Sequence annotation revealed a blaNDM-1 gene in pKOX_NDM1 and two extended-spectrum β-lactamase producers (blaCTX-M-3 and blaSHV-12) and a wide array of resistance genes in pKOX-R1. These findings highlight the difficulty in treating multidrug-resistant bacterial infections and the potential danger of emerging resistant enterobacteria. 23727115 New three-dimensional speckle-tracking echocardiography identifies global impairment of left ventricular mechanics with a high sensitivity in childhood cancer survivors. The aim of this case-control study was to assess the usefulness of three-dimensional (3D) speckle-tracking echocardiography in the evaluation of global left ventricular (LV) myocardial performance in adolescent and adult survivors of childhood cancers. Fifty-three anthracycline-treated survivors of childhood cancers (mean age, 18.6 ± 5.1 years) and 38 controls were studied. Three-dimensional speckle-tracking echocardiography was performed to assess LV 3D global and segmental strain, time to peak segmental 3D strain, LV torsion, and ejection fraction. LV systolic dyssynchrony index (SDI) was calculated as the percentage of the standard deviation of times to peak strain of the 16 segments divided by the RR interval. A global performance index (GPI) was calculated as (global 3D strain × torsion)/SDI. The area under the receiver operating characteristic curve was calculated to determine the capability of various echocardiographic indices to discriminate between patients and controls. Compared with controls, patients had significantly reduced LV global 3D strain (P < .001), torsion (P < .001), and GPI (P < .001) and greater SDI (P < .001). All except the basal anteroseptal segment in patients had reduced regional 3D strain compared with controls (P < .05 for all). Global 3D strain (P = .018), SDI (P = .003), and GPI (P = .02) were correlated with cumulative anthracycline dose. The areas under the curves for GPI, global 3D strain, 1/SDI, torsion, and ejection fraction were 0.92, 0.79, 0.79, 0.79, and 0.78, respectively. A GPI cutoff of 10.6°/cm had sensitivity of 84.9% and specificity of 81.6% of differentiating patients from controls. Three-dimensional speckle-tracking echocardiography enables the derivation of an index of LV global performance that incorporates LV 3D strain, dyssynchrony, and torsion for the sensitive detection of altered LV mechanics in childhood cancer survivors. 23291893 Streptomyces chilikensis sp. nov., a halophilic streptomycete isolated from brackish water sediment. A novel actinobacterial strain, designated RC 1830(T), was isolated from the sediment of estuarine coastal brackish water lagoon of Chilika Lake, in Khurdha district of Odisha, India, and characterized using a polyphasic approach. Strain RC 1830(T) was halophilic and alkali-tolerant and found to hydrolyse chitin, starch, tributyrin, lecithin, Tween 80, cellulose, gelatin and casein. The diagnostic presence of ll-diaminopimelic acid, iso-C15 : 0, anteiso-C15 : 0, iso-C16 : 0, C16 : 0, iso-C17 : 0, anteiso-C17 : 0 as major cellular fatty acids and MK-9(H4 and H6) as major menaquinones noticeably associated the strain to the genus Streptomyces. After comparison and analysis of the near complete 16S rRNA gene sequence with representative strains of other streptomycetes, it was evident that strain RC 1830(T) belonged to the genus Streptomyces, and exhibited the highest sequence similarities of 99.53 %, 99.25 %, 99.11 %, 99.10 % and 99. 06 % to Streptomyces fragilis DSM 40044(T), Streptomyces coelicoflavus NBRC 15399(T), Streptomyces flaveolus NBRC 3715(T), Streptomyces lavenduligrisesus NBRC 13405(T) and Streptomyces eurythermus ATCC 14975(T), respectively. Reconstruction of a phylogenetic tree for the genus Streptomyces revealed that strain RC 1830(T) formed a distinct phyletic line and clustered with its most closely related neighbour S. fragilis DSM 40044(T). The DNA-DNA relatedness values between strain RC 1830(T) and the most closely related type strain S. fragilis DSM 40044(T) were determined to be 17.7±4.55 %. Additionally, morphological, biochemical and physiological tests were able to distinguish the strain from the most closely related type strain S. fragilis DSM 40044(T) and other closely related neighbours, S. coelicoflavus DSM 41471(T) and Streptomyces flaveolus DSM 40061(T). Based on a range of phenotypic and genotypic properties, strain RC 1830(T) is suggested to represent a novel species of the genus Streptomyces for which the name Streptomyces chilikensis sp. nov. is proposed. The type strain is RC 1830(T) ( = JCM 18411(T) = DSM 42072(T)). 23418857 Antibiotic resistance of Helicobacter pylori isolated in the Southeast Coastal Region of China. The resistance of Helicobacter pylori (H. pylori) to antibiotics is increasing worldwide, lowering its efficacy in current eradication therapies. This study evaluated H. pylori resistance to antibiotics in the southeast coastal region of China and suggests appropriate alternatives. Seventeen thousand seven hundred and thirty one H. pylori strains were collected from eight areas of two provinces in coastal southeast China from 2010 to 2012. The resistance of these strains to six antibiotics was tested using the agar dilution method. The resistance rates to clarithromycin, metronidazole, levofloxacin, amoxicillin, gentamicin and furazolidone were 21.5, 95.4, 20.6, 0.1, 0.1 and 0.1%, respectively. Double, triple and quadruple antibacterial resistant percentages were 25.5, 7.5 and 0.1%, respectively. A positive association between the resistance to levofloxacin and to clarithromycin was found, but there was a negative correlation in the resistances to levofloxacin and to metronidazole. The prevalence of H. pylori resistance to clarithromycin, metronidazole, levofloxacin and multiple antibiotics in coastal southeast China is high. Choice of therapy should be individualized based on a susceptibility test in this region of the country. 22431380 Cortical source of blink-related delta oscillations and their correlation with levels of consciousness. Recently, blink-related delta oscillations (delta BROs) have been observed in healthy subjects during spontaneous blinking at rest. Delta BROs have been linked with continuous gathering of information from the surrounding environment, which is classically attributed to the precuneus. Furthermore, fMRI studies have shown that precuneal activity is reduced or missing when consciousness is low or absent. We therefore hypothesized that the source of delta BROs in healthy subjects could be located in the precuneus and that delta BROs could be absent or reduced in patients with disorders of consciousness (DOC). To test these hypotheses, electroencephalographic (EEG) activity at rest was recorded in 12 healthy controls and nine patients with DOC (four vegetative states, and five minimally conscious states). Three-second-lasting EEG epochs centred on each blink instance were analyzed in both time- (BROs) and frequency domains (event-related spectral perturbation or ERSP and intertrial coherence or ITC). Cortical sources of the maximum blink-related delta power, corresponding to the positive peak of the delta BROs, were estimated by standardized Low Resolution Electromagnetic Tomography. In control subjects, as expected, the source of delta BROs was located in the precuneus, whereas in DOC patients, delta BROs were not recognizable and no precuneal localization was possible. Furthermore, we observed a direct relationship between spectral indexes and levels of cognitive functioning in all subjects participating in the study. This reinforces the hypothesis that delta BROs reflect neural processes linked with awareness of the self and of the environment. Hum Brain Mapp 34:2178-2189, 2013. © 2012 Wiley Periodicals, Inc. 23603469 Assessment of exposure to heavy metals and health risks among residents near abandoned metal mines in Goseong, Korea. Metal contamination from mining activity is of great concern because of potential health risks to the local inhabitants. In the present study, we investigated the levels of Cd, Cu, As, Pb, and Zn in environmental samples and foodstuffs grown in the vicinity of the mines in Goseong, Korea, and evaluated potential health risks among local residents. Soils near the mines exceeded the soil quality standard values of Cu, As, and Zn contamination. The concentrations of Cd, Cu, Pb, and Zn in crop samples collected from the study area were significantly higher than those of the reference area. Some rice samples collected from the study area exceeded the maximum permissible level of 0.2 mg Cd/kg. The intake of rice was identified as a major contributor (≥75%) to the estimated daily intake among the residents. The average estimated daily intakes of metals were, however, below the provisional tolerable daily intake. 23940026 Teaching NeuroImages: Diffuse cerebral neurosarcoidosis mimicking gliomatosis cerebri. A 30-year-old man with a history of bipolar disease presented with 6 months of cognitive decline, unsteady gait, urinary retention, and bilateral upper extremity tremors. Multiple punctate enhancing lesions were seen on brain MRI (figure). Differential diagnosis included infection (viral, tuberculosis, or cryptococcus), toxic leukoencephalopathy, gliomatosis cerebri, angiocentric lymphoma, and neurosarcoidosis. CT chest scan, CSF studies, HIV testing, hepatitis panel, drug screen, and vasculitis panel were negative. Brain biopsy revealed neurosarcoidosis. The patient responded well to high-dose steroids and IV cyclophosphamide. MRI in neurosarcoidosis often reveals enhancing periventricular white matter lesions, in this case mimicking diffuse gliomatosis cerebri.(1,2.) 23735110 Surveillance in inflammatory bowel disease: chromoendoscopy and digital mucosal enhancement. Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer. Performing periodic dysplasia screening and surveillance may diminish this risk. To date, chromoendoscopy is the only technique that has consistently yielded positive results in large, well-designed dysplasia-detection trials. Most major society guidelines endorse chromoendoscopy as an adjunct, accepted, or preferred dysplasia-detection tool. This review outlines the available endoscopic technologies for the detection of dysplasia in IBD, considers the evidence supporting their use, and assesses which modalities are ready for use in clinical practice. 23907076 Determination of tetracycline in milk by using nucleotide/lanthanide coordination polymer-based ternary complex. The meta-organic coordination polymers have been emerged as fascinating nanomaterials because of their tunable nature. In this work, we employed lanthanide coordination polymer self-assembled from adenosine monophosphate (AMP) and europium ion (Eu(3+)) as receptor reagent and citrate (Cit) as ancillary ligand to construct a fluorescent sensor for the detection of tetracycline (Tc) in milk. The co-coordination of Cit and Tc with Eu(3+) on the surface of the coordination polymer AMP/Eu leads to the formation of ternary complex which emitted strong fluorescence due to the removal of coordinated water molecules and an intramolecular energy transfer from Tc to Eu(3+). The fluorescent intensity of Eu(3+) displayed a good linear response to Tc concentrations in the range of 0.1-20μM with a detection limit of 60nM. This method was successfully applied to determine the levels of Tc in milk, which is the first application of coordination polymer as a fluorescent sensor in real sample. Compared with other Eu(3+)-based fluorescent methods for Tc detection, the presented method allows simple, direct analysis of Tc without requiring special reaction media or complicated prepreparation processes. This straightforward strategy could be extended to the preparation of other lanthanide coordination polymer-based fluorescent probes for applications in biosensing, imaging, drug delivery, and so on. 23375227 Critical role of a methyl group on the γ-lactone ring of annonaceous acetogenins in the potent inhibition of mitochondrial complex I. C34-epi and C34-epi-C35-trifluoro analogues of solamin, a mono-THF annonaceous acetogenin, were synthesized. Their inhibitory activity, along with previously synthesized analogues (C35-fluoro, C35-difluoro, and C35-trifluorosolamins), against bovine mitochondrial NADH-ubiquinone oxidoreductase (complex I) was determined. The present study revealed that the methyl group on the γ-lactone moiety is critical to the potent inhibition of complex I by natural acetogenins. 23899956 Periodic Drop Thumb, Hypokalemia and Adrenal Adenoma. Objective: To report an unusual involvement of focal distal muscles but not proximal muscles in a patient with hypokalemic periodic paralysis (hypoPP). Clinical Presentation and Intervention: A middle-aged woman presented with episodic weakness of the bilateral thumbs lasting for 2 years. Hypokalemia and a left adrenal mass were subsequently found. Her weakness subsided after surgical removal of the adrenal mass, which was pathologically proven to be an adrenal adenoma. Conclusion: The findings for this patient should alert physicians to consider focal distal motor paresis due to hypoPP. A preexisting occult trauma may predispose to paralysis at an atypical location in secondary hypoPP. 23334268 Clinical and microbiological results following nonsurgical periodontal therapy with or without local administration of piperacillin/tazobactam. We assessed if adjunct administration of piperacillin/tazobactam added clinical and microbiological treatment benefits. Thirty-six subjects (mean age 52.1 years (SD ±â€‰10.3)) (NS by group) with chronic periodontitis were randomly enrolled receiving subgingival debridement and the local administration of piperacillin/tazobactam (test group) or debridement alone (control group). Bleeding on probing (BOP), probing pocket depth (PPD), and microbiological counts of 74 species were studied by checkerboard DNA-DNA hybridization up to month 6 after treatment. Mean PPD changes between baseline and month 6 in the test and control groups were 1.5 and 1.8 mm, respectively (NS between groups). BOP in both groups decreased from about 80 to 40 %. At 4 and 12 weeks, lower counts of the following bacteria were found in the test group (site level): Fusobacterium species, Parvimonas micra, Pseudomonas aeruginosa, Staphylococcus aureus, Tannerella forsythia, Treponema denticola, and a composite load of nine pathogens (p < 0.001). At week 26, subjects receiving local antibiotics had a lower prevalence at tested sites for Fusobacterium nucleatum sp. polymorphum, Fusobacterium periodonticum, P. micra, and T. denticola. At 26 weeks, treatment with or without piperacillin/tazobactam resulted in similar BOP and PPD improvements. At week 26 and at the subject level, the prevalence of 4/74 pathogens was found at lower counts in the group receiving local antibiotics. Administration of piperacillin/tazobactam reduces the prevalence of Fusobacterium, P. micra, and T. denticola to a greater extent than debridement alone but with no short-term differences in PPD or BOP. 23731124 Association between the MDR1 gene variant C3435T and risk of leukaemia: a meta-analysis. Although a number of genetic studies have attempted to link the multidrug resistance (MDR1) C3435T polymorphism to risk of leukaemia, the results were often inconsistent. The present study aimed at investigating the pooled association using a meta-analysis on the published studies. 1933 cases and 2215 controls of 11 published studies in English before June 2012 were involved in the updated meta-analysis. Furthermore, subgroup analysis was performed in different ethnic and leukaemia subtype groups. This meta-analysis suggests that the MDR1 C3435T polymorphism associate with risk of leukaemia. The effect of the variant on the expression levels and the possible functional role of the variant in leukaemia should be addressed in further studies. 23931117 Lethal effects of high-intensity violet 405-nm light on Saccharomyces cerevisiae, Candida albicans, and on dormant and germinating spores of Aspergillus niger. This study assessed the effects of high-intensity violet light on selected yeast and mould fungi. Cell suspensions of Saccharomyces cerevisiae, Candida albicans, and dormant and germinating spores (conidia) of the mould Aspergillus niger were exposed to high-intensity narrow band violet light with peak output at 405 nm generated from a light-emitting diode (LED) array. All three fungal species were inactivated by the 405-nm light without a requirement for addition of exogenous photosensitiser chemicals. Of the fungal species tested, S. cerevisiae was most sensitive and dormant conidia of A. niger were most resistant to 405-nm light exposure. Five-log10 colony forming units per millilitre (CFU ml(-1)) reductions of the tested species required exposure doses of 288 J cm(-2) for S. cerevisiae, 576 J cm(-2) for C. albicans, and a much higher value of 2.3 kJ cm(-2) for dormant conidia of A. niger. During germination, A. niger conidia became more sensitive to 405-nm light exposure and sensitivity increased as germination progressed over an 8 h test period. Light exposure under aerobic and anaerobic conditions, together with results obtained using ascorbic acid as a scavenger of reactive oxygen species, revealed that 405-nm light inactivation in fungi involved an oxygen-dependent mechanism, as previously described in bacteria. The inactivation results achieved with yeast cells and fungal spores together with operational advantages associated with the use of a visible (nonultraviolet (UV)) light source highlight the potential of 405-nm light for fungal decontamination applications. 23252343 Substituent effect in 2-benzoylmethylenequinoline difluoroborates exhibiting through-space couplings. Multinuclear magnetic resonance, X-ray diffraction, and computational study. The series of nine 2-benzoylmethylenequinoline difluoroborates have been synthesized and characterized by multinuclear magnetic resonance, X-ray diffraction (XRD), and computational methods. The through-space spin-spin couplings between (19)F and (1)H/(13)C nuclei have been observed in solution. The NMR chemical shifts have been correlated to the Hammett substituent constants. The crystal structures of six compounds have been solved by XRD. For two derivatives the X-ray wave function refinement was performed to evaluate the character of bonds in the NBF(2)O moiety by topological and integrated bond descriptors. 23820865 Realistic loophole-free Bell test with atom-photon entanglement. The establishment of nonlocal correlations, guaranteed through the violation of a Bell inequality, is not only important from a fundamental point of view but constitutes the basis for device-independent quantum information technologies. Although several nonlocality tests have been conducted so far, all of them suffered from either locality or detection loopholes. Among the proposals for overcoming these problems are the use of atom-photon entanglement and hybrid photonic measurements (for example, photodetection and homodyning). Recent studies have suggested that the use of atom-photon entanglement can lead to Bell inequality violations with moderate transmission and detection efficiencies. Here we combine these ideas and propose an experimental setup realizing a simple atom-photon entangled state that can be used to obtain nonlocality when considering realistic experimental parameters including detection efficiencies and losses due to required propagation distances. 23608173 Emergence and expansion of TFIIB-like factors in the plant kingdom. Many gene families in higher plants have expanded in number, giving rise to diverse protein paralogs with specialized biochemical functions. For instance, plant general transcription factors such as TFIIB have expanded in number and in some cases perform specialized transcriptional functions in the plant cell. To date, no comprehensive genome-wide identification of the TFIIB gene family has been conducted in the plant kingdom. To determine the extent of TFIIB expansion in plants, I used the remote homology program HHPred to search for TFIIB homologs in the plant kingdom and performed a comprehensive analysis of eukaryotic TFIIB gene families. I discovered that higher plants encode more than 10 different TFIIB-like proteins. In particular, Arabidopsis thaliana encodes 14 different TFIIB-like proteins and predicted domain architectures of the newly identified TFIIB-like proteins revealed that they have unique modular domain structures that are divergent in sequence and size. Phylogenetic analysis of selected eukaryotic organisms showed that most life forms encode three major TFIIB subfamilies that include TFIIB, Brf, Rrn7/TAF1B/MEE12 subfamilies, while all plants and some algae species encode one or two additional TFIIB-related protein subfamilies. A subset of A. thaliana GTFs have also expanded in number, indicating that GTF diversification and expansion is a general phenomenon in higher plants. Together, these findings were used to generate a model for the evolutionary history of TFIIB-like proteins in eukaryotes. 23906316 Mono- to Octa-Chlorinated PCDD/Fs in Stack Gas from Typical Waste Incinerators and Their Implications on Emission. Mono- to octa-chlorinated dibenzo-p-dioxins and dibenzofurans (mono- to octa-CDD/Fs) were determined in 14 stack gas samples from two municipal solid waste incinerators and two medical waste incinerators. The total PCDD/F concentrations were 5.1-390 ng/Nm(3), and the mono- to trichlorinated homologues contributed 53.2-94.5% of the total concentrations. The homologue profiles were dominated by the MoCDF, ranged from 1.51 to 113.1 ng/Nm(3), and the proportion that each PCDF homologue group contributed to the total concentration decreased with increasing chlorination level. The toxic equivalent concentrations (I-TEQs) were 0.01-2.81 ng I-TEQ/Nm(3), with 2,3,4,7,8-PeCDF being the biggest contributor, at 30.6-60.0%. Correlations were found among the PCDD/PCDF ratios (D/F ratios), the degree of chlorination, and the TEQ. Stack gases with low I-TEQs had higher proportions of the less chlorinated homologues and lower D/F ratios, which could be attributed to the removal of the more chlorinated isomers by the air pollution control systems used by the incinerators. 2,8-DiCDF, 2,4,8-TrCDF, DiCDF, and TrCDF can be used as TEQ indicators for monitoring PCDD/Fs. 2,8-DiCDF and 2,4,8-TrCDF correlated well with the TEQ because they strongly correlated with 2,3,4,7,8-PeCDF, implying possible correlations in their formation mechanisms. 23906223 Effects of interaction of incubator CO2 levels and mixing hatching eggs of different embryo growth trajectory on embryo physiological and hatching parameters. 1. Two experiments were designed to investigate the effects of mixing eggs of different genotype and incubating with different CO2 concentrations on embryonic parameters. Half of the eggs were incubated in a CO2 controlled incubator (VCO2) during the first 10 d of incubation and the other half was incubated at standard incubation ventilation rate (SV). 2. From 10 to 18 d of incubation, thick albumen and embryos were weighed. Blood samples were collected at d 18 of incubation, at internal pipping and at hatch for determination of triiodothyronine (T3), thyroxine (T4) and corticosterone concentration. During the last 2 d of incubation, hatching events of individual eggs were monitored every 2 h. 3. From 4 to 5 d of incubation in the SV group of Experiment 1, pH values of Ross strain chickens were lower than those of Isa Brown. From d 12 of incubation onwards, Ross embryos grew faster than those of Isa Brown. At 14 and 16 d of incubation, Ross eggs in the CO2 controlled incubator had lower albumen weights compared to all other treatments. 4. T3 concentrations in Ross embryos were higher than those of Isa Brown embryos. Chicken weight at hatch was in the following order: Isa Brown SV < Isa Brown VCO2 = Ross SV < Ross VCO2. 5. In Experiment 2, incubation time of VCO2 eggs until internal pipping, external pipping and hatch was significantly shorter than that of SV eggs. 6. It was concluded that mixing of hatching eggs of differential embryo developmental trajectory affects their hatching process. 23873870 Migrant density and well-being--A national school survey of 15-year-olds in Sweden. The aim of this study was to investigate the impact of migrant density in school on the well-being of pupils with a migrant origin in first as well as second generation. Methods: Cross-sectional analysis of data from a national classroom survey of 15-year-old Swedish schoolchildren. The study population included 76 229 pupils (86.5% participation) with complete data set from 1352 schools. Six dimensions of well-being from the KIDSCREEN were analysed in two-level linear regression models to assess the influence of migrant origin at individual level and percentage of students with a migrant origin at school level, as well as interaction terms between them. Z-scores were used to equalize scales. Results: A high density (>50%) of pupils with a migrant origin in first or second generation was associated with positive well-being on all six scales for foreign-born pupils originating in Africa or Asia compared with schools with low (<10%) migrant density. The effect sizes were 0.56 for boys and 0.29 for girls on the comprehensive KIDSCREEN 10-index (P<0.001) and 0.61 and 0.34, respectively, for psychological well-being (P<0.001). Of the boys and girls born in Africa or Asia, 31.6% and 34.6%, respectively, reported being bullied during the past week in schools with low (<10%) migrant density. Conclusions: Pupils born in Africa or Asia are at high risk for being bullied and having impaired well-being in schools with few other migrant children. School interventions to improve peer relations and prevent bullying are needed to promote well-being in non-European migrant children. 23575194 CD4 decline is associated with increased risk of cardiovascular disease, cancer, and death in virally suppressed patients with HIV. The clinical implications of a considerable CD4 decline despite antiretroviral treatment and viral suppression are unknown. We aimed to test the hypothesis that a major CD4 decline could be a marker of cardiovascular disease or undiagnosed cancer. Patients with human immunodeficiency virus (HIV) were followed in the Danish nationwide, population-based cohort study in the period 1995-2010 with quarterly CD4 measurements. Associations between a CD4 decline of ≥30% and cardiovascular disease, cancer, and death were analyzed using Poisson regression with date of CD4 decline as a time-updated variable. We followed 2584 virally suppressed HIV patients for 13 369 person-years (PY; median observation time, 4.7 years). Fifty-six patients developed CD4 decline (incidence rate, 4.2/1000 PY [95% confidence interval {CI}, 3.2-5.4]). CD4 counts dropped from a median of 492 cells/µL to 240 cells/µL. CD8, CD3, and total lymphocyte counts dropped concomitantly. No HIV-related factors, apart from treatment with didanosine, were associated with CD4 decline. The risk of cardiovascular disease, cancer, and death increased markedly ≤6 months after CD4 decline (incidence rate ratio, 11.7 [95% CI, 3.6-37.4] and 13.7 [95% CI, 4.3-43.6], respectively, and mortality rate ratio 4.3 [95% CI, 1.1-17.6]). A major decline in CD4 count is associated with a marked increased risk of cardiovascular disease, cancer, and death among virally suppressed HIV patients. 23916681 Differences in the Symptom Experience of Older Oncology Outpatients. The relatively low number of older patients in cancer trials limits knowledge of how older adults experience symptoms associated with cancer and its treatment. This study evaluated for differences in the symptom experience across four older age groups (60-64, 65-69, 70-74, ≥75 years). Demographic, clinical, and symptom data from 330 patients aged >60 years who participated in one Australian and two U.S. studies were evaluated. The Memorial Symptom Assessment Scale was used to evaluate the occurrence, severity, frequency, and distress of 32 symptoms commonly associated with cancer and its treatment. On average, regardless of the age group, patients reported 10 concurrent symptoms. The most prevalent symptoms were physical in nature. Worrying was the most common psychological symptom. For 28 (87.5%) of the 32 Memorial Symptom Assessment Scale symptoms, no age-related differences were found in symptom occurrence rates. For symptom severity ratings, an age-related trend was found for difficulty swallowing. As age increased, severity of difficulty swallowing decreased. For symptom frequency, age-related trends were found for feeling irritable and diarrhea, with both decreasing in frequency as age increased. For symptom distress, age-related trends were found for lack of energy, shortness of breath, feeling bloated, and difficulty swallowing. As age increased, these symptoms received lower average distress ratings. Additional research is warranted to examine how age differences in symptom experience are influenced by treatment differences, aging-related changes in biological or psychological processes, or age-related response shift. 23917483 Cross-national disparities in sex differences in life expectancy with and without frailty. Background: with continued ageing, levels of frailty are an increasing concern. Women live longer than men, but how life expectancies (LE) with frailty differ between men and women and whether sex differences are the same for all European countries is unknown. to compare sex differences in LE in phenotypic frailty categories and disability at age ≥50 between European countries. the Survey of Health, Ageing and Retirement in Europe (SHARE). a total of 50,351 people aged ≥50 from SHARE wave 4 (included countries: Austria, Belgium, Czech Republic, Denmark, Estonia, France, Germany, Hungary, Italy, the Netherlands, Poland, Portugal, Slovenia, Spain, Sweden). the SHARE Frailty Instrument for Primary Care and the Global Activity Limitation Indicator were combined to define four phenotypic frailty and disability categories: robust, pre-frail, frail and severely limited. LEs with each state by sex and country were calculated using Sullivan's method. at age 70, the LE robust ranged from 4.1 to 10.4 years (men) and 3.0 to 8.9 years (women), LE pre-frail from 0.8-3.1 years (men) and 2.2-5.5 years (women), LE frail from 0.1-1.8 years (men) and 0.4-5.5 years (women) and LE with severe activity limitation from 1.9 to 4.4 years (men) and 2.9 to 7.5 years (women). At all ages and both sexes the fewest years were spent frail. this study is the first to compare differences in LE in frailty categories across European countries. In most European countries, years spent robust (free of frailty or limitation) are significantly less for women than men, perhaps due to socio-economic as well as biological factors. 23916737 Ventricular Fibrillation Associated With J-Wave Manifestation Following Pericarditis After Catheter Ablation for Paroxysmal Atrial Fibrillation. We present a patient with ventricular fibrillation (VF) associated with J-wave manifestation following pericarditis after catheter ablation of paroxysmal atrial fibrillation (AF). The premature ventricular contraction induced VF with J-waves in the inferior leads 2 days after the procedure. The patient's juvenile onset of AF and a family history of sudden cardiac death strongly suggested an underlying hereditable channelopathy. The late gadolinium enhancement in the posterior wall, viewed by cardiac magnetic resonance imaging, matched the leads of the J-waves. VF might develop in juvenile onset of AF especially in individuals with a family history of sudden cardiac death. 23910561 Appropriate use of positron emission tomography with [(18)F]fluorodeoxyglucose for staging of oncology patients. Positron emission tomography (PET) was developed in the mid-1970, and its initial applications were for heart and brain imaging research. Nowadays, this technology is aimed mainly at staging or restaging tumours as it allows the assessment of biochemical processes that are either specific or associated with tumour biology. The full appreciation of PET potentials and limitations among general practitioners and internists cannot be considered achieved and the appropriate use of PET especially when coupled to X-ray computed tomography (CT) is still suboptimal. The majority of PET studies rely on the use of fluorodeoxyglucose labelled with fluorine-18 (FDG), which is a radiopharmaceutical specific for glucose transport and metabolism. PET with FDG is amenable for studying most type of tumours, including those of the head and neck, lung, oesophagus, colo-rectal, gastrointestinal stromal tumours, pancreas, some types of lymphomas and melanoma, whereas in some tumours, including those of the reproductive system, brain, breast and bones, there is a limited role for PET and there is no substantial role for FDG-PET for the bronchoalveolar, hepatocellular, urinary system, testicular, neuroendocrine, carcinoids and adrenal tumours, differentiated thyroid cancers, and several subtypes of malignant lymphoma. Thus, the limits of FDG have stimulated the use and development of other radiopharmaceuticals. These tracers represent the opportunity for expanding the use of PET to other areas in oncology in the near future. 23753633 Induction of Rapid Cell Death by an Environmental Isolate of Legionella pneumophila in Mouse Macrophages. Legionella pneumophila, the etiological agent for Legionnaires' disease, is ubiquitous in the aqueous environment, where it replicates as an intracellular parasite of free-living protozoa. Our understanding of L. pneumophila pathogenicity is obtained mostly from study of derivatives of several clinical isolates, which employ almost identical virulent determinants to exploit host functions. To determine whether environmental L. pneumophila isolates interact similarly with the model host systems, we analyzed intracellular replication of several recently isolated such strains and found that these strains cannot productively grow in bone marrow-derived macrophages of A/J mice, which are permissive for all examined laboratory strains. By focusing on one strain called LPE509, we found that its deficiency in intracellular replication in primary A/J macrophages is not caused by the lack of important pathogenic determinants because this strain replicates proficiently in two protozoan hosts and the human macrophage U937 cell. We also found that in the early phase of infection, the trafficking of this strain in A/J macrophages is similar to that of JR32, a derivative of strain Philadelphia 1. Furthermore, infection of these cells by LPE509 caused extensive cell death in a process that requires the Dot/Icm type IV secretion system. Finally, we showed that the cell death is caused neither by the activation of the NAIP5/NLRC4 inflammasome nor by the recently described caspase 11-dependent pathway. Our results revealed that some environmental L. pneumophila strains are unable to overcome the defense conferred by primary macrophages from mice known to be permissive for laboratory L. pneumophila strains. These results also suggest the existence of a host immune surveillance mechanism differing from those currently known in responding to L. pneumophila infection. 23770348 7-Ketocholesterol Induces Autophagy in Vascular Smooth Muscle Cells through Nox4 and Atg4B. Oxidized lipoproteins stimulate autophagy in advanced atherosclerotic plaques. However, the mechanisms underlying autophagy induction and the role of autophagy in atherogenesis remain to be determined. This study was designed to investigate the mechanisms by which 7-ketocholesterol (7-KC), a major component of oxidized lipoproteins, induces autophagy. This study was also designed to determine the effect of autophagy induction on apoptosis, a central event in the development of atherosclerosis. Exposure of human aortic smooth muscle cells to 7-KC increased autophagic flux. Autophagy induction was suppressed by treating the cells with either a reactive oxygen species scavenger or an antioxidant. Administration of 7-KC concomitantly up-regulated Nox4 expression, increased intracellular hydrogen peroxide levels, and inhibited autophagy-related gene 4B activity. Catalase overexpression to remove hydrogen peroxide or Nox4 knockdown with siRNA reduced intracellular hydrogen peroxide levels, restored autophagy-related gene 4B activity, and consequently attenuated 7-KC-induced autophagy. Moreover, inhibition of autophagy aggravated both endoplasmic reticulum (ER) stress and cell death in response to 7-KC. In contrast, up-regulation of autophagic activity by rapamycin had opposite effects. Finally, activation of autophagy by chronic rapamycin treatment attenuated ER stress, apoptosis, and atherosclerosis in apolipoprotein E knockout (ApoE(-/-)) mouse aortas. In conclusion, we demonstrate that up-regulation of autophagy is a cellular protective response that attenuates 7-KC-induced cell death in human aortic smooth muscle cells. 23480625 The Emerging Use of Ketamine for Anesthesia and Sedation in Traumatic Brain Injuries. BACKGROUND: Traditionally, the use of ketamine for patients with traumatic brain injuries is contraindicated due to the concern of increasing intracranial pressure (ICP). These concerns, however, originated from early studies and case reports that were inadequately controlled and designed. Recently, the concern of using ketamine in these patients has been challenged by a number of published studies demonstrating that the use of ketamine was safe in these patients. AIMS: The purpose of this article was to review the current literature in regards to using ketamine in patients with traumatic brain injuries in different clinical settings associated with anesthesia, as well as review the potential mechanisms underlying the neuroprotective effects of ketamine. RESULTS: Studies examining the use of ketamine for induction, maintenance, and sedation in patients with TBI have had promising results. The use of ketamine in a controlled ventilation setting and in combination with other sedative agents has demonstrated no increase in ICP. CONCLUSIONS: The role of ketamine as a neuroprotective agent in humans remains inconclusive and adequately powered; randomized controlled trials performed in patients undergoing surgery for traumatic brain injury are necessary. 22517541 Reduction of inflammatory bowel disease-induced tumor development in IL-10 knockout mice with soluble epoxide hydrolase gene deficiency. Soluble epoxide hydrolase (sEH) quickly inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs) by converting them to dihydroxyeicosatrienoic acids (DHETs). Inhibition of sEH has shown effects against inflammation, but little is studied about the role of sEH in inflammatory bowel disease (IBD) and its induced carcinogenesis. In the present study, the effect of sEH gene deficiency on the development of IBD-induced tumor development was determined in IL-10 knockout mice combined with sEH gene deficiency. Tumor development in the bowel was examined at the age of 25 wk for male mice and 35 wk for female mice. Compared to IL-10(-/-) mice, sEH (-/-)/IL-10(-/-) mice exhibited a significant decrease of tumor multiplicity (2 ± 0.9 tumors/mouse vs. 1 ± 0.3 tumors/mouse) and tumor size (344.55 ± 71.73 mm(3) vs. 126.94 ± 23.18 mm(3) ), as well as a marked decrease of precancerous dysplasia. The significantly lower inflammatory scores were further observed in the bowel in sEH(-/-)/IL-10(-/-) mice as compared to IL-10(-/-) mice, including parameters of inflammation-involved area (0.70 ± 0.16 vs. 1.4 ± 0.18), inflammation cell infiltration (1.55 ± 0.35 vs. 2.15 ± 0.18), and epithelial hyperplasia (0.95 ± 0.21 vs. 1.45 ± 0.18), as well as larger ulcer formation. qPCR and Western blotting assays demonstrated a significant downregulation of cytokines/chemokines (TNF-α, MCP-1, and IL-12, 17, and 23) and NF-κB signals. Eicosanoid acid metabolic profiling revealed a significant increase of ratios of EETs to DHETs and EpOMEs to DiOMEs. These results indicate that sEH plays an important role in IBD and its-induced carcinogenesis and could serve as a highly potential target of chemoprevention and treatment for IBD. © 2012 Wiley Periodicals, Inc. 23966504 Improvement rate of acute otitis media caused by Haemophilus influenzae at one week is significantly associated with the time to recovery. Acute otitis media (AOM) is the commonest upper respiratory tract infection in childhood. Children with AOM were enrolled at Tohoku Rosai Hospital between July 2006 and June 2011 if middle ear fluid culture after tympanocentesis yielded only Haemophilus influenzae. Susceptibility to ampicillin was determined, and a microtiter biofilm assay and invasion assay using BEAS-2B cells were performed. The association between these bacterial characteristics and clinical relapse and treatment failure of AOM was evaluated. Seventy-four children (39 boys and 35 girls) with median age of 1 year (IQR: 0.25-2) were enrolled. Among 74 H. influenzae isolates, 37 showed intermediate resistance or resistance to ampicillin (MIC≥2 μg/ml). In the microtiter biofilm assay, median OD600 was 0.68 (IQR: 0.24-1.02) and 70 isolates formed biofilms. The median invasion rate was 15% (IQR: 0-10%) and 46 isolates invaded BEAS-2B cells. Relapse and treatment failure occurred in 19 and 6 children, respectively. There was no significant difference of the invasion rate between patients with/without relapse or treatment failure. Also, there was no significant association between biofilm formation and relapse or treatment failure. The improvement of the severity score after 1 week was significantly associated with the recovery time (P<0.0001). We did not identify any significant association between relapse or treatment failure and bacterial factors. AOM has a multifactorial etiology, and this may explain why we could not find a significant association. Improvement of the severity score after 1 week of treatment may be a useful predictor of the outcome of AOM. 23153455 Overexpression of ATP-binding cassette transporter ABCG2 as a potential mechanism of acquired resistance to vemurafenib in BRAF(V600E) mutant cancer cells. Melanoma is the most serious type of skin cancer with a high potential for metastasis and very low survival rates. The discovery of constitutive activation of the BRAF kinase caused by activating BRAF(V600E) kinase mutation in most melanoma patients led to the discovery of the first potent BRAF(V600E) signaling inhibitor, vemurafenib. Vemurafenib was effective in treating advanced melanoma patients and was proposed for the treatment of other BRAF(V600E) mutant cancers as well. Unfortunately, the success of vemurafenib was hampered by the rapid development of acquired resistance in different types of BRAF(V600E) mutant cancer cells. It becomes important to identify and evaluate all of the potential mechanisms of cellular resistance to vemurafenib. In this study, we characterized the interactions of vemurafenib with three major ATP-binding cassette (ABC) transporters, ABCB1, ABCC1 and ABCG2. We found that vemurafenib stimulated the ATPase activity and potently inhibited drug efflux mediated by ABCB1 and ABCG2. Vemurafenib also restored drug sensitivity in ABCG2-overexpressing cells. Moreover, we revealed that in the presence of functional ABCG2, BRAF kinase inhibition by vemurafenib is reduced in BRAF(V600E) mutant A375 cells. Taken together, our findings indicate that ABCG2 confers resistance to vemurafenib in A375 cells, suggesting involvement of this transporter in acquired resistance to vemurafenib. Thus, combination chemotherapy targeting multiple pathways could be an effective therapeutic strategy to overcome acquired resistance to vemurafenib for cancers harboring the BRAF(V600E) mutation. 23830767 Beyond Rieger's original indication; the dorsal nasal flap revisited. Few reconstructive options are available for nasal defects measuring >2 cm. Staged procedures are often utilized for nasal defect reconstruction, but they are not feasible in some patients. Out of 92 patients operated upon for nasal skin lesions between 2009 and 2011, patients who received reconstructive surgery with a dorsal nasal flap, nasal skin lesions located in lower half of nose (≤5 mm from the alar rim), defect diameter ≥3 cm were included in this study. Patients with nasal lesions larger than 3 cm who refused a staged procedure and were prone to compromised follow up underwent dorsal nasal flap reconstruction. Clear margins were obtained and no flap loss occurred. Minor complications occurred, such as flap dehiscence. The dorsal nasal flap can be effectively utilized for selected lesions as a surrogate for staged procedures that use various local flaps, such as the paramedian flap. 23889361 The history of the idea of allergy. About 100 years ago, a young paediatrician understood that the function of the immune system should be rationalized not in terms of exemption of disease but in terms of change of reactivity. He coined a new word to represent such an idea: 'allergy': the first contact of the immune system with an antigen changes the reactivity of the individual; on the second and subsequent contacts, this change (or allergy) can induce a spectrum of responses from protective (literally, immune) to hypersensitivity ones. The idea was at first hardly understood by the scientific community because it undermined the essentially protective nature of the immune response as it was defined. Nevertheless, in the next years, the growing clinical evidence led to the acceptance of this new point of view, but not of the new word, at least not unconditionally. The original significance of the neologism 'allergy' became perverted and limited to describe hypersensitivity conditions. Perhaps because of the corruption of the term, today 'allergy' does not have a well-delimited significance among health professionals. Furthermore, the word has long ago escaped from physicians and gone to the streets, where it is popularly used also as synonymous with antipathy and rejection. This vulgarization of the term 'allergy' has significantly increased its imprecision. 23934913 Is the Bovine lysosomal phospholipase B-like protein an amidase? The main function of lysosomal proteins is to degrade cellular macromolecules. We purified a novel lysosomal protein to homogeneity from bovine kidneys. By gene annotation this protein is defined as a phospholipase B-like protein 1 (bPLBD1) and, to better understand its biological function, we solved its structure at 1.9 Å resolution. We showed that bPLBD1 has uniform non-complex type N-glycosylation and that it localised to the lysosome. The first step in lysosomal protein transport, the initiation of mannose-6-phosphorylation by a N-acetylglucosamine-1-phosphotransferase, requires recognition of at least two distinct lysines on the protein surface. We identified candidate lysines by analysing the structural and sequentially conserved N-glycosylation sites and lysines in bPLBD1 and in the homologous mouse phospholipase B-like protein 2. Our model suggests that N408 is the primarily phosphorylated glycan, and K358 a key residue for N-acetylglucosamine-1-phosphotransferase recognition. Two other lysines, K334 and K342, provide the required second site for N-acetylglucosamine-1-phosphotransferase recognition. bPLBD1 is an N-terminal nucleophile (Ntn) hydrolase. By comparison with other Ntn-hydrolases, we conclude that the acyl moiety of PLBD1 substrate must be small to fit the putative binding pocket, while the space for the rest of the substrate is a large open cleft. Finally, as all the known substrates of Ntn-hydrolases have amide bonds, we suggest that bPLBD1 may be an amidase or peptidase instead of lipase, explaining the difficulty in finding a good substrate for any members of the PLBD family. © Proteins 2013;. © 2013 Wiley Periodicals, Inc. 23883284 Selective androgen receptor modulators: in vitro and in vivo metabolism and analysis. For future targeted screening in National Residue Control Programmes, the metabolism of seven SARMs, from the arylpropionamide and the quinolinone classes, was studied in vitro using S9 bovine liver enzymes. Metabolites were detected and identified with ultra-performance liquid chromatography (UPLC) coupled to time-of-flight mass spectrometry (ToF-MS) and triple quadrupole mass spectrometry (QqQ-MS). Several metabolites were identified and results were compared with literature data on metabolism using a human cell line. Monohydroxylation, nitro-reduction, dephenylation and demethylation were the main S9 in vitro metabolic routes established. Next, an in vivo study was performed by oral administration of the arylpropionamide ostarine to a male calf and urine samples were analysed with UPLC-QToF-MS. Apart from two metabolites resulting from hydroxylation and dephenylation that were also observed in the in vitro study, the bovine in vivo metabolites of ostarine resulted in glucuronidation, sulfation and carboxylation, combined with either a hydroxylation or a dephenylation step. As the intact mother compounds of all SARMs tested are the main compounds present after in vitro incubations, and ostarine is still clearly present in the urine after the in vivo metabolism study in veal calves, the intact mother molecules were selected as the indicator to reveal treatment. The analytical UPLC-QqQ-MS/MS procedure was validated for three commercially available arylpropionamides according to European Union criteria (Commission Decision 2002/657/EC), and resulted in decision limits ranging from 0.025 to 0.05 µg l(-1) and a detection capability of 0.025 µg l(-1) in all cases. Adequate precision and intra-laboratory reproducibility (relative standard deviation below 20%) were obtained for all SARMs and the linearity was 0.999 for all compounds. This newly developed method is sensitive and robust, and therefore useful for confirmation and quantification of SARMs in bovine urine samples for residue control programmes and research purposes. 23381942 Whither pathogenetic treatments for diabetic polyneuropathy? Diabetic distal symmetric polyneuropathy (DSPN) occurs in around one-third of patients with diabetes and is associated with significant morbidity and increased mortality. Diagnosis and clinical assessment of DSPN remain a challenge, not only for the physician in clinical practice but also for clinical trials. Optimal diabetes control is generally considered an essential first step in the prevention and management of DSPN. However, glycaemic control alone may be insufficient to prevent the development or progression of DSPN, especially in type 2 diabetes. Near-normoglycaemia is also difficult to achieve in a significant proportion of patients. Although considerable advances have been made in symptomatic pain management, these have not addressed the problem of sensory deficits and have no impact on the underlying pathogenesis of DSPN. There remains a lack of treatment options that effectively target the natural history of the disease. Several pathogenetic treatment approaches have been investigated, but evidence from clinical trials is limited with a number of treatments having shown disappointing results. However, some pathogenetic therapies have shown clinically relevant improvements in neuropathic endpoints in randomised controlled trials, in particular α-lipoic acid and Actovegin. These advances in DSPN disease modification need to be confirmed with further robust evidence from clinical trials together with a better understanding of the mechanisms of action of promising treatments. Copyright © 2013 John Wiley & Sons, Ltd. 23728808 Biodegradation of endocrine disruptors in solid-liquid two-phase partitioning systems by enrichment cultures. Naturally occurring and synthetic estrogens and other molecules from industrial sources strongly contribute to the endocrine disruption of urban wastewater. Because of the presence of these molecules in low but effective concentrations in wastewaters, these endocrine disruptors (EDs) are only partially removed after most wastewater treatments, reflecting the presence of these molecules in rivers in urban areas. The development of a two-phase partitioning bioreactor (TPPB) might be an effective strategy for the removal of EDs from wastewater plant effluents. Here, we describe the establishment of three ED-degrading microbial enrichment cultures adapted to a solid-liquid two-phase partitioning system using Hytrel as the immiscible water phase and loaded with estrone, estradiol, estriol, ethynylestradiol, nonylphenol, and bisphenol A. All molecules except ethynylestradiol were degraded in the enrichment cultures. The bacterial composition of the three enrichment cultures was determined using 16S rRNA gene sequencing and showed sequences affiliated with bacteria associated with the degradation of these compounds, such as Sphingomonadales. One Rhodococcus isolate capable of degrading estrone, estradiol, and estriol was isolated from one enrichment culture. These results highlight the great potential for the development of TPPB for the degradation of highly diluted EDs in water effluents. 23500511 Litopenaeus vannamei Toll-interacting protein (LvTollip) is a potential negative regulator of the shrimp Toll pathway involved in the regulation of the shrimp antimicrobial peptide gene penaeidin-4 (PEN4). The Toll-like receptor (TLR)-nuclear factor (NF)-κB signaling pathway is evolutionarily conserved from insects to mammals as a regulator of the expression of immune-related genes. In mammals, TLR-NF-κB signaling is tightly controlled because excessive activation of this pathway can result in severe damage to the host. The mammalian Toll-interacting protein (Tollip) has an important function in the negative regulation of this pathway, but no reports about invertebrate Tollip have been published to date. In this study, we cloned Litopenaeus vannamei Tollip (LvTollip) and investigated its function in the regulation of the NF-κB pathway-controlled antimicrobial peptide genes (AMPs). The LvTollip full-length cDNA is 1231bp long and contains an open reading frame of 813bp that encodes a 270-amino acid protein. LvTollip shares significant similarities to mammalian Tollips, which contain a centrally localized protein kinase C conserved region 2 (C2) domain and a C-terminal CUE domain. After challenges with the white spot syndrome virus (WSSV) or Vibrio alginolyticus, the expression levels of LvTollip were altered in the gill, hemocyte, hepatopancreatic, intestinal, and muscle tissues. In Drosophila S2 cells, LvTollip localized in the membrane and the cytoplasm and significantly inhibited the promoter activities of the NF-κB pathway-controlled AMP penaeidin-4 (PEN4). In LvTollip-knockdown shrimp, the expression level of AMP PEN4 was increased. However, the mortality rates of LvTollip-knockdown shrimp in response to WSSV or V. alginolyticus infections were not significantly different from those of the control group. Our results suggested that LvTollip might be involved in the negative regulation of PEN4 and that LvTollip expression was responsive to microbial infections. 23525524 Serotonergic hallucinogens differentially modify gamma and high frequency oscillations in the rat nucleus accumbens. RATIONALE: The nucleus accumbens (NAc) is a site critical for the actions of many drugs of abuse. Psychoactive compounds, such as N-methyl-D-aspartate receptor (NMDAR) antagonists, modify gamma (40-90) and high frequency oscillations (HFO, 130-180 Hz) in local field potentials (LFPs) recorded in the NAc. Lysergic acid diethylamide (LSD) and 2,5-dimethoxy-4-iodoamphetamine (DOI) are serotonergic hallucinogens and activation of 5HT2A receptors likely underlies their hallucinogenic effects. Whether these compounds can also modulate LFP oscillations in the NAc is unclear. OBJECTIVE: This study aims to examine the effect of serotonergic hallucinogens on gamma and HFO recorded in the NAc and to test whether 5HT2A receptors mediate the effects observed. METHODS: LFPs were recorded from the NAc of freely moving rats. Drugs were administered intraperitoneally. RESULTS: LSD (0.03-0.3 mg/kg) and DOI (0.5-2.0 mg/kg) increased the power and reduced the frequency of HFO. In contrast, the hallucinogens produced a robust reduction in the power of low (40-60 Hz), but not high gamma oscillations (70-90 Hz). MDL 11939 (1.0 mg/kg), a 5HT2A receptor antagonist, fully reversed the changes induced by DOI on HFO but only partially for the low gamma band. Equivalent increases in HFO power were observed after TCB-2 (5HT2A receptor agonist, 0.1-1.5 mg/kg), but not CP 809101 (5H2C receptor agonist, 0.1-3 mg/kg). Notably, hallucinogen-induced increases in HFO power were smaller than those produced by ketamine (25 mg/kg). CONCLUSIONS: Serotonergic hallucinogen-induced changes in HFO and gamma are mediated, at least in part, by stimulation of 5HT2A receptors. Comparison of the oscillatory changes produced by serotonergic hallucinogens and NMDAR antagonists are also discussed. 23832676 Speed modulation of hippocampal theta frequency correlates with spatial memory performance. Hippocampal theta rhythm is believed to play a critical role in learning and memory. In animal models of temporal lobe epilepsy (TLE), there is evidence that alterations of hippocampal theta oscillations are involved in the cognitive impairments observed in this model. However, hippocampal theta frequency and amplitude at both the local field potential (LFP) and single unit level are strongly modulated by running speed, suggesting that the integration of locomotor information into memory processes may also be critical for hippocampal processing. Here, we investigate whether hippocampal speed-theta integration influences spatial memory and whether it could account for the memory deficits observed in TLE rats. LFPs were recorded in both Control (CTR) and TLE rats as they were trained in a spatial alternation task. TLE rats required more training sessions to perform the task at CTR levels. Both theta frequency and power were significantly lower in the TLE group. In addition, speed/theta frequency correlation coefficients and regression slopes varied from session to session and were worse in TLE. Importantly, there was a strong relationship between speed/theta frequency parameters and performance. Our analyses reveal that speed/theta frequency correlation with performance cannot merely be explained by the direct influence of speed on behavior. Therefore, variations in the coordination of theta frequency with speed may participate in learning and memory processes. Impairments of this function could explain at least partially memory deficits in epilepsy. © 2013 Wiley Periodicals, Inc. 23881346 Effect of Consecutive Intragastric Balloon (BIB®) Plus Diet Versus Single BIB® Plus Diet on Eating Disorders Not Otherwise Specified (EDNOS) in Obese Patients. Eating disorders are a group of conditions characterised by abnormal eating habits. Greater than 50 % of patients with eating disorders have an 'eating disorder not otherwise specified' (EDNOS). No specific tools exist to evaluate EDNOS, and patients are identified only with a diagnosis of exclusion from the other eating disorders. The BioEnterics® Intragastric Balloon (BIB®) is used worldwide as a short-term treatment option in obese patients. A new frequency score was used to evaluate the influence of double consecutive BIB® treatment compared with single BIB® treatment followed by diet on four categories of EDNOS (grazing, emotional eating, sweet-eating and after-dinner grazing). A prospective study allocated 50 obese patients (age range 25-35, BMI range 40.0-44.9) into two groups: BIB® (6 months) followed by diet therapy (7 months; group A (N = 25)) and BIB® placement for 6 months followed by another BIB® for 6 months, with a 1-month interval between placement (group B (N = 25)). Baseline demographics were similar across both groups. At the time of removal of the first BIB® device, EDNOS scores in both groups were not significantly different, but decreased significantly from baseline. By the end of the study, all EDNOS scores were significantly lower in patients undergoing consecutive BIB®, compared with single BIB® followed by diet therapy. The placement of an intragastric balloon in obese patients allows for a reduction in the intensity of grazing, emotional eating, sweet-eating and after-dinner grazing. A more significant reduction in the EDNOS score was observed with two consecutive BIBs®. 23891057 Effect of Patellar Thickness on Knee Flexion in Total Knee Arthroplasty: A Biomechanical and Experimental Study. A biomechanical computer-based model was developed to simulate the influence of patellar thickness on passive knee flexion after arthroplasty. Using the computer model of a single-radius, PCL-sacrificing knee prosthesis, a range of patella-implant composite thicknesses was simulated. The biomechanical model was then replicated using two cadaveric knees. A patellar-thickness range of 15mm was applied to each of the knees. Knee flexion was found to decrease exponentially with increased patellar thickness in both the biomechanical and experimental studies. Importantly, this flexion loss followed an exponential pattern with higher patellar thicknesses in both studies. In order to avoid adverse biomechanical and functional consequences, it is recommended to restore patellar thickness to that of the native knee during total knee arthroplasty. 22817767 Adnexal torsion in children and adolescents: new trends to conservative surgical approach -- our experience and review of literature. The purpose of this study is to discuss the surgical treatment for ovarian torsion in children and adolescents with a focus on the procedures of adnexal conservation surgery and its frequency in the literature of the last 10 years. We retrospectively reviewed the medical charts of 127 operative ovarian lesions including 30 ovarian torsions (23.6%) treated in two pediatric centers over a 10-year period. Age at presentation, presenting symptoms, diagnostic studies, surgical procedure and pathological findings were analyzed. Mean age was 13.7 years. Conservative surgery has been performed in 46.7% of the cases and laparoscopic approach in 40%. Ovarian torsion occurred in 56.7% on ovaries with functional lesion, in 23.3% on normal adnexa and in 20% on ovaries with benign neoplasm. The article includes a literature review (2000-2010) and a statistical analysis which shows a slow increase in conservative surgery from 28 to 45%. Laparoscopic surgery accounts for 23.5%. Literature review shows 40.5% normal adnexa, 33.2% non-neoplastic lesions, 25.3% benign neoplasms and 1% malignant neoplasms. The surgical treatment of children and adolescents presenting adnexal torsion should be practiced as an emergency and it should be more conservative as possible in order to maximize the future reproductive potential. 23866761 Effectiveness of green tea mouthwash in postoperative pain control following surgical removal of impacted third molars: double blind randomized clinical trial. Pain following surgical removal of impacted molars has remained an important concern among practitioners. Various protocols have been proposed to reduce postoperative pain. However, each one has special side effects and limitations. As green tea possesses anti-inflammatory and antibacterial properties, the aim of the current study was to evaluate the effectiveness of green tea mouthwash in controlling postoperative pain.Materials and methods: In a study with split-mouth and double blind design, 44 patients in need of bilateral removal of impacted third molars underwent randomized surgical extraction; following one surgery patients rinsed with a green tea mouthwash from the first to seventh postoperative day and after other extraction rinsed with placebo mouthwash in the same duration. Both patients and surgeon were blinded to the type of mouthwash. The predictor variable was type of mouthwash and primary outcome variable was postoperative pain measured by visual analogue scale (VAS) during first week after surgery. In addition, number of analgesics patients used after surgery recorded. To measure the effect of green tea mouthwash, repeated measures test with confidence interval of 95% was performed. Total of 43 patients with mean age of 24 years underwent total of 86 surgeries. VAS value had no statistically difference prior rinsing among groups (P-value > 0.05). However, the mean value of VAS following rinsing with green tea was statistically lower than placebo in postoperative days of 3--7 (P-value < 0.05). In addition, while rinsing with green tea, patients took significantly lower number of analgesics after surgery (P-value < 0.05). No side effects reported. Green tea mouthwash could be an appropriate and safe choice to control postoperative pain after third molar surgery. 23505214 Interplay of Octahedral Tilts and Polar Order in BiFeO3 Films. Heterointerface stabilization of a distinct nonpolar BiFeO3 phase occurs simultaneously with changes in octahedral tilts. The resulting phase arises via suppression of polarization by a structural order parameter and can thus be identified as anti-ferroelectric (Fe displacements - bottom panel). The phase is metastable and can be switched into a polar ferroelectric state (top panel) under an applied electric bias. 23951167 Structures of Streptococcus pneumoniae PiaA and Its Complex with Ferrichrome Reveal Insights into the Substrate Binding and Release of High Affinity Iron Transporters. Iron scarcity is one of the nutrition limitations that the Gram-positive infectious pathogens Streptococcus pneumoniae encounter in the human host. To guarantee sufficient iron supply, the ATP binding cassette (ABC) transporter Pia is employed to uptake iron chelated by hydroxamate siderophore, via the membrane-anchored substrate-binding protein PiaA. The high affinity towards ferrichrome enables PiaA to capture iron at a very low concentration in the host. We presented here the crystal structures of PiaA in both apo and ferrichrome-complexed forms at 2.7 and 2.1 Å resolution, respectively. Similar to other class III substrate binding proteins, PiaA is composed of an N-terminal and a C-terminal domain bridged by an α-helix. At the inter-domain cleft, a molecule of ferrichrome is stabilized by a number of highly conserved residues. Upon ferrichrome binding, two highly flexible segments at the entrance of the cleft undergo significant conformational changes, indicating their contribution to the binding and/or release of ferrichrome. Superposition to the structure of Escherichia coli ABC transporter BtuF enabled us to define two conserved residues: Glu119 and Glu262, which were proposed to form salt bridges with two arginines of the permease subunits. Further structure-based sequence alignment revealed that the ferrichrome binding pattern is highly conserved in a series of PiaA homologs encoded by both Gram-positive and negative bacteria, which were predicted to be sensitive to albomycin, a sideromycin antibiotic derived from ferrichrome. 23968584 An effective community-academic partnership to extend the reach of screenings for fall risk. Older adults should be screened for fall risk annually. Community providers (people without formal medical training who work with older adults in senior centers or aging services) may be a viable group to expand the reach of screenings. Our community-academic partnership developed a program to increase and assess fall risk screenings by community providers. Community sites hosted training workshops and screening events. Community screenings were well attended and received by providers and older adults. With administrative support from the regional fall prevention coalition and technical support from academia, community providers screened 161 older adults from a broad geographic area. Twenty-one community providers completed the training. Knowledge and confidence surveys demonstrated improvements before and after training (P < .001). Skills assessments demonstrated mastery of most skills, but some providers required additional training. Provider feedback indicated screening procedures were complex. Future projects will examine this model using simplified screening procedures. 23757174 A His-Tagged Melanocarpus albomyces Laccase and its Electrochemistry upon Immobilisation on NTA-Modified Electrodes and in Conducting Polymer Films. The article describes the construction, immobilisation and electrochemistry of histidine tagged laccase from Melanocarpus albomyces. A facile method of functionalisation of glassy carbon electrodes with nitrilotriacetic acid (NTA) using diazonium grafting and solid state chemistry is described. NTA-modified electrodes are shown to bind laccase which reduces oxygen at neutral pH in the presence of soluble redox mediator. Laccase-modified electrodes are also prepared by enzyme immobilisation within poly(aniline)/poly(vinylsulfonate) films. The polymer is found to efficiently retain the enzyme as well as provide direct electrical contact between the electrode and the enzyme active centre. Cyclic voltammetry reveals the direct electron transfer to the enzyme is dependent on the redox state of the polymer film. 23906948 Comparison of imputation methods for missing laboratory data in medicine. Missing laboratory data is a common issue, but the optimal method of imputation of missing values has not been determined. The aims of our study were to compare the accuracy of four imputation methods for missing completely at random laboratory data and to compare the effect of the imputed values on the accuracy of two clinical predictive models. Retrospective cohort analysis of two large data sets. A tertiary level care institution in Ann Arbor, Michigan. The Cirrhosis cohort had 446 patients and the Inflammatory Bowel Disease cohort had 395 patients. Non-missing laboratory data were randomly removed with varying frequencies from two large data sets, and we then compared the ability of four methods-missForest, mean imputation, nearest neighbour imputation and multivariate imputation by chained equations (MICE)-to impute the simulated missing data. We characterised the accuracy of the imputation and the effect of the imputation on predictive ability in two large data sets. MissForest had the least imputation error for both continuous and categorical variables at each frequency of missingness, and it had the smallest prediction difference when models used imputed laboratory values. In both data sets, MICE had the second least imputation error and prediction difference, followed by the nearest neighbour and mean imputation. MissForest is a highly accurate method of imputation for missing laboratory data and outperforms other common imputation techniques in terms of imputation error and maintenance of predictive ability with imputed values in two clinical predicative models. 23917739 Effect of cadmium on cytogenetic toxicity in hairy roots of Wedelia trilobata L. and their alleviation by exogenous CaCl2. Effects of cadmium (Cd) alone and in combination with calcium on mitosis and chromosomal aberration in the hairy root tips of Wedelia trilobata were investigated. The results showed that Cd concentrations below 50 Î¼mol/L had a lesser or even a promoting effect on the mitotic index (MI) and the rate of chromosomal aberration in hairy root tips, while those higher than 100 Î¼mol/L significantly decreased the MI and gradually stimulated the rate of chromosomal aberrations with prolonged time and increasing concentrations of Cd. Concentrations of 50 Î¼mol/L Cd mainly induced C-mitosis, while more than 100 Î¼mol/L Cd mainly caused chromosome breakage and chromosome adhesion in hairy root tip cells. When cultured with 300 Î¼mol/L Cd, micronuclei were only observed in the interphase, middle, and late phase of hairy root tip cells. Compared with untreated controls, exogenous calcium had an alleviating effect on Cd-induced cytotoxicity by effectively enhancing the MI and reducing the rate of chromosomal aberration in root tip cells. The results presented here provide evidence that W. trilobata hairy roots with rapid autonomous growth could be used as a sensitive tool for monitoring and evaluation of Cd pollution in the environment. 23799519 Demonstration of permanent porosity in flexible and guest-responsive organic zeolite analogs (now called MOFs). In the late 1990s rigorous proof of coordination polymer framework or MOF integrity in the absence of guest molecules still needed to be developed. A study by Kepert and Rosseinsky presented X-ray crystal structure refinements as one of the first definitive demonstrations of the retention of structural integrity of a porous coordination polymer framework upon complete desolvation and guest re-adsorption. 23948386 Comorbidity: a multidimensional approach. Comorbidity represents an extremely complex domain of research. An individual entity, the patient, is the center of gravity of a system characterized by multiple, complex, and interrelated conditions, disorders, or diseases. Such complexity is influenced by uncertainty that is difficult to decipher and is proportional to the number of associated morbidities. Computational scientists usually provide meta-analysis studies aimed at integrating various types of evidence, but in our opinion they may help reformulate comorbidity by emphasizing, in particular, two aspects: (i) a systems approach, which allows for an ensemble view of comorbidity, and offers a model representation generalizable to multimorbidity; and (ii) a dynamic network inference approach, which is indicated for the analysis of links among morbidities and evaluation of risk. Notably, the main question remains whether such instruments suggest a shift of paradigm providing prospective impact on medical practice. We have identified in the simultaneous consideration of multiple dimensions linked to comorbidity complexity the rationale for such translation. 22473703 Antitrypanosomal properties of Panax ginseng C. A. Meyer: new possibilities for a remarkable traditional drug. African trypanosomiasis is still a major health problem in many sub-Saharan countries in Africa. We investigated the effects of three preparations of Panax ginseng, Panax notoginseng, isolated ginsenosides, and the polyacetylene panaxynol on Trypanosoma brucei brucei and the human cancer cell line HeLa. Hexane extracts and the pure panaxynol were toxic and at the same time highly selective against T. b. brucei, whereas methanol extracts and 12 isolated ginsenosides were significantly less toxic and showed only weak selectivity. Panaxynol was cytotoxic against T. b. brucei at the concentration of 0.01 µg/mL with a selectivity index of 858, superior even to established antitrypanosomal drugs. We suggest that the inhibition of trypanothione reductase, which is only found in trypanosomes, might explain the observed selectivity. The high selectivity together with a cytotoxic concentration in the range of the bioavailability makes panaxynol and other polyacetylenes in general very promising lead compounds for the treatment of African trypanosomiasis. 23815291 Amyloid precursor proteins are constituents of the presynaptic active zone. The amyloid precursor protein (APP) and its mammalian homologs, APLP1, APLP2, have been allocated to an organellar pool residing in the Golgi apparatus and in endosomal compartments, and in its mature form to a cell surface-localized pool. In the brain, all APPs are restricted to neurons; however, their precise localization at the plasma membrane remained enigmatic. Employing a variety of subcellular fractionation steps, we isolated two synaptic vesicle (SV) pools from rat and mouse brain, a pool consisting of synaptic vesicles only and a pool comprising SV docked to the presynaptic plasma membrane. Immunopurification of these two pools using a monoclonal antibody directed against the 12 membrane span synaptic vesicle protein2 (SV2) demonstrated unambiguously that APP, APLP1 and APLP2 are constituents of the active zone of murine brain but essentially absent from free synaptic vesicles. The specificity of immunodetection was confirmed by analyzing the respective knock-out animals. The fractionation experiments further revealed that APP is accumulated in the fraction containing docked synaptic vesicles. These data present novel insights into the subsynaptic localization of APPs and are a prerequisite for unraveling the physiological role of all mature APP proteins in synaptic physiology. 23726664 The effect of road transport in comparison to a novel environment on the physiological, metabolic and behavioural responses of bulls. The objective was to investigate the effect of 18h road transport with a 12h mid-journey rest period in comparison to the exposure of bulls to a novel environment on physiological, metabolic and behavioural responses of beef bulls. Thirty Charolais sired crossbred beef bulls (mean 486.0, s.d. 57.0kg) were assigned by live weight to one of the two treatments, transport (T) (9h+9h) (n=15) and not-transported (NT) (n=15) on day 0. The bulls were transported at a spatial allowance of 1.3m(2)/animal by road for 9h, unloaded and rested for a 12h rest period, re-loaded and transported for a further 9h journey by road followed by a 2h rest period on the transporter, then unloaded and rested in a lairage for 24h with access to hay and water. Plasma albumin and urea concentrations increased (P<0.05) after the first 9h journey with values returning to baseline at the end of the 24h recovery period. There was a transient increase in haematocrit% in T and NT at sampling time points corresponding to the completion of the first 9h journey. Bulls spent longer time lying (P<0.05) during the first 9h journey compared with the percentage time spent lying during the second 9h journey. Differences in live weight, behaviour, and some blood variables show that transport is more stressful for bulls than being subjected to a novel environment and management, and while some biological variables returned to baseline values, others require a longer time (plasma haptoglobin, total protein, glucose and NEFA concentrations). Thus, the effective recovery of bulls exposed to an 18h transport journey by road would suggest that a rest period of at least 24h with access to feed and water is required before further transport. 23931652 East is east and West is west: Perspectives on the menopause in Asia and The West. ABSTRACT There is a school of thought, which believes that menopausal symptoms are a peculiarly 'Western' phenomenon, not experienced by women from other regions and particularly not from Asia where, it has been claimed, dietary, social and cultural factors afforded protection for women living in that region. More recently studies conducted in multi ethnic communities living in Western countries as well as in Asian communities have found that the menopause and its consequences are similar worldwide. Ethnic differences within Asia account for small differences in endogenous hormone levels and age at menopause between Asian and Western women and the type of menopause symptoms and their prevalence also differ between those two communities. However, like the West and perhaps because of a Western influence, the long term health problems of post menopausal women including cardiovascular disease, osteoporosis and breast cancer are of major importance to Asian women and health services in the 21(st) century. 23595637 Protective Effects of HemoHIM on Immune and Hematopoietic Systems Against γ-Irradiation. We examined the effect of HemoHIM on the protective efficacy of hematopoietic stem cells and on the recovery of immune cells against sublethal doses of ionizing radiation. Two-month-old mice were exposed to γ-rays at a dose of 8, 6.5, or 5 Gy for a30-day survival study, endogenous spleen colony formation, or other experiments, respectively. HemoHIM was injected intraperitoneally before and after irradiation. Our results showed that HemoHIM significantly decreased the mortality of sublethally irradiated mice. The HemoHIM administration decreased the apoptosis of bone marrow cells in irradiated mice. On the other hand, HemoHIM increased the formation of endogenous spleen colony in irradiated mice. In irradiated mice, the recovery of total leukocytes in the peripheral blood and lymphocytes in the spleen were enhanced significantly by HemoHIM. Moreover, the function of B cells, T cells, and NK cells regenerated in irradiated mice were significantly improved by the administration of HemoHIM. HemoHIM showed an ideal radioprotector for protecting hematopoietic stem cells and for accelerating the recovery of immune cells. We propose HemoHIM as a beneficial supplement drug during radiotherapy to alleviate adverse radiation-induced effects for cancer patients. Copyright © 2013 John Wiley & Sons, Ltd. 23960445 Urinary biomarkers for early detection of recovery in patients with acute kidney injury. Urinary biomarkers of acute kidney injury (AKI) have been revealed recently to be useful for prior prediction of AKI. However, it is unclear whether these urinary biomarkers can also detect recovery from established AKI. Urinary biomarkers, including neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C, were measured every 2 days for 8 days in 66 patients with AKI. At day 0, there were no significant differences in plasma creatinine, BUN, and urine cystatin C between AKI patients in the recovery (n = 33) and non-recovery (n = 33) groups. Plasma creatinine concentrations were significantly lower in the recovery group (3.0 ± 2.0 mg/dL) than in the non-recovery group (5.4 ± 1.9 mg/dL) on day 4 after AKI diagnosis (P < 0.001). In contrast, there were significant differences in urine NGAL between the two groups starting on day 0 (297.2 ± 201.4 vs 407.6 ± 190.4 ng/mL, P = 0.025) through the end of the study (123.7 ± 119.0 vs 434.3 ± 121.5 ng/mL, P < 0.001). The multiple logistic regression analysis showed that urine NGAL could independently predict recovery from AKI. Conclusively, this prospective observational study demonstrates that urine NGAL can be a highly versatile marker for early detection of the recovery phase in established AKI patients. 23668938 VdTX-1, a reversible nicotinic receptor antagonist isolated from venom of the spider Vitalius dubius (Theraphosidae). Theraphosid spider venoms can block neurotransmission in vertebrate nerve-muscle preparations in vitro, but few of the components involved have been characterized. In this work, we describe the neuromuscular activity of venom from the Brazilian theraphosid Vitalius dubius and report the purification and pharmacological characterization of VdTX-1, a 728 Da toxin that blocks nicotinic receptors. Neuromuscular activity was assayed in chick biventer cervicis preparations and muscle responses to exogenous ACh and KCl were determined before and after incubation with venom or toxin. Changes in membrane resting potential were studied in mouse diaphragm muscle. The toxin was purified by a combination of filtration through Amicon® filters, cation exchange HPLC and RP-HPLC; toxin purity and mass were confirmed by mass spectrometry. Venom caused progressive neuromuscular blockade and muscle contracture; the blockade but not the contracture was reversible by washing. Venom attenuated contractures to exogenous ACh and KCl. Filtration yielded low (LM, <5 kDa) and high (HM, >5 kDa) fractions, with the latter reproducing the contracture seen in venom but with a slight and progressive twitch blockade. The LM fraction caused reversible blockade and attenuated contractures to ACh, but had no effect on contractures to KCl. VdTX-1 (728 Da) purified from the LM fraction was photosensitive and reduced the E(max) to ACh in biventer cervicis muscle without affecting the EC₅₀; VdTX-1 also abolished carbachol-induced depolarizations. V. dubius venom contains at least two components that affect vertebrate neurotransmission. One component, VdTX-1, blocks nicotinic receptors non-competitively to produce reversible blockade without muscle contracture. 23585096 Biocatalytic and structural properties of a highly engineered halohydrin dehalogenase. Two highly engineered halohydrin dehalogenase variants were characterized in terms of their performance in dehalogenation and epoxide cyanolysis reactions. Both enzyme variants outperformed the wild-type enzyme in the cyanolysis of ethyl (S)-3,4-epoxybutyrate, a conversion yielding ethyl (R)-4-cyano-3-hydroxybutyrate, an important chiral building block for statin synthesis. One of the enzyme variants, HheC2360, displayed catalytic rates for this cyanolysis reaction enhanced up to tenfold. Furthermore, the enantioselectivity of this variant was the opposite of that of the wild-type enzyme, both for dehalogenation and for cyanolysis reactions. The 37-fold mutant HheC2360 showed an increase in thermal stability of 8 °C relative to the wild-type enzyme. Crystal structures of this enzyme were elucidated with chloride and ethyl (S)-3,4-epoxybutyrate or with ethyl (R)-4-cyano-3-hydroxybutyrate bound in the active site. The observed increase in temperature stability was explained in terms of a substantial increase in buried surface area relative to the wild-type HheC, together with enhanced interfacial interactions between the subunits that form the tetramer. The structures also revealed that the substrate binding pocket was modified both by substitutions and by backbone movements in loops surrounding the active site. The observed changes in the mutant structures are partly governed by coupled mutations, some of which are necessary to remove steric clashes or to allow backbone movements to occur. The importance of interactions between substitutions suggests that efficient directed evolution strategies should allow for compensating and synergistic mutations during library design. 23361897 The impact of perineural invasion and/or lymphovascular invasion on the survival of early-stage oral squamous cell carcinoma patients. For early-stage oral squamous cell carcinoma (OSCC) patients, the impact of perineural invasion (PNI) and lymphovascular invasion (LVI) on disease control and survival has not been clarified. The medical records of all early-stage OSCC patients who underwent curative surgery between 2004 and 2009 were reviewed. A total of 442 early stage patients were included in this study. There were 360 patients in group A (without PNI or LVI) and 82 patients in group B (with PNI and/or LVI). Between groups A and B patients, there were no significant differences in the 5-year disease-free survival (73.8 vs 68.7 %, p = 0.48) and overall survival (90.9 vs 86.1 %, p = 0.25). Between groups A and B patients without postoperative radiotherapy (PORT), there were no significant differences in the 5-year disease-free survival (73.8 vs 70.2 %, p = 0.51) and overall survival (90.9 vs 85.2 %, p = 0.18). Between group B patients with and without PORT, there was no significant difference in either the disease-free survival (61.1 vs 70.2 %, p = 0.98) and overall survival (88.9 vs 85.2 %, p = 0.64). Multivariate analyses revealed that PNI, LVI, and PORT could not provide significant effect on treatment outcome. PNI and LVI were not significant risk factors for the disease control and overall survival for early stage OSCC patients. Furthermore, PORT could not provide an additional benefit for the disease control and overall survival for stages I and II OSCC patients with PNI and/or LVI. 23700312 Enhancer networks revealed by correlated DNAse hypersensitivity states of enhancers. Mammalian gene expression is often regulated by distal enhancers. However, little is known about higher order functional organization of enhancers. Using ∼100 K P300-bound regions as candidate enhancers, we investigated their correlated activity across 72 cell types based on DNAse hypersensitivity. We found widespread correlated activity between enhancers, which decreases with increasing inter-enhancer genomic distance. We found that correlated enhancers tend to share common transcription factor (TF) binding motifs, and several chromatin modification enzymes preferentially interact with these TFs. Presence of shared motifs in enhancer pairs can predict correlated activity with 73% accuracy. Also, genes near correlated enhancers exhibit correlated expression and share common function. Correlated enhancers tend to be spatially proximal. Interestingly, weak enhancers tend to correlate with significantly greater numbers of other enhancers relative to strong enhancers. Furthermore, strong/weak enhancers preferentially correlate with strong/weak enhancers, respectively. We constructed enhancer networks based on shared motif and correlated activity and show significant functional enrichment in their putative target gene clusters. Overall, our analyses show extensive correlated activity among enhancers and reveal clusters of enhancers whose activities are coordinately regulated by multiple potential mechanisms involving shared TF binding, chromatin modifying enzymes and 3D chromatin structure, which ultimately co-regulate functionally linked genes. 23861596 Safety and efficacy of an add-on therapy with curcumin phytosome and piperine and/or lipoic acid in subjects with a diagnosis of peripheral neuropathy treated with dexibuprofen. We conducted an 8-week, open, randomized controlled clinical trial on 141 subjects affected by neuropathic pain to investigate the role of an adjunctive therapy added to the administration of dexibuprofen (400 mg twice a day) and based on a multi-ingredient formula (Lipicur), consisting of lipoic acid plus curcumin phytosome and piperine, in patients with a diagnosis of lumbar sciatica, lumbar disk herniation, and/or lumbar canal stenosis (96 subjects), or with carpal tunnel syndrome (45 subjects). A total of 135 participants completed the study. Treatment with the multi-ingredient formula (Lipicur) reduced neuropathic pain by more than 66% in both conditions (subjects with lumbar sciatica and with carpal tunnel syndrome), and these reductions were statistically significant. Moreover, the treatment reduced dexibuprofen use by about 40%. An add-on therapy with only lipoic acid has not shown any significant results. On the basis of its safety and efficacy, Lipicur could be considered an effective complementary therapy to be added to conventional treatments to achieve better efficacy in reducing neuropathic pain. 23643699 Evaluation of genotoxicity of nitrile fragrance ingredients using in vitro and in vivo assays. Genotoxicity studies were conducted on a group of 8 fragrance ingredients that belong to the nitrile family. These nitriles are widely used in consumer products however there is very limited data in the literature regarding the genotoxicity of these nitriles. The 8 nitriles were assessed for genotoxicity using an Ames test, in-vitro chromosome aberration test or in-vitro micronucleus test. The positive results observed in the in-vitro tests were further investigated using an in-vivo micronucleus test. The results from these different tests were compared and these 8 nitriles are not considered to be genotoxic. Dodecanitrile and 2,2,3-trimethylcyclopent-3-enylacetonitrile were negative in the in-vitro chromosome aberration test and in-vitro micronucleus test, respectively. While citronellyl nitrile, 3-methyl-5-phenylpentanenitrile, cinnamyl nitrile, and 3-methyl-5-phenylpent-2-enenitrile revealed positive results in the in-vitro tests, but confirmatory in-vivo tests determined these nitriles to be negative in the in-vivo micronucleus assay. The remaining two nitriles (benzonitrile and α-cyclohexylidene benzeneacetonitrile) were negative in the in-vivo micronucleus test. This study aims to evaluate the genotoxicity potential of these nitriles as well as enrich the literature with genotoxicity data on fragrance ingredients. 23702659 Plasmin promotes foam cell formation by increasing macrophage catabolism of aggregated low-density lipoprotein. The plasmin/plasminogen system is involved in atherosclerosis. However, the mechanisms by which it stimulates disease are not fully defined. A key event in atherogenesis is the deposition of low-density lipoprotein (LDL) on arterial walls where it is modified, aggregated, and retained. Macrophages are recruited to clear the lipoproteins, and they become foam cells. The goal of this study was to assess the role of plasmin in macrophage uptake of aggregated LDL and foam cell formation. Plasminogen treatment of macrophages catabolizing aggregated LDL significantly accelerated foam cell formation. Macrophage interaction with aggregated LDL increased the surface expression of urokinase-type plasminogen activator receptor and plasminogen activator activity, resulting in increased ability to generate plasmin at the cell surface. The high local level of plasmin cleaves cell-associated aggregated LDL, allowing a portion of the aggregate to become sequestered in a nearly sealed, yet extracellular, acidic compartment. The low pH in the plasmin-induced compartment allows lysosomal enzymes, delivered via lysosome exocytosis, greater activity, resulting in more efficient cholesteryl ester hydrolysis and delivery of a large cholesterol load to the macrophage, thereby promoting foam cell formation. These findings highlight a critical role for plasmin in the catabolism of aggregated LDL by macrophages and provide a new context for considering the atherogenic role of plasmin. 23941719 Test-retest reliability of biodex system 4 pro for isometric ankle-eversion and -inversion measurement. Context: The lack of knowledge about isometric ankle testing indicates the need for research in this area. Objective: to assess test-retest reliability and to determine the optimal position for isometric ankle-eversion and -inversion testing. Design: Test-retest reliability study. Isometric ankle eversion and inversion were assessed in 3 different dynamometer foot-plate positions: 0°, 7°, and 14° of inversion. Two maximal repetitions were performed at each angle. Both limbs were tested (40 ankles in total). The test was performed 2 times with a period of 7 d between the tests. Setting: University hospital. Participants: The study was carried out on 20 healthy athletes with no history of ankle sprains. Main Outcome Measures: Reliability was assessed using intraclass correlation coefficient (ICC2,1); minimal detectable change (MDC) was calculated using a 95% confidence interval. Paired t test was used to measure statistically significant changes, and P <.05 was considered statistically significant. Results: Eversion and inversion peak torques showed high ICCs in all 3 angles (ICC values .87-.96, MDC values 3.09-6.81 Nm). Eversion peak torque was the smallest when testing at the 0° angle and gradually increased, reaching maximum values at 14° angle. The increase of eversion peak torque was statistically significant at 7 ° and 14° of inversion. Inversion peak torque showed an opposite pattern-it was the smallest when measured at the 14° angle and increased at the other 2 angles; statistically significant changes were seen only between measures taken at 0° and 14°. Conclusions: Isometric eversion and inversion testing using the Biodex 4 Pro system is a reliable method. The authors suggest that the angle of 7° of inversion is the best for isometric eversion and inversion testing. 23561104 Sonicated pineapple juice as substrate for L. casei cultivation for probiotic beverage development: Process optimisation and product stability. The aim of this study was to evaluate the use of sonicated pineapple juice as substrate for producing a probiotic beverage by Lactobacillus casei NRRL B442. Maximal microbial viability was found by cultivating L. casei at 31°C and pH 5.8 (optimised conditions). After fermentation, samples of sweetened and non-sweetened juice were stored. After 42days of storage under refrigeration (4°C), the microbial viability was 6.03LogCFU/mL in the non-sweetened sample and 4.77LogCFU/mL in the sweetened sample. The pH of both samples decreased during storage due to lactic acid production (post acidification). The characteristic colour of the juice was maintained throughout the shelf life and no browning was observed. Sonicated pineapple juice was shown to be a suitable substrate for L. casei cultivation and for the development of an alternative non-dairy probiotic beverage. 23915416 Mycotic keratitis caused by concurrent infections of Exserohilum mcginnisii and Candida parapsilosis. Mycotic keratitis in human cornea has been rarely reported to be associated with a co-infection of filamentous fungi and yeast. This paper aims to report a case of mycotic keratitis concurrently infected by Exserohilum mcginnisii and Candida parapsilosis. A Chinese female presented two superposed corneal infiltrates with different size and texture on her left eye. In vivo confocal microscopy showed hyper-reflective multiple linear with highly branching structures distributing in the anterior corneal stroma. Inoculations of the corneal lesion scrape concurrently grew two similar superposed colonies on Sabouraud dextrose and chocolate agar plate. The larger colony exhibited mould, cottony and floccose at the edge, while the smaller one showed creamy and shiny surface. Modified slide culture for mould revealed hyphae were septate, and conidia were brown, smooth-walled, cylindrical to slight clavate with 6 to 13 pseudosepta. Based on the morphology of microscopic and macroscopic characteristics, the mould was identified as Exserohilum mcginnisii. Smear of the non-mould colony showed ellipse or ovoid budding yeast-like cells with abundant pseudomycelium. Vitek Yeast Biochemical Card test identified the yeast as Candida parapsilosis. With treatment of combined oral itraconazole with topical amphotericin B, a complete resolution of the corneal infiltrate was achieved within 1.5 months. This is the first documented case of human corneal infection by Exserohilum mcginnisii, and also the first report providing evidence of mycotic keratitis in human cornea concurrently infected by filamentous fungi and yeast. 23886661 Sleep disordered breathing in Parkinson's disease: A critical appraisal. Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by resting tremor, rigidity, bradykinesia and postural instability, and is associated with non-motor features, including sleep abnormalities. The high prevalence of excessive daytime sleepiness and snoring in PD patients has led to the suggestion that sleep disordered breathing (SDB) is more common in these individuals than in normal subjects. We aimed to review the literature on SDB prevalence and its clinical repercussions in PD. A PubMed search was performed to identify controlled studies, published from January 1990 through October 2012, which addressed the prevalence of SDB diagnosed by polysomnography in idiopathic PD. From the seven studies included, five reported similar or lower prevalence of SDB in patients when compared to healthy age-matched controls. Two studies reported less oxyhemoglobin desaturation during sleep among patients. These results did not support the idea that PD patients are at increased risk of SDB and indicate that they may not present significant hypoxemia. The prevalence of obstructive sleep apnea syndrome and the long-term outcomes of disordered breathing events during sleep have not been adequately studied in PD. 23757299 Role of GLI-1 in epidermal growth factor-induced invasiveness of ARCaPE prostate cancer cells. Epidermal growth factor (EGF) signaling and Hedgehog (HH) signaling are both involved in prostate cancer (PCa) progression, yet the mechanisms through which these two pathways are synergistically linked require elucidation. In the present study, we aimed to ascertain how EGF and the HH signaling transcription factor GLI-1 are linked in prostate cancer invasiveness. ARCaP human prostate cancer cells, which included ARCaPE and ARCaPM cells, were used as a model in the present study. The expression of EGF receptor (EGFR) and the HH signaling transcriptional factor GLI-1 were detected in ARCaPE cells by immunofluorescence, and the ARCaPE cells were treated with human recombinant EGF protein (hrEGF) for 4 consecutive days in vitro. Transwell invasion assays were performed in the ARCaPE cells following treatment with DMSO (vehicle control), hrEGF, GATN61 (GLI-1-specific inhibitor), hrEGF plus GANT61 and in the ARCaPM cells. The expression of phosphorylated extracellular signal regulated kinase (p-ERK), total ERK and GLI-1 was detected by western blotting in ARCaPE cells at different time-points following treatment with hrEGF. The expression of EGFR and GLI-1 was detected in ARCaPE cells, which exhibited a cobblestone-like morphology, while after treatment with hrEGF, the cell morphology was altered to a spindle-shaped mesenchymal cell morphology. Transwell invasion assays demonstrated that hrEGF dramatically enhanced the invasive capability of the ARCaPE cells (p<0.05). Additionally, western blot assay demonstrated that the expression levels of p-ERK and GLI-1 in ARCaPE cells increased in a time-dependent manner after treatment with hrEGF (p<0.05); however, the expression levels of total ERK in the cells remained relatively unchanged. It also demonstrated that the GLI-1 inhibitor GANT61 could reverse the enhanced invasive effect induced by EGF in ARCaPE cells (p<0.05). Our preliminary in vitro study showed that EGF signaling may increase the invasive capability of ARCaPE human prostate cancer cells via upregulation of p-ERK and the HH signaling transcriptional factor GLI-1. Additionally, this enhanced cell invasive effect was reversed by a GLI-1-specific inhibitor in vitro. Consequently, it indicates that both EGF and HH signaling are synergistically involved in the progression of human prostate cancer ARCaP cells, and GlI-1 may be one of the important effectors, which is activated by EGF downstream signaling, to promote the invasiveness of ARCaPE prostate cancer cells. 23519574 Nicotine-, tobacco particulate matter- and methamphetamine-produced locomotor sensitisation in rats. RATIONALE: Repeated nicotine exposure produces a weak and transient sensitised locomotor response in rats. Since tobacco smoke contains thousands of non-nicotine chemical constituents, these could alter the sensitised response. OBJECTIVES: This study aims to compare the magnitude, persistence and spatial distribution of locomotor sensitisation produced by repeated doses of nicotine, aqueous tobacco particulate matter (TPM) and a positive methamphetamine control. METHODS: Male Sprague-Dawley rats received five nicotine (0.0, 0.2 or 0.4 mg/kg), TPM (containing 0.2 or 0.4 mg/kg nicotine) or methamphetamine (0.5 mg/kg) injections every second day, followed by a 4-day withdrawal before the first challenge (Challenge 1, C1). The animals were re-challenged again at 15 days post C1 to test for the persistence of sensitisation (Challenge 2, C2). RESULTS: There were no major differences in sensitisation profile between nicotine and TPM. At the lowest 0.2 mg/kg nicotine/TPM dose, however, small differences emerged on select test days. CONCLUSIONS: The results indicated that the non-nicotinic agents in TPM did not greatly impact the nicotine-produced locomotor-sensitised response. These findings might suggest that the differential pharmacological properties of TPM do not have major clinical significance. Alternatively, the locomotor model might not expose effects of non-nicotinic constituents, and furthermore, might not closely relate to human tobacco dependence. Different reward-related behavioural models should also be utilised to assess potential effects of non-nicotinic constituents before a role in dependence is discounted. 23825197 The dose-response relationship between in-ear occupational noise exposure and hearing loss. Current understanding of the dose-response relationship between occupational noise and hearing loss is based on cross-sectional studies prior to the widespread use of hearing protection, and with limited data regarding noise exposures below 85 dBA. We report on the hearing loss experience of a unique cohort of industrial workers, with daily monitoring of noise inside of hearing protection devices. At an industrial facility, workers exhibiting accelerated hearing loss were enrolled in a mandatory programme to monitor daily noise exposures inside of hearing protection. We compared these noise measurements (as time-weighted LAVG) to interval rates of high-frequency hearing loss over a 6-year period using a mixed-effects model, adjusting for potential confounders. Workers' high-frequency hearing levels at study inception averaged more than 40 dB Hearing threshold level (HTL). Most noise exposures were less than 85 dBA (mean LAVG 76 dBA, IQR 74-80 dBA). We found no statistical relationship between LAvg and high-frequency hearing loss (p=0.53). Using a metric for monthly maximum noise exposure did not improve model fit. At-ear noise exposures below 85 dBA did not show an association with risk of high-frequency hearing loss among workers with substantial past noise exposure and hearing loss at baseline. Therefore, effective noise control to below 85 dBA may lead to significant reduction in occupational hearing loss risk in such individuals. Further research is needed on the dose-response relationship of noise and hearing loss in individuals with normal hearing and little prior noise exposure. 23880920 Value of ultrasound in detecting central compartment lymph node metastases in differentiated thyroid carcinoma. The value of ultrasound in detecting central compartment lymph node metastasis in patients with well-differentiated thyroid carcinoma (WDTC) is unclear. Prospective patients with WDTC attending a university-affiliated tertiary medical center between July 2010 and June 2011 underwent neck ultrasound for detection of central compartment lymph node metastases prior to surgery. Central lymph node dissection was performed during the initial surgery regardless of ultrasound findings. The sensitivity and specificity of preoperative ultrasound in detecting central lymph node metastases were calculated according to the final histopathological results. Sixty-four patients met the study criteria. Twenty-four had pathologic central compartment lymph nodes according to preoperative ultrasound, 20 of which were confirmed by histological examination. One patient was found to have pathological central lymph nodes by histology which was not detected by US. Sensitivity of preoperative ultrasound was 95 %, specificity 90 %, and negative and positive predictive values 97 and 83 %, respectively. Preoperative ultrasound may serve as an accurate and important tool for deciding the extent of surgery in WDTC. 23910711 Modeling freedom from progression for standard-risk medulloblastoma: a mathematical tumor control model with multiple modes of failure. As pediatric medulloblastoma (MB) is a relatively rare disease, it is important to extract the maximum information from trials and cohort studies. Here, a framework was developed for modeling tumor control with multiple modes of failure and time-to-progression for standard-risk MB, using published pattern of failure data. Outcome data for standard-risk MB published after 1990 with pattern of relapse information were used to fit a tumor control dose-response model addressing failures in both the high-dose boost volume and the elective craniospinal volume. Estimates of 5-year event-free survival from 2 large randomized MB trials were used to model the time-to-progression distribution. Uncertainty in freedom from progression (FFP) was estimated by Monte Carlo sampling over the statistical uncertainty in input data. The estimated 5-year FFP (95% confidence intervals [CI]) for craniospinal doses of 15, 18, 24, and 36 Gy while maintaining 54 Gy to the posterior fossa was 77% (95% CI, 70%-81%), 78% (95% CI, 73%-81%), 79% (95% CI, 76%-82%), and 80% (95% CI, 77%-84%) respectively. The uncertainty in FFP was considerably larger for craniospinal doses below 18 Gy, reflecting the lack of data in the lower dose range. Estimates of tumor control and time-to-progression for standard-risk MB provides a data-driven setting for hypothesis generation or power calculations for prospective trials, taking the uncertainties into account. The presented methods can also be applied to incorporate further risk-stratification for example based on molecular biomarkers, when the necessary data become available. 23912191 Identification and treatment of comorbidities in idiopathic pulmonary fibrosis and other fibrotic lung diseases. The interstitial lung diseases (ILDs) frequently result in considerable disability and reduced survival in affected patients. Unfortunately, they are often poorly responsive to available therapies. Comorbidities, both pulmonary and nonpulmonary, frequently accompany ILDs and contribute to adverse outcomes. Multiple comorbidities, including gastroesophageal reflux disease, venous thromboembolism, coronary artery disease, sleep-disordered breathing, depression, emphysema, pulmonary hypertension, and lung cancer contribute to the morbidity and mortality of fibrotic lung disease. The identification and treatment of comorbidities may improve morbidity and potentially impact mortality in patients with ILD. A high index of suspicion and an awareness of the spectrum of comorbidities are important in optimizing outcomes in this group of patients. 23873437 Time-varying effect moderation using the structural nested mean model: estimation using inverse-weighted regression with residuals. This article considers the problem of examining time-varying causal effect moderation using observational, longitudinal data in which treatment, candidate moderators, and possible confounders are time varying. The structural nested mean model (SNMM) is used to specify the moderated time-varying causal effects of interest in a conditional mean model for a continuous response given time-varying treatments and moderators. We present an easy-to-use estimator of the SNMM that combines an existing regression-with-residuals (RR) approach with an inverse-probability-of-treatment weighting (IPTW) strategy. The RR approach has been shown to identify the moderated time-varying causal effects if the time-varying moderators are also the sole time-varying confounders. The proposed IPTW+RR approach provides estimators of the moderated time-varying causal effects in the SNMM in the presence of an additional, auxiliary set of known and measured time-varying confounders. We use a small simulation experiment to compare IPTW+RR versus the traditional regression approach and to compare small and large sample properties of asymptotic versus bootstrap estimators of the standard errors for the IPTW+RR approach. This article clarifies the distinction between time-varying moderators and time-varying confounders. We illustrate the methodology in a case study to assess if time-varying substance use moderates treatment effects on future substance use. Copyright © 2013 John Wiley & Sons, Ltd. 23922334 Effect of high porosity on biodegradation of poly (4-hydroxybutyrate) in vivo. Poly-4-hydroxybutyrate, P(4HB), is a biosynthetic thermoplastic polymer that has been studied as a bio-absorbable medical material. In order to explore the in vivo biodegradation behaviour of porous P(4HB) membranes with specified apertures (89-150 µm), membranes with different porosities were implanted subcutaneously into the backs of 27 eight-week-old Sprague Dawley® rats. The implanted specimens were examined with Masson and hematoxylin and eosin staining. Masson staining indicated that the P(4HB) membranes were encased in fibrous cysts and that more collagen fibers were present within the sections of the hyper-porosity group. Hematoxylin and eosin staining showed that the residual area of the P(4HB) membranes in the hyper-porosity group decreased sharply compared to the hypo-porosity group, which implied that the P(4HB) membranes with higher porosity degraded faster than those with lower porosity. A slow degradation phase persisted for approximately 14 weeks during the degradation process. After the 16th week, the P(4HB) scaffolds fell into a fast degradation phase. The residual areas of the hyper-porosity P(4HB) membranes at the 32nd week were reduced by 39.76% compared with the second week after implantation. We concluded that P(4HB) membranes manifest a special biodegradation behavior in vivo and that the increased porosity of these membranes is an important factor favoring their biodegradation rates. 23922716 An impact study of the design of exergaming parameters on body intensity from objective and gameplay-based player experience perspectives, based on balance training exergame. Kinect-based exergames allow players to undertake physical exercise in an interactive manner with visual stimulation. Previous studies focused on investigating physical fitness based on calories or heart rate to ascertain the effectiveness of exergames. However, designing an exergame for specific training purposes, with intensity levels suited to the needs and skills of the players, requires the investigation of motion performance to study player experience. This study investigates how parameters of a Kinect-based exergame, combined with balance training exercises, influence the balance control ability and intensity level the player can tolerate, by analyzing both objective and gameplay-based player experience, and taking enjoyment and difficulty levels into account. The exergame tested required participants to maintain their balance standing on one leg within a posture frame (PF) while a force plate evaluated the player's balance control ability in both static and dynamic gaming modes. The number of collisions with the PF depended on the frame's travel time for static PFs, and the leg-raising rate and angle for dynamic PFs. In terms of center of pressure (COP) metrics, significant impacts were caused by the frame's travel time on MDIST-AP for static PFs, and the leg-raising rate on MDIST-ML and TOTEX for dynamic PFs. The best static PF balance control performance was observed with a larger frame offset by a travel time of 2 seconds, and the worst performance with a smaller frame and a travel time of 1 second. The best dynamic PF performance was with a leg-raising rate of 1 second at a 45-degree angle, while the worst performance was with a rate of 2 seconds at a 90-degree angle. The results demonstrated that different evaluation methods for player experience could result in different findings, making it harder to study the design of those exergames with training purposes based on player experience. 23607861 Alterations in bile acid synthesis in carriers of hepatocyte nuclear factor 1α mutations. Heterozygous mutations in hepatocyte nuclear factor 1α (HNF1α) cause maturity onset diabetes of the young 3 (MODY3), an autosomal dominant form of diabetes. Deficiency of HNF1α in mice results in diabetes, hypercholesterolaemia and increased bile acid (BA) and cholesterol synthesis. Little is known about alterations in lipid metabolism in patients with MODY3. The aim of this study was to investigate whether patients with MODY3 have altered cholesterol and BA synthesis and intestinal cholesterol absorption. A secondary aim was to investigate the effects of HNF1α mutations on the transcriptional regulation of BA metabolism. Plasma biomarkers of BA and cholesterol synthesis and intestinal cholesterol absorption were measured in patients with MODY3 (n = 19) and in matched healthy control subjects (n = 15). Cotransfection experiments were performed with several promoters involved in BA metabolism along with expression vectors carrying the mutations found in these patients. Plasma analysis showed higher levels of BA synthesis in patients with MODY3. No differences were observed in cholesterol synthesis or intestinal cholesterol absorption. Cotransfection experiments showed that one of the mutations (P379A) increased the induction of the cholesterol 7α-hydroxylase promoter compared with HNF1α, without further differences in other studied promoters. By contrast, the other four mutations (L107I, T260M, P291fsinsC and R131Q) reduced the induction of the farnesoid X receptor (FXR) promoter, which was followed by reduced repression of the small heterodimer partner promoter. In addition, these mutations also reduced the induction of the apical sodium-dependent bile salt transporter promoter. BA synthesis is increased in patients with MODY3 compared with control subjects. Mutations in HNF1α affect promoters involved in BA metabolism. 23948933 Analysis of HSPA8 and HSPA9 mRNA Expression and Promoter Methylation in the Brain and Blood of Alzheimer's Disease Patients. Alzheimer's disease (AD) is the most common form of dementia in elderly. Chaperones may have a crucial role in AD due to their involvement in protein quality control, folding, and degradation. In this study, we investigated the mRNA and promoter DNA methylation levels of two chaperones, HSPA8 and HSPA9, in postmortem brain tissue (entorhinal and auditory cortices and hippocampus) from healthy elderly and AD subjects as well as in peripheral blood of healthy elderly and AD patients. mRNA quantification was performed by qRT-PCR and DNA methylation by mass spectrometry. In the peripheral blood, we did not observe a significant difference in HSPA8 and HSPA9 expression between elderly controls and AD. A significant downregulation of HSPA8 and HSPA9 was observed in AD across the three brain regions compared to the controls, suggesting their participation in AD pathogenesis. However, no important DNA methylation differences were observed, suggesting that other mechanism may be involved in controlling these genes expression. 23769860 The prevalence of porcine teschovirus in the pig population in northeast of China. The prevalence of porcine teschovirus (PTV) in swine herds in northeast China was investigated. In 2008-2009, 1384 samples of pig sera were collected from 42 farms in Shandong, Hebei, Heilongjiang, and Jilin provinces and in Tianjin City and were tested for specific antibody against PTV-8 by immunofluorescence assay. All 42 pig herds were positive for antibodies against PTV-8, and 61.3% of the serum samples were PTV-8 positive. During the survey, one PTV strain was isolated and named Fuyu/2009; phylogenetic analysis showed that the PTV Fuyu/2009 belongs to the PTV-8 serotype. The serological results indicate that most if not all pig herds in northeast of China have been exposed to PTV. RT-PCR performed on 114 clinical samples indicated a possible association between PTV and disease. According to genotyping based on partial VP1 sequences, four serotypes (PTV-2, -4, -6, and -8) were identified in northeast of China; sequence data also provided evidence of natural recombination between PTV serotypes and indicated that homologous recombination may be a driving force in PTV evolution. The role of PTV in disease remains inconclusive. The current results together with published results indicate that the prevalence of PTV is increasing among swine herds in northeast of China. 23512318 Redox- and pH-Responsive Cysteamine-Modified Poly(aspartic acid) Showing a Reversible Sol-Gel Transition. Synthesis and characterization of a pH- and redox-sensitive hydrogel of poly(aspartic acid) are reported. Reversible gelation and dissolution are achieved both in dimethylformamide and in aqueous medium via a thiol-disulphide interconversion in the side chain of the polymers. Structural changes are confirmed by Raman microscopy and rheological measurements. Injectable aqueous solutions of thiolated poly(aspartic acid) can be converted into mechanically stable gels by oxidation, which can be useful for drug encapsulation and targeted delivery. Reduction-facilitated release of an entrapped drug from disulphide cross-linked hydrogels is studied. 23883240 Extent of Arterial Tumor Enhancement Measured With Preoperative MDCT Gastrography Is a Prognostic Factor in Advanced Gastric Cancer After Curative Resection. OBJECTIVE. The objective of this study was to investigate the correlation between pathologic findings and arterial tumor enhancement at MDCT gastrography of patients with a prognosis of advanced gastric cancer after curative resection. MATERIALS AND METHODS. The cases of 41 patients with advanced gastric cancer (23 men, 18 women; age range, 35-92 years; median, 60 years) who underwent MDCT gastrography and optical endoscopy before surgery were retrospectively evaluated. Two radiologists reviewed virtual endoscopic and multiplanar reconstruction images to measure arterial phase CT values of the inner tumor margin and healthy gastric wall. They used consensus regions of interest on a cross-sectional image of the largest tumor diameter and then calculated tumor-to-normal wall enhancement ratio (TNR). Advanced gastric cancers were divided into high- and low-TNR groups with mean TNR as the cutoff. The correlations between groups and pathologic factors, patient survival, and mode of recurrence were studied. RESULTS. Multivariate logistic regression analysis showed that the arterial tumor enhancement ratio correlated with both microvessel density and lymphatic vessel invasion. The survival rate after curative resection was worse for the high-TNR group than for the low-TNR group. The rate of lymphatic and hematogenous recurrences was also higher in the high-TNR group. Multivariate survival analysis revealed that TNR was an independent prognostic factor. CONCLUSION. The extent of arterial tumor enhancement correlated with tumor angiogenesis and lymphatic vessel invasion and was a useful prognostic indicator after curative resection in patients with advanced gastric cancer. 23836442 Polymorphisms and expression of the WNT8A gene in Hirschsprung's disease. Hirschsprung's disease (HSCR) is a congenital disorder characterized by an absence of intrinsic ganglion cells in the nerves forming the plexus of the lower intestine. The WNT signaling pathway is considered to play an important role in embryonic development. In the present study, we analyzed 2 polymorphisms of the WNT8A gene (rs78301778 and rs6596422) to determine their association with the risk and development of HSCR. Allele frequencies and genotype distributions were analyzed by sequence analysis in patients with HSCR and normal controls. Using real-time PCR, western blot analysis and immunohistochemistry, we detected the mRNA and protein expression of WNT8A in patients with HSCR. The data indicated that the differences in genotype distributions and allele frequencies of rs78301778 and rs6596422 between various clinical classifications were statistically significant. The analysis of the mRNA and protein expression of WNT8A revealed that the expression of WNT8A was increased in the stenotic colon segments compared with the normal colon segments. In conclusion, the data presented in this study suggest that the WNT8A gene is involved in the susceptibility to HSCR, and plays an important role in the occurrence and development of HSCR. These findings warrant further investigation. 23785200 Primary human leukocyte subsets differentially express vaccinia virus receptors enriched in lipid rafts. Poxviruses, including vaccinia virus (VV) and canarypox virus (ALVAC), do not indiscriminately infect all cell types of the primary human leukocytes (PHLs) that they encounter but instead demonstrate an extremely strong bias toward infection of monocytes and monocyte lineage cells. We studied the specific molecular events that determine the VV tropism for major PHL subsets including monocytes, B cells, neutrophils, NK cells, and T cells. We found that VV exhibited an extremely strong bias of cell surface protein-dependent binding to monocytes, B cells, and activated T cells to a similar degree and to neutrophils to a much lesser extent. Resting T cells and resting NK cells exhibited only trace amounts of VV binding. Activated T cells, however, became permissive to VV binding, infection, and replication, while activated NK cells still resisted VV binding. VV binding strongly colocalized with lipid rafts on the surfaces of all VV binding-susceptible PHL subsets, even when lipid rafts were relocated to cell uropods upon cell polarization. Immunosera raised against detergent-resistant membranes (DRMs) from monocytes or activated T cells, but not resting T cells, effectively cross-blocked VV binding to and infection of PHL subsets. CD29 and CD98, two lipid raft-associated membrane proteins that had been found to be important for VV entry into HeLa cells, had no effect on VV binding to and infection of primary activated T cells. Our data indicate that PHL subsets express VV protein receptors enriched in lipid rafts and that receptors are cross-presented on all susceptible PHLs. 23500376 High-performance cholesterol sensor based on the solution-gated field effect transistor fabricated with ZnO nanorods. A high-performance cholesterol sensor based on solution-gated field-effect-transistor (FET) was fabricated by using the vertically aligned ZnO nanorods (ZnO NRs) grown selectively on pre-patterned substrate in solution. The structural characterization showed that the as-grown ZnO NRs are vertically aligned, high purity single crystalline. The active layer of ZnO NRs between source and drain electrodes was immobilized with cholesterol oxidase (ChOx) enzyme. The performance of the fabricated FET sensor has been examined with the cholesterol solutions with and without electroactive species, the human serum (H4522), and the freshly drawn blood sample. The FET sensor provided a real-time response towards a wide range of cholesterol concentration (0.001-45 mM) with high sensitivity (10 μA cm(-2) mM(-1)) and selectivity. 23958800 Depolymerization of crystalline cellulose catalyzed by acidic ionic liquids grafted onto sponge-like nanoporous polymers. The acidic ionic liquid (IL) functionalized polymer (PDVB-SO3H-[C3vim][SO3CF3]) possesses abundant nanoporous structures, strong acid strength and unique capability for deconstruction of crystalline cellulose into sugars in ILs. The polymer shows much improved catalytic activities in comparison with mineral acids, homogeneous acidic ionic liquids and the acidic resins such as Amberlyst 15. The enhanced catalytic activity found in the polymer is attributed to synergistic effects between the strongly acidic group and the ILs grafted onto the polymer, which by itself is capable of breaking down the crystalline structures of cellulose. This study may help develop cost-effective and green routes for conversion of biomass to fuels. 23507558 MicroRNA-365 regulates NKX2-1, a key mediator of lung cancer. MicroRNAs constitute a class of small noncoding RNAs that play roles in tumorigenesis. We found that NKX2-1 protein levels were generally high in the lung cancer tissues whereas miRNA-365 expression levels were downregulated. Ectopic miR-365 expression decreased NKX2-1 expression in lung cancer cell lines. Transfection of a miR-365 mimic led to reduced proliferation of lung cancer cells; conversely, a miR-365 inhibitor slightly increased cell proliferation. The NKX2-1 overexpression significantly increased the cell proliferation by overcoming the suppressive effect of miR-365. Our data suggest that miR-365 is an important regulator of NKX2-1 and can be a target for lung cancer therapies. 23765186 Roux-en-Y gastric bypass vs sleeve gastrectomy for obese patients with type 2 diabetes: a randomised trial. Bariatric surgery is gaining acceptance as a 'metabolic surgical intervention' for patients with type 2 diabetes. The optimal form of surgery and the mechanism of action of these procedures are much debated. We compared two bariatric procedures for obese patients with type 2 diabetes and evaluated their effects on HbA1c and glucose tolerance. We performed a parallel un-blinded randomised trial of Roux-en-Y gastric bypass (RYGB) vs sleeve gastrectomy (SG) in 41 obese patients with type 2 diabetes, who were bariatric surgery candidates attending the obesity clinic. HbA1c, body composition and glucose tolerance were evaluated at baseline, and at 3 and 12 months. Of the 41 patients, 37 completed the follow-up (19 RYGB, 18 SG). Both groups had similar baseline anthropometric and biochemical measures, and showed comparable weight loss and fat:fat-free mass ratio changes at 12 months. A similar normalisation of HbA1c levels was observed as early as 3 months post-surgery (6.37 ±â€‰0.71% vs 6.23 ±â€‰0.69% for RYGB vs SG respectively, p < 0.001 in both groups for baseline vs follow-up). In this study, RYGB did not have a superior effect in comparison to SG with regard to HbA1c levels or weight loss during 12 months of follow-up. ClinicalTrials.gov NCT00667706 FUNDING: This work was supported by grant no. 3-000-8480 from the Israel Ministry of Health Chief Scientist, the Stephen Morse Diabetes Research Foundation and by Johnson & Johnson. 23970783 Protein Kinase D1 is Essential for Bone Acquisition during Pubertal Growth. Bone formation and maintenance represents the summation of the balance of local and endocrine hormonal stimuli within a complex organ. Protein kinase D (PKD) is a member of the Ca(2+)/calmodulin-dependent kinase (CaMK) superfamily of serine/threonine kinases and has been described as the crossroads for the BMP-IGF1 signaling axis, which plays a major role in bone formation. The current study exploits the PKD1-deficient mouse model to examine the role of PKD in vivo in the skeleton. Dual-energy x-ray absorptiometry (DEXA) scan analysis of male and female pubescent mice demonstrated significantly decreased bone mineral density in the whole body and femoral bone compartments of PKD1 (+/-) mice, compared to their wild-type littermates. The body weight, nasal-anal length, and percent body fat of the mice were not significantly different from their wild-type littermates. Cultured bone marrow stromal cells from PKD1 (+/-) mice demonstrated lower alkaline phosphatase activity in early differentiating osteoblasts and decreased mineralized nodule formation in mature osteoblasts. Quantitative RT-PCR analysis of osteoblast differentiation markers and osteoclast markers exhibited lower levels of expression in PKD1 (+/-) male mice than wild-type. In female mice, however, only markers of osteoblast differentiation were reduced. PKD1 (+/-) mice also demonstrated a profound reduction in mRNA expression levels of BMP type II receptor and IGF1 receptor and in BMP-7 responsiveness in vitro. Together, these data suggest that in mice, PKD1 action contributes to regulation of osteoblastogenesis by altering gene expression with gender specific effects on osteoclastogenesis, subsequently affecting skeletal matrix acquisition during puberty. 23884656 Rates and patterns of great ape retrotransposition. We analyzed 83 fully sequenced great ape genomes for mobile element insertions, predicting a total of 49,452 fixed and polymorphic Alu and long interspersed element 1 (L1) insertions not present in the human reference assembly and assigning each retrotransposition event to a different time point during great ape evolution. We used these homoplasy-free markers to construct a mobile element insertions-based phylogeny of humans and great apes and demonstrate their differential power to discern ape subspecies and populations. Within this context, we find a good correlation between L1 diversity and single-nucleotide polymorphism heterozygosity (r(2) = 0.65) in contrast to Alu repeats, which show little correlation (r(2) = 0.07). We estimate that the "rate" of Alu retrotransposition has differed by a factor of 15-fold in these lineages. Humans, chimpanzees, and bonobos show the highest rates of Alu accumulation-the latter two since divergence 1.5 Mya. The L1 insertion rate, in contrast, has remained relatively constant, with rates differing by less than a factor of three. We conclude that Alu retrotransposition has been the most variable form of genetic variation during recent human-great ape evolution, with increases and decreases occurring over very short periods of evolutionary time. 23601378 Who needs an artificial pancreas? (？). The development of a closed-loop "artificial pancreas" would be a welcome advance for both endocrinologists and diabetic patients struggling to attain near normal glycemic control. While great strides in automatically controlling blood sugar in the fasting, sedentary state have been made through complex mathematical modeling, management of blood sugar excursions due to food and exercise have been more problematic. An artificial pancreas is not feasible at this time because of limitations inherent in the currently available technology. 23969321 Beneficial Effects of Fresh and Fermented Kimchi in Prediabetic Individuals. Background: With the increased incidence of diabetes mellitus, the importance of early intervention in prediabetes has been emphasized. We previously reported that fermented kimchi, a traditional Korean food, reduced body weight and improved metabolic factors in overweight participants. We hypothesized that kimchi and its fermented form would have beneficial effects on glucose metabolism in patients with prediabetes. Methods: A total of 21 participants with prediabetes were enrolled. During the first 8 weeks, they consumed either fresh (1-day-old) or fermented (10-day-old) kimchi. After a 4-week washout period, they switched to the other type of kimchi for the next 8 weeks. Results: Consumption of both types of kimchi significantly decreased body weight, body mass index, and waist circumference. Fermented kimchi decreased insulin resistance, and increased insulin sensitivity, QUICKI and disposition index values (p = 0.004 and 0.028, respectively). Systolic and diastolic blood pressure (BP) decreased significantly in the fermented kimchi group. The percentages of participants who showed improved glucose tolerance were 9.5 and 33.3% in the fresh and fermented kimchi groups, respectively. Conclusions: Consumption of kimchi had beneficial effects on glucose metabolism-related and anthropometric factors in participants with prediabetes. Fermented kimchi had additional effects on BP and insulin resistance/sensitivity. The percentage of participants who showed improvement in glucose tolerance was high in the fermented kimchi group. © 2013 S. Karger AG, Basel. 23946672 Product wastage from modern human growth hormone administration devices: a laboratory and computer simulation analysis. Treatment of growth hormone disorders typically involves daily injections of human growth hormone (GH) over many years, incurring substantial costs. We assessed the extent of undesired GH loss due to leakage in the course of pen preparation prior to injection, and differences between the prescribed dose, based on patient weight, and the actual delivered dose based on pen dosing increments in five GH administration devices. Norditropin® prefilled FlexPro®, NordiFlex®, NordiLet®, and durable NordiPen®/SimpleXx® 5 mg pens (Novo Nordisk A/S, Bagsværd, Denmark) and durable Omnitrope® Pen-5 devices (Sandoz, Holzkirchen, Germany) were tested (n = 40 for each device type). Product wastage was measured in accordance with validated protocols in an ISO (International Organization for Standardization) 11608-1 and Good Manufacturing Practice compliant laboratory. The average mass of wasted GH from each device type was measured in simulations of dripping with the needle attached prior to injection and while setting a dose. Statistical significance (P < 0.05) was confirmed by Student's t-test, and a model was constructed to estimate mean annual GH wastage per patient in cohorts of pediatric patients with GH disorders. Mean GH mass wasted with the needle on prior to injection was 0.0 μg with Norditropin pens, relative to 98 μg with Omnitrope Pen-5. During dose dialing, 0.0-2.3 μg of GH was lost with Norditropin pens versus 0.8 μg with Omnitrope Pen-5. All Norditropin and Omnitrope device comparisons were statistically significant. Modeling GH wastage in a US cohort showed 5.5 mg of annual GH wastage per patient with FlexPro versus 43.6 mg with Omnitrope, corresponding to 7-8 additional pens per patient annually. Overall, Norditropin pens resulted in significantly less wastage than the Omnitrope Pen-5. The study suggests that GH devices of the same nominal volume exhibit differences that may affect the frequency of GH prescription refills required to remain adherent to therapy. 23876823 The effect of polymer coatings on physicochemical properties of spray-dried liposomes for nasal delivery of BSA. This work describes the development of spray dried polymer coated liposomes composed of soy phosphatidylcholine (SPC) and phospholipid dimyristoyl phosphatidylglycerol (DMPG) coated with alginate, chitosan or trimethyl chitosan (TMC), that are able to penetrate through the nasal mucosa and offer enhanced penetration over uncoated liposomes when delivered as a dry powder. All the liposome formulations, loaded with BSA as model antigen, were spray-dried to obtain powder size and liposome size in a suitable range for nasal delivery. Although coating resulted in some reduction in encapsulation efficiency, levels were still maintained between 60% and 69% and the structural integrity of the entrapped protein and its release characteristics were maintained. Coating with TMC gave the best product characteristics in terms of entrapment efficiency, glass transition (Tg) and mucoadhesive strength, while penetration of nasal mucosal tissue was very encouraging when these liposomes were administered as dispersions although improved results were observed for the dry powders. 23600534 Titration effectiveness of two autoadjustable continuous positive airway pressure devices driven by different algorithms in patients with obstructive sleep apnoea. Nocturnal application of continuous positive airway pressure (CPAP) is the standard treatment for patients with obstructive sleep apnoea (OSA). Determination of the therapeutic pressure (CPAP titration) is usually performed by a technician in the sleep laboratory during attended polysomnography. One possible alternative to manual titration is automated titration. Indeed, during the last 15 years, devices have been developed that deliver autoadjustable CPAP (A-CPAP). The aim of the present study was to compare the titration effectiveness of two A-CPAP devices using different flow-based algorithms in patients with OSA. This is a randomized study; 79 subjects underwent two consecutive unattended home A-CPAP titration nights with two different devices (Autoset Resmed; Remstar Auto Respironics); during the third and the fourth night, patients underwent portable monitoring in the sleep laboratory during fixed CPAP at the A-CPAP recommended pressure. Bland Altman plots showed good agreement between the recommended median and maximal pressure levels obtained with the two devices. A significant improvement was observed in all the sleep parameters by both A-CPAP machines to a similar degree. It was observed that the two A-CPAP devices using different algorithms are equally effective in initial titration of CPAP. 23775486 Phase 2 trial of afatinib, an ErbB family blocker, in solid tumors genetically screened for target activation. The efficacy of afatinib, an irreversible ErbB Family Blocker, was evaluated in patients who had 1 of 4 categories of solid tumors with epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/HER2) gene amplification or EGFR-activating mutations. Patients with previously treated but ErbB inhibitor-naive esophagogastric, biliary tract, urothelial tract, or gynecologic cancers (lung cancers were excluded) harboring EGFR/HER2 gene amplification or high polysomy were identified by fluorescence in situ hybridization (FISH). Tumors were also screened for EGFR mutations. The primary endpoint was the objective response rate; secondary endpoints included the clinical benefit rate, pharmacokinetics, and safety. Of 385 prescreened patients, 38 had FISH-positive tumors (10 with EGFR amplification and 29 with HER2 amplification or high polysomy [1 tumor had EGFR/HER2 high polysomy]; none had EGFR-activating mutations), and 20 patients received treatment with afatinib 50 mg daily. The objective response rate was 5% (1 of 20 patients), and the best objective response included 1 complete response. Eight patients experienced stable disease. The most frequently reported adverse events were diarrhea, rash, and decreased appetite. The trial closed early because of slow recruitment. Single-agent afatinib activity was limited, yet encouraging, in selected tumors that were screened prospectively for target activation. The implementation of a biomarker-driven approach using a low-frequency biomarker for patient selection across multiple tumor types can be challenging. Cancer 2013;119:3043-3051. © 2013 American Cancer Society. 23880459 Diagnosis and treatment of parkes weber syndrome: a review of 10 consecutive patients. We sought to retrospectively analyze the clinical presentation, diagnosis, treatment, and outcomes of patients with Parkes Weber syndrome (PWS) who were treated at a single institution. A retrospective review was conducted of medical records of all patients with PWS treated at La Paz Children's Hospital between 1994 and 2010. Ten patients (median age, 14.8 years [range, 2-52 years]) were identified, including 7 women and 3 men. Six patients presented with lower limb hypertrophy and capillary malformation at birth, and both the right and left lower extremities were equally involved. Severe tricuspid insufficiency was observed in 1 patient. The median dysmetria between both lower extremities was 2.19 cm. Four patients are being treated successfully with compression garment therapy. Three patients underwent resection of multiple arteriovenous nidus. Three patients had palliative embolizations. One patient required above the knee amputation secondary to ischemia and chronic severe pain. The early recognition of PWS is required to establish the most appropriate treatment and prevent short-term morbidity and unnecessary invasive diagnostic tests. Treatment should be individualized according to the age and clinical features of each patient. Although initial conservative management is recommended, surgery continues to play an important role in order to improve the quality of life in these patients. 23928099 Feline lungworms: what a dilemma. Aelurostrongylus abstrusus is regarded as the major lungworm infecting Felis catus, although other, albeit poorly studied, nematodes have been described from the respiratory system of domestic cats. Recent records of these neglected parasites have renewed the attention of the scientific community, but their actual role in respiratory disease in cats is blurred. The epidemiology, pathogenic role, and diagnosis of Troglostrongylus spp., Oslerus rostratus, and Capillaria aerophila in domestic cats are far from being clarified. Indeed, recent studies have provided novel information but have also given rise to relevant doubts. We discuss here the state of current knowledge regarding felid lungworms together with the dilemmas recently roused in the scientific literature. 23904456 Reducing CTGF/CCN2 slows down mdx muscle dystrophy and improves cell therapy. In Duchenne muscular dystrophy (DMD) and the mdx mouse model, the absence of the cytoskeletal protein dystrophin causes defective anchoring of myofibres to the basal lamina. The resultant myofibre degeneration and necrosis lead to a progressive loss of muscle mass, increased fibrosis and ultimately fatal weakness. Connective tissue growth factor (CTGF/CCN-2) is critically involved in several chronic fibro-degenerative diseases. In DMD, the role of CTGF might extend well beyond replacement fibrosis secondary to loss of muscle fibres, since its overexpression in skeletal muscle could by itself induce a dystrophic phenotype. Using two independent approaches, we here show that mdx mice with reduced CTGF availability do indeed have less severe muscular dystrophy. Mdx mice with hemizygous CTGF deletion (mdx-Ctgf+/-), and mdx mice treated with a neutralizing anti-CTGF monoclonal antibody (FG-3019), performed better in an exercise endurance test, had better muscle strength in isolated muscles and reduced skeletal muscle impairment, apoptotic damage and fibrosis. Transforming growth factor type-β (TGF-β), pERK1/2 and p38 signalling remained unaffected during CTGF suppression. Moreover, both mdx-Ctgf+/- and FG-3019 treated mdx mice had improved grafting upon intramuscular injection of dystrophin-positive satellite cells. These findings reveal the potential of targeting CTGF to reduce disease progression and to improve cell therapy in DMD. 23412667 Facial expressions in common marmosets (Callithrix jacchus) and their use by conspecifics. Facial expressions have been studied mainly in chimpanzees and have been shown to be important social signals. In platyrrhine and strepsirrhine primates, it has been doubted that facial expressions are differentiated enough, or the species socially capable enough, for facial expressions to be part of their communication system. However, in a series of experiments presenting olfactory, auditory and visual stimuli, we found that common marmosets (Callithrix jacchus) displayed an unexpected variety of facial expressions. Especially, olfactory and auditory stimuli elicited obvious facial displays (such as disgust), some of which are reported here for the first time. We asked whether specific facial responses to food and predator-related stimuli might act as social signals to conspecifics. We recorded two contrasting facial expressions (fear and pleasure) as separate sets of video clips and then presented these to cage mates of those marmosets shown in the images, while tempting the subject with food. Results show that the expression of a fearful face on screen significantly reduced time spent near the food bowl compared to the duration when a face showing pleasure was screened. This responsiveness to a cage mate's facial expressions suggests that the evolution of facial signals may have occurred much earlier in primate evolution than had been thought. 23794106 Clinical heterogeneity and outcomes of antisynthetase syndrome. The autoimmune connective tissue disease antisynthetase syndrome (ASS) is an inflammatory myopathy associated with myositis-specific autoantibodies, e.g. anti-tRNA-synthetase antibodies (ASA). Since 1976 eight different ASA have been rigorously identified, of which anti-hystidyl-tRNA synthetase (anti-Jo1) is the most prevalent. Other phenotype features of ASS include interstitial lung disease (ILD), Raynaud's phenomenon, polyarthritis, fever, and mechanic's hands. The clinical presentation of ASS varies greatly, as does the severity of involvement of different organs-both among patients and/or over the course of the disease. ILD has been associated with poor outcomes, but in general the heterogeneity of ASS prevents identification of robust prognosis indicators. Early identification of patients requiring aggressive immunosuppressive treatment is very challenging, and there are very few prospective trials available to help match treatment management to ASS clinical characteristics. This review will focus on the biological, clinical, functional, and morphological features of ASS associated with patient outcome. Our objective is to use compiled data on these subjects to discuss the usefulness of patient stratification in developing future prospective therapeutic trials. 23899465 Validation of a Micellar Liquid Chromatographic Method for Determination of Caffeine and Non-Steroidal Anti-Inflammatories. An accurate, simple, sensitive and selective micellar liquid chromatographic method has been developed for the simultaneous determination of caffeine (CAF) and two non-steroidal anti-inflammatory drugs, namely ibuprofen (IBU) and ketoprofen (KET). The chemometric approach was applied to the optimization of separation of the studied drugs. To optimize their separation, the effect of six experimental parameters on retention was investigated by means of multivariate analysis. Separation was conducted using an ODS C18 (150 × 4.6 mm i.d.) stainless steel column at ambient temperature with UV detection at 260 nm. A mobile phase composed of 40 mM sodium dodecyl sulphate (SDS), 10% 1-propanol and 0.3% tri-ethylamine in 0.02 M phosphoric acid adjusted to pH 3 has been used at a flow rate of 1 mL/min. Regression models were characterized by both descriptive and predictive ability (R(2) ≥ 97.9% and Rcv(2) ≥ 96.2%) and allowed the chromatographic separation of the drugs with a good resolution and a total analysis time within 15 min. The calibration curves were rectilinear over the concentration ranges of 2.0-25.0, 1.5-15.0 and 1.0-10.0 µg/mL for IBU, KET and CAF, respectively, with detection limits of 1.2, 1.0 and 0.6 µg/mL, and quantification limits of 1.6, 1.2 and 0.8 µg/mL, respectively. The results obtained were in good agreement with those obtained by the comparison method. 23865418 Baseline characteristics and prevalence of cardiovascular disease in newly visiting or referred chronic kidney disease patients to nephrology centers in Japan: a prospective cohort study. About 39,000 patients were newly prescribed renal replacement therapy in Japan in 2011, resulting in a total of more than 300,000 patients being treated with dialysis. This high prevalence of treated end stage kidney disease (ESKD) patients is an emergent problem that requires immediate attention. We launched a prospective cohort study to evaluate population specific characteristics of the progression of chronic kidney disease (CKD). In this report, we describe the baseline characteristics and risk factors for cardiovascular disease (CVD) prevalence among this cohort. New patients from 16 nephrology centers who were older than 20 years of age and who visited or were referred for the treatment of CKD stage 2-5, but were not on dialysis therapy, were recruited in this study. At enrollment, medical history, lifestyle behaviors, functional status and current medications were recorded, and blood and urine samples were collected. Estimated glomerular filtration rate (eGFR) was calculated by a modified three-variable equation. We enrolled 1138 patients, 69.6% of whom were male, with a mean age of 68 years. Compared with Western cohorts, patients in this study had a lower body mass index (BMI) and higher proteinuria. The prevalence of CVD was 26.8%, which was lower than that in Western cohorts but higher than that in the general Japanese population. Multivariate analysis demonstrated the following association with CVD prevalence: hypertension (adjusted odds ratio (aOR) 3.57; 95% confidence interval (CI) 1.82-7.02); diabetes (aOR 2.45; 95% CI 1.86-3.23); hemoglobin level less than 11 g/dl (aOR 1.61; 95% CI 1.21-2.15); receiving anti-hypertensive agents (aOR 3.54; 95% CI 2.27-5.53); and statin therapy (aOR 2.73; 95% CI 2.04-3.66). The combination of decreased eGFR and increased proteinuria was also associated with a higher prevalence of CVD. The participants in this cohort had a lower BMI, higher proteinuria and lower prevalence of CVD compared with Western cohorts. Lower eGFR and high proteinuria were associated with CVD prevalence. Prospective follow up of these study patients will contribute to establishment of individual population-based treatment of CKD. 23817048 Insights into neural crest development and evolution from genomic analysis. The neural crest is an excellent model system for the study of cell type diversification during embryonic development due to its multipotency, motility, and ability to form a broad array of derivatives ranging from neurons and glia, to cartilage, bone, and melanocytes. As a uniquely vertebrate cell population, it also offers important clues regarding vertebrate origins. In the past 30 yr, introduction of recombinant DNA technology has facilitated the dissection of the genetic program controlling neural crest development and has provided important insights into gene regulatory mechanisms underlying cell migration and differentiation. More recently, new genomic approaches have provided a platform and tools that are changing the depth and breadth of our understanding of neural crest development at a "systems" level. Such advances provide an insightful view of the regulatory landscape of neural crest cells and offer a new perspective on developmental as well as stem cell and cancer biology. 23697667 Neoplastic pericarditis as the initial manifestation of a papillary thyroid carcinoma. Abstract Neoplastic pericarditis represents approximately 5%-7% of the cases with acute pericarditis and is rarely the initial manifestation of malignancy. The most common cause is lung cancer, followed by breast cancer, lymphomas, leukemia, and esophageal cancer. Neoplastic pericardial disease is extremely rare in thyroid cancer, especially as the first manifestation. Here, we present a papillary thyroid carcinoma that was manifested with pericarditis and cardiac tamponade in a 49-year-old female. 23502076 Seronegative antiphospholipid syndrome. APS is an autoimmune disease that leads to arterial and/or venous thrombosis, recurrent pregnancy loss and persistently positive aPLs. Patients with clinical manifestations highly suggestive of APS but persistently negative conventional aPLs are classified as having seronegative APS. Ongoing research has revealed the existence of non-criteria antibodies proposed to be relevant to APS and that can be potentially included in the disease's classification criteria. We present a literature review on the most promising antibodies of this heterogeneous aPL family, which includes antibodies to a zwitterionic phospholipid, namely phosphatidylethanolamine, phospholipid-binding plasma proteins, phospholipid-protein complexes and anionic phospholipids other than cardiolipin. Although these molecules can increase the diagnostic yield of APS, their clinical relevance is still debatable and needs to be confirmed by interlaboratory efforts toward standardizing diagnostic tools, in addition to experimental data and larger longitudinal studies. 23946241 Ultrafast Photoinduced Electron Transfer in Viologen-Linked BODIPY Dyes. New boron-dipyrromethene (BODIPY) dyes linked to viologen are prepared and their photophysical and electrochemical properties are investigated. Both synthesized molecules have similar electronic absorption spectra with the absorption maximum localized at 517 and 501 nm for dye 1 and dye 2, respectively. They exhibit well-defined redox behavior, highlighting the presence of BODIPY and viologen subunits, with little perturbation of the redox potential of both subunits with respect to the parent compounds. Both dyes are heavily quenched by photoinduced electron transfer from the BODIPY to the viologen subunit. The transient absorption technique demonstrates that dye 2 forms the viologen radical within a timeframe of 7.1 ps, and that the charge-separated species has a lifetime of 59 ps. Sustained irradiation of dye 2 in the presence of a tertiary amine allows for the accumulation of BODIPY-methyl-4,4'-bipyridinium (BODIPY-MV(+) ), as observed by its characteristic absorption at 396 and 603 nm. However, dye 2 does not generate catalytic amounts of hydrogen under standard conditions. 23736640 Mechanical reinforcement fibers produced by gel-spinning of poly-acrylic acid (PAA) and graphene oxide (GO) composites. Graphene oxide (GO) with extraordinary chemical, thermal and mechanical properties offers possibilities in a variety of applications. Many materials have been fabricated through physical blending of GO with other materials, while, the chemical functionalization of GO has generally been considered challenging. Here, we report the preparation of a novel GO-functionalized fibrous material in which individual compliant GO sheets are cross-linked by PAA chains in a near-vertical fashion. This new fibrous material outperforms many other common fibers in stiffness and strength. Combined with straightforward manufacturing methods, the fibers should find applications in a wide range of areas. 23615466 Surgical resection of brain metastases-impact on neurological outcome. Brain metastases (BM) develop in about 30% of all cancer patients. Surgery plays an important role in confirming neuropathological diagnosis, relieving mass effects and improving the neurological status. To select patients with the highest benefit from surgical resection, prognostic indices (RPA, GPA) have been formulated which are solely focused on survival without considering neurological improvement. In this study we analyzed the impact of surgical resection on the neurological status in addition to overall survival in 206 BM patients. Surgical mortality and morbidity was 0.0% and 10.3% respectively. New neurologic deficits occurred in 6.3% of all patients. The median overall survival was 6.3 months. Poor RPA class and short time interval between diagnosis of cancer and the occurrence of BM were independent factors predictive for poor survival. Improvement of neurological performance was achieved in 56.8% of all patients, with the highest improvement rate seen in patients presenting with increased intracranial pressure and hemiparesis. Notably, the neurological benefits were independent from RPA class. In conclusion, surgical resection leads to significant neurological improvement despite poor RPA class and short overall survival. Considering the low mortality and morbidity rates, resection should be considered as a valid option to increase neurological function and quality of life for patients with BM. 23770296 Proteomic changes in HEK-293 cells induced by hepatitis delta virus replication. Hepatitis delta virus (HDV) infection greatly increases the risk of hepatocellular carcinoma in hepatitis B virus chronically infected patients. HDV is highly dependent on host factors for accomplishment of the replication cycle. However, these factors are largely unknown and the mechanisms involved in the pathogenicity of the virus still remain elusive. Here, we made use of the HEK-293 cell line, which was engineered in order to mimic HDV replication. Five different proteomes were analyzed and compared using a MS-based quantitative proteomics approach by (18)O/(16)O stable isotope labeling. About 3000 proteins were quantified and 89 found to be differentially expressed as a consequence HDV RNA replication. The down-regulation of p53 , HSPE, and ELAV as well as the up-regulation of Transportin 1 , EIF3D, and Cofilin 1 were validated by Western blot. A systems biology approach was additionally used to analyze altered pathways and networks. The G2/M DNA damage checkpoint and pyruvate metabolism were among the most affected pathways, and Cancer was the most likely disease associated to HDV replication. Western blot analysis allowed identifying 14-3-3 σ interactor as down-regulated protein acting in the G2/M cell cycle control checkpoint. This evidence supports deregulation of G2/M checkpoint as a possible mechanism involved in the promotion of HDV associated hepatocellular carcinoma. This manuscript provides a description of changes observed in the cellular proteome that arise as result of expression of the hepatitis delta virus (HDV) antigen as well as virus genome replication. Using a systems biology approach cancer was found to be the most probable disease associated with HDV replication. Additionally, results show that HDV alters the regulation of G2/M cell cycle control checkpoint. Taken together, our data provide new insights into probable mechanisms associated with the increased incidence of hepatocellular carcinoma observed in HDV infected patients. 23561591 Predictors of progression of recently diagnosed atrial fibrillation in REgistry on Cardiac Rhythm DisORDers Assessing the Control of Atrial Fibrillation (RecordAF)-United States cohort. The progression of atrial fibrillation (AF) to a more sustained form is associated with increased symptoms and morbidity. The aims of the REgistry on Cardiac Rhythm DisORDers Assessing the Control of Atrial Fibrillation (RecordAF)-United States (US) cohort study were to identify the risk factors of AF progression and the effects of management approaches. RecordAF is the first worldwide, 1-year observational study of the treatment of community-based patients with recent-onset AF. We assessed AF progression at 12 months in the US cohort. AF progression was defined as a change of AF to a more sustained form (either paroxysmal becoming persistent or permanent, or persistent becoming permanent). The US cohort included 955 patients, with mean age of 68.9 years; 56.8% were men and 88.8% were white. At entry, 59.6% of patients were selected for rate-control and 40.4% for rhythm-control therapy. At 12 months, the management strategy was unchanged for 68.2% of the patients in the rate- and 77.7% of the patients in the rhythm-control groups. Overall, AF progression had occurred in 18.6% of patients at 12 months. The progression rate was significantly greater in the rate-control (27.6%) than in the rhythm-control (5.8%) group (p <0.001). Progression to permanent AF occurred in 16.4% of patients. In addition to a rate-control strategy, older age, AF rhythm at entry, persistent AF at baseline, and a history of stroke or transient ischemic attack independently predicted AF progression. Rate control was associated with AF progression, with a propensity score adjusted odds ratio of 2.67 (p <0.001). In conclusion, rate control was the preferred treatment of recent-onset AF in the US but was associated with more AF progression than rhythm control. 23552345 Accounting for variability among individual pigs in deterministic growth models. Inclusion of variation in deterministic nutritional models for growth by repeating simulations using different sets of parameters has been performed in literature without or with only hypothetic consideration of the covariance structure among parameters. However, a description of the structure of links among parameters describing individuals is required to generate realistic sets of parameters. In this study, the mean and covariance structure of model parameters describing feed intake and growth were analyzed from 10 batches of crossbred gilts and barrows. Data were obtained from different crossbreeds, originating from Large White × Landrace sows and nine sire lines. Pigs were group-housed (12 pigs/pen) and performance testing was carried out from 70 days of age to ∼110 kg BW. Daily feed intake (DFI) was recorded using automatic feeding stations and BW was measured at least every 3 weeks. A growth model was used to characterize individual pigs based on the observed DFI and BW. In this model, a Gompertz function was used to describe protein deposition and the resulting BW gain. A gamma function (expressing DFI as multiples of maintenance) was used to express the relationship between DFI and BW. Each pig was characterized through a set of five parameters: BW₇₀ (BW at 70 days of age), B(Gompertz) (a precocity parameter) PDm (mean protein deposition rate) and DFI₅₀ and DFI₁₀₀ (DFI at 50 and 100 kg BW, respectively). The data set included profiles for 1288 pigs for which no eating or growth disorders were observed (e.g. because of disease). All parameters were affected by sex (except for BW₇₀) and batch, but not by the crossbreed (except for PDm). An interaction between sex and crossbreed was observed for PDm (P < 0.01) and DFI₁₀₀ (P = 0.05). Different covariance matrices were computed according to the batch, sex, crossbreed, or their combinations, and the similarity of matrices was evaluated using the Flury hierarchy. As covariance matrices were all different, the unit of covariance (subpopulation) corresponded to the combination of batch, sex and crossbreed. Two generic covariance matrices were compared afterwards, with (median matrix) or without (raw matrix) taking into account the size of subpopulations. The most accurate estimation of observed covariance was obtained with the median covariance matrix. The median covariance matrix can be used, in combination with average parameters obtained on-farm, to generate virtual populations of pigs that account for a realistic description of mean performances and their variability. 23150487 Obtusilactone B from Machilus Thunbergii targets barrier-to-autointegration factor to treat cancer. Targeting specific molecules is a promising cancer treatment because certain types of cancer cells are dependent on specific oncogenes. This strategy led to the development of therapeutics that use monoclonal antibodies or small-molecule inhibitors. However, the continued development of novel molecular targeting inhibitors is required to target the various oncogenes associated with the diverse types and stages of cancer. Obtusilactone B is a butanolide derivative purified from Machilus thunbergii. In this study, we show that obtusilactone B functions as a small-molecule inhibitor that causes abnormal nuclear envelope dynamics and inhibits growth by suppressing vaccinia-related kinase 1 (VRK1)-mediated phosphorylation of barrier-to-autointegration factor (BAF). BAF is important in maintaining lamin integrity, which is closely associated with diseases that include cancer. Specific binding of obtusilactone B to BAF suppressed VRK1-mediated BAF phosphorylation and the subsequent dissociation of the nuclear envelope from DNA that allows cells to progress through the cell cycle. Obtusilactone B potently induced tumor cell death in vitro, indicating that specific targeting of BAF to block cell cycle progression can be an effective anticancer strategy. Our results demonstrate that targeting a major constituent of the nuclear envelope may be a novel and promising alternative approach to cancer treatment. 23952473 Pulsed-Field Gel Electrophoresis Proficiency Testing Trials: Toward European Harmonization of the Typing of Food and Clinical Strains of Listeria monocytogenes. Abstract The European Union Reference Laboratory for Listeria monocytogenes (EURL for Lm) coordinates a European network of 35 National Reference Laboratories (NRLs), most of which perform food, environmental, and veterinary Lm strain surveillance in their respective countries. The EURL activities resulted in the recent creation of a database (EURL Lm DB). Typing and related epidemiological data submitted to the EURL Lm DB will be collected and shared by all the NRLs. For a given NRL, the only criterion required in order to submit pulsed-field gel electrophoresis (PFGE) profiles to the database was the successful participation with at least one EURL PFGE and PFGE profile interpretation Proficiency Testing (PT) trial. In this context, the EURL organized a PT trial in 2012 to evaluate the NRL's ability to perform PFGE and profile interpretation. A total of 18 NRLs took part in this study. Upon request from the Food- and Waterborne Diseases and Zoonoses Programme of the European Centre for Disease Prevention and Control, 10 National Public Health Reference Laboratories (NPHLs) also took part in this PT trial. Of the 28 participating laboratories, 16 obtained results classified as "good" or "satisfactory." These 16 laboratories included 10 NRLs (56%) and 6 NPHLs (60%). Of the 22 NRLs and NHPLs that participated in the part of the PT trial related to PFGE profile interpretation, 11 laboratories obtained good results. These 11 laboratories included eight NRLs, which therefore can now submit profiles to the EURL Lm DB. This PT trial provided a valuable opportunity to facilitate and to stimulate the sharing of reproducible PFGE profiles between human and food reference laboratories. 23813885 Management of retinopathy of prematurity. While current management of retinopathy of prematurity (ROP) is well evidenced, the recent Neonatal Oxygenation Prospective Meta-analysis (NeoPROM) oxygen therapy trials, and the Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) trial of intravitreal injection bevacizumab, have reopened debate on optimal management. Early postnatal manipulation of oxygen therapy, nutrition and serum IGF 1 levels may improve early retinal blood vessel development and prevent later severe ROP. While the use of intravitreal injections of antivascular endothelial growth factor (VEGF) agents may appear to be an attractive alternative to laser ablation of the peripheral retina, caution is needed. The optimal choice of agent and dose remain unknown, and suppression of serum VEGF levels might interfere with normal angiogenesis processes in developing tissues. There is a pressing need for good Phase 1 studies of these agents, and safety trials. 23566935 Hiatal hernias: why and how should they be surgically treated? There is controversy in the literature about the choice of expectant medical treatment versus surgical treatment of hiatal hernias, depending on the presence or absence of symptoms. This study presents the results obtained by our group, considering disease duration and postoperative results. A total of 121 patients were included and divided by age, disease duration, type of hiatal hernia and postoperative outcome. In 32% of the patients younger than 70 years, symptom duration was longer than 11 years and 68% of those aged more than 71 years had long-term symptoms (p<.05). Type iv hernias (complex) and those with diameters measuring more than 16cm were observed in the group with longer symptom duration. Complications were more frequent in the older age group, in those with longer symptom duration and in those with type iv complex hernias. There was no postoperative mortality and only one patient (0.8%) with a type iii hernia and severe oesophagitis required reoperation. We recommend that patients with hiatal hernia undergo surgery at diagnosis to avoid complications and risks. Older patients should not be excluded from surgical indication but should undergo a complete multidisciplinary evaluation to avoid complications and postoperative mortality. 23861751 Regular Moderate or Intense Exercise Prevents Depression-Like Behavior without Change of Hippocampal Tryptophan Content in Chronically Tryptophan-Deficient and Stressed Mice. Regular exercise has an antidepressant effect in human subjects. Studies using animals have suggested that the antidepressant effect of exercise is attributable to an increase of brain 5-hydroxytryptamine (5-HT); however, the precise mechanism underlying the antidepressant action via exercise is unclear. In contrast, the effect of 5-HT on antidepressant activity has not been clarified, in part because the therapeutic response to antidepressant drugs has a time lag in spite of the rapid increase of brain 5-HT upon administration of these drugs. This study was designed to investigate the contribution of brain 5-HT to the antidepressant effect of exercise. Mice were fed a tryptophan-deficient diet and stressed using chronic unpredictable stress (CUS) for 4 weeks with or without the performance of either moderate or intense exercise on a treadmill 3 days per week. The findings demonstrated that the onset of depression-like behavior is attributable not to chronic reduction of 5-HT but to chronic stress. Regular exercise, whether moderate or intense, prevents depression-like behavior with an improvement of adult hippocampal cell proliferation and survival and without the recovery of 5-HT. Concomitantly, the mice that exercised showed increased hippocampal noradrenaline. Regular exercise prevents the impairment of not long-term memory but short-term memory in a 5-HT-reduced state. Together, these findings suggest that: (1) chronic reduction of brain 5-HT may not contribute to the onset of depression-like behavior; (2) regular exercise, whether moderate or intense, prevents the onset of chronic stress-induced depression-like behavior independent of brain 5-HT and dependent on brain adrenaline; and (3) regular exercise prevents chronic tryptophan reduction-induced impairment of not long-term but short-term memory. 23637079 The fetal frontomaxillary facial angle in normal and trisomy 21 ultrasounds at 11-13(+6) weeks of gestation: findings among the ethnic Chinese compared with Caucasian. The aim of this research was to compare the fetal frontomaxillary facial (FMF) angle between normal and trisomy 21 fetuses at 11(+0) -13(+6)  weeks gestation in a Chinese population. A prospective observational study was performed that included 640 euploid and 45 trisomy 21 singleton pregnancies undergoing first trimester ultrasound screening between 11 and 13(+6)  weeks of gestation. The FMF angle was measured in the midsagittal plane using the standard technique. The fetal mean FMF angle decreased with the increasing crown-rump length (CRL) from 88.6°at a CRL of 45 mm to 78.5° at a CRL of 84 mm (FMF angle = 100.212 - 0.258 × CRL, R(2)  = 0.222, p < 0.001). The overall mean FMF angle in the euploid population was 82.9° ± 4.1° and in trisomy 21 cases, 92.3° ± 5.2°. Fetal FMF angle is affected by gestational age in a Chinese population, although it remains a significant predictor of fetal trisomy 21. © 2013 John Wiley & Sons, Ltd. 23849353 Biofilm formation by oral clinical isolates of Candida species. We have conducted a longitudinal study to quantify biofilms in oral clinical isolates of Candida species (spp.) from adults with local and systemic predisposing factors for candidiasis. A total of 69 yeast isolates from 63 Mexican patients were evaluated. These isolates (39 C. albicans, 15 C. tropicalis, 7 C. glabrata, 4 C. krusei, 1 C. lusitaniae, 1 C. kefyr, 1 C. guilliermondii and 1 C. pulcherrima) were obtained from two clinical sites: 62.3% (n=43) from the oral mucosa of totally and partially edentulous patients, and 37.7% (n=26) from the oral mucosa of diabetics. In addition, Candida ATCC strains were used as controls for each experiment. The kinetics of biofilm formation were measured by 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide [XTT] reduction; each isolate was tested at 6, 12 and 24h. Biofilm formation is dependent on the Candida spp. and its clinical origin. On average, the oral isolates of C. glabrata are strong biofilm producers, whereas C. albicans and C. tropicalis are moderate producers. The most common species in our population was C. albicans. While the kinetics of C. albicans biofilm formation varies between oral isolates, it generally maintains steady growth from 2 to 48h, when it reaches its maximum growth. 23453429 Sources of information and factual knowledge in Europeans with inflammatory bowel diseases: A cross-cultural comparison between German and Irish patients. Disease related knowledge may be associated with quality of life, coping skills and medication adherence. However, little is known of cross-cultural variations regarding inflammatory bowel disease knowledge or sources of information and no study has assessed knowledge in diverse European IBD populations. To assess sources of information and patient knowledge in Irish and German inflammatory bowel disease patients. Three hundred and three disease, gender, age and education matched German and Irish patients completed a previously validated knowledge questionnaire. Additional data were collected on age, gender, education, disease type and duration, family history, smoking habits, medication use, previous surgery and quality of life. German patients obtained knowledge from a wider range of sources than Irish patients (p<0.001), most notably from the internet (p<0.001), newspapers and magazines (p=0.002). Both cohorts answered a similar number of questions correctly (Irish, mean 4.4 questions (Standard deviation (S.D.) 2.4); German, mean 4.3 (S.D. 2.2); p=0.67). In addition, both nationalities answered "don't know" to a similar number of questions (Irish, mean 3.3 (S.D. 3.1); German, mean 2.7 (S.D. 2.8); p=0.12) while Irish patients answered slightly fewer questions wrongly (Irish, mean 2.4 (S.D. 1.8); German, mean 3.1 (S.D. 1.9); p=0.002). A multivariate analysis included only Crohn's disease, female gender, young age and higher educational status as being significantly and independently associated with knowledge. Our data suggest few differences between German and Irish IBD patients, despite cultural and linguistic differences, with regard to disease related knowledge of IBD. 23876029 Isometric training with maximal co-contraction instruction does not increase co-activation during exercises against external resistances. Abstract The present investigation verified that strength is improved by a training programme consisting of repetitions of maximal isometric voluntary co-contractions without increasing co-activations during contractions against external resistances. Ten participants performed 12 training sessions (four sets of 6 × 4 second maximal isometric co-contraction of the elbow flexor and extensors, 3 days a week for 4 weeks). Surface electromyograms of triceps and biceps brachii were collected during maximal voluntary isometric elbow flexion and extension against a force transducer. Maximal voluntary isometric force increased significantly after training, by 13.8 ± 6.0% (extension) and 9.6 ± 9.5% (flexion), but the observed increases in EMG of agonist muscles during maximal voluntary contraction were not significant. No significant changes in the levels of co-activation of the elbow flexors and extensors were observed. No significant change was observed for all the parameters in a control group of ten participants. These results indicated that the strength improvements after co-contraction training occur without increases in co-activation level. 23509897 Formal hepatitis C education enhances HCV care coordination, expedites HCV treatment and improves antiviral response. Formal Hepatitis C virus (HCV) education improves HCV knowledge but the impact on treatment uptake and outcome is not well described. We aimed to evaluate the impact of formal HCV patient education on primary provider-specialist HCV comanagement and treatment. Primary care providers within the San Francisco safety-net health care system were surveyed and the records of HCV-infected patients before and after institution of a formal HCV education class by liver specialty (2006-2011) were reviewed retrospectively. Characteristics of 118 patients who received anti-HCV therapy were: mean age 51, 73% males and ~50% White and uninsured. The time to initiation of HCV treatment was shorter among those who received formal education (median 136 vs 284 days, P < 0.0001). When controlling for age, gender, race and HCV viral load, non-1 genotype (OR 6.17, 95% CI 2.3-12.7, P = 0.0003) and receipt of HCV education (OR 3.0, 95% CI 1.1-7.9, P = 0.03) were associated with sustained virologic treatment response. Among 94 provider respondents (response rate = 38%), mean age was 42, 62% were White, and 63% female. Most providers agreed that the HCV education class increased patients' HCV knowledge (70%), interest in HCV treatment (52%), and provider-patient communication (56%). A positive provider attitude (Coef 1.5, 95% CI 0.1-2.9 percent, P = 0.039) was independently associated with referral rate to education class. Formal HCV education expedites HCV therapy and improves virologic response rates. As primary care provider attitude plays a significant role in referral to HCV education class, improving provider knowledge will likely enhance access to HCV specialty services in the vulnerable population. 23912905 The effect of crowding and confinement: a comparison of Yfh1 stability in different environments. Crowding and confinement can affect protein stability, favouring the more compact species amongst the folded and unfolded conformations. An unbiased assessment of the relative efficacy of crowded and confined environments has been hampered so far by the paucity of homogeneous comparisons on the same protein. This paper reports spectroscopic studies on yeast frataxin (Yfh1), a protein which provides an excellent model system for stability studies since it undergoes both cold and heat denaturation at measurable temperatures. The stability of Yfh1 was evaluated in the presence of Ficoll 70 and inside the cavities of polyacrylamide gels as means of mimicking crowding and confinement. We find that both effects influence the thermal stability of Yfh1 to a comparable extent thus providing the first direct comparison of crowding and confinement on the same protein. Thanks to the measurement of the full stability curve we also present the first thermodynamic characterization of the stability of a protein in crowding conditions. 23507383 Dynamic causal modelling of effective connectivity during perspective taking in a communicative task. Previous studies have shown that taking into account another person's perspective to guide decisions is more difficult when their perspective is incongruent from one's own compared to when it is congruent. Here we used dynamic causal modelling (DCM) for functional magnetic resonance imaging (fMRI) to investigate effective connectivity between prefrontal and posterior brain regions in a task that requires participants to take into account another person's perspective in order to guide the selection of an action. Using a new procedure to score model evidence without computationally costly estimation, we conducted an exhaustive search for the best of all possible models. The results elucidate how the activity in the areas from our previously reported analysis (Dumontheil et al., 2010) are causally linked and how the connections are modulated by both the social as well as executive task demands of the task. We find that the social demands modulate the backward connections from the medial prefrontal cortex (MPFC) more strongly than the forward connections from the superior occipital gyrus (SOG) and the medial temporal gyrus (MTG) to the MPFC. This was also the case for the backward connection from the MTG to the SOG. Conversely, the executive task demands modulated the forward connections of the SOG and the MTG to the MPFC more strongly than the backward connections. We interpret the results in terms of hierarchical predictive coding. 23732005 A new procedure of determination of alcohol sulfates and alcohol ethoxysulfates in agricultural soils. The number of analytical methodologies that focus in the determination of alcohol sulfates (AS) and alcohol ethoxysulfates (AES) in terrestrial environment is very limited. In the present work, a new methodology to improve the extraction and determination of AS and AES in agricultural soil samples has been developed. Prior to instrumental analysis, an extraction procedure using pressurized liquid extraction with methanol (PLE) was carried out in order to obtain the highest recoveries and improve sensitivity. The most influential variables affecting the PLE procedure were optimized. Then, the separation and quantification of analytes were performed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The limits of detection (LOD) ranged from 0.03 to 0.08μgg(-1) for AS homologues and in the case of AES ethoxymers from 0.03 to 0.09μgg(-1) for AES-C12Ex and from 0.03 to 0.08μgg(-1) for AES-C14Ex. Matrix-matched calibration was used. Trueness was evaluated by using a spike recovery assay with spiked blank samples, and the recoveries ranged from 98.3% to 101.0% for AS and from 99.9% to 100.1% for AES. The method was satisfactorily applied in a field study designed to evaluate the environmental behavior of these compounds in agricultural soil. 23919138 Manta Matcher: automated photographic identification of manta rays using keypoint features. For species which bear unique markings, such as natural spot patterning, field work has become increasingly more reliant on visual identification to recognize and catalog particular specimens or to monitor individuals within populations. While many species of interest exhibit characteristic markings that in principle allow individuals to be identified from photographs, scientists are often faced with the task of matching observations against databases of hundreds or thousands of images. We present a novel technique for automated identification of manta rays (Manta alfredi and Manta birostris) by means of a pattern-matching algorithm applied to images of their ventral surface area. Automated visual identification has recently been developed for several species. However, such methods are typically limited to animals that can be photographed above water, or whose markings exhibit high contrast and appear in regular constellations. While manta rays bear natural patterning across their ventral surface, these patterns vary greatly in their size, shape, contrast, and spatial distribution. Our method is the first to have proven successful at achieving high matching accuracies on a large corpus of manta ray images taken under challenging underwater conditions. Our method is based on automated extraction and matching of keypoint features using the Scale-Invariant Feature Transform (SIFT) algorithm. In order to cope with the considerable variation in quality of underwater photographs, we also incorporate preprocessing and image enhancement steps. Furthermore, we use a novel pattern-matching approach that results in better accuracy than the standard SIFT approach and other alternative methods. We present quantitative evaluation results on a data set of 720 images of manta rays taken under widely different conditions. We describe a novel automated pattern representation and matching method that can be used to identify individual manta rays from photographs. The method has been incorporated into a website (mantamatcher.org) which will serve as a global resource for ecological and conservation research. It will allow researchers to manage and track sightings data to establish important life-history parameters as well as determine other ecological data such as abundance, range, movement patterns, and structure of manta ray populations across the world. 23848476 Pharmacist-Provided Medication Therapy Management (MTM) Program Impacts Outcomes for Employees With Diabetes. Abstract The objective of this prospective, pre-post longitudinal study was to assess the impact of pharmacist-provided medication therapy management (MTM) services on employees' health and well-being by evaluating their clinical and humanistic outcomes. City of Toledo employees and/or their spouses and dependents with diabetes with or without comorbid conditions were enrolled in the pharmacist-conducted MTM program. Participants scheduled consultations with the pharmacist at predetermined intervals. Overall health outcomes, such as clinical markers, health-related quality of life (HRQoL), disease knowledge, and social and process measures, were documented at these visits and assessed for improvement. Changes in patient outcomes over time were analyzed using Wilcoxon signed rank and Friedman test at an a priori level of 0.05. Spearman correlation was used to measure the relationship between clinical and humanistic outcomes. A total of 101 patients enrolled in the program. At the end of 1 year, patients' A1c levels decreased on average by 0.27 from their baseline values. Systolic and diastolic blood pressure also decreased on average by 6.0 and 4.2 mmHg, respectively. Patient knowledge of disease conditions and certain aspects or components of HRQoL also improved. Improvements in social and process measures also were also observed. Improved clinical outcomes and quality of life can affect employee productivity and help reduce costs for employers by reducing disease-related missed days of work. Employers seeking to save costs and impact productivity can utilize the services provided by pharmacists. Population Health Management 2013;XX:xxx-xxx. 23838696 Risk factors for obesity in children and adults. The purpose of this study was to determine whether modifiable lifestyle factors such as eating habits, physical activity, and screen-viewing time, as well as ethnicity, sex, and family income level, were associated with obesity in children and adults and whether the associations differed across age groups. The data were drawn from the National Health and Nutrition Examination Survey 2009-2010. Multivariable logistic regression analyses were used, with obesity (defined as a body mass index of >30 kg/m for adults and ≥95th percentile for children of the same age and sex) as the outcome variable. For children, screen-viewing (TV/computer) time was the only significant factor; in contrast, for adolescents, eating habits were the only significant predictor. For young and middle-aged adults, lack of physical exercise and time spent in sedentary activities were the determinants of obesity, whereas for older adults, both eating habits and physical activity measures were related to obesity. Distinct lifestyle factors have significant associations with obesity in different age groups, and this study underscores the need for age-specific intervention programs to address the obesity epidemic. 23640715 Sensitivity of salmonid freshwater life history in western US streams to future climate conditions. We projected effects of mid-21st century climate on the early life growth of Chinook salmon (Oncorhynchus tshawytscha) and steelhead (O. mykiss) in western United States streams. Air temperature and snowpack trends projected from observed 20th century trends were used to predict future seasonal stream temperatures. Fish growth from winter to summer was projected with temperature-dependent models of egg development and juvenile growth. Based on temperature data from 115 sites, by mid-21st century, the effects of climate change are projected to be mixed. Fish in warm-region streams that are currently cooled by snow melt will grow less, and fish in suboptimally cool streams will grow more. Relative to 20th century conditions, by mid-21st century juvenile salmonids' weights are expected to be lower in the Columbia Basin and California Central Valley, but unchanged or greater in coastal and mountain streams. Because fish weight affects fish survival, the predicted changes in weight could impact population fitness depending on other factors such as density effects, food quality and quantity changes, habitat alterations, etc. The level of year-to-year variability in stream temperatures is high and our analysis suggests that identifying effects of climate change over the natural variability will be difficult except in a few streams. 23859850 Prevalence of upper limb disorders among female librarians. Background Work as a librarian involves exposure to potential risk factors for developing upper limb disorders. The prevalence of upper limb symptoms has, however, not previously been assessed in this occupational group. Aims To estimate the 7-day and annual prevalence of self-reported neck and upper limb symptoms in librarians and to examine associations with specific tasks and ergonomic risk factors. Methods A cross-sectional study using components of the standardized Nordic questionnaire. The study population consisted of librarians employed by a large local authority, and data collection was by means of a self-administered questionnaire. Results from studies on keyboard workers and on the general population were used as comparators. Results The 7-day prevalence of self-reported neck and upper limb pain in female librarians was 42% (95% confidence interval (CI) 33.7-50.5) and the annual prevalence was 65% (95% CI 56.6-72.8). The prevalence of reported wrist and hand pain increased with increased working involving a wide thumb-index span (P < 0.05) with a significant linear trend in prevalence with increasing exposure (P < 0.01). There was a strong association between reporting hand and/or wrist pain and awareness of work-related upper limb disorder (P < 0.05). Conclusions The annual prevalence of self-reported upper limb symptoms among female librarians was high, but there was insufficient evidence to confirm whether the prevalence was higher than in the general population or among keyboard workers. Working with a wide thumb-index span was associated with reporting upper limb symptoms. 23613469 Phosphorylation of Gβ is crucial for efficient chemotropism in yeast. Mating yeast cells interpret complex pheromone gradients and polarize their growth in the direction of the closest partner. Chemotropic growth depends on both the pheromone receptor and its associated G-protein. Upon activation by the receptor, Gα dissociates from Gβγ and Gβ is subsequently phosphorylated. Free Gβγ signals to the nucleus via a MAPK cascade and recruits Far1-Cdc24 to the incipient growth site. It is not clear how the cell establishes and stabilizes the axis of polarity, but this process is thought to require local signal amplification via the Gβγ-Far1-Cdc24 chemotropic complex, as well as communication between this complex and the activated receptor. Here we show that a mutant form of Gβ that cannot be phosphorylated confers defects in directional sensing and chemotropic growth. Our data suggest that phosphorylation of Gβ plays a role in localized signal amplification and in the dynamic communication between the receptor and the chemotropic complex, which underlie growth site selection and maintenance. 23900896 Adult ECG Criteria for Left Ventricular Hypertrophy in Young Competitive Athletes. Time-tested data indicate that ECG diagnosis of left ventricular hypertrophy in young athletes is challenging due to low sensitivity of the commonly used criteria. We sought to establish whether adult ECG criteria can be appropriate to make diagnosis of both common and uncommon patterns of left ventricular hypertrophy in young trained athletes. A total of 122 athletes, ages 16.2±3.8 years, training at least 5 h per week, were studied with Sokolow-Lyon voltage, Romhilt-Estes, Cornell voltage, Cornell Product, Perugia and Framingham scores. Garson Criteria were also investigated in athletes under 16. Participants were divided into 2 groups based on the presence (group-A, n=56) or absence (group-B, n=66) of at least one positive ECG score. Test performance was calculated with respect to accurate echocardiographic diagnosis of left ventricular hypertrophy. There were no inter-group differences regarding physical characteristics and training burden. 9 athletes from group-A (16%) and 2 from group-B (3%) were found to have left ventricular hypertrophy, likely to be pathological in 2 cases from group-A. Criteria gathering both QRS voltages and ST-T anomalies, like Perugia-score, best identified this subgroup and should be preferred to those based on QRS voltage analysis alone. 23906665 In vitro gastrointestinal model (TIM) with predictive power, even for infants and children? There is a need for information on the bioavailability in pediatric patients of drugs from manipulated dosage forms when applied in combination with food and/or co-medication under realistic daily practice circumstances. We describe the development, validation and application of a dynamic, computer-controlled in vitro system mimicking the conditions in the upper gastrointestinal tract of neonates, infants and toddlers: TIMpediatric. Paracetamol and diclofenac in age-related food matrices and with esomeprazole co-medication were tested. The experiments showed relevant results on the impact of drug manipulation and co-medication on the availability for absorption of active compounds. Without ethical constraints, alternative approaches for oral dosing and new pediatric formulations can be studied in TIMpediatric with a high predictive value. 23435430 ATM kinase activity modulates ITCH E3-ubiquitin ligase activity. Ataxia Telangiectasia Mutated (ATM) kinase, a central regulator of the DNA damage response, regulates the activity of several E3-ubiquitin ligases, and the ubiquitination-proteasome system is a consistent target of ATM. ITCH is an E3-ubiquitin ligase that modulates the ubiquitination of several targets, therefore participating to the regulation of several cellular responses, such as the DNA damage response, tumor necrosis factorα (TNFα), Notch and Hedgehog signaling, and the differentiation of 'naive' lymphocytes into T helper type 2 cells. Here we uncover ATM as a novel positive modulator of ITCH E3-ubiquitin ligase activity. A single residue on ITCH protein, S161, which is part of an ATM SQ consensus motif, is required for ATM-dependent activation of ITCH. ATM activity enhances ITCH enzymatic activity, which in turn drives the ubiquitination and degradation of c-FLIP-L and c-Jun, previously identified as ITCH substrates. Importantly, ATM-deficient mice show resistance to hepatocyte cell death, similarly to Itch-deficient animals, providing in vivo genetic evidence for this circuit. Our data identify ITCH as a novel component of the ATM-dependent signaling pathway and suggest that the impairment of the correct functionality of ITCH caused by Atm deficiency may contribute to the complex clinical features linked to Ataxia Telangiectasia.Oncogene advance online publication, 25 February 2013; doi:10.1038/onc.2013.52. 23103283 Mancozeb-induced behavioral deficits precede structural neural degeneration. Manganese-containing fungicides like Mancozeb have been associated with neurodegenerative conditions like Parkinson's disease. We examined the behavioral damage and differential neuronal vulnerability resulting from Mancozeb exposure using Caenorhabditis elegans, an important mid-trophic level soil organism that is also a powerful model for studying mechanisms of environmental pollutant-induced neurodegenerative disease. The dopamine-mediated swim to crawl locomotory transition behavior is exquisitely vulnerable to Mancozeb, with functional impairment preceding markers of neuronal structural damage. The damage is partially rescued in mutants lacking the divalent metal transporter, SMF-1, demonstrating that some, but not all, of the damage is mediated by manganese. Increasing concentrations of Mancozeb recruit additional behavioral dysfunction, notably serotonin-mediated egg-laying behavior, but without evident serotonergic neuronal structural damage. Thus, measurements of behavioral dysfunction are a sensitive early marker of fungicide toxicity that could be exploited to examine further mechanisms of neuron damage and possible therapeutic interventions. These results also provide important insight into the consequences of fungicide use on the ecological behavior of nematodes. 23878236 Ion channel-kinase TRPM7 is required for maintaining cardiac automaticity. Sick sinus syndrome and atrioventricular block are common clinical problems, often necessitating permanent pacemaker placement, yet the pathophysiology of these conditions remains poorly understood. Here we show that Transient Receptor Potential Melastatin 7 (TRPM7), a divalent-permeant channel-kinase of unknown function, is highly expressed in embryonic myocardium and sinoatrial node (SAN) and is required for cardiac automaticity in these specialized tissues. TRPM7 disruption in vitro, in cultured embryonic cardiomyocytes, significantly reduces spontaneous Ca(2+) transient firing rates and is associated with robust down-regulation of Hcn4, Cav3.1, and SERCA2a mRNA. TRPM7 knockdown in zebrafish, global murine cardiac Trpm7 deletion (KO(αMHC-Cre)), and tamoxifen-inducible SAN restricted Trpm7 deletion (KO(HCN4-CreERT2)) disrupts cardiac automaticity in vivo. Telemetered and sedated KO(αMHC-Cre) and KO(HCN4-CreERT2) mice show episodes of sinus pauses and atrioventricular block. Isolated SAN from KO(αMHC-Cre) mice exhibit diminished Ca(2+) transient firing rates with a blunted diastolic increase in Ca(2+). Action potential firing rates are diminished owing to slower diastolic depolarization. Accordingly, Hcn4 mRNA and the pacemaker current, If, are diminished in SAN from both KO(αMHC-Cre) and KO(HCN4-CreERT2) mice. Moreover, heart rates of KO(αMHC-Cre) mice are less sensitive to the selective If blocker ivabradine, and acute application of the recently identified TRPM7 blocker FTY720 has no effect on action potential firing rates of wild-type SAN cells. We conclude that TRPM7 influences diastolic membrane depolarization and automaticity in SAN indirectly via regulation of Hcn4 expression. 23794335 Optimizing the kinetics and thermodynamics of DNA i-motif folding. Under slightly acidic conditions, single cytidine-rich DNA strands can form four-stranded structures called i-motifs. The stability of the i-motif structure is based on the intercalation of hemiprotonated C-C(+) base pairs. In addition, the stability of these structures is influenced by pH, temperature, salt concentration, number of cytidines per C-rich stretch, and length of sequence; it also depends on the nucleotides in the connecting loop regions. Here, we investigated the influence of the loop nucleotides on i-motif stability, structure, and kinetics of folding, in five structures with the same loop-size but different adenosine and thymidine residues within the loop. The stabilities of the i-motif structures were determined by CD melting, and structure and kinetics of folding were studied by static and time-resolved NMR experiments. 23914076 European American and African American Mothers' Emotion Socialization Practices Relate Differently to their Children's Academic and Social-Emotional Competence. The current study examines whether the relation between mothers' responses to their children's negative emotions and teachers' reports of children's academic performance and social-emotional competence are similar or different for European American and African American families. Two hundred mothers (137 European American, 63 African American) reported on their responses to their 5-year-old children's negative emotions and 150 kindergarten teachers reported on these children's current academic standing and skillfulness with peers. Problem-focused responses to children's negative emotions, which have traditionally been considered a supportive response, were positively associated with children's school competence for European American children, but expressive encouragement, another response considered supportive, was negatively associated with children's competence for African American children. The findings highlight the need to examine parental socialization practices from a culturally-specific lens. 23468176 Clinical trial of etanercept tapering in juvenile idiopathic arthritis during remission. To explore the possibility of step-down method and low dose of etanercept for long-term stable remission of patients with juvenile idiopathic arthritis (JIA). Patients with JIA were enrolled into this study between February 2008 and March 2010 and then followed up for 2 years. The inclusion criteria were clinical remission and use of etanercept for therapy. On the first year of the study, the dose of etanercept was kept at 0.4 mg/kg per week, the half dose of what those patients had been used. On the second year, the dose of etanercept was further lowered to 0.4 mg/kg per month. DMARDs were allowed in this study. MR images were performed to observe joint changes. The primary end point was disease flare defined according to clinical and/or radiological data. The flare rate curve was analyzed by Kaplan-Meier, and logistic regression model was used to find factors associating with disease flare. MRI was performed to prove no active changes or progressions of bone erosions on joints. Thirty-one patients were enrolled in this study. There were 4 patients experiencing disease flare during the first 12th month. During the second year, disease flare was not occurred. Thus, the cumulative flare rate was 12.9 % on 12th month and then unchanged on the second year. Logistic regression model indicates there are no differences in sex, age of disease initiation, disease duration, subtypes, DMARDs, HLA-B27, months of etanercept duration and scores on MRI between patients with remission and those experiencing flares. At the end of the study, MRI found no progressions of joints to the patients keeping stable remission. Step-down method can be used for etanercept tapering. Long-term remission and low flare rate can be got by this method. 23547705 Nanostructured potential of optical trapping using a plasmonic nanoblock pair. We performed two-dimensional mapping of optical trapping potentials experienced by a 100 nm dielectric particle above a plasmon-resonant gold nanoblock pair with a gap of several nanometers. Our results demonstrate that the potentials have nanoscale spatial structures that reflect the near-field landscape of the nanoblock pair. When an incident polarization parallel to the pair axis is rotated by 90°, a single potential well turns into multiple potential wells separated by a distance smaller than the diffraction limit; this is associated with super-resolution optical trapping. In addition, we show that the trap stiffness can be enhanced by approximately 3 orders of magnitude compared to that with conventional far-field trapping. 23968048 Acoustic detection and long-term monitoring of pygmy blue whales over the continental slope in southwest Australia. A 9-yr dataset of continuous sea noise recording made at the Cape Leeuwin station of the Comprehensive Nuclear-Test-Ban Treaty hydroacoustic network in 2002-2010 was processed to detect calls from pygmy blue whales and to analyze diurnal, seasonal, and interannual variations in their vocal activity. Because the conventional spectrogram correlation method for recognizing whale calls in sea noise resulted in a too high false detection rate, alternative algorithms were tested and the most robust one applied to the multi-year dataset. The detection method was based on multivariate classification using two spectrogram features of transients in sea noise and Fisher's linear discriminant, which provided a misclassification rate of approximately 1% for missed and false detections at moderate sensitivity settings. An analysis of the detection results revealed a consistent seasonal pattern in the whale presence and considerable interannual changes with a steady increase in the number of calls detected in 2002-2006. An apparent diurnal pattern of whales' vocal activity was also observed. The acoustic detection range for pygmy blue whales was estimated to vary from about 50 km to nearly 200 km from the Cape Leeuwin station, depending on the ambient noise level, source level, and azimuth to a vocalizing whale. 23964360 Hydrogen storage: beyond conventional methods. The efficient storage of hydrogen is one of three major hurdles towards a potential hydrogen economy. This report begins with conventional storage methods for hydrogen and broadly covers new technology, ranging from physical media involving solid adsorbents, to chemical materials including metal hydrides, ammonia borane and liquid precursors such as alcohols and formic acid. 23958058 Preliminary assessment of nasopharyngeal carcinoma incidence in the Philippines: a second look at published data from four centers. In endemic regions such as southern China and Southeast Asia, the annual incidence of nasopharyngeal carcinoma (NPC) ranges from 3 to 30 per 100,000. In the Philippines, the estimated incidence in 2010 was 1.2 per 100,000. However, this rate is based on data collected from registries covering only two regions in the country. Here, we report the findings from our study to better approximate the incidence of NPC in the Philippines. Between September 1, 2011 and August 31, 2012, data were collected from 49 patients from 4 different institutions--University of Santo Tomas, Makati Medical Center, Philippine Oncology Center Corporation, and Cardinal Santos Memorial Medical Center--using a NPC screening questionnaire. Crude incidence was 0.09 per 100,000. Age-standardized incidences using Segi and WHO standards were 2.08 and 1.79 per 100,000, respectively. Of the 49 patients, 31 were males and 18 were females, and 71% of patients were between 30 and 59 years old. WHO types II and III represented 22% and 78% of the subjects, respectively, and 78% of cases were locally advanced (stages II--IVB). Although the age-standardized incidence from the four institutions was numerically higher than the published age-standardized incidence (2.07 per 100,000 vs. 1.2 per 100,000), two-proportion z-test showed no significant difference between them (P = 0.68). A more concerted effort is needed for a better approximation of the country's NPC disease burden. 23924822 A Potential Mechanism of a Cationic Cyclopeptide for Enhancing Insulin Delivery across Caco-2 Cell Monolayers. Effective delivery of therapeutic biomolecules across biomembranes is a challenging topic. A cationic cyclopeptide named TD-34 (ACSSKKSKHCG) was reported to improve insulin delivery across biomembranes effectively. Based on our previous work, we investigated the mechanism of TD-34 for enhancing insulin across Caco-2 cell monolayers. Transport studies of insulin, TD-34 and insulin accompanied with TD-34 were performed respectively using Caco-2 cell monolayers at different conditions. Transepithelial electrical resistance (TEER) value was monitored for 24 h immediately after the beginning of transport experiments. Moreover, the tight junction protein (Claudin-1) was localized by confocal immunofluorescence microscopy. Results showed the transport of insulin alone across biomembranes was attributable to multiple routes including passive diffusion. When TD-34 accompanied with or without insulin was treated on Caco-2 cell monolayers, TEER values decreased reversibly, and it was correlated with the reappearance of tight junction proteins by immunostaining assay. It was concluded that the cationic cyclopeptide (TD-34) had the potential to enhance paracellular delivery of insulin across Caco-2 cell monolayers by loosening tight junction reversibly. 23806035 The Influences of Reserpine and Imipramine on the 5-HT2 Receptor Binding Site and Its Coupled Second Messenger in Rat Cerebral Cortex. An investigation on the molecular mechanism of depression state, less attention was focused on changes at the intracellular messenger level. In this study the effects of reserpine, a monoamine depletor, and imipramine, an antidepressant, on serotonin-2 (5-HT2) receptor binding and its second messenger system of rat cerebral cortex were studied. The level of inositol 4-monophosphate (IP1) accumulation elicited by 100 μM 5-HT via activation of the 5-HT2 receptor on cerebral cortical slices at twelve hours after a single dose of reserpine (2 mg/kg, i.p.) was significantly higher in treated rats, when compared to that of saline-treated rats ; this significant level lasted for at least four days. The level of IP1 accumulation in rat cerebral cortical slices elicited by 100 μM serotonin was higher in the group pretreated with reserpine (0.25 mg/kg/day) sub-chronically for seven days than the group pretreated with normal saline. In the receptor binding study, the maximum binding (Bmax) of 5-HT2 receptor binding was increased, when compared to the corresponding controls; whereas, the dissociation equilibrium constant (Kd) value of the 5-HT2 receptor was found unchanged in the reserpine treated group. Increases in the sensitivity of phosphoinositol (PI) turnover coupled with the 5-HT2 receptor were also found in the long-term (21 days) low dose (0.1 mg/kg/day) administration of reserpine. However, a long-term administration of imipramine (10 mg/kg/day) reduced the function of the PI turnover coupled with the 5-HT2 receptor. Results obtained from the combined use of reserpine and imipramine demonstrated that this combination was able to antagonize the super-sensitivity of the second messenger responses in 5-HT2 receptor induced by long-term treatment with reserpine. Long term treatment with reserpine but not imipramine also caused an increase in the Bmax of the 5-HT2 receptor. This up-regulation of the 5-HT2 receptor by reserpine could be antagonized by imipramine, if a combined treatment was employed. However, this combination of imipramine with an additional phospholipid liposome did not enhance or decrease the imipramine's effect on the 5-HT2 receptor, or on its coupled second messenger level. In summary, reserpine induced up-regulation of the postsynaptic monoamine receptor and its coupled second messenger responses (such as IP1 formation). Imipramine was capable of antagonizing these same events in a depression animal model with reserpine. This study demonstrated the dynamic changes and adaptability of the receptor system, followed by changes in PI turnover. The results provide an explanation at the molecular level for the bases of depression and the role of antidepressant drugs effects on those pathological linking elements. 23849046 Cardiometabolic health nursing to improve health and primary care access in community mental health consumers: Protocol for a randomised controlled trial. People with a serious mental illness are at significantly greater risk of poor cardiometabolic health with recent studies showing a greater than two-fold increase in the risk of obesity, infectious diseases, diabetes and cardiovascular disease. Contributing factors to this disparity include poorer health behaviours such as suboptimal physical activity, poor diet, smoking, alcohol and illicit drug misuse. In particular, the limited access to primary health care experienced by people with a serious mental illness has been highlighted. Persons with a serious mental illness are around 30% less likely than those without serious mental illness to receive health assessments, hospital admissions or procedures for cardiovascular disease and diabetes, and are less likely to undergo cancer screening or receive vaccinations. Studies show that mental health consumers may be more likely to use mental health services rather than primary care for contact with the health care system. However mental health nurses report several barriers to their capacity to provide cardiometabolic health care crucial for the treatment of people with a serious mental illness. To assess the impact of a specialist Cardiometabolic Health Nurse on the physical health care of community based mental health consumers. Community mental health facility in a large regional centre in Central Queensland, Australia. Community based mental health consumers will be randomised to receive either usual care, or consultations with a Cardiometabolic Health Nurse. The Cardiometabolic Health Nurse will be responsible for assessing the client and coordinating cardiometabolic health care as required. Post intervention review of health records will be performed with the primary outcome measure being self-reported physical health. Secondary outcomes include the utilisation of primary care services and changes in health behaviours. We hypothesise that the Cardiometabolic Health Nurse will increase the utilisation of health care services for mental health consumers. Data collection commenced in March 2013 and will conclude September 2013. Preliminary finding are expected in December 2013. 23964342 Superior Mesenteric Artery Syndrome Diagnosed with Linear Endoscopic Ultrasound (with Video) in a Patient with Normal Body Mass Index. Superior mesenteric artery (SMA) syndrome is an uncommon disease that results from SMA compression of the third portion of the duodenum. Patients with SMA syndrome present with upper gastrointestinal symptoms, such as nausea, vomiting, and abdominal pain. The diagnosis is usually made from an upper barium study or computed tomography. Typically, SMA syndrome is caused by a decreased aortomesenteric angle of 6° to 25°. An underweight body mass index (BMI) is a risk factor for development of SMA syndrome. There are few reports of the role of linear endoscopic ultrasound (EUS) in the diagnosis of SMA syndrome. We report a case of SMA syndrome, with normal BMI, that was diagnosed with the aid of linear EUS. Although SMA syndrome is not typically within the scope of practice of endosonographers, it is useful to get familiar with the findings. 23834335 FUsed in Sarcoma (FUS) is a novel regulator of Manganese Superoxide Dismutase (MnSOD) gene transcription. Aims: FUsed in sarcoma (FUS) is a multifunctional DNA/RNA-binding protein that possesses diverse roles, such as RNA splicing, RNA transport, DNA repair, translation, and transcription. The network of enzymes and processes regulated by FUS is far from being fully described. In this study, we have focused on the mechanisms of FUS-regulated MnSOD gene transcription. Results: Here, we demonstrate that FUS is a component of the transcription complex that regulates the expression of MnSOD. Overexpression of FUS increased MnSOD expression in a dose-dependent manner and knockdown of FUS by siRNA led to the inhibition of MnSOD gene transcription. Reporter analyses, ChIP assay, EMSA, affinity chromatography, and SPR analyses revealed the far upstream region of MnSOD promoter as an important target of FUS-mediated MnSOD transcription and confirmed that FUS binds to the MnSOD promoter and interacts with Sp1. Importantly, overexpression of familial amyotropic lateral sclerosis (fALS)-linked R521G mutant FUS resulted in a significantly reduced level of MnSOD expression and activity, which is consistent with the decline in MnSOD activity observed in fibroblasts from fALS patients with the R521G mutation. R521G-mutant FUS abrogates MnSOD promoter-binding activity and interaction with Sp1. Innovation and Conclusion: This study identifies FUS as playing a critical role in MnSOD gene transcription and reveals a previously unrecognized relationship between MnSOD and mutant FUS in fALS. 23834565 A multi-tiered approach to safety education. Background:  The World Health Organization has recognised that patient safety education should begin at the undergraduate level. This should not just be for medical students, but for all students in the health professions. Although all students in the health professions should receive a basic grounding in patient safety, there is also a need to develop future leaders in this field. As a result of widespread early student exposure, some students may become interested in learning more. It follows that a postgraduate approach is also needed. Innovations:  The New South Wales Clinical Excellence Commission (CEC) has initiated a tiered approach to patient safety education by providing patient safety teaching in medical, nursing and allied health schools. Teaching is provided in cooperation with the host university, and is interactive, using a mixture of interactive lectures, video clips, films and break-out groups to discuss scenarios and feedback from students to their peers about the concepts they have discussed. For medical graduates, the CEC has initiated patient safety teaching in the early postgraduate years, and provides an elective in patient safety for trainee doctor specialists as part of their accredited training. This process helps to identify and mentor future medical leaders in this field. Implications:  In addition to teaching the core principles of patient safety to a wide range of students in the health professions, an approach for developing future leaders will provide additional opportunities for motivated students and create opportunities for continuing development in the early postgraduate years and beyond. 23866054 Circadian Disruption: comparing humans with mice. Disruption of the 24-h light-dark cycle has been implicated as an endocrine disruptor and linked to increased morbidity and mortality in animal studies. Previously reported measurements of circadian disruption in day-shift and rotating-shift nurses were compared with new mouse data where the light-dark patterns simulated shiftwork. Phasor magnitudes, a measure of circadian entrainment, were shown to be similar for humans and for mice when exposed to similar patterns of light and dark. Phasor analyses may be a useful method for quantitatively bridging ecological measurements of circadian disruption in human with parametric studies of health outcomes in a mouse model. 23775816 Dual-Mesoporous ZSM-5 Zeolite with Highly b-Axis-Oriented Large Mesopore Channels for the Production of Benzoin Ethyl Ether. Dual-mesoporous ZSM-5 zeolite with highly b axis oriented large mesopores was synthesized by using nonionic copolymer F127 and cationic surfactant CTAB as co-templates. The product contains two types of mesopores-smaller wormlike ones of 3.3 nm in size and highly oriented larger ones of 30-50 nm in diameter along the b axis-and both of them interpenetrate throughout the zeolite crystals and interconnect with zeolite microporosity. The dual-mesoporous zeolite exhibits excellent catalytic performance in the condensation of benzaldehyde with ethanol and greater than 99 % selectivity for benzoin ethyl ether at room temperature, which can be ascribed to the zeolite lattice structure offering catalytically active sites and the hierarchical and oriented mesoporous structure providing fast access of reactants to these sites in the catalytic reaction. The excellent recyclability and high catalytic stability of the catalyst suggest prospective applications of such unique mesoporous zeolites in the chemical industry. 23686264 An engineered strong promoter for streptomycetes. Well-characterized promoters are essential tools for metabolic engineering and synthetic biology. In Streptomyces coelicolor, the native kasOp is a temporally expressed promoter strictly controlled by two regulators, ScbR and ScbR2. In this work, first, kasOp was engineered to remove a common binding site of ScbR and ScbR2 upstream of its core region, thus generating a stronger promoter, kasOp3. Second, another ScbR binding site internal to the kasOp3 core promoter region was abolished by random mutation and screening of the mutant library to obtain the strongest promoter, kasOp* (where the asterisk is used to distinguish the engineered promoter from the native promoter). The activities of kasOp* were compared with those of two known strong promoters, ermEp* and SF14p, in three Streptomyces species. kasOp* showed the highest activity at the transcription and protein levels in all three hosts. Furthermore, relative to ermEp* and SF14p, kasOp* was shown to confer the highest actinorhodin production level when used to drive the expression of actII-ORF4 in S. coelicolor. Therefore, kasOp* is a simple and well-defined strong promoter useful for gene overexpression in streptomycetes. 23050693 Beads made of α-cyclodextrin and soybean oil: the drying method influences bead properties and drug release. Freeze-dried beads made of α-cyclodextrin and soybean oil were reported previously as an efficient system for the oral delivery of lipophilic drugs. In the present study, oven-drying was evaluated as another method for drying beads. Oven-drying was optimised and the properties of the resulting beads were assessed. The behavior of oven-dried beads and the release of indomethacin from these beads were evaluated in vitro in simulated gastrointestinal fluids and compared with those of freeze-dried beads. The stability of freeze-dried and oven-dried unloaded beads stored at 25°C for 12 months and at 40°C for 6 months in closed and open vials was also studied by different techniques. An oven-drying time of 6 hours at 25°C was chosen as optimal conditions. Oven-dried beads exhibited a sticky texture making them difficult to handle. They were harder, less fragile and smaller than the freeze-dried ones. The characteristics of oven-dried beads make them more resistant in vitro even in media containing bile salt. The rate of indomethacin release from oven-dried beads was much slower than that from the freeze-dried ones. Whatever the drying method, beads must be stored at room temperature protected from humidity. However, no products of oil degradation were detected with both kinds of beads. This work clearly emphasized that the drying method of the beads had a strong influence on their properties, behavior in simulated gastrointestinal fluids and drug release. 23791740 Characterization of the oncogenic function of centromere protein F in hepatocellular carcinoma. Centromere protein F (CENPF) is an essential nuclear protein associated with the centromere-kinetochore complex and plays a critical role in chromosome segregation during mitosis. Up-regulation of CENPF expression has previously been detected in several solid tumors. In this study, we aim to study the expression and functional role of CENPF in hepatocellular carcinoma (HCC). We found CENPF was frequently overexpressed in HCC as compared with non-tumor tissue. Up-regulated CENPF expression in HCC was positively correlated with serum AFP, venous invasion, advanced differentiation stage and a shorter overall survival. Cox regression analysis found that overexpression of CENPF was an independent prognosis factor in HCC. Functional studies found that silencing CENPF could decrease the ability of the cells to proliferate, form colonies and induce tumor formation in nude mice. Silencing CENPF also resulted in the cell cycle arrest at G2/M checkpoint by down-regulating cell cycle proteins cdc2 and cyclin B1. Our data suggest that CENPF is frequently overexpressed in HCC and plays a critical role in driving HCC tumorigenesis. 23707701 Complete mitochondrial genomes resolve phylogenetic relationships within Bombina (Anura: Bombinatoridae). A highly resolved and time-calibrated phylogeny based on nucleotide variation in 18 complete mitochondrial genomes is presented for all extant species and major lineages of fire-bellied toads of the genus Bombina (Bombinatoridae). Two sets of divergence time estimates are inferred by applying alternative fossil constraints as minima. Divergence time estimates from both analyses differed for the two oldest nodes. The earliest phylogenetic split occurred between small- and large-bodied Bombina (subgenera Bombina and Grobina, respectively) either in the Middle Oligocene or the Early Miocene. East Asian B. orientalis and European B. bombina+B. variegata diverged in the early or Middle Miocene. Divergence times inferred using the alternative fossil calibration strategies converged for the younger nodes, with broadly overlapping HPD intervals. The split between Bombina bombina and B. variegata occurred in the Late Miocene of Europe and somewhat preceded another deep mtDNA division between the Balkan B. v. scabra and B. v. variegata inhabiting the Carpathian Mts. Concurrently, the genetically distinct B. maxima diverged from other Grobina in southeast Asia in the Late Miocene or Pliocene. Our mtDNA phylogeny and a new species-tree analysis of published data (nuclear and mtDNA) suggest that B. fortinuptialis, B. lichuanensis and B. microdeladigitora may be conspecific geographic forms that separated due to Pleistocene climatic fluctuations in southeastern Asia. In the western Palearctic, the Late Pliocene to Pleistocene climatic vagaries most probably induced vicariant events in the evolutionary history of B. variegata that led to the formation of the two Balkan B. v. scabra lineages and the allopatric B. v. pachypus in the Apennine Peninsula. Divergence among B. bombina mtDNA lineages is low, with an Anatolian Turkey lineage as the sister group to the European mtDNA clades. In sum, Miocene diversification in the genus Bombina established six allopatrically distributed major mtDNA lineages that diversified during the Pliocene and Pleistocene and have survived until the present. The narrow habitat requirements of fire-bellied toads and extensive environmental changes throughout the Palearctic in the Neogene may have contributed to a putatively high extinction rate in these anurans resulting in the current east/west disjunction of their ranges. 23939022 Targeted drug delivery to intestinal macrophages by bioactive nanovesicles released from grapefruit. The gut mucosal immune system is considered to play an important role in counteracting potential adverse effects of food derived antigens including nanovesicles. Whether nanovesicles naturally released from edible fruit work in a coordinated manner with gut immune cells to maintain the gut in a noninflammatory status is not known. Here, as proof of concept we demonstrate that grapefruit derived nanovesicles (GDNs) are selectively taken up by intestinal macrophages and ameliorate dextran sulfate sodium (DSS) induced mouse colitis. These effects were mediated by up-regulating the expression of heme oxygenase-1 (HO-1) and inhibiting the production of IL-1β and TNF-α in intestinal macrophages. The inherent biocompatibility and biodegradability, stability at wide ranges of pH values and targeting of intestinal macrophages led us to further develop a novel GDN based oral delivery system. Incorporating methotrexate (MTX), an anti-inflammatory drug, into GDNs and delivering the MTX-GDNs to mice significantly lowered the MTX toxicity when compared to free MTX, and remarkably increased its therapeutic effects in DSS induced mouse colitis. These findings demonstrate that GDNs can serve as immune modulators in the intestine, maintain intestinal macrophage homeostasis and can be developed for oral delivery of small molecule drugs to attenuate inflammatory responses in human disease.Molecular Therapy (2013); doi:10.1038/mt.2013.190. 23515307 S-Pechmann dye: a thiolactone-containing organic dye with a pronounced electron-accepting character and its solid-state photophysical properties. A sulfur analogue of a Pechmann dye has been synthesized. In addition to long-wavelength absorption and fluorescence, it showed multiple redox processes with low reduction potentials in cyclic voltammetry. The size effect of sulfur is responsible for its enhanced electron-accepting character. 23843990 Ceruloplasmin: macromolecular assemblies with iron-containing acute phase proteins. Copper-containing ferroxidase ceruloplasmin (Cp) forms binary and ternary complexes with cationic proteins lactoferrin (Lf) and myeloperoxidase (Mpo) during inflammation. We present an X-ray crystal structure of a 2Cp-Mpo complex at 4.7 Å resolution. This structure allows one to identify major protein-protein interaction areas and provides an explanation for a competitive inhibition of Mpo by Cp and for the activation of p-phenylenediamine oxidation by Mpo. Small angle X-ray scattering was employed to construct low-resolution models of the Cp-Lf complex and, for the first time, of the ternary 2Cp-2Lf-Mpo complex in solution. The SAXS-based model of Cp-Lf supports the predicted 1∶1 stoichiometry of the complex and demonstrates that both lobes of Lf contact domains 1 and 6 of Cp. The 2Cp-2Lf-Mpo SAXS model reveals the absence of interaction between Mpo and Lf in the ternary complex, so Cp can serve as a mediator of protein interactions in complex architecture. Mpo protects antioxidant properties of Cp by isolating its sensitive loop from proteases. The latter is important for incorporation of Fe(3+) into Lf, which activates ferroxidase activity of Cp and precludes oxidation of Cp substrates. Our models provide the structural basis for possible regulatory role of these complexes in preventing iron-induced oxidative damage. 23895370 Confero: an integrated contrast data and gene set platform for computational analysis and biological interpretation of omics data. High-throughput omics technologies such as microarrays and next-generation sequencing (NGS) have become indispensable tools in biological research. Computational analysis and biological interpretation of omics data can pose significant challenges due to a number of factors, in particular the systems integration required to fully exploit and compare data from different studies and/or technology platforms. In transcriptomics, the identification of differentially expressed genes when studying effect(s) or contrast(s) of interest constitutes the starting point for further downstream computational analysis (e.g. gene over-representation/enrichment analysis, reverse engineering) leading to mechanistic insights. Therefore, it is important to systematically store the full list of genes with their associated statistical analysis results (differential expression, t-statistics, p-value) corresponding to one or more effect(s) or contrast(s) of interest (shortly termed as " contrast data") in a comparable manner and extract gene sets in order to efficiently support downstream analyses and further leverage data on a long-term basis. Filling this gap would open new research perspectives for biologists to discover disease-related biomarkers and to support the understanding of molecular mechanisms underlying specific biological perturbation effects (e.g. disease, genetic, environmental, etc.). To address these challenges, we developed Confero, a contrast data and gene set platform for downstream analysis and biological interpretation of omics data. The Confero software platform provides storage of contrast data in a simple and standard format, data transformation to enable cross-study and platform data comparison, and automatic extraction and storage of gene sets to build new a priori knowledge which is leveraged by integrated and extensible downstream computational analysis tools. Gene Set Enrichment Analysis (GSEA) and Over-Representation Analysis (ORA) are currently integrated as an analysis module as well as additional tools to support biological interpretation. Confero is a standalone system that also integrates with Galaxy, an open-source workflow management and data integration system. To illustrate Confero platform functionality we walk through major aspects of the Confero workflow and results using the Bioconductor estrogen package dataset. Confero provides a unique and flexible platform to support downstream computational analysis facilitating biological interpretation. The system has been designed in order to provide the researcher with a simple, innovative, and extensible solution to store and exploit analyzed data in a sustainable and reproducible manner thereby accelerating knowledge-driven research. Confero source code is freely available from http://sourceforge.net/projects/confero/. 23036507 Maternal inflammatory bowel disease has short and long-term effects on the health of their offspring: a multicenter study in Israel. There are concerns about the effect of inflammatory bowel diseases (IBD) on fertility, pregnancy and pregnancy outcomes, but no long-term data on the health of offspring born to IBD mothers. The aims were to assess the short- and long-term effects of maternal IBD on the morbidity and development of their offspring. Female IBD patients and controls completed questionnaires on their pregnancy outcome, and their offspring's short- and long-term health and development. IBD and control mothers (159 and 175, respectively) were recruited. Medical data of 412 IBD and 417 control offspring were recorded. IBD mothers had significantly more singleton pregnancies, their offspring's birth weight was significantly lower, and they breastfed significantly less compared to controls (P=0.028, 0.007, and <0.0001, respectively). There were significantly more congenital anomalies (mainly limb deformities) among the IBD offspring (P<0.035). Offspring born post-maternal IBD diagnosis, compared to pre-diagnosis, tended to have more neurodevelopmental problems (e.g., gross motor delay, P=0.03). IBD was significantly more prevalent in the offspring of IBD mothers, while allergies and atopic dermatitis were more frequent in offspring of control mothers. More offspring of IBD mothers taking medications during pregnancy were born preterm and had lower birth weights compared to offspring of IBD mothers not taking medications during pregnancy. Children of mothers taking steroids had the lowest birth weights, compared to those of IBD mothers taking 5ASAs or immunomodulators. Maternal IBD affects pregnancy and the offspring's immediate and long-term morbidity, specifically, congenital anomalies and neurodevelopmental problems. 23864034 Ethanol extract of Cnidium officinale exhibits anti-inflammatory effects in BV2 microglial cells by suppressing NF-κB nuclear translocation and the activation of the PI3K/Akt signaling pathway. Chronic microglial activation endangers neuronal survival through the release of various toxic pro-inflammatory molecules; thus, negative regulators of microglial activation have been identified as potential therapeutic candidates for several neurological diseases. In this study, we investigated the inhibitory effects of an ethanol extract of Cnidium officinale rhizomes (EECO), which has been used as a herbal drug in Oriental medicine, on the production of lipopolysaccharide (LPS)-induced pro-inflammatory mediators, such as nitric oxide (NO) and prostaglandin E2 (PGE2), as well as that of pro-inflammatory cytokines in BV2 microglia cells. EECO significantly inhibited the excess production of NO and PGE2 in LPS-stimulated BV2 microglia cells. It also attenuated the expression of inducible NO synthase, cyclooxygenase-2, as well as that of pro-inflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α. Moreover, EECO exhibited anti-inflammatory properties by suppressing nuclear factor-κB (NF-κB) translocation and the activation of the phosphoinositide 3-kinase/Akt pathway in LPS-stimulated BV2 cells. These results indicate that EECO exerts anti-inflammatory effects in LPS-stimulated BV2 microglial cells by inhibiting pro-inflammatory mediators and cytokine production by blocking the NF-κB pathway. These findings suggest that EECO has substantial therapeutic potential for the treatment of neurodegenerative diseases accompanied by microglial activation. 23926123 Relations Between White Coat Effects and Left Ventricular Mass Index or Arterial Stiffness: Role of Nocturnal Blood Pressure Dipping. Whether independent relationships between white coat effects (office minus day (office-day blood pressure (BP))) and organ damage or arterial stiffness may be explained by associations with an attenuated nocturnal BP dipping, has not been determined. In 750 participants from a sample of African ancestry, office and 24-hour BP, carotid-femoral pulse wave velocity (PWV) (applanation tonometry and SphygmoCor software) (n = 662), and left ventricular mass indexed to height(2.7) (LVMI) (echocardiography) (n = 463) were determined. Office-day systolic BP (SBP) was correlated with day minus night (day-night) SBP, percentage night divided by day (night/day) SBP, and night SBP (P < 0.0005), and these relationships persisted with adjustments for confounders, including day SBP (P < 0.005). With adjustments for 24-hour SBP and additional confounders, office-day SBP was associated with LVMI (P < 0.01) and PWV (P < 0.0001). With adjustments for day SBP and additional confounders, day-night SBP, percentage night/day SBP, and night SBP were related to PWV (P < 0.05) but not to LVMI (P > 0.44). The relationships between office-day SBP and LVMI or PWV persisted with adjustments for either day-night or percentage night/day SBP (LVMI: P = 0.01; PWV: P < 0.0001) or night SBP (LVMI: P < 0.01; PWV: P = 0.0001), and in product of coefficient mediation analysis with appropriate adjustments, neither indexes of nocturnal BP dipping nor nocturnal BP per se contributed toward the impact of office-day BP on LVMI or PWV (P > 0.09). In a group of African ancestry, although white coat effects are independently associated with an attenuated nocturnal decrease in SBP, neither decreased BP dipping nor nocturnal BP contribute toward the independent relationships between white coat effects and LVMI or arterial stiffness. 23831344 Challenging the catechism of therapeutics for chronic neuropathic pain: Targeting CaV2.2 interactions with CRMP2 peptides. Chronic neuropathic pain management is a worldwide concern. Pharmaceutical companies globally have historically targeted ion channels as the therapeutic catechism with many blockbuster successes. Remarkably, no new pain therapeutic has been approved by European or American regulatory agencies over the last decade. This article will provide an overview of an alternative approach to ion channel drug discovery: targeting regulators of ion channels, specifically focusing on voltage-gated calcium channels. We will highlight the discovery of an anti-nociceptive peptide derived from a novel calcium channel interacting partner - the collapsin response mediator protein 2 (CRMP2). In vivo administration of this peptide reduces pain behavior in a number of models of neuropathic pain without affecting sympathetic-associated cardiovascular activity, memory retrieval, sensorimotor function, or depression. A CRMP2-derived peptide analgesic, with restricted access to the CNS, represents a completely novel approach to the treatment of severe pain with an improved safety profile. As peptides now represent one of the fastest growing classes of new drugs, it is expected that peptide targeting of protein interactions within the calcium channel complex may be a paradigm shift in ion channel drug discovery. 23639257 Competing physiological pathways link individual differences in weight and abdominal adiposity to white matter microstructure. Being overweight or obese is associated with reduced white matter integrity throughout the brain. It is not yet clear which physiological systems mediate the association between inter-individual variation in adiposity and white matter. We tested whether composite indicators of cardiovascular, lipid, glucose, and inflammatory factors would mediate the adiposity-related variation in white matter microstructure, measured with diffusion tensor imaging on a group of neurologically healthy adults (N=155). A composite factor representing adiposity (comprised of body mass index and waist circumference) was associated with smaller fractional anisotropy and greater radial diffusivity throughout the brain, a pattern previously linked to myelin structure changes in non-human animal models. A similar global negative association was found for factors representing inflammation and, to a lesser extent, glucose regulation. In contrast, factors for blood pressure and dyslipidemia had positive associations with white matter in isolated brain regions. Taken together, these competing influences on the diffusion signal were significant mediators linking adiposity to white matter and explained up to fifty-percent of the adiposity-white matter variance. These results provide the first evidence for contrasting physiological pathways, a globally distributed immunity-linked negative component and a more localized vascular-linked positive component, that associate adiposity to individual differences in the microstructure of white matter tracts in otherwise healthy adults. 23711092 Experimental verification, and domain definition, of structural alerts for protein binding: epoxides, lactones, nitroso, nitros, aldehydes and ketones. This study outlines how a combination of in chemico and Tetrahymena pyriformis data can be used to define the applicability domain of selected structural alerts within the profilers of the OECD QSAR Toolbox. Thirty-three chemicals were profiled using the OECD and OASIS profilers, enabling the applicability domain of six structural alerts to be defined, the alerts being: epoxides, lactones, nitrosos, nitros, aldehydes and ketones. Analysis of the experimental data showed the applicability domains for the epoxide, nitroso, aldehyde and ketone structural alerts to be well defined. In contrast, the data showed the applicability domains for the lactone and nitro structural alerts needed modifying. The accurate definition of the applicability domain for structural alerts within in silico profilers is important due to their use in the chemical category in predictive and regulatory toxicology. This study highlights the importance of utilizing multiple profilers in category formation. 23406954 The periodontal health of lead-exposed children living in a shipyard industrial area. In a cross-sectional design, 292 schoolchildren living around a shipyard area, known to be contaminated with lead from shipyard industry, were examined to verify the association between lead exposure and periodontal health. The probing pocket depth (PD), bleeding on probing, plaque and calculus, and the presence of Aggregatibacter actinomycetemcomitans (Aa) in subgingival crevices were recorded. Gingival inflammation was the most common (98%) among children in the area. No significant difference in gingival inflammation was observed between high blood lead (PbB) and low PbB children. The prevalence rate of probing PD of ≥5 mm was 14%. The high PbB group showed more deep pockets at tooth 16 (upper right first permanent molar) and tooth 46 (lower right first permanent molar) than the low PbB group. The odds ratios (ORs) for having probing PD ≥5 mm after adjusting for other factors were 3.63 (95% confidence interval (CI), 1.24-10.61; p = 0.02) for tooth 16 and 3.93 (95% CI, 1.18-13.00; p = 0.02) for tooth 46. The presence of Aa was observed in 17% of the children and it significantly increased in high PbB compared with low PbB children at tooth 46 (OR = 5.53, 95% CI: 1.68-18.15; p = 0.005). This study may suggest no association between lead exposure and gingival inflammation, yet there was the involvement of deeper periodontal tissue in lead-exposed children. 23722997 A layered polymorph of rare earth hydroxides. A layered polymorph series of rare earth hydroxides has been developed by the conversion of RE2(OH)5Cl·mH2O to RE(OH)3·nH2O (RE = rare earths) with a typical layered structure with interlayer water molecules. A temperature-induced phase transition from the layered polymorph to its hexagonal form is completed at approximately 300 °C. 23656378 Recent progress in robot-based systems for crystallography and their contribution to drug discovery. X-ray crystallography is the main tool for macromolecular structure solution at atomic resolution. It provides key information for the understanding of protein function, opening opportunities for the modulation of enzymatic mechanisms, and protein-ligand interactions. As a consequence, macromolecular crystallography plays an essential role in drug design, as well as in the a posteriori validation of drug mechanisms. The demand for method developments and also tools for macromolecular crystallography has significantly increased over the past 10 years. As a consequence, access to the facilities required for these investigations, such as synchrotron beamlines, became more difficult and significant efforts were dedicated to the automation of the experimental setup in laboratories. In this article, the authors describe how this was accomplished and how robot-based systems contribute to the enhancement of the macromolecular structure solution pipeline. The evolution in robot technology, together with progress in X-ray beam performance and software developments, contributes to a new era in macromolecular X-ray crystallography. Highly integrated experimental environments open new possibilities for crystallography experiments. It is likely that it will also change the way this technique will be used in the future, opening the field to a larger community. 23583428 Iron uptake in quiescent and inflammation-activated astrocytes: a potentially neuroprotective control of iron burden. Astrocytes play a crucial role in proper iron handling within the central nervous system. This competence can be fundamental, particularly during neuroinflammation, and neurodegenerative processes, where an increase in iron content can favor oxidative stress, thereby worsening disease progression. Under these pathological conditions, astrocytes undergo a process of activation that confers them either a beneficial or a detrimental role on neuronal survival. Our work investigates the mechanisms of iron entry in cultures of quiescent and activated hippocampal astrocytes. Our data confirm that the main source of iron is the non-transferrin-bound iron (NTBI) and show the involvement of two different routes for its entry: the resident transient receptor potential (TRP) channels in quiescent astrocytes and the de novo expressed divalent metal transporter 1 (DMT1) in activated astrocytes, which accounts for a potentiation of iron entry. Overall, our data suggest that at rest, but even more after activation, astrocytes have the potential to buffer the excess of iron, thereby protecting neurons from iron overload. These findings further extend our understanding of the protective role of astrocytes under the conditions of iron-mediated oxidative stress observed in several neurodegenerative conditions. 23601414 Total nitrogen vs. amino-acid profile as indicator of protein content of beef. In most cited food composition studies and tables, the proximate system measures protein as total nitrogen (N) (determined by Kjeldahl or Dumas method) multiplied by a specific factor. A factor of 6.25 is used for determining total protein from total N (Jones, Munsey, & Walker, 1942). Although more expensive, it is considered more accurate to base protein content of foods on amino acid data (Greenfield & Southgate, 2003). A study on the nutrient composition of beef analysed the full amino-acid profile of fifteen retail cuts from three age groups and six fat codes, as well as determined total nitrogen content to determine proximate protein composition. For all cuts, the correlation coefficient of total amino acids to protein (N×6.25) was 0.635. This indicates a poor correlation for predicting actual protein content (as determined by total amino acid count), based on the nitrogen factor of 6.25. On average, the sum of amino acids per cut amounted to 91% of total determined protein (N×6.25) for the same cut. 23846161 Validation of a Helmet-Based System to Measure Head Impact Biomechanics in Ice Hockey. To quantify differences between head acceleration measured by a helmet-based accelerometer system for ice hockey and an anthropomorphic test device (ATD) in order to validate the system's use in measuring head impacts on-ice. A Hybrid III 50th percentile male ATD head and neck was fit with a helmet instrumented with the Head Impact Telemetry (HIT) System for hockey, and impacted at various speeds and directions with different interfaces between the head and helmet. Error between the helmet-based and reference peak accelerations was quantified, and the influence of impact direction and helmet-head interface evaluated. Regression equations were used to reduce error. System-reported impact direction was validated. 19% of impacts were removed from the dataset by a HIT System processing algorithm and were not eligible for analysis. Errors in peak acceleration between the system and ATD varied from 18-31% and 35-64% for linear and rotational acceleration respectively, but were reduced via regression equations. The relationship between HIT System and reference acceleration varied by direction (p < 0.001) and head-helmet interface (p = 0.005). Errors in impact azimuth were approximately 4%, 10%, and 31% for side, back, and oblique back impacts respectively. This is the first comprehensive evaluation of peak head acceleration measured by the HIT System for hockey. The HIT System processing algorithm removed 19% of the impacts from the dataset, 2) the correlation between HIT System and reference peak resultant acceleration was strong and varied by head surface and impact direction, and 3) the system error was larger than reported for the 6 degree of freedom HIT System for football but could be reduced via calibration factors. These findings must be considered when interpreting on-ice data. 23649946 Soluble mediators of diabetic macular edema: the diagnostic role of aqueous VEGF and cytokine levels in diabetic macular edema. Diabetic macular edema (DME) is a significant cause of vision loss and represents an important clinical and public health problem. It is characterized by breakdown of the blood retinal barrier with fluid accumulation in the sub-retinal and intra-retinal spaces. Although several hypotheses exist for the causes of diabetic macular edema, specific molecular mechanisms remain unclear. Current thinking includes the role of vascular endothelial growth factor (VEGF) and inflammatory cytokines in vascular permeability. We review studies showing a relationship between elevated aqueous VEGF, monocyte chemoattractant protein -1, interleukin 6, or interleukin 8 in association with DME and as predictors of DME. The presence of mediators in both the angiogenesis and inflammatory pathways data suggest a multifactorial model for the development of DME. Further studies targeting individual cytokine activity will be important to our understanding of the pathogenesis and treatment. 23537835 Tunable hydrogel-nanoparticles release system for sustained combination therapies in the spinal cord. Poly(methyl methacrylate) (PMMA) nanoparticles (NPs) were prepared by emulsion free radical polymerization. NPs with controlled dimension, as monitored by dynamic light scattering (DLS) and transmission electron microscopy (TEM), were produced by changing experimental parameters, such as the amount of emulsifier and the monomer feeding mode (batch or semi-batch). Then, different sized NPs (60, 80 and 130nm) were loaded in polysaccharide-polyacrylic acid based hydrogels, cross-linked by covalent ester bonds between polyacrylic acid (PAA) and agarose chains, with different pore sizes (30, 60, 90nm). The characteristics of the resulting composite hydrogel-NPs system were firstly studied in terms of rheological properties and ability to release Rhodamine B that presents steric hindrance similar to many neuroprotective agents used in spinal cord injury (SCI) repair. Then, diffusion-controlled release of different sized NPs from different entangled hydrogels was investigated in vitro and correlated with NPs diameter and hydrogel mean mesh size, showing different hindrances to the diffusion pathways. Release experiments and diffusion studies, rationalized by mathematical modeling and verified in vivo, allowed to build a material library able to satisfy different medical drug delivery needs. 23681992 Discovering motion primitives for unsupervised grouping and one-shot learning of human actions, gestures, and expressions. This paper proposes a novel representation of articulated human actions and gestures and facial expressions. The main goals of the proposed approach are: 1) to enable recognition using very few examples, i.e., one or k-shot learning, and 2) meaningful organization of unlabeled datasets by unsupervised clustering. Our proposed representation is obtained by automatically discovering high-level subactions or motion primitives, by hierarchical clustering of observed optical flow in four-dimensional, spatial, and motion flow space. The completely unsupervised proposed method, in contrast to state-of-the-art representations like bag of video words, provides a meaningful representation conducive to visual interpretation and textual labeling. Each primitive action depicts an atomic subaction, like directional motion of limb or torso, and is represented by a mixture of four-dimensional Gaussian distributions. For one--shot and k-shot learning, the sequence of primitive labels discovered in a test video are labeled using KL divergence, and can then be represented as a string and matched against similar strings of training videos. The same sequence can also be collapsed into a histogram of primitives or be used to learn a Hidden Markov model to represent classes. We have performed extensive experiments on recognition by one and k-shot learning as well as unsupervised action clustering on six human actions and gesture datasets, a composite dataset, and a database of facial expressions. These experiments confirm the validity and discriminative nature of the proposed representation. 23466184 Implantation of a stent graft in the right pulmonary artery enables radical resection of a central endothelial sarcoma of the left pulmonary artery. In a patient with a huge endothelial sarcoma of the left pulmonary artery, we report successful implantation of a stent graft in the right pulmonary artery, including the pulmonary arterial trunk. This preoperative measure enabled a safe and radical left-sided pneumonectomy, including the tumor and the central parts of the left pulmonary artery. No major blood loss occurred, and neither use of a heart-lung machine nor cardiopulmonary bypass was necessary. 23899447 Three dimensional spatial separation of cells in response to microtopography. Cellular organization, migration and proliferation in three-dimensions play a critical role in numerous physiological and pathological processes. Nano- and micro-fabrication approaches have demonstrated that nano- and micro-scale topographies of the cellular microenvironment directly impact organization, migration and proliferation. In this study, we investigated these dynamics of two cell types (NIH3T3 fibroblast and MDCK epithelial cells) in response to microscale grooves whose dimensions exceed typical cell sizes. Our results demonstrate that fibroblasts display a clear preference for proliferating along groove ridges whereas epithelial cells preferentially proliferate in the grooves. Importantly, these cell-type dependent behaviours were also maintained when in co-culture. We show that it is possible to spatially separate a mixed suspension of two cell types by allowing them to migrate and proliferate on a substrate with engineered microtopographies. This ability may have important implications for investigating the mechanisms that facilitate cellular topographic sensing. Moreover, our results may provide insights towards the controlled development of complex three-dimensional multi-cellular constructs. 23866312 M-CSF increases proliferation and phagocytosis while modulating receptor and transcription factor expression in adult human microglia. Microglia are the primary immune cells of the brain whose phenotype largely depends on their surrounding micro-environment. Microglia respond to a multitude of soluble molecules produced by a variety of brain cells. Macrophage colony-stimulating factor (M-CSF) is a cytokine found in the brain whose receptor is expressed by microglia. Previous studies suggest a critical role for M-CSF in brain development and normal functioning as well as in several disease processes involving neuroinflammation. Using biopsy tissue from patients with intractable temporal epilepsy and autopsy tissue, we cultured primary adult human microglia to investigate their response to M-CSF. Mixed glial cultures were treated with 25 ng/ml M-CSF for 96 hours. Proliferation and phagocytosis assays, and high through-put immunocytochemistry, microscopy and image analysis were performed to investigate microglial phenotype and function. We found that the phenotype of primary adult human microglia was markedly changed following exposure to M-CSF. A greater number of microglia were present in the M-CSF- treated cultures as the percentage of proliferating (BrdU and Ki67-positive) microglia was greatly increased. A number of changes in protein expression occurred following M-CSF treatment, including increased transcription factors PU.1 and C/EBPβ, increased DAP12 adaptor protein, increased M-CSF receptor (CSF-1R) and IGF-1 receptor, and reduced HLA-DP, DQ, DR antigen presentation protein. Furthermore, a distinct morphological change was observed with elongation of microglial processes. These changes in phenotype were accompanied by a functional increase in phagocytosis of Aβ1-42 peptide. We show here that the cytokine M-CSF dramatically influences the phenotype of adult human microglia. These results pave the way for future investigation of M-CSF-related targets for human therapeutic benefit. 23908401 MC1R and cAMP signaling inhibit cdc25B activity and delay cell cycle progression in melanoma cells. The melanocortin 1 receptor (MC1R) mediates the tanning response through induction of cAMP and downstream pigmentary enzymes. Diminished function alleles of MC1R are associated with decreased tanning and increased melanoma risk, which has been attributed to increased rates of mutation. We have found that MC1R or cAMP signaling also directly decreases proliferation in melanoma cell lines. MC1R overexpression, treatment with the MC1R ligand, or treatment with small-molecule activators of cAMP signaling causes delayed progression from G2 into mitosis. This delay is caused by phosphorylation and inhibition of cdc25B, a cyclin dependent kinase 1-activating phosphatase, and is rescued by expression of a cdc25B mutant that cannot be phosphorylated at the serine 323 residue. These results show that MC1R and cAMP signaling can directly inhibit melanoma growth through regulation of the G2/M checkpoint. 23870755 Meningoencephalocele of the temporal bone: Pictorial essay on transmastoid extradural-intracranial repair. A spontaneous meningoencephalocele of the temporal bone may present with effusion in the middle ear, a cerebrospinal fluid leak, hearing loss, or rarely otitic meningitis. Repair of spontaneous encephaloceles in the temporal bone has been performed using transmastoid and transcranial middle fossa approaches or a combination of the two with varied results. The authors present a technical paper on the transmastoid extradural intracranial approach for the management of temporal lobe encephaloceles. Case reports and cadaver dissections are used to provide a pictorial essay on the technique. Advantages and disadvantages compared with alternative surgical approaches are discussed. Traditional transmastoid approaches are less morbid compared with a transcranial repair as they avoid brain retraction. However, in the past, there has been a higher risk of graft failure and hearing loss due to downward graft migration and a potential need for ossicular disarticulation. For the appropriate lesion, the transmastoid extradural intracranial approach lesion offers a stable meningoencephalocele repair without the comorbidity of brain retraction. The authors describe a transmastoid extradural intracranial technique via case reports and cadaver dissections for the repair of spontaneous meningoencephalocele defects larger than 2 cm. This approach provides more support to the graft compared to the conventional transmastoid repair. 23747498 Effects of quercetin on oxidative stress and memory retrieval in kindled rats. Flavonoids are a class of polyphenolic compounds present in fruits and vegetables. Several studies have demonstrated a relationship between the consumption of flavonoid-rich diets and the prevention of human diseases including neurodegenerative disorders. Thus, we assessed the effect of quercetin (3,3',4',5,7-pentahydroxyflavone) on oxidative stress and memory retrieval using a step-through passive avoidance task in kindled rats. Quercetin (25, 50, and 100 mg/kg) was administered intraperitoneally (i.p.) before pentylenetetrazole (PTZ) every other day prior to the training. Retention tests were performed to assess memory in rats. Compared to control, pretreatment with 50 mg/kg of quercetin could attenuate seizure severity from the beginning of the kindling experiment by lowering the mean seizure stages. Moreover, quercetin 50 mg/kg significantly increased the step-through latency of the passive avoidance response compared to the control in the retention test. Malondialdehyde (MDA) levels were significantly increased in the quercetin groups compared to the PTZ group in the hippocampus and cerebral cortex following PTZ kindling. In the quercetin groups, higher sulfhydryl (SH) contents were not observed compared to the PTZ group. These results indicate that quercetin at a specific dose results in decreased seizure severity during kindling and performance improvement in a passive avoidance task in kindled rats. All doses of quercetin led to increased oxidative stress in the hippocampi and cerebral cortices of kindled rats. 23551662 Low-level light therapy for androgenetic alopecia: a 24-week, randomized, double-blind, sham device-controlled multicenter trial. Androgenetic alopecia (AGA) is a common disorder affecting men and women. Finasteride and minoxidil are well-known, effective treatment methods, but patients who exhibit a poor response to these methods have no additional adequate treatment modalities. To evaluate the efficacy and safety of a low-level light therapy (LLLT) device for the treatment of AGA. This study was designed as a 24-week, randomized, double-blind, sham device-controlled trial. Forty subjects with AGA were enrolled and scheduled to receive treatment with a helmet-type, home-use LLLT device emitting wavelengths of 630, 650, and 660 nm or a sham device for 18 minutes daily. Investigator and subject performed phototrichogram assessment (hair density and thickness) and global assessment of hair regrowth for evaluation. After 24 weeks of treatment, the LLLT group showed significantly greater hair density than the sham device group. Mean hair diameter improved statistically significantly more in the LLLT group than in the sham device group. Investigator global assessment showed a significant difference between the two groups, but that of the subject did not. No serious adverse reactions were detected. LLLT could be an effective treatment for AGA. 23829296 Molecular cytogenetics: recent developments and applications in cancer. Aneuploidy or alteration in chromosome numbers is a characteristic feature in cancer that is generally a consequence of defective chromosome segregation during cell division. Molecular cytogenetic analyses have conferred substantial evidence with regards to the chromosomal architectures in cancer. Most importantly, the fluorescence in situ hybridization (FISH) technique that plays a leading role in diagnostic pathology for its single-cell analysis has provided crucial information regarding genomic variations in malignant cells. Further development of molecular cytogenetic methodologies such as chromosome specific FISH karyotyping and comparative genomic hybridization have also helped in the detection of cryptic genetic changes in cancer. But, the recent advancement of high throughput sequencing technologies have provided a more comprehensive genomic analyses resulting in novel chromosome rearrangements, somatic mutations as well as identification of fusion genes leading to new therapeutic targets. This review highlights the application of early molecular cytogenetics and the recent high throughput genomic approaches in characterizing various cancers and their invaluable support in cancer therapeutics. 23965479 Comparison of Physician and Patient Global Assessments Over Time in Patients With Rheumatoid Arthritis: A Retrospective Analysis From the RADIUS Cohort. In rheumatoid arthritis (RA), there is discordance between patient and physician assessments of disease severity and treatment response. This retrospective analysis of the RADIUS (RA Disease-Modifying Anti-Rheumatic Drug Intervention and Utilization Study) 1 cohort examined specific factors that influence differences in global assessments for therapeutic effectiveness of disease-modifying antirheumatic drugs made by physicians (physician global assessment [PhGA]) and patients (patient global assessment [PtGA]). The RADIUS 1 cohort consisted of primarily community-based private practice patients with RA requiring either the addition of or a switch to a new biologic or nonbiologic disease-modifying antirheumatic drug and who were followed for up to 5 years by their rheumatologists. Periodic assessments included PhGA, PtGA, Health Assessment Questionnaire-Disability Index (HAQ-DI), 28-item tender/painful joint count (TJC28), swollen joint count (SJC28), pain Visual Analog Scale (VAS), and acute-phase reactants. Among 4359 patients (mean disease duration, 7.3 years), PhGA most highly correlated with TJC28 (0.6956; 95% confidence interval [CI], 0.6881-0.7030) and SJC28 (0.6757; 95% CI, 0.6678-0.6834). Moderate overall correlations were observed for PtGA with TJC28 (0.5000; 95% CI, 0.4890-0.5108) and less 50 with SJC28 (0.3754; 95% CI, 0.3628-0.3878). Patient global assessment most strongly correlated with pain VAS (0.8349; 95% CI, 0.8305-0.8392) and moderately correlated with HAQ-DI (0.5979; 95% CI, 0.5886-0.6071). Acute-phase reactants poorly correlated with PhGA and PtGA. Low correlations between PhGA and acute-phase reactants suggest that these measurements have a limited contribution compared with the physical examination when physicians make global assessments. These results also suggest that physicians should consider patients' assessments of their disease activity (HAQ, pain VAS, and PtGA) and put joint counts into proper context. 23868788 Detection of unusual G6 rotavirus strains in Italian children with diarrhoea during the 2011 surveillance season. Two rare G6 rotavirus A (RVA) strains, designated as RVA/human-wt/ITA/CEC06/2011/G6P[6] and RVA/human-wt/ITA/PG05/2011/G6P[9], were identified in stool specimens from children hospitalized in Central Italy. After PCR genotyping, the samples CEC06 and PG05 gave G-UD-P[6] and G-UD-P[9] genotypes, respectively. To determine the G-type and to characterize further the two strains, sequencing of 8 of the 11 genomic segments was performed. CEC06 and PG05 strains were found to possess unusual genotype constellations: G6-P[6]-I2-A2-N2-T2-E2-H2 and G6-P[9]-I2-A3-N2-T3-E3-H3, respectively. This study reports the first detection of rare G6P[6] and G6P[9] RVA strains in peninsular Italy. Phylogenetic analysis of VP4 (VP8*), VP7, VP6, and NSP1-5 showed no evidence of zoonosis or inter-species reassortment, revealing for both strains constellations previously associated to human cases. J Med. Virol. 85:1860-1869, 2013. © 2013 Wiley Periodicals, Inc. 23933291 Preparation and enhanced visible-light photocatalytic activity of graphitic carbon nitride/bismuth niobate heterojunctions. A series of graphitic carbon nitride/bismuth niobate (g-C3N4/Bi5Nb3O15) heterojunctions with g-C3N4 doping level of 10-90wt% were prepared by a facile milling-heat treatment method. The phase and chemical structures, surface compositions, electronic and optical properties as well as morphologies of the prepared g-C3N4/Bi5Nb3O15 were well-characterized. Subsequently, the photocatalytic activity and stability of g-C3N4/Bi5Nb3O15 were evaluated by the degradation of aqueous methyl orange (MO) and 4-chlorophenol (4-CP) under the visible-light irradiation. At suitable g-C3N4 doping levels, g-C3N4/Bi5Nb3O15 exhibited enhanced visible-light photocatalytic activity compared with pure g-C3N4 or Bi5Nb3O15. This excellent photocatalytic activity was revealed in terms of the extension of visible-light response and efficient separation and transportation of the photogenerated electrons and holes due to coupling of g-C3N4 and Bi5Nb3O15. Additionally, the active species yielded in the pure g-C3N4- and g-C3N4/Bi5Nb3O15-catalyzed 4-CP photodegradation systems were investigated by the free radical and hole scavenging experiments. 23675702 Establishment of a Promising Human Nucleus Pulposus Cell Line for Intervertebral Disc Tissue Engineering. Low-back pain caused by intervertebral disc degeneration could be recovered by the regeneration of the nucleus pulposus (NP). This study aimed to establish a chondrogenic recovery model with promising a human NP (hNP) cell line, an immortalized hNP (ihNP), which could be a screening platform to identify regenerative drugs. The ihNP cells were created from primary human NP cells transfected with a retroviral vector-driven HPV16 E6/E7. Growth properties and characteristics of ihNP were evaluated by comparing with parental NP cells. Successful immortalization of ihNP cells stably expressed HPV 16 E6/E7 mRNA. The doubling time of ihNP was shortened to 53.16±2.63 h compared with parental hNP-P1. Cell cycle regulators, including p53, p21, and pRB were downregulated compared to parental hNP-P1. The in vivo neoplastic forming assay also demonstrated that the ihNP was nontumorigenic. After 25 generations of cell cultures, the ihNP cells, yet stably expressed chondrogenic genes, including (SOX9), type II collagen (Col II), aggrecan, decorin, biglycan, and versican. Higher expressions of chondrogenic proteins, including Col II, phosphorylated SOX9 (p-SOX9), and CD44 were also determined. Under the stressful inflammatory conditions induced by lipopolysaccharides (LPS), the regenerative and anti-inflammatory potentials of ihNP in two-dimensional culture with the presence of platelet-rich plasma (PRP) were evaluated by reverse transcriptase polymerase chain reaction. PRP showed significant effects on restoring diminished chondrogenic markers and deleterious inflammatory responses induced by LPS in ihNP. The therapeutic potentials of ihNP in three-dimensional neocartilage model could also be exerted by PRP using histological evaluation and immunological staining. Hence, the established ihNP cells can provide a chondrogenic recovery model as a regenerative drug screening tool for further regenerative drug discovery and development. 23817368 Rapid Emergence of Echinocandin Resistance in Candida glabrata Resulting in Clinical and Microbiologic Failure. We report a case of Candida glabrata candidemia that developed resistance to micafungin within 8 days of initiation of therapy in a patient without previous echinocandin exposure or other known risk factors for clinical or microbiological failure. Pre- and postresistant isolates were confirmed to be isogenic, and sequencing of hot spots known to confer echinocandin resistance revealed a phenylalanine deletion at codon 659 within FKS2. 23886419 Multivariate normal tissue complication probability modeling of heart valve dysfunction in hodgkin lymphoma survivors. To establish a multivariate normal tissue complication probability (NTCP) model for radiation-induced asymptomatic heart valvular defects (RVD). Fifty-six patients treated with sequential chemoradiation therapy for Hodgkin lymphoma (HL) were retrospectively reviewed for RVD events. Clinical information along with whole heart, cardiac chambers, and lung dose distribution parameters was collected, and the correlations to RVD were analyzed by means of Spearman's rank correlation coefficient (Rs). For the selection of the model order and parameters for NTCP modeling, a multivariate logistic regression method using resampling techniques (bootstrapping) was applied. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC). When we analyzed the whole heart, a 3-variable NTCP model including the maximum dose, whole heart volume, and lung volume was shown to be the optimal predictive model for RVD (Rs = 0.573, P<.001, AUC = 0.83). When we analyzed the cardiac chambers individually, for the left atrium and for the left ventricle, an NTCP model based on 3 variables including the percentage volume exceeding 30 Gy (V30), cardiac chamber volume, and lung volume was selected as the most predictive model (Rs = 0.539, P<.001, AUC = 0.83; and Rs = 0.557, P<.001, AUC = 0.82, respectively). The NTCP values increase as heart maximum dose or cardiac chambers V30 increase. They also increase with larger volumes of the heart or cardiac chambers and decrease when lung volume is larger. We propose logistic NTCP models for RVD considering not only heart irradiation dose but also the combined effects of lung and heart volumes. Our study establishes the statistical evidence of the indirect effect of lung size on radio-induced heart toxicity. 23935131 Growth hormone and cancer risk in hypopituitarism: what we know from human studies. It has been difficult to identify factors that affect the risk of cancer, but we know that people are at higher risk as they get older, or have a strong family history of cancer. The potential influence of environmental and behavioral factors remains poorly understood. Early population-based and case-control studies suggested that higher serum levels of IGF-I could be associated with increased cancer risk. Since GH therapy increases IGF-I levels, concern has been raised regarding its potential role as a cancer initiation factor. Experimental evidence and some clinical studies showed that when GH/IGF-I secretion or action was inhibited, a decreased incidence and rate of progression of cancers occurred. However, human populations comprise of garden variety of genotypes which respond differently to the same exposures. Human population studies frequently reveal only very small effects to these exposures. So are GH and cancer guilty by association? After more than 20 yr, leukemia, a major safety issue initially believed associated with GH treatment in children with GH deficiency (GHD) has not been confirmed, but the risk of second malignancies in patients previously treated with irradiation, has been detected or confirmed through the National Cooperative Growth Study. Overall, this large study confirmed the favourable overall safety profile of GH therapy in children with GHD, and also highlighted specific populations at potential risk. The risk of secondary malignancy following radiotherapy is surely related to radiotherapy more than GH therapy which may increase growth but is less likely to start oncogenic process. In GH deficient adults treated with GH, observational studies (KIMS, HypoCCS) have shown that when IGF-I levels were targeted within normal age-related reference ranges, the occurrence of malignancies was not higher than in general population. 23953644 Anti-NMDAR encephalitis misdiagnosed as Hashimoto's encephalopathy. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a well-defined autoimmune disorder. Hashimoto's encephalopathy (HE) is a still controversial entity, lacking definite diagnostic criteria. We described a 14-year-old-girl presenting with a clinical picture consistent with the diagnosis of anti-NMDAR encephalitis, confirmed by NMDAR antibody testing. Four years earlier, she had presented a similar episode of acute encephalopathy diagnosed as HE. Anti-NMDAR encephalitis and HE share similar clinical features so that the differential diagnosis can be difficult if specific antibodies are not tested. The correct diagnosis of anti-NMDAR encephalitis is crucial to plan the appropriate management and follow-up, namely in term of oncological screening, since it can be paraneoplastic in origin. We suggest to re-evaluate the clinical history of all subjects with previous HE diagnosis in order to evaluate the possible diagnosis of anti-NMDAR encephalitis and plan the appropriate management of these patients. 22359276 Interleaved practice enhances skill learning and the functional connectivity of fronto-parietal networks. Practice of tasks in an interleaved order generally induces superior learning compared with practicing in a repetitive order, a phenomenon known as the contextual-interference (CI) effect. Increased neural activity during interleaved over repetitive practice has been associated with the beneficial effects of CI. Here, we used psychophysiological interaction (PPI) analysis to investigate whether the neural connectivity of the dorsal premotor (PM) and the dorsolateral prefrontal (DLPFC) cortices changes when motor sequences are acquired through interleaved practice. Sixteen adults practiced a serial reaction time task where a set of three 4-element sequences were arranged in a repetitive or in an interleaved order on 2 successive days. On Day 5, participants were tested with practiced sequences to evaluate retention. A within-subjects design was used so that participants practiced sequences in the other condition (repetitive or interleaved) 2-4 weeks later. Functional magnetic resonance images were acquired during practice and retention. On Day 2 of practice, there was greater inter-regional functional connectivity in the interleaved compared with the repetitive condition for both PM-seeded and DLPFC-seeded connectivity. The increased functional connectivity between both seeded regions and sensorimotor cortical areas correlated with the benefit of interleaved practice during later retention. During retention, a significant PPI effect was found in DLPFC-seeded connectivity, with increased DLPFC-supplementary motor area connectivity correlated with the benefits of interleaved practice. These data suggest that interleaved practice benefits learning by enhancing coordination of sensorimotor cortical regions, and superior performance of sequences learned under CI is characterized by increased functional connectivity in frontal cortex. 23768624 Tragic outcome of post-menopausal pregnancy: An obstetric commentary. The recent Italian court report regarding the removal and adoption of a 1-year-old child conceived with assisted reproduction treatment from parents deemed to be 'too old' at ages 57 and 70 brings to the fore the complex medical and ethical issues that surround assisted reproduction. This obstetric commentary examines the biology of reproductive ageing, current childbearing trends and the outcomes of post-reproductive age pregnancies, particularly focusing on maternal mortality as 'the tip of the iceberg' of IVF harms. The case highlights the need for global standards to ensure medical accountability. 23807670 Synthesis, structural characterization and cis-trans isomerization of novel (salicylaldiminato)platinum(ii) complexes. The reaction of cis-[PtCl2(dmso)] with the salicylaldimine ligand, N-(2-hydroxybenzylidene)-2,6-di-isopropylaniline, in the presence of sodium acetate in methanol produced both cis- and trans-[PtClLA(dmso)], and . An analogous reaction for the less bulky ligand, N-(2-hydroxybenzylidene)aniline produced only cis-[PtClLB(dmso)], . The reactions of these dmso complexes with triphenylphosphine also yielded complexes with different geometries depending on the nature of the salicylaldiminato ligand. Thus the cis-trans isomerization of cis-[PtClLA(PPh3)] was investigated both experimentally and computationally, and a tetrahedral transition state was detected in this process. A good agreement of the experimental activation parameters with those determined theoretically using DFT was obtained. was also reacted with [PtClMe(cod)] in methanol to yield the corresponding salicylaldiminato complex in which the methyl group is cis to the imine nitrogen. X-ray crystal structures of some compounds obtained are reported. 23903178 Endlessly single-polarization single-mode holey fibers with low confinement loss. We present a novel structure for holey fibers (HFs) with endlessly single-polarization single-mode characteristics, which is realized by introducing four elliptical airholes arranged in a hexagonal matrix in the core region. The validation of the design is done by use of a full-vectorial finite element method. We exhibit one typical design that can deliver a single-polarization single-mode region of more than 2400 nm with a confinement loss level lower than 0.01  dB/km. We have also shown that the persevered polarization state possesses a wide wavelength band of flat dispersion behavior. As a consequence, such HFs are useful in high-speed communication systems or optical-fiber sensors since they are free of polarization mode dispersion and simultaneously immune to cross-talk effect. 23688468 Microencapsulated probiotics using emulsification technique coupled with internal or external gelation process. Alginate-chitosan microcapsules containing probiotics (Yeast, Y235) were prepared by emulsification/external gelation and emulsification/internal gelation techniques respectively. The gel beads by external gelation showed asymmetrical structure, but those by internal gelation showed symmetrical structure in morphology. The cell viability was approximately 80% for these two techniques. However, during cell culture process, emulsification/internal gelation microcapsules showed higher cell growth and lower cell leakage. Moreover, the survival rate of entrapped low density cells with culture (ELDCwc) increased obviously than that directly entrapped high density cells (dEHDC) and free cells when keeping in simulated gastrointestinal conditions. It indicated the growth process of cells in microcapsule was important and beneficial to keep enough active probiotics under harmful environment stress. Therefore, the emulsification/internal gelation technique was the preferred method for application in food or biotechnological industries. 23945917 Magnesium complexes supported by salan-like ligands: Synthesis, characterization and their application in the ring-opening polymerization of rac-lactide. A series of magnesium silylamido complexes bearing salan-like multidentate aminophenolate ligands, [(L(1-4))MgN(SiMe3)2] () and [(L(1))MgN(SiHMe2)2] () (L(1-4) = -OAr(1)N(Me)(CH2)nN(Me)Ar(2), n = 2 or 3), have been synthesized via the reaction of Mg[N(SiMe3)2]2 or Mg[N(SiHMe2)2] with 1 equiv. of the corresponding aminophenol. The monomeric nature of the magnesium complexes , , and the main stoichiometric structure of in the solid state were further confirmed by X-ray diffraction studies, where the four donors of the ligand and the silylamido group coordinated with the magnesium center constructing a distorted trigonal bipyramidal coordination geometry at the metal center. The existence of isomers in complexes and was verified by the variable temperature (1)H NMR spectroscopy, and the non-coordination of OMe group with the central magnesium in complex was deduced from the comparison of the proton chemical shifts in complex and its proligand. All these complexes efficiently initiated the ring-opening polymerization of rac-lactide with the presence/absence of isopropanol, affording isotactic bias polylactides with relatively broad molecular weight distributions (Pm = 0.59-0.70, Mw/Mn = 1.28-2.21) in toluene at r.t. Declining the steric hindrance of the initiating group from N(SiMe3)2 to N(SiHMe2)2 increased the catalytic activity considerably. The steric and electronic characteristics of the ancillary ligands showed some influence on the polymerization performance of the corresponding magnesium complexes. The introduction of bulky ortho-substituents on the phenoxy moiety resulted in some changes both in activity and stereoselectivity, and either the elongation of the amine bridge from NCH2CH2N to NCH2CH2CH2N or the introduction of chloro-substituent on the phenoxy moiety led to a significant decline of the catalytic activity. 23079868 More than re-establishing the partner relationship: Intimate aftercare for Somali parents in diaspora. to explore the sexual relationship and couples' perceptions about intimate partner support following childbirth. a hermeneutic design using a naturalistic inquiry framework as a qualitative proxy for medical anthropology. Data were collected using a fictional and culturally-specific narrative during focus group discussions (FGDs) in early 2011. Analysis was conducted by 'functional narrative analysis' and interpreted for conceptual constructions. Recruitment was by snowball and purposive sampling. a diasporic context among participants living in six urban centres across Sweden. successful recruitment included 16 Somali-Swedish fathers and 27 mothers. Three FDGs were conducted with fathers (3-7 participants) and seven with mothers (3-6 participants). within day 40 post partum, parents learn to rely on each other in the absence of traditional support networks. After the first 40 days, the re-introduction of sexual intimacy is likely to occur. Of the fathers experiencing postpartum sexual aversion, these seemed to experience 'existential angst' resulting from a combination of profound remorse over having put the partner into what they perceived as a life-threatening situation during childbirth and their perceived moral and ethical obligations to provide support in this setting. Mothers in general did not directly discuss their own sexuality. Women could imagine men's sexual aversion after witnessing childbirth. However, they seemed unaware of men's potential for angst. Mothers are situated between the loss of traditional postpartum support networks, comprised of close female kin, and their own newly-defined responsibilities in the host setting. Fathers embrace their new role. Both partners articulated the mother's new role as enhancing autonomy and independence in the host setting. However, women held mixed attitudes about fathers replacing traditional kin support. to date, late postpartum aftercare for immigrant African parents is anecdotally linked to evidence-based recommendations, which have been identified for parents who are ethnically-congruent to a western study setting. Our findings suggest that aftercare meant for Somali parents living in these settings requires an understanding of how traditional intimate support and the postpartum sexual relationship are re-negotiated in the diasporic context. This includes recognition of the father as a willing and supportive partner. 23561915 Emotion regulation through execution, observation, and imagery of emotional movements. According to Damasio's somatic marker hypothesis, emotions are generated by conveying the current state of the body to the brain through interoceptive and proprioceptive afferent input. The resulting brain activation patterns represent unconscious emotions and correlate with subjective feelings. This proposition implies a corollary that the deliberate control of motor behavior could regulate feelings. We tested this possibility, hypothesizing that engaging in movements associated with a certain emotion would enhance that emotion and/or the corresponding valence. Furthermore, because motor imagery and observation are thought to activate the same mirror-neuron network engaged during motor execution, they might also activate the same emotional processing circuits, leading to similar emotional effects. Therefore, we measured the effects of motor execution, motor imagery and observation of whole-body dynamic expressions of emotions (happiness, sadness, fear) on affective state. All three tasks enhanced the corresponding affective state, indicating their potential to regulate emotions. 23947752 Myosin Duty Ratio Tunes Calcium Sensitivity and Cooperative Activation of the Thin Filament. In striated muscle, calcium binding to the thin filament (TF) regulatory complex activates actin-myosin ATPase activity, and actin-myosin kinetics in turn regulates TF activation. Yet a quantitative description of the effects of actin-myosin kinetics on calcium sensitivity (pCa50) and the cooperativity (nH) of TF activation remain unclear. With the assumption that TF structural transitions and TF-myosin binding transitions are inextricably coupled, we advanced the principles established in Kad et al. 2005 and Sich et al. 2011 to develop a simple model of TF regulation, which predicts that pCa50 varies linearly with duty ratio and that nH is a maximum near physiological duty ratios. Using in vitro motility to determine the calcium-sensitivity of TF sliding velocities, we measured pCa50 and nH at different myosin densities and in the presence of ATPase inhibitors. The observed effects of myosin density and actin-myosin duty ratio on pCa50 and nH are consistent with our model predictions. In striated muscle, pCa50 must match cytosolic calcium concentrations and a maximum nH optimizes calcium responsiveness. Our results indicate that pCa50 and nH can be predictably tuned through TF-myosin ATPase kinetics, and that drugs and disease states that alter ATPase kinetics can, through their effects on calcium sensitivity, alter the efficiency of muscle contraction. 23838414 The effects of wastewater effluent and river discharge on benthic heterotrophic production, organic biomass and respiration in marine coastal sediments. We examine effects of high river particulate flux and municipal wastewater effluent on heterotrophic organic carbon cycling in coastal subtidal sediments. Heterotrophic production was a predictable (r(2)=0.95) proportion (56%) of oxidized OC flux and strongly correlated with organic/inorganic flux. Consistent growth efficiencies (36%) occurred at all stations. Organic biomass was correlated with total, OC and buried OC fluxes, but not oxidized OC flux. Near the river, production was modest and biomass high, resulting in low P/B. Outfall deposition resulted in depleted biomass and high bacterial production, resulting in the highest P/B. These patterns explain why this region is production "saturated". The δ(15)N in outfall effluent, sediments and dominant taxa provided insight into where, and which types of organisms feed directly on fresh outfall particulates, on older, refractory material buried in sediments, or utilize chemosynthetic symbiotic bacteria. Results are discussed in the context of declining bottom oxygen conditions along the coast. 23896608 Synergistic effect of additives on cyclopropanation of olefins. An efficient cyclopropanation of olefins with Zn(CH2I)2, a catalytic amount of CCl3CO2H, and 1,2-dimethoxyethane at room temperature is described. A wide variety of olefins, including acid-sensitive substrates, can be cyclopropanated in 71-99% yield. 23410098 A dual flow bioreactor with controlled mechanical stimulation for cartilage tissue engineering. In cartilage, tissue engineering bioreactors can create a controlled environment to study chondrocyte behavior under mechanical stimulation or produce chondrogenic grafts of clinically relevant size. Here we present a novel bioreactor that combines mechanical stimulation with a two compartment system through which nutrients can be supplied solely by diffusion from opposite sides of a tissue-engineered construct. This design is based on the hypothesis that creating gradients of nutrients, growth factors, and growth factor antagonists can aid in the generation of zonal tissue-engineered cartilage. Computational modeling predicted that the design facilitates the creation of a biologically relevant glucose gradient. This was confirmed by quantitative glucose measurements in cartilage explants. In this system, it is not only possible to create gradients of nutrients, but also of anabolic or catabolic factors. Therefore, the bioreactor design allows control over nutrient supply and mechanical stimulation useful for in vitro generation of cartilage constructs that can be used for the resurfacing of articulated joints or as a model for studying osteoarthritis disease progression. 23706526 A sharable cloud-based pancreaticoduodenectomy collaborative database for physicians: emphasis on security and clinical rule supporting. Pancreaticoduodenectomy (PD) is a major operation with high complication rate. Thereafter, patients may develop morbidity because of the complex reconstruction and loss of pancreatic parenchyma. A well-designed database is very important to address both the short-term and long-term outcomes after PD. The objective of this research was to build an international PD database implemented with security and clinical rule supporting functions, which made the data-sharing easier and improve the accuracy of data. The proposed system is a cloud-based application. To fulfill its requirements, the system comprises four subsystems: a data management subsystem, a clinical rule supporting subsystem, a short message notification subsystem, and an information security subsystem. After completing the surgery, the physicians input the data retrospectively, which are analyzed to study factors associated with post-PD common complications (delayed gastric emptying and pancreatic fistula) to validate the clinical value of this system. Currently, this database contains data from nearly 500 subjects. Five medical centers in Taiwan and two cancer centers in Mongolia are participating in this study. A data mining model of the decision tree analysis showed that elderly patients (>76 years) with pylorus-preserving PD (PPPD) have higher proportion of delayed gastric emptying. About the pancreatic fistula, the data mining model of the decision tree analysis revealed that cases with non-pancreaticogastrostomy (PG) reconstruction - body mass index (BMI)>29.65 or PG reconstruction - BMI>23.7 - non-classic PD have higher proportion of pancreatic fistula after PD. The proposed system allows medical staff to collect and store clinical data in a cloud, sharing the data with other physicians in a secure manner to achieve collaboration in research. 23939148 MYC/BCL2 Double-Hit High-Grade B-Cell Lymphoma. Double-hit lymphoma (DHL) has been defined by others as a B-cell lymphoma with MYC/8q24 rearrangement in combination with a translocation involving another gene, such as BCL2, BCL3, or BCL6. The most common form of DHL has translocations involving MYC and BCL2, also known as MYC/BCL2 DHL. In recent years, a number of case series of MYC/BCL2 DHL have been published. Most cases of MYC/BCL2 DHL morphologically resemble diffuse large B-cell lymphoma (DLBCL) or B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma. These tumors are of B-cell lineage, have a germinal center B-cell immunophenotype with a high proliferation rate, and a complex karyotype. Patients with these tumors have an aggressive clinical course and poor prognosis despite high-intensity chemotherapy. More recently, studies have suggested expanding the spectrum of MYC/BCL2 DHL to include cases that have concurrent MYC and BCL2 cytogenetic abnormalities, but not necessarily translocations. In addition, overexpression of MYC and BCL2 has been shown in an appreciable subset of DLBCL tumors. These tumors show overlap with MYC/BCL2 DHL, but are not equivalent. In this review, we discuss the clinicopathologic, immunophenotypic, cytogenetic, and prognostic features of MYC/BCL2 DHL. 23955598 Mapping the fine structure of a eukaryotic promoter input-output function. The precise tuning of gene expression levels is essential for the optimal performance of transcriptional regulatory networks. We created 209 variants of the Saccharomyces cerevisiae PHO5 promoter to quantify how different binding sites for the transcription factor Pho4 affect its output. We found that transcription-factor binding affinities determined in vitro could quantitatively predict the output of a complex yeast promoter. Promoter output was precisely tunable by subtle changes in binding-site affinity of less than 3 kcal mol(-1), which are accessible by modifying 1-2 bases. Our results provide insights into how transcription-factor binding sites regulate gene expression, their possible evolution and how they can be used to precisely tune gene expression. More generally, we show that in vitro binding-energy landscapes of transcription factors can precisely predict the output of a native yeast promoter, indicating that quantitative models of transcriptional regulatory networks are feasible. 23914782 Differential modulation of ROS signals and other mitochondrial parameters by the antioxidants MitoQ, resveratrol and curcumin in human adipocytes. Abstract Mitochondrial reactive oxygen species (ROS) have been demonstrated to play an important role as signaling and regulating molecules in human adipocytes. In order to evaluate the differential modulating roles of antioxidants, we treated human adipocytes differentiated from human bone marrow-derived mesenchymal stem cells with MitoQ, resveratrol and curcumin. The effects on ROS, viability, mitochondrial respiration and intracellular ATP levels were examined. MitoQ lowered both oxidizing and reducing ROS. Resveratrol decreased reducing and curcumin oxidizing radicals only. All three substances slightly decreased state III respiration immediately after addition. After 24 h of treatment, MitoQ inhibited both basal and uncoupled oxygen consumption, whereas curcumin and resveratrol had no effect. Intracellular ATP levels were not altered. This demonstrates that MitoQ, resveratrol and curcumin exert potent modulating effects on ROS signaling in human adipocyte with marginal effects on metabolic parameters. 23881062 Acetabular cup positioning in revision total hip arthroplasty with Paprosky type III acetabular defects: Martell radiographic analysis. This study evaluates acetabular cup position in the setting of revision total hip arthroplasty (THA) with severe acetabular bone defects. With a definition of safe zone of abduction (30-50°) and anteversion (5-25°), acetabular cup position was measured by a digital image analysis program for 34 patients with Paprosky type III acetabular bone defects. There were 24 cups (71 %) for abduction and 26 cups (76 %) for anteversion located in the safe zone. Nineteen cups (56 %) were within the safe zone for both abduction and anteversion. There was no dislocation, however one cup out of the safe zone resulted in early cup failure due to aseptic loosening. The acetabular cup positioning in patients with Paprosky type III defects was 'optimal' in half of the cases. The prevalence of optimal acetabular cup position was similar to those reported in primary THA, suggesting that the presence of a large acetabular bone defect may not be a significant risk factor for suboptimal acetabular cup positioning in the setting of revision THA. 23940353 Structural basis for membrane recruitment and allosteric activation of cytohesin family Arf GTPase exchange factors. Membrane recruitment of cytohesin family Arf guanine nucleotide exchange factors depends on interactions with phosphoinositides and active Arf GTPases that, in turn, relieve autoinhibition of the catalytic Sec7 domain through an unknown structural mechanism. Here, we show that Arf6-GTP relieves autoinhibition by binding to an allosteric site that includes the autoinhibitory elements in addition to the PH domain. The crystal structure of a cytohesin-3 construct encompassing the allosteric site in complex with the head group of phosphatidyl inositol 3,4,5-trisphosphate and N-terminally truncated Arf6-GTP reveals a large conformational rearrangement, whereby autoinhibition can be relieved by competitive sequestration of the autoinhibitory elements in grooves at the Arf6/PH domain interface. Disposition of the known membrane targeting determinants on a common surface is compatible with multivalent membrane docking and subsequent activation of Arf substrates, suggesting a plausible model through which membrane recruitment and allosteric activation could be structurally integrated. 23887563 The Burns Evaluation and Mortality Study (BEAMS): Predicting deaths in Australian and New Zealand burn patients admitted to intensive care with burns. An understanding of prognosis following burns is important. It alleviates patient and familial stress, provides a framework for better resource use, and facilitates benchmarking of performance between specialist centers. Data were collected from eight tertiary referral burns centers in Australia and New Zealand. Our aim was to identify factors independently associated with mortality to develop a mortality prediction model, which accurately quantifies the risk of death among adults with burns who require intensive care. Between January 2005 and December 2011, 1,715 patients were admitted to intensive care unit with acute thermal burns. The mean (SD) age was 41.1 (18.0) years, and 20.3% (n = 348) were female. Median percentage of total body surface area was 17% (6-35%) and percent full-thickness surface area was 4% (0-20%). Inhalational injury was documented as present in 36.2%. Accidental injury was the most common etiology of burn (70.4%) and most frequently via a flame (68.3%). Overall hospital mortality was 10.9% (n = 187). Independent risk factors for death were age (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.06-1.10; p < 0.001), percentage of full-thickness surface area (OR, 1.07; 95% CI 1.06-1.08; p < 0.001), and Acute Physiology and Chronic Health Evaluation II score excluding age (OR, 1.11; 95% CI, 1.07-1.15; p < 0.001) and female sex (OR, 3.35; 95% CI, 1.84-6.11; p = 0.001). There was no association between inhalational injury or deliberate self-harm and death, as well as etiology or type of burn. A highly discriminatory mortality prediction model was developed using logistic regression. Risk of death following major burns can be predicted from a combination of physiologic and burns specific parameters. Female sex is a highly significant risk factor. Prognostic study, level III. 23851418 Comparative Content Review of Children's Participation Measures Using the International Classification of Functioning, Disability and Health-Children and Youth. To evaluate to what extent instruments that intend to measure children's participation actually do so, and to what extent their items can be classified according to the International Classification of Functioning, Disability and Health-Children and Youth (ICF-CY). A systematic search was conducted in MEDLINE, CINAHL, PsycINFO, ERIC, and EMBASE and was limited to the period between January 2000 and May 2011. The search terms of participation, outcome measure, and children were used to identify potential children's participation measures. Instruments were included if they (1) evaluated children's participation based on assessment purpose; (2) were suitable for use with children aged 2 to 12 years; (3) were generic assessments that could be used with a range of disabilities; and (4) involved self-report, proxy report, or interview administrations. Instruments were obtained from identified full-text articles and were evaluated for inclusion through group discussion. Two researchers further independently reviewed each included instrument to determine which of the items measured participation based on a contemporary definition. These items were also classified using the ICF-CY linking rules to reflect each instrument's content coverage. Sixteen instruments were identified with 11 found to have more than half of their items measuring participation, but only the School Function Assessment-Participation section comprised 100% participation items. The participation items in each instrument captured between 3 and 9 ICF-CY Activities and Participation domains. Only the Child and Adolescent Scale of Participation and the Participation and Environment Measure for Children and Youth covered all domains. Among the ICF-CY Activities and Participation domains, the interpersonal interactions and relationships domain was addressed the least. This review revealed differences in the inclusion of participation items in existing children's participation measures and their classification according to the ICF-CY. These differences need to be considered when selecting an instrument. 23522458 Distribution of several activating and inhibitory receptors on CD3(-)CD56(+) NK cells in regional lymph nodes of melanoma patients. Natural killer (NK) cells, as the main effector subpopulation of the innate immune system, play an important role in the control of the rise and spread of malignant tumors. Regional lymph nodes (LN) represent the first immunologic barrier to tumor metastasis. Since there are scarce data on NK cells from regional LN of cancer patients, the aim of this study was to investigate the expression of several activating and inhibitory receptors on the entire NK cell population as well as their CD3(-)CD56(dim) and CD3(-)CD56(bright) functional NK subsets from regional LN of melanoma patients. Mononuclear cells were isolated from 50 regional LN of melanoma patients. The expression of several receptors on NK cells and their functional subsets was analyzed by flow cytometry. We show increased percentages of CD3(-)CD56(+) NK cells in involved LN compared with uninvolved LN, mostly in favor of the CD56(dim) NK cell subset. NK cells in involved LN express similar levels of activating receptor NKG2D, while the level of another activating receptor, CD16, is increased compared with uninvolved LN. Regarding the expression of inhibitory NK cell receptors, we show increased CD158b, but similar low CD158a, inhibitory killer Ig-like cell receptor expression in involved LN compared with uninvolved LN. Furthermore, NK cells in involved compared with uninvolved LN displayed increased CD69 early activation antigen expression. Our results indicate that with tumor infiltration into regional LN of melanoma patients, NK cells, mostly of the CD56(dim) subset, are recruited into draining LN. The invading NK cells show counterbalance of the increased expression of CD16 activating receptor and increased CD158b inhibitory killer Ig-like cell receptor. 23910986 In and ex utero maturation of premature infants electroencephalographic indices. To assess the effect of extra uterine life on continuity and amplitude of premature infants' cerebral activity at different gestational age as compared to soon after birth. Stable infants less than 34weeks gestation were prospectively recruited and EEG was recorded bi-weekly. Interburst interval and different wavelength amplitudes were digitally measured during the most discontinuous and most continuous (periods with longest and shortest interburst intervals, respectively) parts of the tracings. Linear regression was used to assess conceptional age prediction of interburst interval and wavelength amplitudes. Significant regression results were compared to the group of babies recorded close to delivery (newborn group). 144 EEG tracings from 59 infants were analyzed. Interburst intervals were significantly predicted by conceptional age in the newborn group only (p⩽0.002). Delta and theta amplitudes were significantly predicted by conceptional age in the newborn group and most of the other conceptional age groups (p<0.004). No significant differences were detected between the different groups. Our data reiterates the normal maturation of cerebral activity in the premature infant and support the concept of similar in and ex-utero maturation of cerebral activity in stable premature infants. The effect of ex-utero maturation on the brain of stable premature infant is not readily discernible when using specific neonatal EEG indices. 23017782 A review on antioxidants, prooxidants and related controversy: natural and synthetic compounds, screening and analysis methodologies and future perspectives. Many studies have been conducted with regard to free radicals, oxidative stress and antioxidant activity of food, giving antioxidants a prominent beneficial role, but, recently many authors have questioned their importance, whilst trying to understand the mechanisms behind oxidative stress. Many scientists defend that regardless of the quantity of ingested antioxidants, the absorption is very limited, and that in some cases prooxidants are beneficial to human health. The detection of antioxidant activity as well as specific antioxidant compounds can be carried out with a large number of different assays, all of them with advantages and disadvantages. The controversy around antioxidant in vivo benefits has become intense in the past few decades and the present review tries to shed some light on research on antioxidants (natural and synthetic) and prooxidants, showing the potential benefits and adverse effects of these opposing events, as well as their mechanisms of action and detection methodologies. It also identifies the limitations of antioxidants and provides a perspective on the likely future trends in this field. 23281627 One-pot assembly of a hetero-dimeric DNA origami from chip-derived staples and double-stranded scaffold. Although structural DNA nanotechnology, and especially scaffolded DNA origami, hold great promise for bottom-up fabrication of novel nanoscale materials and devices, concerns about scalability have tempered widespread enthusiasm. Here we report a single-pot reaction where both strands of double-stranded M13-bacteriophage DNA are simultaneously folded into two distinct shapes that then heterodimerize with high yield. The fully addressable, two-dimensional heterodimer DNA origami, with twice the surface area of standard M13 origami, formed in high yield (81% of the well-formed monomers undergo dimerization). We also report the concurrent production of entire sets of staple strands by a unique, nicking strand-displacement amplification (nSDA) involving reusable surface-bound template strands that were synthesized in situ using a custom piezoelectric inkjet system. The combination of chip-based staple strand production, double-sized origami, and high-yield one-pot assembly markedly increases the useful scale of DNA origami. 23417626 Everolimus therapy for progressive adrenocortical cancer. Patients with advanced adrenocortical carcinoma (ACC) have limited treatment options after failure of chemotherapy. Tumor IGF2 expression has been shown to be amplified in the majority of cases of ACC and autocrine/paracrine activation of the IGF receptor (IGF-R) is thought to play a major role in the pathogenesis of ACC. It has been shown in vitro that inhibition of the IGF-R inhibits ACC cell proliferation. mTOR is a downstream effector of the IGFR signaling pathway; therefore, the rapamycin analog everolimus could prove to be useful for treatment of patients with ACC. Four women with ACC (ages 25-60 years) developed stage IV disease after surgery. All had progressive disease (PD) despite treatment with mitotane and other treatment modalities (etoposide, doxorubicin, cis-platinum in 3/4 patients, further streptozotocin + 5-FU in 1/4 patients, further thalidomide therapy in 2/4 patients; 1 patient progressed on an IGF-R antagonist). The patients were started on everolimus 10 mg/day orally and 2/4 patients also continued mitotane. Disease progression was monitored monthly by CT in 3/4 and after 3 months in 1/4. In all patients everolimus was well tolerated. In the three patients monitored monthly, PD was evident after 1, 3, and 4 months; in the patient evaluated after 3 months PD was also evident. In this small exploratory study, no clinically meaningful response was observed with everolimus in four patients with advanced ACC. The failure of efficacy could be related to an interaction with mitotane, multiple signaling pathways, and/or other downstream IGF-R effectors operative in the pathogenesis of ACC. 23894098 Microstructure, mechanical property, biodegradation behavior, and biocompatibility of biodegradable Fe-Fe2 O3 composites. In this study, the effects of Fe2 O3 (addition, 2, 5, 10, and 50 wt %) on the microstructure, mechanical properties, corrosion behaviors, and in vitro biocompatibility of Fe-Fe2 O3 composites fabricated by spark plasma sintering were systematically investigated as a novel-structure biodegradable metallic material. The results of X-ray diffraction analysis and optical microscopy indicated that Fe-Fe2 O3 composite is composed of α-Fe and FeO instead of Fe2 O3 . Both eletrochemical measurements and immersion test showed a faster degradation rate of Fe-2Fe2 O3 and Fe-5Fe2 O3 composites than pure iron and Fe-5Fe2 O3 exhibited the fastest corrosion rate among these composites. Besides, the effect of Fe2 O3 on the corrosion behavior of Fe-Fe2 O3 composites was discussed. The extracts of Fe-Fe2 O3 composite exhibited no cytotoxicity to both ECV304 and L929 cells, whereas greatly reduced cell viabilities of vascular smooth muscle cells. In addition, good hemocompatibility of all Fe-Fe2 O3 composites and pure iron was obtained. To sum up, Fe-5Fe2 O3 composite is a promising alternative for biodegradable stent material with elevated corrosion rate, enhanced mechanical properties, as well as excellent biocompatibility. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013. 23483206 Age estimation by magnetic resonance imaging of the distal tibial epiphysis and the calcaneum. Age estimation of living individuals is of critical importance in forensic practice, especially because of the increased migration in developed countries. Recently, the contribution of magnetic resonance imaging (MRI) to age evaluation has been studied, as it seems to be an efficient technique to analyze growth plate maturation and epiphyseal fusion. We developed an MRI staging system for the distal tibial epiphysis and the calcaneal epiphysis and evaluated its reliability on 180 MRI scans of the ankle and foot in a sample of individuals aged from 8 to 25 years old. For both bones, the degree of union between the metaphysis and epiphysis was classified in three stages. Intra- and inter-observer variabilities were good, showing the validity and reproducibility of the method. Our results were consistent with data in the literature indicating that both epiphyses mature earlier in females than in males. Bayesian predictive probabilities were used to assess the validity of our method in estimating the age of an individual in relation to the 18-year threshold. MRI of the ankle and foot can be used in association with other methods to estimate age in living individuals. 23924850 A Decline in Glomerular Filtration Rate Rather than Renal Arterial Stenotic Lesions, per se, Predicts Cardiovascular-Renal Events in Type 2 Diabetic Patients. Background: In diabetic patients with renal artery arteriosclerosis (RAAS), the factors associated with a greater risk for cardiovascular-renal events (CVREs) remain unclear: the decline in estimated glomerular filtration rate (eGFR) caused by RAAS or the advance of arteriosclerosis that causes RAAS. Hence, the features to determine which best predicts the onset of CVREs in such patients were compared. Methods and Results: The renal arteries of 162 type 2 diabetes patients were assessed by using magnetic resonance angiography (RAAS diagnosed as arteriosclerotic stenosis ≥50%) and they were studied longitudinally over 7 years. The influence of the presence/absence of RAAS, a decline in eGFR, clinical factors, surrogate arteriosclerotic markers and ischemic markers on patient's CVREs were assessed. A Cox regression analysis showed the detection of RAAS to be an independent risk factor for CVREs (bilateral RAAS was an extremely strong risk factor for the development of CVREs within 1,000 days), as was the decline in eGFR in a logistic regression analysis; the latter being a more powerful risk factor for CVREs. A multiple regression analysis revealed angiopoietin-2, a marker of ischemia, to be a risk factor for the decline in eGFR. Conclusions: A decline in renal function but not the renal arterial stenotic lesion itself appears to be associated with an increased incidence of CVREs in type 2 diabetic patients with RAAS. 23967262 ACTH- and Cortisol-Associated Neutrophil Modulation in Coronary Artery Disease Patients Undergoing Stent Implantation. Psychosocial stress and activation of neutrophil granulocytes are increasingly recognized as major risk factors of coronary artery disease (CAD), but the possible relationship of these two factors in CAD patients is largely unexplored. Activation of neutrophils was reported to be associated with stenting; however, the issue of neutrophil state in connection with percutaneous coronary intervention (PCI) is incompletely understood from the aspect of stress and its hypothalamic-pituitary-adrenal axis (HPA) background. Thus, we aimed to study cortisol- and ACTH-associated changes in granulocyte activation in patients undergoing PCI. Blood samples of 21 stable angina pectoris (SAP) and 20 acute coronary syndrome (ACS) patients were collected directly before (pre-PCI), after (post-PCI) and on the following day of PCI (1d-PCI). Granulocyte surface L-selectin, CD15 and (neutrophil-specific) lactoferrin were analysed by flow cytometry. Plasma cortisol, ACTH, and lactoferrin, IL-6 were also assayed. In both groups, pre- and post-PCI ratios of lactoferrin-bearing neutrophils were relatively high, these percentages decreased substantially next day; similarly, 1d-PCI plasma lactoferrin was about half of the post-PCI value (all p≤0.0001). Post-PCI ACTH was reduced markedly next day, especially in ACS group (SAP: p<0.01, ACS: p≤0.0001). In ACS, elevated pre-PCI cortisol decreased considerably a day after stenting (p<0.01); in pre-PCI samples, cortisol correlated with plasma lactoferrin (r∼0.5, p<0.05). In 1d-PCI samples of both groups, ACTH showed negative associations with the ratio of lactoferrin-bearing neutrophils (SAP: r = -0.601, p<0.005; ACS: r = -0.541, p<0.05) and with plasma lactoferrin (SAP: r = -0.435, p<0.05; ACS: r = -0.609, p<0.005). Pre- and post-PCI states were associated with increased percentage of activated/degranulated neutrophils indicated by elevated lactoferrin parameters, the 1d-PCI declines of which were associated with plasma ACTH in both groups. The correlation of plasma cortisol with plasma lactoferrin in the extremely stressed ACS before stenting, however, suggests an association of cortisol with neutrophil activation. 23750843 Good radiological and functional results after intramedullary nailing of distal radius fractures. Abstract To evaluate the results after fixation of distal radius fractures using Micronail® internal fixation, a prospective cohort study was performed, including displaced fractures of the distal radius (AO type A 2.2, A3.1, and A3.2). In total, 60 patients were included and 44 patients were available for 1-year follow-up (radiological and clinical examination) and 39 for 5-year follow-up (telephone interview). It was found that all fractures healed, with an average radial volar tilt of 2°, radial length of 11 mm, and a radial inclination of 22°. The functional result was excellent-to-good in 93% of the patients. Thirteen patients (30%) reported paraesthesia of the superficial branch of the radial nerve at the 1-year follow-up. In four patients the paraesthesia of the radial nerve was persistent. No other complications or reoperations were reported by the patients at the 5-year follow-up and only one implant had been removed. The study confirms that the Micronail® is a minimal invasive method that can provide a stable fixation of selected distal radius fractures and provide a good functional outcome with a very low need of implant removal after fracture healing with few complications related to the operation, the main complication being permanent damage to the radial nerve. 23871656 Phoenix 2: A locally installable large-scale 16S rRNA gene sequence analysis pipeline with Web interface. We have developed Phoenix 2, a ribosomal RNA gene sequence analysis pipeline, which can be used to process large-scale datasets consisting of more than one hundred environmental samples and containing more than one million reads collectively. Rapid handling of large datasets is made possible by the removal of redundant sequences, pre-partitioning of sequences, parallelized clustering per partition, and subsequent merging of clusters. To build the pipeline, we have used a combination of open-source software tools and custom-developed Perl scripts. For our project we utilize hardware-accelerated searches, but it is possible to reconfigure the analysis pipeline for use with generic computing infrastructure only, with a considerable reduction in speed. The set of analysis results produced by Phoenix 2 is comprehensive, including taxonomic annotations using multiple methods, alpha diversity indices, beta diversity measurements, and a number of visualizations. To date, the pipeline has been used to analyze more than 1500 environmental samples from a wide variety of microbial communities, which are part of our Hydrocarbon Metagenomics Project (http://www.hydrocarbonmetagenomics.com). The software package can be installed as a local software suite with a Web interface. Phoenix 2 is freely available from http://sourceforge.net/projects/phoenix2. 23941042 Seizure-Sensitivity in Drosophila Is Ameliorated by Dorsal Vessel Injection of the Antiepileptic Drug Valproate. Drosophila is a powerful model organism that can be used for the development of new drugs directed against human disease. A limitation is the ability to deliver drugs for testing. We report on a novel delivery system for treating Drosophila neurological mutants, direct injection into the circulatory system. Using this method, we show that injection of the antiepileptic drug valproate can ameliorate seizure-sensitive phenotypes in several mutant genotypes in the bang-sensitive (BS) paralytic mutant class, sda, eas, and para(bss1). This drug-injection method is superior to drug-feeding methods that we have employed previously, presumably because it bypasses potent detoxification systems present in the fly. In addition, we find that utilizing blood-brain barrier mutations in the background may further improve the injection results under certain circumstances. We propose that this method of drug delivery is especially effective when using Drosophila to model human pathologies, especially neurological syndromes. 23872182 A coupled biogeochemical-Dynamic Energy Budget model as a tool for managing fish production ponds. The sustainability of semi-intensive aquaculture relies on management practices that simultaneously improve production efficiency and minimize the environmental impacts of this activity. The purpose of the present work was to develop a mathematical model that reproduced the dynamics of a semi-intensive fish earth pond, to simulate different management scenarios for optimizing fish production. The modeling approach consisted of coupling a biogeochemical model that simulated the dynamics of the elements that are more likely to affect fish production and cause undesirable environmental impacts (nitrogen, phosphorus and oxygen) to a fish growth model based on the Dynamic Energy Budget approach. The biogeochemical sub-model successfully simulated most water column and sediment variables. A good model fit was also found between predicted and observed white seabream (Diplodus sargus) growth data over a production cycle. In order to optimize fish production, different management scenarios were analysed with the model (e.g. increase stocking densities, decrease/increase water exchange rates, decrease/increase feeding rates, decrease phosphorus content in fish feeds, increase food assimilation efficiency and decrease pellets sinking velocity) to test their effects on the pond environment as well as on fish yields and effluent nutrient discharges. Scenarios were quantitatively evaluated and compared using the Analytical Hierarchical Process (AHP) methodology. The best management options that allow the maximization of fish production while maintaining a good pond environment and minimum impacts on the adjacent coastal system were to double standard stocking densities and to improve food assimilation efficiency. 23831209 Intraperitoneal administration of high doses of polyethylene glycol (PEG) causes hepatic subcapsular necrosis and low-grade peritonitis with a rise in hepatic biomarkers. Polyethylene glycols (PEGs) are commonly employed as excipients in preclinical studies and in vitro experiments to dissolve poorly hydrosoluble drugs. Their use is generally considered safe in both animals and humans; however, limited data is available concerning the safety of PEGs when administered parenterally. The results of our investigation demonstrate that PEG-400 can have an irritant effect on serosal surfaces and causes subcapsular hepatocellular necrosis in mice when administered intraperitoneally at a high dose (4mL/kg). Accordingly, levels of serum biomarkers of liver injury need to be carefully interpreted in studies where PEG is administered intraperitoneally and always in association with the results of the histological assessment. 23108682 Roles of ACL remnants in knee stability. This study evaluated knee laxity in anterior tibial translation and rotation following removal of anterior cruciate ligament (ACL) remnants using a computer navigation system. This prospective study included 50 knees undergoing primary ACL reconstruction using a navigation system. ACL remnants were classified into four morphologic types: Type 1, bridging between the roof of the intercondylar notch and tibia; Type 2, bridging between the posterior cruciate ligament and tibia; Type 3, bridging between the anatomical insertions of the ACL on the lateral wall of the femoral condyle and the tibia; and Type 4, no bridging of ACL remnants. Anterior tibial translation and rotatory laxity were measured before and after remnant resection using a navigation system at 30°, 60°, and 90° of knee flexion. The amount of change in anterior tibial translation and rotatory laxity of each type was compared among the types. The different morphologic types of ACL remnants were as follows: Type 1, 15 knees; Type 2, 9 knees; Type 3, 6 knees; and Type 4, 20 knees. The amount of change in anterior tibial translation and rotatory laxity at 30° knee flexion in Type 3 was significantly larger than in the other types. There were no significant differences in either tibial translation or rotatory laxity at 60° and 90° knee flexion among the types. In Type 3, ACL remnants contributed to anteroposterior and rotatory knee laxity evaluated at 30° knee flexion. The bridging point of the remnants is important to knee laxity. The Type 3 remnant should be preserved as much as possible when ACL reconstruction surgery is performed. Prognostic study, Level II. 23855883 Seasonality, weather and climate affect home range size in roe deer across a wide latitudinal gradient within Europe. Because many large mammal species have wide geographical ranges, spatially distant populations may be confronted with different sets of environmental conditions. Investigating how home range (HR) size varies across environmental gradients should yield a better understanding of the factors affecting large mammal ecology. We evaluated how HR size of a large herbivore, the roe deer (Capreolus capreolus), varies in relation to seasonality, latitude (climate), weather, plant productivity and landscape features across its geographical range in Western Europe. As roe deer are income breeders, expected to adjust HR size continuously to temporal variation in food resources and energetic requirements, our baseline prediction was for HR size to decrease with proxies of resource availability. We used GPS locations of roe deer collected from seven study sites (EURODEER collaborative project) to estimate fixed-kernel HR size at weekly and monthly temporal scales. We performed an unusually comprehensive analysis of variation in HR size among and within populations over time across the geographical range of a single species using generalized additive mixed models and linear mixed models, respectively. Among populations, HR size decreased with increasing values for proxies of forage abundance, but increased with increases in seasonality, stochastic variation of temperature, latitude and snow cover. Within populations, roe deer HR size varied over time in relation to seasonality and proxies of forage abundance in a consistent way across the seven populations. Thus, our findings were broadly consistent across the distributional range of this species, demonstrating a strong and ubiquitous link between the amplitude and timing of environmental seasonality and HR size at the continental scale. Overall, the variability in average HR size of roe deer across Europe reflects the interaction among local weather, climate and seasonality, providing valuable insight into the limiting factors affecting this large herbivore under contrasting conditions. The complexity of the relationships suggests that predicting ranging behaviour of large herbivores in relation to current and future climate change will require detailed knowledge not only about predicted increases in temperature, but also how this interacts with factors such as day length and climate predictability. 23331095 Fundamental studies of electrochemically controlled surface oxidation and hydrophobicity of natural enargite. The surface oxidation and hydrophobicity of natural enargite (Cu(3)AsS(4)) and the formation of oxidation species at the mineral surface have been examined by a novel experimental approach that combines electrochemical techniques and atomic force microscopy (AFM). This approach allows for in-situ, synchronized electrochemical control and examination of the oxidative surface morphology of enargite. Combined with ex-situ cryo X-ray photoelectron spectroscopy surface analysis, the surface speciation of enargite surface oxidation has been obtained, comparing the newly fractured natural enargite surface with those that have been electrochemically oxidized at pHs 4 and 10. At pH 4, surface layer formations consisting of metal-deficient sulfide and elemental sulfur were identified, associated with a limited increase in root-mean-square (rms) roughness (1.228 to 3.143 nm) and apparent heterogeneous distribution of surface products as demonstrated by AFM imaging. A mechanism of initial rapid dissolution of Cu followed by diffusion-limited surface layer deposition was identified. At pH 10, a similar mechanism was identified although the differences between the initial and diffusion-limited phases were less definitive. Surface species were identified as copper sulfate and copper hydroxide. A significant increase in surface roughness was found as rms roughness increased from 0.795 to 9.723 nm. Dynamic (receding) contact angle measurements were obtained by a droplet evaporation method. No significant difference in the contact angle on a surface oxidized at pH 10 and the freshly polished surface was found. A significant difference was found between the polished surface and that oxidized at pH 4, with an increase in contact angle of about 13° (46° to 59°) after oxidation. Competing effects of hydrophilic (copper oxides and hydroxides) and hydrophobic (elemental sulfur) species on the mineral surface under oxidizing conditions at pH 4 and the change in surface roughness at pH 10 may contribute to the observed effects of electrochemically controlled oxidation on enargite hydrophobicity. 23872416 "Are melanocortin receptors constitutively active in vivo?" Constitutive activity is defined as ligand-independent activity, resulting in the production of a second messenger, even in the absence of an agonist. There has been widespread acceptance of the concept of G-protein-coupled receptor constitutive activity, with this activity specifically blocked by inverse agonists, a particular class of ligands often previously characterised as merely antagonists. The melanocortin receptors are highly unusual because their physiological activity is mediated not by a single ligand but by a number of endogenous peptide ligands, with the ability to exhibit agonist, antagonist or potentially inverse agonist behaviour. It remains more contentious to what extent the demonstrable constitutive activity of melanocortin receptors, particularly those expressed within the central nervous system, has in (patho)physiological processes. This review examines evidence from animal and laboratory based studies, focussing particularly upon peripherally expressed melanocortin-1 receptors and centrally expressed melanocortin-4 receptors, to consider how recent insights into both receptor structure itself and the molecules know to play a role in melanocortin signalling continue to shape our understanding of melanocortin biology. 23918006 Electromagnetic tracking system with reduced distortion using quadratic excitation. Electromagnetic tracking systems, frequently used in minimally invasive surgery, are affected by conductive distorters. The influence of conductive distorters on electromagnetic tracking system accuracy can be reduced through magnetic field modifications. This approach was developed and tested. The voltage induced directly by the emitting coil in the sensing coil without additional influence by the conductive distorter depends on the first derivative of the voltage on the emitting coil. The voltage which is induced indirectly by the emitting coil across the conductive distorter in the sensing coil, however, depends on the second derivative of the voltage on the emitting coil. The electromagnetic tracking system takes advantage of this difference by supplying the emitting coil with a quadratic excitation voltage. The method is adaptive relative to the amount of distortion cause by the conductive distorters. This approach is evaluated with an experimental setup of the electromagnetic tracking system. In vitro testing showed that the maximal error decreased from 10.9 to 3.8 mm when the quadratic voltage was used to excite the emitting coil instead of the sinusoidal voltage. Furthermore, the root mean square error in the proximity of the aluminum disk used as a conductive distorter was reduced from 3.5 to 1.6 mm when the electromagnetic tracking system used the quadratic instead of sinusoidal excitation. Electromagnetic tracking with quadratic excitation is immune to the effects of a conductive distorter, especially compared with sinusoidal excitation of the emitting coil. Quadratic excitation of electromagnetic tracking for computer-assisted surgery is promising for clinical applications. 23857176 Integrase-defective Lentiviral Vectors as a Delivery Platform for Targeted Modification of Adenosine Deaminase Locus. We investigated the use of integrase-defective lentiviral vectors (IDLVs) for transient delivery of zinc finger nucleases (ZFNs) and donor templates for site-specific modification of the human adenosine deaminase (hADA) gene. Initially, we constructed IDLVs carrying ZFN monomers (Single-IDLVs) and found them to be able to deliver their gene-editing payload to K562 cells successfully upon cotransduction, with minimal cytotoxicity. To simplify delivery, we designed an IDLV construct to deliver both ZFN monomers from the same vector (Double-IDLV). However, this construct in its original state was prone to rearrangements of the vector genome, resulting in greatly reduced functionality; this was due to recombination between highly similar ZFN monomers arranged in tandem. We modified the Double-IDLV constructs to reduce recombination and restored simultaneous delivery of both ZFNs. We also tested an IDLV construct for delivery of donor templates and demonstrated its efficacy for gene modification. In summary, we highlighted the importance of modifying vector design for co-delivery of highly similar sequences inherent to genome-editing nucleases, and demonstrated significant improvement in the use of IDLVs for delivery of ZFNs and donor templates for genome modification.Molecular Therapy (2013); doi:10.1038/mt.2013.106. 23810163 Mullerian inhibiting substance expression in papillary thyroid cancer. To examine the expression of Mullerian inhibiting substance (MIS) in papillary thyroid cancer. The MIS expression was examined by studying the immunohistochemistry in deparafinized sections prepared from tissue blocks of patients who were diagnosed with papillary thyroid cancer, as given in the pathology archive records (n = 23). In all the cases studied, 50% (n = 10) showed strong staining and 50% showed moderate staining. The percentage of staining was found to be 94.2 ± 3.1% in strongly stained cases and 92.2 ± 2.1% in moderately stained cases. Normal thyroid tissues neighboring the tumor did not display any staining. The MIS expression can be used as a significant tool in differential diagnosis of papillary thyroid cancer and also to shed light on its etiopathogenesis. 23206991 Testosterone positively associated with both male mating effort and paternal behavior in savanna baboons (Papio cynocephalus). Testosterone (T) is often positively associated with male sexual behavior and negatively associated with paternal care. These associations have primarily been demonstrated in species where investment in paternal care begins well after mating activity is complete, when offspring are hatched or born. Different patterns may emerge in studies of species where investment in mating and paternal care overlap temporally, for instance in non-seasonal breeders in which males mate with multiple females sequentially and may simultaneously have multiple offspring of different ages. In a 9-year data set on levels of T in male baboons, fecal concentrations of T (fT) were positively associated with both mate guarding ("consortship") - a measure of current reproductive activity - and with the number of immature offspring a male had in his social group - a measure of past reproductive activity and an indicator of likely paternal behavior. To further examine the relationship between T and potential paternal behavior, we next drew on an intensive 8-month study of male behavior, and found that fathers were more likely to be in close proximity to their offspring than expected by chance. Because male baboons are known to provide paternal care, and because time in proximity to offspring would facilitate such care, this suggests that T concentrations in wild male baboons may be associated with both current reproductive activity and with current paternal behavior. These results are consistent with the predicted positive association between T and mating effort but not with a negative association between T and paternal care; in male baboons, high levels of T occur in males that are differentially associating with their offspring. 23905785 Fate of Naturally Occurring Escherichia coli O157:H7 and Other Zoonotic Pathogens during Minimally Managed Bovine Feedlot Manure Composting Processes. Reducing Escherichia coli O157:H7 in livestock manures before application to cropland is critical for reducing the risk of foodborne illness associated with produce. Our objective was to determine the fate of naturally occurring E. coli O157:H7 and other pathogens during minimally managed on-farm bovine manure composting processes. Feedlot pen samples were screened to identify E. coli O157:H7-positive manure. Using this manure, four piles of each of three different composting formats were constructed in each of two replicate trials. Composting formats were (i) turned piles of manure plus hay and straw, (ii) static stockpiles of manure, and (iii) static piles of covered manure plus hay and straw. Temperatures in the tops, toes, and centers of the conical piles (ca. 6.0 m(3) each) were monitored. Compost piles that were turned every 2 weeks achieved higher temperatures for longer periods in the tops and centers than did piles that were left static. E. coli O157:H7 was not recovered from top samples of turned piles of manure plus hay and straw at day 28 and beyond, but top samples from static piles were positive for the pathogen up to day 42 (static manure stockpiles) and day 56 (static covered piles of manure plus hay and straw). Salmonella, Campylobacter spp., and Listeria monocytogenes were not found in top or toe samples at the end of the composting period, but E. coli O157:H7 and Listeria spp. were recovered from toe samples at day 84. Our findings indicate that some minimally managed composting processes can reduce E. coli O157:H7 and other pathogens in bovine manure but may be affected by season and/or initial levels of indigenous thermophilic bacteria. Our results also highlight the importance of adequate C:N formulation of initial mixtures for the production of high temperatures and rapid composting, and the need for periodic turning of the piles to increase the likelihood that all parts of the mass are subjected to high temperatures. 23936113 Handgrip strength predicts functional decline at discharge in hospitalized male elderly: a hospital cohort study. Functional decline after hospitalization is a common adverse outcome in elderly. An easy to use, reproducible and accurate tool to identify those at risk would aid focusing interventions in those at higher risk. Handgrip strength has been shown to predict adverse outcomes in other settings. The aim of this study was to determine if handgrip strength measured upon admission to an acute care facility would predict functional decline (either incident or worsening of preexisting) at discharge among older Mexican, stratified by gender. In addition, cutoff points as a function of specificity would be determined. A cohort study was conducted in two hospitals in Mexico City. The primary endpoint was functional decline on discharge, defined as a 30-point reduction in the Barthel Index score from that of the baseline score. Handgrip strength along with other variables was measured at initial assessment, including: instrumental activities of daily living, cognition, depressive symptoms, delirium, hospitalization length and quality of life. All analyses were stratified by gender. Logistic regression to test independent association between handgrip strength and functional decline was performed, along with estimation of handgrip strength test values (specificity, sensitivity, area under the curve, etc.). A total of 223 patients admitted to an acute care facility between 2007 and 2009 were recruited. A total of 55 patients (24.7%) had functional decline, 23.46% in male and 25.6% in women. Multivariate analysis showed that only males with low handgrip strength had an increased risk of functional decline at discharge (OR 0.88, 95% CI 0.79-0.98, p = 0.01), with a specificity of 91.3% and a cutoff point of 20.65 kg for handgrip strength. Females had not a significant association between handgrip strength and functional decline. Measurement of handgrip strength on admission to acute care facilities may identify male elderly patients at risk of having functional decline, and intervene consequently. 23813722 Self-assembly of coronene bisimides: mechanistic insight and chiral amplification. The study of the organization of small π-conjugated molecules is imperative to understanding and controlling its properties for various applications. Coronene bisimides (CBIs) are potential candidates for novel liquid-crystalline materials and active n-type semiconductor molecules in organic electronics. To understand the self-assembly of this seldom-studied chromophore, we have designed two derivatives of CBIs bearing chiral and achiral 3,4,5-trialkoxyphenyl groups at the imide position, named as CBI-GCH and CBI-GACH, respectively. CBI-GCH self-assembles mainly through π-stacking and van der Waals interactions in nonpolar methylcyclohexane to result in long 1D fibrillar stacks. The mechanism of supramolecular polymerization was probed by using chiroptical studies, which showed an isodesmic pathway for CBI-GCH. The thermodynamic parameters that govern the self-assembly are detailed. CBI-GACH also shows similar self-assembly behavior as its chiral counterpart. X-ray diffraction studies of both molecules reveals a 2D hexagonal columnar arrangement. The coassembly of CBI-GCH and CBI-GACH shows chiral amplification (sergeant and soldiers experiment) with saturation at 30-50 % of the chiral derivative, which was further used to study the dynamics of the assembly. Thus, this study presents a rare report of chiral amplification in an isodesmic system. 23234568 Mapping the ion current distribution in nanopore/electrode devices. Solid-state nanopores with integrated electrodes have interesting prospects in next-generation single-molecule biosensing and sequencing. These include "gated" nanopores with a single electrode integrated into the membrane, as well as two-electrode designs, such as a transversal tunneling junction. Here we report the first comprehensive analysis of current flow in a three-electrode device as a model for this class of sensors. As a new feature, we observe apparent rectification in the pore current that is rooted in the current distribution of the cell, rather than the geometry or electrostatics of the pore. We benchmark our results against a recently developed theoretical model and define operational parameters for nanopore/electrode structures. Our findings thus facilitate the rational design of such sensor devices. 23444282 Variation in prescribing patterns and therapeutic drug monitoring of intravenous busulfan in pediatric hematopoietic cell transplant recipients. Personalizing intravenous (IV) busulfan doses in children using therapeutic drug monitoring (TDM) is an integral component of hematopoietic cell transplant. The authors sought to characterize initial dosing and TDM of IV busulfan, along with factors associated with busulfan clearance, in 729 children who underwent busulfan TDM from December 2005 to December 2008. The initial IV busulfan dose in children weighing ≤12 kg ranged 4.8-fold, with only 19% prescribed the package insert dose of 1.1 mg/kg. In those children weighing >12 kg, the initial dose ranged 5.4-fold, and 79% were prescribed the package insert dose. The initial busulfan dose achieved the target exposure in only 24.3% of children. A wide range of busulfan exposures were targeted for children with the same disease (eg, 39 target busulfan exposures for the 264 children diagnosed with acute myeloid leukemia). Considerable heterogeneity exists regarding when TDM is conducted and the number of pharmacokinetic samples obtained. Busulfan clearance varied by age and dosing frequency but not by underlying disease. The authors- group is currently evaluating how using population pharmacokinetics to optimize initial busulfan dose and TDM (eg, limited sampling schedule in conjunction with maximum a posteriori Bayesian estimation) may affect clinical outcomes in children. 23871751 Single nucleotide deletion of cqm1 gene results in the development of resistance to Bacillus sphaericus in Culex quinquefasciatus. The entomopathogen Bacillus sphaericus is one of the most effective biolarvicides used to control the Culex species of mosquito. The appearance of resistance in mosquitoes to this bacterium, however, remains a threat to its continuous use in integrated mosquito control programs. Previous work showed that the resistance to B. sphaericus in Culex colonies was associated with the absence of the 60-kDa binary toxin receptor (Cpm1/Cqm1), an alpha-glucosidase present in the larval midgut microvilli. In this work, we studied the molecular basis of the resistance developed by Culex quinquefasciatus to B. sphaericus C3-41. The cqm1 genes were cloned from susceptible (CqSL) and resistant (CqRL/C3-41) colonies, respectively. The sequence of the cDNA and genomic DNA derived from CqRL/C3-41 colony differed from that of CqSL one by a one-nucleotide deletion which resulted in a premature stop codon, leading to production of a truncated protein. Recombinant Cqm1S from the CqSL colony expressed in Escherichia coli specifically bound to the Bin toxin and had α-glucosidase activity, whereas the Cqm1R from the CqRL/C3-41 colony, with a deletion of three quarters of the receptor's C-terminal lost its α-glucosidase activity and could not bind to the binary toxin. Immunoblotting experiments showed that Cqm1 was undetectable in CqRL/C3-41 larvae, although the gene was correctly transcribed. Thus, the cqm1R represents a new allele in C. quinquefasciatus that confers resistance to B. sphaericus. 23846596 T2D@ZJU: a knowledgebase integrating heterogeneous connections associated with type 2 diabetes mellitus. Type 2 diabetes mellitus (T2D), affecting >90% of the diabetic patients, is one of the major threats to human health. A comprehensive understanding of the mechanisms of T2D at molecular level is essential to facilitate the related translational research. Here, we introduce a comprehensive and up-to-date knowledgebase for T2D, i.e. T2D@ZJU. T2D@ZJU contains three levels of heterogeneous connections associated with T2D, which is retrieved from pathway databases, protein-protein interaction databases and literature, respectively. In current release, T2D@ZJU contains 1078 T2D related entities such as proteins, protein complexes, drugs and others together with their corresponding relationships, which include 3069 manually curated connections, 14,893 protein-protein interactions and 26,716 relationships identified by text-mining technology. Moreover, T2D@ZJU provides a user-friendly web interface for users to browse and search data. A Cytoscape Web-based interactive network browser is available to visualize the corresponding network relationships between T2D-related entities. The functionality of T2D@ZJU is shown by means of several case studies. Database URL: http://tcm.zju.edu.cn/t2d. 23543196 Assessment of advanced gastric cancer management in the United States. Increasing attention is being placed on utilization of treatment for advanced malignancies. Though some suggest it is futile, recent reports have advocated noncurative surgery for advanced gastric cancer. Our objectives were to (1) assess treatment trends, (2) identify predictors of surgery, and (3) evaluate the effect of treatment on outcomes. Patients with stage IV gastric adenocarcinoma were identified from the National Cancer Data Base (1998-2007). Patients who underwent emergent surgery were excluded. Models were developed to identify factors associated with treatment receipt and to compare adjusted overall survival by treatment group. Twenty-four percent (n = 22,430) of patients presented with stage IV gastric adenocarcinoma; 1.5 % (n = 414) underwent emergent surgery. Of the remaining 21,039 patients, 62.4 % underwent treatment (87.0 % chemotherapy with or without radiotherapy (C ± RT), 5.6 % surgery, 7.2 % combined surgery and C ± RT). Over the decade, surgery rates increased by 43 %, and C ± RT use increased by 16 % while receipt of no treatment decreased by 26 % (all p < 0.001). Patients who were younger, white, and insured, as well as those with distal tumors were more likely to undergo surgery. Reasons for receiving no treatment were multifactorial but were most strongly associated with advanced age and being uninsured. Median survival was longest for patients selected to undergo surgery and C ± RT (13.5 months) versus C ± RT alone (6.1 months), surgery alone (4.8 months), or no treatment (1.7 months, all p < 0.001). Utilization of nonemergent surgical treatment and C ± RT for metastatic gastric adenocarcinoma has increased considerably over time, especially in certain patient populations; however, the true utility and cost of these treatments remain unknown. 23808353 UV Photodissociation of Pyrroles: Symmetry and Substituent Effects. H (Rydberg) atom photofragment translational spectroscopy and ab initio electronic structure calculations are used to explore ways in which ring substituents affect the photofragmentation dynamics of gas phase pyrroles. S1 ← S0 (σ* ← π) excitation in bare pyrrole is electric dipole forbidden but gains transition probability by vibronic mixing with higher electronic states. The S1 state is dissociative with respect to N-H bond extension, and the resulting pyrrolyl radicals are formed in a limited number of (nontotally symmetric) vibrational levels (Cronin et al. Phys. Chem. Chem. Phys. 2004, 6, 5031-5041). Introducing σ-perturbing groups (e.g., an ethyl group in the 2-position or methyl groups in the 2- and 4-positions) lowers the molecular symmetry (to Cs), renders the S1-S0 transition (weakly) allowed, and causes some reduction in N-H bond strength; the radical products are again formed in a select subset of the many possible vibrational levels but all involve in-plane (a') ring-breathing motions as expected (by Franck-Condon arguments) given the changes in equilibrium geometry upon σ* ← π excitation. The effects of π-perturbers are explored computationally only. Relative to bare pyrrole, introducing an electron donating group like methoxy (at the 3- or, particularly, the 2-position) is calculated to cause a ∼10% reduction in N-H bond strength, while CN substitution (in either position) is predicted to cause a substantial (∼3000 cm(-1)) increase in the S1-S0 energy separation but only a modest (∼2%) increase in N-H bond strength. 23943321 siRNA-mediated DNA methylation and H3K9 dimethylation in plants. Heterochromatic siRNAs regulate transcriptional gene silencing by inducing DNA methylation and histone H3K9 dimethylation. Recent advances have revealed the distinct phases involved in siRNA mediated silencing pathway, although the precise functions of a number of factors remain undesignated, putative mechanisms for the connection between DNA and histone methylation have been investigated, and much effort has been invested to understand the biological functions of siRNA-mediated epigenetic modification. In this review, we summarize the mechanism of siRNA-mediated epigenetic modification, which involves the production of siRNA and the recruitments of DNA and histone methytransferases to the target sequences assisted by complementary pairing between 24-nt siRNAs and nascent scaffold RNAs, the roles of siRNA-mediated epigenetic modification in maintaining genome stability and regulating gene expression have been discussed, newly identified players of the siRNA mediated silencing pathway have also been introduced. 23969342 Improved Quality and Diagnostic Confidence Achieved by Use of Dose-Reduced Gadolinium Blood-Pool Agents for Time-Resolved Intracranial MR Angiography. BACKGROUND AND PURPOSE:Time-resolved MRA with the use of bolus injection of paramagnetic agents has proved valuable in neurovascular imaging. Standard contrast agents have limited blood-pool residence times, motivating the development of highly protein-bound blood-pool agents with greater relaxivity and longer intravascular residence, affording improved image quality at lesser doses. This study represents the first comparison of blood-pool agents to standard agents in time-resolved cerebral MRA.MATERIALS AND METHODS:One hundred datasets were acquired at 1.5T by use of a standardized, time-resolved MRA protocol. Patients received either unit dosing of a standard extracellular agent at 0.1 mmol/kg or a blood-pool agent at 0.03 mmol/kg. Peak arterial and venous enhancement phases were identified and subsequently scored qualitatively by use of a 4-point Likert scale, with attention to 6 vascular segments: 1) intracranial ICA; 2) MCA M1; 3) MCA M2; 4) MCA M3; 5) deep cerebral veins; and 6) dural venous sinuses.RESULTS:Fifty MR angiographies were acquired with each agent. No significant differences were found between agents in generation of uncontaminated arteriograms. Blood-pool agents, at 67% dose reduction, were of significantly greater quality across most vascular segments, including ICA (P = .019), M2 (P = .003), and M3 (P < .01). Superiority in the M1 segment approached significance (P = .059). Significantly better venographic quality was noted for deep venous structures (P = .016) with the use of blood-pool agents.CONCLUSIONS:Blood-pool agents provide superior demonstration of most intracranial vessels in time-resolved MRA compared with standard agents, at reduced doses. The greater relaxation enhancement and more favorable dosing profile make blood-pool agents superior to standard agents for use in cerebral time-resolved MRA. 23821024 Impact of aortic valve calcification severity and impaired left ventricular function on 3-year results of patients undergoing transcatheter aortic valve replacement. To evaluate clinical pre-interventional predictors of 3-year outcome and mortality in high-risk patients with severe aortic valve stenosis treated with transcatheter aortic valve implantation (TAVI). Among 367 patients included in the Aachen TAVI registry, 76 patients with baseline dual-source computed tomography (DSCT) for the quantification of aortic valve calcification (AVC) and a 3-year follow-up were identified. Survival at 30 days was 91 %, and it was 75 %, 66 % and 64 % at 1, 2 years and 3 years, respectively. Non-survivors at 3 years showed a significantly higher Agatston AVC score (2,854 ±â€‰1,651) than survivors (1,854 ±â€‰961, P = 0.007). Multivariate analysis including age, logistic EuroScore, glomerular filtration rate, Agatston AVC score, ejection fraction < 40 %, NYHA class, baseline medication, chronic lung disease and aortic regurgitation revealed that only the Agatston AVC score (P = 0.03) and impaired left ventricular function (P = 0.001) was significantly associated with mortality. Patients with Agatston AVC scores >2,000 had a significantly lower 3-year survival rate compared with patients with scores <2,000 (47 % vs 79 %, P = 0.004). In patients referred for TAVI, aortic valve calcification severity and impaired left ventricular function may serve as a predictor of long-term mortality. Therefore, AVC scores easily determined from pre-procedural CT datasets may be used for patient risk stratification. • Dual-source CT provides excellent valve delineation before transcatheter aortic valve implantation (TAVI). • Aortic valve calcification assessed by cardiac CT predicts mortality in TAVI patients. • Aortic valve calcification scores can help stratify high-risk patients for TAVI. • Three-year results show good long-term outcome without evidence of structural valve deterioration. 23520131 Identification of sucrose non-fermenting-related kinase (SNRK) as a suppressor of adipocyte inflammation. In this study, the role of sucrose non-fermenting-related kinase (SNRK) in white adipocyte biology was investigated. SNRK is abundantly expressed in adipose tissue, and the expression level is decreased in obese mice. SNRK expression is repressed by inflammatory signals but increased by insulin sensitizer in cultured adipocytes. In vivo, adipose tissue SNRK expression can be decreased by lipid injection but enhanced by macrophage ablation. Knocking down SNRK in cultured adipocytes activates both JNK and IKKβ pathways as well as promotes lipolysis. Insulin-stimulated Akt phosphorylation and glucose uptake are impaired in SNRK knockdown adipocytes. Phosphoproteomic analysis with SNRK knockdown adipocytes revealed significantly decreased phosphorylation of 49 proteins by 25% or more, which are involved in various aspects of adipocyte function with a clear indication of attenuated mTORC1 signaling. Phosphorylation of 43 proteins is significantly increased by onefold or higher, among which several proteins are known to be involved in inflammatory pathways. The inflammatory responses in SNRK knockdown adipocytes can be partially attributable to defective mTORC1 signaling, since rapamycin treatment activates IKKβ and induces lipolysis in adipocytes. In summary, SNRK may act as a suppressor of adipocyte inflammation and its presence is necessary for maintaining normal adipocyte function. 23690271 Arrhythmias during and after zoledronic acid infusion patients with bone metastasis. Zoledronic acid (ZA) is one of the important bisphosphonates which is widely used in bone metastatic cancer and osteoporotic patients. In a few studies, it has been reported that treatment with bisphosphonates was associated with an increased risk of atrial fibrillation. We aimed to evaluate the arrhythmias that developed during and immediately after infusion of the ZA. Fifty-two bone metastatic patients were included in the study group. All patients had 24-h Holter monitorization during the first dose ZA infusion day. All of the patients had 4-h basal cardiac rhythm records before ZA infusion and about 19 h after infusion. A short survey including demographic data and past medical history has been completed. None of patients had clinically important arrhythmias before ZA infusion. We divided arrhythmias into two groups as supraventricular and ventricular. We evaluated arrhythmias in pre-infusion, during infusion, and post-infusion periods. ZA was administered 4 mg intravenously (IV) in 15 min. Thirty-three of patients (63.5 %) were male and 19 (36.5 %) patients were female. Mean age of the patients was 53.9 ± 11.8 years. Most frequent cancers were breast (25 %) and lung cancer (15.3 %). Twelve (23 %) patients had history of mediastinal radiotherapy. In basal records, we detected that twenty-four (46 %) of patients had supraventricular premature complexes (SVPC) or ventricular premature complexes (VPC). Fifteen (28.8 %) of patients had SVPC and fourteen (26.9 %) had VPC during infusion period. After infusion period, 48 (92.3 %) of patients had SVPC and 41 (78.8 %) had VPC. Only 3 patients had no arrhythmia after infusion. Three patients had sinus arrhythmia and two had Mobitz type 2 atrioventricular blocks after infusion. One patient, who had no history of comorbidities and had SVPC in the basal records, developed atrial fibrillation that was refractory to medical cardioversion after 10 days of seventh dose of ZA infusion. In this study, we found that both SVPC and VPC increased in cancer patients treated with ZA. Furthermore, ZA may induce clinically important arrhythmias. 23036833 Marking the skin for oral surgical procedures: improving the WHO checklist. We present a system for marking the skin during oral surgical operations. This system identifies teeth to be extracted or exposed under general anaesthesia. Removal of the wrong tooth can cause appreciable morbidity and leaves the surgeon and organisation liable for litigation and scrutiny by regulatory bodies. A recent review of claims to the NHS litigation authority between 1995 and 2010 showed that in the field of oral and maxillofacial surgery, dentoalveolar surgery resulted in the largest number of claims for negligence, of which removal of the wrong tooth was one of the most common. In 2010/2011 the National Reporting and Learning System (NRLS) of the National Patient Safety Agency (NPSA) were notified of 20 incidents when the wrong tooth had been extracted, which accounted for 5% of all incidents reported. We have therefore developed a robust marking system for oral surgical procedures in our hospital, which improves on the World Health Organisation (WHO) checklist. We have audited patients' perceptions and the clinical application of our marking system, and have shown that the system is welcomed by patients, and is simple and effective for clinicians to use. 23180004 Immunohistochemical molecular expression profile of metastatic brain tumor for potent personalized medicine. Recent progress in molecule-targeting therapy may yield personalized therapeutic strategies for patients with metastatic brain tumors (MBT), the most frequently encountered intracranial tumors. For this purpose, we investigated the molecular expression profile of MBT to establish the pathological basis for personalized diagnosis. We studied 166 MBT specimens including 70 cases of lung cancer and 34 cases of breast cancer, and performed immunostaining for EGFR, COX-2, and O-6-methylguanine-DNA methyltransferase (MGMT), among others, which could be target molecules for therapeutic agents or enable prediction of drug efficacy. Loss of MGMT expression was observed in approximately 20-40 % of MBT derived from lung, breast, and gastrointestinal cancers, indicating the possibility of treatment of MBT patients with temozolomide. In addition, MBT expressed a variety of receptor tyrosine kinases, for example EGFR and HER2, and signal transduction molecules, for example phospho-mTOR and COX-2, irrespective of tumor origin, enabling individualized medication with molecule-targeting drugs. We also identified alteration of molecular expression profile in 4 MBT cases during recurrence. Our results not only reveal the molecular characteristics of MBT but also suggest the possibility of potent personalized medicine for MBT patients. 23946346 Carbohydrate Quality and Quantity Affect Glucose and Lipid Metabolism during Weight Regain in Healthy Men. In this controlled, parallel-group feeding trial, we examined the impact of carbohydrate (CHO) intake and glycemic index (GI) on glucose and lipid metabolism during refeeding after weight loss. Healthy men (n = 32 total, age: 25.5 ± 3.9 y, BMI: 23.5 ± 2.0 kg/m(2)) overconsumed diets containing either 50 or 65% CHO for 1 wk (+50% of energy requirements) and then underwent 3 wk of calorie restriction (CR; -50%) followed by 2 wk of overconsuming (refeeding, +50%) the same diet but with either a low or high GI (40 vs.70 during CR, 41 vs.74 during refeeding) so that glycemic load (GL; dietary CHO content x GI) differed between groups during all phases. Glucose profiles were assessed by continuous interstitial glucose monitoring, insulin sensitivity (IS) by fasting blood sampling, oral glucose tolerance test (OGTT) and hyperinsulinemic-euglycemic clamp, and liver fat by MRI. Daytime area under the curve-glucose during refeeding was higher with high compared with low GI (P = 0.01) and 65% compared with 50% CHO intake (P = 0.05) and correlated with dietary GL (r = 0.71; P < 0.001). IS increased with CR and decreased again with refeeding in all groups. The decrease in OGTT-derived IS was greater with high- than with low-GI diets (-41 vs. -15%; P-interaction = 0.01) and correlated with dietary GL during refeeding (r = -0.51; P < 0.01). Serum triglycerides (TGs) and liver fat also improved with CR (-17 ± 38 mg/dL and -1.1 ± 1.3%; P < 0.05 and <0.001) and increased again with refeeding (+48 ± 48 mg/dL and +2.2 ± 1.6%; P < 0.001). After refeeding, serum TGs and liver fat were elevated above baseline values with 65% CHO intake only (+59.9 ± 37.5 mg/dL and +1.1 ± 1.7%, P-interaction <0.001 and <0.05). In conclusion, a diet low in GI and moderate in CHO content (i.e., low GL) may have health benefits by positively affecting daylong glycemia, IS, and liver fat. 23866820 Update on diffusion MRI in Parkinson's disease and atypical parkinsonism. Differentiating Parkinson's disease (PD) from other types of neurodegenerative atypical parkinsonism (AP) can be challenging, especially in early disease stages. Routine brain magnetic resonance imaging (MRI) can show atrophy or signal changes in several parts of the brain with fairly high specificity for particular forms of AP, but the overall diagnostic value of routine brain MRI is limited. In recent years, various advanced MRI sequences have become available, including diffusion weighted imaging (DWI) and diffusion tensor imaging (DTI). Here, we review available literature on the value of diffusion MRI for identifying and quantifying different patterns of neurodegeneration in PD and AP, in relation to what is known of underlying histopathologic changes and clinical presentation of these diseases. Next, we evaluate the value of diffusion MRI to differentiate between PD and AP and the potential value of serial diffusion MRI to monitor disease progression. We conclude that diffusion MRI may quantify patterns of neurodegeneration which could be of additional value in clinical use. Future prospective clinical cohort studies are warranted to assess the added diagnostic value of diffusion MRI. 23876206 Genetic diversity of Influenza B virus in 2009-2010 and 2010-2011 in Tunisia. The authors had for aim to characterize influenza B strains having circulated in Tunisia to identify new mutations and compare them with reference strains. The epidemiological surveillance of influenza allowed identifying 19 patients with symptoms related to respiratory infection, who had been infected by influenza B strains isolated in several regions of Tunisia in 2009-2010 and in 2010-2011. Laboratory identification and detection of mutations in the segment encoding hemagglutinin of influenza viruses was performed by real time PCR and sequencing. The two influenza B Tunisian strains of the 2009-2010 season belonged to the Victoria lineage, whereas 2010-2011 season strains belonged to B/Victoria/2/87 and B/Yamagata/16/88 lineages with a dominance of the Yamagata lineage (76%). This study allowed identifying amino acid substitutions: T121A, S150I, N165Y, T181A, G183R, D196N, S229D, M251V and K253R in the B/Yamagata lineage; L58P, N75K, K109N, N165K, S172P and K257R into the B/Victoria lineage. These mutations were specific of Tunisian groups of variants. Most influenza B-Yamagata lineage viruses (69%) were associated with severe cases. Molecular analysis of the various influenza B strains circulating in Tunisia is useful to detect new mutations that can modify the phenotype of influenza strains. 23489398 Differential impact of isolated psychotic symptoms on treatment outcome of major depressive disorder in the STAR*D cohort of Whites, Blacks and Latinos. To determine whether isolated psychotic symptoms are more likely to be endorsed by depressed Latinos as opposed to other ethnic-racial groups; whether these symptoms affect Latinos similarly to other ethnic-racial groups in terms of treatment response; and whether they are more likely to be associated with anxiety disorders in depressed Latinos. We analyzed data from STAR⁎D subjects who self identified as White, Black, or Latino. Rates of isolated psychotic symptoms were assessed by the self-rated Psychiatric Diagnostic Screening Questionnaire (PDSQ) and compared between ethnic-racial groups. Depressive remission outcomes were compared within each ethnic-racial group between subjects who endorsed psychotic symptoms versus no psychotic symptoms. Associations between isolated psychotic symptoms and anxiety disorders were also examined. Among 2597 eligible subjects with at least one post-baseline assessment and available PDSQ data excluding first-rank symptoms, the prevalence of auditory-visual hallucination was 2.5% in Whites (n=49/1928), 11.3% in Blacks (n=45/398) 6.3% in Latinos (n=17/270) (χ(2)=64.9; df=2; p<0.001). Prevalence of paranoid ideation was 15.5% in Whites (n=299/1927), 31.5% in Blacks (n=126/400), and 21.1% in Latinos (n=57/270) (χ(2)=57.3; df=2; p<0.001). Among Whites and Blacks but not Latinos, depressive remission rates were worse in subjects with auditory-visual hallucinations compared to those without them. Paranoid ideation had a significant negative impact on remission in Whites only. In all ethnic-racial groups, a significant association was found between auditory-visual hallucinations and PTSD and panic disorder. The STAR*D study did not include any structured clinician-based assessment of psychotic symptoms. Latinos do not appear to have worse outcomes when treated for MDD with auditory-visual hallucinations, differently from Whites and Blacks. 23945875 Inhibition of Microglia Activation as a Phenotypic Assay in Early Drug Discovery. Complex biological processes such as inflammation, cell death, migration, proliferation, and the release of biologically active molecules can be used as outcomes in phenotypic assays during early stages of drug discovery. Although target-based approaches have been widely used over the past decades, a disproportionate number of first-in-class drugs have been identified using phenotypic screening. This review details phenotypic assays based on inhibition of microglial activation and their utility in primary and secondary screening, target validation, and pathway elucidation. The role of microglia, both in normal as well as in pathological conditions such as chronic neurodegenerative diseases, is reviewed. Methodologies to assess microglia activation in vitro are discussed in detail, and classes of therapeutic drugs known to decrease the proinflammatory and cytotoxic responses of activated microglia are appraised, including inhibitors of glutaminase, cystine/glutamate antiporter, nuclear factor κB, and mitogen-activated protein kinases. 23897513 Number of embryos for transfer following in vitro fertilisation or intra-cytoplasmic sperm injection. Multiple embryo transfer during in vitro fertilisation (IVF) increases multiple pregnancy rates causing maternal and perinatal morbidity. Single embryo transfer is now being seriously considered as a means of minimising the risk of multiple pregnancy. However, this needs to be balanced against the risk of jeopardising the overall live birth rate. To evaluate the effectiveness and safety of different policies for the number of embryos transferred in couples who undergo assisted reproductive technology (ART). We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE, from inception to July 2013. We handsearched reference lists of articles, trial registers and relevant conference proceedings and contacted researchers in the field. We included randomised controlled trials (RCTs) comparing different policies for the number of embryos transferred following IVF or intra-cytoplasmic sperm injection (ICSI) in subfertile women. Studies of fresh or frozen and thawed transfer of one, two, three or four embryos at cleavage or blastocyst stage were eligible. Two review authors independently assessed trial eligibility and risk of bias and extracted the data. The overall quality of the evidence was graded in a summary of findings table. Fourteen RCTs were included in the review (2165 women). Thirteen compared cleavage-stage transfers (2017 women) and two compared blastocyst transfers (148 women): one study compared both. No studies compared repeated multiple versus repeated single embryo transfer (SET). DET versus repeated SETDET was compared with repeated SET in three studies of cleavage-stage transfer. In these studies the SET group received either two cycles of fresh SET (one study) or one cycle of fresh SET followed by one frozen SET in a natural or hormone-stimulated cycle (two studies). When these three studies were pooled, the cumulative live birth rate after one cycle of DET was not significantly different from the rate after repeated SET (OR 1.22, 95% CI 0.92 to 1.62, three studies, n=811, I(2)=0%, low quality evidence). This suggests that for a woman with a 40% chance of live birth following a single cycle of DET, the chance following repeated SET would be between 30% and 42%. The multiple pregnancy rate was significantly higher in the DET group (OR 30.54, 95% CI 7.46 to 124.95, three RCTs, n = 811, I(2) = 23%, low quality evidence), suggesting that for a woman with a 15% risk of multiple pregnancy following a single cycle of DET, the risk following repeated SET would be between 0% and 2%. Single-cycle DET versus single-cycle SETA single cycle of DET was compared with a single cycle of SET in 10 studies, nine comparing cleavage-stage transfers and two comparing blastocyst-stage transfers. When all studies were pooled the live birth rate was significantly higher in the DET group (OR 2.07, 95% CI 1.68 to 2.57, nine studies, n = 1564, I(2) = 0%, high quality evidence). This suggests that for a woman with a 40% chance of live birth following a single cycle of DET, the chance following a single cycle of SET would be between 22% and 30%. The multiple pregnancy rate was also significantly higher in the DET group (OR 8.47, 95% CI 4.97 to 14.43, 10 studies, n = 1612, I(2) = 45%, high quality evidence), suggesting that for a woman with a 15% risk of multiple pregnancy following a single cycle of DET, the risk following a single cycle of SET would be between 1% and 4%. The heterogeneity for this analysis was attributable to a study with a high rate of cross-over between treatment arms. Other comparisonsOther fresh cycle comparisons were evaluated in three studies which compared DET versus transfer of three or four embryos. Live birth rates did not differ significantly between the groups for any comparison, but there was a significantly lower multiple pregnancy rate in the DET group than in the three embryo transfer (TET) group (OR 0.36, 95% CI 0.13 to 0.99, two studies, n = 343, I(2) = 0%). In a single fresh IVF cycle, single embryo transfer is associated with a lower live birth rate than double embryo transfer. However, there is no evidence of a significant difference in the cumulative live birth rate when a single cycle of double embryo transfer is compared with repeated SET (either two cycles of fresh SET or one cycle of fresh SET followed by one frozen SET in a natural or hormone-stimulated cycle). Single embryo transfer is associated with much lower rates of multiple pregnancy than other embryo transfer policies. A policy of repeated SET may minimise the risk of multiple pregnancy in couples undergoing ART without substantially reducing the likelihood of achieving a live birth. Most of the evidence currently available concerns younger women with a good prognosis. 23926587 1-stage versus 2-stage lateral maxillary sinus lift procedures: 4-month post-loading results of a multicenter randomised controlled trial. To compare the efficacy of 1-stage versus 2-stage lateral maxillary sinus lift procedures. Sixty partially edentulous patients requiring 1 to 3 implants and having 1 to 3 mm of residual bone height and at least 5 mm of bone width below the maxillary sinus, as measured on CT scans, were randomised into two equal groups to receive either a 1-stage lateral window sinus lift with simultaneous implant placement or a 2-stage procedure with implant placement delayed by 4 months using a bone substitute in 3 different centres. Implants were submerged for 4 months and loaded with reinforced provisional prostheses, which were replaced, after 4 months, by definitive prostheses. Outcome measures were augmentation procedure failures, prosthesis failures, implant failures, complications and marginal peri-implant bone loss assessed by a blinded outcome assessor. Patients were followed up to 4 months after loading. Only data of implants placed in 1 to 3 mm of bone height were reported. Two patients dropped out from the 1-stage group and none from the 2-stage group. No sinus lift procedure failed in the 1-stage group but 1 failed in the 2-stage group, the difference was not statistically significant (P = 1.00). Two prostheses failed or could not be placed in the planned time in the 1-stage group and 1 in the 2-stage group, the difference was not statistically significant (P = 0.51). Three implants failed in 3 patients of the 1-stage group versus 1 implant in the 2-stage group, the difference was not statistically significant (P = 0.28). Two complications occurred in the 1-stage group and 1 in the 2-stage group, the difference was not statistically significant (P = 0.61). There were no statistically significant differences in bone loss between groups at loading (0.05 mm). Sites treated in 1 stage lost an average of 0.56 mm (SD: 0.36; 95% CI: -0.70 to -0.42; P < 0.001) of peri-implant bone and 2-stage sites approximately 0.61 mm (SD: 0.34; 95% CI: -0.74 to -0.48; P < 0.001). No statistically significant differences were observed between implants placed according to 1- or 2-stage sinus lift procedures. However, this study may suggest that in patients having a residual bone height between 1 and 3 mm below the maxillary sinus there might be a slightly higher risk for implant failures when performing a 1-stage lateral sinus lift procedure. 23300006 An in vitro model of human acute ethanol exposure that incorporates CXCR3- and CXCR4-dependent recruitment of immune cells. Alcoholic liver disease (ALD) is one of the commonest causes of cirrhosis and liver failure in the developed world. Hepatic inflammation is the critical stage in progression of both ALD and non-ALD, but it remains difficult to study the underlying mechanisms in a human system, and current animal models do not fully recapitulate human liver disease. We developed a human tissue-based system to study lymphocyte recruitment in response to ethanol challenge. Precision-cut liver slices (PCLS) from human livers were incubated in culture, and hepatic function was determined by albumin production, 3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium bromide assay, glucose uptake responses, and morphometric assessment. Responses of tissue and lymphocytes to ethanol exposure were determined by PCR, flow cytometry, histology, and lymphocyte infiltration assays. Human PCLS demonstrated appropriate upregulation of CYP2E1, ADH1α, and ADH3 in response to ethanol treatment. Ethanol also induced expression of endothelial VCAM-1 and ICAM-1, production of sICAM-1 and CXCL8, and the chemokine receptors CXCR3 and CXCR4 on CD4 and CD8 lymphocytes. CXCR3- and CXCR4-dependent migration of lymphocytes into the tissue increased significantly in response to treatment with ethanol. We have demonstrated that ethanol increases chemokine receptor expression and lymphocyte recruitment into human liver tissue, suggesting that it may operate directly to promote hepatitis in ALD. The physiological and pathophysiological responses of the PCLS to ethanol in vitro highlight the potential of this assay for dissecting the molecular mechanisms underlying human liver inflammation and as a screening tool for novel therapeutics. 23222875 Reliability and validity of 4-metre gait speed in COPD. In community-dwelling older adults, usual gait speed over 4 m (4MGS) consistently predicts greater risk of adverse health outcomes. The aims of the present study were to assess the reliability of the 4MGS and the relationship with established health outcome measures in chronic obstructive pulmonary disease (COPD). Test-retest and interobserver reliability of the 4MGS were measured in 80 and 58 COPD patients, respectively. In 586 COPD patients, the 4MGS, as well as forced expiratory volume in 1 s (FEV1), the incremental shuttle walk (ISW), Medical Research Council (MRC) dyspnoea scale and St George's Respiratory Questionnaire (SGRQ) were measured. Participants were stratified according to "slow" (<0.8 m·s(-1)) or "normal" 4MGS (≥0.8 m·s(-1)). Intra-class correlation coefficients for test-retest and interobserver reliability were 0.97 and 0.99, respectively. There was a significant positive correlation between 4MGS with ISW (ρ = 0.78; p<0.001) and a negative correlation with MRC dyspnoea scale and SGRQ (ρ = -0.55 and -0.44; p<0.001 for both). COPD patients with slow 4MGS had significantly reduced ISW and higher MRC dyspnoea scale and SGRQ than those with preserved walking speed, despite similar FEV1 % predicted. The 4MGS is reliable in COPD, correlates with exercise capacity, dyspnoea and health-related quality of life, and has potential as a simple assessment tool in COPD. 23434418 Microwave assisted nano (ZnO-TiO2) catalyzed synthesis of some new 4,5,6,7-tetrahydro-6-((5-substituted-1,3,4-oxadiazol-2-yl)methyl)thieno[2,3-c]pyridine as antimicrobial agents. Combined nano zinc oxide and titanium dioxide [nano (ZnO-TiO(2))] has been reported first time for the synthesis of novel series of 4,5,6,7-tetrahydro-6-((5-substituted-1,3,4-oxadiazol-2-yl)methyl)thieno[2,3-c]pyridine. All the synthesized compounds (7a-7m) are novel and were screened for their antimicrobial activity against four different strains like Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis and antifungal activity was determined against two strains Candida albicans and Aspergillus niger. SAR for the newly synthesised derivatives has been developed by comparing their MIC values with ampicillin, ciprofloxacin and miconazole for antibacterial and antifungal activities, respectively. Among the synthesized compounds, 2,6 dichlorophenyl analogue (7f), 4 fluorophenyl analogue (7k) and 2,6 dichlorophenyl analogue (7l) shows promising antibacterial as well as antifungal activity whereas thiophene substituted compound (7j) shows promising antibacterial activity. 23899442 Adipocyte triglyceride turnover and lipolysis in lean and overweight subjects. ABSTRACT Human obesity is associated with decreased triglyceride turnover and impaired lipolysis in adipocytes. We determined if such defects also occur in subjects with only moderate increase in fat mass. Human abdominal subcutaneous adipose tissue was investigated in healthy nonobese subjects (BMI >17 to 30 kg/m2). Triglyceride age, reflecting lipid turnover, was examined in 41 subjects by assessing the incorporation of atmospheric 14C into adipose lipids. Adipocyte lipolysis was examined as the ability of lipolytic agents to stimulate glycerol release in 333 subjects. Adipocyte triglyceride age was markedly increased in overweight (BMI 25> kg/m2) compared to lean subjects (p=0.017) with triglyceride T1/2 of 14 and 9 months, respectively (p=0.04). Triglyceride age correlated positively with BMI (p=0.002) but not with adipocyte volume (p=0.2). Noradrenaline, isoprenaline or dibutyryl cyclic AMP induced lipolysis was inversely correlated with triglyceride age (p<0.01) and BMI (p<0.0001) independently of basal lipolysis, gender and nicotine use. Current, but not the highest or lowest BMI in adult life, correlated significantly (inversely) with lipolysis. In conclusion, adipocyte triglyceride turnover and lipolytic activity are decreased in overweight subjects and reflect the current BMI status. These changes may confer an increased risk for early development and/or maintenance of excess body fat. 23727343 Genomic mosaicism in two strains of dengue virus type 3. Recombination is a significant factor driving genomic evolution, but it is not well understood in Dengue virus. We used phylogenetic methods to search for recombination in 636 Dengue virus type 3 (DENV-3) genomes and unveiled complex recombination patterns in two strains, which appear to be the outcome of recombination between genotype II and genotype I parental DENV-3 lineages. Our findings of genomic mosaic structures suggest that strand switching during RNA synthesis may be involved in the generation of genetic diversity in dengue viruses. 23618597 Psychophysiological correlates of interpersonal cooperation and aggression. Mimicking real world situations, the Chicken Game allows scientists to examine human decision-making when the outcome is not entirely within one person's control. In this social dilemma task, two players independently choose either to safely cooperate with, or riskily aggress against, the other player, and the unique combination of their choices specifies the outcome for each. Coupling the Chicken Game with psychophysiological measures, we confirmed our two hypotheses: that an individual perceives an outcome as most negative when she chooses to cooperate and the other player violates that trust and aggresses, and that motivational salience of an outcome is greater when an individual chooses to aggress and when she gains money. Collectively, the data demonstrate the utility of pairing true social dilemma tasks like the Chicken Game with psychophysiological measures to better understand decision-making. 23884292 Catalytic MBH reaction of β-substituted nitroalkenes with azodicarboxylates. An unprecedented N-heterocyclic carbene (NHC) catalyzed Morita-Baylis-Hillman (MBH) reaction of β-substituted nitroalkenes and azodicarboxylates has been developed. Both β-aryl and β-alkyl nitroalkenes worked well for the reaction using 5 mol% of NHC catalyst, giving the desired α-hydrazino-α,β-unsaturated nitroalkenes in good to excellent yields. 23605693 Hedgehog Signaling Pathway and Cancer Therapeutics: Progress to Date. The Hedgehog (Hh) pathway is a developmental signaling pathway involved in numerous developmental processes, including determination of cell fate, patterning, proliferation, survival, and differentiation. While this pathway is silenced in most adult tissues, aberrant activation of it has been documented in a variety of malignancies. In cancers such as basal cell carcinoma (BCC), ligand-independent mechanisms lead to constitutive Hh pathway activation through mutations in components of the pathway, including patched-1 (PTCH1) or smoothened (SMO). On the contrary, numerous other solid and hematologic tumors have been shown to harbor ligand-dependent activation of the Hh pathway by autocrine or paracrine mechanisms. Given that aberrant Hh pathway signaling has been seen in a number of malignancies, this pathway has been an attractive target for drug development. While the best-characterized approach is to target the SMO receptor, other rational approaches for inhibiting the Hh pathway include inhibiting downstream components or directly binding Hh ligands. In January of 2012, vismodegib, a SMO antagonist, became the first agent to target the Hh pathway to receive approval by the United States Food and Drug Administration (FDA) after this agent showed remarkable activity in phase I and II trials for the treatment of BCC. Despite promising preclinical studies with Hh pathway inhibitors in other malignancies that have suggested a potential role for these agents, attempts to translate this potential to clinical benefit has been disappointing. Future efforts will require further careful interpretation and analysis to determine the potential determinants and predictors of efficacy. Currently, several phase I and II trials evaluating Hh inhibitors in a variety of tumor settings are underway. 23373651 Taxol: efficacy against oral squamous cell carcinoma. In medicinal chemistry, one of the most studied molecules in recent history is taxol. Taxol is a versatile natural product that is used in various cancer treatment regimens. It is administered to patients with breast, lung, and ovarian cancers, and is currently being studied for the treatment of squamous cell carcinoma of the oral cavity and tongue. Taxol has been tested in a number of research and clinical phase trials to determine feasibility, toxicity, and cytotoxicity against oral squamous cell carcinoma as a single drug regimen and as a contributing drug component in treatment plans. This paper reviews over forty articles that examine cell lines, murine models, and human results for the response of taxol against squamous cell carcinoma (SCC) of the oral cavity and the tongue. 23649350 Structures and stabilities of ScBn (n = 1-12) clusters: an ab initio investigation. The geometries, stabilities, and electronic properties of ScBn (n = 1-12) clusters have been systematically investigated by using density functional theory B3LYP method and coupled-cluster theory CCSD(T) method. It is found that the ground state isomers of ScBn have planar or quasi-planar structure when n ≤ 6, which can be viewed as a B atom of the corresponding Bn+1 cluster is substituted by a Sc atom. From n ≥ 7, the ground state isomers favor nest-like structure, in which the Sc atom sits on a nest-like Bn cluster. The calculated second-order differences of energies manifest that the magic numbers of stability are n = 3, 7, 8, 9 and 11 for the ScB n clusters. Further analysis indicates that the ScB7 cluster with C 6v symmetry represents the outstanding stable ScBn cluster, as confirmed by its electronic structure and molecular orbitals. 23870844 Delivering men's health interventions in English Premier League football clubs: key design characteristics. To investigate the key design characteristics of Premier League Health (PLH), a national programme of men's health improvement delivered in/by 16 English Premier League (EPL) football clubs. Health Trainers (HTs) were hired by EPL clubs to deliver PLH. HTs were the focus of investigations aimed at identifying the active design characteristics of male-specific health promotion interventions. Semi-structured interviews led by researchers were performed with 13/16 HTs and identified the key design characteristics influential in (I) reaching and (II) helping participants adopt health improvement interventions delivered in professional football club settings. HTs believed that combining the appeal of football alongside EPL clubs, offered a unique opportunity to reach adult males, including hard-to-engage-men (HTEM). Awareness raising events held on match days aimed to connect with men, but outreach activities were especially important for engaging participants. Following initial reach, familiar settings, such as the club stadia and community venues were also important for ensuring regular involvement in health improvement sessions. Interventions shaped around men's health needs and delivered at times when participants could more easily attend, were factors which helped to engage men. Supportive social environments and a range of exercise modes and delivery options were also seen by HTs as being similarly important. Both the informality and familiarity of EPL clubs were viewed by HTs as having substantial advantages over conventional NHS settings for reaching and engaging men. Importantly, HTs contributed substantial skills to the delivery of PLH. Although, top flight professional football clubs can recruit men, including those regarded as hard-to-engage into health improvement programmes, considerable attention to delivery refinement is needed to support male participants adopting interventions aimed at promoting healthy lifestyles. 23514570 Robot-assisted versus laparoscopic pyeloplasty for patients with ureteropelvic junction obstruction: An updated systematic review and meta-analysis. Abstract Objective.The aim of this study was to perform an updated systematic review and meta-analysis to compare robot-assisted pyeloplasty (RP) with laparoscopic pyeloplasty (LP) with regard to perioperative results. Material and methods. A search was performed for all available studies comparing the effect of RP versus LP for ureteropelvic junction obstruction (UPJO), published up to August 2012 in PubMed, Embase, Cochrane Library and Science Direct. Three reviewers independently conducted the determination of eligibility, quality assessment and data extraction for each study. All analyses were performed with Review Manager 5.1.5.0 software. Results.In total, 12 studies meeting the eligibility criteria were identified for meta-analysis data extraction, including 347 cases of RP and 299 cases of LP. Meta-analysis showed that RP was associated with a 18.76 min reduction in suturing time [weighted mean difference (WMD) = -18.7 6 min, 95% confidence interval (CI) -28.76 to -8.76, p = 0.0002] and a 0.75 day decrease in mean length of hospital stay (WMD = -0.75 days, 95% CI -1.10 to -0.40, p < 0.0001) compared with LP. There were no obvious differences between the approaches in operative time (WMD = -19.44 min, 95% CI -40.20 to 1.31, p = 0.07), complication rate [odds ratio (OR) = 0.65, 95% CI 0.38 to 1.12, p = 0.12] or success rate (OR = 1.32, 95% CI 0.42 to 4.12, p = 0.64). Conclusion. For patients with UPJO, RP appears to achieve equivalent perioperative results to LP, except that RP has a shorter suturing time and shorter length of hospital stay. Given the significant heterogeneity, inevitable selection bias and limited number of studies, more high-quality clinical studies are needed. 23870440 The influence of fidelity of implementation on teacher-student interaction quality in the context of a randomized controlled trial of the Responsive Classroom approach. This study examined the direct and indirect effects between training in the Responsive Classroom® (RC) approach, teachers' uptake of RC practices, and teacher-student interaction quality, using a structural equation modeling framework. A total of 24 schools were randomly assigned to experimental or control conditions. Third- and fourth-grade teachers in treatment schools (n=132) received training in the RC approach, whereas teachers in control schools (n=107) continued "business as usual." Observers rated teachers' fidelity of implementation (FOI) of RC practices 5 times throughout the year using the Classroom Practices Observation Measure. In addition, teachers completed self-report measures of FOI, the Classroom Practices Teacher Survey and Classroom Practices Frequency Survey, at the end of the school year. Teacher-student interactions were rated during classroom observations using the Classroom Assessment Scoring System. Controlling for teachers' grade level and teacher-student interaction quality at pretest, RC training was expected to predict posttest teacher-student interaction quality directly and indirectly through FOI. Results supported only a significant indirect effect, β=0.85, p=.002. Specifically, RC teachers had higher levels of FOI of RC practices, β=1.62, p<.001, R(2)=.69. In turn, FOI related to greater improvement in teacher-student interaction quality, β=0.52, p=.001, R(2)=.32. Discussion highlights factors contributing to variability in FOI and school administrators roles in supporting FOI. 23628343 Clinical and biochemical aspects of primary and secondary hyperammonemic disorders. An increased concentration of ammonia is a non-specific laboratory sign indicating the presence of potentially toxic free ammonia that is not normally removed. This does occur in many different conditions for which hyperammonemia is a surrogate marker. Hyperammonemia can occur due to increased production or impaired detoxification of ammonia and should, if associated with clinical symptoms, be regarded as an emergency. The conditions can be classified into primary or secondary hyperammonemias depending on the underlying pathophysiology. If the urea cycle is directly affected by a defect of any of the involved enzymes or transporters, this results in primary hyperammonemia. If however the function of the urea cycle is inhibited by toxic metabolites or by substrate deficiencies, the situation is described as secondary hyperammonemia. For removal of ammonia, mammals require the action of glutamine synthetase in addition to the urea cycle, in order to ensure lowering of plasma ammonia concentrations to the normal range. Independent of its etiology, hyperammonemia may result in irreversible brain damage if not treated early and thoroughly. Thus, early recognition of a hyperammonemic state and immediate initiation of the specific management are of utmost importance. The main prognostic factors are, irrespective of the underlying cause, the duration of the hyperammonemic coma and the extent of ammonia accumulation. This paper will discuss the biochemical background of primary and secondary hyperammonemia and will give an overview of the various underlying conditions including a brief clinical outline and information on the genetic backgrounds. 23770610 A simple, fast and highly sensitive assay for the detection of telomerase activity. A highly sensitive and rapid PCR-free telomerase activity assay has been developed that uses SYBR Green intercalation into the G-quadruplex structures in the presence of K(+). 23558743 Human polymerase kappa uses a template-slippage deletion mechanism, but can realign the slipped strands to favour base substitution mutations over deletions. Polymerases belonging to the DinB class of the Y-family translesion synthesis DNA polymerases have a preference for accurately and efficiently bypassing damaged guanosines. These DinB polymerases also generate single-base (-1) deletions at high frequencies with most occurring on repetitive 'deletion hotspot' sequences. Human DNA polymerase kappa (hPolκ), the eukaryotic DinB homologue, displays an unusual efficiency for to extend from mispaired primer termini, either by extending directly from the mispair or by primer-template misalignment. This latter property explains how hPolκ creates single-base deletions in non-repetitive sequences, but does not address how deletions occur in repetitive deletion hotspots. Here, we show that hPolκ uses a classical Streisinger template-slippage mechanism to generate -1 deletions in repetitive sequences, as do the bacterial and archaeal homologues. After the first nucleotide is added by template slippage, however, hPolκ can efficiently realign the primer-template duplex before continuing DNA synthesis. Strand realignment results in a base-substitution mutation, minimizing generation of more deleterious frameshift mutations. On non-repetitive sequences, we find that nucleotide misincorporation is slower if the incoming nucleotide can correctly basepair with the nucleotide immediately 5' to the templating base, thereby competing against the mispairing with the templating base. 23896862 Evoked potentials in the Atlantic cod following putatively innocuous and putatively noxious electrical stimulation: a minimally invasive approach. Aspects of peripheral and central nociception have previously been studied through recording of somatosensory evoked potentials (SEPs) to putative noxious stimuli in specific brain regions in a few freshwater fish species. In the present study, we describe a novel, minimally invasive method for recording SEPs from the central nervous system of the Atlantic cod (Gadus morhua). Cutaneous electric stimulation of the tail in 15 fish elicited SEPs at all stimulus intensities (2, 5, 10 and 20 mA) with quantitative properties corresponding to stimulus intensity. In contrast to previous fish studies, the methodological approach used in Atlantic cod in the current study uncovered a number of additional responses that could originate from multiple brain regions. Several of these responses were specific to stimulation at the highest stimulus intensities, possibly representing qualitative differences in central processing between somatosensory and nociceptive stimuli. 22705452 PTB deficiency causes the loss of adherens junctions in the dorsal telencephalon and leads to lethal hydrocephalus. Polypyrimidine tract-binding protein (PTB) is a well-characterized RNA-binding protein and known to be preferentially expressed in neural stem cells (NSCs) in the central nervous system; however, its role in NSCs in the developing brain remains unclear. To explore the role of PTB in embryonic NSCs in vivo, Nestin-Cre-mediated conditional Ptb knockout mice were generated for this study. In the mutant forebrain, despite the depletion of PTB protein, neither abnormal neurogenesis nor flagrant morphological abnormalities were observed at embryonic day 14.5 (E14.5). Nevertheless, by 10 weeks, nearly all mutant mice succumbed to hydrocephalus (HC), which was caused by a lack of the ependymal cell layer in the dorsal cortex. Upon further analysis, a gradual loss of adherens junctions (AJs) was observed in the ventricular zone (VZ) of the dorsal telencephalon in the mutant brains, beginning at E14.5. In the AJs-deficient VZ, impaired interkinetic nuclear migration and precocious differentiation of NSCs were observed after E14.5. These findings demonstrated that PTB depletion in the dorsal telencephalon is causally involved in the development of HC and that PTB is important for the maintenance of AJs in the NSCs of the dorsal telencephalon. 23953227 Decreased roundabout 1 expression promotes development of intrahepatic cholangiocarcinoma. Roundabout 1 (Robo1) is a transmembrane receptor of the immunoglobulin family. Slit2 is one of its ligands. The function of Slit2/Robo1 signaling in the development of intrahepatic cholangiocarcinoma (ICC) remains to be elucidated. We examined the immunohistochemical expression of Robo1 and Slit2 and their clinicopathologic implications in 132 cases of ICC. Also, small interfering RNA of Robo1 was transfected into a high-expression ICC cell line, and a Robo1 vector was transfected into a low-Robo1 expression ICC cell line. The effect of Robo1 suppression and overexpression in cell proliferation and migration of cultured ICC cells with Slit2 stimulation was investigated. Immunohistochemical study of ICC in the low-Robo1 expression group showed larger tumors (P = .015), a higher Ki-67 labeling index (P = .021), and low expression of Slit2 (P = .0005). The low-Slit2 expression group frequently showed perineural invasion (P = .036) and lymph node metastases (P = .013). Low Robo1 expression was associated with a poor prognosis (P = .0207). Robo1 suppression in Huh28 cells tended to promote cell proliferation and migration, whereas Robo1 overexpression in RBE cells significantly suppressed cell proliferation and migration. Low Robo1 expression was associated with cell proliferation and migration in ICC and was one of the adverse prognostic factors in patients with these tumors. 23561107 Ligands affecting silver antimicrobial efficacy on Listeria monocytogenes and Salmonella enterica. Although silver is being extensively used in food or other applications as the key component to control microbial proliferation, many factors affecting its real potential are still unknown. In the present work, the presence of specific ligands or the contents in organic matter was correlated with silver speciation and its antibacterial performance. Silver was found to be only active in form of free silver ions (FSI). The presence of chloride ions produced an equilibrium of stable silver chloride complexes which were void of antimicrobial efficacy. However, even at relatively high concentrations of chlorides, a small fraction of FSI may still be present, producing a bactericidal effect with concentrations at the nanomolar level under optimum conditions. Low concentrations of thiol groups completely inactivated silver, while methylsulphur groups only affected its efficacy at very high concentrations. Antibacterial performance revealed differences of about 1000-fold between results for environments with high organic matter content and results for aqueous salt buffers. Thiol groups were nonetheless not found directly associated with the decrease in antimicrobial performance in a nutrient rich environment. These results point out the complexity of the antimicrobial systems based on silver and can have relevance in food or other applications of silver as an antimicrobial. 23822607 A Mechanistic Study of Trichoderma reesei Cel7B Catalyzed Glycosidic Bond Cleavage. An ONIOM study is performed to illustrate the mechanism of Trichoderma reesei Cel7B catalyzed p-nitrophenyl lactoside hydrolysis. In both the glycosylation and deglycosylation steps, the reaction proceeds in a concerted way, meaning the nucleophilic attack and the glycosidic bond cleavage occur simultaneously. The glycosylation step is rate limiting with a barrier of 18.9 kcal/mol, comparable to the experimental value derived from the kcat measured in this work. The function of four residues R108, Y146, Y170, and D172, which form a hydrogen-bond network involving the substrate, is studied by conservative mutations. The mutants, including R108K, Y146F, Y170F, and D172N, decrease the enzyme activity by about 150-8000-fold. Molecular dynamics simulations show that the mutations disrupt the hydrogen-bond network, cause the substrate to deviate from active binding and hinder either the proton transfer from E201 to O4(+1) or the nucleophilic attack from E196 to C1(-1). 23845840 Predictive factors and management of rectal bleeding side effects following prostate cancer brachytherapy. To report on the incidence, nature, and management of rectal toxicities following individual or combination brachytherapy following treatment for prostate cancer over a 17-year period. We also report the patient and treatment factors predisposing to acute ≥grade 2 proctitis. A total of 2752 patients were treated for prostate cancer between October 1990 and April 2007 with either low-dose-rate brachytherapy alone or in combination with androgen depletion therapy (ADT) or external beam radiation therapy (EBRT) and were followed for a median of 5.86 years (minimum 1.0 years; maximum 19.19 years). We investigated the 10-year incidence, nature, and treatment of acute and chronic rectal toxicities following BT. Using univariate, and multivariate analyses, we determined the treatment and comorbidity factors predisposing to rectal toxicities. We also outline the most common and effective management for these toxicities. Actuarial risk of ≥grade 2 rectal bleeding was 6.4%, though notably only 0.9% of all patients required medical intervention to manage this toxicity. The majority of rectal bleeding episodes (72%) occurred within the first 3 years following placement of BT seeds. Of the 27 patients requiring management for their rectal bleeding, 18 underwent formalin treatment and nine underwent cauterization. Post-hoc univariate statistical analysis revealed that coronary artery disease (CAD), biologically effective dose, rectal volume receiving 100% of the prescription dose (RV100), and treatment modality predict the likelihood of grade ≥2 rectal bleeding. Only CAD, treatment type, and RV100 fit a Cox regression multivariate model. Low-dose-rate prostate brachytherapy is very well tolerated and rectal bleeding toxicities are either self-resolving or effectively managed by medical intervention. Treatment planning incorporating adjuvant ADT while minimizing RV100 has yielded the best toxicity-free survival following BT. 23830845 Arginase in retinopathy. Ischemic retinopathies, such as diabetic retinopathy (DR), retinopathy of prematurity and retinal vein occlusion are a major cause of blindness in developed nations worldwide. Each of these conditions is associated with early neurovascular dysfunction. However, conventional therapies target clinically significant macula edema or neovascularization, which occur much later. Intra-ocular injections of anti-VEGF show promise in reducing retinal edema, but the effects are usually transient and the need for repeated injections increases the risk of intraocular infection. Laser photocoagulation can control pathological neovascularization, but may impair vision and in some patients the retinopathy continues to progress. Moreover, neither treatment targets early stage disease or promotes repair. This review examines the potential role of the ureahydrolase enzyme arginase as a therapeutic target for the treatment of ischemic retinopathy. Arginase metabolizes l-arginine to form proline, polyamines and glutamate. Excessive arginase activity reduces the l-arginine supply for nitric oxide synthase (NOS), causing it to become uncoupled and produce superoxide and less NO. Superoxide and NO react and form the toxic oxidant peroxynitrite. The catabolic products of polyamine oxidation and glutamate can induce more oxidative stress and DNA damage, both of which can cause cellular injury. Studies indicate that neurovascular injury during retinopathy is associated with increased arginase expression/activity, decreased NO, polyamine oxidation, formation of superoxide and peroxynitrite and dysfunction and injury of both vascular and neural cells. Furthermore, data indicate that the cytosolic isoform arginase I (AI) is involved in hyperglycemia-induced dysfunction and injury of vascular endothelial cells whereas the mitochondrial isoform arginase II (AII) is involved in neurovascular dysfunction and death following hyperoxia exposure. Thus, we postulate that activation of the arginase pathway causes neurovascular injury by uncoupling NOS and inducing polyamine oxidation and glutamate formation, thereby reducing NO and increasing oxidative stress, all of which contribute to the retinopathic process. 23359363 GLP-1 Action and Glucose Tolerance in Subjects With Remission of Type 2 Diabetes Mellitus After Gastric Bypass Surgery. OBJECTIVEGlucagon like peptide-1 (GLP-1) has been suggested as a major factor for the improved glucose tolerance ensuing after Roux-en-Y Gastric Bypass (RYGBP) surgery. We examined the effect of blocking endogenous GLP-1 action on glucose tolerance in subjects with sustained remission of type 2 diabetes (T2DM) present before RYGBP.RESEARCH DESIGN AND METHODSBlood glucose, insulin, C-peptide, glucagon, GLP-1, and glucose-dependent insulinotropic peptide levels were measured after a meal challenge with either exendin-(9-39) (a GLP-1r antagonist) or saline infusion in eight subjects with sustained remission of T2DM after RYGBP and seven healthy controls.RESULTSInfusion of exendin-(9-39) resulted in marginal deterioration of the 2-h plasma glucose after meal intake in RYGBP subjects (saline 78.4 ± 15.1 mg/dL compared with exendin-(9-39) 116.5 ± 22.3 mg/dL; P < 0.001). Furthermore, glucose response to meal intake was similarly enlarged in the two study groups (percent change in the area under the curve of glucose exendin-(9-39)-infusion versus saline-infusion: controls 10.84 ± 8.8% versus RYGBP 9.94 ± 8.4%; P = 0.884). In the RYGBP group, the blockade of the enlarged GLP-1 response to meal intake resulted in reduced insulin (P = 0.001) and C-peptide (P < 0.001), but no change in glucagon (P = 0.258) responses.CONCLUSIONThe limited deterioration of glucose tolerance on blockade of GLP-1 action in our study suggests the resolution of T2DM after RYGBP may be explained by mechanisms beyond enhancement of GLP-1 action. 23877724 Historical Perspectives in the Diagnosis and Treatment of Primary Immune Deficiencies. The field of Primary Immune Deficiency Disorders (PIDD) has advanced rapidly over the past several years with over 200 different gene mutations defined. With the recent institution of newborn screening for T cell deficiencies in many states and earlier recognition of the signs and symptoms of patients with immune deficiency, it is now apparent that PIDD is not as "rare" as was originally thought several decades ago. With the earlier recognition of patients with recurrent infections and various immune perturbations, advancements in the treatment of these immune deficiency disorders have led to enhanced survival and quality of life. In this issue, the diagnosis of PIDD through laboratory testing and skin manifestations is reviewed. The more recently described cellular immune deficiencies, selective immune deficiencies, and advances in the use of bone marrow transplantation in the correction of some of these immune deficiencies are discussed. 23903795 TREATMENT OF PERSISTENT SEROUS RETINAL DETACHMENT IN VOGT-KOYANAGI-HARADA SYNDROME WITH INTRAVITREAL BEVACIZUMAB DURING THE SYSTEMIC STEROID TREATMENT. To report the use of bevacizumab in patients with Vogt-Koyanagi-Harada disease and persistent serous retinal detachment during the systemic steroid treatment. Four patients with bilateral Vogt-Koyanagi-Harada disease with the resolution of ocular inflammation presenting a serous retinal detachment involving the fovea that persisted for at least 1 month, despite systemic corticosteroid treatment, received an intravitreal injection of bevacizumab during the steroid tapering stage. Best-corrected visual acuity, central retinal thickness, and macular sensitivity were evaluated. Of 8 eyes, 7 (87%) had complete resolution of subretinal fluid within 1 month following the treatment. After the treatment, the mean best-corrected visual acuity and macular sensitivity improved significantly (P < 0.001, analysis of variance). Compared with baseline, at all measurements, central retinal thickness decreased significantly (P < 0.01, Tukey-Kramer test). At 6 months, a significant correlation was found between best-corrected visual acuity and macular sensitivity in the central 8° (linear regression, r = -0.73; P = 0.03), whereas no correlation was found between central retinal thickness and both best-corrected visual acuity and macular sensitivity. Intravitreal injection of bevacizumab during the corticosteroid therapy may be a treatment option for patients with decreased visual function because of persistent serous retinal detachment associated with Vogt-Koyanagi-Harada syndrome. 23527701 Sex difference in formation of propofol metabolites: a replication study. Women recover faster from propofol anaesthesia and have been described to have a higher incidence of awareness during surgery, compared to men - an effect that may be inherent in sex differences in propofol metabolism. In an observational study, 98 ASA I-II patients treated with continuous propofol infusion were recruited. The associations between sex and CYP2B6 and UGT1A9 polymorphisms with dose- and weight-adjusted area under the total plasma level time curves (AUC) for propofol, and its metabolites propofol glucuronide (PG), 4-hydroxypropofol (OHP) and hydroxyl glucuronide metabolites 4-hydroxypropofol-1-O-β-D-glucuronide (Q1G) and 4-hydroxypropofol-4-O-β-D-glucuronide (Q4G), were analysed. Significantly higher AUC of PG (1.3 times, p = 0.03), Q1G (2.9 times, p < 0.001), Q4G (2.4 times, p < 0.01) and OHP (4.6 times, p = 0.01) were found in women (n = 53) than in men (n = 45) after intravenous infusion of propofol using target-controlled infusion system. There was, however, no significant impact of gene polymorphisms on propofol biotransformation. The results, which are supported by a previous pilot study using a propofol bolus dose, suggest that, compared to men, more rapid propofol metabolism may occur in women - a factor that may contribute to the mentioned differences in the efficacy of propofol anaesthesia between male and female patients. 23953672 Dynamic regulation of innate immunity by ubiquitin and ubiquitin-like proteins. Protein post-translational modifications (PTMs) are central to the host innate immune regulations. Dynamically, PTMs fine-tune the spatial and temporary responses of immune- and non-immune-cells, in accordance with extracellular and intracellular stresses. Ubiquitin and ubiquitin-like proteins (Ubls) are emerging as the important multi-functional signals, controlling the activation, stability, affinity and location of many signaling proteins. Recent investigations, at the molecular-cellular-animal models, have shed new light on the versatility of the ubiquitin, SUMO and ISG15, for shaping the strength and duration of the innate immune responses. This review summarizes our current knowledge on the functions and regulatory mechanisms of the ubiquitin and Ubls in the innate immunity, the first line of host defense against microbial infection. 23380242 Titanium dioxide nanoparticles increase inflammatory responses in vascular endothelial cells. Atherosclerosis is a chronic inflammatory disease that remains the leading cause of death in the United States. Numerous risk factors for endothelial cell inflammation and the development of atherosclerosis have been identified, including inhalation of ultrafine particles. Recently, engineered nanoparticles (NPs) such as titanium (TiO2) NPs have attracted much attention due to their wide range of applications. However, there are also great concerns surrounding potential adverse health effects in vascular systems. Although TiO2 NPs are known to induce oxidative stress and inflammation, the associated signaling pathways have not been well studied. The focus of this work, therefore, deals with examination of the cellular signaling pathways responsible for TiO2 NP-induced endothelial oxidative stress and inflammation. In this study, primary vascular endothelial cells were treated with TiO2 NPs for 2-16h at concentrations of 0-50μg/mL. TiO2 NP exposure increased cellular oxidative stress and DNA binding of NF-κB. Further, phosphorylation of Akt, ERK, JNK and p38 was increased in cells exposed to TiO2 NPs. TiO2 NPs also significantly increased induction of mRNA and protein levels of vascular cell adhesion molecule-1 (VCAM-1) and mRNA levels of monocyte chemoattractant protein-1 (MCP-1). Pretreatment with inhibitors for NF-κB (pyrrolidine dithiocarbamate), oxidative stress (epigallocatechin gallate and apocynin), Akt (LY294002), ERK (PD98059), JNK (SP600125) and p38 (SB203580) significantly attenuated TiO2 NP-induced MCP-1 and VCAM-1 gene expression. These data indicate that TiO2 NPs can induce endothelial inflammatory responses via redox-sensitive cellular signaling pathways. 23194503 The chemopreventive effect of β-cryptoxanthin from mandarin on human stomach cells (BGC-823). β-Cryptoxanthin, a provitaminic carotenoid, present in many fruits and vegetables, has been associated with decreased risk of chronic diseases, including cancer. The influence of β-cryptoxanthin derived from mandarin on the proliferation of the stomach tumor cell line BGC-823 was tested using MTT and cell count assay at 72 h and dose-response (from 0.01 to 20 μM). β-Cryptoxanthin suppressed the cell migration by the scratch assay. Furthermore, β-cryptoxanthin induced an accumulation of cells in the G1/G0 phase of the cell cycle (as detected by flow cytometry), which was in accordance with an increased expression of p21 and down regulations of cyclin D1 and cyclin E, detected by Western blot analysis, and β-cryptoxanthin increased the mRNA levels of retinoic acid receptor β (RARβ) with the treatment at 10 μM for 24 h. Collectively, the above findings suggest that β-cryptoxanthin could be therapeutic in the treatment of stomach cancer cell in vitro. 23843204 Oxyluciferin Photoacidity: The Missing Element for Solving the Keto-Enol Mystery? The oxyluciferin family of fluorophores has been receiving much attention from the research community and several systematic studies have been performed in order to gain more insight regarding their photophysical properties and photoprotolytic cycles. In this minireview, we summarize the knowledge obtained so far and define several possible lines for future research. More importantly, we analyze the impact of the discoveries on the firefly bioluminescence phenomenon made so far and explain how they re-open again the discussion regarding the identity (keto or enol species) of the bioluminophore. 23878041 General movements in very preterm children and neurodevelopment at 2 and 4 years. Although ∼50% of very preterm (VP) children have neurodevelopmental impairments, early prediction of infants who will experience problems later in life remains a challenge. This study evaluated the predictive value of general movements (GM; spontaneous and endogenous movements) at 1 and 3 months' corrected age for neurodevelopment at 2 and 4 years of age in VP children. At 1 and 3 months' corrected age, infants born <30 weeks' gestation had GM assessed as normal or abnormal. Motor, cognitive, and language development at 2 years was assessed by using the Bayley Scales of Infant and Toddler Development, Third Edition. At 4 years, cognitive and language outcomes were assessed by using the Differential Ability Scale-Second Edition and motor outcomes with the Movement Assessment Battery for Children-Second Edition; a diagnosis of cerebral palsy was documented. Ninety-nine VP infants were recruited, with 97% and 88% of survivors followed up at age 2 and 4 years, respectively. Abnormal GM at 1 month were associated with worse motor outcomes at 2 and 4 years but not language or cognitive outcomes. Abnormal GM at 3 months were associated with worse motor, cognitive, and language outcomes at both 2 and 4 years. Overall, GM at 1 month demonstrated better sensitivity to impairments at 2 and 4 years, whereas GM at 3 months had better specificity and were more accurate overall at distinguishing between children with and without impairment. Abnormal GM in VP infants, particularly at 3 months postterm, are predictive of worse neurodevelopment at ages 2 and 4 years. 23697575 Evaluation of the BioPlex 2200 syphilis system as a first-line method of reverse-sequence screening for syphilis diagnosis. Despite recent technological advances, the diagnosis of syphilis remains a challenging enterprise. Actually, most high-volume laboratories have adopted the "reverse algorithm" due several factors, including the potential to automate testing. Recently, immunoassays processed on random-access systems have been proposed as screening tests. The purpose of this study was to evaluate diagnostic performances of BioPlex 2200 Syphilis IgG and BioPlex 2200 Syphilis IgM, tests based on Multiplex Flow technology, in comparison with the performance of Architect Syphilis TP, a chemiluminescent immunoassay for the detection of IgG and/or IgM anti-Treponema pallidum antibodies. A retrospective study was performed with a panel of 100 blood donor sera, a panel of 350 clinical and laboratory-characterized syphilitic sera, and 170 samples obtained from subjects with potentially interfering conditions. Moreover, 200 unselected samples submitted to the Microbiology Laboratory of St. Orsola Hospital in Bologna for routine screening for syphilis were evaluated. As confirmatory tests, T. pallidum hemagglutination and Western blot assays were used. Considering the IgG Western blot (WB) assay to be the gold standard method, BioPlex 2200 Syphilis IgG specificity was far higher than Architect Syphilis TP specificity (89.7% versus 78.4%, respectively), whereas the sensitivity was 100% for both automated methods. Compared to the IgM WB assay, BioPlex 2200 Syphilis IgM performed with a specificity of 94.9%, whereas the sensitivity was 84.8%. Considering the excellent ease of use and automation, the high sample throughput and its valuable analytical performances, BioPlex Syphilis 2200 IgG could represent a suitable choice for high-volume laboratories. BioPlex Syphilis 2200 IgM could be considered a good addition to IgG testing for uncovering active infections. 23541394 Intraocular lens delivery characteristics of the preloaded AcrySof IQ SN60WS/AcrySert injectable lens system. To evaluate the delivery characteristics of the AcrySof IQ SN60WS intraocular lens (IOL) injected via a preloaded AcrySert delivery system. Prospective observational case series. setting: This study was carried out in the cataract service of an ophthalmic hospital that serves a large sector of inner-city London. patient population: The study included all patients undergoing routine phacoemulsification procedures with implantation of the SN60WS IOL via the preloaded system over 5 consecutive months. A total of 85 patients (85 eyes) were included in this study. intervention: Phacoemulsification procedures conducted by 7 surgeons were digitally captured. outcome measures: Video recordings of the IOL delivery stage were analyzed by a single observer. Of particular interests were the orientation of the leading haptic and optic on insertion, the degree of intrawound manipulation of the injector, and the time required to satisfactorily deliver the IOL into the capsular bag in a correct orientation. Problems of IOL delivery were also noted. In 38 out of 85 eyes (45%), correct IOL delivery behavior was achieved with the leading haptic orientating to the left of the surgeon and thus did not require any intrawound rotational manipulation of the injector. Forty-seven of the 85 eyes (55%) required additional rotational manipulation of IOL orientation. Other problems recorded were trapped trailing haptic, haptic-optic adhesion, overriding of the plunger over the optic, and trauma to optic edge. The average time to achieve satisfactory IOL position was 47 seconds. IOL power and the grade of the operating surgeon did not appear to influence the event of a misdirected leading haptic. The AcrySof SN60WS/AcrySert system does not appear to meet the expectations of pro-viding a predictable means of IOL delivery. 23769167 7-Substituted-sulfocoumarins are isoform-selective, potent carbonic anhydrase II inhibitors. A series of 7-substituted sulfocoumarins and 3,4-dihydrosulfocoumarins was obtained by cyclization of the methanesulfonate of 2,4-dihydroxy- or 2-hydroxy-4-methoxybenzaldehyde, followed by derivatization reactions. The new compounds incorporate a range of substituents in position 7 of the heterocyclic ring (hydroxyl, methoxy, carboxylic and alkylsulfonate ester). The compounds were tested for the inhibition of the zinc enzyme human (h) carbonic anhydrase (hCA, EC 4.2.1.1). Unlike the 6-substituted sulfocoumarins which were potent hCA IX and XII inhibitors and ineffective hCA I and II inhibitors, compounds from this series showed low nanomolar hCA II inhibitory properties, and inhibited the mitochondrial isoform hCA VA with KIs in the range of 91-9960 nM, but were ineffective as hCA I, IX and XII inhibitors. The structure activity relationship for this class of inhibitors was rather clear, with the nature of the 7-substituent strongly influencing hCA VA inhibition, whereas the nature of these groups were less relevant for hCA II inhibition (all reported compounds were highly effective hCA II inhibitors, with KIs in the range of 1.5-8.4 nM). Since both hCA II and hCA VA are important drug targets (hCA II for antiglaucoma agents; hCA VA for antiobesity drugs), these isoform-selective inhibitors reported here may be considered of interest for various biomedical applications. 23918643 Influence of Perfluorinated End Groups on the SFRD of [Pt(cod)Me(Cn F2n+1 )] onto Porous Al2 O3 in CO2 under Reductive Conditions. The optimized synthesis of a range of cyclooctadiene-stabilized Pt complexes that contained different perfluoro-alkane chains, [Pt(cod)Me(Cn F2n+1 )], is presented. These metal-organic compounds were employed in the so-called supercritical fluid reactive deposition (SFRD) in CO2 under reductive conditions to generate metallic nanoparticles on aluminum oxide as a porous support. Thus, Al2 O3 -supported Pt nanoparticles with a narrow particle-size distribution were obtained. At a reduction pressure of 15.5 MPa and a temperature of 353 K, particle diameters of d50 =2.3-2.8 nm were generated. Decreasing the pressure during the reduction reaction led to slightly larger particles whilst decreasing the amount of organometallic precursor in CO2 yielded a decrease in the particle size from x50 =3.2 nm to 2.6 nm and a particle-size distribution of 2.2 nm. Furthermore, substitution of the CH3 end group by the Cn F2n+1 end groups led to a significant drop in Pt loading of about 50 %. Within the series of perfluorinated end groups that were considered, the Pt complex that contained a branched perfluoro-isopropyl group showed the most-interesting results when compared to the control precursor, [Pt(cod)Me2 ] (1). 23937510 The Impact of Telemedicine Intensivist Support and a Pediatric Hospitalist Program on a Community Hospital. Abstract Background: Because of centralization of care, pediatric patients often require transfer for subspecialty care. We evaluated the impact of telemedicine critical care consultation and a pediatric hospitalist program on enabling patients to remain at a community hospital. Patients and Methods: This is a retrospective chart review of pediatric patients at a community hospital receiving critical care consultation from a tertiary children's hospital from January 2006 to October 2009. Patient cohorts differed by modality of intensivist consultation (telephone versus telemedicine) and modality of inpatient ward care at the community hospital (primary care physician versus hospitalist). Patients were compared for differences in transfer rate and rate of diversion from the pediatric intensive care unit to the tertiary ward. Results: One hundred fifty-three charts were analyzed: 41 from prior to hospitalist and telemedicine implementation (Cohort 1), 56 from post-implementation of telemedicine but pre-hospitalist program (Cohort 2), and 56 after implementation of both the telemedicine and hospitalist programs (Cohort 3). Baseline data did not differ among cohorts. Transfer rates after intensivist consultation were lower after implementation of telemedicine consultation (100%, 85.7%, and 87.5% in Cohorts 1-3, respectively; p=0.04). The proportion of transferred patients who were diverted to the tertiary ward decreased over time (19.5%, 14.5%, and 6.1% in Cohorts 1-3, respectively; p=0.003). Conclusions: Telemedicine consultation between pediatric intensivists and community hospital physicians combined with a pediatric hospitalist program at the community hospital has the potential to improve triage of pediatric patients and reduce the need to transfer patients. 23922239 Efficient β-cell regeneration by a combination of neogenesis and replication following β-cell ablation and reversal of pancreatic duct ligation. Achieving efficient β-cell regeneration is a major goal of diabetes research. Previously, we found that a combination of β-cell ablation and pancreatic duct ligation led to β-cell regeneration by direct conversion from α-cells. Here, we studied the effect of surgical reversal of the duct ligation, finding that there was a wave of β-cell replication following reversal. The combination of β-cell neogenesis prior to reversal of the duct ligation and β-cell replication following reversal resulted in efficient β-cell regeneration and eventual recovery of function. This provides an important proof of principle that efficient β-cell regeneration is possible, even from a starting point of profound β-cell ablation. This has important implications for efforts to promote β-cell regeneration. Stem Cells 2013. 23940259 A role for gut-associated lymphoid tissue in shaping the human B cell repertoire. We have tracked the fate of immature human B cells at a critical stage in their development when the mature B cell repertoire is shaped. We show that a major subset of bone marrow emigrant immature human B cells, the transitional 2 (T2) B cells, homes to gut-associated lymphoid tissue (GALT) and that most T2 B cells isolated from human GALT are activated. Activation in GALT is a previously unknown potential fate for immature human B cells. The process of maturation from immature transitional B cell through to mature naive B cell includes the removal of autoreactive cells from the developing repertoire, a process which is known to fail in systemic lupus erythematosus (SLE). We observe that immature B cells in SLE are poorly equipped to access the gut and that gut immune compartments are depleted in SLE. Thus, activation of immature B cells in GALT may function as a checkpoint that protects against autoimmunity. In healthy individuals, this pathway may be involved in generating the vast population of IgA plasma cells and also the enigmatic marginal zone B cell subset that is poorly understood in humans. 23896675 Efficacy of an Evidence-Based Clinical Decision Support in Primary Care Practices: A Randomized Clinical Trial. IMPORTANCE There is consensus that incorporating clinical decision support into electronic health records will improve quality of care, contain costs, and reduce overtreatment, but this potential has yet to be demonstrated in clinical trials. OBJECTIVE To assess the influence of a customized evidence-based clinical decision support tool on the management of respiratory tract infections and on the effectiveness of integrating evidence at the point of care. DESIGN, SETTING, AND PARTICIPANTS In a randomized clinical trial, we implemented 2 well-validated integrated clinical prediction rules, namely, the Walsh rule for streptococcal pharyngitis and the Heckerling rule for pneumonia. INTERVENTIONS AND MAIN OUTCOMES AND MEASURES The intervention group had access to the integrated clinical prediction rule tool and chose whether to complete risk score calculators, order medications, and generate progress notes to assist with complex decision making at the point of care. RESULTS The intervention group completed the integrated clinical prediction rule tool in 57.5% of visits. Providers in the intervention group were significantly less likely to order antibiotics than the control group (age-adjusted relative risk, 0.74; 95% CI, 0.60-0.92). The absolute risk of the intervention was 9.2%, and the number needed to treat was 10.8. The intervention group was significantly less likely to order rapid streptococcal tests compared with the control group (relative risk, 0.75; 95% CI, 0.58-0.97; P = .03). CONCLUSIONS AND RELEVANCE The integrated clinical prediction rule process for integrating complex evidence-based clinical decision report tools is of relevant importance for national initiatives, such as Meaningful Use. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01386047. 23773031 Bioinspired Artificial Single Ion Pump. Bioinspired artificial functional nanochannels for intelligent molecular and ionic transport control at the nanoscale have wide potential applications in nanofluidics, energy conversion, and biosensors. Although various smart passive ion transport properties of ion channels have been artificially realized, it is still hugely challenging to achieve high level intelligent ion transport features in biological ion pumps. Here we show a unique bioinspired single ion pump based on a cooperative pH response double-gate nanochannel, whose gates could be opened and closed alternately/simultaneously under symmetric/asymmetric pH environments. With the stimulation of the double-gate nanochannel by continuous switching of the symmetric/asymmetric pH stimuli, the bioinspired system systematically realized three key ionic transport features of biological ion pumps, including an alternating gates ion pumping process under symmetric pH stimuli, transformation of the ion pump into an ion channel under asymmetric pH stimuli, and a fail-safe ion pumping feature under both symmetric and asymmetric pH stimuli. The ion pumping processes could well be reproduced under a concentration gradient. With the advantages of the extraordinary ionic transport functions of biological ion pumps, the bioinspired ion pump should find widespread applicability in active transportation-controlling smart nanofluidic devices, efficient energy conversions, and seawater desalinization, and open the way to design and develop novel bioinspired intelligent artificial nanochannel materials. 23644081 Evaluation and management of paravalvular aortic regurgitation after transcatheter aortic valve replacement. Paravalvular aortic regurgitation (PAR) negatively affects the prognosis after transcatheter aortic valve replacement (TAVR) with dramatically increased morbidity and mortality in patients with more than mild PAR. Because transcatheter heart valves are implanted in a sutureless fashion using oversizing to anchor the prosthesis stent frame at the level of the virtual aortic annulus, stent frame underexpansion due to heavily calcified cusps, suboptimal placement of the prosthesis, and/or annulus-prosthesis-size mismatch due to malsizing can contribute to paravalvular leakage. In contrast to open heart surgery, TAVR does not offer the opportunity to measure the aortic annulus under direct vision during the procedure. Therefore, the dilemma before each TAVR procedure is the appropriate sizing of the dimensions of the aortic annulus and to choose not only the size but also the transcatheter heart valve type (self-expanding vs. balloon-expandable) that fits the given anatomy best. Because precise echocardiographic quantification of PAR in patients with TAVR remains challenging especially in the acute implantation situation, a multimodal approach for the evaluation of PAR with the use of hemodynamic measurements and imaging modalities is imperative to precisely quantify the severity of aortic regurgitation immediately after valve implantation and to identify patients who will benefit from corrective measures such as post-dilation or valve-in-valve implantation. Every measure has to be taken to prevent or reduce PAR to provide a satisfying long-term clinical outcome. 23695807 Encapsulated fat necrosis mimicking subcutaneous liposarcoma: radiologic findings on MR, PET-CT, and US imaging. We present a case of a subcutaneous encapsulated fat necrosis of the upper extremity that mimicked subcutaneous liposarcoma because of heterogeneous signal intensity, its relatively large size, and pronounced enhancement on magnetic resonance imaging (MRI). For this case, we present the radiologic findings including MRI, positron emission tomography-computed tomography (PET-CT), ultrasonography, and radiography. We emphasize the imaging features of this lesion, which has a fibrous capsule and briefly discuss its nomenclature and pathophysiology. 23408390 The mTOR pathway in hepatic malignancies. The mechanistic/mammalian target of rapamycin (mTOR) pathway plays a critical role in cellular metabolism, growth, and proliferation and has been evaluated as a target for therapy in various malignancies. The mTOR pathway is a major tumor-initiating pathway in hepatocellular carcinoma, with up-regulation seen in up to 50% of tumors. Metformin, which represses mTOR signaling by activating adenosine monophosphate-activated protein kinase, has been shown to decrease liver carcinogenesis in population studies. mTOR inhibitors such as everolimus have been evaluated as adjunctive chemotherapy with some success, although efficacy has been limited by the lack of complete mTOR pathway inhibition. The active site mTOR inhibitors hold greater promise, given that they offer complete mTOR suppression. There is also evidence of mTOR pathway activation in cholangiocarcinoma, although its biological significance in initiating and promoting tumor progression remains ambiguous. This review provides an overview of the complex biochemistry behind the mTOR pathway and its role in carcinogenesis, especially as it pertains to hepatic malignancies. (HEPATOLOGY 2013;58:810-818). 23921500 Lectin-dependent inhibition of antigen-antibody reaction: Application for measuring α2,6-sialylated glycoforms of transferrin. We developed a high-throughput ELISA for measuring α2,6-sialylated transferrin (Tf), based on inhibition of anti-transferrin antibody binding to α2,6-sialylated Tf by a lectin, Sambucus sieboldiana Agglutinin (SSA). The inhibition was not observed with other glycoforms such as periodate-treated, sialidase-treated, and sialidase/galactosidase-treated Tf, suggesting that the assay was glycoform specific. This finding was applied to an automated latex-agglutination immunoassay, using SSA lectin as an inhibitor (SSA-ALI). The concentration of α2,6-sialylated Tf measured by SSA-ALI in human cerebrospinal fluid was correlated with that of ELISA (r(2)=0.8554), previously developed for measuring α2,6-sialylated Tf. 23796726 Feasibility studies into the production of gamma-irradiated oyster tissue reference materials for paralytic shellfish poisoning toxins. A study was conducted to assess the feasibility for the production of sterile, stable and homogenous shellfish reference materials containing known concentrations of paralytic shellfish poisoning (PSP) toxins. Pacific oysters were contaminated with toxins following mass culturing of toxic algae and shellfish feeding experiments. Live oysters were shucked and tissues homogenised, before measuring into multiple aliquots, with one batch subjected to gamma irradiation treatment and the other remaining untreated. The homogeneity of both batches of samples was assessed using a pre-column oxidation liquid chromatography with fluorescence detection (Pre-COX LC-FLD) method and shown to be within the limits of normal within-batch repeatability. A twelve-month stability experiment was conducted for both untreated and gamma irradiated batches, specifically examining the effects of long term storage at -20 °C, +4 °C and +40 °C. Results indicated mostly good stability of PSP toxins in both materials when stored frozen at -20 °C, but with the instability of GTX2&3 concentrations in the untreated tissues eliminated in the irradiated tissues. Analysis using a post-column oxidation (PCOX) LC-FLD method also showed epimerisation in both GTX1&4 and GTX2&3 epimeric pairs in untreated samples after only 6 months frozen storage. This issue was not present in the tissues irradiated before long term storage. Biological activity testing confirmed the absence of bacteria in the irradiated samples throughout the 12 month study period. With such results there was clear evidence for the potential of increasing the scale of the mass culturing and shellfish feeding for the production of large batches of tissue suitable for the preparation of a certified matrix reference material. Overall results demonstrated the feasibility for production of oyster reference materials for PSTs, with evidence for prolonged stability following gamma irradiation treatment and storage at -20 °C. 23906947 Mortality risks in relation to occupational category and position among the Japanese working population: the Jichi Medical School (JMS) cohort study. A well-known demographic finding in modern society is the inverse association between socioeconomic status and mortality. The purpose of the study was to examine socioeconomic indicators, such as occupational category (white-collar vs blue -collar) and occupational position (managerial vs non-managerial) as determinants of all -cause, cardiovascular disease (CVD) and cancer mortality in a Japanese working population. This is a prospective study. Data of a baseline survey were collected between 1992 and 1995, and ultimately 6929 Japanese workers aged 65 years and younger (3333 men and 3596 women) from 12 rural communities across Japan were followed until the end of 2005. The HRs of death and 95% CIs from all causes were calculated using the Cox proportional hazard model. Men in blue-collar jobs showed an increased all-cause mortality risk compared with those in white-collar jobs (HR 1.64, 95% CI 1.10 to 2.45). Stratified by occupational category, non-managerial women in blue-collar jobs showed a decreased CVD mortality risk compared with managerial women (HR 0.15, 95% CI 0.03 to 0.81), after adjusting for confounding factors. However, non-managerial women in white-collar jobs showed an increased mortality risk compared with managerial women, although this was not significant (HR 2.34, 95% CI 0.25 to 21.87). Socioeconomic disparity according to occupational category was related to the risk of all-cause mortality among Japanese men. There is a potential interaction of occupational category and position in CVD mortality among Japanese women. 23880226 Morphological and genetic diversity of Rhipicephalus sanguineus sensu lato from the New and Old Worlds. The taxonomic status of the brown dog tick (Rhipicephalus sanguineus sensu stricto), which has long been regarded as the most widespread tick worldwide and a vector of many pathogens to dogs and humans, is currently under dispute. We conducted a comprehensive morphological and genetic study of 278 representative specimens, which belonged to different species (i.e., Rhipicephalus bursa, R. guilhoni, R. microplus, R. muhsamae, R. pusillus, R. sanguineus sensu lato, and R. turanicus) collected from Europe, Asia, Americas, and Oceania. After detailed morphological examination, ticks were molecularly processed for the analysis of partial mitochondrial (16S rDNA, 12S rDNA, and cox1) gene sequences. In addition to R. sanguineus s.l. and R. turanicus, three different operational taxonomic units (namely, R. sp. I, R. sp. II, and R. sp. III) were found on dogs. These operational taxonomical units were morphologically and genetically different from R. sanguineus s.l. and R. turanicus. Ticks identified as R. sanguineus s.l., which corresponds to the so-called "tropical species" (= northern lineage), were found in all continents and genetically it represents a sister group of R. guilhoni. R. turanicus was found on a wide range of hosts in Italy and also on dogs in Greece. The tropical species and the temperate species (= southern lineage) are paraphyletic groups. The occurrence of R. turanicus in the Mediterranean region is confirmed. A consensual re-description of R. sanguineus s.s. and R. turanicus will be necessary to solve the taxonomic problems within the so-called R. sanguineus group. 23918795 Intestinimonas butyriciproducens gen. nov., sp. nov., a novel butyrate-producing bacterium from the mouse intestine. Whilst creating a bacterial collection of strains from the mouse intestine, we isolated a Gram-negative, spore-forming, non-motile and strictly anaerobic rod-shaped bacterium from the caecal content of a TNFdeltaARE mouse. The isolate, referred to as strain SRB-521-5-IT, was originally cultured on a reduced agar medium containing yeast extract, rumen fluid and lactic acid as energy and carbon sources. Phylogenetic analysis of partial 16S rRNA genes revealed that the species most closely related to strain SRB-521-5-IT (GenBank accession no. KC311367) were Flavonifractor plautii and Pseudoflavonifractor capillosus (< 95 % sequence identity; 1436 bp). In contrast to F. plautii and P. capillosus, strain SRB-521-5-IT contained a substantial amount of C18:0 dimethylacetal. Additional major fatty acids were C14:0 methyl ester, C16:0 dimethylacetal and C18:0 aldehyde. Strain SRB-521-5-IT differed in its enzymatic profile from F. plautii and P. capillosus by being positive for dextrin, maltotriose, turanose, D,L-lactic acid and D-lactic acid methyl ester but negative for D-fructose. In reduced Wilkins-Chalgren-Anaerobe broth, strain SRB-521-5-IT produced approximately 8 mM butyrate and 4 mM acetate. In contrast to F. plautii, the strain did not metabolize flavonoids. It shows intermediate resistance towards the antibiotics ciprofloxacin, colistin and tetracycline. Based on genotypic and phenotypic characteristics, we propose to create the name Intestinimonas butyriciproducens gen. nov., sp. nov. to accommodate strain SRB-521-5-IT (= DSM 26588T = CCUG 63529T). 23824787 A pilot evaluation of a brief non-verbal executive function assessment in Parkinson's disease. Screening for cognitive impairment in the clinical or community setting is often hampered by the lack of a suitable assessment that is not overburdened with complex administration and scoring methods. We have developed non-verbal cognitive screening instrument: the Weigl Token Test (WTT) from two existing instruments, the Weigl's Colour-Form Sorting Test (WCFST) and the Token Test. The aim of this investigation is to compare the modified WTT with a battery of 'Gold Standard' cognitive assessments, to determine its utility, sensitivity and specificity as a brief cognitive screen in a cohort of Parkinson's disease (PD) patients. A total of 50 PD patients consented to participate in this investigation. All participants were assessed with a battery of cognitive screening instruments including the WCFST, Mini Mental Status Examination, Addenbrooke's Cognitive Examination-Revised and Delis Kaplan Executive Function Systems. The sensitivity and specificity of the WTT to detect cognitive impairment were based upon psychiatric interview, neuropsychological assessment and application of DSM-IV criteria. The optimal cut-point of the WTT was 116/120, and its sensitivity and specificity to detect cognitive impairment were 88% and 89%, respectively. The diagnostic accuracy of the WTT as calculated by the area under the receiver operating curve was 0.83 (95% CI 0.76-0.95), suggesting that this instrument has acceptable psychometric properties to discriminate between case and non-cases of cognitive impairment. The WTT demonstrated excellent concurrent validity with existing 'Gold Standard' assessments of cognitive impairment. We believe that this instrument will prove to be a valuable additional screening assessment in epidemiological, primary care, specialist mental health or clinical investigations. Copyright © 2013 John Wiley & Sons, Ltd. 23587944 Hydramacin-1 in action: scrutinizing the barnacle model. Hydramacin-1 (HM1) from the metazoan Hydra exerts antimicrobial activity against a wide range of bacterial strains. Notably, HM1 induces the aggregation of bacterial cells, accompanied by precipitation. To date, the proposed mechanism of peptide-lipid interaction, termed the barnacle model, has not been described on the molecular level. Here, we show by biochemical and biophysical techniques that the lipid-peptide interactions of HM1 are initiated by electrostatic and hydrophobic effects, in particular, by tryptophan and neighboring polar amino acid residues that cause an interfacial localization of the peptide between two self-contained lipid bilayers. The high binding constants of HM1 upon lipid interaction are in the range of other potent antimicrobial peptides, e.g., magainin, and can be reasonably explained by two distinct epitopes on the surface of the peptide's global structure, which both contain SWT(K/R) motifs. The residues of this motif favor localization of the peptide in the head group region of phospholipid bilayers up to a penetration depth of 4 Å and a minor participation of the lipids' hydrocarbon regions. Our results expand the knowledge about the molecular modes of action antimicrobial peptides use to tackle their target cells. Furthermore, the aggregation of living bacteria by HM1 was observed for a broad range of Gram-positive and Gram-negative bacteria. Therefore, the detailed view of peptide-lipid interactions described by the barnacle model consolidates it among the established models. 23142711 Proteasome inhibition attenuates heart failure during the late stages of pressure overload through alterations in collagen expression. Although the role of the ubiquitin-proteasome system (UPS) in cardiac hypertrophy induced by pressure overload has been consistently studied, the fundamental importance of the UPS in cardiac fibrosis has received much less attention. Our previous study found that proteasome inhibitor (MG132) treatment attenuated cardiac fibrosis and heart failure during the early and middle stages of pressure overload. However, the effects of this inhibitor on late-stage pressure overload hearts remain unclear and controversial. The present study was designed to investigate the effects and possible mechanisms of MG132 on cardiac fibrosis and dysfunction during the late stages of pressure overload. Male Sprague Dawley rats with abdominal aortic constriction (AAC) or a sham operation received an intraperitoneal injection of MG132 (0.1 mg kg⁻¹ day⁻¹) or vehicle for 16 weeks. Left ventricular (LV) function, collagen deposition and Ang II levels were evaluated at study termination. Ang II-stimulated adult rat cardiac fibroblasts were utilized to examine the effects of MG132 on collagen synthesis and the relationship between the renin-angiotensin-aldosterone system (RAAS) and the UPS. MG132 treatment attenuated ventricular dysfunction by suppressing cardiac fibrosis rather than inhibiting cardiac hypertrophy during the late-stages of pressure overload. We also found that Ang II activates UPS in the heart and MG132 attenuates Ang II-induced collagen synthesis via suppression of the NF-κB/TGF-β/Smad2 signaling pathways. Proteasome inhibition therefore could provide a new promising therapeutic strategy to prevent cardiac fibrosis and progression of heart failure even during the late-stages of pressure overload. 23900672 Chelerythrine induces reactive oxygen species-dependent mitochondrial apoptotic pathway in a murine T cell lymphoma. Chelerythrine is a well-known protein kinase C inhibitor and potential antiproliferative and antitumor pharmacological agent. Chelerythrine inhibits/suppresses the HSF1 phosphorylation by inhibiting PKC and blocks the nuclear migration and subsequent synthesis of hsp70 leading to reduced cell viability and activation of apoptotic machinery. Chelerythrine is also known to enhance the production of reactive oxygen intermediate that is strong activator of apoptosis in high concentration. Therefore, the present study intended to investigate the role of chelerythrine-induced reactive oxygen intermediate on the viability and apoptosis of Dalton's lymphoma cells. Enhanced production of reactive oxygen species in Dalton's lymphoma (DL) cells was observed upon treatment of chelerythrine only which was seen completely abolished on treatment of mitochondrial complex inhibitors rotenone and malonate, and anti-oxidant, N-acetyl-L-cysteine. Increased number of DL cells undergoing apoptosis, as observed by fluorescent microscopy and flow cytometry analysis, in chelerythrine only-treated group was seen that was significantly inhibited on treatment of mitochondrial complex inhibitors and anti-oxidants. Staurosporine, on the other hand, does not lead to enhanced production of reactive oxygen intermediate in DL cells. 23806854 Use of infrared ocular thermography to assess physiological conditions of pigs prior to slaughter and predict pork quality variation. Infrared thermography (IRT) body temperature readings were taken in the ocular region of 258 pigs immediately before slaughter. Levels of lactate were measured in blood taken in the restrainer. Meat quality was assessed in the longissimus dorsi (LD), semimembranosus (SM), and adductor muscles. Ocular IRT (IROT) temperature was correlated with blood lactate levels (r=0.20; P=0.001), with pH taken 1hour postmortem (pH1: r=-0.18; P=0.03) and drip loss (r=0.20; P=0.02) in the LD muscle, and with pH1 in the SM muscle (r=-0.20; P=0.02). Potentially, IROT may be a useful tool to assess the physiological conditions of pigs at slaughter and predict the variation of important meat quality traits. However, the magnitude of the correlations is rather low, so a further development of image capture technique and further studies under more variable preslaughter conditions ensuring a larger pork quality variation are needed. 23824512 Smoking and prostate cancer in a multi-ethnic cohort. Prostate cancer (PCa) and smoking-related morbidity disproportionately burdens African American (AA) men. Smoking is associated with high-grade PCa and incidence, but few studies have focused on AA men. This study aims to determine the effect of tobacco-use on odds of PCa and of high-grade PCa in a population of predominantly AA men. This is a cross-sectional study evaluating smoking and PCa status in men with incident PCa and screened healthy controls. Altogether, 1,085 men (527 cases and 558 controls), age ≥ 40 years were enrolled through outpatient urology clinics in two US cities from 2001 to 2012. Validated questionnaires were used to gather clinical and socioeconomic data. The cases and controls were predominantly AA (79.9% and 71.3%, respectively, P = 0.01). AA men smoked more frequently (53.4% vs. 47.9%, P < 0.001) and quit less frequently than European American (EA) men (31.5% vs. 40.4%, P = 0.01). AA heavy smokers had increased odds of PCa diagnosis (OR 2.57, 95% CI 1.09, 6.10) and high-grade cancer (OR 1.89, 95% CI 1.03, 3.48) relative to never smokers and light smokers. Among AAs, heavy smokers had lower odds of NCCN low PCa recurrence risk stratification. AA former smokers had a trend for increased odds of high-grade cancer compared to never smokers. The associations between smokings, cancer diagnosis and cancer grade did not reach statistical significance in EA men. We found ethnic differences in smoking behavior. Heavy smoking is associated with increased odds of PCa and of higher Gleason grade in AA men. Prostate 73: 1518-1528, 2013 © 2013 Wiley Periodicals, Inc. 23859103 Identification of a Common Binding Mode for Imaging Agents to Amyloid Fibrils from Molecular Dynamics Simulations. Amyloid diseases are characterized by the misfolding and deposition of proteins in the body in the form of insoluble amyloid fibrils. Alzheimer's disease and type 2 diabetes mellitus are two examples of amyloid diseases which are closely related both with respect to the atomic structures of the amyloid fibrils and the disease pathology. Alzheimer's disease is very difficult to diagnose, and much research is being performed to develop noninvasive diagnostic methods, such as imaging with small-molecule agents. The interactions between amyloid fibrils and imaging agents are challenging to examine experimentally due to the insoluble nature of amyloid fibrils. This study uses molecular dynamics simulations to investigate the interactions between 13 aromatic amyloid imaging agents, entailing 4 different organic scaffolds, and a model of an amyloid fibril. Clustering analysis combined with free energy calculations are used to categorize and rank the resulting complexes. Several binding modes are identified across the different ligand scaffolds, however a common favorable binding mode can be identified in which the agent is placed in surface grooves along the amyloid fibril axis. The existence of multiple binding modes for imaging agents is proposed to originate from subtle differences in amino acid composition of the surface grooves on an amyloid fibril, resulting in fine tuning of the binding affinities for a specific amyloid fibril. 23943505 In-depth proteomic analysis of mouse microglia using a combination of FASP and StageTip-based, high pH, reversed-phase fractionation. Microglia are major immune cells in the central nervous system. A characterization of microglia proteome would facilitate on the study of microglial functions in association with various neurodegenerative diseases. To build a reference proteome, we established a BV-2 microglial proteome to a depth of 5494 unique protein groups using a novel strategy that combined FASP, StageTip-based high pH fractionation, and high-resolution mass spectrometry quickly and cost-efficiently. By bioinformatics analysis, the BV-2 proteome is a valuable resource for studies of microglial function, such as in the immune response, inflammatory response, and phagocytosis. This article is protected by copyright. All rights reserved. 23290590 Optical treatment strategies to slow myopia progression: Effects of the visual extent of the optical treatment zone. In order to develop effective optical treatment strategies for myopia, it is important to understand how visual experience influences refractive development. Beginning with the discovery of the phenomenon of form deprivation myopia, research involving many animal species has demonstrated that refractive development is regulated by visual feedback. In particular, animal studies have shown that optically imposed myopic defocus slows axial elongation, that the effects of vision are dominated by local retinal mechanisms, and that peripheral vision can dominate central refractive development. In this review, the results obtained from clinical trials of traditional optical treatment strategies employed in efforts to slow myopia progression in children are interpreted in light of the results from animal studies and are compared to the emerging results from preliminary clinical studies of optical treatment strategies that manipulate the effective focus of the peripheral retina. Overall, the results suggest that imposed myopic defocus can slow myopia progression in children and that the effectiveness of an optical treatment strategy in reducing myopia progression is influenced by the extent of the visual field that is manipulated. 23419097 Reliability of different methods for measuring the inclination of the maxillary canines on panoramic radiographs. To test the reliability of 4 different methods of measuring maxillary canine inclination (CI) on panoramic radiographs, and to determine whether examiner experience level influenced these measurements under ideal experimental conditions. The sample consisted of 20 high-quality panoramic radiographs obtained under standardized conditions using the same radiological apparatus. Canine inclination (CI) was measured as either the angle formed by the canine long axis and the midline (method A), a line passing through the suborbitary points (method B), the most superior points of condyles (method C) or the mesiobuccal cusp tip of the first molars (method D). Measurements were made at initial observation (T1) and after 3 months (T2) by 5 experienced orthodontists and 5 undergraduate dental students. Mean T1-T2 differences for the measurements were close to zero, with no relationship between their magnitude or direction for each method. Intra-rater reliability was excellent, with the lowest values being observed for method B and the highest for method C. No influence of the examiner experience level was detected. The four methods used in this study to measure CI showed excellent intra-rater and inter-rater reliability, irrespective of examiner experience level. Method B was the least reliable and method C the most reliable, if compared with the others. 23871921 Calibration of hydrodynamic behavior and biokinetics for TOC removal modeling in biofilm reactors under different hydraulic conditions. In this study, total organic carbon (TOC) biodegradation was simulated by GPS-X software in biofilm reactors with carriers of plastic rings and glass beads under different hydraulic conditions. Hydrodynamic model by retention time distribution and biokinetic measurement by in-situ batch test served as two significant parts of model calibration. Experimental results showed that TOC removal efficiency was stable in both media due to the enough height of column, although the actual hydraulic volume changed during the variation of hydraulic condition. Simulated TOC removal efficiencies were close to experimental ones with low theil inequality coefficient values (below 0.15). Compared with glass beads, more TOC was removed in the filter with plastic rings due to the larger actual hydraulic volume and lower half saturation coefficient in spite of its lower maximum specific growth rate of biofilm, which highlighted the importance of calibrating hydrodynamic behavior and biokinetics. 23289502 Visualizing the perturbation of cellular cyclic di-GMP levels in bacterial cells. Cyclic di-GMP (c-di-GMP) has emerged as a prominent intracellular messenger that coordinates biofilm formation and pathogenicity in many bacterial species. Developing genetically encoded biosensors for c-di-GMP will help us understand how bacterial cells respond to environmental changes via the modulation of cellular c-di-GMP levels. Here we report the design of two genetically encoded c-di-GMP fluorescent biosensors with complementary dynamic ranges. By using the biosensors, we found that several compounds known to promote biofilm dispersal trigger a decline in c-di-GMP levels in Escherichia coli cells. In contrast, cellular c-di-GMP levels were elevated when the bacterial cells were treated with subinhibitory concentrations of biofilm-promoting antibiotics. The biosensors also revealed that E. coli cells engulfed by macrophages exhibit lower c-di-GMP levels, most likely as a response to the enormous pressures of survival during phagocytosis. 23752659 An unsymmetrical pentacene derivative with ambipolar behavior in organic thin-film transistors. Three new unsymmetrical anthracenyl-pentacene derivatives have been synthesized, characterized using X-ray crystallography, and used as semiconductors in OTFTs. For one derivative, ambipolar charge carrier transport was observed with a hole mobility of 0.2 cm(2) V(-1) s(-1) and an electron mobility of 0.03 cm(2) V(-1) s(-1). 23815604 Surface and size effects on cell interaction of gold nanoparticles with both phagocytic and nonphagocytic cells. With the development of nanotechnology and its application in biomedicine, studies on the interaction between nanoparticles and cells have become increasingly important. To understand the surface and size effects on cell interaction of nanoparticles, the cellular uptake behaviors of two series of gold nanoparticles (AuNPs) with both positively and negatively charged surfaces and sizes range from ∼16 to ∼58 nm were investigated in both phagocytic RAW 264.7 and nonphagocytic HepG2 cells. The internalization of AuNPs was quantified by ICP-MS, and the intracellular fate of NPs was evaluated by TEM analysis. The results showed that the AuNPs with positive surface charge have much higher cell internalization ability than those with negative surface charge in nonphagocytic HepG2 cells. However, the uptake extent of negatively charged AuNPs was similar with that of the positively charged AuNPs when in phagocytic RAW 264.7 cells. Among the tested size range, negatively charged AuNPs with a diameter of ∼40 nm had the highest uptake in both cells, while the positively charged AuNPs did not show a certain tendency. Intracellular TEM analysis demonstrated the different fate of AuNPs in different cells, where both the positively and negatively charged AuNPs were mainly trapped in the lysosomes in HepG2 cells, but many of them were localized in phagosomes when in RAW 264.7 cells. Cytotoxicity of these AuNPs was tested by both MTT and LDH assays, which suggested NP's toxicity is closely related to the tested cell types besides the surface and size of NPs. It demonstrates that cell interaction between nanoparticles and cells is not only affected by surface and size factors but also strongly depends on cell types. 23416637 Size of urogenital hiatus as a potential risk factor for emptying disorders after pelvic prolapse repair. We correlated urogenital hiatus size and levator ani contraction strength with early postoperative emptying disorders. We also determined whether postoperative emptying disorders could be predicted before anti-incontinence procedures and pelvic organ prolapse repair. We retrospectively reviewed the charts of 225 consecutive patients after surgery for pelvic organ prolapse and/or stress urinary incontinence. Urogenital hiatus size was evaluated using pelvic organ prolapse quantification. Levator contraction strength was determined by the Oxford 0 to 5 classification scale. Emptying disorders were defined as post-void residual urine volume greater than 100 ml 48 hours postoperatively and/or discharge home with a Foley catheter or on intermittent self-catheterization. Median patient age, post-void residual urine volume and urogenital hiatus size were significantly related to levator contraction strength (each p <0.05). Univariate logistic regression analysis revealed a significant association of urogenital hiatus size (p = 0.001), post-void residual urine volume (p = 0.005) and levator contraction strength (p = 0.001) with emptying disorder status. Multivariate logistic regression analysis showed that levator contraction strength (p = 0.001) and post-void residual urine (p = 0.01) were independent predictors of emptying disorders. A wide urogenital hiatus, decreased levator ani contraction strength, increasing age and increased post-void residual urine correlated with an increased chance of early postoperative emptying disorders. The most independent predictors of early emptying disorders were decreased levator contraction strength and increased post-void residual urine. 23599130 Factors related to clinical pregnancy after vitrified-warmed embryo transfer: a retrospective and multivariate logistic regression analysis of 2313 transfer cycles. What factors does multivariate logistic regression show to be significantly associated with the likelihood of clinical pregnancy in vitrified-warmed embryo transfer (VET) cycles? Assisted hatching (AH) and if the reason to freeze embryos was to avoid the risk of ovarian hyperstimulation syndrome (OHSS) were significantly positively associated with a greater likelihood of clinical pregnancy. Single factor analysis has shown AH, number of embryos transferred and the reason of freezing for OHSS to be positively and damaged blastomere to be negatively significantly associated with the chance of clinical pregnancy after VET. It remains unclear what factors would be significant after multivariate analysis. The study was a retrospective analysis of 2313 VET cycles from 1481 patients performed between January 2008 and April 2012. A multivariate logistic regression analysis was performed to identify the factors to affect clinical pregnancy outcome of VET. There were 22 candidate variables selected based on clinical experiences and the literature. With the thresholds of α entry = α removal= 0.05 for both variable entry and variable removal, eight variables were chosen to contribute the multivariable model by the bootstrap stepwise variable selection algorithm (n = 1000). Eight variables were age at controlled ovarian hyperstimulation (COH), reason for freezing, AH, endometrial thickness, damaged blastomere, number of embryos transferred, number of good-quality embryos, and blood presence on transfer catheter. A descriptive comparison of the relative importance was accomplished by the proportion of explained variation (PEV). Among the reasons for freezing, the OHSS group showed a higher OR than the surplus embryo group when compared with other reasons for VET groups (OHSS versus Other, OR: 2.145; CI: 1.4-3.286; Surplus embryos versus Other, OR: 1.152; CI: 0.761-1.743) and high PEV (marginal 2.77%, P = 0.2911; partial 1.68%; CI of area under receptor operator characteristic curve (ROC): 0.5576-0.6000). AH also showed a high OR (OR: 2.105, CI: 1.554-2.85) and high PEV (marginal 1.97%; partial 1.02%; CI of area under ROC: 0.5344-0.5647). The number of good-quality embryos showed the highest marginal PEV and partial PEV (marginal 3.91%, partial 2.28%; CI of area under ROC: 0.5886-0.6343). This was a retrospective multivariate analysis of the data obtained in 5 years from a single IVF center. Repeated cycles in the same woman were treated as independent observations, which could introduce bias. Results are based on clinical pregnancy and not live births. Prospective analysis of a larger data set from a multicenter study based on live births is necessary to confirm the findings. Paying attention to the quality of embryos, the number of good embryos, AH and the reasons for freezing that are associated with clinical pregnancy after VET will assist the improvement of success rates. 23739533 The role of pain coping and kinesiophobia in patients with complex regional pain syndrome type 1 of the legs. The aim of this cross-sectional study was to evaluate to what extent pain coping and kinesiophobia contribute to limitations in activity and participation in patients with complex regional pain syndrome type 1 (CRPS-1) of the lower limbs. A total of 238 patients with CRPS-1 of the legs from 4 pain clinics and 1 Department of Neurology of University Hospitals participated in this study. Pain and CRPS severity were assessed with the pain rating index of the McGill Pain Questionnaire and the CRPS Severity Score, respectively. Activity was measured with the Rising & Walking scale, and participation with the Social Functioning scale of the SF-36. In addition, the Tampa Scale for Kinesiophobia and Pain Coping Inventory were administered. Hierarchical linear regression was used to evaluate to what extent kinesiophobia and pain coping contributed to difficulties with Rising & Walking and Social Functioning. The analyses showed that the "resting" subscale of the Pain Coping Inventory-that is, 1 of the 3 scales evaluating passive pain coping strategies-contributed significantly to difficulties in rising and walking (explaining 12.5% of the variance) and to difficulties in social functioning (explaining 6.5%), whereas kinesiophobia was not associated with either of these measures. These findings indicate that making use of "resting" as a pain coping strategy contributes significantly to limitations in activity and participation in patients with CRPS-1 of the legs. Indications for a negative influence of kinesiophobia or a positive influence of an active pain coping style were not found. 23824828 Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. In this position statement of the ESC Working Group on Myocardial and Pericardial Diseases an expert consensus group reviews the current knowledge on clinical presentation, diagnosis and treatment of myocarditis, and proposes new diagnostic criteria for clinically suspected myocarditis and its distinct biopsy-proven pathogenetic forms. The aims are to bridge the gap between clinical and tissue-based diagnosis, to improve management and provide a common reference point for future registries and multicentre randomised controlled trials of aetiology-driven treatment in inflammatory heart muscle disease. 23855353 Motivational interviewing: a part of the weight loss program for overweight and obese women prior to fertility treatment. Abstract This is a retrospective study to investigate whether motivational interviewing increases weight loss among obese or overweight women prior to fertility treatment. Women with body mass index (BMI) > 30 kg/m(2) approaching the Fertility Clinic, Regional Hospital Skive, were given advice about diet and physical activity with the purpose of weight loss. In addition, they were asked if they wanted to receive motivational interviewing. Among other data, age, height and weight were obtained. Main outcomes were weight loss measured in kg and decrease in BMI. We studied 187 women: 110 received sessions of motivational interviewing (intervention group, n = 110), 64 received motivational support by phone or e-mail only and 13 women did not wish any motivational support (control group, n = 77). The mean weight loss and decrease in BMI was greater in the intervention group compared with the control group (9.3 kg versus 7.3 kg, difference p = 0.01, 3.3 kg/m(2) versus 2.6 kg/m(2), difference p = 0.02). The mean period of intervention was comparable in the two groups, 7.9 month and 7.3 month, respectively, (difference non significant: NS). The study indicates that motivational interviewing may be a valuable tool in weight loss programs for obese and overweight women prior to fertility treatment. 23651254 Inhibition of Dengue Virus 2 Replication by Artificial MicroRNAs Targeting the Conserved Regions. Dengue virus (DENV), a mosquito-borne flavivirus, causes serious diseases and threatens public health in tropical and subtropical areas worldwide. RNA interference (RNAi) is a prevailing strategy for antiviral therapy. In this paper, 6 single artificial microRNAs (amiRNAs) targeting the highly conserved regions of the DENV-2 genome were identified and inhibited virus replication efficiently. Then, effective tandem amiRNAs targeting 2 different DENV-2 genome regions were constructed and expressed simultaneously from a single microRNA-like polycistron to avoid virus variation or mutation escape. Finally, the most high-performance tandem amiRNA was embedded in a lenti-viral vector and inhibited DENV-2 virus replication stably and dose-dependently. Overall, these results indicated that RNAi based on multiple amiRNAs targeting viral conserved regions was an effective approach for improvements of nucleic acid inhibitors of DENV and provided a new therapeutic strategy for DENV infection in humans. 23814262 Changes in presentation, treatment, and outcomes of adult low-grade gliomas over the past fifty years. Background To identify changes in patient presentation, treatment, and outcomes of low-grade gliomas (LGGs) over the past 50 years. Methods Records of 852 adults who received a diagnosis at Mayo Clinic from 1960 through 2011 with World Health Organization grade II LGGs were reviewed and grouped by those who received a diagnosis before (group I: 1960-1989) and after (group II: 1990-2011) the routine use of postoperative MRI. Results Median follow-up was 23.3 and 8.7 years for groups I and II, respectively. Patients in group I more often presented with seizures, headaches, sensory/motor impairment, and astrocytoma histology. Over time, more gross total resections (GTRs) were achieved, fewer patients received postoperative radiotherapy (PORT), and more received chemotherapy. Median progression-free survival (PFS) and overall survival (OS) were 4.4 and 8.0 years, respectively. Although PFS was similar, 10-year OS was better in group II (47%) than in group I (33%; P < .0001). Improved PFS in multivariate analysis was associated with group I patients, nonastrocytoma histology, small tumor size, successful GTR, or radical subtotal resection (rSTR), PORT, and postoperative chemotherapy. Factors associated with improved OS in multivariate analysis were younger age, nonastrocytoma histology, small tumor size, and GTR/rSTR. Conclusions OS for LGG has improved over the past 50 years, despite similar rates of progression. In the modern cohort, more patients are receiving a diagnosis of oligodendroglioma and are undergoing extensive resections, both of which are associated with improvements in OS. Because of risk factor stratification by clinicians, the use of PORT has decreased and is primarily being used to treat high-risk tumors in modern patients. 23642478 Carbonic anhydrase inhibitors. Benzenesulfonamides incorporating cyanoacrylamide moieties strongly inhibit Saccharomyces cerevisiae β-carbonic anhydrase. A series of benzenesulfonamides incorporating cyanoacrylamide moieties (tyrphostine analogs) were assayed as inhibitors of the β-carbonic anhydrase (CA, EC 4.2.1.1) from Saccharomyces cerevisiae, ScCA. Some of these compounds were low nanomolar or subnanomolar ScCA inhibitors and showed selectivity ratios in the range of 4.91-69.86 for inhibiting the yeast enzyme over the offtarget human (h) isoforms hCA I and of 6.46-13.52 for inhibiting ScCA over hCA II. The model organism S. cerevisiae and this particular enzyme may be useful for detecting antifungals with a novel mechanism of action compared to the classical azole drugs to which significant drug resistance emerged. Indeed, some of these sulfonamides inhibited the growth of the yeast with CC50-s in the range of 0.73-6.54μM. 23728733 Gap-freezing approach for shortening the lyophilization cycle time of pharmaceutical formulations-demonstration of the concept. During gap freezing, vials are placed on a metal tray, which is separated from the shelf surface with a small air gap that eliminates significant conductive heat transfer from the shelf to the bottom of the vial. The purpose of this freezing approach is to reduce the lyophilization cycle time of various amorphous formulations by nearly isothermal freezing. Such isothermal freezing promotes the formation of large ice crystals, and thus large pores throughout the cake, which subsequently accelerates the primary drying rate. The nucleation temperature using gap freezing, for the experimental conditions tested, was in the range of -1°C to -6°C, much higher than the range of -10°C to -14°C found using conventional shelf freezing. Isothermal freezing becomes effective when the gap is greater than 3 mm. The pore sizes and cake resistance during primary drying for various formulations were determined using the pore diffusion model developed by Kuu et al. (Pharm Dev Technol, 2011, 16(4): 343-357). Reductions in primary drying time were 42% (for 10% sucrose), 45% (for 10% trehalose), and 33% (for 5% sucrose). © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2572-2588, 2013. 23855478 Avidity Modulation of Folate-Targeted Multivalent Dendrimers for Evaluating Biophysical Models of Cancer Targeting Nanoparticles. We investigated two types of generation 5 PAMAM dendrimers, each conjugated stochastically with a mean number of five or ten methotrexate (MTX) ligands per dendrimer (G5-MTX5, G5-MTX10), for their binding to surface-immobilized folate binding protein (FBP) as a function of receptor density. The binding study was performed under flow by surface plasmon resonance (SPR) spectroscopy. Two multivalent models were examined to simulate binding of the dendrimer to the receptor surface, showing that at relatively high receptor density, both dendrimer conjugates exhibit high avidity. However, upon reducing the receptor density by a factor of three and thirteen relative to the high density level, the avidity of the lower-valent G5-MTX5 decreases by up to several orders of magnitude (KD = nM to µM), whereas the avidity of G5-MTX10 remains largely unaffected regardless of the density variation. Notably, on the 13-fold reduced FBP surface, G5-MTX5 displays binding kinetics similar to that of monovalent methotrexate, which is patently different from the still tight binding of the higher-valent G5-MTX10. Thus, the binding analysis demonstrates that avidity displayed by multivalent MTX conjugates varies in response to the receptor density, and it can be modulated for achieving tighter, more specific binding to the higher receptor density by modulation of ligand valency. We believe this study provides experimental evidence supportive of the mechanistic hypothesis of multivalent NP uptake to a cancer cell over a healthy cell where the diseased cell expresses the folate receptor at higher density. 23950634 Rare occurrence of mix stromal tumours: a case report of gastrointestinal and extra-intestinal stromal tumour on the jejunum and omentum of a nine year old girl from adamawa state, Nigeria. Stromal tumors of the jejunum (GIST) and omentum (EGIST) are uncommon and dearth of information still exists on their occurrence concurrently. Here, we report a nine year old girl that presented with tender abdominal mass measuring 14 × 8 cm associated with features of gastric outlet obstruction and hyponatremia of 115mmol/L. A diagnosis of hyponatremia in a child with gastric outlet obstruction secondary to intraabdominal mass was made for which exploratory laparotomy was carried out. Histology of the tumour revealed stromal spindle epithelioid as well as myxoid cells. Complete resection of the tumour and correction for hyponatremia was done in addition to antibiotics therapy with remarkable improvement. Index case is that of mixed stromal tumours that presented with features of gastric outlet obstruction, and the patient did well after surgery. 23598668 Agreement between event-based and trend-based glaucoma progression analyses. PurposeTo evaluate the agreement between event- and trend-based analyses to determine visual field (VF) progression in glaucoma.MethodsVFs of 175 glaucoma eyes with ≥5 VFs were analyzed by proprietary software of VF analyzer to determine progression. Agreement (κ) between trend-based analysis of VF index (VFI) and event-based analysis (glaucoma progression analysis, GPA) was evaluated. For eyes progressing by event- and trend-based methods, time to progression by two methods was calculated.ResultsMedian number of VFs per eye was 7 and follow-up 7.5 years. GPA classified 101 eyes (57.7%) as stable, 30 eyes (17.1%) as possible and 44 eyes (25.2%) as likely progression. Trend-based analysis classified 122 eyes (69.7%) as stable (slope >-1% per year or any slope magnitude with P>0.05), 53 eyes (30.3%) as progressing with slope <-1% per year, P≤0.05 (sensitive criteria), and 37 eyes (21.1%) as progressing with slope <-1% per year, P≤0.01 (specific criteria). κ between sensitive criteria of GPA (possible combined with likely progression) and trend-based analysis was 0.48, and between specific criteria of GPA (possible clubbed with no progression) and trend-based analysis was 0.50. In eyes progressing by sensitive criteria of both methods (42 eyes), median time to progression by GPA (4.9 years) was similar (P=0.30) to trend-based method (5.0 years). This was also similar in eyes progressing by specific criteria of both methods (25 eyes; 5.6 years versus 5.9 years, P=0.23).ConclusionAgreement between event- and trend-based progression analysis was moderate. GPA seemed to detect progression earlier than trend-based analysis, but this wasn't statistically significant. 23899051 Distributed nonlocal feedback delays may destabilize fronts in neural fields, distributed transmission delays do not. The spread of activity in neural populations is a well-known phenomenon. To understand the propagation speed and the stability of stationary fronts in neural populations, the present work considers a neural field model that in- volves intra-cortical and cortico-cortical synaptic interactions. This includes distributions of axonal transmission speeds and nonlocal feedback delays as well as general classes of synaptic interactions. The work proves the spec- tral stability of standing and travelling fronts subject to general transmission speeds for large classes of spatial interactions and derives conditions for the front instabilities subjected to nonlocal feedback delays. Moreover it turns out that the uniqueness of the stationary travelling fronts guarantees its exponential stability for vanishing feedback delay. Numerical simulations complement the analytical findings. 22776545 Co-learning facilitates memory in mice: a new avenue in social neuroscience. Social context affects brain function but our understanding of its neurobiology is at an early stage. The mere presence of one individual can alter the cognitive capacities of another and social learning has been demonstrated in many species, including the mouse. We asked several questions: 1. How can active engagement of two familiar mice in the same learning activity (co-learning) alter their memory? 2. Under which environmental conditions (aversive vs non-aversive) can we expect the memory to be enhanced, impaired, or not affected? 3. Can a genetic factor modify the co-learning effect on memory? More specifically, can co-learning correct memory deficits in autistic-like BTBR inbred mice with deficient sociability? We demonstrated that pairs of familiar inbred mice of the same or different genotypes (C57BL/6J and BTBR) that were habituated to new objects and their spatial location, had enhanced episodic memory in the spatial object recognition test, whereas individually-trained animals failed to solve this task. Notably, the co-learning effect was genotype-dependent. BTBR mice paired with BTBR cage-mates in the habituation session modestly ameliorated their performance in the object recognition test but co-learning with a familiar C57BL/6J mouse completely normalized episodic memory deficit. Next, we explored the co-learning effect on fear memory in these inbred strains. Interestingly, mice of both genotypes displayed significantly enhanced contextual fear memory once they had been conditioned together with BTBR animals. The same influence of BTBR presence was observed on cued fear memory in C57BL/6J mice, whereas a modest co-learning effect was found on cued fear conditioning in the BTBR strain. Taken together, we demonstrated for the first time the co-learning effect on cognitive capacities in mice, which can be modified by genetic background and environmental conditions. The possible implications of this methodological approach in social neuroscience are discussed. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23900921 Device localization and dynamic scan plane selection using a wireless magnetic resonance imaging detector array. A prototype wireless guidance device using single sideband amplitude modulation (SSB) is presented for a 1.5T magnetic resonance imaging system. The device contained three fiducial markers each mounted to an independent receiver coil equipped with wireless SSB technology. Acquiring orthogonal projections of these markers determined the position and orientation of the device, which was used to define the scan plane for a subsequent image acquisition. Device localization and scan plane update required approximately 30 ms, so it could be interleaved with high temporal resolution imaging. Since the wireless device is used for localization and does not require full imaging capability, the design of the SSB wireless system was simplified by allowing an asynchronous clock between the transmitter and receiver. When coupled to a high readout bandwidth, the error caused by the lack of a shared frequency reference was quantified to be less than one pixel (0.78 mm) in the projection acquisitions. Image guidance with the prototype was demonstrated with a phantom where a needle was successfully guided to a target and contrast was delivered. The feasibility of active tracking with a wireless detector array is demonstrated. Wireless arrays could be incorporated into devices to assist in image-guided procedures. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc. 23967921 Mechanisms of microbubble-vessel interactions and induced stresses: A numerical study. Oscillating microbubbles within microvessels could induce stresses that lead to bioeffects or vascular damage. Previous work has attributed vascular damage to the vessel expansion or bubble jet. However, ultra-high speed images of recent studies suggest that it could happen due to the vascular invagination. Numerical simulations of confined bubbles could provide insight into understanding the mechanism behind bubble-vessel interactions. In this study, a finite element model of a coupled bubble/fluid/vessel system was developed and validated with experimental data. Also, for a more realistic study viscoelastic properties of microvessels were assessed and incorporated into this comprehensive numerical model. The wall shear stress (WSS) and circumferential stress (CS), metrics of vascular damage, were calculated from these simulations. Resultant amplitudes of oscillation were within 15% of those measured in experiments (four cases). Among the experimental cases, it was numerically found that maximum WSS values were between 1.1-18.3 kPa during bubble expansion and 1.5-74 kPa during bubble collapse. CS was between 0.43-2.2 MPa during expansion and 0.44-6 MPa while invaginated. This finding confirmed that vascular damage could occur during vascular invaginations. Predicted thresholds in which these stresses are higher during vessel invagination were calculated from simulations. 23930613 Magnetic resonance imaging for intratesticular and extratesticular scrotal lesions. To evaluate magnetic resonance imaging (MRI) utility in intratesticular and extratesticular scrotal diseases. Two radiologists retrospectively reviewed images of patients who underwent ultrasound followed by MRI, categorizing them as intratesticular or extratesticular and malignant, benign, indeterminate, or inadequate study. For patients who underwent surgical excision, pathologic results were also correlated to the presurgical ultrasound and MRI diagnoses. Of 69 cases, 38 were intratesticular lesions and 31 were extratesticular lesions. MRI and ultrasound diagnoses were discordant in 21 (55.32%) intratesticular and 19 (61.3%) extratesticular lesions. MRI diagnosis was malignant after an indeterminate ultrasound in 0 and 4 (12.9%) intratesticular and extratesticular lesions, respectively. MRI diagnosis was benign after an indeterminate ultrasound in 18 (47.43%) and 14 (45.2%) intratesticular and extratesticular lesions, respectively. A malignant ultrasound diagnosis was reversed to benign MRI diagnosis in one (2.6%) intratesticular and one (3.2%) extratesticular lesion. In no case was a benign lesion on ultrasound read as malignant on MRI in either group. The cohort of patients with intratesticular lesions received a mean clinical and radiographic follow up of 2.49 ± 1.97 and 1.85 ± 1.46 years, respectively. The patients with extratesticular lesions received a mean clinical and radiographic follow up of 1.30 ± 1.08 and 2.00 ± 1.28 years, respectively. In no case did repeat imaging change the diagnosis after initial MRI and ultrasound evaluation. MRI was effective at characterizing both intratesticular and extratesticular lesions in the majority of cases. 23907210 USCOM-window to the circulation: utility of supra-sternal Doppler in an elderly anaesthetized patient for a robotic cystectomy. Supra-sternal Doppler (USCOM Ltd., Sydney, Australia) can be used during anaesthesia to measure cardiac output (CO) and related flow parameters. However, before the USCOM can be used routinely, its utility and limitations need to be fully understood and critical information about its use disseminated. In "Window to the Circulation" we use the example of an elderly man undergoing major urological robotic surgery to highlight the utility and limitations of intra-operative USCOM use. USCOM readings were verified against oesophageal Doppler. Despite the lack of major blood loss (<500 ml in 8-h), significant changes in haemodynamics were recorded. CO ranged from 3.2 to 8.3 l/min. The quality of USCOM scans and reliability of data was initially poor, but improved as CO increased as surgery progressed. When USCOM scans became acceptable the correlation with oesophageal Doppler was R(2) = 8.0 (p < 0.001). Several characteristic features of the supra-sternal Doppler scans were identified: Aortic and pulmonary flow waves, valve closure, E and A waves, false A-wave and aberrant arterial flow patterns. Their identification helped with identifying the main flow signal across the aortic valve. The USCOM has the potential to monitor changes in CO and related flow parameters intra-operatively and thus help the anaesthetist to more fully understand the patient's haemodynamics. However, achieving a good quality scan is important as it improves the reliability of USCOM data. The supra-sternal route is rich in flow signals and identifying the aortic valve signal is paramount. Recognizing the other characteristic waveforms in the signal helps greatly. 23745702 CGRP receptor antagonism and migraine therapy. Migraine is the most prevalent of the neurological disorders and can affect the patient throughout the lifetime. Calcitonin gene-related peptide (CGRP) is a neuropeptide that is expressed in the central and peripheral nervous systems. It is now 2 decades since it was proposed to be involved in migraine pathophysiology. The cranial sensory system contains C-fibers storing CGRP and trigeminal nerve activation and acute migraine attacks result in release of CGRP. The CGRP receptor consists of a complex of calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1) and receptor component protein (RCP). At the central synapses in the trigeminal nucleus caudalis, CGRP acts postjunctionally on second-order neurons to transmit pain signals centrally via brainstem and midbrain to thalamus and higher cortical pain regions. CLR and RAMPs are widely expressed throughout the brain, in the trigeminal ganglion and in intracranial arteries. CGRP does not induce neurogenic inflammation or sensitization at peripheral meningeal sites but relays nociceptive information from trigeminal primary afferent neurons to the second-order neurons in the spinal trigeminal nucleus neurons. CGRP receptor antagonists have been developed as novel antimigraine drugs and found to be effective in the treatment of acute migraine attacks. Other ways to stop CGRP activity has been introduced recently through antibodies against CGRP and the CGRP receptor. While the CGRP receptors are expressed both in the CNS and at various places related to the trigeminal system the exact site of action for their therapy effect is still unresolved but the new approaches may resolve this. 23959397 Immunoliposome encapsulation increases cytotoxic activity and selectivity of curcumin and resveratrol against HER2 overexpressing human breast cancer cells. Natural compounds have been studied as a source of countless bioactive compounds with diverse activities. Among them, many dietary phytochemicals have been thoroughly studied for their cytotoxic or apoptotic effects in several cellular models in order to explain their anticancer capacity. Curcumin and resveratrol are two natural compounds with a large body of evidence showing their cytotoxic activity against a wide variety of cancer cells; however, their poor absorption, bioavailability, and low selectivity have limited their clinical use. With the aim of improving bioavailability and selectivity, the antiproliferative effects of free-, liposomed-, and immunoliposomed-curcumin and/or resveratrol formulations have been compared in two human breast cancer cell lines with different HER2 expression levels. The results demonstrate that when HER2-targeted immunoliposomes are coupled to trastuzumab there is a dramatic increase in the antiproliferative effects of curcumin and resveratrol in HER2 positive human breast cancer cells in comparison to regular liposomed or free forms, indicating an increase of its therapeutic effect. The enhancement of the cytotoxic effects was also correlated to the uptake of curcumin at intracellular level, as shown by using ImageStream technique. The striking efficacy of the immunoliposomed formulation containing both resveratrol and curcumin suggests a multitargeted mechanism of action that deserves further study. These findings show the potential of HER2-targeted nanovesicles to develop new drug delivery systems for cancer therapy based on these compounds and justify further preclinical trials. 23249238 Reduced antinociception of opioids in rats and mice by vaccination with immunogens containing oxycodone and hydrocodone haptens. Prescription opioids abuse and associated deaths are an emerging concern in the USA. Vaccination against prescription opioids may provide an alternative to pharmacotherapy. An oxycodone hapten containing a tetraglycine linker at the C6 position (6OXY(Gly)(4)OH) conjugated to keyhole limpet hemocyanin (KLH) has shown early proof-of-efficacy in rodents as a candidate immunogen (6OXY(Gly)(4)-KLH) for the treatment of oxycodone abuse. In this study, oxycodone-based and hydrocodone-based haptens were conjugated to KLH to generate immunogens that would recognize both oxycodone and hydrocodone. Vaccination with 6OXY(Gly)(4)-KLH increased drug binding in serum, reduced drug distribution to brain, and blunted analgesia for both oxycodone and hydrocodone. An analogous C6-linked hydrocodone vaccine blocked hydrocodone effects but less so than 6OXY(Gly)(4)-KLH. C8-Linked hydrocodone immunogens had only limited efficacy. Amide conjugation showed higher haptenation ratios and greater efficacy than thioether conjugation to maleimide activated KLH (mKLH). The 6OXY(Gly)(4)-KLH vaccine may be used for treatment of prescription opioid abuse. 23958676 Surgery, wound healing, and metastasis: Recent insights and clinical implications. Surgery-induced acceleration of tumour growth has been observed since several centuries. We reviewed recent insights from in vitro data, animal experimentation, and clinical studies on how surgery-induced wound healing or resection of a primary cancer influences the tumour-host ecosystem in patients harbouring minimal residual or metastatic disease. Most of the growth factors, chemokines, and cytokines orchestrating surgical wound healing promote tumour growth, invasion, or angiogenesis. In addition, resection of a primary tumour may accelerate synchronous metastatic growth. In the clinical setting, indirect evidence supports the relevance of the above findings. Randomized clinical trials are underway comparing resection versus observation in metastatic breast and colon cancer with asymptomatic primary tumours. In depth knowledge of how surgical intervention alters the tumour-host-metastasis communicating ecosystems could have important implications for clinical decision making in patients with synchronous metastatic disease and for the design and timing of multimodality treatment strategies. 23712792 L-glutamine and L-glutamic Acid facilitate successful agrobacterium infection of recalcitrant tea cultivars. The first step in Agrobacterium tumefaciens infection of plants is the establishment of cell-cell contact between the two partners. However, failure to establish such contact makes many plants and explants recalcitrant to A. tumefaciens infection. Tea is one such example where even the popular inducer, acetosyringone failed to facilitate A. tumefaciens infection due to the presence of high amounts of bactericidal/bacteriostatic polyphenols. Quinones are formed as a result of polyphenols oxidation. They cause tissue browning and necrosis during the process of transformation, and in turn prevent A. tumefaciens infection. Compounds such as polyphenol adsorbents, i.e., polyvinylpyrrolidone and charcoal, and antioxidants like cysteine and ascorbic acid were screened to overcome tissue browning. Although these compounds enhanced the growth of A. tumefaciens, these failed to facilitate the infection of the leaves of either Kangra Jat, Tocklai Variety-1, UPASI-9, UPASI-10, and Stock-449 cultivars of tea. On the contrary, the presence of filter sterilized L-glutamine and L-glutamic acid in the co-cultivation medium facilitated successful A. tumefaciens infection of recalcitrant tea leaves. L-Glutamine and glutamic acid form harmless adducts by binding to quinones. Therefore, their presence in the co-cultivation medium allowed the tea leaves to remain living and appealing to the infecting A. tumefaciens. Successful A. tumefaciens infection of tea leaves was confirmed by positive signals in GUS assay, PCR, and Dot blot. 23409718 Targeting multiplicity: the key factor for anti-cancer nanoparticles. In this mini-review, we focus on different strategies to bring nanotools specifically to cancer cells. We discuss about a better targeting of tumor, combining the characteristics of tumor environment, the increase in nanoparticles life time, the biomarkers overexpressed on cancer cells and different physical methods for non invasive therapies. Here we detail the necessity of a synergy between passive and active targeting for an actual specificity of cancer cells. 23608537 A novel array of chemiluminescence sensors for sensitive, rapid and high-throughput detection of explosive triacetone triperoxide at the scene. Triacetone triperoxide (TATP) is relatively easy to make and has been used in various terrorist acts. Early but easy detection of TATP is highly desired. We designed a new type sensor array for H2O2. The unique CL sensor array was based on CeO2 nanoparticles' membranes, which have an excellent catalytic effect on the luminol-H2O2 CL reaction in alkaline medium. It exhibits a linear range for the detection of H2O2 from 1.0×10(-8) to 5.0×10(-5)M (R(2)=0.9991) with a 1s response time. The detection limit is 1.0×10(-9)M. Notably, the present approach allows the design of CL sensor array assays in a more simple, time-saving, long-lifetime, high-throughput, and economical approach when compared with conventional CL sensor. It is conceptually different from conventional CL sensor assays. The novel sensor array has been successfully applied for the detection of TATP at the scene. 23953744 Use of quantitative 16S rRNA PCR to determine bacterial load does not augment conventional cerebrospinal fluid (CSF) cultures among children undergoing treatment for CSF shunt infection. The aim of this study was to develop a quantitative 16S rRNA assay for determination of bacterial nucleic acid load in cerebrospinal fluid (CSF) shunt infection and to compare quantitative 16S rRNA polymerase chain reaction (PCR) findings to those of conventional bacterial culture in patients treated for CSF shunt infection. We developed a quantitative 16S rRNA PCR assay that detected bacterial load across a range of 2.5 × 10(9) down to 2.5 × 10(4) 16S copies/mL CSF under experimental conditions for numerous Gram-positive and Gram-negative organisms. However, when applied to archived CSF samples from 25 shunt infection episodes, correlations between positive bacterial culture and 16S rRNA levels were seen in only half of infections, and 16S rRNA levels dropped precipitously after an initial peak on the first day of sample collection. Bacterial load measured using 16S rRNA PCR does not provide sufficient information beyond bacterial culture to inform CSF shunt infection treatment. 23726231 Timing is everything-colectomy performed on Monday decreases length of stay. Perioperative care of patients undergoing colon resection requires a multidisciplinary approach by the operating surgeon, residents, and nurses. Operations performed on Monday take full advantage of hospital resources throughout the week to meet expected discharge by Friday. In a current health care environment of diminishing means, improving the timing of surgery in relation to expected length of stay may play an important role in preserving health care resources. A retrospective review of a prospectively collected colorectal surgical database identified all patients who underwent segmental colon resection at a single tertiary care referral center from 2004 to 2010. Length of stay for patients undergoing elective open and minimally invasive segmental colectomy was compared for Monday versus Tuesday through the weekend. Patient and surgeon demographics were recorded as well as postoperative outcomes and complications. A total of 868 segmental colectomies were performed during the study period. Length of stay was significantly decreased by .73 days (P < .01) for all segmental colectomies performed on Monday compared with those performed Tuesday through Sunday. There was also a significant decrease in length of stay looking independently at right (.96 days, P < .01) and left or sigmoid colectomies (.56 days, P < .01). There was no significant difference in patient or surgeon demographics to account for this difference. Segmental colectomies have a significantly decreased length in stay when performed on Monday compared with the rest of the week. The decrease is independent of surgeon, comorbidities, and complications. This difference may be the result of patients' taking full advantage of hospital resources and ancillary support. Cost-effective measures may be evaluated and directed at adjustment of resources available throughout the week to reduce length of stay. 23945239 Anti-EGFL7 antibodies enhance stress-induced endothelial cell death and anti-VEGF efficacy. Many oncology drugs are administered at their maximally tolerated dose without the knowledge of their optimal efficacious dose range. In this study, we describe a multifaceted approach that integrated preclinical and clinical data to identify the optimal dose for an antiangiogenesis agent, anti-EGFL7. EGFL7 is an extracellular matrix-associated protein expressed in activated endothelium. Recombinant EGFL7 protein supported EC adhesion and protected ECs from stress-induced apoptosis. Anti-EGFL7 antibodies inhibited both of these key processes and augmented anti-VEGF-mediated vascular damage in various murine tumor models. In a genetically engineered mouse model of advanced non-small cell lung cancer, we found that anti-EGFL7 enhanced both the progression-free and overall survival benefits derived from anti-VEGF therapy in a dose-dependent manner. In addition, we identified a circulating progenitor cell type that was regulated by EGFL7 and evaluated the response of these cells to anti-EGFL7 treatment in both tumor-bearing mice and cancer patients from a phase I clinical trial. Importantly, these preclinical efficacy and clinical biomarker results enabled rational selection of the anti-EGFL7 dose currently being tested in phase II clinical trials. 23317161 Computational peptidology: a new and promising approach to therapeutic Peptide design. The recent focus on protein-protein interaction networks has increasingly been shifted towards the disruption of protein complexes, which either are mediated by the binding of a globular domain in one protein to a short peptide stretch in another, or involve flat, large, and hydrophobic interfaces that classical small-molecule agents are not always ideally suited. Rational design of therapeutic peptides with high affinity targeting such interactions has emerged as a new and promising tool in discovery of potential drug candidates against associated diseases. The design is commonly based on bioinformatics methods or molecular modeling techniques, indirectly exploiting structure-activity relationship at the level of peptide sequence or directly deriving lead entities from protein complex architecture. Here, a newly rising subfield called computational peptidology that focuses on the use of computational and theoretical approaches to treat peptiderelated problems is comprehensively reviewed on the design and discovery of peptide agents targeting protein-protein interactions. We address a systematic discussion on several representative cases in which the computational peptidology is successfully employed to develop peptide therapeutics. Besides, some problems and pitfalls accompanied with the current use of computational methods in peptide modeling and design are also present. 23200319 Therapeutic alliance in schizophrenia: The role of recovery orientation, self-stigma, and insight. The present study examined variables related to the quality of the therapeutic alliance in out-patients with schizophrenia. We expected recovery orientation and insight to be positively, and self-stigma to be negatively associated with a good therapeutic alliance. We expected these associations to be independent from age, clinical symptoms (i.e. positive and negative symptoms, depression), and more general aspects of relationship building like avoidant attachment style and the duration of treatment by the current therapist. The study included 156 participants with DSM-IV diagnoses of schizophrenia or schizoaffective disorder in the maintenance phase of treatment. Therapeutic alliance, recovery orientation, self-stigma, insight, adult attachment style, and depression were assessed by self-report. Symptoms were rated by interviewers. Hierarchical multiple regressions revealed that more recovery orientation, less self-stigma, and more insight independently were associated with a better quality of the therapeutic alliance. Clinical symptoms, adult attachment style, age, and the duration of treatment by current therapist were unrelated to the quality of the therapeutic alliance. Low recovery orientation and increased self-stigma might undermine the therapeutic alliance in schizophrenia beyond the detrimental effect of poor insight. Therefore in clinical settings, besides enhancing insight, recovery orientation, and self-stigma should be addressed. 23906088 An assessment of point-of-care measurement of INR using the Coaguchek(®) XS Plus system in the setting of acute ischaemic stroke. Thrombolysis with alteplase (rt-PA) is accepted hyperacute therapy for acute ischaemic stroke. Clotting must be normal before this can be administered safely. Laboratory testing of INR takes 30 - 60 minutes which can significantly delay administration of rt-PA. Previous studies have suggested point-of-care testing is useful in patients presenting with stroke and improve door to needle time. We performed a prospective study of point-of-care testing in patients presenting with acute stroke. 50 patients were entered into the study to compare point-of-care testing using the CoaguChek(®) XS system with laboratory testing of INR. Point of care testing correlated well with laboratory levels (R=0.93, P < 0.0001). Only 2 patients had a high INR reading (>1.6). The standard deviation of difference between the two was 0.115. Overall point-of -care testing tended to underestimate INR slightly, meaning that an INR value of 1.1 or less was required to be 95% certain that the laboratory value was 1.3 or below. Simultaneous testing using blood from a syringe was more consistent with laboratory results than testing capillary blood via finger-prick. Point of care INR testing correlates well with laboratory values. The results in this study mostly relate to levels in the normal range. We suggest that it can be appropriately used to shorten door-to-needle time. 23890346 Advancing maternal survival in the global context: are our strategies working? There have been significant gains in improving maternal mortality over the last two decades. Researchers have suggested a variety of interventions and mechanisms to explain these improvements. While it is likely that much of what has been done in research and programs has contributed to this decline, the evidence regarding what works in the settings in which women deliver continues to face many challenges. We review the evidence for these improvements and suggest that there remain areas to focus on, particularly the births which currently take place in an unsupervised or substandard environments. We highlight the main areas where more evidence is needed, and end with a call to determine which of our interventions seem to have the most benefit; which do not; and where to invest future resources. 23884285 Flap Selection and Functional Outcomes in Total Glossectomy with Laryngeal Preservation. ObjectiveReconstruction of total glossectomy defects has been revolutionized by the popularity of free flap use in the head and neck. Challenging defects can be addressed with a variety of different free and pedicled flaps. The purpose of this study is to review our method of flap selection in cases of total glossectomy defects with laryngeal preservation, with an emphasis on the variations of these defects and patient body habitus.Study DesignCase series with chart review.SettingTertiary care referral center.Subjects and MethodsAll patients undergoing total glossectomy with laryngeal preservation (TGLP) by the senior author (YD) from September 1997 to May 2012. Objective data regarding patient demographics, existing defect, method of reconstruction, adjuvant treatment, operative details, outcomes, and complications were recorded. Both means and frequency of prolonged tracheostomy or gastrostomy tube were used to assess outcomes.ResultsOne hundred and three patients were identified. Ninety-four met inclusion criteria. All patients were T3 or T4 stage tumors. Mean follow-up was 3.4 years. Fifty-nine patients (62%) underwent free flap reconstruction while the remaining 35 (37%) were treated with a pedicled pectoralis myocutaneous flap. Tracheostomy decannulation and gastrostomy tube removal rates were 84% and 29%, respectively. No patients were converted to total laryngectomy.ConclusionOptimal reconstruction of TGLP defects may be accomplished with either pedicled or free-tissue flap reconstruction. Selecting an ideal flap for reconstruction of total glossectomy defects should be patient specific and based on matching donor flap bulk. This treatment approach demonstrates high tracheostomy and gastric tube independence. 23465178 Impact of the European Randomized Study of Screening for Prostate Cancer (ERSPC) on prostate-specific antigen (PSA) testing by Dutch general practitioners. To determine the impact of the European Randomized Study of Screening for Prostate Cancer (ERSPC) publication in 2009 on prostate-specific antigen (PSA) level testing by Dutch general practitioners (GPs) in men aged ≥40 years. Retrospective study with a Dutch insurance company database (containing PSA test claims) and a large district hospital-laboratory database (containing PSA-test results). The difference in primary PSA-testing rate as well as follow-up testing before and after the ERSPC was tested using the chi-square test with statistical significance at P < 0.05. Decline in PSA tests 4 months after ERSPC publication, especially for men aged ≥60 years. Primary testing as well as follow-up testing decreased, both for PSA levels of <4 ng/mL as well as for PSA levels of 4-10 ng/mL. Follow-up testing after a PSA level result of >10 ng/mL moderately increased (P = 0.171). Referral to a urologist after a PSA level result of >4 ng/mL decreased slightly after the ERSPC publication (P = 0.044). After the ERSPC publication primary PSA testing as well as follow-up testing decreased. Follow-up testing seemed not to be adequate after an abnormal PSA result. The reasons for this remain unclear. 23319288 Strategic applications of gene expression: from drug discovery/development to bedside. Gene expression is useful for identifying the molecular signature of a disease and for correlating a pharmacodynamic marker with the dose-dependent cellular responses to exposure of a drug. Gene expression offers utility to guide drug discovery by illustrating engagement of the desired cellular pathways/networks, as well as avoidance of acting on the toxicological pathways. Successful employment of gene-expression signatures in the later stages of drug development depends on their linkage to clinically meaningful phenotypic characteristics and requires a biologically meaningful mechanism combined with a stringent statistical rigor. Much of the success in clinical drug development is hinged on predefining the signature genes for their fitness for purposes of application. Specific examples are highlighted to illustrate the breadth and depth of the potential utility of gene-expression signatures in drug discovery and clinical development to targeted therapeutics at the bedside. 23804527 First principle and ReaxFF molecular dynamics investigations of formaldehyde dissociation on Fe(100) surface. Detailed formaldehyde adsorption and dissociation reactions on Fe(100) surface were studied using first principle calculations and molecular dynamics (MD) simulations, and results were compared with available experimental data. The study includes formaldehyde, formyl radical (HCO), and CO adsorption and dissociation energy calculations on the surface, adsorbate vibrational frequency calculations, density of states analysis of clean and adsorbed surfaces, complete potential energy diagram construction from formaldehyde to atomic carbon (C), hydrogen (H), and oxygen (O), simulation of formaldehyde adsorption and dissociation reaction on the surface using reactive force field, ReaxFF MD, and reaction rate calculations of adsorbates using transition state theory (TST). Formaldehyde and HCO were adsorbed most strongly at the hollow (fourfold) site. Adsorption energies ranged from -22.9 to -33.9 kcal/mol for formaldehyde, and from -44.3 to -66.3 kcal/mol for HCO, depending on adsorption sites and molecular direction. The dissociation energies were investigated for the dissociation paths: formaldehyde → HCO + H, HCO → H + CO, and CO → C + O, and the calculated energies were 11.0, 4.1, and 26.3 kcal/mol, respectively. ReaxFF MD simulation results were compared with experimental surface analysis using high resolution electron energy loss spectrometry (HREELS) and TST based reaction rates. ReaxFF simulation showed less reactivity than HREELS observation at 310 and 523 K. ReaxFF simulation showed more reactivity than the TST based rate for formaldehyde dissociation and less reactivity than TST based rate for HCO dissociation at 523 K. TST-based rates are consistent with HREELS observation. © 2013 Wiley Periodicals, Inc. 23947775 Symptoms, signs and nerve conduction velocities in patients with suspected carpal tunnel syndrome. To inform the clinical management of patients with suspected carpal tunnel syndrome (CTS) and case definition for CTS in epidemiological research, we explored the relation of symptoms and signs to sensory nerve conduction (SNC) measurements. Patients aged 20--64 years who were referred to a neurophysiology service for investigation of suspected CTS, completed a symptom questionnaire (including hand diagrams) and physical examination (including Tinel's and Phalen's tests). Differences in SNC velocity between the little and index finger were compared according to the anatomical distribution of symptoms in the hand and findings on physical examination. Analysis was based on 1806 hands in 908 patients (response rate 73%). In hands with numbness or tingling but negative on both Tinel's and Phalen's tests, the mean difference in SNC velocities was no higher than in hands with no numbness or tingling. The largest differences in SNC velocities occurred in hands with extensive numbness or tingling in the median nerve sensory distribution and both Tinel's and Phalen's tests positive (mean 13.8, 95% confidence interval (CI) 12.6-15.0 m/s). Hand pain and thumb weakness were unrelated to SNC velocity CONCLUSIONS: Our findings suggest that in the absence of other objective evidence of median nerve dysfunction, there is little value in referring patients of working age with suspected CTS for nerve conduction studies if they are negative on both Tinel's and Phalen's tests. Alternative case definitions for CTS in epidemiological research are proposed according to the extent of diagnostic information available and the relative importance of sensitivity and specificity. 22940466 Silver nanoparticles induce toxicity in A549 cells via ROS-dependent and ROS-independent pathways. Silver nanoparticles (AgNPs) are incorporated into a large number of consumer and medical products. Several experiments have demonstrated that AgNPs can be toxic to the vital organs of humans and especially to the lung. The present study evaluated the in vitro mechanisms of AgNP (<100 nm) toxicity in relationship to the generation of reactive oxygen species (ROS) in A549 cells. AgNPs caused ROS formation in the cells, a reduction in their cell viability and mitochondrial membrane potential (MMP), an increase in the proportion of cells in the sub-G1 (apoptosis) population, S phase arrest and down-regulation of the cell cycle associated proliferating cell nuclear antigen (PCNA) protein, in a concentration- and time-dependent manner. Pretreatment of the A549 cells with N-acetyl-cysteine (NAC), an antioxidant, decreased the effects of AgNPs on the reduced cell viability, change in the MMP and proportion of cells in the sub-G1population, but had no effect on the AgNP-mediated S phase arrest or down-regulation of PCNA. These observations allow us to propose that the in vitro toxic effects of AgNPs on A549 cells are mediated via both ROS-dependent (cytotoxicity) and ROS-independent (cell cycle arrest) pathways. 23822206 Milk protein for improved metabolic health: a review of the evidence. Epidemiological evidence shows that consumption of dairy products is associated with decreased prevalence of metabolic related disorders, whilst evidence from experimental studies points towards dairy protein as a dietary component which may aid prevention of type 2 diabetes (T2DM). Poor metabolic health is a common characteristic of overweight, obesity and aging, and is the forerunner of T2DM and cardiovascular disease (CVD), and an ever increasing global health issue. Progressive loss of metabolic control is evident from a blunting of carbohydrate, fat and protein metabolism, which is commonly manifested through decreased insulin sensitivity, inadequate glucose and lipid control, accompanied by a pro-inflammatory environment and hypertension. Adverse physiological changes such as excess visceral adipose tissue deposition and expansion, lipid overspill and infiltration into liver, muscle and other organs, and sarcopaenia or degenerative loss of skeletal muscle mass and function all underpin this adverse profile. 'Sarcobesity' and sarcopaenic diabetes are rapidly growing health issues. As well as through direct mechanisms, dairy protein may indirectly improve metabolic health by aiding loss of body weight and fat mass through enhanced satiety, whilst promoting skeletal muscle growth and function through anabolic effects of dairy protein-derived branch chain amino acids (BCAAs). BCAAs enhance muscle protein synthesis, lean body mass and skeletal muscle metabolic function. The composition and processing of dairy protein has an impact on digestion, absorption, BCAA kinetics and function, hence the optimisation of dairy protein composition through selection and combination of specific protein components in milk may provide a way to maximize benefits for metabolic health. 23937961 Left ventricular systolic function in HER2/neu negative breast cancer patients treated with anthracycline chemotherapy: A comparative analysis of left ventricular ejection fraction and myocardial strain imaging over 12 months. Anthracycline agents are undermined by their cardiotoxicity. As life expectancy following treatment is greatly improved, techniques that ensure early detection and timely management of cardiotoxicity are essential. The aim of the present study was to evaluate left ventricular (LV) systolic function with LV ejection fraction (LVEF) and two-dimensional myocardial strain up to 12months after anthracycline chemotherapy, specifically in HER2/neu negative breast cancer patients. Seventy-eight consecutive anthracycline naïve breast cancer patients were studied before and immediately after anthracycline chemotherapy. Fifty HER2/neu negative patients were studied over 12months with serial echocardiograms at four time points. All patients were treated with standard regimens containing anthracyclines. Global systolic strain was significantly reduced immediately after, and 6months after anthracyclines (-19.0±2.3% to -17.5±2.3% (P<0.001) and -18.2±2.2% (P=0.01) respectively). A non-uniform reduction in strain was observed each time with relative sparing of the LV apex. LVEF remained largely unchanged at both time points. Global strain normalised by 12months in the majority of patients. Persistently reduced strain was observed in 16% (n=8); these patients had a greater reduction in strain at 6months (⩽-17.2%), and had received higher cumulative anthracycline doses. Myocardial strain imaging is more sensitive than LVEF for the early detection and intermediate term monitoring of LV systolic function following anthracycline chemotherapy in HER2/neu negative breast cancer patients, and may aid in the development of improved monitoring protocols. 23592770 Survival Outcomes of Breast Cancer Patients Who Receive Neoadjuvant Chemotherapy: Association with Dynamic Contrast-enhanced MR Imaging with Computer-aided Evaluation. Purpose: To retrospectively evaluate whether dynamic contrast agent-enhanced (DCE) magnetic resonance (MR) imaging parameters assessed by a computer-aided evaluation program are associated with recurrence-free and overall survival in breast cancer patients who received neoadjuvant chemotherapy (NAC). Materials and Methods: This study was institutional review board approved and informed consent was waived. Between January 2007 and December 2009, 187 consecutive women (mean age, 46.6 years; range, 24-78 years) who had undergone NAC, DCE MR imaging before and after NAC, and surgery for invasive breast cancers (mean size, 5.0 cm; range, 2.0-14.8 cm on surgical histologic analysis) were identified. The tumor size, volume, and kinetic parameters (persistent, plateau, or washout components) were measured with a computer-aided evaluation program on DCE MR images before and after NAC, and their percentage changes were calculated. The Cox proportional hazards model was used to determine the association between DCE MR imaging parameters and recurrence-free survival and overall survival after controlling for clinical-pathologic variables. Results: There were 50 events, including 38 recurrences (29 distant, six local, and three both) and 12 deaths, at a mean follow-up of 47.4 months. At multivariate analysis, a smaller reduction in tumor volume (recurrence-free survival hazard ratio, 5.75; 95% confidence interval: 1.14, 8.64; and overall survival hazard ratio, 2.12; 95% confidence interval: 1.08, 5.69) and a smaller reduction in washout component (recurrence-free survival hazard ratio, 1.15; 95% CI: 1.06, 1.55; and overall survival hazard ratio, 1.26; 95% confidence interval: 1.03, 1.52) after NAC were independent significant variables for worse recurrence-free survival and overall survival. Conclusion: Smaller reduction in tumor volume and a smaller reduction in washout component on DCE MR images assessed with computer-aided evaluation after NAC were independent parameters of worse recurrence-free survival and overall survival in breast cancer patients who received NAC. © RSNA, 2013. 23419036 Charge screening between anionic and cationic surfactants in ionic liquids. The aggregation and interfacial behavior of mixtures of anionic (sodium dodecylsulfate, SDS) and cationic (dodecylammonium bromide, DTAB) surfactants were investigated. A room-temperature ionic liquid (IL) was explored as a solvent for the SDS/DTAB system and compared to water. The critical micelle concentration (cmc) and composition in mixed micelles were determined for both solvents. Our experiments showed nearly ideal mixing of SDS/DTAB over the entire composition range and suggest that charge screening is prominent in ILs. This behavior is in sharp contrast to the strong electrostatic attraction and a multiphase composition gap in water. Two models by Clint and Rubingh, which describe ideal and nonideal micellar behavior, respectively, are discussed on the basis of our results. According to Rubingh's model, the composition of mixed micelles is gradually changing with the bulk composition in ILs but tends to be a 1:1 ratio in water. The results here are further support of the strong charge screening in ionic liquids. 23640658 Drug-induced thrombosis: an update. Drugs may play an important role in development of thrombosis, and in recent years there has been increased attention to the importance of this issue. Although drug-induced thrombosis usually causes venous thrombotic events, arterial events are also noted due to drug administration. Here we review the different mechanisms through which drugs can exert thrombosis. Drugs can cause direct endothelial damage and expose the underlying subendothelium thus leading to platelet adherence and subsequent thrombus formation. Such an effect is seen by contrast media and chemotherapeutic cytotoxic drugs. Drugs may also attenuate the secretion of pro- and anticoagulation mediators by the endothelial cells and may have prothrombotic effects on platelets by increasing adhesion and aggregation, as for example seen after heparin administration in an immune-mediated mechanism. Red and white cells can also be affected by drugs, by increasing their aggregation or adhesion to the endothelial wall. Some drugs, such as oral contraceptive pills, may promote thrombosis by altering the balance between the different coagulation factors, and many drugs can lead to decreased blood flow by increasing blood viscosity, as seen for example after intravenous immunoglobulin administration. Better understanding of the mechanisms through which drugs exert thrombosis may facilitate their safe use in patients. Additionally, awareness of the drugs that are known to induce thrombosis is important in order to stop their administration in case of a thrombotic event. This review further emphasizes the fact that drug administration is a risk factor that should always be considered together with additional known thromboembolic risk factors such as genetic predisposition or cancer. 23456813 The hazardous effects of the three natural food dyes on developmental stages and longevity of Drosophila melanogaster. Nowadays, food dyes obtained from herbal, animal, microbial and mineral sources are widely used as food additives. In this study, the toxic effects of three different natural food dyes (carmine, turmeric and annatto) on 72 ± 4 h larvae of Oregon-R wild type of Drosophila melanogaster were investigated. For this purpose, four different application doses (50, 75, 100, 125 mg mL(-1)) were chosen by means of preliminary studies. It was determined that larval mortality increased with increasing concentration in the application groups and the toxicity order was carmine > turmeric > annatto. It was observed that the survival rate was highest in the control with 98% and lowest in 125 mg mL(-1) carmine with 16%. In addition, the average lifespan of the adult individuals obtained from third instar larvae was also studied. While the average lifespan was 40.88 ± 1.44 days in the control group, these values were 10.81 ± 0.55-23.90 ± 1.27 days in the carmine group, 15.00 ± 0.80-22.42 ± 1.43 days in the turmeric group and 10.33 ± 1.03-35.68 ± 1.54 days in the annatto group, respectively. According to the obtained results, when both the developmental period from larvae into adults and the lifespan of the developing adults were compared with the control group, the food dyes were found to be toxic and the toxicity order of carmine > turmeric > annatto was identified. 23542640 Identification of 3 Distinct HIV-1 Founding Strains Responsible for Expanding Epidemic Among Men Who Have Sex With Men in 9 Chinese Cities. To investigate the epidemiological relationships between HIV-1 strains that are spread among the men who have sex with men (MSM) populations of 9 cities across China and to analyze the origins and divergence times of the major epidemic strains found in the MSM population. A total of 583 HIV-1-positive subjects were recruited from high-risk MSM populations in 9 cities across China between 2009 and 2011. Nucleotide sequences of 1.0-kb pro-RT regions were amplified and sequenced. Phylogenetic and Bayesian molecular clock analyses were performed. The overall distribution of HIV-1 genotypes was as follows: CRF01_AE, 62.1%; CRF07_BC, 18.2%; subtype B (United States-European), 15.9%; subtype B', 0.7%; other recombinants, 3.1%. In addition to the 2 distinct CRF01_AE clusters [cluster 1 (n = 157, 26.9%) and cluster 2 (n = 196, 33.6%)] previously reported by our group, we identified a novel CRF07_BC cluster (cluster 3) (n = 94, 16.1%) unique to China's MSM population whose strains were homologous and could be detected in all 9 cities. These 3 lineages of HIV-1 strains (clusters 1-3) accounted for 76.7% (447 of 583) of infections among MSM in China as a whole. Clusters 1, 2, and 3 were estimated to have been introduced into the MSM population in 1999, 2001, and 2001, respectively, indicating that the newly identified CRF07_BC cluster 3 is not a young lineage. However, it spread quickly in recent years. We identified 3 distinct HIV-1 lineages (clusters 1-3) responsible for the recent upsurge of the AIDS epidemic among MSM in China. These 3 HIV-1 variants are spread widely among MSM throughout China, demonstrating remarkable founding effects. 23883036 Following the relaxation dynamics of photoexcited aniline in the 273-266 nm region using time-resolved photoelectron imaging. Time-resolved photoelectron imaging was used to investigate the relaxation dynamics of electronically excited aniline in the gas-phase following ultraviolet irradiation in the 273-266 nm region. We find that at all wavelengths studied, excitation is predominantly to the long-lived (>1 ns) S1(ππ(∗)) state, which exhibits ultrafast intramolecular vibrational redistribution on a <1 ps timescale. At excitation wavelengths centred on resonant transitions in the aniline absorption spectrum that have previously been assigned to the higher lying S2(3s∕πσ(∗)) state, we also see clear evidence of this state playing a role in the dynamics. However, we see no indication of any non-adiabatic coupling between the S1(ππ(∗)) and S2(3s∕πσ(∗)) states over the range of excitation wavelengths studied. 23919807 Chlamydia trachomatis homotypic inclusion fusion is promoted by host microtubule trafficking. The developmental cycle of the obligate intracellular pathogen Chlamydia is dependant on the formation of a unique intracellular niche termed the chlamydial inclusion. The inclusion is a membrane bound vacuole derived from host cytoplasmic membrane and is modified significantly by the insertion of chlamydial proteins. A unique property of the inclusion is its propensity for homotypic fusion. The vast majority of cells infected with multiple chlamydial elementary bodies (EBs) contain only a single mature inclusion. The chlamydial protein IncA is required for fusion, however the host process involved are uncharacterized. Here, through live imaging studies, we determined that the nascent inclusions clustered tightly at the cell microtubule organizing center (MTOC) where they eventually fused to form a single inclusion. We established that factors involved in trafficking were required for efficient fusion as both disruption of the microtubule network and inhibition of microtubule trafficking reduced the efficiency of fusion. Additionally, fusion occurred at multiple sites in the cell and was delayed when the microtubule minus ends were either no longer anchored at a single MTOC or when a cell possessed multiple MTOCs. The data presented demonstrates that efficient homotypic fusion requires the inclusions to be in close proximity and that this proximity is dependent on chlamydial microtubule trafficking to the minus ends of microtubules. 23774968 A zinc-salophen/bile-acid conjugate receptor solubilized by CTABr micelles binds phosphate in water. Receptor 1, composed of two deoxycholic acid moieties appended to a Zn-salophen complex, was prepared, characterized and tested for anion binding by (1)H NMR and UV-vis spectroscopic techniques. While in polar DMSO, 1 is able to bind phosphate (K = ∼700 M(-1)), the addition of water severely diminishes the association. In a 1 : 9 water-DMSO mixture, the binding constant K is only ca. 20 M(-1). Notably, in an aqueous solution of CTABr micelles (CTABr 10 mM, cmc = ∼1 mM), the zinc-salophen conjugate 1, due to its two non-polar bile-acid moieties, becomes solubilized and, most importantly, it almost completely recovers its binding ability towards phosphate, displaying a remarkable affinity (K = ∼450 M(-1)) in water. 23828102 A New, Validated Wipe-Sampling Procedure Coupled to LC-MS Analysis for the Simultaneous Determination of 5-Fluorouracil, Doxorubicin and Cyclophosphamide in Surface Contamination. A wipe-sampling procedure followed by a simple liquid chromatography-mass spectrometry method was developed and validated for the simultaneous quantification of three cytotoxic drugs [5-fluorouracil (5FU), doxorubicin and cyclophosphamide (CP)] for the determination of surface contamination. After a solid-phase extraction procedure with wiping filter paper, the separation was performed within 30 min using a gradient mobile phase. The method was validated according to the recommendations of the US Food and Drug Administration. Wiping was performed using Whatman(®) filter paper on different surfaces such as stainless steel, polypropylene and glass. The method was linear, between 10 and 500 ng per wiping sample (i.e., 0.1-5 ng/cm(2)) for 5FU and doxorubicin, and between 1-100 ng per wiping sample (i.e., 0.01-1 ng/cm(2)) for CP. The lower limits of detection and quantification were 5 and 10 ng per wiping sample for 5FU and doxorubicin, and 0.5 and 1 ng per wiping sample for CP. This new sensitive methodology for surface contamination studies was successfully applied on commercial vials and different places in a cancer research hospital. This approach is particularly suitable to assess the risk of occupational exposure to cytotoxic drugs and to optimize the cleaning process, especially for the most toxic molecule studied, CP. 23606650 A High-Throughput Screen of the GTPase Activity of Escherichia coli EngA to Find an Inhibitor of Bacterial Ribosome Biogenesis. The synthesis of ribosomes is an essential process, which is aided by a variety of trans-acting factors in bacteria. Among these is a group of GTPases essential for bacterial viability and emerging as promising targets for new antibacterial agents. Herein, we describe a robust high-throughput screening process for inhibitors of one such GTPase, the Escherichia coli EngA protein. The primary screen employed an assay of phosphate production in a 384-well density. Reaction conditions were chosen to maximize sensitivity for the discovery of competitive inhibitors while maintaining a strong signal amplitude and low noise. In a pilot screen of 31,800 chemical compounds, 44 active compounds were identified. Furthermore, we describe the elimination of nonspecific inhibitors that were detergent sensitive or reactive as well as those that interfered with the high-throughput phosphate assay. Four inhibitors survived these common counterscreens for nonspecificity, but these chemicals were also inhibitors of the unrelated enzyme dihydrofolate reductase, suggesting that they too were promiscuously active. The high-throughput screen of the EngA protein described here provides a meticulous pilot study in the search for specific inhibitors of GTPases involved in ribosome biogenesis. 23794628 Intra-Amniotic IL-1β Induces Fetal Inflammation in Rhesus Monkeys and Alters the Regulatory T Cell/IL-17 Balance. Very low birth weight preterm newborns are susceptible to the development of debilitating inflammatory diseases, many of which are associated with chorioamnionitis. To define the effects of chorioamnionitis on the fetal immune system, IL-1β was administered intra-amniotically at ∼80% gestation in rhesus monkeys. IL-1β caused histological chorioamnionitis, as well as lung inflammation (infiltration of neutrophils or monocytes in the fetal airways). There were large increases in multiple proinflammatory cytokine mRNAs in the lungs at 24 h postadministration, which remained elevated relative to controls at 72 h. Intra-amniotic IL-1β also induced the sustained expression of the surfactant proteins in the lungs. Importantly, IL-1β significantly altered the balance between inflammatory and regulatory T cells. Twenty-four hours after IL-1β injection, the frequency of CD3(+)CD4(+)FOXP3(+) T cells was decreased in lymphoid organs. In contrast, IL-17A-producing cells (CD3(+)CD4(+), CD3(+)CD4(-), and CD3(-)CD4(-) subsets) were increased in lymphoid organs. The frequency of IFN-γ-expressing cells did not change. In this model of a single exposure to an inflammatory trigger, CD3(+)CD4(+)FOXP3(+) cells rebounded quickly, and their frequency was increased at 72 h compared with controls. IL-17 expression was also transient. Interestingly, the T cell profile alteration was confined to the lymphoid organs and not to circulating fetal T cells. Together, these results suggest that the chorioamnionitis-induced IL-1/IL-17 axis is involved in the severe inflammation that can develop in preterm newborns. Boosting regulatory T cells and/or controlling IL-17 may provide a means to ameliorate these abnormalities. 23948616 Community-acquired pneumonia team decreases length of stay in hospitalized, low-risk patients with pneumonia. Background: Team-focused intervention to improve the care of low-risk patients with community-acquired pneumonia (CAP) is a matter of controversy. Our aim was to determine if a community-acquired pneumonia team (CAPT) would shorten hospital length of stay (LOS) and improve health care utilization in low-risk patients with CAP compared with management by a general pulmonary team (GPT). Methods: We performed a prospective cohort study of hospitalized, low-risk patients with CAP (Pneumonia Severity Index [PSI] score class I or II) at a single tertiary hospital from June 2007 to June 2008. Study patients were stratified to management by the CAPT treating group (n = 35), following the Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) CAP guideline recommendations, or to management by the GPT (n = 30) following the standard of care. Primary outcome measure for comparison of the efficacy of the 2 different team-focused interventions was hospital LOS for patients with CAP. Secondary study outcome measures included patient 30- and 90-day all-cause readmission rate, rate of mortality at 30 and 90 days, antibiotic-treatment duration, time to switch patient from intravenous (IV) to oral antibiotic treatment, and time to achieve clinical stability for patients. Results: Hospitalized, low-risk patients with CAP, who were assisted by a CAPT were more likely to have a shorter hospital stay (9 days less; P < 0.001), shorter time to switch from IV to oral antibiotic therapy (8 days less; P <0.001), and total shorter duration of antibiotic treatment (6 days less; P <0.001), when compared with low-risk patients with CAP who were assisted by a GPT. In addition, for both groups of assisted patients, there were no differences in the time to achieve clinical stability, use of guideline-concordant antibiotic therapy, rate of mortality, or rate of readmissions at 30 and 90 days. Conclusions: Management by a dedicated CAPT reduced patient hospital LOS, time to switch from IV to oral antibiotic therapy, and duration of antibiotic treatment, without causing adverse events, compared with standard of care, in low-risk patients with CAP. 23842504 Evaluation of standardized doctor's orders as an educational tool for undergraduate medical students: a prospective cohort study. Standardized doctor's orders are replacing traditional order writing in teaching hospitals. The impact of this shift in practice on medical education is unknown. It is possible that preprinted orders interfere with knowledge acquisition and retention by not requiring active decision-making. The objective of the study was to evaluate the impact of standardized admission orders on disease-specific knowledge among undergraduate medical trainees. This prospective cohort study enrolled Year 3 (n = 121) and Year 4 (n = 54) medical students at two academic hospitals in Toronto (Ontario, Canada) during their general internal medicine rotation. We used standardized orders for patient admissions for alcohol withdrawal (AW) and for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) as the intervention and manual order writing as the control. Educational outcomes were assessed through end-of-rotation questionnaires assessing disease-specific knowledge of AW and AECOPD. Of 175 students, 105 had exposure to patients with alcohol withdrawal during their rotation, and 68 students wrote admission orders. Among these 68 students, 48 used standardized orders (intervention, n = 48) and 20 used manual order writing (control, n = 20). Only 3 students used standardized orders for AECOPD, precluding analysis. There was no significant difference found in mean total score of questionnaires between those who used AW standardized orders and those who did not (11.8 vs. 11.0, p = 0.4). Students who had direct clinical experience had significantly higher mean total scores (11.6 vs. 9.0, p < 0.0001 for AW; 13.8 vs. 12.6, p = 0.02 for AECOPD) compared to students who did not. When corrected for overall knowledge, this difference only persisted for AW. No significant differences were found in total scores between students who used standardized admission orders and traditional manual order writing. Clinical exposure was associated with increase in disease-specific knowledge. 23532932 Bioimaging real-time PXR-dependent mdr1a gene regulation in mdr1a.fLUC reporter mice. The MDR1 gene encodes P-glycoprotein, a transmembrane drug efflux transporter that confers multidrug resistance in cancer cells and affects drug pharmacokinetics by virtue of its expression in the liver, kidney, and colon. Nuclear receptors SXR and CAR are possible master regulators of xenobiotic-inducible MDR1 expression in drug processing organs, but the mechanism of MDR1 regulation has yet to be directly demonstrated in vivo. Moreover, it has previously been impossible to determine the sustained or cumulative effect of repeated doses of xenobiotics on in vivo MDR1 expression. We previously reported a mouse model containing firefly luciferase (fLUC) knocked into the mdr1a genomic locus, allowing non-invasive bioimaging of intestinal mdr1a gene expression in live animals. In the current study, we crossed mdr1a.fLUC mice into the pxr knockout (pxr(-/-)) genetic background and injected mice with pregnenolone-16α-carbonitrile (PCN), a strong PXR ligand, and two therapeutically relevant taxanes, paclitaxel and docetaxel. All three agents induced mdr1a.fLUC expression (bioluminescence), but only PCN and docetaxel appeared to act primarily via PXR. Luminescence returned to baseline by 24-48 hrs after drug injection and was re-inducible over two additional rounds of drug dosing in pxr(+/+) mice. TCPOBOP, a CAR ligand, modestly induced mdr1a.fLUC in pxr(+/+) and pxr(-/-) strains, consistent with CAR's minor role in mdr1a regulation. Collectively, these results demonstrate that the mdr1a.fLUC bioimaging model can capture changes in mdr1 gene expression under conditions of repeated xenobiotic treatment in vivo and that it can be used to probe the mechanism of gene regulation in response to different xenobiotic agents. 23772881 In vitro efficacy of the essential oil from Leptospermum scoparium (manuka) on antimicrobial susceptibility and biofilm formation in Staphylococcus pseudintermedius isolates from dogs. Staphylococcus pseudintermedius is a common pathogen of skin and ear infections in dogs. The widespread and rapid emergence of meticillin-resistant S. pseudintermedius (MRSP) has created therapeutic challenges in veterinary medicine and the need for alternative treatments. We aimed to evaluate the in vitro antimicrobial activity of the essential oil manuka (Leptospermum scoparium) against S. pseudintermedius. This study was performed using S. pseudintermedius strains isolated from dogs with skin and ear infections collected throughout Korea between 2009 and 2011. The in vitro antimicrobial activity of manuka oil against 39 MRSP and 11 meticillin-susceptible S. pseudintermedius (MSSP) strains was analysed by measuring minimal inhibitory concentrations (MICs) using the agar dilution method and biofilm inhibition activity as assessed by the colorimetric microtitre plate assay. Our results indicated that manuka oil had excellent activity against all bacterial isolates. The MICs for MRSP and MSSP to manuka oil were in the range of 2(-9) to 2(-6) and 2(-9) to 2(-7) % (v/v), respectively. Manuka oil was a potent inhibitor of S. pseudintermedius biofilm formation, and the majority of bacteria decreased by >50%. No significant differences were observed in the MICs or biofilm formation between the MRSP and MSSP strains. These results suggest that manuka oil has the potential to be a useful therapeutic option for treating superficial infections caused by MRSP and MSSP; further clinical investigations are required. 23875683 Cloud-based uniform ChIP-Seq processing tools for modENCODE and ENCODE. Funded by the National Institutes of Health (NIH), the aim of the Model Organism ENCyclopedia of DNA Elements (modENCODE) project is to provide the biological research community with a comprehensive encyclopedia of functional genomic elements for both model organisms C. elegans (worm) and D. melanogaster (fly). With a total size of just under 10 terabytes of data collected and released to the public, one of the challenges faced by researchers is to extract biologically meaningful knowledge from this large data set. While the basic quality control, pre-processing, and analysis of the data has already been performed by members of the modENCODE consortium, many researchers will wish to reinterpret the data set using modifications and enhancements of the original protocols, or combine modENCODE data with other data sets. Unfortunately this can be a time consuming and logistically challenging proposition. In recognition of this challenge, the modENCODE DCC has released uniform computing resources for analyzing modENCODE data on Galaxy (https://github.com/modENCODE-DCC/Galaxy), on the public Amazon Cloud (http://aws.amazon.com), and on the private Bionimbus Cloud for genomic research (http://www.bionimbus.org). In particular, we have released Galaxy workflows for interpreting ChIP-seq data which use the same quality control (QC) and peak calling standards adopted by the modENCODE and ENCODE communities. For convenience of use, we have created Amazon and Bionimbus Cloud machine images containing Galaxy along with all the modENCODE data, software and other dependencies. Using these resources provides a framework for running consistent and reproducible analyses on modENCODE data, ultimately allowing researchers to use more of their time using modENCODE data, and less time moving it around. 23411276 Vitexin-2-O-xyloside, raphasatin and (-)-epigallocatechin-3-gallate synergistically affect cell growth and apoptosis of colon cancer cells. Cytotoxic effects of the combination of the food components vitexin-2-O-xyloside (X), raphasatin (4-methylsulphanyl-3-butenyl isothiocyanates; G) and (-)-epigallocatechin-3-gallate (E) were investigated in colon (LoVo and CaCo-2) and breast (MDA-MB-231 and MCF-7) cancer cells. Breast cancer cells were more resistant than colon cells to X, G and E inhibition. On the contrary, marked synergistic effects among X, G and E on cell growth were found in both colon cancer cells. Further analysis revealed a G0/G1 arrest of the phase cell progression and apoptosis, linked to modulation of Bax, Bcl2, caspase-9 and poly(ADP-ribose) polymerase as well as Reactive Oxygen Species (ROS) generation in both colon cancer cells, whereas apoptosis and ROS were not significantly detected in normal human lymphocytes. We conclude that the X, G and E mixture might act by mitochondrial pathway activation of apoptosis, possibly elicited by ROS and the mixture may be effective in the chemoprevention of colon cancer. 23945748 Contrasting modulation of enzyme activity exhibited by graphene oxide and reduced graphene. Here we demonstrate that GO and RGO exhibit contrasting effects on modulation of the peroxidase activity of cyt c. GO could dramatically improve the enzyme activity of cyt c, while RGO showed a strong inhibition effect on cyt c. 23722550 Radioresistant Cancer Cells Can Be Conditioned to Enter Senescence by mTOR Inhibition. Autophagy is frequently activated in radioresistant cancer cells where it provides a cell survival strategy. The mTOR inhibitor rapamycin activates autophagy but paradoxically it also enhances radiosensitivity. In this study, we investigated the mechanisms of these opposing actions in radiation-resistant glioma or parotid carcinoma cells. Radiation treatment transiently enhanced autophagic flux for a period of 72 hours in these cells and treatment with rapamycin or the mTOR inhibitor PP242 potentiated this effect. However, these treatments also increased heterochromatin formation, irreversible growth arrest, and premature senescence, as defined by expression of senescence-associated β-galactosidase activity. This augmentation in radiosensitivity seemed to result from a restoration in the activity of the tumor suppressor RB and a suppression of RB-mediated E2F target genes. In tumor xenografts, we showed that administering rapamycin delayed tumor regrowth after irradiation and increased senescence-associated β-galactosidase staining in the tumor. Our findings suggest that a potent and persistent activation of autophagy by mTOR inhibitors, even in cancer cells where autophagy is occurring, can trigger premature senescence as a method to restore radiosensitivity. Cancer Res; 73(14); 4267-77. ©2013 AACR. 23897392 Real time detection of cell cycle regulator cyclin A on living tumor cells with europium emission. Six water-soluble europium complexes (Eu-- and Eu--, n = 1, 2 and 3) with one antenna chromophore, two different linkers ( and ) and three proposed cyclin A specific peptides (: -GAKRRLIF-NH2; : -GGAKRRLIF-NH2; : -Hex- GAKRRLIF-NH2) have been synthesized. With structural information available, comparisons of the cyclin grooves of cyclin A and the six europium complexes have been made, and insights have been gained into the determinants for peptide binding and the foundation of differential binding. Experiment-wise, the linear and two-photon induced photophysical properties of these conjugates were monitored in aqueous solution. Numerous in situ/in vitro biological assays have been carried out, such as responsive emission changes in situ/in vitro, Western blot and cellular uptake. As imaging agents, complexes with peptides : -Hex-GAKRRLIF-NH2 showed high selectivity to cyclin A in numerous cancer cells. When it comes to responsive optical signal changes, complex Eu-- exhibited a threefold emission enhancement upon binding with cyclin A (100 nM cyclin A, ϕ = 8% to 21%, log KB = 5.83, detection limit = 5 nM), and this could be initiated by the shortened distance between the antenna and the lanthanide after they bind/get into cyclin A. It is promising that our compounds (especially compound Eu--) could serve as the template for structure-guided efforts to develop potential imaging therapeutics on the basis of selective imaging of CDK2/cyclin A activity. 23917170 Potential of phytase-mediated iron release from cereal-based foods: a quantitative view. The major part of iron present in plant foods such as cereals is largely unavailable for direct absorption in humans due to complexation with the negatively charged phosphate groups of phytate (myo-inositol (1,2,3,4,5,6)-hexakisphosphate). Human biology has not evolved an efficient mechanism to naturally release iron from iron phytate complexes. This narrative review will evaluate the quantitative significance of phytase-catalysed iron release from cereal foods. In vivo studies have shown how addition of microbially derived phytases to cereal-based foods has produced increased iron absorption via enzyme-catalysed dephosphorylation of phytate, indicating the potential of this strategy for preventing and treating iron deficiency anaemia. Despite the immense promise of this strategy and the prevalence of iron deficiency worldwide, the number of human studies elucidating the significance of phytase-mediated improvements in iron absorption and ultimately in iron status in particularly vulnerable groups is still low. A more detailed understanding of (1) the uptake mechanism for iron released from partially dephosphorylated phytate chelates, (2) the affinity of microbially derived phytases towards insoluble iron phytate complexes, and (3) the extent of phytate dephosphorylation required for iron release from inositol phosphates is warranted. Phytase-mediated iron release can improve iron absorption from plant foods. There is a need for development of innovative strategies to obtain better effects. 23954845 An overview of current and potential use of information and communication technologies for immunization promotion among adolescents. Information and communication technologies (ICT), such as the Internet or mobile telephony, have become an important part of the life of today's adolescents and their main means of procuring information. The new generation of the Internet based on social-networking technologies, Web 2.0, is increasingly used for health purposes by both laypeople and health professionals. A broad spectrum of Web 2.0 applications provides several opportunities for healthcare workers, in that they can reach large numbers of teenagers in an individualized way and promote vaccine-related knowledge in an interactive and entertaining manner. These applications, namely social-networking and video-sharing websites, wikis and microblogs, should be monitored in order to identify current attitudes toward vaccination, to reply to vaccination critics and to establish a real-time dialog with users. Moreover, the ubiquity of mobile telephony makes it a valuable means of involving teenagers in immunization promotion, especially in developing countries. 23734819 In vitro degradation of oxalate by recombinant Lactobacillus plantarum expressing heterologous oxalate decarboxylase. The aim of the present study is to constitutively express heterologous oxalate decarboxylase (OxdC) in Lactobacillus plantarum and to examine its ability to degrade oxalate in vitro for their future therapy against enteric hyperoxaluria. In this study, we generated a recombinant strain of Lb. plantarum to constitutively overexpress B. subtilis oxalate decarboxylase (oxdC) using a host lactate dehydrogenase promoter (PldhL ). The recombinant Lb. plantarum was able to degrade more than 90% oxalate compared to 15% by the wild type. In addition, the recombinant strain also had higher tolerance up to 500 mmol l(-1) oxalate. We developed a recombinant Lb. plantarum NC8 that constitutively expressed heterologous oxalate decarboxylase and degraded oxalate efficiently under in vitro conditions. The long-term aim is to develop an efficient strain for future therapy against oxalosis. 23842448 Amalgamating Oncolytic Viruses to Enhance Their Safety, Consolidate Their Killing Mechanisms, and Accelerate Their Spread. Oncolytic viruses are structurally and biologically diverse, spreading through tumors and killing them by various mechanisms and with different kinetics. Here, we created a hybrid vesicular stomatitis/measles virus (VSV/MV) that harnesses the safety of oncolytic MV, the speed of VSV, and the tumor killing mechanisms of both viruses. Oncolytic MV targets CD46 and kills by forcing infected cells to fuse with uninfected neighbors, but propagates slowly. VSV spreads rapidly, directly lysing tumor cells, but is neurotoxic and loses oncolytic potency when neuroattenuated by conventional approaches. The hybrid VSV/MV lacks neurotoxicity, replicates rapidly with VSV kinetics, and selectively targets CD46 on tumor cells. Its in vivo performance in a myeloma xenograft model was substantially superior to either MV or widely used recombinant oncolytic VSV-M51.Molecular Therapy (2013); doi:10.1038/mt.2013.164. 23964213 N-Methyl-d-Aspartate Receptor - Nitric Oxide Synthase Pathway in the Cortex of Nogo-A-Deficient Rats in Relation to Brain Laterality and Schizophrenia. It has been suggested that Nogo-A, a myelin-associated protein, could play a role in the pathogenesis of schizophrenia and that Nogo-A-deficient rodents could serve as an animal model for schizophrenic symptoms. Since changes in brain laterality are typical of schizophrenia, we investigated whether Nogo-A-deficient rats showed any signs of disturbed asymmetry in cortical N-methyl-d-aspartate (NMDA) receptor-nitric oxide synthase (NOS) pathway, which is reported as dysfunctional in schizophrenia. In particular, we measured separately in the right and left hemisphere of young and old Nogo-A-deficient male rats the expression of NMDA receptor subunits (NR1, NR2A, and NR2B in the frontal cortex) and activities of NOS isoforms [neuronal (nNOS), endothelial (eNOS), and inducible (iNOS) in the parietal cortex]. In young controls, we observed right/left asymmetry of iNOS activity and three positive correlations (between NR1 in the left and NR2B laterality, between NR2B in the right and left sides, and between NR1 in the right side and nNOS laterality). In old controls, we found bilateral decreases in NR1, an increase in NR2B in the right side, and two changes in correlations in the NR1-nNOS pathway. In young Nogo-A-deficient rats, we observed an increase in iNOS activity in the left hemisphere and two changes in correlations in NR1-nNOS and NR2A-eNOS, compared to young controls. Finally, we revealed in old Nogo-A-deficient animals, bilateral decreases in NR1 and one change in correlation between eNOS-iNOS, compared to old controls. Although some findings from schizophrenic brains did not manifest in Nogo-A-deficient rats (e.g., no alterations in NR2B), others did (e.g., alterations demonstrating accelerated aging in young but not old animals, those occurring exclusively in the right hemisphere in young and old animals and those suggesting abnormal frontoparietal cortical interactions in young animals). 23966984 Environmental impacts on the diversity of methane-cycling microbes and their resultant function. Methane is an important anthropogenic greenhouse gas that is produced and consumed in soils by microorganisms responding to micro-environmental conditions. Current estimates show that soil consumption accounts for 5-15% of methane removed from the atmosphere on an annual basis. Recent variability in atmospheric methane concentrations has called into question the reliability of estimates of methane consumption and calls for novel approaches in order to predict future atmospheric methane trends. This review synthesizes the environmental and climatic factors influencing the consumption of methane from the atmosphere by non-wetland, terrestrial soil microorganisms. In particular, we focus on published efforts to connect community composition and diversity of methane-cycling microbial communities to observed rates of methane flux. We find abundant evidence for direct connections between shifts in the methane-cycling microbial community, due to climate and environmental changes, and observed methane flux levels. These responses vary by ecosystem and associated vegetation type. This information will be useful in process-based models of ecosystem methane flux responses to shifts in environmental and climatic parameters. 23398658 Magnetoelectric control of superparamagnetism. Here we demonstrate electric-field induced magnetic anisotropy in a multiferroic composite containing nickel nanocrystals strain coupled to a piezoelectric substrate. This system can be switched between a superparamagnetic state and a single-domain ferromagnetic state at room temperature. The nanocrystals show a shift in the blocking temperature of 40 K upon electric poling. We believe this is the first example of a system where an electric field can be used to switch on and off a permanent magnetic moment. 23264098 Interferon beta and glatiramer acetate therapy. Interferon beta and glatiramer acetate have been mainstays of treatment in relapsingremitting multiple sclerosis for two decades. Remarkable advances in our understanding of immune function and dysfunction as well as increasingly sophisticated clinical trial design have stemmed from efforts to better understand these drugs. In this chapter, we review the history of their development and elaborate on known and theorized mechanisms of action. We describe the pivotal clinical trials that have led to their widespread use. We evaluate the clinical use of the drugs including tolerability, side effects, and efficacy measures. Finally, we look to the future of interferon beta and glatiramer acetate in the context of an ever growing armamentarium of treatments for relapsing remitting multiple sclerosis. 23680458 Transplantation of human neuro-epithelial-like stem cells derived from induced pluripotent stem cells improves neurological function in rats with experimental intracerebral hemorrhage. Specific targeted therapy for intracerebral hemorrhage (ICH), which has high disability and case-fatality rate, is currently not available. Induced pluripotent stem cells (iPSCs) generated from somatic cells of ICH patients have therapeutic potential for individualized cerebral protection. While, whether ICH patient-originated iPSCs could differentiate into neuro-epithelial-like stem (NES) cells and whether such NES cells could improve functional recovery in the hemorrhage-injured brain are unclear. Here, we showed that fibroblasts from an ICH patient can be efficiently reprogrammed to iPSCs by lentiviral vectors carrying defined transcription factors (OCT4, SOX2, KLF4, and c-MYC). These iPSCs have the typical morphology, surface antigens, capability of self-renewal and differentiating into cell types of all three embryonic germ layers that are similar to human embryonic stem cells (hESCs). Using defined serum-free neural differentiation medium, we induced the iPSCs differentiate into NES cells. Subsequently, the NES cells from ICH patient-originated iPSCs were transplanted into the perihematoma of rats with experimental ICH injury. Intriguingly, recovery of neurological dysfunction in experimental ICH rats was observed post-NES cells graftage. Transplanted NES cells migrated to the surrounding area of hematoma, survived and differentiated into neuron-like cells. Our study demonstrates that the transplantation of human iPS-originated NES cells is an effective approach of treating ICH injury and the improvement of neural function is partially due to neuronal replacement and regeneration. 23681068 ALS-associated mutations in FUS disrupt the axonal distribution and function of SMN. Mutations in the RNA binding protein fused in sarcoma/translated in liposarcoma (FUS/TLS) cause amyotrophic lateral sclerosis (ALS). Although ALS-linked mutations in FUS often lead to a cytosolic mislocalization of the protein, the pathogenic mechanisms underlying these mutations remain poorly understood. To gain insight into these mechanisms, we examined the biochemical, cell biological and functional properties of mutant FUS in neurons. Expression of different FUS mutants (R521C, R521H, P525L) in neurons caused axonal defects. A protein interaction screen performed to explain these phenotypes identified numerous FUS interactors including the spinal muscular atrophy (SMA) causing protein survival motor neuron (SMN). Biochemical experiments showed that FUS and SMN interact directly and endogenously, and that this interaction can be regulated by FUS mutations. Immunostaining revealed co-localization of mutant FUS aggregates and SMN in primary neurons. This redistribution of SMN to cytosolic FUS accumulations led to a decrease in axonal SMN. Finally, cell biological experiments showed that overexpression of SMN rescued the axonal defects induced by mutant FUS, suggesting that FUS mutations cause axonal defects through SMN. This study shows that neuronal aggregates formed by mutant FUS protein may aberrantly sequester SMN and concomitantly cause a reduction of SMN levels in the axon, leading to axonal defects. These data provide a functional link between ALS-linked FUS mutations, SMN and neuronal connectivity and support the idea that different motor neuron disorders such as SMA and ALS may be caused, in part, by defects in shared molecular pathways. 23967298 Conifer Stored Resources and Resistance to a Fungus Associated with the Spruce Bark Beetle Ips typographus. Bark beetles and associated fungi are among the greatest natural threats to conifers worldwide. Conifers have potent defenses, but resistance to beetles and fungal pathogens may be reduced if tree stored resources are consumed by fungi rather than used for tree defense. Here, we assessed the relationship between tree stored resources and resistance to Ceratocystis polonica, a phytopathogenic fungus vectored by the spruce bark beetle Ips typographus. We measured phloem and sapwood nitrogen, non-structural carbohydrates (NSC), and lipids before and after trees were attacked by I. typographus (vectoring C. polonica) or artificially inoculated with C. polonica alone. Tree resistance was assessed by measuring phloem lesions and the proportion of necrotic phloem around the tree's circumference following attack or inoculation. While initial resource concentrations were unrelated to tree resistance to C. polonica, over time, phloem NSC and sapwood lipids declined in the trees inoculated with C. polonica. Greater resource declines correlated with less resistant trees (trees with larger lesions or more necrotic phloem), suggesting that resource depletion may be caused by fungal consumption rather than tree resistance. Ips typographus may then benefit indirectly from reduced tree defenses caused by fungal resource uptake. Our research on tree stored resources represents a novel way of understanding bark beetle-fungal-conifer interactions. 23943782 Donating blood and organs: using an extended theory of planned behavior perspective to identify similarities and differences in individual motivations to donate. Due to the critical shortage and continued need of blood and organ donations (ODs), research exploring similarities and differences in the motivational determinants of these behaviors is needed. In a sample of 258 university students, we used a cross-sectional design to test the utility of an extended theory of planned behavior (TPB) including moral norm, self-identity and in-group altruism (family/close friends and ethnic group), to predict people's blood and OD intentions. Overall, the extended TPB explained 77.0% and 74.6% of variance in blood and OD intentions, respectively. In regression analyses, common contributors to intentions across donation contexts were attitude, self-efficacy and self-identity. Normative influences varied with subjective norm as a significant predictor related to OD intentions but not blood donation intentions at the final step of regression analyses. Moral norm did not contribute significantly to blood or OD intentions. In-group altruism (family/close friends) was significantly related to OD intentions only in regressions. Future donation strategies should increase confidence to donate, foster a perception of self as the type of person who donates blood and/or organs, and address preferences to donate organs to in-group members only. 23384297 Three-dimensional high-resolution rotational tracking with superlocalization reveals conformations of surface-bound anisotropic nanoparticles. The ability to directly follow three-dimensional rotational movement of anisotropic nanoparticles will greatly enhance our understanding of the way nanoparticles interact with surfaces. Herein, we demonstrate dual-color total internal reflection scattering microscopy as a tool to probe the interactions of plasmonic gold nanorods with functional surfaces. By taking advantage of both the short and long axis surface plasmon resonance scattering enhancement, we are able to decipher both in-plane and out-of-plane gold nanorod motion relative to the sample surface with equally high resolution. In combination with superlocalization through point spread function fitting, we overcome the four-quadrant angular degeneracy of gold nanorods in the focal plane of the objective and resolve conformations of surface-bound anisotropic nanoparticles in unprecedented detail. 23876701 Facilitators and barriers to initiating change in medical intensive care unit survivors with alcohol use disorders: A qualitative study. Alcohol abuse and dependence are collectively referred to as alcohol use disorders (AUD). An AUD is present in up to one third of patients admitted to an intensive care unit (ICU). We sought to understand the barriers and facilitators to change in ICU survivors with an AUD to provide a foundation upon which to tailor alcohol-related interventions. We used a qualitative approach with a broad constructivist framework, conducting semistructured interviews in medical ICU survivors with an AUD. Patients were included if they were admitted to 1 of 2 medical ICUs and were excluded if they refused participation, were unable to participate, or did not speak English. Digitally recorded and professionally transcribed interviews were analyzed using a general inductive approach and grouped into themes. Nineteen patients were included, with an average age of 51 (interquartile range, 36-51) years and an average Acute Physiology and Chronic Health Evaluation II score of 9 (interquartile range, 5-13); 68% were white, 74% were male, and the most common reason for admission was alcohol withdrawal (n = 8). We identified 5 facilitators of change: empathy of the inpatient health care environment, recognition of accumulating problems, religion, pressure from others to stop drinking, and trigger events. We identified 3 barriers to change: missed opportunities, psychiatric comorbidity, and cognitive dysfunction. Social networks were identified as either a barrier or facilitator to change depending on the specific context. Alcohol-related interventions to motivate and sustain behavior change could be tailored to ICU survivors by accounting for unique barriers and facilitators. 23886959 Passive sound exposure induces rapid perceptual learning in musicians: Event-related potential evidence. Musicians show enhanced auditory processing compared to nonmusicians. However, the neural basis underlying the effects of musical training on rapid plasticity in auditory processing has not been systematically studied. Here, the rapid (one session) learning-related plastic changes in event-related potential (ERP) responses for pitch and duration deviants between passive blocks were compared between musicians and nonmusicians. Passive blocks were interleaved with an active discrimination task. In addition to musicians having faster and stronger overall source activation for deviating sounds, source analysis revealed rapid plastic changes in the left and right temporal and left frontal sources that were present only in musicians. Source activation decreased in these areas even without focused attention. Furthermore, deviant-related ERP responses above the parietal areas decreased after the active task in both musicians and nonmusicians. Taken together, the results indicate enhanced rapid plasticity in sound change discrimination and perceptual learning in musicians when compared with nonmusicians. 23640761 Implementing Frailty Into Clinical Practice: A Cautionary Tale. Little is known about the contribution of frailty in improving patient-level prediction beyond readily available clinical information. The objective of this study is to compare the predictive ability of 129 combinations of seven frailty markers (cognition, energy, mobility, mood, nutrition, physical activity, and strength) and quantify their contribution to predictive accuracy beyond age, sex, and number of chronic diseases. Two cohorts from the Established Populations for Epidemiologic Studies of the Elderly were used. The model with the best predictive fit in predicting 6-year incidence of disability was determined using the Akaike Information Criterion. Predictive accuracy was measured by the C statistic. Incident disability was 23% in one cohort and 20% in the other cohort. The "best model" in each cohort was found to be a model including between five and seven frailty markers including cognition, mobility, nutrition, physical activity, and strength. Predictive accuracy of the 129 models ranged from 0.73 to 0.77 across both cohorts. Adding frailty markers to age, sex, and chronic disease increased predictive accuracy by up to 3% in both cohorts (p < .001). The contribution of frailty increased up to 9% in the oldest age group. Adding frailty markers provided a modest increase in patient-level prediction of disability. Such a modest increase may still be worthwhile because while age, sex, and the number of chronic diseases are not modifiable, frailty may be. Further studies examining the contribution of frailty in improving prediction are needed before adopting frailty as a prognostic tool. 23725657 Are there sensitive time periods for dementia caregivers? The occurrence of behavioral and psychological symptoms in the early stages of dementia. ABSTRACT Background: The behavioral and psychological symptoms associated with dementia (BPSD) can be burdensome to informal/family caregivers, negatively affecting mental health and expediting the institutionalization of patients. Because the dementia patient-caregiver relationship extends over long periods of time, it is useful to examine how BPSD impact caregiver depressive symptoms at varied stages of illness. The goal of this study was to assess the association of BPSD that occur during early stage dementia with subsequent caregiver depressive symptoms. Methods: Patients were followed from the early stages of dementia every six months for up to 12 years or until death (n = 160). Caregiver symptoms were assessed on average 4.5 years following patient's early dementia behaviors. A generalized estimating equation (GEE) extension of the logistic regression model was used to determine the association between informal caregiver depressive symptoms and BPSD symptoms that occurred at the earliest stages dementia, including those persistent during the first year of dementia diagnosis. Results: BPSD were common in early dementia. None of the individual symptoms observed during the first year of early stage dementia significantly impacted subsequent caregiver depressive symptoms. Only patient agitation/aggression was associated with subsequent caregiver depressive symptoms (OR = 1.76; 95% CI = 1.04-2.97) after controlling for concurrent BPSD, although not in fully adjusted models. Conclusions: Persistent agitation/aggression early in dementia diagnosis may be associated with subsequent depressive symptoms in caregivers. Future longitudinal analyses of the dementia caregiving relationship should continue to examine the negative impact of persistent agitation/aggression in the diagnosis of early stage dementia on caregivers. 23850372 The aftermath of public housing relocation: Relationship to substance misuse. Several cross-sectional studies have examined relationships between neighborhood characteristics and substance misuse. Using data from a sample of African-American adults relocating from US public housing complexes, we examined relationships between changes in exposure to local socioeconomic conditions and substance misuse over time. We tested the hypothesis that adults who experienced greater post-relocation improvements in local economic conditions and social disorder would have a lower probability of recent substance misuse. Data were drawn from administrative sources to describe the census tracts where participants lived before and after relocating. Data on individual-level characteristics, including binge drinking, illicit drug use, and substance dependence, were gathered via survey before and after the relocations. Multilevel models were used to test hypotheses. Participants (N=172) experienced improvements in tract-level economic conditions and, to a lesser degree, in social disorder after moving. A one standard-deviation improvement in tract-level economic conditions was associated with a decrease in recent binge drinking from 34% to 20% (p=0.04) and with a decline in using illicit drugs weekly or more from 37% to 16% (p=0.02). A reduction in tract-level alcohol outlet density of >3.0 outlets per square mile predicted a reduction in binge drinking from 32% to 18% at p=0.05 significance level. We observed relationships between improvements in tract-level conditions and declines in substance misuse, providing further support for the importance of the local environment in shaping substance misuse. These findings have important implications for public housing policies and future research. 23631395 "Strange Kinetics" in the Temperature Dependence of Methionine Ligand Rebinding Dynamics in Cytochrome c. Temperature dependence of methionine ligand dissociation and rebinding dynamics in cytochrome c in aqueous solution has been studied using classical molecular dynamics simulation. Results are compared with previous study of rebinding dynamics at 300K in water in order to understand how the change of protein environment and the underlying protein energy landscape influence the dynamics. Rebinding dynamics at 77K, 180K, and 300K exhibits changes in both timescale and mechanism as the protein and solvent undergo a dynamic "glass transition." At each temperature, the rebinding dynamics yields a subset of trajectories that undergo fast rebinding as well as a subset of trajectories that undergo slower rebinding. At 300K in water, both a fast (4.0 ps) and slow (14.6 ps) rebinding is observed. While fast rebinding occurs from a "downward" (heme pointing) substate of the methionine, the slow rebinding involves interconversion between an "upward" substate, from which rebinding cannot occur, and the downward substate. At lower temperatures (77K and 180K) the upward dissociated substate was not observed due to the high barrier imposed by the "frozen" protein structure. However, a slow rebinding phase is observed at both 77K and 180K and is associated with a process of trapping in downward but "binding forbidden" substates with subsequent slow dynamical conversion to "binding competent" substates from which rebinding is relatively rapid. Distinctive rebinding dynamics at 77K and 180K suggest that different rebinding time scales are predetermined by the protein and solvent structural arrangement prior to photodissociation, which causes either fast rebinding (about 2ps) or slow (> 50ps) rebinding. Suggestions for future experiments to further probe the role of dynamic heterogeneity in the kinetics of methionine ligand binding in cytochrome c protein are proposed. 23246733 Size-dependent toxicity and cell interaction mechanisms of gold nanoparticles on mouse fibroblasts. Gold nanoparticles (AuNPs) are currently used in several fields including biomedical applications, although no conclusive information on their cytotoxicity is available. For this reason this work has investigated the effects of AuNPs in vitro on Balb/3T3 mouse fibroblasts. Results obtained exposing cells for 72 h to AuNPs 5 and 15 nm citrate stabilized, revealed cytotoxic effects only for AuNPs 5 nm at concentration ≥ 50 μM if measured by colony forming efficiency (CFE). To understand the differences in cytotoxicity observed for the two AuNPs sizes, we investigated the uptake and the intracellular distribution of the nanoparticles. By TEM it was observed that 5 and 15 nm AuNPs are internalized by Balb/3T3 cells and located within intracellular endosomal compartments. Quantification of the uptake by ICP-MS showed that AuNPs internalization enhanced even up to 72 h. Disruption of the actin cytoskeleton was evident, with cell footprints narrow and contracted; effects more remarkable in cells exposed to 5 nm AuNP. The mechanism of NPs cell internalization was investigated using immunocytochemistry and western blot. No significant effect was observed in the expression level of caveolin, while reduction of the expression and degradation of the clathrin heavy chain was observed in cells exposed for 72 h to AuNPs. 23911657 A Glucose-6-Phosphate Isomerase Peptide Induces T and B Cell-Dependent Chronic Arthritis in C57BL/10 Mice: Arthritis without Reactive Oxidative Species and Complement. Immunization with human glucose-6-phosphate isomerase (hG6PI) protein or with several of its peptides induces arthritis in DBA/1 mice. We investigated G6PI peptide-induced arthritis in C57BL/10 mice and the effect of oxidative burst on disease. To study the arthritogenicity of G6PI peptides and its immune dependency, we used genetically modified and congenic mice on the C57BL/10 background and in vitro T- and B-cell assays. hG6PI325-339 peptide induced arthritis in C57BL/10 mice. The disease was associated with major histocompatibility complex class II and was dependent on T cells, B cells, and complement C5. Th1 and Th17 cells primed with the hG6PI325-339 peptide cross-reacted with the murine G6PI protein. The severity of the disease increased in mice carrying a mutation in Ncf1 (Ncf1∗/∗), which abolishes the NADPH oxidase 2 complex oxidative burst. Ncf1∗/∗ mice developed arthritis also on immunization with the mouse G6PI325-339 peptide and in the absence of C5. The antibody responses to the G6PI protein and peptides were minimal in both Ncf1∗/∗ and wild-type mice. Herein is described G6PI peptide as the first peptide to induce arthritis in C57BL/10 mice. The differences between the wild-type and Ncf1∗/∗ mice suggest that an alternative complement-independent arthritogenic pathway could be operative in the absence of oxidative burst. 23907791 Role of COMT in ADHD: a Systematic Meta-Analysis. Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable childhood-onset psychiatric disorder with significant genetic contribution. Considerable evidence has implicated involvement of dopaminergic system and the prefrontal cortex (PFC) in the pathomechanism of ADHD. The catechol-O-methyltransferase (COMT) gene is of particular interest for ADHD as its crucial role in the degradation of dopamine in the PFC. We summarized the reported findings investigating associations between COMT gene and ADHD and performed a meta-analysis of previous studies to assess the overall magnitude and significance of the association. 23916490 Expression regulation of zebrafish interferon regulatory factor 9 by promoter analysis. We previously showed that a fish interferon (IFN) regulatory factor 9 (IRF9) homologue, crucian carp Carassius auratus IRF9, displays constitutively nuclear localization and involvement of fish IFN-dependent JAK-STAT signaling; however, little is known about the expression regulation of fish IRF9. Here, we characterized the expression of zebrafish IRF9 by promoter analysis. Zebrafish IRF9 gene promoter contained several putative transcription factor binding sites, including one ISRE (IFN-stimulated response element), one GAS (IFN gamma activation sequence) and three GATEs (IFNγ activated transcriptional element, GATE1/2/3). Further sequence analyses revealed that GAS and GATE motifs existed in all promoters of IRF9 from mammals and fishes. Luciferase assays confirmed that zebrafish IRF9 promoter could be activated by zebrafish IFNφs and zebrafish IFNγ2, as well as transcription factors IRF3, IRF7, and combination of IRF9 and STAT2. Treatment of recombinant crucian carp IFN protein or overexpression of zebrafish IFNγ2 both led to significant increase in CaIRF9 mRNA and protein in cultured fish cells. Comparison of IFN-stimulated promoter activity revealed much more significant induction of zebrafish IRF9 by zebrafish IFNγ2 than by zebrafish IFNφs. Mutation analyses showed that the putative GAS and GATE3 contributed to zebrafish IFNγ2-triggered IRF9 expression, whereas the putative ISRE and the other two GATEs were not functional for induction of zebrafish IRF9. These results together indicated that the expression property of IRF9 might be conserved from fish to mammals and that some not yet identified mechanisms could exist in IRF9 gene transcription regulation in response to IFNs. 23884866 Antibiotic prophylaxis in children with cancer or who have undergone hematopoietic cell transplantation. Bacterial infections are common in children with cancer and can lead to life-threatening complications. Infections in these patients mainly occur during neutropenic periods, and may be caused by Gram-positive or Gram-negative bacteria. The patients at highest risk of serious infections include those with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML), and those undergoing myeloablative hematopoietic cell transplantation (HCT). This is a review with the main aim of making a critical appraisal of the literature, and summarising what is currently known and can be recommended. The most significant studies support the use of floroquinolones (mainly ciprofloxacin) as the most rational approach to treat pediatric patients with probably long-lasting neutropenia, although trimetoprim-sulphametoxazole and amoxicillin/clavulanate may theoretically be valid alternatives. No prophylaxis seems to be needed for children with cancer without severe neutropenia. However, a global evaluation of the studies of antibiotic prophylaxis in children with cancer indicates that there are not enough data to prepare definite guidelines for its use or avoidance in pediatric oncology, and so further studies are needed. It is not only important to define the best antibiotic regimens for the children in whom such prophylaxis is useful, but also to identify precisely those who do not need it. This would avoid the antibiotic misuse that probably occurs at the moment because many low-risk children with cancer are treated. As prophylaxis against infections requires long-term adherence to an antibiotic regimen, the attitudes and beliefs of stakeholders need to be fully considered. 23125371 FlyBase: improvements to the bibliography. An accurate, comprehensive, non-redundant and up-to-date bibliography is a crucial component of any Model Organism Database (MOD). Principally, the bibliography provides a set of references that are specific to the field served by the MOD. Moreover, it serves as a backbone to which all curated biological data can be attributed. Here, we describe the organization and main features of the bibliography in FlyBase (flybase.org), the MOD for Drosophila melanogaster. We present an overview of the current content of the bibliography, the pipeline for identifying and adding new references, the presentation of data within Reference Reports and effective methods for searching and retrieving bibliographic data. We highlight recent improvements in these areas and describe the advantages of using the FlyBase bibliography over alternative literature resources. Although this article is focused on bibliographic data, many of the features and tools described are applicable to browsing and querying other datasets in FlyBase. 23927252 When is the next extending of Fick-Jacobs equation necessary? Applicability of the effective one-dimensional equations, such as Fick-Jacobs equation and its extensions, describing diffusion of particles in 2D or 3D channels with varying cross section A(x) along the longitudinal coordinate x, is studied. The leading nonstationary correction to Zwanzig-Reguera-Rubí equation [R. Zwanzig, J. Phys. Chem. 96, 3926 (1992); D. Reguera and J. M. Rubí, Phys. Rev. E 64, 061106 (2001)] is derived and tested on the exactly solvable model, diffusion in a 2D linear cone. The effects of such correction are demonstrated and discussed on elementary nonstationary processes, a time dependent perturbation of the stationary flow and calculation of the mean first passage time. 23896644 Short- and long-term temporal changes in soil concentrations of selected endocrine disrupting compounds (EDCs) following single or multiple applications of sewage sludge to pastures. Temporal changes in soil burdens of selected endocrine disrupting compounds were determined following application to pasture of either sewage sludge or inorganic fertilizer. Soil polycyclic aromatic hydrocarbon and polychlorinated biphenyl concentrations were not altered. Changes in concentrations of diethylhexyl phthalate (DEHP) and PBDEs 47 and 99 differed with season but concentrations remained elevated for more than three weeks after application, when grazing animals are normally excluded from pasture. It is concluded that single applications of sewage sludge can increase soil concentrations of some, but not all classes of EDCs, possibly to concentrations sufficient to exert biological effects when different chemicals act in combination, but patterns of change depend on season and soil temperature. Analysis of soil from pasture subjected to repeated sludge applications, over 13 years, provided preliminary evidence of greater increases in soil burdens of all of the EDC groups measured, including all of the PBDE congeners measured. 23052613 Your diagnosis? Congenital foot drop. A term infant was noted to have right-sided foot drop. We discuss the role of neurophysiology and diagnostic imaging. 23519015 Large-scale synthesis and in situ functionalization of Zn3P2 and Zn4Sb3 nanowire powders. A simple method for the large-scale synthesis of gram quantities of compound semiconductor nanowires without the need for any external catalysts or templates is presented. This method is demonstrated using zinc phosphide (Zn3P2) and zinc antimonide (β-Zn4Sb3) nanowires as example systems. Large-scale synthesis of Zn3P2 and Zn4Sb3 nanowire powders was accomplished using a hot-walled chemical vapor deposition chamber by transporting phosphorus and antimony, respectively, via the vapor phase onto heated zinc foils. The zinc foils were rolled concentrically into coils to maximize the substrate surface area, and consequently, the nanowire yield. Using this method, 250 mg of Zn3P2 nanowires were obtained on 480 cm(2) of zinc foil in a span of 45 minutes. Furthermore, a process of exposing the synthesized nanowires to a vapor of organic functional molecules immediately after their synthesis and before their removal from the vacuum chamber was developed to obtain large quantities of surface functionalized nanowire powders. This in situ vapor-phase functionalization procedure passivated the nanowire surfaces without adversely affecting their morphology or dimensions. Our studies revealed that both 4-aminothiophenol and 3-propanedithiol functionalized Zn3P2 nanowires were stable over a 120 day duration without any agglomeration or degradation. This method of mass producing nanowires can also be extended to other binary semiconductors. 23205533 Identification of ginkgolic acid (15:1) metabolites in rats following oral administration by high-performance liquid chromatography coupled to tandem mass spectrometry. 1. In this article, metabolites of ginkgolic acid (GA) (15:1) in rats plasma, bile, urine and faeces after oral administration have been investigated for the first time by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) with the aid of on-line hydrogen/deuterium (H/D) exchange technique and β-glucuronidase hydrolysis experiments. 2. After oral administration of GA (15:1, M0) to rats at a dose of 10 mg/kg, it was found that metabolites M1-M5 together with parent compound (M0) existed in rat plasma; parent compound (M0) and metabolites M2-M5 were observed in rat bile, and parent compound (M0) with metabolites M1 and M2 were discovered in rat faeces, and there was no parent compound and metabolite detectable in rat urine. 3. Two oxidative metabolites of GA (15:1, M0) were identified as 2-hydroxy-6-(pentadec-8-enyl-10-hydroxy) benzoic acid (M1) and 2-hydroxy-6-(pentadec-8-enyl-11-hydroxy-13-carbonyl) benzoic acid (M2), respectively. Metabolites M3, M4 and M5 were identified as the mono-glucuronic acid conjugates of parent compound (M0), M1 and M2, respectively. 4. The results indicated that M1 and M2 with parent compound (M0) were mainly eliminated in faeces and three glucuronide metabolites (M3, M4 and M5) excreted in bile as the predominant forms after oral administration of GA (15:1) to rats. 23948291 Epilepsy surgery in children with accompanying impairments. The aim of this study was to assess seizure outcome 2 years after epilepsy surgery in a consecutive series of paediatric patients, with special focus on children with learning disabilities and other neuroimpairments in addition to the epilepsy. Outcome 2 years after surgery was assessed in 110 of 125 children operated upon for drug resistant epilepsy in Gothenburg 1987-2006. More than half of the children had learning disabilities, 43% motor impairments and 30% a neuropsychiatric diagnosis. Fifty-six per cent of those with an IQ < 70 became seizure-free or had a >75% reduction in seizure frequency, and two thirds if the operation was a resection. The corresponding figure in those with more than 100 seizures per month was 15 out of 31, and another seven had a 50-75% reduction in seizure frequency. The message is that learning disability, motor impairment and psychiatric morbidity should not be contraindications for paediatric epilepsy surgery. More than half of the children with learning disabilities had a worthwhile seizure outcome, with even better results after resective surgery. Children with drug resistant epilepsy and additional severe neurological impairments should have the benefit of referral to a tertiary centre for evaluation for epilepsy surgery. 23877314 The effects of NaNbO3 particle size on the photocatalytic activity for 2-propanol photodegradation. The effects of NaNbO3 particle size on the photocatalytic activity were investigated by taking gaseous 2-propanol photodegradation as a model reaction. By varying the loading amount of precursors onto mesoporous SBA-15, nanocrystalline NaNbO3 samples with particle sizes ranging from 3 to 50 nm were successfully synthesized. The particle size and surface area value of templated NaNbO3 change systematically with the change in loading amount of the precursors. The physicochemical characteristics of the samples were examined by techniques such as XRD, SEM, TEM, Raman spectroscopy, and UV-visible diffuse reflectance spectroscopy. The optimum NaNbO3 particle size for the highest photocatalytic activity was found to be 30 nm. The current study also revealed that the NaNbO3 photocatalyst is structure sensitive for 2-propanol photodegradation. The density of active sites on the sample surface decreases as the particle size decreases. Competing effects of factors such as the surface area, changes in electronic structure, defect density, and concentration of reaction active sites determine the optimum particle size of NaNbO3. 23763505 Direct Effects of Vardenafil on the Ureter: In Vitro Investigation and Potential Clinical Applications of Intralumenal Administration. Abstract Local intralumenal administration of substances with beneficial effects over the ureter appears to be a very attractive route for the administration of drugs to the urinary system, avoiding systemic adverse reactions associated with per os administration. This work investigates whether vardenafil is a good candidate for local intralumenal ureteral administration. More precisely, we examined the effect of vardenafil on human ureter contractility and on the viability of cultured human urothelial cells (hUC) and bladder smooth muscle cells (hBSMC). Our study revealed that vardenafil induced a dose-depended relaxation of isolated human ureteral tissue. In addition, growth and cell viability of cultured hBSMC and hUC remained unaltered after vardenafil application. Based on the above, this selective phosphodiesterase type 5 inhibitor can be considered as a promising pharmacologic agent for local intralumenal administration in clinical conditions in which ureteral dilation might be beneficial. 23668342 Reducing redundancy in wireless capsule endoscopy videos. We eliminate similar frames from a wireless capsule endoscopy video of the human intestines to maximize spatial coverage and minimize the redundancy in images. We combine an intensity correction method with a method based an optical flow and features to detect and reduce near-duplicate images acquired during the repetitive backward and forward egomotions due to peristalsis. In experiments, this technique reduced duplicate image of 52.3% from images of the small intestine. 23702804 The role of the innate and adaptive immune system in pediatric inflammatory bowel disease. : Recent translational studies have provided new insights into the pathogenesis of pediatric-onset inflammatory bowel disease. Registry studies have identified distinct clinical phenotypes with increasing age of onset; this has led to a revision of the clinical phenotyping system, now termed the Paris classification system. It is recognized that there are infantile (age, <1 years), very early onset (VEO) (age, 1-10 years), and early onset (age, 10-17 years) forms of disease. Rare genetic mutations affecting antimicrobial and anti-inflammatory pathways have been discovered in infantile and VEO forms, although genetic pathways identified in early onset disease have been similar to adult-onset inflammatory bowel disease. An increasing incidence in the infantile and VEO forms has suggested an important environmental influence. This is likely ultimately expressed through alterations in the enteric flora (dysbiosis) and dysregulated immune responses to the flora, which are recognized as a critical trigger for mucosal inflammation. These data should ultimately guide new pathogenic models of disease, which will inform both therapy in individual patients and disease prevention in their at-risk family members. 23685331 Is serving in the armed forces associated with tobacco or cannabis initiation? A study of onset sequences before and after joining the French armed forces. The aim of this study was to evaluate whether joining the military could constitute a predictor of subsequent tobacco or cannabis use. Data from four cross-sectional surveys conducted between 2005 and 2009 in the French armed forces were used to constitute a retrospective cohort (n=4208). A Markov multi-state model was fitted, estimating the probabilities at 1year for all possible pathways between entry into the military profession, tobacco initiation and cannabis initiation. The model was adjusted for current substance use status. Substance initiation appeared to mainly occur before entering the services than during the service period (3.0 times greater likelihood for tobacco and 2.5 times greater likelihood for cannabis). Probabilities of primo-initiation (i.e. starting with that substance) before joining the services were similar for tobacco (3.6% at one year) and cannabis (3.5%). When the study was restrained to current users, although differences were not statistically significant, probabilities of substance primo-initiation during the service period seemed to be greater than before. While the substance use itinerary in the French general population most often begins by tobacco, military seem to have a higher propensity to cannabis primo-initiation, which could traduce more sensation-seeking behaviors. If certain results in our study could also evoke a propensity to substance initiation during the service period, we did not find evidence to verify the hypothesis of a military social inducing effect. Further research is needed to identify behavioral characteristics which could explain increased use during the service period. 23541152 Implicit sequence learning and working memory: Correlated or complicated? The relationship between implicit/incidental sequence learning and working memory motivated a series of research because it is plausible that higher working memory capacity opens a "larger window" to a sequence, allowing thereby the sequence learning process to be easier. Although the majority of studies found no relationship between implicit sequence learning and working memory capacity, in the past few years several studies have tried to demonstrate the shared or partly shared brain networks underlying these two systems. In order to help the interpretation of these and future results, in this mini-review we suggest the following factors to be taken into consideration before testing the relationship between sequence learning and working memory: 1) the explicitness of the sequence; 2) the method of measuring working memory capacity; 3) online and offline stages of sequence learning; and 4) general skill- and sequence-specific learning. 23204110 Chronic arsenic exposure in nanomolar concentrations compromises wound response and intercellular signaling in airway epithelial cells. Paracrine ATP signaling in the lung epithelium participates in a variety of innate immune functions, including mucociliary clearance, bactericide production, and as an initiating signal in wound repair. We evaluated the effects of chronic low-dose arsenic relevant to U.S. drinking water standards (i.e., 10 ppb [130nM]) on airway epithelial cells. Immortalized human bronchial epithelial cells (16HBE14o-) were exposed to 0, 130, or 330nM arsenic (as Na-arsenite) for 4-5 weeks and examined for wound repair efficiency and ATP-mediated Ca(2+) signaling. We found that chronic arsenic exposure at these low doses slows wound repair and reduces ATP-mediated Ca(2+) signaling. We further show that arsenic compromises ATP-mediated Ca(2+) signaling by altering both Ca(2+) release from intracellular stores (via metabotropic P2Y receptors) and Ca(2+) influx mechanisms (via ionotropic P2X receptors). To better model the effects of arsenic on ATP-mediated Ca(2+) signaling under conditions of natural exposure, we cultured tracheal epithelial cells obtained from mice exposed to control or 50 ppb Na-arsenite supplemented drinking water for 4 weeks. Tracheal epithelial cells from arsenic-exposed mice displayed reduced ATP-mediated Ca(2+) signaling dynamics similar to our in vitro chronic exposure. Our findings demonstrate that chronic arsenic exposure at levels that are commonly found in drinking water (i.e., 10-50 ppb) alters cellular mechanisms critical to airway innate immunity. 23948751 Reversal of boswellic acid analog BA145 induced caspase dependent apoptosis by PI3K inhibitor LY294002 and MEK inhibitor PD98059. PI3K/Akt and ERK pathways are important for growth and proliferation of many types of cancers. Therefore, PI3K inhibitor LY294002 (LY) and MEK1/2 inhibitor PD98059 (PD) are used to sensitize many types of cancer cell lines to chemotherapeutic agents, where AKT and ERK pathways are over activated. However, in this study, we show for the first time that PD could protect the leukemia cells independent of ERK pathway inhibition, besides, we also report a detailed mechanism for antiapoptotic effect of LY in HL-60 cells against the cytotoxicity induced by a boswellic acid analog BA145. Apoptosis induced by BA145 is accompanied by downregulation of PI3K/Akt and ERK pathways in human myelogenous leukemia HL-60 cells, having activating N-Ras mutation. Both LY and PD protected the cells against mitochondrial stress caused by BA145, and reduced the release of cytochrome c and consequent activation of caspase-9. LY and PD also diminished the activation of caspase-8 without affecting the death receptors. Besides, LY and PD also reversed the caspase dependent DNA damage induced by BA145. Further studies revealed that LY and PD significantly reversed the inhibitory effect of BA145 on cell cycle regulatory proteins by upregulating hyperphosphorylated retinoblastoma, pRB (S795) and downregulating p21 and cyclin E. More importantly, all these events were reversed by caspase inhibition by Z-VAD-fmk, suggesting that both LY and PD act at the level of caspases to diminish the apoptosis induced by BA145. These results indicate that inhibitors of PI3K/Akt and ERK pathways can play dual role and act against chemotherapeutic agents. 23688502 Indigenous plasmids of Bacillus megaterium WSH-002 involved in mutualism with Ketogulonicigenium vulgare WSH-001. In the two-step vitamin C fermentation process, the precursor 2-keto-l-gulonic acid (2-KLG) was synthesized using a mixed culture of Ketogulonicigenium vulgare WSH-001 and Bacillus megaterium WSH-002, which contained three plasmids, pBME1, pBME2 and pBME3. The cell growth of B. megaterium was not affected by the elimination of these plasmids. However, elimination of pBME2 and pBME3 significantly affected l-sorbose uptake and 2-KLG production. Sequence analysis of the plasmids showed that many of the pBME2 and pBME3 genes were of unknown function or could not be assigned to a specific metabolic pathway. The current work showed that the indigenous plasmids pBME2 and pBME3 of B. megaterium WSH-002 involved in mutualism with K. vulgare WSH-001. The results provided a promising new route to further demonstrate the mutualism process between the two bacteria. 23873029 Functions of TAp63 and p53 in restraining the development of metastatic cancer. Many tumours harbour mutations in the p53 tumour-suppressor gene that result in the expression of a mutant p53 protein. This mutant p53 protein has, in most cases, lost wild-type transcriptional activity and can also acquire novel functions in promoting invasion and metastasis. One of the mechanisms underlying these novel functions involves the ability of the mutant p53 to interfere with other transcription factors, including the p53 family protein TAp63. To investigate whether simultaneous depletion of both p53 and TAp63 can recapitulate the effect of mutant p53 expression in vivo, we used a mouse model of pancreatic cancer in which the expression of mutant p53 resulted in the rapid appearance of primary tumours and metastases. As shown previously, loss of one allele of wild-type (WT) p53 accelerated tumour development. A change of one WT p53 allele into mutant p53 did not further accelerate tumour development, but did promote the formation of metastasis. By contrast, loss of TAp63 did not significantly accelerate tumour development or metastasis. However, simultaneous depletion of p53 and TAp63 led to both rapid tumour development and metastatic potential, although the incidence of metastases remained lower than that seen in mutant p53-expressing tumours. TAp63/p53-null cells derived from these mice also showed an enhanced ability to scatter and invade in tissue culture as was observed in mutant p53 cells. These data suggest that depletion of TAp63 in a p53-null tumour can promote metastasis and recapitulate-to some extent-the consequences of mutant p53 expression.Oncogene advance online publication, 22 July 2013; doi:10.1038/onc.2013.287. 23847078 Unusual Secondary Metabolites from Astragalus halicacabus Lam. From the whole plant of Astragalus halicacabus (Sect. Halicacabus), a new cycloartane-type glycoside, (20R,24S)-3-O-[α-L-arabinopyranosyl-(1→2)-β-D-xylopyranosyl]-20,24-epoxy-16-O-β-D-glucopyranosyl-3β,6α,16β,25-tetrahydroxycycloartane, and a new glycoside, 3-O-[β-D-apiofuranosyl-(1→2)-β-D-glucopyranosyl]maltol were isolated together with seven known cycloartane-type glycosides, i.e., cyclocanthoside D, askendosides D, F, and G, cyclosieversioside G, cyclostipuloside A, elongatoside, and a known maltol glucoside, 3-O-β-D-glucopyranosylmaltol. The structures were elucidated by means of high-resolution mass spectrometry, and extensive 1D- and 2D-NMR spectroscopic analysis. This is the first phytochemical work on A. halicacabus, and a maltol glycoside was encountered for the first time in the Leguminosae family. 23962466 The use of a modified [(3)H]4-DAMP radioligand binding assay with increased selectivity for muscarinic M3 receptor shows that cortical CHRM3 levels are not altered in mood disorders. (3)H]4-DAMP is a radioligand that has been used to quantify levels of the muscarinic receptor CHRM3 protein in situ. However, in addition to high affinity binding to CHRM3, [(3)H]4-DAMP binds with low affinity to CHRM1 confounding the potential to discriminate between changes in these two muscarinic receptors. We have developed a [(3)H]4-DAMP binding assay, optimised for measuring CHRM3 protein levels in the cortex, with minimal selectivity towards CHRM1. The selectivity of our assay towards CHRM3 was confirmed using recombinant receptor-expressing, cell lysate preparations. [(3)H]4-DAMP binding levels were similar between wildtype and CHRM1 knockout mice, confirming that the amount of [(3)H]4-DAMP binding to CHRM1 was negligible. We used this assay to measure CHRM3 protein levels in the frontal pole, obtained post-mortem from subjects with bipolar disorder (n=15), major depressive disorder (n=15) and matched controls (n=20) and showed that [(3)H]4-DAMP binding was not altered in either bipolar disorder or major depressive disorder. Western blotting confirmed that CHRM3 protein levels were unchanged in these subjects. 23606331 Helicobacter pylori activates NF-κB by inducing Ubc13-mediated ubiquitination of lysine 158 of TAK1. The Helicobacter pylori virulence factor CagA targets a variety of host proteins to alter different cellular responses, including the induction of pro-inflammatory cytokines. We have previously shown that CagA-facilitated lysine 63-linked ubiquitination of TAK1 is essential for the H. pylori-induced NF-κB activation and the expression of proinflammatory cytokines. However, the molecular mechanism for TAK1 ubiquitination and activation in H. pylori-mediated NF-κB activation remains elusive. Here, we identify lysine 158 of TAK1 as the key residue undergoing lysine 63-linked ubiquitination in response to H. pylori infection. Mutation of lysine 158 to arginine prevents the ubiquitination of TAK1 and impairs H. pylori-induced TAK1 and NF-κB activation. Moreover, we demonstrate that E2 ubiquitin conjugating enzyme Ubc13 is involved in H. pylori-mediated TAK1 ubiquitination. Suppressing the activity of Ubc13 by a dominant-negative mutant or siRNA abolishes CagA-facilitated and H. pylori-induced TAK1 and NF-κB activation. These findings further underscore the importance of lysine 63-linked ubiquitination of TAK1 in H. pylori-induced NF-κB activation and NF-κB-mediated inflammatory response. J. Cell. Biochem. 114: 2284-2292, 2013. © 2013 Wiley Periodicals, Inc. 23592597 A Phox2b::FLPo transgenic mouse line suitable for intersectional genetics. Phox2b is a transcription factor expressed in the central and peripheral neurons that control cardiovascular, respiratory, and digestive functions and essential for their development. Several populations known or suspected to regulate visceral functions express Phox2b in the developing hindbrain. Extensive cell migration and lack of suitable markers have greatly hampered studying their development. Reasoning that intersectional fate mapping may help to overcome these impediments, we have generated a BAC transgenic mouse line, P2b::FLPo, which expresses codon-optimized FLP recombinase in Phox2b expressing cells. By partnering the P2b::FLPo with the FLP-responsive RC::Fela allele, we show that FLP recombination switches on lineage tracers in the cells that express or have expressed Phox2b, permanently marking them for study across development. Taking advantage of the dual-recombinase feature of RC::Fela, we further show that the P2b::FLPo transgene can be partnered with Lbx1(Cre) as Cre driver to generate triple transgenics in which neurons having a history of both Phox2b and Lbx1 expression are specifically labeled. Hence, the P2b::FLPo line when partnered with a suitable Cre driver provides a tool for tracking and accessing genetically subsets of Phox2b-expressing neuronal populations, which has not been possible by Cre-mediated recombination alone. genesis 51:506-514. © 2013 Wiley Periodicals, Inc. 23851465 Thiazolidinediones and cancer: results of a meta-analysis of randomized clinical trials. Recent epidemiological data have contributed to the formulation of the hypothesis about the long-term safety of pioglitazone, a thiazolidinedione (TZD), with respect to malignancies, in particular bladder cancer. The primary aim of this meta-analysis of randomized clinical trials, not designed a priori to test this hypothesis, was to explore whether TZDs affect the risk of cancer. A meta-analysis was performed including published and unpublished randomized trials with a duration of at least 52 weeks, enrolling patients with or without diabetes, comparing TZDs with either placebo or other drug therapies on various different outcomes. We found 22 trials reporting at least one cancer and enrolling 13,197 patients to TZD (pioglitazone: n = 3,710 and rosiglitazone: n = 9,487) and 12,359 to placebo or active comparator groups. The mean follow-up was 26.1 months. Overall, those assigned at random to TZDs had a significant reduction (MH-OR 0.85 [0.73-0.98]; p = 0.027) in the incidence of malignancies, with no significant difference in effect between pioglitazone and rosiglitazone. Specifically, subgroup analyses showed a significant reduction for rosiglitazone (MH-OR 0.82 [0.69-0.98]; p = 0.029), but not for pioglitazone (MH-OR 0.66 [0.34-1.28]; p = 0.22). In further subgroup analyses of site-specific malignancies based on the data from four trials, the risk of bladder cancer with pioglitazone (MH-OR) was 2.05 [0.84-5.02]; p = 0.12. Further, rosiglitazone, but not pioglitazone, was associated with a significantly reduced risk of bowel cancer. In contrast, pioglitazone, but not rosiglitazone, was associated with a significant reduction in breast cancer. The present meta-analysis of trials, not designed a priori to test the hypothesis, provides reassuring evidence that TZDs are not associated with risk of overall malignancies. In fact, they are compatible with the possibility of a decreased risk of cancer. In site-specific subgroup analyses, for rosiglitazone, there was a significant decreased risk of bowel cancer. Subgroup analyses for pioglitazone did not allow to exclude an increased risk of bladder cancer, while the risk of breast cancer was significantly decreased. While these data are also useful to formulate not test hypotheses, they provide somewhat more cogent evidence than the previously published epidemiological data. 23830197 Human papillomaviruses and cancer. Human papillomaviruses (HPV) are small oncogenic DNA viruses of which more than 200 types have been identified to date. A small subset of these is etiologically linked to the development of anogenital malignancies such as cervical cancer. In addition, recent studies established a causative relationship between these high-risk HPV types and tonsillar and oropharyngeal cancer. Clinical management of cervical cancer and head and neck squamous cell carcinomas (HNSCCs) is largely standardized and involves surgical removal of the tumor tissue as well as adjuvant chemoradiation therapy. Notably, the response to therapeutic intervention of HPV-positive HNSCCs has been found to be better as compared to HPV-negative tumors. Although the existing HPV vaccine is solely licensed for the prevention of cervical cancer, it might also have prophylactic potential for the development of high-risk HPV-associated HNSCCs. Another group of viruses, which belongs to the beta-HPV subgroup, has been implicated in nonmelanoma skin cancer, however, the etiology remains to be established. Treatment of HPV-induced nonmelanoma skin cancer is based on local excision. However, topically applied immune-modulating substances represent non-surgical alternatives for the management of smaller cutaneous tumors. In this review we present the current knowledge of the role of HPV in cancer development and discuss clinical management options as well as targets for the development of future intervention therapies. 23969901 mRNA expression pattern of retinoic acid and retinoid X nuclear receptor subtypes in human thyroid papillary carcinoma. Retinoids have shown potential for the inhibition of tumour growth and progression. The objective of this study was to investigate retinoic acid nuclear receptor subtypes RAR/RXR and iodothyronine 5'-deiodinase, type I expression pattern in papillary thyroid tumour tissue of 26 patients in order to compare with those of the non-neoplastic thyroid tissue of the corresponding patients. The expression of selected parameters mRNA was examined by semi-quantitative RT-PCR. Papillary thyroid carcinoma (PTC) expressed RXRγ, when compared to non-neoplastic thyroid tissues of the corresponding patients that were lacking expression of RXRγ or its expression was very low. Moreover, we found significantly increased expression of RARα and RARγ in the overall group of PTC. This increase was detected in cases with positive lymph node metastasis (LNM), but not in cases with negative LNM. RARβ was significantly reduced in the subgroup of classic variant (CV). We also detected absence or significantly lower expression of hDIO1 mRNA in tumour tissue when compared to non-neoplastic tissue in both overall PTC cases and in the CV subgroup. However, the significantly decreased levels of hDIO1 mRNA were detected in cases with negative LNM but not in cases with positive LNM when compared to corresponding non-tumour tissue in both overall PTC cases and in the CV subgroup. Differences in RAR and RXR subtype mRNA expression patterns in various PTCs may contribute to the immunochemistry data available, and may thus find exploitation in clinical oncology, particularly in the differential diagnosis of thyroid neoplasms. 22379948 Chemical constituents of Indonesian plant Protium javanicum Burm. f. and their antifeedant activities against Coptotermes formosanus Shiraki. In the continuing study of antifeedant compounds in Protium javanicum Burm. f. against Coptotermes formosanus Shiraki, 6-desacetylnimbin (1), quercitrin (2) and myricitrin (3) were isolated from P. javanicum extract. All compounds were characterised by NMR and MS. Furthermore, the structure of 6-desacetylnimbin was confirmed by X-ray crystallography. The antifeedant activity was evaluated with no-choice feeding tests. At a dose of 0.5 mg, 6-desacetylnimbin exhibited the highest antifeedant activity among the isolates. 23848210 The Effect of Tea Tree Oil (Melaleuca alternifolia) on Wound Healing Using a Dressing Model. Abstract Numerous studies have shown the promising antibacterial effects of Melaleuca alternifolia, or tea tree essential oil. The study detailed here replicates in humans a 2004 in vitro study that used a dressing model over Petri dishes to determine the antimicrobial effects of the fumes of tea tree essential oil. The current study used the same dressing model with patients who had wounds infected with Staphylococcus aureus. Ten participants volunteered for the quasi-experimental study, and four of the 10 were used as matched participants to compare wound healing times between conventional treatment alone and conventional treatment plus fumes of tea tree essential oil. The results demonstrated decreased healing time in all but one of the participants treated with tea tree oil. The differences between the matched participants were striking. The results of this small investigational study indicate that additional study is warranted. 23163316 Stratified approaches to the treatment of asthma. While asthma is a chronic inflammatory disorder that is managed with inhaled controller and reliever drugs, there remains a large unmet need at the severe end of the disease spectrum. Here, a novel stratified approach to its treatment is reviewed, based upon identification of causal pathways, with a focus on biologics. A systematic search of the literature was made using Medline, and publications were selected on the basis of their relevance to the topic. Despite strong preclinical data for many of the more recently identified asthma targets, especially those relating to the T-helper 2 allergic pathway, clinical trials with specific biologics in moderate to severe asthma as a group have been disappointing. However, subgroup analyses based upon pathway-specific biomarkers suggest specific endotypes that are responsive. Application of hypothesis-free analytical approaches (the 'omics') to well-defined phenotypes is leading to the stratification of asthma along causal pathways. Refinement of this approach is likely to be the future for diagnosing and treating this group of diseases, as well as helping to define new causal pathways. The identification of responders and nonresponders to targeted asthma treatments provides a new way of looking at asthma diagnosis and management, especially with biologics that are costly. The identification of novel biomarkers linked to well-phenotyped patients provides a stratified approach to disease management beyond simple disease severity and involving causal pathways. In order to achieve this effectively, a closer interaction will be required between industry (therapeutic and diagnostic), academia and health workers. 23852621 Trends in intracranial meningioma surgery and outcome: a Nationwide Inpatient Sample database analysis from 2001 to 2010. The objective of the present study was to analyze the risk of in-patient mortality, adverse outcome, practice patterns and regional variations in patients who underwent intracranial meningioma surgery in the United States between 2001 and 2010. We performed a retrospective cohort study using the Nationwide Inpatient Sample database. In-patient mortality and adverse outcome at discharge were the outcome predictors. Multivariate analyses were done to analyze the patient, hospital and physician characteristics. The annual case-volume of patients with meningioma increased from 2001 to 2010 by 40 %. The in-patient mortality rate remained the same at 1.3 % and the rate of adverse discharge disposition remained at 35 % between 2001 and 2010. Caucasian female patients in younger age group with private insurance who underwent treatment at a high case-volume center had the best outcomes. In older patients (≥70 years), the in-patient mortality rate decreased by 25 % whereas the adverse discharge disposition rate increased by 19 %. Patients treated at high case-volume centers and by high case-volume physicians had lower rates of in-patient mortality (P < 0.05) and adverse outcome at discharge (P = 0 < 0.05). There was a 54 % decrease in the number of hospitals performing one surgery/year through the decade. A 2 % relative decrease in mortality was observed in lowest volume hospitals. Though the highest increase in admission charges through the decade was seen in hospitals located in the north-east (165 % relative increase), the highest relative decrease in mortality and morbidity was observed in hospitals located in the mid-west and the south (67.6  and 22 % respectively). 23624391 A novel mutation (c. 341A>G) in the SRY gene in a 46,XY female patient with gonadal dysgenesis. SRY (sex-determining region Y) gene, MIM 480000, NM_005634) is crucial for sex differentiation which encodes the protein responsible for initiating testis differentiation. SRY mutations are associated with the presence of XY gonadal dysgenesis symptoms. We studied a 46,XY female patient with primary amenorrhoea and negative family history. The clinical, endocrine, histopathologic and cytogenetic data are consistent with gonadal dysgenesis. Using a molecular analysis, a novel (c.341A>G, p. N65D) missense mutation within the HMGbox of SRY gene was detected. Escherichia coli expression of SRY study showed reduced expression of the mutated protein and gel retardation assay method revealed lowered DNA-binding ability in N65D variant of SRY. The novel mutation detected in the SRY gene may be an aetiopathogenic factor in clinically defined 46,XY complete gonadal dysgenesis (CGD). Because of an increased risk of gonadoblastoma, proper early diagnosis and treatment prevent development of malignancies. 23611021 Methicillin-Resistant Staphylococcus Aureus Nasal Colonization Prevalence among Emergency Medical Services Personnel. Introduction The prevalence of Methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization among Emergency Medical Services (EMS) personnel is not well studied. Methicillin-resistant Staphylococcus aureus colonization can be a health hazard for both EMS personnel and patients. The aim of this study was to quantify the prevalence of MRSA colonization among EMS personnel. This study will help the scientific community understand the extent of this condition so that further protocols and policies can be developed to support the health and wellbeing of EMS personnel. Hypothesis/ Problem The hypothesis of this study was that the prevalence of MRSA colonization among EMS personnel is significantly higher than among the general population. This was a cross-sectional study. A total of 110 subjects were selected from two major US Mid-Atlantic fire departments. Methicillin-resistant Staphylococcus aureus colonization was detected by nasal swabbing. Nasal swabs were inoculated onto a special agar medium (C-MRSAgar) with polymerase chain reaction testing performed. One-sided binomial distribution at the StudySize 2.0 Web calculator was used. Using the Web calculator, p (H0 proportion) = 1.5%; a difference (H1-H0) 'Δ' = 4.53% can be detected at α = 5% and power = 80% with N = 110. Samples were collected from 110 volunteers. Seven samples were positive for MRSA, resulting in a prevalence of 7/110 or 6.4% (95% CI, 1.8%-11%; P < .0003) compared with a 1.5% prevalence of MRSA colonization among the general population. There is evidence that EMS personnel have a higher prevalence of MRSA colonization than the general population. This can be a risk to patients and can be recognized as an occupational hazard. Al Amiry A , Bissell RA , Maguire BJ , Alves DW . Methicillin-resistant Staphylococcus aureus nasal colonization prevalence among Emergency Medical Services personnel. Prehosp Disaster Med. 2013;28(4):1-5 . 23852730 CTIP2 is a negative regulator of P-TEFb. The positive transcription elongation factor b (P-TEFb) is involved in physiological and pathological events including inflammation, cancer, AIDS, and cardiac hypertrophy. The balance between its active and inactive form is tightly controlled to ensure cellular integrity. We report that the transcriptional repressor CTIP2 is a major modulator of P-TEFb activity. CTIP2 copurifies and interacts with an inactive P-TEFb complex containing the 7SK snRNA and HEXIM1. CTIP2 associates directly with HEXIM1 and, via the loop 2 of the 7SK snRNA, with P-TEFb. In this nucleoprotein complex, CTIP2 significantly represses the Cdk9 kinase activity of P-TEFb. Accordingly, we show that CTIP2 inhibits large sets of P-TEFb- and 7SK snRNA-sensitive genes. In hearts of hypertrophic cardiomyopathic mice, CTIP2 controls P-TEFb-sensitive pathways involved in the establishment of this pathology. Overexpression of the β-myosin heavy chain protein contributes to the pathological cardiac wall thickening. The inactive P-TEFb complex associates with CTIP2 at the MYH7 gene promoter to repress its activity. Taken together, our results strongly suggest that CTIP2 controls P-TEFb function in physiological and pathological conditions. 23265536 Determination of fluorine in milk samples via calcium-monofluoride by electrothermal molecular absorption spectrometry. The determination of fluorine in milk samples via the molecular absorption of calcium mono-fluoride (CaF) was performed using a HR-CS-ETAAS. For this purpose, calcium was pipetted to graphite furnace together with samples. The amount of Ca and the graphite furnace program were optimised. Fluorine was determined in pyrolytically coated platforms at 606.440 nm applying a pyrolysis temperature of 700 °C and a molecule forming temperature of 2250 °C. Finally, applying standard addition technique, F contents of several milk samples were determined. The results obtained by linear calibration and standard addition techniques were significantly different which can be attributed to non-spectral interferences in milk due to matrix concomitants. Therefore, in order to tolerate the errors, the F contents of several milk samples were determined applying standard addition technique. However, since the ingredients of milk samples change for different kinds, the F in each sample was determined from its own standard addition curve. The range of F content for the milk samples were 0.027-0.543 μg mL(-1). The limit of detection and characteristic mass of the method were 0.26 and 0.13 ng of F, respectively. 23611819 Quantitative analysis of global phosphorylation changes with high-resolution tandem mass spectrometry and stable isotopic labeling. Quantitative measurement of specific protein phosphorylation sites is a primary interest of biologists, as site-specific phosphorylation information provides insights into cell signaling networks and cellular dynamics at a system level. Over the last decade, selective phosphopeptide enrichment methods including IMAC and metal oxides (TiO2 and ZrO2) have been developed and greatly facilitate large scale phosphoproteome analysis of various cells, tissues and living organisms, in combination with modern mass spectrometers featuring high mass accuracy and high mass resolution. Various quantification strategies have been applied to detecting relative changes in expression of proteins, peptides, and specific modifications between samples. The combination of mass spectrometry-based phosphoproteome analysis with quantification strategies provides a straightforward and unbiased method to identify and quantify site-specific phosphorylation. We describe common strategies for mass spectrometric analysis of stable isotope labeled samples, as well as two widely applied phosphopeptide enrichment methods based on IMAC(NTA-Fe(3+)) and metal oxide (ZrO2). Instrumental configurations for on-line LC-tandem mass spectrometric analysis and parameters of conventional bioinformatic analysis of large data sets are also considered for confident identification, localization, and reliable quantification of site-specific phosphorylation. 23847431 Knowledge and awareness of HIV/AIDS among high school girls in Ghana. HIV/AIDS is recognized as a national priority health issue in Ghana. Consequently, the Ghana AIDS Commission and the National AIDS Control Programme were established, among other things, to enhance the knowledge and awareness on the nature, causes, effects and means of managing the spread of HIV/AIDS among populations at risk in Ghana. Through the efforts of these bodies and other stakeholders in health, several awareness creation and sensitization efforts have been targeted at teenage girls, a high risk group in Ghana. This study therefore assesses the knowledge and awareness of HIV/AIDS among senior high school girls in their teens in Ghana using a sample of 260 female students of West African Senior High School. The data collected were analyzed and discussed under relevant themes and within the context of the literature. The study revealed that generally, senior high school girls were knowledgeable on the nature, modes of transmission, and prevention of HIV/AIDS. There were however some students who exhibited limited knowledge on some issues including the spiritual causes and treatment of HIV/AIDS, contacts and associations with infected persons, as well as determination of HIV infection from appearances rather than testing. The study also raised important concerns about the reluctance of senior high school girls to use condoms as a preventive measure and the need to reorient HIV/AIDS awareness interventions in Ghana. 23935960 Extended Result Reading Window in Lateral Flow Tests Detecting Exposure to Onchocerca volvulus: A New Technology to Improve Epidemiological Surveillance Tools. Onchocerciasis is a neglected tropical disease caused by infection with the parasite Onchocerca volvulus (Ov). An estimated 180 million people are at risk for Ov infection, and 37 million people are infected, mostly in Africa. A lateral flow-based assay to detect human IgG4 antibodies to the Ov-specific antigen Ov-16 was developed as a rapid tool to detect exposure to Ov. The test, when performed on 449 sera specimens from patients with microfiladermia and Ov-negative patients, has a sensitivity of 89.1% (95% confidence interval: 86.2%-92.0%), and specificity of 97% (95% confidence interval: 95.4%-98.6%). Because the intended use of the test is for surveillance, it is highly desirable to have a stable, long-lasting result. An extended read window is thus desirable for a high-volume, busy workflow and facilitates post-surveillance quality assurance. The main restriction on achieving an extended read window for this assay was the erythrocyte lysis that can alter the signal-to-noise ratio, especially in those with low IgG4 levels (weak positives). We describe a test housing that incorporates a user-independent feature driven by assay fluid and an expanding wick that detaches the blood separation membrane from the nitrocellulose used in the assay, but before hemolysis occurs. We demonstrated material functionality at extreme operational conditions (37°C, 80% relative humidity) and a read window of a minimum of 70 days. The fluid-driven assay device performs equally as well with whole blood as with plasma, as demonstrated with 100 spiked clinical specimens (with a correlation coefficient of 0.96). We show a novel, inexpensive, and simple approach to actuating the detachment of the blood separation membrane from the nitrocellulose test with no impact on the performance characteristics of the test. 22734646 Pregabalin reduces cocaine self-administration and relapse to cocaine seeking in the rat. Pregabalin (Lyrica™) is a structural analog of γ-aminobutyric acid (GABA) and is approved by the FDA for partial epilepsy, neuropathic pain and generalized anxiety disorders. Pregabalin also reduces excitatory neurotransmitter release and post-synaptic excitability. Recently, we demonstrated that pregabalin reduced alcohol intake and prevented relapse to the alcohol seeking elicited by stress or environmental stimuli associated with alcohol availability. Here, we sought to extend these findings by examining the effect of pregabalin on cocaine self-administration (0.25 mg/infusion) and on cocaine seeking elicited by both conditioned stimuli and stress, as generated by administration of yohimbine (1.25 mg/kg). The results showed that oral administration of pregabalin (0, 10 or 30 mg/kg) reduced self-administration of cocaine over an extended period (6 hours), whereas it did not modify self-administration of food. In cocaine reinstatement studies, pregabalin (10 and 30 mg/kg) abolished the cocaine seeking elicited by both the pharmacological stressor yohimbine and the cues predictive of cocaine availability. Overall, these results demonstrate that pregabalin may have potential in the treatment of some aspects of cocaine addiction. 23898830 Dietary nutrient intake and metabolic syndrome risk in Chinese adults: a case-control study. Because human diets are composed of a wide variety of nutrients that may work synergistically to prevent or promote disease, assessing dietary nutrient intake status may be informative. The purpose of this study was to assess the dietary nutrient intake status of Chinese adults with metabolic syndrome (MetS) and to evaluate its possible role in MetS. This case-control study was conducted from March 2010 to January 2011. A total of 123 patients with MetS and 135 controls participated in this study at the Health Examination Center of Heping District in Tianjin, China. Dietary intake was estimated by 24-h dietary recalls. We used principal component factor analysis to derive nutrient groups from 17 major nutrients. We examined the odds ratios and 95% confidence intervals using logistic regression models to test the relationship between tertiles of dietary nutrient pattern and MetS. There were 4 major dietary nutrient patterns in this study: "vitamin B group", "protein and lipids", "vitamin E and minerals", and "antioxidant vitamins". After adjustment for potential confounders, the highest tertile of the nutrient pattern factor score for the "vitamin B group" (odds ratio: 0.16; 95% confidence interval: 0.05-0.47) was negatively associated with MetS compared with the lowest tertiles. No relationships were found between other dietary nutrient patterns and MetS. The "vitamin B group" pattern was inversely associated with MetS in Chinese adults. This finding supports the hypothesis that the "vitamin B group" pattern may have a potentially beneficial effect on the prevention of MetS. 23876826 Targeting hyaluronic acid production for the treatment of leukemia: Treatment with 4-methylumbelliferone leads to induction of MAPK-mediated apoptosis in K562 leukemia. The current study examined the effect of modulation of hyaluronic acid (HA) synthesis on leukemia cell survival using the hyaluronic acid synthesis inhibitor 4-methylumbelliferone (4-MU). Treatment of CML cells with 4-MU led to caspase-dependent apoptosis characterized by decreased HA production, PARP cleavage, and increased phosphorylation of p38. Addition of exogenous HA, the pan caspase inhibitor Z-VAD-FMK or the p38 inhibitor SB203580 to 4-MU treated cells was able to protect cells from apoptosis. Treatment of tumor-bearing mice with 4-MU led to a significant reduction in tumor load which was mediated through the induction of apoptosis. 23926182 The direct renin inhibitor aliskiren localizes and persists in rat kidneys. The aims of this study were to 1) determine whether renal localization of aliskiren and its anti-hypertensive and renoprotective effects persist after stopping administration of the drug, and 2) define the renal localization of aliskiren by light microscopy autoradiography. Hypertensive double transgenic rats (dTGR) overexpressing genes for human renin and angiotensinogen were treated with aliskiren (3 mg/kg/day sc; osmotic minipumps) or enalapril (18mg/L in drinking water). After 2 weeks treatment dTGR were assigned to either continued treatment with aliskiren ("continued"), or to cessation of their respective treatment ("stopped") for three weeks washout. One week treatment with aliskiren and enalapril reduced BP and albuminuria vs baseline. After cessation of either treatment, blood pressure had returned to pre-treatment levels and albuminuria remained relatively low for 1 week, but rose thereafter similarly in both groups. In contrast, renal mRNA for TGF-β and renal collagen IV was reduced by aliskiren (continued and stopped groups), but not after cessation of enalapril. Similar patterns were found for collagen IV protein expression. Even 3 weeks after stopping aliskiren treatment, renal levels of the drug exceeded its IC50, whereas enalaprilat was not detected. To localize aliskiren accumulation, Wistar rats were treated with [(3)H]-aliskiren for 7 days. Autoradiography demonstrated specific labeling in glomeruli, arterioles, and afferent arterioles as well as in the distal nephron. Labeling could still be observed even after 7 days washout. These results suggest that the renophilic properties of aliskiren are different from enalapril and could have contributed to the renoprotective mechanism of this renin inhibitor. 23681905 A Chemical Lift-off Process: Removing Non-Specific Adsorption in an Electrochemical Epstein-Barr Virus Immunoassay. Upon contact of sensor surfaces with complex biological samples containing a variety of different proteins, non-specific adsorption hampers the high-sensitive detection of the analyte in question. To substantially decrease the impact of non-specific adsorption at thiol-based self-assembled monolayers, a chemical lift-off process is introduced. A sequence of local hydrolysis of isooctyl 3-mercaptopropionate, covalent binding of an antigen against the Epstein-Barr virus (EBV), stepwise incubation with a serum sample possibly containing the EBV antibody and an enzyme-labeled anti-human antibody is completed with a lift-off by integral hydrolysis of the remaining ester groups at the self-assembled monolayer. The cleavage of the ester removes any non-specifically bound protein during a following stringent washing step. The substantial improvement of the detection limit of an electrochemical immunoassay against EBV using native recombinant antigens, their immobilization after local deprotection using a scanning electrochemical microscope (SECM) and the local read-out using the generator-collector mode of SECM with redox cycling amplification demonstrates the successful application of the proposed lift-off procedure. 23891778 Desensitization of the cough reflex during limb muscle contraction in anesthetized rabbits. The 'cough network' exhibits plasticity at the sensor and integration levels leading to modulation of the strength or pattern of the cough reflex. Little is known about the interactions between cough and human activities, especially during exercise. The present study was designed to determine whether exercise, mimicked by electrically induced muscle contractions, can modify the incidence and/or strength of cough following mechanical stimulation of the trachea in anesthetized rabbits. Thirteen anesthetized, tracheotomized rabbits were studied by a total of 311 tracheal stimulations: 196 at rest and 115 during exercise. During muscle contractions, the incidence of the cough reflex (CR) decreased and the expiration reflex (ER) increased (p < 0.0001). The sensitivity of the CR and ER both decreased during exercise compared to the sensitivity of the CR at rest (p < 0.02), while the strength of the expulsive response remained unchanged. These results indicate that adjustments occurring during muscle contractions likely downregulate tracheal defensive reflexes in anesthetized rabbits. 23855462 Resveratrol analogs: promising chemopreventive agents. Although resveratrol can modulate multiple stages of carcinogenesis, by most common standards it is not a good drug candidate. Resveratrol lacks potency, high efficacy, and target specificity; it is rapidly metabolized and serum concentrations are low. Using resveratrol as a scaffold, we produced over 100 derivatives, some of which have target specificity in the nanomolar range. Aromatase inhibition was enhanced over 6000-fold by using 1,3-thiazole as the central ring of resveratrol. Optimizing the substitution pattern of the two phenyl rings and the central heterocyclic linker led to selective QR1 induction with a CD value of 87 nM. Several derivatives have been selected for evaluation of synergistic effects. Preliminary results with pairs of compounds are promising and further experiments, in a constant multidrug manner, will allow us to create polygonograms for larger combinations of derivatives. The objective is to develop a highly efficacious cocktail of derivatives based on the structure of resveratrol. 22965813 Usefulness of three-dimensional angiographic analysis of perigastric vessels before laparoscopic gastrectomy. Recognition of perigastric vessel anatomy is important to safely perform gastric surgery, especially in the case of laparoscopic gastrectomy. This study was designed to reevaluate the efficacy of preoperative three-dimensional (3D) angiography reconstructed from enhanced multidetector-row computed tomography (MDCT) data and to classify right gastric artery (RGA) branching patterns. Perigastric vessel anatomy was preoperatively analyzed using MDCT-based 3D angiography reconstructed by computer software in patients undergoing laparotomic (n = 75) and laparoscopic (n = 25) gastrectomy. Results were compared with intraoperative findings in all cases, and were also compared with maximum intensity projection (MIP) imaging, which is similar to conventional angiography, in 10 patients. Preoperative diagnoses by 3D angiography were identical to intraoperative findings. The rates of branching patterns of the celiac artery and left gastric vein were comparable with previous reports. The detection rate of the right gastric artery (RGA) was 77.0 %. Branching patterns of the hepatic artery were classified into four types: right hepatic artery (RHA) + left hepatic artery (LHA) type, replaced RHA + LHA type, RHA + replaced LHA type, and replaced RHA + replaced LHA type. RGA ramification patterns were classified into three types according to hepatic arterial running patterns: distal (68.8 %), proximal (14.3 %), and caudal (16.9 %). Because of vessel overlapping, RGA ramified points were misdiagnosed under MIP images in two of ten cases (20 %). Preoperative 3D angiography is useful for a new system of classifying RGA ramification patterns into three types. With this system, surgeons can perform laparoscopic gastrectomy with lymph node dissection more safely. 23248340 A case of clear cell meningioma with tyrosine-rich crystals. We present a case of clear cell meningioma with unusual clinical and pathologic features. The patient was a 54-year-old man who underwent laminectomy and durotomy for an intradural tumor in the lumbar spinal canal. Sections showed a predominance of dense collagenous tissue with irregularly shaped and irregularly sized magenta-colored extracellular deposits. On electron microscopy, these deposits were osmiophilic and "petaloid." The final diagnosis of clear cell meningioma rested on relatively inconspicuous intervening nests of glycogen-containing clear cells that were positive for epithelial membrane antigen. The unusual extracellular deposits seen in this case have previously been characterized as tyrosine-rich crystals of the type most commonly seen in salivary gland tumors. Recognition of this tumor as a clear cell meningioma, despite misleading clinical features and initially challenging histologic findings, is not only a matter of diagnostic accuracy but also imparts important prognostic information. 22995681 In vivo imaging of retinal ganglion cell apoptosis. Apoptosis, or programmed cell death, plays a vital role in normal development and ageing. However, dysregulation of this process is responsible for many disease states including; cancer, autoimmune and neurodegeneration. For this reason, in vivo visualisation of apoptosis may prove a useful tool for both laboratory research and clinical diagnostics. Glaucoma comprises a distinctive group of chronic optic neuropathies, characterised by the progressive loss of retinal ganglion cells (RGCs). Early diagnosis of glaucoma remains a clear and unmet need. Recently, there have been significant advances in the detection of apoptosis in vivo using fluorescent probes to visualise single RGCs undergoing apoptosis, specifically DARC (Detection of Apoptotic Retinal Cells) [1] and capQ technology [2(••)]. 23535345 Long chain lipid based tamoxifen NLC. Part I: Preformulation studies, formulation development and physicochemical characterization. Tamoxifen citrate (Tmx) was formulated in nanostructured lipid carrier system (NLC) using long chain solid lipids (LCSL) and oils (LCO) with the aim to target lymphatic system to improve its bioavailability in plasma and lymphnode (initial sites for metastasis) and reduce its drug associated toxicity. Tamoxifen loaded NLC (Tmx-NLC) was formulated using solvent diffusion technique. Preformulation studies comprised evaluation of drug-excipients compatibility. Solubility of Tmx was screened in LCSL and LCO, surfactants and co-surfactants to identify NLC components. Surfactant co-surfactant combinations were studied for their ability to stabilize the system. Tmx-NLC was physicochemically characterized by TEM, DSC, XRD, and FTIR studies. Drug-excipients chemical compatibility study facilitated anticipation of excipients induced oxidative degradation of Tmx. Suitable storage condition below 30°C could stabilize Tmx. Tmx-NLC with >90% entrapment efficiency and 215.60±7.98nm particle size were prepared and freeze dried. Freeze dried Tmx-NLC could withstand various gastrointestinal tract (GI) media (pH 1.2, pH 3.5, pH 4.5, pH 6.8, pH 7.4). Dissolution profile of Tmx-NLC in various media showed sustained release pattern irrespective of pH of medium. No significant change in characteristics of Tmx-NLC was observed after 3 months of accelerated stability studies. 23848512 Exploring signatures of positive selection in pigmentation candidate genes in populations of East Asian ancestry. Currently, there is very limited knowledge about the genes involved in normal pigmentation variation in East Asian populations. We carried out a genome-wide scan of signatures of positive selection using the 1000 Genomes Phase I dataset, in order to identify pigmentation genes showing putative signatures of selective sweeps in East Asia. We applied a broad range of methods to detect signatures of selection including: 1) Tests designed to identify deviations of the Site Frequency Spectrum (SFS) from neutral expectations (Tajima's D, Fay and Wu's H and Fu and Li's D* and F*), 2) Tests focused on the identification of high-frequency haplotypes with extended linkage disequilibrium (iHS and Rsb) and 3) Tests based on genetic differentiation between populations (LSBL). Based on the results obtained from a genome wide analysis of 25 kb windows, we constructed an empirical distribution for each statistic across all windows, and identified pigmentation genes that are outliers in the distribution. Our tests identified twenty genes that are relevant for pigmentation biology. Of these, eight genes (ATRN, EDAR, KLHL7, MITF, OCA2, TH, TMEM33 and TRPM1,) were extreme outliers (top 0.1% of the empirical distribution) for at least one statistic, and twelve genes (ADAM17, BNC2, CTSD, DCT, EGFR, LYST, MC1R, MLPH, OPRM1, PDIA6, PMEL (SILV) and TYRP1) were in the top 1% of the empirical distribution for at least one statistic. Additionally, eight of these genes (BNC2, EGFR, LYST, MC1R, OCA2, OPRM1, PMEL (SILV) and TYRP1) have been associated with pigmentary traits in association studies. We identified a number of putative pigmentation genes showing extremely unusual patterns of genetic variation in East Asia. Most of these genes are outliers for different tests and/or different populations, and have already been described in previous scans for positive selection, providing strong support to the hypothesis that recent selective sweeps left a signature in these regions. However, it will be necessary to carry out association and functional studies to demonstrate the implication of these genes in normal pigmentation variation. 23903367 High rates of death and hospitalization follow bone fracture among hemodialysis patients. Altered bone structure and function contribute to the high rates of fractures in dialysis patients compared to the general population. Fracture events may increase the risk of subsequent adverse clinical outcomes. Here we assessed the incidence of post-fracture morbidity and mortality in an international cohort of 34,579 in-center hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS). We estimated country-specific rates of fractures requiring a hospital admission and associated length of stay in the hospital. Incidence rates of death and of a composite event of death/rehospitalization were estimated for 1 year after fracture. Overall, 3% of participants experienced a fracture. Fracture incidence varied across countries, from 12 events/1000 patient-years (PY) in Japan to 45/1000 PY in Belgium. In all countries, fracture rates were higher in the hemodialysis group compared to those reported for the general population. Median length of stay ranged from 7 to 37 days in the United States and Japan, respectively. In most countries, postfracture mortality rates exceeded 500/1000 PY and death/rehospitalization rates exceeded 1500/1000 PY. Fracture patients had higher unadjusted rates of death (3.7-fold) and death/rehospitalization (4.0-fold) compared to the overall DOPPS population. Mortality and hospitalization rates were highest in the first month after the fracture and declined thereafter. Thus, the high frequency of fractures and increased adverse outcomes following a fracture pose a significant health burden for dialysis patients. Fracture prevention strategies should be identified and applied broadly in nephrology practices.Kidney International advance online publication, 31 July 2013; doi:10.1038/ki.2013.279. 23333583 Comparative pharmacokinetic profiles of picrosides I and II from kutkin, Picrorhiza kurroa extract and its formulation in rats. Picrosides I and II are the active chemical constituents, present in the roots and rhizomes of Picrorhiza kurroa Royle (family: Scrophulariaceae). The plant is ethnomedically claimed for the treatment of liver and upper respiratory tract infection, fever, dyspepsia and scorpion sting. This study attempts to determine the in vivo pharmacokinetic profile of picrosides I and II in rats after oral administration of three different preparations namely, kutkin (a mixture of picrosides I and II), P. kurroa extract and Picrolax® capsule (marketed formulation). A simple, precise, specific and sensitive method was developed for simultaneous quantification of picrosides I and II in rat plasma and was applied for the pharmacokinetic study. Pharmacokinetic parameters were calculated from the observed plasma concentration of picrosides I and II. The results showed a significant difference (p≤0.05) in oral bioavailability of picrosides I and II from different preparations. Both the compounds were found to be more bioavailable from P. kurroa extract followed by Picrolax® capsule and kutkin. Moreover, we also developed a novel method for isolation of kutkin from roots of P. kurroa with a high yield of 2.4% w/w. The information gained from this study provides a meaningful basis for clinical application and mechanistic study of such phytochemicals. 23889491 A novel hAT element in Bombyx mori and Rhodnius prolixus: its relationship with miniature inverted repeat transposable elements (MITEs) and horizontal transfer. Comparative analysis of transposable elements (TEs) from different species can make it possible to reconstruct their history over evolutionary time. In this study, we identified a novel hAT element in Bombyx mori and Rhodnius prolixus with characteristic GGGCGGCA repeats in its subterminal region. Meanwhile, phylogenetic analysis demonstrated that the elements in these two species might represent a separate cluster of the hAT superfamily. Strikingly, a previously identified miniature inverted repeat transposable element (MITE) shared high identity with this autonomous element across the entire length, supporting the hypothesis that MITEs are derived from the internal deletion of DNA transposons. Interestingly, identity of the consensus sequences of this novel hAT element between B. mori and R. prolixus, which diverged about 370 million years ago, was as high as 96.5% over their full length (about 3.6 kb) at the nucleotide level. The patchy distribution amongst species, coupled with overall lack of intense purifying selection acting on this element, suggest that this novel hAT element might have experienced horizontal transfer between the ancestors of B. mori and R. prolixus. Our results highlight that this novel hAT element could be used as a potential tool for germline transformation of R. prolixus to control the transmission of Trypanosoma cruzi, which causes Chagas disease. 23673243 Solvent-free synthesis, spectral correlations and antimicrobial activities of some aryl E 2-propen-1-ones. Totally 38 aryl E 2-propen-1-ones including nine substituted styryl 4-iodophenyl ketones have been synthesised using solvent-free SiO2-H3PO4 catalyzed Aldol condensation between respective methyl ketones and substituted benzaldehydes under microwave irradiation. The yields of the ketones are more than 80%. The synthesised chalcones were characterized by their analytical, physical and spectroscopic data. The spectral frequencies of synthesised substituted styryl 4-iodophenyl ketones have been correlated with Hammett substituent constants, F and R parameters using single and multi-linear regression analysis. The antimicrobial activities of 4-iodophenyl chalcones have been studied using Bauer-Kirby method. 23855407 Generation of powerful tungsten reductants by visible light excitation. The homoleptic arylisocyanide tungsten complexes, W(CNXy)6 and W(CNIph)6 (Xy = 2,6-dimethylphenyl, Iph = 2,6-diisopropylphenyl), display intense metal to ligand charge transfer (MLCT) absorptions in the visible region (400-550 nm). MLCT emission (λmax ≈ 580 nm) in tetrahydrofuran (THF) solution at rt is observed for W(CNXy)6 and W(CNIph)6 with lifetimes of 17 and 73 ns, respectively. Diffusion-controlled energy transfer from electronically excited W(CNIph)6 (*W) to the lowest energy triplet excited state of anthracene (anth) is the dominant quenching pathway in THF solution. Introduction of tetrabutylammonium hexafluorophosphate, [Bu(n)4N][PF6], to the THF solution promotes formation of electron transfer (ET) quenching products, [W(CNIph)6](+) and [anth](•-). ET from *W to benzophenone and cobalticenium also is observed in [Bu(n)4N][PF6]/THF solutions. The estimated reduction potential for the [W(CNIph)6](+)/*W couple is -2.8 V vs Cp2Fe(+/0), establishing W(CNIph)6 as one of the most powerful photoreductants that has been generated with visible light. 23321249 Anosognosia, neglect, extinction and lesion site predict impairment of daily living after right-hemispheric stroke. Right-hemispheric stroke can give rise to manifold neuropsychological deficits, in particular, impairments of spatial perception which are often accompanied by reduced self-awareness of these deficits (anosognosia). To date, the specific contribution of these deficits to a patient's difficulties in daily life activities remains to be elucidated. In 55 patients with right-hemispheric stroke we investigated the predictive value of different neglect-related symptoms, visual extinction and anosognosia for the performance of standardized activities of daily living (ADL). The additional impact of lesion location was examined using voxel-based lesion-symptom mapping. Step-wise linear regression revealed that anosognosia for visuospatial deficits was the most important predictor for performance in standardized ADL. In addition, motor-intentional and perceptual-attentional neglect, extinction and cancellation task performance significantly predicted ADL performance. Lesions comprising the right frontal and cingulate cortex and adjacent white matter explained additional variance in the performance of standardized ADL, in that damage to these areas was related to lower performance than predicted by the regression model only. Our data show a decisive role of anosognosia for visuospatial deficits for impaired ADL and therefore outcome/disability after stroke. The findings further demonstrate that the severity of neglect and extinction also predicts ADL performance. Our results thus strongly suggest that right-hemispheric stroke patients should not only be routinely assessed for neglect and extinction but also for anosognosia to initiate appropriate rehabilitative treatment. The observation that right frontal lesions explain additional variance in ADL most likely reflects that dysfunction of the supervisory system also significantly impacts upon rehabilitation. 23853040 The Macamide N-3-Methoxybenzyl-Linoleamide Is a Time-Dependent Fatty Acid Amide Hydrolase (FAAH) Inhibitor. The Peruvian plant Lepidium meyenii (Maca) has been shown to possess neuroprotective activity both in vitro and in vivo [1-3]. Previous studies have also demonstrated the activity of the pentane extract and its macamides, the most representative lipophilic constituents of Maca, in the endocannabinoid system as fatty acid amide hydrolase (FAAH) inhibitors. One of the most active macamides, N-3-methoxybenzyl-linoleamide [4, 5], was studied to determine its mechanism of interaction with FAAH and whether it has inhibitory activity on mono-acyl glycerol lipase (MAGL), the second enzyme responsible for endocannabinoid degradation [6]. Macamide concentrations from 1 to 100 Î¼M were tested using FAAH and MAGL inhibitor assay methods and showed no effect on MAGL. Tests with other conditions were performed in order to characterize the inhibitory mechanism of FAAH inhibition. N-3-methoxybenzyl-linoleamide displayed significant time-dependent and dose-dependent FAAH inhibitory activity. The mechanism of inhibition was most likely irreversible or slowly reversible. These results suggest the potential application of macamides isolated from Maca as FAAH inhibitors, as they might act on the central nervous system to provide analgesic, anti-inflammatory, or neuroprotective effects, by modulating the release of neurotransmitters. 23866172 Quantitative structure-activity relationship to predict acute fish toxicity of organic solvents. REACH regulation requires ecotoxicological data to characterize industrial chemicals. To limit in vivo testing, Quantitative Structure-Activity Relationships (QSARs) are advocated to predict toxicity of a molecule. In this context, the topic of this work was to develop a reliable QSAR explaining the experimental acute toxicity of organic solvents for fish trophic level. Toxicity was expressed as log(LC50), the concentration in mmol.L(-1) producing the 50% death of fish. The 141 chemically heterogeneous solvents of the dataset were described by physico-chemical descriptors and quantum theoretical parameters calculated via Density Functional Theory. The best subsets of solvent descriptors for LC50 prediction were chosen both through the Kubinyi function associated with Enhanced Replacement Method and a stepwise forward multiple linear regressions. The 4-parameters selected in the model were the octanol-water partition coefficient, LUMO energy, dielectric constant and surface tension. The predictive power and robustness of the QSAR developed were assessed by internal and external validations. Several techniques for training sets selection were evaluated: a random selection, a LC50-based selection, a balanced selection in terms of toxic and non-toxic solvents, a solvent profile-based selection with a space filling technique and a D-optimality onions-based selection. A comparison with fish LC50 predicted by ECOSAR model validated for neutral organics confirmed the interest of the QSAR developed for the prediction of organic solvent aquatic toxicity regardless of the mechanism of toxic action involved. 23631483 Fungal ABC Transporter-Associated Activity of Isoflavonoids from the Root Extract of Dalea formosa. New potential treatments for disseminated fungal infections are needed, especially for infections caused by the commonly drug-resistant pathogens Candida albicans and C. glabrata. These pathogens cause systemic candidiasis, a significant cause of mortality in immune-compromised patients. ABC transporters of the pleiotropic drug resistance subfamily, such as Cdr1p of C. albicans, play an important role in antifungal resistance and are potential bioassay targets for antifungal therapies against drug-resistant pathogens. We observed strong antifungal growth inhibitory activity in the methanol extract of Dalea formosa roots. This extract afforded six new isoflavonoids, sedonans A-F (1-6), a new but-2-enolide, 4'-O-methylpuerol A (7), and the new pterocarpan ent-sandwicensin (8). The structures and absolute configurations of these compounds were assigned using spectroscopic and chiroptical techniques. The direct antifungal activity of 1 against C. glabrata (MIC = 20 μM) was higher than that of fluconazole. Sedonans A-F and ent-sandwicensin were also active against Saccharomyces cerevisiae strains that express differing ABC transporter-associated resistance mechanisms but differed in their susceptibility to Cdr1p-mediated detoxification. A sedonan A (1)/ent-sandwicensin (8) combination exhibited synergistic growth inhibition. The results demonstrate that multiple crude extract compounds are differentially affected by efflux-mediated resistance and are collectively responsible for the observed bioactivity. 23360367 Intrathecal apelin-13 produced different actions in formalin test and tail-flick test in mice. Apelin was identified as natural ligand for APJ, a G protein-coupled receptor. APJ is expressed in spinal cord and dorsal root ganglion. This study was designed to investigate the effects and mechanisms of intrathecally (i.t.) administered apelin-13 on nociceptive response in formalin test and tail-flick test. In formalin test, i.t. injection of apelin-13 (0.3-3 nmol/mouse) had no effect on the nociceptive response in either acute phase (0-10 min) or interphase (10-20 min), but significantly produced hyperalgesic effect in late phase (20-30 min) at the dose of 3 nmol/mouse. The APJ receptor antagonist apelin-13(F13A) and GABAA receptor antagonist bicuculline methiodide, but not opioid receptor antagonist naloxone, significantly blocked the hyperalgesia caused by apelin-13 in late phase, indicating that i.t. apelin-13- induced hyperalgesia was mediated by APJ and GABAA receptor, rather than opioid receptor. However, in tail-flick test, i.t. injected apelin-13 (1 and 3 nmol/mouse) induced a significant antinociceptive effect, which was significantly antagonized by apelin-13(F13A) and naloxone, suggesting APJ and opioid receptor were involved in the antinociception of spinal apelin-13. 23836775 Characterization of a high field Orbitrap mass spectrometer for proteome analysis. The field of proteomics continues to be driven by improvements in analytical technology, notably in peptide separation, quantitative MS, and informatics. In this study, we have characterized a hybrid linear ion trap high field Orbitrap mass spectrometer (Orbitrap Elite) for proteomic applications. The very high resolution available on this instrument allows 95% of all peptide masses to be measured with sub-ppm accuracy that in turn improves protein identification by database searching. We further confirm again that mass accuracy in tandem mass spectra is a valuable parameter for improving the success of protein identification. The new CID rapid scan type of the Orbitrap Elite achieves similar performance as higher energy collision induced dissociation fragmentation and both allow the identification of hundreds of proteins from as little as 0.1 ng of protein digest on column. The new instrument outperforms its predecessor the Orbitrap Velos by a considerable margin on each metric assessed that makes it a valuable and versatile tool for MS-based proteomics. 22396209 Effects of stick design features on perceptions of characteristics of cigarettes. To examine the extent (if any) that cigarette stick dimension, tipping paper design and other decorative design/branding have on Australian smokers' perceptions of those cigarettes. An internet survey of 160 young Australian adult ever-smokers who were shown computer images of three sets of cigarette sticks-five sticks of different lengths and diameters (set A), five sticks with different tipping paper design (set B) and four sticks of different decorative design (set C). Branding was a between-subjects randomised condition for set C. For each set, respondents ranked sticks on most and least attractive, highest and lowest quality and strongest and weakest taste. Cigarette sticks were perceived as different on attractiveness, quality and strength of taste. Standard stick length/diameter was perceived as the most attractive and highest quality stick, with men more inclined to rate a slim stick as less attractive. A stick with a cork-patterned tipping paper and a gold band was seen as most attractive, of highest quality and strongest in taste compared to other tipping designs. Branded sticks were seen as more attractive, higher in quality and stronger tasting than non-branded designs, regardless of brand, although the effects were stronger for a prestige compared with a budget brand. Characteristics of the cigarette stick affect smokers' perceptions of the attributes of those cigarettes and thus are a potential means by which product differentiation can occur. A comprehensive policy to eliminate promotional aspects of cigarette design and packaging needs to include rules about stick design. 23856159 Sustained release of platelet-derived growth factor and vascular endothelial growth factor from silk/calcium phosphate/PLGA based nanocomposite scaffold. To exploit the therapeutic potential of growth factors in tissue regeneration, it is necessary to design a porous scaffold in order to concurrently accommodate cells and release angiogenic factors in a controlled manner. In an attempt to address these issues, we developed a nanocomposite scaffold based on silk/calcium phosphate/PLGA by freeze-drying and electrospinning in order to control the release of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). The highly porous scaffold possessed appropriate chemical and physical structure as confirmed by FTIR, XRD, SEM, and Zeta potential analysis. Furthermore, the incorporation of PDGF and VEGF in the scaffold was confirmed using Raman spectroscopy while their bioactivity was maintained by 82% and 89% for up to 28 days, respectively. The release of PDGF was slower than VEGF as respected. Additionally, the scaffold could promote proliferation, alkaline phosphatase production and attachment of human osteoblast cells. Histological examination established new bone matrix formation with neovascularization in the angiogenic factors loaded scaffold after 10 weeks of implantation in rabbit model. Finally, it was considered that the fabricated nanocomposite could be useful for bone tissue engineering applications. 23660119 Beta-blocker use and clinical outcomes after primary vascular surgery: a nationwide propensity score-matched study. To explore the associations between beta-blocker use and clinical outcomes (death, hospitalisation with myocardial infarction (MI) or stroke, major amputation and recurrent vascular surgery) after primary vascular reconstruction. Patients who had primary vascular surgical or endovascular reconstruction due to symptomatic peripheral arterial disease, in Denmark between 1996 and 2007 were included. We obtained data on filled prescriptions, clinical outcomes and confounding factors from population-based healthcare registries. Beta-blocker users were matched to non-users by propensity score, and Cox-regression was performed. All medications were included as time-dependent variables. We studied 16,945 matched patients (7828 beta-blocker users and 9117 non-users) with a median follow-up period of 582 days (range, 30-4379 days). The cumulative risks were as follows: all-cause mortality, 17.9%; MI, 5.3%; stroke, 5.6%; major amputation, 9.1%; and recurrent vascular surgery, 23.1%. When comparing beta-blocker users with non-users: adjusted hazard ratio: MI, 1.52 (95% CI, 1.31-1.78); stroke, 1.21 (95% CI, 1.03-1.43); and major amputation, 0.80 (95% CI, 0.70-0.93). Beta-blocker use after primary vascular surgery was associated with a lower risk of major amputation but an increased risk of hospitalisation with MI and stroke. No associations were found between beta-blocker use and all-cause mortality or the risk of recurrent vascular surgery. However, our results are not sufficient to alter the indication for beta-blocker use among symptomatic peripheral arterial disease patients. 23599007 New Diterpenes from a Godavari Mangrove, Ceriops decandra. Eleven new diterpenes, named decandrins A-K (1-11), including nine abietanes (1-9) and two podocarpanes (10-11), were isolated from the barks of an Indian mangrove, Ceriops decandra, collected in the mangrove swamp of Godavari estuary, Andhra Pradesh, together with four known abietanes. The structures of these compounds were established on the basis of spectroscopic data (new compounds) or comparison with data in the literature (known compounds). This is the first report of abietane and podocarpane diterpenoids from C. decandra. 23345168 Blocking the proliferation of human tumor cell lines by peptidase inhibitors from Bauhinia seeds. In cancer tumors, growth, invasion, and formation of metastasis at a secondary site play a pivotal role, participating in diverse processes in the development of the pathology, such as degradation of extracellular matrix. Bauhinia seeds contain relatively large quantities of peptidase inhibitors, and two Bauhinia inhibitors were obtained in a recombinant form from the Bauhinia bauhinioides species, B. bauhinoides cruzipain inhibitor, which is a cysteine and serine peptidase inhibitor, and B. bauhinioides kallikrein inhibitor, which is a serine peptidase inhibitor. While recombinant B. bauhinoides cruzipain inhibitor inhibits human neutrophil elastase cathepsin G and the cysteine proteinase cathepsin L, recombinant B. bauhinioides kallikrein inhibitor inhibits plasma kallikrein and plasmin. The effects of recombinant B. bauhinoides cruzipain inhibitor and recombinant B. bauhinioides kallikrein inhibitor on the viability of tumor cell lines with a distinct potential of growth from the same tissue were compared to those of the clinical cytotoxic drug 5-fluorouracil. At 12.5 µM concentration, recombinant B. bauhinoides cruzipain inhibitor and recombinant B. bauhinioides kallikrein inhibitor were more efficient than 5-fluorouracil in inhibiting MKN-28 and Hs746T (gastric), HCT116 and HT29 (colorectal), SkBr-3 and MCF-7 (breast), and THP-1 and K562 (leukemia) cell lines. Additionally, recombinant B. bauhinoides cruzipain inhibitor inhibited 40 % of the migration of Hs746T, the most invasive gastric cell line, while recombinant B. bauhinioides kallikrein inhibitor did not affect cell migration. Recombinant B. bauhinioides kallikrein inhibitor and recombinant B. bauhinoides cruzipain inhibitor, even at high doses, did not affect hMSC proliferation while 5-fluorouracil greatly reduced the proliferation rates of hMSCs. Therefore, both recombinant B. bauhinoides cruzipain inhibitor and recombinant B. bauhinioides kallikrein inhibitor might be considered for further studies to block peptidase activities in order to target specific peptidase-mediated growth and invasion characteristics of individual tumors, mainly in patients resistant to 5-fluorouracil chemotherapy. 23816643 Leishmania braziliensis: Cytotoxic, cytostatic and chemotactic effects of poly-lysine-methotrexate-conjugates. Chemotactic responses play a significant role during Leishmania differentiation, as well as in the course of parasite-host-cell interaction, a process that precedes a successful infection. The present study uses the modified "two-chamber capillary assay" to quantitatively evaluate the chemotactic properties and the toxic activities of methotrexate containing branched chain polymeric polypeptide conjugates in Leishmania. Our results demonstrate that this methodology quantitatively determines the taxis of Leishmania towards/against gradients of compounds. They also demonstrate that chemotaxis produced by the polypeptide-methotrexate conjugates depends on specific chemical characteristics. For example, the N-terminal amino acid (Ser or Glu) location at the branch significantly influences the elicited chemotaxis. Furthermore, the use of different attachment sites in the methotrexate conjugates (α- or γ-carboxylic groups) affect their chemotactic activity. Specific cytotoxic activities and cytostatic effects of the conjugates on parasites and on murine and human cells of the macrophage/monocyte system respectively, suggest that these ligands may be used as a group of anti-Leishmania substances acting selectively on Leishmania and different hosts. 23824328 Synthesis of some fluorescent benzimidazole derivatives using cobalt(ii) hydroxide as highly efficient catalyst - spectral and physico-chemical studies and ESIPT process. Some fluorescent benzimidazole derivatives have been designed and synthesized using cobalt(ii) hydroxide as highly efficient catalyst. Synthesized compounds have been characterized by (1)H and (13)C-NMR and mass spectral analysis. The solvent effect on the absorption and fluorescence bands has been analyzed and supplemented by computational studies. Solvatochromic effects on the spectral position and profile of the stationary fluorescence spectra clearly indicate the charge transfer (CT) character of the emitting singlet states of all of the compounds studied in both polar and non-polar environments. The fluorescence decays for the benzimidazoles fit satisfactorily to a single exponential kinetics. HOMO and LUMO orbital pictures [DFT/B3LYP/6-31G(d,p)] evidence the existence of excited state intramolecular proton transfer (ESIPT) in benzimidazole derivatives containing a hydroxy group. 23690035 In vitro evolution of glutathione S-transferase using a plasmid display system based on the GAL4 DNA-binding domain. Enzyme characteristics, such as thermal stability and catalytic activity, can be improved in a targeted manner. However, the screening of target mutants is time-consuming and requires highly experimental downstream efforts. Here, we describe a simple strategy based on plasmid display and limited proteolysis for the rapid and easy screening of highly stable and active mutants from a library. When glutathione S-transferase was used as a model enzyme, the resulting mutants obtained in the first round of screening were approximately two- to sevenfold more thermostable than the wild-type enzyme at 50 °C, with similar enzyme activity. This methodology is therefore powerful for the in vitro enrichment and screening of thermostable and active mutants. It can reduce downstream experimental effort and can create a high-quality library using relatively simple steps. 23909434 Systematic review about breast cancer incidence in relation to hormone replacement therapy use. ABSTRACT Background: Several studies report a Breast Cancer (BC) incidence decrease subsequent to the decrease in Hormone replacement therapy (HRT) use. But its magnitude and the time-lag may vary between countries. This may reflect differences in populations, previous type and prevalence of HRT use and BC screening. Aim: To review systematically studies assessing the relation between BC incidence and change of HRT use. Material and method: Descriptive analysis of the methodology of the studies including design limitations and presence of confounding factors, data sources for BC and HRT and regimens of HRT used. Results and discussion: Eighteen articles were selected. Most studies were ecological and confounding factors such as mammography screening and changes in reproductive and life style habits could not be excluded. Sources of data on BC and HRT were heterogeneous and only few data on HRT regimens used were available. Most studies concluded that the decrease in HRT use during the last decade was probably associated with a BC incidence decrease, especially for women aged 50 or more. Conclusions: Data, mostly from epidemiological studies, suggest that the BC incidence decrease can be partly attributed to the HRT use drop. Nevertheless, available studies are hampered by a number of limitations and it remains difficult to evaluate the exact impact of HRT drop on BC incidence decrease. Especially, the studies are seldom based on detailed individual data and don't provide information on used regimens, type of cancers and possible confounding factors. 23685203 Chlamydia positivity in new orleans public high schools, 1996-2005: implications for clinical and public health practices. To describe the trends in chlamydia positivity among New Orleans high school students tested in a schoolwide screening between 1996 and 2005, and to determine factors associated with chlamydia positivity among students during the 10-year period. Between school years 1995-1996 and 2004-2005, students in New Orleans public high schools were tested for chlamydia using nucleic acid amplification tests (NAAT) in urine specimens (LCx assay until 1999-2000; BD assay from 2000-2001 to 2004-2005). For each year, we calculated chlamydia positivity by dividing the number of students testing positive by the total number of students tested. Data were analyzed separately by gender. Logistic regressions were performed to determine independent predictors of chlamydia positivity during the 10-year period. Between 1996 and 2005, the average chlamydia positivity was 7.0% (95% confidence interval 6.6-7.4) in boys and 13.1% (95% confidence interval 12.6-13.7) in girls (P < .001). Chlamydia detection increased with the switch from LCx to BD assay. In multivariate analyses, chlamydia positivity among boys and girls was significantly associated with age, black race, and gonorrhea coinfection. Additionally, positivity was significantly different by school year among boys (P = .03) and by NAAT used among girls (P = .008). The trends in chlamydia positivity observed between 1996 and 2005 more likely reflected a high and stable prevalence of chlamydia in the New Orleans school-age adolescent population. Any benefit of screening on individuals tested was likely to be mitigated by participants' uninterrupted social interactions with the dynamic forces that sustain the sexual transmission of chlamydia in the population. 23970458 Gonadotrophins for idiopathic male factor subfertility. Male factors leading to subfertility account for at least half of all cases of subfertility worldwide. Although some causes of male subfertility are treatable, treatment of idiopathic male factor subfertility remains empirical. Researchers have used gonadotrophins to improve sperm parameters in idiopathic male factor subfertility with the ultimate goal of increasing birth and pregnancy rates, but results have been conflicting. To determine the effect of systemic follicle-stimulating hormone (FSH) on live birth and pregnancy rates when administered to men with idiopathic male factor subfertility . We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register (14 January 2013), the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library, Issue 12 of 12, 2012), Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE (1946 to 14 January 2013), Ovid EMBASE (1980 to week 2 of 2013), Ovid PsycINFO (1806 to week 2 of 2013), trial registers for ongoing and registered trials at ClinicalTrials.gov (19 January 2013), the World Health Organisation International Trials Registry Platform (19 January 2013), The Cochrane Library Database of Abstracts of Reviews of Effects (19 January 2013) and OpenGrey for grey literature from Europe (19 January 2013). Searches were not limited by language. Bibliographies of included and excluded trials and abstracts of major meetings were searched for additional trials. Randomised controlled trials (RCTs) in which gonadotrophins were compared with placebo or no treatment for participants with idiopathic male factor subfertility. Two review authors independently selected the trials, assessed risk of bias and extracted data on live birth, pregnancy and adverse effects. We included data on pregnancies that occurred during or after gonadotrophin therapy. Study authors and pharmaceutical companies were asked to provide missing and unpublished data and/or additional information. Six RCTs with 456 participants and variable treatment and follow-up periods were included. From the limited data, the live birth rate per couple randomly assigned (27% vs 0%; Peto odds ratio (OR) 9.31, 95% confidence interval (CI) 1.17 to 73.75, one study, 30 participants, very low-quality evidence) and the spontaneous pregnancy rate per couple randomly assigned (16% vs 7%; Peto OR 4.94, 95% CI 2.13 to 11.44, five studies, 412 participants, I(2) = 0%, moderate-quality evidence) were significantly higher in men receiving gonadotrophin treatment than in men receiving placebo or no treatment. No significant difference between groups was noted when intracytoplasmic sperm injection (ICSI) or intrauterine insemination (IUI) was performed. None of the included studies reported miscarriage rates, and adverse events data were sparse. Encouraging preliminary data suggest a beneficial effect on live birth and pregnancy of gonadotrophin treatment for men with idiopathic male factor subfertility, but because the numbers of trials and participants are small, evidence is insufficient to allow final conclusions. Large multi-centre trials with adequate numbers of participants are needed. 23696540 Deliveries of normal healthy babies from embryos originating from oocytes showing the presence of smooth endoplasmic reticulum aggregates. Should oocytes showing the presence of smooth endoplasmic reticulum aggregates (SER) be considered for embryo transfer? The present study shows that embryos derived from metaphase II oocyte with visible SER (SER+MII) have the capacity to develop normally and may lead to newborns with no major malformations. It has been reported that the presence of SER in the cytoplasm of oocytes has a negative impact on embryo development, and is associated with a decreased clinical outcome and an increased risk of congenital anomalies. Therefore, it has been recommended that embryos derived from SER-positive oocytes should not be transferred. Consecutive ICSI cycles with at least one SER+MII oocyte were retrospectively analyzed regarding embryological and pregnancy outcome and compared with ICSI cycles showing only oocytes without SER (SER-MII). In total, 394 SER-positive (SER+) cycles and 6845 SER-negative (SER-) cycles were analyzed. The Student's t-test, one-way analysis of variance test and χ(2) test were used for statistical analysis. P value of <0.05 was considered statistically significant. Comparable fertilization rates were observed in SER+ (76.2%) and SER- (73.5%) cycles. In case of blastocyst culture, the cycle efficiency was lower in SER+ than in SER- cycles (mean 42.2 versus 62.8%, P < 0.001). The pregnancy and clinical pregnancy (CP) rates per embryo transfer (ET) were comparable for SER+ and SER- cycles (37.6 versus 37.8% and 33.0 versus 32.4%, respectively). In the SER+ cycles, the fertilization rates of SER+MII and SER-MII (72.9 versus 77.0%), as well as the capacity to develop into good-quality embryos on Days 3 (62.3 versus 63.7%) and 5 (45.4 versus 47.4%), were similar. In the 364 SER+ cycles, the ETs were subdivided in: ET with only SER+MII (n = 31; 8.5%), ET with only SER-MII (n = 235; 64.5%) and ET with mixed SER+ and SER-MII (n = 98; 26.9%). The pregnancy (25.8, 37.4 and 41.8%, respectively) and CP rates (22.6, 32.4 and 37.9%, respectively) were not different between the three subgroups. Among the cycles with known outcome, there was no difference in the rate of major malformations between SER+ cycles (5.3%) and SER- cycles (2.1%). Moreover, no major malformations were reported from the live borns definitely originating from SER+MII embryos. In addition, three newborns, from single ET with frozen-thawed embryos originating from SER+MII oocytes, were delivered and presented no major malformation. Taking into account the previous publications and our neonatal data, a follow-up of the children born after ET with embryos originating from SER+ cycles is encouraged. More studies should be performed to investigate the origin and effect of SER aggregates on the molecular status of oocytes and embryos. No external funding was either sought or obtained for this study and there are no potential competing interests. Not applicable. 23797109 Miniature short hairpin RNA screens to characterize antiproliferative drugs. The application of new proteomics and genomics technologies support a view in which few drugs act solely by inhibiting a single cellular target. Indeed, drug activity is modulated by complex, often incompletely understood cellular mechanisms. Therefore, efforts to decipher mode of action through genetic perturbation such as RNAi typically yields "hits" that fall into several categories. Of particular interest to the present study, we aimed to characterize secondary activities of drugs on cells. Inhibiting a known target can result in clinically relevant synthetic phenotypes. In one scenario, drug perturbation could, for example, improperly activate a protein that normally inhibits a particular kinase. In other cases, additional, lower affinity targets can be inhibited as in the example of inhibition of c-Kit observed in Bcr-Abl-positive cells treated with Gleevec. Drug transport and metabolism also play an important role in the way any chemicals act within the cells. Finally, RNAi per se can also affect cell fitness by more general off-target effects, e.g., via the modulation of apoptosis or DNA damage repair. Regardless of the root cause of these unwanted effects, understanding the scope of a drug's activity and polypharmacology is essential for better understanding its mechanism(s) of action, and such information can guide development of improved therapies. We describe a rapid, cost-effective approach to characterize primary and secondary effects of small-molecules by using small-scale libraries of virally integrated short hairpin RNAs. We demonstrate this principle using a "minipool" composed of shRNAs that target the genes encoding the reported protein targets of approved drugs. Among the 28 known reported drug-target pairs, we successfully identify 40% of the targets described in the literature and uncover several unanticipated drug-target interactions based on drug-induced synthetic lethality. We provide a detailed protocol for performing such screens and for analyzing the data. This cost-effective approach to mammalian knockdown screens, combined with the increasing maturation of RNAi technology will expand the accessibility of similar approaches in academic settings. 23774295 Adherens junctions determine the apical position of the midbody during follicular epithelial cell division. Cytokinesis is asymmetric along the apical-basal axis of epithelial cells, positioning the midbody near the apical domain. However, little is known about the mechanism and purpose of this asymmetry. We use live imaging of Drosophila follicle cell division to show that asymmetric cytokinesis does not result from intrinsic polarization of the main contractile ring components. We show that adherens junctions (AJs) maintain close contact with the apical side of the contractile ring during cytokinesis. Asymmetric distribution of AJ components within follicle cells and in the otherwise unpolarized S2 cells is sufficient to recruit the midbody, revealing that asymmetric cytokinesis is determined by apical AJs in the epithelia. We further show that ectopic midbody localization induces epithelial invaginations, shifting the position of the apical interface between daughter cells relative to the AB axis of the tissue. Thus, apical midbody localization is essential to maintain epithelial tissue architecture during proliferation. 23688464 Extraction optimization of Bruguiera gymnorrhiza polysaccharides with radical scavenging activities. Box-Behnken design including independent variables such as extraction temperature (60-80°C), extraction time (20-40 min) and ratio of water to raw material (30-50 mL/g) was used to optimize the extraction process of Bruguiera gymnorrhiza polysaccharides (BGPs). The experimental data were fitted to a second-order polynomial equation using multiple regression analysis. The optimum conditions were predicted as follows: extraction temperature 71°C, extracting time 31.4 min, and ratio of water to raw material 42. Under these conditions, the yield of BGPs obtained was (16.43 ± 0.08)%, which was in good agreement with the predicted value 16.47%. Additionally, characterization of BGPs was obtained by FT-IR analysis. The antioxidant activities of BGPs were evaluated in vitro. BGPs demonstrated appreciable antioxidant potential on superoxide anion radical, ABTS radical, and hydroxyl radical scavenging. These may provide theoretical basis for further system research and rational development and utilization of mangrove resources. 23764537 Control of humoral immunity and auto-immunity by the CXCR4/CXCL12 axis in lupus patients following influenza vaccine. CXCR4 is a chemokine receptor with multiple effects on the immune system, upregulated in patients with SLE, and correlated with disease severity. This study has investigated whether the levels of CXCR4 expressed on leucocyte subsets in lupus patients are correlated with the efficacy and the safety of the influenza vaccine. Twenty-seven patients were vaccinated and vaccine immunogenicity and tolerance were evaluated. CXCR4 was assayed on leucocyte subsets and correlated with clinical and immunological signs of diseases activity. A significant increase in the titres of antibodies to the three viral strains was observed along with trends towards an increased vaccine efficacy in patients with quiescent disease vs patients with active disease. Recent flu vaccine history and, to a lesser extent, immunosuppressive treatment may influence vaccine immunogenicity. Influenza immunization was not associated with clinical side-effects or clinical lupus flare but with an increase in rheumatoid factor levels. Our study also confirms the correlation of CXCR4 expression with biological autoimmunity as shown by the correlation between the percentage of CXCR4-positive T cells and the ANA titres at D0, and the reverse correlation between CXCR4 expression and vaccine immunogenicity as demonstrated by the higher percentage of CXCR4-positive T cells at D0 and D30 in non-responders vs responders. Altogether, our study confirms the efficacy and the safety of flu vaccine in SLE patients, highlights the role of CXCR4 as a surrogate marker for autoimmunity in lupus and shows that CXCR4 expression on T cells is predictive of vaccine efficacy in SLE patients. 23750995 Use of intravenous immunoglobulin in an Asian paediatric population over a 10-year period. There is a paucity of data on the pattern of intravenous immunoglobulin (IVIG) usage in the paediatric population. This study aimed to assess the prevalence, trends, indications and burden of cost of IVIG usage in the Singaporean paediatric population. Pharmacy data of all IVIG prescriptions between 2000 and 2009 in the two major paediatric public hospitals in Singapore were retrospectively reviewed. Each prescription was cross-referenced with the patient's hospital records to confirm the administration of IVIG and indication of use. Over the 10-year period, a total 78 155 g of IVIG valued at an estimated $5.2 million was prescribed. There was an increasing trend of 445.6 g/year (P = 0.02) over this period. Analysis of patients showed that the most common indication for IVIG use was Kawasaki disease, both in terms of the proportion of patients (60%) and amount of IVIG used (34%). Kawasaki disease was also the only indication where there were significant increasing trends in both patient numbers (7.4 patients/year) and amount of IVIG used (247.5 g/year). The indications with the highest amount of IVIG used per patient were for conditions related to primary immunodeficiency diseases and stem cell transplantation, where repeat transfusions were required. More than 75% of indications were Food and Drug Administration approved. Albeit substantial and increasing, the use of IVIG in Singaporean children is mostly evidence based. 23866828 Efficacy and safety of concentration-controlled everolimus with reduced-dose cyclosporine in Japanese de novo renal transplant patients: 12-month results. No study to date has evaluated the efficacy and safety of everolimus with reduced-exposure cyclosporine in Japanese de-novo renal transplant (RTx) patients. This 12-month, multicenter, open-label study randomized (1:1) 122 Japanese de-novo RTx patients to either an everolimus regimen (1.5 mg/day starting dose (target trough: 3 to 8 ng/ml) + reduced-dose cyclosporine) or a mycophenolate mofetil (MMF) regimen (2 g/day + standard dose cyclosporine). All patients received basiliximab and corticosteroids. Key endpoints at month 12 were composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up) and renal function (estimated glomerular filtration rate; Modification of Diet in Renal Disease-4). Clear cyclosporine exposure reduction was achieved in the everolimus group throughout the study (52% reduction at month 12). Month 12 efficacy failure rates showed everolimus 1.5 mg to be non-inferior to MMF (11.5% vs. 11.5%). The median estimated glomerular filtration rate at month 12 was 58.00 ml/minute/1.73 m2 in the everolimus group versus 55.25 ml/minute/1.73 m2 in the MMF group (P = 0.063). Overall, the incidence of adverse events was comparable between the groups with some differences in line with the known safety profile of the treatments. The everolimus group had a higher incidence of wound healing events and edema, whereas a higher rate of cytomegalovirus infections was reported in the MMF group. This study confirmed the efficacy of everolimus 1.5 mg/day (target trough: 3 to 8 ng/ml) in Japanese RTx patients for preventing acute rejection, while allowing for substantial cyclosporine sparing. Renal function and safety findings were comparable with previous reports from other RTx populations. ClinicalTrials.gov number: NCT00658320. 23426524 Expanding proteostasis by membrane trafficking networks. The folding biology common to all three kingdoms of life (Archaea, Bacteria, and Eukarya) is proteostasis. The proteostasis network (PN) functions as a "cloud" to generate, protect, and degrade the proteome. Whereas microbes (Bacteria, Archaea) have a single compartment, Eukarya have numerous subcellular compartments. We examine evidence that Eukarya compartments use coat, tether, and fusion (CTF) membrane trafficking components to form an evolutionarily advanced arm of the PN that we refer to as the "trafficking PN" (TPN). We suggest that the TPN builds compartments by generating a mosaic of integrated cargo-specific trafficking signatures (TRaCKS). TRaCKS control the temporal and spatial features of protein-folding biology based on the Anfinsen principle that the local environment plays a critical role in managing protein structure. TPN-generated endomembrane compartments apply a "quinary" level of structural control to modify the secondary, tertiary, and quaternary structures defined by the primary polypeptide-chain sequence. The development of Anfinsen compartments provides a unifying foundation for understanding the purpose of endomembrane biology and its capacity to drive extant Eukarya function and diversity. 23159501 Development of a repeated exposure protocol of human bronchial epithelium in vitro to study the long-term effects of atmospheric particles. Chronic exposure to atmospheric particles is suspected of exacerbating chronic inflammatory respiratory diseases but the underlying mechanisms remain poorly understood. An experimental strategy using human bronchial epithelial cells (NHBE) known to be one of the main target cells of particles in the lung was developed to investigate the long term effects of repeated exposure to particles. Primary cultures of NHBE cells were grown at an air-liquid interface and subjected to repeated treatments to particles. Fate of particles, pro inflammatory response and epithelial differentiation were studied during the 5 weeks following the final treatment. Ultrastructural observations revealed the biopersistence of particles in the bronchial epithelium. The expression of cytochrome P450 1A1, was transiently induced, suggesting that organic compounds could have been metabolized. The release of GM-CSF and IL-6 (biomarkers of pro-inflammatory response), was induced by particle treatments and was maintained up to 5weeks after treatments. The release of amphiregulin and TGFα (Growth Factor) was induced after each treatment. The number of cells expressing the mucin MUC5AC, a differentiation marker, was increased in particle-exposed epithelium. The experimental strategy we developed is suitable for investigating in greater depth the long term effects of particles on bronchial epithelial cells repeatedly exposed to atmospheric particles in vitro. 23855829 Prevalence and risk factors of posterior vitreous detachment in a Chinese adult population: the Handan eye study. To describe the prevalence and associations of posterior vitreous detachment (PVD) in a rural adult Chinese population. All eligible subjects were requested to carry out a comprehensive eye examination; PVD was a pre-specified outcome variable and was determined via biomicroscopical examination (slit-lamp biomicroscopy) with a +90-D preset lens after mydriasis. Prevalence was standardized to China population census (2000). 5890 (86.2%) subjects completed the examination of slit-lamp biomicroscopy with a +90-D lens. PVD was present in 160 participants (2.7%); the standardized prevalence was 2.0% (95% confidence interval [CI], 1.6-2.3%). PVD developed increasingly with age (P for trend < 0.001) for both men and women. Using a multivariate regression model, older people were found to run a higher risk of developing PVD than younger people, and women were found to have a higher risk than men (OR, 2.9; 95% CI, 1.5-5.9). Diabetes, hypertension, smoking, drinking, and intraocular pressure (IOP) were not significantly associated with PVD. About one in fifty people is found to have PVD in this population-based study. Age and female are independently associated with PVD occurrence. 23929267 Hepatitis C virus-related lymphoproliferative disorders encompass a broader clinical and morphological spectrum than previously recognized: a clinicopathological study. We describe a retrospective series of B-cell lymphoproliferative disorders associated with hepatitis C virus infection. In addition to splenic marginal zone lymphoma, follicular lymphoma and diffuse large B-cell lymphoma, all of which showed some specific features, we found two poorly described groups of cases. The first featured disseminated marginal zone lymphoma without splenic marginal zone lymphoma features, defying the current marginal zone lymphoma classification; the other consisted of monoclonal B lymphocytes in the peripheral blood, bone marrow or other tissues, with no clinical or histological evidence of lymphoma, and exhibiting a pattern that requires proper identification in order to avoid the misdiagnosis of the lymphoma. Diagnosis of hepatitis C virus infection-associated lymphoproliferative disorders requires the integration of clinical, pathological and molecular findings to establish an adequate diagnosis and decide the appropriate therapy to be applied.Modern Pathology advance online publication, 9 August 2013; doi:10.1038/modpathol.2013.120. 23775667 Nicotianamine is a major player in plant Zn homeostasis. Nicotianamine (NA) is among the most studied plant metal chelators. A large body of evidence supports its crucial role for Fe distribution in plants and as a precursor of phytosiderophore synthesis in grasses. NA forms stable complexes in vitro not only with Fe(II) and Fe(III) but also with various other divalent metal cations including Zn(II). Early observations indicated a possible contribution of NA to Zn trafficking in plants. Numerous studies on transgenic monocot and dicot plants with modulated NA levels have since then reported Zn accumulation phenotypes. NAS genes were shown to represent promising targets for biofortification efforts. For instance, NA was found to bind Zn in rice grains in a form bioavailable for humans. Recently, additional strong support for the existence of Zn-NA complexes in planta has been obtained in rice, Arabidopsis thaliana and the Zn hyperaccumulating plant A. halleri. We review the evidence for a role of NA in the intercellular and long-distance transport of Zn in plants and discuss open questions. 23860393 Symptom Occurrence and Severity on the Therapy-Related Symptom Checklist for Children Among Hispanic Pediatric Oncology Outpatients. A calibrated easy-to-use symptom checklist for children who are under treatment for cancer had been developed and reported in Cancer Nursing. The 30-item Therapy-Related Symptom Checklist for Children (TRSC-C) has good measurement and psychometric properties and uses "kid-friendly" terms to monitor symptom occurrence and severity during oncology treatment. A secondary analysis is reported using participants who self-identified as Hispanic. The objective of this study was to examine among Hispanic pediatric oncology outpatients (a) occurrence and (b) severity of symptoms reported on the TRSC-C, (c) relationships of symptoms to gender and age (<12 vs ≥12), and (d) differences in summated TRSC-C symptom scores between patients with acute lymphoblastic leukemia (ALL) and other diagnoses. This was a cross-sectional analysis using secondary data and descriptive statistics. The sample was composed of 79 children (55% male) aged 5 to 17 years (mean, 10.3 years) with diagnosis of ALL (52%) or other (48%). Instrument used was TRSC-C by patient/parent report (Cronbach'α = .91). (a) Symptom occurrence: 15 symptoms on the TRSC-C were reported by 40% or greater. (b) Severity means on 11 symptoms were greater than "a little bit." (c) No gender or age differences were found on mean TRSC-C summated scores. (d) Mean TRSC-C scores (symptom occurrence and severity) were slightly lower but not significantly different (t = 1.71) between ALL (13.71 [SD, 8.06]) and other diagnoses (15.71 [SD, 7.01]). Symptom occurrence and severity reported on the TRSC-C by this Hispanic subsample are consistent with findings in the calibration study and with those of another Hispanic group and other ethnicities. Use of the TRSC-C is appropriate during pediatric oncology treatment and diagnoses of Hispanic populations. 23685560 Evidence of a polygenic origin of extreme high-density lipoprotein cholesterol levels. There are several known monogenic causes of high and low high-density lipoprotein cholesterol (HDL-C) levels, but traditional sequencing studies have had limited success in identifying mutations in the majority of individuals with extreme HDL-C levels. The aim of this study was to assess the power of a targeted high-throughput sequencing strategy to elucidate the genetic basis of extreme HDL-C phenotypes. We sequenced 195 genes with either established or implicated roles in lipid and lipoprotein metabolism plus 78 lipid-unrelated genes in patients with HDL-C <1st (n=40) or >99th (n=40) percentile values, and the results were compared with those of 498 individuals representative of the Dutch general population and 95 subjects with normal HDL-C (between 40th and 60th percentile values). The extreme HDL cohort carried more rare nonsynonymous variants in the lipid geneset than both the general population (odds ratio, 1.39; P=0.019) and normal HDL-C (odds ratio, 1.43; P=0.040) cohorts. The prevalence of such variants in the lipid-related and lipid-unrelated genesets was similar in the control groups, indicative of equal mutation rates. In the extreme HDL cohort, however, there was enrichment of rare nonsynonymous variants in the lipid versus the control geneset (odds ratio, 2.23; P<0.0001), and 70% of the lipid-related variants altered conserved nucleotides. The lipid geneset comprised 4 nonsense, 10 splice-site, and 8 coding indel variants, whereas the control geneset contained only 1 such variant. In the lipid geneset, 87% and 28% of the patients carried ≥ 2 and ≥ 5 rare variants. This study suggests that most extreme HDL-C phenotypes have a polygenic origin. 22643845 Regulation of intestinal protein metabolism by amino acids. Gut homeostasis plays a major role in health and may be regulated by quantitative and qualitative food intake. In the intestinal mucosa, an intense renewal of proteins occurs, at approximately 50 % per day in humans. In some pathophysiological conditions, protein turnover is altered and may contribute to intestinal or systemic diseases. Amino acids are key effectors of gut protein turnover, both as constituents of proteins and as regulatory molecules limiting intestinal injury and maintaining intestinal functions. Many studies have focused on two amino acids: glutamine, known as the preferential substrate of rapidly dividing cells, and arginine, another conditionally essential amino acid. The effects of glutamine and arginine on protein synthesis appear to be model and condition dependent, as are the involved signaling pathways. The regulation of gut protein degradation by amino acids has been minimally documented until now. This review will examine recent data, helping to better understand how amino acids regulate intestinal protein metabolism, and will explore perspectives for future studies. 23660411 PmSERPIN3 from black tiger shrimp Penaeus monodon is capable of controlling the proPO system. Serpin or serine proteinase inhibitor is a family of protease inhibitors that are involved in controlling the proteolytic cascade in various biological processes. In shrimp, several serpins have been identified but only a few have been characterized. Herein, the PmSERPIN3 gene identified from Penaeus monodon EST database was studied. By using the 5'- and 3'-Rapid Amplification of cDNA Ends (RACE) techniques, the full-length of PmSERPIN3 cDNA was obtained. The cDNA contained an open reading frame of 1233bp encoding for 410 amino acid residue protein. Genome sequence analysis revealed that the PmSERPIN3 was an intronless gene. RT-PCR analysis revealed that it was constitutively expressed in all developmental stages, all shrimp tissues tested, and upon pathogen infections. The recombinant mature PmSERPIN3 protein (rPmSERPIN3) produced in Escherichia coli exhibited inhibitory activity against subtilisin. The rPmSERPIN3 also inhibited the shrimp prophenoloxidase system activation in vitro. Injecting the rPmSERPIN3 along with Vibrio harveyi into the shrimp decreased the clearance rate of bacteria in the hemolymph. Potentially, the PmSERPIN3 functions as a regulator of the proPO activating system. 23756474 Lifetime prognosis of juvenile myoclonic epilepsy. Juvenile myoclonic epilepsy (JME) is among the most common types of genetic epilepsies, displaying a good prognosis when treated with appropriate drugs, but with a well-known tendency to relapse after withdrawal. The majority of patients with JME have continuing seizures after a follow-up of two decades. However, 17% are able to discontinue medication and remain seizure-free thereafter. Clinicians should remember that there is a small but still considerable subgroup of JME patients whose seizures are difficult to treat before informing patients with newly-diagnosed JME about their "benign" prognosis. This resistant course is not fully explained, though there are many suggested factors. The dominating myoclonic seizures disappear or diminish in severity in the fourth decade of life. Despite the favorable seizure outcome in most of the cases, 3/4 of patients with JME have at least one major unfavorable social outcome. The possible subsyndromes of JME, its genetic background, and its pathophysiological and neuroimaging correlates should be further investigated. 23788611 Effects of chitosan particles in periodontal pathogens and gingival fibroblasts. Chitosan is a naturally derived polymer with antimicrobial and anti-inflammatory properties. However, studies evaluating the role of chitosan in the control of periodontal pathogens and the responses of fibroblasts to inflammatory stimuli are lacking. In the present study, we analyzed whether chitosan particles may inhibit the growth of periodontal pathogens and modulate the inflammatory response in human gingival fibroblasts. Chitosan particles were generated through ionic gelation. They inhibited the growth of Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans at 5 mg/mL. Conversely, IL-1β strongly stimulated PGE2 protein levels in gingival fibroblasts, and chitosan inhibited this response at 50 µg/mL. IL-1β-stimulated PGE2 production was dependent on the JNK pathway, and chitosan strongly inhibited this response. IL-1β stimulated NF-κB activation, another signaling pathway involved in PGE2 production. However, chitosan particles were unable to modify NF-κB signaling. The present study shows that chitosan exerts a predominantly anti-inflammatory activity by modulating PGE2 levels through the JNK pathway, which may be useful in the prevention or treatment of periodontal inflammation. 23939463 Hypothalamic Immunopathology in Anti-Ma-Associated Diencephalitis With Narcolepsy-Cataplexy. IMPORTANCE Idiopathic narcolepsy with cataplexy is thought to be an autoimmune disorder targeting hypothalamic hypocretin neurons. Symptomatic narcolepsy with low hypocretin level has been described in Ma antibody-associated encephalitis; however, the mechanisms underlying such an association remain unknown. OBSERVATIONS We described a 63-year-old man with clinical criteria for diencephalic encephalitis with sleepiness, cataplexy, hypocretin deficiency, and central hypothyroidism, together with brainstem encephalitis reflected by supranuclear ophtalmoparesis and rapid eye movement sleep behavior disorder with underlying abnormalities on brain magnetic resonance imaging. An autoimmune process was demonstrated by the detection of antibodies against Ma protein. Death occurred 4 months after disease onset without any tumor detected. Neuropathology, immunohistochemistry, and immunoreactivity results were compared with those obtained in idiopathic narcolepsy-cataplexy and with normal control brains. The principal findings revealed almost exclusive inflammation and tissue injury in the hypothalamus. The type of inflammatory reaction suggests cytotoxic CD8+ T lymphocytes being responsible for the induction of tissue injury. Inflammation was associated with complete loss of hypocretinergic neurons. Autoantibodies of the patient predominantly stained neurons in the hypothalamus and could be absorbed with Ma2. CONCLUSIONS AND RELEVANCE The encephalitic process, responsible for narcolepsy-cataplexy and hypocretin deficiency, reflects a CD8+ inflammatory-mediated response against hypocretin neurons. 23852647 The structurally effect of surface coated rhamnogalacturonan I on response of the osteoblast-like cell line SaOS-2. Osseointegration is important when implants are inserted into the bone and can be improved by biochemical surface coating of the implant. In this paper enzymatically modified rhamnogalacturonan I (RG-I) from apple and lupin was used for biochemical coating of aminated surfaces and the importance of the quality of RG-I, the nature of the binding, the fine structure of RG-I, and its effect on SaOS-2 cell line cultured on coated surfaces was investigated. SaOS-2 cells are osteoblast-like cells and a well-established in vitro model of bone-matrix forming osteoblasts. Purification by gel filtration could remove small fragments of galacturonic acid (GalA) and binding studies showed that the purity of the RG-I molecules was important for the quality of the coating. The structure of RG-I and osteoblast-like cells' viability were positively correlated so that high content of 1,4-linked galactose (Gal) and a low content of arabinose in the RG-I molecules favored cell viability. These results indicate that coating of implants with RG-I affect osseointegration positively. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013. 23622243 The Histone Mark H3K36me3 Regulates Human DNA Mismatch Repair through Its Interaction with MutSα. DNA mismatch repair (MMR) ensures replication fidelity by correcting mismatches generated during DNA replication. Although human MMR has been reconstituted in vitro, how MMR occurs in vivo is unknown. Here, we show that an epigenetic histone mark, H3K36me3, is required in vivo to recruit the mismatch recognition protein hMutSα (hMSH2-hMSH6) onto chromatin through direct interactions with the hMSH6 PWWP domain. The abundance of H3K36me3 in G1 and early S phases ensures that hMutSα is enriched on chromatin before mispairs are introduced during DNA replication. Cells lacking the H3K36 trimethyltransferase SETD2 display microsatellite instability (MSI) and an elevated spontaneous mutation frequency, characteristic of MMR-deficient cells. This work reveals that a histone mark regulates MMR in human cells and explains the long-standing puzzle of MSI-positive cancer cells that lack detectable mutations in known MMR genes. 23819609 Photo- and Radiation-Chemistry of Halide Anions in Ionic Liquids. One- and two- photon excitation of halide anions (X(-)) in polar molecular solvents results in electron detachment from the dissociative charge-transfer-to-solvent state; this reaction yields a solvated halide atom and a solvated electron. How do such photoreactions proceed in ionic liquid (IL) solvents? Matrix isolation electron paramagnetic resonance (EPR) spectroscopy has been used to answer this question for photoreactions of bromide in aliphatic (1-butyl-1-methylpyrrolidinium) and aromatic (1-alkyl-3-methyl-imidazolium) ionic liquids. In both classes of ILs, the photoreaction (both 1- and 2-photon) yields bromine atoms that promptly abstract hydrogen from the alkyl chains of the IL cation; only in concentrated bromide solutions (containing >5-10 mol % bromide) does Br2(-•) formation compete with this reaction. In two-photon excitation, the 2-imidazolyl radical generated via the charge transfer promptly eliminates the alkyl arm. These photolytic reactions can be contrasted with radiolysis of the same ILs, in which large yield of BrA(-•) radicals was observed (where A(-) is a matrix anion), suggesting that solvated Br(•) atoms do not occur in the ILs, as such a species would form three-electron σ(2)σ(*1) bonds with anions present in the IL. It is suggested that chlorine and bromine atoms abstract hydrogen faster than they form such radicals, even at cryogenic temperatures, whereas iodine mainly forms such bound radicals. These XA(-•) radicals convert to X2(•-) radicals in a reaction with the parent halide anion. Ramifications of these observations for photodegradation of ionic liquids are discussed. 23812226 Bolus 5-fluorouracil as an alternative in patients with cardiotoxicity associated with infusion 5-fluorouracil and capecitabine: a case series. 5-Fluorouracil (5-FU) is the backbone of chemotherapy regimens approved for treatment of colorectal cancer. The incidence of cardiotoxicity associated with 5-FU ranges from 1.5% to 18%; 48% as anginal symptoms and 2% as cardiogenic shock. Cardiotoxicity is unpredictable and no alternative chemotherapeutics have been defined so far. We present a case series of six patients who developed cardiotoxicity on infusional fluorouracil and/or capecitabine and were challenged with bolus 5-FU for the treatment of their malignancies. Four patients were tested for polymorphic abnormality of the human dihydropyrimidine dehydrogenase gene (DPYD) with the TheraGuide 5-FU™ (Myriad Genetic Laboratories, Inc., Salt Lake City, UT, USA) pharmacogenetic test. Five patients were challenged with oral capecitabine that reproduced clinical and/or diagnostic concerns. All six patients tolerated bolus 5-FU either as a radiosensitizing agent or as chemotherapy without recurrence of a cardiac insult. DPYD was normal in the four patients tested. Cardiotoxicity induced by 5-FU seems to be schedule-dependent. Bolus 5-FU can be used in patients developing cardiotoxicity due to 5-FU infusion or capecitabine with vigilance. 23958515 Synthesis and biological evaluation of prodigiosene conjugates of porphyrin, estrone and 4-hydroxytamoxifen. To generate the first series of prodigiosene conjugates, the tripyrrolic skeleton was appended to estrone, tamoxifen and porphyrin frameworks by way of ester linkers and various hydrocarbon chain lengths. The ability of the conjugates to inhibit various types of cancer cells was evaluated in vitro. The porphyrin conjugates did not exhibit significant activity. The estrone conjugates exhibited modest activity, for the most part. However, significantly greater growth inhibition activity against certain breast, colon, lung, leukemia, melanoma and prostate cell lines was noted. This unusual effect for this first generation model class of compound warrants further investigation and comparison to cases where estrogens are linked to prodigiosenes via connection points that do not feature in estrogen receptor binding. The 4-hydroxytamoxifen conjugates exhibit nanomolar range activity against the MCF-7 breast cancer cell line, paving the way to expand the scope and connectivity of prodigiosene-tamoxifen conjugates. 22767283 Human neuronal coenzyme Q10 deficiency results in global loss of mitochondrial respiratory chain activity, increased mitochondrial oxidative stress and reversal of ATP synthase activity: implications for pathogenesis and treatment. Disorders of coenzyme Q(10) (CoQ(10)) biosynthesis represent the most treatable subgroup of mitochondrial diseases. Neurological involvement is frequently observed in CoQ(10) deficiency, typically presenting as cerebellar ataxia and/or seizures. The aetiology of the neurological presentation of CoQ(10) deficiency has yet to be fully elucidated and therefore in order to investigate these phenomena we have established a neuronal cell model of CoQ(10) deficiency by treatment of neuronal SH-SY5Y cell line with para-aminobenzoic acid (PABA). PABA is a competitive inhibitor of the CoQ(10) biosynthetic pathway enzyme, COQ2. PABA treatment (1 mM) resulted in a 54 % decrease (46 % residual CoQ(10)) decrease in neuronal CoQ(10) status (p < 0.01). Reduction of neuronal CoQ(10) status was accompanied by a progressive decrease in mitochondrial respiratory chain enzyme activities, with a 67.5 % decrease in cellular ATP production at 46 % residual CoQ(10). Mitochondrial oxidative stress increased four-fold at 77 % and 46 % residual CoQ(10). A 40 % increase in mitochondrial membrane potential was detected at 46 % residual CoQ(10) with depolarisation following oligomycin treatment suggesting a reversal of complex V activity. This neuronal cell model provides insights into the effects of CoQ(10) deficiency on neuronal mitochondrial function and oxidative stress, and will be an important tool to evaluate candidate therapies for neurological conditions associated with CoQ(10) deficiency. 23298261 Systemic leptin increases the electrical activity of supraoptic nucleus oxytocin neurones in virgin and late pregnant rats. In the rat hypothalamus, fasting attenuates the expression of oxytocin and this can be reversed by exogenous leptin administration. In the present study, we investigated the effects of systemically administered leptin on the electrical activity of magnocellular neurones in the supraoptic nucleus of urethane-anaesthetised rats. In virgin female rats, systemic leptin significantly excited identified oxytocin neurones with no detected effects on the patterning of activity, as reflected by hazard function analyses. The lowest dose that was consistently effective was 100 μg/i.v., and this dose had no significant effect on vasopressin neurones. In virgin rats fasted overnight, the spontaneous firing rate of oxytocin neurones was significantly lower than in unfasted rats, although leptin had a similar excitatory effect as in unfasted rats. In late pregnant rats (days 19-21 of pregnancy), spontaneous firing rates of oxytocin neurones were higher than in virgins, and the initial response to leptin was similar to that in virgin rats, although the increase in activity was more persistent. In fasted pregnant rats, the mean spontaneous firing rate of oxytocin neurones was again lower than in unfasted rats, although leptin had no significant effect even at the higher dose of 1 mg/rat. Thus, fasting reduced the spontaneous firing rates of oxytocin neurones in nonpregnant rats, and this effect could be reversed by the excitatory effects of leptin. Pregnant rats showed some evidence of leptin resistance but only after an overnight fast. 23351959 Pharmacokinetics, tissue distribution and excretion study of resveratrol and its prodrug 3,5,4'-tri-O-acetylresveratrol in rats. 3,5,4'-Tri-O-acetylresveratrol (TARES) synthesized by acetylating three hydroxyl groups of resveratrol (RES) is a prodrug of RES. The aim of this study was to investigate and compare the pharmacokinetics, tissue distribution and excretion of TARES and RES in rats following a single intragastric gavage (i.g.) administration. After RES is transformed into TARES, its pharmacokinetic properties are improved, such as the t1/2 has been prolonged and the AUC has been enhanced. And TARES follows linear plasma pharmacokinetics across the investigated dosage range in rats (77.5-310mg/kg). The major distribution tissues of TARES or RES in rats were liver, spleen, heart and lung. TARES can increase the content of RES in lung significantly. There was no long-term accumulation of RES in rat tissues. Whether we administrated to rats of equimolar TARES or RES, total recoveries of RES in urine and feces within 36h were low (0.99% or 0.07% in urine and 1.69% or 0.15% in feces). 23844994 Design of linear ligands for selective separation using a genetic algorithm applied to molecular architecture. Continuous purification of chemical reaction products through adsorption-based operations during workup may present advantages over batch chromatography or crystallization. In pharmaceutical syntheses, however, the desired product is often structurally similar to byproducts or unconverted reactant, so that identifying a suitable adsorption medium is challenging. We developed an in silico screening process to design organic ligands which, when chemically bound to a solid surface, would constitute an effective adsorption for a pharmaceutically relevant mixture of reaction products. This procedure employs automated molecular dynamics simulations to evaluate potential ligands, by measuring the difference in adsorption energy of two solutes which differed by one functional group. Then, a genetic algorithm was used to iteratively improve a population of such ligands through selection and reproduction steps. This procedure identified chemical designs of the surface-bound ligands that were outside the set we considered using chemical intuition. The ligand designs achieved selectivity by exploiting phenyl-phenyl stacking which was sterically hindered in the case of one solution component. The ligand designs had selectivity energies of 0.8-1.6 kcal/mol in single-ligand, solvent-free simulations, if entropic contributions to the relative selectivity are neglected. We believe this molecular evolution technique presents a useful method for the directed exploration of chemical space or for molecular design, when the chemical properties of interest can be efficiently evaluated through simulations. 23800737 Potential effects of environmental conditions on the efficiency of the antifungal tebuconazole controlling Fusarium verticillioides and Fusarium proliferatum growth rate and fumonisin biosynthesis. Fusarium verticillioides and Fusarium proliferatum are important phytopathogens which contaminate cereals in the Mediterranean climatic region with fumonisins. In this study we examined the interaction between the fungicide efficacy of tebuconazole and water potential (Ψw) (-0.7-7.0MPa)×temperature (20-35°C) on growth and FUM1 gene expression by real time RT-PCR (an indicator of fumonisin biosynthesis) in strains of both Fusarium species. Concentrations of tebuconazole required to reduce growth by 50 and 90% (ED50 and ED90 values) were determined. Growth of strains of both species was largely reduced by tebuconazole, with similar efficacy profiles in the interacting water potential×temperature conditions. In contrast, FUM1 expression was not generally reduced by tebuconazole. Moreover, sub-lethal doses in combination with mild water stress and temperatures less than 35°C significantly induced FUM1 expression with slight differences in both species. These results suggest that the efficacy of antifungal compounds to reduce mycotoxin risk would be more effective if consideration is given to both growth rate and toxin biosynthesis in relation to interacting environmental conditions. This is the first study linking fungicide efficacy of tebuconazole with environmental factor effects on control of growth and FUM1 gene expression of F. verticillioides and F. proliferatum. 23926304 Analysis of risk factors influencing outcomes after cord-blood-transplantation in children with juvenile myelomonocytic leukemia. We retrospectively analyzed 110 patients with juvenile myelomonocytic leukemia (JMML), given single-unit, unrelated donor umbilical cord blood transplantation (UCBT). Median age at diagnosis and at transplantation was 1.4 (range 0.1-6.4) and 2.2 years (range 0.5-7.4), respectively. Before transplantation, 88 patients received chemotherapy; splenectomy was performed in 24. Monosomy of chromosome 7 was the most frequent cytogenetic abnormality, found in 24% of patients. All but 8 patients received myeloablative conditioning; cyclosporine+steroids was the most common graft-versus-host disease prophylaxis. Sixteen percent of units were HLA-matched with the recipient, while 43% and 35% had either 1 or 2-3 HLA-disparities, respectively. Median number of nucleated cells infused was 7.1x10(7)/kg (range 1.7-27.6). With a median follow-up of 64 months (range 14-174), the 5-year cumulative incidences of transplantation-related mortality and relapse were 22% and 33%, respectively. The 5-year disease-free survival (DFS) was 44%. In multivariate analysis, factors predicting better DFS were: age younger than 1.4 years at diagnosis (Hazard Ratio, HR, 0.42, p=0.005), 0-1 HLA disparities in the donor/recipient pair (HR=0.4, p=0.009) and karyotype other than monosomy 7 (HR=0.5, p=0.02). UCBT may cure a relevant proportion of JMML children. Since disease recurrence remains the major cause of treatment failure, strategies to reduce relapse incidence are warranted. 23928263 Null Association Between Histology of First and Second Primary Malignancies in Men With Bilateral Testicular Germ Cell Tumors. Testicular germ cell tumors (TGCTs), the most common neoplasms of young men, are categorized histologically as either seminomas or nonseminomas/mixed germ cell tumors. These subtypes differ by age at diagnosis and clinical course, but little is known about etiological distinctions. To test the hypothesis that histological subtypes have distinct sets of unrecognized etiological factors, we used a recently described approach, estimating the association between histological types of first and second tumors of men with 2 primary TGCTs. The study population of 488 men each with 2 primary TGCTs was ascertained through population-based cancer registries in the United States between 1972 and 2006. Univariate logistic regression analysis revealed that the histology of second primary TGCTs was associated with the histology of first TGCTs (odds ratio = 1.70, 95% confidence interval: 1.14, 2.52); however, the association did not persist in analyses adjusted for age at diagnosis of first TGCT (odds ratio = 1.09, 95% confidence interval: 0.71, 1.70). These results would be expected if the subtypes share etiology but experience different rates of progression to diagnosis or if the histological fate of TGCTs is influenced by age-related processes. Men with 2 primary TGCTs provide novel opportunities to learn whether histological subtypes are likely to share etiology, so results may inform research designed to identify causes. 23852692 Enhancement of the synthesis of n-3 PUFAs in fat-1 transgenic mice inhibits mTORC1 signalling and delays surgically induced osteoarthritis in comparison with wild-type mice. An exogenous supplement of n-3 polyunsaturated fatty acids (PUFAs) has been reported to prevent osteoarthritis (OA) through undefined mechanisms. This study investigated the effect of alterations in the composition of endogenous PUFAs on OA, and associations of PUFAs with mammalian target of rapamycin complex 1 (mTORC1) signalling, a critical autophagy pathway in fat-1 transgenic (TG) mice. fat-1 TG and wild-type mice were used to create an OA model by resecting the medial meniscus. The composition of the endogenous PUFAs in mouse tissues was analysed by gas chromatography, and the incidence of OA was evaluated by micro-computed tomography (micro-CT), scanning electron microscopy and histological methods. Additionally, primary chondrocytes were isolated and cultured. The effect of exogenous and endogenous PUFAs on mTORC1 activity and autophagy in chondrocytes was assessed. The composition of endogenous PUFAs of TG mice was optimised both by increased n-3 PUFAs and decreased n-6 PUFAs, which significantly alleviated the articular cartilage destruction and osteophytosis in the OA model (p<0.01), decreased protein expression of matrix metalloproteinase-13 (MMP-13) and ADAMTS-5 (a disintegrin and metalloproteinase with thrombospondin motifs) in the articular cartilage (p<0.01) and reduced chondrocyte number and loss of cartilage extracellular matrix. Both exogenous and endogenous n-3 PUFAs downregulated mTORC1 activity and promoted autophagy in articular chondrocytes. Conversely, mTORC1 pathway activation suppressed autophagy in articular chondrocytes. Enhancement of the synthesis of endogenous n-3 PUFAs from n-6 PUFAs can delay the incidence of OA, probably through inhibition of mTORC1, promotion of autophagy and cell survival in cartilage chondrocytes. Future investigation into the role of the endogenous n-6/n-3 PUFAs composition in OA prevention and treatment is warranted. 23600492 Endothelial microparticles in mild chronic obstructive pulmonary disease and emphysema. The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease study. Basic research implicates alveolar endothelial cell apoptosis in the pathogenesis of chronic obstructive pulmonary disease (COPD) and emphysema. However, information on endothelial microparticles (EMPs) in mild COPD and emphysema is lacking. We hypothesized that levels of CD31(+) EMPs phenotypic for endothelial cell apoptosis would be elevated in COPD and associated with percent emphysema on computed tomography (CT). Associations with pulmonary microvascular blood flow (PMBF), diffusing capacity, and hyperinflation were also examined. The Multi-Ethnic Study of Atherosclerosis COPD Study recruited participants with COPD and control subjects age 50-79 years with greater than or equal to 10 pack-years without clinical cardiovascular disease. CD31(+) EMPs were measured using flow cytometry in 180 participants who also underwent CTs and spirometry. CD62E(+) EMPs phenotypic for endothelial cell activation were also measured. COPD was defined by standard criteria. Percent emphysema was defined as regions less than -950 Hounsfield units on full-lung scans. PMBF was assessed on gadolinium-enhanced magnetic resonance imaging. Hyperinflation was defined as residual volume/total lung capacity. Linear regression was used to adjust for potential confounding factors. CD31(+) EMPs were elevated in COPD compared with control subjects (P = 0.03) and were notably increased in mild COPD (P = 0.03). CD31(+) EMPs were positively related to percent emphysema (P = 0.045) and were inversely associated with PMBF (P = 0.047) and diffusing capacity (P = 0.01). In contrast, CD62E(+) EMPs were elevated in severe COPD (P = 0.003) and hyperinflation (P = 0.001). CD31(+) EMPs, suggestive of endothelial cell apoptosis, were elevated in mild COPD and emphysema. In contrast, CD62E(+) EMPs indicative of endothelial activation were elevated in severe COPD and hyperinflation. 23948597 Hypothesis: Smoking decreases breast feeding duration by suppressing prolactin secretion. A number of studies, including new data summarized here, conclude that breast feeding duration is lower in smoking mothers. Although some have suggested that this merely reflects poor health motivation in those prone to smoke, several lines of evidence support the view that chronic smoking does indeed compromise breast feeding by suppressing prolactin secretion and thereby lowering breast milk volume. Moreover, a recent clinical trial shows that an effective smoking cessation program can boost breast feeding duration in smokers. An analysis of pertinent rodents studies suggests that chronic nicotine administration boosts dopaminergic activity in the tuberoinfundibular tract which functions to inhibit prolactin release; this increase in dopaminergic activity, in turn, may reflect a nicotine-mediated suppression of hypothalamic opioid activity. 23695363 A unified procedure for detecting, quantifying, and validating electrocardiogram T-wave alternans. The precision of T-wave alternans (TWA) quantification depends certainly upon the way we choose to align T-waves and to get feedbacks from the electrocardiogram (ECG) quality. Quantifying the ECG TWA based on assigning automatically the required number of T-waves along with applying a proper T-wave alignment approach is the purpose of this paper. The structure of the proposed method mainly consists of seven sections: preprocessing, ECG events detection-delineation, alignment of cycles, T-wave template extraction, T-wave delineation, T-wave left- and right-lobes synchronization, and T-wave alternans quantification-detection by getting feedback from ECG quality value. The proposed method is examined in two ways. First, some artificially generated ECGs with predefined TWA patterns and qualities are analyzed in order to regulate the parameters of the method to achieve the maximum performance. Finally, the method is applied to PhysioNet/Computing in Cardiology Challenge 2008 database. In this stage, the achieved accuracy is about 91.0 %, which shows marginal improvement in the area of TWA quantification. 23902802 A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains. The mouse inbred line C57BL/6J is widely used in mouse genetics and its genome has been incorporated into many genetic reference populations. More recently large initiatives such as The International Knockout Mouse Consortium (IKMC) are using the C57BL/6N mouse strain to generate null alleles for all mouse genes. Hence both strains are now widely used in mouse genetics studies. Here we perform a comprehensive genomic and phenotypic analysis of the two strains to identify differences that may influence their underlying genetic mechanisms. We undertake genome sequence comparisons of C57BL/6J and C57BL/6N to identify SNPs, indels and structural variants, with a focus on identifying all coding variants. We annotate 34 SNPs and 2 indels that distinguish C57BL/6J and C57BL/6N coding sequences, as well as 15 structural variants that overlap a gene. In parallel we assess the comparative phenotypes of the two inbred lines utilizing the EMPReSSslim phenotyping pipeline, a broad based assessment encompassing diverse biological systems. We perform additional secondary phenotyping assessments to explore other phenotype domains and to elaborate phenotype differences identified in the primary assessment. We uncover significant phenotypic differences between the two lines, replicated across multiple centers, in a number of physiological, biochemical and behavioral systems. Comparison of C57BL/6J and C57BL/6N demonstrates a range of phenotypic differences that have the potential to impact upon penetrance and expressivity of mutational effects in these strains. Moreover, the sequence variants we identify provide a set of candidate genes for the phenotypic differences observed between the two strains. 23553486 MicroRNA miR-24 promotes cell proliferation by targeting the CDKs inhibitors p27Kip1 and p16INK4a. Cell cycle progression is controlled by numerous mechanisms ensuring correct cell division. The transition from one cell cycle phase to another occurs in an orderly fashion and is regulated by different cellular proteins. Therefore an alteration of the regulatory mechanisms of the cell cycle results in uncontrolled cell proliferation, which is a distinctive feature of human cancers. Recent evidences suggest that microRNAs (miRs) may also control the levels of multiple cell cycle regulators and therefore control cell proliferation. In fact miRs are a class of small non-coding RNAs, which modulate gene expression. They are involved in numerous physiological cellular processes and most importantly accumulating evidence indicates that many miRs are aberrantly expressed in human cancers. In this report we describe that miR-24 directly targets p27(Kip1) and p16(Ink4a) in primary keratinocyte and in different cancer derived cell lines promoting their proliferation, suggesting that miR-24 is involved in cyclin-dependent kinase inhibitors post-transcriptional regulation and that upregulation of miR-24 may play a role in carcinogenesis. 23968302 Poly(N-isopropylacrylamide)-stabilized Gold Nanoparticles in Combination with Tricationic Branched Phenylene-ethynylene Fluorophore for Protein Identification. Gold nanoparticles stabilized by thermoresponsive polymer, poly(N-isopropylacrylamide) (PNIPAM-AuNPs), were prepared by surface grafting of thiol-terminated PNIPAM onto citrate-stabilized AuNPs. The color change of the PNIPAM-AuNPs solution from red to blue-purple without precipitation when the solution was heated to 40 ºC, above the lower critical solution temperature (LCST) of PNIPAM, indicated the thermoresponsive property of the synthesized AuNPs. PNIPAM-AuNPs were used to detect proteins by chemical nose approach based on fluorescence quenching of fluorophore by AuNPs. An array-based sensing platform for detection of six proteins, namely bovine serum albumin, lysozyme, fibrinogen, concanavalin A, hemoglobin, holo-transferrin human can be successfully developed from the PNIPAM-AuNPs having different molecular weights (4 and 8 kDa) and conformation (varied heat treatment from 25 to 40oC) in combination with a tricationic branched phenylene-ethynylene fluorophore. From Principal Component Analysis (PCA) followed by Linear Discriminant Analysis (LDA), 100% accuracy of protein classification using Leave One Out (LOO) approach can be achieved by using only two types of PNIPAM-AuNPs. 23915718 How old is my gene? Gene functions, interactions, disease associations, and ecological distributions are all correlated with gene age. However, it is challenging to estimate the intricate series of evolutionary events leading to a modern-day gene and then to reduce this history to a single age estimate. Focusing on eukaryotic gene families, we introduce a framework that can be used to compare current strategies for quantifying gene age, discuss key differences between these methods, and highlight several common problems. We argue that genes with complex evolutionary histories do not have a single well-defined age. As a result, care must be taken to articulate the goals and assumptions of any analysis that uses gene age estimates. Recent algorithmic advances offer the promise of gene age estimates that are fast, accurate, and consistent across gene families. This will enable a shift to integrated genome-wide analyses of all events in gene evolutionary histories in the near future. 23152194 Prevalence of asthma symptoms in schoolchildren, and climate in west European countries: an ecologic study. The aim of the present study was to estimate the associations between the prevalence of asthma symptoms in schoolchildren and meteorological variables in west European countries that participated in the International Study of Asthma and Allergies in Children (ISAAC), Phase III 1997-2003. An ecologic study was carried out. The prevalence of asthma was obtained from this study from 48 centers in 14 countries, and meteorological variables from those stations closest to ISAAC centers, together with other socioeconomic and health care variables. Multilevel mixed-effects linear regression models were used. For schoolchildren aged 6-7 years, the prevalence rate of asthma decreased with an increase in mean annual sunshine hours, showed a positive association with rainy weather, and warm temperature, and a negative one with relative humidity and physician density (PD). Current wheeze prevalence was stronger in autumn/winter seasons and decreased with increasing PD. Severe current wheeze decreased with PD. For schoolchildren aged 13-14 years, the prevalence rates of asthma and current wheeze increased with rainy weather, and these rates decreased with increased PD. Current wheeze, as measured by a video questionnaire, was inversely associated with sunny weather, and nurse density. Severe current wheeze prevalence was stronger during autumn/winter seasons, decreased with PD, and indoor chlorinated public swimming pool density, and increased with rainy weather. Meteorological factors, including sunny and rainy weather, and PD may have some effect on the prevalence rates of asthma symptoms in children from west European countries. 23807539 A practical approach for calculating reliable cost estimates from observational data: application to cost analyses in maternal and child health. Comparative effectiveness research (CER) and cost-effectiveness analysis are valuable tools for informing health policy and clinical care decisions. Despite the increased availability of rich observational databases with economic measures, few researchers have the skills needed to conduct valid and reliable cost analyses for CER. The objectives of this paper are to (i) describe a practical approach for calculating cost estimates from hospital charges in discharge data using publicly available hospital cost reports, and (ii) assess the impact of using different methods for cost estimation in maternal and child health (MCH) studies by conducting economic analyses on gestational diabetes (GDM) and pre-pregnancy overweight/obesity. In Florida, we have constructed a clinically enhanced, longitudinal, encounter-level MCH database covering over 2.3 million infants (and their mothers) born alive from 1998 to 2009. Using this as a template, we describe a detailed methodology to use publicly available data to calculate hospital-wide and department-specific cost-to-charge ratios (CCRs), link them to the master database, and convert reported hospital charges to refined cost estimates. We then conduct an economic analysis as a case study on women by GDM and pre-pregnancy body mass index (BMI) status to compare the impact of using different methods on cost estimation. Over 60 % of inpatient charges for birth hospitalizations came from the nursery/labor/delivery units, which have very different cost-to-charge markups (CCR = 0.70) than the commonly substituted hospital average (CCR = 0.29). Using estimated mean, per-person maternal hospitalization costs for women with GDM as an example, unadjusted charges ($US14,696) grossly overestimated actual cost, compared with hospital-wide ($US3,498) and department-level ($US4,986) CCR adjustments. However, the refined cost estimation method, although more accurate, did not alter our conclusions that infant/maternal hospitalization costs were significantly higher for women with GDM than without, and for overweight/obese women than for those in a normal BMI range. Cost estimates, particularly among MCH-related services, vary considerably depending on the adjustment method. Our refined approach will be valuable to researchers interested in incorporating more valid estimates of cost into databases with linked hospital discharge files. 23689710 HIV-1 Resistance Mechanism to an Electrostatically Constrained Peptide Fusion Inhibitor That Is Active against T-20-Resistant Strains. T-20EK is a novel fusion inhibitor designed to have enhanced α-helicity over T-20 (enfuvirtide) through engineered electrostatic interactions between glutamic acid (E) and lysine (K) substitutions. T-20EK efficiently suppresses wild-type and T-20-resistant variants. Here, we selected T-20EK-resistant variants. A combination of L33S and N43K substitutions in gp41 were required for high resistance to T-20EK. While these substitutions also caused resistance to T-20, they did not cause cross-resistance to other known fusion inhibitors. 23504236 Comparison of posterior pharyngeal wall and nasopharyngeal swabbing as a means of detecting the carriage of Neisseria meningitidis in adolescents. The purpose of this investigation was to evaluate the effectiveness of posterior pharyngeal and nasopharyngeal swabs in identifying and quantifying meningococcal carriage. Two swab samples were obtained from 564 healthy adolescents aged 15-19 years, the first taken from the posterior pharyngeal wall through the mouth and the second through the nose. Bacterial genomic DNA was extracted and screened for Neisseria meningitidis by means of two separate singleplex real-time polymerase chain reactions (real-time PCRs) in order to identify the CtrA and sodC genes. Subsequently, N. meningitidis-positive samples underwent a further singleplex real-time PCR in order to determine the N. meningitidis serogroup, and the DNA was quantified by means of standard curves. Thirty-seven subjects (6.6 %) were found to be carriers of N. meningitidis. The most frequently carried serogroup was serogroup B (15 cases, 40.5 %); serogroups A, Y, X, W135 and Z were found in, respectively, two (5.4 %), five (13.5 %), four (10.8 %), three (8.1 %) and one subject (2.7 %); the serogroup was not identified in seven cases. The detection of carrier status was significantly more frequent using posterior pharyngeal swabs (5.3 % vs. 2.1 %; p = 0.004), which also contained a significantly larger number of N. meningitidis genomic copies (4.91 ±â€‰1.39 vs. 2.50 ±â€‰0.8 log10 genomic copies/mL; p < 0.001). Posterior pharyngeal swabs seem to be better than nasopharyngeal swabs for detecting N. meningitidis carriage in large-scale epidemiological studies because they identify a significantly larger number of pathogen carriers and recover a significantly larger amount of bacterial DNA. 23160179 CD36 homolog divergence is responsible for the selectivity of carotenoid species migration to the silk gland of the silkworm Bombyx mori. Dietary carotenoids are absorbed in the intestine and delivered to various tissues by circulating lipoproteins; however, the mechanism underlying selective delivery of different carotenoid species to individual tissues remains elusive. The products of the Yellow cocoon (C) gene and the Flesh (F) gene of the silkworm Bombyx mori determine the selectivity for transport of lutein and β-carotene, respectively, to the silk gland. We previously showed that the C gene encodes Cameo2, a CD36 family member, which is thought to function as a transmembrane lipoprotein receptor. Here, we elucidated the molecular identity of the F gene product by positional cloning, as SCRB15, a paralog of Cameo2 with 26% amino acid identity. In the F mutant, SCRB15 mRNA structure was severely disrupted, due to a 1.4 kb genomic insertion in a coding exon. Transgenic expression of SCRB15 in the middle silk gland using the binary GAL4-UAS expression system enhanced selective β-carotene uptake by the middle silk gland, while transgenic expression of Cameo2 enhanced selective lutein uptake under the same GAL4 driver. Our findings indicate that divergence of genes in the CD36 family determines the selectivity of carotenoid species uptake by silk gland tissue and that CD36-homologous proteins can discriminate among carotenoid species. 23356880 Bioactives and nutraceutical phytochemicals naturally occurring in virgin olive oil. The case study of the Nocellara del Belice Italian olive cultivar. This work reports on the composition and bionutritional value of organic virgin olive oil from the Nocellara del Belice variety, one cultivated in the olive areas of the Sicily region, Italy. Destoned oils obtained by processing olives with a destoning-based procedure were compared with conventional oils. This innovative technique, consisting in removing the stone from fruits prior to processing, strongly enhanced the already high-quality level of the conventional product. An in-depth analytical investigation from 2008 to 2010 showed how this innovative olive extraction process led to an excellent peculiar final product, mainly attributable to the improved biophenol and volatile composition, as well as higher concentrations of the lipophilic and vitamin antioxidants (tocopherols and tocotrienols). It had higher levels of oleocanthal (p-HPEA-EDA), a nutraceutical compound exerting actions against COX1 and COX2 (cycloxygenases). Its head-space aroma displayed new volatile phytomolecules and also had higher levels of green volatiles from the lipoxygenase (LOX)-pathway (one having as precursors the polyunsaturated fatty acids containing a cis-cis-1,4-pentadiene system). Among the other bioactives, we highlight its significant levels of trans-β-carotene and xanthophylls (lutein, violaxanthin, neoxanthin and other carotenoids). Its enhanced nutritional value was also attributable to the increased intensity of valuable tasting notes. 23952691 When less is more - microRNAs and psychiatric disorders. MicroRNAs are small non-coding RNA molecules that regulate gene expression, including genes involved in neuronal function and plasticity that have relevance for brain function and mental health. We therefore performed a systematic review of miRNAs in general adult psychiatric disorders. Systematic searches in PubMed/MEDLINE and Web of Science were conducted to identify published clinical articles on microRNAs in general adult psychiatric disorders. We also reviewed references from included articles. There is mounting evidence of microRNAs' regulatory roles in a number of central nervous system processes, including neurogenesis and synaptic plasticity. The majority of clinical studies of microRNAs in psychiatric disorders are in schizophrenia, where a number of specific microRNAs have been identified in separate studies. There is some evidence of marked downregulation of some microRNAs in affective disorders. Treatment with antidepressants appears to upregulate microRNA levels. There is currently little evidence from human studies in anxiety, addiction or other psychiatric disorders. MicroRNA research in psychiatry is currently in a nascent period, but represents an emerging and exciting area, with the potential to clarify molecular mechanisms of disease and identify novel biomarkers and therapeutic agents. 23673574 Stiffness of tumours measured by shear-wave elastography correlated with subtypes of breast cancer. To evaluate the correlation between stiffness values obtained by shear-wave elastography (SWE) and breast cancer subtypes. This was an institutional review board-approved retrospective study with a waiver of informed consent. The stiffness of 337 invasive breast cancers in 337 women was evaluated by SWE and mean stiffness values (kPa) and qualitative colour scores (1-5) of tumours were obtained. The results were analysed according to BI-RADS category, tumour size, grade and tumour subtype (triple-negative [TN], human epidermal growth factor receptor 2 [HER2]-positive, and oestrogen receptor [ER]-positive) using a multiple linear regression analysis. The mean stiffness values and colour scores were: 146.8 kPa ± 57.0 and 4.1 ± 1.1; 165.8 kPa ± 48.5 and 4.6 ± 0.7 for TN tumours (n = 64), 160.3 kPa ± 56.2 and 4.3 ± 1.0 for HER2-positive tumours (n = 55) and 136.9 kPa ± 57.2 and 4.0 ± 1.1 for ER-positive tumours (n = 218; P < 0.0001). All three breast cancers classified as BI-RADS category 3 on B-mode ultrasound were TN subtype. A multiple linear regression analysis revealed that tumour size, histological grade and tumour subtype were independent factors that influenced the stiffness values. High stiffness values correlated with aggressive subtypes of breast cancer. • Shear-wave elastography is increasingly used to measure the stiffness of breast tumours. • Triple-negative and HER2-positive tumours showed greater stiffness than ER-positive tumours. • All breast cancers classified as BI-RADS 3 on B-mode ultrasound were triple-negative subtype. • Tumour size, histological grade and subtype were independent factors influencing SWE stiffness. 23830736 Knowledge on musculoskeletal diseases by the Spanish population. To explore knowledge on musculoskeletal-diseases (MSDs) by the Spanish population. This was a cross-sectional study of the general population (> 18 years) using a telephone survey of 1,009 subjects stratified by habitat size, age, sex, and geographic area. A structured questionnaire was used to collect information on the subjects, their general knowledge of MSDs (GK), their specific knowledge of particular MSDs (SK), and their knowledge of their social impact (KSI). Synthetic indicators of the level of knowledge were used to analyze, using univariate and multivariate models, variables associated to the level of knowledge. The KSI level ranges from medium-high (mean: 0.62±0.16 out of 1), suggesting that most subjects recognize MSDs as disabling conditions which affect the ability to work and have a high personal and social cost. The GK level is intermediate (mean: 0.50±0.17); 60% of subjects know something about MSDs, but 54% state that their information is poor/very poor. The SK level is low (mean: 0.18±0.10), and there are some MSDs that are little known (lupus, spondylitis). Being male or retired or having a MSD is associated to a greater knowledge of MSDs. The Spanish population has a medium level of knowledge of the frequency and extent to which MSDs affect performance of activities by those who suffer them. They identify them adequately and have a GK of their symptoms, but have little information about them. The level of knowledge varies depending on social and demographic factors and on whether or not the subject has direct or indirect experience of what a MSD means. 23946243 Assessment of dispersive liquid-liquid microextraction for the simultaneous extraction, preconcentration, and derivatization of Hg(2+) and CH3 Hg(+) for further determination by GC-MS. This work reports the development of a dispersive liquid-liquid microextraction method for the simultaneous extraction, preconcentration, and derivatization of Hg(2+) and CH3 Hg(+) species from water samples for further determination by GC-MS. Some parameters of the proposed microextraction method, such as volume and type of disperser and extraction solvent, and Na[B(C6 H5 )4 ] concentration were investigated using response surface methodology. Suitable recoveries were obtained using 80 μL C2 Cl4 (as extraction solvent), 1000 μL ethanol (as disperser solvent), and 300 μL 2.1 mmol L(-1) Na[B(C6 H5 )4 ] (as derivatizing agent). Accuracy was evaluated in terms of recovery and ranged from 87 to 99% with RSD values lower than 7%. In addition, a certified reference material of water (NIST 1641d) was analyzed and agreed with the certified value of about 107% (for Hg(2+) ), with RSD values lower than 8.5%. Limits of detection were 0.3 and 0.2 μg L(-1) , with enrichment factors of 112 and 115 for Hg(2+) and CH3 Hg(+) , respectively. The optimized method was applied for the determination of Hg(2+) and CH3 Hg(+) in tap, well, and lake water samples. This article is protected by copyright. All rights reserved. 23883921 Chromatographic analysis of methylglyoxal and other α-dicarbonyls using gas-diffusion microextraction. Many α-dicarbonyl compounds such as methylglyoxal, diacetyl and pentane-2,3-dione are important quality markers of processed foods. They are produced by enzymatic and chemical processes, the Maillard reaction is the most known chemical route for α-dicarbonyl formation. In the case of methylglyoxal, there are obstacles to be overcome when analysing this compound due to its high reactivity, low volatility and low concentration. The use of extraction techniques based on the volatilization of methylglyoxal (like solid-phase microextraction) showed to be ineffective for the methylglyoxal extraction from aqueous solutions. Therefore, derivatization is typically applied to increase analyte's volatility. In this work a new methodology for the extraction and analysis of methylglyoxal and also diacetyl and pentane-2,3-dione from selected food matrices is presented. It is based on a gas-diffusion microextraction step followed by high performance liquid chromatographic analysis. It was successfully applied to port wines, black tea and soy sauce. Methylglyoxal, diacetyl and pentane-2,3-dione were quantified in the following concentration ranges: 0.24-1.74 mg L(-1), 0.1-1.85 mg L(-1) and 0.023-0.15 mg L(-1), respectively. The main advantages over existing methodologies are its simplicity in terms of sample handling, not requiring any chemical modification of the α-dicarbonyls prior to the extraction, low reagent consumption and short time of analysis. 23799643 Design, Synthesis, and Evaluation of Multitarget-Directed Resveratrol Derivatives for the Treatment of Alzheimer's Disease. A series of multitarget-directed resveratrol derivatives was designed and synthesized for the treatment of Alzheimer's disease (AD). In vitro studies indicated that most of the target compounds exhibit significant inhibition of self-induced β-amyloid (Aβ) aggregation and Cu(II)-induced Aβ1-42 aggregation and acted as potential antioxidants and biometal chelators. In particular, compounds 5d and 10d are potential lead compounds for AD therapy (5d, IC50 = 7.56 μM and 10d, IC50 = 6.51 μM for self-induced Aβ aggregation; the oxygen radical absorbance capacity assay using fluorescein (ORAC-FL) values are 4.72 and 4.70, respectively). Moreover, these compounds are capable of disassembling the highly structured Aβ fibrils generated by self- and Cu(II)-induced Aβ aggregation. Furthermore, 5d crossed the blood-brain barrier (BBB) in vitro and did not exhibit any acute toxicity in mice at doses of up to 2000 mg/kg. Taken together, the data indicate that 5d is a very promising lead compound for AD. 23644592 Analysis of the activity of virus internal ribosome entry site in silkworm Bombyx mori. Internal ribosome entry site (IRES) has been widely used in genetic engineering; however, the application in silkworm (Bombyx mori) has hardly been reported. In this study, the biological activity of partial sequence of Encephalomyocarditis virus (EMCV) IRES, Rhopalosiphum padi virus (RhPV) IRES, and the hybrid of IRES of EMCV and RhPV were investigated in Spodoptera frugiperda (Sf9) cell line and silkworm tissues. The hybrid IRES of EMCV and RhPV showed more effective than EMCV IRES or RhPV IRES in promoting downstream gene expression in insect and silkworm. The activities of all IRESs in middle silk gland of silkworm were higher than those in the fat body and posterior silk gland. The hybrid IRES of EMCV and RhPV was integrated into silkworm genome by transgenic technology to test biological activity of IRES. Each of the positive transgenic individuals had significant expression of report gene EGFP. These results suggested that IRES has a potential to be used in the genetic engineering research of silkworm. 23820738 Impairments of tight junctions are involved in D-galactose-induced brain aging. Impairments of tight junctions are implicated in the course of various age-related neurodegenerative disorders. Chronic injection of D-galactose can cause a progressive deterioration in learning and memory capacity and serve as an animal model of aging. To investigate the involvement of tight junctions in this model, oxidative stress biomarkers, expression and ultrastructure of tight junctions, and the permeability of blood-brain barrier were examined in the hippocampus of the mice, which received an injection of D-galactose for 6 weeks. D-Galactose-injected mice showed impaired antioxidant systems, decreased levels of tight junction proteins, and ultrastructural pathological changes of tight junctions, accompanied by increased blood-brain barrier permeability in the hippocampus. These results show that impairments in tight junctions are involved in D-galactose-induced brain aging. 23929221 Detection and Perceptual Impact of Side-to-Side Facial Movement Asymmetry. IMPORTANCE In this study, we examined whether specific facial movements have different time-delay detection thresholds, and to what extent such side-to-side facial movement asymmetry affects subjective ratings of movement naturalness. Ratings of dynamic asymmetry in experimentally manipulated video recordings demonstrate that there are different side-to-side time-delay thresholds for distinct regions of the face, with a strong inverse correlation between naturalness rating and the length-of-time delay. These findings will be helpful for counseling patients with unilateral facial paralysis and guide the design of neural interfaces for facial reanimation. OBJECTIVE To determine the detection threshold of side-to-side facial movement timing asymmetry and measure its effect on perceived movement naturalness. DESIGN, SETTING, AND PARTICIPANTS Videos of 5 symmetrical facial movements (eye blink, rapid eyebrow raising, slow eyebrow raising, smiling, and lip depression) were edited to introduce 6 levels of side-to-side timing asymmetry, ranging from 33 to 267 milliseconds. Participants (N = 58) viewed video clips through an online survey service, indicating whether they noticed side-to-side asymmetry and judging movement naturalness on a 5-point scale. RESULTS There was a significant difference among facial movements in asymmetry detection threshold. There was a strong correlation between naturalness ratings and amount of delay across movements (R = 0.823), with greater asymmetry being judged as progressively less natural. Blink was judged as less natural at 33, 67, 100, and 133 milliseconds of side-to-side delay compared with all other movements (P < .005). CONCLUSIONS AND RELEVANCE Side-to-side asymmetry in blink timing is detected sooner and viewed as less natural compared with asymmetry of the eyebrow and lips. At 100 milliseconds of delay, nearly all movements are detected as asymmetric, although blink is judged as the least natural. These findings will help set timing goals for facial pacing technologies treating unilateral paralysis. LEVEL OF EVIDENCE NA. 23898420 The Myrtle rust pathogen, Puccinia psidii, discovered in Africa. Puccinia psidii, the cause of a disease today commonly referred to as Myrtle rust, is considered a high priority quarantine threat globally. It has a wide host range in the Myrtaceae and it is feared that it may result in significant damage to native ecosystems where these plants occur. The fungus is also of considerable concern to plantation forestry industries that propagate Australian Eucalyptus species. In May 2013, symptoms of a rust disease resembling those of P. psidii were observed on an ornamental Myrtaceous shrub in a garden in South Africa. The fungus was identified based on DNA sequence data of the ITS and 5.8S nrRNA gene regions and here we report, for the first time, the presence of P. psidii in Africa. 23475305 Biochemical constituents of a wild strain of Schizophyllum commune isolated from Achanakmar-Amarkantak Biosphere Reserve (ABR), India. A wild strain of Schizophyllum commune (MTCC 9670) isolated from Achanakmar-Amarkantak Biosphere Reserve of Central India was evaluated for the production of bioactive compounds. The chemical constituents of wild and in vitro grown cultures were compared. Under optimized conditions, different organic and aqueous extracts from mycelia and fruiting bodies were used to extract chemical components from the cultures grown in vitro. The gas chromatography combined wih mass spectrometry analysis of extracts identified two phenolic compounds, namely Phenyl benzoate (C13H10O2) and 4-(phenyl methoxy) phenol (C13H12O2) in the ethanolic extract of in vitro grown fruiting bodies and one antibacterial compound Pyrrolo (1, 2-a) piperazine-3, 6-dione (C7H10O2N2) in the methanolic extract of mycelia. High-performance liquid chromatography analysis revealed that the gallic acid and L-ascorbic acid were identifiable antioxidant components in the extracts possessing high free radical scavenging activity. The findings suggest that the wild strain of S. commune may serve as the source of novel bioactive compounds with effective antimicrobial and antioxidant activities. 23933481 Evaluation of Potential Ionizing Irradiation Protectors and Mitigators Using Clonogenic Survival of Human Umbilical Cord Blood Hematopoietic Progenitor Cells. We evaluated the use of colony formation (CFU-GM, BFU-E, and CFU-GEMM) by human umbilical cord blood (CB) hematopoietic progenitor cells for testing novel small molecule ionizing irradiation protectors and mitigators. Each of 11 compounds was added before (protection) or after (mitigation) ionizing irradiation including: GS-nitroxides (JP4-039 and XJB-5-131), the bifunctional sulfoxide MMS-350, the phosphoinositol-3-kinase inhibitor LY294002), TPP-imidazole fatty acid, (TPP-IOA), the nitric oxide synthase inhibitor (MCF-201-89), the p53/mdm2/mdm4 inhibitor (BEB55), methoxamine, isoproterenol, propanolol, and the ATP sensitive potassium channel blocker (glyburide). The drugs XJB-5-131, JP4-039, and MMS-350 were radiation protectors for CFU-GM. JP4-039 was also a radiation protector for CFU-GEMM. The drugs, XJB-5-131, JP4-039, and MMS-350 were radiation mitigators for BFU-E, MMS-350 and JP4-039 were mitigators for CFU-GM, and MMS350 was a mitigator for CFU-GEMM. In contrast, other drugs that were effective in murine assays: TTP-IOA, LY294002, MCF201-89, BEB55, propranolol, isoproterenol, methoxamine, and glyburide showed no significant protection or mitigation in human CB assays. These data support testing of new candidate clinical radiation protectors and mitigators using human CB clonogenic assays early in the drug discovery process, reducing the need for animal experiments. 23901290 An extended paIn relief trial utilizing the infiltration of a long-acting Multivesicular liPosome foRmulation Of bupiVacaine, EXPAREL (IMPROVE): a Phase IV health economic trial in adult patients undergoing ileostomy reversal. Opioid analgesics are effective for postsurgical pain but are associated with opioid-related adverse events, creating a significant clinical and economic burden. Gastrointestinal surgery patients are at high risk for opioid-related adverse events. We conducted a study to assess the impact of an opioid-sparing multimodal analgesia regimen with liposome bupivacaine, compared with the standard of care (intravenous [IV] opioid-based, patient-controlled analgesia [PCA]) on postsurgical opioid use and health economic outcomes in patients undergoing ileostomy reversal. In this open-label, multicenter study, sequential cohorts of patients undergoing ileostomy reversal received IV opioid PCA (first cohort); or multimodal analgesia including a single intraoperative administration of liposome bupivacaine (second cohort). Rescue analgesia was available to all patients. Primary outcome measures were postsurgical opioid use, hospital length of stay, and hospitalization costs. Incidence of opioid-related adverse events was also assessed. Twenty-seven patients were enrolled, underwent the planned surgery, and did not meet any intraoperative exclusion criteria; 16 received liposome bupivacaine-based multimodal analgesia and eleven received the standard IV opioid PCA regimen. The multimodal regimen was associated with significant reductions in opioid use compared with the IV opioid PCA regimen (mean, 20 mg versus 112 mg; median, 6 mg versus 48 mg, respectively; P < 0.01), postsurgical length of stay (median, 3.0 days versus 5.1 days, respectively; P < 0.001), and hospitalization costs (geometric mean, $6482 versus $9282, respectively; P = 0.01). A liposome bupivacaine-based multimodal analgesic regimen resulted in statistically significant and clinically meaningful reductions in opioid consumption, shorter length of stay, and lower inpatient costs than an IV opioid-based analgesic regimen. 23851959 Effects of Ivabradine on 6-Minute Walk Test and Quality of Life in Patients With Previously Implanted CRT-D. We aimed to evaluate clinical effects of additional heart rate control by ivabradine on life quality score and 6-minute walking test in patients with previously implanted biventricular cardiac resynchronization therapy defibrillator (CRT-D) with ischemic heart failure under regular treatment. Fifteen men and 14 women with a median age of 63 years (range, 48-79 years) were studied. Twenty-one patients were in New York Heart Association class II (8 patients were in class III), CRT-D implanted previously, and with resting heart rates greater than 70 beats per minute with sinus rhythm despite conventional medication. Patients were given 2.5- to 7.5-mg ivabradine orally twice a day, and drug dosage was titrated to decrease the patients' average heart rate to 70 beats per minute. Before and 3 months after ivabradine treatment, all patients underwent extensive clinical, echocardiographic, and laboratory evaluation. Ivabradine treatment produced dose-dependent reductions in heart rate at rest and at peak exercise (91.9 ± 6.3 to 71.7 ± 4.8 and 114.4 ± 7.6 to 96.8 ± 4.8; P = 0.001 and P = 0.001, respectively). There were also significant improvements in life quality score (52.4 ± 9.5 to 37.9±7.8; P = 0.001) and 6-minute walking distance (278.7 ± 85.8 to 373.3 ± 94.0; P = 0.001) of patients. All patients with New York Heart Association class III became class II after 3 months of ivabradine treatment. Heart rate reduction in a short-term period by ivabradine produced significant improvements in exercise capacity and life quality in patients with CRT-D and conventional therapy. 23825316 Convergence of Cortical and Sensory Driver Inputs on Single Thalamocortical Cells. Ascending and descending information is relayed through the thalamus via strong, "driver" pathways. According to our current knowledge, different driver pathways are organized in parallel streams and do not interact at the thalamic level. Using an electron microscopic approach combined with optogenetics and in vivo physiology, we examined whether driver inputs arising from different sources can interact at single thalamocortical cells in the rodent somatosensory thalamus (nucleus posterior, POm). Both the anatomical and the physiological data demonstrated that ascending driver inputs from the brainstem and descending driver inputs from cortical layer 5 pyramidal neurons converge and interact on single thalamocortical neurons in POm. Both individual pathways displayed driver properties, but they interacted synergistically in a time-dependent manner and when co-activated, supralinearly increased the output of thalamus. As a consequence, thalamocortical neurons reported the relative timing between sensory events and ongoing cortical activity. We conclude that thalamocortical neurons can receive 2 powerful inputs of different origin, rather than only a single one as previously suggested. This allows thalamocortical neurons to integrate raw sensory information with powerful cortical signals and transfer the integrated activity back to cortical networks. 23918752 Prevalence of Optimal Treatment Regimens in Patients With Apparent Treatment-Resistant Hypertension Based on Office Blood Pressure in a Community-Based Practice Network. Hypertensive patients with clinical blood pressure (BP) uncontrolled on ≥3 antihypertensive medications (ie, apparent treatment-resistant hypertension [aTRH]) comprise ≈28% to 30% of all uncontrolled patients in the United States. However, the proportion receiving these medications in optimal doses is unknown; aTRH is used because treatment adherence and measurement artifacts were not available in electronic record data from our >200 community-based clinics Outpatient Quality Improvement Network. This study sought to define the proportion of uncontrolled hypertensives with aTRH on optimal regimens and clinical factors associated with optimal therapy. During 2007-2010, 468 877 hypertensive patients met inclusion criteria. BP <140/<90 mm Hg defined control. Multivariable logistic regression was used to assess variables independently associated with optimal therapy (prescription of diuretic and ≥2 other BP medications at ≥50% of maximum recommended hypertension doses). Among 468 877 hypertensives, 147 635 (31.5%) were uncontrolled; among uncontrolled hypertensives, 44 684 were prescribed ≥3 BP medications (30.3%), of whom 22 189 (15.0%) were prescribed optimal therapy. Clinical factors independently associated with optimal BP therapy included black race (odds ratio, 1.40 [95% confidence interval, 1.32-1.49]), chronic kidney disease (1.31 [1.25-1.38]), diabetes mellitus (1.30 [1.24-1.37]), and coronary heart disease risk equivalent status (1.29 [1.14-1.46]). Clinicians more often prescribe optimal therapy for aTRH when cardiovascular risk is greater and treatment goals lower. Approximately 1 in 7 of all uncontrolled hypertensives and 1 in 2 with uncontrolled aTRH are prescribed ≥3 BP medications in optimal regimens. Prescribing more optimal pharmacotherapy for uncontrolled hypertensives including aTRH, confirmed with out-of-office BP, could improve hypertension control. 23885349 Nanoparticle-based immunochromatographic test strip with fluorescent detector for quantification of phosphorylated acetylcholinesterase: an exposure biomarker of organophosphorus agents. A nanoparticle-based fluorescence immunochromatographic test strip (FITS) coupled with a hand-held detector for highly selective and sensitive detection of phosphorylated acetylcholinesterase (AChE), an exposure biomarker of organophosphate (OP) pesticides and nerve agents, is reported. In this approach, OP-AChE adducts were selectively captured by quantum dot-tagged anti-AChE antibodies (Qdot-anti-AChE) and zirconia nanoparticles (ZrO2 NPs). The sandwich-like immunoreactions were performed among the Qdot-anti-AChE, OP-AChE and ZrO2 NPs to form a Qdot-anti-AChE-OP-AChE-ZrO2 complex, which was detected by recording the fluorescence intensity of Qdots captured during the test line. Paraoxon was used as the model OP pesticide. Under optimal conditions, this portable FITS immunosensor demonstrates a highly linear absorption response over the range of 0.01 nM to 10 nM OP-AChE, with a detection limit of 4 pM, coupled with good reproducibility. Moreover, the FITS immunosensor has been validated with OP-AChE spiked human plasma samples. This is the first report on the development of ZrO2 NP-based FITS for the detection of the OP-AChE adduct. The FITS immunosensor provides a sensitive and low-cost sensing platform for on-site screening/evaluating OP pesticides and nerve agents poisoning. 23673864 Hippocampal network connectivity and activation differentiates post-traumatic stress disorder from generalized anxiety disorder. Anxiety disorders are a diverse group of clinical states. Post-traumatic stress disorder (PTSD) and generalized anxiety disorder (GAD), eg, share elevated anxiety symptoms, but differ with respect to fear-related memory dysregulation. As the hippocampus is implicated in both general anxiety and fear memory, it may be an important brain locus for mapping the similarities and differences among anxiety disorders. Anxiety and fear also functionally associate with different subdivisions of the hippocampus along its longitudinal axis: the human posterior (rodent dorsal) hippocampus is involved in memory, through connectivity with the medial prefrontal-medial parietal default-mode network, whereas the anterior (rodent ventral) hippocampus is involved in anxiety, through connectivity with limbic-prefrontal circuits. We examined whether differential hippocampal network functioning may help account for similarities and differences in symptoms in PTSD and GAD. Network-sensitive functional magnetic resonance imaging-based resting-state intrinsic connectivity methods, along with task-based assessment of posterior hippocampal/default-mode network function, were used. As predicted, in healthy subjects resting-state connectivity dissociated between posterior hippocampal connectivity with the default-mode network, and anterior hippocampal connectivity to limbic-prefrontal circuitry. The posterior hippocampus and the associated default-mode network, across both resting-state connectivity and task-based measures, were perturbed in PTSD relative to each of the other groups. By contrast, we found only modest support for similarly blunted anterior hippocampal connectivity across both patient groups. These findings provide new insights into the neural circuit-level dysfunctions that account for similar vs different features of two major anxiety disorders, through a translational framework built on animal work and carefully selected clinical disorders. 23462886 Clinical proof-of-concept study with MSDC-0160, a prototype mTOT-modulating insulin sensitizer. It may be possible to achieve insulin sensitivity through the recently identified mitochondrial target of thiazolidinediones (mTOT), thereby avoiding peroxisome proliferator-activated receptor-γ (PPAR-γ)-dependent side effects. In this phase IIb clinical trial, 258 patients with type 2 diabetes completed a 12-week protocol with 50, 100, or 150 mg of MSDC-0160 (an mTOT modulator), 45 mg pioglitazone HCl (a PPAR-γ agonist), or a placebo. The two active treatments lowered fasting glucose levels to the same extent. The decreases in glycated hemoglobin (HbA1c) observed with the two higher doses of MSDC-0160 were not different from those associated with pioglitazone. By contrast, fluid retention as evidenced by reduction in hematocrit, red blood cells, and total hemoglobin was 50% less in the MSDC-0160-treated groups. There was also a smaller increase in high-molecular-weight (HMW) adiponectin with MSDC-0160 than with pioglitazone (P < 0.0001), suggesting that MSDC-0160 produces less expansion of white adipose tissue. Thus, mTOT modulators may have glucose-lowering effects similar to those of pioglitazone but without the adverse effects associated with PPAR-γ agonists. 23887607 Technical and implementation issues in using next-generation sequencing of cancers in clinical practice. Next-generation sequencing (NGS) of cancer genomes promises to revolutionise oncology, with the ability to design and use targeted drugs, to predict outcome and response, and to classify tumours. It is continually becoming cheaper, faster and more reliable, with the capability to identify rare yet clinically important somatic mutations. Technical challenges include sequencing samples of low quality and/or quantity, reliable identification of structural and copy number variation, and assessment of intratumour heterogeneity. Once these problems are overcome, the use of the data to guide clinical decision making is not straightforward, and there is a risk of premature use of molecular changes to guide patient management in the absence of supporting evidence. Paradoxically, NGS may simply move the bottleneck of personalised medicine from data acquisition to the identification of reliable biomarkers. Standardised cancer NGS data collection on an international scale would be a significant step towards optimising patient care. 23816250 A novel A781V mutation in the CSF1R gene causes hereditary diffuse leucoencephalopathy with axonal spheroids. We report a family with a novel CSF1R mutation causing hereditary diffuse leucoencephalopathy with axonal spheroids. Family members presented with neuropsychiatric and behavioural symptoms, with subsequent development of motor symptoms and gait disturbance. MRI brain showed extensive white matter change with a frontal predominance and associated atrophy in two members of the family. Genetic testing revealed a novel mutation c.2342C>T (p.A781V) in the CSF1R gene in two brothers of the family. This report highlights the difficulties in diagnosing HDLS and discusses the indications for testing for mutations in the CSF1R gene. 23907929 Muscle architecture and out-force potential of the thoracic limb in the eastern mole (Scalopus aquaticus). Moles have modified thoracic limbs with hypertrophied pectoral girdle muscles that allow them to apply remarkably high lateral out-forces during the power stroke when burrowing. To further understand the high force capabilities of mole forelimbs, architectural properties of the thoracic limb muscles were quantified in the Eastern mole (Scalopus aquaticus). Architectural properties measured included muscle mass, moment arm, belly length, fascicle length, and pennation angle, and these were used to provide estimates of maximum isometric force, joint torque, and power. Measurements of muscle moment arms and limb lever lengths were additionally used to analyze the out-force contributions of the major pectoral girdle muscles. Most muscles have relatively long fascicles and little-to-no pennation. The humeral abductor/rotators as a functional group are massive and are capable of relatively high force, power, and joint torque. Of this group, the bipennate m. teres major is the most massive and has the capacity to produce the highest force and joint torque to abduct and axially rotate the humerus. In general, the distal limb muscles are relatively small, but have the capacity for high force and mechanical work by fascicle shortening. The muscle architectural properties of the elbow extensors (e.g., m. triceps brachii) and carpal flexors (e.g., m. palmaris longus) are consistent with the function of these muscles to augment lateral out-force application. The humeral abductor/rotators m. latissimus dorsi, m. teres major, m. pectoralis, and m. subscapularis are calculated to contribute 13.9 N to out-force during the power stroke, and this force is applied in a 'frontal' plane causing abduction of the humerus about the sternoclavicular joint. Moles have several specializations of their digging apparatus that greatly enhance the application of out-force, and these morphological features suggest convergence on limb form and burrowing function between New and Old World moles. J. Morphol., 2013. © 2013 Wiley Periodicals, Inc. 23411328 Development of a standardised human in vitro digestion protocol based on macronutrient digestion using response surface methodology. Bioaccessibility studies should be taken into account when evaluating the physiological effects of ingested compounds at the intestine level. Several in vitro digestion protocols have been described, with a wide range of experimental conditions but no optimised protocol exists. In order to fill in this gap, we evaluated the influence of three continuous factors (pH, incubation time, and enzyme concentrations), in the range of values found in literature, on the digestion of standard macronutrients (starch, albumin, triolein) alone or in mixture. Three central composite designs, using response surface methodology, were employed to model the three abiotic steps of pre-colonic digestion. A validated in vitro digestion was eventually set up for the salivary step (pH 6.9, 5 min, 3.9 units α-amylase/ml), the gastric step (pH 2, 90 min, 71.2 units pepsin/ml), and the abiotic duodenal step (pH 7, 150 min, 9.2mg pancreatin and 55.2mg bile extract/ml). 23913326 Trapping and identification of cellular substrates of the Staphylococcus aureus ClpC chaperone. ClpC is an ATP-dependent Hsp100/Clp chaperone involved in protein quality control in low-GC Gram-positive bacteria. Previously, we found that ClpC affected the expression of a large number of genes including capsule genes in Staphylococcus aureus. Here we constructed a His-tagged ClpC variant (ClpC(Trap)) with mutations within the Walker B motifs to identify the direct substrates of ClpC by co-purification with ClpC(trap) followed by GeLC-MS/MS proteomics. We identified a total of 103 proteins that are potential substrates of ClpC in strain Newman. The direct protein-protein interaction of ClpC with a subset of the captured proteins was verified in a bacterial two-hybrid system. The captured proteins could be grouped into various functional categories but most could be related to proteins involved in stress response. Several known ClpC substrates were captured, including ClpP, TrfA/MecA, ClpB, DnaK, DnaJ, GroL, RecA and CodY, supporting the validity of our approach. Our results also revealed many new ClpC substrates, including AgrA, CcpA, RsbW, MurG, FtsA, SrtA. Rex, Atl, ClfA, and SbcC. Analysis of capsule production showed that three of the captured proteins, not previously known to be transcriptional regulators, did affect capsule production. 23745725 Five-year results of a prospective randomised controlled clinical trial of posterior computer-aided design-computer-aided manufacturing ZrSiO4 -ceramic crowns. The aim of this prospective randomised controlled clinical trial was to evaluate the clinical outcome of shrinkage-free ZrSiO4 -ceramic full-coverage crowns on premolars and molars in comparison with conventional gold crowns over a 5-year period. Two hundred and twenty-three patients were included and randomly divided into two treatment groups. One hundred and twenty-three patients were restored with 123 ZrSiO4 -ceramic crowns, and 100 patients received 100 gold crowns, which served as the control. All crowns were conventionally cemented with glass-ionomer cement. After an observation period of 6, 12, 24, 36, 48 and 60 months, the survival probability (Kaplan-Meier) for the shrinkage-free ZrSiO4 -ceramic crowns was 98·3%, 92·0%, 84·7%, 79% and 73·2% and for the gold crowns, 99%, 97·9%, 95·7%, 94·6% and 92·3%, respectively. The difference between the test and control group was statistically significant (P = 0·0027). The gold crowns showed a better marginal integrity with less marginal discoloration than the ceramic crowns. The most common failure in the ceramic crown group was fracture of the crown. The 60-month results of this prospective randomised controlled clinical trial suggest that the use of these shrinkage-free ZrSiO4 -ceramic crowns in posterior tooth restorations cannot be recommended. 23921277 Interobserver Agreement of Centers for Disease Control and Prevention Criteria for Classifying Infections in Critically Ill Patients. Correct classification of the source of infection is important in observational and interventional studies of sepsis. Centers for Disease Control and Prevention criteria are most commonly used for this purpose, but the robustness of these definitions in critically ill patients is not known. We hypothesized that in a mixed ICU population, the performance of these criteria would be generally reduced and would vary among diagnostic subgroups. Prospective cohort. Data were collected as part of a cohort of 1,214 critically ill patients admitted to two hospitals in The Netherlands between January 2011 and June 2011. Eight observers assessed a random sample of 168 of 554 patients who had experienced at least one infectious episode in the ICU. Each patient was assessed by two randomly selected observers who independently scored the source of infection (by affected organ system or site), the plausibility of infection (rated as none, possible, probable, or definite), and the most likely causative pathogen. Assessments were based on a post hoc review of all available clinical, radiological, and microbiological evidence. The observed diagnostic agreement for source of infection was classified as partial (i.e., matching on organ system or site) or complete (i.e., matching on specific diagnostic terms), for plausibility as partial (2-point scale) or complete (4-point scale), and for causative pathogens as an approximate or exact pathogen match. Interobserver agreement was expressed as a concordant percentage and as a kappa statistic. None. A total of 206 infectious episodes were observed. Agreement regarding the source of infection was 89% (183/206) and 69% (142/206) for a partial and complete diagnostic match, respectively. This resulted in a kappa of 0.85 (95% CI, 0.79-0.90). Agreement varied from 63% to 91% within major diagnostic categories and from 35% to 97% within specific diagnostic subgroups, with the lowest concordance observed in cases of ventilator-associated pneumonia. In the 142 episodes for which a complete match on source of infection was obtained, the interobserver agreement for plausibility of infection was 83% and 65% on a 2- and 4-point scale, respectively. For causative pathogen, agreement was 78% and 70% for an approximate and exact pathogen match, respectively. Interobserver agreement for classifying sources of infection using Centers for Disease Control and Prevention criteria was excellent overall. However, full concordance on all aspects of the diagnosis between independent observers was rare for some types of infection, in particular for ventilator-associated pneumonia. 23627748 Paradoxical consequences of prohibitions. Explanations based in attribution theory claim that strong external controls such as parental restrictiveness and punishment undermine moral internalization. In contrast, 3 studies provide evidence that parental punishment does socialize morality, but of a particular sort: a morality focused on prohibitions (i.e., proscriptive orientation) rather than positive obligations (i.e., prescriptive orientation). Study 1 found young adults' accounts of parental restrictiveness and punishment activated their sensitivity to prohibitions and predicted a proscriptive orientation. Consistent with the greater potency of temptations for proscriptively oriented children, as well as past research linking shame to proscriptive morality, Study 2 found that restrictive parenting was also associated with greater suppression of temptations. Finally, Studies 3A and 3B found that suppressing these immoral thoughts is paradoxically harder for those with strong proscriptive orientations; more specifically, priming a proscriptive (versus prescriptive) orientation and inducing mental suppression of "immoral" thoughts led to the most ego depletion for those with restrictive parents. Overall, individuals who had restrictive parents had the lowest self-regulatory ability to resist their "immoral" temptations after prohibitions were activated. In contrast to common attributional explanations, these studies suggest that harsh external control by parents does not undercut moral socialization but rather undermines individuals' ability to resist temptation. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23715748 Immunohistochemical expression and mutation study of Prohibitin gene in Indian female breast cancer cases. Prohibitin (PHB1) is highly conserved and ubiquitously expressed protein. It is mapped to the chromosome 17q12-q21 locus, a region that has been reported to be genetically linked to early onset of breast cancer. Therefore, we carried out the population-based study in a total of 105 Indian female breast cancer cases and analyzed mutation(s) on exon 4 and the introns flanking it. Importantly, it has been found that the region of this exon has specific binding site for Rb and p53 gene. We further did protein expression of Prohibitin through immunohistochemistry in the same set of population where mutation has already been found. Out of 105 breast cancer cases, 46 cases (46/105, 43.8 %) showed low or no expression (+), 19 cases (19/105, 18.0 %) with moderate (++) expression and 40 cases (40/105, 38.0 %) had high (+++) expression for Prohibitin. Highly significant association was observed statistically between Prohibitin protein expression and clinico-pathological variables like nodal status (p = 0.0003), tumor stage (p = 0.0001), histological grade (p = 0.009). Moreover, the previously found mutation(s) when analyzed with the immunohistochemistry data revealed that all the breast cancer cases with mutation representing intron deletion (deletion of T nucleotide) near the intron-exon boundary had low (+) or no expression for Prohibitin. In summary, Prohibitin may be associated with breast cancer and its down expression can serve as a potential biomarker for the effective assessment of the disease. 23253136 Peptide scanning for studying structure-activity relationships in drug discovery. Peptide-based therapeutics have grown in importance over the last few decades. Furthermore, peptides have been extensively used as lead compounds in the drug discovery process to investigate the nature of chemical space required for molecular recognition and activity at a variety of targets. This critical commentary reviews scanning techniques, which employ natural and non-proteinogenic amino acids to facilitate understanding of structural requirements for peptide biological activity. The value of sequence analysis by such methods is highlighted by examples, in which the elements for peptide affinity and activity have been elucidated and employed to prepare peptidomimetic leads for drug development. 23690309 Long-term inflammation and glucocorticoid therapy impair skeletal modeling during growth in childhood crohn disease. Context: Glucocorticoids and inflammation inhibit bone formation; however, the impact on skeletal modeling is unknown. Objectives: The objectives of the study were to examine changes in bone mineral density (BMD) and cortical structure after Crohn disease (CD) diagnosis and identify associations with growth, glucocorticoids, and disease activity. Design/Participants: This was a prospective cohort study among 76 CD participants, aged 5-21 years. Tibia quantitative computed tomography trabecular BMD and cortical dimensions were obtained at diagnosis and 6 and 12 and a median of 42 months later; 51 completed the final visit. Outcomes: Sex, race, and age-specific Z-scores were generated for outcomes based on more than 650 reference participants, and cortical dimension Z-scores were further adjusted for tibia length. Generalized estimating equations were used to model changes in Z-scores. Results: Disease activity improved over the study interval (P < .001). Trabecular BMD Z-scores improved over the first 6 months; increases were associated with improved disease activity (P < .001), younger age (P = .005), and increases in vitamin D levels (P = .02). Greater increases in tibia length were associated with greater increases in cortical area Z-scores (P < .001). Greater glucocorticoid doses and disease activity were significantly associated with failure to accrue cortical area and were more pronounced with greater linear growth (interaction P < .05). Mean (±SD) trabecular BMD (-1.0 ± 1.21) and cortical area (-0.57 ± 1.10) Z-scores at the final visit were significantly reduced. Conclusions: CD was associated with persistent deficits in trabecular BMD, although younger participants demonstrated a greater potential for recovery. In addition, greater linear growth was associated with a greater recovery of cortical dimensions, especially among participants with less glucocorticoid exposure and inflammation. These data suggest that younger age and concurrent growth provide a window of opportunity for skeletal recovery. 23835590 Intrathecal gabapentin to treat chronic intractable noncancer pain. Oral gabapentin is approved as an anticonvulsant medication and to treat postherpetic neuralgia. Its nonopioid properties and presumed spinal site of analgesic action made the study on intrathecal gabapentin attractive to establish the minimum effective dose for a later, pivotal trial. The authors examined the safety and efficacy of intrathecal gabapentin in a randomized, blinded, placebo-controlled, multicenter trial in a heterogeneous cohort of candidates with chronic pain for intrathecal drug therapy. Patients (N = 170) were randomized to receive continuous intrathecal gabapentin (0 [placebo], 1, 6, or 30 mg/day) during 22 days of blinded treatment after implantation of a permanent drug delivery system. The highest dose, 30 mg/day, was selected to maintain a safety margin below the 100-mg/day dose that was explored in a phase 1 study. The authors found no statistically significant difference in the primary outcome measure, which was the numerical pain rating scale and response rate after 3 weeks, for any dose versus placebo. Physical functioning, quality of life, and emotional functioning also revealed no differences. Small, nonsignificant changes occurred in opioid medication use. The most frequent device-related adverse events were transient postimplant (lumbar puncture) headache, pain, and nausea. The most frequent gabapentin-related adverse events were nausea, somnolence, headache, dizziness, fatigue, and peripheral edema. Twenty-two days of intrathecal gabapentin did not demonstrate statistically significant or clinically meaningful analgesic effects. The study sponsor has no current plans for further studies. Drug-related adverse events were similar to those for oral gabapentin. Most device-related adverse events resulted from the implant surgery or anesthesia. 23849629 Division of Labor between the Chromodomains of HP1 and Suv39 Methylase Enables Coordination of Heterochromatin Spread. In Schizosaccharomyces pombe, heterochromatin spread, which is marked by histone 3 lysine 9 methylation (H3K9me), requires the chromodomains (CDs) of the H3K9 methylase Suv39/Clr4 and the HP1/Swi6 protein. It is unclear how the actions of these two H3K9me-recognizing CDs are coordinated. We find that the intrinsic preference of Suv39/Clr4 is to generate dimethylated H3K9 product. The recognition of pre-existing H3K9me marks by the CD of Suv39/Clr4 stimulates overall catalysis, enabling the accumulation of small amounts of trimethylated product in vivo. Coincidentally, the Suv39/Clr4 CD, unlike the HP1/Swi6 CD, has been shown to prefer the trimethyl state over the dimethyl state. We show that this preference enables efficient heterochromatin spread in vivo by reducing competition with HP1 proteins for the more prevalent dimethyl state. Our results reveal a strategy by which "writers" and "readers" of a chromatin mark exploit different methylation states on the same residue in order to facilitate collaboration and avoid competition. 23880533 CTCF demarcates chicken embryonic α-globin gene autonomous silencing and contributes to adult stage-specific gene expression. Genomic loci composed of more than one gene are frequently subjected to differential gene expression, with the chicken α-globin domain being a clear example. In the present study we aim to understand the globin switching mechanisms responsible for the epigenetic silencing of the embryonic π gene and the transcriptional activation of the adult α (D) and α (A) genes at the genomic domain level. In early stages, we describe a physical contact between the embryonic π gene and the distal 3' enhancer that is lost later during development. We show that such a level of regulation is achieved through the establishment of a DNA hypermethylation sub-domain that includes the embryonic gene and the adjacent genomic sequences. The multifunctional CCCTCC-binding factor (CTCF), which is located upstream of the α (D) gene promoter, delimits this sub-domain and creates a transition between the inactive sub-domain and the active sub-domain, which includes the adult α (D) gene. In avian-transformed erythroblast HD3 cells that are induced to differentiate, we found active DNA demethylation of the adult α (D) promoter, coincident with the incorporation of 5-hydroxymethylcytosine (5hmC) and concomitant with adult gene transcriptional activation. These results suggest that autonomous silencing of the embryonic π gene is needed to facilitate an optimal topological conformation of the domain. This model proposes that CTCF is contributing to a specific chromatin configuration that is necessary for differential α-globin gene expression during development. 23956270 Arterial grafts do not counteract target vessel occlusion. Grafted, non-occluded coronary arteries might contribute substantially to the myocardial blood supply and serve as a basis for vascular collateralization which preserves the myocardium in the event of graft occlusion. Early studies indicated that grafting with saphenous vein, but not internal mammary arteries, accelerates coronary atherosclerosis. This has not been extensively studied for the radial artery, which like the internal mammary artery (IMA) is largely resistant to atherosclerosis. A differential effect of various grafts might facilitate identification of disease-modifying principles. Our surgical cohort represented an opportunity to analyse new native coronary occlusions by comparison with preoperative angiograms. One hundred and two patients underwent angiography 1.3-3.9 years after coronary artery bypass surgery, primarily in order to compare the patency of radial artery, IMA and saphenous vein grafts. Out of 290 stenotic, grafted vessels, 67 (23%) occluded during follow-up. Native occlusion occurred in 47% of the patients and correlated with serum-cholesterol. In a per target analysis, independent predictors of postoperative native occlusion were the right coronary artery territory, patent corresponding graft, the corresponding graft being an IMA and end-to-side anastomosis. Target vessel occlusion is similar with radial artery and saphenous vein grafts and proceeds rapidly even in the current era of secondary prophylaxis against atherosclerosis. Competitive graft flow appears to promote occlusion. Contrary to previous studies, we do not find vein grafts to be inferior to IMA grafts with respect to preservation of native vessel patency. 23574520 Antigen presentation by dendritic cells in rheumatoid arthritis. Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disease that affects largely synovial joints. It has been postulated that activated autoreactive CD4 T cells play a key role in triggering and/or maintaining the chronic inflammatory process in RA. Dendritic cells (DCs) are antigen-presenting cells that activate cognate clonal CD4 T cells in the lymph nodes. The activation process involves the formation of a molecular structure at the DC-CD4 T cell contact zone called immunological synapse (IS). In RA, the synovium, a thin layer of tissue below the capsule in the joints, shows a massive infiltration of DCs and CD4 T cells. Subjects bearing HLA-DRB1 alleles of the Major Histocompatibility Complex II gene displaying a motif called RA "shared epitope (SE)", have an enhanced susceptibility to suffer RA. Interestingly, the SE-containing HLA-DRB1 molecules display a pocket with a high affinity for citrullinated antigens, which are found at higher levels in subjects prone to develop RA. Thus, it is possible that the DCs of susceptible individuals may form IS with particular features that may present citrullinated peptides to autorreactive naïve CD4 T clones that, after being activated, contribute to the initiation or development of the disease. Herein I put forward a model of RA initiation based on current information on the immune response and RA. 23892036 Design of a novel LOX-1 receptor antagonist mimicking the natural substrate. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the major receptor for oxidized low-density lipoprotein (ox-LDL) in endothelial cells, is overexpressed in atherosclerotic lesions. LOX-1 specific inhibitors, urgently necessary to reduce the rate of atherosclerotic and inflammation processes, are not yet available. We have designed and synthesized a new modified oxidized phospholipid, named PLAzPC, which plays to small scale the ligand-receptor recognition scheme. Molecular docking simulations confirm that PLAzPC disables the hydrophobic component of the ox-LDL recognition domain and allows the interaction of the l-lysine backbone charged groups with the solvent and with the charged/polar residues located around the edges of the LOX-1 hydrophobic tunnel. Binding assays, in a cell model system expressing human LOX-1 receptors, confirm that PLAzPC markedly inhibits ox-LDL binding to LOX-1 with higher efficacy compared to previously identified inhibitors. 23449733 Acute disseminated encephalomyelitis in two renal transplant patients: is there a role for Epstein-Barr virus reactivation? Acute disseminated encephalomyelitis (ADEM) is a rare inflammatory demyelinating disease of the central nervous system, usually occurring after a vaccination or infectious disease. It has been exceptionally described in transplanted patients. The pathophysiology remains incompletely understood. We report the clinical, biological and magnetic resonance imaging (MRI) presentation and evolution of two kidney-transplanted patients with ADEM associated with local Epstein-Barr virus (EBV) reactivation. ADEM may occur in transplanted patients with favorable evolution. Its pathophysiology is uncertain, and the implication of EBV is discussed. 23941503 Synthetic self-localizing ligands that control the spatial location of proteins in living cells. Small-molecule ligands that control the spatial location of proteins in living cells would be valuable tools for regulating biological systems. However, the creation of such molecules remains almost unexplored because of the lack of a design methodology. Here we introduce a conceptually new type of synthetic ligands, self-localizing ligands (SLLs), which spontaneously localize to specific subcellular regions in mammalian cells. We show that SLLs bind their target proteins and relocate (tether) them rapidly from the cytoplasm to their targeting sites, thus serving as synthetic protein translocators. SLL-induced protein translocation enables us to manipulate diverse synthetic/endogenous signaling pathways. The method is also applicable to reversible protein translocation and allows control of multiple proteins at different times and locations in the same cell. These results demonstrate the usefulness of SLLs in the spatial (and temporal) control of intracellular protein distribution and biological processes, opening a new direction in the design of small-molecule tools or drugs for cell regulation. 23199342 Effects of sirtuin 1 activation on nicotine and lipopolysaccharide-induced cytotoxicity and inflammatory cytokine production in human gingival fibroblasts. Although sirtuin 1 (SIRT1) over-expression and resveratrol exert anti-inflammatory and proinflammatory effects, their effects and the mechanism of action on human gingival fibroblast (HGF)-mediated inflammation are unknown. The aim of this study was to demonstrate the effects of activating SIRT1 using resveratrol and recombinant adenovirus encoding SIRT1 (Ad-SIRT1) on the expression of proinflammatory cytokines and to elucidate its mechanism of action of lipopolysaccharide (LPS) and nicotine stimulated-HGF. Cytotoxicity and the production of reactive oxygen species (ROS) were measured using the 3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry, respectively. The amount of prostaglandin E2 (PGE2 ) released into the culture medium was measured by radioimmunoassay. mRNA and protein levels were analyzed using RT-PCR and western blotting, respectively. Nicotine and LPS up-regulated the expression of SIRT1 mRNA and SIRT1 protein in a time- and concentration-dependent manner. Resveratrol and Ad-SIRT1 decreased LPS and nicotine-induced cytotoxicity, ROS and PGE2 production, and expression of cyclooxygenase-2 in HGFs. Resveratrol and Ad-SIRT1 inhibited nicotine and LPS-mediated protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K), p38, ERK, JNK, MAPK and nuclear factor-kappa B (NF-κB) activation. This study is the first to show that the anti-inflammatory and cytoprotective effects of SIRT1 activation in HGFs occur through the PKC, PI3K, MAPK and NF-κB pathways. 23765393 Exploration of sialic Acid diversity and biology using sialoglycan microarrays. Sialic acids (Sias) are a group of α-keto acids with a nine-carbon backbone, which display many types of modifications in nature. The diversity of natural Sia presentations is magnified by a variety of glycosidic linkages to underlying glycans, the sequences and classes of such glycans, as well as the spatial organization of Sias with their surroundings. This diversity is closely linked to the numerous and varied biological functions of Sias. Relatively large libraries of natural and unnatural Sias have recently been chemically/chemoenzymatically synthesized and/or isolated from natural sources. The resulting sialoglycan microarrays have proved to be valuable tools for the exploration of diversity and biology of Sias. Here we provide an overview of Sia diversity in nature, the approaches used to generate sialoglycan microarrays, and the achievements and challenges arising. © 2013 Wiley Periodicals, Inc. Biopolymers 99: 650-665, 2013. 23962675 Self-referential processing is distinct from semantic elaboration: Evidence from long-term memory effects in a patient with amnesia and semantic impairments. We report data demonstrating that self-referential encoding facilitates memory performance in the absence of effects of semantic elaboration in a severely amnesic patient also suffering semantic problems. In Part 1, the patient, GA, was trained to associate items with the self or a familiar other during the encoding phase of a memory task (self-ownership decisions in Experiment 1 and self-evaluation decisions in Experiment 2). Tests of memory showed a consistent self-reference advantage, relative to a condition where the reference was another person in both experiments. The pattern of the self-reference advantage was similar to that in healthy controls. In Part 2 we demonstrate that GA showed minimal effects of semantic elaboration on memory for items he semantically classified, compared with items subject to physical size decisions; in contrast, healthy controls demonstrated enhanced memory performance after semantic relative to physical encoding. The results indicate that self-referential encoding, not semantic elaboration, improves memory in amnesia. Self-referential processing may provide a unique scaffold to help improve learning in amnesic cases. 23929779 Recent Diversification of a Marine Genus (Tursiops spp.) Tracks Habitat Preference and Environmental Change. Understanding the evolution of diversity and the resulting systematics in marine systems is confounded by the lack of clear boundaries in oceanic habitats, especially for highly mobile species like marine mammals. Dolphin populations and sibling species often show differentiation between coastal and offshore habitats, similar to the pelagic/littoral or benthic differentiation seen for some species of fish. Here we test the hypothesis that lineages within the polytypic genus Tursiops track past changes in the environment reflecting ecological drivers of evolution facilitated by habitat release. We used a known recent time point for calibration (the opening of the Bosphorus) and whole mitochondrial genome (mitogenome) sequences for high phylogenetic resolution. The pattern of lineage formation suggested an origin in Australasia and several early divisions involving forms currently inhabiting coastal habitats. Radiation in pelagic environments was relatively recent, and was likely followed by a return to coastal habitat in some regions. The timing of some nodes defining different ecotypes within the genus clustered near the two most recent interglacial transitions. A signal for an increase in diversification was also seen for dates after the last glacial maximum. Together these data suggest the tracking of habitat preference during geographic expansions, followed by transition points reflecting habitat shifts, which were likely associated with periods of environmental change. 23469845 Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities. Stroke is the second leading cause of death, after ischemic heart disease, and accounts for 9% of deaths worldwide. According to the World Health Organization [WHO], 15 million people suffer stroke worldwide each year. Of these, more than 6 million die and another 5 million are permanently disabled. Reactive oxygen species [ROS] have been implicated in brain injury after ischemic stroke. There is evidence that a rapid increase in the production of ROS immediately after acute ischemic stroke rapidly overwhelm antioxidant defences, causing further tissue damage. These ROS can damage cellular macromolecules leading to autophagy, apoptosis, and necrosis. Moreover, the rapid restoration of blood flow increases the level of tissue oxygenation and accountsfor a second burst of ROS generation, which leads to reperfusion injury. Current measures to protect the brain against severe stroke damage are insufficient. Thus, it is critical to investigate antioxidant strategies that lead to the diminution of oxidative injury. The antioxidant vitamins C and E, the polyphenol resveratrol, the xanthine oxidase [XO] inhibitor allopurinol, and other antioxidant strategies have been reviewed in the setting of strokes. This review focuses on the mechanisms involved in ROS generation, the role of oxidative stress in the pathogenesis of ischemic stroke, and the novel therapeutic strategies to be tested to reduce the cerebral damage related to both ischemia and reperfusion. 23051890 Self-propelled nanojets via template electrodeposition. In this paper, we present a rapid, high-yield, low-end and low-cost fabrication of nanojet motors using a template directed electrochemical deposition method. Using an electrochemical deposition method, the bubble-ejecting nanojets were grown within the alumina template, which is commercially available. These fabricated nanosized devices have typical dimensions of 300 nm (diameter) by 4.5 μm (length), and they are able to move in a hydrogen peroxide fuel solution with velocities up to approximately 40 body lengths per second. They are also capable of exhibiting various modes of movement such as straight, screw-like and circular motions, in a similar manner comparable to larger micro-sized jets. In addition, due to their small dimensions, the movements of these nanojets can be strongly influenced by colliding them with microbubbles. This highly parallel method which is of low-cost and requires the usage of low-end equipment that can be easily located in any laboratory opens up the doors for world-wide nanojet fabrication in the near future. 23916770 Start and the restriction point. Commitment to division requires that cells sense, interpret, and respond appropriately to multiple signals. In most eukaryotes, cells commit to division in G1 before DNA replication. Beyond a point, known as Start in yeast and the restriction point in mammals, cells will proceed through the cell cycle despite changes in upstream signals. In metazoans, misregulated G1 control can lead to developmental problems or disease, so it is important to understand how cells decipher the myriad external and internal signals that contribute to the fundamental all-or-none decision to divide. Extensive study of G1 control in the budding yeast Saccharomyces cerevisiae and mammalian culture systems has revealed highly similar networks regulating commitment. However, protein sequences of functional orthologs often indicate a total lack of conservation suggesting significant evolution of G1 control. Here, we review recent studies defining the conserved and diverged features of G1 control and highlight systems-level aspects that may be common to other biological regulatory networks. 23339629 Photoinduced formation mechanism of the thymine-thymine (6-4) adduct. The photoinduced mechanism leading to the formation of the thymine-thymine (6-4) photolesion has been studied by using the CASPT2//CASSCF approach over a dinucleotide model in vacuo. Following light absorption, localization of the excitation on a single thymine leads to fast singlet-triplet crossing that populates the triplet (3)(nπ*) state of thymine. This state, displaying an elongated C(4)═O bond, triggers (6-4) dimer formation by reaction with the C(5)═C(6) double bond of the adjacent thymine, followed by a second intersystem crossing, which acts as a gate between the excited state of the reactant and the ground state of the photoproduct. The requirement of localized excitation on just one thymine, whose main decay channel (by radiationless repopulation of its ground state) is nonphotochemical, can rationalize the experimentally observed low quantum yield of formation for the thymine-thymine (6-4) adduct. 23938120 Myopia and Age-Related Cataract: A Systematic Review and Meta-analysis. To examine if myopia is a risk factor for age-related cataract. Systematic review and meta-analysis. A systematic review of the literature was performed using PubMed and Embase from their inception to March 2013 for population-based studies with data on myopia and age-related cataract, including nuclear, cortical, and posterior subcapsular (PSC) cataract. Separate meta-analyses for case-control/cross-sectional studies and cohort studies were conducted using random-effects models, with results reported as adjusted odds ratios (ORs) and relative risks (RRs), respectively. A total of 38 007 subjects aged 30-97 years from 12 population-based studies were included in the meta-analysis. Meta-analysis of the 7 cross-sectional studies and 1 case-control study confirmed that myopia was associated with increasingly prevalent nuclear (pooled OR 2.81, 95% CI 1.94-4.06) and PSC cataract (pooled OR 1.93, 95% CI 1.49-2.49) but not with cortical cataract (pooled OR 1.08, 95% CI 0.90-1.30). Meta-analysis from 3 or 4 cohort studies showed nonsignificant associations of myopia with incident nuclear (pooled RR 1.25, 95% CI 0.71-2.21), cortical (pooled RR 1.21, 95% CI 0.67-2.19), and PSC cataract (pooled RR 1.26, 95% CI 0.92-1.74). The associations of myopia with prevalent nuclear and PSC cataract are confirmed in meta-analysis of 8 study findings. The association of myopia with incidence of age-related cataract could not be confirmed in meta-analysis of 4 study findings. 23841530 Antidepressant medication dispensing among montelukast initiators. Abstract Objective: This study investigates the potential association between montelukast use and psychiatric adverse events by monitoring changes in antidepressant medication dispensing rates before and after initiating montelukast. Methods: The primary study group of montelukast initiators was identified using the Wolters Kluwer's SOURCE Lx® pharmacy claims database (WK). This group included 232 159 patients ≤45 years old who had at least two montelukast prescriptions from 2003 to 2007. Comparison groups comprised of 264 704 fluticasone initiators and 89 635 long-acting β-agonist corticosteroid (LABA/ICS) initiators were also identified. Antidepressant medication dispensing rates in these three groups were determined using WK, and changes in rates before and after the first asthma controller medication prescription date were evaluated using interrupted time-series analysis (ITS). ITS was performed separately for four age categories, with a focus on youth (12-17 years) and young adult (18-24 years). Results: For patients 18-24 years old, antidepressant medication dispensing rates increased significantly after initiating montelukast [1.93% (1.55-2.32%, p < 0.001)] but also after initiating fluticasone and LABA/ICS [1.72% (1.30-2.15%, p < 0.001) and 2.76% (2.35-3.17%, p < 0.001)]. Similar patterns were observed across the three medication groups for other age categories but these differences were not all significant. Conclusions: Small increases in antidepressant medication dispensing rates occurred after initiating montelukast. However, similar increases were observed in the fluticasone and LABA/ICS comparison groups. The results of this study cannot support a specific association between initiation of montelukast treatment and an increase in psychiatric adverse effects. 23906559 Polybrominated diphenyl ethers affect the reproduction and development, and alter the sex ratio of zebrafish (Danio rerio). Polybrominated diphenyl ethers (PBDEs) have been commonly used as flame retardants and now become ubiquitous in the global environment. Using zebrafish as a model, we tested the hypothesis that PBDEs may affect the reproduction and development of fish. Zebrafish were exposed to environmentally relevant concentrations of DE-71 (a congener of PBDE commonly found in the environment) throughout their whole life cycle, and the effects of DE-71 on gonadal development, gamete quality, fertilization success, hatching success, embryonic development and sex ratio were investigated. Despite gonadal development was enhanced, reductions in spawning, fertilization success, hatching success and larval survival rate were evident, while significant increases in malformation and percentage of male were also observed in the F1 generation. Our laboratory results suggest that PBDEs may pose a risk to reproductive success and alter the sex ratio of fish in environments highly contaminated with PBDEs. 23957255 Effect on anxiety and depression of a multifactorial risk factor intervention program after stroke and TIA: a randomized controlled trial. Objectives: Depression and anxiety related to stroke are caused by vascular lesions and psychological reactions. Treatment of vascular and modifiable behavioral risk factors reduces the risk of stroke and may also reduce the risk of emotional changes after stroke. We aimed to investigate whether a multifactorial risk factor intervention program in patients with first-ever stroke or transient ischemic attack (TIA) can influence post-stroke anxiety and depressive symptoms in patients one year post-stroke. Method: The study population consisted of first-ever stroke and TIA patients allocated in a randomized, evaluator-blinded, controlled trial to care as usual or a structured and multidisciplinary follow-up including intensive treatment of vascular risk. The primary endpoint (cognition) has previously been reported. The secondary endpoint, reported here, was changes in the Hospital Anxiety and Depression Scale (HADS) from baseline to 12-month follow-up. Results: One hundred and ninety-five patients were randomized. The estimated difference between treatment groups, in changes in HADS, from baseline to 12 months was -1.32 (95% confidence interval: -2.61, -0.04; P = 0.044) in favor of the intervention group. One year post-stroke, 4/85 (4.7%) patients in the intervention group and 12/89 (13.5%) in the control group suffered from depression (P = 0.045), while 7/85 (8.2%) patients in the intervention group and 13/89 (14.6%) patients in the control group suffered from anxiety (P = 0.19). Conclusion: A structured, multidisciplinary, multifactorial risk factor program including vascular risk factor management may be associated with reduced HADS scores and a lower prevalence of depressive symptoms one year after stroke. 23915143 In vivo collection of follicular fluid and granulosa cells from individual follicles of different diameters in cattle by an adapted ovum pick-up system. Most studies on granulosa cell (GC) function in cattle have been performed using GC and follicular fluid (FF) samples collected from slaughterhouse ovaries. Using this approach, the follicular developmental stage and functional status are unknown and indirectly inferred, limiting data interpretation. Ultrasound-guided follicle aspiration has previously been used to recover GC or FF samples, but this was mostly carried out in large follicles or pools of small follicles, without recording the efficiency of recovery. The present study was aimed at adapting and evaluating an ovum pick-up (OPU) system for the in vivo recovery of FF and GC from individual follicles of different diameters. In the first trial, the losses of fluid inside the tubing system were calculated using a conventional or an adapted-OPU system. Blood plasma volumes equivalent to the amount of FF in follicles of different diameters were aspirated using a conventional OPU Teflon circuit. The OPU system was then adapted by connecting 0.25 mL straws to the circuit. A second trial evaluated the efficiency of FF recovery in vivo. Follicles ranging from 4.0 to 16.8 mm in diameter were aspirated individually using the conventional or adapted-OPU systems. A third trial assessed the in vivo recovery of GC and the subsequent amount of RNA obtained from the follicles of different diameters from Holstein and Gir cattle. In Trial I, the plasma recovery efficiency was similar (P > 0.05) for the volumes expected for 12 and 10 mm follicles, but decreased (P < 0.05) for smaller follicles (45.7+/-4.0%, 12.4+/-4.3% and 0.0+/-0.0% for 8, 6, and 4 mm follicles, respectively). Using the adaptation, the losses intrinsic to the aspiration system were similar for all follicle diameters. In Trial II, the expected and recovered volumes of FF were correlated (r = 0.89) and the efficiency of recovery was similar among follicles <12 mm, while larger follicles had a progressive increase in FF losses that was not related to the tubing system. In Trial III, the number of GC and amount of RNA obtained were not affected (P > 0.05) by follicle size, but differed according to breed (615,054+/-58,122 vs 458,095+/-36,407 for Holstein and Gir, respectively; P < 0.05). The adapted-OPU system can be successfully used for the in vivo collection of FF and GC from follicles of different diameters. This will enable further endocrine, cellular, and gene expression analyses. 23861780 Tanshinone IIA Increases the Bystander Effect of Herpes Simplex Virus Thymidine Kinase/Ganciclovir Gene Therapy via Enhanced Gap Junctional Intercellular Communication. The bystander effect is an intriguing phenomenon by which adjacent cells become sensitized to drug treatment during gene therapy with herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV). This effect is reported to be mediated by gap junctional intercellular communication (GJIC), and therefore, we postulated that upregulation of genes that facilitate GJIC may enhance the HSV-tk/GCV bystander effect. Previous findings have shown Tanshinone IIA (Tan IIA), a chemical substance derived from a Chinese medicine herb, promotes the upregulation of the connexins Cx26 and Cx43 in B16 cells. Because gap junctions are formed by connexins, we hypothesized that Tan IIA might increase GJIC. Our results show that Tan IIA increased GJIC in B16 melanoma cells, leading to more efficient GCV-induced bystander killing in cells stably expressing HSV-tk. Additionally, in vivo experiments demonstrated that tumors in mice with 10% HSV-tk positive B16 cells and 90% wild-type B16 cells became smaller following treatment with the combination of GCV and Tan IIA as compared to GCV or Tan IIA alone. These data demonstrate that Tan IIA can augment the bystander effect of HSV-tk/GCV system through increased gap junction coupling, which adds strength to the promising strategy that develops connexins inducer to potentiate the effects of suicide gene therapy. 23546647 Axotomy-induced changes in the chemical coding pattern of colon projecting calbindin-positive neurons in the inferior mesenteric Ganglia of the pig. The present study examines the response of colon-projecting neurons localized in the inferior mesenteric ganglia (IMG) to axotomy in the pig animal model. In all animals (n = 8), a median laparotomy was performed under anesthesia and the retrograde tracer Fast Blue was injected into the descending colon wall. In experimental animals (n = 4), the descending colon was exposed and the bilateral caudal colonic nerves were identified and severed. All animals were euthanized and the inferior mesenteric ganglia were harvested and processed for double-labeling immunofluorescence for calbindin-D28k (CB) in combination with either tyrosine hydroxylase (TH), neuropeptide Y (NPY), somatostatin (SOM), vasoactive intestinal polypeptide (VIP), nitric oxide synthase (NOS), Leu-enkephalin (LENK), substance P, vesicular acetylcholine transporter, or galanin. Immunohistochemistry revealed significant changes in the chemical coding pattern of injured inferior mesenteric ganglion neurons. In control animals, Fast Blue-positive neurons were immunoreactive to TH, NPY, SOM, VIP, NOS, LENK, and CB. In the experimental group, the numbers of TH-, NPY-, and SOM-expressing neurons were reduced, whereas the number of neurons immunoreactive to LENK was increased. Our data indicate that the colon-projecting neurons of the porcine IMG react to the axotomy in a similar, but not an identical manner in a comparison to other species, especially rodents. Further studies are needed to elucidate the detailed factors/mechanisms involved in the response to nerve injury. 23852772 Identifying protein complexes from heterogeneous biological data. With the increasing availability of diverse biological information for proteins, integration of heterogeneous data becomes more useful for many problems in proteomics, such as annotating protein functions, predicting novel protein-protein interactions and so on. In this paper, we present an integrative approach called InteHC (Integrative Hierarchical Clustering) to identify protein complexes from multiple data sources. While integrating multiple sources could effectively improve the coverage of current insufficient protein interactome (the false negative issue), it could also introduce potential false positive interactions which could hurt the performance of protein complex prediction. Our proposed InteHC method can effectively address these issues to facilitate accurate protein complex prediction and it is summarized into the following three steps. First, for each individual source/feature, InteHC computes the matrices to store the affinity scores between a protein pair that indicate their propensity to interact or co-complex relationship. Second, InteHC computes a final score matrix, which is the weighted sum of affinity scores from individual sources. In particular, the weights indicating the reliability of individual sources are learned from a supervised model (i.e., a linear ranking SVM). Finally, a hierarchical clustering algorithm is performed on the final score matrix to generate clusters as predicted protein complexes. In our experiments, we compared the results collected by our hierarchical clustering on each individual feature with those predicted by InteHC on the combined matrix. We observed that integration of heterogeneous data significantly benefits the identification of protein complexes. Moreover, a comprehensive comparison demonstrates that InteHC performs much better than 14 state-of-the-art approaches. All the experimental data and results can be downloaded from http://www.ntu.edu.sg/home/zhengjie/data/InteHC. © Proteins 2013;. © 2013 Wiley Periodicals, Inc. 23968983 Protection by Face Masks against Influenza A(H1N1)pdm09 Virus on Trans-Pacific Passenger Aircraft, 2009. In response to several influenza A(H1N1)pdm09 infections that developed in passengers after they traveled on the same 2 flights from New York, New York, USA, to Hong Kong, China, to Fuzhou, China, we assessed transmission of influenza A(H1N1)pdm09 virus on these flights. We defined a case of infection as onset of fever and respiratory symptoms and detection of virus by PCR in a passenger or crew member of either flight. Illness developed only in passengers who traveled on the New York to Hong Kong flight. We compared exposures of 9 case-passengers with those of 32 asymptomatic control-passengers. None of the 9 case-passengers, compared with 47% (15/32) of control-passengers, wore a face mask for the entire flight (odds ratio 0, 95% CI 0-0.71). The source case-passenger was not identified. Wearing a face mask was a protective factor against influenza infection. We recommend a more comprehensive intervention study to accurately estimate this effect. 23891980 Obestatin prevents analgesic tolerance to morphine and reverses the effects of mild morphine withdrawal in mice. Obestatin is a 23-amino acid gut-derived neuropeptide, encoded by the same gene with ghrelin. The goal of this study was to examine the effects of obestatin on the acute and chronic analgesic actions of morphine and on mild morphine withdrawal. Open-field (OF) and elevated plus maze (EPM) tests were used to assess mild morphine withdrawal-induced behavior changes and the heat-radiant tail-flick assay was used to investigate analgesic actions of morphine. CFLP male mice were treated twice a day with graded doses of morphine in EPM and OF experiments and once a day in tail-flick studies. Obestatin (1.5μg/2μl) was administrated once a day in all experiments. Furthermore, 0.2mg/kg naloxone or saline was administered after the final injection of morphine at a dose of 20mg/kg in EPM and OF. These behavioral parameters were monitored in the OF: the percentage of center ambulation time and distance; whereas in the EPM: the time spent in open arms and the entries into open arms compared to the total time (%OAT) and entries (%OAE). In the OF, obestatin significantly decreased the percentage of time spent in the center in mice undergoing naloxone-precipitated mild morphine withdrawal. EPM results were similar to open field, but obestatin had no significant effect on parameters mentioned above. Besides, obestatin maintained the analgesic effect of morphine 90 and 120min after morphine injection in mice treated with morphine receiving obestatin compared to mice treated with morphine. In tolerance studies, obestatin diminished the analgesic tolerance to morphine on the 5th day. In this study we confirmed that obestatin reversed the effect of mild morphine withdrawal and enhances the analgesic effect of morphine. These data suggest that obestatin may have a role in opioid-induced analgesia and in behavioral responses induced by opioid withdrawal. 23936094 Decrease of miR-202-3p Expression, a Novel Tumor Suppressor, in Gastric Cancer. Emerging studies have indicated that microRNAs are involved in the development and progression of cancer. Here we found that miR-202-3p was frequently down-regulated in gastric cancer tissues. Overexpression of miR-202-3p in gastric cancer cells MKN-28 and BGC-823, markedly suppressed cell proliferation and induced cell apoptosis both in vitro and in vivo. Furthermore, Gli1 expression was frequently positive in gastric cancer tissues and inversely correlated with miR-133b expression. We demonstrate that the transcriptional factor Gli1 was a target of miR-202-3p and plays an essential role as a mediator of the biological effects of miR-202-3p in gastric cancer. MiR-202-3p also inhibited the expression of γ-catenin and BCL-2. Taken together, these findings suggest that miR-202-3p may function as a novel tumor suppressor in gastric cancer and its anti-tumor activity may attribute the direct targeting and inhibition of Gli1. 23895290 Plant Omics: Genome-Wide Analysis of ABA Repressor1 (ABR1) Related Genes in Rice During Abiotic Stress and Development. Abstract Rice is one of the world's most important food crops. Approximately 50% of rice production is affected by drought, an abiotic stress greatly impacting crop quality and yield. Agrigenomics research now offers the promise of understanding the drought stress impacts at a systems level. ABA repressor 1 (ABR1) is a member of the ethylene-responsive element-binding factor (ERF/AP2) superfamily of ERF transcription factors. We report here a global expression analysis of the rice ABR1-related genes where we identified the expression pattern of each Oryza sativa ERF (OsERF) during various developmental stages and abiotic stress treatments. The group X OsERFs, closely related genes orthologous to ABR1, exhibited significant differential expression profiles during certain stages of development and in response to abiotic stresses. We selected a subset of these genes and validated their observed expression profiles in response to abiotic stresses using quantitative RT-PCR. Moreover, we discovered that pairs of recently duplicated group X OsERFs display highly distinct expression profiles from one another. We determined the subcellular localization of two group X OsERF genes and observed localization to the nucleolus. To the best of our knowledge, this is the first report of localization of rice ERF protein to the nucleolus. This study also points out an overlap of expression under abiotic stress and reproductive developmental stages, indicating cross talk among different signaling pathways. This genome-wide expression analysis of rice ABR1 homologs paves the way for future functional analyses, with the goal to develop strategies to improve rice abiotic stress tolerance. 23313337 Anti-apoptotic activity of hydroxytyrosol and hydroxytyrosyl laurate. Hydroxytyrosol (HyT) is a polyphenol primarily released in olive mill wastewater and in olive oil. In animal and cell model studies, HyT and its metabolites have strong antioxidant and antimicrobial activities, as well as beneficial effects on the cardiovascular system and in several human diseases. Differently, many researchers reported that HyT down-regulates tumor cell viability and cell cycle progression, and induces reactive oxygen species (ROS) production and apoptosis. In this study we have investigated the effects of HyT and the corresponding ester hydroxytyrosyl laurate in U937 cells, a human monocytoid cell line, and in C2C12 myoblasts, a murine proliferating muscle cell model, after apoptotic death induction. Inverted, light and transmission electron microscopy have been utilized to characterize cell death patterns. H2O2, at the concentrations known to induce apoptosis, was utilized as cell death trigger. The results obtained show that laur-HyT has a protective antioxidant effect against H2O2 treatment, greater than HyT, so having a role in the prevention of apoptotic death in normal and tumor cells. These data suggest these compounds as good candidate for novel therapeutic strategies. 23465285 A review of the cardiometabolic risk experience among canadian métis populations. Cardiometabolic risk is a growing concern in Western society in which rates of cardiovascular disease, diabetes, and obesity are on the rise. Aboriginal populations currently experience unequal burdens of these chronic conditions. However, limited information regarding the experience of cardiometabolic risk among Métis populations is available. This review sought to evaluate the cardiometabolic risk experience among Métis populations in Canada. Canada's Métis population currently experiences greater burdens of chronic conditions including metabolic syndrome, diabetes, obesity, and cardiovascular disease than that of the non-Aboriginal population. Métis populations also experience poorer life expectancy, education, and employment attainments, and reduced access to health care services compared with non-Aboriginal populations. Interventions addressing the deficiencies in sociodemographic, lifestyle, and social determinants among the Métis population might help combat rising experiences of chronic diseases faced by these people. Though the burden of chronic conditions, sociodemographic, lifestyle challenges, and social determinants of health among Métis populations are generally less than that of First Nations populations, Métis people experience these health challenges and influencing factors are generally more similar to that of First Nations than non-Aboriginal peoples. Subsequently, Métis populations need to be included in plans and strategies to reduce chronic conditions among Aboriginal populations. In conclusion, Métis populations experience greater burden of cardiometabolic risk and its components than the general Canadian population. 23946594 Infective severe acute pancreatitis: A comparison of (99m)Tc-ciprofloxacin scintigraphy and computed tomography. To evaluate (99m)Tc-ciprofloxacin scintigraphy compared with computed tomography (CT) for detecting secondary infections associated with severe acute pancreatitis (SAP) in swine. Six healthy swine were assigned to a normal control group (group A, n = 6). SAP was induced in group B (n = 9) and C (n = 18), followed by inoculation of the resulting pancreatic necroses with inactive Escherichia coli (E. coli) (group B) and active E. coli (group C), respectively. At 7 d after inoculation, a CT scan and a series of analyses using infecton imaging (at 0.5, 1, 2, 3, 4 and 6 h after the administration of 370 MBq of intravenous infecton) were performed. The scintigrams were visually evaluated and semi-quantitatively analyzed using region of interest assignments. The differences in infecton uptake and changes in the lesion-background radioactive count ratios (L/B) in the 3 groups were recorded and compared. After imaging detection, histopathology and bacterial examinations were performed, and infected SAP was regarded as positive. The imaging findings were compared with histopathological and bacteriological results. In group A, 6 animals survived without infection in the pancreas. In group B, 7/9 swine survived and one suffered from infection. In group C, 15/18 animals survived with infection. Hence, the number of normal, non-infected and infected SAP swine was 6, 6 and 16, respectively. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of the infecton method were 93.8% (15/16), 91.7% (11/12), 92.9% (26/28), 93.8% (15/16) and 91.7% (11/12), whereas these values for CT were 12.5% (2/16), 100.0% (12/12), 50.0% (14/28), 100.0% (2/2) and 46.2% (12/26), respectively. The changes in L/B for the infected SAP were significantly different from those of the non-infected and normal swine (P < 0.001). The mean L/B of the infectious foci at 0.5, 1, 2, 3, 4 and 6 h was 1.17 ± 0.10, 1.71 ± 0.30, 2.46 ± 0.45, 3.36 ± 0.33, 2.04 ± 0.37 and 1.1988 ± 0.09, respectively. At 3 h, the radioactive counts (2350.25 ± 602.35 k) and the mean L/B of the infectious foci were significantly higher than that at 0.5 h (P = 0.000), 1 h (P = 0.000), 2 h (P = 0.04), 4 h (P = 0.000) and 6 h (P = 0.000). (99m)Tc-ciprofloxacin scintigraphy may be an effective procedure for detecting SAP secondary infections with higher sensitivity and accuracy than CT. 23780699 Evidence for Low-Temperature Melting of Mercury owing to Relativity. An old problem solved: Monte Carlo simulations using the diatomic-in-molecule method derived from accurate ground- and excited-state relativistic calculations for Hg2 show that the melting temperature for bulk mercury is lowered by 105 K, which is due to relativistic effects. 23933823 Recent Developments in Septic Bursitis. Septic bursitis is a disease that can be difficult to distinguish from aseptic bursitis. There are no definitive treatment guidelines. The optimal duration of antibiotic therapy is not defined. Most of the cases are due to infection with Staphylococcus aureus, although many other pathogens can also cause this infection. The optimal management includes early recognition and prompt initiation of appropriate antibiotic therapy. Surgical management may be necessary, and complications can arise from open procedures. Endoscopic bursectomy may be considered for patients requiring surgical debridement. This approach may lead to decreased morbidity in those requiring surgical intervention. 23688915 Cognitive-behavioural interventions for mood and anxiety disorders in HIV: A systematic review. Mood and anxiety disorders are highly prevalent and comorbid with HIV/AIDS. However, there is a paucity of research on the effectiveness of cognitive-behavioural interventions (CBI) for common mental disorders in HIV-infected adults. The present study sought to review the existing literature on the use of CBI for depression and anxiety in HIV-positive adults and to assess the effect size of these interventions. We did duplicate searches of databases (from inception to 17-22 May 2012). The following online databases were searched: PubMed, The Cochrane Central Register of Controlled Trials and PsychArticles. We identified 20 studies suitable for inclusion. A total of 2886 participants were enroled in these studies, of which 2173 participants completed treatment. The present review of the literature suggests that CBI may be effective in the treatment of depression and anxiety in individuals living with HIV/AIDS. Significant reductions in depression and anxiety were reported in intervention studies that directly and indirectly targeted depression and/or anxiety. Effect sizes ranged from 0.02 to 1.02 for depression and 0.04 to 0.70 for anxiety. Some trials included an immediate postintervention assessment but no follow-up assessments of outcome. This omission makes it difficult to determine whether the intervention effects are sustainable over time. The present review of the literature suggests that CBI may have a positive impact on the treatment of depression and anxiety in adults living with HIV/AIDS. 23122276 Delayed emergence of oseltamivir-resistant seasonal influenza A (H1N1) and pandemic influenza A(H1N1)pdm09 viruses in Myanmar. Please cite this paper as: Dapat et al. (2012) Delayed emergence of oseltamivir-resistant seasonal influenza A (H1N1) and pandemic influenza A(H1N1)pdm09 viruses in Myanmar. Influenza and Other Respiratory Viruses DOI: 10.1111/irv.12030. The prevalence and timing of emergence of oseltamivir-resistant seasonal and pandemic influenza A (H1N1) viruses in Myanmar in 2008 and 2009 are described in this report. In 2008, the oseltamivir-resistant seasonal H1N1 virus was detected at a lower rate (6%) and emerged at least 2 months later when compared with neighboring countries. Similarly, the prevalence of pandemic H1N1 virus was low (3%) and the timing of emergence was late (August 2009) in Myanmar. Interestingly, we detected three isolates that were resistant to both amantadine and oseltamivir. Limited movement of people into the country is attributed to the delayed emergence of drug-resistant seasonal and pandemic A(H1N1) viruses. 23859083 Oxidation of Manganese(II) during Chlorination: Role of Bromide. The oxidation of dissolved manganese(II) (Mn(II)) during chlorination is a relatively slow process which may lead to residual Mn(II) in treated drinking waters. Chemical Mn(II) oxidation is autocatalytic and consists of a homogeneous and a heterogeneous process; the oxidation of Mn(II) is mainly driven by the latter process. This study demonstrates that Mn(II) oxidation during chlorination is enhanced in bromide-containing waters by the formation of reactive bromine species (e.g., HOBr, BrCl, Br2O) from the oxidation of bromide by chlorine. During oxidation of Mn(II) by chlorine in bromide-containing waters, bromide is recycled and acts as a catalyst. For a chlorine dose of 1 mg/L and a bromide level as low as 10 μg/L, the oxidation of Mn(II) by reactive bromine species becomes the main pathway. It was demonstrated that the kinetics of the reaction are dominated by the adsorbed Mn(OH)2 species for both chlorine and bromine at circumneutral pH. Reactive bromine species such as Br2O and BrCl significantly influence the rate of manganese oxidation and may even outweigh the reactivity of HOBr. Reaction orders in [HOBr]tot were found to be 1.33 (±0.15) at pH 7.8 and increased to 1.97 (±0.17) at pH 8.2 consistent with an important contribution of Br2O which is second order in [HOBr]tot. These findings highlight the need to take bromide, and the subsequent reactive bromine species formed upon chlorination, into account to assess Mn(II) removal during water treatment with chlorine. 23969337 Maternal deaths attributable to hypertensive disorders in a tertiary hospital in Ghana. To determine the contribution of hypertensive disorders of pregnancy to maternal deaths at Korle Bu Teaching Hospital (KBTH) in Accra, Ghana. The retrospective descriptive study conducted at KBTH during 2010-2011 involved a comprehensive review of all maternal deaths attributable to hypertensive disorders. There were 21 385 deliveries, 21742 live births, and 199 maternal deaths, resulting in a maternal mortality ratio of 915.3 per 100000 live births. In total, 63 (31.7%) maternal deaths were attributable to hypertensive disorders with a case fatality rate of 3.9%. The incidence of hypertensive disorders of pregnancy was 7.6%. Hypertensive disorders were the most common direct cause of maternal death followed by obstetric hemorrhage (26.6%), unsafe abortion (11.1%), and puerperal sepsis (3.5%). Most (38.1%) hypertension-related maternal deaths occurred within 24hours of admission and the majority (79.4%) had been referred. Eclampsia was the leading immediate cause of hypertension-related death (23.8%), followed by acute renal failure (20.6%), intracerebral hemorrhage (15.9%), and pulmonary edema (12.7%). Hypertensive diseases are the leading cause of maternal death at KBTH, having overtaken obstetric hemorrhage, with eclampsia, acute renal failure, intracerebral hemorrhage, and pulmonary edema representing the major immediate causes of hypertension-related maternal death. 22484424 eIF4F suppression in breast cancer affects maintenance and progression. Levels of eukaryotic initiation factor 4E (eIF4E) are frequently elevated in human cancers and in some instances have been associated with poor prognosis and outcome. Here we utilize transgenic and allograft breast cancer models to demonstrate that increased mammalian target of rapamycin (mTOR) signalling can be a significant contributor to breast cancer progression in vivo. Suppressing mTOR activity, as well as levels and activity of the downstream translation regulators, eIF4E and eIF4A, delayed breast cancer progression, onset of associated pulmonary metastasis in vivo and breast cancer cell invasion and migration in vitro. Translation of vascular endothelial growth factor (VEGF), matrix metallopeptidase 9 (MMP9) and cyclin D1 mRNAs, which encode products associated with the metastatic phenotype, is inhibited upon eIF4E suppression. Our results indicate that the mTOR/eIF4F axis is an important contributor to tumor maintenance and progression programs in breast cancer. Targeting this pathway may be of therapeutic benefit. 23855377 Systemic involvement of acute generalized exanthematous pustulosis: a retrospective study on 58 patients. Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction characterized by rash with sterile pustules, high fever and elevated circulating neutrophil counts. To investigate the frequency and clinical features of AGEP systemic involvement. Methods This retrospective study included all patients hospitalized in our department between 2000 and 2010 with a discharge diagnosis of AGEP. Patients had to fulfill the following criteria: (i) a specific EuroSCAR score > 4 and (ii) biological and radiological work-up available. Among the 58 patients enrolled, 10 had at least one systemic involvement: hepatic function test results were abnormal for seven; six had renal insufficiency; two developed acute respiratory distress, with one patient's bronchoalveolar lavage fluid containing many neutrophils but no microorganisms; and one was agranulocytotic. Mean peripheral neutrophil counts and mean C-reactive protein levels were significantly elevated in patients with systemic involvement. Amoxicillin rechallenge and hospitalization duration were associated with systemic involvement. AGEP systemic involvement was observed in 17·2% of studied cases, including liver, kidney, bone-marrow and lung involvement. Outcomes were favorable after drug withdrawal, and symptomatic and topical steroid treatments. Agranulocytosis was linked to drug toxicity and renal insufficiency to inflammatory status. The neutrophil count-systemic involvement association could suggest a role of neutrophils in AGEP systemic involvement. Physicians should be aware of the possibility of systemic involvement in AGEP and should actively seek extracutaneous involvement. This article is protected by copyright. All rights reserved. 23858031 IL-17RA Is Essential for Optimal Localization of Follicular Th Cells in the Germinal Center Light Zone To Promote Autoantibody-Producing B Cells. Germinal centers (GCs) provide a microenvironment that promotes and regulates the interactions of B cells with follicular Th (TFH) cells. In this study, we show that there are significantly higher frequencies of CXCR5(+)ICOS(+) TFH cells in autoimmune BXD2 mice, and these cells express both IL-21R and IL-17RA. Although IL-17 and IL-21 are both important for the formation of spontaneous GCs and development of pathogenic autoantibodies, IL-21, but not IL-17, is required for the proper development of TFH cells in BXD2 mice. The total numbers of TFH cells and their ability to induce B cell responses in vitro were not affected by a deficiency of IL-17RA in BXD2-Il17ra(-/-) mice, the majority of CXCR5(+) TFH cells from BXD2-Il17ra(-/-) mice were, however, not localized in the GC light zone (LZ). Interruption of IL-17 signaling, either acutely by AdIL-17R:Fc or chronically by Il17ra(-/-), disrupted TFH-B interactions and abrogated the generation of autoantibody-forming B cells in BXD2 mice. IL-17 upregulated the expression of regulator of G-protein signaling 16 (RGS16) to promote the ability of TFH to form conjugates with B cells, which was abolished in TFH cells from BXD2-Rgs16(-/-) mice. The results suggests that IL-17 is an extrinsic stop signal that it acts on postdifferentiated IL-17RA(+) TFH to enable its interaction with responder B cells in the LZ niche. These data suggest a novel concept that TFH differentiation and its stabilization in the LZ are two separate checkpoints and that IL-21 and IL-17 act at each checkpoint to enable pathogenic GC development. 23322091 Late presentation of HIV despite earlier opportunities for detection, experience from an Irish tertiary referral institution. Late presentation of HIV continues to undermine advances in the management of HIV. Opportunities to detect HIV at an earlier stage are often missed. Current estimates suggest that undiagnosed individuals comprise approximately one quarter of all people in the western world living with HIV. 'Testing-and-treating' this group has been proposed as a means to curb the HIV epidemic. In this study we assessed the characteristics of individuals newly diagnosed with HIV, and their utilisation of healthcare services in Ireland prior to their diagnosis. A retrospective review was undertaken of all patients newly diagnosed with HIV over a 27-month period. Patient demographics were recorded, as were details of healthcare contacts in the year preceding diagnosis. Individuals detected via screening of recent immigrants/asylum seekers were excluded. In the period studied 114 patients received a new diagnosis of HIV, 59 met inclusion criteria. The majority (54%) fulfilled the European consensus definition for late presenters (CD4<350 cells/µl). 'Late presenters' were significantly more likely to be symptomatic at diagnosis (OR=4.62; 95% CI 1.45-14.67; p=0.015), diagnosed by acute tertiary hospital services (p=0.015), and 56% reported heterosexual mode of acquisition (OR=2.12; 95% CI 0.73-6.16; p=0.19). Patients detected via screening had significantly higher CD4 counts at diagnosis compared with those diagnosed due to symptoms (Median CD4 422 cells/µl; IQR 285-594 vs. 142 cells/µl; IQR 62-333; p=0.0007). 'Symptomatic' patients were significantly more likely to report prior healthcare contacts (OR 4.71; 95 % CI 1.32-16.79; p=0.013). Current screening activities are inadequate. Unfortunately newly diagnosed HIV patients continue to be symptomatic, at advanced stages of disease, to acute hospital services. Heterosexual groups in particular are at risk for late detection. 23612854 Relations between stimulation of mesolimbic dopamine and place conditioning in rats produced by cocaine or drugs that are tolerant to dopamine transporter conformational change. RATIONALE: Dopamine transporter (DAT) conformation plays a role in the effectiveness of cocaine-like and other DAT inhibitors. Cocaine-like stimulants are intolerant to DAT conformation changes having decreased potency in cells transfected with DAT constructs that face the cytosol compared to wild-type DAT. In contrast, analogs of benztropine (BZT) are among compounds that are less affected by DAT conformational change. METHODS: We compared the displacement of radioligand binding to various mammalian CNS sites, acute stimulation of accumbens shell dopamine levels, and place conditioning in rats among cocaine and four BZT analogs with Cl substitutions on the diphenyl-ether system including two with carboalkoxy substitutions at the 2-position of the tropane ring. RESULTS: Binding assays confirmed high-affinity and selectivity for the DAT with the BZT analogs which also produced significant stimulation of mesolimbic dopamine efflux. Because BZT analogs produced temporal patterns of extracellular dopamine levels different from those by cocaine (3-10 mg/kg, i.p.), the place conditioning produced by BZT analogs and cocaine was compared at doses and times at which both the increase in dopamine levels and rates of increase were similar to those produced by an effective dose of cocaine. Despite this equilibration, none of the BZT analogs tested produced significant place conditioning. CONCLUSIONS: The present results extend previous findings suggesting that cocaine-like actions are dependent on a binding equilibrium that favors the outward conformational state of the DAT. In contrast, BZT analogs with reduced dependence on DAT conformation have reduced cocaine-like behavioral effects and may prove useful in development of medications for stimulant abuse. 23754688 Spatial moving average risk smoothing. This paper introduces spatial moving average risk smoothing (SMARS) as a new way of carrying out disease mapping. This proposal applies the moving average ideas of time series theory to the spatial domain, making use of a spatial moving average process of unknown order to define dependence on the risk of a disease occurring. Correlation of the risks for different locations will be a function of m values (m being unknown), providing a rich class of correlation functions that may be reproduced by SMARS. Moreover, the distance (in terms of neighborhoods) that should be covered for two units to be found to make the correlation of their risks 0 is a quantity to be fitted by the model. This way, we reproduce patterns that range from spatially independent to long-range spatially dependent. We will also show a theoretical study of the correlation structure induced by SMARS, illustrating the wide variety of correlation functions that this proposal is able to reproduce. We will also present three applications of SMARS to both simulated and real datasets. These applications will show SMARS to be a competitive disease mapping model when compared with alternative proposals that have already appeared in the literature. Finally, the application of SMARS to the study of mortality for 21 causes of death in the Comunitat Valenciana will allow us to identify some qualitative differences in the patterns of those diseases. 23955132 Adolescents' reported hearing symptoms and attitudes toward loud music. The aim of the present study was to compare the adolescents' attitudes toward loud music in relation to a set of self-perceived auditory symptoms and psychological variables such as norms, preparedness to take risks and risk-judgment in noisy situations. A questionnaire on hearing and preventive behavior was distributed to 281 upper secondary school students aged 15-19 years. The questionnaire included youth attitude to noise scale, questions about perceived hearing symptoms such as tinnitus and sound sensitivity and finally statements on perceived behavioral norms regarding hearing protection use, risk-taking and risk-judgment in noisy settings. Self-perceived auditory symptoms such as sound sensitivity and permanent tinnitus had a significant relationship with less tolerant attitudes toward loud music. Permanent tinnitus and sound sensitivity together accounted for 15.9% of the variation in attitudes toward loud music. Together with the psychological variables norms, preparedness to take risks and risk-judgment 48.0% of the variation in attitudes could be explained. Although perceived hearing symptoms (sound sensitivity and permanent tinnitus) was associated with less tolerant attitudes toward loud music, psychological variables such as norms, preparedness to take risks and risk-judgment were found to be more strongly associated with attitudes toward loud music and should therefore be considered more in future preventive work. Health promotive strategies should focus on changing not merely individual attitudes, but also societal norms and regulations in order to decrease noise induced auditory symptoms among adolescents. 23673451 Do we measure pleural fluid pH correctly? This review analyzes the current literature available on appropriate measurement of pleural fluid pH and currently used methods of measurement. Current literature continues to support the superiority of blood gas analyzers (BGAs) in the accurate measurement of pleural fluid pH. Despite the compelling evidence, roughly 30-50% of the laboratories across the United States continue to use inaccurate methods for pleural fluid pH measurement. Nearly 40% of pulmonologists were incorrect in believing their laboratory uses BGA for the analysis of pleural fluid pH. It is apparent that the clinical utility of pleural fluid pH is often undermined by its inappropriate measurement. Physicians must be made aware of their laboratory's method of measurement if pleural fluid pH is to be used in the evaluation of pleural diseases. If pleural fluid pH measurement is not done accurately, then other pleural fluid characteristics may be used to aid the clinician. 23337483 Rapid response teams, do not resuscitate orders, and potential opportunities to improve end-of-life care: a multicentre retrospective study. Rapid response teams (RRTs) were created to stabilize acutely ill patients on the ward, but recent studies suggest that RRTs may improve end-of-life care (EOLC). To learn more about the role of the RRT in EOLC at our institutions, we conducted a retrospective review. Retrospective review of 300 RRT consultations at 3 academic hospitals in Toronto, Canada. The typical consultation was for an elderly patient with chronic illness. More than 90% had a "full resuscitation" order at the time of consultation. One third were admitted to the intensive care unit within 48 hours of the RRT consultation, and 24.7% ultimately died. Twenty-seven (9.3%) had a patient/family conference on the ward within 48h of the RRT consultation, 24 (8.3%) of whom changed their resuscitation order as a result. Among those who changed their resuscitation order, fewer than 20% were referred to the palliative care or spiritual care service, or prescribed comfort medications as needed (pro re nata), within 48h of the RRT consultation; 2 patients died without receiving any common EOLC orders, and 15 (63%) died before discharge. RRT consultation is an important milestone for many patients approaching EOL. RRTs frequently participate in EOL discussions and decision-making, but they may miss opportunities to facilitate EOLC. 23927136 Pitch- and spectral-based dynamic time warping methods for comparing field recordings of harmonic avian vocalizations. Quantitative measures of acoustic similarity can reveal patterns of shared vocal behavior in social species. Many methods for computing similarity have been developed, but their performance has not been extensively characterized in noisy environments and with vocalizations characterized by complex frequency modulations. This paper describes methods of bioacoustic comparison based on dynamic time warping (DTW) of the fundamental frequency or spectrogram. Fundamental frequency is estimated using a Bayesian particle filter adaptation of harmonic template matching. The methods were tested on field recordings of flight calls from superb starlings, Lamprotornis superbus, for how well they could separate distinct categories of call elements (motifs). The fundamental-frequency-based method performed best, but the spectrogram-based method was less sensitive to noise. Both DTW methods provided better separation of categories than spectrographic cross correlation, likely due to substantial variability in the duration of superb starling flight call motifs. 23931057 Extracellular matrix mineralization in periodontal tissues: Noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X-linked hypophosphatemia. As broadly demonstrated for the formation of a functional skeleton, proper mineralization of periodontal alveolar bone and teeth - where calcium phosphate crystals are deposited and grow within an extracellular matrix - is essential for dental function. Mineralization defects in tooth dentin and cementum of the periodontium invariably lead to a weak (soft or brittle) dentition in which teeth become loose and prone to infection and are lost prematurely. Mineralization of the extremities of periodontal ligament fibers (Sharpey's fibers) where they insert into tooth cementum and alveolar bone is also essential for the function of the tooth-suspensory apparatus in occlusion and mastication. Molecular determinants of mineralization in these tissues include mineral ion concentrations (phosphate and calcium), pyrophosphate, small integrin-binding ligand N-linked glycoproteins and matrix vesicles. Amongst the enzymes important in regulating these mineralization determinants, two are discussed at length here, with clinical examples given, namely tissue-nonspecific alkaline phosphatase and phosphate-regulating gene with homologies to endopeptidases on the X chromosome. Inactivating mutations in these enzymes in humans and in mouse models lead to the soft bones and teeth characteristic of hypophosphatasia and X-linked hypophosphatemia, respectively, where the levels of local and systemic circulating mineralization determinants are perturbed. In X-linked hypophosphatemia, in addition to renal phosphate wasting causing low circulating phosphate levels, phosphorylated mineralization-regulating small integrin-binding ligand N-linked glycoproteins, such as matrix extracellular phosphoglycoprotein and osteopontin, and the phosphorylated peptides proteolytically released from them, such as the acidic serine- and aspartate-rich-motif peptide, may accumulate locally to impair mineralization in this disease. 23866812 Towards a physically more active lifestyle based on one's own values: study design of a randomized controlled trial for physically inactive adults. This randomised controlled trial demonstrates the effectiveness of a value-based intervention program to encourage a physically more active lifestyle among physically inactive adults aged 30 to 50 years. The conceptual framework of the program is based on an innovative behavioural therapy called Acceptance and Commitment Therapy (ACT) that aims to increase an individual's psychological flexibility and support behaviour change towards a higher quality and more meaningful life. Participants will be randomly allocated to a feedback group (FB) or an Acceptance and Commitment based (ACT + FB) group. Both the groups will receive written feedback about their objectively measured physical activity levels and offered an opportunity to attend a body composition analysis. In addition, the Acceptance and Commitment based group will attend six group sessions and be given a pedometer for self-monitoring of their daily physical activity throughout the 9-week intervention. The group sessions aim to clarify individual values and enhance committed actions towards the goal of achieving a more meaningful life. Participants will also be taught new skills to work on subjective barriers related to physical activity. Physical activity will be measured objectively by an accelerometer over seven consecutive days and by self-reported questionnaires at the baseline, as well as at 3, 6, 9 and 15 months after the baseline measures. In addition, psychological well-being will be measured through the questionnaires, which assess mindfulness skills, psychological flexibility, psychological distress and depressive symptoms. This study's objective is to demonstrate a research protocol for a randomized controlled study motivating a physically more active lifestyle based on one's own values among physically inactive adults. The aim of the study is to evaluate the feasibility and intervention efficacy on physical activity and psychological well-being, and discuss challenges in motivating physically inactive adults towards physically more active lifestyles.Trial registration: ClinicalTrials.gov, number NCT01796990. 23922688 A Scallop Nitric Oxide Synthase (NOS) with Structure Similar to Neuronal NOS and Its Involvement in the Immune Defense. Nitric oxide synthase (NOS) is responsible for synthesizing nitric oxide (NO) from L-arginine, and involved in multiple physiological functions. However, its immunological role in mollusc was seldom reported. In the present study, an NOS (CfNOS) gene was identified from the scallop Chlamys farreri encoding a polypeptide of 1486 amino acids. Its amino acid sequence shared 50.0~54.7, 40.7~47.0 and 42.5~44.5% similarities with vertebrate neuronal (n), endothelial (e) and inducible (i) NOSs, respectively. CfNOS contained PDZ, oxygenase and reductase domains, which resembled those in nNOS. The CfNOS mRNA transcripts expressed in all embryos and larvae after the 2-cell embryo stage, and were detectable in all tested tissues with the highest level in the gonad, and with the immune tissues hepatopancreas and haemocytes included. Moreover, the immunoreactive area of CfNOS distributed over the haemocyte cytoplasm and cell membrane. After LPS, β-glucan and PGN stimulation, the expression level of CfNOS mRNA in haemocytes increased significantly at 3 h (4.0-, 4.8- and 2.7-fold, respectively, P < 0.01), and reached the peak at 12 h (15.3- and 27.6-fold for LPS and β-glucan respectively, P < 0.01) and 24 h (17.3-fold for PGN, P < 0.01). In addition, TNF-α also induced the expression of CfNOS, which started to increase at 1 h (5.2-fold, P < 0.05) and peaked at 6 h (19.9-fold, P < 0.01). The catalytic activity of the native CfNOS protein was 30.3 ± 0.3 U mgprot(-1), and it decreased significantly after the addition of the selective inhibitors of nNOS and iNOS (26.9 ± 0.4 and 29.3 ± 0.1 U mgprot(-1), respectively, P < 0.01). These results suggested that CfNOS, with identical structure with nNOS and similar enzymatic characteristics to nNOS and iNOS, played the immunological role of iNOS to be involved in the scallop immune defense against PAMPs and TNF-α. 23875663 Prevention, identification and treatment of vulvar squamous (pre)malignancies: a review focusing on quality of care. Vulvar squamous cell carcinoma, its precursor lesions (usual and differentiated vulvar intraepithelial neoplasia) and lichen sclerosus are rare diseases that may have a large impact on the lives of affected women and their partners. Proper identification is vital, but the lesions are sometimes difficult to diagnose because of their rarity and variety of symptoms. High quality of care and proper treatment is important in order to minimize the morbidity and mortality caused by these lesions. This review gives an outline of the latest insights regarding the current evidence in this area and unresolved issues. Additionally, it highlights the improvements that should be made in order to optimize prevention and identification of (pre-)malignant vulvar lesions and to increase the quality of care for these patients. 23966191 On the Support of Scientific Workflows over Pub/Sub Brokers. The execution of scientific workflows is gaining importance as more computing resources are available in the form of grid environments. The Publish/Subscribe paradigm offers well-proven solutions for sustaining distributed scenarios while maintaining the high level of task decoupling required by scientific workflows. In this paper, we propose a new model for supporting scientific workflows that improves the dissemination of control events. The proposed solution is based on the mapping of workflow tasks to the underlying Pub/Sub event layer, and the definition of interfaces and procedures for execution on brokers. In this paper we also analyze the strengths and weaknesses of current solutions that are based on existing message exchange models for scientific workflows. Finally, we explain how our model improves the information dissemination, event filtering, task decoupling and the monitoring of scientific workflows. 23659324 Energy expenditure for egg production in arthropod ectoparasites: the effect of host species. We studied the energy cost of egg production in two flea species (Parapulex chephrenis and Xenopsylla ramesis) feeding on principal (Acomys cahirinus and Meriones crassus, respectively) and auxiliary (M. crassus and A. cahirinus, respectively) rodent hosts. We predicted that fleas feeding on principal as compared with auxiliary hosts will (a) expend less energy for egg production; (b) produce larger eggs and (c) live longer after oviposition. Both fleas produced more eggs and spent less energy per egg when exploiting principal hosts. Parapulex chephrenis produced larger eggs after exploiting auxiliary hosts, while the opposite was true for X. ramesis. After oviposition, P. chephrenis fed on the auxiliary hosts survived for a shorter time than those fed on the principal hosts, while in X. ramesis the survival time did not differ among hosts. Our results suggested that one of the proximate causes for lower reproductive performance and subsequent lower abundance of fleas on auxiliary hosts is the higher energy cost of egg production. However, in some species, lower offspring number may be compensated to some extent by their size, although this compensation may also compromise their future reproduction via decreased survival. In addition, the reproductive strategy of exploitation of low profitable (i.e. auxiliary) hosts may differ between flea species. 23838082 Does stress affect the joints? Daily stressors, stress vulnerability, immune and HPA axis activity, and short-term disease and symptom fluctuations in rheumatoid arthritis. Both stressors and stress vulnerability factors together with immune and hypothalamus-pituitary-adrenal (HPA) axis activity components have been considered to contribute to disease fluctuations of chronic inflammatory diseases, such as rheumatoid arthritis (RA). The aim of the present study was to investigate whether daily stressors and worrying as stress vulnerability factor as well as immune and HPA axis activity markers predict short-term disease activity and symptom fluctuations in patients with RA. In a prospective design, daily stressors, worrying, HPA axis (cortisol) and immune system (interleukin (IL)-1β, IL-6, IL-8, interferon (IFN)-γ, tumour necrosis factor α) markers, clinical and self-reported disease activity (disease activity score in 28 joints, RA disease activity index), and physical symptoms of pain and fatigue were monitored monthly during 6 months in 80 RA patients. Multilevel modelling indicated that daily stressors predicted increased fatigue in the next month and that worrying predicted increased self-reported disease activity, swollen joint count and pain in the next month. In addition, specific cytokines of IL-1β and IFN-γ predicted increased fatigue 1 month later. Overall, relationships remained relatively unchanged after controlling for medication use, disease duration and demographic variables. No evidence was found for immune and HPA axis activity markers as mediators of the stress-disease relationship. Daily stressors and the stress-vulnerability factor worrying predict indicators of the short-term course of RA disease activity and fatigue and pain, while specific cytokines predict short-term fluctuations of fatigue. These stress-related variables and immune markers seem to affect different aspects of disease activity or symptom fluctuations independently in RA. 23838363 Ultrasound imaging of long bone fractures and healing with the split-step fourier imaging method. We applied the split-step Fourier imaging method to back-propagate the ultrasound zero-offset wavefields acquired on the bone surface to the sources of scatterers, which are the reflecting interfaces. The method required, as an input, an estimated slowness (reciprocal of half the velocity) model to map the time-dependent sonogram to the depth image, which provides the geometric properties of the interfaces. The slowness was approximated by a depth-dependent term and a first-order spatially varying perturbation. Simulated data sets were used to validate the method. The reconstructed images show proper mapping of the interfaces and the fracture, and a reasonable cortical thickness measurement with 8.3% error. The images also illustrate clearly the bone fracture healing process of a 1-mm-wide 45° inclined crack with different in-filled tissue velocities for various healing stages. Reconstruction of a fractured bone plate using data from an in vitro experiment is also presented. This study suggests that the proposed imaging method has good potential in quantification of bone fractures and monitoring of the fracture healing process. 23617855 Structure--activity relationships and in silico models of P-glycoprotein (ABCB1) inhibitors. Abstract 1. The efflux pump p-glycoprotein (P-gp/ABCB1) has received enormous attention in drug (xenobiotic) disposition due to its role in modulation of the drug availability and in protection of sensitive organs. 2. P-gp mediated efflux is one of main mechanisms for multidrug resistance in cancer cells. A main approach to reverse the resistance and restore the drug efficacy is to use specific inhibitors of P-gp that suppress the efflux activity. 3. This review summarizes the binding capabilities of known chemical inhibitors based on the analyses of structure-activity relationships, and computational modeling of the inhibitors as well as the binding site of P-gp protein. 4. The molecular models will facilitate the design of lead inhibitors as drug candidates. Also, it helps scientists in early drug discovery phase to synthesize chemical series with better understanding of their P-gp binding liabilities. 23933451 An exploratory study on the influence of socio-demographic characteristics on water end uses inside buildings. Any strategy of water demand management needs the collaboration of the population involved and so it is important to know how characteristics as residence area, number of residents, presence/absence of children/elders, income level, and educational level, among others, may influence the use of water. Empirical studies that quantify relationship between socio-demographic factors and the water end use patterns inside buildings are still largely lacking. To help to fill this gap this paper gathers information about the characterization of water end use per domestic device in three regions of north of Portugal with different socio-demographic characteristics. The main research goal was to establish indoor water end use patterns per domestic device and to evaluate possible relations between these patterns with the socio-demographic characteristics of the area where the household is, namely the number of residents, the presence/absence of children/elders, the income level and educational level. The washbasin is in average the domestic device with more number of uses in a day (responsible for 34% of the total use), close followed by the kitchen sink (32%), the toilet flush (23%), the bathtub (6%) and finally the dishwasher (3%) and the washing machine (2%). The results found might reflect differences in rural and urban lifestyles once that, with the exception of the kitchen sink, Valpaços is the city that registers the lowest number of uses in the appliances monitored. Significant correlations were found in the following cases: between the residence area and the number of uses in washbasin and in the toilet flush; between the presence of children in the household and the use in the dishwasher; between the income level and the number of uses in the washbasin, in the bathtub, in the washing machine and in the dishwasher. 23646918 Attitudes regarding life sentences for juvenile offenders. Twice in recent years, the U.S. Supreme Court has considered the constitutionality of life sentences without the possibility of parole (LWOP) for juvenile offenders. Given the public nature of this issue, there is scant information on beliefs about imposing LWOP on juveniles. Attitudes on related issues suggest two possibilities. On the one hand, because public opinion regarding juvenile offenders has become somewhat less punitive recently, LWOP may be viewed as excessively harsh punishment. On the other hand, portrayal of some juvenile offenders as superpredators suggests that LWOP may still have public support. We used survey methodology and the unique "ninth justice paradigm" to examine how an offender's age influences beliefs about the appropriateness of LWOP, and the relationship between those beliefs and punishment-related ideologies. Results showed that, except in the case of murder, the majority of respondents disfavored imposing LWOP on juveniles, though a subset approved broad use of LWOP even for young offenders. In fact, after removing from consideration those who oppose LWOP under any circumstances, youthfulness of the offender has little impact on the beliefs about the types of crimes in which LWOP should be imposed (Study 1) or the mean sentence lengths imposed on juvenile offenders (Study 2). Respondents' punishment goals influenced their attitudes, as did beliefs about the likelihood of rehabilitation and reform. Harsh judgments of juveniles who commit serious crimes may result from dispositional attributions of youthful offenders as irredeemable. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23178848 Structural mechanisms of the agrin-LRP4-MuSK signaling pathway in neuromuscular junction differentiation. The neuromuscular junction (NMJ) is the most extensively studied model of neuronal synaptogenesis. Acetylcholine receptor (AChR) clustering on the postsynaptic membrane is a cardinal event in the differentiation of NMJs. AChR clustering and postsynaptic differentiation is orchestrated by sophisticated interactions among three proteins: the neuron-secreted proteoglycan agrin, the co-receptor LRP4, and the muscle-specific receptor tyrosine kinase MuSK. LRP4 and MuSK act as scaffolds for multiple binding partners, resulting in a complex and dynamic network of interacting proteins that is required for AChR clustering. In this review, we discuss the structural basis for NMJ postsynaptic differentiation mediated by the agrin-LRP4-MuSK signaling pathway. 23726344 Heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 receptor antagonist. A convergent synthesis route for the heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 antagonist 2 was developed and the structure activity relationship of these modifications on NPY1 binding is reported. Two heterocyclic analogs 9 and 10 showed comparable Y1 binding potency to 2, but with improved aqueous solubility. Compound 9 demonstrated reduced spontaneous nocturnal food intake in a rat model when dosed ip. Compound 9 was also shown to be orally bioavailable and brain penetrable. 23385107 Corticomotor facilitation in vegetative state: results of a pilot study. To investigate whether corticomotor facilitation induced by transcranial magnetic stimulation (TMS-CF) could evoke a simple purposeful motor behavior in patients with a diagnosis of vegetative state. Cross-sectional survey. Post-coma and rehabilitation care unit. Patients (N=6) with a diagnosis of vegetative state. A cascade of consecutive motor-evoked potentials (MEPs) was elicited under 3 different conditions: in the first condition, patients were at rest (Rest); in the second, they were asked to open and close the right hand (Execution); in the third, the examiner modeled a movement of abduction of the thumb in front of the patient who was encouraged in advance to imitate the action (Observation to Imitate). Changes in MEP values from the abductor pollicis brevis muscle and improvement in scores on the Coma Recovery Scale-Revised. TMS-CF alone or combined with verbal instructions did not yield any change; only the combination with imitation caused changes in MEPs (shorter latency and increased amplitude) associated with behavioral improvement in 4 patients. Encouraging observation to imitate may favor the transformation of some perceived actions into motor images and performances, probably depending on the activation of mirror motor neurons. In our opinion, combining visual input with TMS-CF might have reinforced the coupling between movement planning and execution, promoting the recovery of elementary motor activities in some patients. The proposed protocol may contribute to unmasking signs of preserved consciousness in patients with latent capacities for recovery. 23792960 Amino-terminal Domain Tetramer Organization and Structural Effects of Zinc Binding in the N-Methyl-D-aspartate (NMDA) Receptor. N-Methyl-d-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian central nervous system. An important feature of these receptors is their capacity for allosteric regulation by small molecules, such as zinc, which bind to their amino-terminal domain (ATD). Zinc inhibition through high affinity binding to the ATD has been examined through functional studies; however, there is no direct measurement of associated conformational changes. We used luminescence resonance energy transfer to show that the ATDs undergo a cleft closure-like conformational change upon binding zinc, but no changes are observed in intersubunit distances. Furthermore, we find that the ATDs are more closely packed than the related AMPA receptors. These results suggest that the stability of the upper lobe contacts between ATDs allow for the efficient propagation of the cleft closure conformational change toward the ligand-binding domain and transmembrane segments, ultimately inhibiting the channel. 23464637 Simultaneously strong and tough ultrafine continuous nanofibers. Strength of structural materials and fibers is usually increased at the expense of strain at failure and toughness. Recent experimental studies have demonstrated improvements in modulus and strength of electrospun polymer nanofibers with reduction of their diameter. Nanofiber toughness has not been analyzed; however, from the classical materials property trade-off, one can expect it to decrease. Here, on the basis of a comprehensive analysis of long (5-10 mm) individual polyacrylonitrile nanofibers, we show that nanofiber toughness also dramatically improves. Reduction of fiber diameter from 2.8 μm to ∼100 nm resulted in simultaneous increases in elastic modulus from 0.36 to 48 GPa, true strength from 15 to 1750 MPa, and toughness from 0.25 to 605 MPa with the largest increases recorded for the ultrafine nanofibers smaller than 250 nm. The observed size effects showed no sign of saturation. Structural investigations and comparisons with mechanical behavior of annealed nanofibers allowed us to attribute ultrahigh ductility (average failure strain stayed over 50%) and toughness to low nanofiber crystallinity resulting from rapid solidification of ultrafine electrospun jets. Demonstrated superior mechanical performance coupled with the unique macro-nano nature of continuous nanofibers makes them readily available for macroscopic materials and composites that can be used in safety-critical applications. The proposed mechanism of simultaneously high strength, modulus, and toughness challenges the prevailing 50 year old paradigm of high-performance polymer fiber development calling for high polymer crystallinity and may have broad implications in fiber science and technology. 23567348 Endoscopic suturing for transoral outlet reduction increases weight loss after Roux-en-Y gastric bypass surgery. Weight regain or insufficient loss after Roux-en-Y gastric bypass (RYGB) is common. This is partially attributable to dilatation of the gastrojejunostomy (GJ), which diminishes the restrictive capacity of RYGB. Endoluminal interventions for GJ reduction are being explored as alternatives to revision surgery. We performed a randomized, blinded, sham-controlled trial to evaluate weight loss after sutured transoral outlet reduction (TORe). Patients with weight regain or inadequate loss after RYGB and GJ diameter greater than 2 cm were assigned randomly to groups that underwent TORe (n = 50) or a sham procedure (controls, n = 27). Intraoperative performance, safety, weight loss, and clinical outcomes were assessed. Subjects who received TORe had a significantly greater mean percentage weight loss from baseline (3.5%; 95% confidence interval, 1.8%-5.3%) than controls (0.4%; 95% confidence interval, 2.3% weight gain to 3.0% weight loss) (P = .021), using a last observation carried forward intent-to-treat analysis. As-treated analysis also showed greater mean percentage weight loss in the TORe group than controls (3.9% and 0.2%, respectively; P = .014). Weight loss or stabilization was achieved in 96% subjects receiving TORe and 78% of controls (P = .019). The TORe group had reduced systolic and diastolic blood pressure (P < .001) and a trend toward improved metabolic indices. In addition, 85% of the TORe group reported compliance with the healthy lifestyle eating program, compared with 53.8% of controls; 83% of TORe subjects said they would undergo the procedure again, and 78% said they would recommend the procedure to a friend. The groups had similar frequencies of adverse events. A multicenter randomized trial provides Level I evidence that TORe reduces weight regain after RYGB. These results were achieved using a superficial suction-based device; greater levels of weight loss could be achieved with newer, full-thickness suturing devices. TORe is one approach to avoid weight regain; a longitudinal multidisciplinary approach with dietary counseling and behavioral changes are required for long-term results. ClinicalTrials.gov identifier: NCT00394212. 23375147 In vivo three-dimensional kinematics of the cervical spine during maximal axial rotation. The cervical spine exhibits considerable mobility, especially in axial rotation. Axial rotation exerts stress on anatomical structures, such as the vertebral artery which is commonly assessed during clinical examination. The literature is rather sparse concerning the in vivo three-dimensional segmental kinematics of the cervical spine. This study aimed at investigating the three-dimensional kinematics of the cervical spine during maximal passive head rotation with special emphasis on coupled motion. Twenty healthy volunteers participated in this study. Low-dose CT scans were conducted in neutral and in maximum axial rotation positions. Each separated vertebra was segmented semi automatically in these two positions. The finite helical-axis method was used to describe 3D motion between discrete positions. The mean (±SD) maximum magnitude of axial rotation between C0 and C1 was 2.5 ± 1.0° coupled with lateral flexion to the opposite side (5.0 ± 3.0°) and extension (12.0 ± 4.5°). At the C1-C2 level, the mean axial rotation was 37.5 ± 6.0° associated with lateral flexion to the opposite side (2.5 ± 6.0°) and extension (4.0 ± 6.0°). For the lower levels, axial rotation was found to be maximal at C4-C5 level (5.5 ± 1.0°) coupled with lateral flexion to the same side (-4.0 ± 2.5°). Extension was associated at levels C2-C3, C3-C4 and C4-C5, whereas flexion occurred between C5-C6 and C6-C7. Coupled lateral flexion occurred to the opposite side at the upper cervical spine and to the same side at the lower cervical spine. 23749438 Model-based identifiable parameter determination applied to a simultaneous saccharification and fermentation process model for bio-ethanol production. In this work, a methodology for the model-based identifiable parameter determination (MBIPD) is presented. This systematic approach is proposed to be used for structure and parameter identification of nonlinear models of biological reaction networks. Usually, this kind of problems are over-parameterized with large correlations between parameters. Hence, the related inverse problems for parameter determination and analysis are mathematically ill-posed and numerically difficult to solve. The proposed MBIPD methodology comprises several tasks: (i) model selection, (ii) tracking of an adequate initial guess, and (iii) an iterative parameter estimation step which includes an identifiable parameter subset selection (SsS) algorithm and accuracy analysis of the estimated parameters. The SsS algorithm is based on the analysis of the sensitivity matrix by rank revealing factorization methods. Using this, a reduction of the parameter search space to a reasonable subset, which can be reliably and efficiently estimated from available measurements, is achieved. The simultaneous saccharification and fermentation (SSF) process for bio-ethanol production from cellulosic material is used as case study for testing the methodology. The successful application of MBIPD to the SSF process demonstrates a relatively large reduction in the identified parameter space. It is shown by a cross-validation that using the identified parameters (even though the reduction of the search space), the model is still able to predict the experimental data properly. Moreover, it is shown that the model is easily and efficiently adapted to new process conditions by solving reduced and well conditioned problems. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 29:1064-1082, 2013. 23205725 Highly efficient preparation of multiscaled quantum dot barcodes for multiplexed hepatitis B detection. Both disease diagnosis and therapeutic treatments require real-time information from assays capable of identifying multiple targets. Among various multiplexed biochips, multiplexed suspension assays of quantum dot (QD)-encoded microspheres are highly advantageous. This arises from the excellent fluorescent properties of the QDs incorporated into these microspheres, thus allowing them to serve as "QD barcodes". QD barcodes can be prepared through various approaches. However, the formulation of improved synthetic techniques that may allow more efficient preparation of QD barcodes with better encoding accuracy still remains a challenge. In this report, we describe a combined membrane emulsification-solvent evaporation (MESE) approach for the efficient preparation of QD barcodes. By combining the advantages of the MESE approach in controlling the barcode sizes with accurate encoding, a three-dimensional barcode library that integrates the signals of the forward scattering, fluorescence 1, and fluorescence 4 channels was established via flow cytometry. The five indexes of hepatitis B viruses were chosen as diagnostic targets to examine the feasibility of the QD barcodes in high-throughput diagnosis. On the basis of showing that singleplex detection is feasible, we demonstrate the ability of these QD barcodes to simultaneously and selectively detect a multitude of diverse biomolecular targets. 23698461 11C-choline PET/CT scan in patients with prostate cancer treated with intermittent ADT: a sequential PET/CT study. The purpose of this preliminary study was to evaluate the usefulness of 11C-choline PET/CT in patients with recurrent prostate cancer and hormone-sensitive disease treated with intermittent antiandrogen therapy scheme. We retrospectively evaluated 10 patients after radical prostatectomy (n = 8) or external beam radiotherapy (n = 2) as primary therapy, studied with sequential 11C-choline PET/CT. The first PET/CT (PET1) was performed during antiandrogen therapy (ADT) and the second PET/CT (PET2) was performed after therapy interruption. Only patients with negative results at PET1 were included in the study. At the time of PET1, all patients were under ADT from at least 6 months (mean PSA 0.54 ng/mL). At the time of PET2, all patients had completed ADT for a mean period of 7 months. 11C-Choline PET/CT findings were validated by a follow-up of at least 12 months or histological confirmation in case of local relapse. PET2 has been able to detect the site of recurrences in all cases. At the time of PET2, mean PSA was 3.88 ng/mL; mean PSAdt was 2.46 months; and mean PSAvel was 6.94 ng/mL/year. Four out of 10 patients showed a single lesion, 5 out of 10 patients showed 2 lesions and 1 patient showed multiple lymph-node lesions. When performed during ADT interruption, 11C-choline PET/CT has been able to detect the site of recurrence in patients with increasing PSA values. In this context, 11C-choline PET/CT may help to assess the burden of disease or to change the therapeutic approach using more aggressive and addressed therapies like guided RT or salvage lymph-node dissection. 23764115 Coupling of small leucine-rich proteoglycans to hypoxic survival of a progenitor cell-like subpopulation in Rhesus Macaque intervertebral disc. Degeneration of the intervertebral disc (IVD) is a major spinal disorder that associates with neck and back pain. Recent studies of clinical samples and animal models for IVD degeneration have identified cells with multi-potency in the IVD. However, IVD tissue-specific progenitor cells and their niche components are not clear, although degenerated IVD-derived cells possess in vitro characteristics of mesenchymal stromal cell (MSCs). Here, we firstly identified the tissue-specific intervertebral disc progenitor cells (DPCs) from healthy Rhesus monkey and report the niche components modulated the survival of DPCs under hypoxia. DPCs possess clonogenicity, multipotency and retain differentiation potential after extended expansion in vitro and in vivo. In particular, the nucleus pulposus-derived DPCs are sensitive to low oxygen tension and undergo apoptosis under hypoxic conditions due to their inability to induce/stabilize hypoxia-inducible factors (HIF). The presence of small leucine-rich proteoglycans (SLRP), biglycan or decorin, can reduce the susceptibility of DPCs to hypoxia-induced apoptosis via promoting the activation/stabilization of HIF-1α and HIF-2α. As IVD is avascular, we propose SLRPs are niche components of DPCs in IVD homeostasis, providing new insights in progenitor cell biology and niche factors under a hypoxic microenvironment. 23906486 Impact of thin aquitards on two-dimensional solute transport in an aquifer. The influence of aquitards on solute transport in an aquifer is an important and often overlooked process for subsurface contaminant transport. In particular, slow advection (leakage) into an aquitard is often neglected in previous analytical treatment of solute transport, making such analytical solutions unsuitable for benchmarking numerical simulations of transport when aquitard leakage exists. In this study, a semi-analytical solution to the two-dimensional conservative solute transport in an aquifer bounded by thin aquitards is derived in the Laplace domain. The governing equation in the aquifer (not aquitard) incorporates terms accounting for advection, longitudinal dispersion, and transverse vertical dispersion. Both one-dimensional vertical advection and molecular diffusion are considered for aquitard transport. The solutions are derived under conditions of steady-state flow and the first- and third-type transport boundary conditions in the aquifer along with assuming the continuity of concentration and vertical mass flux at aquifer and aquitard interfaces. The solutions in the real time domain are obtained by numerically inverting the solutions in the Laplace domain using the Stehfest (1970) algorithm. The semi-analytical solutions are compared with those from Zhan et al. (2009b), which considered aquitard leakage in infinitively thick aquitards. The concentration profiles, breakthrough curves and distribution profiles in the aquifer are different from those of Zhan et al. (2009b) at small ratios of the aquitard/aquifer thickness; whereas, the results of both are consistent for thick bounding aquitards. This study reveals that the residence time distribution (RTD) in the main aquifer is related to the aquitard/aquifer thickness ratios, Peclet numbers and porosities of adjacent aquitards. The results also suggest that MT3DMS (a commonly applied transport code) cannot successfully simulate solute transport at the aquifer-aquitard interfaces. The presented solutions improve available solutions for transport processes in an aquifer bounded by thin aquitards with leakage. The developed solutions can be directly extended to cases when the vertical hydrodynamic dispersion of the aquitards is considered by simply replacing the effective molecular diffusion coefficients of the aquitard by the vertical hydrodynamic dispersion coefficients of the aquitards. 23928997 An ENDOR and DFT analysis of hindered methyl group rotations in frozen solutions of bis(acetylacetonato)-copper(ii). ENDOR spectroscopy and DFT calculations have been used to thoroughly investigate the ligand hyperfine couplings for the bis(acetylacetonato)-copper(ii) complex [Cu(acac)2] in frozen solution. Solutions of [Cu(acac)2] were prepared under anhydrous conditions, and EPR revealed that the g and (Cu)A values were affected by traces of water present in the solvent. The ligand (H)Ai hyperfine couplings were subsequently investigated by CW and pulsed ENDOR spectroscopy. Anisotropic hyperfine couplings to the methine protons ((H)Ai = 1.35, -1.62, -2.12 MHz; aiso = -0.80 MHz) and smaller couplings to the fully averaged methyl group protons ((H)Ai = -0.65, 1.658, -0.9 MHz; aiso = 0.036 MHz) were identified by simulation of the angular selective ENDOR spectra and confirmed by DFT. Since the barrier to methyl group rotation was estimated to be ca. 5 kJ mol(-1) by DFT, rapid rotation of these -CH3 groups, even at 10 K, leads to an averaged value of (H)Ai. However, variable temperature X-band Mims ENDOR revealed an additional set of hyperfine couplings which showed a pronounced temperature dependency. Using CW Q-band ENDOR, these additional couplings were characterised by the hyperfine parameters (H)Ai = 3.45, 2.9, 2.62 MHz, aiso = 2.99 MHz and assigned to a hindered methyl group rotation. This hindered rotation of a sub-set of methyl groups occurs in 120° jumps, such that a large Adip and aiso component is always observed. Whilst the majority of the methyl groups undergo free rotation, a sub-set of methyl groups experience hindered rotation in frozen solution, through proton tunnelling. This hindered rotation appears to be caused by weak outer-sphere solvent interactions with the complex. 23180416 Avoidance of contaminated sediments by an amphipod (Melita plumulosa), A harpacticoid copepod (Nitocra spinipes), and a snail (Phallomedusa solida). The distribution of contaminants is seldom homogeneous in aquatic systems. In the present study, the avoidance response of Melita plumulosa, Nitocra spinipes, and Phallomedusa solida when exposed to contaminated sediments was investigated. Test vessels were designed to allow the congruent placement of two sediments and assessment of the movement of organisms between the sediments. When exposed to reference sediment, each species dispersed evenly between test chambers regardless of differences in sediment particle size. In the presence of contaminated sediment, the magnitude and rate of avoidance varied. Avoidance assays showed that test species avoided contaminated sediment as early as 6, 6, and 24 h following exposure for N. spinipes, P. solida, and M. plumulosa, respectively. The 48-h avoidance response of M. plumulosa for nine contaminated sediments of varying toxicity showed that avoidance was generally greater for sediments which elicited greater 10-d lethality to this species. The study demonstrated that each of these species has the ability to respond to chemical cues in the environment to inhabit sediment that provides the best opportunity for survival. The avoidance response for each species indicates the potential for developing rapid screening methods to assess sediment quality. Evidence suggests that avoidance was related to sediment toxicity and that static 10-d toxicity methods are likely to overestimate toxicity for species, which would avoid contamination in heterogeneous field settings. 23907891 Two polymorphs of N-(2-methoxyphenyl)-4-oxo-4H-chromone-3-carboxamide. The title compound, C17H13NO4, crystallizes in two polymorphic forms, each with two molecules in the asymmetric unit and in the monoclinic space group P21/c. All of the molecules have intramolecular hydrogen bonds involving the amide group. The amide N atoms act as donors to the carbonyl group of the pyrone and also to the methoxy group of the benzene ring. The carbonyl O atom of the amide group acts as an acceptor of the β and β' C atoms belonging to the aromatic rings. These intramolecular hydrogen bonds have a profound effect on the molecular conformation. In one polymorph, the molecules in the asymmetric unit are linked to form dimers by weak C-H...O interactions. In the other, the molecules in the asymmetric unit are linked by a single weak C-H...O hydrogen bond. Two of these units are linked to form centrosymmetric tetramers by a second weak C-H...O interaction. Further interactions of this type link the molecules into chains, so forming a three-dimensional network. These interactions in both polymorphs are supplemented by π-π interactions between the chromone rings and between the chromone and methoxyphenyl rings. 23319419 ICA-105574 interacts with a common binding site to elicit opposite effects on inactivation gating of EAG and ERG potassium channels. Rapid and voltage-dependent inactivation greatly attenuates outward currents in ether-a-go-go-related gene (ERG) K(+) channels. In contrast, inactivation of related ether-a-go-go (EAG) K(+) channels is very slow and minimally reduces outward currents. ICA-105574 (ICA, or 3-nitro-N-[4-phenoxyphenyl]-benzamide) has opposite effects on inactivation of these two channel types. Although ICA greatly attenuates ERG inactivation by shifting its voltage dependence to more positive potentials, it enhances the rate and extent of EAG inactivation without altering its voltage dependence. Here, we investigate whether the inverse functional response to ICA in EAG and ERG channels is related to differences in ICA binding site or to intrinsic mechanisms of inactivation. Molecular modeling coupled with site-directed mutagenesis suggests that ICA binds in a channel-specific orientation to a hydrophobic pocket bounded by the S5/pore helix/S6 of one subunit and S6 of an adjacent subunit. ICA is a mixed agonist of mutant EAG and EAG/ERG chimera channels that inactivate by a combination of slow and fast mechanisms. With the exception of three residues, the specific amino acids that form the putative binding pocket for ICA in ERG are conserved in EAG. Mutations introduced into EAG to replicate the ICA binding site in ERG did not alter the functional response to ICA. Together these findings suggest that ICA binds to the same site in EAG and ERG channels to elicit opposite functional effects. The resultant agonist or antagonist activity is determined solely by channel-specific differences in the mechanisms of inactivation gating. 23327669 Invasive lobular carcinoma stable for 4.5 years in a postmenopausal woman user of hormone therapy for 25 years. We present a case of a 72-year-old woman referred to the breast disorder service due to abnormalities on mammography and breast ultrasound. The patient reported using different hormone therapy (HT) formulations during 25 years and had stopped taking HT for 4 years. Physical examination showed no alterations in the breasts or axilla. Mammography from 2012 detected asymmetry at the 3 o'clock position in the anterior right breast. Ultrasound revealed an irregular, hypoechoic mass with indistinct margins, and posterior acoustic shadowing. A retrospective analysis of mammographies from 2007, 2009 and 2010 showed that a very subtle asymmetry had existed since 2007. Follow-up imaging demonstrated no change in asymmetry during 4.5 years. The patient underwent breast-conserving therapy and sentinel lymph node biopsy. Histopathologic examination demonstrated classic invasive lobular carcinoma. There were no sentinel node metastases. The patient received radiotherapy and endrocrine therapy. This case demonstrates that breast cancer may remain stable and not grow for many years. This aspect should be kept in mind by all professionals dealing with women's healthcare, in particular HT users who may develop breast cancer with a less aggressive behavior. Any suspicious finding on mammography, despite being unchanged for a number of years, must be investigated. 23293126 Effects of smoking on the oxidant/antioxidant balance and the blood lipids in pesticide sprayers. The present study was conducted on 80 pesticide male sprayers (42 nonsmokers and 38 smokers). Our aim was to estimate the smoking effects on blood lipids and oxidant/antioxidant status in pesticide sprayers. Results revealed that cholesterol, low-density lipoprotein (LDL) and glutathion peroxidase (GPx) enzyme were significantly higher in the 38 smoker sprayers than in the 42 nonsmoker sprayers. Cholesterol and LDL were correlated with smoking index and high-density lipoprotein (HDL), superoxide dismutase (SOD) enzyme and zinc (Zn) were inversely correlated with duration of pesticides' exposure. In nonsmokers, LDL and cholesterol were negatively correlated with SOD and correlated with malondialdehyde (MDA), and cholesterol was negatively correlated with Zn. HDL was negatively correlated with MDA in all the sprayers, but was correlated with GPx in smokers and with Zn in nonsmokers. In smokers, LDL was negatively correlated with GPx, HDL was negatively correlated with MDA and triglycerides and very-low-density lipoprotein were negatively correlated with Zn. MDA was negatively correlated with SOD, GPx and Zn. Smoking and pesticide exposure could be responsible for hyperlipidemia and oxidative stress. Therefore, improvement in the antioxidant status is mandatory for pesticide sprayers especially the ones who smoke. 23860191 Plasmapheresis as an Alternative to High-Dose Intravenous Immunoglobulin in the Prevention of Gestational Alloimmune Liver Disease. Gestational alloimmune liver disease occurs due to trans-placental passage of maternal antibodies to a fetal hepatocyte antigen that produces complement-mediated hepatocyte injury. High-dose intravenous immunoglobulin therapy during gestation is highly effective at decreasing the risk to the neonate but treatment is expensive. This case presents for the first time the use of plasmapheresis as a potential cheaper alternative when treatment with immunoglobulins is unavailable. 23707210 Botany, phytochemistry, pharmacology, and potential application of Polygonum cuspidatum Sieb.et Zucc.: A review. Polygonum cuspidatum Sieb. et Zucc. (Polygonum cuspidatum), also known as Reynoutria japonica Houtt and Huzhang in China, is a traditional and popular Chinese medicinal herb. Polygonum cuspidatum with a wide spectrum of pharmacological effects has been used for treatment of inflammation, favus, jaundice, scald, and hyperlipemia, etc. The present paper reviews the traditional applications as well as advances in botany, phytochemistry, pharmacodynamics, pharmacokinetics and toxicology of this plant. Finally, the tendency and perspective for future investigation of this plant are discussed, too. A systematic review of literature about Polygonum cuspidatum is carried out using resources including classic books about Chinese herbal medicine, and scientific databases including Pubmed, SciFinder, Scopus, the Web of Science and others. Polygonum cuspidatum is widely distributed in the world and has been used as a traditional medicine for a long history in China. Over 67 compounds including quinones, stilbenes, flavonoids, counmarins and ligans have been isolated and identified from this plant. The root of this plant is used as the effective agent in pre-clinical and clinical practice for regulating lipids, anti-endotoxic shock, anti-infection and anti-inflammation, anti-cancer and other diseases in China and Japan. As an important traditional Chinese medicine, Polygonum cuspidatum has been used for treatment of hyperlipemia, inflammation, infection and cancer, etc. Because there is no enough systemic data about the chemical constituents and their pharmacological effects or toxicities, it is important to investigate the pharmacological effects and molecular mechanisms of this plant based on modern realization of diseases' pathophysiology. Drug target-guided and bioactivity-guided isolation and purification of the chemical constituents from this plant and subsequent evaluation of their pharmacologic effects will promote the development of new drug and make sure which chemical constituent or multiple ingredients contributes its pharmacological effects. Additionally, chemicals and their pharmacological effects of the other parts such as the aerial part of this plant should be exploited in order to avoid resource waste and find new chemical constituents. 23905584 Alcohol Brand Use and Injury in the Emergency Department: A Pilot Study. In an urban emergency department on weekend nights in 2010 and 2011, 105 interviews assessed feasibility of collecting alcohol brand consumption data from injured patients who drank within 6 h of presentation, with responses to the orally administered survey specifying 331 alcohol brands recorded on a netbook computer. A Kruskal-Wallis test adjusted for tied ranks assessed demographic differences; confidence intervals were created around comparisons with national brand shares. The study found collection of such information feasible; limitations include comparison of national brand market share data with a local sample of drinkers. Funding was provided by the Centers for Disease Control and Prevention. 23910984 Adipogenetic effects of retrofractamide A derivatives in 3T3-L1 cells. In a previous study, retrofractamide A from the fruit of Piper chaba was shown to promote adipogenesis in 3T3-L1 cells. In the present study, retrofractamide A and its derivatives were synthesized, and their adipogenetic effects in 3T3-L1 cells were examined. Among the tested compounds, an amide composed of 9-(3',4'-methylenedioxyphenyl)-nona-2E,4E,8E-trienoic acid and an n-butyl or n-pentyl amine showed strongest activity. Moreover, the amide with the n-pentyl amine moiety significantly increased the uptake of 2-deoxyglucose into the cells, and also increased the mRNA levels of adiponectin, peroxisome proliferator-activated receptor γ2 (PPARγ2), glucose transporter 4 (GLUT4), fatty acid-binding protein (aP2), and CCAAT/enhancer-binding protein (C/EBP) α and β in a similar manner as the PPARγ agonist troglitazone, although it had less agonistic activity against PPARγ. 23756993 Sequence and expression analyses of KIX domain proteins suggest their importance in seed development and determination of seed size in rice, and genome stability in Arabidopsis. The KIX domain, which mediates protein-protein interactions, was first discovered as a motif in the large multidomain transcriptional activator histone acetyltransferase p300/CBP. Later, the domain was also found in Mediator subunit MED15, where it interacts with many transcription factors. In both proteins, the KIX domain is a target of activation domains of diverse transcription activators. It was found to be an essential component of several specific gene-activation pathways in fungi and metazoans. Not much is known about KIX domain proteins in plants. This study aims to characterize all the KIX domain proteins encoded by the genomes of Arabidopsis and rice. All identified KIX domain proteins are presented, together with their chromosomal locations, phylogenetic analysis, expression and SNP analyses. KIX domains were found not only in p300/CBP- and MED15-like plant proteins, but also in F-box proteins in rice and DNA helicase in Arabidopsis, suggesting roles of KIX domains in ubiquitin-mediated proteasomal degradation and genome stability. Expression analysis revealed overlapping expression of OsKIX_3, OsKIX_5 and OsKIX_7 in different stages of rice seeds development. Moreover, an association analysis of 136 in silico mined SNP loci in 23 different rice genotypes with grain-length information identified three non-synonymous SNP loci in these three rice genes showing strong association with long- and short-grain differentiation. Interestingly, these SNPs were located within KIX domain encoding sequences. Overall, this study lays a foundation for functional analysis of KIX domain proteins in plants. 23866380 Patient Protection and Affordable Care Act; Exchange functions: standards for Navigators and non-Navigator assistance personnel; consumer assistance tools and programs of an Exchange and certified application counselors. Final rule. This final rule addresses various requirements applicable to Navigators and non-Navigator assistance personnel in Federally-facilitated Exchanges, including State Partnership Exchanges, and to non-Navigator assistance personnel in State Exchanges that are funded through federal Exchange Establishment grants. It finalizes the requirement that Exchanges must have a certified application counselor program. It creates conflict-of-interest, training and certification, and meaningful access standards; clarifies that any licensing, certification, or other standards prescribed by a state or Exchange must not prevent application of the provisions of title I of the Affordable Care Act; adds entities with relationships to issuers of stop loss insurance to the list of entities that are ineligible to become Navigators; and clarifies that the same ineligibility criteria that apply to Navigators apply to certain non-Navigator assistance personnel. The final rule also directs that each Exchange designate organizations which will then certify their staff members and volunteers to be application counselors that assist consumers and facilitate enrollment in qualified health plans and insurance affordability programs, and provides standards for that designation. 23564289 Normal human embryonic stem cell lines were derived from microsurgical enucleated tripronuclear zygotes. A normal fertilized human zygote contains two pronuclei, but zygotes may also display one, three, or even more pronuclei resulting from irregular insemination or meiotic division. Today diploid and triploid human embryonic stem cell (hESC) lines have been derived from tripronuclear (3PN) triploid zygotes, and an in-vitro fertilization (IVF) baby was born from a rescued diploid zygote by removing the extra male pronucleus of the 3PN zygote. However, whether hESCs can be derived from a rescued 3PN zygote is still unknown. Here, by microsurgical pronuclear removal, we restored 61 diploid zygotes from 3PN zygotes donated by 35 couples, and 11 blastocysts developed with a blastocyst rate of 18.0%, which seems higher than that of nonrescued 3PN zygotes according to previous reports. After the whole zona pellucida free embryos were plated onto feeder cells to grow and passage, 2 hESC lines (CCRM-hESC-22 and CCRM-hESC-23) were generated and both carried normal karyotype (46, XY). The hESC lines were then characterized by morphology, expansion in vitro, and expression of specific markers of alkaline phosphatase, OCT4, SSEA4, TRA-1-60 and TRA-1-81. Furthermore, the pluripotency of these 2 hESC lines was confirmed by in vitro embryoid body formation and in vivo teratoma production. Our study indicates that depronucleared 3PN zygotes can improve the blastocysts formation rate, and normal hESC lines can be derived from those corrected 2PN embryos. Based on their multi-directional differentiation potential in vitro, the established hESC lines could be applied to the developmental risk assessment for IVF babies born from restored zygotes. J. Cell. Biochem. 114: 2016-2023, 2013. © 2013 Wiley Periodicals, Inc. 23890464 Burden of tuberculosis disease among adolescents in a rural cohort in Eastern Uganda. The world health organization (WHO) declared tuberculosis (TB) a global emergency, mainly affecting people in sub-Saharan Africa. However there is little data about the burden of TB among adolescents. We estimated the prevalence and incidence of TB and assessed factors associated with TB among adolescents aged 12--18 years in a rural population in Uganda in order to prepare the site for phase III clinical trials with novel TB vaccines among adolescents. In a prospective cohort study, we recruited 5000 adolescents and followed them actively, every 6 months, for 1--2 years. Participants suspected of having TB were those who had any of; TB signs and symptoms, history of TB contact or a positive tuberculin skin test (TST) of >=10 mm. Laboratory investigations included sputum smear microscopy and culture. Of the 5000 participants, eight culture confirmed cases of TB were found at baseline: a prevalence of 160/100,000 (95% confidence interval (CI), 69--315). There were 13 incident TB cases detected in an average of 1.1 person years: an incidence of 235/100,000 person years (95%CI, 125--402). None of the confirmed TB cases were HIV infected. Predictors for prevalent TB disease were: a history of TB contact and a cough >= 2 weeks at baseline and being out of school, while the only predictor for incident TB was a positive TST during follow-up. The TB incidence among adolescents in this rural part of Uganda seemed too low for a phase III TB vaccine trial. However, the study site demonstrated capability to handle a large number of participants with minimal loss to follow-up and its suitability for future clinical trials. Improved contact tracing in TB program activities is likely to increase TB case detection among adolescents. Future studies should explore possible pockets of higher TB incidence in urban areas and among out of school youth. 23599435 A phase 2 dose-ranging study of subcutaneous tabalumab for the treatment of patients with active rheumatoid arthritis and an inadequate response to methotrexate. To assess the dose-response relationship, efficacy and safety of tabalumab, a human monoclonal antibody that neutralises membrane-bound and soluble B-cell activating factor (BAFF), in patients with rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX). In this phase 2, 24-week, double-blind, placebo-controlled, dose-ranging study, patients with RA (N=158) on stable  MTX were randomised by Bayesian-adaptive method to receive 1, 3, 10, 30, 60, or 120 mg tabalumab or placebo subcutaneously every 4 weeks for 24 weeks. The primary objective was to test for a significant dose-response relationship using a statistical model of the proportion of patients having ≥50% improvement in American College of Rheumatology (ACR) criteria (ACR50) at week 24 (prespecified α=0.10). At week 24, a significant dose-response relationship was observed using ACR50 (p=0.059) and ACR20 (p=0.044) response rates. Using model-estimated data, only 120 mg had significantly higher ACR50 and ACR20 response rates versus placebo (p<0.05). Observed response rates were significantly higher for 120 mg versus placebo as measured by ACR50 at weeks 12 (p=0.039) and 20 (p=0.018), but not week 24, and by ACR20 at weeks 12 (p=0.011) and 24 (p=0.039). Mean DAS28 C-reactive protein  improved with 120 mg at week 24 (p=0.048). Frequency of TEAEs was similar across groups (range 50-69%, p=0.884). Ten (8.2%) tabalumab and 5 (13.9%) placebo patients reported a serious adverse event (SAE). Infections occurred more frequently in patients exposed to tabalumab (30.3% vs 19.4%). Serious infections were reported in 3 (2.5%) tabalumab-treated patients only. A dose-response relationship was detected with monthly subcutaneous tabalumab. A significant effect was detected with the 120 mg dose with no unexpected safety signals. CLINICAL TRIAL #: NCT00785928. 23917705 Biodegradability engineering of biodegradable Mg alloys: Tailoring the electrochemical properties and microstructure of constituent phases. Crystalline Mg-based alloys with a distinct reduction in hydrogen evolution were prepared through both electrochemical and microstructural engineering of the constituent phases. The addition of Zn to Mg-Ca alloy modified the corrosion potentials of two constituent phases (Mg + Mg2Ca), which prevented the formation of a galvanic circuit and achieved a comparable corrosion rate to high purity Mg. Furthermore, effective grain refinement induced by the extrusion allowed the achievement of much lower corrosion rate than high purity Mg. Animal studies confirmed the large reduction in hydrogen evolution and revealed good tissue compatibility with increased bone deposition around the newly developed Mg alloy implants. Thus, high strength Mg-Ca-Zn alloys with medically acceptable corrosion rate were developed and showed great potential for use in a new generation of biodegradable implants. 23911127 A prospective study of fusional convergence parameters in Chinese patients with intermittent exotropia. To evaluate the correlation between different fusional convergence parameters and the Newcastle Control Score (NCS) in children with intermittent exotropia. In this consecutive prospective observational series, 101 Chinese children with intermittent exotropia were examined by a single observer, who assessed the level of control using the revised NCS and measured the angle of deviation and fusional convergence. Levels of control were defined according to the NCS as good (0-3), moderate (4-6), or poor (7-9). The correlation between the different fusional convergence parameters and the NCS was evaluated. The total convergence amplitude was similar among the different control groups (P = 0.288 and P = 0.628 at near and at distance, respectively). The convergence reserve was higher in the good control group compared with the moderate and poor control groups, both at near (P = 0.001) and at distance (P = 0.001). Among all fusional convergence parameters, we determined that the fusional reserve ratio had strongest correlation with control (near ratio: r = -0.66, P = 0.001; distant ratio: r = -0.59, P = 0.001). Among patients with a fusional reserve ratio ≥2 at distance, 100% (5 of 5 patients) of these patients demonstrated good control (NCS ≤ 3). In children with intermittent exotropia, the total convergence amplitude was similar among different levels of control. The convergence reserve was lower in the poor control group. Fusional reserve ratio ≥2 was an indicator of good control in patients. 23893897 Evaluation of a 5-Tier Scheme Proposed for Classification of Sequence Variants Using Bioinformatic and Splicing Assay Data: Inter-Reviewer Variability and Promotion of Minimum Reporting Guidelines. Splicing assays are commonly undertaken in the clinical setting to assess the clinical relevance of sequence variants in disease predisposition genes. A 5-tier classification system incorporating both bioinformatic and splicing assay information was previously proposed as a method to provide consistent clinical classification of such variants. Members of the ENIGMA Consortium Splicing Working Group undertook a study to assess the applicability of the scheme to published assay results, and the consistency of classifications across multiple reviewers. Splicing assay data were identified for 235 BRCA1 and 176 BRCA2 unique variants, from 77 publications. At least six independent reviewers from research and/or clinical settings comprehensively examined splicing assay methods and data reported for 22 variant assays of 21 variants in four publications, and classified the variants using the 5-tier classification scheme. Inconsistencies in variant classification occurred between reviewers for 17 of the variant assays. These could be attributed to a combination of ambiguity in presentation of the classification criteria, differences in interpretation of the data provided, nonstandardized reporting of results, and the lack of quantitative data for the aberrant transcripts. We propose suggestions for minimum reporting guidelines for splicing assays, and improvements to the 5-tier splicing classification system to allow future evaluation of its performance as a clinical tool. 23188048 A gene-centric analysis of activated partial thromboplastin time and activated protein C resistance using the HumanCVD focused genotyping array. Activated partial thromboplastin time (aPTT) is an important routine measure of intrinsic blood coagulation. Addition of activated protein C (APC) to the aPTT test to produce a ratio, provides one measure of APC resistance. The associations of some genetic mutations (eg, factor V Leiden) with these measures are established, but associations of other genetic variations remain to be established. The objective of this work was to test for association between genetic variants and blood coagulation using a high-density genotyping array. Genetic association with aPTT and APC resistance was analysed using a focused genotyping array that tests approximately 50 000 single-nucleotide polymorphisms (SNPs) in nearly 2000 cardiovascular candidate genes, including coagulation pathway genes. Analyses were conducted on 2544 European origin women from the British Women's Heart and Health Study. We confirm associations with aPTT at the coagulation factor XII (F12)/G protein-coupled receptor kinase 6 (GRK6) and kininogen 1 (KNG1)/histidine-rich glycoprotein (HRG) loci, and identify novel SNPs at the ABO locus and novel locus kallikrein B (KLKB1)/F11. In addition, we confirm association between APC resistance and factor V Leiden mutation, and identify novel SNP associations with APC resistance in the HRG and F5/solute carrier family 19 member 2 (SLC19A2) regions. In conclusion, variation at several genetic loci influences intrinsic blood coagulation as measured by both aPTT and APC resistance. 23770028 Technology-Enabled Academic Detailing: Computer-mediated education between pharmacists and physicians for evidence-based prescribing. Academic detailing (AD) is the practice of specially trained pharmacists with detailed medication knowledge meeting with physicians to share best practices of prescribing. AD has demonstrated efficacy in positively influencing physicians' prescribing behavior. Nevertheless, a key challenge has been that physicians in rural and remote locations, or physicians who are time challenged, have limited ability to participate in face-to-face meetings with academic detailers, as these specially trained academic detailers are primarily urban-based and limited in numbers. To determine the feasibility of using information technologies to facilitate communication between academic detailers and physicians (known as Technology-Enabled Academic Detailing or TEAD) through a comparison to traditional face-to-face academic detailing (AD). Specifically, TEAD is compared to AD in terms of the ability to aid physicians in acquiring evidence-informed prescribing information on diabetes-related medications, measured in terms of time efficiency, satisfaction of both physicians and pharmacists, and quality of knowledge exchange. General Practitioner Physicians (n=105) and pharmacists (n=12) were recruited from across British Columbia. Pharmacists were trained to be academic detailers on diabetes medication usage. Physicians were assigned to one of four intervention groups to receive four academic detailing sessions from trained pharmacists. Intervention groups included: (1) AD only, (2) TEAD only, (3) TEAD crossed over to AD at midpoint, and (4) AD crossed over to TEAD at midpoint. Evaluation included physician-completed surveys before and after each session, pharmacist logs after each detailing session, interviews and focus groups with physicians and pharmacists at study completion, as well as a technical support log to record all phone calls and emails from physicians and pharmacists regarding any technical challenges during the TEAD sessions, or usage of the web portal. Because recruitment was very low for the cross over groups, we analyzed the results in two groups instead: AD only and TEAD only. 354 sessions were conducted (AD=161, TEAD=193). Of these, complete data were available for 300 sessions, which were included in analysis (AD=133, TEAD=167). On average, TEAD sessions were 49min long, and AD sessions 81min long. Overall, physicians enjoyed both modalities of academic detailing (AD and TEAD) because they received information that both reinforced their existing diabetes knowledge and also provided new prescribing insights and approaches. The results suggest that TEAD is an acceptable alternative to AD for providing physicians advice about prescribing. TEAD is more time efficient, facilitates effective knowledge exchange and interprofessional collaboration, and can reach those physicians virtually where face-to-face AD is not possible or practical. Due to logistics, physicians were allocated, rather than randomized, to receive AD and/or TEAD. 23652350 ACE2 Activation Confers Endothelial Protection and Attenuates Neointimal Lesions in Prevention of Severe Pulmonary Arterial Hypertension in Rats. Angiotensin-converting enzyme 2 (ACE2), an ACE homolog, hydrolyzes angiotensin II and opposes its actions, and plays a protective role in the pathogenesis of pulmonary arterial hypertension (PAH). However, the underlying mechanisms involved in the effect of ACE2 on PAH are still uncertain. In this study, we observed the effects of ACE2 activation on endothelial dysfunction and vascular remodeling in the development of severe PAH in rats. Severe PAH was induced by monocrotaline injection 1 week following left pneumonectomy, and ACE2 was activated by continuous injection of resorcinolnaphthalein. The PAH-related hemodynamics, pathological changes, and endothelium-dependent vasorelaxation were examined to assess the effects of ACE2 activation. In addition, the changes of the main components of the renin-angiotensin system were identified by ELISA or Western blotting. Severe PAH was established at 3 weeks and was characterized by high pulmonary arterial pressure (45 mmHg), significant right ventricular hypertrophy, neointimal occlusive lesions, and impaired endothelium-dependent relaxation in pulmonary arteries. Coadministration of resorcinolnaphthalein reduced pulmonary arterial pressure, right ventricular hypertrophy, and neointimal formation and shifted the endothelial-dependent responses toward values measured in normal rats. Theses changes were associated with an increase in ACE2 and angiotensin-(1-7) levels and a decrease in ACE and angiotensin II levels, in addition to a decrease in the ACE/ACE2 ratio and the angiotensin II/angiotensin-(1-7) ratio. The beneficial effects of resorcinolnaphthalein were abolished by A-779. These findings suggested that ACE2 activation by resorcinolnaphthalein improved endothelial function and suppressed neointimal formation in the prevention of severe PAH by the mechanism of mediating the levels of the components of the renin-angiotensin system. 23929624 Structure-Guided Rational Design of α/β-Peptide Foldamers with High Affinity for BCL-2 Family Prosurvival Proteins. We have used computational methods to improve the affinity of a foldamer ligand for its target protein. The effort began with a previously reported α/β-peptide based on the BH3 domain of the proapoptotic protein Puma; this foldamer binds tightly to Bcl-xL but weakly to Mcl-1. The crystal structure of the Puma-derived α/β-peptide complexed to Bcl-xL was used as the basis for computational design of variants intended to display improved binding to Mcl-1. Molecular modelling suggested modification of three α residues of the original α/β backbone. Individually, each substitution caused only a modest (4- to 15-fold) gain in affinity; however, together the three substitutions led to a 250-fold increase in binding to Mcl-1. These modifications had very little effect on affinity for Bcl-xL . Crystal structures of a number of the new α/β-peptides bound to either Mcl-1 or Bcl-xL validated the selection of each substitution. Overall, our findings demonstrate that structure-guided rational design can be used to improve affinity and alter partner selectivity of peptidic ligands with unnatural backbones that bind to specific protein partners. 23763428 Criminalization of HIV Transmission and Exposure: Research and Policy Agenda. More than half of US jurisdictions have laws criminalizing knowing exposure to or transmission of HIV, yet little evidence supports these laws' effectiveness in reducing HIV incidence. These laws may undermine prevention efforts outlined in the US National HIV/AIDS Strategy, in which the United States has invested substantial federal funds. Future research should include studies of (1) the impact of US HIV exposure laws on public health systems and practices; (2) enforcement of these laws, including arrests, prosecutions, convictions, and sentencing; (3) alternatives to HIV exposure laws; and (4) direct and opportunity costs of enforcement. Policy efforts to mitigate potential negative impacts of these laws could include developing prosecutorial guidelines, modernized statutes, and model public health policies and protocols. 23639854 Approaches for improving continuity of care in medication management: a systematic review. /st> Medication-related problems frequently occur during transitions and lead to patient harm, increased use of healthcare resources and increased costs. The objective of this systematic review is to synthesize the impact of approaches to optimize the continuity of care in medication management upon hospital admission and/or discharge. /st> MEDLINE, EMBASE, CINAHL, IPA and the Cochrane Database of Systematic Reviews from 1995 through December 2010. /st> Controlled, parallel-group trials. Data extraction Data were extracted by one researcher and checked by another. Both reviewers independently assessed the study quality. /st> Thirty studies met the inclusion criteria, but only 14 reached the predefined minimum quality score. Most studies focused on discharge and targeted the patients, sometimes together with primary care providers. The majority of studies found improvements in process measures. Patient education and counseling provided upon discharge and reinforced after discharge, sometimes together with improved communication with healthcare professionals, was shown to reduce the risk of adverse drug events and hospital re-admissions in some studies, but not all. Heterogeneity in study population as well as in intervention and outcome reporting precluded meta-analysis and limited interpretation. Most studies had important methodological limitations and were underpowered to show significant benefits on clinical outcomes. /st> The evidence for an impact of approaches on optimization of continuity of care in medication management remains limited. Further research should better target high-risk populations, use multicentered designs and have adequate sample size to evaluate the impact on process measures, clinical outcomes and cost-effectiveness. 23535037 MRI of iron oxide nanoparticle-labeled ADSCs in a model of hindlimb ischemia. Adipose-derived stem cells (ADSCs) exhibit tremendous potential for repair of ischemic diseases. However, studies on the fate, migration, differentiation, and body distribution of the labeled ADSCs are rarely reported. In this study, magnetic iron oxide nanoparticles were designed, synthesized, and coated with meso-2,3-dimercaptosuccinic acid (DMSA) to produce DMSA nanoparticles (DMSA-NPs). The properties, size distribution, and characterization of DMSA-NPs were evaluated. Green fluorescent protein expressing ADSCs (GFP-ADSCs) were obtained and labeled with DMSA-NPs. The viability, cytotoxicity and multi-differentiation capacity of labeled GFP-ADSCs were evaluated in vitro. Labeled and non-labeled GFP-ADSCs were injected into a mouse model of hindlimb ischemia, and 3T magnetic resonance imaging (MRI) was acquired. The synthesized DMSA-NPs efficiently labeled the GFP-ADSCs in vitro and in vivo without affecting cell viability, proliferation, cell cycle, and multi-differentiation capacity. The MRI showed hypointense spots in the labeled GFP-ADSCs that lasted up to 8 weeks. Prussian blue staining and immunofluorescence assay at 4 and 8 weeks indicated that the labeled GFP-ADSCs were in and around the ischemic sites and some differentiated into capillaries. This observation is identical to that seen for transplants of unlabeled cells. Labeled cells were also identified mainly in the liver and spleen, with significantly smaller amounts in the lungs, intestines, heart, and kidney. Developed DMSA-NPs were shown to exhibit a considerable potential for use as nanoprobes for MRI of stem cells, which will enhance our understanding of cell-based therapeutic strategies for ischemic diseases. 23951547 UNC-13L, UNC-13S, and Tomosyn form a protein code for fast and slow neurotransmitter release in Caenorhabditis elegans. Synaptic transmission consists of fast and slow components of neurotransmitter release. Here we show that these components are mediated by distinct exocytic proteins. The Caenorhabditis elegans unc-13 gene is required for SV exocytosis, and encodes long and short isoforms (UNC-13L and S). Fast release was mediated by UNC-13L, whereas slow release required both UNC-13 proteins and was inhibited by Tomosyn. The spatial location of each protein correlated with its effect. Proteins adjacent to the dense projection mediated fast release, while those controlling slow release were more distal or diffuse. Two UNC-13L domains accelerated release. C2A, which binds RIM (a protein associated with calcium channels), anchored UNC-13 at active zones and shortened the latency of release. A calmodulin binding site accelerated release but had little effect on UNC-13's spatial localization. These results suggest that UNC-13L, UNC-13S, and Tomosyn form a molecular code that dictates the timing of neurotransmitter release. DOI:http://dx.doi.org/10.7554/eLife.00967.001. 23675580 In situ analysis of corrosion inhibitors using a portable mass spectrometer with paper spray ionization. Paper spray (PS) ambient ionization is implemented using a portable mass spectrometer and applied to the detection of alkyl quaternary ammonium salts in a complex oil matrix. These salts are commonly used as active components in the formulation of corrosion inhibitors. They were identified in oil and confirmed by their fragmentation patterns recorded using tandem mass spectrometry (MS/MS). The cations of alkyl and benzyl-substituted quaternary ammonium salts showed characteristic neutral losses of CnH2n (n carbon number of the longest chain) and C7H8, respectively. Individual quaternary ammonium compounds were detected at low concentrations (<1 ng μL(-1)) and over a dynamic range of ∼5 pg μL(-1) to 500 pg μL(-1) (ppb). Direct detection of these compounds in complex oil samples without prior sample preparation or pre-concentration was also demonstrated using a home-built miniature mass spectrometer at levels below 1 ng μL(-1). 23359176 Prognostic factors for acute toxicity in prostate cancer patients treated with high-dose hypofractionated radiotherapy. To prospectively study acute genitourinary (GU) and gastrointestinal (GI) toxicity during hypofractionated radiotherapy. One-hundred and seventy-one consecutive men with cT1-T3cN0cM0 prostate cancer were treated at 2.6 Gy/fraction to a total dose of 67.6 for low risk (EQD2 = 79 Gy) and 70.2 Gy for intermediate-high risk (EQD2 = 82 Gy) over 5.2-5.4 weeks (α/β 1.5). Acute toxicity was scored according to RTOG/EORTC toxicity extended criteria after completing a 22-item questionnaire (basal, weekly, at 6 months). Minimum and median follow-up were 36 and 54.2 months, respectively. GU toxicity grades 0, 1, 2 and 3 were found in 30.4, 37, 32 and 0.6 % of patients, respectively. The figures for grades 0, 1, 2 and 3 GI toxicity were 66, 24, 10 and 0 %. The highest degree of acute reactions was reached at 4-5 weeks. At 6 months, 15 % of patients had GU toxicity (11 % grade 1, 4 % grade 2) and 5.8 % GI toxicity (5.3 % grade 1, 0.5 % grade 2). Multivariate analysis shows that bladder volume receiving ≥65 Gy (V 65) is associated with an increased risk of GU complications (p = 0.017, HR = 1.143, 95 % CI = 1.025-1.276), while history of TURP is linked to lower risk (p = 0.002, HR = 0.310, 95 % CI 0.004-0.370). Mean rectal dose (p = 0.013, HR = 1.089, 95 % CI 1.018-1.116) and total dose (p = 0.019, HR = 0.734, 95 % CI 0.567-0.950) are significantly related to GI toxicity. This 5-week dose-escalation hypofractionated radiotherapy schedule that uses 3D-conformal radiotherapy without IGRT has resulted in <1 % grade 3 acute complications. Our study suggests that reducing the mean rectal dose and the bladder V 65 helps prevent acute toxicity. TURP before radiotherapy was associated with lower acute GU toxicity. 23321024 It is the outside that counts: chemical and physical control of dynamic surfaces. Materials capable of dynamically controlling surface chemistry and topography are highly desirable. We have designed a system that is uniquely able to remotely control the presented functionality and geometry at a given time by using a functionalizable shape memory material. This was accomplished by incorporating controlled amounts of an azide-containing monomer into a shape memory polymeric material. These materials are capable of physically changing surface geometry over a broad range of length scales from >1 mm to 100 nm. Using copper-assisted click chemistry, they can be functionalized with a variety of molecules to yield different surfaces. Combining these features gave materials that can change both the presented geometry and functionality at tunable transition temperatures. 23518236 Nanohydroxyapatite increases BMP-2 expression via a p38 MAP kinase dependent pathway in periodontal ligament cells. Bone morphogenetic protein (BMP)-2 promotes the osteoblastic differentiation of human periodontal ligament (PDL) cells, which play a pivotal role in periodontal regeneration. Recently, nano-sized hydroxyapatite (nano-HA) has been highlighted due to its advantageous features over micro-sized materials. We investigated the effect of nano-HA on BMP-2 expression in human PDL cells. Real time PCR analysis revealed that the expression of BMP-2 increased upon stimulation with nano-HA in dose- and time-dependent manners. An immunofluorescence assay demonstrated the synthesis of BMP-2 proteins. Concentrations of Ca(2+) as well as phosphate (Pi) in culture supernatants were unchanged, suggesting that nano-HA functioned as a nanoparticle rather than as a possible source for releasing Ca(2+) and/or Pi extracellularly, which were shown to also enhance the expression of BMP-2. Nano-HA-induced BMP-2 expression was dependent on the p38 MAP kinase pathway because increases in BMP-2 expression were inhibited by treatment with SB203580, a p38 inhibitor, and phosphorylation of p38 was detected by Western blotting. This novel mechanism of nano-HA will be important for the rational design of future periodontal regeneration. 23417025 Increased bacterial hemolytic activity is conferred by expression of TlyA methyltransferase but not by its 2'-O-methylation of the ribosome. Bacterial 2'-O-methyltransferase TlyA methylates either both nucleotide C1409 of 16S rRNA and C1920 of 23S rRNA or only the C1920. Both ribosomal methylations increase bacterial susceptibility to ribosome-targeting antibiotics capreomycin and viomycin. However, TlyA has been suggested to also function as a hemolysin. Here, heterologous expression of TlyA from six diverse bacteria (including Mycobacterium tuberculosis and M. smegmatis) was found to increase hemolytic ability in the Escherichia coli host. Characterizing E. coli strains expressing mycobacterial TlyA with mutated rRNA recognition domain and impaired rRNA methylations showed that the abolished C1409 methylation altogether with significantly reduced C1920 methylation did not affect E. coli hemolytic activity. Thus, the increased bacterial hemolytic function is not likely a consequence of TlyA-mediated methylations of the ribosome. Purified water-soluble TlyA showed a weak concentration-dependent hemolysis in vitro. Therefore, the TlyA isoform alone is not a potent hemolysin. The results suggested that the bacterial hemolytic function might relate to the over-expression of TlyA and its interaction to other non-ribosomal target that is associated with the hemolytic ability. 23664693 Aquaporin 4 molecular mimicry and implications for neuromyelitis optica. Neuromyelitis optica (NMO) is associated with antibodies to aquaporin 4 (AQP4). We hypothesized that antibodies to AQP4 can be triggered by exposure to environmental proteins. We compared human AQP4 to plant and bacterial proteins to investigate the occurrence of significantly similar structures and sequences. High similarity to a known epitope for NMO-IgG, AQP4(207-232), was observed for corn ZmTIP4-1. NMO and non-NMO sera were assessed for reactivity to AQP4(207-232) and the corn peptide. NMO patient serum showed reactivity to both peptides as well as to plant tissue. These findings warrant further investigation into the role of the environment in NMO etiology. 23619127 Overexpression of TNF-α in mitochondrial diseases caused by mutations in mtDNA: evidence for signaling through its receptors on mitochondria. Mitochondrial diseases (MDs) are heterogeneous disorders due to impaired respiratory chain function causing defective ATP production. Although the disruption of oxidative phosphorylation is central to the MD pathophysiology, other factors may contribute to these disorders. We investigated the expression and the cellular localization of TNF-α and its receptors, TNFR1 and TNFR2, in muscle biopsies from 15 patients with mitochondrial respiratory chain dysfunction. Our data unambiguously demonstrate that TNF-α is expressed in muscle fibers with abnormal focal accumulations of mitochondria, so-called ragged red fibers, and is delivered to mitochondria where both receptors are localized. Moreover TNF receptors are differentially regulated in patients' muscle in which the expression levels of TNFR1 mRNA are decreased and those of TNFR2 mRNA are increased compared with controls. These findings suggest for the first time that TNF-α could exert a direct effect on mitochondria via its receptors. 23921302 Transduction of PEP-1-heme oxygenase-1 fusion protein reduces myocardial ischemia/reperfusion injury in rats. Recent studies have uncovered that overexpression of heme oxygenase-1 (HO-1) by induction or gene transfer provides myocardial protection. In the present study, we investigated whether HO-1 protein mediated by cell-penetrating peptide PEP-1 could confer cardioprotection in a rat model of myocardial ischemia/reperfusion (I/R) injury. Male Sprague-Dawley rats were subjected to 30 minutes of ischemia by occluding the left anterior descending coronary artery and to 120 minutes of reperfusion to prepare the model of I/R. Animals were randomized to receive PEP-1-HO-1 fusion protein or saline 30 minutes before a 30-minute occlusion. I/R increased myocardial infarct size and levels of malondialdehyde, serum tumor necrosis factor-α and interleukin 6 and reduced myocardial superoxide dismutase activity. Administration of PEP-1-HO-1 reduced myocardial infarct size and levels of malondialdehyde, serum tumor necrosis factor-α and interleukin 6 and increased myocardial superoxide dismutase and HO-1 activities. His-probe protein was only detected in PEP-1-HO-1-transduced hearts. In addition, transduction of PEP-1-HO-1 markedly reduced elevated myocardial tissue NF-κB induced by I/R. The results suggested that transduction of PEP-1-HO-1 fusion protein decreased myocardial reperfusion injury, probably by attenuating the production of oxidants and proinflammatory cytokines regulated by NF-κB. 23953297 Retrieval of Extensive Gutta-percha Extruded into the Maxillary Sinus: Use of 3-dimensional Cone-Beam Computed Tomography. Close proximity of the maxillary sinus to the roots of maxillary teeth can predispose to the inadvertent deposition of endodontic products into the maxillary sinus. One such material is thermoplasticized injectable gutta-percha, which has gained popularity of late. As a consequence of overfilling, some patients warrant surgical retrieval. A case report of extreme overextension of gutta-percha within the maxillary sinus after endodontic retreatment on tooth #14 was provided. The distobuccal and palatal canals had been obturated with gutta-percha master cones and backfilled with thermoplasticized injectable warm gutta-percha. The mesiobuccal canal had only been filled with thermoplasticized injectable warm gutta-percha, the origin of the extrusion. Imagery with 3-dimensional cone-beam computed tomography was performed for localization of the gutta-percha. The patient underwent a Caldwell-Luc approach for removal of the extruded material. The gutta-percha was successfully removed intact, and the patient had an unremarkable postoperative course. However, the patient continues to have mild tenderness in the sinus region. The featured case exemplified the consequence of overinstrumentation and ensuing inadequate apical stop. In these situations, the obturation of a maxillary tooth with thermoplasticized injectable gutta-percha, without master cones, can potentially result in overfilling and deposition into the antrum. Use of 3-dimensional cone-beam computed tomography could enhance endodontic diagnosis, serve as an aid for visualization of foreign materials within the sinus and contiguous soft tissue structures, and improve clinical outcome. 23444963 Kimchi, a fermented vegetable, improves serum lipid profiles in healthy young adults: randomized clinical trial. Abstract Vegetable-based diets have generally focused on their health benefits including negative associations with the serum cholesterol concentrations. The aim of this study was to investigate whether serum lipid concentrations are influenced by the amount of kimchi intake. For the study, 100 volunteers were assigned to 2 dietary groups, low (15 g/day, n=50) and high (210 g/day, n=50) kimchi intake, and were housed together in a dormitory for 7 days. Identical meals except with different amount of kimchi were provided and subjects were instructed to maintain their normal physical activity. Concentrations of fasting blood glucose (FBG), total glucose, total cholesterol and low density lipoprotein (LDL)-C significantly decreased in both groups after 7 days of kimchi intake, but the effects were dose dependent. Lipid lowering effects of kimchi were more profound in the subjects with total cholesterol and LDL-C level over 190 and 130 mg/dL, respectively, in both groups. FBG was significantly decreased in the high kimchi intake as compared to the low intake group (P=.003). In conclusion, greater consumption of kimchi improved FBG and serum total cholesterol in young healthy adults. 23585396 Shear stress activates extracellular signal-regulated kinase 1/2 via the angiotensin II type 1 receptor. Mechanical factors such as strain, pressure, and shear stress are key regulators of cell function, but the molecular mechanisms underlying the detection and responses to such stimuli are poorly understood. Whether the angiotensin II (AngII) AT1 receptor (AT1R) transduces shear stress in endothelial cells (ECs) is unknown. We exposed human umbilical cord endothelial cells (HUVECs) to a shear stress of 0 (control) or 15 dyn/cm(2) for 5 or 10 min. The colocalization of AT1R with caveolin-1 (Cav1), endosomal markers Rab5, EEA1, and Rab7, and lysosomal marker Lamp-1 increased in shear stimulated cells, detected by immunocytochemistry. Shear stress reduced labeling of wild-type mouse ECs (18±3% of unsheared control, P<0.01) but not Cav1(-/-) ECs (90±10%) with fluorescent AngII, confirming that internalization of AT1R requires Cav1. Shear stress activated ERK1/2 2-fold (P<0.01), which was prevented by the AT1R blocker losartan. NADPH oxidase inhibition with apocynin prevented both the colocalization of AT1R with Cav1 and the induction of ERK1/2 by shear stress. Moreover, shear-dependent ERK1/2 activation was minimal in CHO cells expressing an AT1Ra mutant that does not internalize, compared with cells expressing wild-type AT1Ra (P<0.05). Hence, AT1R may be an important transducer of shear stress-dependent activation of ERK1/2.-Ramkhelawon, B., Rivas, D., Lehoux, S. Shear stress activates extracellular signal-regulated kinase 1/2 via the angiotensin II type 1 receptor. 23962157 High immunohistochemical nestin expression is associated with greater depth of infiltration in dermatofibrosarcoma protuberans: a study of 71 cases. Dermatofibrosarcoma protuberans (DFSP) was recently shown to express nestin, a marker that has been associated with poorer prognosis when present in high levels in certain tumors. The objective of this study is to explore the association between high nestin expression and deep invasion. We performed a retrospective, observational study in which we evaluated the degree of nestin expression in 71 DFSP. The odds of fascial involvement was calculated before and after adjusting for the following confounders: age, sex, tumor size, time to diagnosis, tumor site, the presence of fibrosarcomatous areas, pleomorphism, number of mitotic figures and predominant histopathologic pattern. We also calculated the Spearman Rho correlation coefficient between nestin staining intensity and depth of invasion. Nestin immunopositivity was found in 98.6% of the tumors, and high expression levels were significantly associated with invasion of the fascia. The odds of fascial involvement in tumors with strong nestin staining was 6.56 (p = 0.001) before adjustment for confounders and 14.86 after adjustment (p = 0.007). The Spearman rho correlation coefficient between nestin expression and deep invasion was 0.287 (p = 0.015). High inmunohistochemical nestin expression appears to be associated with deeper invasion in DFSP. 23957608 Theoretical and Experimental Study of the C-H Stretching Overtones of 2,4,6,8,10,12-hexanitro- 2,4,6,8,10,12 hexaazaisowurtzitane (CL20). An understanding of how molecular environment and structure are reflected in optical absorption spectra offers a number of advantages, such as improved detection of materials or providing an easy means of distinguishing crystal polymorphs of the same molecular solid. This study advances this understanding by comparing near IR laser photoacoustic absorption measurements of the first C-H stretch overtones around 5975 cm-1 of beta 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL20) to simulated spectra using density functional calculations and the local mode model of C-H stretches. It was found that accounting for movement of charge throughout the model crystal unit cell with a pure quantum mechanical method in the calculation of the transition dipole moment was critical to matching the experimental data. Vibrational modes in a given molecule induced movement of charge in neighboring molecules, such that calculation of the transition dipole moment had to include the entire crystal unit cell. Movement of charge across the periodic boundary conditions (PBC) of the model had to be accounted for in order to calculate a spectrum validated by the experimental measurement. The Hirshfeld population analysis minimized discontinuities for movement of charge across the PBC. 23523936 Hemocompatibility evaluation of different silver nanoparticle concentrations employing a modified Chandler-loop in vitro assay on human blood. Due to their antibacterial effects, the use of silver nanoparticles (AgNPs) in a great variety of medical applications like coatings of medical devices has increased markedly in the last few years. However, blood in contact with AgNPs may induce adverse effects, thereby altering hemostatic functions. The objective of this study was to investigate the hemocompatibility of AgNPs in whole blood. Human whole blood (n=6) was treated with different AgNPs concentrations (1, 3 and 30mgl(-1)) or with saline/blank solutions as controls before being circulated in an in vitro Chandler-loop model for 60min at 37°C. Before and after circulation, various hematologic markers were investigated. Based on the hematologic parameters measured, no profound changes were observed in the groups treated with AgNP concentrations of 1 or 3mgl(-1). AgNP concentrations of 30mgl(-1) induced hemolysis of erythrocytes and α-granule secretion in platelets, increased CD11b expression on granulocytes, increased coagulation markers thrombin-antithrombin-III complex, kallikrein-like and FXIIa-like activities as well as complementing cascade activation. Overall, we provide for the first time a comprehensive evaluation including all hematologic parameters required to reliably assess the hemocompatibility of AgNPs. We strongly recommend integrating these hemocompatibility tests to preclinical test procedures prior to in vivo application of new AgNP-based therapies. 23905872 Women's perceptions of how pregnancy influences the context of intimate partner violence in Germany. Intimate partner violence during pregnancy is receiving increased attention because of its high prevalence and health effects. Still, little is known about women's perceptions on how their pregnancy influences the context in which intimate partner violence occurs. We conducted 19 in-depth interviews with women who had experienced intimate partner violence around the time of pregnancy. Women clearly perceived pregnancy as a turning point, because it created new expectations and a feeling of being overwhelmed. This led to violence by reducing women's acceptance of their partner's unemployment, alcohol abuse and lack of relationship commitment, or by increasing women's vulnerability because they felt too young to raise a child alone. Pregnancy also led to violence by bringing back childhood memories or by taking attention away from their partners. Understanding how pregnancy influences the context in which intimate partner violence occurs is important to provide abused, pregnant women with the services they need. 23878072 Clinical and biological significance of hepatoma-derived growth factor in Ewing sarcoma. We sought to investigate the clinicopathological significance and biological function of hepatoma derived growth factor (HDGF) in Ewing sarcoma. Our results show that HDGF expression is up-regulated in Ewing sarcoma. Nuclear HDGF expression is significantly associated with tumor volume (p < 0.001), metastases at diagnosis (p < 0.001), low overall survival rate (p < 0.001), and low disease-free survival rate (p < 0.001). HDGF knockdown results in significant reduction of Ewing sarcoma cell growth, proliferation, and tumorigenesis both in vitro and in vivo. Meanwhile, HDGF knockdown causes cell cycle arrest and enhanced sensitization to serum starvation-induced apoptosis. Furthermore, recombinant HDGF promotes proliferation and colony formation of Ewing sarcoma cell. Ninety-eight candidate HDGF down-stream genes were identified in Ewing sarcoma cells using a cDNA microarray analysis. In addition, we found that HDGF knockdown inhibited FLI1 expression in Ewing sarcoma cells at the mRNA and protein levels. In conclusion, our findings suggest that HDGF exhibits oncogenic properties and may be a novel prognostic factor in Ewing sarcoma. Targeting HDGF might be a potential therapeutic strategy for Ewing sarcoma. 23362274 Sialylneolacto-N-tetraose c (LSTc)-bearing liposomal decoys capture influenza A virus. Influenza is a severe disease in humans and animals with few effective therapies available. All strains of influenza virus are prone to developing drug resistance due to the high mutation rate in the viral genome. A therapeutic agent that targets a highly conserved region of the virus could bypass resistance and also be effective against multiple strains of influenza. Influenza uses many individually weak ligand binding interactions for a high avidity multivalent attachment to sialic acid-bearing cells. Polymerized sialic acid analogs can form multivalent interactions with influenza but are not ideal therapeutics due to solubility and toxicity issues. We used liposomes as a novel means for delivery of the glycan sialylneolacto-N-tetraose c (LSTc). LSTc-bearing decoy liposomes form multivalent, polymer-like interactions with influenza virus. Decoy liposomes competitively bind influenza virus in hemagglutination inhibition assays and inhibit infection of target cells in a dose-dependent manner. Inhibition is specific for influenza virus, as inhibition of Sendai virus and respiratory syncytial virus is not observed. In contrast, monovalent LSTc does not bind influenza virus or inhibit infectivity. LSTc decoy liposomes prevent the spread of influenza virus during multiple rounds of replication in vitro and extend survival of mice challenged with a lethal dose of virus. LSTc decoy liposomes co-localize with fluorescently tagged influenza virus, whereas control liposomes do not. Considering the conservation of the hemagglutinin binding pocket and the ability of decoy liposomes to form high avidity interactions with influenza hemagglutinin, our decoy liposomes have potential as a new therapeutic agent against emerging influenza strains. 23386394 PHI: A powerful new program for the analysis of anisotropic monomeric and exchange-coupled polynuclear d- and f-block complexes. A new program, PHI, with the ability to calculate the magnetic properties of large spin systems and complex orbitally degenerate systems, such as clusters of d-block and f-block ions, is presented. The program can intuitively fit experimental data from multiple sources, such as magnetic and spectroscopic data, simultaneously. PHI is extensively parallelized and can operate under the symmetric multiprocessing, single process multiple data, or GPU paradigms using a threaded, MPI or GPU model, respectively. For a given problem PHI is been shown to be almost 12 times faster than the well-known program MAGPACK, limited only by available hardware. © 2013 Wiley Periodicals, Inc. 23891108 Lateral to End-on Conversion of Chromosome-Microtubule Attachment Requires Kinesins CENP-E and MCAK. Proper attachment of chromosomes to microtubules is crucial for the accurate segregation of chromosomes. Human chromosomes attach initially to lateral walls of microtubules. Subsequently, attachments to lateral walls disappear and attachments to microtubule ends (end-on attachments) predominate. While it is known in yeasts that lateral to end-on conversion of attachments occurs through a multistep process, equivalent conversion steps in humans remain unknown. By developing a high-resolution imaging assay to visualize intermediary steps of the lateral to end-on conversion process, we show that the mechanisms that bring a laterally bound chromosome and its microtubule end closer to each other are indispensable for proper end-on attachment because laterally attached chromosomes seldom detach. We show that end-on conversion requires (1) the plus-end-directed motor CENP-E to tether the lateral kinetochore onto microtubule walls and (2) the microtubule depolymerizer MCAK to release laterally attached microtubules after a partial end-on attachment is formed. By uncovering a CENP-E mediated wall-tethering event and a MCAK-mediated wall-removing event, we establish that human chromosome-microtubule attachment is achieved through a set of deterministic sequential events rather than stochastic direct capture of microtubule ends. 23848434 The association of osteopenia with levels of serum 25-hydroxyvitamin d and HOMA-IR values ın a group of early postmenopausal Turkısh women. ABSTRACT Objective: To determine the association of osteopenia with levels of serum 25 hydroxy vitamin D and HOMA-IR values in postmenapousal women. Methods: One hundred healthy postmenopausal women were included in a cross-sectional study. Venous blood was collected after an overnight fast and 25 OH vitamin D, glucose and insulin levels were measured. HOMA-IR was calculated. Bone mineral density (BMD) was measured with a dual x-ray absorbsometer. Results: There was no difference of serum 25 hydroxy vitamin D levels and HOMA-IR values between the two groups. A weak positive correlation between serum 25 hydoxy vitamin D levels and osteopenia was detected. Insulin resistance had a weak negative association with osteopenia. Conclusions: The correlation between osteopenia and serum 25 hydoxy vitamin D levels and HOMA-IR values was weak among early postmenopausal women. 23711919 Synthesis and structure-activity relationship of pyripyropene A derivatives as potent and selective acyl-CoA:cholesterol acyltransferase 2 (ACAT2) inhibitors: part 3. In an effort to develop potent and selective inhibitors toward ACAT2, structure-activity relationship studies were carried out using derivatives based on pyripyropene A (PPPA, 1). In particular, we investigated the possibility of introducing appropriate 1,11-O-benzylidene and 7-O-substituted benzoyl moieties into PPPA (1). The new o-substituted benzylidene derivatives showed higher selectivity for ACAT2 than PPPA (1). Among them, 1,11-O-o-methylbenzylidene-7-O-p-cyanobenzoyl PPPA derivative 7q and 1,11-O-o,o-dimethylbenzylidene-7-O-p-cyanobenzoyl PPPA derivative 7z proved to be potent ACAT2 inhibitors with unprecedented high isozyme selectivity. 23719546 Thiol-based antioxidant supplementation alters human skeletal muscle signaling and attenuates its inflammatory response and recovery after intense eccentric exercise. The major thiol-disulfide couple of reduced glutathione (GSH) and oxidized glutathione is a key regulator of major transcriptional pathways regulating aseptic inflammation and recovery of skeletal muscle after aseptic injury. Antioxidant supplementation may hamper exercise-induced cellular adaptations. The objective was to examine how thiol-based antioxidant supplementation affects skeletal muscle's performance and redox-sensitive signaling during the inflammatory and repair phases associated with exercise-induced microtrauma. In a double-blind, crossover design, 10 men received placebo or N-acetylcysteine (NAC; 20 mg · kg(-1) · d(-1)) after muscle-damaging exercise (300 eccentric contractions). In each trial, muscle performance was measured at baseline, after exercise, 2 h after exercise, and daily for 8 consecutive days. Muscle biopsy samples from vastus lateralis and blood samples were collected before exercise and 2 h, 2 d, and 8 d after exercise. NAC attenuated the elevation of inflammatory markers of muscle damage (creatine kinase activity, C-reactive protein, proinflammatory cytokines), nuclear factor κB phosphorylation, and the decrease in strength during the first 2 d of recovery. NAC also blunted the increase in phosphorylation of protein kinase B, mammalian target of rapamycin, p70 ribosomal S6 kinase, ribosomal protein S6, and mitogen activated protein kinase p38 at 2 and 8 d after exercise. NAC also abolished the increase in myogenic determination factor and reduced tumor necrosis factor-α 8 d after exercise. Performance was completely recovered only in the placebo group. Although thiol-based antioxidant supplementation enhances GSH availability in skeletal muscle, it disrupts the skeletal muscle inflammatory response and repair capability, potentially because of a blunted activation of redox-sensitive signaling pathways. This trial was registered at clinicaltrials.gov as NCT01778309. 23311415 Progress in the synthesis of canthine alkaloids and ring-truncated congeners. The canthines represent a fairly large subclass of β-carboline alkaloids, with the first members described 75 years ago. Over the last 60 years, many members of the parent compound, canthin-6-one (1), have been isolated from various plant sources, principally the Rutaceae and Simaroubaceae families, and recently from fungi. Structures isolated from these sources have been the subject of total synthesis, which continues to the present day. This review gives a broad overview of synthetic approaches to canthines over a 30-year period from 1982 to 2012 and summarizes recent reports on the synthesis of less well known ring-truncated congeners. These include C-ring-truncated ("ABD", 2) and A-ring-truncated ("BCD", 3) ring systems, which are providing new scaffolds for potentially useful therapeutic applications. 23703243 Identification of fusarium from a patient with fungemia after multiple organ injury. Fusarium is a filamentous fungus widely distributed in nature, which is an important opportunistic pathogen and could cause fusariosis both in plants and animals. In human, Fusarium could cause local and disseminated infections both in immunocompetent and immunocompromised patients. We describe here a case of a male patient suffered from multiple organ injury, whose blood fungal culture was positive. The isolate was confirmed as "Fusarium solani" according to the morphology of the fungus and the results of phenotypic and molecular identification. 23932982 First characterization of a teleost Epstein-Barr virus-induced gene 3 (EBI3) reveals a regulatory effect of EBI3 on the innate immune response of peripheral blood leukocytes. Epstein-Barr virus-induced gene 3 (EBI3) encodes a protein that in mammals is known to be a subunit of interleukin (IL)-27 and IL-35, both which regulate cytokine production and inflammatory response. To date, no studies on fish EBI3 have been documented. In this work, we report the identification of an EBI3 homologue, CsEBI3, from tongue sole (Cynoglossus semilaevis) and analysis of its expression and biological effect. CsEBI3 is composed of 245 amino acid residues and possesses a Fibronectin type 3 (FN3) domain that is preserved in lower and higher vertebrates. Expression of CsEBI3 was detected in a wide range of tissues, in particular those of immune relevant organs, and upregulated in a time-dependent manner by experimental challenge with bacterial and viral pathogens. Bacterial infection of peripheral blood leukocytes (PBL) enhanced CsEBI3 expression and caused extracellular secretion of CsEBI3. Purified recombinant CsEBI3 (rCsEBI3) stimulated the respiratory burst activity of PBL and upregulated the expression of IL-1β, IL-8, Myd88, interferon-induced gene 15, CD28, and chemokines. In contrast, rCsEBI3M, a mutant CsEBI3 that lacks the FN3 domain failed to activate PBL and induced much weaker expression of the immune genes. Treatment of PBL with rCsEBI3, but not with the mutant rCsEBI3M, enhanced cellular resistance against bacterial invasion, whereas antibody blocking of CsEBI3 on PBL significantly reduced cellular resistance against bacterial infection. Taken together, these results indicate for the first time that a teleost EBI3 possesses immunoregulatory property in a manner that is dependent on the conserved FN3 domain, and that CsEBI3 is involved in the innate immune defense of PBL against microbial pathogens. 23734653 Treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone is beneficial but toxic in very elderly patients with diffuse large B-cell lymphoma: a population-based cohort study on treatment, toxicity and outcome. To assess treatment strategies, toxicity and outcome in very elderly patients (aged ≥ 75 years) diagnosed with diffuse large B-cell lymphoma (DLBCL) in the rituximab era, an observational population-based cohort study was performed. From 103 patients with a median age of 81 years, data of clinical characteristics, treatment, toxicity and outcome were evaluated. Advanced stage DLBCL was documented in 74 patients. In 80 patients chemotherapy was initiated; 70 patients received rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). In this group, 39 patients completed all cycles and 30 patients achieved a complete remission. Severe chemotherapy-related toxicity occurred in 69%. Two-year overall survival was 70% for elderly patients who completed chemotherapy, 28% for those treated with incomplete or suboptimal chemotherapy and 21% for those receiving palliative radiotherapy or supportive care. In conclusion, the ability to complete R-CHOP was associated with better overall survival compared to other treatment strategies at the expense of severe treatment-related toxicity. 23623290 Meta-analysis of stem cell therapy in chronic ischemic cardiomyopathy. Studies investigating bone marrow stem cell therapy (BMSCT) in patients with chronic ischemic cardiomyopathy have yielded mixed results. A meta-analysis of randomized controlled trials of BMSCT in patients with chronic ischemic cardiomyopathy was undertaken to assess its efficacy and the best route of administration. The MEDLINE, Embase, Cumulative Index to Nursing & Allied Health Literature, and Cochrane Library databases were searched through April 2012 for randomized controlled trials that investigated the impact of BMSCT and its route of administration on left ventricular (LV) function in patients with chronic ischemic cardiomyopathy and systolic dysfunction. Of the 226 reports identified, 10 randomized controlled trials including 519 patients (average LV ejection fraction [LVEF] at baseline 32 ± 7%) were included in the analysis. On the basis of a random-effects model, BMSCT improved the LVEF at 6 months by 4.48% (95% confidence interval [CI] 2.43% to 6.53%, p = 0.0001). A greater improvement in the LVEF was seen with intramyocardial injection compared with intracoronary infusion (5.13% [95% CI 3.17% to 7.10%], p <0.00001, vs 2.32% [95% CI -2.06% to 6.70%], p = 0.30). Overall, there were reductions in LV end-systolic volume of -20.64 ml (95% CI -33.21 to -8.07, p = 0.001) and LV end-diastolic volume of -16.71 ml (95% CI -31.36 to -2.06, p = 0.03). In conclusion, stem cell therapy may improve LVEF and favorably remodel the heart in patients with chronic ischemic cardiomyopathy. On the basis of current limited data, intramyocardial injection may be superior to intracoronary infusion in patients with LV systolic dysfunction. 23631807 Anterior segment changes produced in response to long-term overnight orthokeratology. To evaluate the effect of overnight orthokeratology (OK) on anterior chamber depth (ACD), posterior radius of corneal curvature (PRCC) and axial length (AL) over one year. In this prospective longitudinal study, measurements were made in 34 right eyes of 34 subjects at baseline, 15 days, 1 and 12 months after starting OK treatment. ACD and PRCC measurements were obtained using a Pentacam system and AL was measured using an IOL-Master. ACD and PRCC were measured along the horizontal and vertical meridians at 1 mm intervals. These measurements were expressed as the distance from the center in the nasal (N), temporal (T), superior (S) and inferior (I) directions. A significant reduction in ACD was observed in both meridians during treatment. PRCC flattened significantly in the (T) direction after 15 d (1 mm, p < 0.05), at the corneal center after 15 d (p < 0.01), in the (T) direction after 1 month (1 mm, p < 0.05), in the (S) direction after 12 months (1 mm p < 0.05), in the (N) direction after 12 months (1 mm p < 0.05), in the (N) and (T) directions after 12 months (3 mm, p < 0.05) and in the (T) direction after 12 months (4 mm p < 0.05), at the corneal center after 12 months (p < 0.01). AL was significantly reduced during treatment (p < 0.05). A long period of OK reduces ACD and AL and changes PRCC. 23891717 Effects of isoflurane or propofol on postnatal hippocampal neurogenesis in young and aged rats. An increasing number of in vitro and in vivo studies suggest that anesthesia and surgery could be risk factors for later cognitive impairment in the young and aged brain. General anesthesia has been shown to impair spatial memory in rats and this performance is dependent on hippocampal function and postnatal hippocampal neurogenesis. Anesthetic induced alteration of one or more stages of postnatal hippocampal neurogenesis may in part explain this cognitive impairment following anesthesia. Three different populations of proliferating cells in the dentate gyrus (DG) were labeled with different thymidine analogs (EdU, IdU, and CldU) at 4, 8, and 21 days, respectively, in young (3-month-old) and aged (20-month-old) rats prior to a 3h exposure to isoflurane, control, propofol, or 10% intralipid. 24h following general anesthesia, brains were collected for analysis. The number of cells co-localized with neuronal differentiation and maturation labels with each of the thymidine analogs was quantified. In addition, new cell proliferation 24hr following anesthesia was assessed with anti-Ki67. The effect of anesthesia on astrocytes was also assessed with anti-S100β. Isoflurane or propofol did not affect new cell proliferation, as assessed by Ki67, in the DG of young or aged rats. However, propofol significantly decreased the number of differentiating neurons and increased the number of astrocytes in the DG of young, but not aged, rats. Isoflurane significantly decreased the number of maturing neurons and increased the number of astrocytes in the DG of aged, but not young, rats. Isoflurane and propofol anesthesia altered postnatal hippocampal neurogenesis in an age and agent dependent matter. 23940334 AMPA receptor pHluorin-GluA2 reports NMDA receptor-induced intracellular acidification in hippocampal neurons. NMDA receptor activation promotes endocytosis of AMPA receptors, which is an important mechanism underlying long-term synaptic depression. The pH-sensitive GFP variant pHluorin fused to the N terminus of GluA2 (pH-GluA2) has been used to assay NMDA-mediated AMPA receptor endocytosis and recycling. Here, we demonstrate that in somatic and dendritic regions of hippocampal neurons a large fraction of the fluorescent signal originates from intracellular pH-GluA2, and that the decline in fluorescence in response to NMDA and AMPA primarily describes an intracellular acidification, which quenches the pHluorin signal from intracellular receptor pools. Neurons expressing an endoplasmic reticulum-retained mutant of GluA2 (pH-GluA2 ΔC49) displayed a larger response to NMDA than neurons expressing wild-type pH-GluA2. A similar NMDA-elicited decline in pHluorin signal was observed by expressing cytosolic pHluorin alone without fusion to GluA2 (cyto-pHluorin). Intracellular acidification in response to NMDA was further confirmed by using the ratiometric pH indicator carboxy-SNARF-1. The NMDA-induced decline was followed by rapid recovery of the fluorescent signal from both cyto-pHluorin and pH-GluA2. The recovery was sodium-dependent and sensitive to Na(+)/H(+)-exchanger (NHE) inhibitors. Moreover, recovery was more rapid after shRNA-mediated knockdown of the GluA2 binding PDZ domain-containing protein interacting with C kinase 1 (PICK1). Interestingly, the accelerating effect of PICK1 knockdown on the fluorescence recovery was eliminated in the presence of the NHE1 inhibitor zoniporide. Our results indicate that the pH-GluA2 recycling assay is an unreliable assay for studying AMPA receptor trafficking and also suggest a role for PICK1 in regulating intracellular pH via modulation of NHE activity. 23139353 Neuronal androgen receptor regulates insulin sensitivity via suppression of hypothalamic NF-κB-mediated PTP1B expression. Clinical investigations highlight the increased incidence of metabolic syndrome in prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT). Studies using global androgen receptor (AR) knockout mice demonstrate that AR deficiency results in the development of insulin resistance in males. However, mechanisms by which AR in individual organs coordinately regulates insulin sensitivity remain unexplored. Here we tested the hypothesis that functional AR in the brain contributes to whole-body insulin sensitivity regulation and to the metabolic abnormalities developed in AR-deficient male mice. The mouse model selectively lacking AR in the central nervous system and AR-expressing GT1-7 neuronal cells were established and used to delineate molecular mechanisms in insulin signaling modulated by AR. Neuronal AR deficiency leads to reduced insulin sensitivity in middle-aged mice. Neuronal AR regulates hypothalamic insulin signaling by repressing nuclear factor-κB (NF-κB)-mediated induction of protein-tyrosine phosphatase 1B (PTP1B). Hypothalamic insulin resistance leads to hepatic insulin resistance, lipid accumulation, and visceral obesity. The functional deficiency of AR in the hypothalamus leads to male mice being more susceptible to the effects of high-fat diet consumption on PTP1B expression and NF-κB activation. These findings suggest that in men with PCa undergoing ADT, reduction of AR function in the brain may contribute to insulin resistance and visceral obesity. Pharmacotherapies targeting neuronal AR and NF-κB may be developed to combat the metabolic syndrome in men receiving ADT and in elderly men with age-associated hypogonadism. 23965832 A Hidden Role of the Inactivated FANCD2: Upregulating ΔNp63. A compromised Fanconi Anemia (FA) signaling pathway, often resulting from an inactivated FANCD2, was recently recognized to contribute to the development of non-FA human tumors. However, it is largely unknown as to how an impaired FA pathway or an inactivated FANCD2 promotes tumorigenesis. Here we unexpectedly found that ΔNp63 mRNA was expressed at high levels in human cancer cells carrying an impaired FA pathway compared to the corresponding control cells carrying an intact FA pathway. This observation was recapitulated upon conditionally managing the status of FANCD2 monoubiquitination /activation in 293T cells. Importantly, ΔNp63 elevation upon FANCD2 inactivation was confirmed in human fibroblasts derived from FA patients. Moreover, we have identified a 189 bp DNA fragment downstream of the ΔNp63 promoter (P2) that can mediate the upregulation of ΔNp63 by an inactivated FANCD2, and determined that elevated ΔNp63 is high enough to promote cancer cell proliferation and metastasis. In vivo, the elevation of FAVL, a tumor promotion factor that inhibits FANCD2 activation, was found to be positively associated with ΔNp63 expression in human cancer tissues. Collectively, these results document a novel role of an inactivated FANCD2 in upregulating ΔNp63, advancing our understanding of how an impaired FA pathway contributes to the pathogenesis of human cancer. 23654352 Clinical significance of minimal residual disease in patients with acute leukaemia undergoing haematopoietic stem cell transplantation. In patients with acute leukaemia, the relative risk of relapse influences the choice between chemotherapy and haematopoietic stem cell transplantation (HSCT). The demonstration that minimal residual disease (MRD) is the strongest overall prognostic indicator and can identify patients who are unlikely to be cured by standard chemotherapy has added a powerful new factor to consider when making this decision. There is substantial data indicating that the likelihood of relapse after transplant is directly correlated with levels of MRD before transplant. This knowledge can be used to adjust the timing of HSCT, and guide the selection of donor, conditioning regimen, and post-HSCT strategies to maximize the graft-versus-leukaemia effect. Because MRD emerging post-transplant carries a dire prognosis, its detection can trigger withdrawal of immunosuppression, additional cellular and molecular therapies, or preparations for a second HSCT. Although it is not yet clear whether any of these actions will significantly improve outcome, it is likely that they will be most effective for patients with a relatively low tumour burden, who can be identified only through MRD testing. In this article, we review the clinical significance of MRD in the context of autologous and allogeneic HSCT. 23850353 Ultrasonic vocalizations, predictability and sensorimotor gating in the rat. Prepulse inhibition (PPI) is a measure of sensorimotor gating in diverse groups of animals including humans. Emotional states can influence PPI in humans both in typical subjects and in individuals with mental illness. Little is known about emotional regulation during PPI in rodents. We used ultrasonic vocalization recording to monitor emotional states in rats during PPI testing. We altered the predictability of the PPI trials to examine any alterations in gating and emotional regulation. We also examined PPI in animals selectively bred for high or low levels of 50kHz USV emission. Rats emitted high levels of 22kHz calls consistently throughout the PPI session. USVs were sensitive to prepulses during the PPI session similar to startle. USV rate was sensitive to predictability among the different levels tested and across repeated experiences. Startle and inhibition of startle were not affected by predictability in a similar manner. No significant differences for PPI or startle were found related to the different levels of predictability; however, there was a reduction in USV signals and an enhancement of PPI after repeated exposure. Animals selectively bred to emit high levels of USVs emitted significantly higher levels of USVs during the PPI session and a reduced ASR compared to the low and random selective lines. Overall, the results support the idea that PPI tests in rodents induce high levels of negative affect and that manipulating emotional styles of the animals alters the negative impact of the gating session as well as the intensity of the startle response. 23925646 Intraperitoneal bupivacaine for pain relief after minilaparoscopy in patients with infertility. To evaluate the efficacy of intraperitoneal bupivacaine to reduce post operative pain after diagnostic minilaparoscopy in patients with infertility. A prospective randomized study was performed. The study group consisted of 104 women with infertility undergoing diagnostic minilaparoscopy. At the end of the procedure, the treatment group (Group A) was given 10 mL of intraperitoneal 0.25 % bupivacaine (100 mg) and the control group (Group B) given 10 mL of intraperitoneal saline. Post operative pain was recorded with the use of a visual analog scale with scores ranging from 1 to 10 at 2, 4, 6 and 8 h intervals after the surgery. Additional analgesics given to the patients in the post operative period and any other side effects were noted. The treatment group had significantly lower pain scores at 2, 4, 6 and 8 h after the procedure (P < 0.05). The need for post operative analgesics also was significantly lower in the treatment group (P = 0.007). Post operative intraperitoneal bupivacaine administration is beneficial for patients undergoing diagnostic minilaparoscopy. It can significantly decrease post operative pain for up to 8 h and reduce the need for additional analgesics. 23847630 Plant cell wall lignification and monolignol metabolism. Plants are built of various specialized cell types that differ in their cell wall composition and structure. The cell walls of certain tissues (xylem, sclerenchyma) are characterized by the presence of the heterogeneous lignin polymer that plays an essential role in their physiology. This phenolic polymer is composed of different monomeric units - the monolignols - that are linked together by several covalent bonds. Numerous studies have shown that monolignol biosynthesis and polymerization to form lignin are tightly controlled in different cell types and tissues. However, our understanding of the genetic control of monolignol transport and polymerization remains incomplete, despite some recent promising results. This situation is made more complex since we know that monolignols or related compounds are sometimes produced in non-lignified tissues. In this review, we focus on some key steps of monolignol metabolism including polymerization, transport, and compartmentation. As well as being of fundamental interest, the quantity of lignin and its nature are also known to have a negative effect on the industrial processing of plant lignocellulose biomass. A more complete view of monolignol metabolism and the relationship that exists between lignin and other monolignol-derived compounds thereby appears essential if we wish to improve biomass quality. 23531488 Transport Function and Transcriptional Regulation of a Liver-Enriched Human Organic Anion Transporting Polypeptide 2B1 Transcriptional Start Site Variant. Human Organic Anion Transporting Polypeptide 2B1 (OATP2B1) is a membrane transporter that facilitates the cellular uptake of a number of endogenous compounds and drugs. OATP2B1 is widely expressed in tissues including the small intestine, liver, kidney, placenta, heart, skeletal muscle and platelets. Recently, it has been shown that differential promoter usage in tissues results in expression of five OATP2B1 transcriptional start site variants which utilize distinct first exons but share common subsequent exons. These variants are expected to encode either a full length (OATP2B1-FL) or shortened protein lacking 22 N-terminus amino acids (OATP2B-Short). Little is known regarding the transport activity and regulation of OATP2B1 variants with N-terminus truncation. Here, using absolute quantitative polymerase chain reaction we find the full length variant is the major form expressed in duodenum but the short variant predominates in liver. Using a transient heterologous cell expression system, we find that the transport activities of the short OATP2B1 variant towards substrates estrone sulfate and rosuvastatin are similar to the well-characterized full length variant. Transcriptional activity screening of the liver enriched OATP2B1 variant promoter identified hepatocyte nuclear factor 4 alpha (HNF4α) as a novel transacting factor. With a combination of in silico screening, promoter mutation in cell-based reporter assays, siRNA knockdown and chromatin immunoprecipitation studies, we identified a functional HNF4α binding site close to the transcription start site (-17 to -4 bp). We conclude that the major OATP2B1 protein form in liver is transport competent and its hepatic expression is regulated by HNF4α. 23761673 Regulation of BK-α expression in the distal nephron by aldosterone and urine pH. In the distal nephron, the large-conductance Ca-activated K (BK) channel, comprised of a pore-forming-α (BK-α) and the BK-β4 subunit, promotes K excretion when mice are maintained on a high-K alkaline diet (HK-alk). We examined whether BK-β4 and the acid-base status regulate apical membrane expression of BK-α in the cortical (CCD) and medullary collecting ducts (MCD) using immunohistochemical analysis (IHC) and Western blot. With the use of IHC, BK-α of mice on acontrol diet localized mostly cytoplasmically in intercalated cells (IC) of the CCD and in the perinuclear region of both principle cells (PC) and IC of the MCD. HK-alk wild-type mice (WT), but not BK-β4 knockout mice (β4KO), exhibited increased apical BK-α in both the CCD and MCD. When given a high-K acidic diet (HK-Cl), BK-α expression increased but remained cytoplasmic in the CCD and perinuclear in the MCD of both WT and β4KO. Western blot confirmed that total BK-α expression was enhanced by either HK-alk or HK-Cl but only increased in the plasma membrane with HK-alk. Compared with controls, mice drinking NaHCO3 water exhibited more apical BK-α and total cellular BK-β4. Spironolactone given to mice on HK-alk significantly reduced K secretion and decreased total cellular BK-α but did not affect cellular BK-β4 and apical BK-α. Experiments with MDCK-C11 cells indicated that BK-β4 stabilizes surface BK-α by inhibiting degradation through a lysosomal pathway. These data suggest that aldosterone mediates a high-K-induced increase in BK-α and urinary alkalinization increases BK-β4 expression, which promotes the apical localization of BK-α. 23835853 Nerve enlargement after cold exposure: A pilot study with ultrasound ımaging. Introduction: Changes of electrophysiogical parameters with regard to cold have been studied intensively but not the morphology of nerves. We explored the effects of cold exposure on median nerve morphology. Methods: Cross sectional area (CSA) and depth of the right median nerve were assessed at the carpal tunnel and mid-forearm levels before and after 15 minute ice-pack application in 34 healthy volunteers. Results: After cooling, mean CSA measurements increased at the carpal tunnel and mid-forearm levels (from 8.00 to 8.85 and 6.64 to 7.55, respectively, P<0.05); however, the depth values were similar. Discussion: These preliminary results revealed that cold exposure may cause acute nerve swelling. Further studies with larger samples will be necessary to confirm our findings, to correlate them with electrophysiological data, and to explore when/how the nerve edema resolves. © 2013 Wiley Periodicals, Inc. 23280986 Photoactivable amino acid bioisosteres and mass spectrometry: snapshots of in vivo 3D protein structures. From folded to crosslinked proteins. A new promising photo-crosslinking/mass spectrometry method for the structural characterisation of folded proteins is highlighted. A reactive photo-leucine can clamp the front residues in β-turn and β-hairpin domains, thus allowing us to look into the specific native 3D structure of proteins. 23918578 Efficacy of combination of meloxicam and pregabalin for pain in knee osteoarthritis. Purpose: Osteoarthritic pain is largely considered to be inflammatory pain. Sensory nerve fibers innervating the knee have been shown to be significantly damaged in rat models of knee osteoarthritis (OA) in which the subchondral bone junction is destroyed, and this induces neuropathic pain (NP). Pregabalin was developed as a pain killer for NP; however, there are no reports on pregabalin use in OA patients. The purpose of this study was to investigate the efficacy of pregabalin for pain in OA patients. Materials and Methods: Eighty-nine knee OA patients were evaluated in this randomized prospective study. Patients were divided into meloxicam, pregabalin, and meloxicam+pregabalin groups. Pain scores were evaluated before and 4 weeks after drug application using a visual analogue scale (VAS), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Pain scales among groups were compared using a Kruskal-Wallis test. Results: Before drug application, there was no significant difference in VAS and WOMAC scores among the three groups (p>0.05). Significant pain relief was seen in the meloxicam+pregabalin group in VAS at 1, 2, and 4 weeks, and WOMAC score at 4 weeks, compared with the other groups (p<0.05). No significant pain relief was seen in the meloxicam only group in VAS during 4 weeks and WOMAC score at 4 weeks compared with the pregabalin only group (p>0.05). Conclusion: Meloxicam+pregabalin was effective for pain in OA patients. This finding suggests that OA pain is a combination of inflammatory and NP. 23558330 The utility of ultrasound in detecting anterior compartment thickness changes in chronic exertional compartment syndrome: a pilot study. To test the hypothesis that patients with chronic exertional compartment syndrome (CECS) of the anterior leg compartment have an increased anterior compartment thickness (ACT) compared with control subjects after exertion using ultrasound. Prospective comparison study. Diagnostic imaging department of a tertiary care hospital. Four patients with CECS and 9 control subjects. Patients with CECS and control subjects ran on a treadmill for up to 10 minutes. Anterior compartment thickness (both groups) and anterior compartment pressure (CECS patients) were measured before exertion and at scheduled intervals after exertion. Anterior compartment thickness, percentage change in ACT from rest, and compartment pressure. Anterior compartment pressures were diagnostic of CECS using the modified Pedowitz criteria in patients with CECS. Mean percentage change in ACT from rest in patients with CECS versus control subjects at 0.5 minutes was 21.3% versus 6.32% [95% confidence interval (CI), 6.92-35.6 and 0.094-12.5, respectively; P = 0.011]; at 2.5 minutes, it was 24.6% versus 4.22% (95% CI, 10.7-38.5 and -1.85-10.3, respectively; P = 0.003); and at 4.5 minutes, it was 24.9% versus 5.08% (95% CI, 14.3-35.5 and -0.813-11.0, respectively; P = 0.003). Mean ACT in patients with CECS versus control subjects significantly increased after exertion (P = 0.003) at 0.5 minutes, 2.5 minutes, and 4.5 minutes. Ultrasonography reveals a significant increase in ACT in patients with CECS of the anterior leg compartment. Further studies are warranted to validate these findings with the goal of developing anterior leg compartment CECS ultrasound diagnostic criteria and exploring the role of using ultrasound to diagnose CECS in other compartments. 23870486 Hormones of adipose tissue and their biologic role in lung cancer. Adipose tissue secretes numerous bioactive peptides, collectively termed "adipocytokines" or "adipokines". Adipokines act in a paracrine, autocrine, or endocrine manner and regulate several physiological and pathological processes. Increasing evidence indicates that adipokines are implicated also in several malignancies, including lung cancer as well. The aim of this study is to summarize data concerning adipokines in lung cancer pathogenesis, prognosis and survival; the role of adipokines in lung cancer cachexia is also examined. A systematic literature search was performed in the electronic database of Medline. Several studies and review articles met the inclusion criteria. Leptin and adiponectin are the best studied adipokines. The majority of the relevant studies has investigated the potential correlations mainly between leptin, adiponectin, and sometimes also resistin, and nutritional status, systemic inflammation of lung cancer or lung cancer cachexia and have also assessed their prognostic significance. Few other studies have studied genetic variations in leptin, leptin receptor and adiponectin genes and their association with lung cancer susceptibility and prognosis. The ongoing list of adipokines associated with lung cancer also includes resistin, chemerin, and visfatin. Increasing evidence points to the involvement of certain adipocytokines in lung cancer development, progression and prognosis. No conclusive evidence exists so far with regards to the role of adipocytokines in lung cancer cachexia. Future, longitudinal studies are warranted in order to clarify the role of adipocytokines in lung cancer and also uncover adipocytokines as novel therapeutic targets. 23849850 Antimicrobials and renal failure in neutropenic patients. Antimicrobial treatment is often indicated to neutropenic patients. Although renal failure is a common complication of many antibiotics, no information could be found in the literature defining which are the best screening criteria for detecting renal injury. In this paper, the authors aim to assess the progress to renal failure in neutropenic patients on antimicrobial use and to compare different diagnostic criteria of renal failure in association to antimicrobial agents used. This is a cohort study conducted from February to August 2006 at the Hospital das Clínicas of the Universidade Federal de Minas Gerais, which included patients with neutropenia and antimicrobial therapy for the treatment of Healthcare Associated Infections notified by the Hospital Infection Control Committee. Renal injury has ensued in 25% of patients and no statistical difference between distinct criteria for renal injury was observed. Association of greater number of antimicrobials was associated with renal impairment. Time required for renal injury was independent of the antimicrobial regimen used, but mortality among patients with renal injury was higher when compared to those who had preserved renal function. 23657849 The Effect of Energy Substrates on PHB Accumulation of Acidiphilium cryptum DX1-1. The effect of glucose and elemental sulfur on the growth and PHB accumulation of Acidiphilium cryptum DX1-1 was investigated. Meanwhile, the differential expressions of 19 genes related with PHB accumulation, sulfur metabolism and carbon fixed in heterotrophy, phytotrophy and mixotrophy were studied by RT-qPCR. The results showed that strain DX1-1 could accumulate PHB with sulfur as the energy substance and atmospheric CO2 as carbon resource. Glucose could improve the growth of strain DX1-1 cultured in medium with sulfur as the energy substance, and almost all the key enzyme-encoding genes related with PHB, sulfur metabolism and carbon fixed were basically up-regulated. PHB polymerase (Arcy_3030), ribulose-bisphosphate carboxylase (Acry_0825), ribulose-phosphate-epimerase (Acry_0022), and cysteine synthase A (Acry_2560) played important role in PHB accumulation, the modified expression of which could influence the PHB yield. With CO2 as carbon resource, the main initial substance of PHB accumulation for strain DX1-1 was acetyl-CoA, instead of acetate with the glucose as the carbon resource. Because of accumulating PHB by fixed atmospheric CO2 while independent of light, A. cryptum DX1-1 may have specifically potential in production of PHB. 23856920 High-Dose Acetylsalicylic Acid is Superior to Low Dose as Well as to Clopidogrel in Preventing LPS-Induced Lung Injury in Mice. Use of aspirin (ASA) was found to improve outcome in animal models of acute lung injury (ALI) or its more severe form ARDS. In ARDS patients, data indicating a protective effect of ASA are less convincing. We hypothesize that ASA in a high dose is superior to low dose ASA in preventing lung injury. Also, the effect on lung injury of inhibiting platelet activation by clopidogrel was investigated. ALI was induced by intranasal instillation of 10 μg lipopolysaccharide (LPS). Before LPS, BALB/c mice were pre-treated with either high dose of ASA (100 μg/g intraperitoneally (i.p.), low dose ASA (12.5 μg/g i.p), clopidogrel (50 μg/g i.p) or clopidogrel in combination with low dose of ASA. Controls received vehicle or LPS without intervention. Five hours after LPS, bronchoalveolar lavage fluid (BALF) and plasma were obtained. All treatment regimes reduced neutrophil influx in the BALF compared to LPS controls (high dose ASA 75±2 (mean±SD), low dose ASA 86±3, clopidogrel 82±1 and low dose ASA-clopidogrel 82±3 vs LPS control 88±2%, P ≤0.05). High dose ASA reduced BALF levels of protein compared to LPS controls (0.2[15] (median [IQR]) vs 75[20] pg/mL, P < 0.01), to a greater extent than after low dose ASA (48[32] pg/mL), clopidogrel (37[23]pg/mL) or low dose ASA-clopidogrel (57[8] pg/mL). High dose ASA is superior to low dose ASA, clopidogrel and to a combination of clopidogrel and low dose ASA in attenuating LPS-induced lung injury in mice, suggesting high dose ASA to be the antiplatelet therapy of choice in further research on preventing ALI. 23936543 Self-sustained motor activity triggered by interlimb reflexes in chronic spinal cord injury, evidence of functional ascending propriospinal pathways. The loss or reduction of supraspinal inputs after spinal cord injury provides a unique opportunity to examine the plasticity of neural pathways within the spinal cord. In a series of nine experiments on a patient, quadriplegic due to spinal cord injury, we investigated interlimb reflexes and self-sustained activity in completely paralyzed and paretic muscles due to a disinhibited propriospinal pathway. Electrical stimuli were delivered over the left common peroneal nerve at the fibular head as single stimuli or in trains at 2-100 Hz lasting 1 s. Single stimuli produced a robust interlimb reflex twitch in the contralateral thumb at a mean latency 69 ms, but no activity in other muscles. With stimulus trains the thumb twitch occurred at variable subharmonics of the stimulus rate, and strong self-sustained activity developed in the contralateral wrist extensors, outlasting both the stimuli and the thumb reflex by up to 20 s. Similar behavior was recorded in the ipsilateral wrist extensors and quadriceps femoris of both legs, but not in the contralateral thenar or peroneal muscles. The patient could not terminate the self-sustained activity voluntarily, but it was abolished on the left by attempted contractions of the paralyzed thumb muscles of the right hand. These responses depend on the functional integrity of an ascending propriospinal pathway, and highlight the plasticity of spinal circuitry following spinal cord injury. They emphasize the potential for pathways below the level of injury to generate movement, and the role of self-sustained reflex activity in the sequelae of spinal cord injury. 23736380 Fine structure and primary sensory projections of sensilla located in the labial-palp pit organ of Helicoverpa armigera (Insecta). The fine structure and primary sensory projections of sensilla located in the labial-palp pit organ of the cotton bollworm Helicoverpa armigera (Insecta, Lepidoptera) are investigated by scanning electron and transmission electron microscopy combined with confocal laser scanning microscopy. The pit organ located on the third segment of the labial palp is about 300 Î¼m deep with a 60-μm-wide opening, each structure containing about 1200 sensilla. Two sensillum types have been found, namely hair-shaped and club-shaped sensilla, located on the upper and lower half of the pit, respectively. Most sensilla possess a single dendrite. The dendrite housed by the club-shaped sensilla is often split into several branches or becomes lamellated in the outer segment. As reported previously, the sensory axons of the sensilla in the labial pit organ form a bundle entering the ipsilateral side of the subesophageal ganglion via the labial palp nerve and project to three distinct areas: the labial pit organ glomerulus in each antennal lobe, the subesophageal ganglion and the ventral nerve cord. In the antennal lobe, the labial pit organ glomerulus is innervated by sensory axons from the labial pit organ only; no antennal afferents target this unit. One neuron has been found extending fine processes into the subesophageal ganglion and innervating the labial palp via one branch passing at the base of the labial palp nerve. The soma of this assumed motor neuron is located in the ipsilateral cell body layer of the subesophageal ganglion. Our results provide valuable knowledge concerning the neural circuit encoding information about carbon dioxide and should stimulate further investigations directed at controlling pest species such as H. armigera. 23969303 Is exposure to secondhand smoke associated with cognitive parameters of children and adolescents?-a systematic literature review. Despite the known association of second hand smoke (SHS) with increased risk of ill health and mortality, the effects of SHS exposure on cognitive functioning in children and adolescents are unclear. Through a critical review of the literature we sought to determine whether a relationship exists between these variables. The authors systematically reviewed articles (dated 1989-2012) that investigated the association between SHS exposure (including in utero due to SHS exposure by pregnant women) and performance on neurocognitive and academic tests. Eligible studies were identified from searches of Web of Knowledge, MEDLINE, Science Direct, Google Scholar, CINAHL, EMBASE, Zetoc, and Clinicaltrials.gov. Fifteen articles were identified, of which 12 showed inverse relationships between SHS and cognitive parameters. Prenatal SHS exposure was inversely associated with neurodevelopmental outcomes in young children, whereas postnatal SHS exposure was associated with poor academic achievement and neurocognitive performance in older children and adolescents. Furthermore, SHS exposure was associated with an increased risk of neurodevelopmental delay. Recommendations should be made to the public to avoid sources of SHS and future research should investigate interactions between SHS exposure and other risk factors for delayed neurodevelopment and poor cognitive performance. 23385844 Transcranial magnetic stimulation as an efficient treatment for psychogenic movement disorders. Management of psychogenic movement disorders (PMDs) is challenging for neurologists and, to date, there is no consensus about their treatment. Recent studies suggested a possible therapeutic effect of repeated transcranial magnetic stimulation (TMS) in psychogenic paralysis and tremor. To document the clinical impact of TMS in PMDs. We blindly video scored symptoms of consecutive patients with PMD who were recorded before and after TMS. TMS was delivered at low frequency (0.25 Hz) over the motor cortex contralateral to symptoms. Twenty-four patients were included. They presented with dystonia, myoclonus, tremor, Parkinsonism or stereotypies. The median duration of symptoms before TMS was 2.8 years (6 months to 30 years). The overall score of 75% of patients improved by >50% and, furthermore, the clinical benefits were sustained upon protracted follow-up (median 19.8 months). There was no correlation between improvement and duration of symptoms before TMS. TMS is a therapeutic option for PMDs, including chronic PMDs. 23537153 Implementation of a clinical pharmacy specialist-managed telephonic hospital discharge follow-up program in a patient-centered medical home. Abstract The objectives of this retrospective study were to examine the feasibility and characteristics that define successful implementation of a Clinical Pharmacy Specialist (CPS) telephonic hospital discharge follow-up quality improvement initiative, as well as the impact of this initiative. Adult patients who were discharged from a safety-net hospital between July 1, 2010 and June 30, 2011 and who were part of a patient-centered medical home were included in this quality improvement initiative. CPSs attempted to contact 470 patients; of those, 207 received the intervention and 263 did not. Patients in the contacted group were more likely to attend a hospital discharge follow-up appointment (66.2% vs. 44.5%, P<0.01) and had lower rates of 30-day readmission (22 vs. 52, P<0.01) compared to those who were not contacted. Institutions should consider allocating resources for pharmacist-managed posthospital discharge follow-up services because of the potential for positive clinical and financial impact. (Population Health Management 2013;16:235-241). 23964224 Neuroimaging, a new tool for investigating the effects of early diet on cognitive and brain development. Nutrition is crucial to the initial development of the central nervous system (CNS), and then to its maintenance, because both depend on dietary intake to supply the elements required to develop and fuel the system. Diet in early life is often seen in the context of "programming" where a stimulus occurring during a vulnerable period can have long-lasting or even lifetime effects on some aspect of the organism's structure or function. Nutrition was first shown to be a programming stimulus for growth, and then for cognitive behavior, in animal studies that were able to employ methods that allowed the demonstration of neural effects of early nutrition. Such research raised the question of whether nutrition could also programme cognition/brain structure in humans. Initial studies of cognitive effects were observational, usually conducted in developing countries where the presence of confounding factors made it difficult to interpret the role of nutrition in the cognitive deficits that were seen. Attributing causality to nutrition required randomized controlled trials (RCTs) and these, often in developed countries, started to appear around 30 years ago. Most demonstrated convincingly that early nutrition could affect subsequent cognition. Until the advent of neuroimaging techniques that allowed in vivo examination of the brain, however, we could determine very little about the neural effects of early diet in humans. The combination of well-designed trials with neuroimaging tools means that we are now able to pose and answer questions that would have seemed impossible only recently. This review discusses various neuroimaging methods that are suitable for use in nutrition studies, while pointing out some of the limitations that they may have. The existing literature is small, but examples of studies that have used these methods are presented. Finally, some considerations that have arisen from previous studies, as well as suggestions for future research, are discussed. 23773875 Hip-femoral acetabular impingement. Magnetic resonance imaging (MRI) has become a valuable technology for the diagnosis and treatment of femoroacetabular impingement (FAI). This article reviews the basic pathophysiology of FAI, as well as the techniques and indications for MRI and magnetic resonance arthrography. Normal MRI anatomy of the hip and pathologic MRI anatomy associated with FAI are also discussed. Several case examples are presented demonstrating the diagnosis and treatment of FAI. 23908340 How can the service user voice be best heard at psychiatric meetings? Service user contributions to mental health conferences are now routine. How effective they are at promoting dialogue is not clear. We report a difficult exchange following a presentation about coercive treatment, with our individual reflections on what we learnt. Suggestions are made to improve both the clinical practice and the dialogue. 23925456 Unexpected helicity control and helix inversion: homochiral helical nanotubes consisting of an achiral ligand. The ligand tppda has been designed and synthesized as molecular leverage for helicity control when reacted with Cd(2+) ions. The guests MeOH or DMF preferentially stabilize the -helical isomer, while the guest H2O causes a helix inversion to give the -helical isomer as the major isomer without any chiral auxiliary. 23869918 Long-term outcomes in children with swallowing dysfunction. Purpose: To evaluate swallowing function using a videofluoroscopic swallow study (VFSS), and to identify factors related to long-term swallowing function in children with swallowing dysfunction. Methods: Ninety children, aged 1-120 months (mean 27.5 months) were randomly selected from among children referred for the evaluation of swallowing dysfunction. We retrospectively reviewed the charts, and long-term outcomes were tracked up to 5 years. Results: Baseline American Speech-Language-Hearing Association National Outcome Measurement System (ASHA NOMS) scale was 3.4 ± 2.5. Supraglottic penetration and subglottic aspiration comfirmed by VFSS were detected in 30 children. After follow-up, oral feeding was possible in 74 patients, and the ASHA NOMS swallowing scale improved significantly, from 3.4 ± 2.5 to 5.8 ± 2.0. Baseline VFSS severity, serum albumin concentration, baseline weight percentile and neurologic conditions were significantly correlated with long-term swallowing function. Conclusions: The long-term outcomes in children with swallowing dysfunction were favorable, and baseline videofluoroscopic severity was significantly correlated with long-term swallowing function. 23914888 Treatment of common skin infections and infestations during pregnancy. In the absence of systematic studies in pregnant and lactating women, recommendations for the treatment of infections during pregnancy are based on animal studies, accumulated evidence from clinical use and case reports, as well as published consensus statements and expert opinion. This article examines the evidence basis for the treatment of common cutaneous infections in women who are pregnant or breast-feeding. 23901139 Phosphatidylcholine transfer protein interacts with thioesterase superfamily member 2 to attenuate insulin signaling. Phosphatidylcholine transfer protein (PC-TP) is a phospholipid-binding protein that is enriched in liver and that interacts with thioesterase superfamily member 2 (THEM2). Mice lacking either protein exhibit improved hepatic glucose homeostasis and are resistant to diet-induced diabetes. Insulin receptor substrate 2 (IRS2) and mammalian target of rapamycin complex 1 (mTORC1) are key effectors of insulin signaling, which is attenuated in diabetes. We found that PC-TP inhibited IRS2, as evidenced by insulin-independent IRS2 activation after knockdown, genetic ablation, or chemical inhibition of PC-TP. In addition, IRS2 was activated after knockdown of THEM2, providing support for a role for the interaction of PC-TP with THEM2 in suppressing insulin signaling. Additionally, we showed that PC-TP bound to tuberous sclerosis complex 2 (TSC2) and stabilized the components of the TSC1-TSC2 complex, which functions to inhibit mTORC1. Preventing phosphatidylcholine from binding to PC-TP disrupted interactions of PC-TP with THEM2 and TSC2, and disruption of the PC-TP-THEM2 complex was associated with increased activation of both IRS2 and mTORC1. In livers of mice with genetic ablation of PC-TP or that had been treated with a PC-TP inhibitor, steady-state amounts of IRS2 were increased, whereas those of TSC2 were decreased. These findings reveal a phospholipid-dependent mechanism that suppresses insulin signaling downstream of its receptor. 23912286 Cost of Bordetella pertussis illness in tertiary hospitals in Argentina. The National Immunization Commission and the National Program for the Control of Vaccine-Preventable Diseases (Programa Nacional de Control de Enfermedades Inmunoprevenibles, ProNaCEI) updated the immunization policy in relation to Bordetella pertussis (BP) in 2009 in order to improve the control of this disease in accordance with international recommendations. To evaluate the fnancial impact of this new immunization policy, we must frst know the cost on the health system of having a hospitalized or outpatient child infected with BP. The objective of this study was to describe the profle of costs of hospitalized or outpatient children with laboratory-confrmed BP infection in three hospitals of Argentina. This was a prospective study of the cost of BP in the period between December 2010 and March 2012. Results. The total cost for the entire cohort was 1 170 663.32 ARS (236 497.64 USD); direct medical costs were 1 124 052.31 ARS (227 081.27 USD); indirect costs and out-of-pocket expenses were 46 611 ARS (9416.6 USD). From this data, it is possible to conclude that the total average cost per patient was 10 546.52 ARS (95% CI: 9009-13 840) (2130.60 USD, 95% CI: 1820-2795), the direct medical cost per patient was 10 126.6 ARS (95% CI: 8607-13 171) (2045.77 USD, 95% CI: 1738-2660), and the indirect plus out-of-pocket costs (transportation and extras) were 419.92 ARS (95% CI: 344.7-565.3) (84 USD, 95% CI: 69-115). Conclusion. The cost of a hospitalized child with confrmed BP is 10 546.52 ARS (95% CI: 9009-13 840) (2130.60 USD, 95% CI: 1820-2795). Direct non-medical costs and overhead costs account for 4% of the total cost, amounting to 419.91 ARS per family (84 USD, 95% CI: 69-115), approximately an 8% of an average salary. 23743254 Polymer-hybridized liposomes of poly(amino acid) derivatives as transepidermal carriers. This work describes the use of a novel transepidermal drug carrier system composed of phospholipids and amphiphilc poly(amino acid)s. We polymerized poly(asparagine) grafted with octadecylamine (PAsn-g-C18), poly(aspartic acid) grafted with octadecylamine (PAsp-g-C18), and poly(aspartic acid) grafted with phytosphingosine (PAsp-g-PHS). We then prepared polymer hybridized liposomes (PHL) anchored with alkyl grafted poly(amino acid)s and encapsulated hydrolyzed ginseng saponins (HGS). We confirmed that the liposomes and PHL reduce the cytotoxicity of HGS, which was not observed with polymeric nano-carriers. A quantitative analysis of the amount of penetrated HGS using the Franz cell method revealed that skin permeation of the lipophilic drugs loaded in liposomes was enhanced by the incorporation of amphiphilic poly(amino acid)s. Fluorescence microscopy observations also demonstrated excellent skin permeation performance of PHL anchored with PAsp-g-PHS. PHL showed better structural stability than liposomes in an O/W emulsion. PHL considerably improved the chemical stability of HGS compared to the liposomes. It is thought that the skin permeability of encapsulated bioactive molecules could be affected by the vesicle structure, membrane fluidity, and the type of anchored polymer. 23665303 Serogroup quantitation of multivalent polysaccharide and polysaccharide-conjugate meningococcal vaccines from China. The active components of most meningococcal vaccines are four antigenic serogroup capsular polysaccharides (A, C, Y, W135). The vaccines, monovalent or multivalent mixtures of either free polysaccharides or polysaccharides conjugated to antigenic carrier proteins, may be in liquid or lyophilised formulations, with or without excipients. Acid hydrolysis and chromatographic methods for serogroup quantitation, which were previously optimised and qualified using polysaccharide-based standards and a narrow range of real vaccines, are here challenged with multiple lots of a broad assortment of additional multivalent polysaccharide-based meningococcal vaccine products. Centrifugal filtration successfully removed all interfering lactose excipient without loss of polysaccharides to allow for the determination of Y and W135 serogroups. Replicate operations by three different analysts indicated high method reproducibility. Results indicated some lot-to-lot and product-to-product variations. However, all vaccines were within general specifications for each serogroup polysaccharide, with the exception of all lots of one polysaccharide vaccine - which by these methods were found to be deficient in the serogroup A component only. These robust techniques are very useful for the evaluation of antigen content and consistency of manufacture. The deformulation, hydrolysis and chromatographic methods may be adaptable for the evaluation of other types of polysaccharide-based vaccines. 23830882 Immunopotentiation of outer membrane protein through anti-idiotype Pasteurella multocida vaccine in rabbits. Pasteurella multocida was isolated from cattle affected with haemorrhagic septicaemia and characterized on the basis of morphological, cultural and biochemical tests. Bacterial outer membrane proteins (OMPs) were extracted with 1% Sarkosyl method. P. multocida anti-idiotype vaccine prepared from OMPs (21.3 mg per 100 ml), was evaluated and compared with bacterin supplemented with 10% OMPs and plain alum-adsorbed bacterin in rabbit models. It was observed that OMPs-anti-idiotype vaccine induced high levels of antibody titres (geomean titres -GMT) detected using indirect haemagglutination (IHA) test. The OMPs anti-idiotype antibody titres of 168.9 GMT were obtained to 42.2 GMT in OMPs supplemented bacterin on 21 days post vaccination, while the plain bacterin had the least titre of 27.9 GMT. The OMPs-anti-idiotype vaccine provoked better immunogenic response in terms of highest GMT titres and long lasting effect in rabbits and 100% protection against the challenge with homologous strain of P. multocida,while 88% protection was obtained in rabbits, given OMPs supplemented bacterin. 23746126 Surgical treatment of hypothalamic hamartoma causing central precocious puberty: long-term follow-up. Hypothalamic hamartoma (HH) is a rare condition that often manifests as central precocious puberty (CPP). There is a lack of information available concerning the long-term effectiveness of surgery for the treatment of CPP due to HH. Here the authors describe 3 cases of CPP due to HH, with a follow-up ranging from 9 to 11 years after surgery. Three girls experienced breast growth and menses at 5-18 months of age and 5-36 months of age, respectively. Serum concentrations of luteinizing hormone, follicle-stimulating hormone, and estradiol concentrations ranged from 2.5 to 6.5 mIU/ml, 4.8-5.9 mIU/ml, and 47.9-133.0 pg/ml, respectively. Magnetic resonance imaging confirmed that CPP was caused by HH. Lesions were resected using a right pterional approach. After surgery, endocrine hormone concentrations were normalized, breasts shrunk, and menses ceased in each patient. Moreover, all of them subsequently developed normally and experienced age-appropriate onset of puberty. Each patient's height and weight were normal at the most recent follow-up (9-11 years after surgery), and none had experienced learning difficulties. Central precocious puberty due to HH can be successfully treated with resection. In the 3 cases presented, this approach was associated with both short- and long-term efficacy. 23863479 Tumor suppressor Nf2 limits expansion of the neural progenitor pool by inhibiting Yap/Taz transcriptional coactivators. Brain development requires a precise balance between expansion of the neural progenitor pool and the production of postmitotic neurons and glia. Disruption of this equilibrium results in a myriad of structural abnormalities and disorders of the nervous system. The molecular mechanism that restricts neural progenitor expansion is poorly understood. Here we show that the tumor suppressor neurofibromatosis 2 (Nf2; merlin) limits the expansion of neural progenitor cells (NPCs) in the mammalian dorsal telencephalon. Nf2 is localized at the apical region of NPCs. In the absence of Nf2, NPCs of the cortical hem, hippocampal primordium and neocortical primordium overexpand, while production of Cajal-Retzius cells and hippocampal neurons decreases, resulting in severe malformation of the hippocampus in adult mice. We further show that Nf2 functions by inhibiting the Yap/Taz transcriptional coactivators, probably through a mechanism that is distinct from the canonical Hippo pathway. Overexpressing human YAP in NPCs causes a hippocampal malformation phenotype that closely resembles that of Nf2 mutants and, importantly, deleting Yap in the Nf2 mutant background largely restores hippocampal development. Our studies uncover Nf2 as an important inhibitor of neural progenitor expansion and establish Yap/Taz as key downstream effectors of Nf2 during brain development. 23897376 Do not forget the contralateral side: late onset bilateral carotid dissecting aneurysms. Internal carotid artery dissection may occur spontaneously or following a blunt or penetrating trauma to the head and/or neck. Bilateral dissections and pseudoaneurysm formations are extremely rare and usually detected simultaneously. In this report, we present a trauma case with bilateral dissecting pseudoaneurysms of the carotid arteries; in whom, the one side was initially occult and then developed during the follow-up of the contralateral side. 23024227 Sports and exercise physicians as medical assessors. To clarify the role of sports and exercise physicians as medical assessors. Group discussion between senior doctors at a previous annual conference of the Australasian College of Sports Physicians, followed by further discussion between the authors. Clarification of the key requirements of insurers, and formulation of practical advice for those performing this work. Our expertise in performing medical assessments for the purpose of fitness to play sport is a transferable skill. It can also be used to provide medical assessments for injured workers. Our expertise in rehabilitation is also of value to insurers and other interested parties. The work is both challenging and rewarding, and can provide additional variety in the working week. 23880367 Arsenic trioxide induced endoplasmic reticulum stress in laryngeal squamous cell line Hep-2 cells. Arsenic trioxide (As2O3) has been used in the treatment of acute promyelocytic leukemia (APL) and many malignant solid tumors. Recently, endoplasmic reticulum (ER) stress plays an important role in As2O3-treated laryngeal squamous cell line Hep-2 cells. In the present work, the expression of ER stress-related proteins was investigated in As2O3-treated Hep-2 cells. The results showed that As2O3 increased the expression of GRP78, CHOP, phosphorylated eIF2α and ATF4, all of which are the molecule of ER stress. Therefore, As2O3 induced ER stress in Hep-2 cells. 23834276 Prevalence of gluten-free diet adherence among individuals without celiac disease in the USA: results from the Continuous National Health and Nutrition Examination Survey 2009-2010. Abstract Objectives. Clinical inference suggests the prevalence of non-celiac gluten sensitivity is substantially higher than that of celiac disease in the USA. Unfortunately, there are currently no data supporting these claims. The authors analyzed nationally representative data to estimate the prevalence of adherence to a gluten-free diet among participants without celiac disease and also to characterize the demographics and general health status of these participants. Study design and setting. The Continuous National Health and Nutrition Examination Survey (NHANES) 2009-2010 enrolled 7762 individuals representing the civilian, non-institutionalized, US population free of celiac disease. Participants responded to interviewer administered questionnaires regarding current adherence to a gluten-free diet. Prevalence estimates were computed using SAS survey procedures. Results. There were 49 individuals who reported current adherence to a gluten-free diet reflecting a weighted prevalence of 0.548% (95% CI 0.206-0.889). The prevalence of a gluten-free diet was higher in females (0.58%) than males (0.37%), although this was not statistically significant (p = 0.34). Participants reporting a gluten-free diet were older (46.6 vs. 40.5 years, p = 0.005), had higher high-density lipoprotein, lower iron and lower body mass index. Conclusions. The estimated national prevalence of non-celiac gluten sensitivity is 0.548%, approximately half that of celiac disease. Future studies are merited in order to better understand the population burden of non-celiac gluten sensitivity. 23639653 Pyrazole derivatives as inhibitors of arachidonic acid-induced platelet aggregation. Antiplatelet drugs are promising therapeutics to intervene with platelet aggregation in arterial thrombosis, most prominently in myocardial infarction and ischemic stroke. Here, we describe the synthesis and structure-activity relationships of potent inhibitors of platelet aggregation based on the 1,5-diarylpyrazol-3-carboxamide scaffold. Analogs from this series demonstrated potent anti-aggregatory activities against arachidonic acid-induced platelet aggregation, as measured by turbidimetric method of Born. 1,5-Diarylpyrazole-3-carboxamides obtained with small-basic amines (7, 8, 50, 51, 61, 62) displayed the strongest activity with IC50 values in low nanomolar range (5.7-83 nM). On the basis of their high potency in cellular environment, these straightforward pyrazole derivatives may possess potential in the design of more potent compounds for intervention with cardiovascular diseases. 23899286 Advancements in pancreatic neuroendocrine tumors. Pancreatic neuroendocrine tumors (PanNETs) have increased in incidence in the USA over the last 20 years. Although PanNETs are often misconceived as being indolent tumors as they have a far more favorable prognosis over pancreatic adenocarcinoma, roughly 60-70% of patients have metastatic disease at the time of diagnosis due to presentation late in the disease process. While improvements in imaging modalities allow for early detection and better tumor localization, recent advancements in basic science, as well as surgical and medical management of PanNETs have further improved the prognosis. The mainstay of therapy for localized PanNETs is surgical intervention, which has become safer and is slowly shifting towards a more minimally invasive approach. However, the prognosis still remains relatively bleak for patients with unresectable disease. Fortunately, novel molecular targeted therapies, such as everolimus and sunitinib, have recently come into the limelight and have shown significant promise for the treatment of locally advanced and metastatic disease. 23694991 Activation of BODIPY fluorescence by the photoinduced dealkylation of a pyridinium quencher. The photoinduced cleavage of a 2-nitrobenzyl group from a pyridinium quencher covalently attached to the meso position of a BODIPY fluorophore activates the emission of the latter. This photochemical transformation prevents the transfer of one electron from the BODIPY platform to its heterocyclic appendage upon excitation and, as a result, permits the radiative deactivation of the excited fluorophore. This versatile mechanism for fluorescence switching can translate into the realization of an entire family of photoactivatable fluorophores based on the outstanding photophysical properties of BODIPY chromophores. 23818128 Perineal trauma in women undergoing vaginal delivery following intra-uterine fetal demise: a case-control analysis. This study aimed to evaluate any differences in the incidence of perineal trauma in women undergoing vaginal delivery following intrauterine fetal death (IUFD) versus live-births. This information would be of interest in evaluating the possible effect of fetal demise on the mechanism of labour in the second stage and thus may provide invaluable insights to contribute to our understanding of the impact of fetal tone on the mechanics of labour and delivery. 323 women who delivered vaginally following IUFD were matched with 1,000 women with a live-birth for age, parity, gestation and birth weight. Women undergoing assisted vaginal delivery and/or episiotomy were excluded. Women with an IUFD had a significantly lower risk of perineal trauma overall (relative risk 0.16) as well as a lower risk of obstetric anal sphincter injury specifically (RR 0.12). Women delivering vaginally after IUFD have a lower incidence of perineal trauma compared with women delivering a live infant. This may be due to differences in biomechanics following an IUFD. 23459281 Pre-post pilot study of noise levels at a university hospital center pharmacy department. Context: Noise interferes with attention, speech understanding, detection of other auditory stimuli, and leads to interruptions. Objectives: This is a pre-post cross-sectional observational study aimed at measuring noise levels in a 500-bed mother-child university hospital center pharmacy department after the implementation of corrective measures, such as work zone reorganization, digitization of the prescription process, and education about the impact of some work habits. Results: A total of 24 measurement points (70 noise level measurements) were taken in 2007 (pre) compared to 30 measurement points (59 noise level measurements) in 2012 (post). There was a statistically significant difference in the average values of the day and night noise measurements (day 59.4 ± 5.3 dB(A) vs night 52.3 ± 8.0 dB(A); P < .001). There were no statistically significant differences in the average values of the noise measurements taken during daytime between the prestudy and poststudy phases (pre 59.4 ± 5.3 vs post 58.07 ± 6.01 dB(A); P = .22). Conclusion: Few data exist on the noise levels in hospital pharmacy departments. In spite of the corrective measures implemented, reducing noise levels in pharmacy departments was difficult to achieve. Average values of approximately 60 dB(A) seem to be unacceptable for work that requires a high level of attention. 23763365 Influence of Oxygenated Organic Aerosols (OOAs) on the Oxidative Potential of Diesel and Biodiesel Particulate Matter. Generally, the magnitude of pollutant emissions from diesel engines running on biodiesel fuel is ultimately coupled to the structure of the fuel's constituent molecules. Previous studies demonstrated the relationship between the organic fraction of particulate matter (PM) and its oxidative potential. Herein, emissions from a diesel engine running on different biofuels were analyzed in more detail to explore the role that different organic fractions play in the measured oxidative potential. In this work, a more detailed chemical analysis of biofuel PM was undertaken using a compact time of flight aerosol mass spectrometer (c-ToF AMS). This enabled a better identification of the different organic fractions that contribute to the overall measured oxidative potentials. The concentration of reactive oxygen species (ROS) was measured using a profluorescent nitroxide molecular probe 9-(1,1,3,3-tetramethylisoindolin-2-yloxyl-5-ethynyl)-10-(phenylethynyl)anthracene (BPEAnit). Therefore, the oxidative potential of the PM, measured through the ROS content, although proportional to the total organic content in certain cases, shows a much higher correlation with the oxygenated organic fraction as measured by the c-ToF AMS. This highlights the importance of knowing the surface chemistry of particles for assessing their health impacts. It also sheds light onto new aspects of particulate emissions that should be taken into account when establishing relevant metrics for assessing health implications of replacing diesel with alternative fuels. 23813886 T1 estimation for aqueous iron oxide nanoparticle suspensions using a variable flip angle SWIFT sequence. T1 quantification of contrast agents, such as super-paramagnetic iron oxide nanoparticles, is a challenging but important task inherent to many in vivo applications in magnetic resonance imaging. In this work, a sweep imaging with Fourier transformation using variable flip angles (VFAs-SWIFT) method was proposed to measure T1 of aqueous super-paramagnetic iron oxide nanoparticle suspensions. T1 values of various iron concentrations (from 1 to 7 mM) were measured using VFA-SWIFT and three-dimensional spoiled gradient-recalled echo with VFAs (VFA-SPGR) sequences on a 7 T MR scanner. For validation, T1 values were also measured using a spectroscopic inversion-recovery sequence on a 7 T spectrometer. VFA-SWIFT demonstrated its advantage for quantifying T1 of highly concentrated aqueous super-paramagnetic iron oxide nanoparticle suspensions, but VFA-SPGR failed at the higher end of iron concentrations. Both VFA-SWIFT and VFA-SPGR yielded linear relationships between the relaxation rate and iron concentrations, with relaxivities of 1.006 and 1.051 s(-1) mM(-1) at 7 T, respectively, in excellent agreement with the spectroscopic measurement of 1.019 s(-1) mM(-1) . VFA-SWIFT is able to achieve accurate T1 quantification of aqueous super-paramagnetic iron oxide nanoparticle suspensions up to 7 mM. Magn Reson Med 70:341-347, 2013. © 2013 Wiley Periodicals, Inc. 23557991 Stochastic models of transcription: From single molecules to single cells. Genes in prokaryotic and eukaryotic cells are typically regulated by complex promoters containing multiple binding sites for a variety of transcription factors leading to a specific functional dependence between regulatory inputs and transcriptional outputs. With increasing regularity, the transcriptional outputs from different promoters are being measured in quantitative detail in single-cell experiments thus providing the impetus for the development of quantitative models of transcription. We describe recent progress in developing models of transcriptional regulation that incorporate, to different degrees, the complexity of multi-state promoter dynamics, and its effect on the transcriptional outputs of single cells. The goal of these models is to predict the statistical properties of transcriptional outputs and characterize their variability in time and across a population of cells, as a function of the input concentrations of transcription factors. The interplay between mathematical models of different regulatory mechanisms and quantitative biophysical experiments holds the promise of elucidating the molecular-scale mechanisms of transcriptional regulation in cells, from bacteria to higher eukaryotes. 23902308 Examining the link between personality and laterality in a feral guppy Poecilia reticulata population. This study examined whether variation in the strength and direction of lateralization in a detour task was linked with variation in three common personality measurements: boldness, activity and sociability, in a population of wild guppies Poecilia reticulata. Additionally, the aim was to determine whether any consistent correlations between these behavioural traits, known as behavioural syndromes, were present in the study population. The results revealed that all three personality traits were highly repeatable over time in both sexes. Evidence of a complex syndrome in the form of a correlation between boldness, sociability and activity was found; however, this relationship was only present in males. Males that were more active in a familiar environment emerged more quickly from shelter into a novel environment and were more social. In general, male P. reticulata were bold, active and antisocial compared to females, with these differences probably a reflection of opposing life-history strategies. Only a weak link between the strength of cerebral lateralisation and personality was discovered and this was mediated by sex. 23508718 Relationship of Dehydroepiandrosterone Sulfate with Overweight and Insulin Sensitivity in 12-16-Year-old Spanish Children. DHEA-S is the most abundant steroid hormone in human circulation. Although a relationship of DHEA-S with obesity-related diseases has been reported, the metabolic role of this hormone remains unclear, particularly in children. In our study, we have investigated the relationship of DHEA-S levels with anthropometric variables, insulin, HOMA, and free fatty acids in adolescents. The study sample included 812 healthy 12-16-year-old children (383 boys and 429 girls). Plasma DHEA-S was determined by RIA, insulin concentrations by IRMA, and free fatty acids by using a commercial kit. Insulin resistance was estimated using the HOMA index. No significant differences in plasma DHEA-S levels were found between sexes. DHEA-S levels in overweight children were significantly higher than in normal-weight children. DHEA-S levels were significantly correlated with weight and BMI after adjusting for age. Significant positive correlations between DHEA-S and free fatty acids levels were found after adjusting for age and BMI, particularly in boys, but not between DHEA-S levels and insulin or HOMA in either gender. DHEA-S levels in 12-16-year-old children are correlated with weight and BMI independently of age. We failed to find any association between DHEA-S and insulin levels, but we did find a -significant correlation between DHEA-S and free fatty acids levels, suggesting that its association with free fatty acids may be related to the onset of the association of DHEA-S with insulin resi-stance. 22818713 Silibinin protects H9c2 cardiac cells from oxidative stress and inhibits phenylephrine-induced hypertrophy: potential mechanisms. Cardiac hypertrophy is the main response of the heart to various extrinsic and intrinsic stimuli, and it is characterized by specific molecular and phenotypic changes. Recent in vitro and in vivo studies indicate the involvement of reactive oxygen species in the hypertrophic response. In this study, silibinin, a plant flavonolignan extracted from milk thistle with potent antioxidant activity, was evaluated for its effects in (a) preventing hydrogen peroxide (H2O2)-induced cellular damage and (b) blocking the phenylephrine-induced hypertrophic response. Using the in vitro model of embryonic rat heart-derived H9c2 cells, we showed that silibinin has a rather safe profile as concentrations up to 200μM did not affect cell viability. Pretreatment of H9c2 cells with silibinin resulted in better protection of H9c2 cells under conditions of H2O2-induced cellular stress compared to untreated cells as indicated by cell viability and DNA fragmentation assays. Furthermore, silibinin attenuated the phenylephrine-induced hypertrophic response as evidenced by the measurement of cell surface, up-regulation of atrial natriuretic peptide and increase of cellular protein levels. Moreover, silibinin repressed the phenylephrine-induced phosphorylation of ERK1/2 kinases, while it appeared to inhibit the weakly activated by phenylephrine phosphorylation of Akt. Based on our results, silibinin may attenuate the phenylephrine-induced hypertrophic response of H9c2 cells via antioxidant mechanisms involving mainly the inhibition of the intracellular signaling pathways mediated by ERK1/2 MAPKs and Akt. 23512986 Cytosolic proteins lose solubility as amyloid deposits in a transgenic mouse model of Alzheimer-type amyloidosis. The extracellular accumulation of β-amyloid peptide is a key trigger in the pathogenesis of Alzheimer's disease (AD). In humans, amyloid deposition precedes the appearance of intracellular inclusion pathology formed by cytosolic proteins such as Tau, α-synuclein and TDP-43. These secondary pathologies have not been observed in mice that model Alzheimer-type amyloidosis by expressing mutant amyloid precursor protein, with or without mutant presenilin 1. The lack of secondary pathology in these models has made it difficult to establish how amyloid deposition initiates the cascade of events that leads to secondary intracellular pathology that characterizes human AD. In transgenic mice that model Alzheimer-type amyloidosis, we sought to determine whether there is evidence of altered cytosolic protein folding by assessing whether amyloid deposition causes normally soluble proteins to misfold. Using a method that involved detergent extraction and sedimentation coupled with proteomic approaches, we identified numerous cytosolic proteins that show specific losses in solubility as amyloid accumulates. The proteins identified included glycolytic enzymes and members of the 14-3-3 chaperone family. A substantial accumulation of lysine 48-linked polyubiquitin was also detected. Overall, the data demonstrate that the accumulation of amyloid by some manner causes the loss of solubility intracellular cytosolic proteins. 23474212 Pre-clinical studies in cough research: Role of Transient Receptor Potential (TRP) channels. Cough is a protective reflex and defence mechanism in healthy individuals, which helps clear excessive secretions and foreign material from the lungs. Cough often presents as the first and most persistent symptom of many respiratory diseases and some non-respiratory disorders, but can also be idiopathic, and is a common respiratory complaint for which medical attention is sought. Chronic cough of various aetiologies is a regular presentation to specialist respiratory clinics, and is reported as a troublesome symptom by a significant proportion of the population. Despite this, the treatment options for cough are limited. The lack of effective anti-tussives likely stems from our incomplete understanding of how the tussive reflex is mediated. However, research over the last decade has begun to shed some light on the mechanisms which provoke cough, and may ultimately provide us with better anti-tussive therapies. This review will focus on the in vitro and in vivo models that are currently used to further our understanding of the sensory innervation of the respiratory tract, and how these nerves are involved in controlling the cough response. Central to this are the Transient Receptor Potential (TRP) ion channels, a family of polymodal receptors that can be activated by such diverse stimuli as chemicals, temperature, osmotic stress, and mechanical perturbation. These ion channels are thought to be molecular pain integrators and targets for novel analgesic agents for the treatment of various pain disorders but some are also being developed as anti-tussives. 23565354 New photostabilizers for polystyrene based on 2,3-dihydro-(5-mercapto-1,3,4-oxadiazol-2-yl)-phenyl-2-(substituted)-1,3,4-oxazepine- 4,7-dione compounds. The photostabilization of polystyrene (PS) films by 2,3-dihydro-(5-mercapto-1,3,4-oxadiazol-2-yl)-phenyl-2-(substituted)-1,3,4-oxazepine-4,7-dione compounds was investigated. PS films containing concentration of complexes 0.5% by weight were produced by the casting method from chloroform as a solvent. The photostabilization activities of these compounds were determined by monitoring the carbonyl and hydroxyl indices with irradiation time. The changes in viscosity average molecular weight of PS with irradiation time were also tracked (using benzene as a solvent). The quantum yield of the chain scission (Φcs) of these complexes in PS films was evaluated and found to range between 3.31 × 10(-6) and 7.89 × 10(-6). Results obtained showed that the rate of photostabilization of PS in the presence of the additive follows the trend (I > II > III > IV). According to the experimental results obtained, several mechanisms were suggested depending on the structure of the additive like UV absorption, peroxide decomposer and radical scavenger. 23702251 A longitudinal study of SLC6A4 DNA promoter methylation and poststroke depression. Serotonin transporter gene (SLC6A4) has been shown to play an important role in the pathophysiology of mood disorders including poststroke depression (PSD). SLC6A4 expression is influenced by DNA methylation status and the SLC6A4 linked promoter region (5-HTTLPR) polymorphism. This study aimed to investigate whether SLC6A4 methylation status was associated with depression ascertained at two weeks and one year after stroke taking into account the 5-HTTLPR polymorphism. A total of 286 patients were evaluated two weeks after stroke, and 222 (78%) were followed one year later. Depression was diagnosed according to DSM-IV criteria, and depression severity was assessed by the Hamilton Depression Rating Scale (HAMD) at each evaluation point. The effects of SLC6A4 methylation status on PSD status and HAMD scores were investigated using multivariate logistic regression models and partial correlation tests, respectively. Analyses were repeated after stratification by 5-HTTLPR genotype groups ('l/l or l/s' and 's/s'). Higher SLC6A4 promoter methylation status was independently associated with PSD both at 2 weeks and more prominently at 1 year after stroke, and was significantly associated with the worsening of depressive symptoms over one year. These findings were significant only in the presence of the 5-HTTLPR s/s genotype. SLC6A4 methylation profile was supported as a potential diagnostic and prognostic biomarker for PSD; associations with SLC6A4 methylation status may represent a target for drug development. 23949276 FIENS Global Health and Neurosurgical Volunteerism. : This is a short prospectus about FIENS, the Foundation for International Education in Neurological Surgery. We would like to give general neurosurgery an idea of FIENS global health and the spirit of neurosurgical involvement. 23604335 Automatic approach bias towards smoking cues is present in smokers but not in ex-smokers. RATIONALE: Drug-addicted individuals show automatic approach tendencies towards drug-related cues, i.e., an approach bias (ApB). Nevertheless, little is known about ApB in tobacco smokers and about the presence of ApB after smoking abstinence. OBJECTIVES: We investigated ApB to smoking cues in heavy tobacco smokers versus never-smokers and studied its relation to smoking characteristics and craving. Second, we compared ApBs of heavy smokers with biases of abstinent heavy smokers. METHOD: A group of current heavy smokers (n = 24), ex-smokers who were abstinent for at least 5 years (n = 20), and never-smokers (n = 20) took part in the experiment. An indirect smoking approach avoidance task was performed, in which participants were required to respond to pictures of smoking and neutral cues by pulling (approach) or pushing (avoid) on a joystick, according to the content-irrelevant format of the picture (landscape or portrait). Craving scores were examined using the Questionnaire of Smoking Urges. RESULTS: Heavy smokers showed an ApB for smoking cues compared to ex-smokers and never-smokers, which correlated positively to craving scores. There were no group differences in ApB scores for ex-smokers and never-smokers. CONCLUSION: These results suggest that ApBs for smoking cues are present in heavy smokers and decrease after long-term successful smoking cessation. 23847003 Efficient and Stable Deep-Red Phosphorescent Organic Light-Emitting Diodes Based on an Iridium Complex Containing a Benzoxazole-substituted Ancillary Ligand. In the deep red: A biscyclometalated deep-red phosphorescent dopant containing a new ancillary ligand, iridium(III) bis(1-phenylisoquinolinato-N,C(2) ') (2-(benzo[d]oxazol-2-yl)phenol) (Ir(piq)2 bop) has been designed and synthesized. By doping the new complex into Bebq2 (Bebq2 =bis(10-hydroxybenzo[h] quinolinato)beryllium), a saturated red-emitting PHOLED device was obtained. At a luminescence of 100 cd m(-2) , the device shows efficiencies of 10.3 cd A(-1) and 9.1 Lm W(-1) with CIE coordinates of (0.67, 0.33). 23432475 Mitochondria and metabolic homeostasis. Mitochondrial function is fundamental to metabolic homeostasis. In addition to converting the nutrient flux into the energy molecule ATP, the mitochondria generate intermediates for biosynthesis and reactive oxygen species (ROS) that serve as a secondary messenger to mediate signal transduction and metabolism. Alterations of mitochondrial function, dynamics, and biogenesis have been observed in various metabolic disorders, including aging, cancer, diabetes, and obesity. However, the mechanisms responsible for mitochondrial changes and the pathways leading to metabolic disorders remain to be defined. In the last few years, tremendous efforts have been devoted to addressing these complex questions and led to a significant progress. In a timely manner, the Forum on Mitochondria and Metabolic Homeostasis intends to document the latest findings in both the original research article and review articles, with the focus on addressing three major complex issues: (1) mitochondria and mitochondrial oxidants in aging-the oxidant theory (including mitochondrial ROS) being revisited by a hyperfunction hypothesis and a novel role of SMRT in mitochondrion-mediated aging process being discussed; (2) impaired mitochondrial capacity (e.g., fatty acid oxidation and oxidative phosphorylation [OXPHOS] for ATP synthesis) and plasticity (e.g., the response to endocrine and metabolic challenges, and to calorie restriction) in diabetes and obesity; (3) mitochondrial energy adaption in cancer progression-a new view being provided for H(+)-ATP synthase in regulating cell cycle and proliferation by mediating mitochondrial OXPHOS, oxidant production, and cell death signaling. It is anticipated that this timely Forum will advance our understanding of mitochondrial dysfunction in metabolic disorders. 23713989 The role of Cnidaria in drug discovery. A review on CNS implications and new perspectives. Many organisms produce bioactive substances used in the production of drugs. In this context, Cnidaria occupy a major position; for this reason, research on new bioactive substances has focused upon them as an interesting target. As a matter of fact, substances and extracts able to fight human diseases have been found in cnidarians, several of which have been studied in laboratories using animal models or cell cultures and, at present, some are in the pre-clinical phase. This review aims to highlight the research on existing drugs or new drug candidates extracted from Cnidaria and the recent patents published in this field; furthermore, as many cnidarian venoms are known to have an impact on the CNS and on neuromuscular transmission, this review particularly considers the research concerning CNS drug discovery and pending patents. 23489555 Effects of antihypertensive and triglyceride lowering agents on splenocyte apoptosis in rats with Fatty liver. Individuals with the metabolic syndrome (MS) and non-alcoholic fatty liver disease (NAFLD) have an increased incidence of infection and infection-related mortality. Rats given fructose-enriched diet (FED) develop the MS including NAFLD. In this study, we characterized changes in splenocyte apoptosis in FED rats given medications to treat various components of the MS. Apoptosis of splenocytes may induce immunosuppression. Splenocyte apoptosis was evaluated by activated caspase-3 immunohistochemistry in the periarterial sheath (PALS), (a T cell area), follicles (B cell area), marginal (B cell area) and in the red pulp zones. FED administration caused an enormous increase in splenocyte apoptosis in all of the spleen zones: PALS (+2966%), follicles (+3025%), marginal (+5228%) and red pulp (+7000%). Administration of captopril to the FED rats was associated with a further increase in the splenocyte apoptosis only in the marginal (150%), PALS (+105%) and red pulp (+67%) zones. Bezafibrate administration to the FED rats was associated with no further increase in apoptosis rates. Amlodipine administration to the FED rats was associated with almost complete amelioration of the splenocyte apoptosis that was induced by the FED diet. These pharmacological manipulations were also associated with changes in the hepatic lipids composition, and oxidative milieu that did not correlate to the changes in splenocyte apoptosis. NAFLD in FED rats is associated with an increase in splenic apoptosis. Agents administered to treat components of the MS in FED rats may lead to divergent changes in the splenic histology and splenocyte apoptosis. 23888243 Recurrent Gastrointestinal Hemorrhage in Treatment with Dasatinib in a Patient Showing SMAD4 Mutation with Acute Lymphoblastic Leukemia Philadelphia Positive and Juvenile Polyposis Hereditary Hemorrhagic Telangiectasia Syndrome. We report a case of a patient affected by juvenile polyposis and hereditary hemorrhagic telangiectasia linked to a SMAD4 mutation who developed acute lymphoblastic leukemia positive for the Philadelphia chromosome translocation and with a complex karyotype. During the treatment with the tyrosine kinase inhibitor dasatinib the patient presented recurrent severe gastrointestinal hemorrhages linked to the genetic background and aggravated by thrombocytopenia. 23711379 Production and characterization of highly purified recombinant thymosin beta 4 in Escherichia coli. Thymosin β4 (Tβ4) is a small peptide composed of 43 amino acids. It has many important biological functions, such as promoting cardiac repair and wound healing, and therefore has great potential in clinical applications. In this report, we describe a novel and efficient way to produce highly purified and active Tβ4. It was expressed in a soluble form using a DsbA and hexahistindine tag in Escherichia coli (E. coli). Using high cell density cultivation, the final biomass concentration was about 50gL(-1) dry cell weight with the expression level of the fusion protein being 40%. To obtain highly purified protein, a purification process involving a five-step column procedure was implemented. The purity of Tβ4 was above 98% and all the host cell related impurities, such as endotoxin, host cell protein and residual DNA levels, were within the permissible range listed in the Chinese Pharmacopoeia. The E-rosette test demonstrated that the bioactivity of purified Tβ4 was consistent with other published work. This is the first report producing highly purified Tβ4 from genetically engineered sources. 23824324 Diabetes mellitus associated with clomipramine treatment: a retrospective analysis. In this retrospective analysis, we analyzed all clinical record data in our Medical Division between January 2005 and December 2006 to evaluate an association between clomipramine treatment and glucose intolerance. Of 1997 patients, 154 (7.7 %) had diabetes and 525 (26.3 %) had depression. Diabetes prevalence was significantly higher in patients treated with clomipramine than in patients not treated [odds ratio 3.9, (2.2-7.0), p < 0.00001], independently by age and BMI. A possible causal role needs to be investigated in a prospective way. 23907576 Prognostic significance of VEGF expression in osteosarcoma: a meta-analysis. Vascular endothelial growth factor (VEGF) is considered as a prime mediator of angiogenesis and has been implicated in carcinogenesis and metastasis. Various studies examined the relationship between VEGF overexpression with the clinical outcome in patients with osteosarcoma but yielded conflicting results. Electronic databases updated to April 2013 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between VEGF overexpression and survival of patients with osteosarcoma. Survival data were aggregated and quantitatively analyzed. We performed a meta-analysis of eight studies that evaluated the correlation between VEGF overexpression and survival in patients with osteosarcoma. Combined hazard ratios suggested that VEGF overexpression had an unfavorable impact on overall survival (hazard ratio (HR) = 1.75, 95 % confidence interval (CI): 1.21-2.28) in patients with osteosarcoma for overall populations, 2.37 (1.35-3.39) in Asian studies but not in non-Asian studies (HR = 1.51, 95 % CI: 0.89-2.14). No significant heterogeneity was observed among all studies. VEGF overexpression indicates a poor prognosis for patients with osteosarcoma. However, the prognostic value of VEGF on survival in osteosarcoma patients still needs further large-scale prospective trials to be clarified. 23617758 Rationale for the higher reactivity of interfacial sites in methanol decomposition on Au13/TiO2(110). Interfacial and perimeter sites have been known for their high activity in various reactions on supported gold nanoparticles. We find that the higher activity of interfacial sites in Au13/TiO2(110) towards methanol decomposition originates from charge-transfer-induced Coulomb interaction among the gold, reactant, and reducible TiO2 support, brought about through the formation of an ionic O-Au bond between gold and methoxy in such sites, which turns the participating perimeter gold atom cationic. A direct result of such charge-transfer-induced repulsive interaction between cationic gold and positively charged C moiety of methoxy is activation of the positively charged C moiety of methoxy, as manifested by the pronounced elongation of O-C bond length and the tilting of the methoxy axis, which facilitate reaction of methoxy through C-H scission with the bridge oxygen atoms that are readily available from the reducible support. More generally, our proposed mechanism for the reactivity of the gold/TiO2 interface should hold for oxidation of organic molecules with the structure of R-O-R', where R and R' are (saturated) hydrocarbons. 23959435 Low-temperature plasma synthesis of carbon nanotubes and graphene based materials and their fuel cell applications. Carbon nanotubes (CNTs) and graphene, and materials based on these, are largely used in multidisciplinary fields. Many techniques have been put forward to synthesize them. Among all kinds of approaches, the low-temperature plasma approach is widely used due to its numerous advantages, such as highly distributed active species, reduced energy requirements, enhanced catalyst activation, shortened operation time and decreased environmental pollution. This tutorial review focuses on the recent development of plasma synthesis of CNTs and graphene based materials and their electrochemical application in fuel cells. 23780720 Inhibition of tumor formation and redirected differentiation of glioblastoma cells in a xenotypic embryonic environment. Background: Tissue microenvironment plays key roles in regulating the progression of aggressive tumors. Tumors are uncommon in the early embryo, suggesting that embryonic tissue microenvironments are nonpermissive for tumors. Yet, the effects of embryonic tissue microenvironments on tumor cells have not been extensively studied. We have, therefore, tested the behavior of human glioblastoma multiforme (GBM) cells transplanted into a central neural tissue microenvironment in the chicken embryo. Results: GBM cells were cultured as spheres to enrich for GBM stem cells (GSCs) and transduced with GFP for identification. Within the proliferative embryonic neural tissue, GSC-enriched GBM cells exhibited reduced proliferation and survival, altered gene expression, and formed no tumors, in marked contrast to their aggressive behavior in vitro and tumor formation in other tissue microenvironments including the chorioallantoic membrane of the chicken embryo and the brain of adult severe combined immunodeficiency (SCID) mice. Surviving cells in the spinal neural tube exhibited tumor-atypical expression profiles of neuron-, glia-, stem cell-, and tumor-related genes. Conclusions: Embryonic neural tissue provides a poor environment for GBM cell survival and tumor formation, and redirects differentiation toward a more benign phenotype. Understanding the anti-tumorigenic effects of this embryonic tissue microenvironment could provide opportunities to develop novel therapies for GBM treatment. Developmental Dynamics 242:1078-1093, 2013. © 2013 Wiley Periodicals, Inc. 23710568 Standardization and cross validation of alloreactive IFNγ ELISPOT assays within the clinical trials in organ transplantation consortium. Emerging evidence indicates memory donor-reactive T cells are detrimental to transplant outcome and that quantifying the frequency of IFNγ-producing, donor-reactive PBMCs by ELISPOT has potential utility as an immune monitoring tool. Nonetheless, differences in assay performance among laboratories limit the ability to compare results. In an effort to standardize assays, we prepared a panel of common cellular reagent standards, developed and cross validated a standard operating procedure (SOP) for alloreactive IFNγ ELISPOT assays in several research laboratories supported by the NIH-funded Clinical Trials in Organ Transplantation (CTOT) Consortium. We demonstrate that strict adherence to the SOP and centralized data analysis results in high reproducibility with a coefficient of variance (CV) of ≈ 30%. This standardization of IFNγ ELISPOT assay will facilitate interpretation of data from multicenter transplantation research studies and provide the foundation for developing clinical laboratory testing strategies to guide therapeutic decision-making in transplant patients. 23918896 Blood Cultures in the Evaluation of Uncomplicated Skin and Soft Tissue Infections. BACKGROUND Blood cultures are often obtained in children hospitalized with skin and soft tissue infections (SSTIs). Because little evidence exists to validate this practice, we examined the yield of blood cultures in the evaluation of immunocompetent children with SSTIs.METHODS:Medical records were reviewed for all children admitted between January 1, 2007 and December 31, 2009 after emergency department evaluation and diagnosis of cellulitis or abscess. We compared patients with SSTIs (n = 482) with those with complicated SSTIs (cSSTIs; n = 98). A cSSTI was defined as surgical or traumatic wound infection, need for surgical intervention, or infected ulcers or burns. The SSTI group included patients without complicating factors.RESULTS:None of the patients in the SSTI group had a positive blood culture. In the cSSTI group, 12.5% of blood cultures were positive. The mean length of hospital stay (LOHS) of children with SSTIs was shorter than that of those with cSSTIs (P < .001). In the SSTI group, obtaining a blood culture was associated with a higher mean LOHS (P = .044).CONCLUSIONS:Blood cultures are not useful in evaluating immunocompetent children who are admitted to the hospital with uncomplicated SSTIs, and they are associated with a nearly 1-day increase in mean LOHS. 23348408 Anti-inflammatory activity of patchouli alcohol in RAW264.7 and HT-29 cells. Patchouli alcohol (PA) is a chemical compound extracted from patchouli which belongs to the genus Pogostemon, herb of mint family. Recently, it has been reported that PA inhibits the production of inflammatory mediators. However, the biological mechanisms of PA for anti-inflammatory activities have not been studied. In this study, we investigated whether PA decreases the production of inflammatory mediators through downregulation of the NF-κB and ERK pathway. Our data indicated that PA inhibits the over-expression of iNOS and IL-6 in protein and mRNA levels in LPS-stimulated RAW264.7 and TNF-α stimulated HT-29 cells. PA inhibited IκB-α degradation and p65 nuclear translocation, and subsequently suppressed transcriptional activity of NF-κB in LPS-stimulated RAW264.7 and TNF-α-stimulated HT-29 cells. In addition, PA inhibited LPS- or TNF-α-stimulated ERK1/2 activation by decreasing phosphorylation of ERK1/2. These findings suggest that PA shows anti-inflammatory activities through suppressing ERK-mediated NF-κB pathway in mouse macrophage and human colorectal cancer cells. 23835101 Hyperthymic temperament and brightness preference in healthy subjects: Further evidence for involvement of left inferior orbitofrontal cortex in hyperthymic temperament. Hyperthymic temperament has been generally accepted as one of premorbid temperament of bipolar disorders. Although several studies indicate that subjects with hyperthymic temperament receive more illuminance, our recent study suggests that the threshold of brightness and darkness judgment is not different between more and less hyperthymic subjects, and that hyperthymic temperament may be associated with left inferior orbitofrontal cortex, which has been reported to be associated with bipolar disorder. Therefore, at the next stage, it can be hypothesized that hyperthymic subjects may prefer brightness (i.e., heliotropism) and thereby seek illuminance, and that percent signal changes of left inferior orbitofrontal cortex during the preference task may be associated with hyperthymic temperament scores. We compared brightness preference and un-preference between more and less hyperthymic subjects, and investigated percent signal changes of left inferior orbitofrontal cortex during brightness preference judgment, brightness un-preference judgment, and control task by using functional Magnetic Resonance Imaging (fMRI). There were significant differences in brightness preference judgment and un-preference judgment, showing that more hyperthymic subjects preferred brighter illuminace levels and un-preferred darker illuminance levels than less hyperthymic subjects. Moreover, fMRI signal changes of left inferior orbitofrontal cortex was significantly and negatively associated with hyperthymic temperament scores. It is unknown why left but not right inferior orbitofrontal cortex was associated with hyperthymic temperament scores. The present findings suggest that more hyperthymic subjects may prefer brightness and un-prefer darkness than less hyperthymic subjects (i.e., heliotropism), and reconfirm that hyperthymic temperament may be associated with left inferior orbitofrontal cortex, which have been reported to be associated with bipolar disorders. 23058474 Dendritic arbor of neurons in the hypothalamic ventromedial nucleus in female prairie voles (Microtus ochrogaster). Female mating behavior in rats is associated with hormone-induced changes in the dendritic arbor of neurons in the ventromedial nucleus of the hypothalamus (VMH), particularly the ventrolateral portion. Regulation of mating behavior in female prairie voles differs substantially from that in rats; therefore, we examined the dendritic morphology of VMH neurons in this species. Sexually naïve adult female prairie voles were housed with a male to activate the females' reproductive endocrine system. Following 48 h of cohabitation, females were tested for evidence of reproductive activation by assessing the level of male sexual interest, after which their brains were processed using Golgi impregnation, which allowed ventrolateral VMH neurons to be visualized and analyzed. Dendritic arborization in the female prairie vole VMH neurons was strikingly similar to that of female rats. The key difference was that in the prairie voles the long primary dendrites extended considerably further than those observed in rats. Although most female voles paired with males exhibited sexual activation, some females did not. These two groups displayed specific differences in their VMH dendrites. In particular, the long primary dendrites were longer in the reproductively active females compared with those in the non-activated females. Overall, dendrite lengths were positively correlated with plasma estradiol levels in females exposed to males, but not in unpaired females. Although causal relationships between the neuroendocrine events, dendrite length, and the outward, behavioral manifestation of reproductive activation cannot be determined from this study, these results suggest an association between ventrolateral VMH dendrite morphology and female mating behavior in prairie voles, akin to what has been observed in female rats. 23279120 Self-management intervention to improve self-care and quality of life in heart failure patients. Self-management intervention is a good method to improve self-care ability, as such, to promote quality of life. However, the research focused on self-management intervention in heart failure patients in Taiwan is very limited. Therefore, the purposes of this study were to test the effectiveness of self-management intervention in patients with heart failure in Taiwan and examine the relationship between self-care ability and quality of life. A quasi-experimental design was used in this study with convenience sampling. Of the 82 subjects participating in this study, 40 of them chose to join the experimental (self-management intervention plus usual care) and 42 of them chose to join control (usual care) group. Three questionnaires were used to collect the data, which were the demographic questionnaire, the self-care questionnaire (Self-Care of HF Index V 6), and the quality of life questionnaire (Minnesota Living with Heart Failure Questionnaire). To examine the effectiveness of the intervention, self-care ability and quality of life were measured, using a pretest, 1- and 2-month follow-up assessment. Generalized estimation equations (GEE) were used to compare changes over time among groups for outcomes to ensure the effectiveness of the intervention. This study confirmed the effectiveness of the self-management intervention. The clinical provider should increase the awareness of the importance of self-management skills and self-care ability especially for heart failure patients. The designated disease-specific self-management patient book and individualize intervention should be dispensing and implementing. 23545343 Reclamation of copper-contaminated soil using EDTA or citric acid coupled with dissolved organic matter solution extracted from distillery sludge. Soil washing using a strong chelating agent is a common practice for restoring contaminated soils, but significant soil fertility degradation and high operation costs are the major disadvantages. Washing soil with a dissolved organic matter (DOM) solution has been identified as a method that can moderate the loss of nutrients in the soil and enhance metal removal. The DOM solutions were extracted from waste sludge obtained from a local whisky distillery. Single chelating washing and chelate-DOM washing were carried out using ethylenediaminetetraacetic acid (EDTA), citric acid, and DOM solutions to remediate highly Cu-contaminated soil. Two-phase washing using 0.34 M citric acid and then 1500 mg L(-1) DOM solution (pH 8.5) was found to be most favorable for the soil. With this treatment, 91% Cu was removed from the topsoil; the organic matter, cation exchange capacity, plant-available nitrogen, and available phosphate content increased by 28.1%, 103%, 17.7%, and 422%, respectively. 23839314 Functional probe for annulus fibrosus-targeted intervertebral disc degeneration imaging. ABSTRACT. Intervertebral disc degeneration (IDD) is closely associated with low back pain. Typically nonsurgical treatment of IDD is the most effective when detected early. As such, establishing reliable imaging methods for the early diagnosis of disc degeneration is critical. The cellular and tissue localization of a facile functional fluorescent probe, HYK52, that labels disc annulus fibrosus is reported. HYK52 was synthesized with high yield and purity via a two-step chemical reaction. Rabbit disc cell studies and ex vivo tissue staining images indicated intracellular localization and intervertebral disc (IVD) tissue binding of HYK52 with negligible cytotoxicity. Moreover, HYK52 is purposefully designed with a functional terminal carboxyl group to allow for coupling with various signaling molecules for multimodal imaging applications. These results suggest that this IVD-targeted probe may have great potential in early diagnosis of IDD. 23860179 Factors Related to Positive Mental Health in a Stigmatized Minority: An Investigation of Older Gay Men. This study investigates factors related to the positive mental health of older Australian gay men, who are challenged by both age- and sexuality-related stigma. A national online survey was conducted among 422 gay-identified men aged 40 years and older. Positive mental health was measured using the Short Warwick-Edinburgh Mental Well-being Scale (SWEMWBS). Regression analyses revealed men were psychologically healthier if they were employed full-time, had a higher income, were in a relationship, received greater social support, had many close friends, felt connected to the gay community, believed the public felt positively toward their group, and had not experienced discrimination in the past year. A multivariate linear regression found social support to be the most important of all these factors, with support from friends particularly critical. These findings provide new guidance to health agencies that seek to improve the mental health and well-being of older gay men. 23680850 The association between caesarean section and childhood obesity revisited: a cohort study. The mode of delivery has recently gained attention as another potential perinatal risk factor for childhood obesity but results are conflicting. To examine whether caesarean section is independently associated with childhood obesity after adjusting for a broad range of confounding factors. The current study used a population-based survey in Grade 5 students linked to a provincial perinatal registry in the Canadian province of Nova Scotia. Associations between caesarean section and childhood overweight and obesity at age 10/11 years were examined using multiple logistic regression. Of the 4298 students who participated in the 2003 Children's Lifestyle and School Performance Study (response rate 51.1%), 3426 (80%) could be linked with information in the Atlee Perinatal Database, and 2988 mother-child pairs (70%) had complete information on the exposure and outcome. Compared to vaginal delivery, caesarean section was associated with offspring obesity (OR) 1.49, 95% CI 1.10 to 2.00) in the univariate analysis. After adding maternal prepregnancy weight to the multiple regression model, the OR for obesity dropped from 1.48 to 1.20 (95% CI 0.87 to 1.65). When caesarean section with and without labour were considered separately, we found no statistically significant associations relative to the vaginal delivery group (OR 1.24, 95% CI 0.84 to 1.82 and OR 1.03, 95% CI 0.58 to 1.84). Our results do not support a causal association between caesarean section and childhood obesity. Maternal prepregnancy weight was an important confounder in the association between caesarean delivery and childhood obesity and needs to be considered in future studies. 23897478 Structures of purine nucleosidase from Trypanosoma brucei bound to isozyme-specific trypanocidals and a novel metalorganic inhibitor. Sleeping sickness is a deadly disease that primarily affects sub-Saharan Africa and is caused by protozoan parasites of the Trypanosoma genus. Trypanosomes are purine auxotrophs and their uptake pathway has long been appreciated as an attractive target for drug design. Recently, one tight-binding competitive inhibitor of the trypanosomal purine-specific nucleoside hydrolase (IAGNH) showed remarkable trypanocidal activity in a murine model of infection. Here, the enzymatic characterization of T. brucei brucei IAGNH is presented, together with its high-resolution structures in the unliganded form and in complexes with different inhibitors, including the trypanocidal compound UAMC-00363. A description of the crucial contacts that account for the high-affinity inhibition of IAGNH by iminoribitol-based compounds is provided and the molecular mechanism underlying the conformational change necessary for enzymatic catalysis is identified. It is demonstrated for the first time that metalorganic complexes can compete for binding at the active site of nucleoside hydrolase enzymes, mimicking the positively charged transition state of the enzymatic reaction. Moreover, we show that divalent metal ions can act as noncompetitive IAGNH inhibitors, stabilizing a nonproductive conformation of the catalytic loop. These results open a path for rational improvement of the potency and the selectivity of existing compounds and suggest new scaffolds that may be used as blueprints for the design of novel antitrypanosomal compounds. 23911293 Evaluation of the TRCRtest NV-W for norovirus detection in stools by the Transcription-Reverse Transcription Concerted method. A novel molecular assay, TRCRtest NV-W, based on a transcription-reverse transcription concerted reaction (TRC) for isothermal amplification and real-time detection of norovirus in stools was assessed and compared with an RT-nPCR. Archived stools positive for either different types or variants of norovirus genogroups I and II or other enteric viruses were used to assess the sensitivity and specificity of the novel assay. The TRC assay was 100% specific since it detected all the noroviruses tested and it did not display cross reactivity with other enteric viruses. When screening a collection of 387 stools with the TRC and RT-nPCR assays, the TRC displayed concordance, sensitivity, specificity, positive and negative predictive values of 96.6%, 81%, 99.7%, 98.1%, and 96.3%, respectively, after retesting the negative specimens. Additional PCRs and/or sequencing, used to understand inconsistent results between TRC and RT-nPCR, confirmed all positive results and did not reveal nucleotide variations in the TRC probe and primers binding sites. The TRC assay may be a rapid and ease of use tool for the detection of noroviruses in clinical virology laboratories even in the face of rapidly evolving noroviruses. 23924073 Merely Misunderstood? Receptive, Expressive, and Pragmatic Language in Young Children With Disruptive Behavior Disorders. Children with disruptive behavior disorders (DBDs) often seem to have poorer language skills compared to same-age peers; however, language as an early risk factor for DBD has received little empirical attention. The present study provides an empirical examination of associations between normal language variation and DBD by investigating receptive, expressive, and pragmatic language skills and preschool DBD symptoms. The sample consisted of 109 preschoolers ages 3 to 6 (M = 4.77 years, SD = 1.10, 59% boys; 73% with DBD, including oppositional defiant disorder [ODD] and attention-deficit/hyperactivity disorder [ADHD]) along with their primary caregivers, who completed a clinician-administered interview, symptom questionnaires, and a questionnaire measure of pragmatic language, and teacher and/or daycare providers completed symptom questionnaires. Children completed objective tests of receptive and expressive vocabulary. Preschoolers with DBD showed poorer receptive, expressive, and pragmatic skills compared to preschoolers without DBD. Preschoolers with ADHD-only or ADHD+ODD exhibited poorer language skills, compared to ODD and non-DBD groups. Specificity analyses suggested that parent-rated hyperactivity-impulsivity were particularly associated with poorer language skills. Thus, preschoolers with DBD exhibited poorer language skills compared to preschoolers without DBD, and preschoolers with increased hyperactivity-impulsivity exhibited particular problems with language skills. This work suggests the need for early assessment of language in preschoolers, particularly those with ADHD, as well as the possible utility of tailored interventions focused on improving language skills, particularly for those with high hyperactivity-impulsivity. 23207887 Positive Effects of Augmented Verbal Feedback on Power Production in NCAA Division I Collegiate Athletes. Staub, JN, Kraemer, WJ, Pandit, AL, Haug, WB, Comstock, BA, Dunn-Lewis, C, Hooper, DR, Maresh, CM, Volek, JS, and Häkkinen, K. Positive effects of augmented verbal feedback on power production in NCAA Division I collegiate athletes. J Strength Cond Res 27(8): 2067-2072, 2013-The purpose of this study was to determine how augmented verbal feedback, specifically knowledge of performance during a countermovement vertical jump (CMVJ) protocol, would affect acute power output. Each subject (N = 14 [9 men and 5 women], 21.4 ± 0.8 years, 179.6 ± 6.1 cm, 87.5 ± 14.8 kg) completed the CMVJ protocol twice in a balanced randomized order, one trial with feedback and one without feedback. At least 48 hours were allowed between sessions for resting. Student-athletes were used because of their trained state and their familiarity with plyometrics and receiving and processing feedback during training. Each testing session began with a 10-minute warm-up consisting of a combination of dynamic stretching and submaximal jumps (no proprioceptive neuromuscular facilitation or static stretching). After completion of the warm-up, the subjects then began the CMVJ protocol. The CMVJ protocol consisted of 3 sets of 5 jumps on a calibrated force plate set to read at 200 Hz (Accupower). Subjects were instructed at the start of the protocol to give maximal effort on each jump. The standard set and repetition scheme for this protocol was 3 sets of 5 maximal repetitions with 3 minutes rest between sets. This was used to mimic the practice of training for maximal power. Before each jump, the subject was told the jump number and given a verbal start cue before the jump's initiation. The verbal performance feedback given consisted of the full kinetic numerical value of the peak power output in watts of the last completed jump. Significance in this study was set at p ≤ 0.05. There was a significant difference between mean power outputs (4,335 ± 366 W to 4,108 ± 345 W, p = 0.003) and the peak power outputs (4,567 ± 381 W to 4,319 ± 371 W, p = 0.018) when comparing feedback to no feedback, respectively. There was a significant difference in peak power output between the feedback and no feedback trials during set 2 (mean difference 361 ± 161 W, p = 0.043) and set 3 (mean difference 283 ± 109 W, p = 0.022). Also, there was a significant difference in mean power output between feedback and no feedback trials during set 2 (mean difference 240 ± 66 W, p = 0.003) and set 3 (mean difference 299 ± 93 W, p = 0.007). When training for maximal power in a plyometric training protocol, verbal feedback can be used as both a simple and effective aid in producing optimal power outputs. 23411247 The physical characteristics and emulsification properties of partially dephosphorylated bovine β-casein. Bovine β-casein was purified from phosphocasein by rennet coagulation and cold solubilisation from the resultant curd. β-Casein was then dephosphorylated using potato acid phosphatase. Urea-polyacrylamide gel electrophoresis (PAGE) of partially dephosphorylated β-casein showed a number of bands, depending on the final level of phosphorylation. Dephosphorylating β-casein increased its pH of minimum solubility from ∼pH 5 to 5.5 and reduced its net negative charge from -30.8 to -27.0 mV. During the acidification of β-casein solutions, partially dephosphorylated β-casein failed to form a gel, unlike the phosphorylated (i.e., control) β-casein. Use of partially dephosphorylated β-casein to stabilise oil-in-water emulsions resulted in larger fat globules compared to control β-casein, but such globules were less susceptible to aggregation in the presence of 15 or 30 mM CaCl(2). Overall, the dephosphorylation of β-casein resulted in a protein similar to human β-casein in terms of physicochemical functionality, with increased stability against calcium-induced aggregation. 23532844 The Joubert Syndrome Associated Missense Mutation (V443D) in the Abelson-helper Integration Site 1 (AHI1) Protein Alters Its Localization and Protein-Protein Interactions. Mutations in AHI1 cause Joubert syndrome (JBTS), a neurodevelopmental ciliopathy, characterized by midbrain-hindbrain malformations and motor/cognitive deficits. Here, we show that primary cilia (PC) formation is decreased in fibroblasts from individuals with JBTS and AHI1 mutations. Most missense mutations in AHI1, causing JBTS, occur in known protein domains, however, a common V443D mutation in AHI1 is found in a region with no known protein motifs. We show that cells transfected with AHI1-V443D, or a new JBTS-causing mutation, AHI1-R351L, have aberrant localization of AHI1 at the basal bodies of PC and at cell-cell junctions, likely through decreased binding of mutant AHI1 to NPHP1 (another JBTS-causing protein). The AHI1-V443D mutation causes decreased AHI1 stability, since there is a 50% reduction in AHI1-V443D protein levels compared to wildtype AHI1. Huntingtin-associated protein-1 (Hap1) is a regulatory protein that binds Ahi1, and Hap1 knockout mice have been reported to have JBTS-like phenotypes, suggesting a role for Hap1 in ciliogenesis. Fibroblasts and neurons with Hap1 deficiency form PC with normal growth factor-induced ciliary signaling, indicating that the Hap1 JBTS-phenotype is likely not through effects at PC. These results also suggest that the binding of Ahi1 and Hap1 may not be critical for ciliary function. However, we show that HAP1 has decreased binding to AHI1-V443D indicating that this altered binding could be responsible for the JBTS-like phenotype through an unknown pathway. Thus, these JBTS-associated missense mutations alter their subcellular distribution and protein interactions, compromising functions of AHI1 in cell polarity and cilium-mediated signaling, thereby contributing to JBTS. 23224072 Lichen Planus-like Lesions as the First Manifestation of Adult T-cell Leukaemia/Lymphoma. Cutaneous involvement is frequent in adult T-cell leukaemia/lymphoma (ATLL), a peripheral T-cell neoplasm caused by human T-cell lymphotropic virus type I (HTLV-I). Patients with ATLL manifest different types of skin lesions, including nodules, plaques, ulcers, erythroderma and purpura. It has been reported that this type of skin eruption is an independent prognostic factor for ATLL. We report here a rare case of a 62-year-old Japanese woman with smouldering-type ATLL, first manifested by lichen planus-like skin lesions on the lower leg. This case report highlights the multiplicity of skin manifestations in ATLL. 23670410 Associations of T helper 1, 2, 17 and regulatory T lymphocytes with mortality in severe sepsis. T helper 17 (Th17) and regulatory T (Treg) lymphocytes might play important roles in patients with severe sepsis. The association of Th17 or Treg lymphocytes with survival is also unclear. Eighty-seven patients with severe sepsis were enrolled from our intensive care units between August 2008 and July 2010. Leukocyte antigens and clinical data were determined on day 1 in all patients and on day 7 in first-year patients. The percentages in peripheral blood mononuclear cells (PBMCs) and circulatory counts of CD4(+) and CD8(+) lymphocytes in survivors were higher than those in non-survivors. Th1/CD4(+) ratios and circulatory Th1 lymphocyte counts in survivors were higher than in non-survivors. Absolute counts of Th17 and Treg lymphocytes in survivors were higher than in non-survivors. The percentages of CD4(+) and CD8(+) in survivors' PBMCs were increased after 6 days. Th17/CD4(+) ratios and circulatory Th17 lymphocyte counts in survivors were increased after 6 days. Higher Th1 differentiation and total CD4(+) T lymphocyte counts were associated with higher survival. The association of circulatory Th17 and Treg lymphocytes with mortality in severe sepsis may be due to the change in total CD4(+) T lymphocytes. In survivors, Th17 differentiation and counts were restored. 23647398 Achieving recommended low density lipoprotein cholesterol goals and the factors associated with target achievement of hypercholesterolemia patients with rosuvastatin in primary care. Hypercholesterolemia is a major risk factor for cardiovascular disease and requires continuous management. The role of primary physicians in this regard is important, yet the factors associated with successful lipid lowering treatments in primary clinics have not been clearly identified. We aimed to evaluate the rate of successful hypercholesterolemia treatment in Korean primary care, and to identify the factors associated with achieving low density lipoprotein cholesterol (LDL-C) targets. We prospectively recruited and retrospectively assessed 1851 Korean patients with hypercholesterolemia who visited family physicians and were prescribed rosuvastatin for the first time. LDL-C lowering targets, defined according to NCEP ATP III guidelines, were evaluated at 6 months after the first prescription. The factors associated with achieving these targets were also assessed. Overall, 87.6% of our participants attained their LDL-C goals. In multiple logistic regression analysis, good adherence to medication was strongly associated with the achievement of target LDL-C levels, whereas higher cardiovascular risk factors including diabetes (in both sexes), low high density lipoprotein, and current smoking status (in males), and hypertension (in females) were related to LDL-C target level failures. Our observations of the short period for hypercholesterolemia in Korean primary care has revealed that the rate of achieving target LDL-C levels was high in these patients, whereas patients at higher risk for cardiovascular disease tended to have lower LDL-C achievement outcomes. Primary care physicians should pay more attention to patients showing higher cardiovascular risk and stress the need for good adherence and management regimens in these individuals. 23857454 Study of the Enantioselective Interaction of Diclofop and Human Serum Albumin by Spectroscopic and Molecular Modeling Approaches In Vitro. In this contribution, the enantioselective interactions between diclofop (DC) and human serum albumin (HSA) were explored by steady-state and 3D fluorescence, ultraviolet-visible spectroscopy (UV-vis), and molecular modeling. The binding constants between R-DC and HSA were 0.9213 × 10(5) , 0.9118 × 10(5) , and 0.9009 × 10(5)  L · mol(-1) at 293, 303, 313 K, respectively. Moreover, the binding constants of S-DC for HSA were 1.4766 × 10(5) , 1.2899 × 10(5) , and 1.0882 × 10(5)  L · mol(-1) at 293, 303, and 313 K individually. Such consequences markedly implied the binding between DC enantiomers and HSA were enantioselective with higher affinity for S-DC. Steady-state fluorescence study evidenced the formation of DC-HSA complex and there was a single class of binding site on HSA. The thermodynamic parameters (ΔH, ΔS, ΔG) of the reaction clearly indicated that hydrophobic effects and H-bonds contribute to the formation of DC-HSA complex, which was in excellent agreement with molecular simulations. In addition, both site-competitive replacement and molecular modeling suggested that DC enantiomers were located within the binding pocket of Sudlow's site II. Furthermore, the alterations of HSA secondary structure in the presence of DC enantiomers were verified by UV-vis absorption and 3D fluorescence spectroscopy. This study can provide important insight into the enantioselective interaction of physiological protein HSA with chiral aryloxyphenoxy propionate herbicides and gives support to the use of HSA for chiral pesticides ecotoxicology and environmental risk assessment. Chirality 00:000-000, 2013. © 2013 Wiley Periodicals, Inc. 22987808 Orthotopic VX rabbit tongue cancer model with FDG-PET and histologic characterization. We present our experience with the use of an immunocompetent medium-sized animal model of tongue cancer that may be suitable for imaging and surgical studies. A New Zealand white rabbit model of tongue cancer was created by injecting a VX tumor cell suspension grown in culture into the tongue of our model. The tumor was examined 7 days following implantation by physical examination, photography, and (18) fluoro 2-deoxyglucose-positron emission tomography (FDG-PET). At 12 days postimplantation, the model was again studied as described above prior to euthanization, and then tongue excision and bilateral neck dissections were performed. All tissue was examined by histology. We confirmed a successful orthotopic tongue cancer model that resulted in cervical nodal metastases. This model may be a useful model of orthotopic head and neck cancer for future surgical or imaging research. © 2012 Wiley Periodicals, Inc. Head Neck, 2013. 23967909 Calculating the spectrum of anisotropic waveguides using a spectral method. The computation of the spectrum of a waveguide with arbitrary anisotropy with spatial dependence is a challenging task due to the coupling between axial and azimuthal harmonics. This problem is tackled in cylindrical coordinates by extending a spectral method for the general case. By considering the matrix representation of the operator on the right-hand side of the governing equations, the latter are exactly reformulated as an infinite set of integro-differential equations. Essential part of this study is taking into account the coupling of different harmonics, which becomes evident from the kernels of these equations. Provided a waveguide is translationally invariant in the axial direction, the coupling of axial harmonics vanishes. A practical approximation and truncation procedure yields a generalized eigenvalue problem, which can be solved numerically to obtain the entire spectrum of the operator and to construct the dispersion curves for the eigenmodes. The spectral method is tested against the results from the measurements of dispersion curves for the monopole, dipole, and quadrupole normal modes of scaled boreholes in tilted transverse isotropy anisotropic rock sample. Besides, the comparison of dispersion curves calculated by the spectral method and those computed from the synthetic data is discussed. 23824332 Income and child mortality in developing countries: a systematic review and meta-analysis. ObjectiveWe aimed to quantify the relationship between national income and infant and under-five mortality in developing countries.Design We conducted a systematic literature search of studies that examined the relationship between income and child mortality (infant and/or under-five mortality) and meta-analysed their results.Setting Developing countries.Main outcome measuresChild mortality (infant and /or under-five mortality).ResultsThe systematic literature search identified 24 studies, which produced 38 estimates that examined the impact of income on the mortality rates. Using meta-analysis, we produced pooled estimates of the relationship between income and mortality. The pooled estimate of the relationship between income and infant mortality before adjusting for covariates is -0.95 (95% CI -1.34 to -0.57) and that for under-five mortality is -0.45 (95% CI -0.79 to -0.11). After adjusting for covariates, pooled estimate of the relationship between income and infant mortality is -0.33 (-0.39 to -0.26) while the estimate for under-five mortality is -0.28 (-0.37 to -0.19). If a country has an infant mortality of 50 per 1000 live births and the gross domestic product per capita purchasing power parity increases by 10%, the infant mortality will decrease to 45 per 1000 live births.ConclusionIncome is an important determinant of child survival and this work provides a pooled estimate for the relationship. 23876036 Investigational anticoagulants for hematological conditions: a new generation of therapies. Introduction: The introduction of novel anticoagulants has had contrasting effects on the agents in the pipeline, fueling the development of some and sinking the others. The complexity of the coagulation cascade offers interesting inhibition choices that might become valid treatment options. Areas covered: This review will highlight some of the anticoagulants in the pipeline. Following the success of the direct thrombin and FXa inhibitors already in the market, new agents are being tested. These include AZD0837, betrixaban, letaxaban, darexaban, and LY517717. Targeting other components of the hemostatic pathway might lead to better safety profiles without influencing efficacy. Inhibitors to FVIIa-tissue factor (FVIIa/TF) complex, FIX, FXI, and FXII are being assessed. New inspiring inhibitors are antisense oligonucleotides (ASOs) and aptamers. These are highly specific agents with readily reversible effect and might be engineered to inhibit any coagulation factor. Currently tested ASOs and aptamers are inhibitors of FXI, FXII, thrombin, FIXa, and platelet GPIV. Expert opinion: Some of the agents in the pipeline offer valid treatment option for long-term therapy, overcoming some of the drawbacks of the novel anticoagulants. Research is being driven by an expanding market in the anticoagulation field that has been unexploited for a long time. 23958942 Mining mouse behavior for patterns predicting psychiatric drug classification. In psychiatric drug discovery, a critical step is predicting the psychopharmacological effect and therapeutic potential of novel (or repurposed) compounds early in the development process. This process is hampered by the need to utilize multiple disorder-specific and labor-intensive behavioral assays. This study aims to investigate the feasibility of a single high-throughput behavioral assay to classify psychiatric drugs into multiple psychopharmacological classes. Using Pattern Array, a procedure for data mining exploratory behavior in mice, we mined ~100,000 complex movement patterns for those that best predict psychopharmacological class and dose. The best patterns were integrated into a classification model that assigns psychopharmacological compounds to one of six clinically relevant classes-antipsychotic, antidepressant, opioids, psychotomimetic, psychomotor stimulant, and α-adrenergic. Surprisingly, only a small number of well-chosen behaviors were required for successful class prediction. One of them, a behavior termed "universal drug detector", was dose-dependently decreased by drugs from all classes, thus providing a sensitive index of psychopharmacological activity. In independent validation in a blind fashion, simulating the process of in vivo pre-clinical drug screening, the classification model correctly classified nine out of 11 "unknown" compounds. Interestingly, even "misclassifications" match known alternate therapeutic indications, illustrating drug "repurposing" potential. Unlike standard animal models, the discovered classification model can be systematically updated to improve its predictive power and add therapeutic classes and subclasses with each additional diversification of the database. Our study demonstrates the power of data mining approaches for behavior analysis, using multiple measures in parallel for drug screening and behavioral phenotyping. 23912755 Safety and efficacy of dexmedetomidine for long-term sedation in critically ill patients. We evaluated the safety and efficacy of long-term administration of dexmedetomidine in patients in the intensive care unit (ICU). Primary endpoint was the incidence of hypotension, hypertension, and bradycardia. Secondary endpoints were withdrawal symptoms, rebound effects, the duration of sedation with Richmond Agitation-Sedation Scale (RASS) â‰¤ 0 relative to the total infusion time of dexmedetomidine, and the dose of additional sedatives or analgesics. Dexmedetomidine 0.2-0.7 μg/kg/h was continuously infused for maintaining RASS â‰¤ 0 in patients requiring sedation in the ICU. Safety and efficacy of short-term (≤24 h) and long-term (>24 h) dexmedetomidine administration were compared. Seventy-five surgical and medical ICU patients were administered dexmedetomidine. The incidence of hypotension, hypertension, and bradycardia that occurred after 24 h (long-term) was not significantly different from that occurring within 24 h (short-term) (P = 0.546, 0.513, and 0.486, respectively). Regarding withdrawal symptoms, one event each of hypertension and headache occurred after the end of infusion, but both were mild in severity. Increases of mean arterial blood pressure and heart rate after terminating the infusion of dexmedetomidine were not associated with the increasing duration of its infusion. The ratio of duration with RASS â‰¤ 0 was â‰¥ 85 % until day 20, except day 9 (70 %) and day 10 (75 %). There was no increase in the dose of additional sedatives or analgesics after the first 24-h treatment period. Long-term safety of dexmedetomidine compared to its use for 24 h was confirmed. Dexmedetomidine was useful to maintain an adequate sedation level (RASS â‰¤ 0) during long-term infusion. 23821583 Greatly increased numbers of histamine cells in human narcolepsy with cataplexy. To determine whether histamine cells are altered in human narcolepsy with cataplexy, and in animal models of this disease. Immunohistochemistry for histidine decarboxylase (HDC) and quantitative microscopy were used to detect histamine cells in human narcoleptics, Hcrt receptor-2 mutant dogs and three mouse narcolepsy models: hypocretin (Hcrt, orexin) knockouts (KOs), ataxin-3-orexin and doxycycline-controlled-diphtheria-toxin-A-orexin (DTA). We find an average 64% increase in the number of histamine neurons in human narcolepsy with cataplexy, with no overlap between narcoleptics and controls. However, we do not see altered numbers of HDC cells in any of the animal models of narcolepsy we examined. Changes in histamine cell numbers are not required for the major symptoms of narcolepsy, since all animal models have these symptoms. The histamine cell changes we saw in humans did not occur in the four animal models of hypocretin dysfunction we examined. Therefore the loss of Hcrt receptor-2, of the Hcrt peptide, or of Hcrt cells is not sufficient to produce these changes. We speculate that the increased histamine cell numbers we see in human narcolepsy may instead be related to the process causing the human disorder. Although research has focused on possible antigens within the Hcrt cells that might trigger their autoimmune destruction, the present findings suggest that the triggering events of human narcolepsy may involve a proliferation of histamine containing cells. We discuss this and other explanations of the difference between human narcoleptics and animal models of narcolepsy, including therapeutic drug use and species differences. ANN NEUROL 2013. © 2013 American Neurological Association. 23578277 Evolutionary and mechanistic insights into substrate and product accommodation of CTP:phosphocholine cytidylyltransferase from Plasmodium falciparum. The enzyme CTP:phosphocholine cytidylyltransferase (CCT) is essential in the lipid biosynthesis of Plasmodia (Haemosporida), presenting a promising antimalarial target. Here, we identified two independent gene duplication events of CCT within Apicomplexa and characterized a truncated construct of Plasmodium falciparum CCT that forms a dimer resembling the molecular architecture of CCT enzymes from other sources. Based on biophysical and enzyme kinetics methods, our data show that the CDP-choline product of the CCT enzymatic reaction binds to the enzyme considerably stronger than either substrate (CTP or choline phosphate). Interestingly, in the presence of Mg(2+) , considered to be a cofactor of the enzyme, the binding of the CTP substrate is attenuated by a factor of 5. The weaker binding of CTP:Mg(2+) , similarly to the related enzyme family of aminoacyl tRNA synthetases, suggests that, with lack of Mg(2+) , positively charged side chain(s) of CCT may contribute to CTP accommodation. Thermodynamic investigations by isothermal titration calorimetry and fluorescent spectroscopy studies indicate that accommodation of the choline phosphate moiety in the CCT active site is different when it appears on its own as one of the substrates or when it is linked to the CDP-choline product. A tryptophan residue within the active site is identified as a useful internal fluorescence sensor of enzyme-ligand binding. Results indicate that the catalytic mechanism of Plasmodium falciparum CCT may involve conformational changes affecting the choline subsite of the enzyme. 23970480 Characterization of changes in total body composition for head and neck cancer patients undergoing chemoradiotherapy using dual-energy X-ray absorptiometry (DEXA). Background: Head and Neck Cancer (HNCa) patients experience significant weight loss secondary to concurrent chemoradiotherapy (CCRT). Using DEXA scans, we characterize total body composition changes during/following CCRT in order to develop novel clinical care models that will improve quality of life (QoL). Methods: 60 DEXA scans were obtained from 12 patients undergoing CCRT for locally advanced squamous cell HNCa. DEXAs were performed at baseline, during treatment, completion of CCRT, and then 1 and 2-months post-treatment. Results: Mean weight loss by treatment end was 9.5 kg (-10.2%,p=0.0002). On average lean body mass (LBM) decreased 10.2% (p=0.001), and fat body mass (FBM) decreased 11.1% (p=0.001) during CCRT. LBM began to normalize following completion of treatment. FBM continued to decline. Conclusions: Substantial loss of muscle and FBM occurs in patients undergoing CCRT for HNCa. To prevent long-term disability and QoL decline following curative CCRT, clinical care interventions incorporating aggressive nutrition/exercise counseling are needed. Head Neck, 2013. 23525200 Enhanced broadband and omnidirectional performance of Cu(In,Ga)Se2 solar cells with ZnO functional nanotree arrays. An effective approach is demonstrated for enhancing photoelectric conversion of Cu(In,Ga)Se2 (CIGS) solar cells with three-dimensional ZnO nanotree arrays. Under a simulated one-sun condition, cells with ZnO nanotree arrays enhance the short-circuit current density by 10.62%. The omnidirectional anti-reflection of CIGS solar cells with various ZnO nanostructures is also investigated. The solar-spectrum weighted reflectance is approximately less than 5% for incident angles of up to 60° and for the wavelengths primarily from 400 nm to 1000 nm. This enhancement in light harvesting is attributable to the gradual refractive index profile between the ZnO nanostructures and air. 23524304 Potentiation of morphine-induced mechanical antinociception by σ1 receptor inhibition: Role of peripheral σ1 receptors. We studied the modulation of morphine-induced mechanical antinociception and side effects by σ1 receptor inhibition. Both wild-type (WT) and σ1 receptor knockout (σ1-KO) mice showed similar responses to paw pressure (100-600 g). The systemic (subcutaneous) or local (intraplantar) administration of σ1 antagonists (BD-1063, BD-1047, NE-100 and S1RA) was devoid of antinociceptive effects in WT mice. However, σ1-KO mice exhibited an enhanced mechanical antinociception in response to systemic morphine (1-16 mg/kg). Similarly, systemic treatment of WT mice with σ1 antagonists markedly potentiated morphine-induced antinociception, and its effects were reversed by the selective σ1 agonist PRE-084. Although the local administration of morphine (50-200 μg) was devoid of antinociceptive effects in WT mice, it induced dose-dependent antinociception in σ1-KO mice. This effect was limited to the injected paw. Enhancement of peripheral morphine antinociception was replicated in WT mice locally co-administered with σ1 antagonists and the opioid. None of the σ1 antagonists tested enhanced morphine-antinociception in σ1-KO mice, confirming a σ1-mediated action. Morphine-induced side-effects (hyperlocomotion and inhibition of gastrointestinal transit) were unaltered in σ1-KO mice. These results cannot be explained by a direct interaction of σ1 ligands with μ-opioid receptors or adaptive changes of μ-receptors in σ1-KO mice, given that [(3)H]DAMGO binding in forebrain, spinal cord, and hind-paw skin membranes was unaltered in mutant mice, and none of the σ1 drugs tested bound to μ-opioid receptors. These results show that σ1 receptor inhibition potentiates morphine-induced mechanical analgesia but not its acute side effects, and that this enhanced analgesia can be induced at peripheral level. 23219701 Discovery of alkenylboronic acids as neuroprotective agents affecting multiple biological targets involved in Alzheimer's disease. Alkenylboronic acids have shown important biological activities that contribute to neuroprotection. We have determined their influence on the β-amyloid (βA) aggregation process, β-secretase and acethylcholinesterase activities on cell-free systems, on the redox and lipid peroxidation status, and on the vulnerability to apoptotic death in an APPswe neuroblastoma cell line, before and after hydrogen peroxide treatment. We have discovered that 2-arylvinylboronic acids and some of their esters possess a set of properties which makes them highly useful as neuroprotective agents affecting multiple biological targets involved in AD. These properties are not paralleled by the related 2-arylboronic acids. 23541843 Posttranslational mechanisms modulating the expression of the cytochrome P450 1A1 gene by methylmercury in HepG2 cells: A role of heme oxygenase-1. Recently we demonstrated the ability of mercuric chloride (Hg(2+)) in human hepatoma HepG2 cells to significantly decrease the TCDD-mediated induction of Cytochrome P450 1A1 (CYP1A1) mRNA, protein, and catalytic activity levels. In this study we investigated the effect of methylmercury (MeHg) on CYP1A1 in HepG2 cells. For this purpose, cells were co-exposed to MeHg and TCDD and the expression of CYP1A1 mRNA, protein, and catalytic activity levels were determined. Our results showed that MeHg did not alter the TCDD-mediated induction of CYP1A1 mRNA, or protein levels; however it was able to significantly decrease CYP1A1 catalytic activity levels in a concentration-dependent manner. Importantly, this inhibition was specific to CYP1A1and was not radiated to other aryl hydrocarbon receptor (AhR)-regulated genes, as MeHg induced NAD(P)H:quinone oxidoreductase 1 mRNA and protein levels. Mechanistically, the inhibitory effect of MeHg on the induction of CYP1A1 coincided with an increase in heme oxygenase-1 (HO-1) mRNA levels. Furthermore, the inhibition of HO-1 activity, by tin mesoporphyrin, caused a complete restoration of MeHg-mediated inhibition of CYP1A1 activity, induced by TCDD. In addition, transfection of HepG2 cells with siRNA targeting the human HO-1 gene reversed the MeHg-mediated inhibition of TCDD-induced CYP1A1. In conclusion, this study demonstrated that MeHg inhibited the TCDD-mediated induction of CYP1A1 through a posttranslational mechanism and confirms the role of HO-1 in a MeHg-mediated effect. 23787347 Characterizing humans on Riemannian manifolds. In surveillance applications, head and body orientation of people is of primary importance for assessing many behavioral traits. Unfortunately, in this context people are often encoded by a few, noisy pixels so that their characterization is difficult. We face this issue, proposing a computational framework which is based on an expressive descriptor, the covariance of features. Covariances have been employed for pedestrian detection purposes, actually a binary classification problem on Riemannian manifolds. In this paper, we show how to extend to the multiclassification case, presenting a novel descriptor, named weighted array of covariances, especially suited for dealing with tiny image representations. The extension requires a novel differential geometry approach in which covariances are projected on a unique tangent space where standard machine learning techniques can be applied. In particular, we adopt the Campbell-Baker-Hausdorff expansion as a means to approximate on the tangent space the genuine (geodesic) distances on the manifold in a very efficient way. We test our methodology on multiple benchmark datasets, and also propose new testing sets, getting convincing results in all the cases. 23838220 Ventilator-associated tracheobronchitis increases the length of intensive care unit stay. Objective. To investigate prospectively the clinical course and risk factors for ventilator-associated tracheobronchitis (VAT) and the impact of VAT on intensive care unit (ICU) morbidity and mortality. Design. Prospective cohort study. Setting. University Hospital Larissa, Larissa, Greece Patients. Critical care patients who received mechanical ventilation for more than 48 hours were prospectively studied between 2009 and 2011. Methods. The modified Clinical Pulmonary Infection Score, white blood cell count, and C-reactive protein level were systematically assessed every 2 days for the first 2 weeks of ICU stay. Bronchial secretions were assessed daily. Quantitative cultures of endotracheal secretions were performed on the first ICU day for every patient and every 2 days thereafter for the first 2 weeks or more at the discretion of the attending physicians. Definition of VAT was based on previously published criteria. Results. A total of 236 patients were observed; 42 patients (18%) presented with VAT. Gram-negative pathogens, which were usually multidrug resistant, were responsible for 92.9% of cases. Patients with a neurosurgical admission presented with VAT significantly more often than did other ICU patients (28.5% vs 14.1%; [Formula: see text]. The occurrence of VAT was a significant risk factor for increased duration of ICU stay (OR [95% CI], 3.04 [1.35-6.85]; [Formula: see text]). Age (OR [95% CI], 1.04 [1.015-1.06]; [Formula: see text]), Acute Physiology and Chronic Health Evaluation II score (OR [95% CI], 1.08 [1.015-1.16]; [Formula: see text]), and C-reactive protein level at admission (OR [95% CI], 1.05 [1.01-1.1]; [Formula: see text]) were independent factors for ICU mortality. Conclusions. VAT is a nosocomial infection that might be associated with prolonged stay in the ICU, especially in neurocritical patients. VAT was not associated with increased mortality in our study. 23886411 Hydrolyzed casein and whey protein meals comparably stimulate net whole-body protein synthesis in COPD patients with nutritional depletion without an additional effect of leucine co-ingestion. Muscle wasting commonly occurs in COPD, negatively affecting outcome. The aim was to examine the net whole-body protein synthesis response to two milk protein meals with comparable absorption rates (hydrolyzed casein (hCAS) vs. hydrolyzed whey (hWHEY)) and the effects of co-ingesting leucine. Twelve COPD patients (GOLD stage II-IV) with nutritional depletion, were studied following intake of a 15 g hCAS or hWHEY protein meal with or without leucine-co-ingestion, according to a double-blind randomized cross-over design. The isotopic tracers L-[ring-(2)H5]-Phenylalanine, L-[ring-(2)H2]-Tyrosine, L-[(2)H3]-3-Methylhistidine (given via continuous intravenous infusion), and L-[(15)N]-Phenylalanine (added to the protein meals) were used to measure endogenous whole-body protein breakdown (WbPB), whole-body protein synthesis (WbPS), net protein synthesis (NetPS), splanchnic extraction and myofibrillar protein breakdown (MPB). Analyses were done in arterialized-venous plasma by LC/MS/MS. WbPS was greater after intake of the hCAS protein meal (P < 0.05) whereas the hWHEY protein meal reduced WbPB more (P < 0.01). NetPS was stimulated comparably, with a protein conversion rate greater than 70%. Addition of leucine did not modify the insulin, WbPB, WbPS or MPB response. Hydrolyzed casein and whey protein meals comparably and efficiently stimulate whole-body protein anabolism in COPD patients with nutritional depletion without an additional effect of leucine co-ingestion. This trial was registered at clinicaltrials.gov as NCT01154400. 23893678 Resveratrol for prenatal-stress-induced oxidative damage in growing brain and its consequences on survival of neurons. Abstract Background: Prenatal-stress-induced neuronal damage in offspring is multifactorial, including oxidative damage in the developing brain. Resveratrol is known to exert its neuroprotective potentials by upregulating several antioxidant systems. Hence, the study was undertaken to evaluate the neuroprotective effect of resveratrol against prenatal-stress-induced hippocampal damage and oxidative damage in neonate rat brains. Methods: Pregnant rats were subjected to restraint stress during early or late gestational period. Another set of rats received resveratrol during the entire gestational period along with early or late gestational stress. The study parameters included several antioxidant studies directly from rat brain homogenate on the 40th postnatal day and hippocampal neuronal assay on the 21st postnatal day. Results: Early as well as late gestational stress resulted in a significant increase in lipid peroxidation and advanced oxidation protein products and decrease in total antioxidant activity and nitric oxide levels in rat brain homogenate. The neurons of the dentate gyrus were severely affected in early and late gestational stress, and only the neurons of the CA3 region were adversely affected in late gestational stress. Administration of resveratrol reversed the prenatal-stress-induced oxidative damage and neurons of dentate gyrus but not the CA3 hippocampal neurons. Conclusions: These results show the neuroprotective abilities of resveratrol against prenatal-stress-induced oxidative damage in neonatal rat brain. 23816500 Antimycobacterial activity of Citrullus colocynthis (L.) Schrad. against drug sensitive and drug resistant Mycobacterium tuberculosis and MOTT clinical isolates. Citrullus colocynthis (Cucurbitaceae), a folk herbal medicine and traditionally used natural remedy for tuberculosis in India has been studied to validate its antitubercular activity against drug sensitive and drug resistant (including multidrug resistant) Mycobacterium tuberculosis and Mycobacterium other than tuberculosis (MOTT) bacilli. Inhibitory and bactericidal activities of crude extracts, fractions and compounds of Citrullus colocynthis plant, consisting of aerial parts and ripe deseeded fruits were performed against the drug sensitive standard strain of Mycobacterium tuberculosis H37Rv (ATCC 27294), 16 drug resistant strains of Mycobacterium tuberculosis and two MOTT strains, using radiometric BACTEC 460TB system. Methanolic extract of ripe deseeded fruit of Citrullus colocynthis has shown good activity (MIC≤62.5µg/ml), whereas among the bioactive fractions, FC IX demonstrated the best activity (MIC 31.2µg/ml) against Mycobacterium tuberculosis H37Rv. Bioactive FC III, IX and X also inhibited 16 clinical isolates of Mycobacterium tuberculosis consisting of seven non-multidrug resistants, eight multidrug resistants, one extensively drug resistant and two of MOTTs with MICs in the range of 50-125, 31.2-125 and 62.5-125µg/ml, respectively. Ursolic acid and cucurbitacin E 2-0-β-d-glucopyranoside were identified as the main biomarkers active against Mycobacterium tuberculosis H37Rv (MICs 50 and 25µg/ml respectively), as well as against the 18 clinical isolates. FC III and FC IX showed better inhibition of drug resistant and MOTT clinical isolates. Minimal bactericidal concentrations of extracts, fractions and compound C-2 were ≥two-fold MIC values. The study provides a scientific rationale for the traditional use of Citrullus colocynthis fruit in the treatment of tuberculosis. In addition, the study elucidates a broad spectrum antimycobacterial action of Citrullus colocynthis fruit, which can contribute to the development of improved preparation of an antitubercular natural drug for the treatment of drug resistant tuberculosis and MOTT infection as well. 23865579 Deficiency of the Cog8 Subunit in Normal and CDG-Derived Cells Impairs the Assembly of the COG and Golgi SNARE Complexes. Multiple mutations in different subunits of the tethering complex Conserved Oligomeric Golgi (COG) have been identified as a cause for Congenital Disorders of Glycosylation (CDG) in humans. Yet, the mechanisms by which COG mutations induce the pleiotropic CDG defects have not been fully defined. By detailed analysis of Cog8 deficiency in either HeLa cells or CDG-derived fibroblasts, we show that Cog8 is required for the assembly of both the COG complex and the Golgi Stx5-GS28-Ykt6-GS15 and Stx6-Stx16-Vti1a-VAMP4 SNARE complexes. The assembly of these SNARE complexes is also impaired in cells derived from a Cog7-deficient CDG patient. Likewise, the integrity of the COG complex is also impaired in Cog1-, Cog4- and Cog6-depleted cells. Significantly, deficiency of Cog1, Cog4, Cog6 or Cog8 distinctly influences the production of COG subcomplexes and their Golgi targeting. These results shed light on the structural organization of the COG complex and its subcellular localization, and suggest that its integrity is required for both tethering of transport vesicles to the Golgi apparatus and the assembly of Golgi SNARE complexes. We propose that these two key functions are generally and mechanistically impaired in COG-associated CDG patients, thereby exerting severe pleiotropic defects. 23770224 A self-assembling peptide reduces glial scarring, attenuates post-traumatic inflammation and promotes neurological recovery following spinal cord injury. The pathophysiology of spinal cord injury (SCI) involves post-traumatic inflammation and glial scarring which interfere with repair and recovery. Self-assembling peptides (SAPs) are molecules designed for tissue engineering. Here, we tested the performance of K2(QL)6K2 (QL6), a SAP that attenuates inflammation and glial scarring, and facilitates functional recovery. We injected QL6 into the spinal cord tissue of rats 24h after clip compression SCI. QL6 led to a significant reduction in post-traumatic apoptosis, inflammation and astrogliosis. It also resulted in significant tissue preservation as determined by quantitative histomorphometry. Furthermore, QL6 promoted axonal preservation/regeneration, demonstrated by BDA anterograde and Fluorogold retrograde tracing. In vitro experiments found that a QL6 scaffold enhanced neuronal differentiation and suppressed astrocytic development. The electrophysiology confirmed that QL6 led to significant functional improvement of axons, including increased conduction velocity, reduced refractoriness and enhanced high-frequency conduction. These neuroanatomical and electrophysiological improvements were associated with significant neurobehavioral recovery as assessed by the Basso-Beattie-Bresnahan technique. As the first detailed examination of the pathophysiological properties of QL6 in SCI, this work reveals the therapeutic potential of SAPs, and may suggest an approach for the reconstruction of the injured spinal cord. 23534455 Realist review to understand the efficacy of culturally appropriate diabetes education programmes. Minority populations often face linguistic, cultural and financial barriers to diabetes education and care. The aim was to understand why culturally appropriate diabetes education interventions work, when they work best and for whom they are most effective. This review used a critical realist approach to examine culturally appropriate diabetes interventions. Beginning with the behavioural model and access to medical care, it reanalysed 11 randomized controlled trials from a Cochrane systematic review and related programme and training documents on culturally appropriate diabetes interventions. The analysis examined context and mechanism to understand their relationship to participant retention and statistically improved outcomes. Minority patients with language barriers and limited access to diabetes programmes responded to interventions using health workers from the same ethnic group and interventions promoting culturally acceptable and financially affordable food choices using local ingredients. Programme incentives improved retention in the programmes and this was associated with improved HbA1c levels at least in the short term. Adopting a positive learning environment, a flexible and less intensive approach, one-to-one teaching in informal settings compared with a group approach in clinics led to improved retention rates. Minority and uninsured migrants with unmet health needs showed the highest participation and HbA1c responses from culturally appropriate programmes. 23549767 A nationwide examination of outcomes of percutaneous cholecystostomy compared with cholecystectomy for acute cholecystitis, 1998-2010. Improvements in percutaneous drainage techniques combined with the recognized advantages of avoiding surgery in critically ill patients have rendered cholecystostomy an attractive treatment option, particularly in those patients with acute acalculus cholecystitis. However, robust data to guide surgeons in choosing cholecystostomy versus cholecystectomy have been lacking. Retrospective analysis of the Nationwide Inpatient Sample (NIS) database from 1998-2010 was performed. Patients identified as having acute cholecystitis (calculus and acalculus) were identified by ICD-9 diagnosis codes and further classified as having undergone cholecystostomy or cholecystectomy. Patients with both procedures were included in the cholecystectomy group. Patients with neither procedure and those younger than age 18 years were excluded. Multivariate analyses examined mortality, length of stay, total charges, gallbladder/gastrointestinal complications, or any complication. Results were adjusted for age, race, gender, Charlson comorbidity index, and teaching-hospital status. Subset analyses were performed among patients who survived and patients who died. A total of 248,229 calculus and 58,518 acalculus acute cholecystitis patients were analyzed. On unadjusted analysis, mortality, length of stay, and total charges were higher, but complication rates were lower, in patients with a cholecystostomy. Adjusted analysis showed lower odds of complications [calculus: odds ratio (OR) 0.3, p < 0.001; acalculus: OR 0.4, p < 0.001] but higher odds of mortality, total charges, and LOS (calculus: mortality OR 5.2, p < 0.001, $29,113, p < 0.001, +5.1 days, p < 0.001; acalculus: mortality OR 3.7, p < 0.001; $43,771, p < 0.001, +6.2 days, p < 0.001) among patients who received cholecystostomy. Results were similar in subset analyses. Patients receiving cholecystostomy were more likely to be older and have more comorbidities. Among patients with calculus or acalculus cholecystitis, patients with cholecystostomy had decreased complication rates compared with patients with cholecystectomy. However, patients who received cholecystostomy had increased odds of death, longer length of stay, and higher total charges. 22794113 The tumor microenvironment: characterization, redox considerations, and novel approaches for reactive oxygen species-targeted gene therapy. Abstract The tumor microenvironment is a complex system that involves the interaction between malignant and neighbor stromal cells embedded in a mesh of extracellular matrix (ECM) components. Stromal cells (fibroblasts, endothelial, and inflammatory cells) are co-opted at different stages to help malignant cells invade the surrounding ECM and disseminate. Malignant cells have developed adaptive mechanisms to survive under the extreme conditions of the tumor microenvironment such as restricted oxygen supply (hypoxia), nutrient deprivation, and a prooxidant state among others. These conditions could be eventually used to target drugs that will be activated specifically in this microenvironment. Preclinical studies have shown that modulating cellular/tissue redox state by different gene therapy (GT) approaches was able to control tumor growth. In this review, we describe the most relevant features of the tumor microenvironment, addressing reactive oxygen species-generating sources that promote a prooxidative microenvironment inside the tumor mass. We describe different GT approaches that promote either a decreased or exacerbated prooxidative microenvironment, and those that make use of the differential levels of ROS between cancer and normal cells to achieve tumor growth inhibition. Antioxid. Redox Signal. 19, 854-895. 23845150 Alcohol consumption and psoriasis: a systematic literature review. The association between alcohol consumption and psoriasis has been frequently discussed since the 1980s, but no systematic review has been elaborated on the subject so far. The aim of this systematic literature review was to assess whether alcohol consumption is more prevalent in psoriasis patients than in the general population and whether alcohol consumption is a risk factor of psoriasis. A systematic literature search was carried out in the Medline, Embase and Cochrane databases using the keywords 'psoriasis' AND 'alcohol drinking' OR 'alcohol-related disorders'. The search was then enlarged with the keywords 'psoriasis' AND 'risk factor' OR 'comorbidity'. Altogether 911 references in English and French were found. Out of these, 837 articles were excluded by reading the abstract and 46 by reading the article. A total of 28 articles were selected. Alcohol consumption in psoriasis patients versus the general population: 23 studies were selected; 18 concluded that alcohol consumption was more prevalent in psoriasis patients, and 5 did not. Three studies compared the prevalence of excessive drinking using a questionnaire on alcohol dependence (CAGE or Self-administered alcohol screening test (SAAST)) or with quantitative criteria for excessive drinking. In these studies, excessive drinking was more prevalent among psoriasis patients than in the general population. Other articles studied the quantity and type of alcohol consumed. In 11 studies, psoriasis patients consumed more alcohol than the controls. Four other studies showed excessive alcohol consumption in psoriasis patients without control group comparison. Conversely, five studies identified no difference in alcohol consumption between psoriasis patients and the general population. The heterogeneity in the measurement of alcohol consumption did not allow performing meta-analysis. Alcohol as a risk factor for psoriasis: only five studies were selected. In four of these studies alcohol was found to be a risk factor for psoriasis. Alcohol consumption seems to be greater in psoriasis patients than in the general population. However, there is not enough evidence to establish whether alcohol consumption is indeed a risk factor for psoriasis. 23907072 Inhibitory effect of phloretin and biochanin A on IgE-mediated allergic responses in rat basophilic leukemia RBL-2H3 cells. Anti-allergic effects and action mechanism of phloretin (Phl) and biochanin A (BioA) on the IgE-antigen complex-mediated allergic responses in rat basophilic leukemia RBL-2H3 cells were investigated. Cell viability, formation of reactive oxygen species (ROS), DPPH radical-scavenging activity, β-hexosaminidase release, production of interleukin (IL)-4, IL-13, and tumor necrosis factor-alpha (TNF-α) and phosphorylation of Akt and mitogen-activated protein kinase (MAPK) were determined by MTT assay, 2,7-dichlorofluorescein diacetate (DCF-DA) assay, DPPH radical-scavenging assay, reverse transcriptase polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA) and western blot analysis, respectively. Ph1 and BioA dose-dependently inhibited the formation of ROS and the release of β-hexosaminidase from the RBL-2H3 cells and also showed DPPH radical-scavenging activity. Ph1 and BioA suppressed the antigen-induced phosphorylation of the downstream signaling intermediates, including MAPK and Akt, which are critical for the production of pro-inflammatory cytokines, and also significantly attenuated the production of IgE-mediated pro-inflammatory cytokines, such as IL-4, IL-13, and TNF-α. Phloretin and biochanin A attenuate the degranulation and allergic cytokine production through inhibition of intracellular ROS production and the phosphorylation of Akt and the MAPKs, such as ERK1/2, p38, and JNK. The results of this study suggested that these two plant flavonoids may have potent anti-allergic activity in vitro. 23844579 FDR Control with Pseudo-Gatekeeping Based on a Possibly Data Driven Order of the Hypotheses. We propose a multiple testing procedure controlling the false discovery rate. The procedure is based on a possibly data driven ordering of the hypotheses, which are tested at the uncorrected level q until a suitable number is not rejected. When the order is data driven, larger effect sizes are considered first, therefore selecting more interesting hypotheses with larger probability. The proposed procedure is valid under independence for the test statistics. We also propose a modification which makes our procedure valid under arbitrary dependence. It is shown in simulation that we compare particularly well when the sample size is small. We conclude with an application to identification of molecular signatures of intracranial ependymoma. The methods are implemented in an R package (someMTP), freely available on CRAN. 23921860 Lidocaine spray compared with submucosal injection for reducing pain during loop electrosurgical excision procedure: a randomized controlled trial. To examine the effectiveness of lidocaine spray compared with conventional lidocaine submucosal injection during a loop electrosurgical excision procedure (LEEP). Women undergoing LEEP for any degrees of cervical intraepithelial neoplasia were invited to participate. The participants were randomly assigned into two groups. In group 1 (injection), the participants were anesthetized with 1.8 mL (36 mg) of 2% lidocaine with 1:100,000 epinephrine injected submucosally using a pressure syringe injector with a 27-gauge needle tip at 3, 6, 9, and 12 o'clock locations of the ectocervix. For group 2 (spray), the patients were locally anesthetized with four puffs (40 mg) of 10% lidocaine spray applied thoroughly to the ectocervix. The patients rated their pain according to a 10-cm visual analog scale at different points during the procedure including baseline, postanesthesia, excision, and 30 minutes postexcision. Primary outcomes were the excision pain score and its difference from the baseline. One hundred one patients (51 in the injection group and 50 in the spray group) participated in the study. The baseline pain scores, the excision pain scores, the difference between the excision and the baseline pain scores, and the postexcision pain scores were comparable between the study groups. The median postanesthesia pain score and the median difference of the postanesthesia score from baseline were significantly higher in the injection group, 3.4 compared with 0.6 and 1.9 compared with 0.0, respectively (P<.01). Lidocaine spray is an effective and practical alternative measure for reducing pain associated with electrical excision of the cervix during LEEP. ClinicalTrials.gov, www.clinicaltrials.gov, NCT01505920. : I. 23337481 Pediatric upper airway obstruction: Interobserver variability is the road to perdition. The purposes of the study are to determine the interobserver variability in the clinical assessment of pediatric upper airway obstruction (UAO) and to explore how variability in assessment of UAO may contribute to risk factors and incidence of postextubation UAO. This is a prospective trial in 2 tertiary care pediatric intensive care units. Bedside practitioners performed simultaneous, blinded UAO assessments on 112 children after endotracheal extubation. Agreement among respiratory therapists, pediatric intensive care nurses, and pediatric intensive care physicians was poor for cyanosis (κ = 0.01) and hypoxemia at rest (κ = 0.14) and fair for consciousness (κ = 0.27), air entry (κ = 0.32), hypoxemia with agitation (κ = 0.27), and pulsus paradoxus (κ = 0.23). When looking at "stridor" and "retractions," defined using more than 2 grades of severity from the Westley Croup Score, the interrelater reliability was moderate (κ = 0.43 and κ = 0.47, respectively). This could be improved marginally by dichotomizing the presence or absence of stridor (κ = 0.54) or retractions (κ = 0.53). The overall incidence of UAO after extubation (stridor plus retractions) could range from 7% to 22%, depending on how many providers were required to agree. Physical findings routinely used for UAO have poor interobserver reliability among bedside providers. This variability may contribute to inconsistent findings regarding incidence, risk factors, and therapies for postextubation UAO. 23855466 Osteogenic effects of resveratrol in vitro: potential for the prevention and treatment of osteoporosis. There are a number of pharmacological agents for the treatment of bone mineral loss and osteoporosis. Hormone replacement therapy (HRT) with estrogen is an established treatment, but it has several adverse side effects and can increase the risk of cancer, heart disease, and stroke. There is increasing interest in nutritional factors and naturally occurring phytochemical compounds with the potential for preventing age-related and postmenopausal bone loss. Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenolic phytoestrogen with osteogenic and osteoinductive properties. It can modify the metabolism of bone cells and has the capacity to modulate bone turnover. This paper provides an overview of current research on resveratrol and its effects on bone cells in vitro, highlighting the challenges and opportunities facing this area of research, especially in the context of providing nutritional support for postmenopausal women who may not benefit from HRT and older patients with various forms of arthritis, metabolic bone disease, and osteoporosis. 23585278 RNA global alignment in the joint sequence-structure space using elastic shape analysis. The functions of RNAs, like proteins, are determined by their structures, which, in turn, are determined by their sequences. Comparison/alignment of RNA molecules provides an effective means to predict their functions and understand their evolutionary relationships. For RNA sequence alignment, most methods developed for protein and DNA sequence alignment can be directly applied. RNA 3-dimensional structure alignment, on the other hand, tends to be more difficult than protein structure alignment due to the lack of regular secondary structures as observed in proteins. Most of the existing RNA 3D structure alignment methods use only the backbone geometry and ignore the sequence information. Using both the sequence and backbone geometry information in RNA alignment may not only produce more accurate classification, but also deepen our understanding of the sequence-structure-function relationship of RNA molecules. In this study, we developed a new RNA alignment method based on elastic shape analysis (ESA). ESA treats RNA structures as three dimensional curves with sequence information encoded on additional dimensions so that the alignment can be performed in the joint sequence-structure space. The similarity between two RNA molecules is quantified by a formal distance, geodesic distance. Based on ESA, a rigorous mathematical framework can be built for RNA structure comparison. Means and covariances of full structures can be defined and computed, and probability distributions on spaces of such structures can be constructed for a group of RNAs. Our method was further applied to predict functions of RNA molecules and showed superior performance compared with previous methods when tested on benchmark datasets. The programs are available at http://stat.fsu.edu/ ∼jinfeng/ESA.html. 23903128 Sensitivity enhancement of an open-cavity-based optoacoustic sensor. We present a new method for sensitive ultrasound detection using an open-cavity optoacoustic sensor. Our results have demonstrated significant enhancement of detection sensitivity when the open-cavity sensor is used in media with large isothermal compressibility. A near-linear relationship between detected optoacoustic signal strength and isothermal compressibility has been found. 23142550 The Effects of Cross-Hemispheric Dorsolateral Prefrontal Cortex Transcranial Direct Current Stimulation (tDCS) on Task Switching. Task switching, defined as the ability to flexibly switch between tasks in the face of goal shifting, is a central mechanism in cognitive control. Task switching is thought to involve both prefrontal cortex (PFC) and parietal regions. Our previous work has shown that it is possible to modulate set shifting tasks using 1 mA tDCS on both the left dorsolateral prefrontal cortex and the left primary motor area. However, it remains unclear whether the effects of PFC tDCS on task switching are hemisphere-dependent. We aimed to test the effects of three types of cross-hemispheric tDCS over the PFC (left anode-right cathode [LA-RC], left cathode-right anode [LC-RA] and sham stimulation) on participants' performance (reaction time) and accuracy (correct responses) in two task-switching paradigms (i.e., letter/digit naming and vowel-consonant/parity tasks). Sixteen participants received cross-hemispheric tDCS over the PFC in two task-switching paradigms. The results show that cross-hemispheric tDCS over the PFC modulates task-switching ability in both paradigms. Our results were task and hemisphere-specific, such that in the letter/digit naming task, LA-RC tDCS increased switching performance, whereas LC-RA tDCS improved accuracy. On the other hand, in the vowel-consonant/parity task, LA-RC improved accuracy, and decreased switching performance. Our findings confirm the notion that involvement of the PFC on task switching depends critically on laterality, implying the existence of different roles for the left hemisphere and the right hemisphere in task switching. 23940037 The phosphatase Ptc7 induces coenzyme Q biosynthesis by activating the hydroxylase Coq7 in yeast. The study of the components of mitochondrial metabolism has potential benefits for health span and lifespan since the maintenance of efficient mitochondrial function and antioxidant capacity is associated with improved health and survival. In yeast, mitochondrial function requires the tight control of several metabolic processes, such as coenzyme Q biosynthesis, assuring an appropriate energy supply and antioxidant functions. Many mitochondrial processes are regulated by phosphorylation cycles mediated by protein kinases and phosphatases. In this report we determined that the mitochondrial phosphatase Ptc7 (Ptc7p), a Ser/Thr phosphatase, was required to regulate coenzyme Q6 biosynthesis, which in turn activated aerobic metabolism and enhanced oxidative stress resistance. We showed that Ptc7 phosphatase specifically activated coenzyme Q6 biosynthesis through the dephosphorylation of the demethoxy-Q6 hydroxylase Coq7 (Coq7p). The current findings revealed that Ptc7p is a regulator of mitochondrial metabolism that is essential to maintain a proper function of the mitochondria by regulating energy metabolism and oxidative stress resistance. 23852678 The prevalence of neutralizing antibodies against AAV serotype 1 in healthy subjects in China: Implications for gene therapy and vaccines using AAV1 vector. Recombinant adeno-associated virus serotype 1 (AAV1) has attracted tremendous interest as a promising vector for gene therapy and vaccine applications. However, the presence of AAV1 neutralizing antibodies as a consequence of exposure to wild type AAV1 can limit significantly effective gene transfer for biologics based AAV1 vector. Prior studies have reported that a prevalence of AAV1 neutralizing antibodies ranged from 10% to 50% in different countries around the world, and up to 79% in Dutch subjects. However, few studies have reported on the AAV1 neutralizing antibody prevalence in Chinese subjects. In this study, a high-throughput luciferase-based virus neutralization assay was established and standardized for critical parameters, including the appropriate cell line, and the optimal viral infection dose, and the infection time with homologous AAV1 vaccinated mice and guinea pig sera. Then, a total of 500 healthy individual serum samples from two separate regions of China were screened for the AAV1 neutralizing antibodies by conducting a non-randomized, cross-sectional analysis. Interestingly, a high prevalence of AAV1 neutralizing antibody (69.8%) was found in all individuals. There was significant difference observed for prevalence by gender (P = 0.042), age range (P = 0.011) and geographic origin (P < 0.001). The percentage of positive AAV1 neutralizing antibodies (NT50  > 10) in teenagers (year <18, as of 2012) was significant lower than that of adults (19-56, as of 2012) (P = 0.011), indicating the optimal vaccination period of childhood. The current study provides a useful insight for the future development of AAV1-based vaccination and gene therapy strategies in Beijing and Anhui provinces of China. J. Med. Virol. 85:1550-1556, 2013. © 2013 Wiley Periodicals, Inc. 23705903 Engineering Three-Dimensional Collagen-IKVAV Matrix to Mimic Neural Microenvironment. Engineering the cellular microenvironment has great potential to create a platform technology toward engineering of tissue and organs. This study aims to engineer a neural microenvironment through fabrication of three-dimensional (3D) engineered collagen matrixes mimicking in-vivo-like conditions. Collagen was chemically modified with a pentapeptide epitope consisting of isoleucine-lysine-valine-alanine-valine (IKVAV) to mimic laminin structure supports of the neural extracellular matrix (ECM). Three-dimensional collagen matrixes with and without IKVAV peptide modification were fabricated by freeze-drying technology and chemical cross-linking with glutaraldehyde. Structural information of 3D collagen matrixes indicated interconnected pores structure with an average pore size of 180 μm. Our results indicated that culture of dorsal root ganglion (DRG) cells in 3D collagen matrix was greatly influenced by 3D culture method and significantly enhanced with engineered collagen matrix conjugated with IKVAV peptide. It may be concluded that an appropriate 3D culture of neurons enables DRG to positively improve the cellular fate toward further acceleration in tissue regeneration. 23477374 Molecular Alterations in Partially-Encapsulated or Well-Circumscribed Follicular Variant of Papillary Thyroid Carcinoma. Background: Studies have described an encapsulated and an infiltrative form of the follicular variant of papillary thyroid carcinoma (FVPTC). Encapsulated FVPTCs have been reported to have virtually no recurrence risk or metastatic potential and to harbor RAS mutations but not BRAF mutations. In contrast, infiltrative tumors have significant metastatic potential, a risk of recurrence, and a BRAF mutation frequency of approximately 25%. In our experience, a substantial number of FVPTCs are neither fully encapsulated nor infiltrative, but instead are partially encapsulated (PE) or well circumscribed (WC). We have previously reported that PE/WC FVPTCs behave in an indolent fashion similar to encapsulated tumors. The purpose of the current study was to evaluate the molecular alterations in PE/WC FVPTC. Methods: We identified 28 PE/WC FVPTCs resected consecutively at our institution. Targeted mutation analysis of 41 genes including members of the RAS and RAF families was performed on DNA extracted from formalin-fixed, paraffin-embedded blocks using single-base extension chemistry and mass spectrometry. Results: Lymph node metastases were absent in all cases with sampled lymph nodes, and no patients developed tumor recurrences (median follow-up time, 72.8 months). Overall, 13 cases (46%) harbored RAS mutations, including seven (25%) with NRAS mutations (p.Gln61Arg) and six (21%) with HRAS mutations (five had p.Gln61Arg and one had a p.Gln61Lys substitution). No PE/WC FVPTCs had BRAF mutations. Conclusions: The results of this study confirm our previous finding that PE/WC FVPTCs pursue an indolent clinical course. Additionally, we found that PE/WC tumors have a similar molecular profile to that of encapsulated FVPTCs with frequent RAS mutations (46%) and no BRAF mutations. These molecular results provide further evidence that PE/WC and encapsulated FVPTCs are biologically similar and should be distinguished from more aggressive infiltrative FVPTCs. 23965392 Effects of composite antimicrobial peptides in weanling piglets challenged with deoxynivalenol: II. Intestinal morphology and function. Deoxynivalenol (DON) affects animal and human health and targets the gastrointestinal tract. The objective of this study was to evaluate the ability of composite antimicrobial peptides (CAP) to repair intestinal injury in piglets challenged with DON. A total of 28 piglets (Duroc x Landrace x Large Yorkshire) weaned at 28 d of age were randomly assigned to receive 1 of 4 treatments (7 pigs/treatment): negative control, basal diet (NC), basal diet + 0.4% composite antimicrobial peptide (CAP), basal diet + 4 ppm DON (DON), and basal diet + 4 ppm DON + 0.4% CAP (DON + CAP). After an adaptation period of 7 d, blood samples were collected on d 15 and 30 after the initiation of treatment for determinations of the concentrations of D-lactate and diamine oxidase. At the end of the study, all piglets were slaughtered to obtain small intestines for the determination of intestinal morphology, epithelial cell proliferation, and protein expression in the mammalian target of rapamycin (mTOR) signaling pathway. The results showed that DON increased serum levels of D-lactate and diamine oxidase, and these values in the CAP and DON + CAP treatments were lower than those in the NC and DON treatments, respectively (P < 0.05). The villous height/crypt depth in the jejunum and ileum and the goblet cell number in the ileum in the CAP and DON + CAP treatments were greater than those in the NC and DON treatments (P < 0.05). The proliferating cell nuclear antigen (PCNA) labeling indexes for the jejunum and ileum in the DON + CAP treatment were greater than those in the DON treatment (P < 0.05). The DON decreased (P < 0.05) the relative protein expression levels of phosphorylated Akt (Protein Kinase B) and mTOR in the jejunal and ileal mucosa and of phosphorylated 4E-binding protein 1 (p-4EBP1) in the jejunal mucosa, while CAP increased (P < 0.05) the protein expression levels of p-4EBP1 in the jejunum. These findings showed that DON could enhance intestinal permeability, damage villi, cause epithelial cell apoptosis and inhibit protein synthesis, whereas CAP improved intestinal morphology and promoted intestinal epithelial cell proliferation and protein synthesis, indicating that CAP may repair the intestinal injury induced by DON. 23947386 Is a standalone inertial measurement unit accurate and precise enough for quantification of movement symmetry in the horse? Standalone 'low-cost' inertial measurement units (IMUs) could facilitate large-scale studies into establishing minimal important differences (MID) for orthopaedic deficits (lameness) in horses. We investigated accuracy and limits of agreement (LoA) after correction of magnitude-dependent differences of a standalone 6 degree-of-freedom IMU compared with an established IMU-based gait analysis system (MTx) in six horses for two anatomical landmarks (sacrum and sternum). Established symmetry measures were calculated from vertical displacement: symmetry index (SI), difference between minima (MinDiff) and difference between maxima (MaxDiff). For the sacrum, LoA were ± 0.095 for SI, ± 6.6 mm for MinDiff and ± 4.3 mm for MaxDiff. For the sternum, LoA values were ± 0.088 for SI, ± 5.0 mm for MinDiff and ± 4.2 mm for MaxDiff. Compared with reference data from mildly lame horses, SI values indicate sufficient precision, whereas MinDiff and MaxDiff values are less favourable. Future studies should investigate specific calibration and processing algorithms further improving standalone IMU performance. 23886592 Associations of Frequency and Duration of Patient-Doctor Contact in Hemodialysis Facilities with Mortality. It is unknown whether regular patient-doctor contact (PDC) contributes to better outcomes for patients undergoing hemodialysis. Here, we analyzed the associations between frequency and duration of PDC during hemodialysis treatments with clinical outcomes among 24,498 patients from 778 facilities in the international Dialysis Outcomes and Practice Patterns Study (DOPPS). The typical facility PDC frequency, estimated by facility personnel, was high (more than once per week) for 55% of facilities, intermediate (once per week) for 24%, and low (less than once per week) for 21%. The mean ± SD estimated duration of a typical interaction between patient and physician was 7.7±5.6 minutes. PDC frequency and duration varied across DOPPS phases and countries; the proportion of facilities with high PDC frequency was 17% in the United States and 73% across the other countries. Compared with high PDC frequency, the adjusted hazard ratio (HR) for all-cause mortality was 1.06 (95% confidence interval [CI], 0.96 to 1.17) for intermediate PDC frequency and 1.11 (95% CI, 1.01 to 1.23) for low PDC frequency (P=0.03 for trend). Furthermore, each 5-minutes-shorter duration of PDC was associated with a 5% higher risk for death, on average (HR, 1.05; 95% CI, 1.01 to 1.09), adjusted for PDC frequency and other covariates. Multivariable analyses also suggested modest inverse associations between both PDC frequency and duration with hospitalization but not with kidney transplantation. Taken together, these results suggest that policies supporting more frequent and longer duration of PDC may improve patient outcomes in hemodialysis. 23500798 Blocking toll-like receptor 2 and 4 signaling during a stressor prevents stress-induced priming of neuroinflammatory responses to a subsequent immune challenge. Acute and chronic stressors sensitize or prime the neuroinflammatory response to a subsequent peripheral or central immunologic challenge. However, the neuroimmune process(es) by which stressors prime or sensitize subsequent neuroinflammatory responses remains unclear. Prior evidence suggested that toll-like receptors (TLRs) might be involved in the mediation of primed neuroinflammatory responses, but the role of TLRs during a stressor has never been directly tested. Here, a novel TLR2 and TLR4 antagonist, OxPAPC, was used to probe the contribution of TLRs in the stress sensitization phenomenon. OxPAPC has not previously been administered to the brain, and so its action in blocking TLR2 and TLR4 action in brain was first verified. Administration of OxPAPC into the CNS prior to stress prevented the stress-induced potentiation of hippocampal pro-inflammatory response to a subsequent peripheral LPS challenge occurring 24 h later. In addition, in vivo administration of OxPAPC prior to stress prevented the sensitized pro-inflammatory response from isolated microglia following administration of LPS ex vivo, further implicating microglia as a key neuroimmune substrate that mediates stress-induced sensitized neuroinflammation. 23456132 Medical complications and outcomes at an onsite rehabilitation unit for older people. The rehabilitation of older patients in Ireland after an acute medical event occurs at dedicated onsite hospital units or at offsite centres. Information on medical complications and outcomes is inadequate. Enumeration of medical complications of patients admitted to a dedicated onsite rehabilitation unit for older people, and the extent of co-morbidity in the population with the effects that this had on the evolution of medical complications. A retrospective analysis of patients admitted to a 58-bed onsite unit over a 1-year period was performed. Information collating co-morbidities, medical complications and functional outcomes was recorded. Medical complications occurred in almost 95% of patients, where full data were available. Over one-third required intravenous therapy. Twenty-four hour medical cover is required for older patients managed at onsite rehabilitation units. Further studies on offsite medical rehabilitation facilities for older patients are required. 23416279 Cyst features and risk of malignancy in intraductal papillary mucinous neoplasms of the pancreas: a meta-analysis. International guidelines for the management of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas recommend surgical resection of those with specific characteristics. We performed a meta-analysis to evaluate the risk of malignancy associated with each of these features of IPMNs. We performed a comprehensive search of MEDLINE from January 1, 1996, to November 11, 2011, for studies that included any of the features mentioned in the consensus guidelines for surgical resection of main duct and branch duct IPMNs. Data were analyzed from 41 studies for the following features: cyst size greater than 3 cm, the presence of mural nodules, dilated main pancreatic duct, symptoms, and main duct vs branch duct IPMNs. Malignant IPMNs were defined as those with carcinoma in situ or more advanced histology. A separate meta-analysis was performed for each risk factor to calculate pooled odds ratios (ORs). A random-effects model was used, based on the assumption of variation among study populations. The risks of malignancy associated with individual cyst features were as follows: cyst size greater than 3 cm (OR, 62.4; 95% confidence interval [CI], 30.8-126.3), presence of a mural nodule (OR, 9.3; 95% CI, 5.3-16.1), dilatation of the main pancreatic duct (OR, 7.27; 95% CI, 3.0-17.4), and main vs branch duct IPMN (OR, 4.7; 95% CI, 3.3-6.9). There was a moderate level of heterogeneity among studies (I(2) range, 34-67). Based on a meta-analysis, cyst features proposed by the international guidelines for resection of IPMN were highly associated with malignancy. However, based on our findings, not all cyst features should be weighted equally when considering risk of malignancy; cyst size greater than 3 cm was associated most strongly with malignant IPMN. 23932424 L-PRP diminishes bone matrix formation around autogenous bone grafts associated with changes in osteocalcin and PPAR-γ immunoexpression. Leucocyte- and platelet-rich plasma (L-PRP) is an autogenous platelet concentrate enriched with leukocytes that releases various growth factors responsible for the proliferation, regulation, and differentiation of mesenchymal cells during wound healing. Since the bone and medullary tissue are contiguous and share the same origin, this study evaluated the effect of L-PRP on the repair of calvaria bone using histomorphometric analysis of the newly formed bone, and compared the results in the presence of osteocalcin (OC) and peroxisome proliferator-activated receptor gamma (PPAR-γ) detected by immunohistochemistry. Artificial circular bone defects (5mm diameter) were produced in the calvaria of 42 rats. The defects were treated with autograft, autograft combined with L-PRP, or without grafting material (sham). The animals were euthanized at 15 or 40 days postsurgery (n=7 in each group). Data obtained were analyzed by Student-Newman-Keuls test for histomorphometric and immunohistochemical interpretation. The development of bone matrix was significantly less in the defects treated with L-PRP, while the medullary area composed of fatty cells was larger. This coincided with the minor expression of OC and expressive presence of PPAR-γ. These results suggest that L-PRP may impair osteoneogenesis and alter the ratio of differentiation between bone matrix and fatty cells, increasing the medullary tissue. 23879480 The entropic nature of protein thermal stabilization. We performed thermodynamic analysis of temperature-induced unfolding of mesophilic and thermophilic proteins. It was shown that the variability in protein thermostability associated with pH-dependent unfolding or linked to the substitution of amino acid residues on the protein surface is evidence of the governing role of the entropy factor. Numerical values of conformational components in enthalpy, entropy and free energy which characterize protein unfolding in the "gas phase" were obtained. Based on the calculated absolute values of entropy and free energy, a model of protein unfolding is proposed in which the driving force is the conformational entropy of native protein, as an energy of the heat motion (T·S (NC)) increasing with temperature and acting as an factor devaluating the energy of intramolecular weak bonds in the transition state. 23915802 Characterization of biological features of a rat F98 GBM model: A PET-MRI study with [(18)F]FAZA and [(18)F]FDG. The prognosis of malignant gliomas remains largely unsatisfactory for the intrinsic characteristics of the pathology and for the delayed diagnosis. Multimodal imaging based on PET and MRI may assess the dynamics of disease onset and progression allowing the validation of preclinical models of glioblastoma multiforme (GBM). The aim of this study was the characterization of a syngeneic rat model of GBM using combined in vivo imaging and immunohistochemistry. Four groups of Fischer rats were implanted in a subcortical region with increasing concentration of rat glioma F98 cells and weekly monitored with Gd-MR, [(18)F]FDG- and [(18)F]FAZA-PET starting one week after surgery. Different targets were evaluated on post mortem brain specimens using immunohistochemistry: VEGF, GFAP, HIF-1α, Ki-67 and nestin. Imaging results indicated that tumor onset but not progression was related to the number of F98 cells. Hypoxic regions identified with [(18)F]FAZA and high-glucose metabolism regions recognized with [(18)F]FDG were located respectively in the core and in external areas of the tumor, with partial overlap and remodeling during disease progression. Histological and immunohistochemical analysis confirmed PET/MRI results and revealed that our model resumes biological characteristics of human GBM. IHC and PET studies showed that necrotic regions, defined on the basis of [(18)F]FDG uptake reduction, may include hypoxic clusters of vital tumor tissue identified with [(18)F]FAZA. This last information is particularly relevant for the identification of the target volume during image-guided radiotherapy. In conclusion, the combined use of PET and MRI allows in vivo monitoring of the biological modification of F98 lesions during tumor progression. 23949323 Confirmation of diosmetin 3-O-glucuronide as major metabolite of diosmin in humans, using micro-liquid-chromatography-mass spectrometry and ion mobility mass spectrometry. Diosmin is a flavonoid often administered in the treatment of chronic venous insufficiency, hemorrhoids, and related affections. Diosmin is rapidly hydrolized in the intestine to its aglicone, diosmetin, which is further metabolized to conjugates. In this study, the development and validations of three new methods for the determination of diosmetin, free and after enzymatic deconjugation, and of its potential glucuronide metabolites, diosmetin-3-O-glucuronide, diosmetin-7-O-glucuronide, and diosmetin-3,7-O-glucuronide from human plasma and urine are presented. First, the quantification of diosmetin, free and after deconjugation, was carried out by high-performance liquid chromatography coupled with tandem mass spectrometry, on an Ascentis RP-Amide column (150 × 2.1 mm, 5 Î¼m), in reversed-phase conditions, after enzymatic digestion. Then glucuronide metabolites from plasma were separated by micro-liquid chromatography coupled with tandem mass spectrometry on a HALO C18 (50 × 0.3 mm, 2.7 Î¼m, 90 Ã…) column, after solid-phase extraction. Finally, glucuronides from urine were measured using a Discovery HSF5 (100 × 2.1 mm, 5 Î¼m) column, after simple dilution with mobile phase. The methods were validated by assessing linearity, accuracy, precision, low limit of quantification, selectivity, extraction recovery, stability, and matrix effects; results in agreement with regulatory (Food and Drug Administration and European Medicines Agency) guidelines acceptance criteria were obtained in all cases. The methods were applied to a pharmacokinetic study with diosmin (450 mg orally administered tablets). The mean C max of diosmetin in plasma was 6,049.3 ±â€‰5,548.6 pg/mL. A very good correlation between measured diosmetin and glucuronide metabolites concentrations was obtained. Diosmetin-3-O-glucuronide was identified as a major circulating metabolite of diosmetin in plasma and in urine, and this finding was confirmed by supplementary experiments with differential ion-mobility mass spectrometry. 23908251 Pelvic fractures: part 1. Evaluation, classification, and resuscitation. Pelvic fractures range in severity from low-energy, generally benign lateral compression injuries to life-threatening, unstable fracture patterns. Initial management of severe pelvic fractures should follow Advanced Trauma Life Support protocols. Initial reduction of pelvic blood loss can be provided by binders, sheets, or some form of external fixation, which serve to reduce pelvic volume, stabilize clot formation, and reduce ongoing tissue damage. Persistently unstable patients may benefit from angiography with selective embolization, pelvic packing, or a combination of these interventions. Open pelvic fractures involving the perineum or bowel injury benefit from fecal diversion by colostomy. Trauma team coordination facilitates efficient resuscitative efforts and may affect definitive management by optimizing incision, ostomy, or catheter placement. Established protocols for both open and closed pelvic fractures help to standardize care. 23558602 Pharmacokinetics of a new immediate-release compound omeprazole capsule and its comparison with the enteric-coated formulation under fasting and fed conditions. The present study was conducted to describe the pharmacokinetic profile of immediate-release compound omeprazole capsule and compare it with the enteric-coated formulation under fasting and fed condition.This study was designed to phase I, open-label, randomized, 3-part clinical trial. 12 subjects in part one received single doses (20 mg and 40 mg) and repeated doses (20 mg). Different 30 subjects in part 2 (fasting condition) and part 3 (fed condition) received either compound omeprazole capsule (40 mg) or delayed-release omeprazole (40 mg) separated by 7 days.Compound omeprazole capsule showed dose non-proportionality in the range from 20 mg to 40 mg. The AUC0-t of 20 mg omeprazole is 78% higher after repeated doses. The C max was higher and T max was lower for compound omeprazole capsule than delayed-release omeprazole. 90% CIs for AUC0-t of the 2 periods (test/reference) under fasting and fed conditions were 106.3% (102.2%~109.2%) and 104.1% (93.4%~109.6%), respectively. Presence of food reduced the rate (C max) and extent (AUC0-t) of systemic exposure of the test and reference formulations from 1 462 to 777 ng · mL-1, 1 055 to 602 ng · mL-1, 2 597 to 1 852 ng · h · mL-1 and 2 454 to 1 873 ng · h · mL-1, respectively.Exposed dose of omeprazole in subjects with compound omeprazole capsule was time- and dose-dependent. Compared with delayed-release omeprazole, compound omeprazole capsule had rapid but similar degree of absorption of omeprazole. 23864522 An Empirical Assessment of the Overlap Between Sexual Victimization and Sex Offending. There has been a recent proliferation in the number of studies that are investigating the phenomenon that has been coined the victim-offender overlap. There has been noticeably less attention toward examining the sexual victimization and sex offending overlap. Acknowledging this gap in the literature, the present study provides an assessment of this overlap among a large sample of male prisoners with a focus on the cycle of violence hypothesis. Bivariate results reveal a considerable degree of overlap between sexual victimization and sex offending, and multivariate results estimated from a series of bivariate probit models simultaneously assessing both outcomes suggest that experiencing emotional abuse early on in the life-course is a robust risk factor for experiencing sexual victimization and demonstrating sex offending behavior. Furthermore, being physically neglected and witnessing family violence also emerged as significant risk factors for sexual victimization. Study limitations and policy implications are also discussed. 23907399 Comparison of Surveillance Sample Demographics Over Two Cycles of the National HIV Behavioral Surveillance Project, Houston, Texas. We examined differences in sample demographics across cycles of the National HIV Behavioral Surveillance project, that examines HIV risk behaviors among men who have sex with men (MSM), injection drug users (IDU), and heterosexuals living in areas of high HIV prevalence (HET). MSM were recruited through venue-based sampling, and IDU and HET through respondent driven sampling (RDS). RDS data were weighted to account for sampling bias. We compared crude prevalence estimates from MSM1 (2004) to those from MSM2 (2008) for demographic factors known to influence risky sexual and drug-use behaviors. We compared crude and adjusted prevalence estimates for IDU1 (2005) and IDU2 (2009) and HET1 (2006) and HET2 (2010). In the MSM cycle, we found differences in age, and the proportions seeking medical care and reporting a recent arrest. There were no differences in the comparison of crude and weighted estimates for the RDS collected samples, nor were there differences comparing HET1 and HET2 weighted estimates. IDU2 recruited a larger proportion of males, and had a higher percent who graduated from high school and who reported recent medical care and a previous HIV test. Differences across MSM cycles may be related to differences in venues identified for each cycle. Differences in the IDU cycles may be due to an effort on our part to increase the racial/ethnic and drug-use diversity of the sample in IDU2. Our findings show the importance of formative work for both venue-based and RDS samples to increase understanding of the dimensions that affect social networks and the dynamics of populations in space and time. With familiarity of the target population, we believe that both venue-based and RDS recruitment approaches for NHBS work well and can be used to evaluate changes in risky sexual and drug use behaviors and in HIV testing behaviors. 23498944 Nuclear positioning. The nucleus is the largest organelle and is commonly depicted in the center of the cell. Yet during cell division, migration, and differentiation, it frequently moves to an asymmetric position aligned with cell function. We consider the toolbox of proteins that move and anchor the nucleus within the cell and how forces generated by the cytoskeleton are coupled to the nucleus to move it. The significance of proper nuclear positioning is underscored by numerous diseases resulting from genetic alterations in the toolbox proteins. Finally, we discuss how nuclear position may influence cellular organization and signaling pathways. 23586841 Activated complement factor 3 is associated with liver fat and liver enzymes: the CODAM study. The complement system may be involved in the pathogenesis of alcoholic and nonalcoholic liver disease, although studies in humans are scarce. For this reason, we investigated whether circulating levels of activated complement factor 3 (C3a) were associated with hepatic steatosis and hepatocellular damage. Plasma C3a, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) were determined in 523 individuals (61% men, age 59 ± 7 years). Liver enzymes (LEs) were standardized and compiled into a LE score. Liver fat content was estimated using a predictive equation that has recently been validated with magnetic resonance spectrometry. Cross-sectional associations between C3a and liver fat or LE s were investigated with multiple linear regression analyses, stratified in no-to-moderate vs. heavy alcohol consumers (men: > 30 g/day; women: > 20 g/day). C3a was associated with liver fat percentage both in the no-to-moderate (β = 0.223; 95%CI 0.036; 0.409) and in the heavy alcohol consumers (β = 0.632; 95%CI 0.259-1.004; P-interaction = 0.047). C3a was also associated with the LE score in heavy alcohol consumers (β = 0.917; 95%CI 0.443-1.392), but not in no-to-moderate alcohol consumers (β = 0.042; 95%CI -0.198 to 0.281; P-interaction = 0.001). C3a levels, as a marker of complement activation, were associated with liver fat content and hepatocellular injury, at least in subjects who consume considerable amounts of alcohol daily. 23871121 Kenya's Health Workforce Information System: A model of impact on strategic human resources policy, planning and management. Countries worldwide are challenged by health worker shortages, skill mix imbalances, and maldistribution. Human resources information systems (HRIS) are used to monitor and address these health workforce issues, but global understanding of such systems is minimal and baseline information regarding their scope and capability is practically non-existent. The Kenya Health Workforce Information System (KHWIS) has been identified as a promising example of a functioning HRIS. The objective of this paper is to document the impact of KHWIS data on human resources policy, planning and management. Sources for this study included semi-structured interviews with senior officials at Kenya's Ministry of Medical Services (MOMS), Ministry of Public Health and Sanitation (MOPHS), the Department of Nursing within MOMS, the Nursing Council of Kenya, Kenya Medical Practitioners and Dentists Board, Kenya's Clinical Officers Council, and Kenya Medical Laboratory Technicians and Technologists Board. Additionally, quantitative data were extracted from KHWIS databases to supplement the interviews. Health sector policy documents were retrieved from MOMS and MOPHS websites, and reviewed to assess whether they documented any changes to policy and practice as having been impacted by KHWIS data. Interviews with Kenyan government and regulatory officials cited health workforce data provided by KHWIS influenced policy, regulation, and management. Policy changes include extension of Kenya's age of mandatory civil service retirement from 55 to 60 years. Data retrieved from KHWIS document increased relicensing of professional nurses, midwives, medical practitioners and dentists, and interviewees reported this improved compliance raised professional regulatory body revenues. The review of Government records revealed few references to KHWIS; however, documentation specifically cited the KHWIS as having improved the availability of human resources for health information regarding workforce planning, management, and development. KHWIS data have impacted a range of improvements in health worker regulation, human resources management, and workforce policy and planning at Kenya's ministries of health. 23685632 Occurrence and risk assessment of organophosphorus and brominated flame retardants in the River Aire (UK). This study presents the occurrence and risk of PBDEs, new brominated and organophosphorus flame retardants along a river affected by urban and industrial pressures (River Aire, UK). Tris(2-choroethyl) phosphate (TCEP), tris(2-chloro-1-methylethyl) phosphate (TCPP), tris[2-chloro-1-(chloromethyl)ethyl] phosphate (TDCP) and triphenyl phosphate (TPhP) were detected in all samples, with TCPP present at the highest concentrations, ranging from 113 to 26,050 ng L⁻¹. BDE-209 was detected in most of the sampled sites, ranging from 17 to 295 ng L⁻¹, while hexabromobenzene (HBB) and pentabromoethyl benzene (PBEB) were seldom detected. A risk quotients based on predicted no effect concentrations (PNEC) and flame retardants water concentration proved significant risk for adverse effects for algae, Daphnia and fish in sites close to industrial and urban sewage discharges. This study provides a protocol for the risk estimation of priority and new generation flame retardants based on river concentrations and toxicological values. 23816396 Impact of targeting insulin-like growth factor signaling in head and neck cancers. The IGF system has been shown to have either negative or negligible impact on clinical outcomes of tumor development depending on specific tumor sites or stages. This review focuses on the clinical impact of IGF signaling in head and neck cancer, the effects of IGF targeted therapies, and the multi-dimensional role of IRS 1/2 signaling as a potential mechanism in resistance to targeted therapies. Similar to other tumor sites, both negative and positive correlations between levels of IGF-1/IGF-1-R and clinical outcomes in head and neck cancer have been reported. In addition, utilization of IGF targeted therapies has not demonstrated significant clinical benefit; therefore the prognostic impact of the IGF system on head and neck cancer remains uncertain. 23336753 Mixed valency in hydrogen bonded 'dimers of dimers'. Dimolybdenum quadruply bonded compounds containing a pendant lactam functional group form self-complementary hydrogen bonded 'dimers of dimers' in the solid-state and CH(2)Cl(2) solutions. Electrochemical studies in CH(2)Cl(2) show two consecutive one-electron redox processes corresponding to oxidation of the Mo(2)(4+) cores. Spectroelectrochemical studies on the 'dimers of dimers' show no evidence of intervalence charge transfer bands in the mixed valence radical cations formed by one-electron oxidation, indicating that they are examples of proton-coupled mixed valency. 23615402 6,7-Dimethoxy-3-(3-methoxyphenyl)isoquinolin-1-amine induces mitotic arrest and apoptotic cell death through the activation of spindle assembly checkpoint in human cervical cancer cells. Previously, we reported that 6,7-dimethoxy-3-(3-methoxyphenyl)isoquinolin-1-amine (CWJ-082) has potent cytotoxic effects on various cancer cells, but the underlying molecular mechanism responsible was not determined. In the present study, CWJ-082 caused cervical cancer cell cycle arrest at the G2/M phase and subsequent caspase-dependent apoptosis. The mitotic arrest caused by CWJ-082 found to be due to increases in the activation of cyclin-dependent kinase 1/cyclin B1 complex and the phosphorylation of histone H3. In addition, CWJ-082 induced the phosphorylation of BubR1 and the association between mitotic arrest deficient 2 (Mad2) and cell division cycle protein 20. These findings suggested that CWJ-082 activated the mitotic spindle checkpoint. Furthermore, knockdown of the spindle checkpoint proteins BubR1 or Mad2 using specific small interfering RNAs significantly reduced CWJ-082-induced mitotic cell accumulation and apoptosis. In addition, CWJ-082 induced the appearance of spindle abnormalities by inducing α-tubulin polymerization. In BALB/c(nu/nu) mice bearing a HeLa xenograft, CWJ-082 significantly inhibited tumor growth. Taken together, these results suggest that CWJ-082 inhibits cell growth via mitotic arrest by activating the mitotic spindle checkpoint and by inducing α-tubulin polymerization and that these events ultimately lead to the apoptosis of human cervical cancer cells and inhibit tumor growth in HeLa xenograft mice. 23831121 Impact of diaphragm muscle fiber atrophy on neuromotor control. In skeletal muscles, motor units comprise a motoneuron and the group of muscle fibers innervated by it, which are usually classified based on myosin heavy chain isoform expression. Motor units displaying diverse contractile and fatigue properties are important in determining the range of motor behaviors that can be accomplished by a muscle. Muscle fiber atrophy and weakness may disproportionately affect specific fiber types across a variety of diseases or clinical conditions, thus impacting neuromotor control. In this regard, fiber atrophy that affects a specific fiber type will alter the relative contribution of different motor units to overall muscle structure and function. For example, in various diseases there is fairly selective atrophy of type IIx and/or IIb fibers comprising the strongest yet most fatigable motor units. As a result, there is muscle weakness (i.e., reductions in force per cross-sectional area) associated with an apparent improvement in resistance to fatiguing contractions. This review will examine neuromotor control of respiratory muscles such as the diaphragm muscle and the impact of muscle fiber atrophy on motor performance. 23553339 RNA interference in the treatment of colon cancer. Colorectal cancer is the third most common cancer in both men and women and has shown a progressive increase over the past 20 years. Current chemotherapy has major limitations, and a novel therapeutic approach is required. Given that neoplastic transformation of colon epithelial cells is a consequence of genetic and epigenetic alterations, RNA interference (RNAi) has been proposed as a new therapeutic strategy that offers important advantages over conventional treatments, with high specificity and potency and low toxicity. RNAi has been employed as an effective tool to study the function of genes, preventing their expression and leading to the development of new approaches to cancer treatment. In malignancies, including colon cancer, RNAi is being used for "silencing" genes that are deregulated by different processes such as gene amplification, mutation, or overexpression and may be the cause of oncogenesis. This strategy not only provides information on the involvement of certain genes in colon cancer, but also opens up a new perspective for its treatment. However, most studies have used adenovirus or lentivirus vectors to transport RNAi into tumor cells or tumors in animal models, because several technical obstacles must be overcome before RNAi can be used in the clinical setting. The aim of this study was to review current knowledge on the use of RNAi techniques in the treatment of colon cancer. 23744075 Pancreatic Acinar Cell Nuclear Factor κB Activation Because of Bile Acid Exposure Is Dependent on Calcineurin. Biliary pancreatitis is the most common etiology of acute pancreatitis, accounting for 30-60% of cases. A dominant theory for the development of biliary pancreatitis is the reflux of bile into the pancreatic duct and subsequent exposure to pancreatic acinar cells. Bile acids are known to induce aberrant Ca(2+) signals in acinar cells as well as nuclear translocation of NF-κB. In this study, we examined the role of the downstream Ca(2+) target calcineurin on NF-κB translocation. Freshly isolated mouse acinar cells were infected for 24 h with an adenovirus expressing an NF-κB luciferase reporter. The bile acid taurolithocholic acid-3-sulfate caused NF-κB activation at concentrations (500 μm) that were associated with cell injury. We show that the NF-κB inhibitor Bay 11-7082 (1 μm) blocked translocation and injury. Pretreatment with the Ca(2+) chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, the calcineurin inhibitors FK506 and cyclosporine A, or use of acinar cells from calcineurin Aβ-deficient mice each led to reduced NF-κB activation with taurolithocholic acid-3-sulfate. Importantly, these manipulations did not affect LPS-induced NF-κB activation. A critical upstream regulator of NF-κB activation is protein kinase C, which translocates to the membranes of various organelles in the active state. We demonstrate that pharmacologic and genetic inhibition of calcineurin blocks translocation of the PKC-δ isoform. In summary, bile-induced NF-κB activation and acinar cell injury are mediated by calcineurin, and a mechanism for this important early inflammatory response appears to be upstream at the level of PKC translocation. 23567439 Criterion Validity of an Attention Deficit Hyperactivity Disorder (ADHD) Screening List for Screening ADHD in Older Adults Aged 60-94 years. To identify Attention Deficit Hyperactivity disorder (ADHD) in older adults, a validated screener is needed. This study evaluates the reliability and criterion validity of an ADHD screener for younger adults on its usefulness in a population-based sample of older adults. Data were collected as a side study in the Longitudinal Aging Study Amsterdam. In a two-phase design the validity of the screener was tested against a structured diagnostic interview (DIVA 2.0). In Phase 1, 1,494 respondents (60-94 years) were assessed with the ADHD screener. In Phase 2, 231 respondents participated in the diagnostic interview. Internal consistency (Cronbach's α) and reliability (ICC) of the screener were 0.71 and 0.56, respectively. The area under the curve was 0.82. The optimal cut-point was found at 2 (sensitivity: 0.80; specificity: 0.77; PPV: 0.13; NPV: 0.99). Despite its low ICC, the ADHD screener may serve as a useful contribution to measure ADHD in the older population. 23947784 Progression of bone metastases in patients with prostate cancer - automated detection of new lesions and calculation of bone scan index. The objective of this study was firstly to develop and evaluate an automated method for the detection of new lesions and changes in bone scan index (BSI) in serial bone scans and secondly to evaluate the prognostic value of the method in a group of patients receiving chemotherapy. The automated method for detection of new lesions was evaluated in a group of 266 patients using the classifications by three experienced bone scan readers as a gold standard. The prognostic value of the method was assessed in a group of 31 metastatic hormone-refractory prostate cancer patients who were receiving docetaxel. Cox proportional hazards were used to investigate the association between percentage change in BSI, number of new lesions and overall survival. Kaplan-Meier estimates of the survival function were used to indicate a significant difference between patients with an increase/decrease in BSI or those with two or more new lesions or less than two new lesions. The automated method detected progression defined as two or more new lesions with a sensitivity of 93% and a specificity of 87%. In the treatment group, both BSI changes and the number of new metastases were significantly associated with survival. Two-year survival for patients with increasing and decreasing BSI from baseline to follow-up scans were 18% and 57% (p = 0.03), respectively. Two-year survival for patients fulfilling and not fulfilling the criterion of two or more new lesions was 35% and 38% (n.s.), respectively. An automated method can be used to calculate the number of new lesions and changes in BSI in serial bone scans. These imaging biomarkers contained prognostic information in a small group of patients with prostate cancer receiving chemotherapy. 23623393 Therapeutic improvement of glucoregulation in newly diagnosed type 2 diabetes patients is associated with a reduction of IL-17 levels. We explored the effect of therapeutic glucoregulation on the blood levels of proinflammatory T helper (Th)17 cytokines interleukin (IL)-17 and IL-23, and Th1 cytokines interferon (IFN)-γ and IL-12 in newly diagnosed type 2 diabetes patients. The investigated group consisted of 23 subjects (17 men and 6 women, age 26-64). The cytokine serum levels, glycated hemoglobin (HbA1c) as a marker of glucoregulation, homeostasis model assessment index as a measure of insulin resistance (HOMA-IR), and body mass index (BMI) were determined before and after 12 weeks of therapy consisting of standard lifestyle modification and metformin (1000 mg b.i.d.). The levels of Th17 and Th1 cytokines before treatment did not correlate with age, BMI or HOMA-IR. The patients with poor glucoregulation (HbA1c>7%, n=12), compared to those with good glucoregulation (HbA1c≤7%, n=11), had higher serum levels of Th17 and Th1 cytokines, but only the differences in IL-17 (median 21.2 pg/ml vs. 4.8 pg/ml) and IFN-γ 5 (0.6 pg/ml vs. 27.7 pg/ml) reached statistical significance (p=0.003 and p=0.012, respectively). The reduction of HbA1c values (from 8.6 to 5.9%, p=0.000) observed upon treatment in patients with poor glucoregulation was associated with a significant decrease in the concentration of IL-17 (from 21.2 to 12.9 pg/ml, p=0.020), but not IFN-γ (50.6 vs. 52.3, p=0.349). These data indicate that therapeutic improvement of glucoregulation might contribute to a reduction of IL-17 levels in newly diagnosed type 2 diabetes patients. 23748129 Actigraphy monitoring of symptoms in patients with Parkinson's disease. Although the Unified Parkinson's Disease Rating Scale (UPDRS) is the "gold-standard" tool in assessing the severity of symptoms in patients with Parkinson's disease (PD), not all activity-related disease symptoms can be accurately captured by the well-established clinical rating scale. Using an alternative approach, this study examined the level of physical activity measured by actigraphy over time and whether change in physical activity was associated with disease severity assessed by UPDRS. We used a longitudinal design in which physical activity and disease severity were assessed repeatedly during a 4-month interval, over a 3-year observational period, in a sample of 61 patients with idiopathic PD and a control group of 32 neurologically intact individuals. Physical activity data during awake-time were analyzed using the power-law exponent (PLE) method. Correlational relationships between changes in maxima values of PLE and scores of total UPDRS, UPDRS-part II (Activities of Daily Living), and UPDRS-part III (Motor Examination) in patients with PD were examined. Results show an increase in maxima values of PLE and the UPDRS total score in PD patients and that there is a positive association between changes in maxima values and total UPDRS score (r=0.746, p=0.032), UPDRS-part II score (r=0.687, p=0.027), and UPDRS-part III score (r=0.893, p=0.018). There was no significant change in the level of physical activity over time for the controls. Findings from this study indicate that change in physical activity, as captured by actigraphy, is associated with increased severity in patients' clinical symptoms of PD over time. Thus, these data suggest that, when used in conjunction with the conventional UPDRS measure, an actigraphic measure of physical activity may provide clinicians an adjunct measurement approach to monitor patients' activity-based disease progression or responses to treatment in outpatient clinic settings. 23664954 Tactile stimulation and hemispheric asymmetries modulate auditory perception and neural responses in primary auditory cortex. Although multisensory integration has been an important area of recent research, most studies focused on audiovisual integration. Importantly, however, the combination of audition and touch can guide our behavior as effectively which we studied here using psychophysics and functional magnetic resonance imaging (fMRI). We tested whether task-irrelevant tactile stimuli would enhance auditory detection, and whether hemispheric asymmetries would modulate these audiotactile benefits using lateralized sounds. Spatially aligned task-irrelevant tactile stimuli could occur either synchronously or asynchronously with the sounds. Auditory detection was enhanced by non-informative synchronous and asynchronous tactile stimuli, if presented on the left side. Elevated fMRI-signals to left-sided synchronous bimodal stimulation were found in primary auditory cortex (A1). Adjacent regions (planum temporale, PT) expressed enhanced BOLD-responses for synchronous and asynchronous left-sided bimodal conditions. Additional connectivity analyses seeded in right-hemispheric A1 and PT for both bimodal conditions showed enhanced connectivity with right-hemispheric thalamic, somatosensory and multisensory areas that scaled with subjects' performance. Our results indicate that functional asymmetries interact with audiotactile interplay which can be observed for left-lateralized stimulation in the right hemisphere. There, audiotactile interplay recruits a functional network of unisensory cortices, and the strength of these functional network connections is directly related to subjects' perceptual sensitivity. 23731491 Phylogenetic analysis based on 18S rRNA gene sequences of Schellackia parasites (Apicomplexa: Lankesterellidae) reveals their close relationship to the genus Eimeria. In the present study we detected Schellackia haemoparasites infecting the blood cells of Lacerta schreiberi and Podarcis hispanica, two species of lacertid lizards from central Spain. The parasite morphometry, the presence of a refractile body, the type of infected blood cells, the kind of host species, and the lack of oocysts in the fecal samples clearly indicated these blood parasites belong to the genus Schellackia. Until now, the species of this genus have never been genetically characterized and its taxonomic position under the Lankesterellidae family is based on the lack of the exogenous oocyst stage. However, the phylogenetic analysis performed on the basis of the 18S rRNA gene sequence revealed that species of the genus Schellackia are clustered with Eimeria species isolated from a snake and an amphibian species but not with Lankesterella species. The phylogenetic analysis rejects that both genera share a recent common ancestor. Based on these results we suggest a revision of the taxonomic status of the family Lankesterellidae. 23955700 Saccharopolyspora cavernae sp. nov., a novel actinomycete isolated from the Swallow Cave in Yunnan, south-west China. A Gram-positive, aerobic, non-motile actinobacterial strain, designated YIM C01235(T), was isolated from a soil sample collected from the Swallow Cave, Yunnan province, south-west China. The isolate grew at 10-30 °C, pH 6.0-9.0 and 0-8 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences revealed highest similarity to Saccharopolyspora gloriosae YIM 60513(T) (96.8 %), and lower 16S rRNA gene sequence similarities (95.1-96.7 %) with the other species of the genus Saccharopolyspora. The whole-cell hydrolysates contained meso-diaminopimelic acid (meso-DAP), arabinose and galactose. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylmethylethanolamine, two unknown glycolipids, two unknown phospholipids and one polar lipid. MK-9(H4) was the predominant menaquinone. The major fatty acids were iso-C15:0, iso-C16:0, anteiso-C15:0 and anteiso-C17:0. Mycolic acids were not detected. The genomic DNA G+C content was 69.1 mol%. These chemotaxonomic data, together with its morphological properties, were consistent with the assignment of strain YIM C01235(T) to the genus Saccharopolyspora. The results of physiological and biochemical tests allowed strain YIM C01235(T) to be differentiated phenotypically from all the recognized Saccharopolyspora species. On the basis of evidence from this polyphasic study, the novel species Saccharopolyspora cavernae sp. nov. is proposed. The type strain is YIM C01235(T) (=DSM 45825(T) = CCTCC AA 2012022(T)). 23706184 Angiotensin-converting enzyme-inhibitors, statins and the risk of hemorrhage from cerebral dural arteriovenous fistulae. Leptomeningeal venous drainage and symptomatic presentation are known risk factors for cerebral dural arteriovenous fistula (dAVF) hemorrhage. An evaluation of potentially modifiable risk factors such as hypertension and medication usage has not been undertaken to our knowledge. The authors thus reviewed a cohort of 45 consecutive patients with cerebral dAVF with leptomeningeal venous drainage and compared the rate of hemorrhagic presentation for patients with and without a history of hypertension, hyperlipidemia or the usage of certain medications. Logistic regression was performed to determine the statistical significance of associations of each factor with hemorrhagic presentation. On univariate analysis, angiotensin-converting enzyme (ACE)-inhibitors (odds ratio [OR] 0.100, 95% confidence interval [CI] 0-0.764, p=0.024) and statins (OR 0.142, 95% CI 0.025-0.825, p=0.030) were associated with a statistically significant lower rate of hemorrhagic presentation. A trend toward a lower rate of hemorrhagic presentation was seen for patients taking aspirin (OR 0.153, 95% CI 0.016-1.43, p=0.10). These trends continued on multivariate analysis; however they did not meet statistical significance (p>0.05). Beta-blockers, calcium channel blockers, warfarin and selective serotonin reuptake inhibitors did not have a statistically significant association with the rate of hemorrhagic presentation (p>0.05). Although limited by small sample size, these results may suggest a beneficial effect of statins and ACE-inhibitors on the rate of dAVF hemorrhagic presentation, potentially as a result of anti-inflammatory, anti-angiogenic or even venous antithrombotic mechanisms. Despite this study's limitations, we hope it encourages further evaluation of potentially modifiable risk factors for vascular malformation hemorrhage. 23966030 Ischaemic heart disease, influenza and influenza vaccination: a prospective case control study. Abundant, indirect epidemiological evidence indicates that influenza contributes to all-cause mortality and cardiovascular hospitalisations with studies showing increases in acute myocardial infarction (AMI) and death during the influenza season. To investigate whether influenza is a significant and unrecognised underlying precipitant of AMI. Case-control study. Tertiary referral hospital in Sydney, Australia, during 2008 to 2010. Cases were inpatients with AMI and controls were outpatients without AMI at a hospital in Sydney, Australia. Primary outcome was laboratory evidence of influenza. Secondary outcome was baseline self-reported acute respiratory tract infection. Of 559 participants, 34/275 (12.4%) cases and 19/284 (6.7%) controls had influenza (OR 1.97, 95% CI 1.09 to 3.54); half were vaccinated. None were recognised as having influenza during their clinical encounter. After adjustment, influenza infection was no longer a significant predictor of recent AMI. However, influenza vaccination was significantly protective (OR 0.55, 95% CI 0.35 to 0.85), with a vaccine effectiveness of 45% (95% CI 15% to 65%). Recent influenza infection was an unrecognised comorbidity in almost 10% of hospital patients. Influenza did not predict AMI, but vaccination was significantly protective but underused. The potential population health impact of influenza vaccination, particularly in the age group 50-64 years, who are at risk for AMI but not targeted for vaccination, should be further explored. Our data should inform vaccination policy and cardiologists should be aware of missed opportunities to vaccinate individuals with ischaemic heart disease against influenza. 23953718 Pulmonary sleeve resection in locally advanced lung cancer using cryopreserved allograft for pulmonary artery replacement. During lobectomy, resection of pulmonary artery, followed by reconstruction or replacement with or without concomitant sleeve bronchial resection, is feasible in selected cases. We report morbidity, mortality, and technical issues in pulmonary artery replacement using a cryopreserved arterial allograft after sleeve resection for centrally located non-small cell lung carcinoma (NSCLC). We reviewed clinical and pathologic data of patients who underwent arterial sleeve lobectomy with pulmonary artery replacement in our institution from 2007 to 2012. Of 178 centrally located NSCLCs, sleeve resections were performed in 92 (51%), pneumonectomies in 33 (18%), and lobectomies in 53 (31%). Of the 32 (34.7%) pulmonary) reconstructions (excluding tangential suture), 20 (21.7%) were end-to-end anastomosis, 2 (2.1%) were pericardial patch reconstructions, and 10 (11%) were PA replacements. Clinical T staging was cT2a in 4 patients, cT2b in 3, cT3 in 2, and cT4 in 1. Four patients received concurrent induction chemoradiotherapy. Three patients underwent a double-sleeve right lobectomy. Cryopreserved allografts used were descending thoracic aorta (n = 3) and pulmonary arteries (n = 7). Complete resection (R0) was achieved in all patients. Final N staging was pN0 (n = 4), pN1 (n = 5), and pN2 (n = 1). There was no operative mortality. Four patients had major morbidity, including 1 early conduit thrombosis treated by pneumonectomy completion. Graft patency, assessed by contrast-enhanced computed tomography scan, was 90%. Mean follow-up was 25 ± 14 (range, 8-47) months (30% for >36 months). Overall 5-year survival was 66.7%, and the estimated median disease-free survival was 42 months. In central NSCLCs, conservative surgery using a cryopreserved arterial allograft to replace the pulmonary artery after extended segmental resection could avoid pneumonectomy in selected patients. 22884612 The mGlu₅ positive allosteric modulator LSN2463359 differentially modulates motor, instrumental and cognitive effects of NMDA receptor antagonists in the rat. Metabotropic glutamate 5 (mGlu₅) receptors are known to functionally interact with N-methyl-d-aspartate (NMDA) receptors at both neuronal and behavioural levels, in a manner that may be of relevance to the treatment of schizophrenia. We have previously described a novel mGlu₅ positive allosteric modulator (PAM), LSN2463359 and provided evidence of its ability to attenuate aspects of the behavioural response to administration of the competitive NMDA receptor antagonist, SDZ 220,581. In addition, LSN2463359 was found to selectively attenuate reversal learning deficits observed in the neurodevelopmental MAM E17 model but not in the acute phencyclidine (PCP) model. In the present study, the interactions between this mGlu₅ PAM and the NMDA receptor were explored further by assessing the effects of LSN2463359 against some of the motor, instrumental and cognitive effects induced by the non-competitive NMDA receptor antagonists PCP and MK-801, the competitive NMDA receptor antagonist SDZ 220,581 and the GluN2B selective NMDA receptor antagonist, Ro 63-1908. LSN2463359 had either no or minor impact on locomotor hyperactivity induced by either PCP or SDZ 220,581. However, in rats lever pressing for food rewards under a variable interval 30s schedule of instrumental responding, the drug clearly attenuated not only the suppression of response rate induced by SDZ 220,581 but also the stimulation of response rate induced by Ro 63-1908. In contrast, LSN2463359 failed to alter both of the instrumental effects induced by the open channel blockers PCP and MK-801. In addition, although PCP and SDZ 220,581 induced similar deficits in a discrimination and reversal learning task, LSN2463359 was again only able to reverse the deficit induced by SDZ 220,581. The results indicate that the interactions between mGlu₅ and NMDA receptors are dependent on both the mechanism of the blockade of the receptor and the behavioural domain under investigation. Our work has implications for the preclinical use of NMDA receptor antagonists in the prediction of potential therapeutic efficacy in the search for novel treatments for schizophrenia. Positive allosteric modulators of the mGlu₅ receptor certainly question the predictive validity of such approaches. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23808807 Label-Free Quantitative Proteomic Analysis of Abscisic Acid Effect in Early-Stage Soybean under Flooding. Flooding is a serious problem for soybean cultivation because it markedly reduces growth. To investigate the role of phytohormones in soybean under flooding stress, gel-free proteomic technique was used. When 2-day-old soybeans were flooded, the content of abscisic acid (ABA) did not decrease in the root, though its content decreased in untreated plant. When ABA was added during flooding treatment, survival ratio was improved compared with that of soybeans flooded without ABA. When 2-day-old soybeans were flooded with ABA, the abundance of proteins related to cell organization, vesicle transport and glycolysis decreased compared with those in root of soybeans flooded without ABA. Furthermore, the nuclear proteins were analyzed to identify the transcriptional regulation. The abundance of 34 nuclear proteins such as histone deacetylase and U2 small nuclear ribonucleoprotein increased by ABA supplementation under flooding; however, 35 nuclear proteins such as importin alpha, chromatin remodeling factor, zinc finger protein, transducin, and cell division 5 protein decreased. Of them, the mRNA expression levels of cell division cycle 5 protein, C2H2 zinc finger protein SERRATE, CCCH type zinc finger family protein, and transducin were significantly down-regulated under the ABA treatment. These results suggest that ABA might be involved in the enhancement of flooding tolerance of soybean through the control of energy conservation via glycolytic system and the regulation on zinc finger proteins, cell division cycle 5 protein and transducin. 23645539 Understanding the Cost-Effectiveness of Influenza Vaccination in Children: Methodological Choices and Seasonal Variability. BACKGROUND: The universal vaccination of children for influenza has recently been recommended in the UK and is being considered in other developed countries. OBJECTIVES: The aim of this study was to explore the potential costs and benefits of childhood influenza vaccination to gain a better understanding of the key drivers of cost-effectiveness. METHODS: As our case study we examined the cost-effectiveness of vaccination in Australian schoolchildren using an age-stratified Susceptible Exposed Infectious Recovered model. RESULTS: The results of this study highlight the critical role that methodological choices play in determining the cost-effectiveness of influenza vaccination. These choices include decisions about the structure of the model (including/excluding herd immunity) and what costs and benefits to include in the analysis. In scenarios where herd protection was included we estimated that the program was likely to be cost-effective. The study also illustrates the importance of the inherent seasonal variability of influenza, which can produce counter-intuitive results, with low transmission seasons being easier to control by vaccination but resulting in fewer benefits. CONCLUSIONS: Universal childhood influenza vaccination is likely to be cost-effective if a substantial herd protection effect can be achieved by the program. However, it is important that decision makers understand the role of seasonal variability and the impact of alternative methodological choices in economic evaluations of influenza vaccination. 23969837 Phytoestrogens regulate the proliferation and expression of stem cell factors in cell lines of malignant testicular germ cell tumors. Phytoestrogens have been shown to exert anti-proliferative effects on different cancer cells. In addition it could be demonstrated that inhibition of proliferation is associated with downregulation of the known stem cell factors NANOG, POU5F1 and SOX2 in tumor cells. We demonstrate the potential of Belamcanda chinensis extract (BCE) and tectorigenin as anticancer drugs in cell lines of malignant testicular germ cell tumor cells (TGCT) by inhibition of proliferation and regulating the expression of stem cell factors. The TGCT cell lines TCam-2 and NTera-2 were treated with BCE or tectorigenin and MTT assay was used to measure the proliferation of tumor cells. In addition, the expression of stem cell factors was analyzed by quantitative PCR and western blot analysis. Furthermore, global expression analysis was performed by microarray technique. BCE and tectorigenin inhibited proliferation and downregulated the stem cell factors NANOG and POU5F1 in TGCT cells. In addition, gene expression profiling revealed induction of genes important for the differentiation and inhibition of oncogenes. Utilizing connectivity map in an attempt to elucidate mechanism underlying BCE treatments we found highly positive association to histone deacetylase inhibitors (HDACi) amongst others. Causing no histone deacetylase inhibition, the effects of BCE on proliferation and stem cell factors may be based on histone-independent mechanisms such as direct hyperacetylation of transcription factors. Based on these findings, phytoestrogens may be useful as new agents in the treatment of TGCT. 23949917 Sonographic findings of pure ductal carcinoma in situ. To investigate the characteristic sonographic (US) findings of pure ductal carcinoma in situ (DCIS) in a large series. We retrospectively reviewed the US findings of 126 cases of pure DCIS in 123 consecutive patients who underwent surgery for breast cancer in our hospital. We analyzed the US findings of the lesions according to mass or nonmass abnormality, shape, margin, orientation, echogenicity, echotexture, boundary echo, posterior acoustic features, presence of associated ductal dilatation, presence of intralesional cystic focus, and presence of microcalcifications on US. We compared the US characteristics of pure DCIS with and without mammographic microcalcifications. Seventy-eight cases of pure DCIS had microcalcifications and 48 had no microcalcifications on mammography (MG). Overall, 109 cases (86.5%) of pure DCIS were demonstrated on US. DCIS with microcalcifications on MG showed positive US findings in 79.5% of cases. The most common US finding was heterogeneous hyper- or isoechoic parenchyma with intralesional microcalcifications and without posterior acoustic features. DCIS without microcalcifications on MG showed positive US findings in 97.9% of cases. The most common US findings were masses with round or oval shape, microlobulated margin, parallel orientation, heterogeneous mild hypoechogenicity, and without boundary echo or posterior acoustic features. Ductal dilatations and intralesional cystic foci were present in 17.5% (22/126) and 23.8% (30/126) of pure DCIS, respectively. Overall, US could demonstrate 85.7% of pure DCIS cases, including 16 (12.7%) cases of clinically and mammographically occult pure DCIS. DCIS with and without microcalcifications on MG showed different US characteristics. © 2013 Wiley Periodicals, Inc. J Clin Ultrasound, 2013; 23615055 Metabolic plasticity and hematopoietic stem cell biology. Hematopoietic stem cells (HSCs) residing in the hypoxic niches can both self-renew and give rise to progeny. Multiple regulatory mechanisms for these cellular processes have been identified. Emerging evidence has revealed that metabolism and bioenergetics play important roles in determining stem cell fate in concert with other regulatory networks. In this review, we will discuss recent advances in this field. Recent studies have helped define and redefine metabolic regulation of HSCs. Resting quiescent stem cells use primarily anaerobic glycolysis for energy production and this metabolic program is required to maintain a functional quiescent state. However, when they exit this state and rapidly proliferate and differentiate into different blood cell types, a robust up-regulation of energy metabolism is expected to meet the quickly rising energy demand. Dysregulation of metabolism in HSCs results in various blood disorders, including leukemia. Energy metabolism and HSC activity influence and interlink each other in a highly sophisticated and orchestrated manner. Understanding metabolic regulation of HSC function has significant implications for HSC-based therapies and leukemogenesis research. 23205606 Comparison of five actigraphy scoring methods with bipolar disorder. The goal of this study was to compare 5 actigraphy scoring methods in a sample of 18 remitted patients with bipolar disorder. Actigraphy records were processed using five different scoring methods relying on the sleep diary; the event-marker; the software-provided automatic algorithm; the automatic algorithm supplemented by the event-marker; visual inspection (VI) only. The algorithm and the VI methods differed from the other methods for many actigraphy parameters of interest. Particularly, the algorithm method yielded longer sleep duration, and the VI method yielded shorter sleep latency compared to the other methods. The present findings provide guidance for the selection of signal processing method based on sleep parameters of interest, time-cue sources and availability, and related scoring time costs for the study. 23124277 A missense polymorphism (rs11466653, Met326Thr) of toll-like receptor 10 (TLR10) is associated with tumor size of papillary thyroid carcinoma in the Korean population. Toll-like receptors (TLRs) are important components of innate immune response. The aim of this study was to investigate whether TLR gene cluster (TLR10-TLR1-TLR6) polymorphisms are associated with the etiology of papillary thyroid carcinoma (PTC) and its clinicopathologic characteristics. We recruited 94 PTC patients and 325 control subjects. Genotypes for each SNP were determined by direct sequencing. SNPStats and SPSS 18.0 were used to evaluate odds ratios (ORs), 95 % confidence intervals (CIs), and P values. Multiple logistic regression analyzes of genetic data were performed. The missense SNP rs11466653 was associated with small tumor size (<1 cm) in PTC. The frequency of the rs11466653 T allele was higher in PTC patients with tumors <1 cm in size than in the control group (95.8 vs. 87.2 %; P = 0.021, OR = 0.30, 95 % CI = 0.11-0.83). The T allele of rs11466653 (T/C, Met326Thr) in TLR10 may be a risk factor for the development of tumors in PTC in the Korean population. 23731923 Clinical characteristics and long-term clinical outcomes of Japanese heart failure patients with preserved versus reduced left ventricular ejection fraction: A prospective cohort of Shinken Database 2004-2011. Clinical data on the mortality and morbidity of unselected Japanese patients with heart failure (HF) are limited. In this study, we aimed to determine the clinical characteristics, long-term outcomes, and prognostic factors of Japanese HF patients with preserved or reduced left ventricular ejection fraction (LVEF). We used a single hospital-based cohort from the Shinken Database 2004-2011 that comprised all new patients (n=17,517) visiting the Cardiovascular Institute Hospital. A total of 1,525 patients diagnosed with symptomatic HF at the initial visit were included in the analysis. Of these, 1121 patients (74%) exhibited a preserved LVEF (>50%) and 404 patients (26%) had a reduced LVEF (≤50%). HF patients with preserved LVEF (HFpEF) were older and more often female than patients with reduced LVEF (HFrEF). Kaplan-Meier curves and log-rank test results showed that HFpEF patients had a better prognosis than HFrEF patients. However, there were no significant differences in clinical outcomes between HFpEF and HFrEF patients when the analysis was limited to inpatients. Cox regression analysis showed that HFpEF patients had a significantly lower risk of all-cause death (p=0.027; hazard ratio, 0.547, 95% confidence interval, 0.321-0.933). Multivariate analyses performed separately showed that the independent predictors of all-cause death in HFrEF were advanced age, lower body mass index, diabetes mellitus, and the absence of statin treatment, whereas those for HFpEF were advanced age, absence of dyslipidemia, anemia, and left ventricular hypertrophy. This prospective cohort study identified the clinical characteristics, long-term outcomes, and prognostic factors of Japanese HF patients with reduced and preserved ejection fractions in a real-world clinical setting. 22899727 Therapeutic efficacy of silymarin from milk thistle in reducing manganese-induced hepatic damage and apoptosis in rats. Oxidative stress has been proposed as a possible mechanism involved in manganese (Mn) toxicity. Using natural antioxidants against metal-induced hepatotoxicity is a modern approach. The present study investigated the beneficial role of silymarin, a natural flavonoid, in Mn-induced hepatotoxicity focusing on histopathology and biochemical approaches. Male Wistar rats were exposed orally to manganese chloride (20 mg/mL) for 30 days followed by intraperitoneal cotreatment with silymarin (100 mg/kg). Exposure to Mn resulted in a significant elevation of the plasma marker enzyme activities and bilirubin level related to liver dysfunction of reactive oxygen species (ROS) production and hepatic oxidative stress indices. This metal reduced the activities of superoxide dismutase, catalase and glutathione peroxidase and nonenzymatic antioxidant levels such as reduced glutathione, total sulfhydryl groups and vitamin C. In addition, it caused hepatic hemorrhage, cellular degeneration and necrosis of hepatocytes as indicated by liver histopathology and DNA fragmentation studies. Coadministration of silymarin alleviated Mn oxidative damage effects by inhibiting ROS generation. Histological studies also supported the beneficial role of silymarin against Mn-induced hepatic damages. Combining all, results suggested that silymarin could protect hepatic tissues against Mn-induced oxidative stress probably through its antioxidant activity. Therefore, its supplementation could provide a new approach for the reduction in hepatic complication due to Mn poisoning. 23816663 Factors that influence fast mapping in children exposed to spanish and english. The purpose of this study was to determine whether children exposed to 2 languages would benefit from the phonotactic probability cues of a single language in the same way as monolingual peers and to determine whether crosslinguistic influence would be present in a fast-mapping task. Two groups of typically developing children (monolingual English and bilingual Spanish-English) took part in a computer-based fast-mapping task that manipulated phonotactic probability. Children were preschool-aged (N = 50) or school-aged (N = 34). Fast mapping was assessed through name-identification and naming tasks. Data were analyzed using mixed analyses of variance with post hoc testing and simple regression. Bilingual and monolingual preschoolers showed sensitivity to English phonotactic cues in both tasks, but bilingual preschoolers were less accurate than monolingual peers in the naming task. School-aged bilingual children had nearly identical performance to monolingual peers. Knowing that children exposed to two languages can benefit from the statistical cues of a single language can help inform ideas about instruction and assessment for bilingual learners. 23421864 The pharmacokinetics and conversion of the lactone to the carboxylate forms of ginkgolide B in rat plasma. Ginkgolide B consists of three lactone groups, which may undergo hydrolysis, and lead to the rings opening in aqueous solution with different pHs. From mechanisms of pharmacological activity in vivo, the lactone appears to be the active form of the drug. Pharmacokinetics of lactone form (GB-lac) and the total of the lactone and carboxylate form (GB-tot) of ginkgolide B were investigated after intravenous administration of a dose of 4 mg/kg ginkgolide B. The rate of lactone hydrolysis was also studied in plasma in vitro. After intravenous administration, ginkgolide B in the original form was converted to its carboxylate form under simulated physiological conditions. The AUC0 - ∞ of GB-lac constituted 63.5 ± 17.4% of the AUC0 - ∞ of GB-tot. The ratio of average cumulation of excretion of lactone to carboxylate reached approximately 1 to 1 in urine. From the equilibrium of lactone hydrolysis in rat plasma in vitro, the k obs was - 0.0176 min(- 1) and t 1/2 was 39.38 min. In conclusion, the equilibrium existed between lactone of ginkgolide B and its carboxylate form in vivo at physiological pH, which suggested that more attention should be focused on the original and the ionization forms of ginkgolide B and the conversion of the lactone into carboxylate in vivo. 23640499 Multiple inflammatory biomarkers in relation to cardiovascular events and mortality in the community. Evidence suggests that chronic low-grade inflammation and oxidative stress are related to cardiovascular disease (CVD) and mortality. We examined 11 established and novel biomarkers representing inflammation and oxidative stress (C-reactive protein, fibrinogen, interleukin-6, intercellular adhesion molecule-1, lipoprotein-associated phospholipase-A2 [mass and activity], monocyte chemoattractant protein-1, myeloperoxidase, CD40 ligand, P-selectin, and tumor necrosis factor receptor II [TNFRII]) in relation to incident major CVD and mortality in the community. We studied 3035 participants (mean age, 61 ± 9 years; 53% women). During follow-up (median, 8.9 years), 253 participants experienced a CVD event and 343 died. C-reactive protein (hazard ratio [HR] reported per SD ln-transformed biomarker, 1.18; 95% confidence interval [CI], 1.02-1.35; nominal P=0.02) and TNFRII (HR, 1.15; 95% CI, 1.01-1.32; nominal P=0.04) were retained in multivariable-adjusted models for major CVD, but were not significant after adjustment for multiple testing. The biomarkers related to mortality were TNFRII (HR, 1.33; 95% CI, 1.19-1.49; P<0.0001), ICAM-1 (HR, 1.24; 95% CI, 1.12-1.37; P<0.0001), and interleukin-6 (HR, 1.25; 95% CI, 1.12-1.39; P<0.0001). The addition of these markers to the model, including traditional risk factors, increased discrimination and reclassification for risk of death (P<0.0001), but not for CVD. Of 11 inflammatory biomarkers tumor necrosis factor receptor II was related to cardiovascular disease and mortality in the Framingham Heart Study. The combination of TNFRII with C-reactive protein in relation to CVD and with interleukin-6 to mortality increased the predictive ability in addition to CVD risk factors for total mortality but not for incident CVD. 22844877 Guided bone regeneration in long-bone defects with a structural hydroxyapatite graft and collagen membrane. There are few synthetic graft alternatives to treat large long-bone defects resulting from trauma or disease that do not incorporate osteogenic or osteoinductive factors. The aim of this study was to test the additional benefit of including a permeable collagen membrane guide in conjunction with a preformed porous hydroxyapatite bone graft to serve as an improved osteoconductive scaffold for bone regeneration. A 10-mm-segmental long-bone defect model in the rabbit radius was used. The hydroxyapatite scaffolds alone or with a collagen wrap were compared as experimental treatment groups to an empty untreated defect as a negative control or a defect filled with autologous bone grafts as a positive control. All groups were evaluated after 4 and 8 weeks of in vivo implantation using microcomputed tomography, mechanical testing in flexure, and histomorphometry. It was observed that the use of the wrap resulted in an increased bone volume regenerated when compared to the scaffold-only group (59% greater at 4 weeks and 27% greater after 8 weeks). Additionally, the increase in density of the regenerated bone from 4 to 8 weeks in the wrap group was threefold than that in the scaffold group. The use of the collagen wrap showed significant benefits of increased interfacial bone in-growth (149% greater) and periosteal remodeling (49%) after 4 weeks compared to the scaffold-alone with the two groups being comparable after 8 weeks, by when the collagen membrane showed close-to-complete resorption. While the autograft and wrap groups showed significantly greater flexural strength than the defect group after 8 weeks, the scaffold-alone group was not significantly different from the other three groups. It is most likely that the wrap shows improvement of function by acting like a scaffold for periosteal callus ossification, maintaining the local bone-healing environment while reducing fibrous infiltration (15% less than scaffold only at 4 weeks). This study indicates that the use of a collagen membrane with a hydroxyapatite structural graft provides benefits for bone tissue regeneration in terms of early interfacial integration. 23914788 State-of the art methodologies dictate new standards for phylogenetic analysis. The intention of this editorial is to steer researchers through methodological choices in molecular evolution, drawing on the combined expertise of the authors. Our aim is not to review the most advanced methods for a specific task. Rather, we define several general guidelines to help with methodology choices at different stages of a typical phylogenetic 'pipeline'. We are not able to provide exhaustive citation of a literature that is vast and plentiful, but we point the reader to a set of classical textbooks that reflect the state-of-the-art. We do not wish to appear overly critical of outdated methodology but rather provide some practical guidance on the sort of issues which should be considered. We stress that a reported study should be well-motivated and evaluate a specific hypothesis or scientific question. However, a publishable study should not be merely a compilation of available sequences for a protein family of interest followed by some standard analyses, unless it specifically addresses a scientific hypothesis or question. The rapid pace at which sequence data accumulate quickly outdates such publications. Although clearly, discoveries stemming from data mining, reports of new tools and databases and review papers are also desirable. 23925352 High electrocatalytic activity of self-standing hollow NiCo2S4 single crystalline nanorod arrays towards sulfide redox shuttles in quantum dot-sensitized solar cells. Self-standing single crystalline NiCo2S4 hollow nanorod arrays are prepared for catalysing the polysulfide redox couple in quantum dot-sensitized solar cells (QDSCs). The QDSCs using NiCo2S4 as a counter electrode (CE) achieved a power conversion efficiency of 4.22%, which exceeds the performance of QDSCs based on a Pt CE by 38.4%. 23665163 Anti-oxidative stress effect of red ginseng in the brain is mediated by peptidyl arginine deiminase type IV (PADI4) repression via estrogen receptor (ER) β up-regulation. Ginseng has been used as an anti-stress agent, and its active ingredient, ginsenoside, is similar in structure to estrogen. However, the effect of ginseng on the stressed brain is not completely understood. The aim of this study is to understand systematically how red ginseng (RG) affects gene expressions in the brain of immobilization (IMO) stressed mice to elucidate its underlying mechanism. For in vivo experiments, mice were stressed by immobilization for 30, 45, or 60 min, and gene expression in the mice brain was analyzed by microarray and system biology. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling (TUNEL) staining, and gene expression by Western blot or qPCR. For in vitro study, the SK-N-SH neuroblastoma cells were stressed by H2O2 exposure. The resultant cytotoxicity was measured by MTT assay, and gene expression by Western blot, ELISA, or qPCR. Microarray analysis of genes in IMO stressed mice brains showed that RG administration prior to IMO stress downregulated >40 genes including peptidyl arginine deiminase type 4 (PADI4). Interestingly, PADI4 was up-regulated by various stresses such as H2O2, acrylamide, and tunicamycin in neuroblastoma SK-N-SH cells but inhibited by RG. IMO stress and in vitro H2O2 stress depressed the estrogen receptor (ER)-β expression but not ERα. However, RG treatment increased ERβ expression both in vivo and in vitro. Comparative analysis regarding the networks by systems biology revealed that TNF-α plays a critical role in IMO stress, and the cell death associated network was much higher than other categories. Consistently, the IMO stress induced TNF-α and Cox-2 expressions, malondialdehyde (MDA), and cell death in the brain, whereas RG administration inhibited these inductions in vivo. siRNA and transient expression studies revealed that ERβ inhibited the PADI4 expression. PADI4 could be used as an oxidative stress marker. RG seems to inhibit oxidative stress-inducible PADI4 by up-regulating ERβ expression in the brain thus protecting brain cells from apoptosis. 23889359 Amphetamine stimulates movement through thalamocortical glutamate release. The ventrolateral thalamus (VL) is a primary relay point between the basal ganglia and the primary motor cortex (M1). Using dual probe microdialysis and locomotor behavior monitoring, we investigated the contribution of VL input into M1 during amphetamine (AMPH)-stimulated monoamine release and hyperlocomotion in rats. Tetrodotoxin (10 Î¼M) perfusion into the VL significantly lowered hyperactivity induced by AMPH (1 mg/kg i.p.). This behavioral response corresponded to reduced cortical glutamate and monoamine release. To determine which glutamate receptors the thalamocortical projections acted upon, we perfused either the α-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA)/kainate receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX) (10 Î¼M) or the N-methyl-D-aspartic acid (NMDA) receptor antagonist (MK-801) intracortically followed by systemic AMPH. The results show that AMPA/kainate, and to a lesser extent NMDA receptors, mediated the observed effects. As glutamate-monoamine interactions could possibly occur through local or circuit-based mechanisms, we isolated and perfused M1 tissue ex vivo to determine the extent of local glutamate-dopamine interactions. Taken together, these results demonstrate that AMPH generates hyperlocomotive states via thalamocortical signaling and that cortical AMPA receptors are an important mediator of these effects. This study utilizes dual probe microdialysis sampling and comprehensive LC-MS analysis to determine the effects of amphetamine (1 mg/kg i.p.) on thalamocortical neurotransmission. Using pharmacological tools such as local thalamic tetrodotoxin (TTX) perfusion and glutamate antagonist at the cortical level, we demonstrate that thalamocortical glutamate (acting primarily through cortical AMPA receptors) is an essential component in amphetamine-induced hyperlocomotion. 23648215 Performance of the i-gel™ during pre-hospital cardiopulmonary resuscitation. Current cardiopulmonary resuscitation (CPR) guidelines recommend airway management and ventilation whilst minimising interruptions to chest compressions. We have assessed i-gel™ use during CPR. In an observational study of i-gel™ use during CPR we assessed the ease of i-gel™ insertion, adequacy of ventilation, the presence of a leak during ventilation, and whether ventilation was possible without interrupting chest compressions. We analysed i-gel™ insertion by paramedics (n=63) and emergency physicians (n=7) in 70 pre-hospital CPR attempts. There was a 90% first attempt insertion success rate, 7% on the second attempt, and 3% on the third attempt. Insertion was reported as easy in 80% (n=56), moderately difficult in 16% (n=11), and difficult in 4% (n=3). Providers reported no leak on ventilation in 80% (n=56), a moderate leak in 17% (n=12), and a major leak with no chest rise in 3% (n=2). There was a significant association between ease of insertion and the quality of the seal (r=0.99, p=0.02). The i-gel™ enabled continuous chest compressions without pauses for ventilation in 74% (n=52) of CPR attempts. There was no difference in the incidence of leaks on ventilation between patients having continuous chest compressions and patients who had pauses in chest compressions for ventilation (83% versus 72%, p=0.33, 95% CI [-0.1282, 0.4037]). Ventilation during CPR was adequate during 96% of all CPR attempts. The i-gel™ is an easy supraglottic airway device to insert and enables adequate ventilation during CPR. 23683070 Fidaxomicin for treatment of clostridium difficile-associated diarrhea and its potential role for prophylaxis. Introduction: Clostridium difficile has become the most important healthcare-associated infection worldwide within the past decade. This is in part due to the emergence of a highly virulent epidemic strain of C. difficile as well as the relative ineffectiveness of current therapies at producing a sustained response. Fidaxomicin is a novel antibiotic that demonstrates a greater sustained response for C. difficile-associated diarrhea (CDAD) compared to existing drugs and its potential role as a prophylactic agent against C. difficile infection (CDI) is being intensely studied. Areas covered: In this article, we address the emergence of CDI and the current treatment options and identify the unmet needs of the marketplace. We also summarize the pharmacodynamic and pharmacokinetic properties of fidaxomicin, and review the current literature related to the use of fidaxomicin for both treatment and prophylaxis of CDI. Expert opinion: Fidaxomicin is clearly as effective in the treatment of CDAD as oral vancomycin. It has also been shown to reduce recurrent CDAD, and we hypothesize that the same properties that confer reduced recurrence make it a promising agent for prophylaxis, particularly in high-risk patients. 23775563 Sox9b Is Required for Epicardium Formation and Plays a Role in TCDD-Induced Heart Malformation in Zebrafish. Activation of the transcription factor aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) prevents the formation of the epicardium and leads to severe heart malformations in developing zebrafish (Danio rerio). The downstream genes that cause heart malformation are not known. Because TCDD causes craniofacial malformations in zebrafish by downregulating the sox9b gene, we hypothesized that cardiotoxicity might also result from sox9b downregulation. We found that sox9b is expressed in the developing zebrafish heart ventricle and that TCDD exposure markedly reduces this expression. Furthermore, we found that manipulation of sox9b expression could phenocopy many but not all of the effects of TCDD at the heart. Loss of sox9b prevented the formation of epicardium progenitors comprising the proepicardium on the pericardial wall, and prevented the formation and migration of the epicardial layer around the heart. Zebrafish lacking sox9b showed pericardial edema, an elongated heart, and reduced blood circulation. Fish lacking sox9b failed to form valve cushions and leaflets. Sox9b is one of two mammalian Sox9 homologs, sox9b and sox9a. Knock down of sox9a expression did not cause cardiac malformations, or defects in epicardium development. We conclude that the decrease in sox9b expression in the heart caused by TCDD plays a role in many of the observed signs of cardiotoxicity. We find that while sox9b is expressed in myocardial cells, it is not normally expressed in the affected epicardial cells or progenitors. We therefore speculate that sox9b is involved in signals between the cardiomyocytes and the nascent epicardial cells. 23652482 Metal ions in sugar binding, sugar specificity and structural stability of Spatholobus parviflorus seed lectin. Spatholobus parviflorus seed lectin (SPL) is a heterotetrameric lectin, with two α and two β monomers. In the crystal structure of SPL α monomer, two residues at positions 240 and 241 are missing. This region was modeled based on the positional and sequence similarities. The role of metal ions in SPL structure was analyzed by 10 ns molecular dynamics simulation. MD simulations were performed in the presence and absence of metal ions to explain the loss of haemagglutinating property of the lectin due to demetallization. Demetallized structure was found to deviate drastically at the metal binding loop region. Affinity of different sugars like N-acetyl galactosamine (GalNAc), D-galactose and lactose towards the native and demetallized protein was calculated by molecular docking studies. It was found that the sugar binding site got severely distorted in demetallized lectin. Consequently, sugar binding ability of lectin might be decreasing in the demetallized condition. Isothermal titration calorimetric (ITC) analysis of the sugars in the presence of native and demetallized protein confirmed the in silico results. It was observed after molecular dynamics simulations, that significant structural deviations were not caused in the quaternary structure of demetallized lectin. It was confirmed that the structural changes modified the sugar binding ability, as well as sugar specificity of the present lectin. The role of metal ions in sugar binding is described based on the in silico studies and ITC analysis. A comprehensive analysis of the ITC data suggests that the sugar specificity of the metal bound lectin and the loss of sugar specificity due to metal chelation are not linear. 23453305 Novel effects of ectoine, a bacteria-derived natural tetrahydropyrimidine, in experimental colitis. Evidence suggests an important role of intestinal barrier dysfunction in the etiology of inflammatory bowel disease (IBD). Therefore stabilizing mucosal barrier function constitutes a new therapeutic approach in its management. Ectoine is a compatible solute produced by aerobic chemoheterotrophic and halophilic/halotolerant bacteria, where it acts as osmoprotectant and effective biomembrane stabilizer, protecting the producing cells from extreme environmental stress. Since this natural compound was also shown to prevent inflammatory responses associated with IBD, its potential usefulness was studied in a model of colitis. Groups of rats were treated orally with different doses of ectoine (30-300mg/kg) or sulfasalazine (reference drug) daily for 11 days. On day 8 colitis was induced by intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid, when overt signs of lesions develop within the next 3 days. On day 12, blood was withdrawn from the retro-orbital plexus of the rats and the animals were sacrificed. The colon was excised and examined macroscopically and microscopically. Relevant parameters of oxidative stress and inflammation were measured in serum and colon homogenates. Induction of colitis led to marked weight loss, significant histopathological changes of the colon, and variable changes in levels of myeloperoxidase, reduced glutathione, malondialdehyde, and all inflammatory markers tested. Treatment with ectoine ameliorated the inflammatory changes in TNBS-induced colitis. This effect was associated with reduction in the levels of TNF-α, IL-1β, ICAM-1, PGE2 and LTB4. The findings suggest that intestinal barrier stabilizers from natural sources could offer new therapeutic measures for the management of IBD. 23327779 Acutely administered antipsychotic drugs are highly selective for dopamine D2 over D3 receptors. We showed previously, using [(3)H]-(+)-4-propyl-9-hydroxynaphthoxazine ([(3)H]-(+)-PHNO) autoradiography, that several antipsychotic drugs do not occupy dopamine D3 receptors at clinically-relevant doses in rat. This is an unexpected finding considering the near-equivalent in vitro affinity of these drugs for D2 and D3 receptors. The purpose of the current study was to address two possible methodological limitations of our previous report, namely that (1) [(3)H]-(+)-PHNO may have been administered at non-tracer dose, potentially causing underestimate of D3 receptor occupancy, and (2) antipsychotic drugs were administered chronically, potentially causing increased D3 receptor expression not accounted for in the vehicle-treated control group. We found that decreasing [(3)H]-(+)-PHNO dose from 5.6nmol/kg (our previous dose) to 0.6nmol/kg caused a >60% increase in [(3)H]-(+)-PHNO binding to D3 receptors in cerebellar lobes 9 and 10, indicating that our previous study was indeed conducted under non-tracer dose conditions. However, neither reducing [(3)H]-(+)-PHNO dose further to 0.3nmol/kg (a tracer dose), nor administering antipsychotics acutely affected antipsychotic receptor occupancy. At clinically-relevant levels of D2 occupancy (57-82% inhibition of striatal binding), neither olanzapine nor haloperidol occupied D3 receptors, while clozapine occupied D3 receptors at levels similar to our previous report (33%). Risperidone moderately occupied D3 receptors (40%), but at a dose occupying >90% of D2 receptors and therefore of questionable clinical relevance. These findings demonstrate that the lack of antipsychotic occupancy of D3 receptors is not attributable to limitations of our previous study. These results suggest that D3 receptor blockade is not necessary for the therapeutic effects of the antipsychotic drugs examined. 23932727 Validity and role of vertebral fracture assessment in detecting prevalent vertebral fracture in patients with rheumatoid arthritis. We aimed to identify the validity and the role of vertebral fracture assessment (VFA) for the diagnosis of prevalent vertebral fracture (VF) in rheumatoid arthritis (RA) patients. Total of 100 women with RA who were 50years or older were enrolled. All participants underwent lateral imaging of the thoraco-lumbar spine by radiography and VFA. All radiographs were analyzed by two radiologists. Discrepancies between radiologists for spine radiography were resolved by consensus and these results were defined as the reference standard. VFA interpretation was done independently by two nuclear medicine physicians. Fracture defined by VFA measure was done only when two physicians both independently reported fracture. The inter-rater agreement for the detection of VF on VFA was evaluated by kappa statistics. We calculated percent values for the diagnostic validity of VFA in detecting VF in the 100 women as a whole and according to the presence of previous fracture or back pain. The prevalence of VF identified by spine radiography was 47%. Inter-rater agreement of VFA per vertebra by two VFA readers showed moderate agreement (kappa=0.60). The sensitivity, PPV, specificity and NPV of VFA compared to spine radiography were 57.3%, 30.9%, 89.1% and 96.1% for total vertebrae. All patients with history of previous VF (n=13) were visualized with VFA with 100% sensitivity but it has 64.7% sensitivity and 79.3% specificity in patients without previous VF (n=87). VFA is most useful to identify patients without VF because of its high specificity and NPV in all spine level. 23872729 FRET-based characterisation of surfactant bilayer protected core-shell carbon nanoparticles: advancement toward carbon nanotechnology. Surfactant bilayer protected core-shell carbon nanoparticles (CNPs) have been synthesised. Förster resonance energy transfer (FRET) between the core-shell CNPs and two strategically chosen organic dyes has been exploited to characterise the protective surfactant bilayer. 23834826 Regulatory mechanisms and the role of calcium and potassium channels controlling supercontractile crop muscles in adult Phormia regina. Bioassays and electrophysiological recordings were conducted in the adult blowfly Phormia regina to provide new insights into the regulatory mechanisms governing the crop filling and emptying processes of the supercontractile crop muscles. The cibarial pump drives ingestion. Simultaneous multisite extracellular recordings show that crop lobe (P5) distension during ingestion of a 4.7 μl sugar meal does not require muscle activity by any of the other pumps of the system. Conversely, pumping of fluids toward the anterior of the crop system during crop emptying is brought about by active muscle contraction, in the form of a highly coordinated peristaltic wave starting from P5 and progressively propagating to P6, P4 and P3 pumps, with P5 contracting with a frequency about 3.4 times higher than the other pumps. The crop contraction rate is also modulated by hemolymph-borne factors such as sugars, through ligand recognition at a presumptive receptor site rather than by an osmotic effect, as assessed by both behavioural and electrophysiological experiments. In this respect, sugars of equal osmolarity produce different effects, glucose being inhibitory and mannose ineffective for crop muscles, while trehalose enhances crop activity. Finally, voltage and current clamp experiments show that the muscle action potentials (mAPs) at the P4 pump are sustained by a serotonin-sensitive calcium conductance. Serotonin enhances calcium entry into the muscle cells and this could lead, as an indirect modulatory effect, to activation of a Ca(2+)-activated K(+) conductance (IK(Ca)), which sustains the following mAP repolarization phase in such a way that further mAPs can be generated early and the frequency consequently increased. 23848290 Isolated tumorous Langerhans cell histiocytosis of the brainstem: a diagnostic and therapeutic challenge. Langerhans cell histiocytosis (LCH) of the CNS is a rare entity, known to involve primarily the hypothalamicpituitary region, with the clinical hallmark of diabetes insipidus. There have been a few reports of CNS LCH involving the brainstem as intraparenchymal enhancing lesions, but this has never been the presenting complaint of LCH. The authors report on a 7-year-old boy who presented with right cerebellopontine syndrome, in whom a well-defined, solid, enhancing lesion in the brainstem was diagnosed. Clinicoradiological differential diagnosis included glioma and tuberculosis. Biopsy revealed atypical histiocytes positive for CD68, CD1a, and S100 protein; these are the diagnostic features of LCH on histopathological examination. The rapid growth of the lesion was controlled with a chemotherapeutic regimen of cladribine. 23878314 CCL22-Producing CD8α- Myeloid Dendritic Cells Mediate Regulatory T Cell Recruitment in Response to G-CSF Treatment. G-CSF prevents type 1 diabetes in the NOD mouse by promoting the local recruitment of T regulatory cells (Tregs). This is an indirect effect because adoptive transfer of G-CSF-induced tolerogenic dendritic cells (DCs) promotes Treg accumulation. However, the identity of the particular DC subset and the molecule(s) mediating this effect remain unknown. We demonstrate in this study that the adoptive transfer of CD11c(high)CD8α(-) DCs isolated from pegylated G-CSF (pegG-CSF) recipients, but not that of other DC subtypes, enhanced the pancreatic recruitment of CD4(+)CD25(+)Foxp3(+) Tregs, which generated increased amounts of TGF-β. Likewise, only CD11c(high)CD8α(-) DCs from pegG-CSF recipients secreted the chemokine CCL22 at levels that effectively attracted Tregs. PegG-CSF was more efficient at enhancing the synthesis of CCL22 by CD11c(high)CD8α(-) DCs from the pancreatic lymph nodes compared with those from the spleen. Accordingly, CD11c(high)CD8α(-) DCs from the pancreatic lymph nodes of pegG-CSF recipients were more efficient than their splenic counterparts in the recruitment of Tregs upon adoptive transfer. Predictably, CD11c(high)CD8α(-) DCs failed to recruit these Tregs both in vivo and in vitro following intracellular neutralization of CCL22. These data assign a key role to CD8α(-) DCs and CCL22 in Treg recruitment in the protection of NOD mice against type 1 diabetes following the treatment with G-CSF. 23954862 Increasing diversity of neural responses to speech sounds across the central auditory pathway. Neurons at higher stations of each sensory system are responsive to feature combinations not present at lower levels. As a result, the activity of these neurons becomes less redundant than lower levels. We recorded responses to speech sounds from the inferior colliculus and the primary auditory cortex neurons of rats, and tested the hypothesis that primary auditory cortex neurons are more sensitive to combinations of multiple acoustic parameters compared to inferior colliculus neurons. We independently eliminated periodicity information, spectral information and temporal information in each consonant and vowel sound using a noise vocoder. This technique made it possible to test several key hypotheses about speech sound processing. Our results demonstrate that inferior colliculus responses are spatially arranged and primarily determined by the spectral energy and the fundamental frequency of speech, whereas primary auditory cortex neurons generate widely distributed responses to multiple acoustic parameters, and are not strongly influenced by the fundamental frequency of speech. We found no evidence that inferior colliculus or primary auditory cortex was specialized for speech features such as voice onset time or formants. The greater diversity of responses in primary auditory cortex compared to inferior colliculus may help explain how the auditory system can identify a wide range of speech sounds across a wide range of conditions without relying on any single acoustic cue. 23810000 The benefit of adjuvant chemotherapy combined with postoperative radiotherapy for endometrial cancer: a meta-analysis. The objective of our study was to determine whether adjuvant chemotherapy combined with postoperative radiotherapy would have benefits for the disease-free survival and overall survival in patients with high-risk endometrial cancer. Electronic searches for studies of adjuvant chemotherapy combined with postoperative radiotherapy in endometrial cancer patients between March 1971 and March 2012 were made on MEDLINE, SCOPUS, and the Cochrane library. Articles with more than 4 stars on the Newcastle-Ottawa scale or a score of more than 4 on the modified Jadad scale were included. A meta-analysis was performed, and pooled hazard ratios (HR) of progression-free survival (PFS) and overall survival (OS) between patients whose adjuvant chemotherapy was combined with radiotherapy (the CTx+RTx group) and patients with adjuvant radiotherapy only (the RTx group) were derived from the fixed effect model or random effect model. Three observational studies and 3 randomized clinical trials (RCTs) were included in the final analysis. Subgroup analysis for FIGO stage showed that the CTx+RTx group had a more significant survival benefit compared to that of the RTx group in advanced stage endometrial cancer (OS HR 0.53, 95% CI 0.36-0.80; PFS HR 0.54, 95% CI 0.37-0.77), but no significant benefit in early stage endometrial cancer (OS HR 0.96, 95% CI 0.70-1.32; PFS HR 1.00, 95% CI 0.39-2.58). This meta-analysis suggests that adjuvant chemotherapy combined with postoperative radiotherapy could probably reduce disease progression and overall death in patients with advanced-stage disease. In order to examine whether the multimodal treatment has benefit in high-risk endometrial cancer, we need further large-scale RCTs. 23295227 X-ray structure of the V301L aldo-keto reductase 1B10 complexed with NADP(+) and the potent aldose reductase inhibitor fidarestat: implications for inhibitor binding and selectivity. Only one crystal structure is currently available for tumor marker AKR1B10, complexed with NADP(+) and tolrestat, which is an aldose reductase inhibitor (ARI) of the carboxylic acid type. Here, the X-ray structure of the complex of the V301L substituted AKR1B10 holoenzyme with fidarestat, an ARI of the cyclic imide type, was obtained at 1.60Å resolution by replacement soaking of crystals containing tolrestat. Previously, fidarestat was found to be safe in phase III trials for diabetic neuropathy and, consistent with its low in vivo side effects, was highly selective for aldose reductase (AR or AKR1B1) versus aldehyde reductase (AKR1A1). Now, inhibition studies showed that fidarestat was indeed 1300-fold more selective for AR as compared to AKR1B10, while the change of Val to Leu (found in AR) caused a 20-fold decrease in the IC50 value with fidarestat. Structural analysis of the V301L AKR1B10-fidarestat complex displayed enzyme-inhibitor interactions similar to those of the AR-fidarestat complex. However, a close inspection of both the new crystal structure and a computer model of the wild-type AKR1B10 complex with fidarestat revealed subtle changes that could affect fidarestat binding. In the crystal structure, a significant motion of loop A was observed between AR and V301L AKR1B10, linked to a Phe-122/Phe-123 side chain displacement. This was due to the presence of the more voluminous Gln-303 side chain (Ser-302 in AR) and of a water molecule buried in a subpocket located at the base of flexible loop A. In the wild-type AKR1B10 model, a short contact was predicted between the Val-301 side chain and fidarestat, but would not be present in AR or in V301L AKR1B10. Overall, these changes could contribute to the difference in inhibitory potency of fidarestat between AR and AKR1B10. 23927502 Gene-Environment Correlation: Difficulties and a Natural Experiment-Based Strategy. Objectives. We explored how gene-environment correlations can result in endogenous models, how natural experiments can protect against this threat, and if unbiased estimates from natural experiments are generalizable to other contexts. Methods. We compared a natural experiment, the College Roommate Study, which measured genes and behaviors of college students and their randomly assigned roommates in a southern public university, with observational data from the National Longitudinal Study of Adolescent Health in 2008. We predicted exposure to exercising peers using genetic markers and estimated environmental effects on alcohol consumption. A mixed-linear model estimated an alcohol consumption variance that was attributable to genetic markers and across peer environments. Results. Peer exercise environment was associated with respondent genotype in observational data, but not in the natural experiment. The effects of peer drinking and presence of a general gene-environment interaction were similar between data sets. Conclusions. Natural experiments, like random roommate assignment, could protect against potential bias introduced by gene-environment correlations. When combined with representative observational data, unbiased and generalizable causal effects could be estimated. (Am J Public Health. Published online ahead of print August 8, 2013: e1-e7. doi:10.2105/AJPH.2013.301415). 23896828 Recent contributions from the asymmetric aza-Michael reaction to alkaloids total synthesis. Covering: 2005 to 2013This review focuses on recent applications of the aza-Michael reaction in alkaloids total synthesis with a special emphasis on stereoselectivity. The report highlights achievements and challenges over the past five years and describes stereoselective intra- and inter-molecular conjugate addition of nitrogen-containing nucleophiles, including tandem and cascade processes. Total asymmetric syntheses of natural scaffolds, such as pyrrolidine, piperidine and "izidine" families, are depicted. Multi-step syntheses of highly challenging natural products are further detailed, assessing the scope of the stereocontrolled aza-Michael reaction as a powerful tool in alkaloid chemistry. 23290424 Identification of proteins related to early changes observed in Human hepatocellular carcinoma cells after treatment with the mycotoxin Zearalenone. Zearalenone (ZEA) is a mycotoxin produced by some Fusarium species. ZEA often occur as a contaminant in cereal grains and animal feeds. Human exposure occurs by ingestion of mycotoxin-contaminated products and can cause serious health problems. It was established that this mycotoxin have an hepato, haemato, immuno and genotoxic properties (Maaroufi et al., 1996; Lioi et al., 2004). While most ZEA toxic effects have been quite well investigated, more studies are required to elucidate its mechanisms of toxicity. In order to better understand the molecular mechanisms involved in ZEA toxicity, we used a proteomic approach, to assess the early changes in protein expression initiated by ZEA in HepG2 cells. Our results showed that, after 8h of exposure, cells were still viable and showed a significant change in a number of proteins involved in diverse cellular processes. These changes may provide the early affected functions and yield further insight into mechanisms underlying the involvement of mycotoxin-induced diseases. 23962885 Smart multifunctional fluids for lithium ion batteries: enhanced rate performance and intrinsic mechanical protection. Lithium ion batteries are attractive power sources for the consumer electronics market and are being aggressively developed for road transportation. Nevertheless, issues with safety and reliability need to be solved prior to the large-scale uptake of these batteries. There have recently been significant development and assessment of materials with resistance to mechanical abuse, with the aims of reinforcing the battery and preventing puncturing during a crash. Most of the work on battery mechanical safety has concentrated on the external packaging of batteries, with little attention being paid to the enclosed electrolyte. We report on smart multifunctional fluids that act as both highly conductive electrolytes and intrinsic mechanical protectors for lithium ion batteries. These fluids exhibit a shear thickening effect under pressure or impact and thus demonstrate excellent resistance to crushing. Also, the fluids show higher ionic conductivities and comparable redox stability windows to the commercial liquid electrolytes. 23318470 Neuroprotective efficacy and pharmacokinetic behavior of novel anti-inflammatory para-phenyl substituted diindolylmethanes in a mouse model of Parkinson's disease. There are currently no registered drugs that slow the progression of neurodegenerative diseases, in part because translation from animal models to the clinic has been hampered by poor distribution to the brain. The present studies examined a selected series of para-phenyl-substituted diindolylmethane (C-DIM) compounds that display anti-inflammatory and neuroprotective efficacy in vitro. We postulated that the pharmacokinetic behavior of C-DIM compounds after oral administration would correlate with neuroprotective efficacy in vivo in a mouse model of Parkinson's disease. Pharmacokinetics and metabolism of 1,1-bis(3'-indolyl)-1-(p-methoxyphenyl)methane (C-DIM5), 1,1-bis(3'-indolyl)-1-(phenyl)methane, 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (C-DIM8), and 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane (C-DIM12) were determined in plasma and brain of C57Bl/6 mice after oral and intravenous administration at 10 and 1 mg/Kg, respectively. Putative metabolites were measured in plasma, liver, and urine. C-DIM compounds given orally displayed the highest area under the curve, Cmax, and Tmax levels, and C-DIM12 exhibited the most favorable pharmacokinetics of the compounds tested. Oral bioavailability of each compound ranged from 6% (C-DIM8) to 42% (C-DIM12). After pharmacokinetic studies, the neuroprotective efficacy of C-DIM5, C-DIM8, and C-DIM12 (50 mg/Kg per oral) was examined in mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid for 14 days, a model of progressive neurodegeneration with a strong neuroinflammatory component. C-DIM5 and C-DIM12 given orally once daily after one week of exposure to MPTP and probenecid prevented further loss of dopaminergic neurons in the substantia nigra pars compacta and striatal dopamine terminals, indicating that these compounds could be effective therapeutic agents to prevent neurodegeneration. 23844658 Evidence for a recent horizontal transmission and spatial spread of Wolbachia from endemic Rhagoletis cerasi (Diptera: Tephritidae) to invasive Rhagoletis cingulata in Europe. The widespread occurrence of Wolbachia in arthropods and nematodes suggests that this intracellular, maternally inherited endosymbiont has the ability to cross species boundaries. However, direct evidence for such a horizontal transmission of Wolbachia in nature is scarce. Here, we compare the well-characterized Wolbachia infection of the European cherry fruit fly, Rhagoletis cerasi, with that of the North American eastern cherry fruit fly, Rhagoletis cingulata, recently introduced to Europe. Molecular genetic analysis of Wolbachia based on multilocus sequence typing and the Wolbachia surface protein wsp showed that all R. cingulata individuals are infected with wCin2 identical to wCer2 in R. cerasi. In contrast, wCin1, a strain identical to wCer1 in R. cerasi, was present in several European populations of R. cingulata, but not in any individual from the United States. Surveys of R. cingulata from Germany and Hungary indicated that in some populations, the frequency of wCin1 increased significantly in just a few years with at least two independent horizontal transmission events. This is corroborated by the analysis of the mitochondrial cytochrome oxidase II gene that showed association of wCin1 with two distinct haplotypes in Germany, one of which is also infected with wCin1 in Hungary. In summary, our study provides strong evidence for a very recent inter-specific Wolbachia transmission with a subsequent spatial spread in field populations. 22744955 Dihydroxy-Isosteviol Methyl Ester from Pulsatilla nigricans Induces Apoptosis in HeLa Cells: Its Cytoxicity and Interaction with Calf Thymus DNA. Dihydroxy-isosteviol methyl ester (DIME), the principal biological compound isolated from the medicinal plant Pulsatilla nigricans (Fam: Ranunculaceae) having the molecular formula of C21 H34 O3 (molecular weight 334.25), was administered to cervical cancer cells (HeLa) in vitro to evaluate its possible apoptotic (anti-cancer) potentials. We analyzed the expression of p53, Bax, Bcl2, Apaf and caspase 3 signal proteins and analyzed the early apoptotic events in HeLa cells induced by DIME using protocols like Annexin V-FITC and PI staining. DIME caused a significant decrease in cell viability, induced nuclear condensation and inter-nucleosomal DNA fragmentation. We further studied the interaction of DIME with calf thymus DNA as target through circular-dichroism spectra. Results showed that DIME interacted with DNA, bringing indiscernible changes in structure and conformation. Thus, DIME showed its capability to induce apoptosis in cancer cells, signifying its utility in drug design as a possible candidate for chemoprevention. Copyright © 2012 John Wiley & Sons, Ltd. 23938132 Metabolic actions of Rho-kinase in periphery and brain. Obesity has increased at an alarming rate in recent years and is now a worldwide public health problem. Elucidating the mechanisms behind the metabolic dysfunctions associated with obesity is of high priority. The metabolic function of Rho-kinase (Rho-associated coiled-coil-containing kinase; ROCK) has been the subject of a great deal of investigation in metabolic-related diseases. It appears that inhibition of ROCK activity is beneficial for the treatment of a wide range of cardiovascular-related diseases. However, recent studies with genetic models of ROCK demonstrate that ROCK plays a positive role in insulin and leptin signaling. Here we discuss the newly identified functions of ROCK in regulating glucose and energy metabolism, with particular emphasis on metabolic actions of insulin and leptin. 23731824 A study of the influence of task familiarity on user behaviors and performance with a MeSH term suggestion interface for PubMed bibliographic search. Previous research has shown that information seekers in biomedical domain need more support in formulating their queries. A user study was conducted to evaluate the effectiveness of a metadata based query suggestion interface for PubMed bibliographic search. The study also investigated the impact of search task familiarity on search behaviors and the effectiveness of the interface. A real user, user search request and real system approach was used for the study. Unlike tradition IR evaluation, where assigned tasks were used, the participants were asked to search requests of their own. Forty-four researchers in Health Sciences participated in the evaluation - each conducted two research requests of their own, alternately with the proposed interface and the PubMed baseline. Several performance criteria were measured to assess the potential benefits of the experimental interface, including users' assessment of their original and eventual queries, the perceived usefulness of the interfaces, satisfaction with the search results, and the average relevance score of the saved records. The results show that, when searching for an unfamiliar topic, users were more likely to change their queries, indicating the effect of familiarity on search behaviors. The results also show that the interface scored higher on several of the performance criteria, such as the "goodness" of the queries, perceived usefulness, and user satisfaction. Furthermore, in line with our hypothesis, the proposed interface was relatively more effective when less familiar search requests were attempted. Results indicate that there is a selective compatibility between search familiarity and search interface. One implication of the research for system evaluation is the importance of taking into consideration task familiarity when assessing the effectiveness of interactive IR systems. 23244582 Assessment of the antineoplastic potential of chalcones in animal models. One part of chemical space that is endowed with interesting biological properties is the area of the chalcones. With this review, we provide a comprehensive overview of the numerous in vivo animal studies on the antineoplastic potential of both natural and synthetic members of this flavonoid subclass (covering: up to mid-2011). The thus far identified modes of action of these compounds are also discussed. We hope that this overview may stimulate deeper investigations into the biochemical mechanisms by which chalcones exert their antineoplastic action. As a result, in the foreseeable future, chalcones may prove suitable lead molecules or early drug candidates for the prevention or treatment of various neoplastic diseases. 23825173 Life-span cognitive activity, neuropathologic burden, and cognitive aging. To test the hypothesis that cognitive activity across the life span is related to late-life cognitive decline not linked to common neuropathologic disorders. On enrollment, older participants in a longitudinal clinical-pathologic cohort study rated late-life (i.e., current) and early-life participation in cognitively stimulating activities. After a mean of 5.8 years of annual cognitive function testing, 294 individuals had died and undergone neuropathologic examination. Chronic gross infarcts, chronic microscopic infarcts, and neocortical Lewy bodies were identified, and measures of β-amyloid burden and tau-positive tangle density in multiple brain regions were derived. In a mixed-effects model adjusted for age at death, sex, education, gross and microscopic infarction, neocortical Lewy bodies, amyloid burden, and tangle density, more frequent late-life cognitive activity (estimate = 0.028, standard error [SE] = 0.008, p < 0.001) and early-life cognitive activity (estimate = 0.034, SE = 0.013, p = 0.008) were each associated with slower cognitive decline. The 2 measures together accounted for 14% of the residual variability in cognitive decline not related to neuropathologic burden. The early-life-activity association was attributable to cognitive activity in childhood (estimate = 0.027, SE = 0.012, p = 0.026) and middle age (estimate = 0.029, SE = 0.013, p = 0.025) but not young adulthood (estimate = -0.020, SE = 0.014, p = 0.163). More frequent cognitive activity across the life span has an association with slower late-life cognitive decline that is independent of common neuropathologic conditions, consistent with the cognitive reserve hypothesis. 23430974 Interleukin-10 promoter variants predict HPV-positive tumors and survival of squamous cell carcinoma of the oropharynx. Interleukin-10 (IL-10) plays an important role in a host's defense against human papillomavirus (HPV) infection. IL-10 promoter variants may affect its expression level or functional efficiency and, subsequently, susceptibility to and survival of HPV16-associated squamous cell carcinoma of oropharynx (SCCOP). We determined tumor HPV16 DNA and genotyped three IL-10 promoter polymorphisms in 309 incident patients with SCCOP. Compared with the patients with corresponding common homozygous genotypes, patients carrying variant genotypes of IL-10 rs1800871 and rs1800872 were ∼2.5 times more likely to have HPV16(+) tumors among patients with SCCOP. Among HPV16(+) patients with SCCOP only, compared to those with the corresponding variant genotypes, the patients with IL-10 rs1800871 and rs1800872 CC genotypes had significantly better survival and ∼70-80% reduced risk of death/recurrence after multivariable adjustment. Additionally, functional relevance of these variants was characterized to explore the genotype-phenotype correlation. Our findings indicate that IL-10 genetic variants may be associated with tumor HPV16(+) SCCOP and predict survival of HPV16(+) patients with SCCOP. Larger studies are needed to validate our findings.-Jin, L., Sturgis, E. M., Cao, X., Song, X., Salahuddin, T., Wei, Q., Li, G. Interleukin-10 promoter variants predict HPV-positive tumors and survival of squamous cell carcinoma of the oropharynx. 23595918 Cognitive enhancement drug use among future physicians: findings from a multi-institutional census of medical students. Nonmedical use of prescription psychostimulants such as methylphenidate and amphetamine salts for the purpose of cognitive enhancement is a growing trend, particularly in educational environments. To our knowledge, no recent studies have evaluated the use of these psychostimulants in a medical academic setting. To conduct an online census of psychostimulant use among medical students. In 2011, we conducted a multi-institutional census using a 31-48 item online survey regarding use of prescription psychostimulants. 2,732 actively enrolled medical students at four private and public medical schools in the greater Chicago area. Prevalence and correlates of psychostimulant use 1,115 (41 %) of students responded to the web-based questionnaire (range 26-47 % among schools). On average, students were 25.1 years of age (SD = 2.7, range 20-49), and single (70 %). Overall, 18 % (198/1,115) of this medical student sample had used prescription psychostimulants at least once in their lifetime, with first use most often in college. Of these, 11 % (117/1,115) of students reported use during medical school (range 7-16 % among schools). Psychostimulant use was significantly correlated with use of barbiturates, ecstasy, and tranquilizers (Pearson's correlation r > 0.5, Student's t-test p < 0.01); male gender (21 % male versus 15 % female, Chi squared p = 0.007); and training at a medical school which by student self-report determined class rank (68 % versus 51 %, Chi-squared p = 0.018). Non-users were more likely to be first year students (Chi-squared p = 0.048) or to have grown up outside of the United States (Chi-squared p = 0.013). Use of psychostimulants, including use without a prescription, is common among medical students. Further study of the side effects, medical implications, and use during post-graduate medical training and medical practice is needed to inform evidence-based policy. 23898309 What is working memory capacity, and how can we measure it? A latent variable study examined whether different classes of working-memory tasks measure the same general construct of working-memory capacity (WMC). Data from 270 subjects were used to examine the relationship between Binding, Updating, Recall-N-back, and Complex Span tasks, and the relations of WMC with secondary memory measures, indicators of cognitive control from two response-conflict paradigms (Simon task and Eriksen flanker task), and fluid intelligence. Confirmatory factor analyses support the concept of a general WMC factor. Results from structural-equation modeling show negligible relations of WMC with response-conflict resolution, and very strong relations of WMC with secondary memory and fluid intelligence. The findings support the hypothesis that individual differences in WMC reflect the ability to build, maintain and update arbitrary bindings. 23871958 Suggested phylogeny of tRNAs based on the construction of ancestral sequences. The origin and evolution of life on the planet is one of the most intriguing challenges in life sciences and, for some researchers, it is centered in the origin of the genetic code. Many hypotheses about the origin and evolution of tRNA have been proposed and in this work a new suggestion is proposed based on the reconstruction of tRNA ancestor sequences. Ancestral sequences of 22 types of tRNA molecules were built by maximum likelihood from 9758 sequences currently reported from different organisms. Phylogenetic analysis showed that the main force for evolutionary diversification of tRNA molecules was a change in the second base of the anticodon. The data revealed that diversification is not correlated with the characteristic of the specified amino acid, indicating that the correlation between tRNA and amino acid was given indirectly, and possibly should have been mediated by proto-aminoacyl-tRNA synthetases. 23601405 Application of Choices criteria in Brazil: impact on nutrient intake and adequacy of food products in relation to compounds associated to the risk of non-transmissible chronic diseases. One of the aims of this work was to evaluate the impact of introducing products that are in agreement with the Choices criteria in the usual diet of the Brazilian population. However, due to the insufficient information on key compounds related to non-transmissible chronic diseases (NTCD) in the national food composition database, the nutritional information of food labels was collected. A food composition database of industrialized products was created (1720 products) and their data were evaluated according to the Choices criteria. The replacement of typical products by products that are in accordance to the Choices criteria may cause a decrease in the intake of saturated (52%) and trans fatty acids (92%), energy (14%) and sodium (47%), as well as an increase in the intake of DF (87%); improving the diet nutritional profile. This procedure can be used as important part in a strategy for decreasing the risk for NTCD. 22382714 Taking health needs seriously: against a luck egalitarian approach to justice in health. In recent works, Shlomi Segall suggests and defends a luck egalitarian approach to justice in health. Concurring with G. A. Cohen's mature position he defends the idea that people should be compensated for "brute luck", i.e. the outcome of actions that it would be unreasonable to expect them to avoid. In his defense of the luck egalitarian approach he seeks to rebut the criticism raised by Norman Daniels that luck egalitarianism is in some way too narrow and in another too wide to uphold justice in health and health care distribution. He points out that a pluralistic outline of luck egalitarianism taking into account the moral requirement of meeting everyone's basic needs can avoid this line of criticism. In this article I argue against the application of such pluralistic luck egalitarianism in matters of health distribution. First of all, Segall has not shown that luck egalitarianism handles well health distributions above a threshold of basic needs. Secondly, his way of avoiding Elizabeth Anderson's abandonment objection is theoretically problematic. Finally, I argue that luck egalitarianism in general fails to acknowledge the moral foundation of health and health care as a basic human entitlement. Thus I conclude that luck egalitarianism fails to take health needs seriously and that it cannot therefore uphold justice in health. 23384580 Philornis sp. bot fly larvae in free living scarlet macaw nestlings and a new technique for their extraction. Bot fly larvae (Philornis genus) are obligate subcutaneous blood-feeding parasites of Neotropical birds including psittacines. We analyze twelve years of data on scarlet macaw (Ara macao) nestlings in natural and artificial nests in the lowland forests of southeastern Peru and report prevalence and intensity of Philornis parasitism. Bot fly prevalence was 28.9% while mean intensity was 5.0 larvae per infected chick. Prevalence in natural nests (11%, N=90 nestlings) was lower than in wooden nest-boxes (39%, N=57) and PVC boxes (39%, N=109). We describe a new technique of removing Philornis larvae using a reverse syringe design snake bite extractor. We compare this new technique to two other methods for removing bots from macaw chicks and find the new method the most suitable. 23587281 Comparison of intravascular ultrasound and histological findings in culprit coronary plaques between ST-segment elevation and non-ST-segment elevation myocardial infarction. It remains uncertain whether the histology of culprit coronary plaques differs between ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI). We compared intravascular ultrasound (IVUS) and histologic findings in coronary culprit plaques among patients presenting with STEMI and NSTEMI. Atherectomy specimens were obtained from 96 patients, 70 with STEMI and 26 with NSTEMI, who underwent directional coronary atherectomy for de novo coronary artery lesions. IVUS examinations were performed before directional coronary atherectomy. IVUS and histologic data were analyzed. Clinical characteristics were largely similar between the 2 groups; however, normal antegrade flow before angioplasty was less frequently observed in patients with STEMI than those with NSTEMI. Plaque rupture was more common on the proximal side of the minimal lumen site. There were no differences in vessel area, lumen area, calcification, plaque burden, or remodelling index at the reference and culprit sites. However, the arc of the ruptured cavity was significantly greater in patients with STEMI than those with NSTEMI (69.4 ± 27.9° vs 51.8 ± 20.0°, respectively, p = 0.008). The proportion of atheroma, fibrocellular, and thrombus areas was not different between the 2 groups. Similarly, the relative areas immunopositive for CD31, smooth muscle α-actin, and CD68 were similar in the 2 groups. In conclusion, coronary culprit lesions in patients with STEMI show more severe plaque rupture with similar histologic features than those in patients with NSTEMI, supporting the idea that a large plaque rupture is more likely in STEMI patients. 23954877 Core promoter analysis of porcine Six1 gene and its regulation of the promoter activity by CpG methylation. Six1, an evolutionary conserved transcription factor, has been shown to play an important role in organogenesis and diseases. However, no reports were shown to investigate its transcriptional regulatory mechanisms. In the present study, we first identified porcine Six1 gene core promoter region (+170/-360) using luciferase reporter assay system and found that promoter activities were significantly higher in the mouse myoblast C2C12 cells than that in the mouse fibroblast C3H10T1/2 cells, implying that Six1 promoter could possess muscle-specific characteristics. Moreover, our results showed that promoter activities of Six1 were decreased as induction of differentiation of C2C12 cells, which was accompanied by the down-regulation of mRNA expression of Six1 gene. In addition, we found that the DNA methylation of Six1 promoters in vitro obviously influences the promoter activities and the DNA methylation level of Six1 promoter core region was negatively correlated to Six1 gene expression in vivo. Taken together, we preliminarily clarified transcriptional regulatory mechanisms of Six1 gene, which should be useful for investigating its subtle transcriptional regulatory mechanisms in the future. On the other hand, based on Six1 involved in tumorigenesis, our data also provide a genetic foundation to control the generation of diseases via pursuing Six1 as therapeutic target gene. 23806031 Light-Induced Magnetostructural Anomalies in a Polymer Chain Complex of Cu(hfac)2 with tert-Butylpyrazolylnitroxides. We report the study of light-induced magnetostructural anomalies in a polymer chain complex of Cu(hfac)2 (hfac = hexafluoroacetylacetonate) with an unusual acyclic tert-butylpyrazolylnitroxide radical (Ltert(Me)) using EPR. This complex ([Cu(hfac)2Ltert(Me)]n) belongs to the family of thermo- and photoswitchable molecular magnets "breathing crystals". Compared to previously studied breathing crystals with nitronyl nitroxides, [Cu(hfac)2Ltert(Me)]n shows much weaker absorption bands in the visible spectral region and therefore is superior for optical manipulation of the spin states. Illumination with light (λ ≈ 540 nm) at cryogenic temperatures leads to formation of a metastable weakly coupled spin state, which relaxes to the ground strongly coupled spin state on a time scale of hours. These phenomena are in many aspects similar to the light-induced excited spin state trapping (LIESST) well-known for spin-crossover compounds. Remarkably, the photoinduced spin state in [Cu(hfac)2Ltert(Me)]n is metastable at temperatures up to TLIESST ≈ 60 K, which is a significant improvement compared to that of previously studied breathing crystals with nitronyl nitroxides (TLIESST ≈ 20 K). We describe LIESST-like behavior observed in [Cu(hfac)2Ltert(Me)]n and discuss possible reasons for the increased stability of the photoinduced spin state. 23815774 Foxc2 regulates osteogenesis and angiogenesis of bone marrow mesenchymal stem cells. The Forkhead/Fox transcription factor Foxc2 is a critical regulator of osteogenesis and angiogenesis of cells. Bone marrow mesenchymal stem cells (BMSCs) have the capacity to differentiate into osteoblasts, chondrocytes, adipocytes, myocytes and fibroblasts. The present study investigates the role of Foxc2 overexpression in osteogenesis and angiogenesis of BMSCs in vitro. BMSCs were isolated from SD rat femurs and tibias, and characterized by cell surface antigen identification and osteoblasts and adipocytes differentiation. The cells were transfected with lentiviral Foxc2 (Lv-Foxc2) or green fluorescent protein (Lv-GFP). Seventy hours later, Foxc2 expression was observed using real time-PCR and Western blot. The transfected cells were stained with Alizarin red S or alkaline phosphatase (ALP) after osteogenic induction. Meanwhile, the expression levels of osteocalcin (OCN), Runt-related transcription factor 2 (Runx2), vascular endothelial growth factor (VEGF) and platelet-derived growth factor-β (PDGF-β) were measured by real time-PCR, Western blot and immunostaining. Results of cell characterization showed that the cells were positive to CD44 (99.56%) and negative to CD34 (0.44%), and could differentiate into osteoblasts and adipocytes. Foxc2 overexpression not only increased the numbers of mineralized nodes and ALP activity, but also enhanced the expressions of Runx2, OCN, VEGF and PDGF-β in transfected BMSCs after osteogenic induction. The effects of Foxc2 on osteogenesis and angiogenesis were significantly different between Lv-Foxc2 transfected BMSCs and Lv-GFP transfected BMSCs (P<0.05). In addition, the MAPK-specific inhibitors, PD98059 and LY294002, blocked the Foxc2-induced regulation of BMSC differentiation. Foxc2 gene is successfully transfected into BMSCs with stable and high expression. The overexpression of Foxc2 acts on BMSCs to stimulate osteogenesis and angiogenesis. The effect of Foxc2 on angiogenesis of the cells is mediated via activating PI3K and ERK. 23756055 Acyclovir-resistant varicella-zoster virus keratitis in an immunocompetent patient. Varicella-zoster virus (VZV) resistance to acyclovir (ACV) has only been reported in rare cases of immunocompromised patients. We report the first case of an immunocompetent patient with ACV-resistant VZV keratitis associated with a nucleotide deletion in the VZV thymidine kinase gene, leading to production of a truncated protein. 23507349 Interpretation of the margin of exposure for genotoxic carcinogens - Elicitation of expert knowledge about the form of the dose response curve at human relevant exposures. The general approach to risk assessment of genotoxic carcinogens has been to advise reduction of exposure to "as low as reasonably achievable/practicable" (ALARA/P). However, whilst this remains the preferred risk management option, it does not provide guidance on the urgency or extent of risk management actions necessary. To address this, the "Margin of Exposure" (MOE) approach has been proposed. The MOE is the ratio between the point of departure for carcinogenesis and estimated human exposure. However, interpretation of the MOE requires implicit or explicit consideration of the shape of the dose-response curve at human relevant exposures. In a structured elicitation exercise, we captured expert opinion on available scientific evidence for low dose-response relationships for genotoxic carcinogens. This allowed assessment of: available evidence for the nature of dose-response relationships at human relevant exposures; the generality of judgments about such dose-response relationships; uncertainties affecting judgments on the nature of such dose-response relationships; and whether this last should differ for different classes of genotoxic carcinogens. Elicitation results reflected the variability in experts' views on the form of the dose-response curve for low dose exposure and major sources of uncertainty affecting the assumption of a linear relationship. 23355059 The reversal of inhibitors in congenital hemophilia. Hemophilias A and B are heritable bleeding disorders characterized by deficient baseline levels of factor VIII (fVIII) and factor IX (fIX), respectively. Standard treatment for acute bleeding events and for prophylaxis in patients with severe disease consists of recombinant fVIII and fIX infusions. The development of alloantibodies, or inhibitors, is a serious complication of congenital hemophilia that may impair the effectiveness of fVIII and fIX, leading to increased morbidity and cost of therapy. When inhibitors are present, bypassing agents such as recombinant activated factor VII and factor eight inhibitor bypass agent are available for treatment of bleeding events. Although usually effective, they are costly treatments. Immune-modulatory therapy may reverse inhibitors, allowing fVIII and fIX to be used again. Immune tolerance induction is the chief treatment option to decrease inhibitor levels, but about 20-30% of patients fail this treatment. Alternatively, multiple immune-modulating agents have been tried with limited success. Rituximab, an anti-CD20 monoclonal antibody, is one therapy that has been successful in reducing inhibitor titers in multiple case reports. Although current evidence is limited and questions regarding its use and place in therapy still exist, this agent shows promise for the future. 23806758 Peptides with angiotensin I converting enzyme (ACE) inhibitory activity generated from porcine skeletal muscle proteins by the action of meat-borne Lactobacillus. Angiotensin I converting enzyme (ACE) inhibitory activity of peptides derived from the hydrolysis of sarcoplasmic and myofibrillar porcine proteins by the action of Lactobacillus sakei CRL1862 and Lactobacillus curvatus CRL705 (whole cells+cell free extracts) was investigated at 30°C for 36h. The protein hydrolysates were subjected to RP-HPLC in order to fractionate the extracts for further evaluation of ACE inhibitory activity. Bioactive fractions were only found from the hydrolysis of sarcoplasmic proteins by both assayed lactobacilli strains. Identification of peptides contained in the bioactive fractions was carried out by tandem mass spectrometry using a nanoLC-ESI-QTOF instrument and the mascot search engine. From the four most active fractions obtained, a total of eighteen and fifty peptides were characterized from L. sakei CRL1862 and L. curvatus CRL705 protein hydrolysates, respectively. The sequence FISNHAY was generated by the proteolytic activity of the two lactobacilli species. Sequence similarity analyses between the peptides identified in this study and those previously identified as ACE inhibitory peptides and detailed in the BIOPEP database were outlined. Results suggest that meat-borne Lactobacillus were able to generate peptides with ACE inhibitory activity, highlighting their potential to be used in the development of functional fermented products. The results of this study would enable the obtention of porcine functional foods by applying lactic acid bacteria generating bioactive peptides. ACE inhibitory peptides obtained by the hydrolytic action of L. curvatus CRL705 and L. sakei CRL1862 on sarcoplasmic proteins were analyzed. Among them, the peptide FISNHAY exhibited the highest activity and its sequence has not yet been reported. 23965932 Shaping medicinal product information: a before and after study exploring physicians' perspectives on the summary of product characteristics. To establish, in the context of the revised European Pharmacovigilance Directive and based on physicians' perspectives, how Summaries of Product Characteristics (SmPCs) could be more user friendly and better support physicians' interactions with patients, thereby improving patients' own understanding of their medicines. Qualitative focus group discussions (step 1), development of an alternative SmPC (step 2) and an online quantitative survey (step 3) comparing the alternative SmPC to the currently approved version. Office-based physicians (n=218) from all federal states of Germany. 218 German physicians participated, with an equal representation of office-based general practitioners and specialists. For step 1 (n=18), physicians were recruited who frequently consulted SmPCs. Planned and performed: Mayring's qualitative content analysis of focus group discussions (step 1), rating on a five-point Likert scale of preference of current versus alternative SmPCs (step 3). Physicians confirmed the importance of SmPCs as a comprehensive source of medicinal product information, but were moderately satisfied with the current SmPCs, utilised it infrequently and were more likely to engage additional sources of information. The alternative SmPC was consistently preferred. It differed in the way information for particular patient groups was presented, included additional sections (synopsis, checklist for patient information) and used a tabular format. Physicians indicated that SmPCs should be available with search and hyperlink functions, as well as be automatically updated and integrated in available practice software or similar solutions. This research contributes to the development of an official, reliable medicinal product information system meeting the needs of a modern information society while providing the reliability of an officially authorised source. In the context of health literacy, SmPCs should be established as the primary information source for healthcare professionals to ensure compliant and safe utilisation of medicinal products. 23853006 Ventilatory response to nitrogen multiple-breath washout in infants. Nitrogen multiple-breath washout (N2 MBW) using 100% oxygen (O2 ) has regained interest to assess efficiency of tracer gas clearance in, for example, children with Cystic Fibrosis (CF). However, the influence of hyperoxia on the infants' respiratory control is unclear. We assessed safety and impact on breathing pattern from hyperoxia, and if exposure to 40% O2 first induces tolerance to subsequent 100% O2 for N2 MBW. We prospectively enrolled 39 infants aged 3-57 weeks: 15 infants with CF (8 sedated for testing) and 24 healthy controls. Infants were consecutively allocated to the protocols comprising of 100% O2 or 40/100% O2 administered for 30 breaths. Lung function was measured using an ultrasonic flowmeter setup. Primary outcome was tidal volume (VT ). None of the infants experienced apnea, desaturation, or bradycardia. Both protocols initially induced hypoventilation. VT temporarily declined in 33/39 infants across 10-25 breaths. Hypoventilation occurred independent of age, disease, and sedation. In the new 40/100% O2 protocol, VT returned to baseline during 40% O2 and remained stable during 100% O2 exposure. End-tidal carbon dioxide monitored online did not change. The classical N2 MBW protocol with 100% O2 may change breathing patterns of the infants. The new protocol with 40% O2 induces hyperoxia-tolerance and does not lead to changes in breathing patterns during later N2 washout using 100% O2 . Both protocols are safe, the new protocol seems an attractive option for N2 MBW in infants. Pediatr Pulmonol. © 2013 Wiley Periodicals, Inc. 23876503 Outbreak-associated Salmonella enterica Serotypes and Food Commodities, United States, 1998-2008. Salmonella enterica infections are transmitted not only by animal-derived foods but also by vegetables, fruits, and other plant products. To clarify links between Salmonella serotypes and specific foods, we examined the diversity and predominance of food commodities implicated in outbreaks of salmonellosis during 1998-2008. More than 80% of outbreaks caused by serotypes Enteritidis, Heidelberg, and Hadar were attributed to eggs or poultry, whereas >50% of outbreaks caused by serotypes Javiana, Litchfield, Mbandaka, Muenchen, Poona, and Senftenberg were attributed to plant commodities. Serotypes Typhimurium and Newport were associated with a wide variety of food commodities. Knowledge about these associations can help guide outbreak investigations and control measures. 23825044 Anti-NKG2A autoantibodies in a patient with systemic lupus erythematosus. Objectives. To characterize a novel anti-NKG2A autoantibody detected in a patient with SLE during a severe flare, and in a cross-sectional study investigate the occurrence of such autoantibodies in patients with SLE and primary SS (pSS).Methods. Serum or IgG from patients with SLE, pSS and healthy volunteers were assayed for blocking of anti-NKG2A or HLA-E binding to peripheral blood mononuclear cells or CD94/NKG2A- and CD94/NKG2C-transfected Ba/F3 cells. The anti-NKG2A autoantibodies were evaluated for effect on NK cell degranulation in response to HLA-E-transfected K562 cells. IFN-α was determined by an immunoassay and disease activity by the SLEDAI score.Results. Anti-NKG2A autoantibodies, which blocked binding of HLA-E tetramers to CD94/NKG2A-transfected cells and impaired NKG2A-mediated inhibition of NK cell activation, were observed in a patient with SLE. The presence of anti-NKG2A autoantibodies was associated with high SLE disease activity (SLEDAI score 14 and 16) and increased serum IFN-α. Of 94 SLE, 60 pSS and 30 healthy donor sera, only the index patient serum contained anti-NKG2A autoantibodies.Conclusion. The presence of autoantibodies targeting NKG2A is a rare event, but when such autoantibodies occur they may promote excessive NK cell function. This can contribute to the pathogenesis by increasing the killing of cells and the release of autoantigens. Our findings highlight the possible importance of NK cells in the SLE disease process. 23958518 Oxaliplatin-induced Liver Injury Mimicking Metastatic Tumor on Images: A Case Report. Oxaliplatin-based chemotherapy is widely used for advanced colorectal cancer treatment, but it occasionally induces liver injury that is characterized histologically by sinusoidal dilatation, hepatic plate atrophy and/or venular obstruction. Most of the patients do not reveal apparent radiological abnormalities, however. Here, we report the case of a 47-year-old man with a radiologically detectable mass-forming oxaliplatin-induced sinusoidal injury that mimicked multiple liver tumors. These mass lesions were found on computed tomography images after the administration of six cycles of folinic acid, fluorouracil and oxaliplatin therapy as adjuvant chemotherapy for Stage III rectal cancer. The patient had to undergo liver resection because imaging studies could not exclude metastases. The histological examination revealed that a resected mass lesion was composed of severe sinusoidal dilatation. Milder dilatation was also seen in the surrounding parenchyma. We diagnosed the patient as having an oxaliplatin-induced sinusoidal injury with severe deviation. As oxaliplatin is a standard agent in colorectal cancer therapy today, all clinicians and pathologists should be aware of such non-neoplastic lesions as one of the rare differential diagnoses of metastatic liver tumor, to prevent overtreatment. 23834226 Detection and molecular characterisation of equine infectious anaemia virus (EIAV) from field outbreaks in Slovenia. In 2009, a surprisingly high number of animals seropositive for equine infectious anaemia virus (EIAV) (26 horses from 13 farms) were detected in Slovenia. To develop a PCR assay for the detection of the proviral nucleic acid, to phylogenetically characterise the Slovenian EIAV strains and to investigate whether transmission in utero occurred. Cross sectional clinical study. In total, 26 horses (including 2 foals and 4 pregnant mares) and 4 foetuses were examined in this study. A PCR assay using the EIAV F1 and EIAV R1 primers was designed and tested using genomic DNA extracted from 28 spleen samples, 18 whole blood samples and 17 peripheral blood leukocyte (PBL) samples. Amplicons of 22 PCRs obtained from the spleen samples were subjected to direct DNA sequencing and phylogenetic analysis. All spleen samples from 22 adult animals were positive for EIAV by PCR, whereas whole blood and the PBL samples were positive from only 4 animals. Spleen samples from foals and foetuses were negative by PCR. The Slovenian EIAV sequences could be mapped to 9 different branches of the phylogenetic tree. The PCR was able to detect different EIAV strains from spleen samples of seropositive animals detected in Slovenia. Phylogenetic analysis revealed high genetic diversity of the EIAV strains detected in Slovenia, with their closest relatives being European strains. In utero transmission in pregnant mares did not occur. The PCR assay used in this study was not sensitive enough to reliably detect EIAV in blood and is not useful as a routine diagnostic tool. However, it was able to detect EIAV in spleen of all adult horses investigated in this study. In addition, the nucleotide sequence analysis of the PCR amplicon gave useful information about the EIAV strains circulating in Slovenia. 23823157 Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. We assessed effectiveness, safety, and tolerability of paclitaxel or fluorouracil when added to radiation plus cisplatin followed by adjuvant chemotherapy in a programme of selected bladder preservation for patients with muscle invasive bladder cancer. In our randomised phase 2 trial, we enrolled patients with T2-4a transitional cell carcinoma of the bladder at 24 medical centres in the USA. We randomly allocated patients to receive paclitaxel plus cisplatin (paclitaxel group) or fluorouracil plus cisplatin (fluorouracil group) with twice-daily radiation in random block sizes per site on the basis of clinical T-stage (T2 vs T3-4). Patients and physicians were aware of treatment assignment. All patients had transurethral resection of bladder tumour and twice-daily radiotherapy to 40·3 Gy, along with allocated chemotherapy, followed by cystoscopic and biopsy assessment of response. Patients who had a tumour response with downstaging to T0, Tcis, or Ta received consolidation chemoradiotherapy to 64·3 Gy, with the same chemotherapy regimen as in the induction phase. Patients received adjuvant cisplatin-gemcitabine-paclitaxel after the end of chemoradiotherapy. If, after induction, persistent disease was graded as T1 or worse, we recommended patients undergo cystectomy and adjuvant chemotherapy. We assessed the primary endpoints of rates of treatment completion and toxic effects in all randomly allocated patients. This study is registered with ClinicalTrials.gov, number NCT00055601. Between Dec 13, 2002, and Jan 11, 2008, we enrolled 97 patients, of whom 93 were eligible for analysis. Median follow-up was 5·0 years (IQR 5·0-6·2). Of 46 patients in the paclitaxel group, 45 (98%) completed induction (16 [35%] with grade 3-4 toxicity), 39 (85%) completed induction and consolidation (11 [24%] with grade 3-4 toxicity due to consolidation), and 31 (67%) completed the entire protocol with adjuvant chemotherapy. 34 (85%) of 40 assessable patients in the paclitaxel group had grade 3-4 toxicity during adjuvant chemotherapy. Of 47 patients in the fluorouracil group, 45 (96%) completed induction (nine [19%] with grade 3-4 toxicity), 39 (83%) completed induction and consolidation (12 [26%] had grade 3-4 toxicity due to consolidation), and 25 (53%) completed the entire protocol with adjuvant chemotherapy. 31 (76%) of 41 assessable patients in the fluorouracil group had grade 3-4 toxicity during adjuvant chemotherapy. Five (11%) patients treated with the paclitaxel regimen and three (6%) patients treated with the fluorouracil regimen developed late grade 3-4 radiotherapy toxicities. 11 (24%) patients treated with the paclitaxel regimen and 16 (34%) patients treated with the fluorouracil regimen developed late grade 3-4 toxicities unrelated to radiotherapy. One patient (in the fluorouracil group) died during follow-up. Six (13%) patients in the paclitaxel group and in three (6%) patients in the fluorouracil group discontinued due to treatment-related toxicity. In the absence of phase 3 data, our findings could inform selection of a bladder-sparing trimodality chemotherapy regimen for patients with muscle invasive bladder cancer. US National Cancer Institute. 23512864 Pharmacokinetic parameter sets of alfentanil revisited: optimal parameters for use in target controlled infusion and anaesthesia display systems. /st> In open TCI and anaesthesia display systems, the choice of pharmacokinetic (PK) parameter sets of opioids is clinically relevant. Accuracy and bias of the PK models may be affected by administration mode and the co-administered hypnotic drug. We retrospectively evaluated the performance of eight PK parameter sets for alfentanil in two data sets (infusion and bolus application). /st> With the dosing history from two studies in orthopaedic patients anaesthetized with propofol or inhalation anaesthetics the alfentanil plasma concentration over time was calculated with eight PK parameter sets. Median absolute performance error (MDAPE), log accuracy, median performance error (MDPE), log bias, Wobble, and Divergence were computed. Mann-Whitney rank test with Bonferroni correction was used for comparison between bolus and infusion data, repeated measures analysis of variance on ranks was used for comparison among parameter sets. /st> The parameters by Scott (original and weight adjusted) and Fragen had a MDAPE ≤30% and a median log accuracy <0.15 independent of the administration mode, while MDPE was within ±20% and log bias nearly within ±0.1, respectively. The sets by Maitre and Lemmens were within these limits only in the bolus data. All other parameter sets were outside these limits. /st> In healthy orthopaedic patients, the PK parameters by Scott and by Maitre were equally valid when alfentanil was given as repeated boluses. When given as infusion, the Maitre parameters were less accurate and subject to a significant bias. We cannot exclude that the difference between bolus and infusion is partially because of the different hypnotics used. 22728760 Pharmacological treatment of tic disorders and Tourette Syndrome. The present review gives an overview of current pharmacological treatment options of tic disorders and Tourette Syndrome (TS). After a short summary on phenomenology, clinical course and comorbid conditions we review indications for pharmacological treatment in detail. Unfortunately, standardized and large enough drug trials in TS patients fulfilling evidence based medicine standards are still scarce. Treatment decisions are often guided by individual needs and personal experience of treating clinicians. The present recommendations for pharmacological tic treatment are therefore based on both scientific evidence and expert opinion. As first-line treatment of tics risperidone (best evidence level for atypical antipsychotics) or tiapride (largest clinical experience in Europe and low rate of adverse reactions) are recommended. Aripiprazole (still limited but promising data with low risk for adverse reactions) and pimozide (best evidence of the typical antipsychotics) are agents of second choice. In TS patients with comorbid attention deficit hyperactivity disorder (ADHD) atomoxetine, stimulants or clonidine should be considered, or, if tics are severe, a combination of stimulants and risperidone. When mild to moderate tics are associated with obsessive-compulsive symptoms, depression or anxiety sulpiride monotherapy can be helpful. In more severe cases the combination of risperidone and a selective serotonin reuptake inhibitor should be given. In summary, further studies, particularly randomized, double-blind, placebo-controlled trials including larger and/or more homogenous patient groups over longer periods are urgently needed to enhance the scientific basis for drug treatment in tic disorders. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. 23932475 Hg bioaccumulation in marine copepods around hydrothermal vents and the adjacent marine environment in northeastern Taiwan. The Hg concentration in seawater and copepod samples collected from the area around hydrothermal vents at Kueishan Island and the adjacent marine environment in northeastern Taiwan were analyzed to study Hg bioaccumulation in copepods living in polluted and clean marine environments. The seawater collected from the hydrothermal vent area had an extremely high concentration of dissolved Hg, 50.6-256ngl(-1). There was slightly higher Hg content in the copepods, 0.08-0.88μgg(-1). The dissolved Hg concentration in the hydrothermal vent seawater was two to three orders of magnitude higher than that in the adjacent environment. The bioconcentration factor of the studied copepods ranged within 10(3)-10(6), and showed higher dissolved concentration as the bioconcentration factor was lower. A substantial abundance, but with less copepod diversity was recorded in the seawater around the hydrothermal vent area. Temora turbinata was the species of opportunity under the hydrothermal vent influence. 23863145 Terminal loop-mediated regulation of miRNA biogenesis: selectivity and mechanisms. Regulating the expression of individual miRNAs (microRNAs) is important for cell development and function. The up- or down-regulation of the processing of specific miRNA precursors to the mature active form represents one tool to control miRNA concentration and is mediated by proteins that recognize the terminal loop of the RNA precursors. Terminal loop recognition is achieved by the combined action of several RNA-binding domains. The proteins can then regulate the processing by recruiting RNA enzymes, changing the RNA structure and preventing or enhancing the accessibility and processing activity of the core processing complexes. The present review focuses on how terminal loop-binding proteins recognize their RNA targets and mediate their regulatory function(s), and highlights how terminal loop-mediated regulation relates to the broader regulation of mRNA metabolism. 22812632 Length-dependent pleural inflammation and parietal pleural responses after deposition of carbon nanotubes in the pulmonary airspaces of mice. Abstract Background: Carbon nanotubes (CNT) are fibre-like nanomaterials whose structural similarity to asbestos has raised concerns that they may also pose a mesothelioma hazard. The objective of this study was to examine the inflammatory potential of three CNT samples of differing length on the lungs and pleural cavity following introduction into the airspaces of mice. ResultsAspiration of the two short/tangled and one long CNT sample into the lungs of mice resulted in a length-dependent inflammatory response at 1 week, i.e., only the long CNT sample caused acute neutrophilic inflammation in bronchoalveolar lavage at 1 week and progressive thickening of the alveolar septa. The authors also report length-dependent inflammatory responses in the pleural lavage after exposure only to the long CNT. The inflammatory response in the pleural cavity to long fibres and the appearance of lesions along the chest wall and diaphragm was not present at 1 week and only evident by 6 weeks post-exposure. Conclusion: Length-dependent pathogenicity is a feature of asbestos and the results presented in this study demonstrate similar length-dependent pathogenicity of CNT in the lungs and pleural space following airspace deposition. The data support the contention that long CNT reach the pleura from the airspaces, and that they are retained at the parietal pleura and cause inflammation and lesion development. The parietal pleura is the site of origin of mesothelioma and inflammation is considered to be a process involved in asbestos carcinogenesis and so the data support the contention that CNT may pose an asbestos-like mesothelioma hazard. 23709621 Protein composition of bronchoalveolar lavage fluid and airway surface liquid from newborn pigs. The airway mucosa and the alveolar surface form dynamic interfaces between the lung and the external environment. The epithelial cells lining these barriers elaborate a thin liquid layer containing secreted peptides and proteins that contribute to host defense and other functions. The goal of this study was to develop and apply methods to define the proteome of porcine lung lining liquid, in part, by leveraging the wealth of information in the Sus scrofa database of Ensembl gene, transcript, and protein model predictions. We developed an optimized workflow for detection of secreted proteins in porcine bronchoalveolar lavage (BAL) fluid and in methacholine-induced tracheal secretions [airway surface liquid (ASL)]. We detected 674 and 3,858 unique porcine-specific proteins in BAL and ASL, respectively. This proteome was composed of proteins representing a diverse range of molecular classes and biological processes, including host defense, molecular transport, cell communication, cytoskeletal, and metabolic functions. Specifically, we detected a significant number of secreted proteins with known or predicted roles in innate and adaptive immunity, microbial killing, or other aspects of host defense. In greatly expanding the known proteome of the lung lining fluid in the pig, this study provides a valuable resource for future studies using this important animal model of pulmonary physiology and disease. 23970424 Characterization of in Vitro ADME Properties of Diosgenin and Dioscin from Dioscorea villosa. Dioscorea villosa (wild yam) is native to North America and has been widely used as a natural alternative for estrogen replacement therapy to improve women's health as well as to treat inflammation, muscle spasm, and asthma. Diosgenin and dioscin (glycoside form of diosgenin) are reported to be the pharmacologically active compounds. Despite the reports of significant pharmacological properties of dioscin and diosgenin in conditions related to inflammation, cancer, diabetes, and gastrointestinal ailments, no reports are available on ADME properties of these compounds. This study was carried out to determine ADME properties of diosgenin and dioscin and their effects on major drug metabolizing enzymes (CYP 3A4, 2D6, 2C9, and 1A2). The stability was determined in simulated gastric and intestinal fluids (SGF, pH 1.2 and SIF, pH 6.8), and intestinal transport was evaluated in Caco-2 model. Phase I and phase II metabolic stability was determined in human liver microsomes and S9 fractions, respectively. Quantitative analysis of dioscin and diosgenin was performed by UPLC-MS system. Dioscin degraded up to 28.3 % in SGF and 12.4 % in SIF, which could be accounted for by its conversion to diosgenin (24.2 %. in SGF and 2.4 % in SIF). The depletion of diosgenin in SGF and SIF was < 10 %. Diosgenin was stable in HLM but disappeared in S9 fraction with a half-life of 11.3 min. In contrast, dioscin was stable in both HLM and S9 fractions. Dioscin showed higher permeability across Caco-2 monolayer with no significant efflux, while diosgenin was subjected to efflux mediated by P-glycoprotein. Diosgenin and dioscin inhibited CYP3A4 with IC50 values of 17 and 33 µM, respectively, while other CYP enzymes were not affected. In conclusion, dioscin showed better intestinal permeability. Conversion of dioscin to diosgenin was observed in both gastric and intestinal fluids. No phase I metabolism was detected for both compounds. The disappearance of diosgenin in S9 fraction indicated phase II metabolism. 23935496 Three-dimensional normal human neural progenitor tissue-like assemblies: a model of persistent varicella-zoster virus infection. Varicella-zoster virus (VZV) is a neurotropic human alphaherpesvirus that causes varicella upon primary infection, establishes latency in multiple ganglionic neurons, and can reactivate to cause zoster. Live attenuated VZV vaccines are available; however, they can also establish latent infections and reactivate. Studies of VZV latency have been limited to the analyses of human ganglia removed at autopsy, as the virus is strictly a human pathogen. Recently, terminally differentiated human neurons have received much attention as a means to study the interaction between VZV and human neurons; however, the short life-span of these cells in culture has limited their application. Herein, we describe the construction of a model of normal human neural progenitor cells (NHNP) in tissue-like assemblies (TLAs), which can be successfully maintained for at least 180 days in three-dimensional (3D) culture, and exhibit an expression profile similar to that of human trigeminal ganglia. Infection of NHNP TLAs with cell-free VZV resulted in a persistent infection that was maintained for three months, during which the virus genome remained stable. Immediate-early, early and late VZV genes were transcribed, and low-levels of infectious VZV were recurrently detected in the culture supernatant. Our data suggest that NHNP TLAs are an effective system to investigate long-term interactions of VZV with complex assemblies of human neuronal cells. 23847196 Impact of donor source on hematopoietic cell transplantation outcomes for patients with myelodysplastic syndromes (MDS). Allogeneic hematopoietic cell transplantation (HCT) from human leukocyte antigen (HLA) matched related donor (MRD) and matched unrelated donors (MUD) produces similar survival for patients with acute myelogenous leukemia. Whether these results can be extended to patients with myelodysplastic syndromes (MDS) is unknown. Therefore, a disease-specific analysis of post-HCT outcomes for MDS was performed. Outcomes of 701 adult MDS patients who underwent HCT between 2002 and 2006 were analyzed (MRD, n=176; 8/8 HLA-A, B, C, DRB1 allele matched MUD, n=413; 7/8 MUD, n=112). Median age was 53 years (range, 22-78). Thirty-one percent had Karnofsky performance scores <90% at HCT. In multivariate analyses, MRD HCT recipients had similar disease free survival (DFS) and survival rates compared to 8/8 MUD HCT recipients (relative risk [RR] 1.13 (95% confidence intervals [CI] 0.91-1.42) and 1.24 (95% CI 0.98-1.56), respectively), and both MRD and 8/8 MUD had superior DFS (RR 1.47 (95% CI 1.10-1.96) and 1.29 (95% CI 1.00-1.66), respectively) and survival (RR 1.62 (95% CI 1.21-2.17) and 1.30 (95% CI 1.01-1.68), respectively) compared to 7/8 MUD HCT recipients. In patients with MDS, MRD remains the best stem cell source followed by 8/8 MUD. Transplantation from 7/8 MUD is associated with significantly poorer outcomes. 23910395 Dechlorination of polychlorinated biphenyl-contaminated soil via anaerobic composting with pig manure. Anaerobic dechlorination is an effective degradation pathway of higher chlorinated polychlorinated biphenyls (PCBs). The efficiency of anaerobic composting remediation of PCB-contaminated soil using pig manure was determined. The results show that the dechlorination of PCB-contaminated soil via anaerobic composting with pig manure is feasible. PCB concentration is the most critical factor. Elevated PCB concentrations can inhibit dechlorination but does not disrupt the anaerobic fermentation process. At 1mgkg(-1) PCBs, the degradation rate of five or more chlorinated biphenyls is 43.8%. The highest dechlorination performance in this experiment was obtained when the soil-to-organic waste ratio, carbon-to-nitrogen ratio, moisture content, and PCB concentration were 2:3, 20, 60%, and 1mgkg(-1), respectively. 23737513 Medication Errors in HIV-Infected Hospitalized Patients: A Pharmacist's Impact. Treatment with highly active antiretroviral therapy (HAART) decreases morbidity and mortality associated with HIV infection. Unfortunately, HAART medication errors are prevalent in hospitalized patients with HIV infection. Appropriate regimen administration and adherence are essential for treatment success. To assess the impact of pharmacist interventions on the rate of medication errors in HIV-infected hospitalized patients who had been prescribed HAART in the outpatient setting. Hospitalized patients aged 18 years or older receiving HAART and/or opportunistic infection (OI) prophylaxis were screened for inclusion. Data collection for each enrolled patient included demographic information, pertinent laboratory results, and inpatient and outpatient medication regimens. Patient medication profiles were reviewed within 72 hours of admission. HAART and/or OI prophylaxis errors were classified by type and frequency. Following the pharmacist intervention, prescribers' responses to each recommendation and the estimated time per intervention were recorded. Eighty-six patients were included in this investigation and 210 HAART and OI prophylaxis errors were documented. Of patients receiving HAART and/or OI prophylaxis, 54.7% had at least 1 medication error on admission. An average of 2.4 errors per patient was identified. Dose omission (45.5%) was the most common error type among combined HAART and OI prophylaxis regimens, followed by incorrect regimen (17.1%) and incorrect dose (15.1%). Prescribers accepted 90% of pharmacist recommendations. A pharmacist was able to amend 94.7% of correctable HAART errors, as well as 89.9% of correctable combined HAART and OI prophylaxis errors. An estimated 18.5 minutes of pharmacist time were spent per patient requiring an intervention. A clinical pharmacist's targeted review of outpatient-prescribed HAART and/or OI primary prophylaxis regimens of hospitalized HIV-infected patients can reduce most medication errors during hospitalization. 23657999 Absolute measurement of species differences in sodium taurocholate cotransporting polypeptide (NTCP/Ntcp) and its modulation in cultured hepatocytes. Species differences among membrane transporters can be remarkable and difficult to properly assess by conventional methods. Herein, we employed the first use of stable isotope labeling in mammals or stable isotope-labeled peptides combined with mass spectrometry to identify species differences in sodium taurocholate cotransporting polypeptide (NTCP/Ntcp) protein expression in liver tissue and to characterize the modulation of protein expression in sandwich-cultured human (SCHH) and rat hepatocytes (SCRH). The lower limit of quantification was established to be 5 fmol on column with a standard curve that was linear up to 2000 fmol. The accuracy and precision were evaluated with three quality control samples and known amounts of synthetic proteotypic peptides that were spiked into the membrane protein extracts. The overall relative error and coefficient of variation were less than 10%. The expression of Ntcp in mouse and rat was significant higher than that in human (five-fold) and monkey (two-fold) and ranked as mouse > rat > monkey > human. In the cultured hepatocytes, although significant downregulation of Ntcp expression in SCRH at day 5 after the culture was detected, NTCP expression in SCHH was comparable to the suspension hepatocytes. The results suggested that NTCP/Ntcp modulation in cultured hepatocytes is species specific. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:3252-3263, 2013. 23274770 In vitro evaluation of cytochrome P450 induction and the inhibition potential of mitragynine, a stimulant alkaloid. CYP450 enzymes are key determinants in drug toxicities, reduced pharmacological effect and adverse drug reactions. Mitragynine, an euphoric compound was evaluated for its effects on the expression of mRNAs encoding CYP1A2, CYP2D6 and CYP3A4 and protein expression and resultant enzymatic activity. The mRNA and protein expression of CYP450 isoforms were carried out using an optimized multiplex qRT-PCR assay and Western blot analysis. CYP1A2 and CYP3A4 enzyme activities were evaluated using P450-Glo™ assays. The effects of mitragynine on human CYP3A4 protein expression were determined using an optimized hCYP3A4-HepG2 cell-based assay. An in silico computational method to predict the binding conformation of mitragynine to the active site of the CYP3A4 enzyme was performed and further validated using in vitro CYP3A4 inhibition assays. Mitragynine was found to induce mRNA and protein expression of CYP1A2. For the highest concentration of 25 μM, induction of mRNA was approximately 70% that of the positive control and was consistent with the increased CYP1A2 enzymatic activity. Thus, mitragynine is a significant in vitro CYP1A2 inducer. However, it appeared to be a weak CYP3A4 inducer at the transcriptional level and a weak CYP3A4 enzyme inhibitor. It is therefore, unlikely to have any significant clinical effects on CYP3A4 activity. 23835937 Peripheral artery disease and risk of cardiovascular events in patients with coronary artery disease: Insights from the Heart and Soul Study. Among patients with coronary artery disease (CAD), those with peripheral artery disease (PAD) have a greater vulnerability to cardiovascular (CV) events than those with CAD alone. In a prospective cohort study of patients with CAD, we evaluated potential mechanisms that might explain the adverse CV outcomes associated with PAD. We performed a prospective cohort study of 1018 patients with stable CAD who were recruited from 2000 to 2002. Incident symptomatic PAD events were adjudicated during a follow-up period of 7.2 ± 2.6 years. We used Cox proportional hazards models to evaluate the association between incident symptomatic PAD events and subsequent risk of CV events or death. Models were adjusted for demographics, traditional risk factors, inflammation, insulin resistance and health behaviors. Among the 1018 patients, 50 patients who did not report a history of PAD at baseline suffered incident symptomatic PAD events during the follow-up period. Those patients had a higher risk of subsequent CV events and death compared to those who did not develop PAD. After adjustment for traditional risk factors, symptomatic PAD events remained associated with a 70% increased risk of subsequent CV events (adjusted HR 1.7; 95% CI 1.0, 2.9; p = 0.04) and an 80% increased risk of death (adjusted HR 1.8; 95% CI 1.2, 2.7; p = 0.006). Inflammatory biomarkers were the strongest risk factor contributing to the excess risk. In a contemporary cohort of patients with CAD, incident symptomatic PAD events were associated with an increased risk for subsequent CV events. The increased vulnerability to CV events was partially explained by shared CV risk factors and inflammation. 23673354 Impact of Endoscopic Surveillance on Mortality From Barrett's Esophagus-Associated Esophageal Adenocarcinomas. Although patients with Barrett's esophagus commonly undergo endoscopic surveillance, its effectiveness in reducing mortality from esophageal/gastroesophageal junction adenocarcinomas has not been evaluated rigorously. We performed a case-control study in a community-based setting. Among 8272 members with Barrett's esophagus, we identified 351 esophageal adenocarcinoma: 70 in persons who had a prior diagnosis of Barrett's esophagus (who were eligible for surveillance); 51 of these patients died, 38 as a result of the cancers (cases). Surveillance histories were contrasted with a sample of 101 living persons with Barrett's esophagus (controls), matched for age, sex, and duration of follow-up evaluation. Surveillance within 3 years was not associated with a decreased risk of death from esophageal adenocarcinoma (adjusted odds ratio, 0.99; 95% confidence interval, 0.36-2.75). Fatal cases were nearly as likely to have received surveillance (55.3%) as were controls (60.4%). A Barrett's esophagus length longer than 3 cm and prior dysplasia each were associated with subsequent mortality, but adjustment for these did not change the main findings. Although all patients should be included in evaluations of effectiveness, excluding deaths related to cancer treatment and patients who failed to complete treatment, changed the magnitude, but not the significance, of the association (odds ratio, 0.46; 95% confidence interval, 0.13-1.64). Endoscopic surveillance of patients with Barrett's esophagus was not associated with a substantially decreased risk of death from esophageal adenocarcinoma. The results do not exclude a small to moderate benefit. However, if such a benefit exists, our findings indicate that it is substantially smaller than currently estimated. The effectiveness of surveillance was influenced partially by the acceptability of existing treatments and the occurrence of treatment-associated mortality. 23500380 Evaluation of the pharmacodynamics and pharmacokinetics of brucine following transdermal administration. Before the design of brucine-containing transdermal formulations, the pharmacodynamics and pharmacokinetics of brucine following transdermal administration should be evaluated. In this study, the effect of addition of ethanol on solubility of bruicne was investigated and 20% ethanol was added into PBS to obtain 10mg/mL brucine solution. Then three transdermal doses (10, 20 and 40mg/kg) were administered to mice to evaluate pharmacological activity. It had been demonstrated that brucine possessed analgesic and anti-inflammatory activity in a dose-dependent manner. Cytotoxicities of brucine against various tumor cells including skin tumor cell were also compared in vitro. Brucine was found to possess antitumor activity in a concentration and time-dependent manner and gastrointestinal tumor cells seemed to be more sensitive to brucine. Then in vitro skin permeation behavior and in vivo pharmacokinetics following transdermal administration were further investigated. The cumulative amounts of brucine across mouse skin in vitro were found to be higher than 90%. The absolute bioavailability of brucine was determined to be 40.83%. And compared with intravenous administration, MRT and T1/2 values were increased about 8~12-fold by transdermal route. Moreover, fluctuations of drug levels were found to be significantly decreased in tissues, especially in brain. Finally, no dermal toxicity of brucine was observed. The results of this study indicated that transdermal administration might be beneficial for the sustained efficacy and reduced toxicity of brucine. 23883274 Complex pelvic fracture urethral distraction defects revisited. Abstract Objective. This study aimed to establish some guidelines for the definition, diagnosis and treatment of complex pelvic fracture urethral distraction defects (PFUDD). Material and methods. A total of 40 patients with complex PFUDD was enrolled in this study. Urethral defects were associated with a paraurethral bladder base fistula (PBBF) (six patients), urethrorectal fistula (eight), urethrocutaneous fistula (nine), urinoma cavity (eight) or bladder neck incompetence (nine). In four patients the urethra had been wrongly reconstructed into a bladder base fistula (three) or urinoma cavity (one), elsewhere. Repair was performed by a perineal anastomotic urethroplasty in 15 patients and by a perineoabdominal transpubic procedure in 25. Results. Repair was successful in nine out of 15 (60%) patients who received a perineal repair and in 23 out of 25 (92%) who underwent a perineoabdominal transpubic procedure. Of the eight patients with unsuccessful outcomes five were successfully recorrected by transpubic urethroplasty. Conclusions. A PFUDD may be considered as complex if it is associated with a PBBF, urethrorectal or urethrocutaneous fistula, urinoma cavity, or bladder neck incompetence. Complete excision of a PBBF usually requires a perineoretropubic approach. The initial trauma-related urethrorectal fistula usually opens into the prostatic urethra and its repair requires an abdominal approach, whereas an iatrogenic rectal fistula usually opens into the proximal bulbar urethra and can be resolved by a relatively simple perineal operation. Excision of a urinoma cavity or urethrocutaneous fistula can usually be accomplished from the perineum, while repair of a bladder neck incompetence requires an abdominal approach. 22911949 Photochromic materials: more than meets the eye. Photochromic materials are a family of compounds which can undergo reversible photo-switches between two different states or isomers with remarkably different properties. Inspired by their smart photo-switchable characteristics, a variety of light-driven functional materials have been exploited, such as ultrahigh-density optical data storage, molecular switches, logic gates, molecular wires, optic/electronic devices, sensors, bio-imaging and so on. This review commences with a brief description of exciting progress in this field, from systems in solution to modified functional surfaces. Further development of these photo-switchable systems into practical applications as well as existing challenges are also discussed and put in prospect. 23821485 Costs and prolonged length of stay of central venous catheter-associated bloodstream infections (CVC BSI): a matched prospective cohort study. Central venous catheter-associated bloodstream infections (CVC BSI) are a common and serious complication among critically ill patients on intensive care units (ICUs), but also result in a financial burden for the health care system. Our aim was to determine the additional costs and length of stay (LOS) of patients with ICU-acquired CVC BSI. We used the surveillance method of the German nosocomial infection surveillance system (Krankenhaus Infections Surveillance System, KISS) to find cases of CVC BSI. The associated costs of CVC BSI were estimated as true costs generated within our hospital. We used a matched cohort design, comparing patients with CVC BSI and patients without BSI. The study period was from January to December 2010. Patients were matched by age, sex, and Simplified Acute Physiology Score (SAPS). The LOS in the ICU of control patients needed to be at least as long as that of CVC BSI patients before the onset of CVC BSI. We matched 40 CVC BSI patients to 40 patients without BSI. The median hospital costs for CVC BSI patients were significantly higher than for patients without BSI (60,445 vs. 35,730 ; p = 0.006) and the CVC BSI patients stayed longer in the hospital than patients without CVC BSI (44 days vs. 30 days; p = 0.110). The median attributable costs per CVC BSI was 29,909 (p = 0.006) and the median attributable LOS was 7 days (p = 0.006). CVC BSI is associated with increased hospital costs and prolonged hospital stay. Hospital management should implement control measurements to keep the incidence of CVC BSI as low as possible. 23768824 Anxiolytic property of Lactuca sativa, effect on anxiety behaviour induced by novel food and height. To study anxiolytic property of hydro alchohol extract and to estimate polyphenols present in the extract by HPLC. To evaluate anxiolytic property two animal models were used viz. Elevated T maze and hyponeophagia. Diazepam (1 mg/kg body wt.) served as the standard anxiolytic agent for all the tests. The dried extract of the plant leaf in doses of 100, 200 and 400 mg/kg body weight was administered orally to mice for duration of 15 or 30 days and locomotor and anxiolytic activities were performed. Polyphenols was estimated using HPLC. The HPLC analysis of the polyphenols revealed the presence chlorogenic acid, vanillin, epicatechin, caffeic acid, rutin hydrate, sinapic acid, quercetin-3-rhamnoside, p-coumeric acid and quercitin. Time spent and number of entries into the open arm was improved in 30 days treated animals than that of 15 days treated groups, 200 and 400 mg/kg body weight treated group showed significant results when comparing with the control group. The hydro alcohol extract rich in Polyphenols and other secondary metabolites is a potent anxiolytic agent. 23963246 Enhanced Raman signals from switchable nanoparticle probes. We demonstrate here a DNA-based conformationally switchable nanodumbell structure that modulates the interparticle distance between two gold-silver core-shell nanoparticles to induce significant changes in the SERS signal. 23860765 Loss of very-long O-antigen chains optimizes capsule-mediated immune evasion by Salmonella enterica serovar Typhi. Expression of capsular polysaccharides is a variable trait often associated with more-virulent forms of a bacterial species. For example, typhoid fever is caused by the capsulated Salmonella enterica serovar Typhi, while nontyphoidal Salmonella serovars associated with gastroenteritis are noncapsulated. Here we show that optimization of the immune evasive properties conferred by the virulence-associated (Vi) capsular polysaccharide involved an additional alteration to the cell envelope of S. Typhi, namely inactivation of the fepE gene, encoding the regulator of very-long O-antigen chains. Introduction of the capsule-encoding viaB locus into the nontyphoidal S. enterica serovar Typhimurium reduced complement deposition in vitro and intestinal inflammation in a mouse colitis model. However, both phenotypes were markedly enhanced when the viaB locus was introduced into an S. Typhimurium fepE mutant, which lacks very-long O-antigen chains. Collectively, these data suggest that during the evolution of the S. Typhi lineage, loss of very-long O-antigen chains by pseudogene formation was an adaptation to maximize the anti-inflammatory properties of the Vi capsular polysaccharide. Genomic comparison illustrates that acquisition of virulence factors by horizontal gene transfer is an important contributor to the evolution of enteric pathogens. Acquisition of complex virulence traits commonly involves horizontal transfer of a large gene cluster, and integration of the gene cluster into the host genome results in the formation of a pathogenicity island. Acquisition of the virulence-associated (Vi) capsular polysaccharide encoded by SPI7 (Salmonella pathogenicity island 7) was accompanied in the human-adapted Salmonella enterica serovar Typhi by inactivation of the fepE gene, encoding the regulator of very-long O-antigen chains. We show that the resulting loss of very-long O-antigen chains was an important mechanism for maximizing immune evasion mediated by the Vi capsular polysaccharide. These data suggest that successful incorporation of a capsular polysaccharide requires changes in the cell envelope of the hosting pathogen. 23521163 A new sesquiterpene from the mangrove endophytic fungus Aspergillus terreus (No. GX7-3B). A new compound 1 (named botryosphaerin F), along with other three known compounds 2 (13,14,15,16-tetranorlabd-7-ene-19,6b:12,17-diolide), 3 (botryosphaerin B) and 4 (LL-Z1271β), has been isolated from the mangrove fungus Aspergillus terreus (No. GX7-3B). The structure of the new compound was established by analysis of spectroscopic data. The hypothetical biogenic relationship of four sesquiterpene analogues was also described in this paper. Furthermore, in the cytotoxicity assays, compound 1 showed potent inhibiting activity towards MCF-7 and HL-60 cancer cell lines with 50% inhibition of cell growth (IC50) values of 4.49 and 3.43 μM, respectively, and compound 4 exhibited promising activity against HL-60 cell line with an IC50 value of 0.6 μM. 23614400 Topological Dangling Bonds with Large Spin Splitting and Enhanced Spin Polarization on the Surfaces of Bi2Se3. We investigate the topological surface state properties at various surface cleaves in the topological insulator Bi2Se3, via first principles calculations and scanning tunneling microscopy/spectroscopy (STM/STS). While the typical surface termination occurs between two quintuple layers, we report the existence of a surface termination within a single quintuple layer where dangling bonds form with giant spin splitting owing to strong spin-orbit coupling. Unlike Rashba split states in a 2D electron gas, these states are constrained by the band topology of the host insulator with topological properties similar to the typical topological surface state, and thereby offer an alternative candidate for spintronics usage. We name these new states "topological dangling-bond states". The degree of the spin polarization of these states is greatly enhanced. Since dangling bonds are more chemically reactive, the observed topological dangling-bond states provide a new avenue for manipulating band dispersions and spin-textures by adsorbed atoms or molecules. 23940341 Communicating science in social settings. This essay examines the societal dynamics surrounding modern science. It first discusses a number of challenges facing any effort to communicate science in social environments: lay publics with varying levels of preparedness for fully understanding new scientific breakthroughs; the deterioration of traditional media infrastructures; and an increasingly complex set of emerging technologies that are surrounded by a host of ethical, legal, and social considerations. Based on this overview, I discuss four areas in which empirical social science helps clarify intuitive but sometimes faulty assumptions about the social-level mechanisms of science communication and outline an agenda for bench and social scientists-driven by current social-scientific research in the field of science communication-to guide more effective communication efforts at the societal level in the future. 23962357 Restructuring of a Model Hydrophobic Surface: Monte-Carlo Simulations Using a Simple Coarse-Grained Model. A lattice model is proposed to explain the restructuring of an ionic surfactant absorbed on a charged surface: When immersed in water, an ionic mica plate initially covered by a monolayer of surfactants rearranges to a surface inhomogeneously covered by patches of surfactant bilayer and bare mica. The model considers four species that can cover lattice sites of a surface. These species include: i) a surfactant molecule with its headgroup down, ii) surfactant molecule with the headgroup up, iii) a surfactant dimer arranged in a tail-to-tail configuration, that is a part of a bilayer, and iv) a mica lattice site covered by water. We consider that only nearest neighbors on the lattice interact and describe the interactions by an interaction matrix. Using this model we perform Monte Carlo simulations and study how the structure of the inhomogeneous surface depends on the interaction between water covered lattice site and its neighboring surfactant species covered sites. We observe that when this interaction is absent, the system undergoes phase separation into a bilayer phase and mica surface covered with water. When this interaction is taken into account, patches of surfactant bilayer and water are present in our system. The interaction between mica surfaces covered by patches of ionic surfactants is studied in experiments to understand the nature of long-ranged "hydrophobic" forces. 23604291 Antiarrhythmic effects and ionic mechanisms of allicin on myocardial injury of diabetic rats induced by streptozotocin. The aim of this study was to evaluate the antiarrhythmic effect of allicin (AL) on streptozotocin (STZ)-induced diabetic rats and explore the possible mechanisms. Hyperglycemia was induced in rats by single intraperitoneal injection of STZ (40 mg/kg). Three days after STZ treatment, the hyperglycemic rats (plasma glucose levels ≥16.7 mM) were administered with AL (4, 8, and 16 mg/kg) by intraperitoneal injection daily for 28 days. The fasting blood glucose levels were measured on every seventh day during the 28 days of treatment. The body weight and blood glucose levels were detected after 28 days. Antiarrhythmic effect of AL was observed in the diabetic rats induced by BaCl2. To determine the ionic mechanism in rat ventricular myocytes of AL, action potential duration (APD), L-type calcium current (ICa-L), and inward rectifier potassium current (IK1) were recorded by the whole cell-patch clamp technique. The expressions of L-type calcium channel protein α1C mRNA and cell potassium channels protein Kir2.1 mRNA were studied by RT-PCR. AL normalized the RR interval and QT interval in diabetic rats. AL obviously delayed the onset of ventricular arrhythmia and reduced the score of arrhythmia induced by BaCl2. Electrophysiological experiment revealed that AL could shorten APD through inhibition of ICa-L and enhancement of IK1. RT-PCR analysis indicated that long-term treatment with AL could decrease the expression of α1C mRNA and increase the expression of Kir2.1 mRNA. AL has antiarrhythmic effect in STZ-induced diabetic rats. It is tempting for the application of AL to be a useful therapeutic approach in diabetes with ventricular arrhythmia. 23215761 Towards an understanding of the lives of families affected by stroke: a qualitative study of home carers. To explore caring and coping among carers of stroke survivors and identify factors that had an impact on their lives. Informal carers carry the main responsibility for the care of stroke survivors in the community, which can have a detrimental effect on the health and well-being of carers. However, the circumstances of caring differ for each carer: this study identifies the diverse factors that can cause caring to be burdensome for some carers and less so for others. Qualitative descriptive study. A convenience sample of 30 carers of stroke survivors were interviewed in 2008-2010, following hospital discharge of the stroke survivor. The impact that the stroke event had on the participants of this study varied enormously. Not only did the health status and well-being of the stroke survivors vary greatly but it was also clear that many different factors had an influence on the impact of the stroke on the carer and on how each of them coped. Nine thematic categories were identified, which fell into three broad categories: (1) the impact of the stroke event on the carer; (2) the extrinsic factors that support the caring scenario; and (3) the intrinsic factors that help a carer to cope with the new role. This study provided an insight into the circumstances where caring for stroke survivors takes place. These factors that have an impact on caring and carers should inform the nursing assessment of needs of carers of stroke survivors in the community. 23420666 Parameterization of a reactive force field using a monte carlo algorithm. Parameterization of a molecular dynamics force field is essential in realistically modeling the physicochemical processes involved in a molecular system. This step is often challenging when the equations involved in describing the force field are complicated as well as when the parameters are mostly empirical. ReaxFF is one such reactive force field which uses hundreds of parameters to describe the interactions between atoms. The optimization of the parameters in ReaxFF is done such that the properties predicted by ReaxFF matches with a set of quantum chemical or experimental data. Usually, the optimization of the parameters is done by an inefficient single-parameter parabolic-search algorithm. In this study, we use a robust metropolis Monte-Carlo algorithm with simulated annealing to search for the optimum parameters for the ReaxFF force field in a high-dimensional parameter space. The optimization is done against a set of quantum chemical data for MgSO4 hydrates. The optimized force field reproduced the chemical structures, the equations of state, and the water binding curves of MgSO4 hydrates. The transferability test of the ReaxFF force field shows the extend of transferability for a particular molecular system. This study points out that the ReaxFF force field is not indefinitely transferable. © 2013 Wiley Periodicals, Inc. 23855332 The effect of host star spectral energy distribution and ice-albedo feedback on the climate of extrasolar planets. Abstract Planetary climate can be affected by the interaction of the host star spectral energy distribution with the wavelength-dependent reflectivity of ice and snow. In this study, we explored this effect with a one-dimensional (1-D), line-by-line, radiative transfer model to calculate broadband planetary albedos as input to a seasonally varying, 1-D energy balance climate model. A three-dimensional (3-D) general circulation model was also used to explore the atmosphere's response to changes in incoming stellar radiation, or instellation, and surface albedo. Using this hierarchy of models, we simulated planets covered by ocean, land, and water-ice of varying grain size, with incident radiation from stars of different spectral types. Terrestrial planets orbiting stars with higher near-UV radiation exhibited a stronger ice-albedo feedback. We found that ice extent was much greater on a planet orbiting an F-dwarf star than on a planet orbiting a G-dwarf star at an equivalent flux distance, and that ice-covered conditions occurred on an F-dwarf planet with only a 2% reduction in instellation relative to the present instellation on Earth, assuming fixed CO2 (present atmospheric level on Earth). A similar planet orbiting the Sun at an equivalent flux distance required an 8% reduction in instellation, while a planet orbiting an M-dwarf star required an additional 19% reduction in instellation to become ice-covered, equivalent to 73% of the modern solar constant. The reduction in instellation must be larger for planets orbiting cooler stars due in large part to the stronger absorption of longer-wavelength radiation by icy surfaces on these planets in addition to stronger absorption by water vapor and CO2 in their atmospheres, which provides increased downwelling longwave radiation. Lowering the IR and visible-band surface ice and snow albedos for an M-dwarf planet increased the planet's climate stability against changes in instellation and slowed the descent into global ice coverage. The surface ice-albedo feedback effect becomes less important at the outer edge of the habitable zone, where atmospheric CO2 could be expected to be high such that it maintains clement conditions for surface liquid water. We showed that ∼3-10 bar of CO2 will entirely mask the climatic effect of ice and snow, leaving the outer limits of the habitable zone unaffected by the spectral dependence of water ice and snow albedo. However, less CO2 is needed to maintain open water for a planet orbiting an M-dwarf star than would be the case for hotter main-sequence stars. Key Words: Extrasolar planets-M stars-Habitable zone-Snowball Earth. Astrobiology 13, 715-739. 23370969 A positive interaction between inhibitors of protein synthesis and cefepime in the fight against methicillin-resistant Staphylococcus aureus. Quinupristin-dalfopristin (Q-D) synergizes with cefepime for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). Here, we studied whether the synergism was restricted to MRSA and if it extended to non-beta-lactam cell wall inhibitors or to other inhibitors of protein synthesis. Three MRSA and two methicillin-susceptible S. aureus (MSSA) strains were tested, including an isogenic pair of mecA (-)/mecA (+) S. aureus Newman. The drug interactions were determined by fractional inhibitory concentration (FIC) indices and population analysis profiles. The antibacterial drugs that we used included beta-lactam (cefepime) and non-beta-lactam cell wall inhibitors (D-cycloserine, fosfomycin, vancomycin, teicoplanin), inhibitors of protein synthesis (Q-D, erythromycin, chloramphenicol, tetracycline, linezolid, fusidic acid), and polynucleotide inhibitors (cotrimoxazole, ciprofloxacin). The addition of each protein inhibitor to cefepime was synergistic (FIC ≤ 0.5) or additive (FIC > 0.5 but < 1) against MRSA, but mostly indifferent against MSSA (FIC ≥ 1 but ≤ 4). This segregation was not observed after adding cotrimoxazole or ciprofloxacin to cefepime. Population analysis profiles were performed on plates in the presence of increasing concentrations of the cell wall inhibitors plus 0.25 × minimum inhibitory concentration (MIC) of Q-D. Cefepime combined with Q-D was synergistic against MRSA, but D-cycloserine and glycopeptides were not. Thus, the synergism was specific to beta-lactam antibiotics. Moreover, the synergism was not lost against fem mutants, indicating that it acted at another level. The restriction of the beneficial effect to MRSA suggests that the functionality of penicillin-binding protein 2A (PBP2A) was affected, either directly or indirectly. Further studies are necessary in order to provide a mechanism for this positive interaction. 23944273 Endogenous fibrinolytic potential in tissue-plasminogen activator-modified thromboelastography analysis is significantly decreased in dogs suffering from diseases predisposing to thrombosis. In people, studies have shown that resistance to fibrinolysis could be a contributing factor to thrombosis. Tissue-plasminogen-activated (t-PA) thromboelastography (TEG) has been used to evaluate endogenous fibrinolytic potential. In dogs, TEG has been used for the diagnosis of various hemostatic disorders, but studies evaluating fibrinolysis are limited. Investigations into the potential of t-PA-modified TEG to monitor endogenous fibrinolytic potential are lacking in both healthy dogs and dogs with diseases predisposing to development of thrombosis. The aim of this study was to compare 3 t-PA-modified TEG assays and compare the endogenous fibrinolytic potential in dogs suffering from diseases associated with thrombosis with a group of healthy dogs. Three different TEG assays, such as native, tissue factor-activated, and kaolin-activated, were modified with t-PA and used to compare whole blood samples from 16 healthy control dogs and 20 diseased dogs. Thromboelastography lysis variables were significantly affected by addition of t-PA in all 3 assays. Lysis results in diseased dogs were comparable to those in healthy dogs prior to addition of t-PA. After addition of t-PA, lysis results were significantly decreased in the diseased group compared with healthy dogs. The lowest median lysis levels were found in dogs with systemic inflammation and protein-losing disorders. Addition of t-PA activates fibrinolysis in TEG of blood from both healthy dogs and dogs with diseases predisposing to thrombosis. The significantly decreased fibrinolysis in diseased dogs suggests that this may be a potential prothrombotic risk factor in dogs. 23830892 Pharmacoeconomic evaluation of caspofungin versus liposomal amphotericin B in empirical treatment of invasive fungal infections in Turkey. Invasive fungal infections (IFIs) are a major concern within healthcare systems. This pharmacoeconomic study evaluated the use of caspofungin (CAS) versus liposomal amphotericin B (L-AmB) in the empirical treatment of IFIs within the Turkish healthcare system. A decision-analytic model was adopted, utilising data from a randomised, non-inferiority clinical trial and a panel of clinical experts in Turkey. A five-point composite outcome measure was used to evaluate both agents. Sensitivity analyses were performed. In the base-case scenario, CAS was preferred over L-AmB by Turkish Lira (TL) 3961 per patient treated, TL 12 904 per successfully treated patient and TL 3972 per death averted. One-way sensitivity analysis did not change the study outcome. Monte Carlo simulation concluded a 71.0% chance of the outcome favouring CAS. The results were most sensitive to changes in length of stay. This is the first economic evaluation of the empirical treatment of IFIs in Turkey and suggests that CAS is more cost effective than L-AmB. 23936166 Age and ethnic differences in volumetric breast density in new zealand women: a cross-sectional study. Breast cancer incidence differs by ethnicity in New Zealand (NZ) with Māori (the indigenous people) women having the highest rates followed by Pakeha (people primarily of British/European descent), Pacific and Asian women, who experience the lowest rates. The reasons for these differences are unclear. Breast density, an important risk factor for breast cancer, has not previously been studied here. We used an automated system, Volpara™, to measure breast density volume from the medio-lateral oblique view of digital mammograms, by age (≤50 years and >50 years) and ethnicity (Pakeha/Māori/Pacific/Asian) using routine data from the national screening programme: age; x-ray system and mammography details for 3,091 Pakeha, 716 Māori, 170 Pacific and 662 Asian (total n = 4,239) women. Linear regression of the natural logarithm of absolute and percent density values was used, back-transformed and expressed as the ratio of the geometric means. Covariates were age, x-ray system and, for absolute density, the natural log of the volume of non-dense tissue (a proxy for body mass index). Median age for Pakeha women was 55 years; Māori 53 years; and Pacific and Asian women, 52 years. Compared to Pakeha women (reference), Māori had higher absolute volumetric density (1.09; 95% confidence interval [95% CI] 1.03-1.15) which remained following adjustment (1.06; 95% CI 1.01-1.12) and was stronger for older compared to younger Māori women. Asian women had the greatest risk of high percentage breast density (1.35; 95% CI 1.27-1.43) while Pacific women in both the ≤50 and >50 year age groups (0.78; 95% CI 0.66-0.92 and 0.81; 95% CI 0.71-0.93 respectively) had the lowest percentage breast density compared to Pakeha. As well as expected age differences, we found differential patterns of breast density by ethnicity consistent with ethnic differences seen in breast cancer risk. Breast density may be a contributing factor to NZ's well-known, but poorly explained, inequalities in breast cancer incidence. 22665054 Stathmin 1 is a potential novel oncogene in melanoma. In previous studies, we demonstrated that miR-193b expression is reduced in melanoma relative to benign nevi, and also that miR-193b represses cyclin D1 and Mcl-1 expression. We suggested that stathmin 1 (STMN1) might be a target of miR-193b. STMN1 normally regulates microtubule dynamics either by sequestering free tubulin heterodimers or by promoting microtubule catastrophe. Increased expression of STMN1 has been observed in a variety of human malignancies, but its association with melanoma is unknown. We now report that STMN1 is upregulated during the progression of melanoma relative to benign nevi, and that STMN1 is directly regulated by miR-193b. Using an experimental cell culture approach, overexpression of miR-193b using synthetic microRNAs repressed STMN1 expression, whereas inhibition of miR-193b with anti-miR oligos increased STMN1 expression in melanoma cells. The use of a luciferase reporter assay confirmed that miR-193b directly regulates STMN1 by targeting the 3'-untranslated region of STMN1 mRNA. We further demonstrated that STMN1 is overexpressed in malignant melanoma compared with nevi in two independent melanoma cohorts, and that its level is inversely correlated with miR-193b expression. However, STMN1 expression was not significantly associated with patient survival, Breslow depth, mitotic count or patient age. STMN1 knockdown by small-interfering RNA in melanoma cells drastically repressed cell proliferation and migration potential, whereas ectopic expression of STMN1 using lentivirus increased cell proliferation and migration rates. Subsequent gene expression analysis indicated that interconnected cytoskeletal networks are directly affected following STMN1 knockdown. In addition, we identified deregulated genes associated with proliferation and migration, and revealed that p21(Cip1/Waf1) and p27(Kip) could be downstream effectors of STMN1 signaling. Taken together, our study suggests that downregulation of miR-193b may contribute to increased STMN1 expression in melanoma, which consequently promotes migration and proliferation of tumor cells. 23517782 Role of oxidative stress in physiological albumin glycation: a neglected interaction. Protein glycation is a key mechanism involved in chronic disease development in both diabetic and nondiabetic individuals. About 12-18% of circulating proteins are glycated in vivo in normoglycemic blood, but in vitro studies have hitherto failed to demonstrate glucose-driven glycation below a concentration of 30mM. Bovine serum albumin (BSA), reduced BSA (mercaptalbumin) (both 40g/L), and human plasma were incubated with glucose concentrations of 0-30mM for 4 weeks at 37°C. All were tested preoxidized for 8h before glycation with 10nM H2O2 or continuously exposed to 10nM H2O2 throughout the incubation period. Fructosamine was measured (nitroblue tetrazolium method) at 2 and 4 weeks. Oxidized BSA (both preoxidized and continuously exposed to H2O2) was more readily glycated than native BSA at all glucose concentrations (p = 0.03). Moreover, only oxidized BSA was glycated at physiological glucose concentration (5mM) compared to glucose-free control (glycation increased by 35% compared to native albumin, p < 0.05). Both 5 and 10mM glucose led to higher glycation when mercaptalbumin was oxidized than when unoxidized (p < 0.05). Fructosamine concentration in human plasma was also significantly higher when oxidized and exposed to 5mM glucose, compared to unoxidized plasma (p = 0.03). The interaction between glucose concentration and oxidation was significant in all protein models (p < 0.05). This study has for the first time demonstrated albumin glycation in vitro, using physiological concentrations of albumin, glucose, and hydrogen peroxide, identifying low-grade oxidative stress as a key element early in the glycation process. 23924735 VPS37 Isoforms Differentially Modulate the Ternary Complex Formation of ALIX, ALG-2, and ESCRT-I. The endosomal sorting complex required for transport (ESCRT) system comprises a series of protein complexes that play essential roles in multivesicular body (MVB) sorting of ubiquitylated membrane proteins, enveloped RNA virus budding, and cytokinesis in mammalian cells. The complex, named ESCRT-I, consists of four subunits (TSG101, VPS28, VPS37, and MVB12). There are four VPS37 isoforms. We have reported that ALIX (an ALG-2-interacting protein and accessory protein in the ESCRT system) is physically linked with TSG101 by ALG-2 in a Ca(2+)-dependent manner, but the role of ALG-2 as an adaptor protein for the ESCRT-I complex remains unknown. To characterize this adaptor function, initially we investigated the binding of ALG-2 to ESCRT-I complexes containing each one of the four different VPS37 isoforms by two approaches: first, Far-Western blot analysis with biotin-labeled ALG-2 probe, and second, a pulldown assay to determine the binding of the four recombinant ESCRT-I complexes to Strep-tagged ALG-2 after co-expression in HEK293T cells. VPS37B and VPS37C appeared to interact with ALG-2 in a stronger manner than TSG101 does. The results of in vitro binding assays using purified recombinant proteins indicated that ALG-2 functions as a Ca(2+)-dependent adaptor protein that bridges ALIX and ESCRT-I to form a ternary complex, ESCRT-I/ALIX/ALG-2. 23931397 Fractional quantization of the magnetic flux in cylindrical unconventional superconductors. The magnetic flux threading a conventional superconducting ring is typically quantized in units of Φ_{0}=hc/2e. The factor of 2 in the denominator of Φ_{0} originates from the existence of two different types of pairing states with minima of the free energy at even and odd multiples of Φ_{0}. Here we show that spatially modulated pairing states exist with energy minima at fractional flux values, in particular, at multiples of Φ_{0}/2. In such states, condensates with different center-of-mass momenta of the Cooper pairs coexist. The proposed mechanism for fractional flux quantization is discussed in the context of cuprate superconductors, where hc/4e flux periodicities were observed. 23551812 Unexpected collapse of healthy newborn infants: risk factors, supervision and hypothermia treatment. To determine the occurrence and risk factors of sudden unexpected postnatal collapse (SUPC) in presumably healthy newborn infants. All live-born infants during a 30-month period, in five major delivery wards in Stockholm, were screened, and possible cases of SUPC thoroughly investigated. Infants were ≥35 weeks of gestation, had an Apgar score >8 at 10 min and collapsed within 24 h after birth. Maternal, infant, event characteristics and outcome data were collected. Twenty-six cases of SUPC were found among 68 364 live-born infants, an incidence of 38/100 000 live births. Sixteen of these cases of SUPC required resuscitation with ventilation >1 min, and 14 of these remained unexplained (21/100 000). Fifteen of the 26 children were found in a prone position, during skin-to-skin contact, 18 were primipara, and 13 occurred during unsupervised breastfeeding at <2 h of age. Three cases occurred during smart cellular phone use by the mother. Five developed hypoxic-ischaemic encephalopathy (HIE) grade 2, and 4 underwent hypothermia treatment. Twenty-five infants had a favourable neurological outcome. SUPC in apparent healthy babies is associated with initial, unsupervised breastfeeding, prone position, primiparity and distractions. Guidelines outlining the appropriate monitoring of newborns and safe early skin-to-skin contact should be implemented. 23890009 PIKfyve, a Class III PI Kinase, Is the Target of the Small Molecular IL-12/IL-23 Inhibitor Apilimod and a Player in Toll-like Receptor Signaling. Toll-like receptor (TLR) signaling is a key component of innate immunity. Aberrant TLR activation leads to immune disorders via dysregulation of cytokine production, such as IL-12/IL-23. Herein, we identify and characterize PIKfyve, a lipid kinase, as a critical player in TLR signaling using apilimod as an affinity tool. Apilimod is a potent small molecular inhibitor of IL-12/IL-23 with an unknown target and has been evaluated in clinical trials for patients with Crohn's disease or rheumatoid arthritis. Using a chemical genetic approach, we show that it binds to PIKfyve and blocks its phosphotransferase activity, leading to selective inhibition of IL-12/IL-23p40. Pharmacological or genetic inactivation of PIKfyve is necessary and sufficient for suppression of IL-12/IL-23p40 expression. Thus, we have uncovered a phosphoinositide-mediated regulatory mechanism that controls TLR signaling. 23937437 Oxygen Sensing, Hypoxia-Inducible Factors, and Disease Pathophysiology. Hypoxia-inducible factors (HIFs) are transcriptional activators that function as master regulators of oxygen homeostasis, which is disrupted in disorders affecting the circulatory system and in cancer. The role of HIFs in these diseases has been elucidated by clinical studies and by analyses of mouse models. HIFs play a protective role in the pathophysiology of myocardial ischemia due to coronary artery disease, limb ischemia due to peripheral arterial disease, pressure-overload heart failure, wound healing, and chronic rejection of organ transplants. In contrast, HIFs contribute to the pathogenesis of pulmonary arterial hypertension, systemic hypertension associated with sleep apnea, ocular neovascularization, hereditary erythrocytosis, and cancer. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 9 is February 28, 2014. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates. 22867273 Absorption of TAK-491, a new angiotensin II receptor antagonist, in animals. The absorption process in animals of TAK-491, designed as ester-based prodrug with medoxomil moiety, was evaluated. In the plasma of rats and dogs, TAK-536, the pharmacologically active metabolite, was present as the main component with hardly detectable concentrations of TAK-491 after oral administration of TAK-491. In the rat portal plasma, TAK-536 was also present as the main component with hardly detectable concentrations of TAK-491 after jejunal loop injection of TAK-491, suggesting TAK-491 was absorbed from small intestine and hydrolyzed almost completely during absorption. Caco-2 study indicated the permeability of TAK-491 was improved by prodrug modification and the compound could be mainly transferred as TAK-491. This is well consistent with the facts that the AUC and T(max) of TAK-536 after oral administration of TAK-491 were higher and shorter than those after oral administration of TAK-536 in dogs Hydrolysis of TAK-491 is observed not only by the intestinal and hepatic S9 fraction, but also by plasma and human serum albumin. However, medoxomil alcohol wasn't detected during the hydrolysis of TAK-491. These metabolic features of TAK-491 were similar to olmesartan medoxomil, suggesting the hydrolytic pathway and enzymes for TAK-491 when catalyzing to TAK-536 would be the same as olmesartan medoxomil. 23789619 Prediction is no panacea: The key to language is in the unexpected. For action systems, the critical task is to predict what will happen next. In language, however, the critical task is not to predict the next auditory event but to extract meaning. Reducing language to an action system, and putting prediction at center, mistakenly marginalizes our core capacity to communicate the novel and unpredictable. 23711968 Heparin-induced thrombocytopenia with abdominal aortic stent-graft acute thrombosis. We report a case of heparin-induced thrombocytopenia in a patient on low molecular weight heparin bridge therapy who developed acute abdominal aortic stent-graft thrombosis 1 week after uncomplicated endovascular abdominal aortic aneurysm repair. The diagnosis was confirmed by a computed tomographic scan of the abdomen. The patient was successfully treated by conversion to open repair. The postoperative course was marked by subacute left limb ischemia related to an in vivo cross-reactivity of danaparoid with the heparin immune complex. To our knowledge, this is the first case report of heparin-induced thrombocytopenia with acute abdominal aortic stent-graft thrombosis. 23465789 Paediatric medical trauma: The impact on parents of burn survivors. In order to identify parents at risk of developing ongoing psychological distress after their child has sustained a burn a greater understanding of paediatric medical trauma is required. To investigate the impact of exposure to paediatric trauma on parents of children with a burn and to identify risk factors and relationships between psychological distress and resilience. Sixty-three parents were recruited. Parents completed standardised assessments measuring symptoms of posttraumatic stress disorder (PTSD), depression, anxiety, stress, and resilience within one week of the burn occurring. Statistical analysis included t-tests, Kruskal-Wallis one way ANOVA and Spearman's Roe. Parents experienced significantly more symptoms of PTSD (p=0.001) than a comparative community population. Factors including having a daughter, witnessing the event, feeling helpless or having past traumatic experiences significantly influenced symptoms of psychological distress and resilience (p=0.05). Parents of burn survivors experience significant psychological distress with low levels of resilience. As part of standard routine care health professionals should screen parents to identify those at greatest risk and provide effective evidence based interventions aimed at improving resilience and reducing stress. 23582223 Application of low-strength ultrasonication to the continuous anaerobic digestion processes: UASBr and dry digester. In this study, the positive effects of low-strength ultrasonication (LS-ultrasonication) on the anaerobic digestion (AD) performance were investigated by continuously operating an upflow anaerobic sludge blanket reactor (UASBr) and a dry digester. In the ultrasonicated UASBr system (1 s per min, 0.05 W/mL), ultrasonication enhanced the CH₄ production by 38% and 19% in an ambient and a mesophilic condition, respectively. In addition, a different sludge yield and a changed electron flow were observed after ultrasonication. In the ultrasonicated dry digestion system (2 s per 30 s, 0.0025 W/mL), a 40% increase in the production of CH₄ was observed after lowering the total solid content of the reactor from 12% to 10%, implying that a high solid content diminished the ultrasonic stimulation effect. Moreover, the ultrasonication strength itself appeared to be a more crucial factor than the ultrasonication density during the application of LS-ultrasonication in the AD system. 23916065 Understanding communication among health care professionals regarding death and dying in pediatrics. Objective: Effective communication regarding death and dying in pediatrics is a vital component of any quality palliative care service. The goal of the current study is to understand communication among health care professionals regarding death and dying in children. The three hypotheses tested were: (1) hospital staff (physicians of all disciplines, nurses, and psychosocial clinicians) that utilize consultation services are more comfortable communicating about death and dying than those who do not use such services, (2) different disciplines of health care providers demonstrate varying levels of comfort communicating about a range of areas pertaining to death and dying, and (3) health care staff that have had some type of formal training in death and dying are more comfortable communicating about these issues. Methods: A primary analysis of a survey conducted in a tertiary care teaching children's hospital. Results: Health care professionals who felt comfortable discussing options for end of life care with colleagues also felt more comfortable: initiating a discussion regarding a child's impending death with his/her family (r = 0.42), discussing options for terminal care with a family (r = 0.58), discussing death with families from a variety of ethnic/cultural backgrounds (r = 0.51), guiding parents in developmentally age-appropriate discussions of death with their children (r = 0.43), identifying and seeking advice from a professional role model regarding management concerns (r = 0.40), or interacting with a family following the death of a child (r = 0.51). Among all three disciplines, physicians were more likely to initiate discussions with regards to a child's impending death (F = 13.07; p = 0.007). Health care professionals that received formal grief and bereavement training were more comfortable discussing death. Significance of the results: The results demonstrated that consultation practices are associated with a higher level of comfort in discussing death and dying in pediatrics. 23355749 Dispersion and Filtration of Carbon Nanotubes (CNTs) and Measurement of Nanoparticle Agglomerates in Diesel Exhaust. Carbon nanotubes (CNTs) tend to form bundles due to their geometry and van der Walls forces, which usually complicates studies of the CNT properties. Dispersion plays a significant role in CNT studies and we summarize dispersion techniques to generate airborne CNTs from suspensions or powders. We describe in detail our technique of CNT aerosolization with controlled degree of agglomeration using an electrospray system. The results of animal inhalation studies using the electrosprayed CNTs are presented. We have performed filtration experiments for CNTs through a screen filter. A numerical model has been established to simulate the CNT filtration experiments. Both the modeling and experimental results show that the CNT penetration is less than the penetration for a sphere with the same mobility diameter, which is mainly due to the larger interception length of the CNTs. There is a need for instruments capable of fast and online measurement of gas-borne nanoparticle agglomerates. We developed an instrument Universal NanoParticle Analyzer (UNPA) and the measurement results for diesel exhaust particulates are presented. The results presented here are pertinent to non-spherical aerosol particles, and illustrate the effects of particle morphology on aerosol behaviors. 23955504 LodB is required for the recombinant synthesis of the quinoprotein L-lysine-ε-oxidase from Marinomonas mediterranea. Marinomonas mediterranea is a marine gamma-proteobacterium that synthesizes LodA, a novel L-lysine-ε-oxidase (E.C. 1.4.3.20). This enzyme oxidizes L-lysine generating 2-aminoadipate 6-semialdehyde, ammonium, and hydrogen peroxide. Unlike other L-amino acid oxidases, LodA is not a flavoprotein but contains a quinone cofactor. LodA is encoded by an operon with two genes, lodA and lodB. In the native system, LodB is required for the synthesis of a functional LodA. In this study, we report the recombinant expression of LodA in Escherichia coli using vectors that allow its expression and accumulation in the cytoplasm. To reveal the L-lysine-ε-oxidase activity using the Amplex Red method for hydrogen peroxide detection, it is necessary to first remove the E. coli cytoplasmic catalases. The flavoprotein LodB is the only M. mediterranea protein required in the recombinant system for the generation of the cofactor of LodA. In the absence of LodB, LodA does not contain the quinone cofactor and remains in an inactive form. The results presented indicate that LodB participates in the posttranslational modification of LodA that generates the quinone cofactor. 23178896 Relationship between DNA damage in sperm after ex vivo exposure and abnormal embryo development in the progeny of the three-spined stickleback. Many xenobiotics released in the aquatic environment exhibit a genotoxic potential toward organisms. Long term exposure to such compounds is expected to lead to multigenerational reproductive defects, further influencing the recruitment rate and hence, the population dynamics. Paternal exposure to genotoxicants was previously shown to increase abnormal development in the progeny of mammalian or aquatic species. The aim of this study was to evaluate the relationship between DNA damage in sperm of the fish three-spined stickleback and progeny developmental defects. Spermatozoa were exposed ex vivo to an alkylating agent (methyl methanesulfonate) before in vitro fertilization and DNA damage was assessed by the alkaline comet assay. A significant relationship between abnormal development and sperm DNA damage was underlined. This study illustrates the interest to use germ cell DNA damage after ex vivo exposure to evaluate the impact of genotoxic compounds on progeny fitness in aquatic organisms. 23619133 Auditory event-related potentials (P3a, P3b) and genetic variants within the dopamine and serotonin system in healthy females. The late positive components of the human event-related brain potential comprise electrocortical reflections of stimulus-driven attentional capture (the anteriorly distributed P3a) and top-down control detection of relevant events (the posteriorly distributed P3b). As of yet, the neuropharmacologic and neurogenetic origin of the P3a and P3b is not fully understood. In this study, we address the contribution of dopaminergic and serotoninergic mechanisms. Sixty healthy females completed an active auditory novelty oddball paradigm while EEG was recorded. In all subjects, genetic polymorphisms within the dopamine system (dopamine transporter [DAT1], catecholamine-O-methyltransferase val158met [COMT val158met]) and the serotonin system (serotonin transporter [5HTTLPR]) were assessed. Across genotypes, novels (relative to standards) elicited a fronto-centrally distributed P3a, and targets (relative to standards) a parieto-centrally distributed P3b. Genotypes effects were observed for both P3a (COMT, 5HTTPLR) and P3b (DAT1, COMT, 5HTTLPR) only at prefrontal electrode location (Fz). Specifically, the frontal P3a was enhanced in COMT met/met homozygotes, but not in DAT1 9R. The target-related P3b was enhanced in COMT met/met and DAT1 9R relative to its genetic counterparts, but only at frontal electrodes. This 'anteriorized' enhancement may reflect either an additional frontal component in the target-related P3 dependent on dopamine, or a more subtle shift in the neural ensemble that generates the target-related P3. Results for 5HTTLPR short allele homozygotes mimicked those in COMT met/met homozygotes. In all, the present findings suggest involvement of frontal-cortical dopaminergic and serotoninergic mechanisms in bottom-up attentional capture (COMT val158met, 5HTTLPR), with an additional top-down component sensitive to striatal signals (DAT1). 23391307 Photoelectrochemical properties of nanomultiple CaFe2O4/ZnFe2O4 pn junction photoelectrodes. Nanomultiple CaFe2O4/ZnFe2O4pn junctions are prepared by a pulsed laser deposition method to explore their photoelectrochemical properties as the photoelectrodes. It is demonstrated that the multiple-pn-junction structure is favorable to enhancing the photocurrent density and the onset potential of the photoelectrode. Furthermore, the 20-junction photoelectrode-based PEC cell yields a high open circuit photovoltage of up to 0.97 V, which is much higher than that for a single pn junction photoelectrode PEC cell that yields an open circuit photovoltage of 0.13 V. A multiple-junction band structure model is assumed to describe the behavior of the CaFe2O4/ZnFe2O4 multiple-junction photoelectrodes. It is suggested that the open circuit photovoltage is dominated by the number of pn junctions in a multiple-junction photoelectrode and the carrier transfer inside the photoelectrode is improved by narrowing the single-layer thickness. These findings provide a new approach to designing the multiple-junction structure to improve the PEC properties of the photoelectrodes. 23452020 Population-based trends in urinary diversion among patients undergoing radical cystectomy for bladder cancer. WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Variations in the type of urinary diversion exist for patients undergoing radical cystectomy. Although its use has been increasing from 2001 to 2008, patients who are older, female, and primary insured by Medicaid are less likely to receive continent diversions. Furthermore, patients treated surgically at high-volume and teaching hospitals are more likely to receive continent diversions. To describe the contemporary trends in urinary diversion among patients undergoing radical cystectomy (RC) for bladder cancer; and elucidate whether socioeconomic disparities persist in the type of diversion performed in the USA from a population-based cohort. Using the Nationwide Inpatient Sample, we identified patients who underwent RC for bladder cancer between 2001 and 2008. Multivariable regression models were used to identify patient and hospital covariates associated with continent urinary diversion and enumerate predicted probabilities for statistically significant variables over time. Overall, 55 635 (92%) patients undergoing RC for bladder cancer received incontinent urinary diversion, while 4552 (8%) patients received continent diversion from 2001 to 2008. Receipt of continent urinary diversion increased from 6.6% in 2001-2002 to 9.4% in 2007-2008 (P < 0.001 for trend). Patients who were older (odds ratio [OR] 0.93; P < 0.001), female (OR 0.52; P < 0.001) and insured by Medicaid (OR 0.54; P = 0.002) were less likely to receive continent urinary diversion. However, patients treated at teaching (OR 2.14; P < 0.001) and high-volume hospitals (OR 2.39; P = 0.04) had higher odds of continent urinary diversion. Predicted probabilities of continent diversion remained lower for female patients, Medicaid insurance status, and non-teaching and medium/low-volume hospitals over time. In this nationally representative sample of hospitals from 2001 to 2008, the use of continent diversion in RC gradually increased. Although variations in urinary diversion exist by hospital teaching status, case volume, patient gender and primary health insurance, increased attention in expanding the use of continent diversions may help reduce these disparities for patients undergoing RC for bladder cancer. 23875688 Simulating the mechanism of antimicrobial lipopeptides with all-atom molecular dynamics. The emergence of antibiotic resistant pathogens is one of the major medical concerns of the 21st century, prompting renewed interest in the development of novel antimicrobial compounds. Here we use microsecond-scale all-atom molecular dynamics simulations to characterize the structure, dynamics, and membrane-binding mechanism of a synthetic antimicrobial lipopeptide, C16-KGGK. Our simulations suggest that these lipopeptides prefer to aggregate in solution and alter the intrinsic order of the lipid bilayer upon binding. From these results and previous coarse-grained simulations, we have developed a simple model for the binding and insertion process for these lipopeptides. 23944975 Individualized management of umbilical endometriosis: A report of seven cases. The aim of this study was to review diagnostic/therapeutic strategies of umbilical endometriosis managed in our department and evaluate the effectiveness of these strategies. Medical records for patients with diagnosis of endometriosis managed from 1999 through 2011 in the University of Tokyo Hospital were retrospectively reviewed. Cases with diagnosis of umbilical endometriosis were identified. Clinical information of age, gravida, parity, histories of surgery and oral contraceptive (OC), management for the disease prior to the first visit, symptoms, patients' desire for pregnancy, diagnostic/therapeutic methods and prognosis were reviewed and summarized. During the period, 2530 patients with diagnosis of endometriosis were identified. Seven patients had diagnosis of umbilical endometriosis, giving an incidence of 0.29% of all endometriosis cases and 5.6% of extragenital endometriosis cases. A definitive diagnosis was made by histological examination following a biopsy (two cases) or a resection (three cases). A clinical diagnosis was made by empirical treatment with OC (one case) or dienogest (one case). With regard to therapy, three patients chose expectant management and did not require therapeutic intervention. Three patients began OC and symptoms were well controlled in all patients. One patient who wished to conceive chose a wide resection followed by umbilical reconstruction. She became pregnant afterwards and recurrence was not reported. There are various options of diagnostic/therapeutic strategies, such as empirical treatments and OC that can provide individualized management of umbilical endometriosis, congruent with the severity of patient symptoms, age and desire for pregnancy. 23846875 OsbZIP58, a basic leucine zipper transcription factor, regulates starch biosynthesis in rice endosperm. Starch composition and the amount in endosperm, both of which contribute dramatically to seed yield, cooking quality, and taste in cereals, are determined by a series of complex biochemical reactions. However, the mechanism regulating starch biosynthesis in cereal seeds is not well understood. This study showed that OsbZIP58, a bZIP transcription factor, is a key transcriptional regulator controlling starch synthesis in rice endosperm. OsbZIP58 was expressed mainly in endosperm during active starch synthesis. osbzip58 null mutants displayed abnormal seed morphology with altered starch accumulation in the white belly region and decreased amounts of total starch and amylose. Moreover, osbzip58 had a higher proportion of short chains and a lower proportion of intermediate chains of amylopectin. Furthermore, OsbZIP58 was shown to bind directly to the promoters of six starch-synthesizing genes, OsAGPL3, Wx, OsSSIIa, SBE1, OsBEIIb, and ISA2, and to regulate their expression. These findings indicate that OsbZIP58 functions as a key regulator of starch synthesis in rice seeds and provide new insights into seed quality control. 23838207 Effects of feed on plasma leptin and ghrelin concentrations in crib-biting horses. The reason why some horses begin an oral stereotypy such as crib-biting is not known. The aim of this study was to measure ghrelin and leptin concentrations in plasma concentrations to determine whether there is a link to crib-biting in horses. Plasma samples (n=3) were collected for plasma leptin and ghrelin assay before and during the morning first feeding in the usual environments of 15 horses with stereotypic crib-biting and 15 matched controls. The crib-biting intensity was scored in three 5-min phases, and a subgroup of verified crib-biters (n=8) was defined as horses that were seen to crib-bite during this study. Plasma leptin concentration (mean and 95% confidence interval [CI]) was lower in horses observed to crib-bite before and after feeding of concentrates (1.2, CI 0.8-1.7ng/mL and 1.0, CI 0.6-1.7) than in non-crib-biters (2.3, CI 1.6-3.4 and 2.3, CI 1.6-3.4ng/mL, respectively) and correlated negatively with crib-biting intensity. Crib-biting intensity was significantly higher shortly after feeding than before or 30min later. Plasma ghrelin concentration was significantly higher before feeding concentrate than before hay feeding or after the concentrate, but did not differ between groups. There was a significant negative correlation between body composition score and plasma ghrelin concentration. These findings suggest that leptin concentrations may be associated with crib-biting behaviour in horses. 23819915 Sub-acute toxicity profile of a modified resveratrol supplement. Longevinex, a nutraceutical formulation containing Resveratrol as the main component along with other polyphenolics exhibits diverse health benefits but systemic safety studies are lacking. Hence, to test the safety of Longevinex use for therapeutic purposes, 50 Sprague Dawley rats were randomly divided into five groups (n=10; 5M, 5F) wherein group I as vehicle treated control, group II and group III received 50mg and 100mg of plain Resveratrol respectively and group IV and group V received 50mg and 100mg of Longevinex respectively for a period of 28days. All toxicological parameters were analyzed as per OECD-407 guidelines. Results showed treatment with Resveratrol and Longevinex did not result in any mortality of rats neither did they exhibit any clinical signs of toxicity. Hematological and biochemical analysis of serum enzymes and metabolites were not significantly altered between Longevinex and control rats. Likewise, histopathological analysis for various organs did not reveal significant changes in the vital organs of the treated rats. The study revealed that there were no significant treatment related adverse effects in rats exposed to Longevinex for 28days and considered safe at the given dose where compared to plain Resveratrol. 23715766 Organisation and practice of radiological ultrasound in Europe: a survey by the ESR Working Group on Ultrasound. To gather information from radiological departments in Europe assessing the organisation and practice of radiological ultrasound and the diagnostic practice and training in ultrasound. A survey containing 38 questions and divided into four groups was developed and made available online. The questionnaire was sent to over 1,000 heads of radiology departments in Europe. Of the 1,038 radiologists asked to participate in this survey, 123 responded. Excluding the 125 invitations to the survey that could not be delivered, the response rate was 13 %. Although there was a low response rate, the results of this survey show that ultrasound still plays a major role in radiology departments in Europe: most departments have the technical capabilities to provide patients with up-to-date ultrasound examinations. Although having a centralised ultrasound laboratory seems to be the way forward, most ultrasound machines are spread between different departments. Ninety-one per cent of answers came from teaching hospitals reporting that training is regarded as an art and is needed in order to learn the basics of scanning techniques, after which working in an organ-oriented manner is the best way to learn how to integrate diagnostic US within the clinical context and with all other imaging techniques. • Hospitals should introduce centralised ultrasound laboratories to allow for different competencies in US under the same roof, share human and technological resources and reduce the amount of equipment needed within the hospital. • Technique-oriented teaching, time and examinations are necessary to learn how to use US properly within the framework of organ-oriented training. • A time period of about 6 months dedicated solely to learning US scanning techniques is deemed sufficient in most cases. 23547001 Two fatty acid elongases possessing C18-Δ6/C18-Δ9/C20-Δ5 or C16-Δ9 elongase activity in Thraustochytrium sp. ATCC 26185. Thraustochytrids, unicellular eukaryotic marine protists, accumulate polyunsaturated fatty acids. Here, we report the molecular cloning and functional characterization of two fatty acid elongase genes (designated tselo1 and tselo2), which could be involved in the desaturase/elongase (standard) pathway in Thraustochytrium sp. ATCC 26185. TsELO1, the product of tselo1 and classified into a Δ6 elongase group by phylogenetic analysis, showed strong C18-Δ6 elongase activity and relatively weak C18-Δ9 and C20-Δ5 activities when expressed in the budding yeast Saccharomyces cerevisiae. TsELO2, classified into a Δ9 elongase subgroup, showed only C16-Δ9 activity. When expressed in Aurantiochytrium limacinum mh0186 using a thraustochytrid-derived promoter and a terminator, TsELO1 exhibited almost the same specificity as expressed in the yeast but TsELO2 showed weak C18-Δ9 activity, in addition to its main C16-Δ9 activity. These results suggest that TsELO1 functions not only as a C18-Δ6 and a C20-Δ5 elongase in the main route but also as a C18-Δ9 elongase in the alternative route of standard pathway, while TsELO2 functions mainly as a C16-Δ9 elongase generating vaccenic acid (C18:1n-7) in thraustochytrids. This is the first report describing a fatty acid elongase harboring C16-Δ9 activity in thraustochytrids. 23886800 Prediction of cadmium concentration in selected home-produced vegetables. Soil contaminated with cadmium presents a potential hazard for humans, animals and plants. The latter play a major role in the transfer of cadmium to the food chain. The uptake of cadmium and its accumulation by plants is dependent on various soil, plants and environmental factors. In order to identify soil properties with statistically significant influence on cadmium concentration in vegetables and to reduce the collection of data, time and costs, regression models can be applied. The main objective of this research was to develop regression models to predict the concentration of cadmium in 9-vegetable species: zucchini, tomato, cabbage, onion, potato, carrot, red beet, endive and chicory, based on soil properties. Soil samples were collected from 123 home gardens of the Municipality of Celje and 59 of these gardens were also included in vegetable sampling. The concentration of elements (e.g. arsenic, cadmium, copper, lead, and zinc) in the samples was determined by Inductively Coupled Plasma Mass Spectrometry. Single (for cabbage, potato, red beet and chicory) and multiple (for tomato, onion, carrot and endive) linear regression models were developed. There was no statistically significant regression model for zucchini. The most significant parameter for the influencing the cadmium concentration in vegetables was the concentration of cadmium in soil. Other important soil properties were the content of organic matter, pH-value and the concentration of manganese. It was concluded that consuming carrots, red beets, endives, onions, potatoes and chicory which are grown in gardens with Cd concentrations (mgkg(-1) DW) above 2.4, 3.2, 6.3, 7.9, 8.3 and 10.9, respectively, might represent an important contribution to dietary Cd exposure. 23760260 Molecular rectifiers based on donor/acceptor assemblies: effect of orientation of the components' magnetic moments. In forming donor/acceptor assemblies that act as molecular rectifiers, we have introduced magnetic organic molecules as electron-donating and electron-accepting moieties. We have oriented the magnetic moment of the donor and acceptor components separately and immobilized them (and their moments) so that the molecular assemblies that act as rectifiers could be formed with moments mutually parallel or anti-parallel to each other. We have characterized the molecular assemblies formed on an electrode with a scanning tunneling microscope tip. Such donor/acceptor assemblies with a control over the orientation of moments of the components provided unique systems to study the effect of the nature of alignment on molecular rectifiers. We have observed that the rectification ratio increased in junctions with moments of the components being parallel to each other. The improvement in the rectification ratio has been explained in terms of an efficient electron-transfer process in a moment-aligned junction between the donor and acceptor moieties. 23921327 Clinical Outcome of Spinal Reconstruction After Total en bloc Spondylectomy at Three or More Levels. Study Design. Retrospective clinical study.Objective. To assess the clinical and radiological outcome of spinal reconstruction after total en bloc spondylectomy (TES) at three or more levels.Summary of Background Data. There have been few reports of multilevel spondylectomy for spinal tumor. This is the first case series on the clinical outcome for reconstructions after three or more levels of TES.Methods. 26 patients treated by three or more levels of TES at our institute were included in the present analysis. Reconstruction was performed with pedicle screw fixation and a titanium mesh cage filled with autograft in all cases. To increase spinal stability in reconstruction, spinal shortening was performed. Instrument failure and radiologic findings were evaluated on radiograph and CT with multiplanar reconstructions (MPRs). The length of spinal shortening was also measured.Results. Excluding 4 patients with deteriorating general condition, radiological evaluation was performed more than one year in 22 patients. All 22 patients had no evidence of local recurrence at the surgical site of the spine during follow-up period. Cage subsidence was seen in 11 patients (50%). Eight of the 11 patients showed the appearance of subsidence one month after the surgery. There was one instrument failure that required revision surgery 8 months after TES surgery. One other patient showed bone resorption on the contact surfaces of the cage at 24 months after the surgery. The mean length of the resection vertebrae was 84.6 mm (52-124 mm), while the length of the shortening was 10.4 mm (3-22 mm).Conclusion. No local recurrence was observed after TES at three or more levels. Cage subsidence was common phenomenon (50%) and already observed one month after surgery in 8 out of 11 cases. Spinal shortening have potentially providing good stability for multi-level TES. 23672307 Integration of Porous Coordination Polymers and Gold Nanorods into Core-Shell Mesoscopic Composites toward Light-Induced Molecular Release. Besides conventional approaches for regulating in-coming molecules for gas storage, separation, or molecular sensing, the control of molecular release from the pores is a prerequisite for extending the range of their application, such as drug delivery. Herein, we report the fabrication of a new porous coordination polymer (PCP)-based composite consisting of a gold nanorod (GNR) used as an optical switch and PCP crystals for controlled molecular release using light irradiation as an external trigger. The delicate core-shell structures of this new platform, composed of an individual GNR core and an aluminum-based PCP shell, were achieved by the selective deposition of an aluminum precursor onto the surface of GNR followed by the replication of the precursor into aluminum-based PCPs. The mesoscopic structure was characterized by electron microscopy, energy dispersive X-ray elemental mapping, and sorption experiments. Combination at the nanoscale of the high storage capacity of PCPs with the photothermal properties of GNRs resulted in the implementation of unique motion-induced molecular release, triggered by the highly efficient conversion of optical energy into heat that occurs when the GNRs are irradiated into their plasmon band. Temporal control of the molecular release was demonstrated with anthracene as a guest molecule and fluorescent probe by means of fluorescence spectroscopy. 23937110 Stable isotope composition of the meteoric precipitation in Croatia. The precipitation is the input into the water system. Its stable isotope composition has to be known for the proper use and management of water resources. Croatia is not well represented in the Global Network of Isotopes in Precipitation (GNIP) database, and the geomorphology of the country causes specific local conditions. Therefore, at the Stable Isotope Laboratory (SILab), Rijeka, we monitor the stable isotope composition (δ(18)O, δ(2)H) of precipitation. Since δ(18)O and δ(2)H are well correlated, we concentrate the discussion on the δ(18)O distribution. Together with GNIP, our database contains 40 stations in Croatia and in the neighbouring countries. Their different latitudes, longitudes and altitudes give information of great detail, including the influence of the topographic structure on the precipitation in the south-eastern part of Europe, as well as the complex interplay of the different climate conditions in the area. Within a few hundred kilometres, the stable isotope values display a significant change from the maritime character in the south (mean δ(18)O around-6 to-8 â€°) to the continental behaviour in the north (mean δ(18)O around-8 to-11 â€°). Depending on the location, the mean δ(18)O values vary with altitude at a rate of approximately-0.2 â€°/100 m and-0.4 â€°/100 m, respectively. Also the deuterium excess has been found to depend on location and altitude. The data are being used to construct a δ(18)O map for the entire area. 23327560 Does perceived life stress mediate the association between HIV status and alcohol use? Evidence from adults living in Cape Town, South Africa. South Africa has the highest prevalence of HIV in the world. Because living with HIV is stressful and because alcohol consumption is often used to cope with stress, we examined whether stress mediates the association between HIV status and alcohol use among adults residing in South African townships. Field workers approached pedestrians or patrons of informal alcohol-serving venues (i.e., shebeens) and invited their participation in a survey. Of the 1717 participants (98% Black, 34% women, mean age = 31 years), 82% were HIV-negative, 9% were HIV-positive, and 9% did not know their test result. Participants living with HIV reported greater perceived life stress compared to participants whose HIV status was negative or unknown. Perceived stress was associated with an increase in the frequency of alcohol use (drinking days, intoxication, and drinking in shebeens/taverns). Subsequent analyses showed that stress mediated the association between HIV status and alcohol use. These findings indicate that greater frequency of drinking days, perceived intoxication, and drinking at shebeens was associated with elevated stress levels among participants who were HIV positive. Perceived life stress mediates the association between HIV status and alcohol use. Programs to enhance stress management among HIV-positive South Africans may help to reduce alcohol consumption, which may, in turn, lead to reduced rates of HIV transmission. 23829196 Gender differences in the association between metabolic syndrome and periodontal disease: the Hisayama Study. Periodontal disease and metabolic syndrome (MS) are more prevalent in males than in females. However, whether there is a gender difference in the association between these health conditions has not yet been investigated. This study examined the gender difference in this association, considering the definition of periodontal disease. We recruited 1040 males and 1330 females, aged ≥40 years, with at least ten teeth from subjects of the 2007 Hisayama health examination. We performed a logistic regression analysis with various definitions of periodontal disease the dependent variable and MS as the independent variable. Following the analysis, the data were reanalysed with the structural equations model. The logistic regression analysis suggested a stronger association between periodontal disease and MS in females than that in males when periodontal disease was more severely defined. When we constructed the structural equations model in each gender, the model showed a good fit to the data of females, suggesting the association between periodontal disease and MS in females, but not in males. Gender differences seem to exist in the association between periodontal disease and MS; MS might show a stronger association with periodontal disease in females than in males. 23665409 Potential role of ATP-binding cassette transporters in the intestinal transport of rhein. Rhein, a lipophilic anthraquinone, exhibits anti-inflammatory and anti-tumor activities; however, it is hepatotoxic. ATP-binding cassette transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 2 (MRP2), can pump toxicants from gut epithelial cells back into the intestinal lumen to prevent poisoning. We investigated their roles in rhein transport using a rat intestinal perfusion model and Caco-2, MDCKII-MDR1 (high expression of P-gp), MDCKII-BCRP (high expression of BCRP) and MDCKII-MRP2 (high expression of MRP2) cell models. The permeability of rhein in the duodenum significantly increased with increasing perfused concentration of rhein in the rat model, suggesting that efflux transporters were involved in rhein transport. In the Caco-2 cells, the permeability of rhein from the basolateral (B) to the apical (A) was significantly higher than that from A to B. In the presence of BCRP or MRP2 inhibitor, the permeability of rhein significantly decreased from B to A direction. In the MDCKII-BCRP cells, rhein was more permeable in B to A side than that in the opposite side. However, no significant differences of rhein permeability were observed in two directions in both MDCKII-MDR1 and MDCKII-MRP2 cells. Taken together, these results suggested that only BCRP was involved in rhein transport. 22517576 Vasodilatory effects of cinnamic acid via the nitric oxide-cGMP-PKG pathway in rat thoracic aorta. Cinnamic acid (CA) and its derivatives have a broad therapeutic spectrum that includes antimicrobial, antifungal, and antitumoral activities. However, the vasodilative effect of CA has not been demonstrated. The present study characterizes the vasodilative activity and the mechanism of CA in rat thoracic aorta. The vasomotion of aortic strips following CA treatment was measured in an organ bath system. In addition, vascular strips and human umbilical vein endothelial cells (HUVECs) were used in organ bath, Western blot, nitrite, and cyclic guanosine monophosphate (cGMP) measurements. CA relaxed phenylephrine-precontracted aortic strips in an endothelium-dependent manner. Pretreatment of the endothelium-intact aortic strips with N(G) -nitro-l-arginine methyl ester (10(-4)  M), 1 H-[1,2,4]-oxadiazolole-[4,3-a] quinoxalin-10-one, (10(-6)  M) and methylene blue (10(-5)  M) inhibited CA-induced vasorelaxation. CA also increased the phosphorylation of endothelial nitric oxide synthase and nitric oxide generation in a concentration-dependent manner in HUVECs. In addition, cGMP generation and cGMP-dependent protein kinase G (PKG) expression in aortic strips were increased by CA treatment. Furthermore, CA-induced vasorelaxation was inhibited by the PKG inhibitor KT5823 (0.3 μM) and the Ca(2+) -activated K(+) channel inhibitor tetraethylammonium (10(-3)  M). These findings suggest that CA exerts an endothelium-dependent vasodilation effect via the nitric oxide-cGMP-PKG-mediated pathway in rat thoracic aorta. 23360104 Bioactive sesterterpenoids from a Korean sponge Monanchora sp. Chemical investigation of a Korean marine sponge, Monanchora sp., yielded nine new sesterterpenoids (1-9) along with phorbaketals A-C (10-12). The planar structures were established on the basis of NMR and MS analysis, and the absolute configurations of 1-9 were defined using the modified Mosher's method and CD spectroscopic data analysis. Compounds 1-8, designated as phorbaketals D-K, possess a spiroketal-modified benzopyran moiety such as phorbaketal A, and their structural variations are due to oxidation and/or reduction of the tricyclic core or the side chain. Compound 9, designated as phorbin A, has a monocyclic structure and is proposed to be a possible biogenetic precursor of the phorbaketals. Compounds 1-9 were evaluated for cytotoxicity against four human cancer cell lines (A498, ACHN, MIA-paca, and PANC-1), and a few of them were found to exhibit cytotoxic activity. 23905801 Thermal Inactivation of a Single Strain Each of Serotype O26:H11, O45:H2, O103:H2, O104:H4, O111:H(-), O121:H19, O145:NM, and O157:H7 Cells of Shiga Toxin-Producing Escherichia coli in Wafers of Ground Beef. For each of two trials, freshly ground beef of variable fat content (higher: 70:30 %lean:%fat; lower: 93:7 %lean:%fat) was separately inoculated with ca. 7.0 log CFU/g of a single strain of Escherichia coli serotypes O26:H11, O45:H2, O103:H2, O104:H4, O111:H(-), O121:H19, O145:NM, and O157:H7. Next, ca. 3-g samples of inoculated beef were transferred into sterile filter bags and then flattened (ca. 1.0 mm thick) and vacuum sealed. For each temperature and sampling time, three bags of the inoculated wafers of beef were submerged in a thermostatically controlled water bath and heated to an internal temperature of 54.4°C (130°F) for up to 90 min, to 60°C (140°F) for up to 4 min, or to 65.6°C (150°F) for up to 0.26 min. In lower fat wafers, D-values ranged from 13.5 to 23.6 min, 0.6 to 1.2 min, and 0.05 to 0.08 min at 54.4, 60.0, and 65.6°C, respectively. Heating higher fat wafers to 54.4, 60.0, and 65.6°C generated D-values of 18.7 to 32.6, 0.7 to 1.1, and 0.05 to 0.2 min, respectively. In addition, we observed reductions of ca. 0.7 to 6.7 log CFU/g at 54.4°C after 90 min, ca. 1.1 to 6.1 log CFU/g at 60.0°C after 4 min, and 0.8 to 5.8 log CFU/g at 65.6°C after 0.26 min. Thus, cooking times and temperatures effective for inactivating a serotype O157:H7 strain of E. coli in ground beef were equally effective against the seven non-O157:H7 Shiga toxin-producing strains investigated herein. 23246124 Long-term safety and efficacy of a tamoxifen-based treatment strategy for idiopathic retroperitoneal fibrosis. Tamoxifen may be a viable treatment option for idiopathic retroperitoneal fibrosis (iRPF) but data are limited and its long-term safety and efficacy is unclear. We describe the long-term course and outcomes in a large group of patients with iRPF treated with tamoxifen monotherapy. This is a single-center prospective, observational study of 55 patients with iRPF treated with tamoxifen for 2years from April 1998 through April 2011. Measurements included clinical improvement, laboratory parameters and follow-up computed tomographic (CT) scanning. Treatment success was the composite endpoint of clinical improvement, mass regression and definite resolution of ureteral obstruction. Forty-seven (85%) patients reported substantial resolution of symptoms after median treatment duration of 3.0weeks (IQR 1.4-4.8weeks). Repeated CT scanning showed mass regression in 39 (71%) patients at 4months and 47 (85%) patients at 8months of follow-up, respectively. Nineteen (34.5%) patients did not meet the composite endpoint of treatment success, 56% of whom responded satisfactorily to second-line immunosuppressive treatment. Recurrence-free survival in patients with treatment success after post-treatment follow-up of 21months (IQR 9.0-35.0months) was 68%. Tamoxifen was well tolerated. Pulmonary embolism occurred in 2 patients receiving tamoxifen and in one patient receiving second-line treatment. Tamoxifen is a safe and viable therapeutic option in the treatment of iRPF. 23764965 Alginate gel microwell arrays using electrodeposition for three-dimensional cell culture. In this study, we developed a novel method for fabricating microwell arrays constructed from alginate gels, and the alginate gel microwells were used for three-dimensional (3D) cell culture. The alginate gel microwells were fabricated on a patterned ITO electrode using alginate gel electrodeposition. Embryonic stem (ES) cells or hepatocellular carcinoma cells (HepG2) were cultured in the alginate gel microwells containing 3T3 cells. During the culture, embryoid bodies (EBs) or HepG2 spheroids were successfully fabricated in the alginate gel microwells. The oxygen consumption of the EBs indicated that they were successfully cultured. Liver-specific gene expressions of the HepG2 spheroids apparently increased by performing 3D co-culture in the microwell arrays with 3T3 cells. These results show that the alginate gel microwells are a useful 3D culture system. 23588536 Standard pentostatin dose reductions in renal insufficiency are not adequate: selected patients with steroid-refractory acute graft-versus-host disease. Pentostatin is an irreversible inhibitor of adenosine deaminase and has been used to prevent graft-versus-host disease (GVHD) and to treat both acute and chronic GVHD. Dose reduction equations for patients with renal insufficiency are based on few patients with limited pharmacokinetic and clinical results. This phase II study (NCT00201786) was conducted to assess pentostatin efficacy and infectious complications seen from our previous phase I study in steroid-refractory acute GVHD (aGVHD). Hospitalized patients with steroid-refractory aGVHD were given pentostatin 1.5 mg/m(2)/day intravenously on days 1-3 of each 14-day cycle. Prior to each dose, dose modifications were based on Cockcroft-Gault estimated creatinine clearance (eCrCL) with 30-50 mL/min/1.73 m(2) leading to a 50 % dose reduction and eCrCL less than 30 mL/min/1.73 m(2) leading to study removal. Plasma pentostatin area under the concentration-time curve (AUC) and incidence of infectious complications were evaluated. Two of the eight patients treated demonstrated excessive pentostatin exposure as determined by measurement of AUC. One of these patients had renal impairment, whereas the other patient demonstrated borderline renal function. Despite dose reduction to 0.75 mg/m(2), AUCs were significantly increased compared to the other patients in this study. Seven of eight patients treated with pentostatin had cytomegalovirus (CMV) viremia after pentostatin treatment; however none developed proven CMV disease. A 50 % dose reduction in patients with eCrCL 30-50 mL/min/1.73 m(2) seems reasonable. However, the eCrCL should be interpreted with extreme caution in patients who are critically ill and/or with poor performance status. Renal function assessment based on the Cockcroft-Gault method could be significantly overestimated thus risking pentostatin overdosing. These results imply a need to closely monitor pentostatin exposure in patients with renal insufficiency. 23726526 Outcomes of aggressive concurrent radiochemotherapy in highly selected septuagenarians with stage IIIB non-small cell lung carcinoma: retrospective analysis of 89 patients. We retrospectively evaluated the toxicity and efficacy of concurrent radiochemotherapy (C-RCT) in medically fit septuagenarians with stage IIIB non-small cell lung carcinoma (NSCLC). Eighty-nine medically fit, stage IIIB NSCLC septuagenarians were included. Thoracic radiotherapy to a total dose of 66 Gy in 2 Gy fractions was delivered concurrently with 1-2 cycles of cisplatin-based doublet chemotherapy. Treatment was relatively well-tolerated with no grade 4/5 acute toxicity. Acute grade 3 hematologic and non-hematologic toxicity rates were 55.1 and 39.3%, respectively. Late toxicity was reported in 3 (3.4%) patients: esophagitis (N = 2) and peripheral neuropathy (N = 1). At median 21.7 months (4.4-42.1), 26 patients (29.2%) were alive. Median overall, local-regional progression-free and progression-free survivals were 17.7, 10.5 and 7.8 months, respectively. On univariate analyses, histology (p < 0.03), nodal status (p = 0.038), number of concomitant chemotherapy (p < 0.001), and weight change during C-RCT (p < 0.001) demonstrated significant association with overall survival; while only number of chemotherapy and weight change (p < 0.001 for each) could retain their significance on multivariate analyses. Current results suggested that C-RCT in highly selected medically fit septuagenarians with LA-NSCLC may improve survival outcomes up to that achieved in younger patients, with a relatively acceptable toxicity profile. 22102529 Fine needle aspiration cytology of Sertoli-Leydig cell tumors of ovary masquerading as dysgerminoma. Herein, we described a case of a 29-year-old female with a large ovarian mass. Fine needle aspiration cytology (FNAC) of the mass showed discrete round to oval cells in a fatty vacuolated background. FNAC diagnosis of dysgerminoma was suggested. The histology of the tumors showed features of poorly differentiated Sertoli-Leydig cell tumors. We discussed the diagnostic pitfalls of this case on FNAC. 23726164 Transperitoneal laparoscopic radical nephrectomy in a patient with severe scoliosis. To report the first case of a left transperitoneal laparoscopic nephrectomy in a patient with a severe left convex lumbar scoliosis and to elaborate on the technical difficulties of this procedure. The surgical procedure was performed by an experienced laparoscopic surgeon after rigorous pre-operative visualization of the altered visceral and vascular abdominal anatomy. A transperitoneal laparoscopic approach with an open introduction technique according to Hasson and a caudo-cranial dissection of the left renal hilum were performed to prevent major vascular and visceral injury in this challenging surgical procedure. The operation time was 102 minutes and the estimated blood loss was 100 mL. The surgeon was able to complete the transperitoneal laparoscopic radical nephrectomy without complications. Transperitoneal laparoscopic radical nephrectomy in patients with severe spinal deformities is feasible, but should only be performed by experienced laparoscopic surgeons to ensure patient safety and cancer control. 23904331 The Role of Water and Sodium Ions in the Activation of the μ-Opioid Receptor. Dual effect of sodium ions: The activation of G-protein-coupled receptors depends on the presence of water molecules inside the receptor and also on allosteric interactions. The binding of sodium ions to the allosteric site of the μ opioid receptor was studied by microsecond molecular dynamics simulations and their seemingly contradictory roles in preventing ligand binding and facilitating receptor activation were explained. 23411302 Purification and characterisation of a novel antioxidant peptide derived from blue mussel (Mytilus edulis) protein hydrolysate. Protein derived from blue mussel (Mytilus edulis) was hydrolysed using four kinds of proteases (pepsin, papain, neutrase and alcalase), and the neutrase hydrolysate (BNH) obtained by 3-h hydrolysis exhibited the highest 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity compared to other hydrolysates. By using ultrafiltration, gel filtration chromatography and reversed phase high performance liquid chromatography (RP-HPLC), a novel antioxidant peptide (BNH-P7) was isolated from BNH, and its amino acid sequence was identified as YPPAK (Tyr-Pro-Pro-Ala-Lys) with molecular weight of 574 Da. BNH-P7 exhibited good scavenging activity on DPPH radical, hydroxyl radical, and superoxide anion radical with EC(50) of 2.62, 0.228, and 0.072 mg/ml, respectively. BNH-P7 was also effectively against lipid peroxidation in a linoleic acid model system. The high activity of BNH-P7 was due to the small size and the presence of antioxidant and hydrophobic amino acid residues (Tyr and Pro) within its sequence. 23205570 More of the same? Treatment in mental health courts. Despite the centrality of community treatment to the identity and mission of mental health courts, research on what treatment is actually provided by mental health courts is scarce. Using longitudinal interview data from a large, well-established mental health court, this study describes the context, amount, and types of treatment for 82 mental health court participants (MHC) and a matched sample of 89 defendants (TAU) who underwent regular criminal court processing. The study compared treatment from the period 6 months prior to entry into the mental health court or arrest to that at a 6-month follow-up. Multivariate analyses were used to estimate the effect of mental health court participation on the amount of outpatient treatment, controlling for demographic, clinical, and legal variables. The research found that mental health court participation increased the frequency of outpatient treatment, but that social services and treatment specialized to address criminal risk factors were uncommon both at the baseline and at the 6-month follow-up. At the baseline, a majority of both samples reported that they had received outpatient treatment, but the MHC sample reported more frequent and more varied treatment. At the 6-month follow-up, the differences between the 2 samples were greater, with the wider gap resulting not only from improvements in the MHC but also from deterioration in the treatment status of the TAU sample. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23884755 Polypharmacy of Osteoarthritis: The Perfect Intestinal Storm. Osteoarthritis is an increasingly prevalent disorder with an incidence rate that rises sharply with age. Unfortunately, the most commonly used medications for providing symptomatic relief, nonsteroidal anti-inflammatory drugs (NSAIDs), can cause significant gastrointestinal (GI) ulceration. There is recent evidence that agents commonly employed to protect the upper GI tract actually increase the incidence and severity of ulceration and bleeding in the lower intestine. Intestinal injury is more difficult to diagnose and treat than upper GI damage, and symptoms correlate poorly with the severity of tissue injury. Moreover, use of low-dose aspirin for cardioprotection (a common co-treatment with the selective cyclooxygenase-2 inhibitors) further augments intestinal damage, particularly when enteric-coated aspirin is used. Thus, by focusing entirely on prevention of NSAID-induced damage to the upper GI tract, physicians may be inadvertently placing their patients at risk of serious, difficult-to-diagnose injury for which there are no proven-effective therapies and are associated with significantly higher rates of morbidity and mortality. 23716610 Protective Efficacy Induced by Recombinant Clostridium difficile Toxin Fragments. Clostridium difficile is a spore-forming bacterium that can reside in animals and humans. C. difficile infection causes a variety of clinical symptoms, ranging from diarrhea to fulminant colitis. Disease is mediated by TcdA and TcdB, two large enterotoxins released by C. difficile during colonization of the gut. In this study, we evaluated the ability of recombinant toxin fragments to induce neutralizing antibodies in mice. The protective efficacies of the most promising candidates were then evaluated in a hamster model of disease. While limited protection was observed with some combinations, coadministration of a cell binding domain fragment of TcdA (TcdA-B1) and the glucosyltransferase moiety of TcdB (TcdB-GT) induced systemic IgGs which neutralized both toxins and protected vaccinated animals from death following challenge with two strains of C. difficile. Further characterization revealed that despite high concentrations of toxin in the gut lumens of vaccinated animals during the acute phase of the disease, pathological damage was minimized. Assessment of gut contents revealed the presence of TcdA and TcdB antibodies, suggesting that systemic vaccination with this pair of recombinant polypeptides can limit the disease caused by toxin production during C. difficile infection. 23820031 Time-specific effect of prenatal stressful life events on gestational weight gain. To investigate the time-specific effect of maternal exposure to prenatal stressful life events (SLEs) on gestational weight gain (GWG) and to determine whether pre-pregnancy body mass index (BMI) modifies the effect. Between March and November 2008, data were collected from 1800 pregnant women who received prenatal check-ups in Hefei, China, after 32 completed weeks of gestation. Participants completed a structured interview on demographic characteristics and a checklist of SLEs during different stages of pregnancy. GWG during pregnancy was determined by self-reported pre-pregnancy weight and measured weight at delivery. There was a significant dose-response relationship between prenatal SLEs in the first, but not the second or third, trimester and GWG. For each 1-unit increase in SLEs during the first trimester, there was a reduction in GWG of approximately 0.497kg (95% confidence interval, 0.176-0.817kg). After stratification by pre-pregnancy BMI, a significant negative association between SLEs in the first trimester and GWG was observed among women with pre-pregnancy normal (β=-0.796; 95% CI, -1.291 to -0.301) and low (β=-1.066; 95% CI, -2.180 to -0.048) weight. The effect of prenatal SLEs on GWG depends on the timing of maternal exposure to stress and varies according to pre-pregnancy BMI. 23924954 Nanog attenuates lipopolysaccharide-induced inflammatory responses by blocking nuclear factor-κB transcriptional activity in BV-2 cells. Nanog, a unique homeobox transcription factor, maintains self-renewal and pluripotency of embryonic stem cells by binding to nuclear factor κB proteins in order to inhibit their transcriptional and prodifferentiation activities. We previously reported that Nanog attenuated inflammatory responses in rat primary microglia cells stimulated by lipopolysaccharide. However, the effects of Nanog on another microglia cell type, BV-2 cells, are still unknown. In this study, we investigated whether Nanog attenuated inflammatory responses in lipopolysaccharide-stimulated BV-2 cells and found that Nanog significantly decreased the release of nitric oxide and the expression of inducible nitric oxide synthase at the mRNA and protein levels. The production of proinflammatory cytokines including tumor necrosis factor-α and interleukin-1β was also significantly inhibited by Nanog. Further, we observed that the transcriptional activity of nuclear factor κB was dramatically reduced by Nanog. These results suggest that Nanog may be a potential anti-inflammatory therapy for neurological diseases caused by persistent microglia activation. 23835060 Cross-reactivities and structure-reactivity relationships of six benzodiazepines to EMIT(®) immunoassay. Benzodiazepines are among the most frequently prescribed drugs due to their sedative, hypnotic, anxiolytic, muscle relaxant and antiepileptic properties. Considering the high consumption of benzodiazepines worldwide, there is increased potential for addiction and abuse in cases of crime, driving under the influence of drugs, suicide and drug-facilitated sexual assault (DFSA). For these reasons, this class of drugs and their metabolites are frequently present in both clinical and forensic cases. In a forensic toxicology laboratory, typical screening analysis for benzodiazepine involves various immunoassay screening methods. The present study investigates the cross-reactivity profiles of six benzodiazepines not included in the manufacturer's instructions (3-hydroxy-flunitrazepam, 7-amino-nitrazepam, brotizolam, delorazepam, pinazepam, α-hydroxy-midazolam) to EMIT(®) II Plus Benzodiazepine Assay. Pinazepam, delorazepam and brotizolam are the most reactive molecules, while the other ones present a very low cross-reactivity. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to confirm the concentrations of the spiked urines for immunoassay test and to make a comparison between the quantitative results of the different methods. Structure-reactivity relationships to EMIT(®) II Plus Benzodiazepine Assay were also evaluated. This paper draws attention to the problem of careless use of immunoassay tests for forensic purposes as they may provide false positive and/or negative results. 23845204 Neighborhood environments, mobility, and health: Towards a new generation of studies in environmental health research. While public policies seek to promote active transportation, there is a lack of information on the social and environmental factors associated with the adoption of active transportation modes. Moreover, despite the consensus on the importance of identifying obesogenic environmental factors, most published studies only take into account residential neighborhoods in the definition of exposures. There are at least three major reasons for incorporating daily mobility in public health research: (i) to identify specific population groups, including socially disadvantaged populations, who experience mobility or spatial accessibility deficits; (ii) to study the environmental determinants of transportation habits and investigate the complex relationships between transportation (as a source of physical activity, pollutants, and accidents) and physical activity and health; and (iii) to improve the assessment of spatial accessibility to resources and exposure to environmental hazards by accounting for daily trajectories for a better understanding of their health effects. There is urgent need to develop novel methods to better assess daily mobility. The RECORD Study relies on (i) an electronic survey of regular mobility to assess the chronic exposure to environmental conditions over a relatively long period, and (ii) Global Positioning System tracking to evaluate precisely acute environmental exposures over a much shorter period. The present article argues that future research should combine these two approaches. Gathering scientific evidence on the relationships between the environments, mobility/transportation, and health should allow public health and urban planning decision makers to better take into account the individual and environmental barriers to the adoption of active transportation and to define innovative intervention strategies addressing obesogenic environments to reduce disparities in excess weight. 23922210 Nanoscale elemental sensitivity study of Nd2 Fe14 B using absorption correlation tomography. Transmission X-ray microscopy (TXM) is a rapidly developing technique with the capability of nanoscale three dimensional (3D) real-space imaging. Combined with the wide range in energy tunability from synchrotron sources, TXM enables the retrieval of 3D microstructural information with elemental/chemical sensitivity that would otherwise be inaccessible. The differential absorption contrast above and below absorption edges has been used to reconstruct the distributions of different elements, assuming the absorption edges of the interested elements are fairly well separated. Here we present an "Absorption Correlation Tomography" (ACT) method based on the correlation of the material absorption across multiple edges. ACT overcomes the significant limitation caused by overlapping absorption edges, significantly expands the capabilities of TXM, and makes it possible for fully quantitative nano-scale 3D structural investigation with chemical/elemental sensitivity. The capability and robustness of this new methodology is demonstrated in a case study of an important type of rare earth magnet (Nd2 Fe14 B). Microsc. Res. Tech., 2013. © 2013 Wiley Periodicals, Inc. 23896028 The fetomaternal interface shows vascular hypoglycosylation in the tammar wallaby Macropus eugenii: Comparison with a range of non-mammalian and eutherian placentae. Blood vessel glycosylation at the fetomaternal interface of four near-term specimens of tammar wallaby, Macropus eugenii, has been examined at days 23-26 of the 26.5 day pregnancy and compared with that of other species. A panel of 23 lectins was used to compare vasculature in tammar with non-mammalian (shark, skink) and eutherian species at early and late gestation (camel, horse and alpaca), and term/near-term (cat, lion, dog, mink and elephant). Strikingly low levels of all the glycans tested, apart from sialic acids, were found in capillary endothelium of both the trilaminar omphalopleure and underlying surface endometrium of the tammar, though deeper endometrial vessels showed normally high levels of glycosylation. Only maternal vasculature of the mink placenta showed a comparable lack of expression. One reason for a reduced endothelial glycocalyx may be to facilitate diffusion of gases and nutrients as the tammar trophoblast lacks the indentation by overlying vessels that is seen in the other near-term placentae. Early epitheliochorial placentae of other species with equal diffusion distances to the tammar, showed normal vascular glycosylation. However, their pregnancies are much longer. The hypoglycosylation of tammar vessels at the fetomaternal interface may allow continued transfer of nutrients and gaseous exchange during the extremely rapid period of organogenesis which occurs during the short 26.5 day pregnancy of this marsupial. Given the short gestation period of the tammar, we suggest that a thinner endothelial glycocalyx has evolved to facilitate diffusion of gases and nutrients between the maternal and fetal compartments. 23721427 Palliative medicine practitioners' views on the concept of depression in the palliative care setting. Abstract Background: Despite its clinical importance in palliative care, depression remains an ambiguous concept. Objective: The purpose of this study was to explore how medical practitioners working in palliative care conceptualize depression in that setting. Design: Medical practitioners who attended a palliative medicine conference (N=185) were invited to respond to a questionnaire, which explored their views on the concept of depression in the palliative care context. Descriptive statistics were used to summarize responses, and comparison between groups was conducted using nonparametric statistics. Themes in free-text comments were identified. Results: Seventy-nine responses were obtained (response rate 43%). Depression was not a unified concept, but was generally considered to be an illness with psychological, spiritual, and existential causes. Respondents were more uncertain about depression being an illness in the palliative care setting compared with other settings, and were ambivalent about its causality. Treatment preferences leaned towards psychological interventions. Depression being different in the palliative care setting was a theme. It was considered to be more prevalent, different in quality, harder to define, and associated with greater barriers to diagnosis and treatment. Conceptual differences were associated with the respondents' area of work, work position, duration of practice, and previous mental health training. Conclusions: Depression in the palliative care setting is a variable concept for palliative medicine practitioners. The conceptual diversity and complexities of depression in this setting must be acknowledged and further explored in order to develop nuanced approaches in clinical practice and in research. 23918967 Auxin induces redox regulation of ascorbate peroxidase 1 activity by S-nitrosylation/denitrosylation balance resulting in changes of root growth pattern in Arabidopsis. S-Nitrosylation of Cys residues is one of the molecular mechanisms driven by nitric oxide (NO) for regulating biological functions of key proteins. While the studies on S-nitrosylation of Cys residues have served for identifying SNO proteomes, the physiological relevance of protein S-nitrosylation/denitrosylation remains poorly understood. In this study, it is shown that auxin influences the balance of S-nitrosylated/denitrosylated proteins in roots of Arabidopsis seedlings. 2D-PAGE allowed the identification of ascorbate peroxidase 1 (APX1) as target of auxin-induced denitrosylation in roots. Auxin causes APX1 denitrosylation and partial inhibition of APX1 activity in Arabidopsis roots. In agreement, the S-nitrosylated form of recombinant APX1 expressed in Escherichia coli is more active than the denitrosylated form. Consistently, Arabidopsis apx1 mutants have increased H2O2 accumulation in roots, shorter roots, and less sensitivity to auxin than the wild type. It is postulated that an auxin-regulated counterbalance of APX1 S-nitrosylation/denitrosylation contributes to a fine-tuned control of root development and determination of root architecture. 23719285 Nucleic acid changes during photodynamic inactivation of bacteria by cationic porphyrins. Light activation of photosensitizing dyes in presence of molecular oxygen generates highly cytotoxic reactive oxygen species leading to cell inactivation. Nucleic acids are molecular targets of this photodynamic action but not considered the main cause of cell death. The in vivo effect of the photodynamic process on the intracellular nucleic acid content of Escherichia coli and Staphylococcus warneri was evaluated herein. Two cationic porphyrins (Tetra-Py(+)-Me and Tri-Py(+)-Me-PF) were used to photoinactivate E. coli (5.0μM; 10(8)cellsmL(-1)) and S. warneri (0.5μM; 10(8)cellsmL(-1)) upon white light irradiation at 4.0mWcm(-2) for 270min and 40min, respectively. Total nucleic acids were extracted from photosensitized bacteria after different times of irradiation and analyzed by agarose gel electrophoresis. The double-stranded DNA was quantified by fluorimetry and the porphyrin binding to bacteria was determined by spectrofluorimetry. E. coli was completely photoinactivated with both porphyrins (5.0μM), whereas S. warneri was only completely inactivated by Tri-Py(+)-Me-PF (0.5μM). The hierarchy of nucleic acid changes in E. coli was in the order: 23S rRNA>16S rRNA>genomic DNA. The nucleic acids of S. warneri were extensively reduced after 5min with Tri-Py(+)-Me-PF but almost unchanged with Tetra-Py(+)-Me after 40min of irradiation. The amount of Tri-Py(+)-Me-PF bound to E. coli after washing the cells is higher than Tetra-Py(+)-Me and the opposite was observed for S. warneri. The binding capacity of the photosensitizers is not directly related to the PDI efficiency or nucleic acid reduction and this reduction occurs in parallel with the decrease of surviving cells. 23889511 The magnetosome proteins MamX, MamZ and MamH are involved in redox control of magnetite biomineralization in Magnetospirillum gryphiswaldense. Magnetospirillum gryphiswaldense uses intracellular chains of membrane-enveloped magnetite crystals, the magnetosomes, to navigate within magnetic fields. The biomineralization of magnetite nanocrystals requires several magnetosome-associated proteins, whose precise functions so far have remained mostly unknown. Here, we analysed the functions of MamX and the Major Facilitator Superfamily (MFS) proteins MamZ and MamH. Deletion of either the entire mamX gene or elimination of its putative haem c-binding magnetochrome domains, and deletion of either mamZ or its C-terminal ferric reductase-like component resulted in an identical phenotype. All mutants displayed WT-like magnetite crystals, flanked within the magnetosome chains by poorly crystalline flake-like particles partly consisting of haematite. Double deletions of both mamZ and its homologue mamH further impaired magnetite crystallization in an additive manner, indicating that the two MFS proteins have partially redundant functions. Deprivation of ΔmamX and ΔmamZ cells from nitrate, or additional loss of the respiratory nitrate reductase Nap from ΔmamX severely exacerbated the magnetosome defects and entirely inhibited the formation of regular crystals, suggesting that MamXZ and Nap have similar, but independent roles in redox control of biomineralization. We propose a model in which MamX, MamZ and MamH functionally interact to balance the redox state of iron within the magnetosome compartment. 23371808 The toxicity of a ternary biocide mixture to two consecutive earthworm (Eisenia fetida) Generations. The aim of the present study was to determine the toxicity of a mixture containing the biocides picoxystrobin, esfenvalerate, and triclosan to the reproduction and adult survival of two consecutive generations of Eisenia fetida (Savigny, 1826). Concentration addition and independent action were used to predict mixture toxicity. Due to degradation of mixture components during the course of the experiment, predictions were based both on the mixture composition at the beginning and the end of the exposure period. As degradations were dose-dependent, none of the calculated predictions were precise for the entire concentration range, although combining both predictions led us to conclude that lethal toxicity was well predicted by concentration addition and sublethal toxicity by independent action. Reproduction of the F1 generation was inhibited more (p < 0.0001) than reproduction of the F0 generation. Adult survival did not differ between generations. The accuracy of the mixture toxicity predictions thus depended on both the time-dependent mixture composition and the earthworm generation. The results of this study underline the need for more advanced mixture toxicity prediction models that consider degradation kinetics and changes in toxic effects over time. 23636989 Buckling-Induced Reversible Symmetry Breaking and Amplification of Chirality Using Supported Cellular Structures. Buckling-induced reversible symmetry breaking and amplification of chirality using macro- and microscale supported cellular structures is described. Guided by extensive theoretical analysis, cellular structures are rationally designed, in which buckling induces a reversible switching between achiral and chiral configurations. Additionally, it is demonstrated that the proposed mechanism can be generalized over a wide range of length scales, geometries, materials, and stimuli. 23475371 Selenium Attenuates Adriamycin-Induced Cardiac Dysfunction via Restoring Expression of ATP-Sensitive Potassium Channels in Rats. The possible mechanism of adriamycin (ADR) and/or selenium (Se) deficiency-induced cardiac dysfunction, and cardioprotective effects of Se against ADR-induced cardiac toxicity were investigated in this study. Cardiac function was evaluated by plasma brain natriuretic peptide level and echocardiographic and hemodynamic parameters. Cardiac glutathione peroxidase (GPx) activity was assessed spectrophotometrically. Expression of ATP-sensitive potassium channels (KATP) subunits-SUR2A and Kir6.2-were examined by real-time PCR and Western blotting. The results showed that cardiac function and cardiac GPx activity decreased remarkably after administration of ADR or Se deficiency; more dramatic impairment of cardiac function and cardiac GPx activity were observed after co-administration of ADR and Se deficiency. Mechanically, it is novel for us to find down-regulation of KATP subunits gene expression in cardiac tissue after administration of ADR or Se deficiency, and more significant inhibition of cardiac KATP gene expression was identified after co-administration of ADR and Se deficiency. Furthermore, cardiac toxicity of ADR was found alleviated by Se supplementation, accompanied by restoring of cardiac GPx activity and cardiac KATP gene expression. These results indicate that decreased expression of cardiac KATP is involved in adriamycin and/or Se deficiency-induced cardiac dysfunction; Se deficiency exacerbates adriamycin-induced cardiac dysfunction by future inhibition of KATP expression; Se supplementation seems to protect against adriamycin-induced cardiac dysfunction via restoring KATP expression, showing potential clinical application in cancer chemotherapy. 23922742 The Human Neutrophil Subsets Defined by the Presence or Absence of OLFM4 Both Transmigrate into Tissue In Vivo and Give Rise to Distinct NETs In Vitro. Neutrophil heterogeneity was described decades ago, but it could not be elucidated at the time whether the existence of different neutrophil subsets had any biological relevance. It has been corroborated in recent years that neutrophil subsets, defined by differential expression of various markers, are indeed present in human blood, calling for renewed attention to this question. The expression of the granule protein olfactomedin 4 (OLFM4) has been suggested to define two such neutrophil subsets. We confirm the simultaneous presence of one OLFM4-positive and one OLFM4-negative neutrophil subpopulation as well as the localization of the protein to specific granules. In vitro, these neutrophil subsets displayed equal tendency to undergo apoptosis and phagocytose bacteria. In addition, the subpopulations were recruited equally to inflammatory sites in vivo, and this was true both in an experimental model of acute inflammation and in naturally occurring pathological joint inflammation. In line with its subcellular localization, only limited OLFM4 release was seen upon in vivo transmigration, and release through conventional degranulation required strong secretagogues. However, extracellular release of OLFM4 could be achieved upon formation of neutrophil extracellular traps (NETs) where it was detected only in a subset of the NETs. Although we were unable to demonstrate any functional differences between the OLFM4-defined subsets, our data show that different neutrophil subsets are present in inflamed tissue in vivo. Furthermore, we demonstrate NETs characterized by different markers for the first time, and our results open up for functions of OLFM4 itself in the extracellular space through exposure in NETs. 23436245 Myeloperoxidase Activity and Its Corresponding mRNA Expression as well as Gene Polymorphism in the Population Living in the Coal-Burning Endemic Fluorosis Area in Guizhou of China. The myeloperoxidase (MPO) activity and its corresponding mRNA expression as well as gene polymorphism were investigated in the population who live in the endemic fluorosis area. In the study, 150 people were selected from the coal-burning endemic fluorosis area and 150 normal persons from the non-fluorosis area in Guizhou province of China. The blood samples were collected from these people. The activity of MPO in the plasma was determined by spectrophotometer; the expression of MPO mRNA was measured by employing real-time polymerase chain reaction; DNAs were extracted from the leucocytes in blood and five SNP genotypes of MPO promoter gene detected by a multiplex genotyping method, adapter-ligation-mediated allele-specific amplification. The results showed that the MPO activity and its corresponding mRNA in blood were significantly increased in the population living in the area of fluorosis. The different genotype frequencies of MPO, including -1228G/A, -585T/C, -463G/A, and -163C/T, and the three haplotypes with higher frequencies, including -163C-463G-585T-1228G-1276T, -163C-463G-585T-1228G-1276C, and -163C-463G-585T-1228A-1276T, were significantly associated with fluorosis. The results indicated that the elevated activity of MPO induced by endemic fluorosis may be connected in mechanism to the stimulated expression of MPO mRNA and the changed gene polymorphism. 23933676 Double helix dipole design applied to magnetic resonance: A novel NMR coil. A new radio frequency coil design for NMR experiments is presented. The coil generates a magnetic field purely perpendicular to the longitudinal axis of the main magnet, and its sensitivity is higher than the traditional transversal resonators. This is achieved by adding the contribution of two tilted solenoid coils fed with opposite currents. The work presents the mathematical model for the new coil, numerical simulations performed to validate that model and a comparison with an equivalent saddle coil. The new design is tested experimentally in low- and high-field NMR experiments and compared with results obtained with equivalent saddle coils. The results lead to conclude that the new design provides better sensitivity than the transverse resonators commonly used in NMR. 23811989 Benzimidazole-embedded N-fused aza-indacenes: synthesis and deprotonation-assisted optical detection of carbon dioxide. N-fused aza-indacene-based fluorophores 1 and 2 were prepared via a three-component condensation involving benzimidazole-carbinol, trifluoroacetic acid, and either pyrrole or indole, respectively. The N-fused aza-indacenes act as optical-based chemosensors for dissolved carbon dioxide gas following fluoride anion-mediated deprotonation. 23927280 Molecular dynamics of polymer crystallization revisited: Crystallization from the melt and the glass in longer polyethylene. Molecular mechanisms of the steady-state growth of the chain folded lamella and the cold crystallization across the glass transition temperature Tg are investigated by molecular dynamics simulation for a system of long polyethylene (PE)-like polymers made of 512 united atoms C512. The present paper aims to reconsider results of our previous simulations for short PE-like polymers C100 by carrying out very long simulations up to 1 μs for more realistic systems of much longer chains, thereby to establish the firm molecular image of chain-folded crystallization and clarify the specific molecular process of cold crystallization. We observe that the chain-folded lamella shows fast thickening-growth keeping marked tapered growth front. Despite the fast growth in much longer chains, the fold-surface is found to be predominantly of adjacent-reentry. Detailed inspections of the molecular pathway give an insightful image that can explain the apparently contradicting results. In addition, the fold-structure with specific spatial heterogeneity is found to give rise to heterogeneous mobility within the crystalline region. On the other hand, investigations of the cold crystallization during slow heating of the glassy film across Tg is found to give a granular texture made of small crystallites. The crystallites are found to nucleate preferentially near the free surfaces having lower Tg, and to be dominantly edge-on showing a definite tendency to orient their chain axes parallel to the free surface. 23648325 Organic compounds in olive mill wastewater and in solutions resulting from hydrothermal carbonization of the wastewater. Organic components in olive mill wastewater (OMW) were analyzed by exhaustive solvent extraction of the lyophilisate followed by pre-chromatographic derivatization techniques and GC/MS-analysis of the extracts. Simple biophenols including tyrosol (Tyr), hydroxytyrosol (OH-Tyr) and homovanillic alcohol as well as complex biophenols including decarbomethoxy ligostride aglycon and decarbomethoxy oleuropein aglycon proved most abundant analytes. Hydroxylated benzoic and cinnamic acids are less abundant, which may indicate a humification process to have occurred. The pattern of organic components obtained from native OMW was compared with that obtained from hydrothermal carbonization (HTC) of the waste product. Former results provided strong evidence that HTC of OMW at 220°C for 14h results in an almost complete hydrolysis of complex aglycons. However, simple biophenols were not decomposed on hydrothermal treatment any further. Phenol and benzenediols as well as low molecular weight organic acids proved most abundant analytes which were generated due to HTC. Similarly to aglycons, lipids including most abundant acylglycerines and less abundant wax esters were subjected almost quantitatively to hydrolysis under hydrothermal conditions. Fatty acids (FAs) released from lipids were further decomposed. The pathways of volatile analytes in both native OMW and aqueous HTC solutions were studied by solventless headspace-Solid Phase Micro Extraction. Basically, a wide array low molecular alcohols and ketones occurring in native OMW survived the HTC process. 23639879 Osteopontin inhibits osmotic swelling of retinal glial (Müller) cells by inducing release of VEGF. Osmotic swelling of retinal neurons and glial cells is an important pathogenic factor of retinal edema formation. Here, we show that the neuroprotective factor osteopontin (OPN), which is released from retinal glial (Müller) cells after stimulation of the cells with glial cell line-derived neurotrophic factor (Del Río et al., 2011, Glia 59:821-832), inhibits the swelling of rat Müller cells induced by hypoosmotic exposure of retinal slices in the presence of barium ions and H₂O₂, respectively, and in slices of postischemic retinas. OPN did not inhibit the hypoosmotic swelling of bipolar cells in slices of control and postischemic retinas. The inhibitory effect of OPN on Müller cell swelling was dose-dependent, with a half-maximal effect at ∼0.6 ng/ml. The effect of OPN was abrogated in the presence of pharmacological blockers of vascular endothelial growth factor (VEGF) receptor-2, metabotropic glutamate receptors, and purinergic receptors (P2Y₁, adenosine A1 receptors), as well as of a neutralizing anti-VEGF antibody. The data suggest that OPN induces the release of VEGF, glutamate, ATP, and adenosine from Müller cells. The effect of OPN was also prevented by blockers of voltage-gated sodium channels (tetrodotoxin), T-type voltage-gated calcium channels (kurtoxin), potassium channels (clofilium), and chloride channels 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB). The swelling-inhibitory effect of OPN was dependent on intracellular calcium signaling, activation of phospholipase C and protein kinase C, and vesicular exocytosis of glutamate. In retinal slices, Müller glial cells display immunoreactivity of OPN. The data suggest that Müller cell-derived OPN has (in addition to the effects on photoreceptors and retinal neurons) autocrine effects. The neuroprotective effects of OPN may be in part mediated by the prevention of cytotoxic Müller cell swelling and the release of VEGF and adenosine from Müller cells. 23350616 The complete mitochondrial genome of the hybrid of Ctenopharyngodon idella (♀) Ã— Squaliobarbus curriculus (♂). The complete mitochondrial genome sequence of the hybrid of Ctenopharyngodon idella (♀) Ã— Squaliobarbus curriculus (♂) was determined using PCR-based method. The total length of the mitogenome is 16,609 bp. It contains the typical structure as that of most other vertebrates, including 2 ribosomal RNA genes, 13 protein-coding genes, 22 transfer RNA genes, and 1 non-coding control region (D-loop region). The overall composition of the mitogenome was estimated to be 31.86% for A, 26.08% for T, 26.38% for C, and 15.68% for G, respectively, indicating that an A+T (57.94%)-rich feature occurs in the hybrid mitogenome. Both the termination-associated sequence and three conserved sequence blocks (CSB1, CSB2, and CSB3) were also detected in the D-loop region. 23949886 The Potential of Stem Cells in the Treatment of Cardiovascular Diseases. Although the adult mammalian heart was once believed to be a post-mitotic organ without any capacity for regeneration, recent findings have challenged this dogma. A modified view assigns to the mammalian heart a measurable capacity for regeneration throughout life. The ultimate goals of the cardiac regeneration field have been pursued by multiple strategies, including understanding the developmental biology of cardiomyocytes and cardiac stem and progenitor cells, applying chemical genetics, and engineering biomaterials and delivery methods that facilitate cell transplantation. Successful stimulation of endogenous regenerative capacity in injured adult mammalian hearts can benefit from studies of natural cardiac regeneration. 23962790 Transforming growth factor-β and epithelial-mesenchymal transition are associated with pulmonary metastasis in adenoid cystic carcinoma. Adenoid cystic carcinoma (ACC) is one of the most common malignancies of salivary glands, characterized by poor prognosis, particularly due to pulmonary metastasis. We previously reported that transforming growth factor (TGF)-β1 promoted ACC cell migration and invasion via the Smad pathway in vitro. The aim of this study was to establish the underlying mechanisms. TGF-β1, phospho-Smad2 and β-catenin expression in ACC tissues derived from patients was evaluated by immunohistochemistry. The role of TGF- β1 on the invasive capacity of ACC cells was determined by transwell assays in SACC-83 cells transfected with TGF-β1 and TGF-β type II dominant-negative receptor (TβRIIDN) plasmids or silenced by TGF-β1 siRNA. Expression of the epithelial-mesenchymal transition (EMT) markers, β-catenin, E-cadherin and Nectin-1, was determined by real-time PCR and immunochemistry. In vivo investigations were performed by inoculating nude mice with the transfected ACC cells and examining metastasis in bilateral lung tissues by immunohistochemistry. Overexpression of TGF-β1 and phospho-Smad2, and reduced expression of membrane β-catenin, were closely associated with lung metastasis in ACC. Furthermore, the EMT markers were downregulated. In vitro, cells transfected with TGF-β1 exhibited altered morphology and increased invasive capacity compared to TβRIIDN-transfected cells or TGF-β1 siRNA silenced cells. In vivo, mice inoculated with TGF-β1 transfected ACC cells exhibited more metastases than other cells. TGF-β1, phospho-Smad2 and β-catenin were significantly correlated with ACC metastasis. Blockade of TGF-β signaling by TβRIIDN or siRNA may offer potential gene therapies against pulmonary metastasis in patients with ACC. 23948928 Using Cerebrospinal Fluid Marker Profiles in Clinical Diagnosis of Dementia with Lewy Bodies, Parkinson's Disease, and Alzheimer's Disease. Background: The diagnosis of dementia with Lewy bodies (DLB) is difficult to differentiate from other degenerative diseases. Patients are often mistaken to suffer from Parkinson's disease (PD) or Alzheimer's disease (AD) because of the overlapping clinical appearances concerning cognition and movement. Objective: We investigated the possibility for a valid differential diagnosis using cerebrospinal fluid (CSF) biomarkers. Methods: In the context of a large retrospective study, we analyzed data of patients suffering from degenerative, ischemic, or inflammatory diseases and identified those with DLB (n = 34), PD (n = 37), and AD (n = 47) for further analyses. Results: We detected abnormalities in the CSF profiles of those patients with DLB while using a combination of decreased amyloid-β (Aβ)42 and increased tau levels. By stratification of data by disease severity, we observed a high sensitivity of this combination especially in the subgroup of patients with advanced stages, while the sensitivity in early forms was lower. In addition, with clinical deterioration, the abnormalities in the CSF profile became more pronounced. Conclusion: We conclude that DLB can be distinguished from PD, in spite of both being synucleinopathies, by CSF profiles using neurodegenerative marker analysis. The pathophysiology of increased tau and decreased Aβ levels in those conditions has to be elucidated further, since both proteins are known to be involved in the pathogenesis of AD, but no clear explanation has been postulated for DLB yet. 23918666 Evaluation of Rhesus Monkey and Guinea Pig Hepatic Cytosol Fractions as Models for Human Aldehyde Oxidase. Aldehyde oxidase (AOX) is a cytosolic enzyme expressed across a wide range of species including guinea pig and rhesus monkey. These species are believed to be the best preclinical models for studying human AO mediated metabolism. We compared AO activity in rhesus monkey, guinea pig and humans using phthalazine and DACA as substrates and raloxifene as an inhibitor. Michaelis-Menten kinetics was observed for phthalazine oxidation in rhesus monkey, guinea pig and human liver cytosol whereas substrate inhibition was seen with DACA oxidase activity in all the 3 livers. Raloxifene inhibited phthalazine and DACA oxidase activity uncompetitively in guinea pig whereas mixed mode inhibition was seen in rhesus monkey. Our analysis of the primary sequence alignment of rhesus monkey, guinea pig and human AOX1 along with homology modelling has led to the identification of several amino acid residue differences within the active site and substrate entrance channel of AOX1. We speculate that some of these residues might be responsible for the differences observed in activity. Overall, our data indicate that rhesus monkey and guinea pig would overestimate intrinsic clearance in human and would be unsuitable to use as animal models. Our study also showed that AO metabolism in species is substrate dependent and no single animal model can be reliably used to predict every drug response in humans. 23900151 Efficacy of DHMEQ, a NF-κB Inhibitor, in Islet Transplantation: I. HMGB1 Suppression by DHMEQ Prevents Early Islet Graft Damage. Pancreatic islet transplantation (PITx) is an attractive treatment option for restoring appropriate glucose homeostasis in type 1 diabetes patients. Although islet grafts can successfully engraft after PITx, large numbers of islet grafts are required mainly because immune reactions, including inflammation, destroy islet grafts. In these processes, nuclear factor (NF)-κB plays a central role. We hypothesized that the inhibition of NF-κB activation would ameliorate inflammatory responses after PITx and aid successful engraftment. To test this hypothesis, a newly developed NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), was used on a syngeneic mouse PITx model. One hundred seventy-five islets from C57BL/6 (B6) mice were transplanted into streptozotocin-induced diabetic B6 mice. The recipient mice were administered DHMEQ for 1, 2, or 3 days after PITx. The underlying mechanisms of DHMEQ on islet graft protection were investigated in an in vitro coculture model of pancreatic islets and macrophages. With a vehicle treatment, only 11.1% of the islet-recipients achieved normoglycemia after PITx. In sharp contrast, DHMEQ treatment markedly improved the normoglycemic rate, which was associated with the suppression of serum high mobility group complex-1 (HMGB1) and proinflammatory cytokines, including tumor necrosis factor-α, monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, interleukin-1β, and interleukin-6, after PITx. In a murine macrophage-like cell line, DHMEQ inhibited HMGB1-driven activation and proinflammatory cytokine secretion and further prevented death isolated islets after coculture with these activated macrophages. Inhibition of NF-κB activation by DHMEQ after PITx reduces the HMGB1-triggered proinflammatory responses and results in engraftment of transplanted islets even with fewer islet grafts. 23922413 Decoding consciousness. Geraint Rees is a Professor of Cognitive Neurology at University College London, where he directs the Institute of Cognitive Neuroscience. His research interests focus on understanding the neural basis of human consciousness in health and disease, using functional neuroimaging techniques in combination with other methodologies. Recently he has pioneered new approaches to analysing functional brain images to individuate the contents of consciousness, and has written and spoken on the potential moral and ethical implications of such techniques. His work has been internationally recognised by award of the Young Investigator Medal of the Organisation for Human Brain Mapping, the Experimental Psychology Prize; and he has given the Francis Crick lecture at the Royal Society and the Goulstonian lecture at the Royal College of Physicians. In 2010 he was elected a Fellow of the Academy of Medical Sciences.   In addition to his research interests, Geraint has a track record of personal and professional commitment to improving clinical academic training both at UCL Partners and throughout the UK. He oversees the NIHR Academic Clinical Fellow and Clinical Lecturer programmes across UCL Partners and is the lead for postgraduate education & training within the UCL/UCLH Comprehensive Biomedical Research Centre and the UCL Faculty of Biomedical Sciences. Nationally, he is a member of the Medical Programme Board for England, Deputy Chair of the BMA's Medical Academic Staff Committee, and a member of the MRC Neurosciences & Mental Health Board. He actively contributes to development of national policy on clinical academic training. Consciousness is central to the human condition, furnishing us with phenomenal awareness of the external world and the ability to reflect upon our own thoughts and experiences. Almost half our communication concerns the contents of our thoughts and experiences. The shared language we use to do this obscures the recent realization that there is substantial variability in how different people experience the same physical environment. Moreover, key aspects of this variability in conscious experience are heritable, suggesting a conscious phenotype with adaptive significance. In this talk I will explore the nature of individual differences in conscious perception and their neural basis, focusing on both structure and function of the human brain. 23807475 Trajectory of human movement during sit to stand: a new modeling approach based on movement decomposition and multi-phase cost function. The purpose of this work is to develop a computational model to describe the task of sit to stand (STS). STS is an important movement skill which is frequently performed in human daily activities, but has rarely been studied from the perspective of optimization principles. In this study, we compared the recorded trajectories of STS with the trajectories generated by several conventional optimization-based models (i.e., minimum torque, minimum torque change and kinetic energy cost models) and also with the trajectories produced by a novel multi-phase cost model (MPCM). In the MPCM, we suggested that any complex task, such as STS, is decomposable into successive motion phases, so that each phase requires a distinct strategy to be performed. In this way, we proposed a multi-phase cost function to describe the STS task. The results revealed that the conventional optimization-based models failed to correctly predict the invariable features of STS, such as hip flexion and ankle dorsiflexion movements. However, the MPCM not only predicted the general features of STS with a sufficient accuracy, but also showed a potential flexibility to distinguish between the movement strategies from one subject to the other. According to the results, it seems plausible to hypothesize that the central nervous system might apply different strategies when planning different phases of a complex task. The application areas of the proposed model could be generating optimized trajectories of STS for clinical applications (such as functional electrical stimulation) or providing clinical and engineering insights to develop more efficient rehabilitation devices and protocols. 23055446 Social contagion of mental health: evidence from college roommates. From a policy standpoint, the spread of health conditions in social networks is important to quantify, because it implies externalities and possible market failures in the consumption of health interventions. Recent studies conclude that happiness and depression may be highly contagious across social ties. The results may be biased, however, because of selection and common shocks. We provide unbiased estimates by using exogenous variation from college roommate assignments. Our findings are consistent with no significant overall contagion of mental health and no more than small contagion effects for specific mental health measures, with no evidence for happiness contagion and modest evidence for anxiety and depression contagion. The weakness of the contagion effects cannot be explained by avoidance of roommates with poor mental health or by generally low social contact among roommates. We also find that similarity of baseline mental health predicts the closeness of roommate relationships, which highlights the potential for selection biases in studies of peer effects that do not have a clearly exogenous source of variation. Overall, our results suggest that mental health contagion is lower, or at least more context specific, than implied by the recent studies in the medical literature. Copyright © 2012 John Wiley & Sons, Ltd. 23574336 Oxidation of CO by Nickel Oxide Clusters Revealed by Post Heating. Reactions of nickel oxide cluster ions, NinOn+x(+) (n = 4-10, x = -1∼+3), with CO in a He buffer gas were investigated using mass spectrometry. When the cluster ions react at room temperature, a CO molecule tends to attach readily to NinOn+x(+) for all of the cluster ions with different stoichiometry, although rate constants of the CO attachment reaction are more or less stoichiometry-dependent. However, CO was found to be released from the cluster ions when the cluster ions were heated up to 523 K after the reaction. This finding is interpreted such that the CO molecule that physisorbs weakly to NinOn+x(+) at room temperature desorbs into the gas phase by the post heating. In addition, we found that an oxygen extraction reaction by a CO molecule actually occurs for oxygen-rich clusters such as Ni6O7(+) and Ni8O9(+). As the oxygen extraction reaction is one order of magnitude slower than physisorption, it lies hidden underneath of the faster physisorption processes in the mass spectrum but is revealed by the elimination of physisorption through the post heating. 23592480 IL-1RI participates in normal growth plate development and bone modeling. The proinflammatory cytokine interleukin-1 (IL-1) signals through IL-1 receptor type I (IL-1RI) and induces osteoclastogenesis and bone resorption mainly during pathological conditions. Little is known about the effect of excess or absence of IL-1 signaling on the physiological development of the growth plate and bone. In this study, we examine growth plate morphology, bone structure, and mechanical properties as well as osteoclast number in IL-1RI knockout mice to evaluate the role of IL-1RI in the normal development of the growth plate and bone. We show for the first time that IL-1RI knockout mice have narrower growth plates due to a smaller hypertrophic zone, suggesting a role for this cytokine in hypertrophic differentiation, together with higher proteoglycan content. The bones of theses mice exhibit higher trabecular and cortical mass, increased mineral density, and superior mechanical properties. In addition, IL-1RI knockout mice have significantly reduced osteoclast numbers in the chondro-osseous junction, trabecular bone, and cortical bone. These results suggest that IL-1RI is involved in normal growth plate development and ECM homeostasis and that it is significant in the physiological process of bone modeling. 23960439 The effects of antihypertensive drugs on bone mineral density in ovariectomized mice. The effects of several antihypertensive drugs on bone mineral density (BMD) and micro-architectural changes in ovariectomized (OVX) mice were investigated. Eight-week-old female C57/BL6 mice were used for this study. Three days after ovariectomy, mice were treated intraperitoneally with nifedipine (15 mg/kg), telmisartan (5 mg/kg), enalapril (20 mg/kg), propranolol (1 mg/kg) or hydrochlorothiazide (12.5 mg/kg) for 35 consecutive days. Uterine atrophy of all mice was confirmed to evaluate estrogen deficiency state. BMD and micro-architectural analyses were performed on tibial proximal ends by micro-computed tomography (micro-CT). When OVX mice with uterine atrophy were compared with mice without atrophy, BMD decreased (P < 0.001). There were significant differences in BMD loss between different antihypertensive drugs (P = 0.005). Enalapril and propranolol increased BMD loss in mice with atrophied uteri compared with control mice. By contrast, thiazide increased BMD in mice with uterine atrophy compared with vehicle-treated mice (P = 0.048). Thiazide (P = 0.032) and telmisartan (P = 0.051) reduced bone loss and bone fraction in mice with uterine atrophy compared with the control. Thiazide affects BMD in OVX mice positively. The reduction in bone loss by thiazide and telmisartan suggest that these drugs may benefit menopausal women with hypertension and osteoporosis. 23892859 Depression in doctors of Zenica-Doboj Canton. Aim To determine prevalence of depression symptoms in doctors in the Zenica-Doboj Canton and establish whether there is any difference in the prevalence between doctors employed at the Cantonal Hospital Zenica and doctors working in health care centers. Methods The completed research was of a projective-descriptive character. The research included 200 examinees, 100 doctors employed at the Cantonal Hospital in Zenica and health care centers. The research was conducted in the period between May and July 2008. A questionnaire designed for this purpose, Beck's Depression Inventory (BDI), Hamilton Rating Scale for Depression (HAM-D), Occupational Stress Questionnaire (OSQ), Work Ability Index (WAI) were used in the study. Results The research confirmed that 68 (34%) examined doctors had mild depressive disorders. The number of examinees with mild depressive disorders in the Cantonal Hospital was slightly higher compared to those employed in health care centers. The number of females with such disorders was twice as higher than males. It has been found that 42 (21%) examinees had sick leave caused by this disease. Such examinees did not have adequate help and support by their superiors and they are not satisfied with the state of interpersonal relations. Conclusion The research data clearly indicate that there is a significant percentage of doctors with depressive disorders in the area of Zenica-Doboj Canton, and their work ability is diminished due to depressive disorders. The achieved results correspond to similar researches conducted in our country and worldwide. Key words: depressive disorder, stress, hospital. 22402254 The Mediator complex in thyroid hormone receptor action. Mediator is an evolutionarily conserved multisubunit complex that plays an essential regulatory role in eukaryotic transcription of protein-encoding genes. The human complex was first isolated as a transcriptional coactivator bound to the thyroid hormone receptor (TR) and has since been shown to play a key coregulatory role for a broad range of nuclear hormone receptors (NRs) as well as other signal-activated transcription factors. We provide a general overview of Mediator structure and function, summarize the mechanisms by which Mediator is targeted to NRs, and outline recent evidence revealing Mediator as a regulatory axis for other distinct coregulatory factors, chromatin modifying enzymes and cellular signal transduction pathways. Besides serving as a functional interface with the RNA polymerase II basal transcription machinery, Mediator plays a more versatile role in regulating transcription including the ability to: a) facilitate gene-specific chromatin looping events; b) coordinate chromatin modification events with preinitiation complex assembly; and c) regulate critical steps that occur during transcriptional elongation. The variably associated MED1 subunit continues to emerge as a pivotal player in Mediator function, not only as the primary interaction site for NRs, but also as a crucial interaction hub for other coregulatory factors, and as an important regulatory target for signal-activated kinases. Mediator plays an integral coregulatory role at NR target genes by functionally interacting with the basal transcription apparatus and by coordinating the action of chromatin modifying enzymes and transcription elongation factors. This article is part of a Special Issue entitled Thyroid hormone signalling. 23846979 Anti-Diabetic Potential of Panax Notoginseng Saponins (PNS): A Review. Herbal medicines have traditionally played a major role in the management of diabetes in Asian countries for centuries. Panax notoginseng (Burk) F. H. Chen (Araliaceae) known as Tiánqī or san qi is a well-known medicinal herb in Asia for its long history of use in Chinese medicine. Qualified as 'the miracle root for the preservation of life', it has been used in China for 600 years, for treatment of various diseases. Panax notoginseng saponins (PNS) are the key active components. PNS have been widely used in China for treatment of cardiovascular diseases. However, scientific studies have shown a wide range of other pharmacological applications including anti-cancer, neuroprotective and anti-inflammatory agents, immunologic adjuvant and prevention of diabetes complications. Recently, hypoglycemic and anti-obesity properties of PNS have also been demonstrated. The present review highlights the effects of PNS on glucose production and absorption, and on inflammatory processes that seem to play an important role in the development of diabetes. Copyright © 2013 John Wiley & Sons, Ltd. 23404491 Radiographic findings in revision anterior cruciate ligament reconstructions from the Mars cohort. The Multicenter ACL (anterior cruciate ligament) Revision Study (MARS) group was developed to investigate revision ACL reconstruction outcomes. An important part of this is obtaining and reviewing radiographic studies. The goal for this radiographic analysis is to establish radiographic findings for a large revision ACL cohort to allow comparison with future studies. The study was designed as a cohort study. Various established radiographic parameters were measured by three readers. These included sagittal and coronal femoral and tibial tunnel position, joint space narrowing, and leg alignment. Inter- and intraobserver comparisons were performed. Femoral sagittal position demonstrated 42% were more than 40% anterior to the posterior cortex. On the sagittal tibia tunnel position, 49% demonstrated some impingement on full-extension lateral radiographs. Limb alignment averaged 43% medial to the medial edge of the tibial plateau. On the Rosenberg view (45-degree flexion view), the minimum joint space in the medial compartment averaged 106% of the opposite knee, but it ranged down to a minimum of 4.6%. Lateral compartment narrowing at its minimum on the Rosenberg view averaged 91.2% of the opposite knee, but it ranged down to a minimum of 0.0%. On the coronal view, verticality as measured by the angle from the center of the tibial tunnel aperture to the center of the femoral tunnel aperture measured 15.8 degree ± 6.9% from vertical. This study represents the radiographic findings in the largest revision ACL reconstruction series ever assembled. Findings were generally consistent with those previously demonstrated in the literature. 23177163 Quantitative analysis of surgical exposure and maneuverability associated with the endoscope and the microscope in the retrosigmoid and various posterior petrosectomy approaches to the petroclival region using computer tomograpy-based frameless stereotaxy. A cadaveric study. Most of the approaches used to expose the petro-clival region require a certain degree of temporal bone resection with its associated approach morbidity such as potential hearing and facial nerve compromise. Endoscopes are becoming more and more popular in neurosurgical practice. To gain insight into the benefits of using endoscopy to operate on the petro-clival region, we evaluated and compared the exposure and maneuverability obtained employing the endoscope and the microscope in retrosigmoid and pre-sigmoid approaches by using quantitative analysis based on frameless stereotaxy. We evaluated the retrosigmoid (RS), retrolabyrinthine (RL), translabyrinthine (TL), and transcochlear (TC) approaches. Each approach was performed 4 times for a total of 16 approaches. We used a navigation system for intraoperative navigation. Each approach was evaluated vis-a-vis the area of the petro-clival/brainstem region exposed and the afforded maneuverability, both using a rigid endoscope or an operating microscope. The TC approach exposed the largest area at the brainstem compared to all other three approaches both in microscopic and endoscopic modes and there was no significant difference between the 2 modes (P=0.42). In the RS approach use of the 30° angled endoscope increased significantly the exposure compared to the operating microscope (respectively 460±49.7 mm(2) vs 235±25 mm(2); P=0.002). On the other hand, maneuverability was significantly decreased with the endoscope compared to the microscope in all the approaches evaluated (P=0.006). Integration of the endoscope into conventional petrosectomy approaches could significantly reduce the amount of temporal bone drilling for adequate visualization of the petro-clival region. However maneuverability as assessed by our model was better with the microscope than with the endoscope. 23954592 Unsupervised biomedical named entity recognition: Experiments with clinical and biological texts. Named entity recognition is a crucial component of biomedical natural language processing, enabling information extraction and ultimately reasoning over and knowledge discovery from text. Much progress has been made in the design of rule-based and supervised tools, but they are often genre and task dependent. As such, adapting them to different genres of text or identifying new types of entities requires major effort in re-annotation or rule development. In this paper, we propose an unsupervised approach to extracting named entities from biomedical text. We describe a stepwise solution to tackle the challenges of entity boundary detection and entity type classification without relying on any handcrafted rules, heuristics, or annotated data. A noun phrase chunker followed by a filter based on inverse document frequency extracts candidate entities from free text. Classification of candidate entities into categories of interest is carried out by leveraging principles from distributional semantics. Experiments show that our system, especially the entity classification step, yields competitive results on two popular biomedical datasets of clinical notes and biological literature, and outperforms a baseline dictionary match approach. Detailed error analysis provides a road map for future work. 23871847 Assessment of regional adipose tissue depots: A DXA and CT comparison in cadavers of elderly persons. Since dual energy X-ray absorptiometry (DXA) cannot distinguish between different adipose tissue (AT) deposits, it remains unclear how DXA-derived body composition variables relate to anatomical tissue (sub)compartments. The aim of the present study was to compare and relate regional DXA variables with absolute tissue masses obtained by computer tomography (CT) scanning of the lower limbs in elderly persons. Eleven well-preserved white Caucasian adults (seven male and four female cadavers) with a median age of 79.0years (ranging from 68 to 96years) were fully scanned with DXA and CT. Separate densities of skin tissue, AT, muscle tissue and bone were obtained by hydrostatic weighing. The leg DXA-variables were significantly related (rho-values between 0.60 and 0.98, P<0.01) to CT-derived tissue counterparts, but showed significant systematic differences except for subcutaneous AT mass (P=0.773). After controlling for other AT depots, fat as measured by DXA (fatDXA) related only to intermuscular AT (rho=0.82, P<0.01) in males and to subcutaneous AT (rho=0.84, P<0.05) in females. Although significantly interrelated, DXA and CT variables should not be used interchangeably since they have different quantitative and physiological significance. Our results suggest that fatDXA represents different parts of AT depots in elderly men and women. Since DXA is not appropriate for assessing tissue variability cautious clinical interpretation is warranted. 23949085 Thermodynamic behaviour of supercritical matter. Since their discovery in 1822, supercritical fluids have been of enduring interest and have started to be deployed in many important applications. Theoretical understanding of the supercritical state is lacking and is seen to limit further industrial deployment. Here we study thermodynamic properties of the supercritical state and discover that specific heat shows a crossover between two different regimes, an unexpected result in view of currently perceived homogeneity of supercritical state in terms of physical properties. We subsequently formulate a theory of system thermodynamics above the crossover, and find good agreement between calculated and experimental specific heat with no free-fitting parameters. In this theory, energy and heat capacity are governed by the minimal length of the longitudinal mode in the system only, and do not explicitly depend on system-specific structure and interactions. We derive a power law and analyse supercritical scaling exponents in the system above the Frenkel line. 23440001 Post-synthesis, characterization and catalytic properties of fluorine-planted MWW-type titanosilicate. F-Ti-MWW was post-synthesized by implanting fluorine species into a Ti-MWW framework through an acid treatment process in the presence of ammonium fluoride. The effects of NH4F addition amount, acid treatment temperature and precursor Ti content were investigated on the incorporation of F species, the zeolite structure and the coordination sites of Ti. Fluorine-implanting improved the surface hydrophobicity of the zeolite and altered the electropositivity nearby the tetrahedral Ti sites through forming the SiO3/2F and SiO4/2F(-) units. The negative effect of SiO4/2F(-) units in F-Ti-MWW was eliminated selectively by convenient anion-exchange with various alkali chlorides. F-Ti-MWW containing the SiO3/2F units possessed better catalytic activity and reusability, and a longer catalyst lifetime than conventional Ti-MWW. 23672826 The connection between inner membrane topology and mitochondrial function. The mitochondrial inner membrane has a complex and dynamic structure that plays an important role in the function of this organelle. The internal compartments called cristae are created by processes that are just beginning to be understood. Crista size and morphology influence the internal diffusion of solutes and the surface area of the inner membrane, which is home to critical membrane proteins including ATP synthase and electron transport chain complexes; metabolite and ion transporters including the adenine nucleotide translocase, the calcium uniporter (MCU), and the sodium/calcium exchanger (NCLX); and many more. Here we provide a brief overview of what is known about crista structure and formation, and discuss mitochondrial function in the context of that structure. We also suggest that mathematical modeling of mitochondria that incorporates accurate information about the organelle's internal architecture can lead to a better understanding of its diverse functions. This article is part of a Special Issue entitled 'Calcium Signalling in Heart'. 23583931 The ATP required for potentiation of skeletal muscle contraction is released via pannexin hemichannels. During repetitive stimulation of skeletal muscle, extracellular ATP levels raise, activating purinergic receptors, increasing Ca(2+) influx, and enhancing contractile force, a response called potentiation. We found that ATP appears to be released through pannexin1 hemichannels (Panx1 HCs). Immunocytochemical analyses and function were consistent with pannexin1 localization to T-tubules intercalated with dihydropyridine and ryanodine receptors in slow (soleus) and fast (extensor digitorum longus, EDL) muscles. Isolated myofibers took up ethidium (Etd(+)) and released small molecules (as ATP) during electrical stimulation. Consistent with two glucose uptake pathways, induced uptake of 2-NBDG, a fluorescent glucose derivative, was decreased by inhibition of HCs or glucose transporter (GLUT4), and blocked by dual blockade. Adult skeletal muscles apparently do not express connexins, making it unlikely that connexin hemichannels contribute to the uptake and release of small molecules. ATP release, Etd(+) uptake, and potentiation induced by repetitive electrical stimulation were blocked by HC blockers and did not occur in muscles of pannexin1 knockout mice. MRS2179, a P2Y1R blocker, prevented potentiation in EDL, but not soleus muscles, suggesting that in fast muscles ATP activates P2Y1 but not P2X receptors. Phosphorylation on Ser and Thr residues of pannexin1 was increased during potentiation, possibly mediating HC opening. Opening of Panx1 HCs during repetitive activation allows efflux of ATP, influx of glucose and possibly Ca(2+) too, which are required for potentiation of contraction. This article is part of a Special Issue entitled 'Connexin based channels'. 23386287 Pairwise comparisons with ordered categorical data. Clinical trials frequently involve pairwise comparisons of different treatments to evaluate their relative efficacy. In this study, we examine methods for conducting pairwise tests of treatments with ordered categorical responses. A modified version of the Wilcoxon-Mann-Whitney test based on a logistic regression model assuming proportional odds is a popular choice for comparing two treatments. This paper discusses the extension of this test to pairwise comparisons involving more than two treatments. However, when the proportional odds assumption is not valid, the Wilcoxon-Mann-Whitney-type test procedure cannot control the overall type I error rate at the prespecified level of significance. We therefore propose a better strategy in which a latent normal model is employed. We presented a simulated comparative study of power and the overall type I error rate to illustrate the superiority of the latent normal model. Examples are also given for illustrative purposes. 23587719 Approximation results for neural network operators activated by sigmoidal functions. In this paper, we study pointwise and uniform convergence, as well as the order of approximation, for a family of linear positive neural network operators activated by certain sigmoidal functions. Only the case of functions of one variable is considered, but it can be expected that our results can be generalized to handle multivariate functions as well. Our approach allows us to extend previously existing results. The order of approximation is studied for functions belonging to suitable Lipschitz classes and using a moment-type approach. The special cases of neural network operators activated by logistic, hyperbolic tangent, and ramp sigmoidal functions are considered. In particular, we show that for C(1)-functions, the order of approximation for our operators with logistic and hyperbolic tangent functions here obtained is higher with respect to that established in some previous papers. The case of quasi-interpolation operators constructed with sigmoidal functions is also considered. 23533289 Knee Derangements: Comparison of Isotropic 3D Fast Spin-Echo, Isotropic 3D Balanced Fast Field-Echo, and Conventional 2D Fast Spin-Echo MR Imaging. Purpose: To compare diagnostic performance, subjective image quality, and artifacts of isotropic three-dimensional (3D) intermediate-weighted (IW) fast spin-echo (SE), isotropic 3D balanced fast field-echo (FFE), and conventional two-dimensional (2D) fast SE 3.0-T MR sequences in evaluation of cartilage, ligaments, menisci, and osseous knee structures in symptomatic patients. Materials and Methods: Institutional review board approval and waiver of informed consent were obtained for this HIPAA-compliant study. One hundred MR studies, each with three data sets (3D IW fast SE, 3D balanced FFE, 2D fast SE), were reviewed retrospectively. Two radiologists independently evaluated images for cartilaginous defects, anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), medial meniscus (MM), lateral meniscus (LM) tears, subchondral bone marrow signal abnormalities, subjective image quality, and image artifacts. Arthroscopic results were the reference standard. Statistical analysis was performed to calculate interobserver agreement and compare diagnostic performance of sequences. Results: Sensitivity and specificity were greater than 85% for all lesions. For cartilaginous defects, sensitivity of 3D IW fast SE was significantly greater than that of 3D balanced FFE (95.5% vs 89.7%). Sensitivity of 3D IW fast SE and 2D fast SE for MM, LM, and ACL tears tended to be greater than that of 3D balanced FFE. IW fast SE had a higher detection rate for subchondral bone marrow signal abnormality than did 3D balanced FFE (34% vs 21%); it also had the best image quality and fewest artifacts, followed by 2D fast SE and 3D balanced FFE. Interobserver agreement was excellent for evaluation of all intraarticular structures (κ = 0.85-1) and good to excellent for detection of subchondral bone marrow signal abnormality (κ = 0.76-0.91). Conclusion: The performance of IW fast SE is superior to that of balanced FFE in evaluation of cartilaginous defects, with no significant difference in performance between 2D fast SE, 3D IW fast SE, and 3D balanced FFE in evaluation of meniscal and ligament tears. Subchondral bone marrow signal abnormality is more easily seen on 3D IW fast SE images, with better subjective image quality and fewer artifacts, than on images obtained with other techniques. © RSNA, 2013. 23772625 miRNAs and HIV: unforeseen determinants of host-pathogen interaction. Our understanding of the complexity of gene regulation has significantly improved in the last decade as the role of small non-coding RNAs, called microRNAs (miRNAs), has been appreciated. These 19-22 nucleotide RNA molecules are critical regulators of mRNA translation and turnover. The miRNAs bind via a protein complex to the 3' untranslated region (3' UTR) of mRNA, ultimately leading to mRNA translational inhibition, degradation, or repression. Although many mechanisms by which human immunodeficiency virus-1 (HIV-1) infection eventually induces catastrophic immune destruction have been elucidated, the important role that miRNAs play in HIV-1 pathogenesis is only now emerging. Accumulating evidence demonstrates that changes to endogenous miRNA levels following infection is important: in maintaining HIV-1 latency in resting CD4(+) T cells, potentially affect immune function via changes to cytokines such as interleukin-2 (IL-2) and IL-10 and may predict disease progression. We review the roles that both viral and host miRNAs play in different cell types and disease conditions that are important in HIV-1 infection and discuss how miRNAs affect key immunomodulatory molecules contributing to immune dysfunction. Further, we discuss whether miRNAs may be used as novel biomarkers in serum and the potential to modulate miRNA levels as a unique approach to combating this pathogen. 23859685 Outpatient antibiotic use and the incidence of acute appendicitis in Finland: a nationwide study from 1990-2008. Abstract Background: The incidence of acute appendicitis (AA) has decreased in Finland. We hypothesized that changing trends in outpatient antibiotic use might explain at least part of this declining incidence of AA. Methods: The number of all patients with AA in Finland was extracted from the national data base from 1990 to 2008. For comparison, the incidence of acute diverticulitis of the colon (AD) was also recorded. All outpatient prescriptions of antibiotics belonging to the major groups of these drugs were also recorded. We used unit root and co-integration analyses for statistical analysis of the data in the study. Results: The incidence of AA in Finland declined from 14.5 to 9.8 per 10,000 inhabitants (32%) and the incidence of AD increased by 47% between 1993 and 2007. The total outpatient use of antibiotics did not increase during this same period, but the use of antibiotics effective widely against colonic pathogens (macrolides, fluoroquinolones, and cephalosporins) increased significantly. No correlation was found between the incidence of AA, that of AD, and the use of different groups of antibiotics. Conclusions: Our nationwide registry study indicated that changes in outpatient antibiotic use do not explain the decreasing trend in AA in Finland. Other factors, such as improved diagnosis of AA, may have some role in the decreasing incidence of AA. 23831800 Anaerobic digestion of different feedstocks: Impact on energetic and environmental balances of biogas process. The possibility of limiting the global warming is strictly linked to the reduction of GHG emissions. Renewable energy both allows reducing emissions and permits to delay fossil fuel depletion. The anaerobic digestion of animal manure and energy crops is a promising way of reducing GHG emissions. In Italy agricultural biogas production was considerably increased; nowadays there are about 520 agricultural biogas plants. The increasing number of biogas plants, especially of those larger than 500kWe (electrical power), involves a high consumption of energy crops, large transport distances of biomass and digestate and difficulties on thermal energy valorization. In this study the energetic (CED) and environmental (GHG emissions) profiles associated with the production of electricity derived from biogas have been identified. Three biogas plants located in Northern Italy have been analyzed. The study has been carried out considering a cradle-to-grave perspective and thus, special attention has been paid on the feedstock production and biogas production process. The influences on the results taking into account different plant sizes and feeding rate has been assessed in detail. Energy analysis was performed using the Cumulative Energy Demand method (CED). The climate change was calculated for a 100-year time frame based on GHG emissions indicated as CO2 equivalents (eq) and defined by the IPCC (2006). In comparison to the fossil reference system, the electricity production using biogas saves GHG emissions from 0.188 to 1.193kgCO2eq per kWhe. Electricity supply from biogas can also contribute to a considerable reduction of the use of fossil energy carriers (from -3.97 to 10.08MJfossil per kWhe). The electricity production from biogas has a big potential for energy savings and reduction of GHG emissions. Efficient utilization of the cogenerated heat can substantially improve the GHG balance of electricity production from biogas. 23845258 Clinical relevance and imaging features of isolated single bundle anterior cruciate tear and single bundle augmentation. The anterior cruciate ligament (ACL) consists of two anatomic and functional bundles, the anteromedial and posterolateral bundle. Depending on the mechanism of injury, there are different injury patterns, demonstrating a wide spectrum of partial ACL tears. Single bundle partial ACL tears can be treated with augmentation. Theoretically, sparing the intact parts of the ACL may increase vascularization and proprioception and may result in better stability and improved clinical outcome for the patient. In this article, we review the anatomy and function of ACL bundles and demonstrate cases of single bundle ACL tear with subsequent augmentation. 23561508 Increased blood-brain barrier vulnerability to systemic inflammation in an Alzheimer disease mouse model. Behavioral and psychological problems are often observed in patients with dementia such as that associated with Alzheimer disease, and these noncognitive symptoms place an extremely heavy burden on the family and caregivers. Although it is well know that these symptoms often are triggered by infection of peripheral organs, the underlying mechanisms for these pathological conditions are still unclear. In this study, using an Alzheimer amyloid precursor protein (APP)-transgenic mouse, we analyzed behavioral changes and brain inflammatory response induced by peripheral administration of lipopolysaccharide. Application of a unique in vivo microdialysis system revealed that the increase in brain inflammatory cytokine (interleukin-6) level was significantly higher in APP-Tg than in wild-type mice after peripheral lipopolysaccharide injection, which was associated with more severe sickness behaviors. The blood-brain barrier became more permeable in APP-Tg mice during peripherally evoked inflammation, suggesting the increased vulnerability of the blood-brain barrier to inflammation in this animal model of Alzheimer's disease. These findings might provide insight into the pathogenesis of noncognitive symptoms in dementia and a basis to develop new therapeutic treatments for them. 23919297 The interaction between human enteroviruses and type I IFN signaling pathway. Abstract Human enteroviruses (HEV), very common and important human pathogens, cause infections in diverse ways. Recently, the large epidemic of HFMD caused by HEV infection became a growing threat to public health in China. As the first line of immune response, the type I interferon (IFN-α/β) pathway plays an essential role in antiviral infection, particularly in limiting both the early and late stages of infection. Because of co-evolution with the host, the viruses have evolved multiple strategies to evade or subvert the host immunity to ensure their survival. In this paper, we systematically reviewed and summarized the interaction between HEV infections and host type I IFN responses. We firstly described the recent findings of HEV recognition and IFN induction, specifically on host pattern-recognition receptors (PRRs) in HEV infection. Then we discussed the antiviral effect of IFN in HEV infection. Finally, we timely summarized the mechanisms of HEV to circumvent the IFN responses. Clarification of the complexity in this battle may provide us new strategies for prevention and antiviral treatment. 23261990 The molecular mystique of tetrodotoxin. In many respects tetrodotoxin (TTX) is the quintessential natural toxin. It is unequivocally toxic to mammals with LD(50) values for mice in the range of 10 μg/kg (intraperitoneal), 16 μg/kg (subcutaneous), and 332 μg/kg (oral) (Kao, 1966). Its biothreat status is recognized by its listing as a "Select Agent" by the US Department of Health and Human Services which includes regulated agents "determined to have the potential to pose a severe threat to both human and animal health" (http://www.selectagents.gov/). It has a well-defined cellular target (i.e., NaV channels) and pharmacological mode of action (i.e., block of nerve and muscle action potentials), and it is an indispensable chemical tool in neuroscience. It is widely distributed in marine and terrestrial ecosystems where it plays a role in the chemical ecology of predator-prey relationships and drives evolutionary selection of TTX-resistance (Hanifin, 2010; Williams, 2010; Zimmer and Ferrer, 2007). Lastly, TTX has acquired a certain mystique in scientific lore attributable to many fascinating aspects of its natural history and molecular interactions as presented in selected summary below. Additional information may be found in other excellent reviews (Fozzard and Lipkind, 2010; Kao, 1966; Lee and Ruben, 2008; Narahashi, 2001, 2008). 23891804 FMRP and myelin protein expression in oligodendrocytes. Fragile X syndrome (FXS) is caused by lack of expression of fragile X mental retardation protein (FMRP), the product of the Fmr1 gene. In many cases FXS is associated with abnormalities in CNS myelination. Although FMRP is expressed in oligodendrocyte progenitor cells and immature oligodendrocytes (OLGs) previous studies have not detected it in mature, myelin-producing OLGs. FMRP represses translation of myelin basic protein (MBP) RNA in vitro and is believed to prevent premature MBP expression in immature OLGs. Lack of FMRP in FXS could lead to premature myelination and/or myelin abnormalities. Here we show that FMRP is expressed in mature, MBP-positive OLGs of rodents and in MBP-positive human OLGs. We confirm that FMRP is a translational repressor of MBP mRNA in vitro, but at concentrations likely too high to be physiologically relevant in vivo. We find MBP expression in cultured Fmr1 KO OLGs to be similar to wild type, and expression of MBP and other myelin proteins in brain homogenates of the Fmr1 KO mouse to be similar to wild type before, during, and after the period of active myelination. These results suggest that while FMRP is expressed in mature OLGs, myelin abnormalities caused by lack of FMRP expression in FXS are not recapitulated in rodents. 23443027 Cellular imaging demonstrates genetic mosaicism in heterozygous carriers of an X-linked ciliopathy gene. X-linked retinitis pigmentosa (XLRP) is the least common genetic type of retinitis pigmentosa; however, it has extremely devastating consequences to patients' activities of daily living. RPGR and RP2 genes expressed in the photoreceptor sensory cilia are predominantly implicated in XLRP; however, the interpretation of genetic mutations and their correlation with clinical phenotypes remain unknown, and the role of these genes in photoreceptor cilia function is not completely elucidated. Therefore, we evaluated structural characteristics in five female obligate carriers of XLRP by using state-of-the-art non-invasive imaging methods, including adaptive optics (AO) scanning laser ophthalmoscopy (SLO). In all five carriers examined, qualitative and quantitative analyses by AO SLO imaging revealed a mosaic pattern of cone disruption, even in the absence of visual symptoms, normal visual acuity and normal macular thickness, on optical coherence tomography and mildly subnormal full-field cone electroretinographic findings. As the technique is sensitive to the level of a single cone, the ability to visualize the cone cells in vivo should be especially useful in other retinal diseases. In addition, further investigation of XLRP carriers may yield insight into how cone structures change over time and ultimately enable understanding of the role of RPGR and RP2 in cone cell survival.European Journal of Human Genetics advance online publication, 27 February 2013; doi:10.1038/ejhg.2013.21. 23747731 Differences in α-β transmembrane domain interactions among integrins enable diverging integrin signaling. Integrins are transmembrane adhesion molecules composed of α and β subunits. In humans, 24 integrins are expressed in a tissue-specific manner. Each integrin plays a specific role within a tissue type to control cell adhesion. We previously found that the degree of transmembrane domain (TMD) interaction between the integrin αIIb and β3 subunits is reversely correlated with the affinity of integrin αIIbβ3 to its ligand. Here, we examined the TMD interactions of various integrins, including α4β1, αLβ2, α5β1, αVβ1, αIIbβ3, and αVβ3. Our findings revealed that the degree of the TMD interactions in integrins α4β1 and αLβ2 expressed in immune cells was low and in integrins αIIbβ3 and αVβ3 expressed in platelets was high, while integrins α5β1 and αVβ1 that are expressed in most adherent cells displayed intermediate TMD interactions. We identified sequence variation within the N-terminal TMD region as a factor responsible for the observed differential degree of TMD interaction among integrins. When the N-terminal interaction that was missing in integrin α5β1 was restored with mutagenesis, the increase in TMD interaction inhibited the outside-in but not inside-out signaling of integrin α5β1 and also accelerated the speed of cell migration. We suggest, therefore, that the degree of TMD interaction is designed to accommodate the specific, desired function of each integrin. 23911710 Staphylococcus aureus lipoteichoic acid inhibits platelet activation and thrombus formation via the Paf receptor. Impaired healing is common in wounds infected with the major human pathogen Staphylococcus aureus, although the underlying mechanisms are poorly understood. Here, we show that S.aureus lipoteichoic acid (LTA) inhibits platelet aggregation caused by physiological agonists and S. aureus and reduced platelet thrombus formation in vitro. The presence of D-alanine on LTA is necessary for the full inhibitory effect. Inhibition of aggregation was blocked using a monoclonal anti-platelet activating factor receptor (PafR) antibody and Ginkgolide B, a well-defined PafR antagonist, demonstrating that the LTA inhibitory signal occurs via PafR. Using a cyclic AMP (cAMP) assay and a western blot for phosphorylated VASP, we determined that cAMP levels increase upon platelet incubation with LTA, an effect which inhibits platelet activation. This was blocked when platelets were preincubated with Ginkgolide B. Furthermore, LTA reduced haemostasis in a mouse tail-bleed assay. 23867143 N,N-Dimethyl-p-toluidine, a Component in Dental Materials, Causes Hematologic Toxic and Carcinogenic Responses in Rodent Model Systems. Because of the potential for exposure to N,N-dimethyl-p-toluidine (DMPT) in medical devices and the lack of toxicity and carcinogenicity information available in the literature, the National Toxicology Program conducted toxicity and carcinogenicity studies of DMPT in male and female F344/N rats and B6C3F1/N mice. In these studies, a treatment-related macrocytic regenerative anemia characterized by increased levels of methemoglobin and Heinz body formation developed within a few weeks of DMPT exposure in rats and mice. DMPT induced nasal cavity, splenic, and liver toxicity in rats and mice at 3 months and 2 years. DMPT carcinogenic effects were seen in the liver of male and female rats and mice, the nasal cavity of male and female rats, and the lung and forestomach of female mice. In rodents, DMPT is distributed to many of the sites where toxic and carcinogenic effects occurred. DMPT-induced oxidative damage at these target sites may be one mechanism for the treatment-related lesions. Methemoglobinemia, as seen in these DMPT studies, is caused by oxidation of the heme moiety, and this end point served as an early alert for other target organ toxicities and carcinogenic responses that followed with longer term exposure. 23888880 ALS-associated protein FIG4 is localized in Pick and Lewy bodies, and also neuronal nuclear inclusions, in polyglutamine and intranuclear inclusion body diseases. FIG4 is a phosphatase that regulates intracellular vesicle trafficking along the endosomal-lysosomal pathway. Mutations of FIG4 lead to the development of Charcot-Marie-Tooth disease type 4J and amyotrophic lateral sclerosis (ALS). Moreover, ALS-associated proteins (transactivation response DNA protein 43 (TDP-43), fused in sarcoma (FUS), optineurin, ubiquilin-2, charged mutivesicular body protein 2b (CHMP2B) and valosin-containing protein) are involved in inclusion body formation in several neurodegenerative diseases. Using immunohistochemistry, we examined the brains and spinal cords of patients with various neurodegenerative diseases, including sporadic TDP-43 proteinopathy (ALS and frontotemporal lobar degeneration). TDP-43 proteinopathy demonstrated no FIG4 immunoreactivity in neuronal inclusions. However, FIG4 immunoreactivity was present in Pick bodies in Pick's disease, Lewy bodies in Parkinson's disease and dementia with Lewy bodies, neuronal nuclear inclusions in polyglutamine and intranuclear inclusion body diseases, and Marinesco and Hirano bodies in aged control subjects. These findings suggest that FIG4 is not incorporated in TDP-43 inclusions and that it may have a common role in the formation or degradation of neuronal cytoplasmic and nuclear inclusions in several neurodegenerative diseases. 23913799 Clinical presentation and early evolution of spastic ataxia of Charlevoix-Saguenay. Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an increasingly recognized form of spastic ataxia worldwide, but early diagnosis remains a challenge. We reviewed the initial presentation (n = 40) and early clinical evolution (n = 50) of a large ARSACS cohort that was followed at the Saguenay Neuromuscular clinic. The average age at presentation was 3.41 ± 1.55 years. Increased deep tendon reflexes were more common than spasticity initially, and the neuropathy only became apparent clinically in the second decade. Despite a homogeneous genetic background, some patients showed no signs of neuropathy or spasticity by the age of 18 years. At presentation, ARSACS lacks certain features that are considered typical in adults after years of evolution. Considering that ARSACS is probably under-diagnosed, it should be included in the differential diagnosis of early onset ataxias with or without pyramidal features and is worthwhile to consider in older patients, even when some features are absent. © 2013 Movement Disorder Society. 23872044 Omega-3 fatty acids can reverse the long-term deficits in hippocampal synaptic plasticity caused by prenatal ethanol exposure. Fetal alcohol spectrum disorders result in long-lasting neurological deficits including decreases in synaptic plasticity and deficits in learning and memory. In this study we examined the effects of prenatal ethanol exposure on hippocampal synaptic plasticity in male and female Sprague-Dawley rats. Furthermore, we looked at the capacity for postnatal dietary intervention to rescue deficits in synaptic plasticity. Animals were fed an omega-3 enriched diet from birth until adulthood (PND55-70) and in vivo electrophysiology was performed by stimulating the medial perforant path input to the dentate gyrus and recording field excitatory post-synaptic potentials. LTP was induced by administering bursts of five 400Hz pulses as a theta-patterned train of stimuli (200ms inter-burst interval). Ethanol-exposed adult males, but not females, exhibited a significant reduction in LTP. This deficit in male animals was completely reversed with an omega-3 enriched diet. These results demonstrate that omega-3 fatty acids can have benefits following prenatal neuropathological insults and may be a viable option for alleviating some of the neurological deficits associated with FASD. 23678928 The shale gas boom and the need for rational policy. High-volume, slick water hydraulic fracturing of shale relies on pumping millions of gallons of surface water laced with toxic chemicals and sand under high pressure to create fractures to release the flow of gas. The process, however, has the potential to cause serious and irreparable damage to the environment and the potential for harm to human and animal health. At issue is how society should form appropriate policy in the absence of well-designed epidemiological studies and health impact assessments. The issue is fraught with environmental, economic, and health implications, and federal and state governments must establish detailed safeguards and ensure regulatory oversight, both of which are presently lacking in states where hydraulic fracturing is allowed. 23885666 Computational fluid dynamic simulation of axial and radial flow membrane chromatography: Mechanisms of non-ideality and validation of the zonal rate model. Membrane chromatography (MC) is increasingly being used as a purification platform for large biomolecules due to higher operational flow rates. The zonal rate model (ZRM) has previously been applied to accurately characterize the hydrodynamic behavior in commercial MC capsules at different configurations and scales. Explorations of capsule size, geometry and operating conditions using the model and experiment were used to identify possible causes of inhomogeneous flow and their contributions to band broadening. In the present study, the hydrodynamics within membrane chromatography capsules are more rigorously investigated by computational fluid dynamics (CFD). The CFD models are defined according to precisely measured capsule geometries in order to avoid the estimation of geometry related model parameters. In addition to validating the assumptions and hypotheses regarding non-ideal flow mechanisms encoded in the ZRM, we show that CFD simulations can be used to mechanistically understand and predict non-binding breakthrough curves without need for estimation of any parameters. When applied to a small-scale axial flow MC capsules, CFD simulations identify non-ideal flows in the distribution (hold-up) volumes upstream and downstream of the membrane stack as the major source of band broadening. For the large-scale radial flow capsule, the CFD model quantitatively predicts breakthrough data using binding parameters independently determined using the small-scale axial flow capsule, identifying structural irregularities within the membrane pleats as an important source of band broadening. The modeling and parameter determination scheme described here therefore facilitates a holistic mechanistic-based method for model based scale-up, obviating the need of performing expensive large-scale experiments under binding conditions. As the CFD model described provides a rich mechanistic analysis of membrane chromatography systems and the ability to explore operational space, but requires detailed knowledge of internal capsule geometries and has much greater computational requirements, it is complementary to the previously described strengths and uses of the ZRM for process analysis and design. 23820623 Dysfunctional mitochondrial bioenergetics and oxidative stress in Akita+/Ins2-derived β-cells. Insulin release from pancreatic β-cells plays a critical role in blood glucose homeostasis, and β-cell dysfunction leads to the development of diabetes mellitus. In cases of monogenic Type 1 diabetes mellitus (T1DM) which involve mutations in the insulin gene we hypothesized misfolding of insulin could result in endoplasmic reticulum (ER) stress, oxidant production, and mitochondrial damage. To address this, we used the Akita(+/Ins2) Type 1 diabetes mellitus (T1DM) model in which misfolding of the insulin 2 gene leads to ER-stress mediated β-cell death, and thapsigargin to induce ER stress in two different β-cell lines and in intact mouse islets. Using transformed pancreatic β-cell lines generated from wild type Ins2(+/+) (WT) and Akita(+/Ins2) mice we evaluated cellular bioenergetics, oxidative stress, mitochondrial protein levels, and autophagic flux to determine whether changes in these processes contribute to β-cell dysfunction. In addition, we induced ER stress pharmacologically using thapsigargin in WT β-cells, INS-1 cells, and intact mouse islets to examine the effects of ER stress on mitochondrial function. Our data reveal that Akita(+/Ins2) derived β-cells have increased mitochondrial dysfunction, oxidant production, mtDNA damage, and alterations in mitochondrial protein levels which are not corrected by autophagy. Together, these findings suggest that deterioration in mitochondrial function due to an oxidative environment and ER stress contributes to β-cell dysfunction and could contribute to Type 1 diabetes in which mutations in insulin occur. 23898182 A functional genomic perspective on human well-being. To identify molecular mechanisms underlying the prospective health advantages associated with psychological well-being, we analyzed leukocyte basal gene expression profiles in 80 healthy adults who were assessed for hedonic and eudaimonic well-being, as well as potentially confounded negative psychological and behavioral factors. Hedonic and eudaimonic well-being showed similar affective correlates but highly divergent transcriptome profiles. Peripheral blood mononuclear cells from people with high levels of hedonic well-being showed up-regulated expression of a stress-related conserved transcriptional response to adversity (CTRA) involving increased expression of proinflammatory genes and decreased expression of genes involved in antibody synthesis and type I IFN response. In contrast, high levels of eudaimonic well-being were associated with CTRA down-regulation. Promoter-based bioinformatics implicated distinct patterns of transcription factor activity in structuring the observed differences in gene expression associated with eudaimonic well-being (reduced NF-κB and AP-1 signaling and increased IRF and STAT signaling). Transcript origin analysis identified monocytes, plasmacytoid dendritic cells, and B lymphocytes as primary cellular mediators of these dynamics. The finding that hedonic and eudaimonic well-being engage distinct gene regulatory programs despite their similar effects on total well-being and depressive symptoms implies that the human genome may be more sensitive to qualitative variations in well-being than are our conscious affective experiences. 23932263 Novel Technique for the Preparation of Corneal Grafts for Descemet Membrane Endothelial Keratoplasty. To report a simple novel technique to facilitate preparation of Descemet membrane grafts for Descemet membrane endothelial keratoplasty (DMEK). Laboratory investigation and retrospective, single-center, consecutive case series. Preparation of the endothelial graft is performed on an artificial anterior chamber, endothelial side up. After an incomplete circular superficial trephination, we describe a simple technique using a 27 gauge cannula to detach the Descemet membrane (DM). Endothelial cell density (ECD) was measured before dissection on 12 human corneas for research and 3 days after storage in organ culture. Histologic and electron microscopy analysis were performed. A DMEK was performed in 50 patients with Fuchs dystrophy. Visual acuity and ECD were evaluated 2 and 6 months after surgery. ECD was 2765 ± 256 cells/mm(2) on corneas for research before dissection and 2651 ± 305 cells/mm(2) after 3 days in organ culture (P < .01). Histologic and electronic sections confirm that the cleavage was between DM and posterior stroma. Clinically, preparation of 2 corneas from a single donor was unsuccessful; 48 corneas were clear at 2 months and 47 at 6 months. At 2 months 77% of the patients had recovered a visual acuity of at least 20/30. At 6 months, 91.5% of the patients had a visual acuity of at least 20/30. ECD was 2656 ± 28 cells/mm(2) (range: 2450-3100 cells/mm(2)) preoperatively, 1797 ± 41 cells/mm(2) (range: 1100-2700 cells/mm(2)) at 2 months, and 1658 ± 43 cells/mm(2) (range: 900-2600 cells/mm(2)) at 6 months. We report here a reliable and efficient technique for the preparation of pure Descemet membrane grafts. 23868527 Home and work neighbourhood environments in relation to body mass index: the Multi-Ethnic Study of Atherosclerosis (MESA). Little is known about the neighbourhood characteristics of workplaces, the extent to which they are independently and synergistically correlated with residential environments, and their impact on health. This study investigated cross-sectional relationships between home and workplace neighbourhood environments with body mass index (BMI) in 1503 working participants of the Multi-Ethnic Study of Atherosclerosis with mean age 59.6 (SD=7.4). Neighbourhood features were socioeconomic status (SES), social environment (aesthetic quality, safety and social cohesion) and physical environment (walking environment, recreational facilities and food stores) derived from census data, locational data on businesses and survey data. Paired t tests and correlations compared environments overall and by distance between locations. Cross-classified multilevel models estimated associations with BMI. Home neighbourhoods had more favourable social environments while workplaces had more favourable SES and physical environments. Workplace and home measures were correlated (0.39-0.70), and differences between home and workplaces were larger as distance increased. Associations between BMI and neighbourhood SES and recreational facilities were stronger for home environment (p≤0.05) but did not significantly differ for healthy food, safety or social cohesion. Healthy food availability at home and work appeared to act synergistically (interaction p=0.01). Consideration of workplace environment may enhance our understanding of how place affects BMI. 23730821 Childhood cancer survivors' school (re)entry: Australian parents' perceptions. Starting or returning to school after intense medical treatment can be academically and socially challenging for childhood cancer survivors. This study aimed to evaluate the school (re)entry experience of children who had recently completed cancer treatment. Forty-two semi-structured telephone interviews were conducted to explore parents' perceptions of their child's (re)entry to school after completing treatment (23 mothers, 19 fathers, parent mean age 39.5 years; child mean age 7.76 years). Interviews were analysed using the framework of Miles and Huberman and emergent themes were organised using QSR NVivo8. Parents closely monitored their child's school (re)entry and fostered close relationships with their child's teacher to ensure swift communication of concerns should they arise. The most commonly reported difficulty related to aspects of peer socialisation; survivors either displayed a limited understanding of social rules such as turn taking, or related more to older children or teachers relative to their peers. Additionally, parents placed a strong emphasis on their child's overall personal development, above academic achievement alone. Improved parent, clinician and teacher awareness of the importance of continued peer socialisation during the treatment period is recommended in order to limit the ongoing ramifications this may have on school (re)entry post-treatment completion. 23894031 Protein nanomachines assembly modes: cell-free expression and biochip perspectives. Large macromolecular assemblies are widespread in all cell types with diverse structural and functional roles. Whether localized to membranes, nuclei, or cytoplasm, multimeric protein-nucleic acid complexes may be viewed as sophisticated nanomachines, an inspiration to chemical design. The formation of large biological assemblies follows a complex and hierarchical self-assembly process via ordered molecular recognition events. Serving a paradigm for biological assembly, extensive past studies of T4 bacteriophage and bacterial ribosomes by many groups have been revealing distinct design strategies, yet these two very different multimeric complexes share common mechanistic motifs. An emerging biochip approach highlights two conceptual notions to promote the study of assembly pathways: cell-free expression provides coupling between synthesis and assembly; surface anchoring allows high-resolution imaging of structural intermediates and opens up opportunities for rewiring a network by defining unnatural scaffolds for synthetic design applications. Conflict of interest: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website. 23556333 Dose-dependent pharmacokinetics of bulleyaconitine A in rats. This study was conducted to determine the pharmacokinetic characteristics of bulleyaconitine A (BLA) after oral gavage and intravenous administration of BLA at a single dose of 0.04, 0.12, 0.36 mg/kg (oral) or 0.02 mg/kg (i.v.) in male Sprague-Dawley rats. Plasma concentration profiles were analysed using a non-compartmental pharmacokinetic method. Following i.v. 0.02 mg/kg and oral administration 0.04, 0.12 or 0.36 mg/kg, the geometric mean Cmax values were 19.97, 2.11, 5.11 and 11.47 ng/ml, respectively; the corresponding geometric mean AUC(0-t) values were 10.50, 3.19, 9.59 and 18.10 ng x h/ml, respectively. The median Tmax values were 0.033, 0.167, 0.167 and 0.167 h, respectively. The terminal elimination half-lives (t1/2) were 1.23, 2.48, 1.93 and 2.17h, respectively. The results showed that Cmax and AUC(0-t) increased with increasing doses of BLA. The increase in exposure with increasing dose was lower than expected under conditions of strict proportionality. 23908368 Family socioeconomic status, household tobacco smoke, and asthma attack among children below 12 years of age: Gender differences. Studies have demonstrated the negative impact of environmental tobacco smoke (ETS) or parental cigarette smoking on pediatric asthma. Little is known, however, regarding whether there is a gender difference in the effect of household ETS on pediatric asthma. Using a nationwide survey in Taiwan, we examined the relationship between asthma prevalence in the past year and household ETS among children below 12 years of age (N = 3761). We used multivariate regression models to assess odds ratios (ORs) and 95% confidence intervals (CIs) for the association of household ETS and asthma attacks by gender. In about 3% of the sample, parents reported that their children had an asthma attack in the past year, confirmed by physicians. Multivariate logistic regression revealed that household ETS predicted asthma attacks for girls (OR = 3.11, 95%CI = 1.24-7.76) but not for boys. Father's education was significantly associated with asthma attack for both girls (OR = 1.24, 95%CI = 1.04-1.47) and boys (OR = 1.15, 95%CI = 1.05-1.26). Girls with lower family income were more likely to have had an asthma attack in the last year (OR = .48, 95%CI = .27-.87). The impact of household ETS and family socioeconomic status on asthma attacks differs by gender among children below 12 years. 23576005 Time-resolved flavin adenine dinucleotide fluorescence study of the interaction between immobilized glucose oxidase and glucose. Time-resolved fluorescence experiments have shown that flavin adenine dinucleotide (FAD) fluorescence emission of sol-gel immobilized glucose oxidase (GOD) exhibits a three-exponential decaying behaviour characterized by long- (about 2.0-3.0 ns), intermediate- (about 300 ps) and short- (less than 10 ps) lifetime, each one being characteristic of a peculiar conformational state of the FAD structure. In the present work time-resolved fluorescence is used to monitor FAD signals in the time interval immediately following the addition of glucose at various concentrations in order to detect the conformational changes occurring during the interaction between sol-gel immobilized GOD and glucose. The analysis of time-dependent fluorescence emission signal has shown that the FAD conformational state changes during the process from a configuration with a prevalence of the state characterized by the long lifetime to a configuration with increased contribution from the process with the intermediate lifetime. The time needed to complete this configuration change decreases with the concentration of added glucose. The results here reported indicate that time-resoled fluorescence can be extremely useful for a better understanding of solid phase biocatalysis that is particularly important in light of their clinical and biotechnological applications. 23524644 Psychosocial stressors and health behaviors: examining sleep, sedentary behaviors, and physical activity in a low-income pediatric sample. Objective. To better understand the relationship between psychosocial stressors and health behaviors in a low-income pediatric sample. Method. Participants were 122 children (8-11 years old, 53.3% female) and their parents recruited from a low-income primary care clinic. Measures assessed child stressors and parental financial strain, and child sleep problems, sedentary behaviors, and physical activity. Results. Parental financial strain and child stressors were independently associated with sleep problems and sedentary behaviors, controlling for age and gender. Though stressors in general accounted for significant variance in physical activity, results indicate a complex relationship as parental financial strain predicted more physical activity and child stressors predicted less physical activity. Conclusion. Stressors are associated with adverse pediatric health behaviors. Consequently, chronic stressors could negatively affect long-term health, and interventions targeting stressors and health behaviors are indicated. Pediatric health care providers play a key role in promoting health behaviors among youth experiencing significant psychosocial stressors. 23862961 Evolution of conductive network and properties of nanorod∕polymer composite under tensile strain. In this work, the conductive network, probability, and percolation threshold of nanorod∕polymer composites under tensile strain are investigated using the molecular dynamics simulation. The internal interactions, including polymer-polymer, polymer-nanorod, and nanorod-nanorod interactions, are taken into account in simulations. In particular, the influence of polymer induced depletion force on the orientation of nanorods is analyzed. Under a constant strain, the conductive stability firstly declines and then rises with the increasing concentration of fillers, and the minimum corresponds to the percolation threshold. As strain increases, the result exhibits a strong anisotropy in the stability of conductive property. 23427814 Decompression-induced crystal polymorphism in a room-temperature ionic liquid, N,N-diethyl-N-methyl-N-(2-methoxyethyl) ammonium tetrafluoroborate. We explore the phase behavior of room-temperature ionic liquids (RTILs) compressed under high pressure to determine whether they crystallize or hold a liquid state. RTILs have attractive supercooling properties compared with ordinary molecular liquids, which easily become a glassy state without crystallizing at ambient pressure. Thus, phase behavior under extreme stress, such as pressure, might yield interesting results. Here, we show that N,N-diethyl-N-methyl-N-(2-methoxyethyl) ammonium tetrafluoroborate ([DEME][BF4]) could be crystallized upon compression, but it usually formed a superpressed liquid. Alternatively, unusual crystallization could be induced by releasing the pressure on the superpressed liquid. Notably, crystal polymorphism was observed in the decompression process. These facts along with visual observations indicate the possibility of [DEME][BF4] serving as a superpressurized glass. Our findings may facilitate the development of a new range of applications for RTILs that have undergone high-pressure recrystallization. 23684370 Mesencephalic area measured by transcranial sonography in the differential diagnosis of parkinsonism. Transcranial B-mode sonography (TCS) has become an important tool in the differential diagnosis of parkinsonism given that current technology enables an adequate assessment of brain structures. In this study we aimed at evaluating the usefulness of midbrain area measured by TCS in the differential diagnosis between Parkinson's Disease (PD) and Progressive Supranuclear Palsy (PSP). Patients with a diagnosis of PD or PSP according to current clinical criteria were recruited. PSP patients were classified as Richardson's syndrome and PSP-parkinsonism. TCS was performed and the mesencephalic area and third ventricle width were measured offline by an examiner blinded to clinical diagnosis. TCS was performed in 60 patients (75% PD, 25% PSP). Eight patients (13,3%) had inadequate acoustic window. Patients with PSP had a smaller mesencephalic area (3.58 cm(2) vs 5.28 cm(2), p < 0.001). A mesencephalic area ≥4.27 cm(2) discriminates PD from PSP with a positive predictive value 100%. Patients with PSP also had a higher third ventricle diameter (8.84 mm vs 5.11 mm, p < 0.001). Within the PSP group patients with Richardson's syndrome had a wider third ventricle than patients with PSP-Parkinsonism phenotype (9.57 mm vs 7 mm, p = 0.01), but no differences were found in the mesencephalic area between both phenotypes. Measurement of the mesencephalic area and the third ventricle width by TCS is a non-invasive, easily accessible technique that is useful in the differential diagnosis between PD and PSP, at least in the late stages of the disease. 23918650 Screening of multiple drugs of abuse and metabolites in urine using LC/MS/MS with polarity switching electrospray ionization. A recent trend in urine drug testing in forensic and clinical toxicology has been the simultaneous determination of different chemical groups of target drugs, which are selected based on their local popularity. Rapid multiple drug analysis, made possible by the use of liquid chromatography-tandem mass spectrometry (LC/MS/MS), has become more widely used, especially in workplace drug testing. Therefore, in the present study, a method for simultaneously analyzing 35 drugs of abuse and relevant metabolites that are most prevalent in Korea, using LC/MS/MS with polarity switching electrospray ionization, was developed and validated. The drugs and metabolites in urine were extracted by using mixed mode strong cation exchange polymeric solid phase extraction cartridges after enzymatic hydrolysis and were then injected into the LC/MS/MS system. The validation results for selectivity, linearity, intra- and inter-assay precision and accuracy for this method were satisfactory, while the results for matrix effects and recovery showed significant variance among the urine samples from different sources. The limits of detection ranged from 0.1 to 10 ng/ml and the limits of quantification were from 1 to 10 ng/ml. To reduce the matrix effects in authentic samples, two different quantitative approaches were compared: quantification using calibration standards prepared by the drug-free pooled urine matrix and quantification using the standard addition. Of these, the latter method was found to be the most suitable. The method developed in this study will be very useful for forensic and clinical toxicology laboratories to adopt for monitoring the inappropriate use of controlled drugs. 23558105 Early visual learning induces long-lasting connectivity changes during rest in the human brain. Spontaneous fluctuations in resting state activity can change in response to experience-dependent plasticity and learning. Visual learning is fast and can be elicited in an MRI scanner. Here, we showed that a random dot motion coherence task can be learned within one training session. While the task activated primarily visual and parietal brain areas, learning related changes in neural activity were observed in the hippocampus. Crucially, even this rapid learning affected resting state dynamics both immediately after the learning and 24h later. Specifically, the hippocampus changed its coupling with the striatum, in a way that was best explained as a consolidation of early learning related changes. Our findings suggest that long-lasting changes in neuronal coupling are accompanied by changes in resting state activity. 23933073 Human defined antigenic region on the nucleoprotein of Crimean-Congo hemorrhagic fever virus identified using truncated proteins and a bioinformatics approach. Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne viral zoonosis widely distributed in Africa, Asia and eastern Europe. In this study, amino acid sequence data for the CCHFV nucleoprotein (NP) was used to identify potential linear epitopic regions which were subsequently included in the design of large and small truncated recombinant NP antigens and peptide libraries. Two truncated recombinant CCHFV NP antigens were prepared based on results of prediction studies to include epitopic regions and exclude hydrophobic regions that could influence protein expression and solubility. Serum samples were collected from acute and convalescent patients. An IgG antibody response was detected in 16/16 samples tested using the large recombinant NP-based ELISA and in 2/16 using the small recombinant NP-based ELISA. A total of 60 peptides covering predicted epitopic regions of the NP were synthesized and peptide NRGGDENPRGPVSR at amino acid position 182-195, reacted with 13/16 human serum samples. In summary, functional assays are required to determine the biological activity of predicted epitopes for development of peptide based assays for antibody detection. Bacterially expressed complete NP antigens have previously been shown to be useful tools for antibody detection. Truncation of the antigen to remove the hydrophobic C terminus had no impact on the ability of the antigen to detect IgG antibody in human sera. The results indicate that the region from amino acids 123 to 396 includes a highly antigenic region of the NP with application in development of antibody detection assays. 23815358 Metal nanoparticle-functionalized DNA tweezers: from mechanically programmed nanostructures to switchable fluorescence properties. DNA tweezers are modified with two 10-nm sized Au NPs and one 5-nm sized Au NP. Upon treatment of the tweezers with fuel and antifuel nucleic acid strands, the switchable closure and opening of the tweezers proceed, leading to the control of programmed nanostructures of the tethered NPs. The tweezers are further modified with a single 10-nm sized nanoparticle, and a fluorophore unit (Cy3), positioned at different distinct sites of the tweezers. The reversible and cyclic fluorescence quenching or fluorescence enhancement phenomena, upon the dynamic opening/closure of the different tweezers, are demonstrated. 23949975 Effects of preventive home visits on health care costs for ambulatory frail elders: a randomized controlled trial. Reducing health care costs through preventive geriatric care has become a high priority in Japan. We analyzed data from a randomized controlled trial to examine the effects of a preventive home visit program on health care costs among ambulatory frail elders. Structured preventive home visits by nurses or care managers were provided to the visit group every 6 months over 2 years. The enrolled participants (N = 323) were randomly assigned to either the visit group (N = 161) or the control group (N = 162). We analyzed the health care costs, including the costs for hospitalizations and outpatient clinic utilization for participants who had health care insurance from the local government (N = 307). The visit group included 154 individuals in the visit group and 153 people in the control group. Total health care costs over the study period were not significantly different between groups, but at most monthly time points costs and those for outpatient clinic utilization in the visit group were lower than those in the control group. Hospitalizations, which accounted for more than ¥500,000 JPY per month, were less likely to occur more often among participants in the visit group (N = 71) than in the control group (N = 113) (OR = 0.63; p = 0.002). These results suggest that a preventive home visit program may reduce monthly health care costs, primarily by reducing hospitalization costs. 23806840 The neural basis of implicit learning and memory: A review of neuropsychological and neuroimaging research. Memory systems research has typically described the different types of long-term memory in the brain as either declarative versus non-declarative or implicit versus explicit. These descriptions reflect the difference between declarative, conscious, and explicit memory that is dependent on the medial temporal lobe (MTL) memory system, and all other expressions of learning and memory. The other type of memory is generally defined by an absence: either the lack of dependence on the MTL memory system (nondeclarative) or the lack of conscious awareness of the information acquired (implicit). However, definition by absence is inherently underspecified and leaves open questions of how this type of memory operates, its neural basis, and how it differs from explicit, declarative memory. Drawing on a variety of studies of implicit learning that have attempted to identify the neural correlates of implicit learning using functional neuroimaging and neuropsychology, a theory of implicit memory is presented that describes it as a form of general plasticity within processing networks that adaptively improve function via experience. Under this model, implicit memory will not appear as a single, coherent, alternative memory system but will instead be manifested as a principle of improvement from experience based on widespread mechanisms of cortical plasticity. The implications of this characterization for understanding the role of implicit learning in complex cognitive processes and the effects of interactions between types of memory will be discussed for examples within and outside the psychology laboratory. 23863152 Regulation of insulin receptor substrate-1 by mTORC2 (mammalian target of rapamycin complex 2). mTOR (mammalian target of rapamycin) responds to the presence of nutrients, energy and growth factors to link cellular metabolism, growth and proliferation. The rapamycin-sensitive mTORC (mTOR complex) 1 activates the translational regulator S6K (S6 kinase), leading to increased protein synthesis in the presence of nutrients. On the other hand, the rapamycin-insensitive mTORC2 responds to the presence of growth factors such as insulin by phosphorylating Akt to promote its maturation and allosteric activation. We recently found that mTORC2 can also regulate insulin signalling at the level of IRS-1 (insulin receptor substrate-1). Whereas mTORC1 promotes IRS-1 serine phosphorylation that is linked to IRS-1 down-regulation, we uncovered that mTORC2 mediates its degradation. In mTORC2-disrupted cells, inactive IRS-1 accumulated despite undergoing phosphorylation at the mTORC1-mediated serine sites. Defective IRS-1 degradation was due to attenuated expression of the CUL7 (Cullin 7) ubiquitin ligase substrate-targeting sub-unit Fbw8. mTORC2 and Fbw8 co-localize at the membrane where mTORC2 phosphorylates Ser86 to stabilize Fbw8 and promotes its cytosolic localization upon insulin stimulation. Under conditions of chronic insulin exposure, inactive serine-phosphorylated IRS-1 and Fbw8 co-localize to the cytosol where the former becomes ubiquitylated via CUL7/Fbw8. Thus mTORC2 negatively feeds back to IRS-1 via control of Fbw8 stability and localization. Our findings reveal that, in addition to persistent mTORC1 signalling, increased mTORC2 signals can promote insulin resistance due to mTORC2-mediated degradation of IRS-1. 23771484 Brain injury and development in newborns with critical congenital heart disease. To determine the relationship between radiologically identifiable brain injuries and delayed brain development as reflected by brain metabolic and microstructural integrity. Term newborns with congenital heart disease (CHD) (120 preoperatively and 104 postoperatively) were studied with MRI to determine brain injury severity (BIS), microstructure reflected by fractional anisotropy (FA) and average diffusivity (Dav), and metabolism reflected by N-acetylaspartate (NAA)/choline (Cho) and lactate/Cho. Brain development is characterized by increasing NAA/Cho and white matter FA, and by decreasing Dav and lactate/Cho. Newly acquired brain injury was common (41% preoperative, 30% postoperative). Lower white matter FA (p = 0.005) and lower NAA/Cho (p = 0.01) were associated with increasing preoperative BIS. Higher neonatal illness severity scores (p = 0.03), lower preoperative oxygen saturation (p = 0.002), hypotension (p < 0.001), and septostomy (p = 0.002) were also predictive of higher preoperative BIS. Preoperative FA, Dav, and NAA/Cho did not predict new postoperative BIS. Increasing preoperative BIS predicted higher postoperative Dav (p = 0.002) and lactate/Cho (p = 0.008). Within the postoperative scan, new brain injuries were associated with lower white matter FA (p = 0.04). Postoperative BIS (new lesions) was associated with lower postoperative systolic (p = 0.03) and mean (p = 0.05) blood pressures. Brain injuries in newborns with CHD are strongly related to abnormalities of brain microstructural and metabolic brain development, especially preoperatively. Both newly acquired preoperative and postoperative brain injuries are related to potentially modifiable clinical risk factors. 23896942 The efficacy and safety of mirabegron in treating OAB: a systematic review and meta-analysis of phase III trials. Mirabegron, a potent and selective β3-adrenoceptor agonist, has been developed for the treatment of overactive bladder (OAB). We carried out a systematic review and meta-analysis to assess the efficacy and safety of the drug for treating OAB. A literature review was performed to identify all published randomized double-blind, placebo-controlled phase III trials of mirabegron for the treatment of OAB. The search included the following databases: MEDLINE, EMBASE and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated. A systematic review and meta-analysis of phase III trials were conducted. Four publications involving a total of 5,761 patients were used in the analysis, including four phase III RCTs that compared mirabegron with placebo. We found that mirabegron was effective in treating OAB in our meta-analysis. Co-primary efficacy end points: the mean number of incontinence episodes per 24 h (the standardized mean difference (SMD) = -0.44, 95 % confidence interval (CI) -0.59 to -0.29, p < 0.00001); the mean number of micturitions per 24 h (SMD = -0.62, 95 % CI -0.80 to -0.45, p < 0.00001) and key secondary efficacy end points: mean volume voided per micturition; mean number of urgency episodes per 24 h indicated that mirabegron was more effective than the placebo. Safety assessments included common treatment-emergent adverse events (TEAEs) [OR 1.10, 95 % CI 0.93-1.31, p = 0.25), hypertension, cardiac arrhythmia TEAEs, urinary retention and discontinuations due to adverse event indicated that mirabegron was well tolerated. This meta-analysis indicates that mirabegron to be an effective and safe treatment for OAB symptoms with a low occurrence of side effects. It offers promise as an effective oral agent for the treatment of OAB with a distinct efficacy/tolerability balance. 23615803 Behavioral sensitivity to broadband binaural localization cues in the ferret. Although the ferret has become an important model species for studying both fundamental and clinical aspects of spatial hearing, previous behavioral work has focused on studies of sound localization and spatial release from masking in the free field. This makes it difficult to tease apart the role played by different spatial cues. In humans and other species, interaural time differences (ITDs) and interaural level differences (ILDs) play a critical role in sound localization in the azimuthal plane and also facilitate sound source separation in noisy environments. In this study, we used a range of broadband noise stimuli presented via customized earphones to measure ITD and ILD sensitivity in the ferret. Our behavioral data show that ferrets are extremely sensitive to changes in either binaural cue, with levels of performance approximating that found in humans. The measured thresholds were relatively stable despite extensive and prolonged (>16 weeks) testing on ITD and ILD tasks with broadband stimuli. For both cues, sensitivity was reduced at shorter durations. In addition, subtle effects of changing the stimulus envelope were observed on ITD, but not ILD, thresholds. Sensitivity to these cues also differed in other ways. Whereas ILD sensitivity was unaffected by changes in average binaural level or interaural correlation, the same manipulations produced much larger effects on ITD sensitivity, with thresholds declining when either of these parameters was reduced. The binaural sensitivity measured in this study can largely account for the ability of ferrets to localize broadband stimuli in the azimuthal plane. Our results are also broadly consistent with data from humans and confirm the ferret as an excellent experimental model for studying spatial hearing. 23958260 Plasma levels of cathepsins L, K, and V and risks of abdominal aortic aneurysms: A randomized population-based study. Cathepsin L (CatL), cathepsin K (CatK), and cathepsin V (CatV) are potent elastases implicated in human arterial wall remodeling. Whether plasma levels of these cathepsins are altered in patients with abdominal aortic aneurysms (AAAs) remains unknown. Plasma samples were collected from 476 male AAA patients and 200 age-matched male controls to determine CatL, CatK, and CatV levels by ELISA. Student's t-test demonstrated significantly higher plasma CatL levels in AAA patients than in controls (P < 0.0001), whereas CatK and CatV levels were lower in AAA patients than in controls (P = 0.052, P = 0.025). ROC curve analysis confirmed higher plasma CatL levels in AAA patients than in controls (P < 0.001). As potential confounders, current smoking and use of angiotensin-converting enzyme (ACE) inhibitors, aspirin, clopidogrel, and statins associated with significantly increased plasma CatL. Pearson's correlation test demonstrated that plasma CatL associated positively with CatS (r = 0.43, P < 0.0001), body-mass index (BMI) (r = 0.07, P = 0.047) and maximal aortic diameter (r = 0.29, P < 0.001), and negatively with lowest measured ankle-brachial index (ABI) (r = -0.22, P < 0.001). Plasma CatL remained associated positively with CatS (r = 0.43, P < 0.0001) and aortic diameter (r = 0.212, P < 0.001) and negatively with ABI (r = -0.10, P = 0.011) after adjusting for the aforementioned potential confounders in a partial correlation analysis. Multivariate logistic regression analysis indicated that plasma CatL was a risk factor of AAA before (odds ratio [OR] = 3.04, P < 0.001) and after (OR = 2.42, P < 0.001) the same confounder adjustment. Correlation of plasma CatL levels with aortic diameter and the lowest ABI suggest that this cysteinyl protease plays a detrimental role in the pathogenesis of human peripheral arterial diseases and AAAs. 23908427 A new radiological method to detect dorsally penetrating screws when using volar locking plates in distal radial fractures: The dorsal horizon view. Penetration of the dorsal screw when treating distal radius fractures with volar locking plates is an avoidable complication that causes lesions of the extensor tendon in between 2% and 6% of patients. We examined axial fluoroscopic views of the distal end of the radius to observe small amounts of dorsal screw penetration, and determined the ideal angle of inclination of the x-ray beam to the forearm when making this radiological view. Six volar locking plates were inserted at the wrists of cadavers. The actual screw length was measured under direct vision through a dorsal approach to the distal radius. Axial radiographs were performed for different angles of inclination of the forearm at the elbow. Comparing axial radiological measurements and real screw length, a statistically significant correlation could be demonstrated at an angle of inclination between 5° and 20°. The ideal angle of inclination required to minimise the risk of implanting over-long screws in a dorsal horizon radiological view is 15°. Cite this article: Bone Joint J 2013;95-B:1101-5. 23266271 Radioprotection by two phenolic compounds: chlorogenic and quinic acid, on X-ray induced DNA damage in human blood lymphocytes in vitro. The present study was designed to determine the radioprotective effect of two phytochemicals, namely, quinic acid and chlorogenic acid, against X-ray irradiation-induced genomic instability in non-tumorigenic human blood lymphocytes. The protective ability of two phenolic acids against radiation-induced DNA damage was assessed using the alkaline comet assay in human blood lymphocytes isolated from two healthy human donors. A Siemens Mevatron MD2 (Siemens AG, USA, 1994) linear accelerator was used for irradiation. The results of the alkaline comet assay revealed that quinic acid and chlorogenic acid decreased the DNA damage induced by X-ray irradiation and provided a significant radioprotective effect. Quinic acid decreased the presence of irradiation-induced DNA damage by 5.99-53.57% and chlorogenic acid by 4.49-48.15%, as determined by the alkaline comet assay. The results show that quinic acid and chlorogenic acid may act as radioprotective compounds. Future studies should focus on determining the mechanism by which these phenolic acids provide radioprotection. 23963288 Distinguishing Alzheimer's Disease from Normal Pressure Hydrocephalus: A Search for MRI Biomarkers. Currently, no clinical or neuroradiological techniques have been validated to distinguish Alzheimer's disease (AD) from idiopathic normal pressure hydrocephalus (iNPH). Both share anatomical and clinical similarities: AD is a form of irreversible degenerative dementia, whereas the dementia manifested in iNPH is potentially "reversible" through various neurosurgical procedures. Hence, it is important to find specific imaging biomarkers that distinguish the two conditions. In addition, the ability to predict the response to neurosurgery in iNPH is something that has yet to be accomplished. In this systematic review, we describe and critically analyze the merits and drawbacks of the MR imaging parameters currently used to distinguish AD from iNPH and assess ways to predict the response after treatment of iNPH. We conclude that the combination of different neuroimaging sequences as well as quantitative and qualitative parameters could provide new insight for better diagnosis and treatment of these two different diseases. 23479080 Selective poisoning of Ctnnb1-mutated hepatoma cells in mouse liver tumors by a single application of acetaminophen. Mouse liver tumors that harbor activating mutations in Ctnnb1, encoding β-catenin, express high levels of various cytochromes P450 (CYP), including CYP2E1 and CYP1A2. Acetaminophen (AAP) is metabolized in hepatocytes by these CYPs to the reactive intermediate N-acetyl-p-benzoquinone-imine, which is toxic to hepatocytes at high doses where depletion of glutathione occurs. We have induced liver tumors in mice by treatment with the liver carcinogen N-nitrosodiethylamine followed by chronic treatment with the tumor promoter phenobarbital. Under this protocol, ~80 % of tumors display Ctnnb1 mutations and express high levels of various CYP isoforms. Tumor-bearing animals were given a single intraperitoneal injection of 300 mg/kg body weight AAP, which was well tolerated by the animals. This dose, however, eradicated essentially all larger Ctnnb1-mutated, CYP-positive liver tumors, killing >90 % of hepatoma cells: at 2 days after AAP, large necrotic areas filled with cell debris were observed in tumors. These were infiltrated in the following days by immune cells starting from the outer parts of the damaged areas slowly closing the "wounds" left from the poisoned tumor cells. During this period, there was increased proliferation of normal hepatocytes, but some residual tumor cells were also proliferating. Our results show that a selective poisoning of Ctnnb1-mutated liver tumors by administration of AAP is possible in this experimental system. Application of an adapted protocol could be envisaged for neo-adjuvant treatment of human hepatoblastoma which are frequently mutated in CTNNB1 and often show high expression of CYP2E1. 23755899 Impact of medication non-adherence on survival after pediatric heart transplantation in the USA. Medication non-adherence (NA) can result in life-threatening illness in children after solid-organ transplantation. Little is known about the incidence, risk factors and outcomes of NA in large numbers of pediatric heart transplant (HT) recipients. Organ Procurement Transplant Network (OPTN) data were used to identify all children <18 years of age in the USA who underwent HT from October 1999 to January 2007. Cox proportional hazards analysis was used to identify risk factors for NA and the effect on graft survival. Of 2,070 pediatric heart transplants performed the median age at transplant was 6 years (interquartile range [IQR] 0 to 13 years); 40% had congenital heart disease (CHD), 7% were re-transplants, 42% were non-white and 43% had Medicaid insurance. Overall, 186 (9%) children had a report of NA at a median age of 15 years with more than two-thirds of NA episodes occurring after 12 years of age. Factors independently associated with NA were: adolescent age at transplant (hazard ratio [HR] 7.0, 95% confidence interval [CI] 4.1 to 12, compared with infants); black race (HR 2.3, 95% CI 1.7 to 3.3, compared with white); Medicaid insurance (HR 2.0, 95% CI 1.5 to 2.7, compared with non-Medicaid insurance); and ventilator or ventricular assist device (VAD) support at transplant. The risk of mortality conditional upon report of NA was 26% at 1 year and 33% at 2 years. Medication NA is an important problem in pediatric HT recipients and is associated with high mortality. Adolescent age, black race, Medicaid insurance and invasive hemodynamic support at transplant were associated with NA, whereas time on the wait list and gender were not. Targeted interventions among at-risk populations may be warranted. 23395718 Ozonolysis efficiency and safety evaluation of aflatoxin B1 in peanuts. Ozonolysis efficiency of aflatoxin-contaminated peanuts (ACPs) was investigated, and the safety of ACPs untreated/treated by ozone was evaluated after 28-day intragastrically administration in male and female Wistar rats. 89.40% of aflatoxin B1 (AFB1) in peanuts was decomposed by ozone with a concentration of 50mg/L, flow rate of 5L/min for 60h. After 60h, the ozonolysis efficiency of AFB1 was not further improved. In the subchronic toxicity experiment, all rats did not have unusual changes in behavior, and no signs of intoxication were observed except for several dead rats due to inappropriate gavage or anesthesia. The results of subchronic toxicity indicated that rats fed on ACPs alone had significantly decreased in body weight gain and feed conversion efficiency. Most serum biochemical indexes of rats had apparently changed compared with those in the negative control, and gender difference significantly affected most indexes of subchronic toxicity except for the ratios of organ to body weight and histopathological observation. Rats fed on ACPs treated by ozone showed significant beneficial health effects. All the results suggested that the deleterious effects of AFB1 could be highly reduced by ozone, and ozone itself did not show any toxic effects on animals in this processing. 23855777 The triterpenoid fraction from Trichosanthes dioica root suppresses experimentally induced inflammatory ascites in rats. Abstract Context. Trichosanthes dioica Roxb. (Cucurbitaceae), called pointed gourd in English, is a dioecious climber found wild throughout the plains of the Indian subcontinent and traditionally used in India for several medicinal purposes. Objective: The present study evaluated the protective effect of the triterpenoid enriched fraction from T. dioica root (CETD) against experimentally induced acute inflammatory ascites in Wistar albino rats. Materials and methods: The CETD was administered orally at the different doses (25, 50 and 100 mg/kg body weight) to overnight fasted rats, and then ascites was induced by intraperitoneal administration of formalin solution. After 7 h, the rats were sacrificed and the volume of ascitic fluid was measured. Results: The CETD demonstrated significant (p < 0.01) reduction of ascitic fluid formation in a dose-dependent manner as compared with control. Conclusion: The CETD produced significant and dose-dependent inhibition of experimentally induced inflammatory ascites in Wistar albino rats. 23801747 Regulation of the Transcriptional Coactivator FHL2 Licenses Activation of the Androgen Receptor in Castrate-Resistant Prostate Cancer. It is now clear that progression from localized prostate cancer to incurable castrate-resistant prostate cancer (CRPC) is driven by continued androgen receptor (AR), signaling independently of androgen. Thus, there remains a strong rationale to suppress AR activity as the single most important therapeutic goal in CRPC treatment. Although the expression of ligand-independent AR splice variants confers resistance to AR-targeted therapy and progression to lethal castrate-resistant cancer, the molecular regulators of AR activity in CRPC remain unclear, in particular those pathways that potentiate the function of mutant AR in CRPC. Here, we identify FHL2 as a novel coactivator of ligand-independent AR variants that are important in CRPC. We show that the nuclear localization of FHL2 and coactivation of the AR is driven by calpain cleavage of the cytoskeletal protein filamin, a pathway that shows differential activation in prostate epithelial versus prostate cancer cell lines. We further identify a novel FHL2-AR-filamin transcription complex, revealing how deregulation of this axis promotes the constitutive, ligand-independent activation of AR variants, which are present in CRPC. Critically, the calpain-cleaved filamin fragment and FHL2 are present in the nucleus only in CRPC and not benign prostate tissue or localized prostate cancer. Thus, our work provides mechanistic insight into the enhanced AR activation, most notably of the recently identified AR variants, including AR-V7 that drives CRPC progression. Furthermore, our results identify the first disease-specific mechanism for deregulation of FHL2 nuclear localization during cancer progression. These results offer general import beyond prostate cancer, given that nuclear FHL2 is characteristic of other human cancers where oncogenic transcription factors that drive disease are activated like the AR in prostate cancer. Cancer Res; 73(16); 5066-79. ©2013 AACR. 23450228 Aluminium coordination complexes in copolymerization reactions of carbon dioxide and epoxides. Al complexes are widely used in a range of polymerization reactions (ROP of cyclic esters and cationic polymerization of alkenes). Since the discovery in 1978 that an Al porphyrin complex could copolymerize propylene oxide with carbon dioxide, Al coordination compounds have been studied extensively as catalysts for epoxide-carbon dioxide copolymerizations. The most widely studied catalysts are Al porphyrin and Al salen derivatives. This is partially due to their ability to act as mechanistic models for more reactive, paramagnetic Cr catalysts. However, this in depth mechanistic understanding could be employed to design more active Al catalysts themselves, which would be beneficial given the wide availability of this metal. Polymerization data (% CO3 linkages, M(n), M(w)/M(n) and TON) for these complexes are presented and mechanisms discussed. In most cases, especially those employing square-based pyramidal Al complexes, co-catalysts are required to obtain high levels of carbon dioxide incorporation. However, in some cases, the use of co-catalysts inhibits the copolymerization reaction. Lewis acidic Al phenolate complexes have been used as activators in CHO-carbon dioxide copolymerizations to increase TOF and this has recently led to the development of asymmetric copolymerization reactions. Given the ready availability of Al, the robustness of many complexes (e.g. use in immortal polymerizations) and opportunity to prepare block copolymers and other designer materials, Al complexes for copolymerization of carbon dioxide are surely worth a second look. 23456857 Screening of high α-arbutin producing strains and production of α-arbutin by fermentation. A mutant Xanthomonas maltophilia BT-112 with high α-anomer-selective glycosylation activity was screened by a series of mutation methods including UV light, N-methyl-N-nitro-N-nitroso-guanidine treatment and quick neutron mutation. The α-arbutin titer increased 15-folds compared with the parent strain. The optimal conditions for culture medium and the operational conditions for lab-scale fermenter were investigated. Under optimized conditions, the maximal hydroquinone (HQ) tolerance of cells and yield of α-arbutin were 120 mM and 30.6 g/l, respectively. The molar conversion yield of α-arbutin based on the amount of HQ supplied reached 93.6 %. The product was identified as α-arbutin by (13)C NMR and (1)H NMR analysis. In conclusion, the results in this work provide a one-step and cost-effective method for the large-scale production of α-arbutin. 23827661 Effects of slanted ergonomic mice on task performance and subjective responses. The biomechanical benefits (e.g., muscular activity) of slanted ergonomic mice have been comprehensively identified; however, their effects on task performance and subjective responses have not been fully investigated. The present study examined the effects of two slanted mice (slant angle = 30° and 50°) in comparison with a conventional mouse (slant angle = 0°) in terms of task performance (task completion time and error rate) and subjective responses (perceived discomfort score and overall satisfaction score). Experimental results showed that all of the task and subjective measures worsened as the slant angle of the target mice increases. For example, the task completion time (unit: ms) and overall satisfaction score (unit: point) of the 30° slanted mouse (time = 0.71, satisfaction = -0.09) and 50° slanted mouse (time = 0.73, satisfaction = -0.79) significantly deteriorated than the conventional mouse (time = 0.65, satisfaction = 1.21). The slanted mice seem to compromise biomechanical benefits with task performance and subjective responses. 23570999 In vivo and in vitro anti-inflammatory potential of pentahydroxy-pregn-14-ol, 20-one-β-d-thevetopyranoside in rats. Polyhydroxy pregnane glycoside (PPG), a steroidal glycoside was isolated from Wattakaka volubilis Linn. (Stap.f.). PPG was evaluated for in vivo and in vitro anti-inflammatory activity using acute inflammation and chronic model of inflammation in rats and LPS-induced RAW 264.7 macrophage cells. PPG seemed to be responsible for the anti-inflammatory activity in the studied models. PPG at dose level of both 5 and 10mg/kg significantly reduced the edema induced by the carrageenan in acute model of inflammation. It also showed significant anti-proliferative effect (dry pellet weight basis) in chronic model of inflammation. Cellular content of granuloma was measured by assaying activity of N-acetyl glucosaminidase (NAG) and total nucleic acid content. PPG at 5 and 10mg/kg significantly suppressed the cellular infiltration measured by total nucleic acid content. In contrast, NAG activity decreased over a period of 10 days resulting in inhibition of granuloma weight gain. PPG had a more effective response than the reference drug diclofenac sodium in both the models of inflammation. Wattakaka volubilis steroidal glycoside mixture (WVSM) and PPG (1-50μM) significantly inhibited the COX-2 and iNOS enzymes resulting in low levels of PGE2 and NO in LPS-induced RAW 264.7 macrophage cells. Hence the study supports the traditional use of Wattakaka volubilis and its constituent PPG in treatment of inflammatory disorders. 23871803 Predictors of Human Papillomavirus Vaccination Among Daughters of Low-Income Latina Mothers: The Role of Acculturation. Human papillomavirus (HPV) vaccination is a safe and effective primary prevention strategy for cervical cancer. Little is known about correlates of HPV vaccination among Hispanic adolescents living in the United States. The purpose of this study was to (1) examine relationships between both U.S./American and Latina acculturation and variables typically associated with HPV vaccine uptake (e.g., physician recommendation); and (2) identify predictors of HPV vaccine uptake among daughters of Latina mothers. Latina mothers (N = 200) recruited from a Federally Qualified Health Center serving low-income families in Florida completed a semistructured interview that assessed awareness of and knowledge about HPV and HPV-vaccines, vaccination beliefs, whether their daughter's physician had recommended the HPV vaccine, health history, U.S./American and Latina acculturation, mother and daughter demographics, and daughter's HPV vaccination status. Only 18% of daughters had received at least one dose of the vaccine. Higher levels of U.S./American acculturation were associated with greater odds of vaccine uptake and other common predictors of HPV vaccination (e.g., physician recommendation, vaccine awareness). A multivariate logistic regression analysis identified three independent predictors of vaccine uptake: physician recommendation, daughter's age, and low worry about how to pay for the vaccine. Despite generally favorable views of HPV vaccination, observed rates of vaccine uptake in this sample were substantially lower than national estimates. Latina mothers who are more integrated into U.S. society may be more likely to vaccinate their daughters against HPV. Findings provide promising directions for future HPV vaccination interventions with Hispanic adolescents. 23836647 Liquid-liquid transition in supercooled water suggested by microsecond simulations. The putative liquid-liquid phase transition in supercooled water has been used to explain many anomalous behaviors of water. However, no direct experimental verification of such a phase transition has been accomplished, and theoretical studies from different simulations contradict each other. We investigated the putative liquid-liquid phase transition using the Water potential from Adaptive Force Matching for Ice and Liquid (WAIL). The simulation reveals a first-order phase transition in the supercooled regime with the critical point at ∼207 K and 50 MPa. Normal water is high-density liquid (HDL). Low-density liquid (LDL) emerges at lower temperatures. The LDL phase has a density only slightly larger than that of the ice-Ih and shows more long-range order than HDL. However, the transformation from LDL to HDL is spontaneous across the first-order phase transition line, suggesting the LDL configuration is not poorly formed nanocrystalline ice. It has been demonstrated in the past that the WAIL potential provides reliable predictions of water properties such as melting temperature and temperature of maximum density. Compared with other simple water potentials, WAIL is not biased by fitting to experimental properties, and simulation with this potential reflects the prediction of a high-quality first-principle potential energy surface. 23954752 High Mitochondrial Priming Sensitizes hESCs to DNA-Damage-Induced Apoptosis. Human embryonic stem cells (hESCs) are highly sensitive to DNA damage and have low survival ability relative to differentiated cells. We investigated the source of this difference by comparing damage response pathways in hESCs and differentiated cells. We found that hESCs undergo more rapid p53-dependent apoptosis after DNA damage than differentiated cells do. However, p53 localization and function are similar between hESCs and differentiated cells, suggesting that p53 alone cannot explain the difference in sensitivity. Instead, we show that mitochondrial readiness for apoptosis, known as mitochondrial priming, differs between hESCs and differentiated cells. Specifically, the balance between proapoptotic and antiapoptotic proteins is shifted closer to the apoptotic threshold in hESCs than in differentiated cells. Altering this balance in differentiated cells increases their sensitivity and results in cell death, suggesting that manipulation of mitochondrial priming could potentially alter the sensitivity of other stem cells, including cancer stem cells. 23829640 A 10-year analysis of cutaneous mesenchymal tumors (sarcomas and related entities) in a skin cancer center. Background  Mesenchymal neoplasms (sarcomas) of skin are rare. Patients with sarcomas were analyzed over the last decade. Methods  Over a 10-year period, we conducted a retrospective analysis of patients diagnosed and treated in an urban academic teaching hospital in Saxony, Germany. Clinical and pathologic files were used. Results  We identified 65 adult patients with 67 primary cutaneous sarcomas. The mean age was 73.1 (±15.5) years with a male predominance (78.5%). None of the sarcomas was detected by a skin cancer screening program. The diagnosis was atypical fibroxanthoma (n = 41 patients with 43 tumors), cutaneous angiosarcoma (eight), dermatofibrosarcoma protuberans (two), nodular epithelioid cell sarcoma (one), Kaposi sarcoma (three), leiomyosarcoma (five), malignant fibrous histiocytoma (two), fibromyxoid sarcoma (one), and cutaneous angiomyxoma (two). The preferred tumor localization was the head and neck area (44 patients). Follow-up was 0.5-5.5 years (mean 18 ± 12 months). We observed metastatic spread of atypical fibroxanthoma in 12.5%, demonstrating that this type of sarcoma can run an aggressive course. Mohs surgery is still the cornerstone of treatment, although new options in palliative or adjuvant treatment are available. Conclusions  Mesenchymal neoplasms (sarcomas) are an important group of cutaneous malignancies. Awareness needs to be improved. 23855040 The Effect of the Pressure-Volume Curve for Positive End-Expiratory Pressure Titration on Clinical Outcomes in Acute Respiratory Distress Syndrome: A Systematic Review. PURPOSE Methods to optimize positive end-expiratory pressure (PEEP) in acute respiratory distress syndrome (ARDS) remain controversial despite decades of research. The pressure-volume curve (PVC), a graphical ventilator relationship, has been proposed for prescription of PEEP in ARDS. Whether the use of PVC's improves survival remains unclear. METHODS In this systematic review, we assessed randomized controlled trials (RCTs) comparing PVC-guided treatment with conventional PEEP management on survival in ARDS based on the search of the National Library of Medicine from January 1, 1960, to January 1, 2010, and the Cochrane Central Register of Controlled Trials. Three RCTs were identified with a total of 185 patients, 97 with PVC-guided treatment and 88 with conventional PEEP management. RESULTS The PVC-guided PEEP was associated with an increased probability of 28-day or hospital survival (odds ratio [OR] 2.7, 95% confidence interval [CI] 1.5, 4.9) using a random-effects model without significant heterogeneity (I (2) test: P = .75). The PVC-guided ventilator support was associated with reduced cumulative risk of mortality (-0.24 (95% CI -0.38, -0.11). The PVC-managed patients received greater PEEP (standardized mean difference [SMD] 5.7 cm H2O, 95% CI 2.4, 9.0) and lower plateau pressures (SMD -1.2 cm H2O, 95% CI -2.2, -0.2), albeit with greater hypercapnia with increased arterial pCO2 (SMD 8 mm Hg, 95% CI 2, 14). Weight-adjusted tidal volumes were significantly lower in PVC-guided than conventional ventilator management (SMD 2.6 mL/kg, 95% CI -3.3, -2.0). CONCLUSION This analysis supports an association that ventilator management guided by the PVC for PEEP management may augment survival in ARDS. Nonetheless, only 3 randomized trials have addressed the question, and the total number of patients remains low. Further outcomes studies appear required for the validation of this methodology. 23784347 A microfluidic cell culture array with various oxygen tensions. Oxygen tension plays an important role in regulating various cellular functions in both normal physiology and disease states. Therefore, drug testing using conventional in vitro cell models under normoxia often possesses limited prediction capability. A traditional method of setting an oxygen tension in a liquid medium is by saturating it with a gas mixture at the desired level of oxygen, which requires bulky gas cylinders, sophisticated control, and tedious interconnections. Moreover, only a single oxygen tension can be tested at the same time. In this paper, we develop a microfluidic cell culture array platform capable of performing cell culture and drug testing under various oxygen tensions simultaneously. The device is fabricated using an elastomeric material, polydimethylsiloxane (PDMS) and the well-developed multi-layer soft lithography (MSL) technique. The prototype device has 4 × 4 wells, arranged in the same dimensions as a conventional 96-well plate, for cell culture. The oxygen tensions are controlled by spatially confined oxygen scavenging chemical reactions underneath the wells using microfluidics. The platform takes advantage of microfluidic phenomena while exhibiting the combinatorial diversities achieved by microarrays. Importantly, the platform is compatible with existing cell incubators and high-throughput instruments (liquid handling systems and plate readers) for cost-effective setup and straightforward operation. Utilizing the developed platform, we successfully perform drug testing using an anti-cancer drug, triapazamine (TPZ), on adenocarcinomic human alveolar basal epithelial cell line (A549) under three oxygen tensions ranging from 1.4% to normoxia. The developed platform is promising to provide a more meaningful in vitro cell model for various biomedical applications while maintaining desired high throughput capabilities. 23612918 Prosopis pubescens (Screw Bean Mesquite) Seedlings are Hyperaccumulators of Copper. Due to health reasons, toxic metals must be removed from soils contaminated by mine tailings and smelter activities. The phytoremediation potential of Prosopis pubescens (screw bean mesquite) was examined by use of inductively-coupled plasma optical emission spectroscopy. Transmission electron microscopy was used to observe ultrastructural changes of parenchymal cells of leaves in the presence of copper. Elemental analysis was used to localize copper within leaves. A 600-ppm copper sulfate exposure to seedlings for 24 days resulted in 31,000 ppm copper in roots, 17,000 ppm in stems, 11,000 in cotyledons and 20 ppm in the true leaves. For a plant to be considered a hyperaccumulator, the plant must accumulate a leaf-to-root ratio <1. Screw bean mesquite exposed to copper had a leaf-to-root ratio of 0.355 when cotyledons were included. We showed that P. pubescens grown in soil is a hyperaccumulator of copper. We recommend that this plant should be field tested. 23840037 The psychological experience of living with head and neck cancer: a systematic review and meta-synthesis. To summarise patients' experiences of head and neck cancer (HNC) by examining the findings of existing qualitative studies METHODS: We undertook a systematic review and meta-synthesis of qualitative studies in 29 published articles using Noblit and Hare's 'meta-ethnography' approach to synthesise findings. The inclusion criteria were primary qualitative studies, focusing on HNC patients' experience and an English abstract. Seven databases were systematically searched. The articles focused on the experience of having HNC, the experience of treatments and the role of information. Our synthesis identified six core concepts-uncertainty and waiting, disruption to daily life, the diminished self, making sense of the experience, sharing the burden and finding a path. People experienced significant disruption to normal daily activities, because of the physical and emotional effects of HNC and its treatment. Day-to-day challenges were compounded by social and existential changes and a palpable loss of the individual's sense of self and future. In order to find a way through the considerable uncertainty and daily challenge of living with and beyond HNC, patients made continual efforts to make sense of their experience. Supportive relationships with their social network, HNC peers and healthcare professionals were particularly important, but support following treatment completion was sometimes limited. Perceptions of the future were affected by whether they saw life as diminished, merely changed or even enhanced by the experience of cancer. This review supports further specific research into these emerging themes and provides a context for future work, informing interventions to improve patients' experiences. Copyright © 2013 John Wiley & Sons, Ltd. 23811943 Critical Tumor Suppressor Function Mediated by Epithelial Mig-6 in Endometrial Cancer. Endometrial cancer is preceded by endometrial hyperplasia, unopposed estrogen exposure, and genetic alterations, but the precise causes of endometrial cancer remain uncertain. Mig-6, mainly known as a negative regulator of the EGF receptor, is an important mediator of progesterone signaling in the uterus, where it mediates tumor suppression by modulating endometrial stromal-epithelial communications. In this study, we investigated the function of Mig-6 in the uterine epithelium using a tissue-specific gene knockout strategy, in which floxed Mig-6 (Mig-6(f/f)) mice were crossed to Wnt7a-Cre mice (Wnt7a(cre+)Mig-6(f/f)). Wnt7a(cre+)Mig-6(f/f) mice developed endometrial hyperplasia and estrogen-dependent endometrial cancer, exhibiting increased proliferation in epithelial cells as well as apoptosis in subepithelial stromal cells. We documented increased expression of NOTCH1 and BIRC3 in epithelial cells of Wnt7a(cre+)Mig-6(f/f) mice and decreased expression of the progesterone receptor (PR) in stromal cells. Progesterone therapy controls endometrial growth and prevents endometrial cancer, but the effectiveness of progesterone as a treatment for women with endometrial cancer is less clear. We noted that the hyperplasic phenotype of Wnt7a(cre+)Mig-6(f/f) mice was prevented by progesterone treatment, whereas this treatment had no effect in PR(cre/+)Mig-6(f/f) mice where Mig-6 was deleted in both the epithelial and stromal compartments of the uterus. In contrast, activation of progesterone signaling in the stroma regulated proliferation and apoptosis in the epithelium via suppression of ERα signaling. In summary, our results establish that epithelial Mig-6 functions as a critical tumor suppressor that mediates the ability of progesterone to prevent the development of endometrial cancer. Cancer Res; 73(16); 5090-9. ©2013 AACR. 23839031 Concurrent adaptation to opposite visual distortions: impairment and cue. The present study compared single and dual adaptation to visuomotor rotations in different cueing conditions. Participants adapted either to a constant rotation or to opposing rotations (dual adaptation) applied in an alternating order. In Experiment 1, visual and corresponding postural cues were provided to indicate different rotation directions. In Experiment 2, either a visual or a postural cue was available. In all cueing conditions, substantial dual adaptation was observed, although it was attenuated in comparison to single adaptation. Analysis of switching costs determined as the performance difference between the last trial before and the first trial after the change of rotation direction suggested substantial advantage of the visual cue compared to the postural cue, which was in line with previous findings demonstrating the dominance of visual sense in movement representation and control. 23874830 Efficacy of Histone Deacetylase and Estrogen Receptor Inhibition in Breast Cancer Cells Due to Concerted down Regulation of Akt. Hormonal therapy resistance remains a considerable barrier in the treatment of breast cancer. Activation of the Akt-PI3K-mTOR pathway plays an important role in hormonal therapy resistance. Our recent preclinical and clinical studies showed that the addition of a histone deacetylase inhibitor re-sensitized hormonal therapy resistant breast cancer to tamoxifen. As histone deacetylases are key regulators of Akt, we evaluated the effect of combined treatment with the histone deacetylase inhibitor PCI-24781 and tamoxifen on Akt in breast cancer cells. We demonstrate that while both histone deacetylase and estrogen receptor inhibition down regulate AKT mRNA and protein, their concerted effort results in down regulation of AKT activity with induction of cell death. Histone deacetylase inhibition exerts its effect on AKT mRNA through an estrogen receptor-dependent mechanism, primarily down regulating the most abundant isoform AKT1. Although siRNA depletion of AKT modestly induces cell death, when combined with an anti-estrogen, cytotoxicity is significantly enhanced. Thus, histone deacetylase regulation of AKT mRNA is a key mediator of this therapeutic combination and may represent a novel biomarker for predicting response to this regimen. 23832325 Limited english proficient patients and time spent in therapeutic range in a warfarin anticoagulation clinic. While anticoagulation clinics have been shown to deliver tailored, high-quality care to patients receiving warfarin therapy, communication barriers with limited English proficient (LEP) patients may lead to disparities in anticoagulation outcomes. We analyzed data on 3770 patients receiving care from the Massachusetts General Hospital Anticoagulation Management Service (AMS) from 2009 to 2010. This included data on international normalized ratio (INR) tests and patient characteristics, including language and whether AMS used a surrogate for primary communication. We calculated percent time in therapeutic range (TTR for INR between 2.0 and 3.0) and time in danger range (TDR for INR <1.8 or >3.5) using the standard Rosendaal interpolation method. There were 241 LEP patients; LEP patients, compared with non-LEP patients, had a higher number of comorbidities (3.2 versus 2.9 comorbidities, P=0.004), were more frequently uninsured (17.0% versus 4.3%, P<0.001), and less educated (47.7% versus 6.0% ≤high school education, P<0.001). LEP patients compared with non-LEP patients spent less TTR (71.6% versus 74.0%, P=0.007) and more TDR (12.9% versus 11.3%, P=0.018). In adjusted analyses, LEP patients had lower TTR as compared with non-LEP patients (OR 1.5, 95% CI [1.1, 2.2]). LEP patients who used a communication surrogate spent less TTR and more TDR. Even within a large anticoagulation clinic with a high average TTR, a small but significant decrease in TTR was observed for LEP patients compared with English speakers. Future studies are warranted to explore how the use of professional interpreters impact TTR for LEP patients. 23969417 Opposing roles for 53BP1 during homologous recombination. Although DNA non-homologous end-joining repairs most DNA double-strand breaks (DSBs) in G2 phase, late repairing DSBs undergo resection and repair by homologous recombination (HR). Based on parallels to the situation in G1 cells, previous work has suggested that DSBs that undergo repair by HR predominantly localize to regions of heterochromatin (HC). By using H3K9me3 and H4K20me3 to identify HC regions, we substantiate and extend previous evidence, suggesting that HC-DSBs undergo repair by HR. Next, we examine roles for 53BP1 and BRCA1 in this process. Previous studies have shown that 53BP1 is pro-non-homologous end-joining and anti-HR. Surprisingly, we demonstrate that in G2 phase, 53BP1 is required for HR at HC-DSBs with its role being to promote phosphorylated KAP-1 foci formation. BRCA1, in contrast, is dispensable for pKAP-1 foci formation but relieves the barrier caused by 53BP1. As 53BP1 is retained at irradiation-induced foci during HR, we propose that BRCA1 promotes displacement but retention of 53BP1 to allow resection and any necessary HC modifications to complete HR. In contrast to this role for 53BP1 in HR in G2 phase, we show that it is dispensable for HR in S phase, where HC regions are likely relaxed during replication. 23944192 Efficient Diels-Alder Addition of Cyclopentadiene to Lithium Ion Encapsulated [60]Fullerene. Much higher reactivity of [Li(+)@C60]PF6(-) for Diels-Alder cycloaddition toward cyclopentadiene (CpH), in comparison with that of empty C60, was observed. The synthetic method, electrochemical and light absorption properties, and X-ray crystal structure of the product [Li(+)@C60(CpH)]PF6(-) are discussed. 23648829 Reshaping molecules through cocrystallization. Comparison of the structures of Hg{Co(CO)4}2 and Hg{Co(CO)4}2·C60·toluene. Cocrystallization of Hg{Co(CO)4}2 with C60 produces Hg{Co(CO)4}2·C60·toluene in which the geometry of the Hg{Co(CO)4}2 molecule is rearranged to fit between the remarkably well ordered fullerenes. 22886891 Prehospital delay in acute stroke and TIA. Early management improves outcome in acute stroke. This study was designed to assess the prehospital path from symptom onset to arrival in hospital and to identify factors associated with prehospital delay. A prospective study was conducted including patients with acute ischaemic stroke, intracerebral haemorrhage and transient ischaemic attack admitted to hospital. Time intervals for prehospital delay, background data, severity, type of first medical contact and mode of transport were recorded. Univariate and multivariate analyses were performed to identify factors influencing prehospital delay. A total of 440 patients were included, with a mean age of 71.4±13.0 years (44.3% female subjects), consisting of 65.9% patients with ischaemic stroke, 11.4% with intracerebral haemorrhage and 22.7% with transient ischaemic attack. The median time from symptom onset to admission was 3.0 h (179 min; IQR 77-542). The median decision delay was 1.5 h (92 min, IQR 25-405) and accounted for 55.1% (median value) of the prehospital delay. 310 (70.5%) patients arrived by ambulance. In the multivariate linear regression analysis, high National Institute of Health Stroke Scale score (p<0.001), transport by ambulance (p<0.001) and lower age (p=0.048) were significantly associated with early admission. Severe strokes, use of ambulance and lower age are associated with reduced prehospital delay. The present study shows that more than half of the delay is caused by the hesitation to contact medical services. Public information campaigns should focus on fast symptom recognition and the importance of immediately contacting the Emergency Medical Services upon symptom onset. 23770924 Advancing healthcare transitions in the medical home: tools for providers, families and adolescents with special healthcare needs. The purpose of the present article is to review recent national guidelines regarding healthcare transition (HCT) planning for adolescents with special healthcare needs (SHCN) and to describe practical tools for use by the primary care pediatrician to implement these guidelines. Approximately one in five adolescents in the United States has SHCN. Achieving successful transitions from child-oriented to adult-oriented healthcare for these patients can be difficult. Despite numerous barriers to HCT, innovations in healthcare delivery, including the patient-centered medical home and accountable care payment structures, may help overcome challenges. The American Academy of Pediatrics, American Academy of Family Physicians, and the American College of Physicians have provided explicit practice-level guidance for supporting HCT. The National Healthcare Transition Center developed the Six Core Elements of Healthcare Transition, recommending six detailed action steps for transitions from pediatric settings. Steps reflect guidelines and, along with novel patient-centered information technologies, may help support individuals and families navigating complex transitions. It is time to integrate transition planning into the medical home. Further evidence is needed to identify transition strategies that improve outcomes. Although innovations in care delivery, payment structures, and information technologies may support HCT, pediatricians can and should implement already available and recommended transition steps. 23824252 A 10-Year Review of Otic Lichen Planus: The Mayo Clinic Experience. IMPORTANCE Lichen planus is an autoimmune inflammatory dermatosis that typically affects the skin but can also involve the stratified squamous epithelium of the external auditory canals and tympanic membranes. Here we report our experience with the clinical presentation, diagnosis, and management of otic lichen planus. OBSERVATIONS We retrospectively reviewed medical records from January 1, 2001, through May 31, 2011, of patients with a diagnosis of otic lichen planus. Nineteen cases were identified (mean age at diagnosis, 57 years; 15 women). The most common concerns were persistent otorrhea and hearing loss. Other symptoms included plugging, pruritus, tinnitus, pain, and bleeding. The mean symptom duration was 4.0 years (n = 13). Most patients responded well to topical tacrolimus within several months. One patient had a dramatic positive response to rituximab. CONCLUSIONS AND RELEVANCE Otic lichen planus can lead to persistent hearing loss and should be considered in the differential diagnosis of relentless otorrhea and external auditory canal stenosis. In our experience, topical tacrolimus is the best primary treatment, but alternative therapies could be instituted in severe cases. Early recognition of the nonspecific symptoms of otic lichen planus may lead to prompt treatment and avoidance of irreparable late sequelae. 23911544 Using the strengths and difficulties questionnaire with adults with Down syndrome. The Strengths and Difficulties Questionnaire (SDQ) has been widely used to screen typically developing children for mental health problems; in recent years it has also been used with children with intellectual disabilities. The present study investigated the possible use of the SDQ to screen adults with Down syndrome (DS). Only four items on the SDQ were changed slightly to remove references to children. Parents or carers completed the SDQ and all 125 adults with DS (aged 18-43 years) were assessed for mental health problems by a psychiatrist. Twenty-eight adults were diagnosed with a psychiatric condition. Parents and carers found the SDQ easy to complete and liked the inclusion of positive behaviours. The SDQ did discriminate significantly between those with and without a diagnosis, however the sensitivity and specificity were insufficient. Exploratory and Confirmatory Factor Analyses showed a four factor model (pro-social behaviour, emotional difficulties, hyperactivity and conduct disorders) to be the best solution. This structure was similar to previous research findings of three factors of pro-social behaviour, internalising disorders and externalising disorders. Construct validity and reliability suggest that the SDQ has potential for use with adults with DS and possibly those with other intellectual disabilities. The SDQ is user friendly for parents and carers, and did highlight behavioural and mental health needs, suggesting that it would be worthwhile to develop the SDQ specifically for adults with intellectual disability. 23954847 Volatile Solvents as Drugs of Abuse: Focus on the Cortico-Mesolimbic Circuitry. Volatile solvents such as those found in fuels, paints and thinners are found throughout the world and are used in a variety of industrial applications. However, these compounds are also often intentionally inhaled at high concentrations to produce intoxication. While solvent use has been recognized as a potential drug problem for many years, research on the sites and mechanisms of action of these compounds lags behind that of other drugs of abuse. In this review, we first discuss the epidemiology of voluntary solvent use throughout the world and then consider what is known about their basic pharmacology and how this may explain their use as drugs of abuse. We next present data from preclinical and clinical studies indicating that these substances induce common addiction sequalae such as dependence, withdrawal, and cognitive impairments. We describe how toluene, the most commonly studied psychoactive volatile solvent, alters synaptic transmission in key brain circuits such as the mesolimbic dopamine system and medial prefrontal cortex (mPFC) that are thought to underlie addiction pathology. Finally, we make the case that activity in mPFC circuits is a critical regulator of the mesolimbic dopamine system's ability to respond to volatile solvents like toluene. Overall, this review provides evidence that volatile solvents have high abuse liability due to their selective effects on critical nodes of the addiction neurocircuitry, and underscores the need for more research into how these compounds induce adaptations in neural circuits that underlie addiction pathology.Neuropsychopharmacology accepted article preview online, 19 August 2013. doi:10.1038/npp.2013.206. 23839924 Type I interferon potentiates T-cell receptor mediated induction of IL-10-producing CD4(+) T cells. Type I interferons (IFNs) have the dual ability to promote the development of the immune response and exert an anti-inflammatory activity. We analyzed the integrated effect of IFN-α, TCR signal strength, and CD28 costimulation on human CD4(+) T-cell differentiation into cell subsets producing the anti- and proinflammatory cytokines IL-10 and IFN-γ. We show that IFN-α boosted TCR-induced IL-10 expression in activated peripheral CD45RA(+) CD4(+) T cells and in whole blood cultures. The functional cooperation between TCR and IFN-α efficiently occurred at low engagement of receptors. Moreover, IFN-α rapidly cooperated with anti-CD3 stimulation alone. IFN-α, but not IL-10, drove the early development of type I regulatory T cells that were mostly IL-10(+) Foxp3(-) IFN-γ(-) and favored IL-10 expression in a fraction of Foxp3(+) T cells. Our data support a model in which IFN-α costimulates TCR toward the production of IL-10 whose level can be amplified via an autocrine feedback loop. 23090210 Liquid crystal pump. We report a dielectrically actuated liquid crystal (LC) pump. A small volume of LC forms a pillar-like droplet in a cylindrical hole which partially touches the bottom substrate with embedded interdigitated electrodes. By applying a voltage, the LC droplet can be largely stretched along the electrode direction by the generated dielectric force, which in turn exerts a pressure to displace a small volume of fluid on the opposite side of the chamber. Once the voltage is removed, the LC droplet returns to its initial state. The LC droplet with such a reciprocating movement behaves like a pump. In this work, the actuation mechanism of the LC pump is presented and the performance evaluated experimentally. Our LC pump has the following advantages: simple structure, easy fabrication, compact size, high precision, low power consumption, and relatively fast response time. It is promising for applications in lens actuators, biotechnology, drug delivery, and other lab-on-a-chip devices. 23969567 Hospital Reputation and Perceptions of Patient Safety. Objective: The objective of this study was to explore the theoretical relationship between the social reputation and the perceived safety of a hospital. Subjects and Methods: A random sample of 316 patients and 27 relatives of patients who were unable to respond themselves at four public hospitals in Madrid, Barcelona and Alicante were interviewed to establish a measure of reputation and perceived safety. Results: There were no different perceptions between patients and relatives regarding hospital reputation or safety perception (p > 0.05). The perception of patients or relatives of health professionals' competence (β = 0.07, 95% CI 0.01-0.12), the perception of a positive treatment output of surgical or medical treatment (β = 0.35, 95% CI 0.22-0.49) and hospital reputation (β = 0.08, 95% CI 0.02-0.14) were directly and positively associated with their perception that the hospital was a safe clinical environment in which few clinical errors are committed. Conclusions: The data suggested that the social reputation of these hospitals and the perceptions of patients or relatives of patient safety were indeed correlated. Future research should assess whether efforts to enhance hospital reputation, by improving patients' perceptions of clinical safety, may contribute to reducing the frequency of litigation cases. © 2013 S. Karger AG, Basel. 23912592 ADAM10 is overexpressed in human hepatocellular carcinoma and contributes to the proliferation, invasion and migration of HepG2 cells. The overexpression of A disintegrin and metalloproteinase 10 (ADAM10) has been found to be closely associated with the development and progression of various types of tumors. However, ADAM10 expression in hepatocellular carcinoma (HCC) and its significance remain largely unknown. The present study aimed to investigate the expression of ADAM10 in human HCC and the effect of ADAM10 gene silencing by siRNA on the proliferation, invasion and migration of HepG2 human hepatoma cells. Immunohistochemistry was performed to examine the expression of ADAM10 in human HCC tissues and in the adjacent non-cancer tissues from 30 patients with HCC. RNA interference was used to knock down ADAM10 expression in HepG2 human hepatoma cells and the proliferation and migration as well as the invasive ability of the treated cells were observed in vitro. The expression of ADAM10 protein in HCC tissues was significantly higher when compared to that in adjacent non-tumor tissues (P<0.05). The high expression of ADAM10 in cancer was significantly correlated with clinical outcomes (P<0.05). Silencing of ADAM10 resulted in inhibition of proliferation and migration as well as invasion of HepG2 human hepatoma cells (P<0.05). These studies suggest that ADAM10 plays an important role in regulating proliferation, invasion and migration of HepG2 cells. High expression of ADAM10 may be a valuable predictive factor for HCC prognosis, and ADAM10 is potentially an important therapeutic target for the prevention of tumor development and progression in HCC. 23787064 An extremely rare case of small-cell lung cancer harboring variant 2 of the EML4-ALK fusion gene. Anaplastic lymphoma kinase (ALK) fuses echinoderm microtubule-associated protein-like 4 (EML4) to acquire a transforming activity in lung adenocarcinomas. However, the presence of an EML4-ALK fusion gene in other lung cancer histologies is an extremely rare phenomenon. A 43-year-old female was referred to our department due to dyspnea on effort and left back pain. Computed tomography (CT) showed a large mass in the upper lobe of the left lung and a massive left pleural effusion, while a CT-guided needle biopsy confirmed a diagnosis of small-cell lung cancer (SCLC). Surprisingly, the tumor was genetically considered to harbor the EML4-ALK fusion gene (variant 2). Although the patient underwent two regimens of cytotoxic chemotherapy for SCLC, she died approximately seven months after the administration of first-line chemotherapy. Our analysis of 30 consecutive patients with SCLC for EML4-ALK revealed that two patients, including the current patient and a patient we previously reported, harbored the EML4-ALK fusion gene. 23228482 Ultrasound-guided radiofrequency ablation of early breast cancer in a resection specimen: lessons for further research. To assess the feasibility and effectiveness of radiofrequency ablation (RFA) in breast cancer, using different histopathologic staining methods to evaluate tissue viability. In twenty patients with unifocal small (≤1, 5 cm) invasive ductal carcinoma, ultrasound-guided RFA was performed immediately after surgery. Cell viability was assessed using cytokeratin 8 (CK 8) and nicotinamide adenine dinucleotide diaphorase (NADHD) in addition to hematoxylin-eosin (HE). At histopathological examination, ex vivo RFA resulted in complete cell death of the target lesion in 17/20 patients. In two cases viable ductal carcinoma in situ (DCIS) was found just outside the completely ablated lesion. RFA of small invasive breast cancer seems to be a feasible treatment option. Both NADHD and CK 8 demonstrate a clear and comparable demarcation between viable and non-viable tissue. A high level of accuracy is required in proper positioning of the needle electrode and a "hot retraction" is mandatory. 23255363 Deep determinism and the assessment of mechanistic interaction. Given two variables that causally influence a binary response, we formalize the idea that their effects operate through a common mechanism, in which case we say that the two variables interact mechanistically. We introduce a mechanistic interaction relationship of "interference" that is asymmetric in the two causal factors. Conditions and assumptions under which such mechanistic interaction can be tested under a given regime of data collection, be it interventional or observational, are expressed in terms of conditional independence relationships between the problem variables, which can be manipulated with the aid of causal diagrams. The proposed method is able, under appropriate conditions, to test for interaction between direct effects, and to deal with the situation where one of the two factors is a dichotomized version of a continuous variable. The method is illustrated with the aid of a study on heart disease. 23904614 Knockdown of prodynorphin gene prevents cognitive decline, reduces anxiety, and rescues loss of group 1 metabotropic glutamate receptor function in aging. Expression of dynorphin, an endogenous opioid peptide, increases with age and has been associated with memory impairments in rats. In human, prodynorphin (Pdyn) gene polymorphisms might be linked to cognitive function in the elderly. Moreover, elevated dynorphin levels have been reported in postmortem samples from Alzheimer's disease patients. However, the cellular and molecular processes affected by higher dynorphin levels during aging remain unknown. Using Pdyn(-/-) mice, we observed significant changes in the function and expression of Group 1 metabotropic glutamate receptor (mGluR). Compared with age-matched wild-type (WT) littermates, we found increased expression of mGluR1α and mGluR5 in the hippocampus and cortex of old, but not young, Pdyn(-/-) mice. Increased Group 1 mGluR expression in aged Pdyn(-/-) mice was associated with enhanced mGluR-mediated long-term depression, a form of synaptic plasticity. Notably, whereas aged WT mice developed spatial and recognition memory deficits, aged Pdyn(-/-) mice performed similarly as young mice. Pharmacological treatments with 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide, a positive modulator of mGlu5 receptors, or norbinaltorphimine, an antagonist for dynorphin-targeted κ-opioid receptor, rescued memory in old WT mice. Conversely, mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride impaired spatial memory of old Pdyn(-/-) mice. Intact cognition in aged Pdyn(-/-) mice paralleled with increased expression of Group 1 mGluR-related genes Homer 1a and Arc. Finally, aged Pdyn(-/-) mice displayed less anxiety-related behaviors than age-matched WT mice. Together, our results suggest that elevated Pdyn expression during normal aging reduces mGluR expression and signaling, which in turn impairs cognitive functions and increases anxiety. 23561202 Tert-butylhydroquinone recognition of molecular imprinting electrochemical sensor based on core-shell nanoparticles. One novel electrochemistry-molecular imprinting sensor for determining tert-butylhydroquinone (TBHQ) in foodstuff was developed. TBHQ-imprinted core-shell nanoparticles (TICSNs) were fabricated using silica nanoparticles as core material. The silica nanoparticles were modified with (3-chloropropyl) trimethoxysilan and polyethylenimine, respectively, and polymerised to form the TICSNs with ethylene glycol dimethacrylate as cross-linker. The specific core-shell structure demonstrates extremely high specific surface area which greatly increases the effective binding sites and improves the recognition capability for model molecules. Under the optimal conditions, the linear range of the calibration curve was 0.1-50.0mgkg(-1) with the detection limit of 0.27mgkg(-1). The sensor has been successfully applied to the determination of TBHQ in food samples and achieved high sensitivity and selectivity. 23887173 Programmed cell death in the marine cyanobacterium Trichodesmium mediates carbon and nitrogen export. The extent of carbon (C) and nitrogen (N) export to the deep ocean depends upon the efficacy of the biological pump that transports primary production to depth, thereby preventing its recycling in the upper photic zone. The dinitrogen-fixing (diazotrophic) Trichodesmium spp. contributes significantly to oceanic C and N cycling by forming extensive blooms in nutrient-poor tropical and subtropical regions. These massive blooms generally collapse several days after forming, but the cellular mechanism responsible, along with the magnitude of associated C and N export processes, are as yet unknown. Here, we used a custom-made, 2-m high water column to simulate a natural bloom and to specifically test and quantify whether the programmed cell death (PCD) of Trichodesmium mechanistically regulates increased vertical flux of C and N. Our findings demonstrate that extremely rapid development and abrupt, PCD-induced demise (within 2-3 days) of Trichodesmium blooms lead to greatly elevated excretions of transparent exopolymers and a massive downward pulse of particulate organic matter. Our results mechanistically link autocatalytic PCD and bloom collapse to quantitative C and N export fluxes, suggesting that PCD may have an impact on the biological pump efficiency in the oceans.The ISME Journal advance online publication, 25 July 2013; doi:10.1038/ismej.2013.121. 22968429 Vascular pancreatic lesions: spectrum of imaging findings of malignant masses and mimics with pathologic correlation. The differential diagnosis of hypervascular pancreatic lesions is complex, and includes endocrine and exocrine tumors of the pancreas, metastases to the pancreas, and masses, or mass-like lesions, arising from the neurovascular networks traversing the pancreas. In this manuscript, we will discuss salient imaging findings of these masses, pertinent differential diagnoses, as well as review clinical symptomatology that may aid in the diagnosis of some of these lesions. 23933040 Battery powered thought: Enhancement of attention, learning, and memory in healthy adults using transcranial direct current stimulation. This article reviews studies demonstrating enhancement with transcranial direct current stimulation (tDCS) of attention, learning, and memory processes in healthy adults. Given that these are fundamental cognitive functions, they may also mediate stimulation effects on other higher-order processes such as decision-making and problem solving. Although tDCS research is still young, there have been a variety of methods used and cognitive processes tested. While these different methods have resulted in seemingly contradictory results among studies, many consistent and noteworthy effects of tDCS on attention, learning, and memory have been reported. The literature suggests that although tDCS as typically applied may not be as useful for localization of function in the brain as some other methods of brain stimulation, tDCS may be particularly well-suited for practical applications involving the enhancement of attention, learning, and memory, in both healthy subjects and in clinical populations. 23918371 Inhibitory role of the transcription repressor Gfi1 in the generation of thymus-derived regulatory T cells. Foxp3(+) regulatory T (Treg) cells are essential for the maintenance of self-tolerance and immune homeostasis. The majority of Treg cells is generated in the thymus as a specific subset of CD4(+) T cells, known as thymus-derived or natural Treg (nTreg) cells, in response to signals from T-cell receptors, costimulatory molecules, and cytokines. Recent studies have identified intracellular signaling and transcriptional pathways that link these signals to Foxp3 induction, but how the production of these extrinsic factors is controlled remains poorly understood. Here, we report that the transcription repressor growth factor independent 1 (Gfi1) has a key inhibitory role in the generation of nTreg cells by a noncell-autonomous mechanism. T cell-specific deletion of Gfi1 results in aberrant expansion of thymic nTreg cells and increased production of cytokines. In particular, IL-2 overproduction plays an important role in driving the expansion of nTreg cells. In contrast, although Gfi1 deficiency elevated thymocyte apoptosis, Gfi1 repressed nTreg generation independently of its prosurvival effect. Consistent with an inhibitory role of Gfi1 in this process, loss of Gfi1 dampens antitumor immunity. These data point to a previously unrecognized extrinsic control mechanism that negatively shapes thymic generation of nTreg cells. 23882204 On the role of crossmodal prediction in audiovisual emotion perception. Humans rely on multiple sensory modalities to determine the emotional state of others. In fact, such multisensory perception may be one of the mechanisms explaining the ease and efficiency by which others' emotions are recognized. But how and when exactly do the different modalities interact? One aspect in multisensory perception that has received increasing interest in recent years is the concept of cross-modal prediction. In emotion perception, as in most other settings, visual information precedes the auditory information. Thereby, leading in visual information can facilitate subsequent auditory processing. While this mechanism has often been described in audiovisual speech perception, so far it has not been addressed in audiovisual emotion perception. Based on the current state of the art in (a) cross-modal prediction and (b) multisensory emotion perception research, we propose that it is essential to consider the former in order to fully understand the latter. Focusing on electroencephalographic (EEG) and magnetoencephalographic (MEG) studies, we provide a brief overview of the current research in both fields. In discussing these findings, we suggest that emotional visual information may allow more reliable predicting of auditory information compared to non-emotional visual information. In support of this hypothesis, we present a re-analysis of a previous data set that shows an inverse correlation between the N1 EEG response and the duration of visual emotional, but not non-emotional information. If the assumption that emotional content allows more reliable predicting can be corroborated in future studies, cross-modal prediction is a crucial factor in our understanding of multisensory emotion perception. 23909823 Cystic local recurrence of renal cell carcinoma after laparoscopic radical nephrectomy in a hemodialysis patient. Although local recurrence of renal cell carcinoma after laparoscopic radical nephrectomy is sometimes reported, cystic local recurrence of renal cell carcinoma has rarely been reported. We report the case of a 59-year-old man with hemodialysis who developed cystic local recurrence of renal cell carcinoma accompanied by acquired cystic disease of the kidney in the retroperitoneal space after laparoscopic radical nephrectomy. A cystic tumor of 5.1 cm in diameter occurred in the left retroperitoneal space 15 months after left laparoscopic radical nephrectomy, and enlarged to 7.2 cm in diameter with enhanced mass along the wall of the cyst 36 months after surgery. The cystic tumor was removed and showed local recurrence of renal cell carcinoma on pathological examination. 23394693 Transforming drug discovery and development through innovation: past, present and future. This annual meeting began in 1998 and was the first industry-led event to focus on the specific needs of industry researchers. The goal of Clinical and Pharmaceutical Solutions Through Analysis (CPSA) is to provide an in-depth review of innovative technology and industry practices through open discussion of industry-related issues and needs. Education and specialized training are the foundation of all CPSA events. As the industry has evolved so has CPSA. Thus, the year the name was changed from Chemical and Pharmaceutical Structural Analysis to CPSA was to reflect the growing focus on clinical applications and the emergence of personalized medicine. Most importantly, the CPSA annual meeting has retained the same high-quality scientific content, open interaction from industry opinion leaders and a collegial environment. 23866686 Safe Delivery Posts: An intervention to provide equitable childbirth care services to vulnerable groups in Zahedan, Iran. recently, there has been a shift towards alternative childbirth services to increase access to skilled care during childbirth. this study aims to assess the past 10 years of experience of the first Safe Delivery Posts (SDPs) established in Zahedan, Iran to determine the number of deliveries and the intrapartum transfer rates, and to examine the reasons why women choose to give birth at a Safe Delivery Post and not in one of the four large hospitals in Zahedan. a mixed-methods research strategy was used for this study. In the quantitative phase, an analysis was performed on the existing data that are routinely collected in the health-care sector. In the qualitative phase, a grounded theory approach was used to collect and analyse narrative data from in-depth interviews with women who had given birth to their children at the Safe Delivery Posts. women were selected from two Safe Delivery Posts in Zahedan city in southeast Iran. nineteen mothers who had given birth in the Safe Delivery Posts were interviewed. during the 10-year period, 22,753 low-risk women gave birth in the Safe Delivery Posts, according to the records. Of all the women who were admitted to the Safe Delivery Posts, on average 2.1% were transferred to the hospital during labour or the postpartum period. Three key categories emerged from the analysis: barriers to hospital use, opposition to home birth and finally, reasons for choosing the childbirth care provided by the SDPs. implementing a model of midwifery care that offers the benefits of modern medical care and meets the needs of the local population is feasible and sustainable. This model of care reduces the cost of giving birth and ensures equitable access to care among vulnerable groups in Zahedan. 23760221 Prevention of sternal wound complications after sternotomy: results of a large prospective randomized multicentre trial. A prospective randomized multicentre trial was performed to analyse the efficacy of a vest (Posthorax support vest®) to prevent sternal wound infection after cardiac surgery, and to identify risk factors. From September 2007 to March 2010, 2539 patients undergoing cardiac surgery via median sternotomy were prospectively randomized into those who received a Posthorax® vest and those who did not. Patients were instructed to wear the vest postoperatively for 24 h a day for at least 6 weeks; the duration of follow-up was 90 days. Patients who did not use the vest within a period of 72 h postoperatively were regarded as study dropouts. Statistical calculations were based on an intention-to-treat (ITT) analysis. Further evaluations comprised all subgroups of patients. Complete data were available for 2539 patients (age 67 ± 11years, 45% female). Of these, 1351 were randomized to receive a vest, while 1188 received no vest. No significant differences were observed between groups regarding age, gender, diabetes, body mass index, chronic obstructive pulmonary disease (COPD), renal failure, the logistic EuroSCORE and the indication for surgery. The frequency of deep wound complications (dWC: mediastinitis and sternal dehiscence) was significantly lower in vest (n = 14; 1.04%) vs non-vest (n = 27; 2.27%) patients (ITT, P < 0.01), but superficial complications did not differ between groups. Subanalysis of vest patients revealed that only 933 (Group A) wore the vest according to the protocol, while 202 (Group BR) refused to wear the vest (non-compliance) and 216 (Group BN) did not use the vest for other reasons. All dWC occurred in Groups BR (n = 7) and BN (n = 7), although these groups had the same preoperative risk profile as Group A. Postoperatively, Group BN had a prolonged intubation time, a longer stay in the intensive care unit, greater use of intra-aortic balloon pump, higher frequency of COPD and a larger percentage of patients who required prolonged surgery. Consistent use of the Posthorax® vest prevented deep sternal wounds. The anticipated risk factors for wound complications did not prove to be relevant, whereas intra- and postoperative complications appear to be very significant. 23341163 Epigenetic regulation of inflammation: progressing from broad acting histone deacetylase (HDAC) inhibitors to targeting specific HDACs. Inhibition of histone deacetylases (HDAC) is emerging as a novel approach to treat a variety of diseases. Recently, broad acting inhibitors of HDAC have been shown to have anti-inflammatory effects both in vitro and in vivo. It is significant that these anti-inflammatory effects are observed at 10-100 fold lower concentrations than their anti-cancer effects. The broad action of these compounds makes it difficult to determine which HDAC enzymes are important in inflammation. Although showing promise it is unlikely that these drugs will progress to the clinic for treating inflammatory diseases due to number of HDACs they affect and the widespread activity of the enzymes throughout the body. Accordingly, research is now progressing to targeting specific HDAC enzymes to improve efficacy of treatment as well as reduce the risk of any unwanted side effects. Understanding the role specific HDACs play in inflammatory disease will help us to identify novel anti-inflammatory treatments. This manuscript is designed to review our limited knowledge in this field. 23470077 Asymmetric Dimethylarginine (ADMA): A Promising Biomarker for Cardiovascular Disease? Asymmetric Dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) production. ADMA is generated from methylation of arginine residues by protein arginine methyltransferases (PRMTs) and subsequent proteolysis, while its elimination is achieved mainly by degradation with dimethylarginine dimethylaminohydrolase (DDAH). Oxidative stress, endothelial nitric oxide synthase (eNOS) inhibition, eNOS uncoupling, inflammation and shear stress play a pivotal role in ADMA pathophysiology by managing PRMT/DDAH expression and NO synthesis and leading to a common result - endothelial dysfunction. Endothelial dysfunction seems to be the common finding in studies investigating the role of ADMA in cardiovascular disease (CVD). High-performance liquid chromatography (HPLC), mass spectrometry (MS) and enzyme-linked immunosorbent assay (ELISA) are the existing methods for ADMA quantification. However, none of them fulfils all the criteria to be characterized as "gold standard". ADMA is significantly associated with risk factors for CVD and almost with every disease of the cardiovascular system; showing an independent, strong prognostic value for mortality and future cardiovascular events. This article aims to review the current knowledge about ADMA biology and metabolism, pathophysiological mechanisms implicating ADMA in CVD, methods for the determination of ADMA and its association with CVD risk factors and established CVDs. 23590833 iNOS: A Potential Therapeutic Target for Malignant Glioma. Glioblastoma is the most aggressive adult primary brain tumor. Although progress has been made in understanding the molecular mechanisms underlying these tumors, current treatments are ineffective. Recent studies have identified iNOS as a critical regulator of glial transformation downstream of EGFRvIII/STAT3 signaling, a key oncogenic pathway in glioblastoma. STAT3 directly binds the promoter of the iNOS gene and thereby stimulates its expression. Importantly, inhibition of iNOS by genetic and pharmacological approaches impedes glial cell proliferation, invasiveness, and tumor growth in vivo. iNOS expression is also elevated in a population of human brain tumor stem cells (BTSCs), and iNOS is required for BTSC proliferation and tumorigenesis. Together, these findings suggest that development of iNOS-targeted therapies may prove valuable in the treatment of glioblastoma. Here, we review our current understanding of iNOS signaling in the regulation of glioblastoma pathogenesis and the potential mechanisms by which iNOS inhibition might suppress the malignant behavior of these devastating tumors. 23798432 Molecular circuit involving KLK4 integrates androgen and mTOR signaling in prostate cancer. The androgen receptor (AR) and the phosphoinositide 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin (mTOR) signaling are two of the major proliferative pathways in a number of tissues and are the main therapeutic targets in various disorders, including prostate cancer (PCa). Previous work has shown that there is reciprocal feedback regulation of PI3K and AR signaling in PCa, suggesting that cotargeting both pathways may enhance therapeutic efficacy. Here we show that proteins encoded by two androgen-regulated genes, kallikrein related peptidase 4 (KLK4) and promyelocytic leukemia zinc finger (PLZF), integrate optimal functioning of AR and mTOR signaling in PCa cells. KLK4 interacts with PLZF and decreases its stability. PLZF in turn interacts with AR and inhibits its function as a transcription factor. PLZF also activates expression of regulated in development and DNA damage responses 1, an inhibitor of mTORC1. Thus, a unique molecular switch is generated that regulates both AR and PI3K signaling. Consistently, KLK4 knockdown results in a significant decline in PCa cell proliferation in vitro and in vivo, decreases anchorage-independent growth, induces apoptosis, and dramatically sensitizes PCa cells to apoptosis-inducing agents. Furthermore, in vivo nanoliposomal KLK4 siRNA delivery in mice bearing PCa tumors results in profound remission. These results demonstrate that the activities of AR and mTOR pathways are maintained by KLK4, which may thus be a viable target for therapy. 23917781 Synovial Hemangioma of Hoffa Fat Pad Demonstrated by RBC SPECT/CT. Synovial hemangioma of Hoffa fat pad is an extremely rare disease, which occurs in the knee joints. Because synovial hemangioma often shows nonspecific symptoms, such as pain, swelling, limping, or limitation of motion, diagnosis could be delayed in many cases. We present a 7-year-old boy referred to our department for Tc red blood cell (RBC) scan for the confirmation of hemangioma suggested by the MRI. RBC scan demonstrated intense radioactivity accumulation in Hoffa pad of right knee joint, and subsequent excision biopsy revealed the mass as venous hemangioma. 23497891 Rapid monitoring of heat-accelerated reactions in vegetable oils using direct analysis in real time ionization coupled with high resolution mass spectrometry. Transmission-mode direct analysis in real time ionization coupled with high resolution mass spectrometry (TM-DART-HRMS) was used to monitor chemical changes in various vegetable oils (olive, rapeseed, soybean and sunflower oil) during their thermally-induced oxidation. This novel instrumental approach enabled rapid fingerprinting of examined samples and detection of numerous sample components, such as triacylglycerols (TAGs), phytosterols, free fatty acids (FFA), and their respective oxidation products. Mass spectra obtained from DART were processed with the use of principal component analysis (PCA) in order to assess the compositional differences between heated and non-heated samples. Good correlation was observed between the normalized intensities of the pre-selected ion corresponding to mono-oxidized TAG and 'classic' criterion represented by the levels of TAG polymers determined by high performance-size exclusion chromatography with refractometric detection (HP-SEC-RID). 23951226 Mutationmapper: a tool to aid the mapping of protein mutation data. There has been a rapid increase in the amount of mutational data due to, amongst other things, an increase in single nucleotide polymorphism (SNP) data and the use of site-directed mutagenesis as a tool to help dissect out functional properties of proteins. Many manually curated databases have been developed to index point mutations but they are not sustainable with the ever-increasing volume of scientific literature. There have been considerable efforts in the automatic extraction of mutation specific information from raw text involving use of various text-mining approaches. However, one of the key problems is to link these mutations with its associated protein and to present this data in such a way that researchers can immediately contextualize it within a structurally related family of proteins. To aid this process, we have developed an application called MutationMapper. Point mutations are extracted from abstracts and are validated against protein sequences in Uniprot as far as possible. Our methodology differs in a fundamental way from the usual text-mining approach. Rather than start with abstracts, we start with protein sequences, which facilitates greatly the process of validating a potential point mutation identified in an abstract. The results are displayed as mutations mapped on to the protein sequence or a multiple sequence alignment. The latter enables one to readily pick up mutations performed at equivalent positions in related proteins. We demonstrate the use of MutationMapper against several examples including a single sequence and multiple sequence alignments. The application is available as a web-service at http://mutationmapper.bioch.ox.ac.uk. 23388045 Updated clinical considerations for dental implant therapy in irradiated head and neck cancer patients. An increasing number of reports indicate successful use of dental implants (DI) during oral rehabilitation for head and neck cancer patients undergoing tumor surgery and radiation therapy. Implant-supported dentures are a viable option when patients cannot use conventional dentures due to adverse effects of radiation therapy, including oral dryness or fragile mucosa, in addition to compromised anatomy; however, negative effects of radiation, including osteoradionecrosis, are well documented in the literature, and early loss of implants in irradiated bone has been reported. There is currently no consensus concerning DI safety or clinical guidelines for their use in irradiated head and neck cancer patients. It is important for health care professionals to be aware of the multidimensional risk factors for these patients when planning oral rehabilitation with DIs, and to provide optimal treatment options and maximize the overall treatment outcome. This paper reviews and updates the impact of radiotherapy on DI survival and discusses clinical considerations for DI therapy in irradiated head and neck cancer patients. 23940788 Patterns of Horse-Rider Coordination during Endurance Race: A Dynamical System Approach. In riding, most biomechanical studies have focused on the description of the horse locomotion in unridden condition. In this study, we draw the prospect of how the basic principles established in inter-personal coordination by the theory of Coordination Dynamics may provide a conceptual and methodological framework for understanding the horse-rider coupling. The recent development of mobile technologies allows combined horse and rider recordings during long lasting natural events such as endurance races. Six international horse-rider dyads were thus recorded during a 120 km race by using two tri-axial accelerometers placed on the horses and riders, respectively. The analysis concentrated on their combined vertical displacements. The obtained shapes and angles of Lissajous plots together with values of relative phase between horse and rider displacements at lower reversal point allowed us to characterize four coordination patterns, reflecting the use of two riding techniques per horse's gait (trot and canter). The present study shows that the concepts, methods and tools of self-organizing dynamic system approach offer new directions for understanding horse-rider coordination. The identification of the horse-rider coupling patterns constitutes a firm basis to further study the coalition of multiple constraints that determine their emergence and their dynamics in endurance race. 23798471 Chaperone-like effects of a scFv antibody on the folding of human muscle creatine kinase. Molecular chaperones play an essential role in assisting the folding of a myriad of nascent peptides to form different biologically active proteins. Therefore, their low substrate specificity is important for the functions of these housekeeping proteins. However, discovering chaperones which assist the folding of a particular protein can shed new light on the folding pathway of the protein, offering an interesting approach for developing specific therapeutic agents to treat protein-misfolding diseases. Screening of antibodies with chaperone-like function represents a novel strategy to meet the challenges. In this study, some single-chain variable fragment (scFv) antibodies were selected from a high-capacity phage antibody library using human muscle creatine kinase (HCK) as antigen. A scFv antibody (scFv A4) was determined to inhibit aggregation and favor recovery of the native conformation of HCK during its refolding. This antibody also increased the stability of HCK during its heat-induced unfolding process. Our findings demonstrate that scFv A4 has dual-chaperone-like activities: assisting in correct protein folding as well as protecting the native protein from unfolding. A molecular mechanism by which scFv A4 exhibits chaperone-like effects on HCK was proposed. This study demonstrates that phage antibody libraries can lead to chaperone-like proteins, and the specificity of the resulting antibody toward its antigen could provide new molecular details regarding how the chaperone interacts with the protein's unfolding and folding pathways. 23873653 A model combining excess and relative mortality for population-based studies. Considering expected mortality provides an attractive approach to analyse mortality of population-based cohorts of patients presenting with a chronic disease. Two classes of methods are available: either modelling the excess mortality using an additive hazard model or modelling the relative mortality using a multiplicative hazard model. Because these two models are informative to look for factors associated with mortality related to a chronic disease, we developed an alternative model modelling both the excess and the relative mortality. We generalised Andersen and Vaeth's model to fit covariates and obtain directly an estimation of the Excess Mortality Ratio and Relative Mortality Ratio for each covariate. We assessed the performances of the combined model by using simulations, and it appeared satisfactorily. We illustrate the combined model by data collected in patients presenting with end-stage renal disease and treated by dialysis. The combined model offers the possibility of performing pure additive and multiplicative models and thus to compare their log-likelihoods. The combined model appears useful to select one of these pure models or to conclude to the need of modelling both excess and relative mortality. In this latter case, our model enabled better describing the effect of covariates on the excess and relative mortality. Copyright © 2013 John Wiley & Sons, Ltd. 23770033 New insights on glucosylated lipids: Metabolism and functions. Ceramide, cholesterol, and phosphatidic acid are major basic structures for cell membrane lipids. These lipids are modified with glucose to generate glucosylceramide (GlcCer), cholesterylglucoside (ChlGlc), and phosphatidylglucoside (PtdGlc), respectively. Glucosylation dramatically changes the functional properties of lipids. For instance, ceramide acts as a strong tumor suppressor that causes apoptosis and cell cycle arrest, while GlcCer has an opposite effect, downregulating ceramide activities. All glucosylated lipids are enriched in lipid rafts or microdomains and play fundamental roles in a variety of cellular processes. In this review, we discuss the biological functions and metabolism of these three glucosylated lipids. 23493568 X-box binding protein 1 is essential for insulin regulation of pancreatic alpha cell function. Type 2 diabetes mellitus (T2D) patients often exhibit hyperglucagonemia despite hyperglycemia suggesting defective α-cell function. While endoplasmic reticulum (ER) stress has been suggested to underlie β-cell dysfunction in T2D, its role in α-cell biology remains unclear. X-box binding protein 1 (XBP1) is a transcription factor that plays a crucial role in the unfolded protein response (UPR) and its deficiency in β-cells has been reported to impair insulin secretion leading to glucose intolerance. To evaluate the role of XBP1 in α-cells, we created complementary in vivo (α-cell specific XBP1 knockout (αXBPKO) mice) and in vitro (stable XBP1 knock down α-cell line, αXBPKD) models. αXBPKO mice exhibited glucose intolerance, mild insulin resistance and an inability to suppress glucagon secretion following glucose stimulation. αXBPKD cells exhibited activation of IRE1, an upstream activator of XBP1, leading to phosphorylation of JNK. Interestingly, insulin treatment of αXBPKD cells reduced tyrosine phosphorylation of IRS-1 (pY(896)), and phosphorylation of Akt, while enhancing serine phosphorylation (pS(307)) of IRS-1. Consequently the αXBPKD cells exhibited blunted suppression of glucagon secretion following insulin treatment in the presence of high glucose. Together, these data indicate that XBP1 deficiency in pancreatic α-cells induces altered insulin signaling and dysfunctional glucagon secretion. 23937994 Assessment of a novel, capsid-modified adenovirus with an improved vascular gene transfer profile. Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Gene therapy may provide a successful approach to improve the clinical outcome of these conditions, but would benefit from the development of more efficient vectors for vascular gene delivery. The aim of this study was to assess whether a novel genetically engineered Adenovirus could be utilised to produce enhanced levels of vascular gene expression. Vascular transduction capacity was assessed in primary human saphenous vein smooth muscle and endothelial cells using vectors expressing the LacZ reporter gene. The therapeutic capacity of the vectors was compared by measuring smooth muscle cell metabolic activity and migration following infection with vectors that over-express the candidate therapeutic gene tissue inhibitor of matrix metalloproteinase-3 (TIMP-3). Compared to Adenovirus serotype 5 (Ad5), the novel vector Ad5T*F35++ demonstrated improved binding and transduction of human vascular cells. Ad5T*F35++ mediated expression of TIMP-3 reduced smooth muscle cell metabolic activity and migration in vitro. We also demonstrated that in human serum samples pre-existing neutralising antibodies to Ad5T*F35++ were less prevalent than Ad5 neutralising antibodies. We have developed a novel vector with improved vascular transduction and improved resistance to human serum neutralisation. This may provide a novel vector platform for human vascular gene transfer. 23585398 Propeptides of eukaryotic proteases encode histidines to exploit organelle pH for regulation. Eukaryotic cells maintain strict control over protein secretion, in part by using the pH gradient maintained within their secretory pathway. How eukaryotic proteins evolved from prokaryotic orthologs to exploit the pH gradient for biological functions remains a fundamental question in cell biology. Our laboratory previously demonstrated that protein domains located within precursor proteins, propeptides, encode histidine-driven pH sensors to regulate organelle-specific activation of the eukaryotic proteases furin and proprotein convertase-1/3. Similar findings have been reported in other unrelated protease families. By analyzing >10,000 unique proteases within evolutionarily unrelated families, we show that eukaryotic propeptides are enriched in histidines compared with prokaryotic orthologs. On this basis, we hypothesize that eukaryotic proteins evolved to enrich histidines within their propeptides to exploit the tightly controlled pH gradient of the secretory pathway, thereby regulating activation within specific organelles. Enrichment of histidines in propeptides may therefore be used to predict the presence of pH sensors in other proteases or even protease substrates.-Elferich, J., Williamson, D. M., Krishnamoorthy, B., Shinde, U. Propeptides of eukaryotic proteases encode histidines to exploit organelle pH for regulation. 23914887 Treatment of acne vulgaris in pregnant patients. The management of acne vulgaris in the setting of pregnancy raises important clinical considerations regarding the efficacy and safety of acne treatments in this special patient population. Particular challenges include the absence of safety data, discrepancy in safety data between different safety rating systems, and lack of evidence-based recommendations for the treatment of acne during pregnancy. Nonetheless, many therapeutic options exist, and the treatment of acne in pregnant women can be safely and often effectively accomplished. For mild or moderate disease, patients can be treated with topical antimicrobial agents, anti-inflammatory agents, as well as glycolic and salicylic acid. Several topical agents, notably benzoyl peroxide, previously viewed as potentially dangerous are cited by many sources as being considered safe. When necessary, systemic therapies that can be safely added include penicillins, amoxicillin, cephalosporins, erythromycin, clindamycin, and tetracyclines or sulfonamides, depending on the stage of fetal development. Adjunct therapy may include phototherapy or laser treatments. Physicians should work with this often highly motivated, safety-conscious patient population to tailor an individualized treatment regimen. This treatment regimen will likely shift throughout the different stages of fetal development, as distinct safety considerations are raised prior to conception as well as during each of the trimesters of pregnancy. Important considerations regarding acne management in breast-feeding mothers is also discussed. 23815242 Copolymer-Incarcerated Nickel Nanoparticles with N-Heterocyclic Carbene Precursors as Active Cross-Linking Agents for Corriu-Kumada-Tamao Reaction. We have developed heterogeneous polymer-incarcerated nickel nanoparticles (NPs), which catalyze cross-coupling reactions. The matrix structure of these catalysts incorporates both N-heterocyclic carbenes (NHCs) as ligands and Ni-NPs, thanks to a new design of cross-linking agents in polymer supports. These embedded NHCs were detected by field gradient swollen-resin magic angle spinning NMR analysis. They were successfully applied to Corriu-Kumada-Tamao reactions with a broad substrate scope including functional group tolerance, and the catalyst could be recovered and reused several times without loss of activity. 23742228 Nanoemulsion contrast agents with sub-picomolar sensitivity for xenon NMR. A new type of contrast agent for Xe NMR based on surfactant-stabilized perfluorocarbon-in-water nanoemulsions has been produced. The contrast agent uses dissolved hyperpolarized xenon gas as a nonperturbing reporting medium, as xenon freely exchanges between aqueous solution and the perfluorocarbon interior of the droplets, which are spectroscopically distinguishable and allow for chemical exchange saturation transfer (CEST) detection of the agent. Nanoemulsions with droplet diameters between 160 and 310 nm were produced and characterized using hyperpolarized (129)Xe combined with CEST detection. Saturation parameters were varied and data were modeled numerically to determine the xenon exchange dynamics of the system. Nanoemulsion droplets were detected at concentrations as low as 100 fM, corresponding to <1 μL of perfluorocarbon per liter of solution. The straightforward, inexpensive production of these agents will facilitate future development toward molecular imaging and chemical sensing applications. 23958442 The utility of behavioral studies for aquatic toxicology testing: A meta-analysis. Behavioral responses have been applied for decades as tools for aquatic toxicity testing, but have received far less attention than studies assessing lethality, development or reproduction. With improved visual and non-visual assessment tools and increased knowledge of the importance of behavior for organism health and fitness, interest in behavioral analysis has increased in recent years. However, to our knowledge there has never been a quantitative assessment of the available techniques for organismal toxicity testing, so it is not clear whether behavioral studies represent valuable additions to environmental monitoring. We performed a meta-analysis comparing the relative sensitivities and average durations of behavioral studies to those assessing acute lethality, development and reproduction. Results demonstrate that the average duration of behavioral studies is consistently less than developmental or reproductive studies, and that behavioral endpoints are generally more sensitive than those assessing development or reproduction. We found effect sizes to be lower but power to be higher in behavioral and reproductive studies compared to studies assessing development, which likely relates to low sample sizes commonly used in developmental studies. Overall, we conclude that behavioral studies are comparatively fast and sensitive, and therefore warrant further attention as tools for assessing the toxicological effects of environmental contaminants. We suggest that research aimed at developing and optimizing techniques for behavioral analysis could prove extremely useful to the field of toxicology, but that future work must be directed at determining what specific behaviors are most sensitive to various classes of contaminants, and at understanding the relevance of changes to discrete behaviors for influencing organismal and population-level health and fitness. 23602877 Artificial extracellular matrix composed of collagen I and highly sulfated hyaluronan interferes with TGFβ(1) signaling and prevents TGFβ(1)-induced myofibroblast differentiation. Sulfated glycosaminoglycans are promising components for functional biomaterials since sulfate groups modulate the binding of growth factors and thereby influence wound healing. Here, we have investigated the influence of an artificial extracellular matrix (aECM) consisting of collagen I (coll) and hyaluronan (HA) or highly sulfated HA (hsHA) on dermal fibroblasts (dFb) with respect to their differentiation into myofibroblasts (MFb). Fibroblasts were cultured on aECM in the presence of aECM-adsorbed or soluble transforming growth factor β1 (TGFβ1). The synthesis of α-smooth muscle actin (αSMA), collagen and the ED-A splice variant of fibronectin (ED-A FN) were analyzed at the mRNA and protein levels. Furthermore, we investigated the bioactivity and signal transduction of TGFβ1 in the presence of aECM and finally made interaction studies of soluble HA or hsHA with TGFβ1. Artificial ECM composed of coll and hsHA prevents TGFβ1-stimulated αSMA, collagen and ED-A FN expression. Our data suggest an impaired TGFβ1 bioactivity and downstream signaling in the presence of aECM containing hsHA, shown by massively reduced Smad2/3 translocation to the nucleus. These data are explained by in silico docking experiments demonstrating the occupation of the TGFβ-receptor I binding site by hsHA. Possibly, HA sulfation has a strong impact on TGFβ1-driven differentiation of dFb and thus could be used to modulate the properties of biomaterials. 23964014 Microscopic evaluation of vesicles shed by erythrocytes at elevated temperatures. The images of human erythrocytes and vesicles were analyzed by a light microscopy system with spatial resolution of better than 90 nm. The samples were observed in an aqueous environment and required no freezing, dehydration, staining, shadowing, marking, or any other manipulation. Temperature elevation resulted in significant concentration increase of structurally transformed erythrocytes (echinocytes) and vesicles in the blood. The process of vesicle separation from spiculated erythrocytes was video recorded in real time. At a temperature of 37°C, mean vesicle concentrations and diameters were found to be 1.50 ± 0.35 × 10(6) vesicles per microliter and 0.365 ± 0.065 μm, respectively. The vesicle concentration increased approximately threefold as the temperature increased from 37 to 40°C. It was estimated that 80% of all vesicles found in the blood are smaller than 0.4 μm. Accurate account of vesicle numbers and dimensions suggest that 86% of the lost erythrocyte material is lost not by vesiculation but by another, as yet, unknown mechanism. Microsc. Res. Tech., 2013. © 2013 Wiley Periodicals, Inc. 23806158 Kaposi's sarcoma: etiology and pathogenesis, inducing factors, causal associations, and treatments: facts and controversies. Kaposi's sarcoma (KS), an angioproliferative disorder, has a viral etiology and a multifactorial pathogenesis hinged on an immune dysfunction. The disease is multifocal, with a course ranging from indolent, with only skin manifestations to fulminant, with extensive visceral involvement. In the current view, all forms of KS have a common etiology in human herpesvirus (HHV)-8 infection, and the differences among them are due to the involvement of various cofactors. In fact, HHV-8 infection can be considered a necessary but not sufficient condition for the development of KS, because further factors (genetic, immunologic, and environmental) are required. The role of cofactors can be attributed to their ability to interact with HHV-8, to affect the immune system, or to act as vasoactive agents. In this contribution, a survey of the current state of knowledge on many and various factors involved in KS pathogenesis is carried out, in particular by highlighting the facts and controversies about the role of some drugs (quinine analogues and angiotensin-converting enzyme inhibitors) in the onset of the disease. Based on these assessments, it is possible to hypothesize that the role of cofactors in KS pathogenesis can move toward an effect either favoring or inhibiting the onset of the disease, depending on the presence of other agents modulating the pathogenesis itself, such as genetic predisposition, environmental factors, drug intake, or lymph flow disorders. It is possible that the same agents may act as either stimulating or inhibiting cofactors according to the patient's genetic background and variable interactions. Treatment guidelines for each form of KS are outlined, because a unique standard therapy for all of them cannot be considered due to KS heterogeneity. In most cases, therapeutic options, both local and systemic, should be tailored to the patient's peculiar clinical conditions. 23927767 The Citrus clementina putative allergens: from the proteomic analysis to the structural features. Several allergens have been identified and characterized in the genus Citrus, which belongs to the germin-like proteins (GPLs), profilins, and non-specific lipid transfer proteins (nsLTPs). In this work, in silico sequences analysis, protein purification, mass spectrometry identification and spectral counting method, were integrated to identify new putative allergens of Citrus clementina and their expression level in the fruit peel. The in silico analysis revealed ten new sequences belonging to GLPs (Cit cl 1), and two more belonging to nsLTPs (Cit cl 3). No other new sequences were found as regards profilins (Cit cl 2). Each putative allergen from fruit peel was obtained using different protein extraction methods, and the protein sequences of the putative allergens were identified by means of LTQ-Orbitrap XL mass spectrometer. The spectral counting strategy revealed that Cit cl 1 had a higher expression level than Cit cl 2 and Cit cl 3. To predict the quaternary structure and deduced function of Cit cl 1, its primary sequence was used as template to search a homologous protein structure in RCSB PDB Database, getting high correspondence with the oxalate oxidase protein in barley. 23602468 Prediction of bacterial meningitis based on cerebrospinal fluid pleocytosis in children. Children with cerebrospinal fluid pleocytosis are frequently treated with parenteral antibiotics, but only a few have bacterial meningitis. Although some clinical prediction rules, such as bacterial meningitis score, are of well-known value, the cerebrospinal fluid white blood cells count can be the initial available information. Our aim was to establish a cutoff point of cerebrospinal fluid white blood cell count that could distinguish bacterial from viral and aseptic meningitis. A retrospective study of children aged 29 days to 17 years who were admitted between January 1st and December 31th, 2009, with cerebrospinal fluid pleocytosis (white blood cell≥7μL(-1)) was conducted. The cases of traumatic lumbar puncture and of antibiotic treatment before lumbar puncture were excluded. There were 295 patients with cerebrospinal fluid pleocytosis, 60.3% females, medium age 5.0±4.3 years distributed as: 12.2% 1-3 months; 10.5% 3-12 months; 29.8% 12 months to 5 years; 47.5% >5 years. Thirty one children (10.5%) were diagnosed with bacterial meningitis, 156 (52.9%) viral meningitis and 108 (36.6%) aseptic meningitis. Bacterial meningitis was caused by Neisseria meningitidis (48.4%), Streptococcus pneumoniae (32.3%), other Streptococcus species (9.7%), and other agents (9.7%). cerebrospinal fluid white blood cell count was significantly higher in patients with bacterial meningitis (mean, 4839cells/μL) compared to patients with aseptic meningitis (mean, 159cells/μL, p<0.001), with those with aseptic meningitis (mean, 577cells/μL, p<0.001) and with all non-bacterial meningitis cases together (p<0.001). A cutoff value of 321white blood cell/μL showed the best combination of sensitivity (80.6%) and specificity (81.4%) for the diagnosis of bacterial meningitis (area under receiver operating characteristic curve 0.837). Therefore, the value of cerebrospinal fluid white blood cell count was found to be a useful and rapid diagnostic test to distinguish between bacterial and nonbacterial meningitis in children. 23341452 Solid-state NMR study reveals collagen I structural modifications of amino acid side chains upon fibrillogenesis. In vivo, collagen I, the major structural protein in human body, is found assembled into fibrils. In the present work, we study a high concentrated collagen sample in its soluble, fibrillar, and denatured states using one and two dimensional {(1)H}-(13)C solid-state NMR spectroscopy. We interpret (13)C chemical shift variations in terms of dihedral angle conformation changes. Our data show that fibrillogenesis increases the side chain and backbone structural complexity. Nevertheless, only three to five rotameric equilibria are found for each amino acid residue, indicating a relatively low structural heterogeneity of collagen upon fibrillogenesis. Using side chain statistical data, we calculate equilibrium constants for a great number of amino acid residues. Moreover, based on a (13)C quantitative spectrum, we estimate the percentage of residues implicated in each equilibrium. Our data indicate that fibril formation greatly affects hydroxyproline and proline prolyl pucker ring conformation. Finally, we discuss the implication of these structural data and propose a model in which the attractive force of fibrillogenesis comes from a structural reorganization of 10 to 15% of the amino acids. These results allow us to further understand the self-assembling process and fibrillar structure of collagen. 23442837 Stepwise combination of simple noninvasive fibrosis scoring systems increases diagnostic accuracy in nonalcoholic Fatty liver disease. Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease ranging from simple fatty liver to steatohepatitis, fibrosis, and cirrhosis. We aimed to analyze the diagnostic performance and clinical utility of simple noninvasive tests alone or in combination for the detection of advanced fibrosis in patients with NAFLD. Data from 323 patients with biopsy-proven NAFLD/NASH who presented to the Clinic for Gastroenterology and Hepatology, University Hospital of Cologne between July 1998 and November 2009, were analyzed retrospectively. Sensitivity, specificity, positive predictive values, and negative predictive values were determined along with the area under receiver operating characteristic curves (AUROC) using published formulas for NAFLD, FIB-4, and BARD fibrosis scores. The area under receiver operating characteristic curves were as follows: NAFLD fibrosis score 0.96 [95% confidence interval (CI), 0.92-0.99], FIB-4 0.95 (95% CI, 0.91-1.00), BARD 0.82 (95% CI, 0.71-0.92) with negative predictive values for advanced fibrosis of 96%, 98%, and 96%, respectively. When applying the NAFLD, FIB-4, or BARD scoring systems 25%, 15%, or 26% of cases with advanced fibrosis would have been missed. Combining FIB-4 and BARD in a stepwise fashion, patients would have been correctly classified without biopsy in 67% of cases without missing a single case of advanced fibrosis. The FIB-4 and NAFLD fibrosis scores perform better than the BARD scoring system. Liver biopsy can securely be replaced only with a stepwise combination of simple noninvasive tests, otherwise the assessment of risk due to advanced fibrosis may be misleading in a clinically meaningful proportion of patients. 23436650 The discovery of novel human androgen receptor antagonist chemotypes using a combined pharmacophore screening procedure. Unraveling the mechanisms involved in castration- and therapy-resistant prostate cancer has led to a renewed interest in androgen receptor (AR)-targeted therapeutics. Anti-androgens that block the activity of the AR therefore remain a valid therapeutic option. However, they must be more effective than, or display a distinct mechanism of action or binding mode from those of bicalutamide and hydroxyflutamide, which are currently in clinical use. For that reason, the second-generation anti-androgen MDV3100 was developed. MDV3100, however, shares its 4-cyano-3-(trifluoromethyl)phenyl group with bicalutamide and hydroxyflutamide required for binding to the AR. In this work, we used a combined strategy to find new antagonist structures distinct from the 4-cyano-3-(trifluoromethyl)phenyl group to avoid cross-resistance for these compounds and to find structures without agonist activity on mutant ARs (AR W741C and AR T877A). We found two novel chemotypes with AR-antagonistic activity (IC(50): 3-6 μM) by virtual screening and confirmed their biological activity in an androgen-responsive reporter assay. The design of our computational approach was validated by the observation of strongly decreased or absence of agonistic activity on the two mutant ARs. Further structural derivatization to optimize the potency of these compounds can render these chemotypes into very promising, alternative AR antagonists for prostate cancer therapy. 23461585 Synthesis of mixed ceramic Mg(x)Zn(1-x)O nanofibers via Mg2+ doping using sol-gel electrospinning. We report on the synthesis of tuned energy band gap Mg(x)Zn(1-x)O nanofibers (NFs) with different Mg(2+) content via the sol-gel electrospinning (ES) technique wherein the addition of the doping material affects not only the morphologies of as-spun ZnAc/PVA and MgAc/ZnAc/PVA nanofibers but also the crystal microstructure and optical properties of calcined ZnO and Mg(x)Zn(1-x)O nanofibers. Following an appropriate aqueous solution preparation of magnesium acetate (MgAc) and zinc acetate (ZnAc) with poly(vinyl alcohol) (PVA), electrospinning is performed and then as-spun nanofibers are calcined in an air atmosphere at 600 °C for 3 h. As-spun and calcined nanofiber diameters and morphologies are evaluated with scanning (SEM) and transmission (TEM) electron microscopies, whereas crystalline microstructural interpretations of ZnO and Mg(x)Zn(1-x)O are conducted with wide-angle X-ray diffraction spectra (XRD). Surface chemical composition and elemental evaluation of calcined nanofibers are examined with X-ray photoelectron spectroscopy (XPS), and optical properties and crystal defect analyses of the calcined nanofibers are conducted with photoluminescence spectra (PL). We observe a sharp reduction in fiber diameter upon calcination as a result of the removal of organic species from the fibers and conversion of ceramic precursors into ceramic nanofibers, and the appearance of a range of fiber morphologies from "bead in a string" to "sesame seed" coverage depending on fiber composition. Because Zn(2+) and Mg(2+) have similar ionicity and atomic radii, some Zn(2+) atoms are replaced by Mg(2+) atoms in the crystals, leading to a change in the properties of crystal lattices. The band gap energy of the calcined fibers increases significantly with addition of Mg(2+) along with an increase in the ultraviolet (UV) photoluminescence emission of the fibers. 23709183 Three prevacuolar compartment Rab GTPases impact Candida albicans hyphal growth. Disruption of vacuolar biogenesis in the pathogenic yeast Candida albicans causes profound defects in polarized hyphal growth. However, the precise vacuolar pathways involved in yeast-hypha differentiation have not been determined. Previously we focused on Vps21p, a Rab GTPase involved in directing vacuolar trafficking through the late endosomal prevacuolar compartment (PVC). Herein, we identify two additional Vps21p-related GTPases, Ypt52p and Ypt53p, that colocalize with Vps21p and can suppress the hyphal defects of the vps21Δ/Δ mutant. Phenotypic analysis of gene deletion strains revealed that loss of both VPS21 and YPT52 causes synthetic defects in endocytic trafficking to the vacuole, as well as delivery of the virulence-associated vacuolar membrane protein Mlt1p from the Golgi compartment. Transcription of all three GTPase-encoding genes is increased under hyphal growth conditions, and overexpression of the transcription factor Ume6p is sufficient to increase the transcription of these genes. While only the vps21Δ/Δ single mutant has hyphal growth defects, these were greatly exacerbated in a vps21Δ/Δ ypt52Δ/Δ double mutant. On the basis of relative expression levels and phenotypic analysis of gene deletion strains, Vps21p is the most important of the three GTPases, followed by Ypt52p, while Ypt53p has an only marginal impact on C. albicans physiology. Finally, disruption of a nonendosomal AP-3-dependent vacuolar trafficking pathway in the vps21Δ/Δ ypt52Δ/Δ mutant, further exacerbated the stress and hyphal growth defects. These findings underscore the importance of membrane trafficking through the PVC in sustaining the invasive hyphal growth form of C. albicans. 23940515 Parathyroidectomy improves survival in patients with severe hyperparathyroidism: a comparative study. Secondary hyperparathyroidism (SHPT) in CKD is associated with an increased risk for mortality, but definitive data showing that parathormone control decreases mortality is still lacking. This study aimed to compare the mortality of patients with severe SHPT submitted to parathyroidectomy(PTX) with those who did not have access to surgery. This is a retrospective study in a cohort of 251 CKD patients with severe SHPT who were referred to a CKD-MBD Center for PTX from 2005 until 2012. Most of our patients had indication of PTX, but only 49% of them had access to this surgical procedure. After a mean follow-up of 23 months, 72 patients had died. Non-survivors were older; more often had diabetes, lower serum 25 vitamin D and mostly had not been submitted to surgery. The relative risk of death was lower in the PTX patients (0.428; 95% CI, 0.28 to 0.67; p<0.0001). After adjustments, mortality risk was dependent on age (1.04; 95% CI, 1.01 to 1.07; p = 0.002), 25 vitamin D (0.43; 95% CI, 0.24 to 0.81; p = 0.006) and no access to PTX (4.13; 95% CI, 2.16 to 7.88; p<0.0001). Results remained the same in a second model using the PTX date as the study start date for the PTX group. Our data confirms the benefit of PTX on mortality in patients with severe SHPT. The high mortality encountered in our population is significant and urges the need to better treat these patients. 23727789 Dextran based sensitive theranostic nanoparticles for near-infrared imaging and photothermal therapy in vitro. Indocyanine green (ICG) nanoparticles were developed via electrostatic interactions of ICG and dextran based block copolymers (PEG-dextran(-SS-NH2)) as near-infrared (NIR) theranostic nanoparticles. The nanoparticles could be activated from "OFF" to "ON" of NIR fluorescence in an intracellular environment and used for NIR imaging and photothermal therapy. 23544794 Nanoscale Imaging of Neutral Atoms with a Pulsed Magnetic Lens. We present a scheme for imaging of neutral atoms to the nanoscale with a pulsed magnetic lens and show its viability through numerical calculations. This scheme achieves focal lengths on the order of several centimeters and focal spots of less than 10 nm. With these results, it is possible to create sub-10 nm structures on surfaces in a parallel and time-efficient manner. When used with metastable noble gas atoms, and in combination with electron spectroscopy, this scheme can create a chemically sensitive microscope which can probe surfaces on the nanometer scale. 22766390 Enhancement of cognitive function in models of brain disease through environmental enrichment and physical activity. This review will provide an overview of the non-drug based approaches that have been demonstrated to enhance cognitive function of the compromised brain, primarily focussed on the two most widely adopted paradigms of environmental enrichment and enhanced physical exercise. Environmental enrichment involves the generation of novelty and complexity in animal housing conditions which facilitates enhanced sensory and cognitive stimulation as well as physical activity. In a wide variety of animal models of brain disorders, environmental enrichment and exercise have been found to have beneficial effects, including cognitive enhancement, delayed disease onset, enhanced cellular plasticity and associated molecular processes. Potential cellular and molecular mechanisms will also be discussed, which have relevance for the future development of 'enviromimetics', drugs which could mimic or enhance the beneficial effects of environmental stimulation. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23828847 Acquired supravalvular pulmonary stenosis due to extrinsic compression by a mediastinal dermoid cyst. Acquired pulmonary stenosis is rare. When it occurs, it usually results from compression of the pulmonary artery or the heart by a mediastinal tumour. As these masses rarely cause compression that results in murmurs, it is hard to make a diagnosis. We describe a 23-year-old female patient who presented with dull, aching chest pain lasting for 6 months. Echocardiography showed a large anterior mediastinal cystic mass compressing the main pulmonary artery. She was operated through a left anterolateral thoracotomy and had an uneventful recovery. 23742852 Reduction of leaf area and symptom severity as proxies of disease-induced plant mortality: The example of the Cauliflower mosaic virus infecting two Brassicaceae hosts. Disease induced effects on host survival are important to understand the evolution of parasitic virulence and host resistance/tolerance. Unfortunately, experiments evaluating such effects are in most cases logistically demanding justifying the measurement of survival proxies. For plant hosts commonly used proxies are leaf area and the nature and severity of visual qualitative disease symptoms. In this study we tested whether these traits are indeed correlated to the host mortality rate induced by viral infection. We infected Brassica rapa and Arabidopsis thaliana plants with different natural isolates of Cauliflower mosaic virus (CaMV) and estimated over time the development of symptoms and the relative reduction of leaf area compared to healthy plants and followed plant mortality. We observed that the mortality of infected plants was correlated with the relative reduction of leaf area of both B. rapa and A. thaliana. Measures of mortality were also correlated with the severity of visual qualitative symptoms but the magnitude of the correlations and the time frame at which they were significant depended on the host plant: stronger and earlier correlations were observed on A. thaliana. 23955261 Mutant Ataxin-3 with an Abnormally Expanded Polyglutamine Chain Disrupts Dendritic Development and Metabotropic Glutamate Receptor Signaling in Mouse Cerebellar Purkinje Cells. Spinocerebellar ataxia type 3 (SCA3) is caused by the abnormal expansion of CAG repeats within the ataxin-3 gene. Previously, we generated transgenic mice (SCA3 mice) that express a truncated form of ataxin-3 containing abnormally expanded CAG repeats specifically in cerebellar Purkinje cells (PCs). Here, we further characterize these SCA3 mice. Whole-cell patch-clamp analysis of PCs from advanced-stage SCA3 mice revealed a significant decrease in membrane capacitance due to poor dendritic arborization and the complete absence of metabotropic glutamate receptor subtype1 (mGluR1)-mediated retrograde suppression of synaptic transmission at parallel fiber terminals, with an overall preservation of AMPA receptor-mediated fast synaptic transmission. Because these cerebellar phenotypes are reminiscent of retinoic acid receptor-related orphan receptor α (RORα)-defective staggerer mice, we examined the levels of RORα in the SCA3 mouse cerebellum by immunohistochemistry and found a marked reduction of RORα in the nuclei of SCA3 mouse PCs. To confirm that the defects in SCA3 mice were caused by postnatal deposition of mutant ataxin-3 in PCs, not by genome disruption via transgene insertion, we tried to reduce the accumulation of mutant ataxin-3 in developing PCs by viral vector-mediated expression of CRAG, a molecule that facilitates the degradation of stress proteins. Concomitant with the removal of mutant ataxin-3, CRAG-expressing PCs had greater numbers of differentiated dendrites compared to non-transduced PCs and exhibited retrograde suppression of synaptic transmission following mGluR1 activation. These results suggest that postnatal nuclear accumulation of mutant ataxin-3 disrupts dendritic differentiation and mGluR-signaling in SCA3 mouse PCs, and this disruption may be caused by a defect in a RORα-driven transcription pathway. 23969761 Early local differentiation of the cell wall matrix defines the contact sites in lobed mesophyll cells of Zea mays. Background and AimsThe morphogenesis of lobed mesophyll cells (MCs) is highly controlled and coupled with intercellular space formation. Cortical microtubule rings define the number and the position of MC isthmi. This work investigated early events of MC morphogenesis, especially the mechanism defining the position of contacts between MCs. The distributions of plasmodesmata, the hemicelluloses callose and (1 → 3,1 → 4)-β-d-glucans (MLGs) and the pectin epitopes recognized by the 2F4, JIM5, JIM7 and LM6 antibodies were studied in the cell walls of Zea mays MCs.MethodsMatrix cell wall polysaccharides were immunolocalized in hand-made sections and in sections of material embedded in LR White resin. Callose was also localized using aniline blue in hand-made sections. Plasmodesmata distribution was examined by transmission electron microscopy.ResultsBefore reorganization of the dispersed cortical microtubules into microtubule rings, particular bands of the longitudinal MC walls, where the MC contacts will form, locally differentiate by selective (1) deposition of callose and the pectin epitopes recognized by the 2F4, LM6, JIM5 and JIM7 antibodies, (2) degradation of MLGs and (3) formation of secondary plasmodesmata clusterings. This cell wall matrix differentiation persists in cell contacts of mature MCs. Simultaneously, the wall bands between those of future cell contacts differentiate with (1) deposition of local cell wall thickenings including cellulose microfibrils, (2) preferential presence of MLGs, (3) absence of callose and (4) transient presence of the pectins identified by the JIM5 and JIM7 antibodies. The wall areas between cell contacts expand determinately to form the cell isthmi and the cell lobes.ConclusionsThe morphogenesis of lobed MCs is characterized by the early patterned differentiation of two distinct cell wall subdomains, defining the sites of the future MC contacts and of the future MC isthmi respectively. This patterned cell wall differentiation precedes cortical microtubule reorganization and may define microtubule ring disposition. 23828840 Towards Compatibility between Ruthenium Sensitizers and Cobalt Electrolytes in Dye-Sensitized Solar Cells. Ruthenium and Co: Ruthenium(II) complexes remain prime candidates for dye-sensitized solar applications; however, current ruthenium sensitizers are not compatible with cobalt(II/III) electrolytes. Herein, the effect of surface insulation on device efficiency is studied by comparing two cyclometalated tris-heteroleptic ruthenium(II) complexes. This approach demonstrates a general principle that leads to unprecedented efficiency for a ruthenium(II) sensitizer used in combination with a cobalt electrolyte. 23683178 Melanocytomas of the Central Nervous System: a clinicopathological and molecular study. Melanocytomas of the Central Nervous System (CNS) are rare and benign lesions. These slow-growing tumours can behave aggressively, with local recurrence. Various genetic aberrations occur in malignant melanomas and raise possible new therapeutic options. However, little information is available regarding these characteristic genetic alterations in melanocytomas of the CNS. This study was designed to better understand the clinicopathological and molecular features of melanocytomas. Twenty cases of melanocytoma were studied by light microscopy, electron microscopy and immunohistochemistry. Clinical characteristics, therapeutic options and prognosis were analysed. BRAF, NRAS and KIT gene mutations were tested by direct DNA sequencing. Fourteen of twenty patients had intracranial tumours including one associated with naevus of Ota and six were spinal. Histologically, these tumours contain fusiform and epithelioid cells with little or no cellular pleomorphism and rare mitoses. Immunohistochemical and ultrastructural findings confirmed the origin of tumour cells as melanocytic. None of the melanocytomas harboured BRAF, NRAS and KIT mutations. Patients with complete resection had no tumour recurrence. Moreover, patients with incomplete tumour resection followed by radiotherapy showed a higher local control (LC) rate than incomplete resection alone (P < 0·05). BRAF, NRAS and KIT mutations appear to be rare, if not completely absent in melanocytomas of the CNS. The complete resection of the tumour or incomplete resection followed by radiotherapy should be considered as better therapeutic options to reduce the tumour recurrence. 22991163 Cost-effectiveness of alendronate for the treatment of osteopenic postmenopausal women in Japan. Many postmenopausal women have osteopenia, a condition characterized by loss of bone mineral density (BMD) that is not as severe as in osteoporosis. The objective of this study was to estimate the cost-effectiveness of alendronate to prevent fractures in osteopenic postmenopausal women without a history of fracture in Japan. An individual simulation model was developed to predict lifetime costs and quality-adjusted life years (QALYs) of 5 years of preventive alendronate therapy versus no preventive therapy. The risk of hip and vertebral fracture associated with age and BMD was derived from epidemiologic studies in Japan. We ran the model with different combinations of age (65, 70, and 75 years), BMD (70%, 75%, and 80% of young adult mean [YAM]), and additional clinical risk factors. For 70-year-old women with a BMD of 70% of the YAM having one of the following risk factors: a family history of hip fracture, high alcohol intake, or current smoking, the incremental cost-effectiveness ratio (ICER) of alendronate was $92,937, $126,251, and $129,067 per QALY, respectively. These results were sensitive to age, BMD, and number of clinical risk factors. Probabilistic sensitivity analysis for the base case showed that in the presence of one, two, and three risk factors, alendronate was cost-effective in 0.2% to 2.6%, 13.1% to 56.1%, and 99.1% of the simulations, respectively, if society is willing to pay $50,000 per QALY. Additional analysis indicated that alendronate can be a good value in osteopenic women if the 10-year probability for a osteoporotic hip or vertebral fracture is more than 26.2%. Our results indicate that whether to treat osteopenia with alendronate should be determined on the basis of age, BMD, and number of clinical risk factors in terms of cost-effectiveness. 23839394 127 Assessment of the impact of comorbidities on perioperative complications in pediatric neurosurgery. Recent governmental attempts to control health care costs have focused on reducing the incidence of complications, hospital-acquired conditions (HACs), and other provider preventable conditions (PPCs). One approach uses reduction or elimination of payments for complications, HACs, and PPCs; however, this method assumes all complications, HACs, and PPCs to be the same with payment restrictions applied uniformly. Patient-related factors, such as pre-existing comorbidities, likely influence perioperative complication incidence. We conducted a retrospective assessment of prospectively collected morbidity and mortality events at a large pediatric neurosurgical unit over 5-years. We examined the impact of specific comorbidities and the cumulative effect of multiple comorbidities on complication incidence. 1990 patients underwent 3195 procedures at our tertiary care facility during the 5-year study period. 298 (15.0%) patients experienced at least 1 complication. At least 1 comorbidity was present in 45.9% of patients. Renal comorbidity was significantly associated with the development of a complication (P = .02), and it was specifically associated with wound-related complications (P = .006). Neurological comorbidities had a borderline association with complications (P = .05), and they were specifically associated with the complication of death (P = .037). An increased number of comorbidities, or patients with multiple comorbidities, did not correlate with an increased risk of complication. There was also a general association between the type of surgery a patient underwent and the incidence of complications (P < .0001). The incidence of perioperative complications in pediatric neurosurgery is dynamic and not subject to application of a uniform standard or definition. Complication incidence is variable and may be influenced by the type of neurosurgical procedure and patient-related factors, such as pre-existing comorbidities, such as renal or neurological. Thus, while patient factors, beyond the control of the provider, can significantly impact complications and HACs in pediatric neurosurgery, an increasing number of comorbidities does not correlate with an increased risk of complications. 23576190 Evolutionary concepts in ecotoxicology: tracing the genetic background of differential cadmium sensitivities in invertebrate lineages. In many toxicological and ecotoxicological studies and experimental setups, the investigator is mainly interested in traditional parameters such as toxicity data and effects of toxicants on molecular, cellular or physiological functions of individuals, species or statistical populations. It is clear, however, that such approaches focus on the phenotype level of animal species, whilst the genetic and evolutionary background of reactions to environmental toxicants may remain untold. In ecotoxicological risk assessment, moreover, species sensitivities towards pollutants are often regarded as random variables in a statistical approach. Beyond statistics, however, toxicant sensitivity of every species assumes a biological significance, especially if we consider that sensitivity traits have developed in lineages of species with common evolutionary roots. In this article, the genetic and evolutionary background of differential Cd sensitivities among invertebrate populations and species and their potential of adaptation to environmental Cd exposure will be highlighted. Important evolutionary and population genetic concepts such as genome structure and their importance for evolutionary adaptation, population structure of affected individuals, as well as micro and macroevolutionary mechanisms of Cd resistance in invertebrate lineages will be stressed by discussing examples of work from our own laboratory along with a review of relevant literature data and a brief discussion of open questions along with some perspectives for further research. Both, differences and similarities in Cd sensitivity traits of related invertebrate species can only be understood if we consider the underlying evolutionary processes and genetic (or epigenetic) mechanisms. Keeping in mind this perception can help us to better understand and interpret more precisely why the sensitivity of some species or species groups towards a certain toxicant (or metal) may be ranked in the lower or higher range of species sensitivity distributions. Hence, such a perspective will transcend a purely statistical view of the sensitivity distributions concept, and will enhance ecotoxicology in many respects. 23648218 Molecular characterization of mosquitocidal Bacillus sphaericus isolated from Tamil Nadu, India. Forty-two Bacillus sphaericus strains were isolated from soil around Tamil Nadu, India. The phylogenetic relationship among the B. sphaericus isolates was analysed by REP-PCR and multiplex PCR was performed for the detection of mosquito larvicidal genes binA, binB, mtx1, mtx2 and mtx3 in B. sphaericus isolates. According to the REP-PCR band pattern, B. sphaericus isolates were divided into group A comprising I-XI clusters and group B comprising cluster XII. Three of the isolates BSTN01, 23 and 24 were gathered under cluster XII showed a high level of larvicidal activity against Culex quinquefasciatus and Anopheles stephensi, the other 39 isolates grouped under I-XI clusters were non-toxic or weak or moderately toxic to mosquito larvae. Even though BSTN23 and 24 were isolated from the same location and both contained all the five mosquito larvicidal genes, their intraspecies difference was clearly elucidated by REP-PCR analysis. Among high toxic isolates, BSTN23 and 24 were observed to contain all the five toxin genes and BSTN01 showed the presence of binary toxin and Mtx1 toxin genes. The isolates BSTN02, 03, 07, 14, 16, 19, 20, 21, 25, 31, 36 and 39 were found to contain mtx1 gene with combination of mtx2 and/or mtx3 showed moderate or low toxicity against mosquito larvae. binA, binB and mtx1 genes were not present in non-toxic isolates. The present study revealed the genetic heterogeneity between both toxic and non-toxic isolates and indicates that there is a good correlation between the presence of toxin genes and toxicity of the strains. These techniques could be developed in screening of novel highly toxic B. sphaericus strains from environment without bioassay on mosquito larvae. 23398317 Defective immunoglobulin A (IgA) glycosylation and IgA deposits in patients with IgA nephropathy. Defective glycosylation and immune complex (IC) formation may be of primary importance in immunoglobulin A nephropathy (IgAN) pathogenesis. The aim of this study was to determine whether defective IgA1 glycosylation might support renal deposition of IgA and disease activity. IgA was isolated from the serum of 44 IgAN patients and 46 controls and glycosylation analysed by ELISA using glycan-specific lectins. IgA was measured by immunodiffusion and immune complexes by ELISA. IgA subclasses in IC deposits in kidney glomeruli were identified by immunohistochemical methods. A significant increase in N-acetylgalactosamine (GalNAc) in terminal position (p = 0.02) observed in some of the IgAN patients, became more pronounced when sialic acid was removed from IgA1, indicating enhanced expression of α-2,6-sialyltransferase in patients compared with controls (p < 0.0001). Patients with defective galactosylation had lower serum IgA than other IgAN patients (p = 0.003). IgAN patients with both IgA1 and IgA2 glomerular deposits (21.7%) had increased GalNAc in terminal position (p = 0.003). Taken together, our results show that increased IgA glycosylation in IgAN associates with low levels of IgA, concomitant IgA1 and IgA2 glomerular deposits and poor clinical outcome. 23930151 Sexualized and dangerous relationships: listening to the voices of low-income african american girls placed at risk for sexual exploitation. Introduction: Youth from low-income, urban backgrounds face significant challenges to maintaining a positive developmental trajectory. Dangerous neighborhoods and stressed relationships are common in these settings and threaten adaptation by weakening the natural assets that undergird resilience. African American girls in these contexts face specific, multiple risks, including gender stereotyping, violence, and sexual exploitation. The commercial sexual exploitation of children (CSEC) is a multibillion-dollar industry victimizing over 1 million children around the globe. The typical victim in 1 city in the southeastern United States is an African American girl 12-14 years old. There has been little research investigating the characteristics of girls placed at risk for CSEC and even less research on the personal perspectives of these girls. Methods: Over 3 school terms we provided preventive intervention groups for 36 African American middle school girls who were placed at risk because they lived in neighborhoods with high rates of interpersonal violence and CSEC. Two group leaders and a process recorder took detailed notes on each group session. Our focus on group conversations over a period of weeks increased the probability of recording spontaneous, open comments by the children and is a promising method with this population. The data were analyzed qualitatively and resulted in an account of the girls' own views of the environmental challenges and personal experiences that may influence their development. Results: The girls' language during the group sessions contained 4 themes: difficulty forming trusting relationships, frequent peer aggression, familiarity with adult prostitution, and sexuality as a commodity. Conclusion: Our research shows how girls placed at risk for CSEC view their own lives. These children described violence and sexual exploitation and cited limited supports to protect them from these risks. Understanding the perspectives of these girls should generate future research and intervention strategies to support their coping and resilience. 23820048 Complete sequence of a reovirus associated with necrotic focus formation in the liver and spleen of Muscovy ducklings. The complete sequence of a reovirus, strain 815-12 associated with necrotic focus formation in the liver and spleen of Muscovy ducklings in China, was determined and compared with sequences of other duck-, goose-, and chicken-origin reoviruses. The 815-12 genome comprised 22,969bp with 10 dsRNA segments ranging from 1125bp (S4) to 3958bp (L1), all of which (except S4) were almost identical in length to the cognate segments of other waterfowl and chicken isolates. Detailed analyses revealed that 815-12 and other waterfowl isolates contained the conserved 3'-terminal pentanucleotide sequence (UCAUC-3') of the orthoreoviruses and 5'-terminal hexanucleotide sequence (5'-GCUUUU) of avian orthoreoviruses (ARVs), and conserved functional motifs previously identified in ARV proteins. Several notable differences, including organization of the polycistronic genome segments and genomic coding assignments of the S segments, existed between viruses represented by 815-12 and the waterfowl reoviruses emerging in China in recent years; the latter was somewhat similar to chicken isolates. Pairwise sequence comparisons demonstrated extensive sequence diversity among the various waterfowl isolates and between waterfowl and chicken isolates. Phylogenetic analyses identified two genetic groups for waterfowl reoviruses, and potential genetic reassortment of segment M2 between waterfowl and chicken reoviruses and segments encoding for λA, λB, μA, μNS and σA between waterfowl reoviruses. Taken together, it was suggested that common designation ARV-Wa should be used to represent ARV isolates from different waterfowl species and that the two ARV-Wa genotypes should be considered as two separate groups distinct from chicken isolates within the species Avian orthoreovirus. 23880344 Senescent endothelial cells are prone to TNF-α-induced cell death due to expression of FAS receptor. The senescent endothelial cells show various phenotypes which can increase the incidence of inflammatory cardiovascular diseases, but the fundamental basis for such phenotypic changes of senescing cells remains to be elucidated. This study was undertaken to find transmembrane receptors that might be highly expressed in senescent endothelial cells and play a key role in cell death signal transduction. Comparison of mRNA expression in young and senescent human umbilical vein endothelial cells, using a cDNA microarray method, provided a list of transmembrane receptors including the FAS receptor (tumor necrosis factor receptor superfamily member 6) whose expression levels were significantly increased by cellular senescence. Additional studies focused on FAS demonstrated that a high expression of FAS receptor in senescent endothelial cells is responsible for the susceptibility to apoptotic cell death, as the siRNA-mediated suppression of FAS expression in senescent cells prevented the cell death, and overexpression of exogenous FAS in young cells increased cell death. We also verified that FAS expression level was closely associated with the activation of caspase-3 and caspase-9 involved in apoptosis. The senescence-induced transmembrane receptors including the FAS receptor may provide novel therapeutic targets to prevent cardiovascular diseases. 23860342 (75)As NMR study of overdoped CeFeAsO0.8F0.2. We report on the results from a (75)As nuclear magnetic resonance (NMR) study of the overdoped iron pnictide superconductor CeFeAsO0.8F0.2. We find two As sites with different shifts at temperatures as high as 100 K, which is above the superconducting transition temperature of 39 K, and hence they cannot be attributed to the effect of vortices in the superconducting state as previously suggested (Ghoshray et al 2009 Phys. Rev. B 79 144512). The much larger spin-lattice relaxation rate compared with that found in other pnictides without magnetic rare earth ions, and the temperature dependence of the (75)As NMR shifts for the two central lines, are consistent with the hyperfine coupling from magnetic Ce to As. The low temperature spectra indicate that there are As ions with two different quadrupole splittings. Our findings appear to be consistent with an electronic phase segregation into regions with two different F dopings or the presence of a correlated spatial charge and spin density variations. 23935051 Identification and characterization of RibN, a novel family of riboflavin transporters from Rhizobium leguminosarum and other Proteobacteria. Rhizobia are symbiotic bacteria able to invade and colonize the roots of legume plants, inducing the formation of nodules, where bacteria reduce atmospheric nitrogen (N2) to ammonia (NH3). Riboflavin availability influences the capacity of rhizobia to survive in the rhizosphere and to colonize roots. In this study we identified the gene RL1692 of Rhizobium leguminosarum downstream of an FMN-riboswitch. RL1692 encodes a putative transmembrane permease with two EamA domains. The presence of an FMN-riboswitch regulating a transmembrane protein is usually observed in riboflavin transporters, suggesting that RL1692 may be involved in riboflavin uptake. The product of RL1692, which we named RibN, is conserved in members of the α, β and γ-Proteobacteria and shares no significant identity with any riboflavin transporter previously identified. In this work we show that RibN is localized in the membrane cellular fraction and its expression is down-regulated by riboflavin. By heterologous expression in a riboflavin auxotrophic Brucella abortus mutant, we demonstrated that RibN possesses flavin-transport activity. Similarly, we also demonstrated that RibN orthologues from Ochrobactrum anthropi and Vibrio cholerae (which lacks the FMN-riboswitch), are able to transport riboflavin. An R. leguminosarum ribN null mutant exhibits lower nodule occupancy levels in pea plants during symbiosis assays. Thus, we propose that RibN and its homologues belong to a novel family of riboflavin transporters. This work provides the first experimental description of riboflavin transporters in Gram-negative bacteria. 23891295 Value of retrospective image fusion of (18)F-FDG PET and MRI for preoperative staging of head and neck cancer: Comparison with PET/CT and contrast-enhanced neck MRI. To assess the clinical value of retrospective image fusion of neck MRI and (18)F-fluorodeoxyglucose ((18)F-FDG) PET for locoregional extension and nodal staging of neck cancer. Thirty patients with carcinoma of the oral cavity or hypopharynx underwent PET/CT and contrast-enhanced neck MRI for initial staging before surgery including primary tumor resection and neck dissection. Diagnostic performance of PET/CT, MRI, and retrospective image fusion of PET and MRI (fused PET/MRI) for assessment of the extent of the primary tumor (T stage) and metastasis to regional lymph nodes (N stage) was evaluated. Accuracy for T status was 87% for fused PET/MRI and 90% for MRI, thus proving significantly superior to PET/CT, which had an accuracy of 67% (p=0.041 and p=0.023, respectively). Accuracy for N status was 77% for both fused PET/MRI and PET/CT, being superior to MRI, which had an accuracy of 63%, although the difference was not significant (p=0.13). On a per-level basis, the sensitivity, specificity and accuracy for detection of nodal metastasis were 77%, 96% and 93% for both fused PET/MRI and PET/CT, compared with 49%, 99% and 91% for MRI, respectively. The differences for sensitivity (p=0.0026) and accuracy (p=0.041) were significant. Fused PET/MRI combining the individual advantages of MRI and PET is a valuable technique for assessment of staging neck cancer. 23943851 Viral suppression following switch to second-line antiretroviral therapy: associations with NRTI resistance and 'sub-therapeutic' drug concentrations prior to switch. Background. High rates of second-line antiretroviral treatment (ART) failure are reported. Associations with resistance and non-adherence on switching to second-line ART requires clarification.Methods. Using prospectively-collected data from patients in South Africa we constructed a cohort of patients switched to second-line ART (1/1/03-31/12/08). Genotyping and drug concentrations (lamivudine, nevirapine, efavirenz) were measured on stored samples pre-switch. Their association with viral load (VL)<400 copies/ml by 15 months was assessed using modified Poisson regression.Results. 122/417 patients (49% male; median age 36yrs) had genotyping (n=115) and/or drug concentrations (n=80) measured. Median CD4 count and VL at switch were 177 cells/mm(3) (IQR 77-263) and log10VL 4.3 (3.8-4.7) respectively. 55% (n=44/80) had 'sub-therapeutic' drug concentrations pre-switch. More patients with 'therapeutic' vs. 'sub-therapeutic' ART had resistance (n=73): no major mutations (3% vs. 51%), NNRTI (94% vs. 44%), M184 V/I (94% vs. 26%) and ≥1 TAM (47% vs. 18%), all p=0.01; NRTI cross-resistance mutations (26% vs. 13%, p=0.23). Following switch, 68% (n=83/122) achieved VL<400 copies/ml. Absence of NRTI mutations and 'sub-therapeutic' ART pre-switch were associated with failure to achieve VL<400 copies/ml.Conclusion. Non-adherence, suggested by 'sub-therapeutic' ART with/without major resistance mutations, significantly contributed to failure when switching regimen. Unresolved non-adherence, not NRTI resistance, drives early second-line failure. 23966973 Hyperphosphorylation-induced tau oligomers. In normal adult brain the microtubule associated protein (MAP) tau contains 2-3 phosphates per mol of the protein and at this level of phosphorylation it is a soluble cytosolic protein. The normal brain tau interacts with tubulin and promotes its assembly into microtubules and stabilizes these fibrils. In Alzheimer disease (AD) brain tau is three to fourfold hyperphosphorylated. The abnormally hyperphosphorylated tau binds to normal tau instead of the tubulin and this binding leads to the formation of tau oligomers. The tau oligomers can be sedimented at 200,000 × g whereas the normal tau under these conditions remains in the supernatant. The abnormally hyperphosphorylated tau is capable of sequestering not only normal tau but also MAP MAP1 and MAP2 and causing disruption of the microtubule network promoted by these proteins. Unlike Aβ and prion protein (PrP) oligomers, tau oligomerization in AD and related tauopathies is hyperphosphorylation-dependent; in vitro dephosphorylation of AD P-tau with protein phosphatase 2A (PP2A) inhibits and rehyperphosphorylation of the PP2A-AD P-tau with more than one combination of tau protein kinases promotes its oligomerization. In physiological assembly conditions the AD P-tau readily self-assembles into paired helical filaments. Missense tau mutations found in frontotemporal dementia apparently lead to tau oligomerization and neurofibrillary pathology by promoting its abnormal hyperphosphorylation. Dysregulation of the alternative splicing of tau that alters the 1:1 ratio of the 3-repeat: 4-repeat taus such as in Down syndrome, Pick disease, and progressive supranuclear palsy leads to the abnormal hyperphosphorylation of tau. 23489393 Altered explicit recognition of facial disgust associated with predisposition to suicidal behavior but not depression. Suicidal acts result from a complex interplay between vulnerability factors, such as reduced social and cognitive abilities, social stressors. To our knowledge nothing is known about the explicit recognition of others' facial emotions, a major component of social interactions, in patients at long-term risk for suicide. Thirty-five non-depressed patients with a history of a serious suicide attempt and mood disorders were compared with 31 patients with a history of mood disorders but no personal history of suicidal acts, and with 37 healthy controls with no personal history of mood disorders or suicide attempts. The explicit recognition of six facial emotions (anger, disgust, fear, sadness, happiness, and neutral) was assessed. Suicide attempters made significantly more errors in the explicit recognition of disgust, relative to the other groups, with no differences between the control groups or for the other emotions examined. Semantic verbal fluency and verbal working memory performances were also reduced in suicide attempters relative to the other two groups but could not explain the facial recognition deficits. Our results need replication with a larger sample size. Most patients were medicated. Explicit recognition of disgust appears to be specifically altered in relation to vulnerability to suicide but not to depression. Reduced ability to recognize some social emotions may impair the patient's capacity to adequately interact with his own social environment, potentially increasing the risk of interpersonal conflict, negative emotions and suicidal crisis. Improving cognitive and social skills may be a target for future individual suicide prevention. 23887936 Integrative analysis of tissue-specific methylation and alternative splicing identifies conserved transcription factor binding motifs. The exact role of intragenic DNA methylation in regulating tissue-specific gene regulation is unclear. Recently, the DNA-binding protein CTCF has been shown to participate in the regulation of alternative splicing in a DNA methylation-dependent manner. To globally evaluate the relationship between DNA methylation and tissue-specific alternative splicing, we performed genome-wide DNA methylation profiling of mouse retina and brain. In protein-coding genes, tissue-specific differentially methylated regions (T-DMRs) were preferentially located in exons and introns. Gene ontology and evolutionary conservation analysis suggest that these T-DMRs are likely to be biologically relevant. More than 14% of alternatively spliced genes were associated with a T-DMR. T-DMR-associated genes were enriched for developmental genes, suggesting that a specific set of alternatively spliced genes may be regulated through DNA methylation. Novel DNA sequences motifs overrepresented in T-DMRs were identified as being associated with positive and/or negative regulation of alternative splicing in a position-dependent context. The majority of these evolutionarily conserved motifs contain a CpG dinucleotide. Some transcription factors, which recognize these motifs, are known to be involved in splicing. Our results suggest that DNA methylation-dependent alternative splicing is widespread and lay the foundation for further mechanistic studies of the role of DNA methylation in tissue-specific splicing regulation. 23640789 2,3-Di(2-pyridyl)-5-phenylpyrazine: a NN-CNN-type bridging ligand for dinuclear transition-metal complexes. A new bridging ligand, 2,3-di(2-pyridyl)-5-phenylpyrazine (dpppzH), has been synthesized. This ligand was designed so that it could bind two metals through a NN-CNN-type coordination mode. The reaction of dpppzH with cis-[(bpy)2RuCl2] (bpy = 2,2'-bipyridine) affords monoruthenium complex [(bpy)2Ru(dpppzH)](2+) (1(2+)) in 64 % yield, in which dpppzH behaves as a NN bidentate ligand. The asymmetric biruthenium complex [(bpy)2Ru(dpppz)Ru(Mebip)](3+) (2(3+)) was prepared from complex 1(2+) and [(Mebip)RuCl3] (Mebip = bis(N-methylbenzimidazolyl)pyridine), in which one hydrogen atom on the phenyl ring of dpppzH is lost and the bridging ligand binds to the second ruthenium atom in a CNN tridentate fashion. In addition, the RuPt heterobimetallic complex [(bpy)2Ru(dpppz)Pt(C≡CPh)](2+) (4(2+)) has been prepared from complex 1(2+), in which the bridging ligand binds to the platinum atom through a CNN binding mode. The electronic properties of these complexes have been probed by using electrochemical and spectroscopic techniques and studied by theoretical calculations. Complex 1(2+) is emissive at room temperature, with an emission λmax = 695 nm. No emission was detected for complex 2(3+) at room temperature in MeCN, whereas complex 4(2+) displayed an emission at about 750 nm. The emission properties of these complexes are compared to those of previously reported Ru and RuPt bimetallic complexes with a related ligand, 2,3-di(2-pyridyl)-5,6-diphenylpyrazine. 23950124 Genome Sequence of a Novel Polymer-Grade L-Lactate-Producing Alkaliphile, Exiguobacterium sp. Strain 8-11-1. Exiguobacterium sp. strain 8-11-1 is a newly isolated alkaliphile, which was reported to efficiently produce l-lactate using NaOH as the neutralizing agent. Here, we present the first 2.9-Mb assembly of its genome sequence, which may provide useful information related to its efficient lactate production and sodium ion tolerance capacities. 23712797 Assessing calves as carriers of Cryptosporidium and Giardia with zoonotic potential on dairy and beef farms within a water catchment area by mutation scanning. In the present study, we undertook a molecular epidemiological survey of Cryptosporidium and Giardia in calves on three dairy and two beef farms within an open drinking water catchment area (Melbourne, Australia). Faecal samples (n = 474) were collected from calves at two time points (5 months apart) and tested using a PCR-based mutation scanning-targeted sequencing phylogenetic approach, employing regions within the genes of small subunit (SSU) of ribosomal RNA (designated partial SSU), 60 kDa glycoprotein (pgp60) and triose phosphate isomerase (ptpi) as genetic markers. Using partial SSU, the C. bovis, C. parvum, C. ryanae and a new genotype of Cryptosporidium were characterised from totals of 74 (15.6%), 35 (7.3%), 37 (7.8%) and 9 (1.9%) samples, respectively. Using pgp60, C. parvum genotype IIa subgenotype A18G3R1 was detected in 29 samples. Using ptpi, G. duodenalis assemblages A and E were detected in totals of 10 (2.1%) and 130 (27.4%) samples, respectively. The present study showed that a considerable proportion of dairy and beef calves in this open water catchment region excreted Cryptosporidium (i.e. subgenotype IIaA18G3R1) and Giardia (e.g. assemblage A) that are consistent with those infecting humans, inferring that they are of zoonotic importance. Future work should focus on exploring, in a temporal and spatial way, whether these parasites occur in the environment and water of the catchment reservoir. 23872463 Heterogeneity in meta-analyses of treatment of acute postoperative pain: a review. /st>Heterogeneity and its causes must be assessed using meta-analyses (meta-analysis). Especially in meta-analysis dealing with treatment of acute postoperative pain, the type of surgery is a source of heterogeneity. We aimed to assess whether the type of surgery is considered a source of heterogeneity in meta-analysis and how it is taken into account in meta-analysis evaluating the efficacy of treatment of acute postoperative pain. We further compared meta-analysis that pooled trials of surgeries with highly heterogeneous postoperative pain levels, the heterogeneous group, with meta-analysis that pooled trials involving surgeries with homogeneous pain levels, the homogenous group. /st>The meta-analysis reports available in Issue 3, 2011 of the electronic database of the Cochrane library and pooling results of randomized or quasi-randomized controlled trials that assessed the efficacy of treatment of acute postoperative pain alone were considered. A survey of experts established a rating of the postoperative pain levels for the type of surgery. For each meta-analysis, the different pain level ratings associated with the trials included in the meta-analysis were considered and the standard deviation (sd) of these ratings calculated. From the distribution of sd values, we defined the heterogeneous and homogeneous groups. /st>Sixty-one meta-analyses were included; all assessed heterogeneity. Twenty-six meta-analyses considered the type of surgery as a subgroup (50% vs 38% in the homogeneous group vs heterogeneous group). Forty-four reports discussed the type of surgery as a source of clinical heterogeneity (85% vs 62% for the homogeneous vs heterogeneous group). Twenty-nine meta-analyses compared 'postoperative pain from dental surgery' to 'other type of surgery'. /st>Meta-analyses evaluating treatment of postoperative pain should explore clinical heterogeneity associated with the type of surgery for better implications for practice. 23949614 Commonality versus specificity among adiposity traits in normal-weight and moderately overweight adults. Background:Many adiposity traits have been related to health complications and premature death. These adiposity traits are intercorrelated, but their underlying structure has not been extensively investigated. We report on the degree of commonality and specificity among multiple adiposity traits in normal-weight and moderately overweight adult males and females (mean BMI=22.9 kg/m(2), s.d.=2.4).Methods:A total of 75 healthy participants were assessed for a panel of adiposity traits including leg, arm, trunk, total fat mass, and visceral adipose tissue (VAT) derived from dual energy X-ray absorptiometry (DXA), hepatic and muscle lipids from proton magnetic resonance spectroscopy (MRS), fat cell volume from an abdominal subcutaneous adipose tissue biopsy (n=36), and conventional anthropometry (BMI and waist girth). Spearman correlations were calculated and were subjected to factor analysis.Results:Arm, leg, trunk, and total fat masses correlated positively (r=0.78 to 0.95) with each other. VAT correlated weakly with fat mass indicators (r=0.24 to 0.31). Intra-hepatic lipids (IHL) correlated weakly with all fat mass traits (r=0.09 to 0.34), while correlations between DXA depots and intra-myocellular lipids (IMCL) were inconsequential. The four DXA fat mass measures, VAT, IHL, and IMCL depots segregated as four independent factors that accounted for 96% of the overall adiposity variance. BMI and waist girth were moderately correlated with arm, leg, trunk, and total fat and weakly with VAT, IHL, and IMCL.Conclusion:Adiposity traits share a substantial degree of commonality, but there is considerable specificity across the adiposity variance space. For instance, VAT, IHL, and IMCL are typically poorly correlated with each other and are poorly to weakly associated with the other adiposity traits. The same is true for BMI and waist girth, commonly used anthropometric indicators of adiposity. These results do not support the view that it will be possible to identify adequate anthropometric indicators of visceral, hepatic, and muscle lipid content in normal-weight and moderately overweight individuals.International Journal of Obesity accepted article preview online, 16 August 2013. doi:10.1038/ijo.2013.153. 23875850 "Hard to crack": Experiences of community integration among first- and second-generation Asian MSM in Canada. Asians are the largest racial minority in Canada making up 11% of the population and represented over 60% of new immigrants between 2001 and 2006. We examined the experiences of community integration for first-generation (n = 27) and second-generation (n = 22) Asian Canadian men who have sex with men (MSM) in their ethnic and gay communities. Through focus group interviews, we explored their level of connectedness and the level of discrimination they experienced in the two communities. Findings indicate that Asian MSM in general perceived their ethnic community as homophobic, stemming from a combination of seeing sex as taboo, stereotypes about being gay, and the affiliation with religion. Although the literature indicates that immigrants rely on the support of their ethnic communities, our finding suggest that this is not the case for Asian immigrant MSM, who in our sample reported feeling less connected compared to their second-generation counterparts. For the gay community, our sample reported mixed experiences as some regarded it as welcoming, whereas others described it as racist. However, these experiences did not differ by generational status. Many were aware of explicit messages stating "No Asians" in dating contexts, while at the same time being aware that some older White men were interested in dating Asians exclusively. Barriers to integration in both communities may contribute to feelings of isolation. Theoretical implications are discussed. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23339417 Imageability of Norwegian nouns, verbs and adjectives in a cross-linguistic perspective. In this article, we present a study of imageability ratings for a set of 1599 Norwegian words (896 nouns, 483 verbs and 220 adjectives) from a web-based survey. To a large extent, the results are in accordance with previous studies of other languages: high imageability scores in general, higher imageability scores for nouns than for verbs, and an inverse relation between frequency and imageability. A more surprising finding is the low imageability of low-frequency verbs. Also, imageability ratings increase systematically and significantly with informant age, reminding us that conceptual learning continues and changes throughout life. This has consequences for our expectations of different linguistic skills in a life span perspective. These findings have an obvious clinical relevance both for choice of items in test construction, for evaluation of performance in clinical groups and for development of therapy material. 23645850 Obesity as a Risk Factor for Clostridium difficile Infection. Background. Obesity and Clostridium difficile infection (CDI) are both related to an increased Firmicutes/Bacteroidetes ratio in the intestinal microbiota. However, an association between obesity and CDI is unknown. We aimed to assess the association between obesity and CDI in hospitalized patients. Methods. We conducted a retrospective case-control study. From January to December 2011, all consecutive patients hospitalized with CDI, in 2 internal medical departments in 2 hospitals, were included. Patients with CDI were compared to hospitalized patients without diarrhea, during the same period and in the same departments, and matched by age, sex, Charlson score, length of hospitalization, and antibiotic use during the last 3 months. Results. Of the 6300 patients hospitalized, 178 were diagnosed with CDI. CDI prevalence was 2.8% (178/6300). Thirty patients were excluded from the study. The 148 cases with CDI were compared to 148 hospitalized controls. Mean body mass index (BMI) in the CDI group was 33.6 (SD, 4.3) versus 28.9 (SD, 5.4) in the control group (P = .001). The multivariable model of conditional logistic regression for matched pairs showed that a history of intra-abdominal surgery (odds ratio [OR] = 2.865; 95% confidence interval [CI], 1.26-6.52) and a high BMI value (OR = 1.196 per 1-unit increase in the BMI scale; 95% CI, 1.12-1.27) were the only variables found to be significantly associated with CDI. Conclusions. Our findings suggest that obesity is associated with the risk of CDI. Further studies are needed to reveal the exact mechanisms underlying this association. 23550942 Dominant role of molybdenum in the electrochemical deposition of biological macromolecules on metallic surfaces. The corrosion of CoCrMo, an alloy frequently used in orthopedic implants, was studied with an electrochemical quartz crystal microbalance (QCM) in three physiologically relevant solutions. Mass changes were measured during potentiodynamic tests, showing material deposition in protein solutions at potential levels that caused mass loss when the proteins were not present. X-ray photoelectron spectroscopy (XPS) data indicated that the deposited material was primarily organic and therefore was most likely derived from proteins in the electrolyte. Material deposition consistently occurred at a critical potential and was not dependent on the current density or total charge released into solution. Corrosion studies on pure Co, Cr, and Mo in protein solutions found material deposition only on Mo. We hypothesize that organic deposition results from the interaction of Mo(VI) with proteins in the surrounding solution. The organic layer is reminiscent of tribochemical reaction layers that form on the surface of CoCrMo hip bearings, suggesting that these types of layers can be formed by purely electrochemical means. 23764176 Mapping the longitudinal wall stiffness heterogeneities within intact canine aortas using Pulse Wave Imaging (PWI) ex vivo. The aortic stiffness has been found to be a useful independent indicator of several cardiovascular diseases such as hypertension and aneurysms. Existing methods to estimate the aortic stiffness are either invasive, e.g. catheterization, or yield average global measurements which could be inaccurate, e.g., tonometry. Alternatively, the aortic pulse wave velocity (PWV) has been shown to be a reliable marker for estimating the wall stiffness based on the Moens-Korteweg (M-K) formulation. Pulse Wave Imaging (PWI) is a relatively new, ultrasound-based imaging method for noninvasive and regional estimation of PWV. The present study aims at showing the application of PWI in obtaining localized wall mechanical properties by making PWV measurements on several adjacent locations along the ascending thoracic to the suprarenal abdominal aortic trunk in its intact vessel form. The PWV estimates were used to calculate the regional wall modulus based on the M-K relationship and were compared against conventional mechanical testing. The findings indicated that for the anisotropic aortic wall, the PWI estimates of the modulus are smaller than the circumferential modulus by an average of -32.22% and larger than the longitudinal modulus by an average of 25.83%. Ongoing work is focused on the in vivo applications of PWI in normal and pathological aortas with future implications in the clinical applications of the technique. 23588198 Binge alcohol-induced alterations in BDNF and GDNF expression in central extended amygdala and pyriform cortex on infant rats. Mothers who consume alcohol during pregnancy may cause a neurotoxic syndrome termed fetal alcohol spectrum disorder (FASD) in the offspring, which includes cognitive deficits and emotional/social disturbances. These alterations are thought to be caused, at least in part, by alcohol-induced imbalance in neurotrophic factor levels, which are critically involved in normal neurodevelopment. Our goal was to study whether brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) expression were affected by alcohol in central extended amygdala (CEXA) and pyriform cortex (Pyr), structures strongly involved in emotional/social behaviors. Further, we evaluated how these changes could be related to blood and brain alcohol concentrations. Postnatal day (PND) pups at 7, 15 and 20-days old were administered alcohol (2.5g/kg s.c. at 0 and 2h) or saline. Immunohistochemistry was used to detect the expression of BDNF and GDNF at 2, 12 and 24h after drug administration. Also, gas chromatography was bused to measure blood alcohol levels (BALs) and brain alcohol levels (BrALs) at each hour, from 2 to 8h after the second alcohol administration. Results showed: (1) alcohol-induced enhancement of BDNF positive cells on PND 7 and 20, a decrease on PND 15 in the CEXA, and no changes in the Pyr on PND 7 and 20, but a diminished on PND 15; (2) GDNF positive cells rise after alcohol administration for the three ages in the CEXA and Pyr except on PND 15, where there was a decline; and (3) pharmacokinetics analysis demonstrated age-related differences showing equal BALs on PND 7 and 20 but higher BALs on PND 15. In contrast, BrALs were higher on PND 7 than 15 and 20. Hence, BALs may not be predictive of BrALs in postnatal rats. Furthermore, we did not find a relationship between age in pharmacokinetic differences and neurotrophins response. In conclusion, the CEXA and Pyr are brain structures sensitive to alcohol-induced imbalance in neurotrophic factors expression; and BALs are not a mirror of BrALs. 23955709 Impact of Vitamin A Supplementation on RAR Gene Expression in Multiple Sclerosis Patients. Vitamin A and its derivatives have been shown to modulate the immune system via retinoic acid receptor (RAR). This study explored the impact of retinyl palmitate supplementation on RAR subtype gene expression in peripheral blood mononuclear cells (PBMCs) in multiple sclerosis (MS) patients. The study designed as a double-blind randomized clinical trial in which relapsing remitting multiple sclerosis patients were evaluated. Both groups received one capsule 50,000 IU vitamin D3 per 2 weeks and one intramuscular injection interferon beta-1a per week. The intervention group received one 25,000 IU retinyl palmitate capsule daily for 6 months and the placebo group received one placebo capsule daily. The PBMCs were isolated from participants and the expression level changes of RAR-α and RAR-γ genes were determined by real-time PCR. After supplementation, in the intervention group, the RAR-α gene expression level was significantly decreased compared to the placebo group (p = 0.03); however, the expression of RAR-γ gene did not significantly change (p = 0.10). These results show that vitamin A supplementation can significantly downregulate the expression of RAR-α gene in PBMCs of MS patients that suggest the presence of in vivo regulatory mechanisms for the action of vitamin A on the immune system. 23891979 Radionuclide emissions from a coal-fired power plant. Current study concerns measurement of radioactivity levels in areas surrounding a 2420MW thermal power plant fueled predominantly by bituminous coal. The concentrations of (226)Ra, (232)Th and (40)K in onsite bottom-ash were found to be 139Bq/kg, 108Bq/kg and 291Bq/kg, respectively, the levels for these radiolnuclides in soil decreasing with distance from the power plant. At the plant perimeter the respective radionuclide concentrations were 87Bq/kg, 74Bq/kg and 297Bq/kg. In a nearby town, the corresponding concentrations were 104Bq/kg, 52Bq/kg and 358Bq/kg, suggestive of use of TENORM affected soils. The mean radium equivalent activities (Raeq) in soil and ash sample in the town were 205Bq/kg and 316Bq/kg, respectively. The Kapar plant ash/slag appears to contain a higher level of TENORM than the world average. The degree of contamination is much higher inside the town where slag has been mixed with topsoil as landfill or as simple domestic waste. For the prevailing levels of exposure and a worst case senario, the predicted committed effective dose due to ingestion and inhalation for intake durations of 1- and 30 years would be 4.2μSv and 220μSv, respectively. 23871312 Functionalized Au/Ag nanocages as a novel fluorescence and SERS dual probe for sensing. We obtained chitosan-protected Au/Ag nanocages (NCs), i.e., hollow and porous metallic nanoparticles, by galvanic replacement reaction. Subsequently, we functionalized the NCs with a fluorescent derivative of 4-methoxy-1,8-naphtalimide (NAFTA6). The plasmonic properties of these structures, which exhibit an extinction maximum in the 700-800nm range, allowed their use as SERS active substrates for excitation at 785nm and an efficient identification of the vibrational bands of NAFTA6, in spite of the low ligand concentration (<10(-5)M). Furthermore, NAFTA6 could also be identified from its fluorescence emission. The proposed functionalization with fluorescent compounds opens the way to the application of metal NCs using double-wavelength detection. Namely, Raman spectroscopy in the near infrared and fluorescence emission in the visible region, with considerable potential especially for in vivo medical applications, as the plasmonic band is centered in the visible light region where biological fluids and tissues are transparent. 23294466 Use of complementary and alternative medicine to treat constipation in the elderly. Many modalities of complementary and alternative medicine, such as probiotic bacteria, traditional herbal medicines, biofeedback and massage, have been used to treat constipation in older adults. Virtually all studies in the published literature have been plagued with methodological problems, such as lack of blinding. Chinese herbal medications have been the most frequent subject of studies in controlled trials, but have suffered from methodological insufficiencies, and few have been published in publications other than Chinese language journals. Several therapies, such as yogurt containing probiotic bacteria and massage, are relatively easy to use by the patient, and are likely to cause few adverse reactions. Therefore, complementary and alternative therapies might show the greatest promise for being adopted as adjunctive therapies to conventional treatment. 23831473 Foreskin retractility following hypospadias repair with preputioplasty - Medium term outcomes. To assess the medium term outcome of hypospadias repair and preputioplasty with regard to foreskin retractility, and whether this could be predicted by assessing retractility at the end of the operation. The data were obtained from a prospectively maintained database regarding patients who had hypospadias repair with preputioplasty between January 2003 and June 2010. The foreskin retractility at the end of the operation was documented in the operation notes, and the latest foreskin status was obtained from clinical notes or by contacting parents. The total number was 207, and 170 (82.1%) had distal hypospadias. At the latest follow up at a median of 2 years and 3 months after the date of operation (range 13 months to 4 years 7 months), 159 boys (76.8%) had a retractile foreskin, 27 (13%) were under observation for a tight foreskin, and 8 (3.9%) had undergone circumcision due to tightness. The foreskin was retractile at the end of the operation in 154 (73.3%) patients. Of these, 130 (84%) had a retractile foreskin at the later follow-up clinic. Of the 49 patients who had a non-retractile foreskin at the end of the operation, 29 went on to have a retractile foreskin, while 20 had a tight foreskin. Fisher's exact test showed that foreskin retractility at the end of the operation has a significant relation to foreskin retractility in the medium term, and that patients with distal hypospadias have a greater probability of achieving a retractile foreskin. A primarily retractile foreskin can be achieved in over 75% with less than 4% requiring a circumcision due to tightness. Distal location of hypospadias and retractility at the end of operation predicted success. 23508985 Vegetarianism as a protective factor for reflux esophagitis: a retrospective, cross-sectional study between buddhist priests and general population. Several risk factors for reflux esophagitis, such as smoking, alcohol consumption, obesity, and metabolic syndrome, are recognized. But vegetarianism as a protective factor for reflux esophagitis has not been reported. The aim of this study is to elucidate the protective effect of vegetarianism for reflux esophagitis. This is a cross-sectional study that compared the prevalence of reflux esophagitis of 148 Buddhist priests, who are obligatory vegetarians with that of age- and sex-matched controls who underwent health checkups in a health promotion center. The prevalence of reflux esophagitis was higher in the control group than in the Buddhist priest group (21.6 vs 12.2 %). Weight, body mass index, waist circumference, waist-to-hip ratio, and abdominal adipose tissue area were higher and high density lipoprotein (HDL) cholesterol and total cholesterol were lower in the Buddhist priest group. The prevalence of metabolic syndrome was higher in the Buddhist priest group than the control group (30.4 vs 17.6 %). In univariate analysis, male sex (odds ratio [OR] = 3.325; 95 % confidence interval [CI], 1.659-6.666), current smoking (OR = 3.37; 95 % CI, 1.439-7.881), alcohol consumption (OR = 2.75; 95 % CI, 1.375-5.481), waist circumference (OR = 1.99; 95 % CI, 1.062-3.739), negative for Helicobacter pylori IgG antibody (OR = 1.89; 95 % CI, 1.018-3.491) and non-vegetarianism (OR = 1.99; 95 % CI, 1.062-3.739) were associated with reflux esophagitis. According to multivariate analysis, male sex (OR = 3.44; 95 % CI, 1.698-6.970), non-vegetarianism (OR = 2.08; 95 % CI, 1.086-3.974) and negative H. pylori IgG antibody (OR = 1.96; 95 % CI, 1.039-3.712) were significantly associated with reflux esophagitis. A non-vegetarian diet is associated with reflux esophagitis. 23964816 Retroelement insertions at the Medicago FTa1 locus in spring mutants eliminate vernalisation but not long day requirements for early flowering. Molecular-genetic control of the flowering time of temperate-climate plants is best understood in Arabidopsis and the cereals wheat and barley. However, key regulators such as FLC and cereal VRN2 are not found in legumes. Therefore, we used forward genetics to identify flowering time genes in the model legume Medicago truncatula (Medicago) which is induced to flower by vernalisation and long day photoperiods. A screen of a Tnt1 retroelement tagging population yielded two mutants, spring2 and spring3, with a dominant early flowering phenotype. These mutants overexpress the floral activator FTa1 and two candidate downstream flowering genes SOC1a and FULb, similar to spring1 a somaclonal variant that we identified previously. We demonstrate here that an increase in the expression of FTa1, SOC1a and FULb and early flowering does not occur in all conditions in the spring mutants. It depends on long day photoperiods, but not on vernalisation. Isolation of flanking sequence tags and linkage analysis identified retroelement insertions at FTa1 that co-segregated with the early flowering phenotype in all three spring mutants. These were Tnt1 insertions in the FTa1 third intron (spring3) or the 3' intergenic region (spring2) and an endogenous MERE1-4 retroelement in the 3' intergenic region in spring1. Thus the spring mutants form an allelic series of gain-of-function mutations in FTa1 which confer a spring growth habit. The spring retroelement insertions at FTa1 separate long day input from vernalisation input into FTa1 regulation, but this is not due to large scale changes in FTa1 DNA methylation or transcript processing in the mutants. This article is protected by copyright. All rights reserved. 23798321 Steady-state plasma concentration of donepezil enantiomers and its stereoselective metabolism and transport in vitro. The aim of the present study was to elucidate the differences in the plasma concentration of two enantiomers of donepezil in Chinese patients with Alzheimer's disease (AD) and investigate in vitro stereoselective metabolism and transport. Donepezil enantiomers were separated and determined by LC-MS/MS using D5-donepezil as an internal standard on a Sepax Chiralomix SB-5 column. In vitro stereoselective metabolism and transport of donepezil were investigated in human liver microsomes and MDCKII-MDR1 cell monolayer. Pre-dose (Css-min) plasma concentrations were determined in 52 patients. The mean plasma level of (R)-donepezil was 14.94 ng/ml and that of (S)-donepezil was 23.37 ng/ml. One patient's plasma concentration of (R)-donepezil was higher than (S)-donepezil and the ratio is 1.51. The mean plasma levels of (S)-donepezil were found to be higher than those of (R)-donepezil in 51 patients and the ratio of plasma (R)- to (S)-donepezil varies from 0.34 to 0.85. In the in vitro microsomal system, (R)-donepezil degraded faster than (S)-donepezil. Vmax of (R)-donepezil was significantly higher than (S)-donepezil. The P-gp inhibition experiment shown that the Papp of the two enantiomers was higher than 200 and the efflux ratios were 1.11 and 0.99. The results of the P-gp inhibition identification experiment showed IC50 values of 35.5 and 20.4 μM, respectively, for the two enantiomers. The results indicate that donepezil exhibits stereoselective hepatic metabolism that may explain the differences in the steady-state plasma concentrations observed. Neither (R)- nor (S)-donepezil was a P-gp substance and the two enantiomers are highly permeable through the blood-brain barrier. Chirality 25:498-505, 2013. © 2013 Wiley Periodicals, Inc. 23926343 Compensatory Mutants of the Bovine Papillomavirus E5 Protein and the Platelet-derived Growth Factor β Receptor Reveal a Complex Direct Transmembrane Interaction. The 44-amino acid E5 protein of bovine papillomavirus is a dimeric type 1 transmembrane protein that exists in a stable complex with the PDGF β receptor, causing receptor activation and cell transformation. The transmembrane domain of the PDGF β receptor is required for complex formation, but it is not known if the two proteins contact one another directly. Here, we studied a PDGF β receptor mutant containing a leucine to isoleucine substitution in its transmembrane domain, which prevents complex formation with the wild-type E5 protein in mouse BaF3 cells and inhibits receptor activation by the E5 protein. We selected E5 mutants containing either a small deletion or multiple substitution mutations that restored binding to the mutant PDGF β receptor, resulting in receptor activation and growth factor independence. These E5 mutants displayed lower activity with PDGF β receptor mutants containing other transmembrane substitutions in the vicinity of the original mutation, and one of them cooperated with a receptor mutant containing a distal mutation in the juxtamembrane domain. These results provide strong genetic evidence that the transmembrane domains of the E5 protein and the PDGF β receptor contact one another directly. They also demonstrate that different mutations in the E5 protein allow it to tolerate the same mutation in the PDGF β receptor transmembrane domain and that a mutation in the E5 protein can allow it to tolerate different mutations in the PDGF β receptor. Thus, the rules governing direct interactions between transmembrane helices are complex and not restricted to local interactions. 23268742 Bioassay-guided isolation of proanthocyanidins with antiangiogenic activities. The proangiogenic members of the vascular endothelial growth factor (VEGF) family and related receptors play a central role in the modulation of pathological angiogenesis. In order to identify plant compounds able to interfere in the VEGFs/VEGFR-1 (Flt-1) recognition by VEGF family members, the extracts of the aerial parts of Campsiandra guayanensis and Feretia apodanthera were screened by a competitive ELISA-based assay. By using this bioassay-oriented approach five proanthocyanindins, including the new natural compounds (2S)-4',5,7-trihydroxyflavan-(4β→8)-afzelechin (1) and (2S)-4',5,7-trihydroxyflavan-(4β→8)-epiafzelechin (2) and the known geranin B (3), proanthocyanidin A2 (4), and proanthocyanidin A1 (5), were isolated. The study of the antiangiogenic activities of compounds 1-5 using ELISA and SPR assays showed compound 1 as being the most active. The antiangiogenic activity of 1 was also confirmed in vivo by the chicken chorioallantoic membrane assay. Our results indicated 1 as a new antiangiogenic compound inhibiting the interaction between VEGF-A or PlGF and their receptor VEGRF-1. 23861774 Effect of acute exercise on prostate cancer cell growth. Physical activity is associated with reduced risk of several cancers, including aggressive prostate cancer. The mechanisms mediating the effects are not yet understood; among the candidates are modifications of endogenous hormone levels. Long-term exercise is known to reduce serum levels of growth stimulating hormones. In contrast, the endocrine effects of acute endurance exercise include increased levels of mitogenic factors such as GH and IGF-1. It can be speculated that the elevation of serum growth factors may be detrimental to prostate cancer progression into malignancy. The incentive of the current study is to evaluate the effect of acute exercise serum on prostate cancer cell growth. We designed an exercise intervention where 10 male individuals performed 60 minutes of bicycle exercise at increasing intensity. Serum samples were obtained before (rest serum) and after completed exercise (exercise serum). The established prostate cancer cell line LNCaP was exposed to exercise or rest serum. Exercise serum from 9 out of 10 individuals had a growth inhibitory effect on LNCaP cells. Incubation with pooled exercise serum resulted in a 31% inhibition of LNCaP growth and pre-incubation before subcutaneous injection into SCID mice caused a delay in tumor formation. Serum analyses indicated two possible candidates for the effect; increased levels of IGFBP-1 and reduced levels of EGF. In conclusion, despite the fear of possible detrimental effects of acute exercise serum on tumor cell growth, we show that even the short-term effects seem to add to the overall beneficial influence of exercise on neoplasia. 23853099 MinC Protein Shortens FtsZ Protofilaments by Preferentially Interacting with GDP-bound Subunits. The interaction of MinC with FtsZ and its effects on FtsZ polymerization were studied under close to physiological conditions by a combination of biophysical methods. The Min system is a widely conserved mechanism in bacteria that ensures the correct placement of the division machinery at midcell. MinC is the component of this system that effectively interacts with FtsZ and inhibits the formation of the Z-ring. Here we report that MinC produces a concentration-dependent reduction in the size of GTP-induced FtsZ protofilaments (FtsZ-GTP) as demonstrated by analytical ultracentrifugation, dynamic light scattering, fluorescence correlation spectroscopy, and electron microscopy. Our experiments show that, despite being shorter, FtsZ protofilaments maintain their narrow distribution in size in the presence of MinC. The protein had the same effect regardless of its addition prior to or after FtsZ polymerization. Fluorescence anisotropy measurements indicated that MinC bound to FtsZ-GDP with a moderate affinity (apparent KD ∼10 μm at 100 mm KCl and pH 7.5) very close to the MinC concentration corresponding to the midpoint of the inhibition of FtsZ assembly. Only marginal binding of MinC to FtsZ-GTP protofilaments was observed by analytical ultracentrifugation and fluorescence correlation spectroscopy. Remarkably, MinC effects on FtsZ-GTP protofilaments and binding affinity to FtsZ-GDP were strongly dependent on ionic strength, being severely reduced at 500 mm KCl compared with 100 mm KCl. Our results support a mechanism in which MinC interacts with FtsZ-GDP, resulting in smaller protofilaments of defined size and having the same effect on both preassembled and growing FtsZ protofilaments. 23859142 Multidetection of paralytic, diarrheic, and amnesic shellfish toxins by an inhibition immunoassay using a microsphere-flow cytometry system. The presence of paralytic shellfish poisoning (PSP), diarrheic shellfish poisoning (DSP), and amnesic shellfish poisoning (ASP) toxins in seafood is a severe and growing threat to human health. In order to minimize the risks of human exposure, the maximum content of these toxins in seafood has been limited by legal regulations worldwide. The regulated limits are established in equivalents of the main representatives of the groups: saxitoxin (STX), okadaic acid (OA), and domoic acid (DA), for PSP, DSP, and ASP, respectively. In this study a multidetection method to screen shellfish samples for the presence of these toxins simultaneously was developed. Multiplexing was achieved using a solid-phase microsphere assay coupled to flow-fluorimetry detection, based on the Luminex xMap technology. The multidetection method consists of three simultaneous competition immunoassays. Free toxins in solution compete with STX, OA, or DA immobilized on the surface of three different classes of microspheres for binding to specific monoclonal antibodies. The IC50 obtained in the buffer was similar in single- and multidetection: 5.6 ± 1.1 ng/mL for STX, 1.1 ± 0.03 ng/mL for OA, and 1.9 ± 0.1 ng/mL for DA. The sample preparation protocol was optimized for the simultaneous extraction of STX, OA, and DA with a mixture of methanol and acetate buffer. The three immunoassays performed well with mussel and scallop matrixes displaying adequate dynamic ranges and recovery rates (around 90% for STX, 80% for OA, and 100% for DA). This microsphere-based multidetection immunoassay provides an easy and rapid screening method capable of detecting simultaneously in the same sample three regulated groups of marine toxins. 23619185 Developmental effects of perinatal exposure to PBDE and PCB on gene expression in sexually dimorphic rat brain regions and female sexual behavior. The developing nervous system is a potential target of environmental contaminants such as polybrominated diphenylethers (PBDE), which accumulate in the biosphere. We compared effects of 2,2',4,4',5-pentabromo-BDE (PBDE99), a PBDE congener present in environmental samples, and PCB on brain development. Time-pregnant rats were subcutaneously injected with PBDE99 (1 or 10mg/kg), the PCB mixture Aroclor 1254 (10mg/kg), or vehicle from gestational day 10-18. mRNA levels of genes involved in central control of reproductive functions and sexual behavior were analyzed by real time RT PCR in two sexually dimorphic brain regions, medial preoptic area (MPO) and ventromedial hypothalamus (VMH) of adult offspring of both sexes. Exposure to PBDE99 or the PCB mixture during pre- and postnatal development affected mRNA expression levels in a treatment-, region- and sex-specific manner, and changed the sensitivity of target genes to estradiol. The sex difference in progesterone receptor mRNA levels of VMH normally seen in untreated controls was abolished by both, PBDE99 and PCB. Estrous cycles were significantly affected, and preliminary experiments suggest an impairment of female sexual behavior. Our data indicate that developmental exposure to PBDE99 at doses below signs of general toxicity affects the regulation of estrogen target genes in rat brain. Since PBDE99 was detected in blood and adipose tissue of adult offspring, these effects may result from interactions with developmental processes, with adult functions, or a combination of both. 23891083 The role of oxidative stress in pro-inflammatory activation of human endothelial cells on Ti6Al4V alloy. Inflammation is an important step in the early phase of tissue regeneration around an implanted metallic orthopaedic device. However, prolonged inflammation, which can be induced by metallic corrosion products, can lead to aseptic loosening and implant failure. Cells in peri-implant tissue as well as metal corrosion can induce reactive oxygen species (ROS) formation, thus contributing to an oxidative microenvironment around an implant. Understanding cellular reactions to implant-induced oxidative stress and inflammatory activation is important to help prevent an adverse response to metallic materials. In an earlier study we have shown that endothelial cells grown on Ti6Al4V alloy are subjected to oxidative stress. Since endothelial cells play a critical role in inflammation, in this study we examined the role of oxidative stress in their response to pro-inflammatory activation. Therefore, we stimulated endothelial cells in contact with Ti6Al4V with tumour necrosis factor-α (TNF-α) and monitored the expression of inflammation-associated molecules, such as E-selectin, intercellular adhesion molecule-1 (ICAM-1) and interleukin-8 (IL-8). The induction of these proteins was lower in endothelial cells on Ti6Al4V compared to control tissue culture conditions. There was, however, a discrepancy in pro-inflammatory activation at protein compared to mRNA level in the cells on Ti6Al4V. To examine the role of oxidative stress in this response we utilized different ROS scavengers and showed that ROS depletion improved cellular response to TNF-α on Ti6Al4V. These results could contribute to developing strategies to improve tissue response to metal implants. 23905788 Additive Approach for Inactivation of Escherichia coli O157:H7, Salmonella, and Shigella spp. on Contaminated Fresh Fruits and Vegetables Using Bacteriophage Cocktail and Produce Wash. The incidence of foodborne outbreaks involving fresh produce is of worldwide concern. Lytic bacteriophage cocktails and a levulinic acid produce wash were investigated for their effectiveness against the foodborne pathogens Escherichia coli O157:H7, Shigella spp., and Salmonella on broccoli, cantaloupe, and strawberries. Inoculated samples were treated with bacteriophage cocktails (BC) before storage at 10°C for 24 h, a levulinic acid produce wash (PW) after storage at 10°C for 24 h, or a combination of the washes (BCPW) before and after storage. All three treatments were compared against a 200-ppm free available chlorine wash. Wash solutions were prepared using potable water and water with an increased organic content of 2.5 g/liter total dissolved solids and total organic carbon. BCPW was the most effective treatment, producing the highest log reductions in the pathogens. Produce treated with BCPW in potable water with a PW exposure time of 5 min resulted in the highest reduction of each pathogen for all samples tested. The type of produce and wash solution had significant effects on the efficacy of the individual treatments. The chlorine wash in water with higher organic content was the least effective treatment tested. An additive effect of BCPW was seen in water with higher organic content, resulting in greater than 4.0-log reductions in pathogens. Our findings indicate that the combination of antimicrobial BC with a commercial produce wash is a very effective method for treating produce contaminated with E. coli O157:H7, Shigella spp., and Salmonella even in the presence of high loads of organic matter. 23790091 ΔJunD overexpression in the nucleus accumbens prevents sexual reward in female Syrian hamsters. Motivated behaviors, including sexual experience, activate the mesolimbic dopamine system and produce long-lasting molecular and structural changes in the nucleus accumbens. The transcription factor ΔFosB is hypothesized to partly mediate this experience-dependent plasticity. Previous research in our laboratory has demonstrated that overexpressing ΔFosB in the nucleus accumbens of female Syrian hamsters augments the ability of sexual experience to cause the formation of a conditioned place preference. It is unknown, however, whether ΔFosB-mediated transcription in the nucleus accumbens is required for the behavioral consequences of sexual reward. We therefore used an adeno-associated virus to overexpress ΔJunD, a dominant negative binding partner of ΔFosB that decreases ΔFosB-mediated transcription by competitively heterodimerizing with ΔFosB before binding at promotor regions on target genes, in the nucleus accumbens. We found that overexpression of ΔJunD prevented the formation of a conditioned place preference following repeated sexual experiences. These data, when coupled with our previous findings, suggest that ΔFosB is both necessary and sufficient for behavioral plasticity following sexual experience. Furthermore, these results contribute to an important and growing body of literature demonstrating the necessity of endogenous ΔFosB expression in the nucleus accumbens for adaptive responding to naturally rewarding stimuli. 23845677 Late presentation of TAPVC with multiple cerebral abscesses. We report the case of a 24-year-old man, presenting with fever, headache, vomiting and seizures, subsequently diagnosed with cyanotic congenital heart disease. Evaluation revealed non-obstructive supracardiac total anomalous pulmonary venous connection (TAPVC) as the underlying disorder. Surprisingly, the patient denied any past cardiac symptoms. Presentation in adulthood is infrequent for TAPVC, and primary manifestation with cerebral abscesses is still more unusual. 23845074 Health and nutrition knowledge, attitudes and practices of pregnant women attending and not-attending ANC clinics in Western Kenya: a cross-sectional analysis. Antenatal care (ANC) is a key strategy to decreasing maternal mortality in low-resource settings. ANC clinics provide resources to improve nutrition and health knowledge and promote preventive health practices. We sought to compare the knowledge, attitude and practices (KAP) among women seeking and not-seeking ANC in rural Kenya. Data from a community-based cross-sectional survey conducted in Western Province, Kenya were used. Nutrition knowledge (NKS), health knowledge (HKS), attitude score (AS), and dietary diversity score (DDS) were constructed indices. χ2 test and Student's t-test were used to compare proportions and means, respectively, to assess the difference in KAP among pregnant women attending and not-attending ANC clinics. Multiple regression analyses were used to assess the impact of the number of ANC visits (none, <4, ≥4) on knowledge and practice scores, adjusting for maternal socio-demographic confounders, such as age, gestational age, education level and household wealth index. Among the 979 pregnant women in the survey, 59% had attended ANC clinics while 39% had not. The mean (±SD) NKS was 4.6 (1.9) out of 11, HKS was 6.2 (1.7) out of 12, DDS was 4.9 (1.4) out of 12, and AS was 7.4 (2.2) out of 10. Nutrition knowledge, attitudes, and DDS were not significantly different between ANC clinic attending and non-attending women. Among women who attended ANC clinics, 82.6% received malaria and/or antihelmintic treatment, compared to 29.6% of ANC clinic non-attendees. Higher number of ANC clinic visits and higher maternal education level were significantly positively associated with maternal health knowledge. Substantial opportunities exist for antenatal KAP improvement among women in Western Kenya, some of which could occur with greater ANC attendance. Further research is needed to understand multi-level factors that may affect maternal knowledge and practices. 23881222 A lab-in-a-droplet bioassay strategy for centrifugal microfluidics with density difference pumping, power to disc and bidirectional flow control. In this paper, we present a lab-in-a-droplet bioassay strategy for a centrifugal microfluidics or lab-on-a-disc (LOAD) platform with three important advancements including density difference pumping, power to disc and bidirectional flow control. First, with the water based bioassay droplets trapped in a micro-channel filled with mineral oil, centrifugal force due to the density difference between the water and oil phases actuates droplet movement while the oil based medium remains stationary. Second, electricity is coupled to the rotating disc through a split-core transformer, thus enabling on-chip real-time heating in selected areas as desired and wireless programmable functionality. Third, an inertial mechanical structure is proposed to achieve bidirectional flow control within the spinning disc. The droplets can move back and forth between two heaters upon changing the rotational speed. Our platform is an essential and versatile solution for bioassays such as those involving DNA amplification, where localized temperature cycling is required. Finally, without the loss of generality, we demonstrate the functionality of our platform by performing real-time polymerase chain reaction (RT-PCR) in a linear microchannel made with PTFE (Teflon) micro-tubing. 23103296 In vitro metabolism, permeation, and brain availability of six major boswellic acids from Boswellia serrata gum resins. Boswellia serrata gum resin extracts (BSE) revealed potent anti-inflammatory actions in preclinical and clinical studies. In 2002 BSE was assigned an orphan drug status by the European Medicines Agency (EMA) for the treatment of peritumoral edema. In the past pharmacological effects of BSE were mainly attributed to 11-keto-β-boswellic acid (KBA) and 3-acetyl-11-keto-β-boswellic acid (AKBA). Therefore pharmacokinetic and pharmacodynamic studies focused mainly on these two boswellic acids (BAs). However, other BAs, like β-boswellic acid (βBA), might also contribute to the anti-inflammatory actions of BSE. Here, we determined the metabolic stability, permeability and brain availability of six major BAs, that is, KBA, AKBA, βBA, 3-acetyl-β-boswellic acid (AβBA), α-boswellic acid (αBA), and 3-acetyl-α-boswellic acid (AαBA). For permeability studies, the Caco-2 model was adapted to physiological conditions by the addition of bovine serum albumin (BSA) to the basolateral side and the use of modified fasted state simulated intestinal fluid (FaSSIF) on the apical side. Under these conditions the four BAs lacking the 11-keto moiety revealed moderate permeability. Furthermore the permeability of AKBA and KBA was improved compared to earlier studies. In contrast to Aα- and AβBA, βBA and αBA were intensively metabolized after incubation with human and rat liver microsomes. Finally, the availability of all six major BAs could be confirmed in rat brain 8h after oral administration of 240mg/kg BSE to rats showing mean concentrations of 11.6ng/g for KBA, 37.5ng/g for AKBA, 485.1ng/g for αBA, 1066.6ng/g for βBA, 43.0ng/g for AαBA and 163.7ng/g for AβBA. 23471517 Variability of the honey bee mite Varroa destructor in Serbia, based on mtDNA analysis. Only two mitochondrial haplotypes (Korea and Japan) of Varroa destructor, the ectoparasitic honey bee mite, are known to be capable of infesting and successfully reproducing in Apis mellifera colonies worldwide. Varroa destructor (then called Varroa jacobsoni) was observed in Serbia for the first time in 1976. In order to obtain insight into the genetic variability of the mites parasitizing A. mellifera we analyzed 45 adult female mites sampled from nine localities dispersed throughout Serbia. Four fragments within cox1, atp6, cox3 and cytb mtDNA genes were sequenced. The Korea haplotype of V. destructor was found to be present at all localities, but also two new haplotypes (Serbia 1 and Peshter 1) were revealed, based on cox1 and cytb sequence variability. The simultaneous occurrence of Korea and Serbia 1 haplotypes was observed at five localities, whereas Peshter 1 haplotype was identifed at only one place. 23651505 Resistance to BH3 mimetic S1 in SCLC cells that up-regulate and phosphorylate Bcl-2 through ERK1/2. B cell lymphoma 2 (Bcl-2) is a central regulator of cell survival that is overexpressed in the majority of small-cell lung cancers (SCLC) and contributes to both malignant transformation and therapeutic resistance. The purpose of this work was to study the key factors that determine the sensitivity of SCLC cells to Bcl-2 homology domain-3 (BH3) mimetic S1 and the mechanism underlying the resistance of BH3 mimetics. Western blot was used to evaluate the contribution of Bcl-2 family members to the cellular response of SCLC cell lines to S1. Acquired resistant cells were derived from initially sensitive H1688 cells. Quantitative PCR and gene silencing were performed to investigate Bcl-2 up-regulation. A progressive increase in the relative levels of Bcl-2 and phosphorylated Bcl-2 (pBcl-2) characterized the increased de novo and acquired resistance of SCLC cell lines. Furthermore, acute treatment of S1 induced Bcl-2 expression and phosphorylation. We showed that BH3 mimetics, including S1 and ABT-737, induced endoplasmic reticulum (ER) stress and then activated MAPK/ERK pathway. The dual function of MAPK/ERK pathway in defining BH3 mimetics was illustrated; ERK1/2 activation leaded to Bcl-2 transcriptional up-regulation and sustained phosphorylation in naïve and acquired resistant SCLC cells. pBcl-2 played a key role in creating resistance of S1 and ABT-737 not only by sequestrating pro-apoptotic proteins, but also sequestrating a positive feedback to promote ERK1/2 activation. These results provide significant novel insights into the molecular mechanisms for crosstalk between ER stress and endogenously apoptotic pathways in SCLC following BH3 mimetics treatment. 23879196 High-Throughput Investigation of Catalysts for JP-8 Fuel Cracking to Liquefied Petroleum Gas. Portable power technologies for military applications necessitate the production of fuels similar to LPG from existing feedstocks. Catalytic cracking of military jet fuel to form a mixture of C2-C4 hydrocarbons was investigated using high-throughput experimentation. Cracking experiments were performed in a gas-phase, 16-sample high-throughput reactor. Zeolite ZSM-5 catalysts with low Si/Al ratios (≤25) demonstrated the highest production of C2-C4 hydrocarbons at moderate reaction temperatures (623-823 K). ZSM-5 catalysts were optimized for JP-8 cracking activity to LPG through varying reaction temperature and framework Si/Al ratio. The reducing atmosphere required during catalytic cracking resulted in coking of the catalyst and a commensurate decrease in conversion rate. Rare earth metal promoters for ZSM-5 catalysts were screened to reduce coking deactivation rates, while noble metal promoters reduced onset temperatures for coke burnoff regeneration. 23830185 Mobilization of hematopoietic stem cells by plerixafor alone in children: A sequential Bayesian trial. The rapid kinetics of hematopoietic stem cells induced by Plerixafor (Mozobil®, Genzyme) should be of particular interest in children. We therefore conducted a prospective trial to determine whether a one-day mobilization by plerixafor alone was efficient enough in children with cancer. Children with solid malignancies were consecutively recruited for this phase-IIA, Bayesian single-center prospective study. Mobilization consisted in one subcutaneous injection of 240μg plerixafor/kg body weight at 8a.m. (h0). Collection by apheresis began at h5 provided that CD34+count exceeded 10×10(6)/L. Our main evaluation criterion was percent of children in which at least 5×10(6)CD34+/kg could be collected during the first apheresis. No patients fulfilled the success criterion, and so a stopping criterion was met after 5 patients. All patients reached the threshold value of 10×10(6)CD34+cells/L post-injection and so all were eligible for apheresis. Peak CD34+cell values were ranged from 11 to 44×10(6)/L and were reached in 4h to 6h. No side-effects were observed. Median number of CD34+cells collected per patient BW was 1.62×10(6)[0.47-3.5]. In 3 of the 5 patients, collection was>1.5×10(6)CD34+/kgBW. In children, a 'one-day' mobilization regimen consisting of one injection of 240μg/kg plerixafor alone in hematological steady state provides a faster and shorter mobilization than in adults. This strategy may be an attractive option for completing an insufficient graft. More studies are warranted to optimize the use of plerixafor in children. 23866006 Inverse associations between light-to-moderate alcohol intake and lipid-related indices in patients with diabetes. Dyslipidemia is a common complication in patients with diabetes and is involved in being prone to cardiovascular disease. The risk of coronary artery disease is known to be lower in light-to-moderate drinkers than in abstainers. The aim of this study was to clarify whether and how alcohol drinking influences the lipid-related indices, good predictors for cardiovascular disease, such as the ratio of LDL cholesterol to HDL cholesterol (LDL-C/HDL-C ratio), the ratio of triglycerides to HDL cholesterol (TG/HDL-C ratio), and the lipid accumulation product (LAP), in patients with diabetes. The subjects were men with diabetes (n = 1477; mean age, 54.0 years) and they were divided into non-, light (< 22 g ethanol/day), moderate (>= 22 and < 44 g ethanol/day) and heavy (>= 44 g ethanol/day) drinkers. The relationships between alcohol intake and the lipid-related indices were investigated by the multivariate analyses with adjustment for age, smoking, regular exercise and drug therapy for diabetes. The odds ratio (OR) vs. nondrinkers for high LDL-C/HDL-C ratio tended to be lower with an increase in alcohol intake (OR with 95% confidence interval (CI): 0.80 [0.50-1.29] in light drinkers; 0.24 [0.15-0.38] in moderate drinkers and 0.10 [0.05-0.19] in heavy drinkers). Alcohol intake showed an inverse association with a high TG/HDL-C ratio (OR with 95% CI vs. nondrinkers for high TG/HDL-C ratio: 0.54 [0.36-0.80] in light drinkers; 0.73 [0.56-0.97] in moderate drinkers and 0.72 [0.53-0.98] in heavy drinkers) and a J-shaped relationship with a high LAP (OR with 95% CI vs. nondrinkers for high LAP: 0.66 [0.43-1.02] in light drinkers; 0.82 [0.61-1.10] in moderate drinkers, and 1.29 [0.95-1.77] in heavy drinkers). Similar associations between alcohol intake and the lipid indices were obtained in a covariance analysis. In patients with diabetes, light-to-moderate alcohol consumption is inversely associated with lipid-related indices, and this correlates with previous findings of cardiovascular risk reduction by modest drinking in patients with diabetes. 23789981 High resolution MRI difference between moyamoya disease and intracranial atherosclerosis. Along with intracranial atherosclerotic disease (ICAD), moyamoya disease (MMD) is the most common cause of middle cerebral artery (MCA) occlusion in Asians. Although they have differing vascular wall pathologies, conventional angiographic evaluation methods cannot easily differentiate MMD from ICAD in certain situations, such as in young patients with atherosclerotic risk factors. High resolution magnetic resonance imaging (HR-MRI) findings for the diseased segments of MCAs in MMD and symptomatic ICAD were compared to further elucidate differences in arterial wall changes. Angiographically confirmed patients, 12 MMD and 20 ICAD, who suffered a stroke due to MCA occlusion were recruited and underwent HR-MRI. The size of the outer diameter and other stenotic vessel wall characteristics revealed by HR-MRI, including enhancement, eccentricity and other lesion patterns, were analyzed by two independent reviewers in a blind fashion. MMD patients were younger than ICAD patients (32.92 ± 11.08 years vs. 51.85 ± 11.97 years; mean ± SD) and displayed a smaller outer diameter in the stenotic portion (1.61 ± 0.43 mm for MMD vs. 3.03 ± 0.53 mm for ICAD, P < 0.0001). Eccentric lesions (three of 12 in MMD vs. 19 of 20 in ICAD, P < 0.0001) and focal enhancements in diseased areas (two of seven in MMD vs. 13 of 17 in ICAD, P = 0.061) were less common in MMD cases. Our HR-MRI findings show that MMD is associated with smaller, concentric occlusive lesions which are rarely enhanced compared with symptomatic ICAD, consistent with the results of previous pathological reports. HR-MRI may therefore have utility in differentiating MMD from ICAD. 23592746 A Surgical Model in Male Obese Rats Uncovers Protective Effects of Bile Acids Post-Bariatric Surgery. Bariatric surgery elevates serum bile acids. Conjugated bile acid administration, such as tauroursodeoxycholic acid (TUDCA), improves insulin sensitivity, while short-circuiting bile acid circulation through ileal interposition surgery in rats raises TUDCA levels. We hypothesized that bariatric surgery outcomes could be recapitulated by short-circuiting the normal entero-hepatic bile circulation. We established a model wherein male obese rats underwent either bile diversion (BD) or Sham (SH) surgery. The BD group had a catheter inserted into the common bile duct and its distal end anchored into the mid-distal jejunum for 4-5 weeks. Glucose tolerance, insulin and glucagon-like peptide-1 (GLP-1) response, hepatic steatosis and endoplasmic reticulum (ER) stress were measured. Rats' post-BD lost significantly more weight than the SH-rats. BD rats gained less fat mass post-surgery. BD rats had improved glucose tolerance, increased higher post-prandial GLP-1 response and serum bile acids but less liver steatosis. Serum bile acid levels including TUDCA concentrations were higher in BD compared to SH pair-fed rats. Fecal bile acid levels were not different. Liver ER stress (CHOP mRNA and pJNK protein) was decreased in BD rats. Bile acid gavage (TUDCA/UDCA) in diet-induced obese rats, elevated serum TUDCA and concomitantly reduced hepatic steatosis and ER stress (CHOP mRNA). These data demonstrate the ability of alterations in bile acids to recapitulate important metabolic improvements seen after bariatric surgery. Further, our work establishes a model for focused study of bile acids in the context of bariatric surgery that may lead to the identification of therapeutics for metabolic disease. 23401067 Quantitative determination of famotidine in human maternal plasma, umbilical cord plasma and urine using high-performance liquid chromatography-mass spectrometry. Liquid chromatography with electrospray ionization mass spectrometry for the quantitative determination of famotidine in human urine, maternal and umbilical cord plasma was developed and validated. The plasma samples were alkalized with ammonium hydroxide and extracted twice with ethyl acetate. The extraction recovery of famotidine in maternal and umbilical cord plasma ranged from 53 to 64% and 72 to 79%, respectively. Urine samples were directly diluted with the initial mobile phase then injected into the HPLC system. Chromatographic separation of famotidine was achieved by using a Phenomenex Synergi™ Hydro-RP™ column with a gradient elution of acetonitrile and 10 mm ammonium acetate aqueous solution (pH 8.3, adjusted with ammonium hydroxide). Mass spectrometric detection of famotidine was set in the positive mode and used a selected ion monitoring method. Carbon-13-labeled famotidine was used as internal standard. The calibration curves were linear (r(2) > 0.99) in the concentration ranges of 0.631-252 ng/mL for umbilical and maternal plasma samples and 0.075-30.0 µg/mL for urine samples. The relative deviation of method was <14% for intra- and inter-day assays, and the accuracy ranged between 93 and 110%. The matrix effect of famotidine in human urine, maternal and umbilical cord plasma was less than 17%. 23722706 N-acetylcysteine reverses cardiac myocyte dysfunction in a rodent model of behavioral stress. Compelling clinical reports reveal that behavioral stress alone is sufficient to cause reversible myocardial dysfunction in selected individuals. We developed a rodent stress cardiomyopathy model by a combination of prenatal and postnatal behavioral stresses (Stress). We previously reported a decrease in percent fractional shortening by echo, both systolic and diastolic dysfunction by catheter-based hemodynamics, as well as attenuated hemodynamic and inotropic responses to the β-adrenergic agonist, isoproterenol (ISO) in Stress rats compared with matched controls (Kan H, Birkle D, Jain AC, Failinger C, Xie S, Finkel MS. J Appl Physiol 98: 77-82, 2005). We now report enhanced catecholamine responses to behavioral stress, as evidenced by increased circulating plasma levels of norepinephrine (P < 0.01) and epinephrine (P < 0.01) in Stress rats vs. controls. Cardiac myocytes isolated from Stress rats also reveal evidence of oxidative stress, as indicated by decreased ATP, increased GSSG, and decreased GSH-to-GSSG ratio in the presence of increased GSH peroxidase and catalase activities (P < 0.01, for each). We also report blunted inotropic and intracellular Ca(2+) concentration responses to extracellular Ca(2+) (P < 0.05), as well as altered inotropic responses to the intracellular calcium regulator, caffeine (20 mM; P < 0.01). Treatment of cardiac myocytes with N-acetylcysteine (NAC) (10(-3) M) normalized calcium handling in response to ISO and extracellular Ca(2+) concentration and inotropic response to caffeine (P < 0.01, for each). NAC also attenuated the blunted inotropic response to ISO and Ca(2+) (P < 0.01, for each). Surprisingly, NAC did not reverse the changes in GSH, GSSG, or GSH-to-GSSG ratio. These data support a GSH-independent salutary effect of NAC on intracellular calcium signaling in this rodent model of stress-induced cardiomyopathy. 23194521 Muscle composition slightly affects in vitro digestion of aged and cooked meat: identification of associated proteomic markers. Meat is an appropriate source of proteins and minerals for human nutrition. Technological treatments modify the physical-chemical properties of proteins, making them liable to decrease the nutritional potential of meat. To counteract this damage, antioxidants and chaperone proteins in muscle cells can prevent oxidation, restore the function of denatured proteins, and thus prevent aggregation. This study aimed to explore the impact of indoor vs outdoor-reared meat protein composition on digestion and to associate protein markers to in vitro digestion parameters. Indoor-reared meat tended to show less oxidation and denaturation than outdoor-reared meat and was characterised by an overexpression of contractile and chaperone proteins. Outdoor-reared meat showed amplification of antioxidant and detoxification metabolism defending against oxidised compounds. Impacts on digestion remained minor. Several protein markers of in vitro digestion parameters were found for aged and cooked meat, linked to the detoxification process and to muscle contraction. 23178413 Student pharmacists' perceptions of barriers to medication adherence counseling. Purpose: To identify the barriers perceived by student pharmacists to counseling on medication adherence in a supermarket community pharmacy chain. Methods: Online surveys were made available to 65 student pharmacists. Subjects completed the survey anonymously and indicated their opinions and perceptions on topics related to medication adherence through the use of a 5-point Likert-type scale. Results: Of the surveyed student pharmacists, 26 completed the survey (40%). All participants (100%) agreed that they have knowledge on the importance of medication adherence. Student pharmacists stated that they did not have the time to cover adherence in a counseling session (72.7%) nor did they have time to perform follow-up phone calls with the patient (54.5%). The majority of student pharmacists (81.8%) were comfortable bringing up the topic of adherence with the patient but thought that they did not have access to resources on adherence to provide to the patient (59%). Conclusions: Surveyed students indicated they were constrained for time to counsel patients on adherence and to perform continued follow-up with patients afterward. Factors cited as barriers to counseling patients on medication adherence include time, lack of specific training in adherence management, lack of resources to provide to the patient, and patient disinterest in the subject. 23463290 The influence of botulinum toxin A injections into the calf muscles on genu recurvatum in children with cerebral palsy. With cerebral palsy (CP), an equinus deformity may lead to genu recurvatum. Botulinum toxin A (BtA) injection into the calf muscles is a well-accepted treatment for dynamic equinus deformity. The purpose of this study was to determine whether BtA injections into the calf muscles to decrease equinus would decrease coexisting genu recurvatum in children with diplegic CP. In a retrospective study, 13 children (mean age, 5 years) with spastic diplegic CP showing equinus and coexisting primary genu recurvatum, who were treated with BtA injections into the calf muscles, were included. Evaluations were done before and 6 and 18 weeks after intervention using three-dimensional gait analysis and clinical examinations according to a standardized protocol. Basic statistical analyses (power analysis, ANOVA) were performed to compare genu recurvatum before treatment and at 6 and 18 weeks after injection with BtA. During stance phase, maximum ankle dorsiflexion was increased substantially from -3.0° ± 14.3° before to 6.2° ± 14.2° 6 weeks after the injections. Despite this, with the numbers available, the amount of recurvatum in stance did not improve with treatment at either 6 or 18 weeks. There was significant improvement of knee hyperextension during stance phase of 6.2° between baseline and 18 weeks after BtA injection, but a genu recurvatum was still present in most patients. Despite improvement of ankle dorsiflexion after injection with BtA, genu recurvatum did not show relevant improvement at 6 or 18 weeks after injection with the numbers available. Because knee hyperextension remained in most patients, other factors leading to genu recurvatum should be taken into consideration. In addition, a botulinum toxin-induced weakness of the gastrocnemius may explain why recurvatum gait was not significantly reduced. Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. 23743777 Classification of time series of multispectral images with limited training data. Image classification usually requires the availability of reliable reference data collected for the considered image to train supervised classifiers. Unfortunately when time series of images are considered, this is seldom possible because of the costs associated with reference data collection. In most of the applications it is realistic to have reference data available for one or few images of a time series acquired on the area of interest. In this paper, we present a novel system for automatically classifying image time series that takes advantage of image(s) with an associated reference information (i.e., the source domain) to classify image(s) for which reference information is not available (i.e., the target domain). The proposed system exploits the already available knowledge on the source domain and, when possible, integrates it with a minimum amount of new labeled data for the target domain. In addition, it is able to handle possible significant differences between statistical distributions of the source and target domains. Here, the method is presented in the context of classification of remote sensing image time series, where ground reference data collection is a highly critical and demanding task. Experimental results show the effectiveness of the proposed technique. The method can work on multimodal (e.g., multispectral) images. 23224405 Production and characterization of recombinant 9 and 15 kDa granulysin by fed-batch fermentation in Pichia pastoris. Granulysin is a cytolytic, proinflammatory protein produced by human cytolytic T-lymphocytes and natural killer cells. Granulysin has two stable isoforms with molecular weight of 9 and 15 kDa; the 9-kDa form is a result of proteolytic maturation of the 15-kDa precursor. Recombinant 9-kDa granulysin exhibits cytolytic activity against a variety of microbes, such as bacteria, parasites, fungi, yeast and a variety of tumor cell lines. However, it is difficult to produce granulysin in large quantities by traditional methods. In this study, we developed a simple and robust fed-batch fermentation process for production and purification of recombinant 9- and 15-kDa granulysin using Pichia pastoris in a basal salt medium at high cell density. The granulysin yield reaches at least 100 mg/l in fermentation, and over 95 % purity was achieved with common His-select affinity and ion exchange chromatography. Functional analysis revealed that the yeast-expressed granulysin displayed dose-dependent target cytotoxicity. These results suggest that fermentation in P. pastoris provides a sound strategy for large-scale recombinant granulysin production that may be used in clinical applications and basic research. 23755884 Design, synthesis, and evaluation of novel VEGFR2 kinase inhibitors: discovery of [1,2,4]triazolo[1,5-a]pyridine derivatives with slow dissociation kinetics. For the purpose of discovering novel type-II inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2) kinase, we designed and synthesized 5,6-fused heterocyclic compounds bearing a anilide group. A co-crystal structure analysis of imidazo[1,2-b]pyridazine derivative 2 with VEGFR2 revealed that the N1-nitrogen of imidazo[1,2-b]pyridazine core interacts with the backbone NH group of Cys919. To retain this essential interaction, we designed a series of imidazo[1,2-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, thiazolo[5,4-b]pyridine, and 1,3-benzothiazole derivatives maintaining a ring nitrogen as hydrogen bond acceptor (HBA) at the corresponding position. All compounds thus designed displayed strong inhibitory activity against VEGFR2 kinase, and the [1,2,4]triazolo[1,5-a]pyridine 13d displayed favorable physicochemical properties. Furthermore, 13d inhibited VEGFR2 kinase with slow dissociation kinetics and also inhibited platelet-derived growth factor receptor (PDGFR) kinases. Oral administration of 13d showed potent anti-tumor efficacy in DU145 and A549 xenograft models in nude mice. 22863599 Dopamine D₂-agonist rotigotine effects on cortical excitability and central cholinergic transmission in Alzheimer's disease patients. Dopamine is a neurotransmitter involved in several brain functions ranging from emotions control, movement organization to memory formation. It is also involved in the regulation of mechanisms of synaptic plasticity. However, its role in Alzheimer's disease (AD) pathogenesis is still puzzling. Several recent line of research instead indicates a clear role for dopamine in both amyloid β formation as well as in cognitive decline progression. In particular it has been shown that dopamine D₂-like receptors (namely D₃ and D₂) could be mostly responsible for dopamine dysfunction in AD. Here we aimed to study the effects of the dopamine agonist Rotigotine on cortical excitability and on central cholinergic transmission in cases of AD. Rotigotine is a dopamine agonist with a pharmacological profile with high affinity for D₃ and D₂ receptors. We used paired pulse protocols assessing short intracortical inhibition (SICI) and intracortical facilitation (ICF) to asses cortical excitability over the primary motor cortex and Short Latency Afferent Inhibition (SLAI) protocols, to verify the effects of the drug on central cholinergic transmission in a group of AD patients compared to age-matched controls. We observed that rotigotine induces unexpected changes in both cortical excitability (increased) and central cholinergic transmission (restored) of AD patients. These unexpected effects might depend on the dopamine D₂-like receptors dysfunction previously described in AD brains. The current findings could indicate that future strategies aimed to ameliorate symptoms of the related AD cognitive decline could also involve some dopaminergic drugs. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23900660 Introducing the composite time trade-off: a test of feasibility and face validity. This study was designed to test the feasibility and face validity of the composite time trade-off (composite TTO), a new approach to TTO allowing for a more consistent elicitation of negative health state values. The new instrument combines a conventional TTO to elicit values for states regarded better than dead and a lead-time TTO for states worse than dead. A total of 121 participants completed the composite TTO for ten EQ-5D-5L health states. Mean values ranged from -0.104 for health state 53555 to 0.946 for 21111. The instructions were clear to 98 % of the respondents, and 95 % found the task easy to understand, indicating feasibility. Further, the average number of steps taken in the iteration procedure to achieve the point of indifference in the TTO and the average duration of each task were indicative of a deliberate cognitive process. Face validity was confirmed by the high mean values for the mild health states (>0.90) and low mean values for the severe states (<0.42). In conclusion, this study demonstrates the feasibility and face validity of the composite TTO in a face-to-face standardized computer-assisted interview setting. 23610082 Factors Associated With Microalbuminuria in 7,549 Children and Adolescents With Type 1 Diabetes in the T1D Exchange Clinic Registry. OBJECTIVETo examine factors associated with clinical microalbuminuria (MA) diagnosis in children and adolescents in the T1D Exchange clinic registry.RESEARCH DESIGN AND METHODST1D Exchange participants <20 years of age with type 1 diabetes ≥1 year and urinary albumin-to-creatinine ratio (ACR) measured within the prior 2 years were included in the analysis. MA diagnosis required all of the following: 1) a clinical diagnosis of sustained MA or macroalbuminuria, 2) confirmation of MA diagnosis by either the most recent ACR being ≥30 mg/g or current treatment with an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB), and 3) no known cause for nephropathy other than diabetes. Logistic regression was used to assess factors associated with MA.RESULTSMA was present in 329 of 7,549 (4.4%) participants, with a higher frequency associated with longer diabetes duration, higher mean glycosylated hemoglobin (HbA1c) level, older age, female sex, higher diastolic blood pressure (BP), and lower BMI (P ≤ 0.01 for each in multivariate analysis). Older age was most strongly associated with MA among participants with HbA1c ≥9.5% (≥80 mmol/mol). MA was uncommon (<2%) among participants with HbA1c <7.5% (<58 mmol/mol). Of those with MA, only 36% were receiving ACEI/ARB treatment.CONCLUSIONSOur results emphasize the importance of good glycemic and BP control, particularly as diabetes duration increases, in order to reduce the risk of nephropathy. Since age and diabetes duration are important nonmodifiable factors associated with MA, the importance of routine screening is underscored to ensure early diagnosis and timely treatment of MA. 23892524 The Prognostic Impact of Occult Lymph Node Metastasis in Node-negative Gastric Cancer: A Systematic Review and Meta-analysis. To conduct a meta-analysis to clarify whether occult lymph node metastasis (OLNM), which is identified by molecular detection techniques but is not detected by routine histological examination within regional lymph nodes, represents a prognostic factor for patients with node-negative gastric cancer. PubMed, Embase, and the Cochrane Library were searched from their inception to November 2012. The published studies that investigated the association between OLNM and the prognosis of patients with node-negative gastric cancer were included. We extracted hazard ratios (HRs) and associated standard errors from the identified studies and performed random-effects model meta-analyses on overall survival and disease-specific survival. Subgroup analyses were also conducted. A total of 14 eligible studies that included 1,478 patients were identified. Meta-analyses revealed that OLNM was associated with poor overall survival [HR 2.72; 95 % confidence interval (CI) 1.61-4.60], and disease-specific survival (HR 2.91; 95 % CI 1.25-6.79). Subgroup analyses suggested that OLNM was associated with poor survival in early gastric cancer (HR 3.57; 95 % CI 1.23-10.33). However, subgroup analyses of studies that exclusively enrolled patients with D2 lymph node dissection demonstrated that OLNM did not have an influence on the prognosis (HR 1.97; 95 % CI 0.82-4.70). OLNM correlates with poor prognosis for patients with node-negative gastric cancer, and D2 lymph node dissection could eliminate this correlation. For OLNM-positive patients with node-negative gastric cancer, D2 lymph node dissection is necessary. 23727560 Semiquantitative and quantitative analysis of protein-DNA interactions using steady-state measurements in surface plasmon resonance competition experiments. One method commonly used to characterize protein-DNA interactions is surface plasmon resonance (SPR). In a typical SPR experiment, chip-bound DNA is exposed to increasing concentrations of protein; the resulting binding data are used to calculate a dissociation constant for the interaction. However, in cases in which knowledge of the specificity of the interaction is required, a large set of DNA variants has to be tested; this is time consuming and costly, in part because of the requirement for multiple SPR chips. We have developed a new protocol that uses steady-state binding levels in SPR competition experiments to determine protein-binding dissociation constants for a set of DNA variants. This approach is rapid and straightforward and requires the use of only a single SPR chip. Additionally, in contrast to other methods, our approach does not require prior knowledge of parameters such as on or off rates, using an estimate of the wild-type interaction as the sole input. Utilizing relative steady-state responses, our protocol also allows for the rapid, reliable, and simultaneous determination of protein-binding dissociation constants of a large series of DNA mutants in a single experiment in a semiquantitative fashion. We compare our approach to existing methods, highlighting specific advantages as well as limitations. 23741733 Electrochemical study of ricin at glassy carbon electrode. Ricin, Ricinus communis agglutinin 60 - RCA 60, is a deadly phytotoxic protein which inhibits ribosomes (class II), and there is no known effective antidote in living organisms. Ricin is composed of two polypeptide chains, A and B, linked covalently by a single disulfide bond. The analytical methods for the detection of RCA 60 are commonly laborious, expensive, require skilled labor, and involve sophisticated equipment. Aimed at the development of electroanalytical methods for RCA 60 detection, here we studied the electrochemical oxidation of RCA 60 on a glassy carbon (GC) electrode over a wide pH range, using cyclic voltammetry, differential pulse voltammetry (DPV) and square wave voltammetry (SWV). Two quasi-reversible electrochemical RCA 60 oxidation peaks were identified on the GC electrode by SWV. For values of 2.2 ≤ pH ≤ 10.2, DPV studies revealed that the peak potentials, EP1 and EP2, display a linear dependence with pH and the reaction mechanism involves the transfer of 2H(+)/2e(-) (peak 1) and 1H(+)/1e(-) (peak 2). The first and second RCA 60 oxidation steps may correspond to the oxidation of cysteine and tyrosine-tryptophan residues, respectively. The oxidation product of the second RCA 60 oxidation step appears at 7.0 ≤ pH ≤ 11.8. For pH ≥ 10.2, both processes are pH independent, resulting in a pKa of ca. 10.2. A third RCA 60 oxidation peak only appears at acidic pH. RCA 60 samples extracted from different castor seed cultivars showed similar electrochemical behavior, enabling the implementation of an analytical voltammetric method. 23931930 Circulating cell-free DNA, SLC5A8 and SLC26A4 hypermethylation, BRAF(V600E): A non-invasive tool panel for early detection of thyroid cancer. In the latest years, high levels of circulating cell-free DNA (cf-DNA) have been found to be associated with cancer diagnosis and progression, and cf-DNA has become a potential candidate as biomarker for tumor detection. cf-DNA has been investigated in plasma or serum of many tumor patients affected by different malignancies, but not yet in thyroid cancer (TC). Furthermore, in TC cells the capability to metabolize iodine is frequently lost. SLC5A8 and SLC26A4 genes are both involved in the iodine metabolism, and SLC5A8 hypermethylation status is associated with the BRAF(V600E) mutation, which is the most frequent genetic event underlying the development of papillary TC. The aim of our study is the development of a new non-invasive tool for the diagnosis and prognosis of TC based on cf-DNA, SLC5A8 and SLC26A4 hypermethylation, and BRAF(V600E) analysis. cf-DNA was measured by quantitative real-time PCR in nine cases of anaplastic thyroid cancer (ATC), 58 medullary thyroid cancers (MTC), five of synchronous medullary and follicular thyroid cancers (SMFC), 23 follicular adenomas (FA), 86 papillary thyroid cancers (PTC). A control group of 19 healthy subjects was taken. Moreover, in the PTC group we analyze the state of hypermethylation of SLC5A8 and SLC26A4, BRAF(V600E) mutation, and their involvement in the loss of function of the thyroid. cf-DNA showed a high ability to discriminate healthy individuals from cancer patients. cf-DNAALU83 and cf-DNAALU244 values were significantly correlated with the histological type of TC (P-value<0.0001). A significant increase in the amount of cf-DNAALU83 and cf-DNAALU244 when methylation occurs was observed (P-value=0.02). A correlation between BRAF(V600E) and cf-DNAALU244/ALU83 was also found (P-value=0.02). According to our experimental results, the panel including cf-DNA, SLC5A8 and SLC26A4 hypermethylation, and BRAF(V600E) analysis appears easy, reproducible, and non-invasive for the diagnosis on TC. Its possible implication in clinical setting remains to be elucidated. 23843617 Interactions between sarco-endoplasmic reticulum and mitochondria in cardiac and skeletal muscle - pivotal roles in Ca2+ and reactive oxygen species signaling. Mitochondria are strategically and dynamically positioned in the cell to spatially coordinate ATP production with energy needs and to allow the local exchange of material with other organelles. Interactions of mitochondria with the sarco-endoplasmic reticulum (SR/ER) have been receiving much attention owing to emerging evidence on the role these sites have in cell signaling, dynamics and biosynthetic pathways. One of the most important physiological and pathophysiological paradigms for SR/ER-mitochondria interactions is in cardiac and skeletal muscle. The contractile activity of these tissues has to be matched by mitochondrial ATP generation that is achieved, at least in part, by propagation of Ca(2+) signals from SR to mitochondria. However, the muscle has a highly ordered structure, providing only limited opportunity for mitochondrial dynamics and interorganellar interactions. This Commentary focuses on the latest advances in the structure, function and disease relevance of the communication between SR/ER and mitochondria in muscle. In particular, we discuss the recent demonstration of SR/ER-mitochondria tethers that are formed by multiple proteins, and local Ca(2+) transfer between SR/ER and mitochondria. 23836506 Mutations in gamma adducin are associated with inherited cerebral palsy. Cerebral palsy is estimated to affect nearly 1 in 500 children, and although prenatal and perinatal contributors have been well-characterized, at least 20% of cases are believed to be inherited. Previous studies have identified mutations in the actin-capping protein KANK1 and the adaptor protein -4 complex in forms of inherited cerebral palsy, suggesting a role for components of the dynamic cytoskeleton in the genesis of the disease. We studied a multiplex consanguineous Jordanian family by homozygosity mapping and exome sequencing, then used patient-derived fibroblasts to examine functional consequences of the mutation we identified in vitro. We subsequently studied the effects of adducin loss of function in drosophila. We identified a homozygous c.1100G>A [p.G367D] mutation in ADD3, encoding gamma adducin in all affected members of the index family. Follow-up experiments in patient fibroblasts found that the p.G367D mutation, which occurs within the putative oligomerization critical region, impairs the ability of gamma adducin to associate with the alpha subunit. This mutation impairs the normal actin capping function of adducin, leading to both abnormal proliferation and migration in cultured patient fibroblasts. Loss of function studies of the Drosophila adducin ortholog hts confirmed a critical role for adducin in locomotion. Although likely a rare cause of cerebral palsy, our findings indicate a critical role for adducins in regulating the activity of the actin cytoskeleton, suggesting that impaired adducin function may lead to neuromotor impairment and further implicating abnormalities of the dynamic cytoskeleton as a pathogenic mechanism contributing to cerebral palsy. ANN NEUROL 2013. © 2013 American Neurological Association. 23450827 Over-the-Counter Access to Emergency Contraception without Age Restriction: An Opinion of the Women's Health Practice and Research Network of the American College of Clinical Pharmacy. Family planning remains a high priority area for the United States, with goals to increase the proportion of pregnancies that are intended, reduce pregnancy rates among adolescents, and increase contraceptive use prioritized in the Healthy People 2020 objectives. Contraception intended for use after unprotected intercourse, known as emergency contraception, remains underutilized. Levonorgestrel is one method of oral emergency contraception, which prevents fertilization and does not disrupt an already established pregnancy; thus, timing of administration is critical. Despite data demonstrating safety and efficacy, evidence-based decision making has been overshadowed by politically charged actions involving levonorgestrel emergency contraception for over a decade. The Women's Health Practice and Research Network of the American College of Clinical Pharmacy supports expanded access to levonorgestrel emergency contraception and removal of barriers such as age restrictions on the nonprescription drug product. Pharmacists remain a key provider of emergency contraceptive services and can help ensure timely access. In states where direct pharmacy access to emergency contraception is available, pharmacists are encouraged to participate. Education, research, and advocacy are other important responsibilities for pharmacists in this arena. 23935985 Development of an Epidermal Growth Factor Derivative with EGFR Blocking Activity. The members of the epidermal growth factor (EGF)/ErbB family are prime targets for cancer therapy. However, the therapeutic efficiency of the existing anti-ErbB agents is limited. Thus, identifying new molecules that inactivate the ErbB receptors through novel strategies is an important goal on cancer research. In this study we have developed a shorter form of human EGF (EGFt) with a truncated C-terminal as a novel EGFR inhibitor. EGFt was designed based on the superimposition of the three-dimensional structures of EGF and the Potato Carboxypeptidase Inhibitor (PCI), an EGFR blocker previously described by our group. The peptide was produced in E. coli with a high yield of the correctly folded peptide. EGFt showed specificity and high affinity for EGFR but induced poor EGFR homodimerization and phosphorylation. Interestingly, EGFt promoted EGFR internalization and translocation to the cell nucleus although it did not stimulate the cell growth. In addition, EGFt competed with EGFR native ligands, inhibiting the proliferation of cancer cells. These data indicate that EGFt may be a potential EGFR blocker for cancer therapy. In addition, the lack of EGFR-mediated growth-stimulatory activity makes EGFt an excellent delivery agent to target toxins to tumours over-expressing EGFR. 23876048 Periodic nanowire array at the crystal interface. A dislocation in a crystalline material has dangling bonds at its core and a strong strain field in its vicinity. Consequently, the dislocation attracts solute atoms and forms a so-called Cottrell atmosphere along the dislocation. A crystalline dislocation can be used as a template to produce nanowires by selectively doping foreign atoms along the dislocation. However, control of the configuration, spacing, and density of the formed periodic nanowire array has heretofore been extremely difficult. Here we show a method for fabricating ordered, electrically conductive nanowire arrays using periodic dislocations at crystal interfaces. As a demonstration, we fabricated arrays of titanium nanowires arranged at intervals of either 13 or 90 nm and then confirmed by scanning probe microscopy that they exhibit electrical conductivity inside an insulating aluminum oxide. Significantly, we were able to precisely control nanowire periodicity by the choice of crystal orientation and/or crystal planes at the crystal interface. This simple method for the fabrication of periodic nanowire arrays of highly controlled density should be widely applicable to electrical, magnetic, and optical devices. 23889717 Enhanced Blood Pressure-Lowering Effect of Olmesartan in Hypertensive Patients With Chronic Kidney Disease-Associated Sympathetic Hyperactivity: HONEST Study. To investigate the blood pressure (BP)-lowering effect of olmesartan in relation to chronic kidney disease (CKD)-associated sympathetic nerve activity, a subanalysis was performed using data from the first 16 weeks of the Home BP Measurement With Olmesartan-Naive Patients to Establish Standard Target Blood Pressure (HONEST) study, a prospective observational study of hypertensive patients. Essential hypertensive patients who took no antihypertensive agent at baseline were classified based on baseline morning home systolic BP (MHSBP) in quartiles. In each class, patients were further classified based on baseline morning home pulse rate (MHPR). A subgroup analysis in patients with/without chronic kidney disease (CKD) was performed. A total of 5458 patients (mean age, 63.0 years; 51.6% women) were included. In the 4th quartile of baseline MHSBP (≥165 mm Hg), patients with MHPR ≥70 beats per minute had a greater BP reduction (by 3.2 mm Hg) than those with MHPR <70 beats per minute after 16 weeks of olmesartan-based treatment (P=.0005). An even greater BP reduction (by 6.6 mm Hg) was observed in patients with CKD than in patients without CKD in this group (P=.0084). Olmesartan was more effective in hypertensive patients with high MHSBP and MHPR ≥70 beats per minute, especially in patients with CKD. Olmesartan may have enhanced BP-lowering effects by improving renal ischemia in hypertensive CKD patients with potential increased sympathetic nerve activity. 23702795 Plug-and-play modules for flexible radiosynthesis. We present a plug-and-play radiosynthesis platform and accompanying computer software based on modular subunits that can easily and flexibly be configured to implement a diverse range of radiosynthesis protocols. Modules were developed that perform: (i) reagent storage and delivery, (ii) evaporations and sealed reactions, and (iii) cartridge-based purifications. The reaction module incorporates a simple robotic mechanism that removes tubing from the vessel and replaces it with a stopper prior to sealed reactions, enabling the system to withstand high pressures and thus provide tremendous flexibility in choice of solvents and temperatures. Any number of modules can rapidly be connected together using only a few fluidic connections to implement a particular synthesis, and the resulting system is controlled in a semi-automated fashion by a single software interface. Radiosyntheses of 2-[(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG), 1-[(18)F]fluoro-4-nitrobenzene ([(18)F]FNB), and 2'-deoxy-2'-[(18)F]fluoro-1-β-d-arabinofuranosyl cytosine (d-[(18)F]FAC) were performed to validate the system and demonstrate its versatility. 23716468 Copy neutral loss of heterozygosity is more frequent in older ovarian cancer patients. Loss of heterozygosity (LOH) is a common type of genomic alterations in ovarian cancer. Analyzing 74,415 copy neutral LOH events in 513 serous ovarian adenocarcinomas samples from the Cancer Genome Atlas, we report that the frequency of LOH events increases with age. Similar trend is observed for LOH involving chromosome 17, which is frequently implicated in ovarian cancer. The results are consistent when we analyze data from the Boston high-grade serous cancer cohort. We further show that germ line and somatic mutations in BRCA1 (in chromosome 17) and BRCA2 (in chromosome 13) loci are not necessary to establish the pattern. We also report significant age-related changes in expression patterns for several genes in the homologous recombination (HR) pathway, such as BRCA1, RAD50, RAD52, XRCC2, XRCC3, and MRE11A in these patient samples. Furthermore, we develop a metric for pathway-level imbalance, and show that increased imbalance in the HR pathway, i.e., increase in expression of some HR genes and decrease in expression of others, is common and correlates significantly with the frequency of LOH events in the patient samples. Taken together, it is highly likely that aging and deregulation of HR pathway contribute to the increased incidence of copy-neutral LOH in ovarian cancer patients. © 2013 Wiley Periodicals, Inc. 23742687 Increased adsorption of sulfamethoxazole on suspended carbon nanotubes by dissolved humic Acid. Although dissolved organic matter (DOM) could effectively disperse carbon nanotubes (CNTs), sorption characteristics of DOM-suspended CNTs are unclear. In this study, we evaluated the relative contribution to the overall sorption from dissolved humic acid (DHA) coating (decreased sorption) and CNT dispersion (increased sorption). We observed that the sorption coefficients of sulfamethoxazole (SMX) on DHA-suspended CNTs were up to 2 orders of magnitude higher than that on aggregated CNTs. Although the mass percent of suspended CNTs were low (generally less than 1%), their contributions to SMX adsorption were up to 20%. Because DHA and SMX did not interact with each other due to their negative charges, the suspended CNTs may not be completely coated by DHA and they had considerable hydrophobic surface exposed. Importantly, this study provided the first evidence in aqueous phase of the significantly increased surface area of DHA-suspended CNTs relative to the aggregated ones based on (1)H NMR relaxometry measurements. This study emphasizes that in comparison to aggregated CNTs, the suspended ones have amply exposed surface area and thus have greater environmental impacts, such as enhancing the mobility, transport, and possibly exposure of organic contaminants. 23758053 Architectural analysis and predicted functional capability of the human latissimus dorsi muscle. The latissimus dorsi is primarily considered a muscle with actions at the shoulder, despite its widespread attachments at the spine. There is some dispute regarding the potential contribution of this muscle to lumbar spine function. The architectural design of a muscle is one of the most accurate predictors of muscle function; however, detailed architectural data on the latissimus dorsi muscle are limited. Therefore, the aim of this study was to quantify the architectural properties of the latissimus dorsi muscle and model mechanical function in light of these new data. One latissimus dorsi muscle was removed from each of 12 human cadavers, separated into regions, and micro-dissected for quantification of fascicle length, sarcomere length, and physiological cross-sectional area. From these data, sarcomere length operating ranges were modelled to determine the force-length characteristics of latissimus dorsi across the spine and shoulder ranges of motion. The physiological cross-sectional area of latissimus dorsi was 5.6 ± 0.5 cm(2) and normalized fascicle length was 26.4 ± 1.0 cm, indicating that this muscle is designed to produce a moderate amount of force over a large range of lengths. Measured sarcomere length in the post-mortem neutral spine posture was nearly optimal at 2.69 ± 0.06 Î¼m. Across spine range of motion, biomechanical modelling predicted latissimus dorsi acts across both the ascending and descending limbs of the force-length curve during lateral bend, and primarily at or near the plateau region (where maximum force generation is possible) during flexion/extension and axial twist. Across shoulder range of motion, latissimus dorsi acts primarily on the plateau region and descending limbs of the force length curve during both flexion/extension and abduction/adduction. These data provide novel insights into the ability of the latissimus dorsi muscle to generate force and change length throughout the spine and shoulder ranges of motion. In addition, these findings provide an improved understanding of the spine and shoulder positions at which the force-generating capacity of this muscle can become jeopardized, and consequently how this may affect its spine-stabilizing ability. 23824819 Expanded co-circulation of stable subtypes, emerging lineages and new sporadic reassortants of porcine influenza viruses in swine populations in Northwest Germany. The emergence of the human 2009 pandemic H1N1 (H1N1pdm) from swine populations re-focused public and scientific attention towards swine as an important source of influenza A viruses bearing zoonotic potential. Widespread and year-round circulation of at least four stable lineages of porcine influenza viruses in Germany in a region with a high density swine population between 2009 and 2012 is documented here. European avian-derived H1N1 (H1N1av) viruses dominated the epidemiology, followed by human-derived subtypes H1N2 and H3N2. H1N1pdm viruses and, in particular, recently emerged reassortants between H1N1pdm and porcine HxN2 viruses (H1pdmN2) were detected in about 8% of cases. Further reassortants between these main lineages were diagnosed sporadically. On-going diversification both at the phylogenetic and the antigenic level was evident for the H1N1av lineage and for some of its reassortants. The H1avN2 reassortant R1931/11 displayed conspicuously distinct genetic and antigenic features and easily transmitted from pig-to-pig in an experimental infection. Continuing diverging evolution was also observed in the H1pdmN2 lineage. These viruses carry seven genome segments of the H1N1pdm virus including a hemagglutinin gene which encodes an antigenically markedly altered protein. The zoonotic potential of this lineage remains to be determined. The results highlight the relevance of surveillance and control of porcine influenza virus infections. This is important with respect to health status of swine herds. In addition, a more exhaustive tracing of the formation, transmission and spread of new reassortant influenza A viruses with unknown zoonotic potential is urgently required. 23588313 Biomarkers for Smoking Cessation. One way to enhance therapeutic development is through the identification and development of evaluative tools such as biomarkers. This review focuses on putative diagnostic, pharmacodynamic, and predictive biomarkers for smoking cessation. These types of biomarkers may be used to more accurately diagnose a disease, personalize treatment, identify novel targets for drug discovery, and enhance the efficiency of drug development. Promising biomarkers are presented across a range of approaches including metabolism, genetics, and neuroimaging. A preclinical viewpoint is also offered, as are analytical considerations and a regulatory perspective summarizing a pathway toward biomarker qualification.Clinical Pharmacology & Therapeutics (2013); advance online publication 8 May 2013. doi:10.1038/clpt.2013.57. 23614709 Sub-nanomolar Detection of Prostate Specific Membrane Antigen in Synthetic Urine by Synergistic, Dual Ligand Phage. The sensitive detection of cancer biomarkers in urine could revolutionize cancer diagnosis and treatment. Such detectors must be inexpensive, easy to interpret, and sensitive. This report describes a bioaffinity matrix of viruses integrated into PEDOT films for electrochemical sensing of prostate specific membrane antigen (PSMA), a prostate cancer biomarker. High sensitivity to PSMA resulted from synergistic action by two different ligands to PSMA on the same phage particle. One ligand was chemically synthesized and wrapped around the phage, and the second was genetically encoded. The dual ligands result in a bidentate binder with high copy, dense ligand display for enhanced PSMA detection through a chelate-based, avidity effect. Biosensing with virus-PEDOT films provides a 100 pM limit of detection for PSMA in synthetic urine without requiring enzymatic or other amplification. 23908338 ENCODE and a new landscape for psychiatric genetics. Despite rigorous research into the genetics of neuropsychiatric disorders, the mechanism by which polygenic risk leads to complex clinical phenotypes remains unclear. The Encyclopedia of DNA Elements (ENCODE) project gives us new insight into gene regulation, and gene-gene and gene-environment interaction. Better understanding of these key genomic mechanisms may provide the answers we have been searching for. 23897110 Supported liquid extraction as an alternative to solid phase extraction for LC-MS/MS aldosterone analysis? Supported liquid extraction (SLE) techniques are relatively new compared to other sample preparation approaches such as solid phase extraction (SPE), liquid-liquid extraction (LLE) and protein precipitation (PPE). We investigated the use of SLE as an alternative to SPE for the liquid chromatography tandem mass spectrometry (LC-MS/MS) measurement of aldosterone. Samples (n = 83) were analysed by the routine method using SPE. The same samples were subsequently analysed using two different SLE 96-well plate devices (Thermo and Biotage) with methyl-tertiary butyl ether extraction. A direct comparison of the three extraction techniques on two different mass spectrometers was also performed. Both results using SLE plates gave excellent agreement with the results from the SPE analysis. The area counts obtained with the Biotage plates were considerably higher than those obtained using the Thermo plate. SLE is an acceptable alternative to SPE for the LC-MS/MS analysis of aldosterone. Using SLE reduces the time required for sample preparation. 23859432 Electromagnetic field-induced converse cell growth during a long-term observation. Purpose: Professional and public concern about the potential adverse effects of man-made electromagnetic fields (EMF) on the human body has dramatically expanded in recent years. Despite numerous attempts to investigate this issue, the long-standing challenge of reproducibility surrounding alternating EMF effects on human health remains unresolved. Our chief aim was to investigate a plausible mechanism for this phenomenon. Materials and methods: Growth of cultured human cancer cells, DU145 and Jurkat, exposed to power frequency magnetic field (MF) (60 Hz, 1 mT) for 3 days, was determined using a 2-(4-Iodophenyl)- 3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST-1) assay and a trypan blue exclusion assay. This experiment was repeated at incubators long-term monitoring period up to 5.3 years. A periodogram analysis was performed to investigate periodic patterns in the MF and sham effects on cell growth. Results: Unlike conventional assumptions, the MF effect on growth in both cell types was promotive or suppressive in a period-dependent manner. The converse cell growth induced by the MF was consistent in incubators, with little variation. Conclusions: Spatiotemporal evidence suggests that the period-dependent converse cell growth by the MF may contribute to the poor reproducibility and explain the adverse effects observed in previous experimental and epidemiological investigations. Additionally, the novel approach of this study may be applied to design features required to experimentally determine the effects of EMF on living organisms in a convincing manner. 23957589 FliS modulates FlgM activity by acting as a non-canonical chaperone to control late flagellar gene expression, motility and biofilm formation in Yersinia pseudotuberculosis. The FlgM-FliA regulatory circuit plays a central role in coordinating bacterial flagellar assembly. In this study, we identified multiple novel binding partners of FlgM using bacterial two-hybrid screening. Among these binding partners, FliS, the secretion chaperone of the filament protein FliC, was identified to compete with FliA for the binding of FlgM. We further showed that by binding to FlgM, FliS protects it from secretion and degradation, thus maintaining an intracellular pool of FlgM reserved as the FliS-FlgM complex. Consequently, we found that the flagellar late-class promoter activities are significantly increased in the fliS deletion mutant. The fliS mutant is weakly motile and shows significantly increased biofilm formation on biotic surface. Based on the results obtained, we established for the first time the regulatory role of the flagellin chaperone FliS to fine-tune late flagellar assembly by modulating FlgM activity. 23414431 Application of the compensated Arrhenius formalism to fluidity data of polar organic liquids. The temperature dependence of viscosity (the reciprocal of fluidity) in polar liquids has been studied for over a century, but the available theoretical models have serious limitations. Consequently, the viscosity is often described with empirical equations using adjustable fitting parameters that offer no insight into the molecular mechanism of transport. We have previously reported a novel approach called the compensated Arrhenius formalism (CAF) to describe ionic conductivity, self-diffusion, and dielectric relaxation in terms of molecular and system properties. Here the CAF is applied to fluidity data of pure n-acetates, 2-ketones, n-nitriles, and n-alcohols over the temperature range 5-85 °C. The fluidity is represented as an Arrhenius-like expression that includes a static dielectric constant dependence in the exponential prefactor. The dielectric constant dependence results from the dependence of mass and charge transport on the molecular dipole moment and the solvent dipole density. The CAF is the only self-consistent description of fluid transport in polar liquids written solely in terms of molecular and system parameters. A scaling procedure is used to calculate the activation energy for transport. We find that the activation energies for fluidity of the aprotic liquids are comparable in value, whereas a higher average E(a) value is observed for the n-alcohol data. Finally, we contrast the molecular description of transport presented here with the conventional hydrodynamic model. 23938379 Effect of zinc and calcium ions on the rat kidney membrane-bound form of dipeptidyl peptidase IV. Dipeptidyl peptidase IV (DPP-IV) is an ectopeptidase with many roles, and a target of therapies for different pathologies. Zinc and calcium produce mixed inhibition of porcine DPP-IV activity. To investigate whether these results may be generalized to mammalian DPP-IV orthologues, we purified the intact membrane-bound form from rat kidney. Rat DPP-IV hydrolysed Gly-Pro-p-nitroanilide with an average Vmax of 0.86 +/- 0.01 meu mol min-1mL-1 and KM of 76 +/- 6 meu M. The enzyme was inhibited by the DPP-IV family inhibitor L-threo-Ile-thiazolidide (Ki=64.0 +/- 0.53 nM), competitively inhibited by bacitracin (Ki=0.16 +/- 0.01 mM) and bestatin (Ki=0.23 +/- 0.02 mM), and irreversibly inhibited by TLCK (IC50 value of 1.20 +/- 0.11 mM). The enzyme was also inhibited by divalent ions like Zn2+ and Ca2+, for which a mixed inhibition mechanism was observed (Ki values of the competitive component: 0.15 +/- 0.01 mM and 50.0 +/- 1.05 mM, respectively). According to bioinformatic tools, Ca2+ ions preferentially bound to the beta-propeller domain of the rat and human enzymes, while Zn2+ ions to the alpha-beta hydrolase domain; the binding sites were essentially the same that were previously reported for the porcine DPP-IV. These data suggest that the cationic susceptibility of mammalian DPP-IV orthologues involves conserved mechanisms. 23963005 Frequency, Timing and Predictors of Neurological Dysfunction in the Non-Myelopathic Patient With Cervical Spinal Cord Compression, Canal Stenosis, and/or Ossification of the Posterior Longitudinal Ligament. Study Design. Systematic Review and Survey.Objective. To perform an evidence synthesis of the literature and obtain information from the global spine-care community assessing the frequency, timing and predictors of symptom development in patients with radiographic evidence of cervical spinal cord compression, spinal canal narrowing, and/or ossification of posterior longitudinal ligament (OPLL) but no symptoms of myelopathy.Summary of Background Data. Evidence for a marker to predict symptom development remains sparse, and there is controversy surrounding the management of asymptomatic patients.Methods. We conducted a systematic review of the English language literature and an international survey of spine surgeons to answer the following key questions in patients with radiographic evidence of cervical spinal cord compression, spinal canal narrowing, and/or OPLL but no symptoms of myelopathy: (1) What are the frequency and timing of symptom development? (2) What are the clinical, radiographic and electrophysiological predictors of symptom development? (3) What clinical and/or radiographic features influence treatment decisions based on an international survey of spine-care professionals?Results. The initial literature search yielded 388 citations. Applying the inclusion/exclusion criteria narrowed this to five articles. Two of these dealt with the same population. For patients with spinal cord compression secondary to spondylosis, one study reported the frequency of myelopathy development to be 22.6%. The presence of symptomatic radiculopathy, cervical cord hyperintensity on magnetic resonance imaging (MRI) and prolonged somatosensory- and motor-evoked potentials were reported in one study as significant independent predictors of myelopathy development. In contrast, the lack of MRI hyper-intensity was found to be a positive predictor of early myelopathy development (≤12 months follow-up). For OPLL subjects, frequency of myelopathy development was reported in three articles and ranged from 0.0 to 61.5% of subjects. One of these studies reported canal stenosis ≥ 60%, lateral deviated OPLL, and increased cervical ROM as significant predictors of myelopathy development. In a survey of 774 spine surgeons, the majority deemed the presence of clinically symptomatic radiculopathy to predict progression to myelopathy in non-myelopathic patients with cervical stenosis. Survey responses pertaining to three patient case vignettes are also presented and discussed in the context of the current literature.Conclusion. Based on these results we provide a series of evidence-based recommendations related to the frequency, timing and predictors of myelopathy development in asymptomatic patients with cervical stenosis secondary to spondylosis or OPLL. Future prospective studies are required to refine our understanding of this topic.Recommendation: Patients with cervical canal stenosis and cord compression secondary to spondylosis, without clinical evidence of myelopathy, and who present with clinical or electrophysiological evidence of cervical radicular dysfunction or central conduction deficits appear to be at higher risk for developing myelopathy and should be counseled to consider surgical treatmentOverall Strength of Evidence: ModerateStrength of Recommendation: StrongSummary StatementsStatement #1: Based on the current literature, for patients with cervical canal stenosis and cord compression secondary to spondylosis, without clinical evidence of myelopathy, approximately 8% at 1 year follow-up and 23% at a median of 44 months follow-up, develop clinical evidence of myelopathy.Statement #2: For patients with cervical canal stenosis and cord compression secondary to spondylosis, without clinical evidence of myelopathy, the absence of MRI intramedullary T2 hyperintensity has shown to predict early myelopathy development (<12 month follow-up) and the presence of such signal has shown to predict late myelopathy development (mean 44 months follow-up). In light of this discrepancy, no definite recommendation can made surrounding the utility of this finding in predicting myelopathy development.Statement #3: For patients with OPLL but without myelopathy no recommendation can be given regarding the incidence or predictors of progression to myelopathy. 23816308 Disinfection by-products and ecotoxicity of ballast water after oxidative treatment - Results and experiences from seven years of full-scale testing of ballast water management systems. Since 2005, five different ballast water management systems (BWMSs) based on chlorination treatment have been tested by Norwegian Institute for Water Research (NIVA) according to guidelines from the International Maritime Organization (IMO). 25% and >50% of all the tested discharge samples exhibited acute and chronic toxic effects on algae, respectively. In most cases this toxicity was plausibly caused by a high free residual oxidant (FRO) level (>0.08mgCl/l). Of the 22 disinfection by-products (DBPs) that were identified in treated water at discharge, four compounds were at times found at concentrations that may pose a risk to the local aquatic environment. However, there seemed to be no clear indication that the measured DBP concentrations contributed to the observed algal toxicity. The addition of methylcellulose instead of lignin in the test water to comply with IMO requirements seemed to limit the formation of DBP. 23924889 Strain Rate Dispersion Index Can Predict Changes in Left Ventricular Volume and Adverse Cardiac Events Following Cardiac Resynchronization Therapy. Background: We previously reported that the strain rate dispersion index (SRDI), an index of left ventricular (LV) contractility loss because of mechanical dyssynchrony, better predicted the acute response to cardiac resynchronization therapy (CRT) than time-delay indices. However, it remains unclear whether the SRDI can predict the chronic response. Additionally, the SRDI needs to be simplified for use in clinical practice. Methods and Results: Echocardiography was performed in 40 heart failure patients who underwent CRT. The SRDI, the average of segmental peak systolic strain rates minus global peak systolic strain rate, was calculated, together with strain-derived time-delay indices (St-SD) in the longitudinal, circumferential and radial directions using a speckle-tracking method. As simplified indices, the longitudinal parameters were calculated from the apical 4-chamber view in addition to 3 apical views. LV end-systolic volume (ESV) significantly decreased 6 months after CRT. Although circumferential St-SD and all SRDIs correlated with the changes in ESV (ΔESV), multivariate analysis revealed that the circumferential SRDI was the single independent determinant of ΔESV. During the 20±14 months after CRT, cardiac events occurred in 14 patients. Kaplan-Meier analyses revealed that all SRDIs were significant predictors of cardiac events whereas none of St-SDs was. Conclusions: The SRDI predicted the reduction in both LV volume and cardiac events after CRT better than time-delay indices. Additionally, a simplified SRDI could be as good a predictor of CRT response as the original. 23862680 Targeting RNA polymerase I transcription and the nucleolus for cancer therapy. The nucleoli are the site of the production of ribosomes, the protein synthetic apparatus of the cell. The presence of enlarged nucleoli, reflecting increased ribosomal gene transcription, has long been used by pathologists as an indicator of aggressive tumors. However, over the last 10 years a growing body of evidence has revealed that the nucleolus contains a dynamic cohort of over 4500 proteins, the majority of which have no function in ribosome production. The activity of some of these proteins is modulated by their regulated sequestration and release from the nucleolus. In particular, the nucleolus plays a central role in sensing cellular stress to modulate the abundance of the critical tumor suppressor protein p53. The finding that p53 activity is dysregulated in up to 50% of all human cancers highlights the importance of the nucleolar stress response in limiting malignant transformation. The development of drugs to selectively inhibit transcription of the ribosomal RNA genes in the nucleolus has paved the way for a new therapeutic approach to hijack nucleolar stress to selectively and non-genotoxically activate p53 in tumor cells. Here, we describe the potential application of this exciting new class of drugs for the treatment of human cancer. 23341088 Imaging of primary bone tumors: determination of tumor extent by non-contrast sequences. Magnetic resonance imaging (MRI) is the modality of choice for determining the extent of a primary bone tumor. This article will discuss the MRI techniques needed to accurately define the intramedullary extent of a bone sarcoma, emphasizing the need for non-contrast T1-weighted sequences and highlighting the role of chemical shift imaging. 23401350 Does C-reactive protein predict the long-term progression of interstitial lung disease and survival in patients with early systemic sclerosis? There are no identified clinical markers that reliably predict long-term progression of interstitial lung disease (ILD) in systemic sclerosis (SSc; scleroderma). Elevated C-reactive protein (CRP) levels have been reported in SSc patients. We examined the predictive significance of CRP level for long-term ILD progression in a large early SSc cohort. First, the CRP levels were compared between baseline samples of 266 SSc patients enrolled in the Genetics Versus Environment in Scleroderma Outcome Study cohort and 97 unaffected matched controls. Subsequently, the correlation between CRP levels and concomitantly obtained markers of disease severity was assessed. Serially obtained % predicted forced vital capacity (FVC) was used to examine the long-term ILD progression. The predictive significance of CRP level was investigated by a joint analysis of longitudinal measurements (serial FVCs up to 13 years) and survival data. This approach allowed inclusion of all 1,016 FVC measurements and accounted for survival dependency. We confirmed that baseline CRP levels were higher in SSc patients than controls. CRP levels were associated with absence of anticentromere antibodies and correlated with the concomitant severity of lung, skin, and joint involvement. More importantly, higher baseline CRP levels were associated with shorter survival (P < 0.001) and predicted the long-term decline in FVC independent of potential confounders (age at baseline, sex, ethnicity, disease type, current smoking, body mass index, topoisomerase status, and treatment with immunosuppressive agents) in the multivariable model (P = 0.006). Baseline CRP levels are predictive of long-term ILD progression. CRP level might aid clinicians in identifying patients that require more intensive monitoring and treatment. 23616381 Pharmacological approaches to the management of schizophrenia: 10 years on. To review the contemporary landscape regarding pharmacological treatments for schizophrenia. Selective literature review. Newer antipsychotic agents include aripiprazole, asenapine, paliperidone, sertindole and ziprasidone. Each has some particular benefits and some shortcomings. Overall treatment efficacy (for positive symptoms at least) has not advanced substantially but some newer agents might have a better profile than older typical agents for negative and cognitive symptoms. Metabolic side effects and hyperprolactinaemia remain a problem with some of the newer agents and appropriate monitoring is required. Whilst newer antipsychotics have been welcome additions to our pharmacological armamentarium, mostly in terms of tolerability, we have still not seen a 'quantum leap' agent brought to market. Mechanisms of action apart from post-synaptic dopamine blockade appear worthy of further investigation in this regard. 23154883 The nonfermentable dietary fiber hydroxypropyl methylcellulose modulates intestinal microbiota. Diet influences host metabolism and intestinal microbiota; however, detailed understanding of this tripartite interaction is limited. To determine whether the nonfermentable fiber hydroxypropyl methylcellulose (HPMC) could alter the intestinal microbiota and whether such changes correlated with metabolic improvements, C57B/L6 mice were normalized to a high-fat diet (HFD), then either maintained on HFD (control), or switched to HFD supplemented with 10% HPMC, or a low-fat diet (LFD). Compared to control treatment, both LFD and HPMC reduced weight gain (11.8 and 5.7 g, respectively), plasma cholesterol (23.1 and 19.6%), and liver triglycerides (73.1 and 44.6%), and, as revealed by 454-pyrosequencing of the microbial 16S rRNA gene, decreased microbial α-diversity and differentially altered intestinal microbiota. Both LFD and HPMC increased intestinal Erysipelotrichaceae (7.3- and 12.4-fold) and decreased Lachnospiraceae (2.0- and 2.7-fold), while only HPMC increased Peptostreptococcaceae (3.4-fold) and decreased Ruminococcaceae (2.7-fold). Specific microorganisms were directly linked with weight change and metabolic parameters in HPMC and HFD mice, but not in LFD mice, indicating that the intestinal microbiota may play differing roles during the two dietary modulations. This work indicates that HPMC is a potential prebiotic fiber that influences intestinal microbiota and improves host metabolism. 23743067 Characterization of the ovarian cycle in the two-toed sloths (Choloepus didactylus): An innovative, reliable, and noninvasive method using fecal hormone analyses. Little is known about reproductive physiology in the two-toed sloth (Choloepus didactylus). Therefore, the aim of this study was to obtain detailed information about the ovarian cycle. Measurements of reliable gonadal steroids in the feces of this species were undertaken. For this purpose, fecal samples were collected one to three times per week from nonpregnant captive females (n = 2) over a 16-month period. Before assay analysis, the fecal samples were extracted with methanol. Radioimmunoassays and enzyme immunoassays for fecal progesterone, estradiol-17β, pregnanediol-glucuronide (PdG), and estrone sulfate were tested for their ability to detect the ovarian activity. Using the lowest and highest progesterone values, the ovarian cycle length was comparatively analyzed. The ovarian cycle (n = 26) averaged between 31.4 ± 9.1 days (lowest progesterone) and 32.5 ± 7.5 days (highest progesterone) throughout the whole year. The length of the follicular phase, as indicated by low progesterone levels, was 18.1 ± 4.4 days (range 12-25 days), and the length of the luteal phase, as characterized by elevated progesterone levels, was 13.2 ± 1.8 days (range 11-16 days). In contrast, estradiol-17β and estrone sulfate were not suitable to detect the cycle due to irregular collection intervals. Fecal progesterone and PdG, as well as estradiol-17β and estrone sulfate, significantly correlated (r = 0.621, P < 0.01 and r = 0.606, P < 0.01). PdG concentrations (dilution factor (DF) 1:40) were considerably higher than progesterone concentrations (DF 1:10), PdG amounted in the range of 1326.7 ± 320.2 ng/g wet feces (animal S1) and 1373.8 ± 468.3 ng/g wet feces (animal S2) compared with progesterone concentrations in the range of 98.0 ± 17.0 ng/g (S1) and 105.9 ± 30.0 ng/g (S2). The estrone sulfate levels (DF 1:2) were similar to estradiol-17β (DF 1:22). The mean fecal estradiol-17β concentrations were 6.7 ± 0.9 ng/g for animal S1 and 7.5 ± 1.6 ng/g for animal S2. In conclusion, the ovarian activity of the two-toed sloth was studied using the noninvasive method by means of the fecal steroid monitoring. Progesterone was the most reliable fecal steroid hormone to determine the duration of the ovarian cycle independent of the weekly defecation rate. The course of progesterone concentrations resulted in a cycle length of 4-5 weeks length in the two-toed sloth. Thus, the reproductive activity of the two-toed sloth does not show any seasonality like the three-toed sloth. 23228695 Identification and characterization of MIP-1α/CCL3 isoform 2 from bovine serum as a potent monocyte/dendritic cell chemoattractant. Bovine serum is a rich source of cytokines and growth factors supporting in vitro cell culture. Here, a novel bovine monocyte chemotactic factor (boMCF-1) was isolated from commercial bovine serum by a four step purification procedure including adsorption to silicic acid, heparin affinity and cation-exchange chromatography and reversed phase HPLC. Homogeneous boMCF-1 was characterized as a 7717Da protein by mass spectrometry and identified by Edman degradation as the predicted product of bovine macrophage inflammatory protein-1α gene (boMIP-1α/CCL3) isoform 2 (lacking three NH₂-terminal amino acids), belonging to the MIP subfamily of CC chemokines. Monocyte chemotactic activity of boCCL3 isoform 2 was completely desensitized by human CCL3 and CCL5, partially by CCL7 and not by CCL2. Its activity was better inhibited by CCR1 than by CCR5 blockade. BoCCL3 isoform 2, present in bovine serum at about 10 ng/ml, functioned as a most potent chemoattractant for immature (but not mature) dendritic cells with a minimal effective concentration of 0.03 ng/ml and a maximal chemotactic index of 30 at 0.3 ng/ml. Its chemotactic activity on immature dendritic cells was significantly desensitized by human CCL3, CCL5 and CCL7. Blockade of CCR5 rather than CCR1 partially prevented chemotactic activity, whereas blockade of both further enhanced this inhibition. BoCCL3 isoform 2 was not chemokinetic but, like human CCL3, synergized with CXCL12 in monocytic cell chemotaxis. Since it cannot be deduced which is the exact human homolog of boCCL3 isoform 2, further research is required to study the biology of other boCCL3 family members. 23902746 First description of seasonality of birth and diagnosis amongst teenagers and young adults with cancer aged 15-24 years in England, 1996-2005. We aimed to examine evidence for an infectious aetiology among teenagers and young adults (TYA) by analysing monthly seasonality of diagnosis and birth amongst 15-24 year olds diagnosed with cancer in England. Cases of leukaemia, lymphoma and central nervous system (CNS) tumours were derived from the national TYA cancer register (1996-2005). Incidence rates (IR) and trends were assessed using Poisson regression. Seasonality of diagnosis and birth was assessed using Poisson and logistic regression respectively with cosine functions of varying periods. There were 6251 cases diagnosed with leukaemia (n = 1299), lymphoma (n = 3070) and CNS tumours (n = 1882), the overall IR was 92 (95% CI 89-96) per 1,000,000 15-24 year olds per year.There was significant evidence of seasonality around the time of diagnosis for Hodgkin's lymphoma (P < 0.001) with a peak in February, and for 'other CNS tumours' (P = 0.010) with peaks in December and June. Birth peaks for those with 'other Gliomas' (Gliomas other than Astrocytoma and Ependymoma) were observed in May and November (P = 0.015). Our novel findings support an infectious aetiological hypothesis for certain subgroups of TYA cancer in England. Further work will examine correlation with specific infections occurring around the time of birth and diagnosis within certain diagnostic groups. 23455658 A treatment-oriented typology of self-identified hypersexuality referrals. Men and women have been seeking professional assistance to help control hypersexual urges and behaviors since the nineteenth century. Despite that the literature emphasizes that cases of hypersexuality are highly diverse with regard to clinical presentation and comorbid features, the major models for understanding and treating hypersexuality employ a "one size fits all" approach. That is, rather than identify which problematic behaviors might respond best to which interventions, existing approaches presume or assert without evidence that all cases of hypersexuality (however termed or defined) represent the same underlying problem and merit the same approach to intervention. The present article instead provides a typology of hypersexuality referrals that links individual clinical profiles or symptom clusters to individual treatment suggestions. Case vignettes are provided to illustrate the most common profiles of hypersexuality referral that presented to a large, hospital-based sexual behaviors clinic, including: (1) Paraphilic Hypersexuality, (2) Avoidant Masturbation, (3) Chronic Adultery, (4) Sexual Guilt, (5) the Designated Patient, and (6) better accounted for as a symptom of another condition. 23796654 Propidium monoazide combined with real-time quantitative PCR to quantify viable Alternaria spp. contamination in tomato products. Alternaria is a common contaminating genus of fungi in fruits, grains, and vegetables that causes severe economic losses to farmers and the food industry. Furthermore, it is claimed that Alternaria spp. are able to produce phytotoxic metabolites, and mycotoxins that are unsafe for human and animal health. DNA amplification techniques are being increasingly applied to detect, identify, and quantify mycotoxigenic fungi in foodstuffs, but the inability of these methods to distinguish between viable and nonviable cells might lead to an overestimation of mycotoxin-producing living cells. A promising technique to overcome this problem is the pre-treatment of samples with nucleic acid intercalating dyes, such as propidium monoazide (PMA), prior to quantitative PCR (qPCR). PMA selectively penetrates cells with a damaged membrane inhibiting DNA amplification during qPCRs. In our study, a primer pair (Alt4-Alt5) to specifically amplify and quantify Alternaria spp. by qPCR was designed. Quantification data of qPCR achieved a detection limit of 10(2)conidia/g of tomato. Here, we have optimized for the first time a DNA amplification-based PMA sample pre-treatment protocol for detecting viable Alternaria spp. cells. Artificially inoculated tomato samples treated with 65μM of PMA, showed a reduction in the signal by almost 7cycles in qPCR between live and heat-killed Alternaria spp. conidia. The tomato matrix had a protective effect on the cells against PMA toxicity, reducing the efficiency to distinguish between viable and nonviable cells. The results reported here indicate that the PMA-qPCR method is a suitable tool for quantifying viable Alternaria cells, which could be useful for estimating potential risks of mycotoxin contamination. 23485017 Computational study of the coordination of methane to first row transition metal dication complexes. The coordination of methane, the first step in methane activation, to coordinately unsaturated first row transition metal dication complexes has been studied computationally to determine the most stable metal-methane interaction. The geometries and the vibrational frequencies of the encounter complexes [M(pyridine)2(CH4)](2+) have been determined using density functional theory with the ωB97XD hybrid functional and triple-ζ basis sets. The structure is dependent on the metal center; for the early transition metals η(3) coordination is favored, whereas η(2) is more favorable for the later transition metals. The periodic trend in methane binding energies in the [M(pyridine)2(CH4)](2+) complexes follows the trend in electron affinity until the Mn complex but then exhibits decreasing energies from Fe to Zn. This is attributed to increasing Pauli repulsion and ligand-ligand repulsion. For the most stable complex, [Cr(pyridine)2(CH4)](2+), the structures, energies, and spin states of the key intermediates and products in the oxidative addition/reductive elimination pathway have been investigated. It is found that the reaction is thermodynamically favorable and indicates that two-state reactivity may play an important role in lowering the energy of the hydridomethyl intermediate. 23302587 Syntheses of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid analogues modified by α-acylaminoamido groups at the C-4 position using isocyanide-based four-component coupling and biological evaluation as inhibitors of human parainfluenza virus type 1. Novel sialidase inhibitors 11 having an α-acylaminoamido group at the C-4 position of Neu5Ac2en 1 against human parainfluenza virus type 1 (hPIV-1) were synthesized using one-pot isocyanide-based four-component condensation, and their inhibitory activities against hPIV-1 sialidase were studied. Compound 11b showed inhibitory activity (IC(50)=5.1 mM) against hPIV-1 sialidase. The degree of inhibition of 11b was much weaker than that of 1 (IC(50)=0.3 mM). 23402857 Monitoring of arsenic levels in some ready-to-use anti-malaria herbal products from drug sales outlets in the Madina area of Accra, Ghana. In Ghana anti-malaria herbal medicines or products are used to compliment commercial drugs in treatment and prevention of Plasmodium falciparum infections. In this study, four common aqueous based anti-malaria herbal products (coded HEB, KFE, MDM and NIB) which are used by Ghanaian population from pharmacy/herbal stores in the Madina area, Accra were blindly and randomly sampled for cadmium (Cd), arsenic (As) and Lead (Pb) analysis using Atomic Absorption Spectrophotometry technique. Arsenic concentrations were 1.087μg/mL (108.7%), 1.027μg/mL (102.7%), 0.330μg/mL (33.0%) and 0.274μg/mL (27.4%) in MDM, KFE, NIB and HEB respectively. Arsenic concentration determined in MDM and KFE were above the maximum permissible limit of 1.0ppm determined by WHO/FAO. Cadmium concentration in each of the four products as well as lead concentration in KFE, NIB and HEB were below the detection limit of <0.002mg/mL (Cd) and <0.005mg/mL (Pb) respectively. The maximum permissible limits for Pb and Cd determined by WHO/FAO are 10.0ppm and 0.3ppm respectively. Thus, random assessment on the safety of some ready-to-use aqueous based anti-malaria herbal products on the market is necessary to prevent public health hazards associated with consuming these plant extracts. Although lead and cadmium concentration in the anti-malaria herbal products were below the maximum permissible limits, their cumulative effect on the health of an individual which consume recommended volume of not less than 1000 mL for effective malaria parasite clearance cannot be ignored. 23720443 ATP-Binding Cassette B10 Regulates Early Steps of Heme Synthesis. Rationale: Heme plays a critical role in gas exchange, mitochondrial energy production, and antioxidant defense in cardiovascular system. The mitochondrial transporter ATP-binding cassette (ABC) B10 has been suggested to export heme out of the mitochondria and is required for normal hemoglobinization of erythropoietic cells and protection against ischemia-reperfusion injury in the heart; however, its primary function has not been established. Objective: The aim of this study was to identify the function of ABCB10 in heme synthesis in cardiac cells. Methods and Results: Knockdown of ABCB10 in cardiac myoblasts significantly reduced heme levels and the activities of heme-containing proteins, whereas supplementation with δ-aminolevulinic acid reversed these defects. Overexpression of mitochondrial δ-aminolevulinic acid synthase 2, the rate-limiting enzyme upstream of δ-aminolevulinic acid export, failed to restore heme levels in cells with ABCB10 downregulation. ABCB10 and heme levels were increased by hypoxia, and reversal of ABCB10 upregulation caused oxidative stress and cell death. Furthermore, ABCB10 knockdown in neonatal rat cardiomyocytes resulted in a significant delay of calcium removal from the cytoplasm, suggesting a relaxation defect. Finally, ABCB10 expression and heme levels were altered in failing human hearts and mice with ischemic cardiomyopathy. Conclusions: ABCB10 plays a critical role in heme synthesis pathway by facilitating δ-aminolevulinic acid production or export from the mitochondria. In contrast to previous reports, we show that ABCB10 is not a heme exporter and instead is required for the early mitochondrial steps of heme biosynthesis. 23856595 Zoonotic potential of Giardia. Giardia duodenalis (syn. Giardia lamblia and Giardia intestinalis) is a common intestinal parasite of humans and mammals worldwide. Assessing the zoonotic transmission of the infection requires molecular characterization as there is considerable genetic variation within G. duodenalis. To date eight major genetic groups (assemblages) have been identified, two of which (A and B) are found in both humans and animals, whereas the remaining six (C to H) are host-specific and do not infect humans. Sequence-based surveys of single loci have identified a number of genetic variants (genotypes) within assemblages A and B in animal species, some of which may have zoonotic potential. Multi-locus typing data, however, has shown that in most cases, animals do not share identical multi-locus types with humans. Furthermore, interpretation of genotyping data is complicated by the presence of multiple alleles that generate "double peaks" in sequencing files from PCR products, and by the potential exchange of genetic material among isolates, which may account for the non-concordance in the assignment of isolates to specific assemblages. Therefore, a better understanding of the genetics of this parasite is required to allow the design of more sensitive and variable subtyping tools, that in turn may help unravel the complex epidemiology of this infection. 23663038 Hippocampal hyperexcitability and specific epileptiform activity in a mouse model of Dravet syndrome. Dravet syndrome (DS) is caused by dominant mutations of the SCN1A gene, encoding the NaV 1.1 sodium channel α subunit. Gene targeted mouse models of DS mutations replicate patients' phenotype and show reduced γ-aminobutyric acid (GABA)ergic inhibition. However, little is known on the properties of network hyperexcitability and on properties of seizure generation in these models. In fact, seizures have been studied thus far with surface electroencephalography (EEG), which did not show if specific brain regions are particularly involved. We have investigated hyperexcitability and epileptiform activities generated in neuronal networks of a mouse model of DS. We have studied heterozygous NaV 1.1 knock-out mice performing field potential recordings in combined hippocampal/cortical slices in vitro and video/depth electrode intracerebral recordings in vivo during hyperthermia-induced seizures. In slices, we have disclosed specific signs of hyperexcitability of hippocampal circuits in both the pre-epileptic and epileptic periods, and a specific epileptiform activity was generated in the hippocampus upon application of the convulsant 4-aminopyridine in the epileptic period. During in vivo hyperthermia-induced seizures, we have observed selective hippocampal activity in early preictal phases and pronounced hippocampal activity in the ictal phase. We have identified specific epileptiform activities and signs of network hyperexcitability, and disclosed the important role of the hippocampus in seizure generation in this model. These activities may be potentially used as targets for screenings of antiepileptic approaches. 23030658 Peptidomimetics as potent and selective PTP1B inhibitors. A series of peptidomimetic containing bidentate pTyr mimetics (9a-w) are reported as potent and selective PTP1B inhibitors. Compounds (9p and 9q) showed excellent selectivity towards PTP1B over various PTPs, including TCPTP (in vitro), which confirms discovery of highly potent and selective PTP1B inhibitors. 23020803 Effects of vitamin D on antigen-specific and non-antigen-specific immune modulation: relevance for type 1 diabetes. Vitamin D is a fat-soluble precursor of the circulating 25-hydroxyvitamin D₃ (25(OH)D₃)which can be converted by the 1α-hydroxylase (1α(OH)ase) enzyme into the bioactive hormonal metabolite 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), generally known to promote bone mineralization through its ability to enhance calcium absorption from the gut. Importantly, in humans, vitamin D is mainly derived from endogenous production of vitamin D₃ from ultraviolet (UV) radiation exposure to the skin while a small part (<10%) is obtained via dietary intake of dairy products and fatty fish (1). Taking these factors into account, geographic distribution and seasonality, skin pigmentation, age, and lifestyle may predispose certain populations to be at a higher risk of developing vitamin D insufficiency or deficiency (2). The first valid reports correlating the importance of an adequate vitamin D status to optimal human health originate from the early part of the 20th century, when vitamin D was described to prevent and treat the bone disease rickets. Since then, the findings that vitamin D receptors (VDR) are present in many body tissues and that vitamin D metabolizing enzymes can be found in various cells outside the kidney, including the intestine, prostate, immune cells, and within the skin itself (reviewed in reference 3), have revolutionized the vitamin D business. In this review, we will mainly focus on vitamin D as a component of immune regulation and on the role of vitamin D in antigen-specific and non-specific therapies with potential relevance for type 1 diabetes (T1D). 23889546 MHC-disassortative mate choice and inbreeding avoidance in a solitary primate. Sexual selection theory suggests that choice for partners carrying dissimilar genes at the major histocompatibility complex (MHC) may play a role in maintaining genetic variation in animal populations by limiting inbreeding or improving the immunity of future offspring. However, it is often difficult to establish whether the observed MHC dissimilarity among mates drives mate choice or represents a by-product of inbreeding avoidance based on MHC-independent cues. Here, we used 454-sequencing and a 10-year study of wild grey mouse lemurs (Microcebus murinus), small, solitary primates from western Madagascar, to compare the relative importance on the mate choice of two MHC class II genes, DRB and DQB, that are equally variable but display contrasting patterns of selection at the molecular level, with DRB under stronger diversifying selection. We further assessed the effect of the genetic relatedness and of the spatial distance among candidate mates on the detection of MHC-dependent mate choice. Our results reveal inbreeding avoidance, along with disassortative mate choice at DRB, but not at DQB. DRB-disassortative mate choice remains detectable after excluding all related dyads (characterized by a relatedness coefficient r > 0), but varies slightly with the spatial distance among candidate mates. These findings suggest that the observed deviations from random mate choice at MHC are driven by functionally important MHC genes (like DRB) rather than passively resulting from inbreeding avoidance and further emphasize the need for taking into account the spatial and genetic structure of the population in correlative tests of MHC-dependent mate choice. 23883069 Antithyroid medications and psychosis. Introduction: Antithyroid drugs (ATDs) are used in the treatment of hyperthyroidism. Very rarely ATDs were reported to trigger acute psychosis in patients with no history of psychiatric disturbances. Our aim is to review the literature on psychosis as a side effect of ATD and to give a personal opinion on this issue. Areas covered: The cases of acute psychosis elicited by ATD are few and most were reported many years ago, before radioimmunoassay for thyroid-stimulating hormone (TSH) and thyroid hormones was introduced. Most of those cases lack a description of serum thyroid hormone profile before, during and after the appearance of the psychiatric disorder; hence, an abrupt shift from hyperthyroidism to euthyroidism or hypothyroidism cannot be excluded. In addition, patients underwent specific psychiatric therapy, so that it is difficult to attribute the disappearance of the mental disorders to the withdrawal of ATD per se. Expert opinion: Patients who develop mental disorders while under ATD should be followed by an accurate evaluation of TSH, free triiodothyronine (FT3), and free thyroxine (FT4) levels throughout the course of the psychiatric disease. The use of new imaging techniques could be helpful in ruling out the encephalopathy associated with autoimmune thyroid diseases and other cerebral pathologies that might be possible causes of these mental disorders. 23905899 Stability of miRNA in human urine supports its biomarker potential. Aim: miRNAs are showing utility as biomarkers in urologic disease, however, a rigorous evaluation of their stability in urine is lacking. Here, we evaluate the stability of miRNAs in urine under clinically relevant storage procedures. Materials & methods: Eight healthy individuals provided clean catch urine samples that were stored at room temperature or at 4°C for 5 days, or subjected to ten freeze-thaw cycles at -80°C. For each condition, two miRNAs, miR-16 and miR-21, were quantitated by quantitative real-time PCR. Results: All conditions demonstrated a surprising degree of stability of miRNAs in the urine: by the end of ten freeze-thaw cycles, 23-37% of the initial amount remained; over the 5-day period of storage at room temperature, 35% of the initial amount remained; and at 4°C, 42-56% of the initial amount remained. Both miRNAs also showed degradation at approximately the same rate. Conclusion: miRNAs are relatively stable in urine under a variety of storage conditions, which supports their utility as urinary biomarkers. 23810386 Update on the diagnosis, pathogenesis, and treatment strategies for central neurocytoma. Central neurocytomas are rare benign tumors of the central nervous system that are typically located in the lateral ventricles. Since they were first reported in the early 1980s, many advancements have been made in terms of their diagnosis and treatment. Despite the progress made, the origin of these rare tumors and effective newer treatment strategies remain elusive. Central neurocytomas represent 0.1-0.5% of all primary brain tumors. Since they are typically intraventricular, these tumors tend to present clinically with hydrocephalus. CT scanning and MRI are useful in localizing these tumors; however, due to their numerous ambiguous features, the ultimate diagnosis relies on immunohistochemistry and electron microscopy studies of sampled tissue. Currently, surgical removal with a gross-total resection of these tumors is the treatment of choice. Various radiotherapy techniques, including both conventional radiotherapy and stereotactic radiosurgery, have been shown to be useful in cases of residual tumor after sub-total resection and tumor recurrence. The benign nature of these tumors tends to offer a favorable outcome for most patients; however, recurrence rates are relatively high and tumors with high-grade features or extraventricular location tend to have a less favorable prognosis. We present a comprehensive review of these rare tumors, including their epidemiology, clinical presentation, radiological presentation, histopathological findings, and options for intervention including surgery, radiation therapy, stereotactic radiosurgery, and chemotherapy. 23101733 Negotiating old and new ways: contextualizing adapted health care-seeking behaviors of Korean immigrants in Hawaii. Objective. Korean immigrants have been identified as one of the most disadvantaged ethnic groups in terms of health insurance coverage and health care access in the USA. Korean immigrants enjoyed access to primary and preventive care services in their home country. This study explores how Korean immigrants' health-seeking behaviors are reconstructed by contextualizing their health care experience and adaptation process in Hawaii. Design. Face-to-face individual in-depth interviews were conducted with 20 recently arrived Korean immigrant adults in Hawaii, who were selected by a purposive sampling method. Results. A diminution of seeking professional health care services after immigration was the prominent change in their health care behaviors. They delayed seeking primary care, underused preventive care, extended self-diagnosis and self-treatment, and practiced more treatment- and emergency-oriented care. New immigrants also adopted ethnic enclave health care and transnational health care as alternative strategies to meet their health care needs given the structural and cultural constraints. Sociocultural contexts of both home and host countries shaped the behavioral changes and adoption of alternative health care strategies, interplaying with an individual's characteristics. Lack of health insurance and unfamiliarity with the health care system were the most important factors in the decision whether to and when to seek professional health care, while the lack of English proficiency and cultural concerns were the major determinants of where to get health care. Conclusions. The study suggested that efforts should be concentrated to minimize structural barriers to health insurance and to improve health care access through policy interventions. Ethnic networks and ethnic media could be used as an effective informational reservoir for introducing various health care resources, disseminating information, and navigating new immigrants to the health system and services. Utilizing ethnic health care facilities and professionals would foster the promotion of immigrant health care without language and cultural challenges. 23620488 The gravitational distribution of ventilation-perfusion ratio is more uniform in prone than supine posture in the normal human lung. The gravitational gradient of intrapleural pressure is suggested to be less in prone posture than supine. Thus the gravitational distribution of ventilation is expected to be more uniform prone, potentially affecting regional ventilation-perfusion (Va/Q) ratio. Using a novel functional lung magnetic resonance imaging technique to measure regional Va/Q ratio, the gravitational gradients in proton density, ventilation, perfusion, and Va/Q ratio were measured in prone and supine posture. Data were acquired in seven healthy subjects in a single sagittal slice of the right lung at functional residual capacity. Regional specific ventilation images quantified using specific ventilation imaging and proton density images obtained using a fast gradient-echo sequence were registered and smoothed to calculate regional alveolar ventilation. Perfusion was measured using arterial spin labeling. Ventilation (ml·min(-1)·ml(-1)) images were combined on a voxel-by-voxel basis with smoothed perfusion (ml·min(-1)·ml(-1)) images to obtain regional Va/Q ratio. Data were averaged for voxels within 1-cm gravitational planes, starting from the most gravitationally dependent lung. The slope of the relationship between alveolar ventilation and vertical height was less prone than supine (-0.17 ± 0.10 ml·min(-1)·ml(-1)·cm(-1) supine, -0.040 ± 0.03 prone ml·min(-1)·ml(-1)·cm(-1), P = 0.02) as was the slope of the perfusion-height relationship (-0.14 ± 0.05 ml·min(-1)·ml(-1)·cm(-1) supine, -0.08 ± 0.09 prone ml·min(-1)·ml(-1)·cm(-1), P = 0.02). There was a significant gravitational gradient in Va/Q ratio in both postures (P < 0.05) that was less in prone (0.09 ± 0.08 cm(-1) supine, 0.04 ± 0.03 cm(-1) prone, P = 0.04). The gravitational gradients in ventilation, perfusion, and regional Va/Q ratio were greater supine than prone, suggesting an interplay between thoracic cavity configuration, airway and vascular tree anatomy, and the effects of gravity on Va/Q matching. 23950932 EMT-Induced Stemness and Tumorigenicity Are Fueled by the EGFR/Ras Pathway. Recent studies have revealed that differentiated epithelial cells would acquire stem cell-like and tumorigenic properties following an Epithelial-Mesenchymal Transition (EMT). However, the signaling pathways that participate in this novel mechanism of tumorigenesis have not been fully characterized. In Runx3 (-/-) p53 (-/-) murine gastric epithelial (GIF-14) cells, EMT-induced plasticity is reflected in the expression of the embryonal proto-oncogene Hmga2 and Lgr5, an exclusive gastrointestinal stem cell marker. Here, we report the concurrent activation of an EGFR/Ras gene expression signature during TGF-β1-induced EMT in GIF-14 cells. Amongst the altered genes was the induction of Egfr, which corresponded with a delayed sensitization to EGF treatment in GIF-14. Co-treatment with TGF-β1 and EGF or the expression of exogenous KRas led to increased Hmga2 or Lgr5 expression, sphere initiation and colony formation in soft agar assay. Interestingly, the gain in cellular plasticity/tumorigenicity was not accompanied by increased EMT. This uncoupling of EMT and the induction of plasticity reveals an involvement of distinct signaling cues, whereby the EGFR/Ras pathway specifically promotes stemness and tumorigenicity in EMT-altered GIF-14 cells. These data show that the EGFR/Ras pathway requisite for the sustenance of gastric stem cells in vivo and in vitro is involved in the genesis and promotion of EMT-induced tumor-initiating cells. 23665136 Penicillin-induced epileptiform activity elevates focal brain temperature in anesthetized rats. To elucidate a relationship between changes in focal brain temperature and severity of abnormal brain activity, epileptiform discharges and behavioral seizures were induced by Penicillin G in anesthetized rats, and focal brain-temperature was measured. Penicillin G was injected into the right primary sensorimotor cortex (400IU/μl). After the injection, epileptiform discharges induced a temperature increase gradually by 0.65±0.24°C. Moreover, when behavioral seizures were induced by reducing the anesthesia level, the temperature was raised by 0.26±0.22°C. These results suggest that elevation of the focal brain temperature is associated with the severity of epileptic activity. 23851614 Melanoma's connections to the tumour microenvironment. Melanoma cells interact with and depend on seemingly normal cells in their tumour microenvironment to allow the acquisition of the hallmarks of solid cancer. In general, there are three types of interaction of melanoma cells with their microenvironment. First, there is bilateral communication between melanoma cells and the stroma, which includes fibroblasts, endothelial cells, immune cells, soluble molecules, and the extracellular matrix. Second, while under normal conditions keratinocytes control localisation and proliferative behaviour of melanocytes in the epidermis, once this balance is disturbed and a melanoma has developed, melanoma cells may take over the control of their epidermal tumour microenvironment. Finally, there are subcompartments within tumours with different microenvironmental milieu defined by their access to oxygen and nutrients. Therefore, different melanoma cells within a tumour face different microenvironments. Interactions between melanoma cells among each other and with the cell types in their microenvironment happen through endocrine and paracrine communication and/or through direct contact via cell-cell and cell-matrix adhesion, and gap junctional intercellular communication (GJIC). Connexins have been identified as key molecules for direct cell-cell communication and are also thought to be important for the release of signalling molecules from cells to the microenvironment. In this review we provide an update of the alterations in cell-cell communication in melanoma and the tumour microenvironment associated with melanoma development and progression. 23924265 The relationship between atherogenic index of plasma and epicardial adipose tissue in hemodialysis and peritoneal dialysis patients. Abstract Introduction: Epicardial adipose tissue (EAT) is the true visceral fat depot of the heart. The relationship between coronary artery disease and EAT was shown in end-stage renal disease (ESRD) patients. One of the established risk factor in this population is dyslipidemia. We aimed to determine the relationship between atherogenic index of plasma (AIP) and EAT in ESRD patients. Methods: This was a cross-sectional study involving 76 ESRD patients receiving PD or HD for ≥6 months and 42 healthy subjects. EAT was measured by using an electrocardiogram-gated 64-multidetector computed tomography (MDCT). Atherogenic index of plasma was calculated as the logarithmically transformed ratio of the serum trigliseride to HDL-cholesterol. Results: The etiology of ESRD patients was diabetic nephropathy (n = 16), chronic glomerulonephritis (n = 10), hypertensive nephropathy (n = 23), polycystic kidney disease (n = 7), nephrolithiasis (n = 5) and unknown (n = 15). There were no differences with respect to the following variables between ESRD patients and healthy subjects: age; sex; BMI; predialysis levels of DBP; serum levels of albumin, HDL-cholesterol and hemoglobin. However, ESRD patients had higher serum levels of trigliseride, hs-CRP and AIP when compared to healthy subjects. There was a statistically significant relationship between EAT, BMI and AIP in ESRD patients (r = 0.42, p < 0.001 and r = 0.25, p = 0.028, respectively). The stepwise linear regression analysis revealed that age, as well as BMI were independent predictors of EAT. Conclusion: We found a relationship between EAT as defined by MDCT and AIP in ESRD patients. Further clinical and experimental studies are needed. 23824809 Endogenous Gammaretrovirus Acquisition in Mus musculus Subspecies Carrying Functional Variants of the XPR1 Virus Receptor. The xenotropic and polytropic mouse leukemia viruses (X-MLVs and P-MLVs, respectively) have different host ranges but use the same functionally polymorphic receptor, XPR1, for entry. Endogenous retroviruses (ERVs) of these 2 gammaretrovirus subtypes are largely segregated in different house mouse subspecies, but both MLV types are found in the classical strains of laboratory mice, which are genetic mosaics of 3 wild mouse subspecies. To describe the subspecies origins of laboratory mouse XP-MLV ERVs and their coevolutionary trajectory with their XPR1 receptor, we screened the house mouse subspecies for known and novel Xpr1 variants and for the individual full-length XP-MLV ERVs found in the sequenced C57BL mouse genome. The 12 X-MLV ERVs predate the origins of laboratory mice; they were all traced to Japanese wild mice and are embedded in the 5% of the laboratory mouse genome derived from the Asian Mus musculus musculus and, in one case, in the <1% derived from M. m. castaneus. While all 31 P-MLV ERVs map to the 95% of the laboratory mouse genome derived from P-MLV-infected M. m. domesticus, no C57BL P-MLV ERVs were found in wild M. m. domesticus. All M. m. domesticus mice carry the fully permissive XPR1 receptor allele, but all of the various restrictive XPR1 receptors, including the X-MLV-restricting laboratory mouse Xpr1(n) and a novel M. m. castaneus allele, originated in X-MLV-infected Asian mice. Thus, P-MLV ERVs show more insertional polymorphism than X-MLVs, and these differences in ERV acquisition and fixation are linked to subspecies-specific and functionally distinct XPR1 receptor variants. 23773393 Stage III melanoma in the axilla: patterns of regional recurrence after surgery with and without adjuvant radiation therapy. To describe the anatomic distribution of regionally recurrent disease in patients with stage III melanoma in the axilla after curative-intent surgery with and without adjuvant radiation therapy. A single-institution, retrospective analysis of a prospective database of 277 patients undergoing curative-intent treatment for stage III melanoma in the axilla between 1992 and 2012 was completed. For patients who received radiation therapy and those who did not, patterns of regional recurrence were analyzed, and univariate analyses were performed to assess for potential factors associated with location of recurrence. There were 121 patients who received adjuvant radiation therapy because their clinicopathologic features conferred a greater risk of regional recurrence. There were 156 patients who received no radiation therapy. The overall axillary control rate was 87%. There were 37 patients with regional recurrence; 17 patients had received adjuvant radiation therapy (14%), and 20 patients (13%) had not. The likelihood of in-field nodal recurrence was significantly less in the adjuvant radiation therapy group (P=.01) and significantly greater in sites adjacent to the axilla (P=.02). Patients with high-risk clinicopathologic features who did not receive adjuvant radiation therapy also tended to experience in-field failure rather than adjacent-field failure. Patients who received adjuvant radiation therapy were more likely to experience recurrence in the adjacent-field regions rather than in the in-field regions. This may not simply reflect higher-risk pathology. Using this data, it may be possible to improve outcomes by reducing the number of adjacent-field recurrences after adjuvant radiation therapy. 23893939 Improved brain delivery of vincristine using dextran sulfate complex solid lipid nanoparticles: Optimization and in vivo evaluation. Vincristine (VC) sulfate, a freely water-soluble cytotoxic agent was incorporated into cetyl palmitate solid lipid nanoparticles (SLNs) with the aid of dextran sodium sulfate (DS), a poly anion, using a microemulsion method. The manufacturing process was optimized using response surface methodology (Box-Behnken design). SLNs were characterized for size, zeta potential, morphology, crystallinity, and release behavior. The drug encapsulation efficiency reached up to 93% and release study revealed sustained drug release. SLN formulation showed comparable cytotoxic effect in comparison to VC sulfate solution against the MDA-MB-231 cells. The in vivo studies following injection to rat revealed higher plasma and tissue concentrations and longer drug mean residence times compared to VC solution. Using cumarin-6 as a model drug, it was shown that drug delivery to the brain was enhanced close to five times using SLNs prepared in this study compared to free cumarin-6. It can be concluded that complexes of cetyl palmitate SLNs with DS could produce high VC-loaded SLNs suitable for delivery of anticancer drugs to brain tumors. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013. 23866792 Transplantation of human fetal-derived neural stem cells improves cognitive function following cranial irradiation. Treatment of CNS malignancies typically involves radiotherapy to forestall tumor growth and recurrence following surgical resection. Despite the many benefits of cranial radiotherapy, survivors often suffer from a wide range of debilitating and progressive cognitive deficits. Thus, while patients afflicted with primary and secondary malignancies of the CNS now experience longer local regional control and progression free survival, there remains no clinical recourse for the unintended neurocognitive sequelae associated with their cancer treatments. Multiple mechanisms contribute to disrupted cognition following irradiation, including the depletion of radiosensitive populations of stem and progenitor cells in the hippocampus. We have explored the potential of using intrahippocampal transplantation of human stem cells to ameliorate radiation-induced cognitive dysfunction. Past studies demonstrated the capability of cranially transplanted human embryonic (hESCs) and neural (hNSCs) stem cells to functionally restore cognition in rats 1 and 4-months post-head-only irradiation. The present study employed an FDA-approved fetal-derived human neural stem cell line capable of large scale-up under good manufacturing practice (GMP). Animals receiving cranial transplantation of these cells 1-month following irradiation showed improved hippocampal spatial memory and contextual fear conditioning performance compared to irradiated, sham surgery controls. Significant newly born (doublecortin positive) neurons and a smaller fraction of glial subtypes were observed within and nearby the transplantation core. Engrafted cells migrated and differentiated into neuronal and glial subtypes throughout the CA1 and CA3 subfields of the host hippocampus. These studies expand our prior findings to demonstrate that transplantation of fetal-derived human neural stem cells improves cognitive deficits in irradiated animals, as assessed by two separate cognitive tasks. 23825124 Estradiol Dose-Dependent Regulation of Membrane Estrogen Receptor-α, Metabotropic Glutamate Receptor-1a, and Their Complexes in the Arcuate Nucleus of the Hypothalamus in Female Rats. Sexual receptivity in the female rat is dependent on dose and duration of estradiol exposure. A 2 μg dose of estradiol benzoate (EB) primes reproductive behavior circuits without facilitating lordosis. However, 50 μg EB facilitates lordosis after 48 hours. Both EB doses activate membrane estrogen receptor-α (mERα) that complexes with and signals through metabotropic glutamate receptor-1a (mGluR1a). This mERα-mGluR1a signaling activates a multisynaptic lordosis-inhibiting circuit in the arcuate nucleus (ARH) that releases β-endorphin in the medial preoptic nucleus (MPN), activating μ-opioid receptors (MOP). MPN MOP activation is maintained, inhibiting lordosis for 48 hours by 2 μg EB, whereas 50 μg EB at 48 hours deactivates MPN MOP, facilitating lordosis. We hypothesized that 50 μg EB down-regulates ERα and mERα-mGluR1a complexes in the ARH to remove mERα-mGluR1a signaling. In experiment I, 48 hours after 2 μg or 50 μg EB, the number of ARH ERα-immunopositive cells was reduced compared with controls. In experiment II, compared with oil controls, total ARH ERα protein was decreased 48 hours after 50 μg EB, but the 2 μg dose was not. These results indicate that both EB doses reduced the total number of cells expressing ERα, but 2 μg EB may have maintained or increased ERα expressed per cell, whereas 50 μg EB appeared to reduce total ERα per cell. In experiment III, coimmunoprecipitation and Western blot revealed that total mERα and coimmunoprecipitated mERα with mGluR1a were greater 48 hours after 2 μg EB treatment vs rats receiving 50 μg EB. These results indicate 2 μg EB maintains but 50 μg EB down-regulates mERα-mGluR1a to regulate the lordosis circuit activity. 23186260 Investigations on the endometrial response to intrauterine administration of N-acetylcysteine in oestrous mares. In mares, mating-induced persistent endometritis contributes to low fertility. The condition is in part related to delayed clearance of mucus accumulated within the uterine lumen. The objective of this study was to investigate the endometrial response of healthy mares to intrauterine (i.u.) treatment with N-acetylcysteine (NAC). Oestrous mares (n = 12) were randomly assigned to a treatment (TM) or control (C) group and received an i.u. infusion of 5% NAC and saline (total volume 140 ml), respectively. Endometrial biopsies were collected in five of the mares 24 h after treatment, in the remaining seven mares 72 h after treatment. Endometrial biopsies were evaluated for integrity of the luminal epithelium, number of polymorphonuclear neutrophils (PMN), staining for cyclooxygenase 2 (COX2), staining with Kiel 67 antigen (Ki-67), lectins and periodic acid-Schiff (PAS). The integrity of endometrial epithelial cells was not affected by treatment (no statistical differences between groups or times). At 24 h after treatment, the mean number of PMN in endometrial biopsies from NAC- and C-mares did not differ, but at 72 h after treatment, number of PMN was significantly higher (p < 0.05) in C (3.9 ± 0.6 PMN/field) compared with NAC-treated mares (2.3 ± 0.2 PMN/field). At 72 h after treatment, the intensity of staining for COX2 was significantly higher after saline than after NAC treatment (p < 0.05). In the epithelium, no differences in staining for the proliferation marker Ki-67 were seen with respect to time and treatment. Score for the lectin wheat germ agglutinin (WGA) was slightly higher in NAC-treated mares than in C-mares 72 h after treatment (p < 0.05). Score for PAS staining of mucus in deep uterine glands differed significantly between groups at 24 h after treatment (p < 0.05). The present study demonstrates that NAC does not adversely affect the endometrial function. Moreover, an anti-inflammatory effect on the equine endometrium was observed. 23911715 Is it dangerous to fantasize revenge in imagery exercises? An experimental study. Imagery rescripting (ImRS), i.e. changing intrusive mental images in imagery, is increasingly recognized as a helpful therapy technique. In ImRS exercises, patients sometimes suggest taking violent revenge on perpetrators. However, it is unclear whether vengeful phantasies can be particularly helpful in giving back feelings of power and control, or whether they rather increase aggressive feelings, with potentially harmful effects. Forty-six healthy participants watched 3 trauma movie segments depicting interpersonal violence. After each movie, one of 3 ImRS strategies (ImRS with violent revenge, ImRS without violence, safe place imagery) was applied. Dependent variables were subjective emotion ratings. Aggressive and positive emotions changed most strongly with the safe place image, no differences between ImRS with and without violence were observed. Sad and anxious emotions were not differently influenced by different strategies. Only a healthy sample with no previous display of aggression has been investigated. Cross-over effects cannot be excluded due to the within-group design with repeated trauma movie segments. Using violent pictures in ImRS does not seem to be particularly risky as it does not increase aggressive emotions in the participants; however it has no added value. For the purpose of emotion regulation after an analog trauma, the safe place imagery does best. 23291037 Study of the recrystallization in coated pellets - Effect of coating on API crystallinity. Coated diltiazem hydrochloride-containing pellets were prepared using the solution layering technique. Unusual thermal behavior was detected with differential scanning calorimetry (DSC) and its source was determined using thermogravimetry (TG), X-ray powder diffraction (XRPD) and hot-stage microscopy. The coated pellets contained diltiazem hydrochloride both in crystalline and amorphous form. Crystallization occurs on heat treatment causing an exothermic peak on the DSC curves that only appears in pellets containing both diltiazem hydrochloride and the coating. Results indicate that the amorphous fraction is situated in the coating layer. The migration of drugs into the coating layer can cause changes in its degree of crystallinity. Polymeric coating materials should therefore be investigated as possible crystallization inhibitors. 23947615 Nasally administered Lactobacillus rhamnosus strains differentially modulate respiratory antiviral immune responses and induce protection against respiratory syncytial virus infection. Some studies have shown that nasally administered immunobiotics had the potential to improve the outcome of influenza virus infection. However, the capacity of immunobiotics to improve protection against respiratory syncytial virus (RSV) infection was not investigated before. The aims of this study were: a) to evaluate whether the nasal administration of Lactobacillus rhamnosus CRL1505 (Lr05) and L. rhamnosus CRL1506 (Lr06) are able to improve respiratory antiviral defenses and beneficially modulate the immune response triggered by TLR3/RIG-I activation; b) to investigate whether viability of Lr05 or Lr06 is indispensable to modulate respiratory immunity and; c) to evaluate the capacity of Lr05 and Lr06 to improve the resistance of infant mice against RSV infection. Nasally administered Lr05 and Lr06 differentially modulated the TLR3/RIG-I-triggered antiviral respiratory immune response. Lr06 administration significantly modulated the production of IFN-α, IFN-β and IL-6 in the response to poly(I:C) challenge, while nasal priming with Lr05 was more effective to improve levels of IFN-γ and IL-10. Both viable Lr05 and Lr06 strains increased the resistance of infant mice to RSV infection while only heat-killed Lr05 showed a protective effect similar to those observed with viable strains. The present work demonstrated that nasal administration of immunobiotics is able to beneficially modulate the immune response triggered by TLR3/RIG-I activation in the respiratory tract and to increase the resistance of mice to the challenge with RSV. Comparative studies using two Lactobacillus rhamnosus strains of the same origin and with similar technological properties showed that each strain has an specific immunoregulatory effect in the respiratory tract and that they differentially modulate the immune response after poly(I:C) or RSV challenges, conferring different degree of protection and using distinct immune mechanisms. We also demonstrated in this work that it is possible to beneficially modulate the respiratory defenses against RSV by using heat-killed immunobiotics. 23894498 Ocular-motor profile and effects of memantine in a familial form of adult cerebellar ataxia with slow saccades and square wave saccadic intrusions. Fixation instability due to saccadic intrusions is a feature of autosomal recessive spinocerebellar ataxias, and includes square wave intrusions (SWI) and macrosaccadic oscillations (MSO). A recent report suggested that the non-competitive antagonist of NMDA receptors, memantine, could decrease MSO and improve fixation in patients with spinocerebellar ataxia with saccadic intrusions (SCASI). We similarly tested two sisters, respectively of 58 and 60 years, with an unrecognized form of recessive, adult-onset cerebellar ataxia, peripheral neuropathy and slow saccades, who showed prominent SWI and also complained with difficulty in reading. We tested horizontal visually guided saccades (10°-18°) and three minutes of steady fixation in each patient and in thirty healthy controls. Both patients showed a significant reduction of peak and mean velocity compared with control subjects. Large SWI interrupting steady fixation were prominent during steady fixation and especially following visually guided saccades. Eye movements were recorded before and during the treatment with memantine, 20 mg/daily for 6 months. The treatment with memantine reduced both the magnitude and frequency of SWI (the former significantly), but did not modified neurological conditions or saccade parameters. Thus, our report suggests that memantine may have some general suppressive effect on saccadic intrusions, including both SWI and MSO, thereby restoring the capacity of reading and visual attention in these and in other recessive forms of ataxia, including Friedreich's, in which saccadic intrusions are prominent. 23922555 The Novel Angiotensin II Receptor Blocker Azilsartan Medoxomil Ameliorates Insulin Resistance Induced by Chronic Angiotensin II Treatment in Rat Skeletal Muscle. Angiotensin receptor (type 1) blockers (ARBs) can reduce both hypertension and insulin resistance induced by local and systemic activation of the renin-angiotensin-aldosterone system. The effectiveness of azilsartan medoxomil (AZIL-M), a novel imidazole-based ARB, to facilitate metabolic improvements in conditions of angiotensin II (Ang II)-associated insulin resistance is currently unknown. The aim of this study was to determine the impact of chronic AZIL-M treatment on glucose transport activity and key insulin signaling elements in red skeletal muscle of Ang II-treated rats. Male Sprague-Dawley rats were treated for 8 weeks with or without Ang II (200 ng/kg/min) combined with either vehicle or AZIL-M (1 mg/kg/day). Ang II induced significant (p < 0.05) increases in blood pressure, which were completely prevented by AZIL-M. Furthermore, Ang II reduced insulin-mediated glucose transport activity in incubated soleus muscle, and AZIL-M co-treatment increased this parameter. Moreover, AZIL-M treatment of Ang II-infused animals increased the absolute phosphorylation of insulin signaling molecules, including Akt [both Ser(473) (81%) and Thr(308) (23%)] and AS160 Thr(642) (42%), in red gastrocnemius muscle frozen in situ. Absolute AMPKα (Thr(172)) phosphorylation increased (98%) by AZIL-M treatment, and relative Thr(389) phosphorylation of p70 S6K1, a negative regulator of insulin signaling, decreased (51%) with AZIL-M treatment. These results indicate that ARB AZIL-M improves the in vitro insulin action on glucose transport in red soleus muscle and the functionality of the Akt/AS160 axis in red gastrocnemius muscle in situ in Ang II-induced insulin-resistant rats, with the latter modification possibly associated with enhanced AMPKα and suppressed p70 S6K1 activation. 23897409 Source Activation of P300 Correlates with Negative Symptom Severity in Patients with Schizophrenia. It is well known that the P300 amplitude is reduced in schizophrenia patients, which may reflect the pathophysiology and symptom severity of schizophrenia, particularly related to negative symptoms. However, the relationship between the underlying neural generator of the P300 and symptomatic outcomes are not yet fully understood. This study aimed to verify the abnormal P300 of schizophrenia in terms of its source activation to and further examine the relationship between reduced source activation and symptom severity of patients. For this purpose, the P300 was recorded from 34 patients with schizophrenia and matched healthy controls using an auditory oddball paradigm. We found that the P300 amplitude of schizophrenia patients was significantly decreased along the midline electrodes and both bilateral temporal areas compared with healthy controls. In comparing the source activation between the two groups, schizophrenia patients showed decreased source activation predominantly over the left hemisphere, including the cingulate, inferior occipital gyrus, middle occipital gyrus, middle temporal gyrus, posterior cingulate, precuneus, and superior occipital gyrus. Furthermore, we found that the decreased activation of the contrasted areas showed significant negative correlation with PANSS negative symptom scores in the middle temporal gyrus, posterior cingulate, precuneus, and superior occipital gyrus. Our findings suggest that the reduced P300 source activation in schizophrenia might reflect deficits in fronto-temporal-parietal circuit. 23258432 Nickel(II) complexes bearing 4,5-bis(arylimino)pyrenylidenes: synthesis, characterization, and ethylene polymerization behaviour. A series of nickel(II) dihalides complexes bearing 4,5-bis(arylimino)pyrenylidenes, NiX2(2,6-R(1)-4-R(2)C6H2N)2C16H8, was synthesized and characterized by FT-IR spectroscopy, elemental analysis, and single crystal X-ray diffraction for the organic compounds (L2 and L3) and the nickel complexes (C1 and C2). The molecular structures of C1 (R(1) = Me, R(2) = H, X = Br) and C2 (R(1) = R(2) = Me, X = Br) revealed a distorted tetrahedral geometry around the nickel centre. Upon treatment with the co-catalysts MAO, EASC and MMAO, all the nickel pre-catalysts exhibited high activities (of up to 4.42 × 10(6) g(PE) mol(Ni)(-1) h(-1)) for ethylene polymerization, and produced polyethylene products with a high degree of branching (up to 130 branched per 1000 carbons) and narrow molecular weight distribution. The influence of the reaction parameters and the nature of the ligands on the catalytic behavior of the title nickel complexes have been investigated. 23494524 Structure of dipeptides having N-terminal selenocysteine residues: a DFT study in gas and aqueous phase. Over the last few decades, dipeptides as well as their analogues have served as important model systems for the computational studies concerning the structure of protein and energetics of protein folding. Here, we present a density functional structural study on a set of seven dipeptides having N-terminal selenocysteine residues (the component in the C-terminus is varied with seven different combinations viz. Ala, Phe, Glu, Thr, Asn, Arg and Sec) in gas and simulated aqueous phase using a polarizable continuum model (PCM). The molecular geometries of the dipeptides are fully optimized at B3LYP/6-311++G(d,p) level and subsequent frequency calculations confirm them as true minima. The effects of solvation and identity of the varying C-terminal residue on the energetics, structural features of the peptide planes, values of the ψ and ф dihedrals, geometry around the α-carbon atoms and theoretically predicted vibrational spectra of the dipeptides are investigated. Two types of intramolecular H-bonds, namely N…H-N and O…H-C, are found to play important roles in influencing the planarity of the peptide planes and geometry around the α-carbon atoms of the dipeptides. The identity of the varying C-terminal residue influences the values of ф, planarity of the peptide planes and geometry around the C7 α-carbon atoms while the solvation effects are evident on the values of bond lengths and bond angles of the amide planes. 23623921 STAT3 mediates TGF-β1-induced TWIST1 expression and prostate cancer invasion. TGF-β1 induces epithelial-mesenchymal transition (EMT) to stimulate cancer cell progression, and TWIST1 is a critical regulator of EMT. In the present study, we determined the underlying mechanisms of TGF-β1-induced TWIST1 expression and its effect on prostate cancer cell invasion. TGF-β1 stimulated STAT3 phosphorylation and HIF-1α expression. Silencing either STAT3 or HIF-1α efficiently attenuated TGF-β1-induced TWIST1 expression. Further ectopic expression of a dominant negative mutant of STAT3 reduced TGF-β1-induced TWIST1 expression. In addition, STAT3 and HIF-1α up-regulated TWIST1 expression by direct binding to a TWIST1 promoter. Strikingly, STAT3 also enhanced TGF-β1-induced TWIST1 expression through HIF-1α stabilization. Collectively, we demonstrate a mechanistic cascade of TGF-β1 up-regulating STAT3 activation and HIF-1α stabilization and subsequent TWIST1 expression, leading to prostate cancer invasion. 23901125 Current Status of Diversity by Race, Hispanic Ethnicity, and Sex in Diagnostic Radiology. Purpose:To assess the diversity of the U.S. diagnostic radiology physician workforce by race, Hispanic ethnicity, and sex in the context of the available pipeline of medical students.Materials and Methods:Institutional review board evaluation and exemption were granted for the study, as primary data were obtained from publicly available registry sources, with no identifiable private or protected information. Publicly available American Medical Association, American Association of Medical Colleges, and U.S. census registries were used to assess differences for 2010 among diagnostic radiology practicing physicians, academic faculty, residents, subspecialty trainees, residency applicants, medical school graduates, and U.S. population by using binomial tests; with adjustment for multiple comparisons among different groups, differences with P < .001 were considered significant. Significant differences in diagnostic radiology resident representation were evaluated for academic years 2003-2004 to 2010-2011 and for 2010, compared among the 20 largest residency training programs.Results:Females and traditionally underrepresented minorities in medicine (URM)-blacks, Hispanics, American Indians, Alaskan Natives, Native Hawaiians, and Pacific Islanders (AI/AN/NH/PI)-are underrepresented as practicing physicians (23.5% and 6.5%, respectively), faculty (26.1%, 5.9%), and diagnostic radiology residents (27.8%, 8.3%), compared with the U.S. population (50.8%, 30.0%) (all P < .001). Although they are increased in percentage as residents compared with practicing physicians, females and URMs remain underrepresented at the resident trainee level, compared with their proportions as medical school graduates (48.3%, 15.3%, respectively). During the past 8 years, there was no significant increase in female or URM resident (all P > .01) representation, suggesting no dramatic change in future representation as practicing physicians. Moreover, diagnostic radiology ranks 17th in female and 20th in URM representation among the 20 largest residency training specialties.Conclusion:Females and URM remain underrepresented in the diagnostic radiology physician workforce despite an available medical student pipeline. Given prevalent health care disparities and an increasingly diverse society, future research and training efforts should address increasing resident diversity with program directors and department chairs.© RSNA, 2013. 23845427 Effects of age and gender on neural networks of motor response inhibition: From adolescence to mid-adulthood. Functional inhibitory neural networks mature progressively with age. However, nothing is known about the impact of gender on their development. This study employed functional magnetic resonance imaging (fMRI) to investigate the effects of age, sex, and sex by age interactions on the brain activation of 63 healthy males and females, between 13 and 38years, performing a Stop task. Increasing age was associated with progressively increased activation in typical response inhibition areas of right inferior and dorsolateral prefrontal and temporo-parietal regions. Females showed significantly enhanced activation in left inferior and superior frontal and striatal regions relative to males, while males showed increased activation relative to females in right inferior and superior parietal areas. Importantly, left frontal and striatal areas that showed increased activation in females, also showed significantly increased functional maturation in females relative to males, while the right inferior parietal activation that was increased in males showed significantly increased functional maturation relative to females. The findings demonstrate for the first time that sex-dimorphic activation patterns of enhanced left fronto-striatal activation in females and enhanced right parietal activation in males during motor inhibition appear to be the result of underlying gender differences in the functional maturation of these brain regions. 23564420 Benefits of catch-up in vaccination against human papillomavirus in medium- and low-income countries. Human papillomavirus (HPV) vaccination of a birth cohort of girls in the 9-13 age range is recommended as a priority, but decreases in HPV vaccine cost may make catch-up of a few additional cohorts more attractive not only in high-income countries. We assessed the reduction in HPV16 and 18 infections that could be achieved in a medium- (Poland) and a low-income (Guinea) country by adding one-time catch-up of 12- to 19-year-old girls to the vaccination of 11-year-old girls. According to our ad hoc adapted dynamic model of HPV infection transmission, the addition of catch-up was estimated to bring forward the 50% reduction of HPV16/18 prevalence due to vaccination in women ≤35 by as much as 5 years. Catch-up of 12- to 15-year olds reduced the cumulative probability of HPV16/18 infections by age 35 in the relevant cohorts by about 30% in both countries. Catch-up of 16- to 19-year-old girls added little. Regardless of the chosen catch-up strategy, 16 to 20% of HPV16/18 prevention from vaccination was attributable to herd immunity. Assuming a sufficiently low vaccine cost, the addition of a catch-up round is, therefore, worth considering in medium/low-income countries to extend vaccine benefits to less young adolescent girls whose future access to cervical screening is uncertain. 23619608 A prospective cohort study of shift work and the risk of death from pancreatic cancer in Japanese men. There is mounting evidence that shift work involving night work increases cancer risk. We examined the relationship between working rotating shifts and the risk of death from pancreatic cancer on the basis of data from the Japanese Collaborative Cohort Study (JACC Study). The present analysis was restricted to 22,224 men who were 40-65 years of age at baseline (1988-1990) and who reported working full time or were self-employed in the JACC Study. The subjects were followed through 31 December 2009. Information on occupation and lifestyle factors was collected using a self-administered questionnaire. The Cox proportional hazards model was used to estimate the relative risk (RR) and 95% confidence interval (CI) for the risk of death from pancreatic cancer in relation to shift work. During the follow-up period, 127 pancreatic cancer deaths were observed. Overall, we found no statistically significant increase in the risk of death from pancreatic cancer associated with rotating shift work. As compared to day-shift workers, the RRs were 0.83 (95% CI 0.43-1.60) for rotating shift workers and 0.61 (95% CI 0.22-1.60) for fixed night-shift workers, after adjustment for potential confounding factors. The multivariable-adjusted RR was 1.34 (95% CI 0.66-2.75) among rotating shift workers in the analysis restricted to men who reported working full time at baseline. Our data did not support the hypothesis that shift work is significantly associated with the risk of death from pancreatic cancer in this cohort of Japanese men. 23815660 Deconstructing heterostyly: the evolutionary role of incompatibility system, pollinators, and floral architecture. Darwin's early work on heterostyly and related style polymorphisms (the presence of two or three style morphs within a population) generated much interest to understand how precise interactions between ecological and genetic mechanisms influence the evolution of floral diversity. Here we tested three key hypotheses proposed to explain the evolution of heterostyly: (i) the presence of self-incompatibility; (ii) the role of pollinators in promoting dissasortative mating; and (iii) floral architecture, which restricts pollinators' movements and ensures more exact pollen deposition on their bodies. We combined data from experiments, field observations, and published studies to test whether evolution of style polymorphism in Narcissus is driven by the incompatibility system, pollinator guilds, or floral architecture, within a phylogenetic framework. Neither differences in pollinator environment nor the presence of genetic self-incompatibility were correlated with presence of style polymorphism. However, our results indicate that the evolution of style polymorphism was driven by the presence of a narrow and long floral tube. 23590565 Aromatic amino acids as precursors of antimicrobial metabolites in Geotrichum candidum. Geotrichum candidum ATCC 204307 was previously found to generate phenyllactic acid (PLA) and indoleacetic acid (ILA) in complex culture media. In this study, a relationship between concentrations of PLA, ILA, and hydroxy PLA (OH-PLA) and initial concentrations of phenylalanine, tryptophan, and tyrosine, added respectively as unique sources of nitrogen in synthetic medium, was established. Phenylpyruvic acid (PPA), an intermediate compound of PLA metabolism, was able to induce not only PLA but also phenylethyl alcohol (PEA) production when used separately as initial substrate. Under pH, temperature, and salt concentrations used for cheese-making, phenylalanine was found to be the most efficient substrate for antimicrobial metabolite production. In excess of substrate, different yeast strains of Geotrichum candidum, Yarrowia lipolytica, Candida natalensis, and Candida catenulata were shown here to produce 1.6 ± 0.5-5.0 ± 0.2 mM of PLA from phenylalanine, 5.0 ± 0.1-10.9 ± 0.3 mM of ILA from tryptophan, and 1.3 ± 0.3-7.0 ± 0.02 of PLA and 0.1 ± 0.0-2.22 ± 0.09 mM of PEA from PPA. Geotrichum candidum ATCC 204307 was the highest producer. This is the first time these antimicrobial metabolites PLA, OH-PLA, ILA, and PEA are being reported as the reaction products of aromatic amino acids catabolism in G. candidum. 23857175 Determination of chidamide in rat plasma by LC-MS and its application to pharmacokinetics study. A sensitive and selective liquid chromatography mass spectrometry method for determination of chidamide in rat plasma was developed. After addition of linezolid as internal standard, protein precipitation by acetonitrile-methanol (9:1, v/v) was used as sample preparation. Chromatographic separation was achieved on a Zorbax SB-C18 (2.1 × 150 mm, 5 µm) column with acetonitrile-0.1% formic acid as mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; selective ion monitoring mode was used for quantification using target fragment ions m/z 391.5 for chidamide and m/z 338.5 for the IS. Calibration plots were linear over the range of 10-2000 ng/mL for chidamide in rat plasma. The lower limit of quantification for chidamide was 10 ng/mL. The mean recovery of chidamide in plasma was in the range of 86.6-92.1%. The coefficients of variation of intra-day and inter-day precision were both <12%. This method is simple and sensitive and was applied successfully in a pharmacokinetic study of chidamide to rats. Copyright © 2013 John Wiley & Sons, Ltd. 23937414 Young women's perceptions of fertility-related information and fertility distress prior to surgery for ovarian cysts. To investigate young women's reproductive desire and perceptions of fertility-related information when scheduled for ovarian cyst surgery with a possible impact on fertility. Cross-sectional study. University Hospital. Women of reproductive age (n=106, mean age 32.3, range 18-44 years) with a diagnosis of ovarian cyst and scheduled ovarian cyst surgery between March/2011 until September/2012 were included. The women answered a questionnaire after the pre-surgery consultation with the gynecologist. The questionnaire included study-specific measures of reproductive desire, perception of fertility-related information received, worry about future fertility and socio-demographic characteristics. Reproductive desire and recalled information on the impact of surgery on fertility. A high proportion of the women (72%) reported a desire for having children in the future and more than half of them (58%) recalled receiving information about the impact of surgery on fertility. In a multivariable logistic regression model adjusted for parity, education and age, a desire to have children increased the likelihood of recalling to have received fertility-related information (OR 3.2, 95%CI 1.1-9.2). Almost half of women with reproductive desire had ovarian surgery without recalling a discussion of fertility issues. Development of written information or interactive information might improve women's perception of fertility-related information. This article is protected by copyright. All rights reserved. 23270327 E-ADA Activity in Serum of Lambs Experimentally Infected with Haemonchus contortus. Abstract :  The aim of this study was to evaluate adenosine deaminase (E-ADA) activity in sera of lambs experimentally infected with Haemonchus contortus . We used 12 lambs divided into 2 groups; Group A had 5 healthy, non-infected animals (control) and Group B had 7 healthy animals infected with H. contortus . Lambs were infected orally with 500 larvae (L3) per animal every 2 days, for a period of 20 days, and later the infection was confirmed by examination of feces (eggs per gram [EPG] via fecal egg count). Blood collection was performed at days 0, 20, 40, 60, and 80 post-infection (PI) for analysis of E-ADA activity. Animals in Group A showed negative EPG throughout the experiment unlike those from Group B that had elevated EPG counts. E-ADA activity was reduced in the serum of animals infected with H. contortus when compared to non-infected controls at days 20, 40, 60, and 80 PI. Therefore, it is concluded that infection with H. contortus influences the E-ADA activity in lambs. 23755834 Control of the size, shape and composition of highly uniform, non-agglomerated, sub-micrometer β-tricalcium phosphate and dicalcium phosphate platelets. Calcium phosphates (CaPs) are widely used as bone graft substitutes but are inherently brittle, hence restricting their use to mechanically protected environments. Combining them with a tough polymer matrix could potentially lead to a composite with load-bearing properties. However, the highest mechanical properties can only be achieved if the CaP particles possess very precise features: they should be uniform in size and shape, non-agglomerated, elongated and thin. The aim of the present study therefore was to assess a novel method to produce such particles. This involved the precipitation of CaP particles in ethylene glycol at moderate temperatures (90-170 °C) and the variation of different reaction parameters (temperature, concentration, pH, etc) to study their influence on particle composition, size, shape and dispersion was studied. As a result, two main CaP phases were obtained as well-dispersed and highly uniform platelets in the form of: (i) β-tricalcium phosphate (β-TCP) hexagonal prisms and (ii) monetite (DCP) flat parallelepipeds. The size dispersion was the narrowest for β-TCP (standard deviation/mean < 5%) whereas the aspect ratio was the highest for DCP (up to 25). In both cases, the thickness of the platelets was below 300 nm which should be ideal for the synthesis of strong CaP-based composites. 23486920 Synthesis and application of FePt/CNTs nanocomposite as a sensor and novel amide ligand as a mediator for simultaneous determination of glutathione, nicotinamide adenine dinucleotide and tryptophan. In this study, we report the synthesis and application of a FePt/CNTs nanocomposite as a highly sensitive sensor and novel amide ligand (9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboximido)-4-ethylbenzene-1,2-diol as a mediator for the determination of glutathione (GSH), nicotinamide adenine dinucleotide (NADH) and tryptophan (Trp). The synthesized materials were characterized with different methods such as NMR, IR spectroscopy, TEM, XRD, FESEM, cyclic voltammetry, electrochemical impedance spectroscopy and square wave voltammetry (SWV). The modified electrode exhibited a potent and persistent electron mediating behavior followed by well-separated oxidation peaks of GSH, NADH and Trp. The peak currents were linearly dependent on GSH, NADH and Trp concentrations in the range of 0.08-220, 1.0-400 and 5.0-500 μmol L(-1), with detection limits of 0.05, 0.8 and 1.0 μmol L(-1), respectively. The modified electrode was used for the determination of these compounds in real samples. 23943872 Targeting of the Arf-GEF GBF1 to lipid droplets and Golgi membranes. Lipid droplet metabolism and secretory pathway trafficking both require activation of the Arf1 small G protein. The spatio-temporal regulation of Arf1 activation is mediated by guanine nucleotide exchange factors (GEFs) of the GBF and BIG families, but the mechanisms of their localization to multiple sites within cells are poorly understood. Here we show that GBF1 has a lipid-binding domain (HDS1) immediately downstream of the catalytic Sec7 domain, which mediates association with both lipid droplets and Golgi membranes in cells, and with bilayer liposomes and artificial droplets in vitro. An amphipathic helix within HDS1 is necessary and sufficient for lipid binding, both in vitro and in cells. The HDS1 domain of GBF1 is stably associated with lipid droplets in cells, and the catalytic Sec7 domain inhibits this potent lipid droplet binding capacity. Additional sequences upstream of the Sec7 domain-HDS1 tandem are required for localization to Golgi membranes. This mechanism provides insight into crosstalk between lipid droplet function and secretory trafficking. 23871268 Aortic Root Dimensions and Stiffness in Healthy Subjects. The aim of the present study was to investigate the full range of aortic root diameters and stiffness in a group of subjects without known cardiovascular risk factors and/or overt cardiovascular disease. Four hundred and twenty-two healthy subjects (mean age 44.35 ± 16.91 years, range 16 to 90, 284 men [67%]) underwent comprehensive transthoracic echocardiography. The leading edge method was used for the end-diastolic aortic root diameters measured at 4 locations (1) the aortic annulus, (2) the sinuses of Valsalva, (3) the sinotubular junction, and (4) the maximum diameter of the proximal ascending aorta. Aortic wall stiffness was assessed using 2-dimensional guided M-mode evaluation of systolic and diastolic aortic diameter, 3 cm above the aortic valve. The absolute aortic root diameters increased with age in both genders. Aortic measurements were significantly greater in men than in women at all levels, whereas body surface area-indexed values were similar in men and women, except for the ascending aorta for which women tended to have greater values. Multivariable regression analysis using age and body size (weight, height, and body surface area) predicted all aortic diameters, whereas blood pressure indexes predicted only the distal part of the aorta. Aortic stiffness increased with age in men and women with no differences between genders; only age predicted aortic stiffness. The increment in aortic diameter with age was lesser when adjusted for aortic stiffness. In conclusion, we define the physiologic range of aortic root diameters and related stiffness in healthy subjects stratified by age and gender. Moreover, aortic stiffness should also be taken into account when the increase of aortic diameter is considered. 23877614 Cognitive control in number magnitude processing: evidence from eye-tracking. The unit-decade compatibility effect describes longer response times and higher error rates for incompatible (e.g., 37_52) than compatible (e.g., 42_57) number comparisons. Recent research indicated that the effect depends on the percentage of same-decade filler items. In the present study, we further examined this relationship by recording participants' eye-fixation behaviour. In four conditions, participants had to compare item sets with different filler item types (i.e., same-decade and same-unit filler items) and different numbers of same-decade filler items (i.e., 25, 50, and 75 %). We found a weaker unit-decade compatibility effect with most fixations on tens in the condition with same-unit filler items. Moreover, the compatibility effect increased with the percentage of same-decade filler items which was accompanied by less fixations on tens and more fixations on units. Thus, our study provides first eye-tracking evidence for the influence of cognitive control in number processing. 23777473 Trehalose glycopolymers as excipients for protein stabilization. Herein, the synthesis of four different trehalose glycopolymers and investigation of their ability to stabilize proteins to heat and lyophilization stress are described. The disaccharide, α,α-trehalose, was modified with a styrenyl acetal, methacrylate acetal, styrenyl ether, or methacrylate moiety resulting in four different monomers. These monomers were then separately polymerized using free radical polymerization with azobisisobutyronitrile (AIBN) as an initiator to synthesize the glycopolymers. Horseradish peroxidase and glucose oxidase were incubated at 70 and 50 °C, respectively, and β-galactosidase was lyophilized multiple times in the presence of various ratios of the polymers or trehalose. The protein activities were subsequently tested and found to be significantly higher when the polymers were present during the stress compared to no additive and to equivalent amounts of trehalose. Different molecular weights (10 kDa, 20 kDa, and 40 kDa) were tested, and all were equivalent in their stabilization ability. However, some subtle differences were observed regarding stabilization ability between the different polymer samples, depending on the stress. Small molecules such as benzyl ether trehalose were not better stabilizers than trehalose, and the trehalose monomer decreased protein activity, suggesting that hydrophobized trehalose was not sufficient and that the polymeric structure was required. In addition, cytotoxicity studies with NIH 3T3 mouse embryonic fibroblast cells, RAW 264.7 murine macrophages, human dermal fibroblasts (HDFs), and human umbilical vein endothelial cells (HUVECs) were conducted with polymer concentrations up to 8 mg/mL. The data showed that all four polymers were noncytotoxic for all tested concentrations. The results together suggest that trehalose glycopolymers are promising as additives to protect proteins from a variety of stressors. 23150921 The kidney and the sympathetic system: a short review. Despite the well documented and very effective non pharmacologic and pharmacologic therapies, hypertension remains often poorly controlled. There is still room for improvements in blood pressure control and recent technological advances have generated a regained interest in the physiopathology of renal sympathetic innervation in hypertension. In this article we review the evidence that renal sympathetic activity is increased in essential hypertension. The postganglionic sympathetic fibers are directed to the afferent and efferent renal arterioles, the juxtaglomerular apparatus, the proximal renal tubule, the loop of Henle, as well as the distal renal tubule and are under the control of many reflex loops, which are summarized in a most comprehensive manner for an unfamiliar reader within this field of research. Studies on renal denervation have provided further insights on the role of the sympathetic system in the kidneys, however their proper interpretation requires a special attention to the experimental protocols, as is explained in the text. Last, the possibility of kidney reinnervation is discussed, as well as the emerging evidence that the kidney is also a sensory organ. In summary, this review article provides a strong scientific background to understand not only the mechanisms of the hypotensive effects, but also those of possible pitfalls, of renal denervation. 23359388 Molecular biomarkers as potential targets for therapeutic strategies in human testicular germ cell tumors: an overview. Testicular germ cell tumors (TGCTs), the most common malignancy in males between 15 and 34 years of age and the most frequent cause of death from solid tumors in this age group. TGCTs can be subdivided into seminoma and non-seminoma germ cell tumors (NSGCTs), including embryonal cell carcinoma, choriocarcinoma, yolk sac tumor, and teratoma. Seminomas and NSGCTs do not only present distinctive clinical features, but they also show significant differences as far as therapy and prognosis are concerned. Seminomas are highly sensitive to both radiation and chemotherapy, with a good prognosis, non-seminomas are sensitive to platinum-based combination chemotherapy and are less susceptible to radiation, with the exception of teratomas. The different therapeutic outcome might be explained by inherent properties of the cells from which testicular neoplasia originate. The unique treatment sensitivity of TGCTs is unexplained so far, but it is likely to be related to intrinsic molecular characteristics of the PGCs/gonocytes, from which these tumors originate. Many discovered bio-markers including OCT3/4, SOX2, SOX17, HMGA1, HMGA2, PATZ1, GPR30, Aurora B, estrogen receptor β, and others have given further advantages to discriminate between histological subgroups. In addition, therapeutic approaches for the treatment of TGCTs have been proposed: humanized antibodies against receptors/surface molecules on cancer cells, inhibitors of serine-threonine, and tyrosine kinases, and others. The mini-review will be an overview on the molecular alterations identified in TGCTs and on novel targeted antineoplastic strategies that might help to treat chemotherapy resistant TGCTs. 23871600 Quantitative nucleation and growth kinetics of gold nanoparticles via model-assisted dynamic spectroscopic approach. Lacking of quantitative experimental data and/or kinetic models that could mathematically depict the redox chemistry and the crystallization issue, bottom-to-up formation kinetics of gold nanoparticles (GNPs) remains a challenge. We measured the dynamic regime of GNPs synthesized by l-ascorbic acid (representing a chemical approach) and/or foliar aqueous extract (a biogenic approach) via in situ spectroscopic characterization and established a redox-crystallization model which allows quantitative and separate parameterization of the nucleation and growth processes. The main results were simplified as the following aspects: (I) an efficient approach, i.e., the dynamic in situ spectroscopic characterization assisted with the redox-crystallization model, was established for quantitative analysis of the overall formation kinetics of GNPs in solution; (II) formation of GNPs by the chemical and the biogenic approaches experienced a slow nucleation stage followed by a growth stage which behaved as a mixed-order reaction, and different from the chemical approach, the biogenic method involved heterogeneous nucleation; (III) also, biosynthesis of flaky GNPs was a kinetic-controlled process favored by relatively slow redox chemistry; and (IV) though GNPs formation consists of two aspects, namely the redox chemistry and the crystallization issue, the latter was the rate-determining event that controls the dynamic regime of the whole physicochemical process. 23910816 Olive oil enema in a pre-term infant with milk curd syndrome. Milk curd syndrome was first reported in the 1960s, but was gradually forgotten because of its low incidence thereafter. This condition in pre-term infants has been reported over the last decade and has again attracted neonatologists' attention. The present report describes a pre-term infant with milk curd syndrome. Abdominal distension was evident 14 days after the start of feeding with fortified expressed milk. Abdominal X-ray showed multiple intraluminal masses surrounded by a halo of air, and ultrasound indicated hyperechoic masses. Along with that history and the appearance of fecal impaction, the diagnosis of milk curd syndrome was confirmed. This baby was treated with olive oil enemas and successive colonic lavage for 3 days, and the symptoms were relieved. Olive oil enema, which softens hard stools and induces smooth movement of these stools, may be an effective and safe first-line treatment in pre-term infants with milk curd syndrome. 23881028 Oxidative stress induced by HIV-1 reverse transcriptase modulates the enzyme's performance in gene immunization. HIV-1 infection induces chronic oxidative stress. The resultant neurotoxicity has been associated with Tat protein. Here, we for the first time describe the induction of oxidative stress by another HIV-1 protein, reverse transcriptase (RT). Expression of HIV-1 RT in human embryonic kidney cells generated potent production of the reactive oxygen species (ROS), detected by the fluorescence-based probes. Quantitative RT-PCR demonstrated that expression of RT in HEK293 cells induced a 10- to 15-fold increased transcription of the phase II detoxifying enzymes human NAD(P)H:quinone oxidoreductase (Nqo1) and heme oxygenase 1 (HO-1), indicating the induction of oxidative stress response. The capacity to induce oxidative stress and stress response appeared to be an intrinsic property of a vast variety of RTs: enzymatically active and inactivated, bearing mutations of drug resistance, following different routes of processing and presentation, expressed from viral or synthetic expression-optimized genes. The total ROS production induced by RT genes of the viral origin was found to be lower than that induced by the synthetic/expression-optimized or chimeric RT genes. However, the viral RT genes induced higher levels of ROS production and higher levels of HO-1 mRNA than the synthetic genes per unit of protein in the expressing cell. The capacity of RT genes to induce the oxidative stress and stress response was then correlated with their immunogenic performance. For this, RT genes were administered into BALB/c mice by intradermal injections followed by electroporation. Splenocytes of immunized mice were stimulated with the RT-derived and control antigens and antigen-specific proliferation was assessed by IFN-γ/IL-2 Fluorospot. RT variants generating high total ROS levels induced significantly stronger IFN-γ responses than the variants inducing lower total ROS, while high levels of ROS normalized per unit of protein in expressing cell were associated with a weak IFN-γ response. Poor gene immunogenicity was also associated with a high (per unit of protein) transcription of antioxidant response element (ARE) dependent phase II detoxifying enzyme genes, specifically HO-1. Thus, we have revealed a direct link between the propensity of the microbial proteins to induce oxidative stress and their immunogenicity. 23799341 Serum 25-hydroxyvitamin d level is associated with arterial stiffness, left ventricle hypertrophy, and inflammation in newly diagnosed hypertension. Vitamin D may modulate vascular inflammation, vascular smooth muscle cell proliferation, the renin-angiotensin system, and cardiomyocyte proliferation, myocardial fibrosis, and proliferation. These mechanisms may play a role on arterial stiffness and left ventricle hypertrophy (LVH) in hypertensive patients. We aimed to evaluate the association between serum vitamin D with arterial stiffness and LVH in patients with hypertension. We studied 133 patients with newly diagnosed hypertension [mean (SD) age, 62.9 (10.6) years]. Pulse wave velocity (PWV), which reflects arterial stiffness, was calculated using the single-point method via the Mobil-O-Graph ARCsolver algorithm. Left ventricular mass index (LVMI) was determined according to Deverux formula. The patients were divided into the following 2 groups according to serum vitamin D level: vitamin Dlow group with less than 20 ng/mL and vitamin Dhigh group with greater than or equal to 20 ng/mL. The highest PWV, high-sensitivity C reactive protein, and LVMI values were observed in vitamin Dlow group compared with vitamin Dhigh group. Multiple linear regression analysis showed that vitamin D level was independently associated with LVMI (β = -0.235, P = 0.002) and PWV (β = -0.432, P < 0.001). Adjustment for age, sex, parathyroid hormone level, body surface area, and mean blood pressure did not modify these associations. Vitamin D level was also independently associated with high-sensitivity C reactive protein (β = -0.143, P = 0.047). However, adjustment for parathyroid hormone level or body surface area and mean blood pressure attenuate this association. Serum 25-hyroxyvitamin D is independently related with arterial stiffness, LVH, and inflammation. Vitamin D may play a role on pathogenesis of arterial stiffness and LVH in patient with newly diagnosed hypertension. 23838832 Evaluation and management of children and adolescents with gender identification and transgender disorders. Gender identity development is poorly understood but impacted by central nervous system (CNS) factors, genes, gonadal hormones and receptors, genitalia, and social/environmental factors. Gender identity disorder (GID) is the diagnostic term to describe persons discontent with the sex they were assigned at birth and/or the gender roles associated with that sex. It is crucial that the diagnosis be verified as persistent, since gender confusion among those young persists among only a portion. Recent publications do not yet provide an overall perspective but involve observations regarding outcome information, unusual variables, incidence of cross-gender behavior, and CNS differences related to GID and bi-gender descriptions. Approaches to therapy for GID and task force guidelines are noted. Although the concept of gender identity is a relatively new paradigm and remains an area of active and exciting investigation, findings reported here provide items of information for understanding and treatment of GIDs and illustrate the need for further research. 23868936 Induction of ATF3 Gene Network by Triglyceride-Rich Lipoprotein Lipolysis Products Increases Vascular Apoptosis and Inflammation. Elevation of triglyceride-rich lipoproteins (TGRLs) contributes to the risk of atherosclerotic cardiovascular disease. Our work has shown that TGRL lipolysis products in high physiological to pathophysiological concentrations cause endothelial cell injury; however, the mechanisms remain to be delineated. We analyzed the transcriptional signaling networks in arterial endothelial cells exposed to TGRL lipolysis products. When human aortic endothelial cells in culture were exposed to TGRL lipolysis products, activating transcription factor 3 (ATF3) was identified as a principal response gene. Induction of ATF3 mRNA and protein was confirmed by quantitative reverse-transcription polymerase chain reaction and Western blot respectively. Immunofluorescence analysis showed that ATF3 accumulated in the nuclei of cells treated with lipolysis products. Nuclear expression of phosphorylated c-Jun N-terminal kinase (JNK), previously shown to be an initiator of the ATF3 signaling cascade, also was demonstrated. Small interfering RNA (siRNA)-mediated inhibition of ATF3 blocked lipolysis products-induced transcription of E-selectin and interleukin-8, but not interleukin-6 or nuclear factor-κB. c-Jun, a downstream protein in the JNK pathway, was phosphorylated, whereas expression of nuclear factor-κB-dependent JunB was downregulated. Additionally, JNK siRNA suppressed ATF3 and p-c-Jun protein expression, suggesting that JNK is upstream of the ATF3 signaling pathway. In vivo studies demonstrated that infusion of TGRL lipolysis products into wild-type mice induced nuclear ATF3 accumulation in carotid artery endothelium. ATF3(-/-) mice were resistant to vascular apoptosis precipitated by treatment with TGRL lipolysis products. Also peripheral blood monocytes isolated from postprandial humans had increased ATF3 expression as compared with fasting monocytes. This study demonstrates that TGRL lipolysis products activate ATF3-JNK transcription factor networks and induce endothelial cells inflammatory response. 23957699 NSE/αNAE positivity in B-lineage acute lymphoblastic leukemia: revisiting a potential cytochemical diagnostic pitfall. Cytochemical staining for leukemia typing is declining in hematology laboratories, but the use of flow cytometry may not be possible in some settings. Aberrant cytochemical nonspecific esterase/α-naphthyl acetate esterase (NSE/αNAE) positive B-lymphoblasts can cause confusion with monoblasts, a potentially dangerous pitfall. This unusual cytochemical NSE/αNAE positivity had been associated with relatively poorer outcome of acute lymphoblastic leukemia (ALL) in the era prior to the advent of routine multicolor flow cytometric immunophenotyping. We reviewed morphological, cytochemical and flow-cytometric data from five cases of B-lineage ALL that showed NSE/αNAE positivity and were diagnosed definitively using multi-parametric flow cytometric immunophenotypic analysis. Diffuse or dot-like (localized) strong cytochemical NSE/αNAE activity was detected in all cases and all showed one or more features of high risk disease. The number of NSE/αNAE positive blasts in the marrow varied from 10 to 75%. The morphological differential diagnoses included T-lymphoid lineage ALL and acute monoblastic leukemia (AML-M5). Flow cytometric data revealed B-lineage antigens and the absence of monocytic or other myeloid markers resolved the diagnosis. These cases underscore the importance of immunophenotyping in all cases of suspected ALL regardless of the cytochemical findings. Although the numbers are small, the association with high risk disease observed in all five of our cases may corroborate the previously reported poor prognostic value of such aberrant cytochemical staining. 23896975 Molecular characterization of Dobrava and Kurkino genotypes of Dobrava-Belgrade hantavirus detected in Hungary and Northern Croatia. Among the Hantavirus genus, Saaremaa virus (SAAV) has been the subject of taxonomical debates. While the International Committee on Taxonomy of Viruses declares SAAV as a distinct species, several European hantavirus experts proposed that SAAV is in fact a genotype of Dobrava-Belgrade virus (DOBV). In the present study we performed S-segment-based phylogenetic analysis of eight DOBV strains identified in rodents in Hungary and Northern Croatia. These new sequences considerably increase the number of complete nucleoprotein gene sequences deposited in the NCBI database. Our phylogenetic analysis clearly support the taxonomical nomenclature recently proposed for DOBV, i.e., genotypes such as Dobrava, Saaremaa, Kurkino, and Sochi should indeed be classified within the DOBV hantavirus species. Moreover, we found that only the Dobrava and Kurkino genotypes of DOBV species are circulating in Hungary while currently there is no evidence for the presence of Saaremaa genotype. 23789936 Phase I clinical trial of oral rigosertib in patients with myelodysplastic syndromes. The multi-kinase inhibitor rigosertib (ON 01910.Na) induces mitotic arrest and apoptosis in myeloblasts, while sparing normal cells. The purpose of this study was to determine the pharmacokinetic profile, maximum-tolerated dose (MTD), safety, and clinical activity of an oral formulation of rigosertib in patients with myelodysplastic syndromes (MDS). For pharmacokinetic studies, patients received rigosertib in single escalating weekly doses. To determine the MTD, patient cohorts received escalating doses of rigosertib twice daily for 14 d of a 21-d cycle. Overall, 37 patients were treated. Rigosertib exposure increased with escalating oral doses. Mean absolute oral bioavailability ranged from 13·9% (fed) to 34·8% (fasting) in 12 patients treated at the 560 mg b.i.d. dose level. Dose-limiting toxicity (grade 3 dysuria and shortness of breath) occurred at the 700 mg b.i.d. dose. Five patients experienced grade 3 non-haematological toxicity, including symptoms of urothelial inflammation, hypotension and syncope, fatigue and abdominal pain. Encouraging signs of clinical activity included two bone marrow complete remissions in refractory anaemia with excess blasts type 1 patients previously treated with azacitidine. In addition, four patients each achieved transfusion independence and haematological improvements. In conclusion, oral rigosertib is bioavailable and well tolerated, and has clinical activity in patients with MDS. 23857386 Targeting of putative fimbrial gene for detection of S. Typhi in typhoid fever and chronic typhoid carriers by nested PCR. It is important to identify Salmonella Typhi infection quickly to treat acute fever patients and to prevent transmission by chronic typhoid carriers; therefore, a very specific and sensitive diagnostic technique is highly desirable, especially in endemic areas. The objective of this study was to develop a PCR protocol targeting the putative fimbrial staA gene of S. Typhi. This is a preferred target gene that is specifically amplified in the S. Typhi serotype compared to the commonly targeted fliC gene which may also be amplified from the non-typhoidal Salmonella Munchen serotype. A new nested PCR primer methodology was designed to target the staA gene, which is a member of the fimbrial gene family specific to Salmonella Typhi only. The primers were found to be very specific as the desired amplicon (377 bp) could be generated exclusively from S. Typhi strains including the reference strain (MTCC 3216) and 78 clinical isolates . Restriction digestion with HinfI confirmed the identity of the amplified DNA fragment in clinical specimens of S. Typhi origin.  Furthermore, these primers were able to detect a minimum of three colony forming units per ml (1fg) in spiked blood samples. The detection sensitivity of the described primers is comparable to that of previously published primers targeting fliC gene sequences. This study indicates that the primers targeting the putative fimbrial staA gene are very specific to the Typhi serotype and may be a better alternative to fliC targeted amplification based diagnosis. 23583259 Agonism of human pregnane X receptor by rilpivirine and etravirine: Comparison with first generation non-nucleoside reverse transcriptase inhibitors. Rilpivirine and etravirine are second generation non-nucleoside reverse transcriptase inhibitors approved recently by the United States Food and Drug Administration for the treatment of human immunodeficiency virus-1 infection. Pregnane X receptor (PXR) is a member of the superfamily of nuclear receptors that regulate the expression of various genes controlling diverse biological functions. The present study investigated the effects of rilpivirine and etravirine on the activity of human PXR (hPXR), including the mode of activation, and compared them to those of efavirenz, nevirapine, and delavirdine, which are first generation non-nucleoside reverse transcriptase inhibitors. In transiently transfected HepG2 cells, rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, activated human, mouse, and rat PXR. Results from mechanistic studies indicated that rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, bound to the ligand-binding domain of hPXR, as assessed by a transactivation assay and by a competitive ligand-binding assay using time-resolved fluorescence resonance energy transfer; triggered nuclear translocation of a green fluorescence protein-tagged hPXR, as visualized by confocal imaging; and recruited steroid receptor coactivator-1 (SRC-1), SRC-2, and SRC-3 to hPXR, as demonstrated by mammalian two-hybrid assays. Rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, increased hPXR target gene (CYP3A4) expression in primary cultures of human hepatocytes. In summary, select non-nucleoside reverse transcriptase inhibitors activated human and rodent PXR. Rilpivirine, etravirine, and efavirenz, but not nevirapine or delavirdine, were identified as agonists of hPXR, as assessed in mechanistic experiments, and inducers of CYP3A4, as determined in primary cultures of human hepatocytes. 23937523 Bacterial motility confers fitness advantage in the presence of phages. Dispersal provides the opportunity to escape harm and colonize new patches, enabling populations to expand and persist. However, the benefits of dispersal associated with escaping harm will be dependent on the structure of the environment and the likelihood of escape. Here, we empirically investigate how the spatial distribution of a parasite influences the evolution of host dispersal. Bacteriophages are a strong and common threat for bacteria in natural environments and offer a good system with which to explore parasite-mediated selection on host dispersal. We used two transposon mutants of the opportunistic bacteria, Pseudomonas aeruginosa, which varied in their motility (a disperser and a nondisperser), and the lytic bacteriophage ФKZ. The phage was distributed either in the central point of colony inoculation only, thus offering an escape route for the dispersing bacteria; or, present throughout the agar, where benefits of dispersal might be lost. Surprisingly, we found dispersal to be equally advantageous under both phage conditions relative to when phages were absent. A general explanation is that dispersal decreased the spatial structuring of host population, reducing opportunities for parasite transmission, but other more idiosyncratic mechanisms may also have contributed. This study highlights the crucial role the parasites can play on the evolution of dispersal and, more specifically, that bacteriophages, which are ubiquitous, are likely to select for bacterial motility. 23790539 Design, synthesis and biological studies of novel tubulin inhibitors. A series of compounds originally derived from the vascular endothelial growth factor receptor tyrosine kinase inhibitor, SU5416, were synthesized and evaluated. The most potent compound in this series, compound 3, which structurally resembles the potent anti-microtubule agent combretastatin A-4, inhibited tubulin polymerization and showed potent growth inhibitory activities on both prostate and breast cancer lines with IC50 values in the low nanomolar range. 23465346 Stem Cell Therapy Is a Promising Tool for Refractory Angina: A Meta-analysis of Randomized Controlled Trials. So far, relatively few studies have addressed the use of stem cells to treat patients with refractory angina. Moreover, the results of current studies were discrepant. The objective of this meta-analysis was to evaluate the efficacy and safety of this treatment on a relatively large scale. Studies were identified through PubMed, CENTRAL, EMBASE, reviews, and reference lists of relevant papers. The weighted mean difference was calculated with random-effect models for net changes in exercise tolerance and angina frequency, and odds ratio (OR) with fixed-effect models for myocardial infarction (MI) and death. Five randomized controlled trials, with a total of 381 patients, were included in the analysis. Compared with the controls, patients who received stem cell therapy had a significant improvement in exercise tolerance of 61.3 seconds (95% confidence interval [CI], 18.1-104.4; P = 0.005; I(2) = 58%); an obvious reduction in angina frequency of 7.3 episodes per week (95% CI, -13.4 to -1.2; P = 0.02; I(2) = 93%); and lower risk of MI, with an OR of 0.37 (95% CI, 0.14-0.95; P = 0.04; I(2) = 0%). No difference was detected for the risk of death (OR, 0.33; 95% CI, 0.08-1.39; P = 0.13; I(2) = 20%). Stem cell therapy appears to be effective and safe in the management of patients with refractory angina. The findings need confirmation in larger-scale studies with longer follow-up. 23666613 The effect of biomass immobilization support material and bed porosity on hydrogen production in an upflow anaerobic packed-bed bioreactor. The aim of this study was to investigate the effect of the support material used for biomass attachment and bed porosity on the potential generation of hydrogen gas in an anaerobic bioreactor treating low-strength wastewater. For this purpose, an upflow anaerobic packed-bed (UAPB) reactor fed with sucrose-based synthetic wastewater was used. Three reactors with various support materials (expanded clay, vegetal coal, and low-density polyethylene) were operated for hydraulic retention time (HRT) of 0.5 and 2 h. Based on the results obtained, three further reactors were operated with low-density polyethylene as a material support using various bed porosities (91, 75, and 50 %) for an HRT of 0.5 h. The UAPB reactor was found to be a feasible technology for hydrogen production, reaching a maximum substrate-based hydrogen yield of 7 mol H₂ mol(-1) sucrose for an HRT of 0.5 h. The type of support material used did not affect hydrogen production or the microbial population inside the reactor. Increasing the bed porosity to 91 % provided a continuous and cyclic production of hydrogen, whereas the lower bed porosities resulted in a reduced time of hydrogen production due to biomass accumulation, which resulted in a decreasing working volume. 23438830 Oncogenic MicroRNA-27a is a Target for Genistein in Ovarian Cancer Cells. MicroRNAs (miRNAs) are emerging as important regulators in various pathobiological processes in cancer. Genistein, as a major isoflavonoid isolated from dietary soybean, possesses a wide variety of biological activities particularly in cancer prevention. However, the molecular mechanisms by which genistein elicits its effects on ovarian cancer cells have not been fully elucidated. In this study, we reported that expression of miR-27a was higher in human ovarian cancer relative to benign ovarian tissues. Meanwhile, transfection of SKOV3 cells with the inhibitor of miR-27a suppressed growth and migration of tumor cells. Our study also found that treatment of ovarian cancer cells with genistein caused an inhibition of ovarian cancer cell growth and migration. Further cellular mechanistic studies revealed that genistein down-regulated miR-27a expression, which was accompanied by significantly increased expression of Sprouty2, a putative miR-27a target gene. Taken together, our findings reveal that oncogenic miR-27a plays an important role in ovarian cancer cell growth and metastasis, and genistein, as nontoxic inactivators of miRNA, can block ovarian cancer cell growth and migration, offering novel insights into the mechanisms of genistein therapeutic actions. 23857870 Paediatric and adolescent alveolar soft part sarcoma: A joint series from European cooperative groups. Alveolar soft part sarcomas (ASPS) are generally chemo- and radio-resistant mesenchymal tumours, with no standardized treatment guidelines. We describe the clinical behaviour of paediatric ASPS and compare these features to previously reported adult series. The clinical data of 51 children and adolescents with ASPS, prospectively enrolled in or treated according to seven European Paediatric trials were analysed. Median age was 13 years [range: 2-21]. Primary sites included mostly limbs (63%). IRS post-surgical staging was: IRS-I (complete resection) 35%, II (microscopic residual disease) 20%, III (gross residual disease) 18% and IV (metastases) 27%. Only 3 of the 18 evaluable patients (17%) obtained a response to conventional chemotherapy. After a median follow-up of 126 months (range: 9-240), 14/18 patients with IRS-I tumour, 10/10 IRS-II, 7/9 IRS-III and 2/14 IRS-IV were alive in remission. Sunitinib treatment achieved two very good partial responses in four patients. Ten-year overall survival (OS) and event free survival (EFS) was 78.0 ± 7% and 62.8 ± 7% respectively. Stage IV, size >5 cm and T2 tumours had a poorer outcome, but only IRS staging was an independent prognostic factor. ASPS is a very rare tumour frequently arising in adolescents and in the extremities, and chemo resistant. Local surgical control is critical. ASPS is a poorly chemo sensitive tumour. For IRS-III/IV tumours, delayed radical local therapies including surgery are essential. Metastatic patients had a poor prognosis but targeted therapies showed promising results. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc. 23896279 The global virome: not as big as we thought? Viruses likely infect all organisms, serving to unknown extent as genetic vectors in complex networks of organisms. Environmental virologists have revealed that these abundant nanoscale entities are global players with critical roles in every ecosystem investigated. Curiously, novel genes dominate viral genomes and metagenomes, which has led to the suggestion that viruses represent the largest reservoir of unexplored genetic material on Earth with literature estimates, extrapolating from 14 mycobacteriophage genomes, suggesting that two billion phage-encoded ORFs remain to be discovered. Here we examine (meta)genomic data available in the decade since this provocative assertion, and use 'protein clusters' to evaluate whether sampling technologies have advanced to the point that we may be able to sample 'all' of viral diversity in nature. 23489255 Trimetallic nitride template endohedral metallofullerenes: discovery, structural characterization, reactivity, and applications. Shortly after the discovery of the carbon fullerene allotrope, C60, researchers recognized that the hollow spheroidal shape could accommodate metal atoms, or clusters, which quickly led to the discovery of endohedral metallofullerenes (EMFs). In the past 2 decades, the unique features of EMFs have attracted broad interest in many fields, including inorganic chemistry, organic chemistry, materials chemistry, and biomedical chemistry. Some EMFs produce new metallic clusters that do not exist outside of a fullerene cage, and some other EMFs can boost the efficiency of magnetic resonance (MR) imaging 10-50-fold, in comparison with commercial contrast agents. In 1999, the Dorn laboratory discovered the trimetallic nitride template (TNT) EMFs, which consist of a trimetallic nitride cluster and a host fullerene cage. The TNT-EMFs (A3N@C2n, n = 34-55, A = Sc, Y, or lanthanides) are typically formed in relatively high yields (sometimes only exceeded by empty-cage C60 and C70, but yields may decrease with increasing TNT cluster size), and exhibit high chemical and thermal stability. In this Account, we give an overview of TNT-EMF research, starting with the discovery of these structures and then describing their synthesis and applications. First, we describe our serendipitous discovery of the first member of this class, Sc3N@Ih-C80. Second, we discuss the methodology for the synthesis of several TNT-EMFs. These results emphasize the importance of chemically adjusting plasma temperature, energy, and reactivity (CAPTEAR) to optimize the type and yield of TNT-EMFs produced. Third, we review the approaches that are used to separate and purify pristine TNT-EMF molecules from their corresponding product mixtures. Although we used high-performance liquid chromatography (HPLC) to separate TNT-EMFs in early studies, we have more recently achieved facile separation based on the reduced chemical reactivity of the TNT-EMFs. These improved production yields and separation protocols have allowed industrial researchers to scale up the production of TNT-EMFs for commercial use. Fourth, we summarize the structural features of individual members of the TNT-EMF class, including cage structures, cluster arrangement, and dynamics. Fifth, we illustrate typical functionalization reactions of the TNT-EMFs, particularly cycloadditions and radical reactions, and describe the characterization of their derivatives. Finally, we illustrate the unique magnetic and electronic properties of specific TNT-EMFs for biomedicine and molecular device applications. 23958513 Complications of Robotic Surgery in Pediatric Urology: A Single Institution Experience. To report our analysis of complications on pediatric robotic urologic procedures. A retrospective review was performed for all robotic surgeries by pediatric urologists at a single pediatric institution, from the start of the robotic surgery program in February 2009 through February 2013. Data included patient demographics, intraoperative details, outcomes, and complications (Clavien system). The analysis included 136 patients. There were 10 different types of procedures performed by 3 pediatric urologists. There were no intraoperative complications, robotic malfunctions, conversions to open or laparoscopic surgery, or mortalities. There were 11 total complications (8.1%): 2 grade I (1.5%), 7 grade II (5.1%), and 2 grade IIIb (1.5%). Complications included ileus in 2 patients (1.5%), port site infection in 2 (1.5%), urinary leak in 2 (1.5%), urinary retention in 2 (1.5%), urinary tract infection in 2 (1.5%), and stent migration in 1 (0.7%). The complication rate was in 3 of 10 infants (30%) and 8 of 126 noninfants (6.3%), P = .035. However, grade I, II, and IIIb complication rates were not significantly higher in infants vs noninfants, P = 1, .084, and .142, respectively. There was no difference in complication rates between the 3 surgeons. Pediatric robotic urologic procedures are safely performed with a relatively low complication rate and a low incidence of additional interventions owing to complications. Ongoing use of robotic technology in the pediatric population can be supported. Further reports are needed to validate our findings. 23954317 Functional and structural amygdala - Anterior cingulate connectivity correlates with attentional bias to masked fearful faces. An attentional bias to threat has been causally related to anxiety. Recent research has linked nonconscious attentional bias to threat with variability in the integrity of the amygdala - anterior cingulate pathway, which sheds light on the neuroanatomical basis for a behavioral precursor to anxiety. However, the extent to which structural variability in amygdala - anterior cingulate integrity relates to the functional connectivity within this pathway and how such functional connectivity may relate to attention bias behavior, remain critical missing pieces of the puzzle. In 15 individuals we measured the structural integrity of the amygdala - prefrontal pathway with diffusion tensor-weighted MRI (magnetic resonance imaging), amygdala-seeded intrinsic functional connectivity to the anterior cingulate, and attentional bias toward backward masked fearful faces with a dot-probe task. We found that greater biases in attention to threat predicted greater levels of uncinate fasciculus integrity, greater positive amygdala - anterior cingulate functional connectivity, and greater amygdala coupling with a broader social perception network including the superior temporal sulcus, tempoparietal junction (TPJ), and somatosensory cortex. Additionally, greater levels of uncinate fasciculus integrity correlated with greater levels of amygdala - anterior cingulate intrinsic functional connectivity. Thus, high bias individuals displayed a heightened degree of amygdala - anterior cingulate connectivity during basal conditions, which we believe predisposes these individuals to focus their attention on signals of threat within their environment. 23704229 Glutathione deficiency in gclm null mice results in complex I inhibition and dopamine depletion following paraquat administration. Depletion of glutathione has been shown to occur in autopsied brains of patients with Parkinson's disease (PD) and in animal models of PD. The goal of this study was to determine whether chronic glutathione (GSH) deficiency per se resulted in complex I inhibition and/or dopamine depletion and whether these indices were further potentiated by aging or administration of paraquat, a redox-cycling herbicide that produces a PD-like neurodegeneration model in rodents (Brooks, A. I., Chadwick, C. A., Gelbard, H. A., Cory-Slechta, D. A., and Federoff, H. J. [1999]. Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. Brain Res. 823, 1-10; McCormack, A. L., Thiruchelvam, M., Manning-Bog, A. B., Thiffault, C., Langston, J. W., Cory-Slechta, D. A., and Di Monte, D. A. [2002]. Environmental risk factors and Parkinson's disease: Selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol. Dis. 10, 119-127.) Deletion of the rate-limiting GSH synthesis gene, glutamate-cysteine ligase modifier subunit (Gclm), leads to significantly lower GSH concentrations in all tissues including brain. Gclm null (Gclm (-/-)) mice provide a model of prolonged GSH depletion to explore the relationship between GSH, complex I inhibition, and dopamine loss in vivo. Despite ~60% depletion of brain GSH in Gclm (-/-) mice of ages 3-5 or 14-16 months, striatal complex I activity, dopamine levels, 3-nitrotyroine/tyrosine ratios, aconitase activity, and CoASH remained unchanged. Administration of paraquat (10mg/kg, twice/week, 3 weeks) to 3- to 5-month-old Gclm (-/-) mice resulted in significantly decreased aconitase activity, complex I activity, and dopamine levels but not in 3- to 5-month-old Gclm (+/+) mice. Furthermore, paraquat-induced inhibition of complex I and aconitase activities in Gclm (-/-) mice was observed in the striatum but not in the cortex. The results suggest that chronic deficiency of GSH in Gclm (-/-) mice was not sufficient to result in complex I inhibition or dopamine depletion perhaps due to homeostatic mechanisms but required an additional oxidative stress insult as shown with paraquat exposure. 23937098 Increased Catecholamine Secretion from Single Adrenal Chromaffin Cells in DOCA-Salt Hypertension is Associated with Potassium Channel Dysfunction. The mechanism of catecholamine release from single adrenal chromaffin cells isolated from normotensive and DOCA-salt hypertensive rats was investigated. These cells were used as a model for sympathetic nerves to better understand how exocytotic release of catecholamines is altered in this model of hypertension. Catecholamine secretion was evoked by local application of acetylcholine (1 mM) or high K+ (70 mM), and continuous amperometry was used to monitor catecholamine secretion as an oxidative current. The total number of catecholamine molecules secreted from a vesicle, the total number of vesicles fusing and secreting, and the duration of secretion in response to a stimulus were all significantly greater for chromaffin cells from hypertensive rats as compared to normotensive controls. The greater catecholamine secretion from DOCA-salt cells results, at least in part, from functionally-impaired large conductance, Ca2+-activated (BK) and ATP-sensitive K+ channels. This work reveals that there is altered vesicular release of catecholamines from these cells and this may contribute to increased vasomotor tone in DOCA-salt hypertension. 23832207 The mannose-specific lectin domains of Flo1p from Saccharomyces cerevisiae and Lg-Flo1p from S. pastorianus: crystallization and preliminary X-ray diffraction analysis of the adhesin-carbohydrate complexes. Flo1p and Lg-Flo1p are two cell-wall adhesins belonging to the Flo (flocculation) protein family from the yeasts Saccharomyces cerevisiae and S. pastorianus. The main function of these modular proteins endowed with calcium-dependent lectin activity is to mediate cell-cell adhesion events during yeast flocculation, a process which is well known at the cellular level but still not fully characterized from a molecular perspective. Recently, structural features of the N-terminal Flo lectin domains, including the N-terminal domain of Lg-Flo1p (N-Lg-Flo1p), and their interactions with carbohydrate molecules have been investigated. However, structural data concerning the N-terminal domain of Flo1p (N-Flo1p), which is the most specific among the Flo proteins, are missing and information about the N-Lg-Flo1p-carbohydrate interaction still lacks detailed structural insight. Here, the crystallization and preliminary X-ray characterization of the apo form and the mannose complex of N-Flo1p and X-ray analysis of N-Lg-Flo1p crystals soaked in α-1,2-mannobiose are reported. The N-Flo1p crystals diffracted to a resolution of 1.43 Å in the case of the apo form and to 2.12 Å resolution for the mannose complex. Both crystals were orthorhombic and belonged to space group P212121, with one molecule in the asymmetric unit. The N-Lg-Flo1p-α-1,2-mannobiose complex crystal diffracted to 1.73 Å resolution and belonged to the monoclinic space group P1211 with two molecules in the asymmetric unit. 23906527 Favorable outcomes of patients with vasospastic angina associated with cardiac arrest. The long-term survival of vasospastic angina (VSA) patients is generally good, so long as they remain on calcium channel blockers (CCBs) and avoid smoking. However, the pathogenesis, appropriate treatments, and prognosis of VSA associated with cardiac arrest remain unclear. This study aimed to elucidate the clinical features and long-term outcomes of patients with VSA associated with cardiac arrest. Eighteen consecutive patients with VSA associated with cardiac arrest [13 patients resuscitated after out-of-hospital cardiac arrest (OHCA) and 5 resuscitated after in-hospital-cardiac arrest] were retrospectively analyzed. Sixteen of the eighteen patients were smokers. None had other cardiac diseases possibly causing cardiac arrest. Although 1 patient resuscitated after OHCA later died of cerebral hypoxia, the remaining 17 were discharged without complications. One patient died of cancer 50 months after resuscitation. The other 16 patients are still alive and none have shown ventricular arrhythmias, syncope, or cardiac arrest during a mean follow-up of 67 months. All are treated with long-acting CCBs/nitrates and successfully quit smoking. Six patients received implantable cardioverter defibrillators (ICD). However, none demonstrated any ventricular arrhythmias and appropriate ICD actuation was achieved. Appropriate medical treatment can achieve favorable long-term outcomes even for patients with VSA associated with cardiac arrest. 23876761 The combined influence of substrate elasticity and surface-grafted molecules on the ex vivo expansion of hematopoietic stem and progenitor cells. Umbilical cord blood (UCB) is an attractive source of hematopoietic stem and progenitor cells (HSPCs) for transplantation. However, the low number of HSPCs from a single UCB donor limits the direct transplantation of UCB to patients. Because little is known about the effects of the physical microenvironment on HSPC expansion, we investigated the ex vivo expansion of HSPCs cultured on biomaterials with different elasticities and grafted with different nanosegments. Polyvinylalcohol-co-itaconic acid (PVA-IA)-coated dishes with different stiffnesses ranging from a 3.7 kPa to 30.4 kPa storage modulus were used. Fibronectin or an oligopeptide (CS1, EILDVPST) was grafted onto the PVA-IA substrates. High ex vivo fold expansion of HSPCs was observed in the PVA-IA dishes grafted with fibronectin or CS1, which displayed an intermediate stiffness ranging from 12.2 kPa to 30.4 kPa. The fold expansion was more than 1.4 times higher than that cultured in tissue culture polystyrene dishes (TCPS, 12 GPa). Furthermore, HSPCs cultured in fibronectin or CS1-grafted PVA-IA-coated dishes with a stiffness of 12.2-30.4 kPa generated more pluripotent colony-forming units (CFU-GM and CFU-GEMM) than those in TCPS dishes. This result indicates that both the physical and biological properties of biomaterials affect the ex vivo expansion of HSPCs. 23533219 Increased activin bioavailability enhances hepatic insulin sensitivity while inducing hepatic steatosis in male mice. The development of insulin resistance is tightly linked to fatty liver disease and is considered a major health concern worldwide, although their mechanistic relationship remains controversial. Activin has emerging roles in nutrient homeostasis but its metabolic effects on hepatocytes remain unknown. In this study, we investigated the effects of increased endogenous activin bioactivity on hepatic nutrient homeostasis by creating mice with inactivating mutations that deplete the circulating activin antagonists, follistatin like-3 (FSTL3) or the follistatin 315 isoform (FST315; FST288-only mice). We investigated liver histology and lipid content, hepatic insulin sensitivity, and metabolic gene expression including the HepG2 cell and primary hepatocyte response to activin treatment. Both FSTL3KO and FST288-only mice had extensive hepatic steatosis and elevated hepatic triglyceride (TG) content. Unexpectedly, insulin signaling, as assessed by phospho-AKT, was enhanced in both mouse models. Pretreatment of HepG2 cells with activin A increased their response to subsequent insulin challenge. Gene expression analysis suggests that increased lipid uptake, enhanced de novo lipid synthesis, decreased lipolysis and/or enhanced glucose uptake contribute to increased hepatic TG content in these models. However, activin treatment recapitulated only some of these gene changes suggesting that increased activin bioactivity may be only partially responsible for this phenotype. Nevertheless, our results indicate that activin enhances hepatocyte insulin response which ultimately leads to hepatic steatosis despite the increased insulin sensitivity. Thus, regulation of activin bioactivity is critical for maintaining normal liver lipid homeostasis and response to insulin while activin agonists may be useful for increasing liver insulin sensitivity. 23895313 Injuries by marine and freshwater stingrays: history, clinical aspects of the envenomations and current status of a neglected problem in Brazil. Stingrays are a group of rays - cartilaginous fish related to sharks - that have whiplike tails with barbed, usually venomous spines and are found around the world, especially the marine species. Despite recent reports of accidents involving these fish, they are not aggressive, reacting only when stepped on or improperly handled. Injuries by stingrays are seldom mentioned by historians, although they have always been present in riverine communities of inland waters and in South American coasts. Indeed, envenomations by stingrays are quite common in freshwater and marine fishing communities. Although having high morbidity, such injuries are neglected because they have low lethality and usually occur in remote areas, which favor the use of folk remedies. In the present review article, historical aspects of injuries caused by stingrays in Brazil and their distribution on the coast of São Paulo state and riverine communities of the North, Midwest and Southeast regions were studied. In addition, other aspects were analyzed such as clinical features, therapeutic methods, preventive measures and trends in occurrence of these accidents in the country, particularly in areas in which freshwater stingrays had not been previously registered, being introduced after breaching of natural barriers. 23890232 Cognitive mapping: using local knowledge for planning health research. Cognitive mapping is a participatory research methodology that documents, in visual form, a construct of the local environment in which people live and work. We adapted this method to provide detailed data about study locales to inform recruitment and retention strategies for HIV prevention community based clinical trials. Four cognitive mapping studies were undertaken between 2005 and 2010, in and around Johannesburg in Orange Farm, and Hillbrow. Participants included members of clinical trial Community Advisory Boards (CAB), young people recruited from schools in Hillbrow and an organization for out of school youth, and men recruited from a database of men in the community interested in taking part in research. These groups participated in reconnaissance walks and in depth interviews, and drew detailed sketch maps. The cognitive maps defined the physical boundaries of the research locales, provided insights into their social histories, and identified important characteristics of the population such as movement, social and sexual networks, ethnic and other divisions. Important differences between the official cartographic maps and the cognitive maps were raised. The mapping data was applied by identifying key areas for recruitment that recruitment staff members were less familiar with and that may otherwise have been overlooked. Cognitive mapping is an effective, rapid and low cost method that can be used to inform recruitment and retention strategies for community-based clinical trial research. The method also provides a means for clinical trial researchers to involve the local community in research and to familiarise them with the social setting. 23942383 Evolution of Lateral Structures during the Functional Stack Build-up of P3HT:PCBM-Based Bulk Heterojunction Solar Cells. Bulk heterojunction (BHJ) solar cells from 1,2-dichlorobenzene solution processed regioregular poly(3-hexylthiophene-2,5-diyl) (P3HT): phenyl-C61-butyric acid methyl ester (PCBM) are prepared and investigated at different steps of the multilayer stack build-up of the device. The inner structure is probed from the molecular to the mesoscale with grazing incidence small/wide-angle X-ray scattering (GISAXS/GIWAXS) and X-ray reflectivity (XRR). The surface morphology is detected with atomic force microscopy (AFM). Therefore, an in-depth knowledge of the three-dimensional morphology of the bulk heterojunction solar cell, starting from the cleaned ITO substrate up to the final post-treated solar cell, is generated. The active layer structure is influenced by the annealing as well as by the top contact deposition. Structures coarsen during the evaporation of the metal contacts. The P3HT crystal structure strongly depends on the device processing as well. These morphological changes together with the diffusion of aluminum atoms to the active layer are of importance for the device efficiency. 23722106 Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar. Although previously considered entirely reversible, general anaesthesia is now being viewed as a potentially significant risk to cognitive performance at both extremes of age. A large body of preclinical as well as some retrospective clinical evidence suggest that exposure to general anaesthesia could be detrimental to cognitive development in young subjects, and might also contribute to accelerated cognitive decline in the elderly. A group of experts in anaesthetic neuropharmacology and neurotoxicity convened in Salzburg, Austria for the BJA Salzburg Seminar on Anaesthetic Neurotoxicity and Neuroplasticity. This focused workshop was sponsored by the British Journal of Anaesthesia to review and critically assess currently available evidence from animal and human studies, and to consider the direction of future research. It was concluded that mounting evidence from preclinical studies reveals general anaesthetics to be powerful modulators of neuronal development and function, which could contribute to detrimental behavioural outcomes. However, definitive clinical data remain elusive. Since general anaesthesia often cannot be avoided regardless of patient age, it is important to understand the complex mechanisms and effects involved in anaesthesia-induced neurotoxicity, and to develop strategies for avoiding or limiting potential brain injury through evidence-based approaches. 23770709 A dual-functional electrochemical biosensor for the detection of prostate specific antigen and telomerase activity. A new dual-functional electrochemical biosensor for the detection of prostate specific antigen (PSA) and telomerase activity was successfully developed based on a sandwich immunobinding format and telomerization assisted hemin-G-quadruplex-based DNAzyme as a biolabel. 23791074 The influence of age at onset and duration of illness on long-term outcome in patients with obsessive-compulsive disorder: A report from the International College of Obsessive Compulsive Spectrum Disorders (ICOCS). Several studies reported a negative effect of early onset and long duration of illness on long-term outcome in psychiatric disorders, including Obsessive-Compulsive Disorder (OCD). OCD is a prevalent, comorbid and disabling condition, associated with reduced quality of life and overall well-being for affected patients and related caregivers. The present multicenter naturalistic study sought to assess the influence of early onset and duration of illness on long-term outcome in a sample of 376 OCD out-patients worldwide, as part of the "International College of Obsessive-Compulsive Spectrum Disorders" (ICOCS) network. Binary logistic regressions were performed with age at the onset and duration of illness, as continuous independent variables, on a series of different outcome dependent variables, including lifetime number of hospitalizations and suicide attempts, poly-therapy and psychiatric comorbidity. Correlations in terms of disability (SDS) were analyzed as well. Results showed that a longer duration of illness (but not earlier age of onset) was associated with hospitalization (odds ratio=1.03, p=0.01), earlier age at onset with CBT (odds ratio=0.94, p<0.001) and both a later age at onset (odds ratio=1.05, p=0.02) and a shorter duration of illness (odds ratio=0.93, p=0.02) with panic disorder comorbidity. In addition, earlier age at onset inversely correlated with higher social disability (r=-0.12, p=0.048) and longer duration of illness directly correlated with higher disability in work, social and family life (r=0.14, p=0.017; r=0.13, p=0.035; r=0.14, p=0.02). The findings from the present large, multicenter study indicate early onset and long duration of illness as overall negative predictors of long-term outcome in OCD. 23768953 Glutathione imbalance in patients with X-linked adrenoleukodystrophy. X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder of X-linked inheritance caused by a mutation in the ABCD1 gene which determines an accumulation of long-chain fatty acids in plasma and tissues. Recent evidence shows that oxidative stress may be a hallmark in the pathogenesis of X-ALD and glutathione plays an important role in the defense against free radicals. In this study we have analyzed glutathione homeostasis in lymphocytes of 14 patients with X-ALD and evaluated the balance between oxidized and reduced forms of glutathione, in order to define the role of this crucial redox marker in this condition. Lymphocytes, plasma and erythrocytes were obtained from the whole blood of 14 subjects with X-ALD and in 30 healthy subjects. Total, reduced and protein-bound glutathione levels were measured in lymphocytes by HPLC analysis. Erythrocyte free glutathione and antioxidant enzyme activities, plasma thiols and carbonyl content were determined by spectrophotometric assays. A significant decrease of total and reduced glutathione was found in lymphocytes of patients, associated to high levels of all oxidized glutathione forms. A decline of free glutathione was particularly significant in erythrocytes. The increased oxidative stress in X-ALD was additionally confirmed by the decrease of plasma thiols and the high level of carbonyls. Our results strongly support a role for oxidative stress in the pathophysiology of X-ALD and strengthen the importance of the balance among glutathione forms as a hallmark and a potential biomarker of the disease. 23855643 Immediate placement and provisionalization of implants into sites with periradicular infection with and without antibiotics: An exploratory study. Abstract This study explored the necessity of peri-operative antibiotics on survival rates of implants immediately placed and provisionalized into sites with infection. Subjects were randomly assigned into antibiotic or placebo groups. Extraction, immediate placement and provisionalization of an implant was performed. 8 subjects received placebo, and 5 subjects received both a pre- and post-operative antibiotic regimen. One implant from each group failed. Peri-operative antibiotic therapy may not be needed in selected immediate implant therapy. 23450079 Incretin secretion stimulated by ursodeoxycholic acid in healthy subjects. Bile acids play an important role in post-prandial glucose metabolism by stimulating release of glucagon-like peptide-1 (GLP-1) via the G-protein-coupled receptor TGR5, which is expressed in intestinal L cells. Thus, bile acid sequestrants are expected to stimulate secretion of endogenous GLP-1 through TGR5. We investigated incretin and insulin secretion after a meal with and without ursodeoxycholic acid (UDCA), a widely used therapeutic agent in liver diseases, in 7 non-diabetic Japanese subjects. We found that UDCA intake resulted in higher GLP-1 secretion (area under the curve [AUC] of 0-60 min after meal without UDCA, 450 ± 162 mmol·min/l; with UDCA, 649 ± 232 mmol·min/l, P = 0.046) and lower blood glucose (AUC of 0-60 min without UDCA, 7191 ± 250 mg·min/dl; with UDCA, 6716 ± 189 mg·min/dl, P = 0.001) , although we did not find statistically significant insulin increase by UDCA intake (AUC of 0-60 min without UDCA, 1551 ± 418 μU·min/ml; with UDCA, 1941 ± 246 μU·min/ml, P = 0.065). These results suggest that UDCA increases bile-induced GLP-1 secretion. Ours is the first report showing increased GLP-1 secretion and decreased blood glucose in response to UDCA. 23215648 Reduced secretion of the inflammatory cytokine IL-1β by stimulated peritoneal macrophages of radiosensitive Balb/c mice after exposure to 0.5 or 0.7Gy of ionizing radiation. Since the beginning of the 20th century, low dose radiotherapy (LD-RT) has been practiced and established as therapy of inflammatory diseases. Several clinical studies already have proven the anti-inflammatory effect of low doses of ionizing irradiation (LDR). However, further research is inevitable to reveal the underlying immune-biological mechanisms. Focus has been set on the modulation of activated macrophages by LDR, since they participate in both, initiation and resolution of inflammation. Here we examined with an ex vivo peritoneal mouse macrophage model how LDR modulates the secretion of the inflammatory cytokines IL-1β and TNF-α by activated macrophages and whether the basal radiosensitivity of the immune cells has influence on it. Peritoneal macrophages of Balb/c mice responded to exposure of 0.5 or 0.7 Gy of ionizing irradiation (X-ray) with significant decreased release of IL-1β and slightly, but not significantly, reduced release of TNF-α. Macrophages of the less radiosensitive C57BL/6 mice did not show this anti-inflammatory reaction. This was observed in both wild type and human TNF-α transgenic animals with C57BL/6 background. We conclude that only the inflammatory phenotype of more radiosensitive macrophages is reduced by LDR and that ex vivo and in vivo models with primary cells should be applied to examine how the immune system is modulated by LDR. 23560466 Pressure modulation of ras-membrane interactions and intervesicle transfer. Proteins attached to the plasma membrane frequently encounter mechanical stresses, including high hydrostatic pressure (HHP) stress. Signaling pathways involving membrane-associated small GTPases (e.g., Ras) have been identified as critical loci for pressure perturbation. However, the impact of mechanical stimuli on biological outputs is still largely terra incognita. The present study explores the effect of HHP on the membrane association, dissociation, and intervesicle transfer process of N-Ras by using a FRET-based assay to obtain the kinetic parameters and volumetric properties along the reaction path of these processes. Notably, membrane association is fostered upon pressurization. Conversely, depending on the nature and lateral organization of the lipid membrane, acceleration or retardation is observed for the dissociation step. In addition, HHP can be inferred as a positive regulator of N-Ras clustering, in particular in heterogeneous membranes. The susceptibility of membrane interaction to pressure raises the idea of a role of lipidated signaling molecules as mechanosensors, transducing mechanical stimuli to chemical signals by regulating their membrane binding and dissociation. Finally, our results provide first insights into the influence of pressure on membrane-associated Ras-controlled signaling events in organisms living under extreme environmental conditions such as those that are encountered in the deep sea and sub-seafloor environments, where pressures reach the kilobar (100 MPa) range. 23583304 Curcumin affects proprotein convertase activity: elucidation of the molecular and subcellular mechanism. Proprotein convertases (PCs) form a group of serine endoproteases that are essential for the activation of proproteins into their active form. Some PCs have been proposed to be potential therapeutic targets for cancer intervention because elevated PC activity has been observed in many different cancer types and because many of the PC substrates, such as pro-IGF-1R, pro-TGF-beta, pro-VEGF, are involved in signaling pathways related to tumor development. Curcumin, reported to possess anticancer activity, also affects many of these pathways. We therefore investigated the effect of curcumin on PC activity. Our results show that curcumin inhibits PC activity in a cell lysate-based assay but not in vitro. PC zymogen maturation in the endoplasmic reticulum appears to be inhibited by curcumin. Treating cells with thapsigargin or cyclopiazonic acid, two structurally unrelated inhibitors of the sarco- and endoplasmic reticulum Ca(2+)ATPase (SERCA), also hampered both the PC zymogen maturation and the PC activity. Importantly, curcumin, like the SERCA inhibitors, impaired ATP-driven (45)Ca(2+) uptake in the endoplasmic reticulum. These results indicate that curcumin likely restrains PC activity by inhibiting SERCA-mediated Ca(2+)-uptake activity. Experiments in three colon cancer cell lines confirm that curcumin inhibits both the (45)Ca(2+) uptake and PC activity, notably the processing of pro-IGF-1R. Both curcumin and thapsigargin inhibit the anchorage-independent growth of these three colon carcinoma cell lines. In conclusion, our findings indicate that curcumin inhibits PC zymogen maturation and consequently PC activity and that its inhibitory effect on Ca(2+) uptake into the ER allows and is sufficient to explain this phenomenon. 23720381 Accuracy and tractability of a kriging model of intramolecular polarizable multipolar electrostatics and its application to histidine. We propose a generic method to model polarization in the context of high-rank multipolar electrostatics. This method involves the machine learning technique kriging, here used to capture the response of an atomic multipole moment of a given atom to a change in the positions of the atoms surrounding this atom. The atoms are malleable boxes with sharp boundaries, they do not overlap and exhaust space. The method is applied to histidine where it is able to predict atomic multipole moments (up to hexadecapole) for unseen configurations, after training on 600 geometries distorted using normal modes of each of its 24 local energy minima at B3LYP/apc-1 level. The quality of the predictions is assessed by calculating the Coulomb energy between an atom for which the moments have been predicted and the surrounding atoms (having exact moments). Only interactions between atoms separated by three or more bonds ("1, 4 and higher" interactions) are included in this energy error. This energy is compared with that of a central atom with exact multipole moments interacting with the same environment. The resulting energy discrepancies are summed for 328 atom-atom interactions, for each of the 29 atoms of histidine being a central atom in turn. For 80% of the 539 test configurations (outside the training set), this summed energy deviates by less than 1 kcal mol(-1). 23665504 Initiated chemical vapor deposition of thermoresponsive poly(N-vinylcaprolactam) thin films for cell sheet engineering. Poly(N-vinylcaprolactam) (PNVCL) is a thermoresponsive polymer known to be nontoxic, water soluble and biocompatible. Here, PNVCL homopolymer was successfully synthesized for the first time by use of a one-step vapor-phase process, termed initiated chemical vapor deposition (iCVD). Fourier transform infrared spectroscopy results showed that radical polymerization took place from N-vinylcaprolactam monomers without damaging the functional caprolactam ring. A sharp lower critical solution temperature transition was observed at 31°C from the iCVD poly(N-vinylcaprolactam) (PNVCL) film. The thermoresponsive PNVCL surface exhibited a hydrophilic/hydrophobic alteration with external temperature change, which enabled the thermally modulated attachment and detachment of cells. The conformal coverage of PNVCL film on various substrates with complex topography, including fabrics and nanopatterns, was successfully demonstrated, which can further be utilized to fabricate cell sheets with aligned cell morphology. The advantage of this system is that cells cultured on such thermoresponsive surfaces could be recovered as an intact cell sheet by simply lowering the temperature, eliminating the need for conventional enzymatic treatments. 23937709 The Vertebrate Trait Ontology: a controlled vocabulary for the annotation of trait data across species. The use of ontologies to standardize biological data and facilitate comparisons among datasets has steadily grown as the complexity and amount of available data have increased. Despite the numerous ontologies available, one area currently lacking a robust ontology is the description of vertebrate traits. A trait is defined as any measurable or observable characteristic pertaining to an organism or any of its substructures. While there are several ontologies to describe entities and processes in phenotypes, diseases, and clinical measurements, one has not been developed for vertebrate traits; the Vertebrate Trait Ontology (VT) was created to fill this void.Description: Significant inconsistencies in trait nomenclature exist in the literature, and additional difficulties arise when trait data are compared across species. The VT is a unified trait vocabulary created to aid in the transfer of data within and between species and to facilitate investigation of the genetic basis of traits. Trait information provides a valuable link between the measurements that are used to assess the trait, the phenotypes related to the traits, and the diseases associated with one or more phenotypes. Because multiple clinical and morphological measurements are often used to assess a single trait, and a single measurement can be used to assess multiple physiological processes, providing investigators with standardized annotations for trait data will allow them to investigate connections among these data types. The annotation of genomic data with ontology terms provides unique opportunities for data mining and analysis. Links between data in disparate databases can be identified and explored, a strategy that is particularly useful for cross-species comparisons or in situations involving inconsistent terminology. The VT provides a common basis for the description of traits in multiple vertebrate species. It is being used in the Rat Genome Database and Animal QTL Database for annotation of QTL data for rat, cattle, chicken, swine, sheep, and rainbow trout, and in the Mouse Phenome Database to annotate strain characterization data. In these databases, data are also cross-referenced to applicable terms from other ontologies, providing additional avenues for data mining and analysis. The ontology is available at http://bioportal.bioontology.org/ontologies/50138. 23863873 Enzyme-catalyzed synthesis of heptyl-β-glycosides: Effect of water coalescence at high temperature. Alkyl glycosides can be synthesized by glycosidases in organic media with limited amounts of water. These systems, however, limit the solubility of the sugar substrates and decrease reaction yields. Herein we report the enzymatic synthesis of heptyl-β-glycosides in heptanol catalyzed by a hyperthermophilic β-glycosidase at 90°C. Our results indicate that dispersion of water in heptanol changes with time producing coalescence of water at the bottom of the reactor, playing a key role in the reaction yield. Water-soluble substrate, enzyme and products are concentrated in the aqueous phase, according to their partition coefficients, promoting side reactions that inactivate the enzyme. Reaction yield of heptyl-β-glycosides was 35% relative to lactose, at 7% water. The increase in the water phase to 12% diminished the enzyme inactivation and increased the heptyl-β-glycosides yield to 52%. Surface-active compounds, SDS and octyl glucoside, increased water dispersion but were unable to prevent coalescence. 23962441 Public-private interactions on health in South Africa: opportunities for scaling up. South Africa has long recognized partnerships between the public and private sectors as a policy objective in health, but experience is still limited and poorly documented. The objectives of this article are to understand the factors that increase the likelihood of success of public-private interactions in South Africa, and identify and discuss opportunities for them to be scaled up. There is a strong legislative framework and a number of guidelines and tools that have been developed by the Treasury for managing partnerships. The review of literature confirmed the need for the state to have effective regulations in order to oversee quality and standards and to provide stewardship and oversight. The public sector requires sufficient capacity not only to manage relationships with the private sector but also to enable innovation and experimentation. Evaluation is an integral part of all interactions not only to learn from successes but also to identify any perverse incentives that may lead to unintended consequences. Four case studies show that the private for-profit sector is already engaged in a number of projects that are closely aligned to current health system reform priorities. Factors that increase the likelihood of interactions being successful include: increasing the government's capacity to manage public-private relationships; choosing public-private interactions that are strategically important to national goals; building a knowledge base on what works, where and why; moving from pilots to large scale initiatives; harnessing the contracting expertise in private providers; and encouraging innovation and learning. 23790294 Determination of acetaldehyde in saliva by gas-diffusion flow injection analysis. The consumption of ethanol is known to increase the likelihood of oral cancer. In addition, there has been a growing concern about possible association between long term use of ethanol-containing mouthwashes and oral cancer. Acetaldehyde, known to be a carcinogen, is the first metabolite of ethanol and it can be produced in the oral cavity after consumption or exposure to ethanol. This paper reports on the development of a gas-diffusion flow injection method for the online determination of salivary acetaldehyde by its colour reaction with 3-methyl-2-benzothiazolinone hydrazone (MBTH) and ferric chloride. Acetaldehyde samples and standards (80 μL) were injected into the donor stream containing NaCl from which acetaldehyde diffused through the hydrophobic Teflon membrane of the gas-diffusion cell into the acceptor stream containing the two reagents mentioned above. The resultant intense green coloured dye was monitored spectrophotometrically at 600 nm. Under the optimum working conditions the method is characterized by a sampling rate of 9h(-1), a linear calibration range of 0.5-15 mg L(-1) (absorbance=5.40×10(-2) [acetaldehyde, mg L(-1)], R(2)=0.998), a relative standard deviation (RSD) of 1.90% (n=10, acetaldehyde concentration of 2.5 mg L(-1)), and a limit of detection (LOD) of 12.3 μg L(-1). The LOD and sampling rate of the proposed method are superior to those of the conventional gas chromatographic (GC) method (LOD=93.0 μg L(-1) and sampling rate=4 h(-1)). The reliability of the proposed method was illustrated by the fact that spiked with acetaldehyde saliva samples yielded excellent recoveries (96.6-101.9%), comparable to those obtained by GC (96.4-102.3%) and there was no statistically significant difference at the 95% confidence level between the two methods when non-spiked saliva samples were analysed. 23906117 Assessing health system performance: A model-based approach. It is difficult to assess countries' relative success in addressing issues of public health because countries are subject to very different background conditions. To address this problem we offer a model-based approach for assessing health system performance. Specifically, an index of public health is regressed against a vector of variables intended to capture economic, educational, cultural, geographic, and epidemiological endowments. The residual from this model is regarded as a plausible measure of public health performance at the national level. We argue that a model-based approach to performance is informative for policymakers and academics as it focuses attention on those aspects of a country's health profile that are not constrained by structural factors. This sharpens comparisons across countries and through time, and also allows one to evaluate the degree to which health systems have lived up to their potential. 23643740 Medicines Combinations Options and Regulatory Hurdles. The number of fixed dose combinations (FDC) on the market is increasing. However, both regulatory guidelines and the evidence for better effectiveness of fixed dose combinations are not established yet. These aspects were the topic for a recent EUFEPS workshop in Copenhagen. The discussion confirms the presence of hurdles and recommendations to further progress and alleviate the problems. The general conclusion was: Refinement of general systems pharmacology tools for identification of key molecular targets in disease development; Precompetitive methodologies and technologies designed for (co-) development of FDCs; Simulation and modeling algorithms applied on pharmacodynamics (synergy), pharmacokinetics and safety; New formulations of FDCs of solid, liquid or inhalation forms; Prospective clinical studies for measuring the efficacy and effectiveness of use of drug-drug combinations in elderly. 23925322 Imaging modalities in keratoconus. Diagnosis of keratoconus has greatly improved from simple clinical diagnosis with the advent of better diagnostic devices like corneal topographers based on placido disc, elevation based topographers and lately optical coherence tomography (OCT). These instruments are quite sensitive to pick up early keratoconus, which could help refractive surgeons to avoid serious complications like ectasia following keratorefractive surgeries. Each of these instruments has their advantages and disadvantages; in spite of that each one of them has its own place in the clinical practice. Currently, placido disc based topographers are the most commonly used topographers all over the world. There are many different companies making such devices, which follow the different techniques and color for the display. Due to these differences they are not directly comparable to each other. Various quantitative indices based on these topographers have been suggested and validated by different authors to aid in the diagnosis and quantification of keratoconus. OCT with its higher resolution and deeper penetration has created its place in the diagnostic armamentarium for keratoconus. 23701531 Physiological regulation of magnocellular neurosecretory cell activity: integration of intrinsic, local and afferent mechanisms. The hypothalamic supraoptic and paraventricular nuclei contain magnocellular neurosecretory cells (MNCs) that project to the posterior pituitary gland where they secrete either oxytocin or vasopressin (the antidiuretic hormone) into the circulation. Oxytocin is important for delivery at birth and is essential for milk ejection during suckling. Vasopressin primarily promotes water reabsorption in the kidney to maintain body fluid balance, but also increases vasoconstriction. The profile of oxytocin and vasopressin secretion is principally determined by the pattern of action potentials initiated at the cell bodies. Although it has long been known that the activity of MNCs depends upon afferent inputs that relay information on reproductive, osmotic and cardiovascular status, it has recently become clear that activity depends critically on local regulation by glial cells, as well as intrinsic regulation by the MNCs themselves. Here, we provide an overview of recent advances in our understanding of how intrinsic and local extrinsic mechanisms integrate with afferent inputs to generate appropriate physiological regulation of oxytocin and vasopressin MNC activity. 23927131 Simulating the effect of interaural mismatch in the insertion depth of bilateral cochlear implants on speech perception. A bilateral advantage for diotically presented stimuli has been observed for cochlear implant (CI) users and is suggested to be dependent on symmetrical implant performance. Studies using CI simulations have not shown a true "bilateral" advantage, but a "better ear" effect and have demonstrated that performance decreases with increasing basalward shift in insertion depth. This study aimed to determine whether there is a bilateral advantage for CI simulations with interaurally matched insertions and the extent to which performance is affected by interaural insertion depth mismatch. Speech perception in noise and self-reported ease of listening were measured using matched bilateral, mismatched bilateral and unilateral CI simulations over four insertion depths for seventeen normal hearing listeners. Speech scores and ease of listening reduced with increasing basalward shift in (interaurally matched) insertion depth. A bilateral advantage for speech perception was only observed when the insertion depths were interaurally matched and deep. No advantage was observed for small to moderate interaural insertion-depth mismatches, consistent with a better ear effect. Finally, both measures were poorer than expected for a better ear effect for large mismatches, suggesting that misalignment of the electrode arrays may prevent a bilateral advantage and detrimentally affect perception of diotically presented speech. 23844597 Cyto/Genotoxicity study of polyoxyethylene (20) sorbitan monolaurate (tween 20). Polyoxyethylene (20) sorbitan monolaurate (tween 20) is a non-ionic surfactant that is widely used as an emulsifier and stabilizer in pharmaceutical formulations, food and cosmetic industries. Although a number of studies have showed its non-toxic impacts on target cells, still, it is essential to investigate its effect on target cells. Therefore, in the present study, the anti-cell proliferation and cyto/genotoxicity effects of tween 20 are reported to address the possible mechanism for induction of apoptosis. At 40%-50% confluency, A549 cells and human umbilical vein endothelial cells were exposed to tween 20 at a recommended concentration for 24 h. After 24 h, to detect apoptosis and DNA damage, the treated cells were subjected to 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, fluorescein isothiocyanate (FITC)-labeled annexin V flow cytometry, DAPI staining, comet, and DNA ladder assays. Tween 20 decreased the growth of treated cells dose and time dependently, and single-strand DNA cleavage has been confirmed by comet assay. In addition, morphological alteration of DAPI-stained cells showed clear fragmentation in the chromatin and DNA rings within the nucleus of tween 20-treated cells. In addition, flow cytometry and DNA fragmentation assays confirmed DAPI staining assay results and indicated the occurrence of a programmed cell death (apoptosis) in the treated cells. These results demonstrate that, despite consideration of tween 20 as a safe non-ionic surfactant, it can induce apoptosis in target cells. 23855926 Adult patients with schizophrenia using violence towards their parents: a phenomenological study of views and experiences of violence in parent-child dyads. To describe the lived experiences of aggression and violence among patients with schizophrenia and their victimized biological parent as the major caregiver being aggressed by their child (parent-adult-child dyads), and to gain an understanding of the precipitating factors influencing violence. Child-to-parent violence, particularly in the mentally ill adult child, is arguably the most stressful and under-researched issue of family violence. Violence in patients with mental illness is most frequently targeted at family members, and most often takes place at home. Both patients and their parents' experiences of violence are relatively unexplored. Qualitative study design. Data were collected using individual in-depth interviews between August 2010-August 2011 in Taiwan. Purposive sample of 14 hospitalized patients with schizophrenia who had aggression and violence in the past year directed towards their biological parent of either gender. Five main themes were identified: violence occurring beyond control in a particular situation translated into parent and patient's possible endangerment, the repetitive nature of violence, distress, ineffective communication, and management of violence and help-seeking. Repetitive violent episodes and tension made both the parent and patient feel uncontrollable. Parents had a perceived fear of adverse consequences such as being punished by receiving more retribution and they also had concerns related to their parental responsibility. Health professionals should be aware of the complexity of phenomena and the interplay of factors inducing violence. A comprehensive dyadic parent-child intervention is suggested for violence prevention. 23565728 Vibrational configuration interaction using a tiered multimode scheme and tests of approximate treatments of vibrational angular momentum coupling: a case study for methane. We present vibrational configuration interaction calculations employing the Watson Hamiltonian and a multimode expansion. Results for the lowest 36 eigenvalues of the zero total angular momentum rovibrational spectrum of methane agree with the accurate benchmarks of Wang and Carrington to within a mean unsigned deviation of 0.68, 0.033, and 0.014 cm(-1) for 4-mode, 5-mode, and 6-mode representations, respectively. We note that in the case of the 5-mode results, this is a factor of 10 better agreement than for 5-mode calculations reported earlier by Wu, Huang, Carter, and Bowman for the same set of eigenvalues, which indicates that the multimode expansion is even more rapidly convergent than previously demonstrated. Our largest calculations employ a tiered approach with matrix elements treated using a variable-order multimode expansion with orders ranging from 4-mode to 7-mode; strategies for assigning matrix elements to particular multimode tiers are discussed. Improvements of 7-mode coupling over 6-mode coupling are small (averaging 0.002 cm(-1) for the first 36 eigenvalues) suggesting that 7-mode coupling is sufficient to fully converge the results. A number of approximate treatments of the computationally expensive vibrational angular momentum terms are explored. The use of optimized vibrational quadratures allows rapid integration of the matrix elements, especially the vibrational angular momentum terms, which require significantly fewer quadrature points than are required to integrate the potential. We assign the lowest 243 states and compare our results to those of Wang and Carrington, who provided assignments for the same set of states. Excellent agreement is observed for most states, but our results are lower for some of the higher-energy states by as much as 20 cm(-1), with the largest deviations being for the states with six quanta of excitation in the F2 bends, suggesting that the earlier results were not fully converged with respect to the basis set. We also provide corrections to several of the state assignments published previously. 23387501 Nevirapine bioactivation and covalent binding in the skin. Nevirapine (NVP) treatment is associated with serious skin rashes that appear to be immune-mediated. We previously developed a rat model of this skin rash that is immune-mediated and is very similar to the rash in humans. Treatment of rats with the major NVP metabolite, 12-OH-NVP, also caused the rash. Most idiosyncratic drug reactions are caused by reactive metabolites; 12-OH-NVP forms a benzylic sulfate, which was detected in the blood of animals treated with NVP or 12-OH-NVP. This sulfate is presumably formed in the liver; however, the skin also has significant sulfotransferase activity. In this study, we used a serum against NVP to detect covalent binding in the skin of rats. There was a large artifact band in immunoblots of whole skin homogenates that interfered with detection of covalent binding; however, when the skin was separated into dermal and epidermal fractions, covalent binding was clearly present in the epidermis, which is also the location of sulfotransferases. In contrast to rats, treatment of mice with NVP did not result in covalent binding in the skin or skin rash. Although the reaction of 12-OH-NVP sulfate with nucleophiles such as glutathione is slow, incubation of this sulfate with homogenized human and rat skin led to extensive covalent binding. Incubations of 12-OH-NVP with the soluble fraction from a 9,000g centrifugation (S9) of rat or human skin homogenate in the presence of 3'-phosphoadenosine-5'-phosphosulfate (PAPS) produced extensive covalent binding, but no covalent binding was detected with mouse skin S9, which suggests that the reason mice do not develop a rash is that they lack the required sulfotransferase. This is the first study to report covalent binding of NVP to rat and human skin. These data provide strong evidence that covalent binding of NVP in the skin is due to 12-OH-NVP sulfate, which is likely responsible for NVP-induced skin rash. Sulfation may represent a bioactivation pathway for other drugs that cause a skin rash. 23964355 Temperature- and flow-enhanced detection specificity of mutated DNA against the wild type with reporter microspheres. Detection of mutated (MT) deoxyribonucleic acid (DNA) amongst the wild type (WT) requires the probe DNA (pDNA) that is complementary to the MT to discriminate the WT by one or two nucleotide mismatches. Traditionally this is achieved by raising the temperature to above the melting temperature (Tm) of the WT (TWT) but below that of the MT (TMT). However, a raised temperature is also accompanied by a weakened binding of the MT to the pDNA which can reduce the detection sensitivity. In this study, we investigated flow as a way to enhance MT detection specificity at a lower temperature. Gold-coated glass (GCG) slides immobilized with pDNA complementary to the target MT were placed at the center of the flow cell. The detection was done by flowing MT or WT at various concentrations followed by flowing 10(5) ml(-1) fluorescent reporter microspheres (FRMs) that were 6 μm in size and coated with reporter DNA complementary to the MT or WT but different from the pDNA at various flow rates and temperatures. The detection of MT or WT was characterized by counting the FRMs captured on the GCG. Hepatitis B virus 1762/1764 double mutation (HBV DM) was the model MT and the TMT and TWT were 47 °C and 22 °C, respectively. It was shown that at room temperature, flow initially increased the binding of both the MT and WT at lower flow rates but decreased the binding at flow rates ≥4 ml min(-1) due to the increase in the flow-induced impingement force on the FRMs to overcome the binding of the MT and the WT to the GCG at higher flow rates. At ≥30 °C the decrease in binding of the WT with an increasing flow rate was more than that of the MT because 30 °C was above the TWT but still well below the TMT. As a result, the detection of MT at 30 °C with a flow rate of 4 ml min(-1) was more specific than at 35 °C without flow. These results indicate that flow can diminish WT binding at a lower temperature than without flow and allow MT detection to occur at a lower temperature with high specificity. 23836125 Disease-based mortality after percutaneous endoscopic gastrostomy: utility of the enterprise data warehouse. Percutaneous endoscopic gastrostomy (PEG) remains a mainstay of enteral access. Thirty-day mortality for PEG has ranged from 16 to 43 %. This study aims to discern patient groups that demonstrate limited survival after PEG placement. The Enterprise Data Warehouse (EDW) concept allows an efficient means of integrating administrative, clinical, and quality-of-life data. On the basis of this concept, we developed the Vanderbilt Procedural Outcomes Database (VPOD) and analyzed these data for evaluation of post-PEG mortality over time. Patients were identified using the VPOD from 2008 to 2010 and followed for 1 year after the procedure. Patients were categorized according to common clinical groups for PEG placement: stroke/CNS tumors, neuromuscular disorders, head and neck cancers, other malignancies, trauma, cerebral palsy, gastroparesis, or other indications for PEG. All-cause mortality at 30, 60, 90, 180, and 360 days was determined by linking VPOD information with the Social Security Death Index. Chi-square analysis was used to determine significance across groups. Nine hundred fifty-three patients underwent PEG placement during the study period. Mortality over time (30-, 60-, 90-, 180-, and 360-day mortality) was greatest for patients with malignancies other than head and neck cancer (29, 45, 57, 66, and 72 %) and least for cerebral palsy or patients with gastroparesis (7 % at all time points). Patients with neuromuscular disorders had a similar mortality curve as head and neck cancer patients. Stroke/CNS tumor patients and patients with other indications had the second highest mortality, while trauma patients had low mortality. PEG mortality was much higher in patients with malignancies other than head and neck cancer compared to previously published rates. PEG should be used with great caution in this and other high-risk patient groups. This study demonstrates the power of an EDW-based database to evaluate large numbers of patients with clinically meaningful results. 23829516 Maple Syrup Urine Disease (MSUD): A Case with Long-Term Follow-up after Liver Transplantation. Maple syrup urine disease (MSUD) is a rare hereditary metabolic condition where the body is unable to breakdown amino acids causing toxic buildup. Acute and long-term management of MSUD involves a restricted diet and regular monitoring of amino acid levels; however, more recently liver transplants have been shown to be successful in treating this condition. Even with successful management of MSUD there is evidence from pediatric cases that shows a distinct pattern of neurocognitive deficits associated with this condition, including impaired nonverbal skills and psychomotor functioning with relatively intact verbal abilities. In the present paper, we report an adult case of MSUD with associated neurocognitive deficits and functional limitations following liver transplantation. Neuroimaging revealed no structural abnormalities, while the results from the neuropsychological evaluation showed impairment in visual-spatial processing, attention, executive functioning, and psychomotor abilities, with relative strengths in verbal skills. The patient also showed reduced adaptive functioning and mild anxiety. This case demonstrates neurocognitive deficiencies within the context of normal magnetic resonance imaging. The possible underlying mechanism of this neuropsychological profile is discussed in relation to other neurodevelopmental models. 23870612 Quetiapine Fumarate for the Treatment of Multiple Sclerosis: Focus on Myelin Repair. Multiple sclerosis (MS) is a central nervous system disorder that is associated with progressive oligodendrocyte and neuronal loss, axonal degeneration, and demyelination. Several medications that mitigate immune abnormalities reduce both the frequency of relapses and inflammation on magnetic resonance imaging, leading to improved outcomes for people with the relapsing-remitting form of MS. However, there are no treatments for the progressive forms of MS where neurons and axons continue to degenerate; here, neuroprotective therapies, or medications that rebuild myelin to confer axonal well-being, may be useful. Quetiapine fumarate is an atypical antipsychotic with reported remyelinating and neuroprotective properties in inflammatory and noninflammatory models of demyelination, including experimental autoimmune encephalomyelitis, and both cuprizone- and global cerebral ischemia-induced demyelination. Preclinical studies suggest that quetiapine may exert these effects by stimulating proliferation and maturation of oligodendrocytes, releasing neurotrophic factors, increasing antioxidant defences, scavenging for free radicals, and inhibiting activated microglia, astrocytes, and T lymphocytes. Additionally, quetiapine may be beneficial for psychiatric and nonpsychiatric symptoms of MS including depression, anxiety, insomnia, and possibly even pain. These data indicate that clinical trials are justified to determine the safety, tolerability, and efficacy of quetiapine fumarate in MS. 23859671 Asymmetric effect of oxygen adsorption on electron and hole mobilities in bilayer graphene: long- and short-range scattering mechanisms. We probe electron and hole mobilities in bilayer graphene under exposure to molecular oxygen. We find that the adsorbed oxygen reduces electron mobilities and increases hole mobilities in a reversible and activated process. Our experimental results indicate that hole mobilities increase due to the screening of long-range scatterers by oxygen molecules trapped between the graphene and the substrate. First principle calculations show that oxygen molecules induce resonant states close to the charge neutrality point. Electron coupling with such resonant states reduces the electron mobilities, causing a strong asymmetry between electron and hole transport. Our work demonstrates the importance of short-range scattering due to adsorbed species in the electronic transport in bilayer graphene on SiO2 substrates. 23869992 Formin-mediated actin polymerization promotes Salmonella invasion. Salmonella invade host cells using Type 3 secreted effectors, which modulate host cellular targets to promote actin rearrangements at the cell surface that drive bacterial uptake. The Arp2/3 complex contributes to Salmonella invasion but is not essential, indicating other actin regulatory factors are involved. Here, we show a novel role for FHOD1, a formin family member, in Salmonella invasion. FHOD1 and Arp2/3 occupy distinct microdomains at the invasion site and control distinct aspects of membrane protrusion formation. FHOD1 is phosphorylated during infection and this modification is required for promoting bacterial uptake by host cells. ROCK II, but not ROCK I, is recruited to the invasion site and is required for FHOD1 phosphorylation and for Salmonella invasion. Together, our studies revealan important phospho-dependent FHOD1 actin polymerization pathway in Salmonella invasion. 23912223 Optimized dynamic framing for PET-based myocardial blood flow estimation. An optimal experiment design methodology was developed to select the framing schedule to be used in dynamic positron emission tomography (PET) for estimation of myocardial blood flow using (82)Rb. A compartment model and an arterial input function based on measured data were used to calculate a D-optimality criterion for a wide range of candidate framing schedules. To validate the optimality calculation, noisy time-activity curves were simulated, from which parameter values were estimated using an efficient and robust decomposition of the estimation problem. D-optimized schedules improved estimate precision compared to non-optimized schedules, including previously published schedules. To assess robustness, a range of physiologic conditions were simulated. Schedules that were optimal for one condition were nearly-optimal for others. The effect of infusion duration was investigated. Optimality was better for shorter than for longer tracer infusion durations, with the optimal schedule for the shortest infusion duration being nearly optimal for other durations. Together this suggests that a framing schedule optimized for one set of conditions will also work well for others and it is not necessary to use different schedules for different infusion durations or for rest and stress studies. The method for optimizing schedules is general and could be applied in other dynamic PET imaging studies. 23929687 Olfactory training is helpful in postinfectious olfactory loss - a randomized controlled multicenter study. The aim of this study was to evaluate the effects of olfactory training (OT) on olfactory function in patients with persistent post-infectious olfactory dysfunction (PIOD). Randomized, single-blind, controlled multicenter cross-over study. 1b SETTING: Twelve tertiary University medical centers participated. Investigations were performed at three visits (baseline; after 18 and 36 weeks), including only subjects with PIOD of less than 24 months duration. At each visit, participants received detailled assessment of olfactory function. Seventy subjects trained with high concentrations of 4 odors for 18 weeks, the other half (n=74) trained with low concentrations of odors; for the following 18 weeks this regimen was switched. After 18 weeks olfactory function improved in the high-training-group in 18 of 70 participants (26%), whereas only 11/74 improved in the low-training group (15%). In subjects with a duration of olfactory dysfunction of less than 12 months olfactory function improved in 15/24 (63%) of the high-training-group and in 6/31 participants (19%) of the low-training-group (p=0.03). OT improves PIOD; use of odors at higher concentrations is beneficial to that. OT is a safe procedure; it seems particularly useful in patients who start OT within 12 months after onset of the disorder. OT is the first successful therapy regime in patients with PIOD. Laryngoscope, 2013. 23936458 Distinct Mechanisms for Induction and Tolerance Regulate the Immediate Early Genes Encoding Interleukin 1β and Tumor Necrosis Factor α. Interleukin-1β and Tumor Necrosis Factor α play related, but distinct, roles in immunity and disease. Our study revealed major mechanistic distinctions in the Toll-like receptor (TLR) signaling-dependent induction for the rapidly expressed genes (IL1B and TNF) coding for these two cytokines. Prior to induction, TNF exhibited pre-bound TATA Binding Protein (TBP) and paused RNA Polymerase II (Pol II), hallmarks of poised immediate-early (IE) genes. In contrast, unstimulated IL1B displayed very low levels of both TBP and paused Pol II, requiring the lineage-specific Spi-1/PU.1 (Spi1) transcription factor as an anchor for induction-dependent interaction with two TLR-activated transcription factors, C/EBPβ and NF-κB. Activation and DNA binding of these two pre-expressed factors resulted in de novo recruitment of TBP and Pol II to IL1B in concert with a permissive state for elongation mediated by the recruitment of elongation factor P-TEFb. This Spi1-dependent mechanism for IL1B transcription, which is unique for a rapidly-induced/poised IE gene, was more dependent upon P-TEFb than was the case for the TNF gene. Furthermore, the dependence on phosphoinositide 3-kinase for P-TEFb recruitment to IL1B paralleled a greater sensitivity to the metabolic state of the cell and a lower sensitivity to the phenomenon of endotoxin tolerance than was evident for TNF. Such differences in induction mechanisms argue against the prevailing paradigm that all IE genes possess paused Pol II and may further delineate the specific roles played by each of these rapidly expressed immune modulators. 23948873 Gyroscope-Driven Mouse Pointer with an EMOTIV® EEG Headset and Data Analysis Based on Empirical Mode Decomposition. This paper presents a project on the development of a cursor control emulating the typical operations of a computer-mouse, using gyroscope and eye-blinking electromyographic signals which are obtained through a commercial 16-electrode wireless headset, recently released by Emotiv. The cursor position is controlled using information from a gyroscope included in the headset. The clicks are generated through the user's blinking with an adequate detection procedure based on the spectral-like technique called Empirical Mode Decomposition (EMD). EMD is proposed as a simple and quick computational tool, yet effective, aimed to artifact reduction from head movements as well as a method to detect blinking signals for mouse control. Kalman filter is used as state estimator for mouse position control and jitter removal. The detection rate obtained in average was 94.9%. Experimental setup and some obtained results are presented. 23032104 Wnt/β-catenin signaling activates bone morphogenetic protein 2 expression in osteoblasts. The BMP and Wnt/β-catenin signaling pathways cooperatively regulate osteoblast differentiation and bone formation. Although BMP signaling regulates gene expression of the Wnt pathway, much less is known about whether Wnt signaling modulates BMP expression in osteoblasts. Given the presence of putative Tcf/Lef response elements that bind β-catenin/TCF transcription complex in the BMP2 promoter, we hypothesized that the Wnt/β-catenin pathway stimulates BMP2 expression in osteogenic cells. In this study, we showed that Wnt/β-catenin signaling is active in various osteoblast or osteoblast precursor cell lines, including MC3T3-E1, 2T3, C2C12, and C3H10T1/2 cells. Furthermore, crosstalk between the BMP and Wnt pathways affected BMP signaling activity, osteoblast differentiation, and bone formation, suggesting Wnt signaling is an upstream regulator of BMP signaling. Activation of Wnt signaling by Wnt3a or overexpression of β-catenin/TCF4 both stimulated BMP2 transcription at promoter and mRNA levels. In contrast, transcription of BMP2 in osteogenic cells was decreased by either blocking the Wnt pathway with DKK1 and sFRP4, or inhibiting β-catenin/TCF4 activity with FWD1/β-TrCP, ICAT, or ΔTCF4. Using a site-directed mutagenesis approach, we confirmed that Wnt/β-catenin transactivation of BMP2 transcription is directly mediated through the Tcf/Lef response elements in the BMP2 promoter. These results, which demonstrate that the Wnt/β-catenin signaling pathway is an upstream activator of BMP2 expression in osteoblasts, provide novel insights into the nature of functional cross talk integrating the BMP and Wnt/β-catenin pathways in osteoblastic differentiation and maintenance of skeletal homeostasis. 23307557 p300-mediated acetylation of TRF2 is required for maintaining functional telomeres. The human telomeric protein TRF2 is required to protect chromosome ends by facilitating their organization into the protective capping structure. Post-translational modifications of TRF2 such as phosphorylation, ubiquitination, SUMOylation, methylation and poly(ADP-ribosyl)ation have been shown to play important roles in telomere function. Here we show that TRF2 specifically interacts with the histone acetyltransferase p300, and that p300 acetylates the lysine residue at position 293 of TRF2. We also report that p300-mediated acetylation stabilizes the TRF2 protein by inhibiting its ubiquitin-dependent proteolysis and is required for efficient telomere binding of TRF2. Furthermore, overexpression of the acetylation-deficient mutant, K293R, induces DNA-damage response foci at telomeres, thereby leading to induction of impaired cell growth, cellular senescence and altered cell cycle distribution. A small but significant number of metaphase chromosomes show no telomeric signals at chromatid ends, suggesting an aberrant telomere structure. These findings demonstrate that acetylation of TRF2 by p300 plays a crucial role in the maintenance of functional telomeres as well as in the regulation of the telomere-associated DNA-damage response, thus providing a new route for modulating telomere protection function. 23875537 Biologic fatigue in psoriasis. Background: Over the past 15 years, biologic medications have greatly advanced psoriasis therapy. However, these medications may lose their efficacy after long-term use, a concept known as biologic fatigue. We sought to review the available data on biologic fatigue in psoriasis and identify strategies to help clinicians optimally manage patients on biologic medications in order to minimize biologic fatigue. Methods: We reviewed phase III clinical trials for the biologic medications used to treat psoriasis and performed a PubMed search for the literature that assessed the loss of response to biologic therapy. Results: In phase III clinical trials of biologic therapies for the treatment of psoriasis, 20-32% of patients lost their PASI-75 response during 0.8-3.9 years of follow-up. A study using infliximab reported the highest percentage of patients who lost their response (32%) over the shortest time-period (0.8 years). Although not consistently reported across all studies, the presence of antidrug antibodies was associated with the loss of response to treatment with infliximab and adalimumab. Conclusion: Biologic fatigue may be most frequent in those patients using infliximab. Further studies are needed to identify risk factors associated with biologic fatigue and to develop meaningful antidrug antibody assays. 22585427 Feasibility study of S-1 adjuvant chemotherapy in patients with colorectal cancer. We evaluated the safety, efficacy, and compliance of 1-year treatment with S-1 in patients with stage II/III resectable colorectal cancer. S-1 was administered orally in two divided doses daily. The dose was assigned according to body surface area (BSA) as follows: BSA <1.25 m(2), 80 mg/day; BSA ≥1.25 to <1.5 m(2), 100 mg/day; and BSA ≥1.5 m(2), 120 mg/day. S-1 was given for 28 consecutive days, followed by a 14-day rest. The study objects were the rate of completion of treatment as planned at 1 year, the ratio of the actually administered dose to the planned dose at 1 year, and the total number of days of treatment. At 1 year, the rate of completion of treatment as planned was 77.7 % (42/54 patients), and the ratio of the actually administered dose to the planned dose was 82.9 %. The mean and median total numbers of days of treatment were 209 and 252, respectively. Grade 3 or higher toxicity (watery eyes) occurred in only 1 patient. S-1 adjuvant chemotherapy had acceptable compliance, safety, and efficacy in patients with colorectal cancer. S-1 adjuvant chemotherapy is considered a possible standard treatment regimen for colorectal cancer. 23931541 When physician-expressed uncertainty leads to patient dissatisfaction: a gender study. Communication guidelines often advise physicians to disclose to their patients medical uncertainty regarding the diagnosis, origin of the problem, and treatment. However, the effect of the expression of such uncertainty on patient outcomes (e.g. satisfaction) has produced conflicting results in the literature that indicate either no effect or a negative effect. The differences in the results of past studies may be explained by the fact that potential gender effects on the link between physician-expressed uncertainty and patient outcomes have not been investigated systematically. On the basis of previous research documenting indications that patients may judge female physicians by more severe criteria than they do male physicians, and that men are more prejudiced than women towards women, we predicted that physician-expressed uncertainty would have more of a negative impact on patient satisfaction when the physician in question was female rather than male, and especially when the patient was a man. We conducted two studies with complementary designs. Study 1 was a randomised controlled trial conducted in a simulated setting (120 analogue patients Analogue patients are healthy participants asked to put themselves in the shoes of real medical patients by imagining being the patients of physicians shown on videos); Study 2 was a field study conducted in real medical interviews (36 physicians, 69 patients). In Study 1, participants were presented with vignettes that varied in terms of the physician's gender and physician-expressed uncertainty (high versus low). In Study 2, physicians were filmed during real medical consultations and the level of uncertainty they expressed was coded by an independent rater according to the videos. In both studies, patient satisfaction was assessed using a questionnaire. The results confirmed that expressed uncertainty was negatively related to patient satisfaction only when the physician was a woman (Studies 1 and 2) and when the patient was a man (Study 2). We believe that patients have the right to be fully informed of any medical uncertainties. If our results are confirmed in further research, the question of import will refer not to whether female physicians should communicate uncertainty, but to how they should communicate it. For instance, if it proves true that uncertainty negatively impacts on (male) patients' satisfaction, female physicians might want to counterbalance this impact by emphasizing other communication skills. 23632781 Computed tomography assessment of lateral pedicle wall perforation by free-hand subaxial cervical pedicle screw placement. To present the technique of free-hand subaxial cervical pedicle screw (CPS) placement without using intra-operative navigating devices, and to investigate the crucial factors for safe placement and avoidance of lateral pedicle wall perforation, by measuring and classifying perforations with postoperative computed tomography (CT) scan. The placement of CPS has generally been considered as technically demanding and associated with considerable lateral wall perforation rate. For surgeons without access to navigation systems, experience of safe free-hand technique for subaxial CPS placement is especially valuable. A total of 214 consecutive traumatic or degenerative patients with 1,024 CPS placement using the free-hand technique were enrolled. In the operative process, the lateral mass surface was decorticated. Then a small curette was used to identify the pedicle entrance by touching the cortical bone of the medial pedicle wall. It was crucial to keep the transverse angle and make appropriate adjustment with guidance of the resistance of the thick medial cortical bone. The hand drill should be redirected once soft tissue breach was palpated by a slim ball-tip prober. With proper trajectory, tapping, repeated palpation, the 26-30 mm screw could be placed. After the procedure, the transverse angle of CPS trajectory was measured, and perforation of the lateral wall was classified by CT scan: grade 1, perforation of pedicle wall by screw placement, with the external edge of screw deviating out of the lateral pedicle wall equal to or less than 2 mm and grade 2, critical perforation of pedicle wall by screw placement, large than 2 mm. A total of 129 screws (12.64 %) were demonstrated as lateral pedicle wall perforation, of which 101 screws (9.86 %) were classified as grade 1, whereas 28 screws (2.73 %) as grade 2. Among the segments involved, C3 showed an obviously higher perforating rate than other (P < 0.05). The difference between the anatomical pedicle transverse angle and the screw trajectory angle was higher in patients of grade 2 perforation than the others. In the 28 screws of grade 2 perforation verified by axial CT, 26 screws had been palpated as abnormal during operation. However, only 19 out of the 101 screws of grade 1 perforation had shown palpation alarming signs during operation. The average follow-up was 36.8 months (range 5-65 months). There was no symptom and sign of neurovascular injuries. Two screws (0.20 %) were broken, and one screw (0.10 %) loosen. Placement of screw through a correct trajectory may lead to grade 1 perforation, which suggests transversal expansion and breakage of the thinner lateral cortex, probably caused by mismatching of the diameter of 3.5 mm screws and the tiny cancellous bone cavity of pedicle. Grade 1 perforation is deemed as relatively safe to the vertebral artery. Grade 2 perforation means obvious deviation of the trajectory angle of hand drill, which directly penetrates into the transverse foramen, and the risk of vertebral artery injury (VAI) or development of thrombi caused by the irregular blood flow would be much greater compared to grade 1 perforation. Moreover, there are two crucial maneuvers for increasing accuracy of screw placement: identifying the precise entry point using a curette or hand drill to touch the true entrance of the canal after decortication, and guiding CPS trajectory on axial plane by the resistant of thick medial wall. 23896375 Carbamoylation abrogates the antioxidant potential of hydrogen sulfide. Hydrogen sulfide (H2S) has been identified as the third gasotransmitter. Beside its role as signaling molecule in the cardiovascular and nervous system the antioxidant and cyto-protective properties of H2S have gained much attention. In the present study we show that cyanate, an uremic toxin which is found in abundant concentration in sera of patients suffering from chronic kidney disease (CKD), can abrogate the antioxidant and cytoprotective activity of H2S via S-carbamoylation reaction, a reaction that previously has only been shown to have a physiological effect on cysteine groups, but not on H2S. Carbamoylation strongly inhibited the free radical scavenging (ABTS(+) and alkylperoxyl ROO) properties of H2S. The extent of intracellular ROS formation induced by ROO was diminished by H2S whereas carbamoylation counteracted the protective effect. Reagent HOCl was rapidly inactivated by H2S in contrast to the carbamoylated compound. Protein modification by HOCl was inhibited by H2S but carbamoylation significantly reduced the effect. Thus, S-carbamoylation of low molecular weight thiols by abrogating their antioxidant potential may contribute to the higher oxidative stress observed in CKD. 23642296 Evaluation and optimization of mass spectrometric settings during data-dependent acquisition mode: focus on LTQ-Orbitrap mass analyzers. Mass-spectrometry-based proteomics has evolved as the preferred method for the analysis of complex proteomes. Undoubtedly, recent advances in mass spectrometry instrumentation have greatly enhanced proteomic analysis. A popular instrument platform in proteomics research is the LTQ-Orbitrap mass analyzer. In this tutorial, we discuss the significance of evaluating and optimizing mass spectrometric settings on the LTQ-Orbitrap during CID data-dependent acquisition (DDA) mode to improve protein and peptide identification rates. We focus on those MS and MS/MS parameters that have been systematically examined and evaluated by several researchers and are commonly used during DDA. More specifically, we discuss the effect of mass resolving power, preview mode for FTMS scan, monoisotopic precursor selection, signal threshold for triggering MS/MS events, number of microscans per MS/MS scan, number of MS/MS events, automatic gain control target value (ion population) for MS and MS/MS, maximum ion injection time for MS/MS, rapid and normal scan rate, and prediction of ion injection time. We furthermore present data from the latest generation LTQ-Orbitrap system, the Orbitrap Elite, along with recommended MS and MS/MS parameters. The Orbitrap Elite outperforms the Orbitrap Classic in terms of scan speed, sensitivity, dynamic range, and resolving power and results in higher identification rates. Several of the optimized MS parameters determined on the LTQ-Orbitrap Classic and XL were easily transferable to the Orbitrap Elite, whereas others needed to be reevaluated. Finally, the Q Exactive and HCD are briefly discussed, as well as sample preparation, LC-optimization, and bioinformatics analysis. We hope this tutorial will serve as guidance for researchers new to the field of proteomics and assist in achieving optimal results. 23945667 Reversion of Methicillin-Resistant Staphylococcus aureus Skin Infections to Methicillin-Susceptible Isolates. IMPORTANCE The rise of methicillin-resistant Staphylococcus aureus (MRSA) infections in the outpatient setting has led to a growing trend of empirical antibiotic treatment for MRSA. The limited oral antibiotics available and the growing resistance to these antibiotics make this a controversial practice. OBJECTIVE To determine the frequency of patients with MRSA skin and soft-tissue infections (SSTIs) reverting to methicillin-susceptible Staphylococcus aureus (MSSA) positivity. DESIGN AND SETTING Retrospective medical record review of inpatients and outpatients from our university hospital and clinics between January 1, 2000, and December 31, 2010. PARTICIPANTS Patients in our institutional microbiological database were included if they had a MRSA-positive SSTI and subsequent culture-proven S aureus SSTI more than 1 month later. No sociodemographic restrictions were applied. A sample of at least 200 patients meeting the above criteria was desired. The database was sorted by ascending medical record number, with the first 1681 patients' medical records reviewed. Of these, 215 patients met our criteria. MAIN OUTCOMES AND MEASURES Whether a patient remained MRSA positive in subsequent SSTIs or reverted to MSSA-positive infections. RESULTS Of the total 215 patients, 64 (29.8%) had at least 1 incident of MSSA reversion, and 55 (25.6%) reverted to MSSA infections for the remainder of the study. We assessed various factors that might increase or decrease the likelihood of reversion. The presence of an invasive device was the only factor to demonstrate a statistically significant risk (relative risk, 1.20; 95% CI, 1.02-1.41; P = .03) toward remaining MRSA positive in subsequent infections. CONCLUSIONS AND RELEVANCE Patients with MRSA SSTIs demonstrated the ability to revert to subsequent MSSA SSTIs with a significant frequency. Further study regarding MRSA risk factors and their effects on subsequent infections would be valuable in guiding empirical treatment. Reculturing new infections in previously MRSA-positive patients is a prudent management strategy as we recognize that susceptibilities of the S aureus organisms change. 23707160 Prospects for oral replicating adenovirus-vectored vaccines. Orally delivered replicating adenovirus (Ad) vaccines have been used for decades to prevent adenovirus serotype 4 and 7 respiratory illness in military recruits, demonstrating exemplary safety and high efficacy. That experience suggests that oral administration of live recombinant Ads (rAds) holds promise for immunization against other infectious diseases, including those that have been refractory to traditional vaccination methods. Live rAds can express intact antigens from free-standing transgenes during replication in infected cells. Alternatively, antigenic epitopes can be displayed on the rAd capsid itself, allowing presentation of the epitope to the immune system both prior to and during replication of the virus. Such capsid-display rAds offer a novel vaccine approach that could be used either independently of or in combination with transgene expression strategies to provide a new tool in the search for protection from infectious disease. 23876432 Emergency department visit data for rapid detection and monitoring of norovirus activity, United States. Noroviruses are the leading cause of gastroenteritis in the United States, but timely measures of disease are lacking. BioSense, a national-level electronic surveillance system, assigns data on chief complaints (patient symptoms) collected during emergency department (ED) visits to 78 subsyndromes in near real-time. In a series of linear regression models, BioSense visits mapped by chief complaints of diarrhea and nausea/vomiting subsyndromes as a monthly proportion of all visits correlated strongly with reported norovirus outbreaks from 6 states during 2007-2010. Higher correlations were seen for diarrhea (R = 0.828-0.926) than for nausea/vomiting (R = 0.729-0.866) across multiple age groups. Diarrhea ED visit proportions exhibited winter seasonality attributable to norovirus; rotavirus contributed substantially for children <5 years of age. Diarrhea ED visit data estimated the onset, peak, and end of norovirus season within 4 weeks of observed dates and could be reliable, timely indicators of norovirus activity. 23871213 The expression ratio of miR-17-5p and miR-155 correlates with grading in canine splenic lymphoma. In dogs as in humans, microRNAs (miRNAs) play a key role in normal and neoplastic hematopoiesis regulation. The general miRNA expression framework varies among different stages of development and differentiation of tumors, and miRNAs are widely investigated as new molecular tools for cancer diagnosis and classification. Canine lymphomas are currently classified according with the WHO classification, but a comprehensive grading study of clinical samples is still lacking, and molecular tools for quick grading are not yet available. In the present work, a retrospective study of the expression profile of a panel of miRNAs in canine primary splenic lymphomas was performed. The formalin fixed, paraffin embedded (FFPE) lymphoma samples were accurately classified according with the WHO classification, and were analyzed for miRNA expression using stem-loop TaqMan real time RT-PCR. For each miRNA investigated, relative and absolute quantification were performed after selecting the best housekeeping genes using the NormFinder and geNorm algorithms. The results of this study show a diversity in miRNA expression in low (L) grade lymphomas compared to intermediate-high (I-H) grade lymphomas. The molar ratio between miR-17-5p and miR-155 correlated with WHO grading. These results highlight the potential use of miR-17-5p/miR-155 molar ratio as a new molecular tool for grading of canine splenic lymphomas. The data here reported further support the utility of monitoring miRNA expression in canine hematopoietic malignancies diagnosis and prognosis. 23560689 Mycoleptodiscins A and B, Cytotoxic Alkaloids from the Endophytic Fungus Mycoleptodiscus sp. F0194. Two novel reddish-orange alkaloids, mycoleptodiscin A (1) and mycoleptodiscin B (2), were isolated from liquid cultures of the endophytic fungus Mycoleptodiscus sp. that had been isolated from Desmotes incomparabilis in Panama. Elucidation of their structures was accomplished using 1D and 2D NMR spectroscopy in combination with IR spectroscopic and MS data. These compounds are indole-terpenes with a new skeleton uncommon in nature. Mycoleptodiscin B (2) was active in inhibiting the growth of cancer cell lines with IC50 values in the range 0.60-0.78 μM. 23792221 Enzymatic polymerization to an alternating N-l-cysteinyl chitin derivative: a novel class of multivalent glycopeptidomimetics. A novel chitin derivative with an alternating N-l-cysteinyl group was successfully prepared. The precursor chitin derivative with an alternating N-l-thioprolinyl group could be obtained via chitinase-catalyzed polymerization of the N'-l-thioprolinyl chitobiose oxazoline derivative as a transition state analog substrate monomer under weak alkaline conditions. Conversion of the l-thioprolinyl group to an l-cysteinyl group in the product chitin derivative proceeded in a dose-dependent manner by methoxyamine hydrochloride, and the reaction could be completed almost quantitatively. The obtained chitin derivative is a uniformly amino acid-branching polysaccharide, which is categorized into a novel class of multivalent glycopeptidomimetics. 23225329 Exploring the polyamine regulatory site of the NMDA receptor: a parallel synthesis approach. The elongated structures of polyamine inverse agonists such as 1,12-diaminododecane (N12N) and 5-(4-aminobutyl)-2-thiopheneoctanamine (N4T8N) lend themselves to a combinatorial chemistry approach to explore a potential polyamine pharmacophore at the NMDA receptor. Herein we describe more than 100 new analogues of N4T8N obtained by breaking up the long octanamine arm into a dipeptide chain of equivalent length. Solid-phase parallel synthesis based on cross-linked polystyrene and a Wang anchor allowed the low-scale preparation of four small libraries based on the combination of two amino acid residues (out of Gly, Leu, Phe, Lys, phenylglycine, Tyr, Trp, His, and Arg). The obtained compounds were tested as modulators of [(3) H]MK-801 binding to rat brain membranes and of NMDA-induced currents in cultured rat hippocampal neurons. Compounds with two aromatic residues acted as binding inhibitors (inverse agonists). Compounds with two Lys residues acted as binding stimulators (agonists) and had stimulatory and inhibitory effects on NMDA-induced currents, depending on the holding potential. High sensitivity of binding inhibition to spermine was conferred by a Tyr residue, whereas a His residue favored high potency at acidic pH. 23609187 Planktonic bacterial community composition of an extremely shallow soda pond during a phytoplankton bloom revealed by cultivation and molecular cloning. Böddi-szék is one of the shallow soda ponds located in the Kiskunság National Park, Hungary. In June 2008, immediately prior to drying out, an extensive algal bloom dominated by a green alga (Oocystis submarina Lagerheim) was observed in the extremely saline and alkaline water of the pond. The aim of the present study was to reveal the phylogenetic diversity of the bacterial communities inhabiting the water of Böddi-szék during the blooming event. Using two different selective media, altogether 110 aerobic bacterial strains were cultivated. According to the sequence analysis of the 16S rRNA gene, most of the strains belonged to alkaliphilic or alkalitolerant and moderately halophilic species of the genera Bacillus and Gracilibacillus (Firmicutes), Algoriphagus and Aquiflexum (Bacteroidetes), Alkalimonas and Halomonas (Gammaproteobacteria). Other strains were closely related to alkaliphilic and phototrophic purple non-sulfur bacteria of the genera Erythrobacter and Rhodobaca (Alphaproteobacteria). Analysis of the 16S rRNA gene-based clone library indicated that most of the total of 157 clone sequences affiliated with the anoxic phototrophic bacterial genera of Rhodobaca and Rhodobacter (Alphaproteobacteria), Ectothiorhodospira (Gammaproteobacteria) and Heliorestis (Firmicutes). Phylotypes related to the phylum Bacteroidetes formed the second most abundant group. Clones related to the mainly anaerobic and alkaliphilic bacterial genera of Anoxynatronum (Firmicutes), Spirochaeta (Spirochaetes) and Desulfonatronum (Deltaproteobacteria) were also abundant. Further clone sequences showed less than 95 % similarity values to cultivated species of the phyla Actinobacteria, Cyanobacteria, Deinococcus-Thermus, Fibrobacteres, Gemmatimonadetes and Lentisphaerae. 23385116 Effects of insect herbivory on induced chemical defences and compensation during early plant development in Penstemon virgatus. Background and Aims The lack of studies assessing the simultaneous expression of tolerance and resistance traits during seedling development and overall seedling defences as compared with adult plants, in general, constitutes a significant research need that can greatly improve our understanding of overall investment in defences during plant ontogeny. Methods Using two seedling and two juvenile stages of the perennial herb Penstemon virgatus (Plantaginaceae) evaluations were made of (a) patterns of investment in constitutive chemical defences [i.e. iridoid glycosides (IGs)], and (b) simultaneous variation in the short-term ability of seedling and juvenile stages to induce resistance traits, measured as induced chemical defences, or tolerance traits, measured as compensatory re-growth following moderate levels of damage by a specialist insect herbivore. Key Results Plants were highly defended during most of their transition from seedling to early juvenile stages, reaching a constant approx. 20 % dry weight total IGs. Furthermore, following 30 % above-ground tissue damage, seedlings and juvenile stages were equally able to induce resistance, by raising their IG concentration by approx. 8 %, whereas compensatory re-growth was only achieved at young juvenile but not seedling stages. Conclusions Two major trends emerged from this study: (1) in contrast to expected and previously observed trends, in this perennial plant species, seedlings seem to be one of the most well-defended stages as compared with adult ones; (2) high levels of constitutive defences did not limit the ability of young developmental stages to induce resistance following damage, although this response may come with a cost (i.e. decreased compensation) in young seedling stages. Hence, as has been previously demonstrated in few other systems, these results points towards an indirect evidence for a trade-off between tolerance and resistance traits at some, but not all, developmental stages; making them often difficult to detect. 23963696 miR-146a-5p circuitry uncouples cell proliferation and migration, but not differentiation, in human mesenchymal stem cells. Administration of mesenchymal stem cells (MSCs) has the potential to ameliorate degenerative disorders and to repair damaged tissues. The homing of transplanted MSCs to injured sites is a critical property of engraftment. Our aim was to identify microRNAs involved in controlling MSC proliferation and migration. MSCs can be isolated from bone marrow and umbilical cord Wharton's jelly (BM-MSCs and WJ-MSCs, respectively), and WJ-MSCs show poorer motility yet have a better amplification rate compared with BM-MSCs. Small RNA sequencing revealed that miR-146a-5p is significantly overexpressed and has high abundance in WJ-MSCs. Knockdown of miR-146a-5p in WJ-MSCs inhibited their proliferation yet enhanced their migration, whereas overexpression of miR-146a-5p in BM-MSCs did not influence their osteogenic and adipogenic potentials. Chemokine (C-X-C motif) ligand 12 (CXCL12), together with SIKE1, which is an I-kappa-B kinase epsilon (IKKε) suppressor, is a direct target of miR-146a-5p in MSCs. Knockdown of miR-146a-5p resulted in the down-regulation of nuclear factor kappa-B (NF-κB) activity, which is highly activated in WJ-MSCs and is known to activate miR-146a-5p promoter. miR-146a-5p is also downstream of CXCL12, and a negative feedback loop is therefore formed in MSCs. These findings suggest that miR-146a-5p is critical to the uncoupling of motility and proliferation of MSCs. Our miRNome data also provide a roadmap for further understanding MSC biology. 23764025 Fracture toughness improvements of dental ceramic through use of yttria-stabilized zirconia (YSZ) thin-film coatings. The aim of this study was to evaluate strengthening mechanisms of yttria-stabilized zirconia (YSZ) thin film coatings as a viable method for improving fracture toughness of all-ceramic dental restorations. Bars (2mm×2mm×15mm, n=12) were cut from porcelain (ProCAD, Ivoclar-Vivadent) blocks and wet-polished through 1200-grit using SiC abrasive. A Vickers indenter was used to induce flaws with controlled size and geometry. Depositions were performed via radio frequency magnetron sputtering (5mT, 25°C, 30:1 Ar/O2 gas ratio) with varying powers of substrate bias. Film and flaw properties were characterized by optical microscopy, scanning electron microscopy (SEM), and X-ray diffraction (XRD). Flexural strength was determined by three-point bending. Fracture toughness values were calculated from flaw size and fracture strength. Data show improvements in fracture strength of up to 57% over unmodified specimens. XRD analysis shows that films deposited with higher substrate bias displayed a high %monoclinic volume fraction (19%) compared to non-biased deposited films (87%), and resulted in increased film stresses and modified YSZ microstructures. SEM analysis shows critical flaw sizes of 67±1μm leading to fracture toughness improvements of 55% over unmodified specimens. Data support surface modification of dental ceramics with YSZ thin film coatings to improve fracture toughness. Increase in construct strength was attributed to increase in compressive film stresses and modified YSZ thin film microstructures. It is believed that this surface modification may lead to significant improvements and overall reliability of all-ceramic dental restorations. 23889289 Jasmonate induction of the monoterpene linalool confers resistance to rice bacterial blight and its biosynthesis is regulated by JAZ protein in rice. Jasmonic acid (JA) is involved in the regulation of host immunity in plants. Recently, we demonstrated that JA signalling has an important role in resistance to rice bacterial blight caused by Xanthomonas oryzae pv. oryzae (Xoo) in rice. Here, we report that many volatile compounds accumulate in response to exogenous application of JA, including the monoterpene linalool. Expression of linalool synthase was up-regulated by JA. Vapour treatment with linalool induced resistance to Xoo, and transgenic rice plants overexpressing linalool synthase were more resistance to Xoo, presumably due to the up-regulation of defence-related genes in the absence of any treatment. JA-induced accumulation of linalool was regulated by OsJAZ8, a rice jasmonate ZIM-domain protein involving the JA signalling pathway at the transcriptional level, suggesting that linalool plays an important role in JA-induced resistance to Xoo in rice. 23219042 Achyrofuran is an antibacterial agent capable of killing methicillin-resistant vancomycin-intermediate Staphylococcus aureus in the nanomolar range. Currently, there is a pressing need for novel antibacterial agents against drug-resistant bacteria, especially those which have been common in our communities and hospitals, such as methicillin-resistant Staphylococcus aureus (MRSA). The South American plant Achyrocline satureioides ("Marcela") has been widely used in traditional medicine for a number of diseases, including infections. Several crude extracts from this plant have shown good antimicrobial activities in vitro. In the search for the active principle(s) that confers these antimicrobial activities, we have processed the dichloromethane extract from the aerial parts of the plant. One of the isolated compounds showed extraordinary antibacterial activities against a set of clinically relevant Gram-positive strains that widely differ in their antibiogram profiles. This compound was identified as achyrofuran on the basis of its spectroscopic and physical data. We determined the MIC to be around 0.1 μM (0.07 μg/ml) for the reference methicillin-resistant and vancomycin-intermediate S. aureus strain NRS402. Moreover, nanomolar concentrations of achyrofuran killed 10(6) bacteria within 12 h. Based on the presence of the 2,2'-biphenol core, we further studied whether achyrofuran killed bacteria through a mechanism of action similar to that reported for the naturally occurring antibiotic MC21-A. Indeed, we found that achyrofuran was not bacteriolytic by itself although it greatly compromised membrane impermeability as determined by increased SYTOX Green uptake. 23952335 Algorithm for the diagnosis of smear-negative pulmonary tuberculosis in high-incidence resource-constrained settings. Diagnosis of smear-negative pulmonary tuberculosis (SNPT) remains a challenge, particularly in resource-constrained settings. We evaluated a diagnostic algorithm that combines affordable laboratory tools and a clinical prediction rule (CPR). We derived, based on published evidence, a diagnostic algorithm for SNPT. Sputum concentration constitutes its first step. In suspects with negative results, SNPT probability is classified with a CPR as low (excluded), high (confirmed) or intermediate. For intermediate patients, sputum Middlebrook 7H9 liquid culture is performed, and they are assessed after 2 weeks. If clinically deteriorated, with still negative liquid culture, bronchoscopy is offered. Otherwise, results of Middlebrook 7H9 culture are awaited. We prospectively evaluated this algorithm against a reference standard of solid and liquid cultures in two reference hospitals in Lima, Peru. 670 SNPT suspects were included from September 2005 to March 2008. The prevalence of SNPT was 27% according to the reference standard. The algorithm's overall accuracy was 0.94 (95% CI 0.91-0.95), its sensitivity was 0.88 (95% CI 0.82-0.92) and its specificity, 0.96 (95% CI 0.94-0.98). Sputum concentration, the CPR, Middlebrook 7H9 sputum culture and bronchoscopic samples defined a diagnosis of SNPT according to the algorithm in 57 (37%), 25 (16%), 63 (41%) and 8(5%) of patients, respectively. 65% of patients were diagnosed within 3 weeks. The algorithm was accurate for SNPT diagnosis. Sputum concentration, CPR and selective Middlebrook 7H9 culture are essential components. 23780529 Study on nanobubble generation: saline solution/water exchange method. In a recently introduced method for nanobubble generation, water is replaced with NaCl solution. It has the same mechanism as alcohol/water exchange: a liquid of higher gas solubility is used to replace one of lower gas solubility. Herein, the opposite process is realized by replacement of saline solutions with water. Interestingly, nanobubbles are also observed by AFM when different concentrations and valences of saline liquids are employed. 23919295 Methanogenesis Facilitated by Geobiochemical Iron Cycle in a Novel Syntrophic Methanogenic Microbial Community. Production and emission of methane have been increasing concerns due to its significant effect on global climate change and the carbon cycle. Here we report facilitated methane production from acetate by a novel community of methanogens and acetate oxidizing bacteria in the presence of poorly crystalline akaganeite slurry. Comparative analyses showed that methanogenesis was significantly enhanced by added akaganeite and acetate was mostly stoichiometrically converted to methane. Electrons produced from anaerobic acetate oxidation are transferred to akaganeite nanorods that likely prompt the transformation into goethite nanofibers through a series of biogeochemical processes of soluble Fe(II) readsorption and Fe(III) reprecipitation. The methanogenic archaea likely harness the biotransformation of akaganeite to goethite by the Fe(III)-Fe(II) cycle to facilitate production of methane. These results provide new insights into biogeochemistry of iron minerals and methanogenesis in the environment, as well as the development of sustainable methods for microbial methane production. 23922800 Identification of Novel Adhesins of M. tuberculosis H37Rv Using Integrated Approach of Multiple Computational Algorithms and Experimental Analysis. Pathogenic bacteria interacting with eukaryotic host express adhesins on their surface. These adhesins aid in bacterial attachment to the host cell receptors during colonization. A few adhesins such as Heparin binding hemagglutinin adhesin (HBHA), Apa, Malate Synthase of M. tuberculosis have been identified using specific experimental interaction models based on the biological knowledge of the pathogen. In the present work, we carried out computational screening for adhesins of M. tuberculosis. We used an integrated computational approach using SPAAN for predicting adhesins, PSORTb, SubLoc and LocTree for extracellular localization, and BLAST for verifying non-similarity to human proteins. These steps are among the first of reverse vaccinology. Multiple claims and attacks from different algorithms were processed through argumentative approach. Additional filtration criteria included selection for proteins with low molecular weights and absence of literature reports. We examined binding potential of the selected proteins using an image based ELISA. The protein Rv2599 (membrane protein) binds to human fibronectin, laminin and collagen. Rv3717 (N-acetylmuramoyl-L-alanine amidase) and Rv0309 (L,D-transpeptidase) bind to fibronectin and laminin. We report Rv2599 (membrane protein), Rv0309 and Rv3717 as novel adhesins of M. tuberculosis H37Rv. Our results expand the number of known adhesins of M. tuberculosis and suggest their regulated expression in different stages. 23644912 Greater risk sensitivity of dorsolateral prefrontal cortex in young smokers than in nonsmokers. RATIONALE: Despite a national reduction in the prevalence of cigarette smoking, ~19 % of the adult US population persists in this behavior, with the highest prevalence among 18-25-year-olds. Given that the choice to smoke imposes a known health risk, clarification of brain function related to decision-making, particularly involving risk-taking, in smokers may inform prevention and smoking cessation strategies. OBJECTIVES: This study aimed to compare brain function related to decision-making in young smokers and nonsmokers. METHODS: The Balloon Analogue Risk Task (BART) is a computerized risky decision-making task in which participants pump virtual balloons, each pump associated with an incremental increase in potential payoff on a given trial but also with greater risk of balloon explosion and loss of payoff. We used this task to compare brain activation associated with risky decision-making in smokers (n = 18) and nonsmokers (n = 25), while they performed the BART during functional magnetic resonance imaging (fMRI). The participants were young men and women, 17-21 years of age. RESULTS: Risk level (number of pumps) modulated brain activation in the right dorsolateral and ventrolateral prefrontal cortices more in smokers than in nonsmokers, and smoking severity (Heaviness of Smoking Index) was positively related to this modulation in an adjacent frontal region. CONCLUSIONS: Given evidence for involvement of the right dorsolateral and ventrolateral prefrontal cortices in inhibitory control, these findings suggest that young smokers have a different contribution of prefrontal cortical substrates to risky decision-making than nonsmokers. Future studies are warranted to determine whether the observed neurobiological differences precede or result from smoking. 23076253 Characterization of tumor differentiation factor (TDF) and its receptor (TDF-R). Tumor differentiation factor (TDF) is an under-investigated protein produced by the pituitary with no definitive function. TDF is secreted into the bloodstream and targets the breast and prostate, suggesting that it has an endocrine function. Initially, TDF was indirectly discovered based on the differentiation effect of alkaline pituitary extracts of the mammosomatotropic tumor MtTWlO on MTW9/PI rat mammary tumor cells. Years later, the cDNA clone responsible for this differentiation activity was isolated from a human pituitary cDNA library using expression cloning. The cDNA encoded a 108-amino-acid polypeptide that had differentiation activity on MCF7 breast cancer cells and on DU145 prostate cancer cells in vitro and in vivo. Recently, our group focused on identification of the TDF receptor (TDF-R). As potential TDF-R candidates, we identified the members of the Heat Shock 70-kDa family of proteins (HSP70) in both MCF7 and BT-549 human breast cancer cells (HBCC) and PC3, DU145, and LNCaP human prostate cancer cells (HPCC), but not in HeLa cells, NG108 neuroblastoma, or HDF-a and BLK CL.4 cells fibroblasts or fibroblast-like cells. Here we review the current advances on TDF, with particular focus on the structural investigation of its receptor and on its functional effects on breast and prostate cells. 23834898 Socio-behavioural factors and early childhood caries: A cross-sectional study of preschool children in central Trinidad. Early childhood caries (ECC) is a public health problem due to its impact on children's health, development and well being. Little is known about early childhood oral health in the West Indies or the influence of social and behavioural factors on the prevalence and severity of early childhood caries in this preschool population. The aims of this study were to describe the prevalence and severity of ECC in preschool children in a region of central Trinidad and to explore its relationship with social and behavioural factors. A cross-sectional survey was undertaken on children aged 3-5-year-olds from a random sample of preschools in central Trinidad. Oral health examinations were conducted for children for whom parental consent was given, using WHO criteria (visual diagnosis / cavitation at d3). A self-reported questionnaire was distributed to all parents and caregivers. Variables included socio-demographics, oral health knowledge, attitudes and behaviours, visible caries experience and treatment need. 251 children were examined, 50.2% were male with a mean age of 3.7 years (SD 0.67) and 71% were of Indian ethnicity. The prevalence of ECC was 29.1% and the prevalence of severe early childhood caries (S-ECC) was 17.5%. 29.9% of children had some treatment need, with 12% in need of urgent care or referral. Poisson generalized linear mixed model analysis found a higher rate of visible caries experience for children who ate sweet snacks more than twice a day (p < 0.001), had poorer parental dental health ratings (p < 0.0001), a previous dental visit (p < 0.0001) and difficulty finding dental care (p < 0.001). The prevalence and severity of ECC in central Trinidad was related to oral health behaviours and access to dental care. Oral health promotion should include more supportive and practical advice for parents and caregivers of preschool children along with improved access to dental care to enable primary prevention and management of ECC. 23817178 CXCR4-SERINE339 regulates cellular adhesion, retention and mobilization, and is a marker for poor prognosis in acute myeloid leukemia. The CXCR4 receptor is a major regulator of hematopoietic cell migration. Overexpression of CXCR4 has been associated with poor prognosis in acute myelogenous leukemia (AML). We have previously shown that ligand-mediated phosphorylation of the Serine339 (CXCR4-S339) residue of the intracellular domain by PIM1 is implicated in surface re-expression of this receptor. Here, we report that phosphorylation of CXCR4-S339 in bone marrow (BM) biopsies correlated with poor prognosis in a cohort of AML patients. To functionally address the impact of CXCR4-S339 phosphorylation, we generated cell lines-expressing CXCR4 mutants that mimic constitutive phosphorylation (S339E) or abrogate phosphorylation (S339A). Whereas the expression of CXCR4 significantly increased, both CXCR4-S339E and the CXCR4-S339A mutants significantly reduced the BM homing and engraftment of Kasumi-1 AML cells in immunodeficient mice. In contrast, only expression of the CXCR4-S339E mutant increased the BM retention of the cells and resistance to cytarabine treatment, and impaired detachment capacity and AMD3100-induced mobilization of engrafted leukemic cells. These observations suggest that the poor prognosis in AML patients displaying CXCR4-S339 phosphorylation can be the consequence of an increased retention to the BM associated with an enhanced chemoresistance of leukemic cells. Therefore, CXCR4-S339 phosphorylation could serve as a novel prognostic marker in human AML.Leukemia advance online publication, 26 July 2013; doi:10.1038/leu.2013.201. 23625813 Glomerular Filtration Rate Equations Overestimate Creatinine Clearance in Older Individuals Enrolled in the Baltimore Longitudinal Study on Aging: Impact on Renal Drug Dosing. OBJECTIVES: To evaluate the performance of kidney function estimation equations and to determine the frequency of drug dose discordance in an older population. DESIGN: Cross-sectional analysis of data from community-dwelling volunteers randomly selected from the Baltimore Longitudinal Study of Aging from January 1, 2005, to December 31, 2010. SUBJECTS: A total of 269 men and women with a mean ± SD age of 81 ± 6 years, mean serum creatinine concentration (Scr ) of 1.1 ± 0.4 mg/dl, and mean 24-hour measured creatinine clearance (mClcr ) of 53 ± 13 ml/minute. MEASUREMENTS AND MAIN RESULTS: Kidney function was estimated by using the following equations: Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). The performance of each equation was assessed by measuring bias and precision relative to mClcr . Dose calculation errors (discordance) were determined for 10 drugs requiring renal dosage adjustments to avoid toxicity when compared with the dosages approved by the Food and Drug Administration. The CG equation was the least biased estimate of mClcr . The MDRD and CKD-EPI equations were significantly positively biased compared with CG (mean ± SD 34 ± 20% and 22 ± 15%, respectively, p<0.001) and mClcr (29 ± 47% and 18 ± 40%, respectively, p<0.001). Rounding low Scr values (less than 1.0 mg/dl) up to an arbitrary value of 1.0 mg/dl resulted in CG values (44 ± 10 ml/minute) that were significantly lower than mClcr (56 ± 12 ml/minute, p<0.001) and CG (56 ± 15 ml/minute, p<0.001). The MDRD and CKD-EPI equations had median dose discordance rates of 28.6% and 22.9%, respectively. CONCLUSION: The MDRD and CKD-EPI equations significantly overestimated creatinine clearance (mClcr and CG) in elderly individuals. This leads to dose calculation errors for many drugs, particularly in individuals with severe renal impairment. Thus equations estimating glomerular filtration rate should not be substituted in place of the CG equation in older adults for the purpose of renal dosage adjustments. In addition, the common practice of rounding or replacing low Scr values with an arbitrary value of 1.0 mg/dl for use in the CG equation should be avoided. Additional studies that evaluate alternative eGFR equations in the older populations that incorporate pharmacokinetic and pharmacodynamic outcomes measures are needed. 23831385 Long-Term Impact of Strength Training on Muscle Strength Characteristics in Older Adults. To evaluate the long-term preventive impact of strength training on muscle performance in older adults. A 7-year follow-up on a 1-year randomized controlled trial comparing the effects of combined resistance training and aerobic training and whole-body vibration training on muscle performance. University training center. Men and women (N=83; control [CON] group, n=27; strength-training intervention [INT] group, n=56) between 60 and 80 years of age. The INT group exercised 3 times weekly during 1 year, performing a combined resistance training and aerobic training program or a whole-body vibration training program. The former training program was designed according to American College of Sports Medicine guidelines. The whole-body vibration training program included unloaded static and dynamic leg exercises on a vibration platform. The CON group did not participate in any training program. Static strength (STAT), dynamic strength at 60°/s (DYN60) and at 240°/s (DYN240), speed of movement at 20% (S20). From baseline to postintervention, muscle performance did not change in the CON group, except for S20 (+6.55%±2.88%, P<.001). One year of strength training increased (P≤.001) STAT (+11.46%±1.86%), DYN60 (+6.96%±1.65%), DYN240 (+9.25%±1.68%), and S20 (+7.73%±2.19%) in the INT group. Between baseline and follow-up, muscle performance decreased (P<.001) in both groups. However, STAT and DYN60 showed a significantly lower loss in the INT group (-8.65%±2.35% and -7.10%±2.38%, respectively) compared with the CON group (-16.47%±2.69% and -15.08%±2.27%, respectively). This positive impact might be due to the preservation of the training-induced gains, given the similar annual decline rates in both groups from postintervention to follow-up. Additionally, in trained participants, aging seems to impact velocity-dependent strength and power more compared with basic strength, as the total losses in DYN240 (CON, -15.93%±2.64%; INT, -11.39%±1.95%) and S20 (CON, -14.39%±2.10%; INT, -13.16%±1.72%) did not differ significantly between the groups. A 1-year strength-training intervention results in an improved muscle performance in older adults 7 years after their enrollment in the intervention. However, an extensive exercise program cannot attenuate the age-related decline once the intervention stops. 23962218 An optimized device for staining electron microscopy grids. Proper staining of grids is critical for transmission electron microscopy (TEM). Staining must be done as quickly as possible using minimal reagents and with consideration for the environment. We developed a new device for efficient staining of multiple TEM grids. We studied reagent evaporation, rinsing volume, flow rate and re-use of uranyl acetate, and provide here a procedure for efficient staining using the new device. Our device permits TEM grids to be stained with less reagent than alternative staining apparatuses; staining requires a total volume of 260 μl for five grids. Reagent evaporation is less than 6% even if used at 37° C. Moreover, our staining apparatus reduces chemical waste and shortens experiment time by staining several grids simultaneously. Our staining device is a compromise between time-consuming single grid processing and expensive commercial devices that consume large amounts of reagents. 23828194 The use of computer-assisted FACE for minimal-invasive caries excavation. Caries excavation is still a demanding procedure today. In the past years, methods using light-induced fluorescence have proven their ability to detect bacteria remaining in the tooth's hard tissues. However, methods to control the complete removal of infected dentine have not yet been validated. The aim of the present study was to evaluate the degree of dentine removal during caries excavation using a camera- and software-based device as a guide for fluorescence-aided caries excavation (FACE) in comparison to visual-tactile inspection and a dye-staining method. One hundred teeth with carious lesions (C3) were randomly allocated to four groups and excavated with the respective method as primary excavation control method. When the first method indicated complete caries excavation, a second method was used to affirm this. Subsequently, dentine samples were taken to determine residual contamination using PCR. After embedding and sectioning the teeth dentine, microhardness was measured perpendicular to the cavity floor. By using the camera- and software-based device, 94 % of the cavities tested were free of bacterial contamination. All cavities excavated with the dye-staining or visual-tactile control method were free of bacterial contamination but resulted in a significantly higher dentine removal. The camera- and software-assisted caries excavation seems to be an adequate method to remove contaminated dentine without removing affected dentine. Beside its original application to monitor carious, the device is safe, effective, and easy to use for guided caries excavation and is of worth for both everyday practice and undergraduate education. 23603474 Patterns in the recording of vital signs and early warning scores: compliance with a clinical escalation protocol. The recognition of patient deterioration depends largely on identifying abnormal vital signs, yet little is known about the daily pattern of vital signs measurement and charting. We compared the pattern of vital signs and VitalPAC Early Warning Score (ViEWS) data collected from admissions to all adult inpatient areas (except high care areas, such as critical care units) of a NHS district general hospital from 1 May 2010 to 30 April 2011, to the hospital's clinical escalation protocol. Main outcome measures were hourly and daily patterns of vital signs and ViEWS value documentation; numbers of vital signs in the periods 08:00-11:59 and 20:00-23:59 with subsequent vital signs recorded in the following 6 h; and time to next observation (TTNO) for vital signs recorded in the periods 08:00-11:59 and 20:00-23:59. 950 043 vital sign datasets were recorded. The daily pattern of observation documentation was not uniform; there were large morning and evening peaks, and lower night-time documentation. The pattern was identical on all days. 23.84% of vital sign datasets with ViEWS ≥ 9 were measured at night compared with 10.12-19.97% for other ViEWS values. 47.42% of patients with ViEWS=7-8 and 31.22% of those with ViEWS ≥ 9 in the period 20:00-23:59 did not have vital signs recorded in the following 6 h. TTNO decreased with increasing ViEWS value, but less than expected by the monitoring protocol. There was only partial adherence to the vital signs monitoring protocol. Sicker patients appear more likely to have vital signs measured overnight, but even their observations were often not followed by timely repeat assessments. The observed pattern of monitoring may reflect the impact of competing clinical priorities. 23933039 Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD. Atomoxetine (ATX), a drug for treatment of depression and ADHD, has a high affinity for the norepinephrine transporter (NET); however, our previous study showed it had a blocking effect similar to fluoxetine on binding of [(11)C]DASB, a selective serotonin transporter (SERT) ligand. Whether the therapeutic effects of ATX are due to inhibition of either or both transporters is not known. Here we report our comparative PET imaging studies with [(11)C]MRB (a NET ligand) and [(11)C]AFM (a SERT ligand) to evaluate in vivo IC50 values of ATX in monkeys. Rhesus monkeys were scanned up to four times with each tracer with up to four doses of ATX. ATX or saline (placebo) infusion began 2h before each PET scan, lasting until the end of the 2-h scan. The final infusion rates were 0.01-0.12mg/kg/h and 0.045-1.054mg/kg/h for the NET and SERT studies, respectively. ATX plasma levels and metabolite-corrected arterial input functions were measured. Distribution volumes (VT) and IC50 values were estimated. ATX displayed dose-dependent occupancy on both NET and SERT, with a higher occupancy on NET: IC50 of 31±10 and 99±21ng/mL plasma for NET and SERT, respectively. At a clinically relevant dose (1.0-1.8mg/kg, approx. 300-600ng/mL plasma), ATX would occupy >90% of NET and >85% of SERT. This extrapolation assumes comparable free fraction of ATX in humans and non-human primates. Our data suggests that ATX at clinically relevant doses greatly occupies both NET and SERT. Thus, therapeutic modes of ATX action for treatment of depression and ADHD may be more complex than selective blockade of NET. 23650116 A pharmacokinetic standard for babies and adults. The pharmacokinetic behavior of medicines used in humans follows largely predictable patterns across the human age range from premature babies to elderly adults. Most of the differences associated with age are in fact due to differences in size. Additional considerations are required to describe the processes of maturation of clearance processes and postnatal changes in body composition. Application of standard approaches to reporting pharmacokinetic parameters is essential for comparative human pharmacokinetic studies from babies to adults. A standardized comparison of pharmacokinetic parameters obtained in children and adults is shown for 46 drugs. Appropriate size scaling shows that children (over 2 years old) are similar to adults. Maturation changes are generally completed within the first 2 years of postnatal life; consequently babies may be considered as immature children, whereas children are just small adults. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2941-2952, 2013. 23517478 Experiences accompanying postpartum weight loss: benefits, successes, and well-being. Obesity is a growing problem in the United States, and research has supported the theory that pregnancy contributes to long-term weight gain. This phenomenological study investigated the postpartum weight loss experiences of 24 women. Women ranged in age from 25 to 35 years, were mostly Caucasian with adequate resources, and about half worked either full or part time. Women described both positive and negative experiences associated with weight loss. Themes included issues related to exercise, weight struggles, pregnancy contributions to weight gain, eating, breastfeeding, motivation for weight loss, time issues, miscellaneous struggles, realizing benefits, social support, quick weight loss, personal well-being, and successes. The overarching theme that represents these women's experiences was the need to balance weight loss activity with other responsibilities, which resulted in challenges and triumphs in women's pursuit of returning to their prepregnancy weights. Realizing benefits, successes, and personal well-being are addressed in this article. 23763512 Synergistic Effects of VOx-Pt Probed by the Oxidation of Propane on VOx/Pt(111). VOx/Pt(111), which was grown layer-by-layer and exhibited a well-defined structure, was used as a model catalytic surface to study the intrinsic catalytic activity of Pt, as well as the effect of VOx additive, for the oxidation of propane. A special sample system was designed to ensure a reliable analysis of the trace amount of model catalytic reaction products. The results show that the catalytic activities for the oxidation of C3H8 on the Pt(111) surface as adding VOx are suppressed apparently at temperatures below 400 K, but enhanced significantly at temperatures above 400 K. Maximum reaction rates are achieved at a VOx coverage of about 0.3 ML at the test temperatures of 423 and 473 K. The infrared reflection-absorption spectroscopy (IRAS) results show that the redox property of the VOx-Pt is much better than that of the bulklike VOx. This is confirmed by CO poisoning tests, in that the oxidation of VOx/Pt(111) is significantly suppressed by the coadsorbed CO. The kinetic data demonstrate that there are at least two catalytically active sites, metallic Pt and VOx-Pt interface, for the activation and oxidation of C3H8. The promotion effects of VOx on Pt for the oxidation of C3H8 can be attributed to the synergy between VOx and Pt. 23871235 Accuracy of gastrocnemius muscles forces in walking and running goats predicted by one-element and two-element Hill-type models. Hill-type models are commonly used to estimate muscle forces during human and animal movement-yet the accuracy of the forces estimated during walking, running, and other tasks remains largely unknown. Further, most Hill-type models assume a single contractile element, despite evidence that faster and slower motor units, which have different activation-deactivation dynamics, may be independently or collectively excited. This study evaluated a novel, two-element Hill-type model with "differential" activation of fast and slow contractile elements. Model performance was assessed using a comprehensive data set (including measures of EMG intensity, fascicle length, and tendon force) collected from the gastrocnemius muscles of goats during locomotor experiments. Muscle forces predicted by the new two-element model were compared to the forces estimated using traditional one-element models and to the forces measured in vivo using tendon buckle transducers. Overall, the two-element model resulted in the best predictions of in vivo gastrocnemius force. The coefficient of determination, r(2), was up to 26.9% higher and the root mean square error, RMSE, was up to 37.4% lower for the two-element model than for the one-element models tested. All models captured salient features of the measured muscle force during walking, trotting, and galloping (r(2)=0.26-0.51), and all exhibited some errors (RMSE=9.63-32.2% of the maximum in vivo force). These comparisons provide important insight into the accuracy of Hill-type models. The results also show that incorporation of fast and slow contractile elements within muscle models can improve estimates of time-varying, whole muscle force during locomotor tasks. 23936483 Canine Adenovirus Type 2 Vector Generation via I-Sce1-Mediated Intracellular Genome Release. When canine adenovirus type 2 (CAdV-2, or also commonly referred to as CAV-2) vectors are injected into the brain parenchyma they preferentially transduce neurons, are capable of efficient axonal transport to afferent regions, and allow transgene expression for at last >1 yr. Yet, translating these data into a user-friendly vector platform has been limited because CAV-2 vector generation is challenging. Generation of E1-deleted adenovirus vectors often requires transfection of linear DNA fragments of >30 kb containing the vector genome into an E1-transcomplementing cell line. In contrast to human adenovirus type 5 vector generation, CAV-2 vector generation is less efficient due, in part, to a reduced ability to initiate replication and poor transfectibility of canine cells with large, linear DNA fragments. To improve CAV-2 vector generation, we generated an E1-transcomplementing cell line expressing the estrogen receptor (ER) fused to I-SceI, a yeast meganuclease, and plasmids containing the I-SceI recognition sites flanking the CAV-2 vector genome. Using transfection of supercoiled plasmid and intracellular genome release via 4-OH-tamoxifen-induced nuclear translocation of I-SceI, we improved CAV-2 vector titers 1,000 fold, and in turn increased the efficacy of CAV-2 vector generation. 23860789 Bony impingement depends on the bone morphology of the hip after total hip arthroplasty. The purpose of this study was to evaluate whether the bone morphology of the hip affects the range of motion (ROM) in total hip arthroplasty (THA). Using the CT data of 63 patients who underwent THA, we calculated the ROM of flexion (Flex), internal rotation (Int-R) and external rotation (Ext-R) using 3D dynamic analysis software. We measured the distance between the anterior surface of the stem and anterior aspect of the greater trochanter (GTa length) at the cutting point and between the tip of the antero-inferior iliac spine (AIIS) and coronal plane of both femoral heads (AIIS length), as a parameter of the femur and pelvis, respectively. The relationship between the ROM, bone anatomy and impingement site was evaluated. We found a significant decrease in the ROM of Flex and the Int-R to be inversely proportional to the GTa and AIIS length. In Flex and Int-R, the anterior intertrochanteric region often impinges on the AIIS in patients with larger bone anatomy. We demonstrated that the bone morphology of the hip substantially affects the ROM of Flex and Int-R, especially in patients with large bone anatomy. For these patients we should consider bony impingement in THA. 23495093 Association of environmental and genetic factors and gene-environment interactions with risk of developing rheumatoid arthritis. We developed rheumatoid arthritis (RA) risk models based on validated environmental factors (E), genetic risk scores (GRS), and gene-environment interactions (GEI) to identify factors that can improve accuracy and reclassification. Models including E, GRS, and GEI were developed among 317 white seropositive RA cases and 551 controls from the Nurses' Health Studies (NHS) and validated in 987 white anti-citrullinated protein antibody-positive cases and 958 controls from the Swedish Epidemiologic Investigation of Rheumatoid Arthritis (EIRA), stratified by sex. Primary analyses included age, smoking, alcohol, parity, weighted GRS using 31 non-HLA alleles and 8 HLA-DRB1 alleles, and the HLA × smoking interaction. Expanded models included reproductive, geographic, and occupational factors and additional GEI terms. Hierarchical models were compared for discriminative accuracy using the area under the receiver operating characteristic curve (AUC) and reclassification using the integrated discrimination improvement (IDI) and the continuous net reclassification improvement. The mean age at RA diagnosis was 56 years in the NHS and 51 years in the EIRA. Primary models produced AUCs of 0.716 in the NHS, 0.716 in women in the EIRA, and 0.756 in men in the EIRA. Expanded models produced improvements in discrimination with AUCs of 0.738 in the NHS, 0.724 in women in the EIRA, and 0.769 in men in the EIRA. Models including genetic factors (G) or G + GEI improved reclassification over E models; the full E + G + GEI model provided the optimal predictive ability by IDI analyses. We have developed comprehensive RA risk models incorporating E, G, and GEI that have improved the discriminative accuracy for RA. Further work developing and assessing highly specific prediction models in prospective cohorts is still needed to inform primary RA prevention trials. 23617601 Acute effects of short-chain alkylglycerols on blood-brain barrier properties of cultured brain endothelial cells. The blood-brain barrier (BBB) restricts drug penetration to the brain preventing effective treatment of patients suffering from brain tumours. Intra-arterial injection of short-chain alkylglycerols (AGs) opens the BBB and increases delivery of molecules to rodent brain parenchyma in vivo. The mechanism underlying AG-mediated modification of BBB permeability is still unknown. Here, we have tested the effects of AGs on barrier properties of cultured brain microvascular endothelial cells. The effects of two AGs, 1-O-pentylglycerol and 2-O-hexyldiglycerol were examined using an in vitro BBB model consisting of primary cultures of rat brain endothelial cells, co-cultured with rat cerebral glial cells. Integrity of the paracellular, tight junction-based, permeation route was analysed by functional assays, immunostaining for junctional proteins, freeze-fracture electron microscopy, and analysis of claudin-claudin trans-interactions. AG treatment (5 min) reversibly reduced transendothelial electrical resistance and increased BBB permeability for fluorescein accompanied by changes in cell morphology and immunostaining for claudin-5 and β-catenin. These short-term changes were not accompanied by alterations of inter-endothelial tight junction strand complexity or the trans-interaction of claudin-5. AG-mediated increase in brain endothelial paracellular permeability was short, reversible and did not affect tight junction strand complexity. Redistribution of junctional proteins and alterations in the cell shape indicate the involvement of the cytoskeleton in the action of AGs. These data confirm the results from in vivo studies in rodents characterizing AGs as adjuvants that transiently open the BBB. 23707329 Mycelia extracts of fungal strains isolated from Cordyceps sinensis differently enhance the function of RAW 264.7 macrophages. Cordyceps sinensis, an entomogenous fungus used in traditional Chinese medicine with multiple pharmacological activities. However, its usage has been limited due to the high price and short supply. Isolate of fungi strains from natural Cordyceps sinensis to achieve a large-scale production by fermentation is an alternative choice. The aim of this study was to investigate and compare the effects of mycelia extracts of different fungal stains isolated from natural Cordyceps sinensis on macrophage functions in vitro. Macrophages' proliferation, phagocytosis, nitric oxide (NO) production, cytokines secretion, iNOS, NF-κB p65 activation and translocation were investigated by the MTT assay, flow cytometry assay, Griess reagent method, ELISA, western blot and immunostaining assay, respectively. The results showed that the effects of cultured Cordyceps mycelia of different fungal strains isolated from natural Cordyceps sinensis on macrophages greatly variant. Among 17 Cordyceps aqueous extracts, only five extracts (UM01, QH11, BNQM, GNCC and DCXC) could significantly increase cell proliferation and NO production of RAW 264.7 mouse macrophages. Moreover, the five extracts, especially UM01 and QH11, significantly enhanced phagocytosis and promoted cytokines release of macrophages. Polysaccharides in cultured UM01 mycelia were found to be the main immune stimulating compounds. The variation of biological effects of fermented mycelia of different fungal strains from natural Cordyceps sinensis may be derived from their chemical diversity, especially polysaccharides, which need further study in future. 23886287 An exploratory study of patient preferences for pain management during intravenous insertion: maybe we should sweat the small stuff. The purpose of this exploratory study was to add to the body of knowledge about patient preferences for pain management during intravenous (IV) insertion. A convenience sample of 30 patients who were scheduled to undergo surgical or nonsurgical procedures requiring an IV catheter were given a choice among intradermal lidocaine, guided imagery, or no pain control strategy. Only four participants chose no pain management strategy, the traditional standard of care. Most (86.6%) desired a pain control strategy. Mean pain ratings on IV insertion were very low for all the three groups, although pain was significantly lower in the intradermal lidocaine group. This study illustrates that patients have preferences for pain control during IV insertion and believe that they should be involved in decisions about pain management. 23301836 Nanoscale Dynamics and Protein Adhesivity of Alkylamine Self-Assembled Monolayers on Graphene. Atomic-scale molecular dynamics computer simulations are used to probe the structure, dynamics, and energetics of alkylamine self-assembled monolayer (SAM) films on graphene and to model the formation of molecular bilayers and protein complexes on the films. Routes toward the development and exploitation of functionalized graphene structures are detailed here, and we show that the SAM architecture can be tailored for use in emerging applications (e.g., electrically stimulated nerve fiber growth via the targeted binding of specific cell surface peptide sequences on the functionalized graphene scaffold). The simulations quantify the changes in film physisorption on graphene and the alkyl chain packing efficiency as the film surface is made more polar by changing the terminal groups from methyl (-CH(3)) to amine (-NH(2)) to hydroxyl (-OH). The mode of molecule packing dictates the orientation and spacing between terminal groups on the surface of the SAM, which determines the way in which successive layers build up on the surface, whether via the formation of bilayers of the molecule or the immobilization of other (macro)molecules (e.g., proteins) on the SAM. The simulations show the formation of ordered, stable assemblies of monolayers and bilayers of decylamine-based molecules on graphene. These films can serve as protein adsorption platforms, with a hydrophobin protein showing strong and selective adsorption by binding via its hydrophobic patch to methyl-terminated films and binding to amine-terminated films using its more hydrophilic surface regions. Design rules obtained from modeling the atomic-scale structure of the films and interfaces may provide input into experiments for the rational design of assemblies in which the electronic, physicochemical, and mechanical properties of the substrate, film, and protein layer can be tuned to provide the desired functionality. 23863868 Preparation, structural diversity and characterization of a family of Cd(ii)-organic frameworks. Two Cd(ii)-organic frameworks based on 5-iodoisophthalate (IIP(2-)), {[Cd(IIP)(bte)(H2O)]·H2O}n (1) and [Cd(IIP)(bpp)(H2O)]n (2), were obtained either at an ambient temperature or under solvothermal conditions at 120 °C in the presence of 1,4-bis(1,2,4-triazol-1-yl)ethane (bte) and 1,3-bis(4-pyridyl)propane (bpp) as auxiliary ligands, respectively. 1 is a novel discrete single-walled Cd(ii)-organic tube (SWCOT) which further extends into a 3D supramolecular interdigitated microporous columnar architecture supported by C-II halogen bonds and hydrogen bonds, while 2 exhibits an interesting two-fold interpenetrated 3D diamond network architecture. When the auxiliary ligands bte or bpp were replaced by a longer spacer ligand with more flexibility, 1,4-bis(triazol-1-ylmethyl)benzene (bbtz), the unique discrete single-walled Cd(ii)-organic nanotube (SWCONT), {[Cd(IIP)(bbtz)(H2O)]·H2O}n (3), which further extends into a 3D supramolecular microporous framework supported by face-to-face ππ stacking interactions and hydrogen bonds, was generated at room temperature. Under solvothermal conditions at 120 °C, an interesting two-fold 2D "embracing" (4,4) topological network, [Cd(IIP)(bbtz)(H2O)] (4), which further extends into a two-fold 3D "embracing" supramolecular framework through O-HO hydrogen bonds, is obtained. 4 loses crystallinity in air, leading to the formation of [Cd(IIP)(bbtz)]·0.5H2O (4A) evidenced by elemental analysis, thermogravimetric analysis (TGA) and powder X-ray diffraction (PXRD). Remarkably, in situ rapid and reversible dehydration-rehydration in static air occurs in 1-3, indicating their potential applications as water absorbent and sensing materials. Dehydrated 1 and 3 show selective gas adsorption of CO2 over N2 and dehydrated 3 can adsorb methanol and ethanol vapors strongly. These compounds exhibit blue fluorescence in the solid state. 23423539 Efficacy of the use of two simultaneously TENS devices for fibromyalgia pain. Fibromyalgia is characterized by a range of symptoms that include muscle pain, fatigue and sleep disorders. Transcutaneous electrical nerve stimulation (TENS) is an established method for pain relief. The purpose of the study was to evaluate the effectiveness and safety of the use of two simultaneously new TENS devices for fibromyalgia pain. After Ethics approval and informed consent, 39 patients were prospectively divided into three groups to evaluate TENS device, applied simultaneously in each patient: (1) at the lower back (perpendicular to the vertebrae canal, at the level of the 5th lumbar vertebrae) and (2) centrally above and below the space between the C7 and T1 spinous processes. The devices were applied for 20 min at 12-h interval during 7 consecutive days. For the placebo group (PG), the devices did not transmitted electrical stimulus. The single-TENS group (STG) (n = 13) had one active and one placebo TENS. The DTG applied both active TENS devices at the low back and cervical areas. Diclofenac was used as rescue analgesic. The efficacy measures were pain relief, reduction in use of daily analgesic tablets, quality of sleep and fatigue. The evaluation within groups revealed that patients from DPG refereed no pain relief when compared to their previous VAS pain score (8 cm, p > 0.05), while patients from the STG refereed improvement of 2.5 cm in the pain VAS (previous 8.5 cm compared to 6 cm after treatment) (p < 0.05), and the DPG refereed daily maintained reduction of 4 cm in the VAS pain (previous 8.5-4.3 cm) (p < 0.02). Concurrent daily consumption of analgesic tablets was reduced in both STG (p < 0.05) and DTG (p < 0.02). Comparison among groups revealed that analgesia, as well as quality of sleep and disposition, was DTG > STG > PG (p < 0.05). Participants subjectively found the active device useful. While the application of a single active TENS improved pain relief in fibromyalgia pain, pain and fatigue were further improved when two active devices were simultaneously applied at the low back and cervical area, with no side effects. 23940660 Akt-Induced Phosphorylation of N-CoR at Serine 1450 Contributes to Its Misfolded Conformational Dependent Loss (MCDL) in Acute Myeloid Leukemia of the M5 Subtype. The nuclear receptor co-repressor (N-CoR) is a key component of the generic co-repressor complex that plays an important role in the control of cellular growth and differentiation. As shown by us recently, the growth suppressive function of N-CoR largely relies on its capacity to repress Flt3, a key regulator of cellular gorwth during normal and malignant hematopoesis. We further demonstrated how de-repression of Flt3 due to the misfolded conformation dependent loss (MCDL) of N-CoR contributed to malignant growth in acute myeloid leukemia (AML). However, the molecular mechanism underlying the MCDL of N-CoR and its implication in AML pathogenesis is not fully understood. Here, we report that Akt-induced phosphorylation of N-CoR at the consensus Akt motif is crucial for its misfolding and subsequent loss in AML (AML-M5). N-CoR displayed significantly higher level of serine specific phosphorylation in almost all AML-M5 derived cells and was subjected to processing by AML-M5 specific aberrant protease activity. To identify the kinase linked to N-CoR phosphorylation, a library of activated kinases was screened with the extracts of AML cells; leading to the identification of Akt as the putative kinase linked to N-CoR phosphorylation. Consistent with this finding, a constitutively active Akt consistently phosphorylated N-CoR leading to its misfolding; while the therapeutic and genetic ablation of Akt largely abrogated the MCDL of N-CoR in AML-M5 cells. Site directed mutagenic analysis of N-CoR identified serine 1450 as the crucial residue whose phosphorylation by Akt was essential for the misfolding and loss of N-CoR protein. Moreover, Akt-induced phosphorylation of N-CoR contributed to the de-repression of Flt3, suggesting a cross talk between Akt signaling and N-CoR misfolding pathway in the pathogenesis of AML-M5. The N-CoR misfolding pathway could be the common downstream thread of pleiotropic Akt signaling activated by various oncogenic insults in some subtypes of leukemia and solid tumors. 23615577 Lanthanum carbonate delays progression of coronary artery calcification compared with calcium-based phosphate binders in patients on hemodialysis: a pilot study. Background and Coronary artery calcification (CAC) is associated with future cardiovascular events and/or death of patients on hemodialysis (HD). We investigated whether progression of CAC in patients on HD could be delayed by switching from a calcium (Ca)-based phosphate (Pi) binder to lanthanum carbonate. Design, Setting, Participants, and Measurements: The CAC scores were evaluated at study enrollment and after 6 months in 52 patients on HD using calcium carbonate (CC) as a Pi binder. Patients were randomly divided into 2 groups assigned to receive either CC or lanthanum carbonate (LC), and the CAC scores were evaluated after a 6-month treatment period. Progression of CAC was assessed, as were serum levels of Ca, Pi, and intact parathyroid hormone (iPTH). Forty-two patients completed the study (23 receiving CC and 19 receiving LC). In the 6 months prior to randomization, all patients were treated with CC. During this 6-month period, the CAC scores increased significantly in all 42 patients. Once randomized, there was significantly less progression in the group treated with LC than with CC. Changes in CAC scores from 6 to 12 months were significantly smaller in the LC group than the CC group (-288.9 ± 1176.4 vs 107.1 ± 559.6, P = .036), and percentage changes were also significantly different (-6.4% vs 41.2%, P = .024). Serum Ca, Pi, and iPTH levels were similar in both groups during the study period. This pilot study suggested that LC delayed progression of CAC in patients on HD compared with CC. 23426224 Novel microwave assisted chemical synthesis of Nd₂Fe₁₄B hard magnetic nanoparticles. The high coercivity and excellent energy product of Nd2Fe14B hard magnets have led to a large number of high value added industrial applications. Chemical synthesis of Nd2Fe14B nanoparticles is challenging due to the large reduction potential of Nd(3+) and the high tendency for Nd2Fe14B oxidation. We report the novel synthesis of Nd2Fe14B nanoparticles by a microwave assisted combustion process. The process consisted of Nd-Fe-B mixed oxide preparation by microwave assisted combustion, followed by the reduction of the mixed oxide by CaH2. This combustion process is fast, energy efficient and offers facile elemental substitution. The coercivity of the resulting powders was ∼8.0 kOe and the saturation magnetization was ∼40 emu g(-1). After removal of CaO by washing, saturation magnetization increased and an energy product of 3.57 MGOe was obtained. A range of magnetic properties was obtained by varying the microwave power, reduction temperature and Nd to Fe ratio. A transition from soft to exchange coupled to hard magnetic properties was obtained by varying the composition of NdxFe1-xB8 (x varies from 7% to 40%). This synthesis procedure offers an inexpensive and facile platform to produce exchange coupled hard magnets. 23873387 Preliminary Phytochemical Screening and Antibacterial Properties of Crude Stem Bark Extracts and Fractions of Parkia biglobosa (Jacq.). A methanolic crude extract of Parkia biglobosa was prepared and later partitioned in succession with different solvents of increasing polarity ranging from n-hexane, chloroform and ethyl acetate to butanol. Phytochemical screening of the extract revealed the presence of alkaloids, tannins, saponins, flavonoids, steroids, glycoside and sugars. The inhibition zones exhibited by the extract against the tested bacteria ranged between 14 ± 0.00 mm (against Escherichia coli) and 28 ± 0.71 mm (against Pseudomonas aeruginosa). The MIC of the methanolic extract of P. biglobosa against isolates ranged between 0.63 mg/mL and 5 mg/mL, while the MIC values exhibited by the n-hexane and aqueous fractions ranged between 0.63 mg/mL and 10 mg/mL. Overall the extract and fractions of P. biglobosa used in this work were found to possess antimicrobial properties which compared favourably with those of streptomycin. These observations make this plant a potential source of bioactive compounds that can be used in management of bacterial infections. The use of this plant as herbal medicaments in African countries and the reports on the toxicity of the plant further show that the plant is non-toxic to humans. 23895454 Synthesis of Highly Water-Dispersible Polydopamine-Modified Multiwalled Carbon Nanotubes for Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Analysis. In this work, we synthesized highly water-dispersible multiwalled carbon nanotubes@polydopamine (MWCNTs@PDA) core-shell composites by a facile in situ oxidative polymerization. The composites were successfully applied as a novel matrix for the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analysis of various water-soluble small molecule compounds. It was found that MWCNTs@PDA composites have a higher sensitivity and peak intensities for small molecules detection. 22495815 Long-term Follow-up Study in Budd-Chiari Syndrome: Single-center Experience in 22 Years. We aimed to present our long-term surveillance experience in patients with Budd-Chiari syndrome (BCS), and we retrospectively evaluated the natural history, results of thrombophilia studies, and the factors related to mortality. Primary BCS is a rare form of vascular disease, secondary to underlying thrombophilia. Because of its rarity and heterogeneous nature, there is a scarcity of knowledge about the natural history of the disease. In 22 years, a total of 62 patients with primary BCS were followed in our tertiary hospital. We identified an acquired cause of BCS in 40 out of 62 patients (64.5%), whereas in 6 patients (9.7%), we found no identifiable cause. One or more thrombophilia causes were identified in 56 patients (90.3%). In 19 patients with myeloproliferative disease, 15 had Janus tyrosine kinase 2 mutation analysis and Janus tyrosine kinase 2 positivity was found in 10 patients. In regression analysis, portal vein thrombosis was found to be the only indicator of mortality, with an estimated instantaneous risk of 8.4. In this study, we present one of the largest series of BCS in the English literature. We have shown that the multifactorial nature of underlying thrombophilia should be thoroughly investigated. In a patient with BCS, a clinician should be alert for the development or coexistence of portal vein thrombosis due to its deleterious effect on mortality. 23893355 Estradiol regulates large dense core vesicles in the hippocampus of adult female rats. Previous work has shown that the steroid hormone estradiol facilitates the release of anticonvulsant neuropeptides from inhibitory neurons in the hippocampus to suppress seizures. Because neuropeptides are packaged in large dense core vesicles, estradiol may facilitate neuropeptide release through regulation of dense core vesicles. In the current study, we used serial section electron microscopy in the hippocampal CA1 region of adult female rats to test three hypotheses about estradiol regulation of dense core vesicles: (1) Estradiol increases the number of dense core vesicles in axonal boutons, (2) Estradiol increases the size of dense core vesicles in axonal boutons, (3) Estradiol shifts the location of dense core vesicles toward the periphery of axonal boutons, potentially lowering the threshold for neuropeptide release during seizures. We found that estradiol increases the number and size of dense core vesicles in inhibitory axonal boutons, consistent with increased neuropeptide content, but does not shift the location of dense core vesicles closer to the bouton periphery. These effects were specific to large dense core vesicles (>80 nm) in inhibitory boutons. Estradiol had no effects on small dense core vesicles or dense core vesicles in excitatory boutons. Our results indicate that estradiol suppresses seizures at least in part by increasing the potentially releasable pool of neuropeptides in the hippocampus, and that estradiol facilitation of neuropeptide release involves a mechanism other than mobilization of dense core vesicles toward sites of release. 23475443 Response of microcrustacean communities from the surface-groundwater interface to water contamination in urban river system of the Jarama basin (central Spain). In order to evaluate the water quality at the surface/groundwater interface (hyporheic zone), the pattern of microcrustacean assemblages in response to environmental stress caused by urban industrial contamination was studied in the Jarama River basin (central Spain) during high water discharges (March and April 2011). The clustering of biological variables and the concentration of urban contaminants in hyporheic waters showed that pristine hyporheic waters have moderate species diversity (two to seven species) and dominance of k strategist stygobites, whereas excessively contaminated sites are devoid by crustaceans. An intermediate level of disturbance in hyporheic waters is associated with a peak of species taxonomic diversity (four to nine species) and proliferation of r strategist more tolerant species. Typical species found in hyporheic zone, e.g., Paracyclops imminutus (Copepoda, Cyclopoida), Cryptocandona vavrai (Ostracoda) and Herpetocypris chevreuxi (Ostracoda), were good indicators of high concentrations of Cr, Mn, Ni, Cd, Pb and VOCs; whereas the stygobites do not show any significant correlation. The effectiveness of hyporheic crustaceans as efficient bioindicators for assessing the current ecological status of river ecosystems is emphasised. 23597726 Association Between Specific Adipose Tissue CD4(+) T-Cell Populations and Insulin Resistance in Obese Individuals. An increased number of macrophages in adipose tissue is associated with insulin resistance and metabolic dysfunction in obese people. However, little is known about other immune cells in adipose tissue from obese people, and whether they contribute to insulin resistance. We investigated the characteristics of T cells in adipose tissue from metabolically abnormal insulin-resistant obese (MAO) subjects, metabolically normal insulin-sensitive obese (MNO) subjects, and lean subjects. Insulin sensitivity was determined by using the hyperinsulinemic euglycemic clamp procedure. We assessed plasma cytokine concentrations and subcutaneous adipose tissue CD4(+) T-cell populations in 9 lean, 12 MNO, and 13 MAO subjects. Skeletal muscle and liver samples were collected from 19 additional obese patients undergoing bariatric surgery to determine the presence of selected cytokine receptors. Adipose tissue from MAO subjects had 3- to 10-fold increases in numbers of CD4(+) T cells that produce interleukin (IL)-22 and IL-17 (a T-helper [Th] 17 and Th22 phenotype) compared with MNO and lean subjects. MAO subjects also had increased plasma concentrations of IL-22 and IL-6. Receptors for IL-17 and IL-22 were expressed in human liver and skeletal muscle samples. IL-17 and IL-22 inhibited uptake of glucose in skeletal muscle isolated from rats and reduced insulin sensitivity in cultured human hepatocytes. Adipose tissue from MAO individuals contains increased numbers of Th17 and Th22 cells, which produce cytokines that cause metabolic dysfunction in liver and muscle in vitro. Additional studies are needed to determine whether these alterations in adipose tissue T cells contribute to the pathogenesis of insulin resistance in obese people. 23963546 Valsartan/Amlodipine Compared to Nifedipine GITS in Patients with Hypertension Inadequately Controlled by Monotherapy. Current hypertension guidelines recommend single-pill combinations because they not only improve convenience and compliance to therapy and thus blood pressure (BP) control, but also reduce health-care costs. This study compared the efficacy and safety of valsartan/amlodipine single-pill combination with nifedipine gastrointestinal therapeutic system (GITS) in Chinese patients with hypertension who were inadequately controlled with monotherapy. In this multicenter, open-label, active-controlled, parallel-group study, 564 patients with hypertension not adequately controlled by prior monotherapy were randomized to receive valsartan/amlodipine 80/5 mg or nifedipine GITS 30 mg once daily for 12 weeks. In the intention-to-treat analysis (n = 540), valsartan/amlodipine (n = 272) showed a least-square mean reduction of -16.6 versus -10.8 mmHg by nifedipine GITS (n = 268; mean between-treatment difference: -5.8 mmHg; P < 0.0001) from baseline to week 12. The corresponding results for mean sitting diastolic BP were -8.6 and -4.6 mmHg, respectively (difference: -4.0 mmHg; P < 0.0001). The percentage of patients achieving the BP target (<140/90 or <130/80 mmHg in the absence or presence of diabetes mellitus, respectively) was significantly higher with valsartan/amlodipine (79.0%) versus nifedipine GITS (57.4%; P < 0.0001). The overall incidence rate of adverse events was lower with valsartan/amlodipine (19.2%) than with nifedipine GITS (29.4%; P = 0.004). The valsartan/amlodipine 80/5 mg single-pill combination is well tolerated and more effective than nifedipine GITS 30 mg for BP control in Chinese patients with hypertension. 23733261 Proteomic analysis revealed the altered tear protein profile in a rabbit model of Sjögren's syndrome-associated dry eye. Sjögren's syndrome (SS) is an autoimmune disease that results in pathological dryness of mouth and eye. The diagnosis of SS depends on both clinical evaluation and specific antibodies. The goal of this study was to use quantitative proteomics to investigate changes in tear proteins in a rabbit model of SS-associated dry eye, induced autoimmune dacryoadenitis (IAD). Proteomic analysis was performed by iTRAQ and nano LC-MS/MS on tears collected from the ocular surface, and specific proteins were verified by high resolution MRM. It was found that in the tears of IAD rabbits at 2 and 4 weeks after induction, S100 A6, S100 A9, and serum albumin were upregulated, whereas serotransferrin (TF), prolactin-inducible protein (PIP), polymeric immunoglobulin receptor (pIgR), and Ig gamma chain C region were downregulated. High resolution MRM with mTRAQ labeling verified the changes in S100 A6, TF, PIP, and pIgR. Our results indicated significant changes of tear proteins in IAD rabbits, suggesting these proteins could potentially be used as biomarkers for the diagnosis and prognosis of dry eye. Several of these proteins were also found in the tears of non-SS dry eye patients indicating a common basis of ocular surface pathology, however, pIgR appears to be unique to SS. 23942344 Papillary Renal Cell Cancer Is Strongly Associated with Simple Renal Cysts. Introduction: The purpose of this study was to evaluate the prevalence of simple renal cysts (SRCs) in patients with renal neoplasia. Patients and Methods: The study population consisted of 482 patients who underwent partial or radical nephrectomy for kidney tumour between 2006 and 2010. Prevalence of cysts was evaluated retrospectively on a preoperative CT or MRI scan. Results: SRCs are more prevalent in patients with papillary renal cell cancer (RCC) than patients with clear cell RCC. All obese (BMI ≥30) patients in our study population had SRCs. Conclusions: This is the first study to show an association between SRCs and papillary RCC. 23925667 CIP2A expression and prognostic role in patients with esophageal adenocarcinoma. CIP2A is overexpressed in many cancers, including esophageal squamous cell carcinoma. The regulation of c-MYC and CIP2A expression is characterized by a positive feedback mechanism facilitating the expression of both of them and accelerating cancer cell proliferation in gastric cancer. Increased CIP2A expression is a predictor of poor survival in some cancers. The incidence of positive CIP2A immunostaining and its association with c-MYC and its predictive value in esophageal adenocarcinoma are unknown. All esophageal adenocarcinoma patients from 1990 to 2007 with sufficient material for analysis of CIP2A and c-MYC in two university hospitals were included in the study. In addition, biopsies from Barrett's epithelium from the cancer patients and control tissue from normal esophageal mucosa adjacent to the tumor were included. CIP2A was moderately or strongly positive in 77.9 %, and c-MYC in 93.8 % of the cancer specimens. These frequencies were statistically different from the expression in normal esophageal epithelium. In addition, there was a positive correlation between CIP2A and c-MYC expression (p = 0.018). According to adjusted Cox regression survival analysis, CIP2A and c-MYC had no effect on survival. However, among patients with stage IVA-IVB cancer, there was a trend toward poor prognosis in CIP2A-positive patients. The expression of CIP2A and c-MYC was associated with each other, and their overexpression was found in most cases of esophageal adenocarcinoma. However, CIP2A and c-MYC had no effect on survival. 23495037 Mechanisms of ceramide-induced COX-2-dependent apoptosis in human ovarian cancer OVCAR-3 cells partially overlapped with resveratrol. Ceramide is a member of the sphingolipid family of bioactive molecules demonstrated to have profound, diverse biological activities. Ceramide is a potential chemotherapeutic agent via the induction of apoptosis. Exposure to ceramide activates extracellular-signal-regulated kinases (ERK)1/2- and p38 kinase-dependent apoptosis in human ovarian cancer OVCAR-3 cells, concomitant with an increase in the expression of COX-2 and p53 phosphorylation. Blockade of cyclooxygenase-2 (COX-2) activity by siRNA or NS398 correspondingly inhibited ceramide-induced p53 Ser-15 phosphorylation and apoptosis; thus COX-2 appears at the apex of the p38 kinase-mediated signaling cascade induced by ceramide. Induction of apoptosis by ceramide or resveratrol was inhibited by the endocytosis inhibitor, cytochalasin D (CytD); however, cells exposed to resveratrol showed greater sensitivity than ceramide-treated cells. Ceramide-treated cells underwent a dose-dependent reduction in trans-membrane potential. Although both ceramide and resveratrol induced the expressions of caspase-3 and -7, the effect of inducible COX-2 was different in caspase-7 expression induced by ceramide compared to resveratrol. In summary, resveratrol and ceramide converge on an endocytosis-requiring, ERK1/2-dependent signal transduction pathway and induction of COX-expression as an essential molecular antecedent for subsequent p53-dependent apoptosis. In addition, expressions of caspase-3 and -7 are observed. However, a p38 kinase-dependent signal transduction pathway and change in mitochondrial potential are also involved in ceramide-induced apoptosis. 23653009 Toll-like receptor (TLR) and matrix metalloproteinase (MMP) polymorphisms and periodontitis susceptibility: a meta-analysis. The aim of this study was to determine whether the toll-like receptor (TLR) and matrix metalloproteinase (MMP) polymorphisms confers susceptibility to periodontitis in ethnically different populations. A literature search using PubMed and Embase provided the data to conduct a meta-analysis on the associations between the TLR2 Arg753Gln, TLR4 Asp299Gly, Thr399Ile, MMP-1 -1607 G1/G2 and MMP-9 -1562 C/T polymorphisms and periodontitis. A total of 32 studies (14 on TLR polymorphisms and 18 on MMP polymorphisms) were considered in the meta-analysis. The meta-analysis showed no association between periodontitis and the TLR2 753Arg allele (Odds ratio [OR] = 0.962, 95 % confidence interval [CI] = 0.662-1.400, p = 0.841). Meta-analysis of the TLR4 Asp299Gly and Thr399Ile polymorphisms showed no association between periodontitis and the TLR4 299Asp allele in all study subjects (OR = 0.984, 95 % CI = 0.761-1.271, p = 0.900; OR = 1.030, 95 % CI = 0.748-1.418, p = 0.854). Meta-analysis showed an association between the MMP-1 -1607 G2G2 genotype and periodontitis in Asians (OR = 3.778, 95 % CI = 1.210-11.80, p = 0.022). Meta-analysis containing only studies in Hardy-Weinberg equilibrium revealed no association between chronic periodontitis and the MMP-9 -1562TT genotype (OR = 0.638, 95 % CI = 0.265-1.533, p = 0.315). This meta-analysis demonstrates a lack of association between the TLR2 Arg753Gln, TLR4 Asp299Gly, Thr399Ile, MMP-9 -1562 C/T polymorphisms and periodontitis, but shows an association between the MMP-1 -1607 G2G2 genotype and periodontitis in Asians. 23901957 A novel Gaussian Binning (1GB) analysis of vibrational state distributions in highly excited H2O from reactive quenching of OH∗ by H2. As shown in experiments by Lester and co-workers [J. Chem. Phys. 110, 11117 (1999)], the reactive quenching of OH∗ by H2 produces highly excited H2O. Previous limited analysis of quasiclassical trajectory calculations using standard Histogram Binning (HB) was reported [B. Fu, E. Kamarchik, and J. M. Bowman, J. Chem. Phys. 133, 164306 (2010)]. Here, we examine the quantized internal state distributions of H2O in more detail, using two versions of Gaussian Binning (denoted 1GB). In addition to the standard version of 1GB, which relies on the harmonic energies of the states (1GB-H), we propose a new and more accurate technique based on exact quantum vibrational energies (1GB-EQ). Data from about 42 000 trajectories from previous calculations that give excited water molecules are used in the two versions of 1GB as well as HB. For the vibrationally hot molecules considered in this study, the classical internal energy distribution serves as a benchmark to estimate the accuracy of the different binning methods analyzed. The 1GB discretization methods, especially the one using exact quantum energies, reconstruct the classical distribution much more accurately than HB and also the original, more elaborate Gaussian Binning method. Detailed quantum state distributions are presented for pure overtone excitations as well as several antisymmetric stretch distributions. The latter are focused on because the antisymmetric stretch has the largest emission oscillator strength of the three water modes. 23959760 Predicting risk of emergency admission to hospital using primary care data: derivation and validation of QAdmissions score. To develop and externally validate a risk algorithm (QAdmissions) to estimate the risk of emergency hospital admission for patients aged 18-100 years in primary care. Prospective open cohort study using routinely collected data from general practice linked to hospital episode data during the 2-year study period 1 January 2010 to 31 December 2011. 405 general practices in England contributing to the national QResearch database to develop the algorithm. Two validation cohorts to validate the algorithm (1) 202 different QResearch practices and (2) 343 practices in England contributing to the Clinical Practice Research DataLink (CPRD). All general practices had data linked to hospital episode statistics at the individual patient level. We studied 2 849 381 patients aged 18-100 years in the derivation cohort with over 4.6 million person-years of follow-up. 265 573 of these patients had one or more emergency admissions during follow-up. For the QResearch validation cohort, we identified 1 340 622 patients aged 18-100 years with over 2.2 million person-years of follow-up. Of these patients, 132 723 had one or more emergency admissions during follow-up. The CPRD cohort included 2 475 360 patients aged 18-100 years with over 3.8 million person-years of follow-up. 234 204 of these patients had one or more emergency admissions during follow-up. We excluded patients without a valid NHS number and a valid Townsend score. First (ie, incident) emergency admission to hospital in the next 2 years as recorded on the linked hospital episodes records. Candidate variables recorded on the general practitioner computer system including (1) demographic variables (age, sex, strategic health authority, Townsend deprivation score, ethnicity); (2) lifestyle variables (smoking, alcohol intake); (3) chronic diseases; (4) prescribed medication; (5) clinical values (body mass index, systolic blood pressure); (6) laboratory test results (haemoglobin, platelets, erythrocyte sedimentation rate, ratio of total serum cholesterol to high density lipoprotein cholesterol concentrations, liver function tests). We also included the number of emergency admissions in the preceding year based on information recorded on the linked hospital episodes records. The final QAdmissions algorithm incorporated 30 variables. When applied to the QResearch validation cohort, it explained 41% of the variation in women and 43% of that in men. The D statistic for QAdmissions was 1.7 in women and 1.8 in men. The receiver operating curve statistic was 0.78 for men and 0.77 for women. QAdmissions had good performance on all measures of discrimination and calibration. The positive predictive value for emergency admissions for the top tenth of patients at highest risk was 42% and the sensitivity was 39%. The results for the CPRD validation cohort were similar. The QAdmissions model provided a valid measure of absolute risk of emergency admission to hospital in the general population as shown by its performance in a separate validation cohort. Further research is needed to evaluate the cost-effectiveness of using these algorithms in primary care. 23664916 Intramuscular challenge of rainbow trout (Oncorhynchus mykiss) with two Norwegian field strains of Flavobacterium psychrophilum. In recent years there has been an increasing occurrence of Flavobacterium psychrophilum infections in farmed salmonids in Norway. The current study describes two field isolates of F. psychrophilum collected from farmed rainbow trout (Oncorhynchus mykiss) fingerlings and post smolts in Norway. Virulence of the two isolates was tested in vivo by intramuscular (IM) and/or intraperitoneal (IP) challenge of disease free, un-vaccinated rainbow trout. The isolates were concluded to be highly virulent compared to a reference isolate as they yielded high mortality after IM challenge even at low challenge doses. The more virulent of the two isolates was further used to establish a challenge model to evaluate the efficacy of vaccines against infections with F. psychrophilum. Three groups were included in the vaccination-challenge study; a vaccinated group given a 6 antigen (Ag) component vaccine containing F. psychrophilum antigens (6 Ag/F.psy(+)), a control vaccinated group administered a similar 5 antigen component vaccine without F. psychrophilum antigens (5 Ag/F.psy(-)), and a non-injected negative control group. Results from the IM challenge demonstrated that 1) our challenge model is able to discriminate between protected and unprotected experimental groups and 2) that the vaccine induced protection is specific against F. psychrophilum as mortality in the 5 Ag/F.psy(-) group was equally high as in the negative control, while the 6 Ag/F.psy(+) induced a high level of protection (RPS60 = 86.7%). The present study is one of the first to describe protection against F. psychrophilum infections induced by a multicomponent injection vaccine. 23855489 Identification of cellular proteome using two-dimensional difference gel electrophoresis in ST cells infected with transmissible gastroenteritis coronavirus. Transmissible gastroenteritis coronavirus (TGEV) is an enteropathogenic coronavirus that causes diarrhea in pigs, which is correlated with high morbidity and mortality in suckling piglets. Information remains limited about the comparative protein expression of host cells in response to TGEV infection. In this study, cellular protein response to TGEV infection in swine testes (ST) cells was analyzed, using the proteomic method of two-dimensional difference gel electrophoresis (2D DIGE) coupled with MALDI-TOF-TOF/MS identification. 33 differentially expressed protein spots, of which 23 were up-regulated and 10 were down-regulated were identified. All the protein spots were successfully identified. The identified proteins were involved in the regulation of essential processes such as cellular structure and integrity, RNA processing, protein biosynthesis and modification, vesicle transport, signal transduction, and the mitochondrial pathway. Western blot analysis was used to validate the changes of alpha tubulin, keratin 19, and prohibitin during TGEV infection. To our knowledge, we have performed the first analysis of the proteomic changes in host cell during TGEV infection. 17 altered cellular proteins that differentially expressed in TGEV infection were identified. The present study provides protein-related information that should be useful for understanding the host cell response to TGEV infection and the underlying mechanism of TGEV replication and pathogenicity. 23922302 Efficacy of chemotherapy in BRCA1/2 mutation carrier ovarian cancer in the setting of poly(ADP-ribose) polymerase inhibitor resistance: a multi-institutional study. Preclinical data suggest that exposure to poly(ADP-ribose) polymerase inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated. We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200mg twice-daily for ≥1 month. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing. Data were collected from 89 patients who received a median of 3 (range 1-11) lines of pre-olaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by RECIST and 45% (35/78) by RECIST and/or GCIG-CA125 criteria with median progression-free (PFS) and overall survival (OS) of 17 weeks (95%-CI: 13-21) and 34 weeks (95%-CI: 26-42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19/48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95%-CI: 15-29) and OS of 45 weeks (95%-CI: 15-75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of 6 PARPi-resistant patients (estimated frequency of such mutations adjusted for sample size: 0.125 [95%-CI: 0-0.375]). Heavily pre-treated, PARPi-resistant PBMCOC retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development of PARPi in PBMCOC. 23600613 Affording to exchange: social capital and online information sharing. Abstract The potential harm and benefit associated with sharing personal information online is a topic of debate and discussion. Using survey methods (n=872), we explore whether attainment of social capital online relates to greater comfort with sharing personal information. We found that perceptions of bridging and bonding social capital earned from using Facebook are significant predictors of overall comfort levels with sharing personal information. This research raises timely questions about how the perceived benefits of social networking sites influence how personal information is shared online. 23946454 Soluble Interleukin-6 Receptor-Mediated Innate Immune Response to DNA and RNA Viruses. The interleukin-6 receptor, which exists as membrane-bound and soluble forms, plays critical roles in the immune response. The soluble receptor (sIL6R) has been identified as a potential therapeutic target for preventing coronary heart disease. However, little is known about the role of this receptor during viral infection. In this study, we show that sIL6R but not IL6 is induced by viral infection via the cyclooxygenase-2 pathway. Interestingly, sIL6R but not IL6 exhibited extensive antiviral activity to DNA and RNA viruses including hepatitis B virus, influenza virus, enterovirus-71, and vesicular stomatitis virus. Synergistic effects on antiviral action were not observed by combination of sIL6R and IL6. Furthermore, sIL6R mediated antiviral action via p28 pathway, and induced IFNα by promoting IRF3 and NF-κB nuclear translocation, which led to activation of IFN downstream effectors including OAS, PKR, and Mx. Thus, our results demonstrate that sIL6R, but not IL6, plays an important role in the host antiviral response. 23858467 Syntaxin1a variants lacking an N-peptide or bearing the LE mutation bind to Munc18a in a closed conformation. In neurons, soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins drive the fusion of synaptic vesicles to the plasma membrane through the formation of a four-helix SNARE complex. Members of the Sec1/Munc18 protein family regulate membrane fusion through interactions with the syntaxin family of SNARE proteins. The neuronal protein Munc18a interacts with a closed conformation of the SNARE protein syntaxin1a (Syx1a) and with an assembled SNARE complex containing Syx1a in an open conformation. The N-peptide of Syx1a (amino acids 1-24) has been implicated in the transition of Munc18a-bound Syx1a to Munc18a-bound SNARE complex, but the underlying mechanism is not understood. Here we report the X-ray crystal structures of Munc18a bound to Syx1a with and without its native N-peptide (Syx1aΔN), along with small-angle X-ray scattering (SAXS) data for Munc18a bound to Syx1a, Syx1aΔN, and Syx1a L165A/E166A (LE), a mutation thought to render Syx1a in a constitutively open conformation. We show that all three complexes adopt the same global structure, in which Munc18a binds a closed conformation of Syx1a. We also identify a possible structural connection between the Syx1a N-peptide and SNARE domain that might be important for the transition of closed-to-open Syx1a in SNARE complex assembly. Although the role of the N-peptide in Munc18a-mediated SNARE complex assembly remains unclear, our results demonstrate that the N-peptide and LE mutation have no effect on the global conformation of the Munc18a-Syx1a complex. 23863618 Sedentary Screen Time and Left Ventricular Structure and Function: the CARDIA Study. Sedentary screen time (watching TV or using a computer) predicts cardiovascular outcomes independently from moderate and vigorous physical activity and could impact left ventricular structure and function through the adverse consequences of sedentary behavior. To determine whether sedentary screen time is associated with measures of left ventricular structure and function. The Coronary Artery Risk Development in Young Adults (CARDIA) Study measured screen time by questionnaire and left ventricular structure and function by echocardiography in 2,854 black and white participants, aged 43-55 years, in 2010-2011. Generalized linear models evaluated cross-sectional trends for echocardiography measures across higher categories of screen time and adjusting for demographics, smoking, alcohol, and physical activity. Further models adjusted for potential intermediate factors (blood pressure, antihypertensive medication use, diabetes, and body mass index (BMI). The relationship between screen time and left ventricular mass (LVM) differed in blacks vs. whites. Among whites, higher screen time was associated with larger LVM (P<0.001), after adjustment for height, demographics, and lifestyle variables. Associations between screen time and LVM persisted when adjusting for blood pressure, antihypertensive medication use, and diabetes (P=0.008) but not with additional adjustment for BMI (P=0.503). Similar relationships were observed for screen time with LVM indexed to height, relative wall thickness, and mass-to-volume ratio. Screen time was not associated with left ventricular structure among blacks or left ventricular function in either race group. Sedentary screen time is associated with greater LVM in white adults and this relationship was largely explained by higher overall adiposity. The lack of association in blacks supports a potential qualitative difference in the cardiovascular consequences of sedentary screen-based behavior. 23510022 Scopoletin and Scopolin Isolated from Artemisia iwayomogi Suppress Differentiation of Osteoclastic Macrophage RAW 264.7 Cells by Scavenging Reactive Oxygen Species. Artemisia iwayomogi has been used as a folk medicine for treating various diseases including inflammatory and immune-related diseases. Scopoletin (1) and scopolin (2) were isolated from this species. Scopoletin (1) showed more potent peroxyl radical-scavenging capacity, reducing capacity, and cellular antioxidant capacity compared to scopolin (2). The inhibitory effect of 1 on the receptor activator of nuclear factor κB ligand-induced osteoclastic differentiation of RAW 264.7 macrophage cells was also more potent than that of 2. The production of general reactive oxygen species (ROS) and superoxide anions during differentiation of preosteoclastic RAW 264.7 cells into osteoclasts was attenuated by compounds 1 and 2. These findings indicate that the suppressive effects of 1 and 2 on the differentiation of preosteoclastic RAW 264.7 cells is partially due to their intracellular antioxidant capacity, as they can scavenge ROS and play an important signaling role in the differentiation process. 23919173 Genetic by environment interactions affect plant-soil linkages. The role of plant intraspecific variation in plant-soil linkages is poorly understood, especially in the context of natural environmental variation, but has important implications in evolutionary ecology. We utilized three 18- to 21-year-old common gardens across an elevational gradient, planted with replicates of five Populus angustifolia genotypes each, to address the hypothesis that tree genotype (G), environment (E), and G × E interactions would affect soil carbon and nitrogen dynamics beneath individual trees. We found that soil nitrogen and carbon varied by over 50% and 62%, respectively, across all common garden environments. We found that plant leaf litter (but not root) traits vary by genotype and environment while soil nutrient pools demonstrated genotype, environment, and sometimes G × E interactions, while process rates (net N mineralization and net nitrification) demonstrated G × E interactions. Plasticity in tree growth and litter chemistry was significantly related to the variation in soil nutrient pools and processes across environments, reflecting tight plant-soil linkages. These data overall suggest that plant genetic variation can have differential affects on carbon storage and nitrogen cycling, with implications for understanding the role of genetic variation in plant-soil feedback as well as management plans for conservation and restoration of forest habitats with a changing climate. 23963723 4D Non-uniformly sampled C,C-NOESY experiment for sequential assignment of (13)C, (15)N-labeled RNAs. A 4D (13)C(aromatic),(13)C(ribose)-edited NOESY experiment is introduced to improve sequential assignment of non-coding RNA, often hampered by a limited dispersion of (1)H and (13)C chemical shifts. The (13)C-labeling of RNA is fully utilized by inclusion of two (13)C evolution periods. These dimensions provide enhanced dispersion of resonances in the 4D spectrum. High spectral resolution is obtained using random non-uniform sampling in three indirect dimensions. The autocorrelation peaks are efficiently suppressed using band-selective pulses. Since the dynamic range of observed resonances is significantly decreased, the reconstruction of the 4D spectrum is greatly simplified. The experiment can replace two conventionally sampled 3D NOESY spectra (either ribose-(13)C- or aromatic-(13)C-separated), and remove most ambiguities encountered during sequential walks. The assignment strategy based on a homonuclear and 4D C,C-edited NOESY experiments is proposed and verified on a 34-nt RNA showing typical structure elements. 23777911 Gadolinium-coordinated elastic nanogels for in vivo tumor targeting and imaging. Coordination polymer gels have been recognized as promising hybrid nanoplatforms for imaging and therapeutic applications. Here we report functional metal-organic coordinated nanogels (GdNGs) for in vivo tumor imaging, whose non-crystalline and elastic nature allows for long blood circulation, as opposed to the rapid systemic clearance of common nanohybrids with rigid/crystalline frameworks. The deformable structure of GdNGs was constructed by random crosslinking of highly flexible polyethyleneimines (PEI) with gadolinium (Gd(3+)) coordination. The in vitro characterization revealed that GdNGs have elasticity with an apparent Young's modulus of 3.0 MPa as well as minimal cytotoxicity owing to the tight chelation of Gd(3+) ions. In contrast to common T1-enhancing gadolinium complexes, GdNGs showed the capability of enhancing negative T2 contrast (r2 = 82.6 mm(-1)s(-1)) due to the Gd(3+)-concentrated nanostructure. Systemic administration of fluorescently labeled GdNGs with core and overall hydrodynamic sizes of ~65 and ~160 nm manifested efficient targeting and dual-modality (magnetic resonance/fluorescence) imaging of tumor in a mouse model. The minimal filtration by the reticuloendothelial system (RES) suggests that the structural deformability helps the large colloids circulate in the blood stream for tumor accumulation. The unusual performance of a large Gd(3+)-complexed colloid (minimal RES sequestration and high T2 contrast enhancement) represents the versatile nature of nanoscopic organic-inorganic hybridization for biomedical applications. 23871077 Evaluation of gallic acid loaded zein sub-micron electrospun fibre mats as novel active packaging materials. The applicability of gallic acid loaded zein (Ze-GA) electrospun fibre mats towards potential active food packaging material was evaluated. The surface chemistry of the electrospun fibre mats was determined using X-ray photon spectroscopy (XPS). The electrospun fibre mats showed low water activity and whitish colour. Thermogravimetric analysis (TGA) and Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) spectroscopy revealed the stability of the fibre mats over time. The Ze-GA fibre mats displayed similar rapid release profiles, with Ze-GA 20% exhibiting the fastest release rate in water as compared to the others. Gallic acid diffuses from the electrospun fibres in a Fickian diffusion manner and the data obtained exhibited a better fit to Higuchi model. L929 fibroblast cells were cultured on the electrospun fibres to demonstrate the absence of cytotoxicity. Overall, the Ze-GA fibre mats demonstrated antibacterial activity and properties consistent with those considered desirable for active packaging material in the food industry. 23551987 The mdx mouse model as a surrogate for Duchenne muscular dystrophy. Research into fundamental principles and the testing of therapeutic hypotheses for treatment of human disease is commonly performed on mouse models of human diseases. Although this is often the only practicable approach, it carries a number of caveats arising from differences between the two species. This review focuses on the example of skeletal muscle disease, in particular muscular dystrophy, to identify some of the principal classes of obstacles to translation of data from mouse to humans. Of these, the difference in scale is one of the most commonly ignored, and is of particular interest because it has quite major repercussions for evaluation of some classes of intervention and of outcome criteria, while having comparatively little bearing on others. Likewise, inter-species differences and similarities in cell and molecular biological mechanisms underlying development, growth and response to pathological processes should be considered on an individual basis. An awareness of such distinctions is crucial if we are to avoid misjudging the likely applicability to humans of results obtained on mouse models. 23957927 Synthesis and characterization of TiO2 pillared montmorillonites: Application for methylene blue degradation. TiO2 pillared clay composites were prepared by modifying of montmorillonite (Mt) with cetyl-trimethyammoniumbromide (CTAB) and then using an acidic solution of hydrolyzed Ti alkoxide to intercalate into the interlayer space of the organic modified Mt. The as-prepared materials were characterized by XRD, FTIR, TEM, SEM TG-DTA, specific surface area and porosity measurements. The composites had a porous delaminated structure with pillared fragments and well dispersed TiO2 nanoparticles. Introduction of CTAB into the synthetic system accelerated the hydrolysis and condensation of the Ti source, which promoted TiO2 formation. In addition, the CTAB also significantly increased the porosity and surface area of the composites. A number of anatase particles, with crystal sizes of 5-10nm, were homogenously distributed on the surface of the Mt as the result of the templating role of CTAB. The resultant TiO2 pillared Mt exhibited good thermal stability as indicated by its surface area after calcination at 800°C. No phase transformations from anatase to rutile were observed even under calcination at 900°C. The grain size of the anatase in prepared sample increased from 2.67nm to 13.42nm as the calcination temperature increased from 300°C to 900°C. The photocatalytic performance of these new porous materials was evaluated by using methylene blue degradation. The composite exhibited better photocatalytic property than P 25. The maximum removal efficiency of this composite was up to 99% within 60min. 23743135 Reduced but broader prefrontal activity in patients with schizophrenia during n-back working memory tasks: A multi-channel near-infrared spectroscopy study. Caudal regions of the prefrontal cortex, including the dorsolateral (DLPFC) and ventrolateral (VLPFC) prefrontal cortex, are involved in essential cognitive functions such as working memory. In contrast, more rostral regions, such as the frontopolar cortex (FpC), have integrative functions among cognitive functions and thereby contribute crucially to real-world social activity. Previous functional magnetic resonance imaging studies have shown patients with schizophrenia had different DLPFC activity pattern in response to cognitive load changes compared to healthy controls; however, the spatial relationship between the caudal and rostral prefrontal activation has not been evaluated under less-constrained conditions. Twenty-six patients with schizophrenia and 26 age-, sex-, and premorbid-intelligence-matched healthy controls participated in this study. Hemodynamic changes during n-back working memory tasks with different cognitive loads were measured using multi-channel near-infrared spectroscopy (NIRS). Healthy controls showed significant task-related activity in the bilateral VLPFC and significant task-related decreased activity in the DLPFC, with greater signal changes when the task required more cognitive load. In contrast, patients with schizophrenia showed activation in the more rostral regions, including bilateral DLPFC and FpC. Neither decreased activity nor greater activation in proportion to elevated cognitive load occurred. This multi-channel NIRS study demonstrated that activation intensity did not increase in patients with schizophrenia associated with cognitive load changes, suggesting hypo-frontality as cognitive impairment in schizophrenia. On the other hand, patients had broader prefrontal activity in areas such as the bilateral DLPFC and FpC regions, thus suggesting a hyper-frontality compensatory response. 23401360 Protein-Carbohydrate Complex Reveals Circulating Metastatic Cells in a Microfluidic Assay. Advances in carbohydrate sequencing technologies reveal the tremendous complexity of the glycome and the role that glycomics might have to bring insight into the biological functions. Carbohydrate-protein interactions, in particular, are known to be crucial to most mammalian physiological processes as mediators of cell adhesion and metastasis, signal transducers, and organizers of protein interactions. An assay is developed here to mimic the multivalency of biological complexes that selectively and sensitively detect carbohydrate-protein interactions. The binding of β-galactosides and galectin-3-a protein that is correlated to the progress of tumor and metastasis-is examined. The efficiency of the assay is related to the expression of the receptor while anchoring to the interaction's strength. Comparative binding experiments reveal molecular binding preferences. This study establishes that the assay is robust to isolate metastatic cells from colon affected patients and paves the way to personalized medicine. 23694682 Binocular coordination of saccades during reading in children with clinically assessed poor vergence capabilities. Prior studies have pointed toward a link between the saccadic and vergence systems, coordinating binocular saccadic movements. Recent studies have shown that vergence deficits in children induce poor binocular coordination during saccades, but none of them have studied ocular motility in children during a daily task such as reading. The present study tests whether vergence deficits in children perturb binocular coordination of saccades and fixation during reading. Our second objective was to explore whether vergence training could improve the quality of binocular coordination. Twelve patients (from 7.3 to 13.4 years old) complaining from vertigo but without vestibular and neurological pathology underwent orthoptic tests and were selected for our study when they presented vergence deficits. Eye movements were recorded during a reading task with a Mobile EyeBrain® Tracker video-oculography system. Data were compared to twelve age-matched controls with normal orthoptic values. While there was no statistically significant difference in saccade amplitudes between the two groups (p=0.29), patients showed higher disconjugacy during and after the saccades compared to controls (p<0.001). After orthoptic training, six patients out of the first 12 examined came back for a second oculomotor test. All showed a significant improvement of their binocular saccade coordination. We suggest that the larger disconjugacy during reading observed in patients before training could be due to poor vergence as initially assessed by orthoptic examination. Such findings support the hypothesis of a tight relationship between the saccadic and vergence systems for controlling the binocular coordination of saccades. The improvement reported after orthoptic training is in line with the hypothesis of an adaptative interaction on a premotor level between the saccadic and vergence system. 23959666 Do we really need high-sensitive troponin immunoassays in the emergency department? Definitely, yes! Abstract Cardiac troponins have changed our understanding of myocardial infarction profoundly during the past 20 years. In fact release of cardiac troponin into the blood has become part of the definition of myocardial infarction. Diagnostics and treatment have taken these new insights into account. The novel high-sensitive assays for cardiac troponins that are available recently clearly constitute a significant further improvement of analytical performance. In addition, the still incomplete clinical data available indicate that these assays will also further improve patient care in many ways. In summary, cardiac troponins are a great example of the potential impact of analytical performance of diagnostic tests on patient care and patient outcome. 23867752 Calcium transport in gill cells of Ucides cordatus, a mangrove crab living in variable salinity environments. Crustaceans show discontinuous growth and have been used as a model system for studying cellular mechanisms of calcium transport, which is the main mineral found in their exoskeleton. Ucides cordatus, a mangrove crab, is naturally exposed to fluctuations in calcium and salinity. To study calcium transport in this species during isosmotic conditions, dissociated gill cells were marked with fluo-3 and intracellular Ca(2+) change was followed by adding extracellular Ca(2+) as CaCl2 (0, 0.1, 0.25, 0.50, 1.0 and 5mM), together with different inhibitors. For control gill cells, Ca(2+) transport followed Michaelis-Menten kinetics with Vmax=0.137±0.001 ∆Ca(2+)i (μM×22.10(4)cells(-1)×180s(-1); N=4; r(2)=0.99); Km=0.989±0.027mM. The use of different inhibitors for gill cells showed that amiloride (Na(+)/Ca(2+) exchange inhibitor) inhibited 80% of Ca(2+) transport in gill cells (Vmax). KB-R, an inhibitor of Ca influx in vertebrates, similarly caused a decrease in Ca(2+) transport and verapamil (Ca(2+) channel inhibitor) had no effect on Ca(2+) transport, while nifedipine (another Ca(2+) channel inhibitor) caused a 20% decrease in Ca(2+) affinity compared to control values. Ouabain, on the other hand, caused no change in Ca(2+) transport, while vanadate increased the concentration of intracellular calcium through inhibition of Ca(2+) efflux probably through the plasma membrane Ca(2+)-ATPase. Results show that transport kinetics for Ca(2+) in these crabs under isosmotic conditions is lower compared to a hyper-regulator freshwater crab Dilocarcinus pagei studied earlier using fluorescent Ca(2+) probes. These kinds of studies will help understanding the comparative mechanisms underlying the evolution of Ca transport in crabs living in different environments. 23951555 Microenvironment-Dependent Phenotypic Changes in a SCID Mouse Model for Malignant Mesothelioma. Background and Aims: Malignant mesothelioma is an aggressive, therapy-resistant tumor. Mesothelioma cells may assume an epithelioid or a sarcomatoid phenotype, and presence of sarcomatoid cells predicts poor prognosis. In this study, we investigated differentiation of mesothelioma cells in a xenograft model, where mesothelioma cells of both phenotypes were induced to form tumors in severe combined immunodeficiency mice. Methods: Xenografts were established and thoroughly characterized using a comprehensive immunohistochemical panel, array comparative genomic hybridization (aCGH) of chromosome 3, fluorescent in situ hybridization, and electron microscopy. Results: Epithelioid and sarcomatoid cells gave rise to xenografts of similar epithelioid morphology. While sarcomatoid-derived xenografts had higher growth rates, the morphology and expression of differentiation-related markers was similar between xenografts derived from both phenotypes. aCGH showed a convergent genotype for both xenografts, resembling the original aggressive sarcomatoid cell sub-line. Conclusion: Human mesothelioma xenografts from sarcomatoid and epithelioid phenotypes converged to a similar differentiation state, and genetic analyses suggested that clonal selection in the mouse microenvironment was a major contributing factor. This thoroughly characterized animal model can be used for further studies of molecular events underlying tumor cell differentiation. 23711973 The value of routine flexible sigmoidoscopy within 48 hours after surgical repair of ruptured abdominal aortic aneurysms. Left-sided colonic and rectal ischemia is commonly seen after surgery for ruptured abdominal aortic aneurysms (rAAAs) and is associated with increased mortality. Earlier studies have shown that flexible sigmoidoscopy (FS) may detect ischemia when performed postoperatively, and suggestions have been made that patients can be selected for FS based on clinical and biochemical parameters. We sought to perform FS in all patients surviving the first 24 hours after surgery for rAAA and to compare the findings of FS to clinical and biochemical parameters. All patients undergoing emergency surgery for rAAA and surviving the first 24 hours underwent FS to assess any degree of ischemia. During the study period, 41 patients survived the first 24 hours after surgery. In 9 (22%) patients, some degree of colonic ischemia was found. Segmental necrosis was only shown in 5% at first FS. Patients with ischemia received more blood transfusions intraoperatively than those with normal findings at FS. They also had longer periods with mean blood pressure <60 mm Hg postoperatively, and lower arterial pH on the first postoperative day. Blood lactate levels did not differ between the groups. None of the parameters were sufficiently discriminative to be used for distinguishing between patients with and without ischemia. Severe colonic ischemia was less common than previously reported. All cases of colonic ischemia were identified by early FS, but none of the clinical and biochemical parameters were sufficiently reliable to distinguish between patients with and without ischemia. It is suggested that all patients initially surviving surgery for rAAA should be offered FS to screen for colonic ischemia. 23847610 Macaque-tropic human immunodeficiency virus type 1: breaking out of the host restriction factors. Macaque monkeys serve as important animal models for understanding the pathogenesis of lentiviral infections. Since human immunodeficiency virus type 1 (HIV-1) hardly replicates in macaque cells, simian immunodeficiency virus (SIV) or chimeric viruses between HIV-1 and SIV (SHIV) have been used as challenge viruses in this research field. These viruses, however, are genetically distant from HIV-1. Therefore, in order to evaluate the efficacy of anti-HIV-1 drugs and vaccines in macaques, the development of a macaque-tropic HIV-1 (HIV-1mt) having the ability to replicate efficiently in macaques has long been desired. Recent studies have demonstrated that host restriction factors, such as APOBEC3 family and TRIM5, impose a strong barrier against HIV-1 replication in macaque cells. By evading these restriction factors, others and we have succeeded in developing an HIV-1mt that is able to replicate in macaques. In this review, we have attempted to shed light on the role of host factors that affect the susceptibility of macaques to HIV-1mt infection, especially by focusing on TRIM5-related factors. 23639601 Education provides significant benefits to patients with hepatitis B virus or hepatitis C virus infection: a systematic review. Education of individuals who are at risk for, or have been diagnosed with, chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections can improve their participation in disease management. We performed a systematic review to evaluate the effects of educational interventions for patients with HBV or HCV infections. We searched multiple databases for peer-reviewed studies of individuals with HBV or HCV infection, or those at risk for infection. Our final analysis included 14 studies that evaluated any educational intervention and reported the effectiveness or patient outcomes relevant to the intervention (7 patients with HCV infection, 4 patients with HBV infection, and 3 patients with either). Data extracted from studies included details on educational interventions, patient populations, comparison groups, and outcome measures. The quality of each study was appraised. Types of educational interventions assessed ranged from information websites and nurse-led sessions to community-wide and institutional programs. The educational interventions showed significant (P < .05) improvements to patients' knowledge about their disease, behaviors (including testing and uptake of vaccination), willingness to commence and adhere to treatment, and other outcomes such as self-efficacy and vitality or energy scores. These significant benefits were shown in 5 of 7 studies of HBV infection and 8 of 10 studies of HCV infection. On a 20-point quality scale, study scores ranged from 6 to 19. Simple educational interventions for patients with HBV or HCV infection significantly increase patients' knowledge about their disease. More complex, multimodal educational interventions seem to cause behavioral changes that increase rates of testing, vaccination (for HBV), and treatment. 23411172 Apple polyphenols suppress antigen presentation of ovalbumin by THP-1-derived dendritic cells. Apple polyphenol extract (AP) and procyanidin contained in AP were investigated for their immunomodulatory effects using THP-1-derived human dendritic cells (TDDCs). The expression levels of HLA-DR (MHC class II) and CD86 (costimulatory molecule) were measured as an indicator of antigen presentation in TDDCs. A significant decrease in HLA-DR expression was observed in the AP and fractionated procyanidin-treated cells in the presence of ovalbumin (OVA), but no effect on CD86 expression was observed. The uptake of OVA was not inhibited by AP treatment, and the gene expression of membrane-associated RING-CH ubiquitin E3 ligase, MARCH1, was up-regulated by AP treatment. It can therefore be presumed that AP suppresses HLA-DR expression via the ubiquitin-proteasome pathway. Furthermore, the up-regulation of IL-12 and TNF-α was found in the procyanidin trimers-treated cells in the presence of OVA. These results suggest that apple polyphenols would be an effective factor for the development of immunomodulatory agents with suppressive effects of antigen presentation. 23820014 Development of a gene/drug dual delivery system for brain tumor therapy: Potent inhibition via RNA interference and synergistic effects. Malignant brain tumors are characterized by three major physiological processes: proliferation, angiogenesis, and invasion. Traditional cytotoxic chemotherapies (e.g. Paclitaxel) control the tumor by blocking growth and proliferation mechanisms, but leave angiogenesis and invasion unchecked. We identified Matrix metalloproteinase-2 (MMP-2), an essential proteinase regulating brain tumor invasion and angiogenesis, as one of the therapeutic target. A designer RNAi plasmid was developed, and complexed with the gene carrier polyethylenimine (PEI), in an effort to specifically suppress MMP-2 expression in tumor cells. The gene and a cytotoxic drug Paclitaxel were then dual-encapsulated in PLGA based submicron implants to achieve a sustained release of both agents. Potent inhibition effects on MMP-2 mRNA and protein expression, in vitro cell angiogenesis and invasion were demonstrated both on the PEI/DNA nanoparticles alone, and on the PEI/DNA nanoparticles embedded in microfibers. Most importantly, through in vivo test on intracranial xenograft tumor model in BALB/c nude mice, it was proved that the gene/drug dual delivery microfibers are able to impose significant tumor regression compared with single drug delivery microfibers and commercial drug treatment, showing evidence for synergistic therapeutic efficacy. 23933186 Seasonal and nonseasonal dynamics of Aedes aegypti in Rio de Janeiro, Brazil: Fitting mathematical models to trap data. Mathematical models suggest that seasonal transmission and temporary cross-immunity between serotypes can determine the characteristic multi-year dynamics of dengue fever. Seasonal transmission is attributed to the effect of climate on mosquito abundance and within host virus dynamics. In this study, we validate a set of temperature and density dependent entomological models that are built-in components of most dengue models by fitting them to time series of ovitrap data from three distinct neighborhoods in Rio de Janeiro, Brazil. The results indicate that neighborhoods differ in the strength of the seasonal component and that commonly used models tend to assume more seasonal structure than found in data. Future dengue models should investigate the impact of heterogeneous levels of seasonality on dengue dynamics as it may affect virus maintenance from year to year, as well as the risk of disease outbreaks. 23912925 A blind spot in the eye of imaging technology: penetrating atheromatous ulcer. Acute aortic syndrome (AAS) is a term that is used to describe a similar clinical profile that may have different underlying pathophysiological mechanisms. It includes classic aortic dissection, intramural aortic hematoma, and penetrating atherosclerotic ulcer. We describe the case of a 77-year-old female who presented with syncope of unknown duration. The chest X-ray was suggestive of a widened mediastinum. The initial work-up with a computed tomography scan and transesophageal echocardiogram failed to diagnose a penetrating atherosclerotic ulcer. We discuss the importance of a high degree of clinical suspicion for AAS and the utility of different imaging technologies in making the diagnosis. 23587800 Nutritional physiology of a rock-inhabiting, model microcolonial fungus from an ancestral lineage of the Chaetothyriales (Ascomycetes). Rock-inhabiting black fungi [also microcolonial or meristematic fungi (MCF)] are a phylogenetically diverse group of melanised ascomycetes with distinctive morphological features that confer extensive stress tolerance and permit survival in hostile environments. The MCF strain A95 Knufia petricola (syn. Sarcinomyces petricola) belongs to an ancestral lineage of the order Chaetothyriales (class Eurotiomycetes). K. petricola strain A95 is a rock-inhabiting MCF and its growth requirements were studied using the 96-well plate-based Biolog System under ∼1070 different conditions (osmotic stress, pH growth optima, growth factor requirements and nutrient catabolism). A95 is an osmotolerant, oligotrophic MCF that grows best around pH 5. Remarkably, A95 shows metabolic activity in the absence of added nitrogen, phosphorus or sulphur. Correlations could be drawn between the known nutrient requirements of A95 and what probably is available in sub-aerial systems (rock and other material surfaces). Detailed knowledge of A95's metabolic requirements allowed formulation of a synthetic medium that supports strong fungal growth. 23592228 Widening the pH Activity Profile of a Fungal Laccase by Directed Evolution. Unnatural selection: A fungal laccase was tailored by directed evolution to be active at neutral/alkaline pH. After five generations, the final mutant showed a broader pH profile while retaining 50 to 80 % of its activity at neutral pH. 23719151 The prognostic efficacy of myocardial perfusion imaging in optimally treated diabetic patients with no manifestations of coronary artery disease. This study investigates the efficacy of radionuclide myocardial perfusion imaging (MPI) in the evaluation of cardiac outcome in optimally treated diabetic patients without manifestations of coronary artery disease (CAD) in relation to the inherent clinical risk. Follow-up data were collected from 86 diabetic patients who had undergone adenosine stressing MPI. These patients either had no symptoms or had noncardiac chest discomfort, had a normal resting electrocardiogram, had no known CAD or prior positive stress test results, and were receiving currently recommended therapy. Endpoints were cardiac death, myocardial infarction, new-onset heart failure, and CAD diagnosed by angiography at least 2 months from the MPI, irrespective of subsequent revascularization. Twenty-six (30%) diabetic patients had abnormal perfusion and the remaining had a normal scan. Over a median follow-up period of 32.5 months 14 cardiac events occurred. In patients with normal MPI, the annual cardiac event rate was 4.0% compared with 12.2% in those with abnormal MPI (P=0.008). In multivariate analysis, myocardial ischemia (hazard ratio 5.3; P=0.006), obesity (hazard ratio 6.8; P=0.005), the ALFEDIAM/SFC risk (hazard ratio 6.8; P=0.002), and type 2 diabetes (hazard ratio 5.3; P=0.035) were found to be independent predictors of cardiac events. The former two variables remained independent determinants of the outcome, together with peripheral arterial disease, when a different clinical risk classification system was applied. MPI provided incremental prognostic information over both clinical models formed. Adenosine MPI can effectively risk-stratify optimally treated diabetic patients without manifestations of CAD. In this subset, clinical variables can also determine the outcome independently, but MPI adds incremental predictability over them. 23640236 Less may be as good as more: feasible and effective method to differentiate gastric uptake solely on planar gallium scan in the era of SPECT/CT. We presented a patient with abnormal focal accumulation of 67Ga in the left upper abdomen. After drinking water, we successfully identified the abnormal radioactivity that was from the stomach. Subsequent endoscopic examination did not reveal gastric pathological condition. Gastric accumulation of 67Ga may relate to pathological conditions or physiological uptake, confounding interpretation of 67Ga scintigraphy. Simple water ingestion method can rapidly identify gastric 67Ga uptake, and the shape of distended stomach can also help to differentiate pathological conditions from physiological uptake, which is especially helpful for a busy nuclear medicine department and for places where the SPECT/CT systems are not available. 22459389 CRP and suPAR are differently related to anthropometry and subclinical organ damage. Low-grade inflammation is a marker for cardiovascular disease (CVD). The inflammatory biomarkers C-reactive protein (CRP) and soluble urokinase plasminogen activator receptor (suPAR) independently predict CVD. We tested the hypothesis that these biomarkers reflect different aspects of the inflammation associated with CVD. We studied 2273 subjects without CVD. Log-transformed CRP and suPAR were included in general linear and logistic regression models to compare associations with measures of anthropometry and subclinical organ damage (SOD). Owing to interactions on body mass index (BMI) (P<0.0001), the population was stratified by gender and smoking concerning anthropometry. In both genders, independent of smoking, log-CRP was positively associated with BMI (β: 0.28 to 0.40, P<0.001) and waist circumference (WC) (β: 0.27 to 0.42, P<0.001). In contrast, in smoking women and men, log-suPAR was negatively associated with BMI and WC (β: -0.09 to -0.19, P<0.05). In non-smoking women, log-suPAR was positively associated with BMI and WC (β: 0.14 and 0.16, P<0.001), whereas no associations were found in non-smoking men. No interactions were found on SOD. Adjusted for age, sex, smoking, and physical activity, log-suPAR was associated with an increased urine albumin/creatinine ratio (standardized odds ratio (95% confidence interval (CI)) for highest vs. lower quartiles: 1.36 (1.21-1.52), whereas log-CRP was not (1.10 (0.99-1.22))), and extent of atherosclerosis (standardized proportional odds ratio (95% CI) for carotid plaques 0, 1≤ to ≤3, >3: 1.31 (1.16-1.47), whereas log-CRP was not (1.00 (0.89-1.11))). CRP is positively associated with anthropometric measures, whereas suPAR is linked to endothelial dysfunction and atherosclerosis. 23624175 Cutaneous nitrogen excretion in the African clawed frog Xenopus laevis: effects of high environmental ammonia (HEA). Ammonia is a highly toxic molecule and often introduced in considerable amounts into aquatic environments due to anthropogenic activities. Many aquatic and semi-aquatic amphibians utilize, in addition to their kidneys, the skin for osmoregulation and nitrogen excretion. In the present study the effects of prolonged (7-21 days) exposure to high environmental ammonia (HEA, 1 mmol l(-1) NH4Cl) on cutaneous nitrogen excretion and gene expression of key-transporters involved in nitrogen excretion and acid-base regulation were investigated in the fully aquatic African clawed frog, Xenopus laevis. The study revealed that X. laevis excretes predominately ammonia of which approximately 50% is excreted via the skin. Both the ventral and dorsal skin were capable to generate a net ammonia efflux, which was significantly activated by 10 mmol l(-1) of the phosphodiesterase blocker theophylline. The obtained data further suggest that the ammonia efflux was promoted by an acidification of the unstirred boundary layer, likely generated by an apical localized V-ATPase, with NH3 being transported via cutaneous expressed ammonia transporters, Rhbg and Rhcg. Prolonged HEA exposure did significantly reduce the net-flux rates over the ventral skin with Vmax changing from 256 nmol cm(-2) h(-1) in control frogs to 196 nmol cm(-2) h(-1) in HEA exposed animals. Further, prolonged HEA exposure caused a decrease in mRNA expression levels of the ammonia transporter Rhbg, Na(+)/K(+)-ATPase (α-subunit) and V-ATPase (subunit H) in the ventral and dorsal skin and the kidney. In contrast, Rhcg expression levels were unaffected by HEA in skin tissues. 23052545 The "vegetarian brain": chatting with monkeys and pigs? An array of brain regions in the fronto-parietal and temporal lobes cooperates to process observation and execution of actions performed by other individuals. Using functional MRI, we hypothesized that vegetarians and vegans might show brain responses to mouth actions performed by humans, monkeys, and pigs different from omnivores. We scanned 20 omnivores, 19 vegetarians, and 21 vegans while watching a series of silent videos, which presented a single mouth action performed by a human, a monkey, and a pig. Compared to omnivores, vegetarians and vegans have increased functional connectivity between regions of the fronto-parietal and temporal lobes versus the cerebellum during observation of mouth actions performed by humans and, to the same degree, animals. Vegans also had increased connectivity with the supplementary motor area. During human mouth actions, increased amygdala activity in vegetarians and vegans was found. More critically, vegetarians recruited the right middle frontal gyrus and insula, which are involved in social mirroring, whereas vegans activated the left inferior frontal gyrus and middle temporal gyrus, which are part of the mirror neuron system. Monkey mouth actions triggered language network activity in both groups, which might be due to the attempt to decode monkey mouth gesture, with an additional recruitment of associative temporo-occipital areas in vegans, whereas pig mouth actions activated empathy-related regions, including the anterior cingulum. These results support the role of the action observation-execution matching system in social cognition, which enables us to interact not only with our conspecifics but also with species in phylogenetic proximity to humans. 23524272 Chlorpyrifos: weight of evidence evaluation of potential interaction with the estrogen, androgen, or thyroid pathways. Chlorpyrifos was selected for EPA's Endocrine Disruptor Screening Program (EDSP) based on widespread use and potential for human and environmental exposures. The purpose of the program is to screen chemicals for their potential to interact with the estrogen, androgen, or thyroid pathways. A battery of 11 assays was completed for chlorpyrifos in accordance with test guidelines developed for EDSP Tier 1 screening. To determine potential endocrine activity, a weight-of-evidence (WoE) evaluation was completed for chlorpyrifos, which included the integration of EDSP assay results with data from regulatory guideline studies and the published literature. This WoE approach was based on the OECD conceptual framework for testing and assessment of potential endocrine-disrupting chemicals and consisted of a systematic evaluation of data, progressing from simple to complex across multiple levels of biological organization. The conclusion of the WoE evaluation is that chlorpyrifos demonstrates no potential to interact with the estrogen, androgen, or thyroid pathways at doses below the dose levels that inhibit cholinesterase. Therefore, regulatory exposure limits for chlorpyrifos, which are based on cholinesterase inhibition, are sufficient to protect against potential endocrine alterations. Based on the results of this WoE evaluation, there is no scientific justification for pursuing additional endocrine testing for chlorpyrifos. 23950899 Estimating Kidney Function in HIV-Infected Adults in Kenya: Comparison to a Direct Measure of Glomerular Filtration Rate by Iohexol Clearance. More than two-thirds of the world's HIV-positive individuals live in sub-Saharan Africa, where genetic susceptibility to kidney disease is high and resources for kidney disease screening and antiretroviral therapy (ART) toxicity monitoring are limited. Equations to estimate glomerular filtration rate (GFR) from serum creatinine were derived in Western populations and may be less accurate in this population. We compared results from published GFR estimating equations with a direct measure of GFR by iohexol clearance in 99 HIV-infected, ART-naïve Kenyan adults. Iohexol concentration was measured from dried blood spots on filter paper. The bias ratio (mean of the ratio of estimated to measured GFR) and accuracy (percentage of estimates within 30% of the measured GFR) were calculated. The median age was 35 years, and 60% were women. The majority had asymptomatic HIV, with median CD4+ cell count of 355 cells/mm(3). Median measured GFR was 115 mL/min/1.73 m(2). Overall accuracy was highest for the Chronic Kidney Disease Epidemiology Consortium (CKD-EPI) equation. Consistent with a prior report, bias and accuracy were improved by eliminating the coefficient for black race (85% of estimates within 30% of measured GFR). Accuracy of all equations was poor in participants with GFR 60-90 mL/min/1.73 m(2) (<65% of estimates within 30% of measured GFR), although this subgroup was too small to reach definitive conclusions. Overall accuracy was highest for the CKD-EPI equation. Eliminating the coefficient for race further improved performance. Future studies are needed to determine the most accurate GFR estimate for use in individuals with GFR <90 mL/min/1.73 m(2), in whom accurate estimation of kidney function is important to guide drug dosing. Direct measurement of GFR by iohexol clearance using a filter paper based assay is feasible for research purposes in resource-limited settings, and could be used to develop more accurate GFR estimates in African populations. 23307075 DNA integrity of onion root cells under catechol influence. Catechol is a highly toxic organic pollutant, usually abundant in the waste effluents of industrial processes and agricultural activities. The environmental sources of catechol include pesticides, wood preservatives, tanning lotion, cosmetic creams, dyes, and synthetic intermediates. Genotoxicity of catechol at a concentration range 5 × 10(-1)-5 mM was evaluated by applying random amplified polymorphic DNA (RAPD) and time-lapse DNA laddering tests using onion (Allium cepa) root cells as the assay system. RAPD analysis revealed polymorphisms in the nucleotidic sequence of DNA that reflected the genotoxic potential of catechol to provoke point mutations, or deletions, or chromosomal rearrangements. Time-lapse DNA laddering test provided evidence that catechol provoked DNA necrosis and apoptosis. Acridine orange/ethidium bromide staining could distinguish apoptotic from necrotic cells in root cells of A. cepa. 23735585 In vivo Identification of Periodontal Progenitor Cells. The periodontal ligament contains progenitor cells; however, their identity and differentiation potential in vivo remain poorly characterized. Previous results have suggested that periodontal tissue progenitors reside in perivascular areas. Therefore, we utilized a lineage-tracing approach to identify and track periodontal progenitor cells from the perivascular region in vivo. We used an alpha-smooth muscle actin (αSMA) promoter-driven and tamoxifen-inducible Cre system (αSMACreERT2) that, in combination with a reporter mouse line (Ai9), permanently labels a cell population, termed 'SMA9'. To trace the differentiation of SMA9-labeled cells into osteoblasts/cementoblasts, we utilized a Col2.3GFP transgene, while expression of Scleraxis-GFP was used to follow differentiation into periodontal ligament fibroblasts during normal tissue formation and remodeling following injury. In uninjured three-week-old SMA9 mice, tamoxifen labeled a small population of cells in the periodontal ligament that expanded over time, particularly in the apical region of the root. By 17 days and 7 weeks after labeling, some SMA9-labeled cells expressed markers indicating differentiation into mature lineages, including cementocytes. Following injury, SMA9 cells expanded, and differentiated into cementoblasts, osteoblasts, and periodontal ligament fibroblasts. SMA9-labeled cells represent a source of progenitors that can give rise to mature osteoblasts, cementoblasts, and fibroblasts within the periodontium. 23054428 Continuous sedation until death: moral justifications of physicians and nurses--a content analysis of opinion pieces. Continuous sedation until death (CSD), the act of reducing or removing the consciousness of an incurably ill patient until death, often provokes medical-ethical discussions in the opinion sections of medical and nursing journals. A content analysis of opinion pieces in medical and nursing literature was conducted to examine how clinicians define and describe CSD, and how they justify this practice morally. Most publications were written by physicians and published in palliative or general medicine journals. Terminal Sedation and Palliative Sedation are the most frequently used terms to describe CSD. Seventeen definitions with varying content were identified. CSD was found to be morally justified in 73% of the publications using justifications such as Last Resort, Doctrine of Double Effect, Sanctity of Life, Autonomy, and Proportionality. The debate over CSD in the opinion sections of medical and nursing journals lacks uniform terms and definitions, and is profoundly marked by 'charged language', aiming at realizing agreement in attitude towards CSD. Not all of the moral justifications found are equally straightforward. To enable a more effective debate, the terms, definitions and justifications for CSD need to be further clarified. 23877050 Elaboration of Stable and Antibody Functionalized Positively Charged Colloids by Polyelectrolyte Complexation between Chitosan and Hyaluronic Acid. In this study, we describe the elaboration of multifunctional positively charged polyelectrolyte complex (PEC) nanoparticles, designed to be stable at physiological salt concentration and pH, for effective targeted delivery. These nanoparticles were obtained by charge neutralization between chitosan (CS) as polycation and hyaluronic acid (HA) as polyanion. We showed that the course of the complexation process and the physico-chemical properties of the resulting colloids were impacted by (i) internal parameters such as the Degree of Acetylation (DA, i.e., the molar ration of acetyl glucosamine residues) and molar mass of CS, the HA molar mass and (ii) external parameters like the charge mixing ratio and the polymer concentrations. As a result, nonstoichiometric colloidal PECs were obtained in water or PBS (pH 7.4) and remained stable over one month. The polymer interactions were characterized by thermal analysis (DSC and TGA) and the morphology was studied by scanning electron microscopy. A model antibody, anti-ovalbumine (OVA) immunoglobulin A (IgA) was sorbed on the particle surface in water and PBS quantitatively in 4 h. The CS-HA/IgA nanoparticles average size was between 425-665 nm with a positive zeta potential. These results pointed out that CS-HA can be effective carriers for use in targeted drug delivery. 23792135 Distinct functional brain regional integration of Casp3, Ascl1 and S100a6 gene expression in spatial memory. Evaluating the brain structural expression of defined genes involved in basic biological processes of neurogenesis, apoptosis or neural plasticity may facilitate the understanding of genetic mechanisms underlying spatial memory. The aim of the present study was to compare Ascl1, Casp3 and S100a6 gene expression in the hippocampus, prefrontal cortex and cerebellum of adult rats in water maze spatial memory performance. After four days training, the mean platform time (<10s) was evidence of stable long-term spatial memory formation. Real time PCR analysis revealed a positive inter-structural correlation for S100a6/Casp gene expression between the prefrontal cortex and the cerebellum but a negative correlation for S100a6/Ascl1 transcribed genes between the prefrontal cortex and hippocampus during swimming in the active controls. However, during spatial memory performance there was only one inter-structural correlation between the prefrontal cortex and cerebellum with respect to Casp3 expression, though there were intra-structural correlations between Casp3/Ascl1 transcriptions within the prefrontal cortex and hippocampus as well as between Ascl1/S100a6 in the cerebellum. In active learners versus naive controls, the transcrption of all genes was augmented in the prefrontal cortex but Casp3 and Ascl1 were also elevated in hippocampus whilst only S100a6 increased in the cerebellum. The findings endorsed the role of the hippocampus in memory acquisition in addition to an integrative relationship with the prefrontal cortex and cerebellum. This structural and molecular configuration is important for creation of novel neural circuitry for consolidation and reconsolidation of memory trace with an involvement of coupled processes of neurogenesis, apoptosis or neural plasticity. 23919150 Alternative trait combinations and secondary resource partitioning in sexually selected color polymorphism. Resource partitioning within a species, trophic polymorphism is hypothesized to evolve by disruptive selection when intraspecific competition for certain resources is severe. However, in this study, we reported the secondary partitioning of oviposition resources without resource competition in the damselfly Ischnura senegalensis. In this species, females show color polymorphism that has been evolved as counteradaptation against sexual conflict. One of the female morphs is a blue-green (andromorph, male-like morph), whereas the other morph is brown (gynomorph). These female morphs showed alternative preferences for oviposition resources (plant tissues); andromorphs used fresh (greenish) plant tissues, whereas gynomorphs used decaying (brownish) plants tissues, suggesting that they chose oviposition resources on which they are more cryptic. In addition, the two-color morphs had different egg morphologies. Andromorphs have smaller and more elongated eggs, which seemed to adapt to hard substrates compared with those of gynomorphs. The resource partitioning in this species is achieved by morphological and behavioral differences between the color morphs that allow them to effectively exploit different resources. Resource partitioning in this system may be a by-product of phenotypic integration with body color that has been sexually selected, suggesting an overlooked mechanism of the evolution of resource partitioning. Finally, we discuss the evolutionary and ecological consequences of such resource partitioning. 23680876 Categorization of two-photon microscopy images of human cartilage into states of osteoarthritis. The degeneration of articular cartilage is part of the clinical syndrome of osteoarthritis (OA) and one of the most common causes of pain and disability in middle-aged and older people(1). However, the objective detection of an initial state of OA is still challenging. In order to categorize cartilage into states of OA, an algorithm is presented which offers objective categorization on the basis of two-photon laser-scanning microscopy (TPLSM) images. The algorithm is based on morphological characteristics of the images and results in a topographical visualization. This paper describes the algorithm and shows the result of a categorization of human cartilage samples. The resulting map of the analysis of TPLSM images can be divided into areas which correspond to the grades of the Outerbridge-Categorization. The algorithm is able to differentiate the samples in coincidence with the macroscopic impression. The method is promising for early OA detection and categorization. In order to achieve a higher benefit for the physician the method must be transferred to an endoscopic setup for an application in surgery. 23851330 Prognostic Significance of COX-2 Expression and Correlation With Bcl-2 and VEGF Expression, Microvessel Density, and Clinical Variables in Classical Hodgkin Lymphoma. Vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) play important roles in tumor angiogenesis. Recent reports found that COX-2 expression had prognostic value in classical Hodgkin lymphoma (cHL). The purpose of this study was to measure the expression of COX-2, B-cell lymphoma-2 (Bcl-2), VEGF, and CD31 and assess their prognostic significance and potential correlation with clinical variables in cHL. A total of 167 cHL specimens were evaluated retrospectively by immunohistochemical methods for COX-2, Bcl-2, and VEGF expression and for CD31 to measure the microvessel density (MVD). Correlations between COX-2, Bcl-2, VEGF, MVD, and clinicopathologic factors were assessed, and prognostic significance was determined. COX-2, Bcl-2, and VEGF were expressed in 27.5%, 8.3%, and 33.5% of the specimens, respectively. A positive correlation was found between COX-2 and VEGF expression (P<0.001). The MVD was significantly higher in tumors positive for both COX-2 and VEGF compared with that in tumors negative for both markers (P=0.047). COX-2 expression was associated with a lower overall survival rate (P=0.015). High MVD was associated with a lower event-free survival rate (P=0.014). COX-2 was an independent prognostic factor for overall survival on multivariate analysis (P=0.013). COX-2 and VEGF correlated with angiogenesis and tumor progression in cHL. The findings support targeting COX-2 as a potential new therapeutic approach in cHL. 23750319 Comparative study of guanidine-based and lysine-based brush copolymers for plasmid delivery. Polyethylenimine (PEI), one of the most frequently used polycations for non-viral nucleic acid delivery, exhibits good transfection efficiency to cultured cells but generally has to be used in restricted concentration ranges due to high cytotoxicity. We recently reported a family of HPMA-co-oligolysine brush copolymers that show nucleic acid delivery efficiencies approaching that of PEI. Guanidine-containing polymers have been reported in some systems to be more effective at cellular delivery of cargo than their primary-amine analogs. The goal of this work is to investigate the effect of guanidinylation on gene transfer ability of HPMA-co-oligolysine copolymers. Several parameters were evaluated: arginine versus homoarginine monomers, oligopeptide length, and charge density within the peptide. Using reversible addition-fragmentation chain transfer (RAFT) polymerization, a series of six copolymers were synthesized containing the cationic peptides K10, R10, K5, and (GK)5. Lysine-containing copolymers were functionalized with guanidine by reaction with O-methylisourea to generate an additional five homoarginine-based copolymers. All eleven copolymers readily condensed DNA into small, < 150 nm polyplexes and remained stable in physiological salt conditions. The best performing copolymers provided more efficient gene transfection with less associated cytotoxicity than PEI. Reducing the number of charge centers (from 10 to 5) further reduced toxicity while retaining comparable transfection efficiency to PEI. 23506834 Mortality after prostate cancer treatment with radical prostatectomy, external-beam radiation therapy, or brachytherapy in men without comorbidity. Medical comorbidity is a confounding factor in prostate cancer (PCa) treatment selection and mortality. Large-scale comparative evaluation of PCa mortality (PCM) and overall mortality (OM) restricted to men without comorbidity at the time of treatment has not been performed. To evaluate PCM and OM in men with no recorded comorbidity treated with radical prostatectomy (RP), external-beam radiation therapy (EBRT), or brachytherapy (BT). Data from 10 361 men with localized PCa treated from 1995 to 2007 at two academic centers in the United States were prospectively obtained at diagnosis and retrospectively reviewed. We identified 6692 men with no recorded comorbidity on a validated comorbidity index. Median follow-up after treatment was 7.2 yr. Treatment with RP in 4459 men, EBRT in 1261 men, or BT in 972 men. Univariate and multivariate Cox proportional hazards regression analysis, including propensity score adjustment, compared PCM and OM for EBRT and BT relative to RP as reference treatment category. PCM was also evaluated by competing risks analysis. Using Cox analysis, EBRT was associated with an increase in PCM compared with RP (hazard ratio [HR]: 1.66; 95% confidence interval [CI], 1.05-2.63), while there was no statistically significant increase with BT (HR: 1.83; 95% CI, 0.88-3.82). Using competing risks analysis, the benefit of RP remained but was no longer statistically significant for EBRT (HR: 1.55; 95% CI, 0.92-2.60) or BT (HR: 1.66; 95% CI, 0.79-3.46). In comparison with RP, both EBRT (HR: 1.71; 95% CI, 1.40-2.08) and BT (HR: 1.78; 95% CI, 1.37-2.31) were associated with increased OM. In a large multicenter series of men without recorded comorbidity, both forms of radiation therapy were associated with an increase in OM compared with surgery, but there were no differences in PCM when evaluated by competing risks analysis. These findings may result from an imbalance of confounders or differences in mortality related to primary or salvage therapy. 23947333 Templated Non-Oxide Sol-Gel Preparation of Well-Ordered Macroporous (inverse opal) Ta3N5 Films. Reactions of Ta(NMe2)5 and n-propylamine are shown to be an effective system for sol-gel processing of Ta3N5. Ordered macroporous films of Ta3N5 on silica substrates have been prepared by infiltration of such a sol into close-packed sacrificial templates of cross-linked 500 nm polystyrene spheres followed by pyrolysis under ammonia to remove the template and crystallize the Ta3N5. Templates with long-range order were produced by controlled humidity evaporation. Pyrolysis of a sol-infiltrated template at 600 °C removes the polystyrene but does not crystallize Ta3N5, and X-ray diffraction shows nanocrystalline TaN plus amorphous material. Heating at 700 °C crystallizes Ta3N5 while retaining a high degree of pore ordering, whereas at 800 °C porous films with a complete loss of order are obtained. 23508685 Repressive Epigenetic Changes at the Mglu2 Promoter in Frontal Cortex of 5-HT2A Knockout Mice. Serotonin 5-HT2A and metabotropic glutamate 2 (mGlu2) are G protein-coupled receptors suspected in the pathophysiology of psychiatric disorders such as schizophrenia, depression and suicide. Previous findings demonstrate that mGlu2 mRNA expression is down-regulated in brain cortical regions of 5-HT2A knockout (KO) mice. However, the molecular mechanism responsible for this alteration remains unknown. We show here repressive epigenetic changes at the promoter region of the mGlu2 gene in frontal cortex of 5-HT2A-KO mice. Disruption of 5-HT2A receptor-dependent signaling in mice was associated with decreased acetylation of histone H3 (H3ac) and H4 (H4ac), and increased tri-methylation of histone H3 at lysine 27 (H3K27me3) at the mGlu2 promoter-epigenetic changes that correlate with transcriptional repression. Neither methylation of histone H3 at lysine 4 (H3K4me1/2/3) nor tri-methylation of histone H3 at lysine 9 (H3K9me3) was affected. We found that Egr1, a transcription factor whose promoter activity was positively regulated by the 5-HT2A receptor agonist TCB-2, binds less to the mGlu2 promoter in frontal cortex of 5-HT2A-KO as compared to wild-type mice. Furthermore, expression of mGlu2 was increased by viral-mediated gene transfer of Flag-tagged Egr1 in mouse frontal cortex. Together, these observations suggest that 5-HT2A receptor-dependent signaling epigenetically affects mGlu2 transcription in mouse frontal cortex. 23903235 User evaluation of the effects of a text simplification algorithm using term familiarity on perception, understanding, learning, and information retention. Adequate health literacy is important for people to maintain good health and manage diseases and injuries. Educational text, either retrieved from the Internet or provided by a doctor's office, is a popular method to communicate health-related information. Unfortunately, it is difficult to write text that is easy to understand, and existing approaches, mostly the application of readability formulas, have not convincingly been shown to reduce the difficulty of text. To develop an evidence-based writer support tool to improve perceived and actual text difficulty. To this end, we are developing and testing algorithms that automatically identify difficult sections in text and provide appropriate, easier alternatives; algorithms that effectively reduce text difficulty will be included in the support tool. This work describes the user evaluation with an independent writer of an automated simplification algorithm using term familiarity. Term familiarity indicates how easy words are for readers and is estimated using term frequencies in the Google Web Corpus. Unfamiliar words are algorithmically identified and tagged for potential replacement. Easier alternatives consisting of synonyms, hypernyms, definitions, and semantic types are extracted from WordNet, the Unified Medical Language System (UMLS), and Wiktionary and ranked for a writer to choose from to simplify the text. We conducted a controlled user study with a representative writer who used our simplification algorithm to simplify texts. We tested the impact with representative consumers. The key independent variable of our study is lexical simplification, and we measured its effect on both perceived and actual text difficulty. Participants were recruited from Amazon's Mechanical Turk website. Perceived difficulty was measured with 1 metric, a 5-point Likert scale. Actual difficulty was measured with 3 metrics: 5 multiple-choice questions alongside each text to measure understanding, 7 multiple-choice questions without the text for learning, and 2 free recall questions for information retention. Ninety-nine participants completed the study. We found strong beneficial effects on both perceived and actual difficulty. After simplification, the text was perceived as simpler (P<.001) with simplified text scoring 2.3 and original text 3.2 on the 5-point Likert scale (score 1: easiest). It also led to better understanding of the text (P<.001) with 11% more correct answers with simplified text (63% correct) compared to the original (52% correct). There was more learning with 18% more correct answers after reading simplified text compared to 9% more correct answers after reading the original text (P=.003). There was no significant effect on free recall. Term familiarity is a valuable feature in simplifying text. Although the topic of the text influences the effect size, the results were convincing and consistent. 23838413 Recurrent Peripheral Facial Palsy in a Child With Familial Mediterranean Fever. Recurrent peripheral facial palsy is uncommon in children. It mostly occurs as an idiopathic disorder and to a lesser extent in the setting of some infectious, genetic, or systemic disorders. However, its association with familial Mediterranean fever has not been reported before. This article presents a 14-year-old girl who experienced three episodes of right-sided peripheral facial palsy during a 9-month period. She had a diagnosis of familial Mediterranean fever (homozygous with M694V mutation) and she had been receiving colchicine treatment for 8 years. Recurrent peripheral facial palsy may be a neurological manifestation of vasculitis in familial Mediterranean fever. Recurrent peripheral facial palsy may be a manifestation of familial Mediterranean fever in children. 23749959 SVGenes: a library for rendering genomic features in scalable vector graphic format. Drawing genomic features in attractive and informative ways is a key task in visualization of genomics data. Scalable Vector Graphics (SVG) format is a modern and flexible open standard that provides advanced features including modular graphic design, advanced web interactivity and animation within a suitable client. SVGs do not suffer from loss of image quality on re-scaling and provide the ability to edit individual elements of a graphic on the whole object level independent of the whole image. These features make SVG a potentially useful format for the preparation of publication quality figures including genomic objects such as genes or sequencing coverage and for web applications that require rich user-interaction with the graphical elements. SVGenes is a Ruby-language library that uses SVG primitives to render typical genomic glyphs through a simple and flexible Ruby interface. The library implements a simple Page object that spaces and contains horizontal Track objects that in turn style, colour and positions features within them. Tracks are the level at which visual information is supplied providing the full styling capability of the SVG standard. Genomic entities like genes, transcripts and histograms are modelled in Glyph objects that are attached to a track and take advantage of SVG primitives to render the genomic features in a track as any of a selection of defined glyphs. The feature model within SVGenes is simple but flexible and not dependent on particular existing gene feature formats meaning graphics for any existing datasets can easily be created without need for conversion. The library is provided as a Ruby Gem from https://rubygems.org/gems/bio-svgenes under the MIT license, and open source code is available at https://github.com/danmaclean/bioruby-svgenes also under the MIT License. dan.maclean@tsl.ac.uk. 23957043 Assessment of lip position preferences in a Saudi population using computer imaging. This study aimed to evaluate the perception of lip position preferences in a Saudi population and compare it to the perception of other populations. Master pictures of a male and female Saudi model were prepared with the upper lip 3 mm from Ricketts' E-line and the lower lip 1 mm behind. The lip position was then altered using computer imaging to create a range of pictures from the upper lip 15 mm behind the E-line to the upper lip 6 mm beyond the E-line. One hundred and fifty-six individuals (60 male, 96 female) were asked to rate the pictures in terms of acceptability and also which picture they liked best. The preferences were compared based on gender, perception of their own lateral profile and history of previous orthodontic treatment. The study found that regardless of gender, the Saudi population has a distinct preference for lip positions that are further away from the E-line than the current Western standard. The population studied also showed a greater tolerance for deviation in the lip position away from the E-line than deviations towards the E-line. 23344961 Topoisomerase IIβ deficiency enhances camptothecin-induced apoptosis. Camptothecin (CPT), a topoisomerase (Top) I-targeting drug that stabilizes Top1-DNA covalent adducts, can induce S-phase-specific cytotoxicity due to the arrest of progressing replication forks. However, CPT-induced non-S-phase cytotoxicity is less well characterized. In this study, we have identified topoisomerase IIβ (Top2β) as a specific determinant for CPT sensitivity, but not for many other cytotoxic agents, in non-S-phase cells. First, quiescent mouse embryonic fibroblasts (MEFs) lacking Top2β were shown to be hypersensitive to CPT with prominent induction of apoptosis. Second, ICRF-187, a Top2 catalytic inhibitor known to deplete Top2β, specifically sensitized MEFs to CPT. To explore the molecular basis for CPT hypersensitivity in Top2β-deficient cells, we found that upon CPT exposure, the RNA polymerase II large subunit (RNAP LS) became progressively depleted, followed by recovery to nearly the original level in wild-type MEFs, whereas RNAP LS remained depleted without recovery in Top2β-deficient cells. Concomitant with the reduction of the RNAP LS level, the p53 protein level was greatly induced. Interestingly, RNAP LS depletion has been well documented to lead to p53-dependent apoptosis. Altogether, our findings support a model in which Top2β deficiency promotes CPT-induced apoptosis in quiescent non-S-phase cells, possibly due to RNAP LS depletion and p53 accumulation. 23348617 Enzyme nanoarchitectonics: organization and device application. Fabrication of ultrasmall functional machines and their integration within ultrasmall areas or volumes can be useful for creation of novel technologies. The ultimate goal of the development of ultrasmall machines and device systems is to construct functional structures where independent molecules operate as independent device components. To realize exotic functions, use of enzymes in device structures is an attractive solution because enzymes can be regarded as efficient machines possessing high reaction efficiencies and specificities and can operate even under ambient conditions. In this review, recent developments in enzyme immobilization for advanced functions including device applications are summarized from the viewpoint of micro/nano-level structural control, or nanoarchitectonics. Examples are roughly classified as organic soft matter, inorganic soft materials or integrated/organized media. Soft matter such as polymers and their hybrids provide a medium appropriate for entrapment and encapsulation of enzymes. In addition, self-immobilization based on self-assembly and array formation results in enzyme nanoarchitectures with soft functions. For the confinement of enzymes in nanospaces, hard inorganic mesoporous materials containing well-defined channels play an important role. Enzymes that are confined exhibit improved stability and controllable arrangement, which are useful for formation of functional relays and for their integration into artificial devices. Layer-by-layer assemblies as well as organized lipid assemblies such as Langmuir-Blodgett films are some of the best media for architecting controllable enzyme arrangements. The ultrathin forms of these films facilitate their connection with external devices such as electrodes and transistors. Artificial enzymes and enzyme-mimicking catalysts are finally briefly described as examples of enzyme functions involving non-biological materials. These systems may compensate for the drawbacks of natural enzymes, such as their instabilities under harsh conditions. We believe that enzymes and their mimics will be freely coupled, organized and integrated upon demand in near future technologies. 23749960 Network2Canvas: network visualization on a canvas with enrichment analysis. Networks are vital to computational systems biology research, but visualizing them is a challenge. For networks larger than ∼100 nodes and ∼200 links, ball-and-stick diagrams fail to convey much information. To address this, we developed Network2Canvas (N2C), a web application that provides an alternative way to view networks. N2C visualizes networks by placing nodes on a square toroidal canvas. The network nodes are clustered on the canvas using simulated annealing to maximize local connections where a node's brightness is made proportional to its local fitness. The interactive canvas is implemented in HyperText Markup Language (HTML)5 with the JavaScript library Data-Driven Documents (D3). We applied N2C to visualize 30 canvases made from human and mouse gene-set libraries and 6 canvases made from the Food and Drug Administration (FDA)-approved drug-set libraries. Given lists of genes or drugs, enriched terms are highlighted on the canvases, and their degree of clustering is computed. Because N2C produces visual patterns of enriched terms on canvases, a trained eye can detect signatures instantly. In summary, N2C provides a new flexible method to visualize large networks and can be used to perform and visualize gene-set and drug-set enrichment analyses. N2C is freely available at http://www.maayanlab.net/N2C and is open source. avi.maayan@mssm.edu Supplementary data are available at Bioinformatics online. 23918867 Teaching NeuroImages: Reversible cognitive impairment with bithalamic lesions caused by a dural arteriovenous fistula. A 54-year-old man developed apathy and memory impairment in 3 months. MRI showed bilateral thalamic hyperintensities with dilated cortical veins in the right cerebellum. Angiography revealed dural arteriovenous fistula (dAVF) at right transverse-sigmoid sinuses with retrograde flow through the vein of Galen (figure 1). Transvenous coil embolization improved his MRI findings (figure 2) and Wechsler Memory Scale-Revised scores from 55 at baseline to 105 in the delayed recall index. 23763459 FADD expression is associated with regional and distant metastasis in squamous cell carcinoma of the head and neck. The Fas-associated death domain gene (FADD) is often overexpressed in squamous cell carcinoma of the head and neck (HNSCC), and is considered to be a driver gene in amplification of the chromosomal 11q13.3 region. Amplification of 11q13.3 is associated with increased metastasis in HNSCC and breast cancer. The aim of this study was to investigate the association between FADD protein expression in advanced-stage HNSCC and clinicopathological features and outcome. Tumour tissues of 177 HNSCC patients uniformly treated with primary surgery and postoperative radiotherapy were collected. FADD expression was assessed on pretreatment tumour biopsies using immunohistochemistry. High FADD expression was detected in 44% of the HNSCC patients. High expression was associated with an increased rate of lymph node metastasis (P = 0.001) and with a shorter distant metastasis-free interval (DMFI) (HR 2.6, 95% CI 1.0-6.7, P = 0.046) when lymph node metastases were present. Our data show that an increase in FADD expression is associated with a higher incidence of lymph node metastasis at presentation, and with shorter DMFI when lymph node metastases are present. High FADD expression in the primary tumour could be a useful marker to select patients for systemic treatment strategies that reduce the risk of distant metastases. 23898858 Recurrent K3E mutation in Cu/Zn superoxide dismutase gene associated with amyotrophic lateral sclerosis. Cu/Zn superoxide dismutase (SOD1) gene mutations are the most frequently reported genetic causes of amyotrophic lateral sclerosis (ALS). The objective of the study was to describe a clinical phenotype and haplotype background of Polish and Japanese ALS patients harbouring the K3E SOD1 mutation. The K3E mutation was identified by direct sequencing, high resolution melting analysis or high-throughput microarray-based resequencing system. Microsatellite polymorphic markers flanking SOD1 were genotyped in members of six kindreds and two SALS patients. Results demonstrated that the K3E mutation was responsible for classic ALS. The median age of onset was 54 years. The clinical phenotype did not substantially differ between SALS and FALS cases of either ethnic origin, with some intrafamiliar variabilities. There was a limb onset in 92% of patients. In patients with bulbar syndrome, dysphagia predominated over dysarthria. Respiratory insufficiency was found in 61.1% of patients (19-84 months after the first symptoms onset). Median survival was 101 months with age of death ranging from 45 to 77 years. K3E was the most frequent SOD1 mutation among Polish FALS patients. It originated independently, on different haplotype background in the Polish and Japanese populations. In conclusion, recurrent K3E mutation results in a relatively slowly progressing limb onset ALS with classic phenotype. 23142791 Toxicogenomic biomarkers for renal papillary injury in rats. Renal papillary injury is a common side effect observed during nonclinical and clinical investigations in drug development. The present study aimed to identify genomic biomarkers for early and sensitive detection of renal papillary injury in rats. We hypothesized that previously identified genomic biomarkers for tubular injury might be applicable for the sensitive detection of papillary injury in rats. We selected 18 genes as candidate biomarkers for papillary injury based on previously published studies and analyzed their expression profiles by RT-PCR in each kidney region, namely the cortex, cortico-medullary junction, and papilla in various nephrotoxicity models. Comparative analysis of gene expression profiles revealed that some genes were commonly upregulated or downregulated in the renal papilla, reflecting papillary injuries induced by 2-bromoethylamine hydrobromide, phenylbutazone, or n-phenylanthranilic acid. By applying receiver operator characteristics analysis, six candidate biomarkers were identified and their usefulness was confirmed by using an independent data set. The three top-ranked genes, Timp1, Igf1, and Lamc2, exhibited the best prediction performance in an external data set with area under the curve (AUC) values of greater than 0.91. An optimized support vector machine model consisting of three genes achieved the highest AUC value of 0.99. In conclusion, even though definitive validation studies are required for the establishment of their usefulness and reliability, these identified genes may prove to be the most promising candidate genomic biomarkers of renal papillary injury in rats. 23920200 Three-dimensional imaging of cerebellar mossy fiber rosettes by ion-abrasion scanning electron microscopy. The detailed knowledge of the three-dimensional (3D) organization of the nervous tissue provides essential information on its functional elucidation. We used serial block-face scanning electron microscopy with focused ion beam (FIB) milling to reveal 3D morphologies of the mossy fiber rosettes in the mice cerebellum. Three-week-old C57 black mice were perfused with a fixative of 1% paraformaldehyde/1% glutaraldehyde in phosphate buffer; the cerebellum was osmicated and embedded in the Araldite. The block containing granule cell layer was sliced with FIB and observed by field-emission scanning electron microscopy. The contrast of backscattered electron image of the block-face was similar to that of transmission electron microscopy and processed using 3D visualization software for further analysis. The mossy fiber rosettes on each image were segmented and rendered to visualize the 3D model. The complete 3D characters of the mossy fiber rosette could be browsed on the A-Works, in-house software, and some preliminary quantitative data on synapse of the rosette could be extracted from these models. Thanks to the development of two-beam imaging and optimized software, we could get 3D information on cerebellar mossy fiber rosettes with ease and speedily, which would be an additive choice to explore 3D structures of the nervous systems and their networks. 23882236 Phenomenology of future-oriented mind-wandering episodes. Recent research suggests that prospective and non-prospective forms of mind-wandering possess distinct properties, yet little is known about what exactly differentiates between future-oriented and non-future-oriented mind-wandering episodes. In the present study, we used multilevel exploratory factor analyses (MEFA) to examine the factorial structure of various phenomenological dimensions of mind-wandering, and we then investigated whether future-oriented mind-wandering episodes differ from other classes of mind-wandering along the identified factors. We found that the phenomenological dimensions of mind-wandering are structured in four factors: representational format (inner speech vs. visual imagery), personal relevance, realism/concreteness, and structuration. Prospective mind-wandering differed from non-prospective mind-wandering along each of these factors. Specifically, future-oriented mind-wandering episodes involved inner speech to a greater extent, were more personally relevant, more realistic/concrete, and more often part of structured sequences of thoughts. These results show that future-oriented mind-wandering possesses a unique phenomenological signature and provide new insights into how this particular form of mind-wandering may adaptively contribute to autobiographical planning. 23899012 Multi-omics Approach for Estimating Metabolic Networks Using Low-Order Partial Correlations. Abstract Two typical purposes of metabolome analysis are to estimate metabolic pathways and to understand the regulatory systems underlying the metabolism. A powerful source of information for these analyses is a set of multi-omics data for RNA, proteins, and metabolites. However, integrated methods that analyze multi-omics data simultaneously and unravel the systems behind metabolisms have not been well established. We developed a statistical method based on low-order partial correlations with a robust correlation coefficient for estimating metabolic networks from metabolome, proteome, and transcriptome data. Our method is defined by the maximum of low-order, particularly first-order, partial correlations (MF-PCor) in order to assign a correct edge with the highest correlation and to detect the factors that strongly affect the correlation coefficient. First, through numerical experiments with real and synthetic data, we showed that the use of protein and transcript data of enzymes improved the accuracy of the estimated metabolic networks in MF-PCor. In these experiments, the effectiveness of the proposed method was also demonstrated by comparison with a correlation network (Cor) and a Gaussian graphical model (GGM). Our theoretical investigation confirmed that the performance of MF-PCor could be superior to that of the competing methods. In addition, in the real data analysis, we investigated the role of metabolites, enzymes, and enzyme genes that were identified as important factors in the network established by MF-PCor. We then found that some of them corresponded to specific reactions between metabolites mediated by catalytic enzymes that were difficult to be identified by analysis based on metabolite data alone. 23872177 Ionically-crosslinked milk protein nanoparticles as flutamide carriers for effective anticancer activity in prostate cancer-bearing rats. In this study, casein (CAS) nanoparticles were used to encapsulate the hydrophobic anticancer drug, flutamide (FLT), aiming at controlling its release, enhancing its anti-tumor activity, and reducing its hepatotoxicity. The nanoparticles were prepared by emulsification of CAS, at pH below its isoelectric point, and stabilized via ionic-crosslinking with sodium tripolyphosphate (TPP). The nanoparticles were spherical and positively charged with a size below 100nm and exhibited a sustained drug release up to 4days. After intravenous administration into prostate cancer-bearing rats for 28days, FLT-loaded CAS nanoparticles showed a higher anti-tumor efficacy as revealed by a significantly higher % reduction in PSA serum level (75%) compared to free FLT (55%). Moreover, the nanoparticles demonstrated a marked reduction in the relative weights of both prostate tumor and seminal vesicle (43% and 32%) compared to free FLT (12% and 18%), respectively. A significantly higher anti-proliferative, anti-angiogenic, and apoptotic effects was demonstrated by the nanoparticles compared to drug solution as evidenced by their ability to decrease the expression of the proliferative marker (Ki-67) and reduce the level of tumor angiogenic markers (VEGF and IGF-1) as well as their ability to activate caspase-3 with subsequent induction of apoptosis in prostate cancer cells. Conclusively, these novel ionically-crosslinked milk protein nanovehicles offer a promising carrier to allow controlled intravenous delivery of hydrophobic anticancer drugs. 23818454 Wnt5a evokes cortical axon outgrowth and repulsive guidance by tau mediated reorganization of dynamic microtubules. Wnt5a guides cortical axons in vivo by repulsion and in vitro evokes cortical axon outgrowth and repulsion by calcium signaling pathways. Here we examined the role of microtubule (MT) reorganization and dynamics in mediating effects of Wnt5a. Inhibiting MT dynamics with nocodazole and taxol abolished Wnt5a evoked axon outgrowth and repulsion of cultured hamster cortical neurons. EGFP-EB3 labeled dynamic MTs visualized in live cell imaging revealed that growth cone MTs align with the nascent axon. Wnt5a increased axon outgrowth by reorganization of dynamic MTs from a splayed to a bundled array oriented in the direction of axon extension, and Wnt5a gradients induced asymmetric redistribution of dynamic MTs toward the far side of the growth cone. Wnt5a gradients also evoked calcium transients that were highest on the far side of the growth cone. Calcium signaling and the reorganization of dynamic MTs could be linked by tau, a MT associated protein (MAP) that stabilizes MTs. Tau is phosphorylated at the Ser 262 MT binding site by CaMKII, and is required for Wnt5a induced axon outgrowth and repulsive turning. Phosphorylation of tau at Ser262 is known to detach tau from MTs to increase their dynamics. Using transfection with tau constructs mutated at Ser262, we found that this site is required for the growth and guidance effects of Wnt5a by mediating reorganization of dynamic MTs in cortical growth cones. Moreover, CaMKII inhibition also prevents MT reorganization required for Wnt5a induced axon outgrowth, thus linking Wnt/calcium signaling to tau mediated MT reorganization during growth cone behaviors. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013. 23603237 Innate immune responses and efficacy of using mushroom beta-glucan mixture (MBG) on orange-spotted grouper, Epinephelus coioides, aquaculture. This study attempts to describe the effects of innate immunity responses and field application of mushroom beta-glucan mixture (MBG) in cultured orange-sported grouper, Epinephelus coioides. Chemical analysis for MBG showed that the mixture contains 34.06% of macro-molecular polymers with bio-active linkage such as 3-; 3,4- and 4,6-glucopyranosyl and 6-linked galactopyranosyl residues. Study performed on the innate immunity showed that oral ingestion of MBG at 1.0 g and 2.0 g per kilogram of feed levels may significantly enhance the lysozyme activity, alternative complement activity, phagocytic activity and respiration burst of the experimental groupers. Observation on the experimental challenge of pathogen showed that uses of MBG at 0.1% and 0.2% levels in feed might significantly enhance the protection of grouper against Vibrio alginolyticus. Field trials performed on short and long-term culture showed that feeding of diet containing 0.1% or 0.2% of MBG may significantly enhance the survival of cultured groupers up to 16% when compared with those obtained from controls. 23721918 Synthesis and functional analysis of deferriferrichrysin derivatives: application to colorimetric pH indicators. Deferriferrichrysin belongs to the siderophore peptide family which are Fe(III)-coordinating cyclic peptides. The common structure of this family is three consecutive hydroxamate moieties, such as N(δ)-acetyl-N(δ)-hydroxy-l-ornithine (Aho). We have designed two deferriferrichrysin derivatives where three Aho residues were arranged as: cyclo(-Aho-Gly-Aho-Gly-Aho-Gly-) and cyclo(-Aho-Ser-Aho-Ser-Aho-Ser-). Comparative evaluation of the physicochemical properties of their Fe(III) complexes revealed that naturally occurring deferriferrichrysin formed a more stable Fe(III) complex when compared with the two derivatives. This result shows that three consecutive Aho residues are indispensable for high affinity Fe(III) binding by deferriferrichrysin. Of note, the observed pH-dependent chromogenic response of the Fe(III) complexes of the derivatives suggests that these two derivatives should function as sensitive pH indicators in acidic environments. 23790335 Expression and effect of TLR4 in rats with diabetic nephropathy. To observe the expression of TLR4 in kidney tissue of rats with diabetic nephropathy and discuss the role of TLR4 in the occurrence and development of the diabetic nephropathy. A total of 60 clean male SD rats were selected and randomly divided into the modeling group and control group after 1 week of breeding, including 30 rats in each group. Biochemical indices as well as the protein expression of TLR4 were observed and compared between two groups at 2 w, 4 w, 6 w, 8 w and 12 w after the modeling, and the correlation between TLR4 and each biochemical indexes was analyzed. Rats in the modeling group had higher levels of blood glucose, 24-hour urine protein and blood urea nitrogen after the modeling, and showed the increase in the serum creatinine, kidney/body weight ratio, CRP and serum TNF-α at 4w after the modeling, with the significant difference compared to results of the control group (P<0.05). The cross-section area and mean volume of glomerulus in the modeling group at 4 w, 6 w, 8 w and 12 w were significantly higher than those in the control group, with the statistically significant difference (P<0.05). The expression of TLR4 at each time point in the control group was relatively low. Rats in the modeling group had the high expression of TLR4 in kidney's glomerular basement membrane, proximal convoluted tubule and renal interstitial area since 2 w, with the significant difference compared to the control group (P<0.05). The expression in rats of the modeling group was higher than the one of the control group since the 2nd week. As the time flied, its expression increased, with the statistically significant difference between two groups (P<0.05). There was certain correlation between the protein expression of TLR4 and the increased serum titer of 24-hour urine protein excretion, serum creatinine, CRP and TNF-α. TLR4 may activate the immuno-inflammatory reactions to play a role in the occurrence and development of the diabetic nephropathy. 23918813 Concerns about eroding the ethical barrier to in vitro eugenics: lessons from the hESC debate. In his discussion of in vitrogametogenesis, Rob Sparrow claims that an ethical barrier to development of this technology is that many jurisdictions currently prohibit the practice of creating embryos solely for the purpose of research. However, he suggests that this ethical barrier will soon be eroded, in view of the fact that in vitro gametogenesis could serve as a powerful new technology to overcome infertility. In this commentary, I argue that Sparrow is being overly optimistic in his analysis here. I claim that the debate over so-called compromise positions in the human embryonic stem cell debate suggests that the purpose of the research for which a research embryo is created is unlikely to be considered as having any significant bearing on the moral permissibility of the practice for those who oppose it. Even though in vitro gametogenesis could serve as a powerful new technology to overcome infertility, I argue that opponents of the practice of creating embryos solely for research purposes would still view the creation of research embryos that the development of in vitro gametogenesis would require, as being incompatible with affording the embryo proper moral respect. I conclude by suggesting that Sparrow's analysis of the potential benefits of in vitro gametogenesis provides us with further reasons to scrutinise the unconvincing arguments that are often cited in favour of prohibiting the practice of creating embryos solely for research purposes. 23337520 Drug shortages in the United States: a critical evaluation of root causes and the need for action. Every day it is easy to find news articles detailing the impact of drug shortages on patients. Where this was once only a concern of patients with rare, orphan diseases, it is now the concern of patients receiving even the most common chemotherapeutic regimens, the most efficacious antimicrobial therapy, or even the most rapid-acting analgesics, largely as a result of manufacturing quality problems. Unfortunately for many of these patients, there are no efficacious alternatives. 23562829 Structural studies on the forward and reverse binding modes of peptides to the chaperone DnaK. Hsp70 chaperones have been implicated in assisting protein folding of newly synthesized polypeptide chains, refolding of misfolded proteins, and protein trafficking. For these functions, the chaperones need to exhibit a significant promiscuity in binding to different sequences of hydrophobic peptide stretches. To characterize the structural basis of sequence specificity and flexibility of the Escherichia coli Hsp70 chaperone DnaK, we have analyzed crystal structures of the substrate binding domain of the protein in complex with artificially designed peptides as well as small proline-rich antimicrobial peptides. The latter peptides from mammals and insects were identified to target DnaK after cell penetration. Interestingly, the complex crystal structures reveal two different peptide binding modes. The peptides can bind either in a forward or in a reverse direction to the conventional substrate binding cleft of DnaK in an extended conformation. Superposition of the two binding modes shows a remarkable similarity in the side chain orientations and hydrogen bonding pattern despite the reversed peptide orientation. The DnaK chaperone has evolved to bind peptides in both orientations in the substrate binding cleft with comparable energy without rearrangements of the protein. Optimal hydrophobic interactions with binding pockets -2 to 0 appear to be the main determinant for the orientation and sequence position of peptide binding. 23591117 Synthesis and cytotoxic evaluation of novel pyrimidine deoxyapiothionucleosides. The synthesis of novel pyrimidine deoxyapiothionucleosides of d- and l-series was realized following application of a versatile and high-yielding scheme, which utilized inexpensive l- and d-arabinose as starting materials, respectively, and which makes use of a regio- and stereo-selective Pummerer rearrangement reaction for the coupling of the nucleobase with the thiosugar moiety. Some of the targeted compounds have shown selective cytotoxic effects (with IC50<10μM) against specific cancer cell lines. All of the tested compounds had no cytotoxic effect on the normal cell line tested. 23928556 Generation of Recombinant Arenavirus for Vaccine Development in FDA-Approved Vero Cells. The development and implementation of arenavirus reverse genetics represents a significant breakthrough in the arenavirus field (4). The use of cell-based arenavirus minigenome systems together with the ability to generate recombinant infectious arenaviruses with predetermined mutations in their genomes has facilitated the investigation of the contribution of viral determinants to the different steps of the arenavirus life cycle, as well as virus-host interactions and mechanisms of arenavirus pathogenesis (1, 3, 11) . In addition, the development of trisegmented arenaviruses has permitted the use of the arenavirus genome to express additional foreign genes of interest, thus opening the possibility of arenavirus-based vaccine vector applications (5) . Likewise, the development of single-cycle infectious arenaviruses capable of expressing reporter genes provides a new experimental tool to improve the safety of research involving highly pathogenic human arenaviruses (16) . The generation of recombinant arenaviruses using plasmid-based reverse genetics techniques has so far relied on the use of rodent cell lines (7,19) , which poses some barriers for the development of Food and Drug Administration (FDA)-licensed vaccine or vaccine vectors. To overcome this obstacle, we describe here the efficient generation of recombinant arenaviruses in FDA-approved Vero cells. 23948163 Opposing influence of intracellular and membrane thiols on the toxicity of reducible polycations. Toxicity of polycations has been recognized since their first use in gene delivery. Bioreducible polycations attract attention because of their improved safety due to selective intracellular degradation by glutathione (GSH). Here we present a systematic study of the toxicity of bioreducible poly(amido amine)s (PAA). PAA with increasing content of disulfide bonds were synthesized by Michael addition. Toxicity of PAA was evaluated in two cell lines with different innate levels of intracellular GSH. Increasing the content of disulfide bonds decreased the toxicity of PAA, with more significant decrease observed in cells with high GSH. Depleting intracellular GSH by diethyl maleate resulted in increased toxicity of bioreducible PAA. In contrast, increasing the GSH concentrations by growing cells in hypoxic conditions resulted in further decreased toxicity compared with cells grown in normoxic conditions. The presence of exofacial plasma membrane thiols selectively increased toxicity of bioreducible PAA while having no effect on non-degradable controls. These results improve our understanding of the cellular mechanisms of polycation toxicity. They also shed light on the opposing effects of different cellular thiol pools on the toxicity of bioreducible polycations. 23894519 Middle Palaeolithic and Neolithic Occupations around Mundafan Palaeolake, Saudi Arabia: Implications for Climate Change and Human Dispersals. The Arabian Peninsula is a key region for understanding climate change and human occupation history in a marginal environment. The Mundafan palaeolake is situated in southern Saudi Arabia, in the Rub' al-Khali (the 'Empty Quarter'), the world's largest sand desert. Here we report the first discoveries of Middle Palaeolithic and Neolithic archaeological sites in association with the palaeolake. We associate the human occupations with new geochronological data, and suggest the archaeological sites date to the wet periods of Marine Isotope Stage 5 and the Early Holocene. The archaeological sites indicate that humans repeatedly penetrated the ameliorated environments of the Rub' al-Khali. The sites probably represent short-term occupations, with the Neolithic sites focused on hunting, as indicated by points and weaponry. Middle Palaeolithic assemblages at Mundafan support a lacustrine adaptive focus in Arabia. Provenancing of obsidian artifacts indicates that Neolithic groups at Mundafan had a wide wandering range, with transport of artifacts from distant sources. 23796713 MicroRNA-124 targets CCNA2 and regulates cell cycle in STHdh(Q111)/Hdh(Q111) cells. Mutation in huntingtin (HTT) gene causes Huntington's disease (HD). Expression of many micro RNAs is known to alter in cell, animal models and brains of HD patients, but their cellular effects are not known. Here, we show that expression of microRNA-124 (miR-124) is down regulated in HD striatal mutant STHdh(Q111)/Hdh(Q111) cells, a cell model of HD compared to STHdh(Q7)/Hdh(Q7) cells. STHdh(Q7)/Hdh(Q7) and STHdh(Q111)/Hdh(Q111) cells express endogenously full length wild type and mutant HTT respectively. We confirmed this result in R6/2 mouse, an animal model of HD, expressing mutant HTT. Gene Ontology terms related to cell cycle were enriched significantly with experimentally validated targets of miR-124. We observed that expression of Cyclin A2 (CCNA2), a putative target of miR-124 was increased in mutant STHdh(Q111)/Hdh(Q111) cells and brains of R6/2 mice. Fraction of cells in S phase was higher in asynchronously growing mutant STHdh(Q111)/Hdh(Q111) cells compared to wild type STHdh(Q7)/Hdh(Q7) cells and could be altered by exogenous expression or inhibition of miR-124. Exogenous expression or knock down of CCNA2, a target of miR-124, also alters proportion of cells in S phase of HD cell model. In summary, decreased miR-124 expression could increase CCNA2 in cell and animal model of HD and is involved in deregulation of cell cycle in STHdh(Q111)/Hdh(Q111) cells. 22963552 Pharmacological and dietary antioxidant therapies for chronic obstructive pulmonary disease. The progression and exacerbations of chronic obstructive pulmonary disease (COPD) are intimately associated with tobacco smoke/biomass fuel-induced oxidative and aldehyde/carbonyl stress. Alterations in redox signaling proinflammatory kinases and transcription factors, steroid resistance, unfolded protein response, mucus hypersecretion, extracellular matrix remodeling, autophagy/apoptosis, epigenetic changes, cellular senescence/aging, endothelial dysfunction, autoimmunity, and skeletal muscle dysfunction are some of the pathological hallmarks of COPD. In light of the above it would be prudent to target systemic and local oxidative stress with agents that can modulate the antioxidants/ redox system or by boosting the endogenous levels of antioxidants for the treatment and management of COPD. Identification of various antioxidant agents, such as thiol molecules (glutathione and mucolytic drugs, such as N-acetyl-Lcysteine, N-acystelyn, erdosteine, fudosteine, ergothioneine, and carbocysteine lysine salt), dietary natural productderived polyphenols and other compounds (curcumin, resveratrol, green tea catechins, quercetin sulforaphane, lycopene, acai, alpha-lipoic acid, tocotrienols, and apocynin) have made it possible to modulate various biochemical aspects of COPD. Various researches and clinical trials have revealed that these antioxidants can detoxify free radicals and oxidants, control expression of redox and glutathione biosynthesis genes, chromatin remodeling, and ultimately inflammatory gene expression. In addition, modulation of cigarette smoke-induced oxidative stress and related cellular changes have also been reported to be effected by synthetic molecules. This includes specific spin traps like α-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (ECSOD mimetic), porphyrins (AEOL 10150 and AEOL 10113), and a superoxide dismutase mimetic M40419, lipid peroxidation and protein carbonylation blockers/inhibitors, such as edaravone and lazaroids/tirilazad, myeloperoxidase inhibitors, as well as specialized pro-resolving mediators/inflammatory resolving lipid mediators, omega-3 fatty acids, vitamin D, and hydrogen sulfide. According to various studies it appears that the administration of multiple antioxidants could be a more effective mode used in the treatment of COPD. In this review, various pharmacological and dietary approaches to enhance lung antioxidant levels and beneficial effects of antioxidant therapeutics in treating or intervening the progression of COPD have been discussed. 23882105 Evaluation of Blind Nasotracheal Suctioning and Non bronchoscopic Mini-Bronchoalveolar Lavage in Critically Ill Patients with Infectious Pneumonia: A Preliminary Study. We evaluated the diagnostic performance and safety of combined blind nasotracheal suctioning (NTS) and non-bronchoscopic mini-bronchoalveolar lavage (BAL) to obtain respiratory secretion specimens from spontaneously breathing, non-intubated patients with infectious pneumonia in intensive care. Patients suspected of having infectious pneumonia were included prospectively. Three samples were obtained: expectorated sputum, and NTS and mini-BAL with a double telescopic catheter (Combicath®). After administering local anesthesia, NTS was done according to standard recommendations. Then, mini-BAL was performed; the bronchial aspiration tube serves as a guide for the mini-BAL catheter, with tracheal position being verified by colorimetric capnography. Thirty-six patients (29 men, median age 69 years, median Simplified Acute Physiology Score II 32) were included. Thirty-two (89%) underwent NTS and mini-BAL; 13 (36%) had expectorated sputum. Based on colorimetric capnography confirmation of the tracheal position, 75% (24 /32) of the successful combined procedures were achieved on the first attempt. The median duration of the combined procedure was 7 min. Bacterial pneumonia was diagnosed in 24/36 (67%) patients, among whom, 21 (88%) had undergone NTS and mini-BAL, successful respectively, for 8/21 (38% [confidence interval 0.17-0.58] and 14/21 (67% [confidence interval 0.46-0.86]). Mini-BAL diagnosed a significantly higher percentage of bacterial pneumonias than NTS. Expectorated sputum yielded no diagnoses. Blind NTS associated with colorimetric capnography allows microbiological diagnosis that can be enhanced by non-bronchoscopic mini-BAL. It is probably useful to consider colorimetric capnography when the anatomical bronchial tube position is clinically doubtful. Non-bronchoscopic mini-BAL is a new and innovative way to collect bronchial secretions without fibroscopy. The results of our preliminary study demonstrated the feasibility of this procedure. 23810512 The scaffold protein atg11 recruits fission machinery to drive selective mitochondria degradation by autophagy. As the cellular power plant, mitochondria play a significant role in homeostasis. To maintain the proper quality and quantity of mitochondria requires both mitochondrial degradation and division. A selective type of autophagy, mitophagy, drives the degradation of excess or damaged mitochondria, whereas division is controlled by a specific fission complex; however, the relationship between these two processes, especially the role of mitochondrial fission during mitophagy, remains unclear. In this study, we report that mitochondrial fission is important for the progression of mitophagy. When mitophagy is induced, the fission complex is recruited to the degrading mitochondria through an interaction between Atg11 and Dnm1; interfering with this interaction severely blocks mitophagy. These data establish a paradigm for selective organelle degradation. 23505965 Boosting Immunity to Small Tumor-Associated Carbohydrates with Bacteriophage Qβ Capsids. The development of an effective immunotherapy is an attractive strategy toward cancer treatment. Tumor associated carbohydrate antigens (TACAs) are overexpressed on a variety of cancer cell surfaces, which present tempting targets for anticancer vaccine development. However, such carbohydrates are often poorly immunogenic. To overcome this challenge, we show here that the display of a very weak TACA, the monomeric Tn antigen, on bacteriophage Qβ virus-like particles elicits powerful humoral responses to the carbohydrate. The effects of adjuvants, antigen display pattern, and vaccine dose on the strength and subclasses of antibody responses were established. The local density of antigen rather than the total amount of antigen administered was found to be crucial for induction of high Tn-specific IgG titers. The ability to display antigens in an organized and high density manner is a key advantage of virus-like particles such as Qβ as vaccine carriers. Glycan microarray analysis showed that the antibodies generated were highly selective toward Tn antigens. Furthermore, Qβ elicited much higher levels of IgG antibodies than other types of virus-like particles, and the IgG antibodies produced reacted strongly with the native Tn antigens on human leukemia cells. Thus, Qβ presents a highly attractive platform for the development of carbohydrate-based anticancer vaccines. 23230450 Continuum- and particle-based modeling of shapes and dynamics of red blood cells in health and disease. We review recent advances in multiscale modeling of the mechanics of healthy and diseased red blood cells (RBCs), and blood flow in the microcirculation. We cover the traditional continuum-based methods but also particle-based methods used to model both the RBCs and the blood plasma. We highlight examples of successful simulations of blood flow including malaria and sickle cell anemia. 23831243 Partial extinction of a conditioned context enhances preference for elements previously associated with cocaine but not with chocolate. Drug-associated stimuli are crucial to reinstatement of drug-seeking after periods of abstinence, representing a central problem in treatment of addiction. The present study investigated the influence of partial extinction of the conditioned context on the expression of conditioned place preference (CPP). Mice of the inbred DBA/2J strain were conditioned with cocaine or chocolate in a context identified by multiple elements (A+B) and subsequently CPP expression was evaluated in a context containing only one element (A or B) or both (A+B). Cocaine- and chocolate-conditioned mice showed CPP in presence of the original compound stimulus. However, cocaine-conditioned mice did not show CPP when tested in A or B context, while chocolate-conditioned mice did show CPP to single element context. After conditioning mice were exposed to extinction training of the context A or B and then tested for CPP 1 and 9days after the end of the extinction (days 9 and 18). Cocaine-conditioned mice showed CPP 9days after extinction while chocolate-conditioned mice were relatively insensitive to the extinction procedure on day 1 after extinction, but they did not show CPP for the partial or the original compound 9days after extinction. Cocaine-conditioned mice not submitted to the extinction training (simple passage of time) or submitted to a Sham-extinction procedure (saline injections and confinement in a new environment) did not show CPP on day 9 or 18. Cocaine-conditioned mice exposed to extinction training showed increased c-Fos expression in several brain areas in comparison to mice exposed to Sham-extinction. The extinction procedure did not specifically reduce behavioral sensitization. The results suggest that extinction training involving only elements of a drug-associated context can result in increased associative strength of those elements. 23317571 A multivalent approach towards linked dual-pharmacology prostaglandin F receptor agonist/carbonic anhydrase-II inhibitors for the treatment of glaucoma. Lowering of intra-ocular pressure is the primary pharmacologic approach for the treatment of glaucoma and a number of distinct mechanisms of action have been clinically validated. Targeting of multiple mechanisms in combination therapies has proven effective both clinically and commercially although potential improvements with regards to efficacy, tolerability and dosing frequency remain. Application of Theravance's multivalent approach to drug discovery towards linked dual-pharmacology prostaglandin F receptor (FP) agonist/carbonic anhydrase (CA)-II inhibitor compounds is described. Compound 29 exhibits weak potency (pEC(50)=5.7, IA>1.0) as an FP agonist with high binding affinity (pK(i)=8.1) to the CA-II enzyme, and has comparable corneal permeability to the CA-II inhibitor dorzolamide. 23571427 Stereoselective Glucuronidation of Ornidazole in Humans: Predominant Contribution of UDP-Glucuronosyltransferases 1A9 and 2B7. Ornidazole [R,S-1-chloro-3-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ol] is a chiral 5-nitroimidazole class antimicrobial agent. This study aimed to investigate the principal metabolic pathway of ornidazole in humans and identify the major enzymes involved. A total of 19 metabolites were identified in human urine collected from patients with hepatobiliary diseases after an intravenous drip infusion of 500 mg of racemic ornidazole. Stereoselective glucuronidation, followed by renal excretion, was the principal metabolic pathway of ornidazole in humans, accounting for 37.3% of the administered dose. Screening assays with 12 available human recombinant UDP-glucuronosyltransferases (UGTs) demonstrated that UGT1A9 was the predominant UGT isoform involved in R-ornidazole glucuronidation, whereas S-ornidazole glucuronidation was almost exclusively catalyzed by UGT2B7. Chemical inhibition study with niflumic acid and flurbiprofen supported these findings. Enzyme kinetic parameters were then determined in human liver microsomes (HLMs), human kidney microsomes (HKMs), UGT1A9 and 2B7. The Km values for UGT1A9 (15.6 ± 1.6 mM for R-ornidazole) and 2B7 (3.8 ± 0.9 mM for S-ornidazole) were quite similar to those determined in HLMs and HKMs (20.1 ± 1.4 and 17.7 ± 4.0 mM for R-ornidazole; 6.6 ± 1.3 and 3.2 ± 0.4 mM for S-ornidazole). The in vitro intrinsic clearance (CLint) ratios of S- and R-ornidazole were approximately 4.3 in HLMs and 6.5 in HKMs, respectively. The hepatic and renal clearances were estimated based on the well-stirred model. Overall, stereoselective glucuronidation was the principal metabolic pathway of ornidazole in humans. Furthermore, UGT1A9 and 2B7 were the predominant UGT isoforms responsible for R- and S-ornidazole glucuronidation in humans, respectively. 23411308 Detection, isolation and characterisation of cyclolinopeptides J and K in ageing flax. Methionine sulfone containing peptides CLs J (11) and K (12) may be produced from their reduced forms by oxidation but it is not known if these compounds occur in foods that contain flax. These compounds have been reported to possess greater immunosuppressive activity than their reduced methionine sulfoxide peptide forms 4 and 6, respectively. Since 11 and 12 have not been detected in commercial flax oil and milled flax seed, we tested for their presence in flax food products. Here we report that 11 and 12 accumulate in ground flaxseed that is exposed to air and heat (100°C) for more than 4h. Standards of 11 and 12 were prepared, isolated and extensively characterised using HPLC-MS/MS, 1D and 2D NMR methods. We also report the excellent thermal and oxidative stability of these peptides. Due to the harsh conditions required to produce 11 and 12, it is expected that their levels in flax based foods would be low and therefore their presence could serve as an indicative measure of severe oxidation of a food product. 23871474 A Genome-Wide Association Analysis of a Broad Psychosis Phenotype Identifies Three Loci for Further Investigation. Genome-wide association studies (GWAS) have identified several loci associated with schizophrenia and/or bipolar disorder. We performed a GWAS of psychosis as a broad syndrome rather than within specific diagnostic categories. 1239 cases with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder; 857 of their unaffected relatives, and 2739 healthy controls were genotyped with the Affymetrix 6.0 single nucleotide polymorphism (SNP) array. Analyses of 695,193 SNPs were conducted using UNPHASED, which combines information across families and unrelated individuals. We attempted to replicate signals found in 23 genomic regions using existing data on nonoverlapping samples from the Psychiatric GWAS Consortium and Schizophrenia-GENE-plus cohorts (10,352 schizophrenia patients and 24,474 controls). No individual SNP showed compelling evidence for association with psychosis in our data. However, we observed a trend for association with same risk alleles at loci previously associated with schizophrenia (one-sided p = .003). A polygenic score analysis found that the Psychiatric GWAS Consortium's panel of SNPs associated with schizophrenia significantly predicted disease status in our sample (p = 5 × 10(-14)) and explained approximately 2% of the phenotypic variance. Although narrowly defined phenotypes have their advantages, we believe new loci may also be discovered through meta-analysis across broad phenotypes. The novel statistical methodology we introduced to model effect size heterogeneity between studies should help future GWAS that combine association evidence from related phenotypes. Applying these approaches, we highlight three loci that warrant further investigation. We found that SNPs conveying risk for schizophrenia are also predictive of disease status in our data. 23892741 Multilocus sequence typing reveals evidence of homologous recombination linked to antibiotic resistance in the genus Salinispora. The three closely related species that currently comprise the genus Salinispora were analyzed using a multilocus sequencing approach targeting 48 strains derived from four geographic locations. Phylogenetic congruence and a well-supported concatenated tree provide strong support for the delineation of the three species as currently described and the basal relationship of S. arenicola to the more recently diverged sister taxa S. tropica and S. pacifica. The phylogeny of the initial region of the rpoB gene sequenced was atypical, placing the related genera Micromonospora and Verrucosispora within the Salinispora clade. This phylogenetic incongruence was subsequently ascribed to a homologous recombination event in a portion of the gene associated with resistance to compounds in the rifamycin class, which target RpoB. All S. arenicola strains produced compounds in this class and possessed resistance conferring amino acid changes in RpoB. The phylogeny of a region of the rpoB gene that is not associated with rifamycin resistance was congruent with the other housekeeping genes. The link between antibiotic resistance and homologous recombination suggests that incongruent phylogenies provide opportunities to identify the molecular targets of secondary metabolites, an observation with potential relevance for drug discovery efforts. Low ratios of interspecies recombination to mutation, even among co-occurring strains, coupled with high levels of within species recombination suggests that the three species have been described in accordance with natural barriers to recombination. 23825310 Notch Signaling Regulates T Cell Accumulation and Function in the Central Nervous System during Experimental Autoimmune Encephalomyelitis. Systemic inhibition of Notch signaling was previously shown to attenuate experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis in mice. Different studies attributed these effects to decreased T-bet and IFN-γ expression, enhanced regulatory T cell function, reduced T cell chemotaxis to the CNS, or impaired Th9 cell differentiation. Interpretation of these heterogeneous findings is difficult because past experimental strategies did not ensure complete Notch inhibition in T cells and because many cell populations could be affected by systemic Notch blockade. To resolve the role of Notch in T cells during EAE, we used the pan-Notch inhibitor dominant-negative form of Mastermind-like 1 (DNMAML), as well as several complementary loss-of-function approaches specifically in myelin-reactive T cells. Notch inhibition in T cells profoundly decreased EAE incidence and severity. Notch-deprived myelin-reactive T cells had preserved activation and effector differentiation in secondary lymphoid tissues. However, Notch-deprived T cells failed to accumulate in the CNS after immunization. Parking wild-type and DNMAML T cells together in bone marrow chimeras increased accumulation of Notch-deprived T cells in the CNS after immunization but did not prevent EAE, indicating the absence of dominant suppression by DNMAML T cells. Analysis of CNS-infiltrating DNMAML T cells revealed markedly defective IL-17A and IFN-γ production, despite preserved T-bet expression. Collectively, our findings capture the profound overall effects of Notch signaling in myelin-reactive T cells and demonstrate that Notch controls the accumulation and pathogenic functions of CD4(+) T cells within their target organ but not in lymphoid tissues during EAE. 23387921 A thrombospondin structural repeat containing rhoptry protein from Plasmodium falciparum mediates erythrocyte invasion. Host cell invasion by Plasmodium falciparum requires multiple molecular interactions between host receptors and parasite ligands. A family of parasite proteins, which contain the conserved thrombospondin structural repeat motif (TSR), has been implicated in receptor binding during invasion. In this study we have characterized the functional role of a TSR containing blood stage protein referred to as P. falciparum thrombospondin related apical merozoite protein (PfTRAMP). Both native and recombinant PfTRAMP bind untreated as well as neuraminidase, trypsin or chymotrypsin-treated human erythrocytes. PfTRAMP is localized in the rhoptry bulb and is secreted during invasion. Adhesion of microneme protein EBA175 with its erythrocyte receptor glycophorin A provides the signal that triggers release of PfTRAMP from the rhoptries. Rabbit antibodies raised against PfTRAMP block erythrocyte invasion by P. falciparum suggesting that PfTRAMP plays an important functional role in invasion. Combination of antibodies against PfTRAMP with antibodies against microneme protein EBA175 provides an additive inhibitory effect against invasion. These observations suggest that targeting multiple conserved parasite ligands involved in different steps of invasion may provide an effective strategy forthe development of vaccines against blood stage malaria parasites. 23875699 Solid-State NMR Approaches to Internal Dynamics of Proteins: From Picoseconds to Microseconds and Seconds. Solid-state nuclear magnetic resonance (NMR) spectroscopy has matured to the point that it is possible to determine the structure of proteins in immobilized states, such as within microcrystals or embedded in membranes. Currently, researchers continue to develop and apply NMR techniques that can deliver site-resolved dynamic information toward the goal of understanding protein function at the atomic scale. As a widely-used, natural approach, researchers have mostly measured longitudinal (T1) relaxation times, which, like in solution-state NMR, are sensitive to picosecond and nanosecond motions, and motionally averaged dipolar couplings, which provide an integral amplitude of all motions with a correlation time of up to a few microseconds. While overall Brownian tumbling in solution mostly precludes access to slower internal dynamics, dedicated solid-state NMR approaches are now emerging as powerful new options. In this Account, we give an overview of the classes of solid-state NMR experiments that have expanded the accessible range correlation times from microseconds to many milliseconds. The measurement of relaxation times in the rotating frame, T1ρ, now allows researchers to access the microsecond range. Using our recent theoretical work, researchers can now quantitatively analyze this data to distinguish relaxation due to chemical-shift anisotropy (CSA) from that due to dipole-dipole couplings. Off-resonance irradiation allows researchers to extend the frequency range of such experiments. We have built multidimensional analogues of T2-type or line shape experiments using variants of the dipolar-chemical shift correlation (DIPSHIFT) experiment that are particularly suited to extract intermediate time scale motions in the millisecond range. In addition, we have continuously improved variants of exchange experiments, mostly relying on the recoupling of anisotropic interactions to address ultraslow motions in the ms to s ranges. The NH dipolar coupling offers a useful probe of local dynamics, especially with proton-depleted samples that suppress the adverse effect of strong proton dipolar couplings. We demonstrate how these techniques have provided a concise picture of the internal dynamics in a popular model system, the SH3 domain of α-spectrin. T1-based methods have shown that large-amplitude bond orientation fluctuations in the picosecond range and slower 10 ns low-amplitude motions coexist in these structures. When we include T1ρ data, we observe that many residues undergo low amplitude motions slower than 100 ns. On the millisecond to second scale, mostly localized but potentially cooperative motions occur. Comparing different exchange experiments, we found that terminal NH2 groups in side chains can even undergo a combination of ultraslow large-angle two-site jumps accompanied by small-angle fluctuations that occur 10 times more quickly. 23400365 Chemically-synthesised, atomically-precise gold clusters deposited and activated on titania. Synchrotron XPS was used to investigate a series of chemically-synthesised, atomically-precise gold clusters Au(n)(PPh(3))(y) (n = 8, 9, 11 and 101, with y depending on cluster size) immobilized on titania nanoparticles. The gold clusters were washed with toluene at 100 °C or calcined at 200 °C to remove the organic ligand. From the position of the Au 4f(7/2) peak it is concluded that cluster size is not altered through the deposition. From the analysis of the phosphorous spectra, it can be concluded that the applied heat treatment removes the organic ligands. Washing and calcination leads to partial oxidation and partial agglomeration of the clusters. Oxidation of the clusters is most likely due to the interaction of the cluster core with the oxygen of the titania surface after removal of ligands. The position of the Au 4f(7/2) peak indicates that the size of the agglomerated clusters is still smaller than that of Au(101). 22392970 Aromatherapy as treatment for postoperative nausea: a randomized trial. Postoperative nausea (PON) is a common complication of anesthesia and surgery. Antiemetic medication for higher-risk patients may reduce but does not reliably prevent PON. We examined aromatherapy as a treatment for patients experiencing PON after ambulatory surgery. Our primary hypothesis was that in comparison with inhaling a placebo, PON will be reduced significantly by aromatherapy with (1) essential oil of ginger, (2) a blend of essential oils of ginger, spearmint, peppermint, and cardamom, or (3) isopropyl alcohol. Our secondary hypothesis was that the effectiveness of aromatherapy will depend upon the agent used. A randomized trial of aromatherapy with patients who reported nausea in the postanesthesia care unit was conducted at one ambulatory surgical center. Eligibility criteria were adult, able to give consent, and no history of coagulation problems or allergy to the aromatherapy agents. Before surgery, demographic and risk factors were collected. Patients with a nausea level of 1 to 3 on a verbal descriptive scale (0-3) received a gauze pad saturated with a randomly chosen aromatherapy agent and were told to inhale deeply 3 times; nausea (0-3) was then measured again in 5 minutes. Prophylactic and postnausea antiemetics were given as ordered by physicians or as requested by the patient. A total of 1151 subjects were screened for inclusion; 303 subjects reporting nausea were enrolled (26.3%), and 301 meeting protocol were analyzed (26.2%). The change in nausea level was significant for the blend (P < 0.001) and ginger (P = 0.002) versus saline but not for alcohol (P < 0.76). The number of antiemetic medications requested after aromatherapy was also significantly reduced with ginger or blend aromatherapy versus saline (P = 0.002 and P < 0.001, respectively). The hypothesis that aromatherapy would be effective as a treatment for PON was supported. On the basis of our results, future research further evaluating aromatherapy is warranted. Aromatherapy is promising as an inexpensive, noninvasive treatment for PON that can be administered and controlled by patients as needed. 23282998 Characterization of arsenic induced cytotoxicity in liver with stress in erythrocytes and its reversibility with Pleurotus florida lectin. Arsenic is one of the most hazardous substances in the environment known to cause toxicity in multiple organs. Cell adhesion, morphological alterations, cell proliferation, terminal deoxyuridine triphosphate nick-end labeling (TUNEL) and caspase-3/CPP32 fluorometric protease assay were important biomarkers to assess apoptosis in cells. This study aimed to evaluate arsenic-induced apoptosis in the hepatocytes of rat and its protective efficacy with coadministration of ascorbic acid (AA) and Pleurotus florida lectin (PFL) individually. Results of the present study also showed that arsenic caused cytotoxicity by elevating morphological alterations, TUNEL-positive nuclei, caspase-3 activity and DNA damage and reducing cell adhesion and cell proliferation in a time-dependent manner. The apoptosis in hepatocytes was reverted to normal value after coadministration of mushroom lectin in arsenic-exposed rat. The study provided significant evidence that PFL has antiapoptotic property against arsenic-induced toxicity. The beneficial effect of PFL was proportional to its duration of exposure. Retard activities of superoxide dismutase and catalase, enhanced lipid peroxidation as well as protein carbonyl in erythrocytes caused by arsenic could also be maintained toward normalcy by supplementation of AA and PFL. These antioxidative effects were exhibited in a time-dependant manner. In rat, treatment with AA and PFL prevented alteration of plasma enzyme activities caused by arsenic. The results concluded that treatment with PFL has significant role in protecting animals from arsenic-induced erythrocytic damage. This finding might be of therapeutic benefit in people suffering from chronic exposure to arsenic from natural sources, a global problem especially relevant to millions of people on the Indian subcontinent. 23650158 Selection and recombinant phenotyping of a novel CMX001 and cidofovir resistance mutation in human cytomegalovirus. CMX001 is an orally available lipid acyclic nucleotide phosphonate that delivers high intracellular levels of cidofovir (CDV)-diphosphate and exhibits enhanced in vitro antiviral activity against a wide range of double-stranded DNA viruses, including cytomegalovirus (CMV). Mutations in the DNA polymerase of CMV that impart resistance to CDV also render the virus resistant to CMX001. Here, we report a novel resistance mutation that arose under the selective pressure of CMX001. The wild-type CMV strain AD169 was propagated in human foreskin fibroblasts under increasing concentrations of CMX001 over 10 months, and the resulting strain (named CMX001(R)) was less susceptible to CDV and CMX001 in a plaque reduction assay. Genotypic analysis of virus strain CMX001(R) via conventional sequencing of the genes encoding the CMV DNA polymerase (UL54) and UL97 kinase (UL97) demonstrated one mutation that changed the wild-type aspartate to glutamate at position 542 in UL54. A recombinant virus with this novel D542E mutation was generated via bacterial artificial chromosome-mediated marker transfer experiments. Subsequent phenotypic resistance analysis of the D542E mutant demonstrated reductions in susceptibility of greater than 10-fold to CMX001 and CDV, but no resistance to foscarnet (FOS) or ganciclovir (GCV). Analysis of replicative fitness showed that both strain CMX001(R) and the D542E mutant viruses demonstrated a smaller plaque phenotype and slower replication kinetics than their respective parent viruses. These data describe the first resistance mutation generated under the selective pressure of CMX001 and suggest that CMX001 may have a unique resistance profile associated with reduced viral replication and maintenance of sensitivity to FOS and GCV. 23850343 Vitamin K status and cognitive function in healthy older adults. Evidence is accumulating that vitamin K could have a role in cognition, especially in aging. Using data from the Québec Longitudinal Study on Nutrition and Successful Aging (NuAge), a cross-sectional analysis was conducted to examine the associations between vitamin K status, measured as serum phylloquinone concentrations, and performance in verbal and non-verbal episodic memory, executive functions, and speed of processing. The sample included 320 men and women aged 70 to 85 years who were free of cognitive impairment. After adjustment for covariates, higher serum phylloquinone concentration (log-transformed) was associated with better verbal episodic memory performances (F = 2.43, p = 0.048); specifically with the scores (Z-transformed) on the second (β = 0.47; 95% confidence interval [CI] = 0.13-0.82), third (β = 0.41; 95% CI = 0.06-0.75), and 20-minute delayed (β = 0.47; 95% CI = 0.12-0.82) free recall trials of the RL/RI-16 Free and Cued Recall Task. No associations were found with non-verbal episodic memory, executive functions, and speed of processing. Our study adds evidence to the possible role of vitamin K in cognition during aging, specifically in the consolidation of the memory trace. 23855344 Student engagement and examination performance in a team-based learning course. With calls for innovation in nursing education from national bodies of nursing, nurse educators must determine the best teaching strategies to meet educational standards. Team-based learning (TBL), an innovative teaching strategy, offers educators a structured, student-centered learning environment. The purpose of this study was to compare TBL and traditional lecture (a commonly used teaching method) in regard to student engagement and performance on examinations. In addition, the relationship between student engagement and examination scores was examined. Findings showed significant differences in student engagement (p < 0.001). Analysis of examination scores indicated a significant effect within participants (p < 0.001). Mixed findings were found regarding the relationship between student engagement and examination scores. This research contributes to the body of knowledge related to TBL and suggests this teaching strategy is, at minimum, equally as effective as traditional lecture. [J Nurs Educ. 2013;52(8):475-479.]. 23637354 Secular changes in the age-specific prevalence of diabetes among u.s. Adults: 1988-2010. OBJECTIVE To examine the age-specific changes of prevalence of diabetes among U.S. adults during the past 2 decades. RESEARCH DESIGN AND METHODS This study included 22,586 adults sampled in three periods of the National Health and Nutrition Examination Survey (1988-1994, 1999-2004, and 2005-2010). Diabetes was defined as having self-reported diagnosed diabetes or having a fasting plasma glucose level ≥126 mg/dL or HbA1c ≥6.5% (48 mmol/mol). RESULTS The number of adults with diabetes increased by 75% from 1988-1994 to 2005-2010. After adjusting for sex, race/ethnicity, and education level, the prevalence of diabetes increased over the two decades across all age-groups. Younger adults (20-34 years of age) had the lowest absolute increase in diabetes prevalence of 1.0%, followed by middle-aged adults (35-64) at 2.7% and older adults (≥65) at 10.0% (all P < 0.001). Comparing 2005-2010 with 1988-1994, the adjusted prevalence ratios (PRs) by age-group were 2.3, 1.3, and 1.5 for younger, middle-aged, and older adults, respectively (all P < 0.05). After additional adjustment for body mass index (BMI), waist-to-height ratio (WHtR), or waist circumference (WC), the adjusted PR remained statistically significant only for adults ≥65 years of age. CONCLUSIONS During the past two decades, the prevalence of diabetes increased across all age-groups, but adults ≥65 years of age experienced the largest increase in absolute change. Obesity, as measured by BMI, WHtR, or WC, was strongly associated with the increase in diabetes prevalence, especially in adults <65. 22410653 Recurrent Intracerebral Hemorrhage in Patients With Hypertension is Associated With APOE Gene Polymorphism: A Preliminary Study. Recurrent intracerebral hemorrhage (ICH) in patients with hypertension has been reported in Asia and is attributed to poor control of blood pressure, but there may be a genetic basis. This study evaluates the roles of apolipoprotein E (APOE) and α-1 antichymotrypsin (ACT) genes in patients with recurrent hypertensive ICH and compares patients with nonrecurring hypertensive ICH and normal controls. Thirty-three recurrent and 101 nonrecurrent patients with hypertension and ICH were included. The demographic, stroke risk factors, and computed tomographic or magnetic resonance imaging findings were recorded. Magnetic resonance angiography or digital subtraction angiography and vasculitic profile were done in recurrent group to exclude secondary causes of ICH. APOE and ACT gene polymorphisms were assessed with polymerase chain reaction studies in patients with ICH and 188 healthy controls. The demographic and clinical variables were similar in patients with recurrent and nonrecurrent ICH, but patients with recurrent ICH were older (61.1 vs 57.2 years). In the recurrent ICH group, only 7 (10%) out of 69 episodes were lobar; the remaining were deep-seated hematomas. In the nonrecurrent group, 7 (6.9%) patients had lobar ICH. The E2 (odds ratio 4.32; 95% confidence interval 1.65-11.28; P = .003) and E4 alleles of APOE (odds ratio 11.33; 95% confidence interval 5.37-23.02; P < .0001) were significantly related to recurrent ICH compared to healthy controls. The E4 allele was also independently related to recurrent compared to nonrecurrent ICH, even after adjustment for stroke risk factors (odds ratio 25.99; 95% confidence interval 11.65-57.97; P < .0001). ACT gene polymorphism, however, was not related to recurrent ICH compared to controls and nonrecurrent ICH. APOE polymorphism may contribute to the recurrence of hypertensive ICH. 23561586 Clinical features of patients with decompensated heart failure after the Great East Japan Earthquake. The occurrence of heart failure (HF) and its clinical features after a great disaster have not been rigorously examined. We retrospectively examined the effect of the Great East Japan Earthquake on the occurrence of decompensated HF. The number of patients admitted for treatment of decompensated HF and their clinical features were compared between 2 periods, March 11, 2011 to September 10, 2011 (after the earthquake) and the same period in the previous year. The number of admissions increased from 55 in 2010 to 84 in 2011. A comparison of the clinical features showed that the patients admitted after the earthquake had (1) older age (p = 0.031), (2) greater systolic blood pressure (p = 0.039), (3) a greater incidence of new-onset HF due to valvular heart disease (p = 0.040), (4) interruption of drugs (p = 0.001), (5) a greater incidence of infection (p = 0.019), (6) greater B-type natriuretic peptide (p = 0.005) and C-reactive protein (p = 0.003) levels, (7) a lower estimated glomerular filtration rate (p = 0.048) and lower albumin levels (p = 0.021), and (8) a larger diameter of the inferior vena cava (p = 0.008). In conclusion, these results suggest that the earthquake increased the incidence of HF in association with high blood pressure, interruption of drugs, inflammation, malnutrition, and fluid retention. Taking appropriate measures to control blood pressure, nutritional status, and hygiene environment might decrease the occurrence of HF in future disasters. 23824212 Prediction of non-alcoholic fatty-liver disease and liver fat content by serum molecular lipids. We examined whether analysis of lipids by ultra-performance liquid chromatography (UPLC) coupled to MS allows the development of a laboratory test for non-alcoholic fatty-liver disease (NAFLD), and how a lipid-profile biomarker compares with the prediction of NAFLD and liver-fat content based on routinely available clinical and laboratory data. We analysed the concentrations of molecular lipids by UPLC-MS in blood samples of 679 well-characterised individuals in whom liver-fat content was measured using proton magnetic resonance spectroscopy ((1)H-MRS) or liver biopsy. The participants were divided into biomarker-discovery (n = 287) and validation (n = 392) groups to build and validate the diagnostic models, respectively. Individuals with NAFLD had increased triacylglycerols with low carbon number and double-bond content while lysophosphatidylcholines and ether phospholipids were diminished in those with NAFLD. A serum-lipid signature comprising three molecular lipids ('lipid triplet') was developed to estimate the percentage of liver fat. It had a sensitivity of 69.1% and specificity of 73.8% when applied for diagnosis of NAFLD in the validation series. The usefulness of the lipid triplet was demonstrated in a weight-loss intervention study. The liver-fat-biomarker signature based on molecular lipids may provide a non-invasive tool to diagnose NAFLD, in addition to highlighting lipid molecular pathways involved in the disease. 23392987 Gastrointestinal bleeding complication of gastric fistula after sleeve gastrectomy: consider pseudoaneurysms. Gastric fistula (GF) is the most serious complication after longitudinal sleeve gastrectomy (LSG), with an incidence ranging from 0 to 5 %. In this context, concomitant upper gastrointestinal bleeding (UGIB) has never been described. Here, we describe our experience of this situation and suggest a procedure for the standardized management of this life-threatening complication. We retrospectively analyzed all patients having been treated for post-LSG UGIB in our university medical center between November 2004 and February 2012. Data on GF and UGIB (time to onset, diagnosis and management) were assessed. Forty patients were treated for post-LSG GF in our institution, 18 of whom (45 %) had been referred by tertiary centers. Four patients presented UGIB (10 %): two had undergone primary LSG, one had undergone simultaneous gastric band removal and LSG, and one had undergone repeat LSG. The median time interval between GF and UGIB was 15 days. The four cases of UGIB included three pseudoaneurysms (75 %, with two affecting the left gastric artery and one affecting the upper pole of the splenic artery) and one case of bleeding related to stent-induced gastric ulceration. Computed tomography enabled diagnosis of the pseudoaneurysm in all cases. Two of the four patients (50 %) were treated with selective embolization during arteriography, and two (50 %) were treated surgically with arterial ligation. One of the surgically treated patients died during follow-up. UGIB after LSG was investigated in the context of a postoperative GF and was found to have been caused by a pseudoaneurysm in 75 % of cases. When looking for a pseudoaneurysm, a primary angiography should be preferred to endoscopy allowing selective arterial embolization in hemodynamically stable patients, whereas surgery should be reserved for treatment failures or hemodynamically instability. 23664798 Reliable support: Measuring calibration of likelihood ratios. Calculation of likelihood ratios (LR) in evidence evaluation still presents major challenges in many forensic disciplines: for instance, an incorrect selection of databases, a bad choice of statistical models, low quantity and bad quality of the evidence are factors that may lead to likelihood ratios supporting the wrong proposition in a given case. However, measuring performance of LR values is not straightforward, and adequate metrics should be defined and used. With this objective, in this work we describe the concept of calibration, a property of a set of LR values. We highlight that some desirable behavior of LR values happens if they are well calibrated. Moreover, we propose a tool for representing performance, the Empirical Cross-Entropy (ECE) plot, showing that it can explicitly measure calibration of LR values. We finally describe some examples using speech evidence, where the usefulness of ECE plots and the measurement of calibration is shown. 23863012 Highly ordered noncrystalline metallic phase. We report the characterization of a unique metallic glass that, during rapid cooling of an Al-Fe-Si melt, forms by nucleation, followed by growth normal to a moving interface between the solid and melt with partitioning of the chemical elements. We determine experimentally that this is not a polycrystalline composite with nanometer-sized grains, and conclude that this may be a new kind of structure: an atomically ordered, isotropic, noncrystalline solid, possessing no long-range translational symmetry. 23817568 An atlas of over 90,000 conserved noncoding sequences provides insight into crucifer regulatory regions. Despite the central importance of noncoding DNA to gene regulation and evolution, understanding of the extent of selection on plant noncoding DNA remains limited compared to that of other organisms. Here we report sequencing of genomes from three Brassicaceae species (Leavenworthia alabamica, Sisymbrium irio and Aethionema arabicum) and their joint analysis with six previously sequenced crucifer genomes. Conservation across orthologous bases suggests that at least 17% of the Arabidopsis thaliana genome is under selection, with nearly one-quarter of the sequence under selection lying outside of coding regions. Much of this sequence can be localized to approximately 90,000 conserved noncoding sequences (CNSs) that show evidence of transcriptional and post-transcriptional regulation. Population genomics analyses of two crucifer species, A. thaliana and Capsella grandiflora, confirm that most of the identified CNSs are evolving under medium to strong purifying selection. Overall, these CNSs highlight both similarities and several key differences between the regulatory DNA of plants and other species. 23010163 The continuing saga of snake venom disintegrins. Disintegrins, a family of polypeptides released in the venoms of viperid snakes (vipers and rattlesnakes) by the proteolytic processing of multidomain metalloproteinases, selectively block the function of β(1) and β(3) integrin receptors. Few of the proteins isolated and characterized from snake venoms have proven to be more structural and functional versatile than the disintegrins. Not surprisingly, 25 years after their discovery, our knowledge on the evolutionary history and the molecular determinants modulating the integrin inhibitory activity of disintegrins still remain fragmentary. This paper highlights some seminal contributions, including personal accounts of pioneer authors, related to basic and applied research on disintegrins. Investigators have evaluated disintegrin applications in therapies for a number of pathologies in which integrin receptors play relevant roles, particularly myocardial infarction and inappropriate tumor angiogenesis. Completing the continuing story of the disintegrin family by applying novel research approaches may hold the key to learn how to use deadly toxins as therapeutic agents. 23920119 Optimisation of single-phase dry-thermophilic anaerobic digestion under high organic loading rates of industrial municipal solid waste: Population dynamics. Different high feed organic loading rates (OLRs) (from 5.7g to 46.0g TVS/l/d) or hydraulic retention times (HRTs) (from 15d to 2d) in single-phase dry-thermophilic anaerobic digestion (AD) of organic fraction municipal solid waste (OFMSW) were investigated. The specific gas production (SGP) values (0.25-0.53m(3)/kg TVS) and the percentages of Eubacteria, Archaea, H2-utilising methanogens (HUMs) and acetate-utilising methanogens (AUMs) were stable within the ranges 80.2-91.1%, 12.4-18.5%, 4.4-9.8% and 5.5-10.9%, respectively. A HUM/AUM ratio greater than 0.7 seems to be necessary to maintain very low partial pressures of H2 required for dry AD process. Increasing OLR resulted in an increase in all the populations, except for propionate-utilising acetogens (PUAs). Optimal conditions were obtained at 3d HRT (OLR=30.7g TVS/l/d), which is lower than the doubling time of acetogens and methanogens. The methane production (MP) was clearly higher than those reported in AD of OFMSW. 23821302 Regulation of URG4/URGCP and PPARα gene expressions after retinoic acid treatment in neuroblastoma cells. Neuroblastoma (NB), originating from neural crest cells, is the most common extracranial tumor of childhood. Retinoic acid (RA) which is the biological active form of vitamin A regulates differentiation of NB cells, and RA derivatives have been used for NB treatment. PPARα (peroxisome proliferator-activated receptor) plays an important role in the oxidation of fatty acids, carcinogenesis, and differentiation. URG4/URGCP gene is a proto-oncogene and that overexpression of URG4/URGCP is associated with metastasis and tumor recurrence in osteosarcoma. It has been known that URG4/URGCP gene is an overexpressed gene in hepatocellular carcinoma and gastric cancers. This study aims to detect gene expression patterns of PPARα and URG4/URGCP genes in SH-SY5Y NB cell line after RA treatment. Expressions levels of PPARα and URG4/URGCP genes were analyzed after RA treatment for reducing differentiation in SH-SY5Y NB cell line. To induce differentiation, the cells were treated with 10 Î¼M RA in the dark for 3-10 days. Gene expression of URG4/URGCP and PPARα genes were presented as the yield of polymerase chain reaction (PCR) products from target genes compared with the yield of PCR products from the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene. SH-SY5Y cells possess small processes in an undifferentiated state, and after treatment with RA, the cells developed long neurites, resembling a neuronal phenotype. PPARα gene expression increased in RA-treated groups; URG4/URGCP gene expression decreased in SH-SY5Y cells after RA treatment compared with that in the control cells. NB cell differentiation might associate with PPARα and URG4/URGCP gene expression profile after RA treatment. 23500256 Role of the waist/height ratio in the cardiometabolic risk assessment of children classified by body mass index. The aim of this study was to determine the utility of waist/height ratio (WHtR) in the specification of cardiometabolic risk in children already stratified by body mass index (BMI). Reflective of its association with cardiometabolic risk, BMI is a commonly used indirect indicator of adiposity in children. The WHtR, a marker of central adiposity, has been advocated as a possibly superior indicator of cardiometabolic risk. Cross-sectional analysis of 5 National Health and Nutrition Examination Surveys from 1999 to 2008 (ages 5 to 18 years of age). The BMI percentile categories (normal, overweight, and obese) were further stratified on the basis of WHtR (<0.5, 0.5 to <0.6, ≥0.6). Outcome measures were lipid and glycemic profiles, C-reactive protein, liver transaminases, prevalence of hypertension, and metabolic syndrome. Data were available for 14,493 subjects. Overweight and obese subjects with a WHtR <0.5 had a cardiometabolic risk approaching that of subjects with a normal BMI percentile category. Increasing WHtR was significantly associated with increased cardiometabolic risk in overweight and obese subjects, with the greatest associations observed in the obese population. Of obese subjects with WHtR ≥0.6, 26% had elevated non-high-density lipoprotein levels, 18% had elevated C-reactive protein levels, 69% had an elevated homeostatic model assessment-insulin resistance, and 32% had metabolic syndrome. The WHtR further specifies cardiometabolic risk within classifications stratification on the basis of BMI percentile. A significant proportion of obese children with increased WHtRs have abnormal cardiometabolic risk factor levels. The WHtR should be included in the routine screening and assessment of overweight and obese children, and those with an elevated WHtR should undergo a further cardiometabolic risk assessment. 23941420 Distinct Activation Phenotype of a Highly Conserved Novel HLA-B57-Restricted Epitope during Dengue Virus Infection. Variation in the sequence of T cell epitopes between dengue virus (DENV) serotypes is believed to alter memory T cell responses during second heterologous infections. We identified a highly conserved, novel, HLA-B57-restricted epitope on the DENV NS1 protein. We predicted higher frequencies of B57-NS126-34 -specific CD8(+) T cells in PBMC from individuals undergoing secondary rather than primary DENV infection. However, high tetramer-positive T cell frequencies during acute infection were seen in only 1 of 9 subjects with secondary infection. B57-NS126-34 -specific and other DENV epitope-specific CD8(+) T cells, as well as total CD8(+) T cells, expressed an activated phenotype (CD69(+) and/or CD38(+) ) during acute infection. In contrast, expression of CD71 was largely limited to DENV epitope-specific CD8(+) T cells. In vitro stimulation of cell lines indicated that CD71 expression was differentially sensitive to stimulation by homologous and heterologous variant peptides. CD71 may represent a useful marker of antigen-specific T cell activation. This article is protected by copyright. All rights reserved. 23927372 UGT2B17 copy number gain in a large ankylosing spondylitis multiplex family. The primary objective of this study is to identify novel copy number variations (CNVs) associated with familial ankylosing spondylitis (AS). A customized genome-wide microarray was designed to detect CNVs and applied to a multiplex AS family with six (6) affected family members. CNVs were detected using the built-in DNA analytics aberration detection method-2 (ADM-2) algorithm. Gene enrichment analysis was performed to observe the segregation. Subsequent validation was performed using real time quantitative fluorescence polymerase reaction (QF-PCR). The frequency of copy number variation for the UGT2B17 gene was then performed on two well-defined AS cohorts. Fisher exact test was performed to quantify the association. Our family-based analysis revealed ten gene-enriched CNVs that segregate with all six family members affected with AS. Based on the proposed function and the polymorphic nature of the UGT2B17 gene, the UGT2B17 gene CNV was selected for validation using real time QF-PCR with full concordance. The frequency of two copies of the UGT2B17 gene CNV was 0.41 in the Newfoundland AS cases and 0.35 in the Newfoundland controls (OR = 1.26(0.99-1.59); p < 0.05)), whereas the frequency of two (2) copies of the UGT2B17 gene CNV was 0.40 in the Alberta AS cases and 0.39 in the Alberta controls (OR = 1.05(95% CI: 0.83-1.33); p < 0.71)). A genome-wide microarray interrogation of a large multiplex AS family revealed segregation of the UGT2B17 gene CNV among all affected family members. The association of the UGT2B17 CNV with AS is particularly interesting given the recent association of this CNV with osteoporosis and the proposed function as it encodes a key enzyme that inhibits androgens. However, two copies of the UGT2B17 gene CNV were only marginally significant in a uniplex AS cohort from Newfoundland but not in a uniplex AS cohort from Alberta. 23892853 Sexual dysfunction in women with rheumatoid arthritis. Aim Rheumatoid Arthritis (RA) is a widespread disease which leads to various degrees of disability and profound impact on overall life quality of the patient with regard to social, economic, psychological and sexual aspects. It may be assumed that RA can affect sexual function. The aim of this study was to evaluate the sexual function in female subjects with RA. Methods A total of 186 married women (age range 30-60 years) were included in this study. Of the total participants, 104 were RA patients and 82 were healthy women. Hospital anxiety and depression scale (HADS), Health Assessment Questionnaire (HAQ) and Disease Activity Score (DAS) were used to evaluate the differences between the controls and patient group. Sexual functions were evaluated using the validated Female Sexual Function Index (FSFI). Results The mean age of the RA patients and controls was 46.71 ± 7.65 and 43.98 ± 7.97, respectively. According to the total sexual function score evaluation, 97 out of 104 women with RA (93.7 %) and in 53 out of 82 women in control group (64.6 %) were regarded as having sexual dysfunction (SD). There was significant difference between these two subgroups with regard to only depression factor. Conclusion Current results have demonstrated that patients with RA have had a higher sexual dysfunction rate, when compared with the control group. SD may be related to perceived depression, which are frequently encountered conditions in patients with RA. Key words: autoimmunity, rheumatic diseases, sexual health. 23872858 Sea lice infestations on juvenile chum and pink salmon in the Broughton Archipelago, Canada, from 2003 to 2012. Juvenile pink salmon Oncorhynchus gorbuscha and chum salmon O. keta were sampled by beach or purse seine to assess levels of sea lice infestation in the Knight Inlet and Broughton Archipelago regions of coastal British Columbia, Canada, during the months of March to July from 2003 to 2012. Beach seine data were analyzed for sea lice infestation that was described in terms of prevalence, abundance, intensity, and intensity per unit length. The median annual prevalence for chum was 30%, ranging from 14% (in 2008 and 2009) to 73% (in 2004), while for pink salmon, the median was 27% and ranged from 10% (in 2011) to 68% (in 2004). Annual abundance varied from 0.2 to 5 sea lice per fish with a median of 0.47 for chum and from 0.1 to 3 lice (median 0.42) for pink salmon. Annual infestation followed broadly similar trends for both chum and pink salmon. However, the abundance and intensity of Lepeophtheirus salmonis and Caligus clemensi, the 2 main sea lice species of interest, were significantly greater on chum than on pink salmon in around half of the years studied. Logistic regression with random effect was used to model prevalence of sea lice infestation for the combined beach and purse seine data. The model suggested inter-annual variation as well as a spatial clustering effect on the prevalence of sea lice infestation in both chum and pink salmon. Fish length had an effect on prevalence, although the nature of this effect differed according to host species. 23886349 Fluorescent labels in biosensors for pathogen detection. Abstract Infectious diseases caused by pathogens have become a life-threatening problem for millions of people around the world in recent years. Therefore, the need of efficient, fast, low-cost and user-friendly biosensing systems to monitor pathogen has increased enormously in the last few years. This paper presents an overview of different fluorescent labels and the utilization of fluorescence-based biosensor techniques for rapid, direct, sensitive and real-time identification of bacteria. In these biosensors, organic dyes, nanomaterials and rare-earth elements are playing an increasing role in the design of biosensing systems with an interest for applications in bacterial analysis. 22278172 Allergic and immunologic reactions to food additives. For centuries, food additives have been used for flavouring, colouring and extension of the useful shelf life of food, as well as the promotion of food safety. During the last 20 years, the studies implicating the additives contained in foods and medicine as a causative factor of allergic reactions have been proliferated considerably. In this review, we aimed to overview all of the food additives which were approved to consume in EU and find out how common and serious allergic reactions come into existence following the consuming of food additives. 23959844 Pathology imaging informatics for quantitative analysis of whole-slide images. With the objective of bringing clinical decision support systems to reality, this article reviews histopathological whole-slide imaging informatics methods, associated challenges, and future research opportunities. This review targets pathologists and informaticians who have a limited understanding of the key aspects of whole-slide image (WSI) analysis and/or a limited knowledge of state-of-the-art technologies and analysis methods. First, we discuss the importance of imaging informatics in pathology and highlight the challenges posed by histopathological WSI. Next, we provide a thorough review of current methods for: quality control of histopathological images; feature extraction that captures image properties at the pixel, object, and semantic levels; predictive modeling that utilizes image features for diagnostic or prognostic applications; and data and information visualization that explores WSI for de novo discovery. In addition, we highlight future research directions and discuss the impact of large public repositories of histopathological data, such as the Cancer Genome Atlas, on the field of pathology informatics. Following the review, we present a case study to illustrate a clinical decision support system that begins with quality control and ends with predictive modeling for several cancer endpoints. Currently, state-of-the-art software tools only provide limited image processing capabilities instead of complete data analysis for clinical decision-making. We aim to inspire researchers to conduct more research in pathology imaging informatics so that clinical decision support can become a reality. 23138115 A Single-institution Retrospective Cases Series of Childhood Undifferentiated Embryonal Liver Sarcoma (UELS): Success of Combined Therapy and the Use of Orthotopic Liver Transplant. Undifferentiated embryonal liver sarcoma (UELS) makes up 9% to 15% of all malignant liver tumors in children. UELS is characteristically diagnosed between the ages of 6 and 10 years and presents with abdominal pain, vomiting, and an abdominal mass. There is currently no standardized treatment for UELS except attempt at complete surgical resection. There have been only about 150 cases of UELS reported in the literature all with historically poor overall survival of <37.5% at 5 years. This report is one of the largest single-institution reports of UELS consisting of 5 patients over 2 decades. The purpose of this study is to characterize presentation and to report treatment success in UELS in children, adolescents, and young adults and the use of liver transplantation and, lastly, to suggest a use of positron emission tomography/computed tomography (PET/CT) in monitoring of this disease process. We conducted an Institutional Review Board-approved retrospective chart review. Data were collected from UELS patients younger than 21 years seen at the University of California Los Angeles over the past 20 years (January 2001 to September 2011). Descriptive analysis was conducted including multiple parameters of patient demographics, tumor characteristics, treatment modalities, and morbidity and mortality. Five patients with UELS were identified. Patients initially presented with fever, abdominal pain, or nausea. Ages ranged from 10 to 19 years old (median age 13 y old), and there was a 4:1 male-to-female predominance. Tumor size ranged from 6 to 22 cm in largest diameter. One patient presented with metastatic disease to the lungs and heart and 1 patient recurred 2 years from diagnosis with bilateral paraspinal masses. Treatment included local control surgery with neoadjuvant and adjuvant chemotherapy with an anthracycline/alkylating agent combination. One patient with recurrent and refractory disease achieved local control with an orthotopic liver transplantation (OLT). Metastatic disease was controlled with surgery and radiation therapy. 18-Fluorodeoxyglucose PET/CT was a useful imaging tool for judging response to therapy with complete loss of metabolic activity in tumor after neoadjuvant chemotherapy in 2 representative cases. Although follow-up is short for some patients, overall survival in these 5 patients was 100% with follow-up ranging from 21 to 68 months. Disease-free survival ranged from 8 to 46 months with no patients with residual disease. UELS is an aggressive high-grade primary liver sarcoma with high metastatic potential. This report represents one of the largest single-institution studies of UELS. Using multimodality therapy, patients have achieved 100% overall survival even in the setting of extensive disease, metastases, and recurrence. In cases of unresectable primary tumor or recurrent and refractory disease isolated to the liver, OLT is a potential therapeutic option. We report success with adjuvant chemotherapy and complete surgical resection with OLT as an alternative in unresectable or refractory cases. We also suggest a possible utility of PET/CT in monitoring treatment response in this disease. 23841447 The Role of Soluble Guanylyl Cyclase in Chronic Obstructive Pulmonary Disease. Rationale: Soluble guanylyl cyclase (sGC), a cyclic guanosine 5´-monophosphate (cGMP) generating enzyme, regulates smooth muscle tone and exerts anti-inflammatory effects in animal models of asthma and acute lung injury. In Chronic Obstructive Pulmonary Disease (COPD), primarily caused by cigarette smoke (CS), lung inflammation persists and smooth muscle tone remains elevated, despite ample amounts of nitric oxide (NO) that could activate sGC. Objective: To determine the expression and function of sGC in patients with COPD and in a murine model of COPD. Methods: Expression of sGCα1, α2 and β1 subunits was examined in lungs of never smokers, smokers without airflow limitation and patients with COPD; and in C57BL/6 mice after 3 days, 4 and 24 weeks of CS exposure. The functional role of sGC was investigated in vivo by measuring bronchial responsiveness to serotonin (5-HT) in mice using genetic and pharmacological approaches. Measurements and Main Results: Pulmonary expression of sGC, both at mRNA and protein level, was decreased in smokers without airflow limitation and in patients with COPD, and correlated with disease severity (FEV1%). In mice, exposure to CS reduced sGC, cGMP levels and protein kinase G activity. sGCα1-/- mice exposed to CS exhibited bronchial hyperresponsiveness (BHR) to serotonin. Activation of sGC by BAY 58-2667 restored the sGC signaling and attenuated BHR in CS-exposed mice. Conclusions: Downregulation of soluble guanylyl cyclase due to cigarette smoke exposure might contribute to airflow limitation in COPD. 23322259 Prevalence of sleepiness while driving four-wheel motor vehicles in Fiji: a population-based survey (TRIP 9). Sleepiness has been shown to be a risk factor for road crashes in high-income countries, but has received little attention in low- and middle-income countries. We examined the prevalence of sleepiness and sleep-related disorders among drivers of four-wheel motor vehicles in Fiji. Using a two-stage cluster sampling roadside survey conducted over 12 months, we recruited a representative sample of people driving four-wheel motor vehicles on the island of Viti Levu, Fiji. A structured interviewer-administered questionnaire sought self-report information on driver characteristics including sleep-related measures. The 752 motor vehicle drivers recruited (84% response rate) were aged 17-75 years, with most driving in Viti Levu undertaken by male subjects (93%), and those identifying with Indian (70%) and Fijian (22%) ethnic groups. Drivers who reported that they were not fully alert accounted for 17% of driving, while a further 1% of driving was undertaken by those who reported having difficulty staying awake or feeling sleepy. A quarter of the driving time among 15-24-year-olds included driving while sleepy or not fully alert, with a similar proportion driving while chronically sleep deprived (ie, with less than five nights of adequate sleep in the previous week=27%). Driving while acutely or chronically sleep deprived was generally more common among Fijians compared with Indians. Driving while not fully alert is relatively common in Fiji. Sleepiness while driving may be an important contributor to road traffic injuries in this and other low- and middle-income countries. 23706347 Effect of parallel segmented flow chromatography on the height equivalent to a theoretical plate. I-performance of 4.6mm×30mm columns packed with 3.0μm Hypurity-C18 fully porous particles. The mass transfer kinetics in short and wide 4.6mm×30mm columns packed with 3.0μm Hypurity-C18 fully porous particles were measured for three different configurations of the inlet sample distribution and outlet sample collection: (1) both the inlet and outlet column endfittings are standard, (2) the inlet endfitting is standard while the outlet endfitting allows parallel segmentation of the exiting flow between a central and a peripheral region across the column diameter, and (3) both the inlet and outlet endfittings allow a parallel segmentation of the flow entering and exiting the column, respectively. The total reduced heights equivalent to a theoretical plate (HETP) were carefully measured, using the first and second central moments of the elution band profiles, obtained by its accurate numerical integration. The longitudinal diffusion term was measured at the lowest experimental reduced velocity applied. The solid-liquid mass transfer resistance was estimated from measurements of the intra-particle diffusivity using the Torquato's model of effective diffusion in packed beds. The trans-channel and short-range interchannel eddy diffusion HETP terms were taken from data obtained by solving numerically the Navier-Stokes equations and simulating advective-diffusive transport in computer-generated random sphere packings. The results clearly show that the trans-column eddy diffusion HETP term can account for up to 85% of the total intrinsic HETP (corrected for extra-column contributions) of the standard columns. Parallel segmented flow chromatography can reduce this contribution by half at high velocities, by eliminating most of the baseline peak tailing. This holds true irrespective of the retention factor of the analyte. It was found also that segmenting the inlet/outlet flow increases detection sensitivity by 25-50% for peaks with large to small retention factors, respectively. In practice, the advantage of parallel segmented flow chromatography in gradient elution (thin peak widths) is essentially limited by post-column bandspreading and diffusion in the dwell volume of the instrument used. Analyst should minimize post-column bandspreading (caused by connectors and detection cell volume) and synchronize the eluent composition in the peripheral and central inlet ports of the column, by using two separate pumps with appropriate dwell volumes. 23540428 Quality of life after maxillectomy and prosthetic obturator rehabilitation. Surgical resection of midface neoplasms and subsequent reconstruction have been shown to have significant negative effects on quality of life (QOL). The purpose of this pilot study was to assess individuals' health-related QOL after maxillectomy and reconstruction with a prosthetic obturator. The QOL of 25 of 43 patients who underwent maxillectomy and prosthetic obturator reconstruction at the University of California-San Francisco was assessed using 3 questionnaires: University of Washington Quality of Life version 4 (UWQOL), Obturator Functioning Scale (OFS), and Mental Health Inventory (MHI). The response rate to the QOL questionnaires was 92% (23 of 25 patients). Time elapsed from maxillectomy and prosthetic obturator reconstruction to the QOL survey response ranged from 0.3 to 6.6 years (mean, 2.7 years; standard deviation [SD], 1.9 years). The post-treatment mean QOL scores were 77.3 (SD, 13.6) for UWQOL, 72.0 (SD, 12.6) for OFS, and 4.5 (SD, 0.9) for Mental Health Inventory. Individuals who received adjuvant radiation scored lower for speech and appearance (OFS, P = .05, P = .03, respectively) as well as for saliva and overall QOL (UWQOL, P = .02, P = .08, respectively). There was a strong correlation between QOL scores in OFS and UWQOL questionnaires (r = 0.78, P < .001). The results of this pilot study suggest that postoperative radiation therapy was the strongest variable affecting QOL in patients with maxillectomy and prosthetic obturator reconstruction. There is further need for a multicenter trial with a larger sample to identify how factors affecting QOL of patients after maxillectomy might influence the choice of reconstruction. 23900059 Lower urinary tract symptoms following female genital mutilation. To estimate the prevalence of lower urinary tract symptoms (LUTS) following female genital mutilation (FGM). A hospital-based, cross-sectional study was conducted from January 1, 2009, through January 1, 2012, at the urogynecology clinic of Sohag University Hospital. The participants were 251 women who had undergone different forms of FGM. A total of 251 women agreed to participate. All had the clitoris amputated, 7.1% had some form of mutilation to the labia majora, 33.8% had adhesions of the labia minora, 19.2% had clitoral retention cysts, and 38.8% reported at least 1 LUTS. Nocturia (38.6%) was the most prevalent LUTS, intermittency (23.5%) was the most prevalent voiding LUTS, and incomplete voiding (22.7%) was the most common post-micturition LUTS. All 3 types of LUTS were reported by 11.6% of the women. Those with Type II and Type III FGM had a significantly higher risk of having all 3 LUTS than those with Type I. Women with FGM are significantly more likely to have LUTS than women without FGM, and LUTS seem to be more burdensome in those with more extensive FGM. 23950116 Noncontiguous Genome Sequence of Mycobacterium septicum Strain DSM 44393T. The rapidly growing Mycobacterium septicum rarely causes pulmonary infections. We report here the draft genome sequence of M. septicum strain DSM 44393(T), isolated from catheter-related bacteremia and initially identified as a member of Mycobacterium fortuitum. 23590522 Theoretical and Kinetic Study of the Reaction of Ethyl Methyl Ketone with HO2 for T = 600 - 1, 600 K. Part II: Addition Reaction Channels. The temperature and pressure dependence of the addition reaction of ethyl methyl ketone (EMK) with HO2 radical has been calculated with the master equation method employing conventional transition state theory estimates for the microcanonical rate coefficients in the temperature range of 600-1600 K. Geometries, frequencies, and hindrance potentials were obtained at the B3LYP/6-311G(d,p) level of theory. A modified G3(MP2,CC) method has been used to calculate accurate electronic energies for all of the species involved in the reactions. The rigid-rotor harmonic oscillator approximation has been used for all of the vibrations except for the torsional degrees of freedom which are being treated as 1D hindered rotor. Asymmetric Eckart barriers were used to model tunneling effect in a one-dimensional reaction coordinate through saddle points. Our calculated results show that the four reaction channels forming 1-buten-2-ol + HÿO2 radical (R5), 2-buten-2-ol + HÿO2 radical (R10), acetic acid + ethylene + ÿO H radical (R13), 2-methyl-2-oxetanol + ÿOH radical (R15) are the dominant channels. When the temperature is below 1000 K, the reaction R15 forming the cyclic ether, 2-methyl-2-oxetanol, is dominant; while the reaction R13 forming acetic acid + ethylene + ÿOH radical becomes increasingly dominant at temperatures above 1000 K. The other two channels forming 1-buten-2-ol, 2-buten-2-ol and HO2 radical are not dominant but are still important product channels over the whole temperature range investigated here. No pressure dependence has been found for the reaction channels forming 2-methyl-2-oxetanol + OH radical and acetic acid + ethylene + OH radical. A slightly negative pressure dependence has been found for the reaction channels producing the two butenols. Rate constants for the four important reaction channels at 1 atm (in cm3mol-1s-1) are: kR5 = 2.67 × 1015 × T-1.32 exp(-16637/T ) kR10 = 1.62 × 108 × T 0.57 exp(-13142/T ) kR13 = 2.29 × 1017 × T-1.66 exp(-18169/T ) kR15 = 6.17 × 10-2 × T 3.35 exp(-10136/T ) A comparison of the total rate constants for the addition of HO2 radical to EMK and that for H-atom abstraction by HO2 radical from EMK has also been carried out. We find that the abstraction reaction channels are dominant over the entire temperature range of 600-1600 K. 23895624 c-Yes Tyrosine Kinase Is a Potent Suppressor of ES Cell Differentiation and Antagonizes the Actions of Its Closest Phylogenetic Relative, c-Src. Embryonic stem (ES) cells are derived from the inner cell mass of the blastocyst stage embryo and are characterized by self-renewal and pluripotency. Previous work has shown that Src-family tyrosine kinases display dynamic expression and activity changes during ES cell differentiation, suggesting distinct functions in the control of developmental fate. Here we used ES cells to test the hypothesis that c-Src and its closest phylogenetic relative, c-Yes, act in biological opposition despite their strong homology. Unlike c-Src, enforced expression of active c-Yes blocked ES cell differentiation to embryoid bodies by maintaining pluripotency gene expression. To explore the interplay of c-Src and c-Yes in ES cell differentiation, we engineered c-Src and c-Yes mutants that are resistant to A-419259, a potent pyrrolopyrimidine inhibitor of the Src kinase family. Previous studies have shown that A-419259 treatment blocks all Src-family kinase activity in ES cells, preventing differentiation while maintaining pluripotency. Expression of inhibitor-resistant c-Src but not c-Yes rescued the A-419259 differentiation block, resulting in a cell population with properties of both primitive ectoderm and endoderm. Remarkably, when inhibitor-resistant c-Src and c-Yes were expressed together in ES cells, c-Yes activity suppressed c-Src-mediated differentiation. These studies show that even closely related kinases such as c-Src and c-Yes have unique and opposing functions in the same cell type. Selective agonists or inhibitors of c-Src versus c-Yes activity may allow more precise pharmacological manipulation of ES cell fate and have broader applications in other biological systems that express multiple Src family members such as tumor cells. 23651563 Proteomic approach to Pseudomonas aeruginosa adaptive resistance to benzalkonium chloride. This study aimed to assess the membrane modifications in Pseudomonas aeruginosa after continuous exposure to increasing doses of benzalkonium chloride (BC). Two different concentrations were used, 0.9 and 12.0mM. Proteomic investigations revealed that the range of the outer membrane proteome alterations following continuous exposure is very low, i.e. about 10% and BC concentration dependent. Adapted cells revealed different expressions of key proteins frequently reported as involved in acquired resistance mechanisms. Porins (OprF and OprG) and lipoproteins (OprL and OprI) were underexpressed when the higher adaptation concentration (12mM) was used. Some of these membrane alterations have been described as involved in the acquired resistance to antibiotics, suggesting possible common mechanisms between these two types of resistance. Results obtained after P. aeruginosa adaptation to benzalkonium chloride suggest that the bacterial adaptation to BC do not mobilize complete outer membrane systems. Though, we showed that adaptive resistance to BC promoted some changes in proteins previously described as involved in antibiotic resistance. These results contribute to the assumption that there are common resistance mechanisms, between adaptive and acquired resistance of P. aeruginosa. 23903383 Structural Changes in a Macrozoobenthos Assemblage After Imidacloprid Pulses in Aquatic Field-Based Microcosms. A field-based microcosm experiment was performed to investigate the effects of repeated pulses of the neonicotinoid insecticide imidacloprid on a lentic benthos assemblage. This specific microcosm method was chosen because it allows for both testing of a wide range of organisms under natural conditions and as well as gaining insight into intraspecific and interspecific interactions. The macrozoobenthos that colonised the microcosms was exposed to three pulses each 1 week apart at nominal concentrations ranging from 0.6 to 40 Î¼g/L. Imidacloprid underwent fast aqueous photolysis due to optimal sunlight conditions during the test phase (half-life = 28 ± 8 h [monitored for 21 days]). Nonetheless, decreased abundance and emergence of Ephemeroptera and decreased survival of chironomid species of the subfamilies Tanypodinae and Orthocladiinae were observed at time-weighted average concentrations of 2.3 Î¼g/L. In contrast, the gastropod Radix sp. became dominant at high imidacloprid concentrations, probably due to decreased competition for food with sensitive species. The results of this study show that repeated short-term contamination of imidacloprid at low concentration levels may affect aquatic ecosystems even under optimal conditions for photodegradation. The microcosm approach, with its simple and field-relevant design, proved to be a useful tool for assessing the effects of imidacloprid contamination. 23759294 Appendicitis and diverticulitis of the colon: Misleading forms. Appendicitis and diverticulitis of the colon are the two main causes of febrile acute abdomen in adults. Diagnosis from imaging (ultrasound and CT) is usually easy. However, an imaging procedure which is not suitable for the clinical situation and an examination performed with the wrong protocol are sources of error and must be avoided. Anatomical variants, inflammatory cancers, complicated forms (perforation, secondary occlusion of the small intestine, peripheral abscesses, fistulae, pylephlebitis, liver abscesses) and associated signs related to a peritoneal inflammatory reaction (reflex ileus, reactive ileitis or salpingitis) can also lead to a wrong diagnosis. 23747696 PCR Characterization Suggests that an Unusual Range of Bartonella Species Infect the Striped Field Mouse (Apodemus agrarius) in Central Europe. Blood samples from Apodemus agrarius from Poland yielded PCR amplicons of Bartonella species. These included B. grahamii, B. taylorii, and B. birtlesii, as is typical of European Apodemus, as well as B. elizabethae-like forms and a recombinant strain of B. taylorii, most closely related to an American isolate from Tamiasciurus hudsonicus. 23886856 Epimorphin deletion inhibits polyposis in the Apcmin/+ mouse model of colon carcinogenesis via decreased myofibroblast HGF secretion. Interactions between the epithelium and surrounding mesenchyme/stroma play an important role in normal gut morphogenesis, the epithelial response to injury, and epithelial carcinogenesis. The tumor microenvironment, composed of stromal cells including myofibroblasts and immune cells, regulates tumor growth and the cancer stem cell niche. Deletion of epimorphin (Epim), a syntaxin family member expressed in myofibroblasts and macrophages, results in partial protection from colitis and from inflammation-induced colon cancer in mice. We sought to determine whether epimorphin deletion protects from polyposis in the Apc(min/+) mouse model of intestinal carcinogenesis. Methods: Epim(-/-) mice were crossed to Apc(min/+) mice; Apc(min/+) and Apc(min/+) /Epim(-/-) mice were sacrificed at 3 months of age. Polyp numbers and sizes were quantified in small intestine and colon, and gene expression analyses for pathways relevant to epithelial carcinogenesis were performed. Primary myofibroblast cultures were isolated, and expression and secretion of selected growth factors from Apc(min/+) and Apc(min/+) /Epim(-/-) myofibroblasts was examined by ELISA. Results: Small bowel polyposis was significantly inhibited in Apc(min/+) /Epim(-/-) compared to Apc(min/+) mice. Apc(min/+) /Epim(-/-) compared to Apc(min/+) polyps and adjacent uninvolved intestinal mucosa had increased TGFβ expression and signaling with increased P-Smad2/3 expression. Myofibroblasts isolated from Apc(min/+) /Epim(-/-) vs. Apc(min/+) mice had markedly decreased hepatocyte growth factor (HGF) expression and secretion. Conclusions: Epim deletion inhibits polyposis in Apcmin/+ mice, associated with increased mucosal TGFβ signaling and decreased myofibroblast HGF expression and secretion. Our data suggest that Epim deletion reduces tumorigenicity of the stromal microenvironment. 23680877 OARSI recommended performance-based tests to assess physical function in people diagnosed with hip or knee osteoarthritis. To recommend a consensus-derived set of performance-based tests of physical function for use in people diagnosed with hip or knee osteoarthritis (OA) or following joint replacement. An international, multidisciplinary expert advisory group was established to guide the study. Potential tests for consideration in the recommended set were identified via a survey of selected experts and through a systematic review of the measurement properties for performance-based tests. A multi-phase, consensus-based approach was used to prioritize and select performance-based tests by applying decision analysis methodology (1000Minds software) via online decision surveys. The recommended tests were chosen based on available measurement-property evidence, feasibility of the tests, scoring methods and expert consensus. Consensus incorporated the opinions of 138 experienced clinicians and researchers from 16 countries. The five tests recommended by the advisory group and endorsed by Osteoarthritis Research Society International (OARSI) were the 30-s chair-stand test, 40 m fast-paced walk test, a stair-climb test, timed up-and-go test and 6-min walk test. The first three were recommended as the minimal core set of performance-based tests for hip or knee OA. The OARSI recommended set of performance-based tests of physical function represents the tests of typical activities relevant to individuals diagnosed with hip or knee OA and following joint replacements. These tests are complementary to patient-reported measures and are recommended as prospective outcome measures in future OA research and to assist decision-making in clinical practice. Further research should be directed to expanding the measurement-property evidence of the recommended tests. 23881150 Use of Multilocus Variable Number of Tandem Repeats Analysis Genotyping to Determine the Role of Asymptomatic Carriers in Clostridium difficile Transmission. Background. Previous studies have suggested that asymptomatic carriers of toxigenic Clostridium difficile are a source of hospital-associated (HA) infections. Multilocus variable number of tandem repeats analysis (MLVA) is a highly discriminatory molecular subtyping tool that helps to determine possible transmission sources. Methods. Clostridium difficile isolates were recovered from perirectal swabs collected for vancomycin-resistant Enterococcus (VRE) surveillance as well as from clinical C. difficile toxin-positive stool samples from July to November 2009 at the University of Pittsburgh Medical Center Presbyterian (UPMC). MLVA was performed to determine the genetic relationships between isolates from asymptomatic carriers and patients with HA C. difficile infection (HA-CDI). Asymptomatic carriage and HA-CDI isolates were considered to be associated if the carriage isolate was collected before the HA-CDI isolate and if the MLVA genotypes had a summed tandem-repeat difference of ≤2. Results. Of 3006 patients screened, 314 (10.4%) were positive for toxigenic C. difficile, of whom 226 (7.5%) were detected only by VRE surveillance cultures. Of 56 incident cases of CDI classified as HA at UPMC during the study with available isolates, 17 (30%) cases were associated with CDI patients, whereas 16 (29%) cases were associated with carriers. Transmission events from prior bed occupants with CDI (n = 2) or carriers (n = 2) were identified in 4 of 56 cases. Conclusions. In our hospital with an established infection control program designed to contain transmission from symptomatic CDI patients, asymptomatic carriers appear to have played an important role in transmission. Identification and isolation of carriers may be necessary to further reduce transmission of C. difficile in such settings. 23703646 Risk adjustment for health care financing in chronic disease: what are we missing by failing to account for disease severity? Adjustment for differing risks among patients is usually incorporated into newer payment approaches, and current risk models rely on age, sex, and diagnosis codes. It is unknown the extent to which controlling additionally for disease severity improves cost prediction. Failure to adjust for within-disease variation may create incentives to avoid sicker patients. We address this issue among patients with chronic obstructive pulmonary disease (COPD). Cost and clinical data were collected prospectively from 1202 COPD patients at Kaiser Permanente. Baseline analysis included age, sex, and diagnosis codes (using the Diagnostic Cost Group Relative Risk Score) in a general linear model predicting total medical costs in the following year. We determined whether adding COPD severity measures-forced expiratory volume in 1 second, 6-Minute Walk Test, dyspnea score, body mass index, and BODE Index (composite of the other 4 measures)-improved predictions. Separately, we examined household income as a cost predictor. Mean costs were $12,334/y. Controlling for Relative Risk Score, each ½ SD worsening in COPD severity factor was associated with $629 to $1135 in increased annual costs (all P<0.01). The lowest stratum of forced expiratory volume in 1 second (<30% normal) predicted $4098 (95% confidence interval, $576-$8773) additional costs. Household income predicted excess costs when added to the baseline model (P=0.038), but this became nonsignificant when also incorporating the BODE Index. Disease severity measures explain significant cost variations beyond current risk models, and adding them to such models appears important to fairly compensate organizations that accept responsibility for sicker COPD patients. Appropriately controlling for disease severity also accounts for costs otherwise associated with lower socioeconomic status. 23747379 Synthesis, spectral and antimicrobial activity of Zn(II) complexes with Schiff bases derived from 2-hydrazino-5-[substituted phenyl]-1,3,4-thiadiazole and benzaldehyde/2-hydroxyacetophenone/indoline-2,3-dione. Zn(II) complexes have been synthesized by reacting zinc acetate with Schiff bases derived from 2-hydrazino-5-[substituted phenyl]-1,3,4-thiadiazole and 2-hydroxyacetophenone/benzaldehyde/indoline-2,3-dione. All these complexes are soluble in DMF and DMSO; low molar conductance values indicate that they are non electrolytes. Elemental analyses suggest that the complexes have 1:2 metal to ligands stoichiometry of the types [ZnL2(H2O)2](L=monoanionic Schiff bases derived from 2-hydrazino-5-[substituted phenyl]-1,3,4-thiadiazole and 2-hydroxyacetophenone/indoline-2,3-dione) [ZnL2(')(OOCCH3)2(H2O)2](L'=neutral Schiff bases derived from 2-hydrazino-5-[substituted phenyl]-1,3,4-thiadiazole and benzaldehyde), and they were characterized by IR, (1)H NMR, and (13)C NMR. Particle sizes of synthesized compounds were measured with dynamic light scattering (DLS) analyser which indicates that particle diameter are of the range ca. 100-200nm. All these Schiff bases and their complexes have also been screened for their antibacterial (Bacillus subtilis (B. subtilis), Escherichia coli (E. coli) and antifungal activities (Colletotrichum falcatum (C. falcatum), Aspergillus niger (A. niger), Fusarium oxysporium (F. oxysporium) Curvularia pallescence (C. pallescence). The antimicrobial activities have shown that upon complexation the activity increases. 23595053 Structural and Immunochemical Studies of the Lipopolysaccharide from the Fish Pathogen, Aeromonas bestiarum Strain K296, Serotype O18. Chemical analyses and mass spectrometry were used to study the structure of the lipopolysaccharide (LPS) isolated from Aeromonas bestiarum strain K296, serotype O18. ESI-MS revealed that the most abundant A. bestiarum LPS glycoforms have a hexa-acylated or tetra-acylated lipid A with conserved architecture of the backbone, consisting of a 1,4'-bisphosphorylated β-(1→6)-linked d-GlcN disaccharide with an AraN residue as a non-stoichiometric substituent and a core oligosaccharide composed of Kdo1Hep6Hex1HexN1P1. 1D and 2D NMR spectroscopy revealed that the O-specific polysaccharide (OPS) of A. bestiarum K296 consists of a branched tetrasaccharide repeating unit containing two 6-deoxy-l-talose (6dTalp), one Manp and one GalpNAc residues; thus, it is similar to that of the OPS of A. hydrophila AH-3 (serotype O34) in both the sugar composition and the glycosylation pattern. Moreover, 3-substituted 6dTalp was 2-O-acetylated and additional O-acetyl groups were identified at O-2 and O-4 (or O-3) positions of the terminal 6dTalp. Western blots with polyclonal rabbit sera showed that serotypes O18 and O34 share some epitopes in the LPS. The very weak reaction of the anti-O34 serum with the O-deacylated LPS of A. bestiarum K296 might have been due to the different O-acetylation pattern of the terminal 6dTalp. The latter suggestion was further confirmed by NMR. 23775668 The response of the TonB-dependent transport network in Anabaena sp. PCC 7120 to cell density and metal availability. TonB dependent transporters (TBDT) are an essential protein family in bacteria involved in the uptake of a broad variety of molecules such as siderophore-chelated iron, which was the first described substrate. Meanwhile it is known that TBDTs are involved in the uptake of many metals, sugars and polypeptides. The action of TBDTs is regulated and energized by the plasma membrane anchored TonB, which is charged by a proton pump. The number of the genes coding for TBDTs varies in different species, which might reflect environmental adaptations or evolutionary variations of the system. For example, in the cyanobacterium Anabaena sp. PCC 7120 the large number of 22 genes coding for TBDTs has been identified and the expression of these genes has been explored in the absence of iron or copper as well as under nitrogen starvation. We describe the analysis of the expression of the TBDT genes and the according cytoplasmic-membrane localized components; the latter appear to have a lower degree of complexity in Anabaena sp. PCC 7120. This analysis unravels that the response is not sole dependent on the metal supply, but also on cell culture densities. In addition, we present a large group of FhuA-like genes which is expressed highest under standard conditions suggesting a function distinct from iron or copper transport. The genes are clustered according to the expression profile and the consequences for our understanding of the transport systems in Anabaena sp. PCC 7120 are discussed. 23740528 Growth or longevity: the TOR's decision on lifespan regulation. TOR (target of rapamycin) pathway has been well known for its central role in growth control. Interestingly, recent studies also implicate the TOR pathway in lifespan regulation in various organisms ranging from budding yeast to mammals. TOR gains momentum in a study showing that rapamycin administration later in life significantly extends lifespan in mice. How the TOR kinase controls these two seemingly distinct biological processes is an especially intriguing question yet to be answered. Here, we summarize the literatures concerning TOR's role in growth control, stress response and lifespan regulation, hoping to obtain a better understanding of how cell growth and maintenance are balanced by TOR and how TOR-mediated shift in metabolisms or energy allocations may translate into lifespan extension at the organismal level. We also evaluate the undergoing efforts to target the TOR pathway for health in human, with focus on looking for new drugs that can bypass the unwanted side effects of rapamycin derivatives. 23563286 Layer-by-layer assembled polyaspartamide nanocapsules for pH-responsive protein delivery. Biodegradable shell cross-linked nanocapsules were prepared via layer-by-layer assembly of PADH (tertiary amine and hydrazide grafted polyaspartamide) and PACA (carboxyl and aldehyde grafted polyaspartamide) on silica spheres. Both of the polyaspartamide derivatives are water-soluble and biodegradable polymers with a protein-like structure, and obtained by aminolysis reaction of polysuccinimide. The latter is prepared by thermal polycondensation of aspartic acid. Dynamic light scattering and zeta potential measurements were used to analyze the layer-by-layer assembly process. Bovine serum albumin (BSA), as a model protein, was entrapped in the nanocapsules via electrostatic adsorption. Nanocapsules encapsulating BSA were prepared via layer-by-layer assembly on protein-entrapping amino-functionalized silica spheres, hydrazone cross-linking and silica core removal. The BSA release profiles exhibited a pH-dependent behavior. BSA release rate increased significantly as the ambient pH dropped from the physiological pH to acidic. Cell viability study suggests that the obtained polymeric nanocapsules have good biocompatibility. These kinds of novel composite nanocapsules may offer a promising delivery system for proteins. 23247919 Mitochondrial VDAC and hexokinase together modulate plant programmed cell death. The voltage-dependent anion channel (VDAC) and mitochondrially located hexokinase have been implicated both in pathways leading to cell death on the one hand, and immortalization in tumor formation on the other. While both proteins have also been implicated in death processes in plants, their interaction has not been explored. We have examined cell death following heterologous expression of a rice VDAC in the tobacco cell line BY2 and in leaves of tobacco plants and show that it is ameliorated by co-expression of hexokinase. Hexokinase also abrogates death induced by H2O2. We conclude that the ratio of expression of the two proteins and their interaction play a major role in modulating death pathways in plants. 23756063 The discovery of potent selective NPY Y(2) antagonists. A series of small molecules with a piperidinyl core were synthesized and tested for binding affinity (IC50) at human Neuropeptide Y Y2 receptor. Various amide related analogs (ureas, reversed amides, and sulfonamides) were evaluated. Several potent and selective NPY Y2 antagonists were identified. 23800685 Synthesis and cytotoxic activities of novel hybrid 2-phenyl-3-alkylbenzofuran and imidazole/triazole compounds. A series of novel hybrid compounds of 2-phenyl-3-alkylbenzofuran and imidazole or triazole were prepared and evaluated in vitro against a panel of human tumor cell lines. The results suggest that the 2-ethyl-imidazole ring, and substitution of the imidazolyl-3-position with a 2-bromobenzyl or naphthylacyl group, were vital for modulating inhibitory activity. In particular, hybrid compound 31 was found to be the most potent derivative with IC₅₀ values of 0.08-0.55 μM against five strains human tumor cell lines and was found to be more selective against breast carcinoma (MCF-7) and colon carcinoma (SW480) (IC₅₀ values 40.8-fold and 40.1-fold lower than cisplatin (DDP)). 23628885 Adaptive microbial population shifts in response to a continuous ethanol blend release increases biodegradation potential. The fate of fuel releases largely depends on the poorly-understood response in microbial community structure and function. Here, we evaluate the impacts to the microbial community resulting from a pilot-scale continuous release (10 months) of a 10% v:v ethanol solution mixed with benzene and toluene (50 mg/L each). Microbial population shifts were characterized by pyrosequencing-based 16S rRNA analysis and by quantitative PCR targeting Bacteria, Archaea, and functional genes for methanogenesis (mcrA), acetogenesis (fhs) and aerobic degradation of aromatic hydrocarbons (PHE), which could occur in hypoxic micro-environments. The release stimulated microbial growth, increased species richness and diversity, and selected for genotypes involved in fermentative degradation (the relative abundance of mcrA and fhs increased 18- and 6-fold, respectively). The growth of putative hydrocarbon degraders and commensal anaerobes, and increases in microbial diversity and in degradation rates suggest an adaptive response that increases the potential for natural attenuation of ethanol blend releases. 23860661 Toll-like receptor 2 controls acute immune complex-driven arthritis by regulating the inhibitory Fcγ receptor IIB. Objective. Previous studies demonstrated protective role of Toll-like receptor (TLR) 2 and proinflammatory function of TLR4 during chronic T cell-driven arthritis. Involvement of TLRs in T cell-independent arthritic processes remains, however, unclear. This study aimed to determine the functional significance of TLR2 and TLR4 in T cell-independent immune complex-driven arthritis. Methods. Serum-transfer arthritis was induced in wild-type and TLR-deficient mice by intraperitoneal injections of arthritogenic K/BxN serum. Arthritis was assessed macroscopically and on histology. Influence of TLR2 on macrophage cytokine profile, Fcγ receptor (FcγR) expression and response to immune complexes was determined. Results. While TLR4, unexpectedly, did not play any significant role, TLR2 deficiency accelerated the onset and markedly increased the severity of acute immune complex-driven arthritis. TLR2 deficiency resulted in substantial increase of joint inflammation, bone erosion and cartilage pathology, indicating a protective function of TLR2 in passive FcγR-driven disease. Ex vivo study of macrophage inflammatory phenotype revealed increased production of TNFα and IL-6 despite similar IL-10, along with a significant increase of FcγR specific response in TLR2(-/-) macrophages early in the disease. Although mRNA expression of distinct FcγRs was not affected, cell surface protein expression of the inhibitory FcγRIIB in TLR2(-/-) naïve primary macrophages was specifically diminished, resulting in higher proinflammatory response. Accordingly, TLR2 stimulation specifically upregulated FcγRIIB, but not the activating FcγRs, on macrophages. Conclusion. TLR2 regulates acute immune complex-driven arthritis by controlling macrophage FcγR response. The protective role of TLR2 is hereby extended beyond its previously-described role in promoting regulatory T cells during T cell-mediated arthritis. © 2013 American College of Rheumatology. 23857225 The use of probiotic strains in caries prevention: a systematic review. This paper aims to provide a systematic review of the caries-prevention effect of probiotics in human. The hypothesis was that the administration of probiotic strains might play a role in caries lesion prevention and in the control of caries-related risk factors. The main relevant databases (Medline, Embase) were searched. Quality of the Randomized Clinical Trials (RCTs) was classified using the "Consolidated Standards of Reporting Trials" (CONSORT) checklist and the Impact Factor (IF) value of each journal was recorded. Sixty-six papers were identified, and 23 fulfilled the inclusion criteria. Only three studies had caries lesion development as outcome, all the others reported caries risk factors as interim evaluation. Using the CONSORT Score, the papers were coded as 4 excellent, 9 good and 10 poor. The mean IF value recorded was 1.438. Probiotics may play a role as antagonistic agent on mutans streptococci (MS), acidogenic/aciduric bacteria that contributes to the caries process. In two-thirds of the selected papers, probiotics have demonstrated the capacity to reduce MS counts in saliva and/or plaque in short-term. The effect of probiotics on the development of caries lesion seems encouraging, but to date, RCTs on this topic are insufficient to provide scientific clinical evidence. 23765872 Photolithographic boronate affinity molecular imprinting: a general and facile approach for glycoprotein imprinting. Better than expected: With a regular boronic acid as the functional monomer, a general and facile approach for glycoprotein imprinting exhibited several highly favorable features that are beyond normal expectation, which make the prepared MIPs feasible for the recognition of trace glycoproteins in complicated real samples. 23913254 Paternal deprivation affects the functional maturation of corticotropin-releasing hormone (CRH)- and calbindin-D28k-expressing neurons in the bed nucleus of the stria terminalis (BNST) of the biparental Octodon degus. While the critical role of maternal care on the development of brain and behavior of the offspring has been extensively studied, our knowledge about the importance of paternal care for brain development of his offspring is still comparatively scarce. The aim of this study in the biparental caviomorph rodent Octodon degus was to analyze the impact of paternal care on the development of corticotropin-releasing hormone (CRH)-expressing neurons in the bed nucleus of the stria terminalis (BNST) and hypothalamic paraventricular nucleus (PVN). Both brain areas are key players in neuronal circuits that regulate hypothalamic-pituitary-adrenal axis (HPA) activity. At the age of postnatal day (PND) 21, we found that paternal deprivation resulted in a decreased density of CRH-containing neurons in the medial, but not in the lateral BNST, whereas no changes were observed in the PVN. These deprivation-induced changes were still prominent in adulthood. At PND 21, the density of Ca-binding protein calbindin D28K (CaBP-D28K)-expressing neurons was specifically increased in the medial, but not lateral BNST of father-deprived animals. In contrast, adult father-deprived animals show significantly decreased density of CaBP-D28K-expressing neurons in the lateral, but not medial BNST. Taken together, these results may have important implications for our understanding of the experience-driven development of neural circuits that regulate HPA activity mediating acute responses to stress and chronic anxiety. 23419500 Dual-specificity phosphatase 6 (Dusp6), a negative regulator of FGF2/ERK1/2 signaling, enhances 17β-estrodial-induced cell growth in endometrial adenocarcinoma cell. Dual-specificity phosphatase 6 (Dusp6) is a negative feedback mechanism of fibroblast growth factors (FGFs)/mitogen-activated protein kinase (MAPK)/ERK1/2 signaling. The aim of this study was to explore the expression of Dusp6 in human endometrial adenocarcinomas and the role of Dusp6 expression in the growth regulation of endometrial adenocarcinoma cell. We found that Dusp6 was over-expressed in human endometrial adenocarcinomas. In Ishikawa cells, plasmid-driven Dusp6 expression efficiently blocked the activity of FGF2-induced MAPK/ERK1/2 signaling. Unexpectedly, Dusp6 expression significantly enhanced the growth of Ishikawa cells. In Dusp6 forced-expression cells, 17β-estradiol stimulation increased the cell growth by all most threefolds. In addition, progesterone treatment reduced the cell growth to about half both in Ishikawa cells with and without forced-Dusp6-expression. Dusp6 over-expression is involved in the pathogenesis and development of human endometrial adenocarcinomas. Dusp6 functions as a negative regulator of FGF2/ERK1/2 signaling but enhances the growth and 17β-estradiol-induced cell growth in endometrial adenocarcinoma cell. 23846116 Hybridization chain reaction engineered DNA nanopolylinker for amplified electrochemical sensing of biomarkers. A DNA nanopolylinker was designed as a three dimensional nanoprobe with high loading of signal molecules for amplifying the biosensing signal. The nanoprobe was prepared by hybridization chain reaction engineering dsDNA polymerization on initiator DNA modified Au nanoparticle with two kinds of small molecule, for example, FITC-labeled DNA hairpins. The core-shell conjugate that was formed contained approximately 320 FITC molecules for further binding of signal molecules. With a sandwich-type immunoreaction and a biotin-streptavidin affinity reaction, the biotinylated core-shell nanoprobe was immobilized on the immunosensor surface, and the FITC molecules then bound enzyme labeled anti-FITC antibody to catalyze a silver deposition process, leading to a novel cascade signal amplification strategy. By combining the proposed strategy with stripping analysis of the deposited silver, an ultrasensitive immunoassay method for biomarker detection was developed. Under optimal conditions, this method showed a linear detection range over 5 orders of magnitude for carcinoembryonic antigen with a detection limit of 1.2 fg mL(-1) (about 18 molecules in 5.0 μL sample). The preparation of DNA nanopolylinker was simple and economic, and it could be used as a universal and multifarious probe for different bioanalytical techniques and showed the promising potential of the signal amplification strategy in the future design of biosensing methodology. 23063209 Comparison of a 3-hour versus a 6-hour sampling-protocol using high-sensitivity cardiac troponin T for rule-out and rule-in of non-STEMI in an unselected emergency department population. Current European guidelines recommend the use of sensitive or high-sensitivity cardiac troponin assays to reduce the minimal sampling interval from 6 to 3h. We compared a 3-hour versus a 6-hour protocol for diagnosis of non-STEMI and used the 99th percentile for rule-out, and relative and absolute concentration changes for rule-in of non-STEMI. 459 patients with either an NSTE-ACS or elevated hs-cTnT not due to MI and hs-cTnT measurements at 0, 3 and 6h were enrolled. Among the 404 patients excluded due to an incomplete sampling protocol performance was comparable to the 459 patients with a complete sampling protocol (AUC 0.79 vs 0.80, p=ns). In the study group, non-STEMI was diagnosed in 111 cases (24.2%) and elevated hs-cTnT not due to MI was observed in 215 cases (46.8%). For rule-out of non-STEMI, NPVs were 94.9%, 98.7% and 100% on admission, at 3 and 6h with comparable performance at 3 and 6h (AUC 0.782 vs 0.790, p=ns). For rule-in a 3-hour protocol performed as well as a 6-hour protocol, with a significantly (p<0.0001) better performance of absolute (AUC 0.851 vs. 0.845, p=0.740) as compared to relative concentration changes (AUC 0.771 vs. 0.739, p=0.169). Rule-in and rule-out of non-STEMI may be accomplished comparably effective at 3 or 6h. For rule-in, absolute kinetic changes perform better than relative changes at all time points. ROC-optimal absolute δ-change was 6.95ng/L at 3h and 8.9ng/L at 6h. 23542814 Mitochondrial complex I dysfunction induced by cocaine and cocaine plus morphine in brain and liver mitochondria. Mitochondrial function and energy metabolism are affected in brains of human cocaine abusers. Cocaine is known to induce mitochondrial dysfunction in cardiac and hepatic tissues, but its effects on brain bioenergetics are less documented. Furthermore, the combination of cocaine and opioids (speedball) was also shown to induce mitochondrial dysfunction. In this work, we compared the effects of cocaine and/or morphine on the bioenergetics of isolated brain and liver mitochondria, to understand their specific effects in each tissue. Upon energization with complex I substrates, cocaine decreased state-3 respiration in brain (but not in liver) mitochondria and decreased uncoupled respiration and mitochondrial potential in both tissues, through a direct effect on complex I. Morphine presented only slight effects on brain and liver mitochondria, and the combination cocaine+morphine had similar effects to cocaine alone, except for a greater decrease in state-3 respiration. Brain and liver mitochondrial respirations were differentially affected, and liver mitochondria were more prone to proton leak caused by the drugs or their combination. This was possibly related with a different dependence on complex I in mitochondrial populations from these tissues. In summary, cocaine and cocaine+morphine induce mitochondrial complex I dysfunction in isolated brain and liver mitochondria, with specific effects in each tissue. 23746354 Amoebicidal activity of phytosynthesized silver nanoparticles and their in vitro cytotoxicity to human cells. Acanthamoeba causes infections in humans and other animals and it is important to develop treatment therapies. Jatropha curcas, Jatropha gossypifolia and Euphorbia milii plant extracts synthesized stable silver nanoparticles (AgNPs) that were relatively stable. Amoebicidal activity of J. gossypifolia, J. curcas and E. milii leaf extracts showed little effect on viability of Acanthamoeba castellanii trophozoites. Plant-synthesized AgNPs showed higher amoebicidal activity. AgNPs synthesized by J. gossypifolia extract were able to kill 74-27% of the trophozoites at concentrations of 25-1.56 Î¼g mL(-1) . AgNPs were nontoxic at minimum inhibitory concentration with peripheral blood mononuclear cells. These results suggest biologically synthesized nanoparticles as an alternative candidate for treatment of Acanthamoeba infections. 23817792 The social ecology of resolving family conflict among west african immigrants in new york: a grounded theory approach. The current study employs a grounded theory approach to examine West African immigrants' resolution of parent-child conflict and intimate partner conflict. Data from 59 participants present an interactive social ecological framework, where a lack of resolution at one level results in attempts to resolve problems at higher levels. Four levels are identified within West African immigrants' problem solving ecology, each with specific actors in positions of authority: individual/dyadic (parents and spouses), extended family (which includes distant relatives and relatives living in home countries), community leadership (non-family elders and religious leaders), and state authorities. From participants' descriptions of family challenges emerged a picture of a social ecology in flux, with traditional, socially conservative modes of resolving family conflict transposed across migration into the more liberal and state-oriented familial context of the United States. This transposition results in a loss spiral for the traditional social ecology, differentially affecting individual actors within families. Implications for helping professionals working with new immigrant communities include identifying variability in openness to adapting structures that are not working well (e.g., patriarchal protection of abusive husbands) and supporting structures known to be associated with well being (e.g., collective monitoring of youth). 23250746 Palmitate and lipopolysaccharide trigger synergistic ceramide production in primary macrophages. Macrophages play a key role in host defense and in tissue repair after injury. Emerging evidence suggests that macrophage dysfunction in states of lipid excess can contribute to the development of insulin resistance and may underlie inflammatory complications of diabetes. Ceramides are sphingolipids that modulate a variety of cellular responses including cell death, autophagy, insulin signaling, and inflammation. In this study we investigated the intersection between TLR4-mediated inflammatory signaling and saturated fatty acids with regard to ceramide generation. Primary macrophages treated with lipopolysaccharide (LPS) did not produce C16 ceramide, whereas palmitate exposure led to a modest increase in this sphingolipid. Strikingly, the combination of LPS and palmitate led to a synergistic increase in C16 ceramide. This response occurred via cross-talk at the level of de novo ceramide synthesis in the ER. The synergistic response required TLR4 signaling via MyD88 and TIR-domain-containing adaptor-inducing interferon beta (TRIF), whereas palmitate-induced ceramide production occurred independent of these inflammatory molecules. This ceramide response augmented IL-1β and TNFα release, a process that may contribute to the enhanced inflammatory response in metabolic diseases characterized by dyslipidemia. 23915287 Lipophilic Extracts of Cynara cardunculus L. var. altilis (DC): A Source of Valuable Bioactive Terpenic Compounds. Lipophilic extracts of Cynara cardunculus L. var. altilis (DC) from the south of Portugal (Baixo Alentejo) were studied by gas chromatography-mass spectrometry. One sesquiterpene lactone, four pentacyclic triterpenes, and four sterols were reported for the first time as cultivated cardoon components, namely, deacylcynaropicrin, β- and α-amyrin, lupenyl and ψ-taraxasteryl acetates, stigmasterol, 24-methylenecholesterol, campesterol, and Δ(5)-avenasterol. In addition, other new compounds were identified: ten fatty acids, eight long-chain aliphatic alcohols, and six aromatic compounds. Four triterpenyl fatty acid esters were also detected. Sesquiterpene lactones and pentacyclic triterpenes were the major lipophilic families, representing respectively 2-46% and 10-89% of the detected compounds. Cynaropicrin was the most abundant sesquiterpene lactone, while taraxasteryl acetate was the main pentacyclic triterpene. Fatty acids and sterols, mainly hexadecanoic acid and β-sitosterol, were present at lower amounts (1-20% and 1-11% of the detected compounds). Long-chain aliphatic alcohols and aromatic compounds were detected at reduced abundances (1-6% of the detected compounds). 23443933 Baculovirus replication induces the expression of heat shock proteins in vivo and in vitro. A recent handful of studies have linked baculovirus infection with the induction of heat shock proteins, a highly conserved family of cytoprotective proteins. Here, we demonstrate baculovirus-stimulated upregulation of hsp70 transcription in the natural host, Helicoverpa zea. Larvae lethally infected with Helicoverpa zea single nucleopolyhedrovirus (HzSNPV) accumulated hsp70 transcripts throughout the 72-hour course of infection in the midgut, hemocytes, and fat body. While a maximal 17- or 15-fold induction of hsp70 was noted in the midgut and hemocytes, respectively, by 72 hours postinfection, the level of hsp70 transcription in the fat body of larvae was greater than two orders of magnitude higher than in mock-infected larvae. These results were largely mirrored in cultures of infected cells, and a potentiation effect was observed in cells that were both heat shocked and infected. In contrast, Spodoptera frugiperda multiple nucleopolyhedrovirus and ultraviolet-inactivated HzSNPV did not stimulate hsp70 transcription in these non-permissive larvae and in cell culture, respectively. Taken together, this report documents baculovirus-mediated upregulation of hsp70 in the host and demonstrates the requirement for productive infection for hsp70 induction in vitro and in vivo. 23771688 Angiotensin receptor-mediated oxidative stress is associated with impaired cardiac redox signaling and mitochondrial function in insulin-resistant rats. Activation of angiotensin receptor type 1 (AT1) contributes to NADPH oxidase (Nox)-derived oxidative stress during metabolic syndrome. However, the specific role of AT1 in modulating redox signaling, mitochondrial function, and oxidative stress in the heart remains more elusive. To test the hypothesis that AT1 activation increases oxidative stress while impairing redox signaling and mitochondrial function in the heart during diet-induced insulin resistance in obese animals, Otsuka Long Evans Tokushima Fatty (OLETF) rats (n = 8/group) were treated with the AT1 blocker (ARB) olmesartan for 6 wk. Cardiac Nox2 protein expression increased 40% in OLETF compared with age-matched, lean, strain-control Long Evans Tokushima Otsuka (LETO) rats, while mRNA and protein expression of the H2O2-producing Nox4 increased 40-100%. ARB treatment prevented the increase in Nox2 without altering Nox4. ARB treatment also normalized the increased levels of protein and lipid oxidation (nitrotyrosine, 4-hydroxynonenal) and increased the redox-sensitive transcription factor Nrf2 by 30% and the activity of antioxidant enzymes (SOD, catalase, GPx) by 50-70%. Citrate synthase (CS) and succinate dehydrogenase (SDH) activities decreased 60-70%, whereas cardiac succinate levels decreased 35% in OLETF compared with LETO, suggesting that mitochondrial function in the heart is impaired during obesity-induced insulin resistance. ARB treatment normalized CS and SDH activities, as well as succinate levels, while increasing AMPK and normalizing Akt, suggesting that AT1 activation also impairs cellular metabolism in the diabetic heart. These data suggest that the cardiovascular complications associated with metabolic syndrome may result from AT1 receptor-mediated Nox2 activation leading to impaired redox signaling, mitochondrial activity, and dysregulation of cellular metabolism in the heart. 23959439 Microbial oxidation of dispersed graphite by nitrifying bacteria 2011.2. A facile and green microbial method to produce graphite oxide nanosheets and nanoparticles is described. The obtained graphite oxide nanosheets have few layers with 0.7-1.5 nm height and 50-300 nm size. The carbon nanoparticles possess the size of 20-60 nm and the height of 2-4 nm. 23598884 The far infrared spectrum of naphthalene characterized by high resolution synchrotron FTIR spectroscopy and anharmonic DFT calculations. Using synchrotron radiation, we performed the rotationally resolved Fourier transform infrared absorption spectroscopy of three bands of naphthalene C10H8, namely ν(46)-0 (centered at 782 cm(-1), 12.7 μm), ν(47)-0 (centered at 474 cm(-1), 21 μm), and ν(48)-0 (centered at 167 cm(-1), 60 μm). The intense CH bending out of plane ν(46)-0 band was recorded under supersonic jet-cooled conditions using a molecular beam (the Jet-AILES apparatus) and the low frequency ν(47)-0 and ν(48)-0 bands were measured at room temperature in a long absorption path cell. The simultaneous rotational analysis of these bands permitted us to refine the ground state (GS) and ν(46) rotational spectroscopic constants and to provide the first sets of constants for the ν(47) and ν(48) modes. The experimental rotational constants were then used as reference data to calibrate theoretical models in order to provide new insights into the accuracy of anharmonic calculations. The B97-1 functional associated with the cc-pVTZ and ANO-RCC basis sets gave a consistent set of results, for rotational constants and fundamental frequencies. The data presented here pave the way for the search of naphthalene through its far-infrared spectrum in different objects of the interstellar medium. 23837589 Effects of Osteochondrin S and select connective tissue ribonucleinate components on human osteoclasts in vitro. Osteochondrin S, a natural product derived from connective tissues and yeast, is used to treat osteoarthritis. The aim of this study was to determine the effect of Osteochondrin S on human osteoclast activity in vitro. Osteoclasts were derived from human peripheral blood mononuclear cells stimulated with macrophage colony-stimulating factor and receptor activator of nuclear factor kappa B (RANK) ligand. Cells were treated with 23.5-587.2 ng/ml Osteochondrin S or 0.2-5 mg/ml of RNA components (synovia, placenta, intervertebral disc or cartilage). The effects on osteoclast formation and resorptive activity were assessed. Real-time polymerase chain reaction was conducted to assess the expression of key osteoclast genes. Osteochondrin S and the individual RNA extracts resulted in a concentration-dependent inhibition of human osteoclast activity. Osteochondrin S did not affect RANK, nuclear factor of activated T cells (NFATc1), osteoclast-associated receptor or cathepsin K expression. However, there was a significant (P < 0.05) reduction in mRNA expression of calcitonin receptor. Osteochondrin S treatment also significantly increased the expression of osteoclast inhibitory factor interferon-β and, interestingly, increased the expression of tumour necrosis-α-like weak inducer of apoptosis (TWEAK). Osteochondrin S inhibited the resorptive ability of osteoclasts. These actions are likely to occur at a late stage during osteoclast formation, downstream of NFATc1. Overall, the findings show that Osteochondrin S inhibition of osteoclast activity may be responsible for its beneficial effects on diseases such as osteoarthritis. 23829467 "Inclusive working life in Norway": a registry-based five-year follow-up study. In 2001, the Norwegian authorities and major labour market partners signed an agreement regarding 'inclusive working life' (IW), whereby companies that participate are committed to reducing sickness absence. Our main aim was to determine the effect of the IW program and work characteristics by gender on long-term (>8 weeks) sickness absence (LSA). Self-reported data on work characteristics from the Oslo Health Study were linked to registry-based data on IW status, education and LSA. From 2001-2005, 10,995 participants (5,706 women and 5,289 men) aged 30, 40, 45 and 60 years were followed. A Cox regression was used to compute hazard ratios (HR) for LSA risk. The cohort was divided into an IW group (2,733 women and 2,058 men) and non-IW group (2,973/3,231). 43.2% and 41.6% of women and 22.3%/24.3% of men (IW / non-IW, respectively) experienced at least one LSA. In a multivariate model, statistically significant risk factors for LSA were low education (stronger in men), shift work/night work or rotating hours (strongest in men in the non-IW group), and heavy physical work or work involving walking and lifting (men only and stronger in the non-IW group). Among men who engaged in shift work, the LSA risk was significantly lower in the IW group. Our results could suggest that IW companies that employ many men in shift work have implemented relevant efforts for reducing sickness absence. However, this study could not demonstrate a significant effect of the IW program on the overall LSA risk. 23188469 Automated intracranial pressure-controlled cerebrospinal fluid external drainage with LiquoGuard®. LiquoGuard is a new device for intracranial pressure (ICP)-controlled drainage of cerebrospinal fluid (CSF). This present study evaluates the accuracy of ICP measurement via the LiquoGuard device in comparison with Spiegelberg. Thus, we compared data ascertained from simultaneous measurement of ICP using tip-transducer and tip-sensor devices. A total of 1,764 monitoring hours in 15 patients (range, 52-219 h) were analysed. All patients received an intraventricular Spiegelberg III probe with the drainage catheter connected to the LiquoGuard system. ICP reading of both devices was performed on an hourly basis. Statistical analysis was done by applying Pearson correlation and Wilcoxon-matched pair test (p < 0.05). Mean ICP values were 11 ±â€‰5 mmHg (Spiegelberg) and 10 ±â€‰7 mmHg (LiquoGuard); the values measured with both devices correlated well (p = 0.001; Pearson correlation =0.349; n = 1,764). In two of the 15 patients with slit ventricles, episodes of significant differences in measured values could be observed. Both patients suffering from slit ventricles failed to produce reliable measurement with the external transducer of the LiquoGuard. LiquoGuard is a valuable new device for ICP-controlled CSF drainage. However, LiquoGuard tends to provide misleading results in slit ventricles. Thus, before these drawbacks are further analysed, the authors recommend additional ICP measurement with internal tip-sensor devices to avoid dangerous erroneous interpretation of ICP data. 23542023 The Recent Reversal of the Growth Trend in MRI: A Harbinger of the Future? Diagnostic imaging services have been repeatedly targeted as a source of excess health care expenditure. In particular, MRI is considered a high-tech and high-cost imaging service that saw rapid increases in utilization in the early 2000s. However, the most recent trends in the utilization of MR are not known. The aim of this study was to quantify trends in MR utilization overall and by body system from 1998 to 2010 in the Medicare population. Medicare Part B data sets were obtained for 1998 to 2010 for all MR examinations performed in the Medicare population. Using Current Procedural Terminology codes, the total volume and utilization rates of all MR examinations were tabulated for each year of the study period. MR volume was then categorized by body system. The utilization rate of MR examinations in the Medicare population was 73 per 1,000 beneficiaries in 1998, increased to a peak of 189 in 2008, and decreased to 183 in 2010. The compound annual growth rate from 1998 to 2008 was 10%. The utilization rate in 2010 represents a decrease of 3.1% from the 2009 utilization rate. The most frequently imaged body section in every year was the head, which accounted for 2,404,250 examinations in 2010, 37.3% of all MR examinations in that year. The overall MRI utilization rate sharply increased from 1998 until 2008 but then decreased in each of the next 2 years. A similar trend was noted for MR examinations performed in most body sections. These trends are likely to be the result of a number of possible causative factors. 23398844 Increased PD-1 on CD4(+)CD28(-) T cell and soluble PD-1 ligand-1 in patients with T2DM: Association with atherosclerotic macrovascular diseases. OBJECTIVE: To study the role of the programmed death-1 (PD-1)/programmed death-1 ligand 1 (PD-L1) coinhibitory pathway in regulating CD4(+)CD28(-) T cells, and to explore the association of soluble PD-L1 (sPD-L1) in the development of T2DM with atherosclerotic macrovascular diseases. METHODS: The percentage of CD4(+)CD28(-) T lymphocyte subsets from peripheral blood mononuclear cells (PBMCs) and the expression of PD-1/PD-L1 on lymphocytes were analyzed by immunostaining and flow cytometry, respectively. The serum levels of sPD-L1 and IFN-γ were determined by ELISA system. T cell proliferation was determined by cocultivation and WST-8 incorporation. RESULTS: In 125 T2DM patients and 48 healthy donors, CD4(+)CD28(-) T cells from patients with T2DM expressed higher PD-1 than that of the cells from healthy individuals, and the proliferation response of CD4(+)CD28(-) T cells could be enhanced by advanced glycation end products (AGEs). The levels of sPD-L1 in patients were also much higher than those of healthy donors, and the increase was displayed in an exacerbation-dependent manner in the T2DM with atherosclerotic macrovascular patients especially with acute coronary syndrome (ACS). The production of sPD-L1 was significantly positively correlated with the level of IFN-γ and could enhance T cell proliferation. CONCLUSION: Both the upregulation of PD-1 and the increase of sPD-L1 were closely associated with the severity of diabetic atherosclerotic macrovascular diseases. sPD-L1 may contribute to the continuous T cell activation and development of diabetic macrovascular diseases. 23820787 Association of the FTO Obesity Risk Variant rs8050136 With Percentage of Energy Intake From Fat in Multiple Racial/Ethnic Populations: The PAGE Study. Common obesity risk variants have been associated with macronutrient intake; however, these associations' generalizability across populations has not been demonstrated. We investigated the associations between 6 obesity risk variants in (or near) the NEGR1, TMEM18, BDNF, FTO, MC4R, and KCTD15 genes and macronutrient intake (carbohydrate, protein, ethanol, and fat) in 3 Population Architecture using Genomics and Epidemiology (PAGE) studies: the Multiethnic Cohort Study (1993-2006) (n = 19,529), the Atherosclerosis Risk in Communities Study (1987-1989) (n = 11,114), and the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) Study, which accesses data from the Third National Health and Nutrition Examination Survey (1991-1994) (n = 6,347). We used linear regression, with adjustment for age, sex, and ethnicity, to estimate the associations between obesity risk genotypes and macronutrient intake. A fixed-effects meta-analysis model showed that the FTO rs8050136 A allele (n = 36,973) was positively associated with percentage of calories derived from fat (βmeta = 0.2244 (standard error, 0.0548); P = 4 × 10(-5)) and inversely associated with percentage of calories derived from carbohydrate (βmeta = -0.2796 (standard error, 0.0709); P = 8 × 10(-5)). In the Multiethnic Cohort Study, percentage of calories from fat assessed at baseline was a partial mediator of the rs8050136 effect on body mass index (weight (kg)/height (m)(2)) obtained at 10 years of follow-up (mediation of effect = 0.0823 kg/m(2), 95% confidence interval: 0.0559, 0.1128). Our data provide additional evidence that the association of FTO with obesity is partially mediated by dietary intake. 23106789 Arsenic control during aquifer storage recovery cycle tests in the floridan aquifer. Implementation of aquifer storage recovery (ASR) for water resource management in Florida is impeded by arsenic mobilization. Arsenic, released by pyrite oxidation during the recharge phase, sometimes results in groundwater concentrations that exceed the 10 µg/L criterion defined in the Safe Drinking Water Act. ASR was proposed as a major storage component for the Comprehensive Everglades Restoration Plan (CERP), in which excess surface water is stored during the wet season, and then distributed during the dry season for ecosystem restoration. To evaluate ASR system performance for CERP goals, three cycle tests were conducted, with extensive water-quality monitoring in the Upper Floridan Aquifer (UFA) at the Kissimmee River ASR (KRASR) pilot system. During each cycle test, redox evolution from sub-oxic to sulfate-reducing conditions occurs in the UFA storage zone, as indicated by decreasing Fe(2+) /H2 S mass ratios. Arsenic, released by pyrite oxidation during recharge, is sequestered during storage and recovery by co-precipitation with iron sulfide. Mineral saturation indices indicate that amorphous iron oxide (a sorption surface for arsenic) is stable only during oxic and sub-oxic conditions of the recharge phase, but iron sulfide (which co-precipitates arsenic) is stable during the sulfate-reducing conditions of the storage and recovery phases. Resultant arsenic concentrations in recovered water are below the 10 µg/L regulatory criterion during cycle tests 2 and 3. The arsenic sequestration process is appropriate for other ASR systems that recharge treated surface water into a sulfate-reducing aquifer. 23888004 Analysis of 118 Pesticides in Tobacco after Extraction With the Modified QuEChRS Method by LC-MS-MS. A liquid chromatography-tandem quadrupole mass spectrometry (LC-MS-MS) multi-residue method for the simultaneous target analysis of a wide range of pesticides in tobacco has been developed. Gradient elution has been used in conjunction with positive mode electrospray ionization tandem mass spectrometry to detect up to 118 pesticides in tobacco. The recoveries obtained for each pesticide ranged between 70 and 118% at two spiked concentration levels. Good linear relationships were observed with correlation coefficients r(2) > 0.992 for all analytes. The established method was successfully applied to the determination of pesticide residues in real tobacco samples in order to validate the suitability for routine analysis. 23775551 Diagnosis and management of the patient with suspected dementia in primary care. Dementia is a complex progressive syndrome characterised by impairment of cognition (including memory, language, visuospatial skills and executive function), changes in personality and diminished activities of daily living. The impact of dementia is enormous and poses a huge challenge to patients, their carers, society at large and health systems around the world, in terms of the direct cost of medical care, social care and unpaid care provided by family members and others. In this review, we combine evidence and clinical opinion, using guidelines and reviews from 2006, 2009 and 2010 to present a practical guide for primary care physicians to the diagnosis, treatment and ongoing care of patients with suspected or diagnosed dementia. This review summarises the epidemiology of dementia syndrome, and offers detailed evidence-based advice on recognition of dementia (including subtyping) and responses to it and its associated symptoms. The roles of neuroimaging and biomarkers are discussed, as are both non-pharmacological and pharmacological therapies. 23898424 A systematic review of evidence for education and training interventions in microsurgery. Over the past decade, driven by advances in educational theory and pressures for efficiency in the clinical environment, there has been a shift in surgical education and training towards enhanced simulation training. Microsurgery is a technical skill with a steep competency learning curve on which the clinical outcome greatly depends. This paper investigates the evidence for educational and training interventions of traditional microsurgical skills courses in order to establish the best evidence practice in education and training and curriculum design. A systematic review of MEDLINE, EMBASE, and PubMed databases was performed to identify randomized control trials looking at educational and training interventions that objectively improved microsurgical skill acquisition, and these were critically appraised using the BestBETs group methodology. The databases search yielded 1,148, 1,460, and 2,277 citations respectively. These were then further limited to randomized controlled trials from which abstract reviews reduced the number to 5 relevant randomised controlled clinical trials. The best evidence supported a laboratory based low fidelity model microsurgical skills curriculum. There was strong evidence that technical skills acquired on low fidelity models transfers to improved performance on higher fidelity human cadaver models and that self directed practice leads to improved technical performance. Although there is significant paucity in the literature to support current microsurgical education and training practices, simulated training on low fidelity models in microsurgery is an effective intervention that leads to acquisition of transferable skills and improved technical performance. Further research to identify educational interventions associated with accelerated skill acquisition is required. 23895205 Power of magic hands: Parent-driven application of habit reversal to treat complex stereotypy in a 3-year-old. Objective: The authors assessed the effectiveness of habit reversal training (HRT) to treat a complex motor stereotypy in a healthy 3-year-old female. Method: This data-based case study involved training parents in HRT to deliver the parent-driven intervention to the child. The frequency of the child's behaviors was estimated daily in 30-min intervals by her parents. Results: Outcomes supported the effectiveness of the intervention, with the estimated frequency of the stereotypy decreasing from occurring during approximately 85% of recorded intervals to less than 2% over a period of 4 weeks. Further record keeping over 19 weeks suggested treatment gains were generally maintained over time. Conclusions: The current case study provides preliminary evidence supporting the effectiveness of modified HRT to reduce stereotypies in young children. Further, data suggest that the intervention may be extended to younger ages by teaching parents how to facilitate treatment delivery. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23674059 Synthesis of poly-(3-hydroxybutyrate-co-12 mol % 3-hydroxyvalerate) by Bacillus cereus FB11: its characterization and application as a drug carrier. The synthesis of microbial polyhydroxyalkanoate is investigated in this work for it potential application as drug carrier for cancer therapy. The bacterial isolate Bacillus cereus FB11 has synthesized poly-(3-hydroxybutyrate-co-3-hydroxyvalerate) copolymer under nutrient stress conditions using glucose as a sole carbon source. The FTIR spectrum of the purified copolymer showed the characteristic absorption bands at 1,719, 1,260 and 2,931 cm(-1) attributing to C=O, C-O stretching and C-H vibrations, respectively. The result of (1)H-NMR confirmed that it was composed of 88 mol % of 3-hydroxybutyrate and 12 mol % of 3-hydroxyvalerate monomeric subunits. The nanoparticles were fabricated from copolymer and used as a carrier for anticancer drug ellipticine. The in vitro drug release studies showed that % inhibition of A549 cancer cell line receiving ellipticine loaded poly-(3-hydroxybutyrate-co-3-hydroxyvalerate) nanoparticles was two-fold higher in comparison to ellipticine alone. This drug delivery system offers exciting possibilities for cancer therapy by increasing the bioavailability of anti-neoplastic drug to the tumor site. 23265579 Paraganglioma of the maxillary sinus. Primary paragangliomas of the paranasal sinuses are very rare conditions with only few cases described in the literature. Paragangliomas are locally aggressive, often recur and can metastasize. Usually, open surgery is used to resect such tumors from the sinonasal tract. Here, a case of a large paraganglioma of the left maxillary sinus and nasal cavity, which was successfully removed using the Onyx® embolic agent two days prior to minimally invasive image guided endoscopic sinus surgery, is reported. This case demonstrates that large vascular tumors of the sinonasal tract can be successfully managed by endoscopic endonasal sinus surgery. The patient has no evidence of recurrence after 12 months of follow-up. 23846682 The feasibility of a randomised controlled trial for the axillary management of a select group of invasive breast cancer patients: SLNB vs. no-SLNB. The results of ZOO11 have shaken our thinking and approach for the axillary management of small invasive breast cancers where the incidence and burden of axillary metastasis would be much less than that of ZOO11 population. The traditional approach of sentinel lymph node biopsy (SLNB) for "all invasive cancers" is challenged because of the diminishing role of axillary lymph nodes (ALNs) status in guiding the adjuvant systemic therapy. Certainly this raises the question of whether SLNB can be avoided in a select group of patients without compromising clinical outcomes. The aim of this study was to identify such a group of patients in whom SLNB is no longer required. Patients with breast cancers ≤2 cm in size and clinically negative axilla who underwent breast conserving surgery (BCS) and SLNB were identified. Patients were divided into different groups; incidence of ALNs metastasis, further non-SLNs metastasis and a total number of tumour positive ALNs of ≥4 were determined. A total of 194 patients met the criteria; incidence of tumour positive SLNs, further non-SLNs metastasis and a total number of tumour positive ALNs of ≥4 varied between different groups and was 9.3-15.5 %, 0-35 % and 0-2.6 %, respectively. Patients with T1b, grade 1-2 tumours had less than 5 % risk of ALNs macrometastasis. It is possible to identify a group of patients whose burden of axillary disease is acceptably low enough that SLNB can be avoided. Feasibility of a non-inferiority randomised controlled trial (RCT) in a select group of patients with or without SLNB has been explored to compare the distant disease free, disease free and overall survival and axillary relapse rate (ARR). 23764459 Fluoxetine exposure during pregnancy and lactation: Effects on acute stress response and behavior in the novelty-suppressed feeding are age and gender-dependent in rats. Fluoxetine (FLX) is commonly used to treat anxiety and depressive disorders in pregnant women. Since FLX crosses the placenta and is excreted in milk, maternal treatment with this antidepressant may expose the fetus and neonate to increased levels of serotonin (5-HT). Long-term behavioral abnormalities have been reported in rodents exposed to higher levels of 5-HT during neurodevelopment. In this study we evaluated if maternal exposure to FLX during pregnancy and lactation would result in behavioral and/or stress response disruption in adolescent and adult rats. Our results indicate that exposure to FLX influenced restraint stress-induced Fos expression in the amygdala in a gender and age-specific manner. In male animals, a decreased expression was observed in the basolateral amygdala at adolescence and adulthood; whereas at adulthood, a decrease was also observed in the medial amygdala. A lack of FLX exposure effect was observed in females and also in the paraventricular nucleus of both genders. Regarding the behavioral evaluation, FLX exposure did not induce anhedonia in the sucrose preference test but decreased the latency to feed of both male and female adolescent rats evaluated in the novelty-suppressed feeding test. In conclusion, FLX exposure during pregnancy and lactation decreases acute amygdalar stress response to a psychological stressor in males (adolescents and adults) as well as influences the behavior of adolescents (males and females) in a model that evaluates anxiety and/or depressive-like behavior. Even though FLX seems to be a developmental neurotoxicant, the translation of these findings to human safe assessment remains to be determined since it is recognized that not treating a pregnant or lactating woman may also impact negatively the development of the descendants. 23610117 Prognosis of women with primary breast cancer diagnosed during pregnancy: results from an international collaborative study. PURPOSE We aimed to determine the prognosis of patients with breast cancer diagnosed during pregnancy (BCP). PATIENTS AND METHODS In this cohort study, a multicentric registry of patients with BCP (from Cancer in Pregnancy, Leuven, Belgium, and GBG 29/BIG 02-03) compiled pro- and retrospectively between 2003 and 2011 was compared with patients who did not have associated pregnancies, using an age limit of 45 years. Patients with a diagnosis postpartum were excluded. The main analysis was performed using Cox proportional hazards regression of disease-free survival (DFS) and overall survival (OS) on exposure (pregnant or not), adjusting for age, stage, grade, hormone receptor status, human epidermal growth factor 2 status, histology, type of chemotherapy, use of trastuzumab, radiotherapy, and hormone therapy. Results The registry contained 447 women with BCP, mainly originating from Germany and Belgium, of whom 311 (69.6%) were eligible for analysis. The nonpregnant group consisted of 865 women. Median age was 33 years for the pregnant and 41 years for the nonpregnant patients. Median follow-up was 61 months. The hazard ratio of pregnancy was 1.34 (95% CI, 0.93 to 1.91; P = .14) for DFS and 1.19 (95% CI, 0.73 to 1.93; P = .51) for OS. Cox regression estimated that the 5-year DFS rate for pregnant patients would have increased from 65% to 71% if these patients had not been pregnant. Likewise, the 5-year OS rate would have increased from 78% to 81%. CONCLUSION The results show similar OS for patients diagnosed with BCP compared with nonpregnant patients. This information is important when patients are counseled and supports the option to start treatment with continuation of pregnancy. 23956249 Evolution of radiographic damage in ankylosing spondylitis: a 12 year prospective follow-up of the OASIS study. To describe the evolution of radiographic abnormalities of the spine in patients with ankylosing spondylitis (AS). Patients with AS were followed prospectively with 2 yearly radiographs for 12 years. The modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) was scored by two readers (R1 and R2). New syndesmophytes at uninvolved vertebral corners were computed. Radiographic progression was investigated using generalised estimating equations. 809 radiographs (presenting 520 at 2 yearly intervals) from 186 patients (70% men, mean age 43 (SD 12) years, mean 20 (SD 12) years since symptom onset and 83% HLA-B27 positive) were included. Mean mSASSS at baseline was 11.6 (16.2). While the course of progression in individual patients was highly variable, and still occurred in patients with decades of symptom duration, mean 2 year progression was 2.0 (3.5) mSASSS units. Over the entire follow-up, at least one new syndesmophyte was found in 55% (R1) and 63% (R2) of patients (38% (R1) and 39% (R2) of all intervals). In 24% of patients (39% of intervals), there was no progression. A progression ≥5 mSASSS units occurred in 22% of patients (or in 12% of intervals). At the group level, a linear time course model fitted the data best, with a constant rate over the entire 12 year interval of 0.98 mSASSS units/year. Radiographic progression occurred significantly faster in men, in HLA-B27 positive patients and in patients with a baseline mSASSS≥10. Long term radiographic progression in AS is highly variable in the individual patient, more severe in HLA-B27 positive men and still occurs after decades of disease. At the group level, however, progression in AS follows an approximately linear course. 23594961 Unique transcriptional profile of liver-resident memory CD8(+) T cells induced by immunization with malaria sporozoites. Sterile immunity against live Plasmodium infection can be achieved by immunization with radiation-attenuated sporozoites. This protection is known to be mediated in part by antigen-specific memory CD8(+) T cells, presumably those residing in the liver. We characterized and compared the transcriptional profile of parasite-specific memory CD8(+) T cells residing in the liver and spleen after immunization of mice with irradiated sporozoites. Microarray-based expression analysis of these memory CD8(+) T cells indicated that liver-resident memory cells display a distinct gene expression profile. We found major differences in the expression of immune function genes as well as genes involved in the cell cycle, cell trafficking, transcription and intracellular signaling. Importantly, the malaria parasite-induced liver-resident CD8(+) T cells display a transcriptional profile different to that described for CD8(+) T cells following other microbial challenges. 22527414 The effects of plasma rich in growth factors (PRGF-Endoret) on healing of medial collateral ligament of the knee. Platelet-rich plasma (PRP) has been increasingly used in sports-related injuries for therapeutic applications. However, there are numerous manufacturing procedures and treatment protocols of PRP use, which make difficult to assess its real efficacy for tissue healing. This study addressed to evaluate the therapeutic effects of locally delivered plasma rich in growth factors (PRGF-Endoret) on the early healing of medial collateral ligament (MCL) in rabbit knees. Thirty-one Japanese white rabbits were subjected to a mop-end tear in the MCL of the left knee. PRGF-Endoret was prepared using Anitua's technique. Two groups were set up. In 17 knees, prepared 1.0 ml of PRGF-Endoret after clotting was applied on the tear site, while in 14 knees the tear site was untreated serving as a control. Quantitative aspects of PRGF-Endoret, the concentration of platelets, leukocytes and erythrocytes and therapeutic growth factors such as PDGF-BB and TGF-β1 were measured. Rabbits were sacrificed at 3 and 6 weeks after the operation and histological and biomechanical evaluation were performed. No leukocytes were measured and certain amount of growth factors such as PDGF-BB and TGF-β1 were confirmed in the PRGF-Endoret. PRGF-Endoret stimulated proliferation of fibroblasts and neovascularization, and induced statistically better structural properties in repaired MCL. Our findings provide evidence that local administration of PRGF-Endoret promotes early steps in ligament healing and the repair of structural properties in a rabbit model. PRGF-Endoret would be a useful product in clinical treatment of ligament injuries. 23642466 Heat and ultraviolet light treatment of colostrum and hospital milk: Effects on colostrum and hospital milk characteristics and calf health and growth parameters. The aim of this study was to evaluate the effects of different physical treatments of bovine colostrum and hospital milk on milk bacteriology, immunoglobulin G (IgG) and lactoferrin concentrations, calf serum IgG concentrations and calf health, growth and survivability. Pooled colostrum samples (n=297) were heat treated (HTC; 63°C for 60min), exposed to ultraviolet light (UVC; 45J/cm(2)) or untreated ('raw', RC). Hospital milk (n=712) was subjected to high temperature short time pasteurization (HTST; 72°C for 15s), ultraviolet light irradiation (UVH; 45J/cm(2)) or was untreated. Neonatal Holstein heifer calves (n=875) were randomly enrolled (309 HTC, 285 UVC, 281 RC) and block randomized (by colostrum treatment) into hospital milk treatments HTST (n=449) or UVH (n=426). HTC was more effective than UVC and HTST was more effective than UVH in reducing bacterial counts. IgG and lactoferrin concentrations were significantly lower in HTC and UVC than in RC. Lactoferrin concentrations were significantly lower in HTST than in UVH or untreated hospital milk. There were no significant differences in serum IgG concentrations among calves fed HTC, UVC or RC. Colostrum and hospital milk treatments did not have any significant effect on calf body weight gain, survivability, or frequency of diarrhea or pneumonia. 23868478 Delivering colonoscopy screening for low-income populations in Suffolk County: Strategies, outcomes, and benchmarks. Current and pending legislation provides colorectal cancer screening reimbursement for previously uninsured populations. Colonoscopy is currently the screening method most frequently recommended by physicians for insured patients. The experience of the SCOPE (Suffolk County Preventive Endoscopy) demonstration project (Project SCOPE) at Stony Brook University Medical Center provides a model for delivering colonoscopy screening to low-income populations to meet anticipated increasing demands. Project SCOPE, based in the Department of Preventive Medicine, featured internal collaboration with the academic medical center's large gastroenterology practice and external collaboration with the Suffolk County Department of Health Services' network of community health centers. Colonoscopies were performed by faculty gastroenterologists or supervised fellows. Measures of colonoscopy performance were compared with quality indicators and differences between faculty and supervised fellows were identified. During a 40-month screening period, 800 initial colonoscopies were performed. Approximately 21% of women screened were found to have adenomatous polyps compared with 36% of men. Five cancers were detected. The majority of the population screened (70%) were members of minority populations. African American individuals had a higher percentage of proximally located adenomas (78%) compared with white individuals (65%) and Hispanics (49%), based on the location of the most advanced lesion. Hispanic individuals had a 36% lower risk of adenomas compared with white individuals. Performance measures including the percentage of procedures with adequate bowel preparation, cecum reached, scope withdrawal time, and adenoma detection rate met quality benchmarks when performed by either faculty or supervised fellows. Project SCOPE's operational strategies demonstrated a feasible method for an academic medical center to provide high-quality screening colonoscopy for low-income populations. Cancer 2013;119(15 suppl):2842-8. © 2013 American Cancer Society. 23603358 Neuronal injury, but not microglia activation, is associated with ketamine-induced experimental schizophrenic model in mice. Schizophrenia is a chronic debilitating psychiatric disorder affecting as many as 1% of the population worldwide. Unfortunately, its etiology and pathophysiology are poorly defined. Previous studies have shown that neuronal injury and microglia activation were observed in the schizophrenic patients. The present study aims to evaluate the role of neurons and microglia in ketamine-induced experimental schizophrenic model to further understand its pathophysiology. Firstly, ketamine was used to simulate the behavior abnormalities associated with schizophrenia. The effects of ketamine on mouse locomotor activity, Y-maze task, novel object recognition, and forced swimming test were studied. The results showed that ketamine (25, 50, and 100mg/kg i.p.) administered acutely or repeatedly (for 7days) can increase the locomotor number significantly. In Y-maze task, ketamine (25, 50, and 100mg/kg) impaired spontaneous alternation after both acute and repeated treatments. In novel object recognition test, acute or chronic ketamine treatment showed no significant effect on mouse exploratory preference behavior. In forced swimming test, repeated treatment of ketamine (100mg/kg) enhanced the immobility duration. Secondly, immunohistochemical method was used to study the changes of neurons and microglia. The results showed that acute treatment of ketamine (100mg/kg) had no effect on neurons in the prefrontal cortex or hippocampus (1, 3, 5, and 7days after the treatment). In contrast, repeated treatment of ketamine caused neuronal impairment in mouse hippocampus (3rd day, 5th day and 7th day after the final administration). The results of immunohistochemistry demonstrated that microglia in the prefrontal cortex and hippocampus were not affected after acute or repeated administration of ketamine. Finally, the neuronal impairment caused by repeated administration of ketamine was further investigated from the oxidative stress aspects. The results showed that repeated administration of ketamine increased nitric oxide (NO) and nitric oxide synthase (NOS) in prefrontal cortex, hippocampus and serum, while decreased SOD in hippocampus and serum. In summary, chronic ketamine treatment to mice successfully mimics the core behavioral deficits in schizophrenia. It is demonstrated for the first time that neuronal injury was associated with the chronic ketamine-induced experimental schizophrenic model, while microglial cells may play little role in this model. Oxidative stress may contribute to the significant neuronal injury in mouse brain induced by chronic ketamine treatment. 23864178 Reverse total shoulder arthroplasty for primary glenohumeral osteoarthritis in patients with a biconcave glenoid. The biconcave glenoid in patients with primary glenohumeral osteoarthritis represents a surgical challenge because of the associated static posterior instability of the humeral head and secondary posterior glenoid erosion. The purpose of the present study was to evaluate the clinical and radiographic results of reverse total shoulder arthroplasty for the treatment of primary osteoarthritis in patients with a biconcave glenoid without rotator cuff insufficiency. We performed a retrospective review of twenty-seven reverse shoulder arthroplasties that were performed from 1998 to 2009 for the treatment of primary glenohumeral osteoarthritis and biconcave glenoid. Eighty-one percent of the patients were female, and the mean age of the patients at the time of surgery was 74.1 years (range, sixty-six to eighty-two years). All patients had a preoperative computed tomography arthrogram to allow for the measurement of glenoid retroversion and humeral head subluxation. The mean preoperative retroversion was 32°, and the mean subluxation of the humeral head with respect to the scapular axis was 87%. Seventeen patients had a reverse shoulder arthroplasty without bone graft, whereas ten had an associated bone graft to compensate for posterior glenoid erosion. Clinical outcomes were evaluated with the Constant score and shoulder range of motion. The mean duration of follow-up was fifty-four months (range, twenty-four to 139 months). The mean Constant score increased from 31 points preoperatively to 76 points at the time of the latest follow-up (p < 0.0001). Active forward flexion, external rotation, and internal rotation also significantly increased (p < 0.0001). Complications occurred in four patients (15%) and included early loosening of the glenoid component (one patient) and neurologic complications (three patients). No radiolucent lines were observed around the central peg or screws of the glenoid component. Grade-1 or 2 scapular notching was present in ten shoulders (37%). No recurrence of posterior instability was observed. Reverse shoulder arthroplasty for the treatment of primary glenohumeral osteoarthritis in patients with a biconcave glenoid without rotator cuff insufficiency can result in excellent clinical outcomes. Reverse shoulder arthroplasty is a viable surgical option to solve both the problem of severe static posterior glenohumeral instability and severe glenoid erosion. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. 23572388 Biomechanical comparison of single-row, double-row, and transosseous-equivalent repair techniques after healing in an animal rotator cuff tear model. The transosseous-equivalent (TOE) rotator cuff repair technique increases failure loads and contact pressure and area between tendon and bone compared to single-row (SR) and double-row (DR) repairs, but no study has investigated if this translates into improved healing in vivo. We hypothesized that a TOE repair in a rabbit chronic rotator cuff tear model would demonstrate a better biomechanical profile than SR and DR repairs after 12 weeks of healing. A two-stage surgical procedure was performed on 21 New Zealand White Rabbits. The right subscapularis tendon was transected and allowed to retract for 6 weeks to simulate a chronic tear. Repair was done with the SR, DR, or TOE technique and allowed to heal for 12 weeks. Cyclic loading and load to failure biomechanical testing was then performed. The TOE repair showed greater biomechanical characteristics than DR, which in turn were greater than SR. These included yield load (p < 0.05), energy absorbed to yield (p < 0.05), and ultimate load (p < 0.05). For repair of a chronic, retracted rotator cuff tear, the TOE technique was the strongest biomechanical construct after healing followed by DR with SR being the weakest. 22989012 The effectiveness of pharmacological approaches in the treatment of alcohol withdrawal syndrome (AWS): a literature review. Excessive drinking can cause a variety of physical, psychological, social and legal problems. Some heavy/dependent users will experience the symptoms of withdrawal when they cut down or stop. Symptoms can vary from mild to severe to life threatening such as seizures (fits) and delirium tremens (DT's). The class of drugs known as the benzodiazepines have been shown to be the most effective in controlling the symptoms of alcohol withdrawal and remain the drug of choice to treat this condition. However the benzodiazepines can cause significant problems such as tolerance and addiction and therefore there has been a search for safer alternatives. Recent findings have shown that there are several viable alternative drug treatment options to the benzodiazepines, particularly the use of Baclofen and psychotropic analgesic nitrous oxide (PAN). However more research is needed, especially on service user who are detoxified in community settings. Mortality statistics for excessive alcohol consumption show no signs of abatement, with a report published in 2011 from the World Health Organization (WHO) estimating that 2.5 million people worldwide died because of their alcohol consumption. Serious physiological, psychological, social and legal problems are thought to affect many more. Alcohol withdrawal syndrome (AWS) is a potentially life-threatening condition that often occurs in those individuals who significantly reduce or stop their intake after a prolonged and excessive period of drinking. Pharmacological treatment of the AWS has traditionally been undertaken by the use of the benzodiazepines, but recent years have witnessed the emergence of several alternatives. The aim of this paper was (1) to review the evidence base supporting the use of various pharmacological agents currently employed to treat AWS, and (2) to consider the efficacy and safety of the emerging alternatives to the benzodiazepines. The Cochrane Database of Systematic Reviews, CINAHL, Embase, PsycINFO, MEDLINE and BNI databases were extensively searched in order to retrieve the maximum number of relevant articles. Reference lists from relevant literature were also used to identify other potential studies for inclusion. All studies concerned with measuring the efficacy and safety of the various pharmacological treatment options for AWS were considered and a total of 63 trials were included in this review. Findings support the use of benzodiazepines as the recommended drug of choice for the treatment of AWS in the absence of adequate evidence to support the use of alternative agents. There is a lack of evidence of a superior pharmacological agent to the benzodiazepines for the treatment of AWS. There are several studies that have shown that there are pharmacological alternatives that could compete or act as an adjunct with the benzodiazepines in terms of high efficacy and safety in the treatment of AWS, but there is a need for further quality research to be carried out before definitive conclusions can be drawn. 22616770 Prospective parallel randomized trial of the MultiCyte™ ThinPrep(®) imaging system: the Scottish experience. T.J. Palmer, S.M. Nicoll, M.E. McKean, A.J. Park, D. Bishop, L. Baker and J.E.A. Imrie Prospective parallel randomized trial of the MultiCyte™ ThinPrep(®) imaging system: the Scottish experience Background:  Computer-assisted screening of cervical liquid-based cytology (LBC) preparations using the ThinPrep® Imaging System (TIS) has shown improved qualitative and quantitative gains. The use of Multicyte™ has not been described in a well-established national screening programme with a low incidence of high-grade dyskaryosis. Objectives:  To assess the impact of computer-assisted screening within the Scottish Cervical Screening Programme (SCSP). Methods:  Two groups of three laboratories, each sharing a ThinPrep® Imager, screened 79 366 slides randomized to test and 90 551 to control arms by laboratory accession. Screeners were not blinded. Standard laboratory reporting profiles of the SCSP, sensitivity, specificity and false-negative rates of all grades of LBC abnormalities with respect to final cytology reports, predictive value for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) on histology; and screening rates were compared for both arms. Results:  Inadequate and negative reporting rates were significantly lower and low-grade reporting rates significantly higher in the imager arm. Imager-assisted screening showed significantly better specificity than manual screening with respect to the final cytology result. There was no evidence of a significant difference in the detection of CIN2 +  or CIN3 + . Positive, abnormal and total predictive values (high-grade, low-grade and all abnormal cytology found to be CIN2 + , respectively) were similar in both arms. Productivity was significantly higher in the imager arm. Conclusion:  Computer-assisted screening in a well established screening programme showed significantly improved productivity without loss of quality. These findings should inform future policy for cervical screening programmes. 23793631 Haloarchaeal-Type β-Ketothiolases Involved in Poly(3-Hydroxybutyrate-co-3-Hydroxyvalerate) Synthesis in Haloferax mediterranei. The key enzymes for poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) biosynthesis in haloarchaea have been identified except the β-ketothiolase(s), which condense two acetyl coenzyme A (acetyl-CoA) molecules to acetoacetyl-CoA, or one acetyl-CoA and one propionyl-CoA to 3-ketovaleryl-CoA. Whole-genome analysis has revealed eight potential β-ketothiolase genes in the haloarchaeon Haloferax mediterranei, among which the PHBV-specific BktB and PhaA were identified by gene knockout and complementation analysis. Unlike all known bacterial counterparts encoded by a single gene, the haloarchaeal PhaA that was involved in acetoacetyl-CoA generation, was composed of two different types of subunits (PhaAα and PhaAβ) and encoded by the cotranscribed HFX_1023 (phaAα) and HFX_1022 (phaAβ) genes. Similarly, the BktB that was involved in generation of acetoacetyl-CoA and 3-ketovaleryl-CoA, was also composed of two different types of subunits (BktBα and BktBβ) and encoded by cotranscribed HFX_6004 (bktBα) and HFX_6003 (bktBβ). BktBα and PhaAα were the catalytic subunits and determined substrate specificities of BktB and PhaA, respectively. Their catalytic triad "Ser-His-His" was distinct from the bacterial "Cys-His-Cys." BktBβ and PhaAβ both contained an oligosaccharide-binding fold domain, which was essential for the β-ketothiolase activity. Interestingly, BktBβ and PhaAβ were functionally interchangeable, although PhaAβ preferred functioning with PhaAα. In addition, BktB showed biotechnological potential for the production of PHBV with the desired 3-hydroxyvalerate fraction in haloarchaea. This is the first report of the haloarchaeal type of PHBV-specific β-ketothiolases, which are distinct from their bacterial counterparts in both subunit composition and catalytic residues. 23333998 Hydrophobicity of rare-earth oxide ceramics. Hydrophobic materials that are robust to harsh environments are needed in a broad range of applications. Although durable materials such as metals and ceramics, which are generally hydrophilic, can be rendered hydrophobic by polymeric modifiers, these deteriorate in harsh environments. Here we show that a class of ceramics comprising the entire lanthanide oxide series, ranging from ceria to lutecia, is intrinsically hydrophobic. We attribute their hydrophobicity to their unique electronic structure, which inhibits hydrogen bonding with interfacial water molecules. We also show with surface-energy measurements that polar interactions are minimized at these surfaces and with Fourier transform infrared/grazing-angle attenuated total reflection that interfacial water molecules are oriented in the hydrophobic hydration structure. Moreover, we demonstrate that these ceramic materials promote dropwise condensation, repel impinging water droplets, and sustain hydrophobicity even after exposure to harsh environments. Rare-earth oxide ceramics should find widespread applicability as robust hydrophobic surfaces. 23888161 Quantitative patterns between plant volatile emissions induced by biotic stresses and the degree of damage. Plants have to cope with a plethora of biotic stresses such as herbivory and pathogen attacks throughout their life cycle. The biotic stresses typically trigger rapid emissions of volatile products of lipoxygenase (LOX) pathway (LOX products: various C6 aldehydes, alcohols, and derivatives, also called green leaf volatiles) associated with oxidative burst. Further a variety of defense pathways is activated, leading to induction of synthesis and emission of a complex blend of volatiles, often including methyl salicylate, indole, mono-, homo-, and sesquiterpenes. The airborne volatiles are involved in systemic responses leading to elicitation of emissions from non-damaged plant parts. For several abiotic stresses, it has been demonstrated that volatile emissions are quantitatively related to the stress dose. The biotic impacts under natural conditions vary in severity from mild to severe, but it is unclear whether volatile emissions also scale with the severity of biotic stresses in a dose-dependent manner. Furthermore, biotic impacts are typically recurrent, but it is poorly understood how direct stress-triggered and systemic emission responses are silenced during periods intervening sequential stress events. Here we review the information on induced emissions elicited in response to biotic attacks, and argue that biotic stress severity vs. emission rate relationships should follow principally the same dose-response relationships as previously demonstrated for different abiotic stresses. Analysis of several case studies investigating the elicitation of emissions in response to chewing herbivores, aphids, rust fungi, powdery mildew, and Botrytis, suggests that induced emissions do respond to stress severity in dose-dependent manner. Bi-phasic emission kinetics of several induced volatiles have been demonstrated in these experiments, suggesting that next to immediate stress-triggered emissions, biotic stress elicited emissions typically have a secondary induction response, possibly reflecting a systemic response. The dose-response relationships can also vary in dependence on plant genotype, herbivore feeding behavior, and plant pre-stress physiological status. Overall, the evidence suggests that there are quantitative relationships between the biotic stress severity and induced volatile emissions. These relationships constitute an encouraging platform to develop quantitative plant stress response models. 23940209 Identification of a Human Monoclonal Antibody to Replace Equine Diphtheria Anti-toxin for the Treatment of Diphtheria Intoxication. Diphtheria anti-toxin (DAT) has been the cornerstone of the treatment of Corynebacterium diphtheriae infection for over one hundred years. While the global incidence of diphtheria has declined steadily over the last quarter of the 20(th) century, the disease remains endemic in many parts of the world and significant outbreaks still occur. DAT is an equine polyclonal antibody which is not commercially available in the United States and is in short supply globally. A safer, more readily available alternative to DAT would be desirable. In the current study, we obtained human monoclonal antibodies (hMAbs) directly from antibody secreting cells in the circulation of immunized human volunteers. We isolated a panel of diverse hMAbs that recognized diphtheria toxoid as well as a variety of recombinant protein fragments of diphtheria toxin. Forty-five unique hMAbs were tested for neutralization of diphtheria toxin in in vitro cytotoxicity assays with an EC50 value of 0.65 ng/mL for the lead-candidate hMAb, 315C4. Additionally, 25 μg of 315C4 completely protected guinea pigs from intoxication in an in vivo lethality model yielding an estimated relative potency of 64 IU/mg. In comparison, 1.6 IU of DAT was necessary for full protection from morbidity and mortality in this model. We further established that our lead candidate hMAb binds to the receptor binding domain of diphtheria toxin and physically blocks the toxin from binding to the putative receptor, heparin-binding epidermal growth factor-like growth factor (HB-EBF). The discovery of a specific and potent human neutralizing antibody against diphtheria toxin holds promise as a potential therapeutic. 23545283 Dynamic state allocation for MEG source reconstruction. Our understanding of the dynamics of neuronal activity in the human brain remains limited, due in part to a lack of adequate methods for reconstructing neuronal activity from noninvasive electrophysiological data. Here, we present a novel adaptive time-varying approach to source reconstruction that can be applied to magnetoencephalography (MEG) and electroencephalography (EEG) data. The method is underpinned by a Hidden Markov Model (HMM), which infers the points in time when particular states re-occur in the sensor space data. HMM inference finds short-lived states on the scale of 100ms. Intriguingly, this is on the same timescale as EEG microstates. The resulting state time courses can be used to intelligently pool data over these distinct and short-lived periods in time. This is used to compute time-varying data covariance matrices for use in beamforming, resulting in a source reconstruction approach that can tune its spatial filtering properties to those required at different points in time. Proof of principle is demonstrated with simulated data, and we demonstrate improvements when the method is applied to MEG. 23946130 Agglomeration of Mesoporous Silica by Melt and Steam Granulation. Part II: Screening of Steam Granulation Process Variables Using a Factorial Design. The objectives of this study were to identify the key process parameters during steam granulation of disordered mesoporous silica material Syloid® 244 FP (244) and to compare two different binders: polyvinylpyrrolidone (PVP) K25 and hydroxypropylmethyl cellulose (HPMC). Itraconazole (ITZ) was selected as the model compound for the development of an oral dosage form for enhanced release. Six factors: binder content, steam amount, mixing time, impeller speed, spray pause time, and filler content were investigated using a two-level quarter-fraction factorial design of experiment (DOE) for each binder type. As experimental responses, characteristics correlating to both granules and tablets were selected. Granules prepared from PVP resulted in an overall higher bulk density, granule size, increased flow properties, and better compression and compaction behavior. Although granulation with PVP resulted in the most ITZ to extract from the pores during processing, the premature drug release was less than 5%. The results of the DOE indicate that the risk of extracting the drug from the pores during processing is governed both by the process parameters and the binder properties. Centerpoint replicates of granules prepared with HPMC were highly variable. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci. 23428140 Hemorrhage rates of external ventricular drain (EVD), intracranial pressure gauge (ICP) or combined EVD and ICP gauge placement within 48h of endovascular coil embolization of cerebral aneurysms. In single patients with a cerebral aneurysm an external ventricular drain (EVD), an intracranial pressure (ICP) gauge or a combined EVD and ICP gauge placement is necessary after coil embolization and initiation of postprocedural anticoagulation. The aim of this study was to examine the hemorrhage rates of drain placement within 48h after aneurysm coiling and under anticoagulation or antiplatelet therapy. We retrospectively analyzed hemorrhage rates of EVD, ICP gauge or combined EVD and ICP gauge placement in 27 patients within 48h after coil embolization under different anticoagulation or antiplatelet schemes (heparin, acetylsalicylic acid, clopidogrel). In patients with continuous heparin via perfusor the application was stopped periprocedurally. The results were compared to literature. Four hemorrhages (14.8%) were observed. Three hemorrhages were petechial and one was by definition a larger hemorrhage with 8mm×10mm in diameter. EVD, ICP gauge or combined EVD and ICP gauge placements within 48h after cerebral aneurysm coiling and under different anticoagulation or antiplatelet regimens seem to have no increased risk of hemorrhages compared to literature. 23494938 Nickel sulfide/nitrogen-doped graphene composites: phase-controlled synthesis and high performance anode materials for lithium ion batteries. Phase-controlled nickel sulfide (Ni3 S4 and NiS1.03 ) nanoparticle (NP)/nitrogen-doped graphene (NG) composites are prepared through a facile one-pot hydrothermal process. The composites show ultrahigh capacity retentions of 98.87% and 95.94% for Ni3 S4 /NG and NiS1.03 /NG electrodes, respectively, as anode materials for lithium ion batteries. 23698349 Ribosome profiling reveals resemblance between long non-coding RNAs and 5' leaders of coding RNAs. Large-scale genomics and computational approaches have identified thousands of putative long non-coding RNAs (lncRNAs). It has been controversial, however, as to what fraction of these RNAs is truly non-coding. Here, we combine ribosome profiling with a machine-learning approach to validate lncRNAs during zebrafish development in a high throughput manner. We find that dozens of proposed lncRNAs are protein-coding contaminants and that many lncRNAs have ribosome profiles that resemble the 5' leaders of coding RNAs. Analysis of ribosome profiling data from embryonic stem cells reveals similar properties for mammalian lncRNAs. These results clarify the annotation of developmental lncRNAs and suggest a potential role for translation in lncRNA regulation. In addition, our computational pipeline and ribosome profiling data provide a powerful resource for the identification of translated open reading frames during zebrafish development. 23644657 Siah2 regulates tight junction integrity and cell polarity through control of ASPP2 stability. Changes in cell adhesion and polarity are closely associated with epithelial cell transformation and metastatic capacity. The tumor suppressor protein ASPP (Apoptosis-Stimulating Proteins of p53) 2 has been implicated in control of cell adhesion and polarity through its effect on the PAR complex. Here we demonstrate that under hypoxic conditions, the ubiquitin ligase Siah (seven in absentia homolog)2 controls ASPP2 availability, with concomitant effect on epithelial cell polarity. LC-MS/MS analysis identified ASPP2 and ASPP1 as Siah2-interacting proteins. Biochemical analysis confirmed this interaction and mapped degron motifs within ASPP2, which are required for Siah2-mediated ubiquitination and proteasomal-dependent degradation. Inhibition of Siah2 expression increases ASPP2 levels and enhances ASPP2-dependent maintenance of tight junction (TJ) integrity, and polarized architecture in three dimensional (3D) organotypic culture. Conversely, increase of Siah2 expression under hypoxia decreases ASPP2 levels and the formation of apical polarity in 3D culture. In all, our studies demonstrate the role of Siah2 in regulation of TJ integrity and cell polarity under hypoxia, through its regulation of ASPP2 stability.Oncogene advance online publication, 6 May 2013; doi:10.1038/onc.2013.149. 23742712 Population-Level Administration of AlcoholEdu for College: An ARIMA Time-Series Analysis. Autoregressive integrated moving averages (ARIMA) is a powerful analytic tool for conducting interrupted time-series analysis, yet it is rarely used in studies of public health campaigns or programs. This study demonstrated the use of ARIMA to assess AlcoholEdu for College, an online alcohol education course for first-year students, and other health and safety programs introduced at a moderate-size public university in the South. From 1992 to 2009, the university administered annual Core Alcohol and Drug Surveys to samples of undergraduates (Ns = 498 to 1032). AlcoholEdu and other health and safety programs that began during the study period were assessed through a series of quasi-experimental ARIMA analyses. Implementation of AlcoholEdu in 2004 was significantly associated with substantial decreases in alcohol consumption and alcohol- or drug-related negative consequences. These improvements were sustained over time as succeeding first-year classes took the course. Previous studies have shown that AlcoholEdu has an initial positive effect on students' alcohol use and associated negative consequences. This investigation suggests that these positive changes may be sustainable over time through yearly implementation of the course with first-year students. ARIMA time-series analysis holds great promise for investigating the effect of program and policy interventions to address alcohol- and drug-related problems on campus. 23936109 Fractalkine depresses cardiomyocyte contractility. Our laboratory reported that male mice with cardiomyocyte-selective knockout of the prostaglandin E2 EP4 receptor sub-type (EP4 KO) exhibit reduced cardiac function. Gene array on left ventricles (LV) showed increased fractalkine, a chemokine implicated in heart failure. We therefore hypothesized that fractalkine is regulated by PGE2 and contributes to depressed contractility via alterations in intracellular calcium. Fractalkine was measured in LV of 28-32 week old male EP4 KO and wild type controls (WT) by ELISA and the effect of PGE2 on fractalkine secretion was measured in cultured neonatal cardiomyocytes and fibroblasts. The effect of fractalkine on contractility and intracellular calcium was determined in Fura-2 AM-loaded, electrical field-paced cardiomyocytes. Cardiomyocytes (AVM) from male C57Bl/6 mice were treated with fractalkine and responses measured under basal conditions and after isoproterenol (Iso) stimulation. LV fractalkine was increased in EP4 KO mice but surprisingly, PGE2 regulated fractalkine secretion only in fibroblasts. Fractalkine treatment of AVM decreased both the speed of contraction and relaxation under basal conditions and after Iso stimulation. Despite reducing contractility after Iso stimulation, fractalkine increased the Ca(2+) transient amplitude but decreased phosphorylation of cardiac troponin I, suggesting direct effects on the contractile machinery. Fractalkine depresses myocyte contractility by mechanisms downstream of intracellular calcium. 23929795 How does a specific learning and memory system in the mammalian brain gain control of behaviour? This review addresses a fundamental, yet poorly understood set of issues in systems neuroscience. The issues revolve around conceptualizations of the organization of learning and memory in the mammalian brain. One intriguing, and somewhat popular, conceptualization is the idea that there are multiple learning and memory systems in the mammalian brain and they interact in different ways to influence and/or control behaviour. This approach has generated interesting empirical and theoretical work supporting this view. One issue that needs to be addressed is how these systems influence or gain control of voluntary behaviour. To address this issue, we clearly specify what we mean by a learning and memory system. We then review two types of processes that might influence which memory system gains control of behaviour. One set of processes are external factors that can affect which system controls behaviour in a given situation including task parameters like the kind of information available to the subject, types of training experience, and amount of training. The second set of processes are brain mechanisms that might influence what memory system controls behaviour in a given situation including executive functions mediated by the prefrontal cortex; switching mechanisms mediated by ascending neurotransmitter systems, the unique role of the hippocampus during learning. The issue of trait differences in control of different learning and memory systems will also be considered in which trait differences in learning and memory function are thought to potentially emerge from differences in level of prefrontal influence, differences in plasticity processes, differences in ascending neurotransmitter control, differential access to effector systems like motivational and motor systems. Finally, we present scenarios in which different mechanisms might interact. This review was conceived to become a jumping off point for new work directed at understanding these issues. The outcome of this work, in combination with other approaches, might improve understanding of the mechanisms of volition in human and non-human animals. © 2013 Wiley Periodicals, Inc. 23957819 Emerging treatments for chronic constipation. Introduction: Chronic constipation (CC) is a common problem worldwide and, for some sufferers, a cause of considerable morbidity. Recent definitions of CC have moved from the former emphasis on stool frequency alone to a broader concept that strives to encompass the various symptoms that may bother afflicted individuals. Accordingly, new therapies attempt to not only increase frequency of defecation but also to address such symptoms as satisfaction with bowel action, straining, bloating, and distension. Areas covered: To provide context the relative merits and problems related to conventional laxative-based approaches to constipation are first reviewed and then more recent novel pharmacological approaches to the management of constipation assessed. The focus is on two classes of compounds, selective prokinetics and prosecretory agents, and studies on their efficacy and safety in chronic idiopathic constipation were retrieved and evaluated. Expert opinion: While undoubtedly effective, high-quality evidence to support laxatives, the traditional remedies for constipation, is remarkably scarce due, in large part, to the absence, until very recently, of high-quality randomized controlled clinical trials. The selective prokinetic agent prucalopride and the prosecretory agents lubiprostone and linaclotide have shown efficacy and been associated with a good safety record in large well-conducted clinical studies. Other novel approaches, such as the inhibition of ileal bile salt absorption, offer particular promise. 23452271 Adhesion of Mussel Foot Protein-3 to TiO2 Surfaces: the Effect of pH. The underwater adhesion of marine mussels relies on mussel foot proteins (mfps) rich in the catecholic amino acid 3,4-dihydroxyphenylalanine (Dopa). As a side chain, Dopa is capable of strong bidentate interactions with a variety of surfaces, including many minerals and metal oxides. Titanium is among the most widely used medical implant material and quickly forms a TiO2 passivation layer under physiological conditions. Understanding the binding mechanism of Dopa to TiO2 surfaces is therefore of considerable theoretical and practical interest. Using a surface forces apparatus, we explored the force-distance profiles and adhesion energies of mussel foot protein 3 (mfp-3) to TiO2 surfaces at three different pHs (pH 3, 5.5 and 7.5). At pH 3, mfp-3 showed the strongest adhesion force on TiO2, with an adhesion energy of ∼-7.0 mJ/m(2). Increasing the pH gives rise to two opposing effects: (1) increased oxidation of Dopa, thus, decreasing availability for the Dopa-mediated adhesion, and (2) increased bidentate Dopa-Ti coordination, leading to the further stabilization of the Dopa group and, thus, an increase in adhesion force. Both effects were reflected in the resonance-enhanced Raman spectra obtained at the three deposition pHs. The two competing effects give rise to a higher adhesion force of mfp-3 on the TiO2 surface at pH 7.5 than at pH 5.5. Our results suggest that Dopa-containing proteins and synthetic polymers have great potential as coating materials for medical implant materials, particularly if redox activity can be controlled. 23261591 Central nervous system damage due to acute paraquat poisoning: an experimental study with rat model. Paraquat (PQ) is a common herbicide and PQ poisoning is a major medical problem in Asia. However, few studies have focused on the acute neurotoxic changes caused by PQ. Here we report the acute neurotoxicological findings of rats treated with lethal dose of PQ. In substantia nigra (SN) and striatum we found obvious microglia (labeled by Iba-1) activation within one week. In SN and hippocampus, we detected increased oxidative stress in the neurons based on NeuN/8-OHdG immunofluorescence double labeling and laser cofocal microscopy. Moreover, we provided ultrastructural evidences of astrocyte edema and neurons apoptosis in rat brain by electron microscopy. Further studies will be needed with non-lethal dose of PQ to confirm these results and demonstrate the direct CNS toxicity of PQ. 23932286 Green microalga Scenedesmus acutus grown on municipal wastewater to couple nutrient removal with lipid accumulation for biodiesel production. The green microalga Scenedesmus acutus was cultivated in two different municipal wastewater discharges (pre- and post-treated), and was compared to a culture medium with basic nutrients (20% of N, P, K), in order to study the simultaneous potential of nutrient removal and lipid accumulation ability. The highest level of nutrient removal was found in the pretreated wastewater discharge (achieving a high removal of phosphorus [66%] and organic nitrogen [94%]). Likewise, better results on biomass productivity and lipid accumulation were found in cultures using pretreated wastewater compared to enriched medium, obtaining 79.9mg/L, and 280mg/L, respectively. Since the best results were found in pretreated wastewater, the biodiesel preparation was performed using said medium at small-scale. After cultivation, 249.4mg/L of biodiesel were obtained. According to this analysis, S. acutus could be used for wastewater treatment producing biomass with a suitable content of lipids, convenient for biodiesel production. 23726425 Angiopoietin-2 (ANGPT2) as a candidate gene for somatic cell score in German Holstein cattle. This study evaluated the bovine angiopoietin-2 (ANGPT2) gene as a functional and positional candidate gene underlying a previously fine mapped quantitative trait locus (QTL) for somatic cell score on bovine chromosome 27. The gene product angiopoietin-2 is directly involved in the extravasation of neutrophils, making it a promising candidate to control the amount of somatic cells in milk. A total of 11 polymorphisms were identified within the gene by comparatively resequencing the entire open reading frame of the gene as well as adjacent intronic regions. Four selected variants were genotyped in the same granddaughter design used for QTL mapping and an association study was carried out applying 2 complementary approaches. A variable number of tandem repeats in intron 7 of the gene was found to be significantly associated with cell score in all approaches and explains approximately half of the QTL variance. Analysis of ANGPT2 mRNA expression in different localizations of the udder in animals putatively carrying divergent QTL alleles revealed differential expression in the udder lymph node. Together with the physiological role of angiopoietin-2, these results support a role of ANGPT2 in the genetic control of somatic cell score. Further studies are, however, needed to further underpin this hypothesis. 23884754 Discordance Between Conventional and Detailed Lymph Node Analysis in Resected Biliary Carcinoma at or Above the Cystic Duct: Are We Understaging Patients? Analysis of portal lymph node (LN) metastases following resection of biliary carcinomas at or above the cystic duct (BC) is used to select patients for adjuvant therapy, but no guidelines exist and LN yield is low. Some consider analysis of 7 LNs necessary for accurate staging. Conventional LN analysis may understage patients. Portal LNs from 38 node-negative patients following resection of BC from 2000 to 2008 were re-examined in detail for occult metastases (OM) using a modified Weaver protocol. Outcomes measured were discordance in LN positivity and patient survival. On detailed examination, 5 of 38 patients had OM. There was no difference in survival between patients with and without OM (24 vs 17 months; p = .382). There was no association between OM and patient demographics or adverse tumor characteristics. The median LN yield was 3. Of the 27 patients with <7 LNs retrieved, 1 had OM, compared with 4 of 11 patients with ≥7 LNs retrieved (p = .030). OM in these well-staged patients were associated with reduced survival (9 vs 41 months; p = .032). There is discordance between conventional and detailed LN analysis in resected BC. LN yield â‰¥7 was associated with OM. The presence of OM may be associated with decreased survival. Conventional LN analysis may understage patients with resected BC. 23343761 In-plane coassembly route to atomically thick inorganic-organic hybrid nanosheets. Control over the anisotropic assembly of small building blocks into organized structures is considered an effective way to design organic nanosheets and atomically thick inorganic nanosheets with nonlayered structure. However, there is still no available route so far to control the assembly of inorganic and organic building blocks into a flattened hybrid nanosheet with atomic thickness. Herein, we highlight for the first time a universal in-plane coassembly process for the design and synthesis of transition-metal chalcogenide-alkylamine inorganic-organic hybrid nanosheets with atomic thickness. The structure, formation mechanism, and stability of the hybrid nanosheets were investigated in detail by taking the Co₉S₈-oleylamine (Co₉S₈-OA) hybrid nanosheets as an example. Both experimental data and theoretical simulations demonstrate that the hybrid nanosheets were formed by in-plane connection of small two-dimensional (2D) Co₉S₈ nanoplates via oleylamine molecules adsorbed at the side surface and corner sites of the nanoplates. X-ray absorption fine structure spectroscopy study reveals the structure distortion of the small 2D Co₉S₈ nanoplates that endows structural stability of the atomically thick Co₉S₈-OA hybrid nanosheets. The brand new atomically thick nanosheets with inorganic-organic hybrid network nanostructure will not only enrich the family of atomically thick 2D nanosheets but also inspire more interest in their potential applications. 23852950 Role of the Oxidative DNA Damage Repair Gene OGG1 in Colorectal Tumorigenesis. Biallelic inherited mutations in the oxidative DNA damage repair gene MUTYH predispose to colorectal adenomas and colorectal carcinoma (CRC) with high penetrance. We investigated whether rare inherited variants in other oxidative DNA damage repair genes predisposed to CRC. Single marker association analyses were assessed under an allelic model with Bonferroni correction for multiple testing. All statistical tests were two-sided. A rare inherited nonsynonymous variant in OGG1 (Gly308Glu), the functional partner of MUTYH, was over-represented in case patients with advanced CRC compared with population-based control subjects (n = 36 of 2142 case patients vs n = 15 of 2175 control subjects in the training phase, P = 1.8×10(-3); and n = 22 of 1005 case patients vs n = 8 of 1389 control subjects in the validation phase, P = 4.8×10(-4); P = 1.4×10(-5) combined; odds ratio = 2.92, 95% confidence interval = 1.80 to 4.74). Glycine at residue 308 was highly conserved through evolution, and the glutamic acid substitution was predicted as likely to interfere with function. Biallelic inherited and somatic OGG1 mutations were rarely observed in OGG1 (Gly308Glu) carriers, nor did we find any associated somatic mutator phenotype. These data suggest that OGG1 (Gly308Glu) may act as a low-penetrance allele that contributes to colorectal tumorigenesis. 23800308 Combining a photocatalyst with microtopography to develop effective antifouling materials. Polydimethylsiloxane surfaces textured with a square-wave linear grating profile (0, 20, 200, 300 and 600 μm), and embedded with a range of photocatalytic titanium dioxide (TiO2) nanoparticle loadings (3.75, 7.5, 11.25 and 15 wt.%), were used to test the combined efficacy of these technologies as antifouling materials. Settlement of the fouling bryozoan species Bugula neritina was quantified in the laboratory under two intensities of UV light. The lowest settlement rates were observed on 20 μm surfaces. However, texture effects were not as critical to larval settlement as the presence of TiO2. In conjunction with UV light, TiO2 completely inhibited larval metamorphosis even at the lowest loading (3.75 wt.%) and the lowest intensity of UV light (24 W m(-2)). Recruitment of B. neritina was also quantified in field trials and showed similar results to laboratory assays. The lowest recruitment was observed on 20 and 200 μm surfaces, with recruitment being significantly lower on all surfaces containing TiO2. Therefore for B. neritina, although all TiO2 loadings were effective, 3.75 wt.% can be used as a minimum inhibitory concentration to deter larval settlement and the addition of a 20 μm texture further increases the deterrent effect. 23954072 Literature review of HIV among female sex workers in the Central Asian Republics, Afghanistan, and Mongolia: Contexts and convergence with drug use. Central Asia is culturally and demographically diverse, both between and within its respective countries. That diversity is represented in the range of individual, network, community, and structural risks for female sex workers (FSWs) regionally. FSWs have several risk factors for HIV acquisition and transmission including behavioral, biological, and structural risk factors. Across Central Asia, sexual risks have become conflated with risks associated with injection and non-injection illicit drug use. Peer-reviewed literature databases and gray literature were searched for articles on sex work in Central Asia. The medial subject heading (MeSH) of "sex work" was cross-referenced with terms associated with Uzbekistan, Tajikistan, Turkmenistan, Kazakhstan, Kyrgyzstan, Mongolia, and Afghanistan. HIV prevalence data for FSWs suggest sustained or increasing prevalence in the region. There are increasing data directly linking HIV among FSWs to injection drug use; odds of HIV are up to 20 times higher among FSWs reporting injecting drug use. Though injecting drug use among FSWs is rare in some settings, recreational drugs and alcohol use limits other risk reduction behaviors, such as condom use. The Central Asian HIV epidemic has traditionally been assumed to be driven nearly exclusively by drug use, resulting in surveillance systems focused on parenteral transmission. The reviewed data highlight limited attention to characterizing the burden of HIV and risk factors for HIV acquisition and transmission among FSWs who use drugs. Moving forward will require enhanced HIV surveillance and research to inform HIV prevention approaches to address all levels of HIV risks affecting FSWs in Central Asia. 23708815 Electrochemical impedimetric immunosensor for the detection of measles-specific IgG antibodies after measles infections. The detection of measles-specific primary antibodies (IgG) using electrochemical impedimetric immunosensors is reported. The optimum conditions for electrode saturation were reached after 40min for 1μgml(-1) antibody concentrations. Surface roughness using AFM increased with each immobilization or antigen-antibody reaction step clearly confirming the surface modification and recognition between antigen and antibody. The human serum (HS) and new-born calf serum (NCS) spiked with antigen-specific antibody were studied to mimic the real sample analysis. The HS and NCS sera containing antibodies due to measles exhibited correlation between the increasing antibody serum concentrations and the charge-transfer resistance (electrochemically measured). This work clearly showed the potential use of impedance as the preferred electrochemical method for detecting measles-antibodies in label-free manner. 23947344 The expanding role of NLRs in antiviral immunity. Nucleotide oligomerization and binding domain (NOD)-like receptors (NLRs) are a major constituent of the cytosolic innate immune-sensing machinery and participate in a wide array of pathways including nuclear factor κB (NF-κB), mitogen-activated protein kinase (MAPK), inflammasome, and type I interferon (IFN) signaling. NLRs have known roles in autoimmune, autoinflammatory, and infectious diseases. With respect to virus infection, NLRP3 is the most extensively studied NLR, including mechanisms of activation and inhibition. Furthermore, the importance of NLRP3 in both innate and adaptive immunity has been demonstrated. In comparison to NLRP3, the roles of other NLRs during virus infection are only just emerging. NLRC2 is an important activator of innate antiviral signaling and was recently found to mitigate inflammation during virus infection through autophagy. Finally, functions for NLRX1 in immune modulation and reactive oxygen species production require further examination and the importance of NLRC5 as a transactivator of major histocompatibility complex (MHC) class I and antigen presentation is currently developing. In this review, we discuss current knowledge pertaining to viruses and NLRs as well as areas of potential research, which will help advance the study of NLR biology during virus infection. 23253128 Expanding the number of 'druggable' targets: non-enzymes and protein-protein interactions. Following sequencing and assembly of the human genome, the preferred methods for identification of new drug targets have changed dramatically. Modern tactics such as genome-wide association studies (GWAS) and deep sequencing are fundamentally different from the pharmacology-guided approaches used previously, in which knowledge of small molecule ligands acting at their cellular targets was the primary discovery engine. A consequence of the 'target-first, pharmacology-second' strategy is that many predicted drug targets are non-enzymes, such as scaffolding, regulatory or structural proteins, and their activities are often dependent on protein-protein interactions (PPIs). These types of targets create unique challenges to drug discovery efforts because enzymatic turnover cannot be used as a convenient surrogate for compound potency. Moreover, it is often challenging to predict how ligand binding to non-enzymes might affect changes in protein function and/or pathobiology. Thus, in the postgenomic era, targets might be strongly implicated by molecular biology-based methods, yet they often later earn the designation of 'undruggable'. Can the scope of available targets be widened to include these promising, but challenging, non-enzymes? In this review, we discuss advances in high-throughput screening (HTS) technology and chemical library design that are emerging to deal with these challenges. 23878377 Ionic mechanisms limiting cardiac repolarization-reserve in humans compared to dogs. The species-specific determinants of repolarization are poorly understood. This study compared the contribution of various currents to cardiac repolarization in canine and human ventricle. Conventional microelectrode, whole-cell patch-clamp, molecular biological and mathematical-modelling techniques were used. Selective IKr-block (50 100 nmol/L dofetilide) lengthened APD90>3-fold more in human than dog, suggesting smaller repolarization-reserve in humans. Selective IK1-block (10-µmol/L BaCl2) and IKs block (1-μmol/L HMR-1556) increased APD90 more in canine than human right-ventricular papillary muscle. Ion-current measurements in isolated cardiomyocytes showed that IK1- and IKs-density were 3- and 4.5-fold larger in dogs than humans respectively. IKr-density and kinetics were similar in human versus dog. ICa and Ito were respectively ~30% larger and ~29% smaller in human, and Na(+),Ca(2+)-exchange current was comparable. Cardiac mRNA-levels for the main IK1 ion-channel subunit Kir2.1 and the IKs accessory-subunit minK were significantly lower, but mRNA-expression of ERG and KvLQT1 (IKr and IKs α-subunits) were significantly higher in human versus dog. Immunostaining suggested lower Kir2.1 and minK, and higher KvLQT1 protein-expression in human versus canine cardiomyocytes. IK1 and IKs inhibition increased the APD-prolonging effect of IKr-block more in dog (by 55% and 51% respectively) than human (33 and 16%), indicating that both currents contribute to increased repolarization-reserve in the dog. A mathematical model incorporating observed human-canine ion-current differences confirmed the role of IK1 and IKs in repolarization-reserve differences. Thus, humans show greater repolarization-delaying effects of IKr-block than dogs, because of lower repolarization-reserve contributions from IK1 and IKs, emphasizing species-specific determinants of repolarization and the limitations of animal models for human disease. 23835726 Characteristics and outcome of children admitted to adult intensive care units in England, Wales and Northern Ireland (1996-2011). Despite centralisation of paediatric intensive care units (PICU) in the UK, children continue to be admitted to adult intensive care units (AICU). We aimed to analyse trends in the admission of children to AICUs over a 16-year period from 1996, and describe their case mix, outcome and resource use in a recent cohort (2009-2011). We extracted data from consecutive admissions of children (1996-2011) to AICUs from the Intensive Care National Audit and Research Centre Case Mix Programme Database. We studied case mix, outcome and resource use as well as regional, seasonal and temporal variations in admissions of children to AICU. A total of 13,430 children were admitted to AICUs between 1996 and 2011 (representing 1.3 % of all admissions). This proportion decreased from 2.8 % in 1996 to 0.6 % in 2011. Crude mortality fell from 6.7 to 2.8 %, and the proportion transferred out to a PICU rose from 18.9 to 51.4 %. In recent years (2009-2011), half of the 2,320 admissions of children occurred in just three English Strategic Health Authorities. The median length of unit stay was 7.7 h (IQR 3.8-19.7) for survivors and 11.5 h (IQR 5.0-36.2) for non-survivors. The number of children admitted to AICUs in England, Wales and Northern Ireland has been steadily declining since 1996. In recent years, half of all children admitted to AICUs are transferred to PICU, usually following a short stay. The reasons for regional variation in paediatric admissions to AICUs, and the cause of death in the small number of children who die in AICUs, are unclear. 23910483 The life care planning process. This article discusses the history and evolution of what is now known as a life care plan. The qualifications of professionals who perform the specialty practice of life care planning are reviewed. The standards of practice for life care planning have been a long-standing guide for the practitioner and its core components are discussed. 23832500 The role of TMEM16A (ANO1) and TMEM16F (ANO6) in cell migration. Members of the TMEM16 family have recently been described as Ca(2+)-activated Cl(-) channels. They have been implicated in cancer and appear to be associated with poor patient prognosis. Here, we investigate the role of TMEM16 channels in cell migration, which is largely unknown. We focused on TMEM16A and TMEM16F channels that have the highest expression of TMEM16 channels in Ehrlich Lettre ascites (ELA) cells. Due to the lack of specific pharmacological modulators, we employed a miRNA approach and stably knocked down the expression of TMEM16A and TMEM16F channels, respectively. Migration analysis shows that TMEM16A KD clones are affected in their directional migration, whereas TMEM16F KD clones show a 40 % reduced rate of cell migration. Moreover, TMEM16A KD clones have a smaller projected cell area, and they are rounder than TMEM16F KD clones. The morphological changes are linearly correlated with the directionality of cells. TMEM16A and TMEM16F, thus, have an important function in cell migration-TMEM16A in directional migration, TMEM16F in determination of the speed of migration. We conclude that TMEM16A and TMEM16F channels have a distinct impact on the steering and motor mechanisms of migrating ELA cells. 23905720 The Effects of Alcohol on the Nonhuman Primate Brain: A Network Science Approach to Neuroimaging. Animal studies have long been an important tool for basic research as they offer a degree of control often lacking in clinical studies. Of particular value is the use of nonhuman primates (NHPs) for neuroimaging studies. Currently, studies have been published using functional magnetic resonance imaging (fMRI) to understand the default-mode network in the NHP brain. Network science provides an alternative approach to neuroimaging allowing for evaluation of whole-brain connectivity. In this study, we used network science to build NHP brain networks from fMRI data to understand the basic functional organization of the NHP brain. We also explored how the brain network is affected following an acute ethanol (EtOH) pharmacological challenge. Baseline resting-state fMRI was acquired in an adult male rhesus macaque (n = 1) and a cohort of vervet monkeys (n = 10). A follow-up scan was conducted in the rhesus macaque to assess network variability and to assess the effects of an acute EtOH challenge on the brain network. The most connected regions in the resting-state networks were similar across species and matched regions identified as the default-mode network in previous NHP fMRI studies. Under an acute EtOH challenge, the functional organization of the brain was significantly impacted. Network science offers a great opportunity to understand the brain as a complex system and how pharmacological conditions can affect the system globally. These models are sensitive to changes in the brain and may prove to be a valuable tool in long-term studies on alcohol exposure. 23122648 E-learning initiatives in forensic interpretation: report on experiences from current projects and outlook. This paper reports on the purpose, design, methodology and target audience of E-learning courses in forensic interpretation offered by the authors since 2010, including practical experiences made throughout the implementation period of this project. This initiative was motivated by the fact that reporting results of forensic examinations in a logically correct and scientifically rigorous way is a daily challenge for any forensic practitioner. Indeed, interpretation of raw data and communication of findings in both written and oral statements are topics where knowledge and applied skills are needed. Although most forensic scientists hold educational records in traditional sciences, only few actually followed full courses that focussed on interpretation issues. Such courses should include foundational principles and methodology - including elements of forensic statistics - for the evaluation of forensic data in a way that is tailored to meet the needs of the criminal justice system. In order to help bridge this gap, the authors' initiative seeks to offer educational opportunities that allow practitioners to acquire knowledge and competence in the current approaches to the evaluation and interpretation of forensic findings. These cover, among other aspects, probabilistic reasoning (including Bayesian networks and other methods of forensic statistics, tools and software), case pre-assessment, skills in the oral and written communication of uncertainty, and the development of independence and self-confidence to solve practical inference problems. E-learning was chosen as a general format because it helps to form a trans-institutional online-community of practitioners from varying forensic disciplines and workfield experience such as reporting officers, (chief) scientists, forensic coordinators, but also lawyers who all can interact directly from their personal workplaces without consideration of distances, travel expenses or time schedules. In the authors' experience, the proposed learning initiative supports participants in developing their expertise and skills in forensic interpretation, but also offers an opportunity for the associated institutions and the forensic community to reinforce the development of a harmonized view with regard to interpretation across forensic disciplines, laboratories and judicial systems. 23850729 Structure, variation and expression analysis of glutenin gene promoters from Triticum aestivum cultivar Chinese Spring shows the distal region of promoter 1Bx7 is key regulatory sequence. In this study, ten glutenin gene promoters were isolated from model wheat (Triticum aestivum L. cv. Chinese Spring) using a genomic PCR strategy with gene-specific primers. Six belonged to high-molecular-weight glutenin subunit (HMW-GS) gene promoters, and four to low-molecular-weight glutenin subunit (LMW-GS). Sequence lengths varied from 1361 to 2554bp. We show that the glutenin gene promoter motifs are conserved in diverse sequences in this study, with HMW-GS and LMW-GS gene promoters characterized by distinct conserved motif combinations. Our findings show that HMW-GS promoters contain more functional motifs in the distal region of the glutenin gene promoter (> -700bp) compared with LMW-GS. The y-type HMW-GS gene promoters possess unique motifs including RY repeat and as-2 box compared to the x-type. We also identified important motifs in the distal region of HMW-GS gene promoters including the 5'-UTR Py-rich stretch motif and the as-2 box motif. We found that cis-acting elements in the distal region of promoter 1Bx7 enhanced the expression of HMW-GS gene 1Bx7. Taken together, these data support efforts in designing molecular breeding strategies aiming to improve wheat quality. Our results offer insight into the regulatory mechanisms of glutenin gene expression. 23832847 Peritoneal carcinomatosis of gastric origin: A population-based study on incidence, survival and risk factors. Peritoneal carcinomatosis (PC) is an important cause of morbidity and mortality among patients with gastric cancer. The aim of the current study was to provide reliable population-based data on the incidence, risk factors and prognosis of PC of gastric origin. All patients diagnosed with gastric cancer in the area of the Eindhoven Cancer Registry between 1995 and 2011 were included. Incidence and survival were computed and risk factors for peritoneal carcinomatosis were determined using multivariate logistic regression analysis. In total, 5,220 patients were diagnosed with gastric cancer, of whom 2,029 (39%) presented with metastatic disease. PC was present in 706 patients (14%) of whom 491 patients (9%) had PC as the only metastatic site. Younger age (<60 years), female gender, advanced T- and N-stage, primary tumor of signet ring cells or linitis plastica and primary tumors covering multiple anatomical locations of the stomach were all associated with a higher odds ratios of developing PC. Median survival of patients without metastases was 14 months, but only 4 months for patients with PC. PC is a frequent condition in patients presenting with gastric cancer, especially in younger patients with advanced tumor stages. Given the detrimental influence of PC on survival, efforts should be undertaken to further explore the promising results that were obtained in preventing or treating this condition with multimodality strategies. 23814783 Multiplexed detection of microRNAs by tuning DNA-scaffolded silver nanoclusters. A universal silver-nanocluster method coupled with target-triggered isothermal exponential amplification reaction (TIEAR) is developed for light-up fluorescent detection of multiple microRNAs (miRNAs) in a label-free format. Taking advantage of the interesting feature of the fine-tuned emission spectrum of fluorescent DNA-scaffolded silver nanoclusters (DNA/AgNCs), our proposed assay is designed such that the different miRNA targets are transferred to the different oligonucleotide reporters via the TIEAR, in which unimolecular DNAs designed for different targets are employed as the amplification templates, polymerases and nicking enzymes as mechanical activators and miRNA targets as the trigger. The produced oligonucleotide reporters act as templates for the synthesis of multicolor DNA/AgNC probes, which correspond to different target inputs. This proposed method has been well validated on the multiplex detection of miRNAs and DNAs, as well as in practical application. 23912041 E-NTPDase and E-ADA activities in lymphocytes associated with the immune response of rats experimentally infected with Toxoplasma gondii. An investigation of E-NTPDase and E-ADA activities in lymphocytes from rats experimentally infected with Toxoplasma gondii was carried out in this study. For this purpose, twenty four adult male Wistar rats were divided in two groups/four subgroups (A1 and A2; B1 and B2-6 animal/each group), with "A" as uninfected and "B" inoculated with T. gondii (RH strain). Sampling was performed on days 5 and 10 post-infection (p.i.), with evaluation of hemogram, immunoglobulins (IgM and IgG) and activity of E-NTPDase and E-ADA in lymphocytes. Enzymes essays showed ATP hydrolysis increased on days 5 (P<0.05) and 10 (P<0.01) p.i., as well as an increase of ADP hydrolysis on day 10 (P<0.01) p.i. E-ADA activity on lymphocytes was also increased in both evaluated periods (P<0.01). Based on E-NTPDase and E-ADA increased activities observed on lymphocytes, it is possible to suggest their involvement in an anti-inflammatory response, consisting of a modulatory response, preventing excessive tissue damage caused by the infection with Toxoplasma gondii. 23519171 Immobilised enzymes in biorenewables production. Oils, fats, carbohydrates, lignin, and amino acids are all important raw materials for the production of biorenewables. These compounds already play an important role in everyday life in the form of wood, fabrics, starch, paper and rubber. Enzymatic reactions do, in principle, allow the transformation of these raw materials into biorenewables under mild and sustainable conditions. There are a few examples of processes using immobilised enzymes that are already applied on an industrial scale, such as the production of High-Fructose Corn Syrup, but these are still rather rare. Fortunately, there is a rapid expansion in the research efforts that try to improve this, driven by a combination of economic and ecological reasons. This review focusses on those efforts, by looking at attempts to use fatty acids, carbohydrates, proteins and lignin (and their building blocks), as substrates in the synthesis of biorenewables using immobilised enzymes. Therefore, many examples (390 references) from the recent literature are discussed, in which we look both at the specific reactions as well as to the methods of immobilisation of the enzymes, as the latter are shown to be a crucial factor with respect to stability and reuse. The applications of the renewables produced in this way range from building blocks for the pharmaceutical and polymer industry, transport fuels, to additives for the food industry. A critical evaluation of the relevant factors that need to be improved for large-scale use of these examples is presented in the outlook of this review. 23838848 High levels of divergent HIV-1 quasispecies in patients with neurological opportunistic infections in China. Despite the fact that the survival of people infected with human immunodeficiency virus (HIV) has improved worldwide because of the increasingly powerful and highly active antiretroviral therapy, opportunistic infections (OIs) of the central nervous system (CNS) remain a serious burden. HIV-1 is capable of entering the CNS through infected peripheral monocytes, but its effect on OIs of CNS remains unclear. In this study, we investigated the characteristics of HIV-1 in acquired immunodeficiency syndrome (AIDS) patients with CNS OIs. A total of 24 patients with CNS OIs and 16 non-CNS OIs (control) cases were selected. These AIDS patients were infected with HIV-1 by paid blood donors in China. HIV-1 loads in plasma and cerebrospinal fluid (CSF) were detected using RT-PCR, and the C2-V5 region of HIV-1 envelope gene was amplified from viral quasispecies isolated from CSF using nested PCR. The CSF HIV-1 load of CNS OIs was higher than that of non-CNS OIs, but plasma HIV-1 load of CNS OIs was not higher than that of non-CNS OIs. The nucleotide sequence of C2-V5 region of the HIV-1 quasispecies isolated from the CSF of CNS OIs had a high diversity, and the HIV-1 quasispecies isolated from the CSF of CNS OIs revealed R5 tropism as 11/25 charge rule. These results suggest that high levels of divergent HIV-1 quasispecies in the CNS probably contribute to opportunistic infections. 23658109 Functional Zeolitic-Imidazolate-Framework-Templated Porous Carbon Materials for CO2 Capture and Enhanced Capacitors. Three types of zeolitic imidazolate frameworks (ZIFs) with different topological structures and functional imidazolate-derived ligands, namely, ZIF-8, ZIF-68, and ZIF69, have been directly carbonized to prepare porous carbon materials at 1000 °C. These as-synthesized porous carbon materials were activated with fused KOH to increase their surface areas and pore volumes for use in gas storage and supercapacitors. The relationship between the local structure of the products and the composition of the precursors has been investigated in detail. The BET surface areas of the resultant activated carbon materials are 2437 (CZIF8a), 1861 (CZIF68a), and 2264 m(2)  g(-1) (CZIF69a). CZIF8a exhibits the highest H2 -storage capacities of 2.59 wt. % at 1 atm and 77 K, whereas CZIF69a has the highest CO2 uptake of 4.76 mmol g(-1) at 1 atm and 273 K, owing to its local structure and pore chemical environment. The specific capacities are calculated from the CV curves. CZIF69a exhibits the highest supercapacitor performance of 168 F g(-1) at a scan speed of 5 mV s(-1) . These results indicate that the functional chloride group on the benzimidazolate ligand plays a very important role in improving the surface area, pore volume, and, therefore, CO2 -capture and supercapacitor properties of the corresponding porous carbon materials. 23631605 Advanced glycation end products assessed by skin autofluorescence: a new marker of diabetic foot ulceration. Abstract Background: Accumulation of advanced glycation end products (AGEs) may contribute to diabetic foot ulceration (DFU). Our goal was to determine whether AGEs measurement by skin autofluorescence (SAF) would be an additional marker for DFU management. Patients and Methods: We performed SAF analysis in 66 patients with a history of DFU prospectively included and compared the results with those of 84 control patients with diabetic peripheral neuropathy without DFU. We then assessed the prognostic value of SAF levels on the healing rate in the DFU group. Results: Mean SAF value was significantly higher in the DFU group in comparison with the control group, even after adjustment for other diabetes complications (3.2±0.6 arbitrary units vs. 2.9±0.6 arbitrary units; P=0.001). In the DFU group, 58 (88%) patients had an active wound at inclusion. The mean DFU duration was 14±13 weeks. The healing rate was 47% after 2 months of appropriate foot care. A trend for a correlation between SAF levels and healing time in DFU subjects was observed but was not statistically significant (P=0.06). Conclusions: Increased SAF levels are associated with neuropathic foot complications in diabetes. Use of SAF measurement to assess foot vulnerability and to predict DFU events in high-risk patients appears to be promising. 23237813 Metabolomic profiles in individuals with negative affectivity and social inhibition: a population-based study of Type D personality. Individuals with negative affectivity who are inhibited in social situations are characterized as distressed, or Type D, and have an increased risk of cardiovascular disease (CVD). The underlying biomechanisms that link this psychological affect to a pathological state are not well understood. This study applied a metabolomic approach to explore biochemical pathways that may contribute to the Type D personality. Type D personality was determined by the Type D Scale-14. Small molecule biochemicals were measured using two complementary mass-spectrometry based metabolomics platforms. Metabolic profiles of Type D and non-Type D participants within a population-based study in Southern Germany were compared in cross-sectional regression analyses. The PHQ-9 and GAD-7 instruments were also used to assess symptoms of depression and anxiety, respectively, within this metabolomic study. 668 metabolites were identified in the serum of 1502 participants (age 32-77); 386 of these individuals were classified as Type D. While demographic and biomedical characteristics were equally distributed between the groups, a higher level of depression and anxiety was observed in Type D individuals. Significantly lower levels of the tryptophan metabolite kynurenine were associated with Type D (p-value corrected for multiple testing=0.042), while no significant associations could be found for depression and anxiety. A Gaussian graphical model analysis enabled the identification of four potentially interesting metabolite networks that are enriched in metabolites (androsterone sulfate, tyrosine, indoxyl sulfate or caffeine) that associate nominally with Type D personality. This study identified novel biochemical pathways associated with Type D personality and demonstrates that the application of metabolomic approaches in population studies can reveal mechanisms that may contribute to psychological health and disease. 23876293 Knockdown of both mitochondrial isocitrate dehydrogenase enzymes in pancreatic beta cells inhibits insulin secretion. There are three isocitrate dehydrogenases (IDHs) in the pancreatic insulin cell; IDH1 (cytosolic) and IDH2 (mitochondrial) use NADP(H). IDH3 is mitochondrial, uses NAD(H) and was believed to be the IDH that supports the citric acid cycle. With shRNAs targeting mRNAs for these enzymes we generated cell lines from INS-1 832/13 cells with severe (80%-90%) knockdown of the mitochondrial IDHs separately and together in the same cell line. With knockdown of both mitochondrial IDH's mRNA, enzyme activity and protein level, (but not with knockdown of only one mitochondrial IDH) glucose- and BCH (an allosteric activator of glutamate dehydrogenase)-plus-glutamine-stimulated insulin release were inhibited. Cellular levels of citrate, α-ketoglutarate, malate and ATP were altered in patterns consistent with blockage at the mitochondrial IDH reactions. We were able to generate only 50% knockdown of Idh1 mRNA in multiple cell lines (without inhibition of insulin release) possibly because greater knockdown of IDH1 was not compatible with cell line survival. The mitochondrial IDHs are redundant for insulin secretion. When both enzymes are severely knocked down, their low activities (possibly assisted by transport of IDH products and other metabolic intermediates from the cytosol into mitochondria) are sufficient for cell growth, but inadequate for insulin secretion when the requirement for intermediates is certainly more rapid. The results also indicate that IDH2 can support the citric acid cycle. As almost all mammalian cells possess substantial amounts of all three IDH enzymes, the biological principles suggested by these results are probably extrapolatable to many tissues. 23932859 Intrapulmonary shear stress enhancement: A new therapeutic approach in acute myocardial ischemia. Ischemic heart disease (IHD) is a leading cause of mortality with insufficient results of current therapies, most probably due to maintained endothelial dysfunction conditions. Alternatively, we propose a new treatment that promotes endothelial shear stress (ESS) enhancement using an intrapulmonary pulsatile catheter. Twelve piglets, divided in equal groups of 6: pulsatile (P) and non-pulsatile (NP), underwent permanent left anterior descending coronary artery ligation through sternotomy. After 1h of ischemia and heparin injection (150IU/kg): in P group, a pulsatile catheter was introduced into the pulmonary trunk and pulsated intermittently over 1h, and irrespective of heart rate (110bpm). In NP group, nitrates were given (7±2mg/kg/min) for 1h. In P group all 6 animals survived ischemia for 120min, but in NP group only 2 animals survived. The 4 animals that died during the experiment in NP group survived for 93±14min. Hemodynamics and cardiac output (CO) were significantly improved in P group compared with NP group: CO was 0.92±0.15 vs. 0.52±0.08 in NP group (L/min; p<0.05), respectively. Vascular resistances (dynes.s.cm(-5)/kg) were significantly (p<0.05) lower in P group versus NP group: pulmonary resistance was 119±13 vs. 400±42 and systemic resistance was 319±43 vs. 1857±326, respectively. Myocardial apoptosis was significantly (p<0.01) lower in P group (0.66±0.07) vs. (4.18±0.27) in NP group. Myocardial endothelial NO synthase mRNA expression was significantly (p<0.01) greater in P group (0.90±0.09) vs. (0.25±0.04) in NP group. Intrapulmonary pulsatile catheter could improve hemodynamics and myocardial contractility in acute myocardial ischemia. This represents a cost-effective method, suitable for emergency setting as a first priority, regardless of classical coronary reperfusion. 23219383 Available processing resources influence encoding-related brain activity before an event. Effective cognitive functioning not only relies on brain activity elicited by an event, but also on activity that precedes it. This has been demonstrated in a number of cognitive domains, including memory. Here, we show that brain activity that precedes the effective encoding of a word into long-term memory depends on the availability of sufficient processing resources. We recorded electrical brain activity from the scalps of healthy adult men and women while they memorized intermixed visual and auditory words for later recall. Each word was preceded by a cue that indicated the modality of the upcoming word. The degree to which processing resources were available before word onset was manipulated by asking participants to make an easy or difficult perceptual discrimination on the cue. Brain activity before word onset predicted later recall of the word, but only in the easy discrimination condition. These findings indicate that anticipatory influences on long-term memory are limited in capacity and sensitive to the degree to which attention is divided between tasks. Prestimulus activity that affects later encoding can only be engaged when the necessary cognitive resources can be allocated to the encoding process. 23847010 Ultrathin Limit of Exchange Bias Coupling at Oxide Multiferroic/Ferromagnetic Interfaces. Exchange bias coupling at the multiferroic- ferromagnetic interface in BiFeO3 /La0.7 Sr0.3 MnO3 heterostructures exhibits a critical thickness for ultrathin BiFeO3 layers of 5 unit cells (2 nm). Linear dichroism measurements demonstrate the dependence on the BiFeO3 layer thickness with a strong reduction for ultrathin layers, indicating diminished antiferromagnetic ordering that prevents interfacial exchange bias coupling. 23557033 Antioxidant activity of Tunisian Geranium robertianum L. (Geraniaceae). The present investigation focuses on the methanolic extract obtained from Geranium robertianum L. (Geraniaceae) (Herb Robert), a herbal plant used in traditional medicine for the treatment of human and animal diseases. The antioxidant capacities of the extract were evaluated using 1,1-diphenyl-2-picrylhydrazyl radical, β-carotene/linoleic acid and reducing power and metal chelating activity assays. The amount of total phenolic content, flavonoids and condensed tannins was very high, and the correlation between the antioxidant activity potential and total phenolic level of the extract was pointed out. 23772070 Effect of an Oxygen-Tolerant Bifurcating Butyryl Coenzyme A Dehydrogenase/Electron-Transferring Flavoprotein Complex from Clostridium difficile on Butyrate Production in Escherichia coli. The butyrogenic genes from Clostridium difficile DSM 1296(T) have been cloned and expressed in Escherichia coli. The enzymes acetyl-coenzyme A (CoA) C-acetyltransferase, 3-hydroxybutyryl-CoA dehydrogenase, crotonase, phosphate butyryltransferase, and butyrate kinase and the butyryl-CoA dehydrogenase complex composed of the dehydrogenase and two electron-transferring flavoprotein subunits were individually produced in E. coli and kinetically characterized in vitro. While most of these enzymes were measured using well-established test systems, novel methods to determine butyrate kinase and butyryl-CoA dehydrogenase activities with respect to physiological function were developed. Subsequently, the individual genes were combined to form a single plasmid-encoded operon in a plasmid vector, which was successfully used to confer butyrate-forming capability to the host. In vitro and in vivo studies demonstrated that C. difficile possesses a bifurcating butyryl-CoA dehydrogenase which catalyzes the NADH-dependent reduction of ferredoxin coupled to the reduction of crotonyl-CoA also by NADH. Since the reoxidation of ferredoxin by a membrane-bound ferredoxin:NAD(+)-oxidoreductase enables electron transport phosphorylation, additional ATP is formed. The butyryl-CoA dehydrogenase from C. difficile is oxygen stable and apparently uses oxygen as a co-oxidant of NADH in the presence of air. These properties suggest that this enzyme complex might be well suited to provide butyryl-CoA for solventogenesis in recombinant strains. The central role of bifurcating butyryl-CoA dehydrogenases and membrane-bound ferredoxin:NAD oxidoreductases (Rhodobacter nitrogen fixation [RNF]), which affect the energy yield of butyrate fermentation in the clostridial metabolism, is discussed. 23861915 Transcriptome/Degradome-Wide Identification of R. glutinosa miRNAs and Their Targets: The Role of miRNA Activity in the Replanting Disease. Rehmannia glutinosa, a traditional Chinese medicine herb, is unable to grow normally in a soil where the same species has recently been cultivated. The biological basis of this so called "replanting disease" is unknown, but it may involve the action of microRNAs (miRNAs), which are known to be important regulators of plant growth and development. High throughput Solexa/Illumina sequencing was used to generate a transcript library of the R. glutinosa transcriptome and degradome in order to identify possible miRNAs and their targets implicated in the replanting disease. A total of 87,665 unigenes and 589 miRNA families (17 of which have not been identified in plants to date) was identified from the libraries made from a first year (FP) and a second year (SP) crop. A comparison between the FP and SP miRNAs showed that the abundance of eight of the novel and 295 of the known miRNA families differed between the FP and SP plants. Sequencing of the degradome sampled from FP and SP plants led to the identification of 165 transcript targets of 85 of the differentially abundant miRNA families. The interaction of some of these miRNAs with their target(s) is likely to form an important part of the molecular basis of the replanting disease of R. glutinosa. 23892898 CRISPR RNA-guided activation of endogenous human genes. Short guide RNAs (gRNAs) can direct catalytically inactive CRISPR-associated 9 nuclease (dCas9) to repress endogenous genes in bacteria and human cells. Here we show that single or multiple gRNAs can direct dCas9 fused to a VP64 transcriptional activation domain to increase expression of endogenous human genes. This proof-of-principle work shows that clustered regularly interspaced short palindromic repeat (CRISPR)-Cas systems can target heterologous effector domains to endogenous sites in human cells. 23625138 Relationship between bifenthrin sediment toxic units and benthic community metrics in urban california streams. The objective of this study was to use ecologically relevant field measurements for determining the relationship between bifenthrin sediment toxic units (TUs) (environmental concentrations/Hyalella acute LC50 value) and 15 benthic metrics in four urban California streams sampled from 2006 to 2011. Data from the following four California streams were used in the analysis: Kirker Creek (2006, 2007), Pleasant Grove Creek (2006, 2007, and 2008), Arcade Creek (2009, 2010, and 2011), and Salinas streams (2009, 2010, and 2011). The results from univariate analysis of benthic metrics versus bifenthrin TU calculations for the four California streams with multiple-year datasets combined by stream showed that there were either nonsignificant relationships or lack of metric data for 93 % of cases. For 7 % of the data (4 cases) where significant relationships were reported between benthic metrics and bifenthrin TUs, these relationships were ecologically meaningful. Three of these significant direct relationships were an expression of tolerant benthic taxa (either % tolerant taxa or tolerance values, which are similar metrics), which would be expected to increase in a stressed environment. These direct significant tolerance relationships were reported for Kirker Creek, Pleasant Grove Creek, and Arcade Creek. The fourth significant relationship was an inverse relationship between taxa richness and bifenthrin TUs for the 3-year Pleasant Grove Creek dataset. In summary, only a small percent of the benthic metric Ã— bifenthrin TU relationships were significant for the four California streams. Therefore, the general summary conclusion from this analysis is that there is no strong case for showing consistent meaningful relationships between various benthic metrics used to characterize the status of benthic communities and bifenthrin TUs for these four California streams. 23430021 Patient-Reported Outcomes Assessed by the CAMPHOR Questionnaire Predict Clinical Deterioration in Idiopathic Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension. The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) is a disease-specific assessment tool used for the evaluation and follow-up of patients with pulmonary hypertension (PH). We describe a novel use for this questionnaire in its potential to predict clinical deterioration (CD) in two patient cohorts with subtypes of PH, idiopathic pulmonary arterial hypertension (IPAH), and chronic thromboembolic pulmonary hypertension (CTEPH) during an 8-year period. We retrospectively analyzed CAMPHOR scores obtained at baseline and at follow-up visits in patients under the care of our unit over an 8-year period to assess CD and survival, as well as 6-min walk distance (6MWD) and New York Heart Association (NYHA) class. Using Cox regression, we demonstrated a significant predictive effect of CD from total CAMPHOR scores at study enrollment in IPAH and CTEPH (hazard ratios, 1.03 [95% CI, 1.01-1.05] and 1.04 [95% CI, 1.02-1.06] per unit score increase, respectively), as well as from CAMPHOR subscales as independent predictors. This predictive effect is diluted after adjusting for the prognostic effect of 6MWD and NYHA class. Repeated CAMPHOR assessment over time appears not to add predictive value of CD to that obtained at diagnosis, although it still informs physicians of important changes in self-reported symptoms. When emphasis is placed on the evaluation of patient perceptions, CAMPHOR may represent an alternative method of estimating the likelihood of CD. 23892633 Targeting the Mitochondrial Respiratory Chain of Cryptococcus through Antifungal Chemosensitization: A Model for Control of Non-Fermentative Pathogens. Enhanced control of species of Cryptococcus, non-fermentative yeast pathogens, was achieved by chemosensitization through co-application of certain compounds with a conventional antimicrobial drug. The species of Cryptococcus tested showed higher sensitivity to mitochondrial respiratory chain (MRC) inhibition compared to species of Candida. This higher sensitivity results from the inability of Cryptococcus to generate cellular energy through fermentation. To heighten disruption of cellular MRC, octyl gallate (OG) or 2,3-dihydroxybenzaldehyde (2,3-DHBA), phenolic compounds inhibiting mitochondrial functions, were selected as chemosensitizers to pyraclostrobin (PCS; an inhibitor of complex III of MRC). The cryptococci were more susceptible to the chemosensitization (i.e., PCS + OG or 2,3-DHBA) than the Candida with all Cryptococcus strains tested being sensitive to this chemosensitization. Alternatively, only few of the Candida strains showed sensitivity. OG possessed higher chemosensitizing potency than 2,3-DHBA, where the concentration of OG required with the drug to achieve chemosensitizing synergism was much lower than that required of 2,3-DHBA. Bioassays with gene deletion mutants of the model yeast Saccharomyces cerevisiae showed that OG or 2,3-DHBA affect different cellular targets. These assays revealed mitochondrial superoxide dismutase or glutathione homeostasis plays a relatively greater role in fungal tolerance to 2,3-DHBA or OG, respectively. These findings show that application of chemosensitizing compounds that augment MRC debilitation is a promising strategy to antifungal control against yeast pathogens. 23580445 Small Molecule Inhibitors of ERCC1-XPF Protein-Protein Interaction Synergize Alkylating Agents in Cancer Cells. The benefit of cancer chemotherapy based on alkylating agents is limited due to the action of DNA repair enzymes which mitigate the damage induced by these agents. The interaction between the proteins ERCC1 and XPF, involves two major components of the nucleotide excision repair pathway. Here, novel inhibitors of this interaction were identified by virtual screening based on available structures using the National Cancer Institute (NCI) diversity set and a panel of DrugBank-small-molecules. Subsequently, experimental validation of the in silico screening was undertaken. Top hits were evaluated on A549 and HCT116 cancer cells. In particular, the compound labeled NSC130813 was shown to act synergistically with cisplatin and mitomycin C, to increase UVC mediated cytotoxicity, to modify DNA repair as indicated by the staining of phosphorylated H2AX and to disrupt interaction between ERCC1 and XPF in cells. In addition, using the Biacore technique, we showed that this compound interacts with the domain of XPF responsible for interaction with ERCC1. This study shows that small molecules targeting the protein-protein interaction of ERCC1 and XPF can be developed in order to enhance the effects of alkylating agents on cancer cells. 23937791 The different biological effects of single, fractionated and continuous low dose rate irradiation on CL187 colorectal cancer cells. Purpose: To determine the biological effectiveness of single, fractionated and continuous low dose rate irradiation on the human colorectal cancer cell line CL187 in vitro and explore the cellular mechanisms.Materials and methods: The CL187 cells were exposed to radiation of 6 MV X-ray at a high dose rate of 4Gy/min and 125I seed at a low dose rate of 2.77 cGy/h. Three groups were employed: single dose radiation group (SDR), fractionated dose radiation group (FDR) by 2Gy/f and continuous low dose rate radiation group (CLDR). Four radiation doses 2, 4, 6 and 8Gy were chosen and cells without irradiation as the control. The responses of CL187 cells to distinct modes of radiation were evaluated by the colony-forming assay, cell cycle progression as well as apoptosis analysis. In addition, we detected the expression patterns of DNA-PKcs, Ku70 and Ku80 by Western blotting. The relative biological effect for 125I seeds compared with 6 MV X-ray was 1.42. 48 hrs after 4Gy irradiation, the difference between proportions of cells at G2/M phase of SDR and CLDR groups were statistically significant (p = 0.026), so as the FDR and CLDR groups (p = 0.005). 48 hrs after 4Gy irradiation, the early apoptotic rate of CLDR group was remarkably higher than SDR and FDR groups (CLDR vs. SDR, p = 0.001; CLDR vs. FDR, p = 0.02), whereas the late apoptotic rate of CLDR group increased significantly compared with SDR and FDR group (CLDR vs. SDR, p = 0.004; CLDR vs. FDR, p = 0.007). Moreover, DNA-PKcs and Ku70 expression levels in CLDR-treated cells decreased compared with SDR and FDR groups. Compared with the X-ray high dose rate irradiation, 125I seeds CLDR showed more effective induction of cell apoptosis and G2/M cell cycle arrest. Furthermore, 125I seeds CLDR could impair the DNA repair capability by down-regulating DNA-PKcs and Ku70 expression. 23355087 3-Methylglutaconic aciduria-lessons from 50 genes and 977 patients. Elevated urinary excretion of 3-methylglutaconic acid is considered rare in patients suspected of a metabolic disorder. In 3-methylglutaconyl-CoA hydratase deficiency (mutations in AUH), it derives from leucine degradation. In all other disorders with 3-methylglutaconic aciduria the origin is unknown, yet mitochondrial dysfunction is thought to be the common denominator. We investigate the biochemical, clinical and genetic data of 388 patients referred to our centre under suspicion of a metabolic disorder showing 3-methylglutaconic aciduria in routine metabolic screening. Furthermore, we investigate 591 patients with 50 different, genetically proven, mitochondrial disorders for the presence of 3-methylglutaconic aciduria. Three percent of all urine samples of the patients referred showed 3-methylglutaconic aciduria, often in correlation with disorders not reported earlier in association with 3-methylglutaconic aciduria (e.g. organic acidurias, urea cycle disorders, haematological and neuromuscular disorders). In the patient cohort with genetically proven mitochondrial disorders 11 % presented 3-methylglutaconic aciduria. It was more frequently seen in ATPase related disorders, with mitochondrial DNA depletion or deletion, but not in patients with single respiratory chain complex deficiencies. Besides, it was a consistent feature of patients with mutations in TAZ, SERAC1, OPA3, DNAJC19 and TMEM70 accounting for mitochondrial membrane related pathology. 3-methylglutaconic aciduria is found quite frequently in patients suspected of a metabolic disorder, and mitochondrial dysfunction is indeed a common denominator. It is only a discriminative feature of patients with mutations in AUH, TAZ, SERAC1, OPA3, DNAJC19 TMEM70. These conditions should therefore be referred to as inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature. 23605849 Survival of Trichomonas vaginalis in wet preparation and on wet mount. Microscopy is an insensitive method for detection of Trichomonas vaginalis, but is widely used because it is both rapid and inexpensive. Diagnosis of trichomoniasis by microscopy requires that motile forms be identified in vaginal fluid samples. However, microscopy cannot always be performed immediately after sample collection. The objective of this study was to assess the impact of sample storage at room temperature on trichomonad motility. Vaginal swab samples from 77 women positive for T vaginalis infection were collected to determine the impact of storage on wet preparations (swabs in plastic tubes with saline) and wet mounts (samples placed onto a glass slide with a coverslip). Samples were read at 400× every 30 min for the first hour and then once per hour thereafter until there were no motile trichomonads observed. For wet preparations, motility was 100% at 30 min, 99% at 60 min and decreased by 3%-15% each subsequent hour, with samples having a lower density of trichomonads losing motility more quickly. Trichomonad motility diminished more rapidly in wet mounts compared with wet preparations, with a 20% decrement in motility in 60 min. These data suggest that vaginal fluid samples for diagnosis of trichomoniasis should be stored in saline rather than on microscope slides until they are examined under the microscope and samples should be evaluated by microscopy within an hour of collection. These findings also suggest that clinical sites which cannot perform microscopy within 1 h of sample collection should consider the use of other diagnostic tests. 23088293 Endothelial peroxisomal dysfunction and impaired pexophagy promotes oxidative damage in lipopolysaccharide-induced acute kidney injury. We examined that (a) how the endotoxic stress affects peroxisomal function and autophagic degradation of peroxisomes-pexophagy, (b) how a superimposed dysfunction of lysosomes and pexophagy modifies responses to lipopolysaccharide (LPS), and (c) the mechanisms of peroxisomal contribution to renal injury. To accomplish this, we used lysosome-defective Lyst-mice in vivo and primary endothelial cells in vitro, and compared the responses with wild-type (WT) littermates. LPS induced pexophagic degradation, followed by proliferation of peroxisomes in WT mice, which was abolished in Lyst-mice. Lyst-mice exhibited impaired activation of catalase, which together with preserved hydrogen peroxide-generating β-oxidation resulted in redox disequilibrium. LPS treatment induced a heightened inflammatory response, increased oxidative damage, and aggravated renal injury in Lyst-mice. Similarly, as in vivo, LPS-activated lysosomal (LYS) pexophagy and transiently repressed peroxisomes in vitro, supported by reduced peroxisomal density in the vicinity of lysosomes. Peroxisomal dynamics was also abolished in lysosome-defective cells, which accumulated peroxisomes with compromised functions and intraorganellar redox imbalance. We demonstrated that pexophagy is a default response to endotoxic injury. However, when LYS dysfunction (a frequent companion of chronic diseases) is superimposed, recycling and functioning of peroxisomes are impaired, and an imbalance between hydrogen peroxide-generating β-oxidation and hydrogen peroxide-detoxifying catalase ensues, which ultimately results in peroxisomal burnout. Our data strongly suggest that pexophagy, a cellular mechanism per se, is essential in functional maintenance of peroxisomes during LPS exposure. Inhibition of pexophagy results in accumulation of impaired peroxisomes, redox disequilibrium, and aggravated renal damage. 23937371 Long-term Impact of Parental Well-Being on Adult Outcomes and Dementia Status in Individuals With Down Syndrome. Abstract Parental characteristics were significant predictors of health, functional abilities, and behavior problems in adults with Down syndrome (n  =  75) over a 22-year time span, controlling for initial levels and earlier changes in these outcomes. Lower levels of behavior problems were predicted by improvements in maternal depressive symptoms. Higher levels of functional abilities were predicted by prior measures of and improvements in maternal depressive symptoms. Better health was predicted by prior measures of maternal depressive symptoms, paternal positive psychological well-being, relationship quality between fathers and their adult children, and improvements in maternal positive psychological well-being. Dementia status was also predicted by parental characteristics. The study suggests the importance of the family context for healthy aging in adults with Down syndrome. 23354677 DNA bacterial load in children with bacteremic pneumococcal community-acquired pneumonia. This study was conducted to evaluate the association between pneumococcal DNA load and parapneumonic pleural effusion (PPE) in children with community-acquired pneumonia. Bacterial load was quantified and related to the presence of PPE with or without empyema in 72 otherwise healthy children aged ≤5 years who were hospitalised because of radiographically confirmed CAP and showed a real-time polymerase chain reaction that was positive for Streptococcus pneumoniae. The proportion of children with a high bacterial load (i.e. ≥265 DNA copies/mL) was larger among the subjects with PPE than those without it. Multivariate analysis showed that a high bacterial load was significantly associated with PPE (OR 8.65; 95% CI 1.10-67.8 vs a bacterial load of <125 copies/mL). Children with infection due to pneumococcal serotype 19A were at highest risk of developing PPE (OR 7.44; 95% CI 1.10-50.4 vs all other typeable serotypes). The patients with CAP due to pneumococcal serotypes that are not included in the 13-valent conjugate vaccine (PCV13) were more frequently affected by PPE than those with infections associated with serotypes included in the vaccine, except for serotype 19A. Bacterial loads of ≥265 DNA copies/mL are significantly associated with PPE, and serotype 19A is significantly associated with a high bacterial load and the development of PPE. The mean bacterial load of the patients with empyema was higher than that of patients with simple PPE. Although further studies are required, it seems that serotypes not included in PCV13 can play a major role in causing a higher bacterial load and PPE. 23959769 Multivariate statistical data analysis as a tool to analyze ex-vivo expansion dynamics of cytokine induced killer (CIK) cells. Background: CIK cells, obtained after mononucleated cell stimulation with IFN-γ, IL-2 and anti-CD3 antibody, are constituted by CD3+CD56+ (CIK) cells and a minority of natural killer (NK, CD3-CD56+) and T-lymphocytes (CD3+CD56-) with antitumor effect against haematological malignancies thus representing a promising immunotherapy strategy. To ensure in vivo antitumor activity it is mandatory to maximize the percentage of CD3+56+ effector cells, that is highly variable depending on the starting sample and the harvesting day. Based on cytofluorimetric data, we have retrospectively applied multivariate statistical data analysis (MVDA) to 30 expansions building mathematical models able to predict the expansion fate and the optimal CIK harvesting day. Methods: Cell phenotype was monitored during culture; Multivariate Batch Statistical Process Control was applied to monitor cell expansion and Orthogonal Projections to Latent Structures to predict CIK percentage. Results: 10 expansions had CD3+CD56+ cells ≥40% (good batches) and 20 had CD3+CD56+ cells ≤40%. In 36.7%, CD3+CD56+ cells reached the highest concentration at day 17 and the others at day 21. We built a highly predictive regression model for estimating CD3+CD56+ cells during culture. Three variables resulted highly informative: NK % at day 0, cytotoxic T-lymphocytes % (CTL, CD3+CD8+) at day 4 and CIK % at day 7. "Good batches" are characterized by an high percentage of CTL and CD3+CD56+ cells at day 4 and 7 respectively. Conclusion: by applying MVDA it is possible to optimize CIK expansion, deciding the optimal cell harvesting day. A predictive role for CTL and CIK was evidenced. © 2013 Clinical Cytometry Society. 23622542 Microfluidic cytometer based on dual photodiode detection for cell size and deformability analysis. Cellular mechanical properties play an important role in disease diagnosis. Distinguishing cells based on their mechanical properties provides a potential method for label-free diagnosis. In this work, a convenient and low-cost microfluidic cytometer was developed to study cell mechanical properties and cell size based on the change of transmission intensity, using a low-cost commercial laser as a light source and two photodiodes as detectors. The cells pass through a narrow microchannel with a width smaller than the cell dimension, integrated in a polydimethylsiloxane chip, below which the laser is focused. The transit time of individual cells is measured by the time difference detected by two photodiodes. This device was used to study the difference in cell mechanical properties between HL60 cells treated with and without Cytochalasin D. Furthermore, it was also applied to distinguish cells with different diameters, HL60 cells and red blood cells, by measuring the transmission intensity. 23891820 Association between the Pro12Ala polymorphism of PPAR-γ gene and the non-alcoholic fatty liver disease: A meta-analysis. Several studies have been conducted to examine the association between PPAR-γ2 Pro12Ala polymorphism and non-alcoholic fatty liver disease (NAFLD), but the results remain inconsistent. In this study, a meta-analysis was performed to assess the association of PPAR-γ Pro12Ala polymorphism with NAFLD risk. A total of 8 case-control studies, including 1697 cases and 2427 controls, were selected. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model. Overall, no evidence has indicated that the Pro12Ala polymorphism was associated with the susceptibility to NAFLD. Besides, stratified analysis with ethnicity also indicated that no significant association between PPAR-γ Pro12Ala and the risk of NAFLD under all for genetic model in both Asian and Caucasian populations was observed. This meta-analysis indicated that the Pro12Ala polymorphism is not associated with NAFLD risk. Large and well-designed studies are warranted to validate our findings. 23911823 Estimation of health risk by using toxicokinetic modelling: A case study of polychlorinated biphenyl PCB153. To assess potential PCB153-associated human health effects and risks, it is necessary to model past exposure. PCB153 blood concentrations, obtained from the AMAP biomonitoring programme, in Inuit women covering the years 1994-2006 at Disko Bay, 1999-2005 at Nuuk, and 1992-2007 at Nunavik were used to extrapolate body burden and exposure to the whole lifespan of the population by the one-compartment toxicokinetic model. By using risk characterisation modelling, calculated Hazard Quotients were higher than 1 between the years 1955 and 1987 for the 90th population percentile and during 1956-1984 for the 50th population percentile. Cancer risk for overall exposure of PCB153 ranged from 4.6×10(-5) to 1.8×10(-6) for the 90th percentile and 3.6×10(-5) to 1.4×10(-10) for the 50th percentile between 1930 and 2049, when central estimates or upper-bound slope factors were applied. Cancer risk was below 1×10(-6) for the same time period when a lower slope factor was applied. Significant future research requirements to improve health risk characterisation include, among others, larger sample sizes, better analytical accuracy, fewer assumptions in exposure assessment, and consequently, a better choice of the toxicity benchmark used to develop the hazard quotient. 23895191 An evolving role of Piperazine moieties in drug design and discovery. This article purposes to provide insights to piperazine based molecular designs that will facilitate drug discovery program in future. In our pursuit to summarize the reservoir of bioactive agents, and in line with the synthetic economy of new heterocycles, many new roles are being identified for the multiple biotargets of piperazine moieties. We mark out how series of different scaffolds provide an extensive range of various piperazine-based analogues displaying antimicrobial, antituberculosis, anticancer, antiviral and antimalarial activities. We believe that piperazine family of compounds, and their various co-components, highlight the existence of several potential leads for the furtherance of novel bioactive agents. 23701246 Stabilization of the angiotensin-(1-7) receptor Mas through interaction with PSD95. The functions and signalling mechanisms of the Ang-(1-7) [angiotensin-(1-7)] receptor Mas have been studied extensively. However, less attention has been paid to the intracellular regulation of Mas protein. In the present study, PSD95 (postsynaptic density 95), a novel binding protein of Mas receptor, was identified, and their association was characterized further. Mas specifically interacts with PDZ1-2, but not the PDZ3, domain of PSD95 via Mas-CT (Mas C-terminus), and the last four amino acids [ETVV (Glu-Thr-Val-Val)] of Mas-CT were determined to be essential for this interaction, as shown by GST pull-down, co-immunoprecipitation and confocal co-localization experiments. Gain-of-function and loss-of-function studies indicated that PSD95 enhanced Mas protein expression by increasing the stabilization of the receptor. Mas degradation was robustly inhibited by the proteasome inhibitor MG132 in time- and dose-dependent manners, and the expression of PSD95 impaired Mas ubiquitination, indicating that the PSD95-Mas association inhibits Mas receptor degradation via the ubiquitin-proteasome proteolytic pathway. These findings reveal a novel mechanism of Mas receptor regulation by which its expression is modulated at the post-translational level by ubiquitination, and clarify the role of PSD95, which binds directly to Mas, blocking the ubiquitination and subsequent degradation of the receptor via the ubiquitin-proteasome proteolytic pathway. 23749288 Oral Health Considerations in HIV-Infected Children. Children with the human immunodeficiency virus (HIV) have a higher probability of hard and soft oral tissue diseases because of their compromised immune systems and socioeconomic factors such as poor access to medical and dental care and limited availability of fluoridated water or toothpaste. To improve health outcomes and help monitor the progression of HIV, a preventive, child-specific oral health protocol for children with HIV that is easy to use and appropriate for all different resource settings should be established. Further, both medical and dental health practitioners should incorporate such a protocol into their care routine for HIV-infected children. Using proactive oral health risk assessments complemented by scheduled follow-up visits based on individual risk determination can prevent opportunistic infection, track the HIV disease trajectory, and monitor the effectiveness of highly active antiretroviral therapy (HAART) while improving the quality of life and longevity of children living with HIV. 23873137 Cardiac output assessed by non-invasive monitoring is associated with ECG changes in children with critical asthma. The primary aim of this study was to determine changes in CI and SI, if any, in children hospitalized with status asthmatics during the course of treatment as measured by non-invasive EC monitoring. The secondary aim was to determine if there is an association between Abnormal CI (defined as <5 or >95 % tile adjusted for age) and Abnormal ECG (defined as ST waves changes) Non-invasive cardiac output (CO) recordings were obtained daily from admission (Initial) to discharge (Final). Changes in CI and SI measurements were compared using paired t tests or 1-way ANOVA. The association between Abnormal CI on Initial CO recording and Abnormal ECG was analyzed by Fischer's exact test. Data are presented as mean ± SEM with mean differences reported with 95 % confidence interval; p < 0.05 was considered significant. Thirty-five children with critical asthma were analyzed. CI decreased from 6.2 ± 0.2 to 4.5 ± 0.1 [-1.6 (-0.04 to -0.37)] L/min/m(2) during hospitalization. There was no change in SI. There was a significant association between Abnormal Initial CI and Abnormal ECG (p = 0.02). In 11 children requiring prolonged hospitalization CI significantly decreased from 7.2 ± 0.5 to 4.0 ± 0.2 [-3.2 (-4.0 to -2.3)] L/min/m(2) and SI decreased from 51.2 ± 3.8 to 40.3 ± 2.0 [-11.0 (-17.6 to -4.4)] ml/beat/m(2) There was a significant decrease in CI in all children treated for critical asthma. In children that required a prolonged course of treatment, there was also a significant decrease in SI. Abnormal CI at Initial CO recording was associated with ST waves changes on ECG during hospitalization. Future studies are required to determine whether non-invasive CO monitoring can predict which patients are at risk for developing abnormal ECG. 23929984 Towards the chemoenzymatic synthesis of heparan sulfate oligosaccharides: Oxidative cleavage of p-nitrophenyl group with ceric ammonium salts. We have developed an efficient chemoenzymatic synthesis of heparan sulfate oligosaccharides employing the para-nitrophenyl (p-NP) β-glucuronide as an acceptor compatible with enzymatic elongation and one that significantly simplifies oligosaccharide purification on C-18 resin. Employing ceric ammonium nitrate as oxidative reagent to remove the p-NP group unexpectedly also removed the glucuronic acid residue at the reducing-end, affording a smaller oligosaccharide. The application of ceric ammonium sulfate allowed the removal of the p-NP without concomitant loss of the adjacent glucuronic acid offering a route to longer heparin sulfate oligosaccharide products. 23881548 Calibration of self-reported dietary measures using biomarkers: an approach to enhancing nutritional epidemiology reliability. Reports from nutritional epidemiology studies lack reliability if based solely on self-reported dietary consumption estimates. Consumption biomarkers are available for some components of diet. These can be collected in subsets of study cohorts, along with corresponding self-report assessments. Linear regression of (log-transformed) biomarker values on corresponding self-report values and other pertinent study subject characteristics yields calibration equations for dietary consumption, from which calibrated consumption estimates can be calculated throughout study cohorts. Nutritional epidemiology disease association studies of enhanced reliability can be expected from analyses that relate disease risk to calibrated consumption estimates. Applications to the study of energy and protein consumption in relation to cardiovascular diseases, type 2 diabetes, and cancer in the Women's Health Initiative will be briefly summarized. Also, challenges related to variables that may either mediate or confound associations of interest will be described, along with the need for longitudinal biomarker and self-report data, and the need for additional nutritional biomarker development. 23524005 Strain engineering of Saccharomyces cerevisiae for enhanced xylose metabolism. Efficient and rapid fermentation of all sugars present in cellulosic hydrolysates is essential for economic conversion of renewable biomass into fuels and chemicals. Xylose is one of the most abundant sugars in cellulosic biomass but it cannot be utilized by wild type Saccharomyces cerevisiae, which has been used for industrial ethanol production. Therefore, numerous technologies for strain development have been employed to engineer S. cerevisiae capable of fermenting xylose rapidly and efficiently. These include i) optimization of xylose-assimilating pathways, ii) perturbation of gene targets for reconfiguring yeast metabolism, and iii) simultaneous co-fermentation of xylose and cellobiose. In addition, the genetic and physiological background of host strains is an important determinant to construct efficient and rapid xylose-fermenting S. cerevisiae. Vibrant and persistent researches in this field for the last two decades not only led to the development of engineered S. cerevisiae strains ready for industrial fermentation of cellulosic hydrolysates, but also deepened our understanding of operational principles underlying yeast metabolism. 23930877 Airway management in a patient with bullous pemphigoid. Airway management in patients with pemphigoid lesions has anaesthetic implications. We report a case of a 23 years old female with bullous pemphigoid who presented with laryngeal stenosis and critical airway narrowing. The airway was initially managed with jet ventilation. Anaesthesia was maintained with propofol infusion and ventilation was performed by introducing a size 10 French gauge suction catheter through the stenotic laryngeal orifice. Thirty minutes into anaesthesia, she developed subcutaneous emphysema and decreased air entry on right side of the chest but remained hemodynamically stable. The airway was further managed by tracheostomy. This case report highlights complications that can occur during the anaesthetic management of such cases. 23932998 Enhancing inhibition: How impulsivity and emotional activation interact with different implementation intentions. Implementation intentions, a strategy in which a strong link is created between a cue and a to-be-performed action, have been shown to be efficacious in improving self-regulation. The relative efficacy of verbal and visual implementation intentions, however, has yet to be determined. Implementation intentions have also been shown to be inefficacious in participants with high impulsivity, specifically in individuals who reported having a high tendency to commit rash or regrettable actions as a result of intense affect (high urgency). Nevertheless, previous studies did not assess whether the individuals were in an emotional context at the time of the experiment. In the current study, we compared different forms of implementation intentions (verbal/visual/combined verbal-visual) on a computerized inhibition task while assessing impulsivity and emotional activation. The results showed that all types of implementation intentions improved inhibition performances significantly in participants with high urgency, but only when their emotional activation was low. There was no difference between the three types of implementation intentions. 23603320 Biodegradable nanoparticles for controlled subconjunctival delivery of latanoprost acid: in vitro and in vivo evaluation. Preliminary results. Purpose of the study was to develop and assess a novel controlled drug delivery system of latanoprost acid (LA). Poly(lactide)/Monomethoxy-poly(ethyleneglycol) (PLA-PEG) nanoparticles (NPs) were prepared using an emulsification-solvent evaporation technique. NPs were characterized in vitro according to their size, ζ-potential, drug entrapment efficiency and LA release. LA-loaded NPs (equivalent to 8.5 Î¼g LA) were administered into the subconjunctival space of normotensive rabbits (group A). A free LA solution of the same drug content was subconjunctivally injected in a second rabbit group (group B), while blank NPs were administered in a third group (group C). A group of untreated animals (group D) served as the control. Intraocular pressure (IOP) was monitored for 8 consecutive days, using the Tono-pen XL. Aqueous humor (AH) levels of LA were evaluated for 6 days post-administration, by means of HPLC. Mean nanoparticle size was 80 nm. The drug entrapment efficiency was 18.3%. NPs sustained the release of LA over several days in vitro. Non-significant differences in baseline IOP were found between groups (p = 0.22). LA-loaded NPs exerted a significant hypotensive effect on group A, while IOP values remained significantly lower compared to the rest groups, throughout the study (p = 0.04). LA AH concentrations in group B continuously decreased with time, while LA levels in group A steadily increased. On day 6, LA levels were higher in group A compared to group B (344 ± 73.5 ng/ml and 228 ± 41.01 ng/ml, respectively). No adverse effects were observed. In conclusion, after subconjunctival administration, the LA-loaded NPs provided sustained LA delivery in vivo. They appear to be a promising system for the controlled subconjunctival delivery of LA. 23257114 Attentional switching forms a genetic link between attention problems and autistic traits in adults. Attention deficit hyperactivity disorder (ADHD) symptoms and autistic traits often occur together. The pattern and etiology of co-occurrence are largely unknown, particularly in adults. This study investigated the co-occurrence between both traits in detail, and subsequently examined the etiology of the co-occurrence, using two independent adult population samples. Method Data on ADHD traits (Inattention and Hyperactivity/Impulsivity) were collected in a population sample (S1, n = 559) of unrelated individuals. Data on Attention Problems (AP) were collected in a population-based family sample of twins and siblings (S2, n = 560). In both samples five dimensions of autistic traits were assessed (social skills, routine, attentional switching, imagination, patterns). Hyperactive traits (S1) did not correlate substantially with the autistic trait dimensions. For Inattention (S1) and AP (S2), the correlations with the autistic trait dimensions were low, apart from a prominent correlation with the attentional switching scale (0.47 and 0.32 respectively). Analyses in the genetically informative S2 revealed that this association could be explained by a shared genetic factor. Our findings suggest that the co-occurrence of ADHD traits and autistic traits in adults is not determined by problems with hyperactivity, social skills, imagination or routine preferences. Instead, the association between those traits is due primarily to shared attention-related problems (inattention and attentional switching capacity). As the etiology of this association is purely genetic, biological pathways involving attentional control could be a promising focus of future studies aimed at unraveling the genetic causes of these disorders. 23265874 Near native binding of a fluorescent serotonin conjugate to serotonin type 3 receptors. Described is the synthesis of 5-hydroxytryptamine-tetramethylrhodamine (5HT*); an indole nitrogen linked fluorescent conjugate of serotonin. Through a series fluorescence quenching experiments and experiments in the presence of a known competitive antagonist (Granisetron), it was shown that 5HT* specifically binds to purified homo-pentameric type-3 human serotonin receptors (5HT(3A)). The measured dissociation constant and Hill coefficient are K(d) = 83 ± 3 nM and n = 3.1 ± 0.3, respectively which is indicative of multi-ligand binding and cooperativity similar to that of unconjugated serotonin. 23867300 Effects of Remote Ischemic Preconditioning on the Coagulation Profile of Patients with Aneurysmal Subarachnoid Hemorrhage: A Case-Control Study. Animal studies suggest that ischemic preconditioning prolongs coagulation times. Because coagulation changes could hinder the translation of preconditioning into clinical settings where hemorrhage may be an issue, such as ischemic or hemorrhagic stroke, we evaluated the effects of remote ischemic preconditioning (RIPC) on coagulation in patients undergoing RIPC after aneurysmal subarachnoid hemorrhage (SAH). 21 patients with SAH (mean age 56.3) underwent 137 RIPC sessions, 2-12 days following SAH, each consisting of 3-4 cycles of 5-10 minutes of lower limb ischemia followed by reperfusion. Partial thromboplastin time (PTT), prothrombin time (PT), and international normalized ratio (INR) were analyzed before and after sessions. Patients were followed for hemorrhagic complications. No immediate effect was identified on PTT (mean pre-RIPC 27.62 sec, post-RIPC 27.54, p=0.82), PT (pre-RIPC 10.77 sec, post-RIPC 10.81, p=0.59) or INR (pre-RIPC 1.030, post-RIPC 1.034, p=0.57) after each session. However, a statistically significant increase of PT and INR was identified after exposure to at least 4 sessions (mean PT pre-RIPC 11.33 sec, post-RIPC 12.1, p=0.01; INR pre-RIPC 1.02, post-RIPC 1.09, p=0.014, PTT pre-RIPC 27.4, post-RIPC 27.85, p=0.092) with a direct correlation between the number of sessions and the degree of increase in PT (Pearson=0.59, p=0.007) and INR (Pearson=0.57, p=0.010). Prolonged coagulation times were not observed in controls. No hemorrhagic complications were associated with the procedure. RIPC by limb ischemia appears to prolong the PT and INR in human subjects with SAH after at least 4 sessions, correlating with the number of sessions. However, values remained within normal range and there were no hemorrhagic complications. 23916661 Marginal association between SNP rs2046571 of the HAS2 gene and Parkinson's disease in the Chinese female population. Recent GWASs have implicated many novel SNPs in the development of Parkinson's disease (PD). Single nucleotide polymorphism (SNP) rs2046571 of the HSA2 (encoding hyaluronan synthase 2) was reported to have marginal association with PD. Herein, we conducted a case-control study to evaluate the possible association between SNP rs2046571 and PD in Chinese. All subjects (1043 PD patient and 1044 normal control) were successfully genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. No statistically significant difference in genotype frequency between cases and controls was observed (P=0.074), no statistically significant difference in genotype frequency between early-onset and late-onset was observed (P=0.264 and P=0.120, respectively). No statistically significant difference in genotype frequency between male cases and controls (P=0.108). But surprisingly, there was statistically marginal significant difference in genotype frequency between female cases and controls (P=0.042). Our findings suggested that rs2046571 of the HSA2 has marginal association with PD in Chinese population. 23866831 Associations between capsular serotype, multilocus sequence type, and macrolide resistance in Streptococcus agalactiae isolates from Japanese infants with invasive infections. SUMMARY Streptococcus agalactiae (group B streptococcus; GBS) isolates (n = 150) from infants with invasive infections between 2006 and 2011 were analysed for capsular serotype, multilocus sequence type, and antibiotic susceptibility. In cases with late-onset disease (n = 115), primary meningitis was predominant (62·6%), but represented only 39·1% in cases with early-onset disease (n = 23). The most common serotype was III (58·7%), followed by Ia (21·3%) and Ib (12·7%). Sequence types (STs) of serotype III strains included ST17 (50·0%), ST19 (26·1%), ST335 (18·2%), ST27 (4·5%), and ST1 (1·1%). Predominant STs of serotypes Ia and Ib were ST23 (81·3%) and ST10 (84·2%), respectively. No penicillin-resistant strains were detected, but 22·0% of strains had mef(A/E), erm(A), or erm(B) genes, which mediate macrolide resistance. A new ST335, possessing an mef(A/E) gene belonging to clonal complex 19 gradually increased in frequency. Improved prevention of invasive GBS infections in infants requires timely identification, and ultimately vaccine development. 23927843 Endothelial permeability in vitro and in vivo: Protective actions of ANP and omapatrilat in experimental atherosclerosis. Increased arterial endothelial cell permeability (ECP) is considered an initial step in atherosclerosis. Atrial natriuretic peptide (ANP) which is rapidly degraded by neprilysin (NEP) may reduce injury-induced endothelial cell leakiness. Omapatrilat represents a first in class of pharmacological agents which inhibits both NEP and angiotensin converting enzyme (ACE). We hypothesized that ANP prevents thrombin-induced increases of ECP in human aortic ECs (HAECs) and that omapatrilat would reduce aortic leakiness and atherogenesis and enhance ANP mediated vasorelaxation of isolated aortas. Thrombin induced ECP determined by I(125) albumin flux was assessed in HAECs with and without ANP pretreatment. Next we examined the effects of chronic oral administration of omapatrilat (12mg/kg/day, n=13) or placebo (n=13) for 8 weeks on aortic leakiness, atherogenesis and ANP-mediated vasorelaxation in isolated aortas in a rabbit model of atherosclerosis produced by high cholesterol diet. In HAECs, thrombin-induced increases in ECP were prevented by ANP. Omapatrilat reduced the area of increased aortic leakiness determined by Evans-blue dye and area of atheroma formation assessed by Oil-Red staining compared to placebo. In isolated arterial rings, omapatrilat enhanced vasorelaxation to ANP compared to placebo with and without the endothelium. ANP prevents thrombin-induced increases in ECP in HAECs. Chronic oral administration of omapatrilat reduces aortic leakiness and atheroma formation with enhanced endothelial independent vasorelaxation to ANP. These studies support the therapeutic potential of dual inhibition of NEP and ACE in the prevention of increased arterial ECP and atherogenesis which may be linked to the ANP/cGMP system. 23907956 Immunopathological effects of malaria pigment or hemozoin and other crystals. Blood-stage malaria parasites produce insoluble hemozoin (Hz) crystals that are released in the blood circulation upon schizont rupture. In general, endogenous crystal formation or inhalation of crystalline materials is often associated with pathology. As the immune system responds differently to crystalline particles than to soluble molecules, in this review, the properties, immunological recognition, and pathogenic responses of Hz are discussed, and compared with two other major pathogenic crystals, monosodium urate (MSU) and asbestos. Because of the size and shape of MSU crystals and asbestos fibers, phagolysosomal formation is inefficient and often results in leakage of lysosomal content in the cell cytoplasm and/or in the extracellular environment with subsequent cell damage and cell death. Phagolysosomal formation after Hz ingestion is normal, but Hz remains stored inside these cells for months or even longer without any detectable degradation. Nonetheless, the different types of crystals are recognized by similar immune receptors, involving Toll-like receptors, the inflammasome, antibodies, and/or complement factors, and through similar signaling cascades, they activate both proinflammatory and anti-inflammatory immune responses that contribute to inflammation-associated pathology. BioFactors, 2013. 23861099 Correlation Between Endodontic Broken Instrument and Nickel Level in Urine. This study aims to evaluate the correlation between the presences of separated endodontic instrument inside the dental canal and the nickel (Ni) level in the urine samples of subjected patients. Same-gendered and near-aged participants were selected and were instructed to collect their urine in sterile nickel-free plastic containers. The procedures were carried out in the office, and samples were stored in low-temperature cooler for 1 day and then they were transferred to the laboratory for electrothermal atomic absorption spectrometry. The level of Ni was measured and the correlation coefficient was calculated. Data were analyzed using t tests, Pearson's correlation coefficients, and linear regression analysis, at a level of significance P < 0.05. The statistical analysis has showed significant difference in Ni level between endodontic and control groups (P < 0.05). There was no correlation between Ni level in urine and the age or time period of broken instrument inside the canal; however, Ni level of urine and the age of participants in experimental group has demonstrated a positive correlation. The amount of Ni element can be increased in the urine of patients who have experienced broken endodontic instrument inside the dental canal. However, there is no positive correlation between the remaining pieces of instruments inside the canal and the elevation of nickel amount in urine during the tested time period. This issue suggested that the aging of remaining broken instrument inside the canal does not show any remarkable concern regarding the Ni elevation in the urine excreted by an individual. 23645509 The prevalence of psychiatric disease in emergency department patients with unexplained syncope. Current data suggest that up to 60 % of patients presenting to the emergency department with syncope leave the hospital without a defined etiology. Prior studies suggest a prevalence of psychiatric disease as high as 26 % in patients with syncope of unknown etiology. The objective of this study was to determine whether psychiatric disease is associated with an increased incidence of syncope of unknown etiology. Prospective, observational, cohort study of consecutive ED patients >18 presenting with syncope was conducted from 6/03 to 7/06. Patients were queried in the ED and charts reviewed for a history of psychiatric disease and use of psychiatric medication. Data were analyzed using SAS v9.2 with Fisher's exact tests. We enrolled 518 patients who presented to the ED after syncope, 161 (31 %) did not have an identifiable etiology for their syncopal event; 166 patients (32 %) had a history of or current psychiatric disease. Among men with psychiatric disease, 37 % had an unknown etiology of their syncopal event, compared to 23 % of men without psychiatric disease (p = 0.04). However, among women with syncope of unknown etiology, there was no significant difference between those with and without psychiatric disease (34.4 vs. 32.7 %) with p = 0.77. Our results suggest that men with psychiatric disease have an increased incidence of syncope of unknown etiology. Given this relationship, clinicians might consider screening for psychiatric disorders in syncopal patients when no clear etiology can be identified. 23712609 Proteomics analysis of the Flp regulon in Lactococcus lactis subsp. cremoris. Lactococcus lactis subsp. cremoris MG1363 genome sequence was completed and encodes two flp genes flpA and flpB. Research carried out has suggested that the flpB proteins are transcriptional regulators that respond to the environmental oxygen level. A variety of flp deletion mutant strains with single and double mutation were created. Wild-type (MG1363) and its flp(-) derivatives were compared by 2DE to identify changes in protein intensity under different aerobic/anaerobic growth conditions. In total, 416 ± 20 and 444 ± 32 protein spots were quantified from anaerobic and aerobic cells, respectively, on pH 4-7 gels. Forty-five protein spots that changed were excised from 2DE gel, digested with trypsin and identified from their MALDI-TOF MS Peptide Mass Fingerprint. A variety of proteins were affected by the flp mutations and oxygen level. Some proteins were controlled by FlpA and FlpB independently and some required both FlpA and B for regulation. The identified proteins that are regulated by the Flp proteins can be grouped by biochemical function. These groups are oxidative stress, electron transfer, sugars, cell wall, ABC transporters, arginine metabolism, and pyrimidine biosynthesis pathway. 23590233 Inhibition of fibroblast proliferation in vitro using red light-emitting diodes. Red light is part of the visible light spectrum. The effects of light-emitting diode (LED)-generated red light on human skin are not well-characterized. To study the effect of red LED-generated low-level light therapy (LLLT) on fibroblast proliferation and viability in vitro. Irradiation of normal human skin fibroblasts using red LED panels was performed in vitro, and modulation of proliferation and viability was quantified using trypan blue dye exclusion assay. Statistically significant decreases in cell proliferation were noted at the following fluences (time): 160 J/cm(2) (30 minutes, 34 seconds), 320 J/cm(2) (61 minutes, 07 seconds) and 640 J/cm(2) (122 minutes, 14 seconds) (Figure 1). Irradiation at the 160- (98.5 ± 1.2%) and 320-J/cm(2) (98.0 ± 3.1%) doses did not significantly alter viability. At certain fluences, red LLLT can effectively inhibit fibroblast proliferation in vitro without altering viability and holds promise for the treatment of scars and other proliferative skin diseases. 23732846 Molecular cloning and expression analysis of polymeric immunoglobulin receptor in flounder (Paralichthys olivaceus). The polymeric immunoglobulin receptor (pIgR) is one of the most important mucosal effectors mediating the transcytosis of polymeric immunoglobulins (pIgs) to protect the organisms. In this paper, a full-length cDNA of pIgR was firstly cloned from flounder (Paralichthys olivaceus) using rapid amplification of cDNA ends approaches, and it was of 1384 bp, containing an open reading frame (ORF) of 1005 bp encoding a polypeptide of 335 amino acids with the predicted molecular mass of 37.6 kDa. The flounder pIgR exhibited a unique structure containing only two immunoglobulin-like domains (ILD) corresponding to mammalian pIgR ILD1 and ILD5. The mRNA transcripts of pIgR were detected in all the tested tissues of flounder by semi-quantitative RT-PCR, and the pIgR was expressed at the highest level in liver and higher levels in intestine, gill, skin, spleen and head kidney than in stomach and muscle. The ORF was successfully expressed in Escherichia coli BL21 (DE3) and the recombinant protein displayed binding capability to the purified mucus IgM and serum IgM of flounder by ELISA. The polyclonal antibody against flounder recombinant pIgR was developed by immunization of Balb/C mice, which specifically reacted to the recombinant pIgR in Western blot. Moreover, a secretory component-like molecule was detected in the skin mucus but not in the serum of flounder, which molecular mass (about 37 kDa) was near the theoretical mass obtained from the sequence of flounder pIgR. All these results indicated that flounder pIgR probably involved in the pIgs transport and provided insights into the roles of fish pIgR in the mucosal immunity. 23294008 Spiroketal formation and modification in avermectin biosynthesis involves a dual activity of AveC. Avermectins (AVEs), which are widely used for the treatment of agricultural parasitic diseases, belong to a family of 6,6-spiroketal moiety-containing, macrolide natural products. AVE biosynthesis is known to employ a type I polyketide synthase (PKS) system to assemble the molecular skeleton for further functionalization. It remains unknown how and when spiroketal formation proceeds, particularly regarding the role of AveC, a unique protein in the pathway that shares no sequence homology to any enzyme of known function. Here, we report the unprecedented, dual function of AveC by correlating its activity with spiroketal formation and modification during the AVE biosynthetic process. The findings in this study were supported by characterizing extremely unstable intermediates, products and their spontaneous derivative products from the simplified chemical profile and by comparative analysis of in vitro biotransformations and in vivo complementations mediated by AveC and MeiC (the counterpart in biosynthesizing the naturally occurring, AVE-like meilingmycins). AveC catalyzes the stereospecific spiroketalization of a dihydroxy-ketone polyketide intermediate and the optional dehydration to determine the regiospecific saturation characteristics of spiroketal diversity. These reactions take place between the closures of the hexene ring and 16-membered macrolide and the formation of the hexahydrobenzofuran unit. MeiC can replace the spirocyclase activity of AveC, but it lacks the independent dehydratase activity. Elucidation of the generality and specificity of AveC-type proteins allows for the rationalization of previously published results that were not completely understood, suggesting that enzyme-mediated spiroketal formation was initially underestimated, but is, in fact, widespread in nature for the control of stereoselectivity. 23554268 Graphene in Light: Design, Synthesis and Applications of Photo-active Graphene and Graphene-Like Materials. Graphene functionalized with photo-active units has become one of the most exciting topics of research in the last few years, which remarkably sustains and expands the graphene boom. The rise of photo-active graphene in photonics and optoelectronics is evidenced by a spate of recent reports on topics ranging from photodetectors, photovoltaics, and optoelectronics to photocatalysis. For these applications, the fabrication of photo-active graphene through appropriate chemical functionalization strategies is essential as pristine graphene has zero bandgap and only weak absorption of photons. Written from the chemists' point of view, up-to-date chemical functionalization of graphene with various small organic molecules, conjugated polymers, rare-earth components, and inorganic semiconductors is reviewed. Particular attention is paid to the development of graphene functionalized with light-harvesting moieties, including materials synthesis, characterization, energy/charge-transfer processes, and applications in photovoltaics. Challenges currently faced by researchers and future perspectives in this field are also discussed. 23863114 Engineering Multicellular Logic in Bacteria with Metabolic Wires. Aromatic biodegradation pathways of environmental bacteria are vast sources of matching trios of enzymes, substrates and regulators that can be refactored to run logic operations through cell-to-cell communication. As a proof of concept, the connection between two Pseudomonas putida strains using benzoic acid as the wiring molecule is presented. In this system, a sender strain harboring the TOL pathway for biodegradation of aromatics processed toluene as input and generated benzoate as the output signal. Diffusion of such metabolic intermediate to the medium was then sensed by a second strain (the receiver) that used benzoate as input for a new logic gate producing a visual output (i.e., light emission). The setup was functional irrespective of whether sender and receiver cells were in direct contact or in liquid culture. These results highlight the potential of environmental metabolic pathways as sources of building blocks for the engineering of multicellular logic in prokaryotic systems. 23549898 Biomechanical phenotyping of central arteries in health and disease: advantages of and methods for murine models. The stiffness and structural integrity of the arterial wall depends primarily on the organization of the extracellular matrix and the cells that fashion and maintain this matrix. Fundamental to the latter is a delicate balance in the continuous production and removal of structural constituents and the mechanical state in which such turnover occurs. Perturbations in this balance due to genetic mutations, altered hemodynamics, or pathological processes result in diverse vascular phenotypes, many of which have yet to be well characterized biomechanically. In this paper, we emphasize the particular need to understand regional variations in the biaxial biomechanical properties of central arteries in health and disease and, in addition, the need for standardization in the associated biaxial testing and quantification. As an example of possible experimental methods, we summarize testing protocols that have evolved in our laboratory over the past 8 years. Moreover, we note advantages of a four fiber family stress-stretch relation for quantifying passive biaxial behaviors, the use of stored energy as a convenient scalar metric of the associated material stiffness, and the utility of appropriate linearizations of the nonlinear, anisotropic relations both for purposes of comparison across laboratories and to inform computational fluid-solid-interaction models. We conclude that, notwithstanding prior advances, there remain many opportunities to advance our understanding of arterial mechanics and mechanobiology, particularly via the diverse genetic, pharmacological, and surgical models that are, or soon will be, available in the mouse. 23825112 Prediction of fracture healing under axial loading, shear loading and bending is possible using distortional and dilatational strains as determining mechanical stimuli. Numerical models of secondary fracture healing are based on mechanoregulatory algorithms that use distortional strain alone or in combination with either dilatational strain or fluid velocity as determining stimuli for tissue differentiation and development. Comparison of these algorithms has previously suggested that healing processes under torsional rotational loading can only be properly simulated by considering fluid velocity and deviatoric strain as the regulatory stimuli. We hypothesize that sufficient calibration on uncertain input parameters will enhance our existing model, which uses distortional and dilatational strains as determining stimuli, to properly simulate fracture healing under various loading conditions including also torsional rotation. Therefore, we minimized the difference between numerically simulated and experimentally measured courses of interfragmentary movements of two axial compressive cases and two shear load cases (torsional and translational) by varying several input parameter values within their predefined bounds. The calibrated model was then qualitatively evaluated on the ability to predict physiological changes of spatial and temporal tissue distributions, based on respective in vivo data. Finally, we corroborated the model on five additional axial compressive and one asymmetrical bending load case. We conclude that our model, using distortional and dilatational strains as determining stimuli, is able to simulate fracture-healing processes not only under axial compression and torsional rotation but also under translational shear and asymmetrical bending loading conditions. 23946256 Reactivity of Dicoordinated Stannylones (Sn(0) ) versus Stannylenes (Sn(II) ): An Investigation Using DFT-Based Reactivity Indices. The reactivity of dicoordinated Sn(0) compounds, stannylones, is probed using density functional theory (DFT)-based reactivity indices and compared with the reactivity of dicoordinated Sn(II) compounds, stannylenes. For the former compounds, the influence of different types of electron-donating ligands, such as cyclic and acyclic carbenes, stannylenes and phosphines, on the reactivity of the central Sn atom is analyzed in detail. Sn(0) compounds are found to be relatively soft systems with a high nucleophilicity, and the plots of the Fukui function f(-) for an electrophilic attack consistently predict the highest reactivity on the Sn atom. Next, complexes of dicoordinated Sn compounds with different Lewis acids of variable hardness are computed. In a first part, the double-base character of stannylones is demonstrated in interactions with the hardest Lewis acid H(+) . Both the first and second proton affinities (PAs) are high and are well correlated with the atomic charge on the Sn atom, probing its local hardness. These observations are also in line with electrostatic potential plots that demonstrate that the tin atom in Sn(0) compounds bears a higher negative charge in comparison to Sn(II) compounds. Stannylones and stannylenes can be distinguished from each other by the partial charges at Sn and by various reactivity indices. It also becomes clear that there is a smooth transition between the two classes of compounds. We furthermore demonstrate both from DFT-based reactivity indices and from energy decomposition analysis, combined with natural orbitals for chemical valence (EDA-NOCV), that the monocomplexed stannylones are still nucleophilic and as reactive towards a second Lewis acid as towards the first one. The dominating interaction is a strong σ-type interaction from the Sn atom towards the Lewis acid. The interaction energy is higher for complexes with the cation Ag(+) than with the non-charged electrophiles BH3 , BF3 , and AlCl3 . 23845151 Risk of cancer in psoriasis: a systematic review and meta-analysis of epidemiological studies. The relationship between psoriasis and increased cancer risk is debated. The aim of this study was to evaluate if there is an increase in the background risk of cancer in psoriasis patients compared with the general population. A systematic literature search was performed on PubMed, Embase and Cochrane databases, using the keywords 'Psoriasis [Majr] AND Neoplasms', from 1980 to January 2012. Meta-analysis was performed based on observational studies showing consistency in cancer risk assessment methods. Of the 1080 articles retrieved, 37 references were selected. There may be an increased risk of some solid cancers in psoriasis: respiratory tract cancer [standardized incidence ratio (SIR) = 1.52, 95% confidence interval (CI) 1.35-1.71], upper aerodigestive tract cancer (SIR = 3.05, 95% CI 1.74-5.32), urinary tract cancer (SIR = 1.31, 95% CI 1.11-1.55) and liver cancer (SIR = 1.90, 95% CI 1.48-2.44). The risk of non-Hodgkin lymphoma appears slightly increased in psoriasis (SIR = 1.40, 95% CI 1.06-1.86). Psoriasis patients have an increased risk of squamous cell carcinoma (SIR = 5.3, 95% CI 2.63-10.71) and basal cell carcinoma (SIR = 2.00, 95% CI 1.83-2.20), whereas the risk of melanoma is not increased. There was a large heterogeneity in studies assessing cancer risk in psoriasis preventing from including all studies in meta-analysis. This systematic literature review shows a small increased risk of some solid cancers in psoriasis, especially those linked to alcohol drinking and cigarette smoking. A higher risk of non-melanoma skin cancers, especially squamous cell carcinoma, is shown, mainly due to previous exposure to 8-methoxypsoralen-ultraviolet-A (PUVA), ciclosporin and possibly methotrexate. 23086230 Fetal muscle-type nicotinic acetylcholine receptor activation in TE-671 cells and inhibition of fetal movement in a day 40 pregnant goat model by optical isomers of the piperidine alkaloid coniine. Coniine is an optically active toxic piperidine alkaloid and nicotinic acetylcholine receptor (nAChR) agonist found in poison hemlock (Conium maculatum L.). Coniine teratogenicity is hypothesized to be attributable to the binding, activation, and prolonged desensitization of fetal muscle-type nAChR, which results in the complete inhibition of fetal movement. However, pharmacological evidence of coniine actions at fetal muscle-type nAChR is lacking. The present study compared (-)-coniine, (+)-coniine, and nicotine for the ability to inhibit fetal movement in a day 40 pregnant goat model and in TE-671 cells that express fetal muscle-type nAChR. Furthermore, α-conotoxins (CTx) EI and GI were used to antagonize the actions of (+)- and (-)-coniine in TE-671 cells. (-)-Coniine was more effective at eliciting electrical changes in TE-671 cells and inhibiting fetal movement than was (+)-coniine, suggesting stereoselectivity by the receptor. The pyridine alkaloid nicotine did not inhibit fetal movement in a day 40 pregnant goat model, suggesting agonist specificity for the inhibition of fetal movement. Low concentrations of both CTxs potentiated the TE-671 cell response and higher concentrations of CTx EI, and GI antagonized the actions of both coniine enantiomers demonstrating concentration-dependent coagonism and selective antagonism. These results provide pharmacological evidence that the piperidine alkaloid coniine is acting at fetal muscle-type nAChR in a concentration-dependent manner. 23835406 DNA resection proteins Sgs1 and Exo1 are required for G1 checkpoint activation in budding yeast. Double-strand breaks (DSBs) in budding yeast trigger activation of DNA damage checkpoints, allowing repair to occur. Although resection is necessary for initiating damage-induced cell cycle arrest in G2, no role has been assigned to it in the activation of G1 checkpoint. Here we demonstrate for the first time that the resection proteins Sgs1 and Exo1 are required for efficient G1 checkpoint activation. We find in G1 arrested cells that histone H2A phosphorylation in response to ionizing radiation is independent of Sgs1 and Exo1. In contrast, these proteins are required for damage-induced recruitment of Rfa1 to the DSB sites, phosphorylation of the Rad53 effector kinase, cell cycle arrest and RNR3 expression. Checkpoint activation in G1 requires the catalytic activity of Sgs1, suggesting that it is DNA resection mediated by Sgs1 that stimulates the damage response pathway rather than protein-protein interactions with other DDR proteins. Together, these results implicate DNA resection, which is thought to be minimal in G1, as necessary for activation of the G1 checkpoint. 23963876 Female-to-Male Transmasculine Adult Health: A Mixed-Methods Community-Based Needs Assessment. There is a dearth of health research about transgender people. This mixed-methods study sought to formatively investigate the health and perceived health needs of female-to-male transmasculine adults. A cross-sectional quantitative needs assessment (n = 73) and qualitative open-ended input (n = 19) were conducted in June 2011. A latent class analysis modeled six binary health indicators (depression, alcohol use, current smoking, asthma, physical inactivity, overweight status) to identify clusters of presenting health issues. Four clusters of health indicators emerged: (a) depression; (b) syndemic (all indicators); (c) alcohol use, overweight status; and (d) smoking, physical inactivity, overweight status. Transphobic discrimination in health care and avoiding care were each associated with membership in the syndemic class. Qualitative themes included personal health care needs, community needs, and resilience and protective factors. Findings fill an important gap about the health of transmasculine communities, including the need for public health efforts that holistically address concomitant health concerns. 23784375 Dystrophin-deficient pigs provide new insights into the hierarchy of physiological derangements of dystrophic muscle. Duchenne muscular dystrophy (DMD) is caused by mutations in the X-linked dystrophin (DMD) gene. The absence of dystrophin protein leads to progressive muscle weakness and wasting, disability and death. To establish a tailored large animal model of DMD, we deleted DMD exon 52 in male pig cells by gene targeting and generated offspring by nuclear transfer. DMD pigs exhibit absence of dystrophin in skeletal muscles, increased serum creatine kinase levels, progressive dystrophic changes of skeletal muscles, impaired mobility, muscle weakness and a maximum life span of 3 months due to respiratory impairment. Unlike human DMD patients, some DMD pigs die shortly after birth. To address the accelerated development of muscular dystrophy in DMD pigs when compared with human patients, we performed a genome-wide transcriptome study of biceps femoris muscle specimens from 2-day-old and 3-month-old DMD and age-matched wild-type pigs. The transcriptome changes in 3-month-old DMD pigs were in good concordance with gene expression profiles in human DMD, reflecting the processes of degeneration, regeneration, inflammation, fibrosis and impaired metabolic activity. In contrast, the transcriptome profile of 2-day-old DMD pigs showed similarities with transcriptome changes induced by acute exercise muscle injury. Our studies provide new insights into early changes associated with dystrophin deficiency in a clinically severe animal model of DMD. 23950869 No Serological Evidence of Influenza A H1N1pdm09 Virus Infection as a Contributing Factor in Childhood Narcolepsy after Pandemrix Vaccination Campaign in Finland. Narcolepsy cataplexy syndrome, characterised by excessive daytime sleepiness and cataplexy, is strongly associated with a genetic marker, human leukocyte antigen (HLA) DQB1*06:02. A sudden increase in the incidence of childhood narcolepsy was observed after vaccination with AS03-adjuvanted Pandemrix influenza vaccine in Finland at the beginning of 2010. Here, we analysed whether the coinciding influenza A H1N1pdm pandemic contributed, together with the Pandemrix vaccination, to the increased incidence of childhood narcolepsy in 2010. The analysis was based on the presence or absence of antibody response against non-structural protein 1 (NS1) from H1N1pdm09 virus, which was not a component of Pandemrix vaccine. Non-structural (NS) 1 proteins from recombinant influenza A/Udorn/72 (H3N2) and influenza A/Finland/554/09 (H1N1pdm09) viruses were purified and used in Western blot analysis to determine specific antibody responses in human sera. The sera were obtained from 45 patients who fell ill with narcolepsy after vaccination with AS03-adjuvanted Pandemrix at the end of 2009, and from controls. Based on quantitative Western blot analysis, only two of the 45 (4.4%) Pandemrix-vaccinated narcoleptic patients showed specific antibody response against the NS1 protein from the H1N1pdm09 virus, indicating past infection with the H1N1pdm09 virus. Instead, paired serum samples from patients, who suffered from a laboratory confirmed H1N1pdm09 infection, showed high levels or diagnostic rises (96%) in H1N1pdm virus NS1-specific antibodies and very high cross-reactivity to H3N2 subtype influenza A virus NS1 protein. Based on our findings, it is unlikely that H1N1pdm09 virus infection contributed to a sudden increase in the incidence of childhood narcolepsy observed in Finland in 2010 after AS03-adjuvanted Pandemrix vaccination. 23830210 Chylothorax in children with congenital heart disease: Incidence of thrombosis. Postoperative chylothorax is a frequently encountered pathology occurring in up to 4% of patients undergoing surgery for repair of congenital heart disease. Symptomatic thrombosis is associated with chylothorax and may contribute to its severity and duration. Furthermore, vessel thrombosis resulting in persistent vessel occlusion may impede future treatments, diagnostic studies and cardio-surgical interventions. The objective of this study was to determine the incidence of upper system thrombosis in pediatric congenital heart patients with confirmed chylothorax with ultrasound screening of all patients diagnosed with chylothorax. All pediatric patients with confirmed with chylothorax underwent doppler ultrasound of the upper venous system as per hospital standard. This retrospective cohort study enrolled all children between February 1, 2010-August 2012, post cardiac surgery with confirmed chylothorax to determine the incidence of all thrombosis. There were 1396 children who underwent 1396 cardiac surgical procedures during the study time with 760 undergoing cardiopulmonary bypass. Development of chylothorax occurred in 54 of 1396, 3.9% (95%CI 3.0;5.0) procedures in all children. In those children with chylothorax, 28 of 54 episodes, 51.8% (95%CI 38.9;64.6) had confirmed VTE. The 51.8% incidence in this study demonstrates a 2.6 fold increase in risk of thrombosis compared to 20% in children with heart disease and central venous lines and may result in serious clinical consequences. The contribution of upper venous system thrombosis to chylothorax is unknown. Often, clinical suspicion of chylothorax exists, however the lack of a standardized approach to objective diagnosis results in delayed confirmation. Approaches to therapy either treatment of confirmed thrombosis or prevention of thrombosis in patients with chylothorax require formal evaluation. Future studies are urgently needed. 23958588 Role of genotype G hepatitis B virus mixed infection on the progression of hepatic fibrosis in HIV positive patients over 5 years of follow-up. Due to common routes of transmission, HIV and HBV are frequently found as concomitant infections. The dynamic of liver disease in co-infected patients is important to understand for appropriate clinical management. Conflicting data surround the role played by genotype-G HBV (HBV-G) during the course of HIV co-infection. This study aims to assess, using non-invasive methods, liver disease progression in HIV-HBV genotype-G co-infected patients. Co-infected patients with residual HBV replication (n=125) were screened for HBV-G infection by specific real-time PCR. The impact of HBV-G on liver fibrosis progression, as assessed by a non invasive biomarker (Fibrotest), was evaluated first, by a cross sectional analysis comparing fibrosis between HBV-G (n=23) and non-G (n=55) infected patients and second, by a longitudinal study performed over a 5 year period. Selected patients were mostly male (90%), with homogenous characteristics between the HBV-G and non-G infected groups, in terms of age, known duration of HIV disease, immune and virological status and duration of HIV/HBV treatment. HBV-G infected patients were exclusively from Western Europe with homosexual intercourses (83%) as principal risk of transmission. Cross sectional analysis revealed comparable liver disease severity distribution between HBV-G and non-G infected patients. Co-infection with other hepatitis viruses and low CD4-nadir, but not HBV-G co-infection, were associated with a 5-year risk of fibrosis progression. This study suggests that HBV-G infection is not significantly associated with a more severe liver disease and does not have a deleterious impact on fibrosis progression in efficiently treated HIV-HBV co-infected patients. 23820912 The Horse Boy--attending to the stories our patients tell us. In the summer of 2007, Rupert Isaacson and Kirsten Neff set off to Mongolia on an extraordinary journey to heal their 7-year old autistic son. Their story was captured on film by a small crew, and both the resulting documentary, The Horse Boy, and the associated book have reached a wide audience. For those involved in psychiatric education, the film represents a valuable opportunity to explore a range of relevant clinical and ethical issues with their learners, including an introduction to the world of complementary and alternative medicine and the emerging discipline of narrative medicine. Perhaps most importantly, The Horse Boy is an impetus for health professionals to consider their own responsibilities when determined patients in their care undertake such remarkable quests to heal themselves or their loved ones. 23849732 The association between glomus tumors and neurofibromatosis. To determine whether an epidemiologic association exists between glomus tumors and neurofibromatosis. Using a pathology database, we established a study cohort consisting of all patients who had undergone excision of a glomus tumor of the hand between 1995 and 2010. We created a control cohort by randomly selecting 200 patients who had undergone excision of a ganglion cyst over the same period. We reviewed medical records for each cohort to identify patients with a diagnosis of neurofibromatosis. We calculated the odds ratio was calculated and performed Fisher's exact test to determine the significance of the association. We identified 21 patients with glomus tumors of the hand. Six of these patients carried the diagnosis of neurofibromatosis (29%). In contrast, no patients in the control group carried the diagnosis of neurofibromatosis. The odds ratio for a diagnosis of neurofibromatosis in association with a glomus tumor compared with controls was 168:1. This study provides evidence of a strong epidemiologic association between glomus tumors and neurofibromatosis. Glomus tumor should be included in the differential diagnosis in neurofibromatosis patients who present with a painful lesion of the hand or finger. Diagnostic III. 23886751 Proteomic analysis of mature adipocytes from obese patients in relation to aging. Obesity and aging are interrelated conditions that both cause changes in adipocyte metabolism and affect the distribution of fat in both subcutaneous and visceral depots. In addition, both weight gain and aging can lead to similar clinical outcomes such as insulin resistance, cardiovascular disease, type 2 diabetes mellitus, atherosclerosis and stroke. Our objective was to examine the changes in protein expression within the subcutaneous adipose tissue of obese patients, matched for BMI, in relation to age. Mature adipocytes were isolated from liposuction samples of abdominal subcutaneous adipose tissue collected from both young (26.2±4.3 (mean age±SD); n=7) and old (52.2±4.7 (mean age±SD); n=7) obese individuals. Total protein extracts were then compared by two-dimensional difference in gel electrophoresis (2D DIGE). Thirty differentially expressed protein spots (ANOVA test, p≤0.05; fold-change ≥1.8) were detected, of which, 15 were identified by MALDI-TOF mass spectrometry. These were comprised of a total of thirteen unique protein sequences. Nine proteins were more abundant in the adipocytes isolated from old vs. young individuals. These proteins included prohibitin 1, protein disulphide isomerase A3, beta actin, profilin, aldo-ketoreductase 1 C2, alpha crystallin B and the annexins A1, A5 and A6. Four other proteins were less abundant in the adipocytes from old, obese subjects and these included keratin type 2 cytoskeletal 1, keratin type 2 cytoskeletal 10 and hemoglobins A and B. The differentially abundant proteins were investigated by Ingenuity Pathway Analysis (IPA) to reveal their associations with known biological functions. This analysis identified signal transducer and activator of transcription 3 as the central molecule in the connectivity map and the apoptotic pathway as the pathway with the highest score. Differences in the abundances of several proteins were confirmed by immunoblotting: i.e., prohibitin 1, protein disulphide isomerase A3, beta actin, profilin and signal transducer and activator of transcription 3 proteins. In conclusion, proteomic analysis of subcutaneous adipose tissue reveals differences in the abundance of proteins in adipocytes isolated from young vs. old individuals. These differentially abundant proteins are involved in the regulation of apoptosis, cellular senescence and inflammatory response. All these are common pathologic events in both obesity and aging. 23601248 Discovery of a new bioactive molecule for neuroblastoma. Neuroblastoma, a common pediatric malignancy of neural crest origin, is unique in its wide spectrum of clinical and biological behavior, ranging from spontaneous regression or differentiation to rapid progression and metastasis. Overexpression of neurotrophin receptors of the tyrosine kinase (Trk) family has been identified as a major prognostic and biological factor for this disease. Novel molecules were selected using cheminformatics tools (SBVS & LBVS) and screened in cell-based assays to modulate Trk receptor activity. One compound (C390-0031) had a potent anti-proliferative activity in dose-response studies using neuroblastoma cell lines. The molecular effects of this molecule were further characterized by using cell-cycle and western blot analysis. Interestingly, despite the presence of the anchoring fragment to the Trk kinase domain composing its structure, this molecule does not inhibit TrkA like lestaurtinib, constituting a new chemical with a yet unknown mechanism of action. This article is protected by copyright. All rights reserved. 23219852 Studies on percutaneous penetration of chemicals - Impact of storage conditions for excised human skin. According to international guidelines skin penetration experiments can be carried out using freshly excised or frozen stored skin. However, this recommendation refers to data obtained in experiments with human cadaver skin. In our study, the percutaneous penetration of the occupationally relevant chemicals anisole, cyclohexanone and 1,4-dioxane was investigated for freshly excised as well as for 4 and 30 days at -20°C stored human skin using the diffusion cell technique. As indicator for the impairment of skin barrier by freezing cholesterol dissolution was determined in the solvents in exposure chambers of diffusion cells. Considering the percutaneously penetrated amounts, the following ranking was determined: 1,4-dioxane>anisole>cyclohexanone (decline to a factor of 5.9). The differences of fluxes between freshly excised and frozen stored skin (4 and 30 days) were not significant (p>0.05). Cholesterol dissolved from the skin indicates no significant differences between freshly excised and frozen stored skin. This study shows that freezing of human skin for up to 30 days does not alter the skin barrier function and the permeability of chemicals. 23904463 Association of smoking history with cancer recurrence and survival in stage III-IV male gastric cancer patients. Background: Smoking and drinking alcohol are major risk factors for cancer development, and we investigated their effects on gastric cancer prognosis following initial resection. Methods: Data from male patients with stage III-IV gastric adenocarcinoma who underwent surgery between 2001 and 2006 were retrospectively reviewed. Patients were followed up until 2011. Kaplan-Meier plots and Cox proportional hazards regressions were applied for survival rates. Results: Among 238 patients, 151 (63.5%) smoked and 146 (61.3%) drank alcohol. Current smokers had an increased risk of cancer recurrence or death from any cause (adjusted hazard ratio [aHR]: 1.94; 95% confidence interval [CI]: 1.18-3.21), cancer recurrence (aHR: 1.89; 95% CI: 1.12-3.21), and overall mortality (aHR: 2.14; 95% CI: 1.23-3.73) compared to never-smokers. Patients with a lifetime cigarette smoking of <40 and ≥40 pack-years had increased cancer recurrence or death from any cause (aHR: 1.72 and 2.43, respectively; 95% CI: 1.03-2.86 and 1.38-4.30, respectively), cancer recurrence (aHR 1.63 and 2.61, respectively; 95% CI: 0.95-2.80 and 1.43-4.77, respectively), and overall mortality (aHR 1.92 and 2.75, respectively; 95% CI: 1.09-3.38 and 1.47-5.12, respectively) compared to never-smokers. However, drinking alcohol was not associated with post-surgery survival. Conclusions: Cigarette smoking history at time of diagnosis, but not drinking history, is associated with cancer recurrence and poor survival after surgery in male patients with stage III-IV gastric cancer. Impact: These findings encourage physicians to advise gastric cancer patients to stop smoking to obtain a general health benefit and likely improvement in gastric cancer course. 23727387 The dopamine agonist apomorphine enhances conditioned pain modulation in healthy humans. Although cumulative evidence suggests that dopamine plays a role in pain processing, the mechanisms by which dopaminergic transmission affects pain remain elusive. Conditioned pain modulation (CPM) is a psychophysical paradigm based on endogenous descending inhibitory pain modulation. The current study was aimed to test the effects of apomorphine, a non-specific dopamine agonist, on the magnitude of CPM in healthy subjects. One hundred and five healthy subjects participated in this randomized, double-blind study. CPM was assessed by subtracting the response to a phasic painful heat stimulus administered simultaneously with a conditioning cold pain stimulus from the response to the same heat stimulus administered alone. CPM was tested prior to and 25min following a subcutaneous injection of either apomorphine (1.5mg) or a placebo. CPM following apomorphine administration increased by 27.3% and by only 4% following placebo administration. RM-ANOVA revealed a significant interaction between 'session' and 'time' factors (F=5.316, p=0.023, η=0.054), and significant effect for the 'session' (F=5.719, p=0.019, η=0.006), but not for the 'time' (F=0.586, p=0.446, η=0.057). These results suggest that dopaminergic pathways both participate in and enhance pain modulation, represented by CPM. The role of dopamine in pain processing should be further studied. 23681946 Bis(2-hydroxy-3-isopropyl-6-methyl-benzaldehyde)ethylenediamine: a novel cation sensor. Novel substituted phenol-based new symmetrical bis(2-hydroxy-3-isopropyl-6-methyl-benzaldehyde)ethylenediamine (1) has been designed and synthesized. The compound 1 fluorometrically recognized Cu(2+) ion in CH3OH/H2O (90:10, v/v) by exhibiting an increase in emission upon complexation. In addition, Cu(2+) gave rise to a change in colour of the solution of compound 1, which was clearly visible to the naked eye under UV irradiation. The association constant (K) of compound 1 with Cu(2+) ion was computed with the Benesi-Hildebrand plot and Scatchard plot at 43,000 M(-1) and 43,011 M(-1) respectively. 23884940 Feedforward Inhibition Underlies the Propagation of Cholinergically Induced Gamma Oscillations from Hippocampal CA3 to CA1. Gamma frequency (30-80 Hz) oscillations are implicated in memory processing. Such rhythmic activity can be generated intrinsically in the CA3 region of the hippocampus from where it can propagate to the CA1 area. To uncover the synaptic mechanisms underlying the intrahippocampal spread of gamma oscillations, we recorded local field potentials, as well as action potentials and synaptic currents in anatomically identified CA1 and CA3 neurons during carbachol-induced gamma oscillations in mouse hippocampal slices. The firing of the vast majority of CA1 neurons and all CA3 neurons was phase-coupled to the oscillations recorded in the stratum pyramidale of the CA1 region. The predominant synaptic input to CA1 interneurons was excitatory, and their discharge followed the firing of CA3 pyramidal cells at a latency indicative of monosynaptic connections. Correlation analysis of the input-output characteristics of the neurons and local pharmacological block of inhibition both agree with a model in which glutamatergic CA3 input controls the firing of CA1 interneurons, with local pyramidal cell activity having a minimal role. The firing of phase-coupled CA1 pyramidal cells was controlled principally by their inhibitory inputs, which dominated over excitation. Our results indicate that the synchronous firing of CA3 pyramidal cells rhythmically recruits CA1 interneurons and that this feedforward inhibition generates the oscillatory activity in CA1. These findings identify distinct synaptic mechanisms underlying the generation of gamma frequency oscillations in neighboring hippocampal subregions. 23420336 Xerosis is Associated with Atopic Dermatitis, Hand Eczema and Contact Sensitization Independent of Filaggrin Gene Mutations. Atopic dermatitis, hand eczema and contact sensitization are prevalent disorders, and may, in many cases, be secondary to skin barrier abnormality. The aim of this study was to investigate the association between self-reported generalized xerosis, atopic dermatitis, hand eczema and contact sensitization, taking filaggrin gene mutations into account. Questionnaire data were collected from a cross-sectional study performed in a general population in Copenhagen. A total of 3,460 18-69-year-olds were patch-tested and 3,335 were genotyped for the 2282del4 and R501X mutations in the filaggrin gene. Atopic dermatitis and hand eczema were significantly associated with generalized xerosis, whereas contact sensitization (not nickel) showed only a borderline significant association. These results suggest that generalized xerosis may increase the risk of common skin disorders. 23902171 Campaigners lobby for the return of Nightingale to national curriculum. The battle over which nursing icons should be studied by school pupils has taken a new twist, with campaigners lobbying to reinstate Florence Nightingale on the curriculum. 23969057 Complete Genome Sequence of the Arcobacter butzleri Cattle Isolate 7h1h. Arcobacter butzleri strain 7h1h was isolated in the United Kingdom from the feces of a clinically healthy dairy cow. The genome of this isolate was sequenced to completion. Here, we present the annotation and analysis of the completed 7h1h genome, along with a comparison of this genome to the existing A. butzleri genomes. 23787813 Amide bond hydrolysis in peptides and cyclic peptides catalyzed by a dimeric Zr(iv)-substituted Keggin type polyoxometalate. Detailed kinetic studies on the hydrolysis of glycylserine (Gly-Ser) and glycylglycine (Gly-Gly) in the presence of the dimeric zirconium(iv)-substituted Keggin type polyoxometalate (Et2NH2)8[{α-PW11O39Zr(μ-OH)(H2O)}2]·7H2O (1) were performed by a combination of (1)H, (13)C and (31)P NMR spectroscopy. The observed rate constants for the hydrolysis of Gly-Ser and Gly-Gly at pD 5.4 and 60 °C were 63.3 × 10(-7) s(-1) and 4.44 × 10(-7) s(-1) respectively, representing a significant acceleration as compared to the uncatalyzed reactions. The pD dependence of the rate constant for both reactions exhibited a bell-shaped profile with the fastest hydrolysis observed in the pD range of 5.5-6.0. Interaction of 1 with Gly-Ser and Gly-Gly via their amine nitrogen and amide oxygen was proven by (13)C NMR spectroscopy. The effective hydrolysis of Gly-Ser in the presence of 1 is most likely a combination of the polarization of the amide oxygen due to its binding to the Zr(iv) ion in 1 and the intramolecular attack of the Ser hydroxyl group on the amide carbonyl carbon. The effect of temperature, inhibitors, and ionic strength on the hydrolysis rate constant was also examined. The solution structure of 1 was investigated by means of (31)P NMR spectroscopy, revealing that its stability is highly dependent on pH, concentration and temperature. A 2.0 mM solution of 1 was found to be fully stable under hydrolytic conditions (pD 5.4 and 60 °C) both in the presence and in the absence of the dipeptides. 23838543 Measuring speech sound development: An item response model approach. The primary aim of our study is to investigate if there is an ordering in the speech sound development of children aged 3-6, similar to the ordering in general language development. The speech sound development of 1035 children was tested with a revised version of Logo-Articulation Assessment. The data were analyzed with the Mokken Scale Program (MSP) in order to construct scales with satisfactory scalability (H-coefficient) and sufficient reliability (rho). The majority of children over 4.3 years of age turned out to have mastered most speech sounds. An ordering was only found in the youngest age group (3.8-4.3 years of age), for the sounds of /r/ in initial and final position and /s/ in initial position. This resulted in a set of scales. The scales developed for /r/ (in initial and final position) and /s/ were moderately scalable (H>0.43) and reliable (rho>0.83), and independent of gender. Moreover, we found variation in the judgment of speech sound development, which may perhaps have been due to where exactly the examiner was positioned during the assessment procedure: in front of the child, or sitting beside the child. We could not detect an ordering for all speech sounds. We only found an ordering for /r/ in initial and final position and /s/ in initial position. In the Mokken analysis we conducted, these scales turned out to be moderately strong and reliable. Our research also underlines that speech sound development is judged not only in an auditory sense, but judgment also depends on the visual interpretation of the listener. 23889602 Complexation of buffer constituents with neutral complexation agents: Part I. Impact on common buffer properties. The complexation of buffer constituents with the complexation agent present in the solution can very significantly influence the buffer properties, such as pH, ionic strength or conductivity. These parameters are often crucial for selection of the separation conditions in capillary electrophoresis or HPLC and can significantly affect results of separation, particularly for capillary electrophoresis as shown in Part II of this papers series. In this paper the impact of complexation of buffer constituents with a neutral complexation agent is demonstrated theoretically as well as experimentally for the model buffer system composed of benzoic acid/ LiOH or common buffers (e.g. CHES/ LiOH, TAPS/ LiOH, Tricine/ LiOH, MOPS/ LiOH, MES/ LiOH, and acetic acid/ LiOH). Cyclodextrins as common chiral selectors were used as model complexation agents. We were not only able to demonstrate substantial changes of pH, but also to predict the general complexation characteristics of selected compounds. Due to the zwitterion character of the common buffer constituents their charged forms complex stronger with cyclodextrins than the neutral ones do. This was fully proven by NMR measurements. Additionally complexation constants of both forms of selected compounds were determined by NMR and affinity capillary electrophoresis with a very good agreement of obtained values. These data were advantageously used for the theoretical descriptions of variations in pH, depending on the composition and concentration of the buffer. Theoretical predictions were shown to be a useful tool for deriving some general rules and laws for complexing systems. 23904182 A Step Toward Development of Printable Dosage Forms for Poorly Soluble Drugs. The purpose of this study was to formulate printable dosage forms for a poorly soluble drug (piroxicam; PRX) and to gain understanding of critical parameters to be considered during development of such dosage forms. Liquid formulations of PRX were printed on edible paper using piezoelectric inkjet printing (PIJ) and impression printing (flexography). The printed dosage forms were characterized using scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX) and the amount of drug was determined using high-performance liquid chromatography. Solutions of PRX in polyethylene glycol 400 (PEG-400):ethanol (40:60) and in PEG-400 were found to be optimal formulations for PIJ and flexography, respectively. SEM-EDX analysis revealed no visible solid particles on the printed dosage forms indicating the drug most likely remained in solution after printing. More accurate drug deposition was obtained by PIJ as compared with flexography. More than 90% drug release was achieved within 5 min regardless of printing method used. The solubility of drug in solvents/cosolvents, rheological properties of formulations, properties of substrate, feasibility and accuracy of the printing methods, and detection limit of analytical techniques for characterization of printed dosage forms are some of the concerns that need to be addressed for development of printable dosage forms of poorly soluble drugs. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci. 23870085 Administration of chemotherapy with palliative intent in the last 30 days of life: The balance between palliation and chemotherapy. Appropriately timed cessation of chemotherapy is an important aspect of good quality palliative care. There is wide variation in the reported rates of chemotherapy administration within the last 30 days of life. To identify predictors of death within 30 days of receiving palliative chemotherapy, and to propose a standard definition by which oncologists and cancer centres can be compared. Patients who received palliative chemotherapy at a regional cancer centre and its rural outreach unit, between 2009 and 2011 were included. An adjusted logistic regression model, including all variables, was fit to identify predictors of death within 30 days of receiving palliative chemotherapy. Over a 3 year period, 1131 patients received palliative chemotherapy, 138 (12%) died within 30 days of receiving palliative chemotherapy. Predictors of death within 30 days of palliative chemotherapy were: less than 30 days contact with palliative care (OR [Odds Ratio] 3.30 [2.04-5.34], p<0.001) and male gender (OR 2.02 [1.24-3.31], p=0.0049), but treating clinician, tumour chemoresponsiveness, age, body mass index and survival from initial diagnosis were not. Patients who received chemotherapy in the last 30 days of life were more likely to be male, and have a shorter duration of palliative care team involvement. In this study, the observed rate of death within 30 days of chemotherapy is within the range of published data. It is recommended that a standard definition be used to benchmark medical oncology centres and individual oncologists, and to allow comparison over time. 23560747 Altering colloidal surface functionalization using DNA encapsulated inside monodisperse gelatin microsphere templates. Soluble oligonucleotides are typically introduced to bulk solution to promote hybridization activity on DNA-functionalized surfaces. Here, an alternative approach is explored by encapsulating secondary target strands inside semipermeable colloidal satellite assemblies, then triggering their release at 37 °C for subsequent surface hybridization activity. To prepare DNA-loaded satellite assemblies, uniform gelatin microspheres are fabricated using microfluidics, loaded with 15 base-long secondary DNA targets, capped with a polyelectrolyte bilayer, and finally coated with a monolayer of polystyrene microspheres functionalized with duplexes comprised of immobilized probes and soluble, 13 base-long hybridization partner strands. Once warmed to 37 °C, secondary DNA targets are released from the gelatin template and then competitively displace the shorter, original hybridization partners on the polystyrene microspheres. 23780841 Factors related to the development of cat scratch colon during colonoscopy. Cat scratch colon (CSC) is an entity characterized by bright red linear tears which appear in the colonic mucosa during colonoscopy. Although they do not generally have clinical implications, cases of secondary pneumoperitoneum have been reported. To date, the prevalence, associated diseases, and factors that determine the appearance of CSC have not been adequately determined. We report a series of 20 cases of CSC found in 10715 consecutive colonoscopies. Demographic data, indication for the colonoscopy, endoscopy findings, and complications related to the procedure were recorded. Older age and male sex were significantly associated with CSC. In 15 of the 20 cases the CSC was related to diversion colitis, and 5 cases appeared in patients with collagenous colitis. In patients with diversion colitis, the longer the time elapsed since surgery, the greater the risk of these lesions occurring. None of the patients with CSC had complications related to the colonoscopy. 23503725 Change in Nox4 expression is accompanied by changes in myogenic marker expression in differentiating C2C12 myoblasts. Myoblast differentiation is mediated by a cascade of changes in gene expression including transcription factors such as myogenin. Subsequent to myoblast differentiation, there is an increase in expression of the transmembrane protein NADPH oxidase (Nox). Nox is one of the primary factors for the generation of reactive oxygen species (ROS) in myogenic (C2C12) cells. Recently, ROS have been shown to be important regulators of several intracellular signaling pathways, and the full extent of their regulatory roles is yet to be discovered. In the present study, qRT PCR analysis demonstrated that Nox4 isoform is primarily expressed in differentiating C2C12 cells and contributes to the generation of ROS in C2C12 myoblast during differentiation. Over-expression and silencing of Nox4 expression during myoblast differentiation was accompanied by a reduction in intracellular ROS concentrations and an alteration in the expression patterns of Myf5, Pax7, MyoD1, and myogenin. This modulation was found to be associated with ERK1/2 phosphorylation. In both over-expression and reduced expression of Nox4, we found significant reductions in ERK1/2 phosphorylation. This indicates that cellular differentiation may be affected by Nox4-mediated endogenous ROS generation. These data suggest a new opportunity to study the temporal expression of Nox4 in the generation of ROS accompanying changes in myogenic differentiation. 23578629 Extraction of oak volatiles and ellagitannins compounds and sensory profile of wine aged with French winewoods subjected to different toasting methods: Behaviour during storage. In Merlot wines the evolution of volatile and non-volatile (ellagitannins) compounds extracted from winewoods while being macerated for 12months was studied. Seven types of winewoods subjected to different toasting methods were used. Different rates of extraction, depending mainly on wood compounds origin (toasting or naturally present in wood) and on the watering process during toasting, were observed, which were reflected in sensory differences. Globally, volatile phenols together with aldehydes, phenols and lactones showed an increase with increasing maceration time. Ellagitannins were extracted faster during the first 3months; after 6months an important decrease was observed. Wines with winewoods subjected to watering during toasting were lower in ellagitannins concentrations and demonstrated the greatest decrease of these compounds during maceration. Astringency and bitterness intensified with increasing ellagitannins. Lactones induced positive sweetness sensations, whereas furanic and guaiacol compounds influenced bitterness and astringency. Spicy and vanilla descriptors were related to eugenol, vanillin and other odorous chemicals. 23890575 Evaluation of serological transfusion-transmitted viral diseases and mutliplex nucleic acid testing in malaysian blood donors. Transmission of infectious diseases is a recognized complication of blood transfusion and blood products. Nucleic acid testing (NAT) may contribute to improved efficiency of blood screening and thereby increase the safety margin for transfused blood. Unscreened blood samples from 1388 randomized donors were selected for this study at the Transfusion Medicine Unit of Hospital Universiti Sains Malaysia (HUSM). Informed consent was obtained from all donors and blood samples were tested for HIV, HBV and HCV serologically and by NAT assay. Of the 1,388 tested samples, 1,360 were non-reactive for both assays. Four samples (0.29%) were both serologically and NAT reactive. The remaining twenty-four samples were divided into two groups. Of these, five samples (0.366%) were NAT reactive and nineteen samples (1.37%) were serologically reactive. However, serology confirmation tests run on the latter nineteen samples were non-reactive. Hence, NAT adds benefit of detecting "false positive" reactions via standard serology, the cost of administering NAT also need further consideration and study. 23756351 Methane emissions from MBT landfills. Within the scope of an investigation for the German Federal Environment Agency ("Umweltbundesamt"), the basics for the estimation of the methane emissions from the landfilling of mechanically and biologically treated waste (MBT) were developed. For this purpose, topical research including monitoring results regarding the gas balance at MBT landfills was evaluated. For waste treated to the required German standards, a methane formation potential of approximately 18-24m(3)CH4/t of total dry solids may be expected. Monitoring results from MBT landfills show that a three-phase model with differentiated half-lives describes the degradation kinetics in the best way. This is due to the fact that during the first years of disposal, the anaerobic degradation processes still proceed relatively intensively. In addition in the long term (decades), a residual gas production at a low level is still to be expected. Most of the soils used in recultivation layer systems at German landfills show a relatively high methane oxidation capacity up to 5lCH4/(m(2)h). However, measurements at MBT disposal sites indicate that the majority of the landfill gas (in particular at non-covered areas), leaves the landfill body via preferred gas emission zones (hot spots) without significant methane oxidation. Therefore, rather low methane oxidation factors are recommended for open and temporarily covered MBT landfills. Higher methane oxidation rates can be achieved when the soil/recultivation layer is adequately designed and operated. Based on the elaborated default values, the First Order Decay (FOD) model of the IPCC Guidelines for National Greenhouse Gas Inventories, 2006, was used to estimate the methane emissions from MBT landfills. Due to the calculation made by the authors emissions in the range of 60,000-135,000t CO2-eq./a for all German MBT landfills can be expected. This wide range shows the uncertainties when the here used procedure and the limited available data are applied. It is therefore necessary to generate more data in the future in order to calculate more precise methane emission rates from MBT landfills. This is important for the overall calculation of the climate gas production in Germany which is required once a year by the German Government. 23697572 A multiepitope fusion antigen elicits neutralizing antibodies against enterotoxigenic Escherichia coli and homologous bovine viral diarrhea virus in vitro. Diarrhea is one of the most important bovine diseases. Enterotoxigenic Escherichia coli (ETEC) and bovine viral diarrhea virus (BVDV) are the major causes of diarrhea in calves and cattle. ETEC expressing K99 (F5) fimbriae and heat-stable type Ia (STa) toxin are the leading bacteria causing calf diarrhea, and BVDV causes diarrhea and other clinical illnesses in cattle of all ages. It is reported that maternal immunization with K99 fimbrial antigens provides passive protection to calves against K99 fimbrial ETEC and that BVDV major structural protein E2 elicits antibodies neutralizing against BVDV viral infection. Vaccines inducing anti-K99 and anti-STa immunity would protect calves more effectively against ETEC diarrhea, and those also inducing anti-E2 neutralizing antibodies would protect calves and cattle against diarrhea caused by both ETEC and BVDV. In this study, we used the ETEC K99 major subunit FanC as a backbone, genetically embedded the STa toxoid STaP12F and the most-antigenic B-cell epitope and T-cell epitope predicted from the BVDV E2 glycoprotein into FanC for the multivalent antigen FanC-STa-E2, and examined immunogenicity of this multivalent antigen to assess vaccine potential against bovine diarrhea. Mice intraperitoneally (i.p.) immunized with this multivalent antigen developed anti-K99, anti-STa, and anti-BVDV antibodies. Moreover, elicited antibodies showed neutralization activities, as they inhibited adherence of K99 fimbrial E. coli, neutralized STa toxin, and prevented homologous BVDV viral infection in vitro. Results from this study suggest that this multiepitope fusion antigen can potentially be developed as a vaccine for broad protection against bovine diarrhea and that the multiepitope fusion strategy may be generally applied for multivalent vaccine development against heterogeneous pathogens. 23642249 Engineered culture models for studies of tumor-microenvironment interactions. Heterogeneous microenvironmental conditions play critical roles in cancer pathogenesis and therapy resistance and arise from changes in tissue dimensionality, cell-extracellular matrix (ECM) interactions, soluble factor signaling, oxygen as well as metabolic gradients, and exogeneous biomechanical cues. Traditional cell culture approaches are restricted in their ability to mimic this complexity with physiological relevance, offering only partial explanation as to why novel therapeutic compounds are frequently efficacious in vitro but disappoint in preclinical and clinical studies. In an effort to overcome these limitations, physical sciences-based strategies have been employed to model specific aspects of the cancer microenvironment. Although these strategies offer promise to reveal the contributions of microenvironmental parameters on tumor initiation, progression, and therapy resistance, they, too, frequently suffer from limitations. This review highlights physicochemical and biological key features of the tumor microenvironment, critically discusses advantages and limitations of current engineering strategies, and provides a perspective on future opportunities for engineered tumor models. 23499543 Serum homocysteine and methylmalonic acid concentrations in Chinese Shar-Pei dogs with cobalamin deficiency. Cobalamin deficiency is suspected to be hereditary in Chinese Shar-Pei dogs (Shar-Peis), and inherited causes of cobalamin deficiency may affect the cellular processing of cobalamin. In humans, a defect of the two main cobalamin-dependent intracellular enzymes (i.e., methionine synthase and methylmalonyl-CoA mutase) may lead to hyperhomocysteinemia and hypermethylmalonic acidemia. The aim of this retrospective study was to evaluate serum homocysteine (HCY) and methylmalonic acid (MMA) concentrations in cobalamin-deficient Shar-Peis and dogs of six other breeds. Serum samples (n=297) from cobalamin-deficient dogs (Shar-Peis, German Shepherd dogs, Labrador Retrievers, Yorkshire Terriers, Boxers, Cocker Spaniels, and Beagles) were analyzed for serum HCY and MMA concentrations. A Fisher's exact test was used to evaluate if cobalamin deficiency in Shar-Peis is associated with hyperhomocysteinemia. Serum HCY and MMA concentrations were higher in cobalamin-deficient Shar-Peis compared to cobalamin-deficient dogs of the six other breeds (P<0.0001). Hyperhomocysteinemia was associated with cobalamin deficiency in Shar-Peis (P=0.009). In addition, serum HCY and MMA concentrations did not differ between cobalamin-deficient German Shepherd dogs with and without exocrine pancreatic insufficiency (EPI), a potential cause of secondary cobalamin deficiency. These findings suggest that the function of the two intracellular cobalamin-dependent enzymes is impaired in Shar-Peis with cobalamin deficiency. 23615162 Antiatherosclerotic effects of the novel Angiotensin receptor antagonist fimasartan on plaque progression and stability in a rabbit model: a double-blind placebo-controlled trial. To evaluate the effect of the novel angiotensin receptor blocker Fimasartan on the development of atherosclerosis and plaque stabilization in an animal model. Twenty-four rabbits received an aortic balloon injury from 30 cm to a level just above the aortic valve to the iliac bifurcation using 3 Fr Fogarty catheters on third day of the experiment, followed by a 1% cholesterol diet for 8 weeks. The rabbits were randomized to receive placebo or 3 or 6 mg·kg·d Fimasartan. The study was double blinded. The rabbits started receiving their medications 2 days before the aortic balloon injury and treatment continued. Atherosclerosis burden was determined by calculating the intima-media ratio of the infrarenal portion of the aorta because the bulk of the atherosclerotic burden was limited to the infrarenal region. The frequency of plaque disruption with thrombosis and the proportions of the plaques that were occupied by macrophages, smooth muscle cells, and collagen were determined. Relative to the placebo group, the Fimasartan-treated rabbits had less atherosclerosis [intima-media ratio (mean ± SEM) of 1.14 ± 0.21 vs. 1.51 ± 0.26, P = 0.005], fewer disrupted plaques with thrombi (3 of 16 vs. 5 of 8, P = 0.047), lower proportion of macrophages (17.5% ± 2.5% vs. 26% ± 3.5%, P = 0.03), higher proportion of smooth muscle cells (43.5% ± 8.3% vs. 11.9% ± 2.1%, P = 0.001), and higher proportion of collagen (34.3% ± 6.4% vs. 19.7% ± 2.1%, P = 0.02). These results show that the newly developed angiotensin receptor blocker, Fimasartan, attenuated atherosclerosis progression and reduced macrophage accumulation in the rabbit aortic plaques. 23806231 A dominant adenocarcinoma with multifocal ground glass lesions does not behave as advanced disease. Invasive lung adenocarcinomas increasingly present with synchronous, multifocal, in situ lesions that appear as ground glass opacities (GGOs). The optimal approach in this circumstance (often nonsmokers) remains unclear. We evaluated a general strategy of anatomic resection of the dominant tumor (DT) and wedge resection of accessible ipsilateral GGOs. This is a retrospective review of 39 patients with suspected multifocal in situ adenocarcinomas and 1 DT in a predominantly Caucasian population. Mean follow-up is 30.7 months. Forty-nine percent of patients had no or minimal smoking history; 21% were Asian. The resected DT was pathologically "bronchioloalveolar carcinoma" (26%), minimally invasive adenocarcinoma (5%), adenocarcinoma with bronchioloalveolar features (41%), or moderate well-differentiated adenocarcinoma (28%). The p stage of the DT was IA in 20, IB in 15, and IIA in 4, with mean diameter of 2.6 cm. Thirty-two patients (82%) underwent anatomic resection of the DT; 7 (18%) underwent wedge resection. The mean number of GGOs present initially was 2.7 (range, 1 to 7) with a 5.2-mm mean diameter. An unresected nodule increased in size during follow-up in only 9 patients (23%). The mean diameter growth among these was 3.2 mm, with mean doubling time of 49 months. New GGOs (range, 1 to 8) developed in 16 patients (41%), all of which remained at 7 mm or less. Distant metastasis developed in 2 patients (5.2%); only 1 patient has required intervention for progression of a GGO. The overall survival is 100%. Patients with limited, multifocal, in situ adenocarcinomas and a clinical N0 DT enjoy prolonged survival with generally anatomic resection of the DT and wedge resection of accessible GGOs. These patients should not be considered to harbor T4 or M1a disease. 22889207 New precursor of tetraterpenoids from the soft coral Sarcophyton glaucum. One new precursor of tetraterpenoids, Sarglaucol (1), along with eight known compounds have been isolated from the soft coral Sarcophyton glaucum collected from the Sanya Bay, Hainan Island, China. Their structures were elucidated through spectroscopic techniques including 1D- and 2D-NMR, and their relative configurations were also assigned by NMR and NOESY analysis. Compounds 1 showed weak antitumour activities. 23834914 Toxicity assessment of Leonuri Herba aqueous extract orally administered to rats for 13 consecutive weeks. The Leonuri Herba has been traditionally used for women's disease in Asian countries. The objective of the present study was to evaluate the subchronic toxicity of Leonuri Herba aqueous extract in male and female F344 rats. Leonuri Herba aqueous extract was administered orally once daily at dose levels of 0, 125, 250, 500, 1000 and 2000mg/kg/day for 13 weeks. Toxicological assessment was performed including mortality, clinical signs, body and organ weights, food consumption, ophthalmology, urinalysis, hematology, serum chemistry, gross findings and histopathologic examination. There were no treatment related differences in clinical signs, urinalysis, hematology and serum chemistry, except for a histopathologic examination. The squamous cell hyperplasia in the forestomach was observed in both sexes of rats given 2000mg/kg/day of Leonuri Herba aqueous extract. In conclusion, the NOAEL (No Observed Adverse Effect Level) for Leonuri Herba aqueous extract was determined as 1000mg/kg/day in both sexes of rats under the present experimental conditions. And the acceptable daily intake value for Leonuri Herba aqueous extract was calculated to be 10mg/kg body weight per day using a safety factor of 100 to the NOAEL. 23745637 S100A11 is involved in the regulation of the stability of cell cycle regulator p21(CIP) (1/) (WAF) (1) in human keratinocyte HaCaT cells. The cyclin-dependent kinase inhibitor p21(CIP1/WAF1) is a regulatory factor of the cell cycle. Its transcriptional activation and protein stability are tightly controlled by several distinct mechanisms. S100A11 is a member of the S100 family of Ca(2+) -binding proteins involved in several biological processes, including cell cycle progression and signal transduction. In the present study, we show that down-regulation of S100A11 results in the reduction of p21 protein in human HaCaT keratinocytes. It appears that a ubiquitin-independent proteasomal degradation process is involved in p21 degradation in S100A11 down-regulated cells. The application of a proteasome inhibitor stabilized p21 protein in these cells. Analysis of distinct signal transduction pathways revealed a disturbed phosphatidylinositol-3-kinase/Akt pathway after S100A11 knockdown. We determined that the glycogen synthase kinase-3, which is negatively regulated by phosphatidylinositol 3-kinase/Akt, was activated in cells possessing knocked-down S100A11 and appears to be involved in p21 protein destabilization. The application of a specific inhibitor of glycogen synthase kinase 3 resulted in an increase of the p21 protein level in S100A11 down-regulated HaCaT cells. Glycogen synthase kinase 3 is able to phosphorylate p21 at T57, which induces p21 proteasomal turnover. Mutation of the glycogen synthase kinase 3 site threonine 57 into alanine (T57A) stabilizes p21 in HaCaT cells lacking S100A11. Beside decreased p21 protein, down-regulation of S100A11 triggered the induction of apoptosis in HaCaT cells. These observations suggest that S100A11 is involved in the maintenance of p21 protein stability and appears to function as an inhibitor of apoptosis in human HaCaT keratinocyte cells. Thus, the data shed light on a novel pathway regulating p21 protein stability. 23811345 Extensive evaluations of the cytotoxic effects of gold nanoparticles. Many in vitro studies have revealed that the interference of dye molecules in traditional nanoparticle cytotoxicity assays results in controversial conclusions. The aim of this study is to establish an extensive and systematic method for evaluating biological effects of gold nanoparticles in mammalian cell lines. We establish the cell-impedance measurement system, a label-free, real-time cell monitoring platform that measures electrical impedance, displaying results as cell index values, in a variety of mammalian cell lines. Cytotoxic effects of gold nanoparticles are also evaluated with traditional in vitro assays. Among the six cell lines, gold nanoparticles induce a dose-dependent suppression of cell growth with different levels of severity and the suppressive effect of gold nanoparticles was indirectly associated with their sizes and cellular uptake. Mechanistic studies revealed that the action of gold nanoparticles is mediated by apoptosis induction or cell cycle delay, depending on cell type and cellular context. Although redox signaling is often linked to the toxicity of nanoparticles, in this study, we found that gold nanoparticle-mediated reactive oxygen species generation was not sustained to notably modulate proteins involved in antioxidative defense system. The cell-impedance measurement system, a dye-free, real-time screening platform, provides a reliable analysis for monitoring gold nanoparticle cytotoxicity in a variety of mammalian cell lines. Furthermore, gold nanoparticles induce cellular signaling and several sets of gene expression to modulate cellular physical processes. The systematic approach, such as cell-impedance measurement, analyzing the toxicology of nanomaterials offers convincing evidence of the cytotoxicity of gold nanomaterials. 23544368 Pediatric patients with asthma: a high-risk population for subsequent hospitalization. Objectives. Asthma is one of the most common chronic conditions among children and is one of the leading causes for pediatric hospitalizations. More evidence is needed to clarify the risks of repeat hospitalization and the underlying factors contributing to adverse health outcomes among pediatric patients hospitalized with asthma. The purpose of this study was to examine the risk of subsequent hospitalizations among pediatric patients hospitalized with asthma compared to a reference cohort of children hospitalized for all other diagnoses. Methods. The Washington State (WA) Comprehensive Hospital Abstract Reporting System (CHARS) was used to obtain data for the study. Data describing 81,946 hospitalized pediatric patients admitted from 2004 to 2008 were available. The risk of subsequent hospitalization among children admitted for asthma as compared to a reference cohort was examined. Results. The asthma cohort had a 33% (HR = 1.33 [99% confidence interval (CI) 1.21-1.46]; p < .001) increased risk of subsequent hospitalization from 2004 to 2008. Children in the asthma cohort under the age of 13 years demonstrated a significant increased risk of subsequent hospitalization as compared to the age-matched reference cohort of children without asthma. Those in the asthma cohort who were 3-5 years old demonstrated the highest risk (50%) of subsequent hospitalization (HR = 1.50 [99% CI 1.23-1.83]; p < .001). Conclusions. Study results can be utilized in the development of appropriate interventions aimed at preventing and reducing hospital admissions, improving patient care, decreasing overall costs, and lessening complications among pediatric patients with asthma. 23600667 Polymer-based protein engineering can rationally tune enzyme activity, pH-dependence, and stability. The attachment of inert polymers, such as polyethyleneglycol, to proteins has driven the emergence of a multibillion dollar biotechnology industry. In all cases, proteins have been stabilized or altered by covalently coupling the pre-existing polymer to the surface of the protein. This approach is inherently limited by a lack of exquisite control of polymer architecture, chain length, site and density of attachment. Using a novel water-soluble atom transfer radical polymerization initiator, we have grown temperature- and pH-responsive polymers from the surface of a model protein, the enzyme chymotrypsin. Poly(2-(dimethylamino)ethyl methacrylate) changes in conformation with altered temperature and pH. Growing the polymer from the surface of chymotrypsin we were able to demonstrate that changes in temperature or pH can change predictably the conformation of the polymer surrounding the enzyme, which in turn enabled the rational tailoring of enzyme activity and stability. Using what we now term "Polymer-Based Protein Engineering" we have increased the activity and stability of chymotrypsin by an order of magnitude at pH's where the enzyme is usually inactive or unstable. 23818602 Rickettsia Sca2 has evolved formin-like activity through a different molecular mechanism. Sca2 (surface cell antigen 2) is the only bacterial protein known to promote both actin filament nucleation and profilin-dependent elongation, mimicking eukaryotic formins to assemble actin comet tails for Rickettsia motility. We show that Sca2's functional mimicry of formins is achieved through a unique mechanism. Unlike formins, Sca2 is monomeric, but has N- and C-terminal repeat domains (NRD and CRD) that interact with each other for processive barbed-end elongation. The crystal structure of NRD reveals a previously undescribed fold, consisting of helix-loop-helix repeats arranged into an overall crescent shape. CRD is predicted to share this fold and might form together with NRD, a doughnut-shaped formin-like structure. In between NRD and CRD, proline-rich sequences mediate the incorporation of profilin-actin for elongation, and WASP-homology 2 (WH2) domains recruit actin monomers for nucleation. Sca2's α-helical fold is unusual among Gram-negative autotransporters, which overwhelmingly fold as β-solenoids. Rickettsia has therefore "rediscovered" formin-like actin nucleation and elongation. 23815824 Experimental model of equine alveolar macrophage stimulation with TLR ligands. Pulmonary diseases are common in horses and have a major economic impact on the equine industry. Some of them could be associated with an inadequate immune response in the lung, but methods to evaluate this response in horses are lacking. The aim of this study was to develop and validate an experimental model that could be applied in several physiological and pathological conditions to assess the innate immune response of equine pulmonary cells. Equine alveolar macrophages (AMs) obtained from bronchoalveolar lavages were isolated from other cells by adhesion. TLR2, 3, and 4 expression in AMs was studied and their responses to commercial ligands (respectively FSL-1, Poly(I:C), and LPS) were evaluated after determination of the appropriate dose and time of incubation. TLR responses were assessed by measuring cytokine production using (1) gene expression of TNFα, IFNβ, Il-1β, and IFNα by qPCR (indirect method); and (2) cytokine production for TNFα and IFNβ by ELISA (direct method). TLR 2, 3, and 4 were expressed by AMs. TLR 2 stimulation with 10ng/mL of FSL-1 during 3h significantly increased IL-1β and TNFα gene expression. TLR 3 stimulation with 1000ng/mL of Poly(I:C) during 1h increased IFNβ, IFNα, Il-1β and TNFα expression. TLR 4 stimulation with 100ng/mL of LPS during 3h increased TNFα, IFNβ, and Il-1β expression. Results obtained by ELISA quantification of TNFα and IFNβ produced by AMs following stimulation during 6h were similar: FSL-1 increased TNFα production but not IFNβ, Poly(I:C) and LPS increased production of IFNβ and TNFα. In conclusion, pulmonary innate immunity of horses can be assessed ex vivo by measuring cytokine production following stimulation of AMs with TLR agonists. This experimental model could be applied under several conditions especially to improve the understanding of equine respiratory disease pathogenesis, and to suggest novel therapeutic opportunities. 23969833 Microscopy ambient ionization top-down mass spectrometry reveals developmental patterning. There is immense cellular and molecular heterogeneity in biological systems. Here, we demonstrate the utility of integrating an inverted light microscope with an ambient ionization source, nanospray electrospray desorption ionization, attached to a high-resolution mass spectrometer to characterize the molecular composition of mouse spinal cords. We detected a broad range of molecules, including peptides and proteins, as well as metabolites such as lipids, sugars, and other small molecules, including S-adenosyl methionine and glutathione, through top-down MS. Top-down analysis revealed variation in the expression of Hb, including the transition from fetal to adult Hb and heterogeneity in Hb subunits consistent with the genetic diversity of the mouse models. Similarly, temporal changes to actin-sequestering proteins β-thymosins during development were observed. These results demonstrate that interfacing microscopy with ambient ionization provides the means to perform targeted in situ ambient top-down mass spectral analysis to study the pattern of proteins, lipids, and sugars in biologically heterogeneous samples. 23477576 Understanding HIV transmission risk behavior among HIV-infected South Africans receiving antiretroviral therapy: An Information-Motivation-Behavioral Skills Model analysis. Objective: The current study applied the Information-Motivation-Behavioral Skills (IMB) model (Fisher & Fisher, 1992; Fisher & Fisher, 1993) to identify factors associated with human immunodeficiency virus (HIV) transmission risk behavior among HIV-infected South Africans receiving antiretroviral therapy (ART), a population of considerable significance for curtailing, or maintaining, South Africa's generalized HIV epidemic. Methods: HIV prevention information, HIV prevention motivation, HIV prevention behavioral skills, and HIV transmission risk behavior were assessed in a sample of 1,388 South Africans infected with HIV and receiving ART in 16 clinics in KwaZulu-Natal, South Africa. Results: Findings confirmed the assumptions of the IMB model and demonstrated that HIV prevention information and HIV prevention motivation work through HIV prevention behavioral skills to affect HIV transmission risk behavior in this population. Subanalyses confirmed these relationships for HIV transmission risk behavior overall and for HIV transmission risk behavior with partners perceived to be HIV-negative or HIV-status unknown. A consistent pattern of gender differences showed that for men, HIV prevention information and HIV prevention motivation may have direct links with HIV preventive behavior, whereas for women, the effect of HIV prevention motivation works through HIV prevention behavioral skills to affect HIV preventive behavior. Conclusion: These IMB model-based findings suggest directions for HIV prevention interventions with South African men and women living with HIV and on ART as an important component of overall strategies to contain South Africa's generalized HIV epidemic. (PsycINFO Database Record (c) 2013 APA, all rights reserved). 23726343 Design, synthesis and biological evaluation of novel estrogen-derived steroid metal complexes. A new series of estrogen-derived metal complexes were synthesized and characterized. The functionalized estrogen receptor ligands were prepared by a four-step synthetic strategy, and then three transition metal Pd, Ni, Zn were introduced readily to give the title metal complexes, in which the squaramide was introduced as ion acceptor for the first time in the development of estrogen-derived metal complexes for estrogen receptor. Upon binding to estrogen receptors, all of the estrogen conjugates exhibited acceptable binding affinity (up to 4.04% relative to estradiol), and in transcription assays, all the compounds are agonists on ERα. Molecular modeling studies suggest a structural basis for the agonist activity of these compounds. 23650280 Chain folding controlled by an isomeric repeat unit: helix formation versus random aggregation in acetylene-bridged carbazole-bipyridine co-oligomers. An unprecedented, positional effect of the isomeric repeat unit on chain folding in donor–acceptor-linked oligomers, which contain alternating bipyridine and carbazole moieties that are connected through an acetylinic linkage, is reported. 4,4′-Linked oligomer 1 adopts an intrachain helical conformation (CD-active) in CHCl3/MeCN (20:80 v/v), whereas oligomer 2, which contains an isomeric 6,6′-linkage, forms interchain randomly coiled aggregates (CD-inactive). The substitution position plays a significant role in controlling the variations in electronic effects and dipole moments around the bipyridyl moiety, which are responsible for this observed phenomenon. Two model compounds of oligomers 1 and 2 (3 and 4, respectively) were prepared and their properties were compared. A systematic investigation of the photophysical and CD properties of these structures, as well as theoretical studies, support our conclusions. 23812632 Curcumin protects the developing lung against long-term hyperoxic injury. Curcumin, a potent anti-inflammatory and antioxidant agent, modulates peroxisome proliferator-activated receptor-γ signaling, a key molecule in the etiology of bronchopulmonary dysplasia (BPD). We have previously shown curcumin's acute protection against neonatal hyperoxia-induced lung injury. However, its longer-term protection against BPD is not known. Hypothesizing that concurrent treatment with curcumin protects the developing lung against hyperoxia-induced lung injury long-term, we determined if curcumin protects against hyperoxic neonatal rat lung injury for the first 5 days of life, as determined at postnatal day (PND) 21. One-day-old rat pups were exposed to either 21 or 95% O2 for 5 days with or without curcumin treatment (5 mg/kg) administered intraperitoneally one time daily, following which the pups grew up to PND21 in room air. At PND21 lung development was determined, including gross and cellular structural and functional effects, and molecular mediators of inflammatory injury. To gain mechanistic insights, embryonic day 19 fetal rat lung fibroblasts were examined for markers of apoptosis and MAP kinase activation following in vitro exposure to hyperoxia for 24 h in the presence or absence of curcumin (5 μM). Curcumin effectively blocked hyperoxia-induced lung injury based on systematic analysis of markers for lung injury (apoptosis, Bcl-2/Bax, collagen III, fibronectin, vimentin, calponin, and elastin-related genes) and lung morphology (radial alveolar count and alveolar septal thickness). Mechanistically, curcumin prevented the hyperoxia-induced increases in cleaved caspase-3 and the phosphorylation of Erk1/2. Molecular effects of curcumin, both structural and cytoprotective, suggest that its actions against hyperoxia-induced lung injury are mediated via Erk1/2 activation and that it is a potential intervention against BPD. 23373649 The GABA A receptor subunits heterologously expressed in Xenopus oocytes. The γ-aminobutyric acid (GABA) A receptor is composed of a variety of subunits and combinations and shows a characteristic distribution in the CNS. To date, 20 subunits of the GABA A receptor have been cloned: α1-6, β1-4, γ1-3, δ, π, ε , Θ, and ρ1-3. Oocyte of Xenopus laevis is one of the most frequently used heterologous expression systems, which are used to design and analyze specific combinations of GABA A receptor subunits. In oocytes, a certain GABA A receptor function is studied only by comparing the amplitude of the response to GABA and other drugs by physiological and pharmacological methods. According to the studies on Xenopus laevis oocytes, the α1β2γ2S receptor combination is mostly used. The α1-containing receptors mediate sedative and anticonvulsant acts. The results of studies on oocytes show that PKA, NKCC1, P2X3 receptors, and GABA A receptor-associated protein, etc., are existing systems that show different reactivity to the GABA A receptors. The GABA A receptor subunits contain distinct binding sites for BZDs, neurosteroids, general anesthetics, etc., which are responsible for the numerous functions of the GABA A receptor. A variety of other drugs, such as topiramate, TG41, (+)- and (-)-borneol, apigenin, and 6-methylflavone could also have modulatory effects on the GABA A receptors. Some of the different models and hypotheses on GABA A receptor structure and function have been achieved by using the two-electrode voltage clamp method in oocytes. 23906994 Substance use disorders increase the odds of subsequent mood disorders. There is a well-known association between mood disorders and substance use disorders (SUD), but little research has been conducted on SUDs as risk factors for the development of subsequent mood disorders. We analyzed data from the National Comorbidity Survey Replication study. Diagnoses were determined using DSM-IV criteria. Odds ratios (aORs) of subsequently developing mood disorders were adjusted for age, sex and race/ethnicity. Data from 5217 individuals were included (6.6% male; mean age 45.3 years; 72.6% White, 11.2% Black, 12.5% Hispanic and 3.7% other). Subsequent mood disorders developed in 26.4% of individuals with primary adolescent-onset SUD (12-17 years), 21.7% of those with SUD onset at 18-25 years, and 14.0% of those with SUD onset between the ages of 26 and 34 years. The mean lagtime between SUD onset and development of a mood disorder was about 11 years. Controlling for demographic variables, the aORs of developing a mood disorder in these three age groups were 2.44, 3.65, and 3.25. Substance dependence was associated with higher odds of mood disorders than was abuse. Among the specific mood disorders, the increased odds of developing bipolar disorder were particularly high among individuals with drug dependence. Individuals with adolescent and young adult-onset SUD had increased odds of developing a secondary mood disorder. This indicates that adolescents and young adults with SUD should be closely monitored for both positive and negative mood symptoms. SUD treatment and aftercare offer opportunities for the early identification of secondary mood disorders. 23903542 Molecular epidemiology of Clostridium difficile infection in a major Chinese hospital: an under recognised problem in Asia? BackgroundClostridium difficile infection (CDI) is almost unrecognised in mainland China. We have undertaken a study in a large Chinese teaching hospital in Changsha, Hunan, China to identify cases of CDI, record patient characteristics and define the molecular epidemiology with respect to ribotype distribution and cross infection.MethodsWe examined a faecal sample from 70 hospitalised patients between April 2009 and February 2010 with diarrhoea who were receiving or had received antibiotics within the last six weeks. Clinical information was collected and the samples cultured for C. difficile retrospectively. Isolates were ribotyped and MLVA sub typing performed on clusters of the same ribotype.ResultsThe mean age of patients from whom C. difficile was cultured was 58 years with only 4/21 patients >65years. All patients with a single exception had received a third generation cephalosporin and/or a quinolone antibiotic. Twenty one isolates of C. difficile were recovered and seven different ribotypes identified, the dominant types being: 017 (48%), 046 (14%) and 012 (14%). We identified two clusters of cross infection by indistinguishable isolates of ribotype 017 with evidence of spread both within and between wardsConclusionsWe have identified CDI as a possibly significant problem in a large Chinese hospital with cross infection and a distinct ribotype distribution. CDI may be under recognised in China and further epidemiological studies across the country together with the introduction of routine diagnostic testing are needed to ascertain the size of this potentially significant problem. 22994918 Cross-sectional and longitudinal associations of functional and health status with institutional care use: results from the Survey of Health and Living Status of the Elderly in Taiwan. This study evaluated the cross-sectional and longitudinal associations of functional and health status with institutional care, and examined determinants of institutional care use over time. Data of this study were obtained from the Survey of Health and Living Status of the Elderly in Taiwan (SHLSET), which was launched in 1989 and involved a nationally representative sample of nearly-old and old Taiwanese. The baseline data in this present study were collected in 1999, and followed in 2003 and 2007. Participants with institutional care use had a higher activities of daily living (ADL) score, more self-reported diseases and poorer self-reported health status than participants without institutional care use (all P<0.05). Cross-sectional analysis showed that a higher ADL score, having heart diseases and having a stroke were positively associated with institutional care use (P<0.05); whereas the number of self-reported diseases and poor self-reported health status were not associated with institutional care use. Longitudinal analysis showed that increased ADL scores and the number of self-reported diseases over 4- and 8 years were associated with an increased likelihood of subsequent institutional care use (all P<0.05). Worsening health status over 4 years was associated with an increased likelihood of subsequent institutional care use, but this association did not exist over 8 years. Only ADL and ADL deterioration over time are cross-sectionally and longitudinally associated with increased institutional care use. Declining functional status is a major determinant of institutional care use for Taiwanese aged over 53 years. 23806795 Frequency of EGFR and KRAS mutations in patients with non small cell lung cancer by racial background: Do disparities exist? Mutations in EGFR and KRAS can impact treatment decisions for patients with NSCLC. The incidence of these mutations varies, and it is unclear whether there is a decreased frequency among African Americans (AfAs). We performed a retrospective chart review of 513 NSCLC patients undergoing EGFR and KRAS mutational analysis at the Hospital of the University of Pennsylvania between May 2008 and November 2011. Clinical and pathologic data were abstracted from the patients' electronic medical record. Of 497 patients with informative EGFR mutation analyses, the frequency of EGFR mutation was 13.9%. The frequency of EGFR mutations was associated with race (p<0.001) and was lower in AfA patients compared to Caucasian (C) patients but did not reach statistical significance (4.8% vs. 13.7%, p=0.06). Mean Charlson Comorbidity Index and number of cigarette pack years were significantly lower in patients with EGFR mutations (p=0.01 and p<0.001, respectively). Multivariable logistic regression analysis showed a significant association between race and EGFR mutation (p=0.01), even after adjusting for smoking status (p<0.001) and gender (p=0.03). KRAS mutation (study frequency 28.1%) was not associated with race (p=0.08; p=0.51 for Afa vs. C patients), but was more common among smokers (p<0.001) and females (p=0.01). Based on multivariable analysis, even after adjusting for smoking status and gender, we found that race was statistically significantly associated with EGFR mutation, but not KRAS mutational status. To the best of our knowledge, this is the largest single institution series to date evaluating racial differences in EGFR and KRAS mutational status among patients with NSCLC. 23578872 Animal communication: sniffing is about more than just smell. A recent study shows that subordinate rats reduce their rate of sniffing while dominants explore their faces thus delaying dominants' subsequent aggression. Sniffing not only facilitates acquisition of olfactory information, but unexpectedly, also serves as a medium for communication. 23878724 An essential and NSF independent role for α-SNAP in store-operated calcium entry. Store-operated calcium entry (SOCE) by calcium release activated calcium (CRAC) channels constitutes a primary route of calcium entry in most cells. Orai1 forms the pore subunit of CRAC channels and Stim1 is the endoplasmic reticulum (ER) resident Ca(2+) sensor. Upon store-depletion, Stim1 translocates to domains of ER adjacent to the plasma membrane where it interacts with and clusters Orai1 hexamers to form the CRAC channel complex. Molecular steps enabling activation of SOCE via CRAC channel clusters remain incompletely defined. Here we identify an essential role of α-SNAP in mediating functional coupling of Stim1 and Orai1 molecules to activate SOCE. This role for α-SNAP is direct and independent of its known activity in NSF dependent SNARE complex disassembly. Importantly, Stim1-Orai1 clustering still occurs in the absence of α-SNAP but its inability to support SOCE reveals that a previously unsuspected molecular re-arrangement within CRAC channel clusters is necessary for SOCE. DOI:http://dx.doi.org/10.7554/eLife.00802.001. 23727419 Clinical Evaluation of Transcatheter Arterial Chemoembolization with 2-Day-soluble Gelatin Sponge Particles for Hepatocellular Carcinoma-Comparison with Insoluble Gelatin Sponge Particles. To compare therapeutic effect, adverse events, and embolized hepatic artery impairment in transcatheter arterial chemoembolization between Lipiodol plus insoluble gelatin sponge particles (Gelpart) and Lipiodol plus 2-day-soluble gelatin sponge particles (2DS-GSPs). In a single-center, prospective, randomized controlled trial, patients with hepatocellular carcinoma were assigned to the 2DS-GSP group or the Gelpart group. Radiographic response at 3 months per modified Response Evaluation Criteria In Solid Tumors was evaluated as the primary endpoint; secondary endpoints were safety (per Common Terminology Criteria for Adverse Events, version 4.0) within 3 months and hepatic branch artery impairment at the time of repeat chemoembolization (grade 0, no damage; grade I, mild vessel wall irregularity; grade II, overt stenosis; grade III, occlusion of more peripheral branch artery than subsegmental artery; grade IV, occlusion of subsegmental artery). Grade II, III, or IV indicated significant hepatic artery impairment. Thirty-seven patients with 143 nodules were randomized to the 2DS-GSP group and 36 patients with 137 nodules were randomized to the Gelpart group. No significant differences in patient background existed between groups. Target lesion response and overall tumor response in the 2DS-GSP and Gelpart groups were 77.7% versus 76.9% and 78.3% versus 77.8%, respectively, with no significant differences. No significant difference in adverse events existed between groups. Hepatic artery impairment was observed in 5% of patients in the 2DS-GSP group (n = 32) and in 16% in the Gelpart group (n = 33; P< .001). Transcatheter arterial chemoembolization with 2DS-GSPs resulted in the same therapeutic and adverse effects as chemoembolization with Gelpart while causing significantly less hepatic artery impairment. 23315406 Mesorhizobium sangaii sp. nov., isolated from the root nodules of Astragalus luteolus and Astragalus ernestii. Our previous published data indicated that the two rhizobial strains SCAU7(T) and SCAU27, which were isolated from the root nodules of Astragalus luteolus and Astragalus ernestii respectively, in Sichuan Province, China, might be novel species of the genus Mesorhizobium. Their exact taxonomic position was determined in the present study by using polyphasic approaches. Comparative analysis of nearly full-length 16S rRNA gene sequences showed that these strains belonged to the genus Mesorhizobium, with Mesorhizobium ciceri USDA 3383(T), Mesorhizobium loti NZP 2213(T), Mesorhizobium shangrilense CCBAU 65327(T) and Mesorhizobium australicum WSM2073(T) as the closest neighbours (>99 % 16S rRNA gene sequence similarity). Phylogenies of the housekeeping genes atpD and recA confirmed their distinct position, showing low similarity with respect to those of M. loti LMG 6125(T) (96.5 % and 92.3 % similarity respectively), M. ciceri USDA 3383(T) (96.8 % and 93.3 % similarity, respectively), M. shangrilense CCBAU 65327(T) (96.5 % and 92.7 % similarity, respectively) and M. australicum WSM2073(T) (95.4 % and 90.6 % similarity, respectively). The DNA-DNA relatedness values between strain SCAU7(T) and strain SCAU27 were 83.0 %, showing that they belong to the same species. The DNA-DNA relatedness values of SCAU7(T) with M. loti NZP 2213(T), M. ciceri USDA 3383(T) and M. shangrilense CCBAU 65327(T) were 41.1 %, 48.8 % and 23.4 %, respectively, clearly indicating that strain SCAU7(T) represents a novel species. A series of phenotypic and genotypic tests and comparison of cellular fatty acids indicated that the novel group of isolates was distinct from previously described species. Therefore, we propose that strains SCAU7(T) and SCAU27 represent a novel species of the genus Mesorhizobium, Mesorhizobium sangaii sp. nov., with strain SCAU7(T) ( = HAMBI 3318(T) = ACCC 13218(T)) as the type strain. 23959114 Probiotic Dosing of Ruminococcus flavefaciens Affects Rumen Microbiome Structure and Function in Reindeer. Highly cellulolytic bacterial species such as Ruminococcus flavefaciens are regarded essential for the microbial breakdown of cellulose in the rumen. We have investigated the effect of ruminal dosing of R. flavefaciens strain 8/94-32 during realimentation of starved reindeer (males, n = 3). Microbiome function measured as in situ digestion of cellulose and food pellets (percent DMD; dry matter disappearance) decreased after probiotic dosing. Microbial community analyses (>100,000 16S rDNA gene sequences for 27 samples) demonstrated that ruminal dosing influenced the microbiome structure; reflected by increased phylogenetic distances from background samples (unweighted UniFrac analysis) and reduced species diversity and evenness. Despite the inability to detect strain 8/94-32 post-dosing, the relative abundance of its affiliate family Ruminococcaceae remained consistent throughout the trial, whilst a dominant peak in the genus Prevotella and decline in uncharacterized Bacteroidetes (uBacNR) were observed in treatment samples. No clear relationships were observed between the relative abundance of Ruminococcaceae, Prevotella and uBacNR with cellulose DMD; however, Prevotella (negative) and uBacNR (positive) exhibited relationships with pellet DMD. These unexpected effects of ruminal dosing of a cellulolytic bacterium on digestibility are relevant for other studies on rumen manipulation. 23624436 Consumer acceptance of fermented sausages made from boars is not distracted by respective information. This study investigated the impact of two information conditions and two androstenone concentrations on the acceptability of fermented sausages made from boar meat. Two batches of salamis were produced by mixing bellies and lean meat resulting in average androstenone levels of 0.408 μg/g vs. 1.585 μg/g melted fat, respectively. Skatole levels were kept below 0.05 μg/g melted fat in the final products. The consumers were provided with either the information that the products consisted of 100% pork or 100% boar meat. In total, 478 visitors of an animal husbandry fair, assumed to be familiar with the consequences of not castrating male piglets, evaluated the salami following a monadic between-subject design. The information did not significantly affect the hedonic scores. The percentage of dislikes was very low, i.e. 3 vs. 6% (p=0.24) for salami LOW and HIGH, respectively. The batch with lower androstenone content was liked slightly but significantly better (p=0.03). 23877365 Development and characterization of a new cell line CF from caudal fin of knifefish, Chitala chitala (Hamilton-Buchanan). A new cell line was successfully obtained from caudal fin tissue of the economically important freshwater fish Chitala chitala. The cell line was optimally maintained at 28°C in Leibovitz's L-15 supplemented with 20% fetal bovine serum (FBS). The effects of temperature and concentration of FBS on the growth of CF cells were examined. The CF cell line consisted predominantly of fibroblastic-like cells. Moderately low plating efficiencies 8%, 11%, and 17% were observed, with CF cell line in L-15 Medium with 20% FBS. Chromosomal analysis of the cell line revealed a diploid number of 42 chromosomes in C. chitala. Molecular characterization of mitochondrial 16S rRNA and cytochrome oxidase subunit I confirmed the origin of the cell line. The cells were successfully cryopreserved in liquid nitrogen (-196°C) for 6 mo, and more than 85-90% of CF cells were revived. 23942120 R-spondin3 prevents mesenteric ischemia/reperfusion-induced tissue damage by tightening endothelium and preventing vascular leakage. Inflammation and vascular injury triggered by ischemia/reperfusion (I/R) represent a leading cause of morbidity and mortality in a number of clinical settings. Wnt and its homolog partners R-spondins, in addition to regulating embryonic development have recently been demonstrated to serve as wound-healing agents in inflammation-associated conditions. Here we ask whether R-spondins could prevent inflammation-associated tissue damage in ischemic disorders and thus investigate the role of R-spondin3 (R-spo3) in a mouse model of mesenteric I/R. We demonstrate that R-spo3 ameliorates mesenteric I/R-induced local intestinal as well as remote lung damage by suppressing local and systemic cytokine response and deposition of IgM and complement in intestinal tissues. We also show that decreased inflammatory response is accompanied by tightening of endothelial cell junctions and reduction in vascular leakage. We conclude that R-spo3 stabilizes endothelial junctions and inhibits vascular leakage during I/R and thereby mitigates the inflammatory events and associated tissue damage. Our findings uniquely demonstrate a protective effect of R-spo3 in I/R-related tissue injury and suggest a mechanism by which it may have these effects. 23260861 Preoperative localization of parathyroid adenomas using 4-dimensional computed tomography: a pictorial essay. Accurate preoperative localization is the key to successful parathyroid surgery in the era of minimally invasive parathyroid surgery. This article presents and discusses the embryologic basis of parathyroid gland and ectopic location and different imaging modalities helpful in diagnosing and localizing parathyroid adenomas and/or hyperplasia. We also aim to review the current surgical concepts in treatment of parathyroid adenomas and/or hyperplasia, the utility of 4-dimensional computed tomography for accurate preoperative localization of hyperfunctioning parathyroid glands, imaging classification of adenomas and/or hyperplasia, and, finally, present some of the limitations of 4-dimensional computed tomography. 23773439 Vasoactive-inotropic score after pediatric heart transplant: A marker of adverse outcome. VIS, a quantitative index of pressor support, has been shown to be a predictor of morbidity and mortality in infants younger than six months who underwent CPB. Data on its prognostic utility following pediatric OHT are lacking. This study compared clinical outcomes in children with differential VIS after pediatric OHT. A retrospective cohort study of 51 consecutive heart transplants from 2004 to 2011 was performed at a pediatric tertiary care facility. Peak VIS was computed within initial 24 and 48 h after OHT and was weighted for peak dose and administration of any or all of six pressors. Patients with peak VIS ≥ 15 constituted high VIS group. Children who persistently required a higher magnitude of pressor support for the first 48 h after OHT, as reflected by high peak VIS, had significantly longer ICU stay (30.2 vs. 15.9 days, p = 0.01), pressor (11.4 vs. 6.8 days, p = 0.02) and ventilatory durations (12.4 vs. 5.9 days, p = 0.05), and higher rates of short-term morbidities. Patients with longer CPB (213 vs. 153 min, p = 0.005) time have higher peak VIS. High peak VIS at 48 h is an effective, yet simple clinical marker for adverse outcomes in pediatric OHT recipients. 23686428 Is premorbid glenoid anatomy altered in patients with glenohumeral osteoarthritis? Restoration of native, premorbid glenoid anatomy may be a goal in component placement during total shoulder arthroplasty. However, if patients with unilateral glenohumeral osteoarthritis are predisposed to the development of arthritis owing to abnormal native glenoid anatomy, this recommendation may be inappropriate. The purpose of this study was to determine if patients with glenohumeral osteoarthritis have abnormal premorbid glenoid version or inclination, thereby predisposing them to subsequent glenoid disorders. We specifically tested whether: (1) premorbid glenoid version or inclination in the pathologic shoulder of patients with unilateral osteoarthritis, as determined by the glenoid vault model, is different from glenoid version or inclination in the contralateral nonpathologic shoulder of these patients; (2) there are differences between glenoid version or inclination in normal cadaver shoulders and the nonpathologic side of patients with unilateral osteoarthritis; and (3) there are differences between glenoid version or inclination in normal cadaver shoulders and the premorbid glenoid version and inclination in the pathologic shoulder of patients with unilateral osteoarthritis, as determined by the glenoid vault model. Bilateral CT scans were obtained in 27 patients with unilateral glenohumeral osteoarthritis. Thirty normal cadaver control shoulders also underwent CT scans. Premorbid glenoid version and inclination in the pathologic shoulder, as measured by the glenoid vault model, were compared with the contralateral nonpathologic shoulder and the normal cadaver control shoulders. Glenoid version and inclination of the normal shoulders were compared with the nonpathologic side from patients with unilateral osteoarthritis. Measurements were made by two different methods using three-dimensional surgical simulation software: (1) a direct measurement technique and (2) measurements derived from placement of a glenoid vault model. Mean differences in these parameters were compared between shoulder groups using paired and unpaired Student's t-tests. Premorbid glenoid version and inclination in the pathologic shoulder as measured by the vault model averaged -7° (SD, 5) and 10° (SD, 6), respectively, compared with -7° (SD, 5) and 12° (SD, 6) as directly measured on the nonpathologic side, and -7° (SD, 4) and 12° (SD, 5) as directly measured in the normal cadaver control shoulders. There were no differences in glenoid version or inclination between the normal shoulders and the nonpathologic side of patients with unilateral osteoarthritis or between these shoulders and the premorbid version and inclination of the arthritic shoulder as measured by the vault model. Patients with glenohumeral osteoarthritis do not appear to have abnormal premorbid glenoid retroversion or inclination. The glenoid vault model can be used to determine premorbid glenoid version and inclination. The glenoid vault model may be a clinically useful tool to estimate patient-specific premorbid glenoid anatomy, which may help in preoperative or intraoperative surgical planning for total shoulder arthroplasty. Level III, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. 23911070 Engineering multi-stage nanovectors for controlled degradation and tunable release kinetics. Nanovectors hold substantial promise in abating the off-target effects of therapeutics by providing a means to selectively accumulate payloads at the target lesion, resulting in an increase in the therapeutic index. A sophisticated understanding of the factors that govern the degradation and release dynamics of these nanovectors is imperative to achieve these ambitious goals. In this work, we elucidate the relationship that exists between variations in pore size and the impact on the degradation, loading, and release of multistage nanovectors. Larger pored vectors displayed faster degradation and higher loading of nanoparticles, while exhibiting the slowest release rate. The degradation of these particles was characterized to occur in a multi-step progression where they initially decreased in size leaving the porous core isolated, while the pores gradually increased in size. Empirical loading and release studies of nanoparticles along with diffusion modeling revealed that this prolonged release was modulated by the penetration within the porous core of the vectors regulated by their pore size. 23949296 Oropharyngeal candidiasis and Candida colonization in HIV positive patients in northern India. Oropharyngeal candidiasis (OPC) is the most common opportunistic fungal infection reported in human immunodeficiency virus (HIV) positive patients worldwide. This prospective study was undertaken to investigate OPC and Candida colonization (CC) and their correlation with CD4+ cell counts and antiretroviral therapy (ART) in HIV-positive patients. In total, 190 HIV-positive patients were enrolled for study in three groups as follows: Group A, 90 patients without ART; Group B, 100 patients undergoing treatment with ART; and Group C, 75 HIV-negative control patients. All HIV patients underwent clinical examination and were subjected to CD4+ cell counts. Swabs were collected from the oral cavity of all individuals and plated on Sabouraud's dextrose agar. Identification of Candida species was performed by conventional methods. Candida species were isolated in 84/190 (44.2%) and 20/75 (26.6%) of the HIV-positive subjects and controls respectively (p<0.01). OPC was noted in 21/190 (11%) of the HIV-positive patients. Candida albicans was the most frequently isolated species. Patients with CD4+ cell counts ≤ 200 cells/mm3 were significantly (p<0.001) more frequently colonized (37/63; 58.7%) and infected (18/21; 85.7 %) with Candida species. Candida species was seen in patients with CC and OPC with CD4+cell counts between 201 and 500 (21/63; 33.4% vs 3/21; 14.3%) and > 500 cell/mm3 (5/63; 7.9% versus 0/21 0%) respectively. OPC and Candida colonization occur more frequently in HIV-positive patients with CD4+ cell counts ≤ 200 cell/mm3. ART significantly reduces OPC. C. albicans is the most frequently isolated species in both OPC and colonization, suggesting endogenous infection. 23887955 Accuracy of sonographic diagnosis of superficial masses. Objectives- The purpose of this study was to retrospectively review the diagnostic accuracy of sonography in the evaluation of superficial masses with surgical and histologic findings as the reference standard. Methods- Institutional Review Board approval was obtained, informed consent was waived, and Health Insurance Portability and Accountability Act compliance was maintained. Seventy-two superficial masses in 62 patients were examined sonographically by a single radiologist (reader 1) and subsequently underwent surgical therapy. Three radiologists experienced in sonography, blinded to the original interpretation and surgical findings, retrospectively and independently reviewed the sonographic images and assigned the cases to 1 of 14 diagnostic categories. For all lesions, the rendered diagnosis was compared with the reference standard to determine concordance. For the specific diagnosis of lipoma, sensitivity, specificity, and accuracy were assessed for all readers individually and collectively. Results- Surgery and histolopathologic analysis yielded 39 lipomas, 6 hernias, 4 foreign bodies, 4 hemangiomas, and 19 other nonlipomatous lesions, including 1 malignancy. The rendered diagnosis was concordant with the reference standard in 93% of cases for reader 1 and in 89% of cases for all readers. The sensitivity, specificity, and accuracy for the diagnosis of lipoma were 92%, 100%, and 96% for reader 1 and 96%, 97%, and 96% for all readers. Conclusions- Sonography has high accuracy in the evaluation of superficial masses, particularly lipomas. 23662782 Rituximab therapy for refractory idiopathic scleritis. To report 2 cases of refractory idiopathic scleritis treated with rituximab. Interventional case series. Case 1: A 54-year-old woman, presented with anterior idiopathic scleritis in her right eye. Treatment with systemic steroids was not effective. Intravenous cyclophosphamide was discontinued after an adverse event. Case 2: A 43-year-old woman presented with idiopathic posterior scleritis in her left eye. Initial treatment with steroids was ineffective. In both cases, long-lasting remission without further relapses was achieved after 4 weekly doses (375 mg/m(2)) of rituximab. Rituximab was found to be an effective treatment for refractory idiopathic anterior and posterior scleritis. 22853942 Cusp height in aortic valves. Successful aortic valve repair must normalize cusp and root dimensions. Limited information is available on the normal dimensions of human cusps, in particular the cusp height. The cusp height was measured intraoperatively in 621 patients during aortic valve repair procedures. A tricuspid anatomy was present in 329 patients and bicuspid in 286 patients. In addition, patient age, gender, height, weight, preoperative degree of aortic regurgitation, and aortic dimensions were recorded. The data were analyzed for possible interrelation between the cusp height and clinical variables. In the bicuspid valves, the geometric height of the nonfused cusp ranged from 15 to 30 mm (mean, 23.8 ± 2.0). Significant correlations were found between the cusp height and all clinical variables. In the tricuspid valves, the height of the noncoronary cusp ranged from 14 to 28 mm (mean, 20.7 ± 2.2). The height of the left coronary cusp varied from 12 to 25 mm (mean, 20.0 ± 2.1) and that of the right coronary cusp from 12 to 25 mm (mean, 20.0 ± 2.1). The noncoronary cusp was significantly greater than the left and the right coronary cusp (P = .000). No difference was found between the left and right cusps (P = .513). Significant correlations between the geometric height and clinical parameters were found for most clinical variables, excluding the degree of aortic regurgitation. We found the cusp height was larger than previously published. It shows marked variability and correlates with the clinical variables. These data might serve as the basis for decision making in aortic valve repair. 23799333 Mitigating the allergic effects of fire ant envenomation with biologically based population reduction. To describe the current efforts to use biological control agents to reduce fire ant population levels, thus ultimately reducing the number of human sting and allergic reaction incidents. Climate change and worldwide fire ant expansion will increase the frequency of human encounters and allergenic events, putting additional pressure on the public health sector. Six species of fire ant decapitating flies are now established in the United States. The microsporidium Kneallhazia solenopsae is well established and new fire ant hosts have been identified. The fire ant virus Solenopsis invicta virus 3 shows good potential for use as an environmentally friendly biopesticide because of its virulence and host specificity. During separate founding events in the United States, Australia, mainland China, and Taiwan, fire ants native to South America escaped their native pathogens and parasites. Consequently, fire ant populations in these introduced regions pose a serious public health threat to the human populations by envenomation and subsequent allergic reactions. Specific, self-sustaining biological control agents have been discovered, studied, and released into fire ant populations in the United States in an effort to re-establish an ecological/competitive balance, resulting in reduced fire ant densities and human exposure. 23471771 Providing pastoral care services in a clinical setting to veterans at-risk of suicide. The value of enhanced spiritual wellbeing has largely been overlooked as part of suicide prevention efforts in Veterans. The aim of this qualitative study is to examine the clinical pastoral care services provided by VA Chaplains to Veterans at-risk of suicide. This study was conducted using in-depth interviews with five Chaplains affiliated with a medical center located in upstate New York. This study was able to show that some at-risk individuals do actively seek out pastoral care, demonstrating a demand for such services. In conclusion, a pastoral care framework may already exist in some clinical settings, giving at-risk Veterans the opportunity to access spiritual care. 23632957 PET-based delineation of tumour volumes in lung cancer: comparison with pathological findings. The objective of the study was to validate an adaptive, contrast-oriented thresholding algorithm (COA) for tumour delineation in (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for non-small cell lung cancer (NSCLC) in comparison with pathological findings. The impact of tumour localization, tumour size and uptake heterogeneity on PET delineation results was also investigated. PET tumour delineation by COA was compared with both CT delineation and pathological findings in 15 patients to investigate its validity. Correlations between anatomical volume, metabolic volume and the pathology reference as well as between the corresponding maximal diameters were determined. Differences between PET delineations and pathological results were investigated with respect to tumour localization and uptake heterogeneity. The delineated volumes and maximal diameters measured on PET and CT images significantly correlated with the pathology reference (both r > 0.95, p < 0.0001). Both PET and CT contours resulted in overestimation of the pathological volume (PET 32.5 ± 26.5%, CT 46.6 ± 27.4%). CT volumes were larger than those delineated on PET images (CT 60.6 ± 86.3 ml, PET 48.3 ± 61.7 ml). Maximal tumour diameters were similar for PET and CT (51.4 ± 19.8 mm for CT versus 53.4 ± 19.1 mm for PET), slightly overestimating the pathological reference (mean difference CT 4.3 ± 3.2 mm, PET 6.2 ± 5.1 mm). PET volumes of lung tumours located in the lower lobe were significantly different from those determined from pathology (p = 0.037), whereas no significant differences were observed for tumours located in the upper lobe (p = 0.066). Only minor correlation was found between pathological tumour size and PET heterogeneity (r = -0.24). PET tumour delineation by COA showed a good correlation with pathological findings. Tumour localization had an influence on PET delineation results. The impact of tracer uptake heterogeneity on PET delineation should be considered carefully and individually in each patient. Altogether, PET tumour delineation by COA for NSCLC patients is feasible and reliable with the potential for routine clinical application. 22942363 Epidemiological study of acute poisoning in children: a 5-year retrospective study in the Paediatric University Hospital in Bialystok, Poland. Poisoning among children and youths in the northeastern part of Poland accounted for 25% of the total number of patients admitted to the Hospital Emergency Department of the Paediatric University Hospital of Bialystok. We hypothesise that the epidemiology of poisoned paediatric patients admitted is related to increase in 'designer drugs' (mainly amphetamine- and ecstasy-like psychostimulants, hallucinogens and synthetic cannabinoids ('spice') intake, which became popular 5 years ago in our country. A retrospective chart review of medical records of 489 patients admitted due to poisoning in the 5-year period (2006-2010). The data included: age, sex, place of residence, nature of the substance, causes of poisoning, former use of psychoactive stimulants, accompanying self-mutilation and injuries and length of hospitalisation. Categorical variables were expressed as percentages, and continuous variables as mean and SD. The data were collected in a Microsoft Excel database. Statistical analysis was performed using the Statistical Programme for Social Sciences. Out of 2176 hospitalised children, 489 were admitted because of poisoning. Out of these, 244 (49.9%) were hospitalised due to intoxication by alcohol. Only eight children used designer drugs. The mean age of all patients in our group was 12.86±5.04 years, of which 52.4% were male. Poisoning was intentional in 75.5%, and accidental in 24.5% of cases. Appearance of 'designer drugs' had no significant impact on the number and epidemiology of poisonings in our group. 23740473 Acid-catalyzed liquefaction of bagasse in the presence of polyhydric alcohol. Bagasse was subjected to a liquefaction process with polyethylene glycol/glycerol using sulfuric acid as catalyst. The effects of various liquefaction conditions, such as reaction time, liquefaction temperature, catalyst content, and liquid ratio (liquefaction solvents/bagasse), on the liquefied residue (LR) content and hydroxyl and acid numbers of liquefied products were investigated. The preferred liquefaction condition of bagasse was determined through orthogonal experiments. The results showed that the catalyst content and reaction time have a greater influence than liquid ratio and liquefaction temperature on the percentage of LR. The hydroxyl and acid numbers of the liquefied products were influenced by many factors, including liquefaction temperature, reaction time, acid content, and liquid ratio. The hydroxyl number of liquefied products decreased as the liquefaction reaction progressed, but the acid number of liquefied products increased. Based on the obtained data, the kinetics for liquefaction was modeled using the first-order reaction rate law and the apparent activation energy for the liquefaction of bagasse was estimated to be 38.30 kJ mol(-1). 23914778 Phenotypic and genotypic characterization of meningococcal carriage and disease isolates in Burkina Faso after mass vaccination with a serogroup a conjugate vaccine. The conjugate vaccine against serogroup A Neisseria meningitidis (NmA), MenAfriVac, was first introduced in mass vaccination campaigns of the 1-29-year-olds in Burkina Faso in 2010. The aim of this study was to genetically characterize meningococcal isolates circulating in Burkina Faso before and up to 13 months after MenAfriVac mass vaccination. A total of 1,659 meningococcal carriage isolates were collected in a repeated cross-sectional carriage study of the 1-29-year-olds in three districts of Burkina Faso in 2010 and 2011, before and up to 13 months after mass vaccination. Forty-two invasive isolates were collected through the national surveillance in Burkina Faso in the same period. All the invasive isolates and 817 carriage isolates were characterized by serogroup, multilocus sequence typing and porA-fetA sequencing. Seven serogroup A isolates were identified, six in 2010, before vaccination (4 from carriers and 2 from patients), and one in 2011 from an unvaccinated patient; all were assigned to sequence type (ST)-2859 of the ST-5 clonal complex. No NmA carriage isolate and no ST-2859 isolate with another capsule were identified after vaccination. Serogroup X carriage and disease prevalence increased before vaccine introduction, due to the expansion of ST-181, which comprised 48.5% of all the characterized carriage isolates. The hypervirulent serogroup W ST-11 clone that was responsible for most of meningococcal disease in 2011 and 2012 was not observed in 2010; it appeared during the epidemic season of 2011, when it represented 40.6% of the serogroup W carriage isolates. Successive clonal waves of ST-181 and ST-11 may explain the changing epidemiology in Burkina Faso after the virtual disappearance of NmA disease and carriage. No ST-2859 strain of any serogroup was found after vaccination, suggesting that capsule switching of ST-2859 did not occur, at least not during the first 13 months after vaccination. 23261716 New enzymatic assay for the AKR1C enzymes. The imbalance in expression of the human aldo-keto reductases AKR1C1-AKR1C3 is related to different hormone dependent and independent cancers and some other diseases. The AKR1C1-3 enzymes thus represent emerging targets for the development of new drugs. Currently, various enzymatic assays are used in the search for AKR1C inhibitors, and consequently the results of different research groups are not necessarily comparable. During our recent search for AKR1C inhibitors, we found a cyclopentanol derivative (2-(4-chlorobenzylidene)cyclopentanol, CBCP-ol) and its respective cyclopentanone counterpart (2-(4-chlorobenzylidene)cyclopentanone, CBCP-one) that acted as AKR1C substrates. We determined the kinetic parameters KM, kcat and kcat/KM for oxidation of CBCP-ol and reduction of CBCP-one by AKR1C enzymes in the presence of NAD(+)/NADP(+) and NADH/NADPH, respectively. The catalytic efficiencies for the oxidation of CBCP-ol in the presence of NAD(+) or NADP(+) were in general higher when compared to the catalytic efficiencies for reduction of CBCP-one in the presence of NADH or NADPH. When NADPH was used, as compared to NADH, the reductions of CBCP-one by AKR1C1, AKR1C2 and AKR1C3 were 14-, 51- and 31-fold more efficient, respectively. When comparing to oxidations of the well-known artificial substrates, 1-acenaphthenol and S-tetralol, we observed similar catalytic efficiencies as for CBCP-ol oxidation with NAD(+) and NADP(+). The comparison of CBCP-one reduction with NADPH to reductions of physiological substrates revealed in general higher efficiencies, except for reduction of 9-cis-retinaldehyde by AKR1C3. This NADPH-dependent reduction of CBCP-one was then used to re-evaluate inhibitory potencies of the known inhibitors of the target AKR1C3 and the anti-target AKR1C2, medroxyprogesterone acetate and ursodeoxycholic acid, respectively, showing Ki constants similar to the reported values. Our data thus confirm that the new enzymatic assays with two cyclopentane substrates CBP-ol and CBP-one, and especially reduction of CBCP-one with NADPH, are appropriate for the evaluation of AKR1C inhibitors. 23859024 Women's intentions to breastfeed: a population-based cohort study. Given that intention to breastfeed is a strong predictor of breastfeeding initiation and duration, the objectives of this study were to estimate the population-based prevalence and the factors associated with the intention to breastfeed. Retrospective population-based cohort study. All hospitals in Ontario, Canada (1 April 2009-31 March 2010). Women who gave birth to live, term, singletons/twins. Patient, healthcare provider, and hospital factors that may be associated with intention to breastfeed were analysed using univariable and multivariable regression. Population-based prevalence of intention to breastfeed and its associated factors. The study included 92 364 women, of whom 78 806 (85.3%) intended to breastfeed. The odds of intending to breastfeed were higher amongst older women with no health problems and women who were cared for exclusively by midwives (adjusted OR 3.64, 95% CI 3.13-4.23). Being pregnant with twins (adjusted OR 0.73, 95% CI 0.57-0.94), not attending antenatal classes (adjusted OR 0.58, 95% CI 0.54-0.62), having previous term or preterm births (adjusted OR 0.79, 95% CI 0.78-0.81, and adjusted OR 0.87, 95% CI 0.82-0.93, respectively), and delivering in a level-1 hospital (adjusted OR 0.85, 95% CI 0.77-0.93) were associated with a lower intention to breastfeed. In this population-based study ~85% of women intended to breastfeed their babies. Key factors that are associated with the intention to breastfeed were identified, which can now be targeted for intervention programmes aimed at increasing the prevalence of breastfeeding and improving overall child and maternal health. 23952029 Medulloblastoma invading the transverse sinus. Medulloblastoma is a highly malignant brain tumor of childhood. Although craniospinal dissemination within the subarachnoid space is common, invasion of the dural sinuses is rare. Here, the authors report on a 15-year-old girl who presented with a right cerebellar mass, obstructive hydrocephalus, and radiographic evidence of tumor invasion into the right transverse-sigmoid sinus junction. The patient underwent posterior fossa craniotomy, gross-total resection of the intraparenchymal component of the right cerebellar tumor, and coagulation of the tumor invading the transverse sinus. After pathological confirmation of anaplastic medulloblastoma, the patient underwent craniospinal radiation therapy and high-dose chemotherapy. At 2 years posttreatment, the child was neurologically intact with no radiographic evidence of residual disease or recurrence. The implications for disease prognosis and management are discussed. 23628797 Significant association of urokinase plasminogen activator Pro141Leu with serum lipid profiles in a Japanese population. Urokinase plasminogen activator (uPA) plays important physiological and pathological roles in fibrinolysis, cancer metastasis, and atherosclerosis. One study suggested that uPA also has a major role in cholesterol biosynthesis in humans via its receptor uPAR. Thus, we investigated the associations of functional uPA polymorphism (plasminogen activator, urokinase; PLAU Pro141Leu, rs2227564) with serum lipid profiles in a Japanese cohort. The study included 5152 participants (1465 male, 3687 female; age range, 35-69 years) of the Daiko Study, a part of the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study). Subjects were enrolled at the Daiko Medical Center from June 2008 to May 2010. Low-density lipoprotein cholesterol (LDL-C) and non-HDL-C (subtraction of high-density lipoprotein cholesterol from total cholesterol) in fasting blood of participants were each classified into two groups, < or ≥ 140 mg/dL, and < or ≥ 170 mg/dL, respectively. Genotype frequencies of PLAU Pro141Leu (rs2227564) were 59.1% for ProPro, 35.6% for ProLeu, and 5.3% for LeuLeu, and were in Hardy-Weinberg equilibrium (p=0.789). The allele frequencies were 0.769 for Pro and 0.231 for Leu. The multivariate-adjusted odd ratios (ORs) and 95% confidence intervals (CIs) for high LDL-C and non-HDL-C were 1.11 (95%CI; 1.00-1.23) and 1.16 (95%CI; 1.03-1.30) for those with Leu allele relative to ProPro. This study suggested that PLAU Pro141Leu (rs2227564) is significantly associated with serum lipid levels in a Japanese population. 23955311 The neural regulation of the kidney in hypertension and renal failure. Autonomic control is central to cardiovascular homeostasis and this is exerted not only at the level of the heart and blood vessels but also at the kidney. At the kidney the sympathetic neural regulation of renin release and fluid reabsorption may influence fluid balance and in the longer term the level at which blood pressure is set. The role of the renal innervation in the regulation of blood pressure has received renewed attention over the past few years following the reports that bilateral renal denervation of resistant hypertensive patients caused a marked reduction in blood pressure which has been maintained for several years. Such has been the interest that this approach of renal denervation is being applied in other patient groups with diabetes, obesity and renal failure with the hope that there may be a sustained reduction in blood pressure as well as the amelioration of some aspects of the metabolic syndrome. However, the factors that come into play to cause the rise in blood pressure in these patient groups, particularly the resistant hypertensive patients, is far from clear. Moreover, the mechanisms leading to the fall in blood pressure following renal denervation of resistant hypertensive patients currently eludes our understanding and is therefore an area that requires much more investigation to enhance our insight. 23159884 Human paraoxonase double mutants hydrolyze V and G class organophosphorus nerve agents. Variants of human paraoxonase 1 (PON1) are being developed as catalytic bioscavengers for the organophosphorus chemical warfare agents (OP). It is preferable that the new PON1 variants have broad spectrum hydrolase activities to hydrolyze both G- and V-class OPs. H115W PON1 has shown improvements over wild type PON1 in its capacity to hydrolyze some OP compounds. We improved upon these activities either by substituting a tryptophan (F347W) near the putative active site residues for enhanced substrate binding or by reducing a bulky group (Y71A) at the periphery of the putative enzyme active site. When compared to H115W alone, we found that H115W/Y71A and H115W/F347W maintained VX catalytic efficiency but showed mixed results for the capacity to hydrolyze paraoxon. Testing our double mutants against racemic sarin, we observed reduced values of KM for H115W/F347W that modestly improved catalytic efficiency over wild type and H115W. Contrary to previous reports, we show that H115W can hydrolyze soman, and the double mutant H115W/Y71A is nearly 4-fold more efficient than H115W for paraoxon hydrolysis. We also observed modest stereoselectivity for hydrolysis of the P(-) stereoisomer of tabun by H115W/F347W. These data demonstrate enhancements made in PON1 for the purpose of developing an improved catalytic bioscavenger to protect cholinesterase against chemical warfare agents. 23722076 Long-term reproducibility of Edinger-Westphal stimulated accommodation in rhesus monkeys. If longitudinal studies of accommodation or accommodation restoration procedures are undertaken in rhesus monkeys, the methods used to induce and measure accommodation must remain reproducible over the study period. Stimulation of the Edinger-Westphal (EW) nucleus in anesthetized rhesus monkeys is a valuable method to understand various aspects of accommodation. A prior study showed reproducibility of EW-stimulated accommodation over 14 months after chronic electrode implantation. However, reproducibility over a period longer than this has not been investigated and therefore remains unknown. To address this, accommodation stimulation experiments in four eyes of two rhesus monkeys (13.7 and 13.8 years old) were evaluated over a period of 68 months. Carbachol iontophoresis stimulated accommodation was first measured with a Hartinger coincidence refractometer (HCR) two weeks before electrode implantation to determine maximum accommodative amplitudes. EW stimulus-response curves were initially measured with the HCR one month after electrode implantation and then repeated at least six times for each eye in the following 60 months. At 64 months, carbachol iontophoresis induced accommodation was measured again. At 68 months, EW stimulus-response curves were measured with an HCR and photorefraction every week over four consecutive weeks to evaluate the short-term reproducibility over one month. In the four eyes studied, long-term EW-stimulated accommodation decreased by 7.00 D, 3.33 D, 4.63 D, and 2.03 D, whereas carbachol stimulated accommodation increased by 0.18 D-0.49 D over the same time period. The short-term reproducibility of maximum EW-stimulated accommodation (standard deviations) over a period of four weeks at 68 months after electrode implantation was 0.48 D, 0.79 D, 0.55 D and 0.39 D in the four eyes. Since the long-term decrease in EW-stimulated accommodation is not matched by similar decreases in carbachol iontophoresis stimulated accommodation, the decline in accommodation cannot be due to the progression of presbyopia but is likely to result from variability in EW electrode position. Therefore, EW-stimulated accommodation in anesthetized monkeys is not appropriate for long-term longitudinal studies of age-related loss of accommodation or accommodation restoration procedures. 23898117 High efficacy of chemoradiation therapy sensitized by weekly docetaxel for anaplastic thyroid cancer. Although rare, treatment of anaplastic thyroid carcinoma (ATC) is very difficult due to its aggressiveness and resistance to therapeutic efforts. We reviewed outcomes for six patients who underwent a unique chemoradiotherapy regimen consisting of external irradiation (45 to 60 Gy) combined with concurrent low-dose weekly docetaxel administration at 10 mg/m(2). The scheduled treatment was completed and showed local disease control in all patients. Two patients showed complete response lasting for 166 and 257 days, three patients showed partial response for 58, 107 and 194 days, and one showed stable disease for 382 days. Overall, patients treated with this chemoradiotherapy survived from 86 to 1,901 days with additional systemic chemotherapy. No toxicities over grade 3 were observed. This chemoradiotherapy is useful for locoregional control of ATC, while offering acceptable toxicity. The effect lasted temporally but long enough to maintain patients' quality of life for this highly aggressive malignancy. 23869602 In vitro measures of membrane changes reveal differences between red blood cells stored in saline-adenine-glucose-mannitol and AS-1 additive solutions: a paired study. Saline-adenine-glucose-mannitol (SAGM) and a variant solution, AS-1, have been used for more than 30 years to preserve red blood cells (RBCs). Reputedly these RBC components have similar quality, although no paired study has been reported. To determine whether differences exist, a paired study of SAGM RBCs and AS-1 RBCs was conducted to identify membrane changes, including microparticle (MP) quantitation and in vitro RBC-endothelial cell (EC) interaction. Two whole blood packs were pooled and split and RBCs were prepared (n = 6 pairs). One pack was suspended in SAGM and one in AS-1. Samples were collected during 42 days of refrigerated storage. RBC shape and size and glycophorin A (GPA)(+) and phosphatidylserine (PS)(+) MPs were measured by flow cytometry. RBC adhesion to ECs was determined by an in vitro flow perfusion assay. Routine variables (pH, hemolysis) were also measured. Compared to SAGM RBCs, AS-1 RBCs had lower hemolysis (p < 0.04), lower GPA(+) MPs (p < 0.03), and lower PS(+) MPs (p < 0.03) from Day 14 onward. AS-1 RBCs had higher (p < 0.02) side scatter from Day 28 onward compared to SAGM RBCs. SAGM RBCs were more adherent to ECs on Day 28 of storage compared to AS-1 RBCs (p = 0.04), but reversed on Day 42 (p = 0.02). SAGM RBCs lose more membrane during storage. SAGM RBCs had increased adherence to ECs on Day 28 of storage, while AS-1 RBCs were more adherent on Day 42. The effect of these differences on the function and survival of SAGM RBCs and AS-1 RBCs after transfusion remains to be determined. 23592830 Relationship Between Weight, Efavirenz Exposure, and Virologic Suppression in HIV-Infected Patients on Rifampin-Based Tuberculosis Treatment in the AIDS Clinical Trials Group A5221 STRIDE Study. Background. Rifampin (RIF) upregulates CYP 450 isoenzymes, potentially lowering efavirenz (EFV) exposure. The US EFV package insert recommends an EFV dose increase for patients on RIF weighing ≥50 kg. We conducted a pharmacokinetic study to evaluate EFV trough concentrations (Cmin) and human immunodeficiency virus (HIV) virologic suppression in patients on EFV (600 mg) and RIF-based tuberculosis treatment in the multicenter randomized trial (ACTG A5221). Methods. EFV Cmin was measured 20-28 hours post-EFV dose at weeks 4, 8, 16, 24 on-RIF and weeks 4, 8 off-RIF. Results were evaluated with 2-sided Wilcoxon rank-sum, χ(2), Fisher exact tests and logistic regression (5% type I error rate). Results. Seven hundred eighty patients received EFV; 543 provided ≥1 EFV Cmin. Median weight was 52.8 kg (interquartile range [IQR], 48.0-59.5), body mass index 19.4 kg/m(2) (IQR, 17.5-21.6), and age 34 years (IQR, 29-41); 63% were male, 74% black. Median Cmin was 1.96 µg/mL on-RIF versus 1.80 off-RIF (P = .067). Cmin were significantly higher on-RIF versus off-RIF in blacks (2.08 vs 1.75, P = .005). Weight ≥60 kg on-RIF, compared to <60 kg, was associated with lower EFV Cmin (1.68 vs 2.02, P = .021). However, weight ≥60 kg was associated with more frequent HIV RNA < 400 copies/mL at week 48, compared to weight <60 kg (81.9% vs 73.8%, P = .023). Conclusions. EFV and RIF-based tuberculosis therapy coadministration was associated with a trend toward higher, not lower, EFV Cmin compared to EFV alone. Patients weighing ≥60 kg had lower median EFV Cmin versus those <60 kg, but there was no association of higher weight with reduced virologic suppression. These data do not support weight-based dosing of EFV with RIF. 23955537 Entropies of defect formation in ceria from first principles. We calculate entropies of formation for fully charged point defects, including the small polaron , in undoped fluorite-structured ceria by means of density functional theory in the GGA + U approximation. We discuss the behaviour of the entropy for the constant volume and the constant pressure case. Our results for constant pressure (p = 0) suggest that the change in volume, due to the formation of defects, dominates the entropy of formation. From the individual entropies of formation the entropies of Frenkel, anti-Frenkel and Schottky disorder as well as the entropy of reduction of ceria are obtained. At temperatures of about 1000 K the entropic contributions to the Gibbs energy are up to 0.9 eV per defect and thus are no longer negligible. For our calculated entropy of reduction of about 17 kB we find a remarkable agreement with experimental data from the literature. 23815997 The green operating room: simple changes to reduce cost and our carbon footprint. Generating over four billion pounds of waste each year, the healthcare system in the United States is the second largest contributor of trash with one-third produced by operating rooms. Our objective is to assess improvement in waste reduction and recycling after implementation of a Green Operating Room Committee (GORC) at our institution. A surgeon and nurse-initiated GORC was formed with members from corporate leadership, nursing, anesthesia, and OR staff. Initiatives for recycling opportunities, reduction of energy and water use as well as solid waste were implemented and the results were recorded. Since formation of GORC in 2008, our OR has diverted 6.5 tons of medical waste. An effort to recycle all single-use devices was implemented with annual solid waste reduction of approximately 12,860 lbs. Disposable OR foam padding was replaced with reusable gel pads at greater than $50,000 per year savings. Over 500 lbs of previously discarded batteries were salvaged from the OR and donated to charity or redistributed in the hospital ($9,000 annual savings). A "Power Down" initiative to turn off all anesthesia and OR lights and equipment not in use resulted in saving $33,000 and 234.3 metric tons of CO2 emissions reduced per year. Converting from soap to alcohol-based waterless scrub demonstrated a potential saving of 2.7 million liters of water annually. Formation of an OR committee dedicated to ecological initiatives can provide a significant opportunity to improve health care's impact on the environment and save money. 23893527 Health-Related Quality of Life and Functional Outcomes from a Randomized, Controlled Study of Lisdexamfetamine Dimesylate in Children and Adolescents with Attention Deficit Hyperactivity Disorder. Optimal management of attention deficit hyperactivity disorder (ADHD) aims not only to ameliorate patients' symptoms, but also to improve health-related quality of life (HRQL) and functioning. A pivotal, 7-week, randomized, double-blind, placebo-controlled, phase III study in children and adolescents in ten European countries demonstrated that the stimulant prodrug lisdexamfetamine dimesylate (LDX) is an effective and generally well-tolerated treatment for symptoms of ADHD. The aim of this study was to assess HRQL and functional impairment outcomes in this clinical trial, using the Child Health and Illness Profile-Child Edition: Parent Report Form (CHIP-CE:PRF) and the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P), respectively. Patients (aged 6-17 years) with diagnosed ADHD and a baseline ADHD Rating Scale IV total score ≥28 were randomized (1:1:1) to 7 weeks of double-blind treatment with once-daily LDX, placebo or the reference treatment, osmotic-release oral system methylphenidate (OROS-MPH). Participants' parents (or legally authorized representatives) completed the CHIP-CE:PRF and WFIRS-P questionnaires at baseline, at weeks 4 and 7, and/or at early termination. Endpoint was defined as the last on-treatment visit with valid data (≤30 % missing items). The CHIP-CE:PRF Achievement domain was pre-specified as the primary HRQL outcome. The full analysis set comprised 317 patients (LDX, n = 104; placebo, n = 106; OROS-MPH, n = 107), the majority of whom completed the study (LDX, n = 77; placebo, n = 42; OROS-MPH, n = 72). Baseline CHIP-CE:PRF T-scores in four of the five domains were ≥1 standard deviation below norms (US community samples). Compared with placebo, LDX was associated with statistically significantly improved T-scores from baseline to endpoint in these four domains, with effect sizes of 1.280 (p < 0.001) in Achievement, 1.079 (p < 0.001) in Risk Avoidance, 0.421 (p < 0.01) in Resilience and 0.365 (p < 0.05) in Satisfaction. In LDX-treated patients, placebo-adjusted improvements from baseline to endpoint in WFIRS-P scores were statistically significant (p < 0.001) for total score and four of the six domains, with effect sizes of 0.924 (total score), 1.249 (Learning and School), 0.730 (Family), 0.643 (Social Activities) and 0.640 (Risky Activities). OROS-MPH treatment showed similar patterns of improvement from baseline to endpoint in both CHIP-CE:PRF and WFIRS-P scores. Baseline HRQL and functional impairment scores reflect the burden of untreated ADHD. The benefits of short-term stimulant treatment in children and adolescents with ADHD extend beyond symptomatic relief and impact positively on HRQL and daily functioning. 23881912 New Horizons for Lipoprotein ReceptorsCommunication by β-propellers. The lipoprotein receptor (LR) family constitutes a large group of structurally close-related receptors with broad ligand binding specificity. Traditionally, ligand binding to LRs has been anticipated to involve merely the complement type repeat (CR)-domains omnipresent in the family. Recently, this dogma has transformed with the observation that β-propellers of some LRs actively engage in complex formation too. Based on an in-depth decomposition of current structures and sequences, we suggest that exploitation of the β-propellers as binding targets depends on receptor subgroups. In particular we highlight the shutter mechanism of β-propellers as a general recognition motif for NxI-containing ligands, and present indications, that the generalized β-propeller-induced ligand release mechanism is not applicable for the larger LRs. For the giant LR members, we present evidence that their β-propellers may also actively engage in ligand binding. We therefore advocate for an increased focus on solving the structure-function relationship of this group of important biological receptors. 23852921 An attenuated temperature-sensitive strain of cytomegalovirus (tsm5) establishes immunity without development of CD8(+) T cell memory inflation. Cytomegalovirus (CMV) is a widely prevalent herpesvirus that is well tolerated by an immune competent host yet establishes a state of chronic infection. The virus is thought to undergo frequent subclinical episodes of reactivation which leads to an unusually large accumulation of CMV-specific CD8(+) T lymphocytes in the peripheral blood, a phenomenon termed "memory inflation." The high magnitude of the CMV T cell response has been implicated in impaired immunity to heterologous pathogens such as EBV, influenza and West Nile virus. Here, using murine CMV (MCMV), we show that memory inflation of virus-specific CD8(+) T cells is avoided if mice are infected with a replication defective virus called temperature-sensitive mutant 5 (tsm5), which carries an attenuating mutation within the DNA primase gene. Mice infected with tsm5 do generate primary T cell responses towards viral proteins but these do not amass to skew the memory repertoire of CD8(+) T cells. Therefore, attenuation of the virus replication machinery may be valuable in future CMV vaccine designs because the virus remains immunogenic but does not contribute to CMV associated T cell immune senescence. J Med. Virol. 85:1968-1974, 2013. © 2013 Wiley Periodicals, Inc. 23862628 Stomata actively regulate internal aeration of the sacred lotus Nelumbo nucifera. The sacred lotus Nelumbo nucifera (Gaertn.) possesses a complex system of gas canals that channel pressurized air from its leaves, down through its petioles and rhizomes, before venting this air back to the atmosphere through large stomata found in the centre of every lotus leaf. These central plate stomata (CPS) lie over a gas canal junction that connects with two-thirds of the gas canals within the leaf blade and with the larger of two discrete pairs of gas canals within the petiole that join with those in the rhizome. It is hypothesized that the lotus actively regulates the pressure, direction and rate of airflow within its gas canals by opening and closing these stomata. Impression casting the CPS reveal that they are open in the morning, close at midday and reopen in the afternoon. The periodic closure of the CPS during the day coincides with a temporary reversal in airflow direction within the petiolar gas canals. Experiments show that the conductance of the CPS decreases in response to increasing light level. This behaviour ventilates the rhizome and possibly directs benthic CO2 towards photosynthesis in the leaves. These results demonstrate a novel function for stomata: the active regulation of convective airflow. 23460412 Borderline personality features and harmful dysregulated behavior: the mediational effect of mindfulness. The current preliminary study investigated whether deficits in mindfulness (awareness, attentiveness, and acceptance of the present experience) may underlie the relationship of borderline personality disorder (BPD) features to self-injury and overall acts of harmful dysregulated behavior. Nonparametric bootstrapping procedures were used to examine theoretical relationships among variables in a psychiatric sample of adults (N = 70). Participants were asked to imagine themselves in distress-inducing situations and then write what they would actually do to decrease distress in such situations. As hypothesized, mindfulness statistically mediated the relationship of BPD features to reported acts of (a) self-injury and (b) overall harmful dysregulated behaviors. Difficulties in the ability to be aware, attentive, and accepting of ongoing experience may play a role in the relationship of BPD features to harmful dysregulated behaviors. Future research should clarify potential reciprocal effects between BPD features and mindfulness with prospective, multioccasion designs. 23597630 Functional analysis of Abp1p-interacting proteins involved in endocytosis of the MCC component in Aspergillus oryzae. We have investigated the functions of three endocytosis-related proteins in the filamentous fungus Aspergillus oryzae. Yeast two-hybrid screening using the endocytic marker protein AoAbp1 (A.oryzae homolog of Saccharomyces cerevisiae Abp1p) as a bait identified four interacting proteins named Aip (AoAbp1 interacting proteins). In mature hyphae, EGFP (enhanced green fluorescent protein) fused to Aips colocalized with AoAbp1 at the hyphal tip region and the plasma membrane, suggesting that Aips function in endocytosis. aipA is a putative AAA ATPase and its function has been dissected (Higuchi et al., 2011). aipB, the homolog of A. nidulans myoA, encodes an essential class I myosin and its conditional mutant showed a germination defect. aipC and aipD do not contain any recognizable domains except some proline-rich regions which may interact with two SH3 (Src homology 3) domains of AoAbp1. Neither aipC nor aipD disruptants showed any defects in their growth, but the aipC disruptant formed less conidia compared with the control strain. In addition, the aipC disruptant was resistant to the triazole antifungal drugs that inhibit ergosterol biosynthesis. Although no aip disruptants showed any defects in the uptake of the fluorescent dye FM4-64, the endocytosis of the arginine permease AoCan1, one of the MCC (membrane compartment of Can1p) components, was delayed in both aipC and aipD disruptants. In A. oryzae, AoCan1 localized mainly at the plasma membrane in the basal region of hyphae, suggesting that different endocytic mechanisms exist in apical and basal regions of highly polarized cells. 23850684 A diagnostic gene chip for hereditary spastic paraplegias. Hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous monogenic neurodegenerative disorders. The gene screen of hereditary spastic paraplegias patients remains time consuming and costly because of their highly heterogeneous. As we know, there are some hot spots of mutation in many genes causing HSPs. Our aim was to develop a quick method for gene screen of HSP patients. The online mutation data banks of HSPs were searched and Chinese data for point mutations were mainly considered. Then mutations were comprehensively analyzed and ninety-six more common point mutations of HSPs disease genes were chose for the 96-plex GoldenGate assay diagnostic gene chip for HSPs. After that, we used this diagnostic gene chip to detect ninety-six clinically diagnosed HSP patients. For validation purpose, six previously Sanger sequenced cases with known point mutations were redetected on this array. The scores of all the ninety-six point mutations were between 0.601 and 0.993, and the call rate of the whole gene chip was 97.7% and its consistency was 99.0%. A patient suspected with a c.316G>C substitution in SPG6 was detected by the chip, which was further confirmed by polymerase chain reaction and sequencing. The high successful performance of this GoldenGate assay makes it a useful technique for preliminary genetic screening for HSP patients and it may be used in clinic in the future. 23442901 Relationship between burden of infection in ungulate populations and wildlife/livestock interfaces. In southern African transfrontier conservation areas (TFCAs), people, livestock and wildlife share space and resources in semi-arid landscapes. One consequence of the coexistence of wild and domestic herbivores is the risk of pathogen transmission. This risk threatens local livelihoods relying on animal production, public health in the case of zoonoses, national economies in the context of transboundary animal diseases, and the success of integrated conservation and development initiatives. The level of interaction between sympatric wild and domestic hosts, defining different wildlife/livestock interfaces, characterizes opportunities of pathogen transmission between host populations. Exploring the relationship between infection burden and different types of wildlife/domestic interfaces is therefore necessary to manage the sanitary risk in animal populations through control options adapted to these multi-host systems. Here, we assessed the infection burdens of sympatric domestic cattle (Bos taurus/Bos indicus) and African buffalo (Syncerus caffer) at an unfenced interface and compared the infection burdens of cattle populations at different wildlife/livestock interfaces in the Great Limpopo TFCA. Patterns of infection in ungulate populations varied between wild and domestic hosts and between cattle populations at different wildlife/livestock interfaces. Foot-and-mouth disease, Rift Valley fever and theileriosis infections were detected in buffalo and cattle at unfenced interfaces; bovine tuberculosis was only present in buffalo; and brucellosis and lumpy skin disease only in cattle. At unfenced interfaces, cattle populations presented significantly higher Theileria parva and brucellosis prevalence. We hypothesize that cattle populations at wildlife/livestock interfaces face an increased risk of infection compared to those isolated from wildlife, and that the type of interface could influence the diversity and quantity of pathogens shared. Additional host behavioural and molecular epidemiological studies need to be conducted to support this hypothesis. If it is confirmed, the management of wildlife/livestock interfaces will need to be considered through the prism of livestock and public health. 23628801 Association of the CAG repeat polymorphisms in androgen receptor gene with polycystic ovary syndrome: a systemic review and meta-analysis. Many studies have reported the associations of polymorphic CAG repeats in androgen receptor (AR) gene with PCOS risk, but with inconsistent results. So, the aim of present meta-analysis was to clarify such inconsistence, so as to provide more conclusive results. PubMed was searched for the eligible reports published until February 2012 without language limitation. The studies reporting the relationship between CAG repeat length and PCOS were selected for the meta-analysis according to the inclusion criteria. Two reviewers independently extracted the data and evaluated the study quality. As for the relationship between CAG repeat length and PCOS risk, the pooled results showed that the biallelic mean was not significantly different between PCOS and controls (SMD -0.03, 95% CI -0.16-0.10, P=0.603), and that the ORs of PCOS were not demonstrated for the individuals with the biallelic mean less than median (OR 0.96, 95% CI 0.68-1.35, P=0.794), with the short CAG allele (OR 0.94, 95% CI 0.80-1.10, P=0.424), or with the X-weighted biallelic mean (OR 0.81, 95% CI 0.46-1.41, P=0.447). Further, as for the relationship between CAG repeat length and T levels in PCOS patients, the biallelic mean was not significantly different between PCOS patients with high T and those with low T (SMD 0.79, 95% CI -0.12-1.70, P=0.088), while the summary correlation r indicated that the CAG biallelic mean appeared to be positively associated with T levels in PCOS (r 0.20, 95% CI 0.11-0.30, p=0.000). This meta-analysis demonstrates no evident association between the CAG length variations in AR gene and PCOS risk, while the CAG length appears to be positively associated with T levels in PCOS patients. 23800062 Functional and molecular genetic analyses of nine newly identified XPD-deficient patients reveal a novel mutation resulting in TTD as well as in XP/CS complex phenotypes. The xeroderma pigmentosum (XP) group D protein is involved in nucleotide excision repair (NER) as well as in basal transcription. Determined by the type of XPD mutation, six different clinical entities have been distinguished: XP, XP with neurological symptoms, trichothiodystrophy (TTD), XP⁄TTD complex, XP⁄Cockayne syndrome (CS) complex or the cerebro-oculo-facio-skeletal syndrome (COFS). We identified nine new XPD-deficient patients. Their fibroblasts showed reduced post-UV cell survival, reduced NER capacity, normal XPD mRNA expression and partly reduced XPD protein expression. Six patients exhibited a XP phenotype in accordance with established XP-causing mutations (c.2079G>A, p.R683Q; c.2078G>T, p.R683W; c.1833G>T, p.R601L; c.1878G>C, p.R616P; c.1878G>A, p.R616Q). One TTD patient was homozygous for the known TTD-causing mutation p.R722W (c.2195C>T). Two patients were compound heterozygous for a TTD-causing mutation (c.366G>A, p.R112H) and a novel p.D681H (c.2072G>C) amino acid exchange, but exhibited different TTD and XP/CS complex phenotypes, respectively. Interestingly, the XP/CS patient's cells exhibited a reduced but well detectable XPD protein expression compared with hardly detectable XPD expression of the TTD patient's cells. Same mutations with different clinical outcomes in NER-defective patients demonstrate the complexity of phenotype-genotype correlations, for example relating to additional genetic variations (parental consanguinity), different allelic expression due to SNPs or differences in the methylation status. 23899889 Association between Serum Vitamin D Status and Metabolic Syndrome in Korean Young Men. The study examined the relations of serum vitamin D levels to body fatness, cardiorespiratory fitness (CRF), and metabolic risk factors in young adults in Korea. Between 2007 and 2009, 799 young men completed a health examination. Body fatness, CRF based on a maximal treadmill exercise test, and measurements of metabolic risk factors were measured in study participants. Participants were classified by serum vitamin D levels as deficient (< 12.5 ng•mL), insufficient (≥12.5 ∼ <20 ng•mL), and sufficient (>20 ng•mL) and by CRF as unfit (lowest 20%) and fit (remaining 80%) based on age-standardized distribution of VO2max values in this study population. Body fatness, CRF, and metabolic risk factors were evaluated according to serum vitamin D classification. A clustered metabolic risk score was computed by summing standardized scores for waist circumference, resting blood pressures, triacylglycerols, the inverse of high-density lipoprotein cholesterol, glucose, and insulin. Linear decreases in body fatness and metabolic risk factors were observed, as was a linear increase for CRF across incremental vitamin D categories. A linear decrease was found in the clustered metabolic risk score across incremental vitamin D categories. Compared to the fit group (referent), the unfit group had significantly higher risks for serum vitamin D inadequacy before and after adjusting for age, smoking, and body fatness parameters. The findings of the study suggest that increasing vitamin D intake, eating a healthy diet, and getting enough outdoor physical activity should be promoted as non-pharmacologic means to improve CRF and prevent a clustering of metabolic risk factors in young adults. 23794193 The use of computed tomography in determining developmental changes, anomalies, and trauma of the thyroid cartilage. Recognition of injury to the hyoid bone and thyroid and cricoid cartilages is intrinsic to post-mortem examination. Due to its increasing brittleness with age the thyroid cartilage is particularly susceptible to injury following neck trauma, although there is inconsistency in the patterns of injury reported. In this study computed tomography scans of the head and neck of 431 deceased persons (235 males and 196 females) between the ages of 1 day and 100 years (mean age 35.93 ± 24.15), and including 25 victims of hangings, were examined to reveal the pattern of age-related change and the types of injury that occurred. Thyroid cartilage anomalies likely to cause confusion and be misinterpreted as trauma-related are documented. Angulation of the thyroid cartilage horns was found to change with age, and it is suggested this may be a significant factor in traumatic neck injury. Unlike in previous reports, the average age of hanging victims with fractures to the thyroid cartilage was 34 years. The base of the superior horn was the most common fracture site and in 50 % of hanging cases was associated with a ligature positioned on the thyrohyoid membrane or thyroid lamina. Although an age-related relationship exists it was not possible to establish narrow age-prediction ranges from calcification of the thyroid cartilage. 23736856 Raman spectroscopy of serum: an exploratory study for detection of oral cancers. Early diagnosis of oral cancers, one of the major cancers, is of utmost importance as 5-year disease-free survival rates are some of the lowest, despite advances in treatment and surgical modalities. In vivo Raman spectroscopy has shown efficacy in the detection of normal, premalignant and malignant lesions and even of early changes such as cancer-field-effects/malignancy-associated-changes. However, the need for a dedicated instrument and stringent laboratory conditions, at all diagnostic centers, limits wide screening applications of this method. In light of this, it is pertinent to explore ex vivo samples like serum due to its ease of collection, storage, transport and analysis at a centralized facility. Hence, Raman studies were carried out on serum from 14 buccal mucosa and 40 tongue cancers as well as 16 healthy control samples. Spectral features indicate differential contributions of proteins, DNA, and amino acids like Phe, Trp and Tyr and β-carotene in the analyzed groups. Highly intense Raman bands assigned to β-carotene could be due to resonance Raman, and were observed in all sera with the highest relative intensity in normal samples. Higher DNA and protein content were observed in the mean cancer spectra. Principal component-linear discriminant analysis (PC-LDA) followed by cross-validation using leave-one-out cross-validation (LOOCV) were employed for data analysis which was carried out both spectra- and patient-wise. Findings indicate the possibility of classifying normal and oral cancer sera in both these approaches; however, the patient-wise approach could be the preferred mode for prospective studies. Besides, a tendency of classification for buccal mucosa and tongue cancers was also observed. Prospective validation of these results on a large sample size may help in the translation of this methodology to clinics. 23513212 Development and validation of an integrated diagnostic algorithm derived from parameters monitored in implantable devices for identifying patients at risk for heart failure hospitalization in an ambulatory setting. We developed and validated a heart failure (HF) risk score combining daily measurements of multiple device-derived parameters. Heart failure patients from clinical studies with implantable devices were used to form two separate data sets. Daily HF scores were estimated by combining changes in intra-thoracic impedance, atrial fibrillation (AF) burden, rapid rate during AF, %CRT pacing, ventricular tachycardia, night heart rate, heart rate variability, and activity using a Bayesian model. Simulated monthly follow-ups consisted of looking back at the maximum daily HF risk score in the preceding 30 days, categorizing the evaluation as high, medium, or low risk, and evaluating the occurrence of HF hospitalizations in the next 30 days. We used an Anderson-Gill model to compare survival free from HF events in the next 30 days based on risk groups. The development data set consisted of 921 patients with 9790 patient-months of data and 91 months with HF hospitalizations. The validation data set consisted of 1310 patients with 10 655 patient-months of data and 163 months with HF hospitalizations. In the validation data set, 10% of monthly evaluations in 34% of the patients were in the high-risk group. Monthly diagnostic evaluations in the high-risk group were 10 times (adjusted HR: 10.0; 95% CI: 6.4-15.7, P < 0.001) more likely to have an HF hospitalization (event rate of 6.8%) in the next 30 days compared with monthly evaluations in the low-risk group (event rate of 0.6%). An HF score based on implantable device diagnostics can identify increased risk for HF hospitalization in the next 30 days. 23938324 Cytokine and Chemokine Profiles in Lung Tissues from Fatal Cases of 2009 Pandemic Influenza A (H1N1): Role of the Host Immune Response in Pathogenesis. Pathological studies on fatal cases caused by 2009 pandemic influenza H1N1 virus (2009 pH1N1) reported extensive diffuse alveolar damage and virus infection predominantly in the lung parenchyma. However, the host immune response after severe 2009 pH1N1 infection is poorly understood. Herein, we investigated viral load, the immune response, and apoptosis in lung tissues from 50 fatal cases with 2009 pH1N1 virus infection. The results suggested that 7 of the 27 cytokines/chemokines showed remarkably high expression, including IL-1 receptor antagonist protein, IL-6, tumor necrosis factor-α, IL-8, monocyte chemoattractant protein-1, macrophage inflammatory protein 1-β, and interferon-inducible protein-10 in lung tissues of 2009 pH1N1 fatal cases. Viral load, which showed the highest level on day 7 of illness onset and persisted until day 17 of illness, was positively correlated with mRNA levels of IL-1 receptor antagonist protein, monocyte chemoattractant protein-1, macrophage inflammatory protein 1-β, interferon-inducible protein-10, and regulated on activation normal T-cell expressed and secreted. Apoptosis was evident in lung tissues stained by the TUNEL assay. Decreased Fas and elevated FasL mRNA levels were present in lung tissues, and cleaved caspase-3 was frequently seen in pneumocytes, submucosal glands, and lymphoid tissues. The pathogenesis of the 2009 pH1N1 virus infection is associated with viral replication and production of proinflammatory mediators. FasL and caspase-3 are involved in the pathway of 2009 pH1N1 virus-induced apoptosis in lung tissues, and the disequilibrium between the Fas and FasL level in lung tissues could contribute to delayed clearance of the virus and subsequent pathological damages. 23568478 Image texture in dental panoramic radiographs as a potential biomarker of osteoporosis. Previous studies have shown an association between osteoporosis and automatic measurements of mandibular cortical width on dental panoramic radiographs (DPRs). In this study, we show that additional image texture features increase this association and propose the combined features as a potential biomarker for osteoporosis. We used an existing dataset of 663 DPRs of female patients with bone mineral density (BMD) measurements. The mandibular cortex was located using a previously described computer algorithm. Texture features, based on co-occurrence matrices and fractal dimension, were measured in the bone within the cortex and also in the superior basal bone above the cortex. These, augmented by cortical width measurements, were used by a random forest classifier to identify osteoporosis at femoral neck, total hip, and lumbar spine. Classification performance was assessed by ROC analysis. Area-under-curve (AUC) values for identifying osteoporosis at femoral neck were 0.830, 0.824, and 0.872 using, respectively, cortical width alone, cortical texture (co-occurrence matrix features) alone, and combined width and texture. At 80% sensitivity, these classifiers produced specificity values of 74.4%, 73.6%, and 80.0%, respectively. Fractal dimension was a less effective texture feature. Prediction of osteoporosis at the lumbar spine was poorer, but a combined width and superior basal bone texture classifier gave a significant improvement in AUC at over the use of width alone. 23491640 Differential Expression of Human Cytochrome P450 Enzymes from the CYP3A Subfamily in the Brains of Alcoholics and Drug Free Controls. Cytochrome P450 (P450, CYP) enzymes are responsible for the metabolism of most commonly used drugs. Amongst these enzymes, CYP3A forms mediate the clearance of around 40-50 % of drugs and may also play roles in the biotransformation of endogenous compounds. CYP3A forms are expressed both in the liver and extrahepatically. However little is known about the expression of CYP3A proteins in specific regions of the human brain. In this study, form-selective antibodies raised to CYP3A4 and CYP3A5 were utilized to characterize the expression of these forms in the human brain. Both CYP3A4 and CYP3A5 immunoreactivity was found to varying extents in the microsomal fractions of cortex, hippocampus, basal ganglia, amygdala and cerebellum. However, only CYP3A4 expression was observed in the mitochondrial fractions of these brain regions. N-terminal sequencing confirmed the principal antigen detected by the anti-CYP3A4 antibody in cortical microsomes to be CYP3A4. Immunohistochemical analysis revealed that CYP3A4 and CYP3A5 expression was primarily localized in the soma and axonal hillock of neurons and varied according to cell type and cell layer within brain regions. Finally, analysis of the frontal cortex of chronic alcohol abusers revealed elevated expression of CYP3A4 in microsomal but not mitochondrial fractions; CYP3A5 expression was unchanged. The site-specific expression of CYP3A4 and CYP3A5 in the human brain may have implications for the role of these enzymes in both normal brain physiology and the response to drugs. 22833051 Public stigma of mental illness in the United States: a systematic literature review. Public stigma is a pervasive barrier that prevents many individuals in the U.S. from engaging in mental health care. This systematic literature review aims to: (1) evaluate methods used to study the public's stigma toward mental disorders, (2) summarize stigma findings focused on the public's stigmatizing beliefs and actions and attitudes toward mental health treatment for children and adults with mental illness, and (3) draw recommendations for reducing stigma towards individuals with mental disorders and advance research in this area. Public stigma of mental illness in the U.S. was widespread. Findings can inform interventions to reduce the public's stigma of mental illness. 23957413 Combined Effect of Dimethyl Dicarbonate (DMDC) and Nisin on Indigenous Microorganisms of Litchi Juice and its Microbial shelf life. The individual and combined influences of dimethyl dicarbonate (DMDC) and nisin (200 IU/mL) at mild heat on the inactivation of indigenous microorganisms in litchi juice, including bacteria, molds and yeasts (M&Y), were investigated. The fresh litchi juice with or without nisin were exposed to 250 mg/L DMDC at 30, 40, or 45 °C for 0.5, 1, 2, 3, 4, or 6 h. A complete inactivation of M&Y in the litchi juice with or without nisin was achieved as exposed to 250 mg/L DMDC at 30, 40, or 45 °C for 0.5 h. The bacteria, especially Bacillus sp. and Leuconstoc mesenteroides showed higher resistance than M&Y in the litchi juice. Bacillus sp. and Leuconstoc mesenteroides in the litchi juice was not completely inactivated by 250 mg/L DMDC at 30, 40, or 45 °C. However, nisin addition can enhanced the inactivation of these bacteria by DMDC, and nisin and DMDC also showed a synergistic effect on the inactivation of bacteria. M&Y and bacteria were not detected in the litchi juice added with 200 IU/mL nisin as exposed to 250 mg/L DMDC at 45 °C for 3 h. In addition, microbial shelf life of the litchi juice during storage at 4 °C also was evaluated as treated by 250 mg/L DMDC or combination with nisin at 45 °C for 3 h. 23916804 Octogenarians With Uncomplicated Acute Type A Aortic Dissection Benefit From Emergency Operation. The management of acute type A aortic dissection (aTAAD) in octogenarian patients is controversial. This study analyzed the surgical outcomes to identify patients who should undergo operations. Beginning in January 2000, we established a registry including all octogenarian patients operated on for type A acute aortic dissection. We evaluated 79 consecutive patients enrolled up to December 2010. Their median age was 81.6 years (range, 80 to 89 years). Sixteen patients (20%) presented a complicated type because of a neurologic deficit, mesenteric ischemia, a requirement for cardiopulmonary resuscitation, or some combination of those features. Operations followed the standard procedure recommended for younger patients. Follow-up was 95% complete (mean, 4.6 ± 2.8 years). The overall in-hospital mortality was 44.3%. The in-hospital mortality among patients with uncomplicated aTAAD was 33.3%. Multivariate analysis identified complicated aTAAD as the only risk factors for in-hospital mortality (p < 0.0001). Postoperative complications occurred in 50 patients (68.5%) and were associated with a higher mortality (p < 0.0001). The overall survival was 53% at 1 year and 32% at 5 years. In uncomplicated aTAAD, the overall survival was 63% at 1 year and 38% at 5 years. Octogenarians with uncomplicated aTAAD benefit from emergency surgical repair. In those patients, early and midterm outcomes are good and are similar to those in published series of younger patients. Complicated aTAAD should be medically managed. 23898391 Radiotherapy prolongs biliary metal stent patency in malignant pancreatobiliary obstructions. Biliary stenting is the most effective decompressive method for treating malignant biliary obstructive jaundice. Although the main cause of stent occlusion is tumor growth, few studies have investigated whether stent patency is affected by the combination of cancer-treatment modalities. The aim of this study was to evaluate the effects of local radiotherapy on metal-stent patency in patients with malignant biliary obstruction. Patients who underwent self-expandable biliary metallic stenting for malignant biliary obstruction from 1999 to 2007 were included. Forty patients received chemotherapy and radiation therapy (radiation group, RG), and 31 patients received only chemotherapy (nonradiation group, NRG). The cumulative median stent patency was significantly longer in the RG than in the NRG (17.7 months; 95% confidence interval [CI], 1.8 to 33.6 months vs 8.7 months; 95% CI, 4.9 to 12.5 months; p=0.025). Stent occlusion caused by tumor growth or stent migration occurred in two (5%) and three (7.5%) cases in the RG and in six (19.3%) and two (6.5%) cases in the NRG, respectively. The patency of biliary metal stents in pancreatobiliary cancer patients who receive chemoradiation therapy is significantly longer than that in patients who do not receive radiotherapy, which suggests that local cancer control significantly affects stent patency. 23275232 An examination of iconic memory in children with autism spectrum disorders. Iconic memory is the ability to accurately recall a number of items after a very brief visual exposure. Previous research has examined these capabilities in typically developing (TD) children and individuals with intellectual disabilities (ID); however, there is limited research on these abilities in children with Autism Spectrum Disorders (ASD). Twenty-one TD and eighteen ASD children were presented with circular visual arrays of letters for 100 ms and were asked to recall as many letters as possible or a single letter that was cued for recall. Groups did not differ in the number of items recalled, the rate of information decay, or speed of information processing. These findings suggest that iconic memory is an intact skill for children with ASD, a result that has implications for subsequent information processing. 23896260 Patterns of care in testicular torsion: Influence of hospital transfer on testicular outcomes. To investigate patterns of care for testicular torsion and influence of hospital transfers on testicular outcomes. Hospital transfer may be a source of treatment delay in a condition where delays increase likelihood of orchiectomy. We used a retrospective cohort of Californian males with ICD-9/CPT-defined torsion from inpatient, emergency department (ED), and ambulatory surgery center (ASC) data. Logistic regression assessed predictors of orchiectomy. Predictors of orchiectomy were ages <1 year (OR 19.2, 95% CI 6.3-58.9), 1-9 years (OR 2.7, 95% CI 1.4-5.2), and ≥40 years (OR 6.6, 95% CI 3.1-13.9) (vs. masked age). Treatment at mid-volume (vs. high-volume) facilities was associated with lower odds of orchiectomy (OR 0.5, 95% CI 0.3-0.7). Rural location, non-private insurance, and hospital transfer were associated with orchiectomy on univariate but not multivariate analysis. During 2008-2010, 2794 subjects experienced torsion (average incidence 5.08 per 100,000 males yearly). Encounters occurred in ASCs (55%), inpatient facilities (36%), and EDs (9%). 60% of subjects were privately insured, 2% experienced hospital transfer, and 31% underwent orchiectomy. Our census found that most cases of testicular torsion were treated in outpatient settings. Hospital transfer was not associated with orchiectomy. 23825109 Loss of c-Jun N-terminal kinase-interacting protein-1 does not affect axonal transport of the amyloid precursor protein or Aβ production. Disruption to axonal transport is an early pathological feature in Alzheimer's disease. The amyloid precursor protein (APP) is a key axonal transport cargo in Alzheimer's disease since perturbation of its transport increases APP processing and production of amyloid-β peptide (Aβ) that is deposited in the brains of Alzheimer's disease patients. APP is transported anterogradely through axons on kinesin-1 motors. One favoured route for attachment of APP to kinesin-1 involves the scaffolding protein c-Jun N-terminal kinase-interacting protein-1 (JIP1), which has been shown to bind both APP and kinesin-1 light chain (KLC). However, direct experimental evidence to support a role of JIP1 in APP transport is lacking. Notably, the effect of loss of JIP1 on movement of APP through axons of living neurons, and the impact of such loss on APP processing and Aβ production has not been reported. To address these issues, we monitored how siRNA mediated loss of JIP1 influenced transport of enhanced green fluorescent protein (EGFP)-tagged APP through axons and production of endogenous Aβ in living neurons. Surprisingly, we found that knockdown of JIP1 did not affect either APP transport or Aβ production. These results have important implications for our understanding of APP trafficking in Alzheimer's disease. 23945383 Lung cancer and prognosis in taiwan: a population-based cancer registry. Lung cancer is the leading cause of cancer death in Taiwan. This study investigated the prognostic factors affecting survival of patients with lung cancer in Taiwan. Data were obtained from the National Health Insurance Research Database published in Taiwan. Clinicopathologic profiles and prognostic factors of 33,919 lung cancer patients were analyzed between 2002 and 2008 in this retrospective review. The impact of the clinicopathologic factors on overall survival was assessed. Nearly two thirds of the patients were men. The 5-year survival rate was 15.9%, with a median survival of 13.2 months. The clinical staging of the patients included stage I (n = 4254; 12.5%), stage II (n = 1140; 3.4%), stage III (n = 10,161; 30.0%), and stage IV (n = 18,364; 54.1%). In the multivariate analysis, age more than 65 years, sex, cell type, histologic grade, and primary tumor location were identified as independent prognostic factors. In additional to tumor-nodes-metastasis (TNM) staging system, patient sex and age, tumor location, cell type, and differentiation were independent prognostic factors. We recommend incorporation of these factors to subclassify lung cancer patients. 23727158 Greater diaphragm fatigability in individuals with recurrent low back pain. The diaphragm plays an important role in spinal control. Increased respiratory demand compromises spinal control, especially in individuals with low back pain (LBP). The objective was to determine whether individuals with LBP exhibit greater diaphragm fatigability compared to healthy controls. Transdiaphragmatic twitch pressures (TwPdi) were recorded in 10 LBP patients and 10 controls, before and 20 and 45min after inspiratory muscle loading (IML). Individuals with LBP showed a significantly decreased potentiated TwPdi, 20min (-20%) (p=0.002) and 45min (-17%) (p=0.006) after IML. No significant decline was observed in healthy individuals, 20min (-9%) (p=0.662) and 45min (-5%) (p=0.972) after IML. Diaphragm fatigue (TwPdi fall ≥10%) was present in 80% (20min after IML) and 70% (45min after IML) of the LBP patients compared to 40% (p=0.010) and 30% (p=0.005) of the controls, respectively. Individuals with LBP exhibit propensity for diaphragm fatigue, which was not observed in controls. An association with reduced spinal control warrants further study. 23761409 Genomic analysis of coxsackieviruses A1, A19, A22, enteroviruses 113 and 104: viruses representing two clades with distinct tropism within enterovirus C. Coxsackieviruses (CV) A1, CV-A19 and CV-A22 have historically comprised a distinct phylogenetic clade within Enterovirus (EV) C. Several novel serotypes that are genetically similar to these three viruses have been recently discovered and characterized. Here, we report the coding sequence analysis of two genotypes of a previously uncharacterized serotype EV-C113 from Bangladesh and demonstrate that it is most similar to CV-A22 and EV-C116 within the capsid region. We sequenced novel genotypes of CV-A1, CV-A19 and CV-A22 from Bangladesh and observed a high rate of recombination within this group. We also report genomic analysis of the rarely reported EV-C104 circulating in the Gambia in 2009. All available EV-C104 sequences displayed a high degree of similarity within the structural genes but formed two clusters within the non-structural genes. One cluster included the recently reported EV-C117, suggesting an ancestral recombination between these two serotypes. Phylogenetic analysis of all available complete genome sequences indicated the existence of two subgroups within this distinct Enterovirus C clade: one has been exclusively recovered from gastrointestinal samples, while the other cluster has been implicated in respiratory disease. 23943523 The Expression and Release of Hsp60 in 6-OHDA Induced In Vivo and In Vitro Models of Parkinson's Disease. In Parkinson's disease, dopaminergic neuron damage/death causes the release of soluble substances that are selectively toxic to neighboring/additional dopaminergic neurons through the activation of microglia. Hsp60 can be released from injured cells of central nervous system to activate microglia. However, its expression and role in Parkinson's disease has not been well understood. Here, we performed a 6-OHDA treated Parkinson's disease model in adult rats. Western blot analysis showed a time-course expression of Hsp60, which decreased gradually and then rose back. Immunofluorescence staining showed that Hsp60 was decreased in dopaminergic neuron, and most Hsp60 located on the surface of activated microglia. Furthermore, in cellular Parkinson's disease model, Hsp60 was obviously detected in the culture supernatants after 6-OHDA treatment, and a concomitant decrease in cell extracts. Taken together, our results suggested that Hsp60 could be released extracellularly to activate microglia in Parkinson's disease model. 23962656 Towards Precision Medicine: Advances in Computational Approaches for the Analysis of Human Variants. Variations and similarities in our individual genomes are part of our history, our heritage, and our identity. Some human genomic variants are associated with common traits such as hair and eye color, while others are associated with susceptibility to disease or response to drug treatment. Identifying the human variations producing clinically relevant phenotypic changes is critical for providing accurate and personalized diagnosis, prognosis, and treatment for diseases. Furthermore, a better understanding of the molecular underpinning of disease can lead to development of new drug targets for precision medicine. Several resources have been designed for collecting and storing human genomic variations in highly structured, easily accessible databases. Unfortunately, a vast amount of information about these genetic variants and their functional and phenotypic associations is currently buried in the literature, only accessible by manual curation or sophisticated text text-mining technology to extract the relevant information. In addition, the low cost of sequencing technologies coupled with increasing computational power has enabled the development of numerous computational methodologies to predict the pathogenicity of human variants. This review provides a detailed comparison of current human variant resources, including HGMD, OMIM, ClinVar, and UniProt/Swiss-Prot, followed by an overview of the computational methods and techniques used to leverage the available data to predict novel deleterious variants. We expect these resources and tools to become the foundation for understanding the molecular details of genomic variants leading to disease, which in turn will enable the promise of precision medicine. 23376799 Reduction of Hepatitis B Surface Antigen and Covalently Closed Circular DNA by Nucleos(t)ide Analogues of Different Potency. Few studies have investigated the effects of different nucleos(t)ide analogues against hepatitis B virus (HBV) on levels of covalently closed circular DNA (cccDNA) and hepatitis B surface antigen (HBsAg) in patients. We measured the magnitude of reduction of cccDNA and HBsAg by nucleos(t)ide analogue therapy and assessed the correlation between their reductions. We recruited 124 patients who were treated with 1 of the 5 nucleos(t)ide analogues (lamivudine, adefovir, entecavir, telbivudine, or clevudine). All patients had undergone liver biopsy when treatment began (baseline) and 1 year later. The cccDNA and HBsAg levels were measured by real-time polymerase chain reaction and the Elecsys II HBsAg Assay, respectively. After 1 year of treatment, HBV in 7 patients had become resistant to the nucleos(t)ide analogue. The remaining 117 patients had an average reduction of approximately 0.2 log10 IU/mL in HBsAg, 5 log10 IU/mL in serum level of HBV DNA, 2 log10 copies/cell in intrahepatic total HBV DNA, and 1 log10 copies/cell in cccDNA. Although 88 of 117 patients (75%) had undetectable serum levels of HBV DNA (<12 IU/mL), all had detectable levels of HBsAg, and only 5 (4%) had undetectable levels of cccDNA. On treatment with nucleos(t)ide analogues, patients with greater reductions in levels of cccDNA had greater reductions in HBsAg, but these reductions did not reach statistically significant correlations. Although nucleos(t)ide analogues potently reduced serum levels of HBV DNA, the reduction of HBsAg and cccDNA was small. In short-term therapy, the magnitude of HBsAg reduction does not correlate with that of cccDNA reduction. 23958226 Tony (Anthony James) Pawson, a giant in the field of cell signaling research, dies unexpectedly at the age of 60. Tony was widely recognized as a world leader in the field of signal transduction and conducted seminal work especially on signaling processes related to protein -- protein interactions and cancers. He will be much missed by many colleagues around the world. 23572528 A Role for Cargo in the Activation of ADP-Ribosylation Factors (Arf) and Adaptor Recruitment. Membrane traffic requires the specific concentration of protein cargos and exclusion of other proteins into nascent carriers. Critical components of this selectivity are the protein adaptors that bind to short, linear motifs in the cytoplasmic tails of transmembrane protein cargos and sequester them into nascent carriers. The recruitment of the adaptors is mediated by activated Arf GTPases and the Arf-adaptor complexes mark sites of carrier formation. However, the nature of the signal(s) that initiate carrier biogenesis remains unknown. We examined the specificity and initial sites of recruitment of Arf-dependent adaptors (AP-1 and GGAs) in response to the Golgi or endosomal localization of specific cargo proteins (furin, mannose-6-phosphate receptor (M6PR) and M6PR lacking a C-terminal domain M6PRΔC). We find that cargo promotes the recruitment of specific adaptors, suggesting that it is part of an upstream signaling event. Cargos do not promote adaptor recruitment to all compartments in which they reside and thus additional factors regulate the cargo's ability to promote Arf activation and adaptor recruitment. We document that within a given compartment different cargos recruit different adaptors suggesting that there is little or no free, activated Arf at the membrane and that Arf activation is spatially and temporally coupled to the cargo and the adaptor. Using temperature block, Brefeldin A, and recovery from each, we found that the cytoplasmic tail of M6PR causes the recruitment of AP-1 and GGAs to recycling endosomes and not at the Golgi, as predicted by steady state staining profiles. These results are discussed with respect to the generation of novel models for cargo-dependent regulation of membrane traffic. 23665102 Initial reactivity and magnitude of the acute stress response associated with personality in wild great tits (Parus major). Phenotypic correlations, such as those between functionally distinct behavioral traits, can emerge through the action of selection on individual traits, on trait combinations, and through pleiotropic mechanisms. Steroid hormones are known to have pleiotropic effects on a suite of behavioral and physiological traits, including stable individual differences in coping with stress. Characterizing the stress axis in relation to personality, however, has typically focused on estimating baseline and peak levels of glucocorticoids, principally in captive animals. In contrast, the reactivity of the stress response-how quickly it turns on and persists-may better indicate the ability of an individual to cope with challenges, particularly in free-living animals. Using wild great tits (Parus major) we tested the hypothesis that cautious individuals respond to a standardized stressor with a more reactive stress response compared to bolder individuals. Wild birds were captured and tested for exploration behavior in a novel environment-an operational measure of personality in this species-and assessed separately for their glucocorticoid response to a standardized stressor. Slower explorers exhibited a greater elevation in glucocorticoid levels within the first three minutes after capture. Further, slower explorers reached a higher maximum CORT concentration and had higher total exposure to glucocorticoids during the stressor period. These data provide evidence that the temporal reactivity of the endocrine stress response, specifically its speed and magnitude, is associated with stable behavioral traits in free-living animals. 23919455 Anesthesia and Duchenne or Becker muscular dystrophy: review of 117 anesthetic exposures. Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are associated with life-threatening perioperative complications, including rhabdomyolysis, hyperkalemia, and hyperthermia. Current recommendations contraindicate use of succinylcholine and volatile anesthetics; however, the latter recommendation remains controversial. To review the perioperative outcomes of patients with DMD and BMD. We reviewed records of patients with DMD or BMD who underwent anesthetic management at our institution from January 1990 through December 2011. We identified 47 patients (DMD, 37; BMD, 10) who underwent 117 anesthetic exposures (DMD, 101; BMD, 16). Volatile anesthetic agents were used 66 times (DMD, 59; BMD, 7). One patient with undiagnosed BMD received succinylcholine and developed acute rhabdomyolysis and hyperkalemic cardiac arrest. All other major complications were attributed to the procedure (i.e., large bleeding), to preexisting comorbidities (i.e., respiratory failure, cardiac disease), or to both. Use of succinylcholine in children with dystrophinopathy is contraindicated. These patients have significant comorbidities and are frequently undergoing extensive operations; complications related to these factors can develop, as evidenced by our series. These complications may occur with use of volatile and nonvolatile anesthetics. However, because most of our patients were older than 8 years at the time of surgery, our observation cannot be generalized to younger dystrophin-deficient children. 23839423 156 Adult Deformity Surgery (ASD) Patients Recall Fewer Than 50% of the Risks Discussed in the Informed Consent Process Preoperatively and the Recall Rate Worsens Significantly in the Postoperative Period. Complication rates in ASD are high. Although informed consent is standard, there is a paucity of data to assess retention. Patients who experience complications may claim they were never informed of the risks simply because they cannot recall them. The goal of this study was to objectively quantitate retention of key portions of the consent process. Patients having ASD surgery underwent standard surgeon guided informed consent followed by watching a 20 minutes video detailing 11 complications. At preop, hospital discharge, 6wks, and 3 and 6mos post-op, patients completed a quiz assessing recall of the 11 complications and rating of both the commonality and severity of each complication: 0 (minor) 10 (very severe). Patients were also scored on a 16 point mini-mental status exam (MMSE-BV). Thirty patients (median age = 60.5 yrs [range = 26-83)]). Immediate preoperative recall after video viewing was 41%. Postoperative recall (vs preop) was worse on discharge (23%, P < .001), 6weeks (21%, P < .001) and 6mos (20%, P = .004). Preoperative MMSE-BV was 15, discharge (14), postop visit (15), and 6mos (15). Patients rated the process important (10, scale 0-10) and the video helpful (9). Patient severity scores were lower than surgeons for need for additional surgery, medical complications, new weakness, blindness, and death (all P < .05). Patient severity scores were higher than surgeons for transfusion and CSF leak (all P < .05). There was no association at any postoperative timepoint between recall and the following: subjective severity score, prior spinal surgery, ICU stay, total hospital stay, ASA class, MMSE-2 and postoperative complications (P > .5). Patients feel the informed consent process is important, but their recall of key risks remains poor and declines over time, despite video augmentation. Significant progress remains to improve informed consent retention. Despite being well informed in an augmented informed consent process, patients cannot recall most surgical risks discussed. 23697798 The in vivo regulation of heart rate in the murine sinoatrial node by stimulatory and inhibitory heterotrimeric G proteins. Reciprocal physiological modulation of heart rate is controlled by the sympathetic and parasympathetic systems acting on the sinoatrial (SA) node. However, there is little direct in vivo work examining the role of stimulatory and inhibitory G protein signaling in the SA node. Thus, we designed a study to examine the role of the stimulatory (Gαs) and inhibitory G protein (Gαi2) in in vivo heart rate regulation in the SA node in the mouse. We studied mice with conditional deletion of Gαs and Gαi2 in the conduction system using cre-loxP technology. We crossed mice in which cre recombinase expression was driven by a tamoxifen-inducible conduction system-specific construct with "Gαs floxed" and "Gαi2 floxed" mice. We studied the heart rate responses of adult mice compared with littermate controls by using radiotelemetry before and after administration of tamoxifen. The mice with conditional deletion of Gαs and Gαi2 had a loss of diurnal variation and were bradycardic or tachycardic, respectively, in the daytime. In mice with conditional deletion of Gαs, there was a selective loss of low-frequency power, while with deletion of Gαi2, there was a loss of high-frequency power in power spectral analysis of heart rate variability. There was no evidence of pathological arrhythmia. Pharmacological modulation of heart rate by isoprenaline was impaired in the Gαs mice, but a muscarinic agonist was still able to slow the heart rate in Gαi2 mice. We conclude that Gαs- and Gαi2-mediated signaling in the sinoatrial node is important in the reciprocal regulation of heart rate through the autonomic nervous system. 23918956 Origin, trafficking, and intraepithelial fate of gut-tropic T cells. The small intestine epithelium (SI-Ep) harbors millions of unconventional (γδ and CD4(-) CD8(-) NK1.1(-) TCRαβ) and conventional (CD8αβ and CD4) T cells, designated intraepithelial lymphocytes (IELs). Here, we identified the circulating pool of SI-Ep-tropic T cells and studied their capacity to colonize the SI-Ep under steady-state conditions in SPF mice. Developmentally regulated levels of α4β7 endowed recent thymic emigrants (RTEs) of unconventional types with higher SI-Ep tropism than their conventional homologues. SI-Ep-tropic RTEs, which in all lineages emerged naive, homed to the SI-Ep, but this environment was inadequate to stimulate them to cycle. In contrast, conventional and, unexpectedly, unconventional T cells, particularly Vγ7(+) (hallmark of γδ IELs), previously stimulated to cycle in the gut-associated lymphoid tissue (GALT), proliferated in the SI-Ep. Cycling unconventional SI-Ep immigrants divided far more efficiently than their conventional homologues, thereby becoming predominant. This difference impacted on acquisition of high Granzyme B content, which required extensive proliferation. In conclusion, SI-Ep-tropic T cells follow a thymus-SI-Ep or a GALT-SI-Ep pathway, the latter generating highly competitive immigrants that are the sole precursors of cytotoxic IELs. These events occur continuously as part of the normal IEL dynamics. 23920244 A Profile of Residents in Prairie Nursing Homes. ABSTRACT Nursing homes have become complex care environments where residents have significant needs and most have age-related dementia. Building on research by Hirdes et al. (2011), we describe a resident profile in a representative sample of 30 urban nursing homes in the prairie provinces using Resident Assessment Instrument - Minimum Data Set 2.0 data from 5,196 resident assessments completed between 1 October 2007 and 31 December 2011. Residents were chiefly over age 85, female, and with an age-related dementia. We compared facility support and related services and resident characteristics by province, owner-operator model, and number of facility units. We observed differences in support and related services by both unit count and province. We also found that public facilities tend to care for residents with more demanding characteristics: notably cognitive impairment, aggressive behaviours, and incontinence. No clear trends associating the number of units in a facility with resident characteristics were observed. 23671054 Oligonorbornenes with hammock-like crown ether pendants as artificial transmembrane ion channel. Trimeric oligonorbornenes with hammock-like crown ether pendants 3b and 3c were selectively synthesized by cascade metathetical cyclopolymerization upon treatment with the first generation Grubbs catalyst. These crown-ether-containing oligonorbornenes are impregnated in egg yolk phosphatidylcholine (EYPC) liposome as an artificial ion channel. The efficiency of the sodium ion transport properties has been examined. Oligomer 3c having a polar hydroxy end group exhibits the highest transport efficiency, which is comparable with the best efficiencies reported in literature. The orientation of the crown ether moieties in these oligomers may be critical for the ion transport properties. 23842001 Identification of a Novel Proteoform of Prostate Specific Antigen (SNP-L132I) in Clinical Samples by Multiple Reaction Monitoring. Prostate specific antigen (PSA) is a well-established tumor marker, which is frequently employed as model biomarker to develop and evaluate emerging quantitative proteomics techniques, partially due to wide access to commercialized immunoassays serving as "gold standard". We designed a multiple reaction monitoring (MRM) assay to detect PSA proteoforms in clinical samples (n=72), utilizing specificity and sensitivity of the method. We report for the first time, a PSA proteoform, coded by SNP-L132I (rs2003783), observed in 9 samples in both heterozygous (n=7) and homozygous (n=2) expression profiles. Other isoforms of PSA, derived from protein databases, were not identified by four unique proteotypic tryptic peptides. We have also utilized our MRM assay for precise quantitative analysis of PSA concentrations in both seminal and blood plasma samples. The analytical performance was evaluated, providing close agreement between each quantitation based on three selected peptides (LSEPAELTDAVK, IVGGWECEK and SVILLGR) and a routinely used commercialized immunoassay. Additionally, we have disclosed that the peptide IVGGWECEK is shared with kallikrein-related peptidase 2 and therefore not unique for PSA. Hence, we propose to use another tryptic sequence (SVILLGR) for accurate MRM-quantification of PSA in clinical samples. 23628608 Microdroplet-based multiplex PCR on chip to detect foodborne bacteria producing biogenic amines. The development of fast, reliable and culture-independent molecular tools to detect bacteria producing biogenic amines deserves the attention of research and ultimately of the food industry in order to protect consumers' health. Here we present the application of a simple, low-cost, fast and sensitive method to perform microdroplet-based multiplex PCR, directly on a food matrix, for the simultaneous detection of bacterial genes involved in biogenic amine biosynthesis. After inoculating wine with Lactobacillus brevis IOEB 9809, cell lysis and DNA amplification are performed in one single step, without preliminary nucleic acid extraction or purification treatments. The assay is performed in about 30 min, requiring 150 nL of starting sample and it enables the detection of down to 15 bacterial cells. With respect to traditional culture techniques, the speed, the simplicity and the cheapness of this procedure allow an effective monitoring of microbial cells during food-making and processing. 23867920 Effect of Lip Closure on Early Maxillary Growth in Patients With Cleft Lip and Palate. IMPORTANCE Debate continues about the cause of midfacial growth disturbance in patients with facial clefts. OBJECTIVE To evaluate the functional effect of surgical closure of the lip before palatal closure according to the technique by Delaire on early maxillary growth in patients with complete unilateral cleft lip and palate. DESIGN, SETTING, AND PARTICIPANTS Twenty-two patients with unilateral cleft lip and palate were studied using plaster casts obtained at the time of cheilorhinoplasty and 6 months later before palatal closure. The interrupted lateral muscles were anatomically repositioned using the surgical technique by Delaire. No patients had received preoperative orthodontic treatment or a passive palatal plate. Cast analyses were performed using a digital caliper. MAIN OUTCOMES AND MEASURES Landmark positioning was performed 3 times by 2 different examiners to define intraobserver and interobserver differences. The final maxilla dimensions were recorded as the distances between the mean landmark positions. Using the t test, dimensions obtained before palatal closure were compared with dimensions obtained before lip closure. RESULTS The method allowed good reproducibility. Functional closure of the lip significantly narrowed the transverse anterior cleft areas by -2.36 mm (P < .05). Sagittal variables were increased by 1.68 mm on the nonaffected side and by 1.48 mm on the affected side (P < .05 for both). CONCLUSIONS AND RELEVANCE Functional closure according to the technique by Delaire narrows the transverse dimensions of the maxilla, while simultaneously preserving initial sagittal growth. LEVEL OF EVIDENCE 4. 23614491 Regulation of circadian locomotor rhythm by neuropeptide Y-like system in Drosophila melanogaster. Circadian rhythms in behaviour and physiology exist widely in animals, plants, fungi and cyanobacteria. Although much work has been carried out to characterize the endogenous clock circuit, the output signals coupling the circadian pacemaker to behaviour and physiology remain elusive. Here, we show that neuropeptide F (NPF), a homologue of mammalian neuropeptide Y, and its G protein-coupled receptor NPFR1 regulate the locomotor rhythm in Drosophila melanogaster. Flies with loss of function in NPF or NPFR1 were unable to ramp up their activity before lights off under light : dark (LD) cycles, and oscillations in npf/NPF and npfr1/NPFR1 were found to correlate temporally with the locomotor rhythm. Furthermore, NPF is expressed in clock neurones including dorsolateral neurones (LNd s) and ventrolateral neurones (LNv s), whereas NPFR1 is expressed in dorsal neurone 1 (DN1) and LNd s. These results show that NPF signalling is involved in the circadian locomotor rhythm in LD cycles. 23850090 Treatment of pyoderma gangrenosum with mycophenolate mofetil as a steroid-sparing agent. Mycophenolate mofetil (MMF) has enjoyed increasing popularity as an emerging immunosuppressant treatment for various autoimmune dermatologic conditions, including pyoderma gangrenosum (PG). The aim of this study was to examine the efficacy and safety of MMF as used in PG. A retrospective chart review was conducted for all patients with PG treated with MMF at our institution (Victoria, Australia) for the past 11 years (2001-2012). We identified 26 patients, 14 female and 12 male. Nine patients (34.6%) had associated systemic conditions. All patients received prednisolone. MMF was used as a first-line steroid-sparing agent in 11 patients (42.3%), second-line in 14 (53.8%), and third-line in 1 (3.85%). The average duration of treatment was 12.1 months. Fourteen patients experienced side effects (53.8%), although most were mild (26.9%). One patient died after a sigmoid colon perforation (3.85%). Overall 22 patients demonstrated clinical improvement during MMF treatment (84.6%). Thirteen patients achieved complete ulcer healing (50%), 10 while taking MMF and 3 after ceasing it. This is a retrospective study based on a single-center cohort. Our experience suggests that MMF is highly efficacious in PG together with prednisolone, or as part of combination therapy with other immunosuppressants. 23670972 Limitations of IL-2 and Rapamycin in Immunotherapy of Type 1 Diabetes. Administration of low-dose interleukin-2 (IL-2) alone or combined with rapamycin (RAPA) prevents hyperglycemia in NOD mice. Also, low-dose IL-2 cures recent-onset type 1 diabetes (T1D) in NOD mice, partially by boosting pancreatic regulatory T cells (Treg cells). These approaches are currently being evaluated in humans. Our objective was to study the effect of higher IL-2 doses (250,000-500,000 IU daily) as well as low-dose IL-2 (25,000 IU daily) and RAPA (1 mg/kg daily) (RAPA/IL-2) combination. We show that, despite further boosting of Treg cells, high doses of IL-2 rapidly precipitated T1D in prediabetic female and male mice and increased myeloid cells in the pancreas. Also, we observed that RAPA counteracted IL-2 effects on Treg cells, failed to control IL-2-boosted NK cells, and broke IL-2-induced tolerance in a reversible way. Notably, the RAPA/IL-2 combination failure to cure T1D was associated with an unexpected deleterious effect on glucose homeostasis at multiple levels, including β-cell division, glucose tolerance, and liver glucose metabolism. Our data help to understand the therapeutic limitations of IL-2 alone or RAPA/IL-2 combination and could lead to the design of improved therapies for T1D. 23298744 Facile sonochemical synthesis of novel pyrazolyne derivates at ambient conditions. Claisen-Schmidt condensation reaction of 4-acetamidoacetophenone with aromatic aldehydes under ultrasonic irradiation affords acetylaminochalcones (yields: 71-90%) which also under ultrasonic irradiation and in the presence of sodium acetate and acetic acid aqueous undergo facile and clean cyclocondensation with hydrazine to afford 3-(4-acetamidophenyl)-5-(aryl)-1-H-pyrazolines. The pyrazolines were obtained in good to excellent yields (81-89%), and were characterized by conventional spectral data. The work-up is simple and the results obtained indicate that, unlike classical heating, ultrasonic irradiation results in higher yields, shorter reaction times (1.5-2.3 h) and milder conditions. 23307694 Development and characterization of new peptidomimetic inhibitors of the West Nile virus NS2B-NS3 protease. A series of new substrate analogue inhibitors of the WNV NS2B-NS3 protease containing decarboxylated arginine mimetics at the P1 position was developed. Among the various analogues, trans-(4-guanidino)cyclohexylmethylamide (GCMA) was identified as the most suitable P1 residue. In combination with dichloro-substituted phenylacetyl groups at the P4 position, three inhibitors with inhibition constants of <0.2 μM were obtained. These GCMA inhibitors have a better selectivity profile than the previously described agmatine analogues, and possess negligible affinity for the trypsin-like serine proteases thrombin, factor Xa, and matriptase. A crystal structure in complex with the WNV protease was determined for one of the most potent inhibitors, 3,4-dichlorophenylacetyl-Lys-Lys-GCMA (K(i)=0.13 μM). The inhibitor adopts a horseshoe-like conformation, most likely due to a hydrophobic contact between the P4 phenyl ring and the P1 cyclohexyl group, which is further stabilized by an intramolecular hydrogen bond between the P1 guanidino group and the P4 carbonyl oxygen atom. These inhibitors are stable, readily accessible, and have a noncovalent binding mode. Therefore, they may serve as suitable lead structures for further development. 23968973 Response inhibition during avoidance of virtual obstacles while walking. While walking, one often has to suppress and adjust a planned step in order to avoid a fall. Given that steps are preprogrammed this requires some form of motor inhibition. Motor inhibition is commonly tested in hand function and only recently attempts have been made to evaluate inhibition in the lower limbs, during step initiation. As adequate motor inhibition might play a role in avoiding falls a test to assess response inhibition during walking would be valuable. We developed a task in which subjects walked on a treadmill by stepping on projected patches of light, which could suddenly change color forcing the subjects to avoid it by shortening or lengthening their steps. The difficulty level was manipulated in 4 conditions by changing the distance available to respond. We hypothesized that larger demands on motor inhibition during walking would produce more failures and tested the performance of young adults (n=12) in order to establish the protocol for use in older adults. The failure rate on the walking test was analyzed. Reducing the available response distance by 150 mm from the easiest condition resulted in a significant increase in failure rates from 15.6% to 65.1%. Therefore, results indicate this novel test can be used to assess the level of motor inhibition during walking. Additionally, in comparison to previous literature on obstacle avoidance, our experiment shows that changing a precise aiming movement is considerably more challenging than changing the same movement executed automatically. 23748072 Chronic treatment with DCPCX, an adenosine A1 antagonist, worsens long-term memory. Alzheimer's disease is characterized by progressive cognitive disturbances and neurotransmitter dysfunction. Previous studies targeting the adrenergic A1 pathway suggest that this plays a role in cognitive impairment in Alzheimer's disease. Previous studies have reported that acute treatment with A1 antagonists appears to improve behavioral deficits in rodent models of memory and behavioral impairment. In this study, we addressed whether the chronic administration of 8-cyclopentyl-1,3-dipropylxanthine, a potent and selective adenosine A1 antagonist, could reverse the memory deficits found in aged APPswe/PS1dE9 mice. Chronic treatment did not improve memory in the APPswe/PS1dE9 mouse model and resulted in reduced exploratory behavior, suggestive of reduced anxiety, and a worsening of long-term memory in nontransgenic mice. These results have important implications for understanding the mechanisms of A1 receptor modulation as a target in Alzheimer's disease therapy. 23901058 N-terminal pro brain natriuretic peptide but not copeptin improves prediction of heart failure over other routine clinical risk parameters in older men with and without cardiovascular disease: population-based study. Measurement of NT-proBNP and copeptin may help identify those at high risk of heart failure (HF). However the value of NT-proBNP and copeptin has been little studied in the older population in primary care. This study aims to examine the use of NT-proBNP and copeptin in improving risk prediction and stratification of HF in older men with and without cardiovascular disease (CVD). This was a prospective study of 3870 men aged 60-79 years with no diagnosed HF followed up for a mean period of 11 years, during which there were 254 incident HF cases. NT-proBNP was associated with HF in those with and without established CVD [diagnosed myocardial infarction (MI), angina, or stroke]. NT-proBNP improved prediction beyond routine conventional risk factors (age, obesity, diabetes, hypertension, history of MI, and history of angina) and the Health ABC Heart Failure Score in all men and in men with and without established CVD (P<0.0001 for improvement in c-statistics). The net reclassification index (NRI) beyond conventional risk factors was 18.8% overall (27.4% for men without CVD and 17.4% for men with CVD). In contrast, copeptin was associated with HF in men with CVD only and did not improve prediction of HF after inclusion of conventional risk factors (P = 0.95 for improvement in c-statistics). NT-proBNP, but not copeptin significantly improves prediction and risk stratification of HF beyond routine clinical parameters obtained in general practice settings in older men both with and without established CVD. 23939632 Mutation of the CgPDR16 gene attenuates azole tolerance and biofilm production in pathogenic Candida glabrata. The PDR16 gene encodes the homologue of Sec14p, participating in protein secretion, regulation of lipid synthesis and turnover in vivo and acting as a phosphatidylinositol transfer protein in vitro. This gene is also involved in the regulation of multidrug resistance in Saccharomyces cerevisiae and pathogenic yeasts. Here we report the results of functional analysis of the CgPDR16 gene, whose mutation has been previously shown to enhance fluconazole sensitivity in Candida glabrata mutant cells. We have cloned the CgPDR16 gene, which was able to complement the pdr16Δ mutation in both C. glabrata and S. cerevisiae. Along with fluconazole, the pdr16Δ mutation resulted in increased susceptibility of mutant cells to several azole antifungals without changes in sensitivity to polyene antibiotics, cycloheximide, NQO, 5-fluorocytosine and oxidants inducing the intracellular formation of reactive oxygen species. The susceptibility of the pdr16Δ mutant strain to itraconazole and 5-fluorocytosine was enhanced by CTBT [7-chlorotetrazolo(5,1-c)benzo(1,2,4)triazine] inducing oxidative stress. The pdr16Δ mutation increased the accumulation of rhodamine 6G in mutant cells, decreased the level of itraconazole resistance caused by gain-of-function mutations in the CgPDR1 gene, and reduced cell surface hydrophobicity and biofilm production. These results point to the pleiotropic phenotype of the pdr16Δ mutant and support the role of the CgPDR16 gene in the control of drug susceptibility and virulence in the pathogenic C. glabrata. Copyright © 2013 John Wiley & Sons, Ltd. 23401471 Species difference in the mechanism of nonlinear pharmacokinetics of e2074, a novel sodium channel inhibitor, in rats, dogs, and monkeys. New chemical entities often exhibit nonlinear pharmacokinetics (PK) profiles in experimental animals. However, the number of studies that have focused on species differences in nonlinear PK is very limited; thus, the aim of this study was to clarify the mechanism of the nonlinear PK of E2074 (2-[(2R)-2-fluoro-3-{(3r)-[(3-fluorobenzyl)oxy]-8-azabicyclo[3.2.1]oct-8-yl}propyl]-4,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one), a novel sodium channel inhibitor, in rats, dogs, and monkeys. Nonlinear PK profiles with more than dose-proportional increases of Cmax and area under the plasma concentration curve were observed in all species after oral administration. The Michaelis-Menten constant (Km) values of hepatic microsomal metabolism were 7.23 and 0.41 μM in rats and dogs in vitro, respectively, which were lower than the unbound maximum plasma concentrations after oral administration in vivo, indicating that the nonlinear PK in rats and dogs was attributable to the saturation of hepatic metabolism. However, we do not believe that the saturation of hepatic metabolism was the mechanism of nonlinearity in monkeys because of the high Km value (42.44 μM) observed in liver microsomes. Intestinal metabolism was observed in monkey intestinal microsomes but not in rats and dogs, and the nonlinear PK in monkeys was diminished by inhibition of intestinal metabolism with a concomitant oral dose of ketoconazole. These results suggest that saturation of the intestinal metabolism is the potential mechanism of nonlinearity in monkeys. P-glycoprotein was not involved in the nonlinear PK profiles in any species. In conclusion, the mechanism of the nonlinear PK of E2074 is species dependent, with the saturation of hepatic metabolism in rats and dogs and that of intestinal metabolism in monkeys being the primary cause. 23548583 Nrf2-dependent neuroprotective activity of diterpenoids isolated from Sideritis spp. ETHNOPHARMACOLOGICAL RELEVANCE: The species of the genus Sideritis are extensively used in the Mediterranean area in folk medicine for their digestive, antimicrobial, anti-inflammatory and antioxidant properties, among others. Moreover, Sideritis species as tea infusions are popularly known for improving memory function and cognitive ability. Diterpenoids are one of the most abundant and important pharmacological interest of the classes of natural products presented in these medicinal plants. AIM OF THE STUDY: To determine for the first time the neuroprotective effects, based on their antioxidant properties, of the three isolated major diterpenoids andalusol, conchitriol and lagascatriol in an oxidative stress model. MATERIALS AND METHODS: H2O2 was used as oxidant inductor and rat adrenal pheochromocytoma PC12 cells as cellular model. Cell viability was measured using MTT and LDH assays, lipid peroxidation was determined by HPLC, GSH and GSSG levels assessed by fluorometric techniques, enzymatic activity and protein expression were determined by spectrofometric techniques and Western blot, respectively. RESULTS: Pretreatments with the three diterpenoids significantly attenuated H2O2-induced changes in mitochondrial integrity and activity (MTT assay), in cell membrane integrity (LDH assay) and in cell morphology. Moreover, these diterpenoids inhibited intracellular ROS production H2O2-induced, reduced lipid peroxidation and counteracted GSH/GSSG changes. Furthermore, both activities and protein expression of the endogenous antioxidant enzymes (CAT, SOD, GR, GPx and HO-1) were increased. The Nrf2 pathway was involved, at least in part, in the protective effects of these diterpenoids. CONCLUSION: These findings suggest that these natural compounds provide significant antioxidant effects in PC12 under for counteracting the oxidative damage H2O2-induced and their potential role as useful agents for the prevention of those oxidative stress-mediated dementia disorders. Andalusol was the most active compound among the studied diterpenoids. 23914907 Association of Interleukin-18 (-137G/C) Polymorphism with Rheumatoid Arthritis and Systemic Lupus Erythematosus: A Meta-Analysis. Background: Recent studies have suggested that interleukin (IL)-18 gene (-137G/C) polymorphism is associated with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, other studies did not confirm this correlation. Objective: The objective of this study was to evaluate the relationships of IL-18 -137G/C and RA and SLE using a meta-analysis. Methods: Pubmed, Embase and Cochrane library databases were systemically searched. Data were extracted by two independent reviewers and pooled odds ratio (OR) with 95% confidence interval (CI) was calculated. Results: In RA, the overall ORs and 95% CIs of -137C were 1.03, 0.88-1.22 (p = 0.391); 1.22, 0.89-1.68 (p = 0.020) and 1.06, 0.93-1.21 (p = 0.110) in dominant, recessive, and additive models, respectively. Furthermore, in SLE, the overall ORs and 95% CIs of -137C were 1.10, 0.94-1.29 (p = 0.980); 1.21, 0.91-1.60 (p = 0.010) and 1.10, 0.97-1.24 (p = 0.454) in dominant, recessive, and additive models, respectively. IL-18 -137G/C could increase the risk of RA and SLE. No publication bias was found in this meta-analysis. After population stratification analysis, under recessive model, the pooled ORs and 95% CIs of -137C were 1.14, 0.82-1.60 (p = 0.008) and 1.01, 0.66-1.55 (p = 0.004) in European RA patients and Asian SLE patients, respectively. Conclusions: This meta-analysis showed that IL-18 -137G/C was a risk factor for RA and SLE, especially for RA in Europeans and SLE in Asians. 23924473 Association between the polymorphisms of interleukin-4, the interleukin-4 receptor gene and asthma. Interleukin-4 (IL4) is one of the most important cytokines involved in a variety of allergic disorders, particularly, asthma. A number of genetic epidemiological studies have identified an association between the gene polymorphisms of IL4 and interleukin-4 receptor (IL4R) and asthma in different populations. However, these studies have been inconsistent and inconclusive. The aim of this study was to investigate the association between the single nucleotide polymorphism (SNP) of IL-4, IL-4R and asthma risk in case-controlled studies using meta-analysis. A genetic model-free approach was used to perform the meta-analysis. Asthma (atopy status nondefined), nonatopic and atopic asthma subgroups were separately analyzed. Next, the ethnic subgroup was analyzed. Heterogeneity and publication bias were also explored. Only two polymorphisms of IL4 (rs2243250 and rs2070874) and four polymorphisms of IL4R (rs1801275, rs1805011, rs1805010, and rs1805015) were included in the meta-analysis. Polymorphisms rs2243250 and rs2070874 of IL-4 and rs1801275 and rs1805011 of IL4R were associated with asthma. The overall odds ratio (OR) of rs2243250 in the CC versus TT+TC genotypes was 0.84 (95% CI: 0.75-0.94), and the Z-test for the overall effect was 3.0 (P = 0.003). We obtained significant results from this polymorphism in the Caucasian ethnicity and adult groups. However, the overall OR of rs1801275 for the GG+AG versus AA genotype was 1.16 (95% CI: 1.00-1.35), and the Z-test for the overall effect was 1.87 (P = 0.06). Moreover, significant results were only obtained from the sub-group analysis in Asians (P = 0.02). In the rs1805011 polymorphism of IL4R, the overall OR for the CC +AC versus AA genotypes was 0.39 (95% CI: 0.16-0.95), and the Z-test for the overall effect was 2.08 (P = 0.04). Both the IL4 and IL4R polymorphisms were associated with asthma. The rs2243250 polymorphism of IL4 was more important in the white and adult groups. Individuals who carried the C allele for rs2070874 of the IL4 gene demonstrated increased asthma risk compared to TT homozygotes. An individual with an AA genotype in rs1805011 of the IL4R gene was less likely to suffer from asthma compared to the other two genotypes. 23770414 Up-regulation of emotional responses to reward-predicting stimuli: An ERP study. Altered reward processing is a hallmark symptom of many psychiatric disorders. It has recently been shown that people are capable of down-regulating reward processing. Here, we examined whether people are capable of up-regulating emotional responses to reward-predicting stimuli. Participants passively viewed colored squares that predicted a reward or no reward, and up- or down-regulated their emotional responses to these reward-predicting stimuli by focusing on the reward meaning or the color of the squares respectively. The amplitude of the late positive potential (LPP) was taken as an objective index of regulation success. The LPP in response to reward-predicting squares was enhanced by up-regulation, suggesting that up-regulation of emotional responses to reward-predicting stimuli using a cognitive strategy is feasible. These results are highly relevant for the treatment of disorders characterized by diminished motivation, and for reward-based decision making in daily life. 22476860 Conservative management of post-transplant central nervous system lymphoma. Primary CNS lymphoma (PCNSL) is a rare B cell variant non-Hodgkins lymphoma that is confined to the brain, leptomeninges, spinal cord and eyes. Its incidence is increasing, primarily due to increase in the number of organ transplantations being undertaken. The majority of the PTLD (post-transplant lymphoproliferative disorder) is seen in kidney transplant recipients simply because they constitute a larger group of transplant recipients each year as compared to other solid organ transplantations. Primary infection of previously infected EBV seronegative patients and immunosuppression are found to be the main etiologic factors in the development of PTLD-PCNSL. There are no clear guidelines on treatment regimens, and it should be individualized according to patient comorbidities. We report a case of PCNS lymphoproliferative disorder in a kidney transplant recipient, which underwent complete remission with decreasing immunosuppression. The patient could not undergo chemotherapy/radiotherapy due to underlying comorbidities. We highlight the available treatment modalities for PTLD-PCNSL. 23805957 Synthesis and Biological Properties of Novel Brefeldin A Analogues. New brefeldin A (1) analogues were obtained by introducing a variety of substituents at C15. Most of the analogues exhibited significant biological activity. (15R)-Trifluoromethyl-nor-brefeldin A (3), (15R)-vinyl-nor-brefeldin A (5), their epimers 4 and 6 as well as (15S)-ethyl-nor-brefeldin A (2) were prepared from the key building blocks 12 or 24 by Julia-Kocienski olefination with tetrazolyl sulfones and subsequent macrolactonization. The vinyl derivative 5 allowed analogues to be synthesized by hydroboration and Suzuki-Miyaura coupling. The following biological properties were assessed: (a) inhibition of cell growth of human cancer cells (NCI), (b) induction of morphological changes of the Golgi apparatus of plant and mammalian cells, and (c) influence on the replication of the enterovirus CVB3. Furthermore, conformational aspects were studied by X-ray crystal structure analysis and molecular mechanics calculations, including docking of the analogues into the brefeldin A binding site of an Arf1/Sec7-complex. 23831140 Technical and Patient-related Characteristics Associated with Challenging Retrieval of Inferior Vena Cava Filters. To identify patient-related and device-specific predictors of challenging and failed inferior vena cava (IVC) filter retrievals. Retrospective single center review of consecutive retrievable IVC filters placed between 2004 and 2009. Retrieval was defined as challenging when it was unsuccessful owing to reported technical failure or when adjunctive endovascular maneuvers or access sites were recruited. Data regarding patient- and filter-specific information were collected. Logistic regression models were used to identify predictors of the reported outcomes. Statistical significance was set at p < .05. Four hundred and one patients underwent retrievable IVC filter placement-the majority indicated for prophylaxis (67%). Two hundred and fifty-nine retrievals were attempted and 237 filters were successfully retrieved (overall retrieval rate: 59.1%). Eleven out of 259 (4.2%) attempts were aborted owing to significant thrombus within the filter and 11 (4.2%) were technically unsuccessful. In 142 patients no attempt for filter retrieval was made-the major reason being physician oversight (44.3%). Thirty-eight out of 248 (15.3%) non-aborted filter retrievals were recorded as challenging. Failed retrievals were predicted by prolonged dwell time (96.9 ± 111.9 vs. 29.5 ± 25.1 days, odds ratio [OR] 1.034, 95% confidence interval [CI] 1.016-1.053, p < .001), therapeutic indication (OR 5.197, 95% CI 1.200-22.511, p = .028), and filter wall apposition (OR 11.857, 95% CI 2.069-67.968, p = .006). Challenging retrievals were predicted by dwell time (51.1 ± 69.8 vs. 29.1 ± 24.5 days, OR 1.017, 95% CI 1.005-1.029, p = .007), filter tilt (OR 2.607, 95% CI 1.045-6.508, p = .040) and filter wall apposition (OR 6.149, 95% CI 2.398-15.763, p = <.001). Physician oversight leads to poor IVC filter retrieval rates. Retrievals can be challenging or fail when the dwell time is >50 days and >90 days, respectively, and when the filter hook apposes the caval wall. Filter tilt increases retrieval difficulty but not failure rates. 23873416 Polymorphism of UBC9 Gene Encoding the SUMO-E2-Conjugating Enzyme and Breast Cancer Risk. UBC9 protein (E2-conjugating enzyme) plays a key role in post-translation modification named sumoylation. Proteins, which are sumoylated take part in many cellular processes including cell growth, maintaining the genome integrity and stability and cancer development. The aim of this study was to investigate an association between three polymorphisms of the UBC9 gene: c.73G>A (rs11553473), c.430T>G (rs75020906) and g.1289209T>C (rs7187167) and a risk of ductal breast cancer occurrence. We performed a case-control study in 181 breast cancer cases and 277 controls using PCR-RLFP and ASO-PCR. In the case of the 430T>G polymorphism of the UBC9 gene lack of variability suggests that there is not a polymorphic site in polish population. We observed that a risk of breast cancer occurrence is elevated in patients with the G/A genotype (OR 5.03; 95 % Cl 3.05-8.28), the A/A genotype (OR 11.3; 95 % Cl 4.24-30.3) and the A allele (OR 6.86; 95 % Cl 4.43-10.6) of the c.73G>A polymorphism. In the case of the g.1289209T>C polymorphism we found a correlation between estrogen receptor (ER) expression and the T/T genotype (OR 0.22; 95 % Cl 0.07-0.64) and the T allele (OR 0.53; 95 % Cl 0.32-0.88). We also found a correlation between the T/T genotype (OR 4.13; 95 % Cl 1.21-14.1) and the T allele (OR 2.09; 95 % Cl 1.07-4.08) of the g.1289209T>C polymorphism with triple negative breast cancer. Our results suggest that the variability of the UBC9 gene can play a role in breast cancer occurrence. 23865524 Highly ordered protein nanorings designed by accurate control of glutathione s-transferase self-assembly. Protein self-assembly into exquisite, complex, yet highly ordered architectures represents the supreme wisdom of nature. However, precise manipulation of protein self-assembly behavior in vitro is a great challenge. Here we report that by taking advantage of the cooperation of metal-ion-chelating interactions and nonspecific protein-protein interactions, we achieved accurate control of the orientation of proteins and their self-assembly into protein nanorings. As a building block, we utilized the C2-symmetric protein sjGST-2His, a variant of glutathione S-transferase from Schistosoma japonicum having two properly oriented His metal-chelating sites on the surface. Through synergic metal-coordination and non-covalent interactions, sjGST-2His self-assembled in a fixed bending manner to form highly ordered protein nanorings. The diameters of the nanorings can be regulated by tuning the strength of the non-covalent interaction network between sjGST-2His interfaces through variation of the ionic strength of the solution. This work provides a de novo design strategy that can be applied in the construction of novel protein superstructures. 23962857 Cortisol levels in cats' hair in presence or absence of Microsporum canis infection. The purpose of this work was to perform a preliminary screening in the domestic cat to assess the concentration of cortisol in hairs by radioimmunoassay technique (RIA) in presence or absence of Microsporum canis infections. A total of 245 cats (7 with cutaneous lesions referable to dermatophytosis and 238 apparently healthy) coming from 14 shelters were examined. M. canis was isolated in 126 (51.4%) cats. The cortisol levels were significantly higher in cats with lesions or without lesions but with a high number of colonies in the plates (⩾10CFU) than in cats negative or with a lower number of colonies. The results obtained seem to highlight that chronic high levels of cortisol in cats could possibly promote the dermatophytes infections. Furthermore, in High-CFU asymptomatic cats, it could be present a state of infectious, and they, therefore, represents not a simple mechanical carrier. 23864540 Thiamine pharmacokinetics in Cambodian mothers and their breastfed infants. Thiamine deficiency is common in parts of Asia and causes beriberi. Pharmacokinetics of thiamine in deficient populations are unknown. We characterized thiamine pharmacokinetics in Cambodian mothers and their breastfed infants. Total plasma thiamine, whole-blood thiamine diphosphate (TDP), and breast milk total thiamine were measured in 16 healthy Cambodian mothers and their infants before and after mothers received oral thiamine hydrochloride (100 mg for 5 d). Assays were also performed in 16 healthy American mothers. On day 1, Cambodian mothers were thiamine deficient, with median (range) total plasma thiamine and TDP concentrations of 2.4 nmol/L (0-4.4 nmol/L) and 58.0 nmol/L (27-98 nmol/L), respectively. After a single oral dose, the mean ± SD maximal concentration of thiamine and net area under the thiamine concentration-time curve were 73.4 ± 45.6 nmol/L and 465 ± 241 h · nmol ⋅ L(-1). Day 6 median maternal total plasma thiamine and TDP concentrations were normal [18.6 nmol/L (13.4-25.3 nmol/L) and 76.5 nmol/L (48-107 nmol/L), respectively; P ≤ 0.001 compared with day 1]. Median Cambodian total breast milk thiamine concentration increased from 180 nmol/L (85-359 nmol/L) on day 1 to 403 nmol/L (314-415 nmol/L) on day 2 and 503 nmol/L (360-808 nmol/L) on day 6; the corresponding American breast milk value was 500 nmol/L (114-622 nmol/L). Median Cambodian infant total plasma thiamine and TDP concentrations increased from 3.0 nmol/L (0-7.3 nmol/L) and 38.5 nmol/L (23-57 nmol/L), respectively, on day 1 to 5.6 nmol/L (0-9.7 nmol/L) and 45.5 nmol/L (32-70 nmol/L), respectively, on day 6. Thiamine-deficient Cambodian mothers effectively absorb oral thiamine, with sharp increases in breast milk thiamine concentrations, but their breastfed infants remain thiamine deficient after 5 d of maternal supplementation. Longer-term maternal supplementation may be necessary to correct thiamine deficiency in breastfed infants. This trial was registered at clinicaltrials.gov as NCT01864057. 23884281 Cell pairing using a dielectrophoresis-based device with interdigitated array electrodes. We present a chip device with an array of 900 gourd-shaped microwells designed to pair single cells of different types. The device consists of interdigitated array (IDA) electrodes and uses positive dielectrophoresis to trap cells within the microwells. Each side of a microwell is on a different comb of the IDA, so that cells of different types are trapped on opposite sides of the microwells, leading to close cell pairing. Using this device, a large number of cell pairs can be formed easily and rapidly, making it a highly attractive tool for controllable cell pairing in a range of biological applications. 23857602 Estrogen Receptor Alpha regulates ATM expression through miRNAs in breast cancer. Estrogen receptor α (ERα) is an essential element regulating mammary gland development and it contributes to breast cancer development and progression. Most of the ER negative breast cancers display more aggressive clinical behaviors and are resistant to anti-estrogen therapies. In addition, many ER negative tumors show insensitivity to many chemotherapeutic drugs and radiation therapy, although mechanisms underlying this phenotype are less clear. We conducted immunohistochemistry on 296 cases of breast cancer tissues using a variety of antibodies. Based on the clinical data, we performed siRNA knock-down to study the role of ERα on ATM expression in breast cancer cell lines. Further we used antisense oligonucleotides against miRNAs or miRNA overexpression plasmids to study the role of miRNA 18a and 106a on ATM expression. Finally we employed in situ hybridization to assess miRNA 18a and 106a expression in breast cancer tissues. We found that in ER negative breast cancer tissues, expression of the ATM kinase, a critical DNA damage response protein, is aberrantly up-regulated. We also found that the locoregional recurrence rate after radiotherapy positively correlates with ATM expression. On the cellular level, we demonstrated that ERα, but not ERβ, negatively regulates ATM expression. Furthermore, we identified that ERα activates miRNA- 18a and 106a to down-regulate ATM expression. We also demonstrated that miRNA-18a and 106a were significantly under-expressed in ER negative breast cancer tissues. We reveal a novel mechanism involving ERα and miRNA 18a and 106a regulation of ATM in breast cancer. 23809416 Initial management of patients with acute heart failure. Pressure exists to manage patients with acute decompensated heart failure (ADHF) efficiently in the acute-care environment. Although most patients present with worsening of chronic heart failure, some may present with undifferentiated dyspnea and new-onset heart failure. Others have significant comorbidities that complicate both the diagnosis and treatment. The treatment of patients with ADHF is prioritized based on vital signs and presenting phenotype. The risk stratification of patients is the subject of ongoing evaluation. The disposition of patients to areas other than a monitored inpatient bed, such as an emergency department-based observation unit, may prove effective. 23831248 Validity of the neurological examination in diagnosing diabetic peripheral neuropathy. The aim of this study was to evaluate the prevalence of diabetic peripheral neuropathy in children and adolescents with type 1 diabetes mellitus and examine whether the neurological examination validly diagnoses diabetic peripheral neuropathy as compared with the gold standard of nerve conduction velocity in these patients. Nerve conduction velocity was measured in an unselected consecutive series of patients aged 8-18 years who had been suffering from type 1 diabetes mellitus for at least 1 year. For the neurological examination, neuropathy disability scores and neuropathy sign scores were used. Of the 39 patients, six (15%) had clinically evident diabetic peripheral neuropathy, whereas nerve conduction velocity testing revealed diabetic peripheral neuropathy in 15 (38%) patients. Sensitivity and specificity of the neurological examination for the diagnosis of diabetic peripheral neuropathy were 40% and 100%, respectively. The corresponding positive and negative predictive values were 100% and 72.7%, respectively. This conclusions from this study are that in children and adolescents with type 1 diabetes mellitus, diabetic peripheral neuropathy is highly prevalent, but in the majority of patients it is subclinical. Sensitivity and negative predictive values of the neurological examination are low. Therefore, routine nerve conduction velocity measurement for the assessment of diabetic peripheral neuropathy appears to be warranted in these patients. 22354384 A neuropsychological perspective on attention problems in neurofibromatosis type 1. Cognitive problems are common in children with neurofibromatosis type 1 and they can often complicate treatment. The current literature review examines cognitive functioning in neurofibromatosis type 1, with a specific focus on executive functioning. This includes exploration of how deficits in executive functioning are expressed in children with neurofibromatosis type 1 and how these deficits contrast with ADHD. The value of investigating subcomponents of executive functioning is discussed, as are implications for effective treatment and future research. 23837748 Dim Light at Night Does Not Disrupt Timing or Quality of Sleep in Mice. Artificial nighttime illumination has recently become commonplace throughout the world; however, in common with other animals, humans have not evolved in the ecological context of chronic light at night. With prevailing evidence linking the circadian, endocrine, immune, and metabolic systems, understanding these relationships is important to understanding the etiology and progression of several diseases. To eliminate the covariate of sleep disruption in light at night studies, researchers often use nocturnal animals. However, the assumption that light at night does not affect sleep in nocturnal animals remains unspecified. To test the effects of light at night on sleep, we maintained Swiss-Webster mice in standard light/dark (LD) or dim light at night (DLAN) conditions for 8-10 wks and then measured electroencephalogram (EEG) and electromyogram (EMG) biopotentials via wireless telemetry over the course of two consecutive days to determine differences in sleep timing and homeostasis. Results show no statistical differences in total percent time, number of episodes, maximum or average episode durations in wake, slow-wave sleep (SWS), or rapid eye movement (REM) sleep. No differences were evident in SWS delta power, an index of sleep drive, between groups. Mice kept in DLAN conditions showed a relative increase in REM sleep during the first few hours after the dark/light transition. Both groups displayed normal 24-h circadian rhythms as measured by voluntary running wheel activity. Groups did not differ in body mass, but a marked negative correlation of body mass with percent time spent awake and a positive correlation of body mass with time spent in SWS was evident. Elevated body mass was also associated with shorter maximum wake episode durations, indicating heavier animals had more trouble remaining in the wake vigilance state for extended periods of time. Body mass did not correlate with activity levels, nor did activity levels correlate with time spent in different sleep states. These data indicate that heavier animals tend to sleep more, potentially contributing to further weight gain. We conclude that chronic DLAN exposure does not significantly affect sleep timing or homeostasis in mice, supporting the use of dim light with nocturnal rodents in chronobiology research to eliminate the possible covariate of sleep disruption. 23588092 Antiulcer and gastric antisecretory effects of dichloromethane fraction and piplartine obtained from fruits of Piper tuberculatum Jacq. in rats. ETHNOPHARMACOLOGICAL RELEVANCE: Piper tuberculatum Jacq. (Piperaceae) is medicinally used as an analgesic and as a treatment for gastric complaints. Thus, the current study aimed to investigate the gastroprotective and antisecretory properties of the dichloromethane fraction of the fruit of Piper tuberculatum (DFPT) and piplartine, a compound isolated from the DFPT, in rats. MATERIALS AND METHODS: Gastric ulcers were induced in fasted rats by oral administration of absolute ethanol and then mucus content and glutathione (GSH) levels were measured. Mechanisms underlying the antisecretory action were studied through gastric H(+),K(+)-ATPase activity of highly purified rabbit gastric microsomes and pylorus ligature method in rats. RESULTS: In the acute toxicity test the values of estimated LD50 for oral and intraperitoneal administration of DFPT were 1.6266 and 0.2684g/kg, respectively. The DFPT (ED50=29mg/kg, p.o.) and piplartine (4.5mg/kg, p.o.) promoted gastroprotection against acute lesions induced by ethanol, effect that could be related with the maintenance of GSH levels in the gastric mucosa. However, only DFPT stimulated gastric mucus secretion. In vitro, the DFPT and piplartine inhibited the H(+),K(+)-ATPase activity and, in vivo DFPT and piplartine also reduced basal gastric acid secretion, as well as that stimulated by pentagastrin. CONCLUSIONS: These results demonstrate that DFPT and piplatine cause marked gastroprotective effects accompanied by the increase and maintenance of gastric mucus and GSH levels, as well as a reduction in gastric acid secretion through the gastrinergic pathway. 23281219 A comparison of allogeneic and autologous mesenchymal stromal cells and osteoprogenitor cells in augmenting bone formation around massive bone tumor prostheses. Spraying autologous mesenchymal stromal cells (MSCs) onto hydroxyapatite (HA)-coated ingrowth collars, located at the shoulder of massive bone tumor implants, significantly increased extracortical bone-bridging and osteointegration in an ovine model. In this study, we investigated the hypothesis that allogeneic MSCs and osteoprogenitor cells (OPCs) will augment bone growth equally when compared with autologous BMSCs. All collars were HA coated. In group i, the HA collar was coated with fibrin glue only. Cells were combined with fibrin glue and implants received (ii) 2 × 10(6) autologous MSCs, (iii) 10 × 10(6) autologous MSCs, (iv) 2 × 10(6) OPCs, (v) 10 × 10(6) OPCs, or (vi) 10 × 10(6) allogeneic MSCs. In group vii, collars were HA coated only. New bone area and bone-implant contact onto the ingrowth collar was quantified radiographically and using histological techniques. Results showed that no extracortical bone formed adjacent to any collars sprayed with allogeneic MSCs and significantly more new bone was measured when all other experimental groups were compared (p < 0.05 in all cases). Most bone growth and bone-implant contact occurred in the 10 × 10(6) OPC group. Spraying MSCs or OPCs onto the implant surface may be used in patients; however, further work is needed to determine the role of allogeneic cells in bone augmentation in vivo. 23453426 Clinical and oncological results of the pathological complete response in rectal cancer after neoadjuvant treatment. Neoadjuvant chemo-radiotherapy is the treatment of choice for rectal cancer in order to reduce local recurrence. Patients with a pathological complete response (PCR) have a better prognosis. The aim of this study was to determine the influence of PCR on the oncological outcomes in our patients. All patients with stage ii/iii rectal cancer treated with neoadjuvant chemo-radiotherapy and radical resection between 2007 and 2011were identified from a prospective database, and grouped based on whether they achieved PCR or not (non-PCR). Clinical, histological and oncological outcome data were compared. A total of 162 patients were included (62% men), with a mean age of 65 years. In terms of pre-operative TNM staging, 82 patients (50%) were T2, 75 (46%) were T3, and 5 (3%) were T4. Forty-two patients (25%) were N1, and 87 (53%) were N2. Low anterior resection and abdominoperineal resection were performed in 125 (77%) and 25 (15%) patients. Forty-three patients (26.5%) had postoperative morbidity. PCR was achieved in 19 patients (11.7%). After a median follow-up of 26 months, there are no recurrences in the PCR group, and in the non-PCR group, local recurrence was 1.4% (P=.78), and distant metastasis was 8.4% (P=.21). Overall survival (P=.39) and survival free of diseases (P=.23) were better in the PCR group, but the differences were not significant. Patients with pathological complete response have better oncological outcome. 23898439 Treatment of diabetic foot ulcer using matriderm in comparison with a skin graft. For patients with neuropathy, vasculopathy, and impairment of wound healing, treatment of a diabetic foot ulcer poses many challenges. A large number of dermal analogues have been invented in an effort to overcome these challenges. Matriderm, a dermal analogue, is made from bovine collagen and elastin. This study was conducted in order to evaluate the effectiveness of Matriderm for treatment of diabetic foot ulcers, in comparison with skin grafting. Sixty patients with diabetic foot ulcer were included in this prospective study. The average age of the patients, who had type II diabetes mellitus, was 58 years old. The patients were allocated to an experimental or control group with their consents. The patients were selected with their consent for inclusion in an experimental group and a control group. Patients in the experimental group received a Matriderm appliance and a split-thickness skin graft, while those in the control group received only a split-thickness skin graft. A shorter hospitalization period (7.52 weeks) was observed in the experimental group than in the control group (9.22 weeks), and a shorter period of time (8.61 weeks) was required for complete healing, compared with the control group (12.94 weeks), with statistical significance (P<0.05). A higher elasticity ratio of the affected side to the non-affected side was observed in the experimental group, compared with the control group (P<0.01). Matriderm enables effective healing and improves elasticity in treatment of patients with diabetic foot ulcer. 23869670 Conservation surgery for hypopharyngeal cancer: changing paradigm from open to endoscopic. Abstract Conclusions: Endoscopic laser microsurgery (ELM) provides comparable oncological outcomes, and improved functional recovery and laryngeal preservation compared with open partial laryngopharyngectomy (OPLP) in patients with early squamous cell carcinoma of the hypopharynx (HPSCC). The use of open surgery is declining. The outcome of the study provides evidence-based recommendations for surgical choices in HPSCC treatment. However, it is not conclusive without a larger prospective study. Objectives: To compare the functional and oncological results of ELM and OPLP in HPSCC and examine surgical trends. Methods: From 1990 to 2008, 53 HPSCC patients undergoing ELM (n = 25) and OPLP (n = 28) were included. Functional recovery, oncological results, and laryngeal preservation rate were analyzed. Results: Patients who underwent ELM demonstrated a shorter decannulation period (7 vs 11 days, p = 0.010), time using a nasogastric tube (7 vs 16 days, p = 0.043), and hospitalization stay (12 vs 22 days, p = 0.0061) than those who underwent OPLP. The 3-year overall and disease-specific survival rates were comparable between ELM and OPLP (79% vs 64%, p = 0.151, and 83% vs 71%, p = 0.320, respectively). The ELM patients had better laryngeal preservation (92% vs 71%, p = 0.048). The number of OPLPs performed has decreased since 2000 (68% before vs 32% after, p < 0.0001). 23968172 A proposal to evaluate mechanistic efficacy of hallucinogens in addiction treatment. Abstract Current treatments for addiction are frequently ineffective. Hallucinogenic therapy has been indicated as helpful for a range of substance use disorders, yet this approach remains understudied and publicly unavailable. It is nonetheless a promising treatment, which has significant, long-term beneficial effects with single doses and a profile characterized by general safety, low toxicity, and non-addictiveness. However, pharmacological interventions, such as hallucinogens, should not be offered if the same effects (e.g. psychological insights/mystical experiences) and outcomes (e.g. decreased drug use) could be achieved absent pharmacological intervention. To date, there have been no clinical comparisons of drug-induced altered states with non-drug-induced states for addiction treatment. We propose and then outline a clinical trial to address this gap in knowledge. The proposed design would evaluate abstinence outcomes in a population of prescription opioid abusers after exposure to one of three conditions: a drug-induced altered state using psilocybin, a non-drug-induced altered state via hyperventilation (Holotropic Breathwork), and an active placebo with niacin. The outcomes of such a study would reveal important differences in therapeutic potential by discriminating hallucinogen-dependent effects from those psychological effects resulting from altered states. 23832203 Protein expression, crystallization and preliminary X-ray crystallographic analysis of the isolated Shigella flexneri VapC toxin. Upon release from the stable complex formed with its antitoxin VapB, the toxin VapC (MvpT) of the Gram-negative pathogen Shigella flexneri is capable of globally down-regulating translation by specifically cleaving initiator tRNA(fMet) in the anticodon region. Recombinant Shigella flexneri VapC(D7A) harbouring an active-site mutation was overexpressed in Escherichia coli, purified to homogeneity and crystallized by the vapour-diffusion technique. A preliminary X-ray crystallographic analysis shows that the crystals diffracted to at least 1.9 Å resolution at a synchrotron X-ray source and belonged to the trigonal space group in the hexagonal setting, H3, with unit-cell parameters a = b = 120.1, c = 52.5 Å, α = β = 90, γ = 120°. The Matthews coefficient is 2.46 Å(3) Da(-1), suggesting two molecules per asymmetric unit and corresponding to a solvent content of 50.0%. 23478260 Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1. Synonymous single nucleotide polymorphisms (SNPs) within a transcript's coding region produce no change in the amino acid sequence of the protein product and are therefore intuitively assumed to have a neutral effect on protein function. We report that two common variants of high-temperature requirement A1 (HTRA1) that increase the inherited risk of neovascular age-related macular degeneration (NvAMD) harbor synonymous SNPs within exon 1 of HTRA1 that convert common codons for Ala34 and Gly36 to less frequently used codons. The frequent-to-rare codon conversion reduced the mRNA translation rate and appeared to compromise HtrA1's conformation and function. The protein product generated from the SNP-containing cDNA displayed enhanced susceptibility to proteolysis and a reduced affinity for an anti-HtrA1 antibody. The NvAMD-associated synonymous polymorphisms lie within HtrA1's putative insulin-like growth factor 1 (IGF-1) binding domain. They reduced HtrA1's abilities to associate with IGF-1 and to ameliorate IGF-1-stimulated signaling events and cellular responses. These observations highlight the relevance of synonymous codon usage to protein function and implicate homeostatic protein quality control mechanisms that may go awry in NvAMD. 23123255 Strategies for the selection of catalytic antibodies against organophosphorus nerve agents. Among the strategies aimed at biocompatible means for organophosphorus nerve agents neutralization, immunoglobulins have attracted attention in the 1990's and 2000's both for their ability to immobilize the toxicants, but also for their ability to be turned into enzymatically active antibodies known as catalytic antibodies or abzymes (antibodies - enzymes). We will present here a critical review of the successive strategies used for the selection of these nerve agent-hydrolyzing abzymes, based on hapten design, namely antibodies raised against a wide variety of transition state analogs, and eventually the strategies based on anti-idiotypic antibodies and reactibodies. 23787289 Synthesis and in vitro evaluation of new ethyl and methyl quinoxaline-7-carboxylate 1,4-di-N-oxide against Entamoeba histolytica. In our search for new antiamoebic agents, a new series of ethyl and methyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives have been synthesized using the Beirut reaction. All compounds were characterized by spectroscopic techniques and elemental analysis. Antiamoebic activity was evaluated in vitro against Entamoeba histolytica strain HM1:IMSS by the microdilution method, and the structure-activity relationship was analyzed. We found that eleven quinoxaline derivatives showed greater activity than metronidazole and nitazoxanide with IC₅₀ values in the range 1.99-0.35 μM. Compounds T-001 and T-016 shows IC₅₀ values of 1.41 and 1.47 μM, respectively, with a value of selectivity index >60. 23933490 Inactivation of Tgfbr2 in Osterix-Cre expressing dental mesenchyme disrupts molar root formation. It has been difficult to examine the role of TGF-ß in post-natal tooth development due to perinatal lethality in many of the signaling deficient mouse models. To address the role of Tgfbr2 in postnatal tooth development, we generated a mouse in which Tgfbr2 was deleted in odontoblast- and bone-producing mesenchyme. Osx-Cre;Tgfbr2(fl/fl) mice were generated (Tgfbr2(cko)) and post-natal tooth development was compared in Tgfbr2(cko) and control littermates. X-ray and μCT analysis showed that in Tgfbr2(cko) mice radicular dentin matrix density was reduced in the molars. Molar shape was abnormal and molar eruption was delayed in the mutant mice. Most significantly, defects in root formation, including failure of the root to elongate, were observed by postnatal day 10. Immunostaining for Keratin-14 (K14) was used to delineate Hertwig's epithelial root sheath (HERS). The results showed a delay in elongation and disorganization of the HERS in Tgfbr2(cko) mice. In addition, the HERS was maintained and the break up into epithelial rests was attenuated suggesting that Tgfbr2 acts on dental mesenchyme to indirectly regulate the formation and maintenance of the HERS. Altered odontoblast organization and reduced Dspp expression indicated that odontoblast differentiation was disrupted in the mutant mice likely contributing to the defect in root formation. Nevertheless, expression of Nfic, a key mesenchymal regulator of root development, was similar in Tgfbr2(cko) mice and controls. The number of osteoclasts in the bone surrounding the tooth was reduced and osteoblast differentiation was disrupted likely contributing to both root and eruption defects. We conclude that Tgfbr2 in dental mesenchyme and bone is required for tooth development particularly root formation. 23940662 Estimating Temporal Causal Interaction between Spike Trains with Permutation and Transfer Entropy. Estimating the causal interaction between neurons is very important for better understanding the functional connectivity in neuronal networks. We propose a method called normalized permutation transfer entropy (NPTE) to evaluate the temporal causal interaction between spike trains, which quantifies the fraction of ordinal information in a neuron that has presented in another one. The performance of this method is evaluated with the spike trains generated by an Izhikevich's neuronal model. Results show that the NPTE method can effectively estimate the causal interaction between two neurons without influence of data length. Considering both the precision of time delay estimated and the robustness of information flow estimated against neuronal firing rate, the NPTE method is superior to other information theoretic method including normalized transfer entropy, symbolic transfer entropy and permutation conditional mutual information. To test the performance of NPTE on analyzing simulated biophysically realistic synapses, an Izhikevich's cortical network that based on the neuronal model is employed. It is found that the NPTE method is able to characterize mutual interactions and identify spurious causality in a network of three neurons exactly. We conclude that the proposed method can obtain more reliable comparison of interactions between different pairs of neurons and is a promising tool to uncover more details on the neural coding. 23887021 Second Allogeneic Stem Cell Transplantation in Hematologic Malignancies: A Single-center Experience. Patients with hematologic malignancies who relapse after their first hematopoietic stem cell transplantation tend to have poor prognoses. One option for these patients is a second allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there are few reports of second allo-HSCT therapy in children with relapsed hematologic malignancies. Patient outcomes in 27 individuals with acute leukemia who received at least 2 allo-HSCTs at the Samsung Medical Center between May 1997 and September 2010 were analyzed retrospectively. After a median follow-up of 33 months, 11 of 27 patients (40.7%) were alive and in stable remission. The 5-year overall survival rate for all 27 patients was 32.6%. There was no statistically significant difference in the survival rates of patients differing in their sex, the stem cell source, the donor type, or the presence of acute or chronic graft-versus-host disease. Remission before the second allo-HSCT was the only prognostic factor that influenced the survival rates (44.1% vs. 11.1%, P=0.009). Of 16 cases of mortality, 9 mortality cases (56.3%) were associated with relapse and 7 cases (43.7%) were associated with treatment-related mortality. Therefore, a second allo-HSCT offers the chance of stable remission for some patients with acute hematologic malignancies who relapse after their first allo-HSCT. 23684545 Ultrasonic-assisted preparation of nano eggshell powder: a novel catalyst in green and high efficient synthesis of 2-aminochromenes. The nano eggshell powder (NESP) has been prepared by ultrasound irradiation and used as a novel and biodegradable catalyst with high catalytic activity and reusability in green synthesis of 2-aminochromenes via condensation of α- or β-phathol, malononitrile and aromatic aldehydes at 120 °C under solvent-free conditions. The reaction proceeds to completion within 10-35 min in 91-98% yield. Nano eggshell catalyst was characterized by scanning electron microscopy, X-ray powder diffraction, IR spectroscopy and X-ray fluorescence, thermal gravimetric, surface area and elemental analyses. In addition, the catalytic activity and chemical structure of nano-sized eggshell were compared with pure CaCO3. 23940751 Auditory Responses of Engrailed and Invected-Expressing Johnston's Organ Neurons in Drosophila melanogaster. The roles of the transcription factor Engrailed (En), and its paralogue Invected (Inv), in adult Drosophila Johnston's Organ sensory neurons are unknown. We used en-GAL4 driven CD8-GFP and antibody staining to characterize these neurons in the pedicel (second antennal segment). The majority of En and Inv-expressing Johnston's Organ neurons (En-JONs) are located in the ventral part of the posterior group of JONs, with only a few in the medial group. Anatomical classification of En-JON axon projections shows they are mainly type A and E, with a few type B. Extracellular recording of sound-evoked potentials (SEPs) from the antennal nerve was used along with Kir2.1 silencing to assess the contribution that En-JONs make to the auditory response to pure-tone sound stimuli. Silencing En-JONs reduces the SEP amplitude at the onset of the stimulus by about half at 100, 200 and 400 Hz, and also reduces the steady-state response to 200 Hz. En-JONs respond to 82 dB and 92 dB sounds but not 98 dB. Despite their asymmetrical distribution in the Johnston's Organ they respond equally strongly to both directions of movement of the arista. This implies that individual neurons are excited in both directions, a conclusion supported by reanalysis of the morphology of the pedicel-funicular joint. Other methods of silencing the JONs were also used: RNAi against the voltage-gated Na(+) channel encoded by the para gene, expression of attenuated diphtheria toxin, and expression of a modified influenza toxin M2(H37A). Only the latter was found to be more effective than Kir2.1. Three additional JON subsets were characterized using Flylight GAL4 lines. inv-GAL4 88B12 and Gycβ100B-GAL4 12G03 express in different subsets of A group neurons and CG12484-GAL4 91G04 is expressed in B neurons. All three contribute to the auditory response to 200 Hz tones. 23910879 A comparison of surface features on submerged and non-submerged bone using scanning electron microscopy. Skeletal remains are excellent sources of information regarding the deceased individual and the taphonomic history of their body. However, the accuracy of this information is governed by our ability to interpret features on the surface of a bone. Little research in this respect has been carried out on remains found in aquatic environments. This study compares damage features created on the surface of modern and archaeological bone found in a seawater environment, to surface features present on unmodified bone, archaeological bone, pathological bone and burned bone. Results show that no similarities with regard to surface pores were identified between submerged modern bone and archaeological, pathological and burned bone. Similarities were seen between submerged and dry archaeological bones. Thus it is argued that the misinterpretation of the taphonomic history of isolated bones recovered from bodies of water should be avoidable in the forensic context. 23893049 C7orf10 encodes succinate-hydroxymethylglutarate CoA-transferase, the enzyme that converts glutarate to glutaryl-CoA. Glutarate, a side-product in the metabolism of tryptophan and lysine, is metabolized by conversion to glutaryl-CoA by a transferase using succinyl-CoA as a coenzyme donor. The enzyme catalyzing this conversion has not been formally identified. However, a benign form of glutaric aciduria (glutaric aciduria type III) is due to mutations in C7orf10, a putative member of the coenzyme A transferase class III family. In the present work, we show that recombinant human C7orf10 catalyzes the succinyl-CoA-dependent conversion of glutarate to glutaryl-CoA. C7orf10 could use many dicarboxylic acids as CoA acceptors, the best ones being glutarate, succinate, adipate, and 3-hydroxymethylglutarate. Confocal microscopy analysis of CHO cells transfected with a C7orf10-GFP fusion protein indicated that C7orf10 is a mitochondrial protein, in agreement with the presence of a predicted mitochondrial propeptide at its N-terminus. The effect of a missense mutation (p.Arg336Trp) found in the homozygous state in several patients with glutaric aciduria type III and present in the general population at a low frequency was also investigated. The p.Arg336Trp mutation led to the production of insoluble and inactive C7orf10 both in Escherichia coli and in HEK293T cells. These findings indicate that C7orf10 is implicated in the metabolism of glutarate, but possibly also of longer dicarboxylic acids. Homologues of this enzyme are found in numerous bacterial operons comprising also a putative glutaryl-CoA dehydrogenase, indicating that an enzyme with similar specificity exists in prokaryotes. 23795878 Assistant District Attorney decision making when referring to drug treatment court. Contact with the criminal justice system represents a critical point for drug involved offenders to access treatment and prevention services. Treatment and service provision under community supervision are known to be more likely than incarceration to affect positive change in terms of reduced substance use, reduced HIV risk behaviors, and increments in community reintegration. The decision-making process by Assistant District Attorneys (ADAs), frequent primary gate-keepers of jail diversion programming, when referring to diversion programs (as opposed to traditional adjudication) is poorly understood. To contribute to literature regarding the optimization of jail diversion referral practice, the current study sought to investigate what influences such decisions by Dane County ADAs. We surveyed 24 ADAs and received 19 completed questionnaires. ADA decision making was in agreement with existing literature regarding offender factors associated with drug court completion, including social factors, criminal history, and primary substance used. ADA beliefs conflicted with current literature regarding drug treatment facilitating reductions in criminal behavior. Additional research is needed to further assess the decision-making process by primary diversion program gatekeepers. Dissemination of relevant findings to prosecutors will facilitate optimization of referral to therapeutic jurisprudence programming and the matching of offenders to services. 23969585 Variation in Inpatient Tonsillectomy Costs Within and Between US Hospitals Attributable to Postoperative Complications. Tonsillectomy is the second most common inpatient procedure in US children. However, the factors that influence tonsillectomy-related costs are unknown. The objective of the study was to describe variation in US inpatient tonsillectomy costs and examine whether postoperative complications contribute to these disparities in costs. This is a retrospective cohort study of the 2009 Nationwide Inpatient Sample. Hierarchical, mixed-effects linear regression modeling was used to analyze the association between postoperative complications and cost, controlling for clinically relevant characteristics such as age, number of chronic comorbidity indicators, and hospital mean complication rates. We also estimated the variance in cost attributable to the treating hospital using the intraclass correlation coefficient. The study cohort comprised 12,512 adult and pediatric patients undergoing tonsillectomy or adenotonsillectomy in the inpatient setting. Cost, posttonsillectomy hemorrhage, and mechanical ventilator use at the individual encounter and at hospital level were evaluated. The aggregate cost of tonsillectomies in the cohort was $94.2 million. The median cost per encounter across all hospitals was $4393 (interquartile range, $3279-$6981), whereas the mean cost was $7525 (95% confidence interval, $6453-$8597). Mechanical ventilation was associated with an adjusted increase of $30,081 per encounter (95% confidence interval, $18,199-$41,964). The intraclass correlation coefficient declined from 0.117 to 0.070 after adjusting for mean hospital mechanical ventilation rate, which accounted for 40.2% of the interhospital variation in cost. Use of mechanical ventilation significantly increases the cost of inpatient tonsillectomy care. Further research should examine risk factors contributing to higher rates of mechanical ventilation after tonsillectomy, which in turn can guide systemic quality improvement interventions to reduce costs. 23948802 Long-Term Survival following Gross Total Resection of Pediatric Supratentorial Ependymomas without Adjuvant Therapy. Pediatric supratentorial ependymoma is very rare. In pediatric patients with supratentorial ependymoma, surgery alone may be an acceptable treatment when postoperative imaging confirms a gross total resection. Surgical resection is the standard and the most important treatment for ependymoma. The role of radiation therapy and/or chemotherapy following a gross total resection of supratentorial ependymoma has been uncertain. We report 2 cases of pediatric supratentorial ependymomas treated by gross total resection without postoperative adjuvant therapy. The first patient was a 7-year-old girl who presented with motor weakness and a hemiconvulsion of the right leg. Magnetic resonance imaging (MRI) revealed a large heterogeneously enhanced tumor in the left frontal lobe. The second patient was an 8-year-old girl who presented with headache. MRI revealed a huge heterogeneously enhanced tumor in the left frontal lobe. Gross total resection was achieved in both patients. Postoperative radiotherapy and chemotherapy were avoided following gross total resection. Histologically, the lesions demonstrated grade II ependymoma and anaplastic ependymoma, respectively. After follow-up of 120 months, neither patient had recurrence or dissemination. These results suggest that patients with pediatric supratentorial ependymoma treated by gross total resection alone have a favorable outcome, and postoperative radiotherapy and chemotherapy may be avoided. © 2013 S. Karger AG, Basel. 23919818 Physical and virtual screening methods for marine toxins and drug discovery targeting nicotinic acetylcholine receptors. Introduction: Nicotinic acetylcholine receptors (nAChRs) have been extensively studied because of their importance in physiological processes and their involvement in a number of muscle and neuronal human pathologies. However, the role of specific subtypes remains poorly understood due to the lack of selective nAChR probes. During the last decade, drug design strategies have been powered by a wide variety of natural compounds with diverse chemical structures, and by the structural characterization of several nAChRs structural homologs. Areas covered: In this review, the authors present a short overview of nAChRs, and some natural sources of bioactive molecules targeting these receptors. The authors provide an emphasis on α-conotoxins from Conus venoms, which provide the most diverse selective antagonists of nAChRs known to date, as well briefly discussing macrocyclic imine toxins. The authors, furthermore, review valuable radioactive and non-radioactive methods used for discovering novel ligands targeting nAChRs and highlight high-throughput developments in receptor-binding and electrophysiological assays. Finally, the authors review the molecular modeling approaches used in the last few years with an aim to provide an overview of their potential to identify and optimize selective nAChR ligands. Expert opinion: Recent years have provided new valuable techniques for the detection and identification of new nAChRs ligands, along with an increasing use of different molecular modeling tools. This furthering of knowledge has had an impact on the design and discovery of more potent and selective nAChRs ligands. There is still however a lack of high-resolution structural information that will require new developments. 23546009 Design, Synthesis and Antiviral Activity of 2-(3-Amino-4-piperazinylphenyl)chromone Derivatives. Previously, we have confirmed that the antiviral activities of the chromone derivatives were controlled by the type as well as the position of the substituents attached to the chromone core structure. In the course of our ongoing efforts to optimize the antiviral activity of the chromone derivatives, we have been attempting to derivatize the chromone scaffold via introduction of various substituents. In this proof-of-concept study, we introduced a 3-amino-4-piperazinylphenyl functionality to the chromone scaffold and evaluated the antiviral activities of the resulting chromone derivatives. The synthesized 2-(3-amino-4-piperazinylphenyl)-chromones showed severe acute respiratory syndrome-corona virus (SARS-CoV)-specific antiviral activity. In particular, the 2-pyridinylpiperazinylphenyl substituents provided the resulting chromone derivatives with selective antiviral activity. Taken together, this result indicates the possible pharmacophoric role of the 2-pyridinylpiperazine functionality attached to the chromone scaffold, which warrants further in-depth structure-activity relationship study. 23738581 Current knowledge on oxidative stress in hepatic ischemia/reperfusion. Abstract Ischemia/reperfusion (I/R) injury associated with hepatic resections and liver transplantation remains a serious complication in clinical practice, despite several attempts to solve the problem. The redox balance, which is pivotal for normal function and integrity of tissues, is dysregulated during I/R, leading to an accumulation of reactive oxygen species (ROS). Formation of ROS and oxidant stress are the disease mechanisms most commonly invoked in hepatic I/R injury. The present review examines published results regarding possible sources of ROS and their effects in the context of I/R injury. We also review the effect of oxidative stress on marginal livers, which are more vulnerable to I/R-induced oxidative stress. Strategies to improve the viability of marginal livers could reduce the risk of dysfunction after surgery and increase the number of organs suitable for transplantation. The review also considers the therapeutic strategies developed in recent years to reduce the oxidative stress induced by hepatic I/R, and we seek to explain why some of them have not been applied clinically. New antioxidant strategies that have yielded promising results for hepatic I/R injury are discussed. 23875602 Inability to Detect Human T Cell Lymphotropic Virus Type 2-Specific Antibodies in a Patient Coinfected with HIV-1, Human T Cell Lymphotropic Virus Type 1, Human T Cell Lymphotropic Virus Type 2, and Hepatitis C Virus. Abstract HIV-1, human T cell lymphotropic virus type 1 and type 2 (HTLV-1 and HTLV-2) and hepatitis C virus (HCV) are common among intravenous drug users (IDUs) and can cause chronic infections in the host. Usually, the diagnosis of such viruses employs serological assays; however, some difficulties in confirming HTLV-2 infection have been reported in high-risk populations in Brazil. We present data of an unusual case of coinfection with HIV-1, HTLV-1, HTLV-2, and HCV in a male IDU in which HTLV-2 was detected only by molecular assays. Comparative analysis of retroviruses from 2002 and 2012 showed identical HTLV-1 and HTLV-2 sequences (LTR, env, and tax), and a change in HIV-1 tropism from CXCR4 to CCR5. No mutation was detected in the hot points of the env region of the HTLV-2 isolate that justified the lack of rgp46-II-specific antibodies. These data emphasize the need for molecular assays to diagnose HTLV-2 in high-risk populations in Brazil. 23726372 Migraine, headache and development of metabolic syndrome: an 11-year follow-up in the Nord-Trøndelag Health Study (HUNT). Migraine with aura is associated with an increased incidence of stroke and cardiovascular disease, but the biological mechanisms are poorly understood. This study examined the incidence of metabolic syndrome and its relationship to migraine with and without aura and to nonmigraine headache. In the population-based the Nord-Trøndelag Health Study (HUNT), 19,895 individuals were followed for the development of metabolic syndrome, with a median follow-up time of 11.3 years. Headache diagnoses were based on a validated headache questionnaire, and metabolic syndrome was based on a modified version of the National Cholesterol Education Program's Adult Treatment Panel (ATP) III criteria, using objective anthropometric measurements and blood biochemistry. Using the Poisson regression model, migraine with aura was associated with an increased risk for developing metabolic syndrome. The effect was modified by smoking, with an adjusted incident risk ratio (IRR) among smokers of 2.10 (95% CI 1.53-2.89) and among nonsmokers of 1.39 (95% CI 1.03-1.86), when compared to headache-free controls. A moderate risk increase was seen for migraine without aura (IRR 1.26, 95% CI 1.12-1.42) and nonmigraine headache (IRR 1.22, 95% CI 1.13-1.32), not modified by smoking. The results suggest that traditional risk factors may be one of the mechanisms through which migraine with aura is linked to an increased risk for cardiovascular disease. A heightened vigilance concerning cardiovascular risk factors in this patient group may be warranted. 23931879 Successful treatment of severe hantavirus nephritis with corticosteroids: a case report and literature review. Hantaviruses can be associated with severe form of hemorrhagic fever with renal syndrome although there are only a few cases reporting chronic kidney disease after hantavirus infection. We report a severe nonresolving chronic renal failure after protracted Dobrava hantavirus infection successfully treated with corticosteroids. Ten days after working in a basement a 33-year-old man fell seriously ill, with high fever, chills, diffuse myalgia, headache and abdominal pain. After hospital admission a diagnosis of hemorrhagic fever with renal syndrome caused by Dobrava hantavirus was made. Acute oliguric kidney injury developed in the first 3 days after admission, in a few days diuresis restored and he became polyuric. Nevertheless renal failure persisted and he needed hemodialysis. Because of nonresolving kidney failure, nephrogenic diabetes insipidus and renoparenchymal arterial hypertension persisting 2 months after onset of symptoms, a kidney biopsy was performed, showing severe necrotizing tubulointerstitial nephritis. High dose methylprednisolone therapy was started and his renal function significantly improved. Two months later a second renal biopsy showed persisting elements of active necrotizing tubulointerstitial nephritis. We decided to stop corticosteroid treatment and introduced aldosterone antagonist eplerenon as anti-fibrotic agent, and his renal function further improved and remained stable. Nine months later his serum creatinine concentration was 227 μmol/L, proteinuria 0.156 g/day and well controlled nephrogenic diabetes insipidus. 23925828 Trends in childhood brain tumor incidence, 1973-2009. In the mid-1980s, there was a rise in incidence rates of childhood brain tumors (CBT) in the United States that appeared to stabilize at a higher rate in the early 1990s. An updated analysis of the pattern of CBT over the past 2 decades, with commentary on whether the elevated incidence rate has continued, is past due. We used Surveillance, Epidemiology and End Results (SEER) data to examine trends in incidence of CBT from 1973 through 2009. We examined age-adjusted incidence rates (AAIRs) and secular trends for all malignant brain tumors combined (SEER classification) by histologic tumor type and anatomic site. The incidence of CBT remained stable from 1987 to 2009 [annual percent change (APC) = 0.10; 95 % confidence intervals (CI) -0.39 to 0.61] with an AAIR for all CBT of 3.32 (95 % CI 3.22-3.42). The stability of rates in these two decades contrast the change that occurred in the mid-1980s (1983-1986), when the incidence of CBT increased by 53 % (APC = 14.06; 95 % CI 4.05-25.0). From 1983 to 1986, statistically significant rate increases were observed for pilocytic astrocytoma, PNET/medulloblastoma, and mixed glioma. Further, the rate of increase in pilocytic astrocytoma was similar to the rate of decrease for astrocytomas NOS from 1981 to 2009, suggesting a change from a more general to more specific classification. After the increase in rates in the mid-1980s, rates of CBT over the past two decades have stabilized. Changes in incidence rates of subtypes of tumors over this time period reflect changes both in classification of CBT and in diagnostic techniques. 23876715 Biomechanical maturation of joint dynamics during early childhood: Updated conclusions. Dynamic parameters have been commonly explored to characterize the biomechanical maturation of children's gaits, i.e., age-revealing joint moment and power patterns similar to adult patterns. However, the literature revealed a large disparity of conclusions about maturation depending on the study, which was most likely due to an inappropriate scaling strategy and uncontrolled walking speed. With the first years of independent walking, a large growth in height and a large variability of dimensionless walking speed are observed. Moreover, the dynamic parameters were not well studied during early childhood. In the present study, seventy-five healthy children between 1 and 6 years of age were assessed during gait trials at a self-selected speed. Four hundred and sixty-two gait trials constituting five age groups with comparable dimensionless walking speeds were selected. 3D joint moments and the power of the lower limbs were computed and expressed using a dimensionless scaling strategy (according to body weight, leg length and the acceleration of gravity). Statistical analysis was performed to examine inter-group differences. Based on the current results, we concluded the biomechanical maturation of joint dynamics occurred around an age of 4 years for the ankle and between 6 and 7 years for the knee and the hip. Moreover, age group comparisons seemed more appropriate in young children using both the dimensionless strategy and a similar walking speed. Future investigations will be conducted on an older population (i.e., adding children older than 6 years) to clearly define the status of knee and hip biomechanical maturation. 23872728 Use of mastoid obliteration techniques in cholesteatoma. To evaluate the choice of techniques, safety and long-term outcome of mastoid obliteration and assess the place of imaging in the postoperative monitoring of residual cholesteatoma. All recent reports on mastoid obliteration for the management of cholesteatoama were favourable. Long-term follow-up reports did not show problems arising from hidden cholesteatoma, even for the paediatric population. Non-EPI DW MR imaging has shown great promise in detecting residual cholesteatoma in obliterated cavities. Canal wall down technique with primary mastoid obliteration for cholesteatoma has low recurrent and residual cholesteatoma rates. Most ears remained dry and waterproof on long-term follow-up. 23839264 No time for candy: passionfruit (Passiflora edulis) plants down-regulate damage-induced extra floral nectar production in response to light signals of competition. Plant fitness is often defined by the combined effects of herbivory and competition, and plants must strike a delicate balance between their ability to capture limiting resources and defend against herbivore attack. Many plants use indirect defenses, such as volatile compounds and extrafloral nectaries (EFN), to attract canopy arthropods that are natural enemies of herbivorous organisms. While recent evidence suggests that upon perception of low red to far-red (R:FR) ratios, which signal the proximity of competitors, plants down-regulate resource allocation to direct chemical defenses, it is unknown if a similar phytochrome-mediated response occurs for indirect defenses. We evaluated the interactive effects of R:FR ratio and simulated herbivory on nectar production by EFNs of passionfruit (Passiflora edulis f. flavicarpa). The activity of petiolar EFNs dramatically increased in response to simulated herbivory and hormonal treatment with methyl jasmonate (MeJA). Low R:FR ratios, which induced a classic "shade-avoidance" repertoire of increased stem elongation in P. edulis, strongly suppressed the EFN response triggered by simulated herbivory or MeJA application. Strikingly, the EFN response to wounding and light quality was localized to the branches that received the treatments. In vines like P. edulis, a local response would allow the plants to precisely adjust their light harvesting and defense phenotypes to the local conditions encountered by individual branches when foraging for resources in patchy canopies. Consistent with the emerging paradigm that phytochrome regulation of jasmonate signaling is a central modulator of adaptive phenotypic plasticity, our results demonstrate that light quality is a strong regulator of indirect defenses. 23957711 Facile Synthesis of Unsymmetrical Acridines and Phenazines by a Rh(III)-Catalyzed Amination/Cyclization/Aromatization Cascade. We report formal [3 + 3] annulations of aromatic azides with aromatic imines and azobenzenes to give acridines and phenazines, respectively. These transformations proceed through a cascade process of Rh(III)-catalyzed amination followed by intramolecular electrophilic aromatic substitution and aromatization. Acridines can be directly prepared from aromatic aldehydes by in situ imine formation using catalytic benzylamine. 23030741 Identification of the metabolites of lesogaberan using linear trap quadrupole orbitrap mass spectrometry and hydrophilic interaction liquid chromatography. 1. In this study, hydrophilic interaction liquid chromatography (HILIC), radiochemical activity monitoring and linear trap quadrupole orbitrap mass spectrometry (MS) and tandem mass spectrometry (MS/MS) were used to identify the metabolites of a highly polar novel γ-aminobutyric acid type-B receptor agonist, lesogaberan, in rats. 2. Urine was collected from three male Wistar rats for 24 h after dosing with (14)C-labelled lesogaberan (170 mg/kg, 10 MBq/kg); plasma samples were taken 2 and 24 h after dosing. Pooled samples were separated by HILIC and eluents were analysed by radiochemical activity monitoring, MS and MS/MS. 3. Only the parent compound was detected in plasma, but six metabolites (M1-M6) were detected in urine. Analysis of MS and MS/MS data and comparison with synthetic reference standards enabled the identification of the structure of each metabolite. M1 was identified as the N-acetylated species [(2R)-3-acetamido-2-fluoropropyl]-phosphinic acid, and M6 as [(2R)-3-amino-2-fluoropropyl]-phosphonic acid. Metabolites M2 and M5 were the alcohol and carboxylic acid species 3-hydroxypropyl-phosphinic acid and 3-hydroxyphosphonoyl-propanoic acid, respectively, both of which had lost the fluorine atom present in the parent compound. M3 was the corresponding carboxylic acid species retaining the fluorine atom, (2R)-2-fluoro-3-hydroxyphosphonoyl-propanoic acid. Finally M4 was identified as [(2R)-2-fluoro-3-guanidino-propyl]-phosphinic acid. 23174560 Osteochondral tissue engineering: current strategies and challenges. Osteochondral defect management and repair remain a significant challenge in orthopedic surgery. Osteochondral defects contain damage to both the articular cartilage as well as the underlying subchondral bone. In order to repair an osteochondral defect the needs of the bone, cartilage and the bone-cartilage interface must be taken into account. Current clinical treatments for the repair of osteochondral defects have only been palliative, not curative. Tissue engineering has emerged as a potential alternative as it can be effectively used to regenerate bone, cartilage and the bone-cartilage interface. Several scaffold strategies, such as single phase, layered, and recently graded structures have been developed and evaluated for osteochondral defect repair. Also, as a potential cell source, tissue specific cells and progenitor cells are widely studied in cell culture models, as well with the osteochondral scaffolds in vitro and in vivo. Novel factor strategies being developed, including single factor, multi-factor, or controlled factor release in a graded fashion, not only assist bone and cartilage regeneration, but also establish osteochondral interface formation. The field of tissue engineering has made great strides, however further research needs to be carried out to make this strategy a clinical reality. In this review, we summarize current tissue engineering strategies, including scaffold design, bioreactor use, as well as cell and factor based approaches and recent developments for osteochondral defect repair. In addition, we discuss various challenges that need to be addressed in years to come. 23030812 Preparation and culture of precision-cut organ slices from human and animal. 1.Human and animal precision-cut organ slices are being widely used to obtain drug metabolism and toxicity profiles in vitro. These data are then used to predict what might be seen in human patients. The accuracy of this prediction and extrapolation of the findings based on human or animal in vitro systems to the findings that occur in vivo is dependent on both the quality of the tissue itself and the quality of the in vitro system. 2.The quality of human organs used in research is dependent on procurement methods, warm ischaemia time, preservation solutions, cold ischaemia time, and donor-specific factors. It is important to confirm that the organs being used are highly viable and fully functional before using them in scientific studies. 3.The optimal preparation and incubation of organ slices is also essential in maintaining slice viability and function. It is important to prepare the slices in a cold preservation solution, to prepare the slices at a correct thickness, and to incubate the slices in a system where the slice rotates in out of the oxygen atmosphere and medium. 4.Meeting the criteria outlined here will lead to successful organ slice cultures for investigating drug-induced mechanisms and organ-specific toxicity. 23664905 Identification of Veillonella tobetsuensis in tongue biofilm by using a species-specific primer pair. Veillonella atypica, Veillonella denticariosi, Veillonella dispar, Veillonella parvula, and Veillonella rogosae have been reported to be isolated from human oral cavities. The recently detected Veillonellatobetsuensis in human tongue biofilms was proposed as a novel Veillonella sp. In this study, to determine the distribution and frequency of V. tobetsuensis, we established a method for the detection and identification of V. tobetsuensis by using polymerase chain reaction (PCR) using a species-specific primer pair. The primer pair for V. tobetsuensis was designed on the basis of the nucleotide sequence of the 70-kDa heat shock protein (dnaK) gene of V. tobetsuensis JCM 17976(T) (=ATCC BAA-2400(T)). The primer pair generated a specific PCR product for V. tobetsuensis but not for other oral Veillonella spp. With the PCR procedure using the primer pair, we could detect less than 10 ng of genomic DNA extracted from V. tobetsuensis. Thus, the PCR method using this primer pair is suitable for the specific detection and identification of V. tobetsuensis. The distribution and frequency of V. tobetsuensis were investigated by PCR using this species-specific primer pair. V. tobetsuensis was detected in 5 of 27 subjects. V. tobetsuensis was recovered from 19% (5/27) of subjects with other Veillonella species. And, prevalence of V. tobetsuensis ranged from 7.6% to 20.0% in these subjects. V. tobetsuensis is likely to coexist with other Veillonella spp. in tongue biofilm. In this study, the species-specific PCR primer pair for V. tobetsuensis was designed using partial sequences of the dnaK gene. This is the first report using a species-specific primer pair for PCR to determine the distribution and frequency of V. tobetsuensis in tongue biofilm. 23774110 A grounded patient-centered approach generated the Personal and Societal Burden of Osteoarthritis model. To develop a conceptual model to describe the burden of osteoarthritis in individuals with this condition and on the broader community. Six concept mapping workshops were undertaken: three with patients (n = 26) and three with health professionals (n = 27) in Australia and Sweden. The participants were asked to generate statements describing how osteoarthritis affects individuals with this condition and those around them. The results were used to construct an integrated theoretical model of the personal burden of osteoarthritis (PBO) and its extended version, the personal and societal burden of osteoarthritis (PSBO) model. We identified eight potentially independent aspects of PBO, including physical distress, fatigue, physical limitations, psychosocial distress, physical deconditioning, financial hardship, sleep disturbances, and lost productivity. Physical distress and impaired physical function combined to produce psychosocial problems, reduced work productivity, financial difficulties, and loss of physical fitness at the individual level, and increased health and welfare cost at the societal level. The PBO and PSBO models were developed directly from the views of patients and clinicians and provide new insights for managing the individual and societal burden of osteoarthritis. 23850225 Self-reported sleep disturbance is associated with lower CD4 count and 24-h urinary dopamine levels in ethnic minority women living with HIV. Sleep disturbance is associated with dopamine dysregulation, which can negatively impact immune status. Individuals living with HIV experience more sleep difficulties, and poor sleep may compound immune decrements associated with HIV infection. Little research has examined associations between sleep, dopamine, and immune status (CD4 count) in individuals with HIV. As ethnic minority women living with HIV (WLWH) are at heightened risk for HIV disease progression, we related sleep reports to both CD4 count and dopamine levels in a cohort of ethnic minority WLWH. Participants were 139 low-income WLWH (ages 20-62; 78.3% African-American or Caribbean) who reported both overall sleep quality and sleep disturbance on the Pittsburgh sleep quality index (PSQI). CD4 count and HIV viral load were measured via morning peripheral venous blood samples, and concentrations of dopamine were measured via 24-h urine collection. Covariates included HIV viral load, length of time since HIV diagnosis, HAART adherence, perceived stress and depression. After controlling for all covariates, greater sleep disturbance was associated with significantly lower CD4 count (β=-.20, p=.03) and lower levels of dopamine (β=-.25, p=.04). Poorer overall sleep quality was marginally associated with lower CD4 count (β=-.16, p=.08), and was not associated with dopamine. Our analyses suggest that sleep disturbance is independently related with immune status and dopamine levels in WLWH. Lower levels of dopamine may indicate neuroendocrine dysregulation and may impact immune and health status. Results highlight sleep disturbance rather than overall sleep quality as potentially salient to neuroendocrine and immune status in ethnic minority WLWH. 23927678 Human Tracheobronchial Basal Cells: Normal Versus Remodeling/Repairing Phenotypes in vivo and in vitro. Rational: Human tracheobronchial epithelial (TBE) basal cells (BC) function as progenitors in normal tissue. However, mechanistic studies are typically performed in vitro and frequently use BC recovered from patients that die of non-respiratory disease. It is not known if the cadaveric epithelium: 1) is undergoing homeostatic remodeling and/or repair; or 2) yields BC clones that represent homeostatic processes identified in tissue. Objective: To compare the phenotype of TBE-BC with that of BC cultured under optimal clone-forming conditions. Methods: TBE pathology was evaluated using quantitative histomorphometry. Cultured BC phenotype was determined by FACS analysis. Clone organization and cell phenotype was determined by immunostaining. Results: The cadaveric TBE is 20% normal. In these regions, BC are keratin (K) 5+ and tetraspanin CD151+, and have a low mitotic index. In contrast, 80% of the cadaveric TBE exhibits homeostatic remodeling/repair processes. In these regions, BC are K5+/K14+ and a subset expresses tissue factor (TF). Passage 1 TBE cells are BC that are K5+/TF+, and half co-express CD151. Optimal clone formation conditions utilize an irradiated NIH3T3 fibroblast feeder layer and serum-supplemented Epicult-BTM medium. The TF+/CD151- BC subpopulation is the most clonogenic BC subtype and is enriched with K14+ cells. TF+/CD151- BC generate clones that contain BC that are K5+/Trp63+ but K14-/CD151-. TF+ cells are limited to the clone edge. Conclusion: Clonogenic human TBE BC: 1) exhibit a molecular phenotype that is a composite of the normal and remodeling/reparative basal cell phenotypes observed in tissue; and 2) generate organoid clones that contain phenotypically distinct BC subpopulations. 23933362 Red ginseng protects against gentamicin-induced balance dysfunction and hearing loss in rats through antiapoptotic functions of ginsenoside Rb1. The authors evaluated the protective effects of Korean red ginseng (KRG) against gentamicin (GM)-induced unilateral vestibular and hearing dysfunction and investigated its effective mechanism using in vitro cell cultures. Vestibular function was comprehensively evaluated by a scoring system that ranged from 0 (normal) to 3 (worst) points, using head tilt, tail hanging, and swimming tests. The GM group showed significantly more deteriorated vestibular function (0 point - 5 rats, 1 point - 1 rat, 2 points - 3 rats, and 3 points - 3 rats) than the KRG+GM group (0 point - 9 rats and 1 point - 1 rat) (p<0.01). The hearing thresholds were better in the KRG+GM group than in the GM group (p<0.05). Quantitative analysis of hair cell damage in the scanning electron microscopy was closely related with vestibular and hearing functional results. In vitro study showed that ginsenoside Rb1 (gRb1) attenuated reactive oxygen species production, suppressed JNK activation, up-regulated Bcl-xL and down-regulated Bax, cytochrome c, caspase 3, and cleaved poly (ADP-ribose) polymerase in GM-treated VOT-E36 cells. These findings suggest that KRG including gRb1 component protects against vestibular/hearing dysfunction by inhibiting apoptotic pathways when ototoxicity is induced by unilateral intratympanic injection with GM in rats. 23673388 Mapping of two suppressors of OVATE (sov) loci in tomato. Tomato fruit shape varies significantly in the cultivated germplasm. To a large extent, this variation can be explained by four genes including OVATE. While most varieties with the OVATE mutation bear elongated fruits, some accessions carry round fruit, suggesting the existence of suppressors of OVATE in the germplasm. We developed three intraspecific F2 populations with parents that carried the OVATE mutation but differed in fruit shape. We used a bulk segregant analysis approach and genotyped the extreme classes using a high-throughput genotyping platform, the SolCAP Infinium Assay. The analyses revealed segregation at two quantitative trait loci (QTLs), sov1 and sov2. These loci were confirmed by genotyping and QTL analyses of the entire population. More precise location of those loci using progeny testing confirmed that sov1 on chromosome 10 controlled obovoid and elongated shape, whereas sov2 on chromosome 11 controlled mainly elongated fruit shape. Both loci were located in intervals of <2.4 Mb on their respective chromosomes. 23636254 Herpes simplex virus 1 DNA polymerase processivity factor UL42 inhibits TNF-α-induced NF-κB activation by interacting with p65/RelA and p50/NF-κB1. Herpes simplex virus 1 (HSV-1) is the archetypal member of the alphaherpesvirus with a large genome encoding over 80 viral proteins, many of which are involved in virus-host interactions and show immune modulatory capabilities. In this study, we demonstrated that the HSV-1 UL42 protein, a DNA polymerase processivity factor, was a novel antagonism of the canonical NF-κB signaling pathway. UL42 was shown to significantly suppress TNF-α mediated NF-κB activation. Co-immunoprecipitation experiment revealed that UL42 bound to the NF-κB subunits p65 and p50. Fluorescence microscopy demonstrated that UL42 abolished nuclear translocation of p65 and p50 upon TNF-α-stimulation. But the inhibiting capacity of UL42 2R/2A (R279A, R280A) and UL42 3R/3A (R113A, R279A and R280A) mutants were less than wild type UL42. Also UL42 bound to the Rel homology domain of the NF-κB subunit p65 and p50. Notably, the N-terminal of UL42 was sufficient to interact with p65 and p50 and abolished NF-κB reporter gene activity. Thus, it was first time we demonstrated that HSV-1 UL42 appeared to prevent NF-κB-dependent gene expression by retaining p65 and p50 in the cytoplasm, and UL42-dependent transcriptional activation were inherently coupled to promote HSV-1 lytic replication, which also may contribute to immune evasion and pathogenesis of HSV-1. 23654250 Real-Time mRNA Measurement during an in Vitro Transcription and Translation Reaction Using Binary Probes. In vitro transcription and translation reactions have become popular for a bottom-up approach to synthetic biology. Concentrations of the mRNA intermediate are rarely determined, although knowledge of synthesis and degradation rates could facilitate rational engineering of in vitro systems. We designed binary probes to measure mRNA dynamics during cell-free protein synthesis by fluorescence resonance energy transfer. We tested different mRNA variants and show that the location and sequence environment of the probe target sites are important parameters for probe association kinetics and output signal. Best suited for sensitive real-time quantitation of mRNA was a target site located in the 3' untranslated region, which we designed to reduce secondary structure. We used this probe-target pair to refine our knowledge of mRNA dynamics in the commercially available PURE cell-free protein synthesis system and characterized the effect of TetR repressor on mRNA synthesis rates from a T7 promoter. 23665700 New insight into singlet oxygen generation at surface modified nanocrystalline TiO2--the effect of near-infrared irradiation. The generation of singlet oxygen in aqueous colloids of nanocrystalline TiO2 (anatase) modified by organic chelating ligands forming surface Ti(IV) complexes was studied. Detailed studies revealed a plausible and to date unappreciated influence of near-infrared irradiation on singlet oxygen generation at the surface of TiO2. To detect (1)O2, direct and indirect methods have been applied: a photon counting technique enabling time-resolved measurements of (1)O2 phosphorescence, and fluorescence measurements of a product of singlet oxygen interaction with Singlet Oxygen Sensor Green (SOSG). Both methods proved the generation of (1)O2. Nanocrystalline TiO2 modified with salicylic acid appeared to be the most efficient photosensitizer among the tested materials. The measured quantum yield reached the value of 0.012 upon irradiation at 355 nm, while unmodified TiO2 colloids appeared to be substantially less efficient generators of singlet oxygen with the corresponding quantum yield of ca. 0.003. A photocatalytic degradation of 4-chlorophenol, proceeding through oxidation by OH˙, was also monitored. The influence of irradiation conditions (UV, vis, NIR or any combination of these spectral ranges) on the generation of both singlet oxygen and hydroxyl radicals has been tested and discussed. Simultaneous irradiation with visible and NIR light did not accelerate OH˙ formation; however, for TiO2 modified with catechol it influenced (1)O2 generation. Singlet oxygen is presumably formed according to Nosaka's mechanism comprising O2˙(-) oxidation with a strong oxidant (hole, an oxidized ligand); however, the energy transfer from NIR-excited titanium(iii) centers (trapped electrons) plays also a plausible role. 23716191 Egg yolk: structures, functionalities and processes. Hen egg yolk is an ideal example of natural supramolecular assemblies of lipids and proteins with different organization levels. These assemblies are mainly due to interactions between proteins and phospholipids, and these interactions are essential in understanding and controlling the production of food made with yolk, and particularly emulsions. Furthermore, these assemblies can be modulated by external constraints among which thermo-mechanical and high-pressure treatments. This review focuses on multi-scale structures present in egg yolk, and their modulation by processes, in relation with their emulsifying properties. Egg yolk is mainly composed of two fractions-plasma and granules-which are natural nano- and micro-assemblies. These two fractions possess different composition, structures and functionalities and exhibit specific behaviour under treatments such as high pressure and temperature. Plasma contains a large quantity of lipids structured as lipoproteins (low-density lipoproteins), whereas granules are mainly composed of proteins aggregated in micrometric assemblies. If plasma is responsible for the important emulsifying properties of yolk, granules bring interesting emulsifying properties when assemblies are in the form of micelles in presence of salts. High-pressure or thermal treatments, applied before or after emulsion fabrication, alter their functionalities and could be used to commercially exploit these fractions. © 2013 Society of Chemical Industry. 23959371 Assessing the guest-accessible volume in MOFs using two-photon fluorescence microscopy. The assessment of guest-accessible volume in MOFs can be reliably done by using two-photon confocal fluorescence microscopy (TPM) with a tool-box of dyes with a wide range of sizes. It would be applicable to any porous materials, whose single-crystal structures are not available, or non-crystalline materials. 23940817 Generation of mouse small intestinal epithelial cell lines that allow the analysis of specific innate immune functions. Cell lines derived from the small intestine that reflect authentic properties of the originating intestinal epithelium are of high value for studies on mucosal immunology and host microbial homeostasis. A novel immortalization procedure was applied to generate continuously proliferating cell lines from murine E19 embryonic small intestinal tissue. The obtained cell lines form a tight and polarized epithelial cell layer, display characteristic tight junction, microvilli and surface protein expression and generate increasing transepithelial electrical resistance during in vitro culture. Significant up-regulation of Cxcl2 and Cxcl5 chemokine expression upon exposure to defined microbial innate immune stimuli and endogenous cytokines is observed. Cell lines were also generated from a transgenic interferon reporter (Mx2-Luciferase) mouse, allowing reporter technology-based quantification of the cellular response to type I and III interferon. Thus, the newly created cell lines mimic properties of the natural epithelium and can be used for diverse studies including testing of the absorption of drug candidates. The reproducibility of the method to create such cell lines from wild type and transgenic mice provides a new tool to study molecular and cellular processes of the epithelial barrier. 23666366 An evolutionary perspective on the causes and treatment of inflammatory bowel disease. To use insights from evolutionary biology to assess the current evidence for the causes, treatment, and prevention of inflammatory bowel disease (IBD). When analyzed in the context of evolutionary adaptation, recent assessments of genetic, microbial, and environmental associations with IBD implicate infectious causation. An evolutionary perspective provides insight into the causes of IBD, interpretation of its manifestations, and assessment of interventions. The evidence implicating infectious causation suggests that future studies of IBD would benefit from increased focus on infectious causes and interventions that prevent or inhibit them. 23961721 Cluster Size Effects in the Photocatalytic Hydrogen Evolution Reaction. The photocatalytic water reduction reaction on CdS nanorods was studied as function of Pt cluster size. Maximum H2 production is found for Pt46. This effect is attributed to the size dependent electronic properties (e.g., LUMO) of the clusters with respect to the band edges of the semiconductor. This observation may be applicable for the study and interpretation of other systems and reactions, e.g. H2O oxidation or CO2 reduction. 23792101 Symptomatic calcified perineural cyst after use of bone morphogenetic protein in transforaminal lumbar interbody fusion: a case report. Human recombinant bone morphogenetic protein-2 (BMP-2) is commonly used in spinal surgery to augment arthrodesis, and a number of potential complications have been documented. To present the case of a delayed radiculopathy that occurred because of a calcified perineural cyst that formed after an L4-L5 transforaminal lumbar interbody fusion (TLIF) in which BMP-2 was used. Case report of a 70-year-old man presented with back and right lower extremity pain. A 70-year-old man who had previously undergone a right L4-L5 TLIF presented 20 months after surgery with progressively radiating right leg pain. Imaging revealed a right-sided L4-L5 cystic lesion posterior to the interbody cage. The patient underwent reexploration, and a calcified mass was discovered. Histopathology revealed fragments of organized collagenous connective tissue, new collagen, and partially calcified fragments of fibrocartilage, bone, and ligament. This is the first reported case of a symptomatic calcified perineural cyst developing after a fusion procedure in which BMP-2 was used. The presence of connective tissue with metaplastic bone formation and maturation within the lesion suggests that formation of the cyst was secondary to application of BMP-2, as it possesses both osteogenic and chondrogenic capabilities. 23499503 Identification of pyrrolo[2,3-g]indazoles as new Pim kinase inhibitors. The synthesis and Pim kinase inhibition potency of a new series of pyrrolo[2,3-g]indazole derivatives is described. The results obtained in this preliminary structure-activity relationship study pointed out that sub-micromolar Pim-1 and Pim-3 inhibitory potencies could be obtained in this series, more particularly for compounds 10 and 20, showing that pyrrolo[2,3-g]indazole scaffold could be used for the development of new potent Pim kinase inhibitors. Molecular modeling experiments were also performed to study the binding mode of these compounds in Pim-3 ATP-binding pocket. 23566699 Total hip arthroplasty in young females with congenital dislocation of the hip, radically improves their long-term quality of life. Eighty-two female patients with low dislocation (67 hips) or high dislocation (48 hips) were assessed using clinical scores and EQ-5D quality of life (QoL) questionnaire. Assessment was performed at the first to secondyear postoperatively and at the final follow-up, after a minimum of 12years (12-37). Patients reported with a high EQ-5D health state VAS scale, VAS index and TTO index at 1 to 2years follow-up (94,21/0,907/0,931) that remained considerably high despite the long-term follow-up (73,8/0,721/0,746). The scores for pain and range of motion presented with a statistically significant improvement at 1 to 2years postoperatively and at the time of final follow-up. Function scores have declined with age. Total hip arthroplasty in CHD patients radically improves QoL for a long period of time. 23194883 Evaluation of gastrointestinal drug supersaturation and precipitation: Strategies and issues. Supersaturating drug delivery systems (SDDS) hold the promise of enabling intestinal absorption for difficult-to-formulate, poorly soluble drug candidates based on a design approach that includes (1) converting the drug into a high energy or rapidly dissolving system which presents a supersaturated solution to the gastrointestinal environment and (2) dosage form components that act to stabilize the formed metastable drug solution through nucleation and/or crystal growth inhibition. The appropriate development and study of SDDS require that useful and biorelevant supersaturation and precipitation assays are available. This review summarizes different methodological aspects of currently available in vitro assays, including the generation of supersaturation (solvent shift, pH shift or formulation-induced), the quantification of supersaturation and the detection of precipitation. Also down-scaled approaches, including 96-well plate setups, are described and situated in the pharmaceutical development cycle based on their consumption of API as well as time requirements. Subsequently, the ability to extrapolate in vitro supersaturation assessment to the in vivo situation is discussed as are direct and indirect clinical tools that can shed light on SDDS. By emphasizing multiple variables that affect the predictive power of in vitro assays (e.g. the nature of the test media, hydrodynamics, temperature and sink versus non-sink conditions), this review finally highlights the need for further harmonization and biorelevance improvement of currently available in vitro procedures for supersaturation and precipitation evaluation. 23616427 Improving the default data analysis workflow for large autoimmune biomarker discovery studies with protoarrays. Contemporary protein microarrays like the ProtoArray® are used for autoimmune antibody screening studies to discover biomarker panels. For ProtoArray data analysis the software Prospector and a default workflow are suggested by the manufacturer. While analyzing a large data set of a discovery study for diagnostic biomarkers of the Parkinson's Disease ("ParkCHIP") we have revealed the need for distinct improvements of the suggested workflow concerning raw data acquisition, normalization and pre-selection method availability, batch effects, feature selection, and feature validation. In this work appropriate improvements of the default workflow are proposed and it is shown that completely automatic data acquisition as a batch, a re-implementation of Prospector's pre-selection method, multivariate or hybrid feature selection, and validation of the selected protein panel using an independent test set define in combination an improved workflow for large studies. This article is protected by copyright. All rights reserved. 23942596 Does it matter what you call it? A randomized trial of language used to describe palliative care services. Integration of palliative care into oncology practice remains suboptimal. Misperceptions about the meaning of palliative care may negatively impact utilization. We assessed whether the term and/or description of palliative care services affected patient views. 2x2 between-subject randomized factorial telephone survey of 169 patients with advanced cancer. Patients were randomized into one of four groups that differed by name (supportive care vs. palliative care) and description (patient-centered vs. traditional). Main outcomes (0-10 Likert scale) were patient understanding, impressions, perceived need, and intended use of services. When compared to palliative care, the term supportive care was associated with better understanding (7.7 vs. 6.8; p = 0.021), more favorable impressions (8.4 vs. 7.3; p = 0.002), and higher future perceived need (8.6 vs. 7.7; p = 0.017). There was no difference in outcomes between traditional and patient-centered descriptions. In adjusted linear regression models, the term supportive care remained associated with more favorable impressions (p = 0.003) and higher future perceived need (p = 0.022) when compared to palliative care. Patients with advanced cancer view the name supportive care more favorably than palliative care. Future efforts to integrate principles of palliative medicine into oncology may require changing impressions of palliative care or substituting the term supportive care. 23528945 Sono-respond on thermosensitive polymer microgels based on cross-linked poly(N-isopropylacrylamide-co-acrylic acid). Ultrasound (US) exposure strongly influenced thermosensitivity of microgels attracted with both N-isopropylacrylamide (NIPAM) and acrylic acid (AA) segments, due to that hydrogen bonds of carboxylic acid segments in microgels were broken by US and then the hydration with water occurred. US induced critical effects on the volume phase transition temperature of the swelled NIPAM gel (PNAM). It was observed after the US exposure that the particle size was increased and the phase transition of the microgels shifted toward larger temperature regions of the hydrodynamic diameter. FT-IR spectroscopic data of the swelled microgel showed that the free OH stretching band intensity of the COOH segments was enhanced by the exposure, but the band intensity returned to its original level without the US exposure. This meant that the US stimulus broke hydrogen bonding of the microgel and induced hydration of water in the hydrogel environment. Finally, regeneration of the hydrogen bonds in the microgel was occurred after the US exposure. 23440895 Fluorescent probes for G-quadruplex structures. Mounting evidence supports the presence of biologically relevant G-quadruplexes in single-cell organisms, but the existence of endogenous G-quadruplex structures in mammalian cells remains highly controversial. This is due, in part, to the common misconception that DNA and RNA molecules are passive information carriers with relatively little structural or functional complexity. For those working in the field, however, the lack of available tools for characterizing DNA structures in vivo remains a major limitation to addressing fundamental questions about structure-function relationships of nucleic acids. In this review, we present progress towards the direct detection of G-quadruplex structures by using small molecules and modified oligonucleotides as fluorescent probes. While most development has focused on cell-permeable probes that selectively bind to G-quadruplex structures with high affinity, these same probes can induce G-quadruplex folding, thereby making the native conformation of the DNA or RNA molecule (i.e., in the absence of probe) uncertain. For this reason, modified oligonucleotides and fluorescent base analogues that serve as "internal" fluorescent probes are presented as an orthogonal means for detecting conformational changes, without necessarily perturbing the equilibria between G-quadruplex, single-stranded, and duplex DNA. The major challenges and motivation for the development of fluorescent probes for G-quadruplex structures are presented, along with a summary of the key photophysical, biophysical, and biological properties of reported examples. 23255529 Physicochemical and biological properties of biomimetic mineralo-protein nanoparticles formed spontaneously in biological fluids. Recent studies indicate that mineral nanoparticles (NPs) form spontaneously in human body fluids. These biological NPs represent mineral precursors that are associated with ectopic calcifications seen in various human diseases. However, the parameters that control the formation of mineral NPs and their possible effects on human cells remain poorly understood. Here a nanomaterial approach to study the formation of biomimetic calcium phosphate NPs comparable to their physiological counterparts is described. Particle sizing using dynamic light scattering reveals that serum and ion concentrations within the physiological range yield NPs below 100 nm in diameter. While the particles are phagocytosed by macrophages in a size-independent manner, only large particles or NP aggregates in the micrometer range induce cellular responses that include production of mitochondrial reactive oxygen species, caspase-1 activation, and secretion of interleukin-1β (IL-1β). A comprehensive proteomic analysis reveals that the particle-bound proteins are similar in terms of their identity and number, regardless of particle size, suggesting that protein adsorption is independent of particle size and curvature. In conclusion, the conditions underlying the formation of mineralo-protein particles are similar to the ones that form in vivo. While mineral NPs do not activate immune cells, they may become pro-inflammatory and contribute to pathological processes once they aggregate and form larger mineral particles. 23892932 Decreased liver peroxisomal β-oxidation accompanied by changes in brain fatty acid composition in aged rats. Peroxisomal β-oxidation is primarily responsible for the degradation of very long chain fatty acids (VLCFAs), dicarboxylic acids, unsaturated fatty acids and branched fatty acids. The genes encoding β-oxidation enzymes are transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPARα). Age-related decreases in acyl-CoA oxidase 1 (ACOX1) activity, a key enzyme involved in peroxisomal β-oxidation, have been found in aged rodents. To determine whether decreased peroxisomal β-oxidation with aging affects brain fatty acid composition, 22-month-old (old) and 3-month-old (young) male Sprague-Dawley rats were used. We confirmed the decreased expression of liver ACOX1 and PPARα in old rats. In addition, a gas chromatography assay showed significant changes in the percentage of fatty acids in the cerebral cortices between old and young rats. In the cerebral cortices of old rats, the increased fatty acids included VLCFAs (C20:0, C22:0, C24:0) and monounsaturated fatty acids (C16:1, C18:1, C20:1, C22:1, C24:1), whereas the decreased fatty acids included C18:0, C20:4 and C22:6. These results indicated that decreased liver peroxisomal β-oxidation was accompanied by changes in brain fatty acid composition with aging and suggested that peroxisomal β-oxidation dysfunction may play a potential role in the progression of brain aging. 23483309 A novel degenerated primer pair detects diverse genes of acyl homoserine lactone synthetase in Rhizobiaceae family. A novel degenerated primer set was designed to amplify acyl homoserine lactone (AHL) synthetase genes from members of the family Rhizobiaceae. The primer set successfully amplified AHL synthetase genes from pure cultures of AHL producers from Rhizobiaceae, but not from AHL producers out of the Rhizobiaceae family, indicating the specificity of this primer set to the Rhizobiaceae family. An inoculation experiment showed that the minimal detectable concentration of AHL producers from the soil was around 2.5 Ã— 10(7) CFU/g soil. When applying to environmental samples, 7 and 14 different genotypes of AHL synthetase genes were identified in the rhizosphere of Glycine max and Vigna unguiculata, respectively, which revealed complicated and unknown AHL-based quorum-sensing networks in the rhizosphere. This is the first primer set that covers diverse AHL synthetase genes from different genera. It will be a useful culture-independent approach for better understanding of the ecological significance of QS in natural habitats. 23792659 Evaluation of integrated anaerobic-aerobic biofilm reactor for degradation of azo dye methyl orange. This study was to investigate the mineralization of wastewater containing methyl orange (MO) in integrated anaerobic-aerobic biofilm reactor with coconut fiber as bio-material. Different aeration periods (3h in phase 1 and 2; 3, 6 and 15h in phase 3; 24h in phase 4 and 5) in aerobic chamber were studied with different MO concentration 50, 100, 200, 200 and 300mg/L as influent from phase 1-5. The color removals estimated from the standard curve of dye versus optical density at its maximum absorption wavelength were 97%, 96%, 97%, 97%, and 96% and COD removals were 75%, 72%, 63%, 81%, and 73% in phase 1-5, respectively. The MO decolorization and COD degradation followed first-order kinetic model and second-order kinetic model, respectively. GC-MS analysis indicated the symmetrical cleavage of azo bond and the reduction in aromatic peak ensured the partial mineralization of MO. 23894139 mpMoRFsDB: a database of molecular recognition features in membrane proteins. Molecular recognition features (MoRFs) are small, intrinsically disordered regions in proteins that undergo a disorder-to-order transition on binding to their partners. MoRFs are involved in protein-protein interactions and may function as the initial step in molecular recognition. The aim of this work was to collect, organize and store all membrane proteins that contain MoRFs. Membrane proteins constitute ∼30% of fully sequenced proteomes and are responsible for a wide variety of cellular functions. MoRFs were classified according to their secondary structure, after interacting with their partners. We identified MoRFs in transmembrane and peripheral membrane proteins. The position of transmembrane protein MoRFs was determined in relation to a protein's topology. All information was stored in a publicly available mySQL database with a user-friendly web interface. A Jmol applet is integrated for visualization of the structures. mpMoRFsDB provides valuable information related to disorder-based protein-protein interactions in membrane proteins. http://bioinformatics.biol.uoa.gr/mpMoRFsDB CONTACT: shamodr@biol.uoa.gr. 23911843 Plasmodium vivax infection induces expansion of activated naïve/memory T cells and differentiation into a central memory profile. Immunity to malaria is widely believed to wane in the absence of reinfection, but direct evidence for the presence or absence of durable immunological memory to malaria is limited. Here, we characterized the profile of circulating naïve and memory (including central and effector) CD4(+) T cells responses of individuals naturally infected by Plasmodium vivax. In the current study, we demonstrated that acute P. vivax infection induces a significant increase in the absolute number of both naïve and memory cells, which were responsible for the production of anti-inflammatory (IL-10) and pro-inflammatory (IFN-γ) cytokines. Finally, we described the profile of memory cell subtypes (TCM-CD45RO(high)CCR7(+) and TEM-CD45RO(high)CCR7(-)), as well as the pattern of cell migration based on CD62L selectin expression, demonstrating that P. vivax-infected donors presented with a predominantly central memory cell profile. Our results indicate that the expansion of both naïve and memory T cells, responsible for the production of both pro-inflammatory and regulatory cytokines, which might also contribute to the modulation of immune responses during P. vivax infection. 23550626 Decreased Nox4 levels in the myocardium of patients with aortic valve stenosis. The NADPH oxidases are a key family of ROS (reactive oxygen species)-producing enzymes which may differentially contribute to cardiac pathophysiology. Animal studies show uncertain results regarding the regulation of cardiac Nox4 by pressure overload and no data are available on human myocardial Nox4. In the present study, we evaluated Nox4 expression and its relationship with myocardial remodelling and LV (left ventricular) function in patients with severe AS (aortic valve stenosis). Endomyocardial biopsies from 34 patients with AS were obtained during aortic valve replacement surgery. LV morphology and function were assessed by echocardiography. Myocardial samples from subjects deceased of non-CVDs (cardiovascular diseases) were analysed as controls. Nox4 localization was evaluated by immunohistochemistry and quantified by Western blot. Myocardial capillary density, fibrosis and cardiomyocyte dimensions and apoptosis were assessed histologically to evaluate myocardial remodelling. Nox4 was present in samples from all subjects and expressed in cardiomyocytes, VSMCs (vascular smooth muscle cells), endothelium and fibroblasts. Nox4 levels were reduced 5-fold in AS patients compared with controls (P<0.01). Nox4 levels directly correlated with cardiomyocyte cross-sectional area (r=0.299, P<0.05) and diameter (r=0.406, P<0.05) and capillary density (r=0.389, P<0.05), and inversely with cardiomyocyte apoptosis (r=-0.316, P<0.05) in AS patients. In addition, Nox4 levels correlated with echocardiographic parameters (LV ejection fraction: r=0.353, P<0.05; midwall fractional shortening: r=0.355, P<0.05; deceleration time: r=-0.345, P<0.05) in AS patients. Nox4 is expressed in human myocardium and reduced in AS patients. The observed associations of Nox4 with cardiomyocyte parameters and capillary density in AS patients suggest a potential role of Nox4 deficiency in the myocardial remodelling present in the human pressure-overloaded heart. 23530756 Activation of mitochondrial function and Hb expression in non-haematopoietic cells by an EPO inducer ameliorates ischaemic diseases in mice. Many organs suffer from ischaemic injuries that reduce their ability to generate sufficient energy, which is required for functional maintenance and repair. Erythropoietin (EPO) ameliorates ischaemic injuries by pleiotropic effects. The aim of this study was to investigate the effect and mechanism of a small molecule EH-201, and found it as a potent EPO inducer and its effect in non-haematopoietic cells for therapeutic potential in ischemic disorders. Mice kidney slices, primary hepatocytes, primary cardiomyocytes and C2C12 myoblasts were treated with EH-201. The effects of this treatment on EPO, Hb expression and mitochondrial biogenesis were analysed. In vivo, doxorubicin-induced cardiomyopathic mice were treated with EH-201. The mice were subjected to an endurance test, electrocardiography and echocardiography, and a histological examination of the isolated hearts was performed. EH-201 was also administered to cisplatin-induced nephropathic mice. In non-haematopoietic cells, EH-201 was potent at inducing EPO. EH-201 also stimulated mitochondrial biogenesis and enhanced the expression of Hb by a mechanism dependent on EPO-mediated signalling. In mechanistic studies, using EPO and EPO receptor-neutralizing antibodies, we confirmed that EH-201 enhances EPO-EPOR autocrine activity. EH-201 robustly increased the endurance performance activity of healthy and cardiomyopathic mice during hypoxic stress, enhanced myocardial mitochondrial biogenesis and Hb expression, and also improved cardiac function. EH-201 ameliorated anaemia and renal dysfunction in nephropathic mice. The enhancement and recovery of cellular functions through the stimulation of mitochondrial activity and Hb production in non-haematopoietic cells by an inducer of endogenous EPO has potential as a therapeutic strategy for ischaemic diseases. 23838269 Studies on β-sitosterol and ceramide-induced alterations in the properties of cholesterol/sphingomyelin/ganglioside monolayers. Phytosterol-β-sitosterol promotes apoptosis in various cancer cells and inhibits their growth. Supplementation of cancer cells with this compound causes modifications in membrane composition, namely, substitution of cholesterol (Chol), decrease of sphingomyelin (SM) content and increase of ceramide (Cer) level. The aim of this work was to investigate the influence of partial replacement of cholesterol by plant sterol, substitution of sphingomyelin by ceramide and both these factors simultaneously on the properties of the monolayers composed of major lipids identified in breast cancer membranes, namely Chol/SM/GM3 mixtures. Brewster Angle Microcopy experiments and the analysis of the isotherms recorded during films compression and resulting parameters evidenced that β-sitosterol weakens the interactions between molecules, decreases films stability and condensation. The influence of ceramide on sterol/SM/GM3 films was reflected in strong modifications of their texture, however, the morphology of monolayer was determined by the structure of sterol present in the system. It was also found, that simultaneous replacement of 50mol% of Chol and SM by phytosterol and Cer, respectively, induces lipids segregation, which is manifested in large diversity of phases observed in BAM images. To facilitate the analysis of the data collected for multicomponent monolayers, the properties of selected sterol/GM3, sterol/Cer, SM/GM3, Cer/GM3 binary films were also investigated. The obtained results evidenced that the studied herein modifications in the composition of Chol/SM/GM3 monolayer, reflecting compositional alterations induced by phytosterol in cancer membranes, strongly affect the organization of model system, therefore they should be considered in the studies on anticancer mechanism of β-sitosterol. 23608020 Renal accumulation and effects of intraperitoneal injection of extracted microcystins in omnivorous crucian carp (Carassius auratus). An acute toxicological experiment was designed to characterize the sequence of renal ultrastructural changes with accumulated MCs in crucian carp injected intraperitoneally (i.p.) with extracted microcystins (mainly MC-RR and -LR) at two doses, 50 and 200 μg MC-LReq. kg(-1) body weight. Quantitative and qualitative determinations of MCs in the kidney were conducted by HPLC and LC-MS, respectively. MC-RR content in kidney of crucian carp showed a time dose-dependent increase within 48 h post-injection, followed by a sharp decline afterward, while no MC-LR in kidney was detectable throughout the experiment. Ultrastructural changes in the kidney of crucian carp progressed with increasing accumulated MCs and exposure times within 48 h post-injection, whereas renal ultrastructural recovery of crucian carp in the 50 μg MC-LReq. kg(-1) dose group was evident at 168 h post-injection. Our ultrastructural observation suggests that the membranous structure is the main action site of MCs in the kidney, among which mitochondria damage in the tubules is clearly an early, and presumably a critically important effect of MCs. The increases in blood urea nitrogen (BUN) and creatinine (CR) in both dose groups further revealed severe impairment occurred in the kidney of crucian carp. 23481648 Substituted 1,6-diphenylnaphthalenes as FtsZ-targeting antibacterial agents. Bacterial cell division occurs in conjunction with the formation of a cytokinetic Z-ring structure comprised of FtsZ subunits. Agents that disrupt Z-ring formation have the potential, through this unique mechanism, to be effective against several of the newly emerging multidrug-resistant strains of infectious bacteria. Several 1-phenylbenzo[c]phenanthridines exhibit notable antibacterial activity. Based upon their structural similarity to these compounds, a distinct series of substituted 1,6-diphenylnaphthalenes were synthesized and evaluated for antibacterial activity against Staphylococcus aureus and Enterococcus faecalis. In addition, the effect of select 1,6-diphenylnaphthalenes on the polymerization dynamics of S. aureus FtsZ and mammalian β-tubulin was also assessed. The presence of a basic functional group or a quaternary ammonium substituent on the 6-phenylnaphthalene was required for significant antibacterial activity. Diphenylnaphthalene derivatives that were active as antibiotics, did exert a pronounced effect on bacterial FtsZ polymerization and do not appear to cross-react with mammalian tubulin to any significant degree. 23666759 Brain morphometric changes associated with childhood-onset systemic lupus erythematosus and neurocognitive deficit. To use structural magnetic resonance imaging (MRI) to characterize changes in gray matter and white matter volumes between patients with childhood-onset systemic lupus erythematosus (SLE) and matched controls, between patients with childhood-onset SLE with and those without neurocognitive deficit, and in relation to disease duration and treatment with steroids. Twenty-two patients with childhood-onset SLE and 19 healthy controls underwent high-resolution structural MRI. Probability density maps for gray matter and white matter were compared between groups. Neuropsychological testing confirmed the presence of neurocognitive deficit in 8 patients with childhood-onset SLE. Multiple brain regions had reduced gray matter volume in the patients with childhood- onset SLE with neurocognitive deficit versus controls or patients with childhood-onset SLE without neurocognitive deficit. Neither disease duration nor cumulative oral or intravenous steroid doses accounted for decreases in gray matter. White matter volume was also reduced in patients with childhood-onset SLE with neurocognitive deficit, and the reduction was positively associated with both disease duration and cumulative oral steroid dose. Conversely, higher cumulative intravenous steroid doses were associated with higher white matter volumes. Neurocognitive deficit in patients with childhood-onset SLE is associated with multifocal decreases in both gray and white matter volumes. Since only white matter volume changes are related to disease duration and cumulative oral steroid use, this may suggest that gray and white matter alterations relate to different underlying mechanisms. Further work is needed to understand the relationship between gray and white matter alterations in childhood-onset SLE, whether the underlying mechanisms relate to immunologic, vascular, or other causes, and whether the changes are reversible or preventable. Likewise, the protective properties of intravenous steroids in maintaining white matter volumes require confirmation in larger cohorts. 22886682 Enhanced nestin expression and small blood vessels in human pituitary adenomas. The role of angiogenesis in human pituitary tumor progression is questioned. Our aim was to characterize the morphologic changes that occur in the vasculature of pituitary adenomas, in correlation with the expression of nestin, a protein found in endothelial cells of newly formed vessels of developing organs. We also evaluated the relation of angiogenic markers and nestin with Ki-67 index. Immunohistochemical studies were performed on paraffin embedded samples of 47 pituitary adenomas and six normal pituitaries. We determined microvessel density (number of CD31+ or CD34+ vessels per square millimetre), vascular area (cumulative area occupied by vessels), average vessel size, and further classified vessels as small (<100 Î¼m(2)) or large (>100 Î¼m(2)). We correlated the above parameters with nestin expression and Ki-67 index. Lower vascular area compared to normal tissue was found in adenomas (p < 0.05). Interestingly, pituitary adenomas had significantly more small vessels than control pituitaries (p < 0.04 for CD31 and CD34). In tumors many capillaries were positive for nestin, while scarce staining was detected in controls, so that nestin positive area was significantly higher in tumors. Furthermore, nestin area correlated positively with the % of small vessels. Ki-67 correlated neither with vascular area nor with nestin expression. In human pituitary tumors there was a predominance of small capillaries in correlation with increased expression of the progenitor marker nestin. We suggest that angiogenesis is an active process in these tumors, in spite of their low total vascular area when compared to normal pituitaries. 23464650 Diameter-Dependent Photocurrent in InAsSb Nanowire Infrared Photodetectors. Photoconductors using vertical arrays of InAs/InAs1-xSbx nanowires with varying Sb composition x have been fabricated and characterized. The spectrally resolved photocurrents are strongly diameter dependent with peaks, which are red-shifted with diameter, appearing for thicker wires. Results from numerical simulations are in good agreement with the experimental data and reveal that the peaks are due to resonant modes that enhance the coupling of light into the wires. Through proper selection of wire diameter, the absorptance can be increased by more than 1 order of magnitude at a specific wavelength compared to a thin planar film with the same amount of material. A maximum 20% cutoff wavelength of 5.7 μm is obtained at 5 K for a wire diameter of 717 nm at a Sb content of x = 0.62, but simulations predict that detection at longer wavelengths can be achieved by increasing the diameter. Furthermore, photodetection in InAsSb nanowire arrays integrated on Si substrates is also demonstrated. 23734965 Investigating polypharmacy and drug burden index in hospitalised older people. To investigate the changes in polypharmacy and the drug burden index (DBI) occurring during hospitalisation for older people. The secondary aim was to examine the associations of these two measures with the length of hospital stay and admission for falls or delirium. A retrospective analysis of patients' medical records was undertaken at a large university teaching hospital (Sydney, Australia) for patients with the age of ≥65 years and admitted under the care of the geriatric medicine or rehabilitation teams. Polypharmacy was defined as the use of more than five regular medications. The DBI measures exposure to drugs with anticholinergic and sedative effects. Logistic regression analysis was conducted to investigate the associations between polypharmacy and DBI with outcome measures. Data are presented using odds ratios with 95% confidence intervals. A total of 329 patients was included in this study. The mean (± standard deviation) age of the population was 84.6 ± 7.0 years, 62% were female and 40% were admitted from residential aged-care facilities. On admission, polypharmacy was observed in 60% of the cohort and DBI exposure for 50%. DBI and polypharmacy exposure decreased during hospitalisation, but only the number of medications taken decreased by a statistically significant margin (P = 0.02). Patients with a high DBI (≥1) were approximately three times more likely to be admitted for delirium than those with no DBI exposure (odds ratio, 2.95; 95% confidence interval, 1.34-6.51). In the present study, DBI was associated with an increased risk of hospital admission for delirium only. Polypharmacy was not associated with any of the clinical measures. 23779083 (NH4)2S, a highly reactive molecular precursor for low temperature anion exchange reactions in nanoparticles. Ammonium sulfide ((NH4)2S) exhibits high reactivity as a sulfide reagent in anion exchange reactions that transform CoO to cobalt sulfide nanoparticles (NPs). The faster diffusion of Co(2+) and O(2-) than the incoming S(2-) during the anion exchange causes a significant expansion of the NP voids. The low temperature (70 °C) anion exchange reaction produces amorphous cobalt sulfide NPs with Co : S ratio of ca. 3 : 4, which are converted into crystalline NPs with a major phase of cubic Co3S4 by annealing at high temperature in an organic solution. 23543111 Use of a support vector machine for categorizing free-text notes: assessment of accuracy across two institutions. Electronic health record (EHR) users must regularly review large amounts of data in order to make informed clinical decisions, and such review is time-consuming and often overwhelming. Technologies like automated summarization tools, EHR search engines and natural language processing have been shown to help clinicians manage this information. To develop a support vector machine (SVM)-based system for identifying EHR progress notes pertaining to diabetes, and to validate it at two institutions. We retrieved 2000 EHR progress notes from patients with diabetes at the Brigham and Women's Hospital (1000 for training and 1000 for testing) and another 1000 notes from the University of Texas Physicians (for validation). We manually annotated all notes and trained a SVM using a bag of words approach. We then used the SVM on the testing and validation sets and evaluated its performance with the area under the curve (AUC) and F statistics. The model accurately identified diabetes-related notes in both the Brigham and Women's Hospital testing set (AUC=0.956, F=0.934) and the external University of Texas Faculty Physicians validation set (AUC=0.947, F=0.935). Overall, the model we developed was quite accurate. Furthermore, it generalized, without loss of accuracy, to another institution with a different EHR and a distinct patient and provider population. It is possible to use a SVM-based classifier to identify EHR progress notes pertaining to diabetes, and the model generalizes well. 23546855 Performance evaluation of various stormwater best management practices. Many best management practices have been developed and implemented to treat the nonpoint source pollution of the aquatic environment in Korea's four major river basins. The performance and cost of these facilities were evaluated and compared using broad categories, including grassed swales, constructed wetlands, vegetated filter strips, hydrodynamic separators, media filters, and infiltration trenches, based on the monitoring and maintenance work undertaken between 2005 and 2012. Constructed wetlands, media filters, and infiltration trenches generally performed better in removing pollutants than other types of facilities, while media filters were the most expensive factor in terms of construction and operational costs. In addition, constructed wetlands incurred the least operational cost, as well as helping to control the quantity of runoff. This illustrates that a high cost facility does not necessarily give a better performance. A slightly more expensive facility, such as wetland, could prove to be a reasonably effective treatment. The selection of the most appropriate treatment for stormwater runoff should be based on an overall analysis of performance and cost. 23928177 Efficient preloading of the ventricles by a properly timed atrial contraction underlies stroke work improvement in the acute response to cardiac resynchronization therapy. The acute response to cardiac resynchronization therapy (CRT) has been shown to be due to three mechanisms: resynchronization of ventricular contraction, efficient preloading of the ventricles by a properly timed atrial contraction, and mitral regurgitation reduction. However, the contribution of each of the three mechanisms to the acute response of CRT, specifically stroke work improvement, has not been quantified. The goal of this study was to use an MRI-based anatomically accurate 3D model of failing canine ventricular electromechanics to quantify the contribution of each of the three mechanisms to stroke work improvement and identify the predominant mechanisms. An MRI-based electromechanical model of the failing canine ventricles assembled previously by our group was further developed and modified. Three different protocols were used to dissect the contribution of each of the three mechanisms to stroke work improvement. Resynchronization of ventricular contraction did not lead to significant stroke work improvement. Efficient preloading of the ventricles by a properly timed atrial contraction was the predominant mechanism underlying stroke work improvement. Stroke work improvement peaked at an intermediate AV delay, as it allowed ventricular filling by atrial contraction to occur at a low diastolic LV pressure but also provided adequate time for ventricular filling before ventricular contraction. Diminution of mitral regurgitation by CRT led to stroke work worsening instead of improvement. Efficient preloading of the ventricles by a properly timed atrial contraction is responsible for significant stroke work improvement in the acute CRT response. 23937213 Shear strengthens fibrin: the knob-hole interactions display "catch-slip" kinetics. The polymerization of fibrin occurs primarily via intermolecular non-covalent binding between knobs 'A' exposed by cleavage of fibrinopeptides A in the Aα chains of fibrinogen and holes 'a' constitutively present in the γ chains [1]. We have previously investigated the interactions between knobs 'A' and holes 'a' at the single-molecule level and have found that they are strong and stable [2] with complex forced unbinding mechanisms [3]. The structural complexity and thermodynamics of these interactions must be reflected in the non-trivial dynamics of the mechanical response of the knob-hole bond to stress. By applying an original model system to quantify the mechanical dissociation of individual knob-hole complexes, we revealed an unusual strengthening of A:a knob-hole bonds in response to increasing pulling force, referred to as a "catch" bond. This article is protected by copyright. All rights reserved. 23884835 Identification of microRNAs present in congenital heart disease associated copy number variants. Congenital heart disease (CHD) is the most common congenital anomaly in newborns and about 1.35 million infants are born with CHD each year worldwide. Recently a large category of copy number variants (CNVs), were established to be a major contributor of the pathophysiology of CHD. To date most studies focused on the analysis of CNV categories or the protein coding regions without investigation on the impact of non-coding regulatory microRNAs (miRNAs). Here with an array comparative genome hybridisation data set and a gene expression profile data set, we investigated the contribution of miRNAs in CNVs towards the development of CHD. Approximately 18% of the identified high frequency CNV loci were shown to harbor miRNAs. According the expression profile analysis, 52 target genes of 16 miRNAs showed association with CHD. Targets of hsa-miR-650 was reported to be enriched with genes of cardiac dysfunctions and heart failure categories previously. In the constructed network, all 12 miRNAs directly or indirectly interacts with CHD related genes and hsa-miR-570 showed the highest degree. Our study highlights the significance of CNV-microRNAs and their target genes in the pathogenesis of CHD. This knowledge will facilitate the identification of miRNA biomarkers and the development of new therapeutics for CHD. 23740599 Prevalence of cardiovascular disorders and risk factors in two 75-year-old birth cohorts examined in 1976-1977 and 2005-2006. The number of older people are increasing worldwide, and cardiovascular diseases are the major causes of death in western societies. This study examines birth cohort differences in cardiovascular disorders and risk factors in Swedish elderly. Representative samples of 75-year-olds living in Gothenburg, Sweden, examined in 1976-1977 and in 2005-2006. Blood pressure, s-cholesterol, s-triglycerides, height, body weight, body mass index, history of myocardial infarction, angina pectoris and stroke/TIA, and diabetes mellitus were measured. The prevalence of total cardiovascular disorders, hypertension and hypercholesterolemia decreased, and the prevalence of stroke increased in both genders. The prevalence of cardiovascular disorders was higher in women than in men in 1976-1977, and higher in men than in women in 2005-2006. The decrease in blood pressure occurred independently of antihypertensive treatment. The prevalence of current smokers decreased in men and increased in women. The prevalence of life-time smokers and diabetes mellitus increased only in women. The proportion on antihypertensive treatment and overweight and obesity increased only in men. Hypertension, overweight and obesity were more common in women in 1976-1977. These sex differences were not observed in 2005-2006. The overall prevalence of cardiovascular disorders decreased, and sex differences reversed between the 1970s and 2000s among Swedish septuagenarians. Our findings emphasize the importance of environmental factors, not only for the prevalence of cardiovascular disorders, but also as explanations for sex differences. Reasons for changes could be increased survival in those with disorders and risk factors, changes in lifestyle and diet, and better preventive strategies, such as treatment of hypercholesterolemia and hypertension. 23754288 Mapping the Binding Region on the Low Density Lipoprotein Receptor for Blood Coagulation Factor VIII. Low density lipoprotein receptor (LDLR) was shown to mediate clearance of blood coagulation factor VIII (FVIII) from the circulation. To elucidate the mechanism of interaction of LDLR and FVIII, our objective was to identify the region of the receptor necessary for binding FVIII. Using surface plasmon resonance, we found that LDLR exodomain and its cluster of complement-type repeats (CRs) bind FVIII in the same mode. This indicated that the LDLR site for FVIII is located within the LDLR cluster. Similar results were obtained for another ligand of LDLR, α-2-macroglobulin receptor-associated protein (RAP), a common ligand of receptors from the LDLR family. We further generated a set of recombinant fragments of the LDLR cluster and assessed their structural integrity by binding to RAP and by circular dichroism. A number of fragments overlapping CR.2-5 of the cluster were positive for binding RAP and FVIII. The specificity of these interactions was tested by site-directed mutagenesis of conserved tryptophans within the LDLR fragments. For FVIII, the specificity was also tested using a single-chain variable antibody fragment directed against the FVIII light chain as a competitor. Both cases resulted in decreased binding, thus confirming its specificity. The mutagenic study also showed an importance of the conserved tryptophans in LDLR for both ligands, and the competitive binding results showed an involvement of the light chain of FVIII in its interaction with LDLR. In conclusion, the region of CR.2-5 of LDLR was defined as the binding site for FVIII and RAP. 23873083 Single-cell gene expression analysis reveals genetic associations masked in whole-tissue experiments. Gene expression in multiple individual cells from a tissue or culture sample varies according to cell-cycle, genetic, epigenetic and stochastic differences between the cells. However, single-cell differences have been largely neglected in the analysis of the functional consequences of genetic variation. Here we measure the expression of 92 genes affected by Wnt signaling in 1,440 single cells from 15 individuals to associate single-nucleotide polymorphisms (SNPs) with gene-expression phenotypes, while accounting for stochastic and cell-cycle differences between cells. We provide evidence that many heritable variations in gene function-such as burst size, burst frequency, cell cycle-specific expression and expression correlation/noise between cells-are masked when expression is averaged over many cells. Our results demonstrate how single-cell analyses provide insights into the mechanistic and network effects of genetic variability, with improved statistical power to model these effects on gene expression. 23834962 The association between blood pressure and blood cadmium in a Chinese population living in cadmium polluted area. Cadmium exposure may be associated with high risk of hypertension. But inconsistent results have been reported. In this study, the association of blood pressure (BP) with blood cadmium (BCd) and the possible influencing factors were investigated. A total of 181 persons (71 men and 110 women) living near a cadmium smelter participated in this study. The participants completed a questionnaire and BP, BCd and related biochemical indicators were measured. The geometric mean of BCd was 3.84μg/L and 3.32μg/L for women and men. The systolic blood pressure (SBP) and diastolic blood pressure both increased with the increasing of BCd. The BP in women was positively correlated with BCd (p<0.05). The BCd level of participants with hypertension was obvious higher (+28%) than those with normal BP. The prevalence of hypertension was increased with the increasing of BCd, in particular to women (χ(2)=3.896, p=0.048). Cadmium level in blood was associated with elevation in blood pressure, especially for women. 22822932 The role of symbol-based experience in early learning and transfer from pictures: evidence from Tanzania. Extensive exposure to representational media is common for infants in Western culture, and previous research has shown that soon after their 1st birthday, infants can acquire and extend new information from pictures to real objects. Here we explore the extent to which lack of exposure to pictures during infancy affects children's learning from pictures. Infants were recruited from a rural village in Tanzania and had no prior experience with pictures. After a picture book interaction during which a novel depicted object was labeled, we assessed infants' learning and transfer of the label from pictures to their referents. In a 2nd study, we assessed infants' learning and generalization of new names using real objects, rather than pictures. Tanzanian infants demonstrated a similar pattern of learning and generalization from real objects, when compared with infants in Western culture. However, there was a significant difference in learning and generalization from pictures to real objects. These findings provide evidence for the important role of early experience with representational media in children's ability to use pictures as a source of information about the world. 23542578 A novel method for preparing complete antigens of gonyautoxin 2,3 and their feature of immunogenicity. In this paper, a novel method was proposed to prepare artificial antigens of gonyaulax parlaytic shellfish toxin 2 and 3 (GTX2,3). An intermediate GTX2,3-aldehyde was first synthesized by activating the NH2 group of the 2nd and 8th amino acid residues with three different aldehydes and two artificial complete antigens GTX2,3-aldehyde-bovine serum albumin (BSA) and GTX2,3-aldehyde- keyhole limpet hemocyanin (KLH) were then prepared by cross-linking the intermediate with BSA or KLH. The successful preparation of the two complete antigens was confirmed by UV spectral scanning, HPLC, production of antibodies with titer of 1.28 × 10(4) from mice immunized with the two complete antigens, indirect ELISA and Western-blot. In conclusion, the synthesized complete antigens have strong immunogenicity, which provides a solid foundation for preparing GTX2,3 monoclonal antibody and rapid detection kit. 23044938 Neuropeptide Y is a critical modulator of leptin's regulation of cortical bone. Leptin signaling is required for normal bone homeostasis; however, loss of leptin results in differing effects on cortical and cancellous bone, as well as altered responses between the axial and appendicular regions. Local β-adrenergic actions are responsible for the greater cancellous bone volume in leptin-deficient (ob/ob) mice; however, the mechanism responsible for the opposing reduction in cortical bone in ob/ob mice is not known. Here we show that blocking the leptin-deficient increase in neuropeptide Y (NPY) expression reverses the cortical bone loss in ob/ob mice. Mice null for both NPY and leptin (NPY(-/-) ob/ob), display greater cortical bone mass in both long-bones and vertebra, with NPY(-/-) ob/ob mice exhibiting thicker and denser cortical bone, associated with greater endocortical and periosteal mineral apposition rate (MAR), compared to ob/ob animals. Importantly, these cortical changes occurred without significant increases in body weight, with NPY(-/-) ob/ob mice showing significantly reduced adiposity compared to ob/ob controls, most likely due to the reduced respiratory exchange ratio seen in these animals. Interestingly, cancellous bone volume was not different between NPY(-/-) ob/ob and ob/ob, suggesting that NPY is not influencing the adrenergic axis. Taken together, this work demonstrates the critical role of NPY signaling in the regulation of bone and energy homeostasis, and more importantly, suggests that reduced leptin levels or leptin resistance, which occurs in obesity, could potentially inhibit cortical bone formation via increased central NPY signaling. 23932346 Geoepidemiology of primary sclerosing cholangitis: A critical review. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown origin, characterized by progressive destruction of bile ducts caused by diffuse inflammation and fibrosis. Previous epidemiological studies in Northern Europe and North America demonstrated that incidence and prevalence rates are ranging from 0.5 to 1.3 and from 3.85 to 16.2 per 100,000 inhabitants per year, respectively. It is of note that the incidence of PSC appears to be gradually increasing. We have extensively reviewed the geoepidemiology of PSC and attempted to place it in context with the incidence in Japan. In 2012, the clinical diagnostic criteria of IgG4-SC were established and published by the Japan Biliary Association, rendering it possible for physicians to clinically differentiate PSC from IgG4-SC. We conducted a new nationwide survey for PSC as well as IgG4-SC, and have identified 197 patients with PSC and 43 patients with IgG4-SC without pancreatic involvement. In this survey we estimated prevalence rate of PSC in Japan as 0.95, lower than those in North America and European countries. Also we identified other unique features of Japanese PSC patients, including 2 peaks in age distribution at diagnosis and fewer presences of comorbid inflammatory bowel diseases, occurring in only 34% of PSC. This data is placed in the perspective of the international experience on PSC. 23853127 In vitro protein binding of liraglutide in human plasma determined by reiterated stepwise equilibrium dialysis. Liraglutide is a human glucagon-like peptide-1 (GLP-1) analogue approved for the treatment of type 2 diabetes. It is based on human GLP-1 with the addition of a 16-carbon fatty acid, which facilitates binding to plasma proteins, thus prolonging the elimination half-life and allowing once-daily administration. It has not been possible to quantify liraglutide protein binding by ultrafiltration (the usual method of choice), as the lipophilic molecule becomes trapped in the filter membrane. Therefore, the aim of this study was to develop a methodology that could determine the extent of liraglutide binding to plasma proteins in vitro. We report here the details of a novel reiterated stepwise equilibrium dialysis assay that has successfully been used to quantify liraglutide plasma protein binding. The assay allowed quantification of liraglutide binding to proteins in purified plasma protein solutions and human plasma samples and was effective at plasma dilutions as low as 5%. At a clinically relevant liraglutide concentration (10(4) pM), greater than 98.9% of liraglutide was bound to protein. Specific binding to human serum albumin and α1-acid glycoprotein was 99.4% and 99.3%, respectively. The novel methodology described herein could have an application in the quantification of plasma protein binding of other highly lipophilic drug molecules. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2882-2888, 2013. 23962220 Evaluation of multisystemic therapy pilot services in the Systemic Therapy for At Risk Teens (START) trial: study protocol for a randomised controlled trial. There is an urgent need for clinically effective and cost-effective methods to manage antisocial and criminal behaviour in adolescents. Youth conduct disorder is increasingly prevalent in the UK and is associated with a range of negative outcomes. Quantitative systematic reviews carried out for the National Institute for Health and Clinical Excellence have identified multisystemic therapy, an intensive, multimodal, home-based, family intervention for youth with serious antisocial behaviour, as one of the most promising interventions for reducing antisocial or offending behaviour and improving individual and family functioning. Previous international trials of multisystemic therapy have yielded mixed outcomes, and it is questionable to what extent positive US findings can be generalised to a wider UK mental health and juvenile justice context. This paper describes the protocol for the Systemic Therapy for At Risk Teens (START) trial, a multicentre UK-wide randomised controlled trial of multisystemic therapy in antisocial adolescents at high risk of out-of-home placement. The trial is being conducted at 10 sites across the UK. Seven hundred participants and their families will be recruited and randomised on a 1:1 basis to multisystemic therapy or management as usual. Treatments are offered over a period of 3 to 5 months, with follow-up to 18 months post-randomisation. The primary outcome is out-of-home placement at 18 months. Secondary outcomes include offending rates, total service and criminal justice sector costs, and participant well-being and educational outcomes. Data will be gathered from police computer records, the National Pupil Database, and interview and self-report measures administered to adolescents, parents and teachers. Outcomes will be analysed on an intention-to-treat basis, using a logistic regression with random effects for the primary outcome and Cox regressions and linear mixed-effects models for secondary outcomes depending on whether the outcome is time-to-event or continuous. The START trial is a pragmatic national trial of sufficient size to evaluate multisystemic therapy, to inform policymakers, service commissioners, professionals, service users and their families about its potential in the UK. It will also provide data on the clinical and cost-effectiveness of usual services provided to youth with serious antisocial behaviour problems. ISRCTN77132214. 23632239 A 914-bp promoter is sufficient to reproduce the endogenous prolyl oligopeptidase gene localization in the mouse placenta if not subject to position effect. Prolyl oligopeptidase (POP) is a widely distributed multifunctional protein which has an endopeptidase activity to cleave a Pro-X peptide bond. In spite of numerous studies about POP, the mechanism by which its transcription is controlled has not been well investigated. Here we generated transgenic mice bearing a transgene which contained a 914-bp POP gene promoter linked to the enhanced green fluorescent protein (EGFP) gene to assess the in vivo promoter activity. We established six transgenic lines with different copy numbers, but no EGFP signal was observed in four lines due to a high level of DNA methylation, which suggested that the transgene was subject to position effect. However, in the other two lines, we detected the EGFP expression in many tissues, and its placental localization showed a similar change to POP. A strong EGFP signal was observed in the junctional and labyrinthine zones of E10.5-E12.5 placentas and in the junctional zone and the maternal decidua after that. This placental gene activation might be attributed to AP-2γ because we detected its binding to the POP promoter. In contrast, we did not obtain any evidence that EGFP was expressed in a similar pattern compared with POP in the ovary. The current data demonstrated that the 914-bp promoter had sufficient activity to reproduce the POP localization in the placenta if it was not subject to position effect and suggest that the regulatory mechanism of the POP gene expression differs between tissues. 23500625 Pro-oxidant and antioxidant response elicited by CH2Cl2, CHCl3 and BrCHCl2 in Goodea gracilis using non-invasive methods. The development of non-invasive methods aimed to evaluate the effects of many toxicants is required. Although there are some studies conducted in successful ways, a lack of information prevails especially for those substances that could be formed autochthonously in the water bodies, such as halomethanes (HMs). In this study, induction of pro-oxidant forces (CH2O, O2, H2O2), oxidative stress (TBARS, RCO) and antioxidant defenses (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) in the skin mucus layer regarding to the liver of Goodea gracilis exposed to CH2Cl2, CHCl3 and BrCHCl2 were evaluated, in addition to the hepatic cytochrome P450 (CYP 2E1) and glutathione S-transferase theta (GSTT) activities. Regardless of the implicit toxicity involved in the bioactivation of the HMs, carried out by the CYP 2E1 and GST, it was noticeable that this process induces oxidative stress. The usefulness of the mucus layer for the evaluation of the oxidative stress response was demonstrated, despite some peculiar characteristics concerning induction of oxidative stress in liver and skin mucous layer. However, for the understanding of the induction of reactive oxygen species in both targets it is essential to evaluate the activity of antioxidant defenses; otherwise the interpretation of toxic effects elicited by HMs would be erroneous. In the skin mucus layer, lower activities of the enzymes involved in antioxidant defense than in liver were observed. The evaluation of the biomarkers in the skin mucus layer involved in the oxidative stress is useful due the consistent response regarding to concentration of the HMs. 23696377 Synthesis and degradation jointly determine the responsiveness of the cellular proteome. It is of fundamental importance to understand how the individual processes of gene expression, transcription, and translation, as well as mRNA and protein stability, act in concert to produce dynamic cellular proteomes. We use the concept of response times to illustrate the relation between degradation processes and responsiveness of the proteome to system changes and to provide supporting experimental evidence: proteins with short response times tend to be more strongly up-regulated after 1 hour of TNFα stimulation than proteins with longer response times. Furthermore, based on process-dependent response times, we demonstrate that synthesis and degradation act in concert to enable rapid responses. Finally, by building on a previously published data set quantifying the mammalian gene expression cascade, we speculate on how combinations of stable and unstable mRNAs and proteins may be wired to transcriptional or translational regulation to support gene function. 23940280 Clonal genetic and hematopoietic heterogeneity among human induced pluripotent stem cell lines. Induced pluripotent stem cells hold great promise for modeling human hematopoietic diseases. However, intrinsic variability in the capacities of different iPSC lines for hematopoietic development complicates comparative studies and is currently unexplained. We created and analyzed three separate iPSC clones from fibroblasts of three different normal individuals using a standardized approach that included excision of integrated reprogramming genes by Cre-Lox mediated recombination. Gene expression profiling and hematopoietic differentiation assays showed that independent lines from the same individual were generally more similar to each other than those from different individuals. However, one iPSC line (WT2.1) exhibited distinctly different gene expression, proliferation rate and hematopoietic developmental potential relative to all other iPSC lines. This "outlier" clone also acquired extensive copy number variations during reprogramming, which may be responsible for its divergent properties. Our data indicate how inherent and acquired genetic differences can influence iPSC properties, including hematopoietic potential. 23774474 Hydroxysafflor yellow A protects methylglyoxal-induced injury in the cultured human brain microvascular endothelial cells. Individuals with diabetes have high concentration of methylglyoxal (MGO) and have advanced glycation end-products (AGEs) which play an important role in vascular complications, such as stroke. Our previous data demonstrated that hydroxysafflor yellow A (HSYA), a major active chemical component of the safflower yellow pigment, had antiglycation effect on the AGEs formation in vitro. It is not known whether HSYA can protect against MGO-induced injury in cultured human brain microvascular endothelial cells (HBMEC). Using cultured HBMEC, cell injury was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) formation, lactate dehydrogenase (LDH) release and AnnexinV/PI staining. Advanced glycogen end-products and caspase-3 formation were measured by Western blotting. Incubation of MGO for 24h concentration-dependently induced HBMEC injury, which was protected by HSYA from 10 to 100μmol/l. Caspase-3 expression and AnnexinV/PI staining illustrated that the protection of HSYA was probably associated with inhibiting cell apoptosis. What's more, MGO promoted AGEs accumulation in the cultured HBMEC, which was also inhibited by 100μmol/l HSYA. Thus, our results proved that HSYA could inhibit MGO-induced injury in the cultured HBMEC, which was associated with its antiglycation effect. 23122153 Antioxidant activity comparison between [6S]-5-methyltetrahydrofolic acid calcium salt and the related racemate form. Folates, such as [6S]-5-methyltetrahydrofolic acid, have been introduced in the market both in vitamin pills and in fortified foods. Their antioxidant activity has been evaluated, but stereoisomer influence on activity has not been proven. In this study, a comparison between [6S]-5-methyltetrahydrofolic acid (5-MTHF) and its racemate [6R,S] form was made by TEAC assay at different pHs, FRAP assay, and ORAC assay. The results showed that the [6S] form had higher antioxidant activity than its racemate form in the TEAC assay at all pHs, with similar values in the FRAP and ORAC assays. Results suggest that stereoisomeric difference could influence the antioxidant activity of 5-MTHF and hence should be taken into account when folates are added to foodstuffs to improve their nutritional value. 23850244 Whole-Genome Bisulfite Sequencing of Two Distinct Interconvertible DNA Methylomes of Mouse Embryonic Stem Cells. The use of two kinase inhibitors (2i) enables derivation of mouse embryonic stem cells (ESCs) in the pluripotent ground state. Using whole-genome bisulfite sequencing (WGBS), we show that male 2i ESCs are globally hypomethylated compared to conventional ESCs maintained in serum. In serum, female ESCs are hypomethyated similarly to male ESCs in 2i, and DNA methylation is further reduced in 2i. Regions with elevated DNA methylation in 2i strongly correlate with the presence of H3K9me3 on endogenous retroviruses (ERVs) and imprinted loci. The methylome of male ESCs in serum parallels postimplantation blastocyst cells, while 2i stalls ESCs in a hypomethylated, ICM-like state. WGBS analysis during adaptation of 2i ESCs to serum suggests that deposition of DNA methylation is largely random, while loss of DNA methylation during reversion to 2i occurs passively, initiating at TET1 binding sites. Together, our analysis provides insight into DNA methylation dynamics in cultured ESCs paralleling early developmental processes. 23920440 New strigolactone mimics: Structure-activity relationship and mode of action as germinating stimulants for parasitic weeds. Strigolactones (SLs) are new plant hormones with varies important bio-functions. This Letter deals with germination of seeds of parasitic weeds. Natural SLs have a too complex structure for synthesis. Therefore, there is an active search for SL analogues and mimics with a simpler structure with retention of activity. SL analogues all contain the D-ring connected with an enone moiety through an enol ether unit. A new mechanism for the hydrolysis SL analogues involving bidentate bound water and an α,β-hydrolase with a Ser-His-Asp catalytic triad has been proposed. Newly discovered SL mimics only have the D-ring with an appropriate leaving group at C-5. A mode of action for SL mimics was proposed for which now supporting evidence is provided. As predicted an extra methyl group at C-4 of the D-ring blocks the germination of seeds of parasitic weeds. 23859693 Predictors of antenatal alcohol use among Australian women: a prospective cohort study. To identify predictors of antenatal alcohol consumption among women who usually consume alcohol. Prospective cohort study. Australian Longitudinal Study on Women's Health (ALSWH). A total of 1969 women sampled from the ALSWH 1973-78 cohort. Women were included if they were pregnant in 2000, 2003, 2006 or 2009. The relationship between antenatal alcohol consumption and sociodemographics, reproductive health, mental health, physical health, health behaviours, alcohol guidelines and healthcare factors was investigated using a multivariate logistic regression model. Alcohol use during pregnancy. Most (82.0%) women continued to drink alcohol during pregnancy. Women were more likely to drink alcohol during pregnancy if they had consumed alcohol on a weekly basis before pregnancy (odds ratio [OR] 1.47; 95% confidence interval [95% CI] 1.13-1.90), binge drank before pregnancy (OR 2.28; 95% CI 1.76-2.94), or if they were pregnant while alcohol guidelines recommended low alcohol versus abstinence (OR 1.60; 95% CI 1.26-2.03). Drinking during pregnancy was less likely if women had a Health Care Card (OR 0.63; 95% CI 0.45-0.88) or if they had ever had fertility problems (OR 0.64; 95% CI 0.48-0.86). Most Australian women who drank alcohol continued to do so during pregnancy. Prepregnancy alcohol consumption was one of the main predictors of antenatal alcohol use. Alcohol guidelines, fertility problems and Health Care Card status also impacted antenatal alcohol consumption. 23934391 An emission model tracking the life cycle pathways of human pharmaceuticals in Korea. Pharmaceuticals in the environment are of growing public health concern. The main objectives of this study were to develop a new emission estimation model, identify factors critical to reducing emission, and demonstrate the model's applicability for screening and priority setting. A new emission estimation model was developed covering the life cycle pathways of pharmaceuticals from supply to discharge into surface water. The emission estimates of the model were assessed by coupling with SimpleBox to give predicted concentrations and by comparing the predicted concentrations with measured concentrations in Korean surface waters for five selected pharmaceuticals (acetaminophen, cephradine, ibuprofen, mefenamic acid, and naproxen). The sensitivity analysis revealed that the biodegradation rate in the sewage treatment plant and the excretion rate of pharmaceuticals were the most important factors influencing the emission rate. The uncertainty of the emission estimate was found to increase with increases in the value of the emission estimate. Once the intrinsic properties of a pharmaceutical (excretion rate, biodegradation rate, and removal rate by sludge separation) were given, the patient behavior parameters, such as participation in a Take-back program and rate of administration, were determined to have a strong influence on the emission estimate. In our study, the predicted and measured concentrations agreed with each other within one order of magnitude. Several management implications were drawn from the analysis of model outcomes. The model outcomes, alone or in combination with toxicity data, may potentially be used for the purposes of screening, priority setting, and the design of management programs. 23435632 C4.4A Expression Is Associated with a Poor Prognosis of Esophageal Squamous Cell Carcinoma. C4.4A is a glycolipid-anchored membrane protein expressed in several human malignancies. We examined clinical relevance of C4.4A expression in 111 esophageal squamous cell carcinoma (ESCC) tissue samples. Anti-human C4.4A antibody that recognizes the glycosylphosphatidyl inositol (GPI) anchor signaling sequence (C4.4A-GPI Ab) and anti-human C4.4A-119 polyclonal antibody (C4.4A-119 Ab) were used for immunohistochemistry and Western blot testing. Both antibodies detected the C4.4A protein expression at the parabasal layer of normal epithelium of the esophagus. In tumor tissues, the C4.4A protein was detected in 66 (59.5 %) and 95 (85.6 %) of 111 ESCCs by the C4.4A-GPI Ab and the C4.4A-119 Ab, respectively. The C4.4A-GPI Ab mainly detected membranous C4.4A expression (83.3 %, 55 of 66 positive cases), while the C4.4A-119 Ab exclusively detected cytoplasmic C4.4A expression (100 %, 73 cytoplasm alone and 22 cytoplasm plus membrane in 95 positive cases). Western blot analysis indicated that normal epithelium expressed the band of C4.4A at 70 kDa, whereas the tumor tissues displayed the band at the lower molecular weight. Survival analysis indicated that the C4.4A-positive ESCCs had significantly worse 5-year overall survival than the C4.4A-negative ESCC samples (P = 0.021) when using the C4.4A-GPI Ab, but not when using the C4.4A-119 Ab. This difference was most evident with membranous expression of C4.4A (P = 0.005). C4.4A expression was associated with a poor prognosis of ESCC when the GPI-related antibody was used. On the other hand, the C4.4A-119 Ab may be a useful diagnostic tool for ESCC because of its high detection rate. 23601581 Biliary cast syndrome post-liver transplantation: risk factors and outcome. Biliary cast syndrome (BCS) is characterized by the retention of lithogenic material leading to obstructive cholangitis and subsequent liver damage. BCS after orthotopic liver transplantation (OLT) can lead to retransplantation or death. Evaluation of aetiology, risk factors and outcome of BCS after OLT. In a retrospective single centre analysis between 2002 and 2011, all OLT patients with BCS diagnosed by endoscopic retrograde cholangiography were identified and compared with a matched control group at a 2:1 ratio. Thirty patients with BCS after OLT were identified (30/887, 3.4%). Seventy per cent of those patients (21/30) underwent transplantation in the Model for Endstage Liver Disease (MELD) score era. Median time to diagnosis after OLT was 255 days (IQR 107-621). Intensive care unit treatment after OLT was significantly longer in BCS patients [16 days (IQR 8-42) vs. 9 (IQR 7-17) days; P = 0.039]. In a multivariate analysis, hepatic artery stenosis (P = 0.04), biliary strictures (P = 0.032) and need for renal replacement therapy (P = 0.002) were significantly associated with BCS. Immunosuppressant regimen, operation time, cold or warm ischaemia time, graft size, acute cellular rejection and cytomegalovirus infections were not significantly different between both groups. Retransplantation rate and 12-month mortality were significantly higher with BCS (9/30, 30% vs. 4/60, 7%, P = 0.003). BCS is a rare, but severe complication after OLT. Patients with hepatic artery stenosis, biliary strictures or renal replacement therapy have the highest risk to develop BCS and should therefore be monitored carefully. 23231078 Surfactant-free microemulsion composed of oleic acid, n-propanol, and H2O. Generally, a microemulsion consists of oil, water, surfactant, and sometimes cosurfactant. Herein, we report a surfactant-free microemulsion (denoted as SFME), consisting of oleic acid (oil phase), water, and n-propanol without the amphiphilic molecular structure of a traditional surfactant. The phase behavior of the ternary system was investigated, showing that there were a single-phase microemulsion region and a multiphase region in the ternary phase diagram. The electrical conductivity measurement was employed to investigate the microregions of the single-phase microemulsion region, and three different microregions, that is, water-in-oleic acid (W/O), a bicontinuous (B.C.) region, and oleic acid-in-water (O/W), were identified, which were further confirmed by freeze-fracture and cryogenic transmission electron microscopy (FF-TEM and Cryo-TEM) observations. The polarity and the salt solubility of water domains in the W/O SFME were investigated by UV-visible spectroscopy using methyl orange and potassium ferricyanide as probes, respectively. Experimental results showed that the water domains in the W/O microemulsion had a lower polarity than bulk water and a normal solubility for salt species, indicating that the SFMEs have much significance in the preparation of various nanomaterials. 23910457 The effect of postoperative myocardial ischemia on long-term survival after vascular surgery. The impact of a postoperative troponin elevation on long-term survival after vascular surgery is not well-defined. We hypothesize that a postoperative troponin elevation is associated with significantly reduced long-term survival. The Vascular Study Group of New England registry identified all patients who underwent carotid revascularization, open abdominal aortic aneurysm repair (AAA), endovascular AAA repair, or infrainguinal lower extremity bypass (2003-2011). The association of postoperative troponin elevation and myocardial infarction (MI) with 5-year survival was evaluated. Multivariable models identified predictors of survival and of postoperative myocardial ischemia. In the entire cohort (n = 16,363), the incidence of postoperative troponin elevation was 1.3% (n = 211) and for MI was 1.6% (n = 264). Incidences differed across procedures (P < .0001) with the highest incidences after open AAA: troponin elevation, 3.9% (n = 74); MI, 5.1% (n = 96). On Kaplan-Meier analysis, any postoperative myocardial ischemia predicted reduced survival over 5 years postoperatively: no ischemia, 73% (standard error [SE], 0.5%); troponin elevation, 54% (SE, 4%); MI, 33% (SE, 4%) (P < .0001). This pattern was observed for each procedure subgroup analysis (P < .0001). Troponin elevation (hazard ratio, 1.45; 95% confidence interval, 1.1-2.0; P = .02) and MI (hazard ratio, 2.9; 95% confidence interval, 2.3-3.8; P < .0001) were independent predictors of reduced survival at 5 years. Postoperative troponin elevation and MI predict a 26% or a 55% relatively lower survival in the 5 years following a vascular surgical procedure, respectively, compared with patients who do not experience myocardial ischemia. This highlights the need to better characterize factors leading to postoperative myocardial ischemia. Postoperative troponin elevation, either alone, or in combination with an MI, may be a useful marker for identifying high-risk patients who might benefit from more aggressive optimization in hopes of reducing adverse long-term outcomes. 23941977 Efficient liver gene transfer with foamy virus vectors. Liver gene transfer offers hope for the correction of genetic and acquired disorders. Efficient gene transfer in large animals can be obtained with hydrodynamic gene transfer (HGT), a method that can achieve sufficient levels of gene delivery. To test the relative efficiency between plasmid versus foamy virus (FV) vector-based liver gene transfer efficiency, we applied HGT in 4 juvenile pigs, using the same plasmid backbone, either naked or coated as a FV vector particle. Gene transfer efficiency and persistence of expression was assayed by PCR and real-time PCR, respectively, at 1 week and at 1 month after the infusions. HGT was tolerated well and no adverse reactions were observed. Plasmid injections resulted in no detectable DNA sequences at 1 week. At the 1 month time point, 2/15 liver sections analyzed were positive for the presence of plasmid DNA. When FV vectors were infused under identical conditions, 18/28 (64.3%) of the liver samples were positive for the presence of vector sequences, and the expression levels reached 29.7 and 15.6% of the endogenous GAPDH levels in the injected and the adjacent liver lobes. Our results indicate that medium-term therapeutic levels of gene expression can be obtained with FV vectors, an effect that can be attributed to the potential of the HGT procedure and to the natural affinity of FV vectors for hepatocytes. 23721560 New targeting strategies in drug therapy of inflammatory bowel disease: mechanistic approaches and opportunities. Introduction: Inflammatory bowel disease (IBD) is an exceptional scenario with regard to drug targeting, as oral administration has the potential to deliver the drug directly to the site(s) of action. Consequently, retention of the drug within the intestinal lumen and tissue, rather than systemic absorption, is frequently desirable. Areas covered: In this article, the traditional drug-delivery strategies used in IBD are briefly summarized. These include rectal dosage forms and oral systems that target the lower intestine/colon by pH-, time-, microflora-, and pressure-dependent mechanisms. Then, the article offers an updated overview of recently developed delivery systems aimed to achieve maximal drug concentrations in the inflamed intestinal tissues with minimal systemic side effects. These include antibodies, small molecules, Janus kinase inhibitors, particulate carrier systems, anti-inflammatory peptides, gene therapy, and transgenic bacteria. The various approaches are reviewed, and the challenges that still remain to be overcome are discussed. Expert opinion: The molecular revolution of the past decade profoundly influenced the treatment and management of IBD. In the coming years, this trend is expected to continue. Yet, many challenges are still ahead. A strong collaborative effort by experts from different fields is encouraged and necessary to maximize our success in IBD drug targeting. 22943458 Stimulant and non-stimulant attention deficit/hyperactivity disorder drug use: total population study of trends and discontinuation patterns 2006-2009. To explore the prevalence and discontinuation of dispensed medications for attention deficit/hyperactivity disorder (ADHD) drugs from 2006 to 2009. A total population cohort of all individuals aged 6-45 years, alive and registered as residents in Sweden during any calendar year from 2006 to 2009 (N = 5 149 791) included 41 700 patients dispensed with an ADHD drug (methylphenidate, atomoxetine, amphetamine, or dexamphetamine). The dispensing prevalence was calculated for each year, stratified on sex and age. A longitudinal analysis was also performed to compare the rates of treatment discontinuation across the strata. The dispensing prevalence increased from 2.93 per 1000 in 2006 to 6.98 in 2009 (PR = 2.38, 95% CI = 2.34-2.43). The prevalence ratio (PR) was 3.40 for adults, 22-45 years old; 2.41 for adolescents, 15-21 years old; and 1.90 for children aged 6-14. The increase was also greater in women than in men (PR = 2.92 vs. 2.19). Patients aged 15-21 were the most likely to discontinue treatment; after 3 years and 11 months, 27% of those patients were still under treatment. From 2006 to 2009, the number of prescriptions dispensed for ADHD drugs increased substantially. The rate of treatment discontinuation in the age interval 15-21 is higher than expected considering the persistence rates of the disorder. 23936037 Men's Preferences for Women's Femininity in Dynamic Cross-Modal Stimuli. Men generally prefer feminine women's faces and voices over masculine women's faces and voices, and these cross-modal preferences are positively correlated. Men's preferences for female facial and vocal femininity have typically been investigated independently by presenting soundless still images separately from audio-only vocal recordings. For the first time ever, we presented men with short video clips in which dynamic faces and voices were simultaneously manipulated in femininity/masculinity. Men preferred feminine men's faces over masculine men's faces, and preferred masculine men's voices over feminine men's voices. We found that men preferred feminine women's faces and voices over masculine women's faces and voices. Men's attractiveness ratings of both feminine and masculine faces were increased by the addition of vocal femininity. Also, men's attractiveness ratings of feminine and masculine voices were increased by the addition of facial femininity present in the video. Men's preferences for vocal and facial femininity were significantly and positively correlated when stimuli were female, but not when they were male. Our findings complement other evidence for cross-modal femininity preferences among male raters, and show that preferences observed in studies using still images and/or independently presented vocal stimuli are also observed when dynamic faces and voices are displayed simultaneously in video format. 23532445 In vitro read-through of phenylalanine hydroxylase (PAH) nonsense mutations using aminoglycosides: a potential therapy for phenylketonuria. Phenylketonuria (PKU, OMIM 261600) is an autosomal recessive inborn error of phenylalanine metabolism, predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene. Approximately 10 % of patients carry a nonsense mutation, which results in an inactive or unstable truncated protein. In some genetic disorders, including cystic fibrosis and Duchenne muscular dystrophy, restoration of full-length protein has been achieved by aminoglycoside antibiotics, such as gentamicin and G-418 (Geneticin). More recently, nonsense read-through has been induced at greater rates using a non-aminoglycoside drug, PTC124 (Ataluren), which has the advantage of being non-toxic in contrast to the antibiotics. The efficacy of read-through induced by three compounds, aminoglycosides G418 and gentamicin, and PTC124 were evaluated for four nonsense mutations of PAH in an in vitro expression system in two mammalian cell lines (COS-7 and HEK293). The production of full-length PAH was investigated using western blotting and the functionality confirmed by enzyme activity. Gentamicin and G-418 induced read-through of nonsense PAH mutations in HEK293 cells. The read-through product partially restored enzymatic activity, which was significantly less than that of wild-type, but comparable to a missense mutation of PAH associated with less severe forms of PKU. Treatment with PTC124 up to 100 μM did not result in full-length PAH polypeptide. Nonsense read-through drugs are a potential form of treatment for PKU, although the high dosage of aminoglycosides used is not appropriate in a clinical setting. In vitro studies with new non-toxic read-through agents as well as in vivo studies would also be essential to determine the extent of read-through required to restore normal phenylalanine levels. 23809011 SNP-based Bayesian networks can predict oral mucositis risk in autologous stem cell transplant recipients. Approximately 40% of patients receiving conditioning chemotherapy prior to autologous hematopoietic stem cell transplants (aHSCT) develop severe oral mucositis (SOM). Aside from disabling pain, ulcerative lesions associated with SOM predispose to poor health and economic outcomes. Our objective was to develop a probabilistic graphical model in which a cluster of single-nucleotide polymorphisms (SNPs) derived from salivary DNA could be used as a tool to predict SOM risk. Salivary DNA was extracted from 153 HSCT patients and applied to Illumina BeadChips. Using sequential data analysis, we filtered extraneous SNPs, selected loci, and identified a predictive SNP network for OM risk. We then tested the predictive validity of the network using SNP array outputs from an independent HSCT cohort. We identified an 82-SNP Bayesian network (BN) that was related to SOM risk with a 10-fold cross-validation accuracy of 99.3% and an area under the ROC curve of 99.7%. Using samples from a small independent patient cohort (n = 16), we demonstrated the network's predictive validity with an accuracy of 81.2% in the absence of any false positives. Our results suggest that SNP-based BN developed from saliva-sourced DNA can predict SOM risk in patients prior to aHSCT. 23735669 Perioperative outcomes after totally robotic gastric bypass: a prospective nonrandomized controlled study. Perioperative short-term outcomes could be improved after totally robotic Roux-en-Y gastric bypass (TR-RYGBP) compared with conventional laparoscopic gastric bypass. This is a nonrandomized controlled prospective study (N = 200) to evaluate perioperative short-term outcomes. The primary endpoint was to investigate risk factors for 30-day surgical complications. Mean total operative time was shorter in patients who underwent TR-RYGBP (130 vs 147 minutes; P < .0001). However, postoperative surgical complications rate (13% vs 1%; P = .001), and mean overall hospital stay (9.3 vs 6.7 days; P < .0001) were higher after TR-RYGBP. By multivariate analysis, robotic surgery (hazard ratio [HR] = 15.1; 95% confidence interval [CI], 2.8 to 280; P = .01), and conversion to laparotomy (HR = 18.8; 95% CI, 1.7 to 250.8; P = .014) were independent risk factors for 30-day surgical complications. Although robotic gastric bypass reduces mean operative time, TR-RYGBP is associated with an increased postoperative surgical complications rate and longer hospitalization. 23684807 A non-invasive method based on head morphology to sex mature three-spined stickleback (Gasterosteus aculeatus L.) in rearing conditions. A mathematical model to distinguish mature female and male three-spined sticklebacks Gasterosteus aculeatus L. 1758 is proposed. This method is based on sexual dimorphism in the head morphology. The discrimination was established on five distances of interest on the head, adjusted by the standard length of fish. The parameters were estimated based on a training set composed of 102 fish with an equilibrium sex ratio and validated on a test set composed of 69 fish. The model estimates the relationship between the percentage of fish that can be sexed with our model and the percentage of fish correctly sexed. For instance, to reach 1% of error in the sex determination, only 53% of the fish should be considered, whereas to reach 5% of error, 90% of the fish can be used. Compared to other available methods to sex G. aculeatus, the model is non invasive, not expensive, rapid, replicable, and can be calibrated outside of the breeding period. 23884690 Unexpected downshifts in reward magnitude induce variation in human behavior. We investigated how changes in outcome magnitude affect behavioral variation in human volunteers. Our participants entered strings of characters using a computer keyboard, receiving feedback (gaining a number of points) for any string at least ten characters long. During a "surprise" phase in which the number of points awarded was changed, participants only increased their behavioral variability when the reward value was downshifted to a lower amount, and only when such a shift was novel. Upshifts in reward did not have a systematic effect on variability. 23796514 S100A6 Competes with the TAZ2 Domain of p300 for Binding to p53 and Attenuates p53 Acetylation. S100A6 is a calcium binding protein that, like some other members of the S100 protein family, is able to bind p53. This interaction may be physiologically relevant considering the numerous connotations of S100 proteins and of S100A6, in particular, with cancer and metastasis. In this work, we show that the interaction with S100A6 is limited to unmodified or phosphorylated p53 and is inhibited by p53 acetylation. Using in vitro acetylation assay, we show that the presence of S100A6 attenuates p53 acetylation by p300. Furthermore, using ELISA, we show that S100A6 and the TAZ2 domain of p300 bind p53 with similar affinities and that S100A6 effectively competes with TAZ2 for binding to p53. Our results add another element to the complicated scheme of p53 activation. 23719576 Neural coding of nociceptive stimuli-from rat spinal neurones to human perception. Translational studies are key to furthering our understanding of nociceptive signalling and bridging the gaps between molecules and pathways to the patients. This requires use of appropriate preclinical models that accurately depict outcome measures used in humans. Whereas behavioural animal studies classically involve reports related to nociceptive thresholds of, for example, withdrawal, electrophysiological recordings of spinal neurones that receive convergent input from primary afferents permits investigation of suprathreshold events and exploration of the full-range coding of different stimuli. We explored the central processing of nociceptive inputs in a novel parallel investigation between rats and humans. Using radiant laser pulses, we first compared the electrophysiological responses of deep wide dynamic range and superficial nociceptive-specific neurones in the rat dorsal horn with human psychophysics and cortical responses. Secondly, we explored the effects of spatial summation using laser pulses of identical energy and different size. We observed 3 main findings. Firstly, both rodent and human data confirmed that neodymium-yttrium aluminium perovskite laser stimulation is a nociceptive-selective stimulus that never activates Aβ afferents. Secondly, graded laser stimulation elicited similarly graded electrophysiological and behavioural responses in both species. Thirdly, there was a significant degree of spatial summation of laser nociceptive input. The remarkable similarity in rodent and human coding indicates that responses of rat dorsal horn neurones can translate to human nociceptive processing. These findings suggest that recordings of spinal neuronal activity elicited by laser stimuli could be a valuable predictive measure of human pain perception. 23768370 Migration of plasticisers from Tritan™ and polycarbonate bottles and toxicological evaluation. This study is aimed to compare Tritan™ and polycarbonate (PC) from a point of view of migration of monomers and additives and toxicological evaluation. Migration assays were performed according with Commission Regulation (UE) No. 10/2011. Samples were incubated at 40°C for three consecutive periods of 10 days. Identification and quantification of the compounds intended to migrate was done using solid phase extraction (SPE) followed by gas chromatography coupled to mass spectrometry (GC-MS) in scan mode. Compounds identified in Tritan™ were 2-phenoxyethanol (2-PE), 4-nonylphenol (4-NP), bisphenol A (BPA), benzylbuthyl phthalate (BBP) and dimethyl isophthalate (DMIP) at levels from 0.027 ± 0.002 to 0.961 ± 0.092 μg/kg, although in the 3rd migration period, BBP and DMIP were the only compounds detected well below the specific migration limit. On the other hand, BPA was the only compound detected in PC polymers at a mean concentration of 0.748 μg/kg. In vitro bioassays for (anti)estrogenic, (anti)androgenic as well as retinoic acid- and vitamin D-like activity were negative for Tritan™ and PC migrates. BPA and DMIP were estrogenic in high concentrations. Exposure of the estrogen-sensitive molluskan sentinel Potamopyrgus antipodarum confirmed the estrogenic activity of BPA in vivo at 30 μg/L. 23958047 Incidence of Pulmonary Cement Embolism after Real-time CT Fluoroscopy-guided Vertebroplasty. To prospectively evaluate the incidence of pulmonary cement embolism (PCE) after vertebroplasty in procedures performed under real-time computed tomographic (CT) fluoroscopy guidance. A total of 85 vertebroplasties were performed in 51 consecutive patients (31 women, 20 men; mean age, 71.9 y; range, 48-92 y) in 51 sessions. The needle was inserted with guidance from intermittent single-shot CT scans, and intermittent CT fluoroscopy was used during cement injection only. To reduce the risk of extravertebral or extraosseous leakage, several procedures (cement injection stopping/slowing, needle position changes) were employed. The chest and treated bone were scanned immediately after vertebroplasty. These CT images included the entire thorax as well as the treated vertebrae. No cement emboli were observed on CT after vertebroplasty. After 85 vertebroplasty procedures, 44 extravertebral leaks were detected. Epidural leaks were observed on CT in six treated vertebrae (7%), in 12 cases in the anterior external venous plexus (14.1%), in five in the azygos vein (5.8%), in 19 in the disc space (22%), and in two in the foraminal space (2.3%). On a per-patient basis, the odds of leaks increased with the number of vertebroplasties (P = .05) and the volume of cement used (P = .0412). There was also a higher probability of leak (P < .05) for osteoporotic vertebral compression fractures (67.9%; 95% confidence interval, 47.7%-84.1%) than osteolytic spinal metastases (34.8%; 16.4%-57.3%). PCE did not occur after vertebroplasty under CT fluoroscopy guidance. Further larger prospective vertebroplasty studies are needed to compare the rates of PCE for CT versus conventional fluoroscopic guidance. 23884559 A phase II study of intra-arterial cisplatin with concurrent radiation and erlotinib for locally advanced head and neck cancer. Based on the convenient oral dosing of erlotinib and the promising results of biologic therapy, we undertook a phase II study with 21 patients with locally advanced (T3-4) lesions combining radiation with intra-arterial (IA) cisplatin and oral daily erlotinib for a 7-week therapy. Treatment for the primary tumor and upper neck was given to a total dose of 70 Gy. Chemotherapy with IA cisplatin (150 mg/m(2)) was given on days 1, 8, 15, and 22 concurrently with radiotherapy. During the 7-week treatment period, patients were given erlotinib 150 mg/day. Overall survival is 63 %, and the relapse/persistent disease rate stands at 36.8 %. A total of 15.2 % of serious adverse event was considered related to erlotinib. Our study and several others now demonstrate the feasibility of combining anti-epidermal growth factor receptor (EGFR) therapy with chemoradiation, hint at improved survival outcomes with reduced distant metastatic rates, and suggest that maintenance therapy with anti-EGFR agent may be beneficial. 23684248 Delayed Diagnosis of Hypertension in Diabetic Patients Monitored in Primary Care. Delayed diagnosis of hypertension may result in inadequate blood pressure control and increased cardiovascular risk. The aim of this study was to estimate the delay in hypertension diagnosis in patients with type 2 diabetes and the likelihood of a diagnosis within a suitable period (first 6 months), and to analyze the patient and physician characteristics associated with delayed diagnosis. Retrospective dynamic cohort study, with a 7-year follow-up in primary care, of 8074 adult patients with diabetes who met the diagnostic criteria for hypertension. Two thresholds were considered: 140/90mmHg and 130/80 mmHg. The time elapsed between meeting these criteria and recording the diagnosis was estimated; the time course of the likelihood of a missed diagnosis and the variables associated with correct diagnosis were assessed by Kaplan-Meier survival analysis and logistic regression analysis, respectively. The mean diagnostic delay was 8.9 (15.4) months in patients with blood pressure≥140/90 mmHg compared to 15.2 (19.6) months for those with <140/90 mmHg (P<.001). The main variables associated with correct diagnosis were baseline blood pressure ≥140/90 mmHg (odds ratio=2.77; 95% confidence interval, 2.44-3.15), no history of acute myocardial infarction (odds ratio=2.23; 95% confidence interval, 1.67-2.99), obesity (odds ratio=1.70; 95% confidence interval, 1.44-1.99), absence of depression (odds ratio=1.63; 95% confidence interval, 1.27-2.08), female sex (odds ratio=1.29; 95% confidence interval, 1.14-1.46), older age, and taking more intensive antidiabetic therapy. There was an inverse relationship with the age of physicians and a direct relationship with their professional stability. The mean diagnostic delay in hypertension among diabetic patients was greater than 6 months and varied according to the diagnostic threshold used. Patients with baseline blood pressure≥140/90mmHg were more likely to receive a timely diagnosis. Full English text available from:www.revespcardiol.org/en. 23861884 Gene transfection in high serum levels: case studies with new cholesterol based cationic gemini lipids. Six new cationic gemini lipids based on cholesterol possessing different positional combinations of hydroxyethyl (-CH2CH2OH) and oligo-oxyethylene -(CH2CH2O)n- moieties were synthesized. For comparison the corresponding monomeric lipid was also prepared. Each new cationic lipid was found to form stable, clear suspensions in aqueous media. To understand the nature of the individual lipid aggregates, we have studied the aggregation properties using transmission electron microscopy (TEM), dynamic light scattering (DLS), zeta potential measurements and X-ray diffraction (XRD). We studied the lipid/DNA complex (lipoplex) formation and the release of the DNA from such lipoplexes using ethidium bromide. These gemini lipids in presence of a helper lipid, 1, 2-dioleoyl phophatidyl ethanol amine (DOPE) showed significant enhancements in the gene transfection compared to several commercially available transfection agents. Cholesterol based gemini having -CH2-CH2-OH groups at the head and one oxyethylene spacer was found to be the most effective lipid, which showed transfection activity even in presence of high serum levels (50%) greater than Effectene, one of the potent commercially available transfecting agents. Most of these geminis protected plasmid DNA remarkably against DNase I in serum, although the degree of stability was found to vary with their structural features. -OH groups present on the cationic headgroups in combination with oxyethylene linkers on cholesterol based geminis, gave an optimized combination of new genera of gemini lipids possessing high transfection efficiency even in presence of very high percentage of serum. This property makes them preferential transfection reagents for possible in vivo studies. 23713847 A structural chemogenomics analysis of aminergic GPCRs: lessons for histamine receptor ligand design. Chemogenomics focuses on the discovery of new connections between chemical and biological space leading to the discovery of new protein targets and biologically active molecules. G-protein coupled receptors (GPCRs) are a particularly interesting protein family for chemogenomics studies because there is an overwhelming amount of ligand binding affinity data available. The increasing number of aminergic GPCR crystal structures now for the first time allows the integration of chemogenomics studies with high-resolution structural analyses of GPCR-ligand complexes. In this study, we have combined ligand affinity data, receptor mutagenesis studies, and amino acid sequence analyses to high-resolution structural analyses of (hist)aminergic GPCR-ligand interactions. This integrated structural chemogenomics analysis is used to more accurately describe the molecular and structural determinants of ligand affinity and selectivity in different key binding regions of the crystallized aminergic GPCRs, and histamine receptors in particular. Our investigations highlight interesting correlations and differences between ligand similarity and ligand binding site similarity of different aminergic receptors. Apparent discrepancies can be explained by combining detailed analysis of crystallized or predicted protein-ligand binding modes, receptor mutation studies, and ligand structure-selectivity relationships that identify local differences in essential pharmacophore features in the ligand binding sites of different receptors. We have performed structural chemogenomics studies that identify links between (hist)aminergic receptor ligands and their binding sites and binding modes. This knowledge can be used to identify structure-selectivity relationships that increase our understanding of ligand binding to (hist)aminergic receptors and hence can be used in future GPCR ligand discovery and design. This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1. 23932308 The interaction of Urocortin II and Urocortin III with amygdalar and hypothalamic cotricotropin-releasing factor (CRF) - Reflections on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Urocortin II (Ucn II) and Urocortin III (Ucn III) are selective agonists of the CRF receptor type 2 (CRFR2). The aim of the present experiments was to investigate the effects of Ucn II and Ucn III on the central CRF and peripheral glucocorticoids in rats. Increasing doses (0.5-1-2-5μg/2μl) of Ucn II or Ucn III were administered intracerebroventricularly, then CRF concentration was determined by immunoassays in two different brain regions, the amygdala and the hypothalamus, and in two different time paradigms, 5 and 30min after the administration of peptides. In parallel with the second determination, plasma corticosterone concentration was measured by chemofluorescent assay. The amygdalar CRF amount was increased significantly by 0.5 and 5μg of UCN II and 2 and 5μg of UCN III in the 5min experiments and by 5μg of UCN II and 0.5 and 5μg of UCN III in the 30min experiments. The hypothalamic CRF content was not affected considerably in the 5min paradigm, but it was influenced significantly in the 30min paradigm, with 0.5 and 1μg of UCN II and 0.5-2μg of UCN III decreasing, and 2 and 5μg of UCN II and 5μg of UCN III increasing the hormone concentration, respectively. The plasma corticosterone concentration was decreased by 1 and 2μg of UCN II and UCN III and increased by 0.5 and 5μg of UCN III. The present results demonstrate that central administration of Ucn II and Ucn III modulate time-dependently and dose-dependently the amygdalar and the hypothalamic CRF concentration, and, directly or indirectly, the plasma corticosterone concentration. The present experiments suggest that the role of CRFR2 in the regulation of the HPA axis can be inhibitory or stimulatory, depending on the actual concentration of their agonists. 23511897 High density lipoprotein as a source of cholesterol for adrenal steroidogenesis: a study in individuals with low plasma HDL-C. Few studies have addressed the delivery of lipoprotein-derived cholesterol to the adrenals for steroid production in humans. While there is evidence against a role for low-density lipoprotein (LDL), it is unresolved whether high density lipoprotein (HDL) contributes to adrenal steroidogenesis. To study this, steroid hormone profiles in urine were assessed in male subjects suffering from functional mutations in ATP binding cassette transporter A1 (ABCA1) (n = 24), lecithin:cholesterol acyltransferase (LCAT) (n = 40), as well as in 11 subjects with low HDL cholesterol (HDL-C) without ABCA1/LCAT mutations. HDL-C levels were 39% lower in the ABCA1, LCAT, and low HDL-C groups compared with controls (all P < 0.001). In all groups with low HDL-C levels, urinary excretion of 17-ketogenic steroids was reduced by 33%, 27%, and 32% compared with controls (all P < 0.04). In seven carriers of either type of mutation, adrenocorticotropic hormone (ACTH) stimulation did not reveal differences from normolipidemic controls. In conclusion, this study shows that basal but not stimulated corticosteroid metabolism is attenuated in subjects with low HDL-C, irrespective of its molecular origin. These findings lend support to a role for HDL as a cholesterol donor for basal adrenal steroidogenesis in humans. 23918810 Small, smaller, smallest: the origins and evolution of ancient dual symbioses in a phloem-feeding insect. Many insects rely on bacterial symbionts with tiny genomes specialized for provisioning nutrients lacking in host diets. Xylem sap and phloem sap are both deficient as insect diets, but differ dramatically in nutrient content, potentially affecting symbiont genome evolution. For sap-feeding insects, sequenced symbiont genomes are available only for phloem-feeding examples from the suborder Sternorrhyncha and xylem-feeding examples from the suborder Auchenorrhyncha, confounding comparisons. We sequenced genomes of the obligate symbionts, Sulcia muelleri and Nasuia deltocephalinicola, of the phloem-feeding pest insect, Macrosteles quadrilineatus (Auchenorrhyncha: Cicadellidae). Our results reveal that Nasuia-ALF has the smallest bacterial genome yet sequenced (112 kb), and that the Sulcia-ALF genome (190 kb) is smaller than that of Sulcia in other insect lineages. Together, these symbionts retain the capability to synthesize the 10 essential amino acids, as observed for several symbiont pairs from xylem-feeding Auchenorrhyncha. Nasuia retains genes enabling synthesis of two amino acids, DNA replication, transcription, and translation. Both symbionts have lost genes underlying ATP synthesis through oxidative phosphorylation, possibly as a consequence of the enriched sugar content of phloem. Shared genomic features, including reassignment of the UGA codon from Stop to tryptophan, and phylogenetic results suggest that Nasuia-ALF is most closely related to Zinderia, the betaproteobacterial symbiont of spittlebugs. Thus, Nasuia/Zinderia and Sulcia likely represent ancient associates that have co-resided in hosts since the divergence of leafhoppers and spittlebugs >200 million years ago, and possibly since the origin of the Auchenorrhyncha, >260 million years ago. 23824714 Protective effect of melatonin on bone marrow mesenchymal stem cells against hydrogen peroxide-induced apoptosis in vitro. Bone marrow mesenchymal stem cells (MSCs) transplantation has shown great promises for treating various central nervous system (CNS) diseases. However, poor viability of transplanted MSCs in injured CNS has limited the therapeutic efficiency. Oxidative stress is one of major mechanisms underlying the pathogenesis of CNS diseases and has a negative impact on the survival of transplanted MSCs. Melatonin has recently been reported to have the antioxidant and anti-apoptotic properties in serial of cells. This study was designed to investigate the protective effect and potential mechanisms of melatonin against hydrogen peroxide (H2 O2 )-induced apoptosis of MSCs. MSCs were pretreated with melatonin (1, 10, and 100 nM, respectively) for 30 min, followed by exposure to 400 µM H2 O2 and melatonin together for 12 h. The present study reports that melatonin pretreatment significantly attenuated H2 O2 -induced MSC apoptosis in a dose-dependent manner. Consistently, melatonin effectively suppressed the generation of intracellular ROS, expression ratio of Bax/Bcl-2, activation of caspase-3 and expression of phospho-P38MAPK in H2 O2 -induced MSCs. Luzindole, a nonselective melatonin receptor antagonist, significantly counteracted melatonin's promotion effect on cell survival, indicating that melatonin exerts its protective effect on MSCs, at least in part, through the activation of melatonin receptors. The findings suggest that melatonin may be an effectively protective agent against oxidative stress-induced MSC apoptosis. J. Cell. Biochem. 114: 2346-2355, 2013. © 2013 Wiley Periodicals, Inc. 23815668 Reply to "comment on Marden (2013) regarding the interpretation of the earliest trace fossil of a winged insect". Benner, Knecht, and Engel have replied to my critique of their interpretation of a Carboniferous trace fossil produced by an insect at the edge of water. Here I respond by pointing out that their reiterated scenario still requires mutually exclusive paths of motion and I show that their assertions of methodological shortcomings are tangential and lack merit. Overall, this discussion provides an opportunity to examine in greater detail competing hypothesis about behaviors and taxonomic identity of the trace maker, and relevance thereof to competing theories regarding early events in the evolution of pterygote insects. 23911020 Exploration of the perceptions of emergency physicians and interns regarding the medical documentation practices of interns. The primary objective of the present study was to learn the factors that influence the documentation practices of ED interns. A second objective was to identify the expectations of emergency physicians (EPs) towards the medical record documentation of ED interns. A qualitative design was adopted using semi-structured interviews in convenience samples drawn from both groups. Eighteen interviews were conducted with intern volunteers and 10 with EP volunteers. One (5%) intern and two (20%) EPs had received medical documentation training. Factors that encouraged interns' documentation included: patient acuity (the more critical the condition, the more comprehensive the documentation) and the support of senior colleagues. Inhibiting factors included uncertainty about how much to write, and the shift being worked (interns indicated they wrote less at night). Factors of consequence to senior personnel included the apparent reluctance of interns to document management plans. They noted that interns frequently confine their notes to assessment, investigations and treatments, whereas EPs preferred records that demonstrated intern thought processes and included such matters as future actions to follow immediate treatment. A positive theme that emerged included the high level of support interns received from their senior colleagues. Another theme, the influence of patient acuity, held both positive and negative implications for intern writing practices. The lack of formal training is an impediment to the production of useful medical records by ED interns. One solution proposed by both interns and senior personnel was the introduction of the subject into intern education programmes. 23686240 Differential Effects of the Peptides Stomagen, EPF1 and EPF2 on Activation of MAP Kinase MPK6 and the SPCH Protein Level. The positioning and density of leaf stomata are regulated by three secretory peptides, EPIDERMAL PATTERNING FACTOR 1 (EPF1), EPF2 and stomagen. Several lines of published evidence have suggested a regulatory pathway as follows. EPF1 and EPF2 are perceived by receptor complexes consisting of a receptor-like protein, TOO MANY MOUTHS (TMM), and receptor kinases, ERECTA (ER), ERECTA-LIKE (ERL) 1 and ERL2. These receptors activate a mitogen-activated protein (MAP) kinase module. MAP kinases phosphorylate and destabilize the transcription factor SPEECHLESS (SPCH), resulting in a decrease in the number of stomatal lineage cells. Stomagen acts antagonistically to EPF1 and EPF2. However, there is no direct evidence that EPF1 and EPF2 activate or that stomagen inactivates the MAP kinase cascade, through which they might regulate the SPCH level. Experimental modulation of these peptides in Arabidopsis thaliana would change the number of stomatal lineage cells in developing leaves, which in turn would change the expression of SPCH, making the interpretation difficult. Here we reconstructed this signaling pathway in differentiated leaf cells of Nicotiana benthamiana to examine signaling without the confounding effect of cell type change. We show that EPF1 and EPF2 are able to activate the MAP kinase MPK6, and that both EPF1 and EPF2 are able to decrease the SPCH level, whereas stomagen is able to increase it. Our data also suggest that EPF1 can be recognized by TMM together with any ER family receptor kinase, whereas EPF2 can be recognized by TMM together with ERL1 or ERL2, but not by TMM together with ER. 23807172 Synergistic antitumour activity of sorafenib in combination with tetrandrine is mediated by reactive oxygen species (ROS)/Akt signaling. Background:Sorafenib is a potent inhibitor against Raf kinase and several receptor tyrosine kinases that has been approved for the clinical treatment of advanced renal and liver cancer. Combining sorafenib with other agents has been shown to improve its antitumour efficacy by not only reducing the toxic side effects but also preventing primary and acquired resistance to sorafenib. We have previously observed that tetrandrine exhibits potent antitumour effects in human hepatocellular carcinoma. In this study, we investigated the synergistic antitumour activity of sorafenib in combination with tetrandrine.Methods:This was a two-part investigation that included the in vitro effects of sorafenib in combination with tetrandrine on cancer cells and the in vivo antitumour efficacy of this drug combination on tumour xenografts in nude mice.Results:Combined treatment showed a good synergistic antitumour effect yet spared nontumourigenic cells. The potential molecular mechanism may be mainly that it activated mitochondrial death pathway and induced caspase-dependent apoptosis in the cancer cells. Accumulation of intracellular reactive oxygen species (ROS) and subsequent activation of Akt may also be involved in apoptosis induction.Conclusion:The antitumour activity of sorafenib plus tetrandrine may be attributed to the induction of the intrinsic apoptosis pathway through ROS/Akt signaling. This finding provides a novel approach that may broaden the clinical application of sorafenib. 23617697 Hybrid Molecule from O(2)-(2,4-Dinitrophenyl)diazeniumdiolate and Oleanolic Acid: a GSTπ Activated Nitric Oxide Prodrug with Selective Anti-human Hepatocellular Carcinoma Activity and Improved Stability. A series of hybrids from O(2)-(2,4-dinitrophenyl)diazeniumdiolate and oleanolic acid (OA) were designed, synthesized, and biologically evaluated as novel nitric oxide (NO) releasing prodrugs which could be activated by glutathione S-transferase π (GSTπ) overexpressed in a number of cancer cells. It was discovered that the most active compound 21 released high levels of NO selectively in HCC cells but not in the normal cells, and exhibited potent antiproliferative activity in vitro as well as remarkable tumor-retarding effects in vivo. Compared with the reported GSTπ-activated prodrugs JS-K and PABA/NO, 21 exhibited remarkably improved stability in the absence of GSTπ. Importantly, the decomposition of 21 occurred in the presence of GSTπ, and was much more effective than in GSTα. Additionally, 21 induced HepG2 cells apoptosis by arresting cell cycle at G2/M phase, activating both the mitochondria-mediated pathway and the MAPKs pathway, as well as enhancing the intracellular production of ROS. 23825317 Characterizing Thalamo-Cortical Disturbances in Schizophrenia and Bipolar Illness. Schizophrenia is a devastating neuropsychiatric syndrome associated with distributed brain dysconnectivity that may involve large-scale thalamo-cortical systems. Incomplete characterization of thalamic connectivity in schizophrenia limits our understanding of its relationship to symptoms and to diagnoses with shared clinical presentation, such as bipolar illness, which may exist on a spectrum. Using resting-state functional magnetic resonance imaging, we characterized thalamic connectivity in 90 schizophrenia patients versus 90 matched controls via: (1) Subject-specific anatomically defined thalamic seeds; (2) anatomical and data-driven clustering to assay within-thalamus dysconnectivity; and (3) machine learning to classify diagnostic membership via thalamic connectivity for schizophrenia and for 47 bipolar patients and 47 matched controls. Schizophrenia analyses revealed functionally related disturbances: Thalamic over-connectivity with bilateral sensory-motor cortices, which predicted symptoms, but thalamic under-connectivity with prefrontal-striatal-cerebellar regions relative to controls, possibly reflective of sensory gating and top-down control disturbances. Clustering revealed that this dysconnectivity was prominent for thalamic nuclei densely connected with the prefrontal cortex. Classification and cross-diagnostic results suggest that thalamic dysconnectivity may be a neural marker for disturbances across diagnoses. Present findings, using one of the largest schizophrenia and bipolar neuroimaging samples to date, inform basic understanding of large-scale thalamo-cortical systems and provide vital clues about the complex nature of its disturbances in severe mental illness. 23925751 Clinical presentation of posterolateral rotatory instability of the elbow in children. Posterolateral rotatory instability is a type of ulnohumeral instability seen following elbow trauma. It is caused by a deficiency in the lateral collateral ligament complex that allows the radius and ulna to subluxate as a single unit with respect to the distal part of the humerus. There are few studies on this type of instability in children. Our purpose was to evaluate cases of posterolateral rotatory instability in children to better understand its presentation and manifestation as compared with those in adults. This was a retrospective chart review of patients from three academic centers. Eligible for inclusion were patients with a diagnosis of posterolateral rotatory instability who were treated with lateral ulnar collateral ligament reconstruction when they were less than nineteen years of age. Nine patients met the inclusion criteria. The mean age at the initial injury was ten years, and the average time from the initial injury to the final operation was 3.7 years. Six patients had prior elbow dislocation, and three had an isolated elbow fracture. Six of the nine patients had a forearm or elbow contracture. Only one patient had a positive pivot-shift test during the preoperative office examination, but all had a positive pivot-shift test when examined under anesthesia. Six had radiographic evidence of posterolateral rotatory instability. All patients underwent lateral ulnar collateral ligament reconstruction. At the time of follow-up, at a minimum of one year after the ligament reconstruction, there was no evidence of deformity secondary to early physeal closure and all elbows remained stable. Although posterolateral rotatory instability of the elbow is rare, it does exist in children. The instability may not always be recognized because of masking by contracture but, as is the case with adult patients, radiographs may show evidence of the instability. In children with contracture, the clinician should consider the possibility of a masked posterolateral rotatory instability and plan accordingly at the time of contracture release. Surgical correction is technically difficult, and traditional ligament reconstruction in skeletally immature patients may pose a risk to the lateral humeral condylar and epicondylar physes. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. 23228444 Discriminating the endogenous and exogenous urinary estrogens in human by isotopic ratio mass spectrometry and its potential clinical value. Estrogens were prohibited in the food producing animals by European Union (96/22/EC directive) and added to the Report on Carcinogens in United States since 2002. Due to very low concentration in serum or urine (~pg/mL), the method of control its abuse had not been fully developed. The endogenous estrogens were separated from urines of 18 adult men and women. The exogenous estrogens were chemical reference standards and over the counter preparations. Two patients of dysfunctional uterine bleeding (DUB) administered exogenous estradiol and the urines were collected for 72 h. The urinary estrogens were separated by high-performance liquid chromatography (HPLC) and confirmed. The exogenous and exogenous estrogens were analyzed by gas chromatography combustion isotope ratio mass spectrometry (GC-C-IRMS) to determine the (13)C/(12)C ratio (δ(13)C‰). The δ(13)C‰ values of reference standard of E1, E2, and E3 were -29.36±0.72, -27.98±0.35, -27.62±0.51, respectively. The δ(13)C‰ values of the endogenous E1, E2, and E3 were -21.62±1.07, -22.14±0.98, and -21.88±1.16, with P<0.01 (t-test). Two DUB patients' urinary estradiol δ(13)C‰ values was depleted to -28.02±0.33 after the administration. The progesterone, 17α-hydroxyprogesterone, pregnanediol, as well as desogestrel and ethinylestradiol from contraceptives were also determined. Stable carbon isotope analysis can distinguish the endogenous and exogenous urinary estrogen in human. 23692590 Atypical cortical representation of peripheral visual space in children with an autism spectrum disorder. A key feature of early visual cortical regions is that they contain discretely organized retinotopic maps. Titration of these maps must occur through experience, and the fidelity of their spatial tuning will depend on the consistency and accuracy of the eye movement system. Anomalies in fixation patterns and the ballistics of eye movements are well documented in autism spectrum disorder (ASD), with off-center fixations a hallmark of the phenotype. We hypothesized that these atypicalities might affect the development of visuo-spatial maps and specifically that peripheral inputs might receive altered processing in ASD. Using high-density recordings of visual evoked potentials (VEPs) and a novel system-identification approach known as VESPA (visual evoked spread spectrum analysis), we assessed sensory responses to centrally and peripherally presented stimuli. Additionally, input luminance was varied to bias responsiveness to the magnocellular system, given previous suggestions of magnocellular-specific deficits in ASD. Participants were 22 ASD children (7-17 years of age) and 31 age- and performance-IQ-matched neurotypical controls. Both VEP and VESPA responses to central presentations were indistinguishable between groups. In contrast, peripheral presentations resulted in significantly greater early VEP and VESPA amplitudes in the ASD cohort. We found no evidence that anomalous enhancement was restricted to magnocellular-biased responses. The extent of peripheral response enhancement was related to the severity of stereotyped behaviors and restricted interests, cardinal symptoms of ASD. The current results point to differential visuo-spatial cortical mapping in ASD, shedding light on the consequences of peculiarities in gaze and stereotyped visual behaviors often reported by clinicians working with this population. 23743656 Prediction of shrinkage of individual parameters using the bayesian information matrix in non-linear mixed effect models with evaluation in pharmacokinetics. When information is sparse, individual parameters derived from a non-linear mixed effects model analysis can shrink to the mean. The objective of this work was to predict individual parameter shrinkage from the Bayesian information matrix (M BF ). We 1) Propose and evaluate an approximation of M BF by First-Order linearization (FO), 2) Explore by simulations the relationship between shrinkage and precision of estimates and 3) Evaluate prediction of shrinkage and individual parameter precision. We approximated M BF using FO. From the shrinkage formula in linear mixed effects models, we derived the predicted shrinkage from M BF . Shrinkage values were generated for parameters of two pharmacokinetic models by varying the structure and the magnitude of the random effect and residual error models as well as the design. We then evaluated the approximation of M BF FO and compared it to Monte-Carlo (MC) simulations. We finally compared expected and observed shrinkage as well as the predicted and estimated Standard Errors (SE) of individual parameters. M BF FO was similar to M BF MC. Predicted and observed shrinkages were close . Predicted and estimated SE were similar. M BF FO enables prediction of shrinkage and SE of individual parameters. It can be used for design optimization. 23922232 In search of low-frequency and rare variants affecting complex traits. The allelic architecture of complex traits is likely to be underpinned by a combination of multiple common frequency and rare variants. Targeted genotyping arrays and next-generation sequencing technologies at the whole-genome sequencing (WGS) and whole-exome scales (WES) are increasingly employed to access sequence variation across the full minor allele frequency (MAF) spectrum. Different study design strategies that make use of diverse technologies, imputation and sample selection approaches are an active target of development and evaluation efforts. Initial insights into the contribution of rare variants in common diseases and medically relevant quantitative traits point to low-frequency and rare alleles acting either independently or in aggregate and in several cases alongside common variants. Studies conducted in population isolates have been successful in detecting rare variant associations with complex phenotypes. Statistical methodologies that enable the joint analysis of rare variants across regions of the genome continue to evolve with current efforts focusing on incorporating information such as functional annotation, and on the meta-analysis of these burden tests. In addition, population stratification, defining genome-wide statistical significance thresholds and the design of appropriate replication experiments constitute important considerations for the powerful analysis and interpretation of rare variant association studies. Progress in addressing these emerging challenges and the accrual of sufficiently large data sets are poised to help the field of complex trait genetics enter a promising era of discovery. 23947538 Design of the Bottom-up Innovation project--a participatory, primary preventive, organizational level intervention on work-related stress and well-being for workers in Dutch vocational education. In the educational sector job demands have intensified, while job resources remained the same. A prolonged disbalance between demands and resources contributes to lowered vitality and heightened need for recovery, eventually resulting in burnout, sickness absence and retention problems. Until now stress management interventions in education focused mostly on strengthening the individual capacity to cope with stress, instead of altering the sources of stress at work at the organizational level. These interventions have been only partly effective in influencing burnout and well-being. Therefore, the "Bottom-up Innovation" project tests a two-phased participatory, primary preventive organizational level intervention (i.e. a participatory action approach) that targets and engages all workers in the primary process of schools. It is hypothesized that participating in the project results in increased occupational self-efficacy and organizational efficacy. The central research question: is an organization focused stress management intervention based on participatory action effective in reducing the need for recovery and enhancing vitality in school employees in comparison to business as usual? The study is designed as a controlled trial with mixed methods and three measurement moments: baseline (quantitative measures), six months and 18 months (quantitative and qualitative measures). At first follow-up short term effects of taking part in the needs assessment (phase 1) will be determined. At second follow-up the long term effects of taking part in the needs assessment will be determined as well as the effects of implemented tailored workplace solutions (phase 2). A process evaluation based on quantitative and qualitative data will shed light on whether, how and why the intervention (does not) work(s). "Bottom-up Innovation" is a combined effort of the educational sector, intervention providers and researchers. Results will provide insight into (1) the relation between participating in the intervention and occupational and organizational self-efficacy, (2) how an improved balance between job demands and job resources might affect need for recovery and vitality, in the short and long term, from an organizational perspective, and (3) success and fail factors for implementation of an organizational intervention. Netherlands Trial Register NTR3284. 23763625 Assessing the accuracy of inhomogeneous fluid solvation theory in predicting hydration free energies of simple solutes. Accurate prediction of hydration free energies is a key objective of any free energy method that is applied to modeling and understanding interactions in the aqueous phase. Inhomogeneous fluid solvation theory (IFST) is a statistical mechanical method for calculating solvation free energies by quantifying the effect of a solute acting as a perturbation to bulk water. IFST has found wide application in understanding hydration phenomena in biological systems, but quantitative applications have not been comprehensively assessed. In this study, we report the hydration free energies of six simple solutes calculated using IFST and independently using free energy perturbation (FEP). This facilitates a validation of IFST that is independent of the accuracy of the force field. The results demonstrate that IFST shows good agreement with FEP, with an R(2) coefficient of determination of 0.99 and a mean unsigned difference of 0.7 kcal/mol. However, sampling is a major issue that plagues IFST calculations and the results suggest that a histogram method may require prohibitively long simulations to achieve convergence of the entropies, for bin sizes which effectively capture the underlying probability distributions. Results also highlight the sensitivity of IFST to the reference interaction energy of a water molecule in bulk, with a difference of 0.01 kcal/mol changing the predicted hydration free energies by approximately 2.4 kcal/mol for the systems studied here. One of the major advantages of IFST over perturbation methods such as FEP is that the systems are spatially decomposed to consider the contribution of specific regions to the total solvation free energies. Visualizing these contributions can yield detailed insights into solvation thermodynamics. An insight from this work is the identification and explanation of regions with unfavorable free energy density relative to bulk water. These regions contribute unfavorably to the hydration free energy. Further work is necessary before IFST can be extended to yield accurate predictions of binding free energies, but the work presented here demonstrates its potential. 23619192 The validation of synthetic spectra used in the performance evaluation of radionuclide identifiers. This work has evaluated synthetic gamma-ray spectra created by the RASE sampler using experimental data. The RASE sampler resamples experimental data to create large data libraries which are subsequently available for use in evaluation of radionuclide identification algorithms. A statistical evaluation of the synthetic energy bins has shown the variation to follow a Poisson distribution identical to experimental data. The minimum amount of statistics required in each base spectrum to ensure the subsequent use of the base spectrum in the generation of statistically robust synthetic data was determined. A requirement that the simulated acquisition time of the synthetic spectra was not more than 4% of the acquisition time of the base spectrum was also determined. Further validation of RASE was undertaken using two different radionuclide identification algorithms. 23536217 Biocontrol of postharvest Rhizopus decay of peaches with Pichia caribbica. A new yeast antagonist, Pichia caribbica, isolated in our laboratory from the soil collected from unsprayed orchards, was evaluated for its biocontrol capability against Rhizopus stolonifer on peaches and the possible mechanisms involved. The decay incidence and lesion diameter of Rhizopus decay of peaches treated by P. caribbica were significantly reduced compared with the control fruits, and the higher the concentration of P. caribbica, the better the efficacy of the biocontrol. Rapid colonization of the yeast in peach wounds stored at 25 °C was observed. In peaches, the activities of peroxidase (POD), catalase (CAT), and phenylalanine ammonia-lyase (PAL) were significantly induced by P. caribbica treatment compared to those of the control fruits. All these results indicated that P. caribbica has a great potential for the development of commercial formulations to control postharvest Rhizopus decay of peaches. Its modes of action were based on competition for space and nutrients with pathogens, inducement of activities of defense-related enzymes such as POD, CAT, and PAL of peaches. 23943616 Identification of biochemically distinct properties of the SUMO conjugation pathway in Plasmodium falciparum. Small ubiquitin-related modifiers (SUMOs) are post-translationally conjugated to other proteins and are thereby essential regulators of a wide range of cellular processes. Sumoylation, and enzymes of the sumoylation pathway, are conserved in the malaria causing parasite, Plasmodium falciparum. However, the specific functions of sumoylation in P. falciparum, and the degree of functional conservation between enzymes of the human and P. falciparum sumoylation pathways, have not been characterized. Here, we demonstrate that sumoylation levels peak during mid stages of the intra-erythrocyte developmental cycle (IDC), concomitant with hemoglobin consumption and elevated oxidative stress. In vitro studies revealed that P. falciparum E1 and E2 conjugating enzymes interact effectively to recognize and modify RanGAP1, a model mammalian SUMO substrate. However, in heterologous reactions, P. falciparum E1 and E2 enzymes failed to interact with cognate human E2 and E1 partners, respectively, to modify RanGAP1. Structural analysis, binding studies and functional assays revealed divergent amino acid residues within the E1-E2 binding interface that define organism-specific enzyme interactions. Our studies identify sumoylation as a potentially important regulator of oxidative stress response during the P. falciparum IDC, and define E1 and E2 interactions as a promising target for development of parasite-specific inhibitors of sumoylation and parasite replication. 23839070 Morphology of the human xiphoid process: dissection and radiography of cadavers and MDCT of patients. The purpose of this study was to evaluate the morphology of xiphoid process by dissection and using radiography of cadavers and multidetector computed tomography (MDCT) in patients. The xiphoid processes of 41 cadavers were dissected and taken by radiography. Other 902 patients examined by MDCT were revealed by image post-processing used with multiple planar reconstruction, maximum intensity projection and volume rendering. Xiphoid processes displayed pointed shape in 422 cases (44.75 %), oval shape in 387 cases (41.04 %), and forked shape in 134 cases (14.21 %). The sagittal shape of the xiphoid process was observed as ventrally deviated in 217 cases (23.01 %), dorsally deviated in 191 cases (20.25 %), S-shaped (ahead ventral, then dorsal) in 21 cases (2.23 %), and resembling a hook in 14 of ventral deviated patients and in 19 of those dorsal deviated patients. The foramen of xiphoid processes was found in 544 cases (57.69 %). The pattern L (a large foramen with a diameter of more than 5 mm) appeared in 302 cases (55.51 %), pattern S (a small foramen with a diameter of no more than 5 mm) in 155 cases (28.49 %), pattern LS (a mixture of a large and a small foramina) in 37 cases (6.80 %), and pattern SS (two or more small foramina) in 50 cases (9.19 %). Human xiphoid process appeared in morphological diversity. The anatomic structure and ossification degree of xiphoid process was well evaluated by MDCT. Our data may be used for diagnosis and surgical treatment of xiphoid process-related diseases. 23963788 Epigenetics and the Modulation of Neuroinflammation. Innate immune responses in the central nervous system (CNS) have key roles influencing both physiological and pathological processes. Microglia are innate immune effector cells that reside within the CNS. These inflammatory cells are constantly surveying their external environment and rapidly respond to a variety of molecules that signal changes in CNS homeostasis. In response to these signals, microglia influence neuronal connections, modulate the functions of other glia, and mediate inflammatory responses to disease or injury. In parallel with the regulation of inflammatory responses outside of the CNS, investigators have observed that microglia are capable of heterogeneous responses to exogenous and endogenous signals. While much of this molecular and morphological heterogeneity is regulated by gene transcription, there is ample evidence that microglial behavior is determined, in part, by epigenetic regulation. Recent work has demonstrated that processes involving DNA methylation, histone modification, and noncoding RNAs also have important roles in modulating neuroinflammation. Here I will review the evidence supporting a role for epigenetic regulation of neuroinflammation and describe how this might influence the outcome of several CNS disorders, including addiction, infection, multiple sclerosis, and stroke. 23860356 Schizophrenia and dopamine receptors. Schizophrenia patients are behaviorally supersensitive to dopamine-like drugs such as amphetamine or methylphenidate, meaning that patients respond to such drugs with increased psychotic symptoms, as compared to control subjects. A basis of such supersensitivity may be an increased pre-synaptic release of dopamine or a post-synaptic elevation of D2 receptors or of D2High receptors in active stages of schizophrenia. While the pre-synaptic release of dopamine is normal in stable patients with schizophrenia, brain imaging studies find that D2 receptors are increased by an average of 5.8% in antipsychotic-free schizophrenia patients. It is possible that the behavioral supersensitivity may stem from more D2High receptors in schizophrenia. Although the antipsychotic/dopamine D2 receptor can exist in vitro in a state of high affinity for dopamine (as D2High), or in a state of low affinity for dopamine (as D2Low), there is no clear evidence that D2High states can be selectively labeled or stably exist in vivo. Nevertheless, two studies revealed an 80% increase in apparent D2High receptors in schizophrenia patients after reducing endogenous dopamine. The elevation in apparent D2High receptors in vivo in schizophrenia matches the elevation in D2High receptors in vitro in animal models of psychosis, including dopamine-supersensitive animals pretreated with amphetamine, marijuana, or phencyclidine, or animals with gene knockouts in various neurotransmitter pathways, including those for glutamate receptors. The elevation of D2High receptors in vitro and the increased apparent D2High receptors in vivo is consistent with behavioral dopamine supersensitivity in schizophrenia patients. 23334405 Treatment of umbilical hernia and recti muscles diastasis without a periumbilical incision. Postpartum rectus diastasis eventually combined with umbilical hernia is a condition that is frequently treated by plastic surgeons and general surgeons. Standard treatment of this condition is abdominoplasty with a periumbilical incision, which often results in an umbilical incision or an inverted-T scar. Limited incision abdominoplasty differs from traditional abdominoplasty by disconnecting the umbilical stalk from the abdominal wall during flap dissection, thus allowing the resection of excess skin above and under the umbilicus without causing periumbilical scarring. We conducted a retrospective cohort study of women undergoing a limited scar abdominoplasty without a periumbilical incision for the treatment of a separation of the recti muscles and/or an umbilical hernia. We recorded the postoperative complications and patient satisfaction with the results of the treatment. We operated on 50 patients from 2002 to 2010. We followed the patients for 2-8 years. The most common complication, as with other abdominoplasty procedures, was minor dehiscention in the middle part of the wound, which occurred in 16 % (n = 8) of the patients. All of these complications were treated conservatively. No recurrence of diastasis or umbilical hernia was observed. Extended miniabdominoplasty with a low suprapubic incision and umbilical caudalization for treating the diastasis of the abdominal rectus muscles and/or an umbilical hernia is an excellent method that results in a small, hidden scar. This method is especially beneficial for young, slim women with an abdominal wall deformity after pregnancy. 23912394 Frequency of inversions affects senescence phenology of Acer pseudoplatanus and Fagus sylvatica. In mountainous regions, inversion situations with cold-air pools in the valleys occur frequently, especially in fall and winter. With the accumulation of inversion days, trees in lower elevations experience lower temperature sums than those in middle elevations. In a two-year observational study, deciduous trees, such as Acer pseudoplatanus and Fagus sylvatica, on altitudinal transects responded in their fall leaf senescence phenology. Phenological phases were advanced and senescence duration was shortened by the cold temperatures in the valley. This effect was more distinct for late phases than for early phases since they experienced more inversion days. The higher the inversion frequency, the stronger the signal was. Acer pseudoplatanus proved to be more sensitive to cold temperatures compared to Fagus sylvatica. We conclude that cold-air pools have a considerable impact on the vegetation period of deciduous trees. Considering this effect, trees in the mid hillside slopes gain advantages compared to lower elevations. Our findings will help to improve knowledge about ecological drivers and responses in mountainous forest ecosystems. 23230213 Mutation of a zinc-binding residue in the glycine receptor α1 subunit changes ethanol sensitivity in vitro and alcohol consumption in vivo. Ethanol is a widely used drug, yet an understanding of its sites and mechanisms of action remains incomplete. Among the protein targets of ethanol are glycine receptors (GlyRs), which are potentiated by millimolar concentrations of ethanol. In addition, zinc ions also modulate GlyR function, and recent evidence suggests that physiologic concentrations of zinc enhance ethanol potentiation of GlyRs. Here, we first built a homology model of a zinc-bound GlyR using the D80 position as a coordination site for a zinc ion. Next, we investigated in vitro the effects of zinc on ethanol action at recombinant wild-type (WT) and mutant α1 GlyRs containing the D80A substitution, which eliminates zinc potentiation. At D80A GlyRs, the effects of 50 and 200 mM ethanol were reduced as compared with WT receptors. Also, in contrast to what was seen with WT GlyRs, neither adding nor chelating zinc changed the magnitude of ethanol enhancement of mutant D80A receptors. Next, we evaluated the in vivo effects of the D80A substitution by using heterozygous Glra1(D80A) knock-in (KI) mice. The KI mice showed decreased ethanol consumption and preference, and they displayed increased startle responses compared with their WT littermates. Other behavioral tests, including ethanol-induced motor incoordination and strychnine-induced convulsions, revealed no differences between the KI and WT mice. Together, our findings indicate that zinc is critical in determining the effects of ethanol at GlyRs and suggest that zinc binding at the D80 position may be important for mediating some of the behavioral effects of ethanol action at GlyRs. 23122091 Chemical analysis and anti-inflammatory comparison of the cell culture of Glycyrrhiza with its field cultivated variety. Suspended cells of Glycyrrhiza (CG) possessed a similar content of flavonoids and a lower content of triterpenes, when compared with its field cultivated equivalent (NG). Xylene-induced ear oedema and ovalbumin-induced mouse paw oedema were applied, to compare the effects of CG and NG on the acute inflammatory response. Extracts of the cell culture of Glycyrrhiza possessed a similar anti-inflammatory effect to those of NG, through the enhancement of the SOD activity of plasma and liver tissues. The use of a cell culture of liquorice instead of field cultivation would be potentially profitable. 23831869 The association between CYP2D6 genotype and switching antipsychotic medication to clozapine. Genetic variation in the cytochrome P450 2D6 (CYP2D6) enzyme is responsible for interindividual differences in the metabolism of many antipsychotic drugs, but the clinical relevance of polymorphisms in CYP2D6 for response to antipsychotic treatment is relatively unknown. In the Netherlands, clozapine is prescribed only when patients are non-responsive to or intolerant of at least two different antipsychotics. The aim of our study was to determine the association of the CYP2D6 genotype with switching to clozapine, which served as a surrogate outcome marker for treatment response to antipsychotics. CYP2D6 genotype was assessed in patients who had been switched to clozapine and compared with antipsychotic users whose treatment regimen included no more than two different antipsychotic drugs and no clozapine. We also performed the analysis in patients who only used CYP2D6-dependent antipsychotics. A total of 528 patients were included in the study (222 cases, 306 controls). No statistically significant differences were found in the distribution of the polymorphisms among the case and control groups, both in all patients and in only those patients using CYP2D6-dependent antipsychotics. However, a trend was observed, suggesting an inverse association between CYP2D6 genotype and the switch to clozapine. (9.5 vs. 5.1 % poor metabolisers and 1.3 vs. 2.6 % ultrarapid metabolisers in cases vs. controls, respectively). Although the results of our study suggest that the CYP2D6 phenotype is not a major determining factor for patients to be switched to clozapine treatment, larger studies are warranted with a focus on the clinical consequences of the CYP2D6 ultrarapid metaboliser and poor metaboliser phenotypes. 23932378 Microclimate in ski boots - Temperature, relative humidity, and water absorption. Ski boot quality is determined by mechanical properties and comfort. Comfort is strongly affected by cold feet. The purpose of this study was to determine the microclimate in ski boots. Climate chamber tests with five male subjects and field tests with two male subjects were conducted. Temperature and relative humidity were measured using four sensors placed on the foot and one on the liner. Absorbed water in liners and socks was measured with a precision balance. The subjects gave subjective ratings for comfort. The toe sensor temperature dropped below 20 °C at an ambient temperature of 0 °C, -10 °C, and -20 °C. Relative humidity values at the foot were as high as 78% in the climate chamber and 93% in the field. Water absorption in socks and liners ranged from 4 to 10 g in the climate chamber and 19 to 45.5 g in the field. The results reveal the importance of keeping the feet and in particular the toes warm during skiing. One possible improvement may be to construct the liner so that sweat and melted snow are kept as far away as possible from the foot. Liner material with high water absorption capacity and hydrophobic socks were suggested to prevent wet feet. 23871480 Sports Medicine Training and Practice Opportunities for Emergency Physicians. There is growing interest among emergency physicians to seek additional training in Sports Medicine (SM) and to add it to their clinical practice. This presents unique training and practice management issues. The majority of Primary Care SM fellowship programs list that they will accept emergency physicians, and approximately one-third have already had an emergency physician as an SM fellow. The objective of this article is to provide an overview of the key elements for emergency physicians to consider as they pursue SM career goals. Training needs such as continuity of care as it pertains to the athlete, SM skills development, and practice management are reviewed. Practice challenges such as malpractice insurance and billing issues are discussed. Examples of several practice models are presented. Evolving trends in SM practice and training opportunities for emergency physicians are discussed as well. Sports Medicine is a viable career option for emergency physicians and may complement their skills set in the management of acute injuries. Practice and training opportunities will continue to evolve as this pathway into the practice of SM gains further recognition. 23290260 Environmental information for military planning. A study was conducted to consider the implications of presenting Environmental Information (EI; information on current environmental features including weather, topography and visibility maps) for military planning to the growing audience of non-technical users; to provide guidance for ensuring usability and for development of a suitable EI interface, and to produce an EI concept interface mock-up to demonstrate initial design ideas. Knowledge was elicited from current EI users and providers regarding anticipated use of EI by non-specialists. This was combined with human factors and cognition expertise to produce guidance for data usability and development of an EI interface. A simple mock-up of an EI concept interface was developed. Recommendations for further development were made including application of the guidance derived, identification of a user test-bed and development of business processes. 23733767 Randomized Open-Label Phase II Study of Decitabine in Patients With Low- or Intermediate-Risk Myelodysplastic Syndromes. PURPOSE This open-label, randomized phase II trial assessed efficacy and tolerability of two low-dose regimens of subcutaneous (SC) decitabine in patients with low- or intermediate-1-risk myelodysplastic syndrome (MDS). PATIENTS AND METHODS Patients received decitabine 20 mg/m(2) SC per day for 3 consecutive days on days 1, 2, and 3 every 28 days (schedule A) or 20 mg/m(2) SC per day once every 7 days on days 1, 8, and 15 every 28 days (schedule B) for up to 1 year. Primary efficacy end point was overall improvement rate (OIR: complete remission [CR], partial remission [PR], marrow CR [mCR], or hematologic improvement [HI]). Secondary end points were HI, transfusion independence, cytogenetic response, overall survival (OS), and time to acute myeloid leukemia or death. Results Efficacy and safety populations were identical: schedule A, n = 43; schedule B, n = 22. Median time from MDS diagnosis to treatment was 3.6 months; 89% had de novo MDS. The trial was terminated early on achievement of protocol-defined OIR superiority of schedule A over schedule B; OIR was 23% for schedule A (seven CRs, three HIs) and 23% for schedule B (one mCR, one PR, three HIs). No differences were observed in secondary end points. Median OS was not reached; approximately 70% of patients were alive at 500 days. Patients in schedule A (67%) and schedule B (59%) were RBC/platelet independent on study. The most frequent drug-related adverse events overall were neutropenia (28% v 36%), anemia (23% v 18%), and thrombocytopenia (16% v 32%). CONCLUSION In this phase II study, low-dose decitabine showed promising results in patients with low- or intermediate-1-risk MDS. 23912197 Do blood growth factors offer additional benefit in refractory lateral epicondylitis? A prospective, randomized pilot trial of dry needling as a stand-alone procedure versus dry needling and autologous conditioned plasma. To evaluate whether autologous conditioned plasma offers any therapeutic advantage over ultrasound-guided dry needling as a stand-alone procedure in the treatment of refractory lateral epicondylitis. Prospective, randomized pilot study of 28 patients (11 men, 17 women, mean age, 49.1  years) with refractory lateral epicondylitis (mean symptom duration, 19.1 months) who underwent either dry needling (n = 13) or dry needling combined with autologous conditioned plasma (ACP) injection (n = 15). Each patient received two separate injections (0 weeks and 1 month) and analysis of visual analogue pain scores (VAS) and Nirschl scores were performed pre-procedure, at 2 months and final evaluation at 6 months. Successful treatment was defined as more than a 25 % reduction in pain scores without re-intervention. Data was analyzed using the Mann-Whitney test and local research ethics committee approval was obtained. At 2 months, the mean VAS improvement was 0.85 (12.3 %) in the dry needling group compared to 2.19 (27.1 %) in the ACP group (p = 0.76) and there was a 5.83-point and 20.3-point Nirschl score improvement respectively (p = 0.72). At the final follow-up of 6 months, the mean VAS improvement was 2.37 (34 %) in the dry needling group compared to 3.92 (48.5 %) in the ACP group (p = 0.74) and there was a 22.5-point and 40-point Nirschl score improvement, respectively (p = 0.82). There is a trend to greater clinical improvement in the short term for patients treated with additional ACP, however no significant difference between the two treatment groups was demonstrated at each follow-up interval. A larger, multicenter, randomized controlled trial is required to corroborate the results of this pilot study. 23497903 Calcium hydroxy palmitate: possible precursor phase in calcium precipitation by palmitate. Calcium(II) precipitates with palmitate (Pal(-)), a process affecting calcium absorption in the gut, in a first-order reaction, as followed by a calcium electrode in neutral aqueous solution for excess of calcium(II), with a rate constant showing a minimum at physiological ionic strength of 0.32 ± 0.09 d(-1) at 25°C with a stoichiometry of 1.79 ± 0.03, lower than the expected 1:2. During ageing of precipitate, pH increases in the supernatant, while pH decreases for precipitation with excess of palmitate. Increasing pH, as in some aged food products, decreases the solubility, and Ksp(')=[Ca(2+)][Pal(-)][OH(-)] is found constant rather than Ksp=[Ca(2+)][Pal(-)](2) in agreement with an initial precipitation of Ca(OH)(Pal), which slowly may convert into Ca(Pal)2·Ca(OH)(Pal) has a solubility minimum at physiological ionic strength with Ksp(')=(1.4 ± 0.4)10(-16)M(3). X-ray diffraction showed a d-spacing of 44.15Å (different from 45.2Å reported for Ca(Pal)2), and infrared spectroscopy confirmed the presence of a hydroxy group. 23886479 Commercial processed food may have endocrine-disrupting potential: soy-based ingredients making the difference. Processed and packaged food items as well as ready-to-eat snacks are neglected and poorly characterised sources of human exposure to endocrine-disrupting chemicals (EDCs). In this study we investigated the presence of xenoestrogens in commercially processed and packaged Finnish foods, arising from substances deliberately added or inadvertently contaminating the food, substances formed as a result of food processing, or substances leaching from food packaging materials. Samples were obtained in three separate batches of equivalent products from both a supermarket and a local representative of a global chain of hamburger restaurants and extracted by a solid-phase extraction method. Their endocrine-disrupting potential was determined by yeast bioluminescent assay, using two recombinant yeast strains Saccharomyces cerevisiae BMAEREluc/ERα and S. cerevisiae BMA64/luc. In this test system, the majority of samples (both foodstuffs and wrappers) analysed proved negative. However, all batches of industrially prepared hamburgers (but not those obtained from a hamburger restaurant) as well as pepper salami significantly induced luciferase activity in the BMAEREluc/ERα yeast strain indicating the presence of xenoestrogens, with estradiol equivalents of these products ranging from 0.2 to 443 pg g(-1). All three products contained soy-based ingredients, which apparently accounted for, or at least contributed to, their high estrogenic activity, since no signal in the assay was observed with extracts of the packaging material, while two different soy sauces tested yielded an intense signal (28 and 54 pg ml(-1) estradiol-equivalent). These findings imply that by and large chemicals arising in the processing or packaging of foodstuffs in Finland constitute an insignificant source of xenoestrogens to consumers. However, soy-derived ingredients in certain food items might render the entire products highly estrogenic. The estrogenic activity of soy is attributed to isoflavones whose health effects - though widely considered beneficial - are controversial. As hamburgers are a popular type of food among children, the findings are noteworthy and possibly of concern. 23879697 Photoperiod affects the diurnal rhythm of hippocampal neuronal morphology of siberian hamsters. Individuals of many species can regulate their physiology, morphology, and behavior in response to annual changes of day length (photoperiod). In mammals, the photoperiodic signal is mediated by a change in the duration of melatonin, leading to alterations in gene expressions, neuronal circuits, and hormonal secretion. The hippocampus is one of the most plastic structures in the adult brain and hippocampal neuronal morphology displays photoperiod-induced differences. Because the hippocampus is important for emotional and cognitive behaviors, photoperiod-driven remodeling of hippocampal neurons is implicated in seasonal differences of affect, including seasonal affective disorder (SAD) in humans. Because neuronal architecture is also affected by the day-night cycle in several brain areas, we hypothesized that hippocampal neuronal morphology would display a diurnal rhythm and that day length would influence that rhythm. In the present study, we examined diurnal and seasonal differences in hippocampal neuronal morphology, as well as mRNA expression of the neurotrophic factors (i.e., brain-derived neurotrophic factor [Bdnf], tropomyosin receptor kinase B [trkB; a receptor for BDNF], and vascular endothelial growth factor [Vegf]) and a circadian clock gene, Bmal1, in the hippocampus of Siberian hamsters. Diurnal rhythms in total length of dendrites, the number of primary dendrites, dendritic complexity, and distance of the furthest intersection from the cell body were observed only in long-day animals; however, diurnal rhythms in the number of branch points and mean length of segments were observed only in short-day animals. Spine density of dendrites displayed diurnal rhythmicity with different peak times between the CA1 and DG subregions and between long and short days. These results indicate that photoperiod affects daily morphological changes of hippocampal neurons and the daily rhythm of spine density, suggesting the possibility that photoperiod-induced adjustments of hippocampal neuronal dynamics might underlie seasonal difference of affective responses. Bmal1 mRNA showed a diurnal rhythm and different expression levels between long and short days were observed. However, there were no strong effects of day length on Bdnf. trkb, and Vegf gene expression, suggesting that these genes are not involved in the photoperiodic effects on hippocampal neurons. 23601370 LiverAtlas: a unique integrated knowledge database for systems-level research of liver and hepatic disease. A large amount of liver-related physiological and pathological data exist in publicly available biological and bibliographic databases, which are usually far from comprehensive or integrated. Data collection, integration and mining processes pose a great challenge to scientific researchers and clinicians interested in the liver. To address these problems, we constructed LiverAtlas (http://liveratlas.hupo.org.cn), a comprehensive resource of biomedical knowledge related to the liver and various hepatic diseases by incorporating 53 databases. In the present version, LiverAtlas covers data on liver-related genomics, transcriptomics, proteomics, metabolomics and hepatic diseases. Additionally, LiverAtlas provides a wealth of manually curated information, relevant literature citations and cross-references to other databases. Importantly, an expert-confirmed Human Liver Disease Ontology, including relevant information for 227 types of hepatic disease, has been constructed and is used to annotate LiverAtlas data. Furthermore, we have demonstrated two examples of applying LiverAtlas data to identify candidate markers for hepatocellular carcinoma (HCC) at the systems level and to develop a systems biology-based classifier by combining the differential gene expression with topological features of human protein interaction networks to enhance the ability of HCC differential diagnosis. LiverAtlas is the most comprehensive liver and hepatic disease resource, which helps biologists and clinicians to analyse their data at the systems level and will contribute much to the biomarker discovery and diagnostic performance enhancement for liver diseases. 23538635 Genotype-phenotype analysis of Bietti crystalline dystrophy in a family with the CYP4V2 Ile111Thr mutation. The purposes of this study were to evaluate the genotypic and phenotypic correlations of Bietti crystalline dystrophy and to investigate the utility of in vivo corneal confocal microscopy in diagnosing this disorder. A Spanish woman (proband) with a clinical diagnosis of Bietti crystalline dystrophy and 7 members of her family were recruited prospectively for complete clinical ophthalmic examination and genetic study. The medical records of an additional family member were reviewed retrospectively. Genomic DNA was obtained from blood samples, and 11 exons of the CYP4V2 gene were screened for mutations by polymerase chain reaction DNA sequencing. Clinical examination revealed an atypical pattern of corneal dystrophy with central and paracentral distribution not only in the proband but also in 2 elderly heterozygous carriers. Corneal deposits were observed by slit-lamp examination and in vivo corneal confocal microscopy. Genetic analysis revealed the homozygous CYP4V2 Ile111Thr mutation in the proband and identified 5 heterozygous carriers. The authors identified a case of Bietti crystalline dystrophy with central and paracentral keratopathy and the molecular analysis of the causative gene in a Spanish family. Data suggest a dose-dependent phenotype ranging from subclinical corneal changes in subjects carrying 1 mutant Ile111Thr CYP4V2 allele to the complete manifestation of the disease in homozygous subjects. In vivo corneal confocal microscopy is a useful technique in the diagnosis of this disorder. 23966078 Accidental Interaction between PDZ Domains and Diclofenac Revealed by NMR-Assisted Virtual Screening. In silico approaches have become indispensable for drug discovery as well as drug repositioning and adverse effect prediction. We have developed the eF-seek program to predict protein-ligand interactions based on the surface structure of proteins using a clique search algorithm. We have also developed a special protein structure prediction pipeline and accumulated predicted 3D models in the Structural Atlas of the Human Genome (SAHG) database. Using this database, genome-wide prediction of non-peptide ligands for proteins in the human genome was performed, and a subset of predicted interactions including 14 PDZ domains was then confirmed by NMR titration. Surprisingly, diclofenac, a non-steroidal anti-inflammatory drug, was found to be a non-peptide PDZ domain ligand, which bound to 5 of 15 tested PDZ domains. The critical residues for the PDZ-diclofenac interaction were also determined. Pharmacological implications of the accidental PDZ-diclofenac interaction are further discussed. 23855486 Acacetin inhibits expression of E-selectin on endothelial cells through regulation of the MAP kinase signaling pathway and activation of NF-κB. Abstract Since E-selectin-mediated adhesion of leukocytes or tumor cells to the vascular endothelium is a key early event in the initiation of inflammatory response and cancer metastasis, E-selectin inhibition is thought to be a good target for therapeutic intervention. Several flavones have been shown to have anti-inflammatory and anticancer properties. In the present study, we investigated the effects of plant flavones on expression of E-selectin in human umbilical vein endothelial cells. Among 11 flavones, acacetin strongly inhibited TNF-α-induced E-selectin expression in HUVECs. Acacetin suppressed the TNF-α-induced phosphorylation of p38 but did not inhibit TNF-α-induced phosphorylations of JNK and ERK. Acacetin also inhibited the activation of NF-κB by stimulation with TNF-α. Furthermore, adhesion of monocytes to TNF-α-treated endothelial cells was inhibited by cotreatment with acacetin. These results suggest that acacetin inhibits the expression of E-selectin by regulation of the p38 MAPK signaling pathway and activation of NF-κB. 23852339 Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy. The nuclear receptor Rev-erb-α modulates hepatic lipid and glucose metabolism, adipogenesis and the inflammatory response in macrophages. We show here that Rev-erb-α is highly expressed in oxidative skeletal muscle and that its deficiency in muscle leads to reduced mitochondrial content and oxidative function, as well as upregulation of autophagy. These cellular effects resulted in both impaired mitochondrial biogenesis and increased clearance of this organelle, leading to compromised exercise capacity. On a molecular level, Rev-erb-α deficiency resulted in deactivation of the Lkb1-Ampk-Sirt1-Ppargc-1α signaling pathway. These effects were recapitulated in isolated fibers and in muscle cells after knockdown of the gene encoding Rev-erb-α, Nr1d1. In complementary experiments, Rev-erb-α overexpression in vitro increased the number of mitochondria and improved respiratory capacity, whereas muscle overexpression or pharmacological activation of Rev-erb-α in vivo increased exercise capacity. This study identifies Rev-erb-α as a pharmacological target that improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function. 23575383 Nocturnal urinary melatonin excretion is associated with non-dipper pattern in elderly hypertensives. Although oral melatonin administration may enhance a nocturnal blood pressure fall, it remains unclear whether endogenous melatonin, which is present at considerably lower levels than pharmacological melatonin, is associated with the non-dipper pattern. The present cross-sectional study aimed to determine the association between urinary melatonin excretion, an index of endogenous melatonin, and the non-dipper pattern. We measured the following variables in 141 elderly hypertensives: overnight urinary melatonin excretion, ambulatory blood pressure and actigraphic physical activity. We defined a non-dipper pattern as a <10% fall in sleep systolic blood pressure compared with awake systolic blood pressure. When participants were divided into two groups (high and low melatonin groups) by the cutoff value for identifying the top tertile, the characteristics, except for age, did not significantly differ between the two groups. Crude logistic regression analysis showed significant associations of the non-dipper pattern with age, diabetes, higher urinary melatonin excretion (high vs. low) and daytime activity. In a multivariate analysis after adjustment for age, diabetes and daytime activity, the odds ratio for the non-dipper pattern in the high melatonin group was significantly lower than that in the low melatonin group (odds ratio: 0.39, 95% confidence interval (CI): 0.17-0.91, P=0.03). Moreover, the mean percentage systolic blood pressure nocturnal fall, adjusted for the former covariates, was significantly higher in the high melatonin group than the low melatonin group (difference 3.5%, 95% CI: 0.0-7.0%, P=0.048). Among elderly hypertensive individuals, nocturnal urinary melatonin excretion is significantly and inversely associated with the non-dipper pattern. 23498364 Surgical treatment results of intestinal and diffuse type gastric cancer. Implications for a differentiated therapeutic approach? To study the outcome of patients who were surgically treated for primary gastric cancer with specific attention to differences in treatment results for intestinal and diffuse type tumours. All patients who underwent a potentially curative gastric resection between 1995 and 2011 in our institute were included. Patient, tumour and treatment characteristics were obtained retrospectively. Binary logistic and Cox regression models were used for multivariate analysis. A consecutive series of 132 patients was included. Median follow-up was 53 months. There were no significant differences between patients with intestinal (N = 62) versus diffuse type (N = 70) gastric cancer with regard to the proportion of patients who underwent (neo)adjuvant treatment. Postoperative mortality was 2%. Pathological T- and N-stage were significantly more advanced for patients with diffuse type tumours. There was a significant difference in the percentage of microscopically irradical resections (2% versus 24%, p < 0.001) and median overall survival (129 versus 17 months, p < 0.001) between patients with intestinal type tumours and those with diffuse type tumours. On multivariate analysis, diffuse type histology was the only factor significantly associated with an R1 resection. In a multivariate Cox regression model, diffuse type histology was a significant adverse prognostic factor for overall survival. Striking differences were found between patients with diffuse type tumours and those with intestinal type tumours. These differences call for a differentiated approach in the potentially curative treatment of these two tumour types. 23628779 Intracellular trafficking of solid lipid nanoparticles and their distribution between cells through tunneling nanotubes. The intracellular fate of nanosized drug delivery systems is still not well understood. Various internalization pathways have been discovered, but knowledge of their intracellular trafficking is still incomplete. The aim of this study was to examine the internalization, pathways, and positioning taken by solid lipid nanoparticles (SLNs) in cells. SLNs were fluorescence labeled with a newly synthesized fluorescent probe, 14-DACA. The probe was strongly incorporated into the nanoparticle core under the influence of its long lipophilic chain, enabling superior visualization of SLNs under complex and dynamic intracellular conditions. The intracellular distribution of SLNs was studied qualitatively using a co-localization technique and quantitatively using fluorescence intensity profiles. SLNs were seen inside the cells as distinct bright blue dots that underwent dynamic movement and were finally positioned in the proximity of the nucleus. A few SLNs were shown to be present in mitochondria and between actin filaments, but none in the cell nucleus or lysosomes. SLNs are here reported to be present in tunneling nanotubes (TNTs), which could be a new route of SLN transfer between cells. More TNTs were observed in cells treated with SLNs. The presence of TNTs was additionally confirmed by atomic force microscopy analysis, which indicated that treated cells were more rough than control cells. Detailed investigation of the subcellular localization of SLNs and the evidence for their transfer and distribution via TNTs to the cells, which are not in direct contact with the source of SLNs, are important for understanding the mechanism of targeted drug delivery. Understanding the possible intercellular distribution of SLNs via TNTs can significantly influence approaches to treating organelle-specific diseases. 23868178 Distinct patterns of DNA methylation in conventional adenomas involving the right and left colon. Recent studies have shown two distinct non-CIMP methylation clusters in colorectal cancer, raising the possibility that DNA methylation, involving non-CIMP genes, may play a role in the conventional adenoma-carcinoma pathway. A total of 135 adenomas (65 left colon and 70 right colon) were profiled for epigenome-wide DNA methylation using the Illumina HumanMethylation450 BeadChip. A principal components analysis was performed to examine the association between variability in DNA methylation and adenoma location. Linear regression and linear mixed effects models were used to identify locus-specific differential DNA methylation in adenomas of right and left colon. A significant association was present between the first principal component and adenoma location (P=0.007), even after adjustment for subject age and gender (P=0.009). A total of 168 CpG sites were differentially methylated between right- and left-colon adenomas and these loci demonstrated enrichment of homeobox genes (P=3.0 × 10(-12)). None of the 168 probes were associated with CIMP genes. Among CpG loci with the largest difference in methylation between right- and left-colon adenomas, probes associated with PRAC (prostate cancer susceptibility candidate) gene showed hypermethylation in right-colon adenomas whereas those associated with CDX2 (caudal type homeobox transcription factor 2) showed hypermethylation in left-colon adenomas. A subgroup of left-colon adenomas enriched for current smokers (OR=6.1, P=0.004) exhibited a methylation profile similar to right-colon adenomas. In summary, our results indicate distinct patterns of DNA methylation, independent of CIMP genes, in adenomas of the right and left colon.Modern Pathology advance online publication, 19 July 2013; doi:10.1038/modpathol.2013.104. 23354955 Analogical reasoning in baboons (Papio papio): Flexible reencoding of the source relation depending on the target relation. Analogical reasoning is a cornerstone of human cognition, but the extent and limits of analogical reasoning in animals remains unclear. Recent studies have demonstrated that apes and monkeys can match relations with relations, suggesting that these species have the basic abilities for analogical reasoning. However, analogical reasoning in humans entails two additional cognitive processes that remain unexplored in animals. These include the ability to (1) flexibly reencode the relations instantiated by the source domain as a function of the relational properties of the target domain, and (2) to match relations across different stimulus dimensions. Using a two-dimensional relational matching-to-sample task, the present study demonstrates that these two abilities are in the scope of baboons, given appropriate training. These findings unveil the richness of the cognitive processes implicated during analogical reasoning in nonhuman primates and further reduce the apparent gap between animal and human cognition. 23912619 Quantitative Elastography of Liver Fibrosis and Spleen Stiffness in Chronic Hepatitis B Carriers: Comparison of Shear-Wave Elastography and Transient Elastography with Liver Biopsy Correlation. Purpose:To document utility of shear-wave (SW) elastography for assessing liver fibrosis in chronic hepatitis B and to compare its performance with that of transient elastography.Materials and Methods:Ethics committee approved the study, and informed consent was obtained. Patients with liver biopsy correlation (n = 226) and healthy patients (n = 171) were analyzed. Results of SW elastography of liver, SW elastography of spleen, and transient elastography of liver were compared and correlated according to METAVIR scores. Areas under the receiver operating characteristic curve (AUCs), binary logistic regression, and Delong test were used.Results:AUC for SW elastography of liver, transient elastography of liver, and SW elastography of spleen was, respectively, 0.86, 0.80, and 0.81 for fibrosis (≥F1 stage); 0.88, 0.78, and 0.82 for moderate fibrosis (≥F2 stage); 0.93, 0.83, and 0.83 for severe fibrosis (≥F3 stage); and 0.98, 0.92, and 0.84 for cirrhosis (F4 stage). SW elastography of liver showed significantly higher accuracy than transient elastography of liver and SW elastography of spleen in all fibrosis stages (P = .01-.04). SW elastography of spleen showed similar accuracy with transient elastography of liver (P = .21-.99). Combination SW elastography of liver and SW elastography of spleen to predict fibrosis staging showed diagnostic accuracy not further improved compared with SW elastography of liver alone (similar AUC; ≥F1, P = .87; ≥F2, P = .81; ≥F3, P = .84; ≥F4, P = .88). SW elastography of liver had higher successful rate than transient elastography of liver (98.9% vs 89.6%). Prevalence of discordance in at least two stages with liver histologic staging was 10.2% (23 of 226) for SW elastography of liver and 28.2% (58 of 206) for SW elastography of spleen.Conclusion:SW elastography provides more accurate correlation of liver elasticity with liver fibrosis stage compared with transient elastography, especially in identification of stage F2 or greater.© RSNA, 2013. 23876099 Limited Utility of Fluorescence in Situ Hybridization for Common Abnormalities of Myelodysplastic Syndrome at First Presentation and Follow-up of Myeloid Neoplasms. ABSTRACT Fluorescence in situ hybridization for abnormalities common to myelodysplastic syndrome (MDS FISH) is often used with traditional karyotype in the diagnosis and monitoring of myeloid neoplasms. However, its value in these roles has been questioned. To evaluate its utility, we compared MDS FISH results with karyotype in 544 bone marrow specimens obtained for diagnosis (180 cases) or follow-up (364 cases) of myeloid neoplasia. We found excellent concordance between FISH and karyotype, such that FISH is rarely abnormal (1.7% at diagnosis and 3.0% at follow-up) in cases with normal karyotype. Even in the rare discordant cases, the abnormal FISH has little or no clinical value. Thus, we propose that this test should be limited to cases with inadequate karyotype only. Such guidelines could result in significant cost savings with no impact on patient diagnosis. 23934300 Mechanisms on electrical breakdown strength increment of polyethylene by acetophenone and its analogues addition: a theoretical study. A theoretical investigation is completed on the mechanism of electrical breakdown strength increment of polyethylene. It is shown that it is one of the most important factors for increasing electrical breakdown strength of polyethylene through keto-enol isomerization of acetophenone and its analogues at the ground state S0 and the lowest triplet state T1. The minimum structures and transition states of the keto- and the enol-tautomer of acetophenone and its analogues at the S0 and T1 states are obtained at the B3LYP/6-311+G(d,p) level, as well as the harmonic vibration frequencies of the equilibrium geometries and the minimum energy path (MEP) by the intrinsic reaction coordinate (IRC) theory at the same level. The two C-C bond cleavage reaction channels have been identified in acetophenone. The calculated results show that the energy barriers of keto-enol isomerization of acetophenone and its analogues at S0 and T1 states are much smaller than the average C-C bond energy of polyethylene, and the acetophenone doping or bond linked into polyethylene can increase the electrical breakdown strength and inhibit polyethylene electrical tree initiation and aging. 23265500 Effects of ozone microbubble treatment on removal of residual pesticides and quality of persimmon leaves. This study investigated the effects of ozone microbubble (OMCB) treatment on the removal of residual fenitrothion (FT) and benomyl pesticides from red and green persimmon leaves, and also the treatment effect on the leaf colours, physical properties and flavour. The continuous bubbling OMCB treatment was more effective than the non-bubbling OMCB treatments at reducing the FT and benomyl agricultural pesticide residues from both the red and green persimmon leaves. Moreover, the bubbling OMCB treatment had no effect on the colour and pulling strength of the leaves. These results indicate that the treatment by bubbling OMCB is an extremely effective method for removing the residues of FT and benomyl in persimmon leaves and has relatively little effect on leaf quality characteristics. 23603902 The structure of the biliverdin cofactor in the Pfr state of bathy and prototypical phytochromes. The structures of the chromophore binding pockets in the Pfr states of various bathy and prototypical biliverdin-binding phytochromes were analysed by using a combined spectroscopic-theoretical approach. For the Pfr state of the bathy phytochrome from Pseudomonas aeruginosa (PaBphP) the very good agreement between calculated Raman spectra of the tetrapyrrole cofactor, obtained by quantum-mechanical / molecular-mechanical hybrid methods, and the experimental resonance Raman (RR) spectra confirms important conclusions derived from the previous crystallographic analyses, particularly the ZZEssa configuration of the chromophore and its attachment to the thiol side chain of Cys12 via the exocyclic vinyl group of ring A. The match between the RR spectra of the Pfr states of PaBphP and the bathy phytochrome Agp2 from Agrobacterium tumefaciens indicates very similar structures of the chromophore binding pockets. The homogeneous chromophore conformation in bathy phytochromes is in sharp contrast to the Pfr states of prototypical phytochromes as demonstrated by comparative RR spectroscopic analyses. The Pfr states of prototypical phytochromes, thoroughly studied for Agp1 (A. tumefaciens), display conformational equilibria between two sub-states differing with respect to the CD methine bridge torsional angle and the AB methine bridge geometry. These differences may mainly root in the interactions of the cofactor with the highly conserved Asp194 (PaBphP) that occur via its carboxylate function in bathy phytochromes. The weaker interactions via the carbonyl function in prototypical phytochromes may lead to a higher structural flexibility of the chromophore binding pocket that opens the reaction channel for the thermal (ZZE → ZZZ) Pfr-to-Pr back-conversion. 23640894 X-ray structure analysis and characterization of AFUEI, an elastase inhibitor from Aspergillus fumigatus. Elastase from Aspergillus sp. is an important factor for aspergillosis. AFUEI is an inhibitor of the elastase derived from Aspergillus fumigatus. AFUEI is a member of the I78 inhibitor family, and has a high inhibitory activity against elastases of Aspergillus fumigatus and Aspergillus flavus, human neutrophil elastase and bovine chymotrypsin, but does not inhibit bovine trypsin. Here we report the crystal structure of AFUEI in two crystal forms. AFUEI is a wedge-shaped protein composed of an extended loop and a scaffold protein core. The structure of AFUEI shows remarkable similarity to serine protease inhibitors of the potato inhibitor I family, although they are classified into different inhibitor families. A structural comparison with the potato I family inhibitors suggests that the extended loop of AFUEI corresponds to the binding loop of the potato inhibitor I family and AFUEI inhibits its cognate proteases through the same mechanism as the Potato I family inhibitors. 23744273 Deletion of integrin-linked kinase from neural crest cells in mice results in aortic aneurisms and embryonic lethality. Neural crest cells (NCCs) participate in the remodeling of the cardiac outflow tract and pharyngeal arch arteries during cardiovascular development. Integrin-linked kinase (ILK) is a serine/threonine kinase and a major regulator of integrin signaling. It links integrins to the actin cytoskeleton and recruits other adaptor molecules into a large complex to regulate actin dynamics and integrin function. Using the Cre-lox system, we deleted Ilk from NCCs of mice to investigate its role in NCC morphogenesis. The resulting mutants developed a severe aneurismal arterial trunk that resulted in embryonic lethality during late gestation. Ilk mutants showed normal cardiac NCC migration but reduced differentiation into smooth muscle within the aortic arch arteries and the outflow tract. Within the conotruncal cushions, Ilk-deficient NCCs exhibited disorganization of F-actin stress fibers and a significantly rounder morphology with shorter cellular projections. Additionally, absence of ILK resulted in reduced in vivo phosphorylation of Smad3 in NCCs, which correlated with reduced αSMA levels. Our findings resemble those seen in Pinch1 and β1 integrin conditional mutant mice, and therefore support that, in neural crest-derived cells, ILK and Pinch1 act as cytoplasmic effectors of β1 integrin in a pathway that protects against aneurysms. In addition, our conditional Ilk mutant mice might prove useful as a model to study aortic aneurysms caused by reduced Smad3 signaling, as occurs in the newly described aneurysms-osteoarthritis syndrome, for example. 23701996 Circulating CD31+ leukocyte frequency is associated with cardiovascular risk factors. CD31 identifies a heterogeneous population of cells in the blood, consisting of mature leukocytes and platelets, as well as smaller numbers of endothelial and progenitor cells. Because unfractionated CD31+ blood cells have demonstrated angiogenic properties in vivo, we hypothesized that circulating CD31+ cells would be related to the presence of cardiovascular risk factors in humans. We studied 1487 participants, free of cardiovascular disease, from the Framingham Offspring Study. Using anti-human CD31 and CD45 antibodies, distinct CD31+/CD45+ leukocyte populations were enumerated in blood samples by FACS analysis. We used linear regression analyses to investigate the relation of each cell phenotype with cardiovascular risk factors. We identified 3 distinct leukocyte populations: CD31-, CD31 dim, and CD31 bright cells. Using forward/side scatter analyses, CD31- and CD31 dim cells mapped to lymphoid gates while CD31 bright cells were monocytoid. In multivariable analyses, higher frequency of CD31 bright cells was associated with older age, male sex, HDL cholesterol, and CRP (all P < 0.01). In contrast, CD31 dim was inversely associated with age, male sex, CRP, and smoking (all P < 0.01). Framingham Risk Score was positively associated with CD31 bright frequency (P = 0.002), and negatively associated with CD31 dim frequency (P = 0.020). CD31+ staining identifies 2 major leukocyte populations, CD31 bright and CD31 dim, which demonstrated significant and opposite associations with cardiovascular risk in humans. Further research is needed to define the biological and potential therapeutic roles of CD31+ subpopulations in vascular disease. 23424090 Studies of the metabotropic glutamate receptor 5 radioligand [¹¹C]ABP688 with N-acetylcysteine challenge in rhesus monkeys. Detecting changes in receptor binding at the metabotropic glutamate receptor 5 (mGluR5) with the PET allosteric antagonist, [¹¹C]ABP688, may be valuable for studying dysfunctional glutamate transmission associated with psychiatric illnesses. This study was designed to validate the findings of a recent pilot study in baboons which reported a significant global decrease from baseline [¹¹C]ABP688 binding after increasing endogenous glutamate with 50 mg/kg N-acetylcysteine (NAC), with no change from test to retest. In rhesus monkeys (n = 5), paired [¹¹C]ABP688 scans were performed on the same day on the Focus-220 as follows (n = 3 per group): test-retest, baseline-NAC (50 mg/kg), and baseline-NAC (100 mg/kg). Multiple modeling methods were evaluated for kinetic analysis to estimate the total volume of distribution (VT ) and non-displaceable binding potential (BP(ND)) in regions-of-interest (ROIs), with the cerebellum gray matter (CGM) as the reference region. There was an increasing trend from test to retest BP(ND) across ROIs (13%). NAC (50 mg/kg and 100 mg/kg) increased VT (5% and 19%) and decreased BP(ND) (3% and 10%), respectively, significant only for VT in ROIs at the 100 mg/kg dose. High intersubject variability in BP(ND) was comparable to that reported in the baboon study. However, interpretability of BP(ND) is difficult with increases in VT in the CGM reference region at the higher NAC dose. Additionally, the net reduction in BP(ND) from the baseline-NAC scans may be obscured due to observed increases in test-retest BP(ND). Thus, we did not strictly replicate the findings in the baboon study based on BP(ND). 23443934 Phylogenetic analysis of two Chinese orf virus isolates based on sequences of B2L and VIR genes. Orf virus (ORFV) is an enveloped virus with a double-stranded DNA genome, causing a contagious pustular dermatitis, mainly in goats and sheep. In this study, two strains of ORFV were isolated from sheep and goat samples in Xinjiang and Shaanxi, China. The B2L and virus interferon resistance (VIR) genes of these two isolates were sequenced and analyzed after PCR amplification. Phylogenetic analysis showed that the two isolates clustered with other ORFV strains but were separated into different subgroups. The Xinjiang strain shared the highest homology with the Gansu strain, whereas the Shaanxi strain shared higher homology with the Taiwan and Hubei strains. This is the first report of the molecular characterization of ORFV in Northwest China, and it provides new information on the genotyping of the causative agents responsible for contagious ecthyma dermatitis outbreaks in China. 23379995 Multifunctional conducting fibres with electrically controlled release of ciprofloxacin. We hereby present a new method of producing coaxial conducting polymer fibres loaded with an antibiotic drug that can then be subsequently released (or sustained) in response to electrical stimulation. The method involves wet-spinning of poly(3,4-ethylenedioxythiophene) poly(styrenesulfonate) (PEDOT:PSS) fibre, which served as the inner core to the electropolymerised outer shell layer of polypyrrole (Ppy). Ciprofloxacin hydrochloride (Cipro) was selected as the model drug and as the dopant in the Ppy synthesis. The release of Cipro in phosphate buffered saline (PBS) from the fibres was controlled by switching the redox state of Ppy.Cipro layer. Released Cipro under passive and stimulated conditions were tested against Gram positive (Streptococcus pyogenes) and Gram negative (Escherichia coli) bacteria. Significant inhibition of bacterial growth was observed against both strains tested. These results confirm that Cipro retains antibacterial properties during fibre fabrication and electrochemically controlled release. In vitro cytotoxicity testing utilising the neural B35 cell line confirmed the cytocompatibility of the drug loaded conducting fibres. Electrical conductivity, cytocompatibility and tuning release profile from this flexible fibre can lead to promising bionic applications such as neuroprosthetics and localised drug delivery. 23836254 Ionic liquid lubrication: influence of ion structure, surface potential and sliding velocity. Colloid probe atomic force microscopy (AFM) has been employed to investigate the nanotribology of the ionic liquid (IL)-Au(111) interface. Data is presented for four ILs, 1-ethyl-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate ([EMIM] FAP), 1-butyl-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate ([BMIM] FAP), 1-hexyl-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate ([HMIM] FAP) and 1-butyl-3-methylimidazolium iodide ([BMIM] I), at different Au(111) surface potentials. Lateral forces vary as a function of applied surface potential and ion structure because the composition of the confined ion layer changes from cation-enriched (at negative potentials) to mixed (at 0 V), and to anion-enriched (at positive potentials). ILs with FAP(-) anions all exhibit similar nanotribology: low friction at negative potentials and higher friction at positive potentials. [BMIM] I displays the opposite behaviour, as an I(-) anion-enriched layer is more lubricating than either the [BMIM](+) or FAP(-) layers. The effect of cation charged group (charge-delocalised versus charged-localised) was investigated by comparing [BMIM] FAP with 1-butyl-1-methylpyrrolidinium tris(pentafluoroethyl)trifluorophosphate ([Py1,4] FAP). [BMIM] FAP is less lubricating at negative potentials, but more lubricating at positive potentials. This indicated that even at positive potentials the cation concentration in the boundary layer is sufficiently high to influence lubricity. The influence of sliding velocity on lateral force was investigated for the [EMIM] FAP-Au(111) system. At neutral potentials the behaviour is consistent with a discontinuous sliding process. When a positive or negative potential bias is applied, this effect is less pronounced as the colloid probe slides along a better defined ion plane. 23224515 Viewing social scenes: a visual scan-path study comparing fragile x syndrome and williams syndrome. Fragile X syndrome (FXS) and Williams syndrome (WS) are both genetic disorders which present with similar cognitive-behavioral problems, but distinct social phenotypes. Despite these social differences both syndromes display poor social relations which may result from abnormal social processing. This study aimed to manipulate the location of socially salient information within scenes to investigate the visual attentional mechanisms of: capture, disengagement, and/or general engagement. Findings revealed that individuals with FXS avoid social information presented centrally, at least initially. The WS findings, on the other hand, provided some evidence that difficulties with attentional disengagement, rather than attentional capture, may play a role in the WS social phenotype. These findings are discussed in relation to the distinct social phenotypes of these two disorders. 23429044 Effects of maternally exposed coloring food additives on receptor expressions related to learning and memory in rats. Exposure to artificial food colors and additives (AFCAs) has been implicated in the induction and severity of some childhood behavioral and learning disabilities. N-methyl-D-aspartate receptors (NMDARs) and nicotinic acetylcholine receptors (nACHRs) are thought to be effective in the learning and memory-generating process. In this study, we investigated the effects of intrauterine exposure to AFCAs on subunit concentrations of NMDARs and nAChRs isoforms in rats. We administered a mixture of AFCAs (Eritrosin, Ponceau 4R, Allura Red AC, Sunset Yellow FCF, Tartrazin, Amaranth, Brilliant Blue, Azorubin and Indigotin) to female rats before and during gestation. The concentration of NR2A and NR2B subunits and nAChR α7, α4β2 isoforms in their offspring's hippocampi were measured by Western Blotting. Expressions of NR2B and nAChR β2 were significantly increased (17% and 6.70%, respectively), whereas expression of nAChR α4 was significantly decreased (5.67%) in male experimental group compared to the male control group (p<0.05). In the female experimental group, AFCAs caused a 14% decrease in NR2B expression when compared to the female control group (p<0.05). Our results indicate that exposure to AFCAs during the fetal period may lead to alterations in expressions of NMDARs and nAChRs in adulthood. These alterations were different between male and female genders. 23712483 Amine-N-heterocyclic carbene cascade catalysis for the asymmetric synthesis of fused indane derivatives with multiple chiral centres. An aminocatalytic asymmetric Diels-Alder reaction of 2,4-dienals and labile 1-indenones in situ generated from 3-bromo-1-indanones was developed, producing highly fused indane products with multiple chiral centres followed by a cascade N-heterocyclic carbene-mediated benzoin condensation. 23959194 ADIBO-Based "Click" Chemistry for Diagnostic Peptide Micro-Array Fabrication: Physicochemical and Assay Characteristics. Several azide-derivatized and fluorescently-labeled peptides were immobilized on azadibenzocyclooctyne (ADIBO)-activated slide surfaces via a strain-promoted alkyne-azide cycloaddition (SPAAC) reaction revealing excellent immobilization kinetics, good spot homogeneities and reproducible fluorescence signal intensities. A myc-peptide micro-array immunoassay showed an antibody limit-of-detection (LOD) superior to a microtiter plate-based ELISA. Bovine serum albumin (BSA) and dextran covalently attached via "click" chemistry more efficiently reduced non-specific binding (NSB) of fluorescently-labeled IgG to the microarray surface in comparison to immobilized hexanoic acid and various types of polyethylene glycol (PEG) derivatives. Confirmation of these findings via further studies with other proteins and serum components could open up new possibilities for human sample and microarray platform-based molecular diagnostic tests. 23821564 A high-throughput system for boron microsublimation and isotope analysis by total evaporation thermal ionization mass spectrometry. Research on the ocean carbon cycle is vitally important due to the projected impacts of atmospheric CO2 on global temperatures and climate change, but also on ocean chemistry. The direct influence of this CO2 rise on the seawater pH can be evaluated from the boron isotopic composition in biogenic carbonates; however, conscientious laboratory techniques and data treatment are vital in obtaining accurate and precise results. A rapid-throughput boron purification and Total Evaporation Thermal Ionization Mass Spectrometry method was developed for high accuracy and precision boron isotopic analysis for small (ng) sample sizes. An improved microsublimation method, in which up to 20 samples can be processed simultaneously under identical temperature conditions, was developed. Several tests have confirmed the viability of this technique. First, seawater and Porites coral samples were processed with H2 O2 and the results compared with those obtained using microsublimation; second, the impact of various sublimation times was evaluated; and third, quantitative recovery was assessed using standard addition. Microsublimation provides a valid method for the quantitative recovery and separation of boron from both major elements and organic matter under low-blank conditions. The close agreement of our results with published values validates the accuracy of the measurements. The isotopic ratio for SRM 951a boric acid isotopic standard was 4.0328 ± 0.0054 (2 STD, n = 25). The reproducibility of boron isotopic composition for standards including AE121, IAEA B-1 and an in-house coral standard UM-CP1 was ±0.68‰ (2 STD, n = 15), ±1.12‰ (2 STD, n = 24), and ±1.17‰ (2 STD, n = 14), respectively. The sample sizes were <1 ng for each measurement. The developed method for preparing and measuring boron isotopic values in a variety of carbonate materials should facilitate the reconstruction of past ocean pH conditions with decadal-scale resolution. 23872787 Solvent-free mechanochemical glycosylation in ball mill. Starting from acetobromosugars and an alcohol (alkyl/substituted alkyl/akenyl/alkynyl/glyceryl/cyclohexyl/steryl) various O-glycosides have been prepared mechanochemically under solvent-free conditions employing a planetary ball mill in the presence of metal carbonates (environmentally benign or otherwise) as promoters. The method was proven to be mild and efficient and applicable on preparative scale for the synthesis of various mono- and disaccharide glycosides. 4-Pentenyl glycoside so produced could, in four successive reactions in the same pot, be converted in high isolated yields into triazole-substituted pentyl glycoside that can find application in the area of medicinal chemistry. 23928313 Direct stent puncture technique for intraluminal stent recanalization in the superficial femoral and popliteal arteries in-stent occlusion: Outcomes from a prospective clinical analysis of diabetics with critical limb ischemia. To evaluate the efficacy and safety of "Direct Stent Puncture" technique for intraluminal stent recanalization in the femoro-popliteal segments. A cohort of diabetics who had symptomatic in-stent occlusion of the superficial femoral or popliteal arteries underwent endovascular recanalization. After antegrade failure, direct stent puncture technique was performed. The primary end-point was to efficacy assessment, intended as technical success and clinical improvement. The secondary end-point was safety assessment, intended as free of complication rate. Fifty-four patients (37 men; 73.6±8.5years) underwent direct stent puncture technique, after several unsuccessful antegrade attempts to cross the occluded stent. Technical success for intraluminal stent recanalization was achieved in 53/54 (98.2%) of cases and failed in 1/54 (1.8%). Clinical improvement was obtained in 51/54 (94.4%) of cases, with regression of the clinical symptoms and improvement of the TcPO2, from 3±18mmHg to 43±11mmHg after 15days (p<0.001). Free of complications rate was 92.5%. In 2/54 (3.7%) of cases distal embolization occurred, in 1/54 (1.9%) case a sudden vessel thrombosis was diagnosed after 12hours and in 1/54 (1.9%) case hematoma at the stent puncture site was observed. Direct Stent Puncture technique is an efficacy and safety option for intraluminal stent recanalization in the femoro-popliteal segment in-stent occlusion. 23463696 Gram-scale synthesis of graphene sheets by a catalytic arc-discharge method. Flake graphite is used as carbon source and ZnO or ZnS as catalyst in the synthesis of high-quality graphene sheets. A catalytic growth mechanism for cathode-part graphene synthesis in the arc-discharge apparatus and an exfoliation mechanism for wall-part graphene synthesis are introduced. N-doped cathode-part graphene and undoped wall-part graphene are formed simultaneously. 23389640 The association between fecal incontinence and sexual activity and function in women attending a tertiary referral center. To determine whether fecal incontinence (FI) is associated with sexual activity and to compare sexual function in women with and without FI. We conducted a retrospective chart review of all new patients seen in an academic urogynecology clinic. Women who reported fecal incontinence, as defined by loss of fecal material on the Wexner scale, were compared with those without fecal incontinence. We compared sexual activity and Pelvic Organ Prolapse Incontinence Sexual Questionnaire-12 (PISQ-12) scores between groups. In our population of women with pelvic floor disorder, 588 women reported FI compared with 527 who did not. On multivariate analysis, FI was not associated with sexual activity status, but was associated with worsened PISQ-12 scores (p < 0.001). PISQ-12 item analysis found that women with FI reported more dyspareunia, fear, and avoidance of sexual activity with greater partner problems (all p <0.05) than women without FI. Women with FI were as likely to engage in sexual relations as women without FI; however, sexually active women with FI had poorer sexual function than those without FI. 23791149 Development of a liquid chromatography-electrospray chemical ionization tandem mass spectrometry analytical method for analysis of eleven hydroxylated polybrominated diphenyl ethers. Recently, hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have emerged as environmentally relevant pollutants due to recent reports of their natural production and metabolism. Recent mechanistic studies in human and rats have shown that some OH-PBDEs are more potent than parent compounds (PBDEs) and may contribute substantially to neurodevelopmental disorders by direct neurotoxicity, or indirectly through altered thyroid disruption. However, analytical methodologies for determination of OH-PBDEs are currently limited. In this study a robust liquid chromatography-electrospray tandem triple quadrupole-linear ion trap mass spectrometer (LC-ESI-QqLIT-MS-MS) in negative mode method was developed for the determination of eleven OH-tri- to OH-hexa-PBDEs. Two different columns were tested and compared for chromatographic separation: a C18 BetaBasic and a Purospher STAR RP 18, working at pH 8 and 10, respectively. Mobile phase (acetonitrile:water) was optimized by changing the pH of the aqueous phase and the concentration of the organic modifier (methanol). The MS-MS parameters (declustering potential (DP), collision energy (CE) and cell exit potential (CXP)) were optimized. Selected reaction monitoring (SRM) was used in order to increase sensitivity. Two SRM transitions ([M-H](-)>[Br](-)) were selected for each OH-PBDE, one for quantification and the second one for confirmation. Under the optimized conditions, the instrumental limits of detection were between 0.17 and 0.72injectedpg. The method provided good linearity (r>0.99 for a concentration range of 0.30-100ng/mL), accuracy and precision (%Dev and %RSD≤20% for intra- and inter-assays). 23792238 Density functional theory study, FT-IR and FT-Raman spectra and SQM force field calculation for vibrational analysis of 1, 3-Bis (hydroxymethyl) benzimidazolin-2-one. FT-IR and FT-Raman spectra of 1, 3-Bis (hydroxymethyl) benzimidazolin-2-one were recorded and analyzed in the solid phase. The optimized molecular geometry and vibrational wavenumbers have also been calculated in optimized structure by using DFT method. Scaled quantum mechanical force fields have also been used to calculate potential energy distributions in order to make conspicuous vibrational assignments. The red shifting of the OH stretching wavenumber is due to the formation of OH⋯O intermolecular hydrogen bonding. The lowering and splitting of the carbonyl stretching vibrational modes is assigned to the intermolecular association based on CO⋯H type hydrogen bonding in the molecule. Chemical interpretation of hyperconjugative interactions was done by natural bond orbital analysis. 23942055 A longitudinal examination of psychosocial impairment across the anxiety disorders. Anxiety disorders are highly prevalent disorders associated with substantial psychosocial impairment, but few studies have examined impairment within specific anxiety disorders. Furthermore, it is unclear how change in different types of anxiety has an impact on change in impairment, particularly given high rates of co-morbidity. The current study assessed the temporal associations of impairment and symptoms of three common anxiety disorders in a large, diagnostically heterogeneous clinical sample. Method Data were collected from 606 treatment-seeking individuals at an anxiety clinic, most of whom subsequently enrolled in cognitive-behavioral therapy. Symptoms of panic, social anxiety and generalized anxiety disorder (GAD), as well as levels of impairment, were assessed three times over 2 years. In addition to examining levels of impairment across diagnostic groups, latent growth modeling was used to evaluate the longitudinal associations of anxiety symptoms and impairment. Those with a principal diagnosis of GAD reported higher levels of impairment in some domains at baseline; however, at follow-up assessments individuals with social anxiety disorder reported greater impairment than those with panic disorder. Anxiety symptoms and impairment both declined over time. Change in all three anxiety symptoms was closely associated with change in impairment, but only GAD remained a significant (positive) predictor of change in impairment after accounting for co-morbidity. Impairment and all three anxiety disorders were closely associated, both cross-sectionally and longitudinally. Because change in GAD was most specifically related to change in impairment, treatment for those with multiple anxiety disorders could focus on treating GAD symptoms first or treating transdiagnostic processes. 23319075 Long-term physicochemical and immunological stability of a liquid formulated intact ovine immunoglobulin-based antivenom. An antivenom should be stable under the conditions that it will be both transferred and stored. Thus instability may lead to a loss of efficacy and an increased incidence and severity of adverse effects. Stability is a particular problem in countries where the temperatures and humidity are high. Here we investigate the stability of a liquid-formulated, intact ovine immunoglobulin-based antivenom, EchiTAbG™, which is used extensively in Nigeria to treat envenoming by the West African saw-scaled viper, Echis ocellatus. Ampoules of antivenom were assessed as to their specific antibody content by small scale affinity chromatography and their purity by size exclusion gel filtration and turbidity. Three different batches of the antivenom revealed no significant changes, using these assessment techniques, during 42 months storage at 4 °C or at ambient temperature, followed by one month at 37 °C. These real-time studies indicate that the antivenom remains stable for a minimum of 3.5 years and that it can be exposed to tropical temperatures without any loss in immunoglobulin binding activity. This further highlights the clinical utility of liquid formulated ovine IgG antivenoms by demonstrating their retention of potency in the event of a short term failing in the cold chain. 23955647 Vitamin D deficiency does not predict progression of coronary artery calcium, carotid intima-media thickness or high-sensitivity C-reactive protein in systemic lupus erythematosus. Objective. Vitamin D deficiency is common in SLE. Cardioprotective effects of vitamin D have been postulated due to modulation of inflammatory cytokines. However, the effects of vitamin D supplementation on inflammatory cytokines in trials have been inconsistent. We determined whether levels of vitamin D at baseline were associated with subclinical measures of atherosclerosis, or with changes in subclinical measures over 2 years.Methods. Of the 200 patients enrolled in the Lupus Atherosclerosis Prevention Study, complete baseline and follow-up data [including coronary artery calcium (CAC), carotid intima-media thickness (IMT), 25-hydroxy vitamin D [25(OH)D] and high-sensitivity CRP (hsCRP) levels] were available for 154 patients. Assessments were repeated 2 years later.Results. 25(OH)D values ranged from 4 to 79 ng/ml. Among African American patients, 25(OH)D values ranged from 4 to 55 ng/ml. With low 25(OH)D (vitamin D <21 ng/ml), a higher proportion had a CAC score >100 (11%) compared with those with vitamin D insufficiency (21-32 ng/ml) (10%) and normal (≥32 ng/ml) 25(OH)D (3%), which was not statistically significant. 25(OH)D was neither associated with nor did it predict progression of CAC or carotid IMT over 2 years. The mean hsCRP decreased over 2 years.Conclusion. 25(OH)D was not associated with any measure of subclinical atherosclerosis. 25(OH)D deficiency was associated with higher hsCRP at baseline, but did not predict a change in hsCRP over 2 years. 23587852 Cocoon formation in patients with midgut neuroendocrine tumors: a rare and unrecognized final pathway. Neuroendocrine tumors (NETs) are relatively rare with an indolent nature. As a result, treatment is often delayed and passive. The most commonly recognized disease progression leading to death is from the sequelae of bowel obstruction, ischemia, or liver failure secondary to liver metastasis. We recently recognized a rare cocoon-like formation in patients with metastatic gastroenteropancreatic NETs and hypothesize that this may be a distinct, final pathway for these patients. Ten patients with stage IV gastroenteropancreatic NETs, seen at our center between October 2008 and November 2011, who developed a cocoon were identified. Patient's charts, operative reports, pathology, and tumor markers were reviewed. No discernable predictors were identified as precursors to this condition. One patient survived 13 months after cocoon diagnosis, and the remaining 9 patients were all deceased within 5 months. Surgical treatment was attempted in 6 patients and was only partially successful in 1 patient who had the earliest stage of cocoon formation (type 1). Cocoon-like formations in patients with stage IV gastroenteropancreatic NETs is rare and may be a terminal disease progression that has not been previously recognized. The best treatment option remains unknown. Surgical treatment is not advisable, with the exception of type 1 abdominal cocoons. 23696009 Synthesis, redox activity of rigid ferrocenyl dendrimers, and isolation of robust ferricinium and class-II mixed-valence dendrimers. The coupling reactions of ethynylferrocene with trihalogenoarenes do not lead to ethynylferrocenyl arenes that are soluble enough to form the basis of a suitable construction of stiff ferrocenylethynyl arene-cored dendrimers, which explains the previous lack of reports on stiff ferrocenyl dendrimers. However, rigid ferrocenyl-terminated dendrimers have been synthesized from 1,3,5-tribromo- and triiodobenzene through Sonogashira and Negishi reactions with 1,2,3,4,5-pentamethyl-1'-ethylnylferrocene (1a), according to 1→2 connectivity. With compound 1a, the construction of a soluble dendrimer (10a) that contained 12 ethynylpentamethylferrocenyl termini was achieved. Stiff dendrimer 10a shows a single, reversible cyclic voltammetry (CV) wave (with adsorption), which disfavors the hopping heterogeneous electron-transfer mechanism that is postulated for redox-terminated dendrimers that contain flexible tethers. The selectivity of these Sonogashira reactions allows the synthesis of an arene-cored dendron (2c) that contains both ethynylferrocenyl and 1,2,3,4,5-pentamethyl-ferrocenylethynyl redox groups, thus leading to the construction of a dendrimer (7c) that contains both types of differently substituted ferrocenyl groups with two well-separated reversible CV waves. Upon selective oxidation, this mixed dendrimer (7c) leads to a class-II mixed-valence dendrimer, 7c[PF6]3, as shown by Mössbauer spectroscopy, whereas oxidation of the related fully pentamethylferrocenylated dendrimer (7a) leads to the all-ferricinium dendrimer, 7a[PF6]6. 23938445 A novel solid-state electrochemiluminescence sensor for the determination of hydrogen peroxide based on an Au nanocluster-silica nanoparticle nanocomposite. A gold nanocluster@bovine serum albumin-silica nanoparticle composite has been synthesized and used for the solid-state electrochemiluminescence (ECL) sensing of hydrogen peroxide. The ECL characteristics have also been studied. 23948311 Modeling of the thermoluminescence mechanisms in ZrO2. In this paper, simulations of thermoluminescence experiments are carried out using the comprehensive model for thermoluminescence cited in the literature by several authors, for both natural and laboratory irradiated aliquots. In the present work, we propose a possible, alternative model to explain the thermoluminescence (TL) process in zirconium oxide (ZrO2). The model includes four trapping states and one recombination center (4T1C model). The aim of the present study is to present a model that, by using as guess values the parameters obtained by employing the GOK model, fits very well the experimental glow curve. It is a goal point that the physical model does not need to resort to the quasi-equilibrium approximation. The results of these simulations are in general qualitative agreement with the experiments and confirm that the proposed model in this study presents a good explanation of these phenomena. A linear behavior was also observed between the response and dose range from 1×10(9) to 9×10(9)cm(-3). 23931989 K(+) channel regulation of multicompartmental signal integration. Determining how neurons integrate different streams of information is critical to understanding circuit computational functions. In this issue of Neuron, Harnett et al. (2013) show that voltage-gated K(+) channels control multiple layers of dendritic integration in layer 5 pyramidal neurons. 23959087 Catheter-associated bloodstream infection after bowel surgery in patients with inflammatory bowel disease. Catheter-associated bloodstream infections (CABSIs) are a leading cause of nosocomial infections. The objectives of this study were to establish the incidence of CABSIs after bowel surgery and to identify the risk factors. We reviewed the prospectively collected data of patients who underwent abdominal surgery with central venous catheter (CVC) insertion between March, 2006 and September, 2009. We analyzed all possible variables, including age, sex, disease, CVC duration, insertion frequency, CVC site, infliximab, corticosteroid, and immunosuppressant administration, preoperative serum albumin level, surgical wound class, and emergency surgery. A total of 1261 patients were prospectively surveyed. The underlying diseases comprised ulcerative colitis (UC; n = 428), Crohn's disease (CD; n = 334), colorectal cancer (CA; n = 344), esophageal cancer (ESO; n = 28), gastric cancer (GAST; n = 44), and others (n = 83). The incidences of CABSI were 6.9/1000 catheter days for UC, 7.4 for CD, 4.3 for CA, 3.7 for ESO, 3.7 for GAST, and 5.1 for others. CD patients had the highest rate of CABSI. The risk factors for CABSI were CD with an odds ratio (OR) of 1.63, dirty/infected wound class (OR 3.34), and CVC insertion via the internal jugular vein (OR 9.89). A high CABSI incidence was found in association with CD, especially in dirty/infected surgery. Thus, the use of CVCs should be restricted in the presence of these risk factors. 23735839 Identification of genes influencing formation of the Type III Brush Hair in Yangtze River Delta white goats by differential display of mRNA. Yangtze River Delta white goat is an exclusive indigenous Chinese goat breeds that can produce Brush Hair specialized in making valuable writing brush. The high-grade (Type III) Brush Hair is conical coarse hair but with a tip, which only grows in the cervical carina and back regions of Yangtze River Delta white goats. Screening of genes influencing the formation of Type III Brush Hair was conducted using differential display of mRNA technique in skin including the hair follicles of different goat groups and the differential bands were identified using reverse Northern dot blot, and the positive bands were subsequently cloned and sequenced. The results showed that 20 differentially displayed bands were obtained, seven of which were identified positive as expressed in skin. Three of these seven cDNAs were homologous to certain sequences from GenBank and the other four were respectively homologous to CKLF-like MARVEL transmembrane domain containing 3 (CMTM3), S100 calcium binding protein A4 (S100A4), protein kinase inhibitor gamma (PKIG) and fibulin 1-D. The study would provide a new view to elucidate their roles in hair growth and hair follicle cycle and increase our understanding of the formation of Type III Brush Hair. 23878291 Disorder of sex development as a diagnostic clue in the first Spanish known newborn with P450 oxidoreductase deficiency. We report the first known case of p450 oxidoreductase deficiency (PORD) in a Spanish boy who presented ambiguous genitalia at birth as a unique feature. He had palpable gonads in the inguinal canal and a normal 46,XY karyotype. Blood tests showed increased lanosterol and androgen precursors (17-OH-pregnenolone and 17-OH-progesterone) and low adrenal androgens (dehydroepiandrosterone and its sulfate). Blood pressure and serum electrolytes were normal. As he had low-testosterone response to human chorionic gonadotropin stimulation but responded to exogenous testosterone with phallic growth, male sex was assigned. Testosterone/dihydrotestosterone ratio and inhibin B were normal. Adrenal insufficiency was detected by corticotropin test. Hydrocortisone replacement treatment was administered. Congenital adrenal hyperplasia was ruled out and molecular analysis of POR gene showed the missense mutation p.Gly539Arg in compound heterozygosity located at splice acceptor site of intron 2 and the coding variant p.Gly80Arg. Surgery for cryptorchidism and hypospadias was performed. 23490060 Digoxin Reduces 30-day All-cause Hospital Admission in Older Patients with Chronic Systolic Heart Failure. Heart failure is a leading cause of hospital admission and readmission in older adults. The new United States healthcare reform law has created provisions for financial penalties for hospitals with higher than expected 30-day all-cause readmission rates for hospitalized Medicare beneficiaries aged ≥65 years with heart failure. We examined the effect of digoxin on 30-day all-cause hospital admission in older patients with heart failure and reduced ejection fraction. In the main Digitalis Investigation Group trial, 6800 ambulatory patients with chronic heart failure (ejection fraction ≤45%) were randomly assigned to digoxin or placebo. Of these, 3405 were aged ≥65 years (mean age, 72 years; 25% were women; 11% were nonwhite). The main outcome in the current analysis was 30-day all-cause hospital admission. In the first 30 days after randomization, all-cause hospitalization occurred in 5.4% (92/1693) and 8.1% (139/1712) of patients in the digoxin and placebo groups, respectively, (hazard ratio {HR} when digoxin was compared with placebo, 0.66; 95% confidence interval {CI}, 0.51-0.86; P=.002). Digoxin also reduced both 30-day cardiovascular (3.5% vs 6.5%; HR, 0.53; 95% CI, 0.38-0.72; P<.001) and heart failure (1.7 vs 4.2%; HR, 0.40; 95% CI, 0.26-0.62; P<.001) hospitalizations, with similar trends for 30-day all-cause mortality (0.7% vs 1.3%; HR, 0.55; 95% CI, 0.27-1.11; P=.096). Younger patients were at lower risk of events but obtained similar benefits from digoxin. Digoxin reduces 30-day all-cause hospital admission in ambulatory older patients with chronic systolic heart failure. Future studies need to examine its effect on 30-day all-cause hospital readmission in hospitalized patients with acute heart failure. 23872306 STAT3 mutations identified in human hematological neoplasms induce myeloid malignancies in a mouse bone marrow transplantation model. STAT3 protein phosphorylation is a frequent event in various hematological malignancies and solid tumors. Acquired STAT3 mutations have been recently identified in 40% of patients with T large granular lymphocytic leukemia, a rare T-cell disorder. In this study we investigated the mutational status of STAT3 in a large series of patients with lymphoid and myeloid diseases. STAT3 mutations were identified in 1.6% (4/258) of patients with T-cell neoplasms, in 2.5% (2/79) of patients with diffuse large B-cell lymphoma but in no other B-cell lymphoma patients (0/104) or patients with myeloid malignancies (0/96). Functional in vitro assays indicated that the STAT3Y640F mutation leads to a constitutive phosphorylation of the protein. STA21, a STAT3 small molecule inhibitor, inhibited the proliferation of two distinct STAT3 mutated cell lines. Using a mouse bone marrow transplantation assay, we observed that STAT3Y640F expression leads to the development of myeloproliferative neoplasms with expansion of either myeloid cells or megakaryocytes. Together, these data indicate that the STAT3Y640F mutation leads to constitutive activation of STAT3, induces malignant hematopoiesis in vivo and may represent a novel therapeutic target in some lymphoid malignancies. 23652723 Laterality affects spontaneous recovery of contralateral hand motor function following motor cortex injury in rhesus monkeys. The purpose of this study was to test whether brain laterality influences spontaneous recovery of hand motor function after controlled brain injuries to arm areas of M1 and lateral premotor cortex (LPMC) of the hemisphere contralateral to the preferred hand in rhesus monkeys. We hypothesized that monkeys with stronger hand preference would exhibit poorer recovery of skilled hand use after such brain injury. Degree of handedness was assessed using a standard dexterity board task in which subjects could use either hand to retrieve small food pellets. Fine hand/digit motor function was assessed using a modified dexterity board before and after the M1 and LPMC lesions in ten monkeys. We found a strong negative relationship between the degree of handedness and the recovery of manipulation skill, demonstrating that higher hand preference was associated with poorer recovery of hand fine motor function. We also observed that monkeys with larger lesions within M1 and LPMC had greater initial impairment of manipulation and poorer recovery of reaching skill. We conclude that monkeys with a stronger hand preference are likely to show poorer recovery of contralesional hand fine motor skill after isolated brain lesions affecting the lateral frontal motor areas. These data may be extended to suggest that humans who exhibit weak hand dominance, and perhaps individuals who use both hands for fine motor tasks, may have a more favorable potential for recovery after a unilateral stroke or brain injury affecting the lateral cortical motor areas than individuals with a high degree of hand dominance. 23831364 Incidence of postoperative elbow contracture release in new york state. To determine the incidence of elbow contracture requiring release after surgically treated elbow trauma and to identify patient, injury, and treatment factors that may predict contracture development. The New York Statewide Planning and Research Cooperative System database identified 32,708 patients who were surgically treated for elbow trauma from 1997 to 2009. The database identified 270 of those patients who underwent subsequent contracture release. The median time from index fracture procedure to contracture release was 31 weeks. Patients requiring a contracture release were younger (43 vs 56 y) and more commonly male (57%). Injuries classified as severe were more common in the contracture group (11% vs 5%), as were open fractures (17% vs 11%). A multivariate regression analysis revealed that patients with burns were 16 times more likely to require surgical contracture release, and the use of internal fixation to treat the fracture was protective against contracture development. The incidence of elbow contractures treated with release after surgically treated elbow trauma was low but increased with the severity of the initial trauma. Prognostic II. 23229494 Anthocyanins protect human endothelial cells from mild hyperoxia damage through modulation of Nrf2 pathway. The detrimental effects of high oxygen supplementation have been widely reported. Conversely, few is known about the effects of exposure to mild hyperoxic conditions, an interesting issue since the use of oxygen-enriched mixture is now increasingly used in clinical practice and especially for professional and recreational reasons. Our study investigated if in vitro exposure of human umbilical vein endothelial cells (HUVECs) to moderate hyperoxia (O2 32 %) induces cellular alterations, measured as changes in cell signaling pathways. Furthermore, by means of an ex vivo experimental model where human volunteers were used as bioreactors, we studied whether anthocyanin metabolites are able to protect HUVECs against mild hyperoxia-induced damage. We observed that the cytotoxic effect of mild hyperoxia came along with a significant decrease in nuclear accumulation of the transcription factor Nrf2, as well as in the expression of Nrf2-regulated antioxidant and cytoprotective genes. Furthermore, under normoxic conditions, anthocyanin metabolites appeared able to activate the Nrf2 pathway, through the involvement of specific kinases (ERK1/2); this adaptive effect may explain the protective effect observed in mild hyperoxia-exposed HUVECs following anthocyanin pretreatment. This study confirms that dietary anthocyanins and/or their metabolites can protect endothelial cells against mild hyperoxia-induced alterations acting as cell signaling modulators. 23745839 Copper-induced deregulation of microRNA expression in the zebrafish olfactory system. Although environmental trace metals, such as copper (Cu), can disrupt normal olfactory function in fish, the underlying molecular mechanisms of metal-induced olfactory injury have not been elucidated. Current research has suggested the involvement of epigenetic modifications. To address this hypothesis, we analyzed microRNA (miRNA) profiles in the olfactory system of Cu-exposed zebrafish. Our data revealed 2, 10, and 28 differentially expressed miRNAs in a dose-response manner corresponding to three increasing Cu concentrations. Numerous deregulated miRNAs were involved in neurogenesis (e.g., let-7, miR-7a, miR-128, and miR-138), indicating a role for Cu-mediated toxicity via interference with neurogenesis processes. Putative gene targets of deregulated miRNAs were identified when interrogating our previously published microarray database, including those involved in cell growth and proliferation, cell death, and cell morphology. Moreover, several miRNAs (e.g., miR-203a, miR-199*, miR-16a, miR-16c, and miR-25) may contribute to decreased mRNA levels of their host genes involved in olfactory signal transduction pathways and other critical neurological processes via a post-transcriptional mechanism. Our findings provide novel insight into the epigenetic regulatory mechanisms of metal-induced neurotoxicity of the fish olfactory system and identify novel miRNA biomarkers of metal exposures. 23884853 Radiologic measurement of submandibular gland ptosis. Objective Ptosis of the submandibular glands is a well-recognized yet poorly quantified element of the aging face and neck. The goal of this study is to describe and quantify the rate and extent of age-related submandibular gland ptosis. A novel grading system is proposed to quantify the degree of descent of the submandibular gland in relation to the inferior border of the mandible. Implications for facial rejuvenation surgery are discussed.Study Design Retrospective review.Methods Consecutive computed tomography (CT) imaging studies performed at a university-affiliated hospital were selected for review. Using cross-referenced images in the coronal and axial planes, distance measurements were obtained from the bottom of the submandibular gland to the plane of the inferior border of the mandible. These data points were plotted against subject age for statistical analysis. The position of the submandibular gland was then categorized as grade I when distance below the mandible was < 20 mm, grade II for 20 to 25 mm, grade III for 25 to 30 mm, and grade IV for > 30 mm. Volumetric analysis was performed in a subset of subjects to assess for the possibility of age-related submandibular gland volume changes as a potential confounding factor in distance measurements.Results One hundred consecutive CT imaging studies were selected for review (50 men, 50 women). A statistically significant linear relationship was identified between subject age and ptosis of the submandibular gland (r = 0.52, p < 0.001), as measured by the distance from the bottom of the submandibular gland from the plane of the inferior border of the mandible. The average rate of descent was 0.17 mm per year. Overall, the position of the submandibular gland was categorized as grade I in 18% of patients, grade II in 27% of patients, grade III in 32% of patients, and grade IV in 23% of patients. No statistically significant gender differences were identified in any of the data points. Volumetric analysis did not demonstrate any age-related changes in submandibular gland volume, and as such, this was excluded as a potential confounding factor in distance measurements.Conclusion A linear relationship exists between patient age and submandibular gland ptosis, as measured by the distance of the gland from the inferior border of the mandible. To our knowledge, this is the first quantification of the rate and extent of submandibular gland ptosis. A novel grading system for submandibular gland ptosis has been proposed. 23866848 Operative diagnosis for revision total hip arthroplasty is associated with patient-reported outcomes (PROs). Little is known about the impact of the reason for revision total hip arthroplasty (THA) on the outcomes following revision THA. In this study, our objective was to assess the association of operative diagnosis with patient-reported outcomes (PROs) after revision THA. We used prospectively collected data from the Mayo Clinic Total Joint Registry that collects pre- and post-operative pain and function outcomes using a validated Hip questionnaire, on all revision THAs from 1993-2005. We used logistic regression to assess the odds of moderate-severe index hip pain and moderate-severe limitation in activities of daily living (ADLs) 2- and 5-years after revision THA. We calculated odds ratios (OR) and 95% confidence intervals (CIs). For the 2- and 5-year cohorts, the operative diagnosis was loosening/wear/osteolysis in 73% and 75%; dislocation/bone or prosthesis fracture/instability or non-union in 17% and 15%; and failed prior arthroplasty with components removed/infection in 11% and 11%, respectively. In multivariable-adjusted analyses that included preoperative ADL limitations, compared to patients with loosening/wear/osteolysis, patients with dislocation/fracture/instability/non-union had OR of 2.2 (95% CI, 1.3-3.5; p = 0.002) for overall moderate-severe ADL limitation and those with failed prior arthroplasty/infection had OR of 1.6 (95% CI, 1.0-2.8; p = 0.06). At 5-years, ORs were lower and differences were no longer significant. Moderate-severe pain did not differ significantly by diagnosis, at 2- or 5-years in multivariable adjusted analyses, with one exception, i.e. failed prior arthroplasty/infection had a trend towards significance with odds ratio of 1.9 (95% CI, 0.9-3.8; p = 0.07). Operative diagnosis is independently associated with ADL limitations, but not pain, at 2-years after revision THA. Patients should be informed of the risk of poorer short-term outcomes based on their diagnosis. 23848066 Fracture Strength and Fracture Patterns of Root-Filled Teeth Restored With Direct Resin Composite Restorations Under Static and Fatigue Loading. SUMMARY Aim : To assess fracture strength and fracture patterns of root-filled teeth with direct resin composite restorations under static and fatigue loading. Methodology : MOD cavities plus endodontic access were prepared in 48 premolars. Teeth were root filled and divided into three restorative groups, as follows 1) resin composite; 2) glass ionomer cement (GIC) core and resin composite; and 3) open laminate technique with GIC and resin composite. Teeth were loaded in a servohydraulic material test system. Eight samples in each group were subjected to stepped fatigue loading: a preconditioning load of 100 N (5000 cycles) followed by 30,000 cycles each at 200 N and higher loads in 50-N increments until fracture. Noncycled teeth were subjected to a ramped load. Fracture load, number of cycles, and fracture patterns were recorded. Data were analyzed using two-way analysis of variance and Bonferroni tests. Results : Fatigue cycling reduced fracture strength significantly (p<0.001). Teeth restored with a GIC core and a laminate technique were significantly weaker than the composite group (379±56 N, 352±67 N vs 490±78 N, p=0.001). Initial debonding occurred before the tooth underwent fracture. All failures were predominantly adhesive, with subcrestal fracture of the buccal cusp. Conclusions : Resin composite restorations had significantly higher fracture strength than did other restorations. Fatigue cycled teeth failed at lower load than did noncycled teeth. 23930712 Effect of diet composition and lysine supply on growth and body composition in juvenile turbot (Psetta maxima). A 10-week feeding trial was conducted to study the effect of feeding level and dietary lysine concentration on growth, protein and lysine retention, and body composition in juvenile turbot. Maintenance requirement for lysine and the efficiency of lysine utilisation were determined as well. Two experimental diets were formulated based on fishmeal or wheat gluten as main protein sources, containing 6.4 g (Diet A, control) and 4.5 g lysine per 100 g CP (Diet B), respectively. Diets were fed once daily at six feeding levels (per day 0.3%, 0.6%, 0.9%, 1.2%, and 1.5% of body weight [BW] and ad libitum) to a total of 432 fish of 48 g initial BW. No differences in the growth parameters were observed between diets at the same feeding level, except a lower feed to gain ratio (p < 0.05) at the highest feeding level at Diet B. Whole-body composition was not affected by diet, whereas muscle protein concentration was significantly lower for fish fed Diet B. Amino acid concentration in whole-body protein was affected by dietary treatment and fish fed Diet B showed lower concentrations of all essential amino acids. In fish muscle protein, lysine, methionine, leucine, isoleucine, and valine concentrations were significantly lower in Diet B. Efficiency of lysine utilisation for growth (klys) was determined by linear regression analysis and amounted for 0.69 for Diet B. The maintenance lysine requirement defined at zero lysine retention was 6.5 mg · kg(-0.8) · d(-1). Lysine intakes at zero protein retention were 13.0 mg and 12.9 mg · kg(-0.8) · d(-1) for Diet A and B, respectively. Growth and nutrient retention were similar for both diets and, therefore, a lysine deficiency in Diet B did not occur. In conclusion, a proportion of 330 g wheat gluten per kg feed did not influence growth performance and maintenance requirement for lysine in juvenile turbot. However, the effect of diet composition on the amino acid profile of body protein might be relevant for the derivation of the amino acid requirement from protein retention. 23915142 Reactivity of Inorganic Mn and Mn Desferrioxamine B with O2, O2(-), and H2O2 in Seawater. Manganese (Mn) is a required element for oceanic phytoplankton as it plays a critical role in photosynthesis, through its unique redox chemistry, as the active site in photosystem II, and in enzymes that act as defenses against reactive oxygen species (ROS), most notably for protection against superoxide (O2(-)), through the action of superoxide dismutase (SOD), and against hydrogen peroxide (H2O2) via peroxidases and catalases. The distribution and redox speciation of Mn in the ocean is also apparently controlled by reactions with ROS. Here we examine the connections between ROS and dissolved Mn species in the upper ocean using field and laboratory experimental data. Our results suggest it is unlikely that significant concentrations of Mn(III) are produced in the euphotic zone, as in the absence of evidence for the existence of strong Mn(III) ligands, Mn(II) reacts with O2(-) to form the short-lived transient manganous superoxide, MnO2(+), which may react rapidly with other redox species in a manner similar to O2(-). Experiments with the strong Mn(III) chelator, desferrioxamine B (DFB), in seawater indicated that the Mn(III) species are unlikely to form, as formation of the precursor Mn(II) complex is hindered due to the stability of the Ca complex with DFB. 23242454 M1 is a major subtype of muscarinic acetylcholine receptors on mouse colonic epithelial cells. Muscarinic acetylcholine receptors (mAChRs) are major regulators of gut epithelial functions. However, the precise subtype composition has not been clarified. We characterized the pharmacological profile of mAChRs on mouse colonic crypts, employing [(3)H]-N-methyl scopolamine chloride as a radioligand and several subtype-selective chemicals, and the functional aspect by measuring short-circuit current (I sc) in Ussing chambers and by evaluating MAP kinase phosphorylation in mouse colonic mucosal sheets. The mAChRs were detected on the crypts (K d = 163.2 ± 32.3 pM, B max = 47.3 ± 2.6 fmol/mg of total cell protein). Muscarinic toxin 7 (MT-7, M1 subtype selective) gave a displacement curve with high affinity, but there was a part insensitive to MT-7 (18.8 ± 0.4 % of the total specific binding). The MT-7-insensitive component was displaced completely by darifenacin (M3 selective) with high affinity. ACh induced an increase in I sc, which was significantly enhanced by MT-7 but was completely inhibited by darifenacin or atropine. Colitis induction resulted in a significant decrease in the density of mAChRs, which occurred mainly in the MT-7-sensitive component (M1 subtype). Immunological experiments exhibited a reduction of M1 but not of M3 signal after colitis induction. Muscarinic stimulation induced an increase in MAP kinase phosphorylation, which was completely suppressed by MT-7 and was attenuated by inflammation, in mouse colonic epithelium. These results suggest that mAChRs in mouse colonic epithelial cells consist of two subtypes, M1 (80 %) and M3 (20 %). The major M1 subtype was likely to regulate epithelial chloride secretion negatively and was susceptible to inflammation and may be relevant to inflammatory gut dysfunction. 23299435 Structure-based redesign of proteins for minimal T-cell epitope content. The protein universe displays a wealth of therapeutically relevant activities, but T-cell driven immune responses to non-"self" biological agents present a major impediment to harnessing the full diversity of these molecular functions. Mutagenic T-cell epitope deletion seeks to mitigate the immune response, but can typically address only a small number of epitopes. Here, we pursue a "bottom-up" approach that redesigns an entire protein to remain native-like but contain few if any immunogenic epitopes. We do so by extending the Rosetta flexible-backbone protein design software with an epitope scoring mechanism and appropriate constraints. The method is benchmarked with a diverse panel of proteins and applied to three targets of therapeutic interest. We show that the deimmunized designs indeed have minimal predicted epitope content and are native-like in terms of various quality measures, and moreover that they display levels of native sequence recovery comparable to those of non-deimmunized designs. 23827044 Innovation in youth mental health services in Australia: common characteristics across the first headspace centres. headspace centres comprise a significant innovation in community-based youth mental health service delivery in Australia. This paper examines the service activity of the first headspace centres to determine common and unique practice characteristics across headspace centres in this new approach to mental health service delivery. Data come from quarterly progress reports provided by the first 30 headspace centres during the 2010-2011 financial year. The information from 120 reports was analysed qualitatively using thematic analysis techniques to determine the types of activities reported by centres against key performance indicators. The main finding was the large number and wide range of centre activity. This heterogeneity may be explained in part by the diversity of communities across Australia and the importance that headspace places on addressing the specific needs of the local community as well as drawing upon the existing capacity that is available within a community. The most common activities were community engagement, building local partnerships and providing a youth friendly environment. There was a particularly strong focus by the majority of centres on establishing and supporting a Youth Reference Group to guide centre development and implementation. The progressive upscaling of headspace centres across Australia provides a unique opportunity to observe how a significant reorientation in health service delivery is implemented in practice to meet the needs of diverse communities. Further investigation of the headspace experience will provide critical lessons for other countries investing in new approaches to youth mental health. 23456425 CD73(+) adipose-derived mesenchymal stem cells possess higher potential to differentiate into cardiomyocytes in vitro. Adipose-derived mesenchymal stem cells (ADMSCs) are an attractive adult-derived stem cell population for cardiovascular repair. ADMSCs are heterogeneous cell populations with pluripotent capacity to differentiate into different types of cells. In the present study, we investigated the biological characteristics and differentiation potential of CD73-positive (CD73(+)) and CD73-negative (CD73(-)) ADMSCs. Our results show that in terms of morphological shape, CD73(+)-ADMSCs are mainly small-sized cells, whereas CD73(-)-ADMSCs are big-sized cells; both subpopulations can equally differentiate into adipocytes and osteoblasts in vitro. However, the CD73(+)-ADMSCs possess a higher potential to differentiate into cardiomyocytes than the CD73(-)-ADMSCs. The expression of the cardiac-specific genes, cTnT, Gata4, and Nkx2.5, is much higher in the CD73(+)-ADMSCs than in the CD73(-)-ADMSCs. Furthermore, Nanog expression at both the mRNA and protein levels is significantly higher in CD73(+)-ADMSCs than in CD73(-)-ADMSCs, suggesting that CD73(+)-ADMSCs are an undifferentiated subpopulation that can differentiate into cardiomyocytes in vitro more efficiently. Therefore, this study facilitates a better understanding of the differentiation of the ADMSCs subgroups and attempts to identify if CD73 is a useful marker for sorting and purifying the subpopulation of ADMSCs with a higher capacity for differentiation into cardiomyocytes. 23529381 A critical examination of best dose analysis for determining cognitive-enhancing potential of drugs: studies with rhesus monkeys and computer simulations. RATIONALE: Best dose analysis involves identifying the dose associated with the greatest improvement in performance for each subject and comparing performances associated with these individually determined best doses to control performances. OBJECTIVES: The current experiments were conducted to examine whether significant best dose effects might result from the selective analysis of data rather than an actual drug effect. METHODS: Experiment 1 examined the effects of nicotine and methylphenidate on delayed matching-to-sample (DMTS) and self-ordered spatial search (SOSS) performances in rhesus monkeys (DMTS: n = 7; SOSS: n = 6) to determine the validity and reliability of best dose effects. Experiment 2 used Monte Carlo computer simulations to estimate the likelihood of obtaining a significant outcome when the best dose method was applied to randomly generated data sets for which no difference existed. RESULTS: Significant effects were obtained when the best dose analysis was applied to performances from nondrug sessions, and best dose performances were not significantly different from the best nondrug performances. The doses identified as best doses from two nicotine dose-response curve determinations were unrelated, and the improvement associated with the best dose observed during the first dose-response curve determination was not reliable when the dose was administered repeatedly. Finally, there was a high likelihood of obtaining a statistically significant difference when no real difference existed. CONCLUSIONS: Best dose analysis for the identification of potential therapeutic agents should be replaced by single-subject designs. 23745524 Brine shrimp lethality assay 'an effective prescreen': Microwave-assisted synthesis, BSL toxicity and 3DQSAR studies-based designing, docking and antitumor evaluation of potent chalcones. Abstract Context: In the course of searching potential antitumor agents from a library of chalcones synthesized under microwave irradiations, the brine shrimp lethality (BSL) assay and a 3D structure-activity relationship (3DQSAR) studies were followed by the antitumor evaluation of most potent analogues. Objective: The objective of the current study was to effectively use the BSL assay for the identification of potential cytotoxic analogues from a set of compounds. Methods: We applied the comparative molecular field analysis (CoMFA) and devised 3DQSAR on 33 synthesized chalcones leading to prediction of five related compounds with improved activity. The scope of BSL assay for the prediction of antitumor potency was tested through the in vitro antitumor studies against six human tumor cell-lines, docking studies and the tubulin-polymerization assay. Results: The newly designed compounds 34-38 displayed very promising cytotoxic potency. From our results, the BSL toxicity, antitumor efficacy and docking outcomes could be easily co-related. Conclusion: The study draws a very good relationship between a simple, inexpensive, and bench-top BSL assay and the antitumor potential of the cytotoxic compounds. Devising the CoMFA analysis helped in designing chalcones with improved cytotoxic potential as displayed through their BSL and cytotoxic activity against human tumor cell lines. The studies are noteworthy as such comprehensive studies were never performed before on the BSL assay. The present studies widen the scope of the BSL model that may prove quite helpful as a preliminary screen in the antitumor drug designing and synthesis expeditions. 23906574 Multiple myeloma following essential thrombocythemia. The association of essential thrombocythemia and multiple myeloma is extremely rare, with only three patients previously treated with hydroxyurea reported in the literature until now. In this paper, we report the case of a 66 year old male who developed IgG-kappa M six years after the diagnosis of essential thrombocythemia, for which he had received hydroyurea. The possible etiological and pathogenic link between both these entities is here discussed. 23948165 Design of a multiple drug delivery system directed at periodontitis. Periodontal disease is highly prevalent, with 90% of the world population affected by either periodontitis or its preceding condition, gingivitis. These conditions are caused by bacterial biofilms on teeth, which stimulate a chronic inflammatory response that leads to loss of alveolar bone and, ultimately, the tooth. Current treatment methods for periodontitis address specific parts of the disease, with no individual treatment serving as a complete therapy. The present research sought to demonstrate development of a multiple drug delivery system for stepwise treatment of different stages of periodontal disease. More specifically, multilayered films were fabricated from an association polymer comprising cellulose acetate phthalate and Pluronic F-127 to achieve sequential release of drugs. The four types of drugs used were metronidazole, ketoprofen, doxycycline, and simvastatin to eliminate infection, inhibit inflammation, prevent tissue destruction, and aid bone regeneration, respectively. Different erosion times and adjustable sequential release profiles were achieved by modifying the number of layers or by inclusion of a slower-eroding polymer layer. Analysis of antibiotic and anti-inflammatory bioactivity showed that drugs released from the devices retained 100% bioactivity. The multilayered CAPP delivery system offers a versatile approach for releasing different drugs based on the pathogenesis of periodontitis and other conditions. 23956130 Investigating the relationship between COMt polymorphisms and working memory performance among childhood brain tumor survivors. Survivors of childhood brain tumors are at increased risk for neurocognitive impairments, including deficits in abilities supported by frontal brain regions. Catechol-O-methyltransferase (COMT) metabolizes dopamine in the prefrontal cortex, with the Met allele resulting in greater dopamine availability and better performance on frontally mediated tasks compared to the Val allele. Given the importance of identifying resiliency factors against the emergence of cognitive late effects, the current study examined the relationship between COMT genotype and working memory performance among childhood brain tumor survivors. Children treated for a brain tumor with conformal radiation therapy (N = 50; mean age at irradiation = 7.41 ± 3.41; mean age at assessment = 13.18 ± 2.88) were administered two computerized measures of working memory (self-ordered search verbal and object tasks). Buccal (cheek) swabs were used to provide tissue from which DNA was extracted. Findings revealed an association between COMT genotype and performance on the self-ordered verbal (P = 0.03) but not object task (P = 0.33). Better performance was found for the Met/Val group compared to either Met/Met or Val/Val. COMT may indicate a potential resiliency factor against neurocognitive effects of cancer and its treatment; however, there is a need for replication with larger samples of childhood brain tumor survivors. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc. 23829661 Surface Self-Diffusion of Organic Glasses. Surface self-diffusion coefficients have been determined for the organic glass Nifedipine using the method of surface grating decay. The flattening of 1000 nm surface gratings occurs by viscous flow at 12 K or more above the glass transition temperature and by surface diffusion at lower temperatures. Surface diffusion is at least 10(7) times faster than bulk diffusion, indicating a highly mobile surface. Nifedipine glasses have faster surface diffusion than the previously studied Indomethacin glasses, despite their similar bulk relaxation times. Both glasses exhibit fast surface crystal growth, and its rate scales with surface diffusivity. The observed rate of surface diffusion implies substantial surface rearrangement during the preparation of low-energy glasses by vapor deposition. The Random First Order Transition Theory and the Coupling Model successfully predict the large surface-enhancement of mobility and its increase on cooling, but disagree with the experimental observation of the faster surface diffusion of Nifedipine. 23831070 A Report on Major Complications and Biochemical Recurrence After Primary and Salvage Cryosurgery for Prostate Cancer in Patients With Prior Resection for Benign Prostatic Hyperplasia: A Single-center Experience. To report on biochemical recurrence (BCR) and major complications in patients with prior prostate resection that underwent cryosurgery (CS) for prostate cancer. The Columbia University Urologic Oncology database identified patients that underwent CS after resection. Patient demographics, surgical details, prostate volume, prostate-specific antigen (PSA) levels, biopsy results, major complications, and BCR were recorded. Prior resection for benign prostatic hyperplasia was identified in 32 patients who underwent CS. Median age was 70.7 years (range 54.9-83.1 years). Median prostate volume before and after resection was 40 (range 30-90) and 20 cm(3) (range 9-54), respectively. Median time from resection to CS was 50.4 months (range 0-178.1 months). Twenty-one (16 full and 5 focal gland ablations) and 11 patients underwent primary and salvage CS, respectively. Median prostate-specific antigen at CS was 5.9 ng/mL (range 0.1-18.4 ng/mL), with a median nadir post-CS of 0.1 ng/mL (range 0.04-12.2 ng/mL). Median follow-up was 41.2 months (range 8.9-154.2 months). According to Stuttgart and Phoenix definitions, 11 and 10 patients, respectively, experienced BCR. Three patients underwent further CS for disease recurrence. Overall complications were rare and minor. Patients with smaller glands postresection (<20 cc(3)) experienced a similar incidence of BCR as those with larger glands after CS in all the settings. Although no patients experienced major complications after primary CS, 18% (2/11) had grade III or higher complications in the salvage setting. Postresection gland volume was not associated with BCR. Further research is needed to evaluate functional and oncological outcomes in postresection patients after CS because they are considered high-risk for major complications. 23901801 Recurrent Hepatitis C Virus Infection and Outcome After Living-Donor Liver Transplant. In living-donor liver transplant recipients with hepatitis C virus infection, outcomes of recurrent hepatitis C virus infection and fibrosis progression are not well documented. We evaluated fibrosis progression, response to pegylated interferon treatment, and long-term graft survival in living-donor liver transplant recipients who had hepatitis C virus infection. In 48 transplant recipients, including 29 recipients who had follow-up liver biopsy ≥ 6 months after transplant, histology and clinical courses were reviewed. Outcomes were evaluated for patients grouped into slow and rapid fibrosis groups. Treatment with pegylated interferon and ribavirin was assessed in 18 patients. Clinical features were similar between recipients with slow or rapid fibrosis. The time interval from transplant to recurrence of hepatitis C virus infection was significantly shorter in the recipients with rapid fibrosis. Recipients with rapid fibrosis had significantly greater confluent necrosis, acidophil bodies, and fibrosis score than recipients with slow fibrosis. Graft survival rates were similar between patients with slow or rapid fibrosis. Cumulative proportion of long-term graft survival was 60% at 7 years after transplant. Sustained virologic response was noted in 5 of 18 patients (28%) who received pegylated interferon and ribavirin. In recipients of living-donor liver transplant with early recurrence of hepatitis C have worse fibrosis progression but graft survival was not affected. Therapy with pegylated interferon and ribavirin achieved sustained virologic response only in a small proportion of the patients. 23801281 Laser-Induced Azomethine Ylide Formation and Its Covalent Entrapment by Fulleropyrrolidine Derivatives During MALDI Analysis. Two novel monofunctionalized fulleropyrrolidine derivatives (Prato adducts) were prepared and characterized by matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI). MALDI experiments conducted in the positive-ion mode on pure and mixed samples of both monofunctionalized fullerene derivatives revealed the efficient formation of bisadducts (in the case of the pure samples) and mixed bisadducts (in the case of a mixed sample). Bisadducts were not observed in the ESI experiments and thus not present in the sample. A mechanism for the MALDI formation of these bisadduct ions is proposed in which an azomethine ylide fragment is formed in situ from the monofunctionalized fulleropyrrolidine species upon laser irradiation. This fragment, which can survive as an intact moiety in the gas phase in the special environment provided by the MALDI experiment, is then able to attach to a fulleropyrrolidine monoadduct which acts as a dipolarophile, thus leading to the formation of a bisadduct fullerene derivative. The unprecedented re-attachment of the azomethine ylide implies that the establishment of the ligand attainment of Prato adducts based on MALDI analysis alone can lead to wrong assignments. 23950699 Top-Down Beta Rhythms Support Selective Attention via Interlaminar Interaction: A Model. Cortical rhythms have been thought to play crucial roles in our cognitive abilities. Rhythmic activity in the beta frequency band, around 20 Hz, has been reported in recent studies that focused on neural correlates of attention, indicating that top-down beta rhythms, generated in higher cognitive areas and delivered to earlier sensory areas, can support attentional gain modulation. To elucidate functional roles of beta rhythms and underlying mechanisms, we built a computational model of sensory cortical areas. Our simulation results show that top-down beta rhythms can activate ascending synaptic projections from L5 to L4 and L2/3, responsible for biased competition in superficial layers. In the simulation, slow-inhibitory interneurons are shown to resonate to the 20 Hz input and modulate the activity in superficial layers in an attention-related manner. The predicted critical roles of these cells in attentional gain provide a potential mechanism by which cholinergic drive can support selective attention. 23887305 The pathogenesis of atypical proliferative Brenner tumor: an immunohistochemical and molecular genetic analysis. Brenner tumors are ovarian tumors, usually benign, containing epithelium that resembles transitional epithelium. As with other epithelial tumors there exist frankly malignant tumors and tumors that display greater proliferation than the benign Brenner tumors but lack destructive infiltrative growth, and these have been designated 'atypical proliferative' (borderline) Brenner tumors. There have been no well-documented cases of atypical proliferative Brenner tumors that have exhibited malignant behavior. Based on shared morphologic features it is generally believed that atypical proliferative Brenner tumors develop from benign Brenner tumors. The aim of the present study was to confirm this impression by investigating the immunohistochemical and molecular genetic features of benign and atypical proliferative Brenner tumors. Immunohistochemical staining for p16, fluorescence in-situ hybridization (FISH) for CDKN2A (p16-encoding gene) and mutational analysis of the genes commonly mutated in ovarian tumors were performed. p16 immunostaining was positive in the epithelial component of 12 (92%) of 13 benign Brenner tumors, but completely negative in all 7 atypical proliferative Brenner tumors. FISH identified homozygous deletion of CDKN2A in the epithelial component of all atypical proliferative Brenner tumors, but CDKN2A was retained in all benign Brenner tumors. Two PIK3CA somatic mutations were detected in the stromal component in 1 (5%) of 20 Brenner tumors and 3 somatic mutations (1 in KRAS and 2 in PIK3CA) were identified in the atypical epithelial component of 2 (29%) of 7 atypical proliferative Brenner tumors. In summary, our findings suggest that loss of CDKN2A and, to a lesser extent, KRAS and PIK3CA somatic mutations have a role in the progression of a benign to an atypical proliferative Brenner tumor.Modern Pathology advance online publication, 26 July 2013; doi:10.1038/modpathol.2013.142. 23791541 Phase II study of first-line bortezomib and cisplatin in malignant pleural mesothelioma and prospective validation of progression free survival rate as a primary end-point for mesothelioma clinical trials (European Organisation for Research and Treatment of Cancer 08052). This was a prospective phase II study of cisplatin and bortezomib (CB) in the first line treatment of malignant pleural mesothelioma (MPM) with validation of progression free survival rate at 18weeks (PFSR-18)(1) as primary end-point. Chemotherapy-naïve patients with histologically proven MPM and performance status (PS) 0/1, were treated with cisplatin 75mg/m(2) on day 1 and bortezomib 1.3mg/m(2) on days 1, 4, 8, 11 every 3weeks. The primary end-point validation utilised the landmark method. Between 2007 and 2010 82 patients were entered. PFSR-18 was 53% (80% confidence intervals, CIs, 42-64%). The overall survival (OS) was 13.5months (95% CI 10.5-15) with 56% (95% CI 44-66%) alive at 1year. The median PFS was 5.1months (95% CI 3.3-6.5) and the response rate was 28.4% (95% CI 18.9-39.5%). The most frequent grade 3-4 toxicities were hyponatremia (46%), hypokalaemia (17%), fatigue (12.2%), thrombocytopenia (11%), neutropenia (9.7%) and neurotoxicity (motor, sensory, other: 1.2%, 8.5%, 2.4%). There were two toxic deaths (32 and 74days) due to acute pneumonitis and cardiac arrest. End-point validation showed that patients with no progression/progression at 18weeks had median OS of 16.9/11.9months, respectively. Hazard ratio was 0.46 (CI 0.32-0.67), logrank test and C-index were 0.007 and 0.60. The 50% PFSR-18 for CB was contained within the 80% CI for (42-64%). Therefore the null hypothesis could not be rejected. Accordingly this combination does not warrant further investigation. PFSR-18 was confirmed as a strong predictor of survival. 23344956 Depletion of molecular chaperones from the endoplasmic reticulum and fragmentation of the Golgi apparatus associated with pathogenesis in Pelizaeus-Merzbacher disease. Missense mutations in the proteolipid protein 1 (PLP1) gene cause a wide spectrum of hypomyelinating disorders, from mild spastic paraplegia type 2 to severe Pelizaeus-Merzbacher disease (PMD). Mutant PLP1 accumulates in the endoplasmic reticulum (ER) and induces ER stress. However, the link between the clinical severity of PMD and the cellular response induced by mutant PLP1 remains largely unknown. Accumulation of misfolded proteins in the ER generally leads to up-regulation of ER chaperones to alleviate ER stress. Here, we found that expression of the PLP1-A243V mutant, which causes severe disease, depletes some ER chaperones with a KDEL (Lys-Asp-Glu-Leu) motif, in HeLa cells, MO3.13 oligodendrocytic cells, and primary oligodendrocytes. The same PLP1 mutant also induces fragmentation of the Golgi apparatus (GA). These organelle changes are less prominent in cells with milder disease-associated PLP1 mutants. Similar changes are also observed in cells expressing another disease-causing gene that triggers ER stress, as well as in cells treated with brefeldin A, which induces ER stress and GA fragmentation by inhibiting GA to ER trafficking. We also found that mutant PLP1 disturbs localization of the KDEL receptor, which transports the chaperones with the KDEL motif from the GA to the ER. These data show that PLP1 mutants inhibit GA to ER trafficking, which reduces the supply of ER chaperones and induces GA fragmentation. We propose that depletion of ER chaperones and GA fragmentation induced by mutant misfolded proteins contribute to the pathogenesis of inherited ER stress-related diseases and affect the disease severity. 23807550 A new method to graft titania using Grignard reagents. A new method to graft titania with organic groups has been developed. In contrast to common condensation based grafting methods, this method uses organometallic chemistry to bond organic groups directly at the surface. Thereby the introduction of hetero elements at the bonding interface is avoided. 23831982 Synthesis, FT-IR investigation and computational study of 5-[(4-Bromophenyl)acetamido]-2-(4-tert-butylphenyl) benzoxazole. The synthesis and antimicrobial properties of 5-[(4-Bromophenyl)acetamido]-2-(4-tertbutylphenyl) benzoxazole are reported in the present work. The optimized molecular structure, (1)H NMR, vibrational frequencies, corresponding vibrational assignments of 5-[(4-Bromophenyl)acetamido]-2-(4-tert-butylphenyl) benzoxazole have been investigated experimentally and theoretically using Gaussian09 software package. Potential energy distribution of the normal modes of vibrations was done using GAR2PED program. The HOMO and LUMO analysis is used to determine the charge transfer within the molecule. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. MEP was performed by the SDD method and the predicted infrared intensities have also been reported. The calculated geometrical parameters are in agreement with that of similar derivates. The first hyperpolarizability is high and the title compound is suitable for further NLO studies. Microbiological results indicated that the title compound possessed a broad spectrum activity against the tested Gram-positive, Gram-negative bacteria. 23197043 Increased protein kinase A type Iα regulatory subunit expression in parathyroid gland adenomas of patients with primary hyperparathyroidism. Protein kinase A (PKA) regulatory subunit type Iα (RIα) is a major regulatory subunit that functions as an inhibitor of PKA kinase activity. We have previously demonstrated that elevated RIα expression is associated with diffuse-to-nodular transformation of hyperplasia in parathyroid glands of renal hyperparathyroidism. The aim of the current study was to determine whether or not RIα expression is increased in adenomas of primary hyperparathyroidism (PHPT), because monoclonal proliferation has been demonstrated in both adenomas and nodular hyperplasia. Surgical specimens comprising 22 adenomas and 11 normal glands, obtained from 22 patients with PHPT, were analyzed. Western blot and immunohistochemical analyses were employed to evaluate RIα expression. PKA activities were determined in several adenomas highly expressing RIα. RIα expression was also separately evaluated in chief and oxyphilic cells using the "Allred score" system. Expression of proliferating cell nuclear antigen (PCNA), a proliferation marker, was also immunohistochemically examined. Western blot analysis revealed that 5 out of 8 adenomas highly expressed RIα, compared with normal glands. PKA activity in adenomas was significantly less than in normal glands. Immunohistochemical analysis further demonstrated high expression of RIα in 20 out of 22 adenomas. In adenomas, the greater RIα expression and more PCNA positive cells were observed in both chief and oxyphilic cells. The present study suggested that high RIα expression could contribute to monoclonal proliferation of parathyroid cells by impairing the cAMP/PKA signaling pathway. 23319293 Calcium intake is not related to breast cancer risk among Singapore Chinese women. There is experimental evidence that calcium protects against breast cancer development. Prospective epidemiologic studies supporting a protective effect of calcium on breast cancer risk have mainly been limited to Western populations. We examined the association between calcium intake and breast cancer risk in the Singapore Chinese Health Study, a large population-based prospective cohort. Calcium intake and supplement use was assessed by in-person interviewer using a validated food frequency questionnaire. After a mean follow-up of 14.2±3.5 years, 823 cohort participants developed invasive breast cancer. Multivariate proportional hazards regression models were fitted to examine the associations between calcium intake and breast cancer risk. Vegetables were the primary food source of calcium in this study population, followed by dairy products, grains and soy foods. Calcium intake was not associated with breast cancer risk, comparing highest quartile (>345.6 mg/1,000 kcal/day) to lowest quartile (<204.5 mg/1,000 kcal/day) of intake. There was no evidence of effect modification by menopausal status, body mass index, dietary vitamin D or stage of disease at diagnosis. Our findings do not support a hypothesis for calcium in breast cancer chemoprevention, contrary to findings from previous studies among Western populations with higher calcium intake primarily from dairy products and supplements. 23895388 From inventory to functional mechanisms: Regulation of the mitochondrial protein import machinery by phosphorylation. For decades, the pyruvate dehydrogenase complex in the mitochondrial matrix was considered as a rare example of how protein kinases and phosphatases can regulate important functions within this organelle. During the last decade, several proteomic studies revealed that a large fraction of mitochondrial proteins are indeed phosphorylated. A surprisingly high number of phosphorylation sites was found at the preprotein import machinery, TOM, in the outer membrane that provides the central protein import gate for most mitochondrial precursors synthesized in the cytosol. This review describes current knowledge of the mitochondrial phosphoproteome and introduces the first regulatory mechanisms of protein import dynamics by reversible phosphorylation, which have been uncovered mainly in the model organism Saccharomyces cerevisiae. 23965611 Use of electroconvulsive therapy in an adolescent with systemic lupus erythematosus for management of depression. Use of electroconvulsive therapy (ECT) has been infrequently described in patients with systemic lupus erythematosus and is most commonly used in patients with catatonia. In this report, we describe the use of ECT in a young adolescent girl who had bipolar affective disorder associated with systemic lupus erythematosus and was treated with ECT for the depressive episode. The patient achieved remission with a course of 6 ECT treatments. 23703381 (129) Xe NMR chemical shift in Xe@C60 calculated at experimental conditions: Essential role of the relativity, dynamics, and explicit solvent. The isotropic (129) Xe nuclear magnetic resonance (NMR) chemical shift (CS) in Xe@C60 dissolved in liquid benzene was calculated by piecewise approximation to faithfully simulate the experimental conditions and to evaluate the role of different physical factors influencing the (129) Xe NMR CS. The (129) Xe shielding constant was obtained by averaging the (129) Xe nuclear magnetic shieldings calculated for snapshots obtained from the molecular dynamics trajectory of the Xe@C60 system embedded in a periodic box of benzene molecules. Relativistic corrections were added at the Breit-Pauli perturbation theory (BPPT) level, included the solvent, and were dynamically averaged. It is demonstrated that the contribution of internal dynamics of the Xe@C60 system represents about 8% of the total nonrelativistic NMR CS, whereas the effects of dynamical solvent add another 8%. The dynamically averaged relativistic effects contribute by 9% to the total calculated (129) Xe NMR CS. The final theoretical value of 172.7 ppm corresponds well to the experimental (129) Xe CS of 179.2 ppm and lies within the estimated errors of the model. The presented computational protocol serves as a prototype for calculations of (129) Xe NMR parameters in different Xe atom guest-host systems. © 2013 Wiley Periodicals, Inc. 23500059 Delivery of definable number of drug or growth factor loaded poly(dl-lactic acid-co-glycolic acid) microparticles within human embryonic stem cell derived aggregates. Embryoid bodies (EBs) generated from embryonic stem cells are used to study processes of differentiation within a three dimensional (3D) cell environment. In many instances however, EBs are dispersed to single cell suspensions with a subsequent monolayer culture. Moreover, where the 3D integrity of an EB is maintained, cytokines or drugs of interest to stimulate differentiation are often added directly to the culture medium at fixed concentrations and effects are usually limited to the outer layers of the EB. The aim of this study was to create an EB model with localised drug and or growth factor delivery directly within the EB. Using poly(DL-lactic acid-co-glycolic acid) microparticles (MPs) with an average diameter of 13μm, we have demonstrated controllable incorporation of defined numbers of MPs within human ES cell derived EBs, down to 1 MP per EB. This was achieved by coating MPs with human ES cell lysate and centrifugation of specific ratios of ES cells and MPs to form 3D aggregates. Using MPs loaded with simvastatin (pro or active drug) or BMP-2, we have demonstrated osteogenic differentiation within the 3D aggregates, maintained in culture for up to 21days, and quantified by real time QPCR for osteocalcin. Immunostaining for RUNX2 and osteocalcin, and also histochemical staining with picrosirius red to demonstrate collage type 1 and Alizarin red to demonstrate calcium/mineralisation further demonstrated osteogenic differentiation and revealed regional staining associated with the locations of MPs within the aggregates. We also demonstrated endothelial differentiation within human ES cell-derived aggregates using VEGF loaded MPs. In conclusion, we demonstrate an effective and reliable approach for engineering stem aggregates with definable number of MPs within the 3D cellular structure. We also achieved localised osteogenic and endothelial differentiation associated with MPs releasing encapsulated drug molecules or cytokines directly within the cell aggregate. This provides a powerful tool for controlling and investigating differentiation within 3D cell cultures and has applications to drug delivery, drug discovery, stem cell biology, tissue engineering and regenerative medicine. 22066915 Management of complicated crown-root fractures using intentional replantation: two case reports. Abstract -  The management of complicated crown-root fractures is a challenge. Intentional replantation with 180° rotation may be a useful procedure to overcome this problem. In Case 1, a 23-year-old woman with complicated crown-root fractured teeth #11, #21, and #22 was referred for treatment. All fractured teeth were extracted, rotated 180°, and replanted in a slightly extruded position. After 3 months, root canal treatment was completed and the final restorations fabricated. At the 18-month follow up, the patient was asymptomatic, the tooth was functional, and no root resorption was observed radiographically. At the 90-month follow up, slight cervical root resorption of tooth #11 was noted. In Case 2, a 27-year-old woman with a crown-root fractured tooth #21 was referred for treatment. Despite immediate repositioning of the coronal fragment and a 2-week stabilization with a wire splint, the coronal fragment remained separated from the apical tooth segment. The apical segment was extracted, rotated 180°, and replanted in a slightly extruded position. After 1 and 4 weeks, the root canal treatment was completed and the final restoration fabricated, respectively. At the 24-month follow up, the patient was asymptomatic and apical healing was completed. 23746655 Anti-proliferative actions of T-type calcium channel inhibition in thy1 nephritis. Aberrant proliferation of mesangial cells (MCs) is a key finding in progressive glomerular disease. TH1177 is a small molecule that has been shown to inhibit low-voltage activated T-type Ca(2+) channels (TCCs). The current study investigates the effect of TH1177 on MC proliferation in vitro and in vivo. The effect of Ca(2+) channel inhibition on primary rat MC proliferation in vitro was studied using the microculture tetrazolium assay and by measuring bromodeoxyuridine incorporation. In vivo, rats with Thy1 nephritis were treated with TH1177 or vehicle. Glomerular injury and average glomerular cell number were determined in a blinded fashion. Immunostaining for Ki-67 and phosphorylated ERK were also performed. The expression of TCC isoforms in healthy and diseased tissue was investigated using quantitative real-time PCR. TCC blockade caused a significant reduction in rat MC proliferation in vitro, whereas L-type inhibition had no effect. Treatment of Thy1 nephritis with TH1177 significantly reduced glomerular injury (P < 0.005) and caused a 49% reduction in glomerular cell number (P < 0.005) compared to the placebo. TH1177 also reduced Ki-67-positive and pERK-positive cells per glomerulus by 52% (P < 0.01 and P < 0.005, respectively). These results demonstrate that TH1177 inhibits MC proliferation in vitro and in vivo, supporting the hypothesis that TCC inhibition may be a useful strategy for studying and modifying MC proliferative responses to injury. 23959680 Stomatin-domain protein interactions with acid sensing ion channels modulate nociceptor mechanosensitivity. Acid sensing ion channels (ASICs) and their interaction partners of the stomatin family have all been implicated in sensory transduction. Single gene deletion of asic3, asic2, stomatin, or stoml3 all result in deficits in the mechanosensitivity of distinct cutaneous afferents in the mouse. Here, we generated asic3-/-:stomatin-/-, asic3-/-:stoml3-/- and asic2-/-:stomatin-/- double mutant mice to characterize the functional consequences of stomatin-ASIC protein interactions on sensory afferent mechanosensitivity. The absence of ASIC3 led to a clear increase in mechanosensitivity in rapidly adapting mechanoreceptors (RAMs) and a decrease in the mechanosensitivity in both Aδ- and C-fibre nociceptors. The increased mechanosensitivity of RAMs could be accounted for by a loss of adaptation which could be mimicked by local application of APETx2 a toxin that specifically blocks ASIC3. There is a substantial loss of mechanosensitivity in stoml3-/- mice in which ~35% of the myelinated fibres lack a mechanosensitive receptive field and this phenotype was found to be identical in asic3-/-:stoml3-/- mutant mice. However, Aδ-nociceptors showed much reduced mechanosensitivity in asic3-/-:stoml3-/- mutant mice compared to asic3-/- controls. Interestingly, in asic2-/-:stomatin-/- mutant mice many Aδ-nociceptors completely lost their mechanosensitivity which was not observed in asic2-/- or stomatin-/- mice. Examination of stomatin-/-:stoml3-/- mutant mice indicated that a stomatin/STOML3 interaction is unlikely to account for the greater Aδ-nociceptor deficits in double mutant mice. A key finding from these studies is that the loss of stomatin or STOML3 in asic3-/- or asic2-/- mutant mice markedly exacerbates deficits in the mechanosensitivity of nociceptors without affecting mechanoreceptor function. 23043449 Breast surgeons' perceptions and attitudes towards contralateral prophylactic mastectomy. The rates of contralateral prophylactic mastectomy (CPM) are increasing worldwide. This study investigated Australian and New Zealand's breast surgeons' perceptions, knowledge and attitudes towards CPM, and explored if demographic characteristics of surgeons were associated with an increased tendency to recommend or perform CPM. A cross sectional research design was employed, with breast surgeons completing a self-report questionnaire. The questionnaire collected information including surgeons' perceptions on CPM in their clinical practice, their attitudes and knowledge of CPM and surgeons' demographic information. Eighty-one of 220 (37%) breast surgeons contacted via BreastSurgANZ participated in this study. Forty-four per cent of surgeons perceived that the rates of CPMs they performed had increased over the last year. CPM rates were found to be unrelated to surgeons' age (P = 0.773) or gender (P = 0.941). The main reasons a surgeon recommended a CPM to patients included known BRCA+ mutation, family history of breast cancer and patient factors including fear and anxiety and a desire to avoid further breast cancer treatment. Breast surgeons perceived that rates of CPM were increasing in their own clinical practice. CPM rates were unrelated to surgeon demographics including age and gender. While surgeons are aware of the objective risk factors that make performing a CPM advisable, they also report taking into account subjective factors, including patient fear and anxiety and a desire for breast symmetry when recommending a CPM. 23815356 Second-degree burn within a tattoo after intense-pulsed-light epilation. The use of high energy light sources [laser, intense pulsed light (IPL)] is booming in aesthetic surgery. A trend, especially concerning usage of photoepilation in cosmetic institutes, is detectable. Photoepilation works through selective photothermolysis, by heating the chromophore melanin within the hair follicles. We present a case impressionably demonstrating that high-energy light demands profound knowledge of its mechanism of action, and can cause severe harm in absence of basic knowledge. Photoepilation is a balancing act between maximal therapeutic effect and minimal side effect risk. Nevertheless, complications have to be clearly distinguished from professional errors. The latter are rising especially with IPL devices, mainly because its use depicts a legal grey area in most of the countries and is not bound to physicians' supervision. Due to its worse risk-benefit profile as compared with that of laser therapy, we advise against the use of IPL devices and claim for stricter regulation of its use, similar to laser devices. 22457042 In vivo chondrocyte and transforming growth factor-β1 delivery using the thermosensitive chitosan/starch/β-glycerol phosphate hydrogel. In present study, the chitosan/starch/β-glycerol phosphate hydrogel was investigated as an effective carrier for chondrocytes and delivery of transforming growth factor-β1. In vitro study indicated that transforming growth factor-β1 was released sustainably for 14 days with its biological activity to stimulate chondrocyte functions, as indicated by the strong expression of type II collagen protein. Subcutaneous implantation to rats revealed the strong expressions of type II collagen and aggrecan messenger ribonucleic acids, and also type II collagen protein was observed in the hydrogel in combination with transforming growth factor-β1 within 2 weeks. Our collective results showed the potential of chitosan/starch/β-glycerol phosphate hydrogel for effective delivery of chondrocytes and transforming growth factor-β1, and preserve chondrocytes' phenotype and functions in vitro. 23933331 Propensities for loop structures of RNA & DNA backbones. RNA oligonucleotides exhibit a large tendency to bend and form a loop conformation which is a major motif contributing to their complex three-dimensional structure. This is in contrast to DNA molecules that predominantly form the double-helix structure. In this paper we investigate by molecular dynamics simulation, as well as, by its combination with the replica-exchange method, the propensity of RNA chains containing the GCUAA pentaloop to form spontaneously a hairpin conformation. The results were then compared with those of analogous hybrid oligonucleotides in which the ribose groups in the loop-region were substituted by deoxyriboses. We find that the RNA oligomers exhibit a marginal excess stability to form loop structures. The equilibrium constant for opening the loop to an extended conformation is twice as large in the hybrid than it is in the RNA chain. Analyses of the hydrogen bonds indicate that the excess stability for forming a hairpin is a result of hydrogen bonds the 2'-hydroxyls in the loop region form with other groups in the loop. Of these hydrogen bonds, the most important is the hydrogen bond donated from the 2'-OH at the first position of the loop to N7 of adenine at the forth position. RNA and DNA backbones are characterized by different backbone dihedral angles and sugar puckering that can potentially facilitate or hamper the hydrogen bonds involving the 2'-OH. Nevertheless, the sugar puckerings of all the pentaloop nucleotides were not significantly different between the two chains displaying the C3'-endo conformation characteristic to the A-form double helix. All of the other backbone dihedrals also did not show any considerable difference in the loop-region except of the δ-dihedral. In this case, the RNA loop exhibited bimodal distributions corresponding to, both, the RNA and DNA backbones, whereas the loop of the hybrid chain behaved mostly as that of a DNA backbone. Thus, it is possible that the behavior of the δ-dihedrals in the loop-region of the RNA adopts conformations that facilitate the intra-nucleotide hydrogen bondings of the 2'-hydroxyls, and consequently renders loop structures in RNA more stable. 23864608 Cyclic AMP-Rap1A Signaling Mediates Cell Surface Translocation of Microvascular Smooth Muscle α2C-adrenoceptors Through the Actin Binding Protein Filamin-2. The second messenger cyclic AMP (cAMP) plays a vital role in vascular physiology, including vasodilation of large blood vessels. We recently demonstrated cAMP activation of Epac-Rap1A and RhoA-ROCK-F-actin signaling in arteriolar derived smooth muscle cells to increase expression and cell surface translocation of functional α2C-adrenoceptors (α2C-ARs) that mediate vasoconstriction in small blood vessels (arterioles). The Ras-related small GTPAse Rap1A increased expression of α2C-ARs and also increased translocation of perinuclear α2C-ARs to intracellular F-actin and to the plasma membrane. This study examined the mechanism of translocation to better understand the role of these newly discovered mediators of blood flow control, potentially activated in peripheral vascular disorders. We utilized a yeast two-hybrid screen with human microVSM cDNA library and the α2C-AR C-terminus to identify a novel interaction with the actin cross-linker, filamin-2. Yeast α-galactosidase assays, site-directed mutagenesis, and co-immunoprecipitation experiments in heterologous HEK 293 cells and in human microVSM demonstrated that α2C-ARs, but not α2A-AR subtype, interacted with filamin. In Rap1-stimulated human microVSMs, α2C-ARs co-localized with filamin on intracellular filaments and at the plasma membrane. siRNA mediated knockdown of filamin-2 inhibited Rap1-induced redistribution of α2C-ARs to the cell surface and inhibited receptor function. The studies suggest that cAMP-Rap1-Rho-ROCK signaling facilitates receptor translocation and function via phosphorylation of filamin-2 Ser-2113. Together, these studies extend our previous findings to show that functional rescue of α2C-ARs is mediated through Rap1-filamin signaling. Perturbation of this signaling pathway may lead to alterations in α2C-AR trafficking and physiological function. 23949315 Rapid detection of IDH2 (R140Q and R172K) mutations in acute myeloid leukemia. NADP-dependent enzyme isocitrate dehydrogenase (IDH) mutations, IDH1 and IDH2, have been described in acute myeloid leukemia (AML) using next generation sequencing approaches. IDH2 mutations are heterozygous; they alter a single arginine residue at position 140 or 172 and have distinct prognostic significance. The current detection methods of IDH2 mutations are laborious and time consuming as they require DNA sequencing. Herein, we report a new allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) method to detect the IDH2 mutations. Analysis of leukemic DNA samples from 120 AML patients enabled to identify IDH2 mutations in 22 cases which were confirmed by direct DNA sequencing. Of these, 17 harbored IDH2 (R140Q) and 5 IDH2 (R172K) mutations. Serial dilution experiments showed that the assay enable to detect mutations in 10(-3) dilutions. Our ASO-PCR method appears useful for routine diagnostic screening of these prognostically relevant alterations in AML and may be conveniently included in the diagnostic workup. 23830314 Comparative methods for handling missing data in large databases. Analysis of complex survey databases is an important tool for health services researchers. Missing data elements are challenging because the reasons for "missingness" are multifactorial, especially categorical variables such as race. We simulated missing data for race and analyzed the bias from five methods used in predicting major amputation in patients with critical limb ischemia (CLI). Patient discharges with fully observed data containing lower extremity revascularization or major amputation and CLI were selected from the 2003 to 2007 Nationwide Inpatient Sample, a complex survey database (weighted n = 684,057). Considering several random missing data schemes, we compared five missing data methods: complete case analysis, replacement with observed frequencies, missing indicator variable, multiple imputation, and reweighted estimating equations. We created 100 simulated data sets, with 5%, 15%, or 30% of subjects' race drawn to be missing from the full data set. Bias was estimated by comparing the estimated regression coefficients averaged over 100 simulated data sets (βmiss) from each method vs estimates from the fully observed data set (βfull), with relative bias calculated as (βfull - βmiss/βfull) Ã— 100%. Our results demonstrate that reweighted estimating equations produce the least biased and the missing indicator variable produces the most biased coefficients. Complete case analysis, replacement with observed frequencies, and multiple imputation resulted in moderate bias. Sensitivity analysis demonstrated the optimal method choice depends on the quantity and type of missing data encountered. Missing data are an important analytic topic in research with large databases. The commonly used missing indicator variable method introduces severe bias and should be used with caution. We present empiric evidence to guide method selection for handling missing data. 23557686 Does 4-tert-octylphenol affect estrogen signaling pathways in bank vole Leydig cells and tumor mouse Leydig cells in vitro? Primary Leydig cells obtained from bank vole testes and the established tumor Leydig cell line (MA-10) have been used to explore the effects of 4-tert-octylphenol (OP). Leydig cells were treated with two concentrations of OP (10(-4)M, 10(-8)M) alone or concomitantly with anti-estrogen ICI 182,780 (1μM). In OP-treated bank vole Leydig cells, inhomogeneous staining of estrogen receptor α (ERα) within cell nuclei was found, whereas it was of various intensity among MA-10 Leydig cells. The expression of ERα mRNA and protein decreased in both primary and immortalized Leydig cells independently of OP dose. ICI partially reversed these effects at mRNA level while at protein level abrogation was found only in vole cells. Dissimilar action of OP on cAMP and androgen production was also observed. This study provides further evidence that OP shows estrogenic properties acting on Leydig cells. However, its effect is diverse depending on the cellular origin. 23926146 Tracking multi-generational colonization of the breeding grounds by monarch butterflies in eastern North America. Insect migration may involve movements over multiple breeding generations at continental scales, resulting in formidable challenges to their conservation and management. Using distribution models generated from citizen scientist occurrence data and stable-carbon and -hydrogen isotope measurements, we tracked multi-generational colonization of the breeding grounds of monarch butterflies (Danaus plexippus) in eastern North America. We found that monarch breeding occurrence was best modelled with geographical and climatic variables resulting in an annual breeding distribution of greater than 12 million km(2) that encompassed 99% occurrence probability. Combining occurrence models with stable isotope measurements to estimate natal origin, we show that butterflies which overwintered in Mexico came from a wide breeding distribution, including southern portions of the range. There was a clear northward progression of monarchs over successive generations from May until August when reproductive butterflies began to change direction and moved south. Fifth-generation individuals breeding in Texas in the late summer/autumn tended to originate from northern breeding areas rather than regions further south. Although the Midwest was the most productive area during the breeding season, monarchs that re-colonized the Midwest were produced largely in Texas, suggesting that conserving breeding habitat in the Midwest alone is insufficient to ensure long-term persistence of the monarch butterfly population in eastern North America. 23895046 Discriminative Learning of Propagation and Spatial Pattern for Motor Imagery EEG Analysis. Effective learning and recovery of relevant source brain activity patterns is a major challenge to brain-computer interface using scalp EEG. Various spatial filtering solutions have been developed. Most current methods estimate an instantaneous demixing with the assumption of uncorrelatedness of the source signals. However, recent evidence in neuroscience suggests that multiple brain regions cooperate, especially during motor imagery, a major modality of brain activity for brain-computer interface. In this sense, methods that assume uncorrelatedness of the sources become inaccurate. Therefore, we are promoting a new methodology that considers both volume conduction effect and signal propagation between multiple brain regions. Specifically, we propose a novel discriminative algorithm for joint learning of propagation and spatial pattern with an iterative optimization solution. To validate the new methodology, we conduct experiments involving 16 healthy subjects and perform numerical analysis of the proposed algorithm for EEG classification in motor imagery brain-computer interface. Results from extensive analysis validate the effectiveness of the new methodology with high statistical significance. 23954576 Biocompatibility effects of indirect exposure of base-metal dental casting alloys to a human-derived three-dimensional oral mucosal model. The study employed a three-dimensional (3D) human-derived oral mucosal model to assess the biocompatibility of base-metal dental casting alloys ubiquitous in fixed prosthodontic and orthodontic dentistry. Oral mucosal models were generated using primary human oral keratinocyte and gingival fibroblast cells seeded onto human de-epidermidised dermal scaffolds. Nickel-chromium (Ni-Cr) and cobalt-chromium (Co-Cr) base-metal alloy immersion solutions were exposed to oral mucosal models for increasing time periods (2-72h). Analysis methodologies (histology, viable cell counts, oxidative stress, cytokine expression and toxicity) were performed following exposure. Ni-based alloy immersion solutions elicited significantly decreased cell viability (P<0.0004) with increased oxidative stress (P<0.0053), inflammatory cytokine expression (P<0.0077) and cellular toxicity levels (P<0.0001) compared with the controls. However, the Ni-free Co-Cr-based alloy immersion solutions did not elicit adverse oxidative stress (P>0.4755) or cellular toxicity (P<0.2339) responses compared with controls. Although the multiple analyses highlighted Ni-Cr base-metal alloy immersion solutions elicited significantly detrimental effects to the oral mucosal models, it was possible to distinguish between Ni and Cr alloys using the approach employed. The study employed a 3D human-derived full-thickness differentiated oral mucosal model suitable for biocompatibility assessment of base-metal dental casting alloys through discriminatory experimental parameters. Increasing incidences of Ni hypersensitivity in the general population warrants serious consideration from dental practitioners and patients alike where fixed prosthodontic/orthodontic dental treatments are the treatment modality involved. The novel and analytical oral mucosal model has the potential to significantly contribute to the advancement of reproducible dental medical device and dental material appraisals. 23963809 Comparison of different cooling rates for fibroblast and keratinocyte cryopreservation. Easy, cost-effective and reliable cryopreservation protocols are crucial for the successful and effective application of tissue engineering. Several different protocols are in use, but no comprehensive comparisons across different machine-based and manual methods have been made. Here, we compare the effects of different cooling rates on the post-thaw survival and proliferative capacity of two basic cell lines for skin tissue engineering fibroblasts and keratinocytes, cultured and frozen in suspension or as a monolayer. We demonstrate that effectiveness of cryopreservation cannot be reliably determined immediately after thawing: the results at this stage were not indicative of cell growth in culture 3 days post-thaw. Cryopreservation of fibroblasts in an adherent state greatly diminishes their subsequent growth potential. This was not observed when freezing in suspension. In keratinocytes, however, adherent freezing is as effective as freezing in suspension, which could lead to significant cost and labour savings in a tissue-engineering environment. The 'optimal' cryopreservation protocol depends on cell type and intended use. Where time, ease and cost are dominant factors, the direct freezing into a nitrogen tank (straight freeze) approach remains a viable method. The most effective solution across the board, as measured by viability 3 days post-thaw, was the commonly used, freezing container method. Where machine-controlled cryopreservation is deemed important for tissue-engineering Good Manufacturing Practice, we present results using a portfolio of different cooling rates, identifying the 'optimal' protocol depending on cell type and culture method. Copyright © 2013 John Wiley & Sons, Ltd. 23773366 Socio-demographic factors and oral health conditions in the elderly: A population-based study. The aim of the present study was to analyze the relationship between oral health conditions and socio-demographic factors in an elderly population from Macaíba/RN (Brazil). A questionnaire was used to characterize the socio-demographic profiles and a clinical examination was performed to assess oral health conditions such as tooth decay, gum disease, use of dental prosthesis, need for dental prosthesis and soft tissue injuries. The technique of random sampling by conglomerates was used, taken from randomly selected census drafts, with a total sample of 441 individuals. The prevalence of edentulism, bleeding and dental calculus was 50.8%, 27.2% and 32%, respectively, excluding all sextants in 59% of the elderly. Data analysis was conducted using the chi-squared test with the level of significance set at 5%. Prior to association tests, the dependant variables were submitted to principal component analysis. Four factors were extracted to represent the oral health conditions of elderly individuals. A statistically significant association was found between the following variables: gender and the presence of a caregiver with gum disease; age, residence area, presence of a caregiver and household density with need for dental prosthesis; and household density with soft tissue injuries. Therefore, precarious oral health conditions were found among the elderly and associations were found between these conditions and the socio-demographic factors, particularly gender, age and residence area. The results obtained demonstrated the need for improved oral health conditions in the elderly. The study of these conditions, allied to socio-demographic factors, is important in terms of both dental care and public policy planning related to these individuals. 23359513 RKIP: much more than Raf kinase inhibitory protein. From its discovery as a phosphatidylethanolamine-binding protein in bovine brain to its designation as a physiological inhibitor of Raf kinase protein, RKIP has emerged as a critical molecule for maintaining subdued, well-orchestrated cellular responses to stimuli. The disruption of RKIP in a wide range of pathologies, including cancer, Alzheimer's disease, and pancreatitis, makes it an exciting target for individualized therapy and disease-specific interventions. This review attempts to highlight recent advances in the RKIP field underscoring its potential role as a master modulator of many pivotal intracellular signaling cascades that control cellular growth, motility, apoptosis, genomic integrity, and therapeutic resistance. Specific biological and functional niches are highlighted to focus future research towards an enhanced understanding of the multiple roles of RKIP in health and disease. 23447425 Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo-controlled and active-comparator trials. The extent to which individual statins vary in terms of clinical outcomes across all populations, in addition to secondary and primary prevention has not been studied extensively in meta-analyses. We systematically studied 199,721 participants in 92 placebo-controlled and active-comparator trials comparing atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin in participants with, or at risk of developing, cardiovascular disease. We performed pairwise and network meta-analyses for major coronary events and all-cause mortality outcomes, taking into account the dose differences across trials. Systematic review registration: PROSPERO 2011:CRD42011001470. There were only a few trials that evaluated fluvastatin. Most frequent comparisons occurred between pravastatin and placebo, atorvastatin and placebo, and rosuvastatin and atorvastatin. No trial directly compared all six statins to each other. Across all populations, statins were significantly more effective than control in reducing all-cause mortality (OR 0.87, 95% credible interval 0.82-0.92) and major coronary events (OR 0.69, 95% CI 0.64-0.75). In terms of reducing major coronary events, atorvastatin (OR 0.66, 95% CI 0.48-0.94) and fluvastatin (OR 0.59, 95% CI 0.36-0.95) were significantly more effective than rosuvastatin at comparable doses. In participants with cardiovascular disease, statins significantly reduced deaths (OR 0.82, 95% CI 0.75-0.90) and major coronary events (OR 0.69, 95% CI 0.62-0.77). Atorvastatin was significantly more effective than pravastatin (OR 0.65, 95% CI 0.43-0.99) and simvastatin (OR 0.68, 95% CI 0.38-0.98) for secondary prevention of major coronary events. In primary prevention, statins significantly reduced deaths (OR 0.91, 95% CI 0.83-0.99) and major coronary events (OR 0.69, 95% CI 0.61-0.79) with no differences among individual statins. Across all populations, atorvastatin (80%), fluvastatin (79%), and simvastatin (62%) had the highest overall probability of being the best treatment in terms of both outcomes. Higher doses of atorvastatin and fluvastatin had the highest number of significant differences in preventing major coronary events compared with other statins. No significant heterogeneity or inconsistency was detected. Statins significantly reduce the incidence of all-cause mortality and major coronary events as compared to control in both secondary and primary prevention. This analysis provides evidence for potential differences between individual statins, which are not fully explained by their low-density lipoprotein cholesterol-reducing effects. The observed differences between statins should be investigated in future prospective studies. 23527663 Supramolecular Structure of TTBC J-Aggregates in Solution and on Surface. The aggregation behavior of cationic 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidacarbocyanine with chloride (TTBC-Cl) or iodide counterions (TTBC-I) in aqueous solution is investigated by absorption, linear dichroism, and fluorescence spectroscopies, as well as cryogenic transmission electron microscopy (cryo-TEM) and atomic force microscopy (AFM). TTBC-Cl is found to form J-aggregates with a classical Davydov-split absorption band (type I spectrum) even under different preparation conditions. These aggregates remain stable for months. Unlike the chloride salt, the iodide salt TTBC-I forms two different types of J-aggregates depending on the pH of the aqueous solution. The TTBC-I aggregates prepared in pure water (pH = 6) are characterized by a single redshifted absorption band (type III spectrum), whereas those prepared in alkaline solution at pH = 13 show a typical Davydov-split (type I) absorption band. Despite differences in counterions, preparation method, stability, and spectroscopic behavior, cryo-TEM reveals an identical tubular architecture for all these J-aggregates. Among the new structure models discussed here is a cylindrical brickwork layer of dye molecules for single-banded J-aggregates (type III). For Davydov-split aggregates (type I), a molecular herringbone-like pattern is proposed instead. Moreover, absorption spectra have revealed an additional single redshifted absorption band (type II spectrum) that is assigned to a surface aggregate and is induced by a specific interaction of the dye cation with the negatively charged cuvette wall. AFM measurements of analogous preparations on negatively charged mica surfaces have supported this interpretation and revealed the formation of monolayered sheet structures. 23873210 The evaluation of the consistency of quantified assertions. Consistency is a hallmark of rationality, and this article reports three experiments examining how reasoners determine the consistency of quantified assertions about the properties of individuals-for example, All of the actors are waiters. The mental model theory postulates that reasoners determine consistency by trying to construct a model of all of the assertions in a set. As the theory predicts, consistency is easier to establish when many different sorts of individuals satisfy the assertions (Exp. 1), when the predicted initial mental model satisfies them (Exp. 2), and otherwise when the model satisfying them is not too distant from the initial model, according to Levenshtein's metric (Exp. 3). 22374078 Epigenetic Modifications and Chromosome Conformations of the Beta Globin Locus throughout Development. Human embryonic stem cells provide an alternative to using human embryos for studying developmentally regulated gene expression. The co-expression of high levels of embryonic ε and fetal γ globin by the hESC-derived erythroblasts allows the interrogation of ε globin regulation at the transcriptional and epigenetic level which could only be attained previously by studying cell lines or transgenic mice. In this study, we compared the histone modifications across the β globin locus of the undifferentiated hESCs and hESC-, FL-, and mobilized PB CD34(+) cells-derived erythroblasts, which have distinct globin expression patterns corresponding to their developmental stages. We demonstrated that the histone codes employed by the β globin locus are conserved throughout development. Furthermore, in spite of the close proximity of the ε globin promoter, as compared to the β or γ globin promoter, with the LCR, a chromatin loop was also formed between the LCR and the active ε globin promoter, similar to the loop that forms between the β or γ globin promoters and the LCR, in contrary to the previously proposed tracking mechanism. 23886081 Facial Growth and Development in Unilateral Cleft Lip and Palate: Comparison Between Secondary Alveolar Bone Grafting and Primary Periosteoplasty. Objective :  To describe the effect of secondary alveolar bone grafting in patients with unilateral cleft lip and palate by comparison with a sample of patients who have undergone primary periosteoplasty. Design :  Cephalometric analysis of lateral x-ray films in a retrospective semilongitudinal study. Patients :  Lateral x-ray films of 18 secondary alveolar bone grafting patients and 48 primary periosteoplasty patients at 10 years of age and again at 15 years of age. Settings :  The treatment of secondary alveolar bone grafting patients included lip repair according to Tennison, palatoplasty including retropositioning, pharyngeal flap surgery, and secondary alveolar bone grafting. The lips of primary periosteoplasty patient were repaired using the methods of Tennison and Veau, followed by primary periosteoplasty, palatoplasty including retropositioning, and pharyngeal flap surgery. Methods :  Lateral radiographs were assessed using classical morphometry. Results :  There were few significant differences at 10 years of age between the secondary alveolar bone grafting and primary periosteoplasty patients. At 15 years of age, there were several significant differences. Compared with primary periosteoplasty patients, subsequent development in patients who had undergone secondary alveolar bone grafting was characterized by a significantly better position of the upper and lower dentoalveolar components in relation to the facial plane, a higher increase in the global convexity of the soft profile, a significantly better maxillary inclination, and a more favorable development of vertical intermaxillary relationships. Conclusion :  Craniofacial development in secondary alveolar bone grafting patients was better than that in primary periosteoplasty patients due to the more marked facial convexity, the increased prominence of the nose, and better vertical intermaxillary relationships. 23606399 A Polymorphism Affecting MYB Binding within the Promoter of the PDCD4 Gene is Associated with Severe Asthma in Children. A previous genome-wide association study in asthma revealed putative associations that merit further investigation. In this study, the genome-wide significant associations of SNPs at the 5% false discovery rate were examined in independent groups of severe asthmatics. The panel consisted of 397 severe asthmatic adults, 116 severe asthmatic children, and a collection of 207 family-trios with an asthmatic proband. Three SNPs in the PDCD4 gene (rs6585018:G>A, rs1322997:C>A, and rs34104444:G>A) were significantly associated with severe childhood asthma (P values: 0.003, 0.002, 0.004) and total immunoglobulin E (IgE) levels (P values: 0.034, 0.041, 0.052). In an independent group of 234 asthmatic children and 652 controls, PDCD4 SNPs rs1407696:T>G and rs11195360:T>C were associated with total IgE levels (P values: 0.006, 0.014). In silico analysis of PDCD4 locus showed that rs6585018:G>A had the potential to affect MYB transcription factor binding, shown to act as a PDCD4-transcription inducer. Electromobility shift assays and reporter assays revealed that rs6585018:G>A alters MYB binding thereby influencing the expression of PDCD4. SNPs within MYB itself confer susceptibility to eosinophilia and asthma. Our association between a variant MYB binding site in PDCD4 and the severest form of childhood asthma therefore suggests that PDCD4 is a novel molecule of importance to asthmatic inflammatory responses. 23898911 Rs12218 In SAA1 gene was associated with serum lipid levels. Serum amyloid A (SAA) is a kind of apolipoprotein. Several studies indicated that SAA genetic polymorphism rs12218 was associated with carotid atherosclerosis, peripheral arterial disease, and serum uric acid levels. However, the relation between rs12218 and lipid levels remains unclear. This study assessed the correlation between SAA1 gene rs12218 polymorphism and lipid levels in a Chinese population. A total of 823 participants were selected from the subjects for health check in Shanghai Huashan hospital from Jan. 2013 to Mach. 2013. Correlations between rs12218 polymorphism and lipid levels were investigated through the identification of rs12218 genotypes using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We found that the SNP rs12218 was associated with triglyceride (TG), total cholesterol (TC), and low-density lipoprotein (LDL-C) levels by analyses of a dominant model (P<0.001, P=0.002, P=0.003, respectively), a recessive model (P <0.001, P=0.001, P=0.005, respectively) and an additive model (P < 0.001, P=0.001, P=0.002, respectively), and the difference remained significant after the adjustment of sex, age, alcohol intake, and smoking (All P < 0.01). Our results indicated that the rs12218 in the SAA1gene was associated with lipid levels in a Chinese population. 23942199 New TRPM6 missense mutations linked to hypomagnesemia with secondary hypocalcemia. Despite recent progress in our understanding of renal magnesium (Mg(2+)) handling, the molecular mechanisms accounting for transepithelial Mg(2+) transport are still poorly understood. Mutations in the TRPM6 gene, encoding the epithelial Mg(2+) channel TRPM6 (transient receptor potential melastatin 6), have been proven to be the molecular cause of hypomagnesemia with secondary hypocalcemia (HSH; OMIM 602014). HSH manifests in the newborn period being characterized by very low serum Mg(2+) levels (<0.4 mmol/l) accompanied by low serum calcium (Ca(2+)) concentrations. A proportion of previously described TRPM6 mutations lead to a truncated TRPM6 protein resulting in a complete loss-of-function of the ion channel. In addition, five-point mutations have been previously described. The aim of this study was to complement the current clinical picture by adding the molecular data from five new missense mutations found in five patients with HSH. To this end, patch-clamp analysis and cell surface measurements were performed to assess the effect of the various mutations on TRPM6 channel function. All mutant channels, expressed in HEK293 cells, showed loss-of-function, whereas no severe trafficking impairment to the plasma membrane surface was observed. We conclude that the new TRPM6 missense mutations lead to dysregulated intestinal/renal Mg(2+) (re)absorption as a consequence of loss of TRPM6 channel function.European Journal of Human Genetics advance online publication, 14 August 2013; doi:10.1038/ejhg.2013.178. 23739299 An on-bacterium flow cytometric immunoassay for protein quantification. The polystyrene bead-based flow cytometric immunoassay has been widely reported. However, the preparation of functional polystyrene bead is still inconvenient. This study describes a simple and easy on-bacterium flow cytometric immunoassay for protein quantification, in which Staphylococcus aureus (SAC) is used as an antibody-antigen carrier to replace the polystyrene bead. The SAC beads were prepared by carboxyfluorescein diacetate succinimidyl ester (CFSE) labeling, paraformaldehyde fixation and antibody binding. Carcinoembryonic antigen (CEA) and cytokeratin-19 fragment (CYFRA 21-1) proteins were used as models in the test system. Using prepared SAC beads, biotinylated proteins, and streptavidin-phycoerythrin (SA-PE), the on-bacterium flow cytometric immunoassay was validated by quantifying CEA and CYFRA 21-1 in sample. Obtained data demonstrated a concordant result between the logarithm of the protein concentration and the logarithm of the PE mean fluorescence intensity (MFI). The limit of detection (LOD) in this immunoassay was at least 0.25 ng/ml. Precision and accuracy assessments appeared that either the relative standard deviation (R.S.D.) or the relative error (R.E.) was <10%. The comparison between this immunoassay and a polystyrene bead-based flow cytometric immunoassay showed a correlation coefficient of 0.998 for serum CEA or 0.996 for serum CYFRA 21-1. In conclusion, the on-bacterium flow cytometric immunoassay may be of use in the quantification of serum protein. 23906960 Predicting and preventing postconcussive problems in paediatrics (5P) study: protocol for a prospective multicentre clinical prediction rule derivation study in children with concussion. Persistent postconcussive symptoms (PCSs) is the persistence of somatic, cognitive, physical, psychological and/or behavioural changes lasting more than 1 month following concussion. Persistent concussion impacts the quality of life through impaired cognition, memory and attention affecting school performance, mood and social engagement. No large epidemiological studies have determined the true prevalence of persistent concussion symptoms. Validated, easy-to-use prognosticators do not exist for clinicians to identify children at highest risk. The goal of Predicting and Preventing Postconcussive Problems in Pediatrics study is to derive a clinical prediction rule for the development of persistent postconcussion symptoms in children and adolescents presenting to emergency department following acute head injury. This study is a prospective, multicentre cohort study across nine academic Canadian paediatric emergency departments. We will recruit the largest prospective epidemiological cohort of children with concussion. Eligible children will be followed using Post-Concussion Symptom Inventory, a validated tool in children as young as 5 years. Patients will follow-up at 1, 2, 4, 8 and 12 weeks postinjury. The main outcome will be the presence/absence of PCSs defined as three or more persistent concussion symptoms 1 month following the injury. 1792 patients provide adequate power to derive a clinical decision rule using multivariate analyses to find predictor variables sensitive for detecting cases of persistent postconcussion symptoms. Results of this large prospective study will enable clinicians to identify children at highest risk, optimise treatment and provide families with realistic and appropriate anticipatory guidance. Ethics has been obtained through the Children's Hospital of Eastern Ontario Research Ethics Board. Results will be disseminated at international conferences and in four manuscripts to peer-reviewed journals. This study is registered at Clinicaltrials.gov through the US National Institute of Health/National Library of Medicine (NCT01873287; http://clinicaltrials.gov/ct2/show/NCT01873287). 23558138 Cellular uptake of Clostridium difficile TcdA and truncated TcdA lacking the receptor binding domain. The combined repetitive oligopeptides (CROPs) of Clostridium difficile toxins A (TcdA) and B (TcdB) induce clathrin-mediated endocytosis of the toxins. Inconsistently, CROP-truncated TcdA(1-1874) is also capable of entering host cells and displaying full cytotoxic properties although with less potency. Pre-incubation of cells with isolated CROPs, however, reconstitutes the reduced uptake of TcdA(1-1874) to the level of the full-length toxin. We believe that TcdA exhibits an additional binding motif beyond the C-terminally located CROP domain, which might interact with cellular receptor structures that are associated with alternative internalization pathways. This study therefore evaluated endocytosis routes of CROP-dependent cellular uptake for TcdA and CROP-independent cellular uptake for TcdA(1-1874). Clathrin knockdown or inhibition with chlorpromazine affected subsequent internalization of TcdA and TcdA(1-1874), although only to some extent, arguing for alternative, clathrin-independent endocytosis routes. Inhibition of dynamin, a GTPase essentially involved in clathrin-mediated endocytosis as well as in various clathrin-independent uptake mechanisms, affected uptake of TcdA to the same extent as clathrin inhibition. In contrast, uptake of TcdA(1-1874) was almost completely eliminated in dynamin-inhibited cells. Thus, clathrin-independent uptake of TcdA(1-1874) presumably depends on dynamin. These findings demonstrate that the toxins are endocytosed via complex pathways involving clathrin and dynamin, putatively enabling them to adapt to mechanisms of various cell types. With regard to the emergence of C. difficile strains producing C-terminally truncated toxins, this study emphasizes the relevance of elucidating toxin uptake as a prerequisite for the development of toxin intervention strategies. 23959558 Knockdown of the Hypertension-Associated Gene NOSTRIN Alters Glomerular Barrier Function in Zebrafish (Danio rerio). Hypertension is one of the major risk factors for chronic kidney disease. Using quantitative trait loci analysis, we identified the gene of the F-BAR protein NOSTRIN in the center of an overlapping region in rat and human quantitative trait loci that are associated with hypertension. Immunohistochemical analysis revealed a predominantly podocytic expression pattern of NOSTRIN in human and mouse glomeruli. Further, NOSTRIN colocalizes with cell-cell contact-associated proteins β-catenin and zonula occludens-1 and interacts with the slit-membrane-associated adaptor protein CD2AP. In zebrafish larvae, knockdown of nostrin alters the glomerular filtration barrier function, inducing proteinuria and leading to ultrastructural morphological changes on the endothelial and epithelial side and of the glomerular basement membrane of the glomerular capillary loop. We conclude that NOSTRIN expression is an important factor for the integrity of the glomerular filtration barrier. Disease-related alteration of NOSTRIN expression may not only affect the vascular endothelium and, therefore, contribute to endothelial cell dysfunction but might also contribute to the development of podocyte disease and proteinuria. 23774877 Viral load monitoring as a tool to reinforce adherence: a systematic review. Viral load monitoring has been proposed as a tool to reinforce adherence, but outcomes have never been systematically assessed. A meta-analysis was conducted to systematically analyze the research on viral load monitoring as a tool to reinforce adherence. Viremic resuppression is defined here as a decrease in viral load beneath a particular threshold following viral load levels that have been elevated despite antiretroviral treatment. Six databases were searched for studies published up to November 2012, which reported the use of viral load monitoring as a tool to identify patients in need of adherence support. Three conference abstract sites were reviewed for studies reported in the last 2 years. Randomized and quasi-randomized trials and observational studies, were eligible. No language or geographical restrictions were applied. Six retrospective and 2 prospective observational studies reported data from 8 countries: South Africa, the United States, Thailand, Mali, Burkina Faso, Swaziland, India, and France. Five studies reported on viremic resuppression, with a pooled estimate of 70.5% (95% confidence interval: 56.6% to 84.4%) resuppressed. The remaining 3 studies all reported declines in mean viral load. Delayed onset of routine viral load monitoring was associated with the emergence of drug resistance. The clear trend of resuppression, following viral load testing and adherence support, demonstrates the utility of viral load as a tool to identify patients in need of enhanced adherence support. 23948694 Epithelial expression of extracellular matrix metalloproteinase inducer/CD147 and matrix metalloproteinase-2 in neoplasms and precursor lesions derived from cutaneous squamous cells: An immunohistochemical study. Extracellular matrix metalloproteinase inducer (CD147) is a transmembrane glycoprotein involved in the regulation of matrix metalloproteinases (MMPs). The study investigated CD147 and MMP-2 expression in epidermis of cutaneous squamous lesions. CD147 and MMP-2 expressions were evaluated immunohistochemically in 44 specimens: 18 actinic keratoses (AK), 6 squamous cell carcinomas in situ (SCCIS), 13 squamous cell carcinomas (SCC; peritumoral and invasive portions assessed), and 7 normal skins. Patterns of expression were assessed, with MMP-2 in nuclei (MMP-2n) and cytoplasm (MMP-2c) evaluated separately. The expression of each marker was quantified using a calculated immunohistochemical/histologic score (H-score). Correlations were analyzed for the marker H-scores in each study group. Associations between H-scores and histopathologic parameters were also evaluated. CD147 H-score was the highest in SCC (invasive islands), followed by AK, SCCIS, and control specimens, respectively. MMP-2n and MMP-2c H-scores were the highest in AK, followed by SCCIS, SCC, and control specimens, respectively. MMP-2c and MMP-2n H-scores were significantly higher in peritumoral epidermis than in invasive islands of SCC. MMP-2c and CD147 H-scores were positively correlated in the peritumoral SCCs. CD147 H-score was positively correlated with tumor differentiation in SCC. The findings suggest that overexpression of CD147 plays a role in the development of SCC. 23709603 Rats selectively bred for differences in aerobic capacity have similar hypertensive responses to chronic intermittent hypoxia. Exposure to chronic intermittent hypoxia (CIH) is an animal model that mimics the repetitive bouts of hypoxemia experienced by humans with sleep apnea. Rats exposed to CIH develop hypertension that depends on the activation of sympathetic nerve activity (SNA). Since obesity and metabolic syndrome have been linked to neurogenic hypertension and sleep apnea, and because sleep apnea can adversely affect aerobic exercise capacity, we tested the hypothesis that rats bred for selection of low aerobic capacity running (LCR) would have a greater hypertensive response to CIH than rats bred for high aerobic capacity running (HCR). Blockade of ganglionic transmission was performed to compare the contribution of SNA to the maintenance of resting mean arterial pressure (MAP). Next, hypertensive responses to 7 days of CIH were compared across LCR and HCR rats (14-16 mo old). Finally, the contribution of the hypothalamic paraventricular nucleus (PVN) to the maintenance of SNA and hypertension after CIH was determined and compared across groups. Although LCR rats were less active and had greater body weights than HCR rats, resting MAP, the contribution of ongoing SNA to the maintenance of MAP, and hypertensive responses to CIH were similar between groups. Contrary to our hypothesis, chemical inhibition of the PVN with muscimol (1 mmol/100 nl) caused a larger fall of MAP in HCR rats than in LCR rats. We conclude that LCR rats do not have resting hypertension or an exaggerated hypertensive response to CIH. Interestingly, the maintenance of CIH hypertension in LCR rats compared with HCR rats appears less reliant on ongoing PVN neuronal activity. 22585389 Walking the walk while thinking about the talk: embodied interpretation of metaphorical narratives. Two sets of experiments examined people's embodied understanding of metaphorical narratives. Participants heard one of two stories about a romantic relationship; either one that was successful or one that was not, that initially described it in metaphorical terms as "Your relationship was moving along in a good direction" or nonmetaphorical terms as "Your relationship was very important to you." Participants were then blindfolded and attempted to accurately walk, or imagine walking, to a marker 40 feet away while they thought about the story they just heard. People who heard about the successful metaphorical story walked longer and further than those presented with the unsuccessful relationship story. But these walking and imagining differences disappeared when the critical metaphorical statement "moving along in a good direction" was replaced by a nonmetaphorical expression. These findings, and those from another set of experiments, suggest that people's understanding of metaphorical narratives is partly based on their embodied simulations of the metaphorical actions referred to in these stories. 23828564 Endoplasmic reticulum stress sensitizes pancreatic beta cells to interleukin-1β-induced apoptosis via Bim/A1 imbalance. We have recently shown that the crosstalk between mild endoplasmic reticulum (ER) stress and low concentrations of the pro-inflammatory cytokine interleukin (IL)-1β exacerbates beta cell inflammatory responses via the IRE1α/XBP1 pathway. We presently investigated whether mild ER stress also sensitizes beta cells to cytokine-induced apoptosis. Cyclopiazonic acid (CPA)-induced ER stress enhanced the IL-1β apoptosis in INS-1E and primary rat beta cells. This was not prevented by XBP1 knockdown (KD), indicating the dissociation between the pathways leading to inflammation and cell death. Analysis of the role of pro- and anti-apoptotic proteins in cytokine-induced apoptosis indicated a central role for the pro-apoptotic BH3 (Bcl-2 homology 3)-only protein Bim (Bcl-2-interacting mediator of cell death), which was counteracted by four anti-apoptotic Bcl-2 (B-cell lymphoma-2) proteins, namely Bcl-2, Bcl-XL, Mcl-1 and A1. CPA+IL-1β-induced beta cell apoptosis was accompanied by increased expression of Bim, particularly the most pro-apoptotic variant, small isoform of Bim (BimS), and decreased expression of A1. Bim silencing protected against CPA+IL-1β-induced apoptosis, whereas A1 KD aggravated cell death. Bim inhibition protected against cell death caused by A1 silencing under all conditions studied. In conclusion, mild ER stress predisposes beta cells to the pro-apoptotic effects of IL-1β by disrupting the balance between pro- and anti-apoptotic Bcl-2 proteins. These findings link ER stress to exacerbated apoptosis during islet inflammation and provide potential mechanistic targets for beta cell protection, namely downregulation of Bim and upregulation of A1. 23848400 Emerging drugs on methicillin-resistant Staphylococcus aureus. Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) has proven to be a prominent pathogen in hospitals and in the community, which is capable of causing a variety of severe infections. Until now, there has been a limited antimicrobial armamentarium for use against MRSA, of which glycopeptides and linezolid are the main agents used. Areas covered: This review assesses current treatment and the agents being developed for MRSA infections. A search was conducted in PubMed for English-language references published from 2000 to 2013, using combinations of the following terms: 'MRSA', 'MRSA therapy', 'gram (+) infections therapy', 'new antibiotics', 'vancomycin', 'staphylococcus resistance', 'oritavancin', 'ceftaroline', 'linezolid' and 'tigecycline'. The clinicalTrials website was also searched with keywords regarding the new antibiotic agents against MRSA infections. Expert opinion: There are a number of new agents, the place of which in therapeutic regimens is yet to emerge. New glycopeptides, such as dalbavancin and oritavancin, with long half-lives, enabling once-weekly dosing, and oral agents, such as iclaprim, may provide a treatment approach for outpatient therapy. A decision must be made regarding the most suitable agent for an individual patient, the site of infection and the place of therapy. 23378034 Nonshared environmental effects on adulthood psychopathic personality traits: results from a monozygotic twin difference scores analysis. An emerging body of empirical research has revealed that nonshared environmental factors are associated with explaining variance in measures of psychopathy and psychopathic personality traits. The current study adds to this existing knowledge base by analyzing a measure of psychopathy derived, in part, from the five factor model in a sample of monozygotic (MZ) twin pairs drawn from the National Longitudinal Study of Adolescent Health. The results of the MZ twin difference scores analysis revealed that nonshared environmental factors found within the family were unrelated to between-twin differences in psychopathic personality traits. Only one nonshared factor-levels of self-control-consistently predicted psychopathy. We conclude by discussing the implications of our findings and the limitations of our study. 23666494 Evaluation of zona pellucida function for sperm penetration during in vitro fertilization in pigs. In porcine oocytes, the function of the zona pellucida (ZP) with regard to sperm penetration or prevention of polyspermy is not well understood. In the present study, we investigated the effects of the ZP on sperm penetration during in vitro fertilization (IVF). We collected in vitro-matured oocytes with a first polar body (ZP+ oocytes). Some of them were freed from the ZP (ZP- oocytes) by two treatments (pronase and mechanical pipetting), and the effects of these treatments on sperm penetration parameters (sperm penetration rate and numbers of penetrated sperm per oocyte) were evaluated. There was no evident difference in the parameters between the two groups. Secondly, we compared the sperm penetration parameters of ZP+ and ZP- oocytes using frozen-thawed epididymal spermatozoa from four boars. Sperm penetration into ZP+ oocytes was found to be accelerated relative to ZP- oocytes. Thirdly, we evaluated the sperm penetration of ZP+ and ZP- oocytes at 1-10 h after IVF (3 h gamete co-incubation). The proportions of oocytes penetrated by sperm increased significantly with time in both groups; however, the number of penetrated sperm per oocyte did not increase in ZP- oocytes. Finally, we performed IVF using ZP- oocytes divided into control (3 h) and prolonged gamete co-incubation (5 h) groups. Greater numbers of sperm penetrated in the 5 h group than in the control group. These results suggest that the ZP and oolemma are not competent factors for prevention of polyspermy in our present porcine IVF system. However, it appears that ZP removal is one of the possibilities for reducing polyspermic penetration in vitro in pigs. 23665750 Right but not left angular gyrus modulates the metric component of the mental body representation: a tDCS study. The parietal lobes contribute to body-space representation. The present work aims at characterizing the functional role of the inferior parietal lobe in body-space representation and at studying the different roles of the angular gyrus in the right and left hemisphere. We conducted three separate transcranial direct current stimulation (tDCS) experiments using "tactile distance task" as an implicit measure of body representation. Whereas anodal tDCS on the right angular gyrus influences vocal reaction times (vRT) for stimuli delivered on the ipsilateral body parts without changes of accuracy, right tDCS improved both vRT and accuracy for tactile stimuli on the contralateral limbs. Sham or left parietal anodal tDCS had no effect. These evidences support the view that right parietal areas have a crucial role in the metric component of the body representation. 23899187 Aberrant NDRG1 methylation associated with its decreased expression and clinicopathological significance in breast cancer. Cancer cell differentiation is an important characteristic of malignant tumor and has a great impact on prognosis and therapeutic decision for patients. The N-myc downstream regulated gene 1 (NDRG1), a putative tumor suppression gene, is involved in the regulation of human cell differentiation and metastasis in various cancers. Changes in the status of methylation of the NDRG1 gene have not been studied in detail in human breast cancer. The MDA-MB-231 breast tumor cell line could express NDRG1. However, it was only expressed after treatment with 5-Aza-2'-deoxycytidine (AZA) in T47D cell line, which revealed that NDRG1 expression could modulated by DNA methylation. Therefore, the fragment surrounding the transcript start site of NDRG1 gene promoter was cloned after sodium bisulfite DNA treatment. A high density (66%) of methylation for human NDRG1 gene promoter was detected in T47D; however, there was only 16% of methylated CpG dinucleotides in the NDRG1 gene promoter in MDA-MB-231. DNA methylation in the NDRG1 promoter was detected in 31.1% of primary breast cancer samples. Furthermore, the NDRG1 promoter methylation correlated with the Tumor Node Metastasis (TNM) at stage III/IV, metastasis, lymph invasion, moderate and poor histological grade in the breast cancer patients. These findings suggest that the DNA methylation status of NDRG1 gene may play an important role in the pathogenesis and/or development of breast cancer, and the expression could be regulated by aberrant DNA methylation. 23936216 Mitogenomes from Two Uncommon Haplogroups Mark Late Glacial/Postglacial Expansions from the Near East and Neolithic Dispersals within Europe. The current human mitochondrial (mtDNA) phylogeny does not equally represent all human populations but is biased in favour of representatives originally from north and central Europe. This especially affects the phylogeny of some uncommon West Eurasian haplogroups, including I and W, whose southern European and Near Eastern components are very poorly represented, suggesting that extensive hidden phylogenetic substructure remains to be uncovered. This study expanded and re-analysed the available datasets of I and W complete mtDNA genomes, reaching a comprehensive 419 mitogenomes, and searched for precise correlations between the ages and geographical distributions of their numerous newly identified subclades with events of human dispersal which contributed to the genetic formation of modern Europeans. Our results showed that haplogroups I (within N1a1b) and W originated in the Near East during the Last Glacial Maximum or pre-warming period (the period of gradual warming between the end of the LGM, ∼19 ky ago, and the beginning of the first main warming phase, ∼15 ky ago) and, like the much more common haplogroups J and T, may have been involved in Late Glacial expansions starting from the Near East. Thus our data contribute to a better definition of the Late and postglacial re-peopling of Europe, providing further evidence for the scenario that major population expansions started after the Last Glacial Maximum but before Neolithic times, but also evidencing traces of diffusion events in several I and W subclades dating to the European Neolithic and restricted to Europe. 23519637 LC analysis and pharmacokinetic study of synthetic piperlonguminine in rat plasma after oral administration. Only one kind of synthesized alkaloid, piperlonguminine, was used to understand the interference of the other alkaloids in pharmacokinetic study using HPLC/UV in rat plasma after oral administration. Compared with the previous report, it was clarified that mixed alkaloids such as piperine and the other extract from Piper longum Linn did not interfere with the results. 23831564 When pictures lie: Children's misunderstanding of photographs. In three experiments we examined duality of representation for photographs in young children. Three- to four-year-olds were shown a target item which was then hidden. A sticker was placed on a photograph of this target and children, asked to retrieve the referent, were faced with a choice between a stickered and un-stickered version. Children brought back a stickered distracter object, as if the action to the photograph had modified the object. Control conditions demonstrated that these errors could not be attributed to memory failure or bias towards stickered objects. Experiment 2 indicated that children's errors depended on the sticker being placed directly on the image on the photograph and were not due to signalling which object to choose. A final experiment demonstrated that this effect could be observed under circumstances involving more substantial changes to objects: Here, children acted as if wetting a photograph of an object would cause the object itself to become wet. We interpret these results as evidence that an immature comprehension of photographs fails to take into account the episodic and symbolic referential nature of photographs. 23848294 Modifications of plasma 5-HT concentrations during the allergic bronchoconstriction in guinea pigs. ABSTRACT Several contractile mediators involved in the antigen-induced airway obstruction have been identified, but the role of 5-HT (5-hydroxytryptamine or serotonin) has been scantily investigated. In this work, the potential role of 5-HT in the allergic bronchoconstriction was evaluated through a pharmacological approach and plasma 5-HT measurement in blood samples from the right and left ventricles of anesthetized guinea-pigs. Intravenous 5-HT caused a dose-dependent increase of the lung resistance in anesthetized, nonsensitized guinea pigs. Likewise, in sensitized animals the antigenic challenge with ovalbumin also caused a transient bronchoconstriction (356 ± 60% the basal value), which was largely inhibited by the blockade of serotonergic receptors with methiothepin plus tropisetron (134 ± 10%, P = .007). Sensitized animals tended to have plasma 5-HT concentrations higher than nonsensitized controls, and shortly after the peak of the allergic bronchoconstriction the 5-HT levels in the left ventricle (blood flowing out from lungs) tended to be higher than in the right ventricle (blood entering the lungs), although data dispersion precluded the obtaining of statistical significance. Interestingly, the degree of bronchoconstriction highly correlated with the concentrations of 5-HT found in the left ventricle and measured either in platelet-rich plasma (r = 0.97 P = .007) or platelet-poor plasma (r = 0.97, P = .006). After the obstructive response subsided these correlations were lost, but now the degree of bronchoconstriction turned to be correlated with 5-HT concentration in platelet concentrate (r = 0.76, P = .03). In conclusion, our results suggested that 5-HT is actively released from lungs during the antigenic challenge and that this autacoid is involved in the generation of the airway obstruction. 23607283 Morphometric and Functional Changes of Salivary Gland Dysfunction after Radioiodine Ablation in a Murine Model. Background: Ablation of the thyroid tissue using radioiodine (RI) after the surgical removal of well-differentiated thyroid cancer (WDTC) can induce radiation-related salivary gland (SG) dysfunction. However, in vivo changes of SGs following RI administration in appropriate animal models are not well described in the literature. This study was undertaken to document morphometric and functional changes during the 12 months following RI administration in a murine model of RI-induced SG dysfunction. Methods: Female C57BL/6, 4-week-old mice (n=60) were divided into a RI-treated group (n=30) that received RI orally (0.01 mCi/g body weight) or an unexposed control group (n=30). Mice in both groups were divided into five subgroups (n=6 per subgroup) and sacrificed at 1, 2, 3, 6, and 12 months post-RI administration. Salivary flow rates (SFR) and salivary lag times were measured at 1, 2, 3, 6, and 12 months after RI administration. Morphological and histological examinations and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were performed. In addition, changes in salivary 99m Tc pertechnetate uptake and excretion were observed by single-photon emission computed tomography (SPECT). Results: In RI-treated mice, the SGs were significantly lighter compared to unexposed controls at all study time points. Lag times to salivation in the RI-treated group were greater than in the unexposed controls, but mean SFR were lower. Histologic examinations of SGs in the RI-group showed pale cytoplasm, atypical ductal configuration, septal widening, cytoplasmic vacuolization with pleomorphism, lymphocyte infiltration, and increased fibrosis. Furthermore, more apoptotic cells were observed in acini and ducts in the RI group. In addition, patterns of 99m Tc pertechnetate uptake and excretion in the RI-group were quite different from those observed in controls at 1 and 12 months post-RI. Conclusion: Various histological alterations were observed in mice exposed to radioiodine, that is, an increase in apoptotic acini and ductal cells and functional SG deterioration. The murine model of RI-induced SG dysfunction used in the present study appears to be applicable to preclinical research on RI -induced sialadenitis in patients with WDTC. 23194538 Characterization and identification of the chemical constituents from tartary buckwheat (Fagopyrum tataricum Gaertn) by high performance liquid chromatography/photodiode array detector/linear ion trap FTICR hybrid mass spectrometry. In recent years tartary buckwheat has become popular healthful food due to its antioxidant, antidiabetic and antitumor activities. However, its chemical constituents have not yet been fully characterized and identified. In this paper, a novel high performance liquid chromatography coupled with photodiode array detector and linear ion trap FTICR hybrid mass spectrometry (HPLC-PDA/LTQ-FTICRMS) method was established to characterize and identify a total of 36 compounds by a single run. The retention time, maximum UV absorption wavelength, accurate mass weight and characteristic fragment ions were collected on line. To confirm the structures, 11 compounds were isolated and identified by MS and NMR experiments. 1, 3, 6, 6'-tetra-feruloyl sucrose named taroside was a new phenlypropanoid glycoside, together with 3, 6-di-p-coumaroyl-1, 6'-di-feruloyl sucrose, 1, 6, 6'-tri-feruloyl-3-p-coumaroyl sucrose, N-trans-feruloyltyramine and quercetin-3-O-[β-D-xyloxyl-(1→2)-α-L-rhamnoside] were isolated for the first time from the Fagopyrum species. The research enriched the chemical information of tartary buckwheat. 23924102 Hospitals take up students' designs. Innovative ideas for improving patient care created by a university's nursing and midwifery students are being used or considered by NHS trusts. 23831575 NO/cGMP/PKG signaling pathway induces magnesium release mediated by mitoKATP channel opening in rat hippocampal neurons. Intracellular Mg(2+) concentration ( [Formula: see text] ) and NO regulate cell survival and death. To reveal the involvement of NO in intracellular Mg(2+) regulation, we visualized intracellular Mg(2+) using the fluorescent Mg(2+) indicator KMG-104-AM in rat hippocampal neurons. Pharmacological experiments using SNAP, 8-Br-cGMP, diazoxide and several inhibitors revealed that the NO/cGMP/Protein kinsase G (PKG) signaling pathway triggers an increase in [Formula: see text] , and that Mg(2+) mobilization is due to Mg(2+) release from mitochondria induced by mitoKATP channel opening. In addition, Mg(2+) release is potentiated by the positive feedback loop including mitoKATP channel opening, mitochondrial depolarization and PKC activation. 23948724 Overproduction of poly(β-malic acid) (PMA) from glucose by a novel Aureobasidium sp. P6 strain isolated from mangrove system. After over 100 strains of Aureobasidium spp isolated from mangrove system were screened for their ability to produce poly(β-malic acid) (PMA), it was found that Aureobasidium sp. P6 strain among them could produce high level of Ca(2+)-PMA. Fourteen percent glucose and 6.5 % CaCO3 in the medium were the most suitable for Ca(2+)-PMA production. Then, 100.7 g/l of Ca(2+)-PMA was produced using Aureobasidium sp. P6 strain within 168 h at flask level. During 10-l batch fermentation, when the medium contained 12.0 % glucose, 98.7 g/l of Ca(2+)-PMA in the culture and 14.7 g/l of cell dry weight were obtained within 156 h, leaving 0.34 % reducing sugar in the fermented medium. When glucose concentration in the fermentation medium was 14.0 %, 118.3 g/l of Ca(2+)-PMA in the culture and 16.4 g/l of cell dry weight were obtained within 168 h, leaving 0.4 % reducing sugar in the fermented medium. After purification of Ca(2+)-PMA from the culture and acid hydrolysis of the pure Ca(2+)-PMA, analysis of HPLC showed that Aureobasidium sp. P6 strain only produced two main components of Ca(2+)-PMA and minor amount of calcium malate and that the hydrolysate of PMA was mainly composed of calcium malate. This is the first time to report that the novel yeast strain Aureobasidium sp. P6 strain isolated from the mangrove systems can produce such high amount of Ca(2+)-PMA. 23860911 Combining sperm plug genotyping and coat color chimerism predicts germline transmission. There has been a significant increase in the use of C57BL/6N-derived ES cells for the production of gene knockout mice. However, the potential for germline transmission (GLT) from chimeras on this genetic background has been observed to be highly variable. Using coat color as an indicator of somatic chimerism to infer the extent of chimeric contribution to the germ cell population, even highly agouti C57BL/6N-derived chimeras can fail to achieve GLT. We investigated the extent to which quantitative PCR genotyping for a marker gene expressed in gene targeted ES cells can be performed on DNA extracted from sperm present in copulatory plugs to determine the contribution of ES cells to the germ cells. We found that an objective assessment of sperm DNA from copulatory plugs combined with a subjective assessment of coat color chimerism can be used to accurately inform the selection of chimeras for breeding that are likely to achieve GLT. These results indicate that, compared to random selection of chimeras, including an analysis of copulatory plugs to set chimeras for breeding can help to reduce costs, minimize time, and facilitate research for projects requiring the production, selection, breeding, and testing of chimeras to generate gene-targeted mice. 23470554 Contribution made by parabiosis to the understanding of energy balance regulation. Parabiosis is a chronic preparation that allows exchange of whole blood between two animals. It has been used extensively to test for involvement of circulating factors in feedback regulation of physiological systems. The total blood volume of each animal exchanges approximately ten times each day, therefore, factors that are rapidly cleared from the circulation do not reach equilibrium across the parabiotic union whereas those with a long half-life achieve a uniform concentration and bioactivity in both members of a pair. Involvement of a circulating factor in the regulation of energy balance was first demonstrated when one member of a pair of parabiosed rats became hyperphagic and obese following bilateral lesioning of the ventromedial hypothalamus. The non-lesioned partner stopped eating, lost a large amount of weight and appeared to be responding to a circulating "satiety" factor released by the obese rat. These results were confirmed using different techniques to induce obesity in one member of a pair. Studies with phenotypically similar ob/ob obese and db/db diabetic mice indicated that the obese mouse lacked a circulating signal that regulated energy balance, whereas the diabetic mouse appeared insensitive to such a signal. Positional cloning studies identified leptin as the circulating factor and subsequent parabiosis studies confirmed leptin's ability to exchange effectively between parabionts. These studies also suggest the presence of additional unidentified factors that influence body composition. This article is part of a Special Issue entitled: Animal Models of Disease. 23829673 The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration. Most neurons are born with the potential to live for the entire lifespan of the organism. In addition, neurons are highly polarized cells with often long axons, extensively branched dendritic trees and many synaptic contacts. Longevity together with morphological complexity results in a formidable challenge to maintain synapses healthy and functional. This challenge is often evoked to explain adult-onset degeneration in numerous neurodegenerative disorders that result from otherwise divergent causes. However, comparably little is known about the basic cell biological mechanisms that keep normal synapses alive and functional in the first place. How the basic maintenance mechanisms are related to slow adult-onset degeneration in different diseasesis largely unclear. In this review we focus on two basic and interconnected cell biological mechanisms that are required for synaptic maintenance: endomembrane recycling and calcium (Ca2+) homeostasis. We propose that subtle defects in these homeostatic processes can lead to late onset synaptic degeneration. Moreover, the same basic mechanisms are hijacked, impaired or overstimulated in numerous neurodegenerative disorders. Understanding the pathogenesis of these disorders requires an understanding of both the initial cause of the disease and the on-going changes in basic maintenance mechanisms. Here we discuss the mechanisms that keep synapses functional over long periods of time with the emphasis on their role in slow adult-onset neurodegeneration. 23906997 HIV and HCV among people who inject drugs in Central Asia. Over the last decade, Central Asia has become a focal point of HIV and hepatitis C virus (HCV) transmission among people who inject drugs (PWID). PWID account for the majority of HIV infections in most countries in the region, while a large proportion have been exposed to HCV. Shared modes of transmission of these infections point to an increasing burden of HIV/HCV co-infection in this population. HIV/HCV co-infection is more likely to result in progressive liver disease, increased mortality and hepatic complications from antiretroviral therapy (ART). While the HIV treatment response has improved, less than a quarter of people living with HIV (PLHIV) in the region are receiving ART, with treatment uptake among PWID particularly low. HCV treatment is available in some areas, though at a very high cost to patients thereby preventing access to those at most need. Robust surveillance of HIV/HCV infection among PWID is needed to inform a comprehensive response to HIV and HCV prevention and treatment among PWID, including increasing coverage of opioid substitution therapy (OST) and needle and syringe programs (NSPs), improving access and uptake of ART, and lowering costs and other barriers to HCV treatment across the five republics. Optimising uptake of these initiatives by increasing prevention and treatment literacy among PWID and decreasing barriers to screening and testing will also be necessary to mitigate the increasing burden of HIV/HCV co-infection in the region. 23348151 New insight into the discharge mechanism of silicon-air batteries using electrochemical impedance spectroscopy. The mechanism of discharge termination in silicon-air batteries, employing a silicon wafer anode, a room-temperature fluorohydrogenate ionic liquid electrolyte and an air cathode membrane, is investigated using a wide range of tools. EIS studies indicate that the interfacial impedance between the electrolyte and the silicon wafer increases upon continuous discharge. In addition, it is shown that the impedance of the air cathode-electrolyte interface is several orders of magnitude lower than that of the anode. Equivalent circuit fitting parameters indicate the difference in the anode-electrolyte interface characteristics for different types of silicon wafers. Evolution of porous silicon surfaces at the anode and their properties, by means of estimated circuit parameters, is also presented. Moreover, it is found that the silicon anode potential has the highest negative impact on the battery discharge voltage, while the air cathode potential is actually stable and invariable along the whole discharge period. The discharge capacity of the battery can be increased significantly by mechanically replacing the silicon anode. 23861238 In-situ Formation and Assembly of Gold Nanoparticles by Gum Arabic as Efficient Photothermal Agent for Killing Cancer Cells. Gold nanoparticles (AuNPs) have been established to sufficiently eradicate tumors by means of heat production for photothermal therapy. However, the translation of the AuNPs from bench to the clinic still remains to be solved until realizing high bioclearance after treatment. Herein, we developed a simple strategy for simultaneous formation and assembly of small-size gold nanoparticles (Au-SNPs) to form a novel nanocomposite in the presence of gum arabic (GA) by synchrotron X-ray irradiation in an aqueous solution within 5 min. GA, a porous polysaccharide, can not only provide a confined space in which to produce uniform Au-SNPs (1.6 ± 0.7 nm in diameter), but can also facilitate the formation of Au-SNPs@GA (diameter ≈ 40 nm) after irradiating synchrotron X-rays. Specifically, the Au-SNPs@GA possesses high thermal stability and a strong photothermal effect for killing cancer cells. Importantly, a bioclearance study demonstrated that the Au-SNPs@GA can be gradually excreted by the renal and hepatobiliary system, which might be due to the breakdown and oxidation of GA under irradiating synchrotron X-rays. Thus, the novel gold nanocomposite can be promising photothermal agents for cancer treatment at the therapeutic level, minimizing toxicity concerns regarding long-term accumulation in vivo. 23640082 Molecular characterization and primary functional analysis of PeVDE, a violaxanthin de-epoxidase gene from bamboo (Phyllostachys edulis). PeVDE was expressed primarily in bamboo leaves, which was up-regulated under high light. The protein encoded by PeVDE had enzyme activity of catalyzing violaxanthin (V) to zeaxanthin (Z) through antheraxanthin (A) as assay shown in vitro. Violaxanthin de-epoxidase (VDE), a key enzyme of xanthophyll cycle, catalyzes conversion from violaxanthin (V) to zeaxanthin (Z) through antheraxanthin (A) to protect photosynthesis apparatus. A cDNA, PeVDE, encoding a VDE was isolated from bamboo (Phyllostachys edulis) by RT-PCR and RACE methods. PeVDE is 1,723 bp and contains an ORF encoding 451 amino acids, with a transit peptide of 103 amino acids. The mature protein is deduced to have 348 amino acids with a calculated molecular weight of 39.6 kDa and a theoretic isoelectric point of 4.5. Semi-quantitative RT-PCR assay indicated that the highest expression level of PeVDE was in leaf, which agreed with the accumulation pattern of PeVDE protein. Real time PCR results showed that PeVDE was up-regulated and reached the highest level after the treatment (1,200 Î¼mo1 m(-2) s(-1)) for 2 h, then decreased and kept at the level similar to that of 0.5 h after treatment for 8 h. To investigate the function of PeVDE, mature protein was heterologously expressed in Escherichia coli and the enzymatic activity assay was carried out using V as substrate. The pigments that formed in the reaction mixture were extracted and analyzed by HPLC method. Besides V, A and Z were detected in the reaction mixture, which indicated that the recombinant protein exhibited enzymatic activity of catalyzing V into Z through A. This study indicates that PeVDE functions through regulating the components of xanthophyll cycle, which might be one of the critical factors that contribute to the growth of bamboo under naturally varying light conditions. 23456945 Cadmium adsorption by willow root: the role of cell walls and their subfractions. Plant cell walls may play an important role in the uptake and accumulation of heavy metals. This study was undertaken to obtain a better understanding of the role of the root cell walls (RCW) and their subfractions on adsorption of cadmium (Cd) in a promising woody phytoremediation species, Salix jiangsuensis J172. In order to examine how Cd binding was affected by pectin and hemicellulose, RCW were isolated and sequentially fractioned by removing pectin (RCW1), partial removal of hemicellulose (RCW2), and complete removal of hemicellulose (RCW3). The RCW and fractions were characterized by Fourier transform infrared spectroscopy, which suggested decomposition of hemicellulose and a decline in nitrogen content following cell wall isolation and fractionation. The adsorption affinity of Cd increased gradually following the sequential extraction of root cells, suggesting that hemicellulose negatively impacted Cd adsorption, while pectin and cellulose enhanced Cd adsorption. Cd adsorption dynamics and isotherms could be best described by the pseudo-second-order (R > 0.99) and Freundlich (R > 0.97) models, respectively. Thermodynamic properties (∆G, ∆H, and ∆S), determined using the van't Hoff equation, indicated that while Cd adsorption was endothermic, and spontaneous for RCW2 and RCW3, adsorption was not spontaneous for the root, RCW, and RCW1. The results provide evidence for the importance of the root cell walls in the adsorption of Cd by willow roots. 23098820 Four disruptive strategies for removing drug discovery bottlenecks. Drug discovery is shifting focus from industry to outside partners and, in the process, creating new bottlenecks. Technologies like high throughput screening (HTS) have moved to a larger number of academic and institutional laboratories in the USA, with little coordination or consideration of the outputs and creating a translational gap. Although there have been collaborative public-private partnerships in Europe to share pharmaceutical data, the USA has seemingly lagged behind and this may hold it back. Sharing precompetitive data and models may accelerate discovery across the board, while finding the best collaborators, mining social media and mobile approaches to open drug discovery should be evaluated in our efforts to remove drug discovery bottlenecks. We describe four strategies to rectify the current unsustainable situation. 23543158 The triple gene block movement proteins of a grape virus in the genus Foveavirus confer limited cell-to-cell spread of a mutant Potato virus X. Grapevine rupestris stem pitting-associated virus (GRSPaV) is a member of the genus Foveavirus in the family Betaflexiviridae. The genome of GRSPaV encodes five proteins, among which are three movement proteins designated the triple gene block (TGB) proteins. The TGB proteins of GRSPaV are highly similar to their counterparts in Potato virus X (PVX), as reflected in size, modular structure, conservation of critical amino acid sequence motifs, as well as similar cellular localization. Based on these similarities, we predicted that the TGB proteins of these two viruses would be interchangeable. To test this hypothesis, we replaced the entire or partial sequence of PVX TGB with the corresponding regions from GRSPaV, creating chimeric viruses that contain the PVX backbone and different sequences from GRSPaV TGB. These chimeric constructs were delivered into plants of Nicotiana benthamiana through agro-infiltration to test whether they were capable of cell-to-cell and systemic movement. To our surprise, viruses derived from pPVX.GFP(CH3) bearing GRSPaV TGB in place of PVX TGB lost the ability to move either cell-to-cell or systemically. Interestingly, another chimeric virus resulting from pPVX.GFP(HY2) containing four TGB genes (TGB1 from PVX and TGB1-3 from GRSPaV), exhibited limited cell-to-cell, but not systemic, movement. Our data question the notion that analogous movement proteins encoded by even distantly related viruses are functionally interchangeable and can be replaced by each other. These data suggest that other factors, besides the TGB proteins, may be required for successful intercellular and/or systemic movement of progeny viruses. This is the first experimental demonstration that the GRSPaV TGB function as movement proteins in the context of a chimeric virus and that four TGB genes were required to support the intercellular movement of the chimeric virus. 23835227 Protein engineering with unnatural amino acids. Protein engineering has become an extensively used tool in many fields, allowing us to probe protein function, characterize proteins using a range of biophysical techniques, chemically modify proteins and improve protein function for medical and industrial applications. It is now possible to site-specifically incorporate unnatural, or non-canonical, amino acids (uAAs) into proteins, which has had a major impact on protein engineering. In this review, we discuss the recent technical developments in the field and how uAA-protein engineering is becoming an increasingly valuable molecular tool, with the unique chemical functionalities of some uAAs allowing a range of otherwise impossible experiments to be performed. Finally, the impediments that have resulted in a relatively small number of recent studies in which uAA-protein engineering has been used to improve protein function are discussed, alongside some of the recent technical developments that may serve to overcome these obstacles. 23930745 Syntheses and Structural Characterizations of Inorganic ansa-Metallocene Analogues: ansa-Ferratricarbadecaboranes. New linked cyclopentadienyl-tricarbadecaboranyl and bis-tricarbadecaboranyl dianions have been used to form the first examples of ansa-metallatricarbadecaboranyl complexes. The hybrid cyclopentadienyl-tricarbadecaboranyl dianion, Li2(+)[6-C5H4-(CH2)2-nido-5,6,9-C3B7H9](2-) (1), was produced by an initial carbon-insertion reaction of a nitrile-substituted cyclopentadiene with the arachno-4,6-C2B7H12(-) anion, followed by deprotonation to the dianion with LiH. The linked-cage bis-tricarbadecaboranyl dianion, Li2(+)[6,6'-(CH2)2-nido-(5,6,9-C3B7H9)2](2-) (2), was produced by a similar carbon-insertion route involving the reaction of two equivalents of arachno-4,6-C2B7H12(-) with succinonitrile. The reaction of 1 with an equivalent of FeCl2 produced the hybrid complex, ansa-(2-(CH2)2)-(1-η(5)-C5H4-closo-1,2,3,4-C3B7H9)Fe (3), with a crystallographic determination confirming the formation of a sandwich structure where the ring and cage are linked by the ansa -CH2CH2- group with attachment to the cage at the C2 carbon. The reaction of 2 with FeCl2 produced three isomeric ansa-(CH2)2-ferrabistricarbadecaboranyl sandwich complexes, ansa-(CH2)2-(closo-C3B7H9)2Fe (4, 5 and 6). Crystallographic determinations showed that in 4, the two tricarbadecaboranyl ligands are linked by the ansa-CH2CH2- group at the C2 and C2' cage carbons, whereas in 5 and 6 they are linked at their C2 and C4' carbons, with the structures of 5 and 6 differing in the relative positions of the C4' carbons in the two cages of each complex. The structural determinations also showed that, depending upon the linking position of the ansa-tether, constraints in cage-orientation, such as observed in 4, produce unfavorable intercage steric interactions. However, the cage fragments in these complexes can readily undergo a cage-carbon migration that moves one -carbon and its tether linkage to the more favorable 4-position. This isomerization reduces the cage steric interactions and produces configurations, such as those found for 5 and 6, where the iron cage bonding is enhanced as a result of the binding effect of the tether. 23713583 Antiphospholipid antibodies mediate autoimmunity against dying cells. The Antiphospholipid Syndrome (APS) is characterized by thrombosis and pregnancy loss, clinical events mediated by pathogenic anti-phospholipid autoantibodies (aPL). β2-glycoprotein I (β2GPI) is the major autoantigens recognized by aPL. β2GPI is a cationic protein that binds to negatively charged surfaces such as those of apoptotic cells. This feature may lead to two major events: i) immunization with β2GPI fosters the Fc-receptor-mediated uptake by antigen presenting cells of apoptotic material decorated with β2GPIand the activation ofβ2GPI-specific T cells which in turn provide help to β2GPI-specific B cells for the production of anti-β2GPI; ii) apoptotic bodies decorated with β2GPI can be opsonized by anti-β2GPI and shifted towards a pro-inflammatory clearance by macrophages; epitope spread can occur with the generation of autoimmunity against nuclear autoantigens. In the presence of a predisposing genetic background and of a particular cytokine environment (type I interferons), the sequential emergence of autoantibodies can evolve into overt clinical disease. The spectrum of clinical phenotypes of the patients can be modulated by several factors affecting the pathogenicity of anti-β2GPI (e.g. domain specificity). We conclude that dying cells may play a dual role in APS: (I) as immunogen for the induction of aPL (etiology) and (II) as targets of aPL for the chronification of inflammation and the development of autoimmune diseases (pathology). 23543825 Cold tolerance in Osmotin transgenic tomato (Solanum lycopersicum L.) is associated with modulation in transcript abundance of stress responsive genes. Our containment trials have established cold tolerance in Nicotiana tabacum osmotin (Nt Osm) transgenic tomato (Solanum lycopersicum L. cv. Pusa Ruby). Though, the stress tolerance mechanisms have been studied at physio-biochemical levels, molecular mechanisms underlying the tolerant response are still not well studied. Therefore, quantitative transcript expression of Osmotin and other stress responsive genes (CBF1, P5CS and APX) was studied in response to cold (4°C; 2 and 24 h) treatment in the transgenic and wild type tomato plants. The expression analysis revealed differential transcript regulation in the transgenic and wild type plants on the cold exposure. In general, the genes were either earlier induced or the extent of fold change in transcript expression over the respective untreated controls was higher in transgenic than in the wild type plants on cold exposure. The transcript expression data also supported the metabolite analysis on free Proline and ascorbate content. The results thus suggest that constitutive over expression of the Osmotin modulate transcript abundance and functional expression products of the other stress responsive genes thereby, imparting cold tolerance in the transgenic tomato plants. 23886971 A multidirectional fracture stiffness model to determine the principal stiffness properties of a healing human tibia. A model for the stiffness of a fractured human tibia has been developed. The model is based on Mohr's circle of inertia and relies on tibial fracture stiffness being measured in a number of planes. Using in vitro data, it has been shown that this model can be used to identify the principal stiffness values and their associated planes. It has also been shown that only 4/5 independent measurements are required to generate good correlation between experimental data and fitted data. Initial in vivo experiments show that this model transfers from the laboratory to clinical practice. The model illustrated that the maximum plane for a complete tibia is about 12°-14° relative to anterior-posterior, which correlates with previous publications. It is postulated that the model can be used for further in vitro studies to confirm the most common angle of the minimum stiffness plane. The knowledge of this angle may help orthopaedic surgeons to better assess fracture stiffness and may be the starting point for further discussion about the current minimum value of 15 N m/°. 23883177 The Active for Life Year 5 (AFLY5) school-based cluster randomised controlled trial protocol detailed statistical analysis plan. The Active For Life Year 5 (AFLY5) randomised controlled trial protocol was published in this journal in 2011. It provided a summary analysis plan. This publication is an update of that protocol and provides a detailed analysis plan.Update: This update provides a detailed analysis plan of the effectiveness and cost-effectiveness of the AFLY5 intervention. The plan includes details of how variables will be quality control checked and the criteria used to define derived variables. Details of four key analyses are provided: (a) effectiveness analysis 1 (the effect of the AFLY5 intervention on primary and secondary outcomes at the end of the school year in which the intervention is delivered); (b) mediation analyses (secondary analyses examining the extent to which any effects of the intervention are mediated via self-efficacy, parental support and knowledge, through which the intervention is theoretically believed to act); (c) effectiveness analysis 2 (the effect of the AFLY5 intervention on primary and secondary outcomes 12 months after the end of the intervention) and (d) cost effectiveness analysis (the cost-effectiveness of the AFLY5 intervention. The details include how the intention to treat and per-protocol analyses were defined and planned sensitivity analyses for dealing with missing data. A set of dummy tables are provided in Additional file 1. This detailed analysis plan was written prior to any analyst having access to any data and was approved by the AFLY5 Trial Steering Committee. Its publication will ensure that analyses are in accordance with an a priori plan related to the trial objectives and not driven by knowledge of the data.Trial registration: ISRCTN50133740. 23561852 The functional demand (FD) placed on the knee and hip of older adults during everyday activities. Age-related decline in physical capacity and diminishing physiological reserves may increase the demand placed on lower extremity joints during everyday activities. This study aimed to characterize the FD at the knee and hip joints of older adults during various mobility activities. Eighty-four healthy participants (60-88 years) performed strength tests using a custom-built dynamometer. Biomechanical assessment of gait, chair rise (CR) and sit-down (CSt), stair ascent (SA) and descent (SD) was performed using an 8-camera VICON system (120Hz) and Kistler force plates. Comparisons between groups (60s, 70s and 80s) were made using ANOVA. The FD was defined as the muscle moment generated during a task, divided by the maximum isometric strength (expressed as a percentage). FD was higher in the 80s age group compared to those in the 60s. The demand on hip and knee extensors was normally higher than those of flexors across all the activities. The knee extensor demand during gait (101%), SA (103%) and SD (120%), and hip extensor demand during gait (127%) were high requiring moments in excess of the maximum isometric muscle strength available at these joints. FD during CR and CSt was comparatively lower with knee extensor demands of 73% and 69% and hip extensor demands of 88% and 51%, respectively. Gait, SA and SD placed high demands on the knee extensors while hip extensor demand was high for gait, CR, CSt and SA. The levels of demand leave little reserve capacity for the older adult to draw on in unexpected circumstances. 23910798 Sensitivity to reinforcer delay predicts ethanol's suppressant effects, but itself is unaffected by ethanol. Relative preference for smaller, sooner rewards over larger, later rewards ("delay discounting") is increased by acute ethanol. Additionally, drug-naïve levels of delay discounting can predict subsequent ethanol consumption. However, it is unknown whether these phenomena are driven by a difference in sensitivity to the reinforcer delay or a difference in sensitivity to the reinforcer magnitude, because typical delay discounting tasks manipulate both parameters simultaneously. To disambiguate these factors, two tasks were developed in which animals chose between levers with either different delay contingencies (adjusting delay task) or different magnitude contingencies (adjusting magnitude task). When task performance was stable, rats received ethanol (0, 0.6, and 0.9g/kg, i.p.). Ethanol did not affect sensitivity to delay or sensitivity to magnitude. However, responding was suppressed at the highest dose of ethanol (0.9g/kg). Less suppression was found in animals exhibiting high levels of drug-naïve sensitivity to delay. Thus, this study suggests that ethanol's effect on standard delay discounting tasks is not due to an alteration in sensitivity to delay or magnitude. Additionally, these data show that animals with high sensitivity to delay are resistant to the behaviorally suppressant effects of ethanol, which suggests that low tolerance for delayed rewards and low sensitivity to the behaviorally suppressant effects of ethanol may partly be driven by the same underlying mechanism. 23912456 Coordinate phosphorylation of multiple residues on single AKT1 and AKT2 molecules. Aberrant AKT activation is prevalent across multiple human cancer lineages providing an important new target for therapy. Twenty-two independent phosphorylation sites have been identified on specific AKT isoforms likely contributing to differential isoform regulation. However, the mechanisms regulating phosphorylation of individual AKT isoform molecules have not been elucidated because of the lack of robust approaches able to assess phosphorylation of multiple sites on a single AKT molecule. Using a nanofluidic proteomic immunoassay (NIA), consisting of isoelectric focusing followed by sensitive chemiluminescence detection, we demonstrate that under basal and ligand-induced conditions that the pattern of phosphorylation events is markedly different between AKT1 and AKT2. Indeed, there are at least 12 AKT1 peaks and at least 5 AKT2 peaks consistent with complex combinations of phosphorylation of different sites on individual AKT molecules. Following insulin stimulation, AKT1 was phosphorylated at Thr308 in the T-loop and Ser473 in the hydrophobic domain. In contrast, AKT2 was only phosphorylated at the equivalent sites (Thr309 and Ser474) at low levels. Further, Thr308 and Ser473 phosphorylation occurred predominantly on the same AKT1 molecules, whereas Thr309 and Ser474 were phosphorylated primarily on different AKT2 molecules. Although basal AKT2 phosphorylation was sensitive to inhibition of phosphatidylinositol 3-kinase (PI3K), basal AKT1 phosphorylation was essentially resistant. PI3K inhibition decreased pThr451 on AKT2 but not pThr450 on AKT1. Thus, NIA technology provides an ability to characterize coordinate phosphorylation of individual AKT molecules providing important information about AKT isoform-specific phosphorylation, which is required for optimal development and implementation of drugs targeting aberrant AKT activation.Oncogene advance online publication, 5 August 2013; doi:10.1038/onc.2013.301. 23235697 Plasticity of rhizosphere hydraulic properties as a key for efficient utilization of scarce resources. It is known that the soil near roots, the so-called rhizosphere, has physical and chemical properties different from those of the bulk soil. Rhizosphere properties are the result of several processes: root and soil shrinking/swelling during drying/wetting cycles, soil compaction by root growth, mucilage exuded by root caps, interaction of mucilage with soil particles, mucilage shrinking/swelling and mucilage biodegradation. These processes may lead to variable rhizosphere properties, i.e. the presence of air-filled gaps between soil and roots; water repellence in the rhizosphere caused by drying of mucilage around the soil particles; or water accumulation in the rhizosphere due to the high water-holding capacity of mucilage. The resulting properties are not constant in time but they change as a function of soil condition, root growth rate and mucilage age. We consider such a variability as an expression of rhizosphere plasticity, which may be a strategy for plants to control which part of the root system will have a facilitated access to water and which roots will be disconnected from the soil, for instance by air-filled gaps or by rhizosphere hydrophobicity. To describe such a dualism, we suggest classifying rhizosphere into two categories: class A refers to a rhizosphere covered with hydrated mucilage that optimally connects roots to soil and facilitates water uptake from dry soils. Class B refers to the case of air-filled gaps and/or hydrophobic rhizosphere, which isolate roots from the soil and may limit water uptake from the soil as well water loss to the soil. The main function of roots covered by class B will be long-distance transport of water. This concept has implications for soil and plant water relations at the plant scale. Root water uptake in dry conditions is expected to shift to regions covered with rhizosphere class A. On the other hand, hydraulic lift may be limited in regions covered with rhizosphere class B. New experimental methods need to be developed and applied to different plant species and soil types, in order to understand whether such dualism in rhizosphere properties is an important mechanism for efficient utilization of scarce resources and drought tolerance. 23931593 Simultaneous digital quantification and fluorescence-based size characterization of massively parallel sequencing libraries. Due to the high cost of failed runs and suboptimal data yields, quantification and determination of fragment size range are crucial steps in the library preparation process for massively parallel sequencing (or next-generation sequencing). Current library quality control methods commonly involve quantification using real-time quantitative PCR and size determination using gel or capillary electrophoresis. These methods are laborious and subject to a number of significant limitations that can make library calibration unreliable. Herein, we propose and test an alternative method for quality control of sequencing libraries using droplet digital PCR (ddPCR). By exploiting a correlation we have discovered between droplet fluorescence and amplicon size, we achieve the joint quantification and size determination of target DNA with a single ddPCR assay. We demonstrate the accuracy and precision of applying this method to the preparation of sequencing libraries. 23953632 Testosterone and acute stress are associated with fibrinogen and von Willebrand factor in African men: The SABPA study. Low testosterone, acute and chronic stress and hypercoagulation are all associated with hypertension and hypertension-related diseases. The interaction between these factors and future risk for coronary artery disease in Africans has not been fully elucidated. In this study, associations of testosterone, acute cardiovascular and coagulation stress responses with fibrinogen and von Willebrand factor in African and Caucasian men in a South African cohort were investigated. Cardiovascular variables were studied by means of beat-to-beat and ambulatory blood pressure monitoring. Fasting serum-, salivary testosterone and citrate coagulation markers were obtained from venous blood samples. Acute mental stress responses were evoked with the Stroop test. The African group demonstrated a higher cardiovascular risk compared to Caucasian men with elevated blood pressure, low-grade inflammation, chronic hyperglycemia (HbA1c), lower testosterone levels, and elevated von Willebrand factor (VWF) and fibrinogen levels. Blunted testosterone acute mental stress responses were demonstrated in African males. In multiple regression analyses, higher circulating levels of fibrinogen and VWF in Africans were associated with a low T environment (R(2) 0.24-0.28; p≤0.01), but only circulating fibrinogen in Caucasians. Regarding endothelial function, a low testosterone environment and a profile of augmented α-adrenergic acute mental stress responses (diastolic BP, D-dimer and testosterone) were associated with circulating VWF levels in Africans (Adj R(2) 0.24; p<0.05). An interdependence between acute mental stress, salivary testosterone, D-dimer and vascular responses existed in African males in their association with circulating VWF but no interdependence of the independent variables occurred with fibrinogen levels. 22628170 Intergenerational transmission of gambling: links between young adult and perceived grandparent gambling attitudes and behavior. This study examined associations between the gambling attitudes and behavior of 213 young adults and their perceptions of the gambling attitudes and behavior of their closest grandparent. Regression analyses showed that young adult gambling attitudes mediated the relations between perceived grandparent gambling attitudes and behavior and young adult gambling behavior. Grandparent-grandchild relationship quality experienced while growing up did not moderate the relations between young adult and perceived grandparent gambling attitudes and behavior. Men experienced gambling at a younger age and reported more positive gambling attitudes, more frequent gambling activity, higher levels of gambling pathology, and higher levels of gambling affinity than women. Implications of results and suggestions for future research are discussed. 23933721 Dinosaur energetics: setting the bounds on feasible physiologies and ecologies. Abstract The metabolic status of dinosaurs has long been debated but remains unresolved as no consistent picture has emerged from a range of anatomical and isotopic evidence. Quantitative analysis of dinosaur energetics, based on general principles applicable to all vertebrates, shows that many features of dinosaur lifestyle are compatible with a physiology similar to that of extant lizards, scaled up to dinosaur body masses and temperatures. The analysis suggests that sufficient metabolic scope would have been available to support observed dinosaur growth rates and allow considerable locomotor activity, perhaps even migration. Since at least one dinosaur lineage evolved true endothermy, this study emphasizes there was no single dinosaur physiology. Many small theropods were insulated with feathers and appear to have been partial or full endotherms. Uninsulated small taxa, and all juveniles, presumably would have been ectothermic, with consequent diurnal and seasonal variations in body temperature. In larger taxa, inertial homeothermy would have resulted in warm and stable body temperatures but with a basal metabolism significantly below that of extant mammals or birds of the same size. It would appear that dinosaurs exhibited a range of metabolic levels to match the broad spectrum of ecological niches they occupied. 23872236 Postembryonic lineages of the Drosophila brain: II. Identification of lineage projection patterns based on MARCM clones. The Drosophila central brain is largely composed of lineages, units of sibling neurons derived from a single progenitor cell or neuroblast. During the early embryonic period neuroblast generates the primary neurons that constitute the larval brain. Neuroblasts reactivate in the larva, adding to their lineages a large number of secondary neurons which, according to previous studies in which selected lineages were labeled by stably expressed markers, differentiate during metamorphosis, sending terminal axonal and dendritic branches into defined volumes of the brain neuropil. We call the overall projection pattern of neurons forming a given lineage the "projection envelope" of that lineage. By inducing MARCM clones at the early larval stage, we labeled the secondary progeny of each neuroblast. For the supraesophageal ganglion excluding mushroom body (the part of the brain investigated in the present work) we obtained 81 different types of clones, Based on the trajectory of their secondary axon tracts (described in the accompanying paper), we assigned these clones to specific lineages defined in the larva. Since a labeled clone reveals all aspects (cell bodies, axon tracts, terminal arborization) of a lineage, we were able to describe projection envelopes for all secondary lineages of the supraesophageal ganglion. This work provides a framework by which the secondary neurons (forming the vast majority of adult brain neurons) can be assigned to genetically and developmentally defined groups. It also represents a step towards the goal to establish, for each lineage, the link between its mature anatomical and functional phenotype, and the genetic make-up of the neuroblast it descends from. 23259840 pH tuning of DNA translocation time through organically functionalized nanopores. Controlling DNA translocation speed is critically important for nanopore sequencing as free electrophoretic threading is far too rapid to resolve individual bases. A number of promising strategies have been explored in recent years, largely driven by the demands of next-generation sequencing. Engineering DNA-nanopore interactions (known to dominate translocation dynamics) with organic coatings is an attractive method as it does not require sample modification, processive enzymes, or complicated and expensive fabrication steps. In this work, we show for the first time 4-fold tuning of unfolded, single-file translocation time through small, amine-functionalized solid-state nanopores by varying the solution pH in situ. Additionally, we develop a simple analytical model based on electrostatic interactions to explain this effect which will be a useful tool in designing future devices and experiments. 23615117 Immunopathogenesis of simian immunodeficiency virus infection in nonhuman primates. Soon after the discovery of HIV-infected humans, rhesus macaques in a colony at the New England Primate Research Center showed similar signs of a progressive immune suppression. The discovery of the simian immunodeficiency virus (SIV)-associated disease opened the door to study an AIDS-like illness in nonhuman primates (NHP). Even after 3 decades, this animal model remains an invaluable tool to provide a greater insight into HIV immunopathogenesis. In this review, recent progress in deciphering pathways of immunopathogenesis in SIV-infected NHP is discussed. The immense diversity of mutations in SIV stocks prepared at different laboratories has recently been realized. The massive expansion of the enteric virome is a key finding in SIV-induced immunopathogenesis. Defining the function of host restriction factors, like the recently discovered SAMHD1, helps to evaluate the impact of the innate immune responses on virus replication. Utilization of pyrosequencing and defining molecular mechanisms of major histocompatibility complex (MHC) class I restriction helps to understand how the virus evades CD8 T-cell responses. The definition of MHC class I molecules in different NHP species provides new animal models to study SIV immunopathogenesis. T follicular helper cells have gained major interest in characterizing humoral immune responses in SIV infection and AIDS vaccine strategies. The ability of natural hosts to remain disease-free despite ongoing replication of SIV is continuing to puzzle the field. The HIV research field continues to realize the immense complexity of the host virus interaction. NHP present an invaluable tool to make progress towards an effective AIDS vaccine. 23810052 Implant rehabilitation of canines in case of bilaterally missing maxillary lateral incisors. This article reports the successful treatment of a patient with a malocclusion and missing maxillary lateral incisors with an unusual implant-prosthetic rehabilitation in place of the canines. A man, 25 years 5 months of age, was referred by his general dentist with the chief complaint of retained maxillary deciduous canines. He had a skeletal Class I and an Angle Class I malocclusion with an open-bite tendency and prolonged retention of both deciduous canines. The malocclusion was treated with extraction of the maxillary deciduous canines, a fixed edgewise appliance, and implant-prosthesis rehabilitation in place of the canines. A functional and an esthetic occlusion was achieved. 23903135 Spiral laser beams in inhomogeneous media. Explicit solutions of the inhomogeneous paraxial wave equation in a linear and quadratic approximation are applied to wave fields with invariant features, such as oscillating laser beams in a parabolic waveguide and spiral light beams in varying media. A similar effect of superfocusing of particle beams in a thin monocrystal film, harmonic oscillations of cold trapped atoms, and motion in magnetic field are also mentioned. 23831222 Traumatic Wound Dehiscence After Deep Anterior Lamellar Keratoplasty. To analyze the outcomes of traumatic wound dehiscence after deep anterior lamellar keratoplasty (DALK). Retrospective and interventional case series. setting: Single hospital. patients: A total of 338 consecutive cases were reviewed. Eleven eyes that had wound dehiscence related to ocular trauma were included. main outcome measures: Incidence and causes, best-corrected visual acuity (BCVA), and endothelial cell density were evaluated. Complications and secondary surgeries were recorded. Seven patients were male (63.6%) and 4 patients were female (36.4%), with a mean age of 30.6 years (range, 24-40 years). The incidence of wound dehiscence was 3.2% (11/338). The mean interval between the initial DALK procedure and wound dehiscence was 9.45 months (range, 2-16 months). The mean follow-up time was 6 years. The most common trauma was a fist blow injury (36.3%). Descemet membrane perforation was observed in 8 eyes (72.7%); lens damage and vitreous prolapse occurred in 2 eyes (18.1%). The final BCVA was 0.51 and was maintained in 4 eyes (36.3%). At the final visit, 10 grafts (90.9%) were clear. The mean endothelial cell loss was 55.8% between before DALK and last visit. Although the intact Descemet membrane protects against dehiscing traumas after DALK, a relative weakness at the graft-host junction tends to persist and a severe deforming force may result in graft dehiscence. This case series indicates that despite the fact that the visual results following the repair are acceptable, corneal endothelium seems to be subjected to severe damage, which puts graft survival chances at risk in the long term. 23246863 Ameliorating effects of extracellular polymeric substances excreted by Thalassiosira pseudonana on algal toxicity of CdSe quantum dots. Quantum dots (QDs) are engineered nanoparticles (ENs) that have found increasing applications and shown great potential in drug delivery, biological imaging and industrial products. Knowledge of their stability, fate and transport in the aquatic environment is still lacking, including details of how these nanomaterials interact with marine phytoplankton. Here, we examined the toxicity of functionalized CdSe/ZnS QDs (amine- and carboxyl-) by exposing them for five days to Thalassiosira pseudonana (marine diatom) grown under different nutrient-conditions (enriched versus nitrogen-limited media). The released polysaccharides and proteins, the major components of extracellular polymeric substances (EPS), were measured to assess their potential effects on the interactions between QDs and T. pseudonana. The partitioning of QDs was analyzed by monitoring the concentration of Cd in different size fractions of the cultures (i.e., filtrate, <0.22 μm and permeate, <3 kDa). We found that the Cd release of QDs in the T. pseudonana culture was dependent on the nutrient conditions and nature of QDs' surface coating. Both amine- and carboxyl-functionalized QDs exhibited higher rates of Cd release in N-limited cultures than in nutrient enriched cultures. The results also showed that amine-functionalized QDs aggregate with minimal Cd release, independent of nutrient conditions. Laser scanning confocal microscopy images confirmed that aggregates are composed of QDs and the culture matrix (EPS). In addition, both types of QDs showed limited toxicity to T. pseudonana. The increasing production of proteins induced by QDs suggests that extracellular proteins might be involved in the detoxification of QDs to T. pseudonana via the Cd release of QDs. Our results here demonstrated that EPS can play an ameliorating role in QD toxicity, fate and transport in the aquatic environment. 23880368 Evaluation of the vestibulo-ocular reflex using sinusoidal off-vertical axis rotation in patients with canal paresis. The vestibulo-ocular reflex (VOR) was studied to determine the utility of off-vertical axis rotation (OVAR) in evaluating vestibular function in patients with canal paresis (CP). Our goal was to determine whether there is any correlation between caloric responses and sinusoidal rotatory responses. Subjects were rotated in a sinusoidal pattern with eyes open in complete darkness. Frequencies of 0.4 and 0.8Hz with a maximum angular velocity of 60°/s at either earth-vertical axis rotation (EVAR) or OVAR were used. Twenty-three control subjects and 21 patients with CP were investigated. Results showed that (1) the VOR gain difference between EVAR and OVAR in the CP patients was not significant at 0.4Hz and at 0.8Hz; (2) the gain during 0.4Hz EVAR was less in the bilateral CP patients compared to controls; and (3) the VOR gain of the affected side at 0.8Hz was significantly less during OVAR than during EVAR. We concluded that the absence or reduction of caloric responses does not indicate the absence of vestibular function. In addition, separation analysis of the VOR gain of affected and intact sides is useful for evaluating laterality of otolith function in patients with CP. 23826887 Systematic tailoring for the implementation of guideline recommendations for anxiety and depressive disorders in general practice: perceived usefulness of tailored interventions. The uptake of guideline recommendations in general practice can potentially be improved by designing implementation interventions that are tailored to prospectively identify barriers. However, there is insufficient evidence regarding the most effective and efficient approaches to tailoring. Our study provides an insight into the usefulness of tailored interventions to prospectively identified barriers affecting the uptake of guideline recommendations for anxiety and depressive disorders experienced by general practitioners (GPs) in their local context. A qualitative study was conducted, in which 23 GPs gave informed consent and 14 finally participated. To explore the barriers affecting the uptake of guideline recommendations, a face-to-face interview was conducted with each GP to generate a personalised list. In response to this list, interventions were tailored to remove the barriers experienced by the GPs. To examine the perceived usefulness of the tailored interventions, telephone interviews were conducted after one year and coded through thematic coding. The analysis was descriptive in nature. The most frequently perceived barriers were: a lack of knowledge and skills, no agreement on guideline recommendations, negative outcome expectancy, low self-efficacy, no consensus with patients, and a lack of information about treatments provided by mental health professionals, together with waiting lists. The tailored interventions 'peer group supervision' and 'individualised telephone consultations' were perceived as useful by most GPs. Besides the tailored interventions, a perceived benefit of using a self-rating scale, measuring depressive and anxiety symptoms, and the idea of delivering better patient care, were supportive in the uptake of guideline recommendations. Our findings suggest that tailoring interventions to prospectively identified barriers, affecting the uptake of guideline recommendations for anxiety and depressive disorders, as perceived by GPs, may enhance the implementation of these guideline recommendations. 23577826 Assessing Arrhythmia Burden After Catheter Ablation of Atrial Fibrillation Using an Implantable Loop Recorder: The ABACUS Study. Arrhythmia monitoring in patients undergoing atrial fibrillation (AF) ablation is challenging. Transtelephonic monitors (TTMs) are cumbersome to use and provide limited temporal assessment. Implantable loop recorders (ILRs) may overcome these limitations. We sought to evaluate the utility of ILRs versus conventional monitoring (CM) in patients undergoing AF ablation. Forty-four patients undergoing AF ablation received ILRs and CM (30-day TTM at discharge and months 5 and 11 postablation). Over the initial 6 months, clinical decisions were made based on CM. Subjects were then randomized for the remaining 6 months to arrhythmia assessment and management by ILR versus CM. The primary endpoint was arrhythmia recurrence. The secondary endpoint was actionable clinical events (change of antiarrhythmic drugs [AADs], anticoagulation, non-AF arrhythmia events, etc.) due to either monitoring strategy. Over the study period, 6 patients withdrew. In the first 6 months, AF recurred in 18 patients (7 noted by CM, 18 by ILR; P = 0.002). Five patients in the CM (28%) and 5 in the ILR arm (25%; P = NS) had AF recurrence during the latter 6 months. AF was falsely diagnosed frequently by ILR (730 of 1,421 episodes; 51%). In more patients in the ILR compared with the CM arm, rate control agents (60% vs 39%, P = 0.02) and AADs (71% vs 44%, P = 0.04) were discontinued. In AF ablation patients, ILR can detect more arrhythmias than CM. However, false detection remains a challenge. With adequate oversight, ILRs may be useful in monitoring these patients after ablation. 23639849 Smoking and social anxiety: the roles of gender and smoking motives. Although social anxiety appears to be a risk factor for smoking and nicotine dependence, little work has identified factors that may play a role in these relationships. The current study examined the role of gender and smoking motives in these relationships among 945 (73.0% female) undergraduates, 91 of whom were current daily smokers. Among women, social anxiety was related to daily smoking status, whereas it was related to dependence severity among men. After controlling for past-week smoking frequency, social anxiety was related to affiliative attachment and behavioral choice-melioration smoking motives. Both motives mediated the relationship between social anxiety and nicotine dependence severity, although affiliative attachment motives uniquely mediated this relationship. Results suggest that socially anxious individuals who view cigarettes as having some of the same characteristics as social interactions may be particularly vulnerable to more severe nicotine dependence. Results also highlight the importance of considering gender in the relationships between social anxiety and smoking behaviors. 23959926 Identifying parentage using molecular markers: Improving accuracy of studbook records for a captive flock of marabou storks (Leptoptilus crumeniferus). Extra-pair copulations (EPCs) leading to extra-pair fertilization (EPF) are common in avian mating systems, despite the prevalence of observed social monogamy in many species. Colonially breeding birds are interesting species to investigate the prevalence of EPCs and EPF because they show nesting habits including close proximity of nest sites and sexual partners, which are proposed to promote alternative reproductive tactics. Endemic to Africa, the colonial marabou stork (Leptoptilos crumeniferus) is one of the most commonly held avian species in North American zoos. The aims of this study were to use genetic information to verify parentage in a population of marabou stork housed at Disney's Animal Kingdom® based on five microsatellite loci and to investigate reproductive behavior. We compared genetic analyses of parents and offspring to studbook data collected through behavioral observations of parental behavior at the nest. Using genetic analyses to reconstruct the pedigree of the marabou stork flock using the program COLONY led to improvement of studbook records by determining parentage of an individual that had previously unknown parentage, and identified one individual that had a sire that differed genetically from studbook records. An important contribution of our analyses was the identification and verification of the most likely parents for offspring hatched in this colony and improving incorrect or undocumented parentage in the studbook. Additionally, the colonial nature of this species makes it difficult to observe and understand reproductive behavior. Gaining better understanding of the mating system of a species is essential for successful breeding and captive management. Zoo Biol. XX:XX-XX, 2013. © 2013 Wiley Periodicals, Inc. 23850303 Cervical mucus monitoring prevalence and associated fecundability in women trying to conceive. To assess the use of cervical mucus monitoring (CMM) in women trying to conceive and determine whether monitoring is associated with increased cycle-specific probability of conception (fecundability). Time-to-pregnancy cohort study. Population-based cohort. Three hundred thirty-one women trying to conceive, ages 30 to 44 years, without known infertility. None. CMM prevalence and fecundability. During the first cycle of the study, CMM was performed consistently (checked on >66% of pertinent cycle days) by 20 women (6%), inconsistently (34% to 66% of days) by 60 women (18%), infrequently (≤33% of days) by 73 women (22%), and not performed by 178 women (54%). Cycles in which CMM was consistently performed were statistically significantly more likely to result in conception after adjusting for age, race, previous pregnancy, body mass index, intercourse frequency, and urinary luteinizing hormone (LH) monitoring. Fecundability also increased with increasing consistency of CMM. Among women trying to conceive, CMM is uncommon, but our study suggests that CMM-a free, self-directed method to determine the fertile window-is associated with increased fecundability independent of intercourse frequency or use of urinary LH monitoring. 23354619 Regeneration of spent TiO2 nanoparticles for Pb (II), Cu (II), and Zn (II) removal. Spent sorbents in water treatment processes have potential risks to the environment if released without proper treatment. The aim of this work was to investigate the potential regeneration of commercially prepared nano-TiO2 (anatase) for the removal of Pb (II), Cu (II), and Zn (II) by pH 2 and ethylenediaminetetraacetic acid (EDTA) solutions. The percent of metal adsorption/desorption decreased with the increasing number of regeneration cycles, and the extent of decrease varied for each metal. Competitive effects were observed for the adsorption/desorption of different metals when the nano-TiO2 was regenerated by EDTA solutions. Nano-TiO2 was able to treat simulated metal polluted water with greater than 94 % adsorption and greater than 92 % desorption after four cycles of regeneration using pH 2 solution. These results demonstrated that nano-TiO2 can be regenerated and reused using pH 2 solution compared to an EDTA solution for aquatic metal removal, which makes nanosorbents promising and economically and environmentally more attractive in the application of water purification. 23525236 Diverse topologies in dynamic combinatorial libraries from tri- and mono-thiols in water: sensitivity to weak supramolecular interactions. We describe here the use of disulfide exchange reactions to generate distinct supramolecular topologies within a dynamic combinatorial library (DCL) derived from tri- and mono-functionalised thiol components in water. This approach allows for the effective expansion of structural diversity within a DCL, and also provides a sensitive probe for weak supramolecular interactions. 22525570 Effects of environmental manipulations in genetically targeted animal models of affective disorders. Mental illness is the leading cause of disability worldwide. We are only just beginning to reveal and comprehend the complex interaction that exists between the genetic makeup of an organism and the potential modifying effect of the environment in which it lives, and how this translates into mediating susceptibility to neurological and psychiatric conditions. The capacity to address this issue experimentally has been facilitated by the availability of rodent models which allow the precise manipulation of genetic and environmental factors. In this review, we discuss the valuable nature of animal models in furthering our understanding of the relationship between genetic and environmental factors in affective illnesses, such as anxiety and depressive disorders. We first highlight the behavioral impairments exhibited by genetically targeted animal models of affective disorders, and then provide a discussion of the underlying neurobiology, focusing on animal models that involve exposure to stress. This is followed by a review of recent studies that report of beneficial effects of environmental manipulations such as environmental enrichment and enhanced physical activity and discuss the likely mechanisms that mediate those benefits. 23664057 Generation of functional antibodies for mammalian membrane protein crystallography. Membrane proteins act as gateways to cells, and they are responsible for much of the communication between cells and their environments. Crystallography of membrane proteins is often limited by the difficulty of crystallization in detergent micelles. Co-crystallization with antibody fragments has been reported as a method to facilitate the crystallization of membrane proteins; however, it is widely known that the generation of mouse monoclonal antibodies that recognize the conformational epitopes of mammalian integral membrane proteins is typically difficult. Here, we present our protocols to generate functional mouse antibodies for the membrane protein crystallography, which have enabled us to solve crystal structures of mammalian receptors and transporters complexed with antibody fragments. 23557541 A density-functional theory-based neural network potential for water clusters including van der waals corrections. The fundamental importance of water for many chemical processes has motivated the development of countless efficient but approximate water potentials for large-scale molecular dynamics simulations, from simple empirical force fields to very sophisticated flexible water models. Accurate and generally applicable water potentials should fulfill a number of requirements. They should have a quality close to quantum chemical methods, they should explicitly depend on all degrees of freedom including all relevant many-body interactions, and they should be able to describe molecular dissociation and recombination. In this work, we present a high-dimensional neural network (NN) potential for water clusters based on density-functional theory (DFT) calculations, which is constructed using clusters containing up to 10 monomers and is in principle able to meet all these requirements. We investigate the reliability of specific parametrizations employing two frequently used generalized gradient approximation (GGA) exchange-correlation functionals, PBE and RPBE, as reference methods. We find that the binding energy errors of the NN potentials with respect to DFT are significantly lower than the typical uncertainties of DFT calculations arising from the choice of the exchange-correlation functional. Further, we examine the role of van der Waals interactions, which are not properly described by GGA functionals. Specifically, we incorporate the D3 scheme suggested by Grimme (J. Chem. Phys. 2010, 132, 154104) in our potentials and demonstrate that it can be applied to GGA-based NN potentials in the same way as to DFT calculations without modification. Our results show that the description of small water clusters provided by the RPBE functional is significantly improved if van der Waals interactions are included, while in case of the PBE functional, which is well-known to yield stronger binding than RPBE, van der Waals corrections lead to overestimated binding energies. 23953472 Surface modified BaTiO3 nanoparticles as the matrix for phospholipids and as extracting probes for LLME of hydrophobic proteins in Escherichia coli by MALDI-MS. In this paper, we report the dual function of 12-hydroxy octadecanoic acid (HOA)-modified barium titanate nanoparticles (BaTiO3 NPs) as the matrix for phospholipids (PLs) and as hydrophobic affinity probes for liquid-liquid microextraction (LLME) of hydrophobic proteins in Escherichia coli prior to their identification by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-MS). FT-IR, SEM and TEM were used for the characterization of the HOA-modified BaTiO3 NPs. The surface modified BaTiO3 NPs acted as multifunctional probes (as extracting probes and as the matrix) for the analysis of PLs by MALDI-MS. Compared to 2,5-dihydroxybenzoic acid (2,5-DHB), the HOA-modified BaTiO3 NPs provided good PLs mass spectra with similar or improved signal-to-noise (S/N) ratio, which demonstrated the potentiality of HOA-modified BaTiO3 NPs as a PLs purpose matrix. This method was found to be linear in concentration ranges of 1.0-5.0μM and 1.0-10.0μM for L-A-phosphatidyl-l-serine (PS) and L-A-phsophatidic acid sodium (PA) with correlation coefficient (R(2)) values from 0.9905 to 0.9987. The detection limits were 0.20-0.35μM and 0.25-0.40μM for PS and PA, respectively. We also demonstrated the HOA-modified BaTiO3 NPs as extracting and as preconcentrating probes for the LLME of hydrophobic proteins in E. coli prior to their identification by MALDI-MS. Thus, the surface modified BaTiO3 NPs-assisted LLME coupled with MALDI-MS provides a simple methodology for the efficient extraction and determination of hydrophobic molecules in biological samples. 23417039 Toll-like receptor 3 and 4 signalling through the TRIF and TRAM adaptors in haematopoietic cells promotes atherosclerosis. Members of the Toll-like receptor (TLR) family initiate innate immune responses and were recently shown to play a role in atherosclerosis. However, the mechanisms that link TLR ligation to vascular inflammation and atherogenesis remain unclear. To identify which signalling pathways downstream of TLRs in immune cells are pro-atherogenic, we analysed the role of the TLR-specific adaptors MyD88 adaptor-like (MAL), TRIF-related adaptor molecule (TRAM), and TIR-domain-containing adaptor-inducing interferon-β (TRIF) in atherosclerosis. Using a bone-marrow transplantation strategy into low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice, we could specifically study the absence of the TLR adaptors in immune cells. We showed that haematopoietic deficiency of TRAM and TRIF, but not MAL, reduces atherosclerosis without affecting cholesterol metabolism. This was mediated by decreased aortic inflammation, indicated by lower aortic levels of pro-inflammatory mediators, and reduced influx of macrophages and T cells. Furthermore, by studying Tlr3(-/-) chimeric Ldlr(-/-) mice, we found that deleting TLR3 in immune cells significantly reduced both aortic inflammation and atherosclerotic burden. By studying hypercholesterolaemic mice with defects in TLR-signalling adaptors, we demonstrated that deleting either TRAM or TRIF in immune cells is sufficient to attenuate vessel inflammation and protect against atherosclerosis. In addition, these adaptors elicit partly different sets of inflammatory mediators and can independently inhibit the disease process. Furthermore, we identify TLR3 as a pro-atherogenic receptor in haematopoietic immune cells. The identification of these pro-atherogenic pathways downstream of TLR3 and TLR4 contributes to a better understanding of TLRs and their signalling pathways in the pathogenesis of atherosclerosis. 23723259 The abrupt climate change at the Eocene-Oligocene boundary and the emergence of South-East Asia triggered the spread of sapindaceous lineages. Paleoclimatic data indicate that an abrupt climate change occurred at the Eocene-Oligocene (E-O) boundary affecting the distribution of tropical forests on Earth. The same period has seen the emergence of South-East (SE) Asia, caused by the collision of the Eurasian and Australian plates. How the combination of these climatic and geomorphological factors affected the spatio-temporal history of angiosperms is little known. This topic is investigated by using the worldwide sapindaceous clade as a case study. Analyses of divergence time inference, diversification and biogeography (constrained by paleogeography) are applied to a combined plastid and nuclear DNA sequence data set. Biogeographical and diversification analyses are performed over a set of trees to take phylogenetic and dating uncertainty into account. Results are analysed in the context of past climatic fluctuations. An increase in the number of dispersal events at the E-O boundary is recorded, which intensified during the Miocene. This pattern is associated with a higher rate in the emergence of new genera. These results are discussed in light of the geomorphological importance of SE Asia, which acted as a tropical bridge allowing multiple contacts between areas and additional speciation across landmasses derived from Laurasia and Gondwana. This study demonstrates the importance of the combined effect of geomorphological (the emergence of most islands in SE Asia approx. 30 million years ago) and climatic (the dramatic E-O climate change that shifted the tropical belt and reduced sea levels) factors in shaping species distribution within the sapindaceous clade. 23746569 Contribution of flagellin subunit FliC to piglet epithelial cells invasion by F18ab E. coli. Flagellar structures contribute to the virulence of multiple gastrointestinal pathogens either as the effectors of motility, as adhesins, or as a secretion apparatus for virulence factors. Escherichia coli F18ab variant strains are associated with edema disease (ED) in pig industries worldwide. These strains use flagella to increase the efficiency of epithelial cell invasion. In this study, we aimed to elucidate the mechanism by which flagella contribute to F18ab E. coli invasion. To explore the role of flagella in the invasion process, we performed invasion assays with either flagellated and motile, flagellated but non-motile, or non-flagellated non-motile bacteria. We observed that flagellated but non-motile bacteria invade piglet epithelial cells even more efficiently than the parent wild-type (WT) strain in vitro. By contrast, the non-flagellated bacteria have significantly reduced invasion as compared with the parent strain. These results demonstrate that flagella function mainly as adhesins to enhance the ability of F18ab E. coli to target piglet epithelial cells. 23353902 Gender-specific effects of fluoxetine on hippocampal glucocorticoid receptor phosphorylation and behavior in chronically stressed rats. Chronic psychosocial isolation stress (CPSI) modulates glucocorticoid receptor (GR) functioning in Wistar male rat hippocampus (HIPPO) through alteration of nuclear GR phosphorylation and its upstream kinases signaling, which parallels animal depressive-like behavior. The current study investigated potential gender specificities regarding the effect of chronic therapy by an antidepressant fluoxetine (FLU) on GR signaling in HIPPO and depressive-like behavior in CPSI animals. FLU was administrated to female and male naïve or CPSI rats for 21 days and GR protein, its phosphorylation status and upstream kinases, as well as GR and BDNF mRNA were followed in HIPPO together with animal serum corticosterone (CORT) and depressive-like behavior. The results showed that CPSI increased immobility in males versus hyperactivity in females and disrupted nuclear pGR232-Cdk5 pathway and JNK signaling in a gender-specific way. In contrast, in both genders CPSI increased the nuclear levels of GR and pGR246 but decreased CORT and mRNA levels of GR and BDNF. Concomitant FLU normalized the depressive-like behavior and altered the nuclear pGR232-Cdk5 signaling in a gender-specific manner. In both females and males, FLU reversed the nuclear levels of GR and pGR246 without affecting CORT and GR mRNA levels. In contrast, FLU exhibited gender-specific effect on BDNF mRNA in CPSI animals, by increasing it in females, but not in males. In spite of normalization the total nuclear GR level upon FLU treatment in both gender, down-regulation of GR mRNA is possibly maintained through prevalence of pGR232 isoform only in males. The gender-specific alterations of pGR232-Cdk5 signaling and BDNF gene expression in HIPPO and normalization of depressive-like behavior upon FLU treatment distinguishes this signaling pathway as potential future antidepressant target for gender-specific therapy of stress related mood disorders. 23920086 Diabetes and end-stage renal disease synergistically contribute to increased incidence of cardiovascular events: A nation-wide follow-up study during 1998-2009. ObjectiveThis study aimed to investigate the interaction of diabetes and end-stage renal disease (ESRD) on the risks of cardiovascular (CV) events.Research Design and MethodsBy using two representative national cohorts, we determined the age- and sex-specific incidences, twenty-year risks of incident CV events, including acute myocardial infarction (AMI), stroke and congestive heart failure (CHF), stratified by the presence of diabetes, de novo diabetes after ESRD or ESRD. Individuals were excluded if aged below 18 years or the presence of previous CV events or malignancy before enrollment. Cox proportional hazard models were also constructed with adjustments for competing risk of mortality.ResultsA total 648,851 non-ESRD individuals and 71,397 ESRD patients, including 53,342 and 34,754 diabetic patients respectively, were followed up during 1998-2009. A monotonic risk pattern of CV-related incidences was noted with the presence of diabetes, ESRD or both, respectively, after stratified by age and sex. De novo diabetes showed similar increased risks for CV incidences, especially AMI and stroke. There is a multiplicatively synergistic effect of diabetes and ESRD for CV related risks, especially for AMI and stroke, of which the adjusted hazard ratios (aHRs) [95% confidence intervals] were 5.24 [4.83-5.68] and 2.43[2.32-2.55], respectively in comparison with people without diabetes or ESRD; de novo diabetes after ESRD had similar effects with aHRs of 4.12[3.49-4.87] and 1.75[1.57-1.95], respectively.ConclusionsDiabetes and ESRD synergistically increase risks of CV events. Proactive screening and control for diabetes in patients with ESRD should be built into our daily practice. 23298546 Coagulation and coagulation signalling in fibrosis. Following tissue injury, a complex and coordinated wound healing response comprising coagulation, inflammation, fibroproliferation and tissue remodelling has evolved to nullify the impact of the original insult and reinstate the normal physiological function of the affected organ. Tissue fibrosis is thought to result from a dysregulated wound healing response as a result of continual local injury or impaired control mechanisms. Although the initial insult is highly variable for different organs, in most cases, uncontrolled or sustained activation of mesenchymal cells into highly synthetic myofibroblasts leads to the excessive deposition of extracellular matrix proteins and eventually loss of tissue function. Coagulation was originally thought to be an acute and transient response to tissue injury, responsible primarily for promoting haemostasis by initiating the formation of fibrin plugs to enmesh activated platelets within the walls of damaged blood vessels. However, the last 20years has seen a major re-evaluation of the role of the coagulation cascade following tissue injury and there is now mounting evidence that coagulation plays a critical role in orchestrating subsequent inflammatory and fibroproliferative responses during normal wound healing, as well as in a range of pathological contexts across all major organ systems. This review summarises our current understanding of the role of coagulation and coagulation initiated signalling in the response to tissue injury, as well as the contribution of uncontrolled coagulation to fibrosis of the lung, liver, kidney and heart. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. 23788723 A novel insight into the mechanism of mammalian selenoprotein synthesis. The amino acid selenocysteine is encoded by UGA, usually a stop codon, thus requiring a specialized machinery to enable its incorporation into selenoproteins. The machinery comprises the tRNA(Sec), a 3'-UTR mRNA stem-loop termed SElenoCysteine Insertion Sequence (SECIS), which is mandatory for recoding UGA as a Sec codon, the SECIS Binding Protein 2 (SBP2), and other proteins. Little is known about the molecular mechanism and, in particular, when, where, and how the SECIS and SBP2 contact the ribosome. Previous work by others used the isolated SECIS RNA to address this question. Here, we developed a novel approach using instead engineered minimal selenoprotein mRNAs containing SECIS elements derivatized with photoreactive groups. By cross-linking experiments in rabbit reticulocyte lysate, new information could be gained about the SBP2 and SECIS contacts with components of the translation machinery at various translation steps. In particular, we found that SBP2 was bound only to the SECIS in 48S pre-initiation and 80S pretranslocation complexes. In the complex where the Sec-tRNA(Sec) was accommodated to the A site but transpeptidation was blocked, SBP2 bound the ribosome and possibly the SECIS element as well, and the SECIS had flexible contacts with the 60S ribosomal subunit involving several ribosomal proteins. Altogether, our findings led to broadening our understanding about the unique mechanism of selenocysteine incorporation in mammals. 23839386 119 Cost-Utility Analysis of Anterior Cervical Discectomy and Fusion With Plating (ACDFP) vs Posterior Cervical Foraminotomy (PCF) for Patients With Single-Level Cervical Radiculopathy. Cervical radiculopathy due to cervical spondylosis is commonly treated by either posterior cervical foraminotomy (PCF) or anterior cervical discectomy and fusion with plating (ACDFP). The present study analyzes the cost effectiveness of ACDFP vs PCF for patients with single-level cervical radiculopathy. Forty-five patients who underwent ACDFP and 25 patients who underwent PCF were analyzed. All patients had single-level cervical radiculopathy. 1-year postoperative health outcomes were assessed based on Visual Analogue Scale (VAS), Pain Disability Questionnaire (PDQ), Patient Health Questionnaire (PHQ-9), and EuroQol-5 Dimensions (EQ-5D) questionnaires. Direct medical costs were estimated using Medicare national payment amounts, health resource utilization was recorded from patient electronic medical records, and indirect costs were based on patient missed work days and patient income. Postoperative 1-year cost/utility ratios and the incremental cost effectiveness ratio (ICER) were calculated to assess for cost effectiveness using a threshold of $100,000/QALY gained. Compared with preoperative health states, the ACDFP cohort showed postoperative improvement in VAS, PDQ, and EQ-5D scores at 1 year postoperatively (P < .01). Compared with preoperative health states, the PCF cohort showed postoperative improvement in EQ-5D scores at 1 year postoperatively. The 1-year cost-utility ratio (Total Cost/QALY gained) for the PCF cohort was significantly lower ($79,856/QALY gained) than that for the ACDFP cohort ($131,951/QALY gained) (P < .01). In calculating the 1-year ICER, ACDFP was found to be dominated by PCF (ie, negative ICER - not reported). Statistically and clinically significant (ie, > minimum clinically important differences) improvements in quality of life measures were seen 1 year postoperatively for both cohorts. While both cohorts showed improved health outcomes, ACDFP is not cost effective relative to the threshold of $100,000/QALY gained at 1 year postoperatively while PCF was. 23361400 Indicators show differences in antibiotic use between general practitioners and paediatricians. The purpose of this investigation was to adapt to an individual physician level and to the paediatric context a set of drug-specific indicators of outpatient antibiotic use developed by the European Surveillance of Antimicrobial Consumption (ESAC) project, and to describe the differences in antibiotic prescriptions between general practitioners (GPs) and paediatricians. We conducted a retrospective cross-sectional study analysing antibiotic prescriptions in 2009 for children below 16 years of age in south-eastern France, using the National Health Insurance (NHI) outpatient reimbursement database. A generalised linear model adjusted on physicians' characteristics and patient population characteristics was used to compare indicators between GPs and paediatricians. We included 4,921 self-employed GPs and 301 paediatricians. Penicillins accounted for 47% and 45% of all antibiotics prescribed by GPs and paediatricians, respectively, followed by cephalosporins (33% and 39%) and macrolides (14% and 9%). In both specialties, there were around 70% more antibiotic prescriptions during the winter quarters compared to the summer quarters. The 13 indicators we calculated showed wide variations in antibiotic prescriptions among GPs, among paediatricians, and between GPs and paediatricians. In an adjusted econometric model, GPs were found to issue 54% more antibiotic prescriptions than paediatricians, whereas paediatricians used a significantly higher proportion of co-amoxiclav (18% vs. 12%) and cephalosporins (39% vs. 33%) and a significantly lower proportion of macrolides (9% vs. 14%) compared to GPs. A set of 13 indicators may be calculated using reimbursement data to describe outpatient antibiotic use at the physician level. We observed very different prescribing profiles between GPs and paediatricians. 23151839 Bioluminescent enzymatic rapid assay of water integral toxicity. A bioluminescent rapid method was developed to estimate the integral toxicity of natural and wastewater. This method is based on registering the effect of the polluted water sample on the parameters of the bioluminescent reaction catalyzed by the multi-component reagent containing NADH:FMN oxidoreductase, luciferase, and their substrates co-immobilized in a starch carrier. Several ways to increase the method's sensitivity to toxic substances were suggested; conditions were selected to make it possible to determine, with maximum efficiency, the content of toxic substances corresponding to a certain maximum permissible concentration. The sensitivity of soluble and immobilized coupled enzymatic systems to a series of organic pollutants (phenols, quinones, and salts of heavy metals) was compared. It was shown that the reagent is the most sensitive to the effect of phenols and quinones. The method was tested during analysis of the wastewater from a pulp and paper plant and can be used for biotesting in both laboratory and field conditions. 23893472 Characterization of the ATPase activity of RecG and RuvAB on model fork structures reveals insight into stalled DNA replication fork repair. RecG and RuvAB are proposed to act at stalled DNA replication forks to facilitate replication restart. To clarify the roles of these proteins in fork regression, we used a coupled spectrophotometric ATPase assay to determine how these helicases act on two groups of model fork substrates: the first group mimics nascent stalled forks while the second mimics regressed fork structures. The results show that RecG is active on the substrates in group one whereas these are poor substrates for RuvAB. In addition, in the presence of group one forks, the single stranded DNA binding protein (SSB) enhances the activity of RecG and enables it to compete with excess RuvA. In contrast, SSB inhibits the activity of RuvAB on these substrates. Results also show that the preferred regressed fork substrate for RuvAB is a Holliday Junction not a forked DNA. The active form of the enzyme on the Holliday Junction contains a single RuvA tetramer. In contrast, and although the enzyme is active on a regressed fork structure, RuvB loading by a single RuvA tetramer is impaired and full activity requires the cooperative binding of two, forked DNA substrate molecules. Collectively, the data support a model that RecG is responsible for stalled DNA replication fork regression, not RuvAB. SSB ensures that if the nascent fork has single stranded DNA character, RuvAB is inhibited while the activity of RecG is preferentially enhanced. Only once the fork has been regressed and the DNA is relaxed, can RuvAB bind to a RecG-extruded, Holliday junction. 23829324 Spectral Database for Postage Stamps by Means of FT-IR Spectroscopy. A Fourier transform infrared (FT-IR) spectroscopy study on the entire Italian postage stamps production is presented in this work. Crossing 150 years of issues from the unification of Italy until today, a time line of the major components constituting the stamps has been defined, based on the wide spectral database built on the basis of the numerous analyzed exemplars. Even though it is easy to find reports about stamps' issues history, information arising from these investigations contributes to throw light upon the substances incorporated in the stamps, which could be described as hybrid or composite materials (a sort of undisclosed or hidden story). As a result of the whole spectra acquired in attenuated total reflectance (ATR) mode, changes in paper composition showed the transition from the protein sizing glue to starch sizing; also the employment of kaolin varied through time. First it was used as the extender in the pigment-medium mixture, and finally it constituted the coating on the stamp surface. Also the chemical composition of the adhesive gum on the rear side of stamps has been subjected to modifications, as well as the front side. The earliest back glue was a protein-based adhesive; then it was replaced by gum arabic first and by poly(vinyl acetate) (PVAC) later. FT-IR spectroscopy, supported by the detailed database developed, has been applied, for the first time, in the very useful detection of two counterfeit samples: a fake of the famous Gronchi Rosa, issued in 1961, and a regummed 2 cent red stamp, issued in 1865. The information held in the whole spectral data has been selected and employed in the principal component analysis (PCA) statistical analysis. 23855318 A pilot study comparing two weight loss maintenance interventions among low-income, mid-life women. Despite high obesity prevalence rates, few low-income midlife women participate in weight loss maintenance trials. This pilot study aims to assess the effectiveness of two weight loss maintenance interventions in this under-represented population. Low-income midlife women who completed a 16-week weight loss intervention and lost >= 8 lbs (3.6 kg) were eligible to enroll in one of two 12-month maintenance programs. The programs were similar in content and had the same number of total contacts, but were different in the contact modality (Phone + Face-to-Face vs. Face-to-Face Only). Two criteria were used to assess successful weight loss maintenance at 12 months: (1) retaining a loss of >= 5% of body weight from the start of the weight loss phase and (2) a change in body weight of < 3%, from the start to the end of the maintenance program. Outcome measures of changes in physiologic and psychosocial factors, and evaluations of process measures and program acceptability (measured at 12 months) are also reported. For categorical variables, likelihood ratio or Fisher's Exact (for small samples) tests were used to evaluate statistically significant relationships; for continuous variables, t-tests or their equivalents were used to assess differences between means and also to identify correlates of weight loss maintenance. Overall, during the 12-month maintenance period, 41% (24/58) of participants maintained a loss of >= 5% of initial weight and 43% (25/58) had a <3% change in weight. None of the comparisons between the two maintenance programs were statistically significant. However, improvements in blood pressure and dietary behaviors remained significant at the end of the 12-month maintenance period for participants in both programs. Participant attendance and acceptability were high for both programs. The effectiveness of two pilot 12-month maintenance interventions provides support for further research in weight loss maintenance among high-risk, low-income women.Trial registrationClinicalTrials.gov Identifier: NCT00288301. 23964126 The growth speed of microtubules with XMAP215-coated beads coupled to their ends is increased by tensile force. The generation of pulling and pushing forces is one of the important functions of microtubules, which are dynamic and polarized structures. The ends of dynamic microtubules are able to form relatively stable links to cellular structures, so that when a microtubule grows it can exert a pushing force and when it shrinks it can exert a pulling force. Microtubule growth and shrinkage are tightly regulated by microtubule-associated proteins (MAPs) that bind to microtubule ends. Given their localization, MAPs may be exposed to compressive and tensile forces. The effect of such forces on MAP function, however, is poorly understood. Here we show that beads coated with the microtubule polymerizing protein XMAP215, the Xenopus homolog of Dis1 and chTOG, are able to link stably to the plus ends of microtubules, even when the ends are growing or shrinking; at growing ends, the beads increase the polymerization rate. Using optical tweezers, we found that tensile force further increased the microtubule polymerization rate. These results show that physical forces can regulate the activity of MAPs. Furthermore, our results show that XMAP215 can be used as a handle to sense and mechanically manipulate the dynamics of the microtubule tip. 23792158 Circadian gene Clock contributes to cell proliferation and migration of glioma and is directly regulated by tumor-suppressive miR-124. Although the roles of circadian Clock genes and microRNAs in tumorigenesis have been profoundly studied, mechanisms of cross-talk between them in regulation of gliomagenesis are poorly understood. Here we show that the expression level of CLOCK is significantly increased in high-grade human glioma tissues and glioblastoma cell lines. In contrast miR-124 is attenuated in similar samples. Further studies show that Clock is a direct target of miR-124, and either restoration of miR-124 or silencing of CLOCK can reduce the activation of NF-κB. In conclusion, we suggest that as a target of glioma suppressor miR-124, CLOCK positively regulates glioma proliferation and migration by reinforcing NF-κB activity. 23916662 Effect of Urtica dioica on memory dysfunction and hypoalgesia in an experimental model of diabetic neuropathy. Diabetic neuropathy is considered as a disease of the peripheral nervous system, but recent evidences suggest the involvement of central nervous system as well. In this study we evaluated the effect of Urtica dioica (UD) extract against memory dysfunction and hypoalgesia on a mouse model of streptozotocin (STZ) induced diabetic neuropathy. STZ (50mg/kg, i.p. consecutively for 5 days) was used to induce diabetes, followed by treatment with the UD extract (50mg/kg, oral) and rosiglitazone (5mg/kg, oral) for 8 weeks. Cognitive functions were evaluated using Morris water maze and passive avoidance step through task. Pain thresholds were measured using thermal, mechanical and chemical induced hyperalgesia. We observed that chronic diabetes resulted in a decline in circulating insulin level, elevated blood glucose, reduced body weight, increased water intake, cognitive impairment and hypoalgesia. UD significantly reduced the blood glucose and polydypsia, as well as improved the body weight, insulin level, cognition and insensate neuropathy. In conclusion, UD showed results comparable to rosiglitazone in reversing the long standing diabetes induced complications such as central and peripheral neuronal dysfunction. 23697547 Prediction of relaxin-3-induced downstream pathway resulting in anxiolytic-like behaviors in rats based on a microarray and peptidome analysis. Abstract The effect of the intracerebroventricular (i.c.v.) injection of relaxin-3 (RLX3) was evaluated using anxiety-related behavioral tests in rats. RLX3-injected animals showed normal locomotion activity in a habituated environment and declined anxiety cognition in the elevated plus maze test and the shock probe-burying test. The measurement of spontaneous locomotor activity in a novel environment also suggested that RLX3 reduced the stress response. To elucidate the regulatory mechanisms of the downstream signaling pathways underlying RLX3 activity and its relation to anxiolytic and hyperphagic behavior phenotypes, RLX3-i.c.v.-injected rat hypothalamic responses were examined using a microarray analysis. Ingenuity Pathway Analysis software listed the phenotype-relating genes and they showed characteristic expression patterns in the rat hypothalamus. When peptidome data sets for the same listed genes was analyzed using a semi-quantitative approach, the expressions of two neuropeptides were found to have increased. One of these neuropeptides, oxytocin (Oxt), exhibited increased expression in both the microarray and the peptidomic analysis, and a Western blot analysis validated the mass spectrometry results. A cross-omics data analysis is useful for predicting downstream signaling pathways, and the anxiolytic-like behavior of RLX3 may be mediated by an oxytocin signaling pathway in rats. These results suggest that RLX3 acts as an anxiolytic peptide and that the downstream pathways mediated by its receptors may be potential candidates for the treatment of anxieties in the future. 23905609 Oxidative stress and immunological alteration in women with preeclampsia. Objectives: To determine plasma concentrations of malondialdehyde (MDA) and of inflammatory markers in women with preeclampsia. Methods: A case-control study was conducted on 50 preeclamptic and 50 healthy pregnant women. The concentrations of MDA were determined by the method of thiobarbituric acid reactive substances. Markers of inflammation were determined by the multiplex method. Results: The concentrations of MDA did not differ between groups (p > 0.05) and the preeclampsia group had significantly higher IL-6, IL-10, TNF-α and IL-6/IL-10 ratio, compared to those with normal pregnancy. Conclusions: The MDA is a nonspecific marker for oxidative stress in preeclampsia, and the gestantes with preeclampsia have immune dysfunction. 23878131 Transcription factor interplay in T helper cell differentiation. The differentiation of CD4 helper T cells into specialized effector lineages has provided a powerful model for understanding immune cell differentiation. Distinct lineages have been defined by differential expression of signature cytokines and the lineage-specifying transcription factors necessary and sufficient for their production. The traditional paradigm of differentiation towards Th1 and Th2 subtypes driven by T-bet and GATA3, respectively, has been extended to incorporate additional T cell lineages and transcriptional regulators. Technological advances have expanded our view of these lineage-specifying transcription factors to the whole genome and revealed unexpected interplay between them. From these data, it is becoming clear that lineage specification is more complex and plastic than previous models might have suggested. Here, we present an overview of the different forms of transcription factor interplay that have been identified and how cell T phenotypes arise as a product of this interplay within complex regulatory networks. We also suggest experimental strategies that will provide further insight into the mechanisms that underlie T cell lineage specification and plasticity. 23868068 HDAC Inhibition Suppresses Cardiac Hypertrophy and Fibrosis in DOCA-Salt Hypertensive Rats via Regulation of HDAC6/HDAC8 Enzyme Activity. Background : Inhibition of histone deacetylase (HDAC) was reported to suppress cardiac hypertrophy and fibrosis in various hypertrophic animal models. However, the HDAC expression profile and HDAC enzyme activity have not yet been investigated in DOCA-salt hypertensive rats. Methods : Unilaterally nephrectomized rats were implanted with DOCA strips. DOCA-salt rats then received a control diet with vehicle or valproate. We measured the expression of cardiac hypertrophic markers, class I HDACs, class II HDACs, fibrosis, and HDAC enzyme activity. Results : Here we report that sodium valproate inhibits the cardiac hypertrophy accompanied by fibrosis in the heart of chronic hypertensive rats. We show that expression of GATA6 and HDAC6 is upregulated in DOCA-salt hypertension. In addition, HDAC6 and HDAC8 enzyme activity is attenuated by sodium valproate. Conclusion : These results suggest that a novel HDAC6- and HDAC8-selective inhibitor is needed to treat or prevent pathological cardiac hypertrophy. © 2013 S. Karger AG, Basel. 23790334 Cytokine levels in patients with chikungunya virus infection. To investigate cytokine profile in patients with chikungunya virus (CHIKV) infection. Twenty eight pairs of serum samples collected from CHIKV infected patients during the outbreak of chikungunya fever in South Thailand in 2008 were obtained. A multiple cytokine assay for detection of 17 cytokines was performed. In the acute stage of CHIKV infection, the patients had significantly higher levels of interleukin-6, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein 1 and tumor necrosis factor alpha than the control (P<0.001, P=0.023, P=0.015, P<0.001 and P=0.024, respectively). When the disease developed to the recovery stage, the patients had significantly lower levels of interleukin-6, granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein 1 and macrophage inflammatory protein beta than in the acute stage (P<0.001). This study provides additional information that these cytokines could play roles in pathogenesis of CHIKV infection and could be used as disease biomarkers or drug targets. 23818269 New 23-Spirocholestane Derivatives from Ypsilandra thibetica. Three new unusual 23-spirocholestane derivatives, ypsilanogenin (1), ypsilanogenin 3-O-β-D-glucopyranoside (2), and 4'-acetylypsilanogenin 3-O-β-D-glucopyranoside (3), were isolated from the whole plants of Ypsilandra thibetica. The structures of compounds 1-3 were deduced by spectroscopic and chemical methods, and the structure of 1 was further confirmed by a single-crystal diffraction analysis. All isolates were evaluated for their inhibitory activities against HIV-1. 23680302 An evaluation of marginal fit of three-unit fixed dental prostheses fabricated by direct metal laser sintering system. This in vitro study aimed to evaluate and compare marginal fit of three-unit fixed dental prostheses (FDPs) fabricated using a newly developed direct metal laser sintering (DMLS) system with that of three-unit FDPs by a conventional lost wax technique (LW) method. Ten cobalt-chromium alloy three-unit FDPs using DMLS system and another ten nickel-chromium alloy FDPs using LW method were fabricated. Marginal fit was examined using a light-body silicone. After setting, the silicon film was cut into four parts and the thickness of silicon layer was measured at 160× magnification using a digital microscope to measure absolute marginal discrepancy (AMD), marginal gap (MG) and internal gap (IG). A repeated measure ANOVA for statistical analysis was performed using the SPSS statistical package version 12.0 (α=0.05). The mean values of AMD, MG, and IG were significantly larger in the DMLS group than in the LW group (p<0.001). Means of AMD, MG and IG in the first molars were 83.3, 80.0, and 82.0μm in the LW group; and 128.0, 112.0, and 159.5μm in the DMLS group, respectively. No significant difference between measurements for premolars and molars was found (p>0.05). The marginal fit of the DMLS system appeared significantly inferior compared to that of the conventional LW method and slightly larger than the acceptable range. For clinical application further improvement of DMLS system may be required. 23611630 Comparison of 3 different postimplant dosimetry methods following permanent (125)I prostate seed brachytherapy. Postimplant dosimetry (PID) after Iodine-125 ((125)I) implant of the prostate should offer a reliable qualitative assessment. So far, there is no consensus regarding the optimum PID method, though the latest literature is in favor of magnetic resonance imaging (MRI). This study aims to simultaneously compare 3 PID techniques: (1) MRI-computed tomography (CT) fusion; (2) ultrasound (US)-CT fusion; and (3) manual target delineation on CT. The study comprised 10 patients with prostate cancer. CT/MR scans with urinary catheters in place for PID were done either on day 0 or day 1 postimplantation. The main parameter evaluated and compared among methods was target D90. The results show that CT-based D90s are lower than US-CT D90s (median difference,-6.85%), whereas MR-CT PID gives higher D90 than US-CT PID (median difference, 4.25%). Manual contouring on CT images tends to overestimate the prostate volume compared with transrectal ultrasound (TRUS) (median difference, 23.33%), whereas on US images the target is overestimated compared with MR-based contouring (median difference, 13.25%). Although there are certain differences among the results given by various PID techniques, the differences are statistically insignificant for this small group of patients. Any dosimetric comparison between 2 PID techniques should also account for the limitations of each technique, to allow for an accurate quantification of data. Given that PID after permanent radioactive seed implant is mandatory for quality assurance, any imaging method-based PID (MR-CT, US-CT, and CT) available in a radiotherapy department can be indicative of the quality of the procedure. 23876368 A new pentacyclic triterpene with potent antibacterial activity from Limnophila indica Linn. (Druce). A new pentacyclic triterpenoid constituent, characterized as 3-oxo-olean-12(13),18(19)-dien-29α-carboxylic acid (1) on the basis of detailed spectral studies, was isolated from the aerial parts and roots of Limnophila indica (Scrophulariaceae). Compound 1 exhibited considerable antibacterial activity against three Gram-positive bacteria viz. Bacillus subtilis, Staphylococcus aureus and Listeria monocytogenes (MICs within a range of 25-30μg/ml) and moderate activity against four Gram-negative bacteria Salmonella typhimurium, Escherichia coli, Pseudomonas aeruginosa, and Pantoea ananatis (MICs within a range of 30-100μg/ml). The plant pathogenic bacterium P. ananatis and human pathogenic S. typhimurium responded at comparatively higher concentrations of the compound 1, which were 75 and 100μg/ml respectively. The compound inhibited the growth of Gram-positive B. subtilis and Gram-negative P. aeruginosa completely with a clear bactericidal mode of action at their MIC values. The compound upon treatment on both B. subtilis and P. aeruginosa released substantial amount of nucleic acid in the external medium and also effected the change of morphology towards pleomorphicity, thereby indicating its probable action on cell membrane. Furthermore, the triterpenoid 1 was found not to inhibit a probiotic lactic acid bacterium Lactococcus lactis subsp. lactis LABW4 under in vitro condition and to possess no toxicity in Swiss albino mice. 23828946 Characterization of incidental cardiac masses in oncological patients using a new CT-based tumor volume perfusion technique. Cardiac masses are challenging for non-invasive diagnostic procedures and therapy, respectively. In tumor patients differentiation between primary or secondary cardiac neoplasm and thrombus is a frequent and knowingly difficult task to manage. To avoid complex and unnecessary surgical diagnostic procedures non-invasive methods are in favor. For initiation of adequate therapy and evaluation of prognosis, however, early and reliable diagnosis is mandatory.So far, echocardiography and magnetic resonance imaging represent the mainstay for cardiac imaging diagnosis. Recently, the new technique of CT-based tumor volume perfusion (VPCT) measurement has advanced to a potent, reliable, and easy to perform alternative for cardiac imaging. The purpose of this study was to review the existing spectrum of diagnostic modalities for characterization of cardiac masses in an oncologic patient cohort with emphasis on their strengths and limitations and to present the benefit from using the novel technique called VPCT for this purpose. 23603429 The molecular basis of simple relationships between exposure concentration and toxic effects with time. Understanding the toxicity of chemicals to organisms requires considering the molecular mechanisms involved as well as the relationships between exposure concentration and toxic effects with time. Our current knowledge about such relationships is mainly explained from a toxicodynamic and toxicokinetic perspective. This paper re-introduces an old approach that takes into account the biochemical mode of action and their resulting biological effects over time of exposure. Empirical evidence demonstrates that the Druckrey-Küpfmüller toxicity model, which was validated for chemical carcinogens in the early 1960s, is also applicable to a wide range of toxic compounds in ecotoxicology. According to this model, the character of a poison is primarily determined by the reversibility of critical receptor binding. Chemicals showing irreversible or slowly reversible binding to specific receptors will produce cumulative effects with time of exposure, and whenever the effects are also irreversible (e.g. death) they are reinforced over time; these chemical have time-cumulative toxicity. Compounds having non-specific receptor binding, or involving slowly reversible binding to some receptors that do not contribute to toxicity, may also be time-dependent; however, their effects depend primarily on the exposure concentration, with time playing a minor role. Consequently, the mechanism of toxic action has important implications for risk assessment. Traditional risk approaches cannot predict the impacts of toxicants with time-cumulative toxicity in the environment. New assessment procedures are needed to evaluate the risk that the latter chemicals pose on humans and the environment. An example is shown to explain how the risk of time-dependent toxicants is underestimated when using current risk assessment protocols. 23504628 Inhibition of Protein Misfolding/Aggregation Using Polyglutamine Binding Peptide QBP1 as a Therapy for the Polyglutamine Diseases. Protein misfolding and aggregation in the brain have been recognized to be crucial in the pathogenesis of various neurodegenerative diseases, including Alzheimer's, Parkinson's, and the polyglutamine (polyQ) diseases, which are collectively called the "protein misfolding diseases". In the polyQ diseases, an abnormally expanded polyQ stretch in the responsible proteins causes the proteins to misfold and aggregate, eventually resulting in neurodegeneration. Hypothesizing that polyQ protein misfolding and aggregation could be inhibited by molecules specifically binding to the expanded polyQ stretch, we identified polyQ binding peptide 1 (QBP1). We show that QBP1 does, indeed, inhibit misfolding and aggregation of the expanded polyQ protein in vitro. Furthermore overexpression of QBP1 by the crossing of transgenic animals inhibits neurodegeneration in Drosophila models of the polyQ diseases. We also introduce our attempts to deliver QBP1 into the brain by administration using viral vectors and protein transduction domains. Interestingly, recent data suggest that QBP1 can also inhibit the misfolding/aggregation of proteins responsible for other protein misfolding diseases, highlighting the potential of QBP1 as a general therapeutic molecule for a wide range of neurodegenerative diseases. We hope that in the near future, aggregation inhibitor-based drugs will be developed and bring relief to patients suffering from these currently intractable protein misfolding diseases. 22566158 Preventive effects of North American ginseng (Panax quinquefolius) on diabetic retinopathy and cardiomyopathy. Ginseng (Araliaceae) has multiple pharmacological actions because of its diverse phytochemical constituents. The aims of the present study are to evaluate the preventive effects of North American ginseng on diabetic retinopathy and cardiomyopathy and to delineate the underlying mechanisms of such effects. Models of both type 1 (C57BL/6 mice with streptozotocin-induced diabetes) and type 2 diabetes (db/db mice) and age-matched and sex-matched controls were examined. Alcoholic ginseng root (200 mg/kg body weight, daily oral gavage) extract was administered to groups of both type 1 and type 2 diabetic mice for 2 or 4 months. Dysmetabolic state in the diabetic mice was significantly improved by ginseng treatment. In both the heart and retina of diabetic animals, ginseng treatment significantly prevented oxidative stress and diabetes-induced upregulations of extracellular matrix proteins and vasoactive factors. Ginseng treatment in the diabetic animals resulted in enhancement of stroke volume, ejection fraction, cardiac output, and left ventricle pressure during systole and diastole and diminution of stroke work. In addition, mRNA expressions of atrial natriuretic factor and brain natriuretic factor (molecular markers for cardiac hypertrophy) were significantly diminished in ginseng-treated diabetic mice. These data indicate that North American ginseng prevents the diabetes-induced retinal and cardiac biochemical and functional changes probably through inhibition of oxidative stress. 23879559 An introduction to primary skin imaging. Dermatology is a field in which clinical examination is heavily relied upon for diagnosis. When required, a tissue biopsy may also be performed to confirm the diagnosis. Recent advances in imaging techniques have been applied to cutaneous lesions to improve diagnostic accuracy without the need for biopsy. These new imaging techniques are reviewed for their developing role in dermatology. 23966251 Postictal generalized EEG suppression: An inconsistent finding in people with multiple seizures. To determine the consistency and facilitating cofactors of postictal generalized EEG suppression (PGES) of >20 seconds after convulsive seizures (CS), a suggested predictor of sudden unexpected death in epilepsy risk. We retrospectively reviewed video-EEG data of people with ≥2 recorded CS. Presence and duration of PGES were assessed by 2 independent observers blinded to patient status. Intraindividual consistency of PGES >20 seconds was determined and correlations with clinical characteristics were analyzed after correction for individual effects and the varying number of seizures. One hundred fifty-four seizures in 59 people were analyzed. PGES >20 seconds was found in 37 individuals (63%) and 57 (37%) of CS. The proportion of persons in whom PGES occurred consistently (presence or absence of PGES >20 seconds in all CS) was lower in those with more CS. PGES of >20 seconds was more frequent in seizures arising from sleep (odds ratio 3.29, 95% confidence interval 1.21-8.96) and when antiepileptic medication was tapered (odds ratio 4.80, 95% confidence interval 1.27-18.14). Apparent PGES consistency was less frequent in people with more CS recorded, suggesting that PGES is an inconsistent finding in any one individual. Thus, we believe that PGES >20 seconds is not a reliable predictor of sudden unexpected death in epilepsy. Sleep and antiepileptic drug reduction appear to facilitate the occurrence of PGES. 23395155 Uncoupling of endothelial NO synthase in atherosclerosis and vascular disease. Nitric oxide (NO) produced by the endothelial NO synthase (eNOS) is an antihypertensive, antithrombotic and anti-atherosclerotic molecule. Hypercholesterolemia leads to a reduction in vascular NO bioavailability. This is attributed to a dysfunction of the eNOS enzyme and a reduced eNOS activity. NADPH oxidase-mediated oxidative stress leads to oxidation of tetrahydrobiopterin (BH4), the essential cofactor of eNOS. In BH4 deficiency, oxygen reduction uncouples from NO synthesis, thereby converting eNOS to a superoxide-producing enzyme. As a consequence of eNOS uncoupling, NO production is reduced and the pre-existing oxidative stress is enhanced, which contribute significantly to atherogenesis. Therefore, pharmacological approaches that prevent eNOS uncoupling and enhance eNOS activity are of therapeutic interest. Angiotensin-converting enzyme inhibitors, AT1 receptor blockers, statins, nebivolol and resveratrol have been shown to reverse eNOS uncoupling and to stimulate eNOS activity concurrently. Molecular mechanisms of the aforementioned drugs/compounds on eNOS functionality is summarized and discussed in this review. 23958116 Perceived Social-Ecological Factors Associated with Fruit and Vegetable Purchasing, Preparation, and Consumption among Young Adults. Most young adults do not consume recommended levels of fruits and vegetables (F/V), and interventions to increase F/V-related behaviors among this understudied population are needed. Therefore, it is important to identify correlates of F/V intake among young adults to guide intervention development. This cross-sectional study used data from an online survey to identify factors related to young adults' F/V purchasing, preparation, and consumption, and to explore between-factor relationships using mediation analysis. In 2010, 1,201 college students in Minnesota completed questionnaires assessing F/V behaviors as well as perceptions of F/V-related individual, social, and environmental factors. Factor analysis identified questionnaire items assessing similar constructs. Seven factors were identified (personal barriers, F/V knowledge, family, friends, neighborhood, access barriers, and campus) and evaluated for relationships with F/V purchasing, preparation, and consumption using linear regression. Results revealed that perceived personal barriers (eg, lacking cooking skills) were inversely related to all F/V outcomes. Perception that family and friends eat healthfully and neighborhood access to F/V were positively related to all outcomes. Individual-, social-, and environment-level perceptions were related to purchasing, preparation, and consumption, and the effects of these factors were similar when accounting for mediated effects. Factors at all three levels and the ways in which these various factors operate together may be important to consider in future efforts to improve F/V behaviors among young adults. 23848232 Design and synthesis of imidazolidine-2,4-dione derivatives as selective inhibitors by targeting PTP1B over TCPTP. Owing to its special role as a negative regulator in both insuin and leptin signaling, Protein-tyrosine Phosphatase-1B (PTP1B) has drawn considerable attention as a target for treating type2 diabetes and obesity. It, however, is a great challenge to discover inhibitors specific to each PTP due to the highly homologous. In this study, a serial of compounds were discovered to inhibit PTP1B based on imidazolidine-2,4-dione by means of "Core hopping". A selective PTP1B inhibitor (comp#h) was identified and molecular dynamics simulation and binding free energy calculation were carried out to propose the most likely binding mode of comp#h with PTP1B. The findings reported here may provide a new strategy in discovering selective and effective inhibitors for treating diabetes. This article is protected by copyright. All rights reserved. 23639572 The preventive effect of uncarboxylated osteocalcin against free fatty acid-induced endothelial apoptosis through the activation of phosphatidylinositol 3-kinase/Akt signaling pathway: Uncarboxylated osteocalcin and endothelial apoptosis. OBJECTIVE: Increasing evidence suggests that osteocalcin (OC), one of the osteoblast-specific proteins, has been associated with atherosclerosis, but results are conflicting. The aim of this study was to elucidate the independent effect of uncarboxylated osteocalcin (ucOC), an active form of osteocalcin which has been suggested to have an insulin sensitizing effect, on vascular endothelial cells. MATERIALS AND METHODS: We used human aortic endothelial cells and treated them with ucOC. Linoleic acid (LA) was used as a representative free fatty acid. Apoptosis was evaluated using various methods including a terminal deoxyribonucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling analysis kit and Western blotting for cleaved caspase 3, cleaved poly (ADP-ribose) polymerase and Bcl-xL. The phosphorylations of Akt and endothelial nitric oxide synthase (eNOS) as well as the level of NO were measured to confirm the effect of ucOC on insulin signaling pathway. RESULTS: Pretreatment of ucOC (30ng/ml) prevented LA-induced apoptosis in insulin-stimulated endothelial cells; effects were abolished by pretreatment with the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, wortmannin. Treatment of ucOC (ranged from 0.3 to 30ng/ml) significantly increased the phosphorylation of Akt and eNOS and nitric oxide secretion from endothelial cells in a PI3-kinase dependent manner. CONCLUSIONS: Our study is the first to demonstrate the independent effect of ucOC on vascular endothelial cells. Our results further suggest that ucOC could have beneficial effects on atherosclerosis. 23265535 Reduction of acrylamide formation by vanadium salt in potato French fries and chips. The effects of vanadyl sulphate on the formation of acrylamide have been studied in fried potato products, such as French fries and chips. Acrylamide formation was inhibited by 30.3%, 53.3% and 89.3% when the sliced potato strips were soaked in 0.001, 0.01 and 0.1 M vanadyl sulphate (VOSO(4)) solutions, respectively, for 60 min before frying. Moreover, 57.7%, 71.4% and 92.5% inhibition of acrylamide formation was observed when chips were soaked in the respective vanadyl sulphate solution before frying. In a separate model reaction, a solution containing an equimolar concentration of L-asparagine and D-glucose showed a significant inhibition of acrylamide formation when heated at 150 °C for 30 min in the presence of vanadyl sulphate (VOSO(4)). The results indicate that the binding of VO(2+) to asparagine and the decrease in the pH of the potato samples resulted in a significant reduction of acrylamide formation in fried potato products. 23910165 Base Excess as a Predictor for Injury Severity in Pediatric Trauma Patients. Base excess is considered a predictor of mortality and severity of injury in trauma patients. Base excess had been widely examined in different settings. Only few studies have examined the role of base excess in pediatric trauma patients. To evaluate the value of admission base excess in pediatric trauma patients with respect to intensive care unit (ICU) admission rate and length of hospital stay. Methods: A retrospective study of pediatric trauma patients was conducted at a Level II trauma center. All patients aged 0-16 years for which a trauma team was activated over the years 2006-2009 were included. Study database included admission base excess, mechanism of injury, location and nature of injury, injury severity score, length of hospital stay, and ICU admission. The study group consisted of 359 patients. There was a weak linear correlation between admission base excess, length of stay in the hospital, and ICU admission. Base excess seemed to show a stronger correlation for the youngest age group (0-6 years) and no correlation for the middle age group. There was a positive but weak correlation (R Spearman = 0.26) between admission base excess and Injury Severity Score (ISS). However, 40% of the children with an ISS score >25 had normal admission base excess values. The area under the curve of the receiver operating characteristic curves of base excess for predicting ICU admission was 0.66. The admission base excess in pediatric trauma patients seems to be a weak prognostic factor in our facility. 23090483 Costs of living in metal polluted areas: respiration rate of the ground beetle Pterostichus oblongopunctatus from two gradients of metal pollution. To address the question about costs of living in polluted areas, biomarkers linked to metabolism were measured in Pterostichus oblongopunctatus (Coleoptera: Carabidae) collected along two metal-pollution gradients in the vicinity of the two largest Polish zinc smelters: 'Bolesław' and 'Miasteczko Śląskie' in southern Poland. Both gradients covered a broad range of Zn and Cd concentrations in the humus layer (109-6151 and 1.48-71.4 mg kg(-1), respectively) and body metal concentrations increased with increasing soil metal concentrations. The whole-organism respiration rate was measured as oxygen consumption with Micro-Oxymax respirometer, and cellular energy consumption-as the activity of electron transport system, which is linked to cellular respiration rate. The significant increase in the whole-organism respiration rate with the body metal concentration was found when taking into account other factors such as body mass, gradient (or year of sampling as the beetles were collected on the gradients in different years) and the interactions: body metal concentrations × collection date, body metal concentrations × body mass, and body mass × gradient/sampling year. However, no relationships between metal concentrations in soil or body metal concentrations and the whole-organism or cellular respiration rate could be detected when using mean values per site, underlining the crucial importance of incorporating individual variability in such analyses. The observed increase of the whole-organism respiration rate with increasing body contamination with metals suggests that P. oblongopunctatus incurs energetic expenditures resulting from the necessity to facilitate metal elimination or repair of toxicant-induced damage. 23857990 Formation of gallium arsenide nanostructures in Pyrex glass. In this paper, we report on a simple, low-cost process to grow GaAs nanostructures of a few nm diameter and ∼50 nm height in Pyrex glass wafers. These nanostructures were grown by sequential plasma activation of GaAs and Pyrex glass surfaces using a low-temperature hybrid plasma bonding technology in air. Raman analyses of the activated surfaces show gallium oxide and arsenic oxide, as well as suppressed non-bridging oxygen with aluminate and boroxol chains in glass. The flow of alkaline ions toward the cathode and the replacement of alkaline ions by Ga and As ions in glass result in the growth of GaAs nanostructures in nanopores/nanoscratches in glass. These nanopores/nanoscratches are believed to be the origin of the growth of the nanostructures. It was found that the length of the GaAs nanostructures may be controlled by an electrostatic force. Cross-sectional observation of the bonded interface using high-resolution transmission electron microscopy confirms the existence of the nanostructures. A possible application of the nanostructures in glass is a filtration system for biomolecules. 23750852 Degradation rate of mitochondrial proteins in Arabidopsis thaliana cells. The turnover of the proteomes of organelles in plant cells are known to be governed by both whole cell and organelle-specific processes. However, the rate and specificity of this protein turnover has not been explored in depth to understand how it affects different organellar processes. Here we have used progressive ¹⁵N labeling of Arabidopsis cells, and focused on the turnover rate of proteins in mitochondria. We provide estimates of degradation rate (K(d)) for 224 mitochondrial proteins, showing a range of over 50-fold in K(d). Protein complexes, most notably the respiratory chain complexes, had K(d) values that were generally coordinated and we have interpreted these measurements to outline how protein K(d) differs within protein complexes and between functional categories. The fastest turnover rates were reported for DNA/RNA metabolism enzymes, chaperones, and proteases. 23819862 Limitations in the Application of the Gibbs Equation to Anionic Surfactants at the Air/Water Surface: Sodium Dodecylsulfate and Sodium Dodecylmonooxyethylenesulfate Above and Below the CMC. This is a second paper responding to recent papers by Menger et al. and the ensuing discussion about the application of the Gibbs equation to surface tension (ST) data. Using new neutron reflection (NR) measurements on sodium dodecylsulfate (SDS) and sodium dodecylmonooxyethylene sulfate (SLES) above and below their CMCs and with and without added NaCl, in conjunction with the previous ST measurements on SDS by Elworthy and Mysels (EM), we conclude that (i) ST measurements are often seriously compromised by traces of divalent ions, (ii) adsorption does not generally reach saturation at the CMC, making it difficult to obtain the limiting Gibbs slope, and (iii) the significant width of micellization may make it impossible to apply the Gibbs equation in a significant range of concentration below the CMC. Menger et al. proposed ii as a reason for the difficulty of applying the Gibbs equation to ST data. Conclusions i and iii now further emphasize the failings of the ST-Gibbs analysis for determining the limiting coverage at the CMC, especially for SDS. For SDS, adsorption increases above the CMC to a value of 10 × CMC, which is about 25% greater than at the CMC and about the same as at the CMC in the presence of 0.1 M NaCl. In contrast, the adsorption of SLES reaches a limit at the CMC with no further increase up to 10 × CMC, but the addition of 0.1 M NaCl increases the surface excess by 20-25%. The results for SDS are combined with earlier NR results to generate an adsorption isotherm from 2 to 100 mM. The NR results for SDS are compared to the definitive surface tension (ST) measurements of EM, and the surface excesses agree over the range where they can safely be compared, from 2 to 6 mM. This confirms that the anomalous decrease in the slope of EM's σ - ln c curve between 6 mM and the CMC at 8.2 mM results from changes in activity associated with a significant width of micellization. This anomaly shows that it is impossible to apply the Gibbs equation usefully from 6 to 8.2 mM (i.e., the lack of knowledge of the activity in this range is the same as above the CMC (8.2 mM)). It was found that a mislabeling of the original data in EM may have prevented the use of this excellent ST data as a standard by other authors. Although NR and ST results for SDS in the absence of added electrolyte show that the discrepancies can be rationalized, ST is generally shown to be less accurate and more vulnerable to impurities, especially divalent ions, than NR. The radiotracer technique is shown to be less accurate than ST-Gibbs in that the four radiotracer measurements of the surface excess are consistent neither with each other nor with ST and NR. It is also shown that radiotracer results on aerosol-OT are likely to be incorrect. Application of the mass action (MA) model of micellization to the ST curves of SDS and SLES through and above the CMC shows that they can be explained by this model and that they depend on the degree of dissociation of the micelle, which leads to a larger change in the mean activity, and hence the adsorption, for the more highly dissociated SDS micelles than for SLES. Previous measurements of the activity of SDS above the CMC were found to be semiquantitatively consistent with the change in mean activity predicted by the MA model but inconsistent with the combined ST, NR, and Gibbs equation results. 23537574 Amino acids as co-amorphous stabilizers for poorly water soluble drugs - Part 1: Preparation, stability and dissolution enhancement. Poor aqueous solubility of an active pharmaceutical ingredient (API) is one of the most pressing problems in pharmaceutical research and development because up to 90% of new API candidates under development are poorly water soluble. These drugs usually have a low and variable oral bioavailability, and therefore an unsatisfactory therapeutic effect. One of the most promising approaches to increase dissolution rate and solubility of these drugs is the conversion of a crystalline form of the drug into its respective amorphous form, usually by incorporation into hydrophilic polymers, forming glass solutions. However, this strategy only led to a small number of marketed products usually because of inadequate physical stability of the drug (crystallization). In this study, we investigated a fundamentally different approach to stabilize the amorphous form of drugs, namely the use of amino acids as small molecular weight excipients that form specific molecular interactions with the drug resulting in co-amorphous forms. The two poorly water soluble drugs carbamazepine and indomethacin were combined with amino acids from the binding sites of the biological receptors of these drugs. Mixtures of drug and the amino acids arginine, phenylalanine, tryptophan and tyrosine were prepared by vibrational ball milling. Solid-state characterization with X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) revealed that the various blends could be prepared as homogeneous, single phase co-amorphous formulations indicated by the appearance of an amorphous halo in the XRPD diffractograms and a single glass transition temperature (Tg) in the DSC measurements. In addition, the Tgs of the co-amorphous mixtures were significantly increased over those of the individual drugs. The drugs remained chemically stable during the milling process and the co-amorphous formulations were generally physically stable over at least 6months at 40°C under dry conditions. The dissolution rate of all co-amorphous drug-amino acid mixtures was significantly increased over that of the respective crystalline and amorphous pure drugs. Amino acids thus appear as promising excipients to solve challenges connected with the stability and dissolution of amorphous drugs. 23839491 A specific expression profile of heat-shock proteins and glucose-regulated proteins is associated with response to neoadjuvant chemotherapy in oesophageal adenocarcinomas. Background:Oesophageal adenocarcinomas often show resistances to chemotherapy (CTX), therefore, it would be of high interest to better understand the mechanisms of resistance. We examined the expression of heat-shock proteins (HSPs) and glucose-regulated proteins (GRPs) in pretherapeutic biopsies of oesophageal adenocarcinomas to assess their potential role in CTX response.Methods:Ninety biopsies of locally advanced adenocarcinomas before platin/5-fluorouracil (FU)-based CTX were investigated by reverse phase protein arrays (RPPAs), immunohistochemistry (IHC) and quantitative RT-PCR.Results:CTX response strongly correlated with survival (P=0.001). Two groups of tumours with specific protein expression patterns were identified by RPPA: Group A was characterised by low expression of HSP90, HSP27 and p-HSP27((Ser15, Ser78, Ser82)) and high expression of GRP78, GRP94, HSP70 and HSP60; Group B exhibited the inverse pattern. Tumours of Group A were more likely to respond to CTX, resulting in histopathological tumour regression (P=0.041) and post-therapeutic down-categorisation from cT3 to ypT0-T2 (P=0.040). High HSP60 protein (IHC) and mRNA expression were also associated with tumour down-categorisation (P=0.016 and P=0.004).Conclusion:Our findings may enhance the understanding of CTX response mechanisms, might be helpful to predict CTX response and might have translational relevance as they highlight the role of potentially targetable cellular stress proteins in the context of CTX response. 23940688 Adverse drug events in older hospitalized patients: results and reliability of a comprehensive and structured identification strategy. Older patients are at high risk for experiencing Adverse Drug Events (ADEs) during hospitalization. To be able to reduce ADEs in these vulnerable patients, hospitals first need to measure the occurrence of ADEs, especially those that are preventable. However, data on preventable ADEs (pADEs) occurring during hospitalization in older patients are scarce, and no 'gold standard' for the identification of ADEs exists. The study was conducted in three hospitals in the Netherlands in 2007. ADEs were retrospectively identified by a team of experts using a comprehensive and structured patient chart review (PCR) combined with a trigger-tool as an aid. This ADE identification strategy was applied to a cohort of 250 older hospitalized patients. To estimate the intra- and inter-rater reliabilities, Cohen's kappa values were calculated. In total, 118 ADEs were detected which occurred in 62 patients. This ADE yield was 1.1 to 2.7 times higher in comparison to other ADE studies in older hospitalized patients. Of the 118 ADEs, 83 (70.3%) were pADEs; 51 pADEs (43.2% of all ADEs identified) caused serious patient harm. Patient harm caused by ADEs resulted in various events. The overall intra-rater agreement of the developed strategy was substantial (κ = 0.74); the overall inter-rater agreement was only fair (κ = 0.24). The ADE identification strategy provided a detailed insight into the scope of ADEs occurring in older hospitalized patients, and showed that the majority of (serious) ADEs can be prevented. Several strategy related aspects, as well as setting/study specific aspects, may have contributed to the results gained. These aspects should be considered whenever ADE measurements need to be conducted. The results regarding pADEs can be used to design tailored interventions to effectively reduce harm caused by medication errors. Improvement of the inter-rater reliability of a PCR remains challenging. 23711399 Simultaneous determination of some cholesterol-lowering drugs in their binary mixture by novel spectrophotometric methods. Four simple, specific, accurate and precise spectrophotometric methods manipulating ratio spectra were developed and validated for simultaneous determination of simvastatin (SM) and ezetimibe (EZ) namely; extended ratio subtraction (EXRSM), simultaneous ratio subtraction (SRSM), ratio difference (RDSM) and absorption factor (AFM). The proposed spectrophotometric procedures do not require any preliminary separation step. The accuracy, precision and linearity ranges of the proposed methods were determined, and the methods were validated and the specificity was assessed by analyzing synthetic mixtures containing the cited drugs. The four methods were applied for the determination of the cited drugs in tablets and the obtained results were statistically compared with each other and with those of a reported HPLC method. The comparison showed that there is no significant difference between the proposed methods and the reported method regarding both accuracy and precision. 23740330 Renewed interest in basic and applied research involving monoclonal antibodies against an oncofetal Tn-antigen. Tn-antigen (GalNAcα-Ser/Thr) is one of the most common aberrations associated with cancer progression and metastasis, and thus is an excellent target for development of cancer diagnostics and therapeutics. MLS128 monoclonal antibody (mAb), derived from a mouse immunized with human colon carcinoma cells, was reported to bind to two or three consecutive Tn-antigens (Tn2 or Tn3) with one-order higher affinity for Tn3 than for Tn2. Our recent studies demonstrated that MLS128 significantly inhibits breast and colon cancer cell growth. Molecular cloning of the variable regions of heavy (VH) and light (VL) chains revealed that the VH sequence of MLS128 shared 97% nucleotide sequence identity with the VH of 83D4 mAb, derived from breast cancer-immunized mice, which has a similar affinity for Tn2/Tn3. MLS128 single-chain antibodies (scFv) and scFv-Fc were constructed to confirm the affinity for synthetic Tn2/Tn3 peptides. Thermodynamic studies on MLS128 binding to Tn2/Tn3 revealed its unique nature of temperature-dependent binding. 23726133 Complications and visual outcomes after glued foldable intraocular lens implantation in eyes with inadequate capsules. To evaluate the complications and visual outcomes of glued intrascleral-fixated foldable intraocular lens (IOL) in eyes with deficient capsules. Dr Agarwal's Eye Hospital and Eye Research Centre, Chennai, India. Case series. Data were evaluated from the records of patients with a primary glued foldable IOL for intraoperative capsular loss or subluxated lens or secondary glued foldable IOL for aphakia. Exclusion criteria included preoperative glaucoma, aniridia, macular scar, traumatic subluxation, combined surgeries, incomplete operative medical records, and postoperative follow-up less than 6 months. The intraoperative and postoperative complication rates, reoperation rate, and visual outcomes were analyzed. The study comprised 208 eyes (185 patients). The mean follow-up was 16.7 months ± 10.2 (SD). The intraoperative complications were hyphema (0.4%), haptic breakage (0.4%), and deformed haptics (0.9%). Early complications occurred in 29 eyes (13.9%) and included corneal edema (5.7%), epithelial defect (1.9%), and grade 2 anterior chamber reaction (2.4%). Late complications occurred in 39 eyes (18.7%) and included optic capture (4.3%), IOL decentration (3.3%), haptic extrusion (1.9%), subconjunctival haptic (1.4%), macular edema (1.9%), and pigment dispersion (1.9%). Reoperation was required in 16 eyes (7.7%). Haptic position was altered in eyes with IOL decentration. Corrected distance visual acuity (CDVA) improved or remained unchanged in 84.6% of eyes. The postoperative CDVA was 20/40 or better and 20/60 or better in 38.9% and 48.5% of eyes, respectively. The foldable glued-IOL procedure showed satisfactory visual outcomes without serious complications. Intraocular lens decentration was due to haptic-related problems. Dr. Agarwal is a paid consultant to Staar Surgical Co. No author has a financial or proprietary interest in any material or method mentioned. 23919553 Hemozoin and antimalarial drug discovery. Recent initiatives to develop more effective and affordable drugs, controlling mosquitoes and development of a preventative vaccine have been launched with the goal of completely eradicating malaria. To this end, Novartis (Surrey, UK) and GlaxoSmithKline (Middlesex, UK) screened their chemical libraries of approximately two million small molecules for antimalarial properties, which resulted in a set of over 20,000 'highly druggable' initial hits. Efforts in academia are centered on specific pathway targets. One such high-throughput screening effort has been focused on hemozoin formation, a unique heme detoxification pathway found in the malaria parasite. This review discusses the current approaches and limitations of high-throughput screening discovery of hemozoin inhibitors. In the future, new methods must be developed to validate the mechanism of action of these hit compounds within the parasite. 23582970 Regression of Canine Cutaneous Histiocytoma is Associated with an Orchestrated Expression of Matrix Metalloproteinases. Canine cutaneous histiocytoma (CCH) is a common benign skin tumour originating from epidermal Langerhans cells. These tumours often display spontaneous regression and therefore represent a valuable animal model for investigation of tumour regression. Based on previous studies it was hypothesized that up-regulation of cytokines during CCH regression leads to up-regulation of matrix metalloproteinases (MMPs) favouring infiltration of lymphocytes and enhanced tumour regression. The expression of MMPs and their inhibitors (tissue inhibitors of metalloproteinases, TIMPs) was investigated immunohistochemically in 27 CCHs. The tumours were classified into four groups defined as having no regression (group 1), early regression (group 2), intermediate regression (group 3) or late regression (group 4). The distribution and expression intensity of MMP-1, -2, -3, -7, -9, -13 and -14 and TIMP-1 and -2 were determined in peripheral and central areas of each tumour. Group 3 and 4 CCHs showed up-regulation of expression of MMP-1, -9 and -14 at the periphery. Variable expression of MMP-2 and -3 was observed. Expression of the remaining MMPs and TIMPs showed no group-specific changes. Most MMPs and TIMPs displayed significantly higher expression at the tumour periphery compared with the centre, independently of the stage of regression and indicating more pronounced proteolysis in the peripheral areas. The results are consistent with cytokine-enhanced MMP expression, particularly of MMP-9, leading to enhanced lymphocyte recruitment in combination with elevated cleavage of extracellular matrix and basement membranes. 23847473 Beyond "all-or-nothing" climbing fibers: graded representation of teaching signals in Purkinje cells. Arguments about the function of the climbing fiber (CF) input to the cerebellar cortex have fueled a rabid debate that started over 40 years ago, and continues to polarize the field to this day. The origin of the controversy can be traced back to 1969, the year David Marr published part of his dissertation work in a paper entitled "A theory of cerebellar cortex." In Marr's theory, CFs play a key role during the process of motor learning, providing an instructive signal that serves as a "teacher" for the post-synaptic Purkinje cells. Although this influential idea has found its way into the mainstream, a number of objections have been raised. For example, several investigators have pointed out that the seemingly "all-or-nothing" activation of the CF input provides little information and is too ambiguous to serve as an effective instructive signal. Here, we take a fresh look at these arguments in light of new evidence about the peculiar physiology of CFs. Based on recent findings we propose that at the level of an individual Purkinje cell, a graded instructive signal can be effectively encoded via pre- or post-synaptic modulation of its one and only CF input. 23832953 Exploring Intimate Partner Violence Status Among Male Veterans and Associated Health Outcomes. The World Health Organization has identified intimate partner violence (IPV) as a public health issue affecting both men and women, though significantly more information is available regarding female victimization. This study examines IPV through the lens of male victimization, focusing on a comparison of physical and mental health consequences among men who are and are not military veterans. Results from a secondary analysis of data from the Behavior Risk Factor Survey taken by 13,765 males indicated that all males, regardless of veteran status, should be screened for IPV victimization given the prevalence reported in this sample (9.5% to 12.5%). Furthermore, it was found that veteran status did affect prevalence of particular health consequences, such as depression, smoking, and binge drinking. Based on the specific comparisons examined in this study, implications for Veteran's Administration Health Services are discussed, as is the need for more research on IPV victimization rates for men and the particular health consequences that they suffer. 23948345 Assessment of a sequential extraction method to evaluate mercury mobility and geochemistry in solid environmental samples. The development of a sequential extraction method for mercury in solid environmental samples is presented. The scheme recognizes and quantifies four major phase associations of mercury: "Labile mercury species", "Hg bound to humic and fulvic complexes", "elemental Hg and bound to crystalline oxides" and "Hg sulfide and refractory species". Model solids were used in this study to evaluate different extracting solutions and to determine optimum extraction conditions. Sequential and single-step extractions were conducted to evaluate the interaction among the successive steps. Different variables such as extractant concentration, time, temperature and number of extractions were optimized for each stage when necessary. The selectivity of the selected extractions was assured through experiments with natural and synthetic matrices of some specific Hg-bearing phases. The suitability of the proposed method was evaluated by using four certified reference materials from different Hg sources, physicochemical properties and total Hg content (from 0.3µgg(-1) to 33µgg(-1)). Recovery of total Hg by the sum of fractions in reference materials showed that the accuracy of the method ranges from 85 percent to 105 percent. 23746770 Data-to-text summarisation of patient records: Using computer-generated summaries to access patient histories. We assess the efficacy and utility of automatically generated textual summaries of patients' medical histories at the point of care. Twenty-one clinicians were presented with information about two cancer patients and asked to answer key questions. For each clinician, the information on one of the patients comprised their official hospital records, and for the other patient it comprised summaries that were computer-generated by a natural language generation system from data extracted from the official records. We measured the accuracy of the clinicians' responses to the questions, the time they took to complete them, and recorded their attitude to the computer-generated summaries. Results showed no significant difference in the accuracy of responses to the computer-generated records over the official records, but a significant difference in the time taken to assess the patients' condition from the computer-generated records. Clinicians expressed a positive attitude towards the computer-generated records. AI-based computer-generated textual summaries of patient histories can be as accurate as, and more efficient than, human-produced patient records for clinicians seeking to accurately identify key information about a patients overall history. Computer-generated textual summaries of patient histories can contribute to the management of patients at the point-of-care. 23313635 Bioactive barrigenol type triterpenoids from the leaves of Xanthoceras sorbifolia Bunge. In order to find out new natural barrigenol type triterpenenoids as antitumor agent and reveal the difference on material basis of different parts of Xanthoceras sorbifolia Bunge, the bioassay-directed separation of the saponin fraction from leaves of X. sorbifolia Bunge was carried out to afford 5 new barrigenol type triterpenoids (1-5), together with 2 known ones. The antitumor activities were evaluated and compounds 2 and 7 showed significant cytotoxic activity. Furthermore, the SAR was discussed briefly. On the basis of our research work and related literature, the difference of chemical constituents from different parts of X. sorbifolia was analyzed and concluded. The result can be a useful reference for phytochemistry taxology and safe and rational drug use of X. sorbifolia. 21867594 Construction of Ipr1 expression vector and development of cloned embryos in vitro. The purpose of this study was to prepare intracellular pathogen resistance 1 (Ipr1) transgenic donor cells for somatic cell nuclear transfer (SCNT). Based on our current understanding of Ipr1, a macrophage special expression vector pSP-EGFP-Ipr1was constructed. Bovine fetal fibroblasts were transfected with pSP-EGFP-Ipr1. The green fluorescent protein (GFP)-expressing cells were selected and transferred into enucleated bovine oocytes. Then, the rates of oocyte cleavage and blastocyst formation of transgenic cells and non-transgenic cells were observed, respectively. The results showed that reconstructed embryos derived from transgenic cells could successfully develop into blastocysts, most of which were GFP-positive. This study may provide cloned embryos for the production of anti-tuberculosis transgenic animals. 23893128 Hospital and surgeon caseload are associated with risk of re-operation following breast-conserving surgery. Breast-conserving surgery (BCS) is increasingly used for breast cancer treatment. One of the disadvantages of BCS is the risk of re-operation, associated with additional costs to the woman, health service and society. Hospital and surgeon caseload have been associated with better outcomes in breast cancer. Whether these are related to re-operation rates is not clear. In women who underwent BCS initially, we aimed to quantify re-operation rates and identify the factors related to the risk of undergoing subsequent (i) re-operation and (ii) total mastectomy (TM). From the National Cancer Registry Ireland, we identified women diagnosed with a first invasive breast cancer during 2002-2008, and who initially had BCS. Poisson regression with robust error variance was used to identify factors significantly associated with (i) re-operation (vs no re-operation) or (ii) re-operation by TM (vs re-operation by BCS). 16,551 women were diagnosed with invasive breast cancer and 8,318 underwent initial BCS. Of these, 17 % had one or more subsequent re-operations and, of these, 62 % had TM. Surgeon and hospital volume significantly predicted subsequent re-operation after adjustment for socio-demographic and clinical variables. Women having surgery in lower-volume hospitals by low-volume surgeons significantly increased the risk of re-operation [incidence rate ratio (IRR) = 1.56; 95 % CI 1.33-1.83] compared to those operated in higher-volume hospitals by a higher-volume surgeon. Risk of subsequent TM was increased by 22 % (95 % CI 1.10-1.35) and 21 % (95 % CI 1.09-1.33), if women were operated by a lower or intermediate-volume surgeon. The fact that factors related to healthcare organisation/service provision are associated with re-operations suggests that it may be possible to reduce the overall re-operation rate. The high frequency of subsequent TM raises questions about strategies for selecting women for initial BCS. Our results may inform the development of information strategies to help ensure that women are aware of risks of re-operation following BCS and hence, make appropriate treatment choices. 23558378 Biological Therapies for Rheumatoid Arthritis: Progress to Date. Biologic drugs for the management of rheumatoid arthritis (RA) have revolutionized the therapeutic armamentarium with the development of several novel monoclonal antibodies, which include murine, chimeric, humanized, fully human antibodies and fusion proteins. These biologics bind to their targets with high affinity and specificity. Since 1998, nine different biologics have been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of RA, and several others are in different stages of clinical trials. This field is in continuous evolution and new biologics are tested every year. Therefore a precise analysis is required in order to have a detailed and updated state of the art of this field. In this review, our main aim is to analyse all available biological therapies that are FDA and EMA approved for the treatment of RA and also those that are in clinical trials for the management of RA patients. 23946237 Tri-Diketopyrrolopyrrole Molecular Donor Materials for High-Performance Solution-Processed Bulk Heterojunction Solar Cells. Two new high-performance DPP-containing donor molecules employing a molecular architecture with three DPP chromorphores (tri-DPP) in conjugated backbones are synthesized and characterized. The two tri-DPP molecules with only a structural difference on alkyl substitutions, when blended with PC71 BM, lead to power conversion efficiencies up to 4.8 and 5.5%, respectively. 23892476 The gut microbiota reduces leptin sensitivity and the expression of the obesity suppressing neuropeptides proglucagon (Gcg) and brain-derived neurotrophic factor (Bdnf) in the central nervous system. The gut microbiota contributes to fat mass and the susceptibility to obesity. However, the underlying mechanisms are not completely understood.To investigate if the gut microbiota affects hypothalamic and brainstem body fat regulating circuits, we compared gene expression of food intake regulating neuropeptides between germ-free and conventionally raised mice.We found that conventionally raised mice had decreased expression of the anti-obesity neuropeptide glucagon-like peptide-1 (GLP-1) precursor proglucagon (Gcg) in brainstem. Moreover, in both the hypothalamus and the brainstem, conventional mice had decreased expression of the anti-obesity neuropeptide brain-derived neurotrophic factor (Bdnf). Conventionally raised mice had reduced expression of the pro-obesity peptides neuropeptide-Y (Npy) and agouti-related protein (Agrp), and increased expression of the anti-obesity peptides pro-opiomelanocortin (Pomc) and cocain and amphetamine regulated transcript (Cart) in the hypothalamus. The changes in neuropeptide expression could be secondary to elevated fat mass in conventionally raised mice. Leptin treatment caused less weight reduction and less suppression of orexigenic Npy and Agrp expression in conventional mice compared with germ free mice. The hypothalamic expression of leptin resistance associated suppressor of cytokine signaling 3 (Socs-3) was increased in conventionally raised mice.In conclusion, the gut microbiota reduces the expression of two genes coding for body fat suppressing neuropeptides, Gcg and Bdnf, an alteration that may contribute to fat mass induction by the gut microbiota. Moreover, the presence of body fat inducing gut microbiota is associated with hypothalamic signs of Socs-3 mediated leptin resistance, which may be linked to failed compensatory body fat reduction. 23561020 Hysteroscopic hydrosalpinx occlusion with Essure device in IVF patients when salpingectomy or laparoscopy is contraindicated. To evaluate, in patients with hydrosalpinges, the effect on in vitro fertilization (IVF) outcome of the insertion by hysteroscopy of an intratubal blocking device, in cases where laparoscopic salpingectomy or laparoscopy was contraindicated. A prospective interventional case series study was conducted in fifteen women with unilateral (N=6) or bilateral hydrosalpinges (N=9) submitted for IVF. In all of them, laparoscopic salpingectomy was contraindicated. Hysteroscopic insertion of the Essure intratubal device in a consultation room setting was performed. IVF results were compared with those of women where hydrosalpinx was treated by laparoscopic salpingectomy (48 women, 76 cycles). There were no complications during or immediately after the procedure in any of the patients. There were four pregnancies from 16 embryo-transfers with own oocytes, one spontaneous pregnancy after unilateral Essure insertion, and one pregnancy after oocyte donation. In one case the hydrosalpinx grew and pelvic inflammatory disease developed 6 months after the insertion, requiring bilateral adnexectomy. Although not of statistical significance, IVF pregnancy rates were somewhat lower than in the laparoscopic salpingectomy group, which was attributed to the lower ovarian reserve before Essure insertion. The hysteroscopic insertion of the Essure intratubal device prior to IVF is a reasonable option in cases where laparoscopic salpingectomy is contraindicated. Larger series are required to assess pregnancy outcome. 23839900 Kinetics of structural reorganizations in multilamellar photosynthetic membranes monitored by small-angle neutron scattering. We demonstrate the power of time-resolved small-angle neutron scattering experiments for the investigation of the structure and structural reorganizations of multilamellar photosynthetic membranes. In addition to briefly summarizing our results on thylakoid membranes isolated from higher plants and in unicellular organisms, we discuss the advantages and technical and methodological limitations of time-resolved SANS. We present a detailed and more systematical investigation of the kinetics of light-induced structural reorganizations in isolated spinach thylakoid membranes, which show how changes in the repeat distance and in the long-range order of the multilamellar membranes can be followed with a time resolution of seconds. We also present data from comparative measurements performed on thylakoid membranes isolated from tobacco. 23644980 Measuring nanoparticle flow with the image structure function. We present a technique to measure the velocity and flow profiles of a nanofluid in a microfluidic channel. Importantly, we extract the flow velocity from a series of standard brightfield images without employing particle tracking or laser-enhanced methods. Our analysis retrieves the flow information from the image structure function of sub-diffraction limited nanoparticles in suspension. We are able to spatially resolve the flow velocity and map out the parabolic flow profile across the width of a microfluidic channel. 23841461 Averaged Spacing and 2-D Organization of Collagen Fibrils in the Posterior Cornea of the Rabbit Eye Assessed by Transmission Electron Microscopy. Abstract Purpose: To assess how reproducible collagen fibril spacing might be in the corneal stroma as viewed by transmission electron microscopy by calculating averaged values for the 2-D organization. Methods: One cornea from 8 albino rabbits (2 kg) was fixed in situ to preserve natural shape. Thin sections were stained with 2% phosphotungstic acid (PTA) and images taken of fibrils from the central-posterior stroma. After projection at 250,000 X magnification, an overlay was prepared of the fibrils. Using a 500 × 500 nm region of interest (ROI), the distances to all fibril centers were measured to 2 nm resolution. Results: The sets of fibrils had average diameters between 32.4 and 36.1 nm (group mean ± SD of 34.4 ± 4.2 nm). The mean fibril density was 396 ± 21 per square micrometer, with a fibril area fraction of 38.7 ± 3.9%. The mean distance to the literal nearest neighbor fibril center was 43.2 ± 4.5 nm. A radial distribution analysis showed a distinct nearest neighbors peak at 51 nm. This nearest neighbors peak had an average amplitude of 2.236 ± 0.315, with a broader secondary peak being evident in all data sets centered at 93 nm with an average amplitude of 1.166 ± 0.093 (or 53.3 ± 7.1% of the nearest neighbors peak). Conclusions: Overall, these results show that a predictable 2-D organization can be demonstrated for collagen fibrils in rabbit corneas when consideration is given to sample selection and preparation and the image analysis strategy. 23813537 Diaphragm muscle atrophy in the mouse after long-term mechanical ventilation. Mechanical ventilation (MV) is a life-saving measure, but full ventilator support causes ventilator-induced diaphragm atrophy (VIDA). Previous studies of VIDA have relied on human biopsies or a rat model. If MV can induce diaphragm atrophy in mice, then mechanistic study of VIDA could be explored via genetic manipulation. We show that 18 hours of MV in mice results in a 15% loss of diaphragm weight and a 17% reduction in fiber cross-sectional area. Important catabolic cascades are activated in this mouse model: transcription of the ubiquitin ligases, atrogin and MuRF1, and the apoptotic marker, Bim, are increased; the marker of autophagy, LC3, is induced at the protein level and shows a punctate distribution in diaphragm muscle fibers. This mouse model recapitulates the key pathophysiological findings of other models of VIDA, and it will enable the genetic manipulation required to fully explore the mechanisms underlying this important process. Muscle Nerve, 48: 272-278, 2013. 23302584 Synthesis of novel phosphorylated guanidine derivatives from cyanamide and their anti-inflammatory activity. A series of novel guanidine derivatives were synthesized in three steps and their anti-inflammatory activities in vitro and in vivo evaluated. 2-Aminopyridin-3-ol (1) was reacted with thiophosphoryl chloride (2) to give a monochloride (3). It was further reacted with cyanamide to afford the corresponding cyanamine (4), which was subsequently reacted with different heterocyclic amines to form the title compounds (5a-l). The substituent in the guanidine function affected the potency of anti-inflammatory activity. The compounds having benzothiazole, fluorophenyl, and piperazinyl moieties enhanced the anti-inflammatory activity. 23906116 Exercise, physical activity, and exertion over the business cycle. Shifts in time and income constraints over economic expansions and contractions would be expected to affect individuals' behaviors. We explore the impact of the business cycle on individuals' exercise, time use, and total physical exertion, utilizing information on 112,000 individual records from the 2003-2010 American Time Use Surveys. In doing so, we test a key causal link that has been hypothesized in the relation between unemployment and health, but not heretofore assessed. Using more precise measures of exercise (and other activities) than previous studies, we find that as work-time decreases during a recession, recreational exercise, TV-watching, sleeping, childcare, and housework increase. This, however, does not compensate for the decrease in work-related exertion due to job-loss, and total physical exertion declines. These effects are strongest among low-educated men, which is validating given that employment in the Great Recession has declined most within manufacturing, mining, and construction. We also find evidence of intra-household spillover effects, wherein individuals respond to shifts in spousal employment conditional on their own labor supply. The decrease in total physical activity during recessions is especially problematic for vulnerable populations concentrated in boom-and-bust industries, and may have longer-term effects on obesity and related health outcomes. 23812217 Comparable molecular alterations in 4-nitroquinoline 1-oxide-induced oral and esophageal cancer in mice and in human esophageal cancer, associated with poor prognosis of patients. The murine model of 4-nitroquinoline 1-oxide (4-NQO)-induced oral and esophageal cancer is frequently used to assess the effects of different cancer prevention/ therapy agents in vivo, but the molecular mechanisms in those 4-NQO-induced carcinogenesis are unknown. This study investigated aberrant expression of cell growth-critical genes in 4-NQO-induced oral and esophageal cancer tissues in mice compared to those present in the human disease for association with survival of patients. C57LB6/129Sv mice were given 4-NQO in their drinking water to induce oral and esophageal cancer. Quantitative-reverse transcription polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry were used to detect gene expression in the cancer tissues from mice and in 4-NQO-treated human esophageal cancer cell lines and esophageal cancer tissues. Methylation-specific PCR and DNA sequencing were performed to assess methylation of the Rarb2 promoter in murine tissues. Kaplan-Meier analysis was performed to associate gene expression in esophageal cancer tissues with survival data for patients with esophageal cancer. 4-NQO dose-dependently induced pre-malignant and malignant lesions in the oral cavity and esophagus in mice that pathologically and morphologically mimicked human oral and esophageal cancer. Molecularly, 4-NQO inhibited Rarβ₂ but induced expression of phosphorylated extracellular-signal-regulated kinase-1 and -2 (p-ERK1/2) and Cox2 proteins and Rarβ₂ gene promoter methylation in murine tumors. In vitro treatment with 4-NQO altered expression of RARβ₂, p-ERK1/2, and COX2 in human esophageal cancer cells. In tissues from 90 patients with esophageal cancer, expression of p-ERK1/2 and COX2 was up-regulated, and p-ERK1/2 expression was associated with advanced clinical tumor stage and consumption of hot beverages, while COX2 expression was associated with tumor de-differentiation in esophageal cancer. Furthermore, expression of p-ERK1/2 was associated with a worse overall survival rate of patients (p=0.014), whereas the association of COX2 expression with worse overall survival rate did not reach statistical significance (p=0.19). Knockdown of COX2 expression using transient transfection of a COX2 antisense expression vector inhibited Ki67 expression, an indicator of cell proliferation, in human esophageal cancer cells. 4-NQO-induced cancer in oral cavity and esophagus of mice not only pathologically and morphologically mimicked human oral and esophageal cancer, but also shared some molecular alterations (e.g. aberrant expression of Rarb2, p-ERK1/2, and Cox2). This study further demonstrated that targeting of the altered RARβ₂-led gene pathway could effectively suppress the development of this deadly type of cancer. 23803309 Comparison of cardiac output derived from FloTrac™/Vigileo™ and impedance cardiography during major abdominal surgery. Impedance cardiography (ICG) is a noninvasive technique that provides reasonably accurate measurements of cardiac output, but the usefulness of ICG in patients undergoing open abdominal surgery has not been validated. Cardiac output was measured while patients underwent open gastrectomy using an ICG monitor (niccomo™; ICG-CO); the results were compared with those measured using a FloTrac™/Vigileo™ monitor (Flo-CO), which measures cardiac output by analysing the arterial waveform. Data collection commenced at the beginning of anaesthetic induction and continued until the patient was awake. Data were compared using the Bland-Altman analysis, and the clinical significance of the difference between the two methods was evaluated by calculating the percentage error (%). Eleven patients were monitored during surgery. The bias of the Flo-CO and ICG-CO values was -0.45 l/min. The upper and lower limits of agreement were 0.96 l/min and -1.85 l/min, respectively. The percentage error was 28.5%. Electrocautery induced interference that transiently impaired the performance of the ICG monitor. ICG provided useful information in evaluating the cardiac output of patients during abdominal surgery. 23942172 A pan-Canadian web-based education program to support screening for distress: Evaluation of outcomes. Objective: Cancer-related distress has been endorsed as the sixth vital sign by many international cancer organizations, and some countries such as Canada have implemented national screening for distress programs. The completion of a screening tool is an important first step in improving responsiveness to cancer-related distress, but screening must be followed with skilled supportive care to make a difference in patient-reported outcomes. Our objective was to create a web-based education program to support nurses and other frontline staff in providing an initial response to screening results. Method: To address screening and supportive care learning needs, the Canadian Association of Psychosocial Oncology (CAPO), with support from the Canadian Partnership Against Cancer, created a web-based education program as one component of the national screening for distress agenda. The program provides clinically grounded and interactive learning through the use of PowerPoint presentations, video clips of clinical interactions with patients and family members, and test questions. Presentation topics include, for example, strategies for dealing with screening results, managing referrals, and supportive counseling. We employed a matched pairs, pre-post survey design to assess the effect of the education program on confidence in screening and in providing initial supportive care. Results: Our analysis of the first 147 matched pairs to complete the course suggests that satisfaction with the course was high. Statistically significant increases in confidence in relation to screening for distress and assessing distress, and in providing initial supportive care, were evident. Significance of results: Our ongoing experience with CAPO's Interprofessional Psychosocial Oncology Distance Education (IPODE) project (www.ipode.ca) project suggests that healthcare professionals value web-based learning for its accessibility and convenience. Such programs appear to offer excellent opportunities for cost-effective education that supports practice change. 23863861 Comorbidities and Mortality in Bipolar Disorder: A Swedish National Cohort Study. IMPORTANCE Bipolar disorder is associated with premature mortality, but the specific causes and underlying pathways are unclear. OBJECTIVE To examine the physical health effects of bipolar disorder using outpatient and inpatient data for a national population. DESIGN, SETTING, AND PARTICIPANTS National cohort study of 6 587 036 Swedish adults, including 6618 with bipolar disorder. MAIN OUTCOMES AND MEASURES Physical comorbidities diagnosed in any outpatient or inpatient setting nationwide and mortality (January 1, 2003, through December 31, 2009). RESULTS Women and men with bipolar disorder died 9.0 and 8.5 years earlier on average than the rest of the population, respectively. All-cause mortality was increased 2-fold among women (adjusted hazard ratio [aHR], 2.34; 95% CI, 2.16-2.53) and men (aHR, 2.03; 95% CI, 1.85-2.23) with bipolar disorder, compared with the rest of the population. Patients with bipolar disorder had increased mortality from cardiovascular disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), influenza or pneumonia, unintentional injuries, and suicide for both women and men and cancer for women only. Suicide risk was 10-fold among women (aHR, 10.37; 95% CI, 7.36-14.60) and 8-fold among men (aHR, 8.09; 95% CI, 5.98-10.95) with bipolar disorder, compared with the rest of the population. Substance use disorders contributed only modestly to these findings. The association between bipolar disorder and mortality from chronic diseases (ischemic heart disease, diabetes, COPD, or cancer) was weaker among persons with a prior diagnosis of these conditions (aHR, 1.40; 95% CI, 1.26-1.56) than among those without a prior diagnosis (aHR, 2.38; 95% CI, 1.95-2.90; Pinteraction = .01). CONCLUSIONS AND RELEVANCE In this large national cohort study, patients with bipolar disorder died prematurely from multiple causes, including cardiovascular disease, diabetes, COPD, influenza or pneumonia, unintentional injuries, and suicide. However, chronic disease mortality among those with more timely medical diagnosis approached that of the general population, suggesting that better provision of primary medical care may effectively reduce premature mortality among persons with bipolar disorder. 23642628 Brain CT perfusion provides additional useful information in severe traumatic brain injury. The role of brain CT perfusion (CTP) imaging in severe traumatic brain injury (STBI) is unclear. We hypothesised that in STBI early CTP may provide additional information beyond the non contrast CT (NCCT). Subset analysis of an ongoing prospective observational study on trauma patients with STBI who did not require craniectomy and deteriorated or failed to improve neurologically during the first 48h from trauma. Subsequently to follow-up NCCT, a CTP was obtained. Additional findings were defined as an area of altered perfusion on CTP larger than the abnormal area detected by the simultaneous NCCT. Patients who had additional finding (A-CTP) were compared with patients who did not have additional findings (NA-CTP). Study population was 30 patients [male: 90%, mean age: 38.6 (SD 16.9), blunt trauma: 100%; prehospital intubation: 6 (20%); lowest GCS before intubation: 5.1 (SD 2.0); mean ISS: 30.5 (SD 8.3); mean head and neck AIS: 4.4 (SD 0.8). Days in ICU: 10.2 (SD 6.3). Intracranial pressure (ICP) monitored in 12 (40%). Mean highest ICP in mmHg: 30.1 (SD14.1). There were five (17%) deaths. Findings of NCCT: primarily diffuse axonal injury (DAI) pattern in seven (23%), primarily haematoma in ten (33%), and primarily intracerebral contusion in nine (30%). CTP was performed 24.9 (SD 13) hours from trauma. There were 18 (60%) patients in the A-CTP group and 12 (40.0%) in NA-CTP. The A-CTP group was older (41.7 (SD16.9) vs 27.7 (SD 12.8): P<0.02) and showed on admission NCCT presence of cerebral contusion and absence of DAI. The degree of hypoperfusion was found to be severe enough to be in the ischaemic range in eight patients (27%). CTP altered clinical management in three patients (10%), who were diagnosed with massive and unsurvivable strokes despite minimal changes on NCCT. When compared to NCCT, CTP provided additional diagnostic information in 60% of patients with STBI. CTP altered clinical management in 10% of patients. 23883336 Idiopathic Arterial Calcification of Infancy- Peritoneal Dialysis for Treatment of Hypertension. Idiopathic infantile arterial calcification (IIAC) is a rare autosomal recessive disease usually diagnosed postmortem. The clinical presentation is not typical, but usually implies refractory hypertension and cardiorespiratory failure. We present a case of a newborn with IIAC who had fetal hydrops and refractory hypertension which normalized soon after initialization of peritoneal dialysis. With this case report, we wanted to highlight that peritoneal dialysis may be beneficial an effective therapeutic option for patients with IIAC and severe refractory hypertension. Until now, peritoneal dialysis was never performed in the treatment of patients with IIAC. 23462381 Modulation of membrane phospholipids, the cytosolic calcium influx and cell proliferation following treatment of B16-F10 cells with recombinant phospholipase-D from Loxosceles intermedia (brown spider) venom. The mechanism through which brown spiders (Loxosceles genus) cause dermonecrosis, dysregulated inflammatory responses, hemolysis and platelet aggregation, which are effects reported following spider bites, is currently attributed to the presence of phospholipase-D in the venom. In the present investigation, through two-dimensional immunoblotting, we observed immunological cross-reactivity for at least 25 spots in crude Loxosceles intermedia venom, indicating high expression levels for different isoforms of phospholipase-D. Using a recombinant phospholipase-D from the venom gland of L. intermedia (LiRecDT1) in phospholipid-degrading kinetic experiments, we determined that this phospholipase-D mainly hydrolyzes synthetic sphingomyelin in a time-dependent manner, generating ceramide 1-phosphate plus choline, as well as lysophosphatidylcholine, generating lysophosphatidic acid plus choline, but exhibits little activity against phosphatidylcholine. Through immunofluorescence assays with antibodies against LiRecDT1 and using a recombinant GFP-LiRecDT1 fusion protein, we observed direct binding of LiRecDT1 to the membrane of B16-F10 cells. We determined that LiRecDT1 hydrolyzes phospholipids in detergent extracts and from ghosts of B16-F10 cells, generating choline, indicating that the enzyme can access and modulate and has activity against membrane phospholipids. Additionally, using Fluo-4, a calcium-sensitive fluorophore, it was shown that treatment of cells with phospholipase-D induced an increase in the calcium concentration in the cytoplasm, but without altering viability or causing damage to cells. Finally, based on the known endogenous activity of phospholipase-D as an inducer of cell proliferation and the fact that LiRecDT1 binds to the cell surface, hydrolyzing phospholipids to generate bioactive lipids, we employed LiRecDT1 as an exogenous source of phospholipase-D in B16-F10 cells. Treatment of the cells was effective in increasing their proliferation in a time- and concentration-dependent manner, especially in the presence of synthetic sphingomyelin in the medium. The results described herein indicate the ability of brown spider phospholipase-D to induce the generation of bioactive phospholipids, calcium influx into the cytoplasm and cell proliferation, suggesting that this molecule can be used as a bioactive tool for experimental protocols in cell biology. 23927941 Behavior observation of major noise sources in critical care wards. This study aimed to investigate the behavior patterns of typical noise sources in critical care wards and relate their patterns to health care environment in which the sources adapt themselves in several different forms. An effective observation approach was designed for noise behavior in the critical care environment. Five descriptors have been identified for the behavior observations, namely, interval, frequency, duration, perceived loudness, and location. Both the single-bed and the multiple-bed wards at the selected Critical Care Department were randomly observed for 3 inconsecutive nights, from 11:30 pm to 7:00 am the following morning. The Matlab distribution fitting tool was applied afterward to plot several types of distributions and estimate the corresponding parameters. The lognormal distribution was considered the most appropriate statistical distribution for noise behaviors in terms of the interval and duration patterns. The turning of patients by staff was closely related to the increasing occurrences of noises. Among the observed noises, talking was identified with the highest frequency, shortest intervals, and the longest durations, followed by monitor alarms. The perceived loudness of talking in the nighttime wards was classified into 3 levels (raised, normal, and low). Most people engaged in verbal communication in the single-bed wards that occurred around the Entrance Zone, whereas talking in the multiple-bed wards was more likely to be situated in the Staff Work Zone. As expected, more occurrences of noises along with longer duration were observed in multiple-bed wards rather than single-bed wards. "Monitor plus ventilator alarms" was the most commonly observed combination of multiple noises. 23813663 Tuning the lewis acidity of boranes in frustrated lewis pair chemistry: implications for the hydrogenation of electron-poor alkenes. An analysis of the metal-free reduction of electron deficient olefins by frustrated Lewis pairs indicates that the rate-determining step might be either the heterolytic cleavage of H2 to form an -onium borohydride salt, or the subsequent transfer of the hydride moiety to the substrate following a Michael-type addition reaction. While the use of strong Lewis acids such as B(C6 F5 )3 facilitates the first of these processes, hydride transfer to the olefin should be contrarily favoured by the use of weak Lewis acids which, for this very same reason, might be unable to promote the prior H2 split. After systematic testing of several boranes of different Lewis acidity (assessed by using the Childs' method) and steric demand, an optimal situation that employs tris(2,4,6-trifluorophenyl)borane was reached. Mixtures of this borane with 1,4-diazabicyclo[2.2.2]octane (DABCO) exhibited excellent catalytic activity for the hydrogenation of alkylidene malonates. In fact, this transformation could be achieved under milder conditions than those we reported previously. Moreover, the reaction scope could be expanded to other electron deficient olefins containing esters, sulfones or nitro functionalities as electron-withdrawing substituents. 23950951 Endocine™, N3OA and N3OASq; Three Mucosal Adjuvants That Enhance the Immune Response to Nasal Influenza Vaccination. Annual outbreaks of seasonal influenza are controlled or prevented through vaccination in many countries. The seasonal vaccines used are either inactivated, currently administered parenterally, or live-attenuated given intranasally. In this study three mucosal adjuvants were examined for the influence on the humoral (mucosal and systemic) and cellular influenza A-specific immune responses induced by a nasally administered vaccine. We investigated in detail how the anionic Endocine™ and the cationic adjuvants N3OA and N3OASq mixed with a split inactivated influenza vaccine induced influenza A-specific immune responses as compared to the vaccine alone after intranasal immunization. The study showed that nasal administration of a split virus vaccine together with Endocine™ or N3OA induced significantly higher humoral and cell-mediated immune responses than the non-adjuvanted vaccine. N3OASq only significantly increased the cell-mediated immune response. Furthermore, nasal administration of the influenza vaccine in combination with any of the adjuvants; Endocine™, N3OA or N3OASq, significantly enhanced the mucosal immunity against influenza HA protein. Thus the addition of these mucosal adjuvants leads to enhanced immunity in the most relevant tissues, the upper respiratory tract and the systemic circulation. Nasal influenza vaccination with an inactivated split vaccine can therefore provide an important mucosal immune response, which is often low or absent after traditional parenteral vaccination. 23826901 Effects of selected feed additives on the performance of laying hens given a diet rich in maize dried distiller's grains with solubles (DDGS). 1. A total of 192 ISA Brown hens were given diets containing a high concentration of maize dried distiller's grains with solubles (DDGS) and the effect of selected feed additives on laying performance and egg quality was determined. 2. Birds were allocated to 8 treatment groups with 12 replicates (cages) of two hens and were given, from week 26 to 55, iso-caloric and iso-nitrogenous experimental diets with or without a high concentration of DDGS (200 g/kg). The diet containing DDGS was not supplemented or supplemented with enzymes (xylanase and phytase), sodium butyrate, probiotic bacteria (Lactobacillus salivarius) and a mixture of herbal extracts (Taraxaci siccum, Urticae siccum and Salviae siccum), inulin or chitosan. 3. The inclusion of DDGS in the diet had no effect on number of eggs produced, total egg mass, mean egg weight, feed intake or feed conversion ratio. Egg and eggshell quality parameters were also unaffected by dietary DDGS. The yolk colour score (points in Roche scale) was significantly increased by DDGS inclusion. DDGS in the diet caused some changes in the yolk lipid profile that were rather unfavourable from a dietary perspective (an increase of cholesterol content, and PUFA n-6/PUFA n-3 ratio). 4. During the experimental period (26-55 weeks of age) supplementation of the diet containing a high concentration of DDGS with enzymes, inulin as well as chitosan, increased number of eggs produced and daily egg mass. In older hens (50 weeks of age) inulin positively affected eggshell quality parameters, i.e. shell percentage, thickness and density. Diet supplementation with herb extracts, inulin or chitosan, decreased the content of cholesterol in yolks. 5. The results of this study suggest that DDGS may be incorporated up to a concentration of 200 g/kg in the diet of laying hens without any negative effects on egg performance. Moreover, supplementation of xylanase and phytase, as well as inulin and chitosan, can positively affect the performance of layers given diets with a high concentration of DDGS. 23906242 Submerged (under-liquid) floating of light objects. A counterintuitive submerged floating of objects lighter than the supporting liquid was observed. Polymer plates with dimensions on the order of magnitude of the capillary length were hydrophilized with cold air plasma were floated in an "under-liquid" regime (totally covered by liquid) when immersed in water or glycerol. Profiles of liquid surfaces curved by polymer plates are measured. We propose a model explaining the phenomenon. The floating of Janus plates is reported. 23028137 Portal vein glucose entry triggers a coordinated cellular response that potentiates hepatic glucose uptake and storage in normal but not high-fat/high-fructose-fed dogs. The cellular events mediating the pleiotropic actions of portal vein glucose (PoG) delivery on hepatic glucose disposition have not been clearly defined. Likewise, the molecular defects associated with postprandial hyperglycemia and impaired hepatic glucose uptake (HGU) following consumption of a high-fat, high-fructose diet (HFFD) are unknown. Our goal was to identify hepatocellular changes elicited by hyperinsulinemia, hyperglycemia, and PoG signaling in normal chow-fed (CTR) and HFFD-fed dogs. In CTR dogs, we demonstrated that PoG infusion in the presence of hyperinsulinemia and hyperglycemia triggered an increase in the activity of hepatic glucokinase (GK) and glycogen synthase (GS), which occurred in association with further augmentation in HGU and glycogen synthesis (GSYN) in vivo. In contrast, 4 weeks of HFFD feeding markedly reduced GK protein content and impaired the activation of GS in association with diminished HGU and GSYN in vivo. Furthermore, the enzymatic changes associated with PoG sensing in chow-fed animals were abolished in HFFD-fed animals, consistent with loss of the stimulatory effects of PoG delivery. These data reveal new insight into the molecular physiology of the portal glucose signaling mechanism under normal conditions and to the pathophysiology of aberrant postprandial hepatic glucose disposition evident under a diet-induced glucose-intolerant condition. 23940831 Rapid quantitative pharmacodynamic imaging by a novel method: theory, simulation testing and proof of principle. Pharmacological challenge imaging has mapped, but rarely quantified, the sensitivity of a biological system to a given drug. We describe a novel method called rapid quantitative pharmacodynamic imaging. This method combines pharmacokinetic-pharmacodynamic modeling, repeated small doses of a challenge drug over a short time scale, and functional imaging to rapidly provide quantitative estimates of drug sensitivity including EC 50 (the concentration of drug that produces half the maximum possible effect). We first test the method with simulated data, assuming a typical sigmoidal dose-response curve and assuming imperfect imaging that includes artifactual baseline signal drift and random error. With these few assumptions, rapid quantitative pharmacodynamic imaging reliably estimates EC 50 from the simulated data, except when noise overwhelms the drug effect or when the effect occurs only at high doses. In preliminary fMRI studies of primate brain using a dopamine agonist, the observed noise level is modest compared with observed drug effects, and a quantitative EC 50 can be obtained from some regional time-signal curves. Taken together, these results suggest that research and clinical applications for rapid quantitative pharmacodynamic imaging are realistic. 23808944 Efficacy and safety of a WallFlex enteral stent for malignant gastric obstruction. The aim of the present study was to investigate the efficacy and safety of a newly available enteral WallFlex stent for malignant gastric outlet obstruction (GOO). Twenty-one consecutive patients with symptomatic (unable to take solids) malignant GOO treated by a WallFlex stent from April 2010 to February 2012 were included and analyzed retrospectively. Main outcome measurements were technical success, early complications, clinical response (elimination of the need for nasogastric tube drainage), clinical success (improvement of oral intake to a GOO score of 2 or 3), and duration of sustaining a GOO score of 2 or 3 after clinical success (median duration until reworsening of GOO score to <2 by the Kaplan-Meier method). A four-point GOO scoring system (0-3) was used for estimation of oral intake. Technical success rate was 100%. Bleeding and perforation after stent placement and stent dislocation/migration in the follow-up period did not occur in any patients, whereas one patient (5%) developed moderate post-procedural pancreatitis. Clinical response and clinical success was achieved in all patients and in 81% (17/21), respectively. In 17 patients whose GOO score had improved to 2 or 3 after stent placement, eight (47%) developed reworsening of the GOO score to <2 with a median time of 148 days (95% confidence interval [CI], 0-328; Kaplan-Meier method). Median survival time after the initial intervention was 61 days (95% CI, 40-82). Placement of an enteral WallFlex stent in patients with malignant GOO is safe and effective. 23835170 Deletion of creB in Aspergillus oryzae Increases Secreted Hydrolytic Enzyme Activity. Aspergillus oryzae has been used in the food and beverage industry for centuries, and industrial strains have been produced by multiple rounds of selection. Targeted gene deletion technology is particularly useful for strain improvement in such strains, particularly when they do not have a well-characterized meiotic cycle. Phenotypes of an Aspergillus nidulans strain null for the CreB deubiquitinating enzyme include effects on growth and repression, including increased activity levels of various enzymes. We show that Aspergillus oryzae contains a functional homologue of the CreB deubiquitinating enzyme and that a null strain shows increased activity levels of industrially important secreted enzymes, including cellulases, xylanases, amylases, and proteases, as well as alleviated inhibition of spore germination on glucose medium. Reverse transcription-quantitative PCR (RT-qPCR) analysis showed that the increased levels of enzyme activity in both Aspergillus nidulans and Aspergillus oryzae are mirrored at the transcript level, indicating transcriptional regulation. We report that Aspergillus oryzae DAR3699, originally isolated from soy fermentation, has a similar phenotype to that of a creB deletion mutant of the RIB40 strain, and it contains a mutation in the creB gene. Collectively, the results for Aspergillus oryzae, Aspergillus nidulans, Trichoderma reesei, and Penicillium decumbens show that deletion of creB may be broadly useful in diverse fungi for increasing production of a variety of enzymes. 21723361 Effects of docosahexaenoic acid and methylmercury on child's brain development due to consumption of fish by Finnish mother during pregnancy: a probabilistic modeling approach. Fish contains both beneficial substances e.g. docosahexaenoic acids but also harmful compounds e.g. methylmercury. Importantly, the health effects caused by these two substances can be evaluated in one common end point, intelligence quotient (IQ), providing a more transparent analysis. We estimated health effects of maternal fish consumption on child's central nervous system by creating a model with three alternative maternal fish consumption scenarios (lean fish, fatty fish, and current fish consumption). Additionally, we analyzed impacts of both regular fish consumption and extreme fish consumption habits. At the individual level, the simulated net effects were small, encompassing a range of one IQ point in all scenarios. Fatty fish consumption, however, clearly generated a beneficial net IQ effect, and lean fish consumption evoked an adverse net IQ effect. In view of the current fish consumption pattern of Finnish mothers the benefits and risks seem to more or less compensate each other. This study clearly shows the significance of which fish species are consumed during pregnancy and lactation, and the results can be generalized to apply to typical western population fish consumption habits. 23847640 Small RNA pathways and diversity in model legumes: lessons from genomics. Small non-coding RNAs (smRNA) participate in the regulation of development, cell differentiation, adaptation to environmental constraints and defense responses in plants. They negatively regulate gene expression by degrading specific mRNA targets, repressing their translation or modifying chromatin conformation through homologous interaction with target loci. MicroRNAs (miRNA) and short-interfering RNAs (siRNA) are generated from long double stranded RNA (dsRNA) that are cleaved into 20-24-nucleotide dsRNAs by RNase III proteins called DICERs (DCL). One strand of the duplex is then loaded onto effective complexes containing different ARGONAUTE (AGO) proteins. In this review, we explored smRNA diversity in model legumes and compiled available data from miRBAse, the miRNA database, and from 22 reports of smRNA deep sequencing or miRNA identification genome-wide in three legumes: Medicago truncatula, soybean (Glycine max) and Lotus japonicus. In addition to conserved miRNAs present in other plant species, 229, 179, and 35 novel miRNA families were identified respectively in these 3 legumes, among which several seems legume-specific. New potential functions of several miRNAs in the legume-specific nodulation process are discussed. Furthermore, a new category of siRNA, the phased siRNAs, which seems to mainly regulate disease-resistance genes, was recently discovered in legumes. Despite that the genome sequence of model legumes are not yet fully completed, further analysis was performed by database mining of gene families and protein characteristics of DCLs and AGOs in these genomes. Although most components of the smRNA pathways are conserved, identifiable homologs of key smRNA players from non-legumes, like AGO10 or DCL4, could not yet be detected in M. truncatula available genomic and expressed sequence (EST) databases. In contrast to Arabidopsis, an important gene diversification was observed in the three legume models (for DCL2, AGO4, AGO2, and AGO10) or specifically in soybean for DCL1 and DCL4. Functional significance of these variant isoforms may reflect peculiarities of smRNA biogenesis and functions in legumes. 23835337 Severe Hypoglycemia-Induced Lethal Cardiac Arrhythmias Are Mediated by Sympathoadrenal Activation. For people with insulin-treated diabetes, severe hypoglycemia can be lethal, though potential mechanisms involved are poorly understood. To investigate how severe hypoglycemia can be fatal, hyperinsulinemic, severe hypoglycemic (10-15 mg/dL) clamps were performed in Sprague-Dawley rats with simultaneous electrocardiogram monitoring. With goals of reducing hypoglycemia-induced mortality, the hypotheses tested were that: 1) antecedent glycemic control impacts mortality associated with severe hypoglycemia; 2) with limitation of hypokalemia, potassium supplementation could limit hypoglycemia-associated deaths; 3) with prevention of central neuroglycopenia, brain glucose infusion could prevent hypoglycemia-associated arrhythmias and deaths; and 4) with limitation of sympathoadrenal activation, adrenergic blockers could prevent hypoglycemia-induced arrhythmic deaths. Severe hypoglycemia-induced mortality was noted to be worsened by diabetes, but recurrent antecedent hypoglycemia markedly improved the ability to survive an episode of severe hypoglycemia. Potassium supplementation tended to reduce mortality. Severe hypoglycemia caused numerous cardiac arrhythmias including premature ventricular contractions, tachycardia, and high-degree heart block. Intracerebroventricular glucose infusion reduced severe hypoglycemia-induced arrhythmias and overall mortality. β-Adrenergic blockade markedly reduced cardiac arrhythmias and completely abrogated deaths due to severe hypoglycemia. Under conditions studied, sudden deaths caused by insulin-induced severe hypoglycemia were mediated by lethal cardiac arrhythmias triggered by brain neuroglycopenia and the marked sympathoadrenal response. 23964716 Evaluation of peri-implant bone response in implants retrieved for fracture after more than 20 years of loading. A case series. Abstract Analysis of human retrieved dental implants is a useful tool in the evaluation of implant success and failure. More human histological data are needed from samples of long-term implant service. Aim of the present case series was a histological and histomorphometrical evaluation of the peri-implant bone responses in implants retrieved for fracture after more than 20 years loading. The archives of the Implant Retrieval Center of the Department of Medical, Oral and Biotechnological Sciences of the University of Chieti-Pescara, Italy were searched. A total of 5 implants, retrieved after a loading period of more than 20 years, were found: 2 had been retrieved after 20 years, 1 after 22 years, 1 after 25 years, and 1 after 27 years. All these implants were histologically processed. Compact, mature bone in close contact with the implant surface was observed in all specimens, with no gaps or connective tissue at the interface. Around some implants it was found bone in different maturation stages. Mainly, in proximity of the implant surface it was possible to observe the presence of newly formed bone, while in areas distant from the implant it was detected mature, compact bone with many remodeling areas and cement lines. Many primary and secondary osteons were present. Bone to implant contact percentage varied from 37.2% to 76%. In conclusion, histology and histomorphometry showed that, even after many years of function, all implants presented more than adequate bone to implant contact and they appeared to be very well integrated in the peri-implant bone. 22218636 A case of IgG4-related tubulointerstitial nephritis with left hydronephrosis after a remission of urinary tract tuberculosis. IgG4-related systemic disease encompasses multi-organ disorders, including tubulointerstitial nephritis. This disease is accompanied by a high serum IgG4 concentration and IgG4-positive plasma cell infiltration. We herein describe a 63-year-old woman with renal failure and dryness of the eyes and mouth, who had been treated with antituberculosis agents for urinary tract tuberculosis. She had a negative finding for a PCR analysis for Mycobacterium tuberculosis, a positive QuantiFERON-TB test, high serum IgG4 concentrations (2,660 mg/dl), and low serum IgM and IgA concentrations (34 and 82 mg/dl, respectively). Imaging tests revealed swelling in the submandibular glands, pancreas, and right kidney. A renal biopsy showed IgG4-positive plasma cell infiltration in the interstitium and tubular atrophy. This case was diagnosed as IgG4-related systemic disease. Corticosteroid therapy improved renal failure and swelling in the submandibular glands, pancreas, and right kidney. The case suggests that an abnormal reaction to tuberculosis may be associated with a predominance of type-2 helper T-cell immunity, thus resulting in IgG4-related systemic disease. 23860905 Cationic gold(i) heteroleptic complexes bearing a pyrazole-derived N-heterocyclic carbene: syntheses, characterizations, and cytotoxic activities. A series of cationic gold(i) heteroleptic complexes bearing the pyrazole-derived N-heterocyclic carbene (NHC) FPyr (1,2,3,4,6,7,8,9-octahydropyridazino[1,2-a]indazolin-11-ylidene), and either a 1,3-disubstituted benzimidazole-derived NHC of the type RR'-bimy (3: R = R' = CHPh2; 4: R = CHPh2, R' = (i)Pr; 5: R = R' = CH2Ph; 6: R = R' = (i)Bu; 7: R = R' = n-Pr; 8: R = R' = Et; 9: R = R' = 2-propenyl) or a non-NHC co-ligand L (10: L = PPh3; 11: L = P(OPh)3; 12: L = DMAP) (DMAP = 4-dimethylaminopyridine) have been synthesized from [AuCl(FPyr)] (1). Complexes 3-12 have been characterized using multinuclei NMR spectroscopies, ESI mass spectrometry, and elemental analysis. X-ray diffraction analyses have been performed on complexes 5, 6, and 9-11. To the best of our knowledge, 11 represents the first gold-NHC complex to bear the P(OPh)3 ligand. The cytotoxic activities of complexes 3-12 have been studied in vitro with the NCI-H1666 non-small cell lung cancer cell line. 23495674 Umbilical artery Doppler flow: An examination of current and best practice. A Web-based survey of Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) fellows and trainees who perform or act on umbilical artery Doppler showed heterogeneous reporting practices. Systolic: diastolic ratio is frequently used. Pulsatility index is favoured internationally and by many RANZCOG subspecialists. Unpublished charts are used more often than published. We summarise ideal methods of chart development but recognise that chart choice is guided by professional opinion leaders, day-to-day accessibility and other factors. 23856096 A New Italian Questionnaire to Assess Caregivers of Cancer Patients' Satisfaction With Palliative Care: Multicenter Validation of the Post Mortem Questionnaire-Short Form. Caregiver satisfaction with palliative care is a crucial indicator of its effectiveness. In light of the lack of validated or reliable Italian instruments, the Post Mortem Questionnaire-Short Form (QPM-SF), a self-report questionnaire, has been developed to assess home and inpatient hospice care. The present study was designed to evaluate the psychometric properties of QPM-SF and assess for differences in quality of palliative care between hospice and home care settings. A total of 584 caregivers of terminal cancer patients completed QPM-SF one month after the death of the care recipient. To assess test-retest reliability, a subgroup of 50 caregivers completed the questionnaire a second time, one month later. QPM-SF showed good internal consistency and temporal stability and a four-factor structure: "Integrated home care," "Hospice," "Physical care-Information-Global evaluation," and "Needs." QPM-SF may be considered a valid, reliable, and well-accepted self-report instrument for examining and implementing palliative care interventions. 23824465 Are the precapillary sphincters and metarterioles universal components of the microcirculation? An historical review. The microcirculation is a major topic in current physiology textbooks and is frequently explained with schematics including the precapillary sphincters and metarterioles. We re-evaluated the validity and applicability of the concepts precapillary sphincters and metarterioles by reviewing the historical context in which they were developed in physiology textbooks. The studies by Zweifach up until the 1950s revealed the unique features of the mesenteric microcirculation, illustrated with impressive schematics of the microcirculation with metarterioles and precapillary sphincters. Fulton, Guyton and other authors introduced or mimicked these schematics in their physiology textbooks as representative of the microcirculation in general. However, morphological and physiological studies have revealed that the microcirculation in the other organs and tissues contains no metarterioles or precapillary sphincters. The metarterioles and precapillary sphincters were not universal components of the microcirculation in general, but unique features of the mesenteric microcirculation. 23864532 Evaluation of AlloMax Acellular Dermal Matrix for Objective Collagen Deposition. Acellular dermal matrix products are popular in various aspects of surgical reconstruction including hernia repairs and breast reconstructions. The goal of this study was to determine quantitative collagen weights of AlloMax (C. R. Bard, Inc. [Davol], Warwick, RI) and of contralateral dermis for composition comparison. A rehydrated sample of AlloMax was subcutaneously implanted on the dorsum of 18 male Wistar rats. Rats were randomly assigned to groups on the basis of in vivo implant time: 1, 3, and 6 weeks. At the end of the implant time, the AlloMax was removed and a section of contralateral dermis was excised as a control. Hydroxyproline, rat Collagen I and Collagen III, and neoangiogenesis were determined in the sections. The results are reported as mean ± standard error of the mean. Analysis of variance was used to evaluate the between-group differences. A p value of 0.05 or less was considered significant. Hydroxyproline was significantly increased in the 6-week AlloMax implant (26.19 ± 1.05 vs. 15.03 ± 3.29). Collagen I and Collagen III were significantly increased following 3 weeks in vivo (612.5% ± 98.0 vs. 312.9% ± 82.7, p < 0.05 Collagen I). Neoangiogenesis was significantly increased at 3 and 6 weeks in vivo (2.3 ± 0.3 and 1.9 ± 0.3). Acellular AlloMax was rapidly incorporated into the rat dorsum. The measurement parameters were greater than or equivalent to contralateral dermis in this study. 23917311 Bioluminescence-based neuraminidase inhibition assay for monitoring influenza drug susceptibility in clinical specimens. The QFlu™ prototype bioluminescence-based neuraminidase (NA) inhibition (NI) assay kit was designed to detect NA inhibitor (NAI)-resistant influenza viruses at point-of-care. Here we evaluated its suitability for drug susceptibility assessment at a surveillance laboratory. A comprehensive panel of reference viruses (n=14) and a set of 90 seasonal influenza A and B isolates were included for testing with oseltamivir and/or zanamivir in the QFlu assay using the manufacturer recommended protocol and a modified version to attune to surveillance requirement. The generated IC50s were compared with the NI assays currently used for monitoring influenza drug susceptibility, the fluorescent (FL) and chemiluminescent (CL) assays. To provide proof-of-principal, clinical specimens (n=235) confirmed by real-time RT-PCR to contain influenza A(H1N1)pdm09 virus and pre-screened for the oseltamivir resistance marker H275Y using pyrosequencing, were subsequently tested in the QFlu assay. All three NI assays were able to discriminate the reference NA variants and their matching wild-types based on the difference in their IC50s. Unless the antigenic types were first identified, certain NA variants (e.g. H3N2 with E119V) could only be detected among seasonal viruses using the FL assays. Notably, the QFlu assay identified oseltamivir-resistant A(H1N1)pdm09 viruses carrying the H275Y marker directly in clinical specimens, which is not feasible with the other two phenotypic assays that required prior virus culturing in cells. Furthermore, The QFlu assay allows detection of the influenza A and B virus isolates carrying established and potential NA inhibitor-resistance markers, and may become a useful tool for monitoring drug resistance in clinical specimens. 23803583 A rice virescent-yellow leaf mutant reveals new insights into the role and assembly of plastid caseinolytic protease in higher plants. The plastidic caseinolytic protease (Clp) of higher plants is an evolutionarily conserved protein degradation apparatus composed of a proteolytic core complex (the P and R rings) and a set of accessory proteins (ClpT, ClpC, and ClpS). The role and molecular composition of Clps in higher plants has just begun to be unraveled, mostly from studies with the model dicotyledonous plant Arabidopsis (Arabidopsis thaliana). In this work, we isolated a virescent yellow leaf (vyl) mutant in rice (Oryza sativa), which produces chlorotic leaves throughout the entire growth period. The young chlorotic leaves turn green in later developmental stages, accompanied by alterations in chlorophyll accumulation, chloroplast ultrastructure, and the expression of chloroplast development- and photosynthesis-related genes. Positional cloning revealed that the VYL gene encodes a protein homologous to the Arabidopsis ClpP6 subunit and that it is targeted to the chloroplast. VYL expression is constitutive in most tissues examined but most abundant in leaf sections containing chloroplasts in early stages of development. The mutation in vyl causes premature termination of the predicted gene product and loss of the conserved catalytic triad (serine-histidine-aspartate) and the polypeptide-binding site of VYL. Using a tandem affinity purification approach and mass spectrometry analysis, we identified OsClpP4 as a VYL-associated protein in vivo. In addition, yeast two-hybrid assays demonstrated that VYL directly interacts with OsClpP3 and OsClpP4. Furthermore, we found that OsClpP3 directly interacts with OsClpT, that OsClpP4 directly interacts with OsClpP5 and OsClpT, and that both OsClpP4 and OsClpT can homodimerize. Together, our data provide new insights into the function, assembly, and regulation of Clps in higher plants. 23894575 Analysis of Adaptation Mutants in the Hemagglutinin of the Influenza A(H1N1)pdm09 Virus. Hemagglutinin is the major surface glycoprotein of influenza viruses. It participates in the initial steps of viral infection through receptor binding and membrane fusion events. The influenza pandemic of 2009 provided a unique scenario to study virus evolution. We performed molecular dynamics simulations with four hemagglutinin variants that appeared throughout the 2009 influenza A (H1N1) pandemic. We found that variant 1 (S143G, S185T) likely arose to avoid immune recognition. Variant 2 (A134T), and variant 3 (D222E, P297S) had an increased binding affinity for the receptor. Finally, variant 4 (E374K) altered hemagglutinin stability in the vicinity of the fusion peptide. Variants 1 and 4 have become increasingly predominant, while variants 2 and 3 declined as the pandemic progressed. Our results show some of the different strategies that the influenza virus uses to adapt to the human host and provide an example of how selective pressure drives antigenic drift in viral proteins. 23399722 Synthesis and biological evaluation of guanidino analogues of roscovitine. A series of 2,9-substituted 6-guanidinopurines, structurally related to the cyclin-dependent kinase (CDK) inhibitors olomoucine and roscovitine, has been synthesized and characterized. A new copper-catalyzed method for the synthesis of 2-substituted 6-guanidino-9-isopropylpurines under mild reaction conditions has been developed. All prepared compounds were screened for their CDK1 and CDK2 inhibitory activities, cytotoxicity and antiproliferative effects in the breast cancer-derived cell line MCF7. The most active derivative 16g possessed an identical side chain in the C2 position to roscovitine; this compound displayed approximately five fold higher inhibitory activity towards CDK2/cyclin E and more than ten fold increase in cytotoxicity in MCF7 cells. Interestingly and in contrast to previously described findings, (S)-6-guanidinopurine derivatives were generally more active than their (R)-counterparts. Kinase selectivity profiling of (R)- and (S)-enantiomers 16e and 16g, respectively, revealed that introduction of a guanidino group at the C6 position of the purine moiety decreased selectivity towards protein kinases compared to roscovitine. Nevertheless, increased inhibitory activity and decreased selectivity offer a good starting point for further development of new protein kinase inhibitors. 23549676 An Active Role for Steroid-binding Globulins: An Update. It has been 7 years (can it really be that long?) since we co-edited a volume (#38) of Hormone and Metabolic Research that focused on evidence that steroid-binding globulins play an active role in the actions of steroids. There has been considerable progress in identifying the location, the physiological actions, and of determining the role of binding globulins in the actions of steroids and identifying a membrane-associated receptor for a binding protein since then and this review will discuss this progress. 23879845 Effects of subtherapeutic concentrations of antimicrobials on gene acquisition events in Yersinia, Proteus, Shigella, and Salmonella recipient organisms in isolated ligated intestinal loops of swine. Objective-To assess antimicrobial resistance and transfer of virulence genes facilitated by subtherapeutic concentrations of antimicrobials in swine intestines. Animals-20 anesthetized pigs experimentally inoculated with donor and recipient bacteria. Procedures-4 recipient pathogenic bacteria (Salmonella enterica serotype Typhimurium, Yersinia enterocolitica, Shigella flexneri, or Proteus mirabilis) were incubated with donor bacteria in the presence of subinhibitory concentrations of 1 of 16 antimicrobials in isolated ligated intestinal loops in swine. Donor Escherichia coli contained transferrable antimicrobial resistance or virulence genes. After coincubations, intestinal contents were removed and assessed for pathogens that acquired new antimicrobial resistance or virulence genes following exposure to the subtherapeutic concentrations of antimicrobials. Results-3 antimicrobials (apramycin, lincomycin, and neomycin) enhanced transfer of an antimicrobial resistance plasmid from commensal E coli organisms to Yersinia and Proteus organisms, whereas 7 antimicrobials (florfenicol, hygromycin, penicillin G, roxarsone, sulfamethazine, tetracycline, and tylosin) exacerbated transfer of an integron (Salmonella genomic island 1) from Salmonella organisms to Yersinia organisms. Sulfamethazine induced the transfer of Salmonella pathogenicity island 1 from pathogenic to nonpathogenic Salmonella organisms. Six antimicrobials (bacitracin, carbadox, erythromycin, sulfathiazole, tiamulin, and virginiamycin) did not mediate any transfer events. Sulfamethazine was the only antimicrobial implicated in 2 types of transfer events. Conclusions and Clinical Relevance-10 of 16 antimicrobials at subinhibitory or subtherapeutic concentrations augmented specific antimicrobial resistance or transfer of virulence genes into pathogenic bacteria in isolated intestinal loops in swine. Use of subtherapeutic antimicrobials in animal feed may be associated with unwanted collateral effects. 23522097 Heterogeneity in the risk of Mycobacterium bovis infection in European badger (Meles meles) cubs. The behaviour of certain infected individuals within socially structured populations can have a disproportionately large effect on the spatio-temporal distribution of infection. Endemic infection with Mycobacterium bovis in European badgers (Meles meles) in Great Britain and Ireland is an important source of bovine tuberculosis in cattle. Here we quantify the risk of infection in badger cubs in a high-density wild badger population, in relation to the infection status of resident adults. Over a 24-year period, we observed variation in the risk of cub infection, with those born into groups with resident infectious breeding females being over four times as likely to be detected excreting M. bovis than cubs from groups where there was no evidence of infection in adults. We discuss how our findings relate to the persistence of infection at both social group and population level, and the potential implications for disease control strategies. 23934335 Does a Calculated "NAFLD Fibrosis Score" Reliably Negate the Need for Liver Biopsy in Patients Undergoing Bariatric Surgery? Nonalcoholic fatty liver disease (NAFLD) represents the most common cause of chronic liver disease in the USA. Biopsy has been the standard for determining fibrosis but is invasive, costly, and associated with risk. Previous studies report a calculated "NAFLD fibrosis scores" (cNFS) as a means to overcome the need for biopsy. We compared cNFS versus biopsy-pathological scoring for patients undergoing bariatric surgery. We retrospectively reviewed patients with available preoperative labs and patient information undergoing Roux-en-Y gastric bypass (RYGBP) surgery at a single institution over a 5.5-year period. Biopsy samples were blind scored by a single hepatopathologist and compared with scores calculated using a previously reported cNFS. Of the 225 patients that met the inclusion criteria, the mean body mass index was 44.6 ±â€‰5.4 kg/m(2) and 85 % were female. Using the cNFS, 39.6 % of patients were categorized into low fibrosis, 52 % indeterminate, and 8.4 % high fibrosis groups. Analysis of fibrosis by pathology scoring demonstrated 2 of 89 (2.2 %) and 7 of 110 (3.4 %) had significant fibrosis in the low and intermediate groups, respectively. Conversely, in the high fibrosis group calculated by cNFS, only 6 of 19 (31.6 %) exhibited significant fibrosis by pathology scoring. No definitive model for accurately predicting presence of NAFLD and fibrosis currently exits. Furthermore, under no circumstances should a clinical "NAFLD fibrosis score" replace liver biopsy at this time for RYGBP patients. 23710731 A cross-sectional study of the relationship between serum sexual hormone levels and internal derangement of temporomandibular joint. Temporomandibular disorders (TMD) are defined as clinical conditions that involve the masticatory muscles, temporomandibular joint (TMJ) or both. The aim of this study was to evaluate serum 17β-oestradiol and progesterone levels in menstruating women affected by internal derangement of the TMJ. A total of 142 women (mean age 30·2 ± 6·7) who referred to medical diagnostic laboratory of Iranian Academic Centre for Education, Culture and Research (ACECR), Mashhad Branch, were enrolled during 2007 and 2008. Forty-seven individuals had disc displacement with reduction (Group IIa) according to Research Diagnostic Criteria (RDC)/TMD Axis I diagnosis. Radioimmunoassay was used for the detection of serum 17β-oestradiol and progesterone levels in all 142 subjects. The mean progesterone level was significantly higher in control group (11·6 ± 10·4 ng mL(-1) ) compared to women with TMD (8·4 ± 6·8 ng mL(-1) , P = 0·03). No significant difference was found in two groups regarding 17β-oestradiol level. Lower progesterone level in women with TMD can suggest the more important role of this hormone in the development of the disorder. 23957962 Educational potential of a virtual patient system for caring for traumatized patients in primary care. Virtual Patients (VPs) have been used in undergraduate healthcare education for many years. This project is focused on using VPs for training professionals to care for highly vulnerable patient populations. The aim of the study was to evaluate if Refugee Trauma VPs was perceived as an effective and engaging learning tool by primary care professionals (PCPs) in a Primary Health Care Centre (PHC). A VP system was designed to create realistic and engaging VP cases for Refugee Trauma for training refugee patient interview, use of established trauma and mental health instruments as well as to give feedback to the learners. The patient interview section was based on video clips with a Bosnian actor with a trauma story and mental health problems. The video clips were recorded in Bosnian language to further increase the realism, but also subtitled in English. The system was evaluated by 11 volunteering primary health clinicians at the Lynn Community Health Centre, Lynn, Massachusetts, USA. The participants were invited to provide insights/feedback about the system's usefulness and educational value. A mixed methodological approach was used, generating both quantitative and qualitative data. Self-reported dimensions of clinical care, pre and post questionnaire questions on the PCPs clinical worldview, motivation to use the VP, and IT Proficiency. Construct items used in these questionnaires had previously demonstrated high face and construct validity. The participants ranked the mental status examination more positively after the simulation exercise compared to before the simulation. Follow up interviews supported the results. Even though virtual clinical encounters are quite a new paradigm in PHC, the participants in the present study considered our VP case to be a relevant and promising educational tool. Next phase of our project will be a RCT study including comparison with specially prepared paper-cases and determinative input on improving clinical diagnosis and treatment of the traumatized refugee patient. 23859599 Slow aromatic ring flips detected despite near-degenerate NMR frequencies of the exchanging nuclei. Aromatic ring flips of Phe and Tyr residues are a hallmark of protein dynamics with a long history in molecular biophysics. Ring flips lead to symmetric exchange of nuclei between sites with distinct magnetic environments, which can be probed by NMR spectroscopy. Current knowledge of ring-flip rates originates from rare cases in which the chemical shift difference between the two sites is sufficiently large and the ring-flip rate sufficiently slow, typically kflip < 10(3) s(-1), so that separate peaks are observed in the NMR spectrum for the two nuclei, enabling direct measurement of the flip rate. By contrast, a great majority of aromatic rings show single peaks for each of the pairs of δ or ε nuclei, which commonly are taken as inferential evidence that the flip rate is fast, kflip ≫ 10(3) s(-1), even though rate measurements have not been achieved. Here we report a novel approach that makes it possible to identify slow ring flips in previously inaccessible cases where only single peaks are observed. We demonstrate that Y21 in the bovine pancreatic trypsin inhibitor (BPTI) has a slow ring-flip rate, kflip < 100 s(-1), a result that contrasts with previous estimates of 10(4)-10(6) s(-1) inferred from the single-peak spectrum of Y21. Comparison with a recent 1 ms molecular dynamics trajectory of BPTI shows qualitative agreement and highlights the value of accurate aromatic ring flip data as an important benchmark for molecular dynamics simulations of proteins across wide time scales. 23838275 Contrast, motion, perceptual integration, and neurocognition in schizophrenia: The role of fragile-X related mechanisms. Recent studies demonstrated a reduced expression of Fragile X Mental Retardation Protein (FMRP), an RNA binding protein and translation regulator, in the brain and peripheral lymphocytes of patients with schizophrenia. Low FMRP levels may be related to impaired neurodevelopmental processes and synaptic plasticity. Here, we studied the relationship between peripheral FMRP level, visual perception (contrast sensitivity, perceptual integration, motion/form perception), and neuropsychological functions in schizophrenia as measured with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Results revealed that patients with schizophrenia displayed lower FMRP levels in peripheral lymphocytes as compared to control individuals. We found significant correlations between FMRP levels and contrast sensitivity at low spatial and high temporal frequencies, perceptual integration, and motion perception. The relationship between FMRP level and neuropsychological functions was less pronounced than that seen in the case of visual perception, with the greatest effect for RBANS attention. FMRP level was not related to contrast sensitivity at high spatial and low temporal frequencies and form perception. This pattern of data is reminiscent to that observed in patients with Fragile X Syndrome (FXS). These results suggest that FMRP may be implicated in the pathogenesis of schizophrenia, possibly via the regulation of neurodevelopment, plasticity, GABA-ergic, and glutamatergic neurotransmission. 23755737 Comprehensive structural, surface-chemical and electrochemical characterization of nickel-based metallic foams. Nickel-based metallic foams are commonly used in electrochemical energy storage devices (rechargeable batteries) as both current collectors and active mass support. These materials attract attention as tunable electrode materials because they are available in a range of chemical compositions, pore structures, pore sizes, and densities. This contribution presents structural, chemical, and electrochemical characterization of Ni-based metallic foams. Several materials and surface science techniques (transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy dispersive spectrometer (EDS), focused ion beam (FIB), and X-ray photoelectron spectroscopy (XPS)) and electrochemical methods (cyclic voltammetry (CV)) are used to examine the micro-, meso-, and nanoscopic structural characteristics, surface morphology, and surface-chemical composition of these materials. XPS combined with Ar-ion etching is employed to analyze the surface and near-surface chemical composition of the foams. The specific and electrochemically active surface areas (As, Aecsa) are determined using CV. Though the foams exhibit structural robustness typical of bulk materials, they have large As, in the range of 200-600 cm(2) g(-1). In addition, they are dual-porosity materials and possess both macro- and mesopores. 23905815 Long-term Results of Treatment with Nucleoside and Nucleotide Analogues (Entecavir and Tenofovir) for Chronic Hepatitis B. Chronic hepatitis B virus (HBV) infection, affecting approximately 350 to 400 million people worldwide, is associated with significant morbidity and mortality. Chronic hepatitis B remains a public health issue despite marked progress in public intervention programs. Individuals with chronic HBV infection have an increased risk for cirrhosis, decompensated liver disease, and hepatocellular carcinoma. The availability of safe and effective vaccines has reduced the burden of diseases. The choice of appropriate pharmacotherapy is critical in altering the course of the infection and reducing the costs associated with the management of chronic hepatitis B. 23338532 Brief report: examining driving behavior in young adults with high functioning autism spectrum disorders: a pilot study using a driving simulation paradigm. Although it is speculated that impairments associated with autism spectrum disorder (ASD) will adversely affect driving performance, little is known about the actual extent and nature of the presumed deficits. Ten males (18-24 years of age) with a diagnosis of high functioning autism and 10 age matched community controls were recruited for a driving simulation experiment. Driving behavior, skin conductance, heart rate, and eye tracking measurements were collected. The high functioning ASD participants displayed a nominally higher and unvaried heart rate compared to controls. With added cognitive demand, they also showed a gaze pattern suggestive of a diversion of visual attention away from high stimulus areas of the roadway. This pattern deviates from what is presumed to be optimal safe driving behavior and appears worthy of further study. 23508814 Clinical utility of an endoscopic ultrasound-guided rendezvous technique via various approach routes. The endoscopic ultrasound-guided rendezvous techniques (EUS-rendezvous) provide reliable biliary access after failed endoscopic retrograde cholangiopancreatography (ERCP) cannulation. We evaluated the clinical utility of an EUS-rendezvous technique using various approach routes. Patients undergoing EUS-rendezvous for biliary access after failed bile duct cannulation in ERCP were included. EUS-rendezvous was performed via three approach routes depending on the patient's condition: transgastric, transduodenal in a short endoscopic position, or transduodenal in a long endoscopic position. The main outcomes were the technical success rates. Secondary outcomes were procedure time and complications. Fourteen patients (median age, 77 years) underwent EUS-rendezvous for biliary access resulting from failed biliary cannulation. The reasons for biliary drainage were malignant biliary obstruction in five patients and choledocholithiasis in nine. Transgastric, transduodenal in a short position, and transduodenal in a long position EUS-rendezvous was performed in five, five, and four patients, respectively. Bile duct puncture occurred in the left intrahepatic duct in four patients, right hepatic duct in one, middle common bile duct in four, and lower common bile duct in five. The technical success rate was 100 %. In four patients, the approach route was modified from transduodenal in a short position to transduodenal in a long position or transgastric route. The median procedure time was 81 min. One case each of biliary peritonitis and pancreatitis occurred and were managed conservatively. EUS-rendezvous provided safe and reliable transpapillary bile duct access after failed ERCP cannulation. The selection of the appropriate approach routes, depending on patient condition, is critical. 23907679 Production of a Functional Human Acid Maltase in Tobacco Seeds: Biochemical Analysis, Uptake by Human GSDII Cells, and In Vivo Studies in GAA Knockout Mice. Genetic deficiency of acid alpha glucosidase (GAA) results in glycogen storage disease type II (GSDII) or Pompe's disease. To investigate whether we could generate a functional recombinant human GAA enzyme (tobrhGAA) in tobacco seeds for future enzyme replacement therapy, we subcloned the human GAA cDNA into the plant expression plasmid-pBI101 under the control of the soybean β-conglycinin seed-specific promoter and biochemically analyzed the tobrhGAA. Tobacco seeds contain the metabolic machinery that is more compatible with mammalian glycosylation-phosphorylation and processing. We found the tobrhGAA to be enzymatically active was readily taken up by GSDII fibroblasts and in white blood cells from whole blood to reverse the defect. The tobrhGAA corrected the enzyme defect in tissues at 7 days after a single dose following intraperitoneal (IP) administration in GAA knockout (GAA(-/-)) mice. Additionally, we could purify the tobrhGAA since it bound tightly to the matrix of Sephadex G100 and can be eluted by competition with maltose. These data demonstrate indirectly that the tobrhGAA is fully functional, predominantly proteolytically cleaved and contains the minimal phosphorylation and mannose-6-phosphate residues essential for biological activity. 22796364 Targeted delivery of EV peptide to tumor cell cytoplasm using lipid coated calcium carbonate nanoparticles. Intracellular-acting peptide drugs are effective for inhibiting cytoplasmic protein targets, yet face challenges with penetrating the cancer cell membrane. We have developed a lipid nanoparticle formulation that utilizes a pH-sensitive calcium carbonate complexation mechanism to enable the targeted delivery of the intracellular-acting therapeutic peptide EEEEpYFELV (EV) into lung cancer cells. Lipid-calcium-carbonate (LCC) nanoparticles were conjugated with anisamide, a targeting ligand for the sigma receptor which is expressed on lung cancer cells. LCC EV nanoparticle treatment provoked severe apoptotic effects in H460 non-small cell lung cancer cells in vitro. LCC NPs also mediated the specific delivery of Alexa-488-EV peptide to tumor tissue in vivo, provoking a high tumor growth retardation effect with minimal uptake by external organs and no toxic effects. 23751327 Renal transplantation in 4 patients with methylmalonic aciduria: A cell therapy for metabolic disease. Patients with methylmalonic acidemia (MMA) may develop many complications despite medical treatment, in particular, severe central nervous system damage and chronic kidney disease (CKD). A kidney transplant may partially correct the metabolic dysfunctions. Liver, kidney and combined liver-kidney transplantations have been advocated but no guidelines are available to identify the most suitable organ to transplant. Four patients with MMA (mut° phenotype) received a kidney graft because of repeated metabolic decompensations, with progression to CKD in 3 patients (end-stage kidney disease in two patients and CKD stage III in one patient with an estimated glomerular filtration rate [eGFR] of 40ml/min/1.73m(2)) but normal renal function in one (eGFR of 93ml/min/1.73m(2)) before transplantation. The medium age at transplantation was 7.9y (5-10.2) and the median follow-up was 2.8years (1.8-4.6). Renal transplantation improved the relevant metabolic parameters in 4/4 patients and renal function in the patients with CKD. Plasma and urinary MMA levels immediately decreased and remained normal or subnormal (mean values of plasma MMA before transplantation 1530μmol/L versus 240μmol/L after transplantation, and mean values of urine MMA before transplantation 4700mmol/mol creatinine versus 2300mmol/mol creatinine after transplantation). No further acute metabolic decompensation was observed and protein-intake was increased from 0.60 to 0.83g/Kg/day. One patient transplanted at age 9.7years developed a hepatoblastoma at age 11years with subsequent neurological complications and eventually died. The three other patients are alive. Two of them remained neurologically stable. The 3rd patient who displayed choreoathetosis transiently improved his neurological condition immediately after transplantation and then remained stable. Kidney transplantation represents an interesting alternative therapeutic option in methylmalonic aciduria, for renal complications but also as a "cellular therapy" that may significantly reduce metabolic decompensations and hospitalizations. However, further neurological impairment remains possible. 23964018 Does the Cerebellum Initiate Movement? Opinion is divided on what the exact function of the cerebellum is. Experiments are summarized that support the following views: (1) the cerebellum is a combiner of multiple movement factors; (2) it contains anatomically fixed permanent focal representation of individual body parts (muscles and segments) and movement modes (e.g., vestibular driven vs. cognitive driven); (3) it contains flexible changing representations/memory of physical properties of the body parts including muscle strength, segment inertia, joint viscosity, and segmental interaction torques (dynamics); (4) it contains mechanisms for learning and storage of the properties in item no. 3 through trial-and-error practice; (5) it provides for linkage of body parts, motor modes, and motordynamics via the parallel fiber system; (6) it combines and integrates the many factors so as to initiate coordinated movements of the many body parts; (7) it is thus enabled to play the unique role of initiating coordinated movements; and (8) this unique causative role is evidenced by the fact that: (a) electrical stimulation of the cerebellum can initiate compound coordinated movements; (b) in naturally initiated compound movements, cerebellar discharge precedes that in downstream target structures such as motor cerebral cortex; and (c) cerebellar ablation abolishes the natural production of compound movements in the awake alert individuals. 23448403 Device physics and operation of lateral bulk heterojunction devices. Measurements of lateral bulk heterojunction (BHJ) devices have recently been reported as a means to characterize charge transport and recombination properties within organic photovoltaic (OPV) materials. These structures allow for the direct measurement of the lateral extents of the space charge regions, potential and electric field profiles, current versus voltage characteristics, and other physical and chemical properties. This article describes numerical simulations that show three different transport regimes present within lateral BHJ devices and two different experimental methods, which verify those findings. These measurement techniques utilize typical confocal microscopy tools as well as steady-state current versus voltage measurements on high aspect ratio nanofabricated structures in order to probe the material properties between the electrodes. Experimental results show that the lateral extents of space charge regions within these devices are approximately 1-5 μm, which are related to the drift lengths of the charge carriers, and that the mechanism of bimolecular recombination is shown to be a bulk material property. The results within this article describe a series of methods to evaluate charge transport and recombination along the in-plane direction in BHJ films and provide complementary insights to those obtained from vertical-device-based measurements. 23861436 Regulation of circadian clocks by redox homeostasis. Living organisms possess biological clocks that resonate with environmental cycles in light, temperature and food availability. Recently, circadian oscillations in the redox state of peroxiredoxin have been described as an additional, non-transcriptional timekeeping mechanism. Of note, this redox cycle is conserved in both prokaryotes and eukaryotes. How the classical "transcription-translation feedback loop" model and this redox oscillation are related is still poorly understood. In this review we describe the most recent evidence pointing to crosstalk between the circadian clock and the redox status of the cell. 23952577 Spatiotemporal Characteristics of Internal Radiation Exposure In Evacuees and First Responders after the Radiological Accident in Fukushima. After the Tokyo Electric Power Company Fukushima Daiichi nuclear power plant accident on March 11, 2011, the reconstruction of early internal radiation doses in residents of Fukushima plays a major role in evaluating their future heath risk, including thyroid cancer by internal radioiodine. Internal radioactivity was measured using a whole body counter (WBC) at the Nagasaki University Medical School to evaluate the health risks of residents and short term visitors in Fukushima. Measurable (131)I, (134)Cs and (137)Cs were detected altogether in 49 out of 196 people who were in Fukushima prefecture at any time during March 11 and April 20, 2011. In 49 people, the 90 percentile of the thyroid equivalent dose by (131)I and the committed effective dose (total effective dose over a lifetime) by the sum of (134)Cs and (137)Cs was 3 mSv and 0.06 mSv, respectively. The radionuclide intakes in early evacuees who left Fukushima before March 16 were more than five times as high as in the responders who moved to Fukushima later. The intake ratio of (131)I/(137)Cs of the earlier evacuees was approximately three. The spatial analysis of 16 evacuees to the south indicated a reduction of internal radioactivity depending on the distance from the nuclear power plant. Among them, high internal (131)I radioactivity in 6 people in a particular evacuation route could be explained by the arrival of a radioactive cloud with a high airborne (131)I/(137)Cs ratio to the environment, as predicted by atmospheric dispersion simulations. Overall, the actual internal radioactivity assessed by a WBC examination comparatively agreed with the predicted airborne radioactivity. These results suggest that the accurate estimation of internal doses in the first week after the radiological accident is critical for the dose reconstruction. The evaluation of internal doses of residents based on their evacuation routes and the advanced estimation of airborne radioactivity from the atmospheric dispersion model should continue to be assessed. 23681827 A place for ultrastructural analysis of platelets in cerebral ischemic research. It is well known that estrogen is neuroprotective through various mechanisms which suggest that sex hormone levels, thrombotic mechanisms, and inflammatory processes are strongly interconnected in predicting the outcome and consequences of cerebral ischemia. Because platelet ultrastructure is altered in conditions like thrombosis and associated with stroke, the question arises whether ultrastructural analyses of platelet morphology may provide further insight into the role of estrogen during ischemic insult. In the current study, a hyperglycemic modification to the two-vessel occlusion model for inducing experimental cerebral ischemia was employed, in order to correlate neural tissue integrity levels between three experimental groups to corresponding platelet ultrastructure so as to determine whether there is an association between cerebral ischemia and the presence of inflammatory or necrotic platelet ultrastructure. It is apparent in the results that under the influence of estrogen in cyclic or intact females, there is lesser neural tissue damage as well as a reduced degree of inflammation evident in platelet activation morphology when compared to males and acyclic or ovariectomized females. It is unmistakable that neural injury is closely shadowed, if not preceded, by inflammatory changes in the coagulation system, particularly manifested in platelet ultrastructure. It is therefore suggested that platelets may indeed be used successfully to follow the progression of events of cerebral ischemia and possibly assist in the assessment of treatment strategies and their effects on hemostasis. Microsc. Res. Tech. 76:795-802, 2013. © 2013 Wiley Periodicals, Inc. 23392552 Stock volatility and stroke mortality in a Chinese population. This work was done to study the relationship between stock volatility and stroke mortality in Shanghai, China. Daily stroke death numbers and stock performance data from 1 January 2006 to 31 December 2008 in Shanghai were collected from the Shanghai Center for Disease Control and Prevention and Shanghai Stock Exchange (SSE), respectively. Data were analysed with overdispersed generalized linear Poisson models, controlling for long-term and seasonal trends of stroke mortality and weather conditions with natural smooth functions, as well as Index closing value, air pollution levels and day of the week. We observed a U-shaped relationship between the Index change and stroke deaths: both rising and falling of the Index were associated with more deaths, and the fewest deaths coincided with little or no change of the Index. We also examined the absolute daily change of the Index in relation to stroke deaths: each 100-point Index change corresponded to 3.22% [95% confidence interval (CI) 0.45-5.49] increase of stroke deaths. We found that stroke deaths fluctuated with daily stock changes in Shanghai, suggesting that stock volatility may adversely affect cerebrovascular health. 23811423 Lipid-lowering agents. The role of lipid lowering in reducing the risk of mortality and morbidity from cardiovascular disease (CVD) is well established. Treatment particularly aimed at decreasing low-density lipoprotein cholesterol (LDL-C) is effective in reducing the risk of death from coronary heart disease and stroke. Statins form the cornerstone of treatment. However, in some individuals with a high risk of CVD who are unable to achieve their target LDL-C due to either intolerance or lack of efficacy, there is the need for alternative therapies. This review provides an overview of the different classes of currently available lipid-lowering medications including statins, fibrates, bile acid sequestrants (resins), and omega-3 fatty acids. Data are presented on their indications, pharmacology, and the relevant end point clinical trial data with these drugs. It also discusses the human trial data on some novel therapeutic agents that are being developed including those for homozygous familial hypercholesterolemia-the antisense oligonucleotide mipomersen and the microsomal transfer protein inhibitor lomitapide. Data are presented on phase II and III trials on agents with potentially wider applications, cholesterol ester transfer protein inhibitors and proprotein convertase subtilisin kexin 9 inhibitors. The data on a licensed gene therapy for lipoprotein lipase deficiency are also presented. 23818231 Motor functions in trumpet playing-a real-time MRI analysis. The function of the orofacial and pharyngeal musculature for sound generation in brass instruments is insufficiently investigated. The contribution of muscles defying direct observation remains poorly understood. Time-resolved magnetic resonance imaging (MRI) allows visualization of muscle function as well as changes of the oropharyngeal cavities during muscle activation. We used fast 3-T MRI imaging to analyze motor activation during sound generation in brass instruments. Twelve professional trumpeters were analyzed at different pitch, loudness and dynamic. MR images were analyzed for position of the mouthpiece to lips and teeth, pivoting, nasopharyngeal closure and changes in the area of oral and pharyngeal cavity. Of the 12 subjects, eight positioned the mouthpiece mainly to the upper lip, three in equal parts to upper and lower lip, and only one mostly to the lower lip. The last turned out to be the only subject with upward pivoting. All subjects had a complete velopharyngeal closure. Measurements of the oral and pharyngeal cavities showed an increase when subjects were playing higher pitches. The increase in areas of oral and pharyngeal cavity was present also when switching from lower to higher loudness and when performing crescendo to decrescendo. Enlargement of the oral and pharyngeal cavity was less pronounced with increasing loudness. But no general difference in change of oral and pharyngeal cavity could be observed. The present study shows that it is possible to measure motor function and its implications on oral as well as pharyngeal cavities during sound generation in brass instruments. These changes seem to follow a reproducible pattern. 23873284 Metal-free oxidative hydroxyalkylarylation of activated alkenes by direct sp(3) C-H functionalization of alcohols. A metal-free tandem radical addition/cyclization reaction of activated alkenes and alcohols has been developed. The process provides an efficient and atom economical access to various valuable hydroxyl-containing oxindoles through the direct sp(3) C-H functionalization of alcohols. 23955745 Efficient Halftoning Based on Multiple Look-Up Tables. Look-Up Table (LUT) halftoning is an efficient way to construct halftone images, and approximately simulate the dot distribution of the learned halftone image set. In this study, a general mechanism named Multiple Look-Up Table (MLUT) halftoning is proposed to generate the halftones of Direct Binary Search (DBS), while the high efficient characteristic of the LUT is still preserved. In the MLUT, the standard deviation is adopted as an important feature to classify various tables. Moreover, the proposed Quick Standard Deviation Evaluation (QSDE) is employed to yield an extremely low computational complexity in calculating the standard deviation. In the parameter optimization, the autocorrelation is adopted since it can fully characterize the periodicity of dot distribution. Experimental results demonstrate that the dot distribution generated by the proposed method approximates to that of the DBS, which enables the proposed scheme as a very competitive candidate in coping printing industry. 23758410 Identification and virulence of Aeromonas dhakensis, Pseudomonas mosselii and Microbacterium paraoxydans isolated from Nile tilapia, Oreochromis niloticus, cultivated in Mexico. To identify bacterial pathogens of diseased NiIe tilapia Oreochromis niloticus and determine their virulence. Sixteen bacterial isolates were recovered from diseased Nile tilapias (O. niloticus) reared in floating cages in Adolfo Lopez Mateos (ALM), Sanalona and Dique IV dams in Sinaloa, Mexico, from February to May 2009. The bacterial isolates were identified by phenotypic and molecular (rep-PCR and 16S rRNA sequencing) methods and were mostly isolated from the kidneys and the brain of tilapias. Bacterial cells and extracellular products (ECPs) of strains were characterized and used in experimental infections with sole Solea vulgaris and Mozambican tilapia Oreochromis mossambicus. The fish challenged with Aeromonas dhakensis sp. nov. comb nov, Pseudomonas mosselii and Microbacterium paraoxydans (3·1 Ã— 10(6)  CFU g(-) 1) exhibited mortality between 40 and 100% starting at 6 h postinoculation. The ECPs displayed gelatinase, haemolytic and cytotoxic activity, causing the total destruction of the HeLa cell lines. Aeromonas dhakensis and Ps. mosselii were virulent to O. mossambicus, whereas Mic. paraoxydans displayed virulence to S. vulgaris. This the first time that Aeromonas dhakensis and Ps. mosselii are reported as pathogens to tilapia and Mic. paraoxydans was isolated from fish; then, these fish pathogens could be a threat to farmed Nile tilapia in Mexico. 23886843 Exploring Differences in Pain Beliefs Within and Between a Large Nonclinical (Workplace) Population and a Clinical (Chronic Low Back Pain) Population Using the Pain Beliefs Questionnaire. Beliefs, cognitions and behaviours relating to pain can be associated with a range of negative outcomes. In patients, certain beliefs are associated with increased levels of pain and related disability. There is little data however, showing the extent to which beliefs of patients differ from those of the general population. This study explored pain beliefs in a large non-clinical population and a chronic low back pain (CLBP) sample using the Pain Beliefs Questionnaire (PBQ) in order to identify differences in scores and factor structures between and within the samples. The study was cross-sectional. The samples comprised patients attending a rehabilitation programme and respondents to a workplace survey. Pain beliefs were assessed using the PBQ which incorporates two scales - 'organic' and 'psychological'. Exploratory factor analysis was used to explore variations in factor structure within and between samples. The relationship between the two scales was also examined. Patients reported higher organic scores and lower psychological scores than the nonclinical sample. Within the non-clinical sample, those who reported frequent pain scored higher on the organic scale than those who did not. Factor analysis showed variations in relation to the presence of pain. The relationship between scales was stronger in those not reporting frequent pain. This was a cross-sectional study; therefore, no causal inferences can be made. Patients experiencing CLBP adopt a more biomedical perspective on pain than non-patients. The presence of pain is also associated with increased 'biomedical thinking' in a non-clinical sample. However, the impact is not just on the strength of beliefs, but also on the relationship between elements of belief and the underlying belief structure. 23946416 Elevated occipital β-amyloid deposition is associated with widespread cognitive impairment in logopenic progressive aphasia. Most subjects with logopenic variant of primary progressive aphasia (lvPPA) have β-amyloid (Aβ) deposition on Pittsburgh Compound B positron emission tomography (PiB-PET), usually affecting prefrontal and temporoparietal cortices, with less occipital involvement. To assess clinical and imaging features in lvPPA subjects with unusual topographic patterns of Aβ deposition with highest uptake in occipital lobe. Thirty-three lvPPA subjects with Aβ deposition on PiB-PET were included in this case-control study. Line plots of regional PiB uptake were created, including frontal, temporal, parietal and occipital regions, for each subject. Subjects in which the line sloped downwards in occipital lobe (lvPPA-low), representing low uptake, were separated from those where the line sloped upwards in occipital lobe (lvPPA-high), representing unusually high occipital uptake compared to other regions. Clinical variables, atrophy on MRI, hypometabolism on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and presence and distribution of microbleeds and white matter hyperintensities (WMHs) were assessed. Seventeen subjects (52%) were classified as lvPPA-high. Mean occipital PiB uptake in lvPPA-high was higher than all other regions and higher than all regions in lvPPA-low. The lvPPA-high subjects performed more poorly on cognitive testing, including executive and visuospatial testing, but the two groups did not differ in aphasia severity. Proportion of microbleeds and WMH was higher in lvPPA-high than lvPPA-low. Parietal hypometabolism was greater in lvPPA-high than lvPPA-low. Unusually high occipital Aβ deposition is associated with widespread cognitive impairment and different imaging findings in lvPPA. These findings help explain clinical heterogeneity in lvPPA and suggest that Aβ influences severity of overall cognitive impairment but not aphasia. 23934707 AT1 Receptors Prevent Salt-Induced Vascular Dysfunction in Isolated Middle Cerebral Arteries of 2 Kidney-1 Clip Hypertensive Rats. Elevated blood pressure, elevated angiotensin II (ANG II), and ANG II suppression with high salt (HS) diet all contribute to vascular dysfunction. This study investigated the interplay of HS diet and vascular function in a high renin model of hypertension. Male Sprague-Dawley rats were subjected to 2 kidney-1 clip (2K1C) Goldblatt hypertension for 4 weeks and compared with sham-operated controls. Middle cerebral arteries (MCA) of 2K1C rats and sham-operated controls fed normal salt (NS; 0.4% NaCl) diet dilated in response to acetylcholine (ACh) and reduced partial pressure of oxygen (PO2). Switching to HS (4% NaCl) diet for 3 days to reduce plasma renin activity (PRA) eliminated vasodilation to ACh and reduced PO2 in sham-operated controls, with no effect on vasodilation in 2K1C rats. AT1 receptor blockade (losartan, 20mg/kg/day; 1 week) eliminated vasodilator responses to ACh and reduced PO2 in 2K1C rats fed NS or HS diet. ANG II infusion (5ng/kg/min, intravenous) for 3 days to prevent salt-induced reductions in plasma ANG II restored vascular relaxation in MCA of sham-operated controls fed HS diet. Copper/zinc superoxide dismutase expression and total superoxide dismutase activity were significantly higher in arteries of 2K1C rats fed HS diet vs. sham-operated controls. These results suggest that the sustained effects of elevated ANG II levels in 2K1C hypertension maintain endothelium-dependent vasodilatation via AT1 receptor-mediated preservation of antioxidant defense mechanisms despite significant elevations in blood pressure and salt-induced suppression of PRA. 23966404 Phosphorylation of Measles Virus Nucleoprotein Affects Viral Growth by Changing Gene Expression and Genomic RNA Stability. The measles virus (MV) nucleoprotein associates with the viral RNA genome to form the N-RNA complex, providing a template for viral RNA synthesis. In our previous study, major phosphorylation sites of the nucleoprotein were identified as S479 and S510. However, the functions of these phosphorylation sites have not been clarified. In this study, we rescued recombinant MVs (rMVs) whose phosphorylation sites in the nucleoprotein were substituted (rMV-S479A, rMV-S510A, and rMV-S479A/S510A) by reverse genetics, and used them in subsequent analyses. In a one-step growth experiment, rMVs showed rapid growth kinetics compared with wild-type MV, although the peak titer of the wild-type MV was the same or slightly higher than for rMVs. Time course analysis of nucleoprotein accumulation also revealed that viral gene expression of rMV was enhanced during the early phase of infection. These findings suggest that nucleoprotein phosphorylation has an important role in controlling viral growth rate through the regulation of viral gene expression. Conversely, multi-step growth curves revealed that nucleoprotein-phosphorylation intensity inversely correlated with viral titer at the plateau phase. Additionally, the phosphorylation intensity of the wild-type nucleoprotein in infected cells was significantly reduced through nucleoprotein-phosphoprotein binding. Excessive nucleoprotein-phosphorylation resulted in lower stability against RNase, and faster turnover of viral genomic RNA. These results suggest that nucleoprotein-phosphorylation is also involved in viral genomic RNA stability. 23798495 Ranolazine recruits muscle microvasculature and enhances insulin action in rats. Ranolazine, an anti-anginal compound, has been shown to significantly improve glycaemic control in large-scale clinical trials and short-term ranolazine treatment is associated with an improvement in myocardial blood flow. Since microvascular perfusion plays critical roles in insulin delivery and action, we aimed to determine if ranolazine could improve muscle microvascular blood flow, thereby increase muscle insulin delivery and glucose use. Overnight-fasted, anesthetized Sprague-Dawley rats were used to determine the effects of ranolazine on microvascular recruitment using contrast-enhanced ultrasound, insulin action with euglycemic hyperinsulinemic clamp, and muscle insulin uptake using 125I-insulin. Ranolazine's effects on eNOS phosphorylation, cAMP generation and endothelial insulin uptake were determined in cultured endothelial cells. Ranolazine-induced myographical changes in tension were determined in isolated distal saphenous artery. Ranolazine at therapeutically effective dose significantly recruited muscle microvasculature by increasing muscle microvascular blood volume (~2-fold, p<0.05) and increased insulin-mediated whole body glucose disposal (~30%, p=0.02). These were associated with an increased insulin delivery into the muscle (p<0.04). In cultured endothelial cells, ranolazine increased eNOS phosphorylation and cAMP production without affecting endothelial insulin uptake. In ex vivo studies, ranolazine exerted a potent vasodilatory effect on phenylephrine pre-constricted arterial rings which was partially abolished by endothelium denudement. In conclusion, ranolazine treatment vasodilates pre-capillary arterioles and increases microvascular perfusion, which are partially mediated by endothelium, leading to expanded microvascular endothelial surface area available for nutrient and hormone exchanges and resulting in increased muscle delivery and action of insulin. Whether these actions contribute to improved glycaemic control in patients with insulin resistance warrants further investigation. 23929828 Locomotor Requirements for Bipedal Locomotion: A Delphi Survey. Bipedal locomotor control requirements may be useful as classifications for walking dysfunction because they go beyond gait analysis to address all issues contributing to walking dysfunction. The objective of this study is to determine if locomotor experts could achieve consensus about requirements for bipedal locomotion. Locomotor experts from physical therapy and other related professions participated in an electronic mail Delphi survey. Experts recommended additions, deletions, rewording and merges for 15 proposed locomotor requirements in Round 1. In Rounds 2 and 3 panelists commented on and rated the validity, mutual exclusiveness and understandability of each requirement. Consensus was defined a priori as: 1) 75% or more panelists agree or strongly agree that a requirement is valid, mutually exclusive and understandable in Round 3; 2) no difference between Rounds 2 and 3 ratings with Kappa coefficients ≥ .60; and 3) a reduction in panelists who commented and convergence of comments between Rounds 1 and 3. Content analysis and nonparametric statistics were used (p < 0.05). Fifty-eight panelists reached full consensus on five locomotor requirements: Initiation, Termination, Anticipatory Dynamic Balance, Multi Task Capacity, and Walking Confidence and partial consensus for seven other requirements. There were no significant differences in ratings between Rounds 2 and 3 and a decrease in the percentage of panelists who commented between Rounds 1 and 3. The study's 6 month timeframe may have contributed to panelist attrition. Locomotor experts achieved consensus on several bipedal locomotor requirements. With validation, these requirements can provide the framework for a clinically feasible and systematic diagnostic tool for PTs to categorize locomotor problems and standardize intervention for walking dysfunction. 23921090 Patient preferences for uterine preservation and hysterectomy in women with pelvic organ prolapse. The purpose of this study was to describe patient preferences for uterine preservation and hysterectomy in women with pelvic organ prolapse symptoms and to describe predictors of preference for uterine preservation. This multicenter, cross-sectional study evaluated patient preferences for uterine preservation vs hysterectomy in women with prolapse symptoms who were being examined for initial urogynecologic evaluation. Before meeting the physician, the women completed a questionnaire that asked them to indicate their prolapse treatment preference (uterine preservation vs hysterectomy) for scenarios in which the efficacy of treatment varied. Patient characteristics that were associated with preferences were determined, and predictors for uterine preservation preference were identified with multivariable logistic regression. Two hundred thirteen women participated. Assuming outcomes were equal between hysterectomy and uterine preservation, 36% of the women preferred uterine preservation; 20% of the women preferred hysterectomy, and 44% of the women had no strong preference. If uterine preservation was superior, 46% of the women preferred uterine preservation, and 11% of the women preferred hysterectomy. If hysterectomy was superior, 21% of the women still preferred uterine preservation, despite inferior efficacy. On multivariable logistic regression, women in the South had decreased odds of preferring uterine preservation compared with women in the Northeast (odds ratio [OR], 0.17; 95% CI, 0.05-0.66). Women with at least some college education (OR, 2.87; 95% CI, 1.08-7.62) and those who believed that the uterus is important for their sense of self (OR, 28.2; 95% CI, 5.00-158.7) had increased odds for preferring uterine preservation. A higher proportion of women with prolapse symptoms who were examined for urogynecologic evaluation preferred uterine preservation, compared with hysterectomy. Geographic region, education level, and belief that the uterus is important for a sense of self were predictors of preference for uterine preservation. 23769133 Sustainable sheep production and consumer preference trends: Compatibilities, contradictions, and unresolved dilemmas. There are increasing concerns of society towards the consumption of animal products which have been produced and transformed in a sustainable manner. This trend influences consumer purchasing decision making, particularly in developed countries. On the other hand, in the next years, the pressure to increase the volume and efficiency of meat production will be much higher to cope with the expected unsatisfied demand. At least in part, current and future technologies could contribute to solve this challenge. However, the use of some of these innovations could have a negative effect on consumer preferences. There is no consensus in our society about this dilemma. The objective of this paper is to review the scientific evidence related to these topics and to analyze and discuss the effect of some of the extrinsic and intrinsic factors linked with the sheep industry which could affect the acceptability of lamb meat by consumers. 23628951 Coronary artery bypass grafting vs percutaneous coronary intervention in a 'real-world' setting: a comparative effectiveness study based on propensity score-matched cohorts. Most studies comparing coronary artery bypass grafting (CABG) and percutaneous coronary interventions (PCI) showed that fewer patients who had undergone CABG required repeat revascularizations , but no difference in survival, with the exception of some subgroups of patients. However, long-term real-world evidence on patients in whom both procedures are technically feasible is yet not available. The aim of this study was to compare 5-year rates of death, myocardial infarction (MI), target vessel revascularization (TVR) and stroke in a large cohort of patients with left main coronary artery (LMCA) or multivessel disease, treated with CABG or PCI (with or without DES) or PCI with DES only. Two propensity score (PS)-matched cohorts of patients undergoing revascularization procedures at the regional public and private centres of Emilia-Romagna over the period July 2002-December 2008 were used to compare long-term outcomes of PCI (6246 patients) and CABG (5504 patients). PCI was associated with higher risk of death (HR = 1.6; 95% CI 1.4-1.8, P < 0.0001), MI (HR = 3.3; 95% CI 2.7-4.0, P < 0.0001) and TVR (HR = 4.5; 95% CI 3.8-5.2, P < 0.0001) at 5 years. No significant difference was shown for stroke (HR = 1.1; 95% CI 0.9-1.4, P = 0.43). CABG benefit was more evident in the risk of death in patients with two-vessel disease plus LMCA and in those with three-vessel disease, LVEF <35%, congestive heart failure and diabetes. Adjusted comparison with PS between PCI with DES only and CABG confirmed significant differences in favour of CABG for mortality, MI and TVR rates. Competing risk analysis showed that the difference in the mortality rate was due to higher rate of MI in PCI. In the 'real-world' setting of this study, CABG was associated with significantly lower rates of death, MI and TVR in patients with LMCA or multivessel disease, so it remains the standard of care, particularly for patients with more extensive coronary disease and diabetes. 23899454 Pharmacological classification of herbal extracts by means of comparison to spectral EEG signatures induced by synthetic drugs in the freely moving rat. Herbal extracts targeting at the brain remain a continuous challenge to pharmacology. Usually, a number of different animal tests have to be performed in order to find a potential clinical use. Due to manifold possibly active ingredients biochemical approaches are difficult. A more holistic approach using a neurophysiological technique has been developed earlier in order to characterise synthetic drugs. Stereotactic implantation of four semi-microelectrodes into frontal cortex, hippocampus, striatum and reticular formation of rats allowed continuous wireless monitoring of field potentials (EEG) before and after drug intake. After frequency analysis (Fast Fourier Transformation) electric power was calculated for 6 ranges (delta, theta, alpha1, alpha2, beta1 and beta2). Data from 14 synthetic drugs - tested earlier and representative for different clinical indications - were taken for construction of discriminant functions showing the projection of the frequency patterns in a six-dimensional graph. Quantitative analysis of the EEG frequency pattern from the depth of the brain succeeded in discrimination of drug effects according to their known clinical indication (Dimpfel and Schober, 2003). Extracts from Valerian root, Ginkgo leaves, Paullinia seed, Hop strobile, Rhodiola rosea root and Sideritis scardica herb were tested now under identical conditions. Classification of these extracts based on the matrix from synthetic drugs revealed that Valerian root and hop induced a pattern reminiscent of physiological sleep. Ginkgo and Paullinia appeared in close neighbourhood of stimulatory drugs like caffeine or to an analgesic profile (tramadol). Rhodiola and Sideritis developed similar frequency patterns comparable to a psychostimulant drug (methylphenidate) as well to an antidepressive drug (paroxetine). 23867543 Assessment of the cytotoxic, genotoxic, and antigenotoxic potential of Pycnogenol® in in vitro mammalian cells. Pycnogenol® (PYC), a standardized plant extract obtained from the bark of the French maritime pine Pinus pinaster, has been suggested to exert strong antioxidant activity and used as a phytochemical remedy for various diseases. In this study, we investigated the antioxidant capacity of PYC by the trolox equivalent antioxidant capacity (TEAC) assay and the cytotoxicity by neutral red uptake (NRU) test in Chinese Hamster Ovary (CHO) cells. The genotoxic and antigenotoxic effects of PYC were evaluated by the cytokinesis-blocked micronucleus (CBMN) and alkaline comet assays in human peripheral blood lymphocytes. At the concentrations of 2-200μg/ml, PYC was found to have antioxidant activity. The viability of CHO cells during 24h exposure were not affected at the concentrations of 5-150μg/ml of PYC. IC50 value of PYC was found to be 285μg/ml. At the concentrations above 100μg/ml, PYC alone induced DNA damage and increased MN frequency, although PYC at all concentrations in a dose dependent manner revealed a reduction in the frequency of MN and the extent of DNA damage induced by H2O2. These results suggest PYC might reduce H2O2 induced chromosome breakage and loss and DNA damage in cultured human lymphocytes. 23886401 Internet-based versus face-to-face cognitive-behavioral intervention for depression: A randomized controlled non-inferiority trial. In the past decade, a large body of research has demonstrated that internet-based interventions can have beneficial effects on depression. However, only a few clinical trials have compared internet-based depression therapy with an equivalent face-to-face treatment. The primary aim of this study was to compare treatment outcomes of an internet-based intervention with a face-to-face intervention for depression in a randomized non-inferiority trial. A total of 62 participants suffering from depression were randomly assigned to the therapist-supported internet-based intervention group (n=32) and to the face-to-face intervention (n=30). The 8 week interventions were based on cognitive-behavioral therapy principles. Patients in both groups received the same treatment modules in the same chronological order and time-frame. Primary outcome measure was the Beck Depression Inventory-II (BDI-II); secondary outcome variables were suicidal ideation, anxiety, hopelessness and automatic thoughts. The intention-to-treat analysis yielded no significant between-group difference (online vs. face-to-face group) for any of the pre- to post-treatment measurements. At post-treatment both treatment conditions revealed significant symptom changes compared to before the intervention. Within group effect sizes for depression in the online group (d=1.27) and the face-to-face group (d=1.37) can be considered large. At 3-month follow-up, results in the online group remained stable. In contrast to this, participants in the face-to-face group showed significantly worsened depressive symptoms three months after termination of treatment (t=-2.05, df=19, p<.05). Due to the small sample size, it will be important to evaluate these outcomes in adequately-powered trials. This study shows that an internet-based intervention for depression is equally beneficial to regular face-to-face therapy. However, more long term efficacy, indicated by continued symptom reduction three months after treatment, could be only be found for the online group. 22524318 Predictors of extradyadic sexual involvement in unmarried opposite-sex relationships. Using a sample of unmarried individuals in opposite-sex romantic relationships that was representative of the United States (N = 933), the current study prospectively evaluated predictors of extradyadic sexual involvement (ESI) over 20 months (from 2007-2010). Data were collected with self-report questionnaires via U.S. mail. Participants were 18 to 35 years old, and 34.9% were male. Variables tested as predictors included involved-partner factors such as demographic characteristics, sexual history, and mental health, as well as relationship-related factors including communication, sexual dynamics, and aspects of commitment. Future ESI was significantly predicted by lower baseline relationship satisfaction, negative communication, aggression, lower dedication, absence of plans to marry, suspicion of partners' ESI, and partners' ESI. It was not predicted by sexual frequency, sexual dissatisfaction, or cohabitation status. Although more problems with alcohol use, more previous sex partners, and having parents who never married one another predicted future ESI, there were many involved-partner demographic factors that did not predict later ESI (e.g., gender, age, education, religiosity, having divorced parents, and having children). None of the results were moderated by gender. These results suggest that compared to demographic characteristics, relationship dynamics and negative interactions are more strongly predictive of future ESI. Implications for future research are discussed. 23856833 Microvascular anastomosis guidance and evaluation using real-time three-dimensional Fourier-domain Doppler optical coherence tomography. Vascular and microvascular anastomoses are critical components of reconstructive microsurgery, vascular surgery, and transplant surgery. Intraoperative surgical guidance using a surgical imaging modality that provides an in-depth view and three-dimensional (3-D) imaging can potentially improve outcome following both conventional and innovative anastomosis techniques. Objective postoperative imaging of the anastomosed vessel can potentially improve the salvage rate when combined with other clinical assessment tools, such as capillary refill, temperature, blanching, and skin turgor. Compared to other contemporary postoperative monitoring modalities--computed tomography angiograms, magnetic resonance (MR) angiograms, and ultrasound Doppler--optical coherence tomography (OCT) is a noninvasive high-resolution (micron-level), high-speed, 3-D imaging modality that has been adopted widely in biomedical and clinical applications. For the first time, to the best of our knowledge, the feasibility of real-time 3-D phase-resolved Doppler OCT (PRDOCT) as an assisted intra- and postoperative imaging modality for microvascular anastomosis of rodent femoral vessels is demonstrated, which will provide new insights and a potential breakthrough to microvascular and supermicrovascular surgery. 23889424 Excitation-Induced Dephasing in a Resonantly Driven InAs/GaAs Quantum Dot. We report on coherent emission of the neutral exciton state in a single semiconductor self-assembled InAs/GaAs quantum dot embedded in a one-dimensional waveguide, under resonant picosecond pulsed excitation. Direct measurements of the radiative lifetime and coherence time are performed as a function of excitation power and temperature. The characteristic damping of Rabi oscillations observed is attributed to an excitation-induced dephasing due to a resonant coupling between the emitter and the acoustic phonon bath of the matrix. Other sources responsible for the decrease of the coherence time have been evidenced, in particular an enhancement of the radiative recombination rate due to the resonant strong coupling between the dot and the one-dimensional optical mode. As a consequence, the emission couples very efficiently into the waveguide mode, leading to an additional relaxation term of the excited-state population. 23962196 Making program evaluation activities family-centered: a qualitative study. Abstract Purpose: This study explored ways in which program evaluation activities in pediatric rehabilitation settings can become congruent with family-centered service (FCS) philosophy. Methods: Two Canadian pediatric rehabilitation centers participated in this study, which included focus groups with staff members and interviews with parents. Results: Participants identified seven ways in which program evaluation practices could be made congruent with FCS. Suggestions included: (a) the inclusion of a diverse group of program recipients, (b) the use of processes that facilitate family involvement, (c) the recruitment of family champions, (d) the involvement of families in program development, (e) the establishment of evaluations that are relevant to families (f) the development of center-wide statements about family involvement in evaluation and (g) the compensation of families for their active participation in evaluation. Conclusion: For program evaluation practices to be useful and relevant, they should be improved and made consistent with FCS philosophy. Those evaluating pediatric rehabilitation programs need to use approaches and activities that respect the needs, characteristics, cultures and diversity of the program recipients. Such actions will help to improve the quality of care provided, the nature of program evaluation activities, as well as the overall level of FCS in pediatric rehabilitation settings. Implications for Rehabilitation By incorporating family-centered activities into program evaluation processes, clinicians/evaluators can improve the overall level of and adherence to FCS philosophy in their centers, enhance the quality of care provided and, thus, contribute positively to the outcomes of program recipients and their families. Those evaluating pediatric rehabilitation programs need to use evaluation approaches and activities that respect the needs, characteristics, cultures and diversity of the program recipients. By engaging program recipients and their families in program development, they may become more engaged in program evaluation. 22748289 Permanent seed brachytherapy for locally recurrent prostate cancer after radical prostatectomy: a case report and review of the literature. To describe the management of a patient with locally recurrent prostate cancer in the prostate bed, 10 years after a radical prostatectomy. A 71-year-old man had a radical prostatectomy for a Gleason 7 clinical T2a carcinoma of the prostate in 2000. Final pathologic stage was pT3a pN0. Postoperatively his prostate-specific antigen was undetectable, but by 2008 it was 1.0ng/mL and in 2011 it reached to 1.43ng/mL. He was referred for consideration of salvage radiotherapy. Staging workup was negative but transrectal ultrasound revealed a 15cc recurrence in the prostate bed. A combination of external beam radiation therapy (4600/23/4.5 weeks to the pelvis) and a brachytherapy boost (115Gy) was selected for definitive management. Androgen ablation was not used. The treatment was well tolerated. The brachytherapy boost was planned in a similar fashion to a de novo implant for an intact prostate. The postimplant dosimetry was evaluated using magnetic resonance imaging-computed tomography (MR-CT) fusion and appeared satisfactory. Acute toxicity was minimal. Six months after brachytherapy, the prostate-specific antigen had fallen from 1.43 to 0.05ng/mL. Dose escalation with combined external beam and brachytherapy may be feasible if recurrent disease can be visualized using transrectal ultrasound and encompassed in an implanted volume. Although longer followup and a larger series of patients are required to demonstrate safety and efficacy, consideration should be given this approach. 23280968 Bayesian analysis of recurrent event with dependent termination: an application to a heart transplant study. For a heart transplant patient, the risk of graft rejection and risk of death are likely to be associated. Two fully specified Bayesian models for recurrent events with dependent termination are applied to investigate the potential relationships between these two types of risk as well as association with risk factors. We particularly focus on the choice of priors, selection of the appropriate prediction model, and prediction methods for these two types of risk for an individual patient. Our prediction tools can be easily implemented and helpful to physicians for setting heart transplant patients' biopsy schedule. 23680416 Substantia nigra echogenicity is correlated with nigrostriatal impairment in Machado-Joseph disease. Several studies have demonstrated increased substantia nigra (SN) echogenicity in Parkinson's disease (PD) and Machado-Joseph disease (MJD). Pathological substrate of PD is characterized by dopaminergic nigrostriatal cell loss, also found in MJD. Also, SN hyperechogenicity might be associated with nigrostriatal dysfunction in PD, when comparing dopamine transporter binding with SN echogenicity. The present study aimed to correlate the SN echogenic size and striatal dopamine transporter density in MJD patients. We performed TCS in 30 subjects and SPECT with [(99m)Tc]-TRODAT-1 in 18 subjects with MJD. Fifteen healthy subjects matched for age and gender formed a control group. TCS and [(99m)Tc]-TRODAT-1 SPECT findings from both MJD patients and control subjects were compared. There were no differences regarding age (p = 0.358) or gender (p = 0.566) between groups (MJD versus control group). Mean DAT binding potentials and SN echogenicity were significantly different between groups. There was a significant negative correlation with regard to the SN echogenic size and the ipsilateral striatal TRODAT-1 uptake: the higher the SN echogenicity, the lower the DAT uptake in the ipsilateral cerebral hemisphere. Increase in SN echogenic size likely correlates with presynaptic dopaminergic nigrostriatal dysfunction in MJD, suggesting a concurrent in vivo pathophysiological mechanism. 23913120 A dynamic interplay between alternative polyadenylation and microRNA regulation: Implications for cancer (Review). Alternative polyadenylation and microRNA regulation are both mechanisms of post-transcriptional regulation of gene expression. Alternative polyadenylation often results in mRNA isoforms with the same coding sequence but different lengths of 3' UTRs, while microRNAs regulate gene expression by binding to specific mRNA 3' UTRs. In this sense, different isoforms of an mRNA may be differentially regulated by microRNAs, sometimes resulting in cellular proliferation and this mechanism is being speculated on as a potential cause for cancer development. 23955939 Integrated pest management concepts for red imported fire ants Solenopsis invicta (Hymenoptera: Formicidae). Management of imported fire ant species has evolved since their accidental introduction into the United States and currently uses integrated pest management concepts to design, implement, and evaluate suppression programs. Although eradication is the management goal in certain isolated infestation sites, localized goals vary dramatically in larger infestations where reinvasion of treated areas is likely. These goals are influenced by regulatory policies, medical liabilities, ecological impact, and/or economic considerations. Tactics employed in fire ant management programs presented here include cultural and biological control options along with judicious use of site-specific insecticide products. In addition, program design considerations that include management goal(s), action level(s), ant form (monogyne or polygyne), presence of nontarget ant species, size of treatment area, seasonality, implementation cost, and environmental impact are also presented. Optimally, elegant IPM programs are target specific, threshold driven, environmentally friendly and cost-effective. 23180675 Lattice deformation and domain distortion in the self-assembly of block copolymer thin films on chemical patterns. The self-assembly of cylinder-forming block copolymer (BCP) microdomains confined within chemical stripe patterns of widths incommensurate with the natural period of the copolymers, L0 , is studied. It is shown that this incommensurability causes changes in both the shapes of the microdomains and their spatial period. Specifically, a transition from n to n + 1 rows of microdomains is observed when the stripe width is about n ± 1/2 L0 . When the stripe's width is comparable to L0 , ellipticity of microdomains can be induced with an aspect ratio up to 2.2. Free energy models are applied to describe the energetic origin of such behavior. Although our observations qualitatively resemble results in sphere-forming BCPs confined in topographical trenches, the quantitative difference is noteworthy and technologically important for the design of nanostructures with programmable shapes. 23845744 Clinical evidence on high flow oxygen therapy and active humidification in adults. Recently there has been growing interest in an alternative to conventional oxygen therapy: the heated, humidified high flow nasal cannula oxygen therapy (HFNC). A number of physiological effects have been described with HFNC: pharyngeal dead space washout, reduction of nasopharyngeal resistance, a positive expiratory pressure effect, an alveolar recruitment, greater humidification, more comfort and better tolerance by the patient, better control of FiO2 and mucociliary clearance. There is limited experience of HFNC in adults. There are no established guidelines or decision-making pathways to guide use of the HFNC therapy for adults. In this article we review the existing evidence of HFNC oxygen therapy in adult patients, its advantages, limitations and the current literature on clinical applications. Further research is required to determine the long-term effect of this therapy and identify the adult patient population to whom it is most beneficial. 23881229 TREATMENT OF RETINAL DETACHMENT SECONDARY TO MACULAR HOLE IN HIGHLY MYOPIC EYES: Pars Plana Vitrectomy with Internal Limiting Membrane Peel and Silicon Oil Tamponade. To evaluate efficacy of vitrectomy with internal limiting membrane peel and silicon oil tamponade in highly myopic eyes with retinal detachment secondary to macular hole (MH). Twenty-one consecutive cases of MH-retinal detachment in highly myopic eyes were retrospectively reviewed. Eyes underwent pars plana vitrectomy, internal limiting membrane peeling, and silicon oil tamponade. A face-down or side-lying position was maintained postoperatively. Silicon oil was removed 3 months to 12 months later. Outcomes included MH closure and retinal reattachment rates, best-corrected visual acuity, and complication rates. Mean patient age was 59.3 ± 6.5 years and mean spherical equivalent was -15.2 ± 4.3 diopters. After silicon oil removal, 18 eyes (86%) had MH closure with retinal reattachment and 2 eyes needed reattachment with endolaser photocoagulation and fluid/gas exchange, and 1 patient refused further treatment. At the last follow-up, median best-corrected visual acuity was +1.48 ± 0.12, up from preoperative +2.11 ± 0.17 (P = 0.03). Transient intraocular pressure elevation was observed in 11 eyes (52%). Iatrogenic retinal break occurred in one case. Combining pars plana vitrectomy with internal limiting membrane peel and silicon oil tamponade was safe and effective in treating MH-retinal detachment in highly myopic eyes. Silicon oil tamponade may improve initial anatomical success rates because of longer tamponade duration. 23443821 Oncoplastic breast surgery combining periareolar mammoplasty with volume displacement using a crescent-shaped cutaneous flap for early breast cancer in the upper quadrant. Oncoplastic breast surgery (OBS), which combines the concepts of oncological and plastic surgery, is becoming more common, especially in Western countries; however, only a few reports have been published in Japan. We herein report the results of OBS for Japanese patients with early breast cancer in the upper quadrant. We performed oncoplastic surgery combining partial mastectomy using a periareolar incision with immediate breast reshaping using a crescent-shaped cutaneous flap in three patients with a past history of breast-feeding, ptotic breasts and lesions that were suitable for breast conserving surgery. The lesions were located in the upper quadrant and were 5, 6 and 10 cm from the nipple, respectively. The total length of the operations ranged between 86 and 192 min, with the mean being 164 min. Two patients underwent contralateral surgery to produce symmetrical breasts and one did not. The plastic period after receiving pathological results intraoperatively ranged between 47 and 120 min, with the mean period being 82 min. The observation period ranged between 6 and 12 months, and the cosmetic results were excellent in all three cases. OBS combining partial mastectomy using a periareolar incision with immediate breast reshaping using a crescent-shaped cutaneous flap was successfully performed in patients with early cancer in the upper quadrant. 23784885 MF interactions and heterobimetallics: furthering the understanding of heterobimetallic stabilization. Heterobimetallic complexes containing alkali, alkaline-earth, and divalent europium metals utilizing the perfluoro-tert-butoxide (PFTB) ligand following the general formula, [AM(PFTB)3 (co-ligand)x ] (A=Na, K; M=Mg, Sr, Ba, Eu; co-ligand=THF, toluene), have been isolated. These compounds sublime at low temperatures with low residual weight indicating their potential as metal-organic chemical-vapor deposition (MOCVD) precursors. The complexes have unique molecular architectures that are strongly influenced by MF interactions, as was verified in the solid state by using X-ray crystallography. The significance of these interactions were further reinforced by bond-valence sums analysis and (19) F VT-NMR spectroscopy, in which rotational energies of 18.75 and 19.08 kcal mol(-1) were measured. 23748566 Chromosomal deletions and inversions mediated by TALENs and CRISPR/Cas in zebrafish. Customized TALENs and Cas9/gRNAs have been used for targeted mutagenesis in zebrafish to induce indels into protein-coding genes. However, indels are usually not sufficient to disrupt the function of non-coding genes, gene clusters or regulatory sequences, whereas large genomic deletions or inversions are more desirable for this purpose. By injecting two pairs of TALEN mRNAs or two gRNAs together with Cas9 mRNA targeting distal DNA sites of the same chromosome, we obtained predictable genomic deletions or inversions with sizes ranging from several hundred bases to nearly 1 Mb. We have successfully achieved this type of modifications for 11 chromosomal loci by TALENs and 2 by Cas9/gRNAs with different combinations of gRNA pairs, including clusters of miRNA and protein-coding genes. Seven of eight TALEN-targeted lines transmitted the deletions and one transmitted the inversion through germ line. Our findings indicate that both TALENs and Cas9/gRNAs can be used as an efficient tool to engineer genomes to achieve large deletions or inversions, including fragments covering multiple genes and non-coding sequences. To facilitate the analyses and application of existing ZFN, TALEN and CRISPR/Cas data, we have updated our EENdb database to provide a chromosomal view of all reported engineered endonucleases targeting human and zebrafish genomes. 23963998 Nineteen-channel receive array and four-channel transmit array coil for cervical spinal cord imaging at 7T. To design and validate a radiofrequency (RF) array coil for cervical spinal cord imaging at 7T. A 19-channel receive array with a four-channel transmit array was developed on a close-fitting coil former at 7T. Transmit efficiency and specific absorption rate were evaluated in a B1 (+) mapping study and an electromagnetic model. Receive signal-to-noise ratio (SNR) and noise amplification for parallel imaging were evaluated and compared with a commercial 3T 19-channel head-neck array and a 7T four-channel spine array. The performance of the array was qualitatively demonstrated in human volunteers using high-resolution imaging (down to 300 μm in-plane). The transmit and receive arrays showed good bench performance. The SNR was approximately 4.2-fold higher in the 7T receive array at the location of the cord with respect to the 3T coil. The g-factor results showed an additional acceleration was possible with the 7T array. In vivo imaging was feasible and showed high SNR and tissue contrast. The highly parallel transmit and receive arrays were demonstrated to be fit for spinal cord imaging at 7T. The high sensitivity of the receive coil combined with ultra-high field will likely improve investigations of microstructure and tissue segmentation in the healthy and pathological spinal cord. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc. 22566709 Common mental disorders in immigrant and second-generation respondents: Results from the Israel-based World Mental Health Survey. The contrasting social status of ethnic groups differentially impacts the mental health of their members. This may be the case in Israel despite its egalitarian ideology. However, studies are a few and limited in scope. To study mental health disparities between immigrant and second-generation disadvantaged and advantaged Jewish groups. Data were extracted from the Israel World Mental Health Survey. This included the Composite International Diagnostic Interview and the General Health Questionnaire. We compared 547 first-generation immigrants born in North Africa/Asia and 708 born in Europe/America; and 707 second-generation immigrants of North African/Asian origin and 449 of European/American origin. The prevalence rate of common mental disorders in the preceding year was approximately double for respondents of North African/Asian origin compared with their European/American counterparts following adjustment for socio-demographic confounders. Inmigrants: North African/Asian 12.4%, SE = 1.5; European/American 6.4%, SE = 1.0 (AOR = 2.1, 95% CI 1.4-3.4). Second generation: North African/Asian 10.1%, SE = 1.2; European/American 5.4%, SE = 1.1 (AOR = 1.7, 95% CI 1.1-3.2). Significant differences in emotional distress mean scores were observed only among second-generation respondents: North African/Asian respondents reported higher emotional distress (M = 18.7, SE = 0.5) compared with European/American (M = 17.3, SE = 0.4) (Wald F = 13.31, p < .001). s showed disparities in the mental health measures in both generations. It is likely that social causation factors, such as restricted opportunities in the context of higher aspirations, partially account for the findings. 23354152 Improved pharmaceutical stability of a boronphenylalanine mannitol formulation for boron neutron capture therapy. Boron neutron capture therapy (BNCT) is a radiotherapy based cancer treatment requiring the availability of a low energy thermal neutron beam and a boron containing drug. These requirements limit BNCT availability with the latter pharmaceutical issue related to the extremely short shelf-life and clinical acceptability of the current fructose based L-boronphenylalanine (BPA) formulation. Resolution of the formulation issues would remove this factor and therefore the stability of an alternative mannitol BPA formulation has been investigated. A mannitol BPA solution formulation was prepared and either lyophilised or stored as a solution at varying temperatures. After suitable periods the formulation was analysed by HPLC for BPA and degradation products. Lyophilised and solution mannitol BPA formulations exhibited a temperature and time dependent loss of BPA with concomitant increases in degradation products. Autoclaving the solution induced and accelerated degradation. A solution or lyophilised mannitol BPA formulation has a shelf-life of between 1 and 4 years respectively, a marked improvement over the current fructose formulation. Due to temperature dependent degradation the formulation cannot be terminally sterilised by autoclaving. The enhanced stability of the mannitol formulation removes the requirement for extemporaneous aseptic preparation of BPA just prior to treatment and eliminates one of the issues complicating the delivery of BNCT. 23955062 Nucleophilic addition of carborane anion to Ir, Rh-coordinated Cp* ring: C-C bond formation accompanied by reduction of metal center. Reaction of carboranyl anion or its thiolate derivative with a fully-substituted Cp*-based group 9 (Ir, Rh) metal complex affords respectively a C-C bond formation complex and a salt metathesis product. This example represents the first nucleophilic addition attempt in the area of M-Cp* chemistry. 23946299 Temperature and risk of stroke mortality in China. Based on the latest Global Burden of Disease assessment, stroke is a leading cause of mortality, and years of life lost from stroke have increased in recent years.(1) The health burden of stroke is higher in China than in other regions.(2) This study provides the most comprehensive estimates to date of how risk of stroke mortality is influenced by extreme temperatures in China.(3) The authors applied commonly used statistical approaches to data on 8 large Chinese cities with populations over 47 million. The key contribution of this work is scientific evidence on weather and health for a health outcome and region that are not well-studied in the scientific literature. 23882177 Bidirectional modulation of infralimbic dopamine D1 and D2 receptor activity regulates flexible reward seeking. The development of addictive behavior is marked by a loss of behavioral flexibility. In part, this is due to an increase in the ability of environmental stimuli to elicit responding and decreased importance of the action-outcome relationship in behavioral control. It has previously been demonstrated that both inactivation of and dopamine (DA) infusions in the infralimbic prefrontal cortex (PFC) can restore behavioral flexibility in paradigms measuring habitual reward seeking. Here, we investigated the mechanism by which cortical DA would act to enable goal-directed actions after the transition to habitual behavior has been established. Further, we extended this work to include a novel mouse model of compulsive-like behavior in which we assessed reward seeking despite the possibility of adverse consequences. Our data show that DA receptor D1 inhibition or D2 activation both promote the expression of a flexible responding after the development of habitual or compulsive-like behavior, and we suggest that the ability of DA infusions in the infralimbic PFC to restore sensitivity to changes in outcome value depends on activation of DA D2 receptors. 23935503 Distinct binding and immunogenic properties of the gonococcal homologue of meningococcal factor h binding protein. Neisseria meningitidis is a leading cause of sepsis and meningitis. The bacterium recruits factor H (fH), a negative regulator of the complement system, to its surface via fH binding protein (fHbp), providing a mechanism to avoid complement-mediated killing. fHbp is an important antigen that elicits protective immunity against the meningococcus and has been divided into three different variant groups, V1, V2 and V3, or families A and B. However, immunisation with fHbp V1 does not result in cross-protection against V2 and V3 and vice versa. Furthermore, high affinity binding of fH could impair immune responses against fHbp. Here, we investigate a homologue of fHbp in Neisseria gonorrhoeae, designated as Gonococcal homologue of fHbp (Ghfp) which we show is a promising vaccine candidate for N. meningitidis. We demonstrate that Gfhp is not expressed on the surface of the gonococcus and, despite its high level of identity with fHbp, does not bind fH. Substitution of only two amino acids in Ghfp is sufficient to confer fH binding, while the corresponding residues in V3 fHbp are essential for high affinity fH binding. Furthermore, immune responses against Ghfp recognise V1, V2 and V3 fHbps expressed by a range of clinical isolates, and have serum bactericidal activity against N. meningitidis expressing fHbps from all variant groups. 23908690 Loss of PI(4,5)P2 5-Phosphatase A Contributes to Resistance of Human Melanoma Cells to RAF/MEK Inhibitors. Past studies have shown that the inositol polyphosphate 5-phosphatase, phosphatidylinositol 4,5-bisphosphate 5-phosphatase (PIB5PA), is commonly downregulated or lost in melanomas, which contributes to elevated activation of phosphatidylinositol 3-kinase (PI3K)/Akt in melanoma cells. In this report, we provide evidence that PIB5PA deficiency plays a role in resistance of melanoma cells to RAF/mitogen-activated protein kinase kinase (MEK) inhibitors. Ectopic expression of PIB5PA enhanced apoptosis induced by the RAF inhibitor PLX4720 in BRAF(V600E) and by the MEK inhibitor U0126 in both BRAF(V600E) and wild-type BRAF melanoma cells. This was due to inhibition of PI3K/Akt, as co-introduction of an active form of Akt (myr-Akt) abolished the effect of overexpression of PIB5PA on apoptosis induced by PLX4720 or U0126. While overexpression of PIB5PA triggered activation of Bad and down-regulation of Mcl-1, knockdown of Bad or overexpression of Mcl-1 recapitulated, at least in part, the effect of myr-Akt, suggesting that regulation of Bad and Mcl-1 is involved in PIB5PA-mediated sensitization of melanoma cells to the inhibitors. The role of PIB5PA deficiency in BRAF inhibitor resistance was confirmed by knockdown of PIB5PA, which led to increased growth of BRAF(V600E) melanoma cells selected for resistance to PLX4720. Consistent with its role in vitro, overexpression of PIB5PA and the MEK inhibitor selumetinib cooperatively inhibited melanoma tumor growth in a xenograft model. Taken together, these results identify loss of PIB5PA as a novel resistance mechanism of melanoma to RAF/MEK inhibitors and suggest that restoration of PIB5PA may be a useful strategy to improve the therapeutic efficacy of the inhibitors in the treatment of melanoma. 23454144 Role of oxidative stress in chemical allergens induced skin cells activation. Allergic contact dermatitis (ACD) is an important occupational and environmental disease caused by topical exposure to chemical allergens. It describes the adverse effects that may results when exposure to a chemical elicits a T cell-mediated inflammatory skin disease. The ability of contact sensitizers to induce the oxidative stress pathway in keratinocytes and dendritic cells has been confirmed by several authors. Reactive oxygen species (ROS) can serve as essential second messengers mediating cellular responses resulting in immune cells activation. Oxidative stress may be the starter point, as it leads to the activation of transcription factors and signaling pathways, including NF-kB and p38 MAPK, which leads to the release of cytokines and chemokines. ROS are also involved in the activation of the NLRP3/NALP3 inflammasome, which is required to direct the proteolytic maturation of inflammatory cytokines such as IL-1β and IL-18, which are all integral to the process of dendritic cells mobilization, migration and functional maturation. Moreover, emerging evidence correlates ROS to changes in the constitution of the extracellular microenvironment found to facilitate ACD. The purpose of this review is to provide both conceptual and technical frameworks on the role of oxidative stress in chemical allergy. 23249208 Fe(II) sorption on a synthetic montmorillonite. A combined macroscopic and spectroscopic study. Extended X-ray absorption fine structure (EXAFS) and Mössbauer spectroscopy combined with macroscopic sorption experiments were employed to investigate the sorption mechanism of Fe(II) on an iron-free synthetic montmorillonite (Na-IFM). Batch sorption experiments were performed to measure the Fe(II) uptake on Na-IFM at trace concentrations as a function of pH and as a function of sorbate concentration at pH 6.2 and 6.7 under anoxic conditions (O2 < 0.1 ppm). A two-site protolysis nonelectrostatic surface complexation and cation exchange sorption model was used to quantitatively describe the uptake of Fe(II) on Na-IFM. Two types of clay surface binding sites were required to model the Fe(II) sorption, the so-called strong (≡S(S)OH) and weak (≡S(W)OH) sites. EXAFS data show spectroscopic differences between Fe sorbed at low and medium absorber concentrations that were chosen to be characteristic for sorption on strong and weak sites, respectively. Data analysis indicates that Fe is located in the continuity of the octahedral sheet at trans-symmetric sites. Mössbauer spectroscopy measurements confirmed that iron sorbed on the weak edge sites is predominantly present as Fe(II), whereas a significant part of surface-bound Fe(III) was produced on the strong sites (∼12% vs ∼37% Fe(III) species to total sorbed Fe). 23927314 Failure-probability driven dose painting. Purpose: To demonstrate a data-driven dose-painting strategy based on the spatial distribution of recurrences in previously treated patients. The result is a quantitative way to define a dose prescription function, optimizing the predicted local control at constant treatment intensity. A dose planning study using the optimized dose prescription in 20 patients is performed.Methods: Patients treated at our center have five tumor subvolumes from the center of the tumor (PET positive volume) and out delineated. The spatial distribution of 48 failures in patients with complete clinical response after (chemo)radiation is used to derive a model for tumor control probability (TCP). The total TCP is fixed to the clinically observed 70% actuarial TCP at five years. Additionally, the authors match the distribution of failures between the five subvolumes to the observed distribution. The steepness of the dose-response is extracted from the literature and the authors assume 30% and 20% risk of subclinical involvement in the elective volumes. The result is a five-compartment dose response model matching the observed distribution of failures. The model is used to optimize the distribution of dose in individual patients, while keeping the treatment intensity constant and the maximum prescribed dose below 85 Gy.Results: The vast majority of failures occur centrally despite the small volumes of the central regions. Thus, optimizing the dose prescription yields higher doses to the central target volumes and lower doses to the elective volumes. The dose planning study shows that the modified prescription is clinically feasible. The optimized TCP is 89% (range: 82%-91%) as compared to the observed TCP of 70%.Conclusions: The observed distribution of locoregional failures was used to derive an objective, data-driven dose prescription function. The optimized dose is predicted to result in a substantial increase in local control without increasing the predicted risk of toxicity. 23903010 Alterations in Chemokine Receptor CCR5 Expression on Blood Dendritic Cells Correlate With Acute Graft-Versus-Host Disease. Dendritic cells (DC) are important in the development of acute graft-versus-host disease (GVHD) after allogeneic hemopoietic cell transplantation (alloHCT). The trafficking of immature DC from blood to GVHD target organs is likely to be regulated by chemokine receptors. We performed flow cytometry to document the expression of chemokine receptors on circulating DC and correlated the findings after alloHCT with occurrence of acute GVHD. In normal individuals, plasmacytoid DC (pDC) expressed high levels of CCR5, whereas the major CD16 myeloid DC subpopulation lacked CCR5. However, its expression on CD16 cells was induced by culture in allogeneic mixed lymphocyte reaction supernatant, an effect largely mediated by interferon-γ. CCR5 was expressed on a significant proportion of CD16 DC in 42 alloHCT patients, whereas it was down-regulated on pDC. The maximum percentage of CCR5CD16 DC, at any time after transplantation, correlated with acute GVHD, whereas the minimum CCR5 on pDC showed a similar correlation. Before developing signs of GVHD, the maximum percentage CCR5CD16 DC was higher in patients with GVHD grades II to IV than in GVHD grades 0 and I, whereas the minimum percentage CCR5 on pDC was lower in GVHD grades II to IV than in GVHD grades 0 and I. CCR5 levels more than 20.5% on CD16 myeloid DC and less than 22.6% on CD123 pDC correlated with subsequent GVHD grades II to IV with high sensitivities and specificities. These observations may reflect DC activation and altered homing during the alloimmune response and could allow early diagnosis and therapeutic intervention before the clinical diagnosis of GVHD. 21519219 Ideal antiplatelet therapy for coronary artery disease: focus on adenosine diphosphate receptor inhibitors. With the increasing prevalence of coronary artery disease, antiplatelet therapy after percutaneous coronary intervention is becoming more important. As such realm is still very dynamic, it is important for clinicians to understand the evolution of antiplatelet therapies and current issues that are yet to be settled in the search for an ideal antiplatelet agent. Electronic searches were done using databases such as PubMed and Cochrane Library with appropriate keywords. Randomized controlled trials and retrospective studies found were then assessed for quality, and their references used to find additional studies. The field of study regarding the antiplatelet therapy is still an area in which much has yet to be found. Although clopidogrel and aspirin are cornerstones of therapy currently, other agents such as ticagrelor offer potential alternatives. This review presents an overview of current antiplatelet therapies and their relative risks and benefits. 23828513 A Highly Selective Turn-On Fluorescent Chemosensor for Zinc Ion in Aqueous Media. In the paper, a novel rhodamine6G based fluorescent chemosensor bearing 3-carbaldehyde chromone was designed and synthesized. According to the fluorescence behavior toward several metal ions, it showed highly selectivity and sensitivity to Zn(II) over other commonly coexistent metal ions (Cu(II), Cd(II), Hg(II), Mg(II), K(I), Pb(II), Fe(III) and Cr(III)) in aqueous environment (pH = 7.4). Meanwhile the binding constant between Zn(II) and chemosensor achieved 6.21 × 10(11) M(-1) in aqueous media. Moreover, according to the Job plot, 1:1 stoichiometry between Zn(II) and sensor was deduced in aqueous media (pH = 7.4). The good selectivity and sensitivity in aqueous media effectively enhanced the application value of the fluorescent chemosensor for Zn(II). 23684823 Immunogenicity and safety of pneumococcal conjugate polysaccharide and free polysaccharide vaccines alone or combined in HIV-infected adults in Brazil. Streptococcus pneumoniae is a leading cause of hospitalization in HIV-infected adults therefore pneumococcal vaccine is recommended. The ideal antipneumococcal vaccine and effective vaccination regimen remain controversial and needs further evaluation. To assess the efficacy of pneumococcal vaccines alone and combined, a randomized, blinded clinical trial was conducted in Brazil with 331 HIV-patients aged 18-60, with CD4-T cell count ≥200cells/mm(3). Two interventions 60 days apart were done in three schedules: 23-valent pneumococcal polysaccharide vaccine (PPV23)/placebo; 7-valent pneumococcal conjugate vaccine (PCV7)/placebo; and PCV7 plus PPV23. Safety and reactogenicity were evaluated, and immunogenicity was assessed by an IgG enzyme-linked immunosorbent assay to S. pneumoniae serotypes 6B, 9V and 14, performed at baseline, 60 and 180 days after first intervention. Comparison of immunogenicity was based on geometric mean concentration (GMC), percentages of individuals with serotype-specific IgG≥0.35μg/mL and ≥1.0μg/mL and proportion of individuals with ≥4-fold increase in specific antibody concentrations for each serotype. Demographic and HIV conditions were similar, and both vaccines were well tolerated across vaccine groups. Significant increase in IgG-antibodies was observed to all serotypes evaluated. A greater proportion of PCV7 recipients reached and sustained IgG antibody concentrations at least four times as high as those at baseline, for serotypes 6B and 9V. A PPV23 dose after PCV7 did not enhance immunogenicity. In this first trial conducted with HIV-infected immunologically stable adults in South America, both PPV23 and PCV7 were safe and immunogenic. Evidence suggesting PCV7 was more immunogenic than PPV23, as it elicited higher and persistent ≥4-fold increase of antibodies for 6B and 9V serotypes in a greater proportion of HIV-patients is noteworthy. Despite current recommendation of schedules combining PCV7 and PPV23, there is little evidence to support this practice and we did not observe benefits in this combination. 23535530 Apixaban: a new factor Xa inhibitor for stroke prevention in patients with nonvalvular atrial fibrillation. Atrial fibrillation (AF) is an independent risk factor for ischemic stroke occurrence, severity, recurrence, and mortality. Anticoagulation therapy for the prevention of thromboembolism is critical in patients with AF who are at risk of stroke. Warfarin has been an efficacious anticoagulant for this purpose, but its use has been limited by frequent laboratory monitoring, drug interactions, unpredictable individual response, delayed onset of action, and bleeding. Apixaban is the second oral direct selective factor Xa inhibitor approved for the prevention of stroke/systemic embolism in patients with nonvalvular AF. It was significantly better than aspirin in reducing stroke (ischemic or hemorrhagic) or systemic embolism without increasing the risk of major bleeding in patients with AF who were at increased risk of stroke and for whom warfarin was unsuitable. In a randomized, double-blind trial that was originally designed to test for noninferiority, apixaban was superior to warfarin (target international normalized ratio 2-3) in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality in patients with AF. Apixaban has a half-life of about 12 hours, and the normal dosage is 5 mg orally twice daily. However, it may be reduced to 2.5 mg twice daily based on individual factors of the patient (age, renal function, and body weight) and the concomitant use of potent dual inhibitors of cytochrome P450 3A4 and P-glycoprotein. Similar to other novel oral anticoagulants (dabigatran and rivaroxaban), apixaban has no reversal agent for its anticoagulant effect. Overall, apixaban is a safe and efficacious alternative for stroke prophylaxis in high-risk patients who have AF and who are unable to achieve therapeutic goals with warfarin therapy. 23970475 Laryngeal hibernoma: Case series of a rare tumor. Background: Hibernomas are rare, benign tumors of brown adipose tissue uncommonly found in the head and neck. Methods: A review of the English literature was conducted. We present a series of 2 laryngeal hibernomas treated with transoral laser microsurgical resection at a tertiary referral center over a period of 18 years. Results: Only 2 cases of laryngeal hibernoma have been previously described in the literature. Two additional cases were encountered at our institution. Preoperative imaging demonstrated a well-circumscribed neoplasm with fat density compatible with lipoma, but internal heterogeneity and vascularity seen in the context of liposarcoma. Transoral laser microsurgical resection was successfully performed in each case. Conclusions: Despite unique radiographic features, hibernomas are difficult to distinguish from well-differentiated liposarcoma and lipoma variants without pathologic correlation. Complete surgical resection is indicated. In our experience, transoral laser microsurgical excision of laryngeal hibernomas is a safe, effective treatment modality with little associated morbidity. Head Neck, 2013. 23911948 Cognitive decline in prodromal Huntington Disease: implications for clinical trials. Controversy exists regarding the feasibility of preventive clinical trials in prodromal Huntington disease (HD). A primary limitation is a lack of outcome measures for persons with the gene mutation who have not yet been diagnosed with HD. Many longitudinal studies of cognitive decline in prodromal HD have not stratified samples based on disease progression, thereby obscuring differences between symptomatic and nonsymptomatic individuals. Prodromal participants from PREDICT-HD were stratified by disease progression into one of three groups: those having a High, Medium, or Low probability of motor manifestation within the next 5 years. Data from a total of N=1299 participants with up to 5950 data points were subjected to linear mixed effects regression on 29 longitudinal cognitive variables, controlling for age, education, depression, and gender. Performance of the three prodromal HD groups was characterised by insidious and significant cognitive decline over time. Twenty-one variables from 19 distinct cognitive tasks revealed evidence of a disease progression gradient, meaning that the rate of deterioration varied as a function of progression level, with faster deterioration associated with greater disease progression. Nineteen measures showed significant longitudinal change in the High group, nine showed significant change in the Medium group and four showed significant cognitive decline in the Low group. Results indicate that clinical trials may be conducted in prodromal HD using the outcome measures and methods specified. The findings may help inform interventions in HD as well as other neurodegenerative disorders. 23912649 Vascular Endothelial Cell Injury Partly Induced by Mesenteric Lymph in Heat Stroke. Animal models have shown that mesenteric lymph plays important roles in the pathogenesis of endothelium injury in many critical ill states. Gut-derived septicemia and endothelium injury are the two key pathogenesis of heat stroke (HS); however, it is unclear whether mesenteric lymph is cytotoxic to endothelium in HS. HS rat models were prepared in a prewarmed incubator. Mesenteric lymph, collected pre-, during, and post-HS, was analyzed for biological activity on human umbilical vein endothelial cell (HUVEC) in vitro. The effect of HS lymph on the production of von Willebrand factor (vWF), thrombomodulin (TM), and IL-6 by HUVEC was investigated. In vivo, vascular endothelium injury biomarkers, circulating endothelial cell (CEC), as well as serum soluble vWF and TM were tested in rats of HS and HS with mesenteric lymph duct ligation (HS-LDL). HS but not heat stroke sham mesenteric lymph-injured endothelial cells showed significantly increased HUVEC cytotoxicity and enhanced HUVEC monolayer permeability as well as elevated levels of vWF and TM production by HUVEC. IL-6 production by HUVEC was augmented by HS lymph in vitro. The effects of HS lymph on IL-6 production had a time course resembling that of the toxic effects of HS lymph on HUVEC. In vivo, when compared with HS rats, decreased CEC counts as well as lower serum vWF and TM concentrations were detected in HS-LDL rats. HS mesenteric lymph is probably harmful to vascular endothelium, which indicates that the modulation of mesenteric lymph may have some potential benefits to HS. 23500384 The application of a DNA-based identification technique to over-the-counter herbal medicines. Reliable methods to identify medicinal plant material are becoming more important in an increasingly regulated market place. DNA-based methods have been recognised as a valuable tool in this area with benefits such as being unaffected by the age of the plant material, growth conditions and harvesting techniques. It is possible that the methods of production used for medicinal plant products will degrade or remove DNA. So how applicable are these techniques to processed medicinal plant products? A simple PCR-based identification technique has been developed for St. John's Wort, Hypericum perforatum L. Thirteen St. John's Wort products were purchased including capsules, tablets and tinctures. DNA was extracted from each product, and the species specific PCR test conducted. DNA was successfully extracted from all thirteen products, using a fast and efficient modified method for extracting DNA from tinctures. Only four products yielded the full length ITS region (850bp) due to the quality of the DNA. All of the products tested positive for H. perforatum DNA. DNA-based identification methods can complement existing methods of authentication. This paper shows that these methods are applicable to a wide range of processed products, provided that they are designed to account for the possibility of DNA degradation. 23129525 Arsenic and arsenic species in cultured oyster (Crassostrea gigas and C. corteziensis) from coastal lagoons of the SE Gulf of California, Mexico. The aim of this study was to evaluate the bioavailability of arsenic (As) through cultured oyster Crassostrea gigas and Crassostrea corteziensis from four coastal lagoons (SE Gulf of California). Organisms were collected in two seasons (rainy and dry season), and they were analyzed for total arsenic and chemical speciation of this element. The concentrations of As in oyster soft tissue fluctuated between 5.44 and 9.56 μg/g for rainy season and 6.46 and 8.33 μg/g for dry season (dry weight) in C. gigas. In C. corteziensis, the As concentrations were <5 μg/g for both seasons (dry weight). Arsenic speciation indicated arsenobetaine as the major arseno-compound accounting for 43.2-76.3 % of total content of As. Lower contributions were obtained for non-extractable As (11.3-17.5 %) and other molecules such as arsenocholine and methyl-arsonate (<5 %). Inorganic arsenic was detectable in only two samples, at concentrations lower than <0.1 μg/g. These As data are the first generated for these mollusks in NW Mexico and indicate that C. gigas and C. corteziensis farmed in this area are safe for human consumption in terms of arseno-compounds. 23856015 'Help for Hay Fever', a goal-focused intervention for people with intermittent allergic rhinitis, delivered in Scottish community pharmacies: study protocol for a pilot cluster randomized controlled trial. Despite the availability of evidence-based guidelines for managing allergic rhinitis in primary care, management of the condition in the United Kingdom (UK) remains sub-optimal. Its high prevalence and negative effects on quality of life, school performance, productivity and co-morbid respiratory conditions (in particular, asthma), and high health and societal costs, make this a priority for developing novel models of care. Recent Australian research demonstrated the potential of a community pharmacy-based 'goal-focused' intervention to help people with intermittent allergic rhinitis to self-manage their condition better, reduce symptom severity and improve quality of life. In this pilot study we will assess the transferability of the goal-focused intervention to a UK context, the suitability of the intervention materials, procedures and outcome measures and collect data to inform a future definitive UK randomized controlled trial (RCT). A pilot cluster RCT with associated preliminary economic analysis and embedded qualitative evaluation. The pilot trial will take place in two Scottish Health Board areas: Grampian and Greater Glasgow & Clyde. Twelve community pharmacies will be randomly assigned to intervention or usual care group. Each will recruit 12 customers seeking advice or treatment for intermittent allergic rhinitis. Pharmacy staff in intervention pharmacies will support recruited customers in developing strategies for setting and achieving goals that aim to avoid/minimize triggers for, and eliminate/minimize symptoms of allergic rhinitis. Customers recruited in non-intervention pharmacies will receive usual care. The co-primary outcome measures, selected to inform a sample size calculation for a future RCT, are: community pharmacy and customer recruitment and completion rates; and effect size of change in the validated mini-Rhinoconjunctivitis Quality of Life Questionnaire between baseline, one-week and six-weeks post-intervention. Secondary outcome measures relate to changes in symptom severity, productivity, medication adherence and self-efficacy. Quantitative data about accrual, retention and economic measures, and qualitative data about participants' experiences during the trial will be collected to inform the future RCT. This work will lay the foundations for a definitive RCT of a community pharmacy-based 'goal-focused' self-management intervention for people with intermittent allergic rhinitis. Results of the pilot trial are expected to be available in April 2013. Current Controlled Trials ISRCTN43606442. 23681904 Adenosine signaling inhibits CIITA-mediated MHC class II transactivation in lung fibroblast cells. Efficient antigen presentation by major histocompatibility complex (MHC) molecules represents a critical process in adaptive immunity. Class II transactivator (CIITA) is considered the master regulator of MHC class II (MHC II) transcription. Previously, we have shown that CIITA expression is upregulated in smooth muscle cells deficient in A2b adenosine receptor. Here, we report that treatment with the adenosine receptor agonist adenosine-5'N-ethylcarboxamide (NECA) attenuated MHC II transcription in lung fibro-blast cells as a result of CIITA repression. Further analysis revealed that NECA preferentially abrogated CIITA transcription through promoters III and IV. Blockade with a selective A2b receptor antagonist MRS-1754 restored CIITA-dependent MHC II transactivation. Forskolin, an adenylyl cyclase activator, achieved the same effect as NECA. A2b signaling repressed CIITA transcription by altering histone modifications and recruitment of key factors on the CIITA promoters in a STAT1-dependent manner. MRS-1754 blocked the antagonism of transforming growth factor beta (TGF-β) in CIITA induction by interferon gamma (IFN-γ), alluding to a potential dialogue between TGF-β and adenosine signaling pathways. Finally, A2b signaling attenuated STAT1 phosphorylation and stimulated TGF-β synthesis. In conclusion, we have identified an adenosine-A2b receptor-adenylyl cyclase axis that influences CIITA-mediated MHC II transactivation in lung fibroblast cells and as such have provided invaluable insights into the development of novel immune-modulatory strategies. 23957619 Magnetic resonance imaging of tumor oxygenation and metabolic profile. The tumor microenvironment is distinct from normal tissue as a result of abnormal vascular network characterized by hypoxia, low pH, high interstitial fluid pressure and elevated glycolytic activity. This poses a barrier to treatments including radiation therapy and chemotherapy. Imaging methods which can characterize such features non-invasively and repeatedly will be of significant value in planning treatment as well as monitoring response to treatment. The three techniques based on magnetic resonance imaging (MRI) are reviewed here. Tumor pO2 can be measured by two MRI methods requiring an exogenous contrast agent: electron paramagnetic resonance imaging (EPRI) and Overhauser magnetic resonance imaging (OMRI). Tumor metabolic profile can be assessed by a third method, hyperpolarized metabolic MR, based on injection of hyperpolarized biological molecules labeled with (13)C or (15)N and MR spectroscopic imaging. Imaging pO2 in tumors is now a robust pre-clinical imaging modality with potential for implementation clinically. Pre-clinical studies and an initial clinical study with hyperpolarized metabolic MR have been successful and suggest that the method may be part of image-guided radiotherapy to select patients for tailored individual treatment regimens. 23935717 Effect of Lycopersicon esculentum extract on apoptosis in the rat cerebellum, following prenatal and postnatal exposure to an electromagnetic field. The expansion of mobile phone technology has raised concerns regarding the effect of 900-MHz electromagnetic field (EMF) exposure on the central nervous system. At present, the developing human brain is regularly exposed to mobile telephones, pre- and postnatally. Several studies have demonstrated the acute effects of EMF exposure during pre- or postnatal periods; however, the chronic effects of EMF exposure are less understood. Thus, the aim of the present study was to determine the chronic effects of EMF on the pre- and postnatal rat cerebellum. The control group was maintained in the same conditions as the experimental groups, without the exposure to EMF. In the EMF1 group, the rats were exposed to EMF during pre- and postnatal periods (until postnatal day 80). In the EMF2 group, the rats were also exposed to EMF pre- and postnatally; in addition, however, they were provided with a daily oral supplementation of Lycopersicon esculentum extract (∼2 g/kg). The number of caspase-3-labeled Purkinje neurons and granule cells present in the rats in the control and experimental groups were then counted. The neurodegenerative changes were studied using cresyl violet staining, and these changes were evaluated. In comparison with the control animals, the EMF1 group demonstrated a significant increase in the number of caspase-3-labeled Purkinje neurons and granule cells present in the cerebellum (P<0.001). However, in comparison with the EMF1 group, the EMF2 group exhibited significantly fewer caspase-3-labeled Purkinje neurons and granule cells in the cerebellum. In the EMF1 group, the Purkinje neurons were revealed to have undergone dark neuron degenerative changes. However, the presence of dark Purkinje neurons was reduced in the EMF2 group, compared with the EMF1 group. The results indicated that apoptosis and neurodegeneration in rats exposed to EMF during pre- and postnatal periods may be reduced with Lycopersicon esculentum extract therapy. 23759509 Protective properties of 2-acetylcyclopentanone in a mouse model of acetaminophen hepatotoxicity. Our previous research showed that enolates formed from 1,3-dicarbonyl compounds, such as 2-acetylcyclopentanone (2-ACP), could provide protection in cell culture models from electrophile- or oxidative stress-induced toxicity. In the present study, we evaluated the protective abilities of 2-ACP in a mouse model of acetaminophen (APAP) hepatotoxicity. Results show that oral APAP overdose (500 mg/kg) was nearly 90% lethal within 72 hours and that the resulting hepatotoxicity was associated with substantial changes in plasma liver enzyme activities, histopathological indices, and markers of hepatocyte oxidative stress. 2-ACP administered intraperitoneally 20 minutes before APAP completely prevented lethality over a 7-day observation period. This effect was dose-dependent (0.80-2.40 mmol/kg) and was correlated with normalization of measured parameters. Nearly complete protection was afforded when 2-ACP was administered 20 minutes post-APAP, but not 60 minutes after intoxication. Although intraperitoneal administration of N-acetylcysteine (NAC) was not effective over a broad dose range (2.40-7.20 mmol/kg), temporal studies indicated that intraperitoneal NAC was hepatoprotective when injected 60 minutes after APAP intoxication. Because of a loss of function in stomach acid, oral administration of 2-ACP was associated with modest APAP protection. In contrast, NAC administered orally provided dose-dependent (0.80-2.40 mmol/kg) protection against APAP hepatotoxicity. In chemico studies and quantum mechanical calculations indicated that 2-ACP acted as a surrogate nucleophilic target for the reactive electrophilic APAP metabolite N-acetyl-p-benzoquinone imine. Our findings suggest that 2-ACP or a derivative might be useful in treating acquired toxicities associated with electrophilic drugs and metabolites or environmental toxicants. 23843045 Overanticoagulation is associated with renal function decline. Background: Recent studies suggest that overanticoagulation impairs renal function in patients on warfarin therapy, due to renal tubular obstruction from glomerular hemorrhage.
Methods: Data from the Rotterdam Study (The Netherlands), a prospective population-based cohort study of patients 55 years and older, were used for this study. Information on vitamin K antagonist (VKA) therapy was obtained from the regional anticoagulation clinic, where prothrombin times were monitored every 1-6 weeks depending on target level and stability of the international normalized ratio (INR). Linear regression was performed to study the association between the cumulative number of instances of overanticoagulation (defined as a measurement of an INR >6.0) and the change in renal function between baseline and third examination round based on estimated glomerular filtration rate (CKD-EPI equation). Age, sex, baseline renal function, baseline and incident heart failure, and indication for VKA therapy were included as potential confounders.
Results: Information was available for analysis on 2,802 study participants in whom overanticoagulation was significantly associated with a decline in renal function, after adjustment for confounding by age, sex, heart failure, baseline glomerular filtration rate and indication for VKA therapy (-0.180 ml/min per 1.73 m2 
per year per event for INR >6.0, p = 0.030).
Conclusions: Overanticoagulation (INR >6.0) is associated with a decline in renal function. Further studies are needed to evaluate the causal role of different degrees of overanticoagulation, including transient effects, in high-risk groups, and the association with the new oral anticoagulants. 23043507 Diversity in bacterial lysis systems: bacteriophages show the way. Bacteriophages have developed multiple host cell lysis strategies to promote release of descendant virions from infected bacteria. This review is focused on the lysis mechanisms employed by tailed double-stranded DNA bacteriophages, where new developments have recently emerged. These phages seem to use a least common denominator to induce lysis, the so-called holin-endolysin dyad. Endolysins are cell wall-degrading enzymes whereas holins form 'holes' in the cytoplasmic membrane at a precise scheduled time. The latter function was long viewed as essential to provide a pathway for endolysin escape to the cell wall. However, recent studies have shown that phages can also exploit the host cell secretion machinery to deliver endolysins to their target and subvert the bacterial autolytic arsenal to effectively accomplish lysis. In these systems the membrane-depolarizing holin function still seems to be essential to activate secreted endolysins. New lysis players have also been uncovered that promote degradation of particular bacterial cell envelopes, such as that of mycobacteria. 23629829 Sectioning the medial patellofemoral ligament alters patellofemoral joint kinematics and contact mechanics. Medial patellofemoral ligament (MPFL) disruption may alter patellofemoral joint (PFJ) kinematics and contact mechanics, potentially causing pain and joint degeneration. In this controlled laboratory study, we investigated the hypothesis that MPFL transection would change patellar tracking and PFJ contact pressures and increase the distance between the attachment points of the MPFL. Eight fresh frozen dissected cadaveric knees were mounted in a rig with the quadriceps and ITB loaded to 205 N. An optical tracking system measured joint kinematics, and pressure sensitive film between the patella and trochlea measured PFJ contact pressures. Length patterns of the distance between the femoral and patellar attachments of the MPFL were measured using a suture led to a linear displacement transducer. Measurements were repeated with the MPFL intact and following MPFL transection. A significant increase in the distance between the patellar and femoral MPFL attachment points was noted following transection (p < 0.05). MPFL transection resulted in significantly increased lateral translation and lateral tilt of the patella in early flexion (p < 0.05). Peak and mean medial PFJ contact pressures were significantly reduced and peak lateral contact pressures significantly elevated in early knee flexion following MPFL transection (p < 0.05). MPFL transection resulted in significant alterations to PFJ tracking and contact pressures, which may affect articular cartilage health. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1423-1429, 2013. 23218850 Effect of a combined estrogen and progesterone oral contraceptive on circulating adipocytokines adiponectin, resistin and DLK-1 in normal and obese female rhesus monkeys. Hormonal contraception is the most common medication used by reproductive aged women but there is little understanding of the impact of hormonal contraception on obesity and metabolism. Adipokine levels (adiponectin, resistin) and markers of adipocyte development (DLK-1) are altered in obese animals and humans and are associated with increased cardiovascular risk. We sought to determine the effect of combined hormonal oral contraceptive pills (COCs) on circulating adiponectin, resistin and DLK-1 levels in obese and normal-weight rhesus macaque monkeys. Serum adiponectin, resistin and DLK-1 levels in reproductive-age female rhesus macaques of normal (n = 5, mean = 5.76 kg) and inherently obese (n = 5, mean = 8.11 kg) weight were determined before, during and 2 months after cessation of 8 months of continuous treatment with COCs. The obese group alone showed a significant decrease (p<.01) in weight with COC use, which returned to baseline after COC cessation. Baseline adiponectin levels prior to COC treatment were lower in the obese group (p<.05). Adiponectin levels increased from baseline in both groups, but more so in the obese group (p<.05). Resistin levels were similar at baseline, with an increase in both groups following treatment. Circulating resistin remained elevated above baseline levels after COC cessation, particularly in the obese group (p<.05). While DLK-1 levels did not change significantly in either group, a trend for higher levels in obese animals was observed. COC use may alter metabolic processes via direct (resistin) or indirect (adiponectin) means, while unchanging DLK1 levels suggest they do not affect adipocyte development. COCs may directly increase resistin levels, as observed in both groups. As adiponectin is inversely related to adipocyte mass, increased levels in the obese group are likely attributed to weight loss. 23535329 Enantiocomplementary access to carba-analogs of C-nucleoside derivatives by recombinant Baeyer-Villiger monooxygenases. A novel and stereoselective synthetic route towards carba-C-nucleosides was investigated applying an enantiodivergent biooxidation strategy by two different Baeyer-Villiger monooxygenases. Within only three chemo-enzymatic steps it was possible to introduce four chiral centers starting from commercially available non-chiral starting material. 23870714 Frontal soft tissue analysis using a 3 dimensional camera following two-jaw rotational orthognathic surgery in skeletal class III patients. Although two dimensional cephalometry is the standard method for analyzing the results of orthognathic surgery, it has potential limits in frontal soft tissue analysis. We have utilized a 3 dimensional camera to examine changes in soft tissue landmarks in patients with skeletal class III dentofacial deformity who underwent two-jaw rotational setback surgery. We assessed 25 consecutive Asian patients (mean age, 22 years; range, 17-32 years) with skeletal class III dentofacial deformities who underwent two-jaw rotational surgery without maxillary advancement. Using a 3D camera, we analyzed changes in facial proportions, including vertical and horizontal dimensions, facial surface areas, nose profile, lip contour, and soft tissue cheek convexity, as well as landmarks related to facial symmetry. The average mandibular setback was 10.7 mm (range: 5-17 mm). The average SNA changed from 77.4° to 77.8°, the average SNB from 89.2° to 81.1°, and the average occlusal plane from 8.7° to 11.4°. The mid third vertical dimension changed from 58.8 mm to 57.8 mm (p = 0.059), and the lower third vertical dimension changed from 70.4 mm to 68.2 mm (p = 0.0006). The average bigonial width decreased from 113.5 mm to 109.2 mm (p = 0.0028), the alar width increased from 34.7 mm to 36.1 mm (p-value = 0.0002), and lip length was unchanged. Mean mid and lower facial surface areas decreased significantly, from 171.8 cm(2) to 166.2 cm(2) (p = 0.026) and from 71.23 cm(2) to 61.9 cm(2) (p < 0.0001), respectively. Cheek convexity increased significantly, from 171.8° to 155.9° (p = 0.0007). The 3D camera was effective in frontal soft tissue analysis for orthognathic surgery, and enabled quantitative analysis of changes in frontal soft tissue landmarks and facial proportions that were not possible with conventional 2D cephalometric analysis. 23836932 Local palmitoylation cycles define activity-regulated postsynaptic subdomains. Distinct PSD-95 clusters are primary landmarks of postsynaptic densities (PSDs), which are specialized membrane regions for synapses. However, the mechanism that defines the locations of PSD-95 clusters and whether or how they are reorganized inside individual dendritic spines remains controversial. Because palmitoylation regulates PSD-95 membrane targeting, we combined a conformation-specific recombinant antibody against palmitoylated PSD-95 with live-cell super-resolution imaging and discovered subsynaptic nanodomains composed of palmitoylated PSD-95 that serve as elementary units of the PSD. PSD-95 in nanodomains underwent continuous de/repalmitoylation cycles driven by local palmitoylating activity, ensuring the maintenance of compartmentalized PSD-95 clusters within individual spines. Plasma membrane targeting of DHHC2 palmitoyltransferase rapidly recruited PSD-95 to the plasma membrane and proved essential for postsynaptic nanodomain formation. Furthermore, changes in synaptic activity rapidly reorganized PSD-95 nano-architecture through plasma membrane-inserted DHHC2. Thus, the first genetically encoded antibody sensitive to palmitoylation reveals an instructive role of local palmitoylation machinery in creating activity-responsive PSD-95 nanodomains, contributing to the PSD (re)organization. 23958251 Ezetimibe decreases serum oxidized cholesterol without impairing bile acid synthesis in Japanese hypercholesterolemic patients. Cholesterol and diet-derived oxidized cholesterol are absorbed in the small intestine and eliminated by bile acids. We determined whether ezetimibe, a selective cholesterol absorption inhibitor, changes serum oxidized cholesterol levels. We measured levels of plant sterols, cholesterol precursors, and oxysterols by gas chromatography-mass spectrometry in 47 hypercholesterolemics and 32 controls. Twenty-four hypercholesterolemics received 10 mg ezetimibe/day for 4 weeks. Plant sterols were 30-42% higher in hypercholesterolemics than in controls and positively correlated with low-density lipoprotein-cholesterol (LDL-C). Ezetimibe decreased plant sterols by 21-53%, but did not change bile acid synthesis markers. 7β-hydroxycholesterol, a marker for non-enzymatic oxidation of cholesterol, was 66% higher in hypercholesterolemics than controls. Ezetimibe decreased 7β-hydroxycholesterol levels by 15% regardless of LDL-C reduction. Ezetimibe decreases serum oxidized cholesterol generated by non-enzymatic reactions without impairing bile acid synthesis. Ezetimibe may maintain cholesterol excretion into bile and alleviate the diet-derived oxidative burden. 23054319 Correlation of ultrasonographic measurement of intrarenal arterial resistance index with microalbuminuria in nonhypertensive, nondiabetic obese patients. To determine whether intrarenal arterial resistance index (RI) value is related to increased urinary albumin excretion and whether RI value is an independent good indicator to evaluate early renal damage in nonhypertensive, nondiabetic obese subjects. Sixty-four nonhypertensive, nondiabetic obese patients (OB) and 35 age- and sex-matched normal healthy subjects were involved in this study. Clinical characteristics and blood biochemistry of all the subjects were measured. Urinary albumin/creatinine ratio (ACR) and sonographic evaluation of renal blood flow were determined. ACR and interlobar arterial RI were significantly higher in obese patients than those of normal healthy subjects. Interlobar arterial RI value was higher in patients with microalbuminuria than those with normoalbuminuria. Correlation analysis showed interlobar artery RI value had a positive correlation with ACR (r = 0.615, p < 0.01) and plasma free fatty acids (FFAs, r = 0.407, p < 0.01). ACR had a positive correlation with BMI (r = 0.380, p < 0.01), waist circumference (r = 0.414, p < 0.01), plasma FFAs (r = 0.537, p < 0.01). Multivariate regression analyses showed that ACR was best predicted by interlobar artery RI value even when body mass index, waist circumference, FFAs, and high-sensitive C reaction protein were added in the statistical analysis. Interlobar arterial RI may be an independent predictor of microalbuminuria in nonhypertensive, nondiabetic obese patients, and interlobar arterial RI could be a useful tool for assessment early renal damage in obese patients. 23822526 Evoked prior learning experience and approach to learning as predictors of academic achievement. In separate studies and research from different perspectives, five factors are found to be among those related to higher quality outcomes of student learning (academic achievement). Those factors are higher self-efficacy, deeper approaches to learning, higher quality teaching, students' perceptions that their workload is appropriate, and greater learning motivation. University learning improvement strategies have been built on these research results. To investigate how students' evoked prior experience, perceptions of their learning environment, and their approaches to learning collectively contribute to academic achievement. This is the first study to investigate motivation and self-efficacy in the same educational context as conceptions of learning, approaches to learning and perceptions of the learning environment. Undergraduate students (773) from the full range of disciplines were part of a group of over 2,300 students who volunteered to complete a survey of their learning experience. On completing their degrees 6 and 18 months later, their academic achievement was matched with their learning experience survey data. A 77-item questionnaire was used to gather students' self-report of their evoked prior experience (self-efficacy, learning motivation, and conceptions of learning), perceptions of learning context (teaching quality and appropriate workload), and approaches to learning (deep and surface). Academic achievement was measured using the English honours degree classification system. Analyses were conducted using correlational and multi-variable (structural equation modelling) methods. The results from the correlation methods confirmed those found in numerous earlier studies. The results from the multi-variable analyses indicated that surface approach to learning was the strongest predictor of academic achievement, with self-efficacy and motivation also found to be directly related. In contrast to the correlation results, a deep approach to learning was not related to academic achievement, and teaching quality and conceptions of learning were only indirectly related to achievement. Research aimed at understanding how students experience their learning environment and how that experience relates to the quality of their learning needs to be conducted using a wider range of variables and more sophisticated analytical methods. In this study of one context, some of the relations found in earlier bivariate studies, and on which learning intervention strategies have been built, are not confirmed when more holistic teaching-learning contexts are analysed using multi-variable methods. 23623483 Effects of the herbicide atrazine in neotropical catfish (Rhamdia quelen). The exposure to a world-wide used herbicide atrazine (ATZ) (96h exposure to 2, 10, and 100μgL(-1)), was investigated on the freshwater fish Rhamdia quelen through a multi biomarker approach. Liver histopathology revealed leukocyte infiltration, hepatocyte vacuolization like steatosis and necrosis areas, leading to raised lesion index levels in all tested concentrations. The increase of free melanomacrophage numbers was observed. Gill filaments revealed considerable loss of the microridges on pavement cells at 10 and 100μgL(-1) of ATZ, and a significantly increased of chloride cell (CC) number and density on apical surface area at 100μgL(-1) of ATZ. CAT, GST, GPx, and GR activities were inhibited by all tested concentrations. GSH levels were reduced in individuals exposed to 100µgL(-1). Osmoregulatory function was also disturbed. We observed an increase of plasma magnesium concentrations at 10µgL(-1). Additionally the inhibition of branchial carbonic anhydrase activity was observed at 100µgL(-1). In the kidney, carbonic anhydrase activity decreased only in the group exposed to 2µgL(-1). These results suggest that ATZ, represents a potential ecotoxicological hazard and can be hepatotoxic and nephrotoxic even low concentrations. The current study was the first to show the nephrotoxic effect of ATZ in fish. Besides, in Brazil, the environmental protection agency (CONAMA) establishes that the maximum allowed level of dissolved ATZ in water is 2μgL(-1), but the present results showed that this concentration may cause histopathological, biochemical and physiological changes in R. quelen. 23660089 Comparative pathogenicity of three korean and one lelystad type 1 porcine reproductive and respiratory syndrome virus (pan-European subtype 1) isolates in experimentally infected pigs. The aim of this study was to compare the pathogenicity of three type 1 porcine reproductive and respiratory syndrome virus (PRRSV) isolates that originated from Korean herds with varying severity of respiratory disease with one Lelystad virus. An experimental infection model was used to study virus distribution, sites of viral replication, viraemia, gross and microscopical lesions and the humoural immune response. Each virus isolate was given intranasally to 3-week-old pigs. Differences were found in the severity of gross and microscopical pulmonary lesions and the distribution of virus-labelled cells in lung and lymph nodes (LNs). The gross and microscopical pulmonary lesion scores were significantly greater in pigs inoculated with the SNUVR100744 isolate. The distribution of PRRSV-labelled cells within tissues and organs was similar for the different virus isolates; however, significantly more PRRSV-positive cells were detected in the lung and LNs of pigs inoculated with the SNUVR100744 isolate than were detected in the same tissues of pigs inoculated with Lelystad virus. The results of the present study demonstrate that type 1 PRRSV isolates differ in their ability to induce viral replication in tissues and induce interstitial pneumonia in pigs. 23951105 Weight-Bearing Locomotion in the Developing Opossum, Monodelphis domestica following Spinal Transection: Remodeling of Neuronal Circuits Caudal to Lesion. Complete spinal transection in the mature nervous system is typically followed by minimal axonal repair, extensive motor paralysis and loss of sensory functions caudal to the injury. In contrast, the immature nervous system has greater capacity for repair, a phenomenon sometimes called the infant lesion effect. This study investigates spinal injuries early in development using the marsupial opossum Monodelphis domestica whose young are born very immature, allowing access to developmental stages only accessible in utero in eutherian mammals. Spinal cords of Monodelphis pups were completely transected in the lower thoracic region, T10, on postnatal-day (P)7 or P28 and the animals grew to adulthood. In P7-injured animals regrown supraspinal and propriospinal axons through the injury site were demonstrated using retrograde axonal labelling. These animals recovered near-normal coordinated overground locomotion, but with altered gait characteristics including foot placement phase lags. In P28-injured animals no axonal regrowth through the injury site could be demonstrated yet they were able to perform weight-supporting hindlimb stepping overground and on the treadmill. When placed in an environment of reduced sensory feedback (swimming) P7-injured animals swam using their hindlimbs, suggesting that the axons that grew across the lesion made functional connections; P28-injured animals swam using their forelimbs only, suggesting that their overground hindlimb movements were reflex-dependent and thus likely to be generated locally in the lumbar spinal cord. Modifications to propriospinal circuitry in P7- and P28-injured opossums were demonstrated by changes in the number of fluorescently labelled neurons detected in the lumbar cord following tracer studies and changes in the balance of excitatory, inhibitory and neuromodulatory neurotransmitter receptors' gene expression shown by qRT-PCR. These results are discussed in the context of studies indicating that although following injury the isolated segment of the spinal cord retains some capability of rhythmic movement the mechanisms involved in weight-bearing locomotion are distinct. 23926150 Simple life-history traits explain key effective population size ratios across diverse taxa. Effective population size (Ne) controls both the rate of random genetic drift and the effectiveness of selection and migration, but it is difficult to estimate in nature. In particular, for species with overlapping generations, it is easier to estimate the effective number of breeders in one reproductive cycle (Nb) than Ne per generation. We empirically evaluated the relationship between life history and ratios of Ne, Nb and adult census size (N) using a recently developed model (agene) and published vital rates for 63 iteroparous animals and plants. Nb/Ne varied a surprising sixfold across species and, contrary to expectations, Nb was larger than Ne in over half the species. Up to two-thirds of the variance in Nb/Ne and up to half the variance in Ne/N was explained by just two life-history traits (age at maturity and adult lifespan) that have long interested both ecologists and evolutionary biologists. These results provide novel insights into, and demonstrate a close general linkage between, demographic and evolutionary processes across diverse taxa. For the first time, our results also make it possible to interpret rapidly accumulating estimates of Nb in the context of the rich body of evolutionary theory based on Ne per generation. 23828603 Structure of conjugated polyketone reductase from Candida parapsilosis IFO 0708 reveals conformational changes for substrate recognition upon NADPH binding. Conjugated polyketone reductase C2 (CPR-C2) from Candida parapsilosis IFO 0708, identified as a nicotinamide adenine dinucleotide phosphate (NADPH)-dependent ketopantoyl lactone reductase, belongs to the aldo-keto reductase superfamily. This enzyme reduces ketopantoyl lactone to D-pantoyl lactone in a strictly stereospecific manner. To elucidate the structural basis of the substrate specificity, we determined the crystal structures of the apo CPR-C2 and CPR-C2/NADPH complex at 1.70 and 1.80 Ã… resolutions, respectively. CPR-C2 adopted a triose-phosphate isomerase barrel fold at the core of the structure. Binding with the cofactor NADPH induced conformational changes in which Thr27 and Lys28 moved 15 and 5.0 Ã…, respectively, in the close vicinity of the adenosine 2'-phosphate group of NADPH to form hydrogen bonds. Based on the comparison of the CPR-C2/NADPH structure with 3-α-hydroxysteroid dehydrogenase and mutation analyses, we constructed substrate binding models with ketopantoyl lactone, which provided insight into the substrate specificity by the cofactor-induced structure. The results will be useful for the rational design of CPR-C2 mutants targeted for use in the industrial manufacture of ketopantoyl lactone. 23837714 Hybrid Magnetic Superconductors Formed by TaS2 Layers and Spin Crossover Complexes. The restacking of charged TaS2 nanosheets with molecular counterparts has so far allowed for the combination of superconductivity with a manifold of other molecule-intrinsic properties. Yet, a hybrid compound that blends superconductivity with spin crossover switching has still not been reported. Here we continue to exploit the solid-state/molecule-based hybrid approach for the synthesis of a layered TaS2-based material that hosts Fe(2+) complexes with a spin switching behavior. The chemical design and synthetic aspects of the exfoliation/restacking approach are discussed, highlighting how the material can be conveniently obtained in the form of highly oriented easy-to-handle flakes. Finally, proof of the presence of both phenomena is provided by the use of a variety of physical characterization techniques. The likely sensitivity of the intercalated Fe(2+) complexes to external stimuli such as light opens the door for the study of synergistic effects between the superconductivity and the spin crossover switching at low temperatures. 23370008 Serum amyloid A upsurge precedes standard biomarkers of hepatotoxicity in ritodrine-injected mice. The tocolytic agent ritodrine acts on the β2-adrenoceptor and is an effective treatment option for preterm labor. However, several adverse effects of ritodrine therapy, including liver damage, have been noted. To elucidate the underlying mechanisms of ritodrine-induced adverse effects, development of sensitive biomarkers of these adverse events is necessary. Here, we report the development and analysis of an animal model of ritodrine-induced liver damage. Female mice received daily ritodrine injections for 2 weeks; liver samples were then collected and subjected to DNA microarray analysis. Ritodrine significantly altered the expression of genes related to steroid and lipid metabolism, as well as the metabolism of ritodrine itself. Importantly, expression of the acute-phase reactant serum amyloid A (SAA) significantly increased after ritodrine injection, with values indicating the largest fold-change. This large increase in blood SAA levels serves as a more sensitive biomarker than conventional liver enzymes, such as aspartate aminotransferase and alanine aminotransferase. The increase in SAA expression is specific to ritodrine-induced liver damage, because SAA expression was not induced by other hepatotoxic drugs such as acetaminophen, valproic acid, or metformin. Our in vitro studies showed that cyclic adenosine 3',5'-monophosphate (cAMP) accumulation was not a primary cause of the ritodrine-induced SAA increase. Instead, SAA expression was enhanced by indirect phosphorylation of the signal transducer and activator of transcription-3 (STAT3) mediated by interleukin-6. Therefore, our study provides a method for sensitive and early detection of hepatic injury, and may thus help preclude serious liver damage due to ritodrine use in preterm labor. 23905967 The acute effects of waterpipe smoking on lung function and exercise capacity in a pilot study of healthy participants. Abstract Context: Waterpipe tobacco smoking (WTS) has gained popularity, but its physiologic effects have not been extensively studied: rather, studies have focused on WTS's chronic effects or have evaluated limited respiratory/cardiac parameters. Objective: We sought to characterize in a more detailed manner the acute effects of WTS on lung function and exercise capacity. Method: We recruited 24 healthy WTS males. We used a pilot single-group pre-test (abstained from WTS for ≥48 h) post-test (within 0.5 h of a 45-min WTS session) design. We performed spirometry, diffusing lung capacity and time-limited CPE testing (CPET; cycloergometer; 2-min 20-Watt warm-up and 25-Watt increase every 2-min for 10 min). Results: Mean age was 20.4 years; Post-WTS, the following significant changes were observed: CO level increased from 3.7 ppm to 24.4; oxygen consumption decreased (from 1.86 L/min to 1.7); baseline respiratory rate increased (from 17.7 breath/min to 19.7); forced expiratory flow over the middle half of the forced vital capacity decreased (from 5.51 L to 5.29); and perceived exertion (measured by Borg scale) at mid and peak exercise increased. Baseline resting systolic blood pressure, pulse pressure, and pulse pressure product increased post-WTS (from 118.9 mmHg to 129.2; from 45.3 mmHg to 55.6; and from 9.9 mmHg/min to 11.1 post-WTS, respectively). During exercise, a decrease in oxygen pulse was observed post-WTS (from 10.89 ml/beat to 9.97), while the heart rate-oxygen consumption relationship increased post-WTS (from 3.52 beats/ml/kg to 3.91). Conclusion: Acute WTS appears to induce impairment in lung function and exercise capacity. Larger studies are warranted to further characterize the nature and extent of such impairment. 23918841 Changes in hospitalization rates for acute coronary syndrome after a two-phase comprehensive smoking ban. The impact of a comprehensive stepwise smoking ban (2007 and 2008) was assessed by analysing the hospitalization rate for acute coronary syndrome (ACS) in France, between 2003 and 2009. Between 2003 and 2009, 867,164 hospitalizations for ACS were observed among about 23 million administrative reports. The age-and gender-standardized hospitalization rates were calculated and their variation before and after the smoking ban implementation was investigated by Poisson regression that included the ACS seasonal variations and the historical trend. The hospitalization rate decreased by 12.8% (from 269 to 235/100,000) with a significant historical trend reduction (p < 0.10(-3)) in all groups, but in young women. After adjusting for linear trend, reductions linked to the ban remained not significant in all groups: relative risk (RR) from 0.96 (95% CI 0.91-1.01) in men older than 55 years to 0.99 (95% CI 0.93-1.04) in men aged 55 years or less after the first phase, and from 0.96 (95% CI 0.89-1.04) in men older than 55 years to 1.03 (95% CI 0.94-1.12) in women older than 65 years after the second phase of the ban. This study did not demonstrate a significant effect of a two-phases smoking ban on ACS hospitalization rate. A steadily decrease of this rate over the 7-year period, the past preventive measures in France leading to low levels of passive smoking, and the significant increase in active smoking during the studied period may explain this result. Our study highlights the difficulty of proving an effect of smoking bans in a country with an already low ACS incidence. 23891446 A comparative study of spinel structured Mn3O4, Co3O4 and Fe3O4 nanoparticles in catalytic oxidation of phenolic contaminants in aqueous solutions. Spinel structured Mn3O4, Co3O4 and Fe3O4 nanoparticles were prepared, characterized, and tested in degradation of aqueous phenol in the presence of peroxymonosulfate. It was found that Mn3O4 and Co3O4 nanoparticles are highly effective in heterogeneous activation of peroxymonosulfate to produce sulfate radicals for phenol degradation. The activity shows an order of Mn3O4>Co3O4>Fe3O4. Mn3O4 could fast and completely remove phenol in about 20min, at the conditions of 25ppm phenol, 0.4g/L catalyst, 2g/L oxone®, and 25°C. A pseudo first order model would fit to phenol degradation kinetics and activation energies on Mn3O4 and Co3O4 were obtained as 38.5 and 66.2kJ/mol, respectively. In addition, Mn3O4 exhibited excellent catalytic stability in several runs, demonstrating that Mn3O4 is a promising catalyst alternative to toxic Co3O4 for water treatment. 23517675 The origin of Woltman's sign of myxoedema. Woltman's sign of myxoedema, named after Henry Woltman in 1956, is the delayed relaxation phase of the muscle stretch reflex in patients with myxoedema. Although a change in these reflexes was mentioned as being clinically evident possibly as early as the 1870s, no formal description was published until 1924 when William Calvert Chaney objectively quantified the change. Woltman was involved in training Chaney, and it has been proposed that he guided Chaney's study of these reflexes. Despite the attachment of Woltman's name to the eponym, little evidence exists that directly links him to the first objective study of the muscle stretch reflex in myxoedema performed by Chaney. 23813009 Information-theoretic evaluation of predicted ontological annotations. The development of effective methods for the prediction of ontological annotations is an important goal in computational biology, with protein function prediction and disease gene prioritization gaining wide recognition. Although various algorithms have been proposed for these tasks, evaluating their performance is difficult owing to problems caused both by the structure of biomedical ontologies and biased or incomplete experimental annotations of genes and gene products. We propose an information-theoretic framework to evaluate the performance of computational protein function prediction. We use a Bayesian network, structured according to the underlying ontology, to model the prior probability of a protein's function. We then define two concepts, misinformation and remaining uncertainty, that can be seen as information-theoretic analogs of precision and recall. Finally, we propose a single statistic, referred to as semantic distance, that can be used to rank classification models. We evaluate our approach by analyzing the performance of three protein function predictors of Gene Ontology terms and provide evidence that it addresses several weaknesses of currently used metrics. We believe this framework provides useful insights into the performance of protein function prediction tools. Supplementary data are available at Bioinformatics online. 23064600 Chiral and chemical oscillations in a simple dimerization model. We consider the APED model (activation-polymerization-epimerization-depolymerization) for describing the emergence of chiral solutions within a non-catalytic framework for chiral polymerization. The minimal APED model for dimerization can lead to the spontaneous appearance of chiral oscillations and we describe in detail the nature of these oscillations in the enantiomeric excess, which are the consequence of oscillations of the concentrations of the associated chemical species. 23744766 Endurance training improves insulin sensitivity and body composition in prostate cancer patients treated with androgen deprivation therapy. Insulin resistance and changes in body composition are side effects of androgen deprivation therapy (ADT) given to prostate cancer patients. The present study investigated whether endurance training improves insulin sensitivity and body composition in ADT-treated prostate cancer patients. Nine men undergoing ADT for prostate cancer and ten healthy men with normal testosterone levels underwent 12 weeks of endurance training. Primary endpoints were insulin sensitivity (euglycemic-hyperinsulinemic clamps with concomitant glucose-tracer infusion) and body composition (dual-energy X-ray absorptiometry and magnetic resonance imaging). The secondary endpoint was systemic inflammation. Statistical analysis was carried out using two-way ANOVA. Endurance training increased VO2max (ml(O2)/min per kg) by 11 and 13% in the patients and controls respectively (P<0.0001). The patients and controls demonstrated an increase in peripheral tissue insulin sensitivity of 14 and 11% respectively (P<0.05), with no effect on hepatic insulin sensitivity (P=0.32). Muscle protein content of GLUT4 (SLC2A4) and total AKT (AKT1) was also increased in response to the training (P<0.05 and P<0.01 respectively). Body weight (P<0.0001) and whole-body fat mass (FM) (P<0.01) were reduced, while lean body mass (P=0.99) was unchanged. Additionally, reductions were observed in abdominal (P<0.01), subcutaneous (P<0.05), and visceral (P<0.01) FM amounts. The concentrations of plasma markers of systemic inflammation were unchanged in response to the training. No group×time interactions were observed, except for thigh intermuscular adipose tissue (IMAT) (P=0.01), reflecting a significant reduction in the amount of IMAT in the controls (P<0.05) not observed in the patients (P=0.64). In response to endurance training, ADT-treated prostate cancer patients exhibited improved insulin sensitivity and body composition to a similar degree as eugonadal men. 23872389 Attenuating Aβ1-42-induced toxicity by a novel acetylcholinesterase inhibitor. We explored the attenuating effects of NP-9 on β-amyloid (Aβ) aggregation and amyloid-induced toxicity. NP-9 is a recently reported monoamine oxidase B (MAO-B), and acetylcholinesterase (AChE) inhibitor. In the present study, we found that NP-9 inhibited AChE activity in a dose-dependent manner with a maximal inhibition dose of 8mg/kg, i.p. It inhibited Aβ aggregation, observed through thioflavin-T assay (IC50=60μM) and scanning electron microscopy (S.E.M.) (no fibril formation). NP-9 has shown marked protection against scopolamine and Aβ1-42-induced memory impairments. It also minimized neuronal loss and amyloid plaque deposition in the brains of Aβ1-42-induced mice model. Therefore, NP-9 could be a promising lead molecule for AD, with effects against MAO-B, AChE, Aβ aggregation, and Aβ1-42 induced toxicity. 23733562 Low-risk lifestyle, coronary calcium, cardiovascular events, and mortality: results from MESA. Unhealthy lifestyle habits are a major contributor to coronary artery disease. The purpose of the present study was to investigate the associations of smoking, weight maintenance, physical activity, and diet with coronary calcium, cardiovascular events, and mortality. US participants who were 44-84 years of age (n = 6,229) were followed in the Multi-Ethnic Study of Atherosclerosis from 2000 to 2010. A lifestyle score ranging from 0 to 4 was created using diet, exercise, body mass index, and smoking status. Coronary calcium was measured at baseline and a mean of 3.1 (standard deviation, 1.3) years later to assess calcium progression. Participants who experienced coronary events or died were followed for a median of 7.6 (standard deviation, 1.5) years. Participants with lifestyle scores of 1, 2, 3, and 4 were found to have mean adjusted annual calcium progressions that were 3.5 (95% confidence interval (CI): 0.0, 7.0), 4.2 (95% CI: 0.6, 7.9), 6.8 (95% CI: 2.0, 11.5), and 11.1 (95% CI: 2.2, 20.1) points per year slower, respectively, relative to the reference group (P = 0.003). Unadjusted hazard ratios for death by lifestyle score were as follows: for a score of 1, the hazard ratio was 0.79 (95% CI: 0.61, 1.03); for a score of 2, the hazard ratio was 0.61 (95% CI: 0.46, 0.81); for a score of 3, the hazard ratio was 0.49 (95% CI: 0.32, 0.75); and for a score of 4, the hazard ratio was 0.19 (95% CI: 0.05, 0.75) (P < 0.001 by log-rank test). In conclusion, a combination of regular exercise, healthy diet, smoking avoidance, and weight maintenance was associated with lower coronary calcium incidence, slower calcium progression, and lower all-cause mortality over 7.6 years. 23755861 (3-Aminopropyl)-4-methylpiperazine End-capped Poly(1,4-butanediol diacrylate-co-4-amino-1-butanol)-based Multilayer Films for Gene Delivery. Biodegradable polyelectrolyte surfaces for gene delivery were created through electrospinning of biodegradable polycations combined with iterative solution-based multilayer coating. Poly(β-amino ester) (PBAE) poly(1,4-butanediol diacrylate-co-4-amino-1-butanol) end-capped with 1-(3-aminopropyl)-4-methylpiperazine was utilized because of its ability to electrostatically interact with anionic molecules like DNA, its biodegradability, and its low cytotoxicity. A new DNA release system was developed for sustained release of DNA over 24 h, accompanied by high exogenous gene expression in primary human glioblastoma (GB) cells. Electrospinning a different PBAE, poly(1,4-butanediol diacrylate-co-4,4'-trimethylenedipiperidine), and its combination with polyelectrolyte 1-(3-aminopropyl)-4-methylpiperazine end-capped poly(1,4-butanediol diacrylate-co-4-amino-1-butanol)-based multilayers are promising for DNA release and intracellular delivery from a surface. 23868012 Influencing surgical management in patients with carcinoma of the cervix using a T2- and ZOOM-diffusion-weighted endovaginal MRI technique. Background:Endovaginal MRI (evMRI) at 3.0-T with T2-weighted (T2-W) and ZOnal Oblique Multislice (ZOOM)-diffusion-weighted imaging (DWI) potentially improves the detection of stage Ia/Ib1 cervical cancer. We aimed to determine its sensitivity/specificity, document tumour-to-stromal contrast and establish the effect of imaging on surgical management.Methods:Following ethical approval and written informed consent, 57 consecutive patients with suspected stage Ia/Ib1 cervical cancer underwent evMRI at 3.0-T using T2-W and ZOOM-DWI. Sensitivity/specificity were calculated against histopathology for two independent observers. Tumour-to-stromal contrast was determined on T2-W, and diffusion-weighted (b=800 s mm(-2)) images and apparent diffusion coefficients (ADCs) were recorded. In patients due for radical vaginal trachelectomy (RVT), change of surgical management based on imaging findings was documented.Results:Sensitivity/specificity for detecting tumour was the following: reporting read 88.0/81.8%, anonymised read 92.0/81.8% (observer 1); 84.0/72.7% (observer2; median tumour volume=1.7 cm(3)). Intraobserver agreement was excellent (kappa=0.89) and the interobserver agreement was good (kappa=0.65). Tumour-to-stromal contrast was greater on ZOOM-DWI compared with T2-W images (3.35±2.36 vs 1.39±0.95; P<0.0004). Tumour and stromal ADCs were significantly different (P<0.00001). In 31 patients due for RVT, evMRI altered surgical management in 12 (38.7%) cases (10 cone-biopsy, 2 chemoradiotherapy).Conclusion:T2-W+ZOOM-DWI evMRI has high sensitivity/specificity for detecting stage Ia/Ib1 cervical tumours; in patients due for RVT, the surgical management was altered in ∼39%. 23524314 Phenolic compounds from Jacaranda caroba (Vell.) A. DC.: Approaches to neurodegenerative disorders. Diseases affecting the central nervous system are spread throughout the world. As so, more efficient and safe neuroprotective drugs are required. The present study describes, for the first time, the phenolic composition and bioactivity of Jacaranda caroba (Vell.) A. DC, a species whose infusion is consumed as traditional medicine. The HPLC-DAD-ESI/MS(n) analysis revealed the presence of four dicaffeoyl acid derivatives and nine flavonoids, comprising quercetin, kaempferol and isorhamnetin derivatives. Twelve compounds are described for the first time in Jacaranda genus. Although isorhamnetin-3-O-rhmanoside-7,4'-di-O-glucoside and quercetin-3-O-(2-pentosyl)hexoside are the main metabolites in both aqueous and hydromethanolic extracts, qualitative and quantitative differences were found between them. Aqueous extract is richer in dicaffeoyl acid derivatives. Both extracts proved to be strong radicals' scavengers and effective monoamine-oxidase A inhibitors, but showed weak protection against cholinesterases' activity. The results highlight the value of J. caroba as a source of health-promoting antioxidants and antidepressant compounds. 23694739 Blood lead level and measured glomerular filtration rate in children with chronic kidney disease. Background: The role of environmental exposure to lead as a risk factor for chronic kidney disease (CKD) and its progression remains controversial, and most studies have been limited by a lack of direct glomerular filtration rate (GFR) measurement.Objective: We evaluated the association between lead exposure and GFR in children with CKD.Methods: In this cross-sectional study, we examined the association between blood lead levels (BLLs) and GFR measured by the plasma disappearance of iohexol among 391 participants in the Chronic Kidney Disease in Children (CKiD) prospective cohort study.Results: Median BLL and GFR were 1.2 µg/dL and 44.4 mL/min per 1.73 m2, respectively. The average percent change in GFR for each 1-µg/dL increase in BLL was -2.1 (95% CI: -6.0, 1.8). In analyses stratified by CKD diagnosis, the association between BLL and GFR was stronger among children with glomerular disease underlying CKD; in this group, each 1-µg/dL increase in BLL was associated with a -12.1 (95% CI: -22.2, -1.9) percent change in GFR. In analyses stratified by anemia status, each 1-µg/dL increase in BLL among those with and without anemia was associated with a -0.3 (95% CI: -7.2, 6.6) and -4.6 (95% CI: -8.9, -0.3) percent change in GFR, respectively.Conclusions: There was no significant association between BLL and directly measured GFR in this relatively large cohort of children with CKD, although associations were observed in some subgroups. Longitudinal analyses are needed to examine the temporal relationship between lead and GFR decline, and to further examine the impact of underlying cause of CKD and anemia/hemoglobin status among patients with CKD. 23880112 Sunitinib enhances neuronal survival in vitro via NF-κB-mediated signaling and expression of cyclooxygenase-2 and inducible nitric oxide synthase. Angiogenesis is tightly linked to inflammation and cancer. Regulation of angiogenesis is mediated primarily through activation of receptor tyrosine kinases, thus kinase inhibitors represent a new paradigm in anti-cancer therapy. However, these inhibitors have broad effects on inflammatory processes and multiple cell types. Sunitinib is a multitarget receptor tyrosine kinase inhibitor, which has shown promise for the treatment of glioblastoma, a highly vascularized tumor. However, there is little information as to the direct effects of sunitinib on brain-derived neurons. The objective of this study is to explore the effects of sunitinib on neuronal survival as well as on the expression of inflammatory protein mediators in primary cerebral neuronal cultures. Primary cortical neurons were exposed to various doses of sunitinib. The drug-treated cultures were assessed for survival by MTT assay and cell death by lactate dehydrogenase release. The ability of sunitinib to affect NF-κB, COX2 and NOS2 expression was determined by western blot. The NF-κB inhibitors dicoumarol, SN50 and BAY11-7085 were employed to assess the role of NF-κB in sunitinib-mediated effects on neuronal survival as well as COX2 and NOS2 expression. Treatment of neuronal cultures with sunitinib caused a dose-dependent increase in cell survival and decrease in neuronal cell death. Exposure of neurons to sunitinib also induced an increase in the expression of NF-κB, COX2 and NOS2. Inhibiting NF-κB blunted the increase in cell survival and decrease in cell death evoked by sunitinib. Treatment of cell cultures with both sunitinib and NF-κB inhibitors mitigated the increase in COX2 and NOS2 caused by sunitinib. Sunitinib increases neuronal survival and this neurotrophic effect is mediated by NF-κB. Also, the inflammatory proteins COX2 and NOS2 are upregulated by sunitinib in an NF-κB-dependent manner. These data are in agreement with a growing literature suggesting beneficial effects for inflammatory mediators such as NF-κB, COX2 and NOS2 in neurons. Further work is needed to fully explore the effects of sunitinib in the brain and its possible use as a treatment for glioblastoma. Finally, sunitinib may be useful for the treatment of a range of central nervous system diseases where neuronal injury is prominent. 23668914 Arv1 Regulates PM and ER Membrane Structure and Homeostasis But is Dispensable for Intracellular Sterol Transport. The pan-eukaryotic endoplasmic reticulum (ER) membrane protein Arv1 has been suggested to play a role in intracellular sterol transport. We tested this proposal by comparing sterol traffic in wild-type and Arv1-deficient Saccharomyces cerevisiae. We used fluorescence microscopy to track the retrograde movement of exogenously supplied dehydroergosterol (DHE) from the plasma membrane (PM) to the ER and lipid droplets and high performance liquid chromatography to quantify, in parallel, the transport-coupled formation of DHE esters. Metabolic labeling and subcellular fractionation were used to assay anterograde transport of ergosterol from the ER to the PM. We report that sterol transport between the ER and PM is unaffected by Arv1 deficiency. Instead, our results indicate differences in ER morphology and the organization of the PM lipid bilayer between wild-type and arv1Δ cells suggesting a distinct role for Arv1 in membrane homeostasis. In arv1Δ cells, specific defects affecting single C-terminal transmembrane domain proteins suggest that Arv1 might regulate membrane insertion of tail-anchored proteins involved in membrane homoeostasis. 23933165 Activation of protein kinase A is required for hydroxysafflor yellow A-mediated protection against oleic acid-induced acute lung injury. Inflammation response and oxidative stress play important roles in acute lung injury (ALI). Activation of the cAMP/protein kinase A (PKA) signaling pathway may attenuate ALI by suppressing immune responses and inhibiting the generation of reactive oxygen species (ROS). Hydroxysafflor yellow A (HSYA) is a natural flavonoid compound that reduces oxidative stress and inflammatory cytokine-mediated damage. In this study, we examined whether HSYA could protect the lungs from oleic acid (OA)-induced injury, which was used to mimic ALI, and determined the role of the cAMP/PKA signaling pathway in this process. Arterial oxygen tension (PaO2), carbon dioxide tension, pH, and the PaO2/fraction of inspired oxygen ratio in the blood were detected using a blood gas analyzer. We measured wet/dry lung weight ratio and evaluated tissue morphology. The protein and inflammatory cytokine levels in the bronchoalveolar lavage fluid and serum were determined using enzyme-linked immunoassay. The activities of superoxide dismutase, glutathione peroxidase, PKA, and nicotinamide adenine dinucleotide phosphate oxidase, and the concentrations of cAMP and malondialdehyde in the lung tissue were detected using assay kits. Bcl-2, Bax, caspase 3, and p22(phox) levels in the lung tissue were analyzed using Western blotting. OA increased the inflammatory cytokine and ROS levels and caused lung dysfunction by decreasing cAMP synthesis, inhibiting PKA activity, stimulating caspase 3, and reducing the Bcl-2/Bax ratio. H-89 increased these effects. HSYA significantly increased the activities of antioxidant enzymes, inhibited the inflammatory response via cAMP/PKA pathway activation, and attenuated OA-induced lung injury. Our results show that the cAMP/PKA signaling pathway is required for the protective effect of HSYA against ALI. 23858093 Natural vitamin d content in animal products. Humans derive most vitamin D from the action of sunlight in their skin. However, in view of the current Western lifestyle with most daily activities taking place indoors, sun exposure is often not sufficient for adequate vitamin D production. For this reason, dietary intake is also of great importance. Animal foodstuffs (e.g., fish, meat, offal, egg, dairy) are the main sources for naturally occurring cholecalciferol (vitamin D-3). This paper therefore aims to provide an up-to-date overview of vitamin D-3 content in various animal foods. The focus lies on the natural vitamin D-3 content because there are many countries in which foods are not regularly fortified with vitamin D. The published data show that the highest values of vitamin D are found in fish and especially in fish liver, but offal also provides considerable amounts of vitamin D. The content in muscle meat is generally much lower. Vitamin D concentrations in egg yolks range between the values for meat and offal. If milk and dairy products are not fortified, they are normally low in vitamin D, with the exception of butter because of its high fat content. However, as recommendations for vitamin D intake have recently been increased considerably, it is difficult to cover the requirements solely by foodstuffs. 23692979 Proteomic analysis of differentially expressed proteins in lung cancer in Wistar rats using NNK as an inducer. Lung cancer is one of the commonest cancers detected worldwide with a high mortality rate. The responsible factors affecting survival include delayed prognosis, and lack of effective treatments. To help improve the disease management, there is a need for better screening and development of specific markers that help in the early diagnosis. Analysis of differentially expressed proteins in cancer cells in comparison to their normal counterparts using proteome profiling revealed identification of new biomarkers as therapeutic targets. Therefore, an animal model for lung cancer was developed and monitored by histopathological evaluation. Lung tissue proteins were isolated, solubilized and resolved on 2D gel electrophoresis using broad pH range IPG strips (pH 3-10). Liquid chromatography and mass spectrometry (LC-MS/MS) revealed 66 proteins to be differentially expressed in cancer tissue as compared to normal. The study identified and characterized three of these proteins, namely peroxiredoxin-6, β-actin and collagen α-1 (VI) as potentially prospective biomarkers for early detection of lung cancer. 23801727 Total mortality by elevated transferrin saturation in patients with diabetes. OBJECTIVE It is not known to what extent iron overload predicts prognosis in patients with diabetes after diagnosis or whether iron overload is a risk factor independent of the HFE genotype. We investigated total and cause-specific mortality according to increased transferrin saturation (≥50 vs. <50%), whether mortality is driven by the HFE genotype, and whether early measurement of transferrin saturation helps to predict mortality outcome. RESEARCH DESIGN AND METHODS Cohort 1 included patients with late-onset type 1 diabetes (n = 716) with a cross-sectional measurement of transferrin saturation and HFE genotype. Cohort 2 included consecutively recruited patients with any diabetes (n = 6,120), transferrin saturation measurement at referral, and HFE genotype if transferrin saturation was above 50%. RESULTS In cohort 1, the hazard ratio for total mortality was 2.3 (95% CI 1.3-3.9; P = 0.002) and for cause-specific mortality by neoplasms was 5.8 (2.4-14; P = 0.00007) in patients with transferrin saturation ≥50 vs. <50%. Excluding genotypes C282Y/C282Y and C282Y/H63D gave similar results. The hazard ratio for total mortality was 4.0 (1.2-13; P = 0.01) and for cause-specific mortality by neoplasms was 13 (3.6-49; P = 0.0001) in patients with C282Y/C282Y versus wild type. In cohort 2, total mortality was not different in patients with transferrin saturation ≥50 vs. <50%. In patients with late-onset type 1 diabetes and transferrin saturation ≥50%, the hazard ratio for total mortality was 0.4 (0.2-0.9; P = 0.03) in cohort 2 versus cohort 1. CONCLUSIONS Increased transferrin saturation and HFE genotype C282Y/C282Y predict total mortality in patients with late-onset type 1 diabetes, and increased transferrin saturation after diagnosis is an independent risk factor. Early measurement of transferrin saturation in these patients leading to early intervention improves life expectancy. 23932621 Cystic intratesticular lesions in pediatric patients. Intratesticular cysts are a rare clinical entity in the pediatric population. Recently, testes sparing surgery has been recommended. We share our experience with the management of pediatric testicular cysts. A retrospective review of all pediatric patients referred for intratesticular cysts was conducted at a single pediatric institution from 2002 to 2010. Charts were evaluated for patient demographics, diagnosis, and management. Seven patients were identified and included in this series. After partial orchiectomy, the final diagnosis in three patients was epidermoid cyst. Three further patients were diagnosed as mature cystic teratoma, with two of these demonstrating adjacent intra-tubular germ cell neoplasia (ITGCN). One cyst in the series underwent spontaneous resolution after eight months. All of the cystic lesions in our case series were benign with one undergoing complete resolution. The remainder became smaller and developed a solid component prompting surgery. The pre-pubertal findings of ITGCN in two patients raise a dilemma regarding the optimal long-term management for these patients. Initial conservative observation is an option for the majority of pre-pubertal cystic testicular lesions until such time that testis sparing surgery is deemed technically feasible. Testes sparing surgery should be advocated in those patients undergoing surgical management. 23955631 Sprouty4 regulates endothelial cell migration via modulating integrin β3 stability through c-Src. Angiogenesis is mediated by signaling through receptor tyrosine kinases (RTKs), Src family kinases and adhesion receptors such as integrins, yet the mechanism how these signaling pathways regulate one another remains incompletely understood. The RTK modulator, Sprouty4 (Spry4) inhibits endothelial cell functions and angiogenesis, but the mechanisms remain to be fully elucidated. In this study, we demonstrate that Spry4 regulates angiogenesis in part by regulating endothelial cell migration. Overexpression of Spry4 in human endothelial cells inhibited migration and adhesion on vitronectin (VTN), whereas knockdown of Spry4 enhanced these behaviors. These activities were shown to be c-Src-dependent and Ras-independent. Spry4 disrupted the crosstalk between vascular endothelial growth factor-2 and integrin αVβ3, the receptor for VTN. Spry4 overexpression resulted in decreased integrin β3 protein levels in a post-transcriptional manner in part by modulating its tyrosine phosphorylation by c-Src. Conversely, knockdown of Spry4 resulted in increased integrin β3 protein levels and tyrosine phosphorylation. Moreover, in vivo analysis revealed that Spry4 regulated integrin β3 levels in murine embryos and yolk sacs. Our findings identify an unanticipated role for Spry4 in regulating c-Src activity and integrin β3 protein levels, which contributes to the regulation of migration and adhesion of endothelial cells. Thus, targeting Spry4 may be exploited as a target in anti-angiogenesis therapies. 23842462 DBATE: database of alternative transcripts expression. The use of high-throughput RNA sequencing technology (RNA-seq) allows whole transcriptome analysis, providing an unbiased and unabridged view of alternative transcript expression. Coupling splicing variant-specific expression with its functional inference is still an open and difficult issue for which we created the DataBase of Alternative Transcripts Expression (DBATE), a web-based repository storing expression values and functional annotation of alternative splicing variants. We processed 13 large RNA-seq panels from human healthy tissues and in disease conditions, reporting expression levels and functional annotations gathered and integrated from different sources for each splicing variant, using a variant-specific annotation transfer pipeline. The possibility to perform complex queries by cross-referencing different functional annotations permits the retrieval of desired subsets of splicing variant expression values that can be visualized in several ways, from simple to more informative. DBATE is intended as a novel tool to help appreciate how, and possibly why, the transcriptome expression is shaped. DATABASE URL: http://bioinformatica.uniroma2.it/DBATE/. 23411331 Validation of methods for the detection and quantification of engineered nanoparticles in food. The potential impact of nanomaterials on the environment and on human health has already triggered legislation requiring labelling of products containing nanoparticles. However, so far, no validated analytical methods for the implementation of this legislation exist. This paper outlines a generic approach for the validation of methods for detection and quantification of nanoparticles in food samples. It proposes validation of identity, selectivity, precision, working range, limit of detection and robustness, bearing in mind that each "result" must include information about the chemical identity, particle size and mass or particle number concentration. This has an impact on testing for selectivity and trueness, which also must take these aspects into consideration. Selectivity must not only be tested against matrix constituents and other nanoparticles, but it shall also be tested whether the methods apply equally well to particles of different suppliers. In trueness testing, information whether the particle size distribution has changed during analysis is required. Results are largely expected to follow normal distributions due to the expected high number of particles. An approach of estimating measurement uncertainties from the validation data is given. 23354378 Methods for analysis of citrinin in human blood and urine. Citrinin (CIT), produced by several Penicillium, Aspergillus, and Monascus species, has been detected as contaminant in feeds, grains, and other food commodities. CIT can co-occur with ochratoxin A (OTA), a mycotoxin also known for its nephrotoxicity, and this raises concern regarding possible combined effects. But, in contrast to OTA, data on CIT contamination in foods for human consumption are scarce, and CIT biomonitoring has not been conducted so far due a lack of suitable methods for human specimen. Thus, it was the aim of the present study to develop sensitive methods for the analysis of CIT in human blood and urine to investigate human exposure. To this end, we assessed different methods of sample preparation and instrumental analysis for these matrices. Clean-up of blood plasma by protein precipitation followed by LC-MS/MS-based analysis allowed robust detection of CIT (LOD 0.07 ng/mL, LOQ 0.15 ng/mL). For urine, sample clean-up by an immunoaffinity column (CitriTest(®)) proved to be clearly superior to SPE with RP(18) material for subsequent analysis by LC-MS/MS. For CIT and its metabolite dihydrocitrinone (HO-CIT), the LOD and LOQ determined by external calibration curves in matrix were 0.02 and 0.05 ng/mL for CIT, and those for HO-CIT were 0.05 and 0.1 ng/mL urine. The newly developed method was applied in a small pilot study: CIT was present in all plasma samples from 8 German adults, at concentrations ranging from 0.11 to 0.26 ng/mL. The molar (nM) concentrations of CIT are similar to those measured for OTA in these samples as a result of dietary mycotoxin intake. CIT was detected in 8/10 urines (from 4 adults and 6 infants) in a range of 0.16-0.79 ng/mL, and HO-CIT was present in 5/10 samples at similar concentrations. Thus, CIT is excreted in urine as parent compound and also as metabolite. These first results in humans point to the need for further studies on CIT exposure. 23891581 Curvularia Abscess of the Brainstem: A Case Report. To present a unique case of a brainstem Curvularia fungal infection and review the diagnosis and management of this rare phenomenon. A 33-year-old immunocompetent African American male presented with two weeks of headache, nausea and vomiting in a setting of a recent 20-pound weight loss. Neurologic examination was positive for multiple cranial nerve palsies, hemisensory loss and gait instability. Magnetic resonance imaging demonstrated an enhancing medullary lesion. Metastatic and infectious workup revealed a left lung lesion, which on subsequent biopsy was positive for a granuloma yielding no further clues to the etiology of the brainstem lesion. On surgical exploration of the cranial lesion, a puss-filed, encapsulated lesion was encountered which was tightly adherent to the brainstem. Intraoperative biopsy of the lesion capsule was initially negative but on postoperative day nine, fungal hyphae were encountered identified on morphology as Curvularia species. The patient was started on triple antifungal therapy but necessitated a second surgery for lesion debulking and drainage. The patient was discharged home 10 weeks after initial presentation. At the 13-months follow-up the patient is doing very well and his neurologic exam continues to improve. This is the first reported case of a brainstem Curvularia infection. This case highlights the importance of an aggressive surgical and antibiotic therapy in the treatment of CNS Curvularia infections. There appears to be a strong relationship between heavy marijuana use and Curvularia infection, producing lung granulomas that may extend to other organs such as the CNS of immunocompetent patients. 23970415 Syndecan-4 signaling at a glance. Syndecan-4, a ubiquitous cell surface proteoglycan, mediates numerous cellular processes through signaling pathways that affect cellular proliferation, migration, mechanotransduction and endocytosis. These effects are achieved through syndecan-4 functioning as both a co-receptor for the fibroblast growth factor receptors (FGFR1-FGFR4) and its ability to independently activate signaling pathways upon ligand binding. As an FGFR co-receptor, syndecan-4 strengthens the duration and intensity of downstream signaling upon ligand binding; this is particularly evident with regard to mitogen-activated protein kinase (MAPK) signaling. In contrast, syndecan-4 also functions as an independent receptor for heparin-binding growth factors, such as fibroblast growth factors (FGFs), vascular endothelial growth factors (VEGFs) and platelet-derived growth factors (PDGFs). These signaling cascades affect canonical signaling components, such as the mammalian target of rapamycin (mTOR), AKT1 and the Rho family of GTPases. In combination with the integrin family of proteins, syndecan-4 is also able to form physical connections between the extracellular matrix (ECM) and cytoskeletal signaling proteins, and it has a key role in regulation of integrin turnover. This unique versatility of the interactions of syndecan-4 is characterized in this Cell Science at a Glance article and illustrated in the accompanying poster. 23906728 The ORF4a protein of human coronavirus 229E functions as a viroporin that regulates viral production. In addition to a set of canonical genes, coronaviruses encode additional accessory proteins. A locus located between the spike and envelope genes is conserved in all coronaviruses and contains a complete or truncated open reading frame (ORF). Previously, we demonstrated that this locus, which contains the gene for accessory protein 3a from severe acute respiratory syndrome coronavirus (SARS-CoV), encodes a protein that forms ion channels and regulates virus release. In the current study, we explored whether the ORF4a protein of HCoV-229E has similar functions. Our findings revealed that the ORF4a proteins were expressed in infected cells and localized at the endoplasmic reticulum/Golgi intermediate compartment (ERGIC). The ORF4a proteins formed homo-oligomers through disulfide bridges and possessed ion channel activity in both Xenopus oocytes and yeast. Based on the measurement of conductance to different monovalent cations, the ORF4a was suggested to form a non-selective channel for monovalent cations, although Li(+) partially reduced the inward current. Furthermore, viral production decreased when the ORF4a protein expression was suppressed by siRNA in infected cells. Collectively, this evidence indicates that the HCoV-229E ORF4a protein is functionally analogous to the SARS-CoV 3a protein, which also acts as a viroporin that regulates virus production. This article is part of a Special Issue entitled: Viral Membrane Proteins - Channels for Cellular Networking. 23844555 Emerging Trends for Radioimmunotherapy in Solid Tumors. Abstract Due to its ability to target both known and occult lesions, radioimmunotherapy (RIT) is an attractive therapeutic modality for solid tumors. Poor tumor uptake and undesirable pharmacokinetics, however, have precluded the administration of radioimmunoconjugates at therapeutically relevant doses thereby limiting the clinical utility of RIT. In solid tumors, efficacy of RIT is further compromised by heterogeneities in blood flow, tumor stroma, expression of target antigens and radioresistance. As a result significant efforts have been invested toward developing strategies to overcome these impediments. Further, there is an emerging interest in exploiting short-range, high energy α-particle emitting radionuclides for the eradication of minimal residual and micrometastatic disease. As a result several modalities for localized therapy and models of minimal disease have been developed for preclinical evaluation. This review provides a brief update on the recent efforts toward improving the efficacy of RIT for solid tumors, and development of RIT strategies for minimal disease associated with solid tumors. Further, some of promising approaches to improve tumor targeting, which showed promise in the past, but have now been ignored are also discussed. 23689135 Insights into the Mechanism of Ribosomal Incorporation of Mammalian L13a Protein during Ribosome Biogenesis. In contrast to prokaryotes, the precise mechanism of incorporation of ribosomal proteins into ribosomes in eukaryotes is not well understood. For the majority of eukaryotic ribosomal proteins, residues critical for rRNA binding, a key step in the hierarchical assembly of ribosomes, have not been well defined. In this study, we used the mammalian ribosomal protein L13a as a model to investigate the mechanism(s) underlying eukaryotic ribosomal protein incorporation into ribosomes. This work identified the arginine residue at position 68 of L13a as being essential for L13a binding to rRNA and incorporation into ribosomes. We also demonstrated that incorporation of L13a takes place during maturation of the 90S preribosome in the nucleolus, but that translocation of L13a into the nucleolus is not sufficient for its incorporation into ribosomes. Incorporation of L13a into the 90S preribosome was required for rRNA methylation within the 90S complex. However, mutations abolishing ribosomal incorporation of L13a did not affect its ability to be phosphorylated or its extraribosomal function in GAIT element-mediated translational silencing. These results provide new insights into the mechanism of ribosomal incorporation of L13a and will be useful in guiding future studies aimed at fully deciphering mammalian ribosome biogenesis. 23139355 Metabolite profiling reveals normal metabolic control in carriers of mutations in the glucokinase gene (MODY2). Mutations in the gene encoding glucokinase (GCK) cause a mild hereditary form of diabetes termed maturity-onset diabetes of the young (MODY)2 or GCK-MODY. The disease does not progress over time, and diabetes complications rarely develop. It has therefore been suggested that GCK-MODY represents a metabolically compensated condition, but experimental support for this notion is lacking. Here, we profiled metabolites in serum from patients with MODY1 (HNF4A), MODY2 (GCK), MODY3 (HNF1A), and type 2 diabetes and from healthy individuals to characterize metabolic perturbations caused by specific mutations. Analysis of four GCK-MODY patients revealed a metabolite pattern similar to that of healthy individuals, while other forms of diabetes differed markedly in their metabolite profiles. Furthermore, despite elevated glucose concentrations, carriers of GCK mutations showed lower levels of free fatty acids and triglycerides than healthy control subjects. The metabolite profiling was confirmed by enzymatic assays and replicated in a cohort of 11 GCK-MODY patients. Elevated levels of fatty acids are known to associate with β-cell dysfunction, insulin resistance, and increased incidence of late complications. Our results show that GCK-MODY represents a metabolically normal condition, which may contribute to the lack of late complications and the nonprogressive nature of the disease. 23791923 Opposing effects of dexamethasone, agrin and sugammadex on functional innervation and constitutive secretion of IL-6 in in vitro innervated primary human muscle cells. Neuromuscular junction development is the key process required for successful neuromuscular transmission and functional innervation of skeletal muscle fibres. Various substances can influence these processes, some of which are in common use in clinical practice. In the present study, the effects of the potentially new therapeutic agent agrin were followed, along with the widely used glucocorticoid dexamethasone. The in vitro experimental model used was functional innervation and constitutive interleukin 6 (IL-6) secretion of human muscle cells. Additionally, the selective relaxant binding agent sugammadex and its possible interaction with dexamethasone were followed. Dexamethasone impaired functional innervation while agrin had opposing effects. Furthermore, based on interference with IL-6 secretion, we show potential (chemical) interactions between dexamethasone and sugammadex. The physiological effects of this interaction should be taken into consideration under clinical conditions where these two drugs might be applied simultaneously. 23686108 Up-regulation of Slc39A2(Zip2) mRNA in peripheral blood mononuclear cells from patients with pulmonary tuberculosis. Zinc is the most common trace mineral after iron in the human body. In organisms, zinc transporters help zinc influx and efflux from cells. A previous study has reported that Zip2 was up-regulated over 27-fold in human monocytic THP-1 cells, when intracellular zinc was depleted by TPEN. Our study found Zip2 was over-expressed in leukocytes of asthmatic infants, especially those in which the serum zinc level was lower than those in healthy infants. Pulmonary tuberculosis (PTB) patients have significantly low serum zinc levels. Here we investigated whether Zip2 level was changed in the patients with PTB. Zip2 mRNA and protein levels in peripheral blood mononuclear cells (PBMC) from PTB (n 1 = 23) and healthy controls (n 2 = 42) were detected by quantitative real-time PCR and western blot, respectively. mRNA expression levels of another four zinc transporters, Zip1, Zip6, Zip8 and ZnT1, were detected by quantitative real-time PCR. Zip2 mRNA level was significantly up-regulated in PTB patients (P = 0.001), and Zip8 mRNA level was significantly down-regulated compared with control individuals (P < 0.001). In contrast, there were no significant changes in mRNA levels of Zip1, Zip6 and ZnT1 in either group (P > 0.05). Zip2 protein expression levels increased in PTB patients compared with control individuals. Our study found that knockdown of ZIP2 with siRNA caused a decrease in Zip2 levels in PBMC of PTB patients, while reducing the expression of INF-γ (P < 0.01) and increasing the expression of IL-6(P < 0.01). These data provide evidence that increased expression of Zip2 gene is closely associated with immunity of PTB patients, suggesting that the Zip2 gene may play a key role in the initial infection control of the human body, by promoting and maintaining the immune response of adaptive T cells. 23820327 Principles of assessment of abuse liability: US legal framework and regulatory environment. Identifying the abuse potential of drug products in the premarketing and postmarketing environment has been a critical component in the implementation of drug abuse control laws worldwide. In the US, the Controlled Substances Act of 1970 (CSA) is a comprehensive federal law enacted to prevent the abuse or diversion of substances with abuse liability or addiction potential (for present purposes, these terms are used interchangeably). Under the jurisdiction of the Drug Enforcement Administration, the law applies to the manufacture and distribution of narcotics and other drug substances with potential of abuse. The CSA classifies substances with abuse potential into schedules I-V based on the substance's risk of diversion or abuse, and thus provides a legal framework for the assessment of abuse liability of New Molecular Entities. When the Food and Drug Administration reviews the safety and efficacy of a New Drug Application it also determines whether the drug has potential for abuse, and if so, will begin the process to schedule the drug under the CSA. As the assessment of abuse potential is a critical component of a marketing application, pharmaceutical companies (sponsors) bear the responsibility of generating a comprehensive preclinical and clinical data package for regulators to review and make decisions on labeling and the corresponding postmarketing surveillance. Recent regulatory guidelines adopted in the European Union (EU) (2006), Canada (2007), and USA (2010) provide recommendations to sponsors on preclinical and clinical methodologies for the assessment of abuse potential. This paper reviews the legal framework of the assessment of abuse liability and scheduling of controlled substances in the USA and describes the current global regulatory environment and the challenges that sponsors and regulators face when assessing abuse liability of New Molecular Entities, from the early stages of development through the late stages, review, and approval. 23970952 Pathology is a critical aspect of preclinical aging studies. Experimental design for mouse aging studies has historically involved lifespan, but it is now clear that survival data without pathology data limit the information that can be obtained on aging animals. This limitation becomes more serious when interventions of any sort are implemented. Pathology gives an insight into the health of an animal by revealing lesions not readily observable in the live animal. As such, it is a snapshot of disease conditions at the time of death. Therefore, a long-term goal is to establish pathology information as an essential component of studies involving health span and lifespan of aging animals. Given that pathology assessment is essential to help define the progression of lesions associated with aging, the real challenge is including it in aging studies because there is currently a lack of specialized expertise and resources. An increase in the level and scope of pathology assessment of tissues from old mice involved in aging studies is needed. A focus on the correlation of pathology data with longitudinal and cross-sectional lifespan data and health span physiology data can be established by enhancing standard histologic assessment of lesions observed in tissues from old mice. An environment for the development and integration of pathology data into aging studies of mice is needed to encourage more pathologists and other scientists to specialize in pathology of aging, and establish relevant standards to compare with other species including humans. Such results will have an important positive impact on aging studies because of the significant empowerment on data analyses and interpretation. 23564072 The use of fentanyl buccal tablets for breakthrough pain by using doses proportional to opioid basal regimen in a home care setting. The dose of rapid onset opioids to be given for breakthrough cancer pain (BTcP) is controversial. Dose proportional to the basal opioid regimen seem to be safe and effective in hospital units. However, data in other less protected settings, like home care, are lacking. The aim of this open-label study was to assess the efficacy and safety in a group of patients with BTcP followed at home, after giving a dose of fentanyl buccal tablets (FBT) proportional to the opioid basal regimen, skipping the steps for dose titration. Consecutive patients admitted to a home care program presenting BTcP episodes and receiving stable doses of opioids for background pain were selected. Data from four consecutive episodes of BTcP were collected. For each episode, patients were instructed to routinely collect changes in pain intensity and severe adverse effects when pain got severe (T0) and to reassess the same items 15 min after FBT, given as a rescue medication in doses proportional to the daily opioid doses used for background pain (T15). One hundred twenty episodes of BTcP were recorded in 30 patients. One hundred eight episodes were defined as successfully treated, while 12 episodes required a further administration of opioids. Pain intensity significantly decreased at T15 (p < 0.001). In 95.5 and 90.8 % of episodes treated, there was a reduction in pain intensity of more than 33 and 50 %, respectively. No relevant adverse effects were recorded, even in older patients. This study suggests that FBT given in doses proportional to the basal opioid regimen for the management of BTcP is very effective and safe in clinical practice in the home care setting. 23967085 Aureolib - A Proteome Signature Library: Towards an Understanding of Staphylococcus aureus Pathophysiology. Gel-based proteomics is a powerful approach to study the physiology of Staphylococcus aureus under various growth restricting conditions. We analyzed 679 protein spots from a reference 2-dimensional gel of cytosolic proteins of S. aureus COL by mass spectrometry resulting in 521 different proteins. 4,692 time dependent protein synthesis profiles were generated by exposing S. aureus to nine infection-related stress and starvation stimuli (H2O2, diamide, paraquat, NO, fermentation, nitrate respiration, heat shock, puromycin, mupirocin). These expression profiles are stored in an online resource called Aureolib (http://www.aureolib.de). Moreover, information on target genes of 75 regulators and regulatory elements were included in the database. Cross-comparisons of this extensive data collection of protein synthesis profiles using the tools implemented in Aureolib lead to the identification of stress and starvation specific marker proteins. Altogether, 226 protein synthesis profiles showed induction ratios of 2.5-fold or higher under at least one of the tested conditions with 157 protein synthesis profiles specifically induced in response to a single stimulus. The respective proteins might serve as marker proteins for the corresponding stimulus. By contrast, proteins whose synthesis was increased or repressed in response to more than four stimuli are rather exceptional. The only protein that was induced by six stimuli is the universal stress protein SACOL1759. Most strikingly, cluster analyses of synthesis profiles of proteins differentially synthesized under at least one condition revealed only in rare cases a grouping that correlated with known regulon structures. The most prominent examples are the GapR, Rex, and CtsR regulon. In contrast, protein synthesis profiles of proteins belonging to the CodY and σ(B) regulon are widely distributed. In summary, Aureolib is by far the most comprehensive protein expression database for S. aureus and provides an essential tool to decipher more complex adaptation processes in S. aureus during host pathogen interaction. 23639626 TCDD induces the expression of insulin-like growth factor binding protein 4 in 5L rat hepatoma cells: a cautionary tale of the use of this cell line in studies on dioxin toxicity. Previous quantitative proteomic studies on the actions of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 5L rat hepatoma cells, a cell model frequently used for investigating the mechanisms of TCDD toxicity, had indicated that dioxin exposure reduced the abundance of numerous proteins which are regulated at the level of protein synthesis initiation. In the present study, we have analysed the mechanism mediating this inhibition. TCDD treatment of the cells largely prevented the activation of eukaryotic translation initiation factor 4E-binding protein 1, a regulator of translation initiation and substrate of the mammalian target of rapamycin (mTOR). By "working upwards" from mTOR, we observed that TCDD inhibited endogenous and IGF-I-induced AKT and ERK activation by interfering with tyrosine phosphorylation of insulin receptor substrate 1. This inhibition was mediated by a TCDD-induced secreted factor which was identified as insulin-like growth factor binding protein 4 (IGFBP-4). The induction of IGFBP-4 protein was dependent on a functional aryl hydrocarbon receptor and was preceded by a rapid increase in the level of IGFBP-4 mRNA indicating that IGFBP-4 is a previously unknown transcriptional target of TCDD in 5L cells. IGFBP-4 was not induced by TCDD in the parental cell line of 5L cells, Fao, and in various closely related rat hepatoma cell lines as well as in other unrelated cell types. Analysis of 5L cell chromosomes by multicolour spectral karyotyping (SKY) revealed that the cells carry several hitherto uncharacterised chromosomal translocations. The observations suggest that in 5L cells the Igfbp-4 gene may have got under the control of a promoter containing dioxin responsive element(s) leading to the induction of IGFBP-4 by TCDD. These findings emphasise a particular caution when interpreting and extrapolating results on the action mechanisms of TCDD obtained in studies using 5L cells as a model system. 23832654 Fluorination of BC3 nanotubes: DFT studies. We have studied the adsorption of atomic and molecular fluorines on a BC3 nanotube by using density functional calculations. It was found that the adsorption of atomic fluorine on a C atom of the tube surface is energetically more favorable than that on a B atom by about 0.97 eV. The adsorption of atomic fluorine on both C and B atoms significantly affects the electronic properties of the BC3 tube. The HOMO-LUMO energy gap is considerably reduced from 2.37 to 1.50 and 1.14 eV upon atomic F adsorption on B and C atoms, respectively. Molecular fluorine energetically tends to be dissociated on B atoms of the tube surface. The associative and dissociative adsorption energies of F2 were calculated to be about -0.42 and -4.79 eV, respectively. Electron emission density from BC3 nanotube surface will be increased upon both atomic and molecular fluorine adsorptions due to work function decrement. 23968548 AT1 antagonists: a patent review (2008 - 2012). Introduction: For two decades a class of pharmaceutical molecules with proved beneficial therapeutic properties, especially in hypertension, has been introduced in the market aiming to specifically prevent the detrimental effects of the peptide hormone Angiotensin II at the AT1 receptor. The prototype of this class was losartan and based on its structure, several drugs were launched and also called 'Sartans'. New structural features on these molecules can provide multi-target properties in the RAS or other systems. New methodologies were developed for the treatment of hypertension utilizing either AT1 antagonists alone or as cocktails. Areas covered: In this review article, authors aim to cover information provided by patents of the years 2008 - 2012. The rationale of writing this review article is to cover the most important patents which can forward the field with new important discoveries. Expert opinion: From the patent investigation it is clear that new areas on the subject are still offered for new discoveries. New structural features can be still considered in the synthetic compounds that can advance the knowledge and beneficial effects on diseases related to Angiotensin II and AT1 receptor. There is era also for new formulations (i.e., cyclodextrins, polymers and liposomes). The multitarget approach can be further strengthened and more combinations can be sought in the rational drug design for seeking cocktails. Furthermore, the revealing of the complexity of the RAS offers new avenues for novel targets and this must not be overlooked. 23936586 Surgical treatment of large substernal thyroid goiter: analysis of 12 patients. This study was carried out to evaluate the clinical presentation, surgical treatment, complications, and risk of malignancy for large substernal goiter. From March 2010 to December 2012, 12 patients with large substernal thyroid goiter who underwent surgery in our Department were enrolled in the study. Their medical records were retrospectively analyzed. Collar-shaped incision was adequate for resection of the lesions in 10 (83%) patients, while two (17%) patients required combined cervical-thoracic incision. In addition, one case was subjected to postoperative tracheotomy. Transient hypocalcaemia occurred in one case. The incidence of transient hoarseness, tracheomalacia and hypothyroidism was 8.3%. There was no perioperative bleeding, thyroid storm as well as other serious complications. All patients were clinically cured. Therefore, cervical collar incision is nearly always adequate for most cases of larger substernal goiter, and sternotomy can be avoided. Furthermore, the application of intraoperative ultrasonic knife can effectively reduce intraoperative and postoperative complications. Aggressive perioperative management is crucial for the successful removal of large substernal goiter. 23911881 Effect of fatty acids on the phosphate binding of TRK-390, a novel, highly selective phosphate-binding polymer. Phosphate binders are used for the treatment of hyperphosphatemia in hemodialysis patients with chronic kidney disease. Sevelamer, a phosphate-binding polymer, has been reported to bind bile acids or fatty acids and thereby decrease its phosphate-binding capacity. The novel phosphate binder TRK-390 is a poly (allylamine) polymer that has been shown to have enhanced phosphate selectivity, with low bile-acid-binding. In this study we evaluated the effect of fatty acids on the phosphate-binding capacity of TRK-390. In the absence of fatty acids and bile acids, the phosphate-binding capacity of TRK-390 was similar to that of sevelamer. In the presence of fatty acids and bile acids, the phosphate-binding capacity of TRK-390 was reduced to 83%; in contrast, that of sevelamer was reduced to 35%. TRK-390 and sevelamer showed a similar effect in lowering urinary phosphate excretion in normal rats fed a normal diet. However, urinary phosphate excretion of rats treated with TRK-390 was reduced by about one half of that obtained with sevelamer, when given with a high-fat diet that had a fat content similar to the diet of hemodialysis patients. TRK-390 was superior in terms of phosphate selectivity in the presence of fatty acids and bile acids in vitro, and the phosphate-binding capacity of TRK-390 in vivo was shown to be less affected by fat in comparison with that of sevelamer. Thus, TRK-390 is expected to be useful as a novel highly selective phosphate binder. 23763397 Between Individual Agency and Structure in HIV Prevention: Understanding the Middle Ground of Social Practice. When HIV prevention targets risk and vulnerability, it focuses on individual agency and social structures, ignoring the centrality of community in effective HIV prevention. The neoliberal concept of risk assumes individuals are rational agents who act on information provided to them regarding HIV transmission. This individualistic framework does not recognize the communities in which people act and connect. The concept of vulnerability on the other hand acknowledges the social world, but mainly as social barriers that make it difficult for individuals to act. Neither approach to HIV prevention offers understanding of community practices or collective agency, both central to success in HIV prevention to date. Drawing on examples of the social transformation achieved by community action in Australia and Brazil, this article focuses on this middle ground and its role in effective HIV prevention. 23782346 Inconsistent immunohistochemical expression of lymphatic and blood endothelial cell markers in cutaneous lymphangiomas. We sought to describe expression of the immunohistochemical markers, CD31, D2-40 and LYVE-1 (lymphatic vessel hyaluronan receptor-1), that may assist in differentiating cutaneous lymphangioma and cutaneous hemangioma. Immunohistochemical staining of lymphangioma and hemangioma specimens was completed with CD31, D2-40 and LYVE-1 antibodies. Thirty-three examples of lymphangioma and 13 examples of hemangioma were evaluated. CD31 was positive in 91% of lymphangioma and 100% of hemangioma (sensitivity 0.91, 95% confidence interval 0.75-0.98; specificity 0, 95% confidence interval 0-0.28). D2-40 was positive in 54% of lymphangioma and 23% in hemangioma (sensitivity 0.50 95% confidence interval 0.32-0.68; specificity 0.50 95% confidence interval 0.28-0.72). LYVE-1 was positive in 6% in lymphangioma and 15% hemangioma (sensitivity 0.06 95% confidence interval 0.01-0.22, specificity 0.85 95% confidence interval 0.54-0.97). Due to the similar embryonic origins, it is unlikely that a single marker may accurately differentiate the lymphangioma from hemangioma. A combination of immunohistochemical stains such CD31, D2-40 and LYVE-1 testing may potentially increase the diagnostic accuracy in differentiating lymphangioma from hemangioma. However, our findings suggest that there is no advantage in performing immunohistochemical staining to differentiate lymphangioma from hemangioma. 23868522 Posterior Hindfoot Arthroscopy: A Review. In recent years, minimally invasive surgery has developed and progressed the standard of care in orthopaedics and sports medicine. In particular, the use of posterior hindfoot arthroscopy in the treatment of posterior ankle and hindfoot injury is increasing rapidly as a means of reducing pain, infection rates, and blood loss postoperatively compared with traditional open procedures. In athletes, hindfoot arthroscopy has been used effectively in expediting rehabilitation and ultimately in minimizing the time lost from competition at previous levels. Van Dijk et al were the first to describe the original 2-portal technique, which remains the most commonly used by surgeons today and forms the basis for this review. The current evidence in the literature supports the use of 2-portal hindfoot arthroscopy as a safe, primary treatment strategy for symptoms of posterior ankle impingement, including resection of os trigonum, treatment of flexor hallucis longus and peroneal tendon injury, treatment of osteochondral lesions of the ankle, and the resection of subtalar coalitions. In this review, we present where possible an evidence-based literature review on the arthroscopic treatment of posterior ankle and hindfoot abnormalities. Causes, diagnosis, surgical technique, outcomes, and complications are each discussed in turn. 23715650 A Prospective Randomized Controlled Trial to Compare Pringle Manoeuvre with Hemi-hepatic Vascular Inflow Occlusion in Liver Resection for Hepatocellular Carcinoma with Cirrhosis. The duration of hepatic vascular inflow occlusion and the amount of intraoperative blood loss have significant negative impacts on postoperative morbidity, mortality and long-term survival outcomes of patients who receive partial hepatectomy for hepatocellular carcinoma (HCC) with cirrhosis. This study aimed to compare the perioperative outcomes of partial hepatectomy for HCC superimposed on hepatitis B-related cirrhosis using two different occlusion techniques. A randomized controlled trial was carried out to evaluate the impact of two different vascular inflow occlusion techniques. The postoperative short-term results were compared. During the study period, 252 patients received partial hepatectomy for HCC with cirrhosis. Of these patients, 120 were randomized equally into two groups: the Pringle manoeuvre group (n = 60) and the hemi-hepatic vascular inflow occlusion group (n = 60). The number of patients who had poor liver function on postoperative day 5 with ISLGS grade B or worse was 24 and 13, respectively (P = 0.030). The postoperative complication rate was significantly higher in the Pringle manoeuvre group (40 versus 22 %, P = 0.030). However, the Pringle manoeuvre group had significantly shorter operating time (116 versus 136 min, P = 0.012) although there was no significant difference in intraoperative blood loss between the two groups [200 ml (range 10-5,000 ml) versus 300 ml (range 100-1,000 ml); P = 0.511]. There was no perioperative mortality. The results indicated that for patients with HCC with cirrhosis, hemi-hepatic vascular inflow occlusion was a better inflow occlusion method than Pringle manoeuvre. 23740224 Dabigatran versus warfarin anticoagulation before and after catheter ablation for the treatment of atrial fibrillation. Systemic thromboembolism and bleeding remain the two most common and serious complications of catheter ablation of atrial fibrillation. A variety of periprocedure anticoagulation strategies have been proposed to mitigate these risks. Although operators are now routinely administering dabigatran for anticoagulation in this setting, its relative safety and effectiveness compared to warfarin are unknown. A total of 202 patients received dabigatran as part of their periprocedural anticoagulation regimen at the time of initial or redo catheter ablation for symptomatic atrial fibrillation. A comparison group of 202 patients treated with warfarin was randomly selected from patients undergoing atrial fibrillation (AF) ablation during the same time period. AF types were paroxysmal in 223 patients, persistent in 158 patients, and longstanding persistent in 13 patients. Mean age was 60.0 ±â€‰10.5 years, 55 % had a history of hypertension, and mean CHADS-VASc score was 1.7 ±â€‰1.3. "Continuous" warfarin or dabigatran was administered in 80 and 32 % of patients, respectively. Time to first dose of dabigatran post-procedure was 12.2 ±â€‰10.3 h. Two dabigatran and no warfarin-treated patients had systemic thromboembolism (p = NS); five dabigatran and three warfarin-treated patients had bleeding complications (p = NS, combined endpoint p = 0.116). One dabigatran patient had severe pericardial bleeding (3 L blood loss). In a retrospective pilot trial comparing the risks of systemic thromboembolism or bleeding complications in patients treated with warfarin or dabigatran anticoagulation, the outcomes were similar. A prospective trial is warranted. 23687226 Role of Intestinal Mucosal Integrity in HIV Transmission to Infants Through Breast-feeding: The BAN Study. Background. Increased intestinal permeability may be one of the mechanisms of transmission of human immunodeficiency virus (HIV) to infants through breast-feeding. Intestinal permeability correlates with microbial translocation, which can be measured through quantification of bacterial lipopolysaccharide (LPS). Methods. We evaluated levels of plasma LPS (by the Limulus amebocyte lysate assay) and immune activation markers in serial specimens from infants exposed to but uninfected with HIV and infants infected with HIV from the Breastfeeding, Antiretrovirals, and Nutrition (BAN) study. Results. Plasma LPS levels increased after infants in the BAN study were weaned from the breast, at 24 weeks of age. Cotrimoxazole prophylaxis was associated with higher plasma LPS levels (P = .004). Infants with HIV infection had higher LPS levels, compared with uninfected infants (P = .004). Higher preinfection plasma LPS levels were a significant predictor of infant HIV infection through breast-feeding (hazard ratio = 1.60 for every unit increase in plasma LPS level; P = .01) and of lower infant length-for-age z scores (P = .02). Conclusions. These findings suggest that disruption in intestinal integrity is a mechanism of HIV transmission to infants through breast-feeding. Weaning from breast milk and use of antibiotic prophylaxis was associated with increased levels of microbial translocation, which could facilitate HIV entry through the intestine. Complementary approaches to enhance intestinal mucosal integrity in the infant may further reduce breast-feeding transmission of HIV. 23865651 Longitudinal associations between types of childhood trauma and suicidal behavior among substance users: a cohort study. Objectives. We examined the longitudinal associations between different types and severities of childhood trauma and suicide attempts among illicit drug users. Methods. Data came from 2 prospective cohort studies of illicit drug users in Vancouver, Canada, in 2005 to 2010. We used recurrent event proportional means models to estimate adjusted and weighted associations between types and severities of childhood maltreatment and suicide attempts. Results. Of 1634 participants, 411 (25.2%) reported a history of suicidal behavior at baseline. Over 5 years, 80 (4.9%) participants reported 97 suicide attempts, a rate of 2.6 per 100 person-years. Severe to extreme levels of sexual abuse (adjusted hazard ratio [AHR] = 2.5; 95% confidence interval [CI] = 1.4, 4.4), physical abuse (AHR = 2.0; 95% CI = 1.1, 3.8), and emotional abuse (AHR = 3.5; 95% CI = 1.4, 8.7) predicted suicide attempts. Severe forms of physical and emotional neglect were not significantly associated with an increased risk of suicidal behavior. Conclusions. Severe sexual, physical, and emotional childhood abuse confer substantial risk of repeated suicidal behavior in adulthood. Illicit drug users require intensive secondary suicide prevention efforts, particularly among those with a history of childhood trauma. 23932857 Integral backstepping sliding mode control for underactuated systems: Swing-up and stabilization of the Cart-Pendulum System. In this paper an integral backstepping sliding mode controller is proposed for controlling underactuated systems. A feedback control law is designed based on backstepping algorithm and a sliding surface is introduced in the final stage of the algorithm. The backstepping algorithm makes the controller immune to matched and mismatched uncertainties and the sliding mode control provides robustness. The proposed controller ensures asymptotic stability. The effectiveness of the proposed controller is compared against a coupled sliding mode controller for swing-up and stabilization of the Cart-Pendulum System. Simulation results show that the proposed integral backstepping sliding mode controller is able to reject both matched and mismatched uncertainties with a chattering free control law, while utilizing less control effort than the sliding mode controller. 23023720 Kidney transplantation and enzyme replacement therapy in patients with Fabry disease. During Fabry disease, progressive glycosphingolipid deposition in the kidney causes gradual deterioration of renal function with proteinuria, uremia and hypertension. This results in end-stage renal disease (ESRD) which is one of the leading causes of morbidity and premature mortality in affected patients. Given the excellent graft and patient survival generally nowadays, kidney transplantation is the first choice to correct renal dysfunction and improve the overall prognosis of patients with renal failure because of Fabry disease. The benefit of enzyme-replacement therapy (ERT) in kidney transplanted Fabry patients has been controversially discussed and long-term trials focusing on the effectiveness of agalsidase in this patient population are needed. 23933276 Increased TERC gene copy number and cells in senescence in primary sclerosing cholangitis compared to colitis and control patients. Primary sclerosing cholangitis (PSC) is a chronic cholestatic disorder that involves inflammatory and fibrotic changes in the bile ducts. Up to 80% of patients have concomitant inflammatory bowel disease (IBD) with colitis. PSC patients are predisposed to develop hepatobiliary, colonic and other extrahepatic malignancies, probably related to inflammatory processes that might promote carcinogenesis. Telomerase is an enzyme complex that lengthens telomeres and has enhanced expression in numerous malignancies. In this study, we evaluated the TERC gene copy number, the proportion of cells in senescence and the amount of fragmentation in the senescent state. Fluorescence in situ hybridization (FISH) for the TERC gene was applied to lymphocytes retrieved from PSC (N=19), colitis (N=20) and healthy control patients (N=20) to determine the TERC copy number. On the same FISH slides, cells stained with DAPI were also analyzed for senescence-associated heterochromatin foci (SAHF) status, including the number of cells with fragments (SAHF) and the number of SAHF fragments in each cell. A higher TERC gene copy number was observed in cells from PSC patients compared to colitis and control group patients. It was also higher in the colitis than in the control group. Significantly more cells in the senescent state and more fragmentation in each cell were observed in the PSC group compared to colitis and control groups. The TERC gene copy number and the number of cells in the senescent state were increased in PSC patients compared to the colitis and control groups. These findings are probably related to the genetic instability parameters that reflect the higher tendency of this patient group to develop malignancies. 23194520 Contents of dietary fibre components and their relation to associated bioactive components in whole grain wheat samples from the HEALTHGRAIN diversity screen. A large and diverse material collection of whole grain wheat samples (n=129) was analysed for total dietary fibre (TDF) content and composition, including fructan (11.5-15.5%). Correlations between the dietary fibre components, associated bioactive components (e.g. tocols, sterols, phenolic acids and folates) and agronomic properties previously determined on the same samples were found with multivariate analysis (PCA). Samples from the same countries had similar characteristics. The first PC described variation in components concentrated in the starchy endosperm (e.g. starch, β-glucan and fructan) and the dietary fibre components concentrated in the bran (e.g. TDF, arabinoxylan and cellulose). The second PC described the variation in kernel weight and other bran components such as alkylresorcinols, tocols and sterols. Interestingly, there was no correlation among these different groups of bran components, which reflected their concentration in different bran tissues. The results are of importance for plant breeders who wish to develop varieties with health-promoting effects. 23893248 Glomerular interactions in olfactory processing channels of the antennal lobes. An open question in olfactory coding is the extent of interglomerular connectivity: do olfactory glomeruli and their neurons regulate the odorant responses of neurons innervating other glomeruli? In the olfactory system of the moth Manduca sexta, the response properties of different types of antennal olfactory receptor cells are known. Likewise, a subset of antennal lobe glomeruli has been functionally characterized and the olfactory tuning of their innervating neurons identified. This provides a unique opportunity to determine functional interactions between glomeruli of known input, specifically, (1) glomeruli processing plant odors and (2) glomeruli activated by antennal stimulation with pheromone components of conspecific females. Several studies describe reciprocal inhibitory effects between different types of pheromone-responsive projection neurons suggesting lateral inhibitory interactions between pheromone component-selective glomerular neural circuits. Furthermore, antennal lobe projection neurons that respond to host plant volatiles and innervate single, ordinary glomeruli are inhibited during antennal stimulation with the female's sex pheromone. The studies demonstrate the existence of lateral inhibitory effects in response to behaviorally significant odorant stimuli and irrespective of glomerular location in the antennal lobe. Inhibitory interactions are present within and between olfactory subsystems (pheromonal and non-pheromonal subsystems), potentially to enhance contrast and strengthen odorant discrimination. 23739800 Characterization of Edenia gomezpompae Isolated from a Patient with Keratitis. Edenia gomezpompae, isolated from a patient suffering from keratitis, who was an agricultural worker with a 4-year history of diabetes mellitus, is described. Fungal hyphae were detected in corneal scrapings after microscopic examination and repeated culture. Isolates were identified by morphology and by sequencing the internal transcribed spacer region of ribosomal DNA. Chlamydospore characteristics of E. gomezpompae are described for the first time. The in vitro antifungal susceptibilities of the isolate were tested using five antifungal agents. With the exception of fluconazole, the other drugs (natamycin, amphotericin B, itraconazole, and voriconazole) assayed were highly effective against this fungus. The keratitis was cured after debridement of the corneal ulcer and treatment with 5 % natamycin. After 3 months, when the patient was reexamined, the corneal ulcer showed signs of healing, with no recurrence. To our knowledge, this is the first reported case of keratitis caused by E. gomezpompae, as well as being the first known case of disease in humans caused by this species. 23247057 17β estradiol regulation of connexin 43-based gap junction and mechanosensitivity through classical estrogen receptor pathway in osteocyte-like MLO-Y4 cells. Connexin 43 (Cx43) plays an essential role in osteocyte mechanotransduction. Although estrogen involves in the adaptive responses of bone cells to mechanical loadings, its effects on osteocytic Cx43-based gap junction intercellular communication (GJIC) remain obscure. We found that 17β estradiol (E2) up-regulated Cx43, and enhanced GJIC in osteocyte-like MLO-Y4 cells in fluorescence recovery after photobleaching (FRAP) assay. Combination of E2 pre-treatment and oscillating fluid flow (OFF) further enhanced Cx43 expression and mitogen-activated protein kinase (MAPK) phosphorylation, comparing to E2 or OFF treatment alone. Both blocking of classical estrogen receptors (ERα/β) by fulvestrant and ERα knockdown by small interfering RNA inhibited E2-mediated Cx43 increase, while a GPR30-specific agonist G-1 failed to promote Cx43 expression. Our results suggest that the presence of E2 enhanced Cx43-based GJIC mainly via ERα/β pathway, and sensitized osteocytes to mechanical loading. 23848258 La santé des pasteurs mobiles au Sahel - Bilan de 15 années de recherches et développement. Dans le Sahel, entre la Mauritanie et la Somalie incluant le Nord Kenya, environ 20 à 30 millions de personnes vivent en transhumance. Le rythme de leur migration suit l'évolution saisonnière du climat et la disponibilité des ressources, telle que l'eau, le pâturage et le sel. Malgré une exposition élevée à certaines maladies comme les zoonoses et les problèmes conditionnés liés au climat, les pasteurs mobiles sont parmi les populations quasiment exclues du système de santé, car la mise à disposition des services sociaux adaptés à un mode de vie mobile est difficile. Suivant l'objectif de recherche d'un meilleur accès aux soins des pasteurs mobiles, l'Institut Tropical et de Santé Publique Suisse, en partenariat avec plusieurs institutions dans la région, est actif au Sahel depuis 15 ans, aussi bien dans le domaine de la recherche, que celui des actions de développement. Basées sur une approche orientée vers les besoins des pasteurs mobiles pour leur développement, des recherches interdisciplinaires ont contribué à mieux comprendre la situation et les problèmes des éleveurs. En relation de la proximité entre l'homme et son bétail, une approche unissant la santé humaine et animale s'est avérée bonne et la valeur ajoutée d'une meilleure collaboration entre médecine humaine, animale et l'environnement a été démontrée. Ces approches utiles devraient être poursuivies et consolidées dans les recherches et le développement des actions futurs. 23668814 Model complexity needed for quantitative analysis of high resolution isotope and concentration data from a toluene-pulse experiment. Separating microbial- and physical-induced effects on the isotope signals of contaminants has been identified as a challenge in interpreting compound-specific isotope data. In contrast to simple analytical tools, such as the Rayleigh equation, reactive-transport models can account for complex interactions of different fractionating processes. The question arises how complex such models must be to reproduce the data while the model parameters remain identifiable. In this study, we reanalyze the high-resolution data set of toluene concentration and toluene-specific δ(13)C from the toluene-pulse experiment performed by Qiu et al. (this issue). We apply five reactive-transport models, differing in their degree of complexity. We uniquely quantify degradation and sorption properties of the system for each model, estimate the contributions of biodegradation-induced, sorption-induced, and transverse-dispersion-induced isotope fractionation to the overall isotope signal, and investigate the error introduced in the interpretation of the data when individual processes are neglected. Our results show that highly resolved data of both concentration and isotope ratios are needed for unique process identification facilitating reliable model calibration. Combined analysis of these highly resolved data demands reactive transport models accounting for nonlinear degradation kinetics and isotope fractionation by both reactive and physical processes such as sorption and transverse dispersion. 23405988 Adsorption of model perfumes at the air-solution interface by coadsorption with an anionic surfactant. The adsorption of the model perfumes phenyl ethanol, PE, and linalool, LL, at the air-solution interface by coadsorption with the anionic surfactant sodium dodecyl 6-benezene sulfonate, LAS-6, has been studied primarily by neutron reflectivity, NR. The variation in the mixed surface adsorption with solution composition is highly nonideal, and the more hydrophobic LL is more surface active. At a LAS-6 concentration of 0.5 mM the adsorption of PE and LL is broadly similar but with the LL systematically more surface active, and at 2 mM the LL completes more effectively for the surface than the PE. The variation in surface composition with solution composition and concentration reflect the greater hydrophobicity and hence surface activity of LL, and the greater solubility of PE in aqueous solution. Changing the geometry of the LAS isomer, from the symmetrical LAS-6 geometry to the more asymmetrical LAS-4, results in the LL competing more effectively for the surface due to changes in the packing constraints associated with the hydrophobic region. The results provide insights into the factors that affect coadsorption that can be more broadly applied to the surface delivery of a wide range of molecules other than perfumes. 23838009 Receptor-mediated Ca(2+) and PKC signaling triggers the loss of cortical PKA compartmentalization through the redistribution of gravin. A-Kinase Anchoring Proteins (AKAPs) direct the flow of cellular information by positioning multiprotein signaling complexes into proximity with effector proteins. However, certain AKAPs are not stationary but can undergo spatiotemporal redistribution in response to stimuli. Gravin, a 300kD AKAP that intersects with a diverse signaling array, is localized to the plasma membrane but has been shown to translocate to the cytosol following the elevation of intracellular calcium ([Ca(2+)]i). Despite the potential for gravin redistribution to impact multiple signaling pathways, the dynamics of this event remain poorly understood. In this study, quantitative microscopy of cells expressing gravin-EGFP revealed that Ca(2+) elevation caused the complete translocation of gravin from the cell cortex to the cytosol in as little as 60s of treatment with ionomycin or thapsigargin. In addition, receptor mediated signaling was also shown to cause gravin redistribution following ATP treatment, and this event required both [Ca(2+)]i elevation and PKC activation. To understand the mechanism for Ca(2+) mediated gravin dynamics, deletion of calmodulin-binding domains revealed that a fourth putative calmodulin binding domain called CB4 (a.a. 670-694) is critical for targeting gravin to the cell cortex despite its location downstream of gravin's membrane-targeting domains, which include an N-terminal myristoylation site and three polybasic domains. Finally, confocal microscopy of cells co-transfected with gravin-EYFP and PKA RII-ECFP revealed that gravin redistribution mediated by ionomycin, thapsigargin, and ATP each triggered the gravin-dependent loss of PKA localized at the cell cortex. Our results support the hypothesis that gravin redistribution regulates cross-talk between PKA-dependent signaling and receptor-mediated events involving Ca(2+) and PKC. 23925698 Stability of Si epoxide defects in Si nanowires: a mixed reactive force field/DFT study. Modeling the oxidation process of silicon nanowires through reactive force field based molecular dynamics simulations suggests that the formation of Si epoxide defects occurs both at the Si/SiOx interface and at the nanowire surface, whereas for flat surfaces, this defect is experimentally observed to occur only at the interface as a result of stress. In this paper, we argue that the increasing curvature stabilizes the defect at the nanowire surface, as suggested by our density functional theory calculations. The latter can have important consequences for the opto-electronic properties of thin silicon nanowires, since the epoxide induces an electronic state within the band gap. Removing the epoxide defect by hydrogenation is expected to be possible but becomes increasingly difficult with a reduction of the diameter of the nanowires. 23857505 Detection of small (≤2 cm) HCC in cirrhotic patients: added value of diffusion MR-imaging. To evaluate the usefulness of the diffusion-weighted sequence in the detection of small (≤2 cm) hepatocellular carcinoma (HCC) in patients with cirrhosis. Seventy cirrhotic patients with 93 HCCs underwent MR-Imaging at 1.5 T. MR acquisitions comprised unenhanced T1- and T2-weighted images and post-contrast Gd-BOPTA-enhanced T1W GRE-3D images acquired after approximately 25, 60, 180 s (dynamic phases) and 90 min (hepatobiliary phase). DWI was performed by a SSEPI sequence (b values 0, 50, 400, 800 s/mm(2)). Quantitative analysis was performed to establish significant difference of ADC values of benign lesions compared with that of HCC. Sensitivity, specificity, positive and negative predictive values and diagnostic accuracy of two different protocols with and without diffusion MRI sequence were also calculated and compared each other. A good inverse correlation was found between reference standard and ADC values (ρ = -0.688). The mean ADC value of HCC was significantly lower than the mean value of benign focal liver lesions (p < 0.0001). No significant difference was reported in term of sensitivity, specificity, PPV, NPV and diagnostic accuracy between the two datasets. A trend to a better sensitivity was found when DWI images were considered. The adjunction of DWI does not significantly improve the diagnostic accuracy in the detection of small HCC. 23838948 WHO defined daily doses versus hospital-adjusted defined daily doses: impact on results of antibiotic use surveillance. To investigate effects on surveillance results of hospital antibiotic use when WHO defined daily doses (WHO DDDs) are adjusted to doses recommended for hospitalized patients [hospital-adjusted defined daily doses (haDDDs)]. Data for antibiotic use in 2006-11 for all 22 Norwegian Health Enterprises were analysed with both WHO DDDs and haDDDs as numerators. The haDDDs were determined from recommendations given in regional and national guidelines on antibiotic use in hospitals. The two ways of calculating the amount of antibiotic use were compared, with either the number of bed days (BDs) or the number of discharges as the denominator. The drug utilization 90% methodology was applied for ranking the use of the various antibiotics. DDD adjustments altered the figures for total antibiotic use from 67.1 WHO DDDs/100 BDs to 49.3 haDDDs/100 BDs (-26.4%). The most marked difference was found for penicillins: 31.1 WHO DDDs/100 BDs versus 13.4 haDDDs/100 BDs (-56.8%). The corresponding figures for broad-spectrum antibiotics were 17.3 and 15.5 (-10.4%), respectively; for these antibiotics, the conversion changes varied significantly between institutions, from -16.7% to -3.3%. Ranking antibiotic use based on haDDDs resulted in higher positions for metronidazole, cefuroxime, cefotaxime and cefalotin/cefalexin compared with the WHO DDD-based ranking, where the penicillins dominated. The low-set WHO DDDs for penicillins caused skewed surveillance results that concealed the real magnitude of broad-spectrum antibiotic use and distorted interhospital comparisons. For surveillance of antibiotic use in hospitals, WHO DDDs should be supplemented with haDDDs. 23765069 Preparation of a semiquinonate-bridged diiron(II) complex and elucidation of its geometric and electronic structures. The synthesis and crystal structure of a diiron(II) complex containing a bridging semiquinonate radical are presented. The unique electronic structure of this S = 7/2 complex is examined with spectroscopic (absorption, EPR, resonance Raman) and computational methods. 23684687 Changes in Cardiovascular Risk Factors by Hysterectomy Status With and Without Oophorectomy: Study of Women's Health Across the Nation. The aim of this study was to compare the changes in risk factors for cardiovascular disease (CVD) leading up to and after hysterectomy with or without bilateral oophorectomy with the changes observed up to and after natural menopause. Evidence suggests that hysterectomy status with or without bilateral oophorectomy might increase risk for CVD, but most studies retrospectively assess menopausal status. Study of Women's Health across the Nation enrolled 3,302 pre-menopausal women not using hormone therapy between 42 and 52 years of age and followed them annually for over 11 years for sociodemographic characteristics, menopausal status, surgeries, body mass index, medication use, lifestyle factors, lipids, blood pressure, insulin resistance, and hemostatic and inflammatory factors. By 2008, 1,769 women had reached natural menopause, 77 women had a hysterectomy with ovarian conservation, and 106 women had a hysterectomy with bilateral oophorectomy. Piece-wise hierarchical growth models compared these groups on annual changes in CVD risk factors before and after final menstrual period or surgery. Multivariable analyses showed that annual changes in CVD risk factors did not vary by group, with few exceptions, and the significant group differences that did emerge were not in the anticipated direction. Hysterectomy with or without ovarian conservation is not a key determinant of CVD risk factor status either before or after elective surgery in midlife. These results should provide reassurance to women and their clinicians that hysterectomy in midlife is unlikely to accelerate the CVD risk of women. 23922681 The apgar score and infant mortality. To evaluate if the Apgar score remains pertinent in contemporary practice after more than 50 years of wide use, and to assess the value of the Apgar score in predicting infant survival, expanding from the neonatal to the post-neonatal period. The U.S. linked live birth and infant death dataset was used, which included 25,168,052 singleton births and 768,305 twin births. The outcome of interest was infant death within 1 year after birth. Cox proportional hazard-model was used to estimate risk ratio of infant mortality with different Apgar scores. Among births with a very low Apgar score at five minutes (1-3), the neonatal and post-neonatal mortality rates remained high until term (≥ 37 weeks). On the other hand, among births with a high Apgar score (≥7), neonatal and post-neonatal mortality rate decreased progressively with gestational age. Non-Hispanic White had a consistently higher neonatal mortality than non-Hispanic Black in both preterm and term births. However, for post-neonatal mortality, Black had significantly higher rate than White. The pattern of changes in neonatal and post-neonatal mortality by Apgar score in twin births is essentially the same as that in singleton births. The Apgar score system has continuing value for predicting neonatal and post-neonatal adverse outcomes in term as well as preterm infants, and is applicable to twins and in various race/ethnic groups. 23836769 Determination of the infectious nature of the agent of acute hepatopancreatic necrosis syndrome affecting penaeid shrimp. A new emerging disease in shrimp, first reported in 2009, was initially named early mortality syndrome (EMS). In 2011, a more descriptive name for the acute phase of the disease was proposed as acute hepatopancreatic necrosis syndrome (AHPNS). Affecting both Pacific white shrimp Penaeus vannamei and black tiger shrimp P. monodon, the disease has caused significant losses in Southeast Asian shrimp farms. AHPNS was first classified as idiopathic because no specific causative agent had been identified. However, in early 2013, the Aquaculture Pathology Laboratory at the University of Arizona was able to isolate the causative agent of AHPNS in pure culture. Immersion challenge tests were employed for infectivity studies, which induced 100% mortality with typical AHPNS pathology to experimental shrimp exposed to the pathogenic agent. Subsequent histological analyses showed that AHPNS lesions were experimentally induced in the laboratory and were identical to those found in AHPNS-infected shrimp samples collected from the endemic areas. Bacterial isolation from the experimentally infected shrimp enabled recovery of the same bacterial colony type found in field samples. In 3 separate immersion tests, using the recovered isolate from the AHPNS-positive shrimp, the same AHPNS pathology was reproduced in experimental shrimp with consistent results. Hence, AHPNS has a bacterial etiology and Koch's Postulates have been satisfied in laboratory challenge studies with the isolate, which has been identified as a member of the Vibrio harveyi clade, most closely related to V. parahemolyticus. 23936136 Zinc finger protein 148 is dispensable for primitive and definitive hematopoiesis in mice. Hematopoiesis is regulated by transcription factors that induce cell fate and differentiation in hematopoietic stem cells into fully differentiated hematopoietic cell types. The transcription factor zinc finger protein 148 (Zfp148) interacts with the hematopoietic transcription factor Gata1 and has been implicated to play an important role in primitive and definitive hematopoiesis in zebra fish and mouse chimeras. We have recently created a gene-trap knockout mouse model deficient for Zfp148, opening up for analyses of hematopoiesis in a conventional loss-of-function model in vivo. Here, we show that Zfp148-deficient neonatal and adult mice have normal or slightly increased levels of hemoglobin, hematocrit, platelets and white blood cells, compared to wild type controls. Hematopoietic lineages in bone marrow, thymus and spleen from Zfp148 (gt/gt) mice were further investigated by flow cytometry. There were no differences in T-cells (CD4 and CD8 single positive cells, CD4 and CD8 double negative/positive cells) in either organ. However, the fraction of CD69- and B220-positive cells among lymphocytes in spleen was slightly lower at postnatal day 14 in Zfp148 (gt/gt) mice compared to wild type mice. Our results demonstrate that Zfp148-deficient mice generate normal mature hematopoietic populations thus challenging earlier studies indicating that Zfp148 plays a critical role during hematopoietic development. 23018288 Vomiting should be a prompt predictor of stroke outcome. To predict the outcome of stroke at an acute stage is important but still difficult. Vomiting is one of the commonest symptoms in stroke patients. The aim of this study is threefold: first, to examine the percentage of vomiting in each of the three major categories of strokes; second, to investigate the association between vomiting and other characteristics and third, to determine the correlation between vomiting and mortality. We investigated the existence or absence of vomiting in stroke patients in the Kyoto prefecture cohort. We compared the characteristics of patients with and without vomiting. We calculated the HR for death in both types of patients, adjusted for age, sex, blood pressure, arrhythmia, tobacco and alcohol use and paresis. Of the 1968 confirmed stroke patients, 1349 (68.5%) had cerebral infarction (CI), 459 (23.3%) had cerebral haemorrhage (CH) and 152 (7.7%) had subarachnoid haemorrhage (SAH). Vomiting was seen in 14.5% of all stroke patients. When subdivided according to stroke type, vomiting was observed in 8.7% of CI, 23.7% of CH and 36.8% of SAH cases. HR for death and 95% CI were 5.06 and 3.26 to 7.84 (p<0.001) when all stroke patients were considered, 5.27 and 2.56 to 10.83 (p<0.001) in CI, 2.82 and 1.33 to 5.99 (p=0.007) in CH and 5.07 and 1.87 to 13.76 (p=0.001) in SAH. Compared with patients without vomiting, the risk of death was significantly higher in patients with vomiting at the onset of stroke. Vomiting should be an early predictor of the outcome. 23931302 Force to divide: structural and mechanical requirements for actomyosin ring contraction. One of the unresolved questions in the field of cell division is how the actomyosin cytoskeleton remains structurally organized while generating the contractile force to divide one cell into two. In analogy to the actomyosin-based force production mechanism in striated muscle, it was originally proposed that contractile stress in the actomyosin ring is generated via a sliding filament mechanism within an organized sarcomere-like array. However, over the last 30 years, ultrastructural and functional studies have noted important distinctions between cytokinetic structures in dividing cells and muscle sarcomeres. Myosin-II motor activity is not always required, and there is evidence that actin depolymerization contributes to contraction. In this Review, the architecture and contractile dynamics of the actomyosin ring at the cell division plane will be discussed. We will report the interdisciplinary advances in the field as well as their integration into a mechanistic understanding of contraction in cell division and in other biological processes that rely on an actomyosin-based force-generating system. 23898266 A simple implantation method for flexible, multisite microelectrodes into rat brains. A long term functional and reliable coupling between neural tissue and implanted microelectrodes is the key issue in acquiring neural electrophysiological signals or therapeutically excite neural tissue. The currently often used rigid micro-electrodes are thought to cause a severe foreign body reaction resulting in a thick glial scar and consequently a poor tissue-electrode coupling in the chronic phase. We hypothesize, that this adverse effect might be remedied by probes compliant to the soft brain tissue, i.e., replacing rigid electrodes by flexible ones. Unfortunately, this flexibility comes at the price of a low stiffness, which makes targeted low trauma implantation very challenging. In this study, we demonstrate an adaptable and simple method to implant extremely flexible microprobes even to deep areas of rat's brain. Implantation of flexible probes is achieved by rod supported stereotactic insertion fostered by a hydrogel (2% agarose in PBS) cushion on the exposed skull. We were thus able to implant very flexible micro-probes in 70 rats as deep as the rodent's subthalamic nucleus. This work describes in detail the procedures and steps needed for minimal invasive, but reliable implantation of flexible probes. 23877069 Optical control of mammalian endogenous transcription and epigenetic states. The dynamic nature of gene expression enables cellular programming, homeostasis and environmental adaptation in living systems. Dissection of causal gene functions in cellular and organismal processes therefore necessitates approaches that enable spatially and temporally precise modulation of gene expression. Recently, a variety of microbial and plant-derived light-sensitive proteins have been engineered as optogenetic actuators, enabling high-precision spatiotemporal control of many cellular functions. However, versatile and robust technologies that enable optical modulation of transcription in the mammalian endogenous genome remain elusive. Here we describe the development of light-inducible transcriptional effectors (LITEs), an optogenetic two-hybrid system integrating the customizable TALE DNA-binding domain with the light-sensitive cryptochrome 2 protein and its interacting partner CIB1 from Arabidopsis thaliana. LITEs do not require additional exogenous chemical cofactors, are easily customized to target many endogenous genomic loci, and can be activated within minutes with reversibility. LITEs can be packaged into viral vectors and genetically targeted to probe specific cell populations. We have applied this system in primary mouse neurons, as well as in the brain of freely behaving mice in vivo to mediate reversible modulation of mammalian endogenous gene expression as well as targeted epigenetic chromatin modifications. The LITE system establishes a novel mode of optogenetic control of endogenous cellular processes and enables direct testing of the causal roles of genetic and epigenetic regulation in normal biological processes and disease states. 23728880 'Journeys' in the life-writing of adult-child dementia caregivers. This article explores how Alzheimer's disease caregivers struggle under the impact of a parent's memory loss on their own personality. In particular, it analyses how caregivers perceive and, thus, present their experiences of the ever intensifying caregiving activity in terms of a 'journey'. In doing so, this work takes into account both the patient's continuing bodily as well as cognitive decline and its intricately linked influence on the caregiver's physical and emotional stability. Equally, this study investigates how caregivers portray memory loss, and how their portrayal fits into our conceptualisation of illness narratives and the culture of autobiographical writing. 23353808 Silica-lipid hybrid (SLH) formulations enhance the oral bioavailability and efficacy of celecoxib: An in vivo evaluation. This study is the first to demonstrate in canines the ability of silica-lipid hybrid (SLH) microparticles to enhance the bioavailability and efficacy of a poorly water-soluble drug after oral administration. Spray-dried SLH microparticles comprising Capmul MCM (mono-diglycerides of C8/C12 fatty acids) and silica nanoparticles (Aerosil® 380) were shown to significantly enhance the fasted state oral bioavailability of celecoxib (CEL) (6.5 fold, relative to an aqueous suspension and more than 2-fold higher relative to the fed state) after oral administration to beagle dogs. Comparable bioavailability was observed between the SLH microparticle formulation and a conventional Capmul lipid solution, however, plasma concentrations were observed to be higher (Cmax, 1.1±0.06 vs. 0.8±0.03μg/mL) (p≤0.05) with the SLH microparticle system. The enhanced bioavailability of CEL observed with the SLH microparticles was reflected in a subsequent efficacy study conducted in an adjuvant-induced arthritis model in the rat. Reduced clinical and histological severity was observed at a dose of 3mg/kg/day, with the progression of arthritic symptoms and tissue damage reduced to a similar degree to that of a higher dose administered at 5mg/kg/day and prepared in an aqueous suspension., The enhanced bioavailability and improved efficacy observed with the SLH microparticles were attributed to the maintenance of CEL in a solubilised form during digestion of the lipid vehicle. We hypothesise that the presence of silica in the formulation may have contributed to the prevention of drug precipitation in the intestinal lumen by providing an alternative binding site for CEL to adsorb to prior to re-solubilisation and absorption. The study highlights the potential utility of novel SLH microparticle formulations as stable dry powders that possess the properties of a lipid-based formulation for the enhanced delivery and efficacy of poorly water-soluble drugs. 23293972 Chemical warfare agent and biological toxin-induced pulmonary toxicity: could stem cells provide potential therapies? Chemical warfare agents (CWAs) as well as biological toxins present a significant inhalation injury risk to both deployed warfighters and civilian targets of terrorist attacks. Inhalation of many CWAs and biological toxins can induce severe pulmonary toxicity leading to the development of acute lung injury (ALI) as well as acute respiratory distress syndrome (ARDS). The therapeutic options currently used to treat these conditions are very limited and mortality rates remain high. Recent evidence suggests that human stem cells may provide significant therapeutic options for ALI and ARDS in the near future. The threat posed by CWAs and biological toxins for both civilian populations and military personnel is growing, thus understanding the mechanisms of toxicity and potential therapies is critical. This review will outline the pulmonary toxic effects of some of the most common CWAs and biological toxins as well as the potential role of stem cells in treating these types of toxic lung injuries. 23899389 Novel Interactions of the TRTK12 Peptide with S100 Protein Family Members: Specificity and Thermodynamic Characterization. The S100 protein family consists of small, dimeric proteins that exert their biological functions in response to changing calcium concentrations. S100B is the best-studied member and has been shown to interact with more than 20 binding partners in a calcium-dependent manner. The TRTK12 peptide, derived from the consensus binding sequence for S100B, has previously been found to interact with S100A1 and has been proposed to be a general binding partner of the S100 family. To test this hypothesis and gain a better understanding of the specificity of binding for the S100 proteins, 16 members of the human S100 family were screened against this peptide and its alanine variants. Novel interactions were found with only two family members, S100P and S100A2, indicating that TRTK12 selectively interacts with a small subset of the S100 proteins. Substantial promiscuity was observed in the binding site of S100B thereby accommodating variations in the peptide sequence, while S100A1, S100A2, and S100P exhibited larger differences in the binding constants for the TRTK12 alanine variants. This suggests that single-point substitutions can be used to selectively modulate the affinity of TRTK12 peptides for individual S100 proteins. This study has important implications for the rational drug design of inhibitors for the S100 proteins, which are involved in a variety of cancers and neurodegenerative diseases. 23270378 Discovery of small molecule vanin inhibitors: new tools to study metabolism and disease. Vanins are enzymes with pantetheinase activity and are presumed to play a role in the recycling of pantothenic acid (vitamin B5) from pantetheine. Pantothenic acid is an essential nutrient required to synthesize coenzyme A, a cofactor involved in many biological processes such as fatty acid synthesis and oxidation of pyruvate to fuel the citric acid cycle. Hydrolysis of pantetheine also liberates cysteamine, a known antioxidant. Vanin-1 is highly expressed in liver and is under transcriptional control of PPAR-α and nutritional status, suggesting a role in energy metabolism. The lack of potent and specific inhibitors of vanins has hampered detailed investigation of their function. We hereby report the design, synthesis, and characterization of a novel pantetheine analogue, RR6, that acts as a selective, reversible, and competitive vanin inhibitor at nanomolar concentration. Oral administration of RR6 in rats completely inhibited plasma vanin activity and caused alterations of plasma lipid concentrations upon fasting, thereby illustrating its potential use in chemical biology research. 23445522 Examination of the Mode of Action of the Almiramide Family of Natural Products against the Kinetoplastid Parasite Trypanosoma brucei. Almiramide C is a marine natural product with low micromolar activity against Leishmania donovani, the causative agent of leishmaniasis. We have now shown that almiramide C is also active against the related parasite Trypanosoma brucei, the causative agent of human African trypanosomiasis. A series of activity-based probes have been synthesized to explore both the molecular target of this compound series in T. brucei lysates and site localization through epifluorescence microscopy. These target identification studies indicate that the almiramides likely perturb glycosomal function through disruption of membrane assembly machinery. Glycosomes, which are organelles specific to kinetoplastid parasites, house the first seven steps of glycolysis and have been shown to be essential for parasite survival in the bloodstream stage. There are currently no reported small-molecule disruptors of glycosome function, making the almiramides unique molecular probes for this understudied parasite-specific organelle. Additionally, examination of toxicity in an in vivo zebrafish model has shown that these compounds have little effect on organism development, even at high concentrations, and has uncovered a potential side effect through localization of fluorescent derivatives to zebrafish neuromast cells. Combined, these results further our understanding of the potential value of this lead series as development candidates against T. brucei. 23908282 De Novo Assembly of the Streptomyces sp. Strain Mg1 Genome Using PacBio Single-Molecule Sequencing. We report a draft genome assembly of Streptomyces sp. strain Mg1, a competitive soil isolate with multiple secondary metabolite gene clusters. 23884816 The Optimal Management of Follicular Lymphoma: An Evolving Field. Follicular lymphoma consists of a heterogeneous group of diseases that can vary dramatically in clinical course. As with other indolent lymphomas, follicular lymphoma is felt to be highly treatable, but ultimately incurable. The appropriate management of this disease ranges from close observation to chemoimmunotherapy based on presenting symptoms and comorbidities. In this article, we focus on the optimal management of follicular lymphoma, including prognostication, indications for treatment, and current treatment options. While a number of front-line chemoimmunotherapy options exist, R-CHOP (rituximab, cyclophosphamide, vincristine, prednisone) and BR (bendamustine, rituximab) tend to be favored due to efficacy and tolerability. Post-induction options include maintenance rituximab and radioimmunotherapy, but neither has demonstrated an overall survival benefit. In relapsed disease, patients can receive an alternative chemoimmunotherapy regimen or radioimmunotherapy, or participate in a clinical trial. There are a number of new biologic targeted therapies with promising activity in follicular lymphoma that have the potential to change our approach to this disease. 23823714 Use patterns of leave-on personal care products among Swiss-German children, adolescents, and adults. In order to model exposure to ingredients contained in personal care products (PCPs) and assess their potential risks to human health, access to reliable PCP use data, including co-use patterns, is essential. A postal questionnaire survey was conducted to determine the use patterns of eight leave-on PCP categories among the German-speaking population of Switzerland (N = 1,196; ages 0-97 years), providing for the first time in Europe PCP use data for children <12 years of age. The majority of respondents (99%) reported having used at least one of the investigated PCP categories in the past year. Co-use of two or more PCP categories at the same time was common and more complex amongst adults. Regular use of face cream and body lotion was very high in the youngest group of children aged 0-4 years (more than 79% respondents) who may be more vulnerable to certain adverse effects of some PCP ingredients. A comparison with previously collected information on PCP use patterns in Germany and the Netherlands indicates differences in PCP use patterns among European consumers and suggests that surrogate PCP use data from other countries must be used with caution. This work extends the existing knowledge of PCP use patterns and will be useful for new exposure assessments for ingredients contained in PCPs used by the young consumers. 23839711 Pyrrolic tripodal receptors for the molecular recognition of carbohydrates: ditopic receptors for dimannosides. Synthetic ditopic receptors, designed for the molecular recognition of dimannosides, have been prepared by bridging two monotopic units effectively recognizing mannosides with linkers of the appropriate size and flexibility, endowed with hydrogen-bonding groups. Affinities toward the α and β glycosides of the biologically relevant Manα(1-2)Man disaccharide were measured by NMR spectroscopy and isothermal titration calorimetry (ITC) in polar organic media (30-40 % DMF in chloroform). Significant selectivities and affinities in the micromolar range were observed in most cases, with two newly designed receptors being the most effective receptors of the set, together with a distinct preference of the dimannosides for the (S) enantiomer of the receptor in all cases. A 3D view of the recognition mode was elucidated by a combined NMR spectroscopic/molecular modeling approach, showing the dimannoside included in the cleft of the receptor. Compared to the monotopic precursors, the ditopic receptors showed markedly improved recognition properties, proving the efficacy of the modular receptor design for the recognition of disaccharides. 23604380 IL-17 in lung disease: friend or foe? Interleukin 17 (IL-17) is a key proinflammatory cytokine in the T helper 17 pathway. While it is important in the clearance of certain pathogens, IL-17 has been shown to contribute to the pathogenesis of such inflammatory diseases as rheumatoid arthritis and psoriasis. In the lung, it has been postulated to be involved in the neutrophilic inflammation and airway remodelling of chronic respiratory conditions but the situation is increasingly complex. This review summarises the evidence for its role in several chronic inflammatory lung diseases: asthma, obliterative bronchiolitis, chronic obstructive pulmonary disease, sarcoidosis and cystic fibrosis. 23864423 Osteoarthritis and falls in the older person. Osteoarthritis and falls are common conditions affecting older individuals which are associated with disability and escalating health expenditure. It has been widely assumed that osteoarthritis is an established risk factor for falls in older people. The relationship between osteoarthritis and falls has, quite surprisingly, not been adequately elucidated, and published reports have been conflicting. Our review of the existing literature has found limited evidence supporting the current assumption that the presence of osteoarthritis is associated with increased risk of falls with suggestions that osteoarthritis may actually be protective against falls related fractures. In addition, joint arthroplasty appears to increase the risk of falls in individuals with osteoarthritis. 23804289 Probing the Key Interactions between Human Atg5 and Atg16 Proteins: A Prospective Application of Molecular Modeling. Breaking things down: Disruption of the Atg5-Atg16 protein-protein interaction is a potential strategy for the development of effective inhibitors of autophagy. Using a structural model of the human Atg5-Atg16 complex, a total of 30 Atg16-based peptides were designed and tested for their binding affinity to Atg5. A number of these peptides exhibited binding affinities in the low micromolar range. Furthermore, three Atg16 residues were identified as the key factors in Atg5 binding. 23053785 Depletion of nucleoporins from HeLa nuclear pore complexes to facilitate the production of ghost pores for in vitro reconstitution. During cell division, Nuclear Pore Complexes (NPCs) are broken down into protein subcomplexes that are the basis for reassembly in daughter cells. This is the driving force for the establishment of an in vitro reconstitution system to study aspects of NPC reassembly. In this study, nuclear envelope (NE) was isolated from HeLa cells. NE was treated with increasing concentrations of heparin to extract nucleoporins (Nups) for the production of "ghost pores" which are pores severely deficient in Nups, while still containing Pore Membrane proteins (POM) needed to anchor the NPC. Ghost pores have been subjected to incubation with previously stripped Nups and some re-binding has been shown to occur by western blot analysis. This in vitro assay provides a powerful tool to investigate the protein-protein interactions of NPC reassembly from a human cell line. Through a better understanding of the process of NPC reassembly, we can continue to piece together the puzzle of this macromolecular structure. It is most advantageous to establish a straightforward reconstitution procedure at the mammalian level. 23951365 Hot or not: the effects of exogenous testosterone on female attractiveness to male conspecifics in the budgerigar. An increasing number of studies indicate that not only females but also males can be selective when choosing a mate. In species exhibiting male or mutual mate choice, females may benefit from being attractive. While male attractiveness is often positively influenced by higher plasma levels of the androgenic hormone testosterone, it has been shown that testosterone can masculinise female behavior and morphology in several bird species, potentially rendering them less attractive. In this study, we investigated whether female budgerigars, Melopsittacusundulatus, suffer from increased plasma testosterone levels through a negative effect on their attractiveness to males. We experimentally increased plasma testosterone levels in testosterone-treated females (T-females) compared to controls (C-females) and allowed males to choose between a T- and a C-female in a two-way choice situation. Although testosterone treatment significantly affected female behavioral and morphological characteristics, males did not show a significant difference in preference between T- and C-females. These results suggest that experimentally increasing testosterone levels in females does not appear to influence male preference during initial mate choice. Our findings indicate that selection for higher levels of testosterone in male budgerigars is probably not constrained by a correlated response to selection causing negative effects on female attractiveness during initial mate choice. Evaluating whether or not a potential constraint may arise from negative testosterone-induced effects on other fitness related traits in females requires further work. 23541982 Potential diagnostic applications of side chain oxysterols analysis in plasma and cerebrospinal fluid. The neurospecific cholesterol 24-hydroxylase converts excess brain cholesterol into 24S-hydroxycholesterol (24OHC) which, via the liver X receptor (LXR), can increase the expression and synthesis of astrocyte ApoE. 24OHC effluxes directly from brain into plasma where it is considered an indicator of brain cholesterol turnover. It is reduced in neurodegenerative disease states proportionally to the severity of disease and the degree of brain atrophy. In the early phases of active disease, a higher rate of turnover may result in transitory increases in plasma 24OHC. Less than 1% of the total brain excretion of 24OHC occurs via the cerebrospinal fluid (CSF) whereas almost all 27-hydroxycholesterol (27OHC) excretion is dependent on the function of the blood-cerebrospinal fluid barrier. Iincreased CSF oxysterols were found in patients with neurodegenerative and neuroinflammatory diseases in the presence of barrier dysfunction. In neurodegeneration, free cholesterol released from dying cells may engulf neurons. Cholesterol also increases Amyloid β (Aβ) deposition and tau pathology. ApoE, 24OHC, tau and soluble APP were correlated in Alzheimer disease (AD) samples. Excess of cholesterol converted into 24OHC may up-regulate ApoE synthesis which is a scavenger for Aβ and Tau. In AD this protective mechanism seems to be inefficient, probably due to the presence of high concentrations of 27OHC, microvascular dysfunction and the decreased efficiency of ApoE4 as lipid transporter and Aβ scavenger. 24OHC itself was cytotoxic. Analysis of side chain oxysterols in the CSF is likely to provided useful information about cholesterol metabolism and ApoE function in the pathogenesis of AD. 23830723 Report of the President of the Spanish Society of Internal Medicine 2010-12. This paper presents the activities and projects developed by the Spanish Society of Internal Medicine (SEMI) during the period 2010-2012. A review of the strategic objectives, initiatives to improve and increase the offer for members of the teaching activities at congresses, Working Groups meetings, summer schools for residents, and on-line training activities is made. The institutional and communication relations and information on the Revista Clínica Española are also reviewed. 23907397 Prevalence and genetic diversity of an unusual virus associated with Kobu-sho disease of gentian in Japan. Gentian Kobu-sho-associated virus (GKaV) is a recently discovered novel virus from Kobu-sho (a hyperplastic or tumorous disorder)-affected Japanese gentians. To obtain insight into GKaV transmission and pathogenesis, the genetic diversity of the virus in the putative helicase (Hel) and RNA-dependent RNA polymerase (RdRp) coding regions was studied. The extents of GKaV sequence diversity within single host plants differed within samples and between viral genomic regions. Phylogenetic analysis of 30 kobu-sho-affected samples from different production areas and host cultivars revealed that GKaV populations have diverged as they became prevalent in different geographic regions. The diversification of GKaV was shown to be driven by geographical isolation rather than host adaptation; however, no geographic patterns were found. Therefore, it was not feasible to trace the pathway of GKaV spread. 23230132 Involvement of UDP-glucuronosyltransferases UGT1A9 and UGT2B7 in ethanol glucuronidation, and interactions with common drugs of abuse. Ethyl glucuronide (EtG) determination is increasingly used in clinical and forensic toxicology to document ethanol consumption. The enzymes involved in EtG production, as well as potential interactions with common drugs of abuse, have not been extensively studied. Activities of human liver (HLM), kidney (HKM), and intestinal (HIM) microsomes, as well as of 12 major human recombinant UDP-glucuronosyltransferases (UGTs), toward ethanol (50 and 500 mM) were evaluated in vitro using liquid chromatography-tandem mass spectrometry. Enzyme kinetic parameters were determined for pooled microsomes and recombinant UGTs with significant activity. Individual contributions of UGTs were estimated using the relative activity factor approach, proposed for scaling activities obtained with cDNA-expressed enzymes to HLM. Interaction of morphine, codeine, lorazepam, oxazepam, nicotine, cotinine, cannabinol, and cannabidiol (5, 10, 15 mg/l) with ethanol (1.15, 4.6, 11.5 g/l; i.e., 25, 100, 250 mM) glucuronidation was assessed using pooled HLM. Ethanol glucuronidation intrinsic clearance (Cl(int)) was 4 and 12.7 times higher for HLM than for HKM and HIM, respectively. All recombinant UGTs, except UGT1A1, 1A6, and 1A10, produced EtG in detectable amounts. UGT1A9 and 2B7 were the most active enzymes, each accounting for 17 and 33% of HLM Cl(int), respectively. Only cannabinol and cannabidiol significantly affected ethanol glucuronidation. Cannabinol increased ethanol glucuronidation in a concentration-dependent manner, whereas cannabidiol significantly inhibited EtG formation in a noncompetitive manner (IC(50) = 1.17 mg/l; inhibition constant (K(i)) = 3.1 mg/l). UGT1A9 and 2B7 are the main enzymes involved in ethanol glucuronidation. In addition, our results suggest that cannabinol and cannabidiol could significantly alter ethanol glucuronidation. 23585151 Head and Neck Cancer Stem Cells: The Effect of HPV--An In Vitro and Mouse Study. Objectives To determine if the behavior of cancer stem cells (CSCs) is affected by human papillomavirus (HPV) status. Study Design An in vitro and in vivo analysis of HPV and CSCs. Setting University laboratory. Subjects and Methods We isolated CSCs from HPV-positive and HPV-negative cell lines. Two HPV-negative cell lines underwent lentiviral transduction of E6/E7. Chemoresistence was determined using colony formation assays. Native HPV-positive and HPV E6/E7-transduced cells were compared for lung colonization after tail vein injection in NOD/SCID mice. Results The proportion of CSC is not significantly different in HPV-positive or HPV-negative head and neck squamous cell carcinoma (HNSCC) cell lines. The HNSCC CSCs are more resistant to cisplatin than the non-CSCs, but there were no significant differences between HPV-positive and HPV-negative cells. The HPV-negative cancer cells yielded low colony formation after cell sorting. After transduction with HPV E6/E7, increased colony formation was observed in both CSCs and non-CSCs. Results from tail vein injections yielded no differences in development of lung colonies between HPV E6/E7-transduced cells and nontransduced cells. Conclusions Human papillomavirus status does not correlate with the proportion of CSCs present in HNSCC. The HPV-positive cells and those transduced with HPV E6/E7 have a greater clonogenicity than HPV-negative cells. The HNSCC CSCs are more resistant to cisplatin than non-CSCs. This suggests that common chemotherapeutic agents may shrink tumor bulk by eliminating non-CSCs, whereas CSCs have mechanisms that facilitate evasion of cell death. Human papillomavirus status does not affect CSC response to cisplatin therapy, suggesting that other factors explain the better outcomes for patients with HPV-positive cancer. 23926134 Neuropeptide W Increases Mean Arterial Pressure as a Result of Behavioral Arousal. Neuropeptide W (NPW), an endogenous ligand for G protein-coupled receptors NPBWR1 (GPR7) and NPBWR2 (GPR8), has been detected in neurons in limbic and reticular activating system areas known to be important in arousal, as well as hypothalamic nuclei known to be important in food and water intake and the neuroendocrine response to stress. In rat, central administration of NPW increased mean arterial pressure (MAP) and behaviors associated with locomotion and grooming. We hypothesized that the NPW-induced increase in MAP was secondary to those increases in physical activity. Since peptides that stimulate arousal have been shown to increase sympathetic activity (e.g. orexin), we tested the ability of the mixed α1- and α2-adrenergic antagonist, phentolamine, to block the NPW-23-induced rise in MAP. Phentolamine pretreatment abrogated the NPW-induced MAP increase. However, we noticed the animals no longer exhibited NPW-associated behavioral arousal when pretreated with phentolamine. Anesthesia also blocked the NPW-induced increase in MAP although the animals still were able to respond with an increase in MAP to centrally administered angiotensin II. Additionally, pretreatment with an orexin type 1 receptor antagonist significantly reduced the behavioral action of NPW-23 and completely blocked the peptide's action to increase MAP, suggesting that orexin neurons are downstream targets of NPW. Our results suggest that NPW increased MAP secondary to increased behavioral arousal. 23627900 Ionic liquid assisted dissolution of dissolved organic matter and PAHs from soil below the critical micelle concentration. Increased use and production of ionic liquids (ILs) may result in emissions into the environment. Particularly vulnerable are industrial areas and landfills where ILs are utilized and ultimately disposed of. This study investigates how IL contamination can affect soil properties and the sorption of pre-existing contaminants. The commonly used IL 1-methyl-3-octyl imidazolium chloride ([OMIM][Cl]) was added at various quantities to a landfill soil contaminated with polycyclic aromatic hydrocarbons (PAHs). Subsequently, the release of PAHs and dissolved organic matter (DOM) from this soil was thoroughly investigated. Two fractions of PAH release into the porewater were measured, the freely dissolved fraction (measured using a passive sampler) and the total PAH concentration (which includes the freely dissolved molecules as well as those associated with colloids, micelles and DOM). As expected the highest levels of total PAH porewater concentration occurred when the critical micelle concentration (CMC) of the IL was exceeded. However, as we report here for the first time, enhanced amounts of freely dissolved PAHs were released by sub-CMC concentrations of IL. Additionally, enhanced levels of DOM, due to dissolution of soil organic matter by IL, were also observed upon addition of sub-CMC IL concentrations. Based on this, enhanced release of pre-existing contaminants and DOM is suggested as a potential risk from IL emissions at trace concentrations well below the CMC. Potential mechanisms of this sub-CMC release are discussed. 23937934 The age estimation of blood stains up to 30days old using visible wavelength hyperspectral image analysis and linear discriminant analysis. A novel application of visible wavelength hyperspectral image analysis has been applied to determine the age of blood stains up to 30days old. Reflectance spectra from selected locations within the hyperspectral image, obtained from a portable instrument, were subjected to spectral pre-processing. This was followed by the application of a linear discriminant classification model, making estimations possible with an average error of ±0.27days for the first 7days and an overall average error of ±1.17days up to 30days. This is also the first reported study of the determination of the age of fresh blood stains (less than one day old) with an error of ±0.09h. The studies have been made under controlled conditions and represent, at this stage, proof of concept results but also are the most accurate age estimation results for measurements between 0 and 30days reported to date. The results are consistent with well-established kinetic processes suggesting that the pre-processing stages described are revealing spectroscopic changes which are reliably following the time dependent oxidation of HbO2. The potential for parameterisation of environmental factors to make the method generally applicable at crime scenes is discussed, along with the developments required to further improve classification and to make the instrument genuinely portable. 23677559 H(OEt2)2[P(1,2-O2C6Cl4)3]: synthesis, characterization, and application as a single-component initiator for the carbocationic polymerization of olefins. The development of novel Brønsted acids featuring the hexacoordinate phosphorus(V) anion [TRISPHAT](-) {[1](-)=[P(1,2-O2C6Cl4)3](-)} are reported. The title compound, H(OEt2)2[1], was synthesized from 1,2-(HO)2C6Cl4 (3 equiv) and PCl5 in the presence of diethyl ether. This compound was fully characterized by (1)H, (31)P and (13)C NMR spectroscopy, X-ray crystallography and elemental microanalysis. Dissolution of H(OEt2)2[1] in acetonitrile results in the slow precipitation of crystalline H(OEt2)(NCMe)[1], which was characterized by X-ray diffraction; however, in CD2Cl2 solution the [TRISPHAT](-) anion protonated and ring-opened. The weighable, solid H(OEt2)2[1] was found to be a competent initiator for the polymerization of n-butyl vinyl ether, α-methylstyrene, styrene and isoprene at a variety of temperatures and monomer-to-initiator ratios. At low temperatures, polymers with M(n) >10(5) were obtained for n-butyl vinyl ether and α-methylstyrene whereas slightly lower molecular weights were obtained with styrene and isoprene (10(4) < M(n) <10(5)). The poly(α-methylstyrene) synthesized at -78 °C is syndiotactic-rich (ca. 87% rr) whereas the polystyrene obtained at -50 °C is atactic. The polyisoprene obtained possessed all possible modes of enchainment as well as branched and/or cyclic structures that are often observed in polyisoprene. 23911817 Performance of a semi-pilot tubular microbial electrolysis cell (MEC) under several hydraulic retention times and applied voltages. The influence of applied voltage and hydraulic retention time on the performance of a semi-pilot modular tubular wastewater-fed microbial electrolysis cell (MEC) with high scalability was investigated. A chemical oxygen demand (COD) removal efficiency of 80%, as well as an energy consumption of 0.3-1.1Whg-COD(-1) removed, were achieved. Hydrogen production was limited by the reduced amounts of organic matter fed into the reactor, the poor performance of the cathode, and COD consuming by non electrogenic microorganisms. The presence of COD consuming microorganism that do not contribute to electrogenic metabolism severely affected the MEC performance. 23350992 Computed tomography has low sensitivity for the diagnosis of early colon cancer. The accuracy of computed tomography (CT) in detecting local invasion (T status) and nodal metastasis (N status) of colon cancer was determined. Data on the preoperative CT scan of 153 lesions from 152 patients with colon cancer were reviewed retrospectively. Evaluation included the T stage and N stage of the TNM system. The results were compared with those obtained by histopathological examination of the resected tumour. Of the 153 tumours, 117 (76.5%) were correctly classified as Stage T1 and T2 (33 tumours) and Stage T3 and T4 (84 tumours) by CT. The sensitivity and specificity were 70.2% and 79.2%, respectively, and the positive and negative predictive values were 85.7% and 60.0%. When analysed according to the individual T stage (Tx/Tis, T1, 2, 3, 4) and N stage (N0, 1, 2), the kappa coefficient with linear weighting was 0.208 (fair agreement) for T stage and 0.154 (slight agreement) for N stage. The estimation of tumour size showed good agreement with histopathology (Spearman correlation coefficient 0.865). CT scanning of colonic cancer showed 75% accuracy in identifying T1 and T2 cancers combined, but gave poor agreement between CT and histopathology for individual T stages. 23558363 Impact of ribotype 027 on Clostridium difficile infection in a geriatric department. The purposes of this study were to describe the epidemiology (2001-2009) of Clostridium difficile infections (CDI) in a geriatric department and to compare the clinical data of patients infected with a 027 or non-027 strain. We retrospectively identified all geriatric patients with CDI and analysed the clinical and microbiological data of 133 patients for whom a ribotype was available between March 2003 and December 2009. The incidence of CDI in our geriatric department increased from 0.2 per 100 admissions in 2001 to 8.1 in 2004 and decreased to 1.3 in 2008 before a new rise to 2.1 in 2009. The percentage of ribotype 027 decreased from 2007 but it remained the most prevalent ribotype during the years 2007-2009, with a greater dispersion of ribotypes. The mean age of the patients was 84 years and the median Charlson index was 6.0. Previous use of fluoroquinolones was a significant risk factor for developing a CDI with an 027 strain (p = 0.001). Cure was significantly lower in the 027 group (p = 0.003). The total attributable mortality was 24.1 %. A multiparametric model showed that attributable mortality was influenced by the ribotype 027 (p = 0.037), the severity of clinical symptoms (p = 0.001) and the type of treatment (p = 0.002). Oral vancomycin had a protective effect against mortality. Attention should be paid to elderly patients developing a CDI, especially after the administration of fluoroquinolones. Oral vancomycin could be recommended as the first-line agent not only to protect against recurrence or severe CDI, but to diminish the attributable mortality risk. 23931625 Effects of different doses of soy isoflavones on bone tissue of ovariectomized rats. ABSTRACT Scope: Studies report that hormone replacement prevents osteoporosis, but there are doubts whether isoflavones are really efficient in this process. Objective: to evaluate the effects of different doses of soy isoflavones (Iso) on bone tissue of ovariectomized (Ovx) rats. Methods: 40 female rats at the age of 6 months were Ovx and after three months, the animals were divided in four groups: GI - Control (treated with drug vehicle); GII - treated with Iso (80mg/kg per day); GIII - treated with Iso (200mg/kg per day) and GIV - treated with Iso (350mg/kg per day). Soy isoflavones were administered by gavage for 90 consecutive days. After treatments, the rats were euthanized and their distal femurs were removed for histological routine, histochemistry and biochemical study. Histological sections were stained with hematoxylin-eosin or subjected to picrosirius red and alcian blue methods. Shafts of femurs were submitted to biochemical assay and tibias were subjected to biophysical and biomechanical tests. Results: in distal femurs, the trabecular bone volume was higher in the groups treated with isoflavones, being higher in the GIV, while the cortical bone width and the presence of mature type I collagen fibers were higher in the GII. At the trabecular bone region, the percentage of total glycosaminoglycans (GAGs) was higher in the GII and only sulfated GAGs in the GIII, while the higher content of chondroitin sulfate in shafts of femurs was seen in the GIV. Biophysical and biomechanical tests in tibias did not differ among the groups. Conclusion: Our data indicate that soy isoflavones improve bone quality in femurs of rats by increasing histomorphometric parameters, the content of GAGs and mature type I collagen fibers. These positive effects are dose-dependent and showed to be different in cortical and trabecular bone. 23873910 RflM Functions as a Transcriptional Repressor in the Autogenous Control of the Salmonella Flagellar Master Operon flhDC. Motility of bacteria like Salmonella enterica is a highly regulated process that responds to a variety of internal and external stimuli. A hierarchy of three promoter classes characterizes the Salmonella flagellar system, and the onset of flagellar gene expression depends on the oligomeric regulatory complex and class 1 gene product FlhD4C2. The flhDC promoter is a target for a broad range of transcriptional regulators that bind within the flhDC promoter region and either negatively or positively regulate flhDC operon transcription. In this work, we demonstrate that the RflM protein is a key component of flhDC regulation. Transposon mutagenesis was performed to investigate a previously described autoinhibitory effect of the flagellar master regulatory complex FlhD4C2. RflM is a LuxR homolog that functions as a flagellar class 1 transcriptional repressor. RflM was found to be the negative regulator of flhDC expression that is responsible for the formerly described autoinhibitory effect of the FlhD4C2 complex on flhDC operon transcription (K. Kutsukake, Mol. Gen. Genet. 254:440-448, 1997). We conclude that upon commencement of flagellar gene expression, the FlhD4C2 complex initiates a regulatory feedback loop by activating rflM gene expression. rflM encodes a transcriptional repressor, RflM, which fine-tunes flhDC expression levels. 23659968 ETS2 mediated tumor suppressive function and MET oncogene inhibition in human non-small cell lung cancer. The ETS2 transcription factor is an evolutionarily conserved gene that is deregulated in cancer. We analyzed the transcriptome of lung adenocarcinomas and normal lung tissue by expression profiling and found that ETS2 was significantly downregulated in adenocarcinomas. In this study, we probed the yet unknown functional role of ETS2 in lung cancer pathogenesis. Lung adenocarcinomas (n = 80) and normal lung tissues (n = 30) were profiled using the Affymetrix Human Gene 1.0 ST platform. Immunohistochemical (IHC) analysis was conducted to determine ETS2 protein expression in non-small cell lung cancer (NSCLC) histologic tissue specimens (n = 201). Patient clinical outcome, based on ETS2 IHC expression, was statistically assessed using the log-rank and Kaplan-Meier tests. RNA interference and overexpression strategies were used to assess the effects of ETS2 expression on the transcriptome and on various malignant phenotypes. ETS2 expression was significantly reduced in lung adenocarcinomas compared with normal lung (P < 0.001). Low ETS2 IHC expression was a significant predictor of shorter time to recurrence in NSCLC (P = 0.009, HR = 1.89) and adenocarcinoma (P = 0.03, HR = 1.86). Moreover, ETS2 was found to significantly inhibit lung cancer cell growth, migration, and invasion (P < 0.05), and microarray and pathways analysis revealed significant (P < 0.001) activation of the HGF pathway following ETS2 knockdown. In addition, ETS2 was found to suppress MET phosphorylation and knockdown of MET expression significantly attenuated (P < 0.05) cell invasion mediated by ETS2-specific siRNA. Furthermore, knockdown of ETS2 augmented HGF-induced MET phosphorylation, cell migration, and invasion. Conclusion(s): Our findings point to a tumor suppressor role for ETS2 in human NSCLC pathogenesis through inhibition of the MET proto-oncogene. 23866681 Association of objectively measured physical activity with body components in European adolescents. Physical activity (PA) is suggested to contribute to fat loss not only through increasing energy expenditure "per se" but also increasing muscle mass; therefore, it would be interesting to better understand the specific associations of PA with the different body's components such as fat mass and muscle mass. The aim of the present study was to examine the association between objectively measured PA and indices of fat mass and muscle components independently of each other giving, at the same time, gender-specific information in a wide cohort of European adolescents. A cross-sectional study in a school setting was conducted in 2200 (1016 males) adolescents (14.7 +/-1.2 years). Weight, height, skinfold thickness, bioimpedance and PA (accelerometry) were measured. Indices of fat mass (body mass index,% fat mass, sum of skinfolds) and muscular component (assessed as fat-free mass) were calculated. Multiple regression analyses were performed adjusting for several confounders including fat-free mass and fat mass when possible. Vigorous PA was positively associated with height (p < 0.05) in males, whilst, vigorous PA, moderate-vigorous PA and average PA were negatively associated with all the indices of fat mass (all p < 0.01) in both genders, except for average PA in relation with body mass index in females. Regarding muscular components, vigorous PA showed positive associations with fat-free mass and muscle mass (all p < 0.05) in both genders. Average PA was positively associated with fat-free mass (both p < 0.05) in males and females. The present study suggests that PA, especially vigorous PA, is negatively associated with indices of fat mass and positively associated with markers of muscle mass, after adjusting for several confounders (including indices of fat mass and muscle mass when possible). Future studies should focus not only on the classical relationship between PA and fat mass, but also on PA and muscular components, analyzing the independent role of both with the different PA intensities. 23958728 A pattern matching approach to the automatic selection of particles from low-contrast electron micrographs. Structural information of macromolecular complexes provides key insights into the way they carry out their biological functions. Achieving high-resolution structural details with electron microscopy requires the identification of a large number (up to hundreds of thousands) of single particles from electron micrographs, which is a laborious task if it has to be manually done and constitutes a hurdle towards high-throughput. Automatic particle selection in micrographs is far from being settled and new and more robust algorithms are required to reduce the number of false positives and false negatives. In this article, we introduce an automatic particle picker that learns from the user the kind of particles he is interested in. Particle candidates are quickly and robustly classified as particles or non-particles. A number of new discriminative shape-related features as well as some statistical description of the image grey intensities are used to train two support vector machine classifiers. Experimental results demonstrate that the proposed method: (i) has a considerably low computational complexity and (ii) provides results better or comparable with previously reported methods at a fraction of their computing time. The algorithm is fully implemented in the open-source Xmipp package and downloadable from http://xmipp.cnb.csic.es. vabrishami@cnb.csic.es or coss@cnb.csic.es SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. 23890229 Effect of Melamine Foam Cleaning on the Surface Condition of Composite Resin Artificial Teeth. The purpose of this study was to examine the abrasive and cleaning effects of melamine foam and other cleaning agents on the surfaces of composite resin artificial tooth specimens. A stained composite resin artificial tooth in a used denture was cleaned using a denture brush and melamine foam, and the stain removal effect was evaluated macroscopically. Next, 5 types of cleaning material (fourfold-compression melamine foam, MEL; brush with water, BRU; denture dentifrice without abrasive, POL; denture dentifrice with abrasive, TAF; conventional dentifrice, AQU) and 15 plate-shaped specimens made of composite resin for artificial teeth were used for wear tests. The surface roughness was measured using a laser scanning microscope. Furthermore, the surface properties were observed using a digital microscope. Surface roughness data were analyzed by two-way ANOVA followed by Tukey's test. Artificial tooth stains that could not be removed by brushing became removable using melamine foam. With regard to surface roughness in the context of the wear test, significant differences were not indicated between MEL and POL, whereas BRU-, TAF-, and AQU-treated specimens showed significantly increased surface roughness (p < 0.05). In the comparison among the cleaning materials, TAF- and AQU-treated specimens showed significantly rougher surfaces than those treated with MEL, BRU, and POL (p < 0.05). Macroscopic observations suggest that melamine foam would be effective for the removal of stains on composite resin artificial teeth. Traces of wear were not observed in specimens treated with melamine foam and the denture dentifrice not containing abrasives. It was suggested that these two materials would be desirable and useful to use for composite resin tooth cleaning. 23517405 18-fluorodeoxyglucose positron emission tomography in the early diagnostic workup of differentiated thyroid cancer patients with a negative post-therapeutic iodine scan and detectable thyroglobulin. Background: Surgery and high-dose radioactive iodine ((131)I) treatment are the cornerstones in the treatment of differentiated thyroid cancer. Patients without (131)I uptake on the post-therapeutic whole body scan (WBS), but with detectable thyroglobulin (Tg) during thyroxine withdrawal (Tg-off), are evaluated with an 18-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) for tumor localization within three months. The yield of (18)F-FDG-PET imaging and clinical usefulness of a Tg-off cutoff value to predict a positive scan were assessed. Methods: From 2002 to 2011, 52 patients with a negative WBS and concurrent detectable Tg-off were evaluated. Thirty-five PET scans were performed during initial treatment, 17 after recurrent disease. Thirty-two patients were on substitution therapy, 17 were evaluated with endogenous thyrotropin elevation, and 3 after recombinant human thyrotropin stimulation. To determine the Tg-off cutoff value, a receiver operating characteristic curve was used. Results: Nine (17%) (18)F-FDG-PET scans were true positive, 3 (6%) false positive, 36 (69%) true negative, and 4 (8%) false negative (sensitivity 69%, specificity 92%). In 13%, a true-positive scan resulted in a change in the clinical management. The area under the receiver operating characteristic curve is 0.82 [CI 0.64-0.99] (p<0.01), and the Tg-off cutoff value is 38.00 ng/mL (sensitivity 67%, specificity 95%). Ninety percent of (18)F-FDG-PET true-positive patients had a Tg-off >2.00 ng/mL. Conclusions: An (18)F-FDG-PET within three months after a negative WBS with detectable Tg-off showed additional tumor localization in 17% of the patients, leading to a change in clinical management in 13%. A clinically useful Tg-off cutoff value was not found, but 90% of positive (18)F-FDG-PET scans occurred in patients with a Tg-off >2.00 ng/mL. 23904762 The epidemic of human papillomavirus and oropharyngeal cancer in a Canadian population. Sexually transmitted infection with the human papillomavirus (hpv) is responsible for a significant burden of human cancers involving the cervix, anogenital tract, and oropharynx. Studies in the United States and Europe have demonstrated an alarming increase in the frequency of hpv-positive oropharyngeal cancer, but the same direct evidence does not exist in Canada. Using the London Health Sciences Centre pathology database, we identified tonsillar cancers diagnosed between 1993 and 2011. Real-time polymerase chain reaction was then used on pre-treatment primary-site biopsy samples to test for dna from the high-risk hpv types 16 and 18. The study cohort was divided into three time periods: 1993-1999, 2000-2005, and 2006-2011. Of 160 tumour samples identified, 91 (57%) were positive for hpv 16. The total number of tonsillar cancers significantly increased from 1993-1999 to 2006-2011 (32 vs. 68), and the proportion of cases that were hpv-positive substantially increased (25% vs. 62%, p < 0.002). Those changes were associated with a marked improvement in 5-year overall survival (39% in 1993-1999 vs. 84% in 2006-2011, p < 0.001). When all factors were included in a multivariable model, only hpv status predicted treatment outcome. The present study is the first to provide direct evidence that hpv-related oropharyngeal cancer is increasing in incidence in a Canadian population. Given the long lag time between hpv infection and clinically apparent malignancy, oropharyngeal cancer will be a significant clinical problem for the foreseeable future despite vaccination efforts. 23244212 Self-assembly of segmented anisotropic particles: tuning compositional anisotropy to form vertical or horizontal arrays. Columnar arrays of anisotropic nano- and microparticles, in which the long axes of the particles are oriented perpendicular to the substrate, are of interest for photovoltaics and other applications. Array assembly typically requires applied electric or magnetic fields and/or controlled drying, which are challenging over large areas. Here, we describe a scalable approach to self-assemble multicomponent nanowires into columnar arrays. Self-assembly of partially etched nanowires (PENs) occurred spontaneously during sedimentation from suspension, without drying or applied fields. PENs, which have segments that are either gold or "empty" (solvent-filled) surrounded by a silica shell, were produced from striped metal nanowires by first coating with silica and then removing sacrificial segments by acid etching. Electrostatic repulsion between the particles was necessary for array assembly; however, details of PEN surface chemistry were relatively unimportant. The aspect ratio and relative center of mass (COM) of the PENs were important for determining whether the PEN long axes were vertically or horizontally aligned with respect to the underlying substrate. Arrays with predominantly vertically aligned particles were achieved for PENs with a large offset in COM relative to the geometric center, while other types of PENs formed horizontal arrays. Assemblies were formed over >10 cm(2) areas, with over 60% of particles standing. We assessed array uniformity and reproducibility by imaging many positions within each sample and performing multiple assemblies of differently segmented PENs. This work demonstrates the versatility of gravity-driven PEN array assembly and provides a framework for designing other anisotropic particle systems that self-assemble into columnar arrays. 23918005 Cerium ammonium nitrate (CAN)-catalyzed four-component one-pot synthesis of multi-substituted pyrano[2,3-[Formula: see text]]pyrazoles under ultrasound irradiation. A convenient and efficient synthesis of multi-substituted dihydropyrano[2,3-c]pyrazole derivatives is reported. The four-component reaction of 4-hydrazinobenzoic acid, [Formula: see text]-keto esters, aromatic aldehydes, and malononitrile using 10 mol% CAN catalyst in water under ultrasound irradiation produced the target compounds in good-to-excellent yields. This method has advantages over conventional methods in being economic, non-toxic, and environmentally compatible due to its use of efficient and eco-friendly CAN catalyst and water solvent. 23794022 Variations in biliary ductal and hepatic vascular anatomy and their relevance to the surgical management of choledochal cysts. An aberrant biliary ductal and vascular anatomy presents a technical challenge for choledochal cyst (CDC) surgery. Mismanagement may have unfavourable implications. This study highlights the spectrum, approach to their identification and management. Forty of 117 (34 %) cases were identified to have an aberrant biliary ductal (n = 17) or arterial (n = 26) anatomy; 3 had both. The pancreaticobiliary anatomy was defined by an intraoperative cholangiogram (IOC) before January 2005 and a preoperative magnetic resonance cholangiopancreatogram (MRCP) subsequently. IOC missed 3 of 4 aberrant biliary ducts, while an MRCP accurately delineated 10 of 13 aberrant bile ducts. The significant biliary anomalies were: an aberrant right sectoral/segmental duct joining the common hepatic duct (CHD) or the cyst itself (n = 14), cystic duct (n = 1) and cystic duct-CHD junction (n = 1). The aberrant duct was incorporated into the biliary-enteric anastomosis (B-EA) by: (i) double ostia B-EA (n = 1), (ii) ductoplasty with single ostium B-EA for aberrant duct and CHD (n = 2), and (iii) transection of the CHD/cyst distal to the aberrant duct orifice with a single ostium B-EA (n = 13). The arterial anomalies were (i) replaced or accessory right hepatic artery (RHA) (n = 11) and (ii) RHA crossing anterior to the cyst (n = 15), which was repositioned posterior to the B-EA. It is important to consciously look for, appropriately identify and manage aberrant biliovascular anatomy. MRCP facilitates accurate preoperative delineation of aberrant duct anatomy. All major aberrant ducts need to be incorporated into the B-EA and aberrant arteries should not be ligated. 23896516 A solution NMR investigation into the impaired self-assembly properties of two murine amelogenins containing the point mutations T21→I or P41→T. Amelogenesis imperfecta describes a group of inherited disorders that results in defective tooth enamel. Two disorders associated with human A. imperfecta are the point mutations T21→I or P40→T in amelogenin, the dominant protein present in ameloblasts during the early stages of enamel biomineralization. The biophysical properties of wildtype murine amelogenin (M180) and two proteins containing the equivalent mutations in murine amelogenin, T21→I (M180-I) and P41→T (M180-T), were probed by NMR spectroscopy. At low protein concentration (0.1mM) M180, M180-I, and M180-T are predominately monomeric at pH 3.0 in 2% acetic acid and neither mutation produces a major structural change. Chemical shift perturbation studies as a function of protein (0.1-1.8mM) and NaCl (0-400mM) concentration show that the mutations affect the self-association properties by causing self-assembly at lower protein or salt concentrations, relative to wildtype amelogenin, with the largest effect observed for M180-I. Under both conditions, the premature self-assembly is initiated near the N-terminus, providing further evidence for the importance of this region in the self-assembly process. The self-association of M180-I and M180-T at lower protein concentrations and lower ionic strengths than wildtype M180 may account for the clinical phenotypes of these mutations, defective enamel formation. 23943844 Intergenerational Transfer of Smoking Across Three Generations and Forty-five Years. Although many have examined the linkages between smoking behaviors across 2 generations, few have examined these linkages among 3 generations. U.S. population representative data for 3 generations are drawn from the Panel Study of Income Dynamics (PSID) in order to examine whether smoking behaviors are passed down from generation to generation and the magnitude of the influence of smoking behaviors across generations (N = 830). Results indicate direct linkages between both grandparent (G1) and parent (G2) smoking (OR = 4.53; 95% CI: 2.57-7.97) and parent (G2) and young adult offspring (G3) smoking (OR = 2.91; 95% CI: 1.60-5.31). Although the direct link between grandparent (G1) and grandchildren (G3) was not significant (OR = 2.25; 95% CI: 0.96-5.23, p < .10), mediation analyses reveal that the link between G3 and G1 smoking is significantly mediated by G2 smoking. Regardless of generation, parent smoking behavior has a direct influence on offspring smoking behavior. The link between grandparent (G1) and grandchild (G3) smoking is mediated by parent (G2) smoking, suggesting that smoking behavior is passed from one generation to the next generation and in turn to the next generation. 23885817 Vaccine adjuvants: in search of new paradigms. Interview with Jenaid Rees, Commissioning Editor Nikolai Petrovsky is the Chairman and Research Director of Vaxine Pty Ltd, an Australian biotech company that specializes in novel vaccine adjuvants. He also holds the position of Director of Endocrinology at Flinders Medical Centre (Adelaide, Australia), Professor of Medicine at Flinders University, Vice President and Secretary General of the International Immunomics Society and serves on the Editorial Board of our sister journal, Expert Review of Clinical Immunology. He completed his PhD at the University of Melbourne (Victoria, Australia) then moved to Canberra (Australia) where he held conjoint positions at the Canberra Hospital, University of Sydney, Canberra University, Australian National University and the National Health Sciences Centre. In 2004, he moved to his current position at Flinders Medical Centre. His research interests include vaccine adjuvants, autoimmunity and immuno informatics. In 2009, his company Vaxine won the AMP Innovation Award at the Telstra business awards and Australia's coolest company award from Australian Anthill magazine. He has been an investigator for major international diabetes studies including ADVANCE, FIELD and DREAM and is a principal investigator on several large grants from the NIH. He has authored over 140 scientific papers, and his team has developed novel vaccines against influenza, hepatitis B, sting allergy, malaria, Japanese encephalitis, rabies and HIV, in addition to developing the world's first effective H1N1/2009pdm (swine flu) pandemic influenza vaccine. 23557840 1,3,4-Oxadiazol-2-ones as fatty-acid amide hydrolase and monoacylglycerol lipase inhibitors: Synthesis, in vitro evaluation and insight into potency and selectivity determinants by molecular modelling. Inhibition of the key hydrolytic enzymes of the endocannabinoid system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), has been proposed as potential mode of action for various therapeutic applications. Continuing our previous work, we take the first steps of structure-activity relationship exploration and show that 1,3,4-oxadiazol-2-ones can serve as scaffold for both selective FAAH and MAGL inhibitors, and also function as a dual FAAH/MAGL inhibitor at sub-micromolar IC50 values. Moreover, 10-fold selectivity against MAGL over FAAH was achieved with compound 3d (FAAH and MAGL IC50; 2.0 and 0.22μM). Lastly, enzyme and ligand features contributing to the potency and selectivity differences are analysed by molecular docking. 23861496 Crystal structure of a GroEL-ADP complex in the relaxed allosteric state at 2.7 A resolution. The chaperonin proteins GroEL and GroES are cellular nanomachines driven by the hydrolysis of ATP that facilitate the folding of structurally diverse substrate proteins. In response to ligand binding, the subunits of a ring cycle in a concerted manner through a series of allosteric states (T, R, and R″), enabling work to be performed on the substrate protein. Removing two salt bridges that ordinarily break during the allosteric transitions of the WT permitted the structure of GroEL-ADP in the R state to be solved to 2.7 Å resolution. Whereas the equatorial domain displays almost perfect sevenfold symmetry, the apical domains, to which substrate proteins bind, and to a lesser extent, the intermediate domains display a remarkable asymmetry. Freed of intersubunit contacts, the apical domain of each subunit adopts a different conformation, suggesting a flexibility that permits interaction with diverse substrate proteins. This result contrasts with a previous cryo-EM study of a related allosteric ATP-bound state at lower resolution. After artificially imposing sevenfold symmetry it was concluded that a GroEL ring in the R-ATP state existed in six homogeneous but slightly different states. By imposing sevenfold symmetry on each of the subunits of the crystal structure of GroEL-ADP, we showed that the synthetic rings of (X-ray) GroEL-ADP and (cryo-EM) GroEL-ATP are structurally closely related. A deterministic model, the click stop mechanism, that implied temporal transitions between these states was proposed. Here, however, these conformational states are shown to exist as a structurally heterogeneous ensemble within a single ring. 23906789 PPARγ agonists upregulate sphingosine 1-phosphate (S1P) receptor 1 expression, which in turn reduces S1P-induced [Ca(2+)]i increases in renal mesangial cells. We previously identified peroxisome proliferator-activated receptor gamma (PPARγ) agonists (thiazolidinediones, TZDs) as modulators of the sphingolipid metabolism in renal mesangial cells. TZDs upregulated sphingosine kinase 1 (SK-1) and increased the formation of intracellular sphingosine 1-phosphate (S1P), which in turn reduced the expression of pro-fibrotic connective tissue growth factor. Since S1P also acts as extracellular ligand at specific S1P receptors (S1PR, S1P1-5), we investigated here the effect of TZDs on S1PR expression in mesangial cells and evaluated the functional consequences by measuring S1P-induced increases in intracellular free Ca(2+) concentration ([Ca(2+)]i). Treatment with two different TZDs, troglitazone and rosiglitazone, enhanced S1P1 mRNA and protein expression in rat mesangial cells, whereas S1P2-5 expression levels were not altered. Upregulation of S1P1 mRNA upon TZD treatment was also detected in human mesangial cells and mouse glomeruli. PPARγ antagonism and promoter studies revealed that the TZD-dependent S1P1 mRNA induction involved a functional PPAR response element in the S1P1 promoter. Pharmacological approaches disclosed that S1P-induced [Ca(2+)]i increases in rat mesangial cells were predominantly mediated by S1P2 and S1P3. Interestingly, the transcriptional upregulation of S1P1 by TZDs resulted in a reduction of S1P-induced [Ca(2+)]i increases, which was reversed by the S1P1/3 antagonist VPC-23019, the protein kinase C (PKC) inhibitor PKC-412, and by S1P1 siRNA. These data suggest that PPARγ-dependent upregulation of S1P1 leads to an inhibition of S1P-induced Ca(2+) signaling in a PKC-dependent manner. Overall, these results reveal that TZDs not only modulate intracellular S1P levels but also regulate S1PR signaling by increasing S1P1 expression in mesangial cells. 23959564 Selective detection of guanosine-5'-triphosphate and iodide by fluorescent benzimidazolium-based cyclophanes. New fluorescent benzimidazolium-based receptors selectively display the effective fluorescence quenching effect for biologically important anions, GTP and I(-), in aqueous solution of physiological pH 7.4. These affinities can be attributed to the strong ionic H-bonding along with additional interactions of fluorophore moieties with the nucleic base of GTP and I(-). 23386533 Heterologous expression of human cytochrome P450 (CYP) 2C19 in Escherichia coli and establishment of RP-HPLC method to serve as activity marker. In this study, a simple and reliable reverse-phase high-performance liquid chromatography (RP-HPLC) method was established and validated to analyze S-mephenytoin 4-hydroxylase activity of a recombinant CYP2C19 system. This system was obtained by co-expressing CYP2C19 and NADPH-CYP oxidoreductase (OxR) proteins in Escherichia coli (E. coli) cells. In addition to RP-HPLC, the expressed proteins were evaluated by immunoblotting and reduced CO difference spectral scanning. The RP-HPLC assay showed good linearity (r(2) = 1.00) with 4-hydroxymephenytoin concentration from 0.100 to 50.0 μm and the limit of detection was 5.00 × 10(-2) μm. Intraday and interday precisions determined were from 1.90 to 8.19% and from 2.20 to 14.9%, respectively. Recovery and accuracy of the assay were from 83.5 to 85.8% and from 95.0 to 105%. Enzyme kinetic parameters (Km , Vmax and Ki ) were comparable to reported values. The presence of CYP2C19 in bacterial membranes was confirmed by immunoblotting and the characteristic absorbance peak at 450 nm was determined in the reduced CO difference spectral assay. Moreover, the activity level of co-expressed OxR was found to be comparable to that of the literature. As a conclusion, the procedures described here have generated catalytically active CYP2C19 and the RP-HPLC assay developed is able to serve as CYP2C19 activity marker for pharmacokinetic drug interaction study in vitro. 23718958 Development of the men's prostate awareness church training: church-based workshops for African American men. This article describes the development of a spiritually based intervention to increase informed decision making for prostate cancer screening through African American churches. The intervention used spiritually themed health messages, incorporated women as supportive health partners, and included a health information technology component. The Men's Prostate Awareness Church Training Project followed a community-based participatory research process to develop educational materials, and training for 40 community health advisors to implement the 4-part prostate health workshop series that will be implemented in 20 churches. Implications are discussed for designing culturally relevant interventions to reduce prostate cancer disparities impacting African American men. 23924474 Myogenic differentiation of mesenchymal stem cells for muscle regeneration in urinary tract. This article was to review the current status of adult mesenchymal stem cells transplantation for muscle regeneration in urinary tract and propose the future prospect in this field. The data used in this review were mainly obtained from articles listed in Medline and PubMed (2000-2013). The search terms were "mesenchymal stem cells", "bladder", "stress urinary incontinence" and "tissue engineering". Articles regarding the adult mesenchymal stem cells for tissue engineering of bladder and stress urinary incontinence were selected and reviewed. Adult mesenchymal stem cells had been identified and well characterized in human bone marrow, adipose tissue, skeletal muscle and urine, and demonstrated the capability of differentiating into smooth muscle cells and skeletal muscle cells under myogenic differentiation conditions in vitro. Multiple preclinical and clinical studies indicated that adult mesenchymal stem cells could restore and maintain the structure and function of urinary muscle tissues after transplanted, and potentially improve the quality of life in patients. Smooth or skeletal myogenic differentiation of mesenchymal stem cells with regenerative medicine technology may provide a novel approach for muscle regeneration and tissue repair in urinary tract. The long-term effect and safety of mesenchymal stem cell transplantation should be further evaluated before this approach becomes widely used in patients. 23356718 Parent- and self-reported dimensions of oppositionality in youth: construct validity, concurrent validity, and the prediction of criminal outcomes in adulthood. Background:  Different dimensions of oppositional defiant disorder (ODD) have been found as valid predictors of further mental health problems and antisocial behaviors in youth. The present study aimed at testing the construct, concurrent, and predictive validity of ODD dimensions derived from parent- and self-report measures. Method:  Confirmatory factor analyses were performed to test a three-dimensional model (ODD-irritability, ODD-headstrong, and ODD-hurtful) and a two-dimensional model (ODD-irritability, ODD-headstrong/hurtful) based on items of the Child Behavior Checklist (CBCL) and the Youth Self Report (YSR) collected in a Swiss community study of 1,031 adolescents (519 boys, 512 girls) aged between 10.7 and 17.9 (M = 13.85, SD = 1.63) years. Logistic regression analyses were applied to predict scores in the clinical range of concurrent CBCL/YSR-anxiety/depression, CBCL/YSR-attention problems, and CBCL/YSR-delinquent behavior and depression as measured by the Center for Epidemiological Studies Depression Scale (CES-D) as well as to predict the presence of adult criminal convictions. Results:  CFA findings were in favor of a three-dimensional model rather than a two-dimensional model of ODD. The CBCL/YSR-ODD-irritability scale was related to concurrent self-reported depression, but also to attention problems and delinquent behavior. CBCL/YSR-ODD-hurtful and less strongly also the combined YSR-headstrong/hurtful scale predicted adult criminal outcomes. Conclusions:  As proposed by the DSM-5 workgroup, different ODD-dimensions were confirmed by the present study. ODD-irritability predicts psychiatric comorbidity and ODD-hurtful symptoms should be specifically considered in youth at risk for criminal outcomes. 23876779 Exact analytical results for ADC with oscillating diffusion sensitizing gradients. The apparent diffusion coefficient (ADC) is analyzed for the case of oscillating diffusion sensitizing gradients. Exact analytical expressions are obtained in the high-frequency expansion of the ADC for an arbitrary number of oscillations N. These expressions are universal and valid for arbitrary system geometry. The validity conditions of the high-frequency expansion of ADC are obtained in the framework of a simple 1D model of restricted diffusion. These conditions are shown to be substantially different for cos- and sin-type gradients: for the cos-type gradients, the high-frequency expansion is valid when the period of a single oscillation is smaller than the characteristic diffusion time, the frequency dependence of ADC being practically the same for any N. In contrast, for the sin-type gradients, the high-frequency regime can be achieved only when the total diffusion time is smaller than the characteristic diffusion time, the frequency dependence of ADC being different for different N. 23969418 Angiotensin Receptor Blockers Are Associated with Reduced Fibrosis and Interleukin-6 Expression in Calcific Aortic Valve Disease. Background: Calcific aortic valve disease (CAVD) is a chronic disorder characterized by the mineralization of the aortic valve and involving fibrosis. Objectives: In this work we sought to determine if the fibrotic component of the remodeling process of CAVD was related to the use of angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARBs). Methods: In 477 patients with CAVD, the aortic valve was examined by histology. A semiquantitative score of fibrosis was generated and associations with clinical/cardiometabolic variables examined. In a subset of 103 patients the aortic valve was available to study the infiltration by inflammatory cells and expression of interleukin-6 (IL-6) by quantitative real-time PCR. Results: The fibrosis score of the aortic valve was independently related to the hemodynamic severity of CAVD measured by echocardiography. The fibrotic score of the aortic valve was also related to the expression of IL-6. The use of ARBs but not of ACEi was associated with a lower fibrosis score of the aortic valve even after correction for covariates. In addition, patients under ARBs had lower aortic valve inflammation and expression of IL-6. Conclusions: These findings suggest that ARBs may alter the fibrotic process of the aortic valve in CAVD, possibly by lowering tissue inflammation. 22790358 Berry syndrome: a possible genetic link. Berry syndrome comprises a rare combination of heart defects that includes aortopulmonary window, interrupted aortic arch, intact ventricular septum, and aortic origin of the right pulmonary artery. We report the case of a neonate confirmed to have Berry syndrome by transthoracic echocardiogram and computed tomography (CT). This neonate had the additional finding of an aberrant right subclavian artery arising from the descending aorta. A single-stage repair was successfully performed when the infant was 7 days of age. Genetic testing showed a 102-kb deletion within chromosome band 9p24.2; this deletion has not been previously linked to congenital heart defects. Berry syndrome can be diagnosed accurately by transthoracic echocardiogram and CT. There may be an underlying genetic etiology, and this possibility warrants further investigation. 23350559 Necrotizing fasciitis in a patient with bullous pemphigoid treating with systemic steroid. Abstract Necrotizing fasciitis (NF) is a rarely seen, life-threatening soft tissue infection characterized by progressive necrosis of skin, subcutaneous tissues and fasciae. Herein, we present a case of NF in a patient with bullous pemphigoid. A 78-year-old female patient was admitted with the left leg pain, swelling, redness and blistering. Streptococcus pyogenes was isolated from the wound culture. In the skin biopsy and the left leg magnetic resonance imaging, signs of NF were observed. The diagnosis of NF was considered. Then, urgent surgical debridement was performed by the department of plastic surgery. While under treatment with intravenous antibiotics therapy, unfortunately the patient died of acute renal insufficiency. 23916718 Genome-wide studies of nuclear receptors in cell fate decisions. Nuclear receptors (NRs) are important mediators of the information encoded in the chemical structure of its corresponding ligand, as they interpret such information in the context of the cell identity and physiological status and convert it into sequential transcription regulatory events. At the cell level this can result in temporally coordinated processes such as cell fate transitions, which comprise the regulation of a plethora of gene programs including among others regulation of cell proliferation, metabolism and specific functionalities that are acquired by the differentiated cell. While both the early steps of nuclear receptor function and their impact on animal/organ physiology is rather well understood, little is known about the dynamic gene networks that ultimately cause a particular (cell) physiological phenomenon induced by the cognate NR ligand/hormone. Thanks to advances in massive parallel sequencing and bioinformatics analyses of genome-wide data sets, time has come for the development of NR systems biology. Indeed it is now possible to integrate global transcription factor binding, epigenetic chromatin histone and DNA modification patterns with transcriptomes and 3-dimensional chromatin structures, extract decision points in temporal studies and decipher the temporal control of gene networks that are the ultimate genetic readouts of NR ligand-induced physiological phenomena. In this review we will summarize the chronology of the development of increasingly larger data sets for NR action, with a particular focus on studies performed with the RAR/RXR nuclear receptor family, and discuss the present attempts to integrate a multitude of genome-wide data sets in the ultimate context of the temporal 3-dimensional chromatin structure. 23768619 Prediction of IVF/ICSI outcome based on the follicular output rate. This study assessed the true accuracy of follicular output rate (FORT) as a prognostic indicator of response to FSH and reproductive competence after IVF/intracytoplasmic sperm injection. A total of 1643 cycles, including 140 polycystic ovary syndrome (PCOS) patients who underwent ovarian stimulation, were studied. FORT was calculated as the ratio of preovulatory follicle count on the day of stimulation×100/small antral follicle count (3-10mm in diameter) at baseline. Low, medium and high FORT groups were defined according to tertile values. Among 1503 non-PCOS cycles, numbers of retrieved oocytes and of all embryos that could be transferred, as well as rates of good-quality embryos, embryo implantations and clinical pregnancies, progressively increased with FORT. In PCOS patients, FORT were significantly lower in patients who achieved clinical pregnancy compared with those who did not (0.56±0.21 versus 0.66±0.29, P=0.031). Fertilization and good-quality embryo rates were significantly higher with medium FORT than low and high FORT (P=0.001 and P=0.047, respectively). Medium FORT in PCOS patients and high FORT in non-PCOS patients may predict better outcomes for IVF/ICSI. In the present study, we aimed to assess the true accuracy of the follicular output rate (FORT) as a prognostic indicator of the response to FSH and reproductive competence after IVF/intracytoplasmic sperm injection (ICSI). A total of 1643 IVF/ICSI cycles, including 140 polycystic ovary syndrome (PCOS) patients who underwent ovarian stimulation, were studied. FORT was calculated as the ratio of the preovulatory follicle count (PFC) on the day of human chorionic gonadotrophin stimulation×100/small antral follicle count (AFC; 3-10mm in diameter) at baseline. Low, medium and high FORT groups were defined according to the tertile values. Among 1503 non-PCOS cycles, the numbers of retrieved oocytes and of all embryos that could be transferred, as well as the rates of good-quality embryos, embryo implantations and clinical pregnancies, progressively increased from the lower to higher FORT groups. In PCOS patients, FORT was significantly lower in the patients who achieved clinical pregnancy compared with those who did not (0.56±0.21 versus 0.66±0.29, P<0.05). Fertilization and good-quality embryo rates were significantly higher in the medium FORT group compared with the low and high FORT groups. The data from the present study suggest that medium FORT values in PCOS patients and high FORT values in non-PCOS patients may predict better outcomes for IVF/ICSI. 23905850 Mechanistic insights from the binding of substrate and carbocation intermediate analogues to aristolochene synthase. Aristolochene synthase, a metal-dependent sesquiterpene cyclase from Aspergillus terreus, catalyzes the ionization-dependent cyclization of farnesyl diphosphate (FPP) to form the bicyclic eremophilane (+)-aristolochene with perfect structural and stereochemical precision. Here, we report the X-ray crystal structure of aristolochene synthase complexed with three Mg(2+) ions and the unreactive substrate analogue farnesyl-S-thiolodiphosphate (FSPP), showing that the substrate diphosphate group is anchored by metal coordination and hydrogen bond interactions identical to those previously observed in the complex with three Mg(2+) ions and inorganic pyrophosphate (PPi). Moreover, the binding conformation of FSPP directly mimics that expected for productively bound FPP, with the exception of the precise alignment of the C-S bond with regard to the C10-C11 π system that would be required for C1-C10 bond formation in the first step of catalysis. We also report crystal structures of aristolochene synthase complexed with Mg(2+)3-PPi and ammonium or iminium analogues of bicyclic carbocation intermediates proposed for the natural cyclization cascade. Various binding orientations are observed for these bicyclic analogues, and these orientations appear to be driven by favorable electrostatic interactions between the positively charged ammonium group of the analogue and the negatively charged PPi anion. Surprisingly, the active site is sufficiently flexible to accommodate analogues with partially or completely incorrect stereochemistry. Although this permissiveness in binding is unanticipated, based on the stereochemical precision of catalysis that leads exclusively to the (+)-aristolochene stereoisomer, it suggests the ability of the active site to enable controlled reorientation of intermediates during the cyclization cascade. Taken together, these structures illuminate important aspects of the catalytic mechanism. 23747505 Optimizing the taste-masked formulation of acetaminophen using sodium caseinate and lecithin by experimental design. In a previous study of ours, the association of sodium caseinate and lecithin was demonstrated to be promising for masking the bitterness of acetaminophen via drug encapsulation. The encapsulating mechanisms were suggested to be based on the segregation of multicomponent droplets occurring during spray-drying. The spray-dried particles delayed the drug release within the mouth during the early time upon administration and hence masked the bitterness. Indeed, taste-masking is achieved if, within the frame of 1-2min, drug substance is either not released or the released amount is below the human threshold for identifying its bad taste. The aim of this work was (i) to evaluate the effect of various processing and formulation parameters on the taste-masking efficiency and (ii) to determine the optimal formulation for optimal taste-masking effect. Four investigated input variables included inlet temperature (X1), spray flow (X2), sodium caseinate amount (X3) and lecithin amount (X4). The percentage of drug release amount during the first 2min was considered as the response variable (Y). A 2(4)-full factorial design was applied and allowed screening for the most influential variables i.e. sodium caseinate amount and lecithin amount. Optimizing these two variables was therefore conducted by a simplex approach. The SEM and DSC results of spray-dried powder prepared under optimal conditions showed that drug seemed to be well encapsulated. The drug release during the first 2min significantly decreased, 7-fold less than the unmasked drug particles. Therefore, the optimal formulation that performed the best taste-masking effect was successfully achieved. 23619163 Treating impaired cognition in schizophrenia: The case for combining cognitive-enhancing drugs with cognitive remediation. Cognitive impairment is a well-documented feature of schizophrenia and represents a major impediment to the functional recovery of patients. The therapeutic strategies to improve cognition in schizophrenia have either used medications (collectively referred to as 'cognitive-enhancing drugs' in this article) or non-pharmacological training approaches ('cognitive remediation'). Cognitive-enhancing drugs have not as yet been successful and cognitive remediation has shown modest success. Therefore, we may need to explore new therapeutic paradigms to improve cognition in schizophrenia. The optimal approach may require a combination of cognitive-enhancing drugs with cognitive remediation. We review the available data from animal and human studies that provide the conceptual basis, proof-of-concept and illustrations of success of such combination strategies in experimental and clinical paradigms in other conditions. We address the major design issues relevant to the choice of the cognitive-enhancing drugs and cognitive remediation, as well as the timing and the duration of the intervention as will be relevant for schizophrenia. Finally, we address the practical realities of the development and testing of such combined approaches in the real-world clinical situation and conclude that while scientifically attractive, there are several practical difficulties to be overcome for this approach to be clinically feasible. 23942211 Anti-angiogenic activity of heparin functionalised cerium oxide nanoparticles. Cerium oxide nanoparticles (nanoceria) are widely reported to be non-cytotoxic and modulate intracellular reactive oxygen species (ROS). In this study, nanoceria (dxRD = 12 nm) were functionalised with either 130 or 880 molecules of unfractionated heparin using the organosilane linker, 3-aminopropyltriethoxysilane. Nanoceria with a low level of heparin functionalisation were found to scavenge intracellular ROS to the same extent as unfunctionalised nanoceria and significantly more than cells exposed to medium only. In contrast, nanoceria with the highest level of heparin functionalisation were not as effective at scavenging intracellular ROS. Nanoceria were localised predominantly in the cytoplasm, while heparin-nanoceria were localised in both the cytoplasm and lysosomes. Together these data demonstrated that the level of nanoceria surface functionalisation with heparin determined the intracellular localisation and ROS scavenging ability of these particles. Additionally, heparin-nanoceria were effective in reducing endothelial cell proliferation indicating that they may find application in the control of angiogenesis in cancer in the future. 23934020 The combination of pronuclear and blastocyst morphology: a strong prognostic tool for implantation potential. To (i) investigate a possible association between different features of pronuclear (PN) morphology and different features of blastocyst morphology, (ii) evaluate the combination of PN and blastocyst morphologies as a predictive factor for ICSI outcomes and (iii) identify possible contributing factors to poor PN morphology. This study included 908 normally fertilised zygotes reaching full blastocyst stage, obtained from 350 patients undergoing ICSI cycles, in which the implantations rates were 0 % or 100 %. The influence of PN morphology on blastocyst morphology and on the rates of pregnancy and miscarriage was investigated. Embryos were graded and split into three groups, taking into consideration both the PN and the blastocyst status. The pregnancy rate was compared among these groups. Inner cell mass (ICM) alterations were correlated with the number of nucleolar precursor bodies (NPB), while trophectoderm alterations were correlated with the size of the pronuclei and the distribution of the NPB. The distribution of the NPB had an impact on the chances of pregnancy. A significant difference was observed among the groups regarding the pregnancy rate. The maternal age, number of aspirated follicles and number of retrieved oocytes influenced the incidence of PN defects. These findings suggest that a lower oocyte yield may lead to higher-quality PN zygotes. In addition, different PN features may influence further embryo development, especially the quality of the blastocyst. Moreover, the association between PN and blastocyst morphology may be used as a prognostic tool for implantation. 23896509 Update in the Treatment of High-grade Gliomas. Advances in the molecular classification of high-grade gliomas are laying the groundwork for potential changes in the treatment of high-grade gliomas. Currently, a combined modality approach involving surgery, radiation therapy, and chemotherapy is most often used in the treatment of high-grade gliomas. The authors review recent advances in the treatment of these primary brain tumors. 22548652 Differences in triglyceride and cholesterol metabolism and resistance to obesity in male and female vitamin D receptor knockout mice. A lean phenotype has been detected in vitamin D receptor (VDR) knockout mice; however, the gender differences in fat metabolism between male and female mice both with age and in response to a high-fat diet have not been studied before. The objective of our study was to assess changes in body and fat tissue weight, food intake and serum cholesterol and triglyceride in VDR knockout mice from weaning to adulthood and after a challenge of adult animals with a high-fat diet. Although VDR knockout mice of both sexes consumed more food than wild-type and heterozygous littermates, their body weight and the weight of fat depots was lower after 6 months on a diet with 5% crude fat content. When adult animals were challenged with a high-fat diet containing 21% crude fat content for 8 weeks, VDR knockout mice of both sexes had a significantly higher food intake but gained less weight than their wild-type littermates. Cholesterol levels were higher after 2 days on the high-fat diet in both sexes, but in the VDR knockout mice, less cholesterol was detected in the serum after 8 weeks. Wild-type male mice showed signs of fatty liver disease at the end of the experiment, which was not detected in the other groups. In conclusion, lack of the VDR receptor results in reduced fat accumulation with age and when adult mice are fed a high-fat diet, despite a higher food intake of VDR knockout mice relative to their wild-type littermates. These effects can be detected in both sexes. Wild-type male mice react with the highest weight gain and cholesterol levels of all groups and develop fatty liver disease after 8 weeks on a high-fat diet, while male VDR knockout mice appear to be protected. 23621345 Eccentric muscle damage increases intermuscular coherence during a fatiguing isometric contraction. The purpose of this study was to determine the effect of eccentric muscle damage on muscle activation patterns and intermuscular coherence during a fatiguing isometric contraction involving the elbow flexor muscles. Ten young subjects participated in three experimental sessions that involved the performance of maximum voluntary contractions (MVCs), a constant-force task at 30% MVC, and a fatiguing isometric contraction at 30% MVC. The three sessions were performed before, 2 h after and 2 days after eccentric exercise to induce muscle damage in elbow flexor muscles. Task performance was quantified with electromyography (EMG) from the elbow flexor (biceps brachii, brachialis and brachioradialis) and extensor (triceps brachii) muscles, M-wave amplitude of biceps brachii, elbow flexor force fluctuations and endurance time of a fatiguing contraction. Intermuscular coherence during the fatiguing contraction was quantified from the rectified surface EMGs between muscle pairs. Eccentric exercise resulted in several indicators of muscle damage, such as a prolonged decline in muscle strength and an increase in muscle soreness 2 days after exercise. A 29% reduction in endurance time was observed 2 h after eccentric muscle damage, which returned to baseline 2 days later. The reduced endurance time 2 h after muscle damage was accompanied by an increase in EMG-EMG coherence between biceps brachii and brachialis muscles, which was observed at the end of the fatiguing contraction. These findings suggest that eccentric muscle damage produces a decrease in endurance time that is accompanied by an increase in intermuscular coherence in the presence of fatigue. 23017418 Phytochemical composition and in vitro antimicrobial and antioxidant activities of some medicinal plants. Different parts of three plants (Primula auriculata, Fumaria vaillantii and Falcaria vulgaris) were extracted with three different solvents to yield 72 crude extracts. The phytochemical analysis (chemical screening, GC-MS) of three plants was investigated for their antioxidant and antibacterial activity using nine Gram-positive and Gram-negative bacteria. The principal antioxidant and antimicrobial components were determined using HPLC with UV detection. All extracts possessed antibacterial activity especially methanolic extracts from flowers of P. auriculata. The DPPH-radical scavenging assay exhibited high antioxidant activities in three plants (more than 80% at 50μg). The F. vulgaris showed high content of carvacrol (29.8%) as main component. The contents of carvacrol and fumaric acid in the methanolic-water extracts were 1119 and 1966mg/l respectively. Our results indicate that these plants would be able to promise sources of natural products with potential antibacterial and antioxidant activity. 23956333 Beat-to-beat QT interval variability and T-wave amplitude in patients with myocardial infarction. The purpose of this study was to investigate the effects of T-wave amplitude and ECG lead on beat-to-beat QT interval variability (QTV) in patients with myocardial infarction (MI) compared to healthy subjects. Standard resting 12-lead ECGs of 79 MI patients and 69 healthy subjects were investigated. Beat-to-beat QT intervals were measured separately for each lead using a template matching algorithm. In addition, we extracted the beat-to-beat T-wave amplitude in each lead. We computed the standard deviation of beat-to-beat QT intervals as a marker of QTV for both healthy subjects and MI patients. Significant QTV differences were observed between the 12 ECG leads as well as between the groups of healthy subjects and MI patients. Beat-to-beat QTV was significantly higher in MI patients than in healthy subjects for half of the leads. Furthermore, significant T-wave amplitude differences across leads and between groups were observed. A significant inverse relation between beat-to-beat QTV and T-wave amplitude was demonstrated. The group differences in QTV remained significant after co-varying for the T-wave amplitude. In conclusion, the increase in beat-to-beat QTV that has been repeatedly reported in patients with MI is partly due to the lower T-wave amplitudes. However, QTV remains significantly increased in MI patients after covarying for this effect. 23935993 MiR-146a Regulates SOD2 Expression in H2O2 Stimulated PC12 Cells. SOD2 (superoxide dismutase 2) is one of the endogenous antioxidant enzymes that protect against reactive oxygen species. While explorations of SOD2 expression regulation are mainly focused on transcriptional and post-translational activation, there are few reports about the post-transcriptional regulation of SOD2. MicroRNAs (miRNAs) are 21nt-25nt (nucleotide) small noncoding RNAs that have emerged as indispensable regulators of gene expression. Here we show that miR-146a, a widely expressed miRNA, is up-regulated by H2O2-induced stress. By sequence analysis we found a binding site for miR-146a in the sod2 mRNA 3'UTR, and a luciferase reporter assay confirmed that miR-146a can interact with this sod2 regulatory region. Our results further show that miR-146a could down-regulate the SOD2 protein expression, and antisense-miR-146a could reverse the decrease of both the SOD2 level and cell viability in H2O2 treated PC12 cells. In conclusion, here we have identified a novel function of miR-146a in the post-transcriptional regulation of SOD2 expression. 23283814 Regulation of Involucrin in Psoriatic Epidermal Keratinocytes: The Roles of ERK1/2 and GSK-3β. Psoriasis, a common inflammatory skin disease, is characterized by epidermal hyperplasia, abnormal differentiation, angiogenesis, immune activation, and inflammation. Involucrin is an early terminal differentiation marker of epidermal keratinocytes. In this study, we determined the immunolocalization of involucrin in psoriatic lesions and normal skin of individuals without psoriasis by means of immunofluorescence (IF) assay. Furthermore, the regulation of involucrin by interleukin (IL)-13, IL-17A, endothelin (ET)-1, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ was investigated by Western blot. Extracellular regulate protein kinases 1/2 (ERK1/2) and glycogen syntheses kinase-3β (GSK-3β) inhibitors were also included to define the roles of these signals in the production of involucrin in both psoriatic and normal keratinocytes. In psoriatic lesional skin, involucrin was detected in the stratum spinosum, but not in the basal or the cornified layer. In normal skin, involucrin was restricted to the granular layer and the upper stratum spinosum. IL-13, IL-17A, ET-1, TNF-α, and IFN-γ up-regulate expression of involucrin in both psoriatic and normal keratinocytes. However, this effect was abolished by ERK1/2 and GSK-3β inhibitors. In conclusion, involucrin is up-regulated in psoriatic keratinocytes. IL-13, IL-17A, ET-1, TNF-α, and IFN-γ could increase involucrin protein levels in psoriatic and normal keratinocytes. The ERK1/2 and GSK-3β signaling pathways may play positive roles in regulating epidermal differentiation as observed in psoriasis. 23726362 Virtual volume resection using multi-resolution triangular representation of B-spline surfaces. Computer assisted analysis of organs has an important role in clinical diagnosis and therapy planning. As well as the visualization, the manipulation of 3-dimensional (3D) objects are key features of medical image processing tools. The goal of this work was to develop an efficient and easy to use tool that allows the physician to partition a segmented organ into its segments or lobes. The proposed tool allows the user to define a cutting surface by drawing some traces on 2D sections of a 3D object, cut the object into two pieces with a smooth surface that fits the input traces, and iterate the process until the object is partitioned at the desired level. The tool is based on an algorithm that interpolates the user-defined traces with B-spline surface and computes a binary cutting volume that represents the different sides of the surface. The computation of the cutting volume is based on the multi-resolution triangulation of the B-spline surface. The proposed algorithm was integrated into an open-source medical image processing framework. Using the tool, the user can select the object to be partitioned (e.g. segmented liver), define the cutting surface based on the corresponding medical image (medical image visualizing the internal structure of the liver), cut the selected object, and iterate the process. In case of liver segment separation, the cuts can be performed according to a predefined sequence, which makes it possible to label the temporary as well as the final partitions (lobes, segments) automatically. The presented tool was evaluated for anatomical segment separation of the liver involving 14 cases and virtual liver tumor resection involving one case. The segment separation was repeated 3 different times by one physician for all cases, and the average and the standard deviation of segment volumes were computed. According to the test experiences the presented algorithm proved to be efficient and user-friendly enough to perform free form cuts for liver segment separation and virtual liver tumor resection. The volume quantification of segments showed good correlation with the prior art and the vessel-based liver segment separation, which demonstrate the clinical usability of the presented method. 23867488 Comparison of pharmacy services at critical access hospitals and other rural and small hospitals in Illinois. The results of a survey evaluating pharmacy services and technology use at critical access hospitals (CAHs) and other small and rural hospitals in Illinois are reported. A mail survey was sent to pharmacy directors at 86 CAHs and other rural and small hospitals in Illinois not designated as CAHs. Independent sample t tests and chi-square statistics were used to compare CAHs and non-CAHs in areas such as pharmacy services, staffing, use of technology, and sterile compounding practices. The survey response rate was 46.5%, with usable data received from 40 hospitals. Analysis of the survey data indicated that hospitals designated as CAHs were significantly less likely than non-CAHs to have automatic therapeutic interchange policies (p = 0.012) and more likely to conduct pharmacist-provided educational programs on medication costs for physicians and other health care personnel (p = 0.037). Relative to non-CAHs, CAHs were significantly less likely to have automated dispensing cabinets (p = 0.016) and to out-source the preparation of sterile products to offsite vendors (p = 0.012); pharmacy directors at CAHs were less likely to report the use of technology for remote medication order entry or review (p = 0.038). At both types of facilities, pharmacists typically have both distributive and clinical responsibilities, and patient-specific clinical pharmacy services (e.g., patient education or counseling, other drug therapy monitoring, medication reconciliation, pharmacokinetic consultations) are offered at similar frequencies. A survey of pharmacy departments at small and rural hospitals in Illinois determined that there were more similarities than differences between CAHs and non-CAHs. The survey indicated significant differences in dispensing processes, the use of technology and drug policy tools, and outsourcing of sterile product preparation. 23824808 Functional and structural analysis of influenza virus neuraminidase n3 offers further insight into the mechanisms of oseltamivir resistance. The influenza virus neuraminidase H274Y substitution is a highly prevalent amino acid substitution associated with resistance to the most heavily used influenza drug, oseltamivir. Previous structural studies suggest that the group specific 252 residue (Y252 in group 1 and T252 in group 2) might be a key factor underlying H274Y resistance. However, H274Y has only been reported in N1 subtypes, which indicates that there must be additional key residues that determine H274Y resistance. Furthermore, we found that members of NA serotype N3 also possess Y252, raising the key question as to whether or not H274Y resistance may also be possible for some group 2 NAs. Here, we demonstrate that the H274Y substitution results in mild oseltamivir resistance for N3. Comparative structural analysis of N3, N1, and their 274Y variants indicates that the interaction of residue 296 (H in N1 and nonaromatic for other serotypes) with conserved W295 is another important determinant of oseltamivir resistance. 23770617 Cadmium versus copper toxicity: Insights from an integrated dissection of protein synthesis pathway in the digestive glands of mussel Mytilus galloprovincialis. The main purpose of this study was to investigate the impact of metal-mediated stress on the protein-synthesis pathway in mussels. To this end, mussels (Mytilus galloprovincialis) underwent a 15 days exposure to 100μg/L Cu(2+) or Cd(2+). Both metals, in particular Cd(2+), accumulated in mussel digestive glands and generated a specific status of oxidative-stress. Exposure of mussels to each metal resulted in 40% decrease of the tRNA-aminoacylation efficiency, at the end of exposure. Cu(2+) also caused a progressive loss in the capability of 40S-ribosomal subunits to form 48S pre-initiation complex, which reached 34% of the control at the end of exposure. Other steps of translation underwent less pronounced, but measurable damages. Mussels exposed to Cd(2+) for 5 days presented a similar pattern of translational dysfunctions in digestive glands, but during the following days of exposure the ribosomal efficiency was gradually restored. Meanwhile, metallothionein levels significantly increased, suggesting that upon Cd(2+)-mediated stress the protein-synthesizing activity was reorganized both quantitatively and qualitatively. Conclusively, Cd(2+) and Cu(2+) affect translation at several levels. However, the pattern of translational responses differs, largely depending on the capability of each metal to affect cytotoxic pathways in the tissues, such as induction of antioxidant defense and specific repair mechanisms. 23782240 Systematic review: worldwide variation in the frequency of coeliac disease and changes over time. Coeliac disease (CD), originally thought to be largely confined to Northern Europe and Australasia and uncommon in North America and the Middle East, is now recognised to be equally common in all these countries. It is still thought to be rare in the Orient and Sub-Saharan Africa. To assess geographical differences and time trends in the frequency of CD. Medline and Embase searches were conducted on 10 November 2012, from 1946 and 1980 respectively, using the key words: coeliac disease or celiac disease + prevalence or incidence or frequency. There were significant intra- and inter-country differences in the prevalence and incidence of CD. Only 24 ethnic Chinese and Japanese patients have been reported in the English literature. Of CD-associated HLA DQ antigens, DQ2 occurs in 5-10% of Chinese and sub-Saharan Africans, compared to 5-20% in Western Europe. DQ8 occurs in 5-10% of English, Tunisians and Iranians, but in <5% of Eastern Europeans, Americans and Asians. The prevalence and incidence of both clinically and serologically diagnosed CD increased in recent years. These geographical and temporal differences seem genuine, although variable indices of suspicion and availability of diagnostic facilities are confounding factors. Coeliac disease is increasing in frequency, with significant geographical differences. Although few cases have been described to date in the Orient and Sub-Saharan Africa, there is a significant prevalence of HLA DQ2 and wheat consumption is of the same order as that in Western Europe. CD may therefore become more common in the future in these countries. 23911153 A curious case of glaucoma? An 84-year-old woman diagnosed with primary open-angle glaucoma was referred because her optic nerve appearance did not account for her visual field deficits. Further evaluation showed loss of color vision and rapid progression of visual field defects. Electroretinography revealed abnormal scotopic and photopic responses. Blood samples were positive for anti-retinal antibodies, but a malignancy work-up was negative, consistent with non-paraneoplastic autoimmune retinopathy. 23761408 Highly diversified coronaviruses in neotropical bats. Bats host a broad diversity of coronaviruses (CoVs), including close relatives of human pathogens. There is only limited data on neotropical bat CoVs. We analysed faecal, blood and intestine specimens from 1562 bats sampled in Costa Rica, Panama, Ecuador and Brazil for CoVs by broad-range PCR. CoV RNA was detected in 50 bats representing nine different species, both frugivorous and insectivorous. These bat CoVs were unrelated to known human or animal pathogens, indicating an absence of recent zoonotic spill-over events. Based on RNA-dependent RNA polymerase (RdRp)-based grouping units (RGUs) as a surrogate for CoV species identification, the 50 viruses represented five different alphacoronavirus RGUs and two betacoronavirus RGUs. Closely related alphacoronaviruses were detected in Carollia perspicillata and C. brevicauda across a geographical distance exceeding 5600 km. Our study expands the knowledge on CoV diversity in neotropical bats and emphasizes the association of distinct CoVs and bat host genera. 23930870 Role of Genetic Counselling in Prenatal Diagnosis of β-Thalassaemia in Pakistan. Objective: To compare the response towards prenatal diagnosis (PND) of b-thalassaemia, in individuals who had not received genetic counselling and a genetically counselled population. Study Design: Cross-sectional survey. Place and Duration of Study: Department of Haematology, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from March 2009 to December 2010. Methodology: Using non-probability consecutive sampling, a total of 176 individuals having thalassaemic children, were interviewed regarding PND of thalassaemia, by using a structured questionnaire. Forty two individuals were taken as controls as they had received genetic counselling for PND, whereas the remaining 134 were taken as cases. Responses towards PND were compared using chi-square test. Odds ratio was also calculated for subsequent PND utilization. Results: Seventy (52.2%) cases and 42 (100%) controls were aware of the availability of PND in Pakistan. This difference in awareness was statistically significant (p < 0.001). In the controls, 40 (95.3%) individuals were aware of the appropriate timing of the test, in contrast to 52 (39%) cases (p < 0.001). PND was used in subsequent pregnancies by 50 (37.3%) cases and 32 (80%) controls (p < 0.001). The calculated odds ratio for subsequent PND utilization was 5.37. Conclusion: The study reflects a very positive attitude of genetically counselled thalassaemia affected families towards PND. For better utilization of PND, genetic counselling services should be available at all health strata. 23780881 Enantioselective Synthesis of Quaternary Carbon Stereogenic Centers through Copper-Catalyzed Conjugate Additions of Aryl- and Alkylaluminum Reagents to Acyclic Trisubstituted Enones. Acyclic quaternary carbons by conjugate addition: The first examples of catalytic enantioselective conjugate additions of aryl and alkyl units that generate acyclic all-carbon quaternary stereogenic centers have been developed. The requisite organoaluminum reagents can either be prepared in situ from easily available organolithiums or purchased at low cost. 23817598 Vitamin D status is associated with early markers of cardiovascular disease in prepubertal children. Abstract Background: The associations of 25-hydroxyvitamin D [25(OH)D], non-high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL), and related markers of early cardiovascular disease (CVD) are unclear in prepubertal children. Objective: To investigate the association of 25(OH)D with markers of CVD. The hypothesis was that 25(OH)D would vary inversely with non-HDL-C. Subjects and methods: A prospective cross-sectional study of children (n=45; 26 males, 19 females) of mean age 8.3±2.5 years to investigate the relationships between 25(OH)D and glucose, insulin, high-sensitivity C-reactive protein, and lipids. Vitamin D deficiency was defined as 25(OH)D <20 ng/mL; overweight as body mass index (BMI) ≥85th but <95th percentile; and obesity as BMI >95th percentile. Results: Twenty subjects (44.4%) had BMI <85%, and 25 had BMI of ≥85%. Eleven participants (24.4%) had 25(OH)D of <20 ng/mL, and 10 (22.2%) had 25(OH)D of >30 ng/mL. Patients with 25(OH)D of <20 ng/mL had significantly elevated non-HDL-C (136.08±44.66 vs. 109.88±28.25, p=0.025), total cholesterol (TC)/HDL ratio (3.89±1.20 vs. 3.21±0.83, p=0.042), and triglycerides (TG) (117.09±71.27 vs. 73.39±46.53, p=0.024), while those with 25(OH)D of >30 ng/mL had significantly lower non-HDL-C, TC/HDL, TG, and LDL (82.40±18.03 vs. 105.15±28.38, p=0.006). Multivariate analysis showed significant inverse correlations between 25(OH)D and non-HDL cholesterol (β=-0.337, p=0.043), and TC/HDL ratio (β=-0.339, p=0.028), and LDL (β=-0.359, p=0.016), after adjusting for age, race, sex, BMI, and seasonality. Conclusions: Vitamin D varied inversely with non-HDL, TC/HDL, and LDL. A 25(OH)D level of 30 ng/mL is associated with optimal cardioprotection in children. 23714073 Modulation of anxiety-like behavior by the endocannabinoid 2-arachidonoylglycerol (2-AG) in the dorsolateral periaqueductal gray. Anandamide and 2-arachidonoylglycerol (2-AG) are the two main endocannabinoids, exerting their effects by activating type 1 (CB1r) and type 2 (CB2r) cannabinoid receptors. Anandamide inhibits anxiety-like responses through the activation of CB1r in certain brain regions, including the dorsolateral periaqueductal gray (dlPAG). 2-AG also attenuates anxiety-like responses, although the neuroanatomical sites for these effects remained unclear. Here, we tested the hypothesis that enhancing 2-AG signaling in the dlPAG would induce anxiolytic-like effects. The mechanisms involved were also investigated. Male Wistar rats received intra-dlPAG injections of 2-AG, URB602 (inhibitor of the 2-AG hydrolyzing enzyme, mono-acylglycerol lipase - MGL), AM251 (CB1r antagonist) and AM630 (CB2r antagonist). The behavior was analyzed in the elevated plus maze after the following treatments. Exp. 1: vehicle (veh) or 2-AG (5pmol, 50pmol, and 500pmol). Exp. 2: veh or URB602 (30pmol, 100pmol or 300pmol). Exp. 3: veh or AM251 (100pmol) followed by veh or 2-AG (50pmol). Exp. 4: veh or AM630 (1000pmol) followed by veh or 2-AG. Exp. 5: veh or AM251 followed by veh or URB602 (100pmol). Exp. 6: veh or AM630 followed by veh or URB602. 2-AG (50pmol) and URB602 (100pmol) significantly increased the exploration of the open arms of the apparatus, indicating an anxiolytic-like effect. These behavioral responses were prevented by CB1r (AM251) or CB2r (AM630) antagonists. Our results showed that the augmentation of 2-AG levels in the dlPAG induces anxiolytic-like effects. The mechanism seems to involve both CB1r and CB2r receptors. 23970125 Tubular von Hippel-Lindau Knockout Protects against Rhabdomyolysis-Induced AKI. Renal hypoxia occurs in AKI of various etiologies, but adaptation to hypoxia, mediated by hypoxia-inducible factor (HIF), is incomplete in these conditions. Preconditional HIF activation protects against renal ischemia-reperfusion injury, yet the mechanisms involved are largely unknown, and HIF-mediated renoprotection has not been examined in other causes of AKI. Here, we show that selective activation of HIF in renal tubules, through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO), protects from rhabdomyolysis-induced AKI. In this model, HIF activation correlated inversely with tubular injury. Specifically, VHL deletion attenuated the increased levels of serum creatinine/urea, caspase-3 protein, and tubular necrosis induced by rhabdomyolysis in wild-type mice. Moreover, HIF activation in nephron segments at risk for injury occurred only in VHL-KO animals. At day 1 after rhabdomyolysis, when tubular injury may be reversible, the HIF-mediated renoprotection in VHL-KO mice was associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal, as demonstrated by quantitative PCR, pathway enrichment analysis, and immunohistochemistry. In conclusion, a HIF-mediated shift toward improved energy supply may protect against acute tubular injury in various forms of AKI. 23887629 Thrombocytopenia induced by the histone deacetylase inhibitor abexinostat involves p53-dependent and -independent mechanisms. Abexinostat is a pan histone deacetylase inhibitor (HDACi) that demonstrates efficacy in malignancy treatment. Like other HDACi, this drug induces a profound thrombocytopenia whose mechanism is only partially understood. We have analyzed its effect at doses reached in patient plasma on in vitro megakaryopoiesis derived from human CD34(+) cells. When added at day 0 in culture, abexinostat inhibited CFU-MK growth, megakaryocyte (MK) proliferation and differentiation. These effects required only a short incubation period. Decreased proliferation was due to induction of apoptosis and was not related to a defect in TPO/MPL/JAK2/STAT signaling. When added later (day 8), the compound induced a dose-dependent decrease (up to 10-fold) in proplatelet (PPT) formation. Gene profiling from MK revealed a silencing in the expression of DNA repair genes with a marked RAD51 decrease at protein level. DNA double-strand breaks were increased as attested by elevated γH2AX phosphorylation level. Moreover, ATM was phosphorylated leading to p53 stabilization and increased BAX and p21 expression. The use of a p53 shRNA rescued apoptosis, and only partially the defect in PPT formation. These results suggest that HDACi induces a thrombocytopenia by a p53-dependent mechanism along MK differentiation and a p53-dependent and -independent mechanism for PPT formation. 23967236 Prenatal testosterone exposure worsen the reproductive performance of male rat at adulthood. The reproductive system is extremely susceptible to environmental insults, for example exogenous steroids during gestational development and differentiation. Experimental induction of androgen excess during prenatal life in female animal models reprograms their reproductive physiology, however the fetal programming of the male reproductive system by androgen excess has not been well studied. We aimed to determine the effect of prenatal exposure of two different doses of testosterone on different gestational days, on the male reproductive system using a rat model. Sixteen pregnant rats were randomly divided into two experimental groups and two control groups. Experimental group І were subcutaneously injected with 3 mg free testosterone on gestational days 16-19 and its controls received solvent for that time; experimental group П were subcutaneously injected with 20 mg free testosterone on day 20 of gestational period and its controls received solvent at the same time. The reproductive system morphology and function of 32 male offspring of these study groups were compared at days 6-30-60 of age and after puberty. The anogenital distance of the male offspring of both experimental groups had no significant differences on the different days of measurement, compared with controls. In the offspring of experimental group І, the testes weight, number of Sertoli, Spermatocyte and Spermatid cells, sperm count and motility and the serum concentration of testosterone after puberty were significantly decreased; except for reduction of sperm motility (p< 0.01), the other effects were not observed in the offspring of experimental group ІІ. In summary, our data show that prenatal exposure of male rat fetuses to excess testosterone disrupted reproductive function, an effect highly dependent on the time, duration and level of exposure. It seems that the reproductive system in individuals exposed to high levels of androgens during fetal life should be evaluated at puberty and likely to be treated. 23833182 Highly Efficient Genome Modifications Mediated by CRISPR/Cas9 in Drosophila. We report that Cas9/gRNA mediates efficient genetic modifications in Drosophila. Through targeting seven loci, we achieved a germline efficiency of up to 100%. Genes in both heterochromatin and euchromatin can be modified efficiently. Thus the Cas9/gRNA system is an attractive tool for rapid disruption of essentially any gene in Drosophila. 23532257 Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4. AIMS/HYPOTHESIS: Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians. METHODS: We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations. RESULTS: We identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10(-5) from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (p meta = 2.6 × 10(-8); OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (p meta = 2.3 × 10(-10)) and a population of European descent (p = 8.6 × 10(-3)). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians. CONCLUSIONS/INTERPRETATION: Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes. 23960128 Comparison of breast muscle traits and meat quality characteristics in 2 commercial chicken hybrids. A trial was conducted to compare muscle traits and meat quality characteristics of the pectoralis muscle in 2 chicken commercial hybrids having standard (SBY) and high breast yield (HBY), respectively. A total of 2,124 one-day-old male chicks, equally divided into 2 experimental groups represented by strains (SBY and HBY), were grown using homogenous conditions and fed the same standard diets until reaching live weight of 4.2 kg at 53 and 55 d for the SBY and HBY groups, respectively. Thirty-six birds per each genotype were randomly selected, and their pectoralis major muscles were used to assess meat quality properties (color attributes, pH, drip loss, cook loss, Allo-Kramer shear values after cooking, moisture, proteins, total lipids, and ashes) as well as histological traits (cross-sectional area, frequency of abnormal fibers, and intramuscular fat infiltration). As expected, HBY genotype had higher breast yield (31.0 vs. 30.0%; P ≤ 0.05). Histological evaluations showed that HBY pectoralis muscles had higher cross-sectional fiber area coupled with a dramatically higher (P ≤ 0.001) incidence of abnormal fibers and more abundant infiltration of intramuscular fat. Moreover, histopathological anomalous features such as central nuclei, proliferation of endomysial and perimysial collagen, inflammatory infiltrate, and necrosis of the fibers were also observed. As for meat quality, SBY hybrid showed lower ultimate pH values (5.97 vs. 6.07; P ≤ 0.01), whereas overall color parameters were not affected by genotype. Breast meat from the HBY genotype also exhibited significantly lower ability to retain liquid during refrigerated storage (drip loss, 2.46 vs. 2.06%; P ≤ 0.05) and cooking (26.2 vs. 21.1%; P ≤ 0.05) as well as higher shear-force values (2.59 vs. 2.11 kg/g; P ≤ 0.001). Finally, with regard to chemical composition, significant differences (P ≤ 0.05) were detected in protein (22.8 vs. 23.5%) and lipid (1.65 vs. 1.82%) contents, which were significantly lower in the HBY hybrid, whereas moisture content tended (P = 0.07) to be inferior in the SBY hybrid. 23946962 Reversible hydrogen desorption from LiBH4 catalyzed by graphene supported Pt nanoparticles. This review compared the effectiveness and common adverse events of medication classes used to treat seasonal allergic rhinitis (SAR) in adolescents and adults, in pregnant women, and in children. We sought to compare the following classes of drugs: oral and nasal antihistamines and decongestants; intranasal corticosteroids, mast cell stabilizers (cromolyn), and anticholinergics (ipratropium); oral leukotriene receptor antagonists (montelukast); and nasal saline. We identified English-language studies using a peer-reviewed search strategy. The following databases were searched on July 18, 2012, with no date restrictions: MEDLINE(®) (PubMed(®) and Ovid), Embase(®) (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews, and DARE (Database of Abstracts of Reviews of Effects). We consulted a Technical Expert Panel to identify the treatment comparisons most relevant to patients and providers. Subpopulations of interest were individuals with asthma or eye symptoms. Outcomes of interest were patient-reported symptom scores, quality of life, and adverse events. Inclusion was limited to studies that reported an outcome of interest and directly compared drugs of interest that were approved by the U.S. Food and Drug Administration (FDA). Two independent reviewers performed study selection and data abstraction. Disagreements were resolved by consensus or a third reviewer. We identified 59 trials that addressed 13 of 22 treatment comparisons of interest for adolescents and adults, 0 of 17 comparisons of interest for pregnant women, and 1 of 21 comparisons of interest for children. Across all comparisons, 20 of 39 drugs FDA approved for the treatment of SAR were studied. For adolescents and adults with SAR, evidence was sufficient to form the following conclusions. For the treatment of nasal symptoms, montelukast (oral leukotriene receptor antagonist) and intranasal corticosteroid were similarly effective (high strength of evidence [SOE]). For the treatment of nasal symptoms and eye symptoms, intranasal corticosteroid, nasal antihistamine, and combination intranasal corticosteroid plus nasal antihistamine were similarly effective (high SOE), and montelukast and oral selective antihistamine were similarly effective (moderate SOE). For improved quality of life, montelukast and oral selective antihistamine were similarly effective (moderate SOE), and combination oral selective antihistamine plus intranasal corticosteroid was superior to oral selective antihistamine alone (low SOE). To avoid insomnia, oral selective antihistamine was superior to oral decongestant and to combination oral selective antihistamine plus oral decongestant (moderate SOE). In patients codiagnosed with SAR and asthma, montelukast was superior to oral selective antihistamine for reduced asthma rescue medication use (moderate SOE). In sensitivity analyses using a lower threshold for minimum clinical effectiveness, combination oral selective antihistamine plus oral decongestant was superior to oral selective antihistamine alone for the treatment of nasal symptoms in adolescents and adults with SAR (moderate SOE). In this population, we did not find evidence that any single treatment was both more effective and had lower risk of harms. Evidence for both effectiveness and harms was insufficient regarding the comparison between oral selective and oral nonselective antihistamine in children. All effectiveness and harms outcomes were limited by short trial durations. Several effectiveness comparisons demonstrated similarity of treatments for selected outcomes. For most harms comparisons, the evidence was insufficient. Conclusions were limited by (1) lack of comparative evidence for all drugs within each class and (2) lack of evidence on the magnitude of symptom change that constitutes a minimal clinically important difference. The thermally induced de-/rehydrogenation performance of the graphene supported Pt nanoparticles (Pt/G) doped LiBH4 was greatly improved even at very low catalyst content due to a synergetic effect of Pt addition and nanoconfinement in graphene. For the 5 wt% Pt/G doped LiBH4 sample, the onset hydrogen desorption temperature is about 140 °C lower than that of the pure LiBH4. With increasing loading of the Pt/G catalysts in LiBH4 samples, the onset dehydrogenation temperature and the two main desorption peaks from LiBH4 were found to decrease while the hydrogen release amount increased. About 17.8 wt% can be released from the 50 wt% Pt/G doped LiBH4 sample below 500 °C. Moreover, variation of the equilibrium pressure (350-450 °C) indicates that the dehydrogenation enthalpy is reduced from 74 kJ mol(-1) H2 for the pure LiBH4 to ca. 48 kJ mol(-1) H2 for the 10 wt% Pt/G doped LiBH4, showing improved thermodynamic properties. More importantly, a reversible capacity of ca. 8.1 wt% in the 30th de-/rehydrogenation cycle was achieved under 3 MPa H2 at 400 °C for 10 h, indicating that the Pt/G catalysts play a crucial role in the improvement of the hydrogen uptake reversibility of LiBH4 at lower temperature and pressure conditions. Especially, LiBH4 was reformed and a new product, Li2B10H10, was detected after the rehydrogenation process. 23888844 Convergent evolution of sexual dimorphism in skull shape using distinct developmental strategies. Studies integrating evolutionary and developmental analyses of morphological variation are of growing interest to biologists as they promise to shed fresh light on the mechanisms of morphological diversification. Sexually dimorphic traits tend to be incredibly divergent across taxa. Such diversification must arise through evolutionary modifications to sex differences during development. Nevertheless, few studies of dimorphism have attempted to synthesize evolutionary and developmental perspectives. Using geometric morphometric analysis of head shape for 50 Anolis species, we show that two clades have converged on extreme levels of sexual dimorphism through similar, male-specific changes in facial morphology. In both clades, males have evolved highly elongate faces whereas females retain faces of more moderate proportion. This convergence is accomplished using distinct developmental mechanisms; one clade evolved extreme dimorphism through the exaggeration of a widely shared, potentially ancestral, developmental strategy whereas the other clade evolved a novel developmental strategy not observed elsewhere in the genus. Together, our analyses indicate that both shared and derived features of development contribute to macroevolutionary patterns of morphological diversity among Anolis lizards. 23852807 Which spinal lesions are associated with new bone formation in patients with ankylosing spondylitis treated with anti-TNF agents? A long-term observational study using MRI and conventional radiography. To study the relationship of spinal inflammation and fatty degeneration (FD) as detected by MRI and new bone formation seen on conventional radiographs (CRs) in ankylosing spondylitis (AS). CRs at baseline, 2 years and 5 years and spinal MRIs at baseline and 2 years of 73 AS patients treated with infliximab in European AS Infliximab Cohort were available. Relative risks (RR) were calculated with a general linear model after adjustment for within-patient variation. In a total of 1466 vertebral edges (VEs) without baseline syndesmophytes, 61 syndesmophytes developed at 5 years, the majority of which (57.4%) had no corresponding detectable MRI lesions at baseline. VEs with both inflammation and FD at baseline had the highest risk (RR 3.3, p=0.009) for syndesmophyte formation at 5 years, followed by VEs that developed new FD or did not resolve FD at 2 years (RR=2.3, p=0.034), while inflammation at baseline with no FD at 2 years had the lowest risk for syndesmophyte formation at 5 years (RR=0.8). Of the VEs with inflammation at baseline, >70% resolved completely, 28.8% turned into FD after 2 years, but only 1 syndesmophyte developed within 5 years. Parallel occurrence of inflammation and FD at baseline and development of FD without prior inflammation after 2 years were significantly associated with syndesmophyte formation after 5 years of anti-tumour necrosis factor (TNF) therapy. However, the sequence 'inflammation-FD-new bone formation' was rarely observed, an argument against the TNF-brake hypothesis. Whether an early suppression of inflammation leads to a decrease of the risk for new bone formation remains to be demonstrated. 23423302 No effect of acute L-arginine supplementation on O₂ cost or exercise tolerance. The extent to which dietary supplementation with the nitric oxide synthase (NOS) substrate, L-arginine (ARG), impacts on NO production and NO-mediated physiological responses is controversial. This randomised, double blinded, cross-over study investigated the effects of acute ARG supplementation on NO biomarkers, O₂ cost of exercise and exercise tolerance in humans. In one experiment, 15 subjects completed moderate- and severe-intensity running bouts after acute supplementation with 6 g ARG or placebo (PLA). In another experiment, eight subjects completed moderate- and severe-intensity cycling bouts after acute supplementation with 6 g ARG plus 25 g of carbohydrate (ARG + CHO) or an energy-matched dose of carbohydrate alone (CHO). The plasma nitrite concentration was not different after ARG (Pre: 204 ± 79; Post: 241 ± 114 nM; P > 0.05) or ARG + CHO consumption (Pre: 304 ± 57; Post: 335 ± 116 nM; P > 0.05). During moderate-intensity exercise, the steady-state pulmonary VO₂ was not different, relative to the respective placebo conditions, after ARG (PLA: 2,407 ± 318, ARG: 2,422 ± 333 mL min(-1)) or ARG + CHO (CHO: 1,695 ± 304, ARG + CHO: 1,712 ± 312 mL min(-1)) ingestion (P > 0.05). The tolerable duration of severe exercise was also not significantly different (P > 0.05) after ingesting ARG (PLA: 551 ± 140, ARG: 552 ± 150 s) or ARG + CHO (CHO: 457 ± 182, ARG + CHO: 441 ± 221 s). In conclusion, acute dietary supplementation with ARG or ARG + CHO did not alter biomarkers of NO synthesis, O₂ cost of exercise or exercise tolerance in healthy subjects. 23828779 Determinants of Binding of Oxidized Phospholipids on Apolipoprotein (a) and Lipoprotein (a). Oxidized phospholipids (OxPL) are present on apolipoprotein (a) [apo(a)] and lipoprotein (a) [Lp(a)] but the determinants influencing their binding are not known. The presence of OxPL on apo(a)/Lp(a) was evaluated in plasma from healthy humans, apes, monkeys, mice (wild type, apoE-/-, LDLR-/-, apo(a)/Lp(a) transgenic mice, lysine binding site (LBS) mutant apo(a)/Lp(a) mice with Asp55/57->Ala55/57 substitution of kringle (K) IV10), and a variety of recombinant apo(a) [r-apo(a)] constructs. Using antibody E06, which binds the phosphocholine (PC) headgroup of OxPL, Western and ELISA formats revealed that OxPL were only present in apo(a)s with an intact KIV10 LBS. Lipid extracts of purified human Lp(a) contained both E06- and non-E06-detectable OxPL by tandem liquid chromatography-mass spectrometry (LC-MS/MS). Trypsin digestion of 17K r-apo(a) showed PC-containing OxPL covalently bound to apo(a) fragments by LC-MS/MS that could be saponified by ammonium hydroxide. Interestingly, PC-containing OxPL were also present in 17K r-apo(a) with Asp57->Ala57 substitution in KIV10 that lacked E06 immunoreactivity. In conclusion, E06 and non-E06 detectable OxPL are present in the lipid phase of Lp(a) and covalently bound to apo(a). E06 immunoreactivity, reflecting pro-inflammatory OxPL accessible to the immune system, is strongly influenced by KIV10 LBS and is unique to human apo(a), which may explain Lp(a)s pro-atherogenic potential. 23969424 Fruit and Vegetables: Intake and Sociodemographic Determinants among Portuguese Mothers. Background: Fruit and vegetable intake is crucial in health promotion and disease prevention. Inadequate intake is found among adult populations worldwide. Aims: To assess fruit and vegetable intake among Portuguese mothers and to examine its association with sociodemographic determinants. Methods: A national cross-sectional survey was performed in Portugal as part of the Pro Children study. Data from self-administrated precoded 24-hour recall and food frequency questionnaires answered by 1,853 mothers of 11- to 13-year-old children were analyzed. Descriptive analysis of the data was followed by logistic regression to assess associations between daily fruit and vegetable intake and sociodemographic determinants. Results: The mean fruit and vegetable intake was 221.2 and 170.0 g/day, respectively. Only 46% of the mothers met the WHO recommendations (≥400 g fruit and vegetables/day). Daily fruit intake was significantly higher among mothers who live with a spouse/partner, and who belong to a higher social class. For vegetables, daily intake was significantly higher among mothers with a higher education and social class. Conclusions: This study shows that the mean intake of fruit and vegetables among Portuguese mothers is far below international recommendations. Effective strategies to promote fruit and vegetable intake are needed, especially for mothers belonging to lower social classes and educational levels. 23917588 Pediatric neuroimaging using magnetic resonance imaging during non-sedated sleep. Etiological studies of many neurological and psychiatric disorders are increasingly turning toward longitudinal investigations of infant brain development in order to discern predisposing structural and/or functional differences prior to the onset of overt clinical symptoms. While MRI provides a noninvasive window into the developing brain, MRI of infants and toddlers is challenging due to the modality's extreme motion sensitivity and children's difficulty in remaining still during image acquisition. Here, we outline a broad research protocol for successful MRI of children under 4 years of age during natural, non-sedated sleep. All children were imaged during natural, non-sedated sleep. Active and passive measures to reduce acoustic noise were implemented to reduce the likelihood of the children waking up during acquisition. Foam cushions and vacuum immobilizers were used to limit intra-scan motion artifacts. More than 380 MRI datasets have been successfully acquired from 220 children younger than 4 years of age within the past 39 months. Implemented measures permitted children to remain asleep for the duration of the scan and allowed the data to be acquired with an overall 97% success rate. The proposed method greatly advances current pediatric imaging techniques and may be readily implemented in other research and clinical settings to facilitate and further improve pediatric neuroimaging. 23844615 Xenograft and genetically engineered mouse model systems of osteosarcoma and Ewing's sarcoma: tumor models for cancer drug discovery. Introduction: There are > 75 histological types of solid tumors that are classified into two major groups: bone and soft-tissue sarcomas. These diseases are more prevalent in children, and pediatric sarcomas tend to be highly aggressive and rapidly progressive. Sarcomas in adults may follow a more indolent course, but aggressive tumors are also common. Sarcomas that are metastatic at diagnosis, or recurrent following therapy, remain refractory to current treatment options with dismal overall survival rates. A major focus of clinical trials, for patients with sarcoma, is to identify novel and more effective therapeutic strategies targeted to genomic or proteomic aberrations specific to the malignant cells. Critical to the understanding of the potential for targeted therapies are models of disease that are representative of clinical disease and predictive of relevant clinical responses. Areas covered: In this article, the authors discuss the use of mouse xenograft models and genetically engineered mice in cancer drug discovery. The authors provide a special focus on models for the two most common bone sarcomas: osteosarcoma (OS) and Ewing's sarcoma (ES). Expert opinion: Predicting whether a new anticancer agent will have a positive therapeutic index in patients with OS and ES remains a challenge. The use of mouse sarcoma models for understanding the mechanisms involved in the response of tumors to new treatments is an important step in the process of drug discovery and the development of clinically relevant therapeutic strategies for these diseases. 23911077 Chronic stroke survivors achieve comparable outcomes following virtual task specific repetitive training guided by a wearable robotic orthosis (UL-EXO7) and actual task specific repetitive training guided by a physical therapist. Survivors post stroke commonly have upper limb impairments. Patients can drive neural reorganization, brain recovery and return of function with task specific repetitive training (TSRT). Fifteen community independent stroke survivors (25-75 years, >6 months post stroke, Upper Limb Fugl Meyer [ULFM] scores 16-39) participated in this randomized feasibility study to compare outcomes of upper limb TSRT guided by a robotic orthosis (bilateral or unilateral) or a physical therapist. After 6 weeks of training (18 h), across all subjects, there were significant improvements in depression, flexibility, strength, tone, pain and voluntary movement (ULFM) (p < 0.05; effect sizes 0.49-3.53). Each training group significantly improved ULFM scores and range of motion without significant group differences. Virtual or actual TSRT performed with a robotic orthosis or a physical therapist significantly reduced arm impairments around the shoulder and elbow without significant gains in fine motor hand control, activities of daily living or independence. 23920131 Clinical Effectiveness of Aripiprazole in Short-term Treatment of Tic Disorder in Children and Adolescents: A Naturalistic Study. The purpose of this study was to evaluate the effectiveness and tolerability of aripiprazole in short-term treatment of children and adolescents with tic disorder (TD). This was a 14-week, prospective, open-label flexible dose trial of aripiprazole. We enrolled patients with TD aged between 4 years and 18 years. They received aripiprazole (dose: 2.5 mg/day) initially, which was then adjusted according to clinical response. The severity was assessed by the Yale Global Tic Severity Score (YGTSS) at 0, 2, 6, 10, and 14 weeks. The linear mixed models were used for evaluation of the YGTSSs at each follow-up, which were compared with baseline scores. Eighty-one patients were enrolled in this study. Nine patients withdrew from the study with complaints of adverse side effects. Of the remaining 72 patients, 15 patients discontinued medications prematurely due to being free of symptoms for over 2 weeks. Two patients discontinued medications due to no significant improvement. The mean scores had significantly decreased since the 2nd week (p < 0.01). The mean reduction was 51.0% in the motor tic scores, 67.1% in the vocal tic scores, and 70.0% in the total YGTSSs. The common adverse effects were sedation (32.1%) and increased appetite (22.2%). A slight increase in average body weight was noted, from 32.7 to 33.7 kg (+1.0 kg, p < 0.05). Aripiprazole is effective for short-term treatment of TD, especially vocal tics, in children and adolescents with mild adverse effects. However, further double-blind trials against placebo or other medications are needed to verify the efficacy of aripiprazole in the pharmacotherapy of TD. 23969694 Hybrid optofluidic integration. Complete integration of microfluidic and optical functions in a single lab-on-chip device is one goal of optofluidics. Here, we demonstrate the hybrid integration of a PDMS-based fluid handling layer with a silicon-based optical detection layer in a single optofluidic system. The optical layer consists of a liquid-core antiresonant reflecting optical waveguide (ARROW) chip that is capable of single particle detection and interfacing with optical fiber. Integrated devices are reconfigurable and able to sustain high pressures despite the small dimensions of the liquid-core waveguide channels. We show the combination of salient sample preparation capabilities-particle mixing, distribution, and filtering-with single particle fluorescence detection. Specifically, we demonstrate fluorescent labelling of λ-DNA, followed by flow-based single-molecule detection on a single device. This points the way towards amplification-free detection of nucleic acids with low-complexity biological sample preparation on a chip. 23719301 Gene-centric association study of acute chest syndrome and painful crisis in sickle cell disease patients. Patients with sickle cell disease (SCD) present with a wide range of clinical complications. Understanding this clinical heterogeneity offers the prospects to tailor the right treatments to the right patients and also guide the development of novel therapies. Several environmental (eg, nutrition) and nonenvironmental (eg, fetal hemoglobin levels, α-thalassemia status) factors are known to modify SCD severity. To find new genetic modifiers of SCD severity, we performed a gene-centric association study in 1514 African American participants from the Cooperative Study of Sickle Cell Disease (CSSCD) for acute chest syndrome (ACS) and painful crisis. From the initial results, we selected 36 single nucleotide polymorphism (SNPs) and genotyped them for replication in 387 independent patients from the CSSCD, 318 SCD patients recruited at Georgia Health Sciences University, and 449 patients from the Duke SCD cohort. In the combined analysis, an association between ACS and rs6141803 reached array-wide significance (P = 4.1 × 10(-7)). This SNP is located 8.2 kilobases upstream of COMMD7, a gene highly expressed in the lung that interacts with nuclear factor-κB signaling. Our results provide new leads to gaining a better understanding of clinical variability in SCD, a "simple" monogenic disease. 23376476 OGG1 Ser326Cys polymorphism interacts with cigarette smoking to increase oxidative DNA damage in human sperm and the risk of male infertility. 8-Oxoguanine DNA glycosylase 1 (OGG1) plays an important role in repairing oxidative DNA damage induced by chemical agents, such as tobacco. This study examined the effects of OGG1 Ser326Cys polymorphism and cigarette smoking, alone or combined, on sperm oxidative DNA damage and the risk of male infertility. A total of 620 idiopathic infertile subjects and 480 fertile controls were recruited in this study. Sperm 8-hydroxydeoxyguanine (8-OHdG) was measured by immunofluorescent assay using flow cytometry and genotypes were determined by OpenArray platform with a chip-based Taq-Man genotyping technology. Our results demonstrated that both cigarette smoking and OGG1 polymorphism can affect the sperm 8-OHdG levels. Individuals with variant Cys/Cys homozygote showed higher levels of sperm 8-OHdG than wide-type homozygote carriers (Ser/Ser). Stratified analysis found that the association between OGG1 polymorphism and sperm 8-OHdG levels was only observed among smokers with pack-years ≥5 but not among those subjects with pack-years<5 (pack-years=packs smoked per day×years as a smoker). Further analysis based on the case-control study revealed that variant allele (Cys) of OGG1 was significantly associated with male infertility risk in a dominant model (OR=1.35, 95% CI: 1.01-1.82; trend P<0.001). Furthermore, we found a significant gene-environment interaction between OGG1 Ser326Cys polymorphism and cigarette smoking in relation to male infertility risk (Pinteration=0.0003). These findings provided the first evidence about potential interactive effects of OGG1 polymorphism and cigarette smoking on male infertility risk. 23474593 Mn@Si14+: a singlet fullerene-like endohedrally doped silicon cluster. The electronic structure of Mn@Si14(+) is determined using DFT and CASPT2/CASSCF(14,15) computations with large basis sets. The endohedrally Mn-doped Si cationic cluster has a D3h fullerene-like structure featuring a closed-shell singlet ground state with a singlet-triplet gap of ~1 eV. A strong stabilizing interaction occurs between the 3d(Mn) and the 2D-shell(Si14) orbitals, and a large amount of charge is transferred from the Si14 cage to the Mn dopant. The 3d(Mn) orbitals are filled by encapsulation, and the magnetic moment of Mn is completely quenched. Full occupation of [2S, 2P, 2D] shell orbitals by 18 delocalized electrons confers the doped Mn@Si14(+) cluster a spherically aromatic character. 23582304 A comparative mutational analysis of HIV-1 Vpu subtypes B and C for the identification of determinants required to counteract BST-2/Tetherin and enhance viral egress. We have undertaken a genetic strategy to map Vpu regions necessary for BST-2 antagonism and viral egress. This approach is based on our identification of an egress-defective Vpu variant encoded by an HIV-1 subtype C strain. We constructed a series of chimeric Vpu molecules made from the Vpu C variant and Vpu B from a standard laboratory strain. The TM domain from the inactive Vpu C, which contains multiple non-conserved residues, was responsible for a significant decrease in egress activity and BST-2 downregulation, confirming the functional importance of the Vpu TM domain. However, for complete inactivation, both the N-terminus and TM domain from the inactive Vpu C molecule were required, suggesting a new role for the Vpu N-terminus. In addition, determinants in the C-terminus of Vpu B that may be involved in efficient TGN accumulation were also necessary for enhanced viral egress but are missing or non-functional in Vpu C. 23850163 Quality of Life in Patients with Ileal Conduit Cystectomy Due to Bladder Cancer. To determine the variables that affect quality of life of patients treated by radical cystectomy with ileal conduit. We analyzed quality of life using the EQ-5D-3L questionnaire. This questionnaire evaluates mobility, personal care, daily activities, pain/discomfort, anxiety/depression and a self-rating scale of the health condition. We compared the result with demographic variables (gender, age, work situation, studies, income, partner) and clinical variables (ASA classification, tumor stage, time since cystectomy was performed, adjuvant chemotherapy, recurrent and complications of the stoma). The statistical analysis included a descriptive study, univariate and multivariate analysis. A total of 59 patients were included in the study, with a mean age of 69 years (47-84). Mean time from cystectomy was 43 months (12-83), with 61% complications associated to the stoma. Stoma complications were related with limitations in personal care, pain/discomfort, anxiety, depression and quality of life in general. Female gender was associated with limitations in daily activities and adjuvant chemotherapy with anxiety/depression and quality of life in general. The rest of the variables were not statistically significant in the multivariate analysis. The limitations in quality of life in patients with cystectomy and ileal conduit are associated with the stoma-associated complications. Other related variables are female gender and administration of adjuvant chemotherapy. 23848132 Cystatin C is better than albuminuria as a predictor of pulse wave velocity in hypertensive patients. Abstract Introduction: Arterial stiffness is important in the evaluation of the cardiovascular risk in both general population and hypertensive patients. In this study, we aimed to investigate the associations of both serum cystatin C levels and albuminuria with arterial stiffness in healthy controls and hypertensive patients. Patients and methods: Seventy-six healthy controls (male/female = 44/32) and 76 hypertensive patients (male/female = 43/33) were enrolled. Arterial stiffness parameters such as augmentation index (AIx) and pulse wave velocity (PWV) were non-invasively measured with the Arteriograph (Tensiomed Ltd., Budapest, Hungary). Results: AIx (31.92 ± 14.31 vs. 27.95 ± 11.03, p = 0.03) and PWV (9.84 ± 1.62 vs. 8.87 ± 2.04, p < 0.001) were significantly higher in hypertensive patients compared to healthy controls. Patients with microalbuminuria had significantly higher AIx (43.47 ± 9.91 vs. 30.37 ± 14.13, p = 0.002) and higher serum cystatin C levels [0.76 (0.67-0.95) vs. 0.68 (0.62-0.78) mg/L, p = 0.03]. In the hypertensive group, AIx was significantly correlated with PWV (r = 0.519, p < 0.001), glomerular filtration rate (cystatin C) (r = -0.438, p = 0.003), mean arterial pressure (MAP) (r = 0.288, p = 0.015) and urinary albumin-creatinine ratio (ACR) (r = 0.386, p = 0.004). PWV was associated with serum cystatin C (r = 0.442, p = 0.003) and MAP (r = 0.377, p = 0.001). In the linear regression analysis (model r = 0.577, p = 0.006) for the prediction of PWV in hypertensive patients, MAP, urinary ACR, age and serum cystatin C levels were included as independent variables. Cystatin C was found to be the significant determinant of PWV in hypertensive patients. Conclusion: Multivariate analysis revealed that serum cystatin C but not albuminuria was significantly associated with PWV in hypertensive patients. Serum cystatin C may be better than albuminuria as a predictor of arterial stiffness in hypertensive patients. 23444336 Cytotoxicity and uptake of archaeosomes prepared from Aeropyrum pernix lipids. Archaeon Aeropyrum pernix K1 is an obligate aerobic hyperthermophilic organism with C(25,25)-archeol membrane lipids with head groups containing inositol. Interactions of archaeosomes, liposomes prepared from lipids of A. pernix, with mammalian cells in vitro were studied. In vitro cytotoxicity was tested on five different cell lines: rodent mouse melanoma cells (B16-F1) and Chinese hamster ovary (CHO) cells, and three human cell lines-epithelial colorectal adenocarcinoma cells (CACO-2), liver hepatocellular carcinoma cell line (Hep G2) and endothelial umbilical vein cell line (EA.hy926). Archaeosomes were nontoxic to human Hep G2, CACO-2 and mildly toxic to rodent CHO and B16-F1 cells but showed strong cytotoxic effect on EA.hy926 cells. Confocal microscopy revealed that archaeosomes are taken up by endocytosis. The uptake of archaeosomes and the release of loaded calcein are more prominent in EA.hy926 cells, which is in line with high toxicity toward these cells. The mechanisms of uptake, release and action in these cells as well as in vivo functioning have to be further studied for possible targeted drug delivery. 22806268 Cortical brain morphology in young, estrogen-naive, and adolescent, estrogen-treated girls with turner syndrome. Turner syndrome (TS) is a genetic condition that permits direct investigation of the complex interaction among genes, hormones, behavior, and brain development. Here, we used automated segmentation and surface-based morphometry to characterize the differences in brain morphology in children (n = 30) and adolescents (n = 16) with TS relative to age- and sex-matched control groups (n = 21 and 24, respectively). Our results show that individuals with TS, young and adolescent, present widespread reduction of gray matter volume, white matter volume and surface area (SA) over both parietal and occipital cortices bilaterally, as well as enlarged amygdala. In contrast to the young cohort, adolescents with TS showed significantly larger mean cortical thickness and significantly smaller total SA compared with healthy controls. Exploratory developmental analyses suggested aberrant regional brain maturation in the parahippocampal gyrus and orbitofrontal regions from childhood to adolescence in TS. These findings show the existence of abnormal brain morphology early in development in TS, but also suggest the presence of altered neurodevelopmental trajectories in some regions, which could potentially be the consequences of estrogen deficiency, both pre- and postnatally. 23467277 Noradrenergic synaptic function in the bed nucleus of the stria terminalis varies in animal models of anxiety and addiction. Lewis rats show increased anxiety-like behaviors and drug consumption compared with Sprague-Dawley rats. Prior work suggests norepinephrine (NE) signaling in the bed nucleus of the stria terminalis (BNST) could have a role in mediating these phenotypes. Here, we investigated NE content and dynamics in the ventral BNST (vBNST) using fast-scan cyclic voltammetry in these two rat strains. We found that NE release evoked by electrical stimulus and its subsequent uptake was dysregulated in the more anxious Lewis rats. Because addiction is a multifaceted disease influenced by both genetic and environmental factors, we hypothesized NE dynamics would vary in these strains after the induction of a physical dependence on morphine. Following naloxone-precipitated morphine withdrawal, NE release and uptake dynamics were not changed in Lewis rats but were significantly altered in Sprague-Dawley rats. The alterations in Sprague-Dawley rats were accompanied by an increase in anxiety-like behavior in those animals as measured with the elevated plus maze. These studies suggest novel mechanisms involved in the development of affective disorders, and highlight the noradrenergic system in the vBNST as a common substrate for the manifestation of pathological anxiety and addiction. 23203862 Non-inferiority and superiority tests for partially matched data when a constraint is placed on the number of new tests. Studies for assessing non-inferiority or superiority of a new diagnostic or screening test relative to a standard test use a complete matched-pairs design in which results for both tests are obtained for all subjects. We present alternative tests for the situation where results on the standard test are obtained for all subjects but results on the new test are obtained for a subset of those subjects only. This situation is common when results for the standard test are available from a large biobank. We present a stratified random sampling procedure for drawing the subsample of subjects that receive the new diagnostic test with strata defined by the two outcome categories of the standard test. We derive appropriate statistical tests for non-inferiority and superiority of the new diagnostic test. We will show how the number of subjects that receive the new test can be minimized by non-proportional stratified random sampling. 23938761 The adjuvant effect of hypertension upon diabetic peripheral neuropathy in experimental Type 2 diabetes. Type 2 diabetes (DM) is the most common cause of peripheral neuropathy in the Western world. A comorbidity, hypertension, has been speculated to contribute to initiation or worsening of diabetic peripheral neuropathy. We studied adult rat models using genetic strains with DM (Zucker Diabetic Fat rats)±hypertension (HTN (ZSF-1 rats)) to investigate the relative contributions of DM and HTN and the potential for additive effects of HTN upon existing DM for the development of peripheral neuropathy. Long duration sensorimotor behavioral and electrophysiological testing was complemented by histological and molecular methods. Only DM led to tactile and thermal hyperalgesia and affected motor nerve electrophysiology. Although DM led to marked loss of sensory amplitudes and to sensory conduction slowing, a mild additive effect from HTN contributed after 6months of DM with worsening of slowing of sensory nerve conduction velocities, but without effect upon sensory amplitudes. At the sensory dominant sural nerve, mild (<10%) but greater degrees of myelin thinning were noted with DM and HTN combined, suggesting a mild additive effect. Matrix metalloproteinase (MMP) expression was increased only at the sural nerve in the presence of HTN with co-localization to Schwann cells and myelin. The effects of DM and HTN upon peripheral nerve are dissimilar, with HTN contributing to MMP upregulation at the sites of myelin thinning at sensory nerve fibers, potentially worsening comorbid DM. Together, our results indicate that HTN has a mild additive contribution to diabetic peripheral neuropathy at sensory peripheral nerve fibers manifesting with the loss of myelin thickness. 23443352 Coblation vertebroplasty for complex vertebral insufficiency fractures. Coblation to create a cavity in the affected vertebral body was performed for complex fractures and/or when there was a posterior wall defect. This permitted a low-pressure injection and potentially reduces the risk of extravasation of cement into the spinal canal. Prospective audit for outcome measures and complications allowed retrospective review of cases treated by coblation. A commercial wand inserted via a wide-bore vertebroplasty needle created a cavity before inserting cement. A visual analogue scale assessed pain and Roland Morris scoring assessed mobility. Thirty-two coblation procedures were performed. Primary diagnoses were myeloma, metastases, osteoporosis and trauma. Outcome measures were recorded with a 56 % success rate, 6 % no change and 32 % with mixed but mainly positive results; 6 % died before follow-up. No complications were observed; in particular no patient suffered neurological damage and none have developed subsequent fractures at the treated levels. This technique makes possible cementation of patients who would otherwise be unsuitable for vertebroplasty. The modest pain and disability improvement is partly due to our stringent criteria as well as fracture complexity. Further work will assess the efficacy of the method compared with conservative measures. KEY POINTS : • Treatment of vertebral compression fractures with possible posterior wall defects is controversial. • Coblation before vertebroplasty allows a low-pressure injection into fractured vertebrae. • This technique reduces risk of extravasation of cement. • No serious complication of our coblation procedures was observed. 23434627 Identification of chromosomal copy number variations and novel candidate loci in hereditary nonpolyposis colorectal cancer with mismatch repair proficiency. The pathogenesis of microsatellite stable hereditary non-polyposis colorectal cancers (MSS HNPCC) is unclear. To identify genomic regions that might be involved in MSS HNPCC pathogenesis, we selected 20 pairs of MSS HNPCC for a genome-wide study using copy number variation targeted (CNV-targeted) CytoScan HD Array. A remarkably increased frequency of 20q gain (70%) and high levels of copy-neutral loss of heterozygosity (40%) were observed. The most frequent tumor-specific CNVs included amplifications (7p21.3-15.1, 8q13.3-24.3, 13q14.1-33.3 and 20q12-13.33) and deletions (8p11.23-23.1, 15q11.2-26.1, 17p13.1-13.3 and 18q11.2-21.33). In addition, 10 novel CNVs were discovered and led to identification of WDR16 and RAPGEF5 as candidate genes involved in tumorigenesis, displaying a robust correlation between expression and genomic alterations. Moreover, WDR16 and RAPGEF5 exhibited altered protein expression levels as assessed by immunohistochemistry (IHC) in 41 other independent samples. Finally, high consistencies (68-84%) were observed between CNVs by Array and quantitative PCR. These findings are important for further elucidating MSS HNPCC pathogenesis. 23757761 Amyloid tracers detect multiple binding sites in Alzheimer's disease brain tissue. Imaging fibrillar amyloid-β deposition in the human brain in vivo by positron emission tomography has improved our understanding of the time course of amyloid-β pathology in Alzheimer's disease. The most widely used amyloid-β imaging tracer so far is (11)C-Pittsburgh compound B, a thioflavin derivative but other (11)C- and (18)F-labelled amyloid-β tracers have been studied in patients with Alzheimer's disease and cognitively normal control subjects. However, it has not yet been established whether different amyloid tracers bind to identical sites on amyloid-β fibrils, offering the same ability to detect the regional amyloid-β burden in the brains. In this study, we characterized (3)H-Pittsburgh compound B binding in autopsied brain regions from 23 patients with Alzheimer's disease and 20 control subjects (aged 50 to 88 years). The binding properties of the amyloid tracers FDDNP, AV-45, AV-1 and BF-227 were also compared with those of (3)H-Pittsburgh compound B in the frontal cortices of patients with Alzheimer's disease. Saturation binding studies revealed the presence of high- and low-affinity (3)H-Pittsburgh compound B binding sites in the frontal cortex (K(d1): 3.5 ± 1.6 nM; K(d2): 133 ± 30 nM) and hippocampus (K(d1):5.6 ± 2.2 nM; K(d2): 181 ± 132 nM) of Alzheimer's disease brains. The relative proportion of high-affinity to low-affinity sites was 6:1 in the frontal cortex and 3:1 in the hippocampus. One control showed both high- and low-affinity (3)H-Pittsburgh compound B binding sites (K(d1): 1.6 nM; K(d2): 330 nM) in the cortex while the others only had a low-affinity site (K(d2): 191 ± 70 nM). (3)H-Pittsburgh compound B binding in Alzheimer's disease brains was higher in the frontal and parietal cortices than in the caudate nucleus and hippocampus, and negligible in the cerebellum. Competitive binding studies with (3)H-Pittsburgh compound B in the frontal cortices of Alzheimer's disease brains revealed high- and low-affinity binding sites for BTA-1 (Ki: 0.2 nM, 70 nM), florbetapir (1.8 nM, 53 nM) and florbetaben (1.0 nM, 65 nM). BF-227 displaced 83% of (3)H-Pittsburgh compound B binding, mainly at a low-affinity site (311 nM), whereas FDDNP only partly displaced (40%). We propose a multiple binding site model for the amyloid tracers (binding sites 1, 2 and 3), where AV-45 (florbetapir), AV-1 (florbetaben), and Pittsburgh compound B, all show nanomolar affinity for the high-affinity site (binding site 1), as visualized by positron emission tomography. BF-227 shows mainly binding to site 3 and FDDNP shows only some binding to site 2. Different amyloid tracers may provide new insight into the pathophysiological mechanisms in the progression of Alzheimer's disease. 23963050 Underlying Reading-Related Skills and Abilities Among Adult Learners. This exploratory study identified underlying skill and ability differences among subgroups of adolescent and young adult struggling readers (N = 290) overall and in relation to a fluency-based instructional grouping method. We used principal axis factoring of participants' scores on 18 measures of reading-related skills and abilities identified in the research literature to identify a smaller set of generally uncorrelated constructs. The four underlying factors of the 18 measures explained 62.7% of the variance. We labeled these factors Encode/Decode (44.5%), Vocabulary (9.5%), Processing Speed (5.2%), and Working Memory (3.5%). Regression analysis demonstrated Working Memory, Encode/Decode, and Vocabulary collectively predicted 45.9% functional reading as measured by the Comprehensive Adult Student Assessment System. Alternatively, when measured by the Test of Adult Basic Education, Vocabulary and Encode/Decode predicted 47.1% of variance in reading. Differences in predictive utility of the factors by fluency group suggest approaches to tailoring instruction for each group. Future research might examine the optimal mix of instructional approaches that support the identified factors. 23663287 Validation of SAPS3 admission score and its customization for use in Korean intensive care unit patients: A prospective multicentre study. To externally validate the simplified acute physiology score 3 (SAPS3) and to customize it for use in Korean intensive care unit (ICU) patients. This is a prospective multicentre cohort study involving 22 ICUs from 15 centres throughout Korea. The study population comprised patients who were consecutively admitted to participating ICUs from 1 July 2010 to 31 January 2011. A total of 4617 patients were enrolled. ICU mortality was 14.3%, and hospital mortality was 20.6%. The patients were randomly assigned into one of two cohorts: a development (n = 2309) or validation (n = 2308) cohort. In the development cohort, the general SAPS3 had good discrimination (area under the receiver operating characteristics curve = 0.829), but poor calibration (Hosmer-Lemeshow goodness-of-fit test H = 123.06, P < 0.001, C = 118.45, P < 0.001). The Australasia SAPS3 did not improve calibration (H = 73.53, P < 0.001, C = 70.52, P < 0.001). Customization was achieved by altering the logit of the original SAPS3 equation. The new equation for Korean ICU patients was validated in the validation cohort, and demonstrated both good discrimination (area under the receiver operating characteristics curve = 0.835) and good calibration (H = 4.61, P = 0.799, C = 5.67, P = 0.684). General and regional Australasia SAPS3 admission scores showed poor calibration for use in Korean ICU patients, but the prognostic power of the SAPS3 was significantly improved by customization. Prediction models should be customized before being used to predict mortality in different regions of the world. 23419778 Frailty and incident dementia. We sought to examine whether frailty is associated with dementia, Alzheimer's disease (AD), and non-AD dementia risk. This is a prospective population-based cohort derived from an integrated health maintenance organization. The sample consisted of 2,619 participants aged 65 and older without dementia at baseline followed from 1994 to 2010. Frailty was defined as having at least 3 of the following criteria: weakness (grip strength), slowness (walking speed), weight loss, low physical activity, and self-reported exhaustion. Follow-up occurred every 2 years to identify incident dementia, possible or probable AD, and non-AD dementia using standard research criteria. Covariates came from self-report and study measures. We used adjusted Cox proportional hazards models to examine the association between frailty and each outcome. Over a mean follow-up of 6.5 years, 521 participants developed dementia (of which 448 developed AD). In the model adjusted for age, sex, education, and race, the hazard ratio for frailty was 1.78 (95% confidence interval [CI] 1.32-2.40). In the fully adjusted models, the hazard ratio for frailty was 1.20 for all-cause dementia (95% CI 0.85-1.69), 1.08 for AD (95% CI 0.74-1.57), and 2.57 for non-AD dementia (95% CI 1.08-6.11). For all-cause dementia, we found an interaction between baseline cognitive score and frailty (p = .02); hazard ratio for frailty was 1.78 for those with higher global cognition (95% CI 1.14-2.78) and 0.79 for those with lower global cognition (95% CI 0.50-1.26). Frailty was associated with dementia when adjusting only for demographic variables but not in the fully adjusted model. Frailty was associated with higher risk of developing non-AD dementia but not AD. Although frailty was not associated with all-cause dementia in the entire sample, an association did exist in participants with higher cognitive scores. Mechanisms underlying these associations remain to be elucidated. 23838010 Activation of apoptotic pathway in normal, cancer ovarian cells by epothilone B. The epothilones, a new class of microtubule-targeting agents, seem to be a very promising alternative to the current strategy of cancer treatment. We have analyzed the aspects of epothilone B (Epo B) on cellular metabolism of tumor (OV-90) and normal (MM 14) ovarian cells. The observed effects were compared with those of paclitaxel (PTX), which is now a standard for the treatment of ovarian cancer. The results provide direct evidence that Epo B is considerably more cytotoxic to human OV-90 ovarian cancer cells than PTX. We have found, that antitumor efficacy of this new drug is related to its apoptosis-inducing ability, which was confirmed during measurements typical markers of the process. Epo B induced changes in morphology of cells, mitochondrial membrane potential and cytochrome c release. Also a slight increase of the intracellular calcium level was observed. Moreover, we have found that ROS production, stimulated by Epo B, is directly involved in the induction of apoptosis via mitochondrial pathway. 23148911 Control of stem cells and cancer stem cells by Hedgehog signaling: pharmacologic clues from pathway dissection. Hedgehog is a key morphogen regulating embryonic development and tissue repair. Remarkably, when misregulated, it leads to tumorigenesis. Hedgehog signaling is triggered by binding of ligands with transmembrane receptor Ptch and is subsequently mediated by transcriptional effectors belonging to the Gli family, whose functions is tuned by a number of molecular interactions and post-synthetic modifications. The complex of these regulatory circuitries provides a tight control of developmental processes, mainly involving the modulation of genes determining the fate of stem cells. Similarly, Hedgehog regulates cancer stem cells fostering tumorigenesis. To this regard, these processes represent promising targets for novel therapeutic strategies aiming at the control of stemness reactivation and maintenance in cancer. 23903747 An age difference of two billion years between a metal-rich and a metal-poor globular cluster. Globular clusters trace the formation history of the spheroidal components of our Galaxy and other galaxies, which represent the bulk of star formation over the history of the Universe. The clusters exhibit a range of metallicities (abundances of elements heavier than helium), with metal-poor clusters dominating the stellar halo of the Galaxy, and higher-metallicity clusters found within the inner Galaxy, associated with the stellar bulge, or the thick disk. Age differences between these clusters can indicate the sequence in which the components of the Galaxy formed, and in particular which clusters were formed outside the Galaxy and were later engulfed along with their original host galaxies, and which were formed within it. Here we report an absolute age of 9.9 ± 0.7 billion years (at 95 per cent confidence) for the metal-rich globular cluster 47 Tucanae, determined by modelling the properties of the cluster's white-dwarf cooling sequence. This is about two billion years younger than has been inferred for the metal-poor cluster NGC 6397 from the same models, and provides quantitative evidence that metal-rich clusters like 47 Tucanae formed later than metal-poor halo clusters like NGC 6397. 23123677 The kinase activity of EphA4 mediates homeostatic scaling-down of synaptic strength via activation of Cdk5. Neurons within a network have the ability to homeostatically scale-down their excitatory synaptic strength under conditions of persistent neuronal activity elevation, a process pivotal to neural circuit stability. How this homeostatic regulation is achieved at the molecular level in developing neural circuits, which face gradually elevated neuronal activity as part of circuit wiring, is not well-understood. Using dissociated hippocampal neuronal cultures, we identified a critical and cell autonomous role for the receptor tyrosine kinase EphA4 in mediating activity-induced homeostatic down-regulation of excitatory synaptic strength. Reducing the endogenous level of EphA4 in individual neurons by RNAi effectively blocked activity-induced scaling-down of excitatory synaptic strength, while co-transfection of RNAi resistant EphA4 rescued this effect. Furthermore, interfering with EphA4 forward signaling using EphA4-Fc blocked activity-induced homeostatic synaptic scaling-down, while direct activation of EphA4 with its ligand EphrinA1 weakened excitatory synaptic strength. Up- or down-regulating EphA4 function in individual neurons also did not affect the density of excitatory synapses. The kinase activities of EphA4 and its downstream effector Cdk5 were both required for homeostatic synaptic scaling, as overexpression of EphA4 with constitutively active kinase activity reduced excitatory synaptic strength, while interfering with either the kinase activity of EphA4 or Cdk5 blocked activity-induced synaptic scaling. Consistently, the activities of EphA4 and Cdk5 increased significantly during global and persistent activity elevation. Together, our work demonstrated that the kinase activity of EphA4, via activation of downstream Cdk5 activity, mediates the scaling-down of excitatory synaptic strength under conditions of global activity elevation. 23299756 Simultaneous determination and characterization of tannins and triterpene saponins from the fruits of various species of Terminalia and Phyllantus emblica using a UHPLC-UV-MS method: application to triphala. Terminalia species are a rich source of tannins. Many preparations of these species are used in traditional medicine and have many different ethnobotanical applications. A simple UHPLC method was developed for the simultaneous analysis of such hydrolysable tannins and triterpene saponins from the fruit rinds of different species of Terminalia (T. chebula, T. arjuna, T. bellirica) and Phyllantus emblica. A separation by LC was achieved using a reversed-phase column and a water/acetonitrile mobile phase, both containing formic acid, using a gradient system and a temperature of 40°C. Eight hydrolysable tannins (gallic acid, gallic acid methyl ester, corilagin, chebulagic acid, 1,2,3,6-tetra-O-galloyl-β-D-glucose, ellagic acid, chebulinic acid, and 1,2,3,4,6-penta-O-galloyl-β-D-glucose) and six triterpene saponins (arjunglucoside-I, arjunglucoside-III, chebuloside II, bellericoside, arjunetin, and arjunglucoside-II) could be separated within 20 minutes. The wavelength used for detection with the diode array detector was 254 and 275 nm for tannins and 205 nm for triterpene saponins. The method was validated for linearity, repeatability, limits of detection, and limits of quantification. The developed method is economical, fast, and especially suitable for quality control analysis of tannins and triterpene saponins in various plant samples and commercial products of Terminalia. 23880854 The cellular and molecular carcinogenic effects of radon exposure: a review. Radon-222 is a naturally occurring radioactive gas that is responsible for approximately half of the human annual background radiation exposure globally. Chronic exposure to radon and its decay products is estimated to be the second leading cause of lung cancer behind smoking, and links to other forms of neoplasms have been postulated. Ionizing radiation emitted during the radioactive decay of radon and its progeny can induce a variety of cytogenetic effects that can be biologically damaging and result in an increased risk of carcinogenesis. Suggested effects produced as a result of alpha particle exposure from radon include mutations, chromosome aberrations, generation of reactive oxygen species, modification of the cell cycle, up or down regulation of cytokines and the increased production of proteins associated with cell-cycle regulation and carcinogenesis. A number of potential biomarkers of exposure, including translocations at codon 249 of TP53 in addition to HPRT mutations, have been suggested although, in conclusion, the evidence for such hotspots is insufficient. There is also substantial evidence of bystander effects, which may provide complications when calculating risk estimates as a result of exposure, particularly at low doses where cellular responses often appear to deviate from the linear, no-threshold hypothesis. At low doses, effects may also be dependent on cellular conditions as opposed to dose. The cellular and molecular carcinogenic effects of radon exposure have been observed to be both numerous and complex and the elevated chronic exposure of man may therefore pose a significant public health risk that may extend beyond the association with lung carcinogenesis. 23912057 Intralaboratory validation of kinetic chromogenic Limulus amebocyte lysate assay for bacterial endotoxin determination in anti-bothropic serum. Over the years, substituting in vitro biological methods for in vivo tests has posed an ever increasing challenge for researchers, including those who study the applications for snake antivenom. In the quality control of antivenons, the only official test recommended by pharmacopoeias for detecting pyrogenicity is the rabbit pyrogen test. In the present study, we propose intralaboratory validation of a method to replace the rabbit pyrogen test: in vitro determination of bacterial endotoxin in anti-bothropic serum (ABS) with quantitative kinetic chromogenic limulus amebocyte lysate (LAL) assay. The kinetic chromogenic LAL assay is specific to the detection of gram-negative bacterial endotoxin. The validation of the test involved the determination of performance parameters required by the Agência Nacional de Vigilância Sanitária Brasileira (ANVISA, the Brazilian National Health Surveillance Agency), the United States Food and Drug Administration (FDA) and the United States Pharmacopeia (USP) 35. In all experiments, the correlation coefficient of the curve obtained with the control standard endotoxin (CSE; Escherichia coli 055:B5 strain, range, 0.005-50EU/mL) was between -0.998 and -1.000; and the recovery of endotoxin added to the sample of ABS (0.5EU/mL) at the working dilution (1:10) followed the recuperation criteria (i.e., 50-200%). We performed six determinations, in each of which the coefficient of variation for the intermediate precision was between 5.6% and 13.8% (below the 15% threshold) and the accuracy was between 90.7% and 114.3% (within the acceptable range of 80-120%). The endotoxin concentration limit for the ABS was determined to be ≤2.9EU/mL. The intralaboratory validation of the methodology was considered to have been successful because it met the criteria for all of the performance parameters. 23266207 Management and endoscopic techniques for digestive foreign body and food bolus impaction. Ingested foreign bodies, food bolus impaction, migration or retention of medical devices are frequent, in children as well as in adults. Most of these foreign bodies will naturally pass through the gastro-intestinal tract. Complications are rare but sometimes severe (oesophageal perforations are the most frequent and most feared). We aimed to review the literature on therapeutic management of digestive foreign bodies and food bolus impaction, with special focus on endoscopic indications, material, timing and techniques for removal. The role of the gastroenterologist is to recognise specific situations and to plan endoscopic removal in a timely manner with the most adequate conditions and extraction tools. Risk factors and underlying pathology, for example eosinophilic esophagitis, must be investigated and if necessary treated. 23830766 Three-dimensional intra-rater and inter-rater reliability during a posed smile using a video-based motion analyzing system. The purpose of this study was to determine the three-dimensional reproducibility of lip movement during a posed smile using a video-based motion analyzing system. In six adult volunteers (4 males and 2 females), the lip motions during a posed smile were recorded six times. Using our recently-developed motion analyzing system, range images were produced across the whole sequence during the posed smile. Virtual grids of 5 Ã— 5 were fitted onto the surfaces, and the three-dimensional coordinates of the intersections of these grids were then computed. The magnitude of the shift of the intersections during smiling was calculated and summed in each area. Intraclass correlation coefficients (ICC), ICC (1,1) for intra-rater reliability and ICC (2,1) for inter-rater reliability were calculated. The number of repeated measurements necessary for an ICC level beyond 0.8 was determined using the formula of Spearman-Brown. The ICC (1,1) and ICC (2,1) ranged from 0.71 to 0.83 and from 0.77 to 0.99, respectively. The number of repeated measurements necessary for an ICC beyond 0.8 was 2. From the present study, both the three-dimensional intra-rater and inter-rater reliabilities during a posed smile were considered to be relatively high, and enough reliability could be expected by calculating the average of the values measured two times. However, the sample size was very small, this could not be generalized simplistically. 23305922 Discovery of a small-molecule antiviral targeting the HIV-1 matrix protein. Due to the emergence of drug-resistant strains and the cumulative toxicities associated with current therapies, demand remains for new inhibitors of HIV-1 replication. The HIV-1 matrix (MA) protein is an essential viral component with established roles in the assembly of the virus. Using virtual and surface plasmon resonance (SPR)-based screening, we describe the identification of the first small molecule to bind to the HIV-1 MA protein and to possess broad range anti-HIV properties. 23899833 Aporphine Alkaloids from the Leaves of Phoebe grandis (Nees) Mer. (Lauraceae) and Their Cytotoxic and Antibacterial Activities. The oxoaporphine alkaloid lysicamine (1), and three proaporphine alkaloids, litsericinone (2), 8,9,11,12-tetrahydromecambrine (3) and hexahydromecambrine A (4) were isolated from the leaves of Phoebe grandis (Nees) Merr. (Lauraceae). Compounds 2 and 3 were first time isolated as new naturally occurring compounds from plants. The NMR data for the compounds 2-4 have never been reported so far. Compounds 1 and 2 showed significant cytotoxic activity against a MCF7 (human estrogen receptor (ER+) positive breast cancer) cell line with IC50 values of 26 and 60 µg/mL, respectively. Furthermore, in vitro cytotoxic activity against HepG2 (human liver cancer) cell line was evaluated for compounds 1-4 with IC50 values of 27, 14, 81 and 20 µg/mL, respectively. Lysicamine (1) displayed strong antibacterial activity against Bacillus subtilis (B145), Staphylococcus aureus (S1434) and Staphylococus epidermidis (a clinically isolated strain) with inhibition zones of 15.50 ± 0.57, 13.33 ± 0.57 and 12.00 ± 0.00 mm, respectively. However, none of the tested pathogenic bacteria were susceptible towards compounds 2 and 3. 23966081 Neuroprotective, anti-amyloidogenic and neurotrophic effects of apigenin in an Alzheimer's disease mouse model. Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular senile plaques and intracellular neurofibrillary tangles in the brain. Amyloid-β peptides (Aβ) are considered to play a critical role in the onset and progression of AD. Apigenin (4',5,7-trihydroxyflavone) is a pharmacologically active agent. Even though some evidence suggests that it has potential neuroprotective effects, no preexisting study has reported any therapeutic effects of apigenin in AD models. In the present study, we examined the effects of apigenin on cognitive function in APP/PS1 double transgenic AD mice and explored its mechanism(s) of action. Three-month oral treatment with apigenin rescued learning deficits and relieved memory retention in APP/PS1 mice. Apigenin also showed effects affecting APP processing and preventing Aβ burden due to the down-regulation of BACE1 and β-CTF levels, the relief of Aβ deposition, and the decrease of insoluble Aβ levels. Moreover, apigenin exhibited superoxide anion scavenging effects and improved antioxidative enzyme activity of superoxide dismutase and glutathione peroxidase. In addition, apigenin restored neurotrophic ERK/CREB/BDNF pathway in the cerebral cortex. In conclusion, apigenin may ameliorate AD-associated learning and memory impairment through relieving Aβ burden, suppressing amyloidogenic process, inhibiting oxidative stress, and restoring ERK/CREB/BDNF pathway. Therefore, apigenin appears to represent an alternative medication for the prevention and/or therapy of AD. 23916013 Diet composition as a cause of different contaminant exposure in two sympatric passerines in the Middle Urals, Russia. Contaminant exposure can vary between species but primary causes of it are often unclear. In order to estimate heavy metal intake of two sympatric passerines - Ficedula hypoleuca Pall. and Parus ater L. - we studied nestling diet and metal concentrations in prey invertebrates, near the Middle Ural copper smelter and in an unpolluted area. Diet of P. ater contained more Cu, Cd and Zn compared to F. hypoleuca and the same amount of Pb. Contribution of different prey taxa to bird metal intake was not equal to their dietary proportion. Proportion of Cu, Zn, Pb and Cd provided to birds by spiders and molluscs, as well as Cd and Pb provided by ants and imagoes Diptera, exceeded their dietary fraction by several times. In contrast, the contribution of Lepidoptera and sawfly larvae to bird metal intake was less than their dietary proportion. Pollution-related changes in the diet modified bird contaminant exposure along with pollutant concentrations in preys. 23813488 Testicular Cancer Knowledge among Deaf and Hearing Men. Testicular cancer typically affects young and middle-aged men. An educational video about prostate and testicular cancer was created in American Sign Language, with English open captioning and voice overlay, so that it could be viewed by audiences of diverse ages and hearing characteristics. This study recruited young Deaf (n = 85) and hearing (n = 90) adult males to help evaluate the educational value of the testicular cancer portion of this video. Participants completed surveys about their general, testicular, and total cancer knowledge before and after viewing the video. Although hearing men had higher pre-test scores than Deaf men, both Deaf and hearing men demonstrated significant increases in General, Testicular, and Total Cancer Knowledge scores after viewing the intervention video. Overall, results demonstrate the value of the video to Deaf and hearing men. 23912303 Analysis of graphene TE surface plasmons in the terahertz regime. Unlike common metals, graphene can support transverse electric (TE) surface modes when the imaginary part of its conductivity is negative. We have theoretically investigated and numerically simulated plasmonic properties of graphene TE surface plasmons (SPs) in the terahertz regime. The influence of the external magnetic field, gate voltage and temperature as the tuning schemes of the SPs have been investigated. The results show that graphene TE modes can be realized by tuning the magnetic fields or gate voltage. If the permeability of the dielectrics on both sides of the graphene layer differs enough, the graphene TE modes can still be achieved. The work presented here has the potential for application to graphene-based plasmonic devices in photonics and optoelectronics, such as sensors, polarizers and modulators. 23918095 Shared space, separate processes: Neural activation patterns for auditory description and visual object naming in healthy adults. Historically, both clinicians and cognitive scientists have used visual object naming measures to study naming, and lesion-type studies have implicated the left posterior, temporo-parietal region as a critical component of naming circuitry. However, recent results from behavioral and cortical stimulation studies using auditory description naming as well as visual object naming in left temporal lobe epilepsy patients suggest that discrete sites in anterior temporal cortex are critical for description naming, whereas posterior temporal regions mediate both visual object naming and description naming. To determine whether this task specificity reflects normal cerebral organization and processing, 13 healthy adults performed description naming and visual naming during functional neuroimaging. In addition to standard univariate analysis, multivariate, ordinal trend analysis examined the network character of the regions involved in task-specific naming. Univariate analysis indicated posterior temporal activation for both visual naming and description naming, whereas multivariate analysis revealed broader networks for both tasks, with both overlapping and task-specific regions, as well as task-related differences in the way the tasks utilized common regions. Additionally, multivariate analysis revealed unique, task-specific, regionally covarying activation patterns that were strikingly consistent in all 13 subjects for visual naming and 12/13 subjects for description naming. Results suggest a common neural substrate, yet differentiable neural processes underlying visual naming and description naming in neurologically intact individuals. These findings support the use of both types of tasks for clinical assessment and may have application in the treatment of neurologically based naming deficits. Hum Brain Mapp, 2013. © 2013 Wiley Periodicals, Inc. 23886786 Organophosphorous modifications of multifunctional magnetic nanowires. In the presented study, efforts have been undertaken to obtain the magnetic nanowires of multisegmental internal structure by AC and DC electrodeposition methods. The core-shell nanowires were obtained by wetting chemical deposition followed by thermal crystallization and electrodeposition. Such nanowires were tested to obtain functionalization by organophosphorous compounds and finally immobilize enzymes like trypsin. All obtained nanostructures were tested by X-ray diffraction, infrared spectroscopy and transmission electron microscopy. 23470199 Assessing the accuracy and generalizability of the preoperative and postoperative Karakiewicz nomograms for renal cell carcinoma: results from a multicentre European and US study. WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The preoperative and postoperative Karakiewicz models for RCC are considered among the best prognostic tools available for clinical counseling. Nevertheless, their predictive acuracy was externally validated only in two papers: by the same author and in an independent sample of Asian patients. However, these models have not been externally validated in truly independent multicentre series of patients. Our study demonstrated that these models 1) provide robust prognostic information; 2) were robustly built; 3) are useful also in population far from the original series. The present results are the first to show the validity and generalizability of Karakiewicz nomograms, which are based on surgical series from European centres, for large-, mid- and small-volume European and American centres. To assess the accuracy and generalizability of the pre- and postoperative Karakiewicz nomograms for predicting cancer-specific survival (CSS) in patients with renal cell carcinoma (RCC). This retrospective study included 3231 patients from European and US centres, who were treated by radical or partial nephrectomy for RCC between 1992 and 2010. Prognostic scores for each patient were calculated and the primary endpoint was CSS. Discriminating ability was assessed by Harrell's c-index for censored data. The 'validation by calibration' method proposed by Van Houwelingen was used for checking the calibration of covariate effects. Calibration was graphically explored. Local and systemic symptoms were present in 23.2% and 9.1% of the patients, respectively. The median follow-up (FU) was 49 months. At the last FU, 408 cancer-related deaths were recorded, Kaplan-Meier estimates of CSS (with 95% confidence intervals [CIs]) at 5 and 10 years were 0.86 (0.84-0.87) and 0.77 (0.75-0.80), respectively. Both nomograms discriminated well. Stratified c-indices for CSS were 0.784 (95% CI 0.753-0.814) for the preoperative nomogram, and 0.842 (95% CI 0.816-0.867) for the postoperative one, with a significant difference between the two values (P < 0.001). The covariate-based predictions on our data for both nomograms were valid. The calibration plots showed no relevant departures from ideal predictions. The results suggest that the postoperative Karakiewicz nomogram discriminates substantially better than the preoperative one. These nomogram-based predictions may be used as benchmark data for pretreatment and postoperative decision-making in patients at various stages of RCC. 23601578 Consequence of use of lower dose flat plate fluoroscopy in pediatric patients undergoing ablation for supraventricular tachycardia. Traditional imaging for ablation of supraventricular tachycardia has been fluoroscopy, although 3-dimensional electroanatomic mapping (3D) has been demonstrated to reduce radiation exposure. This study compares a technique for the reduction of radiation, low-dose fluoroscopy (LD), with standard-dose fluoroscopy (SD) and 3D with SD (3D-SD). This was a single institutional retrospective cohort study. All patients undergoing initial ablation for atrioventricular reentrant tachycardia (AVRT) or atrioventricular nodal reentrant tachycardia (AVNRT) from 2009 to 2012 were reviewed and divided into 3 groups: (1) SD, (2) 3D (CARTO or NavX) with SD, or (3) LD. LD uses the same equipment as SD but includes customized changes to the manufacturer's lowest settings by decreasing the requested dose to the detector. Primary outcomes were fluoroscopy time and dose area product exposure. One hundred eighty-one patients were included. The median age was 15.0 years (3.3-20.8); 59% had AVRT, 35% had AVNRT, and 6% had both AVRT and AVNRT. LD decreased the dose area product (DAP) compared with SD (637.0 vs 960.1 cGy*cm², p = 0.01) with no difference in fluoroscopy time. 3D-SD decreased fluoroscopy time compared with SD (9.9 vs 18.3 minutes, p <0.001) with DAP of 570.1.0 versus 960.1 cGy*cm² (p = 0.16). LD and 3D-SD had comparable DAP (637.0 vs 570.1 cGy*cm², p = 0.67), even though LD had significantly longer fluoroscopy time (19.9 vs 9.9 minutes, p <0.001). In conclusion, LD during catheter ablation of AVRT and AVNRT significantly reduced the DAP compared with SD and had similar radiation exposure compared with 3D with SD. 23897663 Separation and Estimation of Process-Related Impurities of Gefitinib by Reverse-Phase High-Performance Liquid Chromatography. A simple and rapid reverse-phase high-performance liquid chromatographic (RP-HPLC) method was developed and validated for the simultaneous separation and estimation of gefitinib (an anti-cancer drug) and its process-related impurities. Five process-related impurities of gefitinib were separated on an Inertsil ODS-3V column (250 × 4.6 mm i.d.; particle size 5 μm) using 130 mM ammonium acetate and acetonitrile (63:37, v/v) as mobile phase (pH 5.0) with a photodiode array (PDA) detector. The correlation coefficients for gefitinib and its process-related impurities were in the range of 0.9991-0.9994 with limit of detection and limit of quantification in the range of 0.012-0.033 and 0.04-0.10 µg/mL, respectively. The recovery values were in the range of 98.26-99.90% for gefitinib and 95.99-100.55% for process-related impurities, while precision values were less than 3%. The method was found to be specific, precise and reliable for the determination of gefitinib and its impurities in gefitinib bulk drug. 23966237 Interactions Between Pregnancy, Obstructive Sleep Apnea, and Gestational Diabetes Mellitus. Context:Questionnaire studies linked symptoms of obstructive sleep apnea (OSA) to the risk of gestational diabetes mellitus (GDM). Whether this association is present when OSA is assessed objectively by polysomnography is not known.Objective:The objective of the study was to assess the relationship between pregnancy, OSA, and GDM.Design, Setting, and Participants:We conducted observational case-control studies using polysomnography in 15 nonpregnant, nondiabetic women (NP-NGT), 15 pregnant women with normal glucose tolerance (P-NGT), and 15 pregnant women with GDM (P-GDM). The groups were frequency matched for age and race/ethnicity. Pregnant women were studied during the late second to early third trimester.Main Outcome Measures:Comparisons of OSA diagnosis and sleep parameters between NP-NGT and P-NGT to assess the impact of pregnancy and between P-NGT and P-GDM to explore the association between GDM and OSA were measured.Results:Compared with NP-NGT, P-NGT women had a higher apnea hypopnea index (AHI) (median 2.0 vs 0.5, P = .03) and more disrupted sleep as reflected by a higher wake time after sleep onset (median 66 vs 21 min, P < .01) and a higher microarousal index (median 16.4 vs 10.6, P = .01). Among the pregnant women, P-GDM had markedly lower total sleep time (median 397 vs 464 min, P = .02) and a higher AHI (median 8.2 vs 2.0, P = .05) than P-NGT women. OSA was more prevalent in P-GDM than in P-NGT women (73% vs 27%, P = .01). After adjustment for prepregnancy body mass index, the diagnosis of GDM was associated with a diagnosis of OSA [odds ratio 6.60 (95% confidence interval 1.15-37.96)]. In pregnancy, after adjusting for prepregnancy body mass index, higher microarousal index significantly associated with higher glycosylated hemoglobin and fasting glucose levels. Higher oxygen desaturation index was associated with higher fasting glucose levels.Conclusion:Pregnancy is associated with sleep disturbances. Sleep is more disturbed in GDM than in P-NGT women. There is a strong association between GDM and OSA. 23886890 Molecular and Functional Alterations in a Mouse Cardiac Model of Friedreich Ataxia: Activation of the Integrated Stress Response, eIF2α Phosphorylation, and the Induction of Downstream Targets. Friedreich ataxia (FA) is a neurodegenerative and cardiodegenerative disease resulting from marked frataxin deficiency. The condition is characterized by ataxia with fatal cardiomyopathy, but the pathogenic mechanisms are unclear. We investigated the association between gene expression and progressive histopathological and functional changes using the muscle creatine kinase conditional frataxin knockout (KO) mouse; this mouse develops a severe cardiac phenotype that resembles that of FA patients. We examined KO mice from 3 weeks of age, when they are asymptomatic, to 10 weeks of age, when they die of the disease. Positive iron staining was identified in KO mice from 5 weeks of age, with markedly reduced cardiac function from 6 weeks. We identified an early and marked up-regulation of a gene cohort responsible for stress-induced amino acid biosynthesis and observed markedly increased phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α), an activator of the integrated stress response, in KO mice at 3 weeks of age, relative to wild-type mice. Importantly, the eIF2α-mediated integrated stress response has been previously implicated in heart failure via downstream processes such as autophagy and apoptosis. Indeed, expression of a panel of autophagy and apoptosis markers was enhanced in KO mice. Thus, the pathogenesis of cardiomyopathy in FA correlates with the early and persistent eIF2α phosphorylation, which precedes activation of autophagy and apoptosis. 23881921 Serum miR-1290 as a marker of pancreatic cancer - Response. Not applicable. 23868024 Brainstem tuberculosis. We present a case of a 38-year-old-man who presented with 1-week history of developing weakness of peripheral and cranial nerves. His MRI scan of the brain showed a large cavitating lesion at the brainstem and two further lesions of the right cerebral cortex and his CT chest showed features of old tuberculosis (TB). The identification of acid-fast bacilli was confirmed by analysis of bronchoalveolar lavage taken during bronchoscopy. He was started on anti-TB medications and repeat MRI 3 months later confirmed shrinkage of the cavitating lesion. 23940057 Photophysics of Structurally Modified Flavin Derivatives in the Blue-Light Photoreceptor YtvA: A Combined Experimental and Theoretical Study. The light-induced processes of two flavin mononucleotide derivatives (1- and 5-deaza flavin mononucleotide, 1DFMN and 5DFMN), incorporated into the LOV domain of YtvA protein from Bacillus subtilis, were studied by a combination of experimental and computational methods. Quantum mechanics/molecular mechanics (QM/MM) calculations were carried out in which the QM part was treated by density functional theory (DFT) using the B3LYP functional for geometry optimizations and the DFT/MRCI method for spectroscopic properties, whereas the MM part was described by the CHARMM force field. 1DFMN is incorporated into the protein binding site, yielding a red-shifted absorption band (λmax =530 nm compared to YtvA wild-type λmax =445 nm), but does not undergo any LOV-typical photoreactions such as triplet and photoadduct formation. QM/MM computations confirmed the absence of a channel for triplet formation and located a radiation-free channel (through an S1 /S0 conical intersection) along a hydrogen transfer path that might allow for fast deactivation. By contrast, 5DFMN-YtvA-LOV shows a blue-shifted absorption (λmax =410 nm) and undergoes similar photochemical processes to FMN in the wild-type protein, both with regard to the photophysics and the formation of a photoadduct with a flavin-cysteinyl covalent bond. The QM/MM calculations predict a mechanism that involves hydrogen transfer in the T1 state, followed by intersystem crossing and adduct formation in the S0 state for the forward reaction. Experimentally, in contrast to wild-type YtvA, dark-state recovery in 5DFMN-YtvA-LOV is not thermally driven but can only be accomplished after absorption of a second photon by the photoadduct, again via the triplet state. The QM/MM calculations suggest a photochemical mechanism for dark-state recovery that is accessible only for the adduct with a C4aS bond but not for alternative adducts with a C5S bond. 23803934 A project to reengineer discharges reduces 30-day readmission rates. A Texas hospital achieves improvement in its readmission rate by implementing Project RED. 23528818 Lymphatic Endothelium Forms Integrin-Engaging 3D Structures during DC Transit across Inflamed Lymphatic Vessels. Dendritic cell (DC) transmigration across the lymphatic endothelium is critical for the initiation and sustenance of immune responses. Under noninflammatory conditions, DC transit across the lymphatic endothelial cell (LEC) has been shown to be integrin independent. In contrast, there is increasing evidence for the participation of integrins and their ligands in DC transit across lymphatic endothelium under inflammation. In this sense, we describe the formation of ICAM-1 (CD54)-enriched three-dimensional structures on LEC/DC contacts, as these DCs adhere to inflamed skin lymphatic vessels and transmigrate into them. In vitro imaging revealed that under inflammation ICAM-1 accumulated on microvilli projections surrounding 60% of adhered DCs. In contrast, these structures were scarcely formed in noninflammatory conditions. Furthermore, ICAM-1-enriched microvilli were important in promoting DC transendothelial migration and DC crawling over the LEC surface. Microvilli formation was dependent on the presence of β-integrins on the DC side and on integrin conformational affinity to ligand. Finally, we observed that LEC microvilli structures appeared in close vicinity of CCL21 depots and that their assembly was partially inhibited by CCL21-neutralizing antibodies. Therefore, under inflammatory conditions, integrin ligands form three-dimensional membrane projections around DCs. These structures offer docking sites for DC transit from the tissue toward the lymphatic vessel lumen. 23951295 Measuring visual field progression in the central 10 degrees using additional information from central 24 degrees visual fields and 'lasso regression'. To measure progression of the visual field (VF) mean deviation (MD) index in longitudinal 10-2 VFs more accurately, by adding information from 24-2 VFs using Lasso regression. A training dataset consisted of 138 eyes from 97 patients with glaucoma or ocular hypertension and a testing dataset consisted of 40 eyes from 34 patients with glaucoma or ocular hypertension. The Lasso method was used to predict total deviation (TD) values in training patients' 10-2 VFs based on information from their 24-2 VFs (52 TD values, foveal sensitivity and mean deviation MD). Then, the MD of each patient's 10-2 VF was estimated as the average of these Lasso-predicted TD values (10-2 VF 'Lasso MD'; LMD). Finally, linear regression was applied to each testing patient's series of longitudinal 10-2 VF MDs with and without additional Lasso-derived LMDs in order to predict future MDs not included in the regression analysis. Absolute prediction errors were compared when only actual 10-2 MDs were regressed against when a combination of actual 10-2 MDs and LMDs were regressed. THE AVERAGE ABSOLUTE PREDICTION ERROR WAS SIGNIFICANTLY SMALLER FOR THE NOVEL METHOD INCORPORATING LMDS (RANGE: 1.6 to 1.8 dB) compared with the standard approach (range: 1.7 to 3.4 dB) (p<0.05, ANOVA test). Deriving 10-2 VF MD values from 24-2 VFs improves the prediction accuracy of progression. This approach will help clinicians to predict patients' visual function in the parafoveal area. 23758229 The role of diet and physical activity in post-transplant weight gain after renal transplantation. Long-term survival of renal transplant recipients (RTR) has not improved over the past 20 yr. The question rises to what extent lifestyle factors play a role in post-transplant weight gain and its associated risks after transplantation. Twenty-six RTR were measured for body weight, body composition, blood lipids, renal function, dietary intake, and physical activity at six wk, and three, six, and 12 months after transplantation. Weight gain ranged between -2.4 kg and 19.5 kg and was largely due to increase in body fat. RTR who remained body fat stable, showed more daily physical activity (p = 0.014), tended to consume less energy from drinks and dairy (p = 0.054), consumed less mono- and disaccharides (sugars) (p = 0.021) and ate more vegetables (p = 0.043) compared with those who gained body fat. Gain in body fat was strongly related to total cholesterol (r = 0.46, p = 0.017) and triglyceride (r = 0.511, p = 0.011) at one yr after transplantation. Gain in adiposity after renal transplantation is related to lifestyle factors such as high consumption of energy-rich drinks, high intake of mono- and disaccharides and low daily physical activity. RCTs are needed to investigate potential benefits of lifestyle intervention on long-term morbidity and mortality. 23720456 Development of a Novel Long-Acting Antidiabetic FGF21 Mimetic by Targeted Conjugation to a Scaffold Antibody. Fibroblast growth factor (FGF)21 improves insulin sensitivity, reduces body weight, and reverses hepatic steatosis in preclinical species. We generated long-acting FGF21 mimetics by site-specific conjugation of the protein to a scaffold antibody. Linking FGF21 through the C terminus decreased bioactivity, whereas bioactivity was maintained by linkage to selected internal positions. In mice, these CovX-Bodies retain efficacy while increasing half-life up to 70-fold compared with wild-type FGF21. A preferred midlinked CovX-Body, CVX-343, demonstrated enhanced in vivo stability in preclinical species, and a single injection improved glucose tolerance for 6 days in ob/ob mice. In diet-induced obese mice, weekly doses of CVX-343 reduced body weight, blood glucose, and lipids levels. In db/db mice, CVX-343 increased glucose tolerance, pancreatic β-cell mass, and proliferation. CVX-343, created by linkage of the CovX scaffold antibody to the engineered residue A129C of FGF21 protein, demonstrated superior preclinical pharmacodynamics by extending serum half-life of FGF21 while preserving full therapeutic functionality. 23589257 Removal and recovery of copper and nickel ions from aqueous solution by poly(methacrylamide-co-acrylic acid)/montmorillonite nanocomposites. Nanocomposite hydrogels based on poly(methacrylamide-co-acrylic acid) and nano-sized montmorillonite were prepared by aqueous dispersion and in situ radical polymerization. Optimum sorption conditions were determined as a function of montmorillonite content, contact time, pH, and temperature. The equilibrium data of Cu(2+) and Ni(2+) conformed to the Freundlich and Langmuir isotherms in terms of relatively high regression values. The maximum monolayer adsorption capacity of the nanocomposite hydrogel (with 3 wt% montmorillonite content), as obtained from the Langmuir adsorption isotherm, was found to be 49.26 and 46.94 mg g(-1) for Cu(2+) and Ni(2+), respectively, at contact time = 60 min, pH = 6.8, adsorbent dose = 100 mg/ml, and temperature = 318 K. Kinetic studies of single system indicated that the pseudo-second order is the best fit with a high correlation coefficient (R (2) = 0.97-0.99). The result of five times sequential adsorption-desorption cycle shows a good degree of desorption and a high adsorption efficiency. 23941611 Influence of integrated services on postpartum family planning use: a cross-sectional survey from urban Senegal. Although the majority of postpartum women indicate a desire to delay a next birth, family planning (FP) methods are often not offered to, or taken up by, women in the first year postpartum. This study uses data from urban Senegal to examine exposure to FP information and services at the time of delivery and at child immunization appointments and to determine if these points of integration are associated with greater use of postpartum FP. A representative, household sample of women, ages 15--49, was surveyed from six cities in Senegal in 2011. This study focuses on women who were within two years postpartum (n = 1879). We also include women who were surveyed through exit interviews after a visit to a high volume health facility in the same six cities; clients included were visiting the health facility for delivery, post-abortion care, postnatal care, and child immunization services (n = 794). Descriptive analyses are presented to examine exposure to FP services among postpartum women and women visiting the health facility. Logistic regression models are used to estimate the effect of integrated services on postpartum FP use in the household sample of women. Analyses were conducted using Stata version 12. Among exit interview clients, knowledge of integrated services is high but only a few reported receiving FP services. A majority of the women who did not receive FP services indicated an interest in receiving such information and services.Among the household sample of women up to two-years postpartum, those who received FP information at the time of delivery are more likely to be using modern FP postpartum than their counterparts who also delivered in a facility but did not receive such information. Exposure to FP services at an immunization visit was not significantly related to postpartum FP use. Another key finding is that women with greater self-efficacy are more likely to use a modern FP method. This study's findings lend strong support for the need to improve integration of FP services into maternal, newborn, and child health services with the goal of increasing postpartum women's use of FP methods in urban Senegal. 23799269 Comparison of confirmed inactive and randomly selected compounds as negative training examples in support vector machine-based virtual screening. The choice of negative training data for machine learning is a little explored issue in chemoinformatics. In this study, the influence of alternative sets of negative training data and different background databases on support vector machine (SVM) modeling and virtual screening has been investigated. Target-directed SVM models have been derived on the basis of differently composed training sets containing confirmed inactive molecules or randomly selected database compounds as negative training instances. These models were then applied to search background databases consisting of biological screening data or randomly assembled compounds for available hits. Negative training data were found to systematically influence compound recall in virtual screening. In addition, different background databases had a strong influence on the search results. Our findings also indicated that typical benchmark settings lead to an overestimation of SVM-based virtual screening performance compared to search conditions that are more relevant for practical applications. 23733583 Correlation of muscle function and bone strain in the hindlimb of the river cooter turtle (Pseudemys concinna). During terrestrial locomotion, limb muscles must generate mechanical work and stabilize joints against the ground reaction force. These demands can require high force production that imposes substantial loads on limb bones. To better understand how muscle contractile function influences patterns of bone loading in terrestrial locomotion, and refine force platform equilibrium models used to estimate limb bone safety factors, we correlated in vivo recordings of femoral strain with muscle activation and strain in a major propulsive hindlimb muscle, flexor tibialis internus (FTI), of a species with a published model of hindlimb force production (river cooter turtles, Pseudemys concinna). Electromyography (EMG) recordings indicate FTI activity prior to footfall that continues through approximately 50% of the stance phase. Large EMG bursts occur just after footfall when the muscle has reached its maximum length and is beginning to actively shorten, concurrent with increasing compressive strain on the anterior femur. The FTI muscle shortens through 35% of stance, with mean fascicle shortening strains reaching 14.0 ± 5.4% resting length (L0 ). At the time of peak compressive strains on the femur, the muscle fascicles remain active, but fascicles typically lengthen until mid-stance as the knee extends. Influenced by the activity of the dorsal knee extensor femorotibialis, the FTI muscle continues to passively lengthen simultaneously with knee extension and a shift to tensile axial strain on the anterior femur at approximately 40% of stance. The near coincidence in timing of peak compressive bone strain and peak muscle shortening (5.4 ± 4.1% stance) indicates a close correlation between the action of the hip extensor/knee flexor, FTI, and femoral loading in the cooter hindlimb. In the context of equilibrium models of limb bone loading, these results may help explain differences in safety factor estimates observed between previous force platform and in vivo strain analyses in cooters. J. Morphol. 274:1060-1069, 2013. © 2013 Wiley Periodicals, Inc. 23969558 Theophylline-dependent Riboswitch as a Novel Genetic Tool for Strict Regulation of Protein Expression in Cyanobacterium Synechococcus elongatus PCC 7942. The cyanobacterium Synechococcus elongatus PCC 7942 is a major model species for studies of photosynthesis. They are also potential cell factories for the production of renewable biofuels and valuable chemicals. We employed engineered riboswitches to control translational initiation of target genes in this cyanobacterium. A firefly luciferase reporter assay revealed that three theophylline-riboswitches performed as expected in the cyanobacterium. Riboswitch-E* exhibited very low leaky expression of luciferase and superior and dose-dependent ON/OFF regulation of protein expression by theophylline. The maximum magnitude of the induction versus basal level was ∼190-fold. Furthermore, the induction level was responsive to a wide range of theophylline concentrations in the medium, from 0 to 2 mM, facilitating the fine-tuning of luciferase expression. We adapted this riboswitch to another gene regulation system, in which expression of the circadian clock kaiC gene product is controlled by the theophylline-concentration in the culture media. Results demonstrated that the adequately adjusted expression level of KaiC restored complete circadian rhythm in the kaiC-deficient arrhythmic mutant. This theophylline-dependent riboswitch system has potential for various applications as a useful genetic tool in cyanobacteria. 23724977 Does high sensitive CRP improve cardiovascular risk prediction in metabolic syndrome among the aged? Abstract Objectives. To analyze whether an elevated level of high hsCRP has an additive effect on metabolic syndrome (MetS) in predicting future cardiovascular events (CVEs) as well as on all-cause mortality among the aged subjects. Design. A prospective, population-based study with a 9-year follow-up. The study population consisted of persons aged 64 and above in 1998-99 without vascular disease and CRP less than 10 mg/l at baseline (n = 733). Adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs) for CVEs and all-cause mortality predicted by baseline MetS (defined by both International Diabetes Federation (IDF) and World Health Organization (WHO)) and hsCRP-level were estimated. Results. During the 9-year follow-up, a total of 142 CVEs and 206 deaths occurred. After multivariable adjustment, no significant interactions were found between hsCRP and MetS in CVEs (IDF: p = 0.828; WHO: p = 0.572) or in all-cause mortality (IDF: p = 0.113; WHO: p = 0.374). HsCRP was not associated with the occurrence of CVEs (IDF: HR = 1.10, 95% CI = 0.92-1.32, p = 0.281; WHO: HR = 1.10, 95% CI = 0.93-1.32, p = 0.247) or with all-cause mortality (IDF: HR = 1.12, 95% CI = 0.97-1.29, p = 0.134; WHO: HR = 1.11, 95% CI = 0.96-1.28, p = 0.146). Conclusions. It seems that hsCRP does not give any extra value in evaluation of CVE risk or all-cause mortality of older subjects with MetS. 23061466 Human ether-a-go-go-related gene channel blockers and its structural analysis for drug design. The human ether-a-go-go-related gene (hERG) is a K+ channel protein mainly expressed in the heart and the nervous systems and its blockade by non-cardiovascular acting drugs resulted in tachycardia and sudden death. In this present review, we have focused the physicochemical properties responsible for the hERG blocking activity of structurally different compounds. The reported research works showed that the hydrophobicity on the van der Waals (vdW) surface of the molecules (aroused from the aromatic ring) necessary for the hERG blocking activity along with topological and electronic properties. The quinolizidine alkaloids (natural products) such as oxymatrine, sophoridine, sophocarpine and matrine carry the common molecular structure of O=C=N-C-C-C-N that possessed positive ionotropic effect and hERG blocking activity. Acehytisine hydrochloride (previously named Guangfu base A) was isolated from the root of Aconitum coreanum (Levl.), is an anti-arrhythmic drug in phase IV clinical trial. The isoquinoline alkaloid, neferine (Nef) induces a concentration-dependent decrease in current amplitude (IC50 of 7.419 MM). Most of these natural product compounds contain non-flexible aromatic structures but have significant activity due to the presence of optimum hydrophobicity. Recent research works revealed that Eag and hERG channels are expressed by a variety of cancer cell lines and tissues. The Eag channel showed an oncogenic potential while hERG channels are associated with more aggressive tumors and have a role in mediating invasion. This review concluded that the consideration of physicochemical properties necessary for the hERG blocking activity will guide to develop novel drugs with less cardiotoxicity. 23761146 Rifampin Resistance Missed in Automated Liquid Culture System for Mycobacterium tuberculosis Isolates with Specific rpoB Mutations. WHO-endorsed phenotypic drug susceptibility testing (DST) methods for Mycobacterium tuberculosis are assumed to be the gold standard for identifying rifampin (RMP) resistance. However, previous results indicated that low-level, yet probably clinically relevant, RMP resistance linked to specific rpoB mutations is easily missed by some growth-based methods. We aimed to compare the level of resistance detected on Löwenstein-Jensen (LJ) medium with resistance detected by the Bactec MGIT 960 automated DST (MGIT-DST) system for various rpoB mutants. Full agreement between LJ and MGIT-DST was observed for mutations located at codons 513 (Lys or Pro) and 531 (Leu, Trp), which were always resistant by both methods. For mutations 511Pro, 516Tyr, 533Pro, 572Phe, and several 526 mutations, LJ and MGIT results were highly discordant, with MGIT-DST failing to give a result or declaring the strains susceptible. Our data show that phenotypic RMP resistance testing of M. tuberculosis is not a binary phenomenon for some rpoB mutations and that the widely used automated MGIT 960 system is prone to miss some RMP resistance-conferring mutations, while careful DST on LJ missed hardly any. Given the association of these mutations with poor clinical outcome, our findings suggest that the gold standard for rifampin resistance should be reconsidered, in order to address the present confusion caused by discrepancies between phenotypic and genotypic results. The impacts of these mutations will depend on the frequency of their occurrence, which may vary from one setting to another. 23752352 Quantification of tumor necrosis factor-α and matrix metalloproteinases-3 in synovial fluid by a fiber-optic particle plasmon resonance sensor. The availability of techniques for sensitive detection of early stage osteoarthritis is critical for improving patient health. This study illustrates the feasibility of a fiber-optic particle plasmon resonance (FOPPR) sensor with gold nanoparticles on the unclad region of optical fiber probes for analysis of osteoarthritis biomarkers, tumor necrosis factor-α (TNF-α) and matrix metalloproteinases-3 (MMP-3). Results show that the sensor can achieve a refractive index resolution of 5.18 × 10(-7) RIU and limits of detection for TNF-α and MMP-3 as low as 8.22 pg ml(-1) (0.48 pM) and 34.3 pg ml(-1) (1.56 pM), respectively. Additionally, the FOPPR sensor shows a good correlation in determining TNF-α and MMP-3 in synovial fluid with the clinically accepted enzyme-linked immunosorbent assay (ELISA) method. Finally, given the FOPPR sensor's nature of being low-cost, label-free, highly sensitive, real-time, simple-to-operate, the FOPPR sensor could offer potential to monitor biomarkers of various diseases, and provide an ideal technical tool for point-of-care diagnostics. 22641178 The road not taken: life experiences in monozygotic twin pairs discordant for major depression. In an effort to understand how environmental experiences contribute to risk for major depression (MD), we conducted joint autobiographical interviews with 14 pairs of monozygotic twins (mean age 51.2) rigorously discordant for a lifetime history of MD. Twelve of the pairs could be sorted into four broad categories. In two pairs, discordance was associated with a single traumatic event occurring to the affected twin. In seven pairs, the well twin had one stable, long-term, successful romantic relationship, whereas the affected co-twin had romantic reversals one or more of which precipitated depressive episodes. These pairs varied in the degree to which the romantic problems seemed to arise from bad luck or poor choices. In one pair, occupational difficulties were strongly related to discordance in experiences with MD. In two pairs, several mechanisms seemed to be at work. Discordance in the quality of intimate love relationships was the most common etiological factor revealed by interview in these discordant pairs, with single dramatic events and occupational problems being considerably rarer. Even in this best of natural experiments, the causal interrelationship between personality, environment and depressive episodes was not always clear. Many pairs illustrated the protective effects of planfulness and the malignant effect of cumulative continuity where early difficulties in relationships shaped the subsequent life course. These results speak both to the importance of environmental influences on human well-being and psychopathology, and the complexity of the causal paths underlying their effects. 23921870 Maternal Morbidity and Risk of Death at Delivery Hospitalization. To examine the effect of underlying maternal morbidities on the odds of maternal death during delivery hospitalization. We used data that linked birth certificates to hospital discharge diagnoses from singleton live births at 22 weeks of gestation or later during 1995-2003 in New York City. Maternal morbidities examined included prepregnancy weight more than 114 kilograms (250 pounds), chronic hypertension, pregestational or gestational diabetes mellitus, chronic cardiovascular disease, pulmonary hypertension, chronic lung disease, human immunodeficiency virus (HIV), and preeclampsia or eclampsia. Associations with maternal mortality were estimated using multivariate logistic regression. During the specified time period, 1,084,862 live singleton births and 132 maternal deaths occurred. Patients with increasing maternal age, non-Hispanic black ethnicity, self-pay or Medicaid, primary cesarean delivery, and premature delivery had higher rates of maternal mortality during delivery hospitalization. From the entire study population, 4.1% had preeclampsia or eclampsia (n=44,004), 1.8% had chronic hypertension (n=19,647), 1.1% of patients were classified as obese (n=11,936), 0.7% had pregestational diabetes (n=7,474), 0.4% had HIV (n=4,665), and 0.01% had pulmonary hypertension (n=166). Preeclampsia or eclampsia (adjusted odds ratio [OR], 8.1; 95% confidence interval [CI], 5.5-12.1), chronic hypertension (adjusted OR, 7.7; 95% CI 4.7-12.5), underlying maternal obesity (adjusted OR, 2.9; 95% CI 1.1-8.1), pregestational diabetes (adjusted OR, 3.3; 95% CI 1.3-8.1), HIV (adjusted OR, 7.7; 95% CI 3.4-17.8), and pulmonary hypertension (adjusted OR, 65.1; 95% CI 15.8-269.3) were associated with an increased risk of death during the delivery hospitalization. The presence of maternal disease significantly increases the odds of maternal mortality at the time of delivery hospitalization. LEVEL OF EVIDENCE:: II. 23953873 Hiking in Suicidal Patients: Neutral Effects on Markers of Suicidality. Regular physical activity promotes physical and mental health. Psychiatric patients are prone to a sedentary lifestyle, and accumulating evidence has identified physical activity as a supplemental treatment option. This prospective, randomized, crossover study evaluated the effects of hiking in high-risk suicidal patients (n = 20) who performed 9 weeks of hiking (2-3 hikes/week, 2-2.5 hours each) and a 9-week control period. All patients participated in the required 2 hikes per week and thus showed a compliance of 100%. Regular hiking led to significant improvement in maximal exercise capacity (hiking period Δ: +18.82 ± 0.99 watt, P < .001; control period: P = .134) and in aerobic capability at 70% of the individual heart rate reserve (hiking period Δ: +8.47 ± 2.22 watt; P = .010; control period: P = .183). Cytokines, associated previously with suicidality (tumor necrosis factor-α, interleukin-6, S100), remained essentially unchanged. Hiking is an effective and safe form of exercise training even in high-risk suicidal patients. It leads to a significant improvement in maximal exercise capacity and aerobic capability without concomitant deterioration of markers of suicidality. Offering this popular mode of exercise to these patients might help them to adopt a physically more active lifestyle. 23063987 Regulation of longevity by the reproductive system. Pioneering work in model organisms reveals that the reproductive system is involved not only in propagation of the species but also regulates organismal metabolism and longevity. In C. elegans, prevention of germline stem cell proliferation results in a 60% extension of lifespan, termed gonadal longevity. Gonadal longevity relies on the transcriptional activities of steroid nuclear receptor DAF-12, the FOXO transcription factor homolog DAF-16, the FOXA transcription factor homolog PHA-4, and the HNF-4-like nuclear receptor NHR-80. These transcription factors work in an integrated transcriptional network to regulate fatty acid lipolysis, autophagy, stress resistance and other processes, which altogether enhance homeostasis and extend life. Because the reproductive system also regulates longevity in other species, studies in C. elegans may shed light on ancient mechanisms governing reproduction and survival. 23822287 Pseudopotentials for correlated electron systems. A scheme is developed for creating pseudopotentials for use in correlated-electron calculations. Pseudopotentials for the light elements H, Li, Be, B, C, N, O, and F, are reported, based on data from high-level quantum chemical calculations. Results obtained with these correlated electron pseudopotentials (CEPPs) are compared with data for atomic energy levels and the dissociation energies, molecular geometries, and zero-point vibrational energies of small molecules obtained from coupled cluster single double triple calculations with large basis sets. The CEPPs give better results in correlated-electron calculations than Hartree-Fock-based pseudopotentials available in the literature. 23951711 Ecosystem engineers on plants: indirect facilitation of arthropod communities by leaf-rollers at different scales. Ecosystem engineering is a process by which organisms change the distribution of resources and create new habitats for other species via non-trophic interactions. Leaf-rolling caterpillars can act as ecosystem engineers because they provide shelter to secondary users. In this study, we report the influence of leaf-rolling caterpillars on speciose tropical arthropod communities along both spatial scales (leaf-level and plant-level effects) and temporal scales (dry and rainy seasons). We predict that rolled leaves can amplify arthropod diversity at both the leaf and plant levels and that this effect is stronger in dry seasons, when arthropods are prone to desiccation. Our results show that the abundance, richness, and biomass of arthropods within several guilds increased up to 22-fold in naturally and artificially created leaf shelters relative to unaltered leaves. These effects were observed at similar magnitudes at both the leaf and plant scales. Variation in the shelter architecture (funnel, cylinders) did not influence arthropod parameters, as diversity, abundance, orbiomass, but rolled leaves had distinct species composition if compared with unaltered leaves. As expected, these arthropod parameters on the plants with rolled leaves were on average approximately twofold higher in the dry season. Empty leaf rolls and whole plants were rapidly recolonized by arthropods over time, implying a fast replacement of individuals; within 15-day intervals the rolls and plants reached a species saturation. This study is the first to examine the extended effects of engineering caterpillars as diversity amplifiers at different temporal and spatial scales. Because shelter-building caterpillars are ubiquitous organisms in tropical and temperate forests, they can be considered key structuring elements for arthropod communities on plants. 23920084 Oxidative Stress and Response in Relation to Coronary Artery Disease in Type 1 Diabetes. OBJECTIVEAlthough oxidative stress (OxS) is thought to contribute to atherosclerosis and coronary artery disease (CAD), little is known about the variability in an individual's ability to respond to OxS. Therefore, we assessed potential indices of response to OxS and evaluated whether they modify the association between OxS and CAD.RESEARCH DESIGN AND METHODSWe evaluated plasma α- and γ-tocopherol per unit cholesterol (potential response markers); urinary 15-isoprostane F2t per milligram creatinine (isoprostane [IsoP], a potential stress marker); and the α-tocopherol-to-IsoP ratio (as a measure of response to stress), measured three times during 20 years of follow up, in relation to CAD incidence in a cohort with childhood onset type 1 diabetes (n = 658; mean age at baseline, 28 years; duration of diabetes, 19 years). Participants with three samples (blood and either 24-h or overnight urine) available before the onset of CAD or the end of follow-up (n = 356) were selected for study.RESULTSIn multivariable mixed models, α-tocopherol over time was inversely associated with CAD (β = -0.27; P = 0.02), whereas a direct association was observed for IsoP (β = 0.0008; P = 0.06). Moreover, the α-tocopherol-to-IsoP ratio was strongly and inversely related to CAD incidence (β = -0.72; P = 0.003), whereas in a separate model including α-tocopherol and IsoP, both biomarkers maintained statistical significance. No association was observed for γ-tocopherol (β = -0.22; P = 0.54).CONCLUSIONSThese data suggest that a greater potential capability (α-tocopherol) to respond to OxS (urinary IsoP) relates to CAD incidence. 23924063 Imaging features of primary Sarcomas of the great vessels in CT, MRI and PET/CT: a single-center experience. To investigate the imaging features of primary sarcomas of the great vessels in CT, MRI and 18 F-FDG PET/CT. Thirteen patients with a primary sarcoma of the great vessels were retrospectively evaluated. All available images studies including F-18 FDG PET(/CT) (n = 4), MDCT (n = 12) and MRI (n = 6) were evaluated and indicative image features of this rare tumor entity were identified. The median interval between the first imaging study and the final diagnosis was 11 weeks (0--12 weeks). The most frequently observed imaging findings suggestive of malignant disease in patients with sarcomas of the pulmonary arteries were a large filling defect with vascular distension, unilaterality and a lack of improvement despite effective anticoagulation. In patients with aortic sarcomas we most frequently observed a pedunculated appearance and an atypical location of the filling defect. The F-18 FDG PET(/CT) examinations demonstrated an unequivocal hypermetabolism of the lesion in all cases (4/4). MRI proved lesion vascularization in 5/6 cases. Intravascular unilateral or atypically located filling defects of the great vessels with vascular distension, a pedunculated shape and lack of improvement despite effective anticoagulation are suspicious for primary sarcoma on MDCT or MRI. MR perfusion techniques can add information on the nature of the lesion but the findings may be subtle and equivocal. F-18 FDG PET/CT may have a potential role in these patients and may be considered as part of the imaging workup. 23851340 Real-time diagnosis of chemically induced hepatocellular carcinoma using a novel mass spectrometry-based technique. Real-time analyses of hepatocellular carcinoma were performed in living mice to assess the applicability of probe electrospray ionization-mass spectrometry (PESI-MS) in medical diagnosis. The number of peaks and the abundance of ions corresponding to triacylglycerols (TAGs) were higher in cancerous tissues than in noncancerous tissues. Multiple sequential scans of the specimens were performed along a predetermined line extending over the noncancerous region to detect the boundary of the cancerous region. Our system successfully discriminated the noncancerous and cancerous tissues based on the intensities of the TAG ions. These results highlight the potential application of PESI-MS for clinical diagnosis in cancer. 23927011 Contemporary chiropractic practice in the UK: a field study of a chiropractor and his patients in a suburban chiropractic clinic. Two recent surveys of chiropractors in Great Britain suggest that there are discrepancies between chiropractic practice as defined in regulatory guidelines and day-to-day chiropractic clinical practice and there is in general a paucity of information regarding the characteristics of contemporary chiropractic practice in the United Kingdom. This field study describes the daily practice of a contemporary British UK-trained chiropractor. The fieldwork took place during the spring and summer of 2008 when the author spent one day per week observing consultations and interviewing patients in a chiropractic clinic. The chiropractor was subjected to interviews on two occasions. The author also registered as a patient. Field notes were taken by the author, interviews were recorded and the transcripts were corrected and analysed by the author. A total of 25 patients took part in the study. The interaction that took place between patients and staff in reception could be considered as a prelude to consultation facilitating the transformation from individual to patient and back to individual. Coupled with the continuous physical contact between the chiropractor and each patient there was a substantial amount of verbal and non-verbal communication throughout treatment visits. The patients presented with predominantly musculo-skeletal pain and the majority had consulted the chiropractor as a result of recommendations from others in their close social environment. The majority of the interviewed patients had either an inaccurate or at best rudimentary understanding of the mechanisms of chiropractic treatment. A few of the interviewed patients indicated that they had at first experienced concerns about the nature of chiropractic treatment or getting undressed. The author was able to gain some insight into how the chiropractor's experiences, opinions and beliefs had shaped his approach to chiropractic treatment and how this formed the basis of his clinical modus operandi. Although no robust conclusions should be drawn from this small scale field study it does show that the clinical chiropractic practice as carried out by this UK trained British chiropractor contains a number of elements described in earlier qualitative studies in the United States, Canada, and Australia. 23817202 Melanoma-related mortality and productivity losses in the USA, 1990-2008. Melanoma remains among the deadliest cancers in the USA, ranking presently as the leading cause of death from skin disease in this country. The present analysis presents national statistics on the health burden (mortality) and productivity losses attributable to this cancer over a 19-year period. Melanoma-related deaths and mortality rates from 1990 through 2008 were identified and calculated using multiple-cause-of-death data and data from the 2000 US Census. Productivity losses were estimated using previously published methods that accounted for life expectancy, labor force participation, productivity growth, and the imputed values of caregiving and housekeeping activities. A total of 155,571 melanoma-related deaths occurred during 1990-2008, resulting in 1,811,701 years of potential life lost. Age-adjusted mortality rates stratified by sex and race/ethnicity revealed differences: whites had the highest rate (3.55 per 100 000 population; 95% confidence interval 3.54, 3.57) and male individuals were 2.21 times more likely than female individuals to succumb to the disease. Cumulatively, the numbers of death for blacks, Hispanics, Asian/Pacific Islanders, and American Indians/Alaskan Natives exceeded 6000 deaths. The total productivity losses attributable to melanoma-related mortality during the sampled period were ∼$66.9 billion. The burden and economic consequences of melanoma-related deaths in the USA are not inconsequential. Understanding the mortality trends and productivity losses attributed to this skin cancer is important for evaluating the feasibility and trade-offs of public health and behavioral counseling interventions that focus on promoting skin cancer prevention. 23873669 Staphylococcus aureus Penicillin-Binding Protein 2 Can Use Depsi-Lipid II Derived from Vancomycin-Resistant Strains for Cell Wall Synthesis. Vancomycin-resistant Staphylococcus aureus (S. aureus) (VRSA) uses depsipeptide-containing modified cell-wall precursors for the biosynthesis of peptidoglycan. Transglycosylase is responsible for the polymerization of the peptidoglycan, and the penicillin-binding protein 2 (PBP2) plays a major role in the polymerization among several transglycosylases of wild-type S. aureus. However, it is unclear whether VRSA processes the depsipeptide-containing peptidoglycan precursor by using PBP2. Here, we describe the total synthesis of depsi-lipid I, a cell-wall precursor of VRSA. By using this chemistry, we prepared a depsi-lipid II analogue as substrate for a cell-free transglycosylation system. The reconstituted system revealed that the PBP2 of S. aureus is able to process a depsi-lipid II intermediate as efficiently as its normal substrate. Moreover, the system was successfully used to demonstrate the difference in the mode of action of the two antibiotics moenomycin and vancomycin. 23958335 Can a theory-based educational intervention change nurses' knowledge and attitudes concerning cancer pain management? a quasi-experimental design. Registered Nurses (RNs) play an important role in caring for patients suffering from cancer pain. A lack of knowledge regarding pain management and the RNs' own perception of cancer pain could act as barriers to effective pain management. Educational interventions that target RNs' knowledge and attitudes have proved promising. However, an intervention consisting of evidence-based practice is a multifaceted process and demands behavioural and cognitive changes to sustain the effects of the intervention. Therefore, our study aimed to investigate if a theory-based educational intervention could change RNs' knowledge and attitudes to cancer pain and pain management, both four and 12 weeks after the start of the intervention. A quasi-experimental design with non-equivalent control groups was used. The primary outcome was measured using a modified version of the instrument Nurses' Knowledge and Attitudes Survey Regarding Pain (NKAS) at baseline, four weeks and 12 weeks after the start of the intervention to evaluate its persistence. The intervention's educational curriculum was based on the principles of Ajzen's Theory of Planned Behaviour and consisted of interactive learning activities conducted in workshops founded on evidence-based knowledge. The RN's own experiences from cancer pain management were used in the learning process. The theory-based educational intervention aimed at changing RNs knowledge and attitudes regarding cancer pain management measured by primary outcome NKAS resulted in a statistical significant (p<0.05) improvement of total mean score from baseline to four weeks at the intervention ward. The findings of this study, suggest that a theory-based educational intervention focused at RNs can be effective in changing RN's knowledge and attitudes regarding cancer pain management. However, the high number of dropouts between baseline and four weeks needs to be taken into account when evaluating our findings. Finally, this kind of theory-based educational intervention with interactive learning activities has been sparsely researched and needs to be evaluated further in larger projects.Trial registration: Clinical Trials. Gov: NCT01313234. 23254335 DYSF mutation analysis in a group of Chinese patients with dysferlinopathy. Dysferlinopathies belong to heterogeneous group of autosomal recessive muscular disorders caused by mutations in the gene encoding dysferlin. The classifications of the dysferlinopathies mainly include limb-girdle muscular dystrophy 2B (LGMD2B) with predominantly proximal weakness, Miyoshi myopathy (MM) with calf muscle weakness and atrophy, and distal myopathy with anterior tibial onset (DMAT) with tibialis muscle atrophy. We describe the genetic character of dysferlinopathies in a group of Chinese patients. DYSF mutations screening were done after muscle biopsy and immunohistochemical staining. Eight patients showed an absence or drastic decrease of dysferlin expression in biopsied muscle. We identified 6 different mutations, including one nonsense mutation, two insertion mutation, two deletion mutations and one splice site mutation. Five of them were novel mutations. We described 8 Chinese patients with dysferlinopathy (four had a distal phenotype of MM; one had a phenotype of DMAT and three presented with LGMD2B). It is the first report of genetic confirmed DMAT in China. Mutations c.3112C>T and c.1045dup, may be recurrent mutations in China. 23208510 The PGC-1/ERR signaling axis in cancer. Proliferating cells need to produce a large amount of energy and, at the same time, need to maintain a constant supply of biosynthetic precursors of macromolecules that are used as building blocks for generating new cells. Indeed, many cancer cells undergo a switch from mitochondrial to glycolytic metabolism and display a truncated tricarboxylic acid cycle to match these specific metabolic requirements of proliferation. Understanding the mechanisms by which cancer cells reprogram various metabolic pathways to satisfy their unique bioenergetic requirements has become an active field of research. Concomitantly, it has emerged that members of a family of orphan nuclear receptors known as the estrogen-related receptors (ERRs), working in concert with members of the PPARγ coactivator (PGC)-1 family, act as central transcriptional regulators of metabolic gene networks involved in maintaining energy homeostasis in normal cells. Recent studies have suggested that the PGC-1/ERR transcriptional axis is also important in the metabolic reprogramming of cancer cells. This review focuses on the functional integration of the PGC-1/ERR axis with known oncogenes and the observation that modulation of the activity of this axis can have both pro- and anti-proliferative properties. 23883043 Accurate evaluation of the angular-dependent direct correlation function of water. The direct correlation function (DCF) plays a pivotal role in addressing the thermodynamic properties with non-mean-field statistical theories of liquid state. This work provides an accurate yet efficient calculation procedure for evaluating the angular-dependent DCF of bulk SPC∕E water. The DCF here represented in a discrete angles basis is computed with two typical steps: the first step involves solving the molecular Ornstein-Zernike equation with the input of total correlation function extracted from simulation; the resultant DCF is then polished in second step at small wavelength for all orientations in order to match correct thermodynamic properties. This function is also discussed in terms of its rotational invariant components. In particular, we show that the component c112(r) that accounts for dipolar symmetry reaches already its long-range asymptotic behavior at a short distance of 4 Å. With the knowledge of DCF, the angular-dependent bridge function of bulk water is thereafter computed and discussed in comparison with referenced hard-sphere bridge functions. We conclude that, even though such hard-sphere bridge functions may be relevant to improve the calculation of Helmholtz free energies in integral equations or density functional theory, they are doomed to fail at a structural level. 23052219 Ancestry of modern Europeans: contributions of ancient DNA. Understanding the peopling history of Europe is crucial to comprehend the origins of modern populations. Of course, the analysis of current genetic data offers several explanations about human migration patterns which occurred on this continent, but it fails to explain precisely the impact of each demographic event. In this context, direct access to the DNA of ancient specimens allows the overcoming of recent demographic phenomena, which probably highly modified the constitution of the current European gene pool. In recent years, several DNA studies have been successfully conducted from ancient human remains thanks to the improvement of molecular techniques. They have brought new fundamental information on the peopling of Europe and allowed us to refine our understanding of European prehistory. In this review, we will detail all the ancient DNA studies performed to date on ancient European DNA from the Middle Paleolithic to the beginning of the protohistoric period. 23831435 Structure determination of α-helical membrane proteins by solution-state NMR: Emphasis on retinal proteins. The biochemical processes of living cells involve a numerous series of reactions that work with exceptional specificity and efficiency. The tight control of this intricate reaction network stems from the architecture of the proteins that drive the chemical reactions and mediate protein-protein interactions. Indeed, the structure of these proteins will determine both their function and interaction partners. A detailed understanding of the proximity and orientation of pivotal functional groups can reveal the molecular mechanistic basis for the activity of a protein. Together with X-ray crystallography and electron microscopy, NMR spectroscopy plays an important role in solving three-dimensional structures of proteins at atomic resolution. In the challenging field of membrane proteins, retinal-binding proteins are often employed as model systems and prototypes to develop biophysical techniques for the study of structural and functional mechanistic aspects. The recent determination of two 3D structures of seven-helical trans-membrane retinal proteins by solution-state NMR spectroscopy highlights the potential of solution NMR techniques in contributing to our understanding of membrane proteins. This review summarizes the multiple strategies available for expression of isotopically labeled membrane proteins. Different environments for mimicking lipid bilayers will be presented, along with the most important NMR methods and labeling schemes used to generate high-quality NMR spectra. The article concludes with an overview of types of conformational restraints used for generation of high-resolution structures of membrane proteins. This article is part of a Special Issue entitled: Retinal Proteins - You can teach an old dog new tricks. 23845661 In vitro hemodynamic model of the arm arteriovenous circulation to study hemodynamics of native arteriovenous fistula and the distal revascularization and interval ligation procedure. Experimental modeling of arteriovenous hemodialysis fistula (AVF) hemodynamics is challenging. Mathematical modeling struggles to accurately represent the capillary bed and venous circulation. In vivo animal models are expensive and labor intensive. We hypothesized that an in vitro, physiologic model of the extremity arteriovenous circulation with provisions for AVF and distal revascularization and interval ligation (DRIL) configurations could be created as a platform for hemodynamic modeling and testing. An anatomic, upper extremity arteriovenous model was constructed of tubing focusing on the circulation from the subclavian artery to subclavian vein. Tubing material, length, diameter, and wall thickness were selected to match vessel compliance and morphology. All branch points were constructed at physiologic angles. The venous system and capillary bed were modeled using tubing and one-way valves and compliance chambers. A glycerin/water solution was created to match blood viscosity. The system was connected to a heart simulator. Pressure waveforms and flows were recorded at multiple sites along the model for the native circulation, brachiocephalic AVF configuration, and the AVF with DR without and with IL (DR no IL and DRIL). A preset mean cardiac output of 4.2 L/min from the heart simulator yielded a subclavian artery pressure of 125/55 mm Hg and a brachial artery pressure of 121/54 mm Hg with physiologic arterial waveforms. Mean capillary bed perfusion pressure was 41 mm Hg, and mean venous pressure in the distal brachial vein was 17 mm Hg with physiologic waveforms. AVF configuration resulted in a 15% decrease in distal pressure and a 65% decrease in distal flow to the hand. DR no IL had no change in distal pressure with a 27% increase in distal flow. DRIL resulted in a 3% increase in distal pressure and a 15% increase in distal flow to the hand above that of DR no IL. Flow through the DR bypass decreased from 329 mL/min to 55 mL/min with the addition of IL. Flow through the AVF for both DR no IL and DRIL was preserved. Through the construction and validation of an in vitro, pulsatile arteriovenous model, the intricate hemodynamics of AVF and treatments for ischemic steal can be studied. DR with or without IL improved distal blood flow in addition to preserving AVF flow. IL decreased the blood flow through the DR bypass itself. The findings of the AVF as a pressure sink and the relative role of IL with DR bypass has allowed this model to provide hemodynamic insight difficult or impossible to obtain in animal or human models. Further study of these phenomena with this model should allow for more effective AVF placement and maturation while personalizing treatment for associated ischemic steal. 23182918 Incidence and predictors of right paraesophageal lymph node metastasis of N0 papillary thyroid carcinoma located in the right lobe. Papillary thyroid carcinoma (PTC) frequently metastasizes to the regional lymph nodes and, thus, guidelines edited by Japan Association of Endocrine Surgeons/Japanese Society of Thyroid Surgery routinely recommend central node dissection even for patients with no clinically detectable node metastasis (N0). However, in the central compartment, metastasis to the right paraesophageal node has not been intensively investigated. We investigated the incidence and predictors of right paraesophageal node metastasis based on pre- and intraoperative findings in 922 patients with N0 PTC in the right lobe. Fourteen percent of patients were microscopically positive for right paraesophageal node metastasis, and the incidence was smaller than that for pre- and right paratracheal node metastasis (46%). On multivariate analysis, a tumor size ≥ 2 cm and significant extrathyroid extension were independent predictors of metastasis. Microscopically pre- and right paratracheal node-positive PTC more often (p < 0.0001) metastasized to the right paraesophageal node. Taken together, in N0 PTC in the right lobe, right paraesophageal node dissection should be considered in tumors 2 cm or larger and/or with significant extrathyroid extension, or when pre- and right paratracheal node metastasis is suspected based on the intraoperative findings. 23856814 LC-MS/MS Analysis of Canine Lipoproteins Fractionated Using the Ultracentrifugation-Precipitation Method. Due to the lack of a gold standard method in canine lipoprotein analysis, it is unclear whether canine high-density lipoprotein (HDL) and low-density lipoprotein (LDL) can be accurately evaluated by the lipoprotein analysis methods used for dogs. This study investigated whether the ultracentrifugation-precipitation (U-P) method was suitable as a gold standard method for analyzing canine lipoprotein. First, the U-P method was compared with a gel permeation high performance liquid chromatography system (GP-HPLC). The concentrations of canine HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C) determined by the U-P method correlated closely with those determined by GP-HPLC. However, the canine HDL-C concentration determined by the U-P method was lower than that by GP-HPLC, and the canine LDL-C concentration by the U-P method was higher than that by GP-HPLC. This study showed that some of the canine HDL could be precipitated with heparin manganese chloride solution. Second, the [HDL] and [LDL] fractions separated by the U-P method were analyzed by LC-MS/MS. The [HDL] fraction was found to contain only apolipoprotein A-I, which is an apolipoprotein of HDL, whereas the [LDL] fraction contained both apolipoprotein A-I and apolipoprotein B-100, which is an apolipoprotein of LDL. This data showed that a certain lipoprotein that includes apolipoprotein A-I might precipitate with canine LDL by use of heparin manganese chloride solution. These results indicated that the U-P method is not currently a gold standard method for analyzing canine lipoproteins. 23261424 Discovering gene-environment interactions in Glioblastoma through a comprehensive data integration bioinformatics method. Glioblastoma multiforme (GBM) is the most common and aggressive type of human brain tumor. Although considerable efforts to delineate the underlying pathophysiological pathways have been made during the last decades, only very limited progress on treatment have been achieved because molecular pathways that drive the aggressive nature of GBM are largely unknown. Recent studies have emphasized the importance of environmental factors and the role of gene-environment interactions (GEI) in the development of GBM. Factors such as small sample sizes and study costs have limited the conduct of GEI studies in brain tumors however. Additionally, advances in high-throughput microarrays have produced a wealth of information concerning molecular biology of glioma. In particular, microarrays have been used to obtain genetic and epigenetic changes between normal non-tumor tissue and glioma tissue. Due to the relative rarity of gliomas, microarray data for these tumors is often the product of small studies, and thus pooling this data becomes desirable. To address the challenge of small sample sizes and GEI study difficulties, we introduce a comprehensive bioinformatics method using genetic variations (copy number variations and small-scale variations) and environmental data integration that links with Glioblastoma (GEG) to identify: (1) genes that interact with chemicals and have genetic variants linked to the development of GBM, (2) important pathways that may be influenced by environmental exposures (or endogenous chemicals), and (3) genes with variants in GBM that have been understudied in relation to GBM development. The first step in our GEG method identified genes responsive to environmental exposures using the Environmental Genome Project, Comparative Toxicology, and Seattle SNPs databases. These environmentally responsive genes were then compared to a curated list of genes containing copy number variation and/or mutations in GBM. This comparison produced a list of genes responsive to the environment and important to GBM that was then further analyzed using gene networking tools such as RSpider, Cytoscape, and DAVID. Using this GEG bioinformatics method we were able to identify 173 genes with the potential to be involved in GEI that may be important to the development of GBM. Sixty five of these environmentally responsive genes have not been reported as important to GBM development, despite several of them having substantial potential for response to chemicals and subsequent disease related actions. The main biological functions of these 173 genes include signaling by Nerve Growth Factor, DNA Repair, Integrin Cell Surface Interactions, Biological Oxidations, Apoptosis, Synaptic Transmission, Cell Cycle Checkpoints, and Arachidonic Acid Metabolism. Importantly, some of these functions have been implicated in the development of several cancers, including glioma. In summary, our GEG bioinformatics approach revealed potential gene-environment interactions, and generated new data for hypothesis generation, in GBM. 23224344 Bilateral vocal palsy following coin cell lithium battery ingestion: a case report and review. Button battery ingestion in children is not a rare occurrence and may be unwitnessed and can be soon life-threatening or responsible for severe sequelae. We report herein an original history of previously healthy 16-month-old boy with an unwitnessed and misdiagnosis of lithium cell coin battery ingestion which leads to bilateral vocal palsy. The patient underwent a unilateral posterior cordotomy and was successfully extubated. Conclusion: Early recognition of a lithium cell coin battery for rapid removal, even if insufficient at first, is the main condition to limit complications. Unusual upper respiratory distress in a young child should alert practitioners in performing a chest and neck X-ray without undue delay. 23930985 Nonuraemic nonfatal idiopathic calciphylaxis in a kitten. Calciphylaxis is a rare cutaneous disorder, characterized by vascular calcification and progressive skin necrosis, not yet described in cats. It is scarcely reported in animals, mostly due to iatrogenic or uraemic disturbances of the calcium-phosphate balance. In human patients, it is most commonly seen with end-stage renal disease, but several nonuraemic disorders, including inherited dysfunctions of tissue calcification inhibitors, have also been described. To describe a case of nonuraemic calciphylaxis in a cat. A 10-week-old male domestic short hair kitten was presented with hyperacute skin lesions. Initial dermatological signs were characterized by sharp demarcated erosions and ulcerations on the face, including the nasal planum and lips. Cutaneous lesions rapidly progressed into thick crusts with ulcerations, involving parts of the face and pinna as well as abdominal skin. Complete blood count, serum chemistry profile, urinalysis, parathyroid hormone measurement and histopathological examination of skin biopsies. Histopathology from newly developed abdominal skin lesions revealed severe epidermal necrosis and calcification, multifocal pannicular calcification and calcified subcutaneous vessels, supporting a diagnosis of calciphylaxis. Treatment consisted of systemic and topical antimicrobials, analgesics, pentoxifylline, Lantharenol(®) , sodium thiosulfate and vitamin K. After initiation of therapy, no further progression was noticed; all medications could be discontinued eventually, and no relapse was seen in the following 2 years. Calciphylaxis should be considered as a differential diagnosis for ulcerative cutaneous disorders in young cats. More information on this disease is needed to elucidate the pathomechanism. 23597660 Testing of instantaneity hypothesis for blind source separation of extensor indicis and extensor digiti minimi surface electromyograms. Human muscle activity can be assessed with surface electromyography (SEMG). Depending on electrode location and size, the recording volume under the sensor is likely to measure electrical potentials emanating from muscles other than the muscle of interest. This crosstalk issue makes interpretation of SEMG data difficult. The purpose of this paper was to study a crosstalk reduction technique called blind source separation (BSS). Most straightforward separation techniques rely on linearity and instantaneity (LI) of signal mixtures on the sensors. Literature on BSS for SEMG often makes hypothesis of linearity and instantaneity of the mixing model. Using simulation of SEMG mixtures and real SEMG recordings on the human extensor indicis (EI) and extensor digiti minimi (EDM) muscles during a task consisting of selective successive activations of EI and EDM muscles, cross-correlation between the sensors was proven to be directly dependent on instantaneity of the sources. Instantaneity hypothesis testing on real SEMG recordings showed that source instantaneity hypothesis is very sensitive to electrode location along the fibers direction. Source separation gains using JADE BSS algorithm depend strongly on instantaneity hypothesis. Using LI BSS on SEMG requires great attention to electrode positioning; we provide a tool to test these on EI/EDM muscles. 23473033 The mitochondrial RNA-binding protein GRSF1 localizes to RNA granules and is required for posttranscriptional mitochondrial gene expression. RNA-binding proteins are at the heart of posttranscriptional gene regulation, coordinating the processing, storage, and handling of cellular RNAs. We show here that GRSF1, previously implicated in the binding and selective translation of influenza mRNAs, is targeted to mitochondria where it forms granules that colocalize with foci of newly synthesized mtRNA next to mitochondrial nucleoids. GRSF1 preferentially binds RNAs transcribed from three contiguous genes on the light strand of mtDNA, the ND6 mRNA, and the long noncoding RNAs for cytb and ND5, each of which contains multiple consensus binding sequences. RNAi-mediated knockdown of GRSF1 leads to alterations in mitochondrial RNA stability, abnormal loading of mRNAs and lncRNAs on the mitochondrial ribosome, and impaired ribosome assembly. This results in a specific protein synthesis defect and a failure to assemble normal amounts of the oxidative phosphorylation complexes. These data implicate GRSF1 as a key regulator of posttranscriptional mitochondrial gene expression. 23703843 Improvement of the Caenorhabditis elegans growth and reproduction test to assess the ecotoxicity of soils and complex matrices. A growth and reproduction test using the nematode Caenorhabditis elegans was recently standardized by the International Organization for Standardization (ISO). Performing the ISO 10872 protocol (2010) revealed some drawbacks when applied to soil or soil mixed with complex matrices. The authors propose some modifications to the current protocol to normalize the test conditions. An appropriate range of moisture conditions was determined as a percentage of the water-holding capacity (WHC) of the soil. According to the authors' results, C. elegans tests can be performed in the range of 60% to 100% WHC. To ensure that the modifications of the protocol did not affect the organisms' recovery, extraction ratios for the juveniles were subsequently estimated. The modified protocol was found to be as reliable as the standard one concerning recovery of juveniles (over 80%). The protocol was also applied to several chemicals to investigate their potential as reference chemicals for soil toxicity tests. Boric acid, copper chloride, and nickel sulfate showed deleterious effects in a concentration-dependent manner for the growth and reproduction of C. elegans. Finally, the modified protocol was used to assess the growth and reproduction of C. elegans in soil amended with a limed sewage sludge. The authors conclude that the C. elegans modified protocol is a promising tool for the assessment of soil toxicity as well as the toxicity of mixtures with complex matrices. Environ Toxicol Chem 2013;32:2100-2108. © 2013 SETAC. 23642382 Comparison of inferolateral early repolarization and its electrocardiographic phenotypes in pre- and postadolescent populations. Inferolateral early repolarization (ER) patterns on standard electrocardiogram (ECG) are associated with increased risk for cardiac and arrhythmic death in general adult population cohorts. We sought to determine the prevalence of inferolateral ER on surface ECG in multiracial pre- and postadolescent populations and to analyze its association with age, race, gender, and ST-segment patterns. A retrospective review was conducted of all ECGs recorded from preadolescent (aged 8-12 years, n = 719) and postadolescent (aged 21-25 years, n = 755) patients seen at a large academic medical center between January 1, 2009, and December 31, 2010. The overall prevalence of inferolateral ER was similar in the preadolescent and postadolescent populations (17% vs 16%, NS). The prevalence of ER increased after puberty in male patients (16% to 25%, p <0.001) and decreased in female patients (18% to 9%, p <0.001). Prevalence of ascending early repolarization (benign variant) also increased in males after puberty (15% to 23%, p <0.004) and decreased in females (11% to 4%, p <0.001). There were no differences in the prevalence of the risk-associated horizontal/descending pattern (3% in both groups). Subgroup analysis was performed on ECGs from the cohort of outpatients without cardiac disease, and the statistical trends remained the same. In conclusion, the overall prevalence of inferolateral ER was higher in pre- and postadolescent populations than in adult populations. However, the prevalence of the risk-associated horizontal/descending ST-segment pattern was only 3%, comparable to prevalence rates in the adult population. The variations in prevalence by gender and age suggest a possible influence of reproductive hormones. 23834035 Use of the Xpert(®) MTB/RIF assay for diagnosing pulmonary tuberculosis comorbidity and multidrug-resistant TB in obstetrics and gynaecology inpatient wards at the University Teaching Hospital, Lusaka, Zambia. In high-tuberculosis (TB)-endemic countries, comorbidity of pulmonary TB in hospitalised patients with non-communicable diseases is well documented. In this study, we evaluated the use of the Xpert(®) MTB/RIF assay for the detection of concomitant pulmonary TB in patients admitted to the University Teaching Hospital, Lusaka, Zambia, with a primary obstetric or gynaecological condition. The Study population were inpatients admitted with a primary obstetric or gynaecological problem who had a concomitant cough and were able to expectorate a sputum sample. Sputum samples from 94 patients were analysed for the presence of Mycobacterium tuberculosis (M.tb) by standard smear microscopy, MGIT culture, MGIT drug-susceptibility testing (DST) and the Xpert(®) MTB/RIF assay. The sensitivity and specificity of the Xpert(®) MTB/RIF assay were evaluated against the culture gold standard. Twenty-six of 94 (27.7%) patients had culture-confirmed pulmonary TB. The Xpert(®) MTB/RIF assay had a sensitivity of 80.8% [95% CI: 60.0-92.7%]) compared against MGIT culture. The Xpert(®) MTB/RIF assay was more sensitive than sputum smear microscopy (21/26 (80.8%) vs. 13/26 (50.0%), P = 0.02) and detected an additional eight culture-confirmed cases. Culture DST analysis identified two monoresistant M.tb strains: one resistant to rifampicin (rifampicin sensitive by the Xpert(®) MTB/RIF assay) and one to ethambutol. HIV infection was linked with a 3-fold increase in risk of TB, accounting for 87.5% (21/24) of TB cases. 50% of cases presented as comorbidities with other communicable diseases (CDs) and non-communicable diseases (NCDs). As an alternative to sputum microscopy, the Xpert(®) MTB/RIF assay provides a sensitive, specific and rapid method for the diagnosis of pulmonary TB in obstetric or gynaecological inpatients. Pulmonary TB is an important cause of concomitant comorbidity to the obstetric or gynaecological condition necessitating admission. TB and HIV comorbidities with other communicable and non-communicable diseases were also common. More proactive screening for TB comorbidity is required in obstetric and gynaecological wards. 23825351 Stability-Indicating LC Method for the Estimation of Bendamustine Hydrochloride and its Related Impurities. A novel, simple, sensitive and stability-indicating high-performance liquid chromatography method was developed and validated for the quantification of impurities (process related and degradants) and the assay determination of Bendamustine hydrochloride. A chromatographic separation of Bendamustine and its impurities was achieved with an Inertsil ODS-2 analytical column, 250 × 4.6 mm, 5 µm, using gradient elution with mobile phase A consisting of a mixture of water and trifluoroacetic acid (1000:1, v/v) and mobile phase B consisting of acetonitrile. The instrumental settings included a flow rate of 1.0 mL/min, column temperature of 27°C and a detector wavelength of 233 nm, using a photodiode array detector. The tailing factor for Bendamustine was 1.10. Bendamustine hydrochloride was exposed to thermal, photolytic, hydrolytic and oxidative stress conditions and the stressed samples were analyzed by the proposed method. Peak homogeneity data of Bendamustine were obtained by using a photodiode array detector in the stressed sample chromatograms, which demonstrated the specificity of the method for estimation in the presence of degradants. The developed method was validated for parameters such as precision, accuracy, linearity, limit of detection, limit of quantification, ruggedness and robustness. The stability tests were also performed on drug substances as per International Conference on Harmonization guidelines. 23850612 A Comparison of Discharge Functional Status after Rehabilitation in Skilled Nursing, Home Health, and Medical Rehabilitation Settings for Patients Following Hip Fracture Repair. To examine differences in rehabilitation outcomes across 3 post-acute care (PAC) rehabilitation settings for patients following hip fracture repair. Prospective, observational cohort study SETTING: Six skilled nursing facilities (SNFs), 4 inpatient rehabilitation facilities (IRFs), and 8 home health agencies (HHAs) in 10 states. Patients receiving PAC rehabilitation following hip fracture with internal fixation (n=116) or total hip replacement (n=64), or no surgical intervention (n=1). Not applicable MAIN OUTCOME MEASURE: Self-care and mobility status at PAC discharge measured by the IRF-PAI. IRF and HHA patients had lower self-care function at discharge relative to SNF patients controlling for patient characteristics, severity, comorbidities, and services. Adding length-of-stay (LOS) resulted in non-significant differences between IRFs and SNFs. In contrast, there was no setting-specific advantage in discharge mobility for patients with or without the addition of LOS. HHA patients' average LOS was 2 weeks longer than SNF patients', whose average LOS was 9 days longer than IRF patients (average 15 days). IRF and SNF patients received about the same total minutes of therapy over their PAC stays (approximately 2100 minutes on average), while HHA patients received only about 25% as many minutes. Setting-specific effects varied depending on whether self-care or mobility was the outcome of focus. It remains unclear the extent to which rehabilitation intensity or natural recovery influences changes in functional status for hip fracture patients. This study points to important directions for PAC setting comparative effectiveness studies in the future including uniform measurement, limited consensus on factors influencing recovery, accounting for selection bias, and using end-point data collection that is at the same follow-up time periods for all settings. 23616030 Effects of pancreatectomy on nutritional state, pancreatic function and quality of life. There are concerns about the extent of impaired endocrine and exocrine pancreatic function and poor quality of life (QoL) after pancreatectomy, but there is little information from large prospective follow-up studies. Consecutive patients undergoing pancreaticoduodenectomy or distal pancreatectomy between 2007 and 2011 were included. Relative bodyweight (RBW), triceps skinfold thickness (TSFT), serum protein, albumin, transferrin, fasting blood glucose, postprandial 2-h glucose (PP2), glycosylated haemoglobin A1c and stool elastase measurements, and European Organization for Research and Treatment of Cancer QLQ-C30 questionnaires were collected serially for 1 year. Some 136 patients undergoing pancreatic resection completed the study. RBW and TSFT recovered to over 90 per cent of the preoperative value by 12 months, whereas transferrin, albumin and protein had returned to preoperative levels by 3 months. Diabetes mellitus, impaired fasting glucose or raised PP2 was present in 42 of 76 patients at 6 months and 36 of 76 at 12 months. Although steatorrhoea and diarrhoea had mainly resolved by 3 months, stool elastase level decreased after operation and showed no recovery. Nutritional status, pancreatic endocrine function and QoL returned to preoperative levels in 63 (46·3 per cent), 72 (52·9 per cent) and 77 (56·6 per cent) of 136 patients within 6 months of pancreatectomy. Multivariable analysis revealed that age 60 years or more, operation type, chronic pancreatitis and malignant disease had a significant impact on nutritional index, pancreatic function and QoL. About half of all patients can expect recovery from pancreatectomy after 6 months, but those with risk factors need more careful follow-up and supportive management. 23571107 The Ras-GTPase activity of neurofibromin restrains ERK-dependent FGFR signaling during endochondral bone formation. The severe defects in growth plate development caused by chondrocyte extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) gain or loss-of-function suggest that tight spatial and temporal regulation of mitogen-activated protein kinase signaling is necessary to achieve harmonious growth plate elongation and structure. We provide here evidence that neurofibromin, via its Ras guanosine triphosphatase -activating activity, controls ERK1/2-dependent fibroblast growth factor receptor (FGFR) signaling in chondrocytes. We show first that neurofibromin is expressed in FGFR-positive prehypertrophic and hypertrophic chondrocytes during growth plate endochondral ossification. Using mice lacking neurofibromin 1 (Nf1) in type II collagen-expressing cells, (Nf1col2(-/-) mutant mice), we then show that lack of neurofibromin in post-mitotic chondrocytes triggers a number of phenotypes reminiscent of the ones observed in mice characterized by FGFR gain-of-function mutations. Those include dwarfism, constitutive ERK1/2 activation, strongly reduced Ihh expression and decreased chondrocyte proliferation and maturation, increased chondrocytic expression of Rankl, matrix metalloproteinase 9 (Mmp9) and Mmp13 and enhanced growth plate osteoclastogenesis, as well as increased sensitivity to caspase-9 mediated apoptosis. Using wildtype (WT) and Nf1(-/-) chondrocyte cultures in vitro, we show that FGF2 pulse-stimulation triggers rapid ERK1/2 phosphorylation in both genotypes, but that return to the basal level is delayed in Nf1(-/-) chondrocytes. Importantly, in vivo ERK1/2 inhibition by daily injection of a recombinant form of C-type natriuretic peptide to post-natal pups for 18 days was able to correct the short stature of Nf1col2(-/-) mice. Together, these results underscore the requirement of neurofibromin and ERK1/2 for normal endochondral bone formation and support the notion that neurofibromin, by restraining RAS-ERK1/2 signaling, is a negative regulator of FGFR signaling in differentiating chondrocytes. 23928058 Small cell lung cancer-specific isoform of RE1-silencing transcription factor (REST) is regulated by neural-specific Ser/Arg repeat-related protein of 100 kDa (nSR100). Small cell lung cancer (SCLC) is a highly malignant form of cancer, which originates from primitive neuroendocrine cells in the lung. SCLC cells express several autocrine neurotransmitters/neuropeptides and their respective receptors. Expression of these neuronal markers is frequently regulated by RE1-silencing transcription factor (REST). In SCLC cells, an SCLC-specific isoform of REST (sREST) is highly expressed while REST expression is undetectable, suggesting that the expression of sREST correlates with the pathogenesis of SCLC. Expression of sREST, which is derived through alternative splicing of REST, is abnormally regulated in SCLC cells, but the mechanism is unknown. Most recently, nSR100 (SRRM4) was described as an activator of REST alternative splicing. We now demonstrate that nSR100 is highly expressed in SCLC cells correlating with high sREST and low REST expression. Adhesion to the extracellular matrix (ECM) is thought to enhance tumorigenicity and confer resistance to apoptosis. Interestingly, nSR100 expression is enhanced in cells grown with ECM. Overexpression of REST caused repression of sREST and nSR100, the latter containing RE1-element controlled by REST. Culturing the SCLC cell line NCI-N417 cells with ECM also up-regulated RE1-containing gene, the voltage-gated calcium channel subunit. Inhibition of the PI3K/Akt/mTOR pathway by LY294002 induced nSR100 expression, while the specific MEK/ERK inhibitor U0126 inhibited nSR100 expression. Repressing nSR100 by siRNA effectively repressed sREST, and conversely increased REST in NCI-N417 cells. Taken together this report clarifies the ECM-dependent signaling pathway that impacts nSR100 expression and its regulation of alternative splicing in SCLC. Implications:The splicing factor nSR100 may be novel SCLC-specific biomarker as well as a therapeutic target. 23893467 'You know I've joined your club… I'm the hot flush boy': a qualitative exploration of hot flushes and night sweats in men undergoing androgen deprivation therapy for prostate cancer. Hot flushes and night sweats are common amongst menopausal women, and psychological interventions for managing these symptoms have recently been developed for women. However, flushes in men with prostate cancer, which commonly occur following androgen deprivation therapy (ADT), remain under-researched. This study is a qualitative exploration of flush-related cognitive appraisals and behavioural reactions reported by a sample of these men. Semi-structured, in-depth interviews were conducted with 19 men who were experiencing flushes after receiving ADT for prostate cancer. Framework analysis was used to generate and categorise emergent themes and explore associations between themes. Five main cognitive appraisals included the following: changes in oneself, impact on masculinity, embarrassment/social-evaluative concerns, perceived control and acceptance/adjustment. There were men who held beliefs about the impact of flushes on their perceptions of traditional gender roles, who experienced shame and embarrassment due to concerns about the salience of flushes and perceptions by others and who experienced feelings of powerlessness over flushes. Powerlessness was associated with beliefs about the potentially fatal consequences of discontinuing treatment. Two other dominant themes included awareness/knowledge about flushes and management strategies. Experiences of flushes appeared to be influenced by upbringing and general experiences of prostate cancer and ADT. The range of men's appraisals of, and reactions to, flushes generated from this qualitative exploration were broadly similar to those of menopausal women but differed in terms of the influence of masculinity beliefs. These findings could be used to inform future research and psychological interventions in this under-researched field. Copyright © 2013 John Wiley & Sons, Ltd. 23831127 An empirical comparison of low-dose extrapolation from points of departure (PoD) compared to extrapolations based upon methods that account for model uncertainty. Experiments with relatively high doses are often used to predict risks at appreciably lower doses. A point of departure (PoD) can be calculated as the dose associated with a specified moderate response level that is often in the range of experimental doses considered. A linear extrapolation to lower doses often follows. An alternative to the PoD method is to develop a model that accounts for the model uncertainty in the dose-response relationship and to use this model to estimate the risk at low doses. Two such approaches that account for model uncertainty are model averaging (MA) and semi-parametric methods. We use these methods, along with the PoD approach in the context of a large animal (40,000+ animal) bioassay that exhibited sub-linearity. When models are fit to high dose data and risks at low doses are predicted, the methods that account for model uncertainty produce dose estimates associated with an excess risk that are closer to the observed risk than the PoD linearization. This comparison provides empirical support to accompany previous simulation studies that suggest methods that incorporate model uncertainty provide viable, and arguably preferred, alternatives to linear extrapolation from a PoD. 23901011 High-resolution definition of the Vibrio cholerae essential gene set with hidden Markov model-based analyses of transposon-insertion sequencing data. The coupling of high-density transposon mutagenesis to high-throughput DNA sequencing (transposon-insertion sequencing) enables simultaneous and genome-wide assessment of the contributions of individual loci to bacterial growth and survival. We have refined analysis of transposon-insertion sequencing data by normalizing for the effect of DNA replication on sequencing output and using a hidden Markov model (HMM)-based filter to exploit heretofore unappreciated information inherent in all transposon-insertion sequencing data sets. The HMM can smooth variations in read abundance and thereby reduce the effects of read noise, as well as permit fine scale mapping that is independent of genomic annotation and enable classification of loci into several functional categories (e.g. essential, domain essential or 'sick'). We generated a high-resolution map of genomic loci (encompassing both intra- and intergenic sequences) that are required or beneficial for in vitro growth of the cholera pathogen, Vibrio cholerae. This work uncovered new metabolic and physiologic requirements for V. cholerae survival, and by combining transposon-insertion sequencing and transcriptomic data sets, we also identified several novel noncoding RNA species that contribute to V. cholerae growth. Our findings suggest that HMM-based approaches will enhance extraction of biological meaning from transposon-insertion sequencing genomic data. 23797009 Trends in bacterial resistance in a tertiary university hospital over one decade. The objective of this study was to investigate bacterial resistance trends, infection sites and the relationship between resistance and admittance to the intensive care unit (ICU). A total of 53,316 bacteria identified between 1999 and 2008 were evaluated. Multidrug resistance was characterized when gram-negative bacilli (GNB) presented resistance to two or more classes of antibiotics. Gram-positive cocci (CPC) were assessed for resistance to penicillin, oxacillin and vancomycin. GNB were the most common (66.1%) isolate. There was a 3.7-fold overall increase in multidrug resistant GNB over the study period; Acinetobacter baumanii and Staphylococcus aureus were the most prevalent. Highest increases were recorded for Klebsiella pneumoniae (14.6-fold) and enterococci (73-fold). The resistance rates for GNB and GPC were 36% and 51.7%, respectively. Most multidrug resistant GNB and GPC were recovered from ICU patients (p-value<0.001). Vancomycin-resistant enterococci were isolated during this decade with an increase of 18.7% by 2008. These data confirm the worldwide trend in multidrug bacterial resistance. 23639696 Structural determination and NMR characterization of a bacterial exopolysaccharide. A strain of Bacillus licheniformis with high exopolysaccharide (EPS) production ability was isolated and identified. A new type of EPS was isolated from the strain fermentation and its structural characteristics were investigated and elucidated by partial and total acid hydrolysis, Fourier transform infrared, and (1)H and (13)C NMR spectroscopy including 2D (1)H, COSY, NOESY, XHCOR and HMBC experiments. Based on obtained data, the EPS was found to be a levan composed of linear chains of (2→6)-linked β-d-fructofuranosyl residues with connections β (2→6). 23945873 Fluorescence-Based High-Throughput Screening of Dicer Cleavage Activity. Production of small RNAs by ribonuclease III Dicer is a key step in microRNA and RNA interference pathways, which employ Dicer-produced small RNAs as sequence-specific silencing guides. Further studies and manipulations of microRNA and RNA interference pathways would benefit from identification of small-molecule modulators. Here, we report a study of a fluorescence-based in vitro Dicer cleavage assay, which was adapted for high-throughput screening. The kinetic assay can be performed under single-turnover conditions (35 nM substrate and 70 nM Dicer) in a small volume (5 µL), which makes it suitable for high-throughput screening in a 1536-well format. As a proof of principle, a small library of bioactive compounds was analyzed, demonstrating potential of the assay. 23360537 A nonribosomal peptide synthetase-derived iron(III) complex from the pathogenic fungus Aspergillus fumigatus. Small molecules (SMs) play central roles as virulence factors of pathogenic fungi and bacteria; however, genomic analyses suggest that the majority of microbial SMs have remained uncharacterized. Based on microarray analysis followed by comparative metabolomics of overexpression/knockout mutants, we identified a tryptophan-derived iron(III)-complex, hexadehydro-astechrome (HAS), as the major product of the cryptic has nonribosomal peptide synthetase (NRPS) gene cluster in the human pathogen Aspergillus fumigatus. Activation of the has cluster created a highly virulent A. fumigatus strain that increased mortality of infected mice. Comparative metabolomics of different mutant strains allowed to propose a pathway for HAS biosynthesis and further revealed cross-talk with another NRPS pathway producing the anticancer fumitremorgins. 23780372 Plasma Levels of Advanced Glycation Endproducts N{epsilon}-(carboxymethyl)lysine, N{epsilon}-(carboxyethyl)lysine, and Pentosidine Are not Independently Associated With Cardiovascular Disease in Individuals With or Without Type 2 Diabetes: The Hoorn and CODAM Studies. Objective: Experimental and histological data suggest a role for advanced glycation end products (AGEs) in cardiovascular disease (CVD), particularly in type 2 diabetes (T2DM). However, the epidemiological evidence of an adverse association between AGEs and CVD remains inconclusive. We therefore investigated, in individuals with various degrees of glucose metabolism, the associations of plasma AGEs with prevalent CVD. Research Design and Methods: We measured plasma levels of protein-bound N(ε)-(carboxymethyl)lysine (CML), N(ε)-(carboxyethyl)lysine (CEL), and pentosidine, in participants from two Dutch cohort studies (n = 1291, mean age 64.7 ± 8.3 years, 45% women), including 573 individuals with normal glucose metabolism, 304 with impaired glucose metabolism, and 414 with T2DM. In addition, we measured free CML, CEL, and 5-hydro-5-methylimidazolone in a subset of participants (n = 554). Data were analyzed with multiple logistic or linear regression analyses. Results: CEL (32 [interquartile range: 25-40] vs 28 [22-35] nmol/mmol lysine) and pentosidine (0.53 [0.43-0.67] vs 0.48 [0.40-0.59] nmol/mmol lysine) as well as free CEL (48 [39-62] vs 45 [36-56] nmol/L) and 5-hydro-5-methylimidazolone (141 [96-209] vs 116 [84-165] nmol/L) were higher in individuals with vs without CVD, whereas protein-bound CML was lower (33 [27-38] vs 34 [29-39] nmol/mmol lysine). However, these differences disappeared after adjustment for confounders. The associations did not differ consistently between individuals with and without T2DM. Conclusions: We found no independent adverse associations of plasma AGEs with CVD in individuals with normal glucose metabolism, impaired glucose metabolism, and T2DM. 23865591 On-demand hyoscine butylbromide for the treatment of self-reported functional cramping abdominal pain. Abstract Objective. Hyoscine butylbromide (HBB) has been used for 60 years to treat cramping abdominal pain, but scientific evidence to support on-demand use is limited. The aim of this study was to identify a meaningful efficacy end point that differentiates between the effects of HBB (20-100 mg/day) and placebo when used on demand. Materials & methods. 175 patients were treated in a randomized, double-blind, placebo-controlled, two-arm parallel group study. After a 4-week run-in period, patients used HBB to treat 2 distinct episodes of abdominal pain associated with cramping (APC). Patients entered data into an electronic diary for up to 4 h/episode. Pain intensity was assessed using an 11-point numerical pain rating scale (NPRS). Patients were allowed to self-medicate with up to 4 additional doses of HBB every 30 min. Results. The adjusted mean difference for the change from baseline during the 4-h observation period for a reduction in abdominal pain was -0.7 (95% confidence interval (CI) -1.3, -0.1, p = 0.016) for episode 1 and -0.6 (95% CI -1.2, 0.0, p = 0.051) for episode 2. Patients in the HBB group recorded a clinically relevant reduction of at least 2 points on the NPRS (approximately 30% pain relief) earlier than patients in the placebo group (HBB: 45 min, placebo: 60 min). Reported adverse events were infrequent in both groups (10.2% and 10.3%). Conclusions. HBB is effective in the treatment of recurrent APC and is safe and well tolerated when used on demand. The change from baseline in the intensity of APC using the 11-point NPRS distinguished HBB from placebo. 23736518 Deep digital flexor tendon injury within the hoof capsule; does lesion type or location predict prognosis? The type and location of deep digital flexor tendon (DDFT) lesions may be important in predicting outcome. The objectives of this study were to determine the frequency of different types of DDFT lesions within the hoof capsule and to determine whether lesion type predicts return to athletic activity. Lesions of the DDFT were divided into: core lesions, dorsal border lesions and parasagittal splits. Lesion location was documented, and follow-up information was obtained by telephone survey at least 18 months after diagnosis. Of 168 horses with primary DDFT injury, 54 horses had dorsal border lesions, 59 had parasagittal splits and 55 had core lesions. Twenty-five per cent of all horses returned to previous levels of athletic activity within 18 months of MRI evaluation. Horses with complete splits or core lesions of the DDFT were significantly less likely to return to some level of athletic activity than horses with dorsal border lesions P<0.001. Dorsal border lesions of the DDFT appear to have a better prognosis than core lesions or parasagittal splits. This study provides additional information that may help clinicians predict the prognosis for different types of DDFT injury. 23918561 Reduced Food Intake is the Major Contributor to the Protective Effect of Rimonabant on Islet in Established Obesity-Associated Type 2 Diabetes. Purpose: Although the presence of cannabinoid type 1 (CB1) receptor in islets has been reported, the major contributor to the protective effect of rimonabant on islet morphology is unknown. We determined whether the protective effect of rimonabant on pancreatic islet morphology is valid in established diabetes and also whether any effect was independent of decreased food intake. Materials and Methods: After diabetes was confirmed, Otsuka Long-Evans Tokushima Fatty rats, aged 32 weeks, were treated with rimonabant (30 mg/kg/d, rimonabant group) for 6 weeks. Metabolic profiles and islet morphology of rats treated with rimonabant were compared with those of controls without treatment (control group), a pair-fed control group, and rats treated with rosiglitazone (4 mg/kg/d, rosiglitazone group). Results: Compared to the control group, rats treated with rimonabant exhibited reduced glycated albumin levels (p<0.001), islet fibrosis (p<0.01), and improved glucose tolerance (p< 0.05), with no differences from the pair-fed control group. The retroperitoneal adipose tissue mass was lower in the rimonabant group than those of the pair-fed control and rosiglitazone groups (p<0.05). Rimonabant, pair-fed control, and rosiglitazone groups showed decreased insulin resistance and increased adiponectin, with no differences between the rimonabant and pair-fed control groups. Conclusion: Rimonabant had a protective effect on islet morphology in vivo even in established diabetes. However, the protective effect was also reproduced by pair-feeding. Thus, the results of this study did not support the significance of islet CB1 receptors in islet protection with rimonabant in established obesity-associated type 2 diabetes. 23146132 Ethnic differences in intraocular pressure reduction and changes in anterior segment biometric parameters following cataract surgery by phacoemulsification. To determine the association between ethnicity and changes in intraocular pressure and anterior segment biometric parameters following cataract surgery by phacoemulsification in nonglaucomatous subjects. Prospective clinical cohort study. Caucasian and Asian subjects. Customized software was used to calculate parameters from anterior segment optical coherence tomography images obtained preoperatively and at 3 months following cataract surgery by phacoemulsification. The percentage changes in intraocular pressure and anterior segment biometric parameters following cataract surgery by phacoemulsification were modelled as a function of ethnicity using linear mixed-effects regression, a likelihood ratio test function that adjusted for age, sex and the use of both eyes in the same subject, to determine the association between ethnicity and postoperative outcomes. Intraocular pressure, angle opening distance, anterior chamber depth, anterior chamber volume, and angle recess area. Fifty Asian and 23 Caucasian nonglaucomatous eyes were analysed. Postoperative decrease in intraocular pressure and increases in angle opening distance, anterior chamber depth, anterior chamber volume and angle recess area were observed within each ethnic group (P < 0.005). The percent changes in intraocular pressure, angle opening distance, anterior chamber depth, anterior chamber volume and angle recess area did not differ between ethnic groups (P > 0.05). In this study, regardless of ethnic classification, subjects who received cataract surgery by phacoemulsification experienced a significant postoperative decrease in intraocular pressure and increases in angle opening distance, anterior chamber depth, anterior chamber volume and angle recess area. The percent changes in postoperative outcomes did not differ significantly by ethnicity. 23835062 Instrumental and socioemotional communications in doctor-patient interactions in urban and rural clinics. Location of practice, such as working in a rural or urban clinic, may influence how physicians communicate with their patients. This exploratory pilot study examines the communication styles used during doctor-patient interactions in urban and rural family practice settings in Western Canada. We analyzed observation and interview data from four physicians practicing in these different locations. Using a grounded theory approach, communications were categorized as either instrumental or socioemotional. Instrumental communication refers to "cure-oriented interactions" and tends to be more task-oriented focusing on the patient's health concerns and reason for the appointment. In contrast, socioemotional communication refers to more "care-oriented interactions" that may make the patient feel comfortable, relieve patient anxiety and build a trusting relationship. The physicians in small, rural towns appear to know their patients and their families on a more personal level and outside of their office, and engage in more socioemotional communications compared to those practicing in suburban clinics in a large urban centre. Knowing patients outside the clinic seems to change the nature of the doctor-patient interaction, and, in turn, the doctor-patient relationship itself. Interactions between urban doctors and their patients had a mixture of instrumental and socioemotional communications, while interactions between rural doctors and their patients tended to be highly interpersonal, often involving considerable socioemotional communication and relationship-building. Despite the different ways that doctors and patients communicate with each other in the two settings, rural and urban doctors spend approximately the same amount of time with their patients. Thus, greater use of socioemotional communication by rural doctors, which may ease patient anxiety and increase patient trust, did not appear to add extra time to the patient visit. Research suggests that socioemotional communication may ultimately lead to better patient outcomes, which implies that health differences between rural and urban settings could be linked to differences in doctor-patient communication styles. 23587785 Frequency of alcohol use in adolescence as a marker for subsequent sexual risk behavior in adulthood. Although a number of studies have demonstrated an association between alcohol use frequency and sexual risk behavior, few have used longitudinal data. This study examined alcohol use frequency in adolescence as a predictor of HIV sexual risk behavior in adulthood. We collected data among 1,368 participants in Colorado. During adolescence (time 1), respondents were asked about the frequency of using alcohol during the previous 12 months. In adulthood (time 2), the same respondents were asked about their sexual risk behavior during the previous 12 months. Sexual risk behavior items were used to construct an index, which was categorized to indicate low-, medium-, and high-risk study participants. The relationship between alcohol use patterns and risky sexual behavior was modeled using ordinal regression. Compared with individuals who drank no alcohol in the past 12 months at time 1, the odds of being in a higher risk group of sexual behavior as opposed to a lower one at time 2 were 1.56 (95% CI, 1.04-2.35) among those who drank 6-19 times. Similarly, the odds of being in a higher risk group relative to a lower one among those who drank ≥20 times or were 1.78 (95% CI, 1.05-3.02). Alcohol use patterns in adolescence may be useful markers for programs that aim to prevent risky sexual behavior. Based on alcohol intake patterns, it may be possible to identify frequent alcohol users that need to be targeted with appropriate alcohol use and HIV risk reduction messages. 22575576 The effects of temperature and salinity on 17-α-ethynylestradiol uptake and its relationship to oxygen consumption in the model euryhaline teleost (Fundulus heteroclitus). The synthetic estrogen 17-α-ethynylestradiol (EE2), a component of birth control and hormone replacement therapy, is discharged into the environment via wastewater treatment plant (WWTP) effluents. The present study employed radiolabeled EE2 to examine impacts of temperature and salinity on EE2 uptake in male killifish (Fundulus heteroclitus). Fish were exposed to a nominal concentration of 100ng/L EE2 for 2h. The rate of EE2 uptake was constant over the 2h period. Oxygen consumption rates (MO(2)), whole body uptake rates, and tissue-specific EE2 distribution were determined. In killifish acclimated to 18°C at 16ppt (50% sea water), MO(2) and EE2 uptake were both lower after 24h exposure to 10°C and 4°C, and increased after 24h exposure to 26°C. Transfer to fresh water (FW) for 24h lowered EE2 uptake rate, and long-term acclimation to fresh water reduced it by 70%. Both long-term acclimation to 100% sea water (32ppt) and a 24h transfer to 100% sea water also reduced EE2 uptake rate by 50% relative to 16ppt. Tissue-specific accumulation of EE2 was highest (40-60% of the total) in the liver plus gall bladder across all exposures, and the vast majority of this was in the bile at 2h, regardless of temperature or salinity. The carcass was the next highest accumulator (30-40%), followed by the gut (10-20%) with only small amounts in gill and spleen. Killifish chronically exposed (15 days) to 100ng/L EE2 displayed no difference in EE2 uptake rate or tissue-specific distribution. Drinking rate, measured with radiolabeled polyethylene glycol-4000, was about 25 times greater in 16ppt-acclimated killifish relative to FW-acclimated animals. However, drinking accounted for less than 30% of gut accumulation, and therefore a negligible percentage of whole body EE2 uptake rates. In general, there were strong positive relationships between EE2 uptake rates and MO(2), suggesting similar uptake pathways of these lipophilic molecules across the gills. These data will be useful in developing a predictive model of how key environmental parameter variations (salinity, temperature, dissolved oxygen) affect EE2 uptake in estuarine fish, to determine optimal timing and location of WWTP discharges. 23470650 Sample collection and platelet function testing: influence of vacuum or aspiration principle on PFA-100 test results. As for other tests of hemostasis, the investigation of platelet function is highly vulnerable to a broad series of preanalytical variables, which span from patient preparation to the final analysis of the specimen and issuance of test results. In particular, there remains much controversy about the influence of manual or vacuum aspiration of blood into primary collection tubes on platelet function testing. Accordingly, we investigated this for the PFA-100. In 12 healthy volunteers, a sample labeled as 'BD-V' was drawn into a 2.7 ml BD Vacutainer tube, whereas two additional samples were collected from the opposite arm into 5.0 ml Sarstedt S-Monovette tubes by vacuum (SD-V) or manual aspiration (SD-A). All sample were tested on PFA-100 with collagen and ADP (CADP) or collagen and epinephrine (CEPI). The values of both CEPI and CADP obtained in SD-A samples were significantly lower than those obtained in SD-V and BD-V tubes, whereas those of the two evacuated tubes did not significantly differ. On average, CEPI values were prolonged by 11% in SD-V and 13% in BD-V, whereas those of CADP were prolonged by 14% in SD-V and 10% in BD-V, respectively. These findings suggests that the lower shear stress generated by the manual aspiration of blood into the primary collection tube would prevent spurious hyper-activation of platelets, thus, preserving the integrity of their function for subsequent testing on PFA-100. This study underscores the need to define or validate local reference ranges for the PFA-100 based on the collection tube used. Different reference ranges of both CEPI and CADP may also be advisable when venous blood samples are collected with manual aspiration or vacuum principle. 23701282 Forearm-finger skin temperature gradient as an index of cutaneous perfusion during steady-state exercise. The purpose of this study was to examine whether the forearm-finger skin temperature gradient (Tforearm-finger ), an index of vasomotor tone during resting conditions, can also be used during steady-state exercise. Twelve healthy men performed three cycling trials at an intensity of ~60% of their maximal oxygen uptake for 75 min separated by at least 48 h. During exercise, forearm skin blood flow (BFF ) was measured with a laser-Doppler flowmeter, and finger skin blood flow (PPG) was recorded from the left index fingertip using a pulse plethysmogram. Tforearm-finger of the left arm was calculated from the values derived by two thermistors placed on the radial side of the forearm and on the tip of the middle finger. During exercise, PPG and BFF increased (P<0·001), and Tforearm-finger decreased (P<0·001) from their resting values, indicating a peripheral vasodilatation. There was a significant correlation between Tforearm-finger and both PPG (r = -0·68; P<0·001) and BFF (r = -0·50; P<0·001). It is concluded that Tforearm-finger is a valid qualitative index of cutaneous vasomotor tone during steady-state exercise. 23933967 Multispectral imaging in the extended near-infrared window based on endogenous chromophores. ABSTRACT. To minimize the problem with scattering in deep tissues while increasing the penetration depth, we explored the feasibility of imaging in the relatively unexplored extended near infrared (exNIR) spectral region at 900 to 1400 nm with endogenous chromophores. This region, also known as the second NIR window, is weakly dominated by absorption from water and lipids and is free from other endogenous chromophores with virtually no autofluorescence. To demonstrate the applicability of the exNIR for bioimaging, we analyzed the optical properties of individual components and biological tissues using an InGaAs spectrophotometer and a multispectral InGaAs scanning imager featuring transmission geometry. Based on the differences in spectral properties of tissues, we utilized ratiometric approaches to extract spectral characteristics from the acquired three-dimensional "datacube". The obtained images of an exNIR transmission through a mouse head revealed sufficient details consistent with anatomical structures. 23274766 Bile acids in the colon, from healthy to cytotoxic molecules. Bile acids are natural detergents mainly involved in facilitating the absorption of dietary fat in the intestine. In addition to this absorptive function, bile acids are also essential in the maintenance of the intestinal epithelium homeostasis. To accomplish this regulatory function, bile acids may induce programmed cell death fostering the renewal of the epithelium. Here we first discuss on the different molecular pathways of cell death focusing on apoptosis in colon epithelial cells. Bile acids may induce apoptosis in colonocytes through different mechanisms. In contrast to hepatocytes, the extrinsic apoptotic pathway seems to have a low relevance regarding bile acid cytotoxicity in the colon. On the contrary, these molecules mainly trigger apoptosis through direct or indirect mitochondrial perturbations, where oxidative stress plays a key role. In addition, bile acids may also act as regulatory molecules involved in different cell signaling pathways in colon cells. On the other hand, there is increasing evidence that the continuous exposure to certain hydrophobic bile acids, due to a fat-rich diet or pathological conditions, may induce oxidative DNA damage that, in turn, may lead to colorectal carcinogenesis as a consequence of the appearance of cell populations resistant to bile acid-induced apoptosis. Finally, some bile acids, such as UDCA, or low concentrations of hydrophobic bile acids, can protect colon cells against apoptosis induced by high concentrations of cytotoxic bile acids, suggesting a dual behavior of these agents as pro-death or pro-survival molecules. 23948565 Spectroscopic investigations on the orientation of 1,4-dibromonaphthalene on silver nanoparticles. Silver nanoparticles (Ag NPs) have been prepared by solution combustion method with glycine as fuel. Silver nanoparticles were characterized by X-Ray Diffraction (XRD), High Resolution Transmission Electron Microscopy (HRTEM) and UV-visible spectroscopy. The prepared silver nanoparticles exhibit cubic crystalline structure with grain size of 59nm. HRTEM image shows that the silver nanoparticles have strain and four-fold symmetry formed by twinning in the crystal structure. The optical adsorption spectrum shows that the surface plasmon resonance peak of silver is observed at 380nm. The orientation of 1,4-dibromonaphthlaene (1,4-DBrN) on silver nanoparticles has been inferred from nRs and SERS spectral features. The absence of a C-H stretching vibrations, the observed high intense C-H out-of-plane bending modes and high intense C-Br stretching vibration suggest that the 1,4-DBrN molecule may be adsorbed in a 'stand-on' orientation to the surface. 23692678 Influence of visible-light irradiation on physicochemical and photocatalytic properties of nitrogen-doped three-dimensional (3D) titanium dioxide. We report highly active visible-light driven nitrogen-doped three-dimensional polycrystalline anatase TiO2 photocatalysts (N-3D TiO2) for environmental and biomedical applications. N-3D TiO2 is synthesized at a low temperature (<90°C) without thermal treatment via a modified hydrothermal process (HP) and ultrasound irradiation (UI). The N-3D TiO2 is additionally irradiated with visible-light to improve the hydroxylation of its surface. Under visible-light irradiation, the photocatalytic activity of visible-light irradiated N-3D TiO2 (*N-3D TiO2; [k]=1.435 h(-1)) is 26.1 times higher than that of 3D TiO2 ([k]=0.055 h(-1)). The *N-3D TiO2 is highly recyclable and retained 91.8% of the initial decolorization rate after fifteen cycles. Interestingly, the *N-3D TiO2 shows very strong antibacterial properties against both Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus) after exposure to visible-light for 3h. The antibacterial properties of *N-3D TiO2 are more effective than those of TiO2, 3D TiO2, and N-3D TiO2. More than 91.3% of the E. coli is sterilized after ten cycles. There are a large increase in the photocatalytic and antibacterial activity of *N-3D TiO2 relative to that of N-3D TiO2 owing to the hydroxylation of the N-3D TiO2 surface as a result of the visible-light irradiation. These results indicate that *N-3D TiO2 might have utility in several promising applications such as highly efficient water/air treatment, inactivation of pathogenic microorganisms, and solar-energy conversion. 23747092 The development of a new methodology for knowledge sharing in the interface between university and society - An example from the meat sector. Design science research was used for the generation, use and evaluation of a model for knowledge sharing in the user community through open educational resources (OER). The focus of interest was on the development process of a model for knowledge sharing that emphasizes the characteristics and the needs of the user community; the empowerment and democratic issues of openness; the collaboration between institutions and dialog with society; and the consideration of quality and sustainability issues. Initially, the community needs were analyzed through surveys and workshops, and the findings used, through negotiations, to formulate the development process. An open-training platform served as an infrastructure and included a repository with OER, a wiki and a discussion forum. The purpose of this article is an attempt to provide universities with a plan and template for integrated knowledge sharing that responds to societal needs. Usability and usefulness has not been evaluated. 23578656 Impact of the Mediterranean fruit fly (Medfly) Ceratitis capitata on different peach cultivars: The possible role of peach volatile compounds. The relationship between susceptibility of different peach cultivars (cvs) to the Mediterranean fruit fly (medfly), Ceratitis capitata, and the volatile composition of ripe fruit of each cv has been investigated, since understanding the fruit-insect interaction mechanism is crucial for developing control strategies for such a pest. Volatile compounds were analyzed by SPME-GC-MS in three cvs highly susceptible to medfly attack (Fair Time, Flaminia, Sicilia Piatta), and in two less susceptible cvs (Percoca Romagnola 7 and Doctor Davis). Among the volatile compounds detected, 88 could be identified. The main differences found in the volatile composition of the cvs, concerned the relative abundance of esters. The least susceptible cvs, above all Percoca Romagnola 7, contained the higher amounts of hexenyl, hexyl, 3-methylbutyl, butyl and 2-methylpropyl esters; among these, some C6 derivatives detected, such as (Z)-3-hexenyl acetate, are known to act as priming agents, enhancing plant defence response to insects. Instead, a lower relative content of methyl esters, such as methyl hexanoate and methyl octanoate, known to act as medfly pheromone and attractant respectively, was found in the least susceptible cvs. 23813399 Taking evidence-based plastic surgery to the next level: report of the second Summit on Evidence-based Plastic Surgery. Applying the principles of evidence-based medicine has the potential to drastically improve quality of care and patient outcomes. For this reason, evidence-based medicine has been held as one of the 15 most important developments in medicine within the past 100 years. In August of 2010, a broad coalition of leaders from numerous organizations representing societies, boards, journals, foundations, and academic institutions met in Colorado Springs, Colorado, for the first Evidence-Based Plastic Surgery Summit. The summit signaled a sea change in the approach of organized plastic surgery to the promotion of evidence-based medicine within the specialty. It was determined that a strategic, coordinated, and sustained effort to drive an evidence-based medicine culture would accelerate adoption and advance quality of care and patient safety. Over the past 2 years, many of the goals of the initial summit have been met. In order to take our evidence-based medicine efforts to the next level, a second summit was recently held to redefine goals, focus efforts, address barriers, and launch new initiatives with broad consensus. This article documents the outcomes of the second Evidence-Based Plastic Surgery Summit. 22807465 ER, PR, and Her2 immunocytochemistry on cell-transferred cytologic smears of primary and metastatic breast carcinomas: a comparison study with formalin-fixed cell blocks and surgical biopsies. The use of formalin-fixed cell blocks (CBs) for detection of ER, PR, and Her2 status of primary and metastatic breast carcinomas sampled by fine-needle aspiration (FNA) has been extensively used in clinical practice; however, CBs sometimes lack adequate cellularity even when direct smears are cellular. The aim of this study is to assess the reliability of ER, PR, and Her2 status as demonstrated by immunocytochemical staining (ICC) on alcohol-fixed direct smears using the cell transfer (CT) technique. FNA cases diagnosed as primary or metastatic breast carcinoma in which the status of ER, PR, and Her2 had been determined either on CB or concurrent biopsy were identified over a period of 18 months. ICC for ER, PR, and Her2 was performed on alcohol-fixed direct smears using the CT technique. Results were compared with those reported for the corresponding formalin-fixed tissue. A total of 47 FNA specimens from 46 patients were included in this study. ICC results were excluded from analysis if the CT smear contained fewer than 50 cells. Correlation between the ICC performed on the CT smears and the corresponding CB or biopsy revealed a sensitivity rate for ER, PR, and Her2 of 95%, 90%, and 88%, respectively with a specificity of 100% for all three markers. ICC performed on the FNA smears using the CT technique is a reliable method for assessment of the ER, PR, and Her2 status of breast carcinomas, especially when the direct smears are highly cellular and the CB lacks adequate cellularity. 23824960 Central administration of metformin into the third ventricle of C57BL/6 mice decreases meal size and number and activates hypothalamic S6 kinase. Administration of metformin is known to reduce both body weight and food intake. While the hypothalamus is recognized as a critical regulator of energy balance and body weight, there is currently no evidence for an effect of metformin in the hypothalamus. Therefore, we sought to determine the central action of metformin on energy balance and body weight as well as its potential involvement with key hypothalamic energy sensors, including AMP-activated protein kinase (AMPK) and S6 kinase (S6K). We used meal pattern analysis and a conditioned taste aversion (CTA) test, and measured energy expenditure in C56BL/6 mice administered metformin (0, 7.5, 15, or 30 μg) into the third ventricle (I3V). Furthermore, we I3V-administered either control or metformin (30 μg) and compared the phosphorylation of AMPK and S6K in the mouse mediobasal hypothalamus. Compared to the control, I3V administration of metformin decreased body weight and food intake in a dose-dependent manner and did not result in CTA. Furthermore, the reduction in food intake induced by I3V administration of metformin was accomplished by decreases in both nocturnal meal size and number. Compared to the control, I3V administration of metformin significantly increased phosphorylation of S6K at Thr(389) and AMPK at Ser(485/491) in the mediobasal hypothalamus, while AMPK phosphorylation at Thr(172) was not significantly altered. Moreover, I3V rapamycin pretreatment restored the metformin-induced anorexia and weight loss. These results suggest that the reduction in food intake induced by the central administration of metformin in the mice may be mediated by activation of S6K pathway. 23902748 Homologous Recombination Drives both Sequence Diversity and Gene Content Variation in Neisseria meningitidis. The study of genetic and phenotypic variation is fundamental for understanding the dynamics of bacterial genome evolution and untangling the evolution and epidemiology of bacterial pathogens. Neisseria meningitidis (Nm) is among the most intriguing bacterial pathogens in genomic studies due to its dynamic population structure and complex forms of pathogenicity. Extensive genomic variation within identical clonal complexes in Nm has been recently reported and suggested to be the result of homologous recombination, but the extent to which recombination contributes to genomic variation within identical clonal complexes has remained unclear. In this study, we sequenced two Nm strains of identical serogroup (C) and multi-locus sequence type (ST60), and conducted a systematic analysis with an additional 34 Nm genomes. Our results revealed that all gene content variation between the two ST60 genomes was introduced by homologous recombination at the conserved flanking genes, and 94.25% or more of sequence divergence was caused by homologous recombination. Recombination was found in genes associated with virulence factors, antigenic outer membrane proteins, and vaccine targets, suggesting an important role of homologous recombination in rapidly altering the pathogenicity and antigenicity of Nm. Recombination was also evident in genes of the restriction and modification systems, which may undermine barriers to DNA exchange. In conclusion, homologous recombination can drive both gene content variation and sequence divergence in Nm. These findings shed new light on the understanding of the rapid pathoadaptive evolution of Nm and other recombinogenic bacterial pathogens. 23407434 Achieving more frequent and longer dialysis for the majority: wearable dialysis and implantable artificial kidney devices. The long-term survival for many chronic kidney failure patients who remain treated by dialysis in economically advanced countries remains similar to that of those with solid-organ malignancy, despite a disproportionate amount of health-care expenditure. As such, the current paradigm of three times weekly in-center hemodialysis for 4 h or shorter sessions needs to change to improve patient outcomes. Although more frequent and longer dialysis sessions have been reported to improve cardiovascular risk surrogates and short-term outcomes, these options are only practically available to a very small fraction of the total dialysis population. As such, radically new approaches are required to improve patient outcomes and quality of life for the majority of dialysis patients. Currently, two different approaches are being developed, wearable devices based on current dialysis techniques and more futuristic implantable devices modeled on the natural nephron. 23791401 Radiosynthesis and biological evaluation of 5-(3-[(18)F]Fluoropropyloxy)-L-tryptophan for tumor PET imaging. [(18)F]FDG PET has difficulty distinguishing tumor from inflammation in the clinic because of the same high uptake in nonmalignant and inflammatory tissue. In contrast, amino acid tracers do not accumulate in inflamed tissues and thus provide an excellent opportunity for their use in clinical cancer imaging. In this study, we developed a new amino acid tracer 5-(3-[(18)F]Fluoropropyloxy)-L-tryptophan ([(18)F]-L-FPTP) by two-step reactions and performed its biologic evaluation. [(18)F]-L-FPTP was prepared by [(18)F]fluoropropylation of 5-hydroxy-L-tryptophan disodium salt and purification on C18 cartridges. The biodistribution of [(18)F]-L-FPTP was determined in normal mice and the incorporation of [(18)F]-L-FPTP into tissue proteins was investigated. In vitro competitive inhibition experiments were performed with Hepa1-6 hepatoma cell lines. [(18)F]-L-FPTP PET imaging was performed on tumor-bearing and inflammation mice and compared with [(18)F]-L-FEHTP PET. The overall uncorrected radiochemical yield of [(18)F]-L-FPTP was 21.1±4.4% with a synthesis time of 60min, the radiochemical purity was more than 99%. Biodistribution studies demonstrate high uptake of [(18)F]-L-FPTP in liver, kidney, pancreas, and blood at the early phase, and fast clearance in most tissues over the whole observed time. The uptake studies in Hepa1-6 cells suggest that [(18)F]-L-FPTP is transported by the amino acid transport system B(0,+), LAT2 and ASC. [(18)F]-L-FPTP displays good stability and is not incorporated into proteins in vitro. PET imaging shows that [(18)F]-L-FPTP can be a better potential PET tracer for differentiating tumor from inflammation than [(18)F]FDG and 5-(3-[(18)F]fluoroethyloxy)-L-tryptophan ([(18)F]-L-FEHTP), with high [(18)F]-L-FPTP uptake ratio (2.53) of tumor to inflammation at 60min postinjection. Using [(18)F]fluoropropyl derivatives as intermediates, the new tracer [(18)F]-L-FPTP was achieved with good yield and radiochemical purity, and the biological evaluation results of [(18)F]-L-FPTP showed that it was a hopeful tracer for PET tumor imaging. 23263197 Poor health, employment transitions and gender: evidence from the British Household Panel Survey. We examined health selection in the context of transitions across employment statuses (employment, unemployment and inactivity), with attention to gender differences. 60,536 transitions from 7,901 individuals were pooled from 17 waves of the British Household Panel Survey. Associations between self-rated health and transitions across employment statuses were examined using multilevel multinomial analysis. Health selective employment transitions between year t-1 and t were observed at entry to as well as exit from employment. Associations for poor health with the transitions were similar for men and women in transitions from employment to both unemployment and to inactivity, but with some differences in other transitions. When leaving employment, transitions from employment to unemployment (ORadjusted(adjusted odds ratio) = 1.51, 95 % CI = 1.21-1.89 for men and ORadjusted = 1.60, 95 % CI = 1.25-2.04 for women) and to inactivity (ORadjusted = 1.58, 95 % CI = 1.21-1.89 for men and ORadjusted = 1.63, 95 % CI = 1.35-1.96 for women) were affected by health status among both men and women. Similarly, poor health lowered the probability of transitions to employment from unemployment and inactivity; however, the negative impact of poor health was statistically significant only for women. There is a strong relationship between health and transitions both into and out of employment suggesting an independent role for poor health, and these associations were similar for men and women. 23898368 Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests. To analyze the validity of applied test criteria and causality assessment methods in assumed Herbalife hepatotoxicity with positive reexposure tests. We searched the Medline database for suspected cases of Herbalife hepatotoxicity and retrieved 53 cases including eight cases with a positive unintentional reexposure and a high causality level for Herbalife. First, analysis of these eight cases focused on the data quality of the positive reexposure cases, requiring a baseline value of alanine aminotransferase (ALT) < 5 upper limit of normal (N) before reexposure, with N as the upper limit of normal, and a doubling of the ALT value at reexposure as compared to the ALT value at baseline prior to reexposure. Second, reported methods to assess causality in the eight cases were evaluated, and then the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale validated for hepatotoxicity cases was used for quantitative causality reevaluation. This scale consists of various specific elements with scores provided through the respective case data, and the sum of the scores yields a causality grading for each individual case of initially suspected hepatotoxicity. Details of positive reexposure test conditions and their individual results were scattered in virtually all cases, since reexposures were unintentional and allowed only retrospective rather than prospective assessments. In 1/8 cases, criteria for a positive reexposure were fulfilled, whereas in the remaining cases the reexposure test was classified as negative (n = 1), or the data were considered as uninterpretable due to missing information to comply adequately with the criteria (n = 6). In virtually all assessed cases, liver unspecific causality assessment methods were applied rather than a liver specific method such as the CIOMS scale. Using this scale, causality gradings for Herbalife in these eight cases were probable (n = 1), unlikely (n = 4), and excluded (n = 3). Confounding variables included low data quality, alternative diagnoses, poor exclusion of important other causes, and comedication by drugs and herbs in 6/8 cases. More specifically, problems were evident in some cases regarding temporal association, daily doses, exact start and end dates of product use, actual data of laboratory parameters such as ALT, and exact dechallenge characteristics. Shortcomings included scattered exclusion of hepatitis A-C, cytomegalovirus and Epstein Barr virus infection with only globally presented or lacking parameters. Hepatitis E virus infection was considered in one single patient and found positive, infections by herpes simplex virus and varicella zoster virus were excluded in none. Only one case fulfilled positive reexposure test criteria in initially assumed Herbalife hepatotoxicity, with lower CIOMS based causality gradings for the other cases than hitherto proposed. 23933542 The 9p21 locus does not affect risk of coronary artery disease through induction of type 1 interferons. To determine if the coronary artery disease (CAD) associated genotype at chromosome 9p21 modulates basal or induced expression of type I interferons. The mechanism responsible for the association between common variants in chromosome 9p21.3 and CAD remains unclear. It has been reported that the CAD risk locus is rich in enhancer-like elements, and that chromosome looping can lead to its physical proximity with the type-I interferon (IFN) gene cluster, raising the possibility that the locus influences CAD risk by modulating expression of type-I IFNs. We therefore examined if genotype at the lead CAD-associated SNP (rs1333049) in 9p21 was associated with: (i) basal levels of type-I IFN in plasma from 148 healthy male subjects, (ii) induction of type-I IFN by Toll-like receptor stimulants in peripheral blood mononuclear cells of 60 healthy volunteers assessed by ELISA, qPCR, Western blot and type-I IFN bioassay and (iii) enhancer activity of predicted interferon regulatory factor (IRF)-3/7 binding sites within the 9p21 CAD risk region in reporter assays. No significant effects of 9p21 genotype were observed for plasma levels of IFN-α, IFN-α21, or CXCL10, or leukocyte induction of IFN-α, IFN-α21, IFN-β, CXCL10 or total type-I IFN measured at the mRNA, protein and biological activity levels. There was also no enhancement of reporter activity by predicted IRF-3/7 binding sites in the CAD risk locus of either genotype. The mechanism underlying the association between common 9p21 variants and CAD does not involve differential regulation of type-I interferon responses. 23965993 Recruitment of the Mint3 Adaptor is Necessary for Export of the Amyloid Precursor Protein (APP) from the Golgi Complex. The amyloid precursor protein (APP) is a ubiquitously expressed, single-pass transmembrane protein that undergoes proteolytic processing by secretases to generate the pathogenic Aβ peptide, the major component in Alzheimer's plaques. The traffic of APP through the cell determines its exposure to secretases, and consequently the cleavages that generate the pathogenic or non-pathogenic peptide fragments. Despite the likely importance of APP traffic to Alzheimer's disease we still lack clear models for the routing and regulation of APP in cells. Like traffic of most transmembrane proteins, the binding of adaptors to its cytoplasmic tail, which is 47 residues long and contains at least four distinct sorting motifs, regulates that of APP. We tested each of these for effects on the traffic of APP from the Golgi by mutating key residues within them and examining adaptor recruitment at the Golgi and traffic to post-Golgi site(s). We demonstrate strict specificity for recruitment of the Mint3 adaptor by APP at the Golgi, a critical role for Y682 (within the YENPTY motif) in Mint3 recruitment and export of APP from the Golgi, and identify LAMP1+ structures as the proximal destination of APP after leaving the Golgi. Together, these data provide a detailed view of the first sorting step in its route to the cell surface and processing by secretases and further highlight the critical role played by Mint3. _______ 23896548 Resection or multi-lobe disconnection for intractable epilepsy with open-lip schizencephaly. The surgical treatment of medication-resistant epilepsy with schizencephaly is difficult. A standardized method of surgical treatment for schizencephalic patients has not yet been established. We present two patients with poorly controlled epilepsy with schizencephaly. The first patient underwent a resection of the right temporal lobe and part of the posterior lip of the schizencephaly, while the other patient underwent a multi-lobe disconnection. Based on the study of these two patients, we conclude that the location of the epileptic zone, reorganization of eloquent areas and anatomical characteristics of the schizencephaly do not allow a universal surgical approach for treating epilepsy with schizencephaly. Every patient has individual characteristics. 23913200 Mirabegron for Male Lower Urinary Tract Symptoms. Benign prostatic hyperplasia (BPH) is a common cause of lower urinary tract symptoms (LUTS) in men. Patients with BPH often present with a combination of obstructive and overactive bladder (OAB) symptoms. It is postulated that bladder outlet obstruction (BOO) from BPH results in concomitant OAB symptoms through ischemic induced variations in the response to neurotransmitters of both the detrusor and the urothelium. This altered response leads to the pathologic activation of the micturition reflex, generating sensory dysfunction and involuntary bladder contractions. Alpha-1 adrenoceptor antagonists (alpha-blockers) and 5-alpha reductase inhibitors (5-ARIs) are commonly used to treat the BOO caused by BPH. Anticholinergic agents are frequently used to treat concurrently OAB symptoms caused by the BOO. Unfortunately, anticholinergic medications demonstrate bothersome side effects and a theoretical risk of urinary retention. Basic science and clinical research has led to the development of a new class of pharmaceuticals for the treatment of overactive bladder with diminished risk of urinary retention and lacking many anticholinergic side effects. This novel compound, mirabegron (Mybertriq, Astellas Pharma US, Inc.), is a β3-adrenoceptor agonist and represents a promising new class of oral agents designed for the treatment of OAB symptoms, with minimal effect on voiding. 23863223 Influence of ICU Case-Volume on the Management and Hospital Outcomes of Acute Exacerbations of Chronic Obstructive Pulmonary Disease* To study the relationship between case-volume and the use of noninvasive ventilation during acute exacerbations of chronic obstructive pulmonary disease in ICUs. A 13-year multicenter retrospective cohort study of prospectively collected data. Medical ICUs. From 1998 to 2010, patients with acute exacerbations of chronic obstructive pulmonary disease were identified through a regional database. The characteristics of hospitalization (including the type of mechanical ventilation) and demographic data of the patients were analyzed. ICUs were categorized into tertiles of the running mean annual volume of admissions. A logistic model performed a conditional multivariate analysis of prognostic factors after matching on a propensity score of being admitted to a high-volume unit and on the year of admission. Fourteen thousand four hundred forty acute exacerbations of chronic obstructive pulmonary disease were identified. The Simplified Acute Physiology Score II and ICU mortality increased during the study period (36 to 41 and 12% to 14%, respectively). The proportion of patients receiving any mechanical ventilation support also increased during the study period (from 64% to 86%), with a marked increase in the use of noninvasive ventilation (from 18% to 49%) and a decrease in the use of invasive ventilation (from 34% to 19%). Participating units were distributed into low-volume (< 25 patients per year), medium-volume (26-47 patients per year), and high-volume (> 47 patients per year) tertiles. There was a significant association between case-volume and 1) the proportion of patients receiving noninvasive ventilation (highest vs lowest case-volume tertiles: odds ratio, 1.43 [95% CI, 1.23-1.66]) and 2) lower mortality. Between 1998 and 2010, severity and mortality of acute exacerbations of chronic obstructive pulmonary disease admitted to Collège des Utilisateurs de Données en Réanimation ICUs increased. There was an increasing use of noninvasive ventilation and a decreasing use of invasive ventilation. Use of noninvasive ventilation was related to case-volume, suggesting that increasing experience favors the use of noninvasive ventilation and was associated with a strong trend toward decreased mortality. 23231832 The course of subjective sleep quality in middle and old adulthood and its relation to physical health. Objectives. Older adults more often complain about sleep disturbances compared with younger adults. However, it is not clear whether there is still a decline of sleep quality after age 60 and whether changes in sleep quality in old age are mere reflections of impaired physical health or whether they represent a normative age-dependent development. Method. Subjective sleep quality and perceived physical health were assessed in a large sample of 14,179 participants (52.7% women; age range 18-85) from the German Socio-Economic Panel Study across four yearly measurement time points. Subjective sleep quality linearly declined from young adulthood until age 60. After age 60, a transient increase in subjective sleep quality occurred that coincides with retirement. After age 66, subjective sleep quality appears to decrease again. Physical health prospectively predicted subjective sleep quality and vice versa. These relations were similar for participants aged over and under 60. Discussion. Around retirement, a transient increase in subjective sleep quality appears to occur, which might reflect a decrease in work-related distress. Perceived physical health appears to be important for subjective sleep quality in old adults but not more important than at younger age. 23276728 Potential antipsoriatic effect of chondroitin sulfate through inhibition of NF-κB and STAT3 in human keratinocytes. Chondroitin sulfate (CS) is a natural glycosaminoglycan, formed by the 1-3 linkage of d-glucuronic acid to N-acetylgalactosamine, present in the extracellular matrix. It is used as a slow acting disease modifying agent in the treatment of osteoarthritis, and part of its beneficial effects are due to its antiinflammatory properties that result from an inhibitory effect on NF-κB signaling pathway. This ability raises the hypothesis that CS might be effective in other chronic inflammatory processes such as psoriasis, in which a deregulation of NF-κB is a key feature. In addition, psoriasis is characterized by an upregulation of STAT3 signaling pathway that is related to the epidermal hyperplasia. In the present study we report the pharmacological modulation of the NF-κB and STAT3 signaling pathways by CS in normal human keratinocytes. CS inhibited NF-κB activation and the release of some of the key psoriatic cytokines such as TNFα, IL-8, IL-6 and CCL27. Moreover, it impaired STAT3 translocation to the nucleus and significantly reduced STAT3 transcriptional activity by a mechanism that was independent from STAT3 phosphorylation. Our results confirm the interest of CS as a candidate for future drug research in the therapeutics of psoriasis given the need of more effective and safer oral medications for these patients. 23845303 MyD88 controls human metapneumovirus-induced pulmonary immune responses and disease pathogenesis. Human metapneumovirus (hMPV) is a common cause of lung and airway infections in infants and young children. Recently, we and others have shown that hMPV infection induces Toll-like receptor (TLR)-dependent cellular signaling. However, the contribution of TLR-mediated signaling in host defenses against pulmonary hMPV infection and associated disease pathogenesis has not been elucidated. In this study, mice deficient in MyD88, a common adaptor of TLRs, was used to investigate the contribution of TLRs to in vivo pulmonary response to hMPV infection. MyD88(-/-) mice have significantly reduced pulmonary inflammation and associated disease compared with wild-type (WT) C57BL/6 mice after intranasal infection with hMPV. hMPV-induced cytokines and chemokines in bronchoalveolar lavage fluid (BALF) and isolated lung conventional dendritic cells (cDC) are also significantly impaired by MyD88 deletion. In addition, we found that MyD88 is required for the recruitment of DC, T cells, and other immune cells to the lungs, and for the functional regulation of DC and T cells in response to hMPV infection. Taken together, our data indicate that MyD88-mediated pathways are essential for the pulmonary immune and pathogenic responses to this viral pathogen. 23932072 Histamine induces proliferation in keratinocytes from patients with atopic dermatitis through the histamine 4 receptor. Epidermal hyperproliferation resulting in acanthosis is an important clinical observation in patients with atopic dermatitis, and its underlying mechanisms are not completely understood. Because increased levels of histamine are present in lesional skin, we investigated the effect of histamine, especially with regard to histamine 4 receptor (H4R) activation, on the proliferation of human and murine keratinocytes. The expression of H4R on human and murine keratinocytes was detected by using real-time PCR. Keratinocyte proliferation was evaluated by using different in vitro cell proliferation assays, scratch assays, and measurement of the epidermal thickness of murine skin. We detected H4R mRNA on foreskin keratinocytes and on outer root sheath keratinocytes; H4R mRNA was more abundant in keratinocytes from patients with atopic dermatitis compared with those from nonatopic donors. Stimulation of foreskin keratinocytes, atopic dermatitis outer root sheath keratinocytes, and H4R-transfected HaCaT cells with histamine and H4R agonist resulted in an increase in proliferation, which was blocked with the H4R-specific antagonist JNJ7777120. Abdominal epidermis of H4R-deficient mice was significantly thinner, and the in vitro proliferation of keratinocytes derived from H4R-deficient mice was lower compared with that seen in control mice. Interestingly, we only detected H4R expression on murine keratinocytes after stimulation with LPS and peptidoglycan. H4R is highly expressed on keratinocytes from patients with atopic dermatitis, and its stimulation induces keratinocyte proliferation. This might represent a mechanism that contributes to the epidermal hyperplasia observed in patients with atopic dermatitis. 23850316 Mitochondrial Regulation in Pluripotent Stem Cells. Due to their fundamental role in energy production, mitochondria have been traditionally known as the powerhouse of the cell. Recent discoveries have suggested crucial roles of mitochondria in the maintenance of pluripotency, differentiation, and reprogramming of induced pluripotent stem cells (iPSCs). While glycolytic energy production is observed at pluripotent states, an increase in mitochondrial oxidative phosphorylation is necessary for cell differentiation. Consequently, a transition from somatic mitochondrial oxidative metabolism to glycolysis seems to be required for successful reprogramming. Future research aiming to dissect the roles of mitochondria in the establishment and homeostasis of pluripotency, as well as combining cell reprogramming with gene editing technologies, may unearth novel insights into our understanding of mitochondrial diseases and aging. 23490434 Inhibition of glycine transporter-1 reduces cue-induced nicotine-seeking, but does not promote extinction of conditioned nicotine cue responding in the rat. Pharmacological stimulation of N-methyl-D-aspartate receptors (NMDAr) could enhance the outcome of cue-exposure therapy for smoking cessation. NMDAr stimulation can be achieved by increasing pharmacologically the synaptic levels of glycine, a necessary co-agonist. Here, we evaluate the effects of SSR504734, a selective inhibitor of glycine type I transporter (GlyT1) in an extinction-reinstatement procedure inducing robust and lasting nicotine-seeking behavior in rats. Male Wistar rats were trained to associate discriminative stimuli (S(D) s) with the availability of nicotine (0.03 mg/kg/65 μL/2 second/infusion) or sucrose (45-mg pellet) versus non-reward in two-lever operant cages. Reinforced response was followed by cue signaling 20-second time-out (CSs). Once the training criterion was met, rats underwent extinction of lever presses, in the absence of reinforcers, S(D) s and CSs. Re-exposure to nicotine or sucrose S(D) (+) /CS(+) , but not non-reward S(D) (-) /CS(-) , revived responding at the previously reinforced lever. Acute pre-treatment with SSR504734 (10 mg/kg i.p.) reduced nicotine-seeking but not sucrose-seeking behavior without influencing rats' locomotor activity. Sub-chronic treatment (10 mg/kg i.p. for 5 days) during daily exposure to S(D) (+) /CS(+) reduced nicotine-seeking; however, this effect was transient, with return to S(D) (+) /CS(+) responding at 72 hours. Full recovery to S(D) (+) /CS(+) responding was observed after 1 month suggesting that SSR504734 sub-acute treatment did not engage the long-term plasticity mechanisms probably involved in nicotine-seeking. In conclusion, GlyT1-inhibitors might offer a therapeutic opportunity for acute cue-controlled nicotine-seeking, but the lack of persistent effects of the sub-chronic treatment associated with nicotine cues exposure suggests that short-term administration of GlyT1-inhibitor SSR504734 is not sufficient to promote extinction of nicotine-cue conditioned responding. 23940641 Topical rosiglitazone is an effective anti-scarring agent in the cornea. Corneal scarring remains a major cause of blindness world-wide, with limited treatment options, all of which have side-effects. Here, we tested the hypothesis that topical application of Rosiglitazone, a Thiazolidinedione and ligand of peroxisome proliferator activated receptor gamma (PPARγ), can effectively block scar formation in a cat model of corneal damage. Adult cats underwent bilateral epithelial debridement followed by excimer laser ablation of the central corneal stroma to a depth of ∼160 µm as a means of experimentally inducing a reproducible wound. Eyes were then left untreated, or received 50 µl of either 10 µM Rosiglitazone in DMSO/Celluvisc, DMSO/Celluvisc vehicle or Celluvisc vehicle twice daily for 2 weeks. Cellular aspects of corneal wound healing were evaluated with in vivo confocal imaging and post-mortem immunohistochemistry for alpha smooth muscle actin (αSMA). Impacts of the wound and treatments on optical quality were assessed using wavefront sensing and optical coherence tomography at 2, 4, 8 and 12 weeks post-operatively. In parallel, cat corneal fibroblasts were cultured to assess the effects of Rosiglitazone on TGFβ-induced αSMA expression. Topical application of Rosiglitazone to cat eyes after injury decreased αSMA expression and haze, as well as the induction of lower-order and residual, higher-order wavefront aberrations compared to vehicle-treated eyes. Rosiglitazone also inhibited TGFβ-induced αSMA expression in cultured corneal fibroblasts. In conclusion, Rosiglitazone effectively controlled corneal fibrosis in vivo and in vitro, while restoring corneal thickness and optics. Its topical application may represent an effective, new avenue for the prevention of corneal scarring with distinct advantages for pathologically thin corneas. 23844063 MicroRNA-23b functions as a tumor suppressor by regulating Zeb1 in bladder cancer. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression by targeted repression of transcription and translation. In this study we show that miRNA-23b (miR-23b) acts as a tumor suppressor in bladder cancer. Quantitative real-time PCR analysis showed that miR-23b is significantly down-regulated in bladder cancer cell lines and tumor tissues compared to non-malignant cells and normal tissue samples. We also demonstrate that miR-23b expression has a potential to be diagnostic and prognostic biomarker in bladder cancer. High miR-23b expression is positively correlated with higher overall survival of bladder cancer patients as revealed by Kaplan-Meier analysis. ROC analysis showed that miR-23b expression can distinguish between normal and bladder cancer tissues. Further we elucidated the biological significance of miR-23b in bladder cancer. Over-expression of miR-23b in bladder cancer cells inhibited cell proliferation and impaired colony formation. Fluorescence activated cell sorting (FACS) analysis revealed that re-expression of miR-23b in bladder cancer cells induced G0/G1 cell cycle arrest and apoptosis while inhibiting cell migration and invasion. Luciferase reporter assays demonstrated that Zeb1, a crucial regulator of epithelial-to-mesenchymal transition (EMT), is a direct target of miR-23b in bladder cancer. These results show that loss of miR-23b confers a proliferative advantage and promotes bladder cancer cell migration and invasion. Furthermore, re-expression of miR-23b may be a beneficial therapeutic strategy for the treatment of human bladder cancer. 23347327 Nanocomposites derived from montmorillonite and metallosupramolecular polyelectrolytes: modular compounds for electrorheological fluids. Nanocomposites made from Na-montmorillonite and metallo-supramolecular polyelectrolytes (MEPE) based on nickel and ditopic bis-terpyridine ligands are prepared by an aqueous synthesis. Intercalation is confirmed by IR-spectroscopy, thermogravimetric analysis, and X-ray powder diffraction. The rheological response in the presence of an electric field of the dispersed nanocomposites in silicone oil is measured with a rheometer. The nanocomposites show a distinct electrorheological effect depending on the concentration and the kind of intercalated species. The effect occurs with a low content of active material while only very small currents are observed. 23939250 Reversible thermally-responsive electrochemical energy storage based on smart LDH@P(NIPAM-co-SPMA) films. A smart supercapacitor was fabricated by loading a thermosensitive polymer P(NIPAM-co-SPMA) onto the surface of NiAl-layered double hydroxide (LDH) nanowalls grown on a flexible Ni foil substrate, which displays temperature-triggered on-off ion channels for controlling the electrochemical behavior. 23859931 Crime, physical activity and outdoor recreation among Latino adolescents in Chicago. The purpose was to examine how fear of crime, crime victimization, and perceived level of community incivilities are related to physical activity participation and outdoor recreation among Latino adolescents. The study utilized a mixed methods approach that included 25 qualitative interviews and 390 school-based surveys collected from youth across three schools in Little Village, Chicago, Illinois. Results showed that Latino adolescents who expressed greater fear of crime also engaged in less physical activity and outdoor recreation. There was no association between crime victimization and physical activity and outdoor recreation. Those who perceived greater levels of community incivilities also engaged in less outdoor recreation, but perception of incivilities had no significant association with physical activity levels. Interview data revealed most of the children believed crime was a serious problem in their neighborhood and it impacted their ability to be physically active and play outside. Fear of crime was related to lower physical activity and outdoor recreation. It is imperative that communities provide safe environments for children to be active. Increasing police and adult presence in parks and school grounds is recommended. Moreover, efforts must be made to reduce the gang problems in Latino communities. 23897688 Exercise and Type 1 Diabetes (T1DM). Physical exercise is firmly incorporated in the management of type 1 diabetes (T1DM), due to multiple recognized beneficial health effects (cardiovascular disease prevention being preeminent). When glycemic values are not excessively low or high at the time of exercise, few absolute contraindications exist; practical guidelines regarding amount, type, and duration of age-appropriate exercise are regularly updated by entities such as the American Diabetes Association and the International Society for Pediatric and Adolescent Diabetes. Practical implementation of exercise regimens, however, may at times be problematic. In the poorly controlled patient, specific structural changes may occur within skeletal muscle fiber, which is considered by some to be a disease-specific myopathy. Further, even in well-controlled patients, several homeostatic mechanisms regulating carbohydrate metabolism often become impaired, causing hypo- or hyperglycemia during and/or after exercise. Some altered responses may be related to inappropriate exogenous insulin administration, but are often also partly caused by the "metabolic memory" of prior glycemic events. In this context, prior hyperglycemia correlates with increased inflammatory and oxidative stress responses, possibly modulating key exercise-associated cardio-protective pathways. Similarly, prior hypoglycemia correlates with impaired glucose counterregulation, resulting in greater likelihood of further hypoglycemia to develop. Additional exercise responses that may be altered in T1DM include growth factor release, which may be especially important in children and adolescents. These multiple alterations in the exercise response should not discourage physical activity in patients with T1DM, but rather should stimulate the quest for the identification of the exercise formats that maximize beneficial health effects. © 2013 American Physiological Society. Compr Physiol 3:1309-1336, 2013. 23815315 Experiences of living with dementia: qualitative content analysis of semi-structured interviews. To describe people's experiences of living with dementia in Iran. A knowledge gap exists regarding the experiences of living with dementia in non-Western contexts. This gap may be especially apparent within the Iranian context, where dementia research is relatively new. Deeper understanding about context-related experiences of dementia is a prerequisite for nurses' ability to provide adequate and meaningful care. Qualitative, cross-sectional design. Qualitative content analysis of semi-structured interviews with people living with dementia in urban Iran (six women and nine men; 60-87 years old). The participants experienced their condition as a state of forgetfulness that was accompanied by losses and dependency on others. They wanted to feel good about themselves and feel important, but they continually struggled with matters such as a loss of accountability, feelings of futility and the frustration of others. Economic dependency and a lack of economic resources were sources of feelings of futility. Experiences of living with dementia in Iran included a substantial struggle to stay connected to the social world and to deal with dramatic life changes, aspects of living with dementia that seem to be universal. However, the feelings of financial burden and the experience of being nagged for their shortfalls by family members have seldom been described in other studies and seem to represent a cultural aspect of their experience. The results of the study call for further nursing efforts in supporting people living with dementia in their struggle with their altered lives and in retaining their connections to everyday life. Furthermore, their family members might benefit from specific nursing interventions including information about dementia and advice on how to help the family members with dementia to interact with others while exercising their individual strengths. 23599377 COPD in Helsinki, Finland: socioeconomic status based on occupation has an important impact on prevalence. Objectives: Chronic obstructive pulmonary disease (COPD) is globally a major, but often undiagnosed, cause of morbidity and mortality. The aims of this study were to assess the prevalence of COPD in Helsinki, Finland, with international diagnostic criteria and to analyse risk factors including socioeconomic status, and disease severity. Methods: A general population sample of 628 adults (368 women) completed flow-volume spirometry with bronchodilation test and a structured interview. Post-bronchodilation spirometry was assessed both using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria and relative to the fifth percentile of the reference value (lower limit of normal, LLN). Results: According to GOLD criteria, 37 (5.9%), and by using the LLN criteria, 43 subjects (6.8%) had airway obstruction consistent with COPD. Using the GOLD criteria, four subjects or 0.6% of the population had severe, 3.0% moderate, and 2.2% mild COPD. Of those with post-bronchodilator obstruction, 49% had no previous diagnosis of obstructive airways disease and did not use medication for any respiratory disease. The prevalence of undiagnosed COPD defined by GOLD was 2.9% (LLN 3.3%). In addition to age, smoking history, and prior history of asthma, socioeconomic status based on occupation was significantly related to COPD in the population. Manual workers in industry (GOLD 10.0%, LLN 11.7%) and non-manual assistant employees (10.2%, 10.2%) had a significantly higher prevalence of COPD than professionals (2.8%, 2.3%). Conclusions: Although smoking is the main modifiable risk factor for COPD, the disease was significantly related to manual workers and non-manual assistant employees, i.e. socioeconomic groups reflecting occupation. 23740930 Mortality differentials 1991-2005 by self-reported ethnicity: findings from the ONS Longitudinal Study. Research on ethnic differentials in mortality in England and Wales has focused on immigrants because, until now, studies collecting data on ethnicity have not covered sufficient deaths to investigate the subject. International migrants are selected for good health and tend to have low mortality. We investigated all-cause mortality at ages 1-79 in 1991-2005 by self-reported ethnicity and country of birth. The data are from the Office for National Statistics Longitudinal Study of England and Wales for the cohort aged 0-64 in 1991 (n=436 195). Poisson regression was used to adjust the estimates for metropolitan residence and three indicators of socioeconomic status. White, Black Caribbean, Other Asian and Other immigrants all had lower mortality than Whites born in the UK. Indian, Pakistani, Bangladeshi and Chinese immigrants had lower mortality than the UK-born Whites living in similar circumstances to them. By contrast, the UK-born Black Caribbean group had higher mortality (RR=1.38, 95% CI 1.03 to 1.86) than the UK-born Whites. This excess mortality was accounted for by their low socioeconomic status. Within the Black Caribbean population, the UK-born individuals had significantly higher mortality than those born abroad whether or not the estimates were adjusted for socioeconomic status and metropolitan residence. Adjusting exposure time for undocumented emigration made little difference to the estimates. Immigrants are selected for good health. This has offset the impact of socioeconomic disadvantage on the mortality of minority ethnic groups. As the immigrant population ages and the UK-born minority ethnic population grows, ethnic differentials in all-cause mortality are likely to change. 23622537 Optimisation and application of accelerated solvent extraction and flash chromatography for quantification of PCBs in tree barks and XAD-2 passive samplers using GC-ECD with dual columns. An analytical method for the quantification of Polychlorinated biphenyls (PCBs) concentrations in XAD-2 passive air samplers (PAS) and tree barks collected close to the Rhine River between France and Germany was developed. This method used Accelerated Solvent Extraction (ASE) followed by a purification step by flash chromatography using a 4gr cartridge (3 g of silica gel and 1 g of 44% acidified silica) and analysis by GC-ECD with dual columns. Quantification (QL) and detection (DL) limits varied 0.5 from and 5.7 ng PAS(-1) and from 0.5 and 3.0 ng PAS(-1) respectively. For tree barks, quantification and detection limits were calculated for each congener on washed tree bark sample with a signal to noise ratio of 3:1 and 10:1 (corresponding to a LQ in the range of 1-4 ng per bark sample by congeners). Uncertainties on each congener concentration were calculated to be in the range of 3-20% XAD-2 passive samplers were field calibrated by using Hi-vol. Samplers. Sampling rates of 4.2, 11.5, 1.6, and 7.9 m(3) PAS(-1) d(-1) for tri-, tetra-, penta- hexa-PCBs, respectively were obtained and are comparable to those already obtained with PUF-PAS for gas phase only (gas/particle distribution was 90/10). Method was applied to real atmospheric samples collected by XAD-2 passive samplers and tree barks in the east of France. 23775599 Effects of zinc transporter on differentiation of bone marrow mesenchymal stem cells to osteoblasts. The differentiation of bone marrow mesenchymal stem cells (MSCs) into osteoblasts is a crucial step during bone formation. However, the exact mechanisms regulating the early stages of osteogenic differentiation remain unknown. In the present study, we found that ZnT7, a member of the zinc transporter family SLC30A(ZnTs), was downregulated during dexamethasone-induced differentiation of rat MSCs into osteoblasts. Dexamethasone treatment resulted in significantly lower levels of ZnT7 compared with cocultured cells without dexamethasone. Differentiation was evaluated by measuring alkaline phosphatase (ALP) activity and staining for ALP, von Kossa, collagen type I, and osteocalcin. Overexpression of ZnT7 decreased the expression of the osteoblast alkaline phosphatase, type I collagen, as well as calcium deposition in mesenchymal cells. In contrast, knockdown of ZnT7 using siRNA promoted gene expression associated with osteoblast differentiation and matrix mineralization in vitro. Moreover, according to the ZnT7 inhibition or activation experiments, Wnt and ERK signaling pathways were found to be important signal transduction pathways in mediating the osteogenic effect of MSCs, and this effect is intensified by a decrease in the level of ZnT7 induced by dexamethasone. These findings suggest that ZnT7 is involved in the switch from the undifferentiated state of MSC to an osteogenic program, and marking the expression level of ZnT7 may be useful in the detection of early osteogenic differentiation. 23919281 Reductive cleavage of aryl o-carbamates to phenols by the schwartz reagent. Expedient link to the directed ortho metalation strategy. A general, mild, and efficient method for the reductive cleavage of aryl O-carbamates to phenols, 1 → 2 using the Schwartz reagent is reported. The method is selective, tolerating a large number of functional groups; may be carried out by direct or by an economical in situ procedure; and, notably, establishes a synthetic connection to the directed ortho metalation strategy (Figure 1 ) allowing new entries into difficult to prepare contiguously substituted aromatics and heteroaromatics. 23838044 Comparing of Different Methods for Prevention Stone Migration During Ureteroscopic Lithotripsy. Aim: To compare the effectiveness of Stone Cone™, PercSys and lidocaine jelly instillation to prevent stone migration during ureterorenoscopy (URS). Materials and Methods: One hundred patients who underwent URS for proximal ureteral stones between 2007 and 2012 were evaluated prospectively. The patients were divided into four groups consecutively. The control group (Group I) consisted of the 25 consecutive patients, in whom no device or method was used to prevent stone migration. Group II consisted of 25 patients treated with the Stone Cone, group III consisted of 25 patients treated with PercSys, and group IV consisted of 25 patients treated with lidocaine jelly instillation. Results: The migration rates were 4.5% in group II, 8.7% in group III, 21.7% in group IV, and 31.8% in group I. The migration rate was found to be statistically significantly lower in the groups treated with the Stone Cone and PercSys compared to the control group (p = 0.014, p = 0.048). However, there was no statistically significant difference between the lidocaine jelly group and the control group in terms of migration rates (p = 0.444). Conclusions: Our results suggested that the Stone Cone and PercSys were the most successful methods with significantly low migration rates (4.5 and 8.7%, respectively). 23857421 How to read post-operative radiographs and CT scans after single-bundle anterior cruciate ligament reconstruction. Reconstruction of the anterior cruciate ligament (ACL) is a well-established surgical procedure. However, post-operative imaging in the early phase is not routinely performed. The rationale for performing such imaging is to provide a baseline examination for future controls, to provide immediate feedback to surgeons regarding tunnel placement, and to assess placement of fixation devices. The purpose of this paper is to enable the reader to accurately read post-operative radiographs and CT scans after single-bundle ACL reconstruction. 23211008 Confined synthesis and integration of functional materials in sub-nanoliter volumes. We present a novel microchip-based approach to combine the synthesis, characterization, and utilization of different functional materials on a single platform. A two-layer microfluidic device comprising 10 parallel actuated reaction chambers with volumes of a few hundred picoliters is used to localize and confine the synthesis, while the surfaces of the reaction chambers comprise an electrode array for direct integration and further characterization of the created crystalline assemblies without the need for further manipulation or positioning devices. First we visualized and evaluated the dynamics of our method by monitoring the formation of a fluorescent metal-organic complex (Zn(bix)). Next, we induced the site-specific growth of two types of organic conductive crystals, AuTTF and AgTCNQ, directly onto the electrode arrays in one- and two-step reactions, respectively. The performance of the created AgTCNQ crystals as memory elements was thoroughly examined. Moreover, we proved for first time that AuTTF composites can be used as label-free sensing elements. 23746578 Epidemiology and aetiology of neonatal seizures. Neonatal seizures constitute the most frequent and distinctive neurological symptom in the neonatal period. Seizures in the neonatal period differ considerably from those observed later in life with respect to their aetiological profile and clinical presentation. In addition, the aetiological profile in preterm infants is different from that seen in term infants. Hypoxic-ischaemic encephalopathy is the most frequent cause of neonatal seizures in term babies followed by focal ischaemia (stroke), cerebral malformations and metabolic disturbances. In preterm neonates, intraventricular haemorrhage and infections cause most of the seizures reported in this group. Better neuroimaging techniques have reduced the number of undiagnosed cases, and the institution of newer neuroprotective strategies has influenced the outcome. 23604074 The nascent polypeptide-associated complex is a key regulator of proteostasis. The adaptation of protein synthesis to environmental and physiological challenges is essential for cell viability. Here, we show that translation is tightly linked to the protein-folding environment of the cell through the functional properties of the ribosome bound chaperone NAC (nascent polypeptide-associated complex). Under non-stress conditions, NAC associates with ribosomes to promote translation and protein folding. When proteostasis is imbalanced, NAC relocalizes from a ribosome-associated state to protein aggregates in its role as a chaperone. This results in a functional depletion of NAC from the ribosome that diminishes translational capacity and the flux of nascent proteins. Depletion of NAC from polysomes and re-localisation to protein aggregates is observed during ageing, in response to heat shock and upon expression of the highly aggregation-prone polyglutamine-expansion proteins and Aβ-peptide. These results demonstrate that NAC has a central role as a proteostasis sensor to provide the cell with a regulatory feedback mechanism in which translational activity is also controlled by the folding state of the cellular proteome and the cellular response to stress. 23434433 Antibody-mediates inhibition of human C1s and the classical complement pathway. Disregulation of complement activation plays a critical role in numerous inflammatory diseases and therefore, inhibition of the complement pathway is of great therapeutic interest. In the classical complement pathway, immune complexes formed by IgM, IgG1, IgG2 and IgG3 antibodies result in the activation of the C1s protease that in turn cleaves C4 and then C4-bound-C2 yielding the proteolytic fragments C4b and C2a which associate to form a C3 convertase enzyme. We report here the engineering of a potent human antibody inhibitor of C1s protease activity. Phage panning of a very large synthetic (F(AB)) antibody fragment library using a truncated version of C1s, comprising the second CCP domain and serine protease domain (CCP₂-SP) and expressed in insect cells, resulted in the isolation of a F(AB) that inhibited the catalytic activity of C1s. An affinity matured variant of the F(AB) format antibody displaying subnanomolar K(D) for C1s was shown to exhibit >80% inhibition of C2 processing at a 5:1 antibody:C1s molar ratio. We show that this engineered antibody, D.35, displays potent inhibition of complement deposition and lysis of Ramos cells by the anti-CD20 therapeutic antibody rituximab relative to the approved, but less-specific, human plasma-derived C1-inhibitor (CINRYZE). C1s inhibitory antibodies should be useful for delineating the role of the classical pathway in disease models and may hold promise as therapeutic agents. 23810982 Effects of dopamine receptor blockade on the intensity-response function of ERG b- and d-waves in dark adapted eyes. The effects of dopamine receptor blockade by sulpiride (D2-class antagonist) and sulpiride plus SCH 23390 (D1-class antagonist) on the V - log I function of the ERG b- and d-waves were investigated in dark adapted frog eyes. We observed that sulpiride enhanced the amplitude of the suprathreshold b- and d-waves in the lower intensity range, where the responses were mediated by rods, but diminished it in the higher intensity range, where the responses were mediated by cones. A similar effect on the b-, but not d-wave amplitude was seen during the perfusion with sulpiride plus SCH 23390. The d-wave amplitude was enhanced over the whole intensity range with the exception of the highest intensities during the combined D1 and D2 receptor blockade. The results obtained indicate that the endogenous dopamine has an overall inhibitory action on the suprathreshold rod-mediated ON and OFF responses, while its action on the cone-mediated responses shows clear ON-OFF asymmetry. It is excitatory upon the ON responses, but inhibitory upon the OFF responses except for those in the highest intensity range. Participation of different types of dopamine receptors (predominantly D2 for the ON versus D1 for the OFF response) is probably responsible for this difference. 23832786 Deciphering the rules by which 5'-UTR sequences affect protein expression in yeast. The 5'-untranslated region (5'-UTR) of mRNAs contains elements that affect expression, yet the rules by which these regions exert their effect are poorly understood. Here, we studied the impact of 5'-UTR sequences on protein levels in yeast, by constructing a large-scale library of mutants that differ only in the 10 bp preceding the translational start site of a fluorescent reporter. Using a high-throughput sequencing strategy, we obtained highly accurate measurements of protein abundance for over 2,000 unique sequence variants. The resulting pool spanned an approximately sevenfold range of protein levels, demonstrating the powerful consequences of sequence manipulations of even 1-10 nucleotides immediately upstream of the start codon. We devised computational models that predicted over 70% of the measured expression variability in held-out sequence variants. Notably, a combined model of the most prominent features successfully explained protein abundance in an additional, independently constructed library, whose nucleotide composition differed greatly from the library used to parameterize the model. Our analysis reveals the dominant contribution of the start codon context at positions -3 to -1, mRNA secondary structure, and out-of-frame upstream AUGs (uAUGs) to phenotypic diversity, thereby advancing our understanding of how protein levels are modulated by 5'-UTR sequences, and paving the way toward predictably tuning protein expression through manipulations of 5'-UTRs. 23247258 Translational research: the changing landscape of drug discovery. Drug discovery represents the first step in the creation of new drugs, and takes place in academic institutions, biotech companies, and large pharmaceutical corporations. Until recently, these sectors have each operated independently with little collaboration between those at the forefront of discovery research and those with experience in developing drugs. With the rise of translational research these relationships are shifting and new hubs are emerging, as key players seek to pool the expertise necessary to generate new therapies by linking laboratory discoveries directly to unmet clinical needs. In this article I discuss how the increasing adoption of translational research is leading to novel integrated discovery nexuses that may change the landscape of drug discovery. 23600654 The effect of inorganic salt type and concentration on hydrophilic drug loading into microspheres using the emulsion/solvent diffusion method. Abstract Aim: In order to avoid gastric irritation caused by tolmetin sodium (TS), gastro resistant Eudragit® S 100 microsphere formulations were prepared with the emulsion/solvent diffusion method. Materials: Considering the high water solubility of the TS molecule, the effects of the presence of inorganic salt (NaCl, NaBr and KH2PO4; 0.1 M and 1.0 M) in external phase and external phase pH on the encapsulation efficiency were evaluated. Results: Percentage yield value was found to vary between 55.8% and 72.1%. Improvement in encapsulation efficiency was determined by increasing concentrations of NaCl, NaBr and KH2PO4. The microspheres were observed to have a spherical shape and the measured particle size values varied between 52.1 and 81.5 µm. The released amounts of the drug were found to be low as the inorganic salt concentrations increased. Conclusion: Conclusively, drug release in stomach pH was significantly prevented by the microspheres prepared using Eudragit® S 100 polymer, and these formulations are considered to be a model for other orally administered drugs with similar problems. 23834386 Predictors of Pain Relief Following Spinal Cord Stimulation in Chronic Back and Leg Pain and Failed Back Surgery Syndrome: A Systematic Review and Meta-Regression Analysis. We sought to assess the extent to which pain relief in chronic back and leg pain (CBLP) following spinal cord stimulation (SCS) is influenced by patient-related factors, including pain location, and technology factors. A number of electronic databases were searched with citation searching of included papers and recent systematic reviews. All study designs were included. The primary outcome was pain relief following SCS, we also sought pain score (pre- and post-SCS). Multiple predictive factors were examined: location of pain, history of back surgery, initial level of pain, litigation/worker's compensation, age, gender, duration of pain, duration of follow-up, publication year, continent of data collection, study design, quality score, method of SCS lead implant, and type of SCS lead. Between-study association in predictive factors and pain relief were assessed by meta-regression. Seventy-four studies (N = 3,025 patients with CBLP) met the inclusion criteria; 63 reported data to allow inclusion in a quantitative analysis. Evidence of substantial statistical heterogeneity (P < 0.0001) in level of pain relief following SCS was noted. The mean level of pain relief across studies was 58% (95% CI: 53% to 64%, random effects) at an average follow-up of 24 months. Multivariable meta-regression analysis showed no predictive patient or technology factors. SCS was effective in reducing pain irrespective of the location of CBLP. This review supports SCS as an effective pain relieving treatment for CBLP with predominant leg pain with or without a prior history of back surgery. Randomized controlled trials need to confirm the effectiveness and cost-effectiveness of SCS in the CLBP population with predominant low back pain. 23861539 Altered Striatal Functional Connectivity in Subjects With an At-Risk Mental State for Psychosis. Recent functional imaging work in individuals experiencing an at-risk mental state (ARMS) for psychosis has implicated dorsal striatal abnormalities in the emergence of psychotic symptoms, contrasting with earlier findings implicating the ventral striatum. Our aims here were to characterize putative dorsal and ventral striatal circuit-level abnormalities in ARMS individuals using resting-state functional magnetic resonance imaging (fMRI) and to investigate their relationship to positive psychotic symptoms. Resting-state fMRI was acquired in 74 ARMS subjects and 35 matched healthy controls. An established method for mapping ventral and dorsal striatal functional connectivity was used to examine corticostriatal functional integrity. Positive psychotic symptoms were assessed using the Comprehensive Assessment of At-Risk Mental State and the Positive and Negative Syndrome Scale. Compared with healthy controls, ARMS subjects showed reductions in functional connectivity between the dorsal caudate and right dorsolateral prefrontal cortex, left rostral medial prefrontal cortex, and thalamus, and between the dorsal putamen and left thalamic and lenticular nuclei. ARMS subjects also showed increased functional connectivity between the ventral putamen and the insula, frontal operculum, and superior temporal gyrus bilaterally. No differences in ventral striatal (ie, nucleus accumbens) functional connectivity were found. Altered functional connectivity in corticostriatal circuits were significantly correlated with positive psychotic symptoms. Together, these results suggest that risk for psychosis is mediated by a complex interplay of alterations in both dorsal and ventral corticostriatal systems. 23771131 Computed 88% TCP dose for SBRT of NSCLC from tumour hypoxia modelling. In small NSCLC, 88% local control at three years from SBRT was reported both for schedule (20-22 Gy Ã—3) (Fakiris et al 2009 Int. J. Radiat. Oncol. Biol. Phys. 75 677-82), actually close to (18-20 Gy Ã—3) if density correction is properly applied, and for schedules (18 Gy Ã—3) and (11 Gy Ã—5) (Palma et al 2012 Int. J. Radiat. Oncol. Biol. Phys. 82 1149-56). Here, we compare our computed iso-TCP = 88% dose per fraction (d88) for three and five fractions (n) with such clinically adopted ones. Our TCP model accounts for tumour repopulation, at rate λ (d(-1)), reoxygenation of chronic hypoxia (ch-), at rate a (d(-1)) and fluctuating oxygenation of acute hypoxia (ah-), with hypoxic fraction (C) of the acutely hypoxic fractional volume (AHF). Out of the eight free parameters whose values we had fitted to in vivo animal data (Ruggieri et al 2012 Int. J. Radiat. Oncol. Biol. Phys. 83 1603-8), we here maintained (a(d(-1)), C, OERch, OERah/OERch, AHF, CHF) = (0.026, 0.17, 1.9, 2.2, 0.033, 0.145) while rescaling the initial total number of clonogens (N(o)) according to the ratio of NSCLC on animal median tumour volumes. From the clinical literature, the usually assumed (αo/βo(Gy), λ(d(-1))) = (10, 0.217) for the well-oxygenated (o-)cells were taken. By normal (lognormal) random sampling of all parameter values over their 95% C.I., the uncertainty on present d88(n) computations was estimated. Finally, SBRT intra-tumour dose heterogeneity was simulated by a 1.3 dose boost ratio on 50% of tumour volume. Computed d88(±1σ) were 19.0 (16.3; 21.7) Gy, for n = 3; 10.4 (8.7; 12.1) Gy, for n = 5; 5.8 (5.2; 6.4) Gy, for n = 8; 4.0 (3.6; 4.3) Gy, for n = 12. Furthermore, the iso-TCP = 88% total dose, D88(n) = d88(n)*n, exhibited a relative minimum around n = 8. Computed d88(n = 3, 5) are strictly consistent with the clinically adopted ones, which confirms the validity of LQ-model-based TCP predictions at the doses used in SBRT if a highly radioresistant cell subpopulation is properly modelled. The computed minimum D88(n) around n = 8 suggests the adoption of 6 ≤ n ≤ 10 instead of n = 3 in SBRT of small NSCLC tumours. 23643644 Emerging roles of Cdk8 in cell cycle control. Cyclin dependent kinase 8 (Cdk8) is a component of Mediator, an evolutionary conserved multiprotein complex that regulates RNA polymerase II-dependent transcription. Cdk8 has been implicated as a regulator of multiple steps in cell cycle progression. We here discuss recent advances in our understanding of Cdk8 function and a possible role for Mediator as a hub for integrating transcription regulation with cell cycle progression. 23927130 Automatic pronunciation error detection in non-native speech: The case of vowel errors in Dutch. This research is aimed at analyzing and improving automatic pronunciation error detection in a second language. Dutch vowels spoken by adult non-native learners of Dutch are used as a test case. A first study on Dutch pronunciation by L2 learners with different L1s revealed that vowel pronunciation errors are relatively frequent and often concern subtle acoustic differences between the realization and the target sound. In a second study automatic pronunciation error detection experiments were conducted to compare existing measures to a metric that takes account of the error patterns observed to capture relevant acoustic differences. The results of the two studies do indeed show that error patterns bear information that can be usefully employed in weighted automatic measures of pronunciation quality. In addition, it appears that combining such a weighted metric with existing measures improves the equal error rate by 6.1 percentage points from 0.297, for the Goodness of Pronunciation (GOP) algorithm, to 0.236. 23417894 Hollow Multilayer Microcapsules for pH-/Thermally Responsive Drug Delivery using Aliphatic Poly(urethane-amine) as Smart Component. Hollow multilayer microcapsules made of aliphatic poly(urethane-amine) (PUA) and sodium poly(styrene sulfonate) (PSS), templated on PSS-doped CaCO3 particles, are prepared for pH-/thermally responsive drug delivery. The electrostatic interaction and hydrogen bonding under weak-acid conditions between aliphatic PUA and PSS contribute to the formation of multilayer microcapsules. Scanning electron microscopy (SEM) results demonstrate an obvious variation of the hollow multilayer microcapsules in response to changes in temperature and pH value. Drug-release behaviors using DOX as a model drug demonstrate that the drug release increases on decreasing the pH value because of the interaction weakness between aliphatic PUA and PSS in acidic conditions. Moreover, the drug release is higher at 55 °C than that at 37 °C for the sake of the shrinkage of aliphatic PUA above its lower critical solution temperature (LCST). 23695501 A pragmatic parallel arm multi-centre randomised controlled trial to assess the effectiveness and cost-effectiveness of a group-based fatigue management programme (FACETS) for people with multiple sclerosis. Fatigue is a common and troubling symptom for people with multiple sclerosis (MS). To evaluate the effectiveness and cost-effectiveness of a six-session group-based programme for managing MS-fatigue (Fatigue: Applying Cognitive behavioural and Energy effectiveness Techniques to lifeStyle (FACETS)). Three-centre parallel arm randomised controlled trial with economic evaluation. Patients with MS and significant fatigue were randomised to FACETS plus current local practice (FACETS) or current local practice alone (CLP), using concealed computer-generated randomisation. Participant blinding was not possible. Primary outcomes were fatigue severity (Fatigue Assessment Instrument), self-efficacy (Multiple Sclerosis-Fatigue Self-Efficacy) and disease-specific quality of life (Multiple Sclerosis Impact Scale (MSIS-29)) at 1 and 4 months postintervention (follow-up 1 and 2). Quality adjusted life years (QALYs) were calculated (EuroQoL 5-Dimensions questionnaire and the Short-form 6-Dimensions questionnaire). Between May 2008 and November 2009, 164 patients were randomised; primary outcome data were available for 146 (89%). Statistically significant differences favour the intervention group on fatigue self-efficacy at follow-up 1 (mean difference (MD) 9, 95% CI (4 to 14), standardised effect size (SES) 0.54, p=0.001) and follow-up 2 (MD 6, 95% CI (0 to 12), SES 0.36, p=0.05) and fatigue severity at follow-up 2 (MD -0.36, 95% CI (-0.63 to -0.08), SES -0.35, p=0.01) but no differences for MSIS-29 or QALYs. No adverse events reported. Estimated cost per person for FACETS is £453; findings suggest an incremental cost-effectiveness ratio of £2157 per additional person with a clinically significant improvement in fatigue. FACETS is effective in reducing fatigue severity and increasing fatigue self-efficacy. However, it is difficult to assess the additional cost in terms of cost-effectiveness (ie, cost per QALY) as improvements in fatigue are not reflected in the QALY outcomes, with no significant differences between FACETS and CLP. The strengths of this trial are its pragmatic nature and high external validity. Current Controlled Trials ISRCTN76517470. 23404148 Miniprobe endoscopic ultrasound accurately stages esophageal cancer and guides therapeutic decisions in the era of neoadjuvant therapy: results of a multicenter cohort analysis. Despite recent advances in imaging techniques, adequate classification of esophageal lesions is still challenging. Accurate staging of tumors of the esophagus is a precondition for targeted therapy. In this retrospective, multicenter study, we report the role of high-frequency endoscopic ultrasound (EUS) catheter probes in pretherapeutic staging of esophageal neoplasms and thus guiding treatment decisions. A total of 143 patients (mean age of 63.8 ± 10.7 years) with esophageal carcinoma were recruited from five German centers (Münster, Oldenburg, Hannover, Wiesbaden, and Lüneburg). Tumor type was adenocarcinoma in 112 (78 %) cases and squamous cell carcinoma in 31 (22 %). Tumor localization was as follows: proximal 3, mid esophagus 7, and distal third 133. Histological correlation either through EMR or surgery was available. In all patients, pretherapeutic uT and uN classifications were compared to pT/pN classification obtained from surgically (esophagectomy, n = 93) or endoscopically (EMR, n = 50) resected tissue. Overall, accuracy of uT classification was 60 % and of uN classification was 74 %. Sensitivity, specificity, and accuracy rates for local tumor extension were as follows (%): T1: 68/97/83; T2: 39/84/75; T3: 72/81/79; T4: 13/97/93; T1/2: 73/81/75; T3/4: 78/82/81. Relating to positive lymph node detection, sensitivity and specificity were 76 and 71 %, respectively. Miniprobe EUS is an established method for the staging of esophageal tumors. Our large multicenter cohort shows a solid accuracy of miniprobe EUS with respect to differentiating locally advanced from limited cancer and assisting to determine the treatment regimen in the era of neoadjuvant therapy; consequently, 78 % of patients would have been assigned to the adequate therapeutic regimen, whereas 11 % of patients would have been overtreated and 11 % undertreated. 23727676 Vibrational spectra, DFT quantum chemical calculations and conformational analysis of P-iodoanisole. The solid phase FT-IR and FT-Raman spectra of P-iodoanisole (P-IA) have been recorded in the regions 400-4000 and 50-4000cm(-1), respectively. The spectra were interpreted in terms of fundamentals modes, combination and overtone bands. The structure of the molecule was optimized and the structural characteristics were determined by ab initio (HF) and density functional theory (B3LYP) methods with LanL2DZ as basis set. The potential energy surface scan for the selected dihedral angle of P-IA has been performed to identify stable conformer. The optimized structure parameters and vibrational wavenumbers of stable conformer have been predicted by density functional B3LYP method with LanL2DZ (with effective core potential representations of electrons near the nuclei for post-third row atoms) basis set. The nucleophilic and electrophilic sites obtained from the molecular electrostatic potential (MEP) surface were calculated. The temperature dependence of thermodynamic properties has been analyzed. Several thermodynamic parameters have been calculated using B3LYP with LanL2DZ basis set. 23883899 Intramuscular transplantation and survival of freshly isolated bone marrow cells following skeletal muscle ischemia-reperfusion injury. Delayed treatment cellular therapies offer an attractive means to treat extremity injuries involving acute skeletal muscle ischemia-reperfusion injury (I/R). Bone marrow is a rich source of stem and progenitor cells with the potential to improve skeletal muscle regeneration. The extent to which bone marrow cells (BMCs) may be useful for I/R is not known. The purposes of this study were twofold: (1) to evaluate BMC survival following intramuscular injection 0, 2, 7, and 14 days after injury and (2) to determine whether BMCs improve functional recovery following I/R. Magnetic-activated cell sorting was used to isolate lineage-negative (Lin) BMCs and enrich for stem and progenitor cells. To evaluate in vivo cell survival following I/R, Lin BMCs were injected intramuscularly 0, 2, 7, and 14 days after I/R, and bioluminescent imaging was performed for up to 28 days after cell injections. To assess their ability to improve muscle regeneration, intramuscular injections were performed 2 days after injury, and in vivo muscle function was assessed 14 days later. Lin BMCs survived throughout the study period regardless of the timing of delivery. Intramuscular injection of Lin BMCs did not improve maximal isometric torque (300 Hz); however, both saline-injected and Lin BMC-injected muscles exhibited an increase in the twitch-tetanus ratio, suggesting that damage incurred with the intramuscular injections may have had deleterious consequences for functional recovery. Although BMCs injected intramuscularly survived cell transplantation, they failed to improve muscle function following I/R. The ability of BMCs to persist in injured muscle following I/R lends to the possibility that with further development, their full potential can be realized. 23154302 Combination treatment with progesterone and vitamin D hormone is more effective than monotherapy in ischemic stroke: The role of BDNF/TrkB/Erk1/2 signaling in neuroprotection. We investigated whether combinatorial post-injury treatment with progesterone (P4) and vitamin D hormone (VDH) would reduce ischemic injury more effectively than P4 alone in an oxygen glucose deprivation (OGD) model in primary cortical neurons and in a transient middle cerebral artery occlusion (tMCAO) model in rats. In the OGD model, P4 and VDH each showed neuroprotection individually, but combination of the "best" doses did not show substantial efficacy; instead, the lower dose of VDH in combination with P4 was the most effective. In the tMCAO model, P4 and VDH were given alone or in combination at different times post-occlusion for 7 days. In vivo data confirmed the in vitro findings and showed better infarct reduction at day 7 and functional outcomes (at 3, 5 and 7 days post-occlusion) after combinatorial treatment than when either agent was given alone. VDH, but not P4, upregulated heme oxygenase-1, suggesting a pathway for the neuroprotective effects of VDH differing from that of P4. The combination of P4 and VDH activated brain-derived neurotrophic factor and its specific receptor, tyrosine kinase receptor-B. Under specific conditions VDH potentiates P4's neuroprotective efficacy and should be considered as a potential partner of P4 in a low-cost, safe and effective combinatorial treatment for stroke. 23836662 Loss of corepressor PER2 under hypoxia up-regulates OCT1-mediated EMT gene expression and enhances tumor malignancy. The circadian clock gene Period2 (PER2) has been suggested to be a tumor suppressor. However, detailed mechanistic evidence has not been provided to support this hypothesis. We found that loss of PER2 enhanced invasion and activated expression of epithelial-mesenchymal transition (EMT) genes including TWIST1, SLUG, and SNAIL. This finding was corroborated by clinical observation that PER2 down-regulation was associated with poor prognosis in breast cancer patients. We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. Hypoxia, a condition commonly observed in tumors, caused PER2 degradation and disrupted the PER2 repressor complex, leading to activation of EMT gene expression. This result was further supported by clinical data showing a significant negative correlation between hypoxia and PER2. Thus, our findings clearly demonstrate the tumor suppression function of PER2 and elucidate a pathway by which hypoxia promotes EMT via degradation of PER2. 23886527 Inhibition of vein graft stenosis with a c-jun targeting DNAzyme in a cationic liposomal formulation containing 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Coronary artery bypass grafting (CABG) is among the most commonly performed heart surgical procedures. Saphenous vein graft failure due to stenosis impedes the longer-term success of CABG. A key cellular event in the process of vein graft stenosis is smooth muscle cell hyperplasia. In this study, we evaluated the effect of a DNAzyme (Dz13) targeting the transcription factor c-Jun in a rabbit model of vein graft stenosis in a cationic liposomal formulation containing 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Dz13 in DOTAP/DOPE has undergone preclinical toxicological testing, and a Phase I clinical trial we recently conducted in basal cell carcinoma cancer patients demonstrates that it is safe and well tolerated after local administration. Effects of Dz13 in a formulation containing DOTAP/DOPE on smooth muscle cell (SMC) growth and c-Jun expression were assessed. Dz13 transfection was determined by cellular uptake of carboxyfluorescein-labeled Dz13. Autologous jugular vein to carotid artery transplantation was performed in New Zealand White rabbits to investigate the effect of the Dz13 in DOTAP/DOPE formulation on intimal hyperplasia. Dz13/DOTAP/DOPE reduced SMC proliferation and c-Jun protein expression in vitro compared with an impotent form of Dz13 bearing a point mutation in its catalytic domain (Dz13.G>C). The Dz13(500μg)/DOTAP/DOPE formed lipoplexes that were colloidally stable for up to 1h on ice (0°C) and 30min at 37°C, allowing sufficient uptake by the veins. Dz13 (500μg) inhibited neointima formation 28d after end-to-side transplantation. This formulation applied to veins prior to transplantation may potentially be useful in efforts to reduce graft failure. 23775860 Idiopathic microscopic colitis of rhesus macaques: quantitative assessment of colonic mucosa. Idiopathic chronic diarrhea (ICD) is a common cause of morbidity and mortality among juvenile rhesus macaques. While lesions may be absent at colonoscopy, the histopathologic evaluation of the biopsy specimens is consistent with human macroscopic colitis (MC). In this study, we developed an isotropic uniform random sampling method to evaluate macroscopic and microscopic changes and applied it on proximal ascending colon in monkeys. Colonic tissue and peripheral blood specimens were collected from six MC and six control juvenile macaques at necropsy. Uniform random samples were collected from the colon using punch biopsy tools. The volume of epithelium and lamina propria were estimated in thick (25 µm) sections using point probes and normalized to the area of muscularis mucosae. Our data suggests a significant increase of the Vs of the lamina propria (1.9-fold, P = 0.02) and epithelium (1.4-fold, P = 0.05) in subjects with MC. The average colonic surface mucosa area in the MC monkeys increased 1.4-fold over the controls (P = 0.02). The volume of the proximal colon in animals with MC showed a 2.4-fold increase over the non-diarrhea control monkeys (P = 0.0001). Cytokine, chemokine, and growth factor levels in peripheral blood were found to be correlated with the volume estimate of the lamina propria and epithelium. We found that ICD in macaques has features which simulates human MC and can be used as a spontaneous animal model for human MC. Furthermore, this developed sampling method can be used for unbiased preclinical evaluation of therapeutics in this animal model. Anat Rec, 2013. © 2013 Wiley Periodicals, Inc. 23966863 The Viral KSHV Chemokine vMIP-II Inhibits the Migration of Naive and Activated Human NK Cells by Antagonizing Two Distinct Chemokine Receptors. Natural killer (NK) cells are innate immune cells able to rapidly kill virus-infected and tumor cells. Two NK cell populations are found in the blood; the majority (90%) expresses the CD16 receptor and also express the CD56 protein in intermediate levels (CD56(Dim) CD16(Pos)) while the remaining 10% are CD16 negative and express CD56 in high levels (CD56(Bright) CD16(Neg)). NK cells also reside in some tissues and traffic to various infected organs through the usage of different chemokines and chemokine receptors. Kaposi's sarcoma-associated herpesvirus (KSHV) is a human virus that has developed numerous sophisticated and versatile strategies to escape the attack of immune cells such as NK cells. Here, we investigate whether the KSHV derived cytokine (vIL-6) and chemokines (vMIP-I, vMIP-II, vMIP-III) affect NK cell activity. Using transwell migration assays, KSHV infected cells, as well as fusion and recombinant proteins, we show that out of the four cytokine/chemokines encoded by KSHV, vMIP-II is the only one that binds to the majority of NK cells, affecting their migration. We demonstrate that vMIP-II binds to two different receptors, CX3CR1 and CCR5, expressed by naïve CD56(Dim) CD16(Pos) NK cells and activated NK cells, respectively. Furthermore, we show that the binding of vMIP-II to CX3CR1 and CCR5 blocks the binding of the natural ligands of these receptors, Fractalkine (Fck) and RANTES, respectively. Finally, we show that vMIP-II inhibits the migration of naïve and activated NK cells towards Fck and RANTES. Thus, we present here a novel mechanism in which KSHV uses a unique protein that antagonizes the activity of two distinct chemokine receptors to inhibit the migration of naïve and activated NK cells. 23523435 The safety of spinal pedicle screws in children ages 1 to 12. Pedicle screws have shown to be a safe and effective method of spinal fixation, offering superior multiplanar correction compared with hooks or sublaminar wires in selected situations. Though only food and drug administration (FDA) approved in the adolescent population, they are commonly used in an off-label manner in the preadolescent population. To determine if the complication rate of the off-label use of pedicle screws for spinal fixation in the preadolescent 0- to 12-year-old population is comparable with the complication rate in the FDA-approved 13- to 18-year-old population. Retrospective medical record and radiograph review. A total of 726 pediatric patients who underwent a spinal fusion procedure at a single tertiary institution between January 2003 and December 2008 were reviewed. Incidence of instrumentation failure, infection, neurological complication, and total complications. The study population was divided into two groups based on age: the younger group included 0- to 12-year olds and the older group included 13- to 18-year olds at the time of surgery. Groups were further subdivided based on diagnosis: "A," neuromuscular scoliosis; "B," idiopathic scoliosis, and "C," other spinal deformities. Rates of neurovascular complications, infections, and instrumentation complications were compared statistically between the younger and the older groups. Only patients with greater than or equal to 1-year follow-up and greater than or equal to 2-year follow-up were included in the calculations for infection and instrumentation complication rates, respectively. There were 206 patients (33% males, 67% females) in the younger group (0 to 12 years) and 520 (41% males, 59% females) in the older group (13 to 18 years). Overall, younger group had a 13.6% complication rate compared with 16.9% in the older group. Younger subjects showed a 13.4% complication rate because of instrumentation-related complications, 0.5% for neurovascular complications, and an infection rate of 9.2%. The older group showed a 15.4% complication rate because of instrumentation-related complications, 1.92% for neurovascular complications, and an infection rate of 11.0%. Complication rates were statistically insignificant between the two groups. Other complications in the younger group included one patient with aspiration pneumonia, two with ileus, and one with pulmonary and other complications in the older group included one patient with aspiration pneumonia, two with ileus, three with superior mesenteric artery syndrome, and three with wound dehiscence. The complication rates in the young pediatric population associated with the off-label use of pedicle screws for spinal fusions are not statistically different from the complication rates associated with the FDA-approved adolescent population. 23943160 Ligand-Activated Peroxisome Proliferator-Activated Receptor β/δ Modulates Human Endometrial Cancer Cell Survival. Endometrial cancer is the fourth most common malignancy among women and is a major cause of morbidity contributing to approximately 8,200 annual deaths in the USA. Despite advances to the understanding of endometrial cancer, novel interventions for the disease are necessary given that many tumors become refractory to therapy. As a strategy to identify novel therapies for endometrial carcinoma, in this study, we examined the contribution of the peroxisome proliferator-activated receptor β/δ (PPARβ/δ) to endometrial cancer cell proliferation and apoptosis. We found that when activated with the highly selective PPARβ/δ agonists, GW0742 and GW501516, PPARβ/δ inhibited the proliferation and markedly induced the apoptosis of three endometrial cancer cell lines. The specificity of the PPARβ/δ-induced effects on cell proliferation and apoptosis was demonstrated using PPARβ/δ-selective antagonists and PPARβ/δ small interfering RNA in combination with PPARβ/δ-selective agonists. Furthermore, we showed that PPARβ/δ activation increased phosphatase and tensin homolog expression, which led to protein kinase B (AKT) and glycogen synthase kinase-3β (GSK3β) dephosphorylation, and increased β-catenin phosphorylation associated with its degradation. Overall, our data suggest that the antitumorigenic effect of PPARβ/δ activation in endometrial cancer is mediated through the negative regulation of the AKT/GSK3β/β-catenin pathway. These findings warrant further investigation of PPARβ/δ as a therapeutic target in endometrial cancer. 23951705 Practical guidance on characterizing availability in resource selection functions under a use-availability design. Habitat selection is a fundamental aspect of animal ecology, the understanding of which is critical to management and conservation. Global positioning system data from animals allow fine-scale assessments of habitat selection and typically are analyzed in a use availability framework, whereby animal locations are contrasted with random locations (the availability sample). Although most use-availability methods are in fact spatial point process models, they often are fit using logistic regression. This framework offers numerous methodological challenges, for which the literature provides little guidance. Specifically, the size and spatial extent of the availability sample influences coefficient estimates potentially causing interpretational bias. We examined the influence of availability on statistical inference through simulations and analysis of serially correlated mule deer GPS data. Bias in estimates arose from incorrectly assessing and sampling the spatial extent of availability. Spatial autocorrelation in covariates, which is common for landscape characteristics, exacerbated the error in availability sampling leading to increased bias. These results have strong implications for habitat selection analyses using GPS data, which are increasingly prevalent in the literature. We recommend that researchers assess the sensitivity of their results to their availability sample and, where bias is likely, take care with interpretations and use cross validation to assess robustness. 23531039 Adhesion and Nanomechanics of Pili from the Probiotic Lactobacillus rhamnosus GG. Knowledge of the mechanisms by which bacterial pili adhere to host cells and withstand external forces is critical to our understanding of their functional roles and offers exciting avenues in biomedicine for controlling the adhesion of bacterial pathogens and probiotics. While much progress has been made in the nanoscale characterization of pili from Gram-negative bacteria, the adhesive and mechanical properties of Gram-positive bacterial pili remain largely unknown. Here, we use single-molecule atomic force microscopy to unravel the binding mechanism of pili from the probiotic Gram-positive bacterium Lactobacillus rhamnosus GG (LGG). First, we show that SpaC, the key adhesion protein of the LGG pilus, is a multifunctional adhesin with broad specificity. SpaC forms homophilic trans-interactions engaged in bacterial aggregation and specifically binds mucin and collagen, two major extracellular components of host epithelial layers. Homophilic and heterophilic interactions display similar binding strengths and dissociation rates. Next, pulling experiments on living bacteria demonstrate that LGG pili exhibit two unique mechanical responses, that is, zipper-like adhesion involving multiple SpaC molecules distributed along the pilus length and nanospring properties enabling pili to resist high force. These mechanical properties may represent a generic mechanism among Gram-positive bacterial pili for strengthening adhesion and withstanding shear stresses in the natural environment. The single-molecule experiments presented here may help us to design molecules capable of promoting or inhibiting bacterial-host interactions. 23568451 Single-photon sources: non-blinking single-photon generation with anisotropic colloidal nanocrystals: towards room-temperature, efficient, colloidal quantum sources (adv. Mater. 14/2013). High-quality core/shell CdSe/CdS colloidal nanocrystals are demonstrated to be efficient sources of non-classical light. As shown by Ferruccio Pisanello and co-workers on page 1974, the intrinsic anisotropy of these nanoparticles allows an independent tuning of shell length and thickness, resulting in a full control of photon statistics. This can be exploited to obtain non-blinking, room-temperature single-photon generation, thus bringing colloidal nanocrystals one step closer to non-classical light sources for quantum applications. 23819683 Coffee, caffeine, and risk of completed suicide: Results from three prospective cohorts of American adults. Objective.To evaluate the association between coffee and caffeine consumption and suicide risk in three large-scale cohorts of US men and women. Methods. We accessed data of 43,599 men enrolled in the Health Professionals Follow-up Study (HPFS, 1988-2008), 73,820 women in the Nurses' Health Study (NHS, 1992-2008), and 91,005 women in the NHS II (1993-2007). Consumption of caffeine, coffee, and decaffeinated coffee, was assessed every 4 years by validated food-frequency questionnaires. Deaths from suicide were determined by physician review of death certificates. Multivariate adjusted relative risks (RRs) were estimated with Cox proportional hazard models. Cohort specific RRs were pooled using random-effect models. Results. We documented 277 deaths from suicide. Compared to those consuming ≤ 1 cup/week of caffeinated coffee (< 8 oz/237 ml), the pooled multivariate RR (95% confidence interval [CI]) of suicide was 0.55 (0.38-0.78) for those consuming 2-3 cups/day and 0.47 (0.27-0.81) for those consuming ≥ 4 cups/day (P trend < 0.001). The pooled multivariate RR (95% CI) for suicide was 0.75 (0.63-0.90) for each increment of 2 cups/day of caffeinated coffee and 0.77 (0.63-0.93) for each increment of 300 mg/day of caffeine. Conclusions. These results from three large cohorts support an association between caffeine consumption and lower risk of suicide. 23642889 Clinical significance of the cross-sectional area of the internal jugular vein. The aim of this study was to compare the cross-sectional area (CSA) of the right internal jugular vein (IJV) with that of the left IJV and to evaluate the anatomic location of the IJV in relation to the common carotid artery, utilizing computed tomography scans of the neck. Retrospective observational study. A tertiary care hospital. Eighty patients with neck computed tomography scans scheduled for thyroid surgery. No. Mean CSA of the right and left IJV were 165±81 and 119±57mm(2), respectively (p<0.01). A relatively larger CSA of the right IJV, compared with that of the left , was seen in 63 (79%) patients. A larger CSA of the right IJV was shown in more right-handed subjects than left-handed subjects (82 v 43%, p<0.05). Small CSA (<50mm(2)) of the right or left IJV were seen in 4 patients. Both IJVs were located commonly either laterally or anterolaterally to their common carotid arteries. A posterolateral position of the IJV was seen in 4 patients. This study suggested one advantage of using the right IJV compared with the left for central venous cannulation. However, anatomic variations of the IJV, such as a small CSA and a medial or posterior position, are not associated with demographic data. Although right-handedness was well-correlated with a larger ipsilateral IJV, a possibility of a larger contralateral IJV should be considered. Therefore, central venous cannulation with ultrasonography is recommended to avoid complications and repeated needling. 23966079 Evaluation of the Effect of Different Growth Media and Temperature on the Suitability of Biofilm Formation by Enterobacter cloacae Strains Isolated from Food Samples in South Africa. This study evaluated the effects of growth medium, temperature, and incubation time on biofilm formation by Enterobacter cloacae strains. The ability to adhere to a surface was demonstrated using a microtiter plate adherence assay whereas the role of cell surface properties in biofilm formation was assessed using the coaggregation and autoaggregation assays. The architecture of the biofilms was examined under scanning electron microscope (SEM). All the strains adhered to the well of the microtiter plate when incubated for 48 h, irrespective of the growth medium and incubation temperature. It was also noted that 90% and 73% of strains prepared from nutrient broth and cultured in brain heart infusion (BHI) broth and tryptic soy broth (TSB), respectively, were able to form biofilms, in contrast to 73% and 60% strains from nutrient agar and cultured in BHI and TSB respectively grown under similar conditions. However, no statistically significant difference was observed when the two methods were compared. The coaggregation index ranged from 12% to 74%, with the best coaggregate activity observed when partnered with Streptococcus pyogenes (54%-74%). The study indicates the suitability of BHI and TSB medium for the cultivation of E. cloacae biofilms, however, temperature and incubation time significantly affect biofilm formation by these bacteria. 23333717 Correlation between the antibacterial activity and the composition of extracts derived from various Spanish Cistus species. Cistaceae is a large family of shrubs commonly distributed in the Mediterranean ecosystem. The aim of this study was to explore the potential antimicrobial properties against Escherichia coli and/or Staphylococcus aureus of different extracts obtained from four Cistaceae species that are especially abundant in Spanish semi-arid regions. MIC50 values of the extracts of C. salviifolius exhibited potent bacteriostatic effects against S. aureus compared with the other Cistus species tested. Spray-drying had less impact on the antimicrobial activities and polyphenolic contents than did evaporation followed by freeze-drying. When C. salviifolius extract was concentrated and the polar fraction was removed, its bacteriostatic and bactericidal activities against both strains were significantly enhanced. Seasonal influences on the composition have also been found. Up to 48 compounds were found in the aqueous extract of C. salviifolius using RRLC-ESI-TOF-MS. The analysis of the composition of the extracts revealed that the inhibitory activity against E. coli may be related to the presence of galloylated flavanols and specific flavonols, whereas the inhibitory capacity against S. aureus may be related primarily to polar compounds and to other flavonols. Potential synergistic effects among polyphenols may deserve further studies. These extracts may serve as an alternative source of antimicrobial ingredients focused on medical devices or cosmetics. 23517015 Preoperative neutrophil/lymphocyte ratio predicts overall survival and extravesical disease in patients undergoing radical cystectomy. Abstract Purpose: To evaluate if hematologic parameters and inflammatory markers could predict extravesical tumor and overall survival after radical cystectomy for patients with recurrent high grade T1 or muscle-invasive bladder cancer. Patients and Methods: A total of 68 consecutive cases of radical cystectomy performed with curative intent at our institution between April 2005 and October 2011 with preoperative hematologic parameters are included in this analysis. We evaluated preoperative characteristics with univariable and multivariate Cox proportional hazard ratios to assist in risk stratification for overall survival. Relative risk (RR) ratios and 95% confidence intervals (CI) were created. We also identified factors associated with extravesical tumor extension with logistic regression analysis. Results: Median overall survival in the total cohort was 25 months (95% CI 13-61). In multivariate analysis, neutrophil/lymphocyte ratio <2.5 (RR 2.49; 95% CI 1.14-6.09), hypoalbuminemia (RR 4.96; 95% CI 2.18-11.67), pT3/4 (RR 7.97, 95% CI 3.16-24.83), and lymph node positive disease (RR 2.62, 95% CI 1.26-5.46) predicted overall survival. These were statistically significant for cancer-specific survival as well. Both elevated neutrophil/lymphocyte ratio (RR 3.18, 95% CI 1.09-9.79) and hypoalbuminemia (RR 3.72, 95% CI 1.12-15.00) were associated with risk for extravesical disease. Conclusions: Serum neutrophil/lymphocyte ratio and hypoalbuminemia predict overall and cancer-specific survival in patients undergoing radical cystectomy for muscle-invasive bladder cancer. These parameters also predict risk for extravesical disease. These could be combined with other established preoperative parameters to improve risk stratification and preoperative counseling. 23686620 Multiple mediators of the relationships among maternal childhood abuse, intimate partner violence, and offspring psychopathology. The aim of the study was to examine whether maternal depression, mothers' and fathers' parenting, child physical punishment and negative life events (NLE) mediate the effect of maternal childhood abuse (CA), intimate partner violence (IPV) and cumulative violence (both CA and IPV) on Spanish children's and adolescents' psychopathology. Furthermore, multiple mediator models examine whether IPV mediates the effect of CA on the contextual and family factors mentioned above. Three hundred and eighteen Spanish outpatients aged 7 to 18 and their parents were assessed using a structured interview and other instruments for measuring the study variables. Structural equation models (SEMs) showed multiple pathways explaining psychopathological problems among offspring of mothers who suffered CA, IPV and both of these violent experiences. In particular, mothers' depression mediated the link between maternal CA, IPV, cumulative violence and children's externalizing, and total behavior problems. Child NLE was an important pathway between maternal CA and total behavior problems, as well as between cumulative violence and both externalizing and total problems. IPV contributed to explaining the link between maternal CA and contextual and family factors, such as child physical punishment and NLE, which were in turn, associated with children's behavior problems. Findings show the complex interconnections between different types of violence and their harmful effects on the mental health of women and their offspring, as well as the need to extend our knowledge on this subject. 23867647 Synthesis of a novel water-soluble zinc phthalocyanine and its CT DNA-damaging studies. A novel 3-(4-methoxybenzylamino) propanoic acid substituted water-soluble zinc phthalocyanine (CNPcZn) was synthesized. The interaction between CNPcZn with calf thymus DNA (CT DNA) was studied using spectroscopic methods. The studies indicated that CNPcZn has strong affinity to CT DNA, and furthermore, CNZnPc showed excellent photodamaging activity to CT DNA. Above results indicated that such CNPcZn has great potential to be used as an effective photosensitizer in the field of photodynamic therapy. 23360449 Organoselenium compounds modulate extracellular redox by induction of extracellular cysteine and cell surface thioredoxin reductase. The effect of selenium compounds on extracellular redox modulating capacity was studied in murine macrophage RAW 264.7 cells and differentiated human THP-1 monocytes. The arylselenium compounds benzeneselenol (PhSeH), dibenzyl diselenide (DBDSe), diphenyl diselenide (DPDSe), and ebselen were capable of inducing extracellular cysteine accumulation via a cystine- and glucose-dependent process. Extracellular cysteine production was dose-dependently inhibited by glutamate, an inhibitor of cystine/glutamate antiporter (Xc(-) transporter), supporting the involvement of Xc(-) transporter for cystine uptake in the above process. These arylselenium compounds also induced cellular thioredoxin reductase (TrxR) expression, particularly at the exofacial surface of cells. TrxR1 knockdown using small interfering RNA attenuated TrxR increases and cysteine efflux induced in cells by DPDSe. Sodium selenite (Na2SeO3), selenomethionine (SeMet), seleno-l-cystine (SeCySS), and Se-methylselenocysteine (MeSeCys) did not have these effects on macrophages under the same treatment conditions. The effects of organoselenium compounds on extracellular redox may contribute to the known, but inadequately understood, biological effects of selenium compounds. 23387807 Essentials of standard chinese phonetics for prosthetic dentistry. Speech adaptation after oral rehabilitation is based on a complex interaction of articulatory and myofunctional factors. The knowledge of basic phonetic principles may help clinicians identify phonetic problems associated with prosthodontic treatment. The purpose of this article is to illustrate basic phonetic terminology, standard Chinese (Putonghua) phonetics, and the anatomic structures relevant for dentistry. In cooperation with a Chinese linguistic specialist, Chinese articulators were selected and are described and compared with English phonetics. Established test words and sentences aid the identification of mispronounced articulators and their related dental structures. The pronunciation of most consonants and vowels in standard Chinese is similar to English, but some of them, such as the retropalatals (/zh/ [tʂ], /ch/ [thʂ], /sh/ [ʂ]), have notable differences. Palatal consonants (/j/ [tɕ], /q/ [tɕh], /x/ [ɕ]) are unique to the Chinese phonetic system and are not found in English phonetics. The comprehension of the basic anatomic regions involved in Chinese phonetics may help prosthodontists treat patients whose native language is standard Chinese. 23810597 Effects of 8 chemical and bacterial additives on the quality of corn silage. This project aimed to evaluate the effects 8 additives on the fermentation, dry matter (DM) losses, nutritive value, and aerobic stability of corn silage. Corn forage harvested at 31% DM was chopped (10mm) and treated with (1) deionized water (control); (2) Buchneri 500 (BUC; 1×10(5) cfu/g of Pediococcus pentosaceus 12455 and 4×10(5) cfu/g of Lactobacillus buchneri 40788; Lallemand Animal Nutrition, Milwaukee, WI); (3) sodium benzoate (BEN; 0.1% of fresh forage); (4) Silage Savor acid mixture (SAV: 0.1% of fresh forage; Kemin Industries Inc., Des Moines, IA); (5) 1×10(6) cfu/g of Acetobacter pasteurianus-ATCC 9323; (6) 1×10(6) cfu/g of Gluconobacter oxydans-ATCC 621; (7) Ecosyl 200T (1×10(5) cfu/g of Lactobacillus plantarum MTD/1; Ecosyl Products Inc., Byron, IL); (8) Silo-King WS (1.5×10(5) cfu/g of L. plantarum, P. pentosaceus and Enterococcus faecium; Agri-King, Fulton, IL); and (9) Biomax 5 (BIO; 1×10(5) cfu/g of L. plantarum PA-28 and K-270; Chr. Hansen Animal Health and Nutrition, Milwaukee, WI). Treated forage was ensiled in quadruplicate in mini silos at a density of 172kg of DM/m(3) for 3 and 120d. After 3d of ensiling, the pH of all silages was below 4 but ethanol concentrations were least in BEN silage (2.03 vs. 3.24% DM) and lactic acid was greatest in SAV silage (2.97 vs. 2.51% DM). Among 120-d silages, additives did not affect DM recovery (mean=89.8% ± 2.27) or in vitro DM digestibility (mean=71.5% ± 0.63). The SAV silage had greater ammonia-N (0.85g/kg of DM) and butyric acid (0.22 vs. 0.0% DM) than other treatments. In contrast, BEN and Silo-King silages had the least ammonia-N concentration and had no butyric acid. The BEN and A. pasteurianus silages had the lowest pH (3.69) and BEN silage had the least ethanol (1.04% DM) and ammonia nitrogen (0.64g/kg DM) concentrations, suggesting that fermentation was more extensive and protein degradation was less in BEN silages. The BUC and BIO silages had greater acetic acid concentrations than control silages (3.19 and 3.19 vs. 2.78% DM), but yeast counts did not differ. Aerobic stability was increased by 64% by BUC (44.30h) and by 35% by BEN (36.49h), but other silages had similar values (27.0±1.13h). 23922931 Analysis of unannotated equine transcripts identified by mRNA sequencing. Sequencing of equine mRNA (RNA-seq) identified 428 putative transcripts which do not map to any previously annotated or predicted horse genes. Most of these encode the equine homologs of known protein-coding genes described in other species, yet the potential exists to identify novel and perhaps equine-specific gene structures. A set of 36 transcripts were prioritized for further study by filtering for levels of expression (depth of RNA-seq read coverage), distance from annotated features in the equine genome, the number of putative exons, and patterns of gene expression between tissues. From these, four were selected for further investigation based on predicted open reading frames of greater than or equal to 50 amino acids and lack of detectable homology to known genes across species. Sanger sequencing of RT-PCR amplicons from additional equine samples confirmed expression and structural annotation of each transcript. Functional predictions were made by conserved domain searches. A single transcript, expressed in the cerebellum, contains a putative kruppel-associated box (KRAB) domain, suggesting a potential function associated with zinc finger proteins and transcriptional regulation. Overall levels of conserved synteny and sequence conservation across a 1MB region surrounding each transcript were approximately 73% compared to the human, canine, and bovine genomes; however, the four loci display some areas of low conservation and sequence inversion in regions that immediately flank these previously unannotated equine transcripts. Taken together, the evidence suggests that these four transcripts are likely to be equine-specific. 23857907 Ku70 and non-homologous end joining protect testicular cells from DNA damage. Spermatogenesis is a complex process that generates haploid germ cells or spores and implements meiosis, a succession of two special cell divisions that are required for homologous chromosome segregation. During prophase to the first meiotic division, homologous recombination (HR) repairs Spo11-dependent DNA double-strand breaks (DSBs) in the presence of telomere movements to allow for chromosome pairing and segregation at the meiosis I division. In contrast to HR, non-homologous end joining (NHEJ), the major DSB repair mechanism during the G1 cell cycle phase, is downregulated during early meiotic prophase. At somatic mammalian telomeres, the NHEJ factor Ku70/80 inhibits HR, as does the Rap1 component of the shelterin complex. Here, we investigated the role of Ku70 and Rap1 in meiotic telomere redistribution and genome protection in spermatogenesis by studying single and double knockout mice. Ku70(-/-) mice display reduced testis size and compromised spermatogenesis, whereas meiotic telomere dynamics and chromosomal bouquet formation occurred normally in Ku70(-/-) and Ku70(-/-)Rap1(Δ/Δ) knockout spermatocytes. Elevated mid-preleptotene frequencies were associated with significantly increased DNA damage in Ku-deficient B spermatogonia, and in differentiated Sertoli cells. Significantly elevated levels of γH2AX foci in Ku70(-/-) diplotene spermatocytes suggest compromised progression of DNA repair at a subset of DSBs. This might explain the elevated meiotic metaphase apoptosis that is present in Ku70-deficient stage XII testis tubules, indicating spindle assembly checkpoint activation. In summary, our data indicate that Ku70 is important for repairing DSBs in somatic cells and in late spermatocytes of the testis, thereby assuring the fidelity of spermatogenesis. 23816000 Surgeon-performed ultrasound for primary hyperparathyroidism. The role of preoperative parathyroid imaging continues to evolve. This study evaluated whether surgeon-performed ultrasound (U/S) obviates the need for other imaging studies and leads to a focused exploration with a high degree of surgical success. From July 2010 to February 2012, 200 patients presenting with nonfamilial primary hyperparathyroidism underwent neck U/S in the surgeon's office. The U/S interpretation was classified as Class 1 if an adenoma was identified with high confidence, Class 2 if a possible but not definite enlarged gland was imaged, and Class 0 (zero) if no adenoma was identified. The findings were correlated with subsequent intraoperative findings. There were 144 Class 1 U/Ss (72%); of 132 patients coming to surgery, 96.2 per cent had surgical findings concordant with preoperative U/S and all had apparent surgical cure. Twenty-nine patients (14.5%) had Class 2 U/S; the 31 per cent confirmed false-positives in this group were usually colloid nodules. Fourteen of 27 with Class 0 U/S underwent surgery after being offered dynamically enhanced computed tomography scan. All 200 patients were apparent surgical cures. Surgeon-performed U/S is expedient, convenient, inexpensive, and accurate. A clearly identified adenoma can safely lead to a focused limited exploration and avoid additional imaging 93 per cent of the time. 23851503 Autocrine/paracrine mechanism of interleukin-17B receptor promotes breast tumorigenesis through NF-κB-mediated antiapoptotic pathway. Gain of function of membrane receptor was a good strategy exploited by cancer cells to benefit own growth and survival. Overexpression of HER2 has been found to serve as a target for developing trastuzumab to treat 20-25% of breast cancer. However, little or none of the other membrane receptor was found to be useful as a potential target for breast cancer treatment since then. Here, we showed that amplified signaling of interleukin-17 receptor B (IL-17RB) and its ligand IL-17B promoted tumorigenicity in breast cancer cells and impeded acinus formation in immortalized normal mammary epithelial cells. External signal transmitted through IL-17RB activated nuclear factor-κB to upregulate antiapoptotic factor Bcl-2 and induced etoposide resistance. Elevated expression of IL-17RB had a stronger correlation with poor prognosis than HER2 in breast cancer patients. Interestingly, breast cancer patients with high expression of IL-17RB and HER2 had the shortest survival rate. Depletion of IL-17RB in trastuzumab-resistant breast cancer cells significantly reduced their tumorigenic activity, suggesting that IL-17RB and HER2 have an independent role in breast carcinogenesis. Furthermore, treatment with antibodies specifically against IL-17RB or IL-17B effectively attenuated tumorigenicity of breast cancer cells. These results suggest that the amplified IL-17RB/IL-17B signaling pathways may serve as a therapeutic target for developing treatment to manage IL-17RB-associated breast cancer.Oncogene advance online publication, 15 July 2013; doi:10.1038/onc.2013.268. 23895778 The efficiency of combined CaO/electrochemical treatment in removal of acid mine drainage induced toxicity and genotoxicity. Acid mine drainage (AMD) is a by-product of the mining industry that has a detrimental effect on aquatic plant and animal life due to high load of heavy metals and sulfates. In the present study, the toxic and genotoxic potential of AMD prior to and following combination of neutralization/electrocoagulation processes was evaluated using several bioassays and selected parameters. Regardless of pH correction of AMD prior to Daphnia bioassay, high acute toxicity was observed in Daphnia magna. The mine leachate also induced strong phyto-, cyto- and genotoxicity to Allium cepa roots. Short term exposure to AMD inhibited duckweed growth and chlorophyll a content and simultaneously promoted lipid peroxidation and DNA damage despite duckweed capability to upregulate antioxidative defense mechanisms. The results show that observed (geno)toxicity could be related to oxidative stress most probably induced by toxic metal action. However, influence of low pH as a contributing factor in the phytotoxicity of AMD cannot be excluded. The application of combined treatment eliminated genotoxicity and was highly efficient in reducing toxicity of AMD. Thus, the method seems to be suitable for treatment of AMD waters enabling their safe discharge to an aquatic environment. 23934505 Internal Mammary Sentinel Node Biopsy in Breast Cancer. Is it Indicated? Axillary sentinel node (A-SN) biopsy is a standard procedure in breast cancer surgery. Sampling of intenal mammary sentinel nodes (IM-SN) is not performed routinly, although it is also considered an important prognostic factor of breast cancer. The role of this latter procedure was investigated in cases of IM-SN visualized on lymphoscintigraphy. Between January 2001 and June 2012 1542 patients with clinically node negative operable primary breast cancer had sentinel node biopsy (SNB). Both axillary and IM-SN were sampled (whenever detected), based on lymphoscintigraphy, intraoperative gamma probe detection and blu dye mapping. Lymphoscintigraphy showed IM-SN in 83 cases. IM-SN biopsy (IM-SNB) was succesfull in 77 patients (93 %). A total of 86 IM-SNs were removed. IM-SN involvement was identified in 14 cases, representing 18 % of patients who underwent IM-SNB. This included macrometastases (MAC) in 5 cases, micrometastases (MIC) in 2 cases, isolated tumor cells (ITC) in 7 cases. No significant differences were found between patients with and without IM-SN involvement in terms of age, tumor location, tumor size, axillary involvement, tumor grade or estrogen receptor status. The IM-SN involvement has lead to new therapeutic indications in 2 cases (2.6 %), both of them due to MAC in the IM-SN: in 1 case change in chemotherapy and in 1 case change in radiotherapy, with the addition of iradiation of the internal mammary chain. Based on this series and information from the literature, we conclude that the indication for an IM-SNB procedure is very limited and its routine use should not be recommended. 23360529 Is Gender Responsible for Everything? The Relationship between Sex and Right Ventricular Remodeling in Metabolic Syndrome. The aim of this study was to examine the impact of metabolic syndrome (MS) on right ventricular (RV) remodeling in different genders. The study included 341 subjects (216 subjects with MS and 125 controls). MS was defined by the presence of ≥3 ATP-NCEP-III criteria. All subjects underwent complete two-dimensional echocardiography. RV structure, diastolic, and global function were significantly impaired in MS subjects, in both genders. The multiple regression analysis of MS parameters showed that systolic blood pressure (BP) and waist circumference were independently associated with RV wall thickness in women, whereas the only independent predictor in men was systolic BP. The multivariate logistic regression analysis revealed that increased BP, impaired fasting glucose, and dyslipidemia were a combination of MS risk factors related with RV hypertrophy solely in women. Increased systolic BP, impaired fasting glucose, and abdominal obesity were independently associated with tricuspid E/e' in women, whereas increased systolic BP was the only independent predictor in men. Impaired fasting glucose, abdominal obesity, and dyslipidemia were a combination of MS criteria, which was independently associated with RV diastolic dysfunction only in women. Different parameters of MS are responsible for RV remodeling in women and men. The metabolic parameters of MS are more important for RV remodeling in women. 23864221 Assessing Thalamocortical Functional Connectivity With Granger Causality. Assessment of network connectivity across multiple brain regions is critical to understanding the mechanisms underlying various neurological disorders. Conventional methods for assessing dynamic interactions include cross-correlation and coherence analysis. However, these methods do not reveal the direction of information flow, which is important for studying the highly directional neurological system. Granger causality (GC) analysis can characterize the directional influences between two systems. We tested GC analysis for its capability to capture directional interactions within both simulated and in-vivo neural networks. The simulated networks consisted of Hindmarsh-Rose neurons; GC analysis was used to estimate the causal influences between two model networks. Our analysis successfully detected asymmetrical interactions between these networks (p<10-10, t-test). Next, we characterized the relationship between the "electrical synaptic strength" in the model networks and interactions estimated by GC analysis. We demonstrated the novel application of GC to monitor interactions between thalamic and cortical neurons following ischemia induced brain injury in a rat model of cardiac arrest (CA). We observed that during the post-CA acute period the GC interactions from the thalamus to the cortex were consistently higher than those from the cortex to the thalamus (1.983±0.278 times higher, p=0.021). In addition, the dynamics of GC interactions between the thalamus and the cortex were frequency dependent. Our study demonstrated the feasibility of GC to monitor the dynamics of thalamocortical interactions after a global nervous system injury such as CA-induced ischemia, and offers preferred alternative applications in characterizing other inter-regional interactions in an injured brain. 23951703 Estimated losses of plant biodiversity in the United States from historical N deposition (1985-2010). Although nitrogen (N) deposition is a significant threat to herbaceous plant biodiversity worldwide, it is not a new stressor for many developed regions. Only recently has it become possible to estimate historical impacts nationally for the United States. We used 26 years (1985-2010) of deposition data, with ecosystem-specific functional responses from local field experiments and a national critical loads (CL) database, to generate scenario-based estimates of herbaceous species loss. Here we show that, in scenarios using the low end of the CL range, N deposition exceeded critical loads over 0.38, 6.5, 13.1, 88.6, and 222.1 million ha for the Mediterranean California, North American Desert, Northwestern Forested Mountains, Great Plains, and Eastern Forest ecoregions, respectively, with corresponding species losses ranging from < 1% to 30%. When we ran scenarios assuming ecosystems were less sensitive (using a common CL of 10 kg x ha(-1) x yr(-1), and the high end of the CL range) minimal losses were estimated. The large range in projected impacts among scenarios implies uncertainty as to whether current critical loads provide protection to terrestrial plant biodiversity nationally and urge greater research in refining critical loads for U.S. ecosystems. 23863006 Ideal gas behavior of a strongly coupled complex (dusty) plasma. In a laboratory, a two-dimensional complex (dusty) plasma consists of a low-density ionized gas containing a confined suspension of Yukawa-coupled plastic microspheres. For an initial crystal-like form, we report ideal gas behavior in this strongly coupled system during shock-wave experiments. This evidence supports the use of the ideal gas law as the equation of state for soft crystals such as those formed by dusty plasmas. 23931382 Concentration of Vacancies at Metal-Oxide Surfaces: Case Study of MgO(100). We investigate the effects of doping on the formation energy and concentration of oxygen vacancies at a metal-oxide surface, using MgO(100) as an example. Our approach employs density-functional theory, where the performance of the exchange-correlation functional is carefully analyzed, and the functional is chosen according to a condition on density-functional theory ionization energies. The approach is further validated by coupled-cluster calculations, including single, double, and perturbative triple substitutions, for embedded clusters. We demonstrate that the concentration of oxygen vacancies at a doped oxide surface is largely determined by the formation of a macroscopically extended space-charge region. 23897686 Plasma membrane-cortical cytoskeleton interactions: a cell biology approach with biophysical considerations. From a biophysical standpoint, the interface between the cell membrane and the cytoskeleton is an intriguing site where a "two-dimensional fluid" interacts with an exceedingly complex three-dimensional protein meshwork. The membrane is a key regulator of the cytoskeleton, which not only provides docking sites for cytoskeletal elements through transmembrane proteins, lipid binding-based, and electrostatic interactions, but also serves as the source of the signaling events and molecules that control cytoskeletal organization and remolding. Conversely, the cytoskeleton is a key determinant of the biophysical and biochemical properties of the membrane, including its shape, tension, movement, composition, as well as the mobility, partitioning, and recycling of its constituents. From a cell biological standpoint, the membrane-cytoskeleton interplay underlies-as a central executor and/or regulator-a multitude of complex processes including chemical and mechanical signal transduction, motility/migration, endo-/exo-/phagocytosis, and other forms of membrane traffic, cell-cell, and cell-matrix adhesion. The aim of this article is to provide an overview of the tight structural and functional coupling between the membrane and the cytoskeleton. As biophysical approaches, both theoretical and experimental, proved to be instrumental for our understanding of the membrane/cytoskeleton interplay, this review will "oscillate" between the cell biological phenomena and the corresponding biophysical principles and considerations. After describing the types of connections between the membrane and the cytoskeleton, we will focus on a few key physical parameters and processes (force generation, curvature, tension, and surface charge) and will discuss how these contribute to a variety of fundamental cell biological functions. © 2013 American Physiological Society. Compr Physiol 3:1231-1281, 2013. 23828607 Biomineral Proteins from Mytilus edulis Mantle Tissue Transcriptome. The common blue mussel, Mytilus edulis, has a bimineralic shell composed of approximately equal proportions of the two major polymorphs of calcium carbonate: calcite and aragonite. The exquisite biological control of polymorph production is the focus of research interest in terms of understanding the details of biomineralisation and the proteins involved in the process of complex shell formation. Recent advances in ease and availability of pyrosequencing and assembly have resulted in a sharp increase in transcriptome data for invertebrate biominerals. We have applied Roche 454 pyrosequencing technology to profile the transcriptome for the mantle tissue of the bivalve M. edulis. A comparison was made between the results of several assembly programs: Roche Newbler assembler versions 2.3, 2.5.2 and 2.6 and MIRA 3.2.1 and 3.4.0. The Newbler and MIRA assemblies were subsequently merged using the CAP3 assembler to give a higher consensus in alignments and a more accurate estimate of the true size of the M. edulis transcriptome. Comparison sequence searches show that the mantle transcripts for M. edulis encode putative proteins exhibiting sequence similarities with previously characterised shell proteins of other species of Mytilus, the Bivalvia Pinctada and haliotid gastropods. Importantly, this enhanced transcriptome has detected several transcripts that encode proteins with sequence similarity with previously described shell biomineral proteins including Shematrins and lysine-rich matrix proteins (KRMPs) not previously found in Mytilus. 23841960 Postprandial effect of dietary fat quantity and quality on arterial stiffness and wave reflection: a randomised controlled trial. Arterial stiffness is a component of vascular function and an established risk factor for cardiovascular disease. There is a lack of conclusive evidence on the effect of a meal rich in monounsaturated fat (MUFA) compared with an isoenergetic meal rich in saturated fat (SFA) on postprandial vascular function and specifically on arterial stiffness. Twenty healthy, non-smoking males (BMI 24 +/- 2 kg/m2; age 37.7 +/- 14.4 y) participated in this single-blind, randomised, cross-over dietary intervention study. Each subject was randomised to receive a high-fat test-meal (3 MJ; 56 +/- 2 g fat) at breakfast on 2 separate occasions, one rich in oleic acid (MUFA-meal) and one rich in palmitic acid (SFA-meal), and the meals were isoenergetic. Blood pressure (BP), arterial stiffness (PWV) and arterial wave reflection (augmentation index, AIx) were measured using applanation tonometry at baseline and every 30 minutes up to 4 hours after the ingestion of the test-meals. All subjects completed both arms of the dietary intervention. There was no significant difference in BP parameters, PWV or AIx at baseline between the two treatments (P > 0.05). There was a significant increase in brachial and aortic BP, mean arterial pressure (MAP), heart rate and PVW (time, P < 0.05) over the four hours after consumption of the fat-rich test-meal although the increase in PWV was no longer significant when adjusted for the increase in MAP. There was no difference in PWV between the two treatments (treatment*time, P > 0.05). There was a significant reduction in AIx (time, P < 0.05) over the four hour postprandial period although this was no longer significant when adjusted for the increase in heart rate and MAP (time, P > 0.05). There was no difference in AIx between the two treatments (treatment*time, P > 0.05). However, the reduction in heart rate corrected augmentation index (AIx75) was significant when corrected for the increase in MAP (time, P < 0.01) with no differential effect of the treatments (treatment*time, P > 0.05). This study has demonstrated a BP dependent increase in PWV and a decrease in arterial wave reflection in the four hour period in response to a high-fat meal. There was no evidence however that replacement of some of the SFA with MUFA had a differential effect on these parameters. The study highlights the need for further research to understand the effects of the substitution of SFA with MUFA on non-serum, new and emerging risk factors for CVD such as arterial stiffness. 23960241 MicroRNA-Mediated Epigenetic Silencing of Sirtuin1 Contributes to Impaired Angiogenic Responses. Rationale: Transforming growth factor (TGF)-beta was linked to abnormal vessel function and can mediate impairment of endothelial angiogenic responses. Its effect on microRNAs and downstream targets in this context is not known. Objective: To study the role of miRNAs in TGF-beta mediated angiogenic activity. Methods and Results: MiRNA profiling after TGF-beta treatment of endothelial cells identified miR-30a-3p, along with other members of the miR-30 family, to be strongly silenced. Supplementation of miR-30a-3p restored function in TGF-beta treated endothelial cells. We identified the epigenetic factor Methyl CpG binding protein 2 (MeCP2) to be a direct and functional target of miR-30a-3p. Viral over-expression of MeCP2 mimicked effects of TGF-beta, suggesting that de-repression of MeCP2 after TGF-beta treatment may be responsible for impaired angiogenic responses. Silencing of MeCP2 rescued detrimental TGF-beta effects on endothelial cells. Microarray transcriptome analysis of MeCP2 over-expressing endothelial cells identified several deregulated genes important for endothelial cell function including Sirtuin1. In vivo, experiments employing endothelial cell-specific MeCP2 null or Sirtuin1 transgenic mice confirmed involvement of MeCP2/Sirt1 in the regulation of angiogenic functions of endothelial cells. Further experiments identified that MeCP2 inhibited endothelial angiogenic characteristics partly by epigenetic silencing of Sirtuin1. Conclusions: TGF-beta impairs endothelial angiogenic responses partly by down-regulating miR-30a-3p and subsequent de-repression of MeCP2-mediated epigenetic silencing of Sirtuin1. 23934765 Butterfly-Shaped Pentanuclear Dysprosium Single-Molecule Magnets. Two new "butterfly-shaped" pentanuclear dysprosium(III) clusters, [Dy5 (μ3 -OH)3 (opch)6 (H2 O)3 ]⋅3 MeOH⋅ 9 H2 O (1) and [Dy5 (μ3 -OH)3 (Hopch)2 (opch)4 (MeOH)(H2 O)2 ]⋅(ClO4 )2 ⋅ 6 MeOH⋅4 H2 O (2), which were based on the heterodonor-chelating ligand o-vanillin pyrazine acylhydrazone (H2 opch), have been successfully synthesized by applying different reaction conditions. Single-crystal X-ray diffraction analysis revealed that the butterfly-shaped cores in both compounds were comparable. However, their magnetic properties were drastically different. Indeed, compound 1 showed dual slow-relaxation processes with a transition between them that corresponded to energy gaps (Δ) of 8.1 and 37.9 K and pre-exponential factors (τ0 ) of 1.7×10(-5) and 9.7×10(-8)  s for the low- and high-temperature domains, respectively, whilst only a single relaxation process was noted for compound 2 (Δ=197 K, τ0 =3.2×10(-9)  s). These significant disparities are most likely due to the versatile coordination of the H2 opch ligands with particular keto-enol tautomerism, which alters the strength of the local crystal field and, hence, the nature or direction of the easy axes of anisotropic dysprosium ions. 23963453 MEKK2 association with 14-3-3 regulates activation of c-Jun N-terminal kinase. MEKK2 (MAP/ERK kinase kinase-2) is a serine/threonine kinase that belongs to the MEKK/STE11 family of MAP(3)Ks. MEKK2 integrates stress- and mitogenic signals to the activation of NF-κB, JNK1/2, p38 and ERK5 pathways. We have found that MEKK2 is regulated through a phosphorylation-dependent association with 14-3-3, a group of adapters that modulate dimerization and association between proteins. We found that MEKK2 was phosphorylated at T283, which resulted in decreased activation loop phosphorylation at S519 and consequently reduced activity. Mechanistically, we found that MEKK2 associated with inactive MEKK2 in the absence of 14-3-3 binding, which led to trans-autophosphorylation of S519. Enforced binding with 14-3-3 reduced S519 trans-autophosphorylation. Expression of T283A MEKK2 within a MEKK2-/- background enhanced stress-activated c-Jun N-terminal kinase activity while elevating IL-6 expression, but also reduced ERK activation with a corresponding reduced proliferation rate. These results indicate that T283 phosphorylation is an important regulatory mechanism for MEKK2 activation. 23792911 Organization and functionality of chlorophyll-protein complexes in thylakoid membranes isolated from Pb-treated Secale cereale. In this study, Secale cereale seedlings cultivated under 0 (control), 2 or 5mM Pb(NO3)2 concentrations were used to examine alterations in the organization and functionality of chlorophyll-protein complexes in thylakoid membranes under Pb ion stress. The studies were conducted on whole leaves of rye seedlings or thylakoid membranes isolated from Pb-treated and control plants. Using non-denaturing electrophoresis, it was assessed that increasing Pb concentrations resulted in an increase in the value of the ratio of the content of LHCII oligomers (mainly trimers) to the content of LHCII monomers. The parameters of chlorophyll fluorescence induction (qp and qn) indicated that the change in the LHCII supramolecular organization in the presence of Pb ions was connected with an increase in non-photochemical fluorescence quenching. Quantification of photosynthetic pigments showed that both Pb concentrations decreased the content of chlorophyll a, chlorophyll b, and carotenoids. The changes in the pigment content led to a significant reduction in light absorption by antenna complexes. However, the absorption spectra showed that red light was preferentially absorbed by antenna complexes in thylakoid membranes isolated from the Pb-treated plants. Examination of fluorescence emission spectra revealed that Pb ions decreased the fluorescence quantum yield of PSII. The emission spectra of thylakoids indicated a relative increase in the intensity of fluorescence emission from the trimeric and aggregated forms of the LHCII complexes in comparison to the intensity of fluorescence emission from PSI antenna complexes under excitation at 440nm. Simultaneously, under excitation at 470nm, we observed a rise in fluorescence intensity from the LHCII trimer after addition of 5mM Pb as well as a decrease in fluorescence intensity from the LHCII aggregates and PSI core and LHCI antenna complexes under both Pb concentrations. Pb treatments also reduced excitation energy absorbed by chlorophyll b and carotenoids within antenna complexes and transferred to chlorophyll a species emitting at 680nm. 23967084 Localisation of Nursery Areas Based on Comparative Analyses of the Horizontal and Vertical Distribution Patterns of Juvenile Baltic Cod (Gadus morhua). Knowledge of the spatial distribution of juvenile cod is essential for obtaining precise recruitment data to conduct sustainable management of the eastern and western Baltic cod stocks. In this study, the horizontal and vertical distribution and density patterns of settled juvenile 0- and 1-group Baltic cod are determined, and their nursery areas are localised according to the environmental factors affecting them. Comparative statistical analyses of biological, hydrographic and hydroacoustic data are carried out based on standard ICES demersal trawl surveys and special integrated trawl and acoustic research surveys. Horizontal distribution maps for the 2001-2010 cohorts of juvenile cod are further generated by applying a statistical log-Gaussian Cox process model to the standard trawl survey data. The analyses indicate size-dependent horizontal and distinct vertical and diurnal distribution patterns related to the seabed topography, water layer depth, and the presence of hydrographic frontal zones (pycnoclines) as well as intraspecific patterns in relation to the presence of adult cod. The extent of the nursery areas also depends on the cod year class strength. Juvenile cod (≥3 cm) are present in all areas of the central Baltic Sea (CBS), showing broad dispersal. However, their highest density in the Baltic Basins is found at localities with a 40-70 m bottom depth in waters with oxygen concentrations above 2 ml O2.l(-1) and temperatures above 5°C. The smallest juveniles are also found in deep sea localities down to a 100 m depth and at oxygen concentrations between 2-4 ml O2.l(-1). The vertical, diurnally stratified and repeated trawling and hydroacoustic target strength-depth distributions obtained from the special surveys show juvenile cod concentrations in frontal zone water layers (pycnocline). However, the analyses indicate that in the CBS, juvenile cod of all sizes do not appear to aggregate in dense schooling patterns, which differs from what has been reported from the North Sea. 23895779 Speciation and toxicity of arsenic in mining-affected lake sediments in the Quinsam watershed, British Columbia. Anthropogenic arsenic inputs into fresh water lakes in the Quinsam watershed, British Columbia, were probed by using multiple methods of inquiry including sediment coring combined with (210)Pb dating, a principal components analysis of elemental composition of sediments, arsenic speciation, bioaccessibility, and toxicity testing. The quantification of arsenic inputs from anthropogenic sources was not trivial because a variety of processes redistribute the element throughout lakes. However, elevated arsenic and sulfate concentrations in Long Lake, a lake that receives arsenic from a seep, suggest that this lake is influenced by mine operations. X-ray absorption near edge structure (XANES) spectra reveal similar arsenic speciation for all sediments within the studied lakes. Bioaccessibility tests, which in this study were used to approximate the solubility and availability of arsenic to benthic organisms, indicate moderate bioaccessibility of arsenic in sediments (7.9-35%). Toxicity testing indicates that not all benthic organisms should be used for evaluating arsenic toxicity, and suggests that the amphipod, Corophium volutator, shows promise as a candidate for widespread use for arsenic sediment toxicity testing. 23721665 Preparation of samples with both hard and soft phases for electron backscatter diffraction: examples from gold mineralization. Preparation of high-quality polished sample surfaces is an essential step in the collection of microanalytical data on the microstructures of minerals and alloys. Poorly prepared samples can yield insufficient or inconsistent results and, in the case of gold, potentially no data due to the "beilby" layer. Currently, preparation of ore samples is difficult as they commonly contain both hard and soft mineral phases. The aim of our research is to produce suitably polished sample surfaces, on all phases, for electron backscatter diffraction analysis. A combination of chemical-mechanical polishing (CMP) and broad ion-beam polishing (BIBP) was used to tackle the problem. Our results show that it is critical to perform CMP first, as it produces a suitable polish on the hard mineral phases but tends to introduce more damage to the soft mineral surfaces. BIBP is essential to produce a high-quality polish to the soft phases (gold). This is a highly efficient method of sample preparation and is important as it allows the complete quantification of ore textures and all constituent mineral phases, including soft alloys. 23909622 Efficient Dendrimer-DNA Complexation and Gene Delivery Vector Properties of Nitrogen-Core Poly(propyl ether imine) Dendrimer in Mammalian Cells. Dendrimers as vectors for gene delivery were established, primarily by utilizing few prominent dendrimer types so far. We report herein studies of DNA complexation efficacies and gene delivery vector properties of a nitrogen-core poly(propyl ether imine) (PETIM) dendrimer, constituted with 22 tertiary amine internal branches and 24 primary amines at the periphery. The interaction of the dendrimer with pEGFPDNA was evaluated through UV-vis, circular dichroism (CD) spectral studies, ethidium bromide fluorescence emission quenching, thermal melting, and gel retardation assays, from which most changes to DNA structure during complexation was found to occur at a weight ratio of dendrimer:DNA ∼ 2:1. The zeta potential measurements further confirmed this stoichiometry at electroneutrality. The structure of a DNA oligomer upon dendrimer complexation was simulated through molecular modeling and the simulation showed that the dendrimer enfolded DNA oligomer along both major and minor grooves, without causing DNA deformation, in 1:1 and 2:1 dendrimer-to-DNA complexes. Atomic force microscopy (AFM) studies on dendrimer-pEGFP DNA complex showed an increase in the average z-height as a result of dendrimers decorating the DNA, without causing a distortion of the DNA structure. Cytotoxicity studies involving five different mammalian cell lines, using [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide] (MTT) assay, reveal the dendrimer toxicity profile (IC50) values of ∼400-1000 μg mL(-1), depending on the cell line tested. Quantitative estimation, using luciferase assay, showed that the gene transfection was at least 100 times higher when compared to poly(ethylene imine) branched polymer, having similar number of cationic sites as the dendrimer. The present study establishes the physicochemical behavior of new nitrogen-core PETIM dendrimer-DNA complexes, their lower toxicities, and efficient gene delivery vector properties. 23815671 Interactive effect of STAT6 and IL13 gene polymorphisms on eczema status: results from a longitudinal and a cross-sectional study. Eczema is a prevalent skin disease that is mainly characterized by systemic deviation of immune response and defective epidermal barrier. Th2 cytokines, such as IL-13 and transcription factor STAT6 are key elements in the inflammatory response that characterize allergic disorders, including eczema. Previous genetic association studies showed inconsistent results for the association of single nucleotide polymorphisms (SNPs) with eczema. Our aim was to investigate whether SNPs in IL13 and STAT6 genes, which share a biological pathway, have an interactive effect on eczema risk. Data from two independent population-based studies were analyzed, namely the Isle of Wight birth cohort study (IOW; n = 1,456) and for the purpose of replication the Swansea PAPA (Poblogaeth Asthma Prifysgol Abertawe; n = 1,445) cross-sectional study. Log-binomial regressions were applied to (i) account for the interaction between IL13 (rs20541) and STAT6 (rs1059513) polymorphisms and (ii) estimate the combined effect, in terms of risk ratios (RRs), of both risk factors on the risk of eczema. Under a dominant genetic model, the interaction term [IL13 (rs20541) × STAT6 (rs1059513)] was statistically significant in both studies (IOW: adjusted P(interaction) = 0.046; PAPA: P(interaction) = 0.037). The assessment of the combined effect associated with having risk genotypes in both SNPs yielded a 1.52-fold increased risk of eczema in the IOW study (95% confidence interval (CI): 1.05 - 2.20; P = 0.028) and a 2.01-fold higher risk of eczema (95% CI: 1.29 - 3.12; P = 0.002) in the PAPA study population. Our study adds to the current knowledge of genetic susceptibility by demonstrating for the first time an interactive effect between SNPs in IL13 (rs20541) and STAT6 (rs1059513) on the occurrence of eczema in two independent samples. Findings of this report further support the emerging evidence that points toward the existence of genetic effects that occur via complex networks involving gene-gene interactions (epistasis). 23943502 MiR-29c inhibits glioma cell proliferation, migration, invasion and angiogenesis. Previous studies reported that miR-29c is significantly downregulated in several tumors. However, little is known about the effect and molecular mechanisms of action of miR-29c in human glioma. Using quantitative RT-PCR, we demonstrated that miR-29c was significantly downregulated in glioma cell lines and human primary glioma tissues, compared to normal human astrocytes and matched non-tumor associated tissues (P < 0.05, χ(2) test). Overexpression of miR-29c dramatically reduced the proliferation and caused cessation of cell cycle. The reduced cell proliferation is due to G1 phase arrest as cyclin D1 and cyclin E are diminished whereas p27 and p21 are upregulated. We further demonstrated that miR-29c overexpression suppressed the glioma cell migration and invasion abilities by targeting MMP-2. In addition, we also found that overexpression of miR-29c sharply inhibited angiogenesis, which correlated with down-regulation of VEGF. The data indicate that miR-29c may be a tumor suppressor involved in the progression of glioma. 23877234 Different regulatory pathways are involved in the proliferative inhibition of two types of leukemia cell lines induced by paclitaxel. Paclitaxel, one of the broadest-spectrum anticancer agents, is currently being used in the treatment of patients with solid tumors. In the present study, we compared the effect of paclitaxel on two types of leukemia cells. Our results showed that paclitaxel could inhibit the proliferation of MEL and K562 cells in a dose- and time-dependent manner. The mechanism of proliferative inhibition in K562 cells treated by paclitaxel was related to the cell cycle arrest in the G2/M phase, as well as the induction of apoptosis. By contrast, MEL cells treated by paclitaxel showed significant characteristics of necrosis, which indicated that the mode of cell death induced by paclitaxel in these two types of leukemia cells differed. Advances in research of the cell cycle, apoptosis and necrosis will extend our understanding of the mechanisms of paclitaxel-induced cell death, particularly in leukemia cells. Further elucidation of the mechanisms of necrosis in MEL cells may expedite the development of improved paclitaxel-based regimens for cancer therapy. 23926328 Seroepidemiology of Hepatitis E Virus Infection in an Urban Population in Zambia: Strong Association With HIV and Environmental Enteropathy. Background. Hepatitis E virus (HEV) infection causes major epidemics of infectious hepatitis, with high mortality rates in pregnant women. Recent reports indicate that HEV coinfections with human immunodeficiency virus (HIV) may have a more protracted course. However, the impact of HEV infections in communities heavily affected by HIV remains poorly studied. We set out to examine age-related seroprevalence in a community where we have previously carried out studies on environmental enteropathy.Methods. Blood samples from 194 children and 106 adults were examined for immunoglobulin G and immunoglobulin M antibodies for HEV. HEV data were correlated with HIV status and morphometric analysis of small intestinal biopsies.Results. Seroprevalence rose throughout childhood, from 8% in children aged 1-4 years, to 36% in children aged 10-14 years. In adults, the overall prevalence was 42%, with 28% in HIV-seronegative adults and 71% in HIV-seropositive adults (odds ratio, 6.2; 95% confidence interval, 2.2-18; P = .0001). In adults, villous height and crypt depth measurements showed that HEV seropositivity was associated with worse enteropathy (P = .05 and P = .005, respectively).Conclusions. HEV infection is common in Zambia. In adults it is strongly associated with HIV status, and also with environmental enteropathy. 23862942 Dissipation of alignment in CO2 gas: A comparison between ab initio predictions and experiments. We present comparisons between measurements and ab initio calculations of the dissipation of the nonadiabatic laser-induced alignment in pure CO2 and CO2-He gas mixtures. The experiments were made for pressures between 2 and 20 bars at 295 K by using short non-resonant linearly polarized laser pulses for alignment and probe. The calculations are carried, free of any adjusted parameter, using refined intermolecular potentials and a requantized Classical Molecular Dynamics Simulations approach presented previously but not yet confronted to experiments. The results demonstrate that the model accurately reproduces the decays with time of both the transient revivals and "permanent" component of the alignment. The significant differences observed between the behaviors resulting from CO2-CO2 and CO2-He collisions are also well predicted by the model. 23848374 A review of longitudinal community and hospital placements in medical education: BEME Guide No. 26. Background: Traditionally, clinical learning for medical students consists of short-term and opportunistic encounters with primarily acute-care patients, supervised by an array of clinician preceptors. In response to educational concerns, some medical schools have developed longitudinal placements rather than short-term rotations. Many of these longitudinal placements are also integrated across the core clinical disciplines, are commonly termed longitudinal integrated clerkships (LICs) and often situated in rural locations. This review aimed to explore, analyse and synthesise evidence relating to the effectiveness of longitudinal placements, for medical students in particular to determine which aspects are most critical to successful outcomes. Method: Extensive search of the literature resulted in 1679 papers and abstracts being considered, with 53 papers ultimately being included for review. The review group coded these 53 papers according to standard BEME review guidelines. Specific information extracted included: data relating to effectiveness, the location of the study, number of students involved, format, length and description of placement, the learning outcomes, research design, the impact level for evaluation and the main evaluation methods and findings. We applied a realist approach to consider what works well for whom and under what circumstances. Findings: The early LICs were all community-based immersion programs, situated in general practice and predominantly in rural settings. More recent LIC innovations were situated in tertiary-level specialist ambulatory care in urban settings. Not all placements were integrated across medical disciplines but were longitudinal in relation to location, patient base and/or supervision. Twenty-four papers focussed on one of four programs from different viewpoints. Most evaluations were student opinion (survey, interview, focus group) and/or student assessment results. Placements varied from one half day per week for six months through to full time immersion for more than 12 months. The predominant mechanism relating to factors influencing effectiveness was continuity of one or more of: patient care, supervision and mentorship, peer group and location. The success of LICs and participation satisfaction depended on the preparation of both students and clinical supervisors, and the level of support each received from their academic institutions. Conclusion: Longitudinal placements, including longitudinal integrated placements, are gaining in popularity as an alternative to traditional block rotations. Although relatively few established LICs currently exist, medical schools may look for ways to incorporate some of the principles of LICs more generally in their clinical education programmes. Further research is required to ascertain the optimum length of time for placements depending on the defined learning outcomes and timing within the programme, which students are most likely to benefit and the effects of context such as location and type of integration. 23925503 Propagation of nanopores during anodic etching of n-InP in KOH. We propose a three-step model of electrochemical nanopore formation in n-InP in KOH that explains how crystallographically oriented etching can occur even though the rate-determining process (hole generation) occurs only at pore tips. The model shows that competition in kinetics between hole diffusion and electrochemical reaction determines the average diffusion distance of holes along the semiconductor surface and this, in turn, determines whether etching is crystallographic. If the kinetics of reaction are slow relative to diffusion, etching can occur at preferred crystallographic sites within a zone in the vicinity of the pore tip, leading to pore propagation in preferential directions. Symmetrical etching of three {111}A faces forming the pore tip causes it to propagate in the (remaining) 〈111〉A direction. As a pore etches, propagating atomic ledges can meet to form sites that can become new pore tips and this enables branching of pores along any of the 〈111〉A directions. The model explains the observed uniform width of pores and its variation with temperature, carrier concentration and electrolyte concentration. It also explains pore wall thickness, and deviations of pore propagation from the 〈111〉A directions. We believe that the model is generally applicable to electrochemical pore formation in III-V semiconductors. 23371014 Screening patterns in patients with a family history of colorectal cancer often do not adhere to national guidelines. Currently, there are no data on adherence to guidelines for colorectal cancer (CRC) screening in patients with a family history. We conducted a retrospective study to assess if such patients were being appropriately screened according to American Gastroenterological Association (AGA) guidelines. Two independent reviewers performed a comprehensive medical record review of family and CRC screening history on 362 adults with a family history of CRC in a first-degree relative who had recently undergone screening colonoscopy. The endpoint was appropriate initiation of screening and endoscopist-recommended subsequent screening intervals, as compared to AGA guideline recommendations. Of 362 subjects, only 146 (40.3 %) were screened appropriately; 213 (58.9 %) had late initiation of screening (i.e., screening was started ≥5 years later than the age recommended by guidelines) and three (0.8 %) had premature initiation (i.e., screening was started ≥1 year too early). Of cases involving delayed screening initiation, 126 were not under primary care at the time when screening was supposed to have started, while most of the remaining received either no or incorrect screening recommendations from their primary care provider. Of 270 subjects with no neoplasia found on initial screening, 112 (41.5 %) had endoscopist-recommended subsequent screening intervals that were ≥2 years shorter than that recommended by guidelines. Results were similar if American Society of Gastrointestinal Endoscopy or American College of Gastroenterology guidelines were used. Patients with a family history often suffer from late initiation of screening and overly short endoscopist-recommended subsequent intervals for colonoscopy. Further education of patients and providers on screening recommendations may be helpful. 23895653 Combating the epigenome: epigenetic drugs against non-Hodgkin's lymphoma. Non-Hodgkin's lymphomas (NHLs) comprise a large and diverse group of neoplasms of lymphocyte origin with heterogeneous molecular features and clinical manifestations. Current therapies are based on standard chemotherapy, immunotherapy, radiation or stem cell transplantation. The discovery of recurrent mutations in epigenetic enzymes, such as chromatin modifiers and DNA methyltransferases, has provided researchers with a rationale to develop novel inhibitors targeting these enzymes. Several clinical and preclinical studies have demonstrated the efficacy of epigenetic drugs in NHL therapy and a few specific inhibitors have already been approved for clinical use. Here, we provide an overview of current NHL classification and a review of the present literature describing epigenetic alterations in NHL, including a summary of different epigenetic drugs, and their use in preclinical and clinical studies. 23901919 The complete nucleotide sequence of white Amur bream (Parabramis pekinensis) mitochondrial genome. Abstract White Amur bream, Parabramis pekinensis (Cypriniformes: Cyprinidae), a freshwater cyprinid fish, is an important economic fish in several countries, especially in China. The complete sequence of P. pekinensis mitochondrial genome has been determined. The genome is 16,622 bp in length, and consists of 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and the noncoding control region, with the genomic organization being identical to that of typical vertebrates. Three conserved sequence blocks (CSB1 to CSB3) were identified in the control region. The complete mitochondrial genome sequence is useful for phylogenetic analysis and studies of population genetics of P. pekinensis. 23265891 Non-benzimidazole containing inhibitors of respiratory syncytial virus. Several non-benzimidazole containing inhibitors of respiratory syncytial virus are described. Core template modification, analysis of antiviral activity, physicochemistry and optimisation of properties led to the thiazole-imidazole 13, that showed a good potency and pharmacokinetic profile in the rat. 23590472 Emergence of whole-cell MALDI-MS biotyping for high-throughput bioanalysis of mammalian cells? Since their inception in the 1970s, methods for classification of microorganisms based on mass spectral fingerprints obtained by MALDI-TOF MS have become a mainstay in environmental as well as in clinical microbiology. Recently, related whole-cell MALDI-TOF fingerprinting workflows have been adopted for the classification of mammalian cells. In this report we summarize this work and discuss the challenges of adapting whole-cell MS fingerprinting methods for the successful classification of mammalian cells. We highlight current limitations as well as opportunities and emerging applications of this technology in industrial and clinical settings, such as cell-line authentication, clinical diagnostics, and quality and productivity control in bioprocesses. 23924070 Comparison of 10% potassium hydroxide solution versus cryotherapy in the treatment of molluscum contagiosum: An open randomized clinical trial. Abstract Introduction: Molluscum contagiosum (MC) is a common cutaneous viral infection. Potassium hydroxide (KOH), as a strong alkali, and cryotherapy have been used for its treatment. The objective of this study was to compare these two treatment modalities. Methods: 30 patients, aged between 1 and 24 years of age, were randomly divided into 2 groups: 15 were treated with KOH 10% solution and 15 were treated with cryotherapy. KOH 10 % was applied by the patient or their parent(s) two times a day until the lesions disappeared completely. Cryotherapy was performed with liquid nitrogen spray, repeated weekly for 4 weeks. The assessment of response and side effects were performed weekly for 4 weeks. Results: In the KOH group, 86.6% had complete response, 6.7% had partial response and 6.7% had no response after 4 weeks. In the cryotherapy group, 93.3% had complete response and 6.7% had partial response. There was no statistically significant difference between the two groups (p > 0.05). Postinflammatory hyperpigmentation, as a side effect, was mostly noted with cryotherapy. Conclusion: Both treatment modalities were equally effective. Since KOH is inexpensive and confers better cosmetic results compared to cryotherapy, it can be used as a suitable treatment modality for MC. 23563057 A biomechanical model of wound contraction and scar formation. We propose a biomechanical model for investigating wound contraction mechanism and resulting scarring. Extracellular matrix is modeled as fiber-reinforced anisotropic soft tissue, with its elastic properties dynamically changing with the density and orientation of collagen fibers. Collagen fibers are deposited by fibroblasts infiltrating the wound space, and are dynamically aligned with both migrating fibroblasts and tissue residing tension field. Our new 2D hybrid agent-based model provides a comprehensive platform for examining the mechanobiology in wound contraction and scar formation. Simulation results are consistent with experimental observations and are able to reveal the effects of wound morphology and mechanical environment on contraction patterns. Our model results support the hypothesis that scar formation is the product of collagen fiber synthesis and alignment in the presence of the tensile stress field generated by a wound contraction process. 23821247 A case of intrauterine diagnosed posterior fossa dermoid presenting in childhood. Intrauterine intracranial brain tumor is a rare entity. Traditionally, the outcome of this tumor had been dismal. In a large series of congenital brain tumor, the commonest have been teratoma followed by astrocytoma and craniopharyngioma. We report a case of intracranial dermoid in post-fossa diagnosed at 8 months of intrauterine life during routine prenatal ultrasonography. The child's clinical picture, the surgery performed and the final outcome have been discussed. As far as our knowledge goes, this is perhaps the first reported case of intrauterine-diagnosed intracranial dermoid. 23771210 Diffusion tensor imaging white matter endophenotypes in patients with schizophrenia or psychotic bipolar disorder and their relatives. OBJECTIVE Both schizophrenia and bipolar disorder are hypothesized to involve disordered brain connectivity. Prior studies show low white matter integrity, measured with diffusion tensor imaging, for both disorders. The authors studied disease specificity and endophenotypic status of these abnormalities by examining patients and their unaffected relatives. METHOD The 513 participants included probands with schizophrenia, probands with psychotic bipolar disorder, their first-degree relatives, and healthy comparison subjects. Fractional anisotropy measures of white matter integrity were collected at two sites as a part of the Bipolar-Schizophrenia Network on Intermediate Phenotypes project. Relatives with cluster A or B personality characteristics were further examined. RESULTS Both the probands with schizophrenia and those with psychotic bipolar disorder showed lower fractional anisotropy than the comparison subjects in multiple white matter regions; differences were more marked in schizophrenia. No significant differences existed between proband groups, but in some brain regions scores on a measure of the dimensional continuum between schizophrenia and bipolar disorder, the Schizo-Bipolar Scale, showed correlations with fractional anisotropy. Many regions affected in schizophrenia probands showed similar but smaller effects in relatives, with a continuous fractional anisotropy decrease from healthy subjects to relatives to cluster A/B relatives to probands. The pattern for psychotic bipolar disorder was similar but involved fewer brain regions. Effects in bipolar relatives were limited to younger subjects. Fractional anisotropy decreased with age in all groups; this decrease was exaggerated in schizophrenia but not psychotic bipolar disorder. CONCLUSIONS Fractional anisotropy was highly heritable, supporting its value as a potential endophenotype. 23926225 Decoy-free protein-level false discovery rate estimation. Statistical validation of protein identifications is an important issue in shotgun proteomics. The false discovery rate (FDR) is a powerful statistical tool for evaluating the protein identification result. Several research efforts have been made for FDR estimation at the protein level. However, there are still certain drawbacks in the existing FDR estimation methods based on the target-decoy strategy. In this article, we propose a decoy-free protein-level FDR estimation method. Under the null hypothesis that each candidate protein matches an identified peptide totally at random, we assign statistical significance to protein identifications in terms of the permutation P-value and use these P-values to calculate the FDR. Our method consists of three key steps: (i) generating random bipartite graphs with the same structure; (ii) calculating the protein scores on these random graphs; and (iii) calculating the permutation P value and final FDR. As it is time-consuming or prohibitive to execute the protein inference algorithms for thousands of times in step ii, we first train a linear regression model using the original bipartite graph and identification scores provided by the target inference algorithm. Then we use the learned regression model as a substitute of original protein inference method to predict protein scores on shuffled graphs. We test our method on six public available datasets. The results show that our method is comparable with those state-of-the-art algorithms in terms of estimation accuracy. The source code of our algorithm is available at: https://sourceforge.net/projects/plfdr/ CONTACT: zyhe@dlut.edu.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. 23846797 Which behavioral and psychological symptoms of dementia are the most problematic? Variability by prevalence, intensity, distress ratings, and associations with caregiver depressive symptoms. Behavioral and psychological symptoms of dementia (BPSD) impact well-being for persons with dementia (PWD) and caregivers. Identifying the most problematic symptoms is vital in targeting interventions and allocating resources. The current study highlights inconsistencies in the "most problematic" symptoms when identified via prevalence, intensity, caregiver distress, or associations with caregiver depressive symptoms. Caregivers (N = 177) were mostly female (77%) and spouses of PWD (73%), with average age of 66.7 years (SD = 16.1). They reported BPSD frequency and distress via the Revised Memory and Behavior Problem Checklist (RMBPC) and Neuropsychiatric Inventory (NPI), and their own depressive symptoms via the Geriatric Depression Scale (GDS). BPSD were ranked by prevalence, average frequency, and average distress ratings. RMBPC subscales were correlated with GDS, and discriminant function analyses used NPI symptoms to discriminate between caregivers' normal (range 0-9) or elevated (10+) GDS. Most prevalent NPI symptoms were Apathy, Depression, and Agitation. Most intense (frequency × severity) were Appetite, Motor behaviors, and Apathy, and most distressing were Delusions, Agitation, and Irritability. For RMBPC, Memory was most frequent but least distressing, whereas Disruptive was least frequent but most distressing. RMBPC frequency and distress subscales were significantly associated with caregiver GDS. Discriminant function analyses were statistically significant (Lambda = 0.822; χ(2) (12) = 30.62; p = 0.002. Canonical correlation = 0.442); NPI symptoms correctly classified caregivers GDS status 72% of the time. Symptoms revealed as "most problematic" varied by measurement criterion. Common or frequent symptoms are not necessarily the most distressing or most predictive of caregiver depression. Copyright © 2013 John Wiley & Sons, Ltd. 23924946 Multiscale distribution of oxygen puddles in 1/8 doped YBa2Cu3O6.67. Despite intensive research a physical explanation of high Tc superconductors remains elusive. One reason for this is that these materials have generally a very complex structure making useless theoretical models for a homogeneous system. Little is known on the control of the critical temperature by the space disposition of defects because of lack of suitable experimental probes. X-ray diffraction and neutron scattering experiments used to investigate y oxygen dopants in YBa2Cu3O6+y lack of spatial resolution. Here we report the spatial imaging of dopants distribution inhomogeneity in YBa2Cu3O6.67 using scanning nano X-ray diffraction. By changing the X-ray beam size from 1 micron to 300 nm of diameter, the lattice inhomogeneity increases. The ordered oxygen puddles size distribution vary between 6-8 nm using 1 × 1 μm(2) beam, while it is between 5-12 nm with a fat tail using the 300 × 300 nm(2) beam. The increased inhomogeneity at the nanoscale points toward a network of superconducting puddles made of ordered oxygen interstitials. 23957451 In Vivo NMR Studies of Regional Cerebral Energetics in MPTP Model of Parkinson's Disease: Recovery of Cerebral Metabolism with Acute Levodopa Treatment. In the current study, we have evaluated cerebral atrophy, neurometabolite homeostasis and neural energetics in MPTP model of Parkinson's disease. In addition, the efficacy of acute L-DOPA treatment for the reversal of altered metabolic functions was also evaluated. Cerebral atrophy and neurochemical profile were monitored in vivo using MRI and (1) H MR Spectroscopy. Cerebral energetics was studied by (1) H-[(13) C]-NMR spectroscopy in conjunction with infusion of (13) C labeled [1,6-(13) C2 ]glucose or [2-(13) C]acetate. MPTP treatment led to reduction in paw grip strength and increased level of GABA and myo-inositol in striatum and olfactory bulb. (13) C Labeling of glutamate-C4 (1.93±0.24 vs 1.48±0.06μmol/g), GABA-C2 (0.24±0.04 vs 0.18±0.02μmol/g) and glutamaine-C4 (0.26±0.04 vs 0.20±0.04μmol/g) from [1,6-(13) C2 ]glucose was found to be decreased with MPTP exposure in striatum as well as in other brain regions. However, glutamine-C4 labeling from [2-(13) C]acetate was found to be increased in the striatum of the MPTP-treated mice. Acute L-DOPA treatment failed to normalize the increased ventricular size and level of metabolites but recovered the paw grip strength and (13) C labeling of amino acids from [1,6-(13) C2 ]glucose and [2-(13) C]acetate in MPTP-treated mice. These data indicate that brain energy metabolism is impaired in Parkinson's disease and acute L-DOPA therapy could temporarily recover the cerebral metabolism. This article is protected by copyright. All rights reserved. 23591494 Image processing using smooth ordering of its patches. We propose an image processing scheme based on reordering of its patches. For a given corrupted image, we extract all patches with overlaps, refer to these as coordinates in high-dimensional space, and order them such that they are chained in the "shortest possible path," essentially solving the traveling salesman problem. The obtained ordering applied to the corrupted image implies a permutation of the image pixels to what should be a regular signal. This enables us to obtain good recovery of the clean image by applying relatively simple one-dimensional smoothing operations (such as filtering or interpolation) to the reordered set of pixels. We explore the use of the proposed approach to image denoising and inpainting, and show promising results in both cases. 23932891 NKCC1 and KCC2 protein expression is sexually dimorphic in the hippocampus and entorhinal cortex of neonatal rats. Seizure susceptibility appears to be greater in males than females during the early developmental stages of the brain when the gamma-aminobutyric acid (GABA), acting through its GABA-A receptor, predominantly produces neuronal depolarization. GABA-mediated excitation has been observed when the NKCC1 (chloride importer) expression level is higher than KCC2 (chloride exporter). In this study, the relative protein expression of NKCC1 and KCC2 over β-actin was evaluated in the hippocampus and entorhinal cortex of male and female rats during postnatal days (PND) 1, 3, 5, 7, 9, 11, 13 and 15 using western blotting assays. For both cerebral regions in the females, the NKCC1/β-actin expression ratio was constant during all evaluated ages, whereas the KCC2/β-actin expression ratio increased gradually until reaching a maximal level at PND9 that was nearly three- and ten-fold higher in the hippocampus and entorhinal cortex, respectively, compared with the initial level. In males, the NKCC1/β-actin expression ratio was constant during the first week, peaking almost three-fold higher than the initial level at PND9 in the hippocampus and at PND11 in the entorhinal cortex and then returning to the initial values at PND13, whereas the KCC2/β-actin expression ratio increased gradually to reach a maximal and steady level at PND5, which were nearly two- and four-fold higher in the hippocampus and entorhinal cortex, respectively. In conclusion, the NKCC1/β-actin and KCC2/β-actin expression ratios displayed a specific expression profile for each gender and cerebral region, which could be related with the differences in seizure susceptibility observed between genders. 23955166 New insights into Shiga toxin-mediated endothelial dysfunction in hemolytic uremic syndrome. Shiga toxin-producing E. coli represents a significant global health concern, especially as hypervirulent pathogens surface amidst outbreaks of hemolytic uremic syndrome (HUS). Shiga toxin (Stx) is key in the microangiopathic events underlying the disease and its central role is underscored by the unprecedented HUS outbreak in Germany in 2011. The mechanisms of Stx-mediated endothelial dysfunction have been a major focus of research that has contributed to the current understanding of the pathogenic changes in endothelial phenotype leading to HUS. Among the newer concepts are Stx-mediated gene regulation in the absence of protein synthesis inhibition, a potential role for complement activation, and accumulating evidence for detectable serum markers before the onset of the classic clinical features of HUS. Further investigation of newer therapeutic targets and potential prognostic markers is essential to assess their utility in mitigating disease and/or predicting outcomes and will provide an improved overall understanding of HUS pathogenesis. 23315088 Fibronectin in the palatine tonsil as a susceptibility marker in Egyptian rheumatic families: Histological and immunohistochemical studies. Rheumatic fever (RF) and rheumatic heart disease (RHD) are the multisystem autoimmune sequel of group A streptococci (GAS) infection of the upper respiratory passages, mainly tonsillopharyngitis. The major receptor on the surface of human palatine tonsil for GAS is fibronectin (FN; adhesin receptor). Early detection of RF susceptibility is considered as an important aim of this study. Therefore, the present study aimed to use FN immunoreactivity (FN-ir) as a marker for early detection of rheumatic susceptible children with palatine tonsil crypts surface epithelium. A total of 30 palatine tonsillar specimens were obtained from children aged from 3 to 15 years. Histological studies showed moderate vascular changes and more than four apparent epithelial disruptions in the crypt epithelium. FN-ir showed a significant increase in FN in the basal layers of surface epithelium, subepithelial connective tissue and interfollicular areas. Tonsils of children in rheumatic families showed significant increase in FN in subepithelial connective tissue areas with more than one apparent crypt epithelial disruption compared to normal children. We can conclude that FN plays a central role in the RF and differentially distributed in the functional compartments of the palatine tonsil in children with RHD, so FN-ir can be used as a marker for rheumatic susceptibility. 23847496 Neural stages of spoken, written, and signed word processing in beginning second language learners. WE COMBINED MAGNETOENCEPHALOGRAPHY (MEG) AND MAGNETIC RESONANCE IMAGING (MRI) TO EXAMINE HOW SENSORY MODALITY, LANGUAGE TYPE, AND LANGUAGE PROFICIENCY INTERACT DURING TWO FUNDAMENTAL STAGES OF WORD PROCESSING: (1) an early word encoding stage, and (2) a later supramodal lexico-semantic stage. Adult native English speakers who were learning American Sign Language (ASL) performed a semantic task for spoken and written English words, and ASL signs. During the early time window, written words evoked responses in left ventral occipitotemporal cortex, and spoken words in left superior temporal cortex. Signed words evoked activity in right intraparietal sulcus that was marginally greater than for written words. During the later time window, all three types of words showed significant activity in the classical left fronto-temporal language network, the first demonstration of such activity in individuals with so little second language (L2) instruction in sign. In addition, a dissociation between semantic congruity effects and overall MEG response magnitude for ASL responses suggested shallower and more effortful processing, presumably reflecting novice L2 learning. Consistent with previous research on non-dominant language processing in spoken languages, the L2 ASL learners also showed recruitment of right hemisphere and lateral occipital cortex. These results demonstrate that late lexico-semantic processing utilizes a common substrate, independent of modality, and that proficiency effects in sign language are comparable to those in spoken language. 23129397 Pelvic floor muscle training program increases muscular contractility during first pregnancy and postpartum: Electromyographic study. The aim of this study was to evaluate the effect of a training program over both pelvic floor muscles contractility and urinary symptoms in primigravid pregnant and postpartum primiparous women. A clinical, prospective and blinded trial was conducted with 33 women divided into three groups: (G1) 13 primigravid pregnant women; (G2) 10 postpartum primiparous women (49.3 ± 5.84 days), after vaginal delivery with right mediolateral episiotomy; (G3) 10 postpartum primiparous women (46.3 ± 3.6 days), after cesarean section delivery. The evaluation was carried out using digital palpation (Modified Oxford Grading Scale), pelvic floor electromyography and, for the investigation of urinary symptoms, validated questionnaires (International Consultation on Incontinence Questionnaire-short form-ICIQ-UI SF and International Consultation on Incontinence Questionnaire Overactive Bladder-ICIQ-OAB). The protocol consisted of 10 individual sessions carried out by the physiotherapist through home visits, three times a week, with 60 min duration each. The statistical analysis was performed using ANOVA and Spearman's correlation coefficient. The pelvic floor muscle contractility increased after the training program (P = 0.0001) for all groups. Decreases in the scores of both ICIQ-UI SF (P = 0.009) and ICIQ-OAB (P = 0.0003) were also observed after training. Pelvic floor muscle training is an effective means for the increase in its own contractility in both primigravid pregnant and primiparous postpartum women, accompanied with a concomitant decrease in urinary symptoms. Neurourol. Urodynam. 32: 998-1003, 2013. © 2012 Wiley Periodicals, Inc. 23265885 Synthesis of new N-(arylcyclopropyl)acetamides and N-(arylvinyl)acetamides as conformationally-restricted ligands for melatonin receptors. N-(Arylcyclopropyl)acetamides and N-(arylvinyl)acetamides or methyl ureas have been prepared as constrained analogues of melatonin. The affinity of these new compounds for chicken brain melatonin receptors and recombinant human MT(1) and MT(2) receptors was evaluated using 2-[(125)I]-iodomelatonin as radioligand. Strict ethylenic or cyclopropyl analogues of the commercialized agonist agomelatine (Valdoxan®) were equipotent to agomelatine in binding bioassays. However, the ethylenic analogue was more effective than the cyclopropyl one in the melanophore aggregation bioassay, but was still less potent than the disubstituted 2,7-dimethoxy-naphtalenic compounds. 23670801 Widely applicable synthesis of enantiomerically pure tertiary alkyl-containing 1-alkanols by zirconium-catalyzed asymmetric carboalumination of alkenes and palladium- or copper-catalyzed cross-coupling. A highly enantioselective and widely applicable method for the synthesis of various chiral 2-alkyl-1-alkanols, especially those of feeble chirality, has been developed. It consists of zirconium-catalyzed asymmetric carboalumination of alkenes (ZACA), lipase-catalyzed acetylation, and palladium- or copper-catalyzed cross-coupling. By virtue of the high selectivity factor (E) associated with iodine, either (S)- or (R)-enantiomer of 3-iodo-2-alkyl-1-alkanols (), prepared by ZACA reaction of allyl alcohol, can be readily purified to the level of ≥99 % ee by lipase-catalyzed acetylation. A variety of chiral tertiary alkyl-containing alcohols, including those that have been otherwise difficult to prepare, can now be synthesized in high enantiomeric purity by Pd- or Cu-catalyzed cross-coupling of or for introduction of various primary, secondary, and tertiary carbon groups with retention of all carbon skeletal features. These chiral tertiary alkyl-containing alcohols can be further converted into the corresponding acids with full retention of the stereochemistry. The synthetic utility of this method has been demonstrated in the highly enantioselective (≥99 % ee) and efficient syntheses of (R)-2-methyl-1-butanol and (R)- and (S)-arundic acids. 23770731 Copper-mediated controlled radical polymerization under biological conditions: SET-LRP in blood serum. The polymerization of hydrophilic monomers is reported utilizing Cu(0)-mediated living radical polymerization, SET-LRP. Highly active Cu(0) is formed in situ as a result of rapid disproportionation of [Cu(I)(Me6-Tren)Br] in serum. Disproportionation and homogenous controlled radical polymerization (PDI 1.09-1.25) are performed for the first time in blood (sheep) serum. 23861147 Comparative study of nickel resistance of pure culture and co-culture of Acidithiobacillus thiooxidans and Leptospirillum ferriphilum. The effect of Ni(2+) on the growth and functional gene expression of the pure culture and co-culture of Acidithiobacillus thiooxidans and Leptospirillum ferriphilum has been studied. Compared with the pure culture, the co-culture showed a stronger sulfur and ferrous ion oxidation activity. At 100 mM, A. thiooxidans in co-culture grew faster and had 48 h shorter lag phases. The cell number of A. thiooxidans in co-culture was about 5 times higher than that in pure culture. The existence of A. thiooxidans in co-culture activated the expression of some metal resistance genes in L. ferriphilum at least 16 h in advance. A. thiooxidans in co-culture tends to chose more efficient pathways to transport nickel ion, ensuring the export of heavy metal was faster and more effective than that in pure culture. All the data indicated that there were synergetic interactions between iron- and sulfur-oxidizing bacteria under the stress of Ni(2+). 23843332 Congenital central hypoventilation syndrome; Safety of early transition to non-invasive ventilation. Congenital central hypoventilation syndrome (CCHS) is a rare disorder of autonomic dysregulation, characterized by alveolar hypoventilation especially during sleep. As a result, lifelong ventilatory assistance is necessary in these patients. Many infants and children initially require positive pressure ventilation via tracheostomy for support. Associated complications and psychosocial pressure may prompt early transition to non-invasive ventilation. We present the details of a patient with CCHS who successfully transitioned from tracheostomy to bilevel positive airway pressure ventilation at an early age of 3 years. Pediatr Pulmonol. © 2013 Wiley Periodicals, Inc. 23249752 Potent microRNA suppression by RNA Pol II-transcribed 'Tough Decoy' inhibitors. MicroRNAs (miRNAs) are key regulators of gene expression and modulators of diverse biological pathways. Analyses of miRNA function as well as therapeutic managing of miRNAs rely on cellular administration of miRNA inhibitors which may be achieved by the use of viral vehicles. This study explores the miRNA-suppressive capacity of inhibitors expressed intracellularly from lentivirus-derived gene vectors. Superior activity of two decoy-type inhibitors, a "Bulged Sponge" with eight miRNA recognition sites and a hairpin-shaped "Tough Decoy" containing two miRNA recognition sites, is demonstrated in a side-by-side comparison of seven types of miRNA inhibitors transcribed as short RNAs from an RNA Pol III promoter. We find that lentiviral vectors expressing Tough Decoy inhibitors are less vulnerable than Bulged Sponge-encoding vectors to targeting by the cognate miRNA and less prone, therefore, to reductions in transfer efficiency. Importantly, it is demonstrated that Tough Decoy inhibitors retain their miRNA suppression capacity in the context of longer RNA transcripts expressed from an RNA Pol II promoter. Such RNA Pol II-transcribed Tough Decoy inhibitors are new tools in managing of miRNAs and may have potential for temporal and spatial regulation of miRNA activity as well as for therapeutic targeting of miRNAs that are aberrantly expressed in human disease. 23902181 RCN quits global body over its fees, but bill for arrears looms. The RCN has decided to leave the International Council of Nurses (ICN) because it is not prepared to pay the Swiss-based organisation £500,000 a year in membership fees. 23407316 Topical ranibizumab as a treatment of corneal neovascularization. To examine the effect of topical ranibizumab on clinically stable corneal neovascularization (NV). This was a prospective, open-label, monocentric, uncontrolled noncomparative study. Ten eyes of 9 patients with corneal NV received topical ranibizumab (1%) 4 times a day for 3 weeks with a follow-up period of 16 weeks. The main corneal NV outcome measures were: neovascular area, the area occupied by the corneal neovessels; vessel caliber (VC), the mean diameter of the corneal neovessels; and invasion area (IA), the fraction of the total cornea area covered by the vessels. This study was conducted at the Massachusetts Eye and Ear Infirmary, Boston, MA. Statistically significant decreases in neovascular area (55.3%, P < 0.001), which lasted through 16 weeks, and VC (59%, P < 0.001), which continued to improve up to week 16, were observed after treatment. No significant decrease was observed in IA (12.3%, P = 0.49). There was no statistically significant change in visual acuity or intraocular pressure. No adverse events ascribed to the treatment were noted. Topical application of ranibizumab is effective in reducing the severity of corneal NV in the context of established corneal NV, mostly through decrease in VC rather than IA. 23220490 Identification and discrimination of snake venoms from Egyptian elapids. The avidity to the corresponding antigens is often higher than to the cross-reactive antigens. This was demonstrated with the highly cross-reactive elapid Egyptian snake venoms Naja haje (Nh), Naja nigricollis (Nn) and Walterinnesia aegyptia (Wa), and used for the differentiation among the three species in a simple ELISA-based assay. A three-step immuno-affinity protocol was followed and the titer and avidity of the different antibody (Ab) preparations were assessed and evaluated. The advantages offered by the avidity power of the venom specific antibodies (VS-Abs) obtained after one step purification, outweigh the specificity of the species-specific antibodies (SS-Abs) obtained after further purification. The efficiency of the VS-Abs as special immunodiagnostics was validated using 16 venom samples collected from individual snakes of different size and age at different time intervals. The avidities of the VS-Abs to the homologous venoms were 2.53 ± 0.4, 2.66 ± 0.31 and 2.8 ± 0.06 for Nh, Nn and Wa venoms respectively; whereas the avidity of the same Abs to the heterologous venoms could hardly exceed 1. Venom concentrations in the range between 10-1250 ng/well were detected with almost the same efficiency, an extra advantage that could be added to the assay to assure equal sensitivity allover the mentioned venom concentration range. 23527497 Amyotrophic lateral sclerosis and cancer: A register-based study in Sweden. Abstract Comorbidity of cancer with ALS has been studied previously. Detailed description of the temporal relationship between cancer and ALS is, however, lacking. We conducted a nested case-control study of ALS in Sweden during 1987-2009, including 5481 cases of ALS identified from the Swedish Patient Register and 27,405 controls randomly selected from the general Swedish population. Odds ratios (ORs) for association of ALS with previous cancer diagnosis and incidence rate ratios (IRRs) of cancer after diagnosis were calculated to compare ALS patients with ALS-free individuals. Overall, a previous cancer diagnosis was not associated with subsequent risk of ALS (OR 1.00; 95% CI 0.91-1.10). No overall association was observed for any specific cancer type. An increased risk of ALS was observed during the first year after cancer diagnosis (OR 1.50; 95% CI 1.17-1.92). In contrast, a lower risk of cancer was observed in ALS patients after diagnosis compared with ALS-free individuals (IRR 0.84; 95% CI 0.69-1.02). The risk reduction was seen primarily two or more years after ALS diagnosis (IRR 0.64; 95% CI 0.45-0.88). Our results provide no evidence for comorbidity of cancer and ALS overall. Surveillance biases seem the most likely explanation for the limited associations detected. 23932133 Early mammary gland metabolic and immune responses during natural-like and forceful drying-off in high-yielding dairy cows. The present work compared metabolic and immune responses in genetically high-producing cows that produced a low amount of milk before expected involution and in cows with the same genetic potential that produced copious amounts of milk before their scheduled drying-off. Ten multiparous lactating Israeli Holstein cows producing approximately 10,500 L in the current lactation, without bacterial infection and scheduled for drying-off approximately 60 d before their expected parturition, were studied. Five of the cows that exhibited a sharp, spontaneous reduction in milk yield at the end of their lactation and produced less than ∼14 L/d were defined as cows approaching natural involution (ANI), and 5 cows that produced between 25 and 35 L/d were defined as cows approaching forced involution (AFI). Three days before scheduled drying-off, milking was stopped and milk samples were collected from each quarter. After milking cessation, only modest swelling was observed in the udders of the ANI cows. In the ANI cows, lactose and fat concentrations decreased and the fat:lactose concentration ratio indicated that on d 1 and 2 fat concentrations decreased faster than lactose concentration, whereas on d 3, the rate of reduction was about the same for lactose and fat. In contrast, in AFI cows, fat concentrations increased on d 1 and the fat:lactose ratio indicated that changes in fat secretion were minor compared with those of lactose secretion. Rennet clotting time of milk after drying-off in the ANI cows increased, whereas curd firmness decreased rapidly, such that mammary secretions did not coagulate on d 3. In the AFI cows, such significant changes were observed only on d 3. The inflammatory response increased in both groups, but at each stage the increase was greater in ANI cows than in AFI cows. On d 1, the increase in leukocyte numbers in the ANI cows was made up of mononuclear cells (i.e., T lymphocytes and macrophages). In contrast, in the AFI cows, we observed a marked increase in leukocyte numbers, mainly in the form of polymorphonuclear cells. Our data indicate that the abrupt mammary involution induced in AFI cows provoked signs of distress, which were associated with neutrophilia in milk. In contrast, in the ANI cows, cessation of milking occurred without evidence of engorgement of the udder. Physiological differences in ANI and AFI cows are distinct and are reflected in the differences in the leukocyte populations in milk. 23750504 The physical interaction of Mcm10 with Cdc45 modulates their DNA-binding properties. The eukaryotic DNA replication protein Mcm10 (mini-chromosome maintenance 10) associates with chromatin in early S-phase and is required for assembly and function of the replication fork protein machinery. Another essential component of the eukaryotic replication fork is Cdc45 (cell division cycle 45), which is required for both initiation and elongation of DNA replication. In the present study we characterize, for the first time, the physical and functional interactions of human Mcm10 and Cdc45. First we demonstrated that Mcm10 and Cdc45 interact in cell-free extracts. We then analysed the role of each of the Mcm10 domains: N-terminal, internal and C-terminal (NTD, ID and CTD respectively). We have detected a direct physical interaction between CTD and Cdc45 by both in vitro co-immunoprecipitation and surface plasmon resonance experiments. On the other hand, we have found that the interaction of the Mcm10 ID with Cdc45 takes place only in the presence of DNA. Furthermore, we found that the isolated ID and CTD domains are fully functional, retaining DNA-binding capability with a clear preference for bubble and fork structures, and that they both enhance Cdc45 DNA-binding affinity. The results of the present study demonstrate that human Mcm10 and Cdc45 directly interact and establish a mutual co-operation in DNA binding. 23561180 Identification and quantification of active alkaloids in Catharanthus roseus by liquid chromatography-ion trap mass spectrometry. Catharanthus roseus is an important dicotyledonous medicinal plant that produces anticancer compounds. The active alkaloids vinblastine, vindoline, ajmalicine, catharanthine, and vinleurosine were identified by direct-injection ion trap-mass spectrometry (IT-MS) for collecting MS(1-2) spectra. The determinations of five alkaloids were accomplished by liquid chromatography (LC) with UV and MS detections. The analytes provided good signals corresponding to the protonated molecular ions [M+H](+) and product ions. The precursor ions and product ions for quantification of vinblastine, vindoline, ajmalicine, catharanthine, and vinleurosine were m/z 825→807, 457→397, 353→144, 337→144 and 809→748 by LC-IT-MS, respectively. Two methods were used to evaluate a number of validation characteristics (repeatability, LOD, calibration range, and recovery). MS provided a high selectivity and sensitivity for determination of five alkaloids in positive mode. After optimisation of the methods, separation, identification and quantification of the five components in C. roseus were comprehensively accomplished by HPLC with UV and MS detection. 23747827 Overexpression of stearoyl-coenzyme A desaturase 1 in macrophages promotes reverse cholesterol transport. Stearoyl-coenzyme A desaturase 1 (SCD1) is the rate-limiting enzyme in the synthesis of monounsaturated fatty acids. However, the impact of SCD1 on atherosclerosis remains unclear. The aim of this study was to determine whether SCD1 affects macrophage reverse cholesterol transport (RCT) in mice. Compared to the control, adenoviral-mediated SCD1 overexpression in RAW264.7 macrophages increased cholesterol efflux to HDL, but not to apoA-I, without clear changes in ABCA1, ABCG1 and SR-BI expressions. While knockdown of ABCG1 and SR-BI did not affect the SCD1-induced cholesterol efflux to HDL, SCD1-overexpressing macrophages promoted the formation of both normal- and large-sized HDL in media, accompanying increased apolipoprotein A-I levels in HDL fractions. Transformation to larger particles of HDL was independently confirmed by nuclear magnetic resonance-based lipoprotein analysis. Interestingly, media transfer assays revealed that HDL generated by SCD1 had enhanced cholesterol efflux potential, indicating that SCD1 transformed HDL to a more anti-atherogenic phenotype. To study macrophage RCT in vivo, (3)H-cholesterol-labeled RAW264.7 cells overexpressing SCD1 or the control were intraperitoneally injected into mice. Supporting the in vitro data, injection of SCD1-macrophages resulted in significant increases in (3)H-tracer in plasma, liver, and feces compared to the control. Moreover, there was a shift towards larger particles in the (3)H-tracer distribution of HDL fractions obtained from the mice. In conclusion, macrophage-specific SCD1 overexpression promotes overall RCT through increased cholesterol efflux to HDL, suggesting that macrophage SCD1 achieves an anti-atherogenic effect by enhancing RCT. 23628454 Scientific evidence for traditional claim of antiobesity activity of Tecomella undulata bark. ETHNOPHARMACOLOGICAL RELEVANCE: The bark of Tecomella undulata is traditionally claimed in the treatment of various disease ailments including obesity and cancer. Till now there are no studies about anti obesity activity of Tecomella undulata bark. AIM OF THE STUDY: The present study was aimed to establish a scientific evidence for anti obesity efficiency of ethyl acetate extract of Tecomella undulata bark (EATUB). Further to standardize the active fractions of EATUB using different biomarkers. MATERIALS AND METHODS: We investigated activity of EATUB fractions (F1-F7) using 3T3-L1 fibroblasts. Further, F1-mediated effects were characterized by determining mRNA and protein levels of SIRT1, one of the key targets for the treatment of obesity, using semi quantitative RT-PCR (sqRT-PCR) and western blot analysis. The consequences of modulation of SIRT1 on mRNA and protein levels of various adipogenesis mediators like PPARγ, C/EBPα, E2F1, leptin, adiponectin and LPL were also studied. In-vivo studies were performed using High Fat Diet (HFD) obese mice. RESULTS: Our data showed that compared to controls, preadipocytes and adipocytes incubated with F1 exhibited a significant decrease in adipogenesis and lipogenesis. In addition, sqRT-PCR and western blot analysis showed significant increase in SIRT1 and adiponectin levels and decrease in PPARγ, C/EBPα, E2F1, leptin and LPL levels in preadipocytes and adipocytes. In-vivo studies of F1 in HFD induced obese mice showed significant improvement in lipid profile and glucose levels. The bioactive fraction (F1) was determined to possess 4.95% of ferulic acid. CONCLUSION: Thus, our findings signified the beneficial effects of Tecomella undulata bark in pharmacologic interventions related to obesity and metabolic disorders. Ferulic acid and rutin are being reported and quantified for the first time from the bark of Tecomella undulata. 23222385 Factors affecting the development of atrial fibrillation and atrial flutter (AF/AFL) following autologous hematopoietic SCT (auto-HSCT). The use of autologous hematopoietic SCT (auto-HSCT) has expanded to include older patients. Increasing age is a well-appreciated risk factor for the development of atrial fibrillation and/or atrial flutter (AF/AFL) in the general population. As more elderly patients undergo auto-HSCT, the risk of developing AF/AFL post transplant may also increase. However, few data evaluating other risk factors for the development of AF/AFL following auto-HSCT exist. Therefore, we performed a retrospective study to determine the incidence of AF/AFL following auto-HSCT and to determine the risk factors associated with the development of AF/AFL. Patients who developed AF/AFL were compared with a group of patients who received auto-HSCT within the same time period (April 1999 to May 2005) and were within 5 years of age. Of the 516 patients who underwent auto-HSCT at the University of Nebraska Medical Center 44 (8.5%) developed AF/AFL at a median time of 4 days (range, days 1-9) following auto-HSCT. In multivariate analysis, risk factors for developing AF/AFL were older age, odds ratio and 95% CI of 1.14 (1.07-1.21), elevated serum creatinine level, 2.69 (1.00-7.22), history of previous arrhythmia, 9.33 (3.01-28.99), and history of previous mediastinal irradiation, 11.12 (1.33-92.96). 23955660 Predictors of Non-adherence to Clinical Follow-up Among Patients Participating in a Randomized Trial of Pharmaceutical Care Intervention in HIV-Positive Adults in Southern Brazil. Pharmaceutical care (PC) has been shown to improve adherence to therapeutic interventions as well as improve clinical outcomes. We assessed the predictors of non-adherence to clinical follow-up (i.e., not attending three scheduled routine clinical visits over a 1 year period) among patients who participated in a clinical trial of PC intervention on adherence to HIV antiretroviral therapy uptake (the PC-HIV trial). A total of 332 patients participated: median age was 39 years, 63 % were male, 76 % had CD4 count ≥200 cells/mm³, and 52 % had undetectable viral load. About half, 52.7 %, were non-adherent to clinical follow-up. Identified risk factors for non-adherence were male gender, age <40 years, and being in the trial's "control" group (adjusted odds ratio [AOR] 1.67, 95 % CI 1.05-2.66; AOR 2.21, 95 % CI 1.42-3.47; AOR 1.67, 95 % CI 1.07-2.61, respectively). Younger, male patients may benefit from interventions such as PC, which facilitates engagement in care. 23483307 Analysis of fecal Lactobacillus community structure in patients with early rheumatoid arthritis. The objective of this study was to analyze human fecal Lactobacillus community and its relationship with rheumatoid arthritis. Samples taken from rheumatoid arthritis (RA) patients and healthy individuals were analyzed by quantitative real-time PCR. Bacterial DNA was extracted from feces, and amplicons of the Lactobacillus-specific regions of 16S rRNA were analyzed by denaturing gradient gel electrophoresis. The richness, Shannon-Wiener index, and evenness of gut microbiota of both groups were analyzed to compare fecal Lactobacillus community structures. Results of this study demonstrated that fecal microbiota of RA patients contained significantly more Lactobacillus (10.62 ± 1.72 copies/g) than the control group (8.93 ± 1.60 copies/g). Significant increases were observed in RA patients in terms of the richness, Shannon-Wiener, and evenness measures, indicating more bacterial species, and increased bacterial diversity and abundance. These results suggest a potential relationship between Lactobacillus communities and the development and progression of rheumatoid arthritis. 23824149 A functional glycoprotein competitive recognition and signal amplification strategy for carbohydrate-protein interaction profiling and cell surface carbohydrate expression evaluation. A simple and sensitive carbohydrate biosensor has been suggested as a potential tool for accurate analysis of cell surface carbohydrate expression as well as carbohydrate-based therapeutics for a variety of diseases and infections. In this work, a sensitive biosensor for carbohydrate-lectin profiling and in situ cell surface carbohydrate expression was designed by taking advantage of a functional glycoprotein of glucose oxidase acting as both a multivalent recognition unit and a signal amplification probe. Combining the gold nanoparticle catalyzed luminol electrogenerated chemiluminescence and nanocarrier for active biomolecules, the number of cell surface carbohydrate groups could be conveniently read out. The apparent dissociation constant between GOx@Au probes and Con A was detected to be 1.64 nM and was approximately 5 orders of magnitude smaller than that of mannose and Con A, which would arise from the multivalent effect between the probe and Con A. Both glycoproteins and gold nanoparticles contribute to the high affinity between carbohydrates and lectin. The as-proposed biosensor exhibits excellent analytical performance towards the cytosensing of K562 cells with a detection limit of 18 cells, and the mannose moieties on a single K562 cell were determined to be 1.8 × 10(10). The biosensor can also act as a useful tool for antibacterial drug screening and mechanism investigation. This strategy integrates the excellent biocompatibility and multivalent recognition of glycoproteins as well as the significant enzymatic catalysis and gold nanoparticle signal amplification, and avoids the cell pretreatment and labelling process. This would contribute to the glycomic analysis and the understanding of complex native glycan-related biological processes. 23866953 Surgical management of auricular defect depending on the size, location, and tissue involved. Auricular reconstruction is a challenging surgical intervention that requires perfect surgical skills, exact planning, and esthetic knowledge. It is necessary to use a suitable method of reconstruction for each patient. From 10 years of experience, the authors have developed a general concept for auricular reconstruction. Seventy-five patients (62 male, 13 female; age range, 8 to 92 yr; mean age, 65.9 yr) underwent partial to total auricular reconstruction. Tissue loss occurred from different causes: 19 cases of squamous cell carcinoma (25.3%), 18 cases of basal cell carcinoma (24%), 14 cases of Bowen disease (18.7), 11 cases of malignant melanoma (14.7%), 7 cases of trauma (9.3%), 3 different malignant tumors (4%), and 3 cases of congenital deformity (4%). Defects smaller than one fourth the vertical auricular size (15 to 20 mm) could be treated by primary closure. A larger defect closed by this method caused visible deformity. In defects larger than one to three fourths the vertical auricular size (40 to 55 mm), a reversed retroauricular flap was used successfully if there was no contraindication or rejection. This flap can be combined with other flaps, depending on the flap location, size, and tissue involved. In defects exceeding three fourths the vertical auricular size, an implant-retained prosthesis was preferred. The location and size of a defect, the medical condition of the patient, and the desired esthetic outcome play an important role in choosing the appropriate method. According to the authors' experience, the only contraindications for the reversed retroauricular flap are medical condition, poor prognosis, and patient refusal. 23591146 High-resolution spectral domain anterior segment optical coherence tomography in type 1 Boston keratoprosthesis. To report the results of imaging using high-resolution, Fourier domain anterior segment optical coherence tomography (AS-OCT) to evaluate patients with a type 1 Boston Keratoprosthesis (KPro). We performed a retrospective comparative study of patients in whom we implanted the Boston KPro. A total of 26 eyes of 23 patients from the Cornea Service at the University of California Davis Eye Center were included. Subjects were evaluated with the Spectralis AS-OCT (Heidelberg Engineering GmbH). Preoperative diagnoses for KPro surgery included failed corneal transplant (69%), chemical burn (23%), and aniridia (8%). The average age of patients was 63.2 years (range, 17-88 years). Fifty-four percent of the patients were female. The mean duration between the KPro surgery and the acquisition of high-resolution AS-OCT imaging was 35.8 months (range, 2-90 months). The most commonly observed finding was retroprosthetic membrane formation, which we found in 77% of KPro eyes. In 65% of KPro eyes, we identified epithelium behind the front plate, and in 54%, we identified an epithelial lip over the anterior surface of the KPro front plate. In 31% of KPro eyes, we identified periprosthetic cysts, gaps or spaces, and thinning in the corneal carrier graft. Fourier domain AS-OCT is a useful noninvasive imaging technique in patients with a KPro and provides the ability to identify changes that are sometimes difficult to appreciate by clinical evaluation. The higher resolution Fourier domain systems may aid in the clinical diagnosis and management of pathology that might not be imaged with instruments of lower resolution. AS-OCT has the potential for monitoring the anatomic stability of an implanted KPro and may also help to monitor for complications. Moreover, high-resolution imaging may enhance our understanding of periprosthetic anatomy. 23707485 State estimation for delayed genetic regulatory networks based on passivity theory. This paper is concerned with the state estimation problem for delayed genetic regulatory networks (GRNs) based on passivity analysis approach. The main purpose of the problem is to design the estimator to approximate the true concentrations of the mRNA and protein through available measurement outputs. Time-varying delays are explicitly assumed to be non-differentiable and constraint on the derivative of the time-varying delay is less than one can be removed. Based on the Lyapunov-Krasovskii functionals involving triple integral terms, using some integral inequalities and convex combination technique, a delay-dependent passivity criterion is established for GRNs in terms of linear matrix inequalities (LMIs) that can efficiently be solved by any available LMI solvers. Finally, numerical examples and simulation are presented to demonstrate the efficiency of the proposed estimation schemes. 22761049 Bioactivity of Diosmetin Glycosides Isolated from the Epicarp of Date Fruits, Phoenix dactylifera, on the Biochemical Profile of Alloxan Diabetic Male Rats. The new natural flavonoid compounds - diosmetin 7-O-β-L-arabinofuranosyl (1 → 2) β-D-apiofuranoside (1) and diosmetin 7-O-β-D-apiofuranoside (2) - were isolated from the acetone extract of date fruits epicarp belonging to family Arecaceae (Palmae). Elucidation of their chemical structures was determined by different spectroscopic methods in addition to the chemical and physical methods of analysis. These compounds were assessed for their biological activity on alloxan diabetic rats. A dose of 1.5 ml of (1) and (2) suspensions/100 gm b. wt were orally administrated to alloxan diabetic rats for 30 days. The treatment of diabetic rats with these compounds resulted in marked improvement of the different biochemical results, i.e. the serum glucose level (highly significant, from 330 + 5.5 mg/dL to 140 + 1.2 mg/dL) treated with (1); liver functions markedly developed both by AST and ALT levels, (reduced significantly from 68.3 + 4.8 μ/L to 54 + 5.5 μ/L and from 61.0 + 3.6 μ/L to 40.1 + 3.6 μ/L, respectively) treated with (2), accompanying with mild decrease in both cholesterol and triglycerides levels with (1) or (2). Decrease of TBARS level was observed in whole blood when treated with (1) or (2), while levels of glutathione peroxidase and superoxide dismutase were increased in liver. Serum testosterone level was highly significantly increased (from 705.1 + 3.6 mg/100 ml to 720 + 4.7 mg/100 ml), total acid phosphatase and prostate acid phosphatase activities were highly significantly decreased (from 16.9 + 0.28 μ/L to 10.7 + 1.2 μ/L and from 9.7 + 0.7 μ/L to 6.5 + 1 μ/L, respectively) for compound (1). Copyright © 2012 John Wiley & Sons, Ltd. 23669387 Caspofungin MICs Correlate with Treatment Outcomes among Patients with Candida glabrata Invasive Candidiasis and Prior Echinocandin Exposure. Mutations in Candida glabrata FKS genes, which encode the echinocandin target enzyme, are independent risk factors for treatment failures during invasive candidiasis. We retrospectively compared the ability of caspofungin susceptibility testing methods to identify C. glabrata FKS mutant isolates and predict outcomes among patients at our center. Eight percent (10/120) of sterile-site C. glabrata isolates harbored FKS1 (n = 3) or FKS2 (n = 7) mutations, including 32% (10/32) recovered from patients with prior echinocandin exposure. Median echinocandin exposures for mutant and nonmutant isolates were 55 (range, 7 to 188) and 13 (3 to 84) days, respectively (P = 0.004). Sensitivity and specificity of the CLSI caspofungin resistance breakpoint MIC (>0.12 μg/ml by broth microdilution using RPMI medium [BMD-RPMI]) were 90% (9/10) and 3% (3/110), respectively, for identifying FKS mutants. Sensitivity and specificity of receiver-operator characteristic (ROC) curve-derived breakpoints by BMD-RPMI, BMD-antibiotic medium 3, Etest, and YeastOne ranged from 70 to 100% and 89 to 95%, respectively; susceptibility rates varied from 83 to 90%. The 14-day echinocandin treatment success rate was 67% (44/66); failure was more likely with prior echinocandin exposure (P = 0.002) or infection with an FKS mutant (P = 0.0001) or echinocandin-resistant isolates by BMD-AM3, Etest, and YeastOne (P ≤ 0.03). The failure rate among patients with prior exposure and infection with a resistant isolate was 91% (10/11); it was 22% (12/55) among others (P < 0.0001). In conclusion, ROC-derived caspofungin MIC breakpoints by several methods were sensitive and specific for identifying C. glabrata FKS mutant isolates. Mutations were seen exclusively among patients with prior echinocandin exposure. A paradigm that considers prior echinocandin exposure and caspofungin MICs accurately classified treatment outcomes for C. glabrata invasive candidiasis. 23180584 Exercise tolerance with helium-hyperoxia versus hyperoxia in hypoxaemic patients with COPD. The purpose of this study was to investigate whether helium-hyperoxia (HeHOx) would allow greater tolerance to maximal and submaximal exercise compared to hyperoxia (HOx) on isolation in hypoxaemic chronic obstructive pulmonary disease (COPD) patients under long-term oxygen therapy. In a double-blind study, 24 males in the Global Initiative for Chronic Obstructive Lung Disease functional class IV (forced expiratory volume in 1 s 35.2±10.1% predicted and arterial oxygen tension 56.2±7.5 mmHg) were submitted to incremental and constant load cycling at 70-80% peak work rate while breathing HOx (60% nitrogen and 40% oxygen) or HeHOx (60% helium and 40% oxygen). HeHOx improved resting airflow obstruction and lung hyperinflation in all but two patients (p<0.05). Peak work rate and time to exercise intolerance were higher with HeHOx than HOx in 17 (70.8%) out of 24 patients and 14 (66.6%) out of 21 patients, respectively (p<0.05). End-expiratory lung volumes were lower with HeHOx, despite a higher ventilatory response (p<0.05). HeHOx speeded on-exercise oxygen uptake kinetics by ∼30%, especially in more disabled and hyperinflated patients. Fat-free mass was the only independent predictor of higher peak work rate with HeHOx (r(2) = 0.66, p<0.001); in contrast, none of the resting characteristics or exercise responses were related to improvements in time to exercise intolerance (p>0.05). Helium is a valuable ergogenic aid when added to HOx for most long-term oxygen therapy-dependent patients with advanced COPD. 23535562 One-pot multi-enzyme (OPME) chemoenzymatic synthesis of sialyl-Tn-MUC1 and sialyl-T-MUC1 glycopeptides containing natural or non-natural sialic acid. A series of STn-MUC1 and ST-MUC1 glycopeptides containing naturally occurring and non-natural sialic acids have been chemoenzymatically synthesized from Tn-MUC1 glycopeptide using one-pot multienzyme (OPME) approaches. In situ generation of the sialyltransferase donor cytidine 5'-monophosphate-sialic acid (CMP-Sia) using a CMP-sialic acid synthetase in the presence of an extra amount of cytidine 5'-triphosphate (CTP) and removal of CMP from the reaction mixture by flash C18 cartridge purification allow the complete consumption of Tn-MUC1 glycopeptide for quantitative synthesis of STn-MUC1. A Campylobacter jejuni β1-3GalT (CjCgtBΔ30-His6) mutant has been found to catalyze the transfer of one or more galactose residues to Tn-MUC1 for the synthesis of T-MUC1 and galactosylated T-MUC1. Sialylation of T-MUC1 using Pasteurella multocida α2-3-sialyltransferase 3 (PmST3) with Neisseria meningitidis CMP-sialic acid synthetase (NmCSS) and Escherichia coli sialic acid aldolase in one pot produced ST-MUC1 efficiently. These glycopeptides are potential cancer vaccine candidates. 23831499 Role of amygdala in drug memory. Drug addiction is a chronic brain disorder with the hallmark of a high rate of relapse to compulsive drug seeking and drug taking even after long-term abstinence. Addiction has been considered as an aberrant memory that has been termed "addiction memory." Drug-related memory plays a critical role in the maintenance of learned addictive behaviors and emergence of relapse. Disrupting these long-lasting memories by administering amnestic agents or other manipulations during specific phases of drug memory is a promising strategy for relapse prevention. Recent studies on the processes of drug addiction and relapse have demonstrated that the amygdala is involved in associative drug addiction learning processes. In this review, we focus on preclinical studies that used conditioned place preference and self-administration models to investigate the differential roles of the amygdala in each phase of drug-related memory, including acquisition, consolidation, retrieval, reconsolidation, and extinction. These studies indicate that the amygdala plays a critical role in both cue-associative learning and the expression of cue-induced relapse to drug-seeking behavior. 23435124 A 35kD Phyllanthus niruri protein modulates iron mediated oxidative impairment to hepatocytes via the inhibition of ERKs, p38 MAPKs and activation of PI3k/Akt pathway. It has been reported that the herb, Phyllanthus niruri, possess antioxidant, anti-infection, anti-asthmatic, anti-diuretic, anti-soresis and many more beneficial activities. The goal of our present study was to evaluate the protective role of a 35kD protein (PNP) isolated from this herb against iron-induced cytotoxicity in murine hepatocytes. Exposure of hepatocytes to iron (FeSO4) caused elevation of reactive oxygen species (ROS) production, enhanced lipid peroxidation and protein carbonylation, depleted glutathione levels, decreased the antioxidant power (FRAP) of the cells and reduced cell viability. Iron mediated cytotoxicity disrupted mitochondrial membrane potential (Δψm) and thereby caused apoptosis mainly by the intrinsic pathway via the down-regulation of IκBα with a concomitant up-regulation of NF-kB as well as the phosphorylation of ERKs and p38 MAP kinases. In addition, iron-induced cytotoxicity disrupted the normal balance of Bcl-2 family proteins in hepatocytes. Incubation of hepatocytes with PNP, however, protected the cells from apoptosis by stabilizing the mitochondria and arresting the release of cytochrome c. It also suppressed caspase activation and cleavage of PARP. Moreover, this protein has strong free radical scavenging activity and thereby scavenged ROS extensively. Combining all, results suggest that simultaneous treatment with PNP might suppress the iron-induced cytotoxicity in hepatocytes. 23644943 Influence of Matrix Metalloproteinase-1 Gene -1607 (1G/2G) (rs1799750) Promoter Polymorphism on Circulating Levels of MMP-1 in Chronic Pancreatitis. This study investigated the role of -1607 (1G/2G) (rs1799750) polymorphism of the MMP-1 gene in chronic pancreatitis. We genotyped 100 patients with chronic pancreatitis and 100 control subjects using tetra-primer ARMS-PCR followed by agarose gel electrophoresis. Serum levels of MMP-1 were determined by Elisa. Statistical analysis was applied to test the significance of the results. The genotypic and allelic distribution varied significantly between the disease group and the control subjects [OD = 1.981 (1.236-3.181), p = 0.004]. MMP-1 levels were higher in subjects homozygous for the 2G allele than in subjects with the 1G allele. The present study revealed a significant association of the MMP-1 -1607 1G/2G (rs1799750) gene promoter polymorphism with chronic pancreatitis, and it can be considered a biological marker in the etiology of chronic pancreatitis. 23843237 Gonocytes, from the Fifties to the Present: Is There a Reason to Change the Name? Historically, the precursor cells to spermatogonia have been identified as "gonocytes", a term created in the fifties to encompass fetal and neonatal germ cells from the time they become resident in testis primordia to the time they relocate at the basement membrane of the seminiferous cords and differentiate. During this period, spreading over several days in rodents and months in humans, germ cell morphology and central location within the cords remain relatively unchanged. Another common trait is the intensive DNA methylation taking place in fetal to neonatal gonocytes. It is only when they reach the periphery of the cords after birth that germ cells acquire the characteristic appearance of spermatogonia. Studies showed that fetal and neonatal germ cells undergo progressive developmental changes comprising three major phases, a fetal mitotic phase followed by a quiescent period during which most of DNA methylation occurs, and a neonatal mitotic phase associated with migration to the basement membrane, morphological changes and differentiation to spermatogonia. Efforts to associate a distinctive gene expression profile to each of these phases have failed, revealing instead gradual changes in gene and protein expression, and the co-existence within each period of unsynchronized cells at different phases of development. In the seventies, the terms pre- or pro-spermatogonia appeared as alternatives for the term gonocyte, but the definition of these terminologies varied between studies. Thus far, the term gonocyte remains the most commonly used, corresponding to a specific location of the cells, morphological appearance and functional traits, which are distinct from the prior and subsequent developmental phases. In view of the present knowledge, one could further distinguish gonocyte subsets by the prefixes M, Q and T, describing respectively fetal mitotic, quiescent and transitional neonatal mitotic/migratory gonocytes, in conjunction with emerging methods allowing better discrimination of these subsets. 23025626 Adrenal cortical carcinoma in a child, a rare cause of paediatric endocrinopathy: case report and literature review. Adrenal cortical carcinomas (ACC) are rare tumours, most commonly reported in adult patients. However, an important peak in incidence occurs in paediatric patients. ACC is a rare cause of paediatric endocrinopathy which may masquerade as a non-neoplastic disease process. Herein we present ACC in a five-year-old female patient. Histopathological features associated with poor outcome included tumour weight >500 g, tumour size >10.5 cm, invasive properties, confluent tumour necrosis, high nuclear grade and high proliferation index assessed by Ki67 immunohistochemistry. This article focuses on clinical features, treatment, pathological characteristics, evolving classification and genetic significance of ACC in paediatric patients. 23876897 Experience of segmentectomy from 36 Chinese patients with non-small cell lung cancer at stage I. Although video-assisted radical operation for lung cancer has been widely accepted for treatment of nonsmall cell lung cancer (NSCLC), the debate over video-assisted thoracic surgery (VATS) segmentectomy still remains. This study analyzed the clinical outcomes using VATS segmentectomy for stage I NSCLC patients to explore the safety and efficacy of VATS segmentectomy for Ia NSCLC. Retrospective review was conducted of patients who underwent VATS segmentectomy for clinical stage I NSCLC at Shanghai Chest Hospital between November 2009 and May 2012. VATS segmentectomy was performed on 36 patients. Analyses of the patient group were performed on patient demographics and clinical characteristics, intraoperative parameters, complications, and postoperative survival. Thirty-five of thirty-six patients underwent VATS segmentectomy with only one conversion to open thoracic surgery. There was one peri-operative mortality from the segmentectomy group and all other patients are alive with a median follow up of 327 days. The mean volume of chest tube drainage after operation for segmentectomy was 1021.4 ml. Among other parameters, the mean blood loss was 162.5 ml (50.0 - 1600.0 ml), the mean operation time 124.8 minutes (75.0 - 271.0 minutes), chest tube duration 4.1 days (2 - 8 days), and the mean length of hospital stay 6.2 days (4 - 11 days). There was one (2.8%) locoregional recurrence after segmentectomy. Two patients successfully underwent bilateral segmentectomies and are still disease free. For patients with stage I NSCLC, VATS segmentectomy offers a safe and equally effective option and can be applied to complicated operations such as bilateral segmentectomy. 23884313 MicroRNA-203 Regulates Melanosome Transport and Tyrosinase Expression in Melanoma Cells by Targeting Kinesin Superfamily Protein 5b. MicroRNA (miR)-203 is known to be downregulated and to act as an anti-oncomir in melanoma cells. At present, we found that exogenous miR-203 increased pigmentation and protein expression levels of the melanoma antigen recognized by T cells (Melan-As/MART1s) and/or tyrosinase (TYR) in the human melanoma cells tested. Inversely, treatment with an inhibitor of miR-203 downregulated the expression level of TYR. The target gene of miR-203 involved in the mechanism was kinesin superfamily protein 5b (kif5b), which was revealed by gene silencing using short interfering RNA and luciferase activity assay. Furthermore, immunocytochemistry showed obvious accumulation of melanosomes around nuclei of human melanoma Mewo cells transfected with miR-203 or siR-kif5b. Importantly, treatment with the miR-203 inhibitor, but not miR-203, exhibited effects on human epidermal melanocytes isolated from lightly pigmented adult skin similar to those on melanoma cells. In addition, the data indicated that exogenous miR-203 also negatively regulated the cAMP response element-binding protein 1 (CREB1)/microphthalmia-associated transcription factor (MITF)/Rab27a pathway, which is one of the main pathways active in melanoma cells. In conclusion, our data indicated that anti-oncogenic miR-203 had a pivotal role in melanoma through reducing melanosome transport and promoting melanogenesis by targeting kif5b and through negative regulation of the CREB1/MITF/Rab27a pathway.Journal of Investigative Dermatology advance online publication, 15 August 2013; doi:10.1038/jid.2013.310. 22456695 Fasting glucose, HbA1c, or oral glucose tolerance testing for the detection of glucose abnormalities in patients with acute coronary syndromes. Due to the negative prognostic impact, it is important to accurately detect undiagnosed glucose perturbations in patients with acute coronary syndromes (ACS). Design: This study compares oral glucose tolerance test (OGTT) to fasting plasma glucose (FPG) and HbA1c as screening tools. Patients hospitalized for ACS had an OGTT, FPG, and HbA1c measured 4-21 (median 6) days after admission as a screening process for an intervention study. Out of 174 patients, 75 (43%) had a normal glucose tolerance, 63 (36%) impaired glucose tolerance (IGT), and 36 (21%) diabetes type 2 (T2DM). Of these, 20 were non-eligible, and of the remaining 79 patients, 52 had IGT and 27 T2DM according to the OGTT. In patients with IGT, the median FPG was 6.0 mmol/l and the median HbA1c was 39 mmol/mol. The corresponding levels in patients with T2DM were 6.3 mmol/l and 41 mmol/mol, respectively. Seventeen of the 27 patients with T2DM according to OGTT had not been disclosed if the screening had been based on FPG. HbA1c identified two patients. Compared to OGTT, the use of FPG or HbA1c alone leaves a majority of patients with IGT or T2DM undetected when screening for unknown glucose perturbations as a part of total risk assessment of patients with ACS. 23603004 Protective effects of naringin against paraquat-induced acute lung injury and pulmonary fibrosis in mice. The present study evaluates protective effects of naringin against paraquat (PQ)-induced acute lung injury (ALI) and pulmonary fibrosis in mice. Survival probability against PQ intoxication was tested by a single intraperitoneal injection of PQ. Results showed that survival rates of mice exposed to PQ only (50mg/kg within 7days) were much lower than that in mice daily treatment with NAC or naringin. Moreover, protection against PQ-induced ALI was tested by daily pretreatment mice with saline, NAC or naringin for 3days before PQ (30mg/kg, i.p.). Results showed that increase in leukocytes infiltration and overexpressions of TNF-α and TGF-β1 caused by 8h of PQ exposure were dose-dependently ameliorated by naringin. Furthermore, protection against PQ-induced pulmonary fibrosis was tested by pretreatment mice with PQ (20mg/kg, i.p.), and then daily administration with saline, NAC or naringin for prolonged 21days. Results showed that naringin of 60 and 120mg/kg significantly reduced PQ-induced upregulations of TNF-α, TGF-β1, MMP-9 and TIMP-1, levels of pulmonary malonaldehyde and hydroxyproline, as well as pulmonary fibrosis deposition, while increased activities of SOD, GSH-Px and HO-1. These results indicated that naringin had effective protection against PQ-induced ALI and pulmonary fibrosis. 23962740 Relationship between early maladaptive schemas and symptom dimensions in patients with obsessive-compulsive disorder. The aims of this study were to evaluate early maladaptive schemas (EMSs) of patients with obsessive-compulsive disorder (OCD) and to clarify relationships between particular EMSs and the five factor-analyzed symptom dimensions and other clinical variables. Fifty-seven patients with OCD and 70 normal controls completed the Young Schema Questionnaire, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the Y-BOCS symptom checklist, and the Beck Depression Inventory. Patients with OCD had significantly higher scores for schema related to defectiveness/shame, social isolation/alienation, and failure than did normal controls. Among the five OCD symptom dimensions, the sexual/religious dimension was only significantly correlated with two schemas of vulnerability to harm or illness and enmeshment/undeveloped self. These two schemas were significant predictors of the sexual/religious dimension, accounting for 33% of the total variance in this dimension. Any EMSs in patients with OCD were not related to clinical variables such as severity of OCD and duration of illness. These findings may constitute evidence to improve our understandings of OCD from a perspective of schema theory. 23835210 Risk factors of liver failure after right-sided hepatectomy. To prevent hepatic failure after major hepatectomy, it is important to assess preoperative factors related to liver failure. We examined 80 patients who underwent right-sided hepatectomy. Hyperbilirubinemia, uncontrolled ascites, and prolonged postoperative hospital stay were defined as liver failure after hepatectomy, and these 3 factors were evaluated in relation to clinicopathological and surgical factors. In the 80 patients, hyperbilirubinemia was observed in 10 (12.7%) patients, uncontrolled ascites in 18 (22.5%) patients, and prolonged hospital stay after surgery in 39 (48.8%) patients. Multivariate analyses identified platelet count as a risk factor of hyperbilirubinemia, uncontrolled ascites, and prolonged postoperative hospital stay, and the ratio of remnant liver volume to body surface area (RLV/BSA ratio) as an additional risk factor of hyperbilirubinemia and prolonged postoperative hospital stay. Platelet count and RLV/BSA ratio are useful risk factors for prediction of liver failure after right-sided hepatectomy. 23353806 Multifunctional terpolymeric MRI contrast agent with superior signal enhancement in blood and tumor. A new multifunctional terpolymeric system for simultaneous imaging and drug delivery has been recently developed in our laboratory. Herein we report the investigation of terpolymeric contrast agent for magnetic resonance imaging and doxorubicin (Dox) delivery. The polymer was synthesized by graft polymerization of methacrylic acid (MAA) and polysorbate 80 (PS 80) onto starch with multiple, chemically bound diethylenetriaminepenta acetic acid (DTPA) groups for gadolinium chelating. The terpolymer self-assembled to form nanoparticles upon addition of doxorubicin which binds with the PMAA chain. The physicochemical, biological and pharmacokinetic properties of the polymeric system were characterized and their contrast enhancement capability was evaluated in vitro and in vivo. The polymer was able to load gadolinium with high thermodynamic stability and exhibited low cytotoxicity. The Gd-loaded polymer (PolyGd), and Gd-Dox co-loaded nanoparticles (PolyGd-Dox) significantly enhanced MR signals, with ionic T1 relaxivities 3-5 times higher than those from Omniscan®, a small molecule contrast agent. In vivo studies showed superior and prolonged contrast enhancement compared to Omniscan® at one fourth the equivalent dose, without adverse effects. The PolyGd and PolyGd-Dox accumulated in the tumor and painted the tumor boundaries clearly for at least 48h. The PolyGd also enhanced angiogram contrast with contrast to noise ratio values of up to 55-fold and a blood half-life time of 200min. Seven days after intravenous administration, only relatively small amounts of gadolinium could be detected in the major organs of the mice (supplementary materials). These results suggest that the new terpolymeric system is useful as a theranostic platform for contrast enhanced MR imaging of vasculature and tumor as well as Dox delivery. 23731169 Sunlight-driven reduction of silver ions by natural organic matter: formation and transformation of silver nanoparticles. Photobiogeochemical reactions involving metal species can be a source of naturally occurring nanoscale materials in the aquatic environment. This study demonstrates that, under simulated sunlight exposure, ionic Ag is photoreduced in river water or synthetic natural water samples that contain natural organic matter (NOM), forming Ag nanoparticles (AgNPs) that transform in size and shape and precipitate out upon extended irradiation. We show that the dissolved oxygen concentration does not appear to affect AgNP formation rates, indicating that reactive transients such as superoxide, hydrated electron, and triplet NOM do not play a large role. By varying pH and NOM concentrations and adding competing cations on the AgNP formation, we present three lines of evidence to show that Ag ion photoreduction likely involves ionic Ag binding to NOM. Our work suggests that photochemical reactions involving ionic Ag and NOM can be a source of nanosized Ag in the environment. 23870195 Genetics of coronary artery calcification among African Americans, a meta-analysis. Coronary heart disease (CHD) is the major cause of death in the United States. Coronary artery calcification (CAC) scores are independent predictors of CHD. African Americans (AA) have higher rates of CHD but are less well-studied in genomic studies. We assembled the largest AA data resource currently available with measured CAC to identify associated genetic variants. We analyzed log transformed CAC quantity (ln(CAC + 1)), for association with ~2.5 million single nucleotide polymorphisms (SNPs) and performed an inverse-variance weighted meta-analysis on results for 5,823 AA from 8 studies. Heritability was calculated using family studies. The most significant SNPs among AAs were evaluated in European Ancestry (EA) CAC data; conversely, the significance of published SNPs for CAC/CHD in EA was queried within our AA meta-analysis. Heritability of CAC was lower in AA (~30%) than previously reported for EA (~50%). No SNP reached genome wide significance (p < 5E-08). Of 67 SNPs with p < 1E-05 in AA there was no evidence of association in EA CAC data. Four SNPs in regions previously implicated in CAC/CHD (at 9p21 and PHACTR1) in EA reached nominal significance for CAC in AA, with concordant direction. Among AA, rs16905644 (p = 4.08E-05) had the strongest association in the 9p21 region. While we observed substantial heritability for CAC in AA, we failed to identify loci for CAC at genome-wide significant levels despite having adequate power to detect alleles with moderate to large effects. Although suggestive signals in AA were apparent at 9p21 and additional CAC and CAD EA loci, overall the data suggest that even larger samples and an ethnic specific focus will be required for GWAS discoveries for CAC in AA populations. 22763381 Haplotype analysis of the 185delAG BRCA1 mutation in ethnically diverse populations. The 185delAG* BRCA1 mutation is encountered primarily in Jewish Ashkenazi and Iraqi individuals, and sporadically in non-Jews. Previous studies estimated that this is a founder mutation in Jewish mutation carriers that arose before the dispersion of Jews in the Diaspora ~2500 years ago. The aim of this study was to assess the haplotype in ethnically diverse 185delAG* BRCA1 mutation carriers, and to estimate the age at which the mutation arose. Ethnically diverse Jewish and non-Jewish 185delAG*BRCA1 mutation carriers and their relatives were genotyped using 15 microsatellite markers and three SNPs spanning 12.5 MB, encompassing the BRCA1 gene locus. Estimation of mutation age was based on a subset of 11 markers spanning a region of ~5 MB, using a previously developed algorithm applying the maximum likelihood method. Overall, 188 participants (154 carriers and 34 noncarriers) from 115 families were included: Ashkenazi, Iraq, Kuchin-Indians, Syria, Turkey, Iran, Tunisia, Bulgaria, non-Jewish English, non-Jewish Malaysian, and Hispanics. Haplotype analysis indicated that the 185delAG mutation arose 750-1500 years ago. In Ashkenazim, it is a founder mutation that arose 61 generations ago, and with a small group of founder mutations was introduced into the Hispanic population (conversos) ~650 years ago, and into the Iraqi-Jewish community ~450 years ago. The 185delAG mutation in the non-Jewish populations in Malaysia and the UK arose at least twice independently. We conclude that the 185delAG* BRCA1 mutation resides on a common haplotype among Ashkenazi Jews, and arose about 61 generations ago and arose independently at least twice in non-Jews. 23896666 International Spinal Cord Injury Urinary Tract Infection Basic Data Set. Objectives:To develop an International Spinal Cord Injury (SCI) Urinary Tract Infection (UTI) Basic Data Set presenting a standardized format for the collection and reporting of a minimal amount of information on UTIs in daily practice or research.Setting:International working group.Methods:The draft of the Data Set developed by a working group was reviewed by the Executive Committee of the International SCI Standards and Data Sets, and later by the International Spinal Cord Society (ISCoS) Scientific Committee and the American Spinal Injury Association (ASIA) Board. Relevant and interested scientific and professional (international) organizations and societies (∼40) were also invited to review the data set, and it was posted on the ISCoS and ASIA websites for 3 months to allow comments and suggestions. The ISCoS Scientific Committee, Executive Committee and ASIA Board received the data set for final review and approval.Results:The International SCI UTI Basic Data Set includes the following variables: date of data collection, length of time of sign(s)/symptom(s), results of urine dipstick test for nitrite and leukocyte esterase, urine culture results and resistance pattern. The complete instructions for data collection and the data form itself are freely available on the website of ISCoS (http://www.iscos.org.uk).Spinal Cord advance online publication, 30 July 2013; doi:10.1038/sc.2013.72. 23732518 Role of oxidants on calcium and sodium movement in healthy and diseased cardiac myocytes. In this review article we give an overview of current knowledge with respect to redox-sensitive alterations in Na(+) and Ca(2+) handling in the heart. In particular, we focus on redox-activated protein kinases including cAMP-dependent protein kinase A (PKA), protein kinase C (PKC), and Ca/calmodulin-dependent protein kinase II (CaMKII), as well as on redox-regulated downstream targets such as Na(+) and Ca(2+) transporters and channels. We highlight the pathological and physiological relevance of reactive oxygen species and some of its sources (such as NADPH oxidases, NOXes) for excitation-contraction coupling (ECC). A short outlook with respect to the clinical relevance of redox-dependent Na(+) and Ca(2+) imbalance will be given. 23541893 Molecular Basis of SMC ATPase Activation: Role of Internal Structural Changes of the Regulatory Subcomplex ScpAB. In many bacteria, a homodimer of structural-maintenance-of-chromosomes proteins associates with two regulatory subunits (known as ScpA and ScpB), assembling a protein complex that plays a crucial role in chromosome organization and segregation. It remains poorly understood, however, how this complex might work at the mechanistic level. Here, we report crystal structures of the ScpAB core complex that display a highly unusual structure in which the central segment of ScpA winds around an asymmetrically oriented ScpB dimer. The two C-terminal domains of the ScpB dimer primarily interact with different regions of ScpA with different affinities. Moreover, flexible interdomain regions of ScpB contribute to a dynamic folding process of the ScpAB subcomplex. Together with other genetic and biochemical assays, we provide evidence that internal structural changes of the ScpAB subcomplex are tightly coupled with activation of the structural-maintenance-of-chromosomes ATPase. 23929174 C-QUALITY: Cost and Quality-of-Life Pharmacoeconomic Analysis of Antidepressants in Major Depressive Disorder in Italy. Major depressive disorder (MDD) is a common and disabling condition across the world. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most commonly used antidepressants. The objective of this study was to assess the cost-effectiveness [ per quality-adjusted life year (QALY)] of all SSRIs and all SNRIs for the treatment of MDD in Italy. A decision analytic model was adapted from the Swedish Dental and Pharmaceutical Benefits agency model to reflect current clinical practice in the treatment of MDD in the largest Italian regions. This adaptation was possible thanks to the collaboration of an expert panel of Italian psychiatrists and health economists. The model evaluated patients with a first diagnosis of MDD and initiating an SSRI or an SNRI for the first time. The time horizon was 12 months. Efficacy and utility data for the model were retrieved from the literature and validated by the expert panel. Local data were considered for resource utilization and for treatment costs based on each regional health service perspective. Population-weighted regional data were used to define a national model. Scenario simulations, one-way sensitivity analyses, and Monte Carlo simulations were performed to test the robustness of the model. The base case analysis showed that escitalopram was associated with a lower total cost ( 1,562) and a larger health gain (QALYs) at 1 year (0.732) per patient and dominated the other treatment strategies since more QALYs were achieved at a lower total cost. Sensitivity analyses support the robustness of the model. The results indicate that escitalopram is the most cost-effective pharmacological treatment strategy for the Italian health service compared with other SSRIs and all SNRIs used in the first-line treatment of MDD. 23803710 Comparison of vascular growth factors in the murine brain reveals placenta growth factor as prime candidate for CNS revascularization. Vascular bypass procedures in the central nervous system (CNS) remain technically challenging, hindered by complications and often failing to prevent adverse outcome such as stroke. Thus, there is an unmet clinical need for a safe and effective CNS revascularization. Vascular endothelial growth factors (VEGFs) are promising candidates for revascularization; however, their effects appear to be tissue-specific and their potential in the CNS has not been fully explored. To test growth factors for angiogenesis in the CNS, we characterized the effects of endothelium-specific growth factors on the brain vasculature and parenchyma. Recombinant adeno-associated virus (AAV) vectors encoding the growth factors were injected transcranially to the frontoparietal cerebrum of mice. Angiogenesis, mural cell investment, leukocyte recruitment, vascular permeability, reactive gliosis and neuronal patterning were evaluated by 3-dimensional immunofluorescence, electron microscopy, optical projection tomography, and magnetic resonance imaging. Placenta growth factor (PlGF) stimulated robust angiogenesis and arteriogenesis without significant side effects, whereas VEGF and VEGF-C incited growth of aberrant vessels, severe edema, and inflammation. VEGF-B, angiopoietin-1, angiopoietin-2, and a VEGF/angiopoietin-1 chimera had minimal effects on the brain vessels or parenchyma. Of the growth factors tested, PlGF emerged as the most efficient and safe angiogenic factor, hence making it a candidate for therapeutic CNS revascularization. 22749842 Dual inhibitor of PDE7 and GSK-3-VP1.15 acts as antipsychotic and cognitive enhancer in C57BL/6J mice. Cognitive deficit is a core of schizophrenia and it is not effectively treated by the available antipsychotic drugs, hence new and more effective therapy is needed. Schizophrenia is considered as a pathway disorder where Disrupted-In-Schizophrenia-1 (DISC1) is important molecular player that regulates multiple cellular cascades. We recently reported synergistic action between phosphodiesterase-4 (PDE4) and glycogen synthase kinase-3 (GSK-3) as DISC1 interacting proteins. In the current study we characterized behavioural effects of a newly developed compound, VP1.15 that inhibits both PDE7 and GSK-3 with main focus on its antipsychotic and cognitive capacities. VP1.15 reduced ambulation in C57BL/6J mice in a dose-dependent manner (7.5 mg/kg and 3 mg/kg, respectively) and, hence, lower dose was chosen for the further analysis. VP1.1.5 facilitated pre-pulse inhibition (PPI), reversed amphetamine- but not MK-801-induced PPI deficit. The drug was able to ameliorate the disrupted latent inhibition (LI) induced by the increased number of conditioning trials and reversed amphetamine-induced LI deficit, supporting further its antipsychotic effects. The drug also significantly improved episodic memory in the spatial object recognition test, facilitated working memory in Y-maze and enhanced cued fear memory, but had no effect on executive function in the Puzzle box and contextual fear conditioning. Taken together, VP1.15 elicited antipsychotic effects and also facilitated cognitive domains in mice, suggesting that multitarget drugs, affecting molecular substrates from the same pathway, perhaps could be antipsychotics of new-generation that open a new possibilities in drug discoveries. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23740715 Comparative and quantitative myology of the forearm and hand of prosimian primates. Associations between the relative development of muscles of the forearm and hand of prosimian primates and locomotor behavior, body size, and grasping specializations have been made on the basis of qualitative observations. These associations are here tested through comparative and quantitative analyses of muscle mass data for a broad sample of prosimian species (i.e., strepsirrhines and tarsiers). The musculature of the forearm and hand of 17 fresh-frozen specimens representing six families and 12 species was dissected and weighed. Muscle weights were scaled relative to body mass of individual specimens using regression and compared by limb compartment and functional group. Forearm and digital flexor muscle masses are highly correlated with body mass (r = 0.97 and r = 0.96, respectively) and scale isometrically. As a general trend within the prosimian sample, the relative mass of the flexor compartment increases with body size. Interspecific comparisons of functional groups of muscles did not identify any association between larger muscle mass and locomotor adaptations or grasping specializations of the hand. However, compared to other prosimians, the adductor pollicis muscle of Nycticebus is more developed (52% of the intrinsic hand musculature sampled) and the flexor digitorum profundus muscle has two well-separated heads with more individualized tendons, with the pollex and digit IV receiving tendinous contributions from both muscle heads. These differences that characterize the forearm and hand of Nycticebus correlate with the extreme thumb divergence and pincer-like grips of lorises. Anat Rec, 2013. © 2013 Wiley Periodicals, Inc. 23895125 Genetic counseling for breast cancer risk: how did we get here and where are we going? Genetic counselors have been helping patients navigate hereditary cancer risk for decades. The rapidly changing landscape of genetic testing options means the field is again at a unique time in its history. Fears that arose when BRCA testing first became available are again being voiced in light of next-generation sequencing. The origins of genetic counseling, best practices, and recommendations that have come about since those early days need to be well understood before these new challenges can be met. The role of a proper risk assessment in preventing adverse outcomes is vital as options for testing change. In addition, an understanding of how various countries have incorporated genetic testing and genetic counseling into their healthcare systems can provide lessons in moving forward and capitalizing on the new technology that is again creating a genetics revolution. 23948127 Food selectivity in children with and without an autism spectrum disorder: Investigation of diagnosis and age. Feeding problems are common in children with autism spectrum disorders (ASDs), with food selectivity being the most frequently reported. Selectivity based on type and/or texture of food is of concern in those with ASD. Variations in symptom presentation of food selectivity in children with different autism spectrum diagnoses across childhood have not often been investigated. Parent-report of food selectivity was examined in 525 children age 2-18 years diagnosed with autistic disorder, PDD-NOS, Asperger's disorder, atypical development, and typical development using information garnered from the Autism Spectrum Disorder-Comorbidity for Children (ASD-CC), a tool to assess emotional issues and comorbid psychopathology. Individuals with an ASD were reported to have significantly more food selectivity than both the atypically developing group and the typically developing group. In addition, the ASD groups, when looked at together, showed a decrease in food selectivity across childhood with significant decrease in the Asperger's disorder group. 23412161 Traumatic and non-traumatic isolated horizontal meniscal tears of the knee in patients less than 40 years of age. The aim of this study is to analyze the characteristics of isolated horizontal meniscal tears in young patients and compared traumatic and non-traumatic isolated horizontal meniscal tear without other type of meniscal tear. Forty patients who underwent partial meniscectomy with isolated horizontal meniscal tears and followed up for more than 2 years were divided into two groups according to the presence of distinct previous traumatic events (defined as contusion or sprain) to the knees. Analyzed variables included in this descriptive statistics were involved side of knee and location of meniscus, physical examinations (joint line tenderness and McMurray's testing), subjective International Knee Documentation Committee (IKDC) criteria, and Lysholm functional questionnaires. Twenty-two of the forty patients (55 %) had distinct previous traumatic events. Fourteen cases (63.6 %) in traumatic group and 14 cases (77.8 %) in non-traumatic group are involved non-dominant knees during locomotion or playing sports. Twenty patients (90.9 %) in traumatic group and eight patients (44.4 %) in non-traumatic group presented with tear in the midportion of the medial meniscus on arthroscopic findings (p < 0.01). Six patients (60.0 %) in traumatic group and twelve patients (85.7 %) in non-traumatic group had meniscal cysts on arthroscopic findings at the time of surgery (p < 0.01). There was no statistic difference between the two groups with respect to physical examinations, subjective IKDC scores, and Lysholm functional scores. Isolated horizontal meniscal tears in young patients predominantly involved non-dominant knees and medial meniscus. Anterior aspect of medial meniscus was more frequently involved in traumatic group. Meniscal cysts were more frequently showed in non-traumatic group. 23835632 Association between HLA alleles and HAM/TSP in individuals infected with HTLV-1. HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) develops in less than 5 % of HTLV-1 carriers. It is unclear which factors trigger the development of disease. The aim of this study was to explore the influence of HLA alleles on the development of HAM/TSP. A total of 40 HTLV-1-infected individuals belonging to the Spanish HTLV-1 cohort were examined. HTLV-1 proviral load was measured by real-time polymerase chain reaction. HLA class I (A, B, C) and class II (DRB1, DQB1) alleles were genotyped using the bead array technology. Median HTLV-1 proviral load in 12 HAM/TSP patients was greater than in 28 asymptomatic carriers (637 vs. 71 copies per 10(4) peripheral blood mononuclear cells; p = 0.006). Moreover, HAM/TSP was significantly associated with HLA-B*07 and HLA-DRB1*01:01 (p = 0.039). Interestingly, individuals with these HLA alleles had greater HTLV-1 proviral load than asymptomatic carriers (p = 0.036). In summary, HLA testing should be considered in asymptomatic HTLV-1 individuals and close monitoring of HTLV-1 proviral load along with periodic neurological evaluations should be prioritized in HLA-DRB1*01:01 and HLA-B*07 carriers. 23968258 Different kinetic pathways of early-stage calcium-phosphate cluster aggregation induced by carboxylate-containing polymers. Acidic proteins are critical to biomineral formation, although their precise mechanistic function remains poorly understood. A number of recent studies have suggested a non-classical mineralization model that emphasizes the importance of the formation of polymer-stabilized mineral clusters or particles; however, it has been difficult to characterize the precursors experimentally due to their transient nature. Here, we successfully captured step-wise evolution of transient CaP clusters in mineralizing solutions and studied the roles of functional polymers with laser light scattering (LLS) to determine how these polymers influence the stability of nanoclusters. We found that the polymer structure can alter CaP aggregation mechanisms, whereas the polymer concentration strongly influences the rate of CaP aggregation. Our results indicate that the ability of acidic biomolecules to control the formation of relatively stable nanoclusters in the early stages may be critical for intrafibrillar mineralization. More importantly, LLS provided information about the size and structural evolution of CaP aggregates, which will help define the process of controlled biomineralization. 23389251 Assessing level of development and successional stages in biological soil crusts with biological indicators. Biological soil crusts (BSCs) perform vital ecosystem services, but the difference in biological components or developmental level still affects the rate and type of these services. In order to differentiate crust successional stages in quantity and analyze the relationship between crust developmental level and successional stages, this work determined several biological indicators in a series of different developmental BSCs in the Shapotou region of China. The results showed that crust developmental level (level of development index) can be well indicated by crust biological indicators. Photosynthetic biomass was the most appropriate to differentiate crust successional stages, although both photosynthetic biomass and respiration intensity increased with the development and succession of BSCs. Based on of the different biological compositions, BSCs were quantificationally categorized into different successional stages including cyanobacterial crusts (lichen and moss coverages <20 %), lichen crusts (lichen coverage >20 % but moss coverage <20 %), semi-moss crusts (moss coverage >20 % but <75 %), and moss crusts (moss coverage >75 %). In addition, it was found that cyanobacterial and microalgal biomass first increased as cyanobacterial crusts formed, then decreased when lots of mosses emerged on the crust surface; however nitrogen-fixing cyanobacteria and heterotrophic microbes increased in the later developmental BSCs. The structural adjustment of biological components in the different developmental BSCs may reflect the requirement of crust survival and material transition. 22676713 Is the way to a man's heart through his stomach? Enteropericardial fistula: case series and literature review. Fistula formation between the pericardium and the gastrointestinal tract is rare. Enteropericardial fistulae may present dramatically, many have prodromal symptoms even though they are not symptoms usually associated with esophageal disease. Prompt diagnosis and expedient surgery can result in survival. We describe three cases of enteropericardial fistulae diagnosed during emergency surgery for sepsis or hemorrhage. All had previous surgery though the details were not available to the operating surgeons because of the time that had passed since their original operation. All three patients survived, albeit with prolonged hospital stay and repeated surgery. A review of the English language literature revealed 95 cases (Table 1). Fifty-eight had a history of previous surgery, particularly fundoplication or esophagectomy. Ten had advanced malignancy and were treated conservatively. All eight patients with fistulae, which were iatrogenic or due to foreign bodies, survived without aggressive surgery. For more extensive pathology, a successful outcome was achieved in 32 of the 36 cases when the upper gastrointestinal (GI) tract was defunctioned because of the presence of major sepsis or because the healthy vascularized tissue was transposed into the area at risk for further fistula formation. Where less aggressive surgery was performed only 12 of 27 patients survived (P < 0.0001). Esophageal surgeons need to be aware of the late complications and associated atypical symptoms of historical procedures which are no longer in common usage. Where an enteropericardial fistula is present, defunctioning of the upper GI tract or repair with transposition of vascularized tissue gives a better chance of a successful outcome. [Table: see text]. 23512156 Pulmonary vein anatomy predicts freedom from atrial fibrillation using remote magnetic navigation for circumferential pulmonary vein ablation. Multidetector computed tomography (MDCT) is frequently used to guide circumferential pulmonary vein ablation (PVA) for treatment of atrial fibrillation (AF) as it offers accurate visualization of the left atrial (LA) and pulmonary vein (PV) anatomy. This study aimed to identify if PV anatomy is associated with outcomes following PVA using remote magnetic navigation (RMN). We analysed data from 138 consecutive patients and 146 ablation procedures referred for PVA due to drug-refractory symptomatic AF (age 63 ± 11 years; 57% men; 69% paroxysmal AF). The RMN using the stereotaxis system and open-irrigated 3.5 mm ablation catheters was used in all procedures. Prior to PVA, all patients underwent electrocardiogram-gated 64-MDCT for assessment of LA dimensions, PV anatomy, and electro-anatomical image integration during the procedure. Regular PV anatomy was found in 68%, a common left PV ostium was detected in 26%, and variant anatomy of the right PVs was detected in 6%. After a mean follow-up of 337 ± 102 days, 63% of the patients maintained sinus rhythm after the initial ablation, and 83% when including repeat PVA. Although acutely successful PV isolation did not differ between anatomical subgroups (regular 3.5 ± 0.8 vs. variant 3.2 ± 1.3; P = 0.31), AF recurrence was significantly higher in patients with non-regular PV anatomy (P = 0.04, hazard ratio 1.72). Pulmonary vein anatomy did not influence complication rates. Pulmonary vein anatomy assessed by MDCT is a good predictor of AF recurrence after PVA using RMN. 23848165 Evaporation of nanodroplets on heated substrates: a molecular dynamics simulation study. Molecular dynamics simulations of Lennard-Jones particles have been performed to study the evaporation behavior of nanodroplets on heated substrates. The influence of the liquid-substrate interaction strength on the evaporation properties was addressed. Our results show that, during the temperature-raising evaporation, the gas is always hotter than the droplet. In contrast to the usual experimental conditions, the droplet sizes in our simulations are in the nanometer scale range and the substrates are ideally smooth and chemically homogeneous. As a result, no pinning was observed in our simulations for substrates denoted either hydrophilic (contact angle θ < 90°) or hydrophobic (contact angle θ > 90°). The evaporative mass flux is stronger with increasing hydrophilicity of the substrate because the heat transfer from the substrate to the droplet is more efficient for stronger attraction between the solid and the droplet. Evaporation and heat transfer to the gas phase occur preferentially in the vicinity of the three-phase contact line in the hydrophilic system. However, in the case of a hydrophobic substrate, there is no preferential location for mass and heat fluxes. During the whole evaporation process, no pure behavior according to either the constant-angle or the constant-radius model was found; both the contact angle and contact radius decrease for the droplets on hydrophilic and hydrophobic substrates alike. 22981808 Brain involvement in glaucoma: advanced neuroimaging for understanding and monitoring a new target for therapy. On the basis of a large body of experimental data the notion that glaucoma damages retinal ganglion cells and central areas of the visual system has been put forward. The mechanisms underlying glaucomatous involvement of the central areas are not known: the most likely hypothesis is that this event is the result of an anterograde transynaptic neurodegeneration triggered by ganglion cells' death. However, it is possible that in some cases it may be the consequence of a neurodegenerative disease of the central nervous system. In any event, novel mechanisms leading to cell demise might be implicated. The development of powerful neuroimaging techniques in conjunction with sophisticated analysis has recently provided compelling support to the involvement of central stations of the visual pathway in patients suffering of glaucoma. Diffusion Tensor-MRI allows the central damage associated with glaucoma to be assessed and therapeutic efficacy of novel neuroprotective interventions to be quantified. 23177787 Discovery of a selective M₄ positive allosteric modulator based on the 3-amino-thieno[2,3-b]pyridine-2-carboxamide scaffold: development of ML253, a potent and brain penetrant compound that is active in a preclinical model of schizophrenia. Herein we report a next generation muscarinic receptor 4 (M(4)) positive allosteric modulator (PAM), ML253 which exhibits nanomolar activity at both the human (EC(50)=56 nM) and rat (EC(50)=176 nM) receptors and excellent efficacy by the left-ward shift of the ACh concentration response curve (fold shift, human=106; rat=50). In addition, ML253 is selective against the four other muscarinic subtypes, displays excellent CNS exposure and is active in an amphetamine-induced hyperlocomotion assay. 23746222 Targeting membrane androgen receptors in tumors. Introduction: In the last decade androgen actions that are originated from non-genomic, rapid signaling have been described in a large number of cell models and tissues. These effects are initiated through the stimulation of membrane androgen-binding sites or receptors (mAR). Although the molecular identity of mARs remains elusive, their activation is known to trigger multiple non-genomic signaling cascades and to regulate numerous cell responses. In recent years specific interest is being paid to the role of mARs in tumors. Specifically, it was demonstrated that mAR activation by non-permeable testosterone conjugates induced potent anti-tumorigenic responses in prostate, breast, colon and glial tumors. In addition, in vivo animal studies further emphasized the potential clinical importance of these receptors. Areas covered: This review will summarize the current knowledge on the mAR-induced non-genomic, rapid androgen actions. It will focus on the molecular signaling pathways governed by mAR activation, discuss latest attempts to elucidate the molecular identity of mAR, address the plethora of cell responses initiated by mAR and evaluate the potential role of mAR and mAR-specific signaling as possible therapeutic targets in tumors. Expert opinion: mAR and mAR-induced specific signaling may represent novel therapeutic targets in tumors through the development of specific testosterone analogs. 23760106 A simple three-dimensional-focusing, continuous-flow mixer for the study of fast protein dynamics. We present a simple, yet flexible microfluidic mixer with a demonstrated mixing time as short as 80 μs that is widely accessible because it is made of commercially available parts. To simplify the study of fast protein dynamics, we have developed an inexpensive continuous-flow microfluidic mixer, requiring no specialized equipment or techniques. The mixer uses three-dimensional, hydrodynamic focusing of a protein sample stream by a surrounding sheath solution to achieve rapid diffusional mixing between the sample and sheath. Mixing initiates the reaction of interest. Reactions can be spatially observed by fluorescence or absorbance spectroscopy. We characterized the pixel-to-time calibration and diffusional mixing experimentally. We achieved a mixing time as short as 80 μs. We studied the kinetics of horse apomyoglobin (apoMb) unfolding from the intermediate (I) state to its completely unfolded (U) state, induced by a pH jump from the initial pH of 4.5 in the sample stream to a final pH of 2.0 in the sheath solution. The reaction time was probed using the fluorescence of 1-anilinonaphthalene-8-sulfonate (1,8-ANS) bound to the folded protein. We observed unfolding of apoMb within 760 μs, without populating additional intermediate states under these conditions. We also studied the reaction kinetics of the conversion of pyruvate to lactate catalyzed by lactate dehydrogenase using the intrinsic tryptophan emission of the enzyme. We observe sub-millisecond kinetics that we attribute to Michaelis complex formation and loop domain closure. These results demonstrate the utility of the three-dimensional focusing mixer for biophysical studies of protein dynamics. 23266428 Additive inhibition of human α1β2γ2 GABAA receptors by mixtures of commonly used drugs of abuse. Yearly, exposure to drugs of abuse results in ∼1 million emergency department visits in the US. In ∼50% of the visits, stimulant drugs like cocaine and amphetamine-like substances (e.g. 3,4-methylenedioxymethamphetamine (MDMA, the main active ingredient of ecstasy)) are involved, whereas in ∼60% multiple drugs are involved. These drugs induce higher dopamine and serotonin levels resulting in drug-induced toxicity. Since GABA receptors (GABA-R) provide the main inhibitory input on dopaminergic and serotonergic neurons, drug-induced inhibition of GABA-R could contribute to higher neurotransmitter levels and thus toxicity. We therefore investigated the effects of combinations of commonly abused stimulant drugs (cocaine, MDMA, 3,4-methylenedioxyamphetamine (MDA) and meta-chlorophenylpiperazine (mCPP)) on the function of the human α1β2γ2 GABAA receptor (hGABAA-R), expressed in Xenopus oocytes, using the two-electrode voltage-clamp technique. These drugs concentration-dependently inhibited the GABA-evoked current (mCPP>cocaine>MDMA>MDA). Most drug combinations decreased the GABA-evoked current stronger than the single drug. Additivity was observed during combined exposure to low concentrations of cocaine and mCPP as well as during combined exposure to MDA with cocaine or mCPP. However, combinations containing MDMA mainly resulted in sub-additivity or no additivity. At drug concentrations relevant for clinical toxicology, co-exposure to ≥2 drugs can decrease the GABA-evoked current in an additive manner. Thus, in patients exposed to multiple drugs, inhibitory GABA-ergic input is reduced more prominently, likely resulting in higher brain dopamine levels. As this will increase the risk for drug-induced toxicity, treatment of drug-intoxicated patients with drugs that enhance GABA-ergic input should be further optimized. 23848843 Effects of positive end-expiratory pressure titration on gas exchange, respiratory mechanics and hemodynamics in anesthetized horses. To assess if positive end-expiratory pressure (PEEP) titration improves gas exchange and respiratory mechanics, without hemodynamic impairment in horses during anesthesia. Prospective, randomized study. Thirteen isoflurane-anesthetized healthy horses. After 60 minutes of anesthesia with spontaneous breathing, mechanical ventilation was initiated with an inspiratory-expiratory ratio of 1:2, PEEP of 5 cmH2 O, tidal volume of 10-20 mL kg(-1) and respiratory rate adjusted to maintain normocapnia. Constant PEEP of 5 cmH2 O was continued (control group; n = 6) or titrated (PEEP group; n = 7) by increasing and decreasing PEEP from 5 to 20 cmH2 O at 15-minute intervals. The horses were instrumented with an arterial catheter to measure blood pressure and allow collection of blood for pH and blood gas analysis and a Swan-Ganz catheter for measurement of cardiac output (CO) using thermodilution. Cardiopulmonary assessment was recorded before PEEP titration and after 15 minutes at each PEEP value. In the PEEP group, static compliance (range) (Cst 278-463 mL cmH2 O(-1) ) was significantly higher and the shunt fraction (Q·s/Q·t 7-20%) and the alveolar-arterial oxygen difference [P(A-a)O2 95-325 mmHg] were significantly lower than in the control group [Cst of 246-290 mL cmH2 O(-1) , Q·s/Q·t of 16-19%, P(A-a)O2 of 253-310 mmHg; p < 0.05]. CO (mean ± SEM) was lower in the PEEP group (23 ± 2 L minute(-1) ) at 20 cmH2 O PEEP than in the control group (26 ± 4 L minute(-1) , p < 0.05), with no significant changes in heart rate, blood pressure or central venous pressure. PEEP titration significantly improved gas exchange and lung compliance, with a small decrease in CO at the highest PEEP level. Gas exchange and respiratory mechanics impairment during inhalation anesthesia can be treated using PEEP titration from 5 to 20 cmH2 O, without clinically important hemodynamic effects in healthy horses. 23734006 Euglycemic clamp insulin sensitivity and longitudinal systolic blood pressure: role of sex. Insulin resistance may be an independent risk factor for the development of hypertension, but change in blood pressure (BP) over time has not been adequately studied in healthy individuals fully characterized for insulin sensitivity. In the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study, we measured insulin sensitivity (M/I) using the euglycemic clamp technique in 1073 healthy European adults (587 women, 486 men) aged 30 to 60 years followed up 3 years later. Systolic BP (SBP) at baseline was higher in insulin-resistant women (ie, those in the low sex-specific M/I tertile) compared with those in the intermediate (P<0.001) or high tertiles (P=0.06; mean±SD: 117±13, 111±12, 114±12 mm Hg, respectively). It did not differ across M/I tertiles in men. After adjustment for age, body mass index, baseline SBP, and other covariates, low insulin sensitivity (M/I) predicted a longitudinal rise in SBP in women but not in men; M/I was not associated with change in diastolic BP. SBP rose over time in both sexes and within all M/I tertiles (P<0.05), except in women with high insulin sensitivity. Therefore, in women (but not in men), low insulin sensitivity was associated with higher SBP at 3 years, and high insulin sensitivity was associated with a lower rise in SBP over time. 23825075 Renal uptake of the antiapoptotic protein survivin is mediated by megalin at the apical membrane of the proximal tubule. The inhibitor of apoptosis protein survivin is a bifunctional molecule which regulates cellular division and survival. We have previously shown that survivin protein can be found at high concentrations in the adult kidney, particularly in the proximal tubules. Here, survivin is localized primarily at the apical membrane, a pattern which may indicate absorption of the protein. Several proteins in primary urine are internalised by megalin, an endocytosis receptor, which is in principle found in the same localization as survivin. Immunolabeling for survivin in different species confirmed survivin signal localising to the apical membrane of the proximal tubule. Immuno-electron microscopy also showed apical localisation of survivin in human kidneys. Furthermore, in polarised human primary tubular cells endogenous as well as external recombinant survivin stored in the apical region of the cells. Co-staining of survivin and megalin by immunohistochemistry and immuno-electron microscopy confirmed colocalization. Finally, by surface plasmon resonance we were able to demonstrate that survivin binds megalin and cubilin and that megalin knockout mice loose survivin through the urine. Survivin accumulates at the apical membrane of the renal tubule by reuptake, which is achieved by the endocytic receptor megalin, collaborating with cubilin. For this to occur, survivin will have to circulate in blood and be filtered into the primary urine. It is not known at this stage what the functional role of tubular survivin is. However, a small number of experimental and clinical reports implicate that renal survivin is important for functional integrity of the kidney. 23723380 Functional genomics studies of the human pathogen Neisseria meningitidis. Neisseria meningitidis is a strictly human pathogen and is one of the major causes of septicemia and meningitis worldwide. Functional genomics approaches have been extensively applied to study how N. meningitidis adapts to grow and survive in different human niches encountered during the infection. DNA microarrays performed in in vitro and ex vivo conditions have revealed changes in the transcriptome profiles of N. meningitidis upon interaction with human cells and after incubation in human serum and blood. Mutagenesis studies allowed detecting mutants in genes crucial for N. meningitidis colonization and systemic infection. The analysis of N. meningitidis genomes has been also successful in the identification of vaccine candidates used to develop an effective protein-based vaccine. The application of all these approaches revealed the potential to identify new virulence factors and vaccine candidates and to assign functions to previously uncharacterized genes providing new insights in the biology and pathogenesis of N. meningitidis. 23951315 The C-Terminal Amino Acid of the MHC-I Heavy Chain Is Critical for Binding to Derlin-1 in Human Cytomegalovirus US11-Induced MHC-I Degradation. Derlin-1 plays a critical role in endoplasmic reticulum-associated protein degradation (ERAD) of a particular subset of proteins. Although it is generally accepted that Derlin-1 mediates the export of ERAD substrates from the ER to the cytosol, little is known about how Derlin-1 interacts with these substrates. Human cytomegalovirus (HCMV) US11 exploits Derlin-1-dependent ERAD to degrade major histocompatibility complex class I (MHC-I) molecules and evade immune surveillance. US11 requires the cytosolic tail of the MHC-I heavy chain to divert MHC-I molecules into the ERAD pathway for degradation; however, the underlying mechanisms remain unknown. Here, we show that the cytosolic tail of the MHC-I heavy chain, although not required for interaction with US11, is required for tight binding to Derlin-1 and thus for US11-induced dislocation of the MHC-I heavy chain to the cytosol for proteasomal degradation. Surprisingly, deletion of a single C-terminal amino acid from the cytosolic tail disrupted the interaction between MHC-I molecules and Derlin-1, rendering mutant MHC-I molecules resistant to US11-induced degradation. Consistently, deleting the C-terminal cytosolic region of Derlin-1 prevented it from binding to MHC-I molecules. Taken together, these results suggest that the cytosolic region of Derlin-1 is involved in ERAD substrate binding and that this interaction is critical for the Derlin-1-mediated dislocation of the MHC-I heavy chain to the cytosol during US11-induced MHC-I degradation. 23017413 Metabolite profiling of phenolic and carotenoid contents in tomatoes after moderate-intensity pulsed electric field treatments. A metabolite profiling approach was used to study the effect of moderate-intensity pulsed electric field (MIPEF) treatments on the individual polyphenol and carotenoid contents of tomato fruit after refrigeration at 4°C for 24h. The MIPEF processing variables studied were electric field strength (from 0.4 to 2.0kV/cm) and number of pulses (from 5 to 30). Twenty four hours after MIPEF treatments, an increase was observed in hydroxycinnamic acids and flavanones, whereas flavonols, coumaric and ferulic acid-O-glucoside were not affected. Major changes were also observed for carotenoids, except for the 5-cis-lycopene isomer, which remain unchanged after 24h of MIPEF treatments. MIPEF treatments, conducted at 1.2kV/cm and 30 pulses, led to the greatest increases in chlorogenic (152%), caffeic acid-O-glucoside (170%) and caffeic (140%) acids. On the other hand, treatments at 1.2kV/cm and 5 pulses led to maximum increases of α-carotene, 9- and 13-cis-lycopene, which increased by 93%, 94% and 140%, respectively. Therefore, MIPEF could stimulate synthesis of secondary metabolites and contribute to production of tomatoes with high individual polyphenol and carotenoid contents. 23738910 Evaluation of insulin initiation on resource utilization and direct costs of treatment over 12 months in patients with type 2 diabetes in Europe: results from INSTIGATE and TREAT observational studies. Abstract Objectives: To describe the changes in resource utilization in seven European countries (Germany, Greece, Portugal, Romania, Sweden, Spain, and Turkey) and direct costs in four European countries (Germany, Spain, Sweden, and Greece) over the first 12 months of insulin treatment in patients with type 2 diabetes mellitus (T2DM). Methods: INSTIGATE and TREAT (2005-2010) were non-interventional, prospective, observational studies in patients with T2DM and initiating insulin for the first time. A 6-month retrospective data capture was conducted at baseline (insulin initiation) followed by prospective data collections at ∼3, 6, and 12 months. Statistical analyses were descriptive; estimated costs are presented as nominal values. Results: This study presents data for 1450 patients. Overall, in the first 6 months after insulin initiation, the use and cost of blood glucose monitoring and insulin increased, while the cost of oral diabetic medication decreased. Contributors to total direct costs differed between countries. Ranges of total mean direct costs over the 6-month period before insulin initiation were €489.10-€658.50 (Greece-Spain); 0-6 months after insulin initiation, €573.40-€1084.70 (Greece-Spain); and 6-12 months after insulin initiation, €495.80-€859.30 (Greece-Germany). Thus, the mean cost of treatment increased in all countries in the first 6 months after insulin initiation and then returned to baseline except in Germany. Limitations: Overall, 15% of patients were lost to follow-up over 12 months. Costs were not pro-rated to account for variation of visits. Participating centres may not have been fully representative of all levels of care. Conclusions: Contributors to total cost differed between countries, potentially reflecting local clinical practice patterns and insulin regimens. In each country, mean direct total costs of T2DM care increased during the first 6 months after insulin initiation and decreased thereafter. 23828940 Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay. The efficacy of therapeutics is dependent on a drug binding to its cognate target. Optimization of target engagement by drugs in cells is often challenging, because drug binding cannot be monitored inside cells. We have developed a method for evaluating drug binding to target proteins in cells and tissue samples. This cellular thermal shift assay (CETSA) is based on the biophysical principle of ligand-induced thermal stabilization of target proteins. Using this assay, we validated drug binding for a set of important clinical targets and monitored processes of drug transport and activation, off-target effects and drug resistance in cancer cell lines, as well as drug distribution in tissues. CETSA is likely to become a valuable tool for the validation and optimization of drug target engagement. 23740549 Perceiving social inequity: when subordinate-group positioning on one dimension of social hierarchy enhances privilege recognition on another. Researchers have suggested that viewing social inequity as dominant-group privilege (rather than subordinate-group disadvantage) enhances dominant-group members' support for social policies aimed at lessening such inequity. However, because viewing inequity as dominant-group privilege can be damaging to dominant-group members' self-images, this perspective is frequently resisted. In the research reported here, we explored the circumstances that enhance the likelihood of dominant-group members' viewing inequity as privilege. Because social hierarchies have multiple vertical dimensions, individuals may have high status on one dimension but low status on another. We predicted that occupying a subordinate position on one dimension of social hierarchy could enhance perceptions of one's own privilege on a different dimension of hierarchy, but that this tendency would be diminished among individuals who felt they had achieved a particularly high level of success. Results from three studies that considered gender-based and race-based hierarchies in organizational settings supported our hypothesis. 23901051 Phosphate control in end-stage renal disease: barriers and opportunities. Hyperphosphatemia is a nearly universal complication of end-stage renal disease that is widely recognized as one of the most important and most challenging clinical targets to meet in the care of dialysis patients. Left untreated, it can lead to bone pain, pruritus and worsening secondary hyperparathyroidism. Data from observational studies demonstrate that an elevated serum phosphorus level is an independent risk factor for mortality, and that treatment with phosphate binders is independently associated with improved survival. Experimental studies provide support for the epidemiologic findings: phosphate excess promotes vascular calcification, induces endothelial dysfunction and may contribute to other emerging chronic kidney disease-specific mechanisms of cardiovascular toxicity. On the basis of this evidence, clinical practice guidelines recommend specific targets for serum phosphorus levels in the dialysis population. The purpose of this review is to summarize common challenges in meeting these targets and to identify potential opportunities for improvement. 23822766 Endothelial Indoleamine 2,3-Dioxygenase Protects against Development of Pulmonary Hypertension. Rationale: A proliferative and apoptosis-resistant phenotype in pulmonary arterial smooth muscle cells (PASMCs) is key to pathologic vascular remodeling in pulmonary hypertension (PH). Expression of indoleamine-2,3-dioxygenase (IDO) by vascular endothelium is a newly identified vasomotor-regulatory mechanism also involved in molecular signaling cascades governing vascular smooth muscle cell (vSMC) plasticity. Objectives: To investigate the therapeutic potential of enhanced endothelial IDO in development of PH and its associated vascular remodeling. Methods: We used loss and gain of function in vivo studies to establish the role and determine the therapeutic effect of endothelial IDO in hypoxia-induced PH in mice and monocrotaline-induced PH in rats. We also studied PASMC phenotype in an IDO-high in vivo and in vitro tissue microenvironment. Measurements and Main Results: The endothelium was the primary site for endogenous IDO production within mouse lung, and the mice lacking this gene had exaggerated hypoxia-induced PH. Conversely, augmented pulmonary endothelial IDO expression, through a human IDO-encoding Sleeping Beauty (SB)-based nonviral gene-integrating approach, halted and attenuated the development of PH, right ventricular hypertrophy, and vascular remodeling in both preclinical models of PH. IDO derived from endothelial cells promoted apoptosis in PH-PASMCs through depolarization of mitochondrial transmembrane potential and down-regulated PH-PASMC proliferative/synthetic capacity through enhanced binding of myocardin to CArG box DNA sequences present within the promoters of vSMC differentiation-specific genes. Conclusions: Enhanced endothelial IDO ameliorates PH and its associated vascular structural remodeling through paracrine phenotypic modulation of PH-PASMCs toward a proapoptotic and less proliferative/synthetic state. 23904278 Adult height of girls with Turner syndrome treated from before six years of age with a fixed per kg growth hormone dose. to evaluate adult height (AH) in 25 girls with Turner Syndrome (TS), who were treated from before 6 years of age for 10.0 ± 1.7 years with a fixed GH dose of 0.33 mg/kg/week. after a 6-month pretreatment assessment all patients were measured 6-monthly under therapy to assess height standard deviation score (H-SDS) and H velocity (HV) until AH achievement. following initial acceleration, HV declined after the first 4 years of therapy. At the end of the 6th year of therapy H-SDS gain was 1.9 ± 1.1. Thereafter, H-SDS gain from baseline decreased, becoming 0.9 ± 0.9 SDS at AH achievement. Bone maturation velocity did not significantly change throughout the prepubertal period. According to Lyon standards for TS, mean AH-SDS was significantly higher than pretreatment H-SDS (p < 0.0001), with a mean H-SDS change of 0.9 ± 0.9. However, the prevalence of patients with AH <-2 SDS (according to Sempé standards) was close to that recorded at start of therapy (16/25 vs 18/25). No significant differences in terms of AH were found between patients with either X monosomy or X-chromosomal abnormalities and between girls with either spontaneous or induced puberty. we infer that the therapeutic regimen adopted in this prospective study is sufficient to induce a significant growth acceleration during the first years, but the response waned after 6 years of treatment. 23943378 Vertically Oriented Graphene Bridging Active-Layer/Current-Collector Interface for Ultrahigh Rate Supercapacitors. Dense networks of graphene nanosheets standing vertically on a current collector can work as numerous electrically conductive bridges to facilitate charge transport and mitigate the constriction/spreading resistance at the interface between the active material and the current collector. The vertically oriented graphene-bridged supercapacitors present excellent rate and power capabilities. 23054081 New markers of apoptosis in children on chronic dialysis. Enhanced apoptosis is characteristic for chronic kidney disease (CKD). A specific type of apoptosis, anoikis, is connected with the extracellular matrix turnover and cell detachment. Although E-cadherin, extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase (MMP)-8 may play an important role in this process, they have not been analyzed in any nephrological aspect, either in CKD. The aim of study was to evaluate the serum concentrations of E-cadherin, EMMPRIN and their potential regulators (MMP-8, MMP-7, TIMP-1, TIMP-2), with relevance to apoptosis/cell damage markers (sFas, sFasL, Hsp27), in children with CKD. 39 CKD children stages 3-4, 26 CKD children stage 5 still on conservative treatment, 19 patients on hemodialysis (HD), 22 children on automated peritoneal dialysis (APD) and 30 controls were examined. Serum concentrations of those parameters were assessed by ELISA. Median E-cadherin, EMMPRIN and MMP-8 values were significantly increased in patients on dialysis versus those in pre-dialysis period and versus controls. The highest values were noticed in the HD subjects. Regression analysis revealed that EMMPRIN and MMP-8 predicted various apoptosis markers, whereas E-cadherin turned out the best predictor of both apoptosis (Hsp27, sFas, sFasL) and matrix turnover (MMP-7, TIMP-1, TIMP-2) indexes in dialyzed patients. Children with CKD are prone to E-cadherin, EMMPRIN and MMP-8 elevation, aggravated by the dialysis commencement and most evident on hemodialysis. Correlations between parameters suggest their role as indexes of apoptosis in children on dialysis. E-cadherin seems the most accurate marker of anoikis in this population. 23954833 Statistical equivalence and test-retest reliability of delay and probability discounting using real and hypothetical rewards. Delay discounting (DD) and probability discounting (PD) refer to the reduction in the subjective value of outcomes as a function of delay and uncertainty, respectively. Elevated measures of discounting are associated with a variety of maladaptive behaviors, and confidence in the validity of these measures is imperative. The present research examined (1) the statistical equivalence of discounting measures when rewards were hypothetical or real, and (2) their 1-week reliability. While previous research has partially explored these issues using the low threshold of nonsignificant difference, the present study fully addressed this issue using the more-compelling threshold of statistical equivalence. DD and PD measures were collected from 28 healthy adults using real and hypothetical $50 rewards during each of two experimental sessions, one week apart. Analyses using area-under-the-curve measures revealed a general pattern of statistical equivalence, indicating equivalence of real/hypothetical conditions as well as 1-week reliability. Exceptions are identified and discussed. 23964632 Can demineralized enamel surfaces be bonded safely? Abstract Objective. To evaluate and compare the effects of enamel demineralization, microabrasion therapy and casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) application on the shear bond strength (SBS) of orthodontic brackets bonded to enamel surfaces and enamel color. Materials and methods. Eighty freshly extracted human maxillary premolar teeth were allocated to one of the four groups. Brackets were bonded directly to non-demineralized enamel surfaces in Group I (control group), directly to the demineralized enamel surfaces in Group II, to demineralized enamel surfaces after CPP-ACP application in Group III and to demineralized enamel surfaces after microabrasion therapy in Group IV. The samples were stored in water for 24 h at 37°C and then underwent thermocycling. The SBS in megapascals (MPa) was determined by a shear test with 0.5 mm/min crosshead speed and failure types were classified with modified adhesive remnant index scores. The data were analyzed with one-way analyses of variance (ANOVA), Tukey and chi-square tests at the α = 0.05 level. Results. Significant differences were found among the four groups (F = 21.57, p < 0.01). No significant difference was found between Group I and III (17.12 ± 2.84 and 15.08 ± 3.42 MPa, respectively) or between Group III and IV (12.82 ± 2.64 MPa). The lowest SBS value was determined in Group II (5.88 ± 2.12 MPa). Enamel demineralization, microabrasion therapy and CPP-ACP application affected enamel color significantly. Conclusion. CPP-ACP application and microabrasion therapy are able to increase the decreased SBS of orthodontic brackets because of enamel demineralization. 23299441 Mercury in small Illinois fishes: historical perspectives and current issues. Documenting long-term trends in mercury deposition and/or accumulation is important in setting regulatory benchmarks, modeling contaminant transfer and flux, measuring success of environmental controls, and even assigning responsibility for pollution. We conducted a study to compare mercury concentrations in small fishes from "high-mercury" and "low-mercury" regions of Illinois, as well as to examine historic patterns of mercury availability using preserved fishes. Mercury concentrations were greater in four species of small fishes collected from a stream in a "high-mercury" region than in those same taxa collected from a stream in a "low-mercury" area in Illinois. Mercury concentrations in blackstripe topminnows (Fundulus notatus) declined dramatically between 1900 and 1961/2006 in the "high-mercury" stream, presumably due reductions in mercury releases from local and regional sources. Preserved fish had an apparent increase in mercury concentrations for up to 12 months, which is consistent with changes in mass and loss of proteins observed in other studies, and we recommend that recent samples be preserved for at least 12 months before comparison with older fluid-preserved material. Based on our results, further studies of mercury in small fishes in Illinois streams appear warranted. 23967089 Aging, Estrogen Loss and Epoxyeicosatrienoic Acids (EETs). Inflammation is a key element in many cardiovascular diseases. Both estrogen loss, caused by menopause, and aging have inflammatory consequences. Epoxyeicosatrienoic acids (EETs) are anti-inflammatory molecules synthesized by various cytochrome P450 (Cyp) enzymes from arachidonic acid. EETs are in the third (Cytochrome P450) pathway of arachindonic acid metabolism, others being cyclooxygenases and lipoxygenases. We hypothesized that aging and estrogen loss would reduce levels of anti-inflammatory EETs. Adult (6 mo) and aged (22 mo) ovariectomized rats with (OP) and without (Ovx) 17-∃-estradiol replacement were used in this study. Mass spectrometry was used to measure levels of EETs and their metabolites, dihydroxyeicosatrienoic acids (DHETs). Levels of Cyp2C2, Cyp2C6, and Cyp2J2, the principal Cyps responsible for EETs synthesis, as well as soluble epoxide hydrolase (sEH), which metabolizes EETS to DHETs, were determined via western blot. Overall Cyp levels decreased with age, though Cyp2C6 increased in the liver. sEH was increased in the kidney with estrogen replacement. Despite protein changes, no differences were measured in plasma or aortic tissue levels of EETs. However, plasma 14,15 DHET was increased in aged Ovx, and 5,6 DHET in adult OP. In conclusion neither aging nor estrogen loss decreased the anti-inflammatory EETs in the cardiovascular system. 23933566 Reversed-phase thin-layer chromatography technique for the comparison of the lipophilicity of selected non-steroidal anti-inflammatory drugs. The chromatographic behavior of a series of coxibs and oxicams, drugs from a group of non-steroidal anti-inflammatory drugs, was studied by reversed-phase thin-layer chromatography with binary mobile phases containing water and the organic modifiers: methanol, acetone, 1,4-dioxane, acetonitrile and 2-propanol. Linear relationships were obtained between the retention RM values of the compounds and the concentration of organic modifier in the mobile phase. Values of RM0, represent the theoretical RM values at 0% organic solvent in the mobile phase were calculated by extrapolation. These experimental lipophilicity values were correlated with lipophilicity (logP) from databases. The obtained results show that reversed-phase chromatography (experimental parameters) may be a good instrument for analytics in describing the lipophilic nature of investigated compounds as well as the activity. 23789856 Capillary Isotachophoresis-Nanoelectrospray Ionization-Selected Reaction Monitoring MS via a Novel Sheathless Interface for High Sensitivity Sample Quantification. A novel sheathless capillary isotachophoresis (CITP/CZE)-mass spectrometry (MS) interface featuring a large inner diameter (i.d.) separation capillary, and a detachable small i.d. porous electrospray ionization (ESI) emitter was developed in this study to simultaneously achieve large sample loading capacity and stable nanoESI operation. Crucial operating parameters, including sample loading volume, flow rate, and separation window, were systematically investigated to attain optimum CITP/CZE separation efficiency and MS detection sensitivity. The performance of CITP/CZE-nanoESI-MS using the new sheathless interface was evaluated for its achievable low limit of quantification (LOQ) by analyzing targeted peptides, leu-enkephalin and angiotensin II, spiked in a BSA tryptic digest matrix at different concentrations. A linear dynamic range spanning 4.5 orders of magnitude and a 10 pM LOQ with measurement reproducibility of the CV < 22% were obtained experimentally for both targeted peptides, representing a 5-fold sensitivity improvement as compared to using the sheath liquid interface developed previously.1. 23940830 Lacosamide adjunctive therapy for partial-onset seizures: a meta-analysis. Background. The relative efficacy and safety of lacosamide as adjunctive therapy compared to other antiepileptic drugs has not been well established. Objective. To determine if lacosamide provides improved efficacy and safety, reduced length of hospital stay and improved quality of life compared with other anti-epileptic therapies for adults with partial-onset seizures. Data Sources. A systematic review of the medical literature using Medline (1946-Week 4, 2012), EMBASE (1980-Week 3, 2012), Cochrane Central Register of Controlled Trials (Issue 1 of 12, January 2012). Additional studies were identified (through to February 7, 2012) by searching bibliographies, the FDA drug approval files, clinical trial registries and major national and international neurology meeting abstracts. No restrictions on publication status or language were applied. Study Selection. Randomized controlled trials of lacosamide in adults with partial-onset seizures were included. Data Extraction. Study selection, extraction and risk of bias assessment were performed independently by two authors. Authors of studies were contacted for missing data. Data Synthesis. All pooled analyses used the random effects model. Results. Three trials (1311 patients) met inclusion criteria. Lacosamide increased the 50% responder rate compared to placebo (RR 1.68 [95% CI 1.36 to 2.08]; I(2) = 0%). Discontinuation due to adverse events was statistically significantly higher in the lacosamide arm (RR3.13 [95% CI 1.94 to 5.06]; I(2) = 0%). Individual adverse events (ataxia, dizziness, fatigue, and nausea) were also significantly higher in the lacosamide group. Limitations. All dosage arms from the included studies were pooled to make a single pair-wise comparison to placebo. Selective reporting of outcomes was found in all of the included RCTs. Conclusions. Lacosamide as adjunctive therapy in patients with partial-onset seizures increases the 50% responder rate but with significantly more adverse events compared to the placebo. 22750271 Fat, fire and muscle--the role of adiponectin in pulmonary vascular inflammation and remodeling. Pulmonary hypertension is a life-threatening condition that results from a heterogeneous group of diseases, many of which demonstrate characteristic pathologic changes of pulmonary vascular inflammation and remodeling. Recent clinical studies indicate obesity to be a risk factor for the development of pulmonary hypertension; however, the mechanisms leading to this association are unknown. Adipocytes secrete multiple bioactive mediators that can influence inflammation and tissue remodeling, suggesting that adipose tissue may directly influence the pathogenesis of pulmonary hypertension. One of these mediators is adiponectin, a protein with a wide range of metabolic, anti-inflammatory, and anti-proliferative activities. Paradoxically, adiponectin is present in high concentration in the serum of lean healthy individuals, but decreases in obesity. Studies suggest that relative adiponectin-deficiency may contribute to the development of inflammatory diseases in obesity, and recent animal studies implicate adiponectin in the pathogenesis of pulmonary hypertension. Most notably, experimental studies show that adiponectin can reduce lung vascular remodeling in response to inflammation and hypoxia. Moreover, mice deficient in adiponectin develop a spontaneous lung vascular phenotype characterized by age-dependent increases in peri-vascular inflammatory cells and elevated pulmonary artery pressures. Emerging evidence indicates adiponectin's effects are mediated through anti-inflammatory and anti-proliferative actions on cells in the lung. This review aims to synthesize the existing data related to adiponectin's effects on the pulmonary vasculature and to discuss how changes in adiponectin levels might contribute to the development of pulmonary hypertension. 23609375 Deliberate self-harm before psychiatric admission and risk of suicide: survival in a Danish national cohort. Psychiatric illness and deliberate self-harm (DSH) are major risk factors of suicide. In largely 15 % of psychiatric admissions in Denmark, the patient had an episode of DSH within the last year before admission. This study examined the survival and predictors of suicide in a suicidal high-risk cohort consisting of hospitalized psychiatric patients with recent DSH. This national prospective register-based study examined all hospitalized psychiatric patients who self-harmed within a year before admission. All admitted patients, in the time period 1998-2006, were followed and survival analyses techniques were used to identify predictors of suicide. The study population consisted of 17,257 patients; 520 (3 %) died by suicide during follow-up; 50 % of the suicides occurred within a year from the index admission. A rate of 1,645 suicides per 100,000 person-years in the first year after psychiatric admission was found. Adjusted analyses showed that a higher degree of education, having DSH within a month before psychiatric admission and contact with a private psychiatrist increased the risk of suicide. Psychiatric hospitalized patients with recent DSH revealed high suicide rates, even during hospitalization. When discharging psychiatric patients with recent DSH careful arrangement of follow-up treatment in the outpatient setting is recommendable. 23672979 New sample preparation approach for mass spectrometry-based profiling of plasma results in improved coverage of metabolome. Sample preparation remains a challenge in untargeted metabolomics studies and no method currently results in complete extraction of all metabolite classes in human plasma. Because a large variety of molecules, with vast differences in dynamic range, could be involved in human disease, there is an urgent need to develop analytical techniques that result in comprehensive coverage of metabolites. Furthermore, analysis of more focused molecular classes could be necessary to more fully interrogate markers of human disease. However, such techniques, which generally involve multiple steps, often result in high variability. We have optimized a combined liquid-liquid and solid phase extraction method for plasma and have compared that to traditional methanol precipitation using spiked internal standards as controls. This method, based largely on previously published methods, results in 5 separate fractions enriched for aqueous species, phospholipids, fatty acids, neutral lipids, and hydrophobic lipids. Using liquid chromatography mass spectrometry as the analytical method, we detect over 3806 metabolites using the new method versus 1851 metabolites using methanol alone. Qualitative analysis and quantitative analysis of both internal standards (ISTDs) and endogenous metabolites demonstrate excellent reproducibility with CV's below 15% for the combined method compared to 30% using the methanol method. While both methods have applications for clinical metabolomics, fractionation resulted in greater overall coverage and can be used for initial classification of molecular species. 23600950 CRP and SAP from different species have different membrane ligand specificities. Human C-reactive protein (CRP) and serum amyloid component P (SAP) are well-characterised ligands for dying and dead cells, while facets of their physiological function still need to be unravelled. We partially characterised CRP and SAP from different species with similar acute-phase systems. Human, rabbit and porcine CRP bound phosphocholine (PC) and phosphoethanolamine (PEt). Human and porcine SAP bound PEt while rabbits seem to have very low levels of SAP or rabbit SAP does not bind PEt. Porcine serum additionally contained other ligands for PC and PEt. Some of them were immunoglobulins. Therefore, rabbits, pigs and humans cover the ability to bind PC and PEt with different extents. 23773208 Effect of Ni Charge States on Structural, Electronic, Magnetic, and Optical Properties of InN. The first-principles study of Ni-doped InN has been carried out to explore the doping effect of various charge states of Ni on the structural, electronic, magnetic, and optical properties of InN using generalized gradient approximation. Structural properties like lattice parameters, aspect ratios, bond lengths, and formation energies of (In, Ni) N are used to determine the stability of each doped system. The formation energies of (In, Ni)N systems decrease with the increase in charge state of nickel, while the bond lengths show an opposite trend. The DOS diagram shows that the introduction of Ni-d states within the bang gap region reduces the band gap for Ni(1+)- and Ni(2+)-doped InN, while the isolated states are generated in the case of Ni(3+)- and Ni(4+)-doped systems. The Ni(1+)-, Ni(3+)-, and Ni(4+)-doped InN systems are ferromagnetic in nature, whereas the (In, Ni(2+))N depicts spin-glass-like behavior. The best possible magnetization is obtained for (In, Ni(4+))N with a total magnet moment of 2.42 μB per supercell. Because of the presence of nickel impurities, the optical properties of InN have been significantly improved. The pure and Ni(3+)- and Ni(4+)-doped InN systems show nearly the same values of absorption edges (∼0.56 eV), in contrast with the Ni(1+)- and Ni(2+)-doped systems, where these values are 0.37 and 0.51 eV, respectively. The shift in absorption edges of Ni(1+)- and Ni(2+)-doped InN to lower energies and increase in the intensity of absorption and broadening of absorption peaks can be attributed to the pronounced band-gap reduction for these systems. A negligible shift of absorption edges in the case of Ni(3+)- and Ni(4+)- doped InN is the characteristic of isolated charge states introduced around the Fermi level, which inhibit the band gap reduction, and hence the optical properties are not improved as expected. This study demonstrates an important fact that for best possible optical device applications Ni(1+)-doped InN system is excellent, while for better magnetic properties the (In, Ni(4+))N is more suitable. 22859437 Regional variation of racial disparities in mental health service use among older adults. Given the paucity of research on the role of geography in mental health care, this study examined whether racial differences in mental health service use varied across geographic regions among older adults. Drawn from the Collaborative Psychiatric Epidemiology Surveys (CPES), blacks (n = 1,008) and whites (n = 1,870) aged 60 and older were selected for analysis. Logistic regression analyses were conducted. Results showed significant racial disparities in mental health service use in the overall sample, as well as significant variation by region. Although no racial differences were observed in the Northeast, West, or Midwest regions, black elders in the South were significantly less likely than whites to use mental health services (odds ratios [OR], 2.08; 95% confidence interval [CI], 1.34-3.23). The findings suggest that improving the access to mental health care in certain regions, the South in particular, may be essential to reduce racial disparities at the national level. Policy implications are discussed. 23731800 Strategies to control the binding mode of de novo designed protein interactions. There has been significant recent progress in the computational design of protein interactions including the creation of novel heterodimers, homodimers, nanohedra, fibril caps and a protein crystal. Essential to these successes has been the use of innovative strategies for finding binding modes that are achievable, that is, identifying binding partners and docked conformations that can be successfully stabilized via sequence optimization and backbone refinement. In many cases this has involved the use of structural motifs commonly found at naturally occurring interfaces including alpha helices inserted into hydrophobic grooves, beta-strand pairing, metal binding, established helix packing motifs, and the use of symmetry to form cooperative interactions. Future challenges include the creation of hydrogen bond networks and antibody-like interactions based on the redesign of protein surface loops. 23946310 Late-onset anti-NMDA receptor encephalitis. To describe the clinical features and outcome of anti-NMDA receptor (NMDAR) encephalitis in patients ≥45 years old. Observational cohort study. In a cohort of 661 patients with anti-NMDAR encephalitis, we identified 31 patients ≥45 years old. Compared with younger adults (18-44 years), older patients were more often male (45% vs 12%, p < 0.0001), had lower frequency of tumors (23% vs 51%, p = 0.002; rarely teratomas), had longer median time to diagnosis (8 vs 4 weeks, p = 0.009) and treatment (7 vs 4 weeks, p = 0.039), and had less favorable outcome (modified Rankin Scale score 0-2 at 2 years, 60% vs 80%, p < 0.026). In multivariable analysis, younger age (odds ratio [OR] 0.15, confidence interval [CI] 0.05-0.39, p = 0.0001), early treatment (OR 0.60, CI 0.47-0.78, p < 0.0001), no need for intensive care (OR 0.09, CI 0.04-0.22, p < 0.0001), and longer follow-up (p < 0.0001) were associated with good outcome. Rituximab and cyclophosphamide were effective when first-line immunotherapies failed (OR 2.93, CI 1.10-7.76, p = 0.031). Overall, 60% of patients older than 45 years had full or substantial recovery at 24 months follow-up. Anti-NMDAR encephalitis is less severe in patients ≥45 years old than in young adults, but the outcome is poorer in older patients. In this age group, delays in diagnosis and treatment are more frequent than in younger patients. The frequency of underlying tumors is low, but if present they are usually carcinomas instead of teratomas in younger patients. Early and aggressive immunotherapy will likely improve the clinical outcome. 23665266 Calcium lignosulphonate: re-evaluation of relevant endpoints to re-confirm validity and NOAEL of a 90-day feeding study in rats. A 90-day feeding study in Han/Wistar rats with calcium lignosulphonate was evaluated by the EFSA. The study was considered to be inadequate due to potentially impaired health status of the animals based upon a high incidence of minimal lymphoid hyperplasia in mesenteric/mandibular lymph nodes and Peyer's patches, and minimal lymphoid cell infiltration in the liver in all animals. The EFSA Panel further disagreed with the conclusion that the treatment-related observation of foamy histiocytosis in mesenteric lymph nodes was non-adverse and asked whether this observation would progress to something more adverse over time. A PWG was convened to assess the sections of lymph nodes, Peyer's patches and liver. In addition, all lymphoid tissues were re-examined. The clinical pathology and animal colony health screening data were re-evaluated. The question whether the foamy histiocytosis could progress to an adverse finding with increasing exposure duration was addressed by read-across. In conclusion, the animals on the 90-day feeding study were in good health, the study was adequate for safety evaluation, and the foamy histiocytes in the mesenteric lymph nodes were not considered adverse, but rather an adaptive response that was considered unlikely to progress to an adverse condition with time. The NOAEL was re-affirmed to be 2000 mg/kgbw/d. 23924123 nlcfn.org.uk. The National Lung Cancer Forum for Nurses was established in 1999 by a small group of nurses working in lung cancer care. 23852460 Cerebral Near-Infrared Spectroscopy Correlates to Vital Parameters During Cardiopulmonary Bypass Surgery in Children. Near-infrared spectroscopy (NIRS) can monitor changes in cerebral regional oxygen saturation (rSO2) and tissue hemoglobin content (HbT). The relation between cerebral NIRS readings and vital parameters has not been analyzed before at a fine temporal scale. This study analyzed this relation during cardiopulmonary bypass (CPB) surgery in 10 children (0-9 years, 1,770 min of data records) by using a novel random-coefficient model. The analysis indicated that a small number of patients is sufficient for obtaining significant results with this model. Changes of vital parameters explained 84.7 % of rSO2 changes and 90.7 % of HbT changes. Cerebral rSO2 correlated positively with perfusion pressure and inversely with body temperature (P < 0.05). Cerebral HbT correlated positively with perfusion pressure, central venous pressure, and temperature and inversely with arterial oxygen saturation (P < 0.05). During hypothermic circulatory arrest, the half-life of the exponential rSO2 decay correlated to the rSO2 reserve (P = 0.016). In conclusion, NIRS readings of cerebral hemoglobin content and tissue oxygen saturation correlate well to vital parameters during CPB surgery in children. NIRS may therefore become a monitoring device for the neuroprotective optimization of those vital parameters. 23805895 Poly(azobenzene acrylate-co-fluorinated acrylate) Spin-Coated Films: Influence of the Composition on the Photo-Controlled Wettability. The wetting properties of spin-coated films of copolymers based on azobenzene and fluorinated units have been investigated. The copolymers, denoted as poly(Azo-co-AcRf6), have been synthesized by free-radical polymerization of different proportions of acrylate monomers bearing either an azobenzene group or a semifluorinated side chain. The UV-visible spectroscopy analysis of the different spin-coating films through a cycle of UV and visible light irradiation indicates the reversible trans-cis isomerization of azobenzene groups. Simultaneously, atomic force microscopy shows that surface roughness does not exceed 1 nm. Advancing and receding contact angles of water and diiodomethane have been measured before and after UV photoirradiation of the different surfaces. In particular, a decrease in the advancing contact angles has been observed upon trans-cis isomerization of azobenzene groups. Switching variations up to 50° have been evidenced without any introduction of surface nanoroughness. Surface free-energy evaluations have been deduced from these measurements, including dispersive and polar components. The results show that, through surface composition and UV photoirradiation, a large range of surface free-energies can be obtained, from 7 to 46 mN·m(-1). 23755876 Ab Initio Chemical Kinetics for H + NCN: Prediction of NCN Heat of Formation and Reaction Product Branching via Doublet and Quartet Surfaces. The reaction of NCN with H atoms has been investigated by ab initio MO and RRKM theory calculations. The mechanisms for formation of major products on the doublet and quartet potential energy surfaces have been predicted at the CCSD(T) level of theory with the complete basis set limit. In addition, the heat of formation for NCN predicted at this rigorous level and those from five isogyric reactions are in close agreement with the best value based on the isodesmic process, (3)CCO + N2 = (3)NCN + CO, 109.4 kcal/mol, which lies within the two existing experimental values. The rate constants for the three possible reaction channels, H + NCN → CH + N2 (kP1), HCN + (4)N (kQP1), and HNC + (4)N (kQP2), have been calculated in the temperature range 298-3000 K. The results show that kP1 is significantly higher than kQP1 and kQP2 and that the total rate constant agrees well with available experimental values in the whole temperature range studied. The kinetics of the reverse CH + N2 reaction has also been revisited at the CCSD(T)/CBS level; the predicted total rate constants at 760 Torr Ar pressure can be represented by kr = 4.01 × 10(-15) T(0.90) exp(-17.42 kcal mol(-1)/RT) cm(3) molecule(-1) s(-1) at T = 800-4000 K. The result agrees closely with the most recent experimental data and the best theoretical result of Harding et al. (J. Phys. Chem. A2008, 112, 522) as well as that of Moskaleva and Lin (Proc. Combust. Inst. 2000, 28, 2393) evaluated with a steady-state approximation after a coding error correction made in this study. 23929258 Isolation of a Mn(IV) acylperoxo complex and its monooxidation ability. The first example of monooxygenation by a high-valent Mn(IV) complex with a peroxide is described. A key Mn(IV) acylperoxo intermediate, which uses m-chloroperoxybenzoic acid as the oxygen donor, is directly observed by electro-spray ionization mass spectrometry and resonance Raman spectroscopy. 23906778 Formation of disinfection by-products after pre-oxidation with chlorine dioxide or ferrate. The effect of pre-oxidation with chlorine dioxide (ClO2) or ferrate (Fe(VI)) on the formation of disinfection by-products (DBPs) during chlorination or chloramination was tested with natural waters from 12 sources (9 surface waters, 1 groundwater, and 2 wastewater effluents). DBPs investigated included trihalomethanes (THM), chloral hydrate (CH), haloketones (HK), haloacetonitriles (HAN) and trichloronitromethane (TCNM), chlorite and chlorate. Chlorite and chlorate were found in the ClO2-treated waters. Application of 1 mg/L ClO2 ahead of chlorination reduced the formation potential for THM by up to 45% and the formation of HK, HAN and TCNM in most of the samples. The CH formation results were mixed. The formation of CH and HK was enhanced with low doses of Fe(VI) (1 mg/L as Fe), but was greatly reduced at higher doses (20 mg/L Fe). Fe(VI) reduced the formation of THM, HAN and TCNM in most of the samples. Reduced potential for the formation of NDMA was observed in most of the samples after both ClO2 and Fe(VI) pre-oxidation. 23860859 Multidisciplinary Management of Recurrent Chordomas. The management of recurrent chordomas are clinically challenging because of its relentless nature. Local therapy, whether surgery or radiation, are important considerations since local progression of disease results in significant morbidity and locally aggressive treatment is often required. Stereotactic radiosurgery, shown to be very effective for radioresistant histologies, may be an important radiotherapeutic approach for recurrent tumors. Ultimately, the treatment of recurrent chordoma is palliative in intent, thus, enthusiasm for improving local control must be tempered against the possible impact of treatment on quality of life. Judicious use of radiotherapy and surgery can often provide meaningful palliation and local control of recurrences. Systemic treatment options, particularly with targeted molecules have great potential for chordomas in the recurrent setting, as the risk of disseminated disease is higher. The development of tools to help assess potential targets for drug therapy will be crucial. The incorporation of locally aggressive therapy and effective systemic therapy will be critical for the successful management of recurrent chordomas. At present, there is a paucity of published data regarding salvage therapy. Nonetheless, advances in surgical, medical, and radiation oncology are providing new avenues of research and potentially may have significant impact upon successful salvage treatment. 23900581 Modulation of the response of prostate cancer cell lines to cisplatin treatment using small interfering RNA. Cisplatin is one of the most effective and widely used chemotherapeutic agents against several types of human cancers. However, the underlying mechanisms of action are not fully understood. We aimed to investigate the possible molecular mechanism(s) of acquired chemoresistance observed in prostate cancer cells treated with cisplatin. Human LNCaP cells (bearing wild-type p53) and PC-3 cells (lacking p53) were used. The expression levels of protein were determined by western blotting, and the mRNA levels were determined by reverse transcription-polymerase chain reaction (RT-PCR). Cell viability was measured by MTT assay, and the transcriptional effect of small interfering RNA (siRNA) was measured by luciferase reporter gene. We showed that cisplatin treatment increased JNK-1 and JNK-2 activity and expression in both LNCaP and PC-3 cells. In addition, the knockdown of JNK-1 expression by siRNA-JNK-1 or siRNA-JNK-2 significantly impaired the upregulation of AP-1 luciferase reporter gene, but failed to decrease the levels of AP-1 reporter gene expression induced by TPA treatment. Our observations indicate that JNK-1 and JNK-2 may be involved in the chemoresistance observed in prostate cancer cells treated with cisplatin and that blocking the stimulation of Jun kinase (JNK) signaling may be important for regulating the susceptibility to cisplatin of prostate cancer. 23885985 Where are we now: assessing the price, availability and affordability of essential medicines in Delhi as India plans free medicine for all. Inequitable access to medicines is a major weakness in the Indian health care system. Baseline data needed to develop effective public health policy and provide equitable access to essential medicines. The present survey was conducted to investigate the price, availability, and affordability of fifty essential medicines in the public and private sector in Delhi, India using standardized WHO/HAI methodology. Data on procurement price and availability was collected (July-October 2011) from three public healthcare providers: the federal (central) government, state government and Municipal Corporation of Delhi (MCD). Data on price and availability of medicines was collected from private retail and chain pharmacies of a leading corporate house. Prices were compared to an international reference price (expressed as median price ratio-MPR). The procurement price of surveyed medicines was 0.53-0.82 times the international reference price-IRP. However, the overall mean availability of surveyed medicines in facilities under state government and MCD was 41.3% and 23.2%, respectively. The overall mean availability of medicines in three tertiary care facilities operated by the federal government was 49.3%. Availability of generic medicines was much higher in the private sector. Off-patented medicines, like diazepam, diclofenac, and doxycycline had the highest MPRs. The price ratio between procurement and retail was as high as 28 (range 11-28) for certain medicines. Seven-day treatment with a popular brand of amoxicillin+clavulanic acid or one inhaler each of budesonide and salbutamol cost 2.3 and 1.4 days' wages for the lowest paid government worker. A majority of India's population cannot afford these prices. This study revealed that procurement prices of surveyed medicines were reasonable in comparison to IRP. However, variation in procurement prices of certain medicines by different public procurement agencies was noted. Availability of medicines was very poor in public sector facilities, which are the primary source of free medicines for a majority of India's low-income population. Availability of medicines is better in private retail pharmacies but affordability remains a big challenge for a majority of the population. These data have significant policy implications that could help in amending policies to increase the access to essential medicines for India's population. 23812115 Dissipation and residue of spinosad in zucchini under field conditions. The dissipation and residue of the insecticide spinosad in zucchini were investigated. An ultra-performance liquid chromatography-tandem mass spectrometry analytical method was developed for spinosad analysis. The half-lives of spinosad were 3.5-3.9 days in zucchini and 3.6-4.1 days in soil. The results showed that the dissipation rate of spinosad was fast, and it is suggested that a combination of rapid growth of zucchini, photodecomposition and the activity of soil microorganisms affected the dissipation rate of spinosad. The terminal residues of spinosad in zucchini were all below the quantification limit. No residue limit currently exists for spinosad in zucchini in China and other countries. Thus, the results can be useful in establishing a maximum residue limit. 23759958 Surface mediated assembly of small, metastable gold nanoclusters. The unique properties of metallic nanoclusters are attractive for numerous commercial and industrial applications but are generally less stable than nanocrystals. Thus, developing methodologies for stabilizing nanoclusters and retaining their enhanced functionality is of great interest. We report the assembly of PPh3-protected Au9 clusters from a heterogeneous mixture into films consisting of sub 3 nm nanocluster assemblies. The depositing nanoclusters are metastable in solution, but the resulting nanocluster assemblies are stabilized indefinitely in air or fresh solvent. The films exhibit distinct structure from Au nanoparticles observed by X-ray diffraction, and film dissolution data support the preservation of small nanoclusters. UV-Vis spectroscopy, electrospray ionization mass spectrometry, X-ray photoelectron spectroscopy and electron microscopy are used to elucidate information regarding the nanocluster formation and assembly mechanism. Preferential deposition of nanocluster assemblies can be achieved on multiple substrates, including polymer, Cr, Si, SiO2, SiNx, and metal-organic frameworks (MOFs). Unlike other vapor phase coating processes, nanocluster assembly on the MIL-68(In) MOF crystal is capable of preferentially coating the external surface and stabilizing the crystal structure in hydrothermal conditions, which should enhance their storage, separation and delivery capabilities. 23927827 Combination of carbonic anhydrase inhibitor, acetazolamide, and sulforaphane, reduces the viability and growth of bronchial carcinoid cell lines. Bronchial carcinoids are pulmonary neuroendocrine cell-derived tumors comprising typical (TC) and atypical (AC) malignant phenotypes. The 5-year survival rate in metastatic carcinoid, despite multiple current therapies, is 14-25%. Hence, we are testing novel therapies that can affect the proliferation and survival of bronchial carcinoids. In vitro studies were used for the dose-response (AlamarBlue) effects of acetazolamide (AZ) and sulforaphane (SFN) on clonogenicity, serotonin-induced growth effect and serotonin content (LC-MS) on H-727 (TC) and H-720 (AC) bronchial carcinoid cell lines and their derived NOD/SCID mice subcutaneous xenografts. Tumor ultra structure was studied by electron microscopy. Invasive fraction of the tumors was determined by matrigel invasion assay. Immunohistochemistry was conducted to study the effect of treatment(s) on proliferation (Ki67, phospho histone-H3) and neuroendocrine phenotype (chromogranin-A, tryptophan hydroxylase). Both compounds significantly reduced cell viability and colony formation in a dose-dependent manner (0-80 muM, 48 hours and 7 days) in H-727 and H-720 cell lines. Treatment of H-727 and H-720 subcutaneous xenografts in NOD/SCID mice with the combination of AZ + SFN for two weeks demonstrated highly significant growth inhibition and reduction of 5-HT content and reduced the invasive capacity of H-727 tumor cells. In terms of the tumor ultra structure, a marked reduction in secretory vesicles correlated with the decrease in 5-HT content. The combination of AZ and SFN was more effective than either single agent. Since the effective doses are well within clinical range and bioavailability, our results suggest a potential new therapeutic strategy for the treatment of bronchial carcinoids. 23645677 Gain-of-function mutations in transient receptor potential C6 (TRPC6) activate extracellular-signal-regulated kinases Erk1/2. Gain-of-function mutations in the canonical transient receptor potential 6 (TRPC6) gene are a cause of autosomal dominant focal segmental glomerulosclerosis (FSGS4). The mechanisms whereby abnormal TRPC6 activity results in proteinuria remain unknown. The Erk1/2 MAP kinases are activated in glomeruli and podocytes in several proteinuric disease models. We therefore examined whether FSGS-associated mutations in TRPC6 result in activation of these kinases. In 293T cells and cultured podocytes, overexpression of gain-of-function TRPC6 mutants resulted in increased Erk1/2 phosphorylation, an effect dependent upon channel function. Pharmacologic inhibitor studies implicated several signaling mediators, including calmodulin and calcineurin, supporting the importance of TRPC6-mediated calcium influx in this process. Through media transfer experiments, we uncovered two distinct mechanisms for Erk activation by mutant TRPC6, a cell autonomous, EGFR-independent mechanism and a cell non-autonomous mechanism involving metalloprotease-mediated release of a presumed EGFR ligand. The inhibitors KN-92 and H89 were able to block both pathways in mutant TRPC6 expressing cells, as well as the prolonged elevation of intracellular calcium levels upon carbachol stimulation seen in these cells. However, these effects appear independent of their effects on CaMKII and PKA, respectively. Phosphorylation of T70, S282 and Y31/Y285 were not necessary for Erk activation by mutant TRPC6, though a phosphomimetic TRPC6 S282E mutant was capable of Erk activation. Taken together, these results identify two pathways downstream of mutant TRPC6 leading to Erk activation that may play a role in the development of FSGS. 23857055 Melatonin in Alzheimer's disease. Alzheimer's disease (AD), an age-related neurodegenerative disorder with progressive cognition deficit, is characterized by extracellular senile plaques (SP) of aggregated β-amyloid (Aβ) and intracellular neurofibrillary tangles, mainly containing the hyperphosphorylated microtubule-associated protein tau. Multiple factors contribute to the etiology of AD in terms of initiation and progression. Melatonin is an endogenously produced hormone in the brain and decreases during aging and in patients with AD. Data from clinical trials indicate that melatonin supplementation improves sleep, ameliorates sundowning and slows down the progression of cognitive impairment in AD patients. Melatonin efficiently protects neuronal cells from Aβ-mediated toxicity via antioxidant and anti-amyloid properties. It not only inhibits Aβ generation, but also arrests the formation of amyloid fibrils by a structure-dependent interaction with Aβ. Our studies have demonstrated that melatonin efficiently attenuates Alzheimer-like tau hyperphosphorylation. Although the exact mechanism is still not fully understood, a direct regulatory influence of melatonin on the activities of protein kinases and protein phosphatases is proposed. Additionally, melatonin also plays a role in protecting the cholinergic system and in anti-inflammation. The aim of this review is to stimulate interest in melatonin as a potentially useful agent in the prevention and treatment of AD. 23832922 Late coronary artery and tricuspid valve injury post pectus excavatum surgery. We report the surgical case of a 25-year old man admitted because of progressive dyspnoea and stabbing chest pain, who had undergone a pectus excavatum correction using a retrosternal strut 8 years previously. The computerized tomography scan showed that the right tip of the pectus bar had migrated across his right ventricle and tricuspid valve into the right atrium. Intraoperatively, it was confirmed that in its path, the right coronary artery and the posterior leaflet of the tricuspid valve had been damaged. After removing the bar and repairing the tricuspid valve, the patient made a full recovery. 23824720 trans Isomeric fatty acids are inversely related to the availability of long-chain PUFAs in the perinatal period. We summarize data on the potential interaction of trans isomeric fatty acids [trans fatty acids (TFAs)] with the availability of long-chain polyunsaturated fatty acids (LC-PUFAs) in the perinatal period. Today, TFA intakes in pregnant and lactating women can be estimated to be ∼1% of energy in the majority of the population. The significant inverse associations seen between TFAs and LC-PUFAs in pregnant women in 3 different European populations investigated in a recent study raise doubts about the nutritional adequacy of high TFA intakes during pregnancy. In a recent study on the TFA content of human milk in a sizable group of mothers at the sixth week of lactation, both arachidonic and docosahexaenoic acids correlated significantly inversely to 18-carbon TFAs but not to 16-carbon TFAs, and at the sixth month of lactation arachidonic acid correlated significantly inversely to 18-carbon TFAs but not to 16-carbon TFAs. Similarly, significant inverse correlations were seen between 18-carbon TFAs and arachidonic and docosahexaenoic acids in both artery and vein wall lipids in a sizable group of healthy term infants. The TFA data obtained in umbilical blood vessel wall lipids were related to the neurologic condition of healthy children at 18 mo of age: children with minimal neurologic dysfunction at age 18 mo had significantly higher cord blood vein wall trans octadecadienoic acid values than did neurologically normal children. Total TFA values as well as total 18-carbon TFA values in umbilical vein wall lipids were significantly inversely associated with neurologic optimality score. Contradictory data renders it impossible to draw firm conclusions on the role of TFAs in modifying fetal growth; however, TFA exposure may be a confounding parameter in studies that investigate the relation between fetal fatty acid supply and intrauterine growth. 23901078 Genetic Variation in IL18R1 and IL18 Genes and Inteferon γ ELISPOT Response to Smallpox Vaccination: An Unexpected Relationship. Background. Genetic association studies demonstrated a role for cytokine proteins and cytokine or cytokine receptor gene polymorphisms in smallpox vaccine-induced adaptive immunity.Methods. We examined the association of genetic polymorphisms with cellular (interferon [IFN] γ enzyme-linked immunospot assay [ELISPOT]) immune response to smallpox vaccine in 1076 immunized individuals.Results. The majority of significant associations were discovered between single-nucleotide polymorphisms/haplotypes in IL18R1 and IL18 genes, in which we previously reported an association with vaccinia virus-induced neutralizing antibody titers in this study cohort. A functional coding IL18R1 polymorphism (rs1035130/Phe251Phe; P = .01) was significantly associated with an allele dose-related increase in IFN-γ production and was also associated with vaccinia-specific neutralizing antibody titers. Significant associations were also found between IL18R1 haplotypes and variations in IFN-γ ELISPOT responses (global P < .0001).Conclusions. Our data suggest the importance of variants in the IL18R1 and IL18 genetic loci for broad-based smallpox vaccine-induced adaptive immunity. 23649462 Functional and molecular imaging of localized and recurrent prostate cancer. Prostate cancer is the most common malignancy among American men. Imaging of localized and recurrent prostate cancer is challenging since conventional imaging techniques are limited. New imaging techniques such as multiparametric MRI and PET with targeted tracers have been investigated extensively in the last decade. As a result, the role of novel imaging techniques for the detection of localized and recurrent prostate cancer has recently expanded. In this review, novel functional and molecular imaging techniques used in the management of localized and recurrent prostate cancer are discussed. 23948784 Estimating Dopamine D2 Receptor Occupancy for Doses of 8 Antipsychotics: A Meta-Analysis. Dose equivalents based on dopamine D2 receptor occupancy can be used to compare antipsychotics on D2 receptor-mediated (adverse) effects such as extrapyramidal symptoms and altered emotional experiences. Previous meta-analyses modeling the dose-occupancy relationship hardly addressed potential heterogeneity of the imaging data. To model the relationship between dose and D2 receptor occupancy for a series of frequently prescribed antipsychotics while addressing the potential heterogeneity of the imaging data. We conducted a meta-analysis on published D2 receptor occupancy data (positron emission tomography and single-photon emission computed tomography) in patients with schizophrenia treated with antipsychotics. A nonlinear mixed effects model estimated the median D2 receptor occupancy for a given antipsychotic dose. Heterogeneity between studies was investigated by incorporating study as a random effect in the model, in addition to patient- and study-specific explanatory variables. Included were 51 studies, describing 606 patients (mean ± SD age, 32.2 ±10.8 years; 25.7% female). The models described the dose-occupancy relationship with narrow confidence bands around the therapeutic dose range. Maximum occupancy (95% confidence interval [CI]) was estimated for haloperidol (91.9%; 95% CI, 86.1-97.8), risperidone (92.4%; 95% CI, 81.8-100), olanzapine (96.5%; 95% CI, 85.8-100), clozapine (61.7%; 95% CI, 49.2-74.2), quetiapine (49.1%; 95% CI, 18.7-79.6), aripiprazole (86.9%; 95% CI, 78.2-95.7), ziprasidone (82.9%; 95% CI, 44.9-100), and amisulpride (85.0%; 95% CI, 68.5-100). Interindividual differences explained most of the variability in occupancy values, besides significant heterogeneity between studies. Dose-occupancy functions estimated the median level of dopamine D2 receptor occupancy for 8 frequently prescribed antipsychotics in patients with schizophrenia. These dose equivalents can be used to compare antipsychotic effects in epidemiological studies and clinical practice. 23955529 The Virulence Factors of Bordetella pertussis: Talented Modulators of Host Immune Response. Approximately 40 million whooping cough cases and between 200,000 and 400,000 pertussis-linked deaths are recorded each year. Although several types of vaccines are licensed and widely used, Bordetella pertussis continues to circulate in populations with high vaccine coverage of infants and children due to the waning of protection induced by the vaccination. B. pertussis typically expresses a wide array of virulence factors which promote bacterial adhesion and invasion by altering the local environment, including pertussis toxin, tracheal cytotoxin, adenylate cyclase toxin, filamentous hemagglutinin, and the lipooligosaccharide. The virulence factors of B. pertussis also possess immunomodulatory properties, exerted through their enzymatic and receptor-binding activities. Both pro- and anti-inflammatory effects are mediated, that can subvert host innate and adaptive immunity and favor the onset of a long-term infection. This review describes the capacities of B. pertussis virulence factors to modulate host immune responses and the mechanisms employed, which have been the subject of extensive research in the recent years, both in murine and human experimental systems. Knowledge of these mechanisms is gaining increasing importance, since it could provide in the near future the basis for the identification of therapeutic agents for modulating the immune system as well as novel molecular targets to treat pertussis. 23790801 New roles of cyclin D1. Cyclins encode regulatory subunits of holoenzymes that phosphorylate a variety of cellular substrates. Although the classic role of cyclins in cell cycle progression and tumorigenesis has been well characterized, new functions have been identified, including the induction of cellular migration and invasion, enhancement of angiogenesis, inhibition of mitochondrial metabolism, regulation of transcription factor signaling via a DNA-bound form, the induction of chromosomal instability, enhancement of DNA damage sensing and DNA damage repair, and feedback governing expression of the noncoding genome. This review describes the mechanisms of these new functions of cyclin D1. 23874875 Identification of a Lifespan Extending Mutation in the Schizosaccharomyces pombe Cyclin Gene clg1 (+) by Direct Selection of Long-Lived Mutants. Model organisms such as budding yeast, worms and flies have proven instrumental in the discovery of genetic determinants of aging, and the fission yeast Schizosaccharomyces pombe is a promising new system for these studies. We devised an approach to directly select for long-lived S. pombe mutants from a random DNA insertion library. Each insertion mutation bears a unique sequence tag called a bar code that allows one to determine the proportion of an individual mutant in a culture containing thousands of different mutants. Aging these mutants in culture allowed identification of a long-lived mutant bearing an insertion mutation in the cyclin gene clg1 (+) . Clg1p, like Pas1p, physically associates with the cyclin-dependent kinase Pef1p. We identified a third Pef1p cyclin, Psl1p, and found that only loss of Clg1p or Pef1p extended lifespan. Genetic and co-immunoprecipitation results indicate that Pef1p controls lifespan through the downstream protein kinase Cek1p. While Pef1p is conserved as Pho85p in Saccharomyces cerevisiae, and as cdk5 in humans, genome-wide searches for lifespan regulators in S. cerevisiae have never identified Pho85p. Thus, the S. pombe system can be used to identify novel, evolutionarily conserved lifespan extending mutations, and our results suggest a potential role for mammalian cdk5 as a lifespan regulator. 23962384 "No-one actually goes to a shop and buys them do they?": Attitudes and behaviours regarding illicit tobacco in a multiply disadvantaged community in England. To explore attitudes towards, and experience of, illicit tobacco usage in a disadvantaged community against a backdrop of austerity and declining national trends in illicit tobacco use. Qualitative study using 10 focus groups. Multiply disadvantaged community in Nottingham, UK. 58 smokers, ex- and non-smokers aged 15-60 years. Focus group topic guides. There was high awareness and use of illegal tobacco sources, with 'fag houses' (individuals selling cigarettes from their own homes) being particularly widespread. Rather than being regarded as marginal behaviour, buying illicit tobacco was perceived as commonplace, even where products were known to be counterfeit. Smokers' willingness to smoke inferior "nasty" counterfeit products may be testament to their need for cheap nicotine. Illicit tobacco was seen to be of mutual benefit to both user (because of its low cost) and seller (because it provided income and support for the local economy). Illicit tobacco sellers were generally condoned, in contrast with the government, which was blamed for unfair tobacco taxation, attitudes possibly heightened by the recession. Easy access to illicit tobacco was seen to facilitate and sustain smoking with the main concern being around underage smokers who were perceived to be able to buy cheap cigarettes without challenge. National strategies to reduce illicit tobacco may have limited impact in communities during a recession and where illicit trade is part of the local culture and economy. There may be potential to influence illicit tobacco use by building on the ambivalence and unease expressed around selling to children. 22907437 ADP-ribosylation factors 1 and 6 regulate Wnt/β-catenin signaling via control of LRP6 phosphorylation. It has been shown that inhibition of GTPase-activating protein of ADP-ribosylation factor (Arf), ArfGAP, with a small molecule (QS11) results in synergistic activation of Wnt/β-catenin signaling. However, the role of Arf in Wnt/β-catenin signaling has not yet been elucidated. Here, we show that activation of Arf is essential for Wnt/β-catenin signaling. The level of the active form of Arf (Arf-GTP) transiently increased in the presence of Wnt, and this induction event was abrogated by blocking the interaction between Wnt and Frizzled (Fzd). In addition, knockdown of Fzds, Dvls or LRP6 blocked the Wnt-mediated activation of Arf. Consistently, depletion of Arf led to inhibition of Wnt-mediated membrane PtdIns (4,5)P2 (phosphatidylinositol 4, 5-bisphosphate) synthesis and LRP6 phosphorylation. Overall, our data suggest that transient activation of Arf modulates LRP6 phosphorylation for the transduction of Wnt/β-catenin signaling. 23557756 Altered circulating levels of matrix metalloproteinases 2 and 9 and their inhibitors and effect of progesterone supplementation in women with endometriosis undergoing in vitro fertilization. To investigate differences in the activity of matrix metalloproteinases (MMPs) 2 and 9 and their respective tissue inhibitors (TIMPs) in follicular fluid of women with endometriosis, to correlate the findings with IVF outcome, and to examine the therapeutic potential of progesterone supplementation in restoring the fine balance between MMPs and TIMPs. Prospective case-control clinical study. Infertility clinic and reproductive health research unit. A total of 340 infertile women undergoing IVF. Natural micronized progesterone capsules were administered for luteal support. Association of MMPs 2 and 9 and TIMP-1 with oocyte maturity and embryo development. An abnormal expression of MMP-2, MMP-9, and TIMP-1 with extensive MMP-9/TIMP-1 imbalance in women with endometriosis undergoing IVF was observed. Transforming growth factor β1 plays an important role in these women with possible involvement of Smad-2 and -3 proteins. Progesterone supplementation improves the imbalance in MMP-9/TIMP-1 ratio significantly in women with endometriosis who conceive after IVF. Increase in MMP-2 and -9 and decrease in TIMP-1 expression was associated with poor oocyte and embryo development in women with endometriosis undergoing IVF. MMP-9/TIMP-1 balance was highly affected in these women, and progesterone supplementation appeared to restore this imbalance to a considerable degree. 23933169 Aging is not a disease: Distinguishing age-related macular degeneration from aging. Age-related macular degeneration (AMD) is a disease of the outer retina, characterized most significantly by atrophy of photoreceptors and retinal pigment epithelium accompanied with or without choroidal neovascularization. Development of AMD has been recognized as contingent on environmental and genetic risk factors, the strongest being advanced age. In this review, we highlight pathogenic changes that destabilize ocular homeostasis and promote AMD development. With normal aging, photoreceptors are steadily lost, Bruch's membrane thickens, the choroid thins, and hard drusen may form in the periphery. In AMD, many of these changes are exacerbated in addition to the development of disease-specific factors such as soft macular drusen. Para-inflammation, which can be thought of as an intermediate between basal and robust levels of inflammation, develops within the retina in an attempt to maintain ocular homeostasis, reflected by increased expression of the anti-inflammatory cytokine IL-10 coupled with shifts in macrophage plasticity from the pro-inflammatory M1 to the anti-inflammatory M2 polarization. In AMD, imbalances in the M1 and M2 populations together with activation of retinal microglia are observed and potentially contribute to tissue degeneration. Nonetheless, the retina persists in a state of chronic inflammation and increased expression of certain cytokines and inflammasomes is observed. Since not everyone develops AMD, the vital question to ask is how the body establishes a balance between normal age-related changes and the pathological phenotypes in AMD. 23736544 One year of sitagliptin treatment protects against islet amyloid-associated β-cell loss and does not induce pancreatitis or pancreatic neoplasia in mice. The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin is an attractive therapy for diabetes, as it increases insulin release and may preserve β-cell mass. However, sitagliptin also increases β-cell release of human islet amyloid polypeptide (hIAPP), the peptide component of islet amyloid, which is cosecreted with insulin. Thus, sitagliptin treatment may promote islet amyloid formation and its associated β-cell toxicity. Conversely, metformin treatment decreases islet amyloid formation by decreasing β-cell secretory demand and could therefore offset sitagliptin's potential proamyloidogenic effects. Sitagliptin treatment has also been reported to be detrimental to the exocrine pancreas. We investigated whether long-term sitagliptin treatment, alone or with metformin, increased islet amyloid deposition and β-cell toxicity and induced pancreatic ductal proliferation, pancreatitis, and/or pancreatic metaplasia/neoplasia. hIAPP transgenic and nontransgenic littermates were followed for 1 yr on no treatment, sitagliptin, metformin, or the combination. Islet amyloid deposition, β-cell mass, insulin release, and measures of exocrine pancreas pathology were determined. Relative to untreated mice, sitagliptin treatment did not increase amyloid deposition, despite increasing hIAPP release, and prevented amyloid-induced β-cell loss. Metformin treatment alone or with sitagliptin decreased islet amyloid deposition to a similar extent vs untreated mice. Ductal proliferation was not altered among treatment groups, and no evidence of pancreatitis, ductal metaplasia, or neoplasia were observed. Therefore, long-term sitagliptin treatment stimulates β-cell secretion without increasing amyloid formation and protects against amyloid-induced β-cell loss. This suggests a novel effect of sitagliptin to protect the β-cell in type 2 diabetes that appears to occur without adverse effects on the exocrine pancreas. 23811342 Cell response to PEGylated poly(dopamine) coated liposomes considering shear stress. Liposomes have gained immerse attention in the field of drug delivery as carriers of therapeutic molecules. Their modification with a polymer either to make them stealth (e.g. using PEG) and/or more stable (e.g. using poly(dopamine) (PDA)) is a crucial aspect to improve their performance e.g. the blood circulation time. Despite their potential, there are only a few commercialized liposome-based formulations for intravenous drug delivery. Hence, there is still considerable need to address the challenges involved in the design and characterization of liposomal therapeutics. In the latter case, it is of paramount importance to consider the dynamic in vivo environment, e.g. the interstitial fluidic pressure in tumors, blood flow, or bile flow in the liver. The PEGylation of PDA films was characterized by quartz crystal microbalance with dissipation monitoring, and the optimized protocol was used to assemble PEGylated PDA coated liposomes (LPDA_PEG). Dynamic light scattering, a plate reader, a flow cytometer and a cytotoxicity assay were used to characterize the liposomes and quantify cellular association/uptake and cell viability in the presence and absence of shear stress after 30min and 4h. The immortalized skeletal mouse myoblast (C2C12) cell line was chosen as model cancer cells, and a hepatic cell line (HepG2) was selected due to their importance in nanosized drug carrier clearance from the system in the liver. The presence of hydrophilic cargo did not affect the PDA assembly process. In the absence of shear stress, there was no difference in cellular uptake/association of both PDA coated liposomes (LPDA) and LPDA_PEG for hepatocytes while myoblasts preferentially internalized/associated with LPDA. In the presence of shear stress, hepatocytes preferentially internalized/associated with LPDA after 30min, while there was only a significant difference for myoblasts after 4h. The cell viability remained unaffected in all cases. LPDA_PEG are a promising platform towards drug delivery. The nature of cells and fluidic flow are important factors to be considered in their characterization using cell cultures. These findings will contribute in the better understanding of polymer coated liposomes with cells. The importance of microfluidics in cell culture based characterization is demonstrated, and this will eventually affect the way advanced drug delivery vehicles are designed and characterized prior to animal experiments. 23872563 Abundant DNase I Sensitive Bacterial DNA in Healthy Porcine Lungs: Implications for the Lung Microbiome. Human lungs are constantly exposed to bacteria in the environment, yet the prevailing dogma is that healthy lungs are sterile. DNA sequencing-based studies of pulmonary bacterial diversity challenge this notion. However, DNA-based microbial analysis currently fails to discern between DNA from live bacteria and bacteria that have been killed by lung immune mechanisms, potentially causing overestimation of bacterial abundance and diversity. We investigated whether bacterial DNA recovered from lungs represents live or dead bacteria in bronchoalveolar lavage (BAL) and lung samples in young healthy pigs. Live bacterial DNA was DNase I-resistant and became DNase I sensitive upon human antimicrobial-mediated killing in vitro. We determined live and total bacterial DNA load in porcine BAL and lung tissue by comparing DNase I treated vs. untreated samples. In contrast to BAL, we were unable to culture bacteria from most lung homogenates. Surprisingly, total bacterial DNA was abundant in both BAL and lung homogenates. In BAL, 63% was DNase I sensitive. In 6 out of 11 lung homogenates, all bacterial DNA was DNase I sensitive suggesting predominance of dead bacteria; in the remaining homogenates, 94% was DNase I sensitive and bacterial diversity determined by 16s rRNA gene sequencing was similar in DNase I-treated and untreated samples.Healthy pig lungs are mostly sterile yet contain abundant DNase I-sensitive DNA from inhaled and aspirated bacteria killed by pulmonary host defense mechanisms. This approach and conceptual framework will improve analysis of the lung microbiome in disease. 23912646 Cytokine Expression Before and After Aspirin Desensitization Therapy in Aspirin-Exacerbated Respiratory Disease. Aspirin exacerbated respiratory disease (AERD) is induced by acetylsalicylic acid (ASA) and/or nonsteroidal antiinflammatory drugs (NSAIDs). Effects of desensitization on many mediators have been examined previously, but few studies addressed the influence of desensitization on T lymphocytes and T lymphocyte-derived cytokines. This study was performed to examine peripheral blood lymphocyte (PBL) cytokine expression in aspirin-sensitive patients who have asthma before and after aspirin desensitization. In this study, the release of interleukin-2 (IL-2), interleukin-4 (IL-4), and interferon-gamma (IFN-γ) by CD4+ T lymphocytes prior to aspirin desensitization were also measured at intracellular levels, and expression of these cytokines after 1 month aspirin desensitization was evaluated. Twelve patients with AERD were included in the study. Two different control groups were formed, one consisted of 15 healthy people and second 12 aspirin tolerant asthmatic (ATA) patients using aspirin. A blood sample was collected prior to desensitization, and the tests were repeated by taking a second blood sample 1 month after the 4-day desensitization treatment. The proportion of lymphocytes secreting IFN-γ in the study group was 15.61 ±â€‰4.40 % before desensitization and 15.08 ±â€‰5.89 % after desensitization. The rate of IFN-γ secreting CD4+ T lymphocytes was 20.51 ±â€‰4.41 % in the normal control group and 16.07 ±â€‰5.7 % in the ATA group (p = 0.021). The ratio of CD4+ T lymphocyte secreting IFN-γ was reduced in patients with AERD before desensitization compared to normal control group (p = 0.040). The levels of IL-2, IL-4, and the subsets of lymphocyte were not different before and after desensitization compared to control groups. 23876703 The current state of fellowship training in pulmonary artery catheter placement and data interpretation: A national survey of pulmonary and critical care fellowship program directors. Given decreasing use of pulmonary artery (PA) catheterization, we sought to evaluate whether current pulmonary and critical care fellows have adequate opportunity to obtain proficiency in PA catheter placement and data interpretation. All US pulmonary and critical care program directors were invited to participate in an anonymous online survey regarding current training opportunities in PA catheterization. The response rate was 51% (69/136). Eighty-three percent reported that the number of PA catheterizations performed by fellows within their program has decreased in the past decade. Fifty-four percent estimated that their fellows currently participate in less than 10 supervised procedures during fellowship. The most frequently identified barriers to training were procedure volume and reluctance to place PA catheters in the medical intensive care unit. Forty-three percent of respondents agreed that training in PA catheter placement is currently adequate within their program, and 55% agreed that training in data interpretation is adequate. Only 39% of respondents believe that PA catheter placement should continue to be an Accreditation Council for Graduate Medical Education training requirement. Many current pulmonary and critical care fellows do not have the opportunity to gain proficiency in PA catheterization. Fellowship training programs should consider alternate means of training fellows in PA catheter data interpretation, such as simulation. 23829182 Synthesis and modeling of hollow intermetallic ni-zn nanoparticles formed by the kirkendall effect. Intermetallic Ni-Zn nanoparticles (NPs) were synthesized via the chemical conversion of nickel NPs using a zerovalent organometallic zinc precursor. After the injection of a diethylzinc solution, Ni NPs progressively transformed from a solid to a hollow Ni-Zn intermetallic structure with time. During the transformation of Ni NPs to intermetallic structures, they retained their overall spherical morphology. The growth mechanism for the solid-to-hollow nanoparticle transformation is ascribed to the nanoscale Kirkendall effect due to unequal diffusion rates of Ni and Zn. We develop a diffusion model for nonreactive, homogeneous, diffusion-controlled intermetallic hollow NP formation including moving boundaries at the interfaces of void-solid and solid-bulk solutions. Apparent diffusion coefficients for both metals and vacancy were evaluated from modeling the time-dependent growth of the void. The apparent diffusion coefficients obtained in this system compared favorably with results from measurement at grain boundaries in bulk Ni-Zn. This study represents the first combined experimental modeling of the formation of hollow nanostructures by the nanoscale Kirkendall effect. 23904053 Trend in SSRI-SNRI antidepressants prescription over a 6-year period and predictors of poor adherence. To describe antidepressant (AD) use in the Emilia-Romagna Region (Italy) and to evaluate adherence to treatment with selective serotonin receptor inhibitors or selective noradrenaline receptor inhibitors (SSRI-SNRI). Reimbursed prescriptions of AD were retrieved from the Emilia-Romagna Regional Health Authority Database. The overall AD consumption from the 2006-2011 period was expressed in terms of prevalence and amount of use. Adherence to treatment was assessed in a cohort of patients who received SSRI-SNRI, and was followed throughout a 6-month period from the start of each treatment episode. Adherence was considered according to three parameters: duration of treatment ≥ 120 days, prescription coverage ≥ 80 %, and gaps between prescriptions < 3 months. Determinants of non-adherent regimen, including sociodemographic and clinical variables, were identified by multivariate logistic regression by calculating adjusted Odds Ratio (adjOR) and the relevant 95 % confidence interval (95CI). From 2006 to 2011, the prevalence of use of AD increased by 5 % (from 86 to 90 per 1,000 inhabitants) and the amount of antidepressant consumption increased by 20 % (from 43 to 51 defined daily dose per thousand inhabitants per day [DDD/TID]), with a 14 % rise in the intensity of drug use (from 182 to 208 DDD per patient). Out of 347,615 SSRI-SNRI treatment episodes, only 23.8 % were adherent. Comorbidity (adjOR:0.69; 95CI:0.67-0.72) and recurrence of AD treatment in the previous year (0.91; 0.89-0.92) were associated with better adherence. Moreover, patients treated with duloxetine (0.58; 0.55-0.60), escitalopram (0.64; 0.62-0.66) or sertraline (0.65; 0.64-0.67) showed better adherence in comparison with paroxetine. Clinical variables resulting in improved adherence seem to identify patients with more severe disorders and who actually need a pharmacological approach, whereas differences in adherence among ADs could in part be caused by channeling and sponsorship bias. Initiatives addressed at improving cooperation between primary care and psychiatrists could decrease AD prescription for cases of sub-threshold or mild depression that easily drop out because of rapid symptom relief or side effects. 23845723 Promotion of exclusive breast-feeding at scale within routine health services: impact of breast-feeding counselling training for community health workers in Recife, Brazil. Breast-feeding counselling has been identified as the intervention with the greatest potential for reducing child deaths, but there is little experience in delivering breast-feeding counselling at scale within routine health systems. The study aim was to compare rates of exclusive breast-feeding associated with a breast-feeding counselling intervention in which community health agents (CHA) received 20 h of training directed at counselling and practical skills with rates pre-intervention when CHA received 4 h of didactic teaching. Cross-sectional surveys of breast-feeding practices were conducted pre- and post-intervention in random samples of 1266 and 1245 infants aged 0-5·9 months, respectively. Recife, Brazil, with a population of 2 million. CHA (n 1449) of Brazil's Family Health Programme were trained to provide breast-feeding counselling at home visits. Rates of exclusive breast-feeding improved when CHA were trained to provide breast-feeding counselling and were significantly higher by 10-13 percentage points at age 3-5·9 months when compared with pre-intervention rates (P < 0·05). Post-intervention point prevalence of exclusive breast-feeding for infants aged <4 months was 63 % and for those aged <6 months was 50 %. Multifunctional CHA were able to deliver breast-feeding counselling at scale within a routine health service and this was associated with a significant increase in rates of exclusive breast-feeding. The study reinforces the need to focus training on counselling and practical skills; a key component was an interactive style that utilized the knowledge and experience of CHA. The findings are relevant to the call by international organizations to scale up breast-feeding counselling. 23222412 Parity and expression of epithelial histopathologic markers in breast tissue. It is well established that pregnancies protect against breast cancer; however, the mechanism involved is not completely understood. We investigated the influence of parity on hormonal and proliferation markers in benign tissue from tumor blocks of breast cancer cases. Women with breast cancer were recruited from a case-control study nested within the Multiethnic Cohort study. Tissue microarrays of benign tissue cores were available for 159 participants. Immunostaining for estrogen receptor α (ERα) and ERβ, progesterone receptor, human epidermal growth factor receptor 2 (Her2/neu), Ki-67, and proliferating cell nuclear antigen (PCNA) in epithelial tissue was evaluated by a pathologic expert. We applied logistic regression models to examine marker expression by parity (0, 1-2, and ≥3 live births with adjustment for age at diagnosis and BMI). Of the 159 women, 24 were nulliparous, 63 had one or two live births, and 72 had three or more live births. Inverse associations were observed between parity and expression of ERα (Ptrend=0.02) and PCNA (Ptrend=0.04). Among nulliparous women, 45.5% were ERα positive in contrast to 18.0 and 18.9% of women with one or two and at least three live births, respectively. The respective values for PCNA were 56.5, 44.3, and 31.1%. No associations were detected for ERβ, progesterone receptor, Her2/neu, and Ki-67. The current findings suggest that pregnancies may protect against breast cancer by reducing susceptibility to estrogenic stimuli and proliferative activity as assessed by the expression of ERα and PCNA in breast tissue. 23624298 Associations between human herpesvirus-6, human papillomavirus and cervical cancer. Cervical cancer (CxCa) is the second most common cancer among women globally. Human papillomavirus (HPV) infection is thought to be a necessary, but not sufficient, causal factor in CxCa development. Why some women are able to clear HPV infection with no adverse effects, whereas others develop cancer, remains unclear. HHV-6 has demonstrated transformative abilities and has been shown to be present in the genital tract. However, based on the current evidence, we cannot conclude that HHV-6 is a co-factor in HPV-associated carcinogenesis. Nonetheless, future research is warranted because of several crucial gaps in the literature. 23903244 Loss of nondrug reinforcement in one context produces alcohol seeking in another context. In the resurgence preparation, extinguished alcohol-maintained responding increases when food reinforcement introduced into the same context during extinction is also subsequently removed. However, drug and nondrug reinforcers may often be obtained in separate specific contexts. Accordingly, we aimed to determine whether extinguished behavior previously maintained by alcohol would increase upon elimination of nondrug reinforcement within a multiple schedule arranging distinct discriminative stimulus contexts of food and alcohol availability. In Experiment 1, rats earned food or alcohol in alternating stimulus contexts within a multiple schedule. First, alcohol-maintained responding was extinguished and then food deliveries in the alternating component were also discontinued. Extinguished alcohol-maintained responding increased upon discontinuation of food deliveries. However, periods of alcohol availability alternated with periods of extinction during a portion of training; thus, elimination of food reinforcers during the resurgence test may have inadvertently served as a cue for alcohol availability. In Experiment 2, the training phase that complicated interpretation of the results of Experiment 1 was eliminated. Alcohol-maintained responding again increased when food-maintained responding was placed on extinction in the other component. The present results indicate that loss of nondrug reinforcement in one discriminative context can increase extinguished alcohol seeking in another context and that multiple schedules of reinforcement might be useful for examining such effects. 23810505 Novel CFTR Variants Identified during the First 3 Years of Cystic Fibrosis Newborn Screening in California. California uses a unique method to screen newborns for cystic fibrosis (CF) that includes gene scanning and DNA sequencing after only one California-40 cystic fibrosis transmembrane conductance regulator (CFTR) panel mutation has been identified in hypertrypsinogenemic specimens. Newborns found by sequencing to have one or more additional mutations or variants (including novel variants) in the CFTR gene are systematically followed, allowing for prospective assessment of the pathogenic potential of these variants. During the first 3 years of screening, 55 novel variants were identified. Six of these novel variants were discovered in five screen-negative participants and three were identified in multiple unrelated participants. Ten novel variants (c.2554_2555insT, p.F1107L, c.-152G>C, p.L323P, p.L32M, c.2883_2886dupGTCA, c.2349_2350insT, p.K114del, c.-602A>T, and c.2822delT) were associated with a CF phenotype (42% of participants were diagnosed at 4 to 25 months of age), whereas 26 were associated with CFTR-related metabolic syndrome to date. Associations with the remaining novel variants were confounded by the presence of other diseases or other mutations in cis or by inadequate follow-up. These findings have implications for how CF newborn screening and follow-up is conducted and will help guide which genotypes should, and which should not, be considered screen positive for CF in California and elsewhere. 23869582 Noncrystalline-to-Crystalline Transformations in Pt Nanoparticles. We show that the noncrystalline-to-crystalline transition of supported Pt nanoparticles (NPs) in the subnanometer to nanometer size range is statistical in nature, and strongly affected by particle size, support, and adsorbates (here we use H2). Unlike in the bulk, a noncrystalline phase exists and is stable in small NPs, reflecting a general mesoscopic feature. Observations of >3000 particles by high-resolution transmission electron microscopy show a noncrystalline-to-crystalline transition zone that is nonabrupt; there is a size regime where disordered and ordered NPs coexist. The NP size at which this transition occurs is strongly dependent on both the adsorbate and the support, and this effect is general for late 5d transition metals. All results are reconciled via a statistical description of particle-support-adsorbate interactions. 23391154 Antimicrobial N-halamine polymers and coatings: a review of their synthesis, characterization, and applications. Antimicrobial N-halamine polymers and coatings have been studied extensively over the past decade thanks to their numerous qualities such as effectiveness toward a broad spectrum of microorganisms, long-term stability, regenerability, safety to humans and environment and low cost. In this review, recent developments are described by emphasizing the synthesis of polymers and/or coatings having N-halamine moieties. Actually, three main approaches of preparation are given in detail: polymerization, generation by electrochemical route with proteins as monomers and grafting with precursor monomers. Identification and characterization of the formation of the N-halamine bonds (>N-X with X = Cl or Br or I) by physical techniques such as Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (NMR), energy-dispersive X-ray spectroscopy (EDX), X-ray photoelectron spectroscopy (XPS), and by chemical reactions are described. In order to check the antimicrobial activity of the N-halamine compounds, bacterial tests are also described. Finally, some examples of application of these N-halamines in the water treatment, paints, healthcare equipment, and textile industries are presented and discussed. 23561074 Plums (Prunus domestica L.) are a good source of yeasts producing organic acids of industrial interest from glycerol. The production of organic acids from several yeasts isolated from mature plums on media containing glycerol as carbon source was analysed by HPLC-UV. The yeasts isolated were identified by sequencing the 5.8S internal transcribed spacer as Pichia fermentans, Wickerhamomyces anomalus and Candida oleophila. The organic acid profiles of these strains comprise acetic, citric, succinic and malic acids that qualitatively and quantitatively vary between different species as well as among strains from the same species. The production from glycerol of succinic, acetic, citric, malic and oxalic acids from C. oleophila and W. anomalus, and that of succinic, oxalic and acetic acids by P. fermentans is reported for the first time in this work, as is the production of oxalic acid from glycerol in yeasts. Our results also showed that mature fruits can be a good source of new yeasts able to metabolise glycerol, producing different organic acids with industrial and biotechnological interest. 23146000 Safe fetal platelet genotyping: new developments. Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is due to maternal alloimmunization against fetal platelet (PLT) antigens. Antenatal management strategies have been developed to avoid complications such as intracranial hemorrhage. The aim of this study was to set up two reliable, noninvasive fetal genotyping assays to determine the fetal risk in pregnancies in which the father is heterozygous for the offending antigen. This study focused on human PLT antigen (HPA)-1, the most frequently implicated antigen in FNAIT in Caucasians. Two assays based on cell-free fetal DNA extracted from maternal blood samples and on real-time polymerase chain reaction (QPCR) were developed: an allele-specific QPCR specifically targeting the polymorphic sequence in HPA-1 and the study of the variation in the high-resolution melting curve of amplicons containing the polymorphic region. All results from the 49 samples obtained from 29 pregnant women were consistent with expectations. Six women were compatible with their fetuses (three HPA-1aa women and three HPA-1bb women), 41 HPA-1bb women were incompatible with their fetuses, as were two HPA-1aa women. Two fetal PLT genotyping assays on maternal blood samples proved to be reliable as of 15 weeks of gestation, thereby avoiding invasive techniques such as amniocentesis. 23541120 Improving the Catalytic Activity of Semiconductor Nanocrystals through Selective Domain Etching. Colloidal chemistry offers an assortment of synthetic tools for tuning the shape of semiconductor nanocrystals. While many nanocrystal architectures can be obtained directly via colloidal growth, other nanoparticle morphologies require alternative processing strategies. Here, we show that chemical etching of colloidal nanoparticles can facilitate the realization of nanocrystal shapes that are topologically inaccessible by hot-injection techniques alone. The present methodology is demonstrated by synthesizing a two-component CdSe/CdS nanoparticle dimer, constructed in a way that both CdSe and CdS semiconductor domains are exposed to the external environment. This structural morphology is highly desirable for catalytic applications as it enables both reductive and oxidative reactions to occur simultaneously on dissimilar nanoparticle surfaces. Hydrogen production tests confirmed the improved catalytic activity of CdSe/CdS dimers, which was enhanced 3-4 times upon etching treatment. We expect that the demonstrated application of etching to shaping of colloidal heteronanocrystals can become a common methodology in the synthesis of charge-separating nanocrystals, leading to advanced nanoparticles architectures for applications in areas of photocatalysis, photovoltaics, and light detection. 23461596 Nasolacrimal system obstruction, ptosis and esotropia due to chemotherapy in acute lymphoblastic leukemia. Abstract Eight-year-old girl was admitted to our clinic with the complaint of constant epiphora in the right eye. It was reported that this complaint began after the start of chemotherapy with a diagnosis of Acute Lymphoblastic Leukemia (ALL) about 5 years ago. In addition, eyelid ptosis associated with esotropia also occurred during that period. We found that nasolacrimal duct obstruction did not improve with medical treatment but ptosis and esotropia improved with pyridoxine and pyridostigmine treatment during that period. Examination of the eye on admission revealed nasolacrimal duct obstruction on the right side. Other ocular findings were normal. Nasolacrimal system obstruction, ptosis and esotropia combination has not been reported previously in patients using systemic drugs or receiving chemotherapy due to ALL. 23864426 Investigation into the feasibility of thioditaloside as a novel scaffold for galectin-3-specific inhibitors. Galectin-3 is extensively involved in metabolic and disease processes, such as cancer metastasis, thus giving impetus for the design of specific inhibitors targeting this β-galactose-binding protein. Thiodigalactoside (TDG) presents a scaffold for construction of galectin inhibitors, and its inhibition of galectin-1 has already demonstrated beneficial effects as an adjuvant with vaccine immunotherapy, thereby improving the survival outcome of tumour-challenged mice. A novel approach-replacing galactose with its C2 epimer, talose-offers an alternative framework, as extensions at C2 permit exploitation of a galectin-3-specific binding groove, thereby facilitating the design of selective inhibitors. We report the synthesis of thioditaloside (TDT) and crystal structures of the galectin-3 carbohydrate recognition domain in complexes with TDT and TDG. The different abilities of galactose and talose to anchor to the protein correlate with molecular dynamics studies, likely explaining the relative disaccharide binding affinities. The feasibility of a TDT scaffold to enable access to a particular galectin-3 binding groove and the need for modifications to optimise such a scaffold for use in the design of potent and selective inhibitors are assessed. 23958262 Fibrate therapy and circulating adiponectin concentrations: A systematic review and meta-analysis of randomized placebo-controlled trials. Several lines of evidence have indicated the insulin-sensitizing, anti-diabetic and anti-atherosclerotic properties of adiponectin, as well as the inverse association between circulating levels of this adipokine and development of cardiovascular outcomes. Improvement of adiponectin status has been reported as a pleiotropic effect of fibrate therapy, but the findings have not been conclusive. To systematically review and meta-analyze available evidence from randomized placebo-controlled trials (RCTs) on the impact of fibrate therapy on circulating levels of adiponectin. A comprehensive literature search in Medline was carried out to identify RCTs comparing the effect of fibrate therapy vs. placebo on circulating concentrations of adiponectin. A meta-analysis of eligible studies was performed using a random-effects model. Quality assessment, sensitivity analysis and publication bias evaluations were conducted using standard methods. Twelve RCTs comprising 443 cases and 437 controls met the selection criteria for systematic review, out of which 9 RCTs (399 cases and 401 controls) were included in the meta-analysis. Quantitative data synthesis revealed a significant effect for fibrate therapy in increasing circulating adiponectin levels (weighed mean difference: 0.38 Î¼g/mL; 95% confidence interval: 0.13-0.63 Î¼g/mL; p = 0.003). The effect size remained statistically significant when restricting the analysis to fenofibrate trials [0.31 (0.21-0.42) μg/mL; p < 0.00001). The observed effect was robust in sensitivity analyses and independent of fibrate dose. Imputation for potential missing studies led to the estimation of a greater effect size for fibrate therapy [0.53 (0.24-0.82) μg/mL]. The present meta-analysis suggests that fibrate therapy increases circulating levels of adiponectin. Whether increase in adiponectin levels contributes to reduction of cardiovascular effects in subjects with dyslipidemia treated with fibrates merits further investigation. 23719051 Brain imaging in chronic epilepsy patients after depth electrode (stereoelectroencephalography) implantation: magnetic resonance imaging or computed tomography? The accurate localization of depth electrodes in epilepsy surgery is important for correct interpretation of stereoelectroencephalography recordings and neurosurgical resection. Unfortunately, image quality in postimplantation magnetic resonance imaging (MRI) is degraded by metal artifacts. The registration of postimplantation computed tomography (CT) or MRI to preimplantation (artifact-free) MRI facilitates electrode imaging and optimal visualization of brain anatomy. However, registration errors negatively affect electrode localization accuracy. To compare the relative registration deviation between postimplantation CT and MRI with preimplantation MRI. Retrospectively, 14 pharmacoresistant epilepsy patients were included who underwent stereotactic insertion of multiple depth electrodes and preimplantation and postimplantation MRI and postimplantation CT. Postimplantation MRI and CT image sets were registered to preimplantation MRI. The registration error between the registered postimplantation MRI and CT was quantified by measuring the geometrical distance between the electrodes of the registered postimplantation CT and the postimplantation MRI. The registration error of postimplantation imaging to preimplantation MRI was dependent on the algorithm used. After optimization, the smallest registration error was 1.22 ± 0.29 mm (mean ± SD) at the tip and 2.25 ± 1.18 mm at the base of the electrode. The good correspondence between the CT/MRI and the MRI/MRI registration suggests that either postimplantation MRI or CT is sufficient for accurate electrode localization. In case of postoperative morphological brain deformations, postimplantation MRI is still recommended. MI, mutual informationNMI, normalized mutual information. 23831370 Comparative proteomic analysis of antimony-resistant and -susceptible Leishmania braziliensis and Leishmania infantum chagasi lines. The emergence of drug-resistant Leishmania species is a significant problem in several countries. A comparative proteomic analysis of antimony-susceptible and antimony-resistant Leishmania braziliensis (LbSbR) and Leishmania infantum chagasi (LcSbR) lines was carried out using two-dimensional gel electrophoresis (2-DE) followed by mass spectrometry (LC/MS/MS) for protein identification. Out of 132 protein spots exclusive or up-regulated submitted to MS, we identified 80 proteins that corresponded to 57 distinct proteins. Comparative analysis of data showed that most of the protein spots with differential abundance in both species are involved in antioxidant defense, general stress response, glucose and amino acid metabolism, and cytoskeleton organization. Five proteins were commonly more abundant in both SbIII-resistant Leishmania lines: tryparedoxin peroxidase, alpha-tubulin, HSP70, HSP83, and HSP60. Analysis of the protein abundance by Western blotting assays confirmed our proteomic data. These assays revealed that cyclophilin-A is less expressed in both LbSbR and LcSbR lines. On the other hand, the expression of pteridine reductase is higher in the LbSbR line, whereas tryparedoxin peroxidase is overexpressed in both LbSbR and LcSbR lines. Together, these results show that the mechanism of antimony-resistance in Leishmania spp. is complex and multifactorial. 23966726 Student preferences regarding teaching methods in a drug-induced diseases and clinical toxicology course. Objectives. To determine which teaching method in a drug-induced diseases and clinical toxicology course was preferred by students and whether their preference correlated with their learning of drug-induced diseases. Design. Three teaching methods incorporating active-learning exercises were implemented. A survey instrument was developed to analyze students' perceptions of the active-learning methods used and how they compared to the traditional teaching method (lecture). Examination performance was then correlated to students' perceptions of various teaching methods. Assessment. The majority of the 107 students who responded to the survey found traditional lecture significantly more helpful than active-learning methods (p=0.01 for all comparisons). None of the 3 active-learning methods were preferred over the others. No significant correlations were found between students' survey responses and examination performance. Conclusions. Students preferred traditional lecture to other instructional methods. Learning was not influenced by the teaching method or by preference for a teaching method. 23836728 Separation and nanoencapsulation of antitumor polypeptide from Spirulina platensis. Spirulina platensis is a multicellular edible blue-green alga with abundant proteins (∼60%). No report is available on the antitumor polypeptides from the whole proteins of S. platensis. In this study, for the first time, an antitumor polypeptide Y2 from trypsin digest of S. platensis proteins was obtained by using freeze-thawing plus ultrasonication extraction, hydrolysis with four enzymes (trypsin, alcalase, papain, and pepsin), and gel filtration chromatography. The results showed that the degree of hydrolysis can be ordered as: trypsin (38.5%) > alcalase (31.2%) > papain (27.8%) > pepsin (7.1%). For MCF-7 and HepG2 cells, at 250 µg/mL, the maximum inhibitory rate of Y2 was 97%, while standard drug 5-FU was 55 and 97%, respectively. Furthermore, the nanoencapsulation of Y2 with chitosan (CS) was also investigated. After nanoencapsulation, the maximum encapsulation efficiency and polypeptides contents are 49 and 15%, respectively; and the antitumor activity is basically not lost. These data demonstrated the potential of nanopolypeptides (Y2-CS) in food and pharmaceutical applications. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 2013. 23377957 Phenotypic redifferentiation and cell cluster formation of cultured human articular chondrocytes in a three-dimensional oriented gelatin scaffold in the presence of PGE2--first results of a pilot study. Modern tissue engineering strategies comprise three elemental parameters: cells, scaffolds and growth factors. Articular cartilage represents a highly specialized tissue which allows frictionless gliding of corresponding articulating surfaces. As the regenerative potential of cartilage is low, tissue engineering-based strategies for cartilage regeneration represent a huge challenge. Prostaglandins function as regulators in cartilage development and metabolism, especially in growth plate chondrocytes. In this study, it was analyzed if prostaglandin E2 (PGE2 ) has an effect on the phenotypic differentiation of human chondrocytes cultured in a three-dimensional (3D) gelatin-based scaffold made by directional freezing and subsequent freeze-drying. As a result, it was clearly demonstrated that low doses of PGE2 revealed beneficial effects on the phenotypic differentiation and collagen II expression of human articular chondrocytes in this 3D cell culture system. In conclusion, PGE2 is an interesting candidate for tissue engineering applications since it represents an already well-studied molecule which is available in pharmaceutical quality. 23702048 Evaluation of fracture toughness and mechanical properties of ternary thiol-ene-methacrylate systems as resin matrix for dental restorative composites. Study and evaluation of fracture toughness, flexural and dynamic mechanical properties, and crosslink density of ternary thiol-ene-methacrylate systems and comparison with corresponding conventional methacrylate system were considered in the present study. Urethane tetra allyl ether monomer (UTAE) was synthesized as ene monomer. Different formulations were prepared based on combination of UTAE, BisGMA/TEGDMA and a tetrathiol monomer (PETMP). The photocuring reaction was conducted under visible light using BD/CQ combination as photoinitiator system. Mechanical properties were evaluated via measuring flexural strength, flexural modulus and fracture toughness. Scanning electron microscopy (SEM) was utilized to study the morphology of the fractured specimen's cross section. Viscoelastic properties of the samples were also determined by dynamic mechanical thermal analysis (DMTA). The same study was performed on a conventional methacrylate system. The data were analyzed and compared by ANOVA and Tukey HSD tests (significance level=0.05). The results showed improvement in fracture toughness of the specimens containing thiol-ene moieties. DMTA revealed a lower glass transition temperature and more homogenous structure for thiol-ene containing specimens in comparison to the system containing merely methacrylate monomer. The flexural modulus and flexural strength of the specimens with higher thiol-ene content were lower than the neat methacrylate system. The SEM micrographs of the fractured surface of specimens with higher methacrylate content were smooth and mirror-like (shiny) which represent brittle fracture. The thiol-ene-methacrylate system can be used as resin matrix of dental composites with enhanced fracture toughness in comparison to the methacrylate analogous. 23438471 The circadian clock circuitry and the AHR signaling pathway in physiology and pathology. Life forms populating the Earth must face environmental challenges to assure individual and species survival. The strategies predisposed to maintain organismal homeostasis and grant selective advantage rely on anticipatory phenomena facing periodic modifications, and compensatory phenomena facing unpredictable changes. Biological processes bringing about these responses are respectively driven by the circadian timing system, a complex of biological oscillators entrained to the environmental light/dark cycle, and by regulatory and metabolic networks that precisely direct the body's adjustments to variations of external conditions and internal milieu. A critical role in organismal homeostatic functions is played by the aryl hydrocarbon receptor (AHR) complex, which senses environmental and endogenous compounds, influences metabolic responses controlling phase I/II gene expression, and modulates vital phenomena such as development, inflammation and adaptive immunity. A physiological cross-talk between circadian and AHR signaling pathways has been evidenced. The alteration of AHR signaling pathway deriving from genetic damage with polymorphisms or mutations, or produced by exogenous or endogenous AHR activation, and chronodisruption caused by mismatch between the body's internal clock and geophysical time/social schedules, are capable of triggering pathological mechanisms involved in metabolic, immune-related and neoplastic diseases. On the other hand, the molecular components of the circadian clock circuitry and AHR signaling pathway may represent useful tools for preventive interventions and valuable targets of therapeutic approaches. 23589193 Dalfampridine in patients with downbeat nystagmus-an observational study. We investigated the effects of dalfampridine, the sustained-release form of 4-aminopyridine, on slow phase velocity (SPV) and visual acuity (VA) in patients with downbeat nystagmus (DBN) and the side effects of the drug. In this proof-of-principle observational study, ten patients received dalfampridine 10 mg bid for 2 weeks. Recordings were conducted at baseline, 180 min after first administration, after 2 weeks of treatment and after 4 weeks of wash-out. Mean SPV decreased from a baseline of 2.12 deg/s ± 1.72 (mean ± SD) to 0.51 deg/s ± 1.00 180 min after first administration of dalfampridine 10 mg and to 0.89 deg/s ± 0.75 after 2 weeks of treatment with dalfampridine (p < 0.05; post hoc both: p < 0.05). After a wash-out period of 1 week, mean SPV increased to 2.30 deg/s ± 1.6 (p < 0.05; post hoc both: p < 0.05). The VA significantly improved during treatment with dalfampridine. Also, 50 % of patients did not report any side effects. The most common reported side effects were abdominal discomfort and dizziness. Dalfampridine is an effective treatment for DBN in terms of SPV. It was well-tolerated in all patients. 23886490 Improving hydrolysis of food waste in a leach bed reactor. This paper examines the rate of degradation of food waste in a leach bed reactor (LBR) under four different operating conditions. The effects of leachate recirculation at a low and high flow rate are examined with and without connection to an upflow anaerobic sludge blanket (UASB). Two dilution rates of the effective volume of the leach bed reactors were investigated: 1 and 6 dilutions per LBR per day. The increase in dilution rate from 1 to 6 improved the destruction of volatile solids without connection to the UASB. However connection to the UASB greatly improved the destruction of volatile solids (by almost 60%) at the low recirculation rate of 1 dilution per day. The increase in volatile solids destruction with connection to the UASB was attributed to an increase in leachate pH and buffering capacity provided by recirculated effluent from the UASB to the leach beds. The destruction of volatile solids for both the low and high dilution rates was similar with connection to the UASB, giving 82% and 88% volatile solids destruction respectively. This suggests that the most efficient leaching condition is 1 dilution per day with connection to the UASB. 23397053 The atypical antipsychotic risperidone reverses the recognition memory deficits induced by post-weaning social isolation in rats. RATIONALE: Rearing rats in isolation from weaning is an established preclinical neurodevelopmental model which induces behavioural deficits with apparent translational relevance to some core symptoms of schizophrenia. OBJECTIVE: This study evaluated the ability of the atypical antipsychotic risperidone to reverse behavioural deficits induced by post-weaning social isolation of rat pups and to further characterise the predictive validity of this model. METHOD: Forty-five male Lister hooded rats were housed in groups of 3-4 (n = 16) or singly (n = 29) for 4 weeks immediately after weaning on postnatal day (PND) 22-24. On PND 51, novel cage-induced locomotor activity (LMA) was assessed to subdivide rats into groups balanced for behavioural response. On PNDs 58, 59, 65 and 72, rats received either vehicle (1 ml/kg; i.p.) or risperidone (0.2 or 0.5 mg/kg; i.p.) 30 min prior to testing in LMA, novel object discrimination (NOD), prepulse inhibition (PPI) of acoustic startle and conditioned emotional response (CER) learning paradigms, respectively. RESULTS: Isolation rearing had no effect on PPI, but produced LMA hyperactivity and impaired NOD and CER compared to group-housed controls. Risperidone caused a dose-dependent reduction in LMA, irrespective of rearing condition, but selectively reversed the NOD deficit in isolation-reared rats. Risperidone did not reverse the isolation rearing-induced CER deficit. CONCLUSIONS: Similar to its clinical profile, risperidone only partially reverses the schizophrenic symptomology; since it reversed some, but not all, of the learning and memory deficits induced by post-weaning isolation, the isolation rearing model may be useful to predict antipsychotic activity of novel therapeutic agents. 23820559 Oxidized glutathione fermentation using Saccharomyces cerevisiae engineered for glutathione metabolism. Glutathione is a valuable tripeptide that is widely used in the pharmaceutical, food, and cosmetic industries. Intracellular glutathione exists in two forms, reduced glutathione (GSH) and oxidized glutathione (GSSG). Most of the glutathione produced by fermentation using yeast is in the GSH form because intracellular GSH concentration is higher than GSSG concentration. However, the stability of GSSG is higher than GSH, which makes GSSG more advantageous for industrial production and storage after extraction. In this study, an oxidized glutathione fermentation method using Saccharomyces cerevisiae was developed by following three metabolic engineering steps. First, over-expression of the glutathione peroxidase 3 (GPX3) gene increased the GSSG content better than over-expression of other identified peroxidase (GPX1 or GPX2) genes. Second, the increase in GSSG brought about by GPX3 over-expression was enhanced by the over-expression of the GSH1/GSH2 genes because of an increase in the total glutathione (GSH + GSSG) content. Finally, after deleting the glutathione reductase (GLR1) gene, the resulting GPX3/GSH1/GSH2 over-expressing ΔGLR1 strain yielded 7.3-fold more GSSG compared with the parental strain without a decrease in cell growth. Furthermore, use of this strain also resulted in an enhancement of up to 1.6-fold of the total glutathione content compared with the GSH1/GSH2 over-expressing strain. These results indicate that the increase in the oxidized glutathione content helps to improve the stability and total productivity of glutathione. 23688450 Ultrasound-assisted formation of the canthaxanthin emulsions stabilized by arabic and xanthan gums. There is interest in incorporating canthaxanthin (CTX) into food emulsions due to its high potential health benefits. The used CTX in this study was produced by the bacterium of Dietzia natronolimnaea HS-1. Then, the influence of main emulsion components (gum arabic (GA), xanthan gum (XG) and coconut oil (CO)) on the surface-weighted mean diameter (D32), polydispersity index (PDI), specific surface area (SSA) of droplets and density of the emulsions containing CTX was optimized using response surface methodology (RSM). Polynomial equations between the responses and independent variables were derived. The linear effect of GA had a significant (p<0.0001) term in all reduced models. The optimal formulation for emulsions was composed of GA content of 9.85% (w/w), XG content of 0.13% (w/w) and CO concentration of 3.50% (w/w). This optimum formulation yielded D32 of 0.752 μm, PDI of 1.533, SSA of 9.995 m(2)/ml and density of 1.0357 g/cm(3). 23734789 Graphene Oxide Induces Toll-like Receptor 4 (TLR4)-Dependent Necrosis in Macrophages. Graphene and graphene-based nanomaterials display novel and beneficial chemical, electrical, mechanical, and optical characteristics, which endow these nanomaterials with promising applications in a wide spectrum of areas such as electronics and biomedicine. However, its toxicity on health remains unknown and is of great concern. In the present study, we demonstrated that graphene oxide (GO) induced necrotic cell death to macrophages. This toxicity is mediated by activation of toll-like receptor 4 (TLR4) signaling and subsequently in part via autocrine TNF-α production. Inhibition of TLR4 signaling with a selective inhibitor prevented cell death nearly completely. Furthermore, TLR4-deficient bone marrow-derived macrophages were resistant to GO-triggered necrosis. Similarly, GO did not induce necrosis of HEK293T/TLR4-null cells. Macrophagic cell death upon GO treatment was partially attributed to RIP1-RIP3 complex-mediated programmed necrosis downstream of TNF-α induction. Additionally, upon uptake into macrophages, GO accumulated primarily in cytoplasm causing dramatic morphologic alterations and a significant reduction of the macrophagic ability in phagocytosis. However, macrophagic uptake of GO may not be required for induction of necrosis. GO exposure also caused a large increase of intracellular reactive oxygen species (ROS), which contributed to the cause of cell death. The combined data reveal that interaction of GO with TLR4 is the predominant molecular mechanism underlying GO-induced macrophagic necrosis; also, cytoskeletal damage and oxidative stress contribute to decreased viability and function of macrophages upon GO treatment. 23747171 Reliability of the hospital nutrition environment scan for cafeterias, vending machines, and gift shops. According to ecological models, the physical environment plays a major role in determining individual health behaviors. As such, researchers have started targeting the consumer nutrition environment of large-scale foodservice operations when implementing obesity-prevention programs. In 2010, the American Hospital Association released a call-to-action encouraging health care facilities to join in this movement and improve their facilities' consumer nutrition environments. The Hospital Nutrition Environment Scan (HNES) for Cafeterias, Vending Machines, and Gift Shops was developed in 2011, and the present study evaluated the inter-rater reliability of this instrument. Two trained raters visited 39 hospitals in southern California and completed the HNES. Percent agreement, kappa statistics, and intraclass correlation coefficients were calculated. Percent agreement between raters ranged from 74.4% to 100% and kappa statistics ranged from 0.458 to 1.0. The intraclass correlation coefficient for the overall nutrition composite scores was 0.961. Given these results, the HNES demonstrated acceptable reliability metrics and can now be disseminated to assess the current state of hospital consumer nutrition environments. 23818204 Effect of serum containing Jinmaitong Capsule on rats' Schwann cell apoptosis induced by high glucose concentration. To evaluate the effect of serum containing Jinmaitong Capsule (JMT) on apoptosis of Schwann cells (SCs) that are cultured in high glucose at the cellular and molecular levels. SCs were cultured in Dulbecco's modified Eagle's medium (control group), high glucose (50 mmol/L) medium supplemented with 20% rat serum (HG group), and 50 mmol/L glucose medium supplemented with serum containing JMT (JMT group). SC apoptosis was detected using a terminal deoxynucleotidyl transferase dUTP nick end labeling kit. The expression of Bcl-2 and the caspase-3 p20 subunit in SCs were detected by realtime fluorogenic quantitative polymerase chain reaction and confocal laser scanning microscopy, respectively. No apoptosis was detected in SCs that were cultured in the control group. The percentage of apoptosis of SCs cultured in the HG group was much higher than that in the control group. The apoptosis of SCs in the JMT group was lower than that in the HG group. Fluorescence intensity of Bcl-2 and the expression of Bcl-2 mRNA in SCs that were cultured in the HG group were much lower than those in the control group and much higher than those in the JMT group (P<0.01). The fluorescence intensity of caspase-3 p20 and the expression of caspase-3 p20 mRNA in SCs that were cultured in the HG group were much higher than those in the control group (P<0.01), and they were remarkably lower in the JMT group (P<0.01). JMT effectively prevents SC apoptosis that is induced by high glucose. This effect may be because of increased expression of Bcl-2 mRNA and protein and decreased expression of caspase-3 p20 mRNA and protein. 23900893 Lifetime prevalence of posttraumatic stress disorder in two american Indian reservation populations. Posttraumatic stress disorder (PTSD) has been found to be more common among American Indian populations than among other Americans. A complex diagnosis, the assessment methods for PTSD have varied across epidemiological studies, especially in terms of the trauma criteria. Here, we examined data from the American Indian Service Utilization, Psychiatric Epidemiology, Risk and Protective Factors Project (AI-SUPERPFP) to estimate the lifetime prevalence of PTSD in two culturally distinct American Indian reservation communities, using two formulas for calculating PTSD prevalence. The AI-SUPERPFP was a cross-sectional probability sample survey conducted between 1997 and 2000. Southwest (n = 1,446) and Northern Plains (n = 1,638) tribal members living on or near their reservations, aged 15-57 years at time of interview, were randomly sampled from tribal rolls. PTSD estimates were derived based on both the single worst and 3 worst traumas. Prevalence estimates varied by ascertainment method: single worst trauma (lifetime: 5.9% to 14.8%) versus 3 worst traumas (lifetime, 8.9% to 19.5%). Use of the 3-worst-event approach increased prevalence by 28.3% over the single-event method. PTSD was prevalent in these tribal communities. These results also serve to underscore the need to better understand the implications for PTSD prevalence with the current focus on a single worst event. 23609230 Expression of cellulase genes in Saccharomyces cerevisiae via δ-integration subject to auxotrophic markers. δ-Integration can improve the expression stability and increase the copy number of exogenous genes in Saccharomyces cerevisiae. Generally, δ-integration vectors employ auxotrophic markers, such as LEU2-d, HIS3, TRP1, and URA3, to screen transformants. In this study, two cellulase genes (β-glucosidase and endoglucanase) were integrated into the S. cerevisiae W303-1A chromosome as reporters, by δ-integration with the aforementioned auxotrophic markers. Eight strains, L-BGL, H-BGL, T-BGL, U-BGL, L-EG, H-EG, T-EG, and U-EG, were selected and tested. After 5 days growth, cellulase activities (U ml(-1)) were 3, 2.3, 1.8, 1.5, 29, 12, 8, and 1.5, respectively. The results showed that auxotrophic markers influenced the expression of cellulase genes. 23833298 Regulation of cell proliferation and migration by keratin19-induced nuclear import of early growth response-1 in breast cancer cells. Keratin19 (KRT19) is the smallest known type I intermediate filament and is used as a marker for reverse transcriptase PCR-mediated detection of disseminated tumors. In this study, we investigated the functional analysis of KRT19 in human breast cancer. Using a short hairpin RNA system, we silenced KRT19 in breast cancer cells. KRT19 silencing was verified by Western blot analysis and immunocytochemistry. We further examined the effect of KRT19 silencing on breast cancer cells by cell proliferation, migration, invasion, colony formation assay, cell-cycle analysis, immunocytochemistry, immunohistochemistry, and mouse xenograft assay. Silencing of KRT19 resulted in increased cell proliferation, migration, invasion, and survival. These effects were mediated by upregulation of Akt signaling as a result of reduced PTEN mRNA expression. Silencing of KRT19 decreased the nuclear import of early growth response-1 (Egr1), a transcriptional factor for PTEN transcription, through reduced association between Egr1 and importin-7. We also confirmed that silencing of KRT19 increased tumor formation in a xenograft model. KRT19 is a potential tumor suppressor that negatively regulates Akt signaling through modulation of Egr1 nuclear localization. Clin Cancer Res; 19(16); 4335-46. ©2013 AACR. 23932986 Properties of Litopenaeus vannamei Dscam (LvDscam) isoforms related to specific pathogen recognition. Arthropod Down syndrome cell adhesion molecules (Dscam) may sometimes function as hypervariable pathogen recognition receptors. They consist of an extracellular region and a cytoplasmic tail, both of which are highly variable. In shrimp, tail-less Dscam proteins (Dscams) have recently been identified, and these appear to be unlike other arthropod extracellular Dscams that are released from the cell membrane by proteolytic cleavage. Here we investigate the properties of these unique shrimp proteins and show that they can be directly secreted from transfected cells. We also investigate the diverse cytoplasmic tail variants of membrane-bound shrimp Dscams, and show that elements E1A and E3 seem to be related to Dscam immune function. Challenge with Vibrio harveyi not only enhanced total Dscam and the immune-related cytoplasmic tail variants, but also induced expression of certain Ig2 + Ig3 combinations. A pathogen binding assay with these Ig2 + Ig3 extracellular variants showed that both the V. harveyi-induced Dscams and Dscams induced by buffer injection could be either pathogen-specific or specific only for Gram-negative pathogens, while other "general" Dscam variants were sensitive to a wide range of pathogens. The same assay also suggested that shrimp Dscam isoforms show a stronger response to the host's natural pathogens. 21735321 Religiosity and sexual involvement within adolescent romantic couples. The impact of religiosity in adolescent romantic partnerships on sexual behavior was assessed. Data were obtained from the National Longitudinal Study of Adolescent Health reciprocated couples database using religious- and relationship-oriented variables to predict sexual involvement in 374 couples (748 participants). We found that individual- and couple-based religiosity impacted sexual behavior. These findings provide evidence for dyad religiosity as a component involved in the expression of sexual behavior in romantic relationships. The current results highlight the importance of incorporating a broad social perspective in order to understand the expression of adolescent sexual behavior. 22820932 Altered gene expression involved in insulin signaling pathway in type II diabetic osteoporosis rats model. It is well established that both estrogen loss and type II diabetes mellitus (DMII) can impair bone metabolism, but whether estrogen loss exacerbates the effects of DMII is unclear. Therefore, we determined if ovariectomy (OVX) of rats on a long-term high-fat/sugar diet and injection of a low dose of streptozotocin (DMII) decreased bone mineral density (BMD) more than OVX or DMII alone. Bone insulin signaling is known to support bone metabolism; therefore, we also tested the hypothesis that OVX DMII rats (DOVX) would exhibit greater reductions in the expression of proteins important in insulin signaling, including IRS-1, IRS-2, and IGF-1. As hypothesized, BMD and plasma estrogen levels were decreased more in DOVX rats than in rats following OVX (NOVX) or DMII (DS) alone. IGF-1 expression was decreased in the liver, kidney, skeletal muscle, and bone of DOVX, DS, and NOVX rats; however, the decrease was larger and occurred sooner in DOVX rats. While IRS-1 and IRS-2 decreased in most groups in all tissues examined, the expression patterns differed in both a group- and tissue-dependent fashion. In conclusion, these data demonstrate that estrogen loss and DMII induced by a high-fat/sugar diet interact to produce osteoporosis and support the hypothesis that the bone loss may be mediated at least in part by concurrent decreases in the insulin signaling proteins in bone. 23922492 Microglial ramification and redistribution concomitant with the attenuation of choroidal neovascularization by neuroprotectin D1. Neuroprotectin D1 (NPD1) attenuates laser-induced choroidal neovascularization (CNV) when administered intraperitoneally. Due to its lipophilicity and low molecular weight, NPD1 is well suited for topical delivery; thus, we investigated the efficacy of topically applied NPD1 in attenuating CNV. We also examined the effect of NPD1 on the recruitment and activation of microglia surrounding CNV lesions. Mice were given laser-induced CNV and treated with NPD1 eye drops. CNV was evaluated by fluorescein leakage using a novel image analysis method and by isolectin B4 immunofluorescence of neovasculature. Microglia; recruitment was assessed by quantification. Using form factor, solidity, convexity, and fractal dimension, microglial activation was quantitatively assessed by two-dimensional, and for the first time, three-dimensional morphology. An ImageJ plugin, 3D Shape, was developed to enable this analysis. NPD1 attenuated leakage and neovascularization. The proximity of microglia to CNV lesions was significantly closer with NPD1. Consistent with the cellular ramification, microglia in NPD1-treated eyes were larger and exhibited a lower form factor and higher fractal dimension. Our data show that NPD1 signaling induces a ramified, non-injury-inducing microglial phenotype coincident with attenuation of CNV. Since microglia are crucial participants in neurodegenerative diseases, the discovery that microglia are potential targets of NPD1 signaling warrants further investigation. 23535156 Impairment of regulatory T cells in myasthenia gravis: studies in an experimental model. Myasthenia gravis (MG) is an antibody mediated, T cell dependent autoimmune disease characterized by muscle fatigability in which autoantibodies directed to the acetylcholine receptor (AChR) impair neuromuscular transmission. The identification of CD4⁺CD25⁺Foxp3⁺Treg cells as important regulators of tolerance opened a major area of investigation raising the possibility that a dysfunction in the Treg compartment is involved in the etiology and pathogenesis of autoimmune diseases, including MG. In this paper we summarize shortly Treg abnormalities that were reported in MG patients and report on our studies of Treg in experimental autoimmune MG (EAMG). Hopefully these studies would pave the way towards the development of novel Treg-based treatment modalities that will restore self-tolerance in MG and other autoimmune diseases. In our previous studies in EAMG we have shown that Treg cells transferred from healthy rat donors to myasthenic rats suppress EAMG. However, Treg cells from sick animals do not have the same in vivo suppressive activity as those from healthy donors. The objective of the present study was to further characterize quantitative and qualitative alterations in Treg cells of rats with EAMG. We found that the frequency of CD4⁺CD25⁺Foxp3⁺Treg cells within the spleen and PBL was decreased in EAMG rats as compared to naïve and CFA-immunized healthy controls. Treg cells from myasthenic rats were less effective than Treg cells from controls in suppressing the proliferation of CD4⁺T effector cells in response to ConA and of B cells in response to LPS. Moreover, CD4⁺CD25⁺ cells from EAMG rats exhibited an elevated extent of apoptosis and expressed upregulated levels of FAS and of Th17-associated cytokines. Since EAMG is an induced disease, these quantitative and qualitative alterations in Treg cells do not reflect predisposing impairments and seem to be associated with the specific autoimmune response resulting from AChR immunization. 23948996 Locomotor Velocity and Striatal Adaptive Gene Expression Changes of the Direct and Indirect Pathways in Parkinsonian Rats. Background: In Parkinson's disease (PD), bradykinesia, or slowness of movement, only appears after a large striatal dopamine depletion. Compensatory mechanisms probably play a role in this delayed appearance of symptoms. Objective: Our hypothesis is that the striatal direct and indirect pathways participate in these compensatory mechanisms. Methods: We used the unilateral 6-hydroxydopamine (6-OHDA) rat model of PD and control animals. Four weeks after the lesion, the spontaneous locomotor activity of the rats was measured and then the animals were killed and their brain extracted. We analyzed the mRNA expression of markers of the striatal direct and indirect pathways as well as the nigral expression of dopamine transporter (DAT) and tyrosine hydroxylase (TH) mRNA. We also carried out an immunohistochemistry for the striatal TH protein expression. Results: As expected, the unilateral 6-OHDA rats presented a tendency to an ipsilateral head turning and a low locomotor velocity. In 6-OHDA rats only, we observed a significant and positive correlation between locomotor velocity and both D1-class dopamine receptor (D1R) (direct pathway) and enkephalin (ENK) (indirect pathway) mRNA in the lesioned striatum, as well as between D1R and ENK mRNA. Conclusions: Our results demonstrate a strong relationship between both direct and indirect pathways and spontaneous locomotor activity in the parkinsonian rat model. We suggest a synergy between both pathways which could play a role in compensatory mechanisms and may contribute to the delayed appearance of bradykinesia in PD. 23122062 Mapping of Saccharomyces cerevisiae metabolites in fermenting wheat straight-dough reveals succinic acid as pH-determining factor. Fermenting yeast does not merely cause dough leavening, but also contributes to the bread aroma and might alter dough rheology. Here, the yeast carbon metabolism was mapped during bread straight-dough fermentation. The concentration of most metabolites changed quasi linearly as a function of fermentation time. Ethanol and carbon dioxide concentrations reached up to 60 mmol/100g flour. Interestingly, high levels of glycerol (up to 10 mmol/100g flour) and succinic acid (up to 1.6 mmol/100g flour) were produced during dough fermentation. Further tests showed that, contrary to current belief, the pH decrease in fermenting dough is primarily caused by the production of succinic acid by the yeast instead of carbon dioxide dissolution or bacterial organic acids. Together, our results provide a comprehensive overview of metabolite production during dough fermentation and yield insight into the importance of some of these metabolites for dough properties. 23831091 Carbon footprint of Canadian dairy products: Calculations and issues. The Canadian dairy sector is a major industry with about 1 million cows. This industry emits about 20% of the total greenhouse gas (GHG) emissions from the main livestock sectors (beef, dairy, swine, and poultry). In 2006, the Canadian dairy herd produced about 7.7Mt of raw milk, resulting in about 4.4Mt of dairy products (notably 64% fluid milk and 12% cheese). An integrated cradle-to-gate model (field to processing plant) has been developed to estimate the carbon footprint (CF) of 11 Canadian dairy products. The on-farm part of the model is the Unified Livestock Industry and Crop Emissions Estimation System (ULICEES). It considers all GHG emissions associated with livestock production but, for this study, it was run for the dairy sector specifically. Off-farm GHG emissions were estimated using the Canadian Food Carbon Footprint calculator, (cafoo)(2)-milk. It considers GHG emissions from the farm gate to the exit gate of the processing plants. The CF of the raw milk has been found lower in western provinces [0.93kg of CO2 equivalents (CO2e)/L of milk] than in eastern provinces (1.12kg of CO2e/L of milk) because of differences in climate conditions and dairy herd management. Most of the CF estimates of dairy products ranged between 1 and 3kg of CO2e/kg of product. Three products were, however, significantly higher: cheese (5.3kg of CO2e/kg), butter (7.3kg of CO2e/kg), and milk powder (10.1kg of CO2e/kg). The CF results depend on the milk volume needed, the co-product allocation process (based on milk solids content), and the amount of energy used to manufacture each product. The GHG emissions per kilogram of protein ranged from 13 to 40kg of CO2e. Two products had higher values: cream and sour cream, at 83 and 78kg of CO2e/kg, respectively. Finally, the highest CF value was for butter, at about 730kg of CO2e/kg. This extremely high value is due to the fact that the intensity indicator per kilogram of product is high and that butter is almost exclusively fat. Protein content is often used to compare the CF of products; however, this study demonstrates that the use of a common food component is not suitable as a comparison unit in some cases. Functionality has to be considered too, but it might be insufficient for food product labeling because different reporting units (adapted to a specific food product) will be used, and the resulting confusion could lead consumers to lose confidence in such labeling. Therefore, simple units might not be ideal and a more comprehensive approach will likely have to be developed. 23967167 Novel three-step pseudo-absence selection technique for improved species distribution modelling. Pseudo-absence selection for spatial distribution models (SDMs) is the subject of ongoing investigation. Numerous techniques continue to be developed, and reports of their effectiveness vary. Because the quality of presence and absence data is key for acceptable accuracy of correlative SDM predictions, determining an appropriate method to characterise pseudo-absences for SDM's is vital. The main methods that are currently used to generate pseudo-absence points are: 1) randomly generated pseudo-absence locations from background data; 2) pseudo-absence locations generated within a delimited geographical distance from recorded presence points; and 3) pseudo-absence locations selected in areas that are environmentally dissimilar from presence points. There is a need for a method that considers both geographical extent and environmental requirements to produce pseudo-absence points that are spatially and ecologically balanced. We use a novel three-step approach that satisfies both spatial and ecological reasons why the target species is likely to find a particular geo-location unsuitable. Step 1 comprises establishing a geographical extent around species presence points from which pseudo-absence points are selected based on analyses of environmental variable importance at different distances. This step gives an ecologically meaningful explanation to the spatial range of background data, as opposed to using an arbitrary radius. Step 2 determines locations that are environmentally dissimilar to the presence points within the distance specified in step one. Step 3 performs K-means clustering to reduce the number of potential pseudo-absences to the desired set by taking the centroids of clusters in the most environmentally dissimilar class identified in step 2. By considering spatial, ecological and environmental aspects, the three-step method identifies appropriate pseudo-absence points for correlative SDMs. We illustrate this method by predicting the New Zealand potential distribution of the Asian tiger mosquito (Aedes albopictus) and the Western corn rootworm (Diabrotica virgifera virgifera). 23344693 A donor-acceptor type organic dye connected with a quinoidal thiophene for dye-sensitized solar cells. A donor-acceptor type organic dye connected with a quinoidal thiophene as a π-conjugated chain, cyano-[5'-(4''-(N,N-dimethylamino)benzylidene)-5H-thiophen-2'-ylidene]acetic acid, was synthesized and applied to dye-sensitized solar cells (DSSCs). The absorption band of this quinoidal thiophene dye appeared at longer wavelengths than those of dyes with similar π-conjugation length, indicating the effective π-conjugation through the quinoidal structure. Although the excited state of the quinoidal thiophene dye is deactivated within several picoseconds even in solution, the DSSCs using the quinoidal thiophene dye showed incident photon to current conversion efficiency (IPCE) values of more than 90%, demonstrating the fast and efficient electron injection from the excited dye to TiO(2). By optimizing the fabrication conditions, the DSSC using this dye afforded a photoelectric conversion efficiency of 5.2%, without enlarging the molecular size. 23894055 Toughening Thin-Film Structures with Ceramic-Like Amorphous Silicon Carbide Films. A significant improvement of adhesion in thin-film structures is demonstrated using embedded ceramic-like amorphous silicon carbide films (a-SiC:H films). a-SiC:H films exhibit plasticity at the nanoscale and outstanding chemical and thermal stability unlike most materials. The multi-functionality and the ease of processing of the films have potential to offer a new toughening strategy for reliability of nanoscale device structures. 23861043 Effects of different influent C/N ratios on the performance of various earthworm eco-filter systems: nutrient removal and greenhouse gas emission. In this study, we sought to identify influent carbon-to-nitrogen (C/N) ratios that yield relatively high nutrient removal efficiency with relatively low greenhouse gas (GHG) emissions. The earthworm eco-filter (EE) system, which is composed of earthworms and plants (EP group), was found to be optimal for maximizing nutrient removal while reducing GHG emissions. In this EE system, the optimal influent C/N ratio for nutrient removal and GHG emission under C2N treatment conditions. Nutrient removal efficiency under this condition was 85.19 ± 6.40 % chemical oxygen demand, 71.99 ± 11.28 % total nitrogen, and 77.91 ± 8.51 % total phosphorus, while the CO2 emission rate was 678.89 ± 201.87 mg m(-2) h(-1). Moreover, the highest nutrient removal and GHG emission rates were both achieved in late summer (August). Thus, carbon variation, season, system variation, as well as synergistic interaction between system variations and seasons, significantly affect nutrient removal efficiencies and GHG emissions. 23527573 Identification of the first synthetic inhibitors of the type II transmembrane serine protease TMPRSS2 suitable for inhibition of influenza virus activation. TMPRSS2 is a multidomain type II transmembrane serine protease that cleaves the surface glycoprotein hemagglutinin (HA) of influenza viruses with monobasic cleavage site, which is a prerequisite for virus fusion and propagation. Furthermore, it activates the fusion protein F of the human metapneumovirus and the spike protein S of the SARS coronavirus. Increased TMPRSS2 expression was also described in several tumor entities. Therefore, TMPRSS2 emerged as a potential target for drug design. The catalytic domain of TMPRSS2 was expressed in E. coli and used for an inhibitor screen with previously synthesized inhibitors of various trypsin-like serine proteases. Two inhibitor types were identified, which inhibit TMPRSS2 in the nanomolar range. The first series comprises substrate analogue inhibitors containing a 4-amidinobenzylamide moiety in P1 position, whereby some of these analogues possess inhibition constants around 20 nM. An improved potency was found for second type derived from sulfonylated 3-amindinophenylalanylamide derivates. The most potent derivative of this series inhibits TMPRSS2 with a Ki value of 0.9 nM and showed an efficient blockage of influenza virus propagation in human airway epithelial cells. Based on the inhibitor studies a series of new fluorogenic substrates containing a d-arginine residue in P3 position was synthesized, some of them were efficiently cleaved by TMPRSS2. 23017391 Stability of bioactive polyphenols from honey during different extraction methods. The LC-MS/MS technique was applied to the stability study of several flavonoids and phenolic acids in honey samples during the ultrasonic extraction (USE) and microwave-assisted extraction (MAE). Phenolic compounds from the standard mixture were stable under ultrasounds action with the mean recovery of (90.4%±7.1%), but during microwave-assisted extraction the benzoic acid derivatives and aglycones of flavonoids showed lower recovery (70-80%). In honey matrix, the phenolic acids and the glycosides exhibited the high stability for MAE and USE treatments. However, the recoveries of tested aglycones were below 10%. In the presence of an artificial sugar matrix, flavonols were almost completely degraded after successive treatment under MAE and USE conditions. The obtained results indicated that standard addition method for flavonoids quantification in honey samples should not be recommended. Application of the USE conditions provided higher and/or similar extraction yields for phenolic acids than usually applied shaking with solvent. It also allowed shortening the time required for the whole sample preparation procedure. Phenolic acids and glycosides such as quercetrin, rutin and hesperidin appeared to be stable under such conditions. 23894109 Are synthetic scaffolds suitable for the development of clinical tissue-engineered tubular organs? Transplantation of tissues and organs is currently the only available treatment for patients with end-stage diseases. However, its feasibility is limited by the chronic shortage of suitable donors, the need for life-long immunosuppression, and by socioeconomical and religious concerns. Recently, tissue engineering has garnered interest as a means to generate cell-seeded three-dimensional scaffolds that could replace diseased organs without requiring immunosuppression. Using a regenerative approach, scaffolds made by synthetic, nonimmunogenic, and biocompatible materials have been developed and successfully clinically implanted. This strategy, based on a viable and ready-to-use bioengineered scaffold, able to promote novel tissue formation, favoring cell adhesion and proliferation, could become a reliable alternative to allotransplatation in the next future. In this article, tissue-engineered synthetic substitutes for tubular organs (such as trachea, esophagus, bile ducts, and bowel) are reviewed, including a discussion on their morphological and functional properties. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013. 23295222 The mechanism of discrimination between oxidized and reduced coenzyme in the aldehyde dehydrogenase domain of Aldh1l1. Aldh1l1, also known as 10-formyltetrahydrofolate dehydrogenase (FDH), contains the carboxy-terminal domain (Ct-FDH), which is a structural and functional homolog of aldehyde dehydrogenases (ALDHs). This domain is capable of catalyzing the NADP(+)-dependent oxidation of short chain aldehydes to their corresponding acids, and similar to most ALDHs it has two conserved catalytic residues, Cys707 and Glu673. Previously, we demonstrated that in the Ct-FDH mechanism these residues define the conformation of the bound coenzyme and the affinity of its interaction with the protein. Specifically, the replacement of Cys707 with an alanine resulted in the enzyme lacking the ability to differentiate between the oxidized and reduced coenzyme. We suggested that this was due to the loss of a covalent bond between the cysteine and the C4N atom of nicotinamide ring of NADP(+) formed during Ct-FDH catalysis. To obtain further insight into the functional significance of the covalent bond between Cys707 and the coenzyme, and the overall role of the two catalytic residues in the coenzyme binding and positioning, we have now solved crystal structures of Ct-FDH in the complex with thio-NADP(+) and the complexes of the C707S mutant with NADP(+) and NADPH. This study has allowed us to trap the coenzyme in the contracted conformation, which provided a snapshot of the conformational processing of the coenzyme during the transition from oxidized to reduced form. Overall, the results of this study further support the previously proposed mechanism by which Cys707 helps to differentiate between the oxidized and reduced coenzyme during ALDH catalysis. 23317014 A pragmatic strategy for the review of clinical evidence. Systematic reviews (SR) of clinical evidence are rightfully considered the basis for developing recommendations to support decisions in current practice. To avoid bias, SRs are expected to be systematic in their research strategy and are exhaustive. The drawback of the latter criteria relies in the substantial work needed to conduct and keep SRs updated. The objective of this paper is to compare a research strategy based on the review of a selected number of core journals, which we consider a 'pragmatic review' (PR), with that derived by an SR in estimating the efficacy of treatments. Five clinical areas were considered for the comparison between the two strategies: chronic obstructive pulmonary disease, dermatology, heart failure, renal diseases and stroke. We extracted a systematic sample from all the Cochrane SRs pertaining to each area and were published before April 2010. Two groups of journals were considered in the PR: six general journals that commonly published research for the five clinical areas, and five specialist journals with the highest impact factor in each area. To assess the agreement in the findings of SRs and PRs, we considered both the direction of the estimates and P-values. A sample of 27 SRs included 171 overall analyses and 259 subgroup analyses related to primary outcomes. The PR captured one or more clinical trials in 24 of the 27 SRs (89%), and 118 of the 171 overall analyses (69%) were replicated. The PR supported the recommendations to use (or not) the study treatment in 11 of the 13 SRs (85%), which ended with a clinical recommendation. We verified in a sample of SRs that the conclusion of a research strategy based on a pre-defined set of general and specialist medical journals is able to replicate almost all the clinical recommendations of a formal SR. 23402840 Characterization of anti-crotalic antibodies. Crotalus durissus terrificus, C. d. collilineatus, C. d. cascavella and C. d. marajoensis are responsible minor but severe snake bites in Brazil. The venoms of these snakes share the presence of crotoxin, a neurotoxin comprising of two associated components, crotapotin and phospholipase A2 (PLA2). Treatment of the victims with specific antiserum is the unique effective therapeutic measure. The ability of anti-Crotalus antisera produced by the routine using crude venom to immunize horses or purified crotoxin and PLA2 as individual immunogens was compared. Antisera obtained from horses immunized with C. durissus terrificus crude venom were able to recognize and neutralize not only the toxins presents in C. durissus terrificus, but also the ones present in the venoms from C. d. collilineatus, C. d. cascavella and C. d. marajoensis. Antisera from horses immunized with individual crotoxin or PLA2, although in lesser titers, were also able of recognizing the toxins in all four Crotalus species and neutralize the lethality of the C. d. terrificus venom. 23875682 Total synthesis of the proposed structure of didemnaketal B. Total synthesis of the proposed structure of didemnaketal B has been accomplished. The C7-C21 spiroacetal domain was synthesized by exploiting our Suzuki-Miyaura coupling/spiroacetalization strategy. The C1-C7 acyclic domain was constructed via an Evans syn-aldol reaction and a vinylogous Mukaiyama aldol reaction. Finally, the C22-C28 side chain was introduced by means of a Nozaki-Hiyama-Kishi reaction. Comparison of the NMR spectroscopic data of our synthetic material with those of the authentic sample revealed that the proposed structure requires stereochemical reassignment. 23820815 Treatment of idiopathic membranous nephropathy. Immunosuppressive treatment of patients with idiopathic membranous nephropathy (iMN) is heavily debated. The controversy is mainly related to the toxicity of the therapy and the variable natural course of the disease-spontaneous remission occurs in 40-50% of patients. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis provides guidance for the treatment of iMN. The guideline suggests that immunosuppressive therapy should be restricted to patients with nephrotic syndrome and persistent proteinuria, deteriorating renal function or severe symptoms. Alkylating agents are the preferred therapy because of their proven efficacy in preventing end-stage renal disease. Calcineurin inhibitors can be used as an alternative although efficacy data on hard renal end points are limited. In this Review, we summarize the KDIGO guideline and address remaining areas of uncertainty. Better risk prediction is needed to identify patients who will benefit from immunosuppressive therapy, and the optimal timing and duration of this therapy is unknown because most of the randomized controlled trials were performed in low-risk or medium-risk patients. Alternative therapies, directed at B cells, are under study. The discovery of anti-M type phospholipase A2 receptor-antibodies is a major breakthrough and we envisage that in the near future, antibody-driven therapy will enable more individualized treatment of patients with iMN. 23809849 N- versus O-alkylation: Utilizing NMR methods to establish reliable primary structure determinations for drug discovery. A classic synthetic issue that remains unresolved is the reaction that involves the control of N- versus O-alkylation of ambident anions. This common chemical transformation is important for medicinal chemists, who require predictable and reliable protocols for the rapid synthesis of inhibitors. The uncertainty of whether the product(s) are N- and/or O-alkylated is common and can be costly if undetermined. Herein, we report an NMR-based strategy that focuses on distinguishing inhibitors and intermediates that are N- or O-alkylated. The NMR strategy involves three independent and complementary methods. However, any combination of two of the methods can be reliable if the third were compromised due to resonance overlap or other issues. The timely nature of these methods (HSQC/HMQC, HMBC. ROESY, and (13)C shift predictions) allows for contemporaneous determination of regioselective alkylation as needed during the optimization of synthetic routes. 23562533 Poly(N-isopropylacrylamide-co-hydroxyethylacrylamide) thermosensitive microspheres: The size of microgels dictates the pulsatile release mechanism. Poly(N-isopropylacrylamide-co-N-hydroxyethylacrylamide) (poly(NIPAAm-co-HEAAm)) was prepared as a new thermosensitive copolymer possessing a sharp phase transition around the human body temperature. The effect of the copolymer concentration on the lower critical solution temperature (LCST) was determined under physiological conditions by cloud point (CP) and differential scanning calorimetric (DSC) methods. Then, thermosensitive microspheres were prepared from preformed copolymers by chemical cross-linking of hydroxyl groups with glutaraldehyde at a temperature situated slightly below LCST of the copolymer solution. The volume phase transition temperature (VPTT) of corresponding cross-linked microspheres was determined from swelling degree-temperature curve. The microspheres were loaded with model drug indomethacin by the solvent evaporation method. The DSC analysis proved that the drug is molecularly dispersed in the polymer network. Finally, the influence of the microsphere size on drug release was investigated. It was established that microspheres with the diameter ranging between 5 and 60μm release the drug with almost the same rate below (in the swollen state) and above the VPTT (in the collapsed state). On the contrary, microspheres with the diameter ranging between 125 and 220μm release a significantly higher amount of indomethacin below than above the VPTT. This different behavior is enough to assure a pulsatile release mechanism when the temperature changes cyclically below and above the VPTT. However, both small and large microspheres release a large amount of the drug during the collapsing process. 23893749 Evaluation of the Use of a Tablet Computer with a High-Resolution Display for Interpreting Emergency CT Scans. Purpose: Evaluation of the potential usability of an iPad 3 with a high-resolution display in CT emergency diagnosis compared to a 3 D PACS workstation.Materials and Methods: 3 readers used a 5-point Likert scale to evaluate 40 CCT scans and 40 CTPA scans to determine the detectability of early signs of infarction in CCT or segmental and subsegmental pulmonary embolisms in CT angiography of the pulmonary arteries (CTPA) on the iPad 3 (Apple Inc., USA) using an application for image viewing (Visage Ease, Visage Imaging GmbH, Berlin) and on a 3 D PACS workstation (Visage 7.1, Visage Imaging, Berlin) using a certified monitor for image viewing. The results were compared using the Wilcoxon rank sum test, Spearman's correlation coefficient, and a kappa statistic.Results: There was no significant difference in the median evaluations for the readings of both the CCT scans and the CTPA scans on the iPad 3 and on the workstation (p > 0.05) for all three readers. The mean Spearman's correlation coefficient for CCT and CTPA was 0.46 (± 0.2) and 0.69 (± 0.16), respectively, for the comparison iPad/PACS, 0.41 (± 0.16) and 0.68 (± 0.06), respectively, for the interobserver agreement on the iPad, and 0.35 (± 0.05) and 0.68 (± 0.10), respectively, for the interobserver agreement on the PACS. Mean kappa values for CCT of 0.52 (± 0.17) for the comparison iPad/PACS and 0.33 (± 0.16) and 0.32 (± 0.16), respectively, for the interobserver agreement on the iPad and the PACS were achieved. For CTPA average kappa values of 0.67 (± 0.19) were calculated for the comparison iPad/PACS and 0.69 (± 0.08) and 0.60 (± 0.14), respectively, for the interobserver concordance on the iPad 3 and the PACS. All differences were not statistically significant (p > 0.05).Conclusion: The variability of the interpretation of typical emergency scans on an iPad 3 with a high-resolution display and on a 3 D PACS workstation does not differ from the interobserver variability.Key Points: Citation Format:Tewes S, Rodt T, Marquardt S et al. Evaluation of the Use of a Tablet Computer with a High-Resolution Display for Interpreting Emergency CT Scans. Fortschr Röntgenstr 2013; DOI: 10.1055/s-0033-1350155. 23872804 Do Children With Blount Disease Have Lower Body Mass Index After Lower Limb Realignment? Children with Blount disease are typically obese. The goal of our study was to assess whether children with Blount disease had lower body mass index (BMI) after surgical correction of their lower limb deformity. A surgical data base was used to identify children with Blount disease. Demographic information including age of disease onset, ethnicity, health insurance status, and laterality was noted. Preoperative and most recent BMI values were documented. Using full-length standing radiographs, the mechanical axis deviation (MAD) and leg length discrepancy (LLD) were measured preoperatively and at latest follow-up. The relationship of the change in BMI with various demographic and radiologic parameters was evaluated. Fifty-one children (32 males, 19 females) with Blount disease (23 early onset, 28 late onset) affecting 70 lower extremities (32 unilateral and 19 bilateral) underwent a variety of surgical procedures. All 47 children who underwent gradual correction with external fixation also underwent nutritional counseling while receiving inpatient rehabilitation. At an average follow-up of 48 months, MAD improved from 80.5 mm medial to 16.1 mm medial (P<0.0001) and LLD improved from 19.6 to 10.9 mm (P=0.0002). During the same time period, the BMI increased from 35 (95% confidence interval, 32-37) to 38 (95% confidence interval, 35-41; P=0.0006). Compared with their preoperative BMI, 76% of the children had an increase in their BMI at the latest follow-up. There was no association of the change in the patient's BMI with their age of disease onset, sex, ethnicity, health insurance status, final MAD, or LLD. There was a tendency for the patient's BMI to increase with longer follow-up (P=0.002). Using multivariate analysis, only the length of follow-up was associated with an increase in BMI (P=0.026). Despite improvement in limb alignment and LLD after surgery, the BMI of the majority of children with Blount disease increased over time. Other strategies for addressing obesity amongst these children are warranted. Level IV-case series. 23951275 Metabolic Characteristics and Response to High Altitude in Phrynocephalus erythrurus (Lacertilia: Agamidae), a Lizard Dwell at Altitudes Higher Than Any Other Living Lizards in the World. Metabolic response to high altitude remains poorly explored in reptiles. In the present study, the metabolic characteristics of Phrynocephaluserythrurus (Lacertilia: Agamidae), which inhabits high altitudes (4500 m) and Phrynocephalusprzewalskii (Lacertilia: Agamidae), which inhabits low altitudes, were analysed to explore the metabolic regulatory strategies for lizards living at high-altitude environments. The results indicated that the mitochondrial respiratory rates of P. erythrurus were significantly lower than those of P. przewalskii, and that proton leak accounts for 74~79% of state 4 and 7~8% of state3 in P. erythrurus vs. 43~48% of state 4 and 24~26% of state3 in P. przewalskii. Lactate dehydrogenase (LDH) activity in P. erythrurus was lower than in P. przewalskii, indicating that at high altitude the former does not, relatively, have a greater reliance on anaerobic metabolism. A higher activity related to β-hydroxyacyl coenzyme A dehydrogenase (HOAD) and the HOAD/citrate synthase (CS) ratio suggested there was a possible higher utilization of fat in P. erythrurus. The lower expression of PGC-1α and PPAR-γ in P. erythrurus suggested their expression was not influenced by cold and low PO2 at high altitude. These distinct characteristics of P. erythrurus are considered to be necessary strategies in metabolic regulation for living at high altitude and may effectively compensate for the negative influence of cold and low PO2. 23942549 Systemic administration of Follistatin288 increases muscle mass and reduces fat accumulation in mice. The present study describes the physiological response associated with daily subcutaneous injection of mice with recombinant follistatin288. This systemic administration of follistatin288 increases the follistatin levels in serum, indicating that the protein enters the circulation. The data suggest that a dose-dependent increase in body lean mass also occurs, together with an increase in muscle mass, possibly as a result of an increase in the size of the muscle fibers. After thirteen weeks of treatment, metabolic changes were observed; additionally, the switching of muscle fiber types was also apparent through myosin heavy chain remodeling, implying that changes are occurring at the molecular level. Furthermore, an increase in the muscle mass was associated with a significant decrease in the body fat mass. Overall, this study raises the possibility for the use of follistatin288 as an agent to treat muscle wasting diseases and/or to restrict fat accumulation by systemic administration of the protein. 23315949 UR-144 in products sold via the Internet: Identification of related compounds and characterization of pyrolysis products. The synthetic cannabinoid, UR-144 ((1-pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone), was identified in commercial 'legal high' products (herbal, resin, and powder). Along with this, six related compounds were detected. The most abundant one (2.1) was identified as 4-hydroxy-3,3,4-trimethyl-1-(1-pentyl-1H-indol-3-yl)pentan-1-one, a product of the electrophilic addition of water to the cyclopropane moiety in UR-144. Compound 2.1 was found to be undergo cyclisation which leads to the formation of two additional interconvertable compounds (2.3, tentatively identified as 1-pentyl-3-(4,4,5,5-tetramethyl-4,5-dihydrofuran-2-yl)-1H-indole which is stable only in absence of water and also observed as GC artifact) and 2.2, a protonated derivative of 2.3 which is formed in acidic solutions. The remaining compounds were identified as possible degradation products of the group 2 compounds (4,4,5,5-tetramethyldihydrofuran-2(3H)-one and 1-pentylindoline-2,3-dione) and intermediates or by-products from the synthesis of UR-144 ((1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone, 1-pentyl-1H-indole and 1-(1-pentyl-1H-indol-3-yl)hexan-1-one). Pyrolysis of herbal products containing the group 2 compounds or UR-144 resulted in the formation of 3,3,4-trimethyl-1-(1-pentyl-1H-indol-3-yl)pent-4-en-1-one (3). This was confirmed by separate pyrolysis of 2.1 and UR-144. Also, the two additional minor compounds, 1-(1-pentyl-1H-indol-3-yl)ethanone and 1-(1-pentyl-1H-indol-3-yl)propan-1-one, were detected. Pathways for these transformations are presented. Copyright © 2013 John Wiley & Sons, Ltd. 23828872 Chronic cerebrospinal venous insufficiency: masked multimodal imaging assessment. Chronic cerebrospinal venous insufficiency (CCSVI) was implicated in the pathophysiology of multiple sclerosis (MS). We evaluated neurosonography (NS), magnetic resonance venography (MRV), and transluminal venography (TLV) in subsets of MS patients drawn from a single-center, prospective, case-control study of 206 MS and 70 non-MS volunteers. As previously reported, findings on high-resolution B-mode NS imaging with color and spectral Doppler of the extracranial and intracranial venous drainage consistent with CCSVI were similar among MS and non-MS volunteers (3.88% vs 7.14%; p = 0.266). Ninety-nine MS participants consented to intravascular contrast-enhanced 3D MRV to assess their major systemic and intracranial venous circulation, and 40 advanced to TLV that included pressure measurements of the superior vena cava, internal jugular, brachiocephalic, and azygous veins. NS findings and MRV patterns were discrepant for 26/98 evaluable subjects, including four with abnormal findings on NS that had normal venous anatomy by MRV. In no instance were TLV pressure gradients indicative of clinically significant functional stenosis encountered. The three imaging approaches provided generally consistent data with discrepancies referable to inherent technique properties. Our findings lend no support for altered venous outflow dynamics as common among MS patients, nor do they likely contribute to the disease process. 23806364 Establishing catalytic activity on an artificial (βα)8-barrel protein designed from identical half-barrels. It has been postulated that the ubiquitous (βα)8-barrel enzyme fold has evolved by duplication and fusion of an ancestral (βα)4-half-barrel. We have previously reconstructed this process in the laboratory by fusing two copies of the C-terminal half-barrel HisF-C of imidazole glycerol phosphate synthase (HisF). The resulting construct HisF-CC was stepwise stabilized to Sym1 and Sym2, which are extremely robust but catalytically inert proteins. Here, we report on the generation of a circular permutant of Sym2 and the establishment of a sugar isomerization reaction on its scaffold. Our results demonstrate that duplication and mutagenesis of (βα)4-half-barrels can readily lead to a stable and catalytically active (βα)8-barrel enzyme. 23615573 Comparison of Chest Computed Tomography Features in the Acute Phase of Cardiogenic Pulmonary Edema and Acute Respiratory Distress Syndrome on Arrival at the Emergency Department. Discriminating cardiogenic pulmonary edema (CPE) from acute respiratory distress syndrome (ARDS) is a serious problem in emergency departments, and the ability of chest radiographs to differentiate between these 2 entities is limited. We compared the chest computed tomography (CT) findings in the acute phase of CPE with those of ARDS. Outpatients with acute respiratory failure presenting to emergency departments with bilateral pulmonary opacities were enrolled. The patients included not only those who visited our hospital first but also those referred from other hospitals. Two intensivists who were blinded to the results of the chest imaging studies reviewed the patients' clinical records independently in order to determine a diagnosis of CPE or ARDS, and the chest CT findings were independently evaluated by 2 radiologists who were unaware of the patients' clinical information. The positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy of the statistically different findings were calculated using standard definitions. Forty-one patients with CPE and 20 patients with ARDS were assessed. Upper-lobe-predominant ground-glass attenuation, central-predominant ground-glass attenuation, and central airspace consolidation were associated with high PPVs (95.2%, 92.3%, and 92.0%, respectively) and moderate NPVs (47.5%, 51.4%, and 50.0%, respectively) to diagnose as CPE. Left-dominant pleural effusion and small ill-defined opacities revealed relatively high PPVs (71.4% and 58.3%, respectively) and NPVs (72.2% and 73.5%, respectively) to diagnose as ARDS. The overall accuracy of the diagnosis by chest CT was 88.5% (54/61). Chest CT may be a useful tool for differentiating CPE from ARDS in the emergency department setting. 23912445 Actinopolyspora dayingensis sp. nov., a novel halophilic actinomycete isolated from a hypersaline lake. A novel halophilic, filamentous actinomycete, designated TRM 4064(T), was isolated from a hypersaline habitat in Sichuan Province, China. Phylogenetic analysis based on an almost-complete 16S rRNA gene sequence of strain TRM 4064(T) showed that it was most closely related to Actinopolyspora mortivallis (99.1 % sequence similarity). The sequence similarities between strain TRM 4064(T) and other Actinopolyspora species with validly-published names were <97.0 %. However, it had relatively low mean values for DNA-DNA relatedness with the A. mortivallis DSM 44261(T) (23.2 %). Optimal growth occurred at 37 °C, pH 7.0 and in the presence of 13 % (w/v) NaCl. The whole-cell sugar pattern consists of xylose, glucose, ribose and arabinose. The predominant menaquinones are MK-10(H4) (38.2 %), MK-9(H4) (25.1 %), MK-9(H2) (28.6 %) and MK-8(H4) (7.3 %). The major fatty acids are anteiso-C17:0 (36.9 %) and iso-C17:0 (19.3 %). The diagnostic phospholipids detected were diphosphatidylglycerol (DPG), phosphatidylglycerol (PG), phosphatidylcholine (PC), phosphatidylinositol (PI) and two unknown phospholipids. The G+C content of the genomic DNA of the type strain is 66.3 mol%. Strain TRM 4064(T) therefore represents a novel species of the genus Actinopolyspora, for which the name Actinopolyspora dayingensis sp. nov. is proposed. The type strain is TRM 4064(T) (= KCTC 19979(T) = CCTCC AA 2010010(T)). 23857584 FcγR Driven Release of IL-6 by Macrophages Requires NOX2-Dependent Production of Reactive Oxygen Species. Activation of the FcγR via antigen containing immune complexes can lead to the generation of reactive oxygen species which are potent signal transducing molecules. However, whether ROS contribute to FcγR signaling has not been studied extensively. We set out to elucidate the role of NADPH oxidase-generated ROS in macrophage activation following FcγR engagement using antigen containing immune complexes. We hypothesized that NOX2 generated ROS is necessary for propagation of downstream FcγR signaling and initiation of the innate immune response. Following exposure of murine bone marrow derived macrophages (BMDMs) to inactivated F. tularensis (iFt) containing immune complexes, we observed a significant increase in the innate inflammatory cytokine IL-6 at 24 hours compared to macrophages treated with Ft LVS-containing immune complexes. Ligation of the FcγR by opsonized Ft also results in significant ROS production. Macrophages lacking the gp91phox subunit of NOX2 fail to produce ROS upon FcγR ligation, resulting in decreased Akt phosphorylation and a reduction in the levels of IL-6 compared to wild type macrophages. Similar results were seen following infection of BMDMs with catalase deficient Ft that fail to scavenge hydrogen peroxide. In conclusion, our findings demonstrate that ROS participate in elicitation of an effective innate immune in response to antigen-containing immune complexes through FcγR. 23898012 Matching by Tone Mapping: Photometric Invariant Template Matching. A fast pattern matching scheme termed Matching by Tone Mapping (MTM) is introduced which allows matching under non-linear tone mappings. We show that, when tone mapping is approximated by a piecewise constant/linear function, a fast computational scheme is possible requiring computational time similar to the fast implementation of Normalized Cross Correlation (NCC). In fact, the MTM measure can be viewed as a generalization of the NCC for non-linear mappings and actually reduces to NCC when mappings are restricted to be linear. We empirically show that the MTM is highly discriminative and robust to noise with comparable performance capability to that of the well performing Mutual Information, but on par with NCC in terms of computation time. 23895107 Additive effect of sirolimus and anti-death receptor 5 agonistic antibody against hepatocellular carcinoma. Despite careful patient selection, hepatocellular carcinoma (HCC) recurs in 10-20% of cases after liver transplantation, and the use of potent adjuvant anticancer drugs would be welcome. The aim of this study was to evaluate the efficiency of a combined therapy of rapamycin (sirolimus) and anti-death receptor (DR)5 monoclonal antibody (mAb) on HCC. We first assessed the side effects of anti-DR5 mAb administration in vivo by giving various doses of anti-DR5 mAb. Cell proliferation assays were then performed using mouse Hepa1-6 cells or human Huh7 cells to quantify the relative cell viability under various concentrations of sirolimus, anti-DR5 mAb or a combination. Next, one million Hepa1-6 cells were transplanted into C.B17-SCID-beige mice subcutaneously, and four groups were created: (1) untreated, (2) anti-DR5 mAb alone, (3) sirolimus alone and (4) anti-DR5 mAb + sirolimus. Anti-DR5 mAb (200 and 300 Î¼g/day) induced liver dysfunction with partial necrosis of the liver, but 100 Î¼g/day was well tolerated with transaminitis, but normal bilirubin and only minor histological liver damage. In vitro, anti-DR5 mAb lysed Hepa1-6 and Huh7 cells in a dose-dependent manner, and combinations of sirolimus and anti-DR5 mAb demonstrated an additive effect. In vivo studies demonstrated that tumour sizes were significantly smaller in the combined therapy group than in the monotherapy groups. Combining sirolimus and low-dose anti-DR5 mAb has a significant effect against HCC. This strategy represents a potential novel approach for the management of HCC. 23474591 Hyposensitivity to gamma-aminobutyric Acid in the ventral tegmental area during alcohol withdrawal: reversal by histone deacetylase inhibitors. Putative dopaminergic (pDAergic) ventral tegmental area (VTA) neurons have an important role in alcohol addiction. Acute ethanol increases the activity of pDAergic neurons, and withdrawal from repeated ethanol administration produces a decreased sensitivity of pDAergic VTA neurons to GABA. Recent studies show that behavioral changes induced by chronic alcohol are reversed by inhibitors of histone deacetylases (HDACs). Whether HDAC-induced histone modifications regulate changes in GABA sensitivity of VTA pDAergic neurons during withdrawal is unknown. Here, we investigated modulation of withdrawal-induced changes in GABA sensitivity of pDAergic VTA neurons by HDAC inhibitors (HDACi), and also measured the levels of HDAC2, histone (H3-K9) acetylation, and GABA-Aα1 receptor (GABA (A-α1) R) subunit in VTA during ethanol withdrawal. Mice were injected intraperitoneally (ip) with either ethanol (3.5 g/kg) or saline twice daily for 3 weeks. In recordings from pDAergic VTA neurons in brain slices from ethanol-withdrawn mice, sensitivity to GABA (50-500 μM) was reduced. In brain slices from ethanol-withdrawn mice incubated with the HDACi SAHA (vorinostat) or trichostatin A (TSA) for 2 h, the hyposensitivity of pDAergic VTA neurons to GABA was significantly attenuated. There was no effect of TSA or SAHA on GABA sensitivity of pDAergic VTA neurons from saline-treated mice. In addition, ethanol withdrawal was associated with an increase in levels of HDAC2 and a decrease in histone (H3-K9) acetylation and levels of GABA (A-α1) R subunits in the VTA. Therefore, blockade of upregulation of HDAC2 by HDACi normalizes GABA hyposensitivity of pDAergic neurons developed during withdrawal after chronic ethanol treatment, which suggests the possibility that inhibition of HDACs can reverse ethanol-induced neuroadaptational changes in reward circuitry. 23951317 PhenoTimer: Software for the Visual Mapping of Time-Resolved Phenotypic Landscapes. Timing common and specific modulators of disease progression is crucial for treatment, but the understanding of the underlying complex system of interactions is limited. While attempts at elucidating this experimentally have produced enormous amounts of phenotypic data, tools that are able to visualize and analyze them are scarce and the insight obtained from the data is often unsatisfactory. Linking and visualizing processes from genes to phenotypes and back, in a temporal context, remains a challenge in systems biology. We introduce PhenoTimer, a 2D/3D visualization tool for the mapping of time-resolved phenotypic links in a genetic context. It uses a novel visualization approach for relations between morphological defects, pathways or diseases, to enable fast pattern discovery and hypothesis generation. We illustrate its capabilities of tracing dynamic motifs on cell cycle datasets that explore the phenotypic order of events upon perturbations of the system, transcriptional activity programs and their connection to disease. By using this tool we are able to fine-grain regulatory programs for individual time points of the cell cycle and better understand which patterns arise when these programs fail. We also illustrate a way to identify common mechanisms of misregulation in diseases and drug abuse. 23853151 Fullerene-Bisadduct Acceptors for Polymer Solar Cells. Polymer solar cells (PSCs) have drawn great attention in recent years for their simple device structure, light weight, and low-cost fabrication in comparison with inorganic semiconductor solar cells. However, the power-conversion efficiency (PCE) of PSCs needs to be increased for their future application. The key issue for improving the PCE of PSCs is the design and synthesis of high-efficiency conjugated polymer donors and fullerene acceptors for the photovoltaic materials. For the acceptor materials, several fullerene-bisadduct acceptors with high LUMO energy levels have demonstrated excellent photovoltaic performance in PSCs with P3HT as a donor. In this Focus Review, recent progress in high-efficiency fullerene-bisadduct acceptors is discussed, including the bisadduct of PCBM, indene-C60 bisadduct (ICBA), indene-C70 bisadduct (IC70 BA), DMPCBA, NCBA, and bisTOQC. The LUMO levels and photovoltaic performance of these bisadduct acceptors with P3HT as a donor are summarized and compared. In addition, the applications of an ICBA acceptor in new device structures and with other conjugated polymer donors than P3HT are also introduced and discussed. 23680005 Bleeding events and activated partial thromboplastin time with dabigatran in clinical practice. Dabigatran has demonstrated promising results for the prevention of strokes in patients with non-valvular atrial fibrillation (NVAF). However, there have been episodes of major bleeding, especially in elderly patients or those with renal dysfunction. The purpose of this study was to retrospectively examine the relationship between the bleeding events and activated partial thromboplastin time (APTT) values under dabigatran usage in the everyday clinical practice. Moreover, we investigated which factors would contribute to the APTT values. A total of 139 NVAF patients (112 men, 65±11 years) were included. We evaluated the influence of the putative etiological variables and the bleeding score, HAS-BLED score, on APTT values: age greater than 70 years, renal function, gender, dose of dabigatran, and the concomitant prescription of a P-glycoprotein inhibitor. There were 50 patients with an age of ≥70 years (36.0%). A P-glycoprotein inhibitor was administered in 18 patients. During the observation period (median 120 days) there was 1 episode of asymptomatic cerebral infarction. There were no intrinsic major bleeding events, however, 11 patients had minor hemorrhagic events. The results of the APTT measurements exhibited a variety of values both among inter- and intra-individuals. On multivariable analysis, significant associations were found between the following risk factors and the APTT values: creatinine clearance, dose of dabigatran, and concomitant use of a P-glycoprotein inhibitor. The minor bleeding events did not correlate with the APTT values, nor HAS-BLED score. The APTT values became prolonged under dabigatran usage and exhibited a remarkable diversity. Although major bleeding did not occur unless APTT was prolonged excessively, minor bleeding arose irrespective of the APTT values even within the range of the APTT values not exceeding 80s. 23830153 Dietary glycemic index is associated with less favorable anthropometric and metabolic profiles in polycystic ovary syndrome women with different phenotypes. To compare glycemic index (GI) in the usual diet of polycystic ovary syndrome (PCOS) and control women and to investigate whether dietary GI is associated with body composition and anthropometric and metabolic variables across PCOS phenotypes. Cross-sectional study. University hospital outpatient clinic. Sixty-one women with PCOS and 44 nonhirsute women with ovulatory cycles. Metabolic work-up, biochemical and hormonal assays, assessment of body composition and rest metabolic rate, physical activity (pedometer), and food consumption (food frequency questionnaire). GI, glycemic load, dietary intake, and hormone and metabolic profile in PCOS versus control and in PCOS women stratified by tertiles of GI and PCOS phenotype. Mean age was 23.7 ± 6.3 years. Participants with PCOS had higher body fat percentage, fasting insulin, insulin resistance, lipid accumulation product, and androgen levels compared with control women. PCOS and control women in the highest tertile of GI had higher body mass index and waist circumference than those in the lowest tertile. Dietary GI was higher in the classic PCOS group. Obesity and this more severe PCOS phenotype explained 28.3% of variance in dietary GI. Dietary GI is increased in the classic PCOS phenotype and associated with a less favorable anthropometric and metabolic profile. Obesity and classic PCOS phenotype are age-independent predictors of higher dietary GI. 23832320 Clinical impact of an adaptive statistical iterative reconstruction algorithm for detection of hypervascular liver tumours using a low tube voltage, high tube current MDCT technique. To investigate the impact of an adaptive statistical iterative reconstruction (ASiR) algorithm on diagnostic accuracy and confidence for the diagnosis of hypervascular liver tumours, as well as the reader's perception of image quality, using a low tube voltage (80 kVp), high tube current computed tomography (CT) technique. Forty patients (29 men, 11 women) with 65 hypervascular liver tumours underwent dual energy CT. The 80 kV set of the dual energy acquisition was reconstructed with standard filtered backprojection (FBP) and ASiR at different blending levels. Lesion contrast-to-noise ratio (CNR), reader's confidence for lesion detection and characterisation, and reader's evaluation of image quality were recorded. ASiR yielded significantly higher CNR values compared with FBP (P < 0.0001 for all comparisons). Reader's perception of lesion conspicuity and confidence in the diagnosis of malignancy were also higher with 60 % and 80 % ASiR, compared with FBP (P = 0.01 and < 0.001, respectively). Compared with FBP, ASiR yielded nearly significantly lower specificity for lesion detection and a substantial decrease in the reader's perception of image quality. Compared with the standard FBP algorithm, ASiR significantly improves conspicuity of hypervascular liver lesions. This improvement may come at the cost of decreased specificity and reader's perception of image quality. • Adaptive statistical iterative reconstruction algorithms (ASiRs) offer increasing potential in multidetector CT. • An ASiR algorithm significantly improves conspicuity of hypervascular liver lesions at MDCT. • Improved lesion conspicuity translates into increased reader's confidence for diagnosis of malignancy. • False positive findings may increase with ASiR, leading to potentially lower specificity. 23900728 Cesarean deliveries among Nepalese mothers: changes over time 2001-2011 and determinants. To examine the most recent trends of cesarean delivery in Nepal and the association with socio-demographic characteristics of mothers. Nationally representative cross-sectional data was used from three Demographic and Health Surveys conducted in Nepal in 2001 (N = 4,745), 2006 (N = 4,066) and 2011 (N = 4,148). Cesarean section delivery was measured in two categories with yes and no responses for the delivery in their latest pregnancy. Data on socio-demographic variables was obtained by interviewing the participants. The data was analysed using logistic regression models. The prevalence of cesarean section delivery was increased by more than 4 times from 2001 to 2011 both among rural and urban residents. After adjusting for mother's age, number of births in last 5 years and mother's education the prevalence of cesarean section delivery among all mothers was 1.71 times higher in 2006 (OR = 1.71, 95 % CI 1.23-2.37) and increased further in 2011 (OR = 2.42, 95 % CI 1.78-3.30) compared with year 2001. When adjusted for all the variables simultaneously, all variables except births in last 5 years remained significantly associated with cesarean section delivery of the mother. Older age, urban resident, being educated, having educated partners and being rich according to wealth index were associated with cesarean section delivery. The prevalence of cesarean section delivery continues to rise but still lower than the World Health Organization recommended rates. More studies are needed to examine the non-medical reason of increasing rates of cesarean section deliveries and their effect in maternal and infant morbidity and mortality in Nepal. 23652786 Recent advances in reconstructive surgery for bone and soft tissue sarcomas. We present the current perspective on reconstructive surgery for soft tissue tumors, especially in the extremities, based on our large series. A total of 1,813 patients with bone and soft tissue sarcomas underwent surgery at our hospital between 1978 and 2011. Reconstructive operations were performed by plastic surgeons. In such reconstructive surgery, to achieve better quality of life for the patient, great effort was made not only for limb salvage but also for functional reconstruction. Although a few surgeries resulted in limb amputation due to multiple tumors, recurrence, or advanced age of the patient, the rate of limb salvage and/or functional recovery has been increasing dramatically using the method of flap surgery and vascular reconstruction. In fact, over more than 30 years, the limb salvage rate at our hospital has increased from 71.6 % around 1980 to 90.5 % around 2010. In this article, we describe our experience in plastic and reconstructive surgeries after operation for bone and soft tissue sarcomas. 23422283 Fractures of the thoracic spine in patients with minor trauma: comparison of diagnostic accuracy and dose of biplane radiography and MDCT. To investigate the accuracy of biplane radiography in the detection of fractures of the thoracic spine in patients with minor trauma using multidetector computed tomography (MDCT) as the reference and to compare the dose of both techniques. 107 consecutive trauma patients with suspected fractures of the thoracic spine on physical examination were included. All had undergone biplane radiography first, followed by a MDCT scan between October 2008 and October 2012. A fourfold table was used for the classification of the screening test results. Both the Chi-square test (χ(2)) and the mean dose-length product (DLP) were used to compare the diagnostic methods. MDCT revealed 77 fractures in 65/107 patients (60.7%). Biplane radiography was true positive in 32/107 patients (29.9%), false positive in 19/107 patients (17.8%), true negative in 23/107 (21.5%) and false negative in 33/107 patients (30.8%), showing a sensitivity of 49.2%, a specificity of 54.7%, a positive predictive value (PPV) of 62.7%, a negative predictive value (NPV) of 41.1%, and an accuracy of 51.4%. The presence of a fracture on biplane radiography was highly statistical significant, if this was simultaneously proven by MDCT (χ(2)=7.6; p=0.01). None of the fractures missed on biplane radiography was unstable. The mean DLP on biplane radiography was 14.5mGycm (range 1.9-97.8) and on MDCT 374.6mGycm (range 80.2-871). The sensitivity and the specificity of biplane radiography in the diagnosis of fractures of the thoracic spine in patients with minor trauma are low. Considering the wide availability of MDCT that is usually necessary for taking significant therapeutic steps, the indication for biplane radiography should be very restrictive. 23584844 Effects of Dietary Factors on the Pharmacokinetics of (58)Fe-labeled Hemin After Oral Administration in Normal Rats and the Iron-deficient Rats. Hemin, iron (III) protoporphyrin chloride (IX), as a stable form of heme iron, has been used in iron absorption studies. The aim of the present study was to elucidate the influences of body iron status and three dietary factors (green tea extract, ascorbic acid, and calcium) on the pharmacokinetics of hemin using stable isotope labeling methods followed by ICP-MS measurement. In this study, a rapid, sensitive, and specific ICP-MS method for the determination of (58)Fe originating from hemin in rat plasma was developed and a rat model of iron deficiency anemia was established. It was found that hemin iron absorption increased significantly under iron deficiency anemia status, with AUC0-t and AUC0-∞ showing significant increase in anemic rats compared to normal ones. Green tea extract strongly inhibited hemin iron absorption in both normal rats and iron-deficient rats. In normal rats administered with green tea extract, C max resulted significantly reduced, whereas in anemic rats administered with green tea extract both AUC0-t and AUC0-∞ were reduced. On the other hand, ascorbic acid significantly affected hemin iron absorption only in iron-deficient rats, in which C max showed a significant increase. Interestingly, calcium slowed down the hemin iron absorption rate in normal rats, MRT0-t being significantly different in calcium-treated animals compared to untreated ones. This trend also appeared in the iron-deficient group but it did not reach statistical significance. Our data suggest that the mechanism of hemin iron absorption is regulated by body iron status and dietary factors can influence hemin iron absorption to varying degrees. Moreover, these results may also have general implication in the iron deficiency treatment with iron supplements and fortification of foods. 23379679 Nuclease-resistant DNA via high-density packing in polymeric micellar nanoparticle coronas. Herein, we describe a polymeric micellar nanoparticle capable of rendering nucleic acids resistant to nuclease digestion. This approach relies on utilizing DNA as the polar headgroup of a DNA-polymer amphiphile in order to assemble well-defined, discrete nanoparticles. Dense packing of DNA in the micelle corona allows for hybridization of complementary oligonucleotides while prohibiting enzymatic degradation. We demonstrate the preparation, purification, and characterization of the nanoparticles, then describe their resistance to treatment with endo- and exonucleases including snake-venom phosphodiesterase (SVP), a common, general DNA digestion enzyme. 23549327 Fecal S100A12: Identifying Intestinal Distress in Very-Low-Birth-Weight Infants. The aim of the study was to determine whether longitudinal measurements of fecal S100A12, a damage-associated molecular pattern protein, which is released from neutrophils or monocytes under stress, can detect very-low-birth-weight (VLBW) infants at risk for intestinal distress apart from necrotizing enterocolitis. This prospective study included 46 VLBW infants with intestinal distress and 49 reference patients. Meconium and stool samples were collected prospectively on alternate days for 4 weeks, and fecal S100A12 was measured by enzyme-linked immunosorbent assay. Gestational age and weight at birth were significantly lower in patients with intestinal distress when compared to unaffected reference infants. Median levels of fecal S100A12 were significantly higher in patients with intestinal distress at onset of disease and before compared with unaffected reference infants. Median levels of fecal S100A12 declined steadily to baseline levels within 2 weeks after disease onset. The ideal cutoff value for identifying patients with intestinal distress within 7 days before disease onset was 60 μg/kg (sensitivity 0.73; specificity 0.55). Fecal S100A12 levels are increased in VLBW infants with intestinal distress; however, the potential for S100A12 as an early biomarker is largely limited by overlaps between values of infants with intestinal distress and the reference population. 23303790 Unwinding of primer-templates by archaeal family-B DNA polymerases in response to template-strand uracil. Archaeal family-B DNA polymerases bind tightly to deaminated bases and stall replication on encountering uracil in template strands, four bases ahead of the primer-template junction. Should the polymerase progress further towards the uracil, for example, to position uracil only two bases in front of the junction, 3'-5' proof-reading exonuclease activity becomes stimulated, trimming the primer and re-setting uracil to the +4 position. Uracil sensing prevents copying of the deaminated base and permanent mutation in 50% of the progeny. This publication uses both steady-state and time-resolved 2-aminopurine fluorescence to show pronounced unwinding of primer-templates with Pyrococcus furiosus (Pfu) polymerase-DNA complexes containing uracil at +2; much less strand separation is seen with uracil at +4. DNA unwinding has long been recognized as necessary for proof-reading exonuclease activity. The roles of M247 and Y261, amino acids suggested by structural studies to play a role in primer-template unwinding, have been probed. M247 appears to be unimportant, but 2-aminopurine fluorescence measurements show that Y261 plays a role in primer-template strand separation. Y261 is also required for full exonuclease activity and contributes to the fidelity of the polymerase. 23881859 Long-lived Plasmodium falciparum-specific memory B cells in naturally exposed Swedish Travellers. Antibodies (Abs) are critical for immunity to malaria. However, Plasmodium falciparum-specific Abs decline rapidly in absence of re-infection, suggesting impaired immunological memory. This study determines whether residents of Sweden that were treated for malaria following international travel maintained long-lasting malaria-specific Abs and memory B cells (MBCs). We compared levels of malaria-specific Abs and MBCs between 47 travellers who had been admitted with malaria at the Karolinska University Hospital between 1 and 16 years previously, eight malaria-naïve adult Swedes without histories of travel, and 14 malaria-immune adult Kenyans. P. falciparum-lysate-specific Ab levels were above naïve control levels in 30% of the travellers, whereas AMA-1, MSP-142 and MSP-3-specific Ab levels were similar. In contrast, 78% of travellers had IgG-MBCs specific for at least one malaria-antigen (59%, 45% and 28% for AMA1, MSP1 and MSP3 respectively) suggesting that malaria-specific MBCs are maintained for longer than the cognate serum Abs in the absence of re-exposure to parasites. Five travellers maintained malaria antigen-specific MBC responses for up to 16 years since the diagnosis of the index episode (and had not traveled to malaria endemic regions in the intervening time). Thus P. falciparum can induce long-lasting MBCs, maintained for up to 16 years without re-exposure. This article is protected by copyright. All rights reserved. 23737478 Elevation of conjunctival epithelial CD45INTCD11b⁺CD16⁺CD14⁻ neutrophils in ocular Stevens-Johnson syndrome and toxic epidermal necrolysis. Ocular complications related to Stevens-Johnson Syndrome (SJS)-Toxic Epidermal Necrolysis (TEN) may persist and progress after resolution of systemic disease. This is thought to be related in part to persistent ocular innate-immune signaling. In this study, our aim was to characterize infiltrative conjunctival cellular profiles during acute (<12 months) and chronic (>12 months) disease. Consecutive patients presenting with SJS-TEN over a 12-month period were followed for 1 year. Detailed clinical examination and conjunctival impression cell recovery was analyzed by flow cytometry for the presence of intraepithelial leukocytes and compared with healthy controls (n = 21). Ten patients were recruited of whom six had acute disease and five were classified as TEN (SCORTEN = 1, n = 4). Conjunctival inflammation was graded as absent/mild in a total of nine patients; but despite this, evidence of fornix shrinkage was observed in nine subjects. This inversely correlated with disease duration (P < 0.05). A reduction in percentage of CD8αβ(+) T cells compared with controls (80% vs. 57%; P < 0.01) was associated with a corresponding increase in the number/percentage of CD45(INT)CD11b(+)CD16(+)CD14(-) neutrophils (186 vs. 3.4, P < 0.01, 31% vs. 0.8%, P < 0.001). Neutrophils inversely correlated with disease duration (r = -0.71, P = 0.03), yet there was no absolute change in the CD8αβ(+) or neutrophil populations during the study period (P = 1.0). These data highlight that a neutrophilic infiltrate is present in mildly inflamed or clinically quiescent conjunctival mucosa in patients with ocular SJS-TEN, where neutrophil numbers inversely correlate with disease duration. Neutrophil persistence endorses the hypothesis of an unresolved innate-inflammatory process that might account for disease progression. 23894639 Has large-scale named-entity network analysis been resting on a flawed assumption? THE ASSUMPTION THAT A NAME UNIQUELY IDENTIFIES AN ENTITY INTRODUCES TWO TYPES OF ERRORS: splitting treats one entity as two or more (because of name variants); lumping treats multiple entities as if they were one (because of shared names). Here we investigate the extent to which splitting and lumping affect commonly-used measures of large-scale named-entity networks within two disambiguated bibliographic datasets: one for co-author names in biomedicine (PubMed, 2003-2007); the other for co-inventor names in U.S. patents (USPTO, 2003-2007). In both cases, we find that splitting has relatively little effect, whereas lumping has a dramatic effect on network measures. For example, in the biomedical co-authorship network, lumping (based on last name and both initials) drives several measures down: the global clustering coefficient by a factor of 4 (from 0.265 to 0.066); degree assortativity by a factor of ∼13 (from 0.763 to 0.06); and average shortest path by a factor of 1.3 (from 5.9 to 4.5). These results can be explained in part by the fact that lumping artificially creates many intransitive relationships and high-degree vertices. This effect of lumping is much less dramatic but persists with measures that give less weight to high-degree vertices, such as the mean local clustering coefficient and log-based degree assortativity. Furthermore, the log-log distribution of collaborator counts follows a much straighter line (power law) with splitting and lumping errors than without, particularly at the low and the high counts. This suggests that part of the power law often observed for collaborator counts in science and technology reflects an artifact: name ambiguity. 23412954 Biomonitoring of arsenic through mangrove oyster (Crassostrea corteziensis Hertlein, 1951) from coastal lagoons (SE Gulf of California): occurrence of arsenobetaine and other arseno-compounds. In this study, we examined the bioavailability of arsenic through the mangrove oyster Crassostrea corteziensis sampled from seven coastal lagoons in SE Gulf of California during the rainy and dry seasons. As concentrations in soft tissue of oysters C. corteziensis fluctuated between 5.2 and 11.6 Î¼g/g on dry weight; organisms from the control site presented the lowest As concentrations in the two sampling seasons. As speciation was evaluated in selected samples and indicated that arsenobetaine was the major arseno-compound accounting for 53.5-74.7 % of total As. Lower percentage contributions were obtained for nonextractable As (9.7-25.5 %) and other molecules such as arsenocholine and methyl-arsonate (<5 %). Inorganic As was detectable in only two samples, at concentrations lower than 0.1 Î¼g/g. These As data are the first generated in NW Mexico and indicate that C. corteziensis is safe for human consumption in terms of arseno-compounds. It is evident that As bioavailability in these lagoons is low. 23844992 Stiffness and ultimate load of osseointegrated prosthesis fixations in the upper and lower extremity. Techniques for the skeletal attachment of amputation-prostheses have been developed over recent decades. This type of attachment has only been performed on a small number of patients. It poses various potential advantages compared to conventional treatment with a socket, but is also associated with an increased risk of bone or implant-bone interface fracture in the case of a fall. We therefore investigated the bending stiffness and ultimate bending moment of such devices implanted in human and synthetic bones. Eight human specimens and 16 synthetic models of the proximal femora were implanted with lower extremity prostheses and eight human specimens and six synthetic humeri were implanted with upper extremity prostheses. They were dissected according to typical amputation levels and underwent loading in a material testing machine in a four-point bending setup. Bending stiffness, ultimate bending moment and fracture modes were determined in a load to failure experiment. Additionally, axial pull-out was performed on eight synthetic specimens of the lower extremity. Maximum bending moment of the synthetic femora was 160.6±27.5 Nm, the flexural rigidity of the synthetic femora was 189.0±22.6 Nm2. Maximum bending moment of the human femora was 100.4±38.5 Nm, and the flexural rigidity was 137.8±29.4 Nm2. The maximum bending moment of the six synthetic humeri was 104.9±19.0 Nm, and the flexural rigidity was 63.7±3.6 Nm2. For the human humeri the maximum bending moment was 36.7±11.0 Nm, and the flexural rigidity at was 43.7±10.5 Nm2. The maximum pull-out force for the eight synthetic femora was 3571±919 N. Significant differences were found between human and synthetic specimens of the lower and upper extremity regarding maximum bending moment, bending displacement and flexural rigidity. The results of this study are relevant with respect to previous finding regarding the load at the interfaces of osseointegrated prosthesis fixation devices and are crucial for the development of safety devices intended to protect the bone-implant interface from damaging loadings. 23904850 High-grade glioma: refined diagnostics steering stratified therapy. An adequately sampled tumor histology that is evaluated by an experienced neuropathologist is the current international standard for the diagnosis of high-grade gliomas. We present the case of a 30-year-old female for whom clinical and radiological information dramatically changed the histological diagnosis. We suggest a new algorithm including these parameters to refine the accuracy of histological diagnosis both for standard treatment and centrally reviewed clinical trials. 23685252 Serum-free cryopreservation of human amniotic epithelial cells before and after isolation from their natural scaffold. Amniotic epithelial cells are a promising source for stem cell-based therapy through their potential capacity to differentiate into the cell lineages of all three germ layers. Long-term preservation is necessary to have a ready-to-use source of stem cells, when required. Reduced differentiation capability, decrease of viability and use of fetal bovine serum (FBS) are three drawbacks of clinical application of cryopreserved stem cells. In this study, we used human amniotic fluid instead of animal serum, and evaluated viability and multipotency of amniotic epithelial cells after cryopreservation in suspension and compared with those cryopreserved on their natural scaffold (in situ cryopreservation). There was no significant difference in viability of the cells cryopreserved in amniotic fluid and FBS. Also, the same results were achieved for expression of pluripotency marker OCT-4 when FBS was replaced by amniotic fluid in the samples with the same cryoprotectant. The cells cryopreserved in presence of scaffold had a higher level of viability compared to the cells cryopreserved in suspension. Although, the number of the cells expressed OCT-4 significantly decreased within cryopreservation in suspension, no decrease in expression of OCT-4 was observed when the cells cryopreserved with their natural scaffold. Upon culturing of post-thawed cells in specific lineage differentiating mediums, the markers of neuronal, hepatic, cardiomyocytic and pancreatic were found in differentiated cells. These results show that replacement of FBS by amniotic fluid and in situ cryopreservation of amniotic epithelial cells is an effective approach to overcome limitations related to long-term preservation including differentiation during cryopreservation and decrease of viability. 23835517 Quantifying proteomes and their post-translational modifications by stable isotope label-based mass spectrometry. Stable isotope labeling coupled with mass spectrometry has revolutionized the scope and impact of protein expression studies. Label incorporation can occur metabolically or chemically, and each method bears specific strengths and weaknesses. Quantitative proteomics confidently identifies specific interactions between proteins and other biological species, such as nucleic acids and metabolites. Extending label-based methods to phosphorylation-modified forms of proteins enables the construction of signaling networks and their temporal responses to stimuli. The integration of multiple data types offers systems-level insight on coordinated biological processes. Finally, the development of methods applicable to tissue quantification suggests the emerging role of label-based, quantitative mass spectrometry in translational science. 23170986 The MSH2 c.388_389del mutation shows a founder effect in Portuguese Lynch syndrome families. The MSH2 c.388_389del mutation has occasionally been described in Lynch families worldwide. At the Portuguese Oncology Institute in Porto, Portugal, we have identified 16 seemingly unrelated families with this germline mutation. To evaluate if this alteration is a founder or a recurrent mutation we performed haplotype analysis in the 16 Portuguese index cases and 55 relatives, as well as in four index cases and 13 relatives reported from Germany, Scotland, England, and Argentina. In the Portuguese families we observed a shared haplotype of approximately 10 Mb and all were originated from the north of Portugal. These results suggest that this alteration is a founder mutation in Portugal with a relatively recent origin. In the reported families outside Portugal with this mutation different haplotype backgrounds were observed, supporting the hypothesis that it occurred de novo on multiple occasions. We also conclude that the high proportion of families with the MSH2 c.388_389del mutation indicates that screening for this alteration as a first step may be cost-effective in the genetic testing of Lynch syndrome suspects of Portuguese ancestry, especially those originating from the north of Portugal. 23845750 Interactions between hyaluronic acid, lysozyme, and the glucose oxidase-mediated lactoperoxidase system in enzymatic and candidacidal activities. To investigate interactions between hyaluronic acid (HA), lysozyme, and the glucose oxidase-mediated lactoperoxidase (GO-LPO) system in enzymatic and candidacidal activities. The influences of HA (0.5, 1.0, and 2.0mg/mL) and lysozyme (30μg/mL hen egg white lysozyme) on the enzymatic activity of GO-LPO system (25μg/mL bovine LPO, 1mM KSCN, 10units/mL GO, and 30μg/mL glucose) were determined by measuring oxidized o-dianisidine production. The influence of the GO-LPO system on lysozyme activity was determined by measuring the turbidity of a Micrococcus lysodeikticus suspension. The effects of interactions between HA, lysozyme, the GO-LPO system on candidacidal activity were examined by pre-incubating various combinations of components. Candidacidal activity was determined by comparing the numbers of colony forming units using Candida albicans ATCC strains 10231, 18804, and 11006. HA inhibited the enzymatic activity of the GO-LPO system in a dose-dependent manner. HA inhibited the candidacidal activities of the GO-LPO system. However, the inhibitory activity of HA was not significantly different according to concentration of HA. The GO-LPO system enhanced the enzymatic activity of lysozyme, though lysozyme did not affect the enzymatic activity of the GO-LPO system. The candidacidal activities of the GO-LPO system and lysozyme were not additive. HA inhibited the enzymatic and candidacidal activity of the GO-LPO system. The GO-LPO system enhanced the enzymatic activity of lysozyme, but the candidacidal activities were not additive. 23529088 Simultaneous facial feature tracking and facial expression recognition. The tracking and recognition of facial activities from images or videos have attracted great attention in computer vision field. Facial activities are characterized by three levels. First, in the bottom level, facial feature points around each facial component, i.e., eyebrow, mouth, etc., capture the detailed face shape information. Second, in the middle level, facial action units, defined in the facial action coding system, represent the contraction of a specific set of facial muscles, i.e., lid tightener, eyebrow raiser, etc. Finally, in the top level, six prototypical facial expressions represent the global facial muscle movement and are commonly used to describe the human emotion states. In contrast to the mainstream approaches, which usually only focus on one or two levels of facial activities, and track (or recognize) them separately, this paper introduces a unified probabilistic framework based on the dynamic Bayesian network to simultaneously and coherently represent the facial evolvement in different levels, their interactions and their observations. Advanced machine learning methods are introduced to learn the model based on both training data and subjective prior knowledge. Given the model and the measurements of facial motions, all three levels of facial activities are simultaneously recognized through a probabilistic inference. Extensive experiments are performed to illustrate the feasibility and effectiveness of the proposed model on all three level facial activities. 23893512 Sensory nerves are frequently involved in the spectrum of Fisher syndrome. Introduction: Differing patterns of neurophysiological abnormalities have been reported in patients with Fisher syndrome. Fisher syndrome is rare and few series have incorporated prospective serial studies, which have proven helpful in defining the natural history of nerve conduction studies in Guillain-Barré syndrome. Methods: In an ongoing prospective study of Guillain-Barré syndrome patients, patients who presented with Fisher syndrome and its spectrum of illness were assessed through serial neurological examinations, nerve conduction studies, and serological testing of IgG against gangliosides and ganglioside complexes. Results: Of 36 Guillain-Barré syndrome patients identified within 2 years, 17 had features of FS. Serial nerve conduction studies detected significant abnormalities in sensory nerve action potential amplitude in 94% of patients associated with 2 patterns of recovery - non-demyelinating reversible distal conduction failure and axonal regeneration. Similar changes were seen in motor nerves of 5 patients. Discussion: Patients with the Fisher syndrome spectrum of illness have significant sensory involvement which may only be evident with serial neurophysiological studies. © 2013 Wiley Periodicals, Inc. 22770642 Relationship of vitamin D levels to blood pressure in a biethnic population. Accumulating epidemiological and clinical studies have suggested that vitamin D insufficiency may be associated with hypertension. Blacks tend to have lower vitamin D levels than Whites, but it is unclear whether this difference explains the higher blood pressure (BP) observed in Blacks in a population with healthy lifestyle practices. We examined cross-sectional data in the Adventist Health Study-2 (AHS-2), a cohort of non-smoking, mostly non-drinking men and women following a range of diets from vegan to non-vegetarian. Each participant provided dietary, demographic, lifestyle and medical history data. Measurements of weight, height, waist circumference, percent body fat and blood pressure and fasting blood samples were obtained from a randomly selected non-diabetic sample of 284 Blacks and 284 Whites aged 30-95 years. Multiple regression analyses were used to assess independent relationships between blood pressure and 25(OH)D levels. Levels of 25(OH)D were inversely associated with systolic BP in Whites after control for age, gender, BMI, and use of BP-lowering medications (β-coefficient -0.23 [95% CI, -0.43, -0.03; p = 0.02]). This relationship was not seen in Blacks (β-coefficient 0.08 [95% CI, -0.14, 0.30; p = 0.4]). Results were similar when controlling for waist circumference or percentage body fat instead of BMI. No relationship between serum 25(OH)D and diastolic BP was seen. Systolic BP is inversely associated with 25(OH)D levels in Whites but not in Blacks. Vitamin D may not be a major contributor to the White-Black differential in BP. 23598085 Greater impairment of postprandial triacylglycerol than glucose response in metabolic syndrome subjects with fasting hyperglycaemia. OBJECTIVE: Studies have started to question whether a specific component or combinations of metabolic syndrome (MetS) components may be more important in relation to cardiovascular disease risk. Our aim was to examine the impact of the presence of raised fasting glucose as a MetS component on postprandial lipaemia. METHODS: Men classified with the MetS underwent a sequential test meal investigation, in which blood samples were taken at regular intervals after a test breakfast (t=0 min) and lunch (t=330 min). Lipids, glucose and insulin were measured in the fasting and postprandial samples. RESULTS: MetS subjects with 3 or 4 components were subdivided into those without (n=34) and with (n=23) fasting hyperglycaemia (≥5.6mmol/l), irrespective of the combination of components. Fasting lipids and insulin were similar in the two groups, with glucose significantly higher in the men with glucose as a MetS component (P<0.001). Following the test meals, there were higher maximum concentration (maxC), area under the curve (AUC) and incremental AUC (P≤0.016) for the postprandial triacylglycerol (TAG) response in men with fasting hyperglycaemia. Greater glucose AUC (P<0.001) and insulin maxC (P=0.010) were also observed in these individuals after the test meals. Multiple regression analysis revealed fasting glucose to be an important predictor of the postprandial TAG and glucose response. CONCLUSION: Our data analysis has revealed a greater impairment of postprandial TAG than glucose response in MetS subjects with raised fasting glucose. The worsening of postprandial lipaemic control may contribute to the greater CVD risk reported in individuals with MetS component combinations which include hyperglycaemia. 23838729 Is There a Limit to the Superiority of Individuals with ASD in Visual Search? Superiority in visual search for individuals diagnosed with autism spectrum disorder (ASD) is a well-reported finding. We administered two visual search tasks to individuals with ASD and matched controls. One showed no difference between the groups, and one did show the expected superior performance for individuals with ASD. These results offer an explanation, formulated in terms of load theory. We suggest that there is a limit to the superiority in visual search for individuals with ASD, related to the perceptual load of the stimuli. When perceptual load becomes so high that no additional task-(ir)relevant information can be processed, performance will be based on single stimulus identification, in which no differences between individuals with ASD and controls have been demonstrated. 23809054 Sequence of novel agents in multiple myeloma: An instrumental variable analysis. Lenalidomide and bortezomib have not been compared prospectively and are currently used in sequence for patients with multiple myeloma; however, it is unknown whether a sequence of administration could result in improved outcomes. We retrospectively reviewed electronic records of patients with multiple myeloma who had used both agents in sequence at our institution: 97 patients had lenalidomide first and 111 had bortezomib first. On multivariable analysis, the sequence of therapy was not associated with outcome. These findings were confirmed with instrumental variable analyses. Finally, use of bortezomib first was associated with improved survival for patients with baseline renal insufficiency. 22287619 Biochemical and histopathological studies of the PTU-induced hypothyroid rat kidney with reference to the ameliorating role of folic acid. Thyroid hormones (THs) are essential for growth and development of the kidney. Also TH influences glomerular filtration and tubular functions. Hypothyroidism negative influences kidney function indirectly by affecting the cardiovascular system and the renal blood flow, and directly by affecting glomerular filtration, tubular functions and the structure of the kidney. The purpose of this study was to evaluate changes in biochemical markers, oxidative stress parameter and histological changes in kidney of hypothyroid rats before and after treatment with folic acid. Hypothyroidism was induced for 6 weeks by the administration of propylthiouracil in drinking water. Urea and creatinine were measured to evaluate the changes in kidney function. Also malondialdehyde, nitrite, nitrate and other oxidative stress parameter were measured in serum and kidney tissue as indicators of oxidative damage. Kidney function and oxidative stress parameters in hypothyroid rats were significantly changed compared to those in control rats. Treatment with folic acid helps in improving the adverse effect of hypothyroidism; the histological study also confirms this finding. 23541908 The effect of ultrasonic and HNO3 treatment of activated carbon from fruit stones on capacitive and pseudocapacitive energy storage in electrochemical supercapacitors. The effect of ultrasonic treatment and modification with nitric acid of activated carbon obtained from fruit stones, on the parameters of electric double-layer (EDL) as well as on farad-volt characteristics of its boundary with electrolyte 7.6 m KОН, 4 m KI and 2 m ZnI2 aqueous solutions has been studied by means of precision porometry, cyclic voltamperometry, electrochemical impedance spectroscopy and computer simulation methods. It is shown that HNO3 treatment results in an increase of the electrostatic capacitance up to 202 F/g in 7.6 m KОН-solution as well as pseudocapacitance up to 1250 F/g in 4 m KI. This increase is supposed to be related both with hydrophilicity and with an increase of the density of states on Fermi level. The ultrasonic treatment enables one to significantly increase (more than 200 times) the density of states on Fermi level which in turn causes both quantitative and qualitative changes in farad-volt dependences. A hybrid supercapacitor with specific capacitance of 1100 F/g and specific energy of 49 Wh/kg per active mass of two electrodes was developed. 23864059 CMR assessment of right ventricular function in patients with combined pulmonary stenosis and insufficiency after correction of tetralogy of Fallot. Tetralogy of Fallot (TOF) is one of the most common types of congenital heart disease and requires prompt surgical correction. Post-correction pulmonary insufficiency (PI) often ensues in adulthood. At times, the PI is accompanied by residual pulmonary stenosis (PS). Little is known regarding right ventricular (RV) function in the setting of combined PS and PI. To compare cardiac magnetic resonance (CMR) parameters for the assessment of RV function between patients with combined pulmonary stenosis and pulmonary insufficiency (PSPI) and isolated PI following surgical repair of TOF. Retrospective review of patients with comparable corrected TOF and similar PI was performed. Seventeen patients (median age, 24 years; range, 10-52 years) had combined PSPI and 30 patients (median age, 30 years; range, 6-70 years) had isolated PI. Cine magnetic resonance (MR) images (Philips Medical Systems, Best, The Netherlands) in the short-axis plane were used to calculate end-systolic, end-diastolic, and stroke volumes (RVESV, RVEDV, RVSV) and to measure RV wall thickness. Velocity-encoded cine MR images were used to measure pulmonary regurgitation fraction (PRF) by calculating the ratio of backward flow and total forward flow, obtained from the main pulmonary flow analysis. Peak pressure gradient across the pulmonary valve was obtained from spectral Doppler echocardiography. RVEF was 51 ± 8% in the PSPI patients and 39 ± 11%, in the patients with isolated PI (P = 0.001). Additionally, RV wall thickness was 5.2 ± 0.8 mm in the PSPI patients compared to 2.6 ± 0.9 mm in the isolated PI patients (P = 0.001). RVESVi and RVEDVi were significantly lower (P < 0.05) in patients with combined PSPI (60 ± 21 mL/m(2), 121 ± 35 mL/m(2), respectively) compared to the patients with isolated PI (95 ± 48 mL/m(2), 152 ± 61 mL/m(2), respectively). RV function is preserved in patients with PSPI when compared to patients with PI following surgical repair of TOF. 23850141 NMR methods for structural studies of large monomeric and multimeric proteins. NMR structural studies of large monomeric and multimeric proteins face distinct challenges. In large monomeric proteins, the common occurrence of frequency degeneracies between residues impedes unambiguous assignment of NMR signals. To overcome this barrier, nonuniform sampling (NUS) is used to measure spectra with optimal resolution within reasonable time, new correlation maps resolve previous impasses in assignment strategies, and novel selective methyl labeling schemes provide additional structural probes without cluttering NMR spectra. These advances push the limits of NMR studies of large monomeric proteins. Large multimeric and multidomain proteins are studied by NMR when individual components can also be studied by NMR and have known structures. The structural properties of large assemblies are obtained by identifying binding surfaces, by orienting domains, and employing limited distance constraints. Segmental labeling and the combination of NMR with other methods have helped popularize NMR studies of such systems. 23311677 Dual routes to cognitive flexibility: learning and response-conflict resolution in the dimensional change card sort task. Cognitive control, the ability to align our actions with goals or context, is largely absent in children under four. How then are preschoolers able to tailor their behavior to best match the situation? Learning may provide an alternative route to context-sensitive responding. This study investigated this hypothesis in the Dimensional Change Card Sort (DCCS), a classic test of cognitive control that most under-fours fail. A training intervention based on learning theoretic principles proved highly effective: Three-year-olds who learned about DCCS rules and game contexts in a card-labeling task, subsequently transferred this knowledge to sorting in the DCCS, passing at more than 3 times the rate of controls (N = 47). This surprising finding reveals much about the nature of the developing mind. 23748734 A lipobead microarray assembled by particle entrapment in a microfluidic obstacle course and used for the display of cell membrane receptors. Platforms which can display cell membrane ligands and receptors as a microarray library of probes for screening against a target are essential tools in drug discovery, biomarker identification, and pathogen detection. Membrane receptors and ligands require their native bilayer environment to retain their selectivity and binding affinity, and this complicates displaying them in a microarray platform. In this study, a design is developed in which the probes are first incorporated in supported lipid bilayers formed around micron-sized particles (lipobeads), and the microbeads themselves are then arrayed on a surface by hydrodynamic capture in a microfluidic obstacle course of traps. The traps are "V" shaped open enclosures, which are arranged in a wide channel of a microfluidic device, and capture the lipobeads (slightly smaller than the channel height) as they are streamed through the course. Screening assays are undertaken directly in the device after assembly, by streaming a fluorescently labeled target through the device and detecting the bead fluorescence. Conditions are first established for which the supported bilayers on the bead surface remain intact during the capture and assay steps, using fluorescent tags in the bilayer to infer bilayer integrity. Numerical calculations of the hydrodynamic drag coefficient on the entrapped beads are presented in conjunction with the stability experiments to develop criteria for the bilayer stability as a function of the screening assay perfusion rate. Simulations of the flow streamlines are also presented to quantify the trapping efficiency of the obstacle course. Screening assays are illustrated, assaying fluorescently labeled NeutrAvidin with biotin, and labeled cholera toxin with its ganglioside binding ligand, GM1. Sequential capturing of sets of lipobeads (one at a time, and with each set bearing a different probe), followed by indexing the bead positions after each set is entrapped, allows for the construction of an indexed array of multiple probes without the need for particle encoding and is illustrated using the NeutrAvidin-biotin pair. Finally, the lipobead platform is used for quantitatively measuring the kinetic rate constants for the binding of a probe (biotin) to a target (NeutrAvidin). 23916093 Morphological evaluation of spermatogenesis in Lake Magadi tilapia (Alcolapia grahami): A fish living on the edge. Spermatogenesis in Lake Magadi tilapia (Alcolapia grahami), a cichlid fish endemic to the highly alkaline and saline Lake Magadi in Kenya, was evaluated using light and transmission electron microscopy. Spermatogenesis, typified by its three major phases (spermatocytogenesis, meiosis and spermiogenesis), was demonstrated by the presence of maturational spermatogenic cells namely spermatogonia, spermatocytes, spermatids and spermatozoa. Primary spermatogonia, the largest of all the germ cells, underwent a series of mitotic divisions producing primary spermatocytes, which then entered two consecutive meiotic divisions to produce secondary spermatocytes and spermatids. Spermatids, in turn, passed through three structurally distinct developmental stages typical of type-I spermiogenesis to yield typical primitive anacrosomal spermatozoa of the externally fertilizing type (aquasperm). The spermatozoon of this fish exhibited a spheroidal head with the nucleus containing highly electron-dense chromatin globules, a midpiece containing ten ovoid mitochondria arranged in two rows and a flagellum formed by the typical 9+2 microtubule axoneme. In addition, the midpiece, with no cytoplasmic sheath, appeared to end blindly distally in a lobe-like pattern around the flagellum; a feature that was unique and considered adaptive for the spermatozoon of this species to the harsh external environment. These observations show that the testis of A. grahami often undergoes active spermatogenesis despite the harsh environmental conditions to which it is exposed on a daily basis within the lake. Further, the spermiogenic features and spermatozoal ultrastructure appear to be characteristic of Cichlidae and, therefore, may be of phylogenetic significance. 23685864 Defective twin boundaries in nanotwinned metals. Coherent twin boundaries (CTBs) are widely described, both theoretically and experimentally, as perfect interfaces that play a significant role in a variety of materials. Although the ability of CTBs in strengthening, maintaining the ductility and minimizing the electron scattering is well documented, most of our understanding of the origin of these properties relies on perfect-interface assumptions. Here we report experiments and simulations demonstrating that as-grown CTBs in nanotwinned copper are inherently defective with kink-like steps and curvature, and that these imperfections consist of incoherent segments and partial dislocations. We further show that these defects play a crucial role in the deformation mechanisms and mechanical behaviour of nanotwinned copper. Our findings offer a view of the structure of CTBs that is largely different from that in the literature, and underscore the significance of imperfections in nanotwin-strengthened materials. 23514042 Assessment of environmental health risks is feasible by secondary use of administrative registers. National register systems include detailed individual-level information. In the Nordic countries, these data sources include personal identification number, which can be used for linkages between registers. A case study on the effects of possible hazardous waste on the former and current residents of Myllypuro in Helsinki, Finland, is presented to assess if the utilisation of pre-collected official health register information is feasible in environmental health research. National register information was used as the primary data source, since large-scale health examination studies are seldom feasible and the use of surveys may result in biased information. The exposure data were based on residence information from the Central Population Register and the outcome data came from three national population and health registers. No evidence of health problems was found. The use of administrative register data was feasible, since the main prerequisites of epidemiological studies - the enumeration of exposed population without selection bias, the tracking of exposed population without loss to follow-up and the formation of different exposure measures - were reached. The small size of study sample and the rarity of several outcome measures impeded the analysis and the evaluation of clinical and public health aspects of the main findings. 23818674 The fundamentals of RNA purification. The ability to purify, analyze, and manipulate RNA is now essential for many laboratories working in the life sciences; however, the skills and practices required to work with RNA are not present in every laboratory, and initiating RNA research can be intimidating. In this article, we provide an overview of RNA purification procedures and discuss strategies to prevent RNA degradation, so that any competent researcher can confidently purify RNA and use it to perform meaningful experiments from the most basic to the highly sophisticated. 23950936 Connective Tissue Growth Factor (CTGF) Expression Modulates Response to High Glucose. Connective tissue growth factor (CTGF) is an important mediator of fibrosis; emerging evidence link changes in plasma and urinary CTGF levels to diabetic kidney disease. To further ascertain the role of CTGF in responses to high glucose, we assessed the consequence of 4 months of streptozotocin-induced diabetes in wild type (+/+) and CTGF heterozygous (+/-) mice. Subsequently, we studied the influence of glucose on gene expression and protein in mice embryonic fibroblasts (MEF) cells derived from wildtype and heterozygous mice. At study initiation, plasma glucose, creatinine, triglyceride and cholesterol levels were similar between non-diabetic CTGF+/+ and CTGF+/- mice. In the diabetic state, plasma glucose levels were increased in CTGF+/+ and CTGF+/- mice (28.2 3.3 mmol/L vs 27.0 3.1 mmol/L), plasma triglyceride levels were lower in CTGF+/- mice than in CTGF+/+ (0.7 0.2 mmol/L vs 0.5 0.1 mmol/L, p<0.05), but cholesterol was essentially unchanged in both groups. Plasma creatinine was higher in diabetic CTGF+/+ group (11.7±1.2 vs 7.9±0.6 µmol/L p<0.01), while urinary albumin excretion and mesangial expansion were reduced in diabetic CTGF+/- animals. Cortices from diabetic mice (both CTGF +/+ and CTGF +/-) manifested higher expression of CTGF and thrombospondin 1 (TSP1). Expression of nephrin was reduced in CTGF +/+ animals; this reduction was attenuated in CTGF+/- group. In cultured MEF from CTGF+/+ mice, glucose (25 mM) increased expression of pro-collagens 1, IV and XVIII as well as fibronectin and thrombospondin 1 (TSP1). In contrast, activation of these genes by high glucose was attenuated in CTGF+/- MEF. We conclude that induction of Ctgf mediates expression of extracellular matrix proteins in diabetic kidney. Thus, genetic variability in CTGF expression directly modulates the severity of diabetic nephropathy. 23463867 Demographic and motor features associated with the occurrence of neuropsychiatric and sleep complications of Parkinson's disease. To determine whether four key neuropsychiatric and sleep related features associated with Parkinson's disease (PD) are associated with the motor handicap and demographic data. The growing number of recognised non-motor features of PD makes routine screening of all these symptoms impractical. Here, we investigated the hypothesis that standard demographic data and the routine assessment of motor signs is associated with the presence of dementia, psychosis, clinically probable rapid eye movement (REM) sleep behavior disorder (cpRBD) and restless legs syndrome (RLS). 775 patients with PD underwent standardised assessment of motor features and the presence of dementia, psychosis, cpRBD and RLS. A stepwise feature elimination procedure with fitted logistic regression models was applied to identify which/if any combination of demographic and motor factors is associated with each of the four studied non-motor features. A within-study out-of-sample estimate of the power of the predicted values of the models was calculated using standard evaluation procedures. Age and Hoehn&Yahr (H&Y) stage were strongly associated with the presence of dementia (p value<0.001 for both factors in the final selected model) while a combination of age, disease duration, H&Y stage, dopamine agonists and catechol-O-methyltransferase (COMT) inhibitors was associated with the presence of psychosis. Disease duration and H&Y stage were the significant indicators of cpRBD, and the lack of significant motor asymmetry was the only significant feature associated with RLS-type symptoms but the evidence of association was weak. Demographic and motor features routinely collected in patients with PD can estimate the occurrence of neuropsychiatric and sleep-related features of PD. 23470840 Cognitive characteristics of PTEN hamartoma tumor syndromes. We sought to characterize cognition in individuals with germline PTEN mutations (n = 23) as well as in PTEN mutation-negative individuals with classic Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (n = 2). Twenty-five individuals completed a comprehensive neuropsychological evaluation. One sample t-tests and effect sizes were used to examine differences in participant test scores compared with normal controls. Composite scores were created for each patient within each of the cognitive domains assessed and classified as above average, average, or below average according to normative standards. χ(2) analyses compared these classifications to expected proportions in normal control samples. The mean intelligence quotient was in the average range, and the range of intellectual functioning was very wide (from extremely low to very superior). However, in a large subset of patients, scores were lower than expected on measures of motor functioning, executive functioning, and memory recall, suggesting disruption of frontal circuits in these participants. This is the first study to characterize cognition in individuals with PTEN mutations and associated syndromes using a comprehensive neuropsychological battery. Contrary to previous reports suggesting an association with intellectual disability, the mean intelligence quotient was average, and there was a broad range of intellectual abilities. Specific evidence of disruption of frontal circuits may have implications for treatment compliance and cancer surveillance, and further investigation is warranted. 23524663 Metabolism Studies of Unformulated Internally [3H]-labeled siRNAs in Mice. Absorption, distribution, metabolism, and excretion properties of two unformulated model siRNAs were determined using a single internal [(3)H]-radiolabeling procedure, where the full-length oligonucleotides were radiolabeled by Br/(3)H-exchange. Tissue distribution, excretion, and mass balance of radioactivity were investigated in male CD-1 mice, following a single intravenous administration of the [(3)H]-siRNAs, at a target dose level of 5 mg/kg. Quantitative whole-body autoradiography (QWBA) and liquid scintillation counting techniques were used to determine tissue distribution. Radiochromatogram profiles were determined in plasma, tissue extracts and urine. Metabolites were separated by liquid chromatography and identified by radiodetection and high-resolution accurate mass spectrometry. In general, there was little difference in the distribution of total radiolabeled components after administration of the two unformulated [(3)H]-siRNAs. The radioactivity was rapidly and widely distributed throughout the body, and remained detectable in all tissues investigated at later time points (24 and 48 hours for [(3)H]-MRP4 and [(3)H]-SSB siRNA, respectively). After an initial rapid decline, concentrations of total radiolabeled components in dried blood declined at a much slower rate. A nearly complete mass balance was obtained for the [(3)H]-SSB siRNA and renal excretion was the main route of elimination (38%). The metabolism of the two model siRNAs was rapid and extensive. Five minutes after administration, no parent compound could be detected in plasma. Instead, radiolabeled nucleosides resulting from nuclease hydrolysis were observed. In the metabolism profiles obtained from various tissues only radiolabeled nucleosides were found, suggesting that siRNAs are rapidly metabolized and that the distribution pattern of total radiolabeled components can be ascribed to small molecular weight metabolites. 23334329 Human skin neural crest progenitor cells are susceptible to BRAF(V600E)-induced transformation. Adult stem cells are multipotent and persist in small numbers in adult tissues throughout the lifespan of an organism. Unlike differentiated cells, adult stem cells are intrinsically resistant to senescence. It is unclear how adult stem cells in solid organs respond to oncogenic stimulation and whether these cells have a role in tumor initiation. We report here that expression of BRAF(V600E) in human neural crest progenitor cells (hNCPCs) did not induce growth arrest as seen in human melanocytes, but instead, increased their cell proliferation capacity. These cells (hNCPCs(V600E)) acquired anchorage-independent growth ability and were weakly tumorigenic in vivo. Unlike in human melanocytes, BRAF(V600E) expression in hNCPCs did not induce p16(INK4a) expression. BRAF(V600E) induced elevated expression of CDK2, CDK4, MITF and EST1/2 protein in hNCPCs, and also induced melanocytic differentiation of these cells. Furthermore, overexpression of MITF in hNCPCs(V600E) dramatically increased their tumorigenicity and resulted in fully transformed tumor cells. These findings indicate that hNCPCs are susceptible to BRAF(V600E)-induced transformation, and MITF potentiates the oncogenic effect of BRAF(V600E) in these progenitor cells. These results suggest that the hNCPCs are potential targets for BRAF(V600E)-induced melanocytic tumor formation.Oncogene advance online publication, 21 January 2013; doi:10.1038/onc.2012.642. 23907232 S100B and lactate dehydrogenase as response and progression markers during treatment with vemurafenib in patients with advanced melanoma. Vemurafenib is a highly efficient BRAF inhibitor for metastatic melanoma patients carrying the V600 mutation: progression-free survival is prolonged to ∼6 months and 50-80% of the patients show objective tumor responses. S100B and lactate dehydrogenase (LDH) are established tumor markers in routine melanoma follow-up. This study evaluated their potential as response and progression markers during vemurafenib treatment. A cohort of 44 patients with stage IV melanoma disease who were treated with vemurafenib was retrospectively analyzed. Staging was performed every 6-8 weeks comprising computed tomography scans and measurement of LDH and S100B levels. Response Evaluation Criteria In Solid Tumors (RECIST) criteria were used for standardized radiological response evaluations. The correlation between response or progression and LDH and S100B levels was analyzed using accuracy tests, Spearman's rank correlation ρ, and polynominal regression analyses. There was a good correlation between S100B and LDH decline and a RECIST-confirmed response, especially when S100B and/or LDH were elevated at baseline (accuracy, 81.2% for S100B and 85.7% for LDH). However, the accuracy in case of RECIST-confirmed progression and S100B/LDH levels was low - 30.3% for S100B and 32.4% for LDH. Neither Spearman's rank correlation ρ nor polynomial regression analyses showed a correlation between the clinical course and S100B/LDH levels. Measurement of S100B and LDH levels during treatment with vemurafenib indicates an initial response; however, this does not seem to be sufficient in detecting tumor progression and is thus not an alternative to monitoring with imaging examinations. 23776162 U6 RNA biogenesis and disease association. U6 snRNA is one of five uridine-rich noncoding RNAs that form the major spliceosome complex. Unlike other U-snRNAs, it reveals many distinctive aspects of biogenesis such as transcription by RNA polymerase III, transcript nuclear retention and particular features of transcript ends: monomethylated 5'-guanosine triphosphate as cap structure and a 2',3'-cyclic phosphate moiety (>P) at the 3' termini. U6-snRNA plays a central role in splicing and thus its transcription, maturation, snRNP formation, and recycling are essential for cellular homeostasis. U6 snRNA enters the splicing cycle as part of the tri-U4/U6.U5snRNP complex, and after significant structural arrangements forms the catalytic site of the spliceosome together with U2 snRNA and Prp8. U6 snRNA also contributes to the splicing reaction by coordinating metal cations required for catalysis. Many human diseases are associated with altered splicing processes. Disruptions of the basal splicing machinery can be lethal or lead to severe diseases such as spinal muscular atrophy, amyotrophic lateral sclerosis, or retinitis pigmentosa. Recent studies have identified a new U6 snRNA biogenesis factor Usb1, the absence of which leads to poikiloderma with neutropenia (PN) (OMIM 604173), an autosomal recessive skin disease. Usb1 is an evolutionarily conserved 3'→5' exoribonuclease that is responsible for removing 3'-terminal uridines from U6 snRNA transcripts, which leads to the formation of a 2',3' cyclic phosphate moiety (>P). This maturation step is fundamental for U6 snRNP assembly and recycling. Usb1 represents the first example of a direct association between a spliceosomal U6 snRNA biogenesis factor and human genetic disease.WIREs RNA 2013, 4:581-592. doi: 10.1002/wrna.1181 Conflict of interest: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website. 23665682 Experimental evidences for a new model in the description of the adsorption-coupled reduction of Cr(VI) by protonated banana skin. This work reports experimental evidences, not previously considered, to evaluate the Cr(VI) removal by protonated banana skin biomass. Variations in the number of hydroxyl groups, quantified by potentiometric titrations, and CO2 evolution during experiments, were attributed mainly to the oxidation of hydroxylic entities present in the studied material. The results indicate that these groups together with the carboxylic moieties are the main functionalities involved on the adsorption-coupled reduction process. The column experiment carried out provides a new approach to obtain the maximum reduction capacity of the material (3.72 mmol g(-1)). Moreover, we hereby propose a model that reports the first evidence for the instant bound of Cr(III) species to the material used, formed after the reduction of Cr(VI) present in solution. The removal process was quantified carrying out experiments under various pHs, biomass doses and Cr(VI) concentrations, and the mechanism underlying chromium removal was identified. 23922778 Deep sequencing analysis of HCV NS3 resistance-associated variants and mutation linkage in liver transplant recipients. Viral variants with decreased susceptibility to HCV protease inhibitors (PIs) occur naturally and preexist at low levels within HCV populations. In patients failing PI monotherapy, single and double mutants conferring intermediate to high-level resistance to PIs have been selected in vivo. The abundance, temporal dynamics and linkage of naturally occurring resistance-associated variants (RAVs), however, have not been characterized in detail. Here, using high-density pyrosequencing, we analyzed HCV NS3 gene segments from 20 subjects with chronic HCV infection, including 12 subjects before and after liver transplantation. Bioinformatics analysis revealed that Q80 substitution was a dominant variant in 40% of the subjects, whereas other RAVs circulate at low levels within quasispecies populations. Low frequency mutation linkage was detectable by Illumina paired-end sequencing in as low as 0.5% of the mock populations constructed from in vitro RNA transcripts but were uncommon in vivo. We show that naturally occurring RAVs are common and can persist long term following liver transplant at low levels not readily detectable by conventional sequencing. Our results indicate that mutation linkage at low levels could be identified using the Illumina paired-end approach. The methods described here should facilitate the analysis of low frequency HCV drug resistance, mutation linkage and evolution, which may inform future therapeutic strategies in patients undergoing direct acting antiviral therapies. 23896584 Orphan nuclear receptor HNF4G promotes bladder cancer growth and invasion through the regulation of the hyaluronan synthase 2 gene. Nuclear receptors (NRs) are a class of transcription factors that are closely involved in the progression of certain types of cancer. We aimed to study the relation between bladder cancer and NRs, with special focus on orphan NRs whose ligands and functions have not been identified. First, we examined the expression levels of 22 genes encoding orphan NRs in clinical bladder cancer and found that hepatocyte nuclear factor 4γ (HNF4G; NR2A2) and NR2F6 were the genes that were upregulated most frequently in cancer tissues compared with their paired normal tissues. Knockdown and overexpression of each of these orphan NRs suppressed and stimulated the growth of bladder cancer cells in vitro, respectively. HNF4G also promoted tumor growth in bladder cancer xenograft models in vivo. Furthermore, HNF4G was both necessary and sufficient for the invasion of bladder cancer cells in vitro. Moreover, using microarray analyses, we identified hyaluronan synthase 2 (HAS2) as one of the genes induced by HNF4G in bladder cancer cells. Transcription was activated by HNF4G in reporter assays using the promoter/enhancer region of the HAS2 gene. The endogenous expression of the HAS2 gene was suppressed by knockdown of HNF4G. In turn, knockdown of HAS2 inhibited the growth and invasion of bladder cancer cells. Taken together, our data suggest that some orphan NRs are involved in bladder cancer progression and that, among them, HNF4G promotes the growth and invasion of bladder cancer, at least in part, via the regulation of the HAS2 gene. 23883241 Imaging evaluation of laparoscopic greater curvature plication: preliminary observations. OBJECTIVE. The purpose of this article is to assess normal imaging findings and complications after laparoscopic greater curvature plication on luminal upper gastrointestinal studies and CT. MATERIALS AND METHODS. This was a retrospective chart review of 24 adults who underwent laparoscopic greater curvature plication between 2008 and 2011. Seventeen patients (70.8%) underwent postoperative luminal upper gastrointestinal studies, and four (16.7%) underwent postoperative CT. Normal imaging features and complications were recorded. The percentage of intraluminal gastric diameter occupied by the plicated segment and the percentage of greater curvature involved on postoperative upper gastrointestinal luminal studies were determined. RESULTS. A multilobular intraluminal filling defect reflecting the surgical plication occupied the proximal third of the greater curvature in 16 of 17 patients (94%), extending to the mid portion in 10 of 17 patients (59%) and to the distal third in one of 17 patients (6%). There was luminal narrowing of 50-75% in 14 of 17 patients (82%) and narrowing of 25-50% in two patients (12%). In 14 of 17 patients (82%), the plication involved 50-75% of the greater curvature length and 25-50% in the remaining three patients (18%). In four patients who underwent CT, a central low-attenuation stripe accompanied the plication. Five of 24 patients (21%) had complications, including extraluminal gastric leak (n = 1), gastric outlet obstruction (n = 2), and plication suture failure (n = 2). CONCLUSION. Laparoscopic greater curvature plication is seen as multilobular filling defects most commonly along the proximal greater curvature with 50-75% narrowing of the gastric lumen. A linear low-attenuation stripe accompanies the filling defect on CT. 23489620 Synthesis and evaluation of cholecystokinin trimers: a multivalent approach to pancreatic cancer detection and treatment. In the quest for novel tools for early detection and treatment of cancer, we propose the use of multimers targeting overexpressed receptors at the cancer cell surface. Indeed, multimers are prone to create multivalent interactions, more potent and specific than their corresponding monovalent versions, thus enabling the potential for early detection. There is a lack of tools for early detection of pancreatic cancer, one of the deadliest forms of cancer, but CCK2-R overexpression on pancreatic cancer cells makes CCK based multimers potential markers for these cells. In this Letter, we describe the synthesis and evaluation of CCK trimers targeting overexpressed CCK2-R. 23966996 Vasomotor regulation of coronary microcirculation by oxidative stress: role of arginase. Overproduction of reactive oxygen species, i.e., oxidative stress, is associated with the activation of redox signaling pathways linking to inflammatory insults and cardiovascular diseases by impairing endothelial function and consequently blood flow dysregulation due to microvascular dysfunction. This review focuses on the regulation of vasomotor function in the coronary microcirculation by endothelial nitric oxide (NO) during oxidative stress and inflammation related to the activation of L-arginine consuming enzyme arginase. Superoxide produced in the vascular wall compromises vasomotor function by not only scavenging endothelium-derived NO but also inhibiting prostacyclin synthesis due to formation of peroxynitrite. The upregulation of arginase contributes to the deficiency of endothelial NO and microvascular dysfunction in various vascular diseases by initiating or following oxidative stress and inflammation. Hydrogen peroxide, a diffusible and stable oxidizing agent, exerts vasodilator function and plays important roles in the physiological regulation of coronary blood flow. In occlusive coronary ischemia, the release of hydrogen peroxide from the microvasculature helps to restore vasomotor function of coronary collateral microvessels with exercise training. However, excessive production and prolonged exposure of microvessels to hydrogen peroxide impairs NO-mediated endothelial function by reducing L-arginine availability through hydroxyl radical-dependent upregulation of arginase. The redox signaling can be a double-edged sword in the microcirculation, which helps tissue survival in one way by improving vasomotor regulation and elicits oxidative stress and tissue injury in the other way by causing vascular dysfunction. The impact of vascular arginase on the development of vasomotor dysfunction associated with angiotensin II receptor activation, hypertension, ischemia-reperfusion, hypercholesterolemia, and inflammatory insults is discussed. 23835916 Molecular Characterization of the Major Histocompatibility Complex Class Ia Gene in the Black-Spotted Frog, Pelophylax nigromaculata. The genes of the major histocompatibility complex (MHC) are attractive candidates for investigating the link between adaptive variation and individual fitness. We improved rapid amplification of cDNA ends to obtain the whole coding sequence of the MHC class Ia gene of the black-spotted frog (Pelophylax nigromaculata), the most common amphibian in China. We also used genome walking to characterize the partial introns adjacent to exon 3 of the MHC Ia gene. Based on the sequences obtained, we designed locus-specific primers to investigate the molecular polymorphisms of this species in southeast China. The MHC class Ia gene showed a high level of genetic diversity, indicating that this species retains a relatively high potential for survival, despite a population decline among frog species in general and many other amphibians. 23398172 Inductive tuning of Fano-resonant metasurfaces using plasmonic response of graphene in the mid-infrared. Graphene is widely known for its anomalously strong broadband optical absorptivity of 2.3% that enables seeing its single-atom layer with the naked eye. However, in the mid-infrared part of the spectrum graphene represents a quintessential lossless zero-volume plasmonic material. We experimentally demonstrate that, when integrated with Fano-resonant plasmonic metasurfaces, single-layer graphene (SLG) can be used to tune their mid-infrared optical response. SLG's plasmonic response is shown to induce large blue shifts of the metasurface's resonance without reducing its spectral sharpness. This effect is explained by a generalized perturbation theory of SLG-metamaterial interaction that accounts for two unique properties of the SLG that set it apart from all other plasmonic materials: its anisotropic response and zero volume. These results pave the way to using gated SLG as a platform for dynamical spectral tuning of infrared metamaterials and metasurfaces. 23578658 Comparison of spectrophotometric and HPLC methods for determination of carotenoids in foods. This report is aimed at intra-laboratory and inter-laboratory comparison of the results obtained during spectrophotometric and HPLC analyses of lycopene, β-carotene and total carotenoids in tomato products and yellow maize flours/grits. Extensive statistical analyses are performed in order to identify the main sources of uncertainties which may occur when using: (i) different techniques/methods/approaches in the same/different laboratories, in various food samples, and (ii) to indicate the facts/conditions under which the biases between results may remain unidentified after applying statistical testing. Our data points to the inertness of t-test to detect significance of differences, particularly at low R values: in general, the higher correlation coefficient, the higher is sensitivity of statistical testing, especially of the paired t-test. Therefore, simple deviation of relationship line slope from unity could be used as additional evaluation parameter. This adds to reliable and objective quality assurance of foods in regard to carotenoids. 23241764 Brown class III maxillectomy defects reconstruction with prefabricated titanium mesh and soft tissue free flap. Midface reconstruction is one of the most challenging tasks for the reconstructive surgeon. We present a technique for the reconstruction of the midface after total maxillectomy with preservation of orbital contents. Skeletal reconstruction is achieved with a preoperatively bent titanium sheet mesh on a universal skeletal model. The alveolar ridge, the anterior wall of the maxillary sinus, the zygomatic prominence, the lower orbital rim, and the orbital floor are reconstructed with a titanium mesh. A soft tissue free flap, preferably anterolateral thigh free flap, is harvested as well. A part of the flap is deepithelized and put in front of the mesh to prevent exposure, and the other part is used for palatal reconstruction. Four male and 1 female patients were reconstructed with titanium mesh. Four free flaps were raised: 3 anterolateral thigh and 1 latissimus dorsi. All free flaps survived. All patients received postoperative irradiation with 64 Gy. Median follow-up was 12 months; no major complications occurred. Mesh was exposed in only 1 case, which was managed successfully with resuspension of the heavy latissimus dorsi myocutaneous flap. Midface projection and height, globe position, ocular movements, and vision where satisfactory in all cases. Midface reconstruction with titanium mesh and soft tissue free flap is a reliable and safe method for functional and aesthetic reconstruction after maxillectomy. 23963319 Deep tissue optical imaging of upconverting nanoparticles enabled by exploiting higher intrinsic quantum yield through use of millisecond single pulse excitation with high peak power. We have accomplished deep tissue optical imaging of upconverting nanoparticles at 800 nm, using millisecond single pulse excitation with high peak power. This is achieved by carefully choosing the pulse parameters, derived from time-resolved rate-equation analysis, which result in higher intrinsic quantum yield that is utilized by upconverting nanoparticles for generating this near infrared upconversion emission. The pulsed excitation approach thus promises previously unreachable imaging depths and shorter data acquisition times compared with continuous wave excitation, while simultaneously keeping the possible thermal side-effects of the excitation light moderate. These key results facilitate means to break through the general shallow depth limit of upconverting-nanoparticle-based fluorescence techniques, necessary for a range of biomedical applications, including diffuse optical imaging, photodynamic therapy and remote activation of biomolecules in deep tissues. 23252880 Dependence of QSAR models on the selection of trial descriptor sets: a demonstration using nanotoxicity endpoints of decorated nanotubes. Little attention has been given to the selection of trial descriptor sets when designing a QSAR analysis even though a great number of descriptor classes, and often a greater number of descriptors within a given class, are now available. This paper reports an effort to explore interrelationships between QSAR models and descriptor sets. Zhou and co-workers (Zhou et al., Nano Lett. 2008, 8 (3), 859-865) designed, synthesized, and tested a combinatorial library of 80 surface modified, that is decorated, multi-walled carbon nanotubes for their composite nanotoxicity using six endpoints all based on a common 0 to 100 activity scale. Each of the six endpoints for the 29 most nanotoxic decorated nanotubes were incorporated as the training set for this study. The study reported here includes trial descriptor sets for all possible combinations of MOE, VolSurf, and 4D-fingerprints (FP) descriptor classes, as well as including and excluding explicit spatial contributions from the nanotube. Optimized QSAR models were constructed from these multiple trial descriptor sets. It was found that (a) both the form and quality of the best QSAR models for each of the endpoints are distinct and (b) some endpoints are quite dependent upon 4D-FP descriptors of the entire nanotube-decorator complex. However, other endpoints yielded equally good models only using decorator descriptors with and without the decorator-only 4D-FP descriptors. Lastly, and most importantly, the quality, significance, and interpretation of a QSAR model were found to be critically dependent on the trial descriptor sets used within a given QSAR endpoint study. 23968074 A quasi-continuum hydrodynamic model for slit shaped nanochannel flow. We propose a quasi-continuum hydrodynamic model for isothermal transport of Lennard-Jones fluid confined in slit shaped nanochannels. In this work, we compute slip and viscous contributions independently and superimpose them to obtain the total velocity profile. Layering of fluid near the interface plays an important role in viscous contribution to the flow, by apparent viscosity change along the confining dimension. This relationship necessitates computing density profiles, which is done using the recently proposed empirical-potential based quasi-continuum theory [A. V. Raghunathan, J. H. Park, and N. R. Aluru, J. Chem. Phys. 127, 174701 (2007)]. Existing correlations for density dependent viscosity provided by Woodcock [AIChE J. 52, 438 (2006)] are used to compute viscosity profile in the nanopores. A Dirichlet type slip boundary condition based on a static Langevin friction model describing center-of-mass motion of fluid particles is used, the parameters of which are dependent on the fluctuations of total wall-fluid force from an equilibrium molecular dynamics simulation. Different types of corrugated surfaces are considered to study wall-fluid friction effects on boundary conditions. Proposed hydrodynamic model yields good agreement of velocity profiles obtained from non-equilibrium molecular dynamics simulations for gravity driven flow. 23847346 A Secondary ROS1 Mutation Confers Crizotinib Resistance. A ROS1 kinase domain mutation in CD74-ROS1 conferred crizotinib resistance in a patient. 23142867 Preoperative prediction of acute kidney injury--from clinical scores to biomarkers. Early acute kidney injury (AKI) diagnosis in critically ill children has been an important recent research focus because of the known association of AKI with poor outcomes and the requirement of early intervention to mitigate negative effects of AKI. In children having surgery, the preoperative period offers a unique opportunity to predict postoperative acute kidney injury (AKI), well before AKI occurs. Pediatric AKI epidemiologic studies have begun to identify which preoperative factors may predict development of postoperative cardiac surgery. Using these clinical risk factors, it may be possible to derive preoperative clinical risk scores and improve upon our ability to risk-stratify children into AKI treatment trials, pre-emptively provide conservative renal injury prevention strategies, and ultimately improve patient outcomes. Developing risk scores requires rigorous methodology and validation before widespread use. There is little information currently on the use of preoperative biological or physiological biomarkers to predict postoperative AKI, representing an important area of future research. This review will provide an overview of methodology of preoperative risk score development, discuss pediatric-specific issues around deriving such risk scores, including the combination of preoperative clinical and biologic biomarkers for AKI prediction, and suggest future research avenues. 23970462 Chemotherapy for thymic carcinoma and advanced thymoma in adults. Thymic carcinoma or advanced thymoma is a rare cancer of the thymus gland that tends to be aggressive and infiltrate neighbouring organs, making total resection very difficult. Induction or adjuvant chemotherapy, or both, are often used in a multimodality approach to treat people affected by this condition, but the effectiveness of chemotherapy for thymic carcinoma or advanced thymoma remains uncertain. To assess the role of chemotherapy in adults with thymic carcinoma or advanced thymoma. We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2012, Issue 7), MEDLINE (accessed via Ovid from 1966 to July 2012), EMBASE (accessed via Ovid, from 1980 to July 2012), Latin American and Caribbean Literature on Health Sciences (LILACS), the Chinese Biological Medicine Database (CBM, 1978 to July 2012), China National Knowledge Infrastructure (CNKI, 1980 to July 2012) and the Chinese scientific periodical database VIP Information (VIP, 1989 to July 2012). There was no language restriction in searching for studies. We planned to include randomised controlled trials (RCTs) of  trials using chemotherapy (either single-agent or combination chemotherapy plus surgery, radiotherapy or not) for thymic carcinoma and/or advanced thymoma. We planned to include all adults (aged 18 years and over) diagnosed with thymic carcinoma and/or with Masaoka stage III or IV thymic tumours. The intended primary outcomes were overall survival (OS) and progression-free survival (PFS). Two review authors independently evaluated the search results according to the inclusion and exclusion criteria. There were no studies identified for inclusion and therefore no data extraction was completed. No RCTs were eligible for inclusion in this review. We report details of excluded prospective studies in an additional table and try to provide some useful evidence regarding current practice. There were no RCTs eligible for inclusion in this review. In current practice the most common regimen for adult patients with thymic carcinoma or advanced thymoma is cisplatin-based chemotherapy. Considering the condition is rare, it is suggested that an international group is set up to organise and evaluate prospective collection of data from cohorts of patients to inform current clinical practice. 23831092 Simultaneous analysis of Nε-(carboxymethyl)lysine, reducing sugars, and lysine during the dairy thermal process. A new analytical method allowing the simultaneous quantification of Nε-(carboxymethyl)lysine (CML), lysine, and reducing sugars (glucose, lactose, and galactose) is described. It is based on high performance anion-exchange chromatography with pulsed amperometric electrochemical detection. This method demonstrated a low limit of quantification (0.385 to 0.866mg/L), excellent linear correlation (R(2)>0.997), and desired calibration range (3.125 to 25mg/L). In addition, lactose-lysine solutions containing sulfite (4 to 400mmol/L) were heated at 110°C for 2h. The results showed that sulfite inhibited the formation of CML and promoted the consumption of reducing sugars and lysine in the Maillard reaction model. The method proved to be useful for simultaneous analysis of CML, lysine, and reducing sugars (glucose, galactose, and lactose) in the Maillard reaction system. Moreover, sulfite was an effective inhibitor of CML formation. 23568277 A beta-complex statistical four body contact potential combined with a hydrogen bond statistical potential recognizes the correct native structure from protein decoy sets. We present a new four-body knowledge-based potential for recognizing the native state of proteins from their misfolded states. This potential was extracted from a large set of protein structures determined by X-ray crystallography using BetaMol, a software based on the recent theory of the beta-complex (β-complex) and quasi-triangulation of the Voronoi diagram of spheres. This geometric construct reflects the size difference among atoms in their full Euclidean metric; property not accounted for in a typical 3D Delaunay triangulation. The ability of this potential to identify the native conformation over a large set of decoys was evaluated. Experiments show that this potential outperforms a potential constructed with a classical Delaunay triangulation in decoy discrimination tests. The addition of a statistical hydrogen bond potential to our four-body potential allows a significant improvement in the decoy discrimination, in such a way that we are able to predict successfully the native structure in 90% of cases. Proteins 2013; 81:1420-1433. © 2013 Wiley Periodicals, Inc. 23863686 Saliency and Saccade Encoding in the Frontal Eye Field During Natural Scene Search. The frontal eye field (FEF) plays a central role in saccade selection and execution. Using artificial stimuli, many studies have shown that the activity of neurons in the FEF is affected by both visually salient stimuli in a neuron's receptive field and upcoming saccades in a certain direction. However, the extent to which visual and motor information is represented in the FEF in the context of the cluttered natural scenes we encounter during everyday life has not been explored. Here, we model the activities of neurons in the FEF, recorded while monkeys were searching natural scenes, using both visual and saccade information. We compare the contribution of bottom-up visual saliency (based on low-level features such as brightness, orientation, and color) and saccade direction. We find that, while saliency is correlated with the activities of some neurons, this relationship is ultimately driven by activities related to movement. Although bottom-up visual saliency contributes to the choice of saccade targets, it does not appear that FEF neurons actively encode the kind of saliency posited by popular saliency map theories. Instead, our results emphasize the FEF's role in the stages of saccade planning directly related to movement generation. 23821307 Progestin-only contraceptives: effects on weight. Progestin-only contraceptives (POCs) are appropriate for many women who cannot or should not take estrogen. Many POCs are long-acting, cost-effective methods of preventing pregnancy. However, concern about weight gain can deter the initiation of contraceptives and cause early discontinuation among users. The primary objective was to evaluate the association between progestin-only contraceptive use and changes in body weight. Through May 2013, we searched MEDLINE, CENTRAL, POPLINE, LILACS, ClinicalTrials.gov, and ICTRP. The 2010 search also included EMBASE. For the initial review, we contacted investigators to identify other trials. All comparative studies were eligible that examined a POC versus another contraceptive method or no contraceptive. The primary outcome was mean change in body weight or mean change in body composition. We also considered the dichotomous outcome of loss or gain of a specified amount of weight. Two authors extracted the data. We computed the mean difference (MD) with 95% confidence interval (CI) for continuous variables. For dichotomous outcomes, the Mantel-Haenszel odds ratio (OR) with 95% CI was calculated. We found 16 studies; one examined progestin-only pills, one studied the levonorgestrel-releasing intrauterine system (LNG-IUS), four examined an implant, and 10 focused on depot medroxyprogesterone acetate (DMPA). Outcomes examined were changes in body weight only (14 studies), changes in both body weight and body composition (1 study), and changes in body composition only (1 study). We did not conduct meta-analysis due to the various contraceptive methods and weight change measures.Comparison groups did not differ significantly for weight change in 12 studies. However, three studies showed weight change differences for POC users compared to women not using a hormonal method. In one study, weight gain (kg) was greater for the DMPA group than the group using a non-hormonal IUD in years one through three [(MD 2.28; 95% CI 1.79 to 2.77), (MD 2.71, 95% CI 2.12 to 3.30), and (MD 3.17; 95% CI 2.51 to 3.83), respectively]. The differences were notable within the normal weight and overweight subgroups. Two implant studies also showed differences in weight change. The implant group (six-capsule) had greater weight gain (kg) compared to the group using a non-hormonal IUD in both studies [(MD 0.47 (95% CI 0.29 to 0.65); (MD 1.10; 95% CI 0.36 to 1.84)]. In one of those studies, the implant group also had greater weight gain than a group using a barrier method or no contraceptive (MD 0.74; 95% CI 0.52 to 0.96).The two studies that assessed body composition change showed differences between POC users and women not using a hormonal method. Adolescents using DMPA had a greater increase in body fat (%) compared to a group not using a hormonal method (MD 11.00; 95% CI 2.64 to 19.36). The DMPA group also had a greater decrease in lean body mass (%) (MD -4.00; 95% CI -6.93 to -1.07). The other study reported differences between an LNG-IUS group and a non-hormonal IUD group in percent change in body fat mass (2.5% versus -1.3%, respectively; reported P value = 0.029) and percent change in lean body mass (-1.4% versus 1.0%, respectively; reported P value = 0.027). The overall quality of evidence was moderate to low, given that the studies were evenly divided across the evidence quality groups (high, moderate, low, or very low quality). We found limited evidence of weight gain when using POCs. Mean gain was less than 2 kg for most studies up to 12 months. Weight change for the POC group generally did not differ significantly from that of the comparison group using another contraceptive. Two studies that assessed body composition showed that POC users had greater increases in body fat and decreases in lean body mass compared to users of non-hormonal methods. Appropriate counseling about typical weight gain may help reduce discontinuation of contraceptives due to perceptions of weight gain. 23767925 Global Increase in Task-related Fronto-parietal Activity after Focal Frontal Lobe Lesion. A critical question for neuropsychology is how complex brain networks react to damage. Here, we address this question for the well-known executive control or multiple-demand (MD) system, a fronto-parietal network showing increased activity with many different kinds of cognitive demand, including standard tests of fluid intelligence. Using fMRI, we ask how focal frontal lobe damage affects MD activity during a standard fluid intelligence task. Despite poor behavioral performance, frontal patients showed increased fronto-parietal activity relative to controls. The activation difference was not accounted for by difference in IQ. Moreover, rather than specific focus on perilesional or contralesional cortex, additional recruitment was distributed throughout the MD regions and surrounding cortex and included parietal MD regions distant from the injury. The data suggest that, following local frontal lobe damage, there is a global compensatory recruitment of an adaptive and integrated fronto-parietal network. 23489985 Could an abandoned mercury mine area be cropped? The Almadén area (Spain) is known for its high natural mercury background as well as for the anthropogenic impact due to mining activities. After the end of these activities, appropriate alternative use of the soil has to be found, and agricultural activities stand out as an environmentally-friendly and potentially profitable alternative, giving to the soil a sustainable use without risks for human or animal health according to current legislation. Experiments performed at different scales (involving hydroponics, growth in pots and lysimeters) allow recommendations to be made regarding the adequacy of cultivation of different crops for animal or human consumption before they are sown in the field. Regarding crops for animal feeding, mercury accumulation in vegetative organs represents a higher potential risk for animals. Nevertheless, seeds and fruits can be used, both for human and animal consumption. Finally, this work will lead the way to obtain a scientific basis for elaborating a list of recommendations on sustainable and safe alternative land use, according to current international legislation. 22968693 Clear evidence of carcinogenic activity by a whole-leaf extract of Aloe barbadensis miller (aloe vera) in F344/N rats. Aloe barbadensis Miller (Aloe vera) is an herbal remedy promoted to treat a variety of illnesses; however, only limited data are available on the safety of this dietary supplement. Drinking water exposure of F344/N rats and B6C3F1 mice to an Aloe vera whole-leaf extract (1, 2, and 3%) for 13 weeks resulted in goblet cell hyperplasia of the large intestine in both species. Based upon this observation, 2-year drinking water studies were conducted to assess the carcinogenic potential of an Aloe vera whole-leaf extract when administered to F344/N rats (48 per sex per group) at 0.5, 1, and 1.5%, and B6C3F1 mice (48 per sex per group) at 1, 2, and 3%. Compared with controls, survival was decreased in the 1.5% dose group of female rats. Treatment-related neoplasms and nonneoplastic lesions in both species were confined primarily to the large intestine. Incidences of adenomas and/or carcinomas of the ileo-cecal and cecal-colic junction, cecum, and ascending and transverse colon were significantly higher than controls in male and female rats in the 1 and 1.5% dose groups. There were no neoplasms of the large intestine in mice or in the 0 or 0.5% dose groups of rats. Increased incidences of mucosa hyperplasia of the large intestine were observed in F344/N rats, and increased incidences of goblet cell hyperplasia of the large intestine occurred in B6C3F1 mice. These results indicate that Aloe vera whole-leaf extract is an intestinal irritant in F344/N rats and B6C3F1 mice and a carcinogen of the large intestine in F344/N rats. 23900973 Virus-encoded endonucleases: expected and novel functions. Endonucleases catalyze critical steps in the processing, function, and turnover of many cellular RNAs. It is, therefore, not surprising that a number of viruses encode endonucleases that play important roles in viral gene expression. The virion host shutoff (Vhs) endonuclease of herpes simplex virus, the SOX protein of Kaposi Sarcoma Herpesvirus (KSHV), and the influenza virus PB1 endonuclease have well-characterized functions that stem from their abilities to cleave RNA. Vhs accelerates turnover of many cellular and viral mRNAs, redirecting the cell from host to viral gene expression, counteracting key elements of the innate immune response, and facilitating sequential expression of different classes of viral genes. SOX reduces synthesis of many host proteins during the lytic phase of KSHV infections. PB1 is a component of the influenza RNA polymerase that snatches capped oligonucleotides from cellular pre-mRNAs to serve as primers during viral mRNA synthesis. However, all three proteins have important second functions. Vhs stimulates translation of the 3' cistron of bicistronic mRNAs that have selected cellular internal ribosome entry sites, and stimulates polysome loading and translation of selected viral mRNAs at late times during productive infections. SOX has an alkaline exonuclease activity that is important for processing and maturation of newly synthesized copies of the KSHV genome. The influenza RNA polymerase binds the cap and 5' region of viral mRNAs and recruits eIF4G and other factors to viral mRNAs, allowing them to be translated under conditions of reduced eIF4E functionality. This review will discuss the novel and expected functions of these viral endonucleases. Conflict of interest: The author has declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website. 23671905 A label-free amplified fluorescence DNA detection based on isothermal circular strand-displacement polymerization reaction and graphene oxide. A label-free fluorescent DNA biosensor has been presented based on isothermal circular strand-displacement polymerization reaction (ICSDPR) combined with graphene oxide (GO) binding. The proposed method is simple and cost-effective with a low detection limit of 4 pM, which compares favorably with other GO-based homogenous DNA detection methods. 23886074 Geometric morphometric footprint analysis of young women. Most published attempts to quantify footprint shape are based on a small number of measurements. We applied geometric morphometric methods to study shape variation of the complete footprint outline in a sample of 83 adult women. The outline of the footprint, including the toes, was represented by a comprehensive set of 85 landmarks and semilandmarks. Shape coordinates were computed by Generalized Procrustes Analysis. The first four principal components represented the major axes of variation in foot morphology: low-arched versus high-arched feet, long and narrow versus short and wide feet, the relative length of the hallux, and the relative length of the forefoot. These shape features varied across the measured individuals without any distinct clusters or discrete types of footprint shape. A high body mass index (BMI) was associated with wide and flat feet, and a high frequency of wearing high-heeled shoes was associated with a larger forefoot area of the footprint and a relatively long hallux. Larger feet had an increased length-to-width ratio of the footprint, a lower-arched foot, and longer toes relative to the remaining foot. Footprint shape differed on average between left and right feet, and the variability of footprint asymmetry increased with BMI. Foot shape is affected by lifestyle factors even in a sample of young women (median age 23 years). Geometric morphometrics proved to be a powerful tool for the detailed analysis of footprint shape that is applicable in various scientific disciplines, including forensics, orthopedics, and footwear design. 22943130 Quantitation of UGT1A1 in human liver microsomes using stable isotope-labelled peptides and mass spectrometry based proteomic approaches. 1. UDP-glucuronosyltransferases (UGTs) are a group of drug-metabolizing enzymes that catalyse the conjugation of endogeonous compounds and xenobiotics to yield hydrophilic glucuronides which subsequently undergo excretion. This report describes an approach for the identification and accurate quantitation of human UGT1A1 in complex biological matrices using liquid chromatography/mass spectrometry/mass spectrometry (LC-MS/MS) analysis of protein digests. 2. A stable isotope-labelled (SIL) peptide of a unique peptide spanning residues 54-69 in exon 1 of the human UGT1A1 protein with the sequence RIYLSADPALVVIEHG was synthesized. The peptide sequence synthesized was in the reverse order of the human peptide with the stable isotope-labels in the amino acid arginine ((13)C6(15)N4) resulting in an increase in the mass of the SIL peptide of 10 amu, from 1753 to 1763. The SIL peptide was quantitated by injecting increasing concentrations of the peptide into the LC-MS to obtain a standard curve. 3. The labelled peptide along with precursor ion monitoring was used to quantify the levels of UGT1A1 in commercial recombinant preparations (supersomes) and individual human liver microsomal samples and pooled human liver micrsomes obtained from BD Biosciences. 4. Glucuronidation activity studies were performed, which demonstrated a positive correlation between enzyme activity levels and the UGT1A1 content in the liver microsomes obtained from individual human donors. 23432183 Peritransplant gastrointestinal symptoms in familial amyloidotic polyneuropathy. Gastrointestinal dysfunction is a common complication in familial amyloidotic polyneuropathy, and gastrointestinal symptoms are associated with a patient's nutritional status. The object of this study was to evaluate changes in peritransplant gastrointestinal symptoms and the nutritional status of familial amyloidotic polyneuropathy patients using the modified body mass index following a living-donor liver transplant. In a retrospective analysis, we compared 17 Japanese familial amyloidotic polyneuropathy patients who underwent living-donor liver transplant in Kumamoto University Hospital between 2000 and 2009 with a control group of 28 patients with chronic liver disease. We analyzed the peritransplant gastrointestinal symptoms, nutritional status, duration of central venous catheterization, and postoperative hospital stay. The Mann-Whitney U test and Fisher exact test were used to analyze relations between the familial amyloidotic polyneuropathy group and control group, and the Wilcoxon signed-rank test, to analyze the relation of perioperative modified body mass index, with a value for P < .05 considered statistically significant. The duration of central venous catheterization and postoperative hospital stay were significantly longer in the familial amyloidotic polyneuropathy group than they were in the control group. There was no significant difference between modified body mass index preoperatively and 1 year after living-donor liver transplant. Although gastrointestinal symptoms were typically mild before living-donor liver transplant, the familial amyloidotic polyneuropathy group experienced a temporary deterioration in gastrointestinal symptoms after receiving the living-donor liver transplant but recovered after approximately 2 months. Although familial amyloidotic polyneuropathy patients experienced temporary exacerbations of gastrointestinal symptoms, their nutritional status was not affected during the peritransplant period, and they generally recovered within 2 months. 23787215 An empirical formula to obtain tissue-phantom ratios from percentage depth-dose curves for small fields. For small photon fields, accurate values of a tissue-phantom ratio (TPR) are difficult to obtain either by direct measurement or by the conventional method of converting from measured percentage depth doses (%dd). This study aims to develop an empirical method to accurately obtain TPRs from %dd curves for small radiosurgery beams. The Monte Carlo simulation codes BEAMnrc/DOSXYZnrc were used to simulate the accelerator head and small, collimated fields including the circular cone accessory. The Monte Carlo directly calculated TPR values as a function of depth were compared with TPRs converted from %dd curves in a water phantom for field sizes ranging from 4 mm diameter to 10 Ã— 10 cm(2) fields. Direct measurements of TPRs were performed with the detector remaining fixed at a SAD of 100 cm and increasing the detector depth by adding water. The %dd curves were measured at 100 cm SSD in a 50 Ã— 50 Ã— 50 cm(3) water tank. Using the Monte Carlo values, we developed an empirical formula to obtain TPRs from %dd and validated its accuracy. The conventional method of obtaining TPRs from %dd underestimate TPR by 3.4% and 0.6% at a depth 1.5 cm and overestimate TPR by 6.4% and 1.7% at a depth of 25 cm for 4 mm and 30 mm diameter circular fields, respectively. The empirical formula is derived from realistic Monte Carlo simulations using field sizes ranging from 4 to 30 mm and depth ranging from 1.5 to 25 cm. TPRs calculated using this function deviate from TPRs directly calculated from Monte Carlo by less than 0.5%. The accuracy of this empirical formula is validated against the directly measured TPRs in water. The developed empirical method has the potential to greatly simply the work in obtaining TPRs from measured %dd curves for small fields. By using this developed empirical formula the uncertainties between directly measured TPRs and converted TPRs from measured %dd curves are within 1%. 23419488 The state of clinical pharmacology today. It has been more than 40 years since a major position paper on clinical pharmacology was published by the World Health Organization (WHO). A recent publication, Clinical Pharmacology in Health Care, Teaching, and Research, provides a current vision of the discipline suitable for the twenty-first century. 23662740 Cytomegalovirus retinitis in immunocompetent patients: case reports and literature review. The purpose of this study was to examine 2 cases of cytomegalovirus (CMV) retinitis, occuring in 2 immunocompentent adult patients. Case selection and literature review. Both patients cited significantly decreased vision despite systemic, topical, and/or local corticosteroid use. Neither patient was using high-dose immunosuppressant therapy at the time of diagnostic testing. Both patients exhibited confirmed CMV infection via polymerase chain reaction DNA testing. Oral antivirals were employed and have stabilized both patients. The cases described herein serve to inform ophthalmologists of the urgent need to include CMV in their differential when encountering an immunocompetent adult with significant comorbidities or with a history of previous exposure. Proper treatment is heavily reliant on proper diagnosis. 23692614 Femoral neck cross-sectional geometry and exercise loading. The aim of this study was to examine the association between different types of exercise loading and femoral neck cross-sectional geometry. Our data comprised proximal femur magnetic resonance (MR) images obtained from 91 female athletes and their 20 age-matched controls. The athletes were categorized according to typical training activity - high impact (high and triple jumping), odd impact (racket and soccer playing), high magnitude (power lifting), repetitive low impact (endurance running) and repetitive non-impact (swimming). Segmented MR images at two locations, narrowest cross-section of the femoral neck (narrowFN) and the cross-section at insertion of articular capsule (distalFN), were investigated to detect between group differences in shape, curvature and buckling ratio derived using image and signal analysis tools. The narrowFN results indicated that the high-impact group had weaker antero-superior (33% larger buckling ratio than controls) but stronger inferior weight-bearing region (32% smaller than controls), while the odd-impact group had stronger superior, posterior and anterior region (21% smaller buckling ratio than controls). The distalFN results indicated that the high-impact group had stronger inferior region (37% smaller buckling ratio), but the odd-impact group had stronger superior region (22% smaller buckling ratio) than the controls. Overall, the results point towards odd-impact exercise loading, with inherently varying directions of impact, associated with more robust cross-sectional geometry along the femoral neck. In conclusion, our one-dimensional polar treatment for geometrical traits and intuitive presentation of differences in trends between exercise groups and controls provides a basis for analysis with high angular accuracy. 23568577 Decreased consumption of sweet fluids in mu opioid receptor knockout mice: a microstructural analysis of licking behavior. RATIONALE: Evidence suggests that the palatability of food (i.e., the hedonic impact produced by its sensory features) can promote feeding and may underlie compulsive eating, leading to obesity. Pharmacological studies implicate opioid transmission in the hedonic control of feeding, though these studies often rely on agents lacking specificity for particular opioid receptors. OBJECTIVES: Here, we investigated the role of mu opioid receptors (MORs) specifically in determining hedonic responses to palatable sweet stimuli. METHODS: In Experiment 1, licking microstructure when consuming sucrose solution (2 to 20 %) was compared in MOR knockout and wildtype mice as a function of sucrose concentration and level of food deprivation. In Experiment 2, a similar examination was conducted using the palatable but calorie-free stimulus sucralose (0.001 to 1 %), allowing study of licking behavior independent of homeostatic variables. RESULTS: In Experiment 1, MOR knockout mice exhibited several alterations in sucrose licking. Although wildtype mice exhibited a twofold increase in the burst length when food deprived, relative to the nondeprived test, this aspect of sucrose licking was generally insensitive to manipulations of food deprivation for MOR knockout mice. Furthermore, during concentration testing, their rate of sucrose licking was less than half that of wildtype mice. During sucralose testing (Experiment 2), MOR knockout mice licked at approximately half the wildtype rate, providing more direct evidence that MOR knockout mice were impaired in processing stimulus palatability. CONCLUSIONS: These results suggest that transmission through MORs mediates hedonic responses to palatable stimuli, and therefore likely contributes to normal and pathological eating. 23903782 Evolutionary instability of zero-determinant strategies demonstrates that winning is not everything. Zero-determinant strategies are a new class of probabilistic and conditional strategies that are able to unilaterally set the expected payoff of an opponent in iterated plays of the Prisoner's Dilemma irrespective of the opponent's strategy (coercive strategies), or else to set the ratio between the player's and their opponent's expected payoff (extortionate strategies). Here we show that zero-determinant strategies are at most weakly dominant, are not evolutionarily stable, and will instead evolve into less coercive strategies. We show that zero-determinant strategies with an informational advantage over other players that allows them to recognize each other can be evolutionarily stable (and able to exploit other players). However, such an advantage is bound to be short-lived as opposing strategies evolve to counteract the recognition. 23880584 IRE1: ER stress sensor and cell fate executor. Cells operate a signaling network termed the unfolded protein response (UPR) to monitor protein-folding capacity in the endoplasmic reticulum (ER). Inositol-requiring enzyme 1 (IRE1) is an ER transmembrane sensor that activates the UPR to maintain the ER and cellular function. Although mammalian IRE1 promotes cell survival, it can initiate apoptosis via decay of antiapoptotic miRNAs. Convergent and divergent IRE1 characteristics between plants and animals underscore its significance in cellular homeostasis. This review provides an updated scenario of the IRE1 signaling model, discusses emerging IRE1 sensing mechanisms, compares IRE1 features among species, and outlines exciting future directions in UPR research. 23874724 KCNE1 rs1805127 Polymorphism Increases the Risk of Atrial Fibrillation: A Meta-Analysis of 10 Studies. Atrial fibrillation (AF) is one of the most common types of arrhythmia in humans. Recently, many studies have investigated the relationship between human atrial fibrillation and the single nucleotide polymorphism (SNP) of rs1805127 (A>G) in KCNE1 gene, but the results were still inconsistent and inconclusive. Electronic databases and bibliographies of retrieved studies were searched. We performed a meta-analysis of ten case-control studies, including 2099 cases and 2252 controls, to evaluate the association of rs1805127 polymorphism (A>G) with the risk of AF. Random-effects model was used when the heterogeneity was obvious; otherwise, fixed-effects model was applied. Meta-regression was performed to examine potential source of heterogeneity. Egger's test and Begg's test were used to detect publication biases. The results showed a significantly increased risk of AF in homozygote comparison (GG vs. AA:OR = 1.899, 95%CI: 1.568, 2.300; Pheterogeneity = 0.217), heterozygote comparison (GA vs. AA:OR = 1.436, 95% CI:1.190, 1.732; Pheterogeneity = 0.739), dominant model(GA /GG vs. AA: OR = 1.624, 95%CI: 1.361, 1.938; Pheterogeneity = 0.778) and recessive model (GG vs. GA/AA: OR = 1.394, 95%CI:1.152, 1.686; Pheterogeneity = 0.03). Meta-regression revealed that the sample size and the types of AF were the source of the heterogeneity. The rs1805127 polymorphism (A>G) of KCNE1 is associated with an increased risk of AF, which suggests the rs1805217 polymorphism of KCNE1 gene may play an important role in the pathogenesis of AF. 23749440 Recent advances in the structure elucidation of small organic molecules by the LSD software. The LSD software proposes the structures of small organic molecules that fit with structural constraints from 1D and 2D NMR spectroscopy. Its initial design introduced limits that needed to be eliminated to extend its scope and help its users choose the most likely structure among those proposed. The LSD software code has been improved, so that it recognizes a wider set of atom types to build molecules. More flexibility has been given in the interpretation of 2D NMR data, including the automatic detection of very long-range correlations. A program named pyLSD was written to deal with problems in which atom types are ambiguously defined. It also provides a (13) C NMR chemical shift-based solution ranking algorithm. PyLSD was able to propose the correct structure of hexacyclinol, a natural product whose structure determination has been highly controversal. The solution was ranked first within a list of ten structures that were produced by pyLSD from the literature NMR data. The structure of an aporphin natural product was determined by pyLSD, taking advantage of the possibility of handling electrically charged atoms. The structure generation of the insect antifeedant azadirachtin by LSD was reinvestigated by pyLSD, considering that three (13) C resonances did not lead to univocal hybridization states. Copyright © 2013 John Wiley & Sons, Ltd. 23760625 Pituitary-adrenal function after prolonged glucocorticoid therapy for systemic inflammatory disorders: an observational study. Context: Glucocorticoid therapy is being used in a wide variety of systemic disorders. Reference papers, published more than 20 years ago, showed no correlation between adrenal insufficiency risk and dose or duration of glucocorticoid therapy. Objective: Our objective was to evaluate the extent to which long-term glucocorticoid therapy damages the pituitary-adrenal axis in patients with systemic inflammatory disorders. Design: We conducted a retrospective observational study from January 2011 to August 2012. Setting: This was a monocentric study at the Department of Internal Medicine, Bichat Hospital, Paris-Diderot University, Paris, France. Participants: Sixty consecutive patients who were receiving long-term prednisone therapy for systemic inflammatory disorders and in whom discontinuation of glucocorticoid treatment was planned. Intervention: A short Synacthen test was performed. A bolus of 0.25 mg 1-24-ACTH was injected in the morning, 24 hours after the most recent dose of prednisone. Cortisol was measured at baseline and 60 minutes after Synacthen injection. Main Outcome Measures: We assessed frequency and risk estimate of pituitary-adrenal dysfunction. Results: Twenty-nine patients (48.3%) had adrenal insufficiency defined by a plasmatic cortisol <100 nmol/L (n = 13) at baseline (time 0) or <550 nmol/L (n = 16) 60 minutes after Synacthen injection. Cumulative dose (area under the receiver operating characteristic curve = 0.77 [95% confidence interval = 0.62-0.91], P = .007) and exposure (area under the receiver operating characteristic curve 0.80 [95% confidence interval = 0.67-0.93], P = .002) to prednisone were predictive for adrenal insufficiency based on a T0 <100 nmol/L. Prednisone was stopped in 29 of 31 patients (93.5%) showing a normal response to short Synacthen test; none of these patients required hydrocortisone replacement with a mean follow-up of 10 (± 6) months. Conclusion: Adrenal insufficiency is frequent in patients treated with long-term glucocorticoids for systemic inflammatory disorders and is related to duration and cumulative dose of steroids. 23881272 Exploring Public Attitudes Towards Approaches to Discussing Costs in the Clinical Encounter. Patients' willingness to discuss costs of treatment alternatives with their physicians is uncertain. To explore public attitudes toward doctor-patient discussions of insurer and out-of-pocket costs and to examine whether several possible communication strategies might enhance patient receptivity to discussing costs with their physicians. Focus group discussions and pre-discussion and post-discussion questionnaires. Two hundred and eleven insured individuals with mean age of 48 years, 51 % female, 34 % African American, 27 % Latino, and 50 % with incomes below 300 % of the federal poverty threshold, participated in 22 focus groups in Santa Monica, CA and in the Washington, DC metro area. Attitudes toward discussing out-of-pocket and insurer costs with physicians, and towards physicians' role in controlling costs; receptivity toward recommended communication strategies regarding costs. Participants expressed more willingness to talk to doctors about personal costs than insurer costs. Older participants and sicker participants were more willing to talk to the doctor about all costs than younger and healthier participants (OR = 1.8, p = 0.004; OR = 1.6, p = 0.027 respectively). Participants who face cost-related barriers to accessing health care were in greater agreement than others that doctors should play a role in reducing out-of-pocket costs (OR = 2.4, p = 0.011). Participants did not endorse recommended communication strategies for discussing costs in the clinical encounter. In contrast, participants stated that trust in one's physician would enhance their willingness to discuss costs. Perceived impediments to discussing costs included rushed, impersonal visits, and clinicians who are insufficiently informed about costs. This study suggests that trusting relationships may be more conducive than any particular discussion strategy to facilitating doctor-patient discussions of health care costs. Better public understanding of how medical decisions affect insurer costs and how such costs ultimately affect patients personally will be necessary if discussions about insurer costs are to occur in the clinical encounter. 22775444 Influence of ethanol on swelling and release behaviors of Carbopol(®)-based tablets. The aim of this work was to investigate the effect of ethanol on the in vitro swelling and release behaviors of Carbopol(®)-based tablets. The swelling behavior of drug-free compacts and the release of model drugs (metformin HCl, caffeine and theophylline) from matrix tablets were evaluated in acidic and buffered media with 0, 20 and 40% (v/v) ethanol. Release data were analyzed by fitting to Higuchi and Peppas models and calculation of similarity factor (f2). ANOVA tests were performed to determine significant factors on swelling and release. It was found that ethanol affects swelling and erosion of drug-free Carbopol(®) compacts, and the effect was highly dependent on medium pH. For matrix tablets, no dose dumping due to ethanol was manifested. The release rate and mechanism, however, were significantly affected by ethanol concentration as indicated by ANOVA applied to the constant, KH, from Higuchi model and the exponent, n, from Peppas model, respectively. The effect of ethanol on release was further confirmed by similarity factor results, which indicated that ethanol led to different release profiles (f2 < 50) in seven of eight cases for matrices containing metformin HCl and in three of eight cases for matrices containing caffeine and theophylline. 23860230 Up-regulation and interaction of the plasma membrane H(+)-ATPase and the 14-3-3 protein are involved in the regulation of citrate exudation from the broad bean (Vicia faba L.) under Al stress. Our previous study showed that citrate excretion coupled with a concomitant release of protons was involved in aluminum (Al) resistance in the broad bean. Furthermore, genes encoding plasma membrane (PM) H(+)-ATPase (vha2) and the 14-3-3 protein (vf14-3-3b) were up-regulated by Al in Al-resistant (YD) broad bean roots. In this study, the roles of PM H(+)-ATPase (E.C. 3.6.3.6) and the 14-3-3 protein in the regulation of citrate secretion were further investigated in Al-resistant (YD) and Al-sensitive (AD) broad bean cultivars under Al stress. The results showed that greater citrate exudation was positively correlated with higher activities of PM H(+)-ATPase in roots of YD than AD. Real-time RT-PCR analysis revealed that vha2 was clearly up-regulated by Al in YD but not in AD roots, whereas the transcription levels of vf14-3-3b were elevated in a time-dependent manner in both YD and AD roots. Immunoprecipitation and Western analysis suggested that phosphorylation and interaction with the vf14-3-3b protein of the VHA2 were enhanced in YD roots but not in AD roots with increasing Al treatment time. Fusicoccin or adenosine 5'-monophosphate increased or decreased the interaction between the phosphorylated VHA2 and the vf14-3-3b protein, followed by an enhancement or reduction of the PM H(+)-ATPase activity and citrate exudation in both cultivars under Al stress conditions, respectively. Taken together, these results suggested that Al enhanced the expression and interaction of the PM H(+)-ATPase and the 14-3-3 protein, which thereby led to higher activity of the PM H(+)-ATPase and more citrate exudation from YD plants. 23886585 Effects of transcranial focal electrical stimulation alone and associated with a sub-effective dose of diazepam on pilocarpine-induced status epilepticus and subsequent neuronal damage in rats. Experiments were conducted to evaluate the effects of transcranial focal electrical stimulation (TFS) applied via tripolar concentric ring electrodes, alone and associated with a sub-effective dose of diazepam (DZP) on the expression of status epilepticus (SE) induced by lithium-pilocarpine (LP) and subsequent neuronal damage in the hippocampus. Immediately before pilocarpine injection, male Wistar rats received TFS (300Hz, 200-μs biphasic square charge-balanced 50-mA constant current pulses for 2min) alone or combined with a sub-effective dose of DZP (0.41mg/kg, i.p.). In contrast with DZP or TFS alone, DZP plus TFS reduced the incidence of, and enhanced the latency to, mild and severe generalized seizures and SE induced by LP. These effects were associated with a significant reduction in the number of degenerated neurons in the hippocampus. The present study supports the notion that TFS combined with sub-effective doses of DZP may represent a therapeutic tool to induce anticonvulsant effects and reduce the SE-induced neuronal damage. 23836871 Time-Delayed In Vivo Assembly of Subunit a into Preformed Escherichia coli FoF1 ATP Synthase. Escherichia coli FOF1 ATP synthase, a rotary nanomachine, is composed of eight different subunits in a α3β3γδεab2c10 stoichiometry. Whereas FOF1 has been studied in detail with regard to its structure and function, much less is known about how this multisubunit enzyme complex is assembled. Single-subunit atp deletion mutants are known to be arrested in assembly, thus leading to formation of partially assembled subcomplexes. To determine whether those subcomplexes are preserved in a stable standby mode, a time-delayed in vivo assembly system was developed. To establish this approach, we targeted the time-delayed assembly of membrane-integrated subunit a into preformed FOF1 lacking subunit a (FOF1-a) which is known to form stable subcomplexes in vitro. Two expression systems (araBADp and T7p-laco) were adjusted to provide compatible, mutually independent, and sufficiently stringent induction and repression regimens. In detail, all structural atp genes except atpB (encoding subunit a) were expressed under the control of araBADp and induced by arabinose. Following synthesis of FOF1-a during growth, expression was repressed by glucose/d-fucose, and degradation of atp mRNA controlled by real-time reverse transcription-PCR. A time-delayed expression of atpB under T7p-laco control was subsequently induced in trans by addition of isopropyl-β-d-thiogalactopyranoside. Formation of fully assembled, and functional, FOF1 complexes was verified. This demonstrates that all subunits of FOF1-a remain in a stable preformed state capable to integrate subunit a as the last subunit. The results reveal that the approach presented here can be applied as a general method to study the assembly of heteromultimeric protein complexes in vivo. 23711501 Sensitivity and specificity of ultrasound in detecting (osteo)chondral defects: a cadaveric study. The long-term prognosis of cartilage lesions evolving into an eroding subchondral bone defect is not known. Longitudinal monitoring using ultrasound could assist in overall understanding. The aim of the work described in this article was to determine the feasibility of using ultrasound to detect small (osteo)chondral defects. On the anterior talar surface of 10 human cadaveric ankles, at most four defects were arthroscopically created: two pure chondral defects 3 and 1.5 mm in diameter and two osteochondral defects 3 and 1.5 mm in diameter. All ankles were examined by two observers, and their ultrasound observations were validated using computed tomography scans and photographs. Overall sensitivity was 96% for observer 1 and 92% for observer 2, and specificity for both observers was 100%. Sixty-eight percent and 79% of defect sizes were within relevant limits of agreement (-0.2 ± 1.0 mm), respectively. Ultrasound imaging has the potential to detect small (osteo)chondral defects located within visible areas. 23881044 Relationship between oral D-amphetamine self-administration and ratings of subjective effects: do subjective-effects ratings correspond with a progressive-ratio measure of drug-taking behavior? The abuse potential of drugs has traditionally been determined in humans using subjective ratings of drug effects. However, drug self-administration procedures also provide valuable information about the reinforcing effects of drugs that may contribute to their potential for abuse. Although ratings of subjective effects and drug self-administration data are generally concordant, some divergent findings have been reported. Therefore, the aim of the present analysis was to directly investigate the relationship between the subjective-effects profile and self-administration of oral D-amphetamine in healthy volunteers with a history of stimulant use or abuse, using Pearson's correlational analyses. The results indicated that positive subjective and reinforcing effects significantly increased as a function of D-amphetamine dose. Further, significant, but modest, correlations were observed between ratings of six of 17 total items (Any Effect, High, Like Drug, Good Effects, Willing to Pay For, and Willing to Take Again) and D-amphetamine self-administration under a progressive-ratio schedule of reinforcement. The current findings suggest that, at least under the current set of conditions with oral D-amphetamine, subjective-effects measures and drug self-administration data likely provide different but complimentary information about abuse potential. The most informative findings will thus be obtained from studies that use ratings of subjective effects and drug self-administration methods. 23819464 Three dimensional (3D) telomere dynamics in follicular thyroid cancer. Background: Over the last decade, annual incidence rates for thyroid cancer have been among the highest of all cancers in the Western world; however the genomic mechanisms impacting thyroid carcinogenesis remain elusive. Methods: We employed an established mouse model of follicular thyroid cancer (FTC) with a homozygous proline to valine mutation (ThrbPV/PV) of thyroid receptor ß1 (TRß1) and applied quantitative three-dimensional (3D) telomere analysis to determine 3D telomeric profiles in ThrbPV/PV, ThrbPV/+, and Thrb+/+ mouse thyrocytes at various stages during follicular thyroid carcinogenesis. Results: Using quantitative fluorescent in situ hybridization (Q-FISH) and TeloView image analysis, we showed altered telomeric signatures specifically in mutant mouse thyrocytes. As early as 1-2 months of age, ThrbPV/PV mouse thyrocytes showed more telomeres than normal and heterozygous age-matched counterparts. Importantly, at the very early age of one month, 3D telomeric profiles of ThrbPV/PV thyrocyte nuclei reveal genetic heterogeneity with several nuclei populations exhibiting different telomere numbers; suggestive of various degrees of aneuploidy within the same animal. This was detected exclusively in ThrbPV/PV mice well before the presentation of histological signs for thyroid carcinoma. Conclusions: We identified quantitative 3D telomere analysis as a novel tool for early detection and monitoring of thyrocyte chromosomal (in)stability. This technique has the potential to identify human patients at risk for developing thyroid carcinoma. 23733456 Evaluation of a Nisin-Eluting Nanofiber Scaffold To Treat Staphylococcus aureus-Induced Skin Infections in Mice. Staphylococcus aureus is a virulent pathogen and a major causative agent of superficial and invasive skin and soft tissue infections (SSSTIs). Antibiotic resistance in S. aureus, among other bacterial pathogens, has rapidly increased, and this is placing an enormous burden on the health care sector and has serious implications for infected individuals, especially immunocompromised patients. Alternative treatments thus need to be explored to continue to successfully treat infections caused by S. aureus, including antibiotic-resistant strains of S. aureus. In this study, an antimicrobial nanofiber wound dressing was generated by electrospinning nisin (Nisaplin) into poly(ethylene oxide) and poly(d,l-lactide) (50:50) blend nanofibers. Active nisin diffused from the nanofiber wound dressings for at least 4 days in vitro, as shown by consecutive transfers onto plates seeded with strains of methicillin-resistant S. aureus (MRSA). The nisin-containing nanofiber wound dressings significantly reduced S. aureus Xen 36 bioluminescence in vivo and viable cell numbers in a murine excisional skin infection model. The bacterial burden of wounds treated with nisin-containing nanofiber wound dressings was 4.3 × 10(2) CFU/wound, whereas wounds treated with control nanofiber wound dressings had 2.2 × 10(7) CFU/wound on the last day of the trial (day 7). Furthermore, the wound dressings stimulated wound closure of excisional wounds, and no adverse effects were observed by histological analysis. Nisin-containing nanofiber wound dressings have the potential to treat S. aureus skin infections and to potentially accelerate wound healing of excisional wounds. 23830620 Ly6e expression is restricted to syncytiotrophoblast cells of the mouse placenta. In the present study, we characterized the expression of lymphocyte antigen 6, locus E (Ly6e) in mouse placental trophoblast. We identified Ly6e mRNA expression in trophoblast stem (TS) cells by a gene expression screen. In vivo, Ly6e was first detectable by mRNA in situ hybridization in the chorion beginning at E8.5 with spatial expression similar to Syncytin a (Syna). At later stages of gestation, Ly6e was restricted to syncytiotrophoblast in the labyrinth. Northern blot confirmed that Ly6e was expressed in both undifferentiated and differentiated TS cell cultures but that its expression increased with differentiation. FACS analysis confirmed these results and allowed us to isolate LY6E(+) cells, which we found to express Syna at a much higher level than did LY6E(-) cells. Our findings suggest that LY6E is expressed in differentiated syncytiotrophoblast and may also be useful as an early marker, expressed in progenitors of this cell-type. 23902603 Continuous glucose monitoring system (CGMS) in kidney-transplanted children. NODAT and IGT are well-known complications of immunosuppressive therapy after transplantation being a risk factor for cardiovascular disease affecting patient and graft survival. Therefore, early identification and treatment are of high importance. In this study, we examined the glycemic homeostasis of 20 renal-transplanted children using routine laboratory tests and the continuous glucose monitoring system (CGMS). Six patients (30%) had IGT, and one patient had NODAT (5%). The HOMA index was in an abnormal range in 35% of all patients and was abnormal in 67% of the IGT patients. CGMS analysis showed that IGT patients had higher "lowest glucose" level, and the incidence of hypoglycemic episodes was significantly lower compared with patients with normal OGTT result. In IGT patients, glucose variability tended to be lower. Furthermore, in the whole patient cohort, glucose variability significantly decreased with time after transplantation. Summarizing, these novel data show that "lowest glucose" level and hypoglycemic episodes are significantly influenced and altered in renal-transplanted patients with IGT. Furthermore, there is a decrease in glucose variability with time after transplantation. The mechanism and relevance of these data need further investigations. 23377542 Trim24-repressed VL30 retrotransposons regulate gene expression by producing noncoding RNA. Trim24 (Tif1α) and Trim33 (Tif1γ) interact to form a co-repressor complex that suppresses murine hepatocellular carcinoma. Here we show that Trim24 and Trim33 cooperatively repress retinoic acid receptor-dependent activity of VL30-class endogenous retroviruses (ERVs) in liver. In Trim24-knockout hepatocytes, VL30 derepression leads to accumulation of reverse-transcribed VL30 cDNA in the cytoplasm that correlates with activation of the viral-defense interferon responses mimicking the preneoplastic inflammatory state seen in human liver following exogenous viral infection. Furthermore, upon derepression, VL30 long terminal repeats (LTRs) act as promoter and enhancer elements deregulating expression of neighboring genes and generating enhancer RNAs that are required for LTR enhancer activity in hepatocytes in vivo. These data reinforce the role of the TRIM family of proteins in retroviral restriction and antiviral defense and provide an example of an ERV-derived oncogenic regulatory network. 23850190 Symplastic intercellular connectivity regulates lateral root patterning. Cell-to-cell communication coordinates the behavior of individual cells to establish organ patterning and development. Although mobile signals are known to be important in lateral root development, the role of plasmodesmata (PD)-mediated transport in this process has not been investigated. Here, we show that changes in symplastic connectivity accompany and regulate lateral root organogenesis in Arabidopsis. This connectivity is dependent upon callose deposition around PD affecting molecular flux through the channel. Two plasmodesmal-localized β-1,3 glucanases (PdBGs) were identified that regulate callose accumulation and the number and distribution of lateral roots. The fundamental role of PD-associated callose in this process was illustrated by the induction of similar phenotypes in lines with altered callose turnover. Our results show that regulation of callose and cell-to-cell connectivity is critical in determining the pattern of lateral root formation, which influences root architecture and optimal plant performance. 23957360 Ginsenoside rh2 improves learning and memory in mice. Abstract A wide range of plant foods and dietary supplements are able to modify the functioning of the central nervous system. In the present study, we observed that oral administration of ginsenoside Rh2 (10 mg/mL) for 3 weeks significantly improved spatial learning and memory. Spatial memory and learning was evaluated in mice by hippocampus-dependent tasks (Morris water maze test) and immunohistochemical marker of cell genesis bromodeoxyuridine. Ginsenoside Rh2 treatment (30 days) promoted cell survival and genesis. Further, ginsenoside Rh2 treatment in enriched condition had no significant effects on cell survival compared with standard condition exposure. These results revealed that ginsenoside Rh2-mediated spatial learning and memory improvement was associated with cell genesis and survival and may be parallel to the mechanism of environmental enrichment. Therefore, ginsenoside Rh2 may have efficacy as a dietary supplement for spatial learning and memory improvement. 23899291 Exquisite Selectivity for Human Toll-Like Receptor 8 in Substituted Furo[2,3-c]quinolines. Toll-like receptor (TLR)-8 agonists activate adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds may be promising candidate adjuvants. We synthesized and evaluated hitherto unexplored furo[2,3-c]quinolines and regioisomeric furo[3,2-c]quinolines derived via a tandem, one-pot Sonogashira coupling and intramolecular 5-endo-dig cyclization strategy in a panel of primary screens. We observed a pure TLR8-agonistic activity profile in select furo[2,3-c]quinolines, with maximal potency conferred by a C2-butyl group (EC50 = 1.6 μM); shorter, longer, or substituted homologues as well as compounds bearing C1 substitutions were inactive, which was rationalized by docking studies using the recently described crystal structure of human TLR8. The best-in-class compound displayed prominent proinflammatory cytokine induction (including interleukin-12 and interleukin-18), but was bereft of interferon-α inducing properties, confirming its high selectivity for human TLR8. 23312885 Olfactory changes after endoscopic sinus surgery in patients with chronic rhinosinusitis. To address the controversy over whether olfactory function is improved or not after endoscopic sinus surgery (ESS) in patients with eosinophilic (ECRS) and non-eosinophilic chronic rhinosinusitis (non-ECRS). Between June 2006 and March 2012, 89 adult patients with CRS underwent ESS at Hyogo College of Medicine. There were 55 men and 34 women with a mean age of 53 years old, ranging from 23 to 79 years. The average follow-up period was 10.7 months (3-24) after ESS. Peripheral blood examination, sinonasal CT imaging, and four kinds of olfaction tests [self-administered olfaction test (SAOQ), visual analog scale (VAS), T&T recognition threshold tests (T&T) and intravenous olfaction test using prosultiamine] were performed. We diagnosed ECRS when (i) symptoms of nasal congestion and olfactory disorder, (ii) bilateral chronic rhinosinusitis with nasal polyps (CRSwNPs), (iii) peripheral blood eosinophilia (>7.0%), and (iv) ethmoid sinus dominant opacification in preoperative CT findings (i.e. ethmoid sinuses (E) were more bilaterally occupied than those of maxillary sinuses (M), E/M≥1), were completely fulfilled. We divided the patients into two groups of ECRS (group A) and non-ECRS (group B). Olfaction tests before operation, and at the 3rd, 6th, 12th, and 24th month postoperation were analyzed. The severity and therapeutic evaluation of olfaction were based on criteria of T&T recognition thresholds. The mean SAOQ and VAS scores showed significant improvement within 6 months after ESS in both group A and group B. In total, the improvement rates were 52.0% (26/50) at 3 months, 58.5% (24/41) at 6 months, 40.5% (15/37) at 12 months, and 41.2% (7/17) at 24 months. The significant improvement of T&T recognition thresholds in group B was maintained for 24 months, whereas those in group A, showing transient improvement, deteriorated after 12 months or more. A significant difference in postoperative T&T recognition between groups A and B was found at the 12th postoperative month. In both A and B, 84% of patients had a response to prosultiamine (positive group) in the preoperative stage. T&T thresholds in the positive group were significantly better that those in the negative groups in the postoperative stage. Olfactory disorders due to ECRS showed transient improvement that deteriorated as time passed after surgery. The olfaction in the non-ECRS patients recovered comparatively well. Postoperative olfactory results were unfavorable in patients without a preoperative reaction to prosultiamine. 23872599 M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. The lack of therapies for progressive multiple sclerosis highlights the need to understand the regenerative process of remyelination that can follow CNS demyelination. This involves an innate immune response consisting of microglia and macrophages, which can be polarized to distinct functional phenotypes: pro-inflammatory (M1) and anti-inflammatory or immunoregulatory (M2). We found that a switch from an M1- to an M2-dominant response occurred in microglia and peripherally derived macrophages as remyelination started. Oligodendrocyte differentiation was enhanced in vitro with M2 cell conditioned media and impaired in vivo following intra-lesional M2 cell depletion. M2 cell densities were increased in lesions of aged mice in which remyelination was enhanced by parabiotic coupling to a younger mouse and in multiple sclerosis lesions that normally show remyelination. Blocking M2 cell-derived activin-A inhibited oligodendrocyte differentiation during remyelination in cerebellar slice cultures. Thus, our results indicate that M2 cell polarization is essential for efficient remyelination and identify activin-A as a therapeutic target for CNS regeneration. 23194556 Accumulation of heavy metals in edible parts of vegetables irrigated with waste water and their daily intake to adults and children, District Mardan, Pakistan. Green vegetable crops irrigated with wastewater are highly contaminated with heavy metals and are the main source of human exposure to the contaminants. In this study accumulation of eight heavy metals (Cu, Ni, Zn, Cr, Fe, Mn, Co and Pb) in green vegetables like Allium cepa, Allium sativum, Solanum lycopersicum and Solanum melongena, irrigated with wastewater in Mardan are studied using Atomic Absorption spectrophotometer. The studied metals in vegetable grown on wastewater irrigated soil were significantly higher than those of tube well water irrigated soil and WHO/FAO permissible limits (P<0.05). The most heavily contaminated vegetable was wastewater irrigated A. cepa, where the accumulation of Mn (28.05 mg kg(-1)) in the edible parts was 50-fold greater than A. cepa irrigated with tube well water irrigated soil. It may be concluded that both adults and children consuming these vegetables grown in wastewater irrigated soil ingest significant amount of these metals and thus can cause serious health problems. 23194567 Endocrine disruptor activity in bottled mineral and flavoured water. A panel of reporter gene assays (RGAs) coupled with a single solid phase extraction (SPE) step was developed and used to screen bottled mineral water for the presence of four classes of endocrine disruptors (EDs), oestrogens, androgens, progestagens and glucocorticoids. Fourteen brands of bottled mineral water in triplicate (42 samples) were analysed. Overall, hormonal activity was found in 78% of the samples. Oestrogenic, androgenic, progestagenic and glucocorticoid activity was found in 38%, 38%, 36% and 55% of the samples, respectively at an average concentration of 10 ng/l 17β-estradiol equivalent (EEQ), 26 ng/l testosterone equivalent (TEQ), 123 ng/l progesterone equivalent (PEQ) and 13.5 ng/l hydrocortisone equivalent (HEQ). The level of oestrogenic, androgenic and progestagenic activity observed is not considered a matter of concern for the consumers' health. It is unknown whether the glucocorticoid levels observed are safe. The ED source, long term exposure and mixture effects remain to be investigated. 23718681 Molecular determinants of co- and post-translational N-glycosylation of type I transmembrane peptides. Type I transmembrane peptides acquire N-linked glycans during and after protein synthesis to facilitate anterograde trafficking through the secretory pathway. Mutations in N-glycosylation consensus sites (NXT and NXS, where X≠P) that alter the kinetics of the initial N-glycan attachment have been associated with cardiac arrhythmias; however, the molecular determinants that define co- and post-translational consensus sites in proteins are not known. In the present study, we identified co- and post-translational consensus sites in the KCNE family of K+ channel regulatory subunits to uncover three determinants that favour co-translational N-glycosylation kinetics of type I transmembrane peptides which lack a cleavable signal sequence: threonine-containing consensus sites (NXT), multiple N-terminal consensus sites and long C-termini. The identification of these three molecular determinants now makes it possible to predict co- and post-translational consensus sites in type I transmembrane peptides. 23351590 Effect of a single dose of escitalopram on serotonin concentration in the non-human and human primate brain. Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for treatment of psychiatric disorders. The exact mechanism underlying the clinical effects of SSRIs remains unclear, although increased synaptic serotonin concentrations have been hypothesized to be an initial step. [¹¹C]AZ10419369 is a novel 5-HT(1B) receptor selective radioligand, which is sensitive to changes in endogenous serotonin concentrations. To assess whether a single dose of the SSRI escitalopram affects endogenous serotonin concentrations in serotonergic projection areas and in the raphe nuclei (RN), three cynomolgus monkeys and nine human subjects underwent PET examinations with [¹¹C]AZ10419369 at baseline conditions and after escitalopram administration. In monkeys, the binding potential (BP(ND)) was significantly lower post dose compared to baseline in dorsolateral prefrontal cortex, occipital cortex, thalamus, midbrain and RN (p < 0.05). In humans, the BP(ND) tended to decrease in RN post dose (p = 0.08). In all serotonergic projection areas, the BP(ND) was conversely higher post dose compared to baseline. The increase was significant in a combined region of all projection areas (p = 0.01) and in occipital and temporal cortex (p < 0.05). SSRIs are generally assumed to elevate endogenous serotonin concentrations in projection areas, evoking the antidepressant effect. In the present study, a single, clinically relevant, dose of escitalopram was found to decrease serotonin concentrations in serotonergic projection areas in humans. Hypothetically, desensitization of inhibitory serotonergic autoreceptors will cause the serotonin concentration in projection areas to increase over time with chronic administration. Thus, the findings in the present study might aid in understanding the mechanism of SSRIs' delayed onset of clinical effect. 23838003 Top-down modulation of hippocampal encoding activity as measured by high-resolution functional MRI. Memory formation is known to be critically dependent upon the medial temporal lobe (MTL). Despite this well-characterized role, it remains unclear whether and how MTL encoding processes are affected by top-down goal states. Here, we examined the manner in which task demands at encoding affect MTL activity and its relation to subsequent memory performance. Participants were scanned using high-resolution neuroimaging of the MTL while engaging in two incidental encoding tasks: one that directed participants' attention to stimulus distinctiveness, and the other requiring evaluation of similarities across stimuli. We hypothesized that attending to distinctiveness would lead to the formation of more detailed memories and would more effectively engage the hippocampal circuit than attending to similarity. In line with our hypotheses, higher rates of subsequent recollection were observed for stimuli studied under the Distinctiveness than Similarity task. Critically, within the hippocampus, CA1 and the subiculum demonstrated an interaction between memory performance and task such that a significant subsequent memory effect was found only when task goals required attention to stimulus distinctiveness. To this end, robust engagement of the hippocampal circuit may underlie the observed behavioral benefits of attending to distinctiveness. Taken together, these findings advance understanding of the effects of top-down intentional information on successful memory formation across subregions of the MTL. 23362838 Intercalation pathway in many-particle LiFePO4 electrode revealed by nanoscale state-of-charge mapping. The intercalation pathway of lithium iron phosphate (LFP) in the positive electrode of a lithium-ion battery was probed at the ∼40 nm length scale using oxidation-state-sensitive X-ray microscopy. Combined with morphological observations of the same exact locations using transmission electron microscopy, we quantified the local state-of-charge of approximately 450 individual LFP particles over nearly the entire thickness of the porous electrode. With the electrode charged to 50% state-of-charge in 0.5 h, we observed that the overwhelming majority of particles were either almost completely delithiated or lithiated. Specifically, only ∼2% of individual particles were at an intermediate state-of-charge. From this small fraction of particles that were actively undergoing delithiation, we conclude that the time needed to charge a particle is ∼1/50 the time needed to charge the entire particle ensemble. Surprisingly, we observed a very weak correlation between the sequence of delithiation and the particle size, contrary to the common expectation that smaller particles delithiate before larger ones. Our quantitative results unambiguously confirm the mosaic (particle-by-particle) pathway of intercalation and suggest that the rate-limiting process of charging is initiating the phase transformation by, for example, a nucleation-like event. Therefore, strategies for further enhancing the performance of LFP electrodes should not focus on increasing the phase-boundary velocity but on the rate of phase-transformation initiation. 23936405 Profiling the cross reactivity of ubiquitin with the nedd8 activating enzyme by phage display. The C-terminal peptides of ubiquitin (UB) and UB-like proteins (UBLs) play a key role in their recognition by the specific activating enzymes (E1s) to launch their transfer through the respective enzymatic cascades thus modifying cellular proteins. UB and Nedd8, a UBL regulating the activity of cullin-RING UB ligases, only differ by one residue at their C-termini; yet each has its specific E1 for the activation reaction. It has been reported recently that UAE can cross react with Nedd8 to enable its passage through the UB transfer cascade for protein neddylation. To elucidate differences in UB recognition by UAE and NAE, we carried out phage selection of a UB library with randomized C-terminal sequences based on the catalytic formation of UB∼NAE thioester conjugates. Our results confirmed the previous finding that residue 72 of UB plays a "gate-keeping" role in E1 selectivity. We also found that diverse sequences flanking residue 72 at the UB C-terminus can be accommodated by NAE for activation. Furthermore heptameric peptides derived from the C-terminal sequences of UB variants selected for NAE activation can function as mimics of Nedd8 to form thioester conjugates with NAE and the downstream E2 enzyme Ubc12 in the Nedd8 transfer cascade. Once the peptides are charged onto the cascade enzymes, the full-length Nedd8 protein is effectively blocked from passing through the cascade for the critical modification of cullin. We have thus identified a new class of inhibitors of protein neddylation based on the profiles of the UB C-terminal sequences recognized by NAE. 23602834 Oncoapoptotic signaling and deregulated target genes in cancers: special reference to oral cancer. Cancer is a class of diseases characterized by uncontrolled cell growth. The development of cancer takes place in a multi-step process during which cells acquire a series of mutations that eventually lead to unrestrained cell growth and division, inhibition of cell differentiation, and evasion of cell death. Dysregulation of oncoapoptotic genes, growth factors, receptors and their downstream signaling pathway components represent a central driving force in tumor development. The detailed studies of signal transduction pathways for mechanisms of cell growth and apoptosis have significantly advanced our understanding of human cancers, subsequently leading to more effective treatments. Oral squamous cell carcinoma represents a classic example of multi-stage carcinogenesis. It gradually evolves through transitional precursor lesions from normal epithelium to a full-blown metastatic phenotype. Genetic alterations in many genes encoding crucial proteins, which regulate cell proliferation, differentiation, survival and apoptosis, have been implicated in oral cancer. As like other solid tumors, in oral cancer these genes include the ones coding for cell cycle regulators or oncoproteins (e.g. Ras, Myc, cyclins, CDKs, and CKIs), tumor suppressors (e.g. p53 and pRb), pro-survival proteins (e.g. telomerase, growth factors or their receptors), anti-apoptotic proteins (e.g. Bcl2 family, IAPs, and NF-kB), pro-apoptotic proteins (e.g. Bax and BH-3 family, Fas, TNF-R, and caspases), and the genes encoding key transcription factors or elements for signal transduction leading to cell growth and apoptosis. Here we discuss the current knowledge of oncoapoptotic regulation in human cancers with special reference to oral cancers. 23969235 Posttranscriptional regulation of SOD1 gene expression under oxidative stress: Potential role of ELAV proteins in sporadic ALS. Increased levels of SOD1 mRNA have been observed in sporadic ALS patients (SALS) compared to controls. Hence, the understanding of the mechanisms by which SOD1 gene expression is modulated may shed new light on SOD1 involvement in ALS. Of interest, some adenine/uracil-rich elements (AREs) in SOD1 3'-untranslated region have been identified. These sequences represent the docking sites for several RNA-binding proteins such as ELAV proteins (ELAVs), positive regulators of gene expression. We first investigated in SH-SY5Y cells whether SOD1 mRNA represents a target of ELAVs. Results from RNA Electrophoretic Mobility Shift and RNA-immunoprecipitation assays showed a molecular interaction between ELAVs and SOD1 mRNA. We also observed that the treatment with H2O2 induced a significant increase of the amount of SOD1 mRNA bound by ELAVs and an up-regulation of SOD1 protein levels. We found a specific increase in ELAV/HuR phosphorylation, suggesting activation of this protein, in peripheral blood mononuclear cells from SALS patients compared to controls. Finally, we found increased levels of ELAV proteins in the motor cortex and spinal cord from SALS patients compared to controls, in parallel with SOD1 up-regulation in the same areas. This study suggests, for the first time, that ELAVs are involved in the regulation of SOD1 gene expression at post-transcriptional level and that these proteins are more activated in ALS pathology. The link between ELAVs and SOD1 may open novel perspectives for ALS research, paving the way for new therapeutic options. 23907981 Comparative effectiveness of drug-eluting stents on long-term outcomes in elderly patients treated for in-stent restenosis: A report from the national cardiovascular data registry. Objectives: We assessed the long-term outcomes of elderly patients who had in-stent restenosis (ISR) treated with drug-eluting stents (DES) compared to other treatment strategies. Background: Elderly patients with ISR represent a vulnerable group of which little is known regarding the safety and efficacy of repeat percutaneous coronary intervention (PCI). Methods: We analyzed patients ≥65 years of age who underwent PCI for ISR in the National Cardiovascular Data Registry(®) (NCDR) from 2004-2008. Death, myocardial infarction (MI), revascularization, stroke, and bleeding were assessed for up to 30 months by a linkage with Medicare re-hospitalization claims. Results: Out of 43,679 linked patients, 30,012 were treated with drug-eluting stents (DES), 8,277 with balloon angioplasty (BA), and 4,917 with bare metal stents (BMS). Compared with BMS, DES use was associated with a lower propensity score-matched (PM) risk of death (hazard ratio [HR] 0.72; 95% confidence interval [CI] 0.66-0.80, p<0.001), MI (HR 0.81; 95% CI 0.70-0.93, p=0.003), and revascularization (HR 0.90; 95% CI 0.82-1.00, p=0.055). Compared with BA, DES use was associated with a lower PM risk of death (HR 0.82; 95% CI 0.76-0.89, p<0.001) and revascularization (HR 0.86; 95% CI 0.80-0.93, p<0.001), but no statistically significant difference across other endpoints. There were no significant differences in long-term outcomes for BA compared to BMS. Conclusions: There was lower mortality and reduced risk for MI, revascularization, and stroke, but a similar rate of bleeding with DES compared to other modalities. Our results indicate that DES use is a comparatively effective strategy to treat elderly patients with ISR. © 2013 Wiley Periodicals, Inc. 23609350 Blood-brain barrier structure and function and the challenges for CNS drug delivery. The neurons of the central nervous system (CNS) require precise control of their bathing microenvironment for optimal function, and an important element in this control is the blood-brain barrier (BBB). The BBB is formed by the endothelial cells lining the brain microvessels, under the inductive influence of neighbouring cell types within the 'neurovascular unit' (NVU) including astrocytes and pericytes. The endothelium forms the major interface between the blood and the CNS, and by a combination of low passive permeability and presence of specific transport systems, enzymes and receptors regulates molecular and cellular traffic across the barrier layer. A number of methods and models are available for examining BBB permeation in vivo and in vitro, and can give valuable information on the mechanisms by which therapeutic agents and constructs permeate, ways to optimize permeation, and implications for drug discovery, delivery and toxicity. For treating lysosomal storage diseases (LSDs), models can be included that mimic aspects of the disease, including genetically-modified animals, and in vitro models can be used to examine the effects of cells of the NVU on the BBB under pathological conditions. For testing CNS drug delivery, several in vitro models now provide reliable prediction of penetration of drugs including large molecules and artificial constructs with promising potential in treating LSDs. For many of these diseases it is still not clear how best to deliver appropriate drugs to the CNS, and a concerted approach using a variety of models and methods can give critical insights and indicate practical solutions. 23892573 Plasma protein S residues 37-50 mediate its binding to factor Va and inhibition of blood coagulation. Protein S (PS) is an anticoagulant plasma protein whose deficiency is associated with increased risk of venous thrombosis. PS directly inhibits thrombin generation by the blood coagulation pathways by several mechanisms, including by binding coagulation factors (F) Va and Xa. To identify PS sequences that mediate inhibition of FVa activity, antibodies and synthetic peptides based on PS sequence were prepared and employed in plasma coagulation assays, purified component prothrombinase assays, binding assays, and immunoblots. In the absence of activated protein C, monoclonal antibody (Mab) S4 shortened FXa-induced clotting in normal plasma but not in PS-depleted plasma. Mab S4 also blocked PS inhibition of FVa-dependent prothrombinase activity in purified component assays in the absence or presence of phospholipids and inhibited binding of PS to immobilised FVa. Epitope mapping identified N-terminal region residues 37-67 of PS as this antibody's epitope. A peptide representing PS residues 37-50 inhibited FVa-dependent prothrombinase activity in a non-competitive manner, with 50% inhibition observed at 11 µM peptide, whereas a peptide with a D-amino acid sequence of 37-50 was ineffective. FVa, but not FXa, bound specifically to the immobilised peptide representing residues 37-50, and the peptide inhibited binding of FVa to immobilised PS. These data implicate PS residues 37-50 as a binding site for FVa that mediates, at least in part, the direct inhibition of FVa-dependent procoagulant activity by PS. 23499293 Antibodies targeting extracellular domain of connexins for studies of hemichannels. Hemichannels are transmembrane channels composed of either a connexin or pannexin hexamer. The docking of the extracellular domains of connexin hemichannels contributed by neighboring cells forms a gap junction channel that joins the cytoplasm of adjacent cells. Connexins are expressed ubiquitously in different organs, but some subtypes are expressed exclusively in certain tissues and tumors. Both gap junction channels and hemichannels participate in diverse physiological and pathological responses. However, the lack of specific reagents that inhibit only gap junction channels or hemichannels is a challenge that makes it different to discern the specific roles of either channel. Fortunately, the available information regarding the connexin sequence, secondary and tertiary structure, and their biochemical and physiological properties permits the development of strategies to block exclusively the hemichannel activity exclusively, with no effect on gap junction activity. This task is accomplished through the use of specifics antibodies that target the extracellular sites of desired connexin subtype. However, the underlying mechanism of how antibodies targeting extracellular connexin epitopes actually inhibit hemichannels remains unknown. Although these antibodies are being used for detecting and blocking of hemichannels in normal and tumor cells, they can also be potentially used for tissue-specific treatment and drug delivery in clinical applications. In this article, we will first review the literature concerning the structure of connexins and the unique properties of extracellular loop domains of the connexins. Furthermore, we will discuss briefly the development of connexin (Cx) 43(E2) antibody, a specific antibody which detects the second extracellular loop of Cx43 and specifically prevents the opening of Cx43 hemichannels. We will then summarize the reported studies of specific reagents used for the inhibition of connexin hemichannels including antibodies developed against extracellular loop domains. This article is part of a Special Issue entitled 'Connexin based channels'. 23639485 Seasonal humidity may influence Pseudomonas aeruginosa hospital-acquired infection rates. The objective of this study was to determine the association of seasonal climatic conditions with the incidence of Pseudomonas aeruginosa infections. A retrospective study was carried out to evaluate all infections caused by P. aeruginosa in a 660-bed tertiary-care hospital in Brazil over a period of 5 years. To assess seasonal patterns, monthly temperature, relative humidity, and precipitation averages were obtained. Correlations of seasonal variations with infection rates (IR) were determined by Pearson correlation coefficient. Linear regression was used to determine trends, and multivariable linear regression was performed using a Poisson distribution. A total of 844 cases of P. aeruginosa infection were identified for 1 058 501 patient-days during 1826 days (overall IR 7.97/10 000 patient-days). The mean temperature was 18.2±2.8°C, relative humidity was 80.3±3.6%, and precipitation was 104.7±64.38mm. The Pearson correlation was significant between urinary tract infection and temperature (R=0.29; p=0.021) and precipitation (R=0.27; p=0.036). A correlation was also significant between hospital-associated pneumonia and precipitation (R=0.29; p=0.022) and relative humidity (R=0.31; p=0.013). Relative humidity was associated with a higher IR of other infections caused by P. aeruginosa, but it was not possible to build a predictive model when multiple linear regression and Poisson regression were tested. Climatic conditions are another factor that may interfere with the IR of Pseudomonas aeruginosa. 23851501 Self-reinforcing loop of amphiregulin and Y-box binding protein-1 contributes to poor outcomes in ovarian cancer. The Y-box binding protein-1 (YB-1) transcription factor is associated with unfavorable clinical outcomes. However, the mechanisms underlying this association remain to be fully elucidated. We demonstrate that YB-1 phosphorylation, indicative of YB-1 activation, is a powerful marker of outcomes for ovarian cancer patients. In ovarian cancer, YB-1 phosphorylation is induced by activation of the lysophosphatidic acid (LPA) receptor (LPAR) via SRC-dependent transactivation of the epidermal growth factor receptor (EGFR) that is coupled to MAPK/p90 ribosomal S6 kinase (p90RSK), but not phosphatidylinositol 3-kinase (PI3K)/AKT signaling. Activation of the LPAR/SRC/EGFR/MAPK/p90RSK/YB-1 axis leads to production of the EGFR ligand amphiregulin (AREG). AREG induces ongoing YB-1 phosphorylation as well as YB-1-dependent AREG expression, thus constituting an AREG/YB-1 self-reinforcing loop. Disruption of transactivation of the EGFR and the downstream self-reinforcing loop decreases invasiveness of ovarian cancer cells in vitro and limits ovarian cancer growth in xenograft models. These findings established the regulation and significance of YB-1 phosphorylation, therefore further exploration of this signaling axis as a therapeutic avenue in ovarian cancer is warranted.Oncogene advance online publication, 15 July 2013; doi:10.1038/onc.2013.259. 23276622 Busulfan-induced pathological changes of the cerebellar development in infant rats. Busulfan, an antineoplastic bifunctional-alkylating agent, is known to induce developmental anomalies and fetal neurotoxicity. We previously reported that busulfan induced p53-dependent neural progenitor cell apoptosis in fetal rat brain (Ohira et al., 2012). The present study was carried out to clarify the characteristics and sequence of busulfan-induced pathological changes in infant rat brain. Six-day-old male infant rats were treated with 10, 20, 30 or 50mg/kg of busulfan, and their brains were examined at 1, 2, 4, 7, and 14 days after treatment (DAT). As a result, histopathological changes were selectively detected in the external granular layer (EGL), deep cerebellar nuclei (DCN) and cerebellar white matter (CWM) in the cerebellum with dose-dependent severity but not in the cerebrum. In the normal infant rat cerebellum, granular cells in the EGL were proliferating and moving to the internal granular layer during the normal developmental process. In the EGL of the busulfan group, apoptotic granular cells increased at 2 DAT simultaneously with increased numbers of p53- and p21-positive cells while mitotic granular cells decreased, suggesting an occurrence of p53-related apoptosis and depression of proliferative activity in granular cells. In the DCN, apoptotic glial cells increased at 2 DAT and glial cells showing abnormal mitosis increased at 4 DAT. In the CWN, edematous change accompanying a few apoptotic cells was found in the CWN, especially in the parafolliculus (PFL), from 2 to 7 DAT. The present study demonstrated for the first time the characteristics and sequence of busulfan-induced pathological changes in infant rat cerebellum. 23927446 Review of fall risk assessment in geriatric populations using inertial sensors. Falls are a prevalent issue in the geriatric population and can result in damaging physical and psychological consequences. Fall risk assessment can provide information to enable appropriate interventions for those at risk of falling. Wearable inertial-sensor-based systems can provide quantitative measures indicative of fall risk in the geriatric population. Forty studies that used inertial sensors to evaluate geriatric fall risk were reviewed and pertinent methodological features were extracted; including, sensor placement, derived parameters used to assess fall risk, fall risk classification method, and fall risk classification model outcomes. Inertial sensors were placed only on the lower back in the majority of papers (65%). One hundred and thirty distinct variables were assessed, which were categorized as position and angle (7.7%), angular velocity (11.5%), linear acceleration (20%), spatial (3.8%), temporal (23.1%), energy (3.8%), frequency (15.4%), and other (14.6%). Fallers were classified using retrospective fall history (30%), prospective fall occurrence (15%), and clinical assessment (32.5%), with 22.5% using a combination of retrospective fall occurrence and clinical assessments. Half of the studies derived models for fall risk prediction, which reached high levels of accuracy (62-100%), specificity (35-100%), and sensitivity (55-99%). Inertial sensors are promising sensors for fall risk assessment. Future studies should identify fallers using prospective techniques and focus on determining the most promising sensor sites, in conjunction with determination of optimally predictive variables. Further research should also attempt to link predictive variables to specific fall risk factors and investigate disease populations that are at high risk of falls. 23927195 A heuristic model of stone comminution in shock wave lithotripsy. A heuristic model is presented to describe the overall progression of stone comminution in shock wave lithotripsy (SWL), accounting for the effects of shock wave dose and the average peak pressure, P+(avg), incident on the stone during the treatment. The model is developed through adaptation of the Weibull theory for brittle fracture, incorporating threshold values in dose and P+(avg) that are required to initiate fragmentation. The model is validated against experimental data of stone comminution from two stone types (hard and soft BegoStone) obtained at various positions in lithotripter fields produced by two shock wave sources of different beam width and pulse profile both in water and in 1,3-butanediol (which suppresses cavitation). Subsequently, the model is used to assess the performance of a newly developed acoustic lens for electromagnetic lithotripters in comparison with its original counterpart both under static and simulated respiratory motion. The results have demonstrated the predictive value of this heuristic model in elucidating the physical basis for improved performance of the new lens. The model also provides a rationale for the selection of SWL treatment protocols to achieve effective stone comminution without elevating the risk of tissue injury. 23547754 Genetics of serotonin receptors and depression: state of the art. Major depression (MD) is a major health problem, partly due to the incomplete understanding of the pathogenic mechanisms of the disease. Research efforts have mainly focused on alterations in monoaminergic neurotransmission, especially in relation to the serotonergic system, due to its key role in the regulation of mood and related biological functions. Given the high heritability of MD (estimated between 31% and 42% for unipolar depression), genes coding for key regulators of the serotonergic neurotransmission have been considered as optimal candidates. The present review is focused on the role of genes coding for serotonin receptors in MD pathogenesis, since the serotonin transporter and enzymes involved in serotonin metabolism have been reviewed elsewhere. Despite the large number of candidate gene studies focusing on genes coding for serotonin receptors, results have been inconsistent. The most replicated findings are the associations between rs6295 (HTR1A gene) G allele or G/G genotype and rs6311 (HTR2A gene) A allele or A/A genotype and MD or depressive symptoms. Preclinical and imaging/post-mortem studies in humans provide strong support for the involvement of HTR1A and HTR2A genes in MD. Nevertheless, the inconsistency across previous studies clearly suggests that innovative approaches should be designed in order to overcome the limitations of candidate gene studies. To date, the most appealing methodologies seem to be full exome or genome sequencing, genome-wide pathway analyses, endophenotypes, and epigenetic biomarkers. The reported tools may assist in the detection of multiple-loci models, which could potentially explain the high percentage of MD susceptibility ascribed to genetic factors. 23888862 Ecological causes of decelerating diversification in carnivoran mammals. Clade diversification is a central topic in macroevolutionary studies. Recently, it has been shown that diversification rates appear to decelerate over time in many clades. What causes this deceleration remains unclear, but it has been proposed that competition for limited resources between sympatric, ecologically similar species slows diversification. Employing carnivoran mammals as a model system, we test this hypothesis using a comprehensive time-calibrated phylogeny. We also explore several conceptually related explanations including limited geographic area and limited rates of niche evolution. We find that diversification slowdowns are strong in carnivorans. Surprisingly, these slowdowns are independent of geographic range overlap between related species and are also decoupled from rates of niche evolution, suggesting that slowdowns are unrelated to competition and niche filling. When controlling for the effects of clade diversity, diversification slowdowns appear independent of geographic area. There is a significant effect of clade diversity on diversification slowdowns, but simulations show that this relationship may arise as a statistical artifact (i.e., greater clade diversity increases the ability of the gamma statistic to refute constant diversification). Overall, our results emphasize the need to test hypotheses about the causes of diversification slowdowns with ecological data, rather than assuming ecological processes from phylogenies alone. 23871236 Right internal jugular venous cannulation complicated by tension hydrothorax. Central Venous Catheter (CVC) is a common procedure performed in patients' management, especially the critically ill ones. CVC has been used as main access in patients requiring large amount of fluid resuscitation, total parenteral nutrition or measuring the central venous pressure. Although most complications associated with central venous cannulation are minimal, local and easy to control, others may be critical and rapidly fatal if not recognized and treated immediately. One of the most serious incidents that can occur post CVC placement is delayed hydrothorax. It usually results from migration and perforation of the catheter through the SVC wall. In this report, we describe a case of tension hydrothorax that occurred a few hours after placement of CVC in the right internal jugular vein. In acutely ill patients that are already unstable, making the diagnosis of tension hydrothorax secondary to CVC placement requires high level of suspicion. Prompt pleural effusion drainage like in our case is crucial for favorable outcome. 23394612 The roles of epigenetic modifications of proapoptotic BID and BIM genes in imatinib-resistant chronic myeloid leukemia cells. In chronic myeloid leukemia (CML), epigenetic modifications such as promoter hypermethylation and inactive histone modification are known mechanisms of drug resistance. In our study, we investigated the roles of promoter hypermethylation of BIM and BID genes and H3K27me3 histone modification on imatinib resistance. We detected higher expression levels of BIM and BID genes and lower expression levels of EZH2, EED2, SIRT1, and SUZ12 genes in imatinib-resistant K562/IMA-3 cells compared to imatinib-non-resistant K562 cells. While we determined the EZH2 and DNMT enzymes as bounded to the promoter of the BIM gene, we did not detect hypermethylation of this promoter. We also found the H3K27me3 histone modification promoter of BIM and BID genes in both cell lines. In conclusion, our results support the notion that DNA promoter methylation may be formed independently from EZH2-H3K27me3 and pro-apoptotic BIM and BID genes are not methyllated in the imatinib resistance of CML cells. 23827381 Pre-hysterectomy cone biopsy is able to predict response in locally advanced cervical cancer patients submitted to neo-adjuvant chemoradiation. To evaluate the feasibility and the predictive value of cone biopsy before performing radical hysterectomy in locally advanced cervical cancer patients showing complete clinical response to neo-adjuvant chemoradiation. Between March 2010 to March 2012 74 consecutive FIGO stage IIA2-IIB patients were submitted to neo-adjuvant chemoradiation. All complete clinical responder patients were enrolled in this pilot trial. Fifty-seven out of 74 patients (77%) showed complete clinical response and were enrolled in the study. Forty-two out of 57 patients (74%) underwent successful pre-completion surgery cone biopsy with a median cone's tissue diameter of 24 mm (range 18-35). In 33 out of 42 patients (58%) a complete pathological response was found. In the remaining 5 (9%) and 4 (7%) a microscopic partial and partial response was found, respectively. All 33 cases (58%) with negative cone showed complete pathological response in the radical hysterectomy specimens. Patients with microscopic residual tumor foci in the cone showed negative residual cervical and paracervical tissue at definitive diagnosis, whereas in patients with partial response macroscopic residual disease in the surgical specimens was found. The negative predictive value of cone biopsy, MRI and PET/CT in the prediction of pathological status of the cervical and paracervical tissue was 100%, 79% and 79%, respectively (Table 2). In this study we observed that, in locally advanced cervical patients showing complete clinical response to neo-adjuvant chemoradiation, the cone biopsy feasibility was almost 75%, and that there is a complete pathological correspondence between cone and definitive pathology. 23880949 Unruptured aneurysm of the left sinus of Valsalva compressing the left main coronary artery : Successful percutaneous treatment. Aneurysm of the left sinus of Valsalva is an extremely rare entity. It may be asymptomatic and incidentally discovered, or may be symptomatic and manifest acutely with compression of adjacent cardiac structures. Encasement of the left main coronary artery by such an aneurysm is a recognized but infrequent complication that can lead to severe coronary insufficiency. Surgical decompression of the left main coronary artery is the standard treatment for such conditions. We describe a patient presenting with extrinsic compression of the left main coronary artery by a large unruptured aneurysm of the left sinus of Valsalva occurring 4 months after unsuccessful surgical repair. Since reoperation was considered high-risk for the patient, successful fractional flow reserve- and intravascular ultrasound-guided percutaneous treatment of the left main coronary artery was performed with implantation of one bare-metal stent. 23710904 A study of pathophysiological factors associated with gastro-esophageal reflux disease in twins discordant for gastro-esophageal reflux symptoms. Differences in lower esophageal sphincter (LES) and peristaltic function and in transient LES relaxations (TLESR) have been described in patients with gastro-esophageal reflux disease (GERD). However, some of these differences may be the result of chronic GERD rather than being an underlying contributory factor. Twins discordant for GERD symptoms, i.e., only one twin had GERD symptoms, underwent standard LES and esophageal body manometry, and then using a sleeve sensor prolonged LES and pH monitoring, 30 min before and 60 min after a 250 mL 1200 kcal lipid meal. Eight monozygotic and 24 dizygotic female twins were studied. Although there was no difference in preprandial LES pressure (symptomatic 13.2 ± 7.1 mmHg vs asymptomatic 15.1 ± 6.2 mmHg, P = 0.4), LES pressure fell further postprandially in symptomatic twins (LES pressure area under the curve 465 ± 126 vs 331 ± 141 mmHg h, P < 0.01). 12/37 (32%) of acid reflux episodes in symptomatic twins occurred due to low LES pressure or deep inspiration/strain and 0/17 in asymptomatic twins (P = 0.01). There was no difference between symptomatic and asymptomatic twins in: peristaltic amplitude, ineffective esophageal body motility, hiatus hernia prevalence, or LES length. There was also no difference in TLESR frequency preprandially (symptomatic median 1(range 0-2) vs asymptomatic 0(0-2), P = 0.08) or postprandially (2.5(1-8) vs 3(1-6), P = 0.81). Twins with GERD symptoms had lower postprandial LES pressure and given the close genetic link between the twins, it is possible that such differences are caused by GERD. Acid reflux episodes associated with a hypotensive LES were seen in symptomatic, but not in asymptomatic twins. 23281098 Assessment of density functional methods for reaction energetics: iridium-catalyzed water oxidation as case study. We investigate basis set convergence for a series of density functional theory (DFT) functionals (both hybrid and nonhybrid) and compare to coupled-cluster with single and double excitations and perturbative triples [CCSD(T)] benchmark calculations. The case studied is the energetics of the water oxidation reaction by an iridium-oxo complex. Complexation energies for the reactants and products complexes as well as the transition state (TS) energy are considered. Contrary to the expectation of relatively weak basis set dependence for DFT, the basis set effects are large, for example, more than 10 kcal mol(-1) difference from converged basis for the activation energy with "small" basis sets (DZ/6-31G** for Ir/other atoms, or SVP) and still more than 6 kcal mol(-1) for def2-TZVPP/6-31G**. Inclusion of the dispersion correction in DFT-D3 schemes affects the energies of reactant complex (RC), TS, and product complex (PC) by almost the same amount; it significantly improves the complexation energy (the formation of RC), but has little effect on the activation energy with respect to RC. With converged basis, some pure GGAs (PBE-D3, BP86-D3) as well as the hybrid functional B3LYP-D3 are very accurate compared to benchmark CCSD(T) calculations. 23728964 Synthesis of nanocomposites from Pd(0) and a hyper-cross-linked functional resin obtained from a conventional gel-type precursor. Hyper-cross-linked resins stemming from a gel-type poly-chloromethylated poly(styrene-co-divinylbenzene) resin (GT) have been investigated by a multi-methodological approach based on elemental analysis, scanning electron microscopy, X-ray microanalysis, and solvent absorption. The hyper-cross-linking of the parent resin was accomplished by Friedel-Crafts alkylation of the phenyl rings of the resins with the chloromethyl groups. This produced a permanent pore system comprising both micropores (<2.0 nm in diameter) and mesopores (2.2 nm). The chloromethyl groups that did not react in the hyper-cross-linking step were transformed into methylmercaptan groups and the latter were then converted into sulfonic groups by oxidation with hydrogen peroxide. By this procedure the extensive permanent porosity of the parent unsulfonated hyper-cross-linked polymer (HGT) was retained by the sulfonated polymer (HGTS). The final exchange capacity of HGTS was determined to be 0.36 mmol g(-1). HGTS was easily metalated with Pd(II) and the subsequent reduction of the metal centers with either aqueous sodium borohydride, formaldehyde, or dihydrogen produced three Pd(0)/HGTS nanocomposites. The metal nanoparticles had diameters in the 1-6 nm range for all the nanocomposites, as determined by TEM, but with somewhat different distributions. When formaldehyde was used, more than 90% of the nanoparticles were less than 3 nm and their radial distribution throughout the polymer beads was quite homogeneous. These findings show that with this reducing agent the metal nanoparticles are generated within the pore system of the polymer matrix, hence their size is controlled by the dimensions of the pores of the polymeric support. 23821442 Quantification of microRNA expression with next-generation sequencing. Rapid advancement of next-generation sequencing technologies has made it possible to study expression profiles of microRNAs (miRNAs) comprehensively and efficiently. Multiplexing miRNA libraries by barcoding can significantly reduce sequencing cost per sample without compromising library quality. This unit provides a step-by-step protocol for isolating miRNAs and constructing multiplexed miRNA libraries. Also described is a custom computational pipeline for analyzing the multiplexed miRNA library sequencing reads generated by Illumina-based technology. 23853420 Modeling the relationships between cognitive-linguistic skills and writing in Chinese among elementary grades students. The present study is a four-year longitudinal study examining the important predictors of writing of 340 Chinese children in elementary grades. Children's transcription skills (handwriting skills and spelling), and syntactic skills in grade 1 were significant predictors of text writing in grade 1-4 while ideation in grade 1 only contributed to text writing in grade 2. Stroke order knowledge was shown as an important handwriting skill in Chinese reflecting the characteristics of the Chinese orthography. A model of Chinese writing in early elementary grades was proposed. In the model, orthographic knowledge, morphological awareness and handwriting skills are proposed to contribute to spelling which is correlated with text writing. Handwriting skills, ideation, and syntactic skills were found to contribute to text writing. Path analysis results suggest that the longitudinal relationship between spelling and text writing is bidirectional. 23567840 Protein kinase C-mediated ATP stimulation of Na(+)-ATPase activity in LLC-PK1 cells involves a P2Y2 and/or P2Y4 receptor. ATP-activated P2Y receptors play an important role in renal sodium excretion. The aim of this study was to evaluate the modulation of ATPase-driven sodium reabsorption in the proximal tubule by ATP or adenosine (Ado). LLC-PK1 cells, a model of porcine proximal tubule cells, were used. ATP (10(-6)M) or Ado (10(-6)M) specifically stimulated Na(+)-ATPase activity without any changes in (Na(+)+K(+))-ATPase activity. Our results show that the Ado effect is mediated by its conversion to ATP. Furthermore, it was observed that the effect of ATP was mimicked by UTP, ATPγS and 2-thio-UTP, an agonist of P2Y2 and P2Y4 receptors. In addition, ATP-stimulated Na(+)-ATPase activity involves protein kinase C (PKC). Our results indicate that ATP-induced stimulation of proximal tubule Na(+)-ATPase activity is mediated by a PKC-dependent P2Y2 and/or P2Y4 pathway. These findings provide new perspectives on the role of the effect of P2Y-mediated extracellular ATP on renal sodium handling. 23412197 Trans-fracture transposition of the radial nerve during the open approach of humeral shaft fractures. The radial nerve constitutes a major problem in humeral shaft fractures; it may be injured immediately or during closed reduction or open reduction and internal fixation with plate and screws. After fixation, the nerve always runs directly over the plate without any interposed structure. If a revision surgery is indicated, the nerve is at high risk as it is usually difficult to dissect from surrounding fibrotic scar tissue or callus formation. To avoid these complications, some authors reported transposition of the radial nerve through the fracture line. We present herein the surgical technique of the trans-fracture transposition of the radial nerve during open reduction and internal fixation of humeral shaft fractures, along with our preliminary results in 6 cases and a review of the literature. 23474324 Can acetylcholinesterase activity be considered as a reliable biomarker for the assessment of cadmium-induced neurotoxicity? Gonçalves et al. (2012) recently reported the findings of a long-awaited study on the effects of long-term dietary-induced exposure to cadmium (Cd) on the acetylcholinesterase (AChE) activity of adult rodents' brain regions. Their study can be regarded as a significant contribution to the field, as there is paucity of information on the AChE activity in brain regions following exposure to Cd. However, the Cd-induced modulation of AChE activity is an issue surrounded by controversy. We, herein, discuss and summarize the relative in vivo and in vitro experimental data, and set out to answer the straightforward question: can AChE activity be considered as a reliable biomarker for the assessment of Cd-induced neurotoxicity? At this time, we can not answer in the affirmative because of the variation in techniques used and conclusions reached. We make a plea that authors aiming to explore this potential use of brain AChE activity in the future: (a) are aware of the biases that their experimental approach might exert upon this neurochemical parameter, (b) avoid the use of anaesthesia as a mode of sacrifice and clarify its timing, (c) decide upon the use of previously-studied in vivo experimental schemes (so that they can provide comparable results), and finally, (d) identify pharmacological, biochemical and molecular approaches that are appropriate to clarify the implicated mechanism(s) through which Cd modifies AChE activity. 23939078 Demonstration of coherent imaging through a phased array of single-mode optical fibers. We demonstrate coherent imaging through a phased array of single-mode optical fibers. Specifically, we show that two laboratory point sources located within the individual-fiber single-mode acceptance angle can be resolved. Such techniques could eventually enable direct imaging with arrays of small collecting telescopes. 23448165 Twisting bilayer graphene superlattices. Bilayer graphene is an intriguing material in that its electronic structure can be altered by changing the stacking order or the relative twist angle, yielding a new class of low-dimensional carbon system. Twisted bilayer graphene can be obtained by (i) thermal decomposition of SiC; (ii) chemical vapor deposition (CVD) on metal catalysts; (iii) folding graphene; or (iv) stacking graphene layers one atop the other, the latter of which suffers from interlayer contamination. Existing synthesis protocols, however, usually result in graphene with polycrystalline structures. The present study investigates bilayer graphene grown by ambient pressure CVD on polycrystalline Cu. Controlling the nucleation in early stage growth allows the constituent layers to form single hexagonal crystals. New Raman active modes are shown to result from the twist, with the angle determined by transmission electron microscopy. The successful growth of single-crystal bilayer graphene provides an attractive jumping-off point for systematic studies of interlayer coupling in misoriented few-layer graphene systems with well-defined geometry. 23959047 Tumor necrosis factor-α-activated mesenchymal stem cells promote endothelial progenitor cell homing and angiogenesis. Mesenchymal stem cells (MSCs) accelerate regeneration of ischemic or injured tissues by stimulation of angiogenesis through a paracrine mechanism. Tumor necrosis factor-α (TNF-α)-activated MSCs secrete pro-angiogenic cytokines, including IL-6 and IL-8. In the present study, using an ischemic hindlimb animal model, we explored the role of IL-6 and IL-8 in the paracrine stimulation of angiogenesis and tissue regeneration by TNF-α-activated MSCs. Intramuscular injection of conditioned medium derived from TNF-α-treated MSCs (TNF-α CM) into the ischemic hindlimb resulted in attenuated severe limb loss and stimulated blood perfusion and angiogenesis in the ischemic limb. Immunodepletion of IL-6 and IL-8 resulted in attenuated TNF-α CM-stimulated tissue repair, blood perfusion, and angiogenesis. In addition, TNF-α CM induced migration of human cord blood-derived endothelial progenitor cells (EPCs) through IL-6- and IL-8-dependent mechanisms in vitro. Intramuscular injection of TNF-α CM into the ischemic limb led to augmented homing of tail vein-injected EPCs into the ischemic limb in vivo and immunodepletion of IL-6 or IL-8 from TNF-α CM attenuated TNF-α CM-stimulated homing of EPCs. In addition, intramuscular injection of recombinant IL-6 and IL-8 proteins resulted in increased homing of intravenously transplanted EPCs into the ischemic limb and improved blood perfusion in vivo. These results suggest that TNF-α CM stimulates angiogenesis and tissue repair through an increase in homing of EPCs through paracrine mechanisms involving IL-6 and IL-8. 23736541 Effects of transaldolase exchange on estimates of gluconeogenesis in type 2 diabetes. Transaldolase (TA) exchange overestimates gluconeogenesis measured with deuterated water ((2)H2O). However, it is unknown whether TA differs in people with type 2 diabetes (T2DM). (2)H2O was ingested, and [1-(13)C]acetate and [3-(3)H]glucose were infused in T2DM (n = 10) and healthy nondiabetic (ND; n = 8) subjects. TA was assessed from the ratio of (13)C3 to (13)C4 glucose enrichment ((13)C3/(13)C4) measured by (13)C NMR. Glucose turnover was measured before (∼16-h fast) and during hyperglycemic (∼10 mM) moderate-dose insulin (∼0.35 mU·kg(-1)·min(-1)) clamp. (13)C3/(13)C4 in T2DM vs. ND was <1.0 and not different at baseline and clamp, indicating equivalent TA. To determine whether incomplete triose phosphate isomerase (TPI) exchange contributed to asymmetric (13)C3/(13)C4, [U-(13)C]glycerol was infused in lieu of [1-(13)C]acetate during a separate visit in a subset of ND (n = 7) subjects. Ratio of (13)C3/(13)C4 obtained following either tracer was <1.0 at baseline and during clamp, indicating that TPI exchange was essentially complete and did not contribute to asymmetric glucose enrichment. Uncorrected and corrected rates of gluconeogenesis were no different (P = not significant) in T2DM vs. ND both at baseline and during clamp. TA correction resulted in equivalent estimates of corrected gluconeogenesis in T2DM and ND that were ∼25-35% lower than uncorrected gluconeogenesis both at baseline and during the clamp. The asymmetric enrichment of glucose from (13)C-gluconeogenic tracers is attributable to TA exchange and can be utilized to correct for TA exchange. In conclusion, TA exchange does not differ between T2DM and ND under fasting or hyperglycemic clamp conditions, and the (2)H2O method continues to provide an accurate estimation of gluconeogenesis. 23470325 Safety assessment of Apoaequorin, a protein preparation: Subchronic toxicity study in rats. Apoaequorin, a calcium-binding protein originally isolated from jellyfish is available commercially as a dietary supplement. The objective of the present study was to investigate potential adverse effects, if any, of Apoaequorin, a recombinant protein preparation, in rats following subchronic administration. For this study, Sprague-Dawley (Hsd:SD®) rats (10/sex/group) were administered via oral gavage 0 (control), 92.6, 462.9, and 926.0mg/kg body weight (bw)/day of Apoaequorin preparation, for 90days. The corresponding amount of Apoaequorin protein was 0, 66.7, 333.3 and 666.7mg/kg bw/day, respectively. Administration of the Apoaequorin preparation did not result in any mortality. There were no clinical or ophthalmological signs, body weight, body weight gain, food consumption, food efficiency, clinical pathology or histopathological changes attributable to administration of Apoaequorin. Any changes noted were incidental and in agreement with those historically observed in the age and strain of rats used in this study. Based on the results of this study, the No Observed-Adverse-Effect Level (NOAEL) for Apoaequorin was determined as 666.7mg/kg bw/day, the highest dose tested. 23918657 TRPA1 receptor stimulation by hydrogen peroxide is critical to trigger pain during MSU-induced inflammation. Objective: Gout is a common cause of inflammatory arthritis provoked by the accumulation of monosodium urate (MSU) crystals, but the underlying mechanisms of the pain in acute gout attacks are poorly understood. The aim of the present study was to evaluate the role of transient receptor potential ankyrin 1 (TRPA1) and TRPA1 stimulants, such as hydrogen peroxide (H2 O2 ), in the MSU-induced inflammation model in rodents. Methods: MSU or H2 O2 were injected into the hind paw of rodents, or applied in cultured sensory neurons and intracellular calcium in vitro and inflammatory or nociceptive responses in vivo were evaluated. Pharmacological, genetic or biochemical tools and methods have been used. Results: We found that TRPA1 antagonism, TRPA1 gene deletion or defunctionalization by capsaicin pretreatment of peptidergic TRP-expressing primary sensory neurons markedly decreased MSU-induced nociception and edema. In addition to these neurogenic effects, MSU increased H2 O2 levels in the injected tissue, an effect that was abolished by the H2 O2 -detoxifing enzyme, catalase. H2 O2 , but not MSU, directly stimulated sensory neurons through the activation of TRPA1. Nociceptive responses evoked by MSU or H2 O2 injection were attenuated by catalase, the reducing agent dithiothreitol. In addition, MSU injection increased the expression of TRPA1 and TRPV1 as well as enhanced cellular infiltration and IL-1β levels, which were blocked by TRPA1 antagonism. Conclusion: Our results suggest that MSU-injection increases tissue H2 O2 thereby stimulating TRPA1 on sensory nerve endings to produce inflammation and nociception. TRPV1, by a hitherto unknown mechanism, also contributes to these responses. © 2013 American College of Rheumatology. 23868196 Ordered Mesoporous Materials Based on Interfacial Assembly and Engineering. Ordered mesoporous materials have inspired prominent research interest due to their unique properties and functionalities and potential applications in adsorption, separation, catalysis, sensors, drug delivery, energy conversion and storage, and so on. Thanks to continuous efforts over the past two decades, great achievements have been made in the synthesis and structural characterization of mesoporous materials. In this review, we summarize recent progresses in preparing ordered mesoporous materials from the viewpoint of interfacial assembly and engineering. Five interfacial assembly and synthesis are comprehensively highlighted, including liquid-solid interfacial assembly, gas-liquid interfacial assembly, liquid-liquid interfacial assembly, gas-solid interfacial synthesis, and solid-solid interfacial synthesis, basics about their synthesis pathways, princples and interface engineering strategies. 23801335 The Pneumocystis Ace2 Transcription Factor Regulates Cell Wall-remodeling Genes and Organism Virulence. Pneumocystis carinii (Pc) β-glucans are major components of the organism cell wall; yet, the regulation of Pc cell wall genesis and remodeling is not well understood. Ace2 transcription factors, which are present in many fungi, regulate glucanases and other enzymes needed for cell wall remodeling. The cloning and heterologous expression of PcAce2 in ace2Δ Saccharomyces cerevisiae demonstrated that PcAce2 can restore the defective glucanase and endochitinase gene expression of the mutant as well as regulate cell wall β-glucan biosynthetic genes. Furthermore, when a reconstructed yeast system was used, PcAce2 activated the transcription of the Pneumocystis gsc1 β-glucan synthetase, confirming the activity of a Pc transcription factor on a native Pneumocystis promoter and gene for the first time. We further observed that Pneumocystis binding to host extracellular matrix proteins and lung epithelial cells induced the phosphorylation (activation) of the PcAce2 transcription factor. Finally, we present a novel method that confirms the role of PcAce2 in modulating organism virulence using ace2Δ Candida glabrata infection in neutropenic mice. Together, these results indicate that the adherence of Pc to lung matrix proteins and epithelial cells leads to the activation of the Ace2 transcription factor, which regulates cell wall degradation and biosynthesis genes that are required for cell wall remodeling. 21838705 The mechanisms responsible for garlic - drug interactions and their in vivo relevance. Garlic phytochemicals and garlic supplements influence the pharmacokinetic and pharmacodynamic behavior of concomitantly ingested drugs. In this paper we have summarized the mechanisms responsible for first-pass intestinal pharmacokinetic interactions by investigating the intestinal permeability of some cardiovascular, antiviral drugs, their transport with hepatic transporters and CYP3A4 metabolism. Transporter-enzyme interplay was studied with several in vitro models of varying complexity: rat small intestine and Caco-2 cell monolayers were used in studies of intestinal processes, and hepatic pharmacokinetics was monitored in HepG2 cells, isolated rat hepatocytes and rat liver slices. Garlic phytochemicals from aged garlic extract modified the activities of secretory and absorptive transporters in both intestine and liver and competitively inhibited CYP3A4 enzyme. The increased activities of the most important intestinal efflux (P-glycoprotein - Pgp, Multidrug Resistance Associated Protein 2 - MRP-2, Breast Cancer Resistance Protein - BCRP) and uptake (MonoCarboxylate Transporter 1 - MCT1, Organic Anion Transporting Polypeptide - OATP, Peptide transporter 1 - PepT1) transporters were caused by changes in electrophysiological membrane properties and by allosteric modifications. Because clinical studies investigating interactions between garlic and human immunodeficiency virus protease inhibitors saquinavir and ritonavir have already been performed, we used these in vivo data to evaluate the in vitro results and the reliability of the models employed as screening tools for forecasting the potential of first-pass intestinal metabolism changes. We also assessed the probability of pharmacokinetic interactions with garlic of the novel drug darunavir and other cardiovascular drugs. Finally, selected garlic phytochemicals were tested for their ability to influence P-glycoprotein and CYP3A4 activities. 23932790 A hit to lead discovery of novel N-methylated imidazolo-, pyrrolo-, and pyrazolo-pyrimidines as potent and selective mTOR inhibitors. A series of N-7-methyl-imidazolopyrimidine inhibitors of the mTOR kinase have been designed and prepared, based on the hypothesis that the N-7-methyl substituent on imidazolopyrimidine would impart selectivity for mTOR over the related PI3Kα and δ kinases. The corresponding N-Me substituted pyrrolo[3,2-d]pyrimidines and pyrazolo[4,3-d]pyrimidines also show potent mTOR inhibition with selectivity toward both PI3α and δ kinases. The most potent compound synthesized is pyrazolo[4,3-d]pyrimidine 21c. Compound 21c shows a Ki of 2nM against mTOR inhibition, remarkable selectivity (>2900×) over PI3 kinases, and excellent potency in cell-based assays. 23603198 The PERICLES research program: An integrated approach to characterize the combined effects of mixtures of pesticide residues to which the French population is exposed. Due to the broad spectrum of pesticide usages, consumers are exposed to mixtures of residues, which may have combined effects on human health. The PERICLES research program aims to test the potential combined effects of pesticide mixtures, which are likely to occur through dietary exposure. The co-exposure of the French general population to 79 pesticide residues present in the diet was first assessed. A Bayesian non-parametric model was then applied to define the main mixtures to which the French general population is simultaneously and most heavily exposed. Seven mixtures made of two to six pesticides were identified from the exposure assessment. An in vitro approach was used for investigating the toxicological effects of these mixtures and their corresponding individual compounds, using a panel of cellular models, i.e. primary rat and human hepatocytes, liver, intestine, kidney, colon and brain human cell lines. A set of cell functions and corresponding end-points were monitored such as cytotoxicity, real-time cell impedance, genotoxicity, oxidative stress, apoptosis and PXR nuclear receptor transactivation. The mixtures were tested in equimolar concentrations. Among the seven mixtures, two appeared highly cytotoxic, five activated PXR and depending on the assay one or two were genotoxic. In some experiments, the mixture effect was quantitatively different from the effect expected from the addition concept. The PERICLES program shows that, for the most pesticides mixtures to which the French general population is exposed, the toxic effects observed on human cells cannot be easily predicted based on the toxic potential of each compound. Consequently, additional studies should be carried on in order to more accurately define the mixtures of chemicals to which the consumers are exposed, as well as to improve the investigation, prediction and monitoring of their potential human health effects. 23889426 Transport Theory of Monolayer Transition-Metal Dichalcogenides through Symmetry. We present a theory that elucidates the major momentum and spin relaxation processes for electrons, holes, and hot excitons in monolayer transition-metal dichalcogenides. We expand on spin flips induced by flexural phonons and show that the spin relaxation is ultrafast for electrons in free-standing membranes while being mitigated in supported membranes. This behavior due to interaction with flexural phonons is universal in two-dimensional membranes that respect mirror symmetry, and it leads to a counterintuitive inverse relation between mobility and spin relaxation. 23561897 Imaging of the female urethral diverticulum. Female urethral diverticulum is a localized out-pouching of the urethra that is becoming increasingly prevalent, but often poses a diagnostic challenge. Traditionally, conventional voiding cystourethrography has been used to make the preoperative diagnosis. With the development of higher-resolution images acquired through ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI), the anatomy and various abnormalities of the female urethra can be better elucidated. This article focuses on the imaging features of female urethral diverticulum, with emphasis on diagnostic pearls, particularly using MRI. Female urethral diverticulum can be best identified by their location in the posterolateral urethra and by their communication with the urethral lumen. Improved imaging techniques combined with increased physician awareness of urethral diverticulum will lead to more prompt and accurate diagnosis of this entity, leading to better treatment of affected patients. 23668808 Re-categorisation of male lower urinary tract symptoms based on the international prostate symptom score questionnaire. The purpose of this study was to develop a new sub-classification system for male lower urinary tract symptoms (LUTS)-mild, moderate and severe-using the conventional International Prostate Symptoms Score (I-PSS). From October 2007 to March 2012, a total of 2234 male patients (≥ 50 years old) presenting with LUTS were enrolled in this study. Patients were sorted according to their I-PSS (ranging from 1 to 35 points) and divided into three groups based on their quality of life (QoL) score. A chi-square automatic interaction detection (CHAID) algorithm, based on adjusted significance testing, was used. The Kappa coefficient was calculated for the agreement of original and new categorisation. Mean total I-PSS and QoL scores were 11.0 and 2.9 respectively. According to the original classification, 838 patients (38.6%) had mild, 1053 (48.5%) had moderate and 282 (13.0%) had severe symptoms. After the CHAID algorithm was applied, the scores were re-categorised as 'mild' (1-6 points), 'moderate' (7-21 points) and 'severe' (22-35 points). The overall model was able to correctly predict whether an I-PSS was associated with mild, moderate or severe symptoms, with 70.1% accuracy. According to this new classification, 704 patients (32.4%) were shown to have mild, 1255 (57.8%) to have moderate and 214 (9.8%) to have severe LUTS. The agreement of conventional and new categorisation is very strong (Kappa coefficient = 0.84). Conventional categorisation of LUTS by I-PSS needs to be updated and the category of moderate LUTS should be broadened. 23938016 Status and costs of primary prevention for ischemic stroke in China. Despite the benefits in reducing the risk of stroke, primary prevention is not well translated into practice. We sought to evaluate patient compliance with guidelines and the cost of primary stroke prevention in southwest China. We consecutively enrolled 305 patients with headaches and/or dizziness who were at high risk of stroke from our hospital. We retrospectively obtained their information, including the extent of their knowledge of stroke risk factors, adherence to guidelines, medications taken, and costs of primary prevention for stroke within the past year. Only 45.9% of patients had any knowledge of primary prevention, and only 17.0% had completely followed guidelines. Moreover, 79.0% of the patients were using medications, but only 39.3% took their medication as recommended. In patients who took medication, 89.6% were prescribed by physicians. The annual costs of primary prevention were estimated to be US$517.8 per capita, which included direct medical costs (US$435.4), direct non-medical costs (US$18.1), and indirect costs (US$64.3). Costs in the hypertension group were less than those reported by a similar international study. Although our population sample may not be representative of the population at high risk of stroke in China, it is appropriate for the evaluation of our primary prevention system. Primary prevention for stroke in southwest China is very challenging, with few medical resource investments. There is a current urgency to improve patient knowledge of primary prevention, which would bridge the gaps between guidelines and practice and increase medical resource investments. 23962036 Residential movement patterns of families of young children with chronic conditions in Ontario, Canada: a population-based cohort study. Care giving for children with chronic diseases can lead to financial strain and compromised family well being. Little is known about whether these stresses lead to changes in residential movement patterns as they relate to income adequacy and proximity to care. We compared the residential movement patterns and associated changes in neighbourhood income of children with mild to severe chronic diseases compared with those that are healthy. A cohort of infants born from 2002--2007 in Ontario, Canada was followed for 5 years and divided into those with single- or multiple- body system complex chronic conditions (CCCs); low birth weight (LBW); asthma/recurrent wheeze (A/RW) and the control group of otherwise healthy children. Of 598,716 children studied, 15,207 had a single CCC, 3,600 multiple CCCs, 33,206 LBW, 57,137 A/RW and 489,566 were healthy. Lowest income quintile children were most likely to move residence. Compared with healthy controls, chronic disease cohorts, apart from those with asthma, were more likely to be born in the lowest income quintile neighbourhood and to move. Among children who moved, all chronic disease cohorts were significantly more likely to move to a low income quintile neighborhood (adjusted odds ratios for all chronic disease cohorts of 1.1-1.2). There were no differences across cohorts in residential movement close to a children's hospital. Young children with chronic conditions, particularly those born in low income neighbourhoods, are more likely to move residence than other healthy young children. However, it does not seem that proximity to specialized care is driving this movement. Further research is required to determine if these movement patterns impact the ability of children with chronic conditions to secure health services. 23769364 Milk lactoferrin in heifers: Influence of health status and stage of lactation. The objective of the current study was to analyze the variations in lactoferrin (LF) concentrations in primiparous cows with intramammary infection and to study how the lactation stage affects these variations. In addition, we aimed to study the potential of the LF concentration in early lactation as a predictive factor for future infections. To accomplish this goal, a longitudinal analysis was performed for 96 primiparous cows. Milk samples were collected each month from individual quarters, and the LF concentration was determined for each sample. Criteria that included both somatic cell count (SCC) and a microbiological analysis were used to assess the health status of the quarters. Of the diseased quarters (SCC >200,000 or positive for pathogen isolation, or both), 62% corresponded to nonspecific mastitis (SCC >200,000 but microbiologically negative) and 25% corresponded to the category "presence of bacterial growth" (SCC <200,000 but microbiologically positive). Diseased quarters showed increased concentrations of LF compared with healthy quarters. However, this increase was greater during the first days of lactation compared with later periods. Kaplan-Meier analysis of time free of infection demonstrated that quarters with LF concentrations at early lactation (3-10d in milk) greater than 0.1mg/mL are more likely to become infected during the following lactation compared with quarters with lower LF concentrations in early lactation. The results support that LF plays a relevant role in combating intramammary infection, particularly during the first days of lactation. In addition, we present evidence of the potential use of LF as a predictive marker of future infections in the individual quarters of dairy heifers. 23492915 A novel fibrinogen mutation (γ Thr277Arg) causes hereditary hypofibrinogenemia in a Chinese family. Congenital hypofibrinogenemia is a rare disorder caused by heterozygous mutations in one of the three fibrinogen genes - fibrinogen α-chain (FGA), fibrinogen β-chain (FGB) and fibrinogen γ-chain (FGG) - which code for the Aα, Bβ and γ chains, respectively. In this study, we identified a genetic defect in the FGG underlying the hypofibrinogenemia. The proposita had a prolonged blood clotting time (thrombin time 24.5 s, prothrombin time 16.8 s) and a low level of plasma fibrinogen (0.71 g/l by Clauss method and 0.79 g/l by immunoturbidimetry). DNA screening of the whole fibrinogen gene revealed a heterozygous GC mutation at nucleotide 7482 in her FGG gene. Her father and her half-brother are also heterozygous for this mutation. This mutation contributes to Thr277 → Arg in the γ chain of fibrinogen. To the best of our knowledge, this is the first report of such a mutation that is associated with hypofibrinogenemia. 23922766 Alternative Immunomodulatory Strategies for Xenotransplantation: CD80/CD86-CTLA4 Pathway-Modified Immature Dendritic Cells Promote Xenograft Survival. Xenotransplantation is a promising approach to circumventing the current organ shortage. However, T-cell-dependent anti-xenoresponses are a major challenge to successful xenografts. Given the advantages of the use of CTLA4-Ig in the survival of allografts, the purpose of the study was to investigate the therapeutic potential of CTLA4-IgG4 modified immature dendritic cells (imDCs) in the prevention of islets xenograft rejection. CTLA4-IgG4 was constructed by the fusion of the extracellular regions of porcine CTLA4 to human the hIgG4 Fc region. The imDCs were induced and cultured from porcine peripheral blood mononuclear cells (PBMC). The CTLA4-IgG4 modified imDCs were delivered via the portal vein to the liver of diabetic mice (insulin-dependent diabetes mellitus) before islet xenografting, and mCTLA4-Ig was administered intravenously after xenotransplantation. The xenograft survival of mice receiving unmodified imDCs was approximately 30 days. However, following administration of CTLA4-IgG4 modified imDCs before grafting and mCTLA4-Ig after grafting, xenografts survived for more than 100 days. Flow cytometric analysis showed that the CD4(+)CD25(+)Foxp3(+) Treg population was increased in spleens. The efficacy of donor CTLA4-IgG4 modified imDCs correlated partially with the amplification of Tregs. These results confirm that selective inhibition of the direct and indirect pathways of T-cell activation by donor CTLA4-IgG4 modified imDCs and receptor CTLA4-Ig is a highly effective strategy to promote survival of xenografts. 23634838 Rice yellow stunt rhabdovirus protein 6 suppresses systemic RNA silencing by blocking RDR6-mediated secondary siRNA synthesis. The P6 protein of Rice yellow stunt rhabdovirus (RYSV) is a virion structural protein that can be phosphorylated in vitro. However its exact function remains elusive. We found that P6 enhanced the virulence of Potato virus X (PVX) in Nicotiana benthamiana and N. tabacum plants, suggesting that it might function as a suppressor of RNA silencing. We examined the mechanism of P6-mediated silencing suppression by transiently expressing P6 in both N. benthamiana leaves and rice protoplasts. Our results showed that P6 could repress the production of secondary siRNAs and inhibit systemic green fluorescent protein RNA silencing but did not interfere with local RNA silencing in N. benthamiana plants or in rice protoplasts. Intriguingly, P6 and RDR6 had overlapping subcellular localization and P6 bound both rice and Arabidopsis RDR6 in vivo. Furthermore, transgenic rice plants expressing P6 showed enhanced susceptibility to infection by Rice stripe virus. Hence, we propose that P6 is part of the RYSV's counter-defense machinery against the plant RNA silencing system and plays a role mainly in affecting RDR6-mediated secondary siRNA synthesis. Our work provides a new perspective on how a plant-infecting nucleorhabdovirus may counteract host RNA silencing-mediated antiviral defense. 23957705 Salusin-alpha and -beta expression in heart and aorta with and without metabolic syndrome. Metabolic syndrome (MetS) is a major health problem throughout the world. The role of salusins has not been investigated in heart and aortic tissues under MetS conditions. We examined the distribution of salusin alpha (sal-α) and salusin beta (sal-β) immunoreactivity in heart and aortic tissues and measured circulating salusin concentrations, glucose, insulin, triglycerides, free fatty acids, uric acid, and total cholesterol in Sprague-Dawley rats with and without MetS. Lipid, glucose, insulin and uric acid levels were determined using an autoanalyzer. Serum and tissue salusin levels were measured using ELISA. The expressions of salusins in the heart and aorta tissues were determined using immunohistochemical methods. Serum high density lipoprotein cholesterol (HDL-C), sal-α and sal-β concentrations were significantly lower in the MetS group than in the control group. Low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), total cholesterol, glucose, uric acid and insulin concentrations were higher in the MetS group than in the control group. Sal-α and sal-β were synthesized locally in the fibroblasts and smooth muscle cells of the media of the aorta and in the muscle cells of the heart. Local synthesis of sal-α and sal-β was decreased with MetS. Our findings indicate that decreased serum concentrations of salusins and HDL-C and increased uric acid, glucose and triglyceride concentrations may be indicators of MetS and could play a role in the development of cardiovascular disease. 23422874 Cardiovascular disease prevention: matching evidence-based algorithms with individualized care. The appropriate use of statins in primary prevention remains a matter of debate. Although statins reduce cardiovascular events at all levels of baseline risk, they are associated with rare but important side effects including incident diabetes. Herein, we review strategies for statin allocation ranging from strict "evidence-based" adherence to randomized controlled clinical trial (RCT) entry criteria to more "personalized" risk assessment using high-sensitivity C-reactive protein (hsCRP), coronary artery calcification (CAC), or genetic testing. Current guidelines advocate an unusual middle ground between an evidence-based approach and a personalized approach. 23681064 Radio-UHPLC: a tool for rapidly determining the radiochemical purity of technetium-99m radiopharmaceuticals? Determining the radiochemical purity (RCP) of technetium-99m ((99m)Tc) radiopharmaceuticals using the method described in the package insert is a time-consuming process, requiring particular attention in order to achieve accurate RCP results. The purpose of this study was to evaluate whether radio-ultra high performance liquid chromatography (radio-UHPLC) may be an alternative method for RCP testing of (99m)Tc-tetrofosmin, (99m)Tc-MAG3 and (99m)Tc-sestamibi. Results obtained using radio-UHPLC were in excellent agreement with the standard method, with total analysis time being reduced to less than 3 min. 23684702 Enhanced killing activity of regulatory T cells ameliorates inflammation and autoimmunity. Regulatory T cells (Treg) are pivotal suppressor elements in immune homeostasis with potential therapeutic applications in inflammatory and autoimmune disorders. Using Treg as vehicles for targeted immunomodulation, a short-lived Fas-ligand (FasL) chimeric protein (killer Treg) was found efficient in preventing the progression of autoimmune insulitis in NOD mice, and amelioration of chronic colitis and graft versus host disease. The main mechanisms of disease suppression by killer Treg are: a) in the acute phase induction of apoptosis in effector cells at the site of inflammation decreases the pathogenic burden, and b) persistent increase in FoxP3(+) Treg with variable CD25 co-expression induced by FasL sustains disease suppression over extended periods of time. Reduced sensitivity of Treg to receptor-mediated apoptosis under inflammatory conditions makes them optimal vehicles for targeted immunotherapy using apoptotic agents. 23935809 Correction: Chronic Prostatic Infection and Inflammation by Propionibacterium acnes in a Rat Prostate Infection Model. [This corrects the article on p. e51434 in vol. 7.]. 22801296 AMPAKINE enhancement of social interaction in the BTBR mouse model of autism. Autism is a neurodevelopmental disorder in which the first diagnostic symptom is unusual reciprocal social interactions. Approximately half of the children diagnosed with an autism spectrum disorder also have intellectual impairments. General cognitive abilities may be fundamental to many aspects of social cognition. Cognitive enhancers could conceivably be of significant benefit to children and adults with autism. AMPAKINE compounds are a novel class of pharmacological agents that act as positive modulators of AMPA receptors to enhance excitatory glutamatergic neurotransmission. This class of compounds was reported to improve learning and memory in several rodent and non-human primate tasks, and to normalize respiratory abnormalities in a mouse model of Rett syndrome. Here we evaluate the actions of AMPA compounds in adult male and female BTBR mice, a well characterized mouse model of autism. Acute treatment with CX1837 and CX1739 reversed the deficit in sociability in BTBR mice on the most sensitive parameter, time spent sniffing a novel mouse as compared to time spent sniffing a novel object. The less sensitive parameter, time in the chamber containing the novel mouse versus time in the chamber containing the novel object, was not rescued by CX1837 or CX1739 treatment. Preliminary data with CX546, in which β-cyclodextrin was the vehicle, revealed behavioral effects of the acute intraperitoneal and oral administration of vehicle alone. To circumvent the artifacts introduced by the vehicle administration, we employed a novel treatment regimen using pellets of peanut butter for drug delivery. Absence of vehicle treatment effects when CX1837 and CX1739 were given in the peanut butter pellets, to multiple cohorts of BTBR and B6 control mice, confirmed that the pharmacologically-induced improvements in sociability in BTBR were not confounded by the administration procedures. The highest dose of CX1837 improved the cognitive deficit in novel object recognition in BTBR. No drug effects were detected on the high levels of repetitive self-grooming in BTBR. In open field tests, CX1837 and CX1739 did not induce hyperactivity or sedation in either strain. It is interesting to speculate that the ability of CX1837 and CX1739 to restore aspects of sociability in BTBR mice could utilize synaptic mechanisms regulating social cognition, suggesting a potential pharmacological target for interventions to treat symptoms of autism. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23970379 Targeting autophagy potentiates the apoptotic effect of histone deacetylase inhibitors in t(8;21) AML cells. The role of autophagy during leukemia treatment is unclear. On the one hand, autophagy might be induced as a pro-survival response to therapy, thereby reducing treatment efficiency. On the other hand, autophagy may contribute to degradation of fusion oncoproteins, as recently demonstrated for PML-RARA and BCR-ABL, thereby facilitating leukemia treatment. Here, we investigated these opposing roles of autophagy in t(8;21) acute myeloid leukemia (AML) cells, which express the most frequently occurring AML fusion oncoprotein, AML1-ETO. We demonstrate that autophagy is induced by AML1-ETO-targeting drugs, such as the histone deacetylase inhibitors (HDACis) valproic acid (VPA) and vorinostat. Furthermore, we show that autophagy does not mediate degradation of AML1-ETO, but rather has a pro-survival role in AML cells as inhibition of autophagy significantly reduced the viability and colony-forming ability of HDACi-treated AML cells. Combined treatment with HDACis and autophagy inhibitors such as chloroquine, led to a massive accumulation of ubiquitinated proteins that correlated with increased cell death. Finally, we show that VPA induced autophagy in t(8;21) AML patient cells, and combined treatment with CQ enhanced cell death. Since VPA and chloroquine are well-tolerated drugs, combinatorial therapy with VPA and CQ could represent an attractive treatment option for AML1-ETO positive leukemia. 23968646 Palmitate induces transcriptional regulation of BACE1 and presenilin by STAT3 in neurons mediated by astrocytes. Deregulation of calcium has been implicated in neurodegenerative diseases, including Alzheimer's disease (AD). Previously, we showed that saturated free-fatty acid, palmitate, causes AD-like changes in primary cortical neurons mediated by astrocytes. However, the molecular mechanisms by which conditioned medium from astrocytes cultured in palmitate induce AD-like changes in neurons are unknown. This study demonstrates that this condition medium from astrocytes elevates calcium level in the neurons, which subsequently increases calpain activity, a calcium-dependent protease, leading to enhance p25/Cdk5 activity and phosphorylation and activation of the STAT3 (signal transducer and activator of transcription) transcription factor. Inhibiting calpain or Cdk5 significantly reduces the upregulation in nuclear level of pSTAT3, which we found to transcriptionally regulate both BACE1 and presenilin-1, the latter is a catalytic subunit of γ-secretase. Decreasing pSTAT3 levels reduced the mRNA levels of both BACE1 and presenilin-1 to near control levels. These data demonstrate a signal pathway leading to the activation of STAT3, and the generation of the amyloid peptide. Thus, our results suggest that STAT3 is an important potential therapeutic target of AD pathogenesis. 23625733 Update on pediatric cancer predisposition syndromes. Hereditary cancer syndromes in children and adolescents are becoming more recognized in the field of pediatric hematology/oncology. A recent workshop held at the American Society of Pediatric Hematology/Oncology (ASPHO) 2012 Annual Meeting included several interactive sessions related to specific familial cancer syndromes, genetic testing and screening, and ethical issues in caring for families with inherited cancer risk. This review highlights the workshop presentations, including a brief background about pediatric cancer predisposition syndromes and the importance of learning about them for the practicing pediatric hematologists/oncologists. This is followed by a brief summary of the newly described cancer predisposition syndromes including Rhabdoid Tumor Predisposition Syndrome, Hereditary Paragangliomas and Pheochromocytoma Syndrome, and Familial Pleuropulmonaryblastoma Tumor Predisposition (DICER1) Syndrome. The next section covers genetic testing and screening for pediatric cancer predisposition syndromes. Ethical issues are also discussed including preimplantation genetic diagnosis or testing (PGD/PGT), suspicious lesions found on tumor screening, and incidental mutations discovered by whole genome sequencing. Finally, the perspective of a family with Li-Fraumeni Syndrome is shared. 23911157 Utility of diffusion-weighted MRI in the diagnosis of bladder carcinoma. The purposes of our study were to investigate the feasibility of diffusion-weighted imaging in the detection of malignant bladder tumors, with comparison to the high-resolution thin-section fast spin-echo (FSE) T2-weighted MRI, and also to compare the apparent diffusion coefficient (ADC) values of the bladder tumors with the surrounding structures. Fifty-three consecutive patients consisting of 44 males and 9 females who presented with a bladder mass were prospectively enrolled in this study. Mean age was 62.53±12.03 (age range, 33-86 years). These patients were evaluated by high-resolution thin-section FSE T2-weighted and diffusion-weighted MRI for the detection of bladder masses. Following MRI, within 2 weeks, all patients were subjected to either surgery or cystoscopic biopsy, and the obtained histopathological proofs were used as the reference standard. Furthermore, ADC values of the bladder tumors, urine, the normal bladder wall, the central and peripheral zones of the prostate, the seminal vesicule, and the uterus outer myometrium were also calculated. ADC values of the bladder carcinomas and the related surrounding structures were compared as to whether a statistically significant difference was present or not. In a total of 47 patients, consisting of 39 males and 8 females, bladder carcinomas were clearly shown as having conspicuous high and intermediate signal intensity masses, relative to the surrounding structures on diffusion-weighted and T2-weighted images, respectively. An 89% sensitivity and a 100% positive predictive value were obtained for both FSE T2-weighted and diffusion-weighted MRI in the diagnosis of bladder carcinoma. Mean ADC values and standard deviations of the bladder tumors and the surrounding structures were as follows: bladder carcinomas (n=47): 1.28±0.31, normal bladder wall (n=47): 1.98±0.41, urine (n=47): 3.12±0.24, seminal vesicle (n=39): 1.82±0.33, peripheral zone of prostate (n=39): 1.80±0.29, central zone of prostate (n=39): 1.55±0.33, and uterus outer myometrium (n=8): 1.53±0.19. It can be clearly seen that the mean ADC values of the bladder carcinomas were significantly lower than the surrounding structures (P<.05). CONCLUSıON: High-resolution thin-section FSE T2 and diffusion-weighted MRI show high diagnostic performance and are comparable in the detection of bladder tumors. Diffusion-weighted MRI provides high quality images of the malignant bladder tumors against a suppressed background signal. Diffusion-weighted MRI using ADC measurements may be useful in the evaluation of tumor invasion to the adjacent organs. 23831156 MALDI mass spectrometry in prostate cancer biomarker discovery. Matrix-assisted laser desorption/ionisation (MALDI) mass spectrometry (MS) is a highly versatile and sensitive analytical technique, which is known for its soft ionisation of biomolecules such as peptides and proteins. Generally, MALDI MS analysis requires little sample preparation, and in some cases like MS profiling it can be automated through the use of robotic liquid-handling systems. For more than a decade now, MALDI MS has been extensively utilised in the search for biomarkers that could aid clinicians in diagnosis, prognosis, and treatment decision making. This review examines the various MALDI-based MS techniques like MS imaging, MS profiling and proteomics in-depth analysis where MALDI MS follows fractionation and separation methods such as gel electrophoresis, and how these have contributed to prostate cancer biomarker research. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge. 23541804 The association of psychosocial factors and obstetric history with depression in pregnant women: focus on the role of emotional support. Depression during pregnancy can negatively affect both maternal and fetal health. The benefits of early detection and treatment for antenatal depression have been emphasized. Therefore, we investigated risk factors for antenatal depression with a focus on emotional support. We conducted a cross-sectional study of pregnant women (n=1262) enrolled from the local division of a community mental health center. All subjects completed self-report questionnaires that assessed depressive mood, emotional support and other risk factors. Associations between antenatal depression and potential risk factors including emotional support were analyzed by logistic regression analysis. Antenatal depression was associated with various biopsychosocial correlates: unmarried state, low education, cigarette smoking, low income, familial history of depression, past history of depression, physical abuse history, sexual abuse history, premenstrual syndrome, primiparity and unplanned pregnancy. When the associations of emotional support with antenatal depression were specified by its resources, current emotional support from partner [odds ratio (OR)=2.26, 95% confidence interval (CI)=1.94-2.64] and mother (OR=1.43, 95% CI=1.26-1.62) and past experience for emotional support from mother (OR=1.52, 95% CI=1.32-1.74), but not from father significantly influenced depression during pregnancy. The multidimensional biopsychosocial approach would be needed to identify and assess antenatal depression. Promoting emotional support from the partner, family member and, possibly, the health provider could be a protective effect against the development of antenatal depression. 23697752 Comprehensive, therapeutic retroperitoneal pelvic and infrarenal aortic lymphadenectomy for advanced cervical carcinoma. This 49-year-old female with stage III cervical carcinoma presented with a PET/CT scan showing bilateral pelvic and common ileac adenopathy. A retroperitoneal approach to resect the nodes well above the highest documented PET positive region was employed in July 2011. The bilateral infrarenal, bulky inframesenteric and pelvic nodes were comprehensively removed, revealing bilaterally positive nodes in 5/36 pelvic nodes, 13/25 inframesenteric nodes, and 3/20 infrarenal nodes (these latter not detected on PET). Image-modulated radiation to 10cm above the renal vein, with concurrent cisplatin chemotherapy was undertaken, resulting in a disease-free status thus far. 23842886 Investigation of activity of monoterpenes and phenylpropanoids against immature stages of Amblyomma cajennense and Rhipicephalus sanguineus (Acari: Ixodidae). The objective of this study was to assess the acaricidal activity of carvacrol, thymol, eugenol, and (E)-cinnamaldehyde on unengorged larvae and nymphs of Amblyomma cajennense and Rhipicephalus sanguineus, using the modified larval packet test. Carvacrol, eugenol, and (E)-cinnamaldehyde were tested at concentrations of 2.5, 5.0, 10.0, 15.0, and 20.0 Î¼l/ml, while thymol was tested at concentrations of 2.5, 5.0, 10.0, 15.0, and 20.0 mg/ml, in all cases with 10 repetitions per treatment. For the A. cajennense larvae, mortality rates caused by carvacrol, thymol, eugenol, and (E)-cinnamaldehyde at the lowest concentration were 45.0, 62.7, 10.2, and 81.6 %, respectively, reached 100 % at the concentration of 5.0 Î¼l/ml for carvacrol and (E)-cinnamaldehyde and 5.0 mg/ml for thymol, while this mortality was observed at 15.0 Î¼l/ml for eugenol. For the nymphs of this species, carvacrol and thymol caused 100 % mortality starting at a concentration of 5.0 Î¼l/ml and 10.0 mg/ml, respectively, while eugenol caused 100 % mortality at 20.0 Î¼l/ml and the mortality caused by (E)-cinnamaldehyde did not exceed 64 %. In the tests with R. sanguineus larvae, the lowest concentration of carvacrol and (E)-cinnamaldehyde resulted in 100 % mortality, while this percentage was observed starting at 10.0 Î¼l/ml for eugenol. For nymphs, carvacrol and thymol at the smallest concentration caused 100 % lethality, unlike the results for eugenol and (E)-cinnamaldehyde, where 100 % mortality was only observed starting at the concentration of 10.0 Î¼l/ml. The results obtained indicate that the tested substances have acaricidal activity on unengorged larvae and nymphs of A. cajennense and R. sanguineus. 23726426 Genetic parameters for body condition score, locomotion, angularity, and production traits in Italian Holstein cattle. The objectives of this research were to estimate genetic parameters for body condition score (BCS) and locomotion (LOC), and to assess their relationships with angularity (ANG), milk yield, fat and protein content, and fat to protein content ratio (F:P) in the Italian Holstein Friesian breed. The Italian Holstein Friesian Cattle Breeders Association collects type trait data once on all registered first lactation cows. Body condition score and LOC were introduced in the conformation scoring system in 2007 and 2009, respectively. Variance (and covariance) components among traits were estimated with a Bayesian approach via a Gibbs sampling algorithm and an animal model. Heritability estimates were 0.114 and 0.049 for BCS and LOC, respectively. The genetic correlation between BCS and LOC was weak (-0.084) and not different from zero; therefore, the traits seem to be genetically independent, but further investigation on possible departures from linearity of this relationship is needed. Angularity was strongly negatively correlated with BCS (-0.612), and strongly positively correlated with LOC (0.650). The genetic relationship of milk yield with BCS was moderately negative (-0.386), and was moderately positive (0.238) with LOC. These results indicate that high-producing cows tend to be thinner and tend to have better locomotion than low-producing cows. The genetic correlation of BCS with fat content (0.094) and F:P (-0.014) was very weak and not different from zero, and with protein content (0.173) was weak but different from zero. Locomotion was weakly correlated with fat content (0.071), protein content (0.028), and F:P (0.074), and correlations were not different from zero. Phenotypic correlations were generally weaker than their genetic counterparts, ranging from -0.241 (BCS with ANG) to 0.245 (LOC with ANG). Before including BCS and LOC in the selection index of the Italian Holstein breed, the correlations with other traits currently used to improve type and functionality of animals need to be investigated. 23770208 Contextual fear cues inhibit eating in food-deprived male and female rats. Previously we have shown that food-deprived male and female rats inhibit food consumption when presented with a discrete conditioned stimulus that signals danger. Here, in a series of three experiments, we examined whether contextual conditioned stimuli can exert the same effect. Experiment 1 paired a distinct context with footshocks, to examine food intake in food-deprived rats upon re-exposure to the context. Experiment 2 used a discrimination protocol with two alternating contexts; rats were given food in one, and received footshocks in the other. This protocol allowed us to monitor food consumption during training in a context never associated with footshocks, and to evaluate consumption at test in a context that had been previously paired with footshocks. Experiments 1 and 2 compared experimental groups to controls that never received footshocks. Experiment 3 used a within-subjects design to assess the specificity of the inhibition by the contextual cues, separate from any generalized effects due solely to the prior experience of footshocks. Our results demonstrate that similar to discrete cues, contextual cues previously associated with aversive events can inhibit feeding in food-deprived animals. These findings are important for our understanding of environmental contributions to the control of food intake. 23333901 Administration of the optimized β-Lapachone-poloxamer-cyclodextrin ternary system induces apoptosis, DNA damage and reduces tumor growth in a human breast adenocarcinoma xenograft mouse model. β-Lapachone (β-Lap) is a 1,2-orthonaphthoquinone that selectively induces cell death in human cancer cells through NAD(P)H:quinone oxidoreductase-1 (NQO1). NQO1 is overexpressed in a variety of tumors, as compared to normal adjacent tissue. However, the low solubility and non-specific distribution of β-Lap limit its suitability for clinical assays. We formulated β-Lap in an optimal random methylated-β-cyclodextrin/poloxamer 407 mixture (i.e., β-Lap ternary system) and, using human breast adenocarcinoma MCF-7 cells and immunodeficient mice, performed in vitro and in vivo evaluation of its anti-tumor effects on proliferation, cell cycle, apoptosis, DNA damage, and tumor growth. This ternary system is fluid at room temperature, gels over 29°C, and provides a significant amount of drug, thus facilitating intratumoral delivery, in situ gelation, and the formation of a depot for time-release. Administration of β-Lap ternary system to MCF-7 cells induces an increase in apoptosis and DNA damage, while producing no changes in cell cycle. Moreover, in a mouse xenograft tumor model, intratumoral injection of the system significantly reduces tumor volume, while increasing apoptosis and DNA damage without visible toxicity to liver or kidney. These anti-tumoral effects and lack of visible toxicity make this system a promising new therapeutic agent for breast cancer treatment. 23845549 Effects of lovastatin, clomazone and methyl jasmonate treatment on the accumulation of purpurin and mollugin in cell suspension cultures of Rubia cordifolia. To determine the IPP origin of the naphthoquinones (NQs) in Rubia cordifolia, and to evaluate the effects of methyl jasmonate (MeJA) treatment, MEP, and MVA pathway inhibitor treatment on the accumulation of anthraquinones (AQs) and NQs in cell suspension cultures of R. cordifolia. Cell suspension cultures of R. cordifolia were established. Specific inhibitors (lovastatin and clomazone) and MeJA were supplied to the media, respectively. Treated cells were sampled every three days. Content determination of purpurin (AQs) and mollugin (NQs) were carried out using RP-HPLC. The yield of the two compounds was compared with the DMSO-supplied group and the possible mechanism was discussed. Lovastatin treatment increased the yield of purpurin and mollugin significantly. Clomazone treatment resulted in a remarkable decrease of both compounds. In the MeJA-treated cells, the purpurin yield increased, meanwhile, the mollugin yield decreased compared with control. The IPP origin of mollugin in R. cordifolia cell suspension cultures was likely from the MEP pathway. To explain the different effects of MeJA on AQs and NQs accumulation, studies on the regulation and expression of the genes, especially after prenylation of 1,4-dihydroxy-2-naphthoic acid should be conducted. 23863470 Fulvene-5 inhibition of Nadph oxidases attenuate activation of epitehlial sodium channels in A6 distal nephron cells. Nadph oxidase 4 is an important cellular source of reactive oxygen species (ROS) generation in the kidney. Novel anti-oxidant drugs, such as Nox4-inhibitor compounds, are being developed. There is however, very little experimental evidence for the biological role and regulation of Nadph oxidase isoforms in the kidney. Herein, we show that Fulvene-5 is an effective inhibitor of Nox-generated ROS and report the role of Nox isoforms in activating epithelial sodium channels (ENaC) in A6 distal nephron cells via oxidant signaling and cell stretch activation. Using single channel patch clamp analysis, we report that Fulvene-5 blocked the increase in ENaC activity that is typically observed with H2O2 treatment of A6 cells: average ENaC NPo values decreased from a baseline level of 1.04±0.18 (mean±SE) to 0.25±0.08 following Fulvene-5 treatment. H2O2 treatment failed to increase ENaC activity in the presence of Fulvene-5. Moreover, Fulvene-5 treatment of A6 cells blocked the osmotic-cell stretch response of A6 cells; indicating that stretch activation of Nox-derived ROS plays an important role in ENaC regulation. Together, these findings indicate that Fulvene-5, and perhaps other classes of antioxidant inhibitors, may represent a novel class of compounds useful for the treatment of pathological disorders stemming from inappropriate ion channel activity, such as hypertention. 23480633 Hidden in plain sight: discovery of sheath-forming, iron-oxidizing Zetaproteobacteria at Loihi Seamount, Hawaii, USA. Lithotrophic iron-oxidizing bacteria (FeOB) form microbial mats at focused flow or diffuse flow vents in deep-sea hydrothermal systems where Fe(II) is a dominant electron donor. These mats composed of biogenically formed Fe(III)-oxyhydroxides include twisted stalks and tubular sheaths, with sheaths typically composing a minor component of bulk mats. The micron diameter Fe(III)-oxyhydroxide-containing tubular sheaths bear a strong resemblance to sheaths formed by the freshwater FeOB, Leptothrix ochracea. We discovered that veil-like surface layers present in iron-mats at the Loihi Seamount were dominated by sheaths (40-60% of total morphotypes present) compared with deeper (> 1 cm) mat samples (0-16% sheath). By light microscopy, these sheaths appeared nearly identical to those of L. ochracea. Clone libraries of the SSU rRNA gene from this top layer were dominated by Zetaproteobacteria, and lacked phylotypes related to L. ochracea. In mats with similar morphologies, terminal-restriction fragment length polymorphism (T-RFLP) data along with quantitative PCR (Q-PCR) analyses using a Zetaproteobacteria-specific primer confirmed the presence and abundance of Zetaproteobacteria. A Zetaproteobacteria fluorescence in situ hybridization (FISH) probe hybridized to ensheathed cells (4% of total cells), while a L. ochracea-specific probe and a Betaproteobacteria probe did not. Together, these results constitute the discovery of a novel group of marine sheath-forming FeOB bearing a striking morphological similarity to L. ochracea, but belonging to an entirely different class of Proteobacteria. 23928606 Summary of: Communicating new policy on antibiotic prophylaxis with patients: a randomised controlled trial. Objectives This trial aimed to assess the effectiveness of two different communication tools on the levels of anxiety and concern when a change in patients' treatment was introduced.Method Patients previously advised to have antibiotic prophylaxis before their dental treatments were randomised to receive information about the new policy either through a video accompanied by a written leaflet or just the leaflet. All patients completed a questionnaire to assess anxiety and concern as well as intentions regarding accepting dental treatment without antibiotic prophylaxis at enrolment point, after intervention and after meeting the cardiologist.Results Ninety questionnaires were analysed (45 in each group). The mean level of anxiety and concern scores were significantly reduced after the intervention point (p <0.05). The ANOVA model revealed a significant reduction in the levels of anxiety and concern during the trial (p <0.001). However, the main effect of group (intervention versus control) and the interaction term were not significant. At the end of trial there was no difference in the number of patients accepting dental treatment without cover in the two groups.Conclusion Patients appear more likely to accept a change if it is communicated directly to them by their practitioners via face to face consultation compared with video or leaflet. When there is a lack of time for in-depth consultation, video could be a more effective method than leaflet alone. 23862659 Guggulipid of Commiphora mukul, with antiallodynic and antihyperalgesic activities in both sciatic nerve and spinal nerve ligation models of neuropathic pain. Abstract Context: Guggulipid is a neutral fraction of ethyl acetate extract of gum resin of the tree Commiphora mukul Engl. (Burseraceae) and used in Ayurvedic medicine for treatment of neurological disorders. Objectives: The present study was undertaken to assess the antiallodynic and antihyperalgesic activities of guggulipid in rats. Materials and methods: The screening study included the CCI and L5-L6 SNL models of neuropathic pain. Guggulipid (100 and 50 mg/kg) or saline was administered intraperitoneally in a blinded, randomized manner from postoperative day (POD) 7 to 13. Paw withdrawal duration (PWD) to spontaneous pain, chemical allodynia and mechanical hyperalgesia and paw withdrawal latency (PWL) to mechanical allodynia and thermal hyperalgesia were tested before surgery, before and after guggulipid or saline administration (from POD7 to 13) and after the withdrawal of treatment (from POD14 to 20). Results: The activity profiles of the different doses of guggulipid were found to vary with time. In CCI rats, guggulipid (100 and 50 mg/kg) significantly (p < 0.05) reduced the spontaneous pain, mechanical allodynia and mechanical and thermal hyperalgesia responses and the LD50 of guggulipid was 1600 mg/kg. In SNL rats, both doses of guggulipid were found to be ineffective in reversing the spontaneous pain but showing antiallodynic and antihyperalgesic activity. Discussion and conclusion: The results demonstrated that guggulipid produce antinociception in the peripheral nerve injury (CCI and SNL) models of neuropathic pain. The underlying mechanisms are expected to be modulating microglial activation occurring due to peripheral nerve injury. 23919641 Narrative environments and the capacity of disability narratives to motivate leisure-time physical activity among individuals with spinal cord injury. Abstract Purpose: Few individuals with spinal cord injury (SCI) engage in the recommended amount of leisure time physical activity (LTPA). Yet little is known about how, and why, active individuals engage in specific types of LTPA. This study explored how a unique narrative environment and disability narratives motivated individuals with SCI to engage in LTPA. Method: Fourteen individuals with SCI from a physical activity program participated in approximately hour-long interviews. Interviews were then subjected to a narrative analysis. Results: Individuals who used a restitution narrative (n = 6) were motivated to engage in functional LTPA because of the desire to maintain the body and restore the past self. The individual who used the chaos narrative (n = 1) preferred solitary LTPA as exposure to others with SCI was a constant reminder of the lost, pre-injury self. Individuals who used a quest narrative (n = 7) explored LTPA options that fit with their interests; these individuals were open to new types of LTPA, such as sport and outdoor recreation. Conclusion: The plot of three disability narratives can all motivate the pursuit of LTPA; however, not all types of LTPA are seen as equal. LTPA interventions can be enhanced through the lessons learned from this unique type of environment. Implications for Rehabilitation Despite individuals' views about their disability, they can still be motivated to engage in routine LTPA. Different theoretical determinants, such as health or social benefits, hold different relevance for LTPA among individuals with differing disability narratives. The environment provided by practitioners can therefore elicit some stories of SCI while stifling others. Open narrative environment will attract individuals to listen and maintain involvement in LTPA. 22907781 Feasibility and safety of minimal-incision thyroidectomy for Graves' disease: A prospective, single-center study. The role of minimally invasive surgery in Graves' disease is still controversial. The aim of this study was to compare the clinical outcomes of patients undergoing minimal-incision thyroidectomy with those undergoing conventional thyroidectomy for Graves' disease. A prospective study was performed on 148 patients undergoing total thyroidectomy. Seventy-one patients underwent minimal-incision thyroidectomy and 77 underwent conventional thyroidectomy. Minimal-incision thyroidectomy was proposed if the thyroid volume was ≤50 mL. There were no significant differences in the operative time between minimal-incision thyroidectomy and conventional thyroidectomy. The length of skin incision was significantly shorter in the minimal-incision thyroidectomy than that in the conventional thyroidectomy group. The incidence of postoperative complications was similar in the 2 groups. Patients undergoing minimal-incision thyroidectomy experienced significantly less postoperative pain and were more satisfied with the cosmetic result than patients who underwent conventional thyroidectomy. Minimal-incision thyroidectomy is a feasible and safe option for the surgical treatment of selected patients with Graves' disease. © 2012 Wiley Periodicals, Inc. Head Neck, 2013. 23582883 Re-laparoscopy in the diagnosis and treatment of postoperative complications following laparoscopic colorectal surgery. Laparoscopic colorectal surgery has increasingly become the standard of care in the management of both benign and malignant colorectal disease. We herein describe our experience with laparoscopy in the management of complications following laparoscopic colorectal surgery. Between November 2010 and July 2012, data were prospectively collected for all patients requiring surgical intervention for colorectal cancer. This was performed by a full-time colorectal cancer data manager. A total of 203 patients had surgery for colorectal cancer during this period, 154 (75.9%) of which were performed laparoscopically and 49 (24.1%) performed by open surgery. Ten patients (4.9%) underwent surgery for complications of which 7 were following laparoscopic surgery. Two of these 7 patients had an exploratory laparotomy due to abdominal distension and haemodynamic instability. Laparoscopic surgical intervention was successful in diagnosing and treating the remaining 5 patients. Three of these patients developed small bowel obstruction which was managed by re-laparoscopy while in 2 patients there was a significant suspicion of an anastomotic leakage despite appropriate diagnostic imaging which was out ruled at laparoscopy. Laparoscopy can frequently be used to diagnose and treat complications following laparoscopic colorectal surgery. This is another benefit associated with laparoscopic colorectal surgery which is rarely described and allows the benefits associated with the laparoscopic approach to be maintained. 23212108 Emerging target-based paradigms to prevent and treat migraine. Migraine is a primary brain disorder resulting from altered modulation of normal sensory stimuli and trigeminal nerve dysfunction. The second edition of the International Classification of Headache Disorders (ICHD-2) defines seven subtypes of migraine. Migraine treatment can be acute or preventive. New targeted therapies include 5-HT(1F) receptor agonists, calcitonin gene-related peptide (CGRP) antagonists, nitric oxide synthetase inhibitors, and ion channel antagonists. A recent development is the creation of antibodies to CGRP and its receptor for migraine prevention. 23846466 Fast Dictionary-Based Reconstruction for Diffusion Spectrum Imaging. Diffusion Spectrum Imaging (DSI) reveals detailed local diffusion properties at the expense of substantially long imaging times. It is possible to accelerate acquisition by undersampling in q-space, followed by image reconstruction that exploits prior knowledge on the diffusion probability density functions (pdfs). Previously proposed methods impose this prior in the form of sparsity under wavelet and total variation (TV) transforms, or under adaptive dictionaries that are trained on example datasets to maximize the sparsity of the representation. These compressed sensing (CS) methods require full-brain processing times on the order of hours using Matlab running on a workstation. This work presents two dictionary-based reconstruction techniques that use analytical solutions, and are two orders of magnitude faster than the previously proposed dictionary-based CS approach. The first method generates a dictionary from the training data using Principal Component Analysis (PCA), and performs the reconstruction in the PCA space. The second proposed method applies reconstruction using pseudoinverse with Tikhonov regularization with respect to a dictionary. This dictionary can either be obtained using the KSVD algorithm, or it can simply be the training dataset of pdfs without any training. All of the proposed methods achieve reconstruction times on the order of seconds per imaging slice, and have reconstruction quality comparable to that of dictionarybased CS algorithm. 23850535 On eukaryotic intelligence: Signaling system's guidance in the evolution of multicellular organization. Communication with the environment is an essential characteristic of the living cell, even more when considering the origins and evolution of multicellularity. A number of changes and tinkering inventions were necessary in the evolutionary transition between prokaryotic and eukaryotic cells, which finally made possible the appearance of genuine multicellular organisms. In the study of this process, however, the transformations experimented by signaling systems themselves have been rarely object of analysis, obscured by other more conspicuous biological traits: incorporation of mitochondria, segregated nucleus, introns/exons, flagellum, membrane systems, etc. Herein a discussion of the main avenues of change from prokaryotic to eukaryotic signaling systems and a review of the signaling resources and strategies underlying multicellularity will be attempted. In the expansion of prokaryotic signaling systems, four main systemic resources were incorporated: molecular tools for detection of solutes, molecular tools for detection of solvent (Donnan effect), the apparatuses of cell-cycle control, and the combined system endocytosis/cytoskeleton. The multiple kinds of enlarged, mixed pathways that emerged made possible the eukaryotic revolution in morphological and physiological complexity. The massive incorporation of processing resources of electro-molecular nature, derived from the osmotic tools counteracting the Donnan effect, made also possible the organization of a computational tissue with huge information processing capabilities: the nervous system. In the central nervous systems of vertebrates, and particularly in humans, neurons have achieved both the highest level of molecular-signaling complexity and the highest degree of information-processing adaptability. Theoretically, it can be argued that there has been an accelerated pace of evolutionary change in eukaryotic signaling systems, beyond the other general novelties introduced by eukaryotic cells in their handling of DNA processes. Under signaling system's guidance, the whole processes of transcription, alternative splicing, mobile elements, and other elements of domain recombination have become closely intertwined and have propelled the differentiation capabilities of multicellular tissues and morphologies. An amazing variety of signaling and self-construction strategies have emerged out from the basic eukaryotic design of multicellular complexity, in millions and millions of new species evolved. This design can also be seen abstractly as a new kind of quasi-universal problem-solving 'engine' implemented at the biomolecular scale-providing the fundamentals of eukaryotic 'intelligence'. Analyzing in depth the problem-solving intelligence of eukaryotic cells would help to establish an integrative panorama of their information processing organization, and of their capability to handle the morphological and physiological complexity associated. Whether an informational updating of the venerable "cell theory" is feasible or not, becomes, at the time being - right in the middle of the massive data deluge/revolution from omic disciplines - a matter to careful consider. 23677978 Mice stage-specific claudin 3 expression regulates progression of meiosis in early stage spermatocytes. Claudin 3 is a protein component of the tight junction strands. Tight junctions between adjacent Sertoli cells form the blood-testis barrier (BTB). During spermatogenesis, seminiferous stage-specific expression of claudin 3 is believed to regulate the migration of preleptotene/leptotene spermatocytes across the BTB. Here, we determined the cell types expressing claudin 3 in adult mouse testis and investigated spermatogenesis after testis-specific in vivo knockdown of claudin 3. The results of in situ hybridization revealed that claudin 3 mRNA was predominantly expressed in germ cells near the basal lamina of seminiferous tubules at stages VI-IX. Furthermore, claudin 3 protein was localized not only to the BTB but also to the cell membrane of STRA8-expressing preleptotene/leptotene spermatocytes in the testis of adult ICR.Cg-Tg(Stra8-EGFP)1Ysa/YsaRbrc mice. Although claudin 3 knockdown did not affect BTB integrity, it did cause a partial delay in spermatocyte migration across the BTB. Moreover, claudin 3 knockdown resulted in a prolonged preleptotene phase during spermatogenesis. These data indicate that the seminiferous stage-specific expression and localization of claudin 3 during spermatogenesis regulate the progression of meiosis by promoting germ cell migration across the BTB. 23754495 Identification of Annexin A1 interacting proteins in chronic myeloid leukemia KCL22 cells. In the present study, we used a functional proteomic approach to identify Annexin A1 (Anxa1) interacting proteins in the Philadelphia-positive KCL22 cell line. We focused on Anxa1 because it is one of the major proteins upregulated in imatinib-sensitive KCL22S cells versus imatinib-resistant KCL22R. Our proteomic strategy revealed 21 interactors. Bioinformatic analysis showed that most of these proteins are involved in cell death processes. Among the proteins identified, we studied the interaction of Anxa1 with two phosphatases, Shp1 and Shp2, which were recently identified as biomarkers of imatinib sensitivity in patients affected by chronic myeloid leukemia. Our data open new perspectives in the search for annexin-mediated signaling pathways and may shed light on mechanisms of resistance to imatinib that are unrelated to Bcr-Abl activity. All mass spectrometry data have been deposited in the ProteomeXchange with identifier PXD000030. 23891994 The role of estrogen in intrusive memories. Intrusive memories are highly vivid, emotional and involuntary recollections which cause significant distress across psychological disorders including posttraumatic disorder (PTSD). Recent evidence has potentially extended our understanding of the development of intrusive memories by identifying biological factors which significantly impact on memories for emotionally arousing stimuli. This study investigated the role of stress on the development of intrusions for negative and neutral images, and indexed the potential contributions of sex (estrogen and progesterone) and stress (noradrenaline and cortisol) hormones. Whilst viewing the images, half the participants underwent a cold pressor stress (CPS) procedure to induce stress while the control participants immersed their hands in warm water. Saliva samples were collected to index estrogen, progesterone and noradrenergic and cortisol response. Participants (55 university students, 26 men, 29 women) viewed a series of negatively arousing and neutral images. Participants completed recall and intrusions measures 2days later. Negative images resulted in greater recall and more intrusions than neutral images. In the cold water condition females recalled fewer neutral memories than males. Cortisol increase predicted decreased recall of negative memories in males, and estrogen predicted increased intrusions of negative images in women. These findings are consistent with evidence that circulating levels of ovarian hormones influence memory for emotionally arousing events, and provides the first evidence of the influence of sex hormones on intrusive memories. These results provide one possible explanation for the higher incidence of anxiety disorders in women. 23951095 Methotrexate Treatment Causes Early Onset of Disease in a Mouse Model of Ross River Virus-Induced Inflammatory Disease through Increased Monocyte Production. Part of the Togaviridae family, alphaviruses, including chikungunya virus (CHIKV), Sindbis virus (SINV) and Ross River virus (RRV), are able to cause significant inflammatory pathologies ranging from arthritis to encephalitis. Following symptomatic infection with arthritis-associated alphaviruses, patients often experience severe joint pain, affecting distal and small joints, which can last six months or longer. Recently, methotrexate (MTX), a disease modifying anti-rheumatic drug (DMARD), was used to treat patients experiencing chronic rheumatic symptoms following infection with CHIKV. Here, the effect of MTX on Ross River virus disease (RRVD) in mice was examined to better understand its therapeutic potential for alphaviral-induced musculoskeletal disease and to further our knowledge of the development of alphaviral pathologies. Using a mouse model, we analyzed the effect of MTX on RRVD. RRV disease pathogenesis in response to MTX treatment was determined by measuring levels of proinflammatory factors, cellular infiltrates, viral titer and histological analysis of infected tissues. RRV-infected mice receiving MTX treatment rapidly developed musculoskeletal disease, which correlated with a significant influx of inflammatory cell infiltrates into the skeletal muscle tissue. Although no difference was observed in the level of proinflammatory cytokines and chemokines, the viral load increased at early time points post infection in the serum and quadriceps of MTX treated mice, possibly contributing to disease pathogenesis. Results suggest that MTX treatment of acute RRVD in mice provides no therapeutic benefit and underline the importance of inflammatory monocytes in alphaviral induced arthritides. 23375236 Biochemical characteristic of biofilm of uropathogenic Escherichia coli Dr(+) strains. Urinary tract infections caused by Escherichia coli are very common health problem in the developed countries. The virulence of the uropathogenic E. coli Dr(+) IH11128 is determined by Dr fimbriae, which are homopolymeric structures composed of DraE subunits with the DraD protein capping the fiber. In this study, we have analyzed the structural and biochemical properties of biofilms developed by E. coli strains expressing Dr fimbriae with or without the DraD tip subunit and the surface-exposed DraD protein. We have also demonstrated that these E. coli strains form biofilms on an abiotic surface in a nutrient-dependent fashion. We present evidence that Dr fimbriae are necessary during the first stage of bacterial interaction with the abiotic surface. In addition, we reveal that the DraD alone is also sufficient for the initial surface attachment at an even higher level than Dr fimbriae and that chloramphenicol is able to reduce the normal attachment of the analyzed E. coli. The action of chloramphenicol also shows that protein synthesis is required for the early events of biofilm formation. Additionally, we have identified reduced exopolysaccharide coverage in E. coli that express only Dr fimbrial polyadhesins at the cell surface with or without the DraD capping subunit. 23929063 Intra-articular synovial sarcoma treated with a transfemoral amputation: a case report and review of the literature. A case of monophasic intra-articular synovial sarcoma in the right knee of a 39-year-old active duty serviceman treated with a transfemoral amputation is presented. The patient was evaluated for right knee pain and fullness. After further workup, the patient underwent computed tomographyguided biopsy, with the tissue specimen consistent with intra-articular synovial sarcoma. The patient elected for a transfemoral amputation rather than limb or joint-sparing surgery. The gross specimen measured 3.5 × 3.0 × 1.7 cm in the posteromedial knee. No metastatic lesions were seen on positron emission tomography-computed tomography. Chemotherapy and radiation therapy have not been utilized. The transfemoral amputation adds to the uniqueness of this report and is discussed with a review of the multimodality treatment toward intra-articular synovial sarcoma in prior published literature. 23940512 Dental informatics to characterize patients with dentofacial deformities. Relevant statistical modeling and analysis of dental data can improve diagnostic and treatment procedures. The purpose of this study is to demonstrate the use of various data mining algorithms to characterize patients with dentofacial deformities. A total of 72 patients with skeletal malocclusions who had completed orthodontic and orthognathic surgical treatments were examined. Each patient was characterized by 22 measurements related to dentofacial deformities. Clustering analysis and visualization grouped the patients into three different patterns of dentofacial deformities. A feature selection approach based on a false discovery rate was used to identify a subset of 22 measurements important in categorizing these three clusters. Finally, classification was performed to evaluate the quality of the measurements selected by the feature selection approach. The results showed that feature selection improved classification accuracy while simultaneously determining which measurements were relevant. 23567384 The relationship between borderline personality disorder and major depression in later life: acute versus temperamental symptoms. A recent issue in the personality disorder field is the prevalence and course of Axis II symptoms in later life. Focusing on the presentation of personality disorder criteria over time may have some utility in exploring the relationship between borderline personality disorder (BPD) and major depression in older adults. Temperamental personality symptoms are relatively resistant to change but tend to be nonspecific to disorders, whereas acute symptoms remit relatively quickly. We predicted that temperamental BPD symptoms would be positively correlated with a history of depression and did not expect to find a relationship between major depression and acute BPD symptoms. A total of 1,630 participants between the ages of 55 and 64 were recruited to participate in a community-based longitudinal study representative of the St. Louis area. Participants completed a battery of assessments at baseline, including diagnostic interviews for all 10 personality disorders and major depressive disorder. Temperamental and acute BPD symptoms were significantly correlated with a history of major depression. After adjustments were made for the effects of temperamental symptoms on depression, acute symptoms were no longer correlated with a history of depression. As predicted, temperamental symptoms remained significantly related to depression, even after controlling for the effects of acute symptoms. BPD acute symptoms showed a unique negative correlation with the amount of time following remission from a depressive episode. Overall, this study supports associations between major depression and borderline personality in older adults. The findings indicate that a history of major depression is primarily related to stable BPD symptoms related to emotional distress, which are more prevalent in older adults than acute features. 23047726 Myelodysplastic syndrome hematopoietic stem cell. Myelodysplastic syndromes (MDSs) are clonal hematopoietic stem cell (HSC) malignancies that are characterized by ineffective hematopoiesis and frequent progression to acute myeloid leukemia (AML). Thus far, few treatments can actually alter the natural history of this disease. Allogeneic stem-cell transplantation for high-risk MDS is becoming the only curative therapy probably because of the improvement of bone marrow transplant procedures. The lack of other options underscores the urgent need to develop new therapy. The prevailing model suggests that genetic and/or epigenetic alterations that occur in HSCs or HSC niche compromise HSC function, resulting in MDS; therefore, MDS HSCs are likely the ideal targets for MDS treatment. Recent encouraging advances--capturing a molecular portrait of the whole genome of MDS CD34(+) cells, including identifying altered signaling pathways and altered microRNAs--have improved our understanding of MDS pathogenesis and provided novel potential clinical targets for MDS. Here, I will briefly review the characteristics of MDS HSCs and discuss the therapeutic promise of targeting MDS HSCs. 23619057 Urban metabolism: a review of research methodologies. Urban metabolism analysis has become an important tool for the study of urban ecosystems. The problems of large metabolic throughput, low metabolic efficiency, and disordered metabolic processes are a major cause of unhealthy urban systems. In this paper, I summarize the international research on urban metabolism, and describe the progress that has been made in terms of research methodologies. I also review the methods used in accounting for and evaluating material and energy flows in urban metabolic processes, simulation of these flows using a network model, and practical applications of these methods. Based on this review of the literature, I propose directions for future research, and particularly the need to study the urban carbon metabolism because of the modern context of global climate change. Moreover, I recommend more research on the optimal regulation of urban metabolic systems. 23924659 Type 2 innate lymphoid cells constitutively express arginase-I in the naive and inflamed lung. Arg1 is produced by AAMs and is proposed to have a regulatory role during asthma and allergic inflammation. Here, we use an Arg1 reporter mouse to identify additional cellular sources of the enzyme in the lung. We demonstrate that ILC2s express Arg1 at rest and during infection with the migratory helminth Nippostrongylus brasiliensis. In contrast to AAMs, which express Arg1 following IL-4/IL-13-mediated STAT6 activation, ILC2s constitutively express the enzyme in a STAT6-independent manner. Although ILC2s deficient in the IL-33R subunit T1/ST2 maintain Arg1 expression, IL-33 can regulate total lung Arg1 by expanding the ILC2 population and by activating macrophages indirectly via STAT6. Finally, we find that ILC2 Arg1 does not mediate ILC2 accumulation, ILC2 production of IL-5 and IL-13, or collagen production during N. brasiliensis infection. Thus, ILC2s are a novel source of Arg1 in resting tissue and during allergic inflammation. 23937972 Consent, including advanced consent, of older adults to research in care homes: a qualitative study of stakeholders' views in South Wales. Care home residents, especially those lacking capacity to provide consent for themselves, are frequently excluded from research, thus limiting generalisability of study findings. We set out to explore stakeholders' views about the ethical and practical challenges associated with recruiting care home residents into research studies. Qualitative individual interviews with care home residents (n = 14), their relatives (n = 14), and general practitioners (GPs) (n = 10), and focus groups (n = 2) with care home staff. Interviews focused on the issues of older adults consenting to research in care homes, including advanced consent, in general and through reference to a particular study on the use of probiotics to prevent Antibiotic Associated Diarrhoea. Data were analysed using a thematic approach incorporating themes that had been identified in advance, and themes derived from the data. Researchers discussed evidence for themes, and reached consensus on the final themes. Respondents were generally accepting of low risk observational studies and slightly less accepting of low risk randomised trials of medicinal products. Although respondents identified some practical barriers to informed consent, consenting arrangements were considered workable. Residents and relatives varied in the amount of detail they wanted included in information sheets and consent discussions, but were generally satisfied that an advanced consent model was acceptable and appropriate. Opinions differed about what should happen should residents lose capacity during a research study. Research staff should be mindful of research guidance and ensure that they have obtained an appropriate level of informed consent without overwhelming the participant with unnecessary detail. For research involving medicinal products, research staff should also be more explicit when recruiting that consent is still valid should an older person lose capacity during a trial provided the individual did not previously state a wish to be withdrawn if they lose capacity, and provided they do not indicate objection or resistance after loss of capacity. 23939301 Ultrahigh Gas Storage both at Low and High Pressures in KOH-Activated Carbonized Porous Aromatic Frameworks. The carbonized PAF-1 derivatives formed by high-temperature KOH activation showed a unique bimodal microporous structure located at 0.6 nm and 1.2 nm and high surface area. These robust micropores were confirmed by nitrogen sorption experiment and high-resolution transmission electron microscopy (TEM). Carbon dioxide, methane and hydrogen sorption experiments indicated that these novel porous carbon materials have significant gas sorption abilities in both low-pressure and high-pressure environments. Moreover the methane storage ability of K-PAF-1-750 is among the best at 35 bars, and its low-pressure gas adsorption abilities are also comparable to the best porous materials in the world. Combined with excellent physicochemical stability, these materials are very promising for industrial applications such as carbon dioxide capture and high-density clean energy storage. 23957847 Analysis of Molecular Aggregation Equilibria using Random Mixing Statistics. Aggregation processes in both the gas phase and aqueous solutions are analyzed by comparing aggregate size distributions obtained from molecular dynamics simulations with analytical predictions pertaining to a non-aggregating random mixture. The latter predictions are obtained by using the binomial distribution to predict the statistical properties of a uniformly mixed solution containing molecules of the same size and concentration as those in the solution of interest. Simulations are performed on systems containing neopentane dissolved in either methane, aqueous methanol, or aqueous NaI solutions. Comparisons of the theoretical and simulation results are used to both classify and quantify the influence of intermolecular interactions on such aggregation processes, including the equilibrium constants and thermodynamic functions pertaining to the partitioning of molecules between the bulk and first coordination shell of neopentane. Although the present results are primarily intended to describe and illustrate the random mixing analysis strategy, they also imply that neopentane has a greater tendency to aggregate with methane in the dense gas phase, than with either methanol or iodide ions in aqueous solutions. 23261758 Effects of p53 knockout on ochratoxin A-induced genotoxicity in p53-deficient gpt delta mice. Ochratoxin A (OTA) is a mycotoxin produced by fungal species and is carcinogenic targeting the S3 segment of the renal proximal tubules in rodents. We previously reported that exposure of gpt delta rats to OTA induced both mutations in the red/gam gene (Spi(-)), suggesting large deletion mutations, and fluctuations in genes transcribed by p53 in the kidneys, which were associated with DNA double-strand break (DSB) repair, particularly homologous recombination (HR) repair. In the present study, to investigate the effects of p53 knockout on OTA-induced mutagenicity, apoptosis, and karyomegaly in renal tubular cells, p53-proficient and p53-deficient gpt delta mice were given 1 and 5mg/kg of OTA for 4 weeks. Significant increases in Spi(-) mutant frequencies (MFs) were observed in the kidneys of p53-deficient gpt delta mice given 5 mg/kg of OTA, but not in the kidneys of p53-proficient gpt delta mice given the same dose. There were no changes in gpt MFs in both genotypes of mice treated with OTA. Western blotting analysis demonstrated that p53 protein levels in the kidneys of p53-proficient mice given OTA were significantly increased compared with the control. Incidences of apoptosis and karyomegaly in not only the outer stripe of outer medulla but also the cortex were significantly higher in p53-deficient at 5mg/kg than in p53-proficient gpt delta mice at same dose, which had no change in the cortex, the inner stripe of outer stripe, and the inner medulla. Given that p53 regulates HR repair in DSBs, these results suggest that OTA may promote large deletion mutations in the process of HR repair for DSBs. Additionally, the lower incidence of karyomegaly and apoptosis found in the p53-proficient gpt delta mice suggests that these phenomena may arise from OTA-induced DNA damage. 23199990 Determination of lead in milk and yoghurt samples by solid phase extraction using a novel aminothioazole-polymeric resin. A preconcentration method was developed by using a new aminothioazole-containing sulfonamide resin in solid phase extraction for the determination of lead and nickel in milk and yoghurt samples. The optimisation of experimental conditions was performed. The optimum parameters for Pb and Ni were found to be 3.5, 30 min and 2.5 mL for pH, contact time, eluate volume, respectively. After preconcentration step, atomic absorption spectrometry was used for the determinations. The enhancement of 350- and 50-fold in the sensitivity of Pb and Ni were achieved by combination of the slotted tube atom trap-atomic absorption spectrometry with the optimised preconcentration method, respectively. Limits of detection were found to be 0.15 ng mL⁻¹ for Pb and 0.75 ng mL⁻¹ for Ni. The lead concentrations in the studied samples were found to be in the range of 15-61 ng Pb mL⁻¹ for milk and 21-42 ng Pb g⁻¹ for yoghurt samples. 23411267 Purification and identification of lipolysis-stimulating peptides derived from enzymatic hydrolysis of soy protein. The aim of this study was to purify and identify lipolysis-stimulating peptides derived from Flavourzyme®-soy protein isolate (SPI) hydrolysate (F-SPIH). Glycerol release was employed as a marker for lipolysis in 3T3-L1 adipocytes. A higher glycerol release represents a better lipolysis-stimulating activity. The peptide fraction with highest glycerol release obtained from F-SPIH fractionated by sequential ultrafiltration membranes was further purified using gel filtration chromatography and two steps of reverse-phase high-performance liquid chromatography. The peptides were identified using liquid chromatography-tandem mass spectrometry (LC/MS/MS). Three lipolysis-stimulating peptides were obtained, and the amino acid sequences were ILL, LLL and VHVV, respectively. The in vitro effect of gastrointestinal proteases on lipolysis-stimulating activity of synthetic ILL, LLL and VHVV, respectively, was also investigated. The result suggested that the gastrointestinal protease did not affect lipolysis-stimulating activity of the three novel peptides, which reveals their potential to act as anti-obesity ingredients. 23938755 Pushing the endogenous envelope. The majority of retroviral envelope glycoproteins characterized to date are typical of type I viral fusion proteins, having a receptor binding subunit associated with a fusion subunit. The fusion subunits of lentiviruses and alpha-, beta-, delta- and gammaretroviruses have a very conserved domain organization and conserved features of secondary structure, making them suitable for phylogenetic analyses. Such analyses, along with sequence comparisons, reveal evidence of numerous recombination events in which retroviruses have acquired envelope glycoproteins from heterologous sequences. Thus, the envelope gene (env) can have a history separate from that of the polymerase gene (pol), which is the most commonly used gene in phylogenetic analyses of retroviruses. Focusing on the fusion subunits of the genera listed above, we describe three distinct types of retroviral envelope glycoproteins, which we refer to as gamma-type, avian gamma-type and beta-type. By tracing these types within the 'fossil record' provided by endogenous retroviruses, we show that they have surprisingly distinct evolutionary histories and dynamics, with important implications for cross-species transmissions and the generation of novel lineages. These findings validate the utility of env sequences in contributing phylogenetic signal that enlarges our understanding of retrovirus evolution. 23899619 Pure Transvaginal Ventral Hernia Repair in Humans. Introduction. Transvaginal natural orifice transluminal endoscopic surgery procedures are at the forefront of minimally invasive innovation, remarkable for shorter recovery times and decreased postoperative pain. We aim to demonstrate a novel technique of pure transvaginal laparoscopic ventral hernia repair in a series of patients performed in our institution. Technique Description. The patient was placed in lithotomy position and steep Trendelenburg. A 2-cm transverse colpotomy incision was made and a SILS port was introduced. One 12-mm trocar and two 5-mm trocars were placed through the SILS port and standard straight laparoscopic instruments were used. An appropriately sized round mesh was deployed within a specimen retrieval bag into the peritoneal cavity. Complete anterior circumferential fixation of the mesh was achieved using an AbsorbaTack device. The colpotomy incision was closed. Results. There were a total of 6 pure transvaginal ventral hernia repair procedures performed in our institution between November 2010 and February 2012. The first case was converted to an open procedure after a rectal injury was recognized and repaired. Two patients had transient urinary retention that resolved after 24 hours. One patient had vaginal wound granulation noted at 2 months postoperatively. No long-term complications or recurrences were noted with a median follow-up of 9 months. The mean operative time was 107 minutes. Conclusion. Our initial experience with transvaginal ventral hernia repair in humans suggests that this procedure is feasible, safe, and associated with improved cosmetic results. 23817370 Characterization of Tn5801.Sag, a Variant of Staphylococcus aureus Tn916 Family Transposon Tn5801 That Is Widespread in Clinical Isolates of Streptococcus agalactiae. Tn5801, originally detected in Staphylococcus aureus Mu50, is a Tn916 family element in which a unique int gene (int5801) replaces the int and xis genes in Tn916 (int916 and xis916). Among 62 tet(M)-positive tetracycline-resistant Streptococcus agalactiae isolates, 43 harbored Tn916, whereas 19 harbored a Tn5801-like element (Tn5801.Sag, ∼20.6 kb). Tn5801.Sag was characterized (PCR mapping, partial sequencing, and chromosomal integration) and compared to other Tn5801-like elements. Similar to Tn5801 from S. aureus Mu50, tested in parallel, Tn5801.Sag was unable to undergo circularization and conjugal transfer. 23945636 HIGH-SPEED OPTICAL COHERENCE TOMOGRAPHY AS A RELIABLE ADJUVANT TOOL TO GRADE OCULAR ANTERIOR CHAMBER INFLAMMATION. To evaluate the high-speed anterior segment optical coherence tomography (AS-OCT) grading of the AS inflammation in patients with ocular inflammation. A retrospective consecutive case series study. Patients with clinically visible AS inflammation in at least one eye underwent AS-OCT (Visante; Zeiss Meditec) with three to eight line scans per eye, performed by a trained masked examiner. The images were reviewed for hyperreflective spots, noise, and artifact, and these were correlated to clinical examination. Seventy-eight eyes of 41 patients were imaged. Forty-seven eyes had anterior chamber cells on clinical examination, and 68 had hyperreflective spots visible on AS-OCT. There was a significant correlation (Spearman r = 0.7274) between clinical examination and Visante OCT images. Several patterns of inflammation and artifacts were apparent. The AS-OCT is a promising technique for grading anterior chamber cells. There was a significant correlation between clinical examination and Visante grading. 22518063 Maximum occusal bite force for children in different dentition stages. This study was carried out to record maximum occlusal bite force (MOBF) among different dentition stages in children and to study the relation of occlusal bite force to weight, height, and gender. A total of 1011 children (500 females and 511 males) aged from 3 to 18 years were examined. The subjects were divided into 5 groups according to their dentition stage as the following:- early primary dentition stage (100 males and 100 females, average age was 3.37 ± 0.23 years), late primary dentition stage (104 males and 100 females, average age was 5.86 ± 1.15 years), early mixed dentition stage (100 males and 100 females, average age was 8.15 ± 0.67 years), late mixed dentition stage (100 males and 100 females, average age was 9.97 ± 0.86 years ), and permanent dentition stage (107 males and 100 females, average age was 14.03 ± 2.14 years). Occlusal bite force was measured using a hydraulic occlusal force gauge. The means of MOBF for the different dentition stages were:- 176 N in early primary stage, 240 N in late primary stage, 289 N in early mixed stage, 433 N in late mixed stage, and 527 N in the permanent dentition stage, respectively. Gender differences were detected in groups 2, 3 and 4. Height and age significantly correlated with the MOBF in all dentition stage groups except group 1. In conclusion, the MOBF increased with age. Age, gender, and height were significant predictors of the MOBF. 23177263 Factors associated with the use of irreversible contraception and continuous use of reversible contraception in a cohort of HIV-positive women. Effective contraception can be lifesaving by reducing maternal mortality linked to childbirth and unsafe abortion and by reducing vertical and horizontal transmission of HIV, in the case of an HIV-positive woman. This study is a secondary analysis of a prospective cohort study. We assessed factors associated with the use of irreversible contraception and the continuous use of reversible contraception in HIV-positive Thai women. We used descriptive statistics to present baseline characteristics and logistic regression to assess the association between contraceptive use and factors in the study. Of 196 women included in the analysis, 87% self-reported always using male condoms and 56% continuously using another effective contraceptive method during the period of the study (12-18 months). The choice of effective contraceptive methods was suboptimal--42% were sterilized, 14% used hormonal contraception and no participant reported the use of an intrauterine device. Sexual activity and past contraceptive use were factors associated positively with current continuous contraceptive use. Live births and lower levels of education were additional factors associated positively with sterilization. Despite high contraceptive use, there are still uncovered contraceptive needs among HIV-positive women in Thailand. HIV-positive women need established specialized family planning services, offering an optimal variety of contraceptive choices and tailored to their individual needs. As sterilization is an irreversible choice, it cannot be a viable alternative for every woman. Due to the positive trend between current and past contraceptive use, we consider that it may be possible to improve family planning programs if they start as early as possible in a woman's life and are continued throughout her sexually active and reproductive years. 23830159 In vivo assessment of endothelial function in human lower extremity arteries. Endothelial function has been measured in preclinical studies in human brachial and coronary arteries but not in lower extremity arteries affected by atherosclerosis. We describe a novel, first-in-man evaluation of endothelial function of the superficial femoral arteries (SFAs) in patients with peripheral arterial disease (PAD). Enrolled were 25 patients with PAD requiring lower extremity angiography. Endothelial-dependent relaxation was measured using intravascular ultrasound (IVUS) imaging and a Doppler flow wire after the infusion of acetylcholine (Ach). IVUS-derived virtual histology of the same vessel was calculated. Endothelial-independent relaxation was measured with an infusion of nitroglycerin (200 Î¼g). Levels of nitric oxide and serum nitric oxide metabolites were determined by laboratory analysis. Patients (48% male; mean age, 62 years) had a history of hypertension (80%), coronary disease (36%), and diabetes (40%). The mean SFA diameter was 5.2 ± 1 mm (range, 3.2-6.9 mm). Patients tolerated Ach infusion with no adverse events. Endothelial-dependent relaxation increased over baseline for all patients with Ach infusion of 10(-6) to 10(-4). At Ach 10(-4), diameter (0.5%) and area (1.8%) changes in the diseased SFAs were modest and insignificant; however, average peak velocity of blood flow significantly increased 26%, 46%, and 63% with an Ach 10(-6) to 10(-4) infusion. Calculations of limb volumetric flow (68% at Ach 10(-4)) were significantly increased after Ach infusion. Lower extremity nitric oxide levels were slightly lower than systemic venous levels (P = .04). Nitroglycerin infusion indicated normal smooth muscle responsiveness (3% diameter, 9% area, and 116% velocity change over baseline). IVUS-virtual histology plaque stratification indicated predominantly fibrous morphology (46%; necrotic core, 29%; calcium, 18%). Atheroma burden was 14.9 ± 5.5 mm(3)/cm and did not correlate with endothelial responsiveness. Endothelial function can be measured directly in human lower extremity arteries at the sites of vascular disease. Despite extensive atherosclerosis, endothelial function is still intact. These data support the application of regional endothelial-specific biologic therapies in patients with PAD. 23963190 Thermo-Electrical Modeling of Bipolar Coagulation on Posterior Spinal Artery in a Porcine Spinal Surgery Model. The primary objective of our study was to develop a thermo-electrical model with both solid and liquid phases to calculate tissue temperature during bipolar coagulation of a posterior spinal artery on the spinal cord. Control of thermal spread caused by coagulation is a concern in spinal surgery. This model utilizes a non-isothermal flow to account for the heat transfer due to the movement of cerebrospinal fluid which is induced by electrical field and temperature gradient. The model is validated by in-situ temperature measurements on a porcine spinal cord model. The maximum error for tissue temperature of this model is 12.6%, and the overall average error is 4.2%. The lesional region (>50ºC) is identified to be as wide as 5 mm, and thermal dose cumulative equivalent minutes at 43°C (CEM43) is also calculated with this model. The incorporation of non-isothermal flow has been shown to be crucial in order to accurately predict thermal dose in tissue. The developed model can be further used to establish a guideline for the use of bipolar coagulation. 23638842 Protective Role of (RS )-glucoraphanin Bioactivated with Myrosinase in an Experimental Model of Multiple Sclerosis. AIM: The discovery of new natural compounds with pharmacological properties is a field of interest widely growing. Recent literature shows that Brassica vegetables (Cruciferae) possess therapeutic effects particularly ascribed due to their content in glucosinolates, which upon myrosinase hydrolysis release the corresponding isothiocyanates. This study examines the potential neuroprotective and immunomodulatory effects of (RS )-glucoraphanin from Tuscan black kale (Brassica oleracea L. var. acephala sabellica) bioactivated with myrosinase (bioactive RS -GRA) (10 mg/kg/day intraperitoneally), in an experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. METHODS: EAE was induced by immunization with myelin oligodendroglial glycoprotein peptide (MOG35-55 ) in mice. After immunization, mice were observed daily for signs of EAE and weight loss. Clinical score was evaluated using a standardized scoring system. RESULTS: By Western blot analysis of spinal cord tissues, we have demonstrated that treatment with bioactive RS -GRA significantly decreased nuclear factor (NF)-kB translocation, pro-inflammatory cytokine production such as interleukin-1β (IL-1β), and apoptosis (Bax and caspase 3 expression). CONCLUSION: Our results clearly demonstrate that bioactive RS -GRA treatment may represent a useful therapeutic perspective in the treatment of this disease. 23648072 Free drugs in clinical trials and their potential cost saving impact on the National Health Service: a retrospective cost analysis in Italy. The cost of new anti-cancer drugs has dramatically increased in recent years, and countermeasures are required in order to limit pharmaceutical expenses. Sponsored clinical trials that provide drugs free of charge may be a useful tool in order to reduce drug costs. The aim of this analysis is to evaluate the effect of clinical trials on pharmaceutical expenditure savings. We evaluated the cost of drugs administered in clinical practice and in clinical trials (considering only the standard regimens that were administered also in clinical practice) in 2010 at the Lung Cancer Unit of the National Institute for Cancer Research in Genoa, Italy. The cost of drugs was calculated on the price charged at our Institute in 2010. The supposed cost of experimental treatment replacing standard therapy was converted in the cost of the treatments that would have been chosen in clinical practice, considering histology, line of treatment and number of administered cycles. From 1/1/2010 to 12/31/2010, 196 patients affected by lung cancer or pleural mesothelioma were treated. 152 patients (78%) received treatment in clinical practice or in non-sponsored trials (18 patients in 4 trials), while 44 (22%) were treated in one of the 12 sponsored clinical trials recruiting in 2010. Globally, 606 cycles of treatment would have been administered to patients, of which 436 (72%) were administered in clinical practice or in non-sponsored trials and 170 (28%) were administered in pharmaceutical company sponsored clinical trials. The overall cost of those anti-neoplastic drugs, based on the prices charged at our Institute in 2010, was €799 803. The cost of drugs administered in clinical practice or in non-sponsored trials was €556 649 (70%), whereas the cost of standard drugs administered in clinical trials was €243 154 (30%). The grants provided by pharmaceutical companies were evaluated and amounted to €235 965. The participation in sponsored clinical trials in which drugs are provided free of charge offers substantial cost savings for the National Health Service; moreover, the grants received for each enrolled patient produced additional income. 23590597 Augmentation index and pulse wave velocity in normotensive and pre-eclamptic pregnancies. Hypertensive disorders during pregnancy remain a major health burden. Normal pregnancy is associated with systemic cardiovascular adaptation. The augmentation index and pulse wave velocity measures may serve as surrogate markers of cardiovascular pathology, including pre-eclampsia. We evaluated these parameters during and after normotensive and pre-eclamptic pregnancies. Longitudinal cohort trial involving a case-control analysis of healthy women and women with pre-eclampsia. University hospital. Fifty-three healthy pregnant women between 11(+6) and 13(+6) gestational weeks, as well as 21 patients with pre-eclampsia. The augmentation index and pulse wave velocity were measured seven times during pregnancy and postpartum. Changes in augmentation index and pulse wave velocity during and after healthy pregnancies were measured. The influence of early-onset and late-onset pre-eclampsia on these measurements both during and after pregnancy was evaluated. The normotensive pregnancies exhibited a significant decrease in the augmentation index from the first trimester to the end of the second trimester; however, the normotensive pregnancies showed an increase in the augmentation index during the third trimester as term approached. The patients with early-onset and late-onset pre-eclampsia displayed a significantly elevated augmentation index during pregnancy. The postpartum augmentation index and pulse wave velocity were significantly elevated in the early-onset pre-eclampsia group. After pregnancy, early-onset and late-onset pre-eclamptic patients exhibit differences in vascular function. This result indicates the presence of a higher cardiovascular risk in patients after early-onset pre-eclampsia. 23946523 In Vitro Activity of Amikacin Against Isolates of Mycobacterium avium complex with Proposed MIC Breakpoints And Finding of a 16S rRNA Gene Mutation in Treated Isolates. Amikacin is a major drug in the treatment of Mycobacterium avium complex (MAC) disease but laboratory guidelines for susceptibility testing are not available. This study presents in vitro amikacin MICs for 462 consecutive clinical isolates of MAC using broth microdilution. Approximately 50% of isolates had amikacin MICs of 8 μg/mL and 86% had MICs of ≤16 μg/mL. Of the eight isolates (1.7%) with MICs of 64 μg/mL, five had an MIC of 32 μg/mL on repeat testing. Ten (2.1%) of isolates had an initial amikacin MIC of >64 μg/mL, of which seven (1.5%) were >64 μg/mL on repeat testing. These seven isolates had a 16S rRNA gene position 1408 A→G mutation and included M. avium, Mycobacterium intracellulare, and Mycobacterium chimaera. Clinical data were available for five of these seven, all of whom had received prolonged (>6 months) prior therapy, four with known amikacin. The 16S mutation was not detected in isolates with MICs of 64 μg/mL or lower. We recommend primary testing of amikacin against isolates of MAC and propose MIC guidelines for breakpoints identical to the CLSI guidelines for M. abscessus: ≤16 μg/mL, susceptible; 32 μg/mL, intermediate; and ≥64 μg/mL, resistant. If considered and approved by CLSI, this will be only the second drug recommended for primary susceptibility testing against MAC, and should facilitate its use for both IV and inhaled therapy. 23603472 Developmental exposure to a brominated flame retardant: an assessment of effects on physiology, growth, and reproduction in a songbird, the zebra finch. Mixtures of polybrominated diphenyl ethers (PBDEs) have been widely used as additive flame retardants, and BDE-99 is one of the most predominant congeners found in the environment. BDE-99 has been reported in avian samples worldwide, yet knowledge of its toxicity to birds is minimal. We assessed the short- and long-term effects of nestling exposure to environmentally relevant levels of BDE-99 in a model passerine, the zebra finch. Early exposure to BDE-99 did not affect hematocrit, oxidative stress, or thyroid hormones in either the juvenile or adult stages, and there were no effects on chick growth or survival. BDE-99 exposure caused a dose-dependent delay in timing of reproduction, but there were no other effects on reproductive success. In zebra finches, endpoints related to reproductive behavior appear to be the most sensitive to BDE-99. However, passerines overall appear to be less sensitive than birds of prey or mammals to PBDE exposure. 23657432 Door-to-implantation time of extracorporeal life support systems predicts mortality in patients with out-of-hospital cardiac arrest. This study aimed to identify predictors of mortality in patients with out-of-hospital cardiac arrest (OHCA) undergoing in-hospital extracorporeal life support system (ECLS) treatment. We retrospectively studied the characteristics and clinical outcomes of 28 patients (January 2010 and December 2011) with OHCA and veno-arterial ECLS implemented during ongoing cardiopulmonary resuscitation (CPR) upon admission to the cath lab. Baseline left ventricular ejection fraction (LVEF) was determined after ECLS implantation and then every 24 h during and after successful weaning from ECLS. Overall 30-day survival rate was 39.3 % (11 of 28 patients). Baseline characteristics, initial laboratory measurements, and LVEF on admission were not significantly different between survivors and non-survivors. There was no difference regarding median CPR duration [survivors 44.0 min (IQR 31.0-45.0) vs. non-survivors 53.0 min (IQR 40.0-61.3); P = 0.23]. Door-to-ECLS implantation time was significantly longer in non-survivors [42.5 min (IQR 28.0-56.5) vs. 25.0 min (IQR 21.0-30.0); P < 0.01]. ECLS treatment duration was not significantly different between the two groups [survivors: 4.0 days (IQR 1.5-7.5) vs. non-survivors 6.5 days (IQR 1.0-8.0); P = 0.69]. LVEF significantly improved in survivors during ECLS treatment (mean ± SD survivor 47.5 ± 14.7 % vs. non-survivor 23.3 ± 14.9 %; P < 0.01). The door-to-ECLS implantation time was the only significant and independent predictor of 30-day mortality in multivariate Cox regression analysis (P = 0.04). Kaplan-Meier survival analysis showed a benefit favouring patients with a door-to-ECLS implantation time <30 min (log rank 6.29; P = 0.01). A door-to-ECLS implantation time <30 min significantly improves 30-day outcomes in patients with OHCA. 23754252 Enhanced antitumor activity of cerulenin combined with oxaliplatin in human colon cancer cells. Fatty acid synthase is highly expressed in many types of human cancers. Cerulenin, a natural inhibitor of fatty acid synthase, induced apoptosis in the human colon cancer cell lines HCT116 and RKO. Oxaliplatin also induced cell death in these cell lines. Cerulenin treatment was associated with reduced levels of phosphorylated Akt, activation of p38 and induced caspase-3 cleavage and finally caused apoptosis. Oxaliplatin induced activation of the p53-p21 pathway and p38. In combination with cerulenin and oxaliplatin, activation of the p53-p21 pathway and p38 occurred in a smaller concentration and finally induced caspase-3 cleavage in a smaller concentration of cerulenin and oxaliplatin. In xenotransplanted SCID mice, the cerulenin + oxaliplatin group significantly inhibited tumor progression compared to the control, cerulenin and oxaliplatin groups. Based on these studies, inhibiting fatty acid synthase would be an effective strategy to treat unresectable colorectal cancer tumors in combination with oxaliplatin. Fatty acid synthase inhibitor would be one of the best counterparts of oxaliplatin, which reduces the dose and side-effects of oxaliplatin and would make it possible to endure the chemotherapy over a longer period. 23740253 α-Synuclein Senses Lipid Packing Defects and Induces Lateral Expansion of Lipids Leading to Membrane Remodeling. There is increasing evidence for the involvement of lipid membranes in both the functional and pathological properties of α-synuclein (α-Syn). Despite many investigations to characterize the binding of α-Syn to membranes, there is still a lack of understanding of the binding mode linking the properties of lipid membranes to α-Syn insertion into these dynamic structures. Using a combination of an optical biosensing technique and in situ atomic force microscopy, we show that the binding strength of α-Syn is related to the specificity of the lipid environment (the lipid chemistry and steric properties within a bilayer structure) and to the ability of the membranes to accommodate and remodel upon the interaction of α-Syn with lipid membranes. We show that this interaction results in the insertion of α-Syn into the region of the headgroups, inducing a lateral expansion of lipid molecules that can progress to further bilayer remodeling, such as membrane thinning and expansion of lipids out of the membrane plane. We provide new insights into the affinity of α-Syn for lipid packing defects found in vesicles of high curvature and in planar membranes with cone-shaped lipids and suggest a comprehensive model of the interaction between α-Syn and lipid bilayers. The ability of α-Syn to sense lipid packing defects and to remodel membrane structure supports its proposed role in vesicle trafficking. 23528606 Purification antibody by thiophilic magnetic sorbent modified with 2-mercapto-1-methylimidazol. An efficient strategy based on the thiophilic magnetic beads was developed to isolate immunoglobulin G (IgG) from human plasma with high efficiency. Depending on the improved surface modification, the surface density of thiophilic ligand (2-mercapto-1-methylimidazol) reached 1.67mmolg(-1) resulting in a high adsorption capacity (qmax=20.7mgg(-1)) toward IgG. This purification of IgG could be carried out in some physiological conditions due to the heterocyclic structure of 2-mercapto-1-methylimidazol. It is found that the recognition region between the thiophilic ligand and IgG was mainly focused on the Fab fragments of IgG using the technology of enzyme digestion. Furthermore, the bound antibodies could be easily recovered without loss of their bioactivity at low salt concentration. These magnetic carries brought great potentials in large-scale antibody purification from human plasma attributing to their high specificity and efficiency, stable structure, sensitive magnetic response and excellent reusability. 23911574 A dynamical model of programmed -1 ribosomal frameshifting. Programmed -1 ribosomal frameshifting is the most widely used translational recoding mechanism of RNA viruses. How the frameshifting occurs at the slippery sequence on the presence of a downstream mRNA pseudoknot has not been fully understood. Here, we present systematical analysis of the -1 frameshifting that can occur during every transition step in elongation phase of protein synthesis by Escherichia coli ribosomes, showing that the -1 frameshifting can occur mainly during three periods. One is during translocation step, another period is after the posttranslocation and before the binding of the ternary complex aminoacyl-tRNA.EF-Tu.GTP, and the third period is after codon recognition and before peptidyl transfer. Of the three periods, the translocation step makes the most contribution to the -1 frameshifting. During the translocation step when the mRNA channel is open, due to the presence of energy barrier to the forward translocation of the ribosome along the mRNA template, which results from unwinding of the mRNA pseudoknot, the reverse ribosomal rotation from ratcheted to non-ratcheted conformation induces the frameshifting and futile translocation besides the effective forward translocation. During the other two slow periods when the mRNA channel is tight, the annealing of the unwound base pair in the mRNA pseudoknot can also promote the -1 frameshifting. Our theoretical results provide a consistent explanation of a lot of independent experimental data and also provide predicted results. 23842291 Buffer strips can pre-empt extinction debt in boreal streamside habitats. Conservation of biological diversity and economical utilization of natural resources form an almost inevitable confrontation between the two. In practice, however, a balance between the two ought to be found, and in managed boreal forests, preservation of woodland key habitats is increasingly used strategy to safeguard biological diversity. According to the Finnish Forests Act, certain Forest Act habitat (FAH) types must be safeguarded, provided they are clearly distinguishable from their surroundings. Furthermore, once the habitat has been identified as a FAH, its special characteristics must not be altered. Both of these aspects contain ambiguities that potentially undermine the practical application of the Act. We designed a replicated sampling study to address these ambiguities at the most common FAH type, riparian habitat of small boreal streams. As response variables we used vascular plants and mosses. We asked i) how wide is the FAH around small streams that is distinguishable from its surrounding and ii) how wide buffer strip around the FAH is sufficient for long term to preserve the natural species community composition of the FAH. We found that an average three meters wide strip around the stream constitutes the distinguishable FAH and that a minimum of 45 meters wide buffers on both sides of the stream are needed for the species community composition to remain unaltered. We conclude that 45 meters wide buffers appear sufficient to safeguard vascular plant and moss species communities within the FAH, prevent local populations from extinctions and thus pre-empt extinction debt that would be realised with more narrow buffers. While 45 meters may seem intolerable from the commercial forestry point of view, anything less than that may be intolerable from the point of view of conservation, and thus against the idea of sustainable use of natural resources. 23846686 Endocytosis of Mycobacterium tuberculosis Heat Shock Protein 60 Is Required to Induce Interleukin-10 Production in Macrophages. Understanding the signaling pathways involved in the regulation of anti-inflammatory and pro-inflammatory responses in tuberculosis is extremely important in tailoring a macrophage innate response to promote anti-tuberculosis immunity in the host. Although the role of toll-like receptors (TLRs) in the regulation of anti-inflammatory and pro-inflammatory responses is known, the detailed molecular mechanisms by which the Mycobacterium tuberculosis bacteria modulate these innate responses are not clearly understood. In this study, we demonstrate that M. tuberculosis heat shock protein 60 (Mtbhsp60, Cpn60.1, and Rv3417c) interacts with both TLR2 and TLR4 receptors, but its interaction with TLR2 leads to clathrin-dependent endocytosis resulting in an increased production of interleukin (IL)-10 and activated p38 MAPK. Blockage of TLR2-mediated endocytosis inhibited IL-10 production but induced production of tumor necrosis factor (TNF)-α and activated ERK1/2. In contrast, upon interaction with TLR4, Mtbhsp60 remained predominantly localized on the cell surface due to poorer endocytosis of the protein that led to decreased IL-10 production and p38 MAPK activation. The Escherichia coli homologue of hsp60 was found to be retained mainly on the macrophage surface upon interaction with either TLR2 or TLR4 that triggered predominantly a pro-inflammatory-type immune response. Our data suggest that cellular localization of Mtbhsp60 upon interaction with TLRs dictates the type of polarization in the innate immune responses in macrophages. This information is likely to help us in tailoring the host protective immune responses against M. tuberculosis. 23574523 Citrullinated peptides in the diagnosis of rheumatoid arthritis. Antibodies directed against citrullinated proteins and peptides (ACPAs) are the most specific serological markers available for diagnosing rheumatoid arthritis (RA). ACPAs may be detected several years before symptoms of RA appear, and their presence at disease onset is a good predictor of the development of erosive joint lesions. RA patients can be classified into two major groups: those who have ACPAs and those who do not. The presence of ACPAs at early stages of RA predicts the development of earlier and more widespread joint erosions, and low remission rates.Synthetic peptides can replace cognate proteins in solid-phase assays for specific autoantibody recognition in RA patients. The use of synthetic peptides instead of proteins represents an advantage in terms of the reproducibility of such immunoassays. Proteins also contain non-citrullinated epitopes that are recognized by non-RA sera and this could reduce the specificity of the test. The use of synthetic citrullinated peptides gives absolute control over the exact epitopes presented. Furthermore, it is difficult to prepare sufficient amounts of high-quality antigenic proteins with a well-defined degree of citrullination. Synthetic citrullinated peptides, in contrast, are easily obtained in a pure form with a well-defined chemical structure and the epitopes can be precisely oriented in the plate by covalent binding of the peptides.Chimeric peptides bearing different citrullinated protein domains have recently been used in the design of RA diagnosis systems. The results of the application of those systems indicate that more than one serological test is required to classify RA patients based on the presence or absence of ACPAs. Each of the target molecules reported (fibrin, vimentin and filaggrin) helps to identify a particular subset of RA patients. 23829465 In-depth study of homogeneity in DBS using two different techniques: results from the EBF DBS-microsampling consortium. Background: At the start of their work, the European Bioanalysis Forum dried blood spots microsampling consortium did not form a dedicated team to investigate the spot homogeneity. However, two teams performed experiments that produced results relating to sample homogeneity. Results: The data, which were produced via two different approaches (a radiolabeled and a nonradiolabeled approach), are highly complementary and demonstrate clear effects on sample inhomogeneity due to the substrate type, compound and hematocrit levels. Conclusion: The results demonstrate that sample inhomogeneity is a significant hurdle to the use of dried blood spots for regulated bioanalysis that should be investigated further in the method establishment phase if the whole spot is not sampled. 23743181 Agreement among dentists' restorative treatment planning thresholds for primary occlusal caries, primary proximal caries, and existing restorations: Findings from The National Dental Practice-Based Research Network. The aim of this study was to quantify the agreement among individual National Dental Practice-Based Research Network dentists' self-reported treatment decisions for primary occlusal caries, primary proximal caries, and existing restorations. Five hypothetical clinical scenarios were presented: primary occlusal caries; primary proximal caries; and whether three existing restorations should be repaired or replaced. We quantified the probability that dentists who recommended later restorative intervention for primary caries were the same ones who recommended that existing restorations be repaired instead of replaced. Dentists who recommended later restorative treatment of primary occlusal caries and proximal caries at a more-advanced stage were significantly more likely to recommend repair instead of replacement. Agreement among dentists on a threshold stage for the treatment of primary caries ranged from 40 to 68%, while that for repair or replacement of existing restorations was 36 to 43%. Dentists who recommended repair rather than replacement of existing restorations were significantly more likely to recommend later treatment of primary caries. Conversely, dentists who recommended treatment of primary caries at an earlier stage were significantly more likely to recommend replacement of the entire restoration. Between-dentist agreement for primary caries treatment was better than between-dentist agreement for repair or replacement of existing restorations. These findings suggest consistency in how individual dentists approach the treatment of primary caries and existing restorations. However, substantial variation was found between dentists in their treatment decisions about the same teeth. 23852370 Dock3 attenuates neural cell death due to NMDA neurotoxicity and oxidative stress in a mouse model of normal tension glaucoma. Dedicator of cytokinesis 3 (Dock3), a new member of the guanine nucleotide exchange factors for the small GTPase Rac1, promotes axon regeneration following optic nerve injury. In the present study, we found that Dock3 directly binds to the intracellular C-terminus domain of NR2B, an N-methyl-D-aspartate (NMDA) receptor subunit. In transgenic mice overexpressing Dock3 (Dock3 Tg), NR2B expression in the retina was significantly decreased and NMDA-induced retinal degeneration was ameliorated. In addition, overexpression of Dock3 protected retinal ganglion cells (RGCs) from oxidative stress. We previously reported that glutamate/aspartate transporter (GLAST) is a major glutamate transporter in the retina, and RGC degeneration due to glutamate neurotoxicity and oxidative stress is observed in GLAST-deficient (KO) mice. In GLAST KO mice, the NR2B phosphorylation rate in the retina was significantly higher compared with Dock3 Tg:GLAST KO mice. Consistently, glaucomatous retinal degeneration was significantly improved in GLAST KO:Dock3 Tg mice compared with GLAST KO mice. These results suggest that Dock3 overexpression prevents glaucomatous retinal degeneration by suppressing both NR2B-mediated glutamate neurotoxicity and oxidative stress, and identifies Dock3 signaling as a potential therapeutic target for both neuroprotection and axonal regeneration. 23210621 Bioresorbable surface-adhered enzymatic microreactors based on physical hydrogels of poly(vinyl alcohol). Hydrogel biomaterials based on poly(vinyl alcohol), PVA, have an extensive history of biomedical applications, yet in their current form suffer from significant shortcomings, such as a lack of mechanism of biodegradation and poor opportunities in controlled drug release. We investigate physical hydrogels of PVA as surface-adhered materials and present biodegradable matrices equipped with innovative tools in substrate-mediated drug release. Toward the final goal, PVA chains with narrow polydispersities (1.1-1.2) and molecular weights of 5, 10, and 28 kDa are synthesized via controlled radical polymerization (RAFT). These molecular weights are shown to be suitably high to afford robust hydrogel matrices and at the same time suitably low to allow gradual erosion of the hydrogels with kinetics of degradation controlled via polymer macromolecular characteristics. For opportunities in controlled drug release, hydrogels are equipped with enzymatic cargo to achieve an in situ conversion of externally added prodrug into a final product, thus giving rise to surface-adhered enzymatic microreactors. Hydrogel-mediated enzymatic activity was investigated as a function of polymer molecular weight and concentration of solution taken for assembly of hydrogels. Taken together, we present, to the best of our knowledge, the first example of bioresorbable physical hydrogel based on PVA with engineered opportunities in substrate-mediated enzymatic activity and envisioned utility in surface-mediated drug delivery and tissue engineering. 23892628 GATA2 and Lmo2 control angiogenesis and lymphangiogenesis via direct transcriptional regulation of neuropilin-2. GATA-binding protein 2 (GATA2) and LIM domain only 2 (Lmo2) form common transcription complexes during hematopoietic differentiation. Here we show that these two transcription factors also play a key role in endothelial cells (EC) and lymphatic EC (LEC) function. Primary EC and tumor-associated blood vessels expressed GATA2 and Lmo2. VEGF-induced sprouting angiogenesis in both differentiating embryonic stem cells (embryoid bodies) and primary EC increased GATA2 and Lmo2 levels. Conversely, silencing of GATA2 and Lmo2 expression in primary EC inhibited VEGF-induced angiogenic activity, including EC migration and sprouting in vitro, two key steps of angiogenesis in vivo. This inhibition of EC function was associated with downregulated expression of neuropilin-2 (NRP2), a co-receptor of VEGFRs for VEGF, at the protein, mRNA and promoter levels. NRP2 overexpression partially rescued the impaired angiogenic sprouting in the GATA2/Lmo2 knockdown EC, confirming that GATA2 and Lmo2 mediated EC function, at least in part, by directly regulating NRP2 gene expression. Furthermore, it was found that primary LEC expressed GATA2 and Lmo2 as well. Silencing of GATA2 and Lmo2 expression in LEC inhibited VEGF-induced LEC sprouting, also in a NRP2-dependent manner. In conclusion, our results demonstrate that GATA2 and Lmo2 cooperatively regulate VEGF-induced angiogenesis and lymphangiogenesis via NRP2. 23891779 Association of FAM13A polymorphisms with COPD and COPD-related phenotypes in Han Chinese. Genome-wide association studies (GWAS) and integrative genomics approaches have demonstrated significant associations between chronic obstructive pulmonary disease (COPD) and FAM13A polymorphisms in non-Asian populations. The aim of this study was to investigate whether FAM13A polymorphisms would be associated with COPD susceptibility and COPD-related phenotypes in a Chinese Han population. Seven single nucleotide polymorphisms (SNPs) (rs7671167, rs10007590, rs2869966, rs2869967, rs2045517, rs1903003, rs6830970) in FAM13A gene were genotyped in a case-control study (680 COPD patients and 687 controls). Allele frequencies and genotype distributions were compared between patients and controls. To estimate the strength of association, odds ratios (OR) (with 95% CI) were calculated and potential confounding variables were tested by using logistic regression analysis. Statistical analysis revealed that SNP rs7671167 was associated with COPD in former smokers with adjusted P-value of 0.026. Five SNPs (rs7671167, rs2869966, rs2869967, rs2045517, and rs6830970) were associated with FEV1/FVC ratio in the entire cohort and rs6830970 was associated with FEV1/FVC ratio in COPD cases (P range 0.003-0.034). Borderline associations with FEV1/FVC ratio were found for rs2869966, rs2869967 and rs2045517 among cases (P=0.05). Six SNPs (rs7671167, rs2869966, rs2869967, rs2045517, rs1903003, rs6830970) showed strong linkage disequilibrium (r(2)≥0.9). Four major haplotypes were observed but showed no significant difference between case and control groups (P=0.2356, 0.1273, 0.6266 and 0.3006 respectively). The current study suggests that the FAM13A locus might be a contributor to COPD susceptibility in Chinese Han population. 23274302 Interference of a novel indolylmaleimide with microtubules induces mitotic arrest and apoptosis in human progenitor and cancer cells. Indolylmaleimides display a broad spectrum of biological activity and offer great opportunity to influence several aspects of cell fate, as proliferation and differentiation. In this study we describe the effect of PDA-66, a newly synthesised indolylmaleimide, showing a strong dose dependent anti-proliferative effect on immortalised human progenitor and cancer cells. We demonstrated a highly depolymerizing effect on in vitro tubulin assembly and conclude that PDA-66 acts as microtubule destabilising agent. In addition we found that PDA-66 induces mitotic arrest of cells in the G₂/M phase of the cell cycle. Subsequently cells undergo apoptosis, indicating the major mechanism of the anti-proliferative effect. To prove a potential anti-cancer activity of PDA-66 we examined the effect of PDA-66 on human SH-SY5Y neuroblastoma and A-459 lung cancer cells, showing a significant reduction in cancer cell proliferation in a dose dependent manner. Thus PDA-66 is a new anti-mitotic compound with an indole-core with the potential to be used for cancer therapy. 23897471 Structure determination of the functional domain interaction of a chimeric nonribosomal peptide synthetase from a challenging crystal with noncrystallographic translational symmetry. The nonribosomal peptide synthetases (NRPSs) are a family of modular proteins that contain multiple catalytic domains joined in a single protein. Together, these domains work to produce chemically diverse peptides, including compounds with antibiotic activity or that play a role in iron acquisition. Understanding the structural mechanisms that govern the domain interactions has been a long-standing goal. During NRPS synthesis, amino-acid substrates are loaded onto integrated carrier protein domains through the activity of NRPS adenylation domains. The structures of two adenylation domain-carrier protein domain complexes have recently been determined in an effort that required the use of a mechanism-based inhibitor to trap the domain interaction. Here, the continued analysis of these proteins is presented, including a higher resolution structure of an engineered di-domain protein containing the EntE adenylation domain fused with the carrier protein domain of its partner EntB. The protein crystallized in a novel space group in which molecular replacement and refinement were challenged by noncrystallographic pseudo-translational symmetry. The structure determination and how the molecular packing impacted the diffraction intensities are reported. Importantly, the structure illustrates that in this new crystal form the functional interface between the adenylation domain and the carrier protein domain remains the same as that observed previously. At a resolution that allows inclusion of water molecules, additional interactions are observed between the two protein domains and between the protein and its ligands. In particular, a highly solvated region that surrounds the carrier protein cofactor is described. 23876511 Diet-induced obesity drives negative mouse vein graft wall remodeling. The heightened inflammatory phenotype associated with obesity has been linked to the development of cardiovascular diseases. Short-term high-fat feeding induces a proinflammatory state that may impact the blood vessel wall. CD11c, a significantly increased dendritic cell biomarker during diet-induced obesity (DIO), may have a mechanistic role in this high-fat feeding effect. We hypothesized that the proinflammatory effect of short-term DIO accelerates vein bypass graft failure via CD11c-dependent mechanisms. Male 9-week-old DIO mice (n = 13, C57BL/6J recipients; n = 6, CD11c(-/-) recipients) and normal chow controls (n = 15, C57BL/6J recipients; n = 6, CD11c(-/-) recipients) underwent unilateral carotid interposition vein isografting (inferior vena cava from the same diet and genetic background donor), with a midgraft or outflow focal stenosis. Vein grafts were harvested at either 1 week (immunohistochemical staining for early CD11c expression) or 4 weeks later (morphometric analyses and CD11c evaluation). Despite a 40% larger body size, C57BL/6J DIO mice had 44% smaller poststenosis vein graft lumens (P = .03) than their controls via an acceleration of overall negative vein graft wall remodeling in the day-28 midgraft focal stenosis model but not in the outflow stenosis model. Higher CD11c expression occurred in DIO midgraft-stenosis vein graft walls, both at postoperative days 7 and 28. In contrast, with in vivo CD11c deficiency, DIO did not elicit this poststenotic negative remodeling but attenuated intimal hyperplasia. These findings highlight negative wall remodeling as a potential factor leading to vein graft failure and provide direct evidence that short-term dietary alterations in the mammalian metabolic milieu can have lasting implications related to acute vascular interventions. DIO induces negative mouse vein graft wall remodeling via CD11c-depedent pathways. 23952265 Testing the Substrate-Envelope Hypothesis with Designed Pairs of Compounds. Acquired resistance to therapeutic agents is a significant barrier to the development of clinically effective treatments for diseases in which evolution occurs on clinical time scales, frequently arising from target mutations. We previously reported a general strategy to design effective inhibitors for rapidly mutating enzyme targets, which we demonstrated for HIV-1 protease inhibition [Altman et al., J. Am. Chem. Soc. 130: 6099-6113 (2008)]. Specifically, we developed a computational inverse design procedure with the added constraint that designed inhibitors bind entirely inside the substrate envelope - a consensus volume occupied by natural substrates. The rationale for the substrate-envelope constraint is that it prevents designed inhibitors from making interactions beyond those required by substrates, and thus limits the availability of mutations tolerated by substrates but not by designed inhibitors. The strategy resulted in subnanomolar inhibitors that bind robustly across a clinically derived panel of drug-resistant variants. To further test the substrate-envelope hypothesis, here we have designed, synthesized, and assayed derivatives of our original compounds that are larger and extend outside the substrate envelope. Our designs resulted in pairs of compounds that are very similar to one another, but one respects and one violates the substrate envelope. The envelope-respecting inhibitor demonstrates robust binding across a panel of drug-resistant protease variants, whereas the envelope-violating one binds tightly to wild type but loses affinity to at least one variant. This study provides strong support for the substrate-envelope hypothesis as a design strategy for inhibitors that reduce susceptibility to resistance mutations. 23150427 In vitro cytochrome p450 activity decreases in children with high pediatric end-stage liver disease scores. To improve the modeling and simulation of pharmacokinetics in pediatric patients, research into developmental and disease-specific determinants is needed. This article describes the evaluation of the activity of in vitro cytochrome P450 (P450), an important enzyme family in drug metabolism, in children with hepatic dysfunction. The activity of six P450 isoforms (CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4) was evaluated in 31 patients with different pathologies, predominantly biliary atresia (n = 23). Hypervariable activity was observed for all the isoforms. Compared with average adult activity, low activity levels were seen for CYP1A2, 2C19, 2E1, and 3A4. For CYP2E1 and 3A4, a positive correlation between activity and abundance was observed. Age, comedication, and genotype could not be used as predictors for P450 activity in this patient population. In contrast, the pediatric end-stage liver disease score was negatively correlated with the ln(activity). This finding suggests a decrease in P450 activity with deteriorating hepatic function. Moreover, the activity of all isoforms was correlated, demonstrating a concomitant decrease of all isoforms in young patients with liver disease. To our knowledge, this is the first study to evaluate P450 activity in children with hepatic impairment. The presented data may provide support in the further optimization of a disease-specific model in this patient population. 23867901 Bladder perforation after TVT-Secur™ procedure: how secure is TVT-Secur™? A rare but challenging complication of midurethral tape procedures is perforation of the tape through the bladder wall. We saw three patients in whom unrecognized bladder perforation during TVT-Securâ„¢ procedures occurred. It took an average follow-up time of 11 months before the bladder perforations were identified by introital ultrasound. Complete excision of the mesh was achieved endoscopically (TURP resectoscope) and/or by traditional vaginal tape removal techniques. Following tape removal, there has been no recurrence of urinary tract infections, and the irritative voiding symptoms have resolved in all three cases. Bladder perforation after mini-sling procedures can be managed using a combined transurethral/vaginal approach. This technique is minimally invasive, safe, and successful. Careful introital ultrasound should be performed in patients presenting with new lower urinary tract symptoms after sling surgery to avoid delays in diagnosing bladder perforation. 23749153 Half-molar sodium lactate infusion to prevent intracranial hypertensive episodes in severe traumatic brain injured patients: a randomized controlled trial. Preventive treatments of traumatic intracranial hypertension are not yet established. We aimed to compare the efficiency of half-molar sodium lactate (SL) versus saline serum solutions in preventing episodes of raised intracranial pressure (ICP) in patients with severe traumatic brain injury (TBI). This was a double-blind, randomized controlled trial including 60 patients with severe TBI requiring ICP monitoring. Patients were randomly allocated to receive a 48-h continuous infusion at 0.5 ml/kg/h of either SL (SL group) or isotonic saline solution (control group) within the first 12 h post-trauma. Serial measurements of ICP, as well as fluid, sodium, and chloride balance were performed over the 48-h study period. The primary outcome was the number of raised ICP (≥20 mmHg) requiring a specific treatment. Raised ICP episodes were reduced in the SL group as compared to the control group within the 48-h study period: 23 versus 53 episodes, respectively (p < 0.05). The proportion of patients presenting raised ICP episodes was smaller in the SL group than in the saline group: 11 (36 %) versus 20 patients (66 %) (p < 0.05). Cumulative 48-h fluid and chloride balances were reduced in the SL group compared to the control group (both p < 0.01). A 48-h infusion of SL decreased the occurrence of raised ICP episodes in patients with severe TBI, while reducing fluid and chloride balances. These findings suggest that SL solution could be considered as an alternative treatment to prevent raised ICP following severe TBI. 23687352 Biomechanical factors and macrophages in plaque stability. Thin-cap fibroatheromas (TCFAs) or vulnerable atherosclerotic plaques are considered a high-risk phenotype for acute cardiovascular events. TCFAs are identified by a thin rupture-prone fibrous cap, a large necrotic core, and a high content of leucocytes. Atherogenesis is dependent upon complex patterns of blood flow. Slow-flowing blood imposing low shear stress on the arterial wall up-regulates inflammatory signalling in endothelial cells and leucocytes, and modulates microRNAs to promote inflammation and monocyte recruitment. Hence, low shear stress is believed to promote conditions conducive to vulnerable plaque development. In this review, we explore how biomechanical factors modulate macrophage phenotype and plaque stability. 23927291 Note: Absolute photoionization cross-section of the vinyl radical. This work measures the absolute photoionization cross-section of the vinyl radical (σvinyl(E)) between 8.1 and 11.0 eV. Two different methods were used to obtain absolute cross-section measurements: 193 nm photodissociation of methyl vinyl ketone (MVK) and 248 nm photodissociation of vinyl iodide (VI). The values of the photoionization cross-section for the vinyl radical using MVK, σvinyl(10.224 eV) = (6.1 ± 1.4) Mb and σvinyl(10.424 eV) = (8.3 ± 1.9) Mb, and using VI, σvinyl(10.013 eV) = (4.7 ± 1.1) Mb, σvinyl(10.513 eV) = (9.0 ± 2.1) Mb, and σvinyl(10.813 eV) = (12.1 ± 2.9) Mb, define a photoionization cross-section that is ∼1.7 times smaller than a previous determination of this value. 23142211 Recurrent major depressive disorder: Imbalance of neurokinin (NK)-1 and NK-2 receptor expression in monocytes. Increasing evidence suggests that tachykinins are involved in the control of different pathological conditions, including psychiatric disorders. In this study we evaluated the expression of NK(1) and NK(2) receptors (NK-1R and NK-2R), as well as the effects of substance P (SP) and neurokinin A (NKA), in monocytes isolated from 15 healthy subjects and 15 patients with recurrent major depressive disorder (RMDD), under stable antidepressant therapy. NK-1R expression in monocytes from RMDD patients was significantly decreased as compared to healthy subjects, whereas NK-2R expression was markedly increased. Both NK-1R and NK-2R expression correlated with HAM-D, but not HAM-A, score. SP, NKA and selective NK-1R and NK-2R agonists stimulated TNF-α release in monocytes of both groups, with a significant higher effect observed in RMDD. Moreover they induced NF-κB activation, which was reversed by selective NK-1R and NK-2R antagonists, so demonstrating that it was receptor-mediated. The occurrence of a profound alteration in NK receptor expression in RMDD is a novel finding that suggests NK-1R and NK-2R pathways as possible relevant players in major depressive disorder, so improving our understanding of the complex pathogenesis of the disease. 23553642 Synthesis, DNA-binding, Cytotoxicity, Photo Cleavage, Antimicrobial and Docking Studies of Ru(II) Polypyridyl Complexes. Three Ruthenium(II) polypyridine complexes, [Ru(phen)2(mipc)](2+)(1), [Ru(bpy)2(mipc)](2+) (2) and [Ru(dmb)2(mipc)](2+)(3) [mipc = 2-(6-methyl-3-(1H-imidazo[4, 5-f][1,10]-phenanthroline-2-yl)-4H-chromene-4-one, phen = 1,10-phenanthroline,bpy = 2, 2'bipyridine,dmb = 4, 4'-dimethyl-2, 2'-bipyridine] have been synthesized and characterized by elemental analysis, IR, UV-Vis, (1)H& (13)C NMR and mass spectra. The DNA-binding properties of the Ruthenium(II) complexes were investigated by spectrophotometric methods, viscosity measurements and light switch studies. These three complexes have been focused on photo activated cleavage studies with pBR-322 and antimicrobial studies. Experimental results indicate that the three complexes intercalate into DNA base pairs and follows the order of 1 > 2 > 3 respectively. Molecular docking studies also support the DNA interactions with complexes through hydrogen bonding and vander Waal's interactions. Cytotoxicity studies with Hela cell lines has been revealing about anti tumor activity of these complexes. 23865506 The impact of metabolic syndrome, recently diagnosed diabetes and hypertension on right ventricular remodeling. Is there difference between risk factors? Abstract The aim of this study was to compare the right ventricular (RV) structure and diastolic function between normotensive and non-diabetic subjects with metabolic syndrome (MS), and new diagnosed diabetic and hypertensive patients. Study included 89 normotensive and non-diabetic subjects with MS which was defined by the presence ≥3 ATP-NCEP-III criteria, 45 diabetic and 117 hypertensive patients, as well as 76 controls with no MS criteria, matched for age and sex. All subjects underwent laboratory blood tests and complete two-dimensional echocardiography including pulsed and tissue Doppler. RV free wall thickness was similar between MS and diabetic patients, but significantly lower than in hypertensive patients (4.6 ± 0.8 versus 4.3 ± 0.7 versus 4.9 ± 0.9 mm; p < 0.01). Tricuspid E/e' ratio was similar between observed groups (5.3 ± 1.2 versus 5.2 ± 1.1 versus 5.7 ± 1.2, p > 0.05). RV systolic function evaluated by tissue Doppler (st) was similar between MS and diabetic participants, but still worse than in hypertensive patients (13.1 ± 2.2 versus 13.5 ± 2.5 versus 12.5 ± 2.4, p < 0.05). Global RV function estimated by Tei index was similar among MS and diabetic patients, and most impaired in hypertensive patients (0.47 ± 0.09 versus 0.45 ± 0.08 versus 0.52 ± 0.1, p < 0.01). Increased fasting glucose level, abdominal obesity and hypertension were independent predictors of biventricular hypertrophy, diastolic dysfunction and global dysfunction in whole population. RV structure and function gradually deteriorated from diabetic patients, across MS subject, to hypertensive patients. Normotensive and non-diabetic subjects with MS had similar level of RV impairment as diabetic patients which emphasize the synergic effects of MS components on cardiac damage. 23958827 Delayed onset of vastii muscle activity in response to rapid postural perturbations following eccentric exercise: a mechanism that underpins knee pain after eccentric exercise? Appropriate timing of activity of the vastus medialis obliqus (VMO) and vastus lateralis (VL) muscles is a key factor for proper tracking of the patella in the trochlear groove during knee extension. This study investigates the relative timing of activation of the VMO and VL muscles during unexpected perturbations performed before and after eccentric exercise. Surface electromyography signals were recorded from the VMO and VL muscles of the right leg in 11 healthy men during rapid postural perturbations performed at baseline, immediately after eccentric exercise of the quadriceps, and at 24 and 48 h after exercise. Participants stood on a moveable platform during which eight randomised postural perturbations were performed (4 repetitions of 2 perturbation types: 8 cm forward slides, 8 cm backward slides). Before the eccentric exercise, the onset of VMO activity was significantly earlier than the VL muscle (average for both forward and backward perturbations: VMO 39.0±7.1 ms; VL 43.7±7.9 ms). However, the onset of VMO activity was significantly later compared with VL muscle immediately after eccentric exercise and this remained 24 and 48 h after eccentric exercise (average across all postexercise sessions and perturbation directions: VMO 72.3±11.1 ms; VL 56.0±8.2 ms; p<0.05). The onset of VMO-VL activity in response to rapid destabilising perturbations is altered immediately after eccentric exercise and during eccentric exercise-induced muscle soreness up to 48 h later. These observations may help explain the high prevalence of knee disorders after high intensity eccentric exercise. 23335392 Group I mGluRs evoke K-ATP current by intracellular Ca2+ mobilization in rat subthalamus neurons. We reported previously that Ca(2+) influx through N-methly-d-aspartate-gated channels evokes ATP-sensitive K(+) (K-ATP) currents in rat subthalamic nucleus (STN) neurons. By using whole-cell patch clamp recordings in brain slices, we investigated the ability of (RS)-3,5-dihydroxyphenylglycine (DHPG), a group I metabotropic glutamate receptor (mGluR) agonist, to evoke K-ATP currents. DHPG (20 µM) evoked outward current at -70 mV and was associated with a positive slope conductance of 2.7 nS. The sulfonylurea agent tolbutamide (100 µM) converted the positive slope to negative slope conductance, indicating mediation by K-ATP channels (ATP-sensitive K+ channels). Currents evoked by DHPG were significantly reduced by a combination of mGluR1 and mGluR5 negative allosteric modulators. DHPG-evoked outward current was blocked by cyclopiazonic acid and thapsigargin and mimicked by caffeine, suggesting mediation by release of intracellular Ca(2+). DHPG outward current was also blocked by ryanodine and 2-aminoethoxydiphenylborane, suggesting mediation by ryanodine- and inositol 1,4,5-triphosphate-sensitive Ca(2+) release. The nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester and inhibitors of protein kinase G activity also suppressed DHPG-induced outward current. Voltage recordings showed that tolbutamide prolonged depolarizing plateau potentials and increased the spontaneous firing rate of STN neurons recorded in the presence of DHPG. These results show that group I mGluR stimulation generates K-ATP current by a nitric oxide- and protein kinase G-dependent process that is mediated by release of Ca(2+) from intracellular stores. Because burst firing is linked to symptoms of Parkinson's disease, we suggest that K-ATP channels might provide a physiologically important inhibitory influence on STN neuronal activity. 22901022 Diversity and isolation of rare actinomycetes: an overview. A renewed interest in the development of new antimicrobial agents is urgently needed to combat the increasing number of antibiotic-resistant strains of pathogenic microorganisms. Actinomycetes continue to be the mainstream supplier of antibiotics used in industry. The likelihood of discovering a new compound with novel chemical structure can be increased with intensive efforts in isolating and screening of rare genera of microorganisms to include in natural-product-screening collections. An unexpected variety of rare actinomycetes is now being isolated worldwide from previously uninvestigated diverse natural habitats, using different selective isolation methods. These isolation efforts include methods to enhance growth (enrichment) of rare actinomycetes, and eliminate unwanted microorganisms (pretreatment). To speed up the strain isolation process, knowledge about the distribution of such unexploited groups of microorganisms must also be augmented. This is a summary of using these microorganisms as new potential biological resources, and a review of almost all of the selective isolation methods, including pretreatment and enrichment techniques that have been developed to date for the isolation of rare actinomycetes. 23784124 A Consortium of Aggregatibacter actinomycetemcomitans, Streptococcus parasanguinis, and Filifactor alocis Is Present in Sites Prior to Bone Loss in a Longitudinal Study of Localized Aggressive Periodontitis. Aggregatibacter actinomycetemcomitans-induced localized aggressive periodontitis (LAP) in African-American adolescents has been documented but is poorly understood. Two thousand fifty-eight adolescents aged 11 to 17 years were screened for their periodontal status and the presence of A. actinomycetemcomitans in their oral cavity. Seventy-one A. actinomycetemcomitans-negative and 63 A. actinomycetemcomitans-positive periodontally healthy subjects were enrolled, sampled, examined, and radiographed yearly for 3 years. Gingival and periodontal pocket depth and attachment levels were recorded. Disease presentation was characterized by bone loss (BL). Subgingival sites were sampled every 6 months to assess (i) the role of A. actinomycetemcomitans in BL and (ii) the association of A. actinomycetemcomitans and other microbes in their relationships to BL. Sixteen of 63 subjects with A. actinomycetemcomitans developed BL (the other 47 subjects with A. actinomycetemcomitans had no BL). No A. actinomycetemcomitans-negative subjects developed BL. Human oral microbe identification microarray (HOMIM) was used for subgingival microbial assessment. On a subject level, pooled data from A. actinomycetemcomitans-positive subjects who remained healthy had higher prevalences of Streptococcus and Actinomyces species, while A. actinomycetemcomitans-positive subjects with BL had higher prevalences of Parvimonas micra, Filifactor alocis, A. actinomycetemcomitans, and Peptostreptococcus sp. human oral taxon 113 (HOT-113). At vulnerable sites, A. actinomycetemcomitans, Streptococcus parasanguinis, and F. alocis levels were elevated prior to BL. In cases where the three-organism consortium (versus A. actinomycetemcomitans alone) was detected, the specificity for detecting sites of future BL increased from 62% to 99%, with a sensitivity of 89%. We conclude that detecting the presence of A. actinomycetemcomitans, S. parasanguinis, and F. alocis together indicates sites of future BL in LAP. A synergistic interaction of this consortium in LAP causation is possible and is the subject of ongoing research. 23631893 Who does well where? Exploring how self-rated health differs across diverse people and neighborhoods. This work establishes whether neighborhood disadvantage amplifies the impact of socioeconomic position (SEP) on a graded measure of self-rated health (SRH). SRH data were taken from 10,932 adults recruited across 200 Brisbane neighborhoods. After adjusting for demographics, those who lived in the most disadvantaged neighborhoods were more likely to report poor SRH than those living in the least disadvantaged neighborhoods (OR=2.67). Those with the lowest SEP and lived in the most advantaged neighborhoods had a similar probability of reporting excellent SRH as those with the highest SEP living in the most disadvantaged neighborhoods. This work highlights the importance of examining SEP and neighborhood-level disadvantage simultaneously when planning communities. 23192842 Theoretical studies on muti-hydroxyimides as highly efficient catalysts for aerobic oxidation. N,N-dihydroxypyromellitimide (NDHPI) and N,N',N''-trihydroxyisocyanuric acid (THICA) have been recently demonstrated to act as better carbon-radical-producing catalysts than the popular N-hydroxyphthalimide (NHPI). To gain a mature understanding of these particular catalysts, herein their geometrical, electronic, and thermochemical properties, as well as their catalytic activities, have been systemically investigated by a theoretical analysis. It appears that THICA, unlike NDHPI and NHPI, is unsuitable for solvent-free catalysis or catalysis in aprotic solvents due to its favorable coexistent planar conformer. Besides, the more remarkable catalytic efficiencies of NDHPI and THICA compared to NHPI can be ascribed to the lower barriers and the endothermicity in the H-abstraction processes by their radicals, especially by their multi-radicals which show stronger electron-withdrawing effects. Furthermore, the generation of THICA radicals would be much feasible at high temperature without co-catalysts. This study provides a new perspective towards the rational design of reactive hydroxyimide organocatalysts for industrial applications. 23728069 Microstructural changes of the corticospinal tract in idiopathic normal pressure hydrocephalus: a comparison of diffusion tensor and diffusional kurtosis imaging. The goals of this study were to examine the usefulness of diffusional kurtosis imaging (DKI) for assessing microstructural changes in the compressed corticospinal tract (CST) among patients with idiopathic normal pressure hydrocephalus (iNPH). Eleven patients with iNPH (mean age: 73.6 years, range: 65-84), who underwent 3-T magnetic resonance imaging, including DKI before surgery, were recruited. Six age-matched, healthy subjects (mean age: 69.8 years, range: 60-75) served as the control group. DKI and diffusion tensor imaging parameters were calculated and compared between the iNPH and the control groups using tract-specific analysis of the CST at the level of the lateral ventricle. Mean diffusional kurtosis (DK) and axial diffusion kurtosis were significantly lower in iNPH patients. However, apparent diffusion coefficient, fractional anisotropy, and axial eigenvalue (λ 1 ) were significantly higher in the iNPH group than in the control group. The mechanical pressure caused by ventricular enlargement in iNPH patients might induce formation of well-aligned fiber tracts and increased fiber density in the CST, resulting in decreased DK. DKI is able to depict both the altered microstructure and water molecule movement within neural axons and intra- or extracellular space. In addition, the investigated DKI parameters provide different information about white matter relative to conventional diffusional metrics for iNPH. 23871740 New silica nanostructure for the improved delivery of topical antibiotics used in the treatment of staphylococcal cutaneous infections. In this paper, we report the synthesis, characterization (FT-IR, XRD, BET, HR-TEM) and bioevaluation of a novel γ-aminobutiric acid/silica (noted GABA-SiO2 or γ-SiO2) hybrid nanostructure, for the improved release of topical antibiotics, used in the treatment of Staphylococcus aureus infections. GABA-SiO2 showed IR bands which were assigned to Si-O-Si (stretch mode). The XRD pattern showed a broad peak in the range of 18-30° (2θ), indicating an amorphous structure. Based on the BET analysis, estimations about surface area (438.14m(2)/g) and pore diameters (4.76nm) were done. TEM observation reveals that the prepared structure presented homogeneity and an average size of particles not exceeding 10nm. The prepared nanostructure has significantly improved the anti-staphylococcal activity of bacitracin and kanamycin sulfate, as demonstrated by the drastic decrease of the minimal inhibitory concentration of the respective antibiotics loaded in the GABA-SiO2 nanostructure. These results, correlated with the high biocompatibility of this porous structure, are highlighting the possibility of using this carrier for the local delivery of the antimicrobial substances in lower active doses, thus reducing their cytotoxicity and side-effects. 23851359 Switching of a coupled spin pair in a single-molecule junction. Single-molecule spintronics investigates electron transport through magnetic molecules that have an internal spin degree of freedom. To understand and control these individual molecules it is important to read their spin state. For unpaired spins, the Kondo effect has been observed as a low-temperature anomaly at small voltages. Here, we show that a coupled spin pair in a single magnetic molecule can be detected and that a bias voltage can be used to switch between two states of the molecule. In particular, we use the mechanically controlled break-junction technique to measure electronic transport through a single-molecule junction containing two coupled spin centres that are confined on two Co(2+) ions. Spin-orbit configuration interaction methods are used to calculate the combined spin system, where the ground state is found to be a pseudo-singlet and the first excitations behave as a pseudo-triplet. Experimentally, these states can be assigned to the absence and occurrence of a Kondo-like zero-bias anomaly in the low-temperature conductance data, respectively. By applying finite bias, we can repeatedly switch between the pseudo-singlet state and the pseudo-triplet state. 23535913 Targeted Expression in Zebrafish Primordial Germ Cells by Cre/loxP and Gal4/UAS Systems. In zebrafish and other vertebrates, primordial germ cells (PGCs) are a population of embryonic cells that give rise to sperm and eggs in adults. Any type of genetically manipulated lines have to be originated from the germ cells of the manipulated founders, thus it is of great importance to establish an effective technology for highly specific PGC-targeted gene manipulation in vertebrates. In the present study, we used the Cre/loxP recombinase system and Gal4/UAS transcription system for induction and regulation of mRFP (monomer red fluorescent protein) gene expression to achieve highly efficient PGC-targeted gene expression in zebrafish. First, we established two transgenic activator lines, Tg(kop:cre) and Tg(kop:KalTA4), to express the Cre recombinases and the Gal4 activator proteins in PGCs. Second, we generated two transgenic effector lines, Tg(kop:loxP-SV40-loxP-mRFP) and Tg(UAS:mRFP), which intrinsically showed transcriptional silence of mRFP. When Tg(kop:cre) females were crossed with Tg(kop:loxP-SV40-loxP-mRFP) males, the loxP flanked SV40 transcriptional stop sequence was 100 % removed from the germ cells of the transgenic hybrids. This led to massive production of PGC-specific mRFP transgenic line, Tg(kop:loxP-mRFP), from an mRFP silent transgenic line, Tg(kop:loxP-SV40-loxP-mRFP). When Tg(kop:KalTA4) females were crossed with Tg(UAS:mRFP) males, the hybrid embryos showed PGC specifically expressed mRFP from shield stage till 25 days post-fertilization (pf), indicating the high sensitivity, high efficiency, and long-lasting effect of the Gal4/UAS system. Real-time PCR analysis showed that the transcriptional amplification efficiency of the Gal4/UAS system in PGCs can be about 300 times higher than in 1-day-pf embryos. More importantly, when the UAS:mRFP-nos1 construct was directly injected into the Tg(kop:KalTA4) embryos, it was possible to specifically label the PGCs with high sensitivity, efficiency, and persistence. Therefore, we have established two targeted gene expression platforms in zebrafish PGCs, which allows us to further manipulate the PGCs of zebrafish at different levels. 23775537 Foveal and peripheral fields of vision influences perceptual skill in anticipating opponents' attacking position in volleyball. The importance of perceptual-cognitive expertise in sport has been repeatedly demonstrated. In this study we examined the role of different sources of visual information (i.e., foveal versus peripheral) in anticipating volleyball attack positions. Expert (n = 11), advanced (n = 13) and novice (n = 16) players completed an anticipation task that involved predicting the location of volleyball attacks. Video clips of volleyball attacks (n = 72) were spatially and temporally occluded to provide varying amounts of information to the participant. In addition, participants viewed the attacks under three visual conditions: full vision, foveal vision only, and peripheral vision only. Analysis of variance revealed significant between group differences in prediction accuracy with higher skilled players performing better than lower skilled players. Additionally, we found significant differences between temporal and spatial occlusion conditions. Both of those factors interacted separately, but not combined with expertise. Importantly, for experts the sum of both fields of vision was superior to either source in isolation. Our results suggest different sources of visual information work collectively to facilitate expert anticipation in time-constrained sports and reinforce the complexity of expert perception. 23953177 Evaluation of risk factors for cardiovascular diseases among Saudi diabetic patients attending primary health care service. Cardiovascular disease is currently the primary cause of morbidity and mortality in patients with diabetes. For each risk factor present, the risk of cardiovascular death is about three times greater in people with diabetes than people without diabetes. To determine the risk factors for cardiovascular disease among patients with type 2 diabetes. To stratify the patients into risk categories to develop coronary arteries disease (CAD) based on the British Joint Societies risk chart. To assess the awareness and implementation of the risk assessment charts by primary care physicians Cross sectional study was designed. Sixty six (66 patients) diabetic patients were selected randomly by simple selection, from them 29 were males and 37 were females. Patients' medical records were reviewed. The following parameters were detected; blood pressure, lipid profile, weight, height, smoking and degree of glycemic control. A questionnaire was designed and distributed to randomly selected physicians working in primary health care assessed their awareness and implementation of risk assessment charts was done. Uncontrolled diabetes was found to be the common risk factor followed by uncontrolled lipid profile, obesity, uncontrolled systolic blood pressure and smoking. Seven percent (7%) of male group felled in highest risk group in comparison with 1% in female group (P<0.05), while 31% in male group felled in mild risk group in comparison with 90% in female group (P<0.05). Sixty two percent (62%) in male group felled in high risk group in comparison with 9% in female group (P<0.05). Criteria for ranking in risk class differed between male and female group. Forty one physicians were contacted and received the questionnaire. Twenty nine (70.7%) physicians were responded to the questionnaire. Twenty two (22) informed that they were aware about risk assessment score systems. Fourteen (14) physicians informed that they were aware about the BJSs charts but only two informed that they had used it to assess their patients. Clustering of multi risk factors is a serious event which may raise the risk category of diabetic patients. For each risk category the risk factors may differed between male and female patients. More studies are recommended to study distribution of risk factors between male and female diabetic patients. Attention should be directed toward raising the awareness about the risk assessment scoring system and encouraging physicians to use it. 23896941 Prostatic biopsies in selected men aged 75 years and older guide key clinical management decisions. Increasing life expectancy and PSA testing has increased the number of men over the age of seventy-five presenting for investigation of potential prostate malignancies. Prostatic biopsies provide diagnostic information; however, they are invasive and may not alter management decisions. Therefore, this study aimed to investigate whether prostate biopsies in this age group were justified. All men aged 75 years and older who underwent prostatic biopsies between January 2010 and November 2011 at Bedford Hospital were identified and the indication for the biopsies, histopathological results and subsequent management plan investigated. One hundred and thirty-eight (138) prostatic biopsies were undertaken and malignancies identified in 60/138 (43 %) cases. Prebiopsy PSA and examination findings had a poor positive predictive value of 54 %. Fifty-five out of sixty (92 %) cancers were classified as high or medium risk disease with 30/60 (50 %) patients commencing radiotherapy treatment with curative intent. In selected patients aged 75 years or over, prostatic biopsies provide important diagnostic information which directly impacts on clinical decisions, supporting their use in this age group. 23449628 Overdosage of Hand2 causes limb and heart defects in the human chromosomal disorder partial trisomy distal 4q. Partial trisomy distal 4q (denoted 4q+) is a human chromosomal disorder caused by duplication of the distal end of the long arm of chromosome 4 (Chr4). This disorder manifests typical phenotypes, including craniofacial, renal, heart and thumb developmental defects. Although these clinical features are likely caused by a dosage imbalance in the gene network involving the trisomic region, the causative gene or genes and the molecular bases are largely unknown. Here, we report mouse Recombination-induced mutation 4 (Rim4) as a model animal of 4q+. The Rim4 genome contains an insertion of a 6.5 Mb fragment from mouse chromosome 8 into chromosome 6. This insertion fragment contains 17 genes, including Hand2, that encode the basic helix-loop-helix transcription factor and is syntenic to the distal end of human Chr4, 4q32.3 to 4q34.1, which is responsible for 4q+. A comparison of phenotypes between patients with Rim4 and 4q+ revealed that Rim4 shows direct parallels with many phenotypes of 4q+ such as craniofacial, heart, cervical vertebra and limb deformities. Rebalancing the gene dosage by a genetic cross with Hand2 knockout mice ameliorated symptoms of the heart and limb deformities of Rim4. Conversely, an increase in copy number of Hand2 in wild-type mice recaptures the heart and limb deformities of Rim4. Our results collectively demonstrate that overdosage of Hand2 is a major cause for at least the limb and heart phenotypes of 4q+ and that mouse Rim4 provides a unique animal model for understanding the molecular bases underlying the complex phenotypes of 4q+. 23891097 High NOTCH activity induces radiation resistance in non small cell lung cancer. Patients with advanced NSCLC have survival rates <15%. The NOTCH pathway plays an important role during lung development and physiology but is often deregulated in lung cancer, making it a potential therapeutic target. We investigated NOTCH signaling in NSCLC and hypothesized that high NOTCH activity contributes to radiation resistance. NOTCH signaling in NSCLC patient samples was investigated using quantitative RT-PCR. H460 NSCLC cells with either high or blocked NOTCH activity were generated and their radiation sensitivity monitored using clonogenic assays. In vivo, xenograft tumors were irradiated and response assessed using growth delay. Microenvironmental parameters were analyzed by immunohistochemistry. Patients with high NOTCH activity in tumors showed significantly worse disease-free survival. In vitro, NOTCH activity did not affect the proliferation or intrinsic radiosensitivity of NSCLC cells. In contrast, xenografts with blocked NOTCH activity grew slower than wild type tumors. Tumors with high NOTCH activity grew significantly faster, were more hypoxic and showed a radioresistant phenotype. We demonstrate an important role for NOTCH in tumor growth and correlate high NOTCH activity with poor prognosis and radioresistance. Blocking NOTCH activity in NSCLC might be a promising intervention to improve outcome after radiotherapy. 23727173 Specific frequency band of amplitude low-frequency fluctuation predicts Parkinson's disease. Resting-state functional magnetic resonance imaging (RS-fMRI) has been considered for development as a biomarker and analytical tool for evaluation of Parkinson's disease (PD). Here we utilized analysis of the amplitude low-frequency fluctuations (ALFF) to determine changes in intrinsic neural oscillations in 72 patients with PD. Two different frequency bands (slow-5: 0.01-0.027Hz; slow-4: 0.027-0.073Hz) were analyzed. In the slow-5 band, PD patients compared with controls had increased ALFF values mainly in the caudate and several temporal regions, as well as decreased ALFF values in the cerebellum and the parieto-temporo-occipital cortex. Additionally, in the slow-4 band, PD patients relative to controls exhibited reduced ALFF value in the thalamus, cerebellum, and several occipital regions. Together, our data demonstrate that PD patients have widespread abnormal intrinsic neural oscillations in the corticostriatal network in line with the pathophysiology of PD, and further suggest that the abnormalities are dependent on specific frequency bands. Thus, frequency domain analyses of resting state BOLD signals may provide a useful means to study the pathophysiology of PD and the physiology of the brain's dopaminergic pathways. 23261866 Psychostimulant pharmacological profile of paraxanthine, the main metabolite of caffeine in humans. Caffeine induces locomotor activation by its ability to block adenosine receptors. Caffeine is metabolized to several methylxanthines, with paraxanthine being the main metabolite in humans. In this study we show that in rats paraxanthine has a stronger locomotor activating effect than caffeine or the two other main metabolites of caffeine, theophylline and theobromine. As previously described for caffeine, the locomotor activating doses of paraxanthine more efficiently counteract the locomotor depressant effects of an adenosine A(1) than an adenosine A(2A) receptor agonist. In drug discrimination experiments in rats trained to discriminate a maximal locomotor activating dose of caffeine, paraxanthine, unlike theophylline, generalized poorly to caffeine suggesting the existence of additional mechanisms other than adenosine antagonism in the behavioral effects of paraxanthine. Pretreatment with the nitric oxide inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) reduced the locomotor activating effects of paraxanthine, but not caffeine. On the other hand, pretreatment with the selective cGMP-preferring phosphodiesterase PDE9 inhibitor BAY 73-6691, increased locomotor activity induced by caffeine, but not paraxanthine. Ex vivo experiments demonstrated that paraxanthine, but not caffeine, can induce cGMP accumulation in the rat striatum. Finally, in vivo microdialysis experiments showed that paraxanthine, but not caffeine, significantly increases extracellular levels of dopamine in the dorsolateral striatum, which was blocked by l-NAME. These findings indicate that inhibition of cGMP-preferring PDE is involved in the locomotor activating effects of the acute administration of paraxanthine. The present results demonstrate a unique psychostimulant profile of paraxanthine, which might contribute to the reinforcing effects of caffeine in humans. 23715241 Exploiting electron storage in TiO2 nanoparticles for dark reduction of As(V) by accumulated electrons. UV irradiation of an ethanolic sol of TiO2 nanoparticles produces a trapped Ti(III) centre and a noticeable Burstein shift. Direct evidence that the accumulated charges can drive the otherwise forbidden reduction of As(V) by conduction band electrons is presented. 23835789 The Presentation, Recognition and Management of Bipolar Depression in Primary Care. Bipolar disorder is a mood disorder characterized by episodes of major depression and mania or hypomania. Most patients experience chronic symptoms of bipolar disorder approximately half of the time, most commonly subsyndromal depressive symptoms or a full depressive episode with concurrent manic symptoms. Consequently, patients with bipolar depression are often misdiagnosed with major depressive disorder. Individual patient characteristics and population screening tools may be helpful in improving recognition of bipolar depression in primary care. Health risk behaviors including tobacco use, sedentary activity level and weight gain are highly prevalent in patients with bipolar disorder, as are the comorbid chronic diseases such as diabetes mellitus and cardiovascular disease. Patients with bipolar illness have about an eight-fold higher risk of suicide and a two-fold increased risk of death from chronic medical illnesses. Recognition of bipolar depression and its associated health risk behaviors and chronic medical problems can lead to the use of appropriate interventions for patients with bipolar disorder, which differ in important ways from the treatments used for major depressive disorder. The above topics are reviewed in detail in this article. 23859470 Genome damage in testicular seminoma patients seven years after radiotherapy. Purpose: Testicular seminoma cancer incidence has significantly increased over the last few decades, and although it is successfully treated by radiotherapy, long-term health risks are still unclear. The aim of the study was to show long-term genome damage in patients with seminoma after radiotherapy. Materials and methods: Chromosome aberration (CA) and micronucleus (MN) assays seven years after radiotherapy with a total dose of 25 Gy were conducted in 10 testicular seminoma patients aged 23-49 years and results were compared with 10 healthy control subjects matched for age and smoking status. Results: Although mean CA frequency did not deviate from control values, significantly increased frequencies of dicentrics, double minutes, and ring chromosomes were detected in seminoma patients. MN frequency in binuclear lymphocytes of patients was similar to controls (4.60/1000 vs. 5.82/1000, respectively). Significantly higher MN frequency was detected in mononuclear lymphocytes of patients than in controls (2.55/1000 vs. 0.73/1000, respectively). Average percentage of centromere-positive MN was 62.6% in seminoma patients. Conclusion: This study shows the persistence of unstable CA in seminoma patients seven years after radiotherapy and the relevance of long-term follow up. MN frequency in mononuclear lymphocytes was shown to be relevant biomarker of long-term genome damage. 23910511 Hemoglobin A1C as a Marker for Surgical Risk in Diabetic Patients Undergoing Total Joint Arthroplasty. Diabetes is a risk factor for complications following total joint arthroplasty (TJA). This retrospective cohort study of 6088 diabetic patients from the Veterans Health Administration (VHA) undergoing TJA sought to determine if hemoglobin A1c, an accessible and objective lab value, has utility as a predictor of risk of complications in TJA after controlling for demographic, surgical, and medical center effects, and to evaluate the benefits and risks of alternative thresholds. Analysis of the functional relationship between hemoglobin A1c and complications revealed that the risk linearly increases through, rather than surging at, the threshold of 7%. Before delaying surgery to achieve better diabetic control, surgeons and patients should weigh the estimated risks of TJA against the potential benefits. 23494241 Recursive organizer (ROR): an analytic framework for sequence-based association analysis. The advent of next-generation sequencing technologies affords the ability to sequence thousands of subjects cost-effectively, and is revolutionizing the landscape of genetic research. With the evolving genotyping/sequencing technologies, it is not unrealistic to expect that we will soon obtain a pair of diploidic fully phased genome sequences from each subject in the near future. Here, in light of this potential, we propose an analytic framework called, recursive organizer (ROR), which recursively groups sequence variants based upon sequence similarities and their empirical disease associations, into fewer and potentially more interpretable super sequence variants (SSV). As an illustration, we applied ROR to assess an association between HLA-DRB1 and type 1 diabetes (T1D), discovering SSVs of HLA-DRB1 with sequence data from the Wellcome Trust Case Control Consortium. Specifically, ROR reduces 36 observed unique HLA-DRB1 sequences into 8 SSVs that empirically associate with T1D, a fourfold reduction of sequence complexity. Using HLA-DRB1 data from Type 1 Diabetes Genetics Consortium as cases and data from Fred Hutchinson Cancer Research Center as controls, we are able to validate associations of these SSVs with T1D. Further, SSVs consist of nine nucleotides, and each associates with its corresponding amino acids. Detailed examination of these selected amino acids reveals their potential functional roles in protein structures and possible implication to the mechanism of T1D. 23890793 Change in primary midwife-led care in the Netherlands in 2000-2008: A descriptive study of caesarean sections and other interventions among 789,795 low risk births. to study whether an increase in intrapartum referrals in primary midwife-led care births in the Netherlands is accompanied by an increase in caesarean sections. nationwide descriptive study. the Netherlands Perinatal Registry. 789,795 births of nine year cohorts of women with low risk pregnancies in primary midwife-led care at the onset of labour between 2000 and 2008. primary outcome is the caesarean section rate. Vaginal instrumental delivery, augmentation with oxytocin, and pharmacological pain relief are secondary outcomes. Trends in outcomes are described. We used logistic regression to explore whether changes in the planned place of birth and other maternal characteristics influenced the caesarean section rate. the caesarean section rate did not increase and was 5.5 per cent (range 4.9-6.3 per cent) for nulliparous women, and 1.0 per cent (range 0.8-1.1 per cent) for multiparous women. After controlling for the decline in planned home births and other maternal characteristics no increase in the caesarean section rate was found. The vaginal instrumental birth rate showed no increase, and was 18.1 per cent (range 17.9-18.5 per cent) for nulliparous women and 1.5 per cent (range 1.4-1.7 per cent) for multiparous women. Augmentation of labour and/or pharmacological pain relief increased from 24.0 to 38.8 per cent for nulliparous women, and from 5.4 to 10.0 per cent for multiparous women. the rise in intrapartum referrals was not accompanied by an increase in caesarean section rate over the period 2000-2008. Despite a considerable rise in the use of pain relief and augmentation, the rate of spontaneous vaginal birth remained high for low risk women who started labour in primary midwife-led care. the current strict role division between primary care midwives and the obstetrician-led team increasingly results in a change in care provider during labour. In a more integrated care system, more women can receive continuous support of labour from their own primary care midwife, as long as only supportive interventions are needed. 23852042 Gold peroxide complexes and the conversion of hydroperoxides into gold hydrides by successive oxygen-transfer reactions. Gold catalysts are widely studied in chemical and electrochemical oxidation processes. Computational modelling has suggested the participation of Au-OO-Au, Au-OOH or Au-OH surface species, attached to gold in various oxidation states. However, no structural information was available as isolable gold peroxo and hydroperoxo compounds were unknown. Here we report the syntheses, structures and reactions of a series of gold(III) peroxides, hydroperoxides and alkylperoxides. The Au-O bond energy in peroxides is weaker than in oxides and hydroxides; however, the Au-OH bond is also weaker than Au-H. Consequently Au-OH compounds are capable of oxygen-transfer generating gold hydrides, a key reaction in a water splitting cycle and an example that gold can react in a way that other metals cannot. For the first time it has become possible to establish a direct connection from peroxides to hydrides: Au-OO-Au→Au-OOH→Au-OH→Au-H, via successive oxygen-transfer events. 23924758 Fetal growth restriction promotes physical inactivity and obesity in female mice. Background:Environmental exposures during critical periods of prenatal and early postnatal life affect the development of mammalian body weight regulatory mechanisms, influencing lifelong risk of obesity. The specific biologic processes that mediate the persistence of such effects, however, remain poorly understood.Objective:The objectives were to determine the developmental timing and physiological basis of the obesity-promoting effect previously reported in offspring of obese agouti viable yellow (A(vy)/a) mothers.Design:Newborn offspring of obese agouti viable yellow (A(vy)/a) and lean (a/a) mothers were cross-fostered shortly after birth to study separately the effects of in utero or suckling-period exposure to A(vy)/a dams. Body composition, food intake, physical activity, and energy expenditure were measured in offspring shortly after weaning and in adulthood.Results:Offspring of obese A(vy)/a dams paradoxically experienced fetal growth restriction, which was followed by adult-onset obesity specifically in females. Our main analyses focused on wild type (a/a) offspring, because a subset of adult A(vy)/a offspring contracted a kidney disease resembling diabetic nephropathy. Detailed physiological characterization demonstrated that, both shortly after weaning and in adulthood, female wild type mice born to A(vy)/a mothers are not hyperphagic, but have reduced physical activity and energy expenditure. No such coordinated changes were detected in male offspring. Mediational regression analysis of our longitudinal data supported a causal pathway in which fetal growth restriction persistently reduces physical activity, leading to adult obesity.Conclusions:Our data are consistent with several recent human epidemiologic studies showing female-specific effects of perinatal nutritional restriction on later obesity, and provide the novel mechanistic insight that this may occur via permanent and sex-specific changes in one's inherent propensity for physical activity.International Journal of Obesity accepted article preview online, 8 August 2013. doi:10.1038/ijo.2013.146. 23426337 Laparoscopic Surgery for Stage 0/I Rectal Carcinoma: Short-term Outcomes of a Single-Arm Phase II Trial. To examine the technical and oncological feasibility of laparoscopic surgery for rectal carcinoma, we conducted a single-arm phase II trial to evaluate laparoscopic surgery for stage 0/I rectal carcinoma, and short-term surgical outcomes were evaluated. Accredited surgeons from 43 institutions in Japan participated in the study. Eligibility criteria included histologically proven rectal carcinoma; clinical stage 0/I; tumor size 8 cm or smaller; patient age 20 to 75 years; no bowel obstruction; and written informed consent. Patients were registered preoperatively. The planned sample size was 490. Surgical outcomes were evaluated. A total of 495 patients were registered between February 2008 and August 2010. Five patients were ineligible after registration. Conversion to open surgery was needed for 8 (1.6%) patients. Sphincter-preserving procedures were performed in 477 (97%) patients. Median operative time was 270 minutes, and median blood loss was 28 mL. Postoperative median intervals until liquid and solid intake were 1 and 3 days, respectively, and the median postoperative hospital stay was 12 days. The positive resection margin rate was 0.4% (2/490), and 68.6% (336/490) of the patients were graded stage 0/I. There were no perioperative mortalities. Twenty-four intraoperative and 160 postoperative complications occurred, and the morbidity rate was 23.9% (117/490). The anastomotic leakage rate in patients who underwent anterior resection was 8.3% (33/400), and that in patients who underwent intersphincteric resection was 9.1% (7/77). Nineteen (3.9%) patients underwent reoperation. Technically, laparoscopic surgery can be used for safe and radical resection of clinical stage 0/I rectal carcinoma. (ClinicalTrials.gov No. NCT00635466.). 23665692 In situ ethyl ester production from wet algal biomass under microwave-mediated supercritical ethanol conditions. An in situ transesterification approach was demonstrated for converting lipid-rich wet algae (Nannochloropsis salina) into fatty acid ethyl esters (FAEE) under microwave-mediated supercritical ethanol conditions, while preserving the nutrients and other valuable components in the algae. This single-step process can simultaneously and effectively extract the lipids from wet algae and transesterify them into crude biodiesel. Experimental runs were designed to optimize the process parameters and to evaluate their effects on algal biodiesel yield. The algal biomass characterization and algal biodiesel analysis were carried out by using various analytical instruments such as FTIR, SEM-EDS, TLC, GC-MS and transmission electron microscopy (TEM). The thermogravimetric analysis (TGA) under nitrogen and oxygen environments was also performed to examine the thermal and oxidative stability of ethyl esters produced from wet algae. This simple in situ transesterification process using a green solvent and catalyst-free approach can be a potentially efficient route for algal biodiesel production. 23968549 Trimetallic Borohydride Li3MZn5(BH4)15 (M = Mg, Mn) Containing Two Weakly Interconnected Frameworks. The compounds, Li3MZn5(BH4)15, M = Mg and Mn, represent the first trimetallic borohydrides and are also new cationic solid solutions. These materials were prepared by mechanochemical synthesis from LiBH4, MCl2 or M(BH4)2, and ZnCl2. The compounds are isostructural, and their crystal structure was characterized by in situ synchrotron radiation powder X-ray and neutron diffraction and DFT calculations. While diffraction provides an average view of the structure as hexagonal (a = 15.371(3), c = 8.586(2) Å, space group P63/mcm for Mg-compound at room temperature), the DFT optimization of locally ordered models suggests a related ortho-hexagonal cell. Ordered models that maximize Mg-Mg separation have the lowest DFT energy, suggesting that the hexagonal structure seen by diffraction is a superposition of three such orthorhombic structures in three orientations along the hexagonal c-axis. No conclusion about the coherent length of the orthorhombic structure can be however done. The framework in Li3MZn5(BH4)15 is of a new type. It contains channels built from face-sharing (BH4)6 octahedra. While X-ray and neutron powder diffraction preferentially localize lithium in the center of the octahedra, thus resulting in two weakly interconnected frameworks of a new type, the DFT calculations clearly favor lithium inside the shared triangular faces, leading to two interpenetrated mco-nets (mco-c type) with the basic tile being built from three tfa tiles, which is the framework type of the related bimetallic LiZn2(BH4)5. The new borohydrides Li3MZn5(BH4)15 are potentially interesting as solid-state electrolytes, if the lithium mobility within the octahedral channels is improved by disordering the site via heterovalent substitution. From a hydrogen storage point of view, their application seems to be limited as the compounds decompose to three known metal borohydrides. 23889264 Clinical evaluation of propofol as sedative for endotracheal intubation in neonates. To determine the effects of propofol for endotracheal intubation in neonates in daily clinical practice. We prospectively studied the pharmacodynamic effects of intravenous propofol administration in neonates who needed endotracheal intubation at the neonatal intensive care unit. Propofol was used for 62 intubations in neonates with postmenstrual ages ranging from 24 + 3 weeks to 44 + 5 weeks and bodyweights ranging from 520 to 4380 g. A 2 mg/kg bodyweight propofol starting dose was sufficient in 37% of patients; additional propofol was needed less often on the first postnatal day. The mean amount of propofol used was 3.3 (±1.2) mg/kg. The success rate of intubation depended on the experience of the physician and was related to the total administered amount of propofol. Hypotension occurred in 39% of patients and occurred more often at the first postnatal day. In 15% of procedures, propofol mono therapy was insufficient. This study shows that high doses of propofol are needed to reach effective sedation in neonates for intubation, with hypotension as a side effect in a considerable percentage of patients. Further research in newborn patients needs to identify optimal propofol doses and risk factors for hypotension. 23763412 A Sexual Risk and Stress Reduction Intervention Designed for HIV-Positive Bisexual African American Men With Childhood Sexual Abuse Histories. Objectives. HIV transmission risk is high among men who have sex with men and women (MSMW), and it is further heightened by a history of childhood sexual abuse (CSA) and current traumatic stress or depression. Yet, traumatic stress is rarely addressed in HIV interventions. We tested a stress-focused sexual risk reduction intervention for African American MSMW with CSA histories. Methods. This randomized controlled trial compared a stress-focused sexual risk reduction intervention with a general health promotion intervention. Sexual risk behaviors, psychological symptoms, stress biomarkers (urinary cortisol and catecholamines), and neopterin (an indicator of HIV progression) were assessed at baseline and at 3- and 6-month follow-ups. Results. Both interventions decreased and sustained reductions in sexual risk and psychological symptoms. The stress-focused intervention was more efficacious than the general health promotion intervention in decreasing unprotected anal insertive sex and reducing depression symptoms. Despite randomization, baseline group differences in CSA severity, psychological symptoms, and biomarkers were found and linked to subsequent intervention outcomes. Conclusions. Although interventions designed specifically for HIV-positive African American MSMW can lead to improvements in health outcomes, future research is needed to examine factors that influence intervention effects. 23576196 Synovial chondrosarcoma arising in synovial chondromatosis of the temporomandibular joint. Synovial chondromatosis of the temporomandibular joint is rare. Even less commonly documented is the progression of synovial chondromatosis to a synovial chondrosarcoma. The aim of this paper is to present only the third case of synovial chondrosarcoma of the temporomandibular joint. Distinction between these two entities by histology alone is extremely difficult and even though it is advised that the definitive diagnosis should be based on clinical, radiographic and histological evidence, this has proved not to be so simple. The patient, a 63 year old female presented with a swelling associated with her left temporomandibular joint. CT and MRI scans confirmed the presence of a periauricular chondroid mass. Fine needle aspiration biopsy revealed an atypical chondroid lesion that was supicious for a chondrosarcoma. The left temporomandibular joint and surrounding tissues were resected after further imaging and extensive clinical, radiological and cytologic consultations. A diagnosis of synovial chondrosarcoma arising in synovial chondromatosis was made. 23832543 Overexpression of ILK1 in breast cancer associates with poor prognosis. Integrin-linked kinase 1 (ILK1), a member of the serine/threonine kinases, has been demonstrated to be associated with numerous biological and pathological processes. However, the role of ILK1 in breast cancer has not been thoroughly elucidated. The purpose of this study was to assess ILK1 expression and to explore its contribution to breast cancer. The ILK1 mRNA expression was measured by real-time quantitative reverse transcriptase-polymerase chain reaction. In addition, ILK1 expression was analyzed by immunohistochemistry in 163 clinicopathologically characterized breast cancer cases. The relationship between ILK1 expression and clinicopathological features was analyzed by appropriate statistics. Kaplan-Meier analysis and Cox proportional hazard regression models were used to investigate the correlation between ILK1 expression and prognosis of breast cancer patients. The relative mRNA expression of ILK1 was significantly higher in breast cancer tissues than in adjacent noncancerous tissues (P < 0.001). In addition, ILK1 expression was significantly correlated with tumor size (P = 0.016), grade (P = 0.024), stage (P = 0.029), lymph node metastases (P = 0.007), and estrogen receptor status (P = 0.002). Kaplan-Meier analysis indicated that patients with high ILK1 expression had poor overall survival (P < 0.001). Multivariate analysis showed that high ILK1 expression was an independent predictor of overall survival. In conclusion, our data suggest for the first time that the increased expression of ILK1 in breast cancer is associated significantly with aggressive progression and poor prognosis. ILK1 may be an important molecular marker for predicting the carcinogenesis, progression, and prognosis of breast cancer. 23883508 A look at the thoracic surgery workforce in Canada: how demographics and scope of practice may impact future workforce needs. The purpose of this study is to describe the demographics, training and practice characteristics of physicians performing thoracic surgery across Canada to better assess workforce needs. We developed a questionnaire using a modified Delphi process to generate questionnaire items. The questionnaire was administered to all Canadian thoracic surgeons via email (n = 102) or mail (n = 35). In all, 97 surgeons completed the survey (71% response rate). The mean age of respondents was 47.7 (standard deviation 9.1) years; 10.3% were older than 60. Ninety respondents (88.7%) were men, 95 (81.1%) practised in English and 93 (76%) were born in Canada. Most (90.4%) had a medical school affiliation, with an equal proportion practising in community or university teaching hospitals. Only 18% of respondents reported working fewer than 60 hours per week, and 34% were on call more than 1 in 3. Three-quarters of work hours were devoted to clinical care, with the remaining time split among research, administration and teaching. Malignant lung disease accounted for 61.2% of practice time, with the remaining time equally split between benign and malignant thoracic diseases. Preoperative testing (49.4%) and insufficient operating time (49.5%) were the most common factors delaying delivery of care. More than 80% of respondents reported being satisfied with their careers, with 62.1% planning on retiring after age 60. This survey characterizes Canadian thoracic surgeons by providing specific demographic, satisfaction and scope of practice information. Despite challenges in obtaining adequate resources for providing timely care, job satisfaction remains high, with a balanced workforce supply and demand anticipated for the foreseeable future. Abstract available from the publisher. 23836071 Challenges of Spine Surgery in Patients With Chondrodysplasia Punctata. Chondrodysplasia punctata (CDP) is a common manifestation of an etiologically heterogenous group of disorders. There is very little data regarding the development and management of spinal deformity in patients with CDP. The purpose of this study was to present a multicenter series of CDP, to describe the surgical outcomes of spinal deformities in CDP patients and to emphasize important considerations that may influence choice of surgical treatment of spinal deformity in this patient population. The medical records and spinal radiographs of patients with the diagnosis of CDP followed in 2 centers between 1975 and 2011 were retrospectively reviewed. Epiphyseal stippling was present on radiographs in all patients who fulfilled the clinical criteria. Among the 17 patients who were diagnosed with CDP, 13 had spinal deformities. The mean age at diagnosis of spinal deformity was 14.6 months (range, 1 wk to 9 y). Males and females were close to equally represented (10 males and 7 females). Twelve patients (92%) required surgery to correct spinal deformity. Patients were followed for a median of 8.4 years (range, 2.8 to 19.5 y). The total number of surgical procedures performed was 17 averaging 1.5 per patient. Four patients required >1 procedure. Eighty percent of the patients who required >1 surgical procedure were females with probable diagnosis of X-linked dominant CDP. Revision surgery was indicated in 50% of the patients treated with combined anterior and posterior fusion and 20% of the patients treated with posterior fusion alone. Spinal deformity in CPD patients may range from significant kyphoscoliosis to minimal deformity that does not require any treatment. For those patients in whom spine surgery was indicated, a high incidence of revision surgery and curve progression after fusion was recorded. Female patients with probable diagnosis of X-linked dominant CDP were more likely to require a second surgical procedure. Isolated posterior fusion showed less favorable results compared with combined anteroposterior fusion in terms of revision surgery. Level IV-therapeutic study. 23884427 Human telomerase reverse transcriptase regulates MMP expression independently of telomerase activity via NF-κB-dependent transcription. Telomerase plays a pivotal role in the pathology of aging and cancer by controlling telomere length and integrity. However, accumulating evidence indicates that telomerase reverse transcriptase may have fundamental biological functions independent of its enzymatic activity in telomere maintenance. In this study, the ectopic expression of human telomerase reverse transcriptase (hTERT) and its catalytic mutant hTERT K626A induced cancer cell invasion accompanied by the up-regulation of the metalloproteinases (MMPs) MMP1, -3, -9, and -10. Both hTERT and hTERT K626A induced MMP9 mRNA expression and promoter activity in an NF-κB-dependent manner. hTERT and hTERT K626A also regulated the expression of several NF-κB target genes in cancer cell lines. Furthermore, both hTERT and hTERT K626A interacted with NF-κB p65 and increased NF-κB p65 nuclear accumulation and DNA binding. A mammalian 1-hybrid assay showed a functional interplay between hTERT and NF-κB p65 that may mediate NF-κB-dependent transcription activation in cells. Together, these data reveal a telomere-independent role for telomerase as a transcriptional modulator of the NF-κB signaling pathway and a possible contributor to cancer development and progression.-Ding, D., Xi, P., Zhou, J., Wang, M., Cong, Y.-S. Human telomerase reverse transcriptase regulates MMP expression independently of telomerase activity via NF-κB-dependent transcription. 23855676 Influence of Objective Three-Dimensional Measures and Movement Images on Surgeon Treatment Planning for Lip Revision Surgery. Objective: To determine whether a systematic evaluation of facial soft tissues of patients with cleft lip and palate, using facial video images and objective three-dimensional measurements of movement, change surgeons' treatment plans for lip revision surgery. Design: Prospective longitudinal study. Setting: The University of North Carolina School of Dentistry. Patients, Participants: A group of patients with repaired cleft lip and palate (n = 21), a noncleft control group (n = 37), and surgeons experienced in cleft care. Interventions: Lip revision. Main Outcome Measures: (1) facial photographic images; (2) facial video images during animations; (3) objective three-dimensional measurements of upper lip movement based on z scores; and (4) objective dynamic and visual three-dimensional measurement of facial soft tissue movement. Results: With the use of the video images plus objective three-dimensional measures, changes were made to the problem list of the surgical treatment plan for 86% of the patients (95% confidence interval, 0.64 to 0.97) and the surgical goals for 71% of the patients (95% confidence interval, 0.48 to 0.89). The surgeon group varied in the percentage of patients for whom the problem list was modified, ranging from 24% (95% confidence interval, 8% to 47%) to 48% (95% confidence interval, 26% to 70%) of patients, and the percentage for whom the surgical goals were modified, ranging from 14% (94% confidence interval, 3% to 36%) to 48% (95% confidence interval, 26% to 70%) of patients. Conclusions: For all surgeons, the additional assessment components of the systematic valuation resulted in a change in clinical decision making for some patients. 23790331 Antioxidant, hepatoprotective and hypolipidemic effects of methanolic root extract of Cassia singueana in rats following acute and chronic carbon tetrachloride intoxication. To evaluate in vivo antioxidant and hepatoprotective activities of the methanolic extract of the root of Cassia singueana in rats following acute and chronic carbon tetrachloride intoxication. Malondialdehyde (MDA), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin as indices of liver damage and lipid peroxidation were detected in rats after intraperitoneal administration of extract (5 mg/kg). The liver, kidney and heart showed significant reduction (P<0.05) in the levels of MDA from (0.18±0.04), (0.23±0.07) and (0.26±0.10) nmol/mg respectively in the CCl4 control to (0.15±0.03), (0.17±0.04) and (0.17±0.07) nmol/mg protein in groups pre-treated with the extract for three days at 5 mg/kg). Similarly, compared to the CCl4 control, significant reduction (P<0.05) in serum AST, ALT and bilirubin as well as in level of total cholesterol and MDA with concomitant increase in HDL cholesterol, superoxide dismutase and catalase levels when CCl4-intoxicated rats were treated with Cassia singueana root extract for two weeks. These results suggest that methanolic extract of Cassia singueana contain potent antioxidant compounds that can offer significant protection against hepatic and oxidative injuries. 23964198 Thyroid hormone-dependent development of early cortical networks: temporal specificity and the contribution of trkB and mTOR pathways. Early in neocortical network development, triiodothyronine (T3) promotes GABAergic neurons' population increase, their somatic growth and the formation of GABAergic synapses. In the presence of T3, GABAergic interneurons form longer axons and conspicuous axonal arborizations, with an increased number of putative synaptic boutons. Here we show that the increased GABAergic axonal growth is positively correlated with the proximity to non-GABAergic neurons (non-GABA). A differential innervation emerges from a T3-dependent decrease of axonal length in fields with low density of neuronal cell bodies, combined with an increased bouton formation in fields with high density of neuronal somata. T3 addition to deprived networks after the first 2 weeks of development did not rescue deficits in the GABAergic synaptic bouton distribution, or in the frequency and duration of spontaneous bursts. During the critical 2-week-period, GABAergic signaling is depolarizing as revealed by calcium imaging experiments. Interestingly, T3 enhanced the expression of the potassium-chloride cotransporter 2 (KCC2), and accelerated the developmental shift from depolarizing to hyperpolarizing GABAergic signaling in non-GABA. The T3-related increase of spontaneous network activity was remarkably reduced after blockade of either tropomyosin-receptor kinase B (trkB) or mammalian target of rapamycin (mTOR) pathways. T3-dependent increase in GABAergic neurons' soma size was mediated mainly by mTOR signaling. Conversely, the T3-dependent selective increase of GABAergic boutons near non-GABAergic cell bodies is mediated by trkB signaling only. Both trkB and mTOR signaling mediate T3-dependent reduction of the GABAergic axon extension. The circuitry context is relevant for the interaction between T3 and trkB signaling, but not for the interactions between T3 and mTOR signaling. 23673073 Very prolonged stay in the intensive care unit after cardiac operations: early results and late survival. Prolonged intensive care unit (ICU) stay is a surrogate for advanced morbidity or perioperative complications, and resource utilization may become an issue. It is our policy to continue full life support in the ICU, even for patients with a seemingly grim outlook. We examined the effect of duration of ICU stay on early outcomes and late survival. Between 1993 and 2011, 6,385 patients were admitted to the ICU after cardiac surgery. Patients were grouped according to length of stay in the ICU: group 1, 2 days or less (n = 4,631; 73%); group 2, 3 to 14 days (n = 1,423; 22%); group 3, more than 14 days (n = 331; 5%). Length of stay in ICU for group 3 patients was 38 ± 24 days (range, 15 to 160; median 31). Clinical profile and outcomes were compared between groups. Patients requiring prolonged ICU stay were older, underwent more complex surgery, had greater comorbidity, and a higher predicted operative mortality (p < 0.0001). They had a higher incidence of adverse events and increased mortality (p < 0.0001). Of the 331 group 3 patients, 60% were discharged: survival of these patients at 1, 3, and 5 years was 78%, 65%, and 52%, respectively. Operative mortality as well as late survival of discharged patients was proportional to duration of ICU stay. Current technology enables keeping sick patients alive for extended periods of time. Nearly two thirds of patients requiring prolonged ICU leave hospital, and of these, 50% attain 5-year survival. These data support offering full and continued support even for patients requiring very prolonged ICU stay. 23606402 Clinical features, presentation, and tolerance of platinum-based chemotherapy in germ cell tumor patients 50 years of age and older. Germ cell tumors (GCTs) primarily affect adolescent and young adult men. Detailed clinical and treatment characteristics in older men are lacking. Patients with GCT seen over a 20-year period at Memorial Sloan-Kettering Cancer Center were identified. Primary tumor site and histology were compared for patients aged ≥  50 years at diagnosis versus younger men. For patients aged ≥  50, individual chart review was performed and treatment delays, changes, and toxicities were recorded for those treated with first-line chemotherapy. Of 4235 diagnoses of GCT, 3999 (94.4%) were made at age  <  50 versus 236 (5.6%) at age  ≥  50. Compared with patients diagnosed before age 50, older men more frequently had seminoma (62.7% versus 36.7%) and less frequently, nonseminoma (34.7% versus 63.2%) (P  < .0001). Predominant histology switched from nonseminoma to seminoma around age 35. Distribution of primary sites also differed for older versus younger men (testis: 89.4% versus 92.9%; retroperitoneal: 3.8% versus 0.7%; CNS 0% versus 1.7%) except for mediastinal primary tumors, which remained constant across age groups. Fifty patients age  ≥  50 received first-line platinum-based chemotherapy; 30 experienced complications leading to treatment discontinuation, delay  ≥  7 days, or regimen change. Twenty-two (44%) patients experienced neutropenic fever, 6 despite prophylactic growth factor support. Estimated 5-year survival for chemotherapy-treated patients was 84.9%. Men aged ≥ 50 years comprise less than 10% of GCT diagnoses and have distinct clinical and histological characteristics as compared with younger patients. Although complications from chemotherapy occur frequently in older men, prognosis remains excellent when risk-directed treatment is administered with curative intent. 23922034 Detection of tautomer proportions of dimedone in solution: a new approach based on theoretical and FT-IR viewpoint. Molecular structures of stable tautomers of dimedone [5,5-dimethyl-cyclohexane-1,3-dione (1) and 3-hydroxy-5,5-dimethylcyclohex-2-enone (2)] were optimized and vibrational frequencies were calculated in five different organic solvents (dimethylsulfoxide, methanol, acetonitrile, dichloromethane and chloroform). Geometry optimizations and harmonic vibrational frequency calculations were performed at DFT 6-31+G(d,p), DFT 6-311++G(2d,2p), MP2 6-311++G (2d,2p) and MP2 aug-cc-pVDZ levels for both stable forms of dimedone. Experimental FT-IR spectra of dimedone have also been recorded in the same solvents. A new approach was developed in order to determine tautomers' ratio using both experimental and theoretical data in Lambert-Beer equation. Obtained results were compared with experimental results published in literature. It has been concluded that while DFT 6-31+G(d,p) method provides accurate enol ratio in DMSO, MeOH, and DCM, in order to obtain accurate results for the other solvents the MP2 aug-cc-pVDZ level calculations should be used for CH3CN and CHCl3 solutions. 23970853 Cortical region-specific engraftment of embryonic stem cell-derived neural progenitor cells restores axonal sprouting to a subcortical target and achieves motor functional recovery in a mouse model of neonatal hypoxic-ischemic brain injury. Hypoxic-ischemic encephalopathy (HIE) at birth could cause cerebral palsy (CP), mental retardation, and epilepsy, which last throughout the individual's lifetime. However, few restorative treatments for ischemic tissue are currently available. Cell replacement therapy offers the potential to rescue brain damage caused by HI and to restore motor function. In the present study, we evaluated the ability of embryonic stem cell-derived neural progenitor cells (ES-NPCs) to become cortical deep layer neurons, to restore the neural network, and to repair brain damage in an HIE mouse model. ES cells stably expressing the reporter gene GFP are induced to a neural precursor state by stromal cell co-culture. Forty-hours after the induction of HIE, animals were grafted with ES-NPCs targeting the deep layer of the motor cortex in the ischemic brain. Motor function was evaluated 3 weeks after transplantation. Immunohistochemistry and neuroanatomical tracing with GFP were used to analyze neuronal differentiation and axonal sprouting. ES-NPCs could differentiate to cortical neurons with pyramidal morphology and expressed the deep layer-specific marker, Ctip2. The graft showed good survival and an appropriate innervation pattern via axonal sprouting from engrafted cells in the ischemic brain. The motor functions of the transplanted HIE mice also improved significantly compared to the sham-transplanted group. These findings suggest that cortical region specific engraftment of preconditioned cortical precursor cells could support motor functional recovery in the HIE model. It is not clear whether this is a direct effect of the engrafted cells or due to neurotrophic factors produced by these cells. These results suggest that cortical region-specific NPC engraftment is a promising therapeutic approach for brain repair. 23327612 Quasiclassical Trajectory Study of CH(3)NO(2) Decomposition via Roaming Mediated Isomerization Using a Global Potential Energy Surface. We report a global potential energy surface (PES) for CH(3)NO(2) based on fitting roughly 114 000 density functional theory (UB3LYP/6-311+g(d,p)) electronic energies. The PES is a precise, permutationally invariant fit to these energies. Properties of the PES are described, as are some preliminary quasiclassical trajectory calculations. An isomerization-roaming pathway to the CH(3)ONO isomer and then to the CH(3)O + NO products is found. Although the pathway occurs at larger distances than a related loose saddle-point on the PES, the pathway supports the supposition of such a pathway based on locating a loose first-order saddle point and associated IRC, reported previously by Zhu and Lin [ Zhu , R. S. and Lin , M. C. Chem. Phys. Lett. 2009 , 478 , 11 ]. 23624997 Key role of hydrazine to the interaction between oxaloacetic against phosphoenolpyruvic carboxykinase (PEPCK): ONIOM calculations. The interactions between oxaloacetic (OAA) and phosphoenolpyruvic carboxykinase (PEPCK) binding pocket in the presence and absence of hydrazine were carried out using quantum chemical calculations, based on the two-layered ONIOM (ONIOM2) approach. The complexes were partially optimized by ONIOM2 (B3LYP/6-31G(d):PM6) method while the interaction energies between OAA and individual residues surrounding the pocket were performed at the MP2/6-31G(d,p) level of theory. The calculated interaction energies (INT) indicated that Arg87, Gly237, Ser286, and Arg405 are key residues for binding to OAA with the INT values of -1.93, -2.06, -2.47, and -3.16 kcal mol(-1), respectively. The interactions are mainly due to the formation of hydrogen bonding interactions with OAA. Moreover, using ONIOM2 (B3LYP/6-31G(d):PM6) applied on the PEPCKHS complex, two proton transfers were observed; first, the proton was transferred from the carboxylic group of OAA to hydrazine while the second one was from Asp311 to Lys244. Such reactions cause the generation of binding strength of OAA to the pocket via electrostatic interaction. The orientations of Lys243, Lys244, His264, Asp311, Phe333, and Arg405 were greatly deviated after hydrazine incorporation. These indicate that hydrazine plays an important role in terms of not only changing the conformation of the binding pocket, but is also tightly bound to OAA resulting in its conformation change in the pocket. The understanding of such interaction can be useful for the design of hydrazine-based inhibitor for antichachexia agents. 23603202 Adult siRNA-induced knockdown of mGlu7 receptors reduces anxiety in the mouse. Our knowledge regarding the molecular pathophysiology underlying anxiety disorders remains incomplete. Increasing evidence points to a role of glutamate in anxiety. The group III metabotropic glutamate receptors (mGlu4, mGlu6, mGlu7 and mGlu8 receptors) remain the least investigated glutamate receptor subtypes partially due to a delay in the development of specific pharmacological tools. Early work using knockout animals and pharmacological tools aimed at investigating the role of mGlu7 receptor in the pathophysiology of anxiety disorders has yielded exciting yet not always consistent results. To further investigate the role this receptor plays in anxiety-like behaviour, we knocked down mGlu7 receptor mRNA levels in the adult mouse brain using siRNA delivered via an osmotic minipump. This reduced anxiety-like behaviour in the light-dark box coupled with an attenuation of stress-induced hyperthermia (SIH) and a reduction of the acoustic startle response (ASRs) in the fear-potentiated startle paradigm (FPS). These effects on anxiety-like behaviour were independent of any impairment of locomotor activity and surprisingly, no behavioural changes were observed in the forced swim test (FST), which is in contrast to mGlu7 receptor knockout animals. Furthermore, the previously reported epilepsy-prone phenotype seen in mGlu7 receptor knockout animals was not observed following siRNA-induced knockdown of the receptor. These data suggest targeting mGlu7 receptors with selective antagonist drugs may be an effective and safe strategy for the treatment of anxiety disorders. 23958683 Modulation of antitumour immune responses by intratumoural Stat1 expression. Signal transducer and activator of transcription 1 (Stat1) mediates anti-viral responses and cytokine-driven anti-proliferative, apoptotic and immunomodulatory activities. As de-regulated Stat1 function can affect tumour progression we sought to elucidate the effects of tumour cell-intrinsic Stat1 expression on immunosurveillance. Knockout of Stat1 enhanced the development of sarcomas induced by the chemical carcinogen 3-methylcholanthrene (MCA). Growth of transplanted MCA-induced Stat1(-/-) sarcomas was suppressed in wild-type mice compared to growth in Stat1(-/-) and immunocompromised recipients. Co-depletion of NK and CD8(+) T cells from wild-type mice facilitated Stat1-deficient tumour growth whereas depletion of CD4(+) T cells and CD8(+) T cells did not. In vitro and in vivo analysis of the tumours implicated a role for NK cell-mediated, perforin-dependent killing of Stat1-deficient tumours. Interestingly, restoration of Stat1 expression in Stat1(-/-) tumours resulted in diminished involvement of NK cells and increased contribution of CD8(+) T cells in anti-tumour responses. Therefore, Stat1 expression within tumour cells modulated anti-tumour immune responses by altering the dominant immune effector cell involvement from NK cells to CD8(+) T cells in the absence or presence of Stat1 respectively.Immunology and Cell Biology advance online publication, 20 August 2013; doi:10.1038/icb.2013.41. 23529958 Novel albendazole-chitosan nanoparticles for intestinal absorption enhancement and hepatic targeting improvement in rats. To improve the treatment of helminthiasis, filariasis, and colorectal cancer, albendazole-associated chitosan nanoparticles (ABZ-CS-NPs) were prepared using the emulsion crosslinking volatile technique with contained sodium tripolyphosphate as the crosslinking agent and Poloxamer 188 as the auxiliary solvent. The structural characteristics of the NPs were determined using X-ray diffraction to analyze the interaction between CS and the drug. The NPs were then evaluated in terms of their physicochemical characteristics, drug release behavior, in vivo pharmacokinetic parameters, and biodistribution in animal studies. ABZ-loaded NPs with a uniformly spherical particle sizes (157.8 ± 2.82 nm) showed efficient drug loading, encapsulated efficiency, and high physical stability. The drug release from ABZ-CS-NPs was extended over several periods. Kinetic models were then fitted to determine the release mechanisms. ABZ and its metabolite albendazole sulfoxide (ABZSX) were analyzed in rats with mebendazole as the internal standard using reversed-phase high-performance liquid chromatography. Compared with the ABZ suspension groups, the relative bioavailability values of ABZ and ABZSX were 146.05 and 222.15%, respectively. In addition, the plasma concentration versus time curve is consistent with that of the two compartment models in the plasma concentration versus time curve. The results indicate that the ABZ-loaded NPs are promising novel ABZ candidates for passive diffusion in the treatment of hydatid cysts in the liver via oral administration. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013. 23584671 Effects of amisulpride on human resting cerebral perfusion. Quantitative neuroimaging studies show that different neuroleptics have similar effects on resting metabolism/perfusion in the basal ganglia, but vary in their effect on the cortex, especially in the prefrontal and temporal lobes. These differences may represent signatures of the action of medication on distinctive receptor combinations. This study seeks to determine the effect on cerebral perfusion at rest of low-dose amisulpride, a neuroleptic with a receptor profile relatively selective to dopaminergic D2-receptors and both antidepressant and antipsychotic efficacy. Continuous arterial spin labelling in a placebo-controlled, double blind, crossover study at steady state of N = 20 healthy male adults. Relative to placebo, amisulpride was associated with extensive and significant cortical decrements in resting perfusion levels, particularly in the prefrontal lobes (p = 0.01, corrected). Decrements spared the basal ganglia, where perfusion was slightly increased. In contrast to earlier reports on other neuroleptics, amisulpride was associated with intense cortical perfusion decrements at rest. These results are consistent with an existing model in which dopaminergic blockade is associated not only with metabolism/perfusion increases in the basal ganglia, but also with decreases in the cerebral cortex that in most neuroleptics are compensated by action on other receptor systems. The selective receptor profile of amisulpride may explain the extensive cortical decrements. 23465682 Single-session endosonography and endoscopic retrograde cholangiopancreatography for biliopancreatic diseases is feasible, effective and cost beneficial. Endoscopic ultrasonography (EUS) and Endoscopic Retrograde Cholangiopancreatography (ERCP) are often required in patients with pancreaticobiliary disorders. To assess the clinical impact and costs savings of a single session EUS-ERCP. Patient and intervention data from April 2009 to March 2012 were prospectively recruited and retrospectively analyzed from a database at a tertiary hospital. Indications, diagnostic yield, procedure details, complications and costs were evaluated. Fifty-five scheduled combined procedures were done in 53 patients. The accuracy of EUS-fine needle aspiration for malignancy was 90%. The main clinical indication was a malignant obstructing lesion (66%). The ERCP cannulation was successful in 67%, and in 11/15 failed ERCP (73%), drainage was completed thanks to an EUS-guided biliary drainage: 6 transmurals, 5 rendezvous. Eight patients (14%) had related complications: bacteremia (n = 3), pancreatitis (n = 2), bleeding (n = 2) and perforation (n = 1). The mean duration was 65 ± 22.2 min. The mean estimated cost for a single session was €3437, and €4095 for two separate sessions. The estimated cost savings using a single-session strategy was €658 per patient, representing a total savings of €36,189. Combined EUS and ERCP is safe, technically feasible and cost beneficial. Furthermore, in failed ERCP cases, the endoscopic biliary drainage can be completed with EUS-guided biliary access in the same procedure. 23560590 A systematic review and meta-analysis of laparoscopic vs open restorative proctocolectomy. The benefits of a laparoscopic approach to restorative proctocolectomy (RPC) are controversial. The aim of this meta-analysis was to compare the outcome following laparoscopic and open RPC, with particular attention to adverse events and long-term function. A systematic search of the MEDLINE, EMBASE and Ovid databases was performed for studies published until March 2012. The primary end-point was long-term function. Secondary end-points were intra-operative details, short-term postoperative outcome and postoperative adverse events. Weighted mean difference (WMD) and odds ratio (OR) were calculated using fixed/random effect meta-analytic techniques. The final analysis included 27 comparative studies of 2428 patients, of whom 1097 (45.1%) underwent laparoscopic surgery. A laparoscopic approach was associated with a significantly longer operation time (WMD 70.1 min, P < 0.001), shorter length of hospital stay (WMD -1.00 day, P < 0.001), reduced intra-operative blood loss (WMD -89.10 ml, P < 0.001) and a lower incidence of wound infection (OR 0.60, P < 0.005). No significant differences were observed in the rate of pouch failure. Although there was no significant difference in the number of daily bowel movements (OR 0.04, P = 0.950), laparoscopic surgery led to fewer nocturnal bowel movements (WMD -1.14, P < 0.001) and reduced pad usage during the day (OR 0.22, P < 0.001) and night (OR 0.33, P < 0.001). The post hoc power to detect differences in adverse event rates ranged from 5% to 42%. Laparoscopic and open approaches to RPC produced equivalent adverse event rates and long-term functional results. However, the present evidence is underpowered to detect true differences in adverse event rates. 23928576 European Urology: Quality, Impact, Online. European Urology provides contemporary, cutting-edge urologic research, guidance, and discussion. The journal continues to invite collaborative reviews, to invest in rapid but fair peer review, to seek the best research, and to serve the needs of readers and patients. 23925944 Nicotine induces alteration of H3K27 demethylase UTX in kidney cancer cell. Cigarette smoking is one of the most important risk factors for kidney cancer, but the molecular mechanism is poorly understood. To examine the expression change of histone H3 on lysine 27 trimethylase (H3K27me3) demethylases ubiquitously transcribed TPR gene on the X chromosome (UTX) in kidney cancer cell line 786-O after nicotine treatment, quantitative real-time-polymerase chain reaction and western blotting analysis were carried out. These results showed that nicotine can increase UTX messenger RNA and protein levels and also decrease the content of H3K27me3. The decreased content of H3K27me3 may activate specific gene expression and lead to kidney cancer. Future investigation on nicotine induced UTX expression and its epigenetic effect would deepen our understanding on nicotine toxicity and carcinogenicity. 22988953 Psychological distress among university female students and their need for mental health services. The purpose of this research was to assess psychological distress among university female students and identify their mental health service needs. Rates of elevated symptoms of depression and anxiety among university women students was 22.5% and 21.2%, respectively, which is similar to women of the same age in the general population. The mean level of depressive symptoms was however lower among the female students. Results showed that little less than one-third of psychologically distressed women students had received professional help, and only 1.4% had received mental health counselling from nurses. Most of the distressed female students experienced mild to moderate levels of depressive and anxiety symptoms, which indicates a need for prevention or early intervention measures. This need is a challenge for nurses working in the primary care sector, including the educational system. They are in a unique position to screen for psychological distress and provide or initiate preventive services or early interventions, including outreach programmes within schools where most young people are reachable. Psychological distress among university students, especially young women, is of increasing concern. This study focuses on the prevalence of psychological distress among female university students and their need for mental health services. The analysis is based on two cross-sectional surveys, an internet survey among women students attending the University of Iceland in the spring of 2007, and a postal survey of Icelandic female adults conducted in the Fall of 2006. Psychological distress was measured with the Symptom Checklist-90 Depression and Anxiety subscales. The prevalence of above-threshold depression and anxiety among the university women students was 22.5% and 21.2% respectively. Results showed that the mean depression score was significantly lower among the students than among women of the same age in the general population. However, little less than one-third of students with elevated distress levels received any professional help. Only 1.4% of the distressed students received mental help care from nurses. The high proportion of distressed female students not receiving professional help is a challenge to the primary health-care system and the nursing profession. This also raises questions about the adequacy of the current system of health-care delivery and the potential advantages of on-campus health services, in closer proximity to the students. 23924840 Wound healing and the role of fibroblasts. Fibroblasts are critical in supporting normal wound healing, involved in key processes such as breaking down the fibrin clot, creating new extra cellular matrix (ECM) and collagen structures to support the other cells associated with effective wound healing, as well as contracting the wound. This article explores and summarises the research evidence on the role of fibroblasts, their origins and activation, and how they navigate the wound bed, as well as how their activity leads to wound contraction. This article also explores the local conditions at the wound site, which activate, regulate and ultimately reduce the fibroblast activity as the skin's integrity returns on healing. 23942827 The Factor Structure of Anxiety and Depressive Disorders in a Sample of Clinic-Referred Adolescents. The current study used confirmatory factor analysis (CFA) to examine the factor structure of anxiety and depressive disorders in a sample of clinic-referred adolescents, aged between 12 and 18 years, for diagnoses based on parent (N = 655; male = 441) and adolescent (N = 626; male = 417) interviews. Three models were examined: a 1-factor model, with all anxiety and depressive disorders in a single factor; a DSM-based 2-factor model, with anxiety disorders in one factor, and depressive disorders in another factor; and an alternate 2-factor model, with fear related anxiety disorders in one factor, and other anxiety and depressive disorders in another factor. The findings indicated support for all three models. Also, ADHD and ODD/CD were associated with only the shared variances between the latent factors in the 2-factor models, and not their unique variance. The implications of the findings for taxonomy, comorbidity, and clinical practice are discussed. 23756479 What is special about the adolescent (JME) brain? Juvenile myoclonic epilepsy (JME) involves cortico-thalamo-cortical networks. Thalamic, frontal gray matter, connectivity, and neurotransmitter disturbances have been demonstrated by structural/functional imaging studies. Few patients with JME show mutations in genes coding ion channels or GABAA (gamma-aminobutyric acid) receptor subunits. Recent research points to EFHC1 gene mutations leading to microdysgenesis and possible aberrant circuitry. Imaging studies have shown massive structural/functional changes of normally developing adolescent brain structures maturing at strikingly different rates and times. Gray matter (GM) volume diminishes in cortical areas (frontal and parietal) and deep structures (anterior thalamus, putamen, and caudate). Diffusion tensor imaging (DTI) findings support continued microstructural change in WM (white matter) during late adolescence with robust developmental changes in thalamocortical connectivity. The GABAA receptor distribution and specific receptor subunits' expression patterns change with age from neonate to adolescent/adult, contributing to age-related changes in brain excitability. Hormonal influence on brain structure development during adolescence is presented. Possible implications of brain changes during adolescence on the course of JME are discussed. 23680979 Scoring of human acute pancreatitis: state of the art. Acute pancreatitis remains as one of the most difficult and challenging digestive disorder to predict in terms of clinical course and outcome. Every case has an individual course and therefore acute pancreatitis remains challenging and fascinating. Due to this variability, many different scoring systems have evolved during the last decades. Every scoring system has advantages and disadvantages. Not every scoring system is capable of assessing the clinical time course of the disease, some are only suitable for the time of initial presentation. This paper will give an overview on the development of different widely used scoring systems and their performance in assessing severity and prognosis of acute pancreatitis. Severity assessment means objective quantification of overall severity of illness. Early and reliable stratification of severity is required to decide best treatment of the individual patient, preparation for possible evolving complications or for referral to specialist centers. No single scoring system is able to cover the entire range of problems associated with treatment and assessment of acute pancreatitis. In our clinical experience, we recommend hematocrit upon admission, daily sequential organ failure assessment score and procalcitonin, C-reactive protein on day 3 and CT severity index beyond the first week. These scoring tools together with close clinical follow-up of the patient ultimately lead to an optimized treatment of this challenging disease. 23856434 Proactive coping moderates the dietary intention-planning-behavior path. Background: The study examines psychosocial mechanisms in dietary change using the health action process approach (HAPA) as its theoretical backdrop. Previous studies have supported the model in the domain of dietary behaviors but it has not yet been studied in China. Objective: Dietary planning is assumed to mediate between intentions and dietary behaviors. However, among individuals scoring low on proactive coping, this mediation might fail. Therefore, an extension of the model by including proactive coping is examined. Methods: Psychometric scales were administered at two points in time, three months apart, to 240 young Chinese men and women. Intentions, outcome expectancies, risk perception, action self-efficacy, and proactive coping were assessed at Time 1, whereas planning, coping self-efficacy, and dietary behavior were measured at Time 2. Results: Structural equation models replicated previous evidence on the validity of the HAPA. Intentions and planning mediated sequentially the effects of outcome expectancies and self-efficacy on dietary behaviors. Moreover, the inclusion of proactive coping yielded no main effects, but an interaction between intentions and proactive coping on dietary planning. The intention-planning-behavior chain was moderated by proactive coping which means that this connection operates only well when individuals are proactive. Conclusions: A combination of proactive coping and the motivation to eat healthy foods facilitates dietary planning which, in turn, benefits corresponding behaviors. 23843200 Correlating patient-reported outcomes and ambulation success following microsurgical lower extremity reconstruction in comorbid patients. Introduction: Microsurgical lower extremity flap reconstruction provides a valuable option for soft tissue reconstruction in comorbid patients. Limb salvage with flap reconstruction can result in limb length preservation. Despite this, few studies have examined the impact of salvage on patient-centered metrics in this cohort of patients. Therefore, we investigated quality of life and patient satisfaction following microsurgical lower extremity reconstruction in this high-risk patient population. Factors that resulted in improved patient-centered outcomes were also identified. Methods: A retrospective review was conducted of all patients who had lower extremity free flap reconstruction (FFR) following lower extremity wounds. High-risk patients were identified as having multiple comorbidities and chronic wounds. Patients with traumatic wounds were excluded from analysis. Quality of life was evaluated with the Short Form-12 (SF-12) validated survey. Phone interviews were conducted for survey evaluations. Results: From 2005 to 2010, 57 patients had lower extremity flap reconstruction that met the inclusion criteria. Average follow-up was 236.6 weeks (range, 111-461). Comorbidities included diabetes (36%), PVD (24.6%), and ESRD (7%). Limb length preservation and ambulation occurred in 82.5% (47/57). Revisional surgery occurred in 33.3% (19/57). Survey response rate was 63%. Average SF-12 PCS and MCS scores were 44.9 and 59.8 for patients able to achieve ambulation and 27.6 and 61.2 for nonambulatory patients. Conclusions: Microsurgical flap reconstruction is a valuable reconstructive option in high-risk patients. Quality of life is comparable with a normalized population if limb salvage is successful. Quality of life is decreased significantly when failure to ambulate occurs in this patient cohort. © 2013 Wiley Periodicals, Inc. Microsurgery, 2013. 23164617 Ipsilateral feeding-specific circuits between the nucleus accumbens shell and the lateral hypothalamus: regulation by glutamate and GABA receptor subtypes. The nucleus accumbens shell (AcbSh) and the lateral hypothalamus (LH) are both involved in the control of food intake. Activation of GABA(A) receptors or blockade of AMPA and kainate receptors within the AcbSh induces feeding, as does blockade of GABA(A) receptors or activation of NMDA receptors in the LH. Further, evidence suggests that feeding induced via the AcbSh can be suppressed by LH inhibition. However, it is unclear if this suppression is specific to feeding. Adult male Sprague-Dawley rats with 3 intracranial guide cannulas, one unilaterally into the AcbSh and two bilaterally into the LH, were used to explore this issue. DNQX (1.25 μg) or muscimol (100 ng) infused into the AcbSh unilaterally elicited feeding, and this elicited intake was suppressed by bilateral LH injection of d-AP5 (2 μg) or muscimol (25 ng). The effectiveness of d-AP5 or muscimol infusion into either the LH site ipsilateral or contralateral to the AcbSh injection was compared. Ipsilateral LH injection of d-AP5 or muscimol was significantly more effective than contralateral injection in suppressing food intake initiated by AcbSh injection of DNQX or muscimol. These results add to the prior evidence that inhibition of the LH through pharmacological modulation of NMDA or GABA(A) receptors specifically suppresses feeding initiated by AcbSh inhibition, and that these two regions communicate via an ipsilateral circuit to specifically regulate feeding. 23331757 Association between obstructive sleep apnea severity and endothelial dysfunction in an increased background of cardiovascular burden. The objective of this study is to examine whether increasing obstructive sleep apnea (OSA) severity is associated with worsening endothelial function. The design is a cross-sectional examination of the baseline assessment of a multi-centre randomized controlled clinical trial examining the effects of oxygen, continuous positive airway pressure (CPAP) therapy or lifestyle modifications on cardiovascular biomarkers. Participants were recruited from cardiology clinics at four sites. Participants with an apnea-hypopnea index (AHI) of 15-50 and known cardio/cerebrovascular disease (CVD) or CVD risk factors were included. OSA severity indices [oxygen desaturation index (ODI), AHI and percentage of sleep time below 90% oxygen saturation (total sleep time <90)] and a measure of endothelium-mediated vasodilatation [Framingham reactive hyperaemia index (F-RHI) derived from peripheral arterial tonometry (PAT)] were assessed. The sample included 267 individuals with a mean AHI of 25.0 ± 8.5 SD and mean F-RHI 0.44 ± 0.38. In adjusted models, the slope of the relationship between ODI and F-RHI differed above and below an ODI of 24.6 (P = 0.04), such that above an ODI of 24.6 there was a marginally significant decline in the geometric mean of the PAT ratio by 3% [95% confidence interval (CI): 0%, 5%; P = 0.05], while below this point, there was a marginally significant incline in the geometric mean of the PAT ratio by 13% (95% CI: 0%, 27%; P = 0.05) per 5-unit increase in ODI. A similar pattern was observed between AHI and F-RHI. No relation was noted with total sleep time <90 and F-RHI. There was evidence of a graded decline in endothelial function in association with higher levels of intermittent hypoxaemia. 23380860 Rescue of hearing and vestibular function by antisense oligonucleotides in a mouse model of human deafness. Hearing impairment is the most common sensory disorder, with congenital hearing impairment present in approximately 1 in 1,000 newborns. Hereditary deafness is often mediated by the improper development or degeneration of cochlear hair cells. Until now, it was not known whether such congenital failures could be mitigated by therapeutic intervention. Here we show that hearing and vestibular function can be rescued in a mouse model of human hereditary deafness. An antisense oligonucleotide (ASO) was used to correct defective pre-mRNA splicing of transcripts from the USH1C gene with the c.216G>A mutation, which causes human Usher syndrome, the leading genetic cause of combined deafness and blindness. Treatment of neonatal mice with a single systemic dose of ASO partially corrects Ush1c c.216G>A splicing, increases protein expression, improves stereocilia organization in the cochlea, and rescues cochlear hair cells, vestibular function and low-frequency hearing in mice. These effects were sustained for several months, providing evidence that congenital deafness can be effectively overcome by treatment early in development to correct gene expression and demonstrating the therapeutic potential of ASOs in the treatment of deafness. 23888132 Facial reactions in response to dynamic emotional stimuli in different modalities in patients suffering from schizophrenia: a behavioral and EMG study. Emotional facial expression is an important low-level mechanism contributing to the experience of empathy, thereby lying at the core of social interaction. Schizophrenia is associated with pervasive social cognitive impairments, including emotional processing of facial expressions. In this study we test a novel paradigm in order to investigate the evaluation of the emotional content of perceived emotions presented through dynamic expressive stimuli, facial mimicry evoked by the same stimuli, and their functional relation. Fifteen healthy controls and 15 patients diagnosed with schizophrenia were presented with stimuli portraying positive (laugh), negative (cry) and neutral (control) emotional stimuli in visual, auditory modalities in isolation, and congruently or incongruently associated. Participants where requested to recognize and quantitatively rate the emotional value of the perceived stimuli, while electromyographic activity of Corrugator and Zygomaticus muscles was recorded. All participants correctly judged the perceived emotional stimuli and prioritized the visual over the auditory modality in identifying the emotion when they were incongruently associated (Audio-Visual Incongruent condition). The neutral emotional stimuli did not evoke any muscle responses and were judged by all participants as emotionally neutral. Control group responded with rapid and congruent mimicry to emotional stimuli, and in Incongruent condition muscle responses were driven by what participants saw rather than by what they heard. Patient group showed a similar pattern only with respect to negative stimuli, whereas showed a lack of or a non-specific Zygomaticus response when positive stimuli were presented. Finally, we found that only patients with reduced facial mimicry (Internalizers) judged both positive and negative emotions as significantly more neutral than controls. The relevance of these findings for studying emotional deficits in schizophrenia is discussed. 23708554 Differential expression of Arc in the mesocorticolimbic system is involved in drug and natural rewarding behavior in rats. Aim:To investigate the different effects of heroin and milk in activating the corticostriatal system that plays a critical role in reward reinforcement learning.Methods:Male SD rats were trained daily for 15 d to self-administer heroin or milk tablets in a classic runway drug self-administration model. Immunohistochemical assay was used to quantify Arc protein expression in the medial prefrontal cortex (mPFC), the nucleus accumbens (NAc), the dorsomedial striatum (DMS) and the ventrolateral striatum (VLS) in response to chronic self-administration of heroin or milk tablets. NMDA receptor antagonist MK801 (0.1 mg/kg) or dopamine D1 receptor antagonist SCH23390 (0.03 mg/kg) were intravenously injected at the same time as heroin was infused intravenously.Results:Runway training with heroin resulted in robust enhancement of Arc expression in the mPFC, the NAc and the DMS on d 1, 7, and 15, and in the VLS on d 1 and d 7. However, runway training with milk led to increased Arc expression in the mPFC, the NAc and the DMS only on d 7 and/or d 15 but not on d 1. Moreover, runway training with milk failed to induce increased Arc protein in the VLS. Both heroin-seeking behavior and Arc protein expression were blocked by MK801 or SCH23390 administration.Conclusion:The VLS is likely to be critically involved in drug-seeking behavior. The NMDA- and D1 receptor-dependent Arc expression is important in drug-seeking behavior. 23821553 Syntheses and Properties of Graphyne Fragments: Trigonally Expanded Dehydrobenzo[12]annulenes. We present herein the synthesis and properties of the largest hitherto unknown graphyne fragment, namely trigonally expanded tetrakis(dehydrobenzo[12]annulene)s (tetrakis-DBAs). Intramolecular three-fold alkyne metathesis reactions of hexakis(arylethynyl)DBAs 9 a and 9 b using Fürstner's Mo catalyst furnished tetrakis-DBAs 8 a and 8 b substituted with tert-butyl or branched alkyl ester groups in moderate and fair yields, respectively, demonstrating that the metathesis reaction of this protocol is a powerful tool for the construction of graphyne fragment backbones. For comparison, hexakis(arylethynyl)DBAs 9 c-g have also been prepared. The one-photon absorption spectrum of tetrakis-DBA 8 a bearing tert-butyl groups revealed a remarkable bathochromic shift of the absorption cut-off (λcutoff ) compared with those of previously reported graphyne fragments due to extended π-conjugation. Moreover, in the two-photon absorption spectrum, 8 a showed a large cross-section for a pure hydrocarbon because of the planar para-phenylene-ethynylene conjugation pathways. Hexakis(arylethynyl)-DBAs 9 c-e and 9 g and tetrakis-DBA 8 b bearing electron-withdrawing groups aggregated in chloroform solutions. Comparison between the free energies of 9 e and 8 b bearing the same substituents revealed the more favorable association of the latter due to stronger π-π interactions between the extended π-cores. Polarized optical microscopy observations, DSC, and XRD measurements showed that 8 b and 9 e with branched alkyl ester groups displayed columnar rectangular mesophases. By the time-resolved microwave conductivity method, the columnar rectangular phase of 8 b was shown to exhibit a moderate charge-carrier mobility of 0.12 cm(2)  V(-1)  s(-1) . These results indicate that large graphyne fragments can serve as good organic semiconductors. 23451900 Does sacral nerve stimulation improve global pelvic function in women? Many women undergoing sacral neuromodulation for faecal incontinence have coexisting pelvic floor dysfunction. We used a global pelvic-floor assessment questionnaire to evaluate the effect of sacral neuromodulation on non-bowel related symptomatology. The electronic Personnel Assessment Questionnaire - Pelvic Floor (ePAQ-PF) is a validated Web-based electronic pelvic floor questionnaire. Women with faecal incontinence underwent assessment using the ePAQ. Pre- and poststimulator data were analysed over a 4.5-year period. Forty-three women (mean age 56.5 years; median follow up 6.8 months) were included. All (100%) had urinary symptoms, 81.4% had vaginal symptoms and 85.7% described some sexual dysfunction. There was a significant improvement in faecal incontinence and in bowel-related quality of life (P < 0.005) as well as in irritable bowel syndrome (IBS)-related symptoms (P < 0.01) and in bowel-related sexual heath (P < 0.01). Symptoms of vaginal prolapse significantly improved (P = 0.05). There was also improvement in symptoms of overactive bladder (P = 0.005) and in urinary-related quality of life (P < 0.05). A global health improvement was reported in 58.1%, mainly in bowel evacuation (P < 0.01) and in vaginal pain and sensation (P < 0.05). In sexually active female patients, significant improvements in vaginal and bowel-related sexual health were seen (P < 0.005). Improvement in general sex life following stimulation was reported in 53.3%. A Web-based electronic pelvic-floor assessment questionnaire has demonstrated global improvement in pelvic floor function in bowel, urinary, vaginal and sexual dimensions in women following sacral neuromodulation for faecal incontinence. 23912693 Phase II study of ifosfamide and cisplatin for the treatment of recurrent ovarian cancer. The aim of this phase II study was to investigate the efficacy and toxicity of combined ifosfamide and cisplatin chemotherapy in patients with recurrent epithelial ovarian cancer (EOC). Forty-seven patients with recurrent EOC were treated with ifosfamide 5 g/m(2) and cisplatin 50 mg/m(2) on day 1, every 3 weeks for 6 cycles. The primary outcomes were response rate (RR) and toxicity. Other measurements were duration of response, time to progression (TTP), and overall survival (OS). All 47 patients with 160 cycles were assessed for response and toxicity. The overall RR was 31.9 %; there were 3 complete responses (6.4 %) and 12 partial responses (25.5 %). Grade 3 and 4 hematologic toxicities included neutropenia (23.6 %), anemia (12.8 %), and thrombocytopenia (10.7 %). Non-hematologic toxicities were mild, and no drug-related toxic deaths occurred. The median duration of response, TTP, and OS was 5.1, 4.8, and 17.0 months, respectively. In the initially platinum-sensitive group, RR and OS were 44.4 % and 20.4 months, while in the initially platinum-resistant group, these values were 15.0 and 8.7 months, respectively (P = 0.027 and P = 0.002, respectively). Ifosfamide combined with cisplatin is a well-tolerated regimen with modest activity in recurrent EOC. In addition, this regimen was especially effective in patients whose disease was initially platinum-sensitive. 23962300 Trisequential Photooxygenation Reaction: Application to the Synthesis of Carbasugars. 4,5-Dimethylenecyclohex-1-ene was subjected to a photooxygenation reaction to introduce oxygen functionalities. The endoperoxide obtained underwent an ene-reaction to form hydroperoxides with 1,3-diene structures. Further addition of singlet oxygen to the diene units resulted in the formation of tricyclic hydroperoxides having three oxygens in the molecule. Cleavage of the oxygen-oxygen bonds followed by epoxidation of the remaining C-C double bond and concomitant ring-opening reaction furnished the isomeric carbasugars. 23711470 Combined effects of carbonate alkalinity and pH on survival, growth and haemocyte parameters of the Venus clam Cyclina sinensis. Carbonate alkalinity (CA) and pH are considered to be two important stress factors that determine the response of aquatic animals to sudden transfers into saline-alkaline water. To evaluate the potential for aquaculture production of Venus clams (Cyclina sinensis) farmed in saline-alkaline water, the combined effects of CA (2.5 (control), 10.0, 20.0 and 40.0 meq/l) and pH (8.0 (control), 8.5, 9.0 and 9.5) on survival rate was monitored every day for 10 days. Length gain rate (LGR) and weight gain rate (WGR) were also monitored for two months, and total haemocyte count (THC), phagocytic rate (PR) and haemocyte mortality (HM) were measured for 3, 6, 12 and 24 days under the same water temperature (20 °C) and salinity (15‰) conditions. The results showed that survival rates in treatments of CA ≤ 20.0, combined with pH ≤ 9.0, were 100%. LGR and WGR in treatments of CA 2.5 & pH 8.0 (control), CA 2.5 & pH 8.5 and CA 10.0 & pH 8.0 exhibited the largest values (P > 0.05), while in other treatments, they showed a decreasing trend with an increase in either CA or pH or both (P < 0.05). Similarly, for THC, PR and HM, no significant differences were observed among the fast growth treatments during the entire experimental period (P > 0.05), however, in other treatments, they presented significant differences, especially on day 3 and 6 (P < 0.05), most notably with increases in CA or pH, but returned to control levels on day 12. In conclusion, in this study, a strong interaction between CA and pH was observed. Additionally, it was ascertained that the Venus clam C. sinensis can withstand the stress of CA 20.0 combined pH 9.0, although individuals grows slowly and may take approximately 12 days to recover to the unstressed condition. 23869620 Role of glutamate receptors in the dorsal reticular nucleus in formalin-induced secondary allodynia. The role of glutamate receptors present in the medullary dorsal reticular nucleus (DRt) in the formalin test and formalin-induced secondary nociception was studied in rats. Secondary mechanical allodynia was assessed with von Frey filaments applied to the rat's hindpaw, and secondary thermal hyperalgesia was evaluated with the tail-immersion test. The selective glutamate receptor antagonists MK801 (N-methyl-d-aspartate receptor antagonist), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (AMPA/KA receptor antagonist) and A841720 (metabotropic glutamate 1 receptor antagonist) were injected into the DRt before or 6 days after formalin injection in the rat. In the formalin test, the three antagonists significantly reduced the number of flinches in both phases of the test. DRt microinjection of MK801 or A841720, but not of CNQX, reduced both secondary nociceptive behaviors. Moreover, pre-treatment with the three antagonists injected into the DRt prevented the development of secondary mechanical allodynia and secondary thermal hyperalgesia. Similarly, in these rats, the number of c-Fos-like immunoreactive neurons were markedly reduced in both the superficial and deep lamina of the dorsal horn. Our findings support the role of DRt as a pain facilitator in acute and chronic pain states, and suggest a key role of glutamate receptors during the development and maintenance of formalin-induced secondary allodynia. 23932699 Recent childbirth is an adverse prognostic factor in breast cancer and melanoma, but not in Hodgkin lymphoma. The relationship between gestation, childbirth and cancer prognosis is unknown for most cancers (e.g. Hodgkin lymphoma), whereas a body of evidence exists for melanoma and breast cancer. The national cancer registration and hospital discharge data for women in England (1998-2007) were linked, and the records for Hodgkin lymphoma, melanoma and breast cancer were indexed as to whether women had delivered a child in separate time periods prior to their cancer diagnosis. Survival analyses were conducted in order to characterise prognosis in relation to childbirth, with statistical adjustment for age and (where possible) stage. For melanoma and breast cancer, survival was strongly reduced in women who gave birth in the year prior to cancer diagnosis. The age-adjusted hazard ratios (HR) with 95% confidence intervals (CI) were 2.06 (1.42-3.01) for melanoma and 1.84 (1.64-2.06) for breast cancer. The associations were only slightly attenuated by further adjustment for tumour stage. For breast cancer, the excess death rate in women with a recent childbirth peaked at 2years and remained elevated for 6 to 8years. Previous childbirth had no overall effect on the outcome of Hodgkin lymphoma. Melanoma and breast cancer prognosis are adversely affected by recent gestation and childbirth in a way that is not due to stage of the cancer, but rather to inherent biological properties of the tumours. Possible biological mechanisms include immunosuppression (melanoma), the hormonal milieu in gestation and a tumour promoting microenvironment post-partum (breast cancer). 23953612 Electromembrane extraction from aqueous samples containing polar organic solvents. Electromembrane extraction (EME) was performed from aqueous samples and from aqueous samples containing methanol, ethanol, dimethyl sulfoxide, and acetonitrile. The basic drugs pethidine, haloperidol, nortriptyline, methadone and loperamide were used as model analytes. Reversed phase (C18) HPLC with UV (235nm) and MS detection was used for analysis of the samples. With no organic solvent in the sample, maximum recoveries were obtained after 5-10min. The maximum recoveries ranged between 83 and 95%. With 50% (v/v) methanol, ethanol, or dimethyl sulfoxide in the sample, recoveries were comparable to those from an aqueous sample, but the time required reaching maximum recovery increased to 15-25min. With 2-nitrophenyl octyl ether (NPOE) as the supported liquid membrane (SLM), a stable EME system was obtained for 50% (v/v) methanol, 50% (v/v) ethanol, or 75% (v/v) dimethyl sulfoxide in the sample solution. On the other hand, the EME system was unstable with acetonitrile in the sample, as this solvent partly dissolved the SLM. In addition, acetonitrile migrated through the SLM and caused a volume expansion of the acceptor solution. Other SLMs were also tested (ethyl nitrobenzene, isopropyl nitrobenzene, and dodecyl nitrobenzene), but were inferior to NPOE. As a practical example, EME on dried blood spot extracts (80% methanol) were tested, and proved highly successful. These observations showed that EME can be an effective way of preparing aqueous samples containing substantial amounts of an organic solvent. 23830933 Teaching epidemiology in the digital age: considerations for academicians and their students. The way in which we prepare future public health professionals is changing because of the digital age. Online education is expanding the accessibility of public health training to students and practitioners with diverse backgrounds. Online courses offer many advantages for students, including flexible schedules, elimination of commuting time, and fostering interactions among students and the instructor. A few disadvantages of online courses for the student can include a feeling of isolation, difficulty adjusting to the time-intensive nature, and the required self-discipline to regularly tend to online course materials that immature and working students can find challenging. For faculty who are faced with teaching epidemiology in these changing times of the traditional face-to-face classroom and the virtual classroom, the core teaching principles of this science of public health remain unchanged, yet how they are delivered in the online environment adds a layer of complexity not previously encountered. This paper presents practical considerations for faculty who will be teaching online and their students who will be learning online. In addition, a framework for an online epidemiology course is presented as a model by which faculty interested in teaching epidemiology online can modify the course structure, content, and assessment tools to fit their needs. 23947423 Bilateral Macular Folds as a Diagnostic Clue to Late-Presenting Posterior Microphthalmos. Abstract Posterior microphthalmos with macular folds is a very uncommon condition. We report such an unusual late-presenting case of posterior microphthalmos where macular folds uncovered the diagnosis and discuss the possibility of worsening of macular folds with advancing age. 23922158 Treatment of Primary Infected Juxtarenal Aortic Aneurysm With the Multilayer Stent. Purpose: To report the use of multilayer uncovered stent to treat primary infected juxtarenal aortic aneurysm. Case Report: A 50-year-old man was admitted to hospital for rapid onset of intractable abdominal pain and high fever. Computed tomographic scan showed 2 juxtarenal saccular aneurysms of abdominal aorta with morphologic and clinical changes compatible with infectious etiology. Patient was treated with multilayer flow-modulating stent. Follow-up imaging showed persistent aneurysm exclusion and continuous aneurysm shrinkage of the sac until complete regression to a normal aortic configuration was seen at 1 year. During follow-up (24 months), patient continued to do well, and there was no recurrence of infection.Conclusion: Multilayer stent appeared to be an acceptable treatment option for primary infected juxtarenal aortic aneurysms. Aneurysmal sac completely disappeared and visceral branches remained patent at 2-year follow-up. However, longer follow-up is necessary to evaluate the long-term patency of involved visceral arteries. 23864138 (19)F NMR: a valuable tool for studying biological events. With the spectacular advancement of NMR techniques and the flourishing of fluorine chemistry allowing the synthesis of various fluorinated molecules, (19)F NMR represents a compelling option for studying myriad biological events ranging from the structure and function of biomolecules, enzymatic mechanisms, and metabolic pathways, through to drug screening and discovery as well as medical imaging. In this tutorial review, we aim to provide readers with a brief overview of the recent applications of (19)F NMR in various areas relating to biological and biomedical research, together with a brief introduction of specific hardware improvements permitting the practical implementation of (19)F NMR. 23811396 Role of p300 in regulating neuronal nitric oxide synthase gene expression through nuclear factor-κB-mediated way in neuronal cells. Nuclear factor (NF)-κB acetylation has been shown to participate in a number of neurological processes by regulating the expression of certain genes. We have previously demonstrated the neuronal nitric oxide synthase (nNOS) expression and nitric oxide (NO) production may be regulated by NF-κB acetylation via an NF-κB responsive element within the nNOS promoter in neuronal cells. p300 is a ubiquitous transcription coactivator with intrinsic histone acetyltransferase (HAT) activity, which is important in the nervous system. In the present study, we aimed at probing if p300 participated in regulating the nNOS expression through the NF-κB-mediated way. As a result, we found p300 enhanced the nNOS protein and mRNA levels in human neuroblastoma SK-N-SH cells by enhancing the binding of NF-κB to the nNOS promoter and NF-κB-mediated nNOS transcription. Meanwhile, p300 was shown to directly acetylate NF-κB p65 and p50 subunits, interact with NF-κB and bind to the NF-κB responsive element region within the nNOS promoter. Taken together, our results indicate p300 acts as both an HAT and a coactivator in regulating NF-κB-mediated nNOS expression, which provide some correlations between p300 and nNOS in neuronal cell, and suggest that some p300-related neurological disorders may be partially based on its effect on the nNOS expression. 23884813 Clinicopathological features of neuropathy associated with lymphoma. Lymphoma causes various neurological manifestations that might affect any part of the nervous system and occur at any stage of the disease. The peripheral nervous system is one of the major constituents of the neurological involvement of lymphoma. In this study we characterized the clinical, electrophysiological and histopathological features of 32 patients with neuropathy associated with non-Hodgkin's lymphoma that were unrelated to complications resulting from treatment for lymphoma. Nine patients had pathologically-proven neurolymphomatosis with direct invasion of lymphoma cells into the peripheral nervous system. These patients showed lymphomatous cell invasion that was more prominent in the proximal portions of the nerve trunk and that induced demyelination without macrophage invasion and subsequent axonal degeneration in the portion distal from the demyelination site. Six other patients were also considered to have neurolymphomatosis because these patients showed positive signals along the peripheral nerve on fluorodeoxyglucose positron emission tomography imaging. Spontaneous pain can significantly disrupt daily activities, as frequently reported in patients diagnosed with neurolymphomatosis. In contrast, five patients were considered to have paraneoplastic neuropathy because primary peripheral nerve lesions were observed without the invasion of lymphomatous cells, with three patients showing features compatible with chronic inflammatory demyelinating polyneuropathy, one patient showing sensory ganglionopathy, and one patient showing vasculitic neuropathy. Of the other 12 patients, 10 presented with multiple mononeuropathies. These patients showed clinical and electrophysiological features similar to those of neurolymphomatosis rather than paraneoplastic neuropathy. Electrophysiological findings suggestive of demyelination were frequently observed, even in patients with neurolymphomatosis. Eleven of the 32 patients, including five patients with neurolymphomatosis, fulfilled the European Federation of Neurological Societies/Peripheral Nerve Society electrodiagnostic criteria of definite chronic inflammatory demyelinating polyneuropathy. Some of these patients, even those with neurolymphomatosis, responded initially to immunomodulatory treatments, including the administration of intravenous immunoglobulin and steroids. Patients with lymphoma exhibit various neuropathic patterns, but neurolymphomatosis is the major cause of neuropathy. Misdiagnoses of neurolymphomatosis as chronic inflammatory demyelinating polyneuropathy are frequent due to a presence of a demyelinating pattern and the initial response to immunomodulatory treatments. The possibility of the concomitance of lymphoma should be considered in various types of neuropathy, even if the diagnostic criteria of chronic inflammatory demyelinating polyneuropathy are met, particularly in patients complaining of pain. 23959898 Pulsed hydrogen-deuterium exchange mass spectrometry probes conformational changes in amyloid beta (Aβ) peptide aggregation. Probing the conformational changes of amyloid beta (Aβ) peptide aggregation is challenging owing to the vast heterogeneity of the resulting soluble aggregates. To investigate the formation of these aggregates in solution, we designed an MS-based biophysical approach and applied it to the formation of soluble aggregates of the Aβ42 peptide, the proposed causative agent in Alzheimer's disease. The approach incorporates pulsed hydrogen-deuterium exchange coupled with MS analysis. The combined approach provides evidence for a self-catalyzed aggregation with a lag phase, as observed previously by fluorescence methods. Unlike those approaches, pulsed hydrogen-deuterium exchange does not require modified Aβ42 (e.g., labeling with a fluorophore). Furthermore, the approach reveals that the center region of Aβ42 is first to aggregate, followed by the C and N termini. We also found that the lag phase in the aggregation of soluble species is affected by temperature and Cu(2+) ions. This MS approach has sufficient structural resolution to allow interrogation of Aβ aggregation in physiologically relevant environments. This platform should be generally useful for investigating the aggregation of other amyloid-forming proteins and neurotoxic soluble peptide aggregates. 22527709 A collaborative care model to improve access to pediatric mental health services. To examine if an innovative collaborative care model known as Targeted Child Psychiatric Services designed for primary care pediatricians (PCPs) and child psychiatrists (1) was associated with improved access to child psychiatry services, (2) had the potential to identify optimal care settings for pediatric mental health care and (3) examined if pediatricians appeared as likely to accept children back into their practices at discharge from TCPS depending upon diagnostic category, controlling for severity of illness and function. The diagnostic classes examined were ADHD (39%), depression (31%) and anxiety (13%). This prospective cohort design study collected medical records of 329 children referred to TCPS by 139 PCPs. To detect the likelihood of return to referring pediatricians for follow-up care at discharge from TCPS, we employed logistic regression models. Mean age was 12.3 (SD = 4.0); 43% were female. Ninety-three percent of parents complied with pediatricians' recommendations to have their child assessed by a child psychiatrist. A total of 28.0% of referrals returned to PCPs for follow-up care; the remainder were followed in mental health. Regression findings indicated that children with major depression (OR = 7.5) or anxiety disorders (OR = 5.1) were less likely to return to PCPs compared to ADHD even though severity of psychiatric illness and functional levels did not differ across diagnostic groups. Families widely accepted pediatricians' recommendations for referral to child psychiatrists. Depression and anxiety were strong correlates of retention in mental health settings at discharge from TCPS though children with these disorders appeared to be no more severely ill or functionally limited than peers with ADHD. These children possibly could be managed in a less intensive and expensive primary care treatment setting that could access mental health specialty services as needed in a collaborative model of care. TCPS is contrasted with the well-known collaborative model for adult depression in primary care. TCPS could serve as a feasible model of care that addresses the daunting barriers in accessing pediatric mental health services. 23928520 Histopathology of the Inner Ear in Patients With Xeroderma Pigmentosum and Neurologic Degeneration. Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by mutations resulting in defective repair of DNA damage. XP patients have a markedly increased risk of ultraviolet-induced neoplasms and premature aging of sun-exposed tissue. Approximately 25% of XP patients in the United States have neurologic abnormalities including progressive sensorineural hearing loss (SNHL). To describe the temporal bone histopathology in 2 individuals with XP (XPA and XPD) with neurologic degeneration and to discuss the possible causes of deafness in these patients. Temporal bones were removed at autopsy and studied using light microscopy. In the case with XPD, the organ of Corti was missing throughout the cochlea, whereas the case with XPA demonstrated scattered presence of sensory cells in the middle and apical turns. In both cases, there was moderate-to-severe patchy atrophy of the stria vascularis in all turns, and cochlear neurons were severely atrophied compared with age-matched controls, with loss of both peripheral dendrites and central axons. There was severe degeneration of Scarpa's ganglion in the case with XPA. Two cases of XP with neurologic degeneration are reported. The case with XPD demonstrated a more severe audiologic phenotype than XPA, although both had similar findings such as atrophy of the organ of Corti, stria vascularis, and spiral ganglia leading to severe or profound SNHL by the third decade of life. It is not clear if the neuronal degeneration in the inner ear was primary or secondary to loss of neuroepithelial cells. 22200242 Temperature-sensitive hydrogels by graft polymerization of chitosan and N-isopropylacrylamide for drug release. Thermo-responsive polysaccharidic hydrogels were designed and synthesized by a free radical induced grafting procedure. Chitosan was chosen as biopolymer to impart biocompatibility and biodegradability to the macromolecular systems, while N-isopropylacrylamide (NIPAAm) was selected as co-monomer responsive for the thermo-sensitive properties. Ammonium persulfate was the initiator system and different polymeric networks have been synthesized by modulating the amount of NIPAAm in the polymerization feed. The resulting hydrogels were proposed as drug delivery devices and their performance was evaluated by using Diclofenac sodium salt as a model drug. Hydrogels were carefully characterized by FT-IR spectrophotometry, calorimetric analyses and swelling behavior in a temperature range of 15-45°C. Finally, to verify the suitability of these hydrogels as thermo-responsive devices, the drug release profiles were studied performing in vitro experiments around the swelling-shrinking transition temperatures of the macromolecular systems. 23382028 A dose-finding study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcoma. There are few effective therapies for high-risk sarcomas. Initial chemosensitivity is often followed by relapse. In vitro, mammalian target of rapamycin (mTOR) inhibition potentiates the efficacy of chemotherapy on resistant sarcoma cells. Although sarcoma trials using mTOR inhibitors have been disappointing, these drugs were used as maintenance. We conducted a Phase I/II clinical trial to test the ability of temsirolimus to potentiate the cytotoxic effect of liposomal doxorubicin and present here the dose-finding portion of this study. Adult and pediatric patients with recurrent or refractory sarcomas were treated with increasing doses of liposomal doxorubicin and temsirolimus using a continual reassessment method for escalation, targeting a dose-limiting toxicity rate of 20%. Blood samples were drawn before and after the first dose of temsirolimus in Cycles 1 and 2 for pharmacokinetic analysis. The maximally tolerated dose combination was liposomal doxorubicin 30 mg/m(2) monthly with temsirolimus 20 mg/m(2) weekly. Hematologic toxicity was common but manageable. Dose-limiting toxicities were primarily renal. Concurrent administration of liposomal doxorubicin resulted in increased exposure to sirolimus, the active metabolite of temsirolimus. Thus, the combination of liposomal doxorubicin and temsirolimus is safe for heavily pretreated sarcoma patients. Co-administration with liposomal doxorubicin did not alter temsirolimus pharmacokinetics, but increased exposure to its active metabolite. 23863908 Feasibility and Effectiveness in Clinical Practice of a Multifactorial Intervention for the Reduction of Cardiovascular Risk in Patients With Type 2 Diabetes: The 2-year interim analysis of the MIND.IT study: a cluster randomized trial. OBJECTIVE To evaluate the feasibility and effectiveness of an intensive, multifactorial cardiovascular risk reduction intervention in a clinic-based setting. RESEARCH DESIGN AND METHODS The study was a pragmatic, cluster randomized trial, with the diabetes clinic as the unit of randomization. Clinics were randomly assigned to either continue their usual care (n = 5) or to apply an intensive intervention aimed at the optimal control of cardiovascular disease (CVD) risk factors and hyperglycemia (n = 4). To account for clustering, mixed model regression techniques were used to compare differences in CVD risk factors and HbA1c. Analyses were performed both by intent to treat and as treated per protocol. RESULTS Nine clinics completed the study; 1,461 patients with type 2 diabetes and no previous cardiovascular events were enrolled. After 2 years, participants in the interventional group had significantly lower BMI, HbA1c, LDL cholesterol, and triglyceride levels and significantly higher HDL cholesterol level than did the usual care group. The proportion of patients reaching the treatment goals was systematically higher in the interventional clinics (35% vs. 24% for LDL cholesterol, P = 0.1299; 93% vs. 82% for HDL cholesterol, P = 0.0005; 80% vs. 64% for triglycerides, P = 0.0002; 39% vs. 22% for HbA1c, P = 0.0259; 13% vs. 5% for blood pressure, P = 0.1638). The analysis as treated per protocol confirmed these findings, showing larger and always significant differences between the study arms for all targets. CONCLUSIONS A multifactorial intensive intervention in type 2 diabetes is feasible and effective in clinical practice and it is associated with significant and durable improvement in HbA1c and CVD risk profile. 22334483 Slow delayed rectifying potassium current (IKs ) - analysis of the in vitro inhibition data and predictive model development. The excitable cell membranes contain ion channels that allow the ions passage through the specific pores via a passive process. Assessment of the inhibition of the IKr (hERG) current is considered to be the main target during the drug development process, although there are other ionic currents for which drug-triggered modification can either potentiate or mask hERG channel blockade. Information describing the results of in vitro studies investigating the chemical-IKs current interactions has been developed in the current study. Based on the publicly available data sources, 145 records were collected. The final list of publications consists of 64 positions and refers to 106 different molecules connected with IKs current inhibition, with at least one IC50 value measured. Ultimately, 98 of the IC50 values expressed as absolute values were gathered. For 36 records the IC50 was expressed as a relative value. For the 11 remaining records, the inhibition was not clearly expressed. Based on the collected data the predictive models for the IC50 estimation were developed with the use of various algorithms. The extended Quantitative Structure-Activity Relationships (QSAR) methodology was applied and the in vitro research settings were included as independent variables, apart from the physico-chemical descriptors calculated with the use of the Marvin Calculator Plugins. The root mean squared error and normalized root mean squared error values for the best model (an expert system based on two independent artificial neural networks) were 0.86 and 14.04%, respectively. The model was further built into the ToxComp system, the ToxIVIVE tool specialized for cardiotoxicity assessment of drugs. 23644191 Designing, structural elucidation, comparison of DNA binding, cleavage, radical scavenging activity and anticancer activity of copper(I) complex with 5-dimethyl-2-phenyl-4-[(pyridin-2-ylmethylene)-amino]-1,2-dihydro-pyrazol-3-one Schiff base ligand. A novel copper(I) Schiff base complex has been synthesized and fully characterized by spectral, analytical and structural modes. Single crystal X-ray diffraction studies revealed that the copper(I) complex [CuCl(PPh3)L] has a distorted tetrahedral geometry around the central copper(I) ion. The interaction of the ligand and the complex with CT-DNA has been explored by absorption titration method which revealed that the compounds could interact with CT-DNA through intercalation. A gel electrophoresis assay demonstrated the ability of the complex to cleave the pBR322 DNA. The antioxidative properties showed that the copper(I) complex has a strong radical-scavenging potency than ligands. Further the cytotoxic effect of the compounds examined on cancerous cell lines showed that the complex exhibited substantial anticancer activity. 23498713 Acute burn induced coagulopathy. Acute traumatic coagulopathy is well described in the trauma population. Major burns are characterised by a similar endothelial injury and cellular hypoperfusion. These features could be a driver for an acute burn induced coagulopathy (ABIC). Patients admitted to a regional burn centre over a 71 months period with a total body surface area burn of 30% or more were identified. The metavision electronic patient database was scrutinised for a predetermined list of demographics, interventions and admission investigations to identify any clinically significant ABIC. On admission 39.3% of the 117 patients analysed met our criteria for a coagulopathy. Of the patients with a coagulopathy, 71.7% had an elevated Prothrombin Time (PT), 2.2% had an elevated Activated Partial Thromboplastin time (APPT) and 26.1% had an elevation of both. Patients with a coagulopathy received a similar volume of fluid (p=0.08). There was a statistically significant correlation between the PT and the abbreviated burn severity index (p=0.0013, r=0.292) and serum lactate (p=0.0013, r=0.292). ABIC was an independent predictor of 28 day mortality, OR 3.42(1.11-10.56). In patients with major thermal injuries a clinically significant ABIC exists. Early diagnosis and treatment of ABIC should be considered particularly in those undergoing total burn wound excision. 23850408 Comparison of HRQL Between Unicompartmental Knee Arthroplasty and Total Knee Arthroplasty for the Treatment of Osteoarthritis. This retrospective study evaluates the health related quality of life (HRQL) of patients following unicompartmental knee arthroplasty (UKA) compared to total knee arthroplasty (TKA) for osteoarthritis treatment. The Western Ontario and McMaster Osteoarthritis index (WOMAC) and the Oxford Knee score (OKS) were recorded at baseline, 3 and 6months. Analysis of 317 UKAs and 425 TKAs showed no significant differences in HRQL between the two groups at baseline, but the TKA group was significantly older and more likely to be male. Both groups showed an overall improvement in the total WOMAC and OKS over time, with males showing significant improvement over females. Adjusting for age and gender, there was no significant difference between UKA and TKA in HRQL over the first 6months following surgery. 23959075 A human strain of Oxalobacter (HC-1) promotes enteric oxalate secretion in the small intestine of mice and reduces urinary oxalate excretion. Enteric oxalate secretion that correlated with reductions in urinary oxalate excretion was previously reported in a mouse model of primary hyperoxaluria, and in wild type (WT) mice colonized with a wild rat strain (OXWR) of Oxalobacter (Am J Physiol 300:G461-G469, 2010). Since a human strain of the bacterium is more likely to be clinically used as a probiotic therapeutic, we tested the effects of HC-1 in WT. Following artificial colonization of WT mice with HC-1, the bacteria were confirmed to be present in the large intestine and, unexpectedly, detected in the small intestine for varying periods of time. The main objective of the present study was to determine whether the presence of HC-1 promoted intestinal secretion in the more proximal segments of the gastrointestinal tract. In addition, we determined whether HC-1 colonization led to reductions in urinary oxalate excretion in these mice. The results show that the human Oxalobacter strain promotes a robust net secretion of oxalate in the distal ileum as well as in the caecum and distal colon and these changes in transport correlate with the beneficial effect of reducing renal excretion of oxalate. We conclude that OXWR effects on intestinal oxalate transport and oxalate homeostasis are not unique to the wild rat strain and that, mechanistically, HC-1 has significant potential for use as a probiotic treatment for hyperoxaluria especially if it is also targeted to the upper and lower gastrointestinal tract. 23850480 Predicting protein subchloroplast locations with both single and multiple sites via three different modes of Chou's pseudo amino acid compositions. Owing to the fact that location information can indicate important functionalities of proteins, developing computational tools to predict protein subcellular localization is one of the most efficient and meaningful tasks with no doubt. The existence methods dealing with prediction of protein subchloroplast locations can only handle the case of single location site. Therefore, it is meaningful and challenging to make effort in how to deal with the proteins with multiple subchloroplast location sites instead of just excluding them. To solve this problem, new systems for predicting protein subchloroplast localization with single or multiple sites are developed and discussed in the paper. Three different editions of KNN algorithms and four different types of feature extraction were adopted to construct the prediction systems. This is the first effort to predict the proteins with multiple subchloroplast locations. The overall jackknife success rates achieved by the best combination (features+classifier) on three dataset with different levels of homology were 89.08%, 81.29% and 71.11%. The performance of the prediction models indicate that the proposed methods might be applied as a useful and efficient assistant tool for the prediction of sub-subcellular localizations. 23889807 Global health actors no longer in favor of user fees: a documentary study. Since the advent of health user fees in low- and middle-income countries in the 1980s, the discourse of global health actors (GHAs) has changed to the disadvantage of this type of healthcare financing mechanism. The aim of the study was to identify and analyze the stance of GHAs in the debate on user fees. We conducted documentary research using public documents published by and officially attributed to GHAs from 2005 to 2011. We categorized GHAs into four groups: intergovernmental organizations, international non-governmental organizations, government agencies, and working groups and networks. We then classified the GHAs according to their stance relative to the abolition of user fees, and conducted a thematic analysis of their discourse to understand the arguments used by each GHA to justify its stance. We identified 56 GHAs, for which we analyzed 140 documents. Among them, 55% were in favor of the abolition of user fees or in favor of free care at the point of delivery. None of the GHAs stated that they were in favor of user fees; however, 30% did not take a stand. Only the World Bank declares that it is both in favor of user fees and in favor of free care at point of service. GHAs generally circumscribe their stance to specific populations (pregnant women, children under 5 years, etc.) or to specific health services (primary, basic, essential). Three types of arguments are used by GHAs to justify their stance: economic, moral and ethical, and pragmatic. The principle of "user pays" seems to have fizzled. Production and dissemination of evidence, as well as certain advocacy networks, may have contributed to this change in discourse. However, GHAs should go a step further and translate their words into action, so that free healthcare at the point of delivery becomes a reality in low- and middle-income countries. They should provide technical and financial support to those countries that have chosen to implement user fee exemption policies, sometimes influenced by a GHA. 23918153 Single Nucleotide Polymorphisms of Caudal Type Homeobox 1 and 2 Are Associated with Barrett's Esophagus. Barrett's esophagus (BE), the premalignant lesion of esophageal adenocarcinoma, is believed to develop as a result of chronic gastroesophageal reflux disease (GERD). Approximately 10 % of subjects with GERD progress to BE. Genetic, epigenetic and other risk factors may contribute to this inter-individual variability. Caudal type homeobox 1 (Cdx1) and Caudal type homeobox 2 (Cdx2) play important regulatory roles in the development of human BE. To determine associations between Cdx1 and Cdx2 single nucleotide polymorphisms (SNPs) and BE. Genomic DNA was extracted from blood samples collected from BE (n = 109) and GERD (n = 223) patients for genotyping of 5 SNPs each of Cdx1 and Cdx2 using TaqMan allelic discrimination assays. Odds ratios and 95 % confidence intervals of SNPs and haplotypes were calculated with a logistic regression model adjusted for factors including age, sex and hiatal hernia. Interactions between genetic variants and these three risk factors were also analyzed. Older age (≥50 years), male sex and hiatal hernia were significantly associated with BE (P < 0.001). Five variants of Cdx1 SNPs (rs3776082, rs717746 and rs3776083), one Cdx1 haplotype, and three variants of Cdx2 SNPs (rs4769585 and rs3812863) were associated with BE (P < 0.05). Statistically significant interactions were detected between most of these SNPs and the three risk factors (P < 0.05). Certain SNPs of Cdx1 and Cdx2 and their interactions with other risk factors are associated with BE, and may contribute to human susceptibility to BE. 23903146 Calibration-free quantification of absolute oxygen saturation based on the dynamics of photoacoustic signals. Photoacoustic tomography (PAT) is a hybrid imaging technique that has broad preclinical and clinical applications. Based on the photoacoustic effect, PAT directly measures specific optical absorption, which is the product of the tissue-intrinsic optical absorption coefficient and the local optical fluence. Therefore, quantitative PAT, such as absolute oxygen saturation (sO2) quantification, requires knowledge of the local optical fluence, which can only be estimated through invasive measurements or sophisticated modeling of light transportation. In this Letter, we circumvent this requirement by taking advantage of the dynamics in sO2. The new method works when the sO2 transition can be simultaneously monitored with multiple wavelengths. For each wavelength, the ratio of photoacoustic amplitudes measured at different sO2 states is utilized. Using the ratio cancels the contribution from optical fluence and allows calibration-free quantification of absolute sO2. The new method was validated through both phantom and in vivo experiments. 23824483 HIV in the Middle East and North Africa: priority, culture, and control. This study aimed to assess the priority of HIV/AIDS in the Middle East and North Africa region and compare it with other regions. This review examines the social, cultural and religious features of HIV in the region, and considers their influence on perception of risk and approaches to control, such as condom use and antiretroviral therapy. We screened a wide range of sources for comprehensive and reliable data; the search of PubMed, ISI Web of Science, ScienceDirect, and grey literature databases were unrestricted by language and year of publication. Studies of HIV/AIDS in the region are limited, especially studies of social aspects of HIV/AIDS and their relevance for control. Findings suggest low condom use across the region among high-risk groups, and the general population, and low antiretroviral therapy uptake among people with HIV/AIDS. The review indicates gaps in the literature and needs for more academic engagement and political commitment. Cultural norms have notable implications for HIV control, which are discussed, considering implications for the priority, prevention, treatment, and control of HIV/AIDS. 23910664 Pharmacokinetic and Pharmacodynamic Properties of Single- and Multiple-Dose of Dapagliflozin, a Selective Inhibitor of SGLT2, in Healthy Chinese Subjects. Dapagliflozin, a selective, orally active, renal sodium glucose cotransporter 2 (SGLT2) 2 inhibitor, is under investigation as a treatment of type 2 diabetes mellitus (T2DM). Dapagliflozin reduces hyperglycemia by inhibiting renal glucose reabsorption and dose-dependently increasing urinary glucose excretion, independent of insulin secretion or action. These studies assessed the single- and multiple-dose pharmacokinetic and pharmaco dynamic properties of dapagliflozin and its major inactive metabolite, dapagliflozin 3-O-glucuronide (D3OG), in healthy subjects residing in China. In 2 identically designed, open-label, single- and multiple-dose studies (n = 14 for both studies), healthy Chinese subjects were administered oral dapagliflozin 5 or 10 mg. In both studies, subjects received a single dose on day 1 (single-dose administration period) followed by 6 once-daily doses on days 5 to 10 (multiple-dose administration period). Pharmacokinetic parameters (plasma and urinary dapagliflozin and D3OG), pharmacodynamic response (urinary glucose excretion), and tolerability were assessed. Fourteen subjects completed the dapagliflozin 5-mg study, and 13 completed the dapagliflozin 10-mg study. Baseline characteristics were balanced across the two studies: 9 versus 10 men; mean age, 27.1 versus 28.9 years; mean weight, 62.8 versus 62.2 kg; and mean body mass index, 23.0 versus 22.2 kg/m(2) in the dapagliflozin 5- and 10-mg studies, respectively. In both doses, dapagliflozin was rapidly absorbed (Tmax, ≤1.5 h), accumulation (defined as the geometric mean ratio of AUCτ at day 10 to AUCτ at day 1) after multiple dosing was minimal (<1.13 fold), and elimination half-life was 10 to 12 h. D3OG showed a slightly longer median Tmax (≤2 h) but a similar plasma concentration-time profile and half-life compared with dapagliflozin. The majority of D3OG (up to 69.7% of the dapagliflozin dose) was excreted in urine, while ≤1.9% of dapagliflozin was excreted unchanged in urine. Over a 24-hour period and at steady state (day 10), urinary glucose excretion values were 28.1 and 41.1 g with dapagliflozin 5 and 10 mg, respectively. Dapagliflozin was generally well tolerated; one dapagliflozin 10 mg-treated subject discontinued the study because of a serious adverse event (bronchitis) considered by the investigator as unrelated to dapagliflozin dosing. Pharmacokinetic and pharmacodynamic characteristics following single- and multiple-dose dapagliflozin 5 and 10 mg oral administration in healthy Chinese subjects were as predicted from previous studies and were similar to findings observed in non-Chinese healthy subjects. Dapagliflozin dosing was well tolerated. The clinically recommended dapagliflozin dose of 10 mg once daily is expected to be appropriate in patients of Chinese ethnicity; results from an efficacy and tolerability study in Chinese patients with T2DM are awaited. 23924210 Asymmetric catalysis at a distance: catalytic, site-selective phosphorylation of teicoplanin. We report three distinct, peptide-based catalysts that enable site-selective phosphorylation of three distinct hydroxyl groups within the complex glycopeptide antibiotic teicoplanin A2-2. Two of the catalysts are based on a design that capitalizes on a catalyst-substrate interaction that mimics the biological mechanism of action for teicoplanin. These catalysts are based on a dXaa-dXaa peptide motif that is known to target the teicoplanin structure in a specific manner. The third was identified through evaluation of a set of catalysts that had been developed for historically distinct projects. Each catalyst contains additional functionality designed to dispose a catalytic moiety (a nucleophilic alkylimidazole) at a different region of the glycopeptide structure. A combination of mass spectrometry and 2D-NMR spectroscopy allowed structural assignment of the distinct phosphorylated teicoplanin derivatives. Mechanistic studies are also reported that support the hypotheses that led to the discovery of the catalysts. In this manner, small molecule catalysts have been achieved that allow rational, catalytic control over reactions at sites that are separated by 11.6, 16.5, and nearly 17.7 Å, based on the X-ray crystal structure of teicoplanin A2-2. Finally, we report the biological activity of the new phosphorylated teicoplanin analogs and compare the results to the natural product itself. 23384072 Development of quantitative structure-metabolism (QSMR) relationships for substituted anilines based on computational chemistry. Abstract 1. A novel stepwise classification approach for predicting the metabolic fate of substituted anilines, based on calculated physicochemical parameters of the parent anilines, was developed. Based on multivariate pattern recognition methods (PLS-DA or soft independent modelling of class analogy [SIMCA]), these models allowed prediction of N-acetylation and subsequent N-oxanilic acid formation. These classification methods provided an improved classification success when compared with existing quantitative structure-metabolism relationship models for substituted anilines. 2. Modelling the physicochemical properties of the N-acetylated compounds was considered as an addition to the stepwise model. Inclusion of parameters describing the N-acetyl moiety had little effect on the predictive ability of a stepwise parent to N-acetyl to N-oxanilic acid PLS-DA model, and had a negative impact on that of SIMCA models. This was attributed to the relatively small contribution to the total parameter variance caused by differences arising as a result of N-acetylation compared to the contribution made by the substituent effects. 3. Calculation of physicochemical properties incorporating the effect of solvation using ab initio methods improved the classification model in terms of both the visual separation in multivariate projections and prediction accuracy. 23830660 Biowarfare and Bioterrorism. Bioterrorism is not only a reality of the times in which we live but bioweapons have been used for centuries. Critical care physicians play a major role in the recognition of and response to a bioterrorism attack. Critical care clinicians must be familiar with the diagnosis and management of the most likely bioterrorism agents, and also be adequately prepared to manage a mass casualty situation. This article reviews the epidemiology, diagnosis, and treatment of the most likely agents of biowarfare and bioterrorism. 23357365 Point-of-care assays for tuberculosis: role of nanotechnology/microfluidics. Tuberculosis (TB) remains one of the most devastating infectious diseases and its eradication is still unattainable given the limitations of current technologies for diagnosis, treatment and prevention. The World Health Organization's goal to eliminate TB globally by 2050 remains an ongoing challenge as delayed diagnosis and misdiagnosis of TB continue to fuel the worldwide epidemic. Despite considerable improvements in diagnostics for the last few decades, a simple and effective point-of-care TB diagnostic test is yet not available. Here, we review the current assays used for TB diagnosis, and highlight the recent advances in nanotechnology and microfluidics that potentially enable new approaches for TB diagnosis in resource-constrained settings. 23729301 Antioxidant, anticonvulsive and neuroprotective effects of dapsone and phenobarbital against kainic Acid-induced damage in rats. Excitotoxicity due to glutamate receptors (GluRs) overactivation is a leading mechanism of oxidative damage and neuronal death in various diseases. We have shown that dapsone (DDS) was able to reduce both neurotoxicity and seizures associated to the administration of kainic acid (KA), an agonist acting on AMPA/KA receptors (GluK1-GluK5). Recently, it has been shown that phenobarbital (PB) is also able to reduce epileptic activity evoked by that receptor. In the present study, we tested the antioxidative, anticonvulsive and neuroprotective effects of DDS and PB administered alone or in combination upon KA toxicity to rats. Results showed that KA increased lipid peroxidation and diminished reduced glutathione (GSH), 24 h after KA administration and both drugs in combination or individually inhibited these events. Likewise, KA promotes mortality and this event was antagonized by effect of both treatments. Additionally, the behavioral evaluation showed that DDS and PB administered alone or in combination decreased the number of limbic seizures and reduced the percentage of animals showing tonic-clonic seizures versus the control group, which was administered only with KA. Finally, our study demonstrated that all of the treatments prevented the neuronal death of the pyramidal cell layer of hippocampal CA-3. In conclusion, the treatment with DDS and PB administrated alone or in combination exerted antioxidant, anticonvulsive and neuroprotective effects against the neurotoxicity induced by KA in rats, but their effects were not additive. Thus, it may be good options of treatment in diseases such as epilepsy and status epilepicus, administered separately. 23942545 Monitoring Antigen-Specific Biologics: Current Knowledge and Future Prospects. : An increasing number of antigen-specific biologics have been introduced into clinical practice, and the ones that arrived first have already reached the end of their patented life span. Despite the use of these agents for over a decade, individualized dosing is not standard practice. Most patients are treated according to treatment protocols, with a fixed dose administered at fixed time intervals. Although the between-subject variability in the volume of distribution is small, there is a moderate to high between-subject variability in the clearance of these biologics. The formation of neutralizing antidrug antibodies (ADAs) further contributes to the variability in the pharmacokinetics and pharmacodynamics. After the development of assays to detect biologic drug serum concentrations and ADA titers, the first clinical studies in immune-mediated diseases such as rheumatology, gastroenterology, and dermatology have now shown clear concentration-effect relationships. By monitoring the serum trough concentrations of biologics, patients with high drug exposure could be identified and dose reductions in those patients may lead to improved safety and substantial cost savings. Low biologic drug serum concentrations may be due to the development of ADAs, and if these are detected, a switch to an alternative treatment is indicated. We envision a vast expansion of therapeutic drug monitoring to support the use of biologics, and we urge the International Association of Therapeutic Drug Monitoring and Clinical Toxicology to embark on initiatives to investigate the contribution of therapeutic drug monitoring to this field. 23902750 T-cell reconstitution during murine acquired immunodeficiency syndrome (MAIDS) produces neuroinflammation and mortality in animals harboring opportunistic viral brain infection. Highly active antiretroviral therapy (HAART) restores inflammatory immune responses in AIDS patients which may unmask previous subclinical infections or paradoxically exacerbate symptoms of opportunistic infections. In resource-poor settings, 25% of patients receiving HAART may develop CNS-related immune reconstitution inflammatory syndrome (IRIS). Here we describe a reliable mouse model to study underlying immunopathological mechanisms of CNS-IRIS. Utilizing our HSV brain infection model and mice with MAIDS, we investigated the effect of immune reconstitution on MAIDS mice harboring opportunistic viral brain infection. Using multi-color flow cytometry, we quantitatively measured the cellular infiltrate and microglial activation. Infection with the LP-BM5 retroviral mixture was found to confer susceptibility to herpes simplex virus (HSV)-1 brain infection to normally-resistant C57BL/6 mice. Increased susceptibility to brain infection was due to severe immunodeficiency at 8 wks p.i. and a marked increase in programmed death-1 (PD-1) expression on CD4+ and CD8+ T-cells. Both T-cell loss and opportunistic brain infection were associated with high level PD-1 expression because PD-1-knockout mice infected with LP-BM5 did not exhibit lymphopenia and retained resistance to HSV-1. In addition, HSV-infection of MAIDS mice stimulated peripheral immune cell infiltration into the brain and its ensuing microglial activation. Interestingly, while opportunistic herpes virus brain infection of C57BL/6 MAIDS mice was not itself lethal, when T-cell immunity was reconstituted through adoptive transfer of virus-specific CD3+ T-cells, it resulted in significant mortality among recipients. This immune reconstitution-induced mortality was associated with exacerbated neuroinflammation, as determined by MHC class II expression on resident microglia and elevated levels of Th1 cytokines in the brain. Taken together, these results indicate development of an immune reconstitution disease within the central nervous system (CNS-IRD). Experimental immune reconstitution disease of the CNS using T-cell repopulation of lymphopenic murine hosts harboring opportunistic brain infections may help elucidate neuroimmunoregulatory networks that produce CNS-IRIS in patients initiating HAART. 23877016 Pioglitazone does not affect the risk of ovarian cancer: Analysis of a nationwide reimbursement database in Taiwan. The association between pioglitazone and ovarian cancer has not been studied. The reimbursement databases of all Taiwanese patients with a diagnosis of diabetes and under oral anti-diabetic agents or insulin from 1996 to 2009 were retrieved from the National Health Insurance. An entry date was set at 1 January 2006 and a total of 546,632 female patients with type 2 diabetes were followed up for ovarian cancer incidence until the end of 2009. Incidences for ever-users, never-users and subgroups of pioglitazone exposure [using cutoffs of the Kaiser Permanente Northern California study and tertile cutoffs derived from the databases] were calculated and the hazard ratios were estimated by Cox regression in unadjusted, age-adjusted and fully adjusted models. There were 30,783 ever-users and 515,849 never-users, with respective numbers of incident ovarian cancer of 49 (0.16%) and 946 (0.18%), and respective incidence of 43.08 and 51.47 per 100,000 person-years. The overall hazard ratios (95% confidence intervals) in unadjusted, age-adjusted and fully adjusted models were 0.822 (0.616-1.095), 0.823 (0.617-1.097) and 0.968 (0.718-1.305), respectively. In the dose-response analyses, none of the categories showed a significant hazard ratio, and all P-trends were >0.05 without statistical significance. This study does not support a positive or negative association between pioglitazone use and ovarian cancer in female patients with type 2 diabetes. 23736642 Investigation of whole-brain white matter identifies altered water mobility in the pathogenesis of high-altitude headache. Elevated brain water is a common finding in individuals with severe forms of altitude illness. However, the location, nature, and a causative link between brain edema and symptoms of acute mountain sickness such as headache remains unknown. We examined indices of brain white matter water mobility in 13 participants after 2 and 10 hours in normoxia (21% O2) and hypoxia (12% O2) using magnetic resonance imaging. Using a whole-brain analysis (tract-based spatial statistics (TBSS)), mean diffusivity was reduced in the left posterior hemisphere after 2 hours and globally reduced throughout cerebral white matter by 10 hours in hypoxia. However, no changes in T2 relaxation time (T2) or fractional anisotropy were observed. The TBSS identified an association between changes in mean diffusivity, fractional anisotropy, and T2 both supra and subtentorially after 2 and 10 hours, with headache score after 10 hours in hypoxia. Region of interest-based analyses generally confirmed these results. These data indicate that acute periods of hypoxemia cause a shift of water into the intracellular space within the cerebral white matter, whereas no evidence of brain edema (a volumetric enlargement) is identifiable. Furthermore, these changes in brain water mobility are related to the intensity of high-altitude headache. 23963476 Chromogenic detection of Sarin by discolouring decomplexation of a metal coordination complex. An innovative chromogenic sensing concept based on decomplexation of a tris-(bipyridine)iron(ii) coordination complex has been developed for the detection of organophosphorus nerve agents. It was evaluated both on a simulant and real Sarin in vapour and liquid phases. 23340251 IGF-I signaling is essential for FSH stimulation of AKT and steroidogenic genes in granulosa cells. FSH and IGF-I synergistically stimulate gonadal steroid production; conversely, silencing the FSH or the IGF-I genes leads to infertility and hypogonadism. To determine the molecular link between these hormones, we examined the signaling cross talk downstream of their receptors. In human and rodent granulosa cells (GCs), IGF-I potentiated the stimulatory effects of FSH and cAMP on the expression of steroidogenic genes. In contrast, inhibition of IGF-I receptor (IGF-IR) activity or expression using pharmacological, genetic, or biochemical approaches prevented the FSH- and cAMP-induced expression of steroidogenic genes and estradiol production. In vivo experiments demonstrated that IGF-IR inactivation reduces the stimulation of steroidogenic genes and follicle growth by gonadotropins. FSH or IGF-I alone stimulated protein kinase B (PKB), which is also known as AKT and in combination synergistically increased AKT phosphorylation. Remarkably, blocking IGF-IR expression or activity decreased AKT basal activity and abolished AKT activation by FSH. In GCs lacking IGF-IR activity, FSH stimulation of Cyp19 expression was rescued by overexpression of constitutively active AKT. Our findings demonstrate, for the first time, that in human, mouse, and rat GCs, the well-known stimulatory effect of FSH on Cyp19 and AKT depends on IGF-I and on the expression and activation of the IGF-IR. 23957873 Correlation of geographical location with the stable isotope values of hydrogen and carbon of the fatty acids from New Zealand milk and bulk milk powder. The aim of this study was to investigate the correlation of 2H and 13C of bulk milk powder and milk powder fatty acids to its production region. A total of 46 milk powder samples from across New Zealand were collected and analysed. Principal Component Analysis (PCA) showed that the 2H and 13C of four fatty acids, (C4:0, C14:0, C16:0, C18:1) and bulk milk powder were found to be correlated with regional production area. Linear Discriminant Analysis (LDA) models were prepared using different combinations of bulk and fatty acid 2H and 13C. All models were effective in discriminating samples from the North and South Island. The LDA model using just fatty acid 2H and 13C provided the best separation. Therefore the isotopic composition of the aforementioned fatty acids can be utilized as good biomarkers in milk powder that convey reliable isotopic information to track milk powders back to their regional origin. 23846347 Catalytic highly asymmetric 1,5(6)-selective cyclization reaction of α-hydroxyimino cyclic ketones: direct approach to ring-fused hydroxyimino dihydropyrans. Herein, we have disclosed a catalytic asymmetric 1,5(6)-selective Michael/cyclization reaction of α-hydroxyimino cyclic ketones with γ,β-unsaturated α-keto esters. Unlike the previous catalytic strategies, this reaction provides a convenient 1,5(6)-selective asymmetric pathway to access synthetically useful ring-fused dihydropyrans. In general, high levels of yield, enantio- and diastereoselectivity (up to 99% yield, >99% ee and >20 : 1 dr) were obtained. 23186731 Cocoa polyphenols prevent inflammation in the colon of azoxymethane-treated rats and in TNF-α-stimulated Caco-2 cells. Numerous lines of evidence support a relationship between intestinal inflammation and cancer. Therefore, much attention has recently been focused on the identification of natural compounds with anti-inflammatory activities as a strategy to suppress the early stages of colorectal cancer. Because cocoa is a rich source of bioactive compounds, the present study investigated its anti-inflammatory properties in a rat model of azoxymethane (AOM)-induced colon carcinogenesis and in TNF-α-stimulated Caco-2 cells. A total of forty male rats were fed with control or cocoa-enriched diets (12 %) during 8 weeks and injected with saline or AOM (20 mg/kg body weight) during the third and fourth week (n 10 rats/group). At the end of the experiment, colon samples were evaluated for markers of inflammation. The anti-inflammatory activity of a cocoa polyphenolic extract (10 μg/ml) was examined in TNF-α-stimulated Caco-2 cells, an in vitro model of experimentally induced intestinal inflammation. The signalling pathways involved, including NF-κB and the mitogen-activated protein kinase family such as c-Jun NH₂-terminal kinases (JNK), extracellular signal-regulated kinases and p38, were also evaluated. The results show that the cocoa-rich diet decreases the nuclear levels of NF-κB and the expression of pro-inflammatory enzymes such as cyclo-oxygenase-2 and inducible NO synthase induced by AOM in the colon. Additionally, the experiments in Caco-2 cells confirm that cocoa polyphenols effectively down-regulate the levels of inflammatory markers induced by TNF-α by inhibiting NF-κB translocation and JNK phosphorylation. We conclude that cocoa polyphenols suppress inflammation-related colon carcinogenesis and could be promising in the dietary prevention of intestinal inflammation and related cancer development. 23915301 Correlated mRNAs and miRNAs from co-expression and regulatory networks affect porcine muscle and finally meat properties. Physiological processes aiding the conversion of muscle to meat involve many genes associated with muscle structure and metabolic processes. MicroRNAs regulate networks of genes to orchestrate cellular functions, in turn regulating phenotypes. We applied weighted gene co-expression network analysis to identify co-expression modules that correlated to meat quality phenotypes and were highly enriched for genes involved in glucose metabolism, response to wounding, mitochondrial ribosome, mitochondrion, and extracellular matrix. Negative correlation of miRNA with mRNA and target prediction were used to select transcripts out of the modules of trait-associated mRNAs to further identify those genes that are correlated with post mortem traits. Porcine muscle co-expression transcript networks that correlated to post mortem traits were identified. The integration of miRNA and mRNA expression analyses, as well as network analysis, enabled us to interpret the differentially-regulated genes from a systems perspective. Linking co-expression networks of transcripts and hierarchically organized pairs of miRNAs and mRNAs to meat properties yields new insight into several biological pathways underlying phenotype differences. These pathways may also be diagnostic for many myopathies, which are accompanied by deficient nutrient and oxygen supply of muscle fibers. 23889430 Electrical excitation of surface plasmons by an individual carbon nanotube transistor. We demonstrate here the realization of an integrated, electrically driven, source of surface plasmon polaritons. Light-emitting individual single-walled carbon nanotube field effect transistors were fabricated in a plasmonic-ready platform. The devices were operated at ambient conditions to act as an electroluminescence source localized near the contacting gold electrodes. We show that photon emission from the semiconducting channel can couple to propagating surface plasmons developing in the electrical terminals. Our results show that a common functional element can be operated for two different platforms emphasizing thus the high degree of compatibility between state-of-the-art nano-optoelectronics devices and a plasmonic architecture. 23772666 Retrospective analysis of 235 unselected patients with mantle cell lymphoma confirms prognostic relevance of Mantle Cell Lymphoma International Prognostic Index and Ki-67 in the era of rituximab: long-term data from the Czech Lymphoma Project Database. Although a prognostic model (MIPI, Mantle Cell Lymphoma International Prognostic Index) for patients with mantle cell lymphoma (MCL) has been established, its clinical significance for daily practice in the rituximab era remains controversial. Data of 235 unselected patients with MCL from the Czech Lymphoma Project Database were analyzed. MIPI, simplified MIPI (s-MIPI) and Ki-67 proliferation index were assessed for all patients and for a subgroup of 155 rituximab-treated (RT) patients. MIPI divided all patients into subgroups of low-risk (22%), intermediate-risk (29%) and high-risk (49%), with median overall survival 105.8 vs. 54.1 vs. 24.6 months, respectively (p < 0.001). s-MIPI revealed similar results. The validity of both indexes was confirmed in RT patients. We confirmed the Ki-67 index to be a powerful single prognostic factor for overall survival (64.4 vs. 20.1 months, p < 0.001) for all patients and for the RT subset. Our results confirm the clinical relevance of MIPI, s-MIPI and Ki-67 for risk stratification in MCL also in the rituximab era. 23904057 Robotic Sleeve Gastrectomy: Experience of 134 Cases and Comparison with a Systematic Review of the Laparoscopic Approach. Robotic technology has recently emerged in different surgical specialties, but the experience with robotic sleeve gastrectomy (RSG) is scarce in the literature. The purpose of this study is to compare our preliminary experience with RSG versus the descriptive results of a systematic review of the laparoscopic approach. Data from our RSG experience were retrospectively collected. Two surgeons performed all the cases in one single surgery center. Such information was compared with a systematic review of 22 selected studies that included 3,148 laparoscopic sleeve gastrectomy (LSG) cases. RSG were performed using the daVinci® Surgical System. This study included 134 RSG vs 3,148 LSG. Mean age and mean BMI was 43 ±â€‰12.6 vs 40.7 ±â€‰11.6 (p = 0.022), and 45 ±â€‰7.1 vs 43.6 ±â€‰8.1 (p = 0.043), respectively. Leaks were found in 0 RSG vs 1.97 % LSG (p = 0.101); strictures in 0 vs 0.43 % (p = 0.447); bleeding in 0.7 vs 1.21 % (p = 0.594); and mortality in 0 vs 0.1 % (p = 0.714), respectively. Mean surgical time was calculated in 106.6 ±â€‰48.8 vs 94.5 ±â€‰39.9 min (p = 0.006); and mean hospital length of stay was 2.2 ±â€‰0.6 vs 3.3 ±â€‰1.7 days (p = <0.005), respectively. Four (2.9 %) complications were found in our robotic series. Our series shows that RSG is a safe alternative when used in bariatric surgery, showing similar results as the laparoscopic approach. Surgical time is longer in the robotic approach, while hospital length of stay is lower. No leaks or strictures were found in the robotic cases. However, further studies with larger sample size and randomization are warranted. 23639118 Pseudolymphomatous cutaneous angiosarcoma: a report of 2 new cases arising in an unusual setting. Pseudolymphomatous cutaneous angiosarcoma represents a rare, relatively new variant of cutaneous angiosarcoma exhibiting a prominent inflammatory lymphoid infiltrate that can mask the underlying vascular malignant proliferation and mimic a lymphomatous or pseudolymphomatous process. We describe the clinicopathologic characteristics of two new cases of pseudolymphomatous cutaneous angiosarcoma whose originality lies in the unusual setting from which they have arisen. In fact, the first case was an exceedingly lymphocyte-rich recurrence of a typical epithelioid cutaneous angiosarcoma whose primary lesion that was almost devoid of inflammatory infiltrate underwent surgical excision and radiotherapy while the second one was an unexpected histopathological finding associated with a basal cell carcinoma. Immunohistochemically, most of the lymphocytes expressed immunoreactivity for T-cell markers, while the neoplastic endothelial lymphatic cells expressed CD31 and CD34. D2-40 immunoreactivity was observed lining some channels and some neoplastic cells. In the first case a possible relationship between radiotherapy and the pseudolymphomatous reactive pattern is discussed while the second case has been considered as a rare example of collision tumor. 23895694 Development of a panel of seven duplex real-time PCR assays for detecting 13 streptococcal superantigens. Streptococcal superantigens (SAgs) are the major virulence factors of infection in humans for group A Streptococcus (GAS) bacteria. A panel consisting of seven duplex real-time PCR assays was developed to simultaneously detect 13 streptococcal SAgs and one internal control which may be important in the control of GAS-mediated diseases. Primer and probe sequences were selected based on the highly conserved region from an alignment of nucleotide sequences of the 13 streptococcal SAgs. The reaction conditions of the duplex real-time PCR were optimized and the specificity of the duplex assays was evaluated using SAg positive strains. The limit of detection of the duplex assays was determined by using 10-fold serial dilutions of the DNA of 13 streptococcal SAgs and compared to a conventional polymerase chain reaction (PCR) method for evaluating the duplex assays sensitivity. Using the duplex assays, we were able to differentiate between 13 SAgs from Streptococcus strains and other non-Streptococcus bacteria without cross-reaction. On the other hand, the limit of detection of the duplex assays was at least one or two log dilutions lower than that of the conventional PCR. The panel was highly specific (100%) and the limit of detection of these duplex groups was at least ten times lower than that obtained by using a conventional PCR method. 23842210 Inferring multi-target QSAR models with taxonomy-based multi-task learning. A plethora of studies indicate that the development of multi-target drugs is beneficial for complex diseases like cancer. Accurate QSAR models for each of the desired targets assist the optimization of a lead candidate by the prediction of affinity profiles. Often, the targets of a multi-target drug are sufficiently similar such that, in principle, knowledge can be transferred between the QSAR models to improve the model accuracy. In this study, we present two different multi-task algorithms from the field of transfer learning that can exploit the similarity between several targets to transfer knowledge between the target specific QSAR models. We evaluated the two methods on simulated data and a data set of 112 human kinases assembled from the public database ChEMBL. The relatedness between the kinase targets was derived from the taxonomy of the humane kinome. The experiments show that multi-task learning increases the performance compared to training separate models on both types of data given a sufficient similarity between the tasks. On the kinase data, the best multi-task approach improved the mean squared error of the QSAR models of 58 kinase targets. Multi-task learning is a valuable approach for inferring multi-target QSAR models for lead optimization. The application of multi-task learning is most beneficial if knowledge can be transferred from a similar task with a lot of in-domain knowledge to a task with little in-domain knowledge. Furthermore, the benefit increases with a decreasing overlap between the chemical space spanned by the tasks. 23653468 Genomics of the fetal hypothalamic cellular response to transient hypoxia: endocrine, immune, and metabolic responses. Fetuses respond to transient hypoxia (a common stressor in utero) with cellular responses that are appropriate for promoting survival of the fetus. The present experiment was performed to identify the acute genomic responses of the fetal hypothalamus to transient hypoxia. Three fetal sheep were exposed to 30 min of hypoxia and hypothalamic mRNA extracted from samples collected 30 min after return to normoxia. These samples were compared with those from four normoxic control fetuses by the Agilent 019921 ovine array. Differentially regulated genes were analyzed by network analysis and by gene ontology analysis, identifying statistically significant overrepresentation of biological processes. Real-time PCR of selected genes supported the validity of the array data. Hypoxia induced increased expression of genes involved in response to oxygen stimulus, RNA splicing, antiapoptosis, vascular smooth muscle proliferation, and positive regulation of Notch receptor target. Downregulated genes were involved in metabolism, antigen receptor-mediated immunity, macromolecular complex assembly, S-phase, translation elongation, RNA splicing, protein transport, and posttranscriptional regulation. We conclude that these results emphasize that the cellular response to hypoxia involves reduced metabolism, the involvement of the fetal immune system, and the importance of glucocorticoid signaling. 23523939 A novel and easy-to-prepare strontium(II) modified calcium phosphate bone cement with enhanced mechanical properties. The aim of this study was to evaluate two different approaches to obtaining strontium-modified calcium phosphate bone cements (SrCPCs) without elaborate synthesis of Sr-containing calcium phosphate species as cement precursors that could release biologically effective doses of Sr(2+) and thus could improve the healing of osteoporotic bone defects. Using strontium carbonate as a strontium(II) source, it was introduced into a hydroxyapatite-forming cement either by the addition of SrCO3 to an α-tricalcium phosphate-based cement precursor mixture (A-type) or by substitution of CaCO3 by SrCO3 during precursor composition (S-type). The cements, obtained after setting in a water-saturated atmosphere, contained up to 2.2at.% strontium in different distribution patterns as determined by time-of-flight secondary ion mass spectrometry and energy-dispersive X-ray spectroscopy. The setting time of CPC and A-type cements was in the range of 6.5-7.5min and increased for substitution-type cements (12.5-13.0min). Set cements had an open porosity between 26 and 42%. Compressive strength was found to increase from 29MPa up to 90% in substituted S-type cements (58MPa). SrCPC samples released between 0.45 and 1.53mgg(-1) Sr(2+) within 21days and showed increased radiopacity. Based on these findings, the SrCPC developed in this study could be beneficial for the treatment of defects of systemically impaired (e.g. osteoporotic) bone. 23958308 Clinical application of the Melbourne risk prediction tool in a high-risk upper abdominal surgical population: an observational cohort study. (1) To determine the ability of the Melbourne risk prediction tool to predict a pulmonary complication as defined by the Melbourne Group Scale in a medically defined high-risk upper abdominal surgery population during the postoperative period; (2) to identify the incidence of postoperative pulmonary complications; and (3) to examine the risk factors for postoperative pulmonary complications in this high-risk population. Observational cohort study. Tertiary Australian referral centre. 50 individuals who underwent medically defined high-risk upper abdominal surgery. Presence of postoperative pulmonary complications was screened daily for seven days using the Melbourne Group Scale (Version 2). Postoperative pulmonary risk prediction was calculated according to the Melbourne risk prediction tool. (1) Melbourne risk prediction tool; and (2) the incidence of postoperative pulmonary complications. Sixty-six percent (33/50) underwent hepatobiliary or upper gastrointestinal surgery. Mean (SD) anaesthetic duration was 377.8 (165.5) minutes. The risk prediction tool classified 84% (42/50) as high risk. Overall postoperative pulmonary complication incidence was 42% (21/50). The tool was 91% sensitive and 21% specific with a 50% chance of correct classification. This is the first study to externally validate the Melbourne risk prediction tool in an independent medically defined high-risk population. There was a higher incidence of pulmonary complications postoperatively observed compared to that previously reported. Results demonstrated poor validity of the tool in a population already defined medically as high risk and when applied postoperatively. This observational study has identified several important points to consider in future trials. 23604336 Methylphenidate reduces functional connectivity of nucleus accumbens in brain reward circuit. Release of dopamine in the nucleus accumbens (NAcc) is essential for acute drug reward. The present study was designed to trace the reinforcing effect of dopamine release by measuring the functional connectivity (FC) between the NAcc and brain regions involved in a limbic cortical-subcortical circuit during a dopaminergic challenge. Twenty healthy volunteers received single doses of methylphenidate (40 mg) and placebo on separate test days according to a double-blind, cross-over study design. Resting state functional magnetic resonance imaging (fMRI) was measured between 1.5 and 2 h postdosing. FC between regions of interest (ROI) in the NAcc, the medial dorsal nucleus (MDN) of the thalamus and remote areas within the limbic circuit was explored. Methylphenidate significantly reduced FC between the NAcc and the basal ganglia (i.e., subthalamic nucleus and ventral pallidum (VP)), relative to placebo. Methylphenidate also decreased FC between the NAcc and the medial prefrontal cortex (mPFC) as well as the temporal cortex. Methylphenidate did not affect FC between MDN and the limbic circuit. It is concluded that methylphenidate directly affects the limbic reward circuit. Drug-induced changes in FC of the NAcc may serve as a useful marker of drug activity in in the brain reward circuit. 23616258 Presence of EpCAM-positive circulating tumor cells as biomarker for systemic disease strongly correlates to survival in patients with hepatocellular carcinoma. Current imaging technologies do not sufficiently detect micrometastasis and therefore do not allow adequate stratification of patients with hepatocellular carcinoma (HCC) for curative or systemic therapy. In HCC, presence of stem cell-like, epithelial cell adhesion molecule (EpCAM)-positive cells correlates with tumor aggressiveness and formation of metastasis. Therefore, we investigated the prognostic relevance of EpCAM-positive circulating tumor cells (CTCs) in patients with HCC. Blood from 78 patients (19 patients in the control cohort and 59 patients with HCC) was tested for CTCs with the CellSearch™ system. Correlation analysis to overall survival (OS), the Barcelona Clinic Liver Cancer (BCLC) staging system, macroscopic and microscopic vascular invasion and alpha-fetoprotein (AFP) levels were performed. We detected ≥1 CTC in 18/59 HCC patients and in 1/19 patients with cirrhosis or benign hepatic tumor (p = 0.026). OS was significantly shorter (460 vs. 746 days) in the CTC-positive cohort (p = 0.017). Comparing BCLC stages, significant differences in CTC detection rates were also observed: BCLC stages A 1/9, B 6/31 and C 11/19 (p = 0.006). Ten of 18 patients with macroscopic and 10/16 patients with microscopic vascular invasion exhibited positive findings in CTC testing (p = 0.004 and p = 0.006). Furthermore, CTC results correlated to AFP (cutoff > 400 ng/mL) levels (p = 0.050). Our study demonstrates frequent presence of EpCAM-positive CTC in patients with intermediate or advanced HCC and its prognostic value for OS with possible implications for future treatment stratification. 23869167 Next-generation sequencing of mitochondrial targeted AAV transfer of human ND4 in mice. To determine the effects of mitochondrial targeting sequence (MTS) modified AAV gene delivery of wild-type human NADH dehydrogenase subunit 4 (ND4), mutated in most cases of the blinding disease Leber hereditary optic neuropathy (LHON), on the host mouse mitochondrial genome. We injected a modified self-complementary (sc) AAV vector, to which we appended the cytochrome oxidase subunit 8 (COX8) leader to one of the three capsid proteins (VP2) comprising the protein shell of the AAV virion, into the mouse vitreous to deliver the human ND4 gene under the control of a mitochondrial heavy strand promoter (HSP) directly to the mitochondria of the mouse retina. Control viruses consisting of scAAV lacking the COX8 targeting sequence and containing human ND4, or scAAV containing GFP, were also vitreally injected. Using next-generation sequencing of mitochondrial DNA extracted from the pooled mouse retinas of experimental and control eyes, we tested for the presence of the transferred human ND4, and any potential recombination of the transferred human ND4 gene with the endogenous host mitochondrial genome. We found hundreds of human ND4 DNA reads in mitochondrial samples of MTS AAV-ND4-injected eyes, a few human ND4 reads with AAV-ND4 lacking the MTS, and none with AAV-GFP injection. Putative chimeric read pairs at the 5' or 3' ends of human ND4 showed only vector sequences without the flanking mouse sequences expected with homologous recombination of human ND4 with the murine ND4. Examination of mouse mitochondrial ND4 sequences for evidence of intra-molecular small-scale homologous recombination events yielded no significant stretches greater than three to four nucleotides attributable to human ND4. Furthermore, in no instance did human ND4 insert into other non-homologous sites of the 16 kb host mtDNA. Our findings suggest that human ND4 remains episomal in host mitochondria and is not disruptive to any of the endogenous mitochondrial genes of the host genome. Therefore, mitochondrial gene transfer with an MTS-AAV is non-mutagenic and likely to be safe if used to treat LHON patients with mutated ND4. 23619378 Prioritizing breast cancer subtype related miRNAs using miRNA-mRNA dysregulated relationships extracted from their dual expression profiling. Identification of miRNA expression-based breast cancer subtypes is considered a critical means of prognostication. So far, the studies on breast cancer subtypes have not been well characterized, and few studies have performed expression profiling of both miRNA and mRNA from the same breast cancer subtypes samples. In this study we analyzed dual expression profiling data of miRNA and mRNA derived from the expression profiling of 489 miRNAs in 41 luminal-A breast tumors samples and 15 basal-like samples. We defined a correlation coefficient ratio (CCR) and used it to examine the correlative dysregulated relationships between miRNAs and mRNAs. A miRNA-mRNA dysregulated network was arisen from 6222 dysregulated relationships, and from this network, miRNA-miRNA networks specialized for luminal-A and basal-like breast cancer subtypes were extracted according to the CCR values. By analyzing the networks, we found that luminal-A trend and basal-like trend miRNA-miRNA network displayed a change in hubs which connected the most miRNAs, and therefore become the potential breast cancer subtype related miRNAs. In addition, we also used other network analysis methods for miRNA expression profiling data, such as weighted correlation network analysis (WGCNA), Bayesian network analysis, and miRNA similarity (MISIM) analysis to validate the identified miRNAs or miRNA clusters. This study provides a new analyzing method to predict candidate miRNAs of breast cancer subtype from a system biology level and help understanding the relationship between miRNA and mRNA in primary breast cancer subtype. 23891246 Life-Years Gained by Smoking Cessation After Percutaneous Coronary Intervention. Previous studies have shown that smoking cessation after a cardiac event reduces the risk of subsequent mortality in patients. The aim of this study was to describe the effect of smoking cessation in terms of prolonged life-years gained. The study sample comprised 856 patients who underwent percutaneous coronary intervention (PCI; balloon angioplasty) during 1980 to 1985. Patients were followed up for 30 years and smoking status at 1 year could be retrieved in 806 patients. The 27 patients who died within 1 year were excluded from the analysis. The median follow-up was 19.5 years (interquartile range 6.0 to 23.0). Cumulative 30-year survival rate was 29% in the group of patients who quit smoking and 14% in persistent smokers (p = 0.005). After adjustment for baseline characteristics at the time of PCI, smoking cessation remained an independent predictor of lesser mortality (adjusted hazard ratio 0.57, 95% confidence interval 0.46 to 0.71). The estimated life expectancy was 18.5 years in those who quit smoking and 16.4 years in the persistent smokers (p <0.0001). In conclusion, in patients with coronary heart disease who underwent PCI in the late 1980s, smoking cessation resulted in at least 2.1 life-years gained. 23299189 Protective effects of alpha lipoic acid versus N-acetylcysteine on ifosfamide-induced nephrotoxicity. Ifosfamide (IFO) is a highly effective chemotherapeutic agent for treating a variety of pediatric solid tumors. However, its use is limited due to its serious side effect on kidneys. The side-chain oxidation of IFO in renal tubular cells produces a reactive toxic metabolite that is believed to be responsible for its nephrotoxic effect. Therefore, this study was carried out to investigate the possible underlying mechanisms that may be involved in IFO-induced nephrotoxicity, including free radical generation and the possible role of alpha lipoic acid (ALA) versus N-acetylcysteine (NAC) in protection against this toxicity. Male albino rats were injected intraperitoneally with saline, IFO (50 mg/kg daily for 5 days), IFO + ALA (100 mg/kg daily for 8 days) and IFO + NAC (200 mg/kg daily for 8 days). Kidney malondialdehyde, nitric oxide and glutathione contents and serum biochemical parameters and histopathological analysis were determined. Both ALA and NAC markedly reduced the severity of renal dysfunction induced by IFO. NAC was more nephroprotective than ALA. This study suggests that oxidative stress is possibly involved in the IFO-induced nephrotoxicity in rats. The study also suggests the potential therapeutic role for ALA and NAC against IFO-induced nephrotoxicity. 23872454 pH-rate profiles support a general base mechanism for galactokinase (Lactococcus lactis). Galactokinase (GALK), a member the Leloir pathway for normal galactose metabolism, catalyzes the conversion of α-d-galactose to galactose-1-phosphate. For this investigation, we studied the kinetic mechanism and pH profiles of the enzyme from Lactococcus lactis. Our results show that the mechanism for its reaction is sequential in both directions. Mutant proteins D183A and D183N are inactive (<10000 fold), supporting the role of Asp183 as a catalytic base that deprotonates the C-1 hydroxyl group of galactose. The pH-kcat profile of the forward reaction has a pKa of 6.9±0.2 that likely is due to Asp183. The pH-kcat/KGal profile of the reverse reaction further substantiates this role as it is lacking a key pKa required for a direct proton transfer mechanism. The R36A and R36N mutant proteins show over 100-fold lower activity than that for the wild-type enzyme, thus suggesting that Arg36 lowers the pKa of the C-1 hydroxyl to facilitate deprotonation. 23753573 Embryonic Stem Cell-Derived CD166+ Precursors Develop Into Fully Functional Sinoatrial-Like Cells. Rationale: A cell-based biological pacemaker is based on the differentiation of stem cells and the selection of a population displaying the molecular and functional properties of native sinoatrial node (SAN) cardiomyocytes. So far, such selection has been hampered by the lack of proper markers. CD166 is specifically but transiently expressed in the mouse heart tube and sinus venosus, the prospective SAN. Objective: We have explored the possibility of using CD166 expression for isolating SAN progenitors from differentiating embryonic stem cells. Methods and Results: We found that in embryonic day 10.5 mouse hearts, CD166 and HCN4, markers of the pacemaker tissue, are coexpressed. Sorting embryonic stem cells for CD166 expression at differentiation day 8 selects a population of pacemaker precursors. CD166(+) cells express high levels of genes involved in SAN development (Tbx18, Tbx3, Isl-1, Shox2) and function (Cx30.2, HCN4, HCN1, CaV1.3) and low levels of ventricular genes (Cx43, Kv4.2, HCN2, Nkx2.5). In culture, CD166(+) cells form an autorhythmic syncytium composed of cells morphologically similar to and with the electrophysiological properties of murine SAN myocytes. Isoproterenol increases (+57%) and acetylcholine decreases (-23%) the beating rate of CD166-selected cells, which express the β-adrenergic and muscarinic receptors. In cocultures, CD166-selected cells are able to pace neonatal ventricular myocytes at a rate faster than their own. Furthermore, CD166(+) cells have lost pluripotency genes and do not form teratomas in vivo. Conclusions: We demonstrated for the first time the isolation of a nonteratogenic population of cardiac precursors able to mature and form a fully functional SAN-like tissue. 23774336 Standardized endoscopic swallowing evaluation for tracheostomy decannulation in critically ill neurologic patients. Decisions regarding tracheostomy tube removal after mechanical ventilation often depend on the physician's individual experience because evidence-based practice guidelines are still scarce, especially for critically ill neurologic patients. In these patients, the prevalence of aspiration is high and regarded as an important contributor to decannulation failure. The presence of severe neurological deficits may, however, give clinicians the subjective impression that a tracheostomy tube is still necessary although decannulation may actually be safe. It is therefore crucial to test swallowing function reliably prior to decannulation in this patient population. Prospective observational study. University hospital, neurological ICU. One hundred tracheostomized patients with acute neurologic disease completely weaned from mechanical ventilation. An endoscopic protocol evaluating readiness for decannulation and a conventional clinical swallowing examination were carried out by separate, experienced practitioners blinded to each other's decisions. Patient management always followed the decision made with endoscopy. Practitioners' decannulation decisions (yes/no) reached with both assessments were compared. Decannulated patients were monitored throughout their stay for complications related to tube removal. Endoscopy was performed successfully in all subjects without any complications. Following the protocol, the tracheostomy tube was successfully removed in 54 patients, whereas according to the clinical swallowing examination, only 29 patients would have been decannulated at that point. Only one patient needed recannulation due to respiratory problems, resulting in a failure rate of 1.9%. In neurologic patients, speech-language pathologists' impressions about the patient's state when clinically assessing indirect variables of swallowing function often lead to the unnecessary prolongation of cannulation time. Endoscopic evaluation has the advantage of objectively visualizing the patient's ability to manage secretions directly and allows for faster but, nonetheless, safe decannulation. The endoscopic protocol proposed here is a safe, efficient, and objective bedside tool to guide decannulation decisions. 23835334 Skeletal muscle triacylglycerol hydrolysis does not influence metabolic complications of obesity. Intramyocellular triacylglycerol (IMTG) accumulation is highly associated with insulin resistance and metabolic complications of obesity ("lipotoxicity"), whereas comparable IMTG accumulation in endurance-trained athletes is associated with insulin sensitivity ("the athlete's paradox"). Despite these findings, it remains unclear whether changes in IMTG accumulation and metabolism per se influence muscle-specific and systemic metabolic homeostasis and insulin responsiveness. By mediating the rate-limiting step in triacylglycerol hydrolysis, adipose triglyceride lipase (ATGL) has been proposed to influence the storage/production of deleterious as well as essential lipid metabolites. However, the physiological relevance of ATGL-mediated triacylglycerol hydrolysis in skeletal muscle remains unknown. To determine the contribution of IMTG hydrolysis to tissue-specific and systemic metabolic phenotypes in the context of obesity, we generated animal models with decreased (skeletal muscle-specific ATGL knockout or SMAKO mice) and increased (Ckm-ATGL transgenic mice) ATGL action exclusively in skeletal muscle. Despite dramatic changes in IMTG content on both chow and high-fat diet, modulation of ATGL-mediated IMTG hydrolysis did not significantly influence systemic energy, lipid, or glucose homeostasis, nor did it influence insulin responsiveness or mitochondrial function. These data argue against a role for altered IMTG accumulation and lipolysis in muscle insulin resistance and metabolic complications obesity. 23660549 Limb salvage treatment for Gollop-Wolfgang complex (femoral bifurcation, complete tibial hemimelia, and hand ectrodactyly). We reported the findings from three patients with Gollop-Wolfgang complex and demonstrated the results of five limb salvage treatments for this condition. All three femoral bifurcations were accompanied by ipsilateral complete tibial hemimelia. Two patients showed contralateral complete or partial tibial hemimelia, and one patient had hand ectrodactyly. The five limb salvage treatments included resection of the anteromedial bifurcated femur in three limbs, foot centralization in five limbs, tibiofibular fusion in one limb with partial tibial hemimelia, fibular transfer (Brown's procedure) in three limbs with complete tibial hemimelia, and callus distraction lengthening in one limb. The duration from the first operation to the final follow-up ranged from 3.5 to 5.4 years. None of the three knees treated by fibular transfer achieved a successful functional result, but all of the knees were ultimately able to withstand weight bearing. Early knee disarticulation and resection of the protruded bifurcated femur, followed by fitting of a modern prosthesis is likely to be the best treatment for patients with Gollop-Wolfgang syndrome. We note that limb salvage treatment is an alternative in patients who opt to retain their feet and refuse amputation. 23463089 The evolving role of partial breast irradiation in early-stage breast cancer. Whole breast irradiation (WBI) over 5-7 weeks has long been considered standard adjuvant treatment after breast-conserving surgery. Recently the concept of irradiating the whole breast has been challenged by accelerated partial breast irradiation (APBI), which exclusively targets the lumpectomy site plus margin. We review the evidence supporting APBI from modern clinical trials, the pros and cons of various APBI techniques, and the controversies regarding the applicability of APBI to specific patient groups. 23934734 Leonidas Zervas award lecture: Abiotic ligands for new quaternary architectures of peptides and proteins. This review is the result of a kind invitation to provide a report on the basis of the Leonidas Zervas award lecture at the 32nd European Peptide Society in Athens, Greece, September 2012. The lecture covered several topics including contributions toward new methods for the assembly of peptides and chemical modification of proteins. The present review will focus on another topic from the Zervas lecture, namely, our recent efforts at creating new, artificial architectures for the organization of the quaternary structure of proteins. Crucially, this is achieved with abiotic ligands and not protein surface engineering. This concept was demonstrated for the important biopharmaceutical peptide insulin, by using both abiotic metal ion binding ligands and perfluoroalkyl chains. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd. 23718277 Long-term survival with low toxicity after allogeneic transplantation for acute myeloid leukaemia and myelodysplasia using non-myeloablative conditioning without T cell depletion. The toxicity burden and long-term anti-leukaemic effect of non-myeloablative (NMA) allogeneic haematopoietic stem-cell transplantation (AHSCT) for acute myeloid leukaemia (AML) and myelodysplasia (MDS) remains undefined. We report the outcome of 56 patients with AML/MDS transplanted from human leucocyte antigen-matched donors using NMA conditioning without T-cell depletion. With a median follow-up of 5 years, treatment-related mortality was 9% and current disease-free survival (CDFS) was 45% (overall) and 55% (patients transplanted in remission). Development of graft-versus-host disease upon withdrawal of post-transplant immunosuppression was associated with less relapse and better CDFS. These data confirm that NMA AHSCT without T-cell depletion is safe and can result in sustained remissions of AML/MDS. 23523534 Engineering strategies to control vascular endothelial growth factor stability and levels in a collagen matrix for angiogenesis: the role of heparin sodium salt and the PLGA-based microsphere approach. New vessel formation is the result of the complex orchestration of various elements, such as cells, signalling molecules and extracellular matrix (ECM). In order to establish the suitable conditions for an effective cell response, the influence of vascular endothelial growth factor (VEGF) complexation with heparin sodium salt (Hp) on its pro-angiogenic activity has been evaluated by an in vitro capillary-like tube formation assay. VEGF with or without Hp was embedded into collagen gels, and the activated matrices were characterized in terms of VEGF activity and release kinetics. Taking into account the crucial role of Hp in VEGF stability and activity, VEGF/Hp complex was then encapsulated into microspheres based on poly(lactide-co-glycolide) (PLGA), and microsphere properties, VEGF/Hp release kinetics and VEGF in vitro activity over time were evaluated. Integrated microsphere/collagen matrices were developed in order to provide a continuous release of active VEGF/Hp inside the matrix but also a VEGF gradient at the boundary, which is an essential condition for endothelial cell attraction and scaffold invasion. The results confirmed a strong influence of Hp on VEGF configuration and, consequently, on its activity, while the encapsulation of VEGF/Hp complex in PLGA-microspheres guaranteed a sustained release of active VEGF for more than 30days. This paper confirms the importance of VEGF stability and signal presentation to cells for an effective proangiogenic activity and highlights how the combination of two stabilizing approaches, namely VEGF/Hp complexation and entrapment within PLGA-based microspheres, may be a very effective strategy to achieve this goal. 23754846 High-glucose levels and elastin degradation products accelerate osteogenesis in vascular smooth muscle cells. Diabetes mellitus (DM) is a chronic disease in which the body either does not use or produce the glucose metabolising hormone insulin efficiently. Calcification of elastin in the arteries of diabetics is a major predictor of cardiovascular diseases. It has been previously shown that elastin degradation products work synergistically with transforming growth factor-beta 1 (TGF-β1) to induce osteogenesis in vascular smooth muscle cells. In this study, we tested the hypothesis that high concentration of glucose coupled with elastin degradation products and TGF-β1 (a cytokine commonly associated with diabetes) will cause a greater degree of osteogenesis compared to normal vascular cells. Thus, the goal of this study was to analyse the effects of high concentration of glucose, elastin peptides and TGF-β1 on bone-specific markers like alkaline phosphatase (ALP), osteocalcin (OCN) and runt-related transcription factor 2 (RUNX2). We demonstrated using relative gene expression and specific protein assays that elastin degradation products in the presence of high glucose cause the increase in expression of the specific elastin-laminin receptor-1 (ELR-1) and activin receptor-like kinase-5 (ALK-5) present on the surface of the vascular cells, in turn leading to overexpression of typical osteogenic markers like ALP, OCN and RUNX2. Conversely, blocking of ELR-1 and ALK-5 strongly suppressed the expression of the osteogenic proteins. In conclusion, our results indicate that glucose plays an important role in amplifying the osteogenesis induced by elastin peptides and TGF-β1, possibly by activating the ELR-1 and ALK-5 signalling pathways. 23940574 Regulators of global genome repair do not respond to DNA damaging therapy but correlate with survival in melanoma. Nucleotide excision repair (NER) orchestrates the repair of helix distorting DNA damage, induced by both ultraviolet radiation (UVR) and cisplatin. There is evidence that the global genome repair (GGR) arm of NER is dysfunctional in melanoma and it is known to have limited induction in melanoma cell lines after cisplatin treatment. The aims of this study were to examine mRNA transcript levels of regulators of GGR and to investigate the downstream effect on global transcript expression in melanoma cell lines after cisplatin treatment and in melanoma tumours. The GGR regulators, BRCA1 and PCNA, were induced in melanocytes after cisplatin, but not in melanoma cell lines. Transcripts associated with BRCA1, BRCA2, ATM and CHEK2 showed altered expression in melanoma cell lines after cisplatin treatment. In melanoma tumour tissue BRCA1 transcript expression correlated with poor survival and XPB expression correlated with solar elastosis levels. Taken together, these findings provide evidence of the mechanisms underlying NER deficiency in melanoma. 22999780 5-Aminosalicylates and renal function monitoring in inflammatory bowel disease: a nationwide survey. 5-Aminosalicylates (ASA) are widely used in inflammatory bowel disease (IBD). Nephrotoxicity has been described in some IBD patients treated with 5-ASA. Whether physicians managing these patients are monitoring renal function in daily practice is unknown. The aims of this paper were to investigate how private gastroenterologists monitor renal function and manage renal failure in IBD patients treated with oral 5-ASA therapy. This was a web-based cross sectional national survey which was conducted among private gastroenterologists. A total of 249 practitioners completed the survey. Eighty two percent (n=205) of responders declared that they always monitor renal function. The respondents monitored twice a year Glomerular Filtration Rate (eGFR) using Modification of Diet in Renal Disease (MDRD) [90% (n=225)] and Creatinine Clearance (CCr) using a 24-hour urine collection [51% (n=126)]. Blood electrolytes, 24-hour urinary protein rate and dipsticks are performed by 41%, 39% and 22% of practitioners, respectively. Before oral 5-ASA initiation, 59% (n=148) of respondents screen for renal failure. In case of elevated serum creatinine, a nephrologist's opinion is asked by 80% (n=200) of responders and by 76% (n=189) of respondents before treatment initiation. Most gastroenterologists are monitoring renal function once or twice a year in IBD patients on 5-ASA. Less than two thirds of them screen for renal failure before treatment initiation. MDRD is mainly used, but a wide range of parameters is evaluated. 22766166 Investigating the effects of noise-induced hearing loss on serotonin transporters in rat brain using 4-[18F]-ADAM/small animal PET. The serotonin transporter (SERT) is an important marker of the status of serotonergic neurons. The main function of SERT is to regulate the serotonin concentration in the synapse. Recent studies have shown that SERT is expressed in the central auditory pathway and may play a role in the auditory process. However, little is known about the effects of noise on the cerebral serotonin system. In this study, we explored the status of brain SERT in a rat model of noise-induced hearing loss using 4-[(18)F]-ADAM (a SERT imaging agent) and small animal positron emission tomography (PET) imaging. Male Sprague Dawley rats were exposed to an 8 kHz noise at 118 dB sound pressure level for 3.5h. An auditory brainstem response test and 4-[(18)F]-ADAM/small animal PET were performed at different time points after noise exposure. The specific uptake ratios (SURs) for 4-[(18)F]-ADAM were calculated from the PET imaging data in six brain regions. Immunohistochemistry and surface preparation of the cochleae were performed 30 days after noise exposure. Our data clearly showed that the hearing and cochlear outer hair cells of the rats were lost after noise exposure. In the PET study, the SURs of SERT were markedly reduced by 35%-58% in various brain regions one day after noise exposure. The decrement remained on days 8 and 15 and was approximately 26%-48% on day 29. The distribution and intensity of SERT immunostaining in the brain paralleled the PET imaging data. These results suggest that noise-induced hearing loss involves a reduction in SERT expression in various regions of the rat brain and that changes in SERT are detectable by 4-[(18)F]-ADAM/small animal PET in vivo. 23611309 Ultrasensitive Polarized Up-Conversion of Tm(3+)-Yb(3+) Doped β-NaYF4 Single Nanorod. Up-conversion luminescence in rare earth ions (REs) doped nanoparticles has attracted considerable research attention for the promising applications in solid-state lasers, three-dimensional displays, solar cells, biological imaging, and so forth. However, there have been no reports on REs doped nanoparticles to investigate their polarized energy transfer up-conversion, especially for single particle. Herein, the polarized energy transfer up-conversion from REs doped fluoride nanorods is demonstrated in a single particle spectroscopy mode for the first time. Unique luminescent phenomena, for example, sharp energy level split and singlet-to-triplet transitions at room temperature, multiple discrete luminescence intensity periodic variation with polarization direction, are observed upon excitation with 980 nm linearly polarized laser. Furthermore, nanorods with the controllable aspect ratio and symmetry are fabricated for analysis of the mechanism of polarization anisotropy. The comparative experiments suggest that intraions transition properties and crystal local symmetry dominate the polarization anisotropy, which is also confirmed by density functional theory calculations. Taking advantage of the REs based up-conversion, potential application in polarized microscopic multi-information transportation is suggested for the polarization anisotropy from REs doped fluoride single nanorod or nanorod array. 23886484 Walking speed effects on the lower limb electromyographic variability of healthy children aged 7-16years. The evaluation of surface electromyography (sEMG) is commonly performed in children with cerebral palsy (CP) and reliable interpretation necessitates knowledge of the variability in age-matched, typically developing (TD) children. Variance ratio was calculated for inter-trial sEMG linear envelope (LE) and the Instantaneous Mean Frequency (IMNF) variability in the lower limb muscle in TD children, in three different age groups during slow, comfortable speed, and fast walking. Significantly greater variability was found in the 7-9 group compared to the 13-16years. Variability during both slow and fast walking was significantly greater compared to comfortable speed walking and was profound in the 7-9year age group. Variability of the IMNF was significantly greater than LE in the Tibialis-Anterior, Biceps-Femoris (BF), Vastus-Lateralis (VL), and Rectus-Femoris (RF). Clinical implications are that children under 10years are more variable than older children when walking either slower or faster than self-selected walking speed. This suggests that muscle activation patterns in gait mature at a later stage of childhood than do kinematic gait patterns. Greater precaution, therefore, is needed when comparing sEMG patterns of less than 10years of age patient and TD children. 23764426 Selective Estrogen Receptor Modulators and Pharmacogenomic Variation in ZNF423 Regulation of BRCA1 Expression: Individualized Breast Cancer Prevention. The selective estrogen receptor modulators (SERM) tamoxifen and raloxifene can reduce the occurrence of breast cancer in high-risk women by 50%, but this U.S. Food and Drug Administration-approved prevention therapy is not often used. We attempted to identify genetic factors that contribute to variation in SERM breast cancer prevention, using DNA from the NSABP P-1 and P-2 breast cancer prevention trials. An initial discovery genome-wide association study identified common single-nucleotide polymorphisms (SNP) in or near the ZNF423 and CTSO genes that were associated with breast cancer risk during SERM therapy. We then showed that both ZNF423 and CTSO participated in the estrogen-dependent induction of BRCA1 expression, in both cases with SNP-dependent variation in induction. ZNF423 appeared to be an estrogen-inducible BRCA1 transcription factor. The OR for differences in breast cancer risk during SERM therapy for subjects homozygous for both protective or both risk alleles for ZNF423 and CTSO was 5.71. 23647908 The lactase persistence genotype is associated with body mass index and dairy consumption in the D.E.S.I.R. study. The T allele of a functional polymorphism (rs4988235: LCT-13910 C>T), close to the lactase gene, correlates with lactase persistence (LP) in adults. The LP genotype (TT+TC) has been associated with a higher BMI in European populations in cross-sectional studies. In the French D.E.S.I.R. cohort, a high consumption of dairy products was associated with a lower body weight gain over 9-years, and with a lower incidence of high plasma glucose levels and/or the metabolic syndrome. Our aim was to test in this study, the association of rs4988235 with BMI and related metabolic diseases, in interaction with dairy product consumption. Among 5212 subjects from D.E.S.I.R., 3575 Caucasians born in mainland France were genotyped and followed over 9years. Those with the LP genotype (frequency: 78.5%) had a higher dairy product consumption, at inclusion and at year-9 (P<0.001). They also had a higher BMI at both time points (difference=0.3kg/m(2), P=0.05), but this effect was restricted to medium/high dairy product consumers (difference=0.5kg/m(2), P=0.006). This genotype was also associated with the metabolic syndrome (IDF definition), but this association disappeared after adjustment for BMI. In the whole population, the C allele was associated with a higher prevalence of impaired fasting glycemia and/or type 2 diabetes. The lactase persistence genotype was shown to be associated with a higher BMI in a longitudinal study, mainly in those consuming high amounts of dairy products. The association of the C allele, responsible for lactase non-persistence, with the risk of hyperglycemia needs to be replicated. 23242708 Does psychopathology in childhood predict internet addiction in male adolescents? This study investigated childhood psychopathology and Internet addiction in adolescents. Initial assessment data were obtained from 1998 to 1999, and a follow-up assessment was performed in 2006, when the original subjects entered middle school. Personal information for the 524 male subjects was obtained from the original data. The subjects were evaluated with the Korean version of the child behavior checklist, which was administered to the children's parents. Demographic and psychosocial factors were also evaluated. Children were reassessed with the self-reported Korea Internet Addiction Scale. Our results indicated that 3.6 % of the subjects had Internet addiction, and revealed a significant relationship between withdrawal and anxiety/depression and future Internet addiction. The results suggest that withdrawal and anxiety/depression during childhood should be considered in the etiology of problematic Internet use in boys. Accordingly, clinicians should consider anxiety/depression and withdrawal during childhood to prevent Internet addiction. 23568513 Light-Emitting Field-Effect Transistors Having Combined Organic Semiconductor and Metal Oxide Layers. A new organic light-emitting field-effect transistor characterized by a metal oxide layer inserted between the organic layer and the gate insulator is proposed. The metal oxide is indirectly connected with source and drain electrodes through the organic layer. Upon increasing the potential difference between the source and drain electrodes, the emission becomes exceedingly strong and the emission region encompasses the whole channel zone. 23462211 Antitubercular diterpenoids from Vitex trifolia. A new halimane diterpenoid, 13-hydroxy-5(10),14-halimadien-6-one (1) and two new labdane diterpenoids, 6α,7α-diacetoxy-13-hydroxy-8(9),14-labdadien (2) and 9-hydroxy-13(14)-labden-15,16-olide (3), were isolated for the first time, along with fifteen known compounds, from the hexane soluble fraction of methanolic extract of Vitex trifolia leaves. The structures of these new diterpenoids were elucidated by spectral analysis. Their relative configurations were established using analysis of NOESY correlations and coupling constants observed in (1)H NMR. Compounds 2, 3 and another known diterpenoid, isoambreinolide (4) were evaluated for antitubercular activity. 3 and 4 exhibited antitubercular activity (MIC=100 and 25μg/ml) against Mycobacterium tuberculosis H37Rv in BACTEC-460 assay. 23958939 Body size and time-to-pregnancy in black women. Are overall and central obesity associated with reduced fecundability in US black women? Overall and central obesity-based on self-reported measures of body mass index (BMI, kg/m(2)), waist circumference and waist-to-hip ratio-were independent risk factors for subfertility in our cohort. Overall obesity (BMI ≥30 kg/m(2)) has been associated with infertility in several studies. The role of central obesity is less clear. There are no previous studies of time-to-pregnancy (TTP) in black women. Data were derived from the Black Women's Health Study, a prospective cohort study. During 1995-2011, there were 2239 planned pregnancy attempts reported by 1697 women, resulting in 2022 births. Cohort retention was greater than 80%. Eligible women were aged 21-40 years and reported at least one planned pregnancy attempt during 1995-2011. Height and weight were reported in 1995, with weight updated every two years; waist and hip circumferences were reported in 1995 and updated in 2003. A validation study within the cohort showed high correlations between self-reported and technician-measured weight (r = 0.97), height (r = 0.93), waist circumference (r = 0.75) and hip circumference (r = 0.74). In 2011, TTP was reported in months. Proportional probabilities regression models were used to estimate fecundability ratios (FRs) and 95% confidence intervals (CI), adjusting for covariates. High BMI was associated with delayed conception: relative to BMI 18.5-24.9, FRs for BMI categories of <18.5, 25.0-29.9, 30.0-34.9 and ≥35.0 were 0.92 (CI: 0.64-1.32), 0.93 (CI: 0.84-1.03), 0.92 (CI: 0.79-1.06) and 0.73 (CI: 0.61-0.87), respectively. Associations were stronger among nulliparous women (P-interaction = 0.003). After controlling for BMI, reduced fecundability was observed among women with large waist circumferences (≥33 versus <26 inches: FR = 0.73, CI: 0.60-0.88) and large waist-to-hip ratios (≥0.85 versus <0.71: FR = 0.83, CI: 0.71-0.97). TTP was reported retrospectively and error in recall is likely, particularly as time since the pregnancy increases. However, results were similar when based on the most recent versus first pregnancies. Confounding may have been introduced by the lack of control for important determinants of TTP. Nevertheless, control for maternal age and education, which are highly correlated with TTP determinants such as paternal age and persistence in trying, should reduce the extent of confounding. The analysis was confined to planned pregnancies. If pregnancy intention was related both to body size and fecundability, our results could be biased. Bias is likely to be small because we found little difference in body size and other measured characteristics between pregnancy planners and non-planners. Our findings add to the growing body of literature showing that excess BMI is associated with reduced fecundability and further suggest that central obesity is an important independent risk factor for infertility. The relation of obesity to infertility is especially relevant to US black women because they have higher rates of obesity and infertility. Reductions in overall and central obesity may offer the potential to improve fertility outcomes. This work was funded by National Cancer Institute grant CA58420. We have no competing interests to report. 23864442 Do very preterm twins and singletons differ in their neurodevelopment at 5 years of age? Twins have inconsistently shown poorer outcomes than singletons. Although a high proportion of twins are born very preterm, data are sparse on the long-term outcomes in very preterm twins. The objective of this study was to compare mortality and neurodevelopmental outcomes of very preterm singletons and twins and to study outcomes in relation to factors specific to twins. Birth cohort study Etude Epidemiologique sur les Petits Ages Gestationnels (EPIPAGE). Nine regions in France. All very preterm live births occurring from 22 to 32 weeks of gestation in all maternity wards of nine French regions in 1997 (n=2773). Neurodevelopmental status, including cerebral palsy, and a cognitive assessment with the Kaufman Assessment Battery for Children, with scores on the Mental Processing Composite (MPC) scale, was available for 1732 and 1473 children at 5 years of age, respectively. Among live births, twins had higher hospital mortality than singletons (adjusted (a)OR: 1.4 (95% CI 1.1 to 1.9)). Among survivors, there was no crude difference at 5 years between twins and singletons in the prevalence of cerebral palsy (8.0% vs 9.1%, respectively), MPC <70 (9.5% vs 11.1%) and mean MPC (94.6 vs 94.4). However, after adjustment for sex, gestational age, intrauterine growth restriction and social factors, twins were more likely to have lower MPC scores (mean difference: -2.4 (95% CI-4.8 to 0.01)). Live born twins had a higher risk of mortality when birth weight discordance was present (aOR:2.9 (95% CI 1.7 to 4.8)), but there were no differences in long-term outcomes. Compared with very preterm singletons, twins had higher mortality, no difference with respect to severe deficiencies, but slightly lower MPC scores at 5 years. 23971077 Forensic electrochemistry: the electroanalytical sensing of Rohypnol® (flunitrazepam) using screen-printed graphite electrodes without recourse for electrode or sample pre-treatment. The electroanalytical sensing of Rohypnol® (flunitrazepam) is reported for the first time utilising screen-printed graphite electrodes without the requirement for any additional pre-treatment or modification. The methodology is shown to be useful for quantifying low levels (μg mL(-1)) of Rohypnol® in not only buffered solutions but also two internationally favoured drinks: Coca Cola™ and the alcopop WKD™ without any sample pre-treatment. The current analytical approaches for the sensing of Rohypnol® are also summarised within this paper. The niche of this electroanalytical protocol is the lack of the requirement of any pre-treatment of the sample/beverage or electrode modification (cleaning, pre-treatment etc.) for the determination of Rohypnol® in beverages and offers a potential rapid, cost-effective, yet suitably sensitive and accurate screening solution to the problem posed by coloured drinks to products such as the colour changing 'Smart Cup'. 23570823 The impact of early and brief corticosteroids on the clinical course of primary pulmonary coccidioidomycosis. Primary pulmonary coccidioidomycosis can often be associated with hypersensitivity symptoms treatable with a short course of palliative corticosteroids. Long-term use of corticosteroids is a known risk factor for severe or disseminated infection but the effects of short-term use are not known. A retrospective review was conducted of immunocompetent patients with acute pulmonary coccidioidomycosis who received systemic corticosteroids for relief of coccidioidal-related symptoms. Age- and sex-matched controls were also reviewed. Predetermined end-points were assessed. Seventy-four patients met inclusion criteria for the corticosteroid-treated group, and 74 controls were identified. Cumulative corticosteroid (prednisone-equivalent) doses were 10 mg → 3,600 mg (mean = 206 mg; median = 120 mg). Corticosteroids were prescribed most commonly for rash 43/74 [58%] or asthma/wheezing/cough 30/74 [41%]. Coccidioidal-related hospitalization occurred in 19 patients in the corticosteroid group vs. 22 in the control group (P = .58). Coccidioidal-related symptoms resolved within a mean of 19 weeks (median = 8 weeks [range = 2-208 weeks]) vs. 32.3 weeks (median = 8 weeks [range = 1-1040 weeks]) in the corticosteroid and control groups (P = .38). Relapse of symptoms occurred in 12% of both groups (P > .99). Extrapulmonary dissemination occurred in 3% vs. 4.0% (P > .99) in the corticosteroid and control groups, respectively. This study found no adverse effects of short-term corticosteroid therapy for early symptomatic treatment in acute pulmonary coccidioidomycosis. 23000538 The consequences of adolescent chronic unpredictable stress exposure on brain and behavior. There is increasing evidence for adolescence as a time period vulnerable to environmental perturbations such as stress. What is unclear is the persistent nature of the effects of stress and how specific these effects are to the type of stressor. In this review, we describe the effects of chronic, unpredictable stress (CUS) exposure during adolescence on adult behavior and brain morphology and function in animal models. We provide evidence for adolescence as a critical window for the effects of physical CUS that persist into adulthood, with ramifications for morphological development, associated hippocampal-dependent tasks, and anxiety- and depressive-like behaviors. The results of this investigation are contrasted against those of social CUS stress exposure from the same time period that show reversible and, in the case of responses to drugs of abuse, potentially protective effects in adulthood. Finally, we discuss potential underlying mechanisms for these morphological and behavioral findings. It is our aim that the research highlighted in this review will aid in our understanding of the role of stress in adolescent mental health and development. This article is part of a Special Issue entitled: Stress, Emotional Behavior and the Endocannabinoid System. 23881939 Replication-Fork Dynamics. The proliferation of all organisms depends on the coordination of enzymatic events within large multiprotein replisomes that duplicate chromosomes. Whereas the structure and function of many core replisome components have been clarified, the timing and order of molecular events during replication remains obscure. To better understand the replication mechanism, new methods must be developed that allow for the observation and characterization of short-lived states and dynamic events at single replication forks. Over the last decade, great progress has been made toward this goal with the development of novel DNA nanomanipulation and fluorescence imaging techniques allowing for the direct observation of replication-fork dynamics both reconstituted in vitro and in live cells. This article reviews these new single-molecule approaches and the revised understanding of replisome operation that has emerged. 23274742 High-density immobilization of antibodies onto nanobead-coated cyclic olefin copolymer plastic surfaces for application as a sensitive immunoassay chip. Our research efforts have been devoted to development of nanobead multilayer-based sensitive immunoassays on cyclic olefin copolymer (COC) plastic surfaces. To facilitate nanobead attachment and impart antibiofouling properties to a COC substrate, we used an amphiphilic copolymer comprising benzyl, polyethylene glycol, and reactive ester moieties to coat the hydrophobic COC surface in an aqueous environment. Subsequently, NH2-modified polystyrene nanobeads were reacted with the polymer-coated COC surface and further assembled into multilayers that increased the overall surface area available for attaching capture antibodies. After treatment of the nanobead multilayers with an amine-reactive homobifunctional crosslinker, a model capture antibody (anti-rabbit IgG) was covalently immobilized onto the activated surface of nanobeads. Finally, a sandwich immunoassay was carried out using rabbit IgG as a target analyte and rhodamine-labeled anti-rabbit IgG as a probe. Compared with a nanobead-free, polymer-coated COC surface, the nanobead multilayer-based immunoassay exhibited ~4-fold higher fluorescence intensity. In addition, our nanobead-based assay system exhibited a wide dynamic range of detection (0.1 to 1,000 ng/mL) and high specificity for rabbit IgG. Furthermore, much better detection sensitivity for rabbit IgG was attained in the nanobead multilayer-based immunoassay than with a conventional ELISA system (0.1 ng/mL versus 10 ng/mL), indicating the potential value of the proposed immunoassay system in plastic-based portable biochip applications. 23874117 Knowledge, attitude, and practices of infertility among Saudi couples. Infertility places a huge psychological burden on infertile couples, especially for women. Greater knowledge of the factors affecting fertility may help to decrease the incidence of infertility by allowing couples to avoid certain risk factors. The aim of our study was (1) to assess the knowledge and attitudes of infertile and fertile Saudi participants on infertility, possible risk factors, and social consequences; and (2) to determine the practices of infertile Saudi couples to promote their fertility before having them attend an in vitro fertilization (IVF) clinic. We conducted a cross-sectional study on 277 fertile participants from outpatient clinics and 104 infertile patients from the IVF clinic at King Abdulaziz Medical City between June 24, 2012 and July 4, 2012, using a previously validated interview questionnaire. Descriptive and analytical statistics were applied with a significance threshold of P ≤ 0.05. A generally poor level of knowledge (59%) and a neutral attitude (76%) toward infertility were reported by participants. Mistaken beliefs commonly held by the study participants regarding the causes of infertility were Djinns and supernatural causes (58.8%), black magic (67.5%), intrauterine devices (71.3%), and contraceptive pills (42.9%). The healer/Sheikh was reported as the primary and secondary preference for infertility treatment by 6.7% and 44.2% of IVF patients, respectively. Compared with fertile patients, IVF patients were significantly less likely to favor divorce (38.5% versus 57.6%; P = 0.001) or marriage to a second wife (62.5% versus 86.2%; P < 0.001), if the woman could not have a baby. The patients with infertility had more favorable attitudes toward fertility drugs (87.5% versus 68.4%; P = 0.003) and having a test tube baby (92.4% versus 70.3%; P < 0.001). Child adoption was accepted as an option for treatment by the majority of IVF patients (60.6%) and fertile outpatients (71.5%). Alternative treatments previously practiced by the IVF patients to improve fertility include practicing Ruqia (61%), using alternative medicine (42%), engaging in physical exercise (39%), eating certain foods (22%), and quitting smoking (12%). These findings have implications for health care providers regarding the reluctance that couples experiencing fertility problems may have, at least initially, to accept some interventions required for the couple to conceive. 23588378 Visualization of fast calcium oscillations in the parafascicular nucleus. The parafascicular nucleus (Pf) is an ascending target of the pedunculopontine nucleus (PPN) and is part of the "non-specific" intralaminar thalamus. The PPN, part of the reticular activating system, is mainly involved in waking and rapid eye movement sleep. Gamma oscillations are evident in all Pf neurons and mediated by high threshold voltage-dependent N- and P/Q-type calcium channels. We tested the hypothesis that high-speed calcium imaging would reveal calcium-mediated oscillations in synchrony with patch clamp recorded oscillations during depolarizing current ramps. Patch-clamped 9 to 19-day-old rat Pf neurons (n = 148, dye filled n = 61, control n = 87) were filled with Fura 2, Bis Fura, or Oregon Green BAPTA-1. Calcium transients were generated during depolarizing current ramps and visualized with a high-speed, wide-field fluorescence imaging system. Cells manifested calcium transients with oscillations in both somatic and proximal dendrite fluorescence recordings. Fluorescent calcium transients were blocked with the nonspecific calcium channel blocker, cadmium, or the combination of ω-Agatoxin-IVA (AgA), a specific P/Q-type calcium channel blocker and ω-conotoxin-GVIA (CgTx), a specific N-type calcium channel blocker. We developed a viable methodology for studying high-speed oscillations without the use of multi-photon imaging systems. 22974400 Recent developments in antimalarial natural products isolated from medicinal plants. Malaria is an infectious disease causing almost one million deaths each year. There is an urgent need for discovery of new antimalarial compounds. Natural products have been the single most productive source of leads for the development of drugs, because of their great variety of chemical structures. This review covers studies on antimalarial natural products isolated from plants, published from January 2010 until April 2012. A total of 171 structures comprising alkaloids, terpenoids, phenolics and other metabolites are listed in this review, including information on their antiplasmodial and cytotoxic activity. 23921846 Complete biopsy resection of diminutive polyps. Background and study aims: Cold biopsy forceps polypectomy (CBP) is commonly used for the removal of diminutive polyps; however, evidence for the efficacy of CBP is lacking. The aim of this study was to evaluate the adequacy of resection of diminutive polyps and to identify predictors for complete resection using CBP. Patients and methods: This was a prospective study from a tertiary referral hospital in Korea. A total of 196 patients were screened, and 65 patients with diminutive polyps were enrolled. CBP was used to resect diminutive polyps until no polyp was visible by chromoendoscopy using indigo carmine spray. Each polyp base was then resected using endoscopic mucosal resection (EMR) with a 1 - 3-mm free margin. CBP and EMR specimens were sent to the histopathology department for the evaluation of the completeness of the resection. Cross sections of the EMR specimens made at 1-mm intervals were examined by a pathologist.Results: A total of 86 diminutive polyps were available for assessment. Overall, 90.7 % (78/86) of the diminutive polyps were completely resected using CBP (95%CI 84.6 - 96.8 %). The complete resection rate for all diminutive adenomas was 92.3 % (60/65; 95%CI 85.8 - 98.8 %) and for 1 - 3-mm adenomas 100 % (95%CI 81.5 - 100 %). Polyp size, histology, and location, and number of biopsies were not different between the complete and incomplete resection groups.Conclusions: In this small study approximately 90 % of all diminutive polyps and 100 % of 1 - 3-mm adenomatous polyps were completely resected using CBP and chromoendoscopy. CBP appears to be adequate for the resection of the majority of diminutive polyps, especially small sized adenomas (≤ 3 mm) if no residual tissue is visible by chromoendoscopy. 23957965 Kinetic effects of TiO2 fine particles and nanoparticles aggregates on the nanomechanical properties of human neutrophils assessed by force spectroscopy. Increasing applications of titanium dioxide (TiO2) fine particles (FPs) and nanoparticles (NPs) require coupled knowledge improvement concerning their biokinetic effects. Neutrophils are quickly recruited to titanium implantation areas. Neutrophils mechanical properties display a crucial role on cell physiology and immune responsive functions. Then, micro and nanomechanical characterization assessed by force spectroscopy (FS) technique has been largely applied in this field. Scanning electron microscopy (SEM) images highlighted neutrophils morphological changes along TiO2 FPs and NPs aggregates exposure time (1, 5, and 30 min) compared to controls. FS approaches showed an increasing on attraction forces to TiO2 FPs and NPs treated neutrophils. This group depicted stronger stiffness features than controls just at 1 min of exposure. Treated neutrophils showed a tendency to increase adhesive properties after 1 and 5 min of exposure. These cells maintained comparatively higher elasticity behavior for a longer time possibly due to intense phagocytosis and cell stiffness opposing to the tip indentation. Neutrophils activation caused by FPs and NPs uptake could be related to increasing dissipated energy results. Mechanical modifications resulted from TiO2 FPs and NPs aggregates interaction with neutrophils showed increasing stiffness and also cell morphology alteration. Cells treatment by this metal FPs and NPs caused an increase in attractive forces. This event was mainly observed on the initial exposure times probably regarding to the interaction of neutrophils membrane and phagocytosis. Similar results were found to adhesion forces and dissipated energy outcomes. Treated cells presented comparatively higher elasticity behavior for a longer time. SEM images clearly suggested cell morphology alteration along time course probably related to activation, cytoskeleton rearrangement and phagocytosis. This scenario with increase in stiffness strongly suggests a direct relationship over neutrophil rolling, arrest, and transmigration. Scrutinizing these interactions represents an essential step to clarify the mechanisms involved on treatments containing micro and nanomaterials and their fates on the organisms. 23891920 Impedance-High Resolution Manometry Analysis of Patients With Nonerosive Reflux Disease. Transient lower esophageal sphincter relaxations (TLESRs) contribute to episodes of reflux. Few studies have assessed the frequencies or compositions of TLESRs and reflux episodes in patients with reflux disease. We used combined high-resolution manometry and impedance monitoring to analyze reflux episodes and esophageal motility in these patients, compared with those of healthy individuals. We evaluated the frequency of TLESRs and the relationship between the reflux pattern and esophageal pressures during TLESRs in 14 patients with nonerosive reflux disease (NERD) and 11 controls. Study participants underwent combined high-resolution manometry and impedance monitoring before and 60 minutes after a solid and liquid meal. The diagnosis of NERD was confirmed by a 24-hour pH impedance test. The frequency of TLESRs did not differ between patients with NERD and controls. In patients with NERD, TLESRs were associated more often with reflux episodes than in controls (93% ± 6% vs 66% ± 19%; P < .05). Patients with NERD had a higher percentage of pure liquid reflux episodes (33% ± 15% vs 10% ± 2%; P < .05), whereas controls had a higher percentage of mixed reflux episodes (45% ± 16% vs 67% ± 17% in patients with NERD; P < .05). Patients with NERD also had a higher percentage of reflux (liquid and mixed) associated with common cavities (74% ± 18% vs 50% ± 20% in controls; P < .05). In contrast to previous studies, we found that TLESRs are associated more often with reflux in patients with NERD than control subjects; this association increases when only liquid and mixed refluxes are considered. These findings indicate that factors involved in the occurrence of reflux in patients with NERD during TLESRs are different from those in healthy subjects. 23774288 Validity of diabetes self-reports in the saku diabetes study. Background: Diabetes is an important risk factor for cardiovascular disease, certain types of cancer, and death, and self-reports are one of the most convenient methods for ascertaining diabetes status. We evaluated the validity of diabetes self-reports among Japanese who participated in a health checkup.Methods: Self-reported diabetes was cross-sectionally compared with confirmed diabetes among 2535 participants aged 28 to 85 years in the Saku cohort study. Confirmed diabetes was defined as the presence of at least 1 of the following: fasting plasma glucose (FPG) level of 126 mg/dL or higher, 2-hour post-load glucose (2-hPG) level of 200 mg/dL or higher after a 75-gram oral glucose tolerance test, glycated hemoglobin (HbA1c) level of 6.5% or higher, or treatment with hypoglycemic medication(s).Results: Of the 251 participants with self-reported diabetes, 121 were taking hypoglycemic medication(s) and an additional 69 were classified as having diabetes. Of the 2284 participants who did not self-report diabetes, 80 were classified as having diabetes. These data yielded a sensitivity of 70.4%, a specificity of 97.3%, a positive predictive value of 75.7%, and a negative predictive value of 96.5%. The frequency of participants with undiagnosed diabetes was 3.0%. Of these, 64.2% had FPG within the normal range and were diagnosed by 2-hPG and/or HbA1c.Conclusions: Our findings provide additional support for the use of self-reported diabetes as a measure of diabetes in epidemiologic studies performed in similar settings in Japan if biomarker-based diagnosis is difficult. 23280651 Revising the absolute configurations of coatlines via density functional theory calculations of electronic circular dichroism spectra. Coatline A (1) and α-epi-coatline A (4) co-occur in the trunk extract of Andira coriacea. Inspection of their chiroptical properties led to intriguing results. After a careful examination of the experimental data used for the previously reported absolute configuration of these compounds, some uncertainties were identified. A combined theoretical approach including conformational analyses and calculation of electronic circular dichroism (ECD) spectra, in addition with experimental data obtained for schoepfin A (5) and the new schoepfin D (6) isolated from Senna quinquangulata, allowed the revision of the absolute configuration of coatlines A (1) and B (2). 23755874 Weak Ion-Molecule Interactions in the Gas Phase: A High-Pressure Mass Spectrometry and Computational Study of Chloride-Alkane Interactions. High-pressure mass spectrometric equilibrium experiments and electronic structure calculations have been carried out to investigate the energetics of the interactions of chloride ion with a series of normal alkanes and cycloalkanes in the gas phase. The structures of the complexes obtained from the electronic structure calculations provide considerable insight into the nature of the interaction between the negatively charged ion and the alkanes, which has the character of a purely ion-induced dipole interaction. The structural information also shows how the charged species affect the confirmation of the normal alkanes. 23831730 Acute toxicity of some synthetic cyanogens in rats: Time-dependent cyanide generation and cytochrome oxidase inhibition in soft tissues after sub-lethal oral intoxication. Cyanogens include complex nitrile-containing compounds that can generate free cyanide of toxicological significance. Acute toxicity, time-dependent cyanide generation and cytochrome oxidase (CYTOX) inhibition in soft tissues, and urinary thiocyanate levels were measured after acute cyanogen intoxication in rats. Order of cyanogens in terms of LD50 was: malononitrile (MCN)>propionitrile (PCN)≈sodium nitroprusside (SNP)>acrylonitrile (ACN)>succinonitrile (SCN)>acetonitrile (ATCN) for oral, and SNP>MCN>ACN>PCN>SCN>ATCN for intraperitoneal and subcutaneous routes. MCN was most toxic by oral (LD50=66.4mg/kg) and SNP by intraperitoneal (LD50=16.7mg/kg) and subcutaneous (LD50=11.9mg/kg) routes. Minimum survival time (25min) was recorded after 4.0 LD50 ATCN. Order of cyanogens (0.75 LD50; oral) on the basis of maximum blood cyanide and time of peak cyanide generation were: ATCN>SNP>SCN>PCN>MCN>ACN, and MCN (30min) 200 μM at the time of follow-up. Results. We reviewed the records of 3828 patients receiving cardiac surgery in the defined period. A total of 107 adult patients with sCr concentrations < 200 μM were treated with post-operative renal replacement therapy of whom 70 survived to discharge. Fifty-six patients were alive at follow-up and none had required renal replacement therapy after initial discharge. Median sCr concentration at follow-up was 111 [56-257] μM and two patients had sCr above 200 μM. Conclusions. In this study, renal function recovered in patients discharged from hospital following renal replacement therapy after CSA-AKI. No patients needed further renal replacement therapy and only two (4%) had a sCr > 200 μM at follow-up. 23229512 Vitamin K2 covalently binds to Bak and induces Bak-mediated apoptosis. Vitamin K2 (VK2, menaquinone) is known to have anticancer activity in vitro and in vivo. Although its effect is thought to be mediated, at least in part, by the induction of apoptosis, the underlying molecular mechanism remains elusive. Here, we identified Bcl-2 antagonist killer 1 (Bak) as a molecular target of VK2-induced apoptosis. VK2 directly interacts with Bak and induces mitochondrial-mediated apoptosis. Although Bak and Bcl-2-associated X protein (Bax), another member of the Bcl-2 family, are generally thought to be functionally redundant, only Bak is necessary and sufficient for VK2-induced cytochrome c (cyt c) release and cell death. Moreover, VK2-2,3 epoxide, an intracellular metabolite of VK2, was shown to covalently bind to the cysteine-166 residue of Bak. Several lines of evidence suggested that the covalent attachment of VK2 is critical for apoptosis induction. Thus this study reveals a specific role for Bak in mitochondria-mediated apoptosis. This study also provides insight into the anticancer effects of VK2 and suggests that Bak may be a potential target of cancer therapy. 23902344 High-Throughput Continuous Hydrothermal Synthesis of Nanomaterials (Part II): Unveiling the As-Prepared CexZryYzO2-δ Phase Diagram. High-throughput continuous hydrothermal flow synthesis was used to manufacture 66 unique nanostructured oxide samples in the Ce-Zr-Y-O system. This synthesis approach resulted in a significant increase in throughput compared to that of conventional batch or continuous hydrothermal synthesis methods. The as-prepared library samples were placed into a wellplate for both automated high-throughput powder X-ray diffraction and Raman spectroscopy data collection, which allowed comprehensive structural characterization and phase mapping. The data suggested that a continuous cubic-like phase field connects all three Ce-Zr-O, Ce-Y-O, and Y-Zr-O binary systems together with a smooth and steady transition between the structures of neighboring compositions. The continuous hydrothermal process led to as-prepared crystallite sizes in the range of 2-7 nm (as determined by using the Scherrer equation). 23313637 Synthesis of quinoline derivatives: discovery of a potent and selective phosphodiesterase 5 inhibitor for the treatment of Alzheimer's disease. Phosphodiesterase type 5 (PDE5) mediates the degradation of cGMP in a variety of tissues including brain. Recent studies have demonstrated the importance of the nitric oxide/cGMP/cAMP-responsive element-binding protein (CREB) pathway to the process of learning and memory. Thus, PDE5 inhibitors (PDE5Is) are thought to be promising new therapeutic agents for the treatment of Alzheimer's disease (AD), a neurodegenerative disorder characterized by memory loss. To explore this possibility, a series of quinoline derivatives were synthesized and evaluated. We found that compound 7a selectively inhibits PDE5 with an IC(50) of 0.27 nM and readily crosses the blood brain barrier. In an in vivo mouse model of AD, compound 7a rescues synaptic and memory defects. Quinoline-based, CNS-permeant PDE5Is have potential for AD therapeutic development. 23931883 Reasons for refusing kidney transplantation among chronic dialysis patients. The aim of the prospective clinical study was to evaluate the reasons for refusing kidney transplantation among chronic dialysis patients. A total of 164 adult chronic dialysis patients participated in the study. They were asked to complete a detailed questionnaire on specific issues regarding transplantation. The mean age was 60.9 ± 16.0 (20-89) years, 61.6% were male, 11.6% had had a previous transplant. The majority, that is, 72.0%, of the patients believed that transplantation improved the quality of life, and 55.5% believed that transplantation prolonged life. Nevertheless, 45.0% of the patients wanted to be transplanted, 35.0% refused transplantation, and 20.0% were undecided. Patients refusing transplantation were significantly older compared to the patients wanting to be transplanted (67 ± 16 vs. 57 ± 16 years; P < 0.001). The main reasons for refusing transplantation (57 patients) were the side-effects of immunosuppressive therapy (31.6%), unpredictability of transplant outcome (29.8%), and unfavorable outcomes in fellow patients (28.1%). The side-effects of immunosuppressive therapy that patients were most concerned about included mobility problems (29.8%), new-onset diabetes (26.3%), increased risk of severe infections (26.3%), problems with vision (22.8%), and increased risk of cancer (21.1%). Many patients did not want to accept organs from expanded criteria donors (ECD) (44.6% of the patients wanting and 64.9% of those refusing transplantation). The majority believed that patients should be informed if an organ from an ECD donor is being offered (64.9% of patients wanting and 63.2% of those refusing transplantation). The main reasons for refusing kidney transplantation were the side-effects of immunosuppressive therapy, unpredictability of transplant outcome, and unfavorable outcomes in fellow patients. 23746749 Wear of two denture teeth materials in vivo-2-year results. (1) To quantify wear of two different denture tooth materials in vivo with two study designs, (2) to relate tooth variables to vertical loss. Two different denture tooth materials had been used (experimental material=test; DCL=control). In study 1 (split-mouth, 6 test centers) 60 subjects received complete dentures, in study 2 (two-arm, 1 test center) 29 subjects. In study 1 the mandibular dentures were supported by implants in 33% of the subjects, in study 2 only in 3% of the subjects. Impressions of the dentures were taken and poured with improved stone at baseline and after 6, 12, 18 and 24 months. Each operator evaluated the wear subjectively. Wear analysis was carried out with a laser scanning device. Maximal vertical loss of the attrition zones was calculated for each tooth cusp and tooth. A mixed linear model was used to statistically analyse the logarithmically transformed wear data. Due to drop-outs and unmatchable casts, only 47 subjects of study 1 and 14 of study 2 completed the 2-year recall. Overall, 75% of all teeth present could be analysed. There was no statistically difference in the overall wear between the test and control material for either study 1 or study 2. The relative increase in wear over time was similar in both study designs. However, a strong subject effect and center effect were observed. The fixed factors included in the model (time, tooth, center, etc.) accounted for 43% of the variability, whereas the random subject effect accounted for another 30% of the variability, leaving about 28% of unexplained variability. More wear was consistently recorded in the maxillary teeth compared to the mandibular teeth and in the first molar teeth compared to the premolar teeth and the second molars. Likewise, the supporting cusps showed more wear than the non-supporting cusps. The amount of wear did not depend on whether or not the lower dentures were supported by implants. The subjective wear was correct in about 67% of the cases if it is postulated that a wear difference of 100μm should be subjectively detectable. The clinical wear of denture teeth is highly variable with a strong patient effect. More wear can be expected in maxillary denture teeth compared to mandibular teeth, first molars compared to premolars and supported cusps compared to non-supported cusps. Laboratory data on the wear of denture tooth materials may not be confirmed in well-structured clinical trials probably due to the large inter-individual variability. 23943633 Stigmatising attitudes towards people with mental disorders: A comparison of Australian health professionals with the general community. Objective:The aim of this paper was to explore attitudes towards people with mental disorders among Australian health professionals (psychiatrists, psychologists and general practitioners (GPs)) and to compare their attitudes with members of the general community.Methods:The study involved a postal survey of 518 GPs, 506 psychiatrists and 498 clinical psychologists and a telephone survey of 6019 members of the general community. Participants were given a case vignette describing a person with either depression, depression with suicidal thoughts, early schizophrenia, chronic schizophrenia, post-traumatic stress disorder (PTSD) or social phobia and two questionnaires to assess stigmatising attitudes (the Depression Stigma Scale and the Social Distance Scale). Exploratory structural equation modelling was used to elucidate the structure of stigma as measured by the two scales, to establish dimensions of stigma and to compare patterns of association according to gender, age, vignette and professional grouping.Results:The measurement characteristics of stigmatising attitudes in health professionals were found to be comparable to those in members of the general community in social distance and also in personal and perceived attitude stigma, with each forming distinct dimensions and each comprising 'Weak-not-sick' and 'Dangerous/unpredictable' components. Among health professionals, female gender, age and being a GP were associated with higher scores on the personal stigma scales. Mental health professionals had lower scores on the personal 'Weak-not-sick' and 'Dangerous/unpredictable' scales than members of the general community, while there were no significant differences in the desire for social distance between health professionals and the general community.Conclusions:While mental health professionals have less stigmatising attitudes than the general public, the greater beliefs in dangerousness and personal weakness by GPs should be addressed. 23886616 First molecular characterization of Cryptosporidium and Giardia from Bubalus bubalis (water buffalo) in Victoria, Australia. We conducted a molecular epidemiological survey of Cryptosporidium and Giardia from Bubalus bubalis (water buffalo) on two extensive farms (450km apart) in Victoria, Australia. Faecal samples (n=476) were collected from different age groups of water buffalo at two time points (six months apart) and tested using a PCR-based mutation scanning-targeted sequencing-phylogenetic approach, employing markers within the small subunit of ribosomal RNA (designated pSSU) and triose phosphate isomerase (ptpi) genes. Based on pSSU data, Cryptosporidium parvum, Cryptosporidium bovis and Cryptosporidium genotypes 1, 2 (each 99% similar genetically to Cryptosporidium ryanae) and 3 (99% similar to Cryptosporidiumsuis) were detected in two (0.4%), one (0.2%), 38 (8.0%), 16 (3.4%) and one (0.2%) of the 476 samples tested, respectively. Using ptpi, Giardiaduodenalis assemblages A and E were detected in totals of 56 (11.8%) and six (1.3%) of these samples, respectively. Cryptosporidium was detected on both farms, whereas Giardia was detected only on farm B, and both genera were detected in 1.5% of all samples tested. The study showed that water buffaloes on these farms excreted C. parvum and/or G. duodenalis assemblage A, which are consistent with those found in humans, inferring that these particular pathogens are of zoonotic significance. Future work should focus on investigating, in a temporal and spatial manner, the prevalence and intensity of such infections in water buffaloes in various geographical regions in Australia and in other countries. 23529014 Two novel saponins of 20, 26-epoxy derivatives of pseudojujubogenin from the seeds of Hovenia trichocarpa. Two new saponins of 20, 26-epoxy derivatives of pseudojujubogenin, hoduloside XI (1) and hoduloside XII (2) were isolated from the seeds of Hovenia trichocarpa. The structures of the new compounds were established by extensive NMR experiments and chemical methods. Hoduloside XI was confirmed to be 3-O-{β-d-glucopyranosyl(1→3)-[β-d-xylopyranosyl(1→2)]-α-l-arabinopyranosyl}-20, 26-epoxypseudojujubogenin. Hoduloside XII was identified as 3-O-{β-d-xylopyranose(1→2)glucopyranosyl(1→3)[rhamnopyranose(1→2)]β-d-glucopyranosyl}-20, 26-epoxypseudojujubogenin. The in vitro cytotoxic activity of compounds 1 and 2 was assayed. They displayed inhibitive activities against human cancer cell lines HL60 and K562. 23180340 Two new C-benzylated dihydrochalcone derivatives from the leaves of Melodorum siamensis. Two new C-benzylated dihydrochalcone derivatives, 4,2',4'-trihydroxy-6'-methoxy-3'(2''-hydroxybenzyl)dihydrochalcone (1) and 2',4'-dihydroxy-4,6'-dimethoxy-3'(2''-hydroxybenzyl)dihydrochalcone (2), along with six known flavonoid derivatives (3-8), a known dihydrochalcone dimer (9), three known aromatic esters (10-12), and one known aromatic amide (13), were isolated from the leaves of Melodorum siamensis. The structures of the compounds were elucidated by spectroscopic analysis, mainly 1D and 2D NMR techniques (1H, 13C, COSY, HMQC, and HMBC), as well as by comparison with literature data. The isolated compounds with a sufficient amount for biological assays were evaluated for their antimalarial, antimycobactirial, and cytotoxic activities. Compounds 1, 2, and 13 exhibited strong cytotoxicity against human tumor cell lines KB and NCI-H187, with IC50 values in the range of 0.66-7.16 µg/mL. 23764356 Hepatoprotective activity of puerarin against carbon tetrachloride-induced injuries in rats: A randomized controlled trial. The protective effects of puerarin on liver damage were evaluated by carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. Male rats were orally treated with puerarin daily, and received CCl4 intraperitoneally twice a week for 4weeks. Our results showed that puerarin at doses of 50, 100, and 200mg/kgb.w. significantly reduced the elevated activities of serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase at least 15%, 17%, 14% and 18%, respectively. In addition, puerarin at different doses significantly decreased (p<0.05) the level of hepatic thiobarbituric acid reactive substances compared to the CCl4-treated group. Furthermore, the treatment of puerarin was also found to significantly increase the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, and glutathione content at least 40%, 12%, 25%, 52%, 17% and 44% in the liver of CCl4-treated rats, respectively. Liver histopathology also showed that puerarin reduced the incidence of liver lesions induced by CCl4. The results suggest that puerarin exhibits potent hepatoprotective effects on CCl4-induced liver damages in rats, and that the hepatoprotective effects of puerarin may be due to both the inhibition of lipid peroxidation and to increase of antioxidant enzymes activity. 23954632 PGC-1-related coactivator (PRC) negatively regulates endothelial adhesion of monocytes via inhibition of NF κB activity. PGC-1-related coactivator (PRC) is a growth-regulated transcriptional cofactor known to activate many of the nuclear genes specifying mitochondrial respiratory function. Endothelial dysfunction is a prominent feature found in many inflammatory diseases. Adhesion molecules, such as VCAM-1, mediate the attachment of monocytes to endothelial cells, thereby playing an important role in endothelial inflammation. The effects of PRC in regards to endothelial inflammation remain unknown. In this study, our findings show that PRC can be inhibited by the inflammatory cytokine LPS in cultured human umbilical vein endothelial cells (HUVECs). In the presence of LPS, the expression of endothelial cell adhesion molecular, such as VCAM1 and E-selectin, is found to be increased. These effects can be negated by overexpression of PRC. Importantly, monocyte adhesion to endothelial cells caused by LPS is significantly attenuated by PRC. In addition, overexpression of PRC protects mitochondrial metabolic function and suppresses the rate of glycolysis against LPS. It is also found that overexpression of PRC decreases the transcriptional activity of NF-κB. These findings suggest that PRC is a negative regulator of endothelial inflammation. 23777975 Microvascular dysfunction is associated with plasma osteoprotegerin levels in patients with acute myocardial infarction. Osteoprotegerin (OPG) is a glycoprotein that inhibits nuclear factor-κB's regulatory effects on inflammation, skeletal, and vascular systems, and is a potential biomarker of atherosclerosis and seems to be involved in vascular calcifications. The objective of this study was to assess the relationship between OPG, left ventricular function, and microvascular function in patients with acute myocardial infarction (AMI). After successful revascularization, noninvasive assessment of coronary flow reserve (CFR) was performed in the distal part of the left anterior descending artery in 183 patients with first AMI. We performed low-dose dobutamine stress echocardiography to assess viability and finally we assessed the ventriculoarterial coupling (VAC). Plasma OPG was determined by ELISA. Plasma OPG concentrations were higher in patients with impaired microcirculation (CFR<2) than in patients without [median (first; third quartile), 1.939 (1.366; 2.724) vs. 1.451 (0.925; 2.164) ng/l; P=0.001]. OPG was associated with CFR both in linear regression single-variable analysis (P=0.001) and in multivariable analysis adjusting for possible confounders (P=0.024).Eighty-seven patients had resting wall motion abnormalities and 28 patients fulfilled the criteria for viability. In the group with low OPG 20 patients had viability, and in patients with high OPG only eight patients had viability (P=0.03).Both the E/A ratio (1.22±0.65 vs. 1.06±0.39; P=0.04) and the E/e' ratio (10.4±3.1 vs. 12.2±4.6; P=0.002) indicated worse diastolic function in patients with increased levels of OPG.Overall, an increase in the VAC point was observed in the population (1.11±0.6). The VAC point was higher in patients with increased OPG compared with low OPG (1.01±0.51 vs. 1.2±0.67; P=0.03). This is the first study to show an association between OPG levels and CFR, decreased diastolic function, and increased VAC in the setting of AMI. Our results indicate a relationship between OPG and the degree of microvascular dysfunction. 23190578 Interphase-FISH screening for eight common rearrangements in pediatric B-cell precursor acute lymphoblastic leukemia. This is the first pilot study to screen multiple common genetic aberrations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Thirty-two children with BCP-ALL were investigated for chromosomal rearrangements using interphase fluorescence in situ hybridization (FISH). Eight common translocations and rearrangements, including ETV6-RUNX1, TCF3-PBX1, BCR-ABL1, ETV6, TCF3, MLL, IGH@, and PAX5, were tested for using dual-color DNA probes. ETV6-RUNX1 was the most frequent translocation detected in 11 children (34.4%). Two patients with BCR-ABL1 (6.3%) and one with TCF3-PBX1 (3.1%) translocations were also observed. Using break-apart probes, 11 children (34.4%) had a positive FISH result for ETV6, two patients for IGH@ (6.3%), one patient for MLL (3.1%), and one patient for PAX5 rearrangements (3.1%). All patients with the ETV6-RUNX1 fusion were also identified by split signals for ETV6. Other abnormalities, including extra copies and deletion of genes, were observed within the range of 3.1-34.4%. Cytogenetics analysis showed a single case each of BCR-ABL1 fusion, MLL, and IGH@ rearrangements (3.1% each). ETV6-RUNX1 fusion and ETV6 split-apart rearrangements were not visible by cytogenetics. Likewise, one each of cases with TCF3-PBX1 fusion and with PAX5 split signal seen by FISH was not visible by cytogenetics. By using 8 FISH probes in conjunction cytogenetics for the detection of common aberrations, interphase FISH enhanced the detection of chromosomal rearrangements in children with BCP-ALL. 23415363 Occupational burnout and work factors in community and hospital midwives: a survey analysis. community-based midwifery practice has been promoted in the UK maternity policy over the last decade as a means of increasing continuity of care. However, there have been growing concerns to suggest that the community-based continuity model may not be sustainable due to the high levels of occupational burnout in midwives resulted by increased on-call work. this paper attempted to identify work factors associated with the levels of burnout in community midwives as compared to hospital midwives, aiming at contributing to the debate of organising sustainable midwifery care. a statistical analysis was conducted drawing on data from a survey of all midwives working at one Hospital Trust in England (n=238). Occupational burnout was measured using the Maslach Burnout Inventory (MBI). the sample midwives (n=128, 54%) had significantly higher levels of burnout compared to the reference groups. Multiple regression analysis identified as follows: (1) high levels of occupational autonomy were a key protective factor of burnout, and more prevalent in the community, (2) working hours were positively associated with burnout, and community midwives were more likely to have higher levels of stress recognition, and (3) support for work-life-balance from the Trust had a significant protective effect on the levels of burnout. the results should be taken into account in the maternity policy in order to incorporate continuity of care and sustainable organisation of midwifery care. 22968006 Three-year results of a multicenter prospective study of transoral incisionless fundoplication. Background. To date, there are no long-term data on the use of transoral incisionless fundoplication (TIF) for the treatment of chronic gastroesophageal reflux disease (GERD). We sought to prospectively evaluate the long-term safety and durability of TIF in a multi-center setting. Methods. A longitudinal per protocol (PP) and a modified intention-to-treat (mITT) analysis at 1 and 3 years consisted of symptom evaluation using the GERD health-related quality of life (GERD-HRQL) questionnaire, medication use, upper gastrointestinal endoscopy, and pH-metry. Results. Of 79 patients previously reported at 1 year, 12 were lost to follow-up, and 1 died from an unrelated cause. The remaining 66 patients were followed up and analyzed (mITT). Of 66 patients, 12 underwent revisional procedures, leaving 54 patients for PP analysis at a median of 3.1 years (range = 2.9-3.6). No adverse events related to TIF were reported at 2- or 3-year follow-up. On PP analysis, median GERD-HRQL score off proton pump inhibitors (PPIs) improved significantly to 4 (range 0-32) from both off (25 [13-38], P < .0001) and on (9 [0-22], P < .0001) PPIs. Discontinuation of daily PPIs was sustained in 61% (mITT) and 74% (PP) of patients. Of 11 patients with pH data at 3 years (PP), 9 (82%) remained normal. Based on mITT analysis, 9/23 (39%) remained normal at 3 years. Conclusions. The clinical outcomes at 3 years following TIF, patient satisfaction, healing of erosive esophagitis, and cessation of PPI medication support long-term safety and durability of the TIF procedure for those with initial treatment success. Although complete normalization of pH studies occurred in a minority of patients, successful cases showed long-term durability. 23591078 Anoxia promotes gravitropic curvature in rice pulvini but inhibits it in wheat and oat pulvini. Gravitropic curvature of pulvini of wheat and oat stem segments gradually declined with decreasing atmospheric O2 concentration and was almost completely blocked under anoxia, whereas that of rice stem segments was enhanced under hypoxia and anoxia. Anoxia substantially increased the ethanol content in pulvini of gravistimulated stem segments in rice, wheat and oat, but the ethanol content showed no marked difference between rice pulvini and wheat and oat pulvini. The concentrations of exogenous ethanol and acetaldehyde required to inhibit the gravitropic curvature of pulvini were significantly higher in rice segments than in wheat and oat segments. However, in all three species, the concentrations of ethanol and acetaldehyde required to completely inhibit curvature were several-fold higher than the endogenous levels that accumulated in pulvini gravistimulated in N2. The pulvini of rice segments gravistimulated in N2 did not contain much more ATP than those of wheat or oat segments gravistimulated in N2. When applied unilaterally to the pulvini of vertically oriented stem segments incubated in N2, indole-3-acetic acid induced bending in rice stem segments but not in wheat and oat stem segments. Transference of graviresponsive pulvini of rice, as well as those of wheat and oat, from aerobic conditions to anaerobic conditions led to cessation of gravitropic curvature within several minutes, but subsequently only gravitropic curvature of anoxic rice pulvini was completely recovered within 2h. A large portion of this recovery was blocked by cordycepin, a transcription inhibitor. These results suggested that anoxia-induced expression of any gene or genes enables rice pulvini to respond to gravistimulation under anaerobic conditions, and that such a gene or genes might be unrelated to ethanol fermentation and ATP production in anaerobic conditions. 23968552 Rh(III)-Catalyzed Tandem C-H Allylation and Oxidative Cyclization of Anilides: A New Entry to Indoles. Rh(III)-catalyzed tandem C-H allylation and oxidative cyclization of anilides with allyl carbonates in the presence of a slight excess of AgSbF6 salt and Cu(OAc)2 as oxidant affords easy, economical access to important bioactive 2-methylindoles. The new reaction supports a wide range of functional groups on the anilide substrate. A possible mechanism is proposed as a basis for its rational further development. 23154125 Deep brain stimulation for dystonia. The few controlled studies that have been carried out have shown that bilateral internal globus pallidum stimulation is a safe and long-term effective treatment for hyperkinetic disorders. However, most recent published data on deep brain stimulation (DBS) for dystonia, applied to different targets and patients, are still mainly from uncontrolled case reports (especially for secondary dystonia). This precludes clear determination of the efficacy of this procedure and the choice of the 'good' target for the 'good' patient. We performed a literature analysis on DBS for dystonia according to the expected outcome. We separated those with good evidence of favourable outcome from those with less predictable outcome. In the former group, we review the main results for primary dystonia (generalised/focal) and highlight recent data on myoclonus-dystonia and tardive dystonia (as they share, with primary dystonia, a marked beneficial effect from pallidal stimulation with good risk/benefit ratio). In the latter group, poor or variable results have been obtained for secondary dystonia (with a focus on heredodegenerative and metabolic disorders). From this overview, the main results and limits for each subgroup of patients that may help in the selection of dystonic patients who will benefit from DBS are discussed. 23529904 Agreement Between ICU Clinicians and Electrophysiology Cardiologists on the Decision to Initiate a QTc-interval Prolonging Medication in Critically Ill Patients with Potential Risk Factors for Torsade de Pointes: A Comparative, Case-Based Evaluation. STUDY OBJECTIVES: To measure concordance between different intensive care unit (ICU) clinicians and a consensus group of electrophysiology (EP) cardiologists for use of a common rate-corrected QT interval (QTc)-prolonging medication in cases containing different potential risk factor(s) for torsade de pointes (TdP). DESIGN: Prospective case-based evaluation. SETTING: Academic medical center with 320 beds. SUBJECTS: Medical house staff (MDs) and ICU nurses (RNs) from one center and select critical care pharmacists (PHs). INTERVENTION: Completion of a survey containing 10 hypothetical ICU cases in which patients had agitated delirium for which a psychiatrist recommended intravenous haloperidol 5 mg every 6 hours. Each case contained different potential risk factor(s) for TdP in specific combinations. A group of five EP cardiologists agreed that haloperidol use was safe in five cases and not safe in five cases. MEASUREMENTS AND MAIN RESULTS: For each case, participants were asked to document whether they would administer haloperidol, to provide a rationale for their decision, and to state their level of confidence in that decision. Most clinicians (92 of 115 [80%]) invited to participate completed the cases. Among the five cases where EP cardiologists agreed that haloperidol was not safe, 29% of respondents felt that haloperidol was safe. Conversely, in the five cases where EP cardiologists felt haloperidol was safe, 21% of respondents believed that it was not safe. Overall respondent-EP cardiologist agreement for haloperidol use across the 10 cases was moderate (κ = 0.51). MDs and PHs were in agreement with the EP cardiologists more than RNs (p=0.03). Interprofessional variability existed for the TdP risk factors each best identified. Clinician confidence correlated with EP cardiologist concordance for MDs (p=0.002) and PHs (p=0.0002), but not for RNs (p=0.69). CONCLUSION: When evaluating use of a QTc interval-prolonging medication, ICU clinicians often fail to identify the TdP risk factors that EP cardiologists feel should prevent its use. Clinician-EP cardiologist concordance varies by the specific risk factor(s) for TdP and the ICU professional conducting the assessment. 23928934 Pneumococcal urinary antigen positivity in healthy colonized children: is it age dependent? Pneumococcal urinary antigen test is a valuable tool for diagnosing pneumococcal pneumonia and meningitis in adults. Its use in children is generally not accepted because of nonspecificity at this age. It is frequently positive in asymptomatic nasopharyngeal carriers. The aim of our study was to assess the age limit from which the test is no longer positive in asymptomatic healthy carriers. A total of 197 children aged 36-83 months attending 9 day care centers in Prague were enrolled during February and March 2010. Nasopharyngeal swab specimens were collected from each participant and selectively cultivated. The presence of pneumococcal antigen in urine was detected by BinaxNOW® S. pneumoniae kit. Streptococcus pneumoniae was cultivated in 53.3 % of healthy children with the highest colonization rate (59.3 %) in children aged 48-59 months. The most frequently colonizing serotypes were: 19F, 23F, 3, 19A, 6B and 4. The presence of pneumococcal antigen in urine decreased with age from 39.0 % in 36-47 months to 17.9 % in 72-83 months old (p = 0.031). The antigen positivity was serotype-dependent and more frequent in nonvaccinated children. We demonstrated age-dependent linear decrease of pneumococcal antigen excretion into urine in healthy children. The positivity rate of the test in children aged 72-83 months was similar to that referred in healthy adults, irrespective of colonization. To confirm this age limit for use of this test in diagnostics of pneumococcal diseases, further study in school-age children is justified. 23819819 Professional killer cell deficiencies and decreased survival in pulmonary arterial hypertension (PAH). Increasing evidence implicates lymphocytes in PAH pathogenesis. Rats deficient in T-lymphocytes show increased propensity to develop PAH but when injected with endothelial progenitor cells are protected from PAH (a mechanism dependent on natural killer cells). A decreased quantity of circulating cytotoxic CD8+ T lymphocytes and natural killer (NK) cells are now reported in PAH patients; however, the effect of lymphocyte depletion on disease outcome is unknown. This prospective study analysed the lymphocyte profile and plasma BNP levels of patients with idiopathic PAH (IPAH), connective tissue disease associated PAH (CTD-APAH) and matched healthy controls. Lymphocyte surface markers studied include: CD4+ (Helper T-cell marker), CD8+ (Cytotoxic T-cell marker), CD56/CD16 (NK cell marker) and CD19+ (mature B-cell marker). Lymphocyte deficiencies and plasma BNP levels were then correlated with clinical outcome. 14 patients with PAH (9 IPAH, 5CTD) were recruited. Three patients were deceased at one year follow up; all had elevated CD4:CD8 ratios and deficiencies of NK cells and cytotoxic CD8+ T-lymphocytes at recruitment. Patients with normal lymphocyte profiles at recruitment were all alive a year later and none were on the active transplant list. As univariate markers, cytotoxic CD8+ T-cell and NK cell counts were linked to short term survival. Deficiencies in NK cells and cytotoxic CD8+ T-cells may be associated with an increased risk of death in PAH patients. Further research is required in larger numbers of patients and to elucidate the mechanism of these findings. 23211442 Studies on the bioactivity of aqueous extract of pu-erh tea and its fractions: in vitro antioxidant activity and α-glycosidase inhibitory property, and their effect on postprandial hyperglycemia in diabetic mice. Despite abundant research that has been carried out on the potential health benefits of pu-erh tea, no consensus till now, has been reached on which constituent is mainly responsible for its bioactivity. In this work, the aqueous extract (AE) and its fraction enriched with active constituents were prepared from pu-erh tea, and their bioactivities were investigated. It was found that tea polyphenols (TP), tea polysaccharides (TPS), caffeine (Caf), protein (Pro), amino acids (AA) were accumulated in several fractions after solvent extraction despite not being separated completely. Meanwhile, 95% ethanol precipitate (EP) and ethyl acetate fraction (EF) possessed remarkable antioxidant activity and potent inhibitory effects against α-glycosidase in vitro. Furthermore, all the extracts (50 mg/kg BW) showed a significant (p<0.05) effect on postprandial hyperglycemia in diabetic mice as compared with a model group, and the suppression of EP was not significantly (p>0.05) different from that of acarbose at the same dosage (50 mg/kg BW), which indicate that these fractions could be developed as potential anti-diabetic agents. 23921852 Cheek rotation flap reconstruction-an anthropometric appraisal of surgical outcomes. Cheek rotation flaps are an established surgical procedure for coverage of facial skin defects especially of the cheek and infraorbital region. A comparison of pre- and postoperative anthropometric measurements may help to objectify intraoperative estimations with regards to postoperative appearance. We present an evaluation of 31 patients undergoing periorbital reconstruction by a cheek rotation flap on standardized photographs based on reference anthropometric data. Analysis included intercanthal, binocular and eye fissure width, eye fissure, lid sulcus and upper lid height, upper and lower iris coverage, position of cornea to palpebra inferior, scleral show, ectropion, and canthal tilt. Furthermore, it was clearly differentiated whether the defect to cover included eyelid skin or not. Ectropion showed a significant association to surgery (p = 0.03) and time (p = 0.03). If the defect to cover included lower eyelid skin, lower iris coverage values decreased significantly (p = 0.02), meanwhile the rate of scleral show increased significantly (p < 0.01), indicating pre- to postoperative lower eyelid retraction. In all patients analyzed, indices were reproducible and reliable. An association between surgery and ectropion was detectable. Whenever lower eyelid skin is involved in the defect to be covered, the significantly decreased lower iris coverage and increased rate of scleral show indicate an increased risk of lower lid retraction. Whenever eyelid skin is involved in a defect to be covered by a cheek rotation flap, there is an increased risk of postoperative lower lid distortion. Special care has to be taken to perform techniques preventing lower lid retraction. 23891758 An investigational report into the causes of pine mouth events in US consumers. Between July 2008 and June 2012, the US Food and Drug Administration received 501 consumer reports of prolonged taste disturbances consistent with pine mouth syndrome. Consumers consistently reported a delayed bitter or metallic taste beginning hours to days following consumption of pine nuts that recurred with intake of any food or meal. This dysgeusia lasted in some cases up to a few weeks, but would eventually resolve without serious health consequences. To evaluate these reports, a questionnaire was developed to address various characteristics of the pine nuts consumed, pertinent medical history of complainants and other dysgeusia-related factors. Pine nut samples associated with 15 complaints were collected for analysis. The investigation of reports found no clear evidence of an underlying medical cause or common trigger that could adequately explain the occurrence of dysgeusia in complainants. Rather, the results of our investigation suggest that the occurrence of "pine mouth syndrome" in US consumers is correlated with the consumption of the pine nut species Pinus armandii. 23832698 Angiotensin II-mediated post-translational modification of nNOS in the PVN of rats with CHF: Role for PIN. An increased sympathetic drive is an adverse characteristic in chronic heart failure (CHF). The protein expression of neuronal nitric oxide synthase (nNOS) and hence nitric oxide (NO) mediated sympathoinhibition is reduced in the paraventricular nucleus (PVN) of rats with CHF. However, the molecular mechanism(s) of nNOS downregulation remain(s) unclear. The aim of the study was to reveal the underlying molecular mechanism for the downregulation of nNOS in the PVN of CHF rats. Sprague-Dawley rats with CHF (6-8 weeks after coronary artery ligation) demonstrated decreased nNOS dimer/monomer ratio (42%), with a concomitant increase in the expression of PIN (a protein inhibitor of nNOS known to dissociate nNOS dimers into monomers) by 47% in the PVN. Similarly, PIN expression is increased in a neuronal cell line (NG108) treated with angiotensin II (Ang II). Furthermore, there is an increased accumulation of high molecular weight nNOS-ubiquitin (nNOS-Ub) conjugates in the PVN of CHF rats (29%). Ang II treatment in NG108 cells in the presence of a proteasome inhibitor, lactacystin, also leads to a 69% increase in accumulation of nNOS-Ub conjugates immunoprecipitated by an anti-ubiquitin antibody. There is an Ang II-driven, PIN- mediated decrease in the dimeric catalytically active nNOS in the PVN, due to ubiquitin-dependent proteolytic degradation in CHF. Our results show a novel intermediary mechanism which leads to decreased levels of active nNOS in the PVN, involved in subsequent reduction in sympathoinhibition during CHF, offering a new target for the treatment of CHF and other cardiovascular diseases. 23924506 The emerging role of dietary fructose in obesity and cognitive decline. The incidence of obesity has increased dramatically over the past several years, and in parallel, so has the prevalence of type 2 diabetes (T2D). Numerous studies have demonstrated that both obesity and T2D are associated with lower cognitive performance, cognitive decline, and dementia. Intake of dietary fructose has also increased. In fact, high-fructose corn syrup (HFCS) accounts for as much as 40% of caloric sweeteners used in the United States. Given the increase in the incidence of Alzheimer's disease (AD), characterized by an age-related decline in memory and cognitive functioning, in this report we review the effects of obesity on cognitive performance and the impact of high fructose intake in promoting cognitive decline. The paper then considers the effects of omega-3 fatty acids (FAs), which have been linked to promising results in cognitive function including ameliorating the impact of a high-fructose diet. 23345064 Effect of feeding of calcium hydroxide-treated or vitamin E-supplemented cottonseed meal on plasma gossypol levels, blood parameters, and performance of Bikaneri lambs. To study the effect of feeding calcium hydroxide-treated or vitamin E-supplemented cottonseed meal (CSM) incorporated diets on plasma gossypol, blood parameters and animal performance, 24 male Bikaneri lambs of 6-7 months of age and of uniform body weight were divided into four groups of six animals each in a completely randomized design and respectively fed isonitrogenous and isocaloric concentrate mixtures containing 20 % soybean meal (CON) or 40 % raw CSM (RCSM), 40 % raw CSM supplemented with 500 IU of vitamin E per head per day (ERCSM), and 40 %, 1.5 % calcium hydroxide-treated CSM (CaCSM) along with ad libitum wheat straw throughout 510 days of experimental feeding. The lambs on all the diets grew linearly throughout the experimental period. The total weight gain, in turn the average daily gain (ADG), was not affected by dietary variations. The daily intake of dry matter, crude protein (CP), digestible crude protein (DCP) and total digestible nutrients (TDN) were found comparable among lambs of all the groups. Though total gossypol intake was similar in RCSM, ECSM and CaCSM groups, however, free gossypol intake was significantly higher (P < 0.01) in RCSM, ECSM groups as compared to CaCSM group. Serum iron and blood hemoglobin levels were significantly (P < 0.05) lower in RCSM group as compared to CaCSM and CON groups, and ALT activity was significantly (P < 0.05) higher on RCSM group as compared to other groups. Plasma gossypol and osmotic fragility of erythrocytes were significantly (P < 0.05) increased in RCSM group as compared to CaCSM and ERCSM groups. However, there was no significant difference in the concentration of other blood/serum biochemical constituents among the lambs on different groups. Based on the results, it may be concluded that feeding of 40 % CSM in the concentrate mixture of the diet in Bikaneri lambs did not have any major adverse effect in blood parameters and animal performance. Either calcium hydroxide treatment or vitamin E supplementation did not produce any major additional benefits. 23418022 Synthesis of heterocyclic terpenoids by promiscuous squalene-hopene cyclases. PROMISCUOUS ENZYMES: The substrate promiscuity of squalene-hopene cyclases has been explored and applied in the enzyme-catalyzed synthesis of heterocyclic terpenoids. Features of this work include cyclization reactions without pyrophosphate activation, and stereospecific ring closure of substrates of varying chain length and terminal nucleophile. This provides a biocatalytic alternative to traditional chemical catalysts. 23933668 Primary hypothyroidism: an unusual manifestation of Wolcott-Rallison syndrome. Wolcott-Rallison syndrome has been reported to be associated with early-onset diabetes, epiphyseal dysplasia, hepatic and renal dysfunction, mental retardation, severe growth retardation, neutropenia, exocrine pancreatic dysfunction, and central hypothyroidism. We report on primary hypothyroidism, which has not been previously described, of a patient with Wolcott-Rallison syndrome due to novel mutation (W521X), who showed improved growth after thyroid hormone treatment. 23788109 Additive antileukemia effects by GFI1B- and BCR-ABL-specific siRNA in advanced phase chronic myeloid leukemic cells. Previous studies demonstrated selective inhibition of the BCR-ABL (breakpoint cluster region-Abelson murine leukemia oncogene) tyrosine kinase by RNA interference in leukemic cells. In this study, we evaluated the effect of BCR-ABL small interfering RNA (siRNA) and GFI1B siRNA silencing on chronic myeloid leukemia (CML) cells in myeloid blast crises. The GFI1B gene was mapped to chromosome 9 and is, therefore, located downstream of the BCR-ABL translocation in CML cells. Co-transfection of BCR-ABL siRNA and GFI1B siRNA dramatically decreased cell viability and significantly induced apoptosis and inhibited proliferation in K562 cells (P<0.0001) and primary advanced phase CML cells (P<0.0001) versus controls. Furthermore, combining of BCR-ABL siRNA and GFI1B siRNA significantly modified the expression of several relevant genes including Myc, MDR1, MRP1 and tyrosyl-phosphoproteins in primary CML cells. Our data suggest that silencing of both BCR-ABL siRNA and GFI1B siRNA is associated with an additive antileukemic effect against K562 cells and primary advanced CML cells, further validating these genes as attractive therapeutic targets. 23942983 Chemical diversity among populations of Mikania micrantha: geographic mosaic structure and herbivory. Populations of the same species vary in their secondary metabolite content. This variation has been attributed to biotic and abiotic environmental conditions as well as to historical factors. Some studies have focused on the geographic variation of chemical diversity in plant populations, but whether this structure conforms to a central-marginal model or a mosaic pattern remains unclear. Furthermore, assessing the chemical diversity of invasive plants in their native distribution facilitates the understanding of their relationships with natural enemies. We examined the geographic variation of chemical diversity in Mexican populations of the bittervine weed Mikania micrantha and its relationship to herbivore damage. The foliar volatile terpenoid blend was analyzed in 165 individuals of 14 populations in the Pacific and Gulf of Mexico tropical watersheds. A cluster analysis grouped individuals with similar terpenoid blends into 56 compositional types. Chemical diversity was measured using the number of compounds and their concentration within the blends for individuals, and the number and frequency of compositional types for populations. A stepwise multiple regression analysis performed with geographic, climatic, and chemical diversity variables explained herbivore damage. However, population-level chemical diversity was the only variable found to be significant (β = -0.79, P = 0.042) in the model (R (2) = 0.89). A Mantel test using Euclidean distances did not indicate any separation by geographic origin; however, four barriers were identified using Monmonier's algorithm. We conclude that variation in population-level chemical diversity follows a mosaic pattern in which geographic factors (i.e., natural barriers) have some effect and that variation is also associated with the local intensity of herbivore attack. 23872567 Diet Complexity and Estrogen Receptor β Status Affect the Composition of the Murine Intestinal Microbiota. Intestinal microbial dysbiosis contributes to the dysmetabolism of luminal factors, including steroid hormones (sterones) that affect the development of chronic gastrointestinal inflammation and the incidence of sterone-responsive cancers of the breast, prostate, and colon. Little is known, however, about the role of specific host sterone nucleoreceptors, including estrogen receptor β (ERβ), in microbiota maintenance. Herein, we test the hypothesis that ERβ status affects microbiota composition and determine if such compositionally distinct microbiota respond differently to changes in diet complexity that favor Proteobacteria enrichment. To this end, conventionally raised female ERβ(+/+) and ERβ(-/-) C57BL/6J mice (mean age of 27 weeks) were initially reared on 8604, a complex diet containing estrogenic isoflavones, and then fed AIN-76, an isoflavone-free semisynthetic diet, for 2 weeks. 16S rRNA gene surveys revealed that the fecal microbiota of 8604-fed mice and AIN-76-fed mice differed, as expected. The relative diversity of Proteobacteria, especially the Alphaproteobacteria and Gammaproteobacteria, increased significantly following the transition to AIN-76. Distinct patterns for beneficial Lactobacillales were exclusive to and highly abundant among 8604-fed mice, whereas several Proteobacteria were exclusive to AIN-76-fed mice. Interestingly, representative orders of the phyla Proteobacteria, Bacteroidetes, and Firmicutes, including the Lactobacillales, also differed as a function of murine ERβ status. Overall, these interactions suggest that sterone nucleoreceptor status and diet complexity may play important roles in microbiota maintenance. Furthermore, we envision that this model for gastrointestinal dysbiosis may be used to identify novel probiotics, prebiotics, nutritional strategies, and pharmaceuticals for the prevention and resolution of Proteobacteria-rich dysbiosis. 23862574 Elevated platelet expression of CD36 may contribute to increased risk of thrombo-embolism in active inflammatory bowel disease. Abstract Context: Inflammatory bowel disease (IBD) induces increased risk of thrombo-embolism. CD36 is involved in platelet activation, glucose metabolism and inflammation. Objective: The relationship between CD36 expression on platelets and monocytes, plasma sCD36, and CD36-positive platelet-derived microparticles (PDMPs) and inflammation in both active IBD and after one week of anti-tumour necrosis alpha antibody (anti-TNF) treatment was investigated. Material and methods: Patients with exacerbation of Crohn's disease (n = 8) or ulcerative colitis (n = 5) and 13 healthy controls were enrolled. Seven patients underwent anti-TNF treatment for one week. Platelet, monocyte, and PDMP-CD36 were measured by flow-cytometry. Results: Platelet CD36 expression was 34% higher in patients, and correlated with insulin resistance and fasting glucose. sCD36 was 37% lower and restored after anti-TNF treatment. Conclusion: Elevated platelet CD36 expression may contribute to increased risk of thrombo-embolism in active IBD. This may not entirely be attributed to inflammation and secondary insulin resistance may play a role. 23449869 Small molecules inhibit growth, viability and ergosterol biosynthesis in Candida albicans. The aim of this work was to evaluate the anti-Candida efficacy of twenty five molecules of plant origin. Based on their MICs, effective molecules were categorized into four categories. Susceptibility testing of test compounds was carried out by standard methodology (M27-A2) as per CLSI guidelines. Minimum Fungicidal Concentration (MFC) was determined as the lowest concentration of drug killing 99.9% cells. Effect on sterol profile was evaluated by sterol quantitation method. Among the screened molecules, cinnamaldehyde, piperidine, citral, furfuraldehyde and indole were potent inhibitors of growth and viability. Exposure of Candida cells to cinnamaldehyde, piperidine, citral, furfuraldehyde, indole, α- and β- pinene at MIC's, altered ergosterol profile. Our results indicate that the molecules altering sterol profile may exert their antifungal effect through inhibition of ergosterol biosynthesis and could be good candidates for fungal specific drug development. 23939903 In Vitro and In Vivo Activities of Antibiotic PM181104. Drug resistance has become a global threat and if not addressed we may enter into the pre-antibiotic era. A way to overcome growing incidence of global antibiotic resistance issue is to introduce compounds belonging to classes that are new to the clinic. During the screening of marine microbial extract library for new antibiotics, one of the extract showed promising anti-gram positive antibacterial activity. Bioactivity guided isolation and characterization of active metabolite, led to the discovery of a novel thiazolyl cyclic-peptide antibiotic, PM181104. It was isolated and characterised from a marine sponge associated actinobacterium strain of the genus Kocuria (MTCC 5269). The compound exhibited a potent in vitro antibacterial activity against a broad range of Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin resistant enterococci (VRE). The minimum inhibitory concentration (MIC) values evaluated for the compound were found to be in few nano-molar range. In vivo studies of PM181104 in Balb/c murine septicemia model the compound displayed an ED100 value of 2.5 and 5.0 mg/kg against MRSA and 10.0 mg/kg against VRE. In this report, in vitro and in vivo studies of PM181104 are described. 23831027 Prion-like Properties of Pathological TDP-43 Aggregates from Diseased Brains. TDP-43 is the major component protein of ubiquitin-positive inclusions in brains of patients with frontotemporal lobar degeneration (FTLD-TDP) or amyotrophic lateral sclerosis (ALS). Here, we report the characterization of prion-like properties of aggregated TDP-43 prepared from diseased brains. When insoluble TDP-43 from ALS or FTLD-TDP brains was introduced as seeds into SH-SY5Y cells expressing TDP-43, phosphorylated and ubiquitinated TDP-43 was aggregated in a self-templating manner. Immunoblot analyses revealed that the C-terminal fragments of insoluble TDP-43 characteristic of each disease type acted as seeds, inducing seed-dependent aggregation of TDP-43 in these cells. The seeding ability of insoluble TDP-43 was unaffected by proteinase treatment but was abrogated by formic acid. One subtype of TDP-43 aggregate was resistant to boiling treatment. The insoluble fraction from cells harboring TDP-43 aggregates could also trigger intracellular TDP-43 aggregation. These results indicate that insoluble TDP-43 has prion-like properties that may play a role in the progression of TDP-43 proteinopathy. 23747308 miR-150 promotes the proliferation of lung cancer cells by targeting P53. Lung cancer is one of the most common causes for cancer-related death. Previous studies suggested that uncontrolled cell proliferation induced by activation of pro-cancer genes or inhibition of cancer suppressor genes plays an important role in the pathogenesis of lung cancer. Here, we demonstrate that miR-150 is aberrantly upregulated in lung cancer tissue and negatively correlates with the expression of the proapoptotic gene p53 but not EGR2. We show that miR-150 specifically targets the 3'-UTR of p53 and regulates its expression. Inhibition of miR-150 effectively delays cell proliferation and promotes apoptosis, accompanied by increased p53 protein expression. Our data reveals the mechanisms underlying miR-150 regulated lung cancer pathogenesis, which might be beneficial for lung cancer therapy. 23454217 Steroids excreted in urine by neonates with 21-hydroxylase deficiency. 4. Characterization, using GC-MS and GC-MS/MS, of 11oxo-pregnanes and 11oxo-pregnenes. In 21-hydroxylase deficiency, urinary metabolites of 21-deoxycortisol, mainly derived from its 11oxo form 21-deoxycortisone, are indicators of intra-adrenal overproduction of 17-hydroxyprogesterone. In affected neonates these metabolites are numerous and most have not been previously described. This work forms the concluding part of a comprehensive study of urinary steroids, aiming to enhance the diagnosis of this disorder and to further elucidate steroid metabolism in neonates. Cortisol metabolites found in untreated patients, similarly almost exclusively present in their 11oxo form in neonates, have been included for completeness. Steroids were analyzed, after extraction and enzymatic conjugate hydrolysis, as methyloxime-trimethylsilyl ether derivatives on gas-chromatographs coupled to quadrupole and ion-trap mass-spectrometers. GC-MS and GC-MS/MS spectra were used together to determine the structure of hitherto undescribed 11oxo-pregnane(enes). Few GC-MS features were associated with the presence of the non-derivatizeable 11oxo group in pregnane(ene)s. GC-MS/MS contributed only to the characterization of structures outside the C-ring, as described in the preceding parts of this study. Parallels were found between the metabolism of 21-deoxycortisone and cortisone. The major metabolic pathway was that of classical 3α,5β-reduction with a prominent further hydroxylation, predominantly at C6. Oxidation of the 6-hydroxyl was also common. We conclude that further oxygenated metabolites of 21-deoxycortisone have potential as more reliable markers of 21-hydroxylase deficiency in the early neonatal period, because their levels are higher during that period of life than for the classical marker 11oxo-pregnanetriol. 23589405 Dermatoprotective effects of some plant extracts (genus Ficus) against experimentally induced toxicological insults in rabbits. Aim: Present study was conducted to evaluate the dermatoprotective effects of plant extracts (Ficus religiosa, Ficus benghalensis, and Ficus racemosa) against known irritants such as sodium dodecyl sulfate (SDS), atrazine, and petrol. METHODS: The study was conducted in adult male rabbits. Ethanol extracts of plants were obtained through Soxhlet. All irritants and Ficus extracts were topically applied to the backs of rabbits daily for 4 days, while pure ethanol served as control. Skin was examined after 24, 48, and 96 h for erythema. Skin biopsies were taken on 5th day for microscopic examination. RESULTS: Erythema produced by irritants reduced significantly with the simultaneous application of Ficus extracts. The mean ± SEM epidermal thickness (micrometer) with SDS was 45.40 ± 1.89, F. religiosa + SDS was 18.60 ± 0.51, F. benghalensis + SDS was 18.40 ± 0.25, F. racemosa + SDS was 18.80 ± 0.37, and mixture of three Ficus species + SDS was 16.80 ± 0.37. Similar findings were revealed after using plant extracts with atrazine and petrol. The mean ± SEM epidermal layer count for SDS was 3.60 ± 0.25, atrazine was 3.40 ± 0.25, petrol was 3.40 ± 0.25, and ethanol (control) was 1.00 ± 0.20. This count reduced to 1.20 ± 0.20 for three Ficus species + SDS, 1.40 ± 0.25 for Ficus species + atrazine, and 1.40 ± 0.25 for Ficus species + petrol. CONCLUSION: Ficus species demonstrated the potential to block the dermatotoxic effects of topical irritants and could be used successfully to prevent skin toxicity. 23686378 Brief communication: 5-HTTLPR genetic diversity and mode of subsistence in Native Americans. The relationship between the "individualism-collectivism" and the serotonin transporter functional polymorphism (5-HTTLPR), suggested in the previous reports, was tested in Native South Amerindian populations. A total of 170 individuals from 21 populations were genotyped for the 5-HTTLPR alleles. For comparative purposes, these populations were classified as individualistic (recent history of hunter-gathering) or collectivistic (agriculturalists). These two groups showed an almost identical S allele frequency (75 and 76%, respectively). The analysis of molecular variance showed no structural differences between them. Behavioral typologies like those suggested by JY Chiao and KD Blizinsky (Proc R Soc B 277 () 529-537) are always a simplification of complex phenomena and should be regarded with caution. In addition, classification of a whole nation in the individualist/collectivist dichotomy is controversial. The focus on modes of subsistence in preindustrial societies, as was tested here, may be a good alternative although the postulated association between the 5-HTTLPR S allele and the collectivist societies was not confirmed. 23063874 NCTC 2544 and IL-18 production: a tool for the identification of contact allergens. Progress in understanding the mechanisms of skin sensitization, provides us with the opportunity to develop in vitro tests as an alternative to in vivo sensitization testing. Keratinocytes play a key role in all phases of skin sensitization. We have recently identified interleukin-18 (IL-18) production in keratinocyte as a potentially useful endpoint for determination of contact sensitization potential of low molecular weight chemicals. The aim of the present article is to further exploit the performance of the NCTC 2544 assay. NCTC 2544 is a commercially available skin epithelial-like cell line originating from normal human skin, which posses a good expression of cytochrome P450-dependent enzymatic activities. Cells were exposed to contact allergens (2-bromo-2-bromomethyl glutaronitrile, cinnamaldehyde, citral, diethylmaleate, dinitrochlorobenzene, glyoxal, 2-mercaptobenzothiazole, nickel sulfate, 4-nitrobenzylbromide, oxazolone, penicillin G, resorcinol, tetramethylthiuram disulfide), to pre- pro-haptens (cinnamyl alcohol, eugenol, isoeugenol, p-phenylediamine), to respiratory allergens (ammonium hexachloroplatinate, diphenylmethane diisocyanate, glutaraldehyde, hexamethylenediisocyanate, maleic anhydride, trimellitic anhydride) and to irritants (benzaldehyde, cholorobenzene, diethylphtalate, hydrobenzoic acid, lactic acid, octanoic acid, phenol, salicylic acid, sodium lauryl sulphate, sulfamic acid). Cell associated IL-18 was evaluated 24 later by ELISA. At not-cytotoxic concentrations (cell viability higher of 80%, as assessed by MTT reduction assay), all contact sensitizers, including pre-pro-haptens, induced a dose-related increase in IL-18, whereas both irritants, with the exception of sulfamic acid, and respiratory allergens failed. A total of 33 chemicals were tested, with an overall accuracy of 97%. Overall, results obtained indicated that cell-associated IL-18 might provide an in vitro tool for identification and discrimination of contact vs. respiratory allergens and/or irritants. 23856855 Evaluation of predictive tests for screening for dihydropyrimidine dehydrogenase deficiency. 5-Fluorouracil (5-FU) is rapidly degraded by dihyropyrimidine dehydrogenase (DPD). Therefore, DPD deficiency can lead to severe toxicity or even death following treatment with 5-FU or capecitabine. Different tests based on assessing DPD enzyme activity, genetic variants in DPYD and mRNA variants have been studied for screening for DPD deficiency, but none of these are implemented broadly into clinical practice. We give an overview of the tests that can be used to detect DPD deficiency and discuss the advantages and disadvantages of these tests.The Pharmacogenomics Journal advance online publication, 16 July 2013; doi:10.1038/tpj.2013.25. 23570471 DNA repair and cytotoxic drugs: the potential role of RAD51 in clinical outcome of non-small-cell lung cancer patients. Many of the cytotoxic drugs used in the treatment of non-small-cell lung carcinoma patients can interfere with DNA activity and the definition of an individual DNA repair profile could be a key strategy to achieve better response to chemotherapeutic treatment. Although DNA repair mechanisms are important factors in the prevention of carcinogenesis, these molecular pathways are also involved in therapy response. RAD51 is a crucial element in DNA repair by homologous recombination and has been shown to interfere with the prognosis of patients treated with chemoradiotherapy. There is increasing evidence that genetic polymorphisms in repair enzymes can influence DNA repair capacity and, consequently, affect chemotherapy efficacy. We conducted this review to show the possible influence of the RAD51 genetic variants in damage repair capacity and treatment response in non-small-cell lung carcinoma patients. 23831118 Biological and clinical implications of retinoic acid-responsive genes in human hepatocellular carcinoma cells. Accumulating data from epidemiological and experimental studies have suggested that retinoids, which are vitamin A derivatives, exert antitumor activity in various organs. We performed a gene screening based on in silico analysis of retinoic acid response elements (RAREs) to identify the genes facilitating the antitumor activity of retinoic acid (RA) and investigated their clinical significance in hepatocellular carcinoma (HCC). In silico analysis of RAREs was performed in the 5-kb upstream region of EST clusters. Chromatin immunoprecipitation analysis of the retinoic acid receptors and gene expression analysis were performed in HuH7, HepG2, and MCF7 cells treated with all-trans RA (ATRA). mRNA expression of RA-responsive genes was investigated using tumor and non-tumor tissues of clinical HCC samples from 171 patients. The association between gene expression and survival of patients was examined by Cox regression analysis. We identified 201 candidate genes with promoter regions containing consensus RARE and finally selected 26 RA-responsive genes. Of these, downregulation of OTU domain-containing 7B (OTUD7B) gene, which was upregulated by ATRA, in tumor tissue was associated with a low cancer-specific survival of HCC patients. Functional analyses revealed that OTUD7B negatively regulates nuclear factor κB (NF-κB) signaling and decreases the survival of HCC cells. We identified RA-responsive genes which are regulated by retinoid signal and found that low-OTUD7B mRNA expression is associated with a poor prognosis for HCC patients. OTUD7B-mediated inhibition of NF-κB signaling may be an effective target for antitumor therapy for HCC. 23287076 Effects of the benzimidazole anthelmintic drug flubendazole on rat embryos in vitro. Filarial diseases affect millions of people in poverty-stricken areas. In 2011, an investigation of the potential of flubendazole as a safe, highly efficacious, and field-usable macrofilaricidal drug was begun by Drug for Neglected Diseases initiative. As part of the preclinical development program, whole embryo culture was used to investigate the potential embryotoxicity of flubendazole and its metabolites, reduced and hydrolyzed flubendazole. Albendazole was included as a comparator. Flubendazole and albendazole showed similar potency in affecting rat embryonic development in vitro, inducing retardation of growth and dysmorphogenic effects at concentrations ≥0.5μg/mL. The head, optic and otic systems, branchial arches and posterior body portion were affected. Diffuse areas of cell death were seen in various embryonic districts. The No Observed Effect Level (NOEL) was 0.25μg/mL for both drugs. Reduced and hydrolyzed flubendazole were less embryotoxic than the parent compound, with NOELs 4-fold and >40-fold higher than that of flubendazole, respectively. 23911923 Site specific risk assessment of an energy-from-waste thermal treatment facility in Durham Region, Ontario, Canada. Part A: Human health risk assessment. The regions of Durham and York in Ontario, Canada have partnered to construct an energy-from-waste thermal treatment facility as part of a long term strategy for the management of their municipal solid waste. This paper presents the results of a comprehensive human health risk assessment for this facility. This assessment was based on extensive sampling of baseline environmental conditions (e.g., collection and analysis of air, soil, water, and biota samples) as well as detailed site specific modeling to predict facility-related emissions of 87 identified contaminants of potential concern. Emissions were estimated for both the approved initial operating design capacity of the facility (140,000 tonnes per year) and for the maximum design capacity (400,000 tonnes per year). For the 140,000 tonnes per year scenario, this assessment indicated that facility-related emissions are unlikely to cause adverse health risks to local residents, farmers, or other receptors (e.g., recreational users). For the 400,000 tonnes per year scenarios, slightly elevated risks were noted with respect to inhalation (hydrogen chloride) and infant consumption of breast milk (dioxins and furans), but only during predicted 'upset conditions' (i.e. facility start-up, shutdown, and loss of air pollution control) that represent unusual and/or transient occurrences. However, current provincial regulations require that additional environmental screening would be mandatory prior to expansion of the facility beyond the initial approved capacity (140,000 tonnes per year). Therefore, the potential risks due to upset conditions for the 400,000 tonnes per year scenario should be more closely investigated if future expansion is pursued. 23932639 Transfer of Cystoisospora suis-specific colostral antibodies and their correlation with the course of neonatal porcine cystoisosporosis. Cystoisospora suis is the most pathogenic species of coccidia in suckling piglets, affecting them predominantly within their first three weeks of life. The clinical signs of neonatal cystoisosporosis include watery diarrhea and wasting, leading to significant economic losses for the farmer. Since neonatal piglets have an immature immune system, colostral transfer of maternal factors such as immune cells or antibodies is essential for controlling infections at that age. However, the role of C. suis-specific antibodies transferred from the sow to the piglets and possible correlations between antibody levels in the piglets acquired from colostrum with the clinical outcome of disease are currently not understood. To address this issue, 12 non-infected piglets and 14 piglets experimentally infected with C. suis on the third day of life were examined during their first four weeks of life. IgG, IgA, and IgM titers in the blood serum specific for sporozoites and merozoites of C. suis were evaluated, along with oocyst excretion and fecal consistency. Additionally, the antibody content in the colostrum and milk of three mother sows was determined. A transfer of naturally acquired C. suis-specific antibodies from sows to piglets with the colostrum could be demonstrated. Maternal antibodies in piglets' blood sera did not persist for longer than 14-21 days except for IgG which was present in high titers until the end of the study. Within 2-3 weeks after birth the onset of endogenous antibody production was noticed. Titers in blood serum showed a correlation with the severity of diarrhea which was positive for IgG and IgM (possibly due to increased consumption or loss of these antibodies) and negative for IgA. C. suis-specific mucus antibodies isolated from infected and non-infected piglets (n=6/group) on the 28th day of life were present in both groups, showing significantly higher titers of IgA and IgM in infected piglets. Maternally transferred antibodies acquired by natural infections of sows as observed in this study did not provide protection against the clinical manifestation of disease. The level and effect of transferrable maternal factors necessary for protection still need to be elucidated. However, correlations between antibody titers and fecal consistency in the piglets indicate that C. suis-specific antibodies might be useful markers for the expectable clinical severity of cystoisosporosis. 23539282 Predictors of CT Colonography Utilization Among Asymptomatic Medicare Beneficiaries. Although the Centers for Medicare and Medicaid Services (CMS) denied coverage for screening computed tomography colonography (CTC) in March 2009, little is understood about whether CTC was targeted to the appropriate patient population prior to this decision. Evaluate patient characteristics and known relative clinical indications for screening CTC among patients who received CTC compared to optical colonoscopy (OC). Cross-sectional study of all 10,538 asymptomatic Medicare beneficiaries who underwent CTC between January 2007 and December 2008, compared to a cohort of 160,113 asymptomatic beneficiaries who underwent OC, matched on county of residence and year of examination. Patient characteristics and known relative appropriate and inappropriate clinical indications for screening CTC. CTC utilization was higher among women, patients > 65 years of age, white patients, and those with household income > 75 % (p = 0.001). Patients with relatively appropriate clinical indications for screening CTC were more likely to undergo CTC than OC including presumed incomplete OC (OR 80.7, 95 % CI 76.01-85.63); sedation risk (OR 1.11, 95 % CI 1.05-1.17); and chronic anticoagulation risk (OR 1.46, 95 % CI 1.38-1.54), after adjusting for patient characteristics and known clinical indications. Conversely, patients undergoing high-risk screening, an inappropriate indication, were less likely to receive CTC (OR 0.4, 95 % CI 0.37-0.42). Overall, 83 % of asymptomatic patients referred to CTC had at least one clinical indication relatively appropriate for CTC (8,772/10,538). During the 2 years preceding CMS denial for screening, CTC was targeted to asymptomatic patients with relatively appropriate clinical indications for CTC/not receiving OC. However, CTC utilization was lower among certain demographic groups, including minority patients. These findings raise the possibility that future coverage of screening CTC might exacerbate disparities in colorectal cancer screening while increasing overall screening rates. 23918646 Synthesis and negative inotropic effects evaluation of 7-substituted-4,5-dihydro-[1,2,4]oxadiazolo[4,3-a]quinolin-1-ones. A series of 7-alkoxy-4,5-dihydro-[1,2,4]oxadiazolo[4,3-a]quinolin-1-ones was synthesized and their negative inotropic effects were evaluated by measuring the left atrium stroke volume in isolated rabbit heart preparations. All compounds moderated the cardiac workload by decreasing heart rate and contractility (inotropic effects). Among them, compound 6 was found to be best potent with a -28.89 ± 1.91 % decrease in the stroke volume at a concentration of 3 Ã— 10(-5) M in our in vitro study. 23881135 Fluorosomes: Fluorescent Virus-Like Nanoparticles that Represent a Convenient Tool to Visualize Receptor-Ligand Interactions. Viruses are the smallest life forms and parasitize on many eukaryotic organisms, including humans. Consequently, the study of viruses and viral diseases has had an enormous impact on diverse fields of biology and medicine. Due to their often pathogenic properties, viruses have not only had a strong impact on the development of immune cells but also on shaping entire immune mechanisms in their hosts. In order to better characterize virus-specific surface receptors, pathways of virus entry and the mechanisms of virus assembly, diverse methods to visualize virus particles themselves have been developed in the past decades. Apart from characterization of virus-specific mechanisms, fluorescent virus particles also serve as valuable platforms to study receptor-ligand interactions. Along those lines the authors have developed non-infectious virus-like nanoparticles (VNP), which can be decorated with immune receptors of choice and used for probing receptor-ligand interactions, an especially interesting application in the field of basic but also applied immunology research. To be able to better trace receptor-decorated VNP the authors have developed technology to introduce fluorescent proteins into such particles and henceforth termed them fluorosomes (FS). Since VNP are assembled in a simple expression system relying on HEK-293 cells, gene-products of interest can be assembled in a simple and straightforward fashion-one of the reasons why the authors like to call fluorosomes 'the poor-man's staining tool'. Within this review article an overview on virus particle assembly, chemical and recombinant methods of virus particle labeling and examples on how FS can be applied as sensors to monitor receptor-ligand interactions on leukocytes are given. 23378062 The role of attention in the academic attainment of children with autism spectrum disorder. Academic attainment in children with Autism Spectrum Disorder (ASD) is under-studied, with associated factors largely undetermined. Parent-reported attention symptoms, attentional-switching and sustained-attention tasks were examined to determine relationships with mathematics and reading attainment in 124 children aged 7-12 years; sixty-four with high-functioning ASD, half girls, and sixty age- and gender-matched typical children (TYP). With full-scale IQ controlled there were no differences in mathematics, reading, attentional switching or sustained attention. In regression analysis, attentional switching was related to mathematics achievement in ASD but not TYP children. Findings highlight attentional switching difficulties are linked with poorer mathematics outcomes in ASD. 23939801 An eco-friendly enantioselective access to (R)-naringenin as inhibitor of proinflammatory cytokine release. (RS)-Naringenin is a flavanone well-known for its beneficial health-related properties, such as its anti-inflammatory activity. The preparative enantioselective chromatographic resolution of commercial (RS)-naringenin was performed on a Chiralpak AD-H column (500×50 mm i.d., dp 20 μm) using MeOH as eluent. The developed method is in accordance with the principles of green chemistry, since the environmental impact was lowered by recycling of the eluent, and allowed the production of gram amounts of each enantiomer with high purity (chemical purity >99%, enantiomeric excess (ee) >94%). Racemic and enantiomeric naringenin were subjected to an exhaustive in vitro investigation of anti-inflammatory activity, aimed at evaluating the relevance of chirality. The assay with cultured human peripheral blood mononuclear cells (hPBMC) activated by phytohemagglutinin A revealed that (R)-naringenin was more effective in inhibiting T-cell proliferation than the (S)-enantiomer and the racemate. Moreover, (R)-naringenin significantly reduced proinflammatory cytokine levels such as those of TNF-α and, with less potency, IL-6. These results evidenced the anti-inflammatory potential of naringenin and the higher capacity of (R)-naringenin to inhibit both in vitro hPBMC proliferation and cytokine secretion at non toxic doses. Thus, (R)-naringenin is a promising candidate for in vivo investigation. 23497883 The antioxidants in oils heated at frying temperature, whether natural or added, could protect against postprandial oxidative stress in obese people. We have investigated the effects of the intake of oils heated at frying temperature in order to find an oil model for deep-frying that prevents postprandial oxidative stress. Twenty obese people received four breakfasts following a randomised crossover design consisting of different oils (virgin olive oil (VOO), sunflower oil (SFO), and a mixed seed oil (SFO/canola oil) with added dimethylpolysiloxane (SOX) or natural antioxidants from olives (SOP)), which were subjected to 20 heating cycles. The intake of SFO-breakfast reduced plasma GSH levels and the GSH/GSSG ratio, increased protein carbonyl levels, and induced a higher gene expression of the different NADPH-oxidase subunits, Nrf2-Keap1 activation, gene expression of the antioxidant enzymes in peripheral blood mononuclear cells and antioxidant plasma activities than the intake of the breakfasts prepared with VOO, SOP and SOX. Oils with phenolic compounds, whether natural (VOO) or artificially added (SOP), or with artificial antioxidant (SOX), could reduce postprandial oxidative stress compared with sunflower oil. 23887945 The importance of an ergonomic workstation to practicing sonographers. Musculoskeletal disorders have been described in a number of professions over the years. They are defined as injuries that are caused by or aggravated by workplace activities, and they account for up to 60% of all workplace illnesses. They are known by different names, such as musculoskeletal disorder, repetitive strain injury, cumulative trauma disorder, and repetitive motion injury. Musculoskeletal disorders have only been identified in sonographers since 1997 but are increasing in incidence. Surveys done among American and Canadian sonographers in 1997 showed an 84% incidence; however, this incidence had increased to 90% by 2008. Understanding the importance of optimal body mechanics and how to maintain neutral postures will enable sonographers to reduce the risk factors associated with their profession. Even with the most advanced equipment, an ergonomic workstation is only as effective as the person using it. 23943640 BET 1: Intranasal lorazepam is an acceptable alternative to intravenous lorazepam in the control of acute seizures in children. A short-cut review was carried out to determine whether intranasal lorazepam was as effective as intravenous lorazepam in the control of seizures in children. Eighteen papers were found using the reported search, of which one was directly relevant and another compared intranasal lorazepam with intramuscular paraldehyde. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses are shown in table 1. It is concluded that intranasal lorazepam appears to be a safe and effective treatment for this condition. 23941668 Adiposity Has Unique Influence on the Renin-Aldosterone Axis and Blood Pressure in Black Children. To comparatively examine the effects of adiposity on the levels of plasma renin activity (PRA), plasma aldosterone concentration (PAC), and aldosterone-renin ratio (ARR) in young black and white children. We prospectively assessed 248 black and 345 white children and adolescents. A novel analytical technique was used to assess the concurrent influences of age and body mass index (BMI) on PRA, PAC, and ARR. The estimated effects were depicted by colored contour plots. In contrast to whites, blacks had lower PRA (2.76 vs 3.36 ng/mL/h; P < .001) and lower PAC (9.01 vs 14.59 ng/dL; P < .001). In blacks, BMI was negatively associated with PRA (P = .001), consistent with an association with a more expanded plasma volume; there was no association with PAC. In whites, BMI was positively associated with PAC (P = .005); we did not detect a BMI-PRA association. The effects of BMI on ARR were directionally similar in the two race groups but more pronounced in blacks. Mean systolic blood pressure was greater in blacks with lower PRA (P < .01), higher PAC (P = .015), and higher ARR (P = .49). An increase in adiposity was associated with a suppressed PRA in blacks and an increase in PAC in whites. The unique relationship between adiposity and renin-aldosterone axis in blacks suggests the possible existence of a population-specific mechanism characterized by volume expansion, which could in turn enhance the influences of adiposity on blood pressure in black children and adolescents. 23682998 Cortical-striatal gene expression in neonatal hippocampal lesion (NVHL)-amplified cocaine sensitization. Cortical-striatal circuit dysfunction in mental illness may enhance addiction vulnerability. Neonatal ventral hippocampal lesions (NVHL) model this dual diagnosis causality by producing a schizophrenia syndrome with enhanced responsiveness to addictive drugs. Rat genome-wide microarrays containing >24 000 probesets were used to examine separate and co-occurring effects of NVHLs and cocaine sensitization (15 mg/kg/day × 5 days) on gene expression within medial prefrontal cortex (MPFC), nucleus accumbens (NAC), and caudate-putamen (CAPU). Two weeks after NVHLs robustly amplified cocaine behavioral sensitization, brains were harvested for genes of interest defined as those altered at P < 0.001 by NVHL or cocaine effects or interactions. Among 135 genes so impacted, NVHLs altered twofold more than cocaine, with half of all changes in the NAC. Although no genes were changed in the same direction by both NVHL and cocaine history, the anatomy and directionality of significant changes suggested synergy on the neural circuit level generative of compounded behavioral phenotypes: NVHL predominantly downregulated expression in MPFC and NAC while NVHL and cocaine history mostly upregulated CAPU expression. From 75 named genes altered by NVHL or cocaine, 27 had expression levels that correlated significantly with degree of behavioral sensitization, including 11 downregulated by NVHL in MPFC/NAC, and 10 upregulated by NVHL or cocaine in CAPU. These findings suggest that structural and functional impoverishment of prefrontal-cortical-accumbens circuits in mental illness is associated with abnormal striatal plasticity compounding with that in addictive disease. Polygenetic interactions impacting neuronal signaling and morphology within these networks likely contribute to addiction vulnerability in mental illness. 23913269 Transglutaminase 2 and phospholipase A2 interactions in the inflammatory response in human Thp-1 monocytes. Several experimental approaches have demonstrated that transglutaminase 2 (TG2) increased activity is involved in monocyte activation and inflammatory response. Preliminary results also demonstrate a TG-mediated post-translational modification of phospholipase A2 (PLA2), which catalyzes the release of arachidonic acid from its lipid storage sites. The control of PLA2-mediated production of eicosanoids has been found to be of great benefit for inflammatory disease treatment. However, the identification of the mechanisms of PLA2 activation is a very complex issue, because of the presence of multiple PLA2 forms. The aim of this study was to characterize the interactions between TG2 and sPLA2 in LPS-stimulated THP-1 cells, which were treated with TPA to induce early differentiated macrophage-type model. We demonstrated that increases in TG2 enzyme activity and protein expression may be considered an early event in monocyte/macrophage activation by LPS. Under these conditions, TG2 protein was co-immunoprecipitated with PLA2 by monoclonal antibody directed against the secretory form of the enzyme (sPLA2-V). Concomitantly, the PLA2 enzyme activity increased in TPA-treated cells exposed to LPS; these high levels of enzyme activity were significant reduced by R283, a site-specific inhibitor of TG2. Moreover, confocal laser scanning microscopy analysis of double-immunostained cytochemical specimens confirmed a co-localization of BAPA-labeled proteins and sPLA2-V in LPS-treated cells. These findings give evidence of a complex TG2/sPLA2-V, suggesting the possibility that sPLA2-V is a substrate for TG2. These results demonstrated that TG2 increases produced a sustained activation of PLA2 activity, suggesting a functional interaction between these enzymes in the regulation of inflammatory response. 23300078 Identification of propofol binding sites in a nicotinic acetylcholine receptor with a photoreactive propofol analog. Propofol, a widely used intravenous general anesthetic, acts at anesthetic concentrations as a positive allosteric modulator of γ-aminobutyric acid type A receptors and at higher concentration as an inhibitor of nicotinic acetylcholine receptors (nAChRs). Here, we characterize propofol binding sites in a muscle-type nAChR by use of a photoreactive analog of propofol, 2-isopropyl-5-[3-(trifluoromethyl)-3H-diazirin-3-yl]phenol (AziPm). Based upon radioligand binding assays, AziPm stabilized the Torpedo nAChR in the resting state, whereas propofol stabilized the desensitized state. nAChR-rich membranes were photolabeled with [(3)H]AziPm, and labeled amino acids were identified by Edman degradation. [(3)H]AziPm binds at three sites within the nAChR transmembrane domain: (i) an intrasubunit site in the δ subunit helix bundle, photolabeling in the nAChR desensitized state (+agonist) δM2-18' and two residues in δM1 (δPhe-232 and δCys-236); (ii) in the ion channel, photolabeling in the nAChR resting, closed channel state (-agonist) amino acids in the M2 helices (αM2-6', βM2-6' and -13', and δM2-13') that line the channel lumen (with photolabeling reduced by >90% in the desensitized state); and (iii) at the γ-α interface, photolabeling αM2-10'. Propofol enhanced [(3)H]AziPm photolabeling at αM2-10'. Propofol inhibited [(3)H]AziPm photolabeling within the δ subunit helix bundle at lower concentrations (IC50 = 40 μm) than it inhibited ion channel photolabeling (IC50 = 125 μm). These results identify for the first time a single intrasubunit propofol binding site in the nAChR transmembrane domain and suggest that this is the functionally relevant inhibitory binding site. 23897883 Teaching NeuroImages: An unusual cause of conus medullaris syndrome. A 22-year-old man presented with a 3-month history of back pain and numbness of the left lower extremities. Lumbar spine MRI demonstrated conus enlargement and an intramedullary mass of predominant isointensity, heterogeneity with central necrosis, and marked heterogeneous enhancement (figure 1). The tumor was resected and was consist with a glioblastoma multiforme. Two months later, the tumor recurred and extended both cranially and caudally with widespread multifocal dissemination to the leptomeninges and the cauda equina (figure 2). The patient deteriorated rapidly despite radiation therapy and concomitant temozolomide. 23913583 Antioxidants for female subfertility. A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This difficulty with conception may affect up to a quarter of all couples planning a child. The reported prevalence of subfertility has increased significantly over the past twenty years. It is estimated that for 40% to 50% of couples, subfertility may be a result of female problems, including ovulatory disorders, poor egg quality, fallopian tube damage and endometriosis. Antioxidants are thought to reduce the oxidative stress brought on by these conditions. Currently, limited evidence suggests that antioxidants improve fertility, and trials have explored this area with varied results. This review assessed the evidence for the effectiveness of different antioxidants in female subfertility. To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women. We searched the following databases (from inception to April 2013) with no language restrictions applied: Cochrane Menstrual Disorders and Subfertility Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS and OpenSIGLE. We also searched conference abstracts and citation lists in the ISI Web of Knowledge. Ongoing trials were searched in the Trials Registers. Reference lists were checked, and a search on Google was performed. We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment or treatment with another antioxidant, among women attending a reproductive clinic. Trials comparing antioxidants with fertility drugs alone and trials that exclusively included fertile women attending a fertility clinic because of male partner infertility were excluded. Three review authors independently screened 2127 titles and abstracts, and 67 of these potentially eligible trials were appraised for inclusion and quality through review of full texts and contact with authors. Three review authors were involved in data extraction and assessment of risk of bias. Review authors also collected data on adverse events as reported from the trials. Studies were pooled using fixed-effect models; however, if high heterogeneity was found, a random-effects model was used. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for the dichotomous outcomes of live birth, clinical pregnancy and adverse events. Analyses were stratified by type of antioxidant, by indications for subfertility and by those women also undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection techniques (ICSIs). The overall quality of the evidence was assessed by applying GRADE criteria. A total of 28 trials involving 3548 women were included in this review. Investigators compared oral antioxidants, including combinations of antioxidants, pentoxifylline, N-acetyl-cysteine, melatonin, L-arginine, vitamin E, myo-inositol, vitamin C, vitamin D+calcium and omega-3-polyunsaturated fatty acids with placebo, with no treatment/standard treatment or another antioxidant.Antioxidants were not associated with an increased live birth rate compared with placebo or no treatment/standard treatment (OR 1.25, 95% CI 0.19 to 8.26, P = 0.82, 2 RCTs, 97 women, I(2) = 75%, very low-quality evidence). This suggests that among subfertile women with an expected live birth rate of 37%, the rate among women taking antioxidants would be between 10% and 83%.Antioxidants were not associated with an increased clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.30, 95% CI 0.92 to 1.85, P = 0.14, 13 RCTs, 2441 women, I(2)= 55%, very low-quality evidence). This suggests that among subfertile women with an expected clinical pregnancy rate of 23%, the rate among women taking antioxidants would be between 22% and 36%.Only one trial reported on live birth in the antioxidant versus antioxidant comparison, and two trials reported on clinical pregnancy in this comparison. Only subtotals were used in this analysis, and meta-analysis was not possible as each trial used a different antioxidant.Pentoxifylline was associated with an increased clinical pregnancy rate compared with placebo or no treatment (OR 2.03, 95% CI 1.19 to 3.44, P = 0.009, 3 RCTs, 276 women, I(2) = 0%).Adverse events were reported by 14 trials in the meta-analysis and included miscarriage, multiple pregnancy, ectopic pregnancy and gastrointestinal effects. No evidence revealed a difference in adverse effects between antioxidant groups and control groups, but these data were limited.The overall quality of evidence was 'very low' to 'low' because of poor reporting of outcomes, the number of small studies included, high risk of bias within studies and heterogeneity in the primary analysis. The quality of the evidence in the 'antioxidant versus placebo/no treatment' and in the 'antioxidant versus antioxidant' comparisons was assessed to be 'very low'. Antioxidants were not associated with an increased live birth rate or clinical pregnancy rate. There was some evidence of an association of pentoxifylline with an increased clinical pregnancy rate; however, there were only three trials included in this comparison. Future trials may change this result. Variation in the types of antioxidants given meant that we could not assess whether one antioxidant was better than another. There did not appear to be any association of antioxidants with adverse effects for women, but data for these outcomes were limited. 23953393 Implant Standardization for Hemiarthroplasty: Implementation of a Pricing Matrix System at a Level II Community Based Trauma System. Our purpose was to perform a clinical and financial analysis of a pricing matrix system on operative hip fracture care concerning hemiarthroplasty for displaced femoral neck fractures in elderly low demand patients. Data analysis on 81 pre-matrix and 88 post-matrix patients demonstrated no significant differences in age, sex, ASA or fracture pattern between the two groups. No difference in surgical approach, cement use, prosthesis choice, operative time, estimated blood loss, or intra-operative complication rate was observed. No radiographic difference in subsidence or loosening was demonstrated. Readmission form cardiac, UTI, PE or DVT rates were similar between groups and no increase in revision surgery or mortality was observed. Overall, our hospital realized a 37% reduction in implant costs, resulting in $165,500 savings for the calendar year. 23733341 A vasculo-protective circuit centered on lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 operative in murine microcirculation. Endogenous protective pathways mitigate the overshooting of inflammation after sterile or infectious injury. Here we report that formyl peptide receptor 2 (Fpr2/3) null mice display a major phenotype with exacerbated vascular inflammation observed postischemia reperfusion (IR) injury of the mesenteric artery, characterized by marked neutrophil adhesion and extravasation as visualized by intravital microscopy. Analysis of endogenous agonists for Fpr2/3 revealed that lipoxin A4 (LXA4) was generated by platelet/neutrophil aggregates during ischemia: this cellular response was attenuated in Fpr2/3(-/-) mice; hence, LXA4 levels were lower after 30 minutes' ischemia, and associated with augmented vascular inflammation in the reperfusion (45-180 minutes) phase. Exogenous delivery of LXA4 attenuated IR-mediated inflammation in Fpr2/3(+/+) but not Fpr2/3(-/-) mice; conversely, an Fpr2/3 antagonist skewed the vascular phenotype of Fpr2/3(+/+) mice to that of Fpr2/3(-/-) animals. Such LXA4-based circuit could be activated by aspirin (30-100 mg/kg), which triggered formation of 15-epi-LXA4 in wild-type mice, yet it was effective in Fpr2/3(-/-) mice. In summary, we propose that during ischemia, neutrophil Fpr2/3 controls platelet/neutrophil aggregates with the rapid generation of circulating LXA4, which in turn modulates downstream vascular inflammatory responses evident during the reperfusion phase. 23960073 FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of NF2-associated schwannomas. The p21-activated kinases (PAKs) are immediate downstream effectors of the Rac/Cdc42 small G-proteins and implicated in promoting tumorigenesis in various type of cancer including breast and lung carcinomas. Recent studies have established a requirement for the PAKs in the pathogenesis of Neurofibromatosis type 2 (NF2), a dominantly inherited cancer disorder caused by mutations at the NF2 gene locus. Merlin, the protein product of the NF2 gene, has been shown to negatively regulate signaling through the PAKs and the tumor suppressive functions of Merlin are mediated, at least in part, through inhibition of the PAKs. Knockdown of PAK1 and PAK2 expression, through RNAi-based approaches, impairs the proliferation of NF2-null schwannoma cells in culture and inhibits their ability to form tumors in vivo. These data implicate the PAKs as potential therapeutic targets. High-throughput screening of a library of small molecules combined with a structure-activity relationship approach resulted in the identification of FRAX597, a small-molecule pyridopyrimidinone, as a potent inhibitor of the group I PAKs. Crystallographic characterization of the FRAX597/PAK1 complex identifies a phenyl ring that traverses the gatekeeper residue and positions the thiazole in the back cavity of the ATP binding site, a site rarely targeted by kinase inhibitors. FRAX597 inhibits the proliferation of NF2-deficient schwannoma cells in culture and displayed potent anti-tumor activity in vivo, impairing schwannoma development in an orthotopic model of NF2. These studies identify a novel class of orally available ATP-competitive Group I PAK inhibitors with significant potential for the treatment of NF2 and other cancers. 23818618 Transformation of odor selectivity from projection neurons to single mushroom body neurons mapped with dual-color calcium imaging. Although the response properties of most neurons are, to a large extent, determined by the presynaptic inputs that they receive, comprehensive functional characterization of the presynaptic inputs of a single neuron remains elusive. Toward this goal, we introduce a dual-color calcium imaging approach that simultaneously monitors the responses of a single postsynaptic neuron together with its presynaptic axon terminal inputs in vivo. As a model system, we applied the strategy to the feed-forward connections from the projection neurons (PNs) to the Kenyon cells (KCs) in the mushroom body of Drosophila and functionally mapped essentially all PN inputs for some of the KCs. We found that the output of single KCs could be well predicted by a linear summation of the PN input signals, indicating that excitatory PN inputs play the major role in generating odor-selective responses in KCs. When odors failed to activate KC output, local calcium transients restricted to individual postsynaptic sites could be observed in the KC dendrites. The response amplitudes of the local transients often correlated linearly with the presynaptic response amplitudes, allowing direct assay of the strength of single synaptic sites. Furthermore, we found a scaling relationship between the total number of PN terminals that a single KC received and the average synaptic strength of these PN-KC synapses. Our strategy provides a unique perspective on the process of information transmission and integration in a model neural circuit and may be broadly applicable for the study of the origin of neuronal response properties. 23820878 Developing comprehensive and Brief ICF core sets for morbid obesity for disability assessment in Taiwan: a preliminary study. Background: The International Classification of Functioning, Disability, and Health (ICF) provides a framework for measuring functioning and disability based on a biopsychosocial model. Aim: The aim of this study was to develop comprehensive and brief ICF core sets for morbid obesity for disability assessment in Taiwan. Design: Observational Setting: Other Population: Twenty-nine multidisciplinary experts of ICF Methods: The questionnaire contained 112 obesity-relevant and second-level ICF categories. Using a 5-point Likert scale, the participants rated the significance of the effects of each category on the heath status of people with obesity. Correlation between an individual's score and the average score of the group indicated consensus. The categories were selected for the comprehensive core set for obesity if more than 50% of the experts rated them as "important" in the third round of the Delphi exercise, and for the brief core set if more than 80% of the experts rated them "very important." Results. Twenty-nine experts participated in the study. These included 18 physicians, 4 dieticians, 3 physical therapists, 2 nurses, and 2 ICF experts. The comprehensive core set for morbid obesity contained 61 categories. Of these, 26 categories were from the component body function, 8 were from body structure, 18 were from activities and participation, and 9 were from environmental factors. The brief core set for obesity disability contained 29 categories. Of these, 19 categories were from the component body function, 3 were from body structure, 6 were from activities and participation, and one was from environmental factors. The comprehensive and brief ICF core sets provide comprehensive information on the health effects of morbid obesity and concise information for clinical practice. Conclusion: Comprehensive and brief core sets were created after three rounds of Delphi technique. Further validation study of these core sets by applying to patients with morbid obesity is needed. Clinical Rehabilitation Impact: The comprehensive ICF core set for morbid obesity provides comprehensive information on the health effects of morbid obesity; the brief core set can provide concise information for clinical practice. 23559369 Isolated oral histoplasmosis presenting as Fever of unknown origin in a portuguese hemodialysis patient. The authors report a clinical case of an isolated oral histoplasmosis in a hemodialysis patient that presented with fever of unknown origin and had an unremarkable physical examination. During the investigation, a Gallium scan showed uptake in the oral cavity and soon after the oral cavity examination revealed a granulomatous lesion on the tooth 26. Histopathologic findings were compatible with histoplasmosis. The treatment regimen included liposomal amphotericin B followed by itraconazole consolidation therapy, and side effects did not occur. Both clinical evolution and outcome were favorable. Oral histoplasmosis in a non-immunosuppressed patient is extremely rare. 23225776 Design strategies and applications of tissue bioadhesives. In the past two decades tissue adhesives and sealants have revolutionized bleeding control and wound healing. This paper focuses on existing tissue adhesive design, their structure, functioning mechanism, and their pros and cons in wound management. It also includes the latest advances in the development of new tissue adhesives as well as the emerging applications in regenerative medicine. We expect that this paper will provide insightful discussion on tissue bioadhesive design and lead to innovations for the development of the next generation of tissue bioadhesives and their related biomedical applications. 23763420 Adoption and Implementation of Policies to Support Preventive Dentistry Initiatives for Physicians: A National Survey of Medicaid Programs. Objectives. We determined the number of state Medicaid programs adopting initiatives to support preventive dental services provision by nondental health care professionals, their perceived attributes, and implementation barriers. Methods. We used Qualtrics to conduct a cross-sectional survey in 2008 of Medicaid dental program managers to determine organizational stage of adoption classified according to the Transtheoretical Model of Behavior Change with 3-year follow-up. We assessed perceptions of the influence of 18 initiative attributes on the decision to adopt, drawn from Roger's diffusion of innovations theory. Stage and date of adoption are presented descriptively. Attributes and barriers were analyzed by stage of adoption by using analyses of variance or χ(2) statistics. Results. By 2011, 42 states had adopted a policy. Only 9 states included a comprehensive set of preventive services, the most common being fluoride varnish. Adoption was affected by perceived initiative simplicity and its compatibility with other Medicaid programs. Administrative barriers were the most common among the 15 studied. Conclusions. State Medicaid policies to reimburse nondental providers for preventive dental services are becoming widespread. Interventions are needed to ensure oral health services delivery at the practice level. 23780837 The Association of High-Density Lipoprotein Cholesterol with Cancer Incidence in Type II Diabetes: A Case of Reverse Causality? Low high-density lipoprotein cholesterol (HDL-C) and type II diabetes are associated with an increased risk for cancer. Patients with type II diabetes typically have low HDL-C; however, the association between HDL-C and cancer has not been examined in this population. A total of 11,140 patients with type II diabetes were followed for a median of 5 years. Cox proportional hazard models were used to assess the association between baseline HDL-C and risk of cancer incidence and cancer death, with adjustments made for potential confounders. To explore the possibility of reverse causation, analyses were repeated for the cancers occurring in the first and second halves of follow-up. Six hundred and ninety-nine patients developed cancer, with 48% occurring within the first half of follow-up. For every 0.4 mmol/L lower baseline HDL-C, there was a 16% higher risk of cancer [HR 1.16; 95% confidence interval (CI), 1.06-1.28; P = 0.0008] and cancer death (HR 1.16; 95% CI, 1.01-1.32; P = 0.03). After adjustment for confounding, the higher risk remained significant for cancer (adjusted HR 1.10; 95% CI, 1.00-1.22; P = 0.05) but not for cancer death (adjusted HR 1.08; 95% CI, 0.93-1.25; P = 0.31). The association was driven by cancers occurring within the first half of follow-up (adjusted HR 1.22; 95% CI, 1.05-1.41; P = 0.008) as no significant association was found between HDL-C and cancer in the second half of follow-up. Low HDL-C is associated with cancer risk in patients with type II diabetes. However, this association may be explained by confounding and reverse causation. HDL-C is not a risk factor for cancer in type II diabetes. Cancer Epidemiol Biomarkers Prev; 1-6. ©2013 AACR. 23917390 High-dose methylprednisolone pulse therapy upregulated FcγRIIb expression on B cells in primary Sjögren's syndrome patients with thrombocytopenia. Abnormalities in B cell are characteristic feature of primary Sjögren's syndrome (pSS). As FcγRIIb is a key regulator of B cells, the objective of this study is to investigate the role of the inhibitory receptor FcγRIIb in B cells from pSS patients, and whether glucocorticoid can affect B cell subpopulations or FcγRIIb expression. Thirty pSS patients and 15 healthy controls were enrolled in this study. The results showed that the percentage of memory CD19(+)CD27(+) B cells was significantly lower in pSS patients compared to in healthy controls. FcγRIIb expression on memory CD19(+)CD27(+) B cells from active pSS patients was significantly reduced compared with those from inactive or healthy controls. The level of FcγRIIb on memory CD19(+)CD27(+) B cells from active pSS patients was negatively correlated with anti-SSA antibody titers and Sjögren's syndrome disease activity index. After a high-dose methylprednisolone pulse therapy for 3 days, FcγRIIb expression on memory B cells was upregulated, with the raised level of platelets. In vitro, dexamethasone could elevate FcγRIIb expression on B cells of pSS patients in a dose-dependent manner. Taken together, our data suggest that the upregulation of FcγRIIb may be expected to be a new therapeutic strategy in pSS patients. 23934153 Structure of the p300 catalytic core and implications for chromatin targeting and HAT regulation. CBP and p300 are histone acetyltransferases (HATs) that associate with and acetylate transcriptional regulators and chromatin. Mutations in their catalytic 'cores' are linked to genetic disorders, including cancer. Here we present the 2.8-Å crystal structure of the catalytic core of human p300 containing its bromodomain, CH2 region and HAT domain. The structure reveals that the CH2 region contains a discontinuous PHD domain interrupted by a RING domain. The bromodomain, PHD, RING and HAT domains adopt an assembled configuration with the RING domain positioned over the HAT substrate-binding pocket. Disease mutations that disrupt RING attachment led to upregulation of HAT activity, thus revealing an inhibitory role for this domain. The structure provides a starting point for understanding how chromatin-substrate targeting and HAT regulation are coupled and why mutations in the p300 core lead to dysregulation. 22907877 Intrapericardial paraganglioma associated with succinate dehydrogenase complex subunit C mutation syndrome. Paragangliomas are benign neoplasms of neuroendocrine origin. It is estimated that from 20% to 50% of these tumors are familial. Mutations in the succinate dehydrogenase (SDH) gene family have been found to be responsible for a significant percentage of familial paragangliomas. A 33-year-old man who was found to have 3 synchronous primary tumors including a catecholamine-secreting intrapericardial paraganglioma is presented. Genetic workup diagnosed this patient with an underlying germ-line mutation in the succinate dehydrogenase complex subunit C (SDHC) gene; consistent with a diagnosis of hereditary paraganglioma/pheochromocytoma syndrome (PGL/PCC). Current knowledge regarding the clinical implications of an SDHC gene mutation is reviewed. Modern molecular techniques have identified that a significantly greater proportion of paragangliomas are due to underlying hereditary conditions than was previously thought. Appropriate screening in these individuals and their immediate family members may allow for early tumor diagnosis and improved disease outcomes. © 2012 Wiley Periodicals, Inc. Head Neck, 2013. 23132681 Antigenotoxic effect of lipoic acid against mitomycin-C in human lymphocyte cultures. Antitumor agents are used in therapy against many forms of human cancer. One of these is mitomycin-C (MMC). As with many agents, it can interact with biological molecules and can induce genetic hazards in non-tumor cells. One of the possible approaches to protect DNA from this damage is to supply antioxidants that can remove free radicals produced by antitumor agents. Lipoic acid (LA) is known as one of the most powerful antioxidants. The aim of this study was to investigate antigenotoxic effects of LA against MMC induced chromosomal aberrations (CA), sister chromatid exchanges (SCE) and micronucleus (MN) formation in human lymphocytes. Lymphocytes were treated with 0.2 Î¼g MMC/heparinized mL for 48 h. Three different concentrations (0.5, 1, 2 Î¼g/mL) of LA were used together with MMC in three different applications; 1 h pre-treatment, simultaneous treatment and 1 h post-treatment. A negative, a positive and a solvent control were also included. In all the cultures treated with MMC + LA, the frequency of abnormal cells and CA/cell significantly decreased compared to MMC. Statistically significant reduction was also observed in SCE/cell and MN frequencies in all treatments. These results demonstrated anticlastogenic and antimutagenic effects of LA against MMC induced genotoxicity. LA showed the most efficient effect during 1 h pretreatment. On the other hand, MMC + LA treatments induced significant reduction in mitotic index than that of MMC treatment alone. These results are encouraging that LA can be a possible chemopreventive agent in tumorigenesis in both cancer patients and in health care persons handling anti-cancer drugs. 23915316 Label-free mass spectrometry proteome quantification of human embryonic kidney cells following 24 hours of sialic acid overproduction. Cell surface glycoprotein sialylation is one of the most ubiquitous glycan modifications found on higher eukaryotes. The surface sialylation pattern of cells is influenced by the cellular environment but also by the Golgi sialyltransferase activity and flux of metabolites through sialic acid producing pathways. Altered cell surface sialic acid patterns have been observed in several cancers and other pathological conditions. In this experiment we examined the cellular proteomic changes that occur in human embryonic kidney cells after 24 hours of sialic acid overproduction using N-Acetylmannosamine. We utilized high resolution mass spectrometry and label free protein quantification to characterize the relative changes in protein abundance as well as multiple reaction monitoring to quantify the cellular sialic acid levels. Using N-Acetylmannosamine we were able to induce sialic acid production to almost 70-fold compared to non-induced control cells. Mass spectrometric analysis of cellular proteome of control and induced cells identified 1802 proteins of which 105 displayed significant changes in abundance. Functional analysis of the resulting relative changes in protein abundance revealed regulation of several cellular pathways including protein transport, metabolic and signaling pathways and remodeling of epithelial adherens junctions. We also identified several physically interacting co-regulated proteins in the set of changed proteins. In this experiment we show that increased metabolic flux through sialic acid producing pathway affects the abundance of several protein transport, epithelial adherens junction, signaling and metabolic pathway related proteins. 23899369 Specificity and stability of the Acromyrmex-Pseudonocardia symbiosis. The stability of mutualistic interactions is likely to be affected by the genetic diversity of symbionts that compete for the same functional niche. Fungus-growing (attine) ants have multiple complex symbioses and thus provide ample opportunities to address questions of symbiont specificity and diversity. Among the partners are Actinobacteria of the genus Pseudonocardia that are maintained on the ant cuticle to produce antibiotics, primarily against a fungal parasite of the mutualistic gardens. The symbiosis has been assumed to be a hallmark of evolutionary stability, but this notion has been challenged by culturing and sequencing data indicating an unpredictably high diversity. We used 454 pyrosequencing of 16S rRNA to estimate the diversity of the cuticular bacterial community of the leaf-cutting ant Acromyrmex echinatior and other fungus-growing ants from Gamboa, Panama. Both field and laboratory samples of the same colonies were collected, the latter after colonies had been kept under laboratory conditions for up to 10 years. We show that bacterial communities are highly colony-specific and stable over time. The majority of colonies (25/26) had a single dominant Pseudonocardia strain, and only two strains were found in the Gamboa population across 17 years, confirming an earlier study. The microbial community on newly hatched ants consisted almost exclusively of a single strain of Pseudonocardia while other Actinobacteria were identified on older, foraging ants in varying but usually much lower abundances. These findings are consistent with recent theory predicting that mixtures of antibiotic-producing bacteria can remain mutualistic when dominated by a single vertically transmitted and resource-demanding strain. 23868405 Tumor Protein D52 Controls Trafficking of an Apical Endolysosomal Secretory Pathway in Pancreatic Acinar Cells. Zymogen granule (ZG) formation in acinar cells involves zymogen-cargo sorting from trans-Golgi into immature secretory granules (ISGs). ISG maturation progresses by removal of lysosomal membrane and select-content proteins which enter endosomal intermediates prior to their apical exocytosis. Constitutive and stimulated secretion through this mechanism is termed the constitutive-like (CLP) and minor-regulated (MRP) pathways, respectfully. However, the molecular components that control membrane trafficking within these endosomal compartments are unknown. We show that tumor protein D52 is highly expressed in endosomal compartments following pancreatic acinar stimulation and regulates apical exocytosis of an apically directed endolysosomal compartment. Secretion from the endolysosomal compartment was detected by cell-surface labeling of lysosome associated membrane protein LAMP1, which is absent from ZGs, and had incomplete overlap with surface labeling of synaptotagmin, a marker of ZG exocytosis. Although culturing (16-18 h) of isolated acinar cells is accompanied by a loss of secretory responsiveness, levels of SNARE proteins necessary for ZG exocytosis were preserved. However, levels of endolysosomal proteins D52, EEA1, Rab5 and LAMP1 markedly decreased. When D52 levels were restored by adenoviral delivery, the levels of these regulatory proteins and secretion of both LAMP1 (endolysosomal) and amylase was strongly enhanced. These secretory effects were absent in alanine and aspartate substitutions of serine 136, the major D52 phosphorylation site, and were inhibited by brefeldin A, which does not directly affect the ZG compartment. Results indicate D52 directly regulates apical endolysosomal secretion and are consistent with previous studies suggesting this pathway indirectly regulates ZG secretion of digestive enzymes. 23115008 O-Mannosylation and human disease. Glycosylation of proteins is arguably the most prevalent co- and post-translational modification. It is responsible for increased heterogeneity and functional diversity of proteins. Here we discuss the importance of one type of glycosylation, specifically O-mannosylation and its relationship to a number of human diseases. The most widely studied O-mannose modified protein is alpha-dystroglycan (α-DG). Recent studies have focused intensely on α-DG due to the severity of diseases associated with its improper glycosylation. O-mannosylation of α-DG is involved in cancer metastasis, arenavirus entry, and multiple forms of congenital muscular dystrophy [1, 2]. In this review, we discuss the structural and functional characteristics of O-mannose-initiated glycan structures on α-DG, enzymes involved in the O-mannosylation pathway, and the diseases that are a direct result of disruptions within this pathway. 23877198 Selegiline rescues gait deficits and the loss of dopaminergic neurons in a subacute MPTP mouse model of Parkinson's disease. The monoamine oxidase type-B (MAO‑B) inhibitor, selegiline, is often recommended as a first-line treatment for Parkinson's disease (PD) and has been shwon to possess neuroprotective effects. The aim of the present study was to determine whether selegiline increases the levels of the neurotrophic factors (NTFs), glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), and whether it rescues motor dysfunction and the loss of dopaminergic neurons in mice with 1-methyl-4‑phenyl‑1,2,3,6‑tetrahydropyridine (MPTP)-induced lesions. We found that the oral administration of selegiline (1.0 mg/kg/day for 14 days) successfully suppressed the MPTP‑induced reduction of nigral dopaminergic neurons and striatal fibers (192.68 and 162.76% of MPTP‑exposed animals, respectively; both P<0.001). Moreover, improvements in gait dysfunction were observed after 7 and 14 days of a low dose of selegiline that is reported not to inhibit MAO‑B. Furthermore, there was a significant increase in GDNF and BDNF mRNA (2.10 and 2.75-fold) and protein levels (143.53 and 157.05%) in the selegiline‑treated mice compared with the saline‑treated MPTP‑exposed mice. In addition, the Bax/Bcl‑2 gene and protein expression ratios were significantly increased in the MPTP-exposed mice, and this effect was reversed by selegiline. Correlation analysis revealed that gait measurement and GDNF/BDNF levels positively correlated with the number of dopaminergic neurons. These findings demonstrate that selegiline has neurorescue effects that are possibly associated with the induction of NTFs and anti-apoptotic genes. 23801413 Planar Chiral Iridium Complexes with the Δ-TRISPHAT Anion: Toward the First Enantiopure o-Quinone Methide π-Complex. We describe the resolution of a planar chiral cationic iridium complex [Cp*Ir(η(5) -2-methyl-oxodienyl)][OT f] () following the counterion strategy, where anion metathesis by Δ-TRISPHAT generates the two diastereomers (pR, pS)-[Cp*Ir(η(5) -2-methyl-oxodienyl)][Δ-TRISPHAT] (, ). Upon fractional crystallization both compounds were separated as confirmed by (1) H nuclear magnetic resonance (NMR) and circular dichroism studies recorded in solution. The latter represents the key-complex precursors for the enantioselective synthesis of metallated o-quinone methide complexes (, ). Chirality 25:449-454, 2013. © 2013 Wiley Periodicals, Inc. 23906892 Improving communication among health professionals, avoiding mistakes. With each shift change or informal handoff during the workday, critical information can be lost or miscommunicated. Good communication helps catch and correct errors, plan future work, and create a culture of collaboration. It also allows team members to teach and learn. Improving handoffs is a National Patient Safety Goal. Facilities that establish formal procedures and processes tend to have fewer handoff communication problems than those that do not. 23142634 Therapeutic RNA aptamers in clinical trials. RNA aptamers can fold into complex structures and bind with high affinity and selectivity to various macromolecules, viruses, and cells. They are isolated from a large pool of nucleic acids by a conceptually straightforward iterative selection process called SELEX. Aptamers have enormous potential as therapeutics due to their ability to bind to proteins and specifically inhibit their functions with minimal or no harmful side-effects. The first aptamer therapeutic was FDA approved in 2005 and a number of novel aptamer-based therapeutics are currently undergoing clinical trials for treating diseases such as macular degeneration, choroidal neovascularization, intravascular thrombus, acute coronary syndrome, von Willebrand factor related disorders, von Hippel-Lindau syndrome (VHL), angiomas, acute myeloid leukemia, renal cell carcinoma, non-small cell lung cancer, thrombotic thrombocytopenic purpura, and several others. In this review, we present aptamers in on-going, completed, and terminated clinical studies highlighting their mechanism of action as well as the inherent challenges of aptamer production and use. 23877030 DNA electroporation in rabbits as a method for generation of high-titer neutralizing antiserum: Examples of the botulinum toxins types A, B, and E. Raising high titer antibodies in animals is usually performed by protein immunization, which requires the long and sometimes difficult step of production of the recombinant protein. DNA immunization is an alternative to recombinant proteins, only requiring the building of an eukaryotic expression plasmid. Thanks to efficient DNA delivery techniques such as in vivo electroporation, DNA vaccination has proven useful the last few years. In this work, we have shown that it is possible to raise very high antibody titers in rabbit by DNA electroporation of an antigen encoding plasmid in the skeletal muscle with the right set of electrodes and rabbit strain. In a model of botulinum toxins types A and E, the neutralizing titers obtained after three treatments were high enough to fit the European Pharmacopeia, while it did not for type B toxin. Furthermore, the raised antibodies have high avidity and are suitable for in vitro and in vivo immunodetection of proteins. 23474889 Influence of the novel histamine H3 receptor antagonist ST1283 on voluntary alcohol consumption and ethanol-induced place preference in mice. RATIONALE: Growing evidence supports a role for the central histaminergic system to have a modulatory influence on drug addiction in general and alcohol-use disorders in particular through histamine H3 receptors (H3R). OBJECTIVE: In the present study, the effects of systemic injection of the newly synthesized H3R antagonist ST1283 on ethanol (EtOH) voluntary intake and EtOH-conditioned reward in mice have been investigated. METHODS: Oral EtOH, saccharin, and quinine intake was assessed in a two-bottle choice paradigm using escalating concentrations of alcohol or tastant solutions. EtOH-induced place preference (CPP), EtOH-induced locomotor activity, and blood ethanol concentration (BEC) were also measured. RESULTS: Following administration of the H3R antagonist (2.5, 5, and 10 mg/kg, i.p.), there was a significant dose-dependent decrease in alcohol consumption and preference. Importantly, vehicle- and ST1283 (5 mg/kg)-treated mice showed similar consumption and preference to increasing concentration of both sweet and bitter tastes. More interestingly, systemic administration of ST1283 inhibited EtOH-CPP and EtOH-enhanced locomotion. This inhibition was blocked when mice were pretreated with the selective H3R agonist R-(alpha)-methyl-histamine (10 mg/kg). Finally, vehicle- and ST1283-treated mice had similar BECs. CONCLUSION: Our results show that ST1283 may decrease voluntary EtOH consumption and EtOH-CPP by altering its reinforcing effects, suggesting a novel role for histamine signaling in regulation of alcoholism. Lastly, the results add to the growing literature on H3R modulation in the pharmacotherapy of EtOH addiction. 23628157 A novel device for the calibration of sonic and ultrasonic recording transducers. Recently, there has been an increase in the analysis of animal vocalizations in behavioral neuroscience as a social cue or indicator of neurological integrity. Despite the multitude of researchers examining vocalizations in a variety of species, no inexpensive, tunable devices currently exist to calibrate the amplification applied to such vocalizations before data are collected. Many commercially available recording systems have analog adjustments for gain, but such methods are notoriously unreliable and highly variable. Without a consistent level of gain, the amplitudes of recorded acoustic signals cannot be reliably compared. Here, we describe an apparatus designed to fulfill this need, which we have labeled the Calibration Unit for Recording Transducers (CURT). To maximize application to various fields, its emitted frequency and amplitude are tunable to output frequencies in both human-sonic (20 Hz-20 kHz) and human-ultrasonic ranges (20 Hz-100 kHz). Additionally, it is a portable (weighing approximately 180 g), customizable, stand-alone unit, and fits a variety of microphone connector types. The CURT is also relatively low cost to build (under 250.00 USD), thereby making such a device available to as many researchers as possible in animal behavior and neuroscience. 23517131 Human embryonic stem cell-derived cardiomyocytes migrate in response to gradients of fibronectin and wnt5a. An improved understanding of the factors that regulate the migration of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) would provide new insights into human heart development and suggest novel strategies to improve their electromechanical integration after intracardiac transplantation. Since nothing has been reported as to the factors controlling hESC-CM migration, we hypothesized that hESC-CMs would migrate in response to the extracellular matrix and soluble signaling molecules previously implicated in heart morphogenesis. To test this, we screened candidate factors by transwell assay for effects on hESC-CM motility, followed by validation via live-cell imaging and/or gap-closure assays. Fibronectin (FN) elicited a haptotactic response from hESC-CMs, with cells seeded on a steep FN gradient showing nearly a fivefold greater migratory activity than cells on uniform FN. Studies with neutralizing antibodies indicated that adhesion and migration on FN are mediated by integrins α-5 and α-V. Next, we screened 10 soluble candidate factors by transwell assay and found that the noncanonical Wnt, Wnt5a, elicited an approximately twofold increase in migration over controls. This effect was confirmed using the gap-closure assay, in which Wnt5a-treated hESC-CMs showed approximately twofold greater closure than untreated cells. Studies with microfluidic-generated Wnt5a gradients showed that this factor was chemoattractive as well as chemokinetic, and Wnt5a-mediated responses were inhibited by the Frizzled-1/2 receptor antagonist, UM206. In summary, hESC-CMs show robust promigratory responses to FN and Wnt5a, findings that have implications on both cardiac development and cell-based therapies. 23830881 Emotion in voice matters: Neural correlates of emotional prosody perception. The ability to perceive emotions is imperative for successful interpersonal functioning. The present study examined the neural characteristics of emotional prosody perception with an exploratory event-related potential analysis. Participants were 59 healthy individuals who completed a discrimination task presenting 120 semantically neutral word pairs from five prosody conditions (happy/happy, angry/angry, neutral/neutral, angry/happy, happy/angry). The task required participants to determine whether words in the pair were spoken in same or different emotional prosody. Reflective of an initial processing stage, the word 1 N1 component was found to have greatest amplitude in parietal regions of the hemispheres, and was largest for emotional compared to neutral stimuli, indicating detection of emotion features. A second processing stage, represented by word 1 P2, showed similar topographic effects; however, amplitude was largest for happy in the left hemisphere while angry was largest in the right, illustrating differentiation of emotions. At the third processing stage, word 1 N3 amplitude was largest in frontal regions, indicating later cognitive processing occurs in the frontal cortex. N3 was largest for happy, which had lowest accuracy compared to angry and neutral. The present results support Schirmer and Kotz's (2006) model of vocal emotion perception because they elucidated the function and ERP components by reflecting three primary stages of emotional prosody perception, controlling for semantic influence. 23903797 Perceptions, expectations, and attitudes about communication with physicians among Chinese American and non-Hispanic white women with early stage breast cancer. Asian Americans have consistently reported poorer communication with physicians compared with non-Hispanic Whites (NHW). This qualitative study sought to elucidate the similarities and differences in communication with physicians between Chinese and NHW breast cancer survivors. Forty-four Chinese and 28 NHW women with early stage breast cancer (stage 0-IIa) from the Greater Bay Area Cancer Registry participated in focus group discussions or individual interviews. We oversampled Chinese women because little is known about their cancer care experiences. In both interview formats, questions explored patients' experiences and feelings when communicating with physicians about their diagnosis, treatment, and follow-up care. Physician empathy at the time of diagnosis was important to both ethnic groups; however, during treatment and follow-up care, physicians' ability to treat cancer and alleviate physical symptoms was a higher priority. NHW and US-born Chinese survivors were more likely to assert their needs, whereas Chinese immigrants accepted physician advice even when it did not alleviate physical problems (e.g., pain). Patients viewed all physicians as the primary source for information about cancer care. Many Chinese immigrants sought additional information from primary care physicians and stressed optimal communication over language concordance. Physician empathy and precise information were important for cancer patients. Cultural differences such as the Western emphasis on individual autonomy vs. Chinese emphasis on respect and hierarchy can be the basis for the varied approaches to physician communication we observed. Interventions based on cultural understanding can foster more effective communication between immigrant patients and physicians ultimately improving patient outcomes. 23893219 Coexpression patterns indicate that GPI-anchored non-specific lipid transfer proteins are involved in accumulation of cuticular wax, suberin and sporopollenin. The non-specific lipid transfer proteins (nsLTP) are unique to land plants. The nsLTPs are characterized by a compact structure with a central hydrophobic cavity and can be classified to different types based on sequence similarity, intron position or spacing between the cysteine residues. The type G nsLTPs (LTPGs) have a GPI-anchor in the C-terminal region which attaches the protein to the exterior side of the plasma membrane. The function of these proteins, which are encoded by large gene families, has not been systematically investigated so far. In this study we have explored microarray data to investigate the expression pattern of the LTPGs in Arabidopsis and rice. We identified that the LTPG genes in each plant can be arranged in three expression modules with significant coexpression within the modules. According to expression patterns and module sizes, the Arabidopsis module AtI is functionally equivalent to the rice module OsI, AtII corresponds to OsII and AtIII is functionally comparable to OsIII. Starting from modules AtI, AtII and AtIII we generated extended networks with Arabidopsis genes coexpressed with the modules. Gene ontology analyses of the obtained networks suggest roles for LTPGs in the synthesis or deposition of cuticular waxes, suberin and sporopollenin. The AtI-module is primarily involved with cuticular wax, the AtII-module with suberin and the AtIII-module with sporopollenin. Further transcript analysis revealed that several transcript forms exist for several of the LTPG genes in both Arabidopsis and rice. The data suggests that the GPI-anchor attachment and localization of LTPGs may be controlled to some extent by alternative splicing. 23541655 Simultaneous speciation and preconcentration of ultra trace concentrations of mercury and selenium species in environmental and biological samples by hollow fiber liquid phase microextraction prior to high performance liquid chromatography coupled to inductively coupled plasma mass spectrometry. Nowadays, hollow fiber membrane extraction techniques are widely used due to the high enrichment factors obtained with many different types of analytes and samples. In this paper, we propose a new analytical method that allows the simultaneous extraction of methylmercury, inorganic mercury and Se(4+) and determination by high performance liquid chromatography coupled to inductively coupled plasma mass spectrometry (HPLC-ICP-MS). The detection limits obtained are very low (110-230ng/L) with relative standard deviations below 15% for all the analytes and averaged recoveries in fortified samples in the range of 71-99%. The precision of the analytical method is very good which overcomes one of the most important shortcomings of membrane extraction techniques. Several variables were studied to get optimal extraction conditions for the analytes. This method has been validated with real world samples such as water (tap, river and estuarine) and human blood plasma. 23692254 Characterization of the novel broad-spectrum kinase inhibitor CTx-0294885 as an affinity reagent for mass spectrometry-based kinome profiling. Kinase enrichment utilizing broad-spectrum kinase inhibitors enables the identification of large proportions of the expressed kinome by mass spectrometry. However, the existing inhibitors are still inadequate in covering the entire kinome. Here, we identified a novel bisanilino pyrimidine, CTx-0294885, exhibiting inhibitory activity against a broad range of kinases in vitro, and further developed it into a Sepharose-supported kinase capture reagent. Use of a quantitative proteomics approach confirmed the selectivity of CTx-0294885-bound beads for kinase enrichment. Large-scale CTx-0294885-based affinity purification followed by LC-MS/MS led to the identification of 235 protein kinases from MDA-MB-231 cells, including all members of the AKT family that had not been previously detected by other broad-spectrum kinase inhibitors. Addition of CTx-0294885 to a mixture of three kinase inhibitors commonly used for kinase-enrichment increased the number of kinase identifications to 261, representing the largest kinome coverage from a single cell line reported to date. Coupling phosphopeptide enrichment with affinity purification using the four inhibitors enabled the identification of 799 high-confidence phosphosites on 183 kinases, ∼10% of which were localized to the activation loop, and included previously unreported phosphosites on BMP2K, MELK, HIPK2, and PRKDC. Therefore, CTx-0294885 represents a powerful new reagent for analysis of kinome signaling networks that may facilitate development of targeted therapeutic strategies. Proteomics data have been deposited to the ProteomeXchange Consortium ( http://proteomecentral.proteomexchange.org ) via the PRIDE partner repository with the data set identifier PXD000239. 23549894 Multiple-kernel, multiple-instance similarity features for efficient visual object detection. We propose to use the similarity between the sample instance and a number of exemplars as features in visual object detection. Concepts from multiple-kernel learning and multiple-instance learning are incorporated into our scheme at the feature level by properly calculating the similarity. The similarity between two instances can be measured by various metrics and by using the information from various sources, which mimics the use of multiple kernels for kernel machines. Pooling of the similarity values from multiple instances of an object part is introduced to cope with alignment inaccuracy between object instances. To deal with the high dimensionality of the multiple-kernel multiple-instance similarity feature, we propose a forward feature-selection technique and a coarse-to-fine learning scheme to find a set of good exemplars, hence we can produce an efficient classifier while maintaining a good performance. Both the feature and the learning technique have interesting properties. We demonstrate the performance of our method using both synthetic data and real-world visual object detection data sets. 23521140 Chloroprocaine 40 mg produces shorter spinal block than articaine 40 mg in day-case knee arthroscopy patients. Articaine and chloroprocaine have recently gained interest as short-acting spinal anaesthetics. Based on previous work comparing articaine 60 mg with chloroprocaine 40 mg, we hypothesised that articaine 40 mg and chloroprocaine 40 mg would produce similar spinal anaesthesa regarding block onset, maximal spread, and recovery. In this randomised, double-blind study, adult patients (18-70 years, American Society of Anaesthesiologists physical status I-III, BMI < 36 kg/m(2) ) scheduled for day-case knee arthroscopy received either articaine 40 mg (20 mg/ml) (group A40, n = 16) or chloroprocaine 40 mg (20 mg/ml) (group C40, n = 18) intrathecally. Telephone interviews were performed on the first and seventh postoperative day to disclose possible side effects, e.g. transient neurological symptoms (TNS). The groups were comparable regarding demographic data, onset and maximal spread of spinal anaesthesia, and duration of surgery. Surgery could be performed successfully under spinal anaesthesia except once in A40 (insufficient block) and once in C40 (prolonged surgery). Complete recovery was significantly slower in A40 vs. C40 for both motor block (105 (94/120) vs. 75 (71/90) min) [P < 0.001, Mann-Whitney U-test (MW-U)] and sensory block [135 (109/176) vs. 105 min (90/124)] (P < 0.02, MW-U), respectively [data are median (25th/75th percentiles)]. One patient from A40 showed mild TNS. Both A40 and C40 provided mainly adequate spinal anaesthesia for day-case knee arthroscopy. While onset and maximal spread were comparable, the recovery from motor block was clearly faster with chloroprocaine after equivalent doses of spinal articaine and chloroprocaine. 23443931 Recombination in the evolution of human rhinovirus genomes. Human rhinoviruses (HRV) are highly prevalent human respiratory pathogens that belong to the genus Enterovirus. Although recombination within the coding region is frequent in other picornavirus groups, most evidence of recombination in HRV has been restricted to the 5' untranslated region. We analysed the occurrence of recombination within published complete genome sequences of members of all three HRV species and additionally compared sequences from HRV strains spanning 14 years. HRV-B and HRV-C showed very little evidence of recombination within the coding region. In contrast, HRV-A sequences appeared to have undergone a large number of recombination events, typically involving whole type groups. This suggests that HRV-A may have been subject to extensive recombination during the period of diversification into types. This study demonstrates the rare and sporadic nature of contemporary recombination of HRV strains and contrasts with evidence of extensive recombination within HRV-A and between members of different species during earlier stages in its evolutionary diversification. 23878211 HLA targeting efficiency correlates with human T-cell response magnitude and with mortality from influenza A infection. Experimental and computational evidence suggests that HLAs preferentially bind conserved regions of viral proteins, a concept we term "targeting efficiency," and that this preference may provide improved clearance of infection in several viral systems. To test this hypothesis, T-cell responses to A/H1N1 (2009) were measured from peripheral blood mononuclear cells obtained from a household cohort study performed during the 2009-2010 influenza season. We found that HLA targeting efficiency scores significantly correlated with IFN-γ enzyme-linked immunosorbent spot responses (P = 0.042, multiple regression). A further population-based analysis found that the carriage frequencies of the alleles with the lowest targeting efficiencies, A*24, were associated with pH1N1 mortality (r = 0.37, P = 0.031) and are common in certain indigenous populations in which increased pH1N1 morbidity has been reported. HLA efficiency scores and HLA use are associated with CD8 T-cell magnitude in humans after influenza infection. The computational tools used in this study may be useful predictors of potential morbidity and identify immunologic differences of new variant influenza strains more accurately than evolutionary sequence comparisons. Population-based studies of the relative frequency of these alleles in severe vs. mild influenza cases might advance clinical practices for severe H1N1 infections among genetically susceptible populations. 23922228 Underlying the Mechanism of Vancomycin and Human Serum Albumin Interaction: A Biophysical Study. In the present study, the binding mechanism of vancomycin with human serum albumin (HSA) was determined. Upon addition of vancomycin to HSA, the fluorescence emission was quenched and the binding constant of vancomycin with HSA was found to be 6.05 × 10(3) M(-1) at 295 K, which corresponds to -2.16 × 10(4) J·mol(-1) of free energy. The conformation of HSA was altered upon binding of vancomycin with a decrease in α helix and an increase in β sheets and random coils, suggesting partial unfolding of the secondary structure. Molecular docking experiments found that vancomycin binds strongly with HSA at the hydrophobic pocket through hydrogen bonding and van der Waals interactions. An average binding distance of 4.71 nm has been determined on the basis of the Förster resonance energy theory. It was demonstrated that vancomycin binding to HSA causes protein structural changes. 23612885 Outcome of Clinical Stage III Melanoma Patients with FDG-PET and Whole-Body CT Added to the Diagnostic Workup. Combined whole-body FDG-PET and CT provide the most comprehensive staging of melanoma patients with palpable lymph node metastases (LNM). The aim of this study is to analyze survival of FDG-PET and CT negative or positive melanoma patients and to assess which factors have independent prognostic impact on survival of these patients. Patients with palpable and histologically or cytologically proven LNM of melanoma, referred to participating hospitals for examination with FDG-PET and CT, were selected from a previous study. Melanoma-specific survival (MSS) and disease-free period (DFP) were analyzed for FDG-PET and CT positive and negative patients using the Kaplan-Meier method. Cox-regression analysis was performed to analyze which patient or melanoma characteristics had significant impact on MSS or DFP. For all 252 patients 5-year MSS was 38.2 %. For FDG-PET and CT negative and positive patients 5-year MSS was 47.6 and 16.9 %, respectively. Disease-free period for FDG-PET and CT negative patients was 46.0 % after 5 years. Gender, a positive FDG-PET and CT, LNM in axilla compared to head or neck, and presence of extranodal growth were independent factors for worse MSS in all patients. Positive FDG-PET and CT was the most important prognostic factor for MSS with a hazard ratio of 2.54 (95 % CI, 1.55-4.17, P < 0.001). Staging melanoma patients with palpable LNM is more accurate when whole-body FDG-PET and CT is added to the diagnostic workup. Hence, FDG-PET and CT, preferably combined, are indicated in the staging of clinical stage III melanoma patients. 23879618 Parallel analysis of finite element model controlled trial and retrospective case control study on percutaneous internal fixation for vertical sacral fractures. Although percutaneous posterior-ring tension-band metallic plate and percutaneous iliosacral screws are used to fix unstable posterior pelvic ring fractures, the biomechanical stability and compatibility of both internal fixation techniques for the treatment of Denis I, II and III type vertical sacral fractures remain unclear. Using CT and MR images of the second generation of Chinese Digitized Human "male No. 23", two groups of finite element models were developed for Denis I, II and III type vertical sacral fractures with ipsilateral superior and inferior pubic ramus fractures treated with either a percutaneous metallic plate or a percutaneous screw. Accordingly, two groups of clinical cases that were fixed using the above-mentioned two internal fixation techniques were retrospectively evaluated to compare postoperative effect and function. Parallel analysis was performed with a finite element model controlled trial and a case control study. The difference of the postoperative Majeed standards and outcome rates between two case groups was no statistically significant (P > 0.05). Accordingly, the high values of the maximum displacements/stresses of the plate-fixation model group approximated those of the screw-fixation model group. However, further simulation of Denis I, II and III type fractures in each group of models found that the biomechanics of the plate-fixation models became increasingly stable and compatible, whereas the biomechanics of the screw-fixation models maintained tiny fluctuations. When treating Denis III fractures, the biomechanical effects of the pelvic ring of the plate-fixation model were better than the screw-fixation model. Percutaneous plate and screw fixations are both appropriate for the treatment of Denis I and II type vertical sacral fractures; whereas percutaneous plate fixation appears be superior to percutaneous screw fixation for Denis III type vertical sacral fracture. Biomechanical evidence of finite element evaluations combined with clinical evidence will contribute to our ability to distinguish between indications that require plate or screw fixation for vertical sacral fractures. 23823903 Regional molecular genetics centers in thoracic oncology: what and who should be tested? Management of NSCLC patients is more and more individualized especially on the base of bioguided treatments. In order to guarantee an access for all the patients too this type of strategy, the French NCI supports since 2006 a nationwide network of 28 regional genetics center. The financial support is based on public funds. The French NCI recommends today the assessment of seven biomarkers for all stage IV non squamous NSCLC patients. Due to financial and technical reasons, this recommendation must be followed. However, the molecular profiling of lung cancer patients would ideally be extended across all stages and all histological types of the disease in order to improve our knowledge in this field and provides the patient with an opportunity to access a bioguided treatment as frequently as possible. 22922038 Synthesis of NaP zeolite at room temperature and short crystallization time by sonochemical method. NaP zeolite nano crystals were synthesized by sonochemical method at room temperature with crystallization time of 3h. For comparison, to insure the effect of sonochemical method, the hydrothermal method at conventional synthesis condition, with same initial sol composition was studied. NaP zeolites are directly formed by ultrasonic treatment without the application of autogenous pressure and also hydrothermal treatment. The effect of ultrasonic energy and irradiation time showed that with increasing sonication energy, the crystallinity of the powders decreased but phase purity remain unchanged. The synthesized powders were characterized by XRD, IR, DTA TGA, FESEM, and TEM analysis. FESEM images revealed that 50 nm zeolite crystals were formed at room temperature by using sonochemical method. However, agglomerated particles having cactus/cabbage like structure was obtained by sonochemical method followed by hydrothermal treatment. In sonochemical process, formation of cavitation and the collapsing of bubbles produced huge energy which is sufficient for crystallization of zeolite compared to that supplied by hydrothermal process for conventional synthesis. With increasing irradiation energy and time, the crystallinity of the synthesized zeolite samples increased slightly. 23739193 Dynamic article: long-term outcomes of patients undergoing combined endolaparoscopic surgery for benign colon polyps. Patients with large benign colon polyps not amenable to endoscopic removal commonly undergo resections. Polyp removal using combined endolaparoscopic surgery may be an effective alternative to bowel resection in select patients. The aim of this study was to evaluate short-term and long-term outcomes of patients who underwent endolaparoscopy at our institution. Medical records and a prospectively maintained database were reviewed. This study constituted a retrospective review of consecutive patients who underwent endolaparoscopy for benign polyps from 2003 to 2012. Combined endolaparoscopic surgery was performed. The primary outcomes measured were success rate, rate of recurrence, rate of malignancy, length of stay, and complication rate. A total of 75 patients were taken to the operating room with the intention of endolaparoscopy. The most common indications were large polyp size and difficult location. Based on intraoperative findings, 10 patients were suspected of having cancer and underwent immediate laparoscopic colectomy. Of 65 attempted cases, 48 patients (74%) underwent successful combined endolaparoscopic surgery. Median follow-up time was 65 (8-87) months. Patients in whom combined endolaparoscopic surgery was unsuccessful were converted to colectomy (2 open, 15 laparoscopic). Two patients were converted because of concerns of cancer and 15 because of technical difficulties. Median operative time for successful endolaparoscopy was 145 (50-249) minutes. The complication rate was 4.4% (2/48). Median length of stay was 1 (0-6) day for endolaparoscopy vs 5 (3-19) days for those converted to colectomy. Median polyp size was 3 (1.0-7.0) cm. One patient was found to have cancer on final pathology, but refused to have further surgery. Sensitivity and specificity of predicting malignancy based on clinical findings were 33% (4/12) and 98.5% (64/65). Four of 5 patients who had recurrence (10%) after endolaparoscopy had complete endoscopic polypectomy. One patient required delayed laparoscopic colectomy for a second recurrence. This study was limited by its retrospective nature. Combined endolaparoscopic surgery appears to be a safe and effective alternative to colectomy in all parts of the colon in patients who have benign polyps not removable with colonoscopy alone. 23479411 Cooperation between osteoblastic cells and endothelial cells enhances their phenotypic responses and improves osteoblast function. Osteogenesis requires close co-operation with angiogenesis to create vascularized bone tissue. In this study, an indirect co-culture model using osteoblasts (OBs), primary endothelial cells (ECs) and Matrigel interlayer was established to understand the impact of each cell type on the other. ECs synergistically enhanced osteoblastic gene expression by OBs, while OBs were capable of supporting tubule-like structures formed by ECs on Matrigel, enhancing mean tubule length from 146.5 ± 23.5 μm in ECs alone to 192 ± 28.6 μm in co-culture (p < 0.05). Similar improvements were noted in terms of tubule number. An applicability study of the co-culture model to bone tissue engineering, performed on a biopolymer fibrous membrane, showed substantially enhanced deposition of calcified nodules. These results demonstrate the efficacy of co-culture with ECs to improve osteogenesis for bone tissue engineering. 23701754 The addition of a plain or herb-flavored reduced-fat dip is associated with improved preschoolers' intake of vegetables. This quasiexperimental study used a within-subjects experimental design to determine whether adding herbs and/or spices to a reduced-fat dip increased children's willingness to taste, liking of, and consumption of vegetables. Participants were preschool children aged 3 to 5 years who attended a child-care center in Central Pennsylvania in late 2008 and early 2009. First, children's familiarity with and liking of six raw vegetables and five dips (reduced-fat plain, herb, garlic, pizza, and ranch) were assessed. In Experiment 1 (n=34), children tasted a vegetable they liked, one they disliked, and one they refused, with a reduced-fat plain dip and their favorite reduced-fat herb-flavored dip. In Experiment 2 (n=26 or n=27), they rated their liking of celery and yellow squash, with and without their favorite reduced-fat herb dip (pizza or ranch), and their intake of those vegetable snacks was measured. In Experiment 1, the herb-flavored dip was preferred over the plain dip (P<0.01), and children were three times more likely to reject the vegetable alone, compared with eating the vegetable paired with an herb dip (P<0.001). In Experiment 2, children ate significantly more of a previously rejected or disliked vegetable (celery and squash) when offered with a preferred reduced-fat herb dip than when the vegetable was served alone (P<0.05). These findings suggest that offering vegetables with reduced-fat dips containing familiar herb and spice flavors can increase tasting and thereby promote liking, acceptance, and consumption of vegetables, including vegetables previously rejected or disliked. 23959230 Chirality-specific hydrolysis of amino acid substrates by cellulose nanofibers. We demonstrate for the first time that cellulose nanofibers obtained from natural sources have the capability to hydrolyze the amide bonds of amino acid substrates in a chirality-specific manner. The chiral specificities were clearly correlated with the species of amino acid units and the crystal structures of cellulose. 23905945 Predictive factors for worse pathological outcomes of upper tract urothelial carcinoma: experience from a nationwide high-volume centre in China. To analyse the predictive factors for worse pathological outcome (muscle invasive pT2+, non-organ-confined pT3+ or N+ and histological Grade 3) of upper tract urothelial carcinoma (UTUC) in a Chinese population from a nationwide high-volume centre in China. Predictors were studied by retrospectively reviewing the clinicopathological data of 729 consecutive patients with UTUC treated in our centre from January 2002 to December 2010. Univariate and multivariate logistic regression analyses were used. There were more female patients (56.4%) than males and more tumours were located in the ureter (52.7%) than in the pelvis. In multivariate analysis, male gender (hazard ratio [HR] 1.898, P = 0.001), sessile architecture (HR 3.249, P < 0.001), high grade (HR 5.007, P < 0.001), ipsilateral hydronephrosis (HR 4.768, P < 0.001), renal pelvis location (HR 2.620, P < 0.001) and tumour without multifocality (HR 1.639, P = 0.028) were predictive factors for muscle-invasive UTUC. Male gender (HR 2.132, P < 0.001), renal pelvis location (HR 3.466, P < 0.001), tumour without multifocality (HR 2.532, P = 0.001), sessile tumour architecture (HR 3.274, P < 0.001), and high grade (HR 3.019, P < 0.001) were predictive factors for non-organ-confined disease. Chronological old age (HR 1.047, P < 0.001), sessile tumour architecture (HR 25.192, P < 0.001), ipsilateral hydronephrosis (HR 1.689, P = 0.024), and positive urinary cytology (HR 1.997, P = 0.006) were predictive factors for histological Grade 3 UTUC. There was a predominance of female patients and ureteric tumours in UTUCs of this Chinese population. Male gender, sessile architecture, tumour location, tumour without multifocality, high histological grade and preoperative ipsilateral hydronephrosis were independent predictive factors for worse pathological outcome of UTUCs. 23931745 Disseminated tuberculosis in an immunocompetent patient. Miliary tuberculosis refers to the clinical disease resulting from the hematogenous dissemination of Mycobacterium tuberculosis. A tuberculous aneurysm of the aorta is exceedingly rare. Contiguous tuberculosis in the form of lymphadenitis is generally responsible for the aortic involvement. We report a case of tuberculous mycotic aneurysm in patient with miliary disease, not affected by a cellular immunodeficiency and with no other common risk factor for infection. He received anti-tubercular therapy and endovascular stenting before the identification of Mycobacterium tuberculosis in lung, lymph nodes, and gastric lavage. The clinician should be aware that a mycotic abdominal aortic aneurysm could be caused by M. tuberculosis, even if microbiological confirmation is lacking or is negative, especially if a contiguous focus of tubercular infection is detected. 23470094 Prognosis is deteriorating for upper tract urothelial cancer: data for England 1985-2010. To ascertain current trends in the incidence and mortality rates for upper tract urothelial cancer (UTUC) and identify any relationship with age, stage at presentation, social deprivation and treatment method. We used national databases to collect the data: incidence, stage and survival data from the National Cancer Data Repository (NCDR) and British Association of Urological Surgeons (BAUS) audit database; mortality data from the Office for National Statistics (ONS); and treatment method data from the Hospital Episodes Statistics (HES). The incidence of UTUC is increasing (from 1985 to 2009 it increased by 38% in men and 77% in women). It affects mainly those aged >60 years, and diagnoses are increasingly made in those aged >80 years. Diagnoses at advanced stage have increased from 45 to 80%. Mortality has risen faster than incidence; the overall 5-year survival rate has dropped from 60 to 48%. Survival is worst in stage IV disease and in patients aged ≥80 years; when analysed by age or stage group, survival rates are unchanged. Nephroureterectomy has increased by 75%, but endoscopic treatment, which only became available part way through the study period, now accounts for 11% of surgical interventions for UTUC, mainly in stage I disease and in the elderly. Despite sharing its risk factors with bladder cancer, current incidence and mortality trends for UTUC contrast with those in bladder cancer. Increasing use of cross-sectional imaging may explain some of the identified increased incidence. Higher incidence specifically in people >80 years, together with stage migration to more advanced cancers, are likely to have caused at least some of the observed increased mortality. Further study is required to answer the questions of whether there are other hitherto unidentified aetiological or prognostic factors; whether less aggressive treatment of UTUCs in the elderly is always justified; and whether the rising frequency of minimally invasive treatment means suboptimum oncological management. 23924194 Effect of concurrent cognitive tasks on temporo-spatial parameters of gait among children with cerebral palsy and typically developed controls. Abstract Objective: To assess the influence of different concurrent cognitive tasks on gait characteristics in children with cerebral palsy (CP) and typically developed (TD) controls. Methods: Eleven children with CP and eleven TD controls walked under three conditions: at a self-selected speed, at a self-selected speed while memorizing and recalling a series of three random numbers, at a self-selected speed while listening and identifying commonly experienced sounds. Gait parameters were measured with the GAITRite® system. Results: Children with CP walked slower in both assignments as compared to baseline walking; TD controls reduce walking velocity only during the sounds assignment. Step length was constantly reduced and step time and length variability were constantly increased among children with CP as compared to TD controls, throughout assignments. Conclusion: It might be advisable for clinicians when assessing walking performance in children with CP, to assess it during both single and dual-task conditions. 23848423 Preservation of the properties of elastic plasma protein plus platelet film for wound dressing. Abstract Experimental results have previously been reported for a new biological dressing consisting of concentrated plasma proteins and platelet-rich plasma (PRP), which is named Platelet-Protein film (PPF). Based on the results of this experimental study, a clinical trial was begun to examine the usefulness of PPF. Although fresh autologous PPF is being used in the clinical trial, it is considered that the use of a preserved material prepared in advance would enable more convenient application. To verify the usefulness of preserved PPF, this preliminary study was conducted to examine the effects of fresh PPF, preserved PPF or blood clot, as control, applied to excisional skin defects in healing-impaired mice. The wound area and vascular density were analysed on day 9 after wound creation. Significant decrease of the wound size was observed in the preserved PPF and fresh PPF groups (4.2 (3.7), 2.2 (0.53)%) in comparison with that in the control group (38.5 (18.6)%, p < 0.05). Furthermore, a significant increase of the vascular density was also observed in the preserved PPF and fresh PPF groups (0.055 (0.021), 0.050 (0.019) mm(2)/mm(2)) as compared with that in the control group (0.016 (0.010) mm(2), p < 0.01). There was no significant difference in the effect on the wound size or vascular density between the preserved PPF and fresh PPF groups. The results showed that the properties of PPFs could be maintained for at least 1 week under appropriate storage conditions. The possibility of preservation of PPF for future use could be of practical advantage in actual clinical situations. 23575373 Characterization of NaCl tolerance in Desulfovibrio vulgaris Hildenborough through experimental evolution. Desulfovibrio vulgaris Hildenborough strains with significantly increased tolerance to NaCl were obtained via experimental evolution. A NaCl-evolved strain, ES9-11, isolated from a population cultured for 1200 generations in medium amended with 100 mM NaCl, showed better tolerance to NaCl than a control strain, EC3-10, cultured for 1200 generations in parallel but without NaCl amendment in medium. To understand the NaCl adaptation mechanism in ES9-11, we analyzed the transcriptional, metabolite and phospholipid fatty acid (PLFA) profiles of strain ES9-11 with 0, 100- or 250 mM-added NaCl in medium compared with the ancestral strain and EC3-10 as controls. In all the culture conditions, increased expressions of genes involved in amino-acid synthesis and transport, energy production, cation efflux and decreased expression of flagellar assembly genes were detected in ES9-11. Consistently, increased abundances of organic solutes and decreased cell motility were observed in ES9-11. Glutamate appears to be the most important osmoprotectant in D. vulgaris under NaCl stress, whereas, other organic solutes such as glutamine, glycine and glycine betaine might contribute to NaCl tolerance under low NaCl concentration only. Unsaturation indices of PLFA significantly increased in ES9-11. Branched unsaturated PLFAs i17:1 ω9c, a17:1 ω9c and branched saturated i15:0 might have important roles in maintaining proper membrane fluidity under NaCl stress. Taken together, these data suggest that the accumulation of osmolytes, increased membrane fluidity, decreased cell motility and possibly an increased exclusion of Na(+) contribute to increased NaCl tolerance in NaCl-evolved D. vulgaris. 23554049 Furanodiene Presents Synergistic Anti-proliferative Activity With Paclitaxel Via Altering Cell Cycle and Integrin Signaling in 95-D Lung Cancer Cells. Furanodiene (FUR) is a natural terpenoid isolated from Rhizoma Curcumae, a well-known Chinese medicinal herb that presents anti-proliferative activities in several cancer cell lines. Recently, we found that the combined treatment of FUR with paclitaxel (TAX) showed synergetic anti-proliferative activities in 95-D lung cancer cells. Herein, we showed that FUR reduced the cell numbers distributed in mitosis phase induced by TAX while increased those in G1 phase. The protein levels of cyclin D1, cyclin B1, CDK6 and c-Myc were all down-regulated in the group of combined treatment. The dramatically down-regulated expression of integrin β4, focal adhesion kinase and paxillin might partially contribute to the synergic effect. Though FUR alone obviously induced endoplasmic reticulum stress, this signaling pathway may not contribute to the synergetic anti-proliferative effect as the protein expression of CHOP and BIP was similar in FUR alone and combined treatment group. Copyright © 2013 John Wiley & Sons, Ltd. 23822829 Medicolegal Characteristics of Firearm Homicides in Belgrade, Serbia: Before, During, and After the War in the Former Yugoslavia. A comparative analysis of firearm homicides committed in Belgrade was performed including four representative years: 1987 (before the civil war in the Former Yugoslavia), 1991 (beginning of the war), 1997 (end of the war), and 2007 (period of social stabilization). The increase in the number of homicides was established in 1991 and 1997 compared with 1987, with the decrease in 2007, but with the continuous increase in the percentage of firearm homicides in the total number of homicides, from 12% in 1987 up to 56% in 2007. The significant increase in firearm homicides during the last decade of the 20th century can be explained by the social disturbances and the high availability of firearms, while their reduction in 2007 could be linked to the gradual stabilization of social circumstances. The results showed that the actual social, political, and economical changes strongly influenced medicolegal characteristics of homicides and particularly firearm homicides. 23465328 Interstitial brachytherapy with iodine-125 seeds for low grade brain stem gliomas in adults: Diagnostic and therapeutic intervention in a one-step procedure. To report on iodine-125 (I125) interstitial irradiation in the treatment of low grade brain stem gliomas in adults. Ten patients with well-circumscribed lesions of the brainstem and histological confirmation of low grade glioma treated with stereotactically implanted I-125 seed in our department between 1995 and 2012 were retrospectively analyzed. In 9 patients the lesion was treated with one I-125 seed and in one patient, 2 spatial separated lesions were implanted, therefore a total of 11 I-125 seeds were implanted. The mean volume of the 11 lesions was 2.76ml (range: 0.5-7.2ml), mean activity of the seeds was 6.23mCi (range: 1.5-11.1mCi), mean duration of irradiation was 28.5 days (range: 21-41 days) and mean effective dose rate was 9.16cGy/h (range: 6.2-12cGy/h). The 30 days perioperative morbidity and mortality rate was 0%. Median follow up was 72.5 month (range 5-168 months). Six of ten patients were free of progression until last follow up. In our experience at the University Clinic in Freiburg Germany, interstitial radiosurgery based on MRI is a safe and effective method to diagnose and treat low grade gliomas of the brain stem. Furthermore randomized studies are needed to confirm the therapeutic impact of this method in comparison to external beam radiation of brain stem gliomas. 23853204 Investigation of cadmium pollution in contaminated industrial area in Guilan province industrial estates. Toxicity and accumulation of cadmium in body organs by eating contaminated food has an important role in endangering a human's health. Using Environmental Protection Agency (EPA) reports, site 1, site 2 and site 3 were selected as polluted sites and site 4 was selected as the control site. Seedlings of buttonwood were prepared for 12 months then root, stem, and leaf samples were harvested and the amounts of cadmium element in stem and leaf organs together with the growth parameters were measured. This study determines the amount of cadmium accumulated in Platanus occidentalis. The respective cadmium concentrations in the root, leaf, and stem in site 1 were 382, 98, and 87; in site 2 they were 591, 122, and 94; and in site 3 they were 633, 151, and 104 mg/kg dry weight (DW). Furthermore, the comparison between accumulation and transfer of cadmium in the study showed more absorption of this metal by the root than that by the stem and leaf. The result of this research shows that buttonwood has the potential for cadmium accumulation without any serious damage to its growth. To control the extent of contamination in industrial areas, petrochemical industries, power plants and vast contaminated municipal areas, there is a great need for planting plants like buttonwood. 23510527 H3O2 Bridging Ligand in a Metal-Organic Framework. Insight into the Aqua-Hydroxo↔Hydroxyl Equilibrium: A Combined Experimental and Theoretical Study. A metal-organic framework (MOF) bearing the aqua-hydroxo species (O2H3)(-) in the framework, as well as the processes that govern the equilibrium aqua-hydroxo (O2H3)(-)↔hydroxyl (OH) in Sc-MOFs, are studied experimentally and theoretically. Computational studies were employed to determine the relative energies for the two compounds that coexist under certain hydrothermal conditions at pH < 2.8. The thermodynamically more stable [Sc3(3,5-DSB)2(μ-O2H3)(μ-OH)2(H2O)2] (from now on, (O2H3)Sc-MOF; 3,5-DSB = 3,5-disulfobenzoic acid) was obtained as a pure and stable phase. It was impossible to isolate [Sc3(3,5-DSB)2(μ-OH)3(H2O)4] as a pure phase, as it turned out to be the precursor of (O2H3)Sc-MOF. Additionally, a third compound that appears at pH between 3.5 and 4, [Sc3(3,5-DSB)(μ-OH)6(H2O)] and a fourth, [Sc(3,5-DSB)(Phen)(H2O)](H2O), in whose formula neither OH groups nor H3O2(-) anions appear, are reported for comparative purposes. A study of the (O2H3)Sc-MOF electronic structure, and some heterogeneous catalytic tests in cyanosilylation of aldehydes reactions, are also reported. 23950957 Factor Structure and Longitudinal Measurement Invariance of the Demand Control Support Model: An Evidence from the Swedish Longitudinal Occupational Survey of Health (SLOSH). To examine the factor structure and to evaluate the longitudinal measurement invariance of the demand-control-support questionnaire (DCSQ), using the Swedish Longitudinal Occupational Survey of Health (SLOSH). A confirmatory factor analysis (CFA) and multi-group confirmatory factor analysis (MGCFA) models within the framework of structural equation modeling (SEM) have been used to examine the factor structure and invariance across time. FOUR FACTORS: psychological demand, skill discretion, decision authority and social support, were confirmed by CFA at baseline, with the best fit obtained by removing the item repetitive work of skill discretion. A measurement error correlation (0.42) between work fast and work intensively for psychological demands was also detected. Acceptable composite reliability measures were obtained except for skill discretion (0.68). The invariance of the same factor structure was established, but caution in comparing mean levels of factors over time is warranted as lack of intercept invariance was evident. However, partial intercept invariance was established for work intensively. Our findings indicate that skill discretion and decision authority represent two distinct constructs in the retained model. However removing the item repetitive work along with either work fast or work intensively would improve model fit. Care should also be taken while making comparisons in the constructs across time. Further research should investigate invariance across occupations or socio-economic classes. 23870430 2-Amino-[1,2,4]triazolo[1,5-a]pyridines as JAK2 inhibitors. The advancement of a series of ligand efficient 2-amino-[1,2,4]triazolo[1,5-a]pyridines, initially identified from high-throughput screening, to a JAK2 inhibitor with pharmacodynamic activity in a mouse xenograft model is disclosed. 23735159 pH-responsive delivery of doxorubicin from citrate-apatite nanocrystals with tailored carbonate content. In this work, the efficiency of bioinspired citrate-functionalized nanocrystalline apatites as nanocarriers for delivery of doxorubicin (DOXO) has been assessed. The nanoparticles were synthesized by thermal decomplexing of metastable calcium/citrate/phosphate solutions both in the absence (Ap) and in the presence (cAp) of carbonate ions. The presence of citrate and carbonate ions in the solution allowed us to tailor the size, shape, carbonate content, and surface chemistry of the nanoparticles. The drug-loading efficiency of the two types of apatite was evaluated by means of the adsorption isotherms, which were found to fit a Langmuir-Freundlich behavior. A model describing the interaction between apatite surface and DOXO is proposed from adsorption isotherms and ζ-potential measurements. DOXO is adsorbed as a dimer by means of a positively charged amino group that electrostatically interacts with negatively charged surface groups of nanoparticles. The drug-release profiles were explored at pHs 7.4 and 5.0, mimicking the physiological pH in the blood circulation and the more acidic pH in the endosome-lysosome intracellular compartment, respectively. After 7 days at pH 7.4, cAp-DOXO released around 42% less drug than Ap-DOXO. However, at acidic pH, both nanoassemblies released similar amounts of DOXO. In vitro assays analyzed by confocal microscopy showed that both drug-loaded apatites were internalized within GTL-16 human carcinoma cells and could release DOXO, which accumulated in the nucleus in short times and exerted cytotoxic activity with the same efficiency. cAp are thus expected to be a more promising nanocarrier for experiments in vivo, in situations where intravenous injection of nanoparticles are required to reach the targeted tumor, after circulating in the bloodstream. 23410068 Solution effect on diazonium-modified Au(111): reactions and structures. Surface modifications of a Au(111) electrode with 4-bromobenzenediazonium tetrafluoroborate (BBD) in acetonitrile (ACN) and 0.1 M HClO4 have been characterized by scanning tunneling microscopy (STM). In ACN, STM results reveal the formation of disordered thin organic films. The involvement of the radical as an intermediate is evidenced by the negative effect of radical scavengers on organic thin film formation. In contrast, the 4,4'-dibromobiphenyl monolayer is observed when the aqueous solution is used as a medium to carry out the grafting experiment. The biphenyl compound is considered to be generated by a radical-radical coupling reaction. 23936317 Nuclear Translocation of B-Cell-Specific Transcription Factor, BACH2, Modulates ROS Mediated Cytotoxic Responses in Mantle Cell Lymphoma. BACH2, a B-cell specific transcription factor, plays a critical role in oxidative stress-mediated apoptosis. Bortezomib (Velcade(TM)) is widely used to treat relapsed mantle cell lymphoma (MCL) patients despite varying clinical outcomes. As one of the potential mechanisms of action, bortezomib was reported to elicit endoplasmic reticulum (ER) stress which triggers reactive oxygen species (ROS). In the present study, we investigated the redox-sensitive intracellular mechanism that might play a critical role in bortezomib response in MCL cells. We demonstrated that in MCL cells that are sensitive to bortezomib treatments, BACH2 was translocated to the nucleus in response to bortezomib and induced apoptotic responses through the modulation of anti-oxidative and anti-apoptotic genes. On the other hand, in bortezomib resistant cells, BACH2 expression was confined in the cytoplasm and no suppression of antiapoptotic or antioxidative genes, Nrf2, Gss, CAT, HO-1 and MCL1, was detected. Importantly, levels of BACH2 were significantly higher in bortezomib sensitive MCL patient cells, indicating that BACH2 levels could be an indicator for clinical bortezomib responses. BACH2 translocation to the cytoplasm after phosphorylation was inhibited by PI3K inhibitors and combinatory regimens of bortezomib and PI3K inhibitors sensitized MCL cells to bortezomib. These data suggest that cellular distribution of BACH2 in response to ROS determines the threshold for the induction of apoptosis. Therapies that inhibit BACH2 phosphorylation could be the key for increasing bortezomib cytotoxic response in patients. 22407988 Methyl tert butyl ether is anti-angiogenic in both in vitro and in vivo mammalian model systems. Methyl-tertiary butyl ether (MTBE), a well known gasoline oxygenate, and US Food and Drug Administration approved gallstone treatment, has been previously shown to specifically target teleost embryonic angiogenesis. The studies reported here were to determine whether similar vascular disrupting effects occur in higher vertebrate models. Rat brain endothelial cells were isolated and allowed to form microcapillary-like tubes on Matrigel. MTBE (0.34-34.0 mm) exposure resulted in a dose-dependent reduction of tube formation, with the LOAEL at 0.34 mm, while MTBE's primary metabolite, tertiary butyl alcohol had no effect on tube formation. HUVECs, a primary cell line representing macrovascular cells, were able to form tubes on Matrigel in the presence of MTBE (1.25-80 mm), but the tubes were narrower than those formed in the absence of MTBE. In a mouse Matrigel plug implantation assay, 34.0 mm MTBE completely inhibited vessel invasion into plugs containing endothelial cell growth supplement (ECGS) compared with control plugs with ECGS alone. When timed-pregnant Fisher 344 rats were gavaged with MTBE (500-1500 mg kg(-1) ) from day 6 of organogenesis through 10 days post-parturition, no organ toxicity or histological changes in pup vasculature were observed. Results of the in vitro cell culture studies show that MTBE is anti-angiogenic at mm concentrations and has potential use as an anti-angiogenic treatment for solid tumors with minimal toxicity. 23937808 Focused Cardiac Ultrasound Diagnosis of Thoracic Aortic Aneurysm: Two Cases. Thoracic aortic aneurysms (TAAs) are less prevalent than abdominal aortic aneurysms. Symptomatic TAAs need to be identified quickly by the emergency physician (EP) since mortality rates increase dramatically once complications such as rupture or dissection occur. Compared with validated EP-performed ultrasound of the abdominal aorta, EP-performed focused cardiac ultrasound that includes evaluation of the thoracic aorta is relatively unreported. Two cases illustrate EP-performed focused cardiac ultrasound and evaluation of the thoracic aorta for aneurysmal dilation. CASE REPORTS: (1) A 60-year-old man presented to the emergency department (ED) after a blunt traumatic injury to his back while at work. During the focused cardiac ultrasound examination, the aortic outflow tract distal to the aortic valve appeared enlarged and the aortic root measured 5.49 cm. (2) An 82-year-old man with hypertension presented to the ED with 1 month of chest pain radiating to the back. The focused cardiac ultrasound examination demonstrated enlargement of the descending thoracic aorta at 4.82 cm. EPs performing focused cardiac ultrasound can visualize regions of the thoracic aorta that may reveal an aneurysm, particularly in the parasternal long axis view. 23843079 IL-23 protection against Plasmodium berghei infection in mice is partially dependent on IL-17 from macrophages. Although IL-12 is believed to contribute to protective immune responses, the role played by IL-23 (a member of the IL-12 family) in malaria is elusive. Here, we show that IL-23 is produced during infection with Plasmodium berghei NK65. Mice deficient in IL-23 (p19KO) had higher parasitemia and died earlier than wild-type (WT) controls. Interestingly, p19KO mice had lower numbers of IL-17-producing splenic cells than their WT counterparts. Furthermore, mice deficient in IL-17 (17KO) suffered higher parasitemia than the WT controls, indicating that IL-23-mediated protection is dependent on induction of IL-17 during infection. We found that macrophages were responsible for IL-17 production in response to IL-23. We observed a striking reduction in splenic macrophages in the p19KO and 17KO mice, both of which became highly susceptible to infection. Thus, IL-17 appears to be crucial for maintenance of splenic macrophages. Adoptive transfer of macrophages into macrophage-depleted mice confirmed that macrophage-derived IL-17 is required for macrophage accumulation and parasite eradication in the recipient mice. We also found that IL-17 induces CCL2/7, which recruit macrophages. Our findings reveal a novel protective mechanism whereby IL-23, IL-17, and macrophages reduce the severity of infection with blood-stage malaria parasites. 23352547 Reverse shoulder arthroplasty glenoid fixation: is there a benefit in using four instead of two screws? To allow osseous integration to occur and thus provide long-term stability, initial glenoid baseplate fixation must be sufficiently rigid. A major contributing factor to initial rigid fixation is baseplate screw fixation. Current baseplate designs use a 4-screw fixation construct. However, recent literature suggests adequate fixation can be achieved with fewer than 4 screws. The purpose of the present study was to determine whether a 4-screw construct provides more baseplate stability than a 2-screw construct. A flat-backed glenoid baseplate with 4 screw hole options was implanted into 6 matched pairs of cadaver scapulas using standard surgical technique. Within each pair, 2 screws or 4 screws were implanted in a randomized fashion. A glenosphere was attached allowing cyclic loading in an inferior-to-superior direction and in an anterior-to-posterior direction. Baseplate motion was measured using 4 linear voltage displacement transducers evenly spaced around the glenosphere. There was no statistical difference in the average peak central displacements between fixation with 2 or 4 screws (P = .338). Statistical increases in average peak central displacement with increasing load (P < .001) and with repetitive loading (P < .002) were found. This study demonstrates no statistical difference in baseplate motion between 2-screw and 4-screw constructs. Therefore, using fewer screws could potentially lead to a reduction in operative time, cost, and risk, with no significant negative effect on overall implant baseplate motion. 23932220 Barriers to and Consequences of Mandated Reporting of Child Abuse by Nurse Practitioners. The objective of this study was to examine the experiences of pediatric nurse practitioners (PNPs) in the identification and management of child abuse, determine the frequency of their reporting, and describe the effects, attitudes, and confidence in reporting child abuse. A survey based on the 2006 CARES survey was disseminated via e-mail through use of Survey Monkey to 5,764 PNP members of the National Association of Pediatric Nurse Practitioners. The data from this survey were then subjected to statistical analysis, and the resultant findings were compared and contrasted with other similar studies. Data analysis revealed that smaller numbers of PNPs in the sample group failed to report suspected child abuse than did their physician colleagues. PNPs and physicians encountered similar perceived barriers to reporting and used similar processes in dealing with them. Both physicians and PNPs with recent child abuse continuing education hours expressed greater confidence in child abuse management skills and were more likely to report suspected cases of abuse. Much information was learned about PNP reporting practices regarding child abuse. The most significant facts that emerged from this study were that all health care providers require further child abuse education, both in their curriculum preparation and continuing education, to effectively diagnose and manage child abuse. 23542042 Co-oscillation and synchronization between the posterior thalamus and the caudate nucleus during visual stimulation. Recent results suggest significant cross-correlation between the spike trains of the suprageniculate nucleus (SG) of the posterior thalamus and the caudate nucleus (CN) during visual stimulation. In the present study visually evoked local field potentials (LFPs) were recorded simultaneously in the CN and the SG in order to investigate the coupling between these structures at a population level. The effect of static and dynamic visual stimulation was analyzed in 55 SG-CN LFP pairs in the frequency range 5-57Hz. Statistical analysis revealed significant correlation of the relative powers of each investigated frequency band (5-8Hz, 8-12Hz, 12-35Hz and 35-57Hz) during both static and dynamic visual stimulation. The temporal evolution of cross-correlation showed that in the majority of the cases the SG was activated first, and in approximately one third of the cases, the CN was activated earlier. These observations suggest a bidirectional information flow. The most interesting finding of this study is that different frequency bands exhibited significant cross-correlation in a stimulation paradigm-dependent manner. That is, static stimulation usually increased the cross-correlation of the higher frequency components (12-57Hz) of the LFP, while dynamic stimulation induced changes in the lowest frequency band (5-8Hz). This suggests a parallel processing of dynamic and static visual information in the SG and the CN. To our knowledge we are the first to provide evidence on the co-oscillation and synchronization of the CN and the SG at a population level upon visual stimulation, which suggests a significant cooperation between these structures in visual information processing. 23922617 The German Pain Catastrophizing Scale for Children (PCS-C) - psychometric analysis and evaluation of the construct. Objective: The Pain Catastrophizing Scale, adapted for children (PCS-C) by Crombez et al. (2003), was translated into German (SKS-D) and evaluated regarding its factorial structure, its reliability and validity. The association of catastrophizing with various pain characteristics and disability measures was examined as well as its association to neighboring constructs. Method: The paper-and-pencil version of the SKS-D was used in two different samples of children and adolescents. Analyses were conducted on a subgroup of participants from an epidemiological sample [n=898; age: M=12.9 (SD=1.4)] who had experienced monthly headaches in the 6-months period before and a clinical sample [n=60; age: M=12.6 (SD=0.8)] seeking treatment for recurrent headaches. Results: Exploratory factor analysis (PCA) suggested a one-factor model in contrast to the 3-factor model suggested by Crombez et al. (2003). The unidimensional scale showed distinct homogeneity and satisfying reliability. The clinical sample showed significantly higher scores than the epidemiological group. Also girls scored higher than boys. The catastrophizing explained a considerable amount of variance in pain and disability parameters in both samples thus underlining its validity. The psychological variables internalising, anxiety sensitivity and somatosensory amplification showed significant small to moderate associations with pain catastrophizing and also with pain and disability. After controlling for the above mentioned psychological variables, catastrophizing still yielded an independent contribution to the explanation of variance in pain and disability parameters. Conclusions: The PCS-C in its German form is a valid and reliable instrument for assessing catastrophizing in children with recurrent pain, in particular headache, in the age of 10-16 years. Pain catastrophizing is suggested to be assessed especially in pediatric pain patients as it is a significant moderator of pain and disability. In children with a distinct tendency to catastrophize cognitive restructuring should become a target of pediatric pain therapy, as a reduction of catastrophizing cognitions may indirectly help to ameliorate pain and disability. Abstract available from the publisher. 23137301 Association of subgingival colonization of Candida albicans and other yeasts with severity of chronic periodontitis. The aim of this study is to analyze the relationship between the subgingival colonization by Candida albicans and other yeasts with the severity of chronic periodontitis (CP). After sample size calculation, 40 patients with CP and 20 healthy subjects (HS) were included in the study. Cases of slight-moderate (MCP, n = 23) and severe CP (SCP, n = 17) were defined according to the Centers for Disease Control/American Association of Periodontology classification. Subgingival samples were acquired using sterile paper-points from the sulcus or the deepest periodontal pocket of each healthy and subject with CP, respectively, and were cultured aerobically on three selective media. Yeast colonies that grew on the surface of plates were later identified by biochemical reactions. Statistical tests were used to analyze the association between subgingival yeast colonization (number of yeast-positive individuals and colony forming units (CFU) per subject) and periodontal disease status, considering statistical significance when P < 0.05. Although several yeast species were found (C. parapisilosis, Rhodotorula sp., C. dubliniensis and C. tropicalis), only C. albicans was present in all the patients with yeast-positive CP. Twelve patients (30%) with CP presented yeasts in the subgingival biofilm while only three patients (15%) in the HS group were positive for these microorganisms. No statistical difference was found between the CP and HS groups (P = 0.084). However, when the CP group was divided on the basis of severity, statistical differences were observed between the SCP and MCP groups (47% vs. 17%, P = 0.043), and between the SCP and HS groups (47% vs. 15%, P = 0.033). No statistical difference was observed between the MCP and HS groups (17% vs. 15%, P = 0.832). High densities of yeasts were found only in patients with MCP and SCP (mean and range 61.25 (0-100) CFU/plate and mean and range 51 (0-101) CFU/plate, respectively). In this group of patients, subgingival colonization of some yeasts, especially C. albicans, was associated with the severity of CP. 23833214 Combinatorial Effects of Transposable Elements on Gene Expression and Phenotypic Robustness in Drosophila melanogaster Development. Embryonic patterning displays remarkable consistency from individual to individual despite frequent environmental perturbations and diverse genetic contexts. Stochastic influences on the cellular environment may cause transcription rates to fluctuate, but these fluctuations rarely lead to developmental defects or disease. Here we characterize a set of recessive alleles of the Toll pathway component tube that destabilize embryonic dorsoventral patterning in Drosophila melanogaster. Females bearing these tube alleles generate embryos of an unusually wide range of dorsalized phenotypes, with the distributions across this range being unique for each allele. We determine that the mutant lines have in common a retrotransposon insertion upstream of the tube transcription start site. Genetic and molecular approaches demonstrate that this insertion dramatically reduces maternal expression of tube, thereby uncovering the inherent variability in gene expression. We further find that additional transposable element insertions near the tube gene synergistically enhance the phenotype caused by the sensitizing upstream insertion. These studies document how phenotypic variability can arise from normally occurring fluctuations around reduced mean expression and illustrate the contribution of transposons, individually and combinatorially, to such a state. 23076680 Endoscopic procurement of tympano-ossicular allografts: alternative to the transcranial or retroauricular technique. A tympano-ossicular tissue bank complying with European Union regulations on human allografts is feasible and critical to assure that the patient receives tissue which is safe, individually checked and prepared in a suitable environment. The transcranial procurement technique has become the standard approach to procure tympano-ossicular allografts since the 1970s because it can provide en bloc allografts. Over the last 10-20 years, en bloc allografts have been abandoned and only the malleus (hammer) is left attached to the tympanic membrane. This modification enables introduction of the transmeatal procurement technique. Transmeatal procurement using readily available nasal 0° and 30° endoscopes is a feasible alternative which avoids contact with the dura mater and is not esthetically invasive to the donor. It involves a more time-consuming procurement but avoids the need for preparation of the temporal bone plug and is therefore generally more time-efficient. 23336971 Review: The role of vitamin D in nervous system health and disease. Vitamin D and its metabolites have pleomorphic roles in both nervous system health and disease. Animal models have been paramount in contributing to our knowledge and understanding of the consequences of vitamin D deficiency on brain development and its implications for adult psychiatric and neurological diseases. The conflation of in vitro, ex vivo, and animal model data provide compelling evidence that vitamin D has a crucial role in proliferation, differentiation, neurotrophism, neuroprotection, neurotransmission, and neuroplasticity. Vitamin D exerts its biological function not only by influencing cellular processes directly, but also by influencing gene expression through vitamin D response elements. This review highlights the epidemiological, neuropathological, experimental and molecular genetic evidence implicating vitamin D as a candidate in influencing susceptibility to a number of psychiatric and neurological diseases. The strength of evidence varies for schizophrenia, autism, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and is especially strong for multiple sclerosis. 23937675 Oral antigen exposure in extreme early life in lambs influences the magnitude of the immune response which can be generated in later life. Previous investigations in newborn lambs determined that adenovirus-mediated expression of antigen to a localized region of the gut induced antigen-specific mucosal and systemic immunity. These experiments were limited in that the localized region of the gut to which antigen was introduced was sterile and the influence of colostrum on the antigen was not assessed but they do suggest that mucosal vaccines may be an effective vaccination strategy to protect neonatal lambs. We propose that persistent oral antigen exposure introduced in extreme early life can induce immunity in lambs, despite the presence of commensal bacteria and colostrum. To test this hypothesis, conventionally raised newborn lambs (n = 4 per group) were gavaged with ovalbumin (OVA) starting the day after birth for either a single day (2.27 g), every day for 3 days (0.23 g/day), or every day for 3 days then every second day until nine days of age (0.023 g/day). Lambs gavaged with OVA for 3 to 9 days developed significant serum anti-OVA IgG titres (p < 0.05), but not IgA titres, relative to control lambs (n = 4) after 3 and 4 weeks. At 4 weeks of age, lambs were immunized with OVA in Incomplete Freund's Adjuvant via intraperitoneal (i.p.) injection then lambs were euthanized at 7 weeks. Serum anti-OVA IgG titres were further augmented after i.p. immunization indicating immunity persisted and tolerance was not induced. Serum IgA titres remained low regardless of treatment. It is known that i.p. priming of sheep with antigen in Freund's complete adjuvant leads to an enhanced number of IgA and IgG antibody containing cells in the respiratory mucosa (Immunology 53(2):375--384, 1984). Lambs gavaged with a single bolus of 2.27 g OVA prior to i.p. immunization showed very low titres of anti-OVA IgA in the lung lavage. These data suggest that a single, high dose exposure to OVA can promote tolerance which impacts response to systemic vaccination in later life. Lambs gavaged with 0.023 g OVA for 9 days (Group C) generated significant anti-OVA IgA titres in lung (p < 0.001) compared to negative control lambs but no additive effect was observed compared to parenteral control lambs. When splenocytes were re-stimulated with OVA ex vivo, all groups failed to show increased lymphocyte proliferation or interferon (IFN)-gamma production relative to the parenteral control group. In agreement with our hypothesis, persistent low dose antigen exposure primes humoral antibody production in serum in conventionally raised newborn lambs. In contrast, a single high dose bolus of antigen triggered oral tolerance which negatively impacted the quality and magnitude of the immune response to i.p. immunization in later life. These tangential responses are important as they indicate that the dose and/or repeated oral exposure to antigen, such as that which may be found in the neonate's environment, may promote immunity or alternatively it may negatively impact responses to parenteral vaccination. 23898188 Unexpectedly high indoor hydroxyl radical concentrations associated with nitrous acid. The hydroxyl (OH) radical is the most important oxidant in the atmosphere since it controls its self-oxidizing capacity. The main sources of OH radicals are the photolysis of ozone and the photolysis of nitrous acid (HONO). Due to the attenuation of solar radiation in the indoor environment, the possibility of OH formation through photolytic pathways indoors has been ignored up to now. In the indoor air, the ozonolysis of alkenes has been suggested as an alternative route of OH formation. Models and indirect measurements performed up to now according to this hypothesis suggest concentrations of OH radicals on the order of 10(4)-10(5) molecules per cubic centimeter. Here, we present direct measurements of significant amounts of OH radicals of up to 1.8⋅10(6) molecules per cubic centimeter during an experimental campaign carried out in a school classroom in Marseille. This concentration is on the same order of magnitude of outdoor OH levels in the urban scenario. We also show that photolysis of HONO is an important source of OH radicals indoors under certain conditions (i.e., direct solar irradiation inside the room). Additionally, the OH concentrations were found to follow a linear dependence with the product J(HONO)⋅[HONO]. This was also supported by using a simple quasiphotostationary state model on the OH radical budget. These findings force a change in our understanding of indoor air quality because the reactivity linked to OH would involve formation of secondary species through chemical reactions that are potentially more hazardous than the primary pollutants in the indoor air. 23954263 Comparison of 2,2-bis(bromomethyl)-1,3-propanediol induced genotoxicity in UROtsa cells and primary rat hepatocytes: Relevance of metabolism and oxidative stress. 2,2-Bis(bromomethyl)-1,3-propanediol (BMP) is a brominated flame retardant used in urethane foams and polyester resins. In a two year dietary study, BMP caused neoplastic lesions at multiple sites including the urinary bladder of both rats and mice. However, liver was not a target tissue. We previously reported that BMP elicited oxidative DNA damage in a human uroepithelial cell line (UROtsa). The present in vitro study investigated the susceptibility of target (UROtsa cells) and non-target cells (primary rat hepatocytes) to BMP-induced genotoxicity. In contrast to hepatocytes, BMP exhibited greater genotoxic potential in UROtsa cells as evidenced by the concentration dependent increase in DNA strand breaks and DNA binding. Total content of intracellular GSH quantified in UROtsa cells (2.7±1.0nmol/mg protein) was 4 fold lower than that in hepatocytes (10.7±0.3nmol/mg protein). HPLC analysis indicated BMP was not metabolized and/or consumed in UROtsa cells at any of the concentrations tested (10-250μM) but was extensively converted to a mono-glucuronide in hepatocytes. These results demonstrate that a target cell line such as UROtsa cells are more susceptible to BMP-induced DNA damage when compared to non-target cells. This increased susceptibility may relate to the deficiency of antioxidant and/or metabolic capabilities in UROtsa cells. 23944255 Coordination versus Competition in Health Care Reform. Many current proposals to increase the value of care delivered in the U.S. health care system focus on improved coordination - and with good reason. Badly coordinated care, duplicated efforts, bungled handoffs, and failures to follow up result in too much care for some patients, too little care for others, and the wrong care for many. A host of current reform efforts aim to reduce these inefficiencies in both public and private markets. These efforts range from penalizing hospitals with higher-than-expected readmission rates, to rewarding primary care providers when patients receive higher-value care, to providing incentives for the adoption of . . . 23642912 The relationship between job type and development of cerebral stroke in a large, longitudinal cohort study of workers in a railway company in Japan. The aim of this study was to clarify the relationship between occupational factors and the development of cerebral stroke in a large cohort working at a railway company in Japan. A 10-year prospective cohort study was conducted in 32,441 male workers who received annual health check-ups at a Japanese railway company. Diagnosis of cerebral stroke was based on the results of the annual health check-ups and individual medical histories. Cerebral stroke included cerebral hemorrhage, cerebral infarction, and subarachnoid hemorrhage. The relationship between job type and the development of cerebral stroke was investigated using a proportional hazards regression with time-dependent covariates adjusted for age, body mass index, mean arterial pressure, family history of cerebral stroke, tobacco and alcohol consumption, and habitual exercise. A negative relationship between job type and the development of cerebral stroke was observed in train crew members, with a significantly lower hazard ratio (HR) seen in train drivers (HR 0.63, 95% confidence interval (CI), 0.42-0.95) and conductors (HR 0.41, 95% CI, 0.24-0.71) in comparison to clerical workers. Since the present results were adjusted for various behavioral and biological factors, they suggest that train crew work itself is associated with a decreased risk of cerebral stroke. These results suggest that further studies on the effect of driving on health may provide information useful for the future prevention of cerebral stroke. 23938239 Georg Groddeck's Maternal Turn: Its Evolution and Influence on Early Psychoanalysts. The paper examines the biographical, cultural and clinical influences on the "maternal turn" of Georg Groddeck, a German physician and correspondent of Sigmund Freud. It demonstrates Groddeck's influence on Sándor Ferenczi, Frieda Fromm-Reichmann and Karen Horney, each of whom influenced generations of psychoanalysts. The authors explore the resonance of Groddeck's work with several concepts of contemporary psychoanalysis and raise the question as to whether the roots of these psychoanalytic concepts were seeded by Groddeck's "maternal turn", passed on by the above psychoanalysts through intergenerational psychoanalytic training and further elaborated by later investigators who were not necessarily familiar with the work of Groddeck. 23962832 Psychometric Evaluation of the Sophia Observation Withdrawal Symptoms Scale in Critically Ill Children. The Sophia Observation withdrawal Symptoms scale is an instrument for screening benzodiazepine and opioid withdrawal syndrome in pediatric critical care patients. The objectives of this study were to establish cutoff scores and to test sensitivity to change. Second, risk factors for withdrawal syndrome were explored. Prospective observational study with repeated measures. Level IV ICU at a university children's hospital. A total of 154 children with median age 5 months (interquartile range, 0-42 mo) who received continuous infusion of benzodiazepines and/or opioids for 5 or more days. None. Nurses repeatedly applied the Sophia Observation withdrawal Symptoms scale and the Numeric Rating Scale withdrawal when children were weaned off benzodiazepines and opioids. The latter represents the nurse's expert opinion. We analyzed 3,754 paired assessments; the median number per child was 15 (interquartile range, 7-31) over a median of 5 days (interquartile range, 3-11 d). Sensitivity and specificity were 0.83 and 0.93, respectively, for the Sophia Observation withdrawal Symptoms scale cutoff score of 4 or higher against a Numeric Rating Scale-withdrawal score of 4 or higher. Sensitivity to change was determined by comparing 156 Sophia Observation withdrawal Symptoms scale assessments (n = 51 patients) before and after additional sedatives or opioids. Multilevel regression analysis showed a mean decline of 1.5 points (at score range 0-15) after intervention (p < 0.0001). Logistic regression analysis identified duration of preweaning of midazolam, duration of weaning of midazolam, duration of preweaning of morphine, duration of weaning of morphine, and number of additional sedatives/opioids as statistically significant risk factors for withdrawal syndrome in these children. The Sophia Observation withdrawal Symptoms scale is a valid tool with good psychometric properties to assess withdrawal symptoms in PICU patients. 23818519 Non-receptor-tyrosine Kinases Integrate Fast Glucocorticoid Signaling in Hippocampal Neurons. Despite numerous descriptions of rapid effects of corticosterone on neuronal function, the intracellular mechanisms responsible for these changes remain elusive. The present comprehensive analysis reveals that signaling from a membrane-located G protein-coupled receptor activates PKC, Akt/PKB, and PKA, which subsequently trigger the phosphorylation of the tyrosine kinases Pyk2, Src, and Abl. These changes induce rapid cytoskeletal rearrangements (increased PSD-95 co-clustering) within the post-synaptic density; these events are accompanied by increased surface NMDA receptor expression, reflecting corticosterone-induced inhibition of NMDA receptor endocytosis. Notably, none of these signaling mechanisms require de novo protein synthesis. The observed up-regulation of ERK1/2 (downstream of NMDA receptor signaling) together with the fact that c-Abl integrates cytoplasmic and nuclear functions introduces a potential mechanism through which rapid signaling initiated at the plasma membrane may eventually determine the long term integrated response to corticosterone by impacting on the transcriptional machinery that is regulated by classical, nuclear mineralocorticoid, and glucocorticoid receptors. 23561099 Encapsulation of indole-3-carbinol and 3,3'-diindolylmethane in zein/carboxymethyl chitosan nanoparticles with controlled release property and improved stability. Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) are two bioactive compounds from Cruciferous vegetables. The stability of these compounds is a major challenge for their pharmaceutical applications. In this study, zein and zein/carboxymethyl chitosan (CMCS) nanoparticles were prepared to encapsulate I3C and DIM by a combined liquid-liquid phase separation and ionic gelation method. After zein nanoparticles were coated with CMCS, the zeta potential was decreased from around -10 to -20mV, and encapsulation efficiency was greatly improved. Both nanoparticle formulations provided controlled release of I3C and DIM in PBS medium. Zein and zein/CMCS nanoparticles demonstrated similar protection for both I3C and DIM against ultraviolet (UV) light, attributed mainly to the contribution of the zein protein. Compared with zein nanoparticles, zein/CMCS nanoparticles exhibited better protection of I3C against degradation and better inhibition against its oligomerization to DIM under thermal condition (37°C). Based on our results, the encapsulation of hydrophobic bioactives in zein/CMCS nanoparticles is a promising approach to improve their stability against harsh conditions and provide controlled release for food/pharmaceutical applications. 23828236 Influences of traffic on Pb, Cu and Zn concentrations in roadside soils of an urban park in Dublin, Ireland. Soils in the vicinity of roads are recipients of contaminants from traffic emissions. In order to obtain a better understanding of the impacts of traffic on soils, a total of 225 surface soil samples were collected from an urban park (Phoenix Park, Dublin, Ireland) in a grid system. Metal (Pb, Cu and Zn) concentrations were determined using a portable X-ray fluorescence analyzer. Strong spatial variations for the concentrations of Pb, Cu and Zn were observed. The spatial distribution maps created using geographical information system techniques revealed elevated metal concentrations close to the main traffic route in the park. The relationships between the accumulation of Pb, Cu and Zn in the roadside soils and the distance from the road were well fitted with an exponential model. Elevated metal concentrations from traffic pollution extended to a distance of approximately 40 m from the roadside. The results of this study provide useful information for the management of urban parks particularly in relation to policies aimed at reducing the impact of traffic related pollution on soils. 23475588 Effect of annulus dimension and annuloplasty on bicuspid aortic valve repair. We have recently shown that valve sparing reimplantation (VSR) improves the durability of bicuspid aortic valve repair in comparison with subcommissural annuloplasty. The aim of this study was to assess the degree of annular reduction provided by these techniques and to correlate these findings with repair durability. From 1995 to 2010, 161 patients underwent bicuspid valve repair. We included only patients with subcommissural annuloplasty or reimplantation having intraoperative pre- and post-repair transoesophageal echocardiography images. Pre- and post-repair ventriculo-aortic junction (VAJ) diameters were measured on long axis views. Inclusion criteria were met by 53 patients with subcommissual annuloplasty and 65 with reimplantation. Median follow-up was 53 months in the subcommissual annuloplasty group and 42 months in the reimplantation group. Follow-up completeness was 100% in subcommissural annuloplasty and 94% in reimplantation. There was no operative or late mortality. Mean preoperative VAJ was similar in both groups (reimplantation: 28 ± 3 mm vs subcommissural annuloplasty: 28 ± 3, P = 0.16). Preoperative VAJ was larger in patients <40 years and with aortic regurgitation (AR) ≥ 3+ (P < 0.01). Mean postoperative VAJ was smaller in reimplantation compared with subcommissural annuloplasty (21 ± 2 mm vs 24 ± 3 mm, P < 0.01). In univariate analyses, subcommissural annuloplasty, preoperative VAJ ≥30 mm, postoperative VAJ≥25 mm and cusp repair with patch were predictive of recurrent AR > 1+. In the subcommissural annuloplasty group, VAJ≥ 30 mm preoperatively and ≥25 mm postoperatively were associated with decreased 6 years freedom from recurrent AR>1+ (<30 mm: 74% vs ≥30 mm: 39%, P = 0.01; <25 mm: 80% vs ≥25 mm 31%, P = 0.02) In the reimplantation group, VAJ dimension had no effect on recurrent AR >1+ (P = 0.93). In bicuspid aortic valve repair, the circumferential annuloplasty of VSR offers greater reduction of VAJ compared with the non-circumferential annuloplasty provided by the subcommissural annuloplasty. The degree and extent of VAJ reduction in reimplantation seem to be factors among others that positively influence repair durability particularly in patients with a large VAJ (≥30 mm). 23273896 A link between the cytoplasmic engulfment protein Elmo1 and the Mediator complex subunit Med31. The cytoplasmic Elmo1:Dock180 complex acts as a guanine nucleotide exchange factor (GEF) for the small GTPase Rac and functions downstream of the phagocytic receptor BAI1 during apoptotic cell clearance, and in the entry of Salmonella and Shigella into cells. We discovered an unexpected binding between Elmo1 and the Mediator complex subunit Med31. The Mediator complex is a regulatory hub for nearly all gene transcription via RNA polymerase II, bridging the general transcription machinery with gene-specific regulatory proteins. Med31 is the smallest and the most evolutionarily conserved Mediator subunit, and knockout of Med31 results in embryonic lethality in mice; however, Med31 function in specific biological contexts is poorly understood. We observed that in primary macrophages, during Salmonella infection, Elmo1 and Med31 specifically affected expression of the cytokine genes Il10 and Il33 among the >25 genes monitored. Although endogenous Med31 is predominantly nuclear localized, Elmo1 increased the cytoplasmic localization of Med31. We identify ubiquitination as a novel posttranslational modification of Med31, with the cytoplasmic monoubiquitinated form of Med31 being enhanced by Elmo1. These data identify Elmo1 as a novel regulator of Med31, revealing a previously unrecognized link between cytoplasmic signaling proteins and the Mediator complex. 23773532 Patellar tendon adaptation in relation to load-intensity and contraction type. Loading leads to tendon adaptation but the influence of load-intensity and contraction type is unclear. Clinicians need to be aware of the type and intensity of loading required for tendon adaptation when prescribing exercise. The aim of this study was to investigate the influence of contraction type and load-intensity on patellar tendon mechanical properties. Load intensity was determined using the 1 repetition maximum (RM) on a resistance exercise device at baseline and fortnightly intervals in four randomly allocated groups of healthy, young males: (1) control (no training); (2) concentric (80% of concentric-eccentric 1RM, 4×7-8); (3) standard load eccentric only (80% of concentric-eccentric 1RM, 4×12-15 repetitions) and (4) high load eccentric (80% of eccentric 1RM, 4×7-8 repetitions). Participants exercised three times a week for 12 weeks on a leg extension machine. Knee extension maximum torque, patellar tendon CSA and length were measured with dynamometry and ultrasound imaging. Patellar tendon force, stress and strain were calculated at 25%, 50%, 75% and 100% of maximum torque during isometric knee extension contractions, and stiffness and modulus at torque intervals of 50-75% and 75-100%. Within group and between group differences in CSA, force, elongation, stress, strain, stiffness and modulus were investigated. The same day reliability of patellar tendon measures was established with a subset of eight participants. Patellar tendon modulus increased in all exercise groups compared with the control group (p<0.05) at 50-75% of maximal voluntary isometric contraction (MVIC), but only in the high eccentric group compared with the control group at 75-100% of MVIC (p<0.05). The only other group difference in tendon properties was a significantly greater increase in maximum force in the high eccentric compared with the control group (p<0.05). Five repetition maximum increased in all groups but the increase was significantly greater in the high load eccentric compared with the other exercise groups (p<0.05). Load at different intensity levels and contraction types increased patellar tendon modulus whereas muscle strength seems to respond more to load-intensity. High load eccentric was, however, the only group to have significantly greater increase in force, stiffness and modulus (at the highest torque levels) compared with the control group. The effects and clinical applicability of high load interventions needs to be investigated further. 23954951 Evolution of photosystem I and the control of global enthalpy in an oxidizing world. Life on earth is governed by light, chemical reactions, and the second law of thermodynamics, which defines the tendency for increasing entropy as an expression of disorder or randomness. Life is an expression of increasing order, and a constant influx of energy and loss of entropic wastes are required to maintain or increase order in living organisms. Most of the energy for life comes from sunlight and, thus, photosynthesis underlies the survival of all life forms. Oxygenic photosynthesis determines not only the global amount of enthalpy in living systems, but also the composition of the Earth's atmosphere and surface. Photosynthesis was established on the Earth more than 3.5 billion years ago. The primordial reaction center has been suggested to comprise a homodimeric unit resembling the core complex of the current reaction centers in Chlorobi, Heliobacteria, and Acidobacteria. Here, an evolutionary scenario based on the known structures of the current reaction centers is proposed. 23562164 The fibroblast as a therapeutic target in rheumatoid arthritis. Significant advances have been made in the last 5 years that have finally allowed investigators to start targeting stromal cells such as fibroblasts in inflammatory disease. Rheumatoid arthritis is a prototype inflammatory disease, in which fibroblasts maintain the persistence of inflammation in the joint underpinned by a unique pathological phenotype driven by multiple epigenetic modifications. The step changes that are enabling the development of such therapies are an improved understanding of the mechanisms by which fibroblasts mediate persistence and the discovery of new markers that identify discrete functional subsets of fibroblast cells that have potential as disease-specific therapeutic targets. 23568542 Patterned Growth of Crystalline Organic Heterostructures. Organic droplet epitaxy is presented as a method for growing nanopatterned crystalline heterostructures, thanks to the transport of molecules of an amorphous first-layer on top of a crystalline second-layer, where they form an epitaxial interface. Such heterostructures may be transferred to any substrates, raising particular interest for applications (e.g., for organic photovoltaics), where crystallinity and nanopatterning constitute well recognized advantages. 23464985 Combined surgical procedures using laparoendoscopic single-site surgery approach. As our experience with laparoendoscopic single-site (LESS) surgeries increased, we considered how it might be employed if two or more surgeries were to be combined. LESS surgeries' cosmetic advantages, decreased parietal trauma and better patient satisfaction relative to standard multiport laparoscopy have been previously reported, but its special role in combined surgeries has never been stressed. In this series, we present the advantages of LESS procedure over multiport laparoscopy in combined surgical procedures. To the best of our knowledge, this has never been reported before. A retrospective analysis of 27 patients was performed. The patients underwent combined LESS procedures between February 2010 and January 2012 at GEM Hospital, Coimbatore, India. All patients were of ASA grade 1 or 2. Patients with previous surgery in the umbilical region were not offered single-incision surgery. We successfully performed 27 combined LESS procedures over a span of 2 years. Twenty patients were women and seven were men. Mean age was 35.94 years (range, 10-66 years). Mean BMI was 27.2. There were no major intraoperative complications. Mean blood loss was 45.7 mL (range, 0.0-120.0 mL). Mean postoperative hospital stay was 3.08 days (range, 1-5 days). When a suitable case of multiple pathologies is encountered and LESS surgery is feasible for all of them, performing LESS surgery not only has cosmetic advantages over standard laparoscopy, but it also avoids the need for additional ports to achieve adequate visualization and access. All quadrants of the abdomen remain under reach through umbilicus. 23891361 Cost-effectiveness of 12-month treatment with ticagrelor compared with clopidogrel in the management of acute coronary syndromes. The PLATO (Platelet Inhibition and Patient Outcomes) randomized trial (NCT00391872) in patients with acute coronary syndromes (ACS) reported that ticagrelor (in addition to aspirin) reduced the rate of the composite end point of myocardial infarction (MI), stroke, or cardiovascular death compared with clopidogrel (in addition to aspirin) by 16% over 12 months (P < 0.001). No significant difference in the incidence of major bleeding was noted, but ticagrelor was associated with a higher rate of major bleeding not related to coronary artery bypass grafting. By extrapolating the key findings of PLATO, we sought to assess the cost-effectiveness of ticagrelor compared with clopidogrel in the management of ACS in a contemporary Australian setting. A Markov model with 4 health states (free from further ACS events, MI, stroke, and death) was developed to simulate the long-term costs and outcomes associated with ACS. Event risks were based on data derived directly from PLATO, and costs and utilities were drawn from published sources. A 10-year time horizon was simulated, and future costs and benefits were discounted at a 5% annual rate. However, treatment with ticagrelor and clopidogrel was only assumed for the first 12 months, with no benefits applied beyond drug cessation. Sensitivity analyses were undertaken based on variations to key data inputs. All costs for resource use applied in the analysis were based on published Australian prices (in 2010/2011 dollars [A$]). Over 10 years, the estimated quality-adjusted life-years lived per-patient were 5.74 and 5.68 for ticagrelor and clopidogrel, respectively. Net costs were A$19,132 for ticagrelor and A$18,428 for clopidogrel. These equated to an incremental cost-effectiveness ratio of A$9031 per quality-adjusted life-year gained for ticagrelor compared with clopidogrel. Sensitivity analyses indicated the result to be robust. When assessed from the perspective of the Australian health care system, ticagrelor is likely to be cost-effective compared with clopidogrel in preventing downstream morbidity and mortality associated with ACS. 22907838 Rehabilitation of a parotidectomy patient-A systematic approach. Parotidectomy is a common surgical procedure. Resultant contour defect, Frey's syndrome, and facial nerve rehabilitation deserve special consideration. Microsurgical techniques provide unparallel advantage for reconstruction of large-volume defects. Same-stage reconstruction of the defect is advocated and often beneficial to the patient. The importance of full communication between the extirpative and reconstructive surgeon cannot be underscored. Often, institutional and personal biases must be overcome to provide best quality care for the patient. This article provides a comprehensive review of the medical literature on the subject and contrives a systematic approach to the use of various reconstructive techniques. © 2012 Wiley Periodicals, Inc. Head Neck, 2013. 23935187 Galectin LEC-1 plays a defensive role against damage due to oxidative stress in Caenorhabditis elegans. LEC-1 is a major galectin in Caenorhabditis elegans and contains 2 carbohydrate recognition domains (CRDs), N-CRD and C-CRD. To determine the role of LEC-1, we examined the phenotypes of a mutant Caenorhabditis elegans strain lacking lec-1. We observed negligible differences in embryogenesis, morphogenesis, and egg laying at 20°C between the mutant and the wild type. Furthermore, the life spans of the mutant and the wild type were equivalent at either 20°C or 25°C. However, the lec-1 mutant showed a greater susceptibility to H2O2 and paraquat than the wild type. This result suggests an increased susceptibility to oxidative stress, with the phenotypes being similar to those of lec-10 deletion mutants as previously described. To understand the molecular mechanism underlying this phenotype, Caenorhabditis elegans proteins bound by either the LEC-1 N-CRD or C-CRD were isolated and identified using a nano liquid chromatography-tandem mass spectrometry technique. MIG-6 was identified as a major binding partner of LEC-1 with both N- and C-CRD. From these results and previous reports, we speculate that interaction of LEC-1 and MIG-6 in the pharynx may affect susceptibility to paraquat and that LEC-10 has different functions from LEC-1 in regulating H2O2 and paraquat resistance in the intestine. 23418898 Three new norlignans from Glechoma longituba. Three new norlignans, glechomols A-C (1-3, respectively), together with a known compound, 4-ethylcatechol (4), were isolated from the ethyl acetate extract of Glechoma longituba (NaKai) Kupr. Their structures were elucidated by the detailed analysis of 1D and 2D NMR and HR-MS data. Glechomols A-C were the first norlignans reported from genus Glechoma, and compound 4 was also isolated from genus Glechoma for the first time. Intracellular antioxidant assays showed that compounds 1-4 displayed significant protective effects on H(2)O(2)-induced cardiac cell injury. 23838594 Dysmorphology at a distance: results of a web-based diagnostic service. In 2007, the DYSCERNE pilot project funded by the European Commission Public Health Executive Agency (EU DG Sanco) aimed at setting up a network of expertise for patients with rare dysmorphic disorders. As part of DYSCERNE, a Dysmorphology Diagnostic System (DDS) was set up to enable clinicians throughout the EU to submit cases electronically for diagnosis using a secure, web-based interface, hosted at specified access points (Submitting nodes), in 26 different European countries. We report the outcome of this service for 200 cases submitted consecutively between January 2010 and 2012. Each case was reviewed by an average of five expert reviewers. An average of three possible syndromic diagnoses was suggested per case. In 22.5% of the cases, a consensus clinical diagnosis was reached. Genetic testing was suggested in 70.5% of the cases, whereas other laboratory investigations and diagnostic imaging were recommended in 35.5 and 26% of the cases, respectively. Further specialized opinions were suggested in 23.5% of the cases. Overall, a total of 181 very rare or extremely rare genetic syndromes were considered in the differential diagnosis of the 200 cases. In two cases, the reviewers suggested that the findings represented a new syndrome, and in one of these syndromes the underlying genetic cause was subsequently identified. Other benefits of the submission process included the possibility of directing the case submitters to specific centres for diagnostic testing or participation in research and educational benefit derived for both case submitters and reviewers.European Journal of Human Genetics advance online publication, 10 July 2013; doi:10.1038/ejhg.2013.137. 22791513 Tenascin-C, GLUT-1, and syndecan-2 expression in juvenile nasopharyngeal angiofibroma: correlations to vessel density and tumor stage. Juvenile nasopharyngeal angiofibroma (JNA) is a highly vascular tumor with some characteristics resembling those of vascular malformations. The significance of different growth and angiogenesis promoting factors for the etiology of JNA remains unsolved. We analyzed the immunoexpressions of glucose transporter 1 (GLUT-1), tenascin-C (TNC), and syndecan-2 in a series of 27 patients with JNA and compared these with each other and the clinical data to investigate their possible connections and role in the angiogenesis and growth of JNA. We found that frequent stromal TNC expression had a strong correlation with vessel density and tumor stage and endothelial GLUT-1 expression, when present, correlated with higher tumor stage. Stromal TNC and stromal GLUT-1 expressions were also found to correlate with each other. The immunoexpression of stromal TNC correlated with vascular density and higher tumors stage, which supports the idea of TNC having a role in the tumorigenesis of JNA putatively by promoting angiogenesis. 23510876 18F-FDG PET/CT Demonstration of Diffuse Lymphohistiocytic Granulomatous Vasculitis. Surveillance FDG PET/CT was performed in a 75-year-old woman with history of melanoma and colon cancer. She had rash and erythematous papules on the forearms, elbows, knees, and thighs and then developed right-leg weakness, difficulty with fine motor movement, and ptosis. Chest CT identified a right-lung spiculated nodule. Skin and pulmonary nodule biopsies showed lymphohistiocytic infiltrate with granulomatous features, without lymphoid cells, metastatic carcinoma or melanoma cells, or microorganisms. Epstein-Barr immunostain result was negative, making lymphomatoid granuloma unlikely. The inflammatory process involved the peripheral vasculature on FDG PET, and given the related neuropathy, findings were compatible with granulomatous vasculitis. 23870131 Genome-wide Generation and Systematic Phenotyping of Knockout Mice Reveals New Roles for Many Genes. Mutations in whole organisms are powerful ways of interrogating gene function in a realistic context. We describe a program, the Sanger Institute Mouse Genetics Project, that provides a step toward the aim of knocking out all genes and screening each line for a broad range of traits. We found that hitherto unpublished genes were as likely to reveal phenotypes as known genes, suggesting that novel genes represent a rich resource for investigating the molecular basis of disease. We found many unexpected phenotypes detected only because we screened for them, emphasizing the value of screening all mutants for a wide range of traits. Haploinsufficiency and pleiotropy were both surprisingly common. Forty-two percent of genes were essential for viability, and these were less likely to have a paralog and more likely to contribute to a protein complex than other genes. Phenotypic data and more than 900 mutants are openly available for further analysis. PAPERCLIP: 23773826 Comparative pharmacokinetics and bioavailability of four alkaloids in different formulations from Corydalis decumbens. Corydalis decumbens, a Traditional Chinese Medicine listed in Chinese Pharmacopoeia, is clinically used for the treatment of paralytic stroke, headache, rheumatic arthritis and sciatica in China. This study was aimed to compare the pharmacokinetics and bioavailability of protopine, tetrahydropalmatine, bicuculline, and egenine in three formulations prepared from the rhizomes of Corydalis decumbens. Alkaloid extract (CDAs-SFE) was prepared from the rhizomes of Corydalis decumbens by supercritical CO2 fluid extraction; CDAs-SFE/HPβCD (hydroxypropyl-β-cyclodextrin inclusion complex), and CDAs-SFE/HCl (hydrochloride freeze-dried powder) were resulted from CDAs-SFE through complexation with HPβCD and hydrochloride, respectively. An UFLC-MS/MS method was developed for quantitative analysis of protopine, tetrahydropalmatine, bicuculline and egenine simultaneously in rat plasma after oral administration. The differences of pharmacokinetics and bioavailability of the four alkaloids in three formulations were determined by pharmacokinetics analyses. The Cmax, AUC and bioavailability of protopine and tetrahydropalamatine (bioactive components) in CDAs-SFE/HCl were significantly higher than in CDAs-SFE and in CDAs-SFE/HPβCD. In contrast, in CDAs-SFE/HPβCD, AUC and bioavailability of tetrahydropalamatine were significantly lower, while those of bicuculline (toxic compound) appeared to be higher than both in CDAs-SFE and in CDAs-SFE/HCl. The results indicated that CDAs-SFE/HCl was the best beneficial formulation among the three formulations for the alkaloid extract prepared from the rhizomes of Corydalis decumbens, in which protopine and tetrahydropalamatine displayed higher bioavailability, but lower for bicuculline. 23421589 Rational Discovery of Dengue Type 2 Non-competitive Inhibitors. Various works have been carried out in developing therapeutics against dengue. However, to date, no effective vaccine or anti-dengue agent has yet been discovered. The development of protease inhibitors is considered as a promising option, but most previous works have involved competitive inhibition. In this study, we focused on rational discovery of potential anti-dengue agents based on non-competitive inhibition of DEN-2 NS2B/NS3 protease. A homology model of the DEN-2 NS2B/NS3 protease (using West Nile Virus NS2B/NS3 protease complex, 2FP7, as the template) was used as the target and pinostrobin, a flavanone, was used as the standard ligand. Virtual screening was performed involving a total of 13,341 small compounds, with the backbone structures of chalcone, flavanone and flavone, available from the ZINC database. Ranking of the resulting compounds yielded compounds with higher binding affinities compared to the standard ligand. Inhibition assay of the selected top ranking compounds against DEN-2 NS2B/NS3 proteolytic activity resulted in significantly better inhibition compared to the standard and correlated well with in silico results. In conclusion, via this rational discovery technique, better inhibitors were identified. This method can be used in further work to discover lead compounds for anti-dengue agents. © 2013 John Wiley & Sons A/S. 22871141 Gelucire 44/14 based immediate release formulations for poorly water-soluble drugs. Here, we aim to evaluate Gelucire 44/14 as non-ionic surface-active excipient to produce immediate-release solid dosage forms for poorly water-soluble drugs. Gelucires are polyethylene glycol (PEG) glycerides composed of mono-, di- and triglycerides and mono- and diesters of PEG. They are inert semi-solid waxy amphiphilic excipients with surface-active properties that spontaneously form a fine dispersion or emulsion upon contact with water. Monolithic Gelucire 44/14 structures are prone to prolonged erosion times, thereby slowing down drug dissolution. To overcome this issue, we combine either granulation or spray-drying, followed by compression into tablets, with an optimized composition of disintegration promoting agents. This formulation strategy allows obtaining nearly 100% drug release within 10 min dissolution time. 23860908 Synthesis of binuclear phenoxyimino organoaluminum complexes and their use as the catalyst precursors for efficient ring-opening polymerisation of ε-caprolactone. A series of novel binuclear phenoxyimino organoaluminum complexes of the type [(RN[double bond, length as m-dash]CH)C6H3OAlMe2]2 [R = C6H5 (2a), 2,6-(i)Pr2C6H3 (2b), 2,6-Ph2C6H3 (2c), adamantyl (2d), (t)Bu (2e)] have been prepared in high yields, and these complexes were identified by (1)H, (13)C NMR and elemental analysis. Structural analysis for 2a-e revealed that these complexes have a distorted tetrahedral geometry around Al and both the Al-O and the Al-N bond distances were considerably influenced by substituents in the imino groups. The complexes were tested as catalyst precursors for ring-opening polymerisation (ROP) of ε-caprolactone (CL) in the presence of BnOH, and their catalytic activities were strongly affected by the catalyst structures and polymerisation conditions. An efficient living ROP has been achieved using the 2b/BnOH system. 23529301 Natural association of two different betasatellites with Sweet potato leaf curl virus in wild morning glory (Ipomoea purpurea) in India. Wild morning glory (Ipomoea purpurea) was observed to be affected by leaf curl and yellow vein diseases during summer-rainy season of 2009 in New Delhi, India. The virus was experimentally transmitted through whitefly, Bemisia tabaci to I. purpurea that reproduced the two distinct symptoms. Sequence analysis of multiple full-length clones obtained through rolling circle amplification from the leaf curl and yellow vein samples showed 91.8-95.3 % sequence identity with Sweet potato leaf curl virus (SPLCV) and the isolates were phylogenetically distinct from those reported from Brazil, China, Japan and USA. Interestingly, two different betasatellites, croton yellow vein mosaic betasatellite and papaya leaf curl betasatellite were found with SPLCV in leaf curl and yellow vein diseases of I. purpurea, respectively. This study is the first report of occurrence of SPLCV in wild morning glory in India. SPLCV was known to infect other species of morning glory; our study revealed that I. purpurea, a new species of morning glory was a natural host of SPLCV. To date, betasatellite associated with SPLCV in Ipomoea spp. is not known. Our study provides evidence of natural association of two different betasatellites with SPLCV in leaf curl and yellow vein diseases of I. purpurea. 23813501 Characterization and quantification of 10-hydroxycamptothecine in Camptotheca acuminate and its medicinal preparation by liquid chromatography-ion trap mass spectrometry. A rapid and sensitive method for the identification and quantification of 10-hydroxycamptothecine (HCPT) in Camptotheca acuminata Decne is described. The HCPT standard solution was directly infused into the ion trap mass spectrometers (IT/MS) for collecting the MS(n) spectra. The electrospray ionization (ESI) mass spectral fragmentation pathway of HCPT was proposed and the ESI-MS(n) fragmentation behavior of HCPT was deduced in detail. The major fragment ions of HCPT were confirmed by MS(n) in both negative ion and positive ion mode. The possible main cleavage pathway of fragment ions was studied. Quantification of HCPT was assigned in negative-ion mode at a product ion at m/z 363 → 319 by LC-MS. The LC-MS method was validated for linearity, sensitivity, accuracy and precision, and then used to determine the content of the HCPT. Lastly, the LC-MS method was successfully applied to determine HCPT in real samples of Camptotheca acuminate Decne and its medicinal preparation in the first time. Copyright © 2013 John Wiley & Sons, Ltd. 23906347 Glucocorticoid Receptor Ligands Modulate Cardiovirus encephalomyocarditis virus Internal Ribosome Entry Site Activity. Abstract The use of small molecules to modulate cellular processes is a powerful approach to investigate gene function as a complement to genetic approaches. The discovery and characterization of compounds that modulate translation initiation, the rate-limiting step of protein synthesis, is important both to provide tool compounds to explore this fundamental biological process and to further evaluate protein synthesis as a therapeutic target. While most messenger ribonucleic acids (mRNAs) recruit ribosomes via their 5' cap, some viral and cellular mRNAs initiate protein synthesis via an alternative "cap-independent" mechanism utilizing internal ribosome entry sites (IRES) elements, which are complex mRNA secondary structures, localized within the 5' nontranslated region of the mRNA upstream of the AUG start codon. This report describes the design of a functional, high throughput screen of small molecules miniaturized into a 1,536-well format and performed using the luciferase reporter gene under control of the viral Cardiovirus encephalomyocarditis virus (EMCV) IRES element to identify nontoxic compounds modulating translation initiated from the EMCV IRES. One activating compound, validated in a dose response manner, has previously been shown to bind the glucocorticoid receptor (GR). Subsequent testing of additional GR modulators further supported this as the possible mechanism of action. Detailed characterization of this compound activity supported the notion that this was due to an effect at the level of translation. 23079470 Effects of alpha 7 positive allosteric modulators in murine inflammatory and chronic neuropathic pain models. Agonists and positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (nAChRs) are currently being considered as novel therapeutic approaches for managing cognitive deficits in schizophrenia and Alzheimer's disease. Though α7 agonists were recently found to possess antinociceptive and anti-inflammatory properties in rodent models of chronic neuropathic pain and inflammation, the effects of α7 nAChRs PAMs on chronic pain and inflammation remain largely unknown. The present study investigated whether PAMs, by increasing endogenous cholinergic tone, potentiate α7 nAChRs function to attenuate inflammatory and chronic neuropathic pain in mice. We tested two types of PAMS, type I (NS1738) and type II (PNU-120596) in carrageenan-induced inflammatory pain and chronic constriction injury (CCI) neuropathic pain models. We found that both NS1738 and PNU-120596 significantly reduced thermal hyperalgesia, while only PNU-120596 significantly reduced edema caused by a hind paw infusion of carrageenan. Importantly, PNU-120596 reversed established thermal hyperalgesia and edema induced by carrageenan. In the CCI model, PNU-120596 had long-lasting (up to 6 h), dose-dependent anti-hyperalgesic and anti-allodynic effects after a single injection, while NS1738 was inactive. Systemic administration of the α7 nAChR antagonist MLA reversed PNU-120596's effects, suggesting the involvement of central and peripheral α7 nAChRs. Furthermore, PNU-120596 enhanced an ineffective dose of selective agonist PHA-543613 to produce anti-allodynic effects in the CCI model. Our results indicate that the type II α7 nAChRs PAM PNU-120596, but not the type I α7 nAChRs PAM NS1738, shows significant anti-edematous and anti-allodynic effects in inflammatory and CCI pain models in mice. 23792258 Zebrafish locomotor capacity and brain acetylcholinesterase activity is altered by Aphanizomenon flos-aquae DC-1 aphantoxins. Aphanizomenon flos-aquae (A. flos-aquae) is a source of neurotoxins known as aphantoxins or paralytic shellfish poisons (PSPs) that present a major threat to the environment and to human health. Generally, altered neurological function is reflected in behavior. Although the molecular mechanism of action of PSPs is well known, its neurobehavioral effects on adult zebrafish and its relationship with altered neurological functions are poorly understood. Aphantoxins purified from a natural isolate of A. flos-aquae DC-1 were analyzed by HPLC. The major analogs found in the toxins were the gonyautoxins 1 and 5 (GTX1 and GTX5; 34.04% and 21.28%, respectively) and the neosaxitoxin (neoSTX, 12.77%). Zebrafish (Danio rerio) were intraperitoneally injected with 5.3 and 7.61 μg STXeq/kg (low and high dose, respectively) of A. flos-aquae DC-1 aphantoxins. The swimming activity was investigated by observation combined with video at 6 timepoints from 1 to 24 h post-exposure. Both aphantoxin doses were associated with delayed touch responses, reduced head-tail locomotory abilities, inflexible turning of head, and a tailward-shifted center of gravity. The normal S-pattern (or undulating) locomotor trajectory was replaced by a mechanical motor pattern of swinging the head after wagging the tail. Finally, these fish principally distributed at the top and/or bottom water of the aquarium, and showed a clear polarized distribution pattern at 12 h post-exposure. Further analysis of neurological function demonstrated that both aphantoxin doses inhibited brain acetylcholinesterase activity. All these changes were dose- and time-dependent. These results demonstrate that aphantoxins can alter locomotor capacity, touch responses and distribution patterns by damaging the cholinergic system of zebrafish, and suggest that zebrafish locomotor behavior and acetylcholinesterase can be used as indicators for investigating aphantoxins and blooms in nature. 23458455 High quality CdHgTe nanocrystals with strong near-infrared emission: relationship between composition and cytotoxic effects. High quality CdHgTe quasi core/shell nanocrystals (NCs) were prepared via the one-step method. The relationship between the composition, structure, and property was systematically investigated by the combination of X-ray photoelectron spectroscopy (XPS), inductively coupled plasma atomic emission (ICP), and the photoluminescence (PL) measurements. The quantum yield (QY) was ~50% when the feed ratio of Cd(2+) to Hg(2+) was equal to 1. The PL property was further polished, and the QY was improved to ~80% through the variance of the prepared conditions such as the ratio of ligand to metal ion and HTe(-) to metal ion, pH value, and temperature. In addition, the cytotoxic effects of CdHgTe NCs were systematically studied. The results showed that, for Cd0.21Hg0.79Te NCs, its quasi core/shell structure was very stable and little cadmium ions were released. As a result, such NCs showed little cytotoxicity and would find applications in tissue imaging or detection. 23955722 Cadmium exposure and clinical cardiovascular disease: a systematic review. Mounting evidence supports that cadmium, a toxic metal found in tobacco, air and food, is a cardiovascular risk factor. Our objective was to conduct a systematic review of epidemiologic studies evaluating the association between cadmium exposure and cardiovascular disease. Twelve studies were identified. Overall, the pooled relative risks (95 % confidence interval) for cardiovascular disease, coronary heart disease, stroke, and peripheral arterial disease were: 1.36 (95 % CI: 1.11, 1.66), 1.30 (95 % CI: 1.12, 1.52), 1.18 (95 % CI: 0.86, 1.59), and 1.49 (95 % CI: 1.15, 1.92), respectively. The pooled relative risks for cardiovascular disease in men, women and never smokers were 1.29 (1.12, 1.48), 1.20 (0.92, 1.56) and 1.27 (0.97, 1.67), respectively. Together with experimental evidence, our review supports the association between cadmium exposure and cardiovascular disease, especially for coronary heart disease. The number of studies with stroke, heart failure (HF) and peripheral arterial disease (PAD) endpoints was small. More studies, especially studies evaluating incident endpoints, are needed. 23906967 The role of consolidation for perceptual learning in temporal discrimination within and across modalities. Training people on temporal discrimination can substantially improve performance in the trained modality but also in untrained modalities. A pretest-training-posttest design was used to investigate whether consolidation plays a crucial role for training effects within the trained modality and its transfer to another modality. In the pretest, both auditory and visual discrimination performance was assessed. In the training phase, participants performed only the auditory task. After a consolidation interval of either 5min or 24h, participants were again tested in both the auditory and visual tasks. Irrespective of the consolidation interval, performance improved from the pretest to the posttest in both modalities. Most importantly, the training effect for the trained auditory modality was independent of the consolidation interval whereas the transfer effect to the visual modality was larger after 24h than after 5min. This finding shows that transfer effects benefit from extended consolidation. 23880168 Activity of dalbavancin, alone and in combination with rifampicin, against meticillin-resistant Staphylococcus aureus in a foreign-body infection model. The activity of dalbavancin, a representative of the lipoglycopeptide antibiotics, alone and in combination with rifampicin, was investigated against meticillin-resistant Staphylococcus aureus (MRSA) in a foreign-body infection model in guinea pigs. The MIC, MBC and time-kill profile of dalbavancin were determined for MRSA ATCC 43300 in the logarithmic (MBClog) and stationary (MBCstat) growth phases. The pharmacokinetic profile of dalbavancin was determined in sterile cage fluid in guinea pigs. The activity of intraperitoneal dalbavancin (40, 60 or 80mg/kg as a single dose), rifampicin (12.5mg/kg/12h for 4 days) and their combination was assessed against planktonic and biofilm MRSA. The MIC of dalbavancin was 0.078mg/L; MBClog and MBCstat were both >128× MIC. In time-kill studies, bacterial reduction of 3log10CFU/mL was achieved after 48h at ≥32× MIC (logarithmic growth) and at ≥1× MIC (stationary growth). Dalbavancin was neither synergistic nor antagonistic with rifampicin, and prevented the emergence of rifampicin resistance in vitro. The half-life of dalbavancin in cage fluid was 35.8-45.4h and the concentration remained above the MIC of MRSA during 7 days after a single dose. Dalbavancin reduced planktonic MRSA in cage fluid at high dose (60mg/kg and 80mg/kg) but failed to eradicate biofilm MRSA from cages. In combination with rifampicin, dalbavancin at 80mg/kg cured 36% of infected cages, and emergence of rifampicin resistance was completely prevented. Dalbavancin at 80mg/kg and in combination with rifampicin eradicated approximately one-third of cage-associated MRSA infections and prevented emergence of rifampicin resistance. 23624337 Modeled PM2.5 removal by trees in ten U.S. cities and associated health effects. Urban particulate air pollution is a serious health issue. Trees within cities can remove fine particles from the atmosphere and consequently improve air quality and human health. Tree effects on PM2.5 concentrations and human health are modeled for 10 U.S. cities. The total amount of PM2.5 removed annually by trees varied from 4.7 tonnes in Syracuse to 64.5 tonnes in Atlanta, with annual values varying from $1.1 million in Syracuse to $60.1 million in New York City. Most of these values were from the effects of reducing human mortality. Mortality reductions were typically around 1 person yr(-1) per city, but were as high as 7.6 people yr(-1) in New York City. Average annual percent air quality improvement ranged between 0.05% in San Francisco and 0.24% in Atlanta. Understanding the impact of urban trees on air quality can lead to improved urban forest management strategies to sustain human health in cities. 23824562 Effect of ionic strength and pH on the physical and chemical stability of a monoclonal antibody antigen-binding fragment. Monoclonal antibody (mAb) fragments are emerging as promising alternatives to full-length mAbs as protein therapeutic candidates. Antigen-binding fragments (Fabs) are the most advanced with three Fab-based drug products currently approved. This work presents preformulation characterization data on the effect of pH, NaCl concentration, and various cationic excipients on the physical and chemical stability of a Fab molecule with multiple negatively charged Asp residues in the complementarity-determining region. Conformational stability was evaluated using an empirical phase diagram approach based on circular dichroism, intrinsic Trp and extrinsic 8-anilino-1-naphthalene sulfonate (ANS) fluorescence, and static light scattering measurements. The effect of NaCl concentration, various cationic excipients and pH on the Fab molecule's conformational stability, aggregation propensity, and chemical stability (Asp isomerization) was determined by differential scanning calorimetry, optical density measurements at 350 nm (OD350 ), and ion-exchange chromatography, respectively. Increasing NaCl concentration increased the overall conformational stability, decreased aggregation rates, and lowered the rates of Asp isomerization. No such trends were noted for pH or cationic excipients. The potential interrelationships between protein conformational and chemical stability are discussed in the context of designing stable protein formulations. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2520-2537, 2013. 23829894 Capturing the mammalian Hippo: Elucidating its role in cancer. The Hippo pathway is an evolutionarily conserved kinase cascade involved in cell growth, apoptosis, development and migration. It is also crucial for stem cell self-renewal and the maintenance of genomic stability. In addition, this pathway has the unique capacities to sense aspects of tissue architecture, such as cell polarity and mechanical tensions imposed by the surrounding microenvironment, and to control organ size and shape. All of these properties are frequently altered in tumor cells. In this review, we summarize how dysregulation of mammalian Hippo signaling is implicated in cancer. 23967877 Cu-Catalyzed Cross-Dehydrogenative Coupling Reactions of (Benzo)thiazoles with Cyclic Ethers. Copper-catalyzed cross-dehydrogenative coupling (CDC) reactions of (benzo)thiazoles with cyclic ethers were developed under mild conditions. In particular, the formation of C-C bonds via the CDC reactions between non-benzo-fused azoles and ethers are reported for the first time. In addition, the acetals, known as the masked 2-thiazolecarboxaldehydes, could be successfully obtained by this CDC reaction. The preliminary mechanism and supportive DFT calculations are discussed as well. 23903543 RT-PCR/ESI-MS for Rapid Detection of Biothreat and Common Respiratory Pathogens. Electrospray ionization mass spectrometry (ESI-MS) of RT-PCR amplicons from human respiratory samples allows for broad pathogen identification approximately eight hours after collection. We investigated the performance characteristics of a high-throughput RT-PCR coupled ESI-MS assay for distinguishing biothreat (BT) agents from common bacterial, fungal, and viral respiratory pathogens in bronchoalveolar lavages (BALs) from subjects with suspected respiratory infections. In a retrospective case series, 202 BALs were collected from patients with suspected acute respiratory infections at The Johns Hopkins Hospital from August 2010 - February 2011. Samples were processed using gold standard bacterial, viral, and fungal testing in the clinical microbiology laboratory as part of routine care, then blindly mocked with either water or nucleic acids from BT organisms (B. anthracis, Y. pestis, F. tularensis, Brucella spp, Burkholderia spp, Rickettsia prowazekii) and processed by RT-PCR/ESI-MS. Sensitivity and specificity of RT-PCR/ESI-MS versus gold standard clinical methods was as follows: for mocked BT DNA, 98.5% sensitivity (95% CI: 94.2 - 99.7) and 100% specificity (95% CI: 93.1 - 100.0); for bacterial pathogens, 81.8% sensitivity (95% CI: 74.3-87.6) and 73.6% specificity (95% CI: 64.2-81.4); for viral pathogens, 93.3% sensitivity (95% CI: 66.0 - 99.7) and 97.3% specificity (95% CI: 89.7-99.5), and for fungal pathogens, 42.6% sensitivity (95% CI: 29.5 - 56.7) and 97.8% specificity (95% CI: 91.8 - 99.6). Our data suggests that RT-PCR/ESI-MS is a useful adjunctive test to standard culture protocols for rapid detection of both BT and common respiratory pathogens; further study is required for purposes of assay validation, especially fungal detection, and potential implementation. 23865958 Implementing physician orders for life-sustaining treatment in california hospitals: factors associated with adoption. Physician Orders for Life-Sustaining Treatment (POLST) is a tool to document and ensure continuity of end-of-life treatment decisions across healthcare settings that became a legal document in California in January 2009. Hospitals were surveyed to evaluate factors associated with uptake of this intervention and whether a grassroots community coalition intervention facilitated dissemination. A mail and telephone survey of all acute care hospitals in California was conducted between August 2011 and January 2012, and community coalition reports of interaction with hospitals and hospital characteristics from the California Office of Statewide Planning and Development and Census ZIP Code Tabulation Areas were analyzed. Of 349 hospitals, 286 (81.9%) responded to the survey. Sixty-five percent of hospitals had a policy about POLST, 87% had available blank POLST forms, 84% had educated staff, and 94% reported handling POLST properly in the emergency department and on admission. In multivariable analyses, hospitals in poor areas and for-profit (vs nonprofit) hospitals were less likely to stock blank POLST forms and to have educated staff, and hospitals with community coalition interaction and in wealthier areas were more likely to handle POLST forms correctly. Although POLST is widely used in California, a significant minority of hospitals remain unprepared 3 years after implementation. Efforts to improve implementation should emphasize dissemination in poorer areas and in for-profit hospitals. 23436749 Understanding quantitative structure-property relationships uncertainty in environmental fate modeling. In cases in which experimental data on chemical-specific input parameters are lacking, chemical regulations allow the use of alternatives to testing, such as in silico predictions based on quantitative structure-property relationships (QSPRs). Such predictions are often given as point estimates; however, little is known about the extent to which uncertainties associated with QSPR predictions contribute to uncertainty in fate assessments. In the present study, QSPR-induced uncertainty in overall persistence (POV ) and long-range transport potential (LRTP) was studied by integrating QSPRs into probabilistic assessments of five polybrominated diphenyl ethers (PBDEs), using the multimedia fate model Simplebox. The uncertainty analysis considered QSPR predictions of the fate input parameters' melting point, water solubility, vapor pressure, organic carbon-water partition coefficient, hydroxyl radical degradation, biodegradation, and photolytic degradation. Uncertainty in POV and LRTP was dominated by the uncertainty in direct photolysis and the biodegradation half-life in water. However, the QSPRs developed specifically for PBDEs had a relatively low contribution to uncertainty. These findings suggest that the reliability of the ranking of PBDEs on the basis of POV and LRTP can be substantially improved by developing better QSPRs to estimate degradation properties. The present study demonstrates the use of uncertainty and sensitivity analyses in nontesting strategies and highlights the need for guidance when compounds fall outside the applicability domain of a QSPR. Environ. Toxicol. Chem. 2013;32:1069-1076. © 2013 SETAC. 23566885 (1)H NMR-based metabonomic analysis of the serum and urine of rats following subchronic exposure to dichlorvos, deltamethrin, or a combination of these two pesticides. Metabonomic analysis, clinical chemical analysis and histopathology were used to investigate the toxic effects of subchronic exposure to dichlorvos, deltamethrin, and a combination of these two pesticides, in rats. Weight loss, hind limb weakness and histopathological changes in kidney tissue were only observed in rats exposed to high doses of deltamethrin, or a combination of deltamethrin and dichlorvos. Urinary metabonomic analysis indicated that exposure to a mixture of dichlorvos and deltamethrin was followed by increases in urinary lactate, dimethylamine, N-glycoprotein (NAC) and glycine similar to those observed in rats treated with either dichlorvos or deltamethrin alone. Serum metabonomic analysis suggests that dichlorvos induced an increase in lactate and alanine and a decrease in dimethylglycine (DMG), NAC and very low- and low-density lipoprotein (VLDL/LDL). High levels of lactate and low levels of NAC and VLDL/LDL were observed in the deltamethrin treatment group. Treating rats with a mixture of dichlorvos and deltamethrin caused an increase in serum lactate, trimethylamine-N-oxide (TMAO), choline and alanine, with the highest levels of these metabolites observed in those that received the highest dose. Exposure to a mixture of dichlorvos and deltamethrin also resulted in a decrease in serum acetone, DMG, NAC, and VLDL/LDL. Changes in serum TMAO, alanine, choline and acetone in this treatment group were higher than in rats treated with either dichlorvos or deltamethrin. These results suggest that exposing rats to subchronic doses of dichlorvos, deltamethrin, or a combination of these pesticides, disrupted the energy metabolism of the liver and reduced kidney function. 23761678 Urinary exosomal Wilms' tumor-1 as a potential biomarker for podocyte injury. Renal Wilms' tumor-1 (WT-1) staining is used to detect podocyte loss in kidney biopsies. We aimed to determine if urinary exosomal WT-1 could serve as a noninvasive biomarker of podocyte injury. We examined WT-1 by Western blot in a human podocyte-like cell line, a mouse model of podocyte injury, and human subjects with podocyte disorders. WT-1 was detected in exosomal fraction of the conditioned media from podocytes and increased 48 h after hTGF-β1 stimulation. Cellular WT-1 decreased in podocytes following hTGF-β1 incubation. In mice with induced podocyte injury, urinary exosomal WT-1 was detected 1 wk earlier than albuminuria and also tracked the effects of angiotensin receptor blocker (ARB) treatment. In addition, urinary exosomal WT-1 levels at 1 wk post-injury correlated with the severity of glomerular injury at 3 wk later. In human subjects, urinary exosomal WT-1 was significantly increased in focal segmental glomerulosclerosis (FSGS) patients compared with healthy volunteers or steroid-sensitive nephrotic syndrome (SSNS) patients. Urinary exosomal WT-1 was also significantly decreased in patients in remission for either FSGS or SSNS or following steroid treatment in six SSNS subjects. We conclude that urinary exosomal WT-1 is a promising noninvasive biomarker with apparent podocyte specificity that can detect early progression and treatment-induced regression of podocyte injury in FSGS or SSNS. These results warrant longitudinal, prospective studies in a large cohort with a range of podocyte diseases. 23771342 Secondary and primary dystonia: pathophysiological differences. Primary dystonia is thought to be a disorder of the basal ganglia because the symptoms resemble those of patients who have anatomical lesions in the same regions of the brain (secondary dystonia). However, these two groups of patients respond differently to therapy suggesting differences in pathophysiological mechanisms. Pathophysiological deficits in primary dystonia are well characterized and include reduced inhibition at many levels of the motor system and increased plasticity, while emerging evidence suggests additional cerebellar deficits. We compared electrophysiological features of primary and secondary dystonia, using transcranial magnetic stimulation of motor cortex and eye blink classical conditioning paradigm, to test whether dystonia symptoms share the same underlying mechanism. Eleven patients with hemidystonia caused by basal ganglia or thalamic lesions were tested over both hemispheres, corresponding to affected and non-affected side and compared with 10 patients with primary segmental dystonia with arm involvement and 10 healthy participants of similar age. We measured resting motor threshold, active motor threshold, input/output curve, short interval intracortical inhibition and cortical silent period. Plasticity was probed using an excitatory paired associative stimulation protocol. In secondary dystonia cerebellar-dependent conditioning was measured using delayed eye blink classical conditioning paradigm and results were compared with the data of patients with primary dystonia obtained previously. We found no difference in motor thresholds, input/output curves or cortical silent period between patients with secondary and primary dystonia or healthy controls. In secondary dystonia short interval intracortical inhibition was reduced on the affected side, whereas it was normal on the non-affected side. Patients with secondary dystonia had a normal response to the plasticity protocol on both the affected and non-affected side and normal eye blink classical conditioning that was not different from healthy participants. In contrast, patients with primary dystonia showed increased cortical plasticity and reduced eye blink classical conditioning. Normal motor cortex plasticity in secondary dystonia demonstrates that abnormally enhanced cortical plasticity is not required for clinical expression of dystonia, and normal eye blink conditioning suggests an absence of functional cerebellar involvement in this form of dystonia. Reduced short interval intracortical inhibition on the side of the lesion may result from abnormal basal ganglia output or may be a consequence of maintaining an abnormal dystonic posture. Dystonia appears to be a motor symptom that can reflect different pathophysiological states triggered by a variety of insults. 23834930 NADPH oxidase inhibitor diphenyleneiodonium and reduced glutathione mitigate ethephon-mediated leaf senescence, H2O2 elevation and senescence-associated gene expression in sweet potato (Ipomoea batatas). Ethephon, an ethylene releasing compound, promoted leaf senescence, H2O2 elevation, and senescence-associated gene expression in sweet potato. It also affected the glutathione and ascorbate levels, which in turn perturbed H2O2 homeostasis. The decrease of reduced glutathione and the accumulation of dehydroascorbate correlated with leaf senescence and H2O2 elevation at 72h in ethephon-treated leaves. Exogenous application of reduced glutathione caused quicker and significant increase of its intracellular level and resulted in the attenuation of leaf senescence and H2O2 elevation. A small H2O2 peak produced within the first 4h after ethephon application was also eliminated by reduced glutathione. Diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, delayed leaf senescence and H2O2 elevation at 72h, and its influence was effective only within the first 4h after ethephon treatment. Ethephon-induced senescence-associated gene expression was repressed by DPI and reduced glutathione at 72h in pretreated leaves. Leaves treated with l-buthionine sulfoximine, an endogenous glutathione synthetase inhibitor, did enhance senescence-associated gene expression, and the activation was strongly repressed by reduced glutathione. In conclusion, ethephon-mediated leaf senescence, H2O2 elevation and senescence-associated gene expression are all alleviated by reduced glutathione and NADPH oxidase inhibitor DPI. The speed and the amount of intracellular reduced glutathione accumulation influence its effectiveness of protection against ethephon-mediated effects. Reactive oxygen species generated from NADPH oxidase likely serves as an oxidative stress signal and participates in ethephon signaling. The possible roles of NADPH oxidase and reduced glutathione in the regulation of oxidative stress signal in ethephon are discussed. 23419362 Intra- and interoperator variability of lobar pulmonary volumes and emphysema scores in patients with chronic obstructive pulmonary disease and emphysema: comparison of manual and semi-automated segmentation techniques. We aimed to compare the intra- and interoperator variability of lobar volumetry and emphysema scores obtained by semi-automated and manual segmentation techniques in lung emphysema patients. In two sessions held three months apart, two operators performed lobar volumetry of unenhanced chest computed tomography examinations of 47 consecutive patients with chronic obstructive pulmonary disease and lung emphysema. Both operators used the manual and semi-automated segmentation techniques. The intra- and interoperator variability of the volumes and emphysema scores obtained by semi-automated segmentation was compared with the variability obtained by manual segmentation of the five pulmonary lobes. The intra- and interoperator variability of the lobar volumes decreased when using semi-automated lobe segmentation (coefficients of repeatability for the first operator: right upper lobe, 147 vs. 96.3; right middle lobe, 137.7 vs. 73.4; right lower lobe, 89.2 vs. 42.4; left upper lobe, 262.2 vs. 54.8; and left lower lobe, 260.5 vs. 56.5; coefficients of repeatability for the second operator: right upper lobe, 61.4 vs. 48.1; right middle lobe, 56 vs. 46.4; right lower lobe, 26.9 vs. 16.7; left upper lobe, 61.4 vs. 27; and left lower lobe, 63.6 vs. 27.5; coefficients of reproducibility in the interoperator analysis: right upper lobe, 191.3 vs. 102.9; right middle lobe, 219.8 vs. 126.5; right lower lobe, 122.6 vs. 90.1; left upper lobe, 166.9 vs. 68.7; and left lower lobe, 168.7 vs. 71.6). The coefficients of repeatability and reproducibility of emphysema scores also decreased when using semi-automated segmentation and had ranges that varied depending on the target lobe and selected threshold of emphysema. Semi-automated segmentation reduces the intra- and interoperator variability of lobar volumetry and provides a more objective tool than manual technique for quantifying lung volumes and severity of emphysema. 23882089 Cognitive debiasing 1: origins of bias and theory of debiasing. Numerous studies have shown that diagnostic failure depends upon a variety of factors. Psychological factors are fundamental in influencing the cognitive performance of the decision maker. In this first of two papers, we discuss the basics of reasoning and the Dual Process Theory (DPT) of decision making. The general properties of the DPT model, as it applies to diagnostic reasoning, are reviewed. A variety of cognitive and affective biases are known to compromise the decision-making process. They mostly appear to originate in the fast intuitive processes of Type 1 that dominate (or drive) decision making. Type 1 processes work well most of the time but they may open the door for biases. Removing or at least mitigating these biases would appear to be an important goal. We will also review the origins of biases. The consensus is that there are two major sources: innate, hard-wired biases that developed in our evolutionary past, and acquired biases established in the course of development and within our working environments. Both are associated with abbreviated decision making in the form of heuristics. Other work suggests that ambient and contextual factors may create high risk situations that dispose decision makers to particular biases. Fatigue, sleep deprivation and cognitive overload appear to be important determinants. The theoretical basis of several approaches towards debiasing is then discussed. All share a common feature that involves a deliberate decoupling from Type 1 intuitive processing and moving to Type 2 analytical processing so that eventually unexamined intuitive judgments can be submitted to verification. This decoupling step appears to be the critical feature of cognitive and affective debiasing. 23919851 A comparative study of positive rate of placental alpha-microglobulin-1 test in pre-term pregnant women with and without uterine contraction. The aim of this study was to compare positive placental alpha-microglobulin-1 (PAMG-1) test rates with clinical significance of pre-term pregnant women, intact membrane with and without uterine contraction. A prospective analytic study was performed including 100 pre-term pregnant women with intact membranes. Patients were classified into two groups, patients with uterine contraction (n = 50) and patients without contraction (n = 50). Conventional standard methods were performed to exclude rupture of membranes. PAMG-1 test was performed. Positive results of the tests and clinical significance (including time from test to delivery, route of delivery and outcomes of the fetuses) were determined. PAMG-1 positive rate was 10% (5/50) and 0% in contraction group and no contraction group, respectively (p = 0.028). Gestational age at delivery and test-to-delivery interval were less in contraction group than those in no-contraction group. When compared between positive test (n = 5) and negative test (n = 45) in pre-term contraction. Test-to-delivery interval was shorter positive group (20 vs 720 h, p = 0.025). In conclusion, in pre-term pregnant women with intact membranes, PAMG-1 test rates are more positive in cases of uterine contraction. Pre-term pregnant women in labour with a positive PAMG-1 test had a significantly shorter test-to-delivery interval than those with a negative test. 23834555 Evaluating the Association between Pathological Myopia and SNPs in RASGRF1. ACTC1 and GJD2 Genes at Chromosome 15q14 and 15q25 in a Chinese Population. Abstract Background: This study investigated the association of the 27 SNPs located in RASGRF1. GJD2, and ACTC1 genes with pathological myopia in a Chinese Han population. Methods: Myopia patients were stratified according to whether they did (n = 274) or did not (n = 131) have myopic macular degeneration (MMD). The SNPbrowser software was used to identify specific SNPs for analysis and minimal allele frequency of >20%, and a pairwise r(2) < 0.85 were genotyped using MALDI-TOF mass spectrometry. Results: Before controlling for false discovery rate, the frequency of the rs1867315 C/C genotype compared with healthy controls was lower in the myopia group (p = 0.006) and in myopia patients without macular degeneration (p = 0.019). The frequency of the rs670957A/A genotype was also lower in patients without MMD compared with controls (p = 0.045). For rs2070664, the frequency of the A allele was higher in the patients with MMD compared to those without MMD (p = 0.032). After controlling for a false discovery rate of 5%, there was no significant difference in genotype and allele frequencies between these groups. Conclusion: In this study, there was no association of the analyzed SNPs located in RASGRF1. GJD2, and ACTC1 with pathological myopia, suggesting that SNPs included in our study have no or a limited role in causing pathologic myopia in this Chinese Han population. 23935395 CXCL12/CXCR4 Signal Axis Plays an Important Role in Mediating Bone Morphogenetic Protein 9-induced Osteogenic Differentiation of Mesenchymal Stem Cells. Mesenchymal progenitor stem cells (MPCs) are a group of bone marrow stromal progenitor cells processing osteogenic, chondrogenic, adipogenic and myogenic lineages differentiations. Previous studies have demonstrated that bone morphogeneic protein 9(BMP9) is one of the most osteogenic BMPs both in vitro and in vivo, however, the underlying molecular mechanism of osteogenesis induced by BMP9 is needed to be deep explored. Here, we used the recombinant adenoviruses assay to introduce BMP9 into C3H10T1/2 mesenchymal stem cells to elucidate the role of CXCL12/CXCR4 signal axis during BMP9-incuced osteogenic differentiation. The results showed that CXCL12 and CXCR4 expressions were down-regulated at the stage of BMP9-induced osteogenic differentiation, in a dose- and time-dependent. Pretreatment of C3H10T1/2 cells with CXCL12/CXCR4 could significantly affect the early and mid osteogenic markers alkaline phosphatase (ALP), osteocalcin (OCN), the transcription factors of Runx2, Osx, Plzf and Dlx5 expression, through activating the Smad, MAPK signaling pathway. Addition of exogenous CXCL12 did not affect the changes of the late osteogenic marker calcium deposition. Thus, our findings suggest a co-requirement of the CXCL12/CXCR4 signal axis in BMP9-induced the early- and mid-process of osteogenic differentiation of MSCs. 23822166 Homogeneous Hydrogenation and Isomerization of 1-Octene Catalyzed by Nickel(II) Complexes with Bidentate Diarylphosphane Ligands. A systematic library of 24 nickel(II) complexes with bidentate diphosphane ligands was synthesized, and the solid-state structures of five of them were determined with X-ray crystallography. The compounds C1-C3 are common P2Ni(II)X2-type complexes, while C4 contains a unique [P2Ni(II)(NH3)(OAc)](+) square-planar structure with a P2NO donor set and C5 constitutes a rare [(P2Ni(II))2(μ-OH)2](2+) dinuclear compound. The catalytic activity of all complexes was tested in the hydrogenation and/or isomerization of 1-octene in a CH2Cl2/CH3OH reaction medium. Catalyst precursors bearing ligands with o-alkoxy aryl rings selectively hydrogentate 1-octene to n-octane, while catalytic systems comprising ligands without the o-alkoxy functionality selectively isomerize the substrate to a mixture of internal alkenes, mostly cis- and trans-2-octene. The conversion is enhanced by equipping the ligand aryl rings with electron-donating alkoxy groups, by increasing the steric bulk of the backbone and/or the aryl rings, by employing relatively noncoordinating anions, and by adding a base as the cocatalyst. Using the compound [Ni(L3X)I2] as the catalyst precursor and upon application of standard hydrogenation conditions, full conversion of the substrate was achieved in 1 h to isomerization products only (TON = 1940). When a catalytic amount of the base is added, a similar result is obtained even in the absence of H2. A maximum TON of 4500 in 1 h with 96% selectivity for n-octane was achieved by employing [Ni(oMeO-L3X)(NH3)(OAc)]PF6 as the catalyst precursor. 23900029 Roles of pro-angiogenic and anti-angiogenic factors as well as matrix metalloproteinases in healing of NSAID-induced small intestinal ulcers in rats. We examined changes in the expression of a pro-angiogenic factor, vascular endothelial growth factor (VEGF), and an anti-angiogenic factor, endostatin, as well as matrix metalloproteinase (MMP)-2 and MMP-9 in the rat small intestine after administration of indomethacin and investigated the roles of these factors in the healing of indomethacin-induced small intestinal ulcers. Male SD rats were given indomethacin (10mg/kg) p.o. and euthanized at various time points (3-24h and 2-7days) after the administration. To impair the healing of these lesions, low-dose of indomethacin (2mg/kg) was given p.o. once daily for 6days starting 1day after ulceration. Levels of VEGF, endostatin, MMP-2 and MMP-9 were determined by Western blotting. The expression of both VEGF and endostatin was upregulated after the ulceration. Repeated administration of low-dose indomethacin impaired the ulcer healing with a decrease of VEGF expression and a further increase of endostatin expression, resulting in a marked decrease in the ratio of VEGF/endostatin expression. The levels of MMP-2 and MMP-9 were both significantly increased after the ulceration, but these responses were suppressed by the repeated indomethacin treatment. The healing of these ulcers was significantly delayed by the repeated administration of MMP inhibitors such as ARP-101 and SB-3CT. The results confirm the importance of the balance between pro-angiogenic and anti-angiogenic activities in the healing of indomethacin-induced small intestinal damage and further suggest that the increased expression of MMP-2 and MMP-9 is another important factor for ulcer healing in the small intestine. 23893571 Truncating CLCN1 mutations in myotonia congenita: Variable patterns of inheritance. Myotonia congenita due to protein truncating CLCN1 mutations is associated with variable patterns of inheritance. Three family kindreds are described, all of whom possess protein truncating mutations (Y33X, fs503X, R894X). One lineage also has coexistent R894X, A313T, and A320V mutations. The Y33X mutation kinship has autosomal recessive inheritance and a severe phenotype when homozygous. The fs503X family has autosomal dominant inheritance and a moderate-to-severe phenotype. The A313T mutation kindred also has autosomal dominant inheritance but expresses a mild phenotype, except for the more severely affected compound heterozygotes. Early truncating mutations precluding dimerization are expected to be autosomal recessive and express a severe phenotype, while later mutations may be variable. The pedigrees presented here demonstrate that intrafamilial phenotypic variability may result from a dosage effect of an additional mutation, not necessarily variable expressivity. Mutations that have unexpected patterns of inheritance may represent allelic variability. © 2013 Wiley Periodicals, Inc. 23441918 Novel inositol catabolic pathway in Thermotoga maritima. myo-inositol (MI) is a key sugar alcohol component of various metabolites, e.g. phosphatidylinositol-based phospholipids that are abundant in animal and plant cells. The seven-step pathway of MI degradation was previously characterized in various soil bacteria including Bacillus subtilis. Through a combination of bioinformatics and experimental techniques we identified a novel variant of the MI catabolic pathway in the marine hyperthermophilic bacterium Thermotoga maritima. By using in vitro biochemical assays with purified recombinant proteins we characterized four inositol catabolic enzymes encoded in the TM0412-TM0416 chromosomal gene cluster. The novel catabolic pathway in T. maritima starts as the conventional route using the myo-inositol dehydrogenase IolG followed by three novel reactions. The first 2-keto-myo-inositol intermediate is oxidized by another, previously unknown NAD-dependent dehydrogenase TM0412 (named IolM), and a yet unidentified product of this reaction is further hydrolysed by TM0413 (IolN) to form 5-keto-l-gluconate. The fourth step involves epimerization of 5-keto-l-gluconate to d-tagaturonate by TM0416 (IolO). T. maritima is unable to grow on myo-inositol as a single carbon source. The determined in vitro specificity of the InoEFGK (TM0418-TM0421) transporter to myo-inositol-phosphate suggests that the novel pathway in Thermotoga utilizes a phosphorylated derivative of inositol. 23897662 A Systematic Investigation of Coinage Metal Carbonyl Complexes Stabilized by Fluorinated Alkoxy Aluminates. The reaction of Cu(I) , Ag(I) , and Au(I) salts with carbon monoxide in the presence of weakly coordinating anions led to known and structurally unknown non-classical coinage metal carbonyl complexes [M(CO)n ][A] (A=fluorinated alkoxy aluminates). The coinage metal carbonyl complexes [Cu(CO)n (CH2 Cl2 )m ](+) [A](-) (n=1, 3; m=4-n), [Au2 (CO)2 Cl](+) [A](-) , [(OC)n M(A)] (M=Cu: n=2; Ag: n=1, 2) as well as [(OC)3 Cu⋅⋅⋅ClAl(OR(F) )3 ] and [(OC)Au⋅⋅⋅ClAl(OR(F) )3 ] were analyzed with X-ray diffraction and partially IR and Raman spectroscopy. In addition to these structures, crystallographic and spectroscopic evidence for the existence of the tetracarbonyl complex [Cu(CO)4 ](+) [Al(OR(F) )4 ](-) (R(F) =C(CF3 )3 ) is presented; its formation was analyzed with the help of theoretical investigations and Born-Fajans-Haber cycles. We discuss the limits of structure determinations by routine X-ray diffraction methods with respect to the CO bond lengths and apply the experimental CO stretching frequencies for the prediction of bond lengths within the carbonyl ligand based on a correlation with calculated data. Moreover, we provide a simple explanation for the reported, partly confusing and scattered CO stretching frequencies of [Cu(I) (CO)n ] units. 23912964 Perovskite ferroelectric nanomaterials. In this review, the main concept of ferroelectricity of perovskite oxides and related materials at nanometer scale and existing difficulties in the synthesis of those nanocrystals are discussed. Important effects, such as depolarization field and size effect, on the existence of ferroelectricity in perovskite nanocrystals are deliberated. In the discussion of modeling works, different theoretical calculations are pinpointed focusing on their studies of lattice dynamics, phase transitions, new origin of ferroelectricity in nanostructures, etc. As the major part of this review, recent research progress in the facile synthesis, characterization and various applications of perovskite ferroelectric nanomaterials, such as BaTiO3, PbTiO3, PbZrO3, and BiFeO3, are also scrutinized. Perspectives concerning the future direction of ferroelectric nanomaterials research and its potential applications in renewable energy, etc., are presented. This review provides an overview in this area and guidance for further studies in perovskite ferroelectric nanomaterials and their applications. 23880679 Medical malpractice reform measures and their effects. New rules and methods for medical injury dispute resolution have been launched in New Hampshire and New York, and demonstration projects are underway elsewhere. This article describes major medical malpractice reforms undertaken and proposed in recent years. Reforms are classified as (1) liability-limiting initiatives favoring health-care providers; (2) procedural innovations promoted as improving dispute resolution processes, such as patient compensation funds, "sorry" laws, disclosure and early offer laws, health courts, and safe harbor laws; and (3) major conceptual reforms to move liability away from physicians to hospitals or administrative no-fault compensation systems. Empirical evidence about the practical effects of already-implemented reforms, such as damage caps, is reviewed. In light of declining malpractice claim rates, heavier adverse impacts of damage caps on vulnerable groups (people who have severe injuries, who are elderly, and who are unemployed) and repeated findings of state law unconstitutionality, the rationale for nationwide damage caps is questioned. Attention to innovative reform proposals such as patient compensation funds, disclosure and early offer laws, safe harbor laws, enterprise insurance and no-fault compensation systems, is encouraged. 23905577 Combinational delivery of lipid-enveloped polymeric nanoparticles carrying different peptides for anti-tumor immunotherapy. Aim: The authors aimed to investigate whether nanotechnology-based delivery of antigenic peptides is feasible for efficiently inducing anti-tumor cytotoxic T lymphocyte responses through vaccination. Materials & methods: Three different murine melanoma antigens were entrapped in lipid-coated poly(D,L-lactide-co-glycolide) nanoparticles (NPs) by the double emulsion method. Results: The loading efficiency of hydrophilic peptides was greatly improved when lipids were introduced to formulate lipid-coated NPs. The lipid-coated NPs carrying a single peptide and/or combinations of multiple lipid-coated NPs carrying antigenic peptides were characterized in vitro and in vivo in a C57/BL6 (B6) mouse model. Both the single melanoma antigen peptide-loaded NPs and combinational delivery of lipid-coated NPs carrying different peptides could induce antigen-specific T-cell responses. However, single peptide-loaded NPs failed to significantly delay the growth of subcutaneously inoculated B16 melanoma cells in a prophylactic setting. By contrast, the combinational delivery of lipid-coated NPs carrying different peptides significantly suppressed growth of inoculated B16 melanoma cells. Original submitted 17 April 2012; Revision submitted 28 January 2013. 23915913 Immunomodulation therapy with lenalidomide in follicular, transformed and diffuse large B cell lymphoma: current data on safety and efficacy. Lenalidomide is an immunomodulatory agent which has been approved for multiple myeloma. Lenalidomide is also effective in and tolerated well by patients with follicular lymphoma, diffuse large B-cell lymphoma, and transformed large cell lymphoma. This review summarizes the results of current preclinical and clinical studies of lenalidomide, alone or in combination with the monoclonal antibody rituximab, as a therapeutic option for these three lymphoma types. This review will serve as a tool guiding future clinical investigations to improve survival rates for these three lymphomas. 23629053 Diversification of plant species in arid Northwest China: species-level phylogeographical history of Lagochilus Bunge ex Bentham (Lamiaceae). Lagochilus occurs in the arid zones across temperate steppe and desert regions of Northwest China. Cooling with strong dessication in the Pleistocene, along with rapid uplift of mountain ranges peripheral to the Qinghai-Tibet Plateau, appear to have had major impacts on the genetic structure of the flora. To understand the evolutionary history of Lagochilus and the divergence related to these past shifts of habitats among these regions, we sequenced the plastid intergenic spacers, psbA-trnH and trnS-trnG from populations throughout the known distributions of ten species of the genus. We investigated species-level phylogeographical patterns within Lagochilus. Phylogenetic trees were constructed using Neighbor-joining and Bayesian inference. The divergence times of major lineages were estimated with BEAST and IMa. Genetic structure and demographic history were inferred by AMOVA, neutrality tests, mismatch distribution, and Bayesian skyline plot analyses. The results showed that most chloroplast haplotypes were species-specific, and that the phylogeny of Lagochilus is geographically structured. The estimated Bayesian chronology and IMa suggested that the main divergence events for species between major eastern and western portions of the Chinese desert occurred at the Plio-/Pleistocene boundary (ca. 2.1-2.8 Ma ago), and likely coinciding with the formation of these deserts in Northwest China. The regional demographic expansions, in the western region at ca. 0.39 Ma, and in the eastern at ca. 0.06 Ma, or across all regions at ca. 0.26 Ma, showed the response to aridification accompanied by cooling of the Pleistocene sharply increased aridity in the Chinese deserts, which reflects a major influence of geologic and climatic events on the evolution of species of Lagochilus. We suggest that diversification is most likely the result of the past fragmentation due to aridification; the expansion of the range of species along with the deserts was an adaptation to dry and cold environments during the Quaternary. 23729370 Formation of a pt12 cluster by single-atom control that leads to enhanced reactivity: hydrogenation of unreactive olefins. A platinum subnanocluster catalyst composed of 12 atoms was synthesized using a phenylazomethine dendrimer, which can assemble twelve PtCl4 units by stepwise complexation, followed by reduction to Pt(0) . Unreactive olefins that were not activated by conventional 2 nm Pt nanoparticles were successfully hydrogenated by the subnanocluster. EWG=electron-withdrawing group. 23418739 New alkaloid from Streptomyces koyangensis residing in Odontotermes formosanus. A new alkaloid was isolated from the ethyl acetate extract of the culture of a termite-associated Streptomyces koyangensis BY-4. The structure of 1 was elucidated by using MS, NMR, electronic circular dichroism data, and computational approaches. Compound 1 showed weak antimicrobial activities against a panel of test microbes. 23625092 The reliability of cardiogenic impedance and correlation with echocardiographic and plethysmographic parameters for predicting CRT time intervals post implantation. Encouraging data have been reported on the use of cardiogenic impedance (CI) in cardiac resynchronization therapy (CRT) optimization. The purposes of this study were to: evaluate the stability of certain CI vectors 24 h postimplantation, study the correlation between these CI signals and selected echocardiographic parameters, and examine the possibility of non-invasive calibration of the patient-specific impedance-based prediction model. Thirteen patients received a CRT-defibrillator device with monitor capability of the dynamic impedance between several electrodes. At implantation, a patient-specific impedance-based prediction model was created for identification of optimal atrioventricular and interventricular (VV) delays and calibrated on invasive measurements of left ventricular contractility (LV dP/dtmax). Simultaneously, non-invasive measurements of LV dP/dtmax and stroke volume (SV) were obtained using a finger plethysmograph. Patients were re-evaluated with echocardiography and new CI measurements the day after implantation. The hemodynamic benefit achieved by optimal VV setting according to the patient-specific impedance-based prediction model at follow-up was not as large as the one obtained at implantation. In a multivariate partial least square regression analysis, a correlation was found between aortic velocity time integral (VTI) and a generic linear combination of CI features (P < 0,005). No correlation was found between the patient-specific impedance-based prediction models and the non-invasive measurements of LV dP/dtmax and SV. Cardiogenic impedance signals can be used to optimize CRT settings but seem less feasible as an ambulatory tool since calibration is required. The positive correlation between aortic VTI and CI measurements seems promising, although a larger cohort is required to create an echocardiography-based patient-specific model. 23822198 Monolayer properties of 1,3-diamidophospholipids. While nature provides an endless variety of phospholipids presenting hydrolyzable ester linkages for the 1,2-positioned hydrocarbon tails, we designed and synthesized 1,3-diamidophospholipids which contain stable fatty acid amides. These new phospholipids form faceted unilamellar vesicles with mechanosensitive properties. Aiming to understand the mechanism responsible for this behavior at a molecular level, we investigated the 1,3-diamidophospholipid family in monolayers, a simplified model membrane system. Langmuir isotherms combined with in situ grazing incidence X-ray diffraction (GIXD), specular X-ray reflectivity (XR), and infrared reflection-absorption spectroscopy (IRRAS) allowed the characterization of the monolayers from a structural and thermodynamical point of view. The existence of strong headgroup interactions due to the formation of a hydrogen-bonding network was clearly revealed by IRRAS and by the high rigidity of the monolayers. GIXD showed that only the longer chain compounds of the series (Pad-PC-Pad (1,3-dipalmitamidopropan-2-phosphocholine) and Sad-PC-Sad (1,3-distearamidopropan-2-phosphocholine) were able to form ordered monolayers. The chains are strongly tilted in a rigid lattice formed due to these hydrogen-bonding interactions between the headgroups. The thermodynamical analysis leads to a critical temperature of the monolayer which is clearly different from the main phase transition temperature in bulk, indicating that there must be a different structural arrangement of the 1,3-diamidophospholipids in monolayers and in bilayers. 23943091 Calmodulin-like protein AtCML3 mediates dimerization of peroxisomal processing protease AtDEG15 and contributes to normal peroxisome metabolism. Matrix enzymes are imported into peroxisomes and glyoxysomes, a subclass of peroxisomes involved in lipid mobilization. Two peroxisomal targeting signals (PTS), the C-terminal PTS1 and the N-terminal PTS2, mediate the translocation of proteins into the organelle. PTS2 processing upon import is conserved in higher eukaryotes, and in watermelon the glyoxysomal processing protease (GPP) was shown to catalyse PTS2 processing. GPP and its ortholog, the peroxisomal DEG protease from Arabidopsis thaliana (AtDEG15), belong to the Deg/HtrA family of ATP-independent serine proteases with Escherichia coli DegP as their prototype. GPP existes in monomeric and dimeric forms. Their equilibrium is shifted towards the monomer upon Ca(2+)-removal and towards the dimer upon Ca(2+)-addition, which is accompanied by a change in substrate specificity from a general protease (monomer) to the specific cleavage of the PTS2 (dimer). We describe the Ca(2+)/calmodulin (CaM) mediated dimerization of AtDEG15. Dimerization is mediated by the CaM-like protein AtCML3 as shown by yeast two and three hybrid analyses. The binding of AtCML3 occurs within the first 25 N-terminal amino acids of AtDEG15, a domain containing a predicted CaM-binding motif. Biochemical analysis of AtDEG15 deletion constructs in planta support the requirement of the CaM-binding domain for PTS2 processing. Phylogenetic analyses indicate that the CaM-binding site is conserved in peroxisomal processing proteases of higher plants (dicots, monocots) but not present in orthologs of animals or cellular slime molds. Despite normal PTS2 processing activity, an atcml3 mutant exhibited reduced 2,4-DB sensitivity, a phenotype previously reported for the atdeg15 mutant, indicating similarly impaired peroxisome metabolism. 23532913 Social anxiety in physical activity participation in patients with mental illness: a cross-sectional multicenter study. Social anxiety (SA) is a frequent comorbid condition in patients with mental illness. However, no data exist regarding SA in physical activity (PA) situations. The aim of the present study was to measure the level of self-reported SA in PA participation in patients with mental illness compared to healthy controls. Six hundred ninety-three patients with mental illness and 2,888 controls aged between 18 and 65 years completed the Physical Activity and Sport Anxiety Scale (PASAS). Group and gender differences in PASAS scores were tested by ANOVA and Scheffé's post hoc test. After controlling for gender (P < .05), the patient group (men 40.2 ± 14.4; women 49.2 ± 17) scored higher on the PASAS compared to control group (men 30.6 ± 12.2; women 37.3 ± 13.7). Within both groups, women reported higher levels of SA compared to men. Our data indicate that patients with mental illness reported higher levels of SA in PA situations compared to healthy control subjects. Health professionals should consider SA when trying to improve outcome and adherence of patients with mental illness to PA interventions. 23856313 Biodegradation characteristics and size fractionation of landfill leachate for integrated membrane treatment. The fate of organics and nitrogen during the biological treatment with MBR and subsequent membrane filtration processes (nano filtration, NF; reverse osmosis, RO) were investigated for a landfill leachate. The chemical oxygen demand (COD) and total Kjeldahl nitrogen (TKN) removal performances of membrane bioreactor (MBR) were obtained to be around 89% and 85%, respectively. The effluent COD of MBR was measured to be 1935mg/L (30kDa) which is much lower than experimentally determined soluble inert COD of 3200mg/L using 0.45μm filter. The readily and slowly biodegradable COD fractions were estimated to be 17% and 52% of raw influent COD, respectively. The respirometry based modeling test performed on raw leachate exhibited much slower degradation kinetics compared to municipal wastewater. A unique subset of model parameters was extracted from batch respirometry by using acclimated MBR sludge. The sequential ultrafiltration (UF) experiments (particle size distribution, PSD) revealed that most of the organics was below 2nm filter mesh size. In addition, NF/RO post treatment after MBR system was required to increase COD and total nitrogen (TN) removal performances up to 99%. Relatively lower salt rejection rates around 94% was obtained for RO system as a post treatment of MBR system. 23746784 Novel chlorinated dibenzofurans isolated from the cellular slime mold, Polysphondylium filamentosum, and their biological activities. Cellular slime molds are expected to have the huge potential for producing secondary metabolites including polyketides, and we have studied the diversity of secondary metabolites of cellular slime molds for their potential utilization as new biological resources for natural product chemistry. From the methanol extract of fruiting bodies of Polysphondylium filamentosum, we obtained new chlorinated benzofurans Pf-1 (4) and Pf-2 (5) which display multiple biological activities; these include stalk cell differentiation-inducing activity in the well-studied cellular slime mold, Dictyostelium discoideum, and inhibitory activities on cell proliferation in mammalian cells and gene expression in Drosophila melanogaster. 23792943 Signals in inferotemporal and perirhinal cortex suggest an untangling of visual target information. Finding sought visual targets requires our brains to flexibly combine working memory information about what we are looking for with visual information about what we are looking at. To investigate the neural computations involved in finding visual targets, we recorded neural responses in inferotemporal cortex (IT) and perirhinal cortex (PRH) as macaque monkeys performed a task that required them to find targets in sequences of distractors. We found similar amounts of total task-specific information in both areas; however, information about whether a target was in view was more accessible using a linear read-out or, equivalently, was more untangled in PRH. Consistent with the flow of information from IT to PRH, we also found that task-relevant information arrived earlier in IT. PRH responses were well-described by a functional model in which computations in PRH untangle input from IT by combining neurons with asymmetric tuning correlations for target matches and distractors. 23939698 Thyroid nodules. Thyroid nodules are a common finding in the general population. They may present with symptoms of pressure in the neck or may be discovered during physical examination. Although the risk of cancer is small, it is the main reason for workup of these lesions. Measurement of thyroid-stimulating hormone can identify conditions that may cause hyperfunctioning of the thyroid. For all other conditions, ultrasonography and fine-needle aspiration are central to the diagnosis. Lesions larger than 1 cm should be biopsied. Lesions with features suggestive of malignancy and those in patients with risk factors for thyroid cancer should be biopsied, regardless of size. Smaller lesions and those with benign histology can be followed and reevaluated if they grow. The evaluation of thyroid nodules in euthyroid and hypothyroid pregnant women is the same as in other adults. Thyroid nodules are uncommon in children, but the malignancy rate is much higher than in adults. Fine-needle aspiration is less accurate in children, so more aggressive surgical excision may be preferable. 23553052 Plasmacytoid, conventional, and monocyte-derived dendritic cells undergo a profound and convergent genetic reprogramming during their maturation. DCs express receptors sensing microbial, danger or cytokine signals, which when triggered in combination drive DC maturation and functional polarization. Maturation was proposed to result from a discrete number of modifications in conventional DCs (cDCs), in contrast to a cell-fate conversion in plasmacytoid DCs (pDCs). cDC maturation is generally assessed by measuring cytokine production and membrane expression of MHC class II and co-stimulation molecules. pDC maturation complexity was demonstrated by functional genomics. Here, pDCs and cDCs were shown to undergo profound and convergent changes in their gene expression programs in vivo during viral infection. This observation was generalized to other stimulation conditions and DC subsets, by public microarray data analyses, PCR confirmation of selected gene expression profiles, and gene regulatory sequence bioinformatics analyses. Thus, maturation is a complex process similarly reshaping all DC subsets, including through the induction of a core set of NF-κB- or IFN-stimulated genes irrespective of stimuli. 23244684 Band gap engineering via controlling donor-acceptor compositions in conjugated copolymers. Varying composition of π-donor/acceptor moieties has been considered as an effective strategy for fine-tuning of the electronic properties of D-A conjugated copolymers. In this study, the change of optoelectronic properties with the change of donor/acceptor ratios is investigated on the basis of first-principles density functional calculations. Copolymers containing moieties of similar π-electron donating and/or accepting capabilities, e.g., thiophene (T)-methoxythiophene (OT), exhibit a linear dependence of electronic properties (especially, HOMO/LUMO, band gap, and bandwidth) on the D/A content. In contrast, for strong D/A contrast systems, e.g., thiophene (T)-thienopyrazine (TP), the electronic properties vary nonlinearly with D/A compositions. However, when the block size of one parent monomer in a strong D/A contrast system is fixed, the variation of electronic properties shows a remarkable linear correlation against D/A compositions. We found that the deviation of electronic properties from a linear composition dependence is dominated by the strength of orbital interactions between D and A. Weak orbital interactions between D and A moieties tend to lead to a nonlinear composition dependence. Our results provide useful insights for band gap tuning through the adjustment of D/A compositions in D-A conjugated copolymers. 23922901 Spatiotemporal Expression of Matrix Metalloproteinases (MMPs) is Regulated by the Ca(2+)-Signal Transducer S100A4 in the Pathogenesis of Thoracic Aortic Aneurysm. This study investigated whether S100A4 plays a potential role in the formation of thoracic aortic aneurysm (TAA). The thoracic aortas of male Sprague-Dawley rats were exposed to 0.5 M CaCl2 or normal saline (NaCl). Animals were euthanized at specified time-points (2, 4, and 10 weeks post-TAA induction). The treated aortic segments were harvested, and mRNA levels, protein expressions and immunohistochemistry of MMP-2, MMP-9 and S100A4 were analyzed. The A7r5 cell lines were used for an in vitro study. Experiments were also performed using human TAA samples for comparison. Localized aneurysmal dilation was observed in the CaCl2-treated segments. The transcription levels of S100A4 and MMPs were elevated in CaCl2-treated segments versus controls, and a significant correlation between S100A4 and expression of MMPs was observed across all time-points. Immunohistochemical studies revealed similar expression pattern of S100A4 and MMP proteins, as well as co-localization of S100A4 with the cell lineage markers (αSMA and CD68) and inflammatory markers (MMPs and NF-κB P65 subunit). The proliferative ability of A7r5 cells after transfection with S100A4 siRNA was suppressed, and down-regulation of S100A4 inhibited MMP-2 and MMP-9 expression in vitro. Increased expression of S100A4 was observed in all layers of the aorta wall in human TAA specimens. Serum concentrations of S100A4 determined by ELISA were found to be significantly increased in TAA patients. This study established the important roles of S100A4 and MMPs in the development of TAA. 23692073 The cannabinoid-1 receptor inverse agonist taranabant reduces abdominal pain and increases intestinal transit in mice. Constipation-predominant irritable bowel syndrome (IBS-C) is a common functional gastrointestinal (GI) disorder with abdominal pain and decreased motility. Current treatments of IBS-C are insufficient. The aim of this study was to evaluate the potential application of taranabant, a cannabinoid type 1 (CB1) inverse agonist using mouse models mimicking the symptoms of IBS-C. Changes in intestinal contractile activity were studied in vitro, using isolated mouse ileum and colon and intracellular recordings. In vivo, whole gastrointestinal transit (WGT) and fecal pellet output (FPO) were measured under standard conditions and with pharmacologically delayed GI transit. The antinociceptive effect was evaluated in mustard oil- and acetic acid-induced models of visceral pain. Forced swimming and tail suspension tests were performed and locomotor activity was measured to evaluate potential central side effects. In vitro, taranabant (10(-10) -10(-7) mol L(-1)) increased contractile responses in mouse ileum and blocked the effect of the CB agonist WIN 55,212-2. Taranabant had no effect on the amplitude of electrical field stimulation (EFS)-evoked junction potentials. In vivo, taranabant (0.1-3 mg kg(-1), i.p. and 3 mg kg(-1), p.o.) increased WGT and FPO in mice and reversed experimental constipation. The effect of taranabant was absent in CB1(-/-) mice. Taranabant significantly decreased the number of pain-related behaviors in animal models. At the doses tested, taranabant did not display mood-related adverse side effects typical for CB1 receptor inverse agonists. Taranabant improved symptoms related to slow GI motility and abdominal pain and may become an attractive template in the development of novel therapeutics targeting IBS-C. 23846829 Developing Measures of Community-Relevant Outcomes for Violence Prevention Programs: A Community-Based Participatory Research Approach to Measurement. Community-Based Participatory Research is a research paradigm that encourages community participation in designing and implementing evaluation research, though the actual outcome measures usually reflect the "external" academic researchers' view of program effect and the policy-makers' needs for decision-making. This paper describes a replicable process by which existing standardized psychometric scales commonly used in youth-related intervention programs were modified to measure indicators of program success defined by community partners. This study utilizes a secondary analysis of data gathered in the context of a community-based youth violence prevention program. Data were retooled into new measures developed using items from the Alabama Parenting Questionnaire, the Hare Area Specific Self-Esteem Scale, and the Youth Asset Survey. These measures evaluated two community-defined outcome indicators, "More Parental Involvement" and "Showing Kids Love." Results showed that existing scale items can be re-organized to create measures of community-defined outcomes that are psychometrically reliable and valid. Results also show that the community definitions of parent or parenting caregivers exemplified by the two indicators are similar to how these constructs have been defined in previous research, but they are not synonymous. There are nuanced differences that are important and worthy of better understanding, in part through better measurement. 23666162 High glycolytic potential does not predict low ultimate pH in pork. Extent of postmortem pH decline influences meat quality development. To better understand physiological determination of ultimate pH (pHu), we utilized female and castrated male pigs from a line whose selection index includes differentiated pHu. All genotypes of AMP-activated protein kinase γ3 subunit (AMPKγ3) V199I site were present. The mutant 199II genotype increased pHu, but only in castrated males. Genotype affected glycolytic potential (GP), but GP was weakly associated with pHu. A subset of animals was selected based on low (-Gly) and high (+Gly) residual glycogen content, and compared with AMPKγ3 200Q, which is associated with low pHu. Both +Gly and 200Q muscle contained glycolytic substrate at 24h; however, 200Q muscle generated low pHu and greater lactate compared to +Gly. Additionally,-Gly and +Gly groups exhibited similar pHu despite a large difference in GP. In conclusion, high GP does not appear to directly impact the extent of postmortem pH decline. 23969886 Hydrodynamic immunization leads to poor CD8 T-cell expansion, low frequency of memory CTLs and ineffective antiviral protection. Hepatotropic pathogens, such as hepatitis B (HBV) and hepatitis C (HCV), often escape cellular immune clearance resulting in chronic infection. As HBV and HCV infections are the most common causes of hepatocellular carcinoma (HCC), prevention of these infections is believed to be key to the prevention of HCC. It is believed that an effective immune therapy must induce strong cytotonic T lymphocytes (CTLs) that can migrate into the liver, where they can clear infected hepatocytes. Here, we compared the induction of CD8 T cells by two different DNA immunization methods for T-cell differentiation, function, memory programming and their distribution within relevant tissues in a highly controlled fashion. We used hydrodynamic tail vein injection of plasmid to establish liver-specific LCMV-gp antigen (Ag) transient expression, and studied CD8 T cells induced using the P14 transgenic mouse model. CD8 T cells from this group exhibited unique and limited expansion, memory differentiation, polyfunctionality and cytotoxicity compared with T cells generated in intramuscularly immunized mice. This difference in liver-generated expansion resulted in lower memory CD8 T-cell frequency, leading to reduced protection against lethal viral challenge. These data show an unusual induction of naive CD8 T cells contributed to the lower frequency of Ag-specific CTLs observed after immunization in the liver, suggesting that limited priming in liver compared with peripheral tissues is responsible for this outcome.Cancer Gene Therapy advance online publication, 23 August 2013; doi:10.1038/cgt.2013.52. 23776179 Identification and prioritization of merozoite antigens as targets of protective human immunity to Plasmodium falciparum malaria for vaccine and biomarker development. The development of effective malaria vaccines and immune biomarkers of malaria is a high priority for malaria control and elimination. Ags expressed by merozoites of Plasmodium falciparum are likely to be important targets of human immunity and are promising vaccine candidates, but very few Ags have been studied. We developed an approach to assess Ab responses to a comprehensive repertoire of merozoite proteins and investigate whether they are targets of protective Abs. We expressed 91 recombinant proteins, located on the merozoite surface or within invasion organelles, and screened them for quality and reactivity to human Abs. Subsequently, Abs to 46 proteins were studied in a longitudinal cohort of 206 Papua New Guinean children to define Ab acquisition and associations with protective immunity. Ab responses were higher among older children and those with active parasitemia. High-level Ab responses to rhoptry and microneme proteins that function in erythrocyte invasion were identified as being most strongly associated with protective immunity compared with other Ags. Additionally, Abs to new or understudied Ags were more strongly associated with protection than were Abs to current vaccine candidates that have progressed to phase 1 or 2 vaccine trials. Combinations of Ab responses were identified that were more strongly associated with protective immunity than responses to their single-Ag components. This study identifies Ags that are likely to be key targets of protective human immunity and facilitates the prioritization of Ags for further evaluation as vaccine candidates and/or for use as biomarkers of immunity in malaria surveillance and control. 23929523 A single-blind randomized controlled trial to evaluate the effect of 6 months of progressive aerobic exercise training in patients with uraemic restless legs syndrome. Uraemic restless legs syndrome (RLS) affects a significant proportion of patients receiving haemodialysis (HD) therapy. Exercise training has been shown to improve RLS symptoms in uraemic RLS patients; however, the mechanism of exercise-induced changes in RLS severity is still unknown. The aim of the current randomized controlled exercise trial was to investigate whether the reduction of RLS severity, often seen after training, is due to expected systemic exercise adaptations or it is mainly due to the relief that leg movements confer during exercise training on a cycle ergometer. This is the first randomized controlled exercise study in uraemic RLS patients. Twenty-four RLS HD patients were randomly assigned to two groups: the progressive exercise training group (n = 12) and the control exercise with no resistance group (n = 12). The exercise session in both groups included intradialytic cycling for 45 min at 50 rpm. However, only in the progressive exercise training group was resistance applied, at 60-65% of maximum exercise capacity, which was reassessed every 4 weeks to account for the patients' improvement. The severity of RLS symptoms was evaluated using the IRLSSG severity scale, functional capacity by a battery of tests, while sleep quality, depression levels and daily sleepiness status were assessed via validated questionnaires, before and after the intervention period. All patients completed the exercise programme with no adverse effects. RLS symptom severity declined by 58% (P = 0.003) in the progressive exercise training group, while a no statistically significant decline was observed in the control group (17% change, P = 0.124). Exercise training was also effective in terms of improving functional capacity (P = 0.04), sleep quality (P = 0.038) and depression score (P = 0.000) in HD patients, while no significant changes were observed in the control group. After 6 months of the intervention, RLS severity (P = 0.017), depression score (P = 0.002) and daily sleepiness status (P = 0.05) appeared to be significantly better in the progressive exercise group compared with the control group. A 6-month intradialytic progressive exercise training programme appears to be a safe and effective approach in reducing RLS symptom severity in HD patients. It seems that exercise-induced adaptations to the whole body are mostly responsible for the reduction in RLS severity score, since the exercise with no applied resistance protocol failed to improve the RLS severity status of the patients. NCT00942253. 23494657 A decision analysis tool for the assessment of posterior fossa tumour surgery outcomes in children-the "Liverpool Neurosurgical Complication Causality Assessment Tool". Complications may occur following posterior fossa tumour surgery in children. Such complications are subjectively and inconsistently reported even though they may have significant long-term behavioural and cognitive consequences for the child. This makes comparison of surgeons, programmes and treatments problematic. We have devised a causality tool for assessing if an adverse event after surgery can be classified as a surgical complication using a series of simple questions, based on a tool used in assessing adverse drug reactions. This tool, which we have called the "Liverpool Neurosurgical Complication Causality Assessment Tool", was developed by reviewing a series of ten posterior fossa tumour cases with a panel of neurosurgery, neurology, oncology and neuropsychology specialists working in a multidisciplinary paediatric tumour treatment programme. We have demonstrated its use and hope that it may improve reliability between different assessors both in evaluating the outcomes of existing programmes and treatments as well as aiding in trials which may directly compare the effects of surgical and medical treatments. 23220104 Micelles of zinc protoporphyrin conjugated to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer for imaging and light-induced antitumor effects in vivo. We synthesized N-(2-hydroxypropyl)methacrylamide polymer conjugated with zinc protoporphyrin (HPMA-ZnPP) and evaluated its application for tumor detection by imaging and treatment by light exposure using in mouse sarcoma model. To characterize HPMA-ZnPP micelle, we measured its micellar size, surface charge, stability, photochemical, biochemical properties and tissue distribution. In vivo anti-tumor effect and fluorescence imaging were carried out to validate the tumor selective accumulation and therapeutic effect by inducing singlet oxygen by light exposure. HPMA-ZnPP was highly water soluble and formed micelles spontaneously having hydrophobic clustered head group of ZnPP, in aqueous solution, with a hydrodynamic diameter of 82.8±41.8 nm and zeta-potential of +1.12 mV. HPMA-ZnPP had a long plasma half-life and effectively and selectively accumulated in tumors. Although HPMA-ZnPP alone had no toxicity in S-180 tumor-bearing mice, light-irradiation significantly suppressed tumor growth in vivo, similar to the cytotoxicity to HeLa cells in vitro upon endoscopic light-irradiation. HPMA-ZnPP can visualize tumors by fluorescence after i.v. injection, which suggests that this micelle may be useful for both tumor imaging and therapy. Here we describe preparation of a new fluorescence nanoprobe that is useful for simultaneous tumor imaging and treatment, and application to fluorescence endoscopy is now at visible distance. 22828795 Long-term changes in neointimal hyperplasia following implantation of bare metal stents assessed by integrated backscatter intravascular ultrasound. In-stent restenosis (ISR) is a common phenomenon with bare metal stents (BMSs) in the early stage after implantation. However, ISR occurs at a lower rate with long time after BMS implantation. We assessed changes over time in neointimal hyperplasia following BMS implantation using integrated backscatter intravascular ultrasound (IB-IUVS). Thirty-six patients who received target lesion revascularization (TLR) to treat ISR were classified according to the duration of the interval between stent implantation and TLR: the early group (within first year n = 25) and the VL group (very late ISR ≥5 years, n = 11). IB-IUVS was used to evaluate within-stent sites from the proximal to the distal edge of the stent. IB-IVUS color maps were then constructed by tracing the stent struts and vessel lumen. Neointimal tissue was classified as high-IB (IB <-29 dB; a representative cord of calcification), middle-IB (-49 dB â‰¤ IB < -29 dB; fibrosis), or low-IB (-49 dB â‰¤ IB; lipid pool). We compared percent (%) volume, average %area of cross-sectional area (CSA), and %area of minimum CSA of each component between the groups. There were no significant differences in %volume, average %area of CSA, or %area of minimum CSA for the high-IB component between groups. The %low-IB components were 20.0 ± 8.8 % for volume, 20.1 ± 8.9 % for mean CSA, and 17.6 ± 8.5 % for minimum CSA in the early group. On the other hand, in the VL group, the %low-IB components were significantly increased to 31.8 ± 7.9 % for volume (p < 0.01 vs. the early group), 31.2 ± 7.6 % for mean CSA (p < 0.01 vs. the early group), and 33.1 ± 12.3 % for minimum CSA (p < 0.01 vs. the early group). By contrast, the %middle-IB component showed a reduction in extended time, with %volume of the middle-IB decreasing from 78.3 ± 8.1 to 66.4 ± 7.1 %, average mean %area of CSA from 78.2 ± 8.2 to 66.9 ± 6.9 %, and % area of minimum CSA from 80.7 ± 7.9 to 65.5 ± 11.4 % (p < 0.01;. the early vs. the VL group). Our results suggest that in-stent neointimal tissues developing over time consist of an increased low-IB component and a decreased middle-IB component and may contribute an increased of lipidemic component and a decreased of fibrotic component. 23836949 Rectangular groupoids and related structures. The quasivariety of groupoids [Formula: see text] satisfying the implication [Formula: see text] generalises rectangular semigroups and central groupoids. We call them rectangular groupoids and find three combinatorial structures based upon arrays, matrices and graphs that are closely related. These generalise several groupoids of independent interest. The quasivariety generates the variety of all groupoids; they satisfy no nontrivial equations. We see some strong connections with isotopy, this being one of the classes of algebras (along with quasigroups) closed under isotopy. We investigate some constructions and show that a regular automorphism exists iff the groupoid is derived from a group via a Cayley graph construction. 23892687 Synergistic Thrombotic Risk of Antibodies Against Phosphatidylserine and Prothrombin and β-2-Glycoprotein I. Background: Coagulation and anticoagulation systems are good targets of antiphospholipid antibodies. We assessed the contribution of the antiphospholipid antibodies to the thrombotic risk. Methods: Enzyme-linked immunosorbent assays on antibodies against phosphatidylserine and prothrombin (PS/PT), protein C, protein S, protein Z, and thrombomodulin were performed in 164 patients who showed positive results for lupus anticoagulant or anticardiolipin antibody. Results: Anti-β-2-glycoprotein I (β2GPI) and anti-PS/PT were significant risk factors for thrombotic events (P < .001, P = .049). However, there was no association between antiprotein C, antiprotein S, antiprotein Z, or antithrombomodulin and thrombosis. Coexistence of anti-β2GPI and anti-PS/PT antibodies was significantly associated with thrombotic events (P = .001). Interestingly, the absence of both anti-β2GPI and anti-PS/PT antibodies was a significant preventive factor for thrombosis (P = .003). Conclusion: Our data show a lack of association of antiprotein C, antiprotein S, antiprotein Z, and antithrombomodulin antibodies with thrombosis. However, the combination of conventional anti-β2GPI with anti-PS/PT antibody is expected to enhance the predicting power of thrombotic risk. 23314320 A physiologically based pharmacokinetic model for the oxime TMB-4: simulation of rodent and human data. Multiple oximes have been synthesized and evaluated for use as countermeasures against chemical warfare nerve agents. The current U.S. military and civilian oxime countermeasure, 2-[(hydroxyimino)methyl]-1-methylpyridin-1-ium chloride (2-PAM), is under consideration for replacement with a more effective acetylcholinesterase reactivator, 1,1'-methylenebis{4-hydroxyiminomethyl}pyridinium dimethanesulfonate (MMB-4). Kinetic data in the scientific literature for MMB-4 are limited; therefore, a physiologically based pharmacokinetic (PBPK) model was developed for a structurally related oxime, 1,1'-trimethylenebis{4-hydroximinomethyl}pyridinium dibromide. Based on a previous model structure for the organophosphate diisopropylfluorophosphate, the model includes key sites of acetylcholinesterase inhibition (brain and diaphragm), as well as fat, kidney, liver, rapidly perfused tissues and slowly perfused tissues. All tissue compartments are diffusion limited. Model parameters were collected from the literature, predicted using quantitative structure-property relationships or, when necessary, fit to available pharmacokinetic data from the literature. The model was parameterized using rat plasma, tissue and urine time course data from intramuscular administration, as well as human blood and urine data from intravenous and intramuscular administration; sensitivity analyses were performed. The PBPK model successfully simulates rat and human data sets and has been evaluated by predicting intravenous mouse and intramuscular human data not used in the development of the model. Monte Carlo analyses were performed to quantify human population kinetic variability in the human evaluation data set. The model identifies potential pharmacokinetic differences between rodents and humans, indicated by differences in model parameters between species. The PBPK model can be used to optimize the dosing regimen to improve oxime therapeutic efficacy in a human population. 23712835 Iodine excess induces hepatic steatosis through disturbance of thyroid hormone metabolism involving oxidative stress in BALB/c mice. Iodine excess is emerging as a new focus. A better understanding of its hazardous effects on the liver will be of great benefit to health. The aim of this study is to illustrate the effects of iodine excess on hepatic lipid homeostasis and explore its possible mechanisms. One hundred twenty BaLB/c mice were given iodine at different levels (0, 0.3, 0.6, 1.2, 2.4, and 4.8 mg I/L) in drinking water for 1 or 3 months. Lipid parameters and serum thyroid hormones were measured. Hepatic type 1 deiodinase activity and oxidative stress parameters were evaluated. The mRNA expression of sterol regulatory element-binding protein-1c (SREBP-1c) and fatty acid synthase (FAS) was detected by real-time polymerase chain reaction. Dose-dependent increase of hepatic triglyceride content was detected (r = 0.680, P < 0.01) in iodine-loaded groups. Evident hepatic steatosis was observed in 2.4 and 4.8 mg I/L iodine-loaded groups. The activities of antioxidant enzymes (glutathione peroxidase and superoxide dismutase) were decreased, and the malondialdehyde level was increased by excessive iodine in both serum and liver in a dose-dependent manner, accompanying the decrease of hepatic D1 activity. That resulted in the increase of serum total thyroxine and the decrease of serum total triiodothyronine in iodine-loaded groups. The mRNA expression of SREBP-1c and FAS was increased in iodine-loaded groups in response to the change of serum triiodothyronine. Present findings demonstrated that iodine excess could dose dependently induce hepatic steatosis. Furthermore, our data suggested that the disturbance of thyroid hormone metabolism involving oxidative stress may play a critical role in iodine excess-induced hepatic steatosis. 23668967 Connectivity-based neurofeedback: Dynamic causal modeling for real-time fMRI. Neurofeedback based on real-time fMRI is an emerging technique that can be used to train voluntary control of brain activity. Such brain training has been shown to lead to behavioral effects that are specific to the functional role of the targeted brain area. However, real-time fMRI-based neurofeedback so far was limited to mainly training localized brain activity within a region of interest. Here, we overcome this limitation by presenting near real-time dynamic causal modeling in order to provide feedback information based on connectivity between brain areas rather than activity within a single brain area. Using a visual-spatial attention paradigm, we show that participants can voluntarily control a feedback signal that is based on the Bayesian model comparison between two predefined model alternatives, i.e. the connectivity between left visual cortex and left parietal cortex vs. the connectivity between right visual cortex and right parietal cortex. Our new approach thus allows for training voluntary control over specific functional brain networks. Because most mental functions and most neurological disorders are associated with network activity rather than with activity in a single brain region, this novel approach is an important methodological innovation in order to more directly target functionally relevant brain networks. 23924705 Analysis of the genetic diversity of the nematode parasite Baylisascaris schroederi from wild giant pandas in different mountain ranges in China. Baylisascaris schroederi is one of the most common nematodes of the giant panda, and can cause severe baylisascarosis in both wild and captive giant pandas. Previous studies of the giant pandas indicated that this population is genetically distinct, implying the presence of a new subspecies. Based on the co-evolution between the parasite and the host, the aim of this study was to investigate the genetic differentiation in the B. schroederi population collected from giant pandas inhabiting different mountain ranges, and further to identify whether the evolution of this parasite correlates with the evolution of giant pandas. In this study, 48 B. schroederi were collected from 28 wild giant pandas inhabiting the Qinling, Minshan and Qionglai mountain ranges in China. The complete sequence of the mitochondrial cytochrome b (mtCytb) gene was amplified by PCR, and the corresponding population genetic diversity of the three mountain populations was determined. In addition, we discussed the evolutionary relationship between B. schroederi and its host giant panda. For the DNA dataset, insignificant Fst values and a significant, high level of gene flow were detected among the three mountain populations of B. schroederi, and high genetic variation within populations and a low genetic distance were observed. Both phylogenetic analyses and network mapping of the 16 haplotypes revealed a dispersed pattern and an absence of branches strictly corresponding to the three mountain range sampling sites. Neutrality tests and mismatch analysis indicated that B. schroederi experienced a population expansion in the past. Taken together, the dispersed haplotype map, extremely high gene flow among the three populations of B. schroederi, low genetic structure and rapid evolutionary rate suggest that the B. schroederi populations did not follow a pattern of isolation by distance, indicating the existence of physical connections before these populations became geographically separated. 23879520 PTP1B: A simple enzyme for a complex world. Abstract Our understanding of the fundamental regulatory roles that tyrosine phosphatases play within cells has advanced significantly in the last two decades. Out-dated ideas that tyrosine phosphatases acts solely as the "off" switch counterbalancing the action of tyrosine kinases has proved to be flawed. PTP1B is the most characterized of all the tyrosine phosphatases and it acts as a critical negative and positive regulator of numerous signaling cascades. PTP1B's direct regulation of the insulin and the leptin receptors makes it an ideal therapeutic target for type II diabetes and obesity. Moreover, the last decade has also seen several reports establishing PTP1B as key player in cancer serving as both tumor suppressor and tumor promoter depending on the cellular context. Despite many key advances in these fields one largely ignored area is what role PTP1B may play in the modulation of immune signaling. The important recognition that PTP1B is a major negative regulator of Janus kinase - signal transducer and activator of transcription (JAK-STAT) signaling throughout evolution places it as a key link between metabolic diseases and inflammation, as well as a unique regulator between immune response and cancer. This review looks at the emergence of PTP1B through evolution, and then explore at the cell and systemic levels how it is controlled physiologically. The second half of the review will focus on the role(s) PTP1B can play in disease and in particular its involvement in metabolic syndromes and cancer. Finally we will briefly examine several novel directions in the development of PTP1B pharmacological inhibitors. 23343596 Personality and the acute subjective effects of d-amphetamine in humans. There is evidence that subjective responses to psychoactive drugs are related to personality traits. Here, we extend previous findings by examining personality measures in relation to acute responses to d-amphetamine (AMPH) in a large sample of healthy volunteers. Healthy adults (n=286) completed the Multidimensional Personality Questionnaire Brief Form (MPQ-BF) and participated in four sessions during which they received oral AMPH (0, 5, 10, 20 mg), under double-blind conditions. Subjective responses to the drug were measured using the Profile of Mood States, Addiction Research Center Inventory, and Drug Effects Questionnaire. Drug responses were reduced via principal components analysis to three higher-order factors ('Euphoria', 'Arousal', 'Dysphoria'). Participants were rank ordered on selected MPQ-BF scales; the top and bottom third on each trait were compared on the drug response factors. High trait physical fearlessness was significantly associated with greater amphetamine-related Arousal, and high trait reward sensitivity was significantly associated with greater Euphoria. In addition, high trait impulsivity was significantly associated with greater Arousal and Euphoria. These results provide further evidence that individual differences in the subjective effects of AMPH are partially explained by differences in personality, and are consistent with the idea that both personality and responses to stimulants depend upon shared neurochemical systems. 23832181 Community level morbidity control of lymphoedema using self care and integrative treatment in two lymphatic filariasis endemic districts of South India: a non randomized interventional study. Currently there is no global program to manage lymphoedema as a result of lymphatic filariasis (LF). The primary aim of this study was to determine the efficacy of a previously proposed integrative treatment protocol, using locally available resources to address the morbidity, in a community village setting. Two LF endemic districts of south India, Gulbarga in Karnataka (GK) and Alleppey in Kerala (AK), were selected for the study. All known patients were invited to an LF camp. Patients with grade two late or three lymphoedema were enrolled. All patients were given training in the integrative procedure which involved patient education and the domiciliary protocol. A total of 730 patients (851 limbs) completed the three and half month follow up. There was a statistically significant (1%) reduction up to mid thigh level volume measurement for both small (0.7-1.1 liters) and large (1.8-5.0 liters) limbs, p < 0.000. In AK inflammatory episodes at the three months interval reduced from 37.5% (127 patients) to 28.3% (96 patients) and in GK from 37.6% (147 patients) to 10.2% (40 patients), p < 0.000. All patients had reduced bacterial entry points. There was an overall improvement in quality of life in all domains of LF specific quality of life questionnaire p < 0.000. Self care and integrative treatment is possible in resource poor Indian village settings. Further work is needed to explore factors leading to better compliance by randomizing the interventions such as washing and emollient compression vs Ayurvedic and yoga interventions before integrative treatment is considered for national health programmes in developing countries. 23159993 Development of STEADI: A Fall Prevention Resource for Health Care Providers. Falls among people aged ≥65 years are the leading cause of both injury deaths and emergency department visits for trauma. Research shows that many falls are preventable. In the clinical setting, an effective fall intervention involves assessing and addressing an individual's fall risk factors. This individualized approach is recommended in the American and British Geriatrics Societies' (AGS/BGS) practice guideline. This article describes the development of STEADI (Stopping Elderly Accidents, Deaths, and Injuries), a fall prevention tool kit that contains an array of health care provider resources for assessing and addressing fall risk in clinical settings. As researchers at the Centers for Disease Control and Prevention's Injury Center, we reviewed relevant literature and conducted in-depth interviews with health care providers to determine current knowledge and practices related to older adult fall prevention. We developed draft resources based on the AGS/BGS guideline, incorporated provider input, and addressed identified knowledge and practice gaps. Draft resources were reviewed by six focus groups of health care providers and revised. The completed STEADI tool kit, Preventing Falls in Older Patients-A Provider Tool Kit, is designed to help health care providers incorporate fall risk assessment and individualized fall interventions into routine clinical practice and to link clinical care with community-based fall prevention programs. 23749053 The interplay of hydrogen bonding and dispersion in phenol dimer and trimer: structures from broadband rotational spectroscopy. The structures of the phenol dimer and phenol trimer complexes in the gas phase have been determined using chirped-pulse Fourier transform microwave spectroscopy in the 2-8 GHz band. All fourteen (13)C and (18)O phenol dimer isotopologues were assigned in natural abundance. A full heavy atom experimental substitution structure was determined, and a least-squares fit ground state r0 structure was determined by proper constraint of the M06-2X/6-311++g(d,p) ab initio structure. The structure of phenol dimer features a water dimer-like hydrogen bond, as well as a cooperative contribution from inter-ring dispersion. Comparisons between the experimental structure and previously determined experimental structures, as well as ab initio structures from various levels of theory, are discussed. For phenol trimer, a C3 symmetric barrel-like structure is found, and an experimental substitution structure was determined via measurement of the six unique (13)C isotopologues. The least-squares fit rm((1)) structure reveals a similar interplay between hydrogen bonding and dispersion in the trimer, with water trimer-like hydrogen bonding and C-H···π interactions. 23917695 An Analysis of the Acoustic Input Impedance of the Ear. Ear canal acoustics was examined using a one-dimensional lossy transmission line with a distributed load impedance to model the ear. The acoustic input impedance of the ear was derived from sound pressure measurements in the ear canal of healthy human ears. A nonlinear least squares fit of the model to data generated estimates for ear canal radius, ear canal length, and quantified the resistance that would produce transmission losses. Derivation of ear canal radius has application to quantifying the impedance mismatch at the eardrum between the ear canal and the middle ear. The length of the ear canal was found, in general, to be longer than the length derived from the one-quarter wavelength standing wave frequency, consistent with the middle ear being mass-controlled at the standing wave frequency. Viscothermal losses in the ear canal, in some cases, may exceed that attributable to a smooth rigid wall. Resistance in the middle ear was found to contribute significantly to the total resistance. In effect, this analysis "reverse engineers" physical parameters of the ear from sound pressure measurements in the ear canal. 23883769 It takes two to talk: A second-person neuroscience approach to language learning. Language is a social act. We have previously argued that language remains embedded in sociality because the motivation to communicate exists only within a social context. Schilbach et al. underscore the importance of studying linguistic behavior from within the motivated, socially interactive frame in which it is learnt and used, as well as provide testable hypotheses for a participatory, second-person neuroscience approach to language learning. 23716052 Synergistic Activity of Colistin and Rifampin Combination against Multidrug-Resistant Acinetobacter baumannii in an In Vitro Pharmacokinetic/Pharmacodynamic Model. Combination therapy may be required for multidrug-resistant (MDR) Acinetobacter baumannii. This study systematically investigated bacterial killing and emergence of colistin resistance with colistin and rifampin combinations against MDR A. baumannii. Studies were conducted over 72 h in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model at inocula of ∼10(6) and ∼10(8) CFU/ml using two MDR clinical isolates of A. baumannii, FADDI-AB030 (colistin susceptible) and FADDI-AB156 (colistin resistant). Three combination regimens achieving clinically relevant concentrations (constant colistin concentration of 0.5, 2, or 5 mg/liter and a rifampin maximum concentration [Cmax] of 5 mg/liter every 24 hours; half-life, 3 h) were investigated. Microbiological response was measured by serial bacterial counts. Population analysis profiles assessed emergence of colistin resistance. Against both isolates, combinations resulted in substantially greater killing at the low inoculum; combinations containing 2 and 5 mg/liter colistin increased killing at the high inoculum. Combinations were additive or synergistic at 6, 24, 48, and 72 h with all colistin concentrations against FADDI-AB030 and FADDI-AB156 in, respectively, 8 and 11 of 12 cases (i.e., all 3 combinations) at the 10(6)-CFU/ml inoculum and 8 and 7 of 8 cases with the 2- and 5-mg/liter colistin regimens at the 10(8)-CFU/ml inoculum. For FADDI-AB156, killing by the combination was ∼2.5 to 7.5 and ∼2.5 to 5 log10 CFU/ml greater at the low inoculum (all colistin concentrations) and high inoculum (2 and 5 mg/liter colistin), respectively. Emergence of colistin-resistant subpopulations was completely suppressed in the colistin-susceptible isolate with all combinations at both inocula. Our study provides important information for optimizing colistin-rifampin combinations against colistin-susceptible and -resistant MDR A. baumannii. 23628501 Aging is not a barrier to muscle and redox adaptations: Applying the repeated eccentric exercise model. Despite the progress of analytic techniques and the refinement of study designs, striking disagreement exists among studies regarding the influence of exercise on muscle function and redox homeostasis in the elderly. The repeated eccentric exercise model was applied to produce long-lasting and extensive changes in redox biomarkers and to reveal more effectively the potential effects of aging on redox homeostasis. Ten young (20.6±0.5years) and ten elderly men (64.6±1.1years) underwent an isokinetic eccentric exercise session, which was repeated after three weeks. Muscle function/damage indices (torque, range of movement, muscle soreness and creatine kinase) and redox biomarkers (F2-isoprostanes, protein carbonyls, glutathione, catalase, superoxide dismutase, glutathione peroxidase, glucose-6-phosphate dehydrogenase, uric acid, bilirubin and albumin) were assessed in plasma, erythrocytes or urine pre-exercise, immediately post-exercise and at 2 and 4days post-exercise. As expected, the elderly group exhibited oxidative stress in baseline compared to the young group. Extensive muscle damage and extensive alterations in redox homeostasis appeared after the first bout of eccentric exercise. Noteworthy, the redox responses were similar between the age groups despite their differences in baseline values. Likewise, both age groups demonstrated blunted alterations in muscle damage and redox homeostasis after the second bout of eccentric exercise indicating adaptations from the first bout of exercise. Elderly individuals seem to be well fitted to participate in demanding physical activities without suffering detrimental effects on skeletal muscle and/or disturbances on redox homeostasis. The repeated eccentric exercise model may be a useful and practical physiological tool to study redox biology in humans. 23855747 Childbearing in adolescence: intergenerational dejà-vu? Evidence from a Brazilian birth cohort. Pregnancy in adolescence tends to repeat over generations. This event has been little studied in middle and low-income societies undergoing a rapid epidemiological transition. To assess this association it is important to adjust for socioeconomic conditions at different points in lifetime. Therefore, the aim of this study is to analyze the independent effect of adolescent childbearing in a generation on its recurrence in the subsequent generation, after adjusting for socioeconomic status at different points in life. The study was conducted on a prospective cohort of singleton liveborn females from the city of Ribeirão Preto, Brazil, evaluated in 1978/79, and their daughters assessed in 2002/04. A total of 1059 mother-daughter pairs were evaluated. The women who had their first childbirth before 20 years of age were considered to be adolescent mothers. The risk of childbearing in adolescence for the daughter was modeled as a function of the occurrence of teenage childbearing in her mother, after adjustment for socio-demographic variables in a Poisson regression model. The rate of childbearing during adolescence was 31.4% in 1978/79 and 17.1% in 2002/04. Among the daughters of the 1st generation adolescent mothers, this rate was 26.7%, as opposed to 12.7% among the daughters of non adolescent mothers. After adjustments the risk of adolescent childbearing for the 2nd generation was 35% higher for women whose mothers had been pregnant during adolescence - RR = 1.35 (95% CI 1.04-1.74). Adolescent childbearing in the 1st generation was a predictor of adolescent childbearing in the 2nd, regardless of socioeconomic factors determined at different points in lifetime. 23755833 Selectively targeting the toll-like receptor 9 (TLR9)--IRF 7 signaling pathway by polymer blend particles. Signaling through toll-like receptor 9 (TLR9) has been exploited for cancer therapy. The stimulation of TLR9 leads to two bifurcating signaling pathways - NF-κB-dependent pro-inflammatory cytokines pathway and IRF-7-dependent type I interferons (IFNs) pathway. In this study, we employ polymer blend particles to present the synthetic ligand, CpG oligonucleotides (CpG ODNs), to TLR9. The polymer blend particles are made from the blend of pH-insensitive and pH-sensitive copolymer. By tailoring the composition of the pH-sensitive polymer, CpG ODNs are presented to TLR9 in a way that only activates the IRF-7 signaling pathway. CpG ODNs have been used for cancer therapy in both preclinical and clinical studies. The selective activation of IRF-7 could potentially enhance the apoptosis of tumor cells and immunological control of tumor progression without inadvertently activating NF-κB-dependent oncogenesis. 23837566 Pomegranate peel attenuates aluminum-induced hepatorenal toxicity. Abstract The present study was undertaken to determine the potential role of methanolic extract of pomegranate peel (MEPP) in modulating aluminum chloride (AlCl3) induced hepatorenal toxicity in female rats. The effect of MEPP (200 mg/kg bwt) on AlCl3 (34 mg/kg bwt) induced hepatorenal toxicity, accumulation of aluminum (Al), hepatorenal functions and oxidant/antioxidant status of liver and kidney were determined. The changes of liver and kidney structures were investigated with hematoxline and eosin, in addition, anti-apoptotic effect of MEPP was analyzed by immunohistochemistry. The present study showed an indication of carcinogenicity in the AlCl3 treated group representing by an increase in tumor necrosis factor-α and angiogeninand inflammation by inducing an increase in prostaglandin E2 and F2α. MEPP protected liver and kidney through reduce the Al accumulation, stimulated antioxidant activities and elevated the anti-apoptotic protein namely Bcl-2. Therefore, these results indicated that methanolic extract of pomegranate peel has beneficial influences and could be able to inhibit Al-induced oxidative stress and histopathological alternations in liver and kidney of female rats, and these effects may be related to anti-apoptotic and antioxidants activities. 23797032 Roles of ChlR1 DNA helicase in replication recovery from DNA damage. The ChlR1 DNA helicase is mutated in Warsaw breakage syndrome characterized by developmental anomalies, chromosomal breakage, and sister chromatid cohesion defects. However, the mechanism by which ChlR1 preserves genomic integrity is largely unknown. Here, we describe the roles of ChlR1 in DNA replication recovery. We show that ChlR1 depletion renders human cells highly sensitive to cisplatin; an interstrand-crosslinking agent that causes stalled replication forks. ChlR1 depletion also causes accumulation of DNA damage in response to cisplatin, leading to a significant delay in resolution of DNA damage. We also report that ChlR1-depleted cells display defects in the repair of double-strand breaks induced by the I-PpoI endonuclease and bleomycin. Furthermore, we demonstrate that ChlR1-depeleted cells show significant delays in replication recovery after cisplatin treatment. Taken together, our results indicate that ChlR1 plays an important role in efficient DNA repair during DNA replication, which may facilitate efficient establishment of sister chromatid cohesion. 23701042 Direct comparisons of three alternative plasma fibrinogen assays with the von Clauss assay in prediction of cardiovascular disease and all-causes mortality: the Scottish Heart Health Extended Cohort. There is strong evidence from meta-analyses of prospective epidemiological studies that increasing plasma fibrinogen levels are associated with an increasing risk of cardiovascular disease (CVD) and all-cause mortality. However, there are few published direct comparisons of the several different available fibrinogen assays in association with CVD or mortality. We therefore prospectively compared the standardized von Clauss assay of clottable fibrinogen with three other assays: prothrombin time (PT)-derived clottable fibrinogen, immunonephelometric fibrinogen, and heat precipitable fibrinogen in the Scottish Heart Health Extended Cohort. Hazard ratios (HRs) for a standard deviation increase in fibrinogen for risk of CVD, adjusted for age and sex, were 1·17 (95% confidence interval [CI] 1·14; 1·21) for the von Clauss assay; 1·19 (1·06; 1·33) for the heat precipitation assay; 1·16 (1·01; 1·35) for the PT-derived assay; and 1·28 (1·10; 1·51) for the immunonephelometric assay. HRs for all-cause mortality were 1·21 (1·18; 1·24); 1·13 (1·01; 1·26), 1·17 (1·00; 1·37) and 1·17 (0·99; 1·39), respectively. No significant differences were observed between the assays in such comparisons. We therefore conclude that the choice between plasma fibrinogen assays in routine clinical haematology and biochemistry laboratories should depend on practical factors, and not on expected differences in the strength of associations. 23435516 Haploidentical hematopoietic SCT increases graft-versus-tumor effect against renal cell carcinoma. Allogeneic hematopoietic SCT (HSCT) has been shown to be an effective treatment option for advanced renal cell cancer (RCC). However, tumor resistance/relapse remains as the main post transplant issue. Therefore, enhancing graft-versus-tumor (GVT) activity without increasing GVHD is critical for improving the outcome of HSCT. We explored the GVT effect of haploidentical-SCT (haplo-SCT) against RCC in murine models. Lethally irradiated CB6F1 (H2K(b/d)) recipients were transplanted with T-cell-depleted BM cells from B6CBAF1 (H2K(b/k)) mice. Haplo-SCT combined with a low-dose haploidentical (HI) T-cell infusion (1 × 10(5)) successfully provided GVT activity without incurring GVHD. This effect elicited murine RCC growth control and consequently displayed a comparative survival advantage of haplo-SCT recipients when compared with MHC-matched (B6D2F1CB6F1) and parent-F1 (B6CB6F1) transplant recipients. Recipients of haplo-SCT had an increase in donor-derived splenic T-cell numbers, T-cell proliferation and IFN-γ-secreting donor-derived T-cells, a critical aspect for anti-tumor activity. The splenocytes from B6CBAF1 mice had a higher cytotoxicity against RENCA cells than the splenocytes from B6 and B6D2F1 donors after tumor challenge. These findings suggest that haplo-SCT might be an innovative immunotherapeutic platform for solid tumors, particularly for renal cell carcinoma. 23726226 Targeted drug delivery and cross-linking induced apoptosis with anti-CD37 based dual-ligand immunoliposomes in B chronic lymphocytic leukemia cells. Despite advances in chemo and immunotherapeutic agents for B chronic lymphocytic leukemia (B-CLL), the undesirable adverse side effects due to non-specific cellular uptake remain to be addressed. We identified anti-CD37 monoclonal antibody immunoliposomes (ILs) as vehicles for targeted delivery to B chronic lymphocytic leukemia cells. To achieve maximal benefits for all patients, a new strategy of dual-ligand immunoliposomes (dILs) was developed. A combinatorial antibody microarray technology was adapted to quickly identify optimal antibody combinations for individual patient cells. For proof-of-concept, a B-cell specific antibody, either anti-CD19 or anti-CD20, was combined with anti-CD37 to construct dILs with enhanced selectivity and efficacy. Consistent with data from the antibody microarray, these dILs provided highly specific targeting to both leukemia cell lines and B-CLL patient cells. Compared with the single antibody ILs, the anti-CD19/CD37 dILs clearly demonstrated superior delivery efficiency and apoptosis induction to B-CLL patient cells, whereas the anti-CD20/anti-CD37 dILs were found to be the most efficient for delivery to leukemia cell lines. In addition, it was observed that anti-CD37 ILs without payload drug mediated effective CD37 cross-linking and induced potent apoptosis induction. The anti-CD19/CD20 dILs showed the improved cell apoptosis induction compared to either anti-CD19 ILs or anti-CD20 ILs. Our findings suggest that the dual-ligand ILs may provide a preferred strategy of personalized nanomedicine for the treatment of B-cell malignancies. 23733208 Glomus tumor as a cause of coccydynia. Glomus coccygeum is a network of glomus bodies located around pericoccygeal soft tissue. The question of whether it accounts for coccydynia has been debated. We report on a patient whose preoperative symptoms suggested the impression of glomus tumor of the coccyx; pain was relieved after removal of the lesion without coccygectomy. A 57-year-old woman was referred to us with a history of a pain in the coccygeal area lasting longer than 3 years. The patient complained of sharp pain whenever pressure was applied to the coccyx. Pain was aggravated by exposure to cold. MRI revealed a coccygeal lesion measuring 2 cm with a well-circumscribed margin. The lesion was excised without removal of any portion of the coccyx. The pathology report confirmed a glomus tumor, which was an identical finding to the conventional one of the subungual region. Ten months after surgery, she had no pain on the coccygeal region and no difficulty with sitting on a chair and in performing activities of daily living. Findings reported here suggest that although most glomus bodies are normal anatomical variants, development of a glomus tumor could occur in the coccygeal region and could be a cause of coccydynia. 23924095 'Perverse' Treasury pension plan will undermine care. NHS Employers has warned that a proposed £1.7 billion hike in employer contributions to the NHS pension scheme would inevitably result in job cuts. 23927343 Performance parameters of a liquid filled ionization chamber array. Purpose: In this work, the properties of the two-dimensional liquid filled ionization chamber array Octavius 1000SRS (PTW-Freiburg, Germany) for use in clinical photon-beam dosimetry are investigated.Methods: Measurements were carried out at an Elekta Synergy and Siemens Primus accelerator. For measurements of stability, linearity, and saturation effects of the 1000SRS array a Semiflex 31013 ionization chamber (PTW-Freiburg, Germany) was used as a reference. The effective point of measurement was determined by TPR measurements of the array in comparison with a Roos chamber (type 31004, PTW-Freiburg, Germany). The response of the array with varying field size and depth of measurement was evaluated using a Semiflex 31010 ionization chamber as a reference. Output factor measurements were carried out with a Semiflex 31010 ionization chamber, a diode (type 60012, PTW-Freiburg, Germany), and the detector array under investigation. The dose response function for a single detector of the array was determined by measuring 1 cm wide slit-beam dose profiles and comparing them against diode-measured profiles. Theoretical aspects of the low pass properties and of the sampling frequency of the detector array were evaluated. Dose profiles measured with the array and the diode detector were compared, and an intensity modulated radiation therapy (IMRT) field was verified using the Gamma-Index method and the visualization of line dose profiles.Results: The array showed a short and long term stability better than 0.1% and 0.2%, respectively. Fluctuations in linearity were found to be within ±0.2% for the vendor specified dose range. Saturation effects were found to be similar to those reported in other studies for liquid-filled ionization chambers. The detector's relative response varied with field size and depth of measurement, showing a small energy dependence accounting for maximum signal deviations of ±2.6% from the reference condition for the setup used. The σ-values of the Gaussian dose response function for a single detector of the array were found to be (0.72 ± 0.25) mm at 6 MV and (0.74 ± 0.25) mm at 15 MV and the corresponding low pass cutoff frequencies are 0.22 and 0.21 mm(-1), respectively. For the inner 5 × 5 cm(2) region and the outer 11 × 11 cm(2) region of the array the Nyquist theorem is fulfilled for maximum sampling frequencies of 0.2 and 0.1 mm(-1), respectively. An IMRT field verification with a Gamma-Index analysis yielded a passing rate of 95.2% for a 3 mm∕3% criterion with a TPS calculation as reference.Conclusions: This study shows the applicability of the Octavius 1000SRS in modern dosimetry. Output factor and dose profile measurements illustrated the applicability of the array in small field and stereotactic dosimetry. The high spatial resolution ensures adequate measurements of dose profiles in regular and intensity modulated photon-beam fields. 23922862 Maternal Deprivation Enhances Behavioral Vulnerability to Stress Associated with miR-504 Expression in Nucleus Accumbens of Rats. In this study, the effect of maternal deprivation (MD) and chronic unpredictable stress (CUS) in inducing depressive behaviors and associated molecular mechanism were investigated in rats. Maternal deprivation was established by separating pups from their mothers for 6 hours daily from postnatal day 1 to day 14. Chronic unpredictable stress was established by water deprivation, elevated open platform, food deprivation, restraint stress and electric foot shock. The depressive behaviors were determined by use of sucrose preference test and forced swim test. Rats in MD/CUS group exhibited lower sucrose preference rate, longer immobility time, and lighter body weights than rats in other groups (MD/control, non-MD/CUS and non-MD/control group). Meanwhile, higher miR-504 expression and lower dopamine receptor D1 (DRD1) and D2 (DRD2) expression were observed in the nucleus accumbens of rats in the MD/CUS group than in the other three groups. MiR-504 expression correlated negatively with DRD1 gene expression and sucrose preference rate in the sucrose preference test, but correlated positively with immobility time in forced swim test. Both DRD2 mRNA and protein expression correlated negatively with immobility time in forced swim test. These results suggest that MD enhances behavioral vulnerability to stress during adulthood, which is associated with the upregulation of miR-504 and downregulation of DRD2 expression in the nucleus accumbens. 23339514 The development of falling intonation in young children with cochlear implants: a 2-year longitudinal study. This article describes the development of intonation in 12 cochlear implant (CI) recipients. In a previously reported study of the first year of CI use, children who were implanted late (after 24 months) acquired intonation more rapidly than the younger participants. The older children's advantage is plausibly owing to their greater maturity. However, children who were implanted early (before 25 months) did not have an advantage over the still younger control group of infants with normal hearing (NH), suggesting that the advantage requires a critical age of about 30 months. The younger CI-users reached this age in the second year of CI use. The results confirmed our expectation that even the younger CI recipients would acquire intonation more rapidly than infants with NH who had the same amount of robust hearing experience. Clinical implications are discussed in relation to the question of early versus late implantation. CHEMDNER_CORPUS_BIOCREATIVE_4/CHEMDNER_TEST/chemdner_ann_test_13-09-13.txt0000644002344200234200000364025512236173674026170 0ustar mkrallingerBioinfoUnix21723361 A 100 113 methylmercury SYSTEMATIC 21723361 A 46 67 docosahexaenoic acids FAMILY 21723361 T 11 31 docosahexaenoic acid SYSTEMATIC 21723361 T 36 49 methylmercury SYSTEMATIC 21838705 A 1070 1085 MonoCarboxylate SYSTEMATIC 21838705 A 1419 1429 saquinavir TRIVIAL 21838705 A 1434 1443 ritonavir TRIVIAL 21838705 A 1765 1774 darunavir TRIVIAL 22064666 A 112 124 nitric oxide SYSTEMATIC 22064666 A 1493 1503 sildenafil TRIVIAL 22064666 A 168 170 NO FORMULA 22064666 A 278 288 sildenafil TRIVIAL 22064666 A 50 60 sildenafil TRIVIAL 22064666 A 651 661 sildenafil TRIVIAL 22064666 T 12 24 nitric oxide SYSTEMATIC 22064666 T 83 93 sildenafil TRIVIAL 22075688 A 1024 1026 Mg FORMULA 22075688 A 1103 1106 ADP ABBREVIATION 22075688 A 1107 1110 ATP ABBREVIATION 22075688 A 1137 1148 (25)MgPMC16 FORMULA 22075688 A 1154 1165 (25)MgPMC16 FORMULA 22075688 A 1174 1180 Bicarb ABBREVIATION 22075688 A 1264 1275 (25)MgPMC16 FORMULA 22075688 A 1325 1327 Mg FORMULA 22075688 A 1353 1364 (25)MgPMC16 FORMULA 22075688 A 1384 1387 AlP FORMULA 22075688 A 232 250 aluminum phosphide SYSTEMATIC 22075688 A 252 255 AlP FORMULA 22075688 A 258 269 (25)MgPMC16 FORMULA 22075688 A 430 433 AlP FORMULA 22075688 A 447 465 Sodium bicarbonate SYSTEMATIC 22075688 A 467 473 Bicarb ABBREVIATION 22075688 A 64 74 (25)Mg(2+) FORMULA 22075688 A 736 739 ATP ABBREVIATION 22075688 A 740 743 ADP ABBREVIATION 22075688 A 755 757 Mg FORMULA 22075688 A 830 833 AlP FORMULA 22075688 A 900 911 (25)MgPMC16 FORMULA 22075688 A 98 109 (25)MgPMC16 FORMULA 22075688 T 27 36 magnesium SYSTEMATIC 22075688 T 79 97 aluminum phosphide SYSTEMATIC 22082826 A 1011 1022 glutathione TRIVIAL 22082826 A 1030 1040 superoxide TRIVIAL 22082826 A 1056 1067 glutathione TRIVIAL 22082826 A 1351 1355 dUTP ABBREVIATION 22082826 A 794 802 ketamine TRIVIAL 22083351 A 1080 1083 VPA ABBREVIATION 22083351 A 1088 1092 SAHA ABBREVIATION 22083351 A 1150 1159 PD-033299 IDENTIFIER 22083351 A 175 188 valproic acid TRIVIAL 22083351 A 190 193 VPA ABBREVIATION 22083351 A 199 230 suberoylanilide hydroxamic acid TRIVIAL 22083351 A 232 236 SAHA ABBREVIATION 22083351 A 509 512 VPA ABBREVIATION 22083351 A 517 521 SAHA ABBREVIATION 22083351 A 649 652 VPA ABBREVIATION 22083351 A 657 661 SAHA ABBREVIATION 22083351 A 799 802 VPA ABBREVIATION 22083351 A 807 811 SAHA ABBREVIATION 22150026 A 181 192 triterpenes FAMILY 22150026 A 194 202 α-amyrin TRIVIAL 22150026 A 204 212 β-amyrin TRIVIAL 22150026 A 214 220 lupeol TRIVIAL 22150026 A 222 229 betulin TRIVIAL 22150026 A 231 245 betulinic acid TRIVIAL 22150026 A 247 252 uvaol TRIVIAL 22150026 A 254 265 erythrodiol TRIVIAL 22150026 A 270 284 oleanolic acid TRIVIAL 22150026 A 290 303 phenolic acid FAMILY 22150026 A 321 342 4-hydroxybenzoic acid SYSTEMATIC 22150026 A 344 375 gallic and protocatechuic acids MULTIPLE 22150026 A 380 392 isocorilagin TRIVIAL 22150026 A 479 491 isocorilagin TRIVIAL 22150026 A 510 539 2,2-diphenyl-1-picrylhydrazyl SYSTEMATIC 22150026 A 571 583 isocorilagin TRIVIAL 22150026 A 629 635 Trolox TRIVIAL 22150026 A 640 664 butylated hydroxyanisole SYSTEMATIC 22155887 A 1182 1190 fluoride SYSTEMATIC 22155887 A 1256 1264 fluoride SYSTEMATIC 22155887 A 1332 1340 fluoride SYSTEMATIC 22155887 A 420 428 fluoride SYSTEMATIC 22155887 A 491 499 fluoride SYSTEMATIC 22155887 A 900 906 Trolox TRIVIAL 22173956 A 1037 1041 PhIP ABBREVIATION 22173956 A 1109 1113 PhIP ABBREVIATION 22173956 A 1450 1454 PhIP ABBREVIATION 22173956 A 162 202 2-amino-3-methylimidazo[4,5-f] quinoline SYSTEMATIC 22173956 A 212 259 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine SYSTEMATIC 22173956 A 261 265 PhIP ABBREVIATION 22173956 A 296 314 heterocyclic amine FAMILY 22173956 A 469 488 heterocyclic amines FAMILY 22173956 A 515 519 PhIP ABBREVIATION 22173956 A 684 688 PhIP ABBREVIATION 22173956 A 755 774 heterocyclic amines FAMILY 22173956 A 866 885 heterocyclic amines FAMILY 22173956 T 75 94 heterocyclic amines FAMILY 22231567 A 103 109 amines FAMILY 22233192 A 208 220 α-tocopherol TRIVIAL 22233192 A 25 36 fatty acids FAMILY 22233192 A 277 280 ALA ABBREVIATION 22233192 A 285 295 oleic acid TRIVIAL 22233192 A 313 340 linoleic and palmitic acids MULTIPLE 22233192 A 41 53 α-tocopherol TRIVIAL 22233192 A 430 441 fatty acids FAMILY 22233192 A 500 512 α-tocopherol TRIVIAL 22233192 A 530 543 linoleic acid TRIVIAL 22233192 A 557 560 ALA ABBREVIATION 22233192 A 574 577 GLA ABBREVIATION 22284538 A 15 21 serine TRIVIAL 22284538 A 179 191 carbohydrate FAMILY 22284538 A 22 31 threonine TRIVIAL 22287617 A 0 8 Nicotine TRIVIAL 22287617 A 1038 1052 malondialdhyde TRIVIAL 22287617 A 1054 1057 MDA ABBREVIATION 22287617 A 1062 1070 nicotine TRIVIAL 22287617 A 1110 1121 epicatechin TRIVIAL 22287617 A 1124 1129 Vit E ABBREVIATION 22287617 A 1236 1246 superoxide TRIVIAL 22287617 A 1271 1282 glutathione TRIVIAL 22287617 A 1370 1378 nicotine TRIVIAL 22287617 A 1437 1448 glutathione TRIVIAL 22287617 A 1453 1456 MDA ABBREVIATION 22287617 A 1560 1571 epicatechin TRIVIAL 22287617 A 1576 1585 vitamin E FAMILY 22287617 A 1660 1668 nicotine TRIVIAL 22287617 A 194 205 Epicatechin TRIVIAL 22287617 A 503 512 Vitamin E FAMILY 22287617 A 713 722 vitamin E FAMILY 22287617 A 846 857 epicatechin TRIVIAL 22287617 A 881 890 vitamin E FAMILY 22287617 A 937 945 nicotine TRIVIAL 22287617 T 21 30 vitamin E FAMILY 22287617 T 35 46 epicatechin TRIVIAL 22287617 T 55 63 nicotine TRIVIAL 22294440 A 1096 1102 Ni(2+) FORMULA 22294440 A 1202 1208 Ni(2+) FORMULA 22294440 A 172 178 Ni(2+) FORMULA 22294440 A 22 28 nickel SYSTEMATIC 22294440 A 308 314 Ni(2+) FORMULA 22294440 A 325 331 oxygen SYSTEMATIC 22294440 A 384 399 malondialdehyde TRIVIAL 22294440 A 476 485 quercetin TRIVIAL 22294440 A 518 524 Ni(2+) FORMULA 22294440 A 759 765 Ni(2+) FORMULA 22294440 A 859 873 trichostatin A TRIVIAL 22294440 T 30 36 nickel SYSTEMATIC 22294440 T 40 49 quercetin TRIVIAL 22294440 T 72 78 oxygen SYSTEMATIC 22301817 A 1039 1046 cadmium SYSTEMATIC 22301817 A 188 195 Cadmium SYSTEMATIC 22301817 A 228 236 graphite TRIVIAL 22301817 A 308 319 nitric acid SYSTEMATIC 22301817 A 320 335 perchloric acid SYSTEMATIC 22301817 A 461 468 cadmium SYSTEMATIC 22301817 A 533 540 cadmium SYSTEMATIC 22301817 A 60 67 cadmium SYSTEMATIC 22301817 A 627 634 cadmium SYSTEMATIC 22301817 A 759 766 cadmium SYSTEMATIC 22301817 A 886 893 cadmium SYSTEMATIC 22301817 T 0 7 Cadmium SYSTEMATIC 22304229 A 169 186 patchouli alcohol TRIVIAL 22304229 A 254 296 1,1,6,6-tetraphenylhexa-2,4-diyne-1,6-diol SYSTEMATIC 22304229 A 354 371 patchouli alcohol TRIVIAL 22304229 A 452 460 hydrogen SYSTEMATIC 22304229 A 774 791 patchouli alcohol TRIVIAL 22304229 T 24 41 patchouli alcohol TRIVIAL 22317828 A 1026 1036 tartrazine TRIVIAL 22317828 A 1039 1047 vanillin TRIVIAL 22317828 A 1277 1288 glutathione TRIVIAL 22317828 A 1298 1309 glutathione TRIVIAL 22317828 A 1310 1311 S FORMULA 22317828 A 1328 1338 superoxide TRIVIAL 22317828 A 1462 1469 alanine TRIVIAL 22317828 A 1488 1497 aspartate TRIVIAL 22317828 A 1549 1558 bilirubin TRIVIAL 22317828 A 1560 1564 urea TRIVIAL 22317828 A 1566 1576 creatinine TRIVIAL 22317828 A 562 576 Brilliant blue TRIVIAL 22317828 A 631 641 carmoisine TRIVIAL 22317828 A 694 704 tartrazine TRIVIAL 22317828 A 774 788 trans-anethole TRIVIAL 22317828 A 824 840 propylene glycol SYSTEMATIC 22317828 A 878 886 vanillin TRIVIAL 22317828 A 923 937 Brilliant blue TRIVIAL 22317828 A 940 956 propylene glycol SYSTEMATIC 22317828 A 977 987 carmoisine TRIVIAL 22317828 A 990 1004 trans-anethole TRIVIAL 22320163 A 112 120 methanol SYSTEMATIC 22320163 A 258 307 (22E,24R)-6β-methoxyergosta-7,22-diene-3β,5α-diol SYSTEMATIC 22320163 A 313 366 2',3'-diacetoxy-3,4,5',6',4″-pentahydroxy-p-terphenyl SYSTEMATIC 22320163 A 372 385 cerebroside B TRIVIAL 22320163 A 391 414 ergosta-7,22-dien-3β-ol SYSTEMATIC 22320163 A 420 439 ergosterol peroxide TRIVIAL 22320163 A 43 51 steroids FAMILY 22320163 A 445 489 (22E,24R)-3β-hydroxy-ergosta-5,22-dien-7-one SYSTEMATIC 22320163 A 495 507 benzoic acid SYSTEMATIC 22320163 A 513 537 methyl p-hydroxybenzoate SYSTEMATIC 22320163 A 546 571 3,4-dihydroxybenzoic acid SYSTEMATIC 22320163 A 58 67 phenolics FAMILY 22320163 A 76 87 cerebroside FAMILY 22320163 T 0 8 Steroids FAMILY 22320163 T 13 21 phenolic FAMILY 22323477 A 0 10 4-Thujanol SYSTEMATIC 22323477 A 1054 1064 4-thujanol SYSTEMATIC 22323477 A 1067 1070 MMC ABBREVIATION 22323477 A 1075 1085 4-thujanol SYSTEMATIC 22323477 A 12 28 sabinene hydrate SYSTEMATIC 22323477 A 1231 1234 MMC ABBREVIATION 22323477 A 1257 1267 4-thujanol SYSTEMATIC 22323477 A 1345 1348 MMC ABBREVIATION 22323477 A 1427 1437 4-thujanol SYSTEMATIC 22323477 A 279 289 4-thujanol SYSTEMATIC 22323477 A 33 61 bicyclic monoterpene alcohol FAMILY 22323477 A 331 342 mitomycin C TRIVIAL 22323477 A 344 347 MMC ABBREVIATION 22323477 A 353 369 cyclophosphamide TRIVIAL 22323477 A 582 585 MMC ABBREVIATION 22323477 A 672 682 4-thujanol SYSTEMATIC 22323477 A 685 688 MMC ABBREVIATION 22323477 A 734 744 4-thujanol SYSTEMATIC 22323477 A 794 804 4-thujanol SYSTEMATIC 22323477 A 856 859 MMC ABBREVIATION 22323477 A 934 944 4-thujanol SYSTEMATIC 22323477 T 49 59 4-thujanol SYSTEMATIC 22323477 T 68 79 mitomycin-C TRIVIAL 22323477 T 84 100 cyclophosphamide TRIVIAL 22324400 A 324 340 chlorogenic acid TRIVIAL 22324400 A 342 347 rutin TRIVIAL 22324400 A 352 362 hyperoside TRIVIAL 22324400 A 609 614 rutin TRIVIAL 22324400 A 642 652 hyperoside TRIVIAL 22324400 A 683 699 chlorogenic acid TRIVIAL 22324400 A 852 857 rutin TRIVIAL 22324400 A 862 872 hyperoside TRIVIAL 22324400 T 0 16 Chlorogenic acid TRIVIAL 22324400 T 18 23 rutin TRIVIAL 22324400 T 28 38 hyperoside TRIVIAL 22324431 A 324 342 Bromotheoynic acid TRIVIAL 22324431 A 435 453 Bromotheoynic acid TRIVIAL 22324431 A 57 75 bromotheoynic acid TRIVIAL 22324431 A 6 38 brominated C(17) acetylenic acid FAMILY 22324431 T 0 18 Bromotheoynic acid TRIVIAL 22324431 T 22 48 brominated acetylenic acid FAMILY 22335791 A 114 130 diketopiperazine FAMILY 22335791 A 132 151 cis-cyclo-(His,Leu) FORMULA 22335791 A 178 191 ethyl acetate SYSTEMATIC 22335791 A 243 262 cis-cyclo-(Phe,Phe) FORMULA 22335791 A 268 279 tryptophane TRIVIAL 22335791 A 285 304 cis-cyclo-(Leu,Tyr) FORMULA 22335791 A 310 329 cis-cyclo-(Trp,Tyr) FORMULA 22335791 A 338 351 macrolactin A TRIVIAL 22335791 A 572 587 cyclo-(His,Leu) FORMULA 22335791 T 0 15 Cyclo-(His,Leu) FORMULA 22335791 T 33 49 diketopiperazine FAMILY 22340730 A 1196 1212 phosphoinositide FAMILY 22340730 A 56 63 leucine TRIVIAL 22348279 A 267 281 monoterpenoids FAMILY 22348279 A 293 309 sesquiterpenoids FAMILY 22348279 A 311 320 α-Thujone TRIVIAL 22348279 A 331 340 β-thujone TRIVIAL 22348279 A 350 362 germacrene D TRIVIAL 22348279 A 372 383 4-terpineol SYSTEMATIC 22348279 A 393 408 β-caryophyllene TRIVIAL 22348279 A 418 426 camphene TRIVIAL 22348279 A 439 446 borneol TRIVIAL 22349823 A 1183 1186 Met FORMULA 22349823 A 1255 1264 gefitinib TRIVIAL 22349823 A 1459 1462 Phe FORMULA 22349823 A 1554 1563 gefitinib TRIVIAL 22349823 A 1697 1706 gefitinib TRIVIAL 22349823 A 226 234 tyrosine TRIVIAL 22349823 A 430 439 gefitinib TRIVIAL 22349823 A 444 453 erlotinib TRIVIAL 22349823 A 697 706 gefitinib TRIVIAL 22349823 A 808 817 gefitinib TRIVIAL 22349823 A 869 872 ATP ABBREVIATION 22369145 A 143 157 5-Fluorouracil SYSTEMATIC 22369145 A 1469 1473 5-FU SYSTEMATIC 22369145 A 159 163 5-FU SYSTEMATIC 22369145 A 640 654 Eudragit NE30D FAMILY 22369145 A 697 711 Eudragit FS30D FAMILY 22369145 T 21 35 5-fluorouracil SYSTEMATIC 22370636 A 49 65 phosphoinositide FAMILY 22370636 A 626 629 Trp FORMULA 22370636 A 787 795 GDC-0941 IDENTIFIER 22370641 A 1182 1185 Epi ABBREVIATION 22370641 A 1187 1196 cisplatin TRIVIAL 22370641 A 1198 1212 5-fluorouracil SYSTEMATIC 22370641 A 1347 1360 anthracycline FAMILY 22370641 A 693 706 anthracycline FAMILY 22370641 A 725 735 epirubicin TRIVIAL 22370641 A 737 740 Epi ABBREVIATION 22370641 A 746 757 doxorubicin TRIVIAL 22370641 A 759 762 Dox ABBREVIATION 22370641 A 765 768 Epi ABBREVIATION 22370641 A 894 897 Epi ABBREVIATION 22370641 T 71 81 epirubicin TRIVIAL 22376270 A 130 138 n-hexane SYSTEMATIC 22376270 A 169 177 methanol SYSTEMATIC 22376270 A 21 32 epi-mukulin TRIVIAL 22376270 A 272 285 diasesartemin TRIVIAL 22376270 A 287 303 (+)-epi-magnolin TRIVIAL 22376270 A 305 321 (+)-diayangambin TRIVIAL 22376270 A 323 336 gugglsterol I TRIVIAL 22376270 A 338 355 (E)-guggulsterone TRIVIAL 22376270 A 34 65 (Z)-Δ(1,2) dehydroguggulsterone SYSTEMATIC 22376270 A 360 377 (Z)-guggulsterone TRIVIAL 22376270 A 689 702 diasesartemin TRIVIAL 22376270 A 70 106 Δ(6,7)dehydro-20-hydroxygugglsterone SYSTEMATIC 22376270 A 784 792 acarbose TRIVIAL 22376270 A 886 897 epi-mukulin TRIVIAL 22376270 A 902 919 (Z)-guggulsterone TRIVIAL 22379948 A 119 136 6-desacetylnimbin SYSTEMATIC 22379948 A 142 152 quercitrin TRIVIAL 22379948 A 161 171 myricitrin TRIVIAL 22379948 A 295 312 6-desacetylnimbin SYSTEMATIC 22379948 A 443 460 6-desacetylnimbin SYSTEMATIC 22400809 A 308 321 shikimic acid TRIVIAL 22400809 A 323 348 5-O-caffeoylshikimic acid SYSTEMATIC 22400809 A 350 367 trans-resveratrol TRIVIAL 22400809 A 369 378 taxifolin TRIVIAL 22400809 A 380 388 astilbin TRIVIAL 22400809 A 418 427 engeletin TRIVIAL 22400809 A 432 444 isoengeletin TRIVIAL 22400809 A 455 468 syringic acid TRIVIAL 22400809 A 498 514 chlorogenic acid TRIVIAL 22401743 A 1283 1292 estradiol TRIVIAL 22401743 A 501 513 Progesterone TRIVIAL 22401743 A 515 524 estradiol TRIVIAL 22401743 A 529 541 testosterone TRIVIAL 22401743 A 885 892 steroid FAMILY 22401743 A 912 920 estrogen FAMILY 22406206 A 0 11 R,R-Monatin TRIVIAL 22406206 A 1174 1180 arruva FAMILY 22406206 A 13 81 2R,4R- isomer of 2-hydroxy-2-(indol-3-ylmethyl)-4-aminoglutaric acid SYSTEMATIC 22406206 A 177 183 arruva FAMILY 22406206 A 240 251 R,R-monatin TRIVIAL 22406206 A 467 473 arruva FAMILY 22406206 T 42 48 arruva FAMILY 22406206 T 53 65 R, R-monatin TRIVIAL 22417089 A 121 130 grewialin TRIVIAL 22417089 A 139 148 optivanin TRIVIAL 22417089 A 449 531 2S*-(3-hydroxy-4-methoxyphenyl)-3R*-methyl-2H-[1,4]-dioxin [2,3]-chromen-7(3H)-one SYSTEMATIC 22417089 A 539 554 coumarinolignan FAMILY 22417089 A 559 611 3-hydroxy-1-(3-hydroxy-4-methoxyphenyl) propan-1-one SYSTEMATIC 22417089 A 656 668 β-sitosterol TRIVIAL 22417089 A 670 682 stigmasterol TRIVIAL 22417089 A 687 693 lupeol TRIVIAL 22417089 T 0 9 Grewialin TRIVIAL 22417089 T 14 23 optivanin TRIVIAL 22422627 A 1036 1044 SB203580 IDENTIFIER 22422627 A 1181 1190 Berberine TRIVIAL 22422627 A 267 276 berberine TRIVIAL 22422627 A 53 62 berberine TRIVIAL 22422627 A 816 825 berberine TRIVIAL 22422627 A 946 955 Berberine TRIVIAL 22422627 T 0 9 Berberine TRIVIAL 22430919 A 877 889 nitric oxide SYSTEMATIC 22430919 A 891 893 NO FORMULA 22430919 A 939 941 NO FORMULA 22439883 A 508 519 heneicosane SYSTEMATIC 22439883 A 521 529 docosane SYSTEMATIC 22439883 A 534 543 tricosane SYSTEMATIC 22439883 A 713 744 2-Hydroxy-4-methoxybenzaldehyde SYSTEMATIC 22450748 A 1180 1187 phospho SYSTEMATIC 22473703 A 193 205 ginsenosides FAMILY 22473703 A 215 228 polyacetylene SYSTEMATIC 22473703 A 229 238 panaxynol TRIVIAL 22473703 A 305 311 Hexane SYSTEMATIC 22473703 A 334 343 panaxynol TRIVIAL 22473703 A 423 431 methanol SYSTEMATIC 22473703 A 457 469 ginsenosides FAMILY 22473703 A 534 543 Panaxynol TRIVIAL 22473703 A 734 747 trypanothione TRIVIAL 22473703 A 939 948 panaxynol TRIVIAL 22473703 A 959 973 polyacetylenes FAMILY 22473789 A 1138 1146 fructose TRIVIAL 22473789 A 1245 1252 ethanol SYSTEMATIC 22473789 A 261 270 androgens FAMILY 22473789 A 355 365 alkylamide FAMILY 22473789 A 371 378 ethanol SYSTEMATIC 22473789 A 509 516 ethanol SYSTEMATIC 22473789 A 687 699 testosterone TRIVIAL 22473789 A 723 736 N-alkylamides FAMILY 22473789 A 973 985 testosterone TRIVIAL 22473789 T 41 51 alkylamide FAMILY 22473789 T 57 64 ethanol SYSTEMATIC 22484424 A 279 288 rapamycin TRIVIAL 22491023 A 0 16 Xanthurenic acid TRIVIAL 22491023 A 1327 1337 kynurenine TRIVIAL 22491023 A 1698 1707 Glutamate TRIVIAL 22491023 A 197 206 glutamate TRIVIAL 22491023 A 394 404 kynurenine TRIVIAL 22491023 A 47 57 tryptophan TRIVIAL 22491023 A 90 109 3-hydroxykynurenine SYSTEMATIC 22491023 T 11 27 Xanthurenic acid TRIVIAL 22491023 T 73 82 glutamate TRIVIAL 22494023 A 822 833 metal oxide FAMILY 22494023 T 67 78 metal oxide FAMILY 22511564 A 1018 1024 thymol TRIVIAL 22511564 A 1067 1073 thymol TRIVIAL 22511564 A 139 145 thymol TRIVIAL 22511564 A 326 332 thymol TRIVIAL 22511564 A 345 353 p-cymene TRIVIAL 22511564 A 479 495 arachidonic acid TRIVIAL 22511564 A 497 503 phenol SYSTEMATIC 22511564 A 507 516 histamine TRIVIAL 22511564 A 601 607 thymol TRIVIAL 22511564 A 687 703 arachidonic acid TRIVIAL 22511564 A 758 764 phenol SYSTEMATIC 22511564 A 872 878 thymol TRIVIAL 22512576 A 1072 1082 amino acid FAMILY 22512576 A 1179 1180 C FORMULA 22512576 A 1186 1187 N FORMULA 22512576 A 1234 1235 N FORMULA 22512576 A 370 378 N- t-Boc FORMULA 22512576 A 392 400 N-ureido TRIVIAL 22512576 A 562 606 N-formyl-L-methionyl-L-leucyl-Lphenylalanine SYSTEMATIC 22512576 A 608 612 fMLF ABBREVIATION 22512576 A 632 642 superoxide TRIVIAL 22512576 A 688 700 methyl-ester SYSTEMATIC 22512576 A 833 843 amino acid FAMILY 22512587 A 311 328 Thiazolidinedione SYSTEMATIC 22512587 A 410 428 thiazolidinediones FAMILY 22512587 T 56 73 thiazolidinedione FAMILY 22512662 A 20 69 2α,24-diacetoxy-3β-hydroxyolean-12-en-28-oic acid SYSTEMATIC 22512662 A 209 224 hyptatic acid-A TRIVIAL 22512662 A 226 268 2α,3β,24-trihydroxyolean-12-en-28-oic acid SYSTEMATIC 22512662 A 275 288 maslinic acid TRIVIAL 22512662 A 290 330 2α,3β-dihydroxyoleane-12-ene-28-oic acid SYSTEMATIC 22512662 A 333 340 betulin TRIVIAL 22512662 A 345 351 lupeol TRIVIAL 22512662 A 6 18 triterpenoid FAMILY 22512662 T 6 18 triterpenoid FAMILY 22517576 A 0 13 Cinnamic acid TRIVIAL 22517576 A 1082 1086 cGMP ABBREVIATION 22517576 A 1102 1106 cGMP ABBREVIATION 22517576 A 1274 1280 KT5823 IDENTIFIER 22517576 A 1298 1304 Ca(2+) FORMULA 22517576 A 1316 1320 K(+) FORMULA 22517576 A 1339 1357 tetraethylammonium SYSTEMATIC 22517576 A 1462 1474 nitric oxide SYSTEMATIC 22517576 A 1475 1479 cGMP ABBREVIATION 22517576 A 526 533 nitrite SYSTEMATIC 22517576 A 539 569 cyclic guanosine monophosphate SYSTEMATIC 22517576 A 571 575 cGMP ABBREVIATION 22517576 A 602 615 phenylephrine TRIVIAL 22517576 A 738 773 N(G) -nitro-l-arginine methyl ester SYSTEMATIC 22517576 A 787 837 1 H-[1,2,4]-oxadiazolole-[4,3-a] quinoxalin-10-one SYSTEMATIC 22517576 A 855 869 methylene blue TRIVIAL 22517576 A 972 984 nitric oxide SYSTEMATIC 22517576 A 998 1010 nitric oxide SYSTEMATIC 22517576 T 24 37 cinnamic acid TRIVIAL 22517576 T 46 58 nitric oxide SYSTEMATIC 22517576 T 59 63 cGMP ABBREVIATION 22521336 A 1234 1248 prostaglandins FAMILY 22521499 A 1019 1028 VU0360172 IDENTIFIER 22521499 A 1136 1140 CHPG ABBREVIATION 22521499 A 1145 1154 VU0360172 IDENTIFIER 22521499 A 1195 1199 MTEP ABBREVIATION 22521499 A 1202 1206 CHPG ABBREVIATION 22521499 A 1216 1225 VU0360172 IDENTIFIER 22521499 A 1295 1304 VU0360172 IDENTIFIER 22521499 A 1314 1318 CHPG ABBREVIATION 22521499 A 1462 1471 VU0360172 IDENTIFIER 22521499 A 1481 1485 CHPG ABBREVIATION 22521499 A 1634 1639 AM281 IDENTIFIER 22521499 A 1674 1683 VU0360172 IDENTIFIER 22521499 A 1708 1717 VU0360172 IDENTIFIER 22521499 A 1848 1852 ACEA ABBREVIATION 22521499 A 2079 2083 CHPG ABBREVIATION 22521499 A 2223 2232 VU0360172 IDENTIFIER 22521499 A 2378 2387 Glutamate TRIVIAL 22521499 A 426 435 glutamate TRIVIAL 22521499 A 960 964 CHPG ABBREVIATION 22532505 A 668 675 alanine TRIVIAL 22532505 A 743 749 5' AMP SYSTEMATIC 22532505 T 66 78 triglyceride FAMILY 22533633 A 134 179 3',5-dihydroxy-3,4',5',7-tetramethoxy-flavone SYSTEMATIC 22533633 A 185 193 catechin TRIVIAL 22533633 A 199 208 quercetin TRIVIAL 22533633 A 214 243 quercetin-3-O-β-D-glucuronide SYSTEMATIC 22533633 A 252 257 rutin TRIVIAL 22533633 A 4 12 methanol SYSTEMATIC 22533633 A 78 84 lignan FAMILY 22533633 A 86 103 8-oxo-pinoresinol SYSTEMATIC 22538087 A 614 618 GABA ABBREVIATION 22538087 A 71 75 GABA ABBREVIATION 22538087 A 714 718 GABA ABBREVIATION 22538087 T 6 10 GABA ABBREVIATION 22546614 A 1148 1154 AMN082 IDENTIFIER 22546614 A 1193 1212 γ-aminobutyric acid SYSTEMATIC 22546614 A 1214 1218 GABA ABBREVIATION 22546614 A 1247 1256 glutamate TRIVIAL 22546614 A 1293 1301 dopamine TRIVIAL 22546614 A 1384 1390 AMN082 IDENTIFIER 22546614 A 1409 1416 cocaine TRIVIAL 22546614 A 1447 1453 AMN082 IDENTIFIER 22546614 A 1473 1482 glutamate TRIVIAL 22546614 A 1551 1560 glutamate TRIVIAL 22546614 A 1665 1674 glutamate TRIVIAL 22546614 A 1708 1712 GABA ABBREVIATION 22546614 A 1760 1769 glutamate TRIVIAL 22546614 A 1795 1802 cocaine TRIVIAL 22546614 A 180 189 glutamate TRIVIAL 22546614 A 1837 1845 pallidum SYSTEMATIC 22546614 A 1915 1922 cocaine TRIVIAL 22546614 A 1960 1969 glutamate TRIVIAL 22546614 A 2038 2045 cocaine TRIVIAL 22546614 A 2085 2094 glutamate TRIVIAL 22546614 A 228 237 glutamate TRIVIAL 22546614 A 2298 2304 AMN082 IDENTIFIER 22546614 A 2399 2406 cocaine TRIVIAL 22546614 A 2481 2490 Glutamate TRIVIAL 22546614 A 448 454 AMN082 IDENTIFIER 22546614 A 591 597 AMN082 IDENTIFIER 22546614 A 6 15 glutamate TRIVIAL 22546614 A 760 767 cocaine TRIVIAL 22546614 A 769 775 heroin TRIVIAL 22546614 A 780 787 ethanol SYSTEMATIC 22546614 A 869 875 AMN082 IDENTIFIER 22546614 A 926 933 cocaine TRIVIAL 22546614 A 999 1006 cocaine TRIVIAL 22546614 T 100 107 cocaine TRIVIAL 22546614 T 13 22 glutamate TRIVIAL 22566066 A 0 10 Panaxadiol TRIVIAL 22566066 A 1051 1055 EGCG ABBREVIATION 22566066 A 123 127 EGCG ABBREVIATION 22566066 A 1255 1259 EGCG ABBREVIATION 22566066 A 138 146 catechin TRIVIAL 22566066 A 1397 1401 EGCG ABBREVIATION 22566066 A 281 285 EGCG ABBREVIATION 22566066 A 30 39 sapogenin FAMILY 22566066 A 51 59 saponins FAMILY 22566066 A 792 796 EGCG ABBREVIATION 22566066 A 944 948 EGCG ABBREVIATION 22566066 A 97 121 Epigallocatechin gallate TRIVIAL 22566066 T 41 51 panaxadiol TRIVIAL 22566066 T 56 80 epigallocatechin gallate TRIVIAL 22566106 A 615 628 cepharanthine TRIVIAL 22566106 A 630 649 tetrahydropalmatine SYSTEMATIC 22566106 A 655 665 xylopinine TRIVIAL 22566106 A 777 796 tetrahydropalmatine SYSTEMATIC 22566158 A 348 362 streptozotocin TRIVIAL 22566187 A 102 114 carbohydrate FAMILY 22566187 A 1148 1156 warfarin TRIVIAL 22566187 A 1204 1212 warfarin TRIVIAL 22566187 A 254 259 sugar FAMILY 22566187 A 337 345 warfarin TRIVIAL 22566187 A 41 51 polyphenol FAMILY 22566187 A 571 579 warfarin TRIVIAL 22566187 A 622 634 carbohydrate FAMILY 22566187 A 639 650 polyphenols FAMILY 22566187 A 668 677 quercetin TRIVIAL 22566187 A 683 695 ellagic acid TRIVIAL 22566187 A 703 714 polyphenols FAMILY 22566187 A 896 905 midazolam TRIVIAL 22574728 A 299 311 cerebrosides FAMILY 22574728 A 61 85 phenylethanoid glucoside FAMILY 22574728 A 91 124 α-L-rhamnosyl (1 → 2)-β-D-glucose SYSTEMATIC 22574728 T 6 30 phenylethanoid glucoside FAMILY 22574752 A 422 432 terpenoids FAMILY 22574752 A 434 446 hydrocarbons FAMILY 22574752 A 448 456 phenolic FAMILY 22574752 A 489 496 ketones FAMILY 22574752 A 538 557 ethyl homovanillate SYSTEMATIC 22574752 A 579 587 drimenol TRIVIAL 22575576 A 1055 1058 EE2 ABBREVIATION 22575576 A 14 22 estrogen FAMILY 22575576 A 1417 1420 EE2 ABBREVIATION 22575576 A 1448 1451 EE2 ABBREVIATION 22575576 A 1539 1563 polyethylene glycol-4000 TRIVIAL 22575576 A 1776 1779 EE2 ABBREVIATION 22575576 A 1855 1858 EE2 ABBREVIATION 22575576 A 2105 2111 oxygen SYSTEMATIC 22575576 A 2120 2123 EE2 ABBREVIATION 22575576 A 23 44 17-α-ethynylestradiol SYSTEMATIC 22575576 A 238 241 EE2 ABBREVIATION 22575576 A 292 295 EE2 ABBREVIATION 22575576 A 402 405 EE2 ABBREVIATION 22575576 A 426 429 EE2 ABBREVIATION 22575576 A 46 49 EE2 ABBREVIATION 22575576 A 470 476 Oxygen SYSTEMATIC 22575576 A 549 552 EE2 ABBREVIATION 22575576 A 651 654 EE2 ABBREVIATION 22575576 A 801 804 EE2 ABBREVIATION 22575576 A 981 984 EE2 ABBREVIATION 22575576 T 43 64 17-α-ethynylestradiol SYSTEMATIC 22575576 T 96 102 oxygen SYSTEMATIC 22578007 A 0 62 1α-acetoxy-5α, 7β-dihydroxycassa-11,13(15)-diene-16,12-lactone SYSTEMATIC 22578007 A 70 77 cassane TRIVIAL 22578007 A 83 92 diterpene FAMILY 22578007 T 19 26 cassane TRIVIAL 22578007 T 32 41 diterpene FAMILY 22580612 A 444 452 tyrosine TRIVIAL 22585533 A 0 10 β-eudesmol TRIVIAL 22585533 A 1018 1028 β-eudesmol TRIVIAL 22585533 A 187 197 β-eudesmol TRIVIAL 22585533 A 22 36 sesquiterpenol FAMILY 22585533 A 288 298 β-eudesmol TRIVIAL 22585533 A 386 396 β-eudesmol TRIVIAL 22585533 A 504 514 β-eudesmol TRIVIAL 22585533 A 590 607 poly (ADP-ribose) SYSTEMATIC 22585533 A 775 776 N FORMULA 22585533 A 850 860 β-eudesmol TRIVIAL 22585533 A 918 928 β-eudesmol TRIVIAL 22585533 T 0 10 β-Eudesmol TRIVIAL 22594571 A 215 222 saponin FAMILY 22594571 A 224 235 glinoside C TRIVIAL 22594571 A 260 323 16-O-(β-D-glucopyranosyl)-3β,12β,16β,21α,22-pentahydroxy hopane SYSTEMATIC 22594571 A 426 465 3-O-(β-D-xylopyranosyl)-spergulagenin A SYSTEMATIC 22594571 A 471 482 spergulacin TRIVIAL 22594571 A 488 499 spergulin A TRIVIAL 22594571 A 505 518 spergulacin A TRIVIAL 22594571 A 527 538 spergulin B TRIVIAL 22594571 A 76 95 triterpene saponins FAMILY 22594571 T 6 26 triterpenoid saponin FAMILY 22607101 A 1060 1064 PLGA ABBREVIATION 22607101 A 1079 1082 PVA ABBREVIATION 22607101 A 1270 1276 L-DOPA ABBREVIATION 22607101 A 1281 1285 PLGA ABBREVIATION 22607101 A 1520 1524 PLGA ABBREVIATION 22607101 A 1601 1607 L-DOPA ABBREVIATION 22607101 A 1628 1634 L-DOPA ABBREVIATION 22607101 A 1642 1646 PLGA ABBREVIATION 22607101 A 342 346 PLGA ABBREVIATION 22607101 A 36 42 L-DOPA ABBREVIATION 22607101 A 362 379 polyvinyl alcohol SYSTEMATIC 22607101 A 381 384 PVA ABBREVIATION 22607101 A 50 80 poly(D,L-lactide-co-glycolide) FAMILY 22607101 A 82 86 PLGA ABBREVIATION 22607101 T 16 20 PLGA ABBREVIATION 22607101 T 58 64 L-DOPA ABBREVIATION 22609536 A 1020 1029 serotonin TRIVIAL 22609536 A 1056 1066 fluoxetine TRIVIAL 22609536 A 1326 1336 fluoxetine TRIVIAL 22609536 A 1378 1386 ketamine TRIVIAL 22609536 A 1515 1525 Fluoxetine TRIVIAL 22609536 A 159 168 glutamate TRIVIAL 22609536 A 1931 1940 Glutamate TRIVIAL 22609536 A 431 441 fluoxetine TRIVIAL 22609536 A 443 451 ketamine TRIVIAL 22609536 A 496 504 Ketamine TRIVIAL 22609536 A 511 515 NMDA ABBREVIATION 22609536 A 766 775 monoamine FAMILY 22609536 T 144 154 fluoxetine TRIVIAL 22609536 T 98 106 ketamine TRIVIAL 22610968 A 495 514 diallyl monosulfide SYSTEMATIC 22610968 A 516 533 diallyl disulfide SYSTEMATIC 22610968 A 535 539 DADS ABBREVIATION 22610968 A 542 560 diallyl trisulfide SYSTEMATIC 22610968 A 566 586 diallyl tetrasulfide SYSTEMATIC 22610968 A 645 663 dipropyl disulfide SYSTEMATIC 22610968 A 665 669 DPDS ABBREVIATION 22610968 A 672 691 dipropyl trisulfide SYSTEMATIC 22610968 A 697 718 dipropyl tetrasulfide SYSTEMATIC 22610968 A 756 760 DADS ABBREVIATION 22610968 A 765 769 DPDS ABBREVIATION 22610968 A 843 848 allyl SYSTEMATIC 22610968 A 910 917 sulfide SYSTEMATIC 22610968 A 983 987 DADS ABBREVIATION 22610968 T 12 28 diallyl sulfides FAMILY 22610968 T 33 50 dipropyl sulfides FAMILY 22624955 A 121 128 bayarin TRIVIAL 22624955 A 246 256 flavonoids FAMILY 22624955 A 265 273 saponins FAMILY 22624955 A 29 110 myricetin-3-O-[β-xylopyranosyl-(1-2)-α-rhamnopyranoside]-4'-O-α -rhamnopyranoside SYSTEMATIC 22624955 A 6 27 flavonol triglycoside FAMILY 22624955 T 0 10 Flavonoids FAMILY 22624955 T 15 23 saponins FAMILY 22625220 A 119 129 flavonoids FAMILY 22625220 A 152 153 H FORMULA 22625220 A 285 294 flavonoid FAMILY 22625220 A 318 328 flavonoids FAMILY 22625220 A 337 345 phenolic FAMILY 22625220 A 59 69 flavonoids FAMILY 22625220 A 698 707 flavonoid FAMILY 22625220 T 26 36 flavonoids FAMILY 22634112 A 1170 1174 cAMP ABBREVIATION 22634112 A 1326 1330 cAMP ABBREVIATION 22634112 A 289 304 corticosteroids FAMILY 22634112 A 556 560 cAMP ABBREVIATION 22634112 A 612 616 cAMP ABBREVIATION 22634112 A 679 697 prostaglandin E(2) TRIVIAL 22634112 A 764 768 cAMP ABBREVIATION 22634112 A 915 919 cAMP ABBREVIATION 22634112 T 0 4 cAMP ABBREVIATION 22634361 A 1018 1028 Lu AF21934 IDENTIFIER 22634361 A 1041 1051 Lu AF21934 IDENTIFIER 22634361 A 1305 1314 Glutamate TRIVIAL 22634361 A 242 252 Lu AF21934 IDENTIFIER 22634361 A 578 588 Lu AF21934 IDENTIFIER 22634361 A 636 650 benzodiazepine FAMILY 22634361 A 671 681 flumazenil TRIVIAL 22634361 A 705 714 serotonin TRIVIAL 22634361 A 745 754 serotonin TRIVIAL 22634361 A 798 802 5-HT SYSTEMATIC 22634361 A 820 829 WAY100635 IDENTIFIER 22634361 A 834 838 5-HT SYSTEMATIC 22634361 A 859 869 ritanserin TRIVIAL 22634361 A 94 103 LSP1-2111 IDENTIFIER 22634361 T 52 62 Lu AF21934 IDENTIFIER 22646908 A 301 317 piperitone oxide SYSTEMATIC 22646908 A 319 337 piperitenone oxide SYSTEMATIC 22646908 A 339 349 piperitone TRIVIAL 22646908 A 350 358 menthone TRIVIAL 22646908 A 363 371 pulegone TRIVIAL 22648665 A 429 446 sulphorhodamine B TRIVIAL 22659088 A 1173 1174 C FORMULA 22659088 A 1339 1341 Ca FORMULA 22659088 A 1529 1538 Glutamate TRIVIAL 22659088 A 21 30 glutamate TRIVIAL 22659088 A 471 472 C FORMULA 22659088 A 838 845 calcium SYSTEMATIC 22659088 A 865 867 Ca FORMULA 22659088 A 884 886 Ca FORMULA 22659088 A 907 909 Ca FORMULA 22659088 T 39 46 calcium SYSTEMATIC 22659090 A 1111 1123 (2R,4R)-APDC SYSTEMATIC 22659090 A 1125 1133 LY379268 IDENTIFIER 22659090 A 1138 1144 DCG-IV IDENTIFIER 22659090 A 1173 1181 LY541850 IDENTIFIER 22659090 A 1280 1286 Ca(2+) FORMULA 22659090 A 1510 1518 LY541850 IDENTIFIER 22659090 A 1795 1804 Glutamate TRIVIAL 22659090 A 26 35 glutamate TRIVIAL 22659090 A 942 949 calcium SYSTEMATIC 22659090 A 951 957 Ca(2+) FORMULA 22659090 T 58 67 glutamate TRIVIAL 22659408 A 1025 1033 LY379268 IDENTIFIER 22659408 A 1038 1042 NAAG ABBREVIATION 22659408 A 1089 1093 NAAG ABBREVIATION 22659408 A 1103 1138 N-acetylaspartyl-β-linked glutamate SYSTEMATIC 22659408 A 1140 1146 β-NAAG ABBREVIATION 22659408 A 1160 1164 NAAG ABBREVIATION 22659408 A 1169 1177 LY379268 IDENTIFIER 22659408 A 1314 1321 glycine TRIVIAL 22659408 A 1334 1338 NAAG ABBREVIATION 22659408 A 1547 1556 Glutamate TRIVIAL 22659408 A 225 238 [(3)H]glycine SYSTEMATIC 22659408 A 29 38 glutamate TRIVIAL 22659408 A 333 336 KCl FORMULA 22659408 A 369 377 LY379268 IDENTIFIER 22659408 A 392 396 K(+) FORMULA 22659408 A 416 429 [(3)H]glycine SYSTEMATIC 22659408 A 503 511 LY379268 IDENTIFIER 22659408 A 563 571 LY341495 IDENTIFIER 22659408 A 593 618 N-acetylaspartylglutamate SYSTEMATIC 22659408 A 620 624 NAAG ABBREVIATION 22659408 A 636 649 [(3)H]glycine SYSTEMATIC 22659408 A 723 732 glutamate TRIVIAL 22659408 A 778 787 glutamate TRIVIAL 22659408 A 81 88 glycine TRIVIAL 22659408 A 816 820 NAAG ABBREVIATION 22659408 A 873 877 NAAG ABBREVIATION 22659408 A 889 897 LY341495 IDENTIFIER 22659408 A 914 918 NAAG ABBREVIATION 22659408 A 933 946 [(3)H]glycine SYSTEMATIC 22659408 T 0 7 Glycine TRIVIAL 22659408 T 112 137 N-acetylaspartylglutamate SYSTEMATIC 22659408 T 139 143 NAAG ABBREVIATION 22659408 T 45 54 glutamate TRIVIAL 22659409 A 1237 1245 LY379268 IDENTIFIER 22659409 A 1343 1351 LY379268 IDENTIFIER 22659409 A 1409 1413 METH ABBREVIATION 22659409 A 1484 1492 LY379268 IDENTIFIER 22659409 A 1668 1676 LY379268 IDENTIFIER 22659409 A 1714 1722 LY379268 IDENTIFIER 22659409 A 1834 1838 METH ABBREVIATION 22659409 A 1910 1919 Glutamate TRIVIAL 22659409 A 349 364 methamphetamine TRIVIAL 22659409 A 366 370 METH ABBREVIATION 22659409 A 48 57 glutamate TRIVIAL 22659409 A 692 700 LY379268 IDENTIFIER 22659409 A 740 744 METH ABBREVIATION 22659409 A 783 787 METH ABBREVIATION 22659409 A 831 835 METH ABBREVIATION 22659409 A 900 904 METH ABBREVIATION 22659409 T 15 30 methamphetamine TRIVIAL 22659409 T 63 71 LY379268 IDENTIFIER 22676342 A 132 186 4-[(6-O-(E)-caffeoyl)-β-D-glucopyranosyl]vanillic acid SYSTEMATIC 22676342 A 195 262 3-O-[β-D-apiofurarnosyl-(1-6)-β-D-glucopyranoxy]-6-hydroxy-p-cymene SYSTEMATIC 22676342 A 51 58 ethanol SYSTEMATIC 22676342 A 8 27 phenolic glycosides FAMILY 22676342 T 8 27 phenolic glycosides FAMILY 22677456 A 109 125 organophosphorus FAMILY 22677456 A 1182 1208 diisopropylfluorophosphate SYSTEMATIC 22677456 A 1210 1215 sarin TRIVIAL 22677456 A 1217 1222 soman TRIVIAL 22677456 A 1224 1229 tabun TRIVIAL 22677456 A 1234 1244 cyclosarin TRIVIAL 22677456 A 1290 1298 paraoxon TRIVIAL 22677456 A 1303 1318 methyl paraoxon SYSTEMATIC 22677456 T 29 45 organophosphorus FAMILY 22678081 A 130 139 Vitamin C TRIVIAL 22678081 A 228 237 vitamin C TRIVIAL 22678081 A 561 569 hydrogen SYSTEMATIC 22678081 A 64 70 oxygen SYSTEMATIC 22678081 A 733 742 vitamin C TRIVIAL 22678081 A 762 770 hydroxyl SYSTEMATIC 22678081 T 64 73 vitamin C TRIVIAL 22690946 A 103 117 phloroglucinol TRIVIAL 22690946 A 302 313 Hyperinakin TRIVIAL 22690946 T 0 11 Hyperinakin TRIVIAL 22690946 T 37 51 phloroglucinol TRIVIAL 22694056 A 532 548 hydrogen cyanide SYSTEMATIC 22694056 A 943 964 cyanogenic glucosides FAMILY 22695309 A 1668 1684 5-fluorocytosine SYSTEMATIC 22695309 A 1738 1754 5-fluorocytosine SYSTEMATIC 22695677 A 117 127 nucleotide FAMILY 22705396 A 641 654 acetylcholine SYSTEMATIC 22709946 A 1496 1500 MPEP ABBREVIATION 22709946 A 1743 1752 Glutamate TRIVIAL 22709946 A 651 655 DHPG ABBREVIATION 22709946 A 667 688 polyphosphoinositides FAMILY 22709946 A 716 742 (3)H-inositolmonophosphate SYSTEMATIC 22709946 A 784 788 DHPG ABBREVIATION 22709946 A 864 868 DHPG ABBREVIATION 22713807 A 542 552 nucleotide FAMILY 22713807 A 635 643 carboxyl SYSTEMATIC 22713807 T 17 25 carboxyl SYSTEMATIC 22717325 A 146 164 aliphatic alcohols FAMILY 22717325 A 168 208 1-ethyl-3-methylimidazolium ethylsulfate SYSTEMATIC 22717325 A 210 225 [EMIM][EtSO(4)] FORMULA 22717325 A 240 251 imidazolium SYSTEMATIC 22717325 A 409 424 [EMIM][EtSO(4)] FORMULA 22717325 A 455 462 alcohol FAMILY 22717325 A 583 591 alcohols FAMILY 22717325 A 837 855 aliphatic alcohols FAMILY 22717325 A 931 938 alcohol FAMILY 22717325 A 943 958 [EMIM][EtSO(4)] FORMULA 22717325 A 959 966 alcohol FAMILY 22727823 A 1019 1023 GABA ABBREVIATION 22727823 A 1114 1118 GABA ABBREVIATION 22727823 A 219 223 GABA ABBREVIATION 22727823 A 47 66 γ-aminobutyric acid SYSTEMATIC 22727823 A 68 72 GABA ABBREVIATION 22728760 A 1086 1097 atomoxetine TRIVIAL 22728760 A 1113 1122 clonidine TRIVIAL 22728760 A 1201 1212 risperidone TRIVIAL 22728760 A 1314 1323 sulpiride TRIVIAL 22728760 A 1392 1403 risperidone TRIVIAL 22728760 A 1420 1429 serotonin TRIVIAL 22728760 A 672 683 risperidone TRIVIAL 22728760 A 737 745 tiapride TRIVIAL 22728760 A 837 849 Aripiprazole TRIVIAL 22728760 A 925 933 pimozide TRIVIAL 22735770 A 184 191 cocaine TRIVIAL 22735770 A 193 208 methamphetamine TRIVIAL 22735770 A 933 944 galantamine TRIVIAL 22735770 A 946 955 modafinil TRIVIAL 22735770 A 957 968 atomoxetine TRIVIAL 22735770 A 970 985 methylphenidate SYSTEMATIC 22735770 A 991 1001 guanfacine TRIVIAL 22736379 A 0 10 Pinosylvin TRIVIAL 22736379 A 1063 1073 pinosylvin TRIVIAL 22736379 A 108 118 pinosylvin TRIVIAL 22736379 A 16 24 phenolic FAMILY 22736379 A 233 243 pinosylvin TRIVIAL 22736379 A 274 284 pinosylvin TRIVIAL 22736379 A 286 295 etoposide TRIVIAL 22736379 A 397 407 pinosylvin TRIVIAL 22736379 A 459 469 pinosylvin TRIVIAL 22736379 A 504 516 nitric oxide SYSTEMATIC 22736379 A 545 555 pinosylvin TRIVIAL 22736379 A 630 640 pinosylvin TRIVIAL 22736379 A 699 705 L-NAME ABBREVIATION 22736379 A 746 756 pinosylvin TRIVIAL 22736379 A 859 869 pinosylvin TRIVIAL 22736379 A 937 947 pinosylvin TRIVIAL 22736379 T 0 10 Pinosylvin TRIVIAL 22736379 T 91 103 Nitric Oxide SYSTEMATIC 22744955 A 0 33 Dihydroxy-isosteviol methyl ester SYSTEMATIC 22744955 A 184 194 C21 H34 O3 FORMULA 22744955 A 35 39 DIME ABBREVIATION 22744955 A 487 491 DIME ABBREVIATION 22744955 A 545 549 DIME ABBREVIATION 22744955 A 707 711 DIME ABBREVIATION 22744955 A 799 803 DIME ABBREVIATION 22744955 A 893 897 DIME ABBREVIATION 22744955 T 0 33 Dihydroxy-Isosteviol Methyl Ester SYSTEMATIC 22749643 A 429 432 ATP ABBREVIATION 22749643 A 471 481 oxadiazole FAMILY 22749643 A 605 614 acetamide SYSTEMATIC 22749643 A 706 718 benzodioxane SYSTEMATIC 22749643 T 32 42 oxadiazole FAMILY 22749842 A 1080 1091 amphetamine TRIVIAL 22749842 A 894 905 amphetamine TRIVIAL 22749842 A 915 921 MK-801 IDENTIFIER 22750078 A 1020 1073 a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid SYSTEMATIC 22750078 A 1084 1088 AMPA ABBREVIATION 22750078 A 1146 1150 cAMP ABBREVIATION 22750078 A 1192 1198 THPP-1 IDENTIFIER 22750078 A 1315 1321 MK-801 IDENTIFIER 22750078 A 1426 1432 THPP-1 IDENTIFIER 22750078 A 1507 1515 ketamine TRIVIAL 22750078 A 275 279 cAMP ABBREVIATION 22750078 A 284 288 cGMP ABBREVIATION 22750078 A 369 494 2-(6-chloropyridin-3-yl)-4-(2-methoxyethoxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl](imidazo[1,5-a]pyridin-1-yl)methanone SYSTEMATIC 22750078 A 497 503 THPP-1 IDENTIFIER 22750078 A 688 694 THPP-1 IDENTIFIER 22750078 A 898 904 THPP-1 IDENTIFIER 22750078 T 42 48 THPP-1 IDENTIFIER 22750412 A 1218 1226 prazosin TRIVIAL 22750412 A 1276 1286 quetiapine TRIVIAL 22750412 A 1536 1546 quetiapine TRIVIAL 22750412 A 1615 1627 escitalopram TRIVIAL 22750412 A 1732 1742 quetiapine TRIVIAL 22750412 A 1887 1897 quetiapine TRIVIAL 22750412 A 1941 1953 escitalopram TRIVIAL 22750412 A 2074 2084 quetiapine TRIVIAL 22750412 A 29 39 quetiapine TRIVIAL 22750412 A 329 339 quetiapine TRIVIAL 22750412 A 504 514 quetiapine TRIVIAL 22750412 A 541 550 serotonin TRIVIAL 22750412 A 756 766 quetiapine TRIVIAL 22750412 A 771 783 escitalopram TRIVIAL 22750412 A 991 1001 Quetiapine TRIVIAL 22750412 T 0 10 Quetiapine TRIVIAL 22752958 A 1225 1235 prednisone TRIVIAL 22752958 A 1297 1309 prednisolone TRIVIAL 22752958 A 454 466 prednisolone TRIVIAL 22752958 A 518 528 prednisone TRIVIAL 22752958 A 594 606 prednisolone TRIVIAL 22752958 A 833 843 prednisone TRIVIAL 22752958 T 17 27 prednisone TRIVIAL 22752958 T 82 94 prednisolone TRIVIAL 22761049 A 1076 1087 cholesterol TRIVIAL 22761049 A 108 140 diosmetin 7-O-β-D-apiofuranoside SYSTEMATIC 22761049 A 1092 1105 triglycerides FAMILY 22761049 A 1228 1239 glutathione TRIVIAL 22761049 A 1255 1265 superoxide TRIVIAL 22761049 A 1307 1319 testosterone TRIVIAL 22761049 A 16 25 flavonoid FAMILY 22761049 A 170 177 acetone SYSTEMATIC 22761049 A 38 99 diosmetin 7-O-β-L-arabinofuranosyl (1 → 2) β-D-apiofuranoside SYSTEMATIC 22761049 A 465 472 alloxan TRIVIAL 22761049 A 574 581 alloxan TRIVIAL 22761049 A 745 752 glucose TRIVIAL 22761049 T 129 136 Alloxan TRIVIAL 22761049 T 15 35 Diosmetin Glycosides FAMILY 22766107 A 178 185 glucose TRIVIAL 22766107 A 531 538 glucose TRIVIAL 22766107 A 61 70 metformin TRIVIAL 22767283 A 1033 1040 CoQ(10) ABBREVIATION 22767283 A 1124 1131 CoQ(10) ABBREVIATION 22767283 A 1291 1298 CoQ(10) ABBREVIATION 22767283 A 13 27 coenzyme Q(10) TRIVIAL 22767283 A 1473 1480 CoQ(10) ABBREVIATION 22767283 A 167 174 CoQ(10) ABBREVIATION 22767283 A 29 36 CoQ(10) ABBREVIATION 22767283 A 296 303 CoQ(10) ABBREVIATION 22767283 A 445 452 CoQ(10) ABBREVIATION 22767283 A 512 534 para-aminobenzoic acid SYSTEMATIC 22767283 A 536 540 PABA ABBREVIATION 22767283 A 543 547 PABA ABBREVIATION 22767283 A 582 589 CoQ(10) ABBREVIATION 22767283 A 625 629 PABA ABBREVIATION 22767283 A 690 697 CoQ(10) ABBREVIATION 22767283 A 720 727 CoQ(10) ABBREVIATION 22767283 A 769 776 CoQ(10) ABBREVIATION 22767283 A 915 918 ATP ABBREVIATION 22767283 A 947 954 CoQ(10) ABBREVIATION 22767283 T 15 27 coenzyme Q10 TRIVIAL 22767283 T 164 167 ATP ABBREVIATION 22770610 A 475 484 Dasatinib TRIVIAL 22770610 A 556 565 sunitinib TRIVIAL 22770610 A 570 583 staurosporine TRIVIAL 22776507 A 1084 1092 nicotine TRIVIAL 22776507 A 1205 1213 Nicotine TRIVIAL 22776507 A 341 349 nicotine TRIVIAL 22776507 A 370 383 acetylcholine SYSTEMATIC 22776507 A 528 536 nicotine TRIVIAL 22776507 A 645 653 Nicotine TRIVIAL 22776507 A 84 92 nicotine TRIVIAL 22776507 A 862 870 nicotine TRIVIAL 22776507 T 0 8 Nicotine TRIVIAL 22776694 A 934 941 calcium SYSTEMATIC 22788665 A 0 12 Anthocyanins FAMILY 22788665 A 203 214 anthocyanin FAMILY 22788665 A 332 344 anthocyanins FAMILY 22788665 A 440 452 anthocyanins FAMILY 22788665 A 48 59 polyphenols FAMILY 22788665 A 678 690 anthocyanins FAMILY 22788665 T 8 20 anthocyanins FAMILY 22796105 A 1059 1070 bicuculline TRIVIAL 22796105 A 1074 1078 GABA ABBREVIATION 22796105 A 1435 1444 Glutamate TRIVIAL 22796105 A 158 167 glutamate TRIVIAL 22796105 A 568 575 CPCOOEt FORMULA 22796105 A 622 626 MPEP ABBREVIATION 22796105 A 700 704 DHPG ABBREVIATION 22796105 A 791 798 CPCCOEt FORMULA 22796105 A 800 807 CPCOOEt FORMULA 22796105 A 817 821 MPEP ABBREVIATION 22796105 A 971 975 GABA ABBREVIATION 22796105 A 988 997 glutamate TRIVIAL 22796105 T 21 30 glutamate TRIVIAL 22796337 A 44 47 AMP ABBREVIATION 22796337 T 17 20 AMP ABBREVIATION 22797669 A 149 178 tetrakis(dimethylamino)ethane SYSTEMATIC 22797669 A 180 184 TDAE ABBREVIATION 22797669 A 489 493 TDAE ABBREVIATION 22797669 A 499 530 2-nitropyrene-4,5,9,10-tetraone SYSTEMATIC 22797669 A 582 586 TDAE ABBREVIATION 22797669 A 592 634 2,7-dimethyl nitropyrene-4,5,9,10-tetraone SYSTEMATIC 22797669 T 52 81 tetrakis(dimethylamino)ethene SYSTEMATIC 22798247 A 405 413 androgen FAMILY 22799538 A 111 120 β-orcinol TRIVIAL 22799538 A 126 134 depsides FAMILY 22799538 A 182 200 hypothamnolic acid TRIVIAL 22799538 A 206 226 3'-methylevenic acid SYSTEMATIC 22799538 A 232 248 baeomycesic acid TRIVIAL 22799538 A 254 268 squamatic acid TRIVIAL 22799538 A 274 300 methyl 3'-methyllecanorate SYSTEMATIC 22799538 A 306 321 barbatinic acid TRIVIAL 22799538 A 330 339 atranorin TRIVIAL 22799538 T 0 9 β-Orcinol TRIVIAL 22801296 A 1265 1271 CX1837 IDENTIFIER 22801296 A 1275 1281 CX1739 IDENTIFIER 22801296 A 1315 1320 CX546 IDENTIFIER 22801296 A 1331 1345 β-cyclodextrin TRIVIAL 22801296 A 1662 1668 CX1837 IDENTIFIER 22801296 A 1673 1679 CX1739 IDENTIFIER 22801296 A 1925 1931 CX1837 IDENTIFIER 22801296 A 2107 2113 CX1837 IDENTIFIER 22801296 A 2118 2124 CX1739 IDENTIFIER 22801296 A 2235 2241 CX1837 IDENTIFIER 22801296 A 2246 2252 CX1739 IDENTIFIER 22801296 A 419 427 AMPAKINE FAMILY 22801296 A 517 521 AMPA ABBREVIATION 22801296 A 812 816 AMPA ABBREVIATION 22801296 A 928 934 CX1837 IDENTIFIER 22801296 A 939 945 CX1739 IDENTIFIER 22801296 T 0 8 AMPAKINE FAMILY 22812659 A 0 8 Androgen FAMILY 22812659 A 98 106 androgen FAMILY 22812659 T 0 8 Androgen FAMILY 22813462 A 0 12 Thienorphine TRIVIAL 22813462 A 161 173 thienorphine TRIVIAL 22813462 A 207 219 thienorphine TRIVIAL 22813462 A 409 421 thienorphine TRIVIAL 22813462 A 490 502 thienorphine TRIVIAL 22813462 A 731 743 thienorphine TRIVIAL 22813462 T 46 58 thienorphine TRIVIAL 22813462 T 63 66 UDP ABBREVIATION 22818713 A 1001 1014 phenylephrine TRIVIAL 22818713 A 1189 1198 silibinin TRIVIAL 22818713 A 1213 1226 phenylephrine TRIVIAL 22818713 A 1323 1336 phenylephrine TRIVIAL 22818713 A 1383 1392 silibinin TRIVIAL 22818713 A 1411 1424 phenylephrine TRIVIAL 22818713 A 241 247 oxygen SYSTEMATIC 22818713 A 301 310 silibinin TRIVIAL 22818713 A 320 333 flavonolignan FAMILY 22818713 A 444 461 hydrogen peroxide SYSTEMATIC 22818713 A 463 467 H2O2 FORMULA 22818713 A 514 527 phenylephrine TRIVIAL 22818713 A 642 651 silibinin TRIVIAL 22818713 A 771 780 silibinin TRIVIAL 22818713 A 845 849 H2O2 FORMULA 22818713 A 976 985 silibinin TRIVIAL 22818713 T 0 9 Silibinin TRIVIAL 22818713 T 73 86 phenylephrine TRIVIAL 22820555 A 0 9 Modafinil TRIVIAL 22820555 A 1089 1098 modafinil TRIVIAL 22820555 A 1340 1349 modafinil TRIVIAL 22820555 A 1533 1542 modafinil TRIVIAL 22820555 A 334 343 modafinil TRIVIAL 22820555 A 571 580 modafinil TRIVIAL 22820555 A 802 811 modafinil TRIVIAL 22820555 T 0 9 Modafinil TRIVIAL 22820907 A 767 776 glutamate TRIVIAL 22820932 A 1151 1159 estrogen FAMILY 22820932 A 1196 1201 sugar FAMILY 22820932 A 124 132 estrogen FAMILY 22820932 A 260 265 sugar FAMILY 22820932 A 302 316 streptozotocin TRIVIAL 22820932 A 33 41 estrogen FAMILY 22820932 A 679 687 estrogen FAMILY 22824189 A 1329 1342 phencyclidine TRIVIAL 22824189 A 1440 1450 Egis-11150 NO CLASS 22824189 A 1656 1666 Egis-11150 NO CLASS 22824189 A 234 245 risperidone TRIVIAL 22824189 A 247 257 olanzapine TRIVIAL 22824189 A 262 271 clozapine TRIVIAL 22824189 A 31 42 haloperidol TRIVIAL 22824189 A 44 58 chlorpromazine TRIVIAL 22824189 A 603 613 Egis-11150 NO CLASS 22824189 A 657 667 Egis-11150 NO CLASS 22824189 A 720 724 5-HT SYSTEMATIC 22824189 A 927 940 Phencyclidine TRIVIAL 22824189 T 0 10 Egis-11150 NO CLASS 22824191 A 1057 1068 propranolol TRIVIAL 22824191 A 1194 1205 propranolol TRIVIAL 22824191 A 1296 1307 propranolol TRIVIAL 22824191 A 1611 1622 propranolol TRIVIAL 22824191 A 1643 1654 propranolol TRIVIAL 22824191 A 365 376 propranolol TRIVIAL 22824191 A 580 591 Propranolol TRIVIAL 22824191 T 0 11 Propranolol TRIVIAL 22830980 A 0 25 n-Butyl-p-hydroxybenzoate SYSTEMATIC 22830980 A 1055 1070 BPB-glucuronide TRIVIAL 22830980 A 1072 1083 BPB-sulfate SYSTEMATIC 22830980 A 1085 1104 hydroxybenzoic acid SYSTEMATIC 22830980 A 1109 1129 hydroxyhippuric acid SYSTEMATIC 22830980 A 169 179 [(14)C]BPB SYSTEMATIC 22830980 A 245 248 BPB ABBREVIATION 22830980 A 27 41 n-butylparaben SYSTEMATIC 22830980 A 399 418 hydroxybenzoic acid SYSTEMATIC 22830980 A 43 46 BPB ABBREVIATION 22830980 A 449 468 hydroxybenzoic acid SYSTEMATIC 22830980 A 473 493 hydroxyhippuric acid SYSTEMATIC 22830980 A 495 505 [(14)C]BPB SYSTEMATIC 22830980 A 697 700 BPB ABBREVIATION 22830980 T 30 60 [14C]n-butyl-p-hydroxybenzoate SYSTEMATIC 22848037 A 734 738 heme FAMILY 22848037 T 42 46 Heme FAMILY 22859661 A 117 131 streptozotocin TRIVIAL 22859661 A 341 355 streptozotocin TRIVIAL 22859661 A 357 366 Vitamin C TRIVIAL 22859661 A 380 389 vitamin E FAMILY 22859661 A 406 408 Se FORMULA 22859661 A 554 558 urea TRIVIAL 22859661 A 56 65 vitamin C TRIVIAL 22859661 A 563 573 creatinine TRIVIAL 22859661 A 657 668 glutathione TRIVIAL 22859661 A 67 76 vitamin E FAMILY 22859661 A 702 711 vitamin C TRIVIAL 22859661 A 713 722 vitamin E FAMILY 22859661 A 727 729 Se FORMULA 22859661 A 784 793 vitamin C TRIVIAL 22859661 A 795 804 vitamin E FAMILY 22859661 A 809 811 Se FORMULA 22859661 A 81 89 selenium SYSTEMATIC 22859661 A 891 905 streptozotocin TRIVIAL 22859661 A 91 93 Se FORMULA 22859661 T 35 44 vitamin C TRIVIAL 22859661 T 46 55 vitamin E FAMILY 22859661 T 60 68 selenium SYSTEMATIC 22863599 A 0 8 Dopamine TRIVIAL 22863599 A 1226 1236 rotigotine TRIVIAL 22863599 A 1415 1423 dopamine TRIVIAL 22863599 A 362 370 dopamine TRIVIAL 22863599 A 481 489 dopamine TRIVIAL 22863599 A 559 567 dopamine TRIVIAL 22863599 A 629 637 dopamine TRIVIAL 22863599 A 646 656 Rotigotine TRIVIAL 22863599 A 738 748 Rotigotine TRIVIAL 22863599 A 754 762 dopamine TRIVIAL 22863599 T 0 8 Dopamine TRIVIAL 22863599 T 20 30 rotigotine TRIVIAL 22867273 A 1062 1079 medoxomil alcohol TRIVIAL 22867273 A 1121 1128 TAK-491 IDENTIFIER 22867273 A 1158 1165 TAK-491 IDENTIFIER 22867273 A 1182 1202 olmesartan medoxomil TRIVIAL 22867273 A 1254 1261 TAK-491 IDENTIFIER 22867273 A 1281 1288 TAK-536 IDENTIFIER 22867273 A 1310 1330 olmesartan medoxomil TRIVIAL 22867273 A 148 155 TAK-536 IDENTIFIER 22867273 A 273 280 TAK-491 IDENTIFIER 22867273 A 310 317 TAK-491 IDENTIFIER 22867273 A 345 352 TAK-536 IDENTIFIER 22867273 A 37 44 TAK-491 IDENTIFIER 22867273 A 433 440 TAK-491 IDENTIFIER 22867273 A 473 480 TAK-491 IDENTIFIER 22867273 A 493 500 TAK-491 IDENTIFIER 22867273 A 58 63 ester FAMILY 22867273 A 630 637 TAK-491 IDENTIFIER 22867273 A 723 730 TAK-491 IDENTIFIER 22867273 A 798 805 TAK-536 IDENTIFIER 22867273 A 83 92 medoxomil TRIVIAL 22867273 A 835 842 TAK-491 IDENTIFIER 22867273 A 907 914 TAK-536 IDENTIFIER 22867273 A 937 944 TAK-491 IDENTIFIER 22867273 T 14 21 TAK-491 IDENTIFIER 22867273 T 29 43 angiotensin II TRIVIAL 22867529 A 1008 1017 pyridinyl SYSTEMATIC 22867529 A 1059 1070 quinazoline SYSTEMATIC 22867529 A 1207 1208 H FORMULA 22867529 A 1227 1230 N-H FORMULA 22867529 A 1238 1253 ethylenediamine SYSTEMATIC 22867529 A 1274 1282 6-alkoxy FAMILY 22867529 A 1292 1295 Asp FORMULA 22867529 A 1299 1302 Cys FORMULA 22867529 A 229 236 aniline SYSTEMATIC 22867529 A 252 260 6-alkoxy FAMILY 22867529 A 273 307 6,7-dimethoxy-4-anilinoquinazoline SYSTEMATIC 22867529 A 535 555 4-anilinoquinazoline SYSTEMATIC 22867529 A 55 75 4-anilinoquinazoline SYSTEMATIC 22867529 A 595 598 ATP ABBREVIATION 22867529 A 701 708 anilino TRIVIAL 22867529 A 719 727 6-alkoxy FAMILY 22867529 A 740 751 quinazoline SYSTEMATIC 22867529 A 822 823 H FORMULA 22867529 A 852 863 quinazoline SYSTEMATIC 22867529 A 873 876 Thr FORMULA 22867529 A 924 935 quinazoline SYSTEMATIC 22867529 A 945 948 N-H FORMULA 22867529 A 952 955 Met FORMULA 22867529 A 982 988 phenyl SYSTEMATIC 22867529 T 63 83 4-anilinoquinazoline SYSTEMATIC 22867529 T 99 107 tyrosine TRIVIAL 22869589 A 1055 1063 hydrogen SYSTEMATIC 22869589 A 1064 1073 deuterium SYSTEMATIC 22871141 A 172 191 polyethylene glycol SYSTEMATIC 22871141 A 193 196 PEG ABBREVIATION 22871141 A 221 249 mono-, di- and triglycerides MULTIPLE 22871141 A 276 279 PEG ABBREVIATION 22878862 A 124 128 zinc SYSTEMATIC 22878862 A 183 186 His FORMULA 22878862 A 191 194 Tyr FORMULA 22878862 A 613 617 zinc SYSTEMATIC 22878862 A 634 637 His FORMULA 22878862 A 718 721 His FORMULA 22878862 A 885 888 His FORMULA 22878862 T 66 69 His FORMULA 22878862 T 74 77 Tyr FORMULA 22884520 A 188 199 cholesterol TRIVIAL 22884520 A 226 237 cholesterol TRIVIAL 22884520 A 307 317 oxysterols FAMILY 22884520 A 347 358 cholesterol TRIVIAL 22884520 A 428 439 cholesterol TRIVIAL 22884520 A 490 496 sterol FAMILY 22884520 A 5 16 cholesterol TRIVIAL 22884520 A 548 557 oxysterol FAMILY 22884520 A 661 670 oxysterol FAMILY 22884520 A 777 786 oxysterol FAMILY 22884520 A 844 855 cholesterol TRIVIAL 22884520 A 898 909 cholesterol TRIVIAL 22884520 A 966 975 oxysterol FAMILY 22884520 T 0 9 Oxysterol FAMILY 22884520 T 60 71 cholesterol TRIVIAL 22884612 A 1028 1032 NMDA ABBREVIATION 22884612 A 105 109 NMDA ABBREVIATION 22884612 A 1054 1064 Ro 63-1908 IDENTIFIER 22884612 A 1066 1076 LSN2463359 IDENTIFIER 22884612 A 1152 1155 PCP ABBREVIATION 22884612 A 1159 1170 SDZ 220,581 IDENTIFIER 22884612 A 13 22 glutamate TRIVIAL 22884612 A 1369 1380 SDZ 220,581 IDENTIFIER 22884612 A 1434 1444 Ro 63-1908 IDENTIFIER 22884612 A 1459 1469 LSN2463359 IDENTIFIER 22884612 A 1556 1559 PCP ABBREVIATION 22884612 A 1564 1570 MK-801 IDENTIFIER 22884612 A 1594 1597 PCP ABBREVIATION 22884612 A 1602 1613 SDZ 220,581 IDENTIFIER 22884612 A 1687 1697 LSN2463359 IDENTIFIER 22884612 A 1752 1763 SDZ 220,581 IDENTIFIER 22884612 A 1826 1830 NMDA ABBREVIATION 22884612 A 2010 2014 NMDA ABBREVIATION 22884612 A 314 324 LSN2463359 IDENTIFIER 22884612 A 448 452 NMDA ABBREVIATION 22884612 A 474 485 SDZ 220,581 IDENTIFIER 22884612 A 500 510 LSN2463359 IDENTIFIER 22884612 A 643 656 phencyclidine TRIVIAL 22884612 A 658 661 PCP ABBREVIATION 22884612 A 740 744 NMDA ABBREVIATION 22884612 A 804 814 LSN2463359 IDENTIFIER 22884612 A 83 103 N-methyl-d-aspartate SYSTEMATIC 22884612 A 908 912 NMDA ABBREVIATION 22884612 A 934 937 PCP ABBREVIATION 22884612 A 942 948 MK-801 IDENTIFIER 22884612 A 966 970 NMDA ABBREVIATION 22884612 A 991 1002 SDZ 220,581 IDENTIFIER 22884612 T 121 125 NMDA ABBREVIATION 22884612 T 40 50 LSN2463359 IDENTIFIER 22884720 A 1053 1061 [³H]MPEP SYSTEMATIC 22884720 A 113 117 NMDA ABBREVIATION 22884720 A 1286 1291 MPEPy ABBREVIATION 22884720 A 1485 1490 CDPPB ABBREVIATION 22884720 A 1495 1503 ADX47273 IDENTIFIER 22884720 A 1645 1655 LSN2463359 IDENTIFIER 22884720 A 1660 1670 LSN2814617 IDENTIFIER 22884720 A 1733 1737 NMDA ABBREVIATION 22884720 A 1758 1769 SDZ 220,581 IDENTIFIER 22884720 A 2074 2085 SDZ 220,581 IDENTIFIER 22884720 A 2296 2306 LSN2463359 IDENTIFIER 22884720 A 2311 2321 LSN2814617 IDENTIFIER 22884720 A 435 445 LSN2463359 IDENTIFIER 22884720 A 447 510 N-(1-methylethyl)-5-(pyridin-4-ylethynyl)pyridine-2-carboxamide SYSTEMATIC 22884720 A 516 526 LSN2814617 IDENTIFIER 22884720 A 528 638 (7S)-3-tert-butyl-7-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-A]pyridine SYSTEMATIC 22884720 A 56 65 glutamate TRIVIAL 22884720 A 885 894 glutamate TRIVIAL 22884720 A 902 911 glutamate TRIVIAL 22884720 A 91 111 N-methyl-d-aspartate SYSTEMATIC 22884720 A 930 934 DHPG ABBREVIATION 22884720 T 108 118 LSN2814617 IDENTIFIER 22884720 T 93 103 LSN2463359 IDENTIFIER 22885792 A 1008 1044 poly (ethylene-alt-maleic anhydride) FAMILY 22885792 A 1046 1050 PEMA ABBREVIATION 22885792 A 1083 1089 TiO(2) FORMULA 22885792 A 1151 1157 TiO(2) FORMULA 22885792 A 119 125 TiO(2) FORMULA 22885792 A 1280 1288 hydroxyl SYSTEMATIC 22885792 A 1298 1301 ·OH FORMULA 22885792 A 235 241 TiO(2) FORMULA 22885792 A 33 39 TiO(2) FORMULA 22885792 A 339 345 TiO(2) FORMULA 22885792 A 504 512 hydroxyl SYSTEMATIC 22885792 A 535 541 oxygen SYSTEMATIC 22885792 A 664 670 TiO(2) FORMULA 22885792 A 963 971 hydroxyl SYSTEMATIC 22885792 T 8 14 TiO(2) FORMULA 22886720 A 0 9 Vitamin D FAMILY 22886720 A 119 138 25-hydroxyvitamin D SYSTEMATIC 22886720 A 1294 1299 25OHD SYSTEMATIC 22886720 A 1303 1316 1,25(OH)(2) D SYSTEMATIC 22886720 A 140 145 25OHD SYSTEMATIC 22886720 A 150 173 1,25-dihydroxyvitamin D SYSTEMATIC 22886720 A 1563 1576 1,25(OH)(2) D SYSTEMATIC 22886720 A 1694 1707 1,25(OH)(2) D SYSTEMATIC 22886720 A 175 188 1,25(OH)(2) D SYSTEMATIC 22886720 A 1843 1852 vitamin D FAMILY 22886720 A 219 232 1,25(OH)(2) D SYSTEMATIC 22886720 A 326 335 vitamin D FAMILY 22886720 A 497 510 1,25(OH)(2) D SYSTEMATIC 22886720 T 61 84 1,25-dihydroxyvitamin D SYSTEMATIC 22887463 A 185 196 dithioester SYSTEMATIC 22887463 A 2 37 crown-ether dithiol quaterthiophene FAMILY 22887463 A 219 225 Pb(2+) FORMULA 22887463 A 297 304 dithiol SYSTEMATIC 22887463 A 355 359 GaIn FORMULA 22887463 A 477 483 Pb(2+) FORMULA 22887463 T 2 13 crown-ether FAMILY 22887463 T 31 45 oligothiophene FAMILY 22887720 A 2028 2042 bisphosphonate SYSTEMATIC 22887720 A 59 74 bisphosphonates FAMILY 22887720 A 915 929 Bisphosphonate SYSTEMATIC 22889206 A 148 149 O FORMULA 22889206 A 173 196 N-p-coumaroyl serotonin SYSTEMATIC 22889206 A 215 235 N-feruloyl serotonin SYSTEMATIC 22889206 A 244 267 N-isoferuloyl serotonin SYSTEMATIC 22889206 A 312 357 N-feruloyl serotonin-4'-O-β-D-glucopyranoside SYSTEMATIC 22889206 A 366 414 N-isoferuloyl serotonin-3'-O-β-D-glucopyranoside SYSTEMATIC 22889206 A 6 15 serotonin TRIVIAL 22889206 A 89 120 N-p-methoxy cinnamoyl serotonin SYSTEMATIC 22889206 T 21 30 serotonin TRIVIAL 22889207 A 21 36 tetraterpenoids FAMILY 22889207 A 38 48 Sarglaucol TRIVIAL 22889207 T 17 32 tetraterpenoids FAMILY 22890749 A 207 212 ethyl SYSTEMATIC 22890749 A 248 256 ethylene SYSTEMATIC 22890749 A 345 358 glycidic acid TRIVIAL 22890749 A 38 72 ethyl and ethyl 3-phenyl glycidate MULTIPLE 22890749 A 408 416 aldehyde SYSTEMATIC 22890749 A 444 457 glycidic acid TRIVIAL 22890749 T 42 76 ethyl and ethyl 3-phenyl glycidate MULTIPLE 22891925 A 143 160 [Ni(phpy)(m)](2+) FAMILY 22891925 A 178 196 [NiCl(phpy)(n)](+) FAMILY 22891925 A 355 359 phpy ABBREVIATION 22891925 A 363 369 2-phpy SYSTEMATIC 22891925 A 412 425 3- and 4-phpy MULTIPLE 22891925 A 47 62 phenylpyridines FAMILY 22891925 A 579 585 2-phpy SYSTEMATIC 22891925 A 587 590 C-H FORMULA 22891925 A 614 632 [NiCl(phpy)(2)](+) FORMULA 22891925 A 64 68 phpy ABBREVIATION 22891925 A 732 745 3- and 4-phpy MULTIPLE 22891925 A 89 108 nickel(II) chloride SYSTEMATIC 22891925 T 63 78 phenylpyridines FAMILY 22891925 T 88 107 nickel(II) chloride SYSTEMATIC 22893351 A 1015 1017 Hg FORMULA 22893351 A 106 108 Hg FORMULA 22893351 A 194 196 Hg FORMULA 22893351 A 240 251 glutathione TRIVIAL 22893351 A 252 253 S FORMULA 22893351 A 364 366 Hg FORMULA 22893351 A 726 728 Hg FORMULA 22893351 A 88 95 mercury SYSTEMATIC 22893351 A 97 99 Hg FORMULA 22893351 T 50 57 mercury SYSTEMATIC 22893354 A 1210 1217 KMnO(4) FORMULA 22893354 A 1284 1291 KMnO(4) FORMULA 22893354 A 1334 1341 KMnO(4) FORMULA 22893354 A 1362 1364 Mn FORMULA 22893354 A 1521 1523 Mn FORMULA 22893354 A 1622 1627 KMnO4 FORMULA 22893354 A 325 347 Potassium permanganate SYSTEMATIC 22893354 A 349 356 KMnO(4) FORMULA 22893354 A 498 507 Manganese SYSTEMATIC 22893354 A 509 511 Mn FORMULA 22893354 A 550 562 permanganate SYSTEMATIC 22893354 A 564 572 MnO4 (-) FORMULA 22893354 A 578 587 manganous SYSTEMATIC 22893354 A 589 595 Mn(+2) FORMULA 22893354 A 641 648 KMnO(4) FORMULA 22893354 A 718 720 Mn FORMULA 22893354 A 773 780 KMnO(4) FORMULA 22893354 A 991 998 KMnO(4) FORMULA 22893354 T 55 77 potassium permanganate SYSTEMATIC 22898212 A 0 26 Cresyl saligenin phosphate SYSTEMATIC 22898212 A 1003 1007 CBDP ABBREVIATION 22898212 A 137 141 CBDP ABBREVIATION 22898212 A 195 214 tricresyl phosphate SYSTEMATIC 22898212 A 216 219 TCP ABBREVIATION 22898212 A 28 32 CBDP ABBREVIATION 22898212 A 281 285 CBDP ABBREVIATION 22898212 A 391 397 serine TRIVIAL 22898212 A 399 402 Ser FORMULA 22898212 A 451 460 saligenin TRIVIAL 22898212 A 465 473 o-cresol TRIVIAL 22898212 A 491 500 histidine TRIVIAL 22898212 A 502 505 His FORMULA 22898212 A 540 555 o-hydroxybenzyl SYSTEMATIC 22898212 A 590 593 Ser FORMULA 22898212 A 663 667 CBDP ABBREVIATION 22898212 A 697 700 Glu FORMULA 22898212 A 713 728 o-hydroxybenzyl SYSTEMATIC 22898212 A 749 755 lysine TRIVIAL 22898212 A 808 811 His FORMULA 22898212 A 835 843 nitrogen SYSTEMATIC 22898212 A 851 860 imidazole SYSTEMATIC 22898212 A 874 885 l-histidine TRIVIAL 22898212 A 933 937 CBDP ABBREVIATION 22898212 A 953 968 o-hydroxybenzyl SYSTEMATIC 22898212 A 993 1002 histidine TRIVIAL 22898212 T 0 26 Cresyl saligenin phosphate SYSTEMATIC 22898212 T 100 109 histidine TRIVIAL 22898212 T 58 67 histidine TRIVIAL 22899726 A 1118 1123 β-HCH ABBREVIATION 22899726 A 1125 1133 dieldrin TRIVIAL 22899726 A 1138 1145 pp'-DDE ABBREVIATION 22899726 A 263 277 organochlorine FAMILY 22899726 A 318 339 hexachlorocyclohexane SYSTEMATIC 22899726 A 341 344 HCH ABBREVIATION 22899726 A 347 353 aldrin TRIVIAL 22899726 A 355 363 dieldrin TRIVIAL 22899726 A 365 375 endosulfan TRIVIAL 22899726 A 377 413 pp'-dichlorodiphenyldichloroethylene SYSTEMATIC 22899726 A 415 422 pp'-DDE ABBREVIATION 22899726 A 425 432 op'-DDE ABBREVIATION 22899726 A 434 469 pp'-dichlorodiphenyltrichloroethane SYSTEMATIC 22899726 A 471 478 pp'-DDT ABBREVIATION 22899726 A 481 488 op'-DDT ABBREVIATION 22899726 A 490 524 pp'-dichlorodiphenyldichloroethane SYSTEMATIC 22899726 A 526 533 pp'-DDD ABBREVIATION 22899726 A 539 546 op'-DDD ABBREVIATION 22899726 A 686 691 β-HCH ABBREVIATION 22899726 A 761 769 dieldrin TRIVIAL 22899726 A 842 849 pp'-DDE ABBREVIATION 22899726 T 0 14 Organochlorine FAMILY 22899727 A 1124 1126 Mn FORMULA 22899727 A 1259 1261 Mn FORMULA 22899727 A 1373 1375 Mn FORMULA 22899727 A 1553 1555 Mn FORMULA 22899727 A 257 266 flavonoid FAMILY 22899727 A 271 273 Mn FORMULA 22899727 A 392 410 manganese chloride SYSTEMATIC 22899727 A 514 516 Mn FORMULA 22899727 A 596 605 bilirubin TRIVIAL 22899727 A 653 659 oxygen SYSTEMATIC 22899727 A 71 80 manganese SYSTEMATIC 22899727 A 760 770 superoxide TRIVIAL 22899727 A 795 806 glutathione TRIVIAL 22899727 A 82 84 Mn FORMULA 22899727 A 870 881 glutathione TRIVIAL 22899727 A 889 899 sulfhydryl FAMILY 22899727 A 911 920 vitamin C TRIVIAL 22899727 T 64 73 manganese SYSTEMATIC 22899728 A 1001 1012 glutathione TRIVIAL 22899728 A 1152 1158 copper SYSTEMATIC 22899728 A 1176 1182 oxygen SYSTEMATIC 22899728 A 1220 1222 Cu FORMULA 22899728 A 1375 1377 Cu FORMULA 22899728 A 267 269 Cu FORMULA 22899728 A 30 36 copper SYSTEMATIC 22899728 A 358 365 nitrate SYSTEMATIC 22899728 A 371 378 nitrite SYSTEMATIC 22899728 A 38 40 Cu FORMULA 22899728 A 402 411 carbonyls FAMILY 22899728 A 416 435 thiobarbituric acid SYSTEMATIC 22899728 A 520 541 saturated fatty acids FAMILY 22899728 A 587 589 Cu FORMULA 22899728 A 662 664 Cu FORMULA 22899728 A 675 685 Superoxide TRIVIAL 22899728 A 939 951 α-tocopherol TRIVIAL 22899728 A 956 962 ferric SYSTEMATIC 22899728 T 10 16 copper SYSTEMATIC 22902307 A 187 190 MTT ABBREVIATION 22902323 A 0 11 Fatty acids FAMILY 22902323 A 133 143 fatty acid FAMILY 22902323 A 244 255 fatty acids FAMILY 22902323 A 332 343 fatty acids FAMILY 22902323 A 541 551 fatty acid FAMILY 22902323 A 740 756 arachidonic acid TRIVIAL 22902323 T 15 31 arachidonic acid TRIVIAL 22902329 A 0 9 Vitamin E FAMILY 22902329 A 1044 1056 somatostatin TRIVIAL 22902329 A 1082 1091 vitamin E FAMILY 22902329 A 1131 1143 somatostatin TRIVIAL 22902329 A 1181 1189 adenylyl TRIVIAL 22902329 A 1202 1217 phosphotyrosine SYSTEMATIC 22902329 A 1284 1293 vitamin E FAMILY 22902329 A 1329 1344 phosphotyrosine SYSTEMATIC 22902329 A 1569 1581 α-tocopherol TRIVIAL 22902329 A 1714 1723 vitamin E FAMILY 22902329 A 1743 1755 somatostatin TRIVIAL 22902329 A 325 337 α-tocopherol TRIVIAL 22902329 A 375 405 cyclic adenosine monophosphate SYSTEMATIC 22902329 A 515 526 tocopherols FAMILY 22902329 A 554 563 vitamin E FAMILY 22902329 A 565 577 somatostatin TRIVIAL 22902329 A 683 693 tocopherol FAMILY 22902329 A 701 713 somatostatin TRIVIAL 22902329 A 792 804 somatostatin TRIVIAL 22902329 A 833 842 vitamin-E FAMILY 22902329 A 917 929 somatostatin TRIVIAL 22902329 T 0 9 Vitamin E FAMILY 22902329 T 89 104 phosphotyrosine SYSTEMATIC 22906567 A 1013 1023 avobenzone TRIVIAL 22906567 A 1229 1251 octyl methoxycinnamate SYSTEMATIC 22906567 A 1253 1256 OMC ABBREVIATION 22906567 A 1259 1269 avobenzone TRIVIAL 22906567 A 1271 1274 AVB ABBREVIATION 22906567 A 1280 1307 4-methylbenzilidene camphor SYSTEMATIC 22906567 A 1309 1312 MBC ABBREVIATION 22906567 A 151 170 vitamin A palmitate FAMILY 22906567 A 354 373 vitamin A palmitate FAMILY 22906567 A 806 816 Avobenzone TRIVIAL 22906567 A 858 867 vitamin A FAMILY 22906567 A 945 964 vitamin A palmitate FAMILY 22906567 T 100 119 vitamin A palmitate FAMILY 22906570 A 1073 1076 SDS ABBREVIATION 22906570 A 1386 1389 SDS ABBREVIATION 22906570 A 2176 2179 SDS ABBREVIATION 22906570 A 2463 2466 SDS ABBREVIATION 22914798 A 1017 1022 NaLac FORMULA 22914798 A 1043 1048 NaLac FORMULA 22914798 A 1305 1311 CBiPES ABBREVIATION 22914798 A 1313 1318 THIIC ABBREVIATION 22914798 A 1322 1332 alprazolam TRIVIAL 22914798 A 1346 1351 NaLac FORMULA 22914798 A 1369 1374 NaLac FORMULA 22914798 A 1515 1524 glutamate TRIVIAL 22914798 A 1604 1614 alprazolam TRIVIAL 22914798 A 268 282 sodium lactate SYSTEMATIC 22914798 A 284 289 NaLac FORMULA 22914798 A 32 36 GABA ABBREVIATION 22914798 A 403 407 NMDA ABBREVIATION 22914798 A 445 454 glutamate TRIVIAL 22914798 A 508 513 NaLac FORMULA 22914798 A 542 551 glutamate TRIVIAL 22914798 A 62 75 l-allyglycine SYSTEMATIC 22914798 A 664 670 CBiPES ABBREVIATION 22914798 A 675 680 THIIC ABBREVIATION 22914798 A 724 733 glutamate TRIVIAL 22914798 A 79 92 glutamic acid TRIVIAL 22914798 A 811 816 NaLac FORMULA 22914798 A 902 912 alprazolam TRIVIAL 22914798 A 962 976 benzodiazepine FAMILY 22914798 T 22 31 glutamate TRIVIAL 22914798 T 80 94 sodium lactate SYSTEMATIC 22917842 A 100 110 fatty acid FAMILY 22917842 A 1660 1667 glucose TRIVIAL 22917842 A 273 280 glucose TRIVIAL 22917842 A 285 295 fatty acid FAMILY 22917842 A 88 95 glucose TRIVIAL 22917842 T 149 156 glucose TRIVIAL 22918703 A 0 6 SU5416 IDENTIFIER 22918703 A 1258 1265 phospho SYSTEMATIC 22918703 A 1422 1428 SU5416 IDENTIFIER 22918703 A 1666 1672 SU5416 IDENTIFIER 22918703 A 327 333 SU5416 IDENTIFIER 22918703 A 514 520 SU5416 IDENTIFIER 22918703 A 555 561 SU5416 IDENTIFIER 22918703 A 717 724 Phospho SYSTEMATIC 22918703 A 765 771 SU5416 IDENTIFIER 22918703 A 879 887 LY294002 IDENTIFIER 22918703 A 953 961 LY294002 IDENTIFIER 22918703 A 975 981 SU5416 IDENTIFIER 22918703 T 64 70 SU5416 IDENTIFIER 22921426 A 1034 1052 methionine choline TRIVIAL 22921426 A 1095 1101 Pb(2+) FORMULA 22921426 A 1113 1119 Ca(2+) FORMULA 22921426 A 1127 1133 Ca(2+) FORMULA 22921426 A 1282 1288 Pb(2+) FORMULA 22921426 A 1300 1307 calcium SYSTEMATIC 22921426 A 1341 1347 Ca(2+) FORMULA 22921426 A 1357 1375 methionine choline TRIVIAL 22921426 A 1402 1408 Ca(2+) FORMULA 22921426 A 205 212 calcium SYSTEMATIC 22921426 A 330 336 Pb(2+) FORMULA 22921426 A 385 392 calcium SYSTEMATIC 22921426 A 409 415 Ca(2+) FORMULA 22921426 A 425 431 Ca(2+) FORMULA 22921426 A 516 534 methionine choline TRIVIAL 22921426 A 711 717 Pb(2+) FORMULA 22921426 A 729 735 Ca(2+) FORMULA 22921426 A 755 761 Ca(2+) FORMULA 22921426 A 827 833 Pb(2+) FORMULA 22921426 A 867 876 ryanodine TRIVIAL 22921426 A 910 937 inositol-1,4,5-triphosphate SYSTEMATIC 22921426 A 985 991 Ca(2+) FORMULA 22921426 T 16 23 calcium SYSTEMATIC 22921426 T 58 76 methionine choline TRIVIAL 22921427 A 100 109 verapamil TRIVIAL 22921427 A 1073 1082 verapamil TRIVIAL 22921427 A 1095 1108 bufadienolide TRIVIAL 22921427 A 1142 1151 verapamil TRIVIAL 22921427 A 1199 1213 bufadienolides FAMILY 22921427 A 1250 1264 bufadienolides FAMILY 22921427 A 130 144 bufadienolides FAMILY 22921427 A 1331 1340 verapamil TRIVIAL 22921427 A 1349 1362 bufadienolide TRIVIAL 22921427 A 1410 1419 verapamil TRIVIAL 22921427 A 1477 1491 bufadienolides FAMILY 22921427 A 179 192 bufadienolide TRIVIAL 22921427 A 301 315 bufadienolides FAMILY 22921427 A 356 365 verapamil TRIVIAL 22921427 A 446 460 bufadienolides FAMILY 22921427 A 581 590 verapamil TRIVIAL 22921427 A 692 705 bufadienolide TRIVIAL 22921427 A 849 862 bufadienolide TRIVIAL 22921427 A 947 960 bufadienolide TRIVIAL 22921427 A 978 987 verapamil TRIVIAL 22921427 A 988 1001 bufadienolide TRIVIAL 22921427 T 21 35 bufadienolides FAMILY 22921427 T 64 73 verapamil TRIVIAL 22922038 A 0 11 NaP zeolite FORMULA 22922038 A 288 300 NaP zeolites FORMULA 22922038 T 13 24 NaP zeolite FORMULA 22922246 A 1078 1085 Octanol SYSTEMATIC 22923492 A 1099 1110 amino acids FAMILY 22923492 A 1479 1489 amino acid FAMILY 22923492 A 198 214 aryl hydrocarbon FAMILY 22923492 A 57 63 dioxin FAMILY 22923492 A 794 804 amino acid FAMILY 22923492 A 960 970 amino acid FAMILY 22923492 A 999 1034 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 22923492 T 0 10 Amino acid FAMILY 22923492 T 133 139 dioxin FAMILY 22923492 T 56 72 aryl hydrocarbon FAMILY 22925550 A 194 211 glucono-δ-lactone TRIVIAL 22925550 A 482 484 SH FORMULA 22926046 A 1125 1128 Cys FORMULA 22926046 A 613 624 amino acids FAMILY 22926046 A 665 675 amino acid FAMILY 22926046 A 764 767 Cys FORMULA 22926699 A 1041 1057 aryl hydrocarbon FAMILY 22929928 A 463 472 oil-red-O TRIVIAL 22930682 A 1003 1013 monoamines FAMILY 22930682 A 1018 1029 amino acids FAMILY 22930682 A 1133 1135 Pb FORMULA 22930682 A 1234 1236 Pb FORMULA 22930682 A 329 331 Pb FORMULA 22930682 A 693 703 Pb acetate SYSTEMATIC 22931530 A 0 28 α-Amino-α´-halomethylketones FAMILY 22931530 A 103 110 carbons FAMILY 22931530 A 344 350 serine TRIVIAL 22931530 A 355 363 cysteine TRIVIAL 22931530 T 0 28 α-Amino-α´-Halomethylketones FAMILY 22931530 T 100 108 Cysteine TRIVIAL 22931530 T 89 95 Serine TRIVIAL 22931533 A 0 10 Morphinans FAMILY 22931533 A 196 207 Galantamine TRIVIAL 22931533 A 323 336 acetylcholine SYSTEMATIC 22931533 A 408 417 morphinan TRIVIAL 22931533 A 466 473 codeine TRIVIAL 22931533 A 478 487 eseroline TRIVIAL 22931533 A 494 505 galantamine TRIVIAL 22931535 A 382 386 TiO2 FORMULA 22931535 A 44 48 TiO2 FORMULA 22931535 T 48 52 TiO2 FORMULA 22933107 A 1273 1280 glucose TRIVIAL 22933107 A 269 278 manganese SYSTEMATIC 22933107 A 515 524 manganese SYSTEMATIC 22933107 A 621 637 cyclophosphamide TRIVIAL 22933107 A 789 805 cyclophosphamide TRIVIAL 22933107 A 873 882 manganese SYSTEMATIC 22933107 A 913 929 cyclophosphamide TRIVIAL 22933107 T 0 9 Manganese SYSTEMATIC 22933107 T 92 108 cyclophosphamide TRIVIAL 22933114 A 1062 1069 glucose TRIVIAL 22933114 A 1081 1088 NAD(P)H ABBREVIATION 22933114 A 1093 1099 Ca(2+) FORMULA 22933114 A 1152 1159 glucose TRIVIAL 22933114 A 1303 1310 glucose TRIVIAL 22933114 A 327 334 glucose TRIVIAL 22933114 A 359 365 Ca(2+) FORMULA 22933114 A 539 545 Ca(2+) FORMULA 22933114 A 586 589 ATP ABBREVIATION 22933114 A 639 646 glucose TRIVIAL 22933114 A 857 864 glucose TRIVIAL 22933114 A 894 901 NAD(P)H ABBREVIATION 22933114 A 923 929 Ca(2+) FORMULA 22933114 T 26 33 glucose TRIVIAL 22935067 A 1210 1215 V-GCV ABBREVIATION 22935067 A 268 279 ganciclovir TRIVIAL 22935067 A 281 284 GCV ABBREVIATION 22935067 A 296 310 valganciclovir TRIVIAL 22935067 A 312 317 V-GCV ABBREVIATION 22935067 A 322 338 mono-valyl ester SYSTEMATIC 22935067 A 351 354 GCV ABBREVIATION 22935067 A 429 434 V-GCV ABBREVIATION 22935067 A 514 517 GCV ABBREVIATION 22935067 A 626 629 GCV ABBREVIATION 22935067 A 766 771 V-GCV ABBREVIATION 22935067 T 55 69 valganciclovir TRIVIAL 22935616 A 1198 1205 phospho SYSTEMATIC 22935616 A 469 485 phosphoinositide FAMILY 22935616 A 694 697 Ser FORMULA 22935616 A 701 704 Ser FORMULA 22936354 A 103 117 hydroxyapatite TRIVIAL 22936354 A 1199 1213 hydroxyapatite TRIVIAL 22936354 A 243 251 chloride SYSTEMATIC 22936354 A 309 327 phosphatidylserine FAMILY 22936354 A 974 981 calcium SYSTEMATIC 22936354 T 52 70 phosphatidylserine FAMILY 22940465 A 1027 1038 lipoic acid TRIVIAL 22940465 A 1100 1105 lyral TRIVIAL 22940465 A 1110 1116 lilial TRIVIAL 22940465 A 115 120 lyral TRIVIAL 22940465 A 125 131 lilial TRIVIAL 22940465 A 1286 1289 ATP ABBREVIATION 22940465 A 307 312 Lyral TRIVIAL 22940465 A 317 323 lilial TRIVIAL 22940465 A 494 497 ATP ABBREVIATION 22940465 A 659 665 oxygen SYSTEMATIC 22940465 A 706 723 N-acetyl cysteine SYSTEMATIC 22940465 A 728 734 trolox TRIVIAL 22940465 A 763 774 lipoic acid TRIVIAL 22940465 A 830 841 glutathione TRIVIAL 22940465 A 843 854 Lipoic acid TRIVIAL 22940465 A 958 963 lyral TRIVIAL 22940465 A 968 974 lilial TRIVIAL 22940465 A 983 1008 α,β-unsaturated aldehydes FAMILY 22940465 T 137 140 ATP ABBREVIATION 22940465 T 20 25 lyral TRIVIAL 22940465 T 30 36 lilial TRIVIAL 22940466 A 0 6 Silver SYSTEMATIC 22940466 A 345 351 oxygen SYSTEMATIC 22940466 A 777 794 N-acetyl-cysteine SYSTEMATIC 22940466 A 796 799 NAC ABBREVIATION 22940466 T 0 6 Silver SYSTEMATIC 22941424 A 1194 1201 glucose TRIVIAL 22941424 A 1358 1370 carbohydrate FAMILY 22941424 A 371 384 carbohydrates FAMILY 22941424 A 488 495 Glucose TRIVIAL 22941424 A 503 514 cholesterol TRIVIAL 22941424 A 541 552 cholesterol TRIVIAL 22941424 A 569 580 cholesterol TRIVIAL 22941424 A 586 599 triglycerides FAMILY 22941424 A 68 80 carbohydrate FAMILY 22941424 T 16 28 carbohydrate FAMILY 22943130 A 3 6 UDP ABBREVIATION 22943130 A 751 761 amino acid FAMILY 22943130 A 762 770 arginine TRIVIAL 22943130 A 772 784 (13)C6(15)N4 FORMULA 22944045 A 121 125 DiNP ABBREVIATION 22944045 A 140 157 dibutyl phthalate SYSTEMATIC 22944045 A 159 162 DBP ABBREVIATION 22944045 A 283 287 DiNP ABBREVIATION 22944045 A 351 355 DiNP ABBREVIATION 22944045 A 357 360 DBP ABBREVIATION 22944045 A 462 465 DBP ABBREVIATION 22944045 A 596 600 DiNP ABBREVIATION 22944045 A 697 701 DiNP ABBREVIATION 22944045 A 839 848 phthalate FAMILY 22944045 A 874 878 DiNP ABBREVIATION 22944045 A 99 119 diisononyl phthalate SYSTEMATIC 22944045 T 72 92 diisononyl phthalate SYSTEMATIC 22944045 T 94 98 DINP ABBREVIATION 22944069 A 0 7 Lithium SYSTEMATIC 22944069 A 102 109 Lithium SYSTEMATIC 22944069 A 409 416 lithium SYSTEMATIC 22944069 A 508 513 MG132 IDENTIFIER 22944069 A 589 596 lithium SYSTEMATIC 22944069 A 732 739 lithium SYSTEMATIC 22944069 T 0 7 Lithium SYSTEMATIC 22944593 A 0 8 Terpenes FAMILY 22944593 A 1056 1065 nerolidol TRIVIAL 22944593 A 1099 1107 terpenes FAMILY 22944593 A 1112 1123 1,8-cineole SYSTEMATIC 22944593 A 1217 1225 terpenes FAMILY 22944593 A 145 165 5-doxyl stearic acid SYSTEMATIC 22944593 A 167 172 5-DSA SYSTEMATIC 22944593 A 208 221 sesquiterpene FAMILY 22944593 A 222 231 nerolidol TRIVIAL 22944593 A 244 256 monoterpenes FAMILY 22944593 A 503 511 terpenes FAMILY 22944593 A 561 569 terpenes FAMILY 22944593 A 647 659 monoterpenes FAMILY 22944593 A 679 692 sesquiterpene FAMILY 22944593 A 736 748 monoterpenes FAMILY 22944593 A 776 784 terpenes FAMILY 22944593 A 826 837 1,8-cineole SYSTEMATIC 22944593 A 868 879 α-terpineol TRIVIAL 22944593 A 884 893 nerolidol TRIVIAL 22944593 T 12 20 terpenes FAMILY 22945792 A 223 234 cloxacillin TRIVIAL 22945792 A 257 265 warfarin TRIVIAL 22945792 A 295 303 warfarin TRIVIAL 22945792 A 373 381 warfarin TRIVIAL 22945792 A 451 462 cloxacillin TRIVIAL 22945792 A 523 534 penicillins FAMILY 22945792 A 814 822 warfarin TRIVIAL 22945792 T 54 62 warfarin TRIVIAL 22945792 T 67 78 cloxacillin TRIVIAL 22946701 A 1117 1129 progestogens FAMILY 22946701 A 1179 1194 tranexamic acid TRIVIAL 22946701 A 1216 1220 GnRH ABBREVIATION 22946701 A 1232 1239 Danazol TRIVIAL 22946701 A 1244 1258 Levonorgestrel TRIVIAL 22949391 T 139 143 iron SYSTEMATIC 22956307 A 304 315 cholesterol TRIVIAL 22956307 A 322 334 triglyceride FAMILY 22956307 A 345 356 cholesterol TRIVIAL 22956307 A 374 385 cholesterol TRIVIAL 22956307 A 524 528 urea TRIVIAL 22956307 A 529 537 nitrogen SYSTEMATIC 22956307 A 548 558 creatinine TRIVIAL 22956307 A 996 1006 creatinine TRIVIAL 22956627 A 1024 1028 ANIT ABBREVIATION 22956627 A 106 115 adenosine TRIVIAL 22956627 A 1074 1079 DPCPX ABBREVIATION 22956627 A 1103 1107 ANIT ABBREVIATION 22956627 A 1190 1194 ANIT ABBREVIATION 22956627 A 406 435 alpha-naphthyl isothiocyanate SYSTEMATIC 22956627 A 437 441 ANIT ABBREVIATION 22956627 A 558 567 Bile acid FAMILY 22956627 A 719 729 bile acids FAMILY 22956627 A 829 838 bile acid FAMILY 22956627 T 13 22 adenosine TRIVIAL 22956627 T 43 71 alpha-naphthylisothiocyanate SYSTEMATIC 22960442 A 0 15 Methamphetamine TRIVIAL 22960442 A 1001 1005 METH ABBREVIATION 22960442 A 1029 1033 METH ABBREVIATION 22960442 A 1080 1092 nitric oxide SYSTEMATIC 22960442 A 1131 1135 METH ABBREVIATION 22960442 A 1199 1211 nitric oxide SYSTEMATIC 22960442 A 1264 1268 METH ABBREVIATION 22960442 A 1308 1320 nitric oxide SYSTEMATIC 22960442 A 168 172 METH ABBREVIATION 22960442 A 19 23 METH ABBREVIATION 22960442 A 312 316 METH ABBREVIATION 22960442 A 562 566 METH ABBREVIATION 22960442 A 624 628 METH ABBREVIATION 22960442 A 713 717 METH ABBREVIATION 22960442 A 915 919 METH ABBREVIATION 22960442 T 0 15 Methamphetamine TRIVIAL 22960442 T 24 36 nitric oxide SYSTEMATIC 22960624 A 0 16 Organophosphates FAMILY 22960624 A 1024 1030 oximes FAMILY 22960624 A 1031 1037 RS194B NO CLASS 22960624 A 1039 1089 N-(2-(azepan-1-yl)ethyl)-2-(hydroxyimino)acetamide SYSTEMATIC 22960624 A 1095 1100 RS41A NO CLASS 22960624 A 1102 1156 2-(hydroxyimino)-N-(2-(pyrrolidin-1-yl)ethyl)acetamide SYSTEMATIC 22960624 A 1242 1247 sarin TRIVIAL 22960624 A 1249 1259 cyclosarin TRIVIAL 22960624 A 1318 1323 tabun TRIVIAL 22960624 A 1371 1376 oxime SYSTEMATIC 22960624 A 1391 1401 phosphorus SYSTEMATIC 22960624 A 1432 1438 serine TRIVIAL 22960624 A 1550 1561 phosphorate SYSTEMATIC 22960624 A 1563 1574 phosphonate SYSTEMATIC 22960624 A 1579 1594 phosphoramidate SYSTEMATIC 22960624 A 1723 1730 choline FAMILY 22960624 A 1816 1824 triazole FAMILY 22960624 A 1825 1834 imidazole SYSTEMATIC 22960624 A 1846 1855 aldoximes FAMILY 22960624 A 1857 1863 RS113B IDENTIFIER 22960624 A 1865 1871 RS113A IDENTIFIER 22960624 A 1876 1882 RS115A IDENTIFIER 22960624 A 1888 1897 acetamide SYSTEMATIC 22960624 A 1910 1916 RS194B NO CLASS 22960624 A 1928 1932 2PAM ABBREVIATION 22960624 A 220 233 acetylcholine SYSTEMATIC 22960624 A 235 238 ACh ABBREVIATION 22960624 A 372 399 quaternary pyridinium oxime FAMILY 22960624 A 531 537 oximes FAMILY 22960624 A 551 565 tertiary amine SYSTEMATIC 22960624 A 569 578 imidazole SYSTEMATIC 22960624 A 669 674 tabun TRIVIAL 22960624 A 731 737 oximes FAMILY 22960624 A 739 742 DAM ABBREVIATION 22960624 A 744 760 diacetylmonoxime SYSTEMATIC 22960624 A 763 767 MINA ABBREVIATION 22960624 A 769 790 monoisonitrosoacetone SYSTEMATIC 22960624 A 797 802 2-PAM SYSTEMATIC 22960624 A 808 813 oxime SYSTEMATIC 22960624 A 814 820 RS150D IDENTIFIER 22960624 A 822 920 N-((1-(3-(2-((hydroxyimino)methyl)-1H-imidazol-1-yl)propyl)-1H-1,2,3-triazol-4-yl)methyl)benzamide SYSTEMATIC 22960624 A 979 984 tabun TRIVIAL 22960624 T 17 23 oximes FAMILY 22960624 T 43 48 tabun TRIVIAL 22961094 A 0 7 Cadmium SYSTEMATIC 22961094 A 1012 1014 Cd FORMULA 22961094 A 1092 1106 cytochalasin D TRIVIAL 22961094 A 1229 1231 Cd FORMULA 22961094 A 1291 1293 Cd FORMULA 22961094 A 1360 1364 zinc SYSTEMATIC 22961094 A 1386 1388 Cd FORMULA 22961094 A 1446 1448 Cd FORMULA 22961094 A 1646 1648 Cd FORMULA 22961094 A 507 509 Cd FORMULA 22961094 A 717 719 Cd FORMULA 22961094 A 815 817 Cd FORMULA 22961094 A 9 11 Cd FORMULA 22961094 A 965 967 Cd FORMULA 22961094 T 44 51 cadmium SYSTEMATIC 22961427 A 247 271 phosphatidylethanolamine SYSTEMATIC 22961427 A 362 386 phosphatidylethanolamine SYSTEMATIC 22961427 A 47 71 phosphatidylethanolamine SYSTEMATIC 22961427 A 532 538 PEH(+) ABBREVIATION 22961427 A 543 550 PEOH(-) ABBREVIATION 22961427 A 560 584 phosphatidylethanolamine SYSTEMATIC 22961427 T 23 47 phosphatidylethanolamine SYSTEMATIC 22963374 A 116 124 iridoids FAMILY 22963374 A 129 139 flavonoids FAMILY 22963374 A 178 187 flavonoid FAMILY 22963374 A 189 278 3'-hydroxy-isoscutellarein 7-O-[6'″acetyl-β-D-glucopyranosyl-(1 → 2)-β-D-glucopyranoside] SYSTEMATIC 22963374 A 286 304 iridoid glucosides FAMILY 22963374 A 306 315 harpagide TRIVIAL 22963374 A 317 333 acetyl harpagide SYSTEMATIC 22963374 A 374 387 8-epi-loganin SYSTEMATIC 22963374 A 399 430 acetylated flavonoid glycosides FAMILY 22963374 A 432 541 3'-hydroxy-4'-O-methylisoscutellarein 7-O-[6'″acetyl-β-D-allopyranosyl-(1 → 2)-6″-acetyl-β-D-glucopyranoside] SYSTEMATIC 22963374 A 543 642 3'-hydroxy-4'-O-methylisoscutellarein 7-O-[6'″acetyl-β-D-allopyranosyl-(1 → 2)-β-D-glucopyranoside] SYSTEMATIC 22963374 A 649 659 flavonoids FAMILY 22963374 A 664 672 iridoids FAMILY 22963374 T 6 15 flavonoid FAMILY 22963552 A 1050 1061 polyphenols FAMILY 22963552 A 1083 1091 curcumin TRIVIAL 22963552 A 1093 1104 resveratrol TRIVIAL 22963552 A 1116 1125 catechins FAMILY 22963552 A 1127 1149 quercetin sulforaphane TRIVIAL 22963552 A 1151 1159 lycopene TRIVIAL 22963552 A 1167 1184 alpha-lipoic acid TRIVIAL 22963552 A 1186 1198 tocotrienols FAMILY 22963552 A 1204 1212 apocynin TRIVIAL 22963552 A 1435 1446 glutathione TRIVIAL 22963552 A 162 170 aldehyde SYSTEMATIC 22963552 A 171 179 carbonyl FAMILY 22963552 A 1733 1762 α-phenyl-N-tert-butyl nitrone SYSTEMATIC 22963552 A 1805 1815 porphyrins FAMILY 22963552 A 1817 1827 AEOL 10150 IDENTIFIER 22963552 A 1832 1842 AEOL 10113 IDENTIFIER 22963552 A 1851 1861 superoxide TRIVIAL 22963552 A 1880 1886 M40419 IDENTIFIER 22963552 A 1962 1971 edaravone TRIVIAL 22963552 A 1976 1985 lazaroids FAMILY 22963552 A 1986 1995 tirilazad TRIVIAL 22963552 A 2112 2131 omega-3 fatty acids FAMILY 22963552 A 2133 2142 vitamin D FAMILY 22963552 A 2148 2164 hydrogen sulfide SYSTEMATIC 22963552 A 270 277 steroid FAMILY 22963552 A 857 862 thiol FAMILY 22963552 A 874 885 glutathione TRIVIAL 22963552 A 915 933 N-acetyl-Lcysteine SYSTEMATIC 22963552 A 935 946 N-acystelyn TRIVIAL 22963552 A 948 958 erdosteine TRIVIAL 22963552 A 960 970 fudosteine TRIVIAL 22963552 A 972 985 ergothioneine TRIVIAL 22963552 A 991 1011 carbocysteine lysine TRIVIAL 22969061 A 952 958 carbon SYSTEMATIC 22974400 A 478 488 terpenoids FAMILY 22974400 A 490 499 phenolics FAMILY 22975162 A 114 140 coumarinolignoid alkaloids FAMILY 22975162 A 142 157 indicumines A-B MULTIPLE 22975162 A 176 193 coumarinolignoids FAMILY 22975162 A 195 210 indicumines C-D MULTIPLE 22975162 A 243 252 coumarins FAMILY 22975162 A 344 370 coumarinolignoid alkaloids FAMILY 22975162 T 9 26 coumarinolignoids FAMILY 22976785 A 4 12 pregnane TRIVIAL 22976785 A 686 693 phospho SYSTEMATIC 22976785 A 708 715 phospho SYSTEMATIC 22976785 T 66 74 pregnane TRIVIAL 22976914 A 1348 1356 cortisol TRIVIAL 22976914 A 194 201 glucose TRIVIAL 22976914 A 360 368 cortisol TRIVIAL 22976914 A 408 415 glucose TRIVIAL 22976914 A 566 574 cortisol TRIVIAL 22976914 A 824 832 cortisol TRIVIAL 22976914 A 962 970 cortisol TRIVIAL 22976914 T 29 37 cortisol TRIVIAL 22981993 A 1108 1116 cysteine TRIVIAL 22981993 A 1156 1162 lysine TRIVIAL 22981993 A 793 827 5,5'-dithiobis-2-nitrobenzoic acid SYSTEMATIC 22981993 A 864 869 thiol FAMILY 22981993 A 879 887 cysteine TRIVIAL 22981993 A 928 941 fluorescamine TRIVIAL 22981993 A 994 1000 lysine TRIVIAL 22982445 A 1074 1078 LTD4 ABBREVIATION 22982445 A 1161 1171 pranlukast TRIVIAL 22982445 A 1200 1204 LTD4 ABBREVIATION 22982445 A 284 298 leukotriene D4 TRIVIAL 22982445 A 300 304 LTD4 ABBREVIATION 22982445 A 372 376 LTD4 ABBREVIATION 22982445 A 685 689 LTD4 ABBREVIATION 22982445 A 717 738 cysteinyl leukotriene TRIVIAL 22982445 A 825 835 pranlukast TRIVIAL 22982445 A 911 915 LTD4 ABBREVIATION 22982445 A 958 968 Pranlukast TRIVIAL 22982445 A 993 997 LTD4 ABBREVIATION 22982445 T 0 14 Leukotriene D4 TRIVIAL 22983144 A 1025 1036 dizocilpine TRIVIAL 22983144 A 1081 1086 CDPPB ABBREVIATION 22983144 A 115 119 NMDA ABBREVIATION 22983144 A 1156 1169 phencyclidine TRIVIAL 22983144 A 1208 1213 CDPPB ABBREVIATION 22983144 A 1217 1225 ADX47273 IDENTIFIER 22983144 A 1252 1265 phencyclidine TRIVIAL 22983144 A 13 22 glutamate TRIVIAL 22983144 A 1399 1404 CDPPB ABBREVIATION 22983144 A 1641 1645 NMDA ABBREVIATION 22983144 A 314 318 NMDA ABBREVIATION 22983144 A 345 356 dizocilpine TRIVIAL 22983144 A 497 546 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide SYSTEMATIC 22983144 A 548 553 CDPPB ABBREVIATION 22983144 A 559 567 ADX47273 IDENTIFIER 22983144 A 673 678 CDPPB ABBREVIATION 22983144 A 717 752 2-methyl-6-(phenylethynyl)-pyridine SYSTEMATIC 22983144 A 920 924 NMDA ABBREVIATION 22983144 A 93 113 N-methyl-D-Aspartate SYSTEMATIC 22983144 A 958 963 CDPPB ABBREVIATION 22983144 A 979 990 dizocilpine TRIVIAL 22983144 T 209 222 phencyclidine TRIVIAL 22983144 T 95 104 glutamate TRIVIAL 22983867 A 1086 1094 tyrosine TRIVIAL 22983867 A 192 195 MSG ABBREVIATION 22983867 A 283 286 MSG ABBREVIATION 22983867 A 416 423 glucose TRIVIAL 22983867 A 500 508 tyrosine TRIVIAL 22983867 A 554 557 MSG ABBREVIATION 22983867 A 570 573 MSG ABBREVIATION 22983867 A 60 67 glucose TRIVIAL 22983867 A 698 701 MSG ABBREVIATION 22983867 A 739 742 MSG ABBREVIATION 22983867 A 811 814 MSG ABBREVIATION 22983867 A 831 839 tyrosine TRIVIAL 22983867 A 874 877 MSG ABBREVIATION 22983867 A 991 994 MSG ABBREVIATION 22983867 T 17 39 monosodium L-glutamate SYSTEMATIC 22983867 T 90 98 tyrosine TRIVIAL 22986338 A 585 601 juvenile hormone FAMILY 22986338 T 0 16 Juvenile hormone FAMILY 22988818 A 0 9 Friedelin TRIVIAL 22988818 A 14 24 lanosterol TRIVIAL 22988818 A 212 215 MTT ABBREVIATION 22988818 A 347 356 Oil Red O TRIVIAL 22988818 A 438 447 friedelin TRIVIAL 22988818 A 452 462 lanosterol TRIVIAL 22988818 A 581 593 Deoxyglucose SYSTEMATIC 22988818 A 717 726 friedelin TRIVIAL 22988818 A 749 756 glucose TRIVIAL 22988818 A 838 847 friedelin TRIVIAL 22988818 A 852 862 lanosterol TRIVIAL 22988818 T 0 9 Friedelin TRIVIAL 22988818 T 14 24 lanosterol TRIVIAL 22988818 T 60 67 glucose TRIVIAL 22991163 A 1013 1024 alendronate TRIVIAL 22991163 A 1282 1293 alendronate TRIVIAL 22991163 A 1472 1483 alendronate TRIVIAL 22991163 A 1675 1686 alendronate TRIVIAL 22991163 A 219 230 alendronate TRIVIAL 22991163 A 463 474 alendronate TRIVIAL 22991163 A 926 933 alcohol FAMILY 22991163 T 22 33 alendronate TRIVIAL 22991447 A 159 171 nitric oxide SYSTEMATIC 22991447 A 195 196 S FORMULA 22991447 A 378 379 S FORMULA 22991447 A 44 45 S FORMULA 22991447 A 550 551 S FORMULA 22991447 A 691 692 S FORMULA 22991447 A 875 876 S FORMULA 22991447 T 33 45 nitric oxide SYSTEMATIC 22991447 T 79 80 S FORMULA 22996137 A 60 67 glucose TRIVIAL 22996137 A 657 664 glucose TRIVIAL 22996137 A 699 706 glucose TRIVIAL 22996137 A 816 824 tyrosine TRIVIAL 22996307 A 0 20 L- and D-amino acids MULTIPLE 22996307 A 1049 1054 D-Orn ABBREVIATION 22996307 A 1070 1075 L-Orn ABBREVIATION 22996307 A 110 119 Ornithine TRIVIAL 22996307 A 1125 1128 Orn ABBREVIATION 22996307 A 121 124 Orn ABBREVIATION 22996307 A 1261 1273 L- and D-Orn MULTIPLE 22996307 A 1348 1353 D-Orn ABBREVIATION 22996307 A 1387 1397 polyamines FAMILY 22996307 A 172 183 amino acids FAMILY 22996307 A 185 204 nicotinic alkaloids FAMILY 22996307 A 210 220 polyamines FAMILY 22996307 A 276 279 Orn ABBREVIATION 22996307 A 358 368 polyamines FAMILY 22996307 A 381 389 nicotine TRIVIAL 22996307 A 511 521 Putrescine TRIVIAL 22996307 A 559 570 L-ornithine TRIVIAL 22996307 A 572 577 L-Orn ABBREVIATION 22996307 A 589 599 spermidine TRIVIAL 22996307 A 604 612 spermine TRIVIAL 22996307 A 647 658 D-ornithine TRIVIAL 22996307 A 660 665 D-Orn ABBREVIATION 22996307 A 704 712 nicotine TRIVIAL 22996307 A 750 755 L-Orn ABBREVIATION 22996307 A 779 784 D-Orn ABBREVIATION 22996307 A 806 814 nicotine TRIVIAL 22996307 A 887 907 S-adenosylmethionine TRIVIAL 22996307 A 944 954 spermidine TRIVIAL 22996307 A 955 963 spermine TRIVIAL 22996307 T 24 32 nicotine TRIVIAL 22996307 T 37 47 polyamines FAMILY 22996307 T 96 105 ornithine TRIVIAL 22997242 A 1111 1112 N FORMULA 22997242 A 1141 1142 N FORMULA 22997242 A 1161 1176 Fuc3Hex3HexNAc6 FORMULA 22997242 A 1360 1368 LacdiNAc FORMULA 22997242 A 1616 1624 LacdiNAc FORMULA 22997242 A 357 358 N FORMULA 22997242 A 456 498 monofucosylated N,N'-diacetylhexosediamine SYSTEMATIC 22997242 A 524 542 GalNAcβ1 → 4GlcNAc FORMULA 22997242 A 544 552 LacdiNAc FORMULA 22997242 A 637 638 N FORMULA 22997242 A 761 762 N FORMULA 22997242 A 803 804 N FORMULA 22997242 T 39 87 N-linked fucosylated N,N'-diacetyllactosediamine SYSTEMATIC 22997242 T 89 97 LacdiNAc FORMULA 23000076 A 1083 1086 THC ABBREVIATION 23000076 A 1112 1116 pCPA ABBREVIATION 23000076 A 1120 1129 WAY100635 IDENTIFIER 23000076 A 1149 1153 AMPT ABBREVIATION 23000076 A 1174 1184 rimonabant TRIVIAL 23000076 A 1389 1392 THC ABBREVIATION 23000076 A 1481 1491 rimonabant TRIVIAL 23000076 A 1750 1753 THC ABBREVIATION 23000076 A 1805 1815 rimonabant TRIVIAL 23000076 A 1883 1896 catecholamine TRIVIAL 23000076 A 226 235 serotonin TRIVIAL 23000076 A 237 241 5-HT SYSTEMATIC 23000076 A 247 261 catecholamines FAMILY 23000076 A 427 452 Δ(9)-tetrahydrocannabinol SYSTEMATIC 23000076 A 454 457 THC ABBREVIATION 23000076 A 478 488 rimonabant TRIVIAL 23000076 A 567 570 THC ABBREVIATION 23000076 A 606 616 rimonabant TRIVIAL 23000076 A 658 662 5-HT SYSTEMATIC 23000076 A 683 687 pCPA ABBREVIATION 23000076 A 713 717 5-HT SYSTEMATIC 23000076 A 742 751 WAY100635 IDENTIFIER 23000076 A 801 814 catecholamine TRIVIAL 23000076 A 826 830 AMPT ABBREVIATION 23000076 A 850 853 THC ABBREVIATION 23000076 A 858 868 rimonabant TRIVIAL 23000076 A 976 979 THC ABBREVIATION 23000076 A 984 994 rimonabant TRIVIAL 23000076 T 90 99 serotonin TRIVIAL 23001138 A 1055 1067 amphetamines FAMILY 23001138 A 114 118 MDMA ABBREVIATION 23001138 A 120 127 Ecstasy TRIVIAL 23001138 A 1617 1621 MDMA ABBREVIATION 23001138 A 505 509 MDMA ABBREVIATION 23001138 A 511 526 methamphetamine TRIVIAL 23001138 A 528 551 4-methylthioamphetamine SYSTEMATIC 23001138 A 556 569 d-amphetamine TRIVIAL 23001138 A 686 689 MTT ABBREVIATION 23001138 A 79 112 3,4-methylenedioxymethamphetamine SYSTEMATIC 23001138 T 67 74 ecstasy TRIVIAL 23001138 T 85 97 amphetamines FAMILY 23002036 A 0 7 Glucose TRIVIAL 23002036 A 1117 1122 NH(2) FORMULA 23002036 A 1305 1341 12-O-tetradecanoylphorbol-13-acetate SYSTEMATIC 23002036 A 1343 1346 TPA ABBREVIATION 23002036 A 353 356 AMP ABBREVIATION 23002036 A 657 667 fatty acid FAMILY 23002036 T 50 57 glucose TRIVIAL 23007560 A 337 345 fluoride SYSTEMATIC 23007560 A 507 515 fluoride SYSTEMATIC 23007560 A 519 522 NaF FORMULA 23007560 A 533 541 fluoride SYSTEMATIC 23007560 A 598 606 fluoride SYSTEMATIC 23007560 A 623 631 fluoride SYSTEMATIC 23007560 A 645 653 fluoride SYSTEMATIC 23008503 A 1011 1017 SC-560 IDENTIFIER 23008503 A 1022 1031 celecoxib TRIVIAL 23008503 A 1146 1152 PGE(2) ABBREVIATION 23008503 A 1237 1247 cimetidine TRIVIAL 23008503 A 271 277 SC-560 IDENTIFIER 23008503 A 279 288 ketorolac TRIVIAL 23008503 A 301 310 celecoxib TRIVIAL 23008503 A 312 321 meloxicam TRIVIAL 23008503 A 391 401 cimetidine TRIVIAL 23008503 A 440 458 prostaglandin E(2) TRIVIAL 23008503 A 460 466 PGE(2) ABBREVIATION 23008503 A 768 774 PGE(2) ABBREVIATION 23009351 A 1001 1004 Epi ABBREVIATION 23009351 A 1050 1053 Epi ABBREVIATION 23009351 A 111 114 PAA ABBREVIATION 23009351 A 1113 1116 Epi ABBREVIATION 23009351 A 1133 1136 Epi ABBREVIATION 23009351 A 156 166 epirubicin TRIVIAL 23009351 A 168 171 Epi ABBREVIATION 23009351 A 198 201 Plu ABBREVIATION 23009351 A 202 205 PAA ABBREVIATION 23009351 A 206 209 Epi ABBREVIATION 23009351 A 412 415 Plu ABBREVIATION 23009351 A 420 423 PAA ABBREVIATION 23009351 A 430 433 Epi ABBREVIATION 23009351 A 612 615 Epi ABBREVIATION 23009351 A 74 82 pluronic FAMILY 23009351 A 84 87 Plu ABBREVIATION 23009351 A 890 893 Epi ABBREVIATION 23009351 A 93 109 polyacrylic acid FAMILY 23009351 T 24 32 pluronic FAMILY 23009351 T 33 51 poly(acrylic acid) SYSTEMATIC 23010104 A 587 594 steroid FAMILY 23010392 A 1167 1169 Pb FORMULA 23010392 A 1287 1289 Hg FORMULA 23010392 A 327 329 Ca FORMULA 23010392 A 331 333 Cd FORMULA 23010392 A 335 337 Cr FORMULA 23010392 A 339 341 Cu FORMULA 23010392 A 343 345 Fe FORMULA 23010392 A 347 349 Hg FORMULA 23010392 A 351 353 Ni FORMULA 23010392 A 355 357 Pb FORMULA 23010392 A 359 361 Se FORMULA 23010392 A 363 364 V FORMULA 23010392 A 370 372 Zn FORMULA 23010392 A 729 731 Cd FORMULA 23010566 A 296 302 iodine SYSTEMATIC 23010566 A 530 536 iodine SYSTEMATIC 23014811 A 115 126 Lewis acids FAMILY 23014811 A 345 353 fluoride SYSTEMATIC 23014811 A 386 393 halides FAMILY 23014811 A 54 83 metal and non-metal fluorides MULTIPLE 23014811 A 614 623 fluorides FAMILY 23014811 A 628 633 oxide SYSTEMATIC 23014811 A 634 643 fluorides FAMILY 23014811 A 725 748 N-heterocyclic carbenes FAMILY 23014811 A 862 869 halides FAMILY 23014811 A 88 93 oxide SYSTEMATIC 23014811 A 94 103 fluorides FAMILY 23014811 T 32 56 metal/non-metal fluoride MULTIPLE 23014811 T 61 66 oxide SYSTEMATIC 23014811 T 67 75 fluoride SYSTEMATIC 23015541 A 207 215 caffeine TRIVIAL 23015541 A 414 422 caffeine TRIVIAL 23015541 A 644 652 caffeine TRIVIAL 23015541 A 753 761 Caffeine TRIVIAL 23015541 A 86 94 caffeine TRIVIAL 23015541 A 962 970 caffeine TRIVIAL 23015541 T 0 8 Caffeine TRIVIAL 23015691 A 1012 1023 androstenol TRIVIAL 23015691 A 1025 1032 estrone TRIVIAL 23015691 A 1034 1047 17β-estradiol SYSTEMATIC 23015691 A 1049 1056 TCPOBOP TRIVIAL 23015691 A 1062 1067 CITCO ABBREVIATION 23015691 A 17 27 androstane TRIVIAL 23015691 A 556 563 steroid FAMILY 23015691 A 996 1007 Androstanol TRIVIAL 23015691 T 57 67 androstane TRIVIAL 23015691 T 96 103 steroid FAMILY 23016694 A 325 333 dopamine TRIVIAL 23016694 A 384 392 dopamine TRIVIAL 23017387 A 154 178 tert-butyl hydroperoxide SYSTEMATIC 23017387 A 341 350 Quercetin TRIVIAL 23017387 A 448 457 quercetin TRIVIAL 23017387 A 576 583 quinone FAMILY 23017387 A 595 606 glutathione TRIVIAL 23017387 A 621 641 methionine sulfoxide SYSTEMATIC 23017387 A 698 707 quercetin TRIVIAL 23017387 A 772 781 quercetin TRIVIAL 23017387 A 812 823 glutathione TRIVIAL 23017387 A 838 858 methionine sulfoxide SYSTEMATIC 23017391 A 1135 1149 Phenolic acids FAMILY 23017391 A 1173 1183 quercetrin TRIVIAL 23017391 A 1185 1190 rutin TRIVIAL 23017391 A 1195 1205 hesperidin TRIVIAL 23017391 A 196 204 Phenolic FAMILY 23017391 A 363 375 benzoic acid SYSTEMATIC 23017391 A 405 415 flavonoids FAMILY 23017391 A 469 483 phenolic acids FAMILY 23017391 A 653 658 sugar FAMILY 23017391 A 667 676 flavonols FAMILY 23017391 A 69 79 flavonoids FAMILY 23017391 A 831 841 flavonoids FAMILY 23017391 A 84 98 phenolic acids FAMILY 23017391 A 988 1002 phenolic acids FAMILY 23017391 T 23 34 polyphenols FAMILY 23017394 A 0 14 Betulinic acid TRIVIAL 23017394 A 137 144 betulin TRIVIAL 23017394 A 148 162 betulinic acid TRIVIAL 23017394 A 234 241 betulin TRIVIAL 23017394 A 340 354 betulinic acid TRIVIAL 23017394 A 563 570 betulin TRIVIAL 23017394 T 45 52 betulin TRIVIAL 23017394 T 56 70 betulinic acid TRIVIAL 23017395 A 106 113 HMG-CoA ABBREVIATION 23017395 A 148 151 EPA ABBREVIATION 23017395 A 152 155 DHA ABBREVIATION 23017395 A 290 293 EPA ABBREVIATION 23017395 A 294 297 DHA ABBREVIATION 23017395 A 389 405 triacylglycerols FAMILY 23017395 A 426 437 cholesterol TRIVIAL 23017395 A 471 482 cholesterol TRIVIAL 23017395 A 572 579 HMG-CoA ABBREVIATION 23017395 A 661 664 EPA ABBREVIATION 23017395 A 665 668 DHA ABBREVIATION 23017395 A 745 748 EPA ABBREVIATION 23017395 A 749 752 DHA ABBREVIATION 23017395 A 816 823 HMG-CoA ABBREVIATION 23017395 A 889 892 EPA ABBREVIATION 23017395 A 893 896 DHA ABBREVIATION 23017395 T 15 18 EPA ABBREVIATION 23017395 T 19 22 DHA ABBREVIATION 23017397 A 176 185 n-butanol SYSTEMATIC 23017397 A 187 193 n-BuOH FORMULA 23017397 A 251 288 2,6-dideoxyhexose-C-glycosyl flavones FAMILY 23017397 A 300 357 luteolin-8-C-β-digitoxopyranosyl-4'-O-β-d-glucopyranoside SYSTEMATIC 23017397 A 363 396 apigenin-8-C-β-digitoxopyranoside SYSTEMATIC 23017397 A 402 434 apigenin-8-C-β-boivinopyranoside SYSTEMATIC 23017397 A 443 475 luteolin-8-C-β-boivinopyranoside SYSTEMATIC 23017397 A 718 726 luteolin TRIVIAL 23017397 T 0 25 C-dideoxyhexosyl flavones FAMILY 23017402 A 1037 1051 betulinic acid TRIVIAL 23017402 A 1082 1095 carnosic acid TRIVIAL 23017402 A 366 383 triterpenic acids FAMILY 23017402 A 530 544 betulinic acid TRIVIAL 23017402 A 744 756 nitric oxide SYSTEMATIC 23017402 A 758 760 NO FORMULA 23017402 A 821 823 NO FORMULA 23017408 A 103 111 methanol SYSTEMATIC 23017408 A 149 157 phenolic FAMILY 23017408 A 290 297 phenols FAMILY 23017408 A 507 522 l-phenylalanine TRIVIAL 23017408 A 524 529 l-phe FORMULA 23017408 A 558 566 phenolic FAMILY 23017408 A 579 587 phenolic FAMILY 23017408 A 639 644 l-phe FORMULA 23017408 A 704 709 l-phe FORMULA 23017408 A 726 734 phenolic FAMILY 23017408 A 806 817 gallic acid TRIVIAL 23017408 A 819 838 trans-cinnamic acid TRIVIAL 23017408 A 840 855 p-coumaric acid TRIVIAL 23017408 A 861 873 ferulic acid TRIVIAL 23017408 A 974 979 l-phe FORMULA 23017408 A 990 998 phenolic FAMILY 23017408 T 0 21 Phenylalanine ammonia SYSTEMATIC 23017409 A 1022 1031 zingerone TRIVIAL 23017409 A 1127 1131 TNBS ABBREVIATION 23017409 A 223 232 zingerone TRIVIAL 23017409 A 246 282 2,4,6-trinitrobenzene sulphonic acid SYSTEMATIC 23017409 A 284 288 TNBS ABBREVIATION 23017409 A 318 327 zingerone TRIVIAL 23017409 A 340 344 TNBS ABBREVIATION 23017409 A 428 437 zingerone TRIVIAL 23017409 A 496 505 zingerone TRIVIAL 23017409 A 700 709 zingerone TRIVIAL 23017409 A 808 817 zingerone TRIVIAL 23017409 A 829 833 TNBS ABBREVIATION 23017409 A 928 932 TNBS ABBREVIATION 23017409 T 19 28 zingerone TRIVIAL 23017409 T 41 71 trinitrobenzene sulphonic acid SYSTEMATIC 23017413 A 1150 1160 polyphenol FAMILY 23017413 A 142 152 polyphenol FAMILY 23017413 A 427 448 hydroxycinnamic acids FAMILY 23017413 A 453 463 flavanones FAMILY 23017413 A 473 482 flavonols FAMILY 23017413 A 484 521 coumaric and ferulic acid-O-glucoside MULTIPLE 23017413 A 606 620 5-cis-lycopene SYSTEMATIC 23017413 A 791 815 caffeic acid-O-glucoside SYSTEMATIC 23017413 A 827 834 caffeic FAMILY 23017413 A 932 942 α-carotene TRIVIAL 23017413 A 944 966 9- and 13-cis-lycopene MULTIPLE 23017415 A 160 170 amino acid FAMILY 23017415 A 590 597 phytate TRIVIAL 23017415 T 0 10 Amino acid FAMILY 23017416 A 474 491 Dimethyl sulphide SYSTEMATIC 23017416 A 493 506 1-penten-3-ol SYSTEMATIC 23017416 A 508 520 1-hexen-3-ol SYSTEMATIC 23017416 A 525 537 1-octen-3-ol SYSTEMATIC 23017416 A 572 580 pentanal SYSTEMATIC 23017416 A 582 589 hexanal SYSTEMATIC 23017416 A 591 599 heptanal SYSTEMATIC 23017416 A 601 608 octanal SYSTEMATIC 23017416 A 613 628 3-undecen-2-one SYSTEMATIC 23017416 A 662 679 dimethyl sulphide SYSTEMATIC 23017418 A 571 575 DPPH ABBREVIATION 23017418 A 719 728 carvacrol TRIVIAL 23017418 A 772 781 carvacrol TRIVIAL 23017418 A 786 798 fumaric acid TRIVIAL 23017421 A 104 115 fatty acids FAMILY 23017421 A 169 183 ethyl behenate SYSTEMATIC 23017421 A 577 588 cholesterol TRIVIAL 23017421 A 594 605 cholesterol TRIVIAL 23017421 A 607 620 triglycerides FAMILY 23017421 A 654 664 fatty acid FAMILY 23017421 A 908 919 cholesterol TRIVIAL 23017421 A 937 948 cholesterol TRIVIAL 23017422 A 1008 1017 strontium SYSTEMATIC 23017422 A 1022 1028 barium SYSTEMATIC 23017422 A 105 111 Sr(2+) FORMULA 23017422 A 116 122 Ba(2+) FORMULA 23017422 A 296 301 H(2)O FORMULA 23017422 A 316 322 Ba(2+) FORMULA 23017422 A 325 331 Ca(2+) FORMULA 23017422 A 332 338 Mg(2+) FORMULA 23017422 A 339 345 Sr(2+) FORMULA 23017422 A 34 40 sodium SYSTEMATIC 23017422 A 54 59 H(2)O FORMULA 23017422 A 64 69 D(2)O FORMULA 23017422 A 771 776 D(2)O FORMULA 23017422 A 841 847 Ba(2+) FORMULA 23017422 A 848 854 Ca(2+) FORMULA 23017422 A 855 861 Sr(2+) FORMULA 23017422 A 862 868 Mg(2+) FORMULA 23017422 A 89 95 Mg(2+) FORMULA 23017422 A 907 912 D(2)O FORMULA 23017422 A 917 922 H(2)O FORMULA 23017422 A 97 103 Ca(2+) FORMULA 23017422 A 999 1006 calcium SYSTEMATIC 23017422 T 23 44 alkaline earth metals FAMILY 23017422 T 90 96 sodium SYSTEMATIC 23017424 A 584 590 lysine TRIVIAL 23017424 A 615 626 lauric acid TRIVIAL 23017424 A 980 991 lauric acid TRIVIAL 23020803 A 0 9 Vitamin D FAMILY 23020803 A 1075 1084 vitamin D FAMILY 23020803 A 1143 1152 vitamin D FAMILY 23020803 A 1351 1360 vitamin D FAMILY 23020803 A 1411 1420 vitamin D FAMILY 23020803 A 1476 1485 vitamin D FAMILY 23020803 A 190 214 1,25-dihydroxyvitamin D₃ SYSTEMATIC 23020803 A 216 227 1,25(OH)₂D₃ SYSTEMATIC 23020803 A 308 315 calcium SYSTEMATIC 23020803 A 365 374 vitamin D FAMILY 23020803 A 423 433 vitamin D₃ TRIVIAL 23020803 A 56 76 25-hydroxyvitamin D₃ SYSTEMATIC 23020803 A 768 777 vitamin D FAMILY 23020803 A 78 86 25(OH)D₃ SYSTEMATIC 23020803 A 877 886 vitamin D FAMILY 23020803 A 974 983 vitamin D FAMILY 23020803 T 11 20 vitamin D FAMILY 23022015 A 1203 1206 DHP ABBREVIATION 23022015 A 1211 1215 DCHP ABBREVIATION 23022015 A 124 128 DCHP ABBREVIATION 23022015 A 249 252 DHP ABBREVIATION 23022015 A 257 261 DCHP ABBREVIATION 23022015 A 345 357 Testosterone TRIVIAL 23022015 A 413 416 DHP ABBREVIATION 23022015 A 433 437 DCHP ABBREVIATION 23022015 A 473 476 DHP ABBREVIATION 23022015 A 481 485 DCHP ABBREVIATION 23022015 A 551 554 DHP ABBREVIATION 23022015 A 559 563 DCHP ABBREVIATION 23022015 A 60 80 di-n-hexyl phthalate SYSTEMATIC 23022015 A 617 621 DCHP ABBREVIATION 23022015 A 82 85 DHP ABBREVIATION 23022015 A 91 113 dicyclohexyl phthalate SYSTEMATIC 23022015 T 34 54 di-n-hexyl phthalate SYSTEMATIC 23022015 T 59 81 dicyclohexyl phthalate SYSTEMATIC 23022323 A 114 127 acetylcholine SYSTEMATIC 23022323 A 597 610 acetylcholine SYSTEMATIC 23022323 T 66 79 acetylcholine SYSTEMATIC 23023768 A 192 217 poly(methyl methacrylate) SYSTEMATIC 23023768 A 550 558 graphene TRIVIAL 23023768 A 579 586 acetone SYSTEMATIC 23023768 A 591 602 isopropanol SYSTEMATIC 23023768 A 61 69 graphene TRIVIAL 23023768 A 76 82 cobalt SYSTEMATIC 23023768 A 811 819 graphene TRIVIAL 23023768 T 60 68 graphene TRIVIAL 23023768 T 97 122 poly(methyl methacrylate) SYSTEMATIC 23027385 A 101 127 (η(7)-C(7)H(7))ZrCl(tmeda) FORMULA 23027385 A 1055 1099 cycloheptatrienyl transition metal complexes FAMILY 23027385 A 247 274 cycloheptatrienyl zirconium SYSTEMATIC 23027385 A 423 440 cycloheptatrienyl SYSTEMATIC 23027385 A 475 495 (η(7)-C(7)H(7))Zr(Y) FORMULA 23027385 A 510 521 pentadienyl SYSTEMATIC 23027385 A 523 539 cyclopentadienyl SYSTEMATIC 23027385 A 541 546 allyl SYSTEMATIC 23027385 A 548 558 phospholyl SYSTEMATIC 23027385 A 560 573 boratabenzene SYSTEMATIC 23027385 A 575 595 imidazolin-2-iminato SYSTEMATIC 23027385 A 600 605 amido SYSTEMATIC 23027385 A 619 636 cycloheptatrienyl SYSTEMATIC 23027385 A 796 803 Zr(+iv) FORMULA 23027385 A 945 971 (η(7)-C(7)H(7))ZrCl(tmeda) FORMULA 23027385 T 32 59 cycloheptatrienyl zirconium SYSTEMATIC 23028137 A 103 110 glucose TRIVIAL 23028137 A 1217 1224 glucose TRIVIAL 23028137 A 1329 1336 glucose TRIVIAL 23028137 A 1378 1385 glucose TRIVIAL 23028137 A 250 257 glucose TRIVIAL 23028137 A 313 321 fructose TRIVIAL 23028137 A 69 76 glucose TRIVIAL 23028137 T 12 19 glucose TRIVIAL 23028137 T 151 159 fructose TRIVIAL 23028137 T 92 99 glucose TRIVIAL 23030741 A 1062 1069 alcohol FAMILY 23030741 A 1074 1089 carboxylic acid SYSTEMATIC 23030741 A 1098 1129 3-hydroxypropyl-phosphinic acid SYSTEMATIC 23030741 A 1134 1169 3-hydroxyphosphonoyl-propanoic acid SYSTEMATIC 23030741 A 1212 1220 fluorine SYSTEMATIC 23030741 A 1283 1298 carboxylic acid SYSTEMATIC 23030741 A 1321 1329 fluorine SYSTEMATIC 23030741 A 1336 1385 (2R)-2-fluoro-3-hydroxyphosphonoyl-propanoic acid SYSTEMATIC 23030741 A 1416 1466 [(2R)-2-fluoro-3-guanidino-propyl]-phosphinic acid SYSTEMATIC 23030741 A 265 284 γ-aminobutyric acid SYSTEMATIC 23030741 A 310 321 lesogaberan TRIVIAL 23030741 A 410 436 (14)C-labelled lesogaberan SYSTEMATIC 23030741 A 902 903 N FORMULA 23030741 A 923 972 [(2R)-3-acetamido-2-fluoropropyl]-phosphinic acid SYSTEMATIC 23030741 A 984 1029 [(2R)-3-amino-2-fluoropropyl]-phosphonic acid SYSTEMATIC 23030741 T 37 48 lesogaberan TRIVIAL 23030812 A 1063 1069 oxygen SYSTEMATIC 23036451 A 109 113 PCBs ABBREVIATION 23036451 A 1090 1094 PCBs ABBREVIATION 23036451 A 1099 1106 dioxins FAMILY 23036451 A 119 126 dioxins FAMILY 23036451 A 613 617 PCBs ABBREVIATION 23036451 A 622 629 dioxins FAMILY 23036451 A 778 782 PCBs ABBREVIATION 23036451 A 787 794 dioxins FAMILY 23036451 A 82 107 polychlorinated biphenyls FAMILY 23036451 T 21 46 polychlorinated biphenyls FAMILY 23036451 T 51 58 dioxins FAMILY 23036454 A 863 870 glucose TRIVIAL 23036454 A 889 900 cholesterol TRIVIAL 23038767 A 287 293 biotin TRIVIAL 23038767 A 346 352 biotin TRIVIAL 23038767 A 729 735 biotin TRIVIAL 23041113 A 433 440 butanol SYSTEMATIC 23041113 T 0 12 Phlorotannin FAMILY 23041257 A 1040 1045 DBDCT ABBREVIATION 23041257 A 1119 1124 DBDCT ABBREVIATION 23041257 A 1318 1323 DBDCT ABBREVIATION 23041257 A 141 190 Di-n-butyl-di-(4-chlorobenzohydroxamato) Tin (IV) SYSTEMATIC 23041257 A 192 197 DBDCT ABBREVIATION 23041257 A 288 304 diorganotin (IV) FAMILY 23041257 A 33 47 organotin (IV) FAMILY 23041257 A 413 418 DBDCT ABBREVIATION 23041257 A 653 658 DBDCT ABBREVIATION 23041257 A 686 702 propidium iodide TRIVIAL 23041257 A 780 785 DBDCT ABBREVIATION 23041257 A 890 896 oxygen SYSTEMATIC 23041257 A 906 911 DBDCT ABBREVIATION 23041257 T 35 84 Di-n-butyl-di-(4-chlorobenzohydroxamato) Tin (IV) SYSTEMATIC 23042693 A 10 51 tris(o-phenylenedioxy)cyclotriphosphazene SYSTEMATIC 23042693 A 221 224 TPP ABBREVIATION 23042693 A 53 56 TPP ABBREVIATION 23042762 A 494 506 carbohydrate FAMILY 23042762 A 658 670 carbohydrate FAMILY 23042762 A 89 102 carbohydrates FAMILY 23043184 A 1235 1238 BNZ ABBREVIATION 23043184 A 378 391 benzphetamine TRIVIAL 23043184 A 393 396 BNZ ABBREVIATION 23043184 A 477 490 p-nitrophenol SYSTEMATIC 23043184 A 579 603 tert-butyl hydroperoxide SYSTEMATIC 23043184 T 64 69 NADPH ABBREVIATION 23043462 A 16 50 oxygenated oplopane sesquiterpenes FAMILY 23043462 A 52 71 songaricalarins A-E MULTIPLE 23043462 T 0 19 Songaricalarins A-E MULTIPLE 23043462 T 31 54 oplopane sesquiterpenes FAMILY 23044046 A 1012 1022 fumagillin TRIVIAL 23044046 A 245 255 Fumagillin TRIVIAL 23044046 A 322 329 TNP-470 IDENTIFIER 23044046 A 467 474 TNP-470 IDENTIFIER 23044488 A 123 138 organophosphate FAMILY 23044488 A 700 704 acyl FAMILY 23044488 T 0 10 Amino acid FAMILY 23044709 A 1065 1073 Tartrate TRIVIAL 23047022 A 105 118 acetylcholine SYSTEMATIC 23047022 A 1157 1161 EDTA ABBREVIATION 23047022 A 1167 1177 batimastat TRIVIAL 23047022 A 1193 1199 GM6001 IDENTIFIER 23047022 A 1275 1280 thiol FAMILY 23047022 A 1372 1385 acetylcholine SYSTEMATIC 23047022 A 1412 1421 carbachol TRIVIAL 23047022 A 1425 1434 muscarine TRIVIAL 23047022 A 1455 1464 carbachol TRIVIAL 23047022 A 1497 1505 atropine TRIVIAL 23047022 A 494 501 Proline TRIVIAL 23047026 A 1013 1016 ACh ABBREVIATION 23047026 A 1034 1037 ACh ABBREVIATION 23047026 A 1293 1296 ACh ABBREVIATION 23047321 A 28 34 carbon SYSTEMATIC 23051835 A 0 11 Bisphenol A TRIVIAL 23051835 A 1031 1048 ethinyl estradiol TRIVIAL 23051835 A 1089 1106 ethinyl estradiol TRIVIAL 23051835 A 1119 1122 BPA ABBREVIATION 23051835 A 1255 1258 BPA ABBREVIATION 23051835 A 13 16 BPA ABBREVIATION 23051835 A 1312 1315 BPA ABBREVIATION 23051835 A 1375 1378 BPA ABBREVIATION 23051835 A 1457 1460 BPA ABBREVIATION 23051835 A 152 155 BPA ABBREVIATION 23051835 A 1663 1666 BPA ABBREVIATION 23051835 A 388 395 steroid FAMILY 23051835 A 547 564 ethinyl estradiol TRIVIAL 23051835 A 605 608 BPA ABBREVIATION 23051835 A 918 921 BPA ABBREVIATION 23051835 T 60 71 bisphenol A TRIVIAL 23051890 A 254 261 alumina TRIVIAL 23051890 A 436 453 hydrogen peroxide SYSTEMATIC 23052036 A 0 10 Fenhexamid TRIVIAL 23052036 A 1020 1031 fulvestrant TRIVIAL 23052036 A 1036 1044 androgen FAMILY 23052036 A 1065 1077 bicalutamide TRIVIAL 23052036 A 1082 1095 actinomycin D TRIVIAL 23052036 A 1100 1113 cycloheximide TRIVIAL 23052036 A 1178 1194 phosphoinositide FAMILY 23052036 A 1214 1224 Fenhexamid TRIVIAL 23052036 A 1257 1272 arylhydrocarbon FAMILY 23052036 A 1293 1308 α-napthoflavone TRIVIAL 23052036 A 1310 1320 Fenhexamid TRIVIAL 23052036 A 1325 1336 fludioxonil TRIVIAL 23052036 A 1352 1371 dihydrotestosterone SYSTEMATIC 23052036 A 1399 1410 Fludioxonil TRIVIAL 23052036 A 1420 1430 fenhexamid TRIVIAL 23052036 A 1483 1492 estradiol TRIVIAL 23052036 A 15 26 fludioxonil TRIVIAL 23052036 A 150 160 Fenhexamid TRIVIAL 23052036 A 1581 1591 fenhexamid TRIVIAL 23052036 A 1596 1607 fludioxonil TRIVIAL 23052036 A 165 176 fludioxonil TRIVIAL 23052036 A 236 244 androgen FAMILY 23052036 A 432 442 fenhexamid TRIVIAL 23052036 A 447 458 fludioxonil TRIVIAL 23052036 A 605 615 Fenhexamid TRIVIAL 23052036 A 620 631 fludioxonil TRIVIAL 23052036 A 817 827 fenhexamid TRIVIAL 23052036 A 832 843 fludioxonil TRIVIAL 23052036 A 845 855 Fenhexamid TRIVIAL 23052036 A 860 871 fludioxonil TRIVIAL 23052036 A 991 999 estrogen FAMILY 23052036 T 21 32 fludioxonil TRIVIAL 23052036 T 37 47 fenhexamid TRIVIAL 23052197 A 1476 1481 B[a]P ABBREVIATION 23052197 A 1675 1680 B[a]P ABBREVIATION 23052197 A 395 409 benzo[a]pyrene SYSTEMATIC 23052197 A 411 416 B[a]P ABBREVIATION 23052197 A 564 569 B[a]P ABBREVIATION 23052197 A 951 956 B[a]P ABBREVIATION 23052197 T 0 14 Benzo[a]pyrene SYSTEMATIC 23053786 A 1118 1127 malathion TRIVIAL 23053786 A 1248 1257 malathion TRIVIAL 23053786 A 443 452 malathion TRIVIAL 23053786 A 632 641 malathion TRIVIAL 23053786 A 880 889 malathion TRIVIAL 23053786 A 954 963 malathion TRIVIAL 23053787 A 1147 1153 copper SYSTEMATIC 23053787 A 1158 1166 caffeine TRIVIAL 23053787 A 482 497 ethoxyresorufin SYSTEMATIC 23053787 A 498 499 O FORMULA 23053787 A 512 523 glutathione TRIVIAL 23053787 A 524 525 S FORMULA 23053787 A 539 550 glutathione TRIVIAL 23053787 A 566 576 superoxide TRIVIAL 23055538 A 1032 1045 acetaminophen TRIVIAL 23055538 A 650 661 bisphenol A TRIVIAL 23058474 A 1395 1404 estradiol TRIVIAL 23061466 A 10 15 ether SYSTEMATIC 23061466 A 1007 1028 isoquinoline alkaloid FAMILY 23061466 A 1030 1038 neferine TRIVIAL 23061466 A 1040 1043 Nef ABBREVIATION 23061466 A 49 51 K+ FORMULA 23061466 A 606 629 quinolizidine alkaloids FAMILY 23061466 A 657 667 oxymatrine TRIVIAL 23061466 A 669 680 sophoridine TRIVIAL 23061466 A 682 694 sophocarpine TRIVIAL 23061466 A 699 706 matrine TRIVIAL 23061466 A 747 760 O=C=N-C-C-C-N FORMULA 23061466 A 831 856 Acehytisine hydrochloride SYSTEMATIC 23061466 A 875 889 Guangfu base A TRIVIAL 23061466 T 6 11 ether SYSTEMATIC 23061657 A 1427 1437 piplartine TRIVIAL 23061657 A 1582 1592 piplartine TRIVIAL 23061657 A 381 386 amide FAMILY 23061657 A 387 397 piplartine TRIVIAL 23061657 A 72 84 praziquantel TRIVIAL 23061657 A 852 862 piplartine TRIVIAL 23061657 A 899 909 Piplartine TRIVIAL 23061657 T 41 46 amide FAMILY 23061657 T 47 57 piplartine TRIVIAL 23063001 A 1133 1135 Na FORMULA 23063001 A 1140 1142 Cl FORMULA 23063001 A 1202 1204 Pb FORMULA 23063001 A 1209 1213 urea TRIVIAL 23063001 A 1245 1247 Pb FORMULA 23063001 A 1264 1269 Na(+) FORMULA 23063001 A 1270 1274 K(+) FORMULA 23063001 A 1512 1518 silver SYSTEMATIC 23063001 A 163 165 Pb FORMULA 23063001 A 1641 1643 Pb FORMULA 23063001 A 334 339 CO(2) FORMULA 23063001 A 400 404 urea TRIVIAL 23063001 A 406 410 TMAO ABBREVIATION 23063001 A 412 419 lactate FAMILY 23063001 A 456 458 Pb FORMULA 23063001 A 605 610 Na(+) FORMULA 23063001 A 611 615 K(+) FORMULA 23063001 A 693 700 ammonia SYSTEMATIC 23063001 A 705 709 urea TRIVIAL 23063001 A 787 789 Pb FORMULA 23063003 A 1101 1108 cadmium SYSTEMATIC 23063003 A 149 156 cadmium SYSTEMATIC 23063003 A 15 22 cadmium SYSTEMATIC 23063003 A 290 292 Cd FORMULA 23063003 A 645 652 cadmium SYSTEMATIC 23063003 A 846 857 glutathione TRIVIAL 23063003 A 949 956 cadmium SYSTEMATIC 23063003 T 29 36 cadmium SYSTEMATIC 23063413 A 1037 1047 tariquidar TRIVIAL 23063413 A 533 544 Vinblastine TRIVIAL 23063413 A 546 549 Vin ABBREVIATION 23063413 A 580 583 Vin ABBREVIATION 23063413 A 700 703 Vin ABBREVIATION 23063595 A 1308 1319 polyphenols FAMILY 23063595 A 425 428 AMP ABBREVIATION 23063595 A 562 573 polyphenols FAMILY 23063595 T 35 46 polyphenols FAMILY 23063671 A 1152 1155 BEA ABBREVIATION 23063671 A 1160 1163 FUS ABBREVIATION 23063671 A 160 185 enniatins A, A1, B and B1 MULTIPLE 23063671 A 193 204 beauvericin TRIVIAL 23063671 A 206 209 BEA ABBREVIATION 23063671 A 215 229 fusaproliferin TRIVIAL 23063671 A 231 234 FUS ABBREVIATION 23063671 A 705 708 BEA ABBREVIATION 23063671 A 751 754 FUS ABBREVIATION 23063746 A 132 148 pseudosaccharine TRIVIAL 23063746 A 250 261 quinazoline SYSTEMATIC 23063746 T 46 62 pseudosaccharine TRIVIAL 23063874 A 1023 1039 cinnamyl alcohol TRIVIAL 23063874 A 1041 1048 eugenol TRIVIAL 23063874 A 1050 1060 isoeugenol TRIVIAL 23063874 A 1062 1078 p-phenylediamine SYSTEMATIC 23063874 A 1107 1135 ammonium hexachloroplatinate SYSTEMATIC 23063874 A 1137 1165 diphenylmethane diisocyanate SYSTEMATIC 23063874 A 1167 1181 glutaraldehyde TRIVIAL 23063874 A 1183 1208 hexamethylenediisocyanate SYSTEMATIC 23063874 A 1210 1226 maleic anhydride TRIVIAL 23063874 A 1228 1249 trimellitic anhydride SYSTEMATIC 23063874 A 1269 1281 benzaldehyde SYSTEMATIC 23063874 A 1283 1297 cholorobenzene SYSTEMATIC 23063874 A 1299 1314 diethylphtalate SYSTEMATIC 23063874 A 1316 1333 hydrobenzoic acid SYSTEMATIC 23063874 A 1335 1346 lactic acid TRIVIAL 23063874 A 1348 1361 octanoic acid SYSTEMATIC 23063874 A 1363 1369 phenol SYSTEMATIC 23063874 A 1371 1385 salicylic acid TRIVIAL 23063874 A 1387 1409 sodium lauryl sulphate SYSTEMATIC 23063874 A 1411 1424 sulfamic acid SYSTEMATIC 23063874 A 1560 1563 MTT ABBREVIATION 23063874 A 1722 1735 sulfamic acid SYSTEMATIC 23063874 A 762 798 2-bromo-2-bromomethyl glutaronitrile SYSTEMATIC 23063874 A 800 814 cinnamaldehyde TRIVIAL 23063874 A 816 822 citral TRIVIAL 23063874 A 824 838 diethylmaleate SYSTEMATIC 23063874 A 840 860 dinitrochlorobenzene SYSTEMATIC 23063874 A 862 869 glyoxal TRIVIAL 23063874 A 871 894 2-mercaptobenzothiazole SYSTEMATIC 23063874 A 896 910 nickel sulfate SYSTEMATIC 23063874 A 912 932 4-nitrobenzylbromide SYSTEMATIC 23063874 A 934 943 oxazolone SYSTEMATIC 23063874 A 945 957 penicillin G TRIVIAL 23063874 A 959 969 resorcinol TRIVIAL 23063874 A 971 999 tetramethylthiuram disulfide SYSTEMATIC 23063876 A 1143 1153 phthalates FAMILY 23063876 A 1265 1275 phthalates FAMILY 23063876 A 1655 1659 DEHP ABBREVIATION 23063876 A 1811 1815 DEHP ABBREVIATION 23063876 A 189 216 Di-(2-ethylhexyl)-phthalate SYSTEMATIC 23063876 A 1939 1943 DEHP ABBREVIATION 23063876 A 218 222 DEHP ABBREVIATION 23063876 A 324 328 DEHP ABBREVIATION 23063876 A 386 399 phthalic acid TRIVIAL 23063876 A 577 585 estrogen FAMILY 23063876 A 60 70 phthalates FAMILY 23063876 T 127 131 DEHP ABBREVIATION 23063876 T 137 150 phthalic acid TRIVIAL 23063876 T 98 125 Di-(2-ethylhexyl)-phthalate SYSTEMATIC 23064031 A 0 29 Naphtho[1,2-b]furan-4,5-dione SYSTEMATIC 23064031 A 1103 1106 NFD ABBREVIATION 23064031 A 1330 1333 NFD ABBREVIATION 23064031 A 31 34 NFD ABBREVIATION 23064031 A 389 392 NFD ABBREVIATION 23064031 A 425 428 NFD ABBREVIATION 23064031 A 640 643 NFD ABBREVIATION 23064031 A 709 729 phosphatidylinositol TRIVIAL 23064031 A 780 790 wortmannin TRIVIAL 23064031 A 887 893 AG1478 IDENTIFIER 23064031 T 39 68 naphtho[1,2-b]furan-4,5-dione SYSTEMATIC 23064475 A 0 9 Vitamin D FAMILY 23064475 A 103 112 vitamin D FAMILY 23064475 A 1148 1157 vitamin D FAMILY 23064475 A 1331 1338 25(OH)D SYSTEMATIC 23064475 A 1503 1510 25(OH)D SYSTEMATIC 23064475 A 211 220 vitamin D FAMILY 23064475 A 354 373 25-hydroxyvitamin D SYSTEMATIC 23064475 A 375 382 25(OH)D SYSTEMATIC 23064475 A 596 603 25(OH)D SYSTEMATIC 23064475 A 746 753 25(OH)D SYSTEMATIC 23064475 A 884 891 25(OH)D SYSTEMATIC 23064475 T 25 44 25-hydroxyvitamin D SYSTEMATIC 23065140 A 0 8 Ketamine TRIVIAL 23065140 A 1083 1091 ketamine TRIVIAL 23065140 A 1112 1116 NMDA ABBREVIATION 23065140 A 1174 1181 calcium SYSTEMATIC 23065140 A 1187 1194 calcium SYSTEMATIC 23065140 A 1245 1253 ketamine TRIVIAL 23065140 A 1296 1303 calcium SYSTEMATIC 23065140 A 1341 1348 calcium SYSTEMATIC 23065140 A 1366 1372 Ca(2+) FORMULA 23065140 A 1386 1390 NMDA ABBREVIATION 23065140 A 1469 1477 ketamine TRIVIAL 23065140 A 1511 1515 NMDA ABBREVIATION 23065140 A 1607 1614 calcium SYSTEMATIC 23065140 A 1633 1641 ketamine TRIVIAL 23065140 A 1730 1741 L-Carnitine TRIVIAL 23065140 A 1801 1809 ketamine TRIVIAL 23065140 A 196 204 ketamine TRIVIAL 23065140 A 27 47 N-methyl-D-aspartate SYSTEMATIC 23065140 A 318 326 ketamine TRIVIAL 23065140 A 400 408 ketamine TRIVIAL 23065140 A 49 53 NMDA ABBREVIATION 23065140 A 624 632 ketamine TRIVIAL 23065140 A 644 652 ketamine TRIVIAL 23065140 A 658 669 L-carnitine TRIVIAL 23065140 A 744 752 Ketamine TRIVIAL 23065140 A 783 787 NMDA ABBREVIATION 23065140 A 848 854 oxygen SYSTEMATIC 23065140 A 902 914 8-oxoguanine SYSTEMATIC 23065140 A 977 988 L-carnitine TRIVIAL 23065140 T 0 8 Ketamine TRIVIAL 23065140 T 45 65 N-methyl-D-aspartate SYSTEMATIC 23065799 A 531 561 poly(D,L-lactide-co-glycolide) FAMILY 23065799 A 791 801 β-carotene TRIVIAL 23065799 A 987 997 β-Carotene TRIVIAL 23065799 T 60 70 β-carotene TRIVIAL 23065799 T 78 108 poly(D,L-lactide-co-glycolide) FAMILY 23066089 A 0 7 Kainate TRIVIAL 23066089 A 1010 1066 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid SYSTEMATIC 23066089 A 1068 1073 BAPTA ABBREVIATION 23066089 A 1115 1127 okadaic acid TRIVIAL 23066089 A 1151 1159 tyrosine TRIVIAL 23066089 A 1177 1190 lavendustin A TRIVIAL 23066089 A 1320 1351 phorbol 12-myristate,13-acetate SYSTEMATIC 23066089 A 1430 1437 serines FAMILY 23066089 A 1439 1442 Ser FORMULA 23066089 A 1447 1450 Ser FORMULA 23066089 A 1459 1462 Ser FORMULA 23066089 A 1516 1517 C FORMULA 23066089 A 1683 1684 C FORMULA 23066089 A 220 229 glutamate TRIVIAL 23066089 A 49 58 glutamate TRIVIAL 23066089 A 589 596 calcium SYSTEMATIC 23066089 A 993 1000 calcium SYSTEMATIC 23066089 T 35 44 glutamate TRIVIAL 23066089 T 79 86 kainate TRIVIAL 23066091 A 1023 1031 adenylyl TRIVIAL 23066091 A 1167 1177 metoprolol TRIVIAL 23066091 A 1179 1189 bisoprolol TRIVIAL 23066091 A 1195 1204 CGP-20712 IDENTIFIER 23066091 A 1206 1320 1-[2-((3-carbamoyl-4-hydroxy)phenoxy)ethylamino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl)phenoxy]-2-propanol SYSTEMATIC 23066091 A 254 255 N FORMULA 23066091 A 805 818 isoproterenol TRIVIAL 23066091 A 820 833 S-propranolol TRIVIAL 23066091 A 835 844 CGP-12177 IDENTIFIER 23066091 A 846 928 4-[3-[(1,1-dimethylethyl)amino]2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one SYSTEMATIC 23066091 A 931 939 pindolol TRIVIAL 23066091 A 945 952 timolol TRIVIAL 23066091 T 68 69 N FORMULA 23066093 A 1265 1270 AM251 IDENTIFIER 23066093 A 1387 1400 phorbol ester FAMILY 23066093 A 1461 1466 AM251 IDENTIFIER 23066093 A 1652 1657 AM251 IDENTIFIER 23066093 A 28 36 estrogen FAMILY 23066093 A 297 311 biarylpyrazole FAMILY 23066093 A 321 411 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide SYSTEMATIC 23066093 A 413 418 AM251 IDENTIFIER 23066093 A 535 540 AM251 IDENTIFIER 23066093 A 726 731 AM251 IDENTIFIER 23066093 A 838 850 leptomycin B TRIVIAL 23066093 A 867 872 AM251 IDENTIFIER 23066093 A 949 954 MG132 IDENTIFIER 23066093 T 28 33 AM251 IDENTIFIER 23066093 T 4 18 biarylpyrazole FAMILY 23066988 A 1110 1119 Metformin TRIVIAL 23066988 A 218 227 Metformin TRIVIAL 23066988 A 22 31 Metformin TRIVIAL 23066988 A 304 313 Metformin TRIVIAL 23066988 A 396 419 adenosine monophosphate SYSTEMATIC 23066988 A 467 476 Metformin TRIVIAL 23066988 A 625 635 compound C TRIVIAL 23066988 A 669 720 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide SYSTEMATIC 23066988 A 722 727 AICAR ABBREVIATION 23066988 A 837 846 Metformin TRIVIAL 23066988 A 955 964 Metformin TRIVIAL 23066988 A 98 107 Metformin TRIVIAL 23066988 T 0 9 Metformin TRIVIAL 23066988 T 54 57 AMP ABBREVIATION 23067059 A 262 270 titanium SYSTEMATIC 23067059 A 316 322 TiO(2) FORMULA 23067059 A 932 940 titanium SYSTEMATIC 23068768 A 44 52 steroids FAMILY 23068768 A 59 79 nandrolone decanoate SYSTEMATIC 23068768 T 113 133 nandrolone decanoate SYSTEMATIC 23069375 A 0 13 Rosiglitazone TRIVIAL 23069375 A 1416 1420 Rosi ABBREVIATION 23069375 A 1462 1469 glucose TRIVIAL 23069375 A 15 19 Rosi ABBREVIATION 23069375 A 1603 1607 Rosi ABBREVIATION 23069375 A 1826 1830 Rosi ABBREVIATION 23069375 A 242 246 Rosi ABBREVIATION 23069375 A 376 380 Rosi ABBREVIATION 23069375 A 38 55 thiazolidinedione FAMILY 23069375 A 423 427 Rosi ABBREVIATION 23069375 A 746 750 Rosi ABBREVIATION 23069375 T 0 13 Rosiglitazone TRIVIAL 23074026 A 0 25 Perfluorooctane sulfonate SYSTEMATIC 23074026 A 1156 1164 estrogen FAMILY 23074026 A 1220 1224 PFOS ABBREVIATION 23074026 A 1285 1289 PFOS ABBREVIATION 23074026 A 145 149 PFOS ABBREVIATION 23074026 A 27 31 PFOS ABBREVIATION 23074026 A 310 325 thyroid hormone FAMILY 23074026 A 352 356 PFOS ABBREVIATION 23074026 A 584 588 PFOS ABBREVIATION 23074026 A 646 650 PFOS ABBREVIATION 23074026 A 665 673 estrogen FAMILY 23074026 A 695 710 thyroid hormone FAMILY 23074026 A 744 748 PFOS ABBREVIATION 23074026 A 771 783 testosterone TRIVIAL 23074026 A 799 808 estradiol TRIVIAL 23074026 A 936 940 PFOS ABBREVIATION 23074026 T 0 25 Perfluorooctane sulfonate SYSTEMATIC 23074026 T 27 31 PFOS ABBREVIATION 23075005 A 1027 1037 anagliptin TRIVIAL 23075005 A 1164 1174 anagliptin TRIVIAL 23075005 A 164 181 [(14)C]anagliptin SYSTEMATIC 23075005 A 22 32 anagliptin TRIVIAL 23075005 A 297 307 Anagliptin TRIVIAL 23075005 A 489 500 carboxylate SYSTEMATIC 23075005 A 653 663 Anagliptin TRIVIAL 23075005 A 947 957 anagliptin TRIVIAL 23075005 T 35 52 [(14)C]anagliptin SYSTEMATIC 23075165 A 1102 1112 thiophenol SYSTEMATIC 23075165 A 127 133 silver SYSTEMATIC 23075165 A 311 317 quartz TRIVIAL 23075165 A 998 1004 quartz TRIVIAL 23077183 A 0 10 Octreotide TRIVIAL 23077183 A 1082 1092 octreotide TRIVIAL 23077183 A 173 183 octreotide TRIVIAL 23077183 A 23 35 somatostatin TRIVIAL 23077183 T 76 88 somatostatin TRIVIAL 23077183 T 96 106 octreotide TRIVIAL 23079470 A 1036 1046 PNU-120596 IDENTIFIER 23079470 A 1141 1151 PNU-120596 IDENTIFIER 23079470 A 1274 1280 NS1738 IDENTIFIER 23079470 A 1346 1349 MLA ABBREVIATION 23079470 A 1359 1369 PNU-120596 IDENTIFIER 23079470 A 1458 1468 PNU-120596 IDENTIFIER 23079470 A 1519 1529 PHA-543613 IDENTIFIER 23079470 A 1634 1644 PNU-120596 IDENTIFIER 23079470 A 1679 1685 NS1738 IDENTIFIER 23079470 A 67 80 acetylcholine SYSTEMATIC 23079470 A 705 711 NS1738 IDENTIFIER 23079470 A 726 736 PNU-120596 IDENTIFIER 23079470 A 861 867 NS1738 IDENTIFIER 23079470 A 872 882 PNU-120596 IDENTIFIER 23079470 A 938 948 PNU-120596 IDENTIFIER 23079670 A 159 167 nitrogen SYSTEMATIC 23079670 A 446 456 aza-dienes FAMILY 23079670 T 80 88 nitrogen SYSTEMATIC 23081760 A 1531 1538 acetone SYSTEMATIC 23081760 A 1543 1558 dichloromethane SYSTEMATIC 23081760 A 507 517 dichlorvos TRIVIAL 23081760 A 597 607 endosulfan TRIVIAL 23081760 A 773 779 diuron TRIVIAL 23081760 A 904 914 glyphosate TRIVIAL 23082005 A 104 115 aldosterone TRIVIAL 23082005 A 377 388 aldosterone TRIVIAL 23082005 A 949 960 aldosterone TRIVIAL 23085120 A 0 18 Bis(12)-hupyridone SYSTEMATIC 23085120 A 1031 1035 pSer FORMULA 23085120 A 1047 1051 pSer FORMULA 23085120 A 1091 1095 B12H ABBREVIATION 23085120 A 1133 1142 glutamate TRIVIAL 23085120 A 189 193 B12H ABBREVIATION 23085120 A 20 24 B12H ABBREVIATION 23085120 A 234 243 glutamate TRIVIAL 23085120 A 385 389 B12H ABBREVIATION 23085120 A 454 458 NMDA ABBREVIATION 23085120 A 528 532 B12H ABBREVIATION 23085120 A 583 587 NMDA ABBREVIATION 23085120 A 655 668 acetylcholine SYSTEMATIC 23085120 A 708 721 acetylcholine SYSTEMATIC 23085120 A 72 83 huperzine A TRIVIAL 23085120 A 786 790 B12H ABBREVIATION 23085120 A 815 819 B12H ABBREVIATION 23085120 A 907 911 B12H ABBREVIATION 23085120 A 976 985 glutamate TRIVIAL 23085120 T 0 18 Bis(12)-hupyridone SYSTEMATIC 23085120 T 147 160 acetylcholine SYSTEMATIC 23085120 T 170 186 phosphoinositide FAMILY 23085120 T 77 86 glutamate TRIVIAL 23085190 A 1032 1038 MK-886 IDENTIFIER 23085190 A 1043 1052 celecoxib TRIVIAL 23085190 A 665 685 leukotriene (LT)B(4) TRIVIAL 23085190 A 687 709 prostaglandin (PG)E(2) TRIVIAL 23085367 A 1055 1066 xanthohumol TRIVIAL 23085367 A 315 326 xanthohumol TRIVIAL 23085367 A 472 483 Xanthohumol TRIVIAL 23085367 A 49 60 xanthohumol TRIVIAL 23085367 A 723 734 Xanthohumol TRIVIAL 23085367 T 0 11 Xanthohumol TRIVIAL 23085437 A 1060 1069 rapamycin TRIVIAL 23085437 A 1446 1455 rapamycin TRIVIAL 23085437 T 44 53 rapamycin TRIVIAL 23085546 A 1073 1082 piroxicam TRIVIAL 23085546 A 123 132 piroxicam TRIVIAL 23085546 A 224 233 piroxicam TRIVIAL 23085546 A 382 390 Soluplus TRIVIAL 23085546 A 393 468 polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer FAMILY 23085546 A 497 506 piroxicam TRIVIAL 23085546 A 637 646 piroxicam TRIVIAL 23085546 A 658 667 piroxicam TRIVIAL 23085546 A 998 1006 Soluplus TRIVIAL 23085546 T 62 71 piroxicam TRIVIAL 23086230 A 0 7 Coniine TRIVIAL 23086230 A 1256 1263 coniine TRIVIAL 23086230 A 1406 1425 piperidine alkaloid FAMILY 23086230 A 1426 1433 coniine TRIVIAL 23086230 A 157 164 Coniine TRIVIAL 23086230 A 37 56 piperidine alkaloid FAMILY 23086230 A 398 405 coniine TRIVIAL 23086230 A 480 491 (-)-coniine TRIVIAL 23086230 A 493 504 (+)-coniine TRIVIAL 23086230 A 510 518 nicotine TRIVIAL 23086230 A 71 84 acetylcholine SYSTEMATIC 23086230 A 732 752 (+)- and (-)-coniine MULTIPLE 23086230 A 770 781 (-)-Coniine TRIVIAL 23086230 A 888 899 (+)-coniine TRIVIAL 23086230 A 951 968 pyridine alkaloid FAMILY 23086230 A 969 977 nicotine TRIVIAL 23086230 T 169 188 piperidine alkaloid FAMILY 23086230 T 189 196 coniine TRIVIAL 23086230 T 28 41 acetylcholine SYSTEMATIC 23086461 A 120 133 disaccharides FAMILY 23086461 A 367 379 disaccharide FAMILY 23086461 A 50 87 2-O-sulfated-3,6-α-D-anhydrogalactose SYSTEMATIC 23086461 T 43 81 2-O-sulfated 3,6 anhydro-α-D-galactose SYSTEMATIC 23086461 T 89 112 neo-κ- and ι-carrabiose MULTIPLE 23086748 A 1246 1248 Ag FORMULA 23086748 A 1298 1305 lactate FAMILY 23086748 A 1467 1469 Ag FORMULA 23086748 A 1559 1561 Ag FORMULA 23086748 A 1891 1893 Ag FORMULA 23086748 A 336 342 Silver SYSTEMATIC 23086748 A 344 346 Ag FORMULA 23086748 A 992 994 Ag FORMULA 23086748 T 11 17 silver SYSTEMATIC 23086899 A 49 55 Ag(Cu) FORMULA 23086899 A 56 62 ZrO(2) FORMULA 23086899 A 64 66 Pt FORMULA 23086899 T 90 95 oxide SYSTEMATIC 23087260 A 1202 1205 GTP ABBREVIATION 23087260 A 1255 1258 GTP ABBREVIATION 23087260 A 1418 1428 nucleotide FAMILY 23087260 A 186 227 guanosine 5[prime]-O-(3-thio)triphosphate SYSTEMATIC 23087260 A 229 234 GTPγS ABBREVIATION 23087260 A 291 296 GTPγS ABBREVIATION 23087260 A 468 471 GTP ABBREVIATION 23087260 A 56 74 prostaglandin E(2) TRIVIAL 23087260 A 683 686 GTP ABBREVIATION 23087260 A 738 750 [(3)H]PGE(2) SYSTEMATIC 23087260 A 76 82 PGE(2) ABBREVIATION 23087260 A 807 810 GTP ABBREVIATION 23087260 A 816 828 [(3)H]PGE(2) SYSTEMATIC 23087260 A 84 96 E-prostanoid FAMILY 23087260 A 909 914 GTPγS ABBREVIATION 23087260 T 32 35 GTP ABBREVIATION 23087260 T 55 68 prostaglandin FAMILY 23087379 A 283 291 hydrogen SYSTEMATIC 23087379 A 905 913 hydrogen SYSTEMATIC 23087379 T 36 44 hydrogen SYSTEMATIC 23089249 A 1107 1112 Na(+) FORMULA 23089249 A 1114 1118 K(+) FORMULA 23089249 A 1146 1154 carbaryl TRIVIAL 23089249 A 1342 1350 carbaryl TRIVIAL 23089249 A 1558 1566 carbaryl TRIVIAL 23089249 A 1612 1620 carbaryl TRIVIAL 23089249 A 1832 1840 carbaryl TRIVIAL 23089249 A 27 35 carbaryl TRIVIAL 23089249 A 294 302 Carbaryl TRIVIAL 23089249 A 347 355 cortisol TRIVIAL 23089249 A 360 367 glucose TRIVIAL 23089249 A 37 63 1-naphthyl methylcarbamate SYSTEMATIC 23089249 A 473 481 carbaryl TRIVIAL 23089249 A 65 70 sevin TRIVIAL 23089249 A 665 673 carbaryl TRIVIAL 23089249 A 724 726 Na FORMULA 23089249 A 728 729 K FORMULA 23089249 A 731 733 Ca FORMULA 23089249 A 748 757 phosphate SYSTEMATIC 23089249 A 75 84 carbamate FAMILY 23089249 A 770 777 ouabain TRIVIAL 23089249 A 788 793 Na(+) FORMULA 23089249 A 795 799 K(+) FORMULA 23089249 A 911 919 carbaryl TRIVIAL 23089249 A 990 995 Na(+) FORMULA 23089249 A 997 1001 K(+) FORMULA 23089249 T 0 8 Carbaryl TRIVIAL 23090483 A 256 260 zinc SYSTEMATIC 23090483 A 367 369 Zn FORMULA 23090483 A 374 376 Cd FORMULA 23090483 A 595 601 oxygen SYSTEMATIC 23090647 A 0 11 Linaclotide TRIVIAL 23090647 A 1064 1075 linaclotide TRIVIAL 23090647 A 1186 1195 MM-419447 IDENTIFIER 23090647 A 1235 1244 MM-419447 IDENTIFIER 23090647 A 1381 1417 cyclic guanosine-3',5'-monophosphate SYSTEMATIC 23090647 A 1419 1423 cGMP ABBREVIATION 23090647 A 1483 1492 MM-419447 IDENTIFIER 23090647 A 1585 1589 cGMP ABBREVIATION 23090647 A 1746 1757 linaclotide TRIVIAL 23090647 A 22 31 guanylate TRIVIAL 23090647 A 285 296 linaclotide TRIVIAL 23090647 A 359 370 linaclotide TRIVIAL 23090647 A 456 465 MM-419447 IDENTIFIER 23090647 A 533 544 linaclotide TRIVIAL 23090647 A 671 682 linaclotide TRIVIAL 23090647 A 687 696 MM-419447 IDENTIFIER 23090647 A 791 802 Linaclotide TRIVIAL 23090647 A 874 883 MM-419447 IDENTIFIER 23090647 A 912 921 disulfide SYSTEMATIC 23090647 T 57 68 linaclotide TRIVIAL 23090712 A 1067 1074 La(III) FORMULA 23090712 A 1142 1149 nitrate SYSTEMATIC 23090712 A 1161 1170 glutamine TRIVIAL 23090712 A 1183 1192 glutamate TRIVIAL 23090712 A 1207 1216 glutamate TRIVIAL 23090712 A 1242 1252 amino acid FAMILY 23090712 A 1333 1340 La(III) FORMULA 23090712 A 1498 1505 La(III) FORMULA 23090712 A 1558 1566 nitrogen SYSTEMATIC 23090712 A 380 389 lanthanum SYSTEMATIC 23090712 A 391 398 La(III) FORMULA 23090712 A 403 411 nitrogen SYSTEMATIC 23090712 A 664 671 nitrate SYSTEMATIC 23090712 A 683 692 glutamine TRIVIAL 23090712 A 705 714 glutamate TRIVIAL 23090712 A 732 740 nitrogen SYSTEMATIC 23090712 A 787 794 nitrate SYSTEMATIC 23090712 A 859 869 amino acid FAMILY 23090712 T 0 15 Lanthanum (III) SYSTEMATIC 23090712 T 30 38 nitrogen SYSTEMATIC 23091170 A 0 13 Diisocyanates FAMILY 23091170 A 1666 1669 TDI ABBREVIATION 23091170 A 438 448 isocyanate SYSTEMATIC 23091170 A 520 544 toluene-2,4-diisocyanate SYSTEMATIC 23091170 A 546 549 TDI ABBREVIATION 23091170 A 563 570 acetone SYSTEMATIC 23091170 A 616 632 cyclophosphamide TRIVIAL 23091170 A 884 887 TDI ABBREVIATION 23091170 A 926 938 methacholine TRIVIAL 23092130 A 1040 1067 poly(N-isopropylacrylamide) SYSTEMATIC 23092130 A 1075 1082 PNIPAAM ABBREVIATION 23092130 A 1096 1116 poly(ethylene oxide) SYSTEMATIC 23092130 A 1117 1138 poly(propylene oxide) FAMILY 23092130 A 1140 1143 PEO ABBREVIATION 23092130 A 1144 1147 PPO ABBREVIATION 23092130 A 1185 1206 poly(ethylene glycol) SYSTEMATIC 23092130 A 1222 1231 polyester FAMILY 23092679 A 746 755 magnesium SYSTEMATIC 23092679 A 757 764 calcium SYSTEMATIC 23092759 A 1089 1091 NO FORMULA 23092759 A 15 20 NADPH ABBREVIATION 23092759 A 568 584 2-Bromopalmitate SYSTEMATIC 23092759 A 586 590 2-BP SYSTEMATIC 23092759 A 699 705 oxygen SYSTEMATIC 23092759 A 745 757 nitric oxide SYSTEMATIC 23092759 A 783 795 nitric oxide SYSTEMATIC 23092759 A 797 799 NO FORMULA 23092759 A 822 826 2-BP SYSTEMATIC 23092759 T 135 151 2-bromopalmitate SYSTEMATIC 23092759 T 31 36 NADPH ABBREVIATION 23092918 A 1093 1102 rapamycin TRIVIAL 23092918 A 1313 1322 rapamycin TRIVIAL 23092918 A 1758 1767 rapamycin TRIVIAL 23092918 A 176 185 rapamycin TRIVIAL 23092918 A 1810 1819 rapamycin TRIVIAL 23092918 A 198 204 serine TRIVIAL 23092918 A 2017 2026 rapamycin TRIVIAL 23092918 A 205 214 threonine TRIVIAL 23092918 A 824 833 rapamycin TRIVIAL 23092949 A 1021 1027 Cu(II) FORMULA 23092949 A 1031 1037 Zn(II) FORMULA 23092949 A 1098 1105 pyridyl SYSTEMATIC 23092949 A 11 22 polypyridyl FAMILY 23092949 A 1456 1462 Zn(II) FORMULA 23092949 A 1467 1473 Ca(II) FORMULA 23092949 A 1498 1504 Cd(II) FORMULA 23092949 A 1548 1555 pyridyl SYSTEMATIC 23092949 A 1698 1704 Zn(II) FORMULA 23092949 A 1717 1723 Cd(II) FORMULA 23092949 A 1810 1816 Hg(II) FORMULA 23092949 A 1821 1827 Pb(II) FORMULA 23092949 A 188 199 polypyridyl FAMILY 23092949 A 2067 2073 Hg(II) FORMULA 23092949 A 2144 2155 anthracenyl SYSTEMATIC 23092949 A 259 264 benzo SYSTEMATIC 23092949 A 291 310 1,10-phenanthroline SYSTEMATIC 23092949 A 312 316 phen ABBREVIATION 23092949 A 330 344 2,2'-bipyridyl SYSTEMATIC 23092949 A 346 349 bpy ABBREVIATION 23092949 A 461 468 pyridyl SYSTEMATIC 23092949 A 573 574 H FORMULA 23092949 A 584 595 polypyridyl FAMILY 23092949 A 720 724 Phen ABBREVIATION 23092949 A 799 807 alcohols FAMILY 23092949 A 809 815 amides FAMILY 23092949 A 817 829 carboxylates FAMILY 23092949 A 835 841 oximes FAMILY 23092949 A 871 878 pyridyl SYSTEMATIC 23092949 A 915 922 Am(III) FORMULA 23092949 A 928 943 lanthanide(III) SYSTEMATIC 23092949 T 4 11 pyridyl SYSTEMATIC 23099431 A 0 6 GHRP-6 ABBREVIATION 23099431 A 1124 1130 GHRP-6 ABBREVIATION 23099431 A 1402 1408 GHRP-6 ABBREVIATION 23099431 A 189 227 His-(D-Trp)-Ala-Trp-(D-Phe)-Lys-NH(2,) FORMULA 23099431 A 364 370 GHRP-6 ABBREVIATION 23099431 A 497 515 (13)C(3)Ala-GHRP-6 FORMULA 23099431 A 821 827 GHRP-6 ABBREVIATION 23099431 T 25 59 Growth Hormone-Releasing Peptide 6 TRIVIAL 23099431 T 61 67 GHRP-6 ABBREVIATION 23100158 A 0 8 β-ionone TRIVIAL 23100158 A 1029 1037 β-ionone TRIVIAL 23100158 A 145 153 β-ionone TRIVIAL 23100158 A 282 302 phosphatidylinositol TRIVIAL 23100158 A 416 424 β-ionone TRIVIAL 23100158 A 501 509 β-ionone TRIVIAL 23100158 A 549 557 β-ionone TRIVIAL 23100158 A 798 806 β-ionone TRIVIAL 23100158 A 918 926 β-ionone TRIVIAL 23100158 T 24 32 β-ionone TRIVIAL 23100159 A 102 109 arsenic SYSTEMATIC 23100159 A 1049 1053 iron SYSTEMATIC 23100159 A 1063 1070 arsenic SYSTEMATIC 23100159 A 1246 1258 hydrotalcite TRIVIAL 23100159 A 1277 1284 arsenic SYSTEMATIC 23100159 A 1289 1293 iron SYSTEMATIC 23100159 A 1588 1595 arsenic SYSTEMATIC 23100159 A 1600 1604 iron SYSTEMATIC 23100159 A 297 304 arsenic SYSTEMATIC 23100159 A 387 394 arsenic SYSTEMATIC 23100159 A 399 403 iron SYSTEMATIC 23100159 A 550 557 arsenic SYSTEMATIC 23100159 A 562 566 iron SYSTEMATIC 23100159 A 643 650 arsenic SYSTEMATIC 23100159 A 661 665 iron SYSTEMATIC 23100159 A 685 689 Iron SYSTEMATIC 23100159 A 715 722 arsenic SYSTEMATIC 23100159 A 809 813 Iron SYSTEMATIC 23100159 T 42 49 arsenic SYSTEMATIC 23100159 T 54 58 iron SYSTEMATIC 23101934 A 196 202 oxygen SYSTEMATIC 23101934 A 44 58 alkanedithiols FAMILY 23101934 A 466 473 alkanes FAMILY 23101934 A 511 522 oligoethers FAMILY 23101934 A 545 551 alkane FAMILY 23101934 A 63 77 alkoxydithiols FAMILY 23101934 A 79 102 dithiolated oligoethers FAMILY 23101934 A 942 948 alkane FAMILY 23101934 T 14 20 oxygen SYSTEMATIC 23102509 A 0 12 Asiatic acid TRIVIAL 23102509 A 1012 1019 alanine TRIVIAL 23102509 A 1127 1140 glibenclamide TRIVIAL 23102509 A 1481 1493 carbohydrate FAMILY 23102509 A 21 33 triterpenoid FAMILY 23102509 A 274 286 carbohydrate FAMILY 23102509 A 301 315 streptozotocin TRIVIAL 23102509 A 317 320 STZ ABBREVIATION 23102509 A 398 412 streptozotocin TRIVIAL 23102509 A 527 534 glucose TRIVIAL 23102509 A 680 687 glucose TRIVIAL 23102509 A 706 714 fructose TRIVIAL 23102509 A 737 749 carbohydrate FAMILY 23102509 A 814 822 pyruvate TRIVIAL 23102509 A 831 850 glucose-6-phosphate SYSTEMATIC 23102509 A 982 991 aspartate TRIVIAL 23102509 T 12 24 asiatic acid TRIVIAL 23102509 T 123 137 streptozotocin TRIVIAL 23102509 T 28 50 pentacyclic triterpene FAMILY 23102509 T 96 108 carbohydrate FAMILY 23103283 A 0 9 Manganese SYSTEMATIC 23103283 A 216 224 Mancozeb FAMILY 23103283 A 37 45 Mancozeb FAMILY 23103283 A 429 437 dopamine TRIVIAL 23103283 A 521 529 Mancozeb FAMILY 23103283 A 764 773 manganese SYSTEMATIC 23103283 A 804 812 Mancozeb FAMILY 23103283 A 864 873 serotonin TRIVIAL 23103283 T 0 8 Mancozeb FAMILY 23103296 A 1125 1132 11-keto SYSTEMATIC 23103296 A 1204 1208 AKBA ABBREVIATION 23103296 A 1213 1216 KBA ABBREVIATION 23103296 A 1274 1286 Aα- and AβBA MULTIPLE 23103296 A 1288 1291 βBA ABBREVIATION 23103296 A 1296 1299 αBA ABBREVIATION 23103296 A 1559 1562 KBA ABBREVIATION 23103296 A 1577 1581 AKBA ABBREVIATION 23103296 A 1597 1600 αBA ABBREVIATION 23103296 A 1617 1620 βBA ABBREVIATION 23103296 A 1635 1639 AαBA ABBREVIATION 23103296 A 1658 1662 AβBA ABBREVIATION 23103296 A 317 341 11-keto-β-boswellic acid SYSTEMATIC 23103296 A 343 346 KBA ABBREVIATION 23103296 A 352 385 3-acetyl-11-keto-β-boswellic acid SYSTEMATIC 23103296 A 387 391 AKBA ABBREVIATION 23103296 A 476 491 boswellic acids FAMILY 23103296 A 524 540 β-boswellic acid TRIVIAL 23103296 A 542 545 βBA ABBREVIATION 23103296 A 719 722 KBA ABBREVIATION 23103296 A 724 728 AKBA ABBREVIATION 23103296 A 730 733 βBA ABBREVIATION 23103296 A 735 760 3-acetyl-β-boswellic acid SYSTEMATIC 23103296 A 762 766 AβBA ABBREVIATION 23103296 A 769 785 α-boswellic acid TRIVIAL 23103296 A 787 790 αBA ABBREVIATION 23103296 A 797 822 3-acetyl-α-boswellic acid SYSTEMATIC 23103296 A 824 828 AαBA ABBREVIATION 23103296 T 69 84 boswellic acids FAMILY 23103298 A 286 304 naphthodianthrones FAMILY 23103298 A 309 317 phenolic FAMILY 23103298 A 355 364 fagopyrin TRIVIAL 23103298 A 66 75 fagopyrin TRIVIAL 23103298 T 17 26 fagopyrin TRIVIAL 23103347 A 1080 1089 serotonin TRIVIAL 23103347 A 1132 1141 Serotonin TRIVIAL 23103347 A 1307 1316 serotonin TRIVIAL 23103347 A 1345 1357 fenfluramine TRIVIAL 23103347 A 1369 1378 serotonin TRIVIAL 23103347 A 1441 1453 fenfluramine TRIVIAL 23103347 A 540 552 Fenfluramine TRIVIAL 23103347 A 748 757 serotonin TRIVIAL 23103347 A 858 876 potassium chloride SYSTEMATIC 23103347 A 915 924 serotonin TRIVIAL 23103347 A 976 985 serotonin TRIVIAL 23103347 T 105 117 fenfluramine TRIVIAL 23103347 T 74 83 serotonin TRIVIAL 23103450 A 10 15 ether SYSTEMATIC 23103450 A 1077 1086 As(2)O(3) FORMULA 23103450 A 1101 1108 Matrine TRIVIAL 23103450 A 1113 1123 oxymatrine TRIVIAL 23103450 A 1187 1196 As(2)O(3) FORMULA 23103450 A 1444 1451 matrine TRIVIAL 23103450 A 1456 1466 oxymatrine TRIVIAL 23103450 A 1508 1517 potassium SYSTEMATIC 23103450 A 411 427 Arsenic trioxide SYSTEMATIC 23103450 A 429 438 As(2)O(3) FORMULA 23103450 A 736 745 As(2)O(3) FORMULA 23103450 A 847 854 matrine TRIVIAL 23103450 A 94 103 potassium SYSTEMATIC 23103450 A 961 968 matrine TRIVIAL 23103450 A 972 982 oxymatrine TRIVIAL 23103450 T 0 16 Arsenic trioxide SYSTEMATIC 23103450 T 30 34 K(+) FORMULA 23103450 T 72 79 matrine TRIVIAL 23103450 T 84 94 oxymatrine TRIVIAL 23103562 A 0 9 Cisplatin TRIVIAL 23103562 A 1055 1064 cisplatin TRIVIAL 23103562 A 1105 1114 cisplatin TRIVIAL 23103562 A 1170 1179 cisplatin TRIVIAL 23103562 A 142 151 cisplatin TRIVIAL 23103562 A 1641 1650 cisplatin TRIVIAL 23103562 A 1755 1764 cisplatin TRIVIAL 23103562 A 364 373 cisplatin TRIVIAL 23103562 A 415 424 cisplatin TRIVIAL 23103562 A 557 566 cisplatin TRIVIAL 23103562 A 592 601 cisplatin TRIVIAL 23103562 A 69 78 cisplatin TRIVIAL 23103562 A 729 738 cisplatin TRIVIAL 23103562 A 780 789 cisplatin TRIVIAL 23103562 A 893 902 cisplatin TRIVIAL 23103562 T 54 63 cisplatin TRIVIAL 23103563 A 1097 1112 bisphosphonates FAMILY 23103563 A 1205 1208 CpG ABBREVIATION 23103563 A 1346 1354 farnesyl TRIVIAL 23103563 A 31 51 aminobisphosphonates FAMILY 23103563 A 421 432 ibandronate TRIVIAL 23103563 A 57 68 ibandronate TRIVIAL 23103563 A 595 606 Ibandronate TRIVIAL 23103563 A 924 952 geranylgeranyl-pyrophosphate SYSTEMATIC 23103563 A 957 978 farnesylpyrophosphate SYSTEMATIC 23103563 A 993 1004 ibandronate TRIVIAL 23103563 T 0 11 Ibandronate TRIVIAL 23103564 A 1031 1040 glutamine TRIVIAL 23103564 A 1118 1123 (15)N FORMULA 23103564 A 1136 1145 glutamine TRIVIAL 23103564 A 1151 1171 [2,5-(15)N]ornithine SYSTEMATIC 23103564 A 1176 1188 (15)NH(4)(+) FORMULA 23103564 A 1241 1250 glutamine TRIVIAL 23103564 A 1265 1285 [2,5-(15)N]ornithine SYSTEMATIC 23103564 A 1289 1301 (15)NH(4)(+) FORMULA 23103564 A 139 148 Ornithine TRIVIAL 23103564 A 1465 1474 ornithine TRIVIAL 23103564 A 1476 1480 PAGN ABBREVIATION 23103564 A 1597 1604 ammonia SYSTEMATIC 23103564 A 173 180 ammonia SYSTEMATIC 23103564 A 195 204 glutamine TRIVIAL 23103564 A 226 235 glutamine TRIVIAL 23103564 A 27 36 ornithine TRIVIAL 23103564 A 274 287 phenylacetate SYSTEMATIC 23103564 A 296 317 phenylacetylglutamine SYSTEMATIC 23103564 A 319 323 PAGN ABBREVIATION 23103564 A 41 54 phenylacetate SYSTEMATIC 23103564 A 428 437 ornithine TRIVIAL 23103564 A 442 449 ammonia SYSTEMATIC 23103564 A 712 732 [2,5-(15)N]Ornithine SYSTEMATIC 23103564 A 736 748 (15)NH(4)(+) FORMULA 23103564 A 806 811 (15)N FORMULA 23103564 A 815 826 amino acids FAMILY 23103564 A 857 868 amino acids FAMILY 23103564 A 987 994 ammonia SYSTEMATIC 23103564 T 25 48 ornithine phenylacetate SYSTEMATIC 23103565 A 100 106 oxygen SYSTEMATIC 23103565 A 1342 1348 serine TRIVIAL 23103565 A 1542 1546 cAMP ABBREVIATION 23103565 A 619 636 hydrogen peroxide SYSTEMATIC 23103613 A 0 17 Chloroacetic acid SYSTEMATIC 23103613 A 1306 1322 N-acetylcysteine SYSTEMATIC 23103613 A 1324 1327 NAC ABBREVIATION 23103613 A 1462 1465 NAC ABBREVIATION 23103613 A 1499 1507 SB203580 IDENTIFIER 23103613 A 1533 1541 SP600125 IDENTIFIER 23103613 A 54 65 acetic acid SYSTEMATIC 23103613 A 874 885 glutathione TRIVIAL 23103613 T 0 17 Chloroacetic acid SYSTEMATIC 23103954 A 154 170 lawsorosemarinol TRIVIAL 23103954 A 179 192 lawsofructose TRIVIAL 23103954 A 217 262 2-(β-d-glucopyranosyloxy)-1, 4-naphthoquinone SYSTEMATIC 23103954 A 287 306 4-hydroxy coumarine SYSTEMATIC 23103954 A 312 356 3-(4-hyroxyphenyl)-triacontyl-(Z)-propenoate SYSTEMATIC 23103954 A 362 417 3-(4-hydroxy-3-methoxyphenyl)-triacontyl-(Z)-propenoate SYSTEMATIC 23103954 A 426 453 7-hydroxy-4-methyl coumarin SYSTEMATIC 23103983 A 1024 1031 Al(OH)₃ FORMULA 23103983 A 1032 1036 PLGA ABBREVIATION 23103983 A 1106 1113 Al(OH)₃ FORMULA 23103983 A 118 147 poly(lactic-co-glycolic acid) FAMILY 23103983 A 1182 1189 Al(OH)₃ FORMULA 23103983 A 1190 1199 trehalose TRIVIAL 23103983 A 1319 1323 PLGA ABBREVIATION 23103983 A 1417 1424 Al(OH)₃ FORMULA 23103983 A 1428 1432 PLGA ABBREVIATION 23103983 A 1489 1493 PLGA ABBREVIATION 23103983 A 149 153 PLGA ABBREVIATION 23103983 A 1640 1644 PLGA ABBREVIATION 23103983 A 1723 1727 PLGA ABBREVIATION 23103983 A 221 225 PLGA ABBREVIATION 23103983 A 720 724 PLGA ABBREVIATION 23103983 A 832 836 PLGA ABBREVIATION 23103983 A 935 953 aluminum hydroxide SYSTEMATIC 23103983 A 955 962 Al(OH)₃ FORMULA 23103983 A 967 984 calcium phosphate SYSTEMATIC 23103983 T 57 61 PLGA ABBREVIATION 23104136 A 1075 1085 anandamide TRIVIAL 23104136 A 1099 1110 cannabidiol TRIVIAL 23104136 A 1148 1155 calcium SYSTEMATIC 23104136 A 1257 1264 calcium SYSTEMATIC 23104136 A 1446 1455 potassium SYSTEMATIC 23104136 A 1469 1478 adenylate TRIVIAL 23104136 A 1637 1642 NAGly FORMULA 23104136 A 263 268 NAGly FORMULA 23104136 A 28 49 N-arachidonyl glycine SYSTEMATIC 23104136 A 51 56 NAGly FORMULA 23104136 A 537 538 N FORMULA 23104136 A 545 547 Ca FORMULA 23104136 A 555 562 calcium SYSTEMATIC 23104136 A 61 71 carboxylic SYSTEMATIC 23104136 A 809 814 NAGly FORMULA 23104136 A 84 94 anandamide TRIVIAL 23104136 A 859 866 calcium SYSTEMATIC 23104136 T 0 21 N-Arachidonyl glycine SYSTEMATIC 23104247 A 1025 1028 VPA ABBREVIATION 23104247 A 1386 1389 VPA ABBREVIATION 23104247 A 344 357 valproic acid TRIVIAL 23104247 A 359 362 VPA ABBREVIATION 23104247 A 722 725 VPA ABBREVIATION 23104247 A 749 752 VPA ABBREVIATION 23104247 T 131 144 valproic acid TRIVIAL 23104378 A 590 599 berberine TRIVIAL 23104378 A 88 97 berberine TRIVIAL 23104378 T 60 69 berberine TRIVIAL 23104429 A 1211 1218 As(III) FORMULA 23104429 A 1257 1264 As(III) FORMULA 23104429 A 1479 1484 As(V) FORMULA 23104429 A 1675 1682 arsenic SYSTEMATIC 23104429 A 340 355 sodium arsenate SYSTEMATIC 23104429 A 357 362 As(V) FORMULA 23104429 A 365 380 sodium arsenite SYSTEMATIC 23104429 A 382 389 As(III) FORMULA 23104429 A 392 414 monomethylarsonic acid SYSTEMATIC 23104429 A 419 439 dimethylarsinic acid SYSTEMATIC 23104429 A 524 533 phosphate SYSTEMATIC 23104429 A 549 556 As(III) FORMULA 23104429 A 614 621 lactate FAMILY 23104429 A 74 81 arsenic SYSTEMATIC 23104429 A 751 758 As(III) FORMULA 23104429 A 933 945 vitamin D(3) TRIVIAL 23104429 A 991 998 arsenic SYSTEMATIC 23104429 T 0 7 Arsenic SYSTEMATIC 23104969 A 1120 1125 l-EPH ABBREVIATION 23104969 A 1159 1164 l-MPH ABBREVIATION 23104969 A 1166 1173 Ethanol SYSTEMATIC 23104969 A 1193 1198 d-MPH ABBREVIATION 23104969 A 1222 1227 d-MPH ABBREVIATION 23104969 A 1280 1287 ethanol SYSTEMATIC 23104969 A 1355 1361 dl-MPH ABBREVIATION 23104969 A 1362 1369 ethanol SYSTEMATIC 23104969 A 1406 1411 l-MPH ABBREVIATION 23104969 A 1468 1473 d-MPH ABBREVIATION 23104969 A 1475 1482 Ethanol SYSTEMATIC 23104969 A 1497 1502 d-MPH ABBREVIATION 23104969 A 1554 1560 dl-MPH ABBREVIATION 23104969 A 1585 1590 d-MPH ABBREVIATION 23104969 A 1621 1626 d-MPH ABBREVIATION 23104969 A 1627 1634 ethanol SYSTEMATIC 23104969 A 1640 1645 d-MPH ABBREVIATION 23104969 A 166 171 d-MPH ABBREVIATION 23104969 A 1830 1835 d-MPH ABBREVIATION 23104969 A 1901 1906 d-MPH ABBREVIATION 23104969 A 225 230 l-MPH ABBREVIATION 23104969 A 265 271 dl-MPH ABBREVIATION 23104969 A 277 284 ethanol SYSTEMATIC 23104969 A 305 310 d-MPH ABBREVIATION 23104969 A 36 59 racemic methylphenidate TRIVIAL 23104969 A 402 407 l-MPH ABBREVIATION 23104969 A 411 427 l-ethylphenidate SYSTEMATIC 23104969 A 429 432 EPH ABBREVIATION 23104969 A 514 532 dexmethylphenidate TRIVIAL 23104969 A 534 539 d-MPH ABBREVIATION 23104969 A 572 579 ethanol SYSTEMATIC 23104969 A 583 588 d-MPH ABBREVIATION 23104969 A 61 67 dl-MPH ABBREVIATION 23104969 A 667 672 l-MPH ABBREVIATION 23104969 A 676 681 l-EPH ABBREVIATION 23104969 A 723 729 dl-MPH ABBREVIATION 23104969 A 745 750 d-MPH ABBREVIATION 23104969 A 781 788 ethanol SYSTEMATIC 23104969 A 832 838 dl-MPH ABBREVIATION 23104969 A 852 859 ethanol SYSTEMATIC 23104969 A 883 888 d-MPH ABBREVIATION 23104969 A 971 978 ethanol SYSTEMATIC 23104969 T 27 34 ethanol SYSTEMATIC 23104969 T 64 79 methylphenidate SYSTEMATIC 23104969 T 94 112 dexmethylphenidate TRIVIAL 23108167 A 1085 1088 MTX ABBREVIATION 23108167 A 112 115 MTX ABBREVIATION 23108167 A 128 131 MTX ABBREVIATION 23108167 A 185 194 thiol-ene FAMILY 23108167 A 267 270 MTX ABBREVIATION 23108167 A 59 71 polyglycerol FAMILY 23108167 A 591 594 MTX ABBREVIATION 23108167 A 732 735 MTX ABBREVIATION 23108167 A 832 835 MTX ABBREVIATION 23108167 A 914 917 MTX ABBREVIATION 23108167 A 98 110 methotrexate TRIVIAL 23108167 T 0 12 Methotrexate TRIVIAL 23108167 T 42 54 polyglycerol FAMILY 23108167 T 63 68 Fe₃O₄ FORMULA 23108801 A 32 40 graphene TRIVIAL 23108801 T 64 72 graphene TRIVIAL 23109293 A 0 11 Bisphenol A TRIVIAL 23109293 A 1057 1065 nitrogen SYSTEMATIC 23109293 A 1119 1122 BPA ABBREVIATION 23109293 A 1251 1254 BPA ABBREVIATION 23109293 A 13 16 BPA ABBREVIATION 23109293 A 226 229 BPA ABBREVIATION 23109293 A 278 281 BPA ABBREVIATION 23109293 A 300 308 nitrogen SYSTEMATIC 23109293 A 501 504 BPA ABBREVIATION 23109293 A 555 562 nitrate SYSTEMATIC 23109293 A 602 610 ammonium SYSTEMATIC 23109293 A 657 664 nitrate SYSTEMATIC 23109293 A 679 686 nitrite SYSTEMATIC 23109293 A 805 808 BPA ABBREVIATION 23109293 A 851 858 nitrate SYSTEMATIC 23109293 A 891 894 BPA ABBREVIATION 23109293 A 931 938 nitrate SYSTEMATIC 23109293 A 953 960 nitrite SYSTEMATIC 23109293 T 11 22 bisphenol A TRIVIAL 23109293 T 37 45 nitrogen SYSTEMATIC 23109429 A 576 577 N FORMULA 23109429 A 810 811 N FORMULA 23110439 A 125 147 2-arachidonoylglycerol SYSTEMATIC 23111283 A 0 11 Toosendanin TRIVIAL 23111283 A 1023 1026 TSN ABBREVIATION 23111283 A 13 16 TSN ABBREVIATION 23111283 A 205 208 TSN ABBREVIATION 23111283 A 21 33 triterpenoid FAMILY 23111283 A 296 299 TSN ABBREVIATION 23111283 A 651 654 TSN ABBREVIATION 23111283 A 682 686 FITC ABBREVIATION 23111283 A 687 703 propidium iodide TRIVIAL 23111283 A 890 893 TSN ABBREVIATION 23111283 T 0 11 Toosendanin TRIVIAL 23111828 A 1082 1094 griseofulvin TRIVIAL 23111828 A 1110 1115 Wst-1 TRIVIAL 23111828 A 1118 1124 BrdUrd FORMULA 23111828 A 1131 1137 [3H]dT SYSTEMATIC 23111828 A 1261 1273 griseofulvin TRIVIAL 23111828 A 1417 1429 griseofulvin TRIVIAL 23111828 A 246 258 Griseofulvin TRIVIAL 23111828 A 405 417 griseofulvin TRIVIAL 23111828 A 527 539 griseofulvin TRIVIAL 23111828 A 645 657 griseofulvin TRIVIAL 23111828 A 717 722 Wst-1 TRIVIAL 23111828 A 725 731 BrdUrd FORMULA 23111828 A 738 752 [3H]-thymidine SYSTEMATIC 23111828 A 895 907 griseofulvin TRIVIAL 23111828 T 0 12 Griseofulvin TRIVIAL 23111874 A 1277 1283 TiO(2) FORMULA 23111874 A 1375 1381 TiO(2) FORMULA 23111874 A 1527 1533 TiO(2) FORMULA 23111874 A 1626 1632 TiO(2) FORMULA 23111874 A 186 192 TiO(2) FORMULA 23111874 A 350 374 Tetrazolium bromide salt FAMILY 23111874 A 37 53 titanium dioxide SYSTEMATIC 23111874 A 379 386 lactate FAMILY 23111874 A 69 75 TiO(2) FORMULA 23111874 A 743 749 TiO(2) FORMULA 23111874 A 868 874 oxygen SYSTEMATIC 23111874 A 887 902 malondialdehyde TRIVIAL 23111874 A 948 959 glutathione TRIVIAL 23111874 A 961 967 TiO(2) FORMULA 23111874 T 5 21 titanium dioxide SYSTEMATIC 23115222 A 1157 1235 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene monoethanolate SYSTEMATIC 23115222 A 1237 1242 U0126 IDENTIFIER 23115222 A 1341 1351 PNU-120596 IDENTIFIER 23115222 A 1397 1400 MLA ABBREVIATION 23115222 A 1439 1449 PNU-120596 IDENTIFIER 23115222 A 1472 1482 PNU-120596 IDENTIFIER 23115222 A 1555 1565 PNU-120596 IDENTIFIER 23115222 A 1638 1648 PNU-120596 IDENTIFIER 23115222 A 1691 1697 NS1738 IDENTIFIER 23115222 A 17 30 acetylcholine SYSTEMATIC 23115222 A 1746 1756 PNU-120596 IDENTIFIER 23115222 A 1786 1792 NS1738 IDENTIFIER 23115222 A 250 263 acetylcholine SYSTEMATIC 23115222 A 289 296 choline FAMILY 23115222 A 542 609 N-(5-chloro-2-hydroxyphenyl)-N'-[2-chloro-5-(trifluoromethyl)phenyl SYSTEMATIC 23115222 A 612 618 NS1738 IDENTIFIER 23115222 A 634 694 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl) SYSTEMATIC 23115222 A 696 706 PNU-120596 IDENTIFIER 23115222 A 818 828 PNU-120596 IDENTIFIER 23115222 A 885 893 formalin TRIVIAL 23115222 A 926 936 PNU-120596 IDENTIFIER 23116145 A 52 68 2,2'-biquinoline SYSTEMATIC 23116145 A 6 34 cyclometallated iridium(III) FAMILY 23116145 A 69 70 N FORMULA 23116145 T 2 30 cyclometallated iridium(III) FAMILY 23116642 A 0 12 Platycodin D TRIVIAL 23116642 A 1093 1105 nitric oxide SYSTEMATIC 23116642 A 31 49 triterpene saponin FAMILY 23116642 A 452 459 alanine TRIVIAL 23116642 A 484 493 aspartate TRIVIAL 23116642 A 522 531 bilirubin TRIVIAL 23116642 A 747 758 glutathione TRIVIAL 23116642 A 763 773 superoxide TRIVIAL 23116642 A 870 885 malondialdehyde TRIVIAL 23116642 A 890 902 nitric oxide SYSTEMATIC 23116642 T 0 12 Platycodin D TRIVIAL 23116938 A 0 10 Endosulfan TRIVIAL 23116938 A 30 44 organochlorine FAMILY 23116938 A 401 411 endosulfan TRIVIAL 23116938 T 34 44 endosulfan TRIVIAL 23116965 A 0 25 (-)-Epicatechin-3-gallate SYSTEMATIC 23116965 A 1222 1225 ECG ABBREVIATION 23116965 A 1390 1393 ECG ABBREVIATION 23116965 A 1473 1479 sodium SYSTEMATIC 23116965 A 1586 1589 ECG ABBREVIATION 23116965 A 1603 1605 Na FORMULA 23116965 A 190 193 ECG ABBREVIATION 23116965 A 27 30 ECG ABBREVIATION 23116965 A 280 283 ECG ABBREVIATION 23116965 A 35 45 polyphenol FAMILY 23116965 A 557 560 ECG ABBREVIATION 23116965 A 621 626 Na(+) FORMULA 23116965 A 639 641 Na FORMULA 23116965 A 725 728 ECG ABBREVIATION 23116965 A 789 791 Na FORMULA 23116965 A 849 851 Na FORMULA 23116965 A 910 912 Na FORMULA 23116965 A 927 930 ECG ABBREVIATION 23116965 A 970 974 K(+) FORMULA 23116965 A 995 1001 Ca(2+) FORMULA 23116965 T 26 51 (-)-epicatechin-3-gallate SYSTEMATIC 23116965 T 61 67 sodium SYSTEMATIC 23117572 A 1332 1336 SAHA ABBREVIATION 23117572 A 1341 1354 valproic acid TRIVIAL 23117572 A 1519 1530 radioiodine SYSTEMATIC 23117572 A 1690 1701 radioiodine SYSTEMATIC 23117572 A 188 199 Radioiodine SYSTEMATIC 23117572 A 398 403 Na(+) FORMULA 23117572 A 404 408 I(-) FORMULA 23117572 A 468 474 iodide SYSTEMATIC 23117572 T 0 6 Sodium SYSTEMATIC 23117572 T 7 13 iodide SYSTEMATIC 23118328 A 1001 1009 losartan TRIVIAL 23118328 A 1191 1200 valsartan TRIVIAL 23118328 A 1521 1529 losartan TRIVIAL 23118328 A 1534 1543 valsartan TRIVIAL 23118328 A 1591 1602 candesartan TRIVIAL 23118328 A 1606 1617 telmisartan TRIVIAL 23118328 A 258 266 losartan TRIVIAL 23118328 A 268 277 valsartan TRIVIAL 23118328 A 279 290 candesartan TRIVIAL 23118328 A 296 307 telmisartan TRIVIAL 23118328 A 415 426 candesartan TRIVIAL 23118328 A 446 457 telmisartan TRIVIAL 23118328 A 475 483 losartan TRIVIAL 23118328 A 510 519 valsartan TRIVIAL 23118328 A 771 782 telmisartan TRIVIAL 23118328 A 829 840 telmisartan TRIVIAL 23118328 A 957 965 losartan TRIVIAL 23122062 A 144 150 carbon SYSTEMATIC 23122062 A 312 319 Ethanol SYSTEMATIC 23122062 A 324 338 carbon dioxide SYSTEMATIC 23122062 A 418 426 glycerol TRIVIAL 23122062 A 458 471 succinic acid TRIVIAL 23122062 A 673 686 succinic acid TRIVIAL 23122062 A 711 725 carbon dioxide SYSTEMATIC 23122062 T 91 104 succinic acid TRIVIAL 23122063 A 0 12 Sulforaphene TRIVIAL 23122063 A 24 39 isothiocyanates FAMILY 23122063 A 241 253 sulforaphene TRIVIAL 23122063 A 379 387 n-hexane SYSTEMATIC 23122063 A 388 401 ethyl acetate SYSTEMATIC 23122063 A 402 410 methanol SYSTEMATIC 23122063 A 54 67 glucoraphenin TRIVIAL 23122063 A 677 689 sulforaphene TRIVIAL 23122063 A 765 777 sulforaphene TRIVIAL 23122063 A 863 875 sulforaphene TRIVIAL 23122063 A 955 959 (1)H FORMULA 23122063 A 965 970 (13)C FORMULA 23122063 T 43 55 sulforaphene TRIVIAL 23122075 A 154 161 cadmium SYSTEMATIC 23122075 A 167 175 graphite TRIVIAL 23122075 A 290 297 cadmium SYSTEMATIC 23122075 A 340 347 cadmium SYSTEMATIC 23122075 A 640 647 cadmium SYSTEMATIC 23122075 T 9 16 cadmium SYSTEMATIC 23122078 A 1075 1083 catechol TRIVIAL 23122078 A 1145 1155 l-cysteine TRIVIAL 23122078 A 1236 1249 ascorbic acid TRIVIAL 23122078 A 1267 1278 glutathione TRIVIAL 23122078 A 1296 1300 EDTA ABBREVIATION 23122078 A 1321 1332 citric acid TRIVIAL 23122078 A 239 251 Triton X-114 FAMILY 23122078 A 519 535 ammonium sulfate SYSTEMATIC 23122078 A 566 572 Phenyl SYSTEMATIC 23122078 A 733 736 SDS ABBREVIATION 23122078 A 955 964 diphenols FAMILY 23122080 A 162 173 gallic acid TRIVIAL 23122080 T 48 59 gallic acid TRIVIAL 23122087 A 173 186 Ciprofloxacin TRIVIAL 23122087 A 188 191 CIP ABBREVIATION 23122087 A 194 206 danofloxacin TRIVIAL 23122087 A 208 211 DAN ABBREVIATION 23122087 A 214 226 enrofloxacin TRIVIAL 23122087 A 228 231 ENR ABBREVIATION 23122087 A 234 246 sarafloxacin TRIVIAL 23122087 A 248 251 SAR ABBREVIATION 23122087 A 254 267 oxolinic acid TRIVIAL 23122087 A 269 272 OXO ABBREVIATION 23122087 A 275 289 nalidixic acid TRIVIAL 23122087 A 291 294 NAL ABBREVIATION 23122087 A 300 310 flumequine TRIVIAL 23122087 A 312 315 FLU ABBREVIATION 23122087 A 446 466 trifluoroacetic acid SYSTEMATIC 23122087 A 475 487 acetonitrile SYSTEMATIC 23122087 A 492 500 methanol SYSTEMATIC 23122087 A 584 587 OXO ABBREVIATION 23122087 A 589 592 NAL ABBREVIATION 23122087 A 597 600 FLU ABBREVIATION 23122087 A 618 621 CIP ABBREVIATION 23122087 A 623 626 DAN ABBREVIATION 23122087 A 628 631 ENR ABBREVIATION 23122087 A 636 639 SAR ABBREVIATION 23122087 A 689 699 quinolones FAMILY 23122087 A 752 759 citrate FAMILY 23122087 A 90 99 quinolone FAMILY 23122087 T 68 78 quinolones FAMILY 23122091 A 101 112 triterpenes FAMILY 23122091 A 171 177 Xylene FAMILY 23122091 A 67 77 flavonoids FAMILY 23122096 A 16 20 (1)H FORMULA 23122096 A 316 326 fatty acid FAMILY 23122096 A 425 429 FAME ABBREVIATION 23122096 A 468 483 fatty acid acyl FAMILY 23122096 A 498 510 acylglycerol FAMILY 23122096 A 543 548 oleyl TRIVIAL 23122096 A 594 620 polyunsaturated fatty acid FAMILY 23122096 A 80 90 fatty acid FAMILY 23122096 T 100 102 1H FORMULA 23122096 T 30 40 fatty acid FAMILY 23122098 A 163 171 methanol SYSTEMATIC 23122098 A 213 221 phenolic FAMILY 23122098 A 223 278 2-(2-hydroxyl-5-(methoxycarbonyl) phenoxy) benzoic acid SYSTEMATIC 23122098 A 294 304 kaempferol TRIVIAL 23122098 A 306 322 isolariciresinol TRIVIAL 23122098 A 324 336 stigmasterol TRIVIAL 23122098 A 338 362 butylated hydroxytoluene SYSTEMATIC 23122098 A 364 387 3,4-dihydroxyl benzoate SYSTEMATIC 23122098 A 389 405 methyl shikimate SYSTEMATIC 23122098 A 410 425 ethyl shikimate SYSTEMATIC 23122098 A 614 618 DPPH ABBREVIATION 23122098 A 672 725 2-(2-hydroxy-5-(methoxycarbonyl) phenoxy)benzoic acid SYSTEMATIC 23122098 A 727 737 kaempferol TRIVIAL 23122098 A 739 755 isolariciresinol TRIVIAL 23122098 A 757 781 butylated hydroxytoluene SYSTEMATIC 23122098 A 786 808 3,4-dihydroxy benzoate SYSTEMATIC 23122098 A 880 904 butylated hydroxytoluene SYSTEMATIC 23122098 T 26 34 phenolic FAMILY 23122103 A 565 585 flavone-C-glycosides FAMILY 23122103 A 589 611 flavonoid-O-glycosides FAMILY 23122103 A 619 638 polymethoxyflavones FAMILY 23122103 A 726 745 flavone-C-glycoside FAMILY 23122109 A 213 225 resveratrols FAMILY 23122109 A 237 245 methanol SYSTEMATIC 23122109 A 250 263 ethyl acetate SYSTEMATIC 23122109 A 368 380 resveratrols FAMILY 23122109 A 434 442 methanol SYSTEMATIC 23122109 A 447 460 ethyl acetate SYSTEMATIC 23122109 A 624 636 acetonitrile SYSTEMATIC 23122109 A 691 703 resveratrols FAMILY 23122109 A 782 794 resveratrols FAMILY 23122109 A 847 859 resveratrols FAMILY 23122109 A 865 876 resveratrol TRIVIAL 23122109 A 99 111 resveratrols FAMILY 23122109 T 0 12 Resveratrols FAMILY 23122119 A 1046 1093 oxalic, quinic, malic, citric and fumaric acids MULTIPLE 23122119 A 1237 1260 5-O-caffeoylquinic acid SYSTEMATIC 23122119 A 1268 1276 apigenin TRIVIAL 23122119 A 751 764 carbohydrates FAMILY 23122119 A 806 817 tocopherols FAMILY 23122119 A 845 856 fatty acids FAMILY 23122119 A 932 940 phenolic FAMILY 23122119 A 952 962 flavonoids FAMILY 23122119 A 971 980 flavonols FAMILY 23122119 A 985 993 flavones FAMILY 23122119 A 995 1009 phenolic acids FAMILY 23122123 A 0 9 Enniatins FAMILY 23122123 A 338 363 enniatins A, A1, B and B1 MULTIPLE 23122123 A 370 384 deoxynivalenol TRIVIAL 23122123 A 410 436 deoxynivalenol-3-glucoside SYSTEMATIC 23122123 A 520 529 enniatins FAMILY 23122123 A 649 658 enniatins FAMILY 23122123 A 842 851 enniatins FAMILY 23122123 T 63 72 enniatins FAMILY 23122125 A 326 336 lovastatin TRIVIAL 23122125 A 492 498 oxygen SYSTEMATIC 23122125 A 539 549 dityrosine TRIVIAL 23122125 A 554 559 4-HNE SYSTEMATIC 23122125 A 588 590 Mn FORMULA 23122125 A 591 601 superoxide TRIVIAL 23122133 A 425 432 ethanol SYSTEMATIC 23122138 A 0 14 Sulphanilamide TRIVIAL 23122138 A 123 137 sulphanilamide TRIVIAL 23122138 A 176 190 sulphanilamide TRIVIAL 23122138 A 274 286 Sepharose 4B TRIVIAL 23122138 A 287 297 L-tyrosine TRIVIAL 23122138 A 363 377 sulphanilamide TRIVIAL 23122138 A 396 406 L-tyrosine TRIVIAL 23122138 A 430 446 cyanogen bromide SYSTEMATIC 23122138 A 448 452 CNBr FORMULA 23122138 A 464 476 Sepharose 4B TRIVIAL 23122138 A 686 690 ABTS ABBREVIATION 23122138 A 776 779 SDS ABBREVIATION 23122148 A 1050 1058 methanol SYSTEMATIC 23122148 A 1400 1408 methanol SYSTEMATIC 23122148 A 1455 1469 phenolic acids FAMILY 23122148 A 1491 1501 flavonoids FAMILY 23122148 A 1573 1596 luteolin O-acylhexoside FAMILY 23122148 A 174 182 methanol SYSTEMATIC 23122148 A 945 953 phenolic FAMILY 23122148 T 103 111 phenolic FAMILY 23122150 A 1001 1009 paraffin FAMILY 23122150 A 1182 1190 paraffin FAMILY 23122150 A 294 306 hydrocarbons FAMILY 23122150 A 308 315 oleofin FAMILY 23122150 A 317 326 palmitate TRIVIAL 23122150 A 328 334 oleate TRIVIAL 23122150 A 339 366 hydroxypalmitate monoesters FAMILY 23122150 A 405 436 palmitate and oleate monoesters MULTIPLE 23122150 A 453 466 1-octadecanol SYSTEMATIC 23122150 A 471 482 1-eicosanol SYSTEMATIC 23122150 A 695 703 paraffin FAMILY 23122153 A 0 7 Folates FAMILY 23122153 A 17 50 [6S]-5-methyltetrahydrofolic acid SYSTEMATIC 23122153 A 276 309 [6S]-5-methyltetrahydrofolic acid SYSTEMATIC 23122153 A 311 317 5-MTHF SYSTEMATIC 23122153 A 680 686 5-MTHF SYSTEMATIC 23122153 A 731 738 folates FAMILY 23122153 T 40 81 [6S]-5-methyltetrahydrofolic acid calcium SYSTEMATIC 23122156 A 1010 1016 lysine TRIVIAL 23122156 A 1033 1044 amino acids FAMILY 23122156 A 468 476 nitrogen SYSTEMATIC 23122156 A 968 979 amino acids FAMILY 23122156 A 997 1005 arginine TRIVIAL 23122158 A 216 227 polyphenols FAMILY 23122158 A 39 50 polyphenols FAMILY 23122158 A 416 427 polyphenols FAMILY 23122158 A 503 511 phenolic FAMILY 23122158 A 600 616 Chlorogenic acid TRIVIAL 23122158 A 621 630 phlorizin TRIVIAL 23122158 A 671 680 polyamide FAMILY 23122158 A 705 721 chlorogenic acid TRIVIAL 23122158 A 726 735 phlorizin TRIVIAL 23122158 T 50 61 polyphenols FAMILY 23122158 T 63 79 chlorogenic acid TRIVIAL 23122158 T 84 93 phlorizin TRIVIAL 23122159 A 1094 1100 Trolox TRIVIAL 23122159 A 499 504 amino FAMILY 23122159 A 513 517 GABA ABBREVIATION 23122159 A 627 631 GABA ABBREVIATION 23122159 A 754 759 amino FAMILY 23122159 A 774 778 GABA ABBREVIATION 23122159 A 786 794 phenolic FAMILY 23122159 A 954 958 GABA ABBREVIATION 23122162 A 183 194 Fucoxanthin TRIVIAL 23122162 A 28 39 fucoxanthin TRIVIAL 23122162 A 412 423 fucoxanthin TRIVIAL 23122162 A 526 537 fucoxanthin TRIVIAL 23122162 A 640 644 DPPH ABBREVIATION 23122162 A 746 757 fucoxanthin TRIVIAL 23122162 A 818 829 Fucoxanthin TRIVIAL 23122162 T 0 11 Fucoxanthin TRIVIAL 23122164 A 1025 1031 sodium SYSTEMATIC 23122164 A 136 140 NaCl FORMULA 23122164 A 28 34 sodium SYSTEMATIC 23122164 A 304 310 (23)Na FORMULA 23122164 A 401 407 sodium SYSTEMATIC 23122164 A 580 584 NaCl FORMULA 23122164 A 602 608 sodium SYSTEMATIC 23122164 A 689 695 sodium SYSTEMATIC 23122164 A 723 729 sodium SYSTEMATIC 23122164 A 796 800 NaCl FORMULA 23122164 A 845 851 sodium SYSTEMATIC 23122164 A 867 871 NaCl FORMULA 23122164 T 105 111 sodium SYSTEMATIC 23122164 T 53 59 sodium SYSTEMATIC 23122164 T 86 92 sodium SYSTEMATIC 23123250 A 1012 1032 N-methyl-d-aspartate SYSTEMATIC 23123250 A 1034 1038 NMDA ABBREVIATION 23123250 A 1083 1093 amino acid FAMILY 23123250 A 1237 1242 Hup A ABBREVIATION 23123250 A 1381 1390 [+]-Hup A ABBREVIATION 23123250 A 1412 1421 [-]-Hup A ABBREVIATION 23123250 A 1423 1440 [+] and [-]-Hup A MULTIPLE 23123250 A 1450 1455 soman TRIVIAL 23123250 A 1519 1536 [+] and [-]-Hup A MULTIPLE 23123250 A 1661 1670 [+]-Hup A ABBREVIATION 23123250 A 1700 1717 [+] and [-]-Hup A MULTIPLE 23123250 A 1790 1799 [+]-Hup A ABBREVIATION 23123250 A 1861 1878 [+] and [-]-Hup A MULTIPLE 23123250 A 1909 1918 [+]-Hup A ABBREVIATION 23123250 A 400 415 [-]-Huperzine A TRIVIAL 23123250 A 417 426 [-]-Hup A ABBREVIATION 23123250 A 806 815 [-]-Hup A ABBREVIATION 23123250 A 859 868 [+]-Hup A ABBREVIATION 23123250 A 992 1001 [+]-Hup A ABBREVIATION 23123250 T 17 40 [+] and [-]-Huperzine A MULTIPLE 23123250 T 96 111 [+]-Huperzine A TRIVIAL 23123251 A 1160 1170 (RO)2P(O)X FAMILY 23123251 A 1180 1185 alkyl FAMILY 23123251 A 1191 1204 SCH(Hal)COOEt FAMILY 23123251 A 1206 1209 Hal ABBREVIATION 23123251 A 1210 1212 Cl FORMULA 23123251 A 1214 1216 Br FORMULA 23123251 A 1220 1226 SCHCl2 FORMULA 23123251 A 1229 1235 SCH2Br FORMULA 23123251 A 123 130 serines FAMILY 23123251 A 1238 1250 OCH(CF3)R(1) FAMILY 23123251 A 1257 1261 C6H5 FORMULA 23123251 A 1263 1266 CF3 FORMULA 23123251 A 1268 1273 COOEt FORMULA 23123251 A 1275 1280 COOMe FORMULA 23123251 A 58 64 serine TRIVIAL 23123251 A 8 24 organophosphorus FAMILY 23123251 T 0 16 Organophosphorus FAMILY 23123253 A 0 15 Organophosphate FAMILY 23123253 A 396 404 fluoride SYSTEMATIC 23123253 A 675 690 organophosphate FAMILY 23123253 A 702 714 chlorpyrifos TRIVIAL 23123253 A 722 730 diazinon TRIVIAL 23123253 T 106 118 chlorpyrifos TRIVIAL 23123253 T 123 131 diazinon TRIVIAL 23123253 T 63 86 organophosphorothioates FAMILY 23123255 A 54 70 organophosphorus FAMILY 23123255 T 61 77 organophosphorus FAMILY 23123257 A 1260 1273 polyglutamate FAMILY 23123257 A 1387 1400 polyglutamate FAMILY 23123257 A 799 812 polyglutamate FAMILY 23123257 T 75 88 polyglutamate FAMILY 23123298 A 0 9 Helenalin TRIVIAL 23123298 A 1023 1032 helenalin TRIVIAL 23123298 A 120 129 helenalin TRIVIAL 23123298 A 13 34 sesquiterpene lactone FAMILY 23123298 A 190 199 Helenalin TRIVIAL 23123298 A 414 423 helenalin TRIVIAL 23123298 A 750 759 helenalin TRIVIAL 23123298 A 804 813 Helenalin TRIVIAL 23123298 A 861 867 oxygen SYSTEMATIC 23123298 A 912 927 N-acetylcystine SYSTEMATIC 23123298 A 929 932 NAC ABBREVIATION 23123298 A 939 962 glutathione ethyl ester SYSTEMATIC 23123298 A 964 967 GEE ABBREVIATION 23123298 A 978 987 helenalin TRIVIAL 23123298 T 0 9 Helenalin TRIVIAL 23123298 T 67 73 oxygen SYSTEMATIC 23123425 A 1223 1232 quercetin TRIVIAL 23123425 A 173 182 quercetin TRIVIAL 23123425 A 739 748 quercetin TRIVIAL 23123425 A 8 17 quercetin TRIVIAL 23123425 A 870 881 cholesterol TRIVIAL 23123425 A 888 901 triglycerides FAMILY 23123425 A 932 943 cholesterol TRIVIAL 23123425 A 953 960 alanine TRIVIAL 23123425 A 988 997 aspartate TRIVIAL 23123425 T 8 17 quercetin TRIVIAL 23123646 A 0 3 ATP ABBREVIATION 23123646 A 14 23 potassium SYSTEMATIC 23123646 A 197 200 ADP ABBREVIATION 23123646 A 201 204 ATP ABBREVIATION 23123646 A 217 218 K FORMULA 23123646 A 219 222 ATP ABBREVIATION 23123646 A 25 26 K FORMULA 23123646 A 27 30 ATP ABBREVIATION 23123646 A 273 274 K FORMULA 23123646 A 275 278 ATP ABBREVIATION 23123646 A 561 562 K FORMULA 23123646 A 563 566 ATP ABBREVIATION 23123646 A 787 788 K FORMULA 23123646 A 789 792 ATP ABBREVIATION 23123646 A 868 869 K FORMULA 23123646 A 870 873 ATP ABBREVIATION 23123646 T 24 27 ATP ABBREVIATION 23123646 T 38 47 potassium SYSTEMATIC 23123677 A 527 535 tyrosine TRIVIAL 23125001 A 131 139 LiCoO(2) FORMULA 23125001 A 190 198 LiCoO(2) FORMULA 23125001 A 354 356 Li FORMULA 23125001 T 107 115 LiCoO(2) FORMULA 23125001 T 33 40 lithium SYSTEMATIC 23125180 A 0 13 β-Chloroprene TRIVIAL 23125180 A 1028 1039 glutathione TRIVIAL 23125180 A 1329 1340 chloroprene TRIVIAL 23125180 A 15 37 2-chloro-1,3-butadiene SYSTEMATIC 23125180 A 475 486 chloroprene TRIVIAL 23125180 A 525 533 epoxides FAMILY 23125180 A 559 570 chloroprene TRIVIAL 23125180 A 669 680 chloroprene TRIVIAL 23125180 A 76 84 neoprene FAMILY 23125180 T 71 82 chloroprene TRIVIAL 23125282 A 1199 1208 triazolam TRIVIAL 23125282 A 1320 1342 dehydroepiandrosterone TRIVIAL 23126604 A 1020 1023 PTX ABBREVIATION 23126604 A 1063 1071 Pluronic FAMILY 23126604 A 1200 1203 PTX ABBREVIATION 23126604 A 1253 1256 PTX ABBREVIATION 23126604 A 1334 1341 ethanol SYSTEMATIC 23126604 A 1366 1378 PF127-PEI-FA ABBREVIATION 23126604 A 1379 1384 PP123 ABBREVIATION 23126604 A 1458 1461 PTX ABBREVIATION 23126604 A 148 160 PF127-PEI-FA ABBREVIATION 23126604 A 175 188 Pluronic P123 TRIVIAL 23126604 A 190 195 PP123 ABBREVIATION 23126604 A 287 297 paclitaxel TRIVIAL 23126604 A 299 302 PTX ABBREVIATION 23126604 A 360 363 PTX ABBREVIATION 23126604 A 457 469 PF127-PEI-FA ABBREVIATION 23126604 A 46 83 Pluronic F127-polyethylenimine-folate FAMILY 23126604 A 470 475 PP123 ABBREVIATION 23126604 A 85 97 PF127-PEI-FA ABBREVIATION 23126604 A 954 963 verapamil TRIVIAL 23126604 A 968 976 Pluronic FAMILY 23126604 T 34 44 paclitaxel TRIVIAL 23127146 A 213 221 estrogen FAMILY 23127146 A 587 595 estrogen FAMILY 23127146 T 50 58 estrogen FAMILY 23127146 T 90 98 estrogen FAMILY 23127602 A 173 185 (14)C-ethion SYSTEMATIC 23127602 A 212 218 ethion TRIVIAL 23127602 A 401 407 ethion TRIVIAL 23127602 A 426 441 ethion monooxon SYSTEMATIC 23127602 A 443 456 ethion dioxon SYSTEMATIC 23127602 A 458 486 O,O-diethyl phosphorothioate SYSTEMATIC 23127602 A 488 512 O-ethyl phosphorothioate SYSTEMATIC 23127602 A 570 576 ethion TRIVIAL 23127602 A 73 79 ethion TRIVIAL 23127602 A 903 909 ethion TRIVIAL 23127602 A 995 1001 ethion TRIVIAL 23127602 T 52 58 ethion TRIVIAL 23127818 A 12 52 N-sulfonyl-3,7-dioxo-5β-cholan-24-amides FAMILY 23127818 A 151 171 ursodeoxycholic acid TRIVIAL 23127818 A 54 74 ursodeoxycholic acid TRIVIAL 23127818 T 36 76 N-sulfonyl-3,7-dioxo-5β-cholan-24-amides FAMILY 23127818 T 78 98 ursodeoxycholic acid TRIVIAL 23127825 A 1022 1038 Ibuprofen Sodium SYSTEMATIC 23127825 A 1212 1228 Ibuprofen Sodium SYSTEMATIC 23127825 A 94 110 Ibuprofen Sodium SYSTEMATIC 23127825 T 17 33 Ibuprofen Sodium SYSTEMATIC 23127825 T 51 65 carbon dioxide SYSTEMATIC 23127917 A 0 17 Angiotensin-(1-7) TRIVIAL 23127917 A 1050 1055 NADPH ABBREVIATION 23127917 A 1097 1109 nitric oxide SYSTEMATIC 23127917 A 1258 1267 Ang-(1-7) ABBREVIATION 23127917 A 1318 1327 Ang-(1-7) ABBREVIATION 23127917 A 1464 1473 Ang-(1-7) ABBREVIATION 23127917 A 19 28 Ang-(1-7) ABBREVIATION 23127917 A 222 231 Ang-(1-7) ABBREVIATION 23127917 A 488 497 Ang-(1-7) ABBREVIATION 23127917 A 669 685 deoxynucleotidyl FAMILY 23127917 A 707 711 dUTP ABBREVIATION 23127917 A 777 786 Ang-(1-7) ABBREVIATION 23127917 A 839 853 Angiotensin II TRIVIAL 23127917 A 858 872 Angiotensin II TRIVIAL 23127917 A 945 960 malondialdehyde TRIVIAL 23127917 A 980 990 superoxide TRIVIAL 23127917 T 0 17 Angiotensin-(1-7) TRIVIAL 23128353 A 1023 1034 glucosamine TRIVIAL 23128353 A 1207 1218 glucosamine TRIVIAL 23128353 A 237 248 glucosamine TRIVIAL 23128353 A 370 381 trypan blue TRIVIAL 23128353 A 416 427 glucosamine TRIVIAL 23128353 A 655 666 glucosamine TRIVIAL 23128353 A 76 87 Glucosamine TRIVIAL 23128353 A 804 815 glucosamine TRIVIAL 23128353 A 833 844 Glucosamine TRIVIAL 23128353 A 930 934 heme FAMILY 23128353 T 25 36 glucosamine TRIVIAL 23129213 A 0 10 Crizotinib TRIVIAL 23129213 A 1019 1029 crizotinib TRIVIAL 23129213 A 1113 1123 Crizotinib TRIVIAL 23129213 A 12 19 Xalkori TRIVIAL 23129213 A 1311 1321 crizotinib TRIVIAL 23129213 A 1535 1544 midazolam TRIVIAL 23129213 A 1574 1584 crizotinib TRIVIAL 23129213 A 242 252 crizotinib TRIVIAL 23129213 A 423 433 crizotinib TRIVIAL 23129213 A 519 529 crizotinib TRIVIAL 23129213 A 719 729 crizotinib TRIVIAL 23129213 A 73 81 tyrosine TRIVIAL 23129213 A 730 739 midazolam TRIVIAL 23129213 A 818 828 Crizotinib TRIVIAL 23129213 T 14 24 crizotinib TRIVIAL 23129213 T 25 34 midazolam TRIVIAL 23129525 A 1132 1138 arseno SYSTEMATIC 23129525 A 293 300 arsenic SYSTEMATIC 23129525 A 364 366 As FORMULA 23129525 A 532 534 As FORMULA 23129525 A 594 601 Arsenic SYSTEMATIC 23129525 A 61 68 arsenic SYSTEMATIC 23129525 A 623 636 arsenobetaine TRIVIAL 23129525 A 650 656 arseno SYSTEMATIC 23129525 A 70 72 As FORMULA 23129525 A 713 715 As FORMULA 23129525 A 771 773 As FORMULA 23129525 A 816 829 arsenocholine SYSTEMATIC 23129525 A 834 849 methyl-arsonate SYSTEMATIC 23129525 A 868 875 arsenic SYSTEMATIC 23129525 A 958 960 As FORMULA 23129525 T 0 7 Arsenic SYSTEMATIC 23129525 T 12 19 arsenic SYSTEMATIC 23130659 A 1004 1017 DOPE-PAMAM-G4 ABBREVIATION 23130659 A 1042 1054 DDAB-mPEG-G3 ABBREVIATION 23130659 A 1079 1097 DDAB-mPEG-PAMAM-G4 ABBREVIATION 23130659 A 1122 1135 DDAB-PAMAM-G4 ABBREVIATION 23130659 A 1160 1173 DOTAP-mPEG-G3 ABBREVIATION 23130659 A 1198 1217 DOTAP-mPEG-PAMAM-G4 ABBREVIATION 23130659 A 1246 1260 DOTAP-PAMAM-G4 ABBREVIATION 23130659 A 1407 1418 cholesterol TRIVIAL 23130659 A 1428 1432 DDAB ABBREVIATION 23130659 A 1455 1460 DOTAP ABBREVIATION 23130659 A 1490 1504 DDAB-PAMAM-G-4 ABBREVIATION 23130659 A 1507 1521 DOTAP-PAMAM-G4 ABBREVIATION 23130659 A 1524 1535 cholesterol TRIVIAL 23130659 A 1536 1544 PAMAM-G4 ABBREVIATION 23130659 A 180 191 cholesterol TRIVIAL 23130659 A 193 197 Chol ABBREVIATION 23130659 A 200 240 1,2-dioleoyl-3-trimethylammonium-propane SYSTEMATIC 23130659 A 241 246 DOTAP ABBREVIATION 23130659 A 249 283 dioctadecyldimethylammoniumbromide SYSTEMATIC 23130659 A 285 289 DDAB ABBREVIATION 23130659 A 296 328 dioleoylphosphatidylethanolamine SYSTEMATIC 23130659 A 330 334 DOPE ABBREVIATION 23130659 A 384 394 mPEG-PAMAM ABBREVIATION 23130659 A 401 411 mPEG-PAMAM ABBREVIATION 23130659 A 422 427 PAMAM ABBREVIATION 23130659 A 806 818 chol-mPEG-G3 ABBREVIATION 23130659 A 843 861 chol-mPEG-PAMAM-G4 ABBREVIATION 23130659 A 886 899 chol-PAMAM-G4 ABBREVIATION 23130659 A 924 936 DOPE-mPEG-G3 ABBREVIATION 23130659 A 961 979 DOPE-mPEG-PAMAM-G4 ABBREVIATION 23130662 A 1073 1076 ATP ABBREVIATION 23130662 A 803 819 phosphoglycerate SYSTEMATIC 23130662 A 840 848 pyruvate TRIVIAL 23130662 A 874 877 ATP ABBREVIATION 23131042 A 457 474 D-glucuronic acid TRIVIAL 23131042 A 476 484 sulphate SYSTEMATIC 23131042 A 489 500 glutathione TRIVIAL 23131800 A 1010 1030 PEGylated octreotide TRIVIAL 23131800 A 1049 1053 P407 IDENTIFIER 23131800 A 105 114 Poloxamer TRIVIAL 23131800 A 1054 1057 PVA ABBREVIATION 23131800 A 1115 1135 PEGylated octreotide TRIVIAL 23131800 A 1226 1236 octreotide TRIVIAL 23131800 A 1305 1343 PEGylated and non-PEGylated octreotide MULTIPLE 23131800 A 1382 1402 PEGylated octreotide TRIVIAL 23131800 A 1495 1515 PEGylated octreotide TRIVIAL 23131800 A 150 170 PEGylated octreotide TRIVIAL 23131800 A 1547 1551 P407 IDENTIFIER 23131800 A 1552 1555 PVA ABBREVIATION 23131800 A 1764 1784 PEGylated octreotide TRIVIAL 23131800 A 257 267 octreotide TRIVIAL 23131800 A 334 347 Poloxamer 407 TRIVIAL 23131800 A 349 353 P407 IDENTIFIER 23131800 A 369 386 polyvinyl alcohol SYSTEMATIC 23131800 A 388 391 PVA ABBREVIATION 23131800 A 610 614 P407 IDENTIFIER 23131800 A 619 622 PVA ABBREVIATION 23131800 A 752 770 sodium bicarbonate SYSTEMATIC 23131800 A 76 96 PEGylated octreotide TRIVIAL 23131800 A 775 786 lactic acid TRIVIAL 23131800 A 995 1005 octreotide TRIVIAL 23131800 T 85 105 PEGylated octreotide TRIVIAL 23134486 A 295 314 glucose-6-phosphate SYSTEMATIC 23134486 A 316 319 ATP ABBREVIATION 23135544 A 597 616 uridine diphosphate SYSTEMATIC 23135544 A 618 621 UDP ABBREVIATION 23135544 A 623 629 xylose TRIVIAL 23135544 A 631 634 Xyl ABBREVIATION 23135544 A 640 643 UDP ABBREVIATION 23135544 A 644 659 glucuronic acid TRIVIAL 23135544 A 661 665 GlcA ABBREVIATION 23135544 A 676 682 sugars FAMILY 23135544 A 728 731 Xyl ABBREVIATION 23135544 A 736 740 GlcA ABBREVIATION 23135544 T 26 32 xylose TRIVIAL 23135544 T 38 53 glucuronic acid TRIVIAL 23137047 A 13 16 MnO FORMULA 23137047 A 17 23 SiO(2) FORMULA 23137047 A 185 188 MnO FORMULA 23137047 A 236 244 silicate FAMILY 23137047 A 268 276 silicate FAMILY 23137047 A 347 356 Mn(3)O(4) FORMULA 23137047 A 383 391 silicate FAMILY 23137047 A 516 518 Pt FORMULA 23137047 A 557 572 manganese oxide SYSTEMATIC 23137047 A 573 579 silica TRIVIAL 23137047 A 592 601 Mn(3)O(4) FORMULA 23137047 A 649 652 MnO FORMULA 23137047 A 738 747 Mn(3)O(4) FORMULA 23137047 A 822 825 MnO FORMULA 23137047 A 826 832 SiO(2) FORMULA 23137047 A 833 839 Pt(II) FORMULA 23137047 A 955 963 hydrogen SYSTEMATIC 23137047 T 105 120 manganese oxide SYSTEMATIC 23137047 T 125 131 silica TRIVIAL 23137955 A 1253 1262 polydatin TRIVIAL 23137955 A 218 223 urate SYSTEMATIC 23137955 A 242 251 Polydatin TRIVIAL 23137955 A 420 429 polydatin TRIVIAL 23137955 A 549 558 polydatin TRIVIAL 23137955 A 581 590 polydatin TRIVIAL 23137955 A 623 631 xanthine TRIVIAL 23137955 A 670 679 uric acid TRIVIAL 23137955 A 739 748 polydatin TRIVIAL 23137955 A 832 840 fructose TRIVIAL 23137955 A 893 902 polydatin TRIVIAL 23137955 A 993 1002 uric acid TRIVIAL 23137955 T 0 9 Polydatin TRIVIAL 23137955 T 101 109 fructose TRIVIAL 23137955 T 118 123 urate SYSTEMATIC 23138334 A 0 6 Copper SYSTEMATIC 23138334 A 1021 1023 Mg FORMULA 23138334 A 1035 1042 Mg (2+) FORMULA 23138334 A 1062 1064 Cu FORMULA 23138334 A 1088 1090 Cu FORMULA 23138334 A 1133 1140 Mg (2+) FORMULA 23138334 A 1214 1221 Cu (2+) FORMULA 23138334 A 1223 1225 Cu FORMULA 23138334 A 1240 1247 Mg (2+) FORMULA 23138334 A 1345 1347 Mg FORMULA 23138334 A 1351 1353 Cu FORMULA 23138334 A 1426 1432 Mg(2+) FORMULA 23138334 A 1437 1443 Cu(2+) FORMULA 23138334 A 1513 1515 Cu FORMULA 23138334 A 1539 1545 Mg(2+) FORMULA 23138334 A 1619 1621 Cu FORMULA 23138334 A 165 171 Ca(2+) FORMULA 23138334 A 173 179 Mg(2+) FORMULA 23138334 A 181 185 K(+) FORMULA 23138334 A 187 192 Na(+) FORMULA 23138334 A 198 202 H(+) FORMULA 23138334 A 500 502 Mg FORMULA 23138334 A 506 508 Cu FORMULA 23138334 A 721 727 Mg(2+) FORMULA 23138334 A 733 739 Cu(2+) FORMULA 23138334 A 812 814 Cu FORMULA 23138334 A 908 910 Cu FORMULA 23138334 A 913 920 Cu (2+) FORMULA 23138334 T 23 32 magnesium SYSTEMATIC 23138334 T 36 42 copper SYSTEMATIC 23139010 A 1005 1018 sphingomyelin FAMILY 23139010 A 1019 1025 L-α-PC ABBREVIATION 23139010 A 1026 1037 cholesterol TRIVIAL 23139010 A 1125 1135 gramicidin FAMILY 23139010 A 1269 1279 gramicidin FAMILY 23139010 A 384 390 Teflon TRIVIAL 23139010 A 719 762 1,2-diphytanoyl-sn-glycero-3-phosphocholine SYSTEMATIC 23139010 A 764 769 DPhPC ABBREVIATION 23139010 A 775 798 L-α-phosphatidylcholine FAMILY 23139010 A 800 806 L-α-PC ABBREVIATION 23139010 A 808 819 cholesterol TRIVIAL 23139074 A 180 189 digitoxin TRIVIAL 23139074 A 321 336 C3'/C4'-hydroxy SYSTEMATIC 23139074 A 354 363 digitoxin TRIVIAL 23139074 A 364 378 monosaccharide FAMILY 23139074 A 87 96 palladium SYSTEMATIC 23139074 T 34 47 Digitoxigenin TRIVIAL 23139074 T 48 66 α-L-/α-D-Glycoside MULTIPLE 23139353 A 1024 1032 tyrosine TRIVIAL 23139353 A 124 132 androgen FAMILY 23139353 A 181 189 androgen FAMILY 23139353 T 9 17 androgen FAMILY 23139354 A 457 471 streptozotocin TRIVIAL 23139354 A 746 749 STZ ABBREVIATION 23139355 A 1090 1101 fatty acids FAMILY 23139355 A 821 828 glucose TRIVIAL 23139355 A 899 910 fatty acids FAMILY 23139355 A 915 928 triglycerides FAMILY 23139356 A 1319 1327 estrogen FAMILY 23139356 A 294 302 estrogen FAMILY 23139356 A 31 39 estrogen FAMILY 23139356 A 316 323 glucose TRIVIAL 23139356 A 358 365 glucose TRIVIAL 23139356 A 468 477 estradiol TRIVIAL 23139356 A 569 576 glucose TRIVIAL 23139356 A 788 795 glucose TRIVIAL 23139356 A 923 930 glucose TRIVIAL 23139356 T 18 27 estradiol TRIVIAL 23139356 T 38 45 glucose TRIVIAL 23140136 A 174 190 2-deoxyguanosine SYSTEMATIC 23140136 A 236 243 8-oxodG SYSTEMATIC 23140136 A 248 267 2-amino-imidazolone SYSTEMATIC 23140136 A 300 321 2,2-diamino-oxazolone SYSTEMATIC 23140136 A 332 339 8-oxodG SYSTEMATIC 23140136 A 363 384 spiroiminodihydantoin SYSTEMATIC 23140136 A 394 412 guanidinohydantoin SYSTEMATIC 23140136 A 599 610 rose bengal TRIVIAL 23140136 A 631 644 peroxynitrite SYSTEMATIC 23140136 A 872 879 8-OxodG SYSTEMATIC 23140136 T 104 110 oxygen SYSTEMATIC 23140136 T 38 45 guanine TRIVIAL 23140136 T 81 94 peroxynitrite SYSTEMATIC 23141189 A 1124 1126 OH FORMULA 23141189 A 1177 1183 TiO(2) FORMULA 23141189 A 1261 1267 TiO(2) FORMULA 23141189 A 187 193 TiO(2) FORMULA 23141189 A 224 232 platinum SYSTEMATIC 23141189 A 325 331 TiO(2) FORMULA 23141189 A 567 573 TiO(2) FORMULA 23141189 A 744 750 TiO(2) FORMULA 23141189 A 79 95 titanium dioxide SYSTEMATIC 23141189 A 97 103 TiO(2) FORMULA 23141189 T 76 80 TiO2 FORMULA 23142211 A 261 272 substance P TRIVIAL 23142211 A 282 294 neurokinin A TRIVIAL 23142211 A 296 299 NKA ABBREVIATION 23142211 A 691 694 NKA ABBREVIATION 23142325 A 0 9 Abamectin TRIVIAL 23142325 A 1037 1040 ATP ABBREVIATION 23142325 A 11 14 ABA ABBREVIATION 23142325 A 1108 1114 Ca(2+) FORMULA 23142325 A 1175 1178 ABA ABBREVIATION 23142325 A 1334 1337 ATP ABBREVIATION 23142325 A 214 217 ABA ABBREVIATION 23142325 A 244 262 adenine nucleotide TRIVIAL 23142325 A 352 355 ABA ABBREVIATION 23142325 A 477 480 ABA ABBREVIATION 23142325 A 48 59 avermectins FAMILY 23142325 A 508 514 oxygen SYSTEMATIC 23142325 A 579 582 ATP ABBREVIATION 23142325 A 628 634 Ca(2+) FORMULA 23142325 A 717 720 ABA ABBREVIATION 23142325 A 774 783 glutamate TRIVIAL 23142325 A 788 794 malate TRIVIAL 23142325 A 798 807 succinate TRIVIAL 23142325 A 861 870 proadifen TRIVIAL 23142325 A 97 100 ABA ABBREVIATION 23142325 T 50 59 abamectin TRIVIAL 23142425 A 1052 1056 NNAL ABBREVIATION 23142425 A 1068 1077 NNAL-Gluc ABBREVIATION 23142425 A 1150 1153 His FORMULA 23142425 A 1154 1157 Tyr FORMULA 23142425 A 1161 1164 Tyr FORMULA 23142425 A 1165 1168 Tyr FORMULA 23142425 A 1208 1212 NNAL ABBREVIATION 23142425 A 1233 1236 His FORMULA 23142425 A 1237 1240 His FORMULA 23142425 A 1433 1437 NNAL ABBREVIATION 23142425 A 1444 1448 NNAL ABBREVIATION 23142425 A 1469 1473 NNAL ABBREVIATION 23142425 A 1480 1484 NNAL ABBREVIATION 23142425 A 1489 1498 NNAL-Gluc ABBREVIATION 23142425 A 1505 1509 NNAL ABBREVIATION 23142425 A 161 164 UDP ABBREVIATION 23142425 A 1634 1644 nucleotide FAMILY 23142425 A 1662 1665 NNK TRIVIAL 23142425 A 234 237 NNK TRIVIAL 23142425 A 26 72 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone SYSTEMATIC 23142425 A 435 438 NNK TRIVIAL 23142425 A 709 712 NNK TRIVIAL 23142425 A 74 77 NNK TRIVIAL 23142425 T 0 46 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone SYSTEMATIC 23142425 T 100 103 NNK TRIVIAL 23142425 T 48 51 NNK TRIVIAL 23142506 A 1010 1014 K(+) FORMULA 23142506 A 840 844 K(+) FORMULA 23142506 A 855 856 K FORMULA 23142506 T 6 15 potassium SYSTEMATIC 23142577 A 1492 1497 K252a IDENTIFIER 23142577 A 1499 1509 Na(3)VO(4) FORMULA 23142577 A 1511 1516 Bis-1 NO CLASS 23142710 A 1085 1095 diclofenac TRIVIAL 23142710 A 1134 1144 diclofenac TRIVIAL 23142710 A 1149 1164 flufenamic acid TRIVIAL 23142710 A 1173 1182 piroxicam TRIVIAL 23142710 A 1225 1235 superoxide TRIVIAL 23142710 A 1287 1330 nicotinamide adenine dinucleotide phosphate SYSTEMATIC 23142710 A 1332 1337 NADPH ABBREVIATION 23142710 A 1361 1380 diphenyleneiodonium TRIVIAL 23142710 A 1428 1438 diclofenac TRIVIAL 23142710 A 1610 1620 superoxide TRIVIAL 23142710 A 1759 1769 diclofenac TRIVIAL 23142710 A 1940 1945 NADPH ABBREVIATION 23142710 A 1978 1988 superoxide TRIVIAL 23142710 A 310 316 oxygen SYSTEMATIC 23142710 A 428 438 diclofenac TRIVIAL 23142710 A 562 577 flufenamic acid TRIVIAL 23142710 A 579 596 meclofenamic acid TRIVIAL 23142710 A 598 608 diclofenac TRIVIAL 23142710 A 610 622 indomethacin TRIVIAL 23142710 A 624 634 nimesulide TRIVIAL 23142710 A 636 648 flurbiprofen TRIVIAL 23142710 A 650 659 meloxicam TRIVIAL 23142710 A 661 675 phenylbutazone TRIVIAL 23142710 A 677 686 piroxicam TRIVIAL 23142710 A 688 698 ketoprofen TRIVIAL 23142710 A 703 710 aspirin TRIVIAL 23142710 A 909 919 superoxide TRIVIAL 23142710 T 0 10 Superoxide TRIVIAL 23142711 A 1063 1068 MG132 IDENTIFIER 23142711 A 1142 1153 aldosterone TRIVIAL 23142711 A 1181 1186 MG132 IDENTIFIER 23142711 A 1409 1414 MG132 IDENTIFIER 23142711 A 286 291 MG132 IDENTIFIER 23142711 A 603 608 MG132 IDENTIFIER 23142711 A 817 822 MG132 IDENTIFIER 23142712 A 1083 1092 yuwen02f1 TRIVIAL 23142712 A 1418 1427 yuwen02f1 TRIVIAL 23142712 A 1688 1693 NADPH ABBREVIATION 23142712 A 365 381 diphenylpyrazole SYSTEMATIC 23142712 A 418 427 yuwen02f1 TRIVIAL 23142712 A 545 557 nitric oxide SYSTEMATIC 23142712 A 568 574 oxygen SYSTEMATIC 23142712 A 708 717 yuwen02f1 TRIVIAL 23142712 A 919 928 Yuwen02f1 TRIVIAL 23142712 T 0 9 Yuwen02f1 TRIVIAL 23142737 A 332 338 oxygen SYSTEMATIC 23142737 A 339 346 glucose TRIVIAL 23142737 T 66 72 oxygen SYSTEMATIC 23142737 T 73 80 glucose TRIVIAL 23142791 A 855 885 2-bromoethylamine hydrobromide SYSTEMATIC 23142791 A 887 901 phenylbutazone TRIVIAL 23142791 A 906 930 n-phenylanthranilic acid SYSTEMATIC 23143040 A 1079 1083 urea TRIVIAL 23143040 A 1102 1106 urea TRIVIAL 23143040 A 1181 1185 urea TRIVIAL 23143040 A 1191 1195 urea TRIVIAL 23143040 A 127 134 ammonia SYSTEMATIC 23143040 A 1272 1276 urea TRIVIAL 23143040 A 1290 1295 Na(+) FORMULA 23143040 A 1396 1401 Na(+) FORMULA 23143040 A 1417 1419 Na FORMULA 23143040 A 1471 1476 Na(+) FORMULA 23143040 A 1491 1493 Na FORMULA 23143040 A 1542 1544 Na FORMULA 23143040 A 161 166 Na(+) FORMULA 23143040 A 1613 1615 Na FORMULA 23143040 A 1658 1663 Na(+) FORMULA 23143040 A 1751 1753 Na FORMULA 23143040 A 1766 1768 Na FORMULA 23143040 A 1837 1839 Na FORMULA 23143040 A 186 190 urea TRIVIAL 23143040 A 1882 1887 Na(+) FORMULA 23143040 A 1894 1899 Na(+) FORMULA 23143040 A 1990 1997 ammonia SYSTEMATIC 23143040 A 2013 2015 Na FORMULA 23143040 A 202 210 cortisol TRIVIAL 23143040 A 2085 2087 Na FORMULA 23143040 A 2140 2144 K(+) FORMULA 23143040 A 2339 2346 ammonia SYSTEMATIC 23143040 A 2553 2560 ammonia SYSTEMATIC 23143040 A 313 320 ammonia SYSTEMATIC 23143040 A 555 562 ammonia SYSTEMATIC 23143040 A 582 593 NH(4)HCO(3) FORMULA 23143040 A 68 75 ammonia SYSTEMATIC 23143040 A 741 749 cortisol TRIVIAL 23143040 A 810 817 ammonia SYSTEMATIC 23143040 A 831 834 amm ABBREVIATION 23143040 A 942 949 ammonia SYSTEMATIC 23143040 A 988 991 amm ABBREVIATION 23143040 T 141 148 ammonia SYSTEMATIC 23143040 T 26 33 ammonia SYSTEMATIC 23143040 T 45 51 sodium SYSTEMATIC 23143891 A 1152 1175 triamcinolone acetonide TRIVIAL 23143891 A 1177 1187 budesonide TRIVIAL 23143891 A 1193 1215 fluticasone propionate SYSTEMATIC 23143891 A 1230 1241 flunisolide TRIVIAL 23143891 A 1399 1422 triamcinolone acetonide TRIVIAL 23143891 A 1424 1434 budesonide TRIVIAL 23143891 A 1440 1451 flunisolide TRIVIAL 23143891 A 1470 1486 Δ(6)-flunisolide SYSTEMATIC 23143891 A 1601 1611 21-carboxy SYSTEMATIC 23143891 A 1628 1651 triamcinolone acetonide TRIVIAL 23143891 A 1656 1667 flunisolide TRIVIAL 23143891 A 1690 1719 21-nortriamcinolone acetonide SYSTEMATIC 23143891 A 236 243 steroid FAMILY 23143891 A 627 650 triamcinolone acetonide TRIVIAL 23143891 A 652 663 flunisolide TRIVIAL 23143891 A 665 675 budesonide TRIVIAL 23143891 A 681 703 fluticasone propionate SYSTEMATIC 23143930 A 328 330 Au FORMULA 23144004 A 114 120 TiO(2) FORMULA 23144004 A 202 208 TiO(2) FORMULA 23144004 A 316 318 Pt FORMULA 23144004 A 620 626 TiO(2) FORMULA 23144004 T 49 53 TiO2 FORMULA 23144238 A 0 4 NMDA ABBREVIATION 23144238 A 1036 1039 DPA ABBREVIATION 23144238 A 1083 1086 DPA ABBREVIATION 23144238 A 1271 1274 DPA ABBREVIATION 23144238 A 1360 1363 DPA ABBREVIATION 23144238 A 1443 1446 DPA ABBREVIATION 23144238 A 1574 1577 DPA ABBREVIATION 23144238 A 1660 1663 DPA ABBREVIATION 23144238 A 1690 1694 NMDA ABBREVIATION 23144238 A 303 316 dipicrylamine TRIVIAL 23144238 A 318 321 DPA ABBREVIATION 23144238 A 344 348 GABA ABBREVIATION 23144238 A 416 438 sulfated neurosteroids FAMILY 23144238 A 457 470 neurosteroids FAMILY 23144238 A 525 528 DPA ABBREVIATION 23144238 A 575 578 DPA ABBREVIATION 23144238 A 614 618 NMDA ABBREVIATION 23144238 A 767 770 DPA ABBREVIATION 23144238 A 954 976 sulfated neurosteroids FAMILY 23144238 A 978 981 DPA ABBREVIATION 23144238 T 34 38 NMDA ABBREVIATION 23145773 A 153 172 2,5-thiophene amide FAMILY 23145773 A 244 249 amide FAMILY 23145773 A 265 271 phenyl SYSTEMATIC 23145773 A 297 312 phenethylamides FAMILY 23145773 A 346 354 anilides FAMILY 23145773 A 572 580 estrogen FAMILY 23145773 T 27 47 2,5-thiophene amides FAMILY 23145773 T 79 97 17β-hydroxysteroid SYSTEMATIC 23146663 A 1136 1169 purine and pyrimidine nucleotides MULTIPLE 23146663 A 1510 1521 nucleotides FAMILY 23146748 A 163 175 progesterone TRIVIAL 23146748 A 180 193 retinoic acid TRIVIAL 23146748 A 294 308 prostaglandins FAMILY 23146748 A 96 105 estrogens FAMILY 23146754 A 1144 1151 arsenic SYSTEMATIC 23146754 A 162 170 arsenite SYSTEMATIC 23146754 A 455 463 arsenite SYSTEMATIC 23146754 A 520 540 N-methyl-d-aspartate SYSTEMATIC 23146754 A 622 631 adenylate TRIVIAL 23146754 A 63 71 arsenite SYSTEMATIC 23146754 T 11 19 arsenite SYSTEMATIC 23146756 A 1244 1248 APS3 ABBREVIATION 23146756 A 1269 1282 acetylcholine SYSTEMATIC 23146756 A 1352 1365 acetylcholine SYSTEMATIC 23146756 A 1494 1498 APS3 ABBREVIATION 23146756 A 1579 1583 APS3 ABBREVIATION 23146756 A 250 254 APS3 ABBREVIATION 23146756 A 368 372 APS3 ABBREVIATION 23146756 A 523 527 APS3 ABBREVIATION 23146756 A 66 88 3-alkylpyridinium salt FAMILY 23146756 A 727 731 APS3 ABBREVIATION 23146756 A 90 94 APS3 ABBREVIATION 23146756 A 914 918 APS3 ABBREVIATION 23146756 T 104 117 acetylcholine SYSTEMATIC 23146756 T 36 58 3-alkylpyridinium salt FAMILY 23146756 T 60 64 APS3 ABBREVIATION 23147375 A 1010 1014 PAHs ABBREVIATION 23147375 A 1147 1150 PAH ABBREVIATION 23147375 A 1471 1475 PAHs ABBREVIATION 23147375 A 1589 1593 PAHs ABBREVIATION 23147375 A 238 270 polycyclic aromatic hydrocarbons FAMILY 23147375 A 272 276 PAHs ABBREVIATION 23147375 A 338 342 PAHs ABBREVIATION 23147375 A 462 466 PAHs ABBREVIATION 23147375 A 580 584 PAHs ABBREVIATION 23147375 A 685 689 PAHs ABBREVIATION 23147375 A 691 709 benzo[a]anthracene SYSTEMATIC 23147375 A 716 730 benzo[a]pyrene SYSTEMATIC 23147375 A 737 749 phenanthrene SYSTEMATIC 23147375 A 759 770 naphthalene SYSTEMATIC 23147375 A 798 801 PAH ABBREVIATION 23147375 A 906 909 PAH ABBREVIATION 23147375 T 77 109 polycyclic aromatic hydrocarbons FAMILY 23147414 A 0 4 GABA ABBREVIATION 23147414 A 1043 1051 zolpidem TRIVIAL 23147414 A 1081 1090 gaboxadol TRIVIAL 23147414 A 1163 1167 GABA ABBREVIATION 23147414 A 1261 1268 ethanol SYSTEMATIC 23147414 A 132 139 ethanol SYSTEMATIC 23147414 A 1350 1357 ethanol SYSTEMATIC 23147414 A 1452 1459 ethanol SYSTEMATIC 23147414 A 1553 1560 ethanol SYSTEMATIC 23147414 A 197 201 GABA ABBREVIATION 23147414 A 23 27 GABA ABBREVIATION 23147414 A 333 340 ethanol SYSTEMATIC 23147414 A 423 430 ethanol SYSTEMATIC 23147414 A 52 59 ethanol SYSTEMATIC 23147414 A 542 549 ethanol SYSTEMATIC 23147414 A 566 573 ethanol SYSTEMATIC 23147414 A 598 602 GABA ABBREVIATION 23147414 A 714 721 ethanol SYSTEMATIC 23147414 A 901 911 flurazepam TRIVIAL 23147414 T 104 111 alcohol FAMILY 23147414 T 37 44 alcohol FAMILY 23147414 T 8 12 GABA ABBREVIATION 23147417 A 1249 1258 SB-408124 IDENTIFIER 23147417 A 1303 1313 TCS OX2 29 IDENTIFIER 23147417 A 1749 1763 Methylene Blue TRIVIAL 23147417 A 1806 1815 guanylate TRIVIAL 23147417 A 182 194 Nitric oxide SYSTEMATIC 23147417 A 204 216 nitric oxide SYSTEMATIC 23147417 A 222 224 NO FORMULA 23147417 A 2252 2254 NO FORMULA 23147417 A 438 440 NO FORMULA 23147417 A 944 956 nitric oxide SYSTEMATIC 23147417 A 986 998 nitric oxide SYSTEMATIC 23147680 A 119 123 CFCs FAMILY 23147680 A 125 132 CF(3)Cl FORMULA 23147680 A 134 144 CF(2)Cl(2) FORMULA 23147680 A 149 156 CFCl(3) FORMULA 23147680 A 506 513 CF(3)Cl FORMULA 23147680 A 515 525 CF(2)Cl(2) FORMULA 23147680 A 530 537 CFCl(3) FORMULA 23147680 A 552 559 CFCl(3) FORMULA 23147680 A 686 693 CF(3)Cl FORMULA 23147680 A 698 708 CF(2)Cl(2) FORMULA 23147680 A 892 899 CFCl(3) FORMULA 23147680 A 98 117 chlorofluorocarbons FAMILY 23147680 T 40 45 CF3Cl FORMULA 23147680 T 47 53 CF2Cl2 FORMULA 23147680 T 58 63 CFCl3 FORMULA 23147807 A 1061 1067 carbon SYSTEMATIC 23147807 A 1143 1149 carbon SYSTEMATIC 23147807 A 540 546 carbon SYSTEMATIC 23147807 A 626 632 carbon SYSTEMATIC 23147807 A 964 970 carbon SYSTEMATIC 23147869 A 1066 1069 PAH ABBREVIATION 23147869 A 1170 1173 PAH ABBREVIATION 23147869 A 22 28 carbon SYSTEMATIC 23147869 A 222 253 polycyclic aromatic hydrocarbon FAMILY 23147869 A 255 258 PAH ABBREVIATION 23147869 A 351 354 PAH ABBREVIATION 23147869 A 505 509 PAHs ABBREVIATION 23147869 A 671 687 polyoxymethylene FAMILY 23147869 A 689 692 POM ABBREVIATION 23147869 A 748 752 PAHs ABBREVIATION 23147869 A 804 807 PAH ABBREVIATION 23147869 A 834 837 PAH ABBREVIATION 23147869 A 907 911 PAHs ABBREVIATION 23147869 T 34 66 polycyclic aromatic hydrocarbons FAMILY 23147869 T 91 97 carbon SYSTEMATIC 23148227 A 1003 1006 ADR ABBREVIATION 23148227 A 1061 1064 ADR ABBREVIATION 23148227 A 1161 1164 ADR ABBREVIATION 23148227 A 1197 1200 Lys FORMULA 23148227 A 1369 1372 ADR ABBREVIATION 23148227 A 259 269 adriamycin TRIVIAL 23148227 A 271 274 ADR ABBREVIATION 23148227 A 593 596 ADR ABBREVIATION 23148227 A 743 746 ADR ABBREVIATION 23148227 A 932 935 ADR ABBREVIATION 23148920 A 0 16 Hydrogen sulfide SYSTEMATIC 23148920 A 1005 1015 dantrolene TRIVIAL 23148920 A 1019 1033 xestospongin C TRIVIAL 23148920 A 1035 1039 NaHS FORMULA 23148920 A 1090 1103 phosphoserine SYSTEMATIC 23148920 A 1122 1126 NaHS FORMULA 23148920 A 1160 1162 NO FORMULA 23148920 A 1217 1227 wortmannin TRIVIAL 23148920 A 1266 1271 H(2)S FORMULA 23148920 A 1337 1339 NO FORMULA 23148920 A 1364 1371 calcium SYSTEMATIC 23148920 A 151 156 H(2)S FORMULA 23148920 A 18 23 H(2)S FORMULA 23148920 A 273 278 H(2)S FORMULA 23148920 A 378 390 nitric oxide SYSTEMATIC 23148920 A 392 394 NO FORMULA 23148920 A 437 442 H(2)S FORMULA 23148920 A 474 476 NO FORMULA 23148920 A 506 508 NO FORMULA 23148920 A 542 546 NaHS FORMULA 23148920 A 550 555 H(2)S FORMULA 23148920 A 590 592 NO FORMULA 23148920 A 666 673 calcium SYSTEMATIC 23148920 A 684 692 BAPTA-AM ABBREVIATION 23148920 A 735 742 calcium SYSTEMATIC 23148920 A 748 752 NaHS FORMULA 23148920 A 761 763 NO FORMULA 23148920 A 814 823 ryanodine TRIVIAL 23148920 A 834 844 dantrolene TRIVIAL 23148920 A 849 876 inositol 1,4,5-triphosphate SYSTEMATIC 23148920 A 887 901 xestospongin C TRIVIAL 23148920 A 904 908 NaHS FORMULA 23148920 A 947 954 calcium SYSTEMATIC 23148920 T 0 16 Hydrogen sulfide SYSTEMATIC 23148920 T 100 112 nitric oxide SYSTEMATIC 23148920 T 27 39 nitric oxide SYSTEMATIC 23148920 T 56 63 calcium SYSTEMATIC 23148988 A 112 115 PEI ABBREVIATION 23148988 A 118 160 1,2-dioleoyl-3-(trimethylammonium) propane SYSTEMATIC 23148988 A 162 167 DOTAP ABBREVIATION 23148988 A 232 242 folic acid TRIVIAL 23148988 A 434 444 folic acid TRIVIAL 23148988 A 628 634 folate TRIVIAL 23148988 A 704 710 folate TRIVIAL 23148988 A 94 110 polyethylenimine SYSTEMATIC 23148988 T 57 63 folate TRIVIAL 23149809 A 148 156 Fluoride SYSTEMATIC 23149809 A 326 335 aspartate TRIVIAL 23149809 A 350 357 alanine TRIVIAL 23149809 A 412 426 gamma glutamyl SYSTEMATIC 23149809 A 440 447 lactate FAMILY 23149809 A 463 472 bilirubin TRIVIAL 23149809 A 64 76 ferulic acid TRIVIAL 23149809 A 702 716 hydroperoxides FAMILY 23149809 A 718 730 nitric oxide SYSTEMATIC 23149809 A 85 93 fluoride SYSTEMATIC 23149809 A 896 904 fluoride SYSTEMATIC 23149809 A 946 958 ferulic acid TRIVIAL 23149809 A 986 994 fluoride SYSTEMATIC 23149809 T 0 12 Ferulic acid TRIVIAL 23149809 T 23 31 fluoride SYSTEMATIC 23150213 A 1507 1516 ertapenem TRIVIAL 23150213 A 1518 1529 teicoplanin FAMILY 23150213 A 1531 1542 ceftriaxone TRIVIAL 23150213 A 1547 1561 flucloxacillin TRIVIAL 23150485 A 1311 1327 phosphoinositide FAMILY 23150487 A 1090 1105 Obtusilactone B TRIVIAL 23150487 A 425 440 Obtusilactone B TRIVIAL 23150487 A 446 456 butanolide SYSTEMATIC 23150487 A 531 546 obtusilactone B TRIVIAL 23150487 A 903 918 obtusilactone B TRIVIAL 23150487 T 0 15 Obtusilactone B TRIVIAL 23150983 A 12 132 2-(substituted phenyl/benzyl-amino)-6-(4-chlorophenyl)-5-(methoxycarbonyl)-4-methyl-3,6-dihydropyrimidin-1-ium chlorides FAMILY 23150983 A 170 183 hydrochloride FAMILY 23150983 A 249 253 (1)H FORMULA 23150983 A 258 263 (13)C FORMULA 23150983 A 575 578 MTT ABBREVIATION 23150983 T 41 161 2-(substituted phenyl/benzyl-amino)-6-(4-chlorophenyl)-5-(methoxycarbonyl)-4-methyl-3,6-dihydropyrimidin-1-ium chlorides FAMILY 23152001 A 1002 1004 Cu FORMULA 23152001 A 1016 1018 Zn FORMULA 23152001 A 1057 1059 Se FORMULA 23152001 A 106 113 cadmium SYSTEMATIC 23152001 A 1094 1096 Cd FORMULA 23152001 A 115 117 Cd FORMULA 23152001 A 1184 1186 Se FORMULA 23152001 A 1191 1193 Cd FORMULA 23152001 A 1297 1299 Se FORMULA 23152001 A 1320 1322 Se FORMULA 23152001 A 1344 1346 Cd FORMULA 23152001 A 1387 1389 Cd FORMULA 23152001 A 1420 1422 Se FORMULA 23152001 A 190 198 Selenium SYSTEMATIC 23152001 A 225 227 Cd FORMULA 23152001 A 285 287 Se FORMULA 23152001 A 295 297 Cd FORMULA 23152001 A 304 306 Cd FORMULA 23152001 A 355 357 Se FORMULA 23152001 A 386 388 Cd FORMULA 23152001 A 457 459 Cd FORMULA 23152001 A 503 505 Se FORMULA 23152001 A 531 533 Cd FORMULA 23152001 A 57 65 selenium SYSTEMATIC 23152001 A 583 585 Cd FORMULA 23152001 A 617 619 Se FORMULA 23152001 A 621 623 Cd FORMULA 23152001 A 655 657 Ca FORMULA 23152001 A 659 661 Mg FORMULA 23152001 A 663 665 Mn FORMULA 23152001 A 667 669 Cu FORMULA 23152001 A 67 69 Se FORMULA 23152001 A 675 677 Zn FORMULA 23152001 A 688 690 Se FORMULA 23152001 A 812 814 Cd FORMULA 23152001 A 833 835 Cd FORMULA 23152001 A 866 868 Se FORMULA 23152001 A 983 985 Ca FORMULA 23152001 A 987 989 Mg FORMULA 23152001 A 991 992 K FORMULA 23152001 A 994 996 Fe FORMULA 23152001 A 998 1000 Mn FORMULA 23152001 T 15 17 Se FORMULA 23152001 T 21 23 Cd FORMULA 23152001 T 63 65 Cd FORMULA 23152124 A 18 29 phosphonate SYSTEMATIC 23152124 A 346 349 CPT ABBREVIATION 23152124 A 50 56 silica TRIVIAL 23152124 T 67 73 silica TRIVIAL 23153455 A 1024 1035 Vemurafenib TRIVIAL 23153455 A 1188 1199 vemurafenib TRIVIAL 23153455 A 1316 1327 vemurafenib TRIVIAL 23153455 A 1412 1423 vemurafenib TRIVIAL 23153455 A 1562 1573 vemurafenib TRIVIAL 23153455 A 324 335 vemurafenib TRIVIAL 23153455 A 337 348 Vemurafenib TRIVIAL 23153455 A 512 523 vemurafenib TRIVIAL 23153455 A 744 755 vemurafenib TRIVIAL 23153455 A 809 820 vemurafenib TRIVIAL 23153455 A 838 841 ATP ABBREVIATION 23153455 A 917 928 vemurafenib TRIVIAL 23153455 T 108 119 vemurafenib TRIVIAL 23153455 T 18 21 ATP ABBREVIATION 23153547 A 196 209 5-flurouracil SYSTEMATIC 23153547 A 214 225 mitomycin C TRIVIAL 23153671 A 102 110 phenolic FAMILY 23153671 A 1043 1047 DPPH ABBREVIATION 23153671 A 1194 1202 O(2)(·-) FORMULA 23153671 A 1262 1264 NO FORMULA 23153671 A 1269 1271 OH FORMULA 23153671 A 310 313 ·NO FORMULA 23153671 A 315 323 O(2)(·-) FORMULA 23153671 A 328 331 OH· FORMULA 23153671 A 367 375 phenolic FAMILY 23153671 A 459 469 cellobiose TRIVIAL 23153671 A 54 64 cellobiose TRIVIAL 23153671 A 550 558 phenolic FAMILY 23153671 A 762 791 2,2-diphenyl-1-picrylhydrazyl SYSTEMATIC 23153671 A 793 797 DPPH ABBREVIATION 23153671 A 801 807 Trolox TRIVIAL 23153671 A 86 96 cellobiose TRIVIAL 23153671 A 905 926 methoxylated phenolic FAMILY 23153671 A 945 957 sinapic acid TRIVIAL 23153671 A 959 971 ferulic acid TRIVIAL 23153671 A 973 992 2,6-dimethoxyphenol SYSTEMATIC 23154302 A 1106 1114 tyrosine TRIVIAL 23154302 A 177 183 oxygen SYSTEMATIC 23154302 A 184 191 glucose TRIVIAL 23154302 A 65 77 progesterone TRIVIAL 23154302 A 87 96 vitamin D FAMILY 23154302 A 900 904 heme FAMILY 23154302 T 27 39 progesterone TRIVIAL 23154302 T 44 53 vitamin D FAMILY 23154883 A 180 193 hydroxypropyl SYSTEMATIC 23154883 A 596 607 cholesterol TRIVIAL 23154883 A 636 649 triglycerides FAMILY 23154883 T 33 46 hydroxypropyl SYSTEMATIC 23155049 A 735 744 rapamycin TRIVIAL 23155049 A 893 894 N FORMULA 23155049 T 134 143 rapamycin TRIVIAL 23155202 A 10 21 artemisinin TRIVIAL 23155202 A 1002 1021 glucose-6-phosphate SYSTEMATIC 23155202 A 1081 1092 glutathione TRIVIAL 23155202 A 1108 1119 glutathione TRIVIAL 23155202 A 119 131 lumefantrine TRIVIAL 23155202 A 1265 1280 malondialdehyde TRIVIAL 23155202 A 1282 1285 MDA ABBREVIATION 23155202 A 133 143 artemether TRIVIAL 23155202 A 1370 1380 artemether TRIVIAL 23155202 A 1385 1397 lumefantrine TRIVIAL 23155202 A 144 156 lumefantrine TRIVIAL 23155202 A 413 421 Tween 80 TRIVIAL 23155202 A 452 462 artemether TRIVIAL 23155202 A 505 517 lumefantrine TRIVIAL 23155202 A 567 577 artemether TRIVIAL 23155202 A 604 616 lumefantrine TRIVIAL 23155202 A 64 75 artemisinin TRIVIAL 23155202 A 874 884 artemether TRIVIAL 23155202 A 88 98 artemether TRIVIAL 23155202 A 889 901 lumefantrine TRIVIAL 23155202 A 989 1000 glutathione TRIVIAL 23155202 T 33 43 artemether TRIVIAL 23155202 T 48 60 lumefantrine TRIVIAL 23157384 A 596 610 methylene blue TRIVIAL 23157384 A 612 628 brilliant blue G TRIVIAL 23157384 A 634 647 erythrosine B TRIVIAL 23157384 A 806 822 brilliant blue G TRIVIAL 23157384 A 828 841 erythrosine B TRIVIAL 23157384 A 962 976 methylene blue TRIVIAL 23157624 A 1146 1154 dopamine TRIVIAL 23157624 A 1156 1165 serotonin TRIVIAL 23157624 A 1167 1181 norepinephrine TRIVIAL 23157624 A 1183 1196 acetylcholine SYSTEMATIC 23157624 A 1201 1210 glutamate TRIVIAL 23157624 A 350 358 dopamine TRIVIAL 23157624 A 363 372 serotonin TRIVIAL 23157626 A 379 387 dopamine TRIVIAL 23157626 A 389 398 serotonin TRIVIAL 23157626 A 403 412 glutamate TRIVIAL 23157626 A 496 507 [(11)C]PHNO SYSTEMATIC 23157626 A 597 608 amphetamine TRIVIAL 23157626 A 628 636 dopamine TRIVIAL 23157626 A 782 791 serotonin TRIVIAL 23157626 A 883 894 [(11)C]DASB SYSTEMATIC 23157629 A 15 19 5-HT SYSTEMATIC 23157629 A 160 161 C FORMULA 23157629 A 350 364 catecholamines FAMILY 23157629 A 4 13 serotonin TRIVIAL 23157629 A 84 88 5-HT SYSTEMATIC 23157629 T 0 9 Serotonin TRIVIAL 23157633 A 1217 1240 Gamma-aminobutyric-acid SYSTEMATIC 23157633 A 1268 1292 N-Methyl-D-aspartic-acid SYSTEMATIC 23157633 A 301 309 dopamine TRIVIAL 23159329 A 1067 1071 METH ABBREVIATION 23159329 A 1214 1218 METH ABBREVIATION 23159329 A 1270 1274 METH ABBREVIATION 23159329 A 1453 1457 METH ABBREVIATION 23159329 A 179 183 cAMP ABBREVIATION 23159329 A 374 389 methamphetamine TRIVIAL 23159329 A 391 395 METH ABBREVIATION 23159329 A 575 579 METH ABBREVIATION 23159329 A 715 719 METH ABBREVIATION 23159329 A 838 842 METH ABBREVIATION 23159329 T 18 33 methamphetamine TRIVIAL 23159663 A 0 9 Acyclovir TRIVIAL 23159663 A 11 14 ACV ABBREVIATION 23159663 A 1235 1238 ACV ABBREVIATION 23159663 A 1258 1261 ACV ABBREVIATION 23159663 A 1503 1506 ACV ABBREVIATION 23159663 A 1566 1569 ACV ABBREVIATION 23159663 A 1724 1727 ACV ABBREVIATION 23159663 A 573 576 ACV ABBREVIATION 23159663 A 630 646 tripolyphosphate SYSTEMATIC 23159663 A 648 651 TPP ABBREVIATION 23159664 A 1149 1153 ISDN ABBREVIATION 23159664 A 139 159 isosorbide dinitrate SYSTEMATIC 23159664 A 161 165 ISDN ABBREVIATION 23159664 A 180 190 N-succinyl TRIVIAL 23159664 A 475 479 ISDN ABBREVIATION 23159664 A 55 65 N-succinyl TRIVIAL 23159664 A 639 643 ISDN ABBREVIATION 23159664 T 29 39 N-succinyl TRIVIAL 23159664 T 81 101 isosorbide dinitrate SYSTEMATIC 23159708 A 647 655 mannitol TRIVIAL 23159708 A 657 664 sucrose TRIVIAL 23159708 A 669 678 trehalose TRIVIAL 23159728 A 1087 1090 TCS ABBREVIATION 23159728 A 118 133 thyroid hormone FAMILY 23159728 A 1326 1329 TCS ABBREVIATION 23159728 A 377 386 triclosan TRIVIAL 23159728 A 388 391 TCS ABBREVIATION 23159728 A 494 503 thyroxine TRIVIAL 23159728 A 541 544 TCS ABBREVIATION 23159728 A 563 566 TCS ABBREVIATION 23159728 A 993 996 TCS ABBREVIATION 23159728 T 0 9 Triclosan TRIVIAL 23159884 A 1006 1011 soman TRIVIAL 23159884 A 1093 1101 paraoxon TRIVIAL 23159884 A 1199 1204 tabun TRIVIAL 23159884 A 425 435 tryptophan TRIVIAL 23159884 A 764 772 paraoxon TRIVIAL 23159884 A 809 822 racemic sarin TRIVIAL 23159884 A 94 110 organophosphorus FAMILY 23159884 T 57 73 organophosphorus FAMILY 23159887 A 1180 1184 cAMP ABBREVIATION 23159887 A 398 402 cAMP ABBREVIATION 23159887 A 563 567 cAMP ABBREVIATION 23159887 T 14 18 cAMP ABBREVIATION 23159914 A 0 12 Formaldehyde SYSTEMATIC 23159914 A 1060 1068 (13)C-FA SYSTEMATIC 23159914 A 513 518 (13)C FORMULA 23159914 A 587 595 (13)C-FA SYSTEMATIC 23159914 A 788 796 (13)C-FA SYSTEMATIC 23159914 A 921 929 (13)C-FA SYSTEMATIC 23159914 T 31 43 formaldehyde SYSTEMATIC 23159985 A 208 216 triazole FAMILY 23159985 A 229 241 myclobutanil TRIVIAL 23159985 A 243 256 propiconazole TRIVIAL 23159985 A 262 273 triadimefon TRIVIAL 23159985 A 340 349 triazoles FAMILY 23159985 A 673 681 triazole FAMILY 23159985 A 731 740 triazoles FAMILY 23159985 T 54 62 triazole FAMILY 23160090 A 0 23 Hydroxysafflor yellow A SYSTEMATIC 23160090 A 153 157 HSYA ABBREVIATION 23160090 A 25 29 HSYA ABBREVIATION 23160090 A 334 338 HSYA ABBREVIATION 23160090 A 360 364 HSYA ABBREVIATION 23160090 A 524 528 HSYA ABBREVIATION 23160090 A 700 704 HSYA ABBREVIATION 23160090 T 0 23 Hydroxysafflor yellow a TRIVIAL 23160179 A 1059 1065 lutein TRIVIAL 23160179 A 373 379 lutein TRIVIAL 23160179 A 384 394 β-carotene TRIVIAL 23160179 A 702 712 amino acid FAMILY 23160179 A 958 968 β-carotene TRIVIAL 23160270 A 20 33 copper oxides FAMILY 23160270 A 486 504 La(2-x)Sr(x)CuO(4) FAMILY 23160270 T 86 102 La(2-x)Sr(x)CuO4 FAMILY 23160434 A 248 259 nucleotides FAMILY 23160820 A 1002 1008 MG-132 IDENTIFIER 23160820 A 1010 1039 carbobenzoxy-Leu-Leu-leucinal TRIVIAL 23160820 A 1359 1369 rifampicin TRIVIAL 23160820 A 4 12 pregnane TRIVIAL 23160820 A 435 443 pregnane TRIVIAL 23160820 T 72 80 pregnane TRIVIAL 23160931 A 1035 1037 Ti FORMULA 23160931 A 1044 1045 C FORMULA 23160931 A 1056 1065 fullerene TRIVIAL 23160931 A 1082 1086 H(2) FORMULA 23160931 A 115 119 H(2) FORMULA 23160931 A 1159 1161 Ti FORMULA 23160931 A 1184 1193 fullerene TRIVIAL 23160931 A 1241 1242 C FORMULA 23160931 A 125 127 Ti FORMULA 23160931 A 1285 1287 Ti FORMULA 23160931 A 1312 1316 H(2) FORMULA 23160931 A 1376 1391 C(60) fullerene TRIVIAL 23160931 A 1409 1415 TiH(2) FORMULA 23160931 A 143 158 C(60) fullerene TRIVIAL 23160931 A 1445 1461 C( n ) fullerene FAMILY 23160931 A 1523 1529 TiH(2) FORMULA 23160931 A 164 168 H(2) FORMULA 23160931 A 217 226 fullerene TRIVIAL 23160931 A 246 247 C FORMULA 23160931 A 286 290 H(2) FORMULA 23160931 A 325 329 H(2) FORMULA 23160931 A 558 562 H(2) FORMULA 23160931 A 592 593 C FORMULA 23160931 A 603 614 C(60)TiH(2) FORMULA 23160931 A 654 659 C(60) TRIVIAL 23160931 A 777 785 hydrogen SYSTEMATIC 23160931 A 81 82 C FORMULA 23160931 A 907 908 C FORMULA 23160931 A 918 929 C(59)TiH(2) FORMULA 23160931 T 14 15 C FORMULA 23160931 T 27 35 hydrogen SYSTEMATIC 23160931 T 68 70 H2 FORMULA 23160931 T 80 82 Ti FORMULA 23160931 T 98 111 C60 fullerene TRIVIAL 23160941 A 1012 1071 N-formyl-Met-Leu-Phe-Ile-Ile-Lys-fluorescein isothiocyanate SYSTEMATIC 23160941 A 1562 1568 formyl SYSTEMATIC 23160941 A 203 209 formyl SYSTEMATIC 23160941 A 431 432 N FORMULA 23160941 A 71 77 formyl SYSTEMATIC 23160941 A 738 749 hexapeptide FAMILY 23160941 A 781 788 Quin-C1 TRIVIAL 23160941 A 804 817 quinazolinone SYSTEMATIC 23160941 A 839 862 nitrosylated pyrazolone FAMILY 23160941 T 43 49 formyl SYSTEMATIC 23161216 A 1051 1063 somatostatin TRIVIAL 23161216 A 1126 1133 glucose TRIVIAL 23161216 A 1245 1257 somatostatin TRIVIAL 23161216 A 18 27 potassium SYSTEMATIC 23161216 A 385 392 glucose TRIVIAL 23161216 A 553 558 RY796 IDENTIFIER 23161216 A 723 730 glucose TRIVIAL 23161216 A 762 767 RY796 IDENTIFIER 23161216 A 777 789 somatostatin TRIVIAL 23161216 A 993 1005 somatostatin TRIVIAL 23161216 T 26 35 potassium SYSTEMATIC 23161368 A 1214 1224 ivermectin TRIVIAL 23161368 A 166 176 ivermectin TRIVIAL 23161368 A 19 29 ivermectin TRIVIAL 23161368 A 351 361 ivermectin TRIVIAL 23161368 T 30 40 ivermectin TRIVIAL 23161369 A 1011 1017 4A-DNT SYSTEMATIC 23161369 A 1139 1142 RDX TRIVIAL 23161369 A 121 127 4A-DNT SYSTEMATIC 23161369 A 1269 1272 RDX TRIVIAL 23161369 A 133 162 1,3,5-trinitro-1,3,5-triazine SYSTEMATIC 23161369 A 164 167 RDX TRIVIAL 23161369 A 425 431 4A-DNT SYSTEMATIC 23161369 A 541 547 4A-DNT SYSTEMATIC 23161369 A 712 715 RDX TRIVIAL 23161369 A 904 910 4A-DNT SYSTEMATIC 23161369 A 93 119 4-amino-2,6-dinitrotoluene SYSTEMATIC 23161369 T 25 31 4A-DNT SYSTEMATIC 23161369 T 33 59 4-amino-2,6-dinitrotoluene SYSTEMATIC 23161369 T 65 68 RDX TRIVIAL 23161369 T 70 99 1,3,5-trinitro-1,3,5-triazine SYSTEMATIC 23161427 A 11 30 triterpene saponins FAMILY 23161427 A 298 306 aldehyde SYSTEMATIC 23161427 A 32 50 ilexpublesnins C-M MULTIPLE 23161427 A 326 345 triterpene saponins FAMILY 23161427 T 0 18 Ilexpublesnins C-M MULTIPLE 23161427 T 31 50 triterpene saponins FAMILY 23161470 A 126 134 graphene TRIVIAL 23161470 A 162 177 silicon nitride SYSTEMATIC 23161470 A 307 313 SiO(2) FORMULA 23161470 A 315 317 Si FORMULA 23161470 A 387 395 graphene TRIVIAL 23161470 A 432 440 graphene TRIVIAL 23161470 T 69 77 graphene TRIVIAL 23161470 T 87 102 silicon nitride SYSTEMATIC 23161531 A 0 4 Coal TRIVIAL 23161531 A 1264 1272 HCO 3(-) FORMULA 23161531 A 1277 1285 SO 4(2-) FORMULA 23161531 A 1319 1324 Cl(-) FORMULA 23161531 A 232 236 Coal TRIVIAL 23161544 A 1150 1164 methylenedioxy SYSTEMATIC 23161544 A 1251 1257 lignan FAMILY 23161544 A 1440 1459 (-)-podophyllotoxin TRIVIAL 23161544 A 291 307 (-)-matairesinol TRIVIAL 23161544 A 35 54 (-)-podophyllotoxin TRIVIAL 23161544 A 59 78 aryltetralin lignan FAMILY 23161544 A 665 680 podophyllotoxin TRIVIAL 23161544 A 945 961 (-)-matairesinol TRIVIAL 23161544 A 967 983 (-)-pluviatolide TRIVIAL 23161544 A 998 1012 methylenedioxy SYSTEMATIC 23161544 T 58 73 podophyllotoxin TRIVIAL 23161550 A 1059 1066 cocaine TRIVIAL 23161550 A 1074 1121 (-)-2β-carbomethoxy-3β-(4-fluorophenyl) tropane SYSTEMATIC 23161550 A 1123 1126 CFT ABBREVIATION 23161550 A 1222 1225 CFT ABBREVIATION 23161550 A 1236 1239 Ser FORMULA 23161550 A 1265 1269 zinc SYSTEMATIC 23161550 A 1284 1287 CFT ABBREVIATION 23161550 A 1302 1305 Ala FORMULA 23161550 A 1310 1313 Asp FORMULA 23161550 A 1378 1381 Ser FORMULA 23161550 A 1490 1493 Ser FORMULA 23161550 A 152 153 N FORMULA 23161550 A 1616 1623 cocaine TRIVIAL 23161550 A 298 301 Ser FORMULA 23161550 A 30 38 dopamine TRIVIAL 23161550 A 309 316 calcium SYSTEMATIC 23161550 A 357 360 Ser FORMULA 23161550 A 388 391 Ser FORMULA 23161550 A 395 398 Ser FORMULA 23161550 A 406 409 Ser FORMULA 23161550 A 766 769 Ser FORMULA 23161550 A 873 876 Ser FORMULA 23161550 A 984 987 Ser FORMULA 23161550 T 19 27 dopamine TRIVIAL 23161550 T 40 46 serine TRIVIAL 23161550 T 59 66 cocaine TRIVIAL 23161584 A 109 141 polycyclic aromatic hydrocarbons FAMILY 23161584 A 1098 1102 LABs FAMILY 23161584 A 1123 1127 PAHs ABBREVIATION 23161584 A 143 147 PAHs ABBREVIATION 23161584 A 1583 1586 PAH ABBREVIATION 23161584 A 301 311 n-C(15-35) MULTIPLE 23161584 A 313 322 n-alkanes FAMILY 23161584 A 334 340 carbon SYSTEMATIC 23161584 A 350 353 LAB ABBREVIATION 23161584 A 362 381 C(10) to C(13) LABs MULTIPLE 23161584 A 394 397 PAH ABBREVIATION 23161584 A 40 62 aliphatic hydrocarbons FAMILY 23161584 A 409 412 PAH ABBREVIATION 23161584 A 542 554 hydrocarbons FAMILY 23161584 A 64 73 n-alkanes FAMILY 23161584 A 685 689 LABs FAMILY 23161584 A 76 96 linear alkylbenzenes FAMILY 23161584 A 890 902 hydrocarbons FAMILY 23161584 A 98 102 LABs FAMILY 23161747 A 191 199 graphene TRIVIAL 23161747 A 288 296 graphene TRIVIAL 23161747 A 358 366 graphene TRIVIAL 23161747 A 59 67 graphene TRIVIAL 23161747 T 55 63 graphene TRIVIAL 23161751 A 243 251 chlorate SYSTEMATIC 23161751 A 488 496 chlorate SYSTEMATIC 23161751 A 754 762 chlorate SYSTEMATIC 23161751 A 875 883 chlorate SYSTEMATIC 23161751 T 22 30 chlorate SYSTEMATIC 23163352 A 113 118 (13)C FORMULA 23163352 A 495 506 amino acids FAMILY 23163352 A 683 690 glycine TRIVIAL 23163352 A 695 702 alanine TRIVIAL 23163352 A 777 784 Alanine TRIVIAL 23163726 A 1359 1362 GTP ABBREVIATION 23163726 A 70 73 GTP ABBREVIATION 23163726 A 808 811 GTP ABBREVIATION 23163726 A 824 825 C FORMULA 23163726 A 858 868 nucleotide FAMILY 23163726 A 929 932 GTP ABBREVIATION 23163768 A 629 637 tyrosine TRIVIAL 23164602 A 129 134 GA-Mk ABBREVIATION 23164602 A 27 88 3α,22β-diacetoxy-7α-hydroxyl-5α-lanost-8,24E-dien-26-oic acid SYSTEMATIC 23164602 A 6 20 ganoderic acid TRIVIAL 23164602 A 648 656 methanol SYSTEMATIC 23164602 A 737 745 hydroxyl SYSTEMATIC 23164602 T 6 20 ganoderic acid TRIVIAL 23164617 A 1006 1014 muscimol TRIVIAL 23164617 A 1136 1140 DNQX ABBREVIATION 23164617 A 1144 1152 muscimol TRIVIAL 23164617 A 1258 1262 NMDA ABBREVIATION 23164617 A 1266 1270 GABA ABBREVIATION 23164617 A 133 137 GABA ABBREVIATION 23164617 A 166 170 AMPA ABBREVIATION 23164617 A 175 182 kainate TRIVIAL 23164617 A 247 251 GABA ABBREVIATION 23164617 A 282 286 NMDA ABBREVIATION 23164617 A 638 642 DNQX ABBREVIATION 23164617 A 656 664 muscimol TRIVIAL 23164617 A 797 802 d-AP5 IDENTIFIER 23164617 A 813 821 muscimol TRIVIAL 23164617 A 852 857 d-AP5 IDENTIFIER 23164617 A 861 869 muscimol TRIVIAL 23164617 A 997 1002 d-AP5 IDENTIFIER 23164617 T 118 127 glutamate TRIVIAL 23164617 T 132 136 GABA ABBREVIATION 23164673 A 0 11 Cinobufagin TRIVIAL 23164673 A 1201 1212 cinobufagin TRIVIAL 23164673 A 1257 1268 cinobufagin TRIVIAL 23164673 A 1273 1281 SB216367 IDENTIFIER 23164673 A 134 145 cinobufagin TRIVIAL 23164673 A 1408 1419 cinobufagin TRIVIAL 23164673 A 1551 1562 cinobufagin TRIVIAL 23164673 A 279 290 cinobufagin TRIVIAL 23164673 A 343 354 cinobufagin TRIVIAL 23164673 A 590 601 cinobufagin TRIVIAL 23164673 A 76 96 cardenolidal steroid FAMILY 23164673 A 830 841 cinobufagin TRIVIAL 23164673 A 965 976 cinobufagin TRIVIAL 23164673 T 78 89 cinobufagin TRIVIAL 23165153 A 0 9 Cisplatin TRIVIAL 23165153 A 11 39 cis-diamminedichloroplatinum SYSTEMATIC 23165153 A 1124 1128 CDDP ABBREVIATION 23165153 A 1202 1206 CDDP ABBREVIATION 23165153 A 1253 1262 aldehydes FAMILY 23165153 A 1537 1553 Z-Leu-Leu-Leu-al FORMULA 23165153 A 1568 1572 CDDP ABBREVIATION 23165153 A 1665 1681 Z-Leu-Leu-Leu-al FORMULA 23165153 A 1871 1875 CDDP ABBREVIATION 23165153 A 323 327 CDDP ABBREVIATION 23165153 A 365 369 CDDP ABBREVIATION 23165153 A 41 45 CDDP ABBREVIATION 23165153 A 648 652 CDDP ABBREVIATION 23165153 A 763 772 aldehydes FAMILY 23165153 A 774 793 4-hydroxy-2-nonenal SYSTEMATIC 23165153 A 798 813 4-oxo-2-nonenal SYSTEMATIC 23165153 A 953 962 aldehydes FAMILY 23165153 A 967 971 CDDP ABBREVIATION 23165153 T 87 96 cisplatin TRIVIAL 23165215 A 1026 1033 benzene SYSTEMATIC 23165215 A 1060 1067 benzene SYSTEMATIC 23165215 A 113 117 zinc SYSTEMATIC 23165215 A 1175 1182 benzene SYSTEMATIC 23165215 A 149 183 [Zn(4)O(CO(2)C(6)H(4)CO(2))(3)](n) FAMILY 23165215 A 185 192 IRMOF-1 ABBREVIATION 23165215 A 298 305 benzene SYSTEMATIC 23165215 A 395 402 benzene SYSTEMATIC 23165215 A 406 413 IRMOF-1 ABBREVIATION 23165215 A 47 54 benzene SYSTEMATIC 23165215 A 545 552 benzene SYSTEMATIC 23165215 A 652 659 benzene SYSTEMATIC 23165215 A 667 674 IRMOF-1 ABBREVIATION 23165215 A 747 754 benzene SYSTEMATIC 23165215 A 794 801 IRMOF-1 ABBREVIATION 23165215 A 884 891 benzene SYSTEMATIC 23165215 A 935 942 benzene SYSTEMATIC 23165215 T 32 39 benzene SYSTEMATIC 23165215 T 56 63 IRMOF-1 ABBREVIATION 23165312 A 175 181 carbon SYSTEMATIC 23165625 A 1004 1030 1-phenyl-1-methylacetylene SYSTEMATIC 23165625 A 1039 1047 C(8)H(8) FORMULA 23165625 A 1056 1063 styrene TRIVIAL 23165625 A 1142 1162 1,3-butadiene-phenyl SYSTEMATIC 23165625 A 1232 1259 trans-1,3-butadienylbenzene SYSTEMATIC 23165625 A 1271 1293 1,4-dihydronaphthalene SYSTEMATIC 23165625 A 1309 1316 styrene TRIVIAL 23165625 A 1411 1417 phenyl SYSTEMATIC 23165625 A 1430 1443 1,3-butadiene SYSTEMATIC 23165625 A 1445 1459 1-Methylindene SYSTEMATIC 23165625 A 1471 1477 indene TRIVIAL 23165625 A 1489 1501 phenylallene SYSTEMATIC 23165625 A 1517 1543 1-phenyl-1-methylacetylene SYSTEMATIC 23165625 A 1591 1597 phenyl SYSTEMATIC 23165625 A 1617 1625 C(4)H(6) FORMULA 23165625 A 1635 1648 1,2-butadiene SYSTEMATIC 23165625 A 1650 1665 H(2)CCCH(CH(3)) FORMULA 23165625 A 1668 1676 1-butyne SYSTEMATIC 23165625 A 1678 1689 HCCC(2)H(5) FORMULA 23165625 A 1696 1704 2-butyne SYSTEMATIC 23165625 A 1706 1718 CH(3)CCCH(3) FORMULA 23165625 A 1727 1735 C(4)H(6) FORMULA 23165625 A 1763 1776 1,3-butadiene SYSTEMATIC 23165625 A 1781 1789 hydrogen SYSTEMATIC 23165625 A 1861 1874 1,3-butadiene SYSTEMATIC 23165625 A 1885 1893 hydrogen SYSTEMATIC 23165625 A 27 33 phenyl SYSTEMATIC 23165625 A 386 399 C(10)H(10)(+) FORMULA 23165625 A 407 418 C(9)H(8)(+) FORMULA 23165625 A 430 441 C(8)H(8)(+) FORMULA 23165625 A 44 52 C(6)H(5) FORMULA 23165625 A 477 485 hydrogen SYSTEMATIC 23165625 A 487 488 H FORMULA 23165625 A 491 497 methyl SYSTEMATIC 23165625 A 499 504 CH(3) FORMULA 23165625 A 511 516 vinyl FAMILY 23165625 A 518 526 C(2)H(3) FORMULA 23165625 A 59 72 1,3-butadiene SYSTEMATIC 23165625 A 74 88 H(2)CCHCHCH(2) FORMULA 23165625 A 781 791 C(10)H(10) FORMULA 23165625 A 793 801 C(9)H(8) FORMULA 23165625 A 807 815 C(8)H(8) FORMULA 23165625 A 868 878 C(10)H(10) FORMULA 23165625 A 888 915 trans-1,3-butadienylbenzene SYSTEMATIC 23165625 A 917 939 1,4-dihydronaphthalene SYSTEMATIC 23165625 A 941 955 1-methylindene SYSTEMATIC 23165625 A 964 972 C(9)H(8) FORMULA 23165625 A 982 988 indene TRIVIAL 23165625 A 990 1002 phenylallene SYSTEMATIC 23165625 T 60 66 phenyl SYSTEMATIC 23165625 T 81 94 1,3-butadiene SYSTEMATIC 23165754 A 48 56 tyrosine TRIVIAL 23165754 A 952 962 safranin O TRIVIAL 23166317 A 0 9 Efavirenz TRIVIAL 23166317 A 1047 1050 EFV ABBREVIATION 23166317 A 11 14 EFV ABBREVIATION 23166317 A 1104 1107 EFV ABBREVIATION 23166317 A 1282 1285 EFV ABBREVIATION 23166317 A 145 148 EFV ABBREVIATION 23166317 A 384 387 EFV ABBREVIATION 23166317 A 500 503 EFV ABBREVIATION 23166317 A 523 536 8-hydroxy EFV SYSTEMATIC 23166317 A 718 748 7-hydroxy and 8,14-hydroxy EFV MULTIPLE 23166317 T 45 54 efavirenz TRIVIAL 23166320 A 1010 1011 O FORMULA 23166320 A 1016 1017 O FORMULA 23166320 A 1024 1027 N-O FORMULA 23166320 A 1123 1130 sulfate SYSTEMATIC 23166320 A 1367 1368 N FORMULA 23166320 A 1369 1370 O FORMULA 23166320 A 49 56 sulfate SYSTEMATIC 23166320 A 524 535 amino acids FAMILY 23166320 A 570 571 N FORMULA 23166320 A 576 577 C FORMULA 23166320 A 603 606 Arg FORMULA 23166320 A 607 610 Ala FORMULA 23166320 A 632 633 N FORMULA 23166320 A 659 660 C FORMULA 23166320 A 736 737 N FORMULA 23166320 A 974 981 sulfate SYSTEMATIC 23168113 A 1067 1077 PNU-120596 IDENTIFIER 23168113 A 1157 1167 PNU-120596 IDENTIFIER 23168113 A 1196 1205 donepezil TRIVIAL 23168113 A 1377 1395 methyllycaconitine TRIVIAL 23168113 A 1397 1400 MLA ABBREVIATION 23168113 A 1442 1452 PNU-120596 IDENTIFIER 23168113 A 1491 1500 donepezil TRIVIAL 23168113 A 1629 1639 PNU-120596 IDENTIFIER 23168113 A 1724 1733 donepezil TRIVIAL 23168113 A 492 501 donepezil TRIVIAL 23168113 A 562 575 acetylcholine SYSTEMATIC 23168113 A 599 609 PNU-120596 IDENTIFIER 23168113 A 979 988 donepezil TRIVIAL 23168113 T 111 120 donepezil TRIVIAL 23168113 T 51 64 acetylcholine SYSTEMATIC 23168113 T 76 86 PNU-120596 IDENTIFIER 23169263 A 1029 1050 cyclohexane-1,2-diols FAMILY 23169263 A 1170 1172 OH FORMULA 23169263 A 1216 1218 CH FORMULA 23169263 A 198 200 OH FORMULA 23169263 A 205 214 methylene SYSTEMATIC 23169263 A 226 241 ethane-1,2-diol SYSTEMATIC 23169263 A 34 43 1,2-diols FAMILY 23169263 A 354 363 1,2-diols FAMILY 23169263 A 367 374 benzene SYSTEMATIC 23169263 A 47 54 benzene SYSTEMATIC 23169263 A 853 868 ethane-1,2-diol SYSTEMATIC 23169263 A 873 889 propane-1,2-diol SYSTEMATIC 23169263 A 944 969 tert-butylethane-1,2-diol SYSTEMATIC 23169263 A 971 992 phenylethane-1,2-diol SYSTEMATIC 23169263 A 994 1010 butane-2,3-diols FAMILY 23169263 T 0 2 1H FORMULA 23169263 T 18 33 ethane-1,2-diol SYSTEMATIC 23169263 T 44 57 vicinal diols FAMILY 23169263 T 61 68 benzene SYSTEMATIC 23169689 A 24 40 Schaeffer's acid TRIVIAL 23169689 T 13 29 Schaeffer's acid TRIVIAL 23170960 A 221 230 metformin TRIVIAL 23170960 A 232 242 glitazones FAMILY 23170960 A 268 281 sulfonylureas FAMILY 23170960 A 283 291 glinides FAMILY 23171137 A 1008 1015 ethanol SYSTEMATIC 23171137 A 1025 1048 3,6-diketoheptanoyl-CoA SYSTEMATIC 23171137 A 1055 1071 2,5-diketohexane SYSTEMATIC 23171137 A 1073 1083 pyrrolates FAMILY 23171137 A 1089 1095 lysine TRIVIAL 23171137 A 1113 1119 lysine TRIVIAL 23171137 A 1206 1223 cyclic CoA esters FAMILY 23171137 A 1298 1317 4-hydroxypentanoate SYSTEMATIC 23171137 A 149 168 4-hydroxypentanoate SYSTEMATIC 23171137 A 186 193 ethanol SYSTEMATIC 23171137 A 26 36 levulinate TRIVIAL 23171137 A 265 275 levulinate TRIVIAL 23171137 A 280 299 4-hydroxypentanoate SYSTEMATIC 23171137 A 319 332 propionyl-CoA SYSTEMATIC 23171137 A 337 347 acetyl-CoA SYSTEMATIC 23171137 A 368 378 levulinate TRIVIAL 23171137 A 38 54 4-ketopentanoate SYSTEMATIC 23171137 A 397 403 carbon SYSTEMATIC 23171137 A 469 482 levulinyl-CoA TRIVIAL 23171137 A 486 496 acetyl-CoA SYSTEMATIC 23171137 A 500 523 3,6-diketoheptanoyl-CoA SYSTEMATIC 23171137 A 536 554 γ-diketo CoA ester FAMILY 23171137 A 650 695 cyclopentenyl- and cyclopentadienyl-acyl-CoAs MULTIPLE 23171137 A 737 763 methyl-pyrrolyl-acetyl-CoA SYSTEMATIC 23171137 A 777 785 nitrogen SYSTEMATIC 23171137 A 808 818 ε-nitrogen SYSTEMATIC 23171137 A 822 828 lysine TRIVIAL 23171137 A 841 848 carbons FAMILY 23171137 A 85 104 4-hydroxypentanoate SYSTEMATIC 23171137 A 854 860 lysine TRIVIAL 23171137 A 866 883 cyclic CoA esters FAMILY 23171137 A 928 938 levulinate TRIVIAL 23171137 A 987 1005 calcium levulinate SYSTEMATIC 23171137 T 144 154 levulinate TRIVIAL 23171137 T 79 87 pyrrolyl SYSTEMATIC 23171137 T 92 105 cyclopentenyl SYSTEMATIC 23172657 A 35 43 perylene SYSTEMATIC 23172777 A 1072 1088 furanopyrimidine SYSTEMATIC 23172777 A 1183 1194 quinazoline SYSTEMATIC 23172777 A 279 287 pyrazole SYSTEMATIC 23172777 A 302 318 furanopyrimidine SYSTEMATIC 23172777 T 57 68 quinazoline SYSTEMATIC 23174017 A 297 302 sugar FAMILY 23174265 A 1298 1302 5-HT SYSTEMATIC 23174265 A 201 205 5-HT SYSTEMATIC 23174265 A 502 509 CP55940 IDENTIFIER 23174265 A 870 877 JTE-907 IDENTIFIER 23174265 A 92 96 5-HT SYSTEMATIC 23174265 T 110 114 5-HT SYSTEMATIC 23174266 A 231 242 Polyphenols FAMILY 23174266 A 591 602 polyphenols FAMILY 23174266 A 75 86 polyphenols FAMILY 23174266 A 808 819 polyphenols FAMILY 23174266 A 914 925 polyphenols FAMILY 23174266 T 22 33 polyphenols FAMILY 23174754 A 1022 1034 testosterone TRIVIAL 23174754 A 1096 1104 androgen FAMILY 23174754 A 1115 1123 estrogen FAMILY 23174758 A 58 62 cAMP ABBREVIATION 23174758 A 734 738 cAMP ABBREVIATION 23174758 A 778 782 cGMP ABBREVIATION 23174758 T 39 49 cyclic-AMP TRIVIAL 23175666 A 153 161 cortisol TRIVIAL 23175666 T 64 72 cortisol TRIVIAL 23177254 A 11 25 α and β ionone MULTIPLE 23177254 A 32 41 chalcones FAMILY 23177254 A 424 435 miltefosine TRIVIAL 23177254 A 52 72 dihydropyrazolidines FAMILY 23177254 A 73 86 pyrazolidines FAMILY 23177254 T 75 96 terpenyl heterocycles FAMILY 23177257 A 301 311 naringenin TRIVIAL 23177257 A 38 48 naringenin TRIVIAL 23177257 A 387 397 naringenin TRIVIAL 23177257 A 468 477 flavanone TRIVIAL 23177257 A 703 713 naringenin TRIVIAL 23177257 A 861 871 naringenin TRIVIAL 23177257 A 961 970 flavanone TRIVIAL 23177257 T 47 57 naringenin TRIVIAL 23177786 A 239 258 jasmonate glucoside TRIVIAL 23177786 A 308 323 triazoyl-phenyl SYSTEMATIC 23177786 A 325 329 TAzP ABBREVIATION 23177786 A 413 417 TAzP ABBREVIATION 23177786 A 578 584 biaryl FAMILY 23177786 A 658 664 biaryl FAMILY 23177786 A 680 684 TAzP ABBREVIATION 23177786 T 0 15 Triazoyl-phenyl FAMILY 23177786 T 148 167 jasmonate glucoside TRIVIAL 23177787 A 101 106 ML253 IDENTIFIER 23177787 A 261 264 ACh ABBREVIATION 23177787 A 340 345 ML253 IDENTIFIER 23177787 A 455 466 amphetamine TRIVIAL 23177787 T 140 145 ML253 IDENTIFIER 23177787 T 71 114 3-amino-thieno[2,3-b]pyridine-2-carboxamide SYSTEMATIC 23177789 A 318 329 triterpenes FAMILY 23177789 A 380 388 saponins FAMILY 23177789 A 8 16 tyrosine TRIVIAL 23177789 T 130 138 saponins FAMILY 23177789 T 53 62 dammarane TRIVIAL 23177789 T 68 79 triterpenes FAMILY 23177789 T 8 16 tyrosine TRIVIAL 23178164 A 1091 1095 CORT ABBREVIATION 23178164 A 1497 1501 CORT ABBREVIATION 23178164 A 195 199 CORT ABBREVIATION 23178164 A 24 38 corticosterone TRIVIAL 23178164 A 365 369 CORT ABBREVIATION 23178164 A 40 44 CORT ABBREVIATION 23178164 A 596 600 CORT ABBREVIATION 23178164 A 865 869 CORT ABBREVIATION 23178255 A 194 197 MTT ABBREVIATION 23178255 A 242 247 ester FAMILY 23178255 A 287 297 amino acid FAMILY 23178255 A 37 62 25-hydroxyprotopanaxadiol SYSTEMATIC 23178255 A 531 540 25-OH-PPD SYSTEMATIC 23178255 A 64 73 25-OH-PPD SYSTEMATIC 23178255 T 101 112 amino acids FAMILY 23178255 T 45 70 25-hydroxyprotopanaxadiol SYSTEMATIC 23178380 A 1145 1153 paraoxon TRIVIAL 23178380 A 1332 1340 paraoxon TRIVIAL 23178380 A 87 103 organophosphates FAMILY 23178380 T 119 127 paraoxon TRIVIAL 23178381 A 0 10 Aspidin PB TRIVIAL 23178381 A 1060 1070 aspidin PB TRIVIAL 23178381 A 1162 1172 wortmannin TRIVIAL 23178381 A 1308 1318 aspidin PB TRIVIAL 23178381 A 14 28 phloroglucinol TRIVIAL 23178381 A 215 225 aspidin PB TRIVIAL 23178381 A 273 283 aspidin PB TRIVIAL 23178381 A 389 399 aspidin PB TRIVIAL 23178381 A 430 433 MTT ABBREVIATION 23178381 A 511 521 Aspidin PB TRIVIAL 23178381 A 610 625 acridine orange TRIVIAL 23178381 A 644 660 propidium iodide TRIVIAL 23178381 A 676 680 FITC ABBREVIATION 23178381 A 742 752 aspidin PB TRIVIAL 23178381 A 848 858 aspidin PB TRIVIAL 23178381 A 905 908 Ser FORMULA 23178381 A 920 923 Ser FORMULA 23178381 T 0 10 Aspidin PB TRIVIAL 23178381 T 14 28 phloroglucinol TRIVIAL 23178652 A 0 9 Erlotinib TRIVIAL 23178652 A 1010 1022 okadaic acid TRIVIAL 23178652 A 1067 1076 erlotinib TRIVIAL 23178652 A 1110 1119 forskolin TRIVIAL 23178652 A 1159 1168 erlotinib TRIVIAL 23178652 A 1219 1226 MK-2206 IDENTIFIER 23178652 A 1232 1241 erlotinib TRIVIAL 23178652 A 1285 1294 erlotinib TRIVIAL 23178652 A 1344 1353 erlotinib TRIVIAL 23178652 A 1423 1432 Erlotinib TRIVIAL 23178652 A 1585 1594 erlotinib TRIVIAL 23178652 A 1699 1708 erlotinib TRIVIAL 23178652 A 195 204 erlotinib TRIVIAL 23178652 A 258 267 Erlotinib TRIVIAL 23178652 A 336 345 Erlotinib TRIVIAL 23178652 A 463 472 erlotinib TRIVIAL 23178652 A 626 635 erlotinib TRIVIAL 23178652 A 644 653 Erlotinib TRIVIAL 23178652 A 833 840 phospho SYSTEMATIC 23178652 A 876 885 erlotinib TRIVIAL 23178652 A 967 976 erlotinib TRIVIAL 23178652 T 31 40 erlotinib TRIVIAL 23178655 A 1118 1125 boldine TRIVIAL 23178655 A 1141 1151 superoxide TRIVIAL 23178655 A 1156 1169 peroxynitrite SYSTEMATIC 23178655 A 1192 1195 DHE ABBREVIATION 23178655 A 1326 1333 boldine TRIVIAL 23178655 A 1435 1442 NAD(P)H ABBREVIATION 23178655 A 1510 1517 boldine TRIVIAL 23178655 A 1563 1570 glucose TRIVIAL 23178655 A 1634 1637 STZ ABBREVIATION 23178655 A 1706 1708 NO FORMULA 23178655 A 174 181 Boldine TRIVIAL 23178655 A 183 224 [s]-2,9-dihydroxy-1,10-dimethoxyaporphine SYSTEMATIC 23178655 A 401 408 boldine TRIVIAL 23178655 A 422 429 glucose TRIVIAL 23178655 A 600 607 glucose TRIVIAL 23178655 A 645 652 boldine TRIVIAL 23178655 A 682 695 nitrotyrosine SYSTEMATIC 23178655 A 721 733 nitric oxide SYSTEMATIC 23178655 A 735 737 NO FORMULA 23178655 A 771 778 β-NAPDH ABBREVIATION 23178655 A 791 804 acetylcholine SYSTEMATIC 23178655 A 880 887 boldine TRIVIAL 23178655 A 962 976 streptozotocin TRIVIAL 23178655 A 978 981 STZ ABBREVIATION 23178655 T 0 7 Boldine TRIVIAL 23178896 A 627 650 methyl methanesulfonate SYSTEMATIC 23180160 A 176 182 ON123x FAMILY 23180160 A 404 412 ON123300 IDENTIFIER 23180160 A 446 453 ON123xx FAMILY 23180340 A 125 192 2',4'-dihydroxy-4,6'-dimethoxy-3'(2''-hydroxybenzyl)dihydrochalcone SYSTEMATIC 23180340 A 219 228 flavonoid FAMILY 23180340 A 256 271 dihydrochalcone SYSTEMATIC 23180340 A 295 310 aromatic esters FAMILY 23180340 A 334 348 aromatic amide FAMILY 23180340 A 50 116 4,2',4'-trihydroxy-6'-methoxy-3'(2''-hydroxybenzyl)dihydrochalcone SYSTEMATIC 23180340 A 517 519 1H FORMULA 23180340 A 521 524 13C FORMULA 23180340 A 8 36 C-benzylated dihydrochalcone SYSTEMATIC 23180340 T 8 36 C-benzylated dihydrochalcone SYSTEMATIC 23180651 A 27 29 Si FORMULA 23180651 A 275 277 HF FORMULA 23180651 A 278 283 AgNO3 FORMULA 23180651 A 287 289 HF FORMULA 23180651 A 290 294 H2O2 FORMULA 23180651 A 325 342 alkali hydroxides FAMILY 23180651 A 351 355 NaOH FORMULA 23180651 A 359 362 KOH FORMULA 23180651 A 447 449 Si FORMULA 23180651 A 450 455 oxide SYSTEMATIC 23180651 A 573 590 alkali hydroxides FAMILY 23180651 A 656 658 Si FORMULA 23180651 T 37 39 Si FORMULA 23180651 T 83 100 alkali hydroxides FAMILY 23180664 A 15 32 organophosphonate FAMILY 23180664 A 75 107 N-(3,5-dinitrobenzoyl)-S-leucine SYSTEMATIC 23180664 T 26 43 organophosphonate FAMILY 23180664 T 59 105 N-(3,5-dinitrobenzoyl)-L-leucine-n-propylamide SYSTEMATIC 23180678 A 142 176 polysodium N-undecanoyl-L-vanilate FAMILY 23180678 A 222 236 pipecolic acid TRIVIAL 23180678 A 302 309 diamond TRIVIAL 23180678 A 320 328 graphite TRIVIAL 23180678 A 403 409 carbon SYSTEMATIC 23180678 A 505 519 pipecolic acid TRIVIAL 23180678 A 52 62 porphyrins FAMILY 23180678 A 677 691 pipecolic acid TRIVIAL 23180678 A 97 137 polysodium N-undecanoyl-L-leucylvanilate FAMILY 23180678 T 19 33 pipecolic acid TRIVIAL 23182090 A 36 81 2-aminooctahydrocyclopentalene-3a-carboxamide SYSTEMATIC 23182090 T 6 52 2-aminooctahydrocyclopentalene-3a-carboxamides FAMILY 23182463 A 1192 1200 hydrogen SYSTEMATIC 23182463 A 215 221 amides FAMILY 23182463 A 239 247 hydrogen SYSTEMATIC 23182463 A 528 543 amide hydrogens FAMILY 23182954 A 112 117 ozone TRIVIAL 23182954 A 1154 1157 MDA ABBREVIATION 23182954 A 1283 1288 Ozone TRIVIAL 23182954 A 1368 1373 Ozone TRIVIAL 23182954 A 1437 1440 MDA ABBREVIATION 23182954 A 1599 1604 ozone TRIVIAL 23182954 A 1781 1786 ozone TRIVIAL 23182954 A 412 417 ozone TRIVIAL 23182954 A 451 456 ozone TRIVIAL 23182954 A 834 837 MDA ABBREVIATION 23182954 T 11 16 ozone TRIVIAL 23183423 T 12 18 silver SYSTEMATIC 23183587 A 235 239 (2)H FORMULA 23183587 A 45 51 O-(2)H FORMULA 23183587 T 43 45 2H FORMULA 23183772 A 11 18 silicon SYSTEMATIC 23183772 A 162 164 Si FORMULA 23183772 A 20 22 Si FORMULA 23183772 A 244 246 Si FORMULA 23183772 A 282 284 Li FORMULA 23183772 T 11 18 silicon SYSTEMATIC 23183772 T 42 49 lithium SYSTEMATIC 23184152 A 1402 1409 lithium SYSTEMATIC 23184152 A 203 210 lithium SYSTEMATIC 23184152 A 688 695 lithium SYSTEMATIC 23184152 A 725 732 lithium SYSTEMATIC 23186244 A 187 192 allyl SYSTEMATIC 23186244 A 402 408 esters FAMILY 23186244 A 472 480 alcohols FAMILY 23186244 A 528 614 1-(4-chlorophenyl)-3-phenylallyl and 3-(4-chlorophenyl)-1-phenylallyl 4-nitrobenzoates MULTIPLE 23186244 A 747 779 1-(4-chlorophenyl)-3-phenylallyl SYSTEMATIC 23186244 A 841 858 allyl carboxylate SYSTEMATIC 23186244 T 33 68 chiral 1,3-diarylallyl carboxylates FAMILY 23187064 A 82 88 oxygen SYSTEMATIC 23187066 A 1101 1104 ZVI ABBREVIATION 23187066 A 1175 1178 ZVI ABBREVIATION 23187066 A 1313 1316 azo SYSTEMATIC 23187066 A 1321 1325 DB15 ABBREVIATION 23187066 A 154 170 Zero-valent iron SYSTEMATIC 23187066 A 172 175 ZVI ABBREVIATION 23187066 A 259 275 Fenton's reagent FAMILY 23187066 A 26 29 azo SYSTEMATIC 23187066 A 35 49 direct blue 15 TRIVIAL 23187066 A 407 412 Fe(0) FORMULA 23187066 A 419 427 H(2)O(2) FORMULA 23187066 A 51 55 DB15 ABBREVIATION 23187066 A 588 592 DB15 ABBREVIATION 23187066 A 689 698 H(2)CO(3) FORMULA 23187066 A 700 705 Cl(-) FORMULA 23187066 A 707 716 ClO(4)(-) FORMULA 23187066 A 718 726 NO(3)(-) FORMULA 23187066 A 731 740 SO(4)(2-) FORMULA 23187066 A 806 818 H(2)PO(4)(-) FORMULA 23187066 T 19 33 direct blue 15 TRIVIAL 23187066 T 71 87 zero-valent iron SYSTEMATIC 23187687 A 101 108 rapta-C ABBREVIATION 23187687 A 487 495 hydrogen SYSTEMATIC 23187687 A 670 677 rapta-C ABBREVIATION 23187687 T 62 69 rapta-C ABBREVIATION 23188119 A 284 292 fluoride SYSTEMATIC 23188119 A 4 12 fluoride SYSTEMATIC 23188119 A 491 499 fluoride SYSTEMATIC 23188119 T 54 62 fluoride SYSTEMATIC 23188828 A 751 758 phospho SYSTEMATIC 23192842 A 0 28 N,N-dihydroxypyromellitimide SYSTEMATIC 23192842 A 1091 1103 hydroxyimide SYSTEMATIC 23192842 A 134 140 carbon SYSTEMATIC 23192842 A 186 206 N-hydroxyphthalimide SYSTEMATIC 23192842 A 208 212 NHPI ABBREVIATION 23192842 A 30 35 NDHPI ABBREVIATION 23192842 A 41 76 N,N',N''-trihydroxyisocyanuric acid SYSTEMATIC 23192842 A 464 469 THICA ABBREVIATION 23192842 A 478 483 NDHPI ABBREVIATION 23192842 A 488 492 NHPI ABBREVIATION 23192842 A 673 678 NDHPI ABBREVIATION 23192842 A 683 688 THICA ABBREVIATION 23192842 A 701 705 NHPI ABBREVIATION 23192842 A 774 775 H FORMULA 23192842 A 78 83 THICA ABBREVIATION 23192842 A 933 938 THICA ABBREVIATION 23192842 T 28 41 hydroxyimides FAMILY 23193181 A 1305 1316 resveratrol TRIVIAL 23193181 A 153 164 resveratrol TRIVIAL 23193181 A 391 402 resveratrol TRIVIAL 23193181 A 580 591 resveratrol TRIVIAL 23193181 A 671 678 glucose TRIVIAL 23193181 A 901 908 glucose TRIVIAL 23193181 A 960 967 glucose TRIVIAL 23193181 A 988 999 Resveratrol TRIVIAL 23193181 T 10 21 resveratrol TRIVIAL 23193186 A 145 152 glucose TRIVIAL 23193186 A 396 403 glucose TRIVIAL 23193186 A 463 470 glucose TRIVIAL 23193186 A 568 575 glucose TRIVIAL 23193186 A 646 653 glucose TRIVIAL 23193186 A 735 742 glucose TRIVIAL 23193255 A 913 923 nucleotide FAMILY 23194503 A 0 15 β-Cryptoxanthin TRIVIAL 23194503 A 179 194 β-cryptoxanthin TRIVIAL 23194503 A 294 297 MTT ABBREVIATION 23194503 A 367 382 β-Cryptoxanthin TRIVIAL 23194503 A 448 463 β-cryptoxanthin TRIVIAL 23194503 A 714 729 β-cryptoxanthin TRIVIAL 23194503 A 759 772 retinoic acid TRIVIAL 23194503 A 875 890 β-cryptoxanthin TRIVIAL 23194503 T 30 45 β-cryptoxanthin TRIVIAL 23194508 A 219 230 tin dioxide SYSTEMATIC 23194508 A 255 257 Cr FORMULA 23194508 A 262 264 In FORMULA 23194508 T 106 117 tin dioxide SYSTEMATIC 23194511 A 197 208 gallic acid TRIVIAL 23194511 A 268 277 flavonoid FAMILY 23194511 A 342 350 catechin TRIVIAL 23194511 A 389 398 phenolics FAMILY 23194511 A 403 413 flavonoids FAMILY 23194511 A 504 513 phenolics FAMILY 23194511 A 515 526 gallic acid TRIVIAL 23194511 A 528 544 chlorogenic acid TRIVIAL 23194511 A 546 558 (+)-catechin TRIVIAL 23194511 A 560 572 caffeic acid TRIVIAL 23194511 A 574 589 (-)-epicatechin SYSTEMATIC 23194511 A 595 600 rutin TRIVIAL 23194511 A 799 803 DPPH ABBREVIATION 23194511 A 901 910 flavonoid FAMILY 23194511 A 927 936 phenolics FAMILY 23194511 A 941 951 flavonoids FAMILY 23194516 A 564 576 nitric oxide SYSTEMATIC 23194519 A 377 392 hydroxychavicol SYSTEMATIC 23194519 A 542 557 hydroxychavicol SYSTEMATIC 23194519 A 690 705 hydroxychavicol SYSTEMATIC 23194519 T 18 33 hydroxychavicol SYSTEMATIC 23194520 A 266 272 tocols FAMILY 23194520 A 274 281 sterols FAMILY 23194520 A 283 297 phenolic acids FAMILY 23194520 A 302 309 folates FAMILY 23194520 A 792 808 alkylresorcinols FAMILY 23194520 A 810 816 tocols FAMILY 23194520 A 821 828 sterols FAMILY 23194527 A 197 209 carbohydrate FAMILY 23194530 A 123 133 amphenicol FAMILY 23194530 A 205 215 Ampicillin TRIVIAL 23194530 A 217 220 AMP ABBREVIATION 23194530 A 223 235 penicillin G TRIVIAL 23194530 A 242 254 penicillin V TRIVIAL 23194530 A 261 270 oxacillin TRIVIAL 23194530 A 272 275 OXA ABBREVIATION 23194530 A 278 289 cloxacillin TRIVIAL 23194530 A 291 294 CLO ABBREVIATION 23194530 A 297 310 dicloxacillin TRIVIAL 23194530 A 312 317 DICLO ABBREVIATION 23194530 A 320 333 thiamphenicol TRIVIAL 23194530 A 335 338 TAP ABBREVIATION 23194530 A 341 352 florfenicol TRIVIAL 23194530 A 354 357 FFC ABBREVIATION 23194530 A 363 378 chloramphenicol TRIVIAL 23194530 A 380 383 CAP ABBREVIATION 23194530 A 499 515 ammonium acetate SYSTEMATIC 23194530 A 527 539 acetonitrile SYSTEMATIC 23194530 A 623 626 AMP ABBREVIATION 23194530 A 636 639 TAP ABBREVIATION 23194530 A 644 647 FFC ABBREVIATION 23194530 A 662 665 OXA ABBREVIATION 23194530 A 667 670 CLO ABBREVIATION 23194530 A 675 680 DICLO ABBREVIATION 23194530 A 698 701 CAP ABBREVIATION 23194530 A 90 100 penicillin FAMILY 23194530 T 74 84 penicillin FAMILY 23194530 T 95 105 amphenicol FAMILY 23194536 A 1057 1071 ginsenoside F1 TRIVIAL 23194536 A 1076 1092 protopanaxatriol TRIVIAL 23194536 A 1143 1155 ginsenosides FAMILY 23194536 A 223 237 Ginsenoside Re TRIVIAL 23194536 A 33 47 ginsenoside Re TRIVIAL 23194536 A 553 567 ginsenoside Re TRIVIAL 23194536 A 581 596 ginsenoside Rg1 TRIVIAL 23194536 A 610 625 ginsenoside Rg2 TRIVIAL 23194536 A 639 662 ginsenosides Rh1 and F1 MULTIPLE 23194536 A 676 692 protopanaxatriol TRIVIAL 23194536 A 710 717 digoxin TRIVIAL 23194536 A 749 761 ginsenosides FAMILY 23194536 A 785 808 ginsenosides Re and Rg1 MULTIPLE 23194536 A 838 862 ginsenosides Rg2 and Rh1 MULTIPLE 23194536 A 894 905 ginsenoside FAMILY 23194536 A 976 991 ginsenoside Rg1 TRIVIAL 23194536 T 24 38 ginsenoside Re TRIVIAL 23194538 A 716 750 1, 3, 6, 6'-tetra-feruloyl sucrose SYSTEMATIC 23194538 A 776 801 phenlypropanoid glycoside FAMILY 23194538 A 817 862 3, 6-di-p-coumaroyl-1, 6'-di-feruloyl sucrose SYSTEMATIC 23194538 A 864 907 1, 6, 6'-tri-feruloyl-3-p-coumaroyl sucrose SYSTEMATIC 23194538 A 909 933 N-trans-feruloyltyramine TRIVIAL 23194538 A 938 986 quercetin-3-O-[β-D-xyloxyl-(1→2)-α-L-rhamnoside] SYSTEMATIC 23194545 A 104 116 anthocyanins FAMILY 23194545 A 122 147 3-sophoroside-5-glucoside SYSTEMATIC 23194545 A 165 173 cyanidin TRIVIAL 23194545 A 178 186 peonidin TRIVIAL 23194545 A 202 223 p-hydroxybenzoic acid SYSTEMATIC 23194545 A 225 237 ferulic acid TRIVIAL 23194545 A 242 254 caffeic acid TRIVIAL 23194545 A 265 276 anthocyanin FAMILY 23194545 A 278 305 delphinidin-3,5-diglucoside SYSTEMATIC 23194545 A 375 387 anthocyanins FAMILY 23194545 A 642 654 anthocyanins FAMILY 23194545 A 735 747 anthocyanins FAMILY 23194545 A 9 21 anthocyanins FAMILY 23194545 T 68 80 anthocyanins FAMILY 23194547 A 1125 1130 sugar FAMILY 23194547 A 202 207 sugar FAMILY 23194547 A 299 304 sugar FAMILY 23194547 A 38 45 glucose TRIVIAL 23194547 A 47 55 fructose TRIVIAL 23194547 A 550 556 sugars FAMILY 23194547 A 57 64 sucrose TRIVIAL 23194547 A 69 76 maltose TRIVIAL 23194547 A 736 741 sugar FAMILY 23194547 A 935 942 glucose TRIVIAL 23194547 A 944 952 fructose TRIVIAL 23194547 A 954 961 sucrose TRIVIAL 23194547 A 966 973 maltose TRIVIAL 23194547 T 18 24 sugars FAMILY 23194554 A 58 69 lactic acid TRIVIAL 23194554 A 875 891 tetrasaccharides FAMILY 23194556 A 203 205 Cu FORMULA 23194556 A 207 209 Ni FORMULA 23194556 A 211 213 Zn FORMULA 23194556 A 215 217 Cr FORMULA 23194556 A 219 221 Fe FORMULA 23194556 A 223 225 Mn FORMULA 23194556 A 227 229 Co FORMULA 23194556 A 234 236 Pb FORMULA 23194556 A 706 708 Mn FORMULA 23194558 A 347 351 Urea TRIVIAL 23194558 A 69 73 Urea TRIVIAL 23194561 A 466 467 C FORMULA 23194561 A 469 470 N FORMULA 23194561 A 472 473 O FORMULA 23194561 A 479 480 S FORMULA 23194562 A 141 149 melamine TRIVIAL 23194562 A 286 294 melamine TRIVIAL 23194562 T 75 83 melamine TRIVIAL 23194565 A 0 23 Pyrrolizidine alkaloids FAMILY 23194565 A 524 535 retronecine TRIVIAL 23194565 A 540 549 otonecine TRIVIAL 23194565 T 13 36 pyrrolizidine alkaloids FAMILY 23194567 A 214 224 oestrogens FAMILY 23194567 A 226 235 androgens FAMILY 23194567 A 237 249 progestagens FAMILY 23194567 A 584 597 17β-estradiol SYSTEMATIC 23194567 A 624 636 testosterone TRIVIAL 23194567 A 664 676 progesterone TRIVIAL 23194567 A 708 722 hydrocortisone TRIVIAL 23194824 A 0 9 Flavonoid FAMILY 23194824 A 1111 1129 prostaglandin E(2) TRIVIAL 23194824 A 1131 1137 PGE(2) ABBREVIATION 23194824 A 1169 1176 chrysin TRIVIAL 23194824 A 1254 1260 Fe-NTA FORMULA 23194824 A 1334 1345 glutathione TRIVIAL 23194824 A 1355 1358 GSH ABBREVIATION 23194824 A 1464 1468 urea TRIVIAL 23194824 A 1469 1477 nitrogen SYSTEMATIC 23194824 A 1485 1495 creatinine TRIVIAL 23194824 A 1500 1507 lactate FAMILY 23194824 A 1568 1575 chrysin TRIVIAL 23194824 A 1605 1611 Fe-NTA FORMULA 23194824 A 1709 1715 Fe-NTA FORMULA 23194824 A 1755 1762 chrysin TRIVIAL 23194824 A 1835 1838 DEN ABBREVIATION 23194824 A 1853 1859 Fe-NTA FORMULA 23194824 A 186 193 chrysin TRIVIAL 23194824 A 208 217 flavonoid FAMILY 23194824 A 315 336 N-nitrosodiethylamine SYSTEMATIC 23194824 A 338 341 DEN ABBREVIATION 23194824 A 37 49 polyphenolic FAMILY 23194824 A 415 439 ferric nitrilotriacetate SYSTEMATIC 23194824 A 441 447 Fe-NTA FORMULA 23194824 A 454 456 Fe FORMULA 23194824 A 537 544 chrysin TRIVIAL 23194824 A 554 560 Fe-NTA FORMULA 23194824 A 760 767 chrysin TRIVIAL 23194824 A 845 854 ornithine TRIVIAL 23194824 A 938 950 nitric oxide SYSTEMATIC 23194824 T 0 7 Chrysin TRIVIAL 23194826 A 0 8 Selenite TRIVIAL 23194826 A 134 142 selenite TRIVIAL 23194826 A 238 246 selenite TRIVIAL 23194826 A 453 468 sodium selenite SYSTEMATIC 23194826 A 769 788 lanthanum hydroxide SYSTEMATIC 23194826 A 811 819 selenite TRIVIAL 23194826 A 949 957 selenite TRIVIAL 23194826 T 60 68 selenite TRIVIAL 23194827 A 0 13 Cucurbitacins FAMILY 23194827 A 1002 1016 cucurbitacin E TRIVIAL 23194827 A 1043 1046 UDP ABBREVIATION 23194827 A 1095 1119 cucurbitacins I, D and E MULTIPLE 23194827 A 1223 1230 sulfate SYSTEMATIC 23194827 A 1235 1246 glucuronide TRIVIAL 23194827 A 173 194 cucurbitacins I, D, E MULTIPLE 23194827 A 293 314 Cucurbitacins I and D MULTIPLE 23194827 A 380 394 cytochalasin D TRIVIAL 23194827 A 525 546 cucurbitacins I and D MULTIPLE 23194827 A 558 572 cucurbitacin E TRIVIAL 23194827 A 609 630 cucurbitacins I and E MULTIPLE 23194827 A 679 693 cucurbitacin D TRIVIAL 23194827 A 695 698 MTT ABBREVIATION 23194827 A 707 721 Cucurbitacin E TRIVIAL 23194827 A 785 799 cucurbitacin I TRIVIAL 23194827 A 876 889 cucurbitacins FAMILY 23194827 T 4 28 cucurbitacins E, D and I MULTIPLE 23195331 A 205 208 ATP ABBREVIATION 23197043 A 1597 1601 cAMP ABBREVIATION 23197374 A 1097 1099 Se FORMULA 23197374 A 1195 1197 Se FORMULA 23197374 A 1277 1282 sugar FAMILY 23197374 A 1306 1317 amino acids FAMILY 23197374 A 421 436 sodium selenate SYSTEMATIC 23197374 A 764 766 Se FORMULA 23197374 A 918 920 Se FORMULA 23197374 T 0 8 Selenium SYSTEMATIC 23197374 T 10 12 Se FORMULA 23197648 A 0 11 Bisphenol A TRIVIAL 23197648 A 1094 1097 BPA ABBREVIATION 23197648 A 1256 1264 phenolic FAMILY 23197648 A 1269 1280 bisphenolic FAMILY 23197648 A 13 16 BPA ABBREVIATION 23197648 A 1328 1343 R-C(CH(3))(2)-R FAMILY 23197648 A 1345 1369 R-C(CH(3))(CH(2)CH(3))-R FAMILY 23197648 A 1419 1425 carbon SYSTEMATIC 23197648 A 1536 1539 BPA ABBREVIATION 23197648 A 1563 1566 BPA ABBREVIATION 23197648 A 259 262 BPA ABBREVIATION 23197648 A 309 315 Ca(2+) FORMULA 23197648 A 395 398 BPA ABBREVIATION 23197648 A 437 443 Ba(2+) FORMULA 23197648 A 446 452 Ca(2+) FORMULA 23197648 A 498 504 Ca(2+) FORMULA 23197648 A 629 635 Ca(2+) FORMULA 23197648 A 738 741 BPA ABBREVIATION 23197648 A 841 847 Ca(2+) FORMULA 23197648 A 871 874 BPA ABBREVIATION 23197648 T 0 11 Bisphenol A TRIVIAL 23197648 T 39 45 Ca(2+) FORMULA 23198917 A 13 20 bismuth SYSTEMATIC 23199882 A 416 425 Nobiletin TRIVIAL 23199882 A 452 471 polymethoxyflavones FAMILY 23199882 A 473 477 PMFs FAMILY 23199882 T 0 19 Polymethoxyflavones FAMILY 23199882 T 66 75 nobiletin TRIVIAL 23199990 A 159 165 nickel SYSTEMATIC 23199990 A 281 283 Pb FORMULA 23199990 A 288 290 Ni FORMULA 23199990 A 533 535 Pb FORMULA 23199990 A 540 542 Ni FORMULA 23199990 A 55 69 aminothioazole SYSTEMATIC 23199990 A 745 747 Pb FORMULA 23199990 A 769 771 Ni FORMULA 23199990 A 81 92 sulfonamide SYSTEMATIC 23199990 A 862 864 Pb FORMULA 23199990 A 892 894 Pb FORMULA 23199990 T 90 104 aminothioazole SYSTEMATIC 23199991 A 28 38 sitosterol TRIVIAL 23199991 A 321 336 triacylglycerol FAMILY 23199991 A 363 368 ester FAMILY 23199991 A 425 435 sitosterol TRIVIAL 23199991 A 496 504 triolein TRIVIAL 23199991 A 65 73 triolein TRIVIAL 23199991 A 658 666 TG ester FAMILY 23199991 A 730 740 sitosterol TRIVIAL 23199991 A 756 762 sterol FAMILY 23199991 A 766 776 steradiene FAMILY 23199991 A 863 873 sitosterol TRIVIAL 23199991 T 0 10 Sitosterol TRIVIAL 23199994 A 116 127 cholesterol TRIVIAL 23200002 A 1291 1301 fatty acid FAMILY 23200002 A 197 207 fatty acid FAMILY 23200002 A 994 1004 fatty acid FAMILY 23200002 T 39 49 fatty acid FAMILY 23200243 A 315 330 Alexa Fluor 488 TRIVIAL 23200243 A 457 466 adenosine TRIVIAL 23200243 A 498 501 XAC ABBREVIATION 23200243 A 81 90 adenosine TRIVIAL 23200243 T 24 33 adenosine TRIVIAL 23200245 A 1036 1043 azepine SYSTEMATIC 23200245 A 1053 1061 nitrogen SYSTEMATIC 23200245 A 1065 1076 galantamine TRIVIAL 23200245 A 1112 1114 CO FORMULA 23200245 A 1118 1121 Leu FORMULA 23200245 A 1217 1228 galantamine TRIVIAL 23200245 A 1327 1330 Asp FORMULA 23200245 A 1333 1336 Gly FORMULA 23200245 A 167 178 galantamine TRIVIAL 23200245 A 27 38 galantamine TRIVIAL 23200245 A 279 290 Galantamine TRIVIAL 23200245 A 476 487 galantamine TRIVIAL 23200245 A 550 553 Lys FORMULA 23200245 A 556 559 Ala FORMULA 23200245 A 571 572 C FORMULA 23200245 A 590 593 Ile FORMULA 23200245 A 596 599 Val ABBREVIATION 23200245 A 731 734 Asp FORMULA 23200245 A 737 740 Gly FORMULA 23200245 A 822 833 galantamine TRIVIAL 23200245 A 919 922 Phe FORMULA 23200245 A 939 942 Phe FORMULA 23200245 A 974 982 hydrogen SYSTEMATIC 23200245 T 42 53 galantamine TRIVIAL 23200734 A 1013 1020 steroid FAMILY 23200734 A 1163 1177 trimethylsilyl SYSTEMATIC 23200734 A 1324 1378 2,17α-dimethyl-16ξ,17β-dihydroxy-5α-androst-1-en-3-one SYSTEMATIC 23200734 A 1385 1438 2,17α-dimethyl-3α,16ξ,17β-trihydroxy-5α-androst-1-ene SYSTEMATIC 23200734 A 1500 1530 16-hydroxylated steroids O-TMS FAMILY 23200734 A 1684 1700 methylstenbolone SYSTEMATIC 23200734 A 402 410 steroids FAMILY 23200734 A 468 480 testosterone TRIVIAL 23200734 A 600 607 steroid FAMILY 23200734 A 617 633 methylstenbolone SYSTEMATIC 23200734 A 635 683 2,17α-dimethyl-17β-hydroxy-5α-androst-1-en-3-one SYSTEMATIC 23200734 A 742 750 steroids FAMILY 23200734 T 22 29 steroid FAMILY 23200734 T 30 46 methylstenbolone SYSTEMATIC 23200736 A 1122 1133 tigecycline TRIVIAL 23200736 A 115 126 Tigecycline TRIVIAL 23200736 A 1164 1175 tigecycline TRIVIAL 23200736 A 128 131 Tig ABBREVIATION 23200736 A 136 149 glycylcycline FAMILY 23200736 A 178 189 Minocycline TRIVIAL 23200736 A 396 407 tigecycline TRIVIAL 23200736 A 508 519 tigecycline TRIVIAL 23200736 A 692 704 nitric oxide SYSTEMATIC 23200736 A 706 708 NO FORMULA 23200736 A 757 768 tigecycline TRIVIAL 23200736 T 0 11 Tigecycline TRIVIAL 23200945 A 1153 1157 zinc SYSTEMATIC 23200945 A 1218 1230 acetaldehyde SYSTEMATIC 23200945 A 124 137 allyl alcohol SYSTEMATIC 23200945 A 1260 1267 ethanol SYSTEMATIC 23200945 A 1514 1522 dextrose TRIVIAL 23200945 A 1529 1538 antimycin FAMILY 23200945 A 160 167 alcohol FAMILY 23200945 A 1833 1846 allyl alcohol SYSTEMATIC 23200945 A 200 208 acrolein TRIVIAL 23200945 A 337 349 acetaldehyde SYSTEMATIC 23200945 A 363 367 NADH ABBREVIATION 23200945 A 368 374 NAD(+) ABBREVIATION 23200945 A 421 434 allyl alcohol SYSTEMATIC 23200945 A 852 865 pyrophosphate SYSTEMATIC 23200945 A 97 104 glucose TRIVIAL 23200945 T 13 20 alcohol FAMILY 23200945 T 84 97 allyl alcohol SYSTEMATIC 23201310 A 1501 1514 carbamazepine TRIVIAL 23201310 A 409 422 carbamazepine TRIVIAL 23201310 A 554 567 carbamazepine TRIVIAL 23201310 T 112 125 carbamazepine TRIVIAL 23201447 A 1183 1186 OTA ABBREVIATION 23201447 A 1286 1289 OTA ABBREVIATION 23201447 A 1410 1413 ZEA ABBREVIATION 23201447 A 1418 1421 DON ABBREVIATION 23201447 A 1450 1453 DON ABBREVIATION 23201447 A 1496 1499 DON ABBREVIATION 23201447 A 1603 1606 DON ABBREVIATION 23201447 A 22 36 deoxynivalenol TRIVIAL 23201447 A 38 41 DON ABBREVIATION 23201447 A 4 14 aflatoxins FAMILY 23201447 A 44 56 ochratoxin A TRIVIAL 23201447 A 58 61 OTA ABBREVIATION 23201447 A 67 78 zearalenone TRIVIAL 23201447 A 80 83 ZEA ABBREVIATION 23201447 A 889 892 DON ABBREVIATION 23201447 A 984 987 DON ABBREVIATION 23201447 T 17 27 aflatoxins FAMILY 23201447 T 29 43 deoxynivalenol TRIVIAL 23201447 T 45 57 ochratoxin A TRIVIAL 23201447 T 62 73 zearalenone TRIVIAL 23202249 A 0 13 Paclobutrazol TRIVIAL 23202249 A 15 18 PBZ ABBREVIATION 23202249 A 199 213 organochlorine FAMILY 23202249 A 218 234 organophosphorus FAMILY 23202249 A 25 33 triazole FAMILY 23202249 A 365 368 PBZ ABBREVIATION 23202249 A 443 446 PBZ ABBREVIATION 23202249 A 535 547 triglyceride FAMILY 23202249 A 555 566 cholesterol TRIVIAL 23202249 A 571 586 free fatty acid FAMILY 23202249 A 779 787 androgen FAMILY 23202249 A 798 808 acetyl-CoA SYSTEMATIC 23202249 A 824 834 fatty acid FAMILY 23202249 A 846 856 fatty acid FAMILY 23202249 A 903 915 stearoyl-CoA TRIVIAL 23202249 A 948 951 PBZ ABBREVIATION 23202249 A 991 999 triazole FAMILY 23202249 T 20 33 paclobutrazol TRIVIAL 23202888 A 1046 1057 rhodamine B TRIVIAL 23202888 A 1062 1075 methyl orange TRIVIAL 23202888 A 1081 1088 phenols FAMILY 23202888 A 1090 1103 4-nitrophenol SYSTEMATIC 23202888 A 1133 1139 TiO(2) FORMULA 23202888 A 1159 1165 SnS(2) FORMULA 23202888 A 1283 1289 SnS(2) FORMULA 23202888 A 1290 1296 TiO(2) FORMULA 23202888 A 1332 1338 SnS(2) FORMULA 23202888 A 1339 1350 TiO(2) (AR) MULTIPLE 23202888 A 1510 1516 SnS(2) FORMULA 23202888 A 1517 1527 TiO(2) (A) FORMULA 23202888 A 1559 1570 TiO(2) (AR) MULTIPLE 23202888 A 1661 1667 SnS(2) FORMULA 23202888 A 1669 1679 TiO(2) (A) FORMULA 23202888 A 1684 1694 TiO(2) (R) FORMULA 23202888 A 169 175 SnS(2) FORMULA 23202888 A 1712 1718 SnS(2) FORMULA 23202888 A 1719 1730 TiO(2) (AR) MULTIPLE 23202888 A 316 322 TiO(2) FORMULA 23202888 A 373 379 SnS(2) FORMULA 23202888 A 416 422 SnS(2) FORMULA 23202888 A 504 510 TiO(2) FORMULA 23202888 A 542 549 anatase TRIVIAL 23202888 A 563 570 anatase TRIVIAL 23202888 A 571 577 rutile TRIVIAL 23202888 A 595 601 TiO(2) FORMULA 23202888 A 663 669 SnS(2) FORMULA 23202888 A 68 74 TiO(2) FORMULA 23202888 A 685 700 TiO(2) (A or R) MULTIPLE 23202888 A 863 869 SnS(2) FORMULA 23202888 A 870 876 TiO(2) FORMULA 23202888 T 45 49 SnS2 FORMULA 23202888 T 78 82 TiO2 FORMULA 23204110 A 10 13 ATP ABBREVIATION 23204110 A 1094 1105 Na-arsenite SYSTEMATIC 23204110 A 1178 1185 arsenic SYSTEMATIC 23204110 A 1217 1220 ATP ABBREVIATION 23204110 A 1230 1236 Ca(2+) FORMULA 23204110 A 1336 1343 arsenic SYSTEMATIC 23204110 A 248 255 arsenic SYSTEMATIC 23204110 A 440 447 arsenic SYSTEMATIC 23204110 A 452 463 Na-arsenite SYSTEMATIC 23204110 A 524 527 ATP ABBREVIATION 23204110 A 537 543 Ca(2+) FORMULA 23204110 A 577 584 arsenic SYSTEMATIC 23204110 A 644 647 ATP ABBREVIATION 23204110 A 657 663 Ca(2+) FORMULA 23204110 A 696 703 arsenic SYSTEMATIC 23204110 A 716 719 ATP ABBREVIATION 23204110 A 729 735 Ca(2+) FORMULA 23204110 A 763 769 Ca(2+) FORMULA 23204110 A 841 847 Ca(2+) FORMULA 23204110 A 929 936 arsenic SYSTEMATIC 23204110 A 940 943 ATP ABBREVIATION 23204110 A 953 959 Ca(2+) FORMULA 23204110 T 8 15 arsenic SYSTEMATIC 23205533 A 1032 1052 mono-glucuronic acid TRIVIAL 23205533 A 1223 1234 glucuronide TRIVIAL 23205533 A 1334 1343 GA (15:1) ABBREVIATION 23205533 A 284 292 hydrogen SYSTEMATIC 23205533 A 293 302 deuterium SYSTEMATIC 23205533 A 304 305 H FORMULA 23205533 A 306 307 D FORMULA 23205533 A 35 49 ginkgolic acid TRIVIAL 23205533 A 834 887 2-hydroxy-6-(pentadec-8-enyl-10-hydroxy) benzoic acid SYSTEMATIC 23205533 A 897 962 2-hydroxy-6-(pentadec-8-enyl-11-hydroxy-13-carbonyl) benzoic acid SYSTEMATIC 23205533 T 18 39 ginkgolic acid (15:1) TRIVIAL 23205561 A 270 277 silicon SYSTEMATIC 23205561 A 749 752 ZnO FORMULA 23205610 A 132 140 sulfinyl SYSTEMATIC 23205610 A 146 153 sulfone SYSTEMATIC 23205610 A 40 49 modafinil TRIVIAL 23205610 T 48 57 histamine TRIVIAL 23205707 A 842 852 amino acid FAMILY 23206862 A 169 175 oxygen SYSTEMATIC 23206862 T 26 39 benzimidazole SYSTEMATIC 23206991 A 0 12 Testosterone TRIVIAL 23206991 T 0 12 Testosterone TRIVIAL 23207249 A 1017 1025 diazepam TRIVIAL 23207249 A 1120 1128 diazepam TRIVIAL 23207249 A 1155 1163 diazepam TRIVIAL 23207249 A 1488 1496 diazepam TRIVIAL 23207249 A 1605 1620 benzodiazepines FAMILY 23207249 A 323 337 benzodiazepine FAMILY 23207249 A 719 733 benzodiazepine FAMILY 23207249 A 739 747 diazepam TRIVIAL 23207249 A 943 951 diazepam TRIVIAL 23207249 T 141 149 diazepam TRIVIAL 23207249 T 87 101 benzodiazepine FAMILY 23207250 A 1259 1266 benzene SYSTEMATIC 23207250 A 146 162 phenylpropanoids FAMILY 23207250 A 183 197 5-fluorouracil SYSTEMATIC 23207250 A 289 305 phenylpropanoids FAMILY 23207250 A 344 351 eugenol TRIVIAL 23207250 A 352 359 ferulic TRIVIAL 23207250 A 360 368 cinnamic TRIVIAL 23207250 A 369 376 caffeic FAMILY 23207250 A 377 388 chlorogenic FAMILY 23207250 A 389 399 p-coumaric TRIVIAL 23207250 A 400 421 3,4-dimethoxycinnamic TRIVIAL 23207250 A 422 452 2,4,5-trimethoxycinnamic acids FAMILY 23207250 A 454 461 Eugenol TRIVIAL 23207250 A 463 488 ferulic and caffeic acids MULTIPLE 23207250 A 647 654 eugenol TRIVIAL 23207250 A 659 673 5-fluorouracil SYSTEMATIC 23207250 A 928 944 phenylpropanoids FAMILY 23207250 T 15 31 phenylpropanoids FAMILY 23207250 T 37 51 5-fluorouracil SYSTEMATIC 23207251 A 237 272 23-methyl-6-O-desmethylauricepyrone SYSTEMATIC 23207251 A 278 287 quercetin TRIVIAL 23207251 A 296 315 3-O-methylquercetin SYSTEMATIC 23207251 A 383 390 ethanol SYSTEMATIC 23207251 A 529 538 flavonols FAMILY 23207251 A 686 695 flavonols FAMILY 23207322 A 115 121 silica TRIVIAL 23207322 A 149 172 poly (methacrylic acid) FAMILY 23207322 A 174 178 PMAA ABBREVIATION 23207322 A 352 377 Doxorubicin hydrochloride SYSTEMATIC 23207322 A 379 382 DOX ABBREVIATION 23207322 A 498 501 DOX ABBREVIATION 23207322 A 62 67 Fe3O4 FORMULA 23207322 T 66 72 silica TRIVIAL 23208951 A 115 118 PVA ABBREVIATION 23208951 A 1154 1157 PVA ABBREVIATION 23208951 A 1301 1304 PVA ABBREVIATION 23208951 A 1369 1372 PVA ABBREVIATION 23208951 A 243 246 PVA ABBREVIATION 23208951 A 485 488 PVA ABBREVIATION 23208951 A 670 673 PVA ABBREVIATION 23208951 A 703 708 thiol FAMILY 23208951 A 761 764 PVA ABBREVIATION 23208951 A 820 823 PVA ABBREVIATION 23208951 A 94 113 poly(vinyl alcohol) SYSTEMATIC 23208951 T 28 31 PVA ABBREVIATION 23208978 A 107 116 aluminium SYSTEMATIC 23208978 A 139 154 phosphoric acid SYSTEMATIC 23208978 A 197 212 phosphoric acid SYSTEMATIC 23208978 A 316 323 alumina TRIVIAL 23208978 T 35 42 Alumina TRIVIAL 23208978 T 74 78 TiO2 FORMULA 23209193 A 1139 1149 antipyrine TRIVIAL 23209193 A 1151 1159 caffeine TRIVIAL 23209193 A 1161 1170 epiroprim TRIVIAL 23209193 A 1172 1183 propafenone TRIVIAL 23209193 A 1185 1197 theophylline TRIVIAL 23209193 A 1203 1212 verapamil TRIVIAL 23209194 A 1024 1033 midazolam TRIVIAL 23209194 A 1078 1090 testosterone TRIVIAL 23209194 A 1320 1329 midazolam TRIVIAL 23209194 A 445 454 midazolam TRIVIAL 23209194 A 555 558 ATP ABBREVIATION 23209282 A 245 255 methionine TRIVIAL 23209282 A 256 262 valine TRIVIAL 23209282 A 339 347 hydrogen SYSTEMATIC 23209282 A 348 357 deuterium SYSTEMATIC 23209282 A 396 404 hydroxyl SYSTEMATIC 23210621 A 1384 1387 PVA ABBREVIATION 23210621 A 309 312 PVA ABBREVIATION 23210621 A 31 50 poly(vinyl alcohol) SYSTEMATIC 23210621 A 467 470 PVA ABBREVIATION 23210621 A 52 55 PVA ABBREVIATION 23210621 T 85 104 poly(vinyl alcohol) SYSTEMATIC 23210706 A 1006 1009 MnO FORMULA 23210706 A 112 154 poly(ethylene glycol vinyl glycidyl ether) FAMILY 23210706 A 1201 1228 fluoresceine isothiocyanate SYSTEMATIC 23210706 A 1230 1234 FITC ABBREVIATION 23210706 A 16 19 PEG ABBREVIATION 23210706 A 21 29 catechol TRIVIAL 23210706 A 30 51 poly(ethylene glycol) SYSTEMATIC 23210706 A 354 362 catechol TRIVIAL 23210706 A 389 400 metal oxide FAMILY 23210706 A 445 448 PEG ABBREVIATION 23210706 A 492 501 acetonide SYSTEMATIC 23210706 A 512 520 catechol TRIVIAL 23210706 A 531 571 2,2-dimethyl-1,3-benzodioxole-5-propanol SYSTEMATIC 23210706 A 576 578 OH FORMULA 23210706 A 614 616 OH FORMULA 23210706 A 657 671 ethylene oxide SYSTEMATIC 23210706 A 721 729 epoxides FAMILY 23210706 A 730 756 N,N-diallyl glycidyl amine SYSTEMATIC 23210706 A 758 762 DAGA ABBREVIATION 23210706 A 76 79 PEG ABBREVIATION 23210706 A 775 788 primary amino FAMILY 23210706 A 80 83 PGA ABBREVIATION 23210706 A 800 836 ethylene glycol vinyl glycidyl ether SYSTEMATIC 23210706 A 838 842 EVGE ABBREVIATION 23210706 A 84 89 PEVGE ABBREVIATION 23210706 A 91 111 poly(glycidyl amine) FAMILY 23210706 A 911 914 PEG ABBREVIATION 23210706 A 922 925 PEG ABBREVIATION 23210706 A 926 929 PGA ABBREVIATION 23210706 A 930 935 PEVGE ABBREVIATION 23210706 T 0 8 Catechol TRIVIAL 23210706 T 107 118 metal oxide FAMILY 23210706 T 19 29 polyethers FAMILY 23210776 A 1269 1285 aryl hydrocarbon FAMILY 23210776 A 206 217 polyphenols FAMILY 23210776 A 224 235 resveratrol TRIVIAL 23210776 A 237 246 silibinin TRIVIAL 23210776 A 258 269 polyphenols FAMILY 23210776 A 271 281 flavonoids FAMILY 23210776 A 283 295 anthocyanins FAMILY 23210776 T 93 104 polyphenols FAMILY 23210778 A 0 8 Nitrogen SYSTEMATIC 23210778 A 259 269 colchicine TRIVIAL 23210778 A 312 322 Colchicine TRIVIAL 23210778 A 501 511 colchicine TRIVIAL 23210778 A 547 557 colchicine TRIVIAL 23210778 A 612 622 colchicine TRIVIAL 23210778 A 808 818 colchicine TRIVIAL 23210778 A 846 856 colchicine TRIVIAL 23210778 A 890 900 colchicine TRIVIAL 23210778 T 0 10 Colchicine TRIVIAL 23210781 A 1022 1028 thymol TRIVIAL 23210781 A 1030 1040 eurabienol TRIVIAL 23210781 A 1420 1429 reserpine TRIVIAL 23210781 A 889 897 phenolic FAMILY 23210781 A 934 944 terpenoids FAMILY 23210783 A 330 342 Galanthamine TRIVIAL 23210783 A 628 640 Galanthamine TRIVIAL 23210787 A 1021 1029 morphine TRIVIAL 23210787 A 346 355 steroidal FAMILY 23210787 A 646 654 morphine TRIVIAL 23210787 A 910 918 morphine TRIVIAL 23210787 T 23 34 bacopasides FAMILY 23210849 A 226 237 cantharidin TRIVIAL 23210849 A 298 312 norcantharidin TRIVIAL 23210849 A 317 332 norcantharimide TRIVIAL 23210849 A 635 646 cantharidin TRIVIAL 23210849 A 698 709 cantharidin TRIVIAL 23210849 A 94 105 cantharidin TRIVIAL 23210849 T 0 11 Cantharidin TRIVIAL 23211008 A 1014 1019 AuTTF FORMULA 23211008 A 687 694 Zn(bix) FORMULA 23211008 A 784 789 AuTTF FORMULA 23211008 A 794 800 AgTCNQ FORMULA 23211008 A 914 920 AgTCNQ FORMULA 23211362 A 0 8 Nitroxyl SYSTEMATIC 23211362 A 10 13 HNO FORMULA 23211362 A 1085 1088 GSH ABBREVIATION 23211362 A 1094 1106 nitric oxide SYSTEMATIC 23211362 A 1117 1182 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide SYSTEMATIC 23211362 A 114 141 1-Nitrosocyclohexyl acetate SYSTEMATIC 23211362 A 1245 1249 K(+) FORMULA 23211362 A 1315 1318 NCA ABBREVIATION 23211362 A 1351 1354 ATP ABBREVIATION 23211362 A 1365 1369 K(+) FORMULA 23211362 A 1400 1406 Ca(2+) FORMULA 23211362 A 1417 1421 K(+) FORMULA 23211362 A 143 146 NCA ABBREVIATION 23211362 A 1461 1464 NCA ABBREVIATION 23211362 A 1466 1469 NCA ABBREVIATION 23211362 A 155 158 HNO FORMULA 23211362 A 1554 1570 thromboxane A(2) TRIVIAL 23211362 A 1579 1632 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F(2)(α) SYSTEMATIC 23211362 A 1638 1642 cGMP ABBREVIATION 23211362 A 1673 1676 NCA ABBREVIATION 23211362 A 193 196 HNO FORMULA 23211362 A 204 217 Angeli's salt TRIVIAL 23211362 A 222 244 isopropylamine NONOate SYSTEMATIC 23211362 A 269 272 HNO FORMULA 23211362 A 358 361 NCA ABBREVIATION 23211362 A 436 439 NCA ABBREVIATION 23211362 A 595 598 HNO FORMULA 23211362 A 624 627 NCA ABBREVIATION 23211362 A 663 666 HNO FORMULA 23211362 A 677 688 glutathione TRIVIAL 23211362 A 690 693 GSH ABBREVIATION 23211362 A 721 729 guanylyl TRIVIAL 23211362 A 745 753 adenylyl TRIVIAL 23211362 A 821 825 K(+) FORMULA 23211362 A 836 839 NCA ABBREVIATION 23211362 T 36 63 1-nitrosocyclohexyl acetate SYSTEMATIC 23211362 T 79 87 nitroxyl SYSTEMATIC 23211426 A 1027 1038 cholesterol TRIVIAL 23211426 A 12 23 cholesterol TRIVIAL 23211426 A 134 145 Cholesterol TRIVIAL 23211426 A 174 181 steroid FAMILY 23211426 A 247 258 cholesterol TRIVIAL 23211426 A 338 349 cholesterol TRIVIAL 23211426 A 482 492 oxysterols FAMILY 23211426 A 518 529 cholesterol TRIVIAL 23211426 A 588 599 cholesterol TRIVIAL 23211426 A 652 663 cholesterol TRIVIAL 23211426 T 48 59 cholesterol TRIVIAL 23211442 A 1002 1010 acarbose TRIVIAL 23211442 A 390 401 polyphenols FAMILY 23211442 A 435 443 caffeine TRIVIAL 23211442 A 445 448 Caf ABBREVIATION 23211442 A 466 477 amino acids FAMILY 23211442 A 601 608 ethanol SYSTEMATIC 23211442 A 630 643 ethyl acetate SYSTEMATIC 23211523 A 1118 1122 GnRH ABBREVIATION 23211523 A 1721 1725 GnRH ABBREVIATION 23211523 A 1876 1880 GnRH ABBREVIATION 23211523 A 265 269 GnRH ABBREVIATION 23211523 A 376 380 GnRH ABBREVIATION 23211523 A 44 48 GnRH ABBREVIATION 23211523 A 479 480 N FORMULA 23211523 A 618 622 GnRH ABBREVIATION 23211523 A 868 872 GnRH ABBREVIATION 23211523 T 20 24 GnRH ABBREVIATION 23211524 A 171 175 GnRH ABBREVIATION 23211524 T 131 135 GnRH ABBREVIATION 23211937 A 100 113 noradrenaline TRIVIAL 23211937 A 1044 1054 fluoxetine TRIVIAL 23211937 A 1163 1173 reboxetine TRIVIAL 23211937 A 1178 1188 fluoxetine TRIVIAL 23211937 A 1230 1236 l-DOPA ABBREVIATION 23211937 A 1282 1288 l-DOPA ABBREVIATION 23211937 A 346 354 dopamine TRIVIAL 23211937 A 438 444 l-DOPA ABBREVIATION 23211937 A 60 69 serotonin TRIVIAL 23211937 A 759 765 l-DOPA ABBREVIATION 23211937 A 905 911 l-DOPA ABBREVIATION 23211937 A 946 956 reboxetine TRIVIAL 23211937 T 0 6 l-DOPA ABBREVIATION 23211937 T 51 61 reboxetine TRIVIAL 23211937 T 66 76 fluoxetine TRIVIAL 23212108 A 331 335 5-HT SYSTEMATIC 23212108 A 411 423 nitric oxide SYSTEMATIC 23212306 A 0 8 Diazinon TRIVIAL 23212306 A 1102 1106 NMDA ABBREVIATION 23212306 A 1169 1176 calcium SYSTEMATIC 23212306 A 1252 1262 cyclic AMP TRIVIAL 23212306 A 1410 1414 NMDA ABBREVIATION 23212306 A 15 30 organophosphate FAMILY 23212306 A 1654 1662 diazinon TRIVIAL 23212306 A 1795 1799 NMDA ABBREVIATION 23212306 A 200 208 diazinon TRIVIAL 23212306 A 302 322 N-methyl-D-aspartate SYSTEMATIC 23212306 A 324 328 NMDA ABBREVIATION 23212306 A 524 532 diazinon TRIVIAL 23212306 A 852 856 NMDA ABBREVIATION 23212306 A 954 962 Diazinon TRIVIAL 23212306 T 79 87 diazinon TRIVIAL 23212442 A 1009 1015 Cd(2+) FORMULA 23212442 A 1125 1127 Cd FORMULA 23212442 A 250 257 cadmium SYSTEMATIC 23212442 A 259 261 Cd FORMULA 23212442 A 670 672 Cd FORMULA 23212442 A 704 710 Cd(2+) FORMULA 23212442 A 904 910 Cd(2+) FORMULA 23212442 T 87 94 cadmium SYSTEMATIC 23212742 A 1031 1045 24R,25(OH)2 D3 SYSTEMATIC 23212742 A 1066 1077 monohydroxy SYSTEMATIC 23212742 A 1103 1109 25OHD3 SYSTEMATIC 23212742 A 1220 1233 4β,25(OH)2 D3 SYSTEMATIC 23212742 A 1280 1288 rifampin TRIVIAL 23212742 A 1377 1390 1α,25(OH)2 D3 SYSTEMATIC 23212742 A 1440 1454 24R,25(OH)2 D3 SYSTEMATIC 23212742 A 1552 1565 4β,25(OH)2 D3 SYSTEMATIC 23212742 A 158 167 vitamin D FAMILY 23212742 A 1582 1595 1α,25(OH)2 D3 SYSTEMATIC 23212742 A 1630 1641 monohydroxy SYSTEMATIC 23212742 A 1653 1659 25OHD3 SYSTEMATIC 23212742 A 1749 1755 25OHD3 SYSTEMATIC 23212742 A 259 268 vitamin D FAMILY 23212742 A 398 418 25-hydroxyvitamin D3 SYSTEMATIC 23212742 A 420 426 25OHD3 SYSTEMATIC 23212742 A 522 535 phenobarbital TRIVIAL 23212742 A 537 547 hyperforin TRIVIAL 23212742 A 549 562 carbamazepine TRIVIAL 23212742 A 568 576 rifampin TRIVIAL 23212742 A 669 677 rifampin TRIVIAL 23212742 A 762 768 25OHD3 SYSTEMATIC 23212742 A 771 784 4β,25(OH)2 D3 SYSTEMATIC 23212742 A 840 866 6',7'-dihydroxybergamottin SYSTEMATIC 23212742 T 42 62 25-hydroxyvitamin D3 SYSTEMATIC 23212989 A 261 268 uranium SYSTEMATIC 23212989 A 500 507 uranium SYSTEMATIC 23212989 A 754 761 uranium SYSTEMATIC 23212989 T 35 42 uranium SYSTEMATIC 23214434 A 103 106 PEG ABBREVIATION 23214434 A 1173 1176 PEG ABBREVIATION 23214434 A 14 20 carbon SYSTEMATIC 23214434 A 1562 1565 PEG ABBREVIATION 23214434 A 250 253 PEG ABBREVIATION 23214434 A 388 391 PEG ABBREVIATION 23214434 A 578 581 PEG ABBREVIATION 23214434 A 647 650 PEG ABBREVIATION 23214434 A 82 101 polyethylene glycol SYSTEMATIC 23214434 A 831 834 PEG ABBREVIATION 23214434 A 964 967 PEG ABBREVIATION 23214434 T 87 93 carbon SYSTEMATIC 23214511 A 0 10 Fatty acid FAMILY 23214511 A 11 16 amide FAMILY 23214511 A 259 283 N-alkyl-O-arylcarbamates FAMILY 23214511 A 320 329 carbon-11 SYSTEMATIC 23214511 A 336 348 ¹¹C-carbonyl SYSTEMATIC 23214511 A 493 514 [¹¹C]O-arylcarbamates FAMILY 23214511 A 867 877 carbamates FAMILY 23214511 T 34 46 ¹¹C-carbonyl SYSTEMATIC 23214511 T 56 66 carbamates FAMILY 23214511 T 70 80 fatty acid FAMILY 23214511 T 81 86 amide FAMILY 23214931 A 177 195 polyglycerol ester FAMILY 23214931 A 197 200 PGE ABBREVIATION 23214931 A 364 367 PGE ABBREVIATION 23214931 A 547 551 NaCl FORMULA 23214931 A 555 562 CaCl(2) FORMULA 23214931 A 856 859 PGE ABBREVIATION 23214931 T 34 52 polyglycerol ester FAMILY 23214953 A 1308 1311 N–H FORMULA 23214953 A 1320 1323 N–H FORMULA 23214953 A 166 169 15N FORMULA 23214953 T 12 15 15N FORMULA 23214953 T 16 18 1H FORMULA 23215021 A 145 227 poly [(9,9-bis(6'-N,N,N-trimethylammonium)hexyl)-fluorenylene phenylene dibromide] FAMILY 23215021 A 229 232 PFP ABBREVIATION 23215021 A 284 287 PFP ABBREVIATION 23215021 A 339 342 PFP ABBREVIATION 23215021 A 356 359 PFP ABBREVIATION 23215021 A 38 49 fluorescein TRIVIAL 23215021 A 434 437 PFP ABBREVIATION 23215021 A 476 479 PFP ABBREVIATION 23215021 A 51 54 FAM ABBREVIATION 23215021 A 582 585 PFP ABBREVIATION 23215021 A 746 749 PFP ABBREVIATION 23215021 A 866 869 PFP ABBREVIATION 23215021 A 89 103 graphene oxide SYSTEMATIC 23215021 A 941 944 PFP ABBREVIATION 23215021 A 965 968 PFP ABBREVIATION 23215021 T 43 57 graphene oxide SYSTEMATIC 23215035 A 184 185 N FORMULA 23215035 A 189 190 O FORMULA 23215035 A 213 224 phosphonate SYSTEMATIC 23215035 A 249 251 OH FORMULA 23215035 A 256 259 NH₂ FORMULA 23215035 A 365 370 ether SYSTEMATIC 23215035 A 372 377 amide FAMILY 23215035 A 379 383 urea TRIVIAL 23215035 A 389 401 1,4-triazole SYSTEMATIC 23215035 A 510 517 α-azido SYSTEMATIC 23215035 A 57 65 α-carbon SYSTEMATIC 23215035 A 69 81 fosmidomycin TRIVIAL 23215035 T 42 86 3-(acetylhydroxyamino)propyl phosphonic acid SYSTEMATIC 23215035 T 88 96 FR900098 IDENTIFIER 23215155 A 1154 1160 TiO(2) FORMULA 23215155 A 1236 1238 Au FORMULA 23215155 A 369 389 boron-dipyrromethene TRIVIAL 23215155 A 430 439 sulfonate SYSTEMATIC 23215155 A 496 509 dinitrophenyl SYSTEMATIC 23215155 A 745 747 Au FORMULA 23215155 A 771 777 TiO(2) FORMULA 23215155 A 919 925 TiO(2) FORMULA 23215155 T 46 53 titania TRIVIAL 23215439 A 120 131 vinyl ether SYSTEMATIC 23215439 A 132 143 cholesterol TRIVIAL 23215439 A 54 65 cholesteryl TRIVIAL 23215439 A 958 969 cholesterol TRIVIAL 23215439 T 28 39 cholesteryl TRIVIAL 23215584 A 227 264 2,2,6,6-tetramethylpiperidinyl-1-oxyl SYSTEMATIC 23215584 A 266 271 TEMPO ABBREVIATION 23215584 A 902 908 carbon SYSTEMATIC 23218402 A 1029 1040 ceftazidime TRIVIAL 23218402 A 1055 1063 apigenin TRIVIAL 23218402 A 1067 1076 narigenin TRIVIAL 23218402 A 1118 1129 ceftazidime TRIVIAL 23218402 A 113 123 flavonoids FAMILY 23218402 A 1135 1141 5,7-OH SYSTEMATIC 23218402 A 1166 1171 4'-OH SYSTEMATIC 23218402 A 1195 1203 apigenin TRIVIAL 23218402 A 1208 1218 naringenin TRIVIAL 23218402 A 125 133 apigenin TRIVIAL 23218402 A 1300 1311 ceftazidime TRIVIAL 23218402 A 135 144 quercetin TRIVIAL 23218402 A 1368 1379 ceftazidime TRIVIAL 23218402 A 1407 1415 apigenin TRIVIAL 23218402 A 146 156 naringenin TRIVIAL 23218402 A 1493 1504 ceftazidime TRIVIAL 23218402 A 1544 1552 apigenin TRIVIAL 23218402 A 161 172 ceftazidime TRIVIAL 23218402 A 1684 1692 apigenin TRIVIAL 23218402 A 1835 1845 nitrocefin TRIVIAL 23218402 A 1847 1850 NCF ABBREVIATION 23218402 A 1862 1876 crystal violet TRIVIAL 23218402 A 1915 1926 ceftazidime TRIVIAL 23218402 A 1932 1940 apigenin TRIVIAL 23218402 A 2053 2082 o-nitrophenyl-β-D-galactoside SYSTEMATIC 23218402 A 2084 2088 ONPG ABBREVIATION 23218402 A 216 227 ceftazidime TRIVIAL 23218402 A 2172 2183 ceftazidime TRIVIAL 23218402 A 2188 2196 apigenin TRIVIAL 23218402 A 2352 2360 apigenin TRIVIAL 23218402 A 2365 2375 naringenin TRIVIAL 23218402 A 2409 2420 ceftazidime TRIVIAL 23218402 A 2461 2474 cephalosporin FAMILY 23218402 A 2549 2557 apigenin TRIVIAL 23218402 A 2765 2773 Apigenin TRIVIAL 23218402 A 2778 2788 naringenin TRIVIAL 23218402 A 2862 2870 apigenin TRIVIAL 23218402 A 2875 2885 naringenin TRIVIAL 23218402 A 2937 2948 ceftazidime TRIVIAL 23218402 A 2986 3000 cephalosporins FAMILY 23218402 A 646 657 ceftazidime TRIVIAL 23218402 A 659 667 cefepime TRIVIAL 23218402 A 672 680 flomoxef TRIVIAL 23218402 A 744 752 imipenem TRIVIAL 23218402 A 808 819 ceftazidime TRIVIAL 23218402 A 832 840 apigenin TRIVIAL 23218402 A 844 854 naringenin TRIVIAL 23218402 A 940 951 ceftazidime TRIVIAL 23218402 A 957 972 clavulanic acid TRIVIAL 23218402 A 976 985 quercetin TRIVIAL 23218402 T 48 59 ceftazidime TRIVIAL 23218402 T 64 72 apigenin TRIVIAL 23218402 T 93 104 ceftazidime TRIVIAL 23218602 A 11 26 prostaglandin E FAMILY 23218602 A 122 135 prostaglandin FAMILY 23218602 A 136 142 PGH(2) ABBREVIATION 23218602 A 146 152 PGE(2) ABBREVIATION 23218602 A 428 471 sulfonamido-1,2,3-triazole-4,5-dicarboxylic SYSTEMATIC 23218602 A 64 79 prostaglandin E FAMILY 23218602 A 647 726 1-[2-(N-Phenylbenzenesulfonamido)ethyl]-1H-1,2,3-triazole-4,5-dicarboxylic acid SYSTEMATIC 23218602 A 960 972 Triton X-100 TRIVIAL 23218602 T 93 141 sulfonamido-1,2,3-triazole-4,5-dicarboxylic acid SYSTEMATIC 23218715 A 26 47 4-aminothienopyridine SYSTEMATIC 23218715 T 38 60 4-aminothienopyridines FAMILY 23218950 A 1179 1183 dATP ABBREVIATION 23218950 A 1221 1225 dCTP ABBREVIATION 23218950 A 133 164 5'-deoxynucleoside-triphosphate SYSTEMATIC 23218950 A 1372 1382 rifampicin TRIVIAL 23218950 A 1484 1488 dNTP ABBREVIATION 23218950 A 1668 1672 dNTP ABBREVIATION 23218950 A 181 186 dNTPs ABBREVIATION 23218950 A 215 220 dNTPs ABBREVIATION 23218950 A 506 510 dCTP ABBREVIATION 23218950 A 525 547 nucleoside diphosphate FAMILY 23218950 A 612 616 dNTP ABBREVIATION 23218950 A 860 864 dCTP ABBREVIATION 23218950 A 896 900 dGTP ABBREVIATION 23219002 A 0 3 ATP ABBREVIATION 23219002 A 1005 1008 ATP ABBREVIATION 23219002 A 1042 1045 ATP ABBREVIATION 23219002 A 14 18 K(+) FORMULA 23219002 A 20 21 K FORMULA 23219002 A 210 213 ATP ABBREVIATION 23219002 A 215 216 K FORMULA 23219002 A 217 220 ATP ABBREVIATION 23219002 A 22 25 ATP ABBREVIATION 23219002 A 427 430 ATP ABBREVIATION 23219002 A 516 519 ATP ABBREVIATION 23219002 A 624 627 ATP ABBREVIATION 23219002 A 734 737 ATP ABBREVIATION 23219002 A 852 855 ATP ABBREVIATION 23219002 T 38 41 ATP ABBREVIATION 23219002 T 81 90 potassium SYSTEMATIC 23219042 A 1003 1014 methicillin TRIVIAL 23219042 A 1029 1039 vancomycin TRIVIAL 23219042 A 1116 1127 achyrofuran TRIVIAL 23219042 A 1192 1205 2,2'-biphenol SYSTEMATIC 23219042 A 1239 1250 achyrofuran TRIVIAL 23219042 A 1361 1367 MC21-A IDENTIFIER 23219042 A 1391 1402 achyrofuran TRIVIAL 23219042 A 1518 1529 SYTOX Green NO CLASS 23219042 A 182 193 methicillin TRIVIAL 23219042 A 588 603 dichloromethane SYSTEMATIC 23219042 A 865 876 achyrofuran TRIVIAL 23219042 T 0 11 Achyrofuran TRIVIAL 23219042 T 57 68 methicillin TRIVIAL 23219042 T 79 89 vancomycin TRIVIAL 23219337 A 1062 1069 Wogonin TRIVIAL 23219337 A 1304 1311 wogonin TRIVIAL 23219337 A 500 507 wogonin TRIVIAL 23219337 A 649 656 Wogonin TRIVIAL 23219337 A 907 914 Wogonin TRIVIAL 23219337 T 42 49 wogonin TRIVIAL 23219523 A 0 8 Platinum SYSTEMATIC 23219523 A 10 12 Pt FORMULA 23219523 A 1008 1013 PEITC ABBREVIATION 23219523 A 1018 1020 Pt FORMULA 23219523 A 1339 1347 platinum SYSTEMATIC 23219523 A 201 203 Pt FORMULA 23219523 A 243 245 Pt FORMULA 23219523 A 281 292 glutathione TRIVIAL 23219523 A 294 297 GSH ABBREVIATION 23219523 A 442 444 Pt FORMULA 23219523 A 538 541 GSH ABBREVIATION 23219523 A 586 588 Pt FORMULA 23219523 A 671 673 Pt FORMULA 23219523 A 778 806 β-phenylethyl isothiocyanate SYSTEMATIC 23219523 A 808 813 PEITC ABBREVIATION 23219523 A 912 915 GSH ABBREVIATION 23219523 A 963 965 Pt FORMULA 23219523 A 987 989 Pt FORMULA 23219523 T 0 28 β-phenylethyl isothiocyanate SYSTEMATIC 23219523 T 38 46 platinum SYSTEMATIC 23219523 T 63 66 GSH ABBREVIATION 23219524 A 1124 1129 FC131 IDENTIFIER 23219524 A 1163 1168 FC131 IDENTIFIER 23219524 A 1178 1183 MTSEA ABBREVIATION 23219524 A 1238 1243 MTSEA ABBREVIATION 23219524 A 159 167 cysteine TRIVIAL 23219524 A 445 453 cysteine TRIVIAL 23219524 A 538 572 methanethiosulfonate-ethylammonium SYSTEMATIC 23219524 A 574 579 MTSEA ABBREVIATION 23219524 A 646 651 FC131 IDENTIFIER 23219524 A 653 698 cyclo(-D-Tyr(1)-Arg(2)-Arg(3)-Nal(4)-Gly(5)-) FORMULA 23219524 A 735 740 MTSEA ABBREVIATION 23219524 A 790 795 FC131 IDENTIFIER 23219524 A 901 909 cysteine TRIVIAL 23219524 A 989 994 MTSEA ABBREVIATION 23219524 T 24 32 cysteine TRIVIAL 23219701 A 0 20 Alkenylboronic acids FAMILY 23219701 A 392 409 hydrogen peroxide SYSTEMATIC 23219701 A 445 469 2-arylvinylboronic acids FAMILY 23219701 A 488 494 esters FAMILY 23219701 A 685 704 2-arylboronic acids FAMILY 23219701 T 13 33 alkenylboronic acids FAMILY 23219852 A 308 315 anisole TRIVIAL 23219852 A 317 330 cyclohexanone SYSTEMATIC 23219852 A 335 346 1,4-dioxane SYSTEMATIC 23219852 A 536 547 cholesterol TRIVIAL 23219852 A 721 732 1,4-dioxane SYSTEMATIC 23219852 A 733 740 anisole TRIVIAL 23219852 A 741 754 cyclohexanone SYSTEMATIC 23219852 A 905 916 Cholesterol TRIVIAL 23219887 A 11 19 aldehyde SYSTEMATIC 23219887 A 1106 1119 aminoaldehyde SYSTEMATIC 23219887 A 1228 1236 aldehyde SYSTEMATIC 23219887 A 1272 1280 carboxyl SYSTEMATIC 23219887 A 1285 1293 hydroxyl SYSTEMATIC 23219887 A 1315 1323 carbonyl FAMILY 23219887 A 150 165 ω-aminoaldehyde SYSTEMATIC 23219887 A 1564 1567 Asp FORMULA 23219887 A 1575 1578 Phe FORMULA 23219887 A 1793 1796 Met FORMULA 23219887 A 1801 1804 Cys FORMULA 23219887 A 1813 1816 Cys FORMULA 23219887 A 1869 1877 aldehyde SYSTEMATIC 23219887 A 220 229 polyamine FAMILY 23219887 A 231 238 choline FAMILY 23219887 A 243 251 arginine TRIVIAL 23219887 A 319 328 carnitine TRIVIAL 23219887 A 399 415 ω-aminoaldehydes FAMILY 23219887 A 581 594 aminoaldehyde SYSTEMATIC 23219887 A 630 640 amino acid FAMILY 23219887 A 786 794 aldehyde SYSTEMATIC 23219887 A 983 986 Phe FORMULA 23219887 A 994 997 Trp FORMULA 23219887 T 52 60 aldehyde SYSTEMATIC 23220104 A 1096 1100 HPMA ABBREVIATION 23220104 A 1101 1105 ZnPP FORMULA 23220104 A 15 48 N-(2-hydroxypropyl)methacrylamide SYSTEMATIC 23220104 A 244 248 HPMA ABBREVIATION 23220104 A 249 253 ZnPP FORMULA 23220104 A 540 546 oxygen SYSTEMATIC 23220104 A 566 570 HPMA ABBREVIATION 23220104 A 571 575 ZnPP FORMULA 23220104 A 678 682 ZnPP FORMULA 23220104 A 73 92 zinc protoporphyrin SYSTEMATIC 23220104 A 782 786 HPMA ABBREVIATION 23220104 A 787 791 ZnPP FORMULA 23220104 A 884 888 HPMA ABBREVIATION 23220104 A 889 893 ZnPP FORMULA 23220104 A 94 98 HPMA ABBREVIATION 23220104 A 99 103 ZnPP FORMULA 23220104 T 12 31 zinc protoporphyrin SYSTEMATIC 23220104 T 46 79 N-(2-hydroxypropyl)methacrylamide SYSTEMATIC 23220104 T 81 85 HPMA ABBREVIATION 23220105 A 0 34 Hexylsubstituted poly(lactic acid) FAMILY 23220105 A 1116 1122 HexPLA ABBREVIATION 23220105 A 1327 1338 Triptorelin TRIVIAL 23220105 A 1339 1345 hexPLA ABBREVIATION 23220105 A 139 156 poly(lactic acid) SYSTEMATIC 23220105 A 1497 1508 Triptorelin TRIVIAL 23220105 A 198 217 Triptorelin acetate SYSTEMATIC 23220105 A 2048 2059 Triptorelin TRIVIAL 23220105 A 2060 2066 hexPLA ABBREVIATION 23220105 A 36 42 hexPLA ABBREVIATION 23220105 A 361 367 hexPLA ABBREVIATION 23220105 A 432 461 poly(lactic-co-glycolic acid) FAMILY 23220105 A 463 467 PLGA ABBREVIATION 23220105 A 505 511 hexPLA ABBREVIATION 23220105 A 649 653 PLGA ABBREVIATION 23220105 A 668 674 hexPLA ABBREVIATION 23220105 A 805 816 Triptorelin TRIVIAL 23220105 A 828 834 hexPLA ABBREVIATION 23220105 A 972 983 Triptorelin TRIVIAL 23220105 T 61 72 triptorelin TRIVIAL 23220107 A 1430 1433 man ABBREVIATION 23220107 A 1764 1771 mannose TRIVIAL 23220107 A 746 749 man ABBREVIATION 23220294 A 1015 1023 dopamine TRIVIAL 23220294 A 1192 1200 dopamine TRIVIAL 23220294 A 1419 1427 dopamine TRIVIAL 23220294 A 1623 1631 dopamine TRIVIAL 23220294 A 191 199 dopamine TRIVIAL 23220294 A 403 411 dopamine TRIVIAL 23220294 A 685 693 dopamine TRIVIAL 23220294 A 851 859 dopamine TRIVIAL 23220294 T 88 96 dopamine TRIVIAL 23220400 A 1078 1082 DCPG ABBREVIATION 23220400 A 1301 1305 DCPG ABBREVIATION 23220400 A 1641 1645 DCPG ABBREVIATION 23220400 A 1872 1877 MDCPG ABBREVIATION 23220400 A 1933 1937 DCPG ABBREVIATION 23220400 A 432 436 DCPG ABBREVIATION 23220400 A 629 633 DCPG ABBREVIATION 23220400 A 64 68 DCPG ABBREVIATION 23220400 A 733 737 DCPG ABBREVIATION 23220400 A 939 944 MDCPG ABBREVIATION 23220410 A 1150 1164 organochlorine FAMILY 23220410 A 1263 1268 Na(+) FORMULA 23220410 A 1269 1273 K(+) FORMULA 23220410 A 1627 1642 organochlorines FAMILY 23220410 A 374 382 aluminum SYSTEMATIC 23220410 A 384 388 iron SYSTEMATIC 23220410 A 393 397 zinc SYSTEMATIC 23220410 A 409 423 organochlorine FAMILY 23220410 A 425 431 aldrin TRIVIAL 23220410 A 432 440 dieldrin TRIVIAL 23220410 A 442 452 endosulfan TRIVIAL 23220410 A 454 464 heptachlor TRIVIAL 23220410 A 465 483 heptachlor epoxide TRIVIAL 23220410 A 488 499 metolachlor TRIVIAL 23220410 A 564 570 Copper SYSTEMATIC 23220410 A 572 578 chrome TRIVIAL 23220410 A 580 584 iron SYSTEMATIC 23220410 A 589 593 zinc SYSTEMATIC 23220410 A 642 648 aldrin TRIVIAL 23220410 A 649 657 dieldrin TRIVIAL 23220410 A 659 669 endosulfan TRIVIAL 23220410 A 674 684 heptachlor TRIVIAL 23220410 A 685 703 heptachlor epoxide TRIVIAL 23220410 T 0 15 Organochlorines FAMILY 23220561 A 0 5 Equol TRIVIAL 23220561 A 1208 1212 FLUT ABBREVIATION 23220561 A 1289 1297 estrogen FAMILY 23220561 A 1339 1347 estrogen FAMILY 23220561 A 1395 1425 gonadotropin releasing hormone TRIVIAL 23220561 A 1436 1440 GnRH ABBREVIATION 23220561 A 1732 1736 FLUT ABBREVIATION 23220561 A 202 210 androgen FAMILY 23220561 A 2127 2135 androgen FAMILY 23220561 A 2141 2149 estrogen FAMILY 23220561 A 459 467 androgen FAMILY 23220561 A 473 481 estrogen FAMILY 23220561 A 63 73 isoflavone FAMILY 23220561 A 74 82 daidzein TRIVIAL 23220561 A 834 843 flutamide TRIVIAL 23220561 A 845 849 FLUT ABBREVIATION 23220561 A 99 107 estrogen FAMILY 23220561 T 43 48 equol TRIVIAL 23220587 A 0 13 Retinoic acid TRIVIAL 23220587 A 1014 1021 retinol TRIVIAL 23220587 A 1069 1076 retinal TRIVIAL 23220587 A 1251 1258 retinal TRIVIAL 23220587 A 1408 1415 retinal TRIVIAL 23220587 A 1506 1513 retinal TRIVIAL 23220587 A 244 257 retinoic acid TRIVIAL 23220587 A 304 307 NAD ABBREVIATION 23220587 A 318 325 retinal TRIVIAL 23220587 A 36 45 vitamin A FAMILY 23220587 A 375 383 aldehyde SYSTEMATIC 23220587 A 436 443 retinal TRIVIAL 23220587 A 561 568 retinal TRIVIAL 23220587 A 614 621 retinal TRIVIAL 23220587 A 744 751 retinal TRIVIAL 23220587 A 802 809 retinol TRIVIAL 23220587 A 901 908 retinal TRIVIAL 23220587 T 0 13 Retinoic acid TRIVIAL 23220587 T 40 47 retinal TRIVIAL 23220590 A 1071 1078 ethanol SYSTEMATIC 23220590 A 1091 1103 acetaldehyde SYSTEMATIC 23220590 A 1131 1141 cimetidine TRIVIAL 23220590 A 129 136 alcohol FAMILY 23220590 A 1540 1550 cimetidine TRIVIAL 23220590 A 1568 1575 ethanol SYSTEMATIC 23220590 A 163 170 ethanol SYSTEMATIC 23220590 A 189 196 alcohol FAMILY 23220590 A 216 224 aldehyde SYSTEMATIC 23220590 A 301 308 ethanol SYSTEMATIC 23220590 A 36 46 cimetidine TRIVIAL 23220590 A 465 475 cimetidine TRIVIAL 23220590 A 479 486 alcohol FAMILY 23220590 A 585 593 aldehyde SYSTEMATIC 23220590 A 651 657 NAD(+) ABBREVIATION 23220590 A 673 683 Cimetidine TRIVIAL 23220590 A 844 854 cimetidine TRIVIAL 23220590 A 859 866 ethanol SYSTEMATIC 23220590 A 867 879 acetaldehyde SYSTEMATIC 23220590 T 103 110 ethanol SYSTEMATIC 23220590 T 20 27 alcohol FAMILY 23220590 T 32 40 aldehyde SYSTEMATIC 23220590 T 59 69 cimetidine TRIVIAL 23220608 A 536 544 phenolic FAMILY 23220608 A 648 660 nitric oxide SYSTEMATIC 23220608 A 662 664 NO FORMULA 23220608 A 679 685 oxygen SYSTEMATIC 23220608 A 804 806 NO FORMULA 23220608 A 94 102 phenolic FAMILY 23220611 A 119 134 aspergilliamide TRIVIAL 23220611 A 140 159 ferrineoaspergillin TRIVIAL 23220611 A 165 173 flavacol TRIVIAL 23220611 A 179 198 neoaspergillic acid TRIVIAL 23220611 A 214 225 ochratoxins FAMILY 23220611 A 227 253 ochratoxin A n-butyl ester SYSTEMATIC 23220611 A 259 271 ochratoxin A TRIVIAL 23220611 A 277 302 ochratoxin A methyl ester SYSTEMATIC 23220611 A 30 46 aspergillic acid TRIVIAL 23220611 A 61 84 aluminiumneoaspergillin TRIVIAL 23220611 A 737 746 zirconium FAMILY 23220611 A 780 791 ochratoxins FAMILY 23220611 A 90 113 zirconiumneoaspergillin TRIVIAL 23220742 A 1096 1103 P505-15 IDENTIFIER 23220742 A 338 345 P505-15 IDENTIFIER 23220742 A 361 370 PRT062607 IDENTIFIER 23220742 A 58 66 tyrosine TRIVIAL 23220742 A 616 623 P505-15 IDENTIFIER 23220742 A 650 657 P505-15 IDENTIFIER 23220742 A 949 956 P505-15 IDENTIFIER 23220742 A 962 973 fludarabine TRIVIAL 23220742 T 137 148 fludarabine TRIVIAL 23220742 T 28 35 P505-15 IDENTIFIER 23220742 T 37 46 PRT062607 IDENTIFIER 23220748 A 1003 1012 bile acid FAMILY 23220748 A 1063 1073 bile acids FAMILY 23220748 A 1106 1109 TIC ABBREVIATION 23220748 A 1199 1218 phosphatidylcholine FAMILY 23220748 A 129 132 TIC ABBREVIATION 23220748 A 1299 1302 TIC ABBREVIATION 23220748 A 1334 1346 taurocholate TRIVIAL 23220748 A 1407 1417 bile acids FAMILY 23220748 A 1445 1454 bile acid FAMILY 23220748 A 1487 1490 TIC ABBREVIATION 23220748 A 1599 1602 TIC ABBREVIATION 23220748 A 1696 1699 TIC ABBREVIATION 23220748 A 23 34 ticlopidine TRIVIAL 23220748 A 237 240 TIC ABBREVIATION 23220748 A 303 306 TIC ABBREVIATION 23220748 A 36 39 TIC ABBREVIATION 23220748 A 376 415 diethylaminoethyl diphenylpropylacetate SYSTEMATIC 23220748 A 600 611 glutathione TRIVIAL 23220748 A 623 626 TIC ABBREVIATION 23220748 A 640 643 TIC ABBREVIATION 23220748 A 839 842 TIC ABBREVIATION 23220748 T 0 11 Ticlopidine TRIVIAL 23220748 T 176 187 glutathione TRIVIAL 23220748 T 199 210 ticlopidine TRIVIAL 23220749 A 0 11 Apomorphine TRIVIAL 23220749 A 1091 1102 apomorphine TRIVIAL 23220749 A 1246 1255 serotonin TRIVIAL 23220749 A 1343 1354 apomorphine TRIVIAL 23220749 A 1513 1524 apomorphine TRIVIAL 23220749 A 199 210 apomorphine TRIVIAL 23220749 A 407 418 apomorphine TRIVIAL 23220749 A 44 52 morphine TRIVIAL 23220749 A 582 593 apomorphine TRIVIAL 23220749 A 70 78 dopamine TRIVIAL 23220749 A 737 748 apomorphine TRIVIAL 23220749 A 774 785 apomorphine TRIVIAL 23220749 T 0 11 Apomorphine TRIVIAL 23221600 A 0 12 Stearoyl-CoA TRIVIAL 23221600 A 110 122 carbohydrate FAMILY 23221600 A 139 152 carbohydrates FAMILY 23221600 A 196 202 sterol FAMILY 23221600 A 327 342 thyroid hormone FAMILY 23221600 A 73 85 triglyceride FAMILY 23221600 T 125 140 thyroid hormone FAMILY 23221600 T 6 18 stearoyl-CoA TRIVIAL 23221600 T 83 98 thyroid hormone FAMILY 23221636 A 962 972 nucleotide FAMILY 23223176 A 1064 1071 sesamol TRIVIAL 23223176 A 1080 1090 Paroxetine TRIVIAL 23223176 A 1181 1194 acetylcholine SYSTEMATIC 23223176 A 1262 1276 streptozotocin TRIVIAL 23223176 A 1363 1373 paroxetine TRIVIAL 23223176 A 207 213 oxygen SYSTEMATIC 23223176 A 491 501 paroxetine TRIVIAL 23223176 A 630 640 Paroxetine TRIVIAL 23223176 A 875 885 paroxetine TRIVIAL 23223176 A 952 961 serotonin TRIVIAL 23223176 A 96 103 glucose TRIVIAL 23223176 T 32 42 paroxetine TRIVIAL 23223191 A 1122 1131 Co(OH)(2) FORMULA 23223191 A 1292 1299 γ-FeOOH FORMULA 23223191 A 140 147 CoSO(4) FORMULA 23223191 A 17 26 Co(3)O(4) FORMULA 23223191 A 288 292 H(2) FORMULA 23223191 A 294 302 H(2)O(2) FORMULA 23223191 A 304 310 Co(II) FORMULA 23223191 A 315 322 Co(III) FORMULA 23223191 A 526 533 CoSO(4) FORMULA 23223191 A 662 671 Co(OH)(2) FORMULA 23223191 A 675 680 CoOOH FORMULA 23223191 A 693 702 Co(3)O(4) FORMULA 23223191 A 732 738 Co(II) FORMULA 23223191 A 742 749 Co(III) FORMULA 23223191 A 80 87 CoSO(4) FORMULA 23223191 A 845 854 Co(3)O(4) FORMULA 23223191 T 26 38 cobalt oxide SYSTEMATIC 23223382 A 120 140 tungsten oxide salts FAMILY 23223382 A 529 535 yttria TRIVIAL 23223382 A 547 555 zirconia TRIVIAL 23223407 A 1107 1114 glucose TRIVIAL 23223407 A 1296 1309 carbohydrates FAMILY 23223407 A 1326 1333 steroid FAMILY 23223407 A 1355 1362 glucose TRIVIAL 23223407 A 1505 1512 glucose TRIVIAL 23223407 A 289 296 glucose TRIVIAL 23223407 A 823 836 carbohydrates FAMILY 23223407 A 854 865 amino acids FAMILY 23223407 A 979 986 glucose TRIVIAL 23223414 A 1116 1122 TiO(2) FORMULA 23223414 A 1326 1331 oxide SYSTEMATIC 23223414 A 139 144 oxide SYSTEMATIC 23223414 A 336 352 aminophenyl acid SYSTEMATIC 23223414 A 358 361 NK1 TRIVIAL 23223414 A 366 369 NK7 TRIVIAL 23223414 A 497 510 anatase (101) TRIVIAL 23223414 A 522 528 TiO(2) FORMULA 23223414 A 696 702 TiO(2) FORMULA 23223414 A 910 915 H(2)O FORMULA 23223414 T 168 172 TiO2 FORMULA 23223450 A 136 143 proline TRIVIAL 23223450 A 207 223 4-hydroxyproline SYSTEMATIC 23223450 A 430 439 disulfide SYSTEMATIC 23223517 A 1243 1256 acetaminophen TRIVIAL 23223517 A 1258 1262 APAP ABBREVIATION 23223517 A 1567 1571 APAP ABBREVIATION 23223517 A 4 7 UDP ABBREVIATION 23223517 A 983 1020 3'-phosphoadenosine-5'-phosphosulfate SYSTEMATIC 23223517 T 8 11 UDP ABBREVIATION 23223523 A 1066 1078 rhodamine 6G TRIVIAL 23223523 A 1326 1332 silver SYSTEMATIC 23223523 A 1337 1343 copper SYSTEMATIC 23223523 A 526 539 polycarbonate FAMILY 23223523 T 63 76 polycarbonate FAMILY 23224299 A 416 422 carbon SYSTEMATIC 23224299 T 51 57 carbon SYSTEMATIC 23225148 A 1167 1174 silicon SYSTEMATIC 23225329 A 1041 1045 NMDA ABBREVIATION 23225329 A 1142 1150 spermine TRIVIAL 23225329 A 1170 1173 Tyr FORMULA 23225329 A 1193 1196 His FORMULA 23225329 A 135 140 N4T8N SYSTEMATIC 23225329 A 219 228 polyamine FAMILY 23225329 A 250 254 NMDA ABBREVIATION 23225329 A 28 37 polyamine FAMILY 23225329 A 315 320 N4T8N SYSTEMATIC 23225329 A 354 364 octanamine SYSTEMATIC 23225329 A 467 478 polystyrene SYSTEMATIC 23225329 A 587 597 amino acid FAMILY 23225329 A 615 618 Gly FORMULA 23225329 A 620 623 Leu FORMULA 23225329 A 625 628 Phe FORMULA 23225329 A 63 83 1,12-diaminododecane SYSTEMATIC 23225329 A 630 633 Lys FORMULA 23225329 A 635 648 phenylglycine SYSTEMATIC 23225329 A 650 653 Tyr FORMULA 23225329 A 655 658 Trp FORMULA 23225329 A 660 663 His FORMULA 23225329 A 669 672 Arg FORMULA 23225329 A 727 740 [(3) H]MK-801 SYSTEMATIC 23225329 A 779 783 NMDA ABBREVIATION 23225329 A 85 89 N12N SYSTEMATIC 23225329 A 942 945 Lys FORMULA 23225329 A 95 133 5-(4-aminobutyl)-2-thiopheneoctanamine SYSTEMATIC 23225329 T 14 23 polyamine FAMILY 23225329 T 47 51 NMDA ABBREVIATION 23227815 A 0 12 Asiatic acid TRIVIAL 23227815 A 231 243 asiatic acid TRIVIAL 23227815 A 26 48 pentacyclic triterpene FAMILY 23227815 A 329 375 2α,3β,15α,23-tetrahydroxyurs-12-en-28-oic acid SYSTEMATIC 23227815 A 402 414 asiatic acid TRIVIAL 23227815 A 471 517 2α,3β,21β,23-tetrahydroxyurs-12-en-28-oic acid SYSTEMATIC 23227815 A 523 569 2α,3β,23-trihydroxyurs-12-en-28, 30-dioic acid SYSTEMATIC 23227815 A 579 624 2α,3β,23,30-tetrahydroxyurs-12-en-28-oic acid SYSTEMATIC 23227815 T 28 40 asiatic acid TRIVIAL 23227928 A 189 216 transition metal disulfides FAMILY 23227928 A 217 222 MS(2) FAMILY 23227928 A 228 230 Mo FORMULA 23227928 A 234 235 W FORMULA 23227928 A 305 313 graphene TRIVIAL 23227928 A 318 322 h-BN ABBREVIATION 23227928 A 986 991 MS(2) FAMILY 23227928 T 64 80 metal-disulfides FAMILY 23228175 A 111 122 incarvoid C TRIVIAL 23228175 A 23 37 (+)-argutoid A TRIVIAL 23228175 A 53 61 iridoids FAMILY 23228175 A 63 80 ( - )-incarvoid A TRIVIAL 23228175 A 8 21 monoterpenoid FAMILY 23228175 A 86 101 (+)-incarvoid B TRIVIAL 23228175 T 0 10 Terpenoids FAMILY 23228182 A 15 53 zwitterionic poly(serine methacrylate) FAMILY 23228182 A 2 8 serine TRIVIAL 23228182 A 270 276 pSerMA ABBREVIATION 23228182 A 506 512 pSerMA ABBREVIATION 23228182 A 55 61 pSerMA ABBREVIATION 23228182 A 699 720 poly(ethylene glycol) SYSTEMATIC 23228182 A 726 732 pSerMA ABBREVIATION 23228182 A 857 867 amino acid FAMILY 23228182 A 942 948 pSerMA ABBREVIATION 23228182 A 995 1010 ethylene glycol SYSTEMATIC 23228182 T 0 10 Amino acid FAMILY 23228182 T 17 55 zwitterionic poly(serine methacrylate) FAMILY 23228444 A 0 9 Estrogens FAMILY 23228444 A 1122 1131 estradiol TRIVIAL 23228444 A 1133 1138 (13)C FORMULA 23228444 A 1205 1217 progesterone TRIVIAL 23228444 A 1219 1242 17α-hydroxyprogesterone SYSTEMATIC 23228444 A 1244 1256 pregnanediol TRIVIAL 23228444 A 1269 1280 desogestrel TRIVIAL 23228444 A 1285 1301 ethinylestradiol SYSTEMATIC 23228444 A 1351 1357 carbon SYSTEMATIC 23228444 A 1428 1436 estrogen FAMILY 23228444 A 298 307 estrogens FAMILY 23228444 A 376 385 estrogens FAMILY 23228444 A 531 540 estradiol TRIVIAL 23228444 A 593 602 estrogens FAMILY 23228444 A 710 719 estrogens FAMILY 23228444 A 828 833 (13)C FORMULA 23228444 A 834 839 (12)C FORMULA 23228444 A 848 853 (13)C FORMULA 23228444 A 862 867 (13)C FORMULA 23228444 A 979 984 (13)C FORMULA 23228444 T 52 61 estrogens FAMILY 23228695 A 259 271 silicic acid TRIVIAL 23228695 A 581 584 NH₂ FORMULA 23228695 A 594 605 amino acids FAMILY 23228849 A 1001 1005 PLGA ABBREVIATION 23228849 A 1006 1009 GLN FORMULA 23228849 A 1034 1037 PLL ABBREVIATION 23228849 A 124 132 Dopamine TRIVIAL 23228849 A 1268 1276 dopamine TRIVIAL 23228849 A 199 208 glutamine TRIVIAL 23228849 A 220 230 polylysine FAMILY 23228849 A 237 240 PLL ABBREVIATION 23228849 A 266 269 PLL ABBREVIATION 23228849 A 427 448 poly(ethylene glycol) SYSTEMATIC 23228849 A 450 453 PEG ABBREVIATION 23228849 A 462 482 poly(ε-caprolactone) FAMILY 23228849 A 484 487 PCL ABBREVIATION 23228849 A 512 527 PEG-grafted PCL ABBREVIATION 23228849 A 698 701 PCL ABBREVIATION 23228849 A 744 747 PCL ABBREVIATION 23228849 A 759 788 poly(lactic-co-glycolic acid) FAMILY 23228849 A 807 816 glutamine TRIVIAL 23228849 A 818 822 PLGA ABBREVIATION 23228849 A 823 826 GLN FORMULA 23228849 A 856 859 PCL ABBREVIATION 23228849 A 893 896 PCL ABBREVIATION 23228849 A 988 991 GLN FORMULA 23229134 A 174 176 As FORMULA 23229134 A 178 180 Hg FORMULA 23229134 A 182 184 Cd FORMULA 23229134 A 186 188 Cr FORMULA 23229134 A 190 192 Cu FORMULA 23229134 A 194 196 Ni FORMULA 23229134 A 198 200 Pb FORMULA 23229134 A 205 207 Zn FORMULA 23229135 A 1083 1089 copper SYSTEMATIC 23229135 A 1172 1179 calcium SYSTEMATIC 23229135 A 1202 1208 carbon SYSTEMATIC 23229135 A 1235 1241 Copper SYSTEMATIC 23229135 A 1500 1506 copper SYSTEMATIC 23229135 A 1525 1531 copper SYSTEMATIC 23229135 A 215 217 Cu FORMULA 23229135 A 256 261 CaCl2 FORMULA 23229135 A 50 56 copper SYSTEMATIC 23229135 A 556 562 Copper SYSTEMATIC 23229135 T 27 33 copper SYSTEMATIC 23229324 A 102 111 ferrocene TRIVIAL 23229324 A 463 468 GO-Fc ABBREVIATION 23229324 A 519 524 GO-Fc ABBREVIATION 23229324 A 686 691 GO-Fc ABBREVIATION 23229324 A 78 92 graphene oxide SYSTEMATIC 23229324 T 44 58 graphene oxide SYSTEMATIC 23229324 T 63 72 ferrocene TRIVIAL 23229509 A 23 31 adenylyl TRIVIAL 23229509 A 326 330 cAMP ABBREVIATION 23229509 A 688 692 cAMP ABBREVIATION 23229509 A 852 853 N FORMULA 23229509 A 97 101 cAMP ABBREVIATION 23229509 T 11 19 adenylyl TRIVIAL 23229512 A 0 10 Vitamin K2 FAMILY 23229512 A 1037 1040 VK2 ABBREVIATION 23229512 A 12 15 VK2 ABBREVIATION 23229512 A 17 28 menaquinone FAMILY 23229512 A 314 317 VK2 ABBREVIATION 23229512 A 337 340 VK2 ABBREVIATION 23229512 A 595 598 VK2 ABBREVIATION 23229512 A 662 677 VK2-2,3 epoxide SYSTEMATIC 23229512 A 710 713 VK2 ABBREVIATION 23229512 A 751 759 cysteine TRIVIAL 23229512 A 848 851 VK2 ABBREVIATION 23229512 T 0 10 Vitamin K2 FAMILY 23229518 A 1057 1063 3-MCPD SYSTEMATIC 23229518 A 1082 1099 fatty acid esters FAMILY 23229518 A 1178 1184 3-MCPD SYSTEMATIC 23229518 A 133 173 1,2-dipalmitoyl-3-chloropropane-1,2-diol SYSTEMATIC 23229518 A 175 189 3-MCPD diester SYSTEMATIC 23229518 A 195 201 3-MCPD SYSTEMATIC 23229518 A 285 291 3-MCPD SYSTEMATIC 23229518 A 410 416 3-MCPD SYSTEMATIC 23229518 A 462 476 3-MCPD diester SYSTEMATIC 23229518 A 58 82 3-chloropropane-1,2-diol SYSTEMATIC 23229518 A 625 631 3-MCPD SYSTEMATIC 23229518 A 695 701 3-MCPD SYSTEMATIC 23229518 A 724 738 3-MCPD diester SYSTEMATIC 23229518 A 831 837 3-MCPD SYSTEMATIC 23229518 A 84 90 3-MCPD SYSTEMATIC 23229518 A 97 123 3-MCPD fatty acid diesters FAMILY 23229518 T 33 39 3-MCPD SYSTEMATIC 23229518 T 45 69 3-MCPD fatty acid esters FAMILY 23229954 A 107 122 L-phenylglycine TRIVIAL 23229954 A 68 77 xanthones FAMILY 23229954 T 43 52 xanthones FAMILY 23229954 T 75 90 L-phenylglycine TRIVIAL 23230132 A 0 17 Ethyl glucuronide SYSTEMATIC 23230132 A 1039 1046 Ethanol SYSTEMATIC 23230132 A 107 114 ethanol SYSTEMATIC 23230132 A 1226 1229 EtG ABBREVIATION 23230132 A 1364 1374 cannabinol TRIVIAL 23230132 A 1379 1390 cannabidiol TRIVIAL 23230132 A 1414 1421 ethanol SYSTEMATIC 23230132 A 1439 1449 Cannabinol TRIVIAL 23230132 A 1460 1467 ethanol SYSTEMATIC 23230132 A 152 155 EtG ABBREVIATION 23230132 A 1529 1540 cannabidiol TRIVIAL 23230132 A 1565 1568 EtG ABBREVIATION 23230132 A 1715 1722 ethanol SYSTEMATIC 23230132 A 1778 1788 cannabinol TRIVIAL 23230132 A 1793 1804 cannabidiol TRIVIAL 23230132 A 1831 1838 ethanol SYSTEMATIC 23230132 A 19 22 EtG ABBREVIATION 23230132 A 386 389 UDP ABBREVIATION 23230132 A 430 437 ethanol SYSTEMATIC 23230132 A 829 837 morphine TRIVIAL 23230132 A 839 846 codeine TRIVIAL 23230132 A 848 857 lorazepam TRIVIAL 23230132 A 859 867 oxazepam TRIVIAL 23230132 A 869 877 nicotine TRIVIAL 23230132 A 879 887 cotinine TRIVIAL 23230132 A 889 899 cannabinol TRIVIAL 23230132 A 905 916 cannabidiol TRIVIAL 23230132 A 939 946 ethanol SYSTEMATIC 23230132 T 15 18 UDP ABBREVIATION 23230132 T 65 72 ethanol SYSTEMATIC 23230213 A 0 7 Ethanol SYSTEMATIC 23230213 A 1109 1116 ethanol SYSTEMATIC 23230213 A 1262 1269 ethanol SYSTEMATIC 23230213 A 1303 1313 strychnine TRIVIAL 23230213 A 139 146 ethanol SYSTEMATIC 23230213 A 1424 1428 zinc SYSTEMATIC 23230213 A 1471 1478 ethanol SYSTEMATIC 23230213 A 1505 1509 zinc SYSTEMATIC 23230213 A 151 158 glycine TRIVIAL 23230213 A 1603 1610 ethanol SYSTEMATIC 23230213 A 232 239 ethanol SYSTEMATIC 23230213 A 254 258 zinc SYSTEMATIC 23230213 A 357 361 zinc SYSTEMATIC 23230213 A 370 377 ethanol SYSTEMATIC 23230213 A 444 448 zinc SYSTEMATIC 23230213 A 512 516 zinc SYSTEMATIC 23230213 A 568 572 zinc SYSTEMATIC 23230213 A 576 583 ethanol SYSTEMATIC 23230213 A 692 696 zinc SYSTEMATIC 23230213 A 755 762 ethanol SYSTEMATIC 23230213 A 886 890 zinc SYSTEMATIC 23230213 A 916 923 ethanol SYSTEMATIC 23230213 T 111 118 alcohol FAMILY 23230213 T 14 18 zinc SYSTEMATIC 23230213 T 42 49 glycine TRIVIAL 23230213 T 78 85 ethanol SYSTEMATIC 23230214 A 0 12 Nitric oxide SYSTEMATIC 23230214 A 1021 1033 nitric oxide SYSTEMATIC 23230214 A 103 115 nitric oxide SYSTEMATIC 23230214 A 1085 1097 nitric oxide SYSTEMATIC 23230214 A 1131 1143 nitric oxide SYSTEMATIC 23230214 A 1215 1219 METH ABBREVIATION 23230214 A 1224 1228 METH ABBREVIATION 23230214 A 1229 1233 METH ABBREVIATION 23230214 A 1277 1289 nitric oxide SYSTEMATIC 23230214 A 1331 1346 methamphetamine TRIVIAL 23230214 A 1370 1382 nitric oxide SYSTEMATIC 23230214 A 1479 1491 nitric oxide SYSTEMATIC 23230214 A 1530 1542 nitric oxide SYSTEMATIC 23230214 A 1549 1564 methamphetamine TRIVIAL 23230214 A 1632 1647 methamphetamine TRIVIAL 23230214 A 1656 1664 dopamine TRIVIAL 23230214 A 1709 1724 methamphetamine TRIVIAL 23230214 A 1733 1745 nitric oxide SYSTEMATIC 23230214 A 1774 1786 nitric oxide SYSTEMATIC 23230214 A 1819 1834 methamphetamine TRIVIAL 23230214 A 199 207 dopamine TRIVIAL 23230214 A 248 263 methamphetamine TRIVIAL 23230214 A 30 45 methamphetamine TRIVIAL 23230214 A 310 318 dopamine TRIVIAL 23230214 A 338 353 methamphetamine TRIVIAL 23230214 A 398 410 nitric oxide SYSTEMATIC 23230214 A 47 51 METH ABBREVIATION 23230214 A 534 549 methamphetamine TRIVIAL 23230214 A 633 637 METH ABBREVIATION 23230214 A 653 657 METH ABBREVIATION 23230214 A 663 667 METH ABBREVIATION 23230214 A 668 672 METH ABBREVIATION 23230214 A 698 713 methamphetamine TRIVIAL 23230214 A 742 746 METH ABBREVIATION 23230214 A 751 755 METH ABBREVIATION 23230214 A 756 760 METH ABBREVIATION 23230214 A 772 784 nitric oxide SYSTEMATIC 23230214 A 842 857 Methamphetamine TRIVIAL 23230214 A 938 950 nitric oxide SYSTEMATIC 23230214 T 27 39 nitric oxide SYSTEMATIC 23230214 T 61 76 methamphetamine TRIVIAL 23230214 T 94 102 dopamine TRIVIAL 23230273 A 866 869 Ser FORMULA 23230273 A 879 880 C FORMULA 23231078 A 1011 1033 potassium ferricyanide SYSTEMATIC 23231078 A 174 184 oleic acid TRIVIAL 23231078 A 209 219 n-propanol SYSTEMATIC 23231078 A 645 655 oleic acid TRIVIAL 23231078 A 697 707 oleic acid TRIVIAL 23231078 A 993 1006 methyl orange TRIVIAL 23231078 T 42 52 oleic acid TRIVIAL 23231078 T 54 64 n-propanol SYSTEMATIC 23231078 T 70 73 H2O FORMULA 23231413 A 399 403 RI-1 IDENTIFIER 23231413 A 452 467 chloromaleimide SYSTEMATIC 23231413 A 550 555 thiol FAMILY 23231413 A 793 802 maleimide SYSTEMATIC 23231413 A 874 950 1-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)-4-morpholino-1H-pyrrole-2,5-dione SYSTEMATIC 23231413 A 958 962 RI-2 IDENTIFIER 23231492 A 907 917 amino acid FAMILY 23231502 A 1006 1012 biotin TRIVIAL 23231502 A 1154 1157 Cys FORMULA 23231502 A 1191 1194 HNE ABBREVIATION 23231502 A 1305 1308 HNE ABBREVIATION 23231502 A 1439 1450 polyphenols FAMILY 23231502 A 181 190 aldehydes FAMILY 23231502 A 241 257 4-Hydroxynonenal SYSTEMATIC 23231502 A 259 262 HNE ABBREVIATION 23231502 A 341 344 Cys FORMULA 23231502 A 346 349 His FORMULA 23231502 A 354 357 Lys FORMULA 23231502 A 403 409 prolyl TRIVIAL 23231502 A 504 508 pSer FORMULA 23231502 A 509 513 pThr FORMULA 23231502 A 514 517 Pro FORMULA 23231502 A 593 596 HNE ABBREVIATION 23231502 A 644 647 HNE ABBREVIATION 23231502 A 761 764 His FORMULA 23231502 A 773 776 Cys FORMULA 23231502 A 832 835 Cys FORMULA 23231502 A 863 866 HNE ABBREVIATION 23231502 A 946 959 8-alkynyl-HNE FAMILY 23231502 T 9 15 prolyl TRIVIAL 23231586 A 151 168 iridoid glycoside FAMILY 23231586 A 182 204 triterpenoid glycoside FAMILY 23231586 T 26 48 triterpenoid glycoside FAMILY 23231586 T 4 21 iridoid glycoside FAMILY 23231808 A 0 13 Acetazolamide TRIVIAL 23231808 T 0 13 Acetazolamide TRIVIAL 23232447 A 1070 1075 6DBF7 SYSTEMATIC 23232447 A 1112 1116 DB16 NO CLASS 23232447 A 1121 1125 DB21 NO CLASS 23232447 A 1145 1171 fluorescein isothiocyanate TRIVIAL 23232447 A 1279 1283 DB16 NO CLASS 23232447 A 1313 1320 lactose TRIVIAL 23232447 A 1521 1525 DB21 NO CLASS 23232447 A 1597 1602 6DBF7 SYSTEMATIC 23232447 A 1604 1608 DB16 NO CLASS 23232447 A 1622 1626 DB21 NO CLASS 23232447 A 206 211 6DBF7 SYSTEMATIC 23232447 A 215 227 dibenzofuran SYSTEMATIC 23232447 A 229 232 DBF ABBREVIATION 23232447 A 357 362 6DBF7 SYSTEMATIC 23232447 A 396 401 6DBF7 SYSTEMATIC 23232447 A 470 482 carbohydrate FAMILY 23232447 A 509 516 alanine TRIVIAL 23232447 A 525 530 6DBF7 SYSTEMATIC 23232447 A 568 575 lysines FAMILY 23232447 A 818 821 DBF ABBREVIATION 23232447 A 866 867 C FORMULA 23232447 A 877 880 Asp FORMULA 23232447 A 885 892 alanine TRIVIAL 23232447 A 906 911 alkyl FAMILY 23232447 A 925 928 Val ABBREVIATION 23232447 A 930 933 Leu FORMULA 23232447 A 935 938 Ile FORMULA 23232447 A 957 960 Nle FORMULA 23232447 A 962 965 Nva ABBREVIATION 23232447 T 50 55 6DBF7 SYSTEMATIC 23233343 A 1245 1249 PAHs ABBREVIATION 23233343 A 1529 1532 PAH ABBREVIATION 23233343 A 419 450 polycyclic aromatic hydrocarbon FAMILY 23233343 A 452 455 PAH ABBREVIATION 23233343 A 687 690 PAH ABBREVIATION 23233343 A 848 851 PAH ABBREVIATION 23233343 A 896 899 PAH ABBREVIATION 23233534 A 1038 1046 Naloxone TRIVIAL 23233534 A 611 619 naloxone TRIVIAL 23233534 T 73 81 naloxone TRIVIAL 23233535 A 1103 1104 N FORMULA 23233535 A 1159 1162 Met FORMULA 23233535 A 1170 1173 Thr FORMULA 23233535 A 1196 1197 C FORMULA 23233535 A 26 27 C FORMULA 23233535 A 273 276 Met FORMULA 23233535 A 284 287 Thr FORMULA 23233535 A 716 717 N FORMULA 23234496 A 0 6 Oxygen SYSTEMATIC 23234496 A 741 747 oxygen SYSTEMATIC 23234496 T 59 65 oxygen SYSTEMATIC 23234644 A 194 201 noviose TRIVIAL 23234644 A 202 207 sugar FAMILY 23234644 A 250 256 amines FAMILY 23234644 A 374 382 N'-amino SYSTEMATIC 23234644 A 69 79 Novobiocin TRIVIAL 23234644 T 0 10 Novobiocin TRIVIAL 23234644 T 44 51 noviose TRIVIAL 23237625 A 1052 1058 silica TRIVIAL 23237625 A 1077 1083 silver SYSTEMATIC 23237625 A 1151 1157 silver SYSTEMATIC 23237625 A 1202 1208 silver SYSTEMATIC 23237625 A 1228 1234 silica TRIVIAL 23237625 A 1250 1256 silver SYSTEMATIC 23237625 A 1310 1316 silver SYSTEMATIC 23237625 A 1403 1409 silica TRIVIAL 23237625 A 1516 1522 silver SYSTEMATIC 23237625 A 459 465 silver SYSTEMATIC 23237625 A 560 566 silver SYSTEMATIC 23237625 A 651 657 silica TRIVIAL 23237625 A 749 755 silver SYSTEMATIC 23237625 A 839 845 silica TRIVIAL 23237625 A 951 957 silica TRIVIAL 23237625 T 61 67 silver SYSTEMATIC 23237706 A 1096 1106 superoxide TRIVIAL 23237706 A 1118 1120 Cu FORMULA 23237706 A 1121 1123 Zn FORMULA 23237706 A 1132 1140 selenium SYSTEMATIC 23237706 A 1151 1162 glutathione TRIVIAL 23237706 A 1183 1194 glutathione TRIVIAL 23237706 A 1217 1225 retinoid FAMILY 23237706 A 1389 1400 glutathione TRIVIAL 23237706 A 1401 1402 S FORMULA 23237706 A 2206 2212 oxygen SYSTEMATIC 23237706 A 2480 2486 diquat TRIVIAL 23237706 A 2629 2635 diquat TRIVIAL 23237706 A 373 379 Diquat TRIVIAL 23237706 A 522 528 diquat TRIVIAL 23237706 A 665 671 diquat TRIVIAL 23237706 A 829 835 diquat TRIVIAL 23237706 A 985 1001 diquat dibromide SYSTEMATIC 23237706 T 38 44 diquat TRIVIAL 23237836 A 0 8 Dopamine TRIVIAL 23237836 A 248 261 aminothiazole SYSTEMATIC 23237836 A 268 280 benzazepines FAMILY 23237836 A 516 527 amphetamine TRIVIAL 23237836 T 21 34 aminothiazole SYSTEMATIC 23237836 T 41 53 benzazepines FAMILY 23237836 T 67 75 dopamine TRIVIAL 23237840 A 297 343 3-(benzylamino)-5-cyanopyrazine-2-carboxamides FAMILY 23237840 A 348 391 3-(benzylamino)pyrazine-2,5-dicarbonitriles FAMILY 23237840 A 40 52 pyrazinamide SYSTEMATIC 23237840 A 425 431 phenyl SYSTEMATIC 23237840 A 617 629 pyrazinamide SYSTEMATIC 23237840 A 653 695 3-(Benzylamino)pyrazine-2,5-dicarbonitrile SYSTEMATIC 23237840 A 817 824 4-NH(2) SYSTEMATIC 23237840 T 46 58 pyrazinamide SYSTEMATIC 23237840 T 76 87 benzylamino SYSTEMATIC 23237841 A 162 172 lamivudine TRIVIAL 23237841 A 173 182 entecavir TRIVIAL 23237841 A 220 224 FMCA ABBREVIATION 23237841 A 298 308 lamivudine TRIVIAL 23237841 A 309 318 entecavir TRIVIAL 23237841 A 368 381 monophosphate SYSTEMATIC 23237841 A 391 396 FMCAP ABBREVIATION 23237841 A 52 56 FMCA ABBREVIATION 23237841 A 552 556 FMCA ABBREVIATION 23237841 A 58 71 monophosphate SYSTEMATIC 23237841 A 6 50 2'-fluoro-6'-methylene-carbocyclic adenosine FAMILY 23237841 A 682 691 2'-fluoro SYSTEMATIC 23237841 A 702 710 hydrogen SYSTEMATIC 23237841 A 764 775 carbocyclic FAMILY 23237841 A 790 803 phenylalanine TRIVIAL 23237841 A 81 86 FMCAP ABBREVIATION 23237841 T 0 60 2'-Fluoro-6'-methylene-carbocyclic adenosine phosphoramidate FAMILY 23237841 T 117 127 lamivudine TRIVIAL 23237841 T 128 137 entecavir TRIVIAL 23237841 T 62 67 FMCAP ABBREVIATION 23238124 A 311 319 estrogen FAMILY 23238275 A 0 11 Bisphenol A TRIVIAL 23238275 A 1029 1045 thyroid hormones FAMILY 23238275 A 1107 1110 BPA ABBREVIATION 23238275 A 1168 1171 BPA ABBREVIATION 23238275 A 1279 1282 BPA ABBREVIATION 23238275 A 13 16 BPA ABBREVIATION 23238275 A 1371 1374 BPA ABBREVIATION 23238275 A 1561 1564 BPA ABBREVIATION 23238275 A 157 170 polycarbonate FAMILY 23238275 A 184 189 epoxy SYSTEMATIC 23238275 A 245 248 BPA ABBREVIATION 23238275 A 314 317 BPA ABBREVIATION 23238275 A 352 368 thyroid hormones FAMILY 23238275 A 476 492 thyroid hormones FAMILY 23238275 A 564 567 BPA ABBREVIATION 23238275 A 703 706 BPA ABBREVIATION 23238275 A 761 776 thyroid hormone FAMILY 23238275 A 830 833 BPA ABBREVIATION 23238275 T 0 11 Bisphenol A TRIVIAL 23239534 A 1104 1116 Mg(2+)(H2O)3 FORMULA 23239534 A 1121 1133 Mg(2+)(H2O)4 FORMULA 23239534 A 257 269 Mg(2+)(H2O)x FAMILY 23239534 A 32 44 Mg(2+)(H2O)x FAMILY 23239534 A 400 412 Mg(2+)(H2O)3 FORMULA 23239534 A 476 488 MgOH(+)(H2O) FORMULA 23239534 A 493 499 H3O(+) FORMULA 23239534 A 554 566 Mg(2+)(H2O)3 FORMULA 23239534 A 632 644 Mg(2+)(H2O)x FAMILY 23239534 A 955 961 Mg(2+) FORMULA 23239534 T 135 147 Mg(2+)(H2O)x FAMILY 23239534 T 44 62 hydrated magnesium SYSTEMATIC 23239555 A 197 201 acyl FAMILY 23239555 A 299 306 boronic SYSTEMATIC 23239555 A 311 323 borinic acid SYSTEMATIC 23239555 T 0 5 Boron SYSTEMATIC 23239555 T 26 30 acyl FAMILY 23239592 A 186 189 CdS FORMULA 23239592 A 229 231 H2 FORMULA 23239592 A 29 37 titanate FAMILY 23239592 A 94 97 CdS FORMULA 23239592 T 18 21 CdS FORMULA 23239592 T 22 30 Titanate FAMILY 23239592 T 89 97 Hydrogen SYSTEMATIC 23240691 A 1098 1108 amino acid FAMILY 23240866 A 0 16 Polyethylenimine FAMILY 23240866 A 1039 1042 PEI ABBREVIATION 23240866 A 1044 1059 P(GMA-TEPA)(50) ABBREVIATION 23240866 A 1141 1175 N-(2-hydroxypropyl) methacrylamide SYSTEMATIC 23240866 A 1177 1181 HPMA ABBREVIATION 23240866 A 1187 1239 oligo(ethylene glycol) monomethyl ether methacrylate FAMILY 23240866 A 1241 1246 OEGMA ABBREVIATION 23240866 A 1391 1398 P(HPMA) ABBREVIATION 23240866 A 1403 1411 P(OEGMA) ABBREVIATION 23240866 A 1442 1446 HPMA ABBREVIATION 23240866 A 1447 1452 OEGMA ABBREVIATION 23240866 A 1512 1527 P(GMA-TEPA)(50) ABBREVIATION 23240866 A 1709 1739 P(OEGMA)(15)-b-P(GMA-TEPA)(50) ABBREVIATION 23240866 A 18 21 PEI ABBREVIATION 23240866 A 433 460 poly(glycidyl methacrylate) SYSTEMATIC 23240866 A 461 467 P(GMA) ABBREVIATION 23240866 A 630 641 oligoamines FAMILY 23240866 A 649 671 tetraethylenepentamine SYSTEMATIC 23240866 A 673 677 TEPA ABBREVIATION 23240866 A 680 701 pentaethylenehexamine SYSTEMATIC 23240866 A 703 707 PEHA ABBREVIATION 23240866 A 714 737 tris(2-aminoethyl)amine SYSTEMATIC 23240866 A 739 743 TREN ABBREVIATION 23240866 A 780 797 P(GMA-oligoamine) FAMILY 23240866 A 829 835 P(GMA) ABBREVIATION 23240866 A 869 879 oligoamine FAMILY 23240866 A 950 965 P(GMA-TEPA)(50) ABBREVIATION 23240892 A 1090 1103 acetaminophen TRIVIAL 23240892 A 1105 1109 APAP ABBREVIATION 23240892 A 1195 1199 PKAA ABBREVIATION 23240892 A 1201 1205 PKAA ABBREVIATION 23240892 A 1268 1275 alanine TRIVIAL 23240892 A 1326 1330 APAP ABBREVIATION 23240892 A 1384 1388 PKAA ABBREVIATION 23240892 A 184 206 poly(ketal amidoamine) FAMILY 23240892 A 208 212 PKAA ABBREVIATION 23240892 A 291 295 PKAA ABBREVIATION 23240892 A 389 405 poly(amidoamine) SYSTEMATIC 23240892 A 407 411 PKAA ABBREVIATION 23240892 A 619 623 PKAA ABBREVIATION 23240892 A 723 738 secondary amine FAMILY 23240892 A 899 903 PKAA ABBREVIATION 23240892 T 25 47 poly(ketal amidoamine) FAMILY 23241369 A 0 27 5'-Βenzylglycinyl-amiloride SYSTEMATIC 23241369 A 1075 1081 UCD38B IDENTIFIER 23241369 A 122 131 amiloride TRIVIAL 23241369 A 1348 1354 UCD38B IDENTIFIER 23241369 A 1482 1499 poly (ADP-ribose) SYSTEMATIC 23241369 A 244 250 UCD38B IDENTIFIER 23241369 A 29 35 UCD38B IDENTIFIER 23241369 A 41 59 glycinyl-amiloride TRIVIAL 23241369 A 420 426 UCD74A IDENTIFIER 23241369 A 502 508 sodium SYSTEMATIC 23241369 A 554 560 UCD38B IDENTIFIER 23241369 A 594 600 UCD38B IDENTIFIER 23241369 A 61 67 UCD74A IDENTIFIER 23241369 A 968 974 UCD38B IDENTIFIER 23241369 T 0 26 5-Benzylglycinyl-amiloride SYSTEMATIC 23241370 A 0 18 Polyazamacrocycles FAMILY 23241370 A 345 363 polyazamacrocycles FAMILY 23241370 T 0 18 Polyazamacrocycles FAMILY 23244065 A 776 799 S-adenosyl-L-methionine TRIVIAL 23244065 A 801 804 SAM ABBREVIATION 23244065 A 836 846 methionine TRIVIAL 23244065 A 871 874 SAM ABBREVIATION 23244065 A 887 897 methionine TRIVIAL 23244212 A 675 681 silica TRIVIAL 23244212 A 754 760 silica TRIVIAL 23244295 A 274 283 galactose TRIVIAL 23244295 A 396 423 4-nitrophenyl chloroformate SYSTEMATIC 23244295 A 425 428 NPC ABBREVIATION 23244295 A 479 487 arginine TRIVIAL 23244295 A 488 495 glycine TRIVIAL 23244295 A 496 509 aspartic acid TRIVIAL 23244296 A 317 349 tetraoxacalix[2]arene[2]triazine SYSTEMATIC 23244296 A 585 597 acetonitrile SYSTEMATIC 23244296 A 60 92 tetraoxacalix[2]arene[2]triazine SYSTEMATIC 23244296 A 663 671 NO(3)(-) FORMULA 23244296 A 676 684 BF(4)(-) FORMULA 23244296 A 689 697 PF(6)(-) FORMULA 23244296 A 702 708 SCN(-) FORMULA 23244296 A 779 787 triazine FAMILY 23244296 A 797 829 tetraoxacalix[2]arene[2]triazine SYSTEMATIC 23244580 A 1136 1161 phosphatidylinositol 3-OH FAMILY 23244582 A 101 110 chalcones FAMILY 23244582 A 283 292 flavonoid FAMILY 23244582 A 513 522 chalcones FAMILY 23244582 A 598 607 chalcones FAMILY 23244582 T 46 55 chalcones FAMILY 23244684 A 446 455 thiophene SYSTEMATIC 23244684 A 460 476 methoxythiophene SYSTEMATIC 23244684 A 657 666 thiophene SYSTEMATIC 23244684 A 671 685 thienopyrazine SYSTEMATIC 23246353 A 391 400 palmitate TRIVIAL 23246353 A 838 845 glucose TRIVIAL 23246353 A 907 916 palmitate TRIVIAL 23246355 A 12 57 3-(arylsulfonyl)spiroimidazolidine-2,4-diones FAMILY 23246355 A 126 148 arylsulfonyl chlorides FAMILY 23246355 A 150 178 Spiroimidazolidine-2,4-dione SYSTEMATIC 23246355 A 208 218 norcamphor TRIVIAL 23246355 A 391 397 aldose FAMILY 23246355 A 87 120 spiroiminoimidazolidine-2,4-dione SYSTEMATIC 23246355 T 12 48 spirobicycloimidazolidine-2,4-diones FAMILY 23246355 T 88 94 aldose FAMILY 23246435 A 1010 1013 ATP ABBREVIATION 23246435 A 421 424 ATP ABBREVIATION 23246459 A 544 556 nitric oxide SYSTEMATIC 23246471 A 1137 1146 PEG-b-PCL ABBREVIATION 23246471 A 1197 1207 paclitaxel TRIVIAL 23246471 A 1242 1275 3'-deoxy-3'-(18)F-fluorothymidine SYSTEMATIC 23246471 A 1277 1286 (18)F-FLT SYSTEMATIC 23246471 A 1323 1332 (18)F-FLT SYSTEMATIC 23246471 A 1371 1380 PEG-b-PCL ABBREVIATION 23246471 A 1429 1439 paclitaxel TRIVIAL 23246471 A 1474 1483 PEG-b-PCL ABBREVIATION 23246471 A 1536 1546 paclitaxel TRIVIAL 23246471 A 1548 1559 cyclopamine TRIVIAL 23246471 A 1564 1572 gossypol TRIVIAL 23246471 A 1639 1649 paclitaxel TRIVIAL 23246471 A 1869 1878 PEG-b-PCL ABBREVIATION 23246471 A 325 373 Poly(ethylene glycol)-block-poly(ε-caprolactone) FAMILY 23246471 A 375 384 PEG-b-PCL ABBREVIATION 23246471 A 412 422 paclitaxel TRIVIAL 23246471 A 442 453 cyclopamine TRIVIAL 23246471 A 480 488 gossypol TRIVIAL 23246471 A 590 599 PEG-b-PCL ABBREVIATION 23246471 A 824 833 PEG-b-PCL ABBREVIATION 23246471 A 915 925 paclitaxel TRIVIAL 23246471 T 0 48 Poly(ethylene glycol)-block-poly(ε-caprolactone) FAMILY 23246471 T 103 113 paclitaxel TRIVIAL 23246471 T 115 126 cyclopamine TRIVIAL 23246471 T 131 139 gossypol TRIVIAL 23246530 A 595 599 NMDA ABBREVIATION 23246530 A 625 632 calcium SYSTEMATIC 23246619 A 173 183 Tacrolimus TRIVIAL 23246619 A 413 423 tacrolimus TRIVIAL 23246619 T 103 113 tacrolimus TRIVIAL 23246733 A 336 343 citrate FAMILY 23246863 A 1124 1129 amine SYSTEMATIC 23246863 A 1135 1143 carboxyl SYSTEMATIC 23246863 A 1189 1191 Cd FORMULA 23246863 A 1287 1292 amine SYSTEMATIC 23246863 A 1335 1337 Cd FORMULA 23246863 A 1736 1738 Cd FORMULA 23246863 A 406 410 CdSe FORMULA 23246863 A 411 414 ZnS FORMULA 23246863 A 420 425 amine SYSTEMATIC 23246863 A 431 439 carboxyl SYSTEMATIC 23246863 A 576 584 nitrogen SYSTEMATIC 23246863 A 881 883 Cd FORMULA 23246863 A 995 997 Cd FORMULA 23246863 T 117 121 CdSe FORMULA 23247057 A 283 296 17β estradiol SYSTEMATIC 23247057 A 656 664 estrogen FAMILY 23247057 A 86 94 estrogen FAMILY 23247057 T 0 13 17β estradiol SYSTEMATIC 23247057 T 100 108 estrogen FAMILY 23247074 A 123 150 Ti(0.5)Zr(0.25)Hf(0.25)NiSn FORMULA 23247074 A 680 682 Sn FORMULA 23247176 A 1043 1050 halogen FAMILY 23247176 A 1062 1071 bis(urea) SYSTEMATIC 23247176 A 1104 1111 halogen FAMILY 23247176 A 353 361 hydrogen SYSTEMATIC 23247176 A 467 474 halogen FAMILY 23247176 A 639 646 halogen FAMILY 23247176 A 665 672 pyridyl SYSTEMATIC 23247176 A 690 707 bis(pyridyl urea) SYSTEMATIC 23247176 A 712 740 1,4-diiodotetrafluorobenzene SYSTEMATIC 23247176 A 800 808 methanol SYSTEMATIC 23247176 A 821 838 dimethylsulfoxide SYSTEMATIC 23247176 A 863 870 halogen FAMILY 23247176 T 0 7 Halogen FAMILY 23248200 A 1057 1066 glyburide TRIVIAL 23248200 A 1068 1079 glimepiride TRIVIAL 23248200 A 1081 1093 troglitazone TRIVIAL 23248200 A 1095 1107 pioglitazone TRIVIAL 23248200 A 1109 1118 glipizide TRIVIAL 23248200 A 1120 1130 gliclazide TRIVIAL 23248200 A 1136 1147 tolbutamide TRIVIAL 23248200 A 1158 1167 metformin TRIVIAL 23248200 A 1248 1260 rosuvastatin TRIVIAL 23248200 A 1298 1307 E(2)17β-G SYSTEMATIC 23248200 A 1473 1485 rosuvastatin TRIVIAL 23248200 A 1694 1706 rosuvastatin TRIVIAL 23248200 A 222 234 Rosuvastatin TRIVIAL 23248200 A 798 825 estradiol 17β-d-glucuronide SYSTEMATIC 23248200 A 915 927 rosuvastatin TRIVIAL 23248200 T 31 43 rosuvastatin TRIVIAL 23248975 A 36 42 carbon SYSTEMATIC 23248975 A 638 650 Rhodamine 6G TRIVIAL 23248975 A 668 677 Alexa 546 TRIVIAL 23248975 T 74 80 carbon SYSTEMATIC 23249238 A 1024 1033 maleimide SYSTEMATIC 23249238 A 1060 1072 6OXY(Gly)(4) SYSTEMATIC 23249238 A 176 185 oxycodone TRIVIAL 23249238 A 206 218 tetraglycine TRIVIAL 23249238 A 246 260 6OXY(Gly)(4)OH SYSTEMATIC 23249238 A 379 391 6OXY(Gly)(4) SYSTEMATIC 23249238 A 418 427 oxycodone TRIVIAL 23249238 A 450 459 oxycodone TRIVIAL 23249238 A 470 481 hydrocodone TRIVIAL 23249238 A 568 577 oxycodone TRIVIAL 23249238 A 582 593 hydrocodone TRIVIAL 23249238 A 612 624 6OXY(Gly)(4) SYSTEMATIC 23249238 A 729 738 oxycodone TRIVIAL 23249238 A 743 754 hydrocodone TRIVIAL 23249238 A 779 790 hydrocodone TRIVIAL 23249238 A 807 818 hydrocodone TRIVIAL 23249238 A 844 856 6OXY(Gly)(4) SYSTEMATIC 23249238 A 872 883 hydrocodone TRIVIAL 23249238 A 922 927 Amide SYSTEMATIC 23249238 A 999 1008 thioether SYSTEMATIC 23249238 T 108 119 hydrocodone TRIVIAL 23249238 T 94 103 oxycodone TRIVIAL 23249274 A 0 9 Zirconium SYSTEMATIC 23249274 A 1006 1011 oxide SYSTEMATIC 23249274 A 1058 1065 nitrate SYSTEMATIC 23249274 A 1070 1077 nitrite SYSTEMATIC 23249274 A 112 117 NO(2) FORMULA 23249274 A 1136 1141 NO(2) FORMULA 23249274 A 237 242 NO(2) FORMULA 23249274 A 295 299 N(2) FORMULA 23249274 A 41 43 Zr FORMULA 23249274 A 445 450 NO(2) FORMULA 23249274 A 454 456 Zr FORMULA 23249274 A 50 56 UiO-66 IDENTIFIER 23249274 A 500 536 4,4-benzenebiphenyldicarboxylic acid SYSTEMATIC 23249274 A 538 542 BDPC ABBREVIATION 23249274 A 594 599 NO(2) FORMULA 23249274 A 603 609 UiO-67 IDENTIFIER 23249274 A 61 67 UiO-67 IDENTIFIER 23249274 A 704 710 UiO-67 IDENTIFIER 23249274 A 764 788 nitric and nitrous acids MULTIPLE 23249274 A 814 820 UiO-66 IDENTIFIER 23249274 A 831 836 NO(2) FORMULA 23249274 A 906 911 NO(2) FORMULA 23249274 A 931 933 Zr FORMULA 23249274 T 16 19 NO2 FORMULA 23249274 T 25 27 Zr FORMULA 23249274 T 81 84 NO2 FORMULA 23250485 A 0 9 Androgens FAMILY 23250485 A 144 153 androgens FAMILY 23250485 A 269 278 androgens FAMILY 23250485 A 502 510 androgen FAMILY 23250485 A 565 573 androgen FAMILY 23250485 A 829 837 androgen FAMILY 23250485 A 869 875 oxygen SYSTEMATIC 23250485 T 0 9 Androgens FAMILY 23250742 A 1021 1029 H(2)O(2) FORMULA 23250742 A 1354 1362 H(2)O(2) FORMULA 23250742 A 169 175 oxygen SYSTEMATIC 23250742 A 180 188 nitrogen SYSTEMATIC 23250742 A 350 356 oxygen SYSTEMATIC 23250742 A 361 369 nitrogen SYSTEMATIC 23250742 A 683 691 H(2)O(2) FORMULA 23250742 A 735 743 H(2)O(2) FORMULA 23250742 T 14 18 H2O2 FORMULA 23250746 A 1055 1064 palmitate TRIVIAL 23250746 A 1073 1081 ceramide FAMILY 23250746 A 1152 1160 ceramide FAMILY 23250746 A 273 282 Ceramides FAMILY 23250746 A 287 300 sphingolipids FAMILY 23250746 A 513 534 saturated fatty acids FAMILY 23250746 A 550 558 ceramide FAMILY 23250746 A 645 657 C16 ceramide SYSTEMATIC 23250746 A 667 676 palmitate TRIVIAL 23250746 A 719 731 sphingolipid FAMILY 23250746 A 772 781 palmitate TRIVIAL 23250746 A 815 827 C16 ceramide SYSTEMATIC 23250746 A 891 899 ceramide FAMILY 23250746 T 0 9 Palmitate TRIVIAL 23250746 T 53 61 ceramide FAMILY 23252343 A 19 62 2-benzoylmethylenequinoline difluoroborates FAMILY 23252343 A 237 242 (19)F FORMULA 23252343 A 247 251 (1)H FORMULA 23252343 A 252 257 (13)C FORMULA 23252343 A 556 563 NBF(2)O FORMULA 23252343 T 22 65 2-benzoylmethylenequinoline difluoroborates FAMILY 23252447 A 1094 1096 Py FORMULA 23252447 A 1111 1128 HBC(Py)([(R)-Pt]) FORMULA 23252447 A 1132 1149 HBC(Py)([(S)-Pt]) FORMULA 23252447 A 1178 1191 (BINAP)Pt(II) FORMULA 23252447 A 118 121 HBC ABBREVIATION 23252447 A 152 165 (BINAP)Pt(II) FORMULA 23252447 A 202 218 HBC(Py)([(R)-Pt] FORMULA 23252447 A 223 240 HBC(Py)([(S)-Pt]) FORMULA 23252447 A 324 326 Py FORMULA 23252447 A 328 336 [(R)-Pt] FORMULA 23252447 A 344 346 Py FORMULA 23252447 A 348 356 [(S)-Pt] FORMULA 23252447 A 432 434 Py FORMULA 23252447 A 436 444 [(R)-Pt] FORMULA 23252447 A 469 471 Py FORMULA 23252447 A 47 57 CH(2)Cl(2) FORMULA 23252447 A 473 481 [(S)-Pt] FORMULA 23252447 A 5 10 ether SYSTEMATIC 23252447 A 531 544 (BINAP)Pt(II) FORMULA 23252447 A 559 563 MeOH FORMULA 23252447 A 818 831 (BINAP)Pt(II) FORMULA 23252447 A 849 851 Py FORMULA 23252447 A 853 861 [(R)-Pt] FORMULA 23252447 A 869 871 Py FORMULA 23252447 A 873 881 [(S)-Pt] FORMULA 23252447 A 888 903 ethylenediamine SYSTEMATIC 23252447 A 89 116 hexa-peri-hexabenzocoronene SYSTEMATIC 23252447 A 937 939 Py FORMULA 23252447 T 45 62 hexabenzocoronene SYSTEMATIC 23252580 A 1032 1042 dityrosine TRIVIAL 23252580 A 1051 1061 dityrosine TRIVIAL 23252580 A 1169 1179 tryptophan TRIVIAL 23252580 A 1194 1197 Trp FORMULA 23252580 A 1244 1247 Trp FORMULA 23252580 A 1322 1330 carbonyl FAMILY 23252580 A 1422 1429 peroxyl SYSTEMATIC 23252580 A 145 152 peroxyl SYSTEMATIC 23252580 A 1700 1703 Trp FORMULA 23252580 A 204 247 2,2'-azobis(2-amidinopropane) hydrochloride SYSTEMATIC 23252580 A 249 253 AAPH ABBREVIATION 23252580 A 299 302 SDS ABBREVIATION 23252580 A 324 328 AAPH ABBREVIATION 23252580 A 56 75 glucose 6-phosphate SYSTEMATIC 23252580 A 646 650 AAPH ABBREVIATION 23252580 A 728 736 carbonyl FAMILY 23252580 A 756 770 hydroperoxides FAMILY 23252580 A 785 794 carbonyls FAMILY 23252580 A 827 840 hydroperoxide FAMILY 23252580 A 970 973 Met FORMULA 23252580 A 975 978 Trp FORMULA 23252580 A 984 987 Tyr FORMULA 23252580 T 110 117 Peroxyl SYSTEMATIC 23252580 T 147 157 Amino Acid FAMILY 23252580 T 35 54 Glucose 6-Phosphate SYSTEMATIC 23252711 A 1005 1008 DRB ABBREVIATION 23252711 A 1174 1231 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile SYSTEMATIC 23252711 A 386 443 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile SYSTEMATIC 23252711 A 874 875 C FORMULA 23252711 A 957 1003 5,6-dichlorobenzimidazone-1-β-d-ribofuranoside SYSTEMATIC 23252711 T 49 106 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile SYSTEMATIC 23252745 A 307 333 5-nitro-8-hydroxyquinoline SYSTEMATIC 23252745 A 476 487 nitroxoline TRIVIAL 23252745 A 880 891 nitroxoline TRIVIAL 23252745 T 157 168 nitroxoline TRIVIAL 23252795 A 396 405 sirolimus TRIVIAL 23252795 A 407 419 temsirolimus TRIVIAL 23252795 A 421 431 everolimus TRIVIAL 23252795 A 436 447 deforolimus TRIVIAL 23252795 A 46 55 rapamycin TRIVIAL 23252795 A 592 595 ATP ABBREVIATION 23252795 A 95 104 rapamycin TRIVIAL 23252880 A 519 525 carbon SYSTEMATIC 23253136 A 390 401 amino acids FAMILY 23253172 A 151 163 testosterone TRIVIAL 23253172 A 1662 1671 oestrogen FAMILY 23253172 A 169 183 17β-oestradiol SYSTEMATIC 23253172 A 685 699 corticosterone TRIVIAL 23253172 A 701 705 CORT ABBREVIATION 23253172 A 708 726 arginine vasotocin TRIVIAL 23253172 A 728 731 AVT ABBREVIATION 23253172 A 756 776 arginine vasopressin TRIVIAL 23253172 A 943 947 CORT ABBREVIATION 23253172 A 949 952 AVT ABBREVIATION 23253260 A 1001 1004 DON ABBREVIATION 23253260 A 1067 1071 TBTO ABBREVIATION 23253260 A 1242 1245 DON ABBREVIATION 23253260 A 1441 1445 TBTO ABBREVIATION 23253260 A 1450 1453 DON ABBREVIATION 23253260 A 230 244 deoxynivalenol TRIVIAL 23253260 A 246 249 DON ABBREVIATION 23253260 A 304 313 organotin FAMILY 23253260 A 323 340 tributyltin oxide SYSTEMATIC 23253260 A 342 346 TBTO ABBREVIATION 23253260 A 557 561 TBTO ABBREVIATION 23253260 A 713 717 TBTO ABBREVIATION 23253260 A 781 784 DON ABBREVIATION 23253260 A 917 920 DON ABBREVIATION 23254551 A 0 22 Protonated naphthalene SYSTEMATIC 23254551 A 1281 1283 Ar FORMULA 23254551 A 1291 1303 C(10)H(9)(+) FORMULA 23254551 A 1338 1350 C(10)H(9)(+) FORMULA 23254551 A 1667 1681 1-C(10)H(9)(+) SYSTEMATIC 23254551 A 1683 1697 2-C(10)H(9)(+) SYSTEMATIC 23254551 A 1699 1710 1-C(10)H(9) SYSTEMATIC 23254551 A 1716 1727 2-C(10)H(9) SYSTEMATIC 23254551 A 24 36 C(10)H(9)(+) FORMULA 23254551 A 285 299 1-C(10)H(9)(+) SYSTEMATIC 23254551 A 301 315 2-C(10)H(9)(+) SYSTEMATIC 23254551 A 317 328 1-C(10)H(9) SYSTEMATIC 23254551 A 334 345 2-C(10)H(9) SYSTEMATIC 23254551 A 363 376 para-hydrogen SYSTEMATIC 23254551 A 378 384 p-H(2) SYSTEMATIC 23254551 A 483 494 naphthalene SYSTEMATIC 23254551 A 496 505 C(10)H(8) FORMULA 23254551 A 511 517 p-H(2) SYSTEMATIC 23254551 A 578 592 1-C(10)H(9)(+) SYSTEMATIC 23254551 A 674 685 1-C(10)H(9) SYSTEMATIC 23254551 A 68 81 hydronaphthyl SYSTEMATIC 23254551 A 690 701 2-C(10)H(9) SYSTEMATIC 23254551 A 788 802 1-C(10)H(9)(+) SYSTEMATIC 23254551 A 807 818 2-C(10)H(9) SYSTEMATIC 23254551 A 841 852 1-C(10)H(9) SYSTEMATIC 23254551 A 857 871 2-C(10)H(9)(+) SYSTEMATIC 23254551 A 92 101 C(10)H(9) FORMULA 23254551 A 922 936 1-C(10)H(9)(+) SYSTEMATIC 23254551 A 961 972 2-C(10)H(9) SYSTEMATIC 23254551 A 990 1001 1-C(10)H(9) SYSTEMATIC 23254551 T 125 138 para-hydrogen SYSTEMATIC 23254551 T 37 60 protonated naphthalenes FAMILY 23254551 T 62 70 1-C10H9+ SYSTEMATIC 23254551 T 75 83 2-C10H9+ SYSTEMATIC 23255551 A 1033 1038 E-3-S SYSTEMATIC 23255551 A 1079 1091 taurocholate TRIVIAL 23255551 A 1093 1109 bromsulphthalein TRIVIAL 23255551 A 1115 1125 rifampicin TRIVIAL 23255551 A 1267 1279 methotrexate TRIVIAL 23255551 A 663 680 estrone-3-sulfate SYSTEMATIC 23255551 A 682 687 E-3-S SYSTEMATIC 23256441 A 1496 1507 solar salts FAMILY 23256441 A 160 220 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide SYSTEMATIC 23256441 A 1885 1896 solar salts FAMILY 23256441 A 222 225 MTT ABBREVIATION 23256472 A 288 294 (129)I FORMULA 23256472 A 505 511 (129)I FORMULA 23256472 A 559 565 (129)I FORMULA 23256472 A 780 786 (129)I FORMULA 23256472 T 0 10 Iodine-129 SYSTEMATIC 23256532 A 359 398 d-glycero-β-d-manno-heptose 7-phosphate SYSTEMATIC 23256532 A 545 557 carbohydrate FAMILY 23256532 A 596 603 heptose FAMILY 23256532 A 676 685 aspartate TRIVIAL 23256532 A 687 690 Asp FORMULA 23256532 A 844 854 nucleotide FAMILY 23256532 A 957 964 heptose FAMILY 23256532 T 59 96 Glycero-β-d-manno-heptose 7-Phosphate SYSTEMATIC 23256622 A 1109 1117 DRF-4012 IDENTIFIER 23256622 A 123 129 lupane TRIVIAL 23256622 A 1240 1248 DRF-4012 IDENTIFIER 23256622 A 135 146 triterpenes FAMILY 23256622 A 198 212 betulinic acid TRIVIAL 23256622 A 32 92 5'-chloro-2, 3-didehydroindolo [2', 3': 2, 3] betulinic acid SYSTEMATIC 23256622 A 425 433 DRF-4012 IDENTIFIER 23256622 A 6 20 betulinic acid TRIVIAL 23256622 A 662 670 DRF-4012 IDENTIFIER 23256622 A 766 774 DRF-4012 IDENTIFIER 23256622 A 94 102 DRF-4012 IDENTIFIER 23256622 A 960 968 DRF-4012 IDENTIFIER 23256622 T 139 199 5'-chloro-2, 3-didehydroindolo (2', 3': 2, 3) betulinic acid SYSTEMATIC 23256622 T 201 209 DRF-4012 IDENTIFIER 23256623 A 166 176 luotonin A TRIVIAL 23256623 A 205 215 luotonin A TRIVIAL 23256623 A 329 339 luotonin A TRIVIAL 23256623 A 35 45 luotonin A TRIVIAL 23256623 A 394 399 NADPH ABBREVIATION 23256623 A 616 626 luotonin A TRIVIAL 23256623 A 707 720 mono-hydroxyl SYSTEMATIC 23256623 A 753 764 di-hydroxyl SYSTEMATIC 23256623 A 844 853 quinolone FAMILY 23256623 A 934 945 quinazoline SYSTEMATIC 23256623 A 956 966 luotonin A TRIVIAL 23256623 T 44 54 luotonin A TRIVIAL 23256624 A 359 364 (14)C FORMULA 23256725 A 19 29 amino acid FAMILY 23256725 A 443 474 gonadotrophin releasing hormone TRIVIAL 23256725 A 476 480 GnRH ABBREVIATION 23256725 A 891 903 testosterone TRIVIAL 23256867 A 168 173 ester FAMILY 23256867 A 174 179 amide FAMILY 23256867 A 206 232 poly(γ-methyl l-glutamate) FAMILY 23256867 A 234 238 PMLG ABBREVIATION 23256867 A 264 280 ethylene diamine SYSTEMATIC 23256867 A 284 307 4,4'-diamino azobenzene SYSTEMATIC 23256867 A 400 405 amide FAMILY 23256867 A 478 484 quartz TRIVIAL 23256867 A 705 709 PMLG ABBREVIATION 23256867 T 91 117 Poly(γ-methyl-l-glutamate) FAMILY 23257216 A 526 534 retinoid FAMILY 23257267 A 0 7 Genipin TRIVIAL 23257267 A 1044 1054 wortmannin TRIVIAL 23257267 A 1059 1066 calcium SYSTEMATIC 23257267 A 1076 1080 EGTA ABBREVIATION 23257267 A 1092 1099 genipin TRIVIAL 23257267 A 1132 1138 oxygen SYSTEMATIC 23257267 A 1151 1154 ATP ABBREVIATION 23257267 A 1205 1212 genipin TRIVIAL 23257267 A 1302 1309 calcium SYSTEMATIC 23257267 A 1348 1355 glucose TRIVIAL 23257267 A 299 306 genipin TRIVIAL 23257267 A 310 317 glucose TRIVIAL 23257267 A 399 406 genipin TRIVIAL 23257267 A 418 425 glucose TRIVIAL 23257267 A 554 561 genipin TRIVIAL 23257267 A 571 578 glucose TRIVIAL 23257267 A 823 830 genipin TRIVIAL 23257267 A 841 844 ATP ABBREVIATION 23257267 A 860 861 K FORMULA 23257267 A 862 865 ATP ABBREVIATION 23257267 A 917 924 calcium SYSTEMATIC 23257267 A 965 972 Genipin TRIVIAL 23257267 A 984 991 glucose TRIVIAL 23257267 T 0 7 Genipin TRIVIAL 23257267 T 19 26 glucose TRIVIAL 23257267 T 72 79 calcium SYSTEMATIC 23257906 A 114 120 carbon SYSTEMATIC 23257906 A 175 181 carbon SYSTEMATIC 23257906 A 304 307 FTO ABBREVIATION 23257906 A 309 333 fluorine-doped tin oxide SYSTEMATIC 23257906 A 434 437 FTO ABBREVIATION 23257906 A 71 79 graphene TRIVIAL 23257906 T 52 60 graphene TRIVIAL 23257906 T 85 91 carbon SYSTEMATIC 23258195 A 18 66 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine SYSTEMATIC 23258195 A 326 340 MgCl(2)·6H(2)O FORMULA 23258195 A 346 350 NaCl FORMULA 23258195 A 399 404 Ozone TRIVIAL 23258195 A 624 641 secondary ozonide FAMILY 23258195 A 643 646 SOZ ABBREVIATION 23258195 A 667 675 aldehyde SYSTEMATIC 23258195 A 68 72 POPC ABBREVIATION 23258195 A 680 695 carboxylic acid SYSTEMATIC 23258195 A 928 931 SOZ ABBREVIATION 23258195 A 967 968 C FORMULA 23258195 A 999 1000 C FORMULA 23258195 T 29 43 phosphocholine SYSTEMATIC 23258195 T 69 74 ozone TRIVIAL 23258482 A 17 39 (TiO(2))(x)(Cu(2)O)(y) FAMILY 23258482 A 285 287 Ti FORMULA 23258482 A 292 294 Cu FORMULA 23258482 A 298 320 (TiO(2))(x)(Cu(2)O)(y) FAMILY 23258482 A 371 377 TiO(2) FORMULA 23258482 A 382 388 Cu(2)O FORMULA 23258482 A 401 407 TiO(2) FORMULA 23258482 A 409 415 Cu(2)O FORMULA 23258482 A 448 450 Cu FORMULA 23258482 A 619 625 oxides FAMILY 23258482 A 633 652 (TiO(2))(2)(Cu(2)O) FORMULA 23258482 T 14 28 (TiO2)x(Cu2O)y FAMILY 23259840 A 647 652 amine SYSTEMATIC 23259841 A 101 102 S FORMULA 23259841 A 108 116 halogens FAMILY 23259841 A 92 93 C FORMULA 23259841 A 95 96 N FORMULA 23259841 A 98 99 O FORMULA 23259935 A 1270 1277 PEG-HPA ABBREVIATION 23259935 A 277 305 hydroxyphenyl propionic acid SYSTEMATIC 23259935 A 307 310 HPA ABBREVIATION 23259935 A 333 354 poly(ethylene glycol) SYSTEMATIC 23259935 A 356 359 PEG ABBREVIATION 23259935 A 451 454 PEG ABBREVIATION 23259935 A 460 463 HPA ABBREVIATION 23259935 A 601 605 (1)H FORMULA 23259935 A 703 706 HPA ABBREVIATION 23259935 A 820 828 H(2)O(2) FORMULA 23259935 A 941 948 PEG-HPA ABBREVIATION 23259935 T 82 103 poly(ethylene glycol) SYSTEMATIC 23260348 A 95 144 1-aryl-4-methyl[1,2,4]triazolo[4,3-a]quinoxalines FAMILY 23260348 T 29 63 [1,2,4]triazolo[4,3-a]quinoxalines FAMILY 23261424 A 2760 2776 Arachidonic Acid TRIVIAL 23261591 A 0 8 Paraquat TRIVIAL 23261591 A 465 471 8-OHdG SYSTEMATIC 23261591 T 43 51 paraquat TRIVIAL 23261671 A 1000 1002 Se FORMULA 23261671 A 1053 1055 Se FORMULA 23261671 A 1093 1095 Se FORMULA 23261671 A 1176 1178 Se FORMULA 23261671 A 118 124 Se(IV) FORMULA 23261671 A 1257 1263 Se(IV) FORMULA 23261671 A 1300 1302 Se FORMULA 23261671 A 14 20 Se(IV) FORMULA 23261671 A 288 299 Na selenite SYSTEMATIC 23261671 A 307 309 Se FORMULA 23261671 A 326 328 Se FORMULA 23261671 A 365 367 Se FORMULA 23261671 A 525 527 Se FORMULA 23261671 A 621 627 Se(IV) FORMULA 23261671 A 638 650 chlorophylls FAMILY 23261671 A 745 757 chlorophylls FAMILY 23261671 A 797 810 chlorophyll a TRIVIAL 23261671 A 843 845 Se FORMULA 23261671 A 874 880 Se(IV) FORMULA 23261671 A 913 915 Se FORMULA 23261671 A 955 957 Se FORMULA 23261671 T 31 39 selenium SYSTEMATIC 23261671 T 73 79 Se(IV) FORMULA 23261673 A 1257 1269 phytosterols FAMILY 23261677 A 1097 1102 Nec-1 ABBREVIATION 23261677 A 1230 1233 SKN ABBREVIATION 23261677 A 173 181 Shikonin TRIVIAL 23261677 A 183 186 SKN ABBREVIATION 23261677 A 357 360 SKN ABBREVIATION 23261677 A 431 434 SKN ABBREVIATION 23261677 A 480 493 necrostatin-1 TRIVIAL 23261677 A 495 500 Nec-1 ABBREVIATION 23261677 A 586 589 SKN ABBREVIATION 23261677 A 761 764 SKN ABBREVIATION 23261677 A 810 816 oxygen SYSTEMATIC 23261677 A 841 857 N-acetylcysteine SYSTEMATIC 23261677 A 859 862 NAC ABBREVIATION 23261677 A 925 949 butylated hydroxyanisole SYSTEMATIC 23261677 A 951 954 BHA ABBREVIATION 23261677 T 0 8 Shikonin TRIVIAL 23261680 A 0 10 Nucleoside FAMILY 23261680 A 1041 1044 3TC SYSTEMATIC 23261680 A 1049 1052 d4T ABBREVIATION 23261680 A 1079 1082 ddI ABBREVIATION 23261680 A 1130 1133 AZT ABBREVIATION 23261680 A 677 680 AZT ABBREVIATION 23261680 A 681 684 ddI ABBREVIATION 23261680 A 686 689 AZT ABBREVIATION 23261680 A 690 693 3TC SYSTEMATIC 23261680 A 698 701 AZT ABBREVIATION 23261680 A 702 705 d4T ABBREVIATION 23261680 A 821 824 AZT ABBREVIATION 23261680 A 825 828 ddI ABBREVIATION 23261680 A 833 836 AZT ABBREVIATION 23261680 A 837 840 3TC SYSTEMATIC 23261680 A 918 921 AZT ABBREVIATION 23261680 A 922 925 d4T ABBREVIATION 23261716 A 1051 1059 CBCP-one ABBREVIATION 23261716 A 1079 1083 NADH ABBREVIATION 23261716 A 1087 1092 NADPH ABBREVIATION 23261716 A 1099 1104 NADPH ABBREVIATION 23261716 A 1130 1134 NADH ABBREVIATION 23261716 A 1154 1162 CBCP-one ABBREVIATION 23261716 A 1318 1333 1-acenaphthenol SYSTEMATIC 23261716 A 1338 1348 S-tetralol TRIVIAL 23261716 A 1400 1407 CBCP-ol ABBREVIATION 23261716 A 1423 1429 NAD(+) ABBREVIATION 23261716 A 1434 1441 NADP(+) ABBREVIATION 23261716 A 1461 1469 CBCP-one ABBREVIATION 23261716 A 1485 1490 NADPH ABBREVIATION 23261716 A 1598 1617 9-cis-retinaldehyde SYSTEMATIC 23261716 A 1634 1639 NADPH ABBREVIATION 23261716 A 1663 1671 CBCP-one ABBREVIATION 23261716 A 1795 1822 medroxyprogesterone acetate TRIVIAL 23261716 A 1827 1847 ursodeoxycholic acid TRIVIAL 23261716 A 1977 1989 cyclopentane SYSTEMATIC 23261716 A 2001 2007 CBP-ol ABBREVIATION 23261716 A 2012 2019 CBP-one ABBREVIATION 23261716 A 2049 2057 CBCP-one ABBREVIATION 23261716 A 2063 2068 NADPH ABBREVIATION 23261716 A 483 496 cyclopentanol SYSTEMATIC 23261716 A 509 545 2-(4-chlorobenzylidene)cyclopentanol SYSTEMATIC 23261716 A 547 554 CBCP-ol ABBREVIATION 23261716 A 575 589 cyclopentanone SYSTEMATIC 23261716 A 603 640 2-(4-chlorobenzylidene)cyclopentanone SYSTEMATIC 23261716 A 642 650 CBCP-one ABBREVIATION 23261716 A 759 766 CBCP-ol ABBREVIATION 23261716 A 784 792 CBCP-one ABBREVIATION 23261716 A 829 835 NAD(+) ABBREVIATION 23261716 A 836 843 NADP(+) ABBREVIATION 23261716 A 848 852 NADH ABBREVIATION 23261716 A 853 858 NADPH ABBREVIATION 23261716 A 922 929 CBCP-ol ABBREVIATION 23261716 A 949 955 NAD(+) ABBREVIATION 23261716 A 959 966 NADP(+) ABBREVIATION 23261758 A 0 12 Ochratoxin A TRIVIAL 23261758 A 1003 1006 OTA ABBREVIATION 23261758 A 1115 1118 OTA ABBREVIATION 23261758 A 14 17 OTA ABBREVIATION 23261758 A 1549 1552 OTA ABBREVIATION 23261758 A 1779 1782 OTA ABBREVIATION 23261758 A 206 209 OTA ABBREVIATION 23261758 A 545 548 OTA ABBREVIATION 23261758 A 697 700 OTA ABBREVIATION 23261758 A 849 852 OTA ABBREVIATION 23261758 T 27 39 ochratoxin A TRIVIAL 23261859 A 1019 1031 testosterone TRIVIAL 23261859 A 1352 1361 estradiol TRIVIAL 23261859 A 223 235 progesterone TRIVIAL 23261859 A 237 246 estradiol TRIVIAL 23261859 A 252 264 testosterone TRIVIAL 23261859 A 776 785 estradiol TRIVIAL 23261859 A 790 802 testosterone TRIVIAL 23261859 A 932 944 progesterone TRIVIAL 23261865 A 1238 1261 5-bromo-2'-deoxyuridine SYSTEMATIC 23261865 A 1263 1267 BrdU ABBREVIATION 23261865 A 1398 1405 BrdU(+) FORMULA 23261865 A 1495 1503 ZM241385 IDENTIFIER 23261865 A 1557 1564 BrdU(+) FORMULA 23261865 A 1688 1697 adenosine TRIVIAL 23261865 A 1715 1723 ZM241385 IDENTIFIER 23261865 A 298 304 oxygen SYSTEMATIC 23261865 A 309 316 glucose TRIVIAL 23261865 A 412 421 adenosine TRIVIAL 23261865 A 928 937 adenosine TRIVIAL 23261865 A 951 959 ZM241385 IDENTIFIER 23261865 T 103 112 adenosine TRIVIAL 23261865 T 11 17 oxygen SYSTEMATIC 23261865 T 22 29 glucose TRIVIAL 23261866 A 0 8 Caffeine TRIVIAL 23261866 A 1021 1033 paraxanthine TRIVIAL 23261866 A 1043 1051 caffeine TRIVIAL 23261866 A 1104 1108 cGMP ABBREVIATION 23261866 A 1153 1164 BAY 73-6691 IDENTIFIER 23261866 A 118 133 methylxanthines FAMILY 23261866 A 1206 1214 caffeine TRIVIAL 23261866 A 1224 1236 paraxanthine TRIVIAL 23261866 A 1276 1288 paraxanthine TRIVIAL 23261866 A 1298 1306 caffeine TRIVIAL 23261866 A 1319 1323 cGMP ABBREVIATION 23261866 A 140 152 paraxanthine TRIVIAL 23261866 A 1413 1425 paraxanthine TRIVIAL 23261866 A 1435 1443 caffeine TRIVIAL 23261866 A 1493 1501 dopamine TRIVIAL 23261866 A 1553 1559 l-NAME ABBREVIATION 23261866 A 1604 1608 cGMP ABBREVIATION 23261866 A 1703 1715 paraxanthine TRIVIAL 23261866 A 1785 1797 paraxanthine TRIVIAL 23261866 A 1852 1860 caffeine TRIVIAL 23261866 A 225 237 paraxanthine TRIVIAL 23261866 A 286 294 caffeine TRIVIAL 23261866 A 332 340 caffeine TRIVIAL 23261866 A 342 354 theophylline TRIVIAL 23261866 A 359 370 theobromine TRIVIAL 23261866 A 400 408 caffeine TRIVIAL 23261866 A 444 456 paraxanthine TRIVIAL 23261866 A 524 533 adenosine TRIVIAL 23261866 A 547 556 adenosine TRIVIAL 23261866 A 62 71 adenosine TRIVIAL 23261866 A 687 695 caffeine TRIVIAL 23261866 A 697 709 paraxanthine TRIVIAL 23261866 A 718 730 theophylline TRIVIAL 23261866 A 754 762 caffeine TRIVIAL 23261866 A 824 833 adenosine TRIVIAL 23261866 A 83 91 Caffeine TRIVIAL 23261866 A 874 886 paraxanthine TRIVIAL 23261866 A 910 922 nitric oxide SYSTEMATIC 23261866 A 933 967 N(G)-nitro-l-arginine methyl ester SYSTEMATIC 23261866 A 969 975 l-NAME ABBREVIATION 23261866 T 43 55 paraxanthine TRIVIAL 23261866 T 80 88 caffeine TRIVIAL 23261990 A 17 29 tetrodotoxin TRIVIAL 23261990 A 31 34 TTX ABBREVIATION 23261990 A 897 900 TTX ABBREVIATION 23261990 A 978 981 TTX ABBREVIATION 23261990 T 26 38 tetrodotoxin TRIVIAL 23262164 A 130 133 PEG ABBREVIATION 23262164 A 181 190 docetaxel TRIVIAL 23262164 A 192 195 DCX ABBREVIATION 23262164 A 214 217 PEG ABBREVIATION 23262164 A 218 224 Biotin TRIVIAL 23262164 A 241 247 biotin TRIVIAL 23262164 A 369 375 biotin TRIVIAL 23262164 A 437 440 DCX ABBREVIATION 23262164 A 451 454 PEG ABBREVIATION 23262164 A 577 580 DCX ABBREVIATION 23262164 A 672 675 PEG ABBREVIATION 23262164 A 723 726 DCX ABBREVIATION 23262164 A 728 736 Taxotere TRIVIAL 23262164 A 819 822 DCX ABBREVIATION 23262164 A 868 871 DCX ABBREVIATION 23262164 A 936 939 PEG ABBREVIATION 23262164 T 34 55 poly(ethylene glycol) SYSTEMATIC 23262164 T 80 89 docetaxel TRIVIAL 23262269 A 1075 1089 forsythoside B TRIVIAL 23262269 A 1094 1103 acteoside TRIVIAL 23262269 A 138 144 n-BuOH FORMULA 23262269 A 157 161 MeOH FORMULA 23262269 A 39 64 phenylethanoid glycosides FAMILY 23262269 A 425 524 O-α-l-rhamnopyranosyl-(1″→3')-O-[β-d-apiofuranosyl-(1‴→6')] -4'-O-[(E)-caffeoyl]-d-glucopyranoside] SYSTEMATIC 23262269 A 534 642 3,4-dihydroxy-β-phenylethoxy-O-[β-d-apiofuranosyl-(1‴→6')-α-l-rhamnopyranosyl-(1″→3')-O-β-d-glucopyranoside] SYSTEMATIC 23262269 A 66 85 peiioside A(1)/A(2) TRIVIAL 23262269 A 766 791 phenylethanoid glycosides FAMILY 23262269 A 798 812 forsythoside B TRIVIAL 23262269 A 8 21 trisaccharide FAMILY 23262269 A 821 830 acteoside TRIVIAL 23262269 A 98 109 peiioside B TRIVIAL 23262269 T 0 25 Phenylethanoid glycosides FAMILY 23262271 A 168 186 flavanol glucoside FAMILY 23262271 A 188 236 (2S,3S)-2,3-trans-dihydromorin-7-O-β-d-glucoside FAMILY 23262271 A 393 411 trans-dihydromorin TRIVIAL 23262271 A 417 431 oxyresveratrol TRIVIAL 23262271 A 441 452 steppogenin TRIVIAL 23262278 A 553 564 pepstatin A TRIVIAL 23262278 T 65 74 pepstatin TRIVIAL 23262663 A 420 431 polystyrene SYSTEMATIC 23263985 A 1100 1103 CpG ABBREVIATION 23263985 A 217 220 CpG ABBREVIATION 23263985 A 542 545 CpG ABBREVIATION 23263985 A 674 688 phosphodiester SYSTEMATIC 23263985 T 5 8 CpG ABBREVIATION 23263989 A 29 33 zinc SYSTEMATIC 23263989 A 407 408 N FORMULA 23263989 A 704 708 zinc SYSTEMATIC 23263989 A 886 892 lysine TRIVIAL 23264098 A 20 38 glatiramer acetate TRIVIAL 23264098 A 681 699 glatiramer acetate TRIVIAL 23264098 T 20 38 glatiramer acetate TRIVIAL 23264447 A 1184 1201 estrone-3-sulfate SYSTEMATIC 23264447 A 607 624 estrone-3-sulfate SYSTEMATIC 23264447 A 843 855 fexofenadine TRIVIAL 23265459 A 103 126 Selenium chloride oxide SYSTEMATIC 23265459 A 128 136 SeCl(2)O FORMULA 23265459 A 173 181 selenium SYSTEMATIC 23265459 A 201 203 Se FORMULA 23265459 A 296 298 Se FORMULA 23265459 A 326 328 Se FORMULA 23265459 A 343 353 superoxide TRIVIAL 23265459 A 365 373 hydroxyl SYSTEMATIC 23265459 A 420 430 superoxide TRIVIAL 23265459 A 451 462 glutathione TRIVIAL 23265459 A 475 478 GSH ABBREVIATION 23265459 A 510 525 malondialdehyde TRIVIAL 23265459 A 527 530 MDA ABBREVIATION 23265459 A 575 577 Se FORMULA 23265459 A 714 716 Se FORMULA 23265459 A 732 748 cyclophosphamide TRIVIAL 23265459 A 813 815 Se FORMULA 23265459 A 937 939 Se FORMULA 23265459 T 45 53 selenium SYSTEMATIC 23265461 A 315 331 deoxynucleotidyl FAMILY 23265461 A 353 381 deoxyuridine triphosphophate SYSTEMATIC 23265477 A 39 49 sulfhydryl FAMILY 23265477 A 742 752 sulfhydryl FAMILY 23265477 A 820 822 SH FORMULA 23265477 A 847 857 disulphide SYSTEMATIC 23265485 A 277 287 α-naphthol SYSTEMATIC 23265485 T 55 65 α-naphthol SYSTEMATIC 23265490 A 302 309 Menthol TRIVIAL 23265490 A 311 319 menthone TRIVIAL 23265490 A 321 329 pulegone TRIVIAL 23265490 A 334 344 eucalyptol TRIVIAL 23265490 A 925 930 β-CDs FAMILY 23265490 A 968 972 β-CD ABBREVIATION 23265500 A 101 113 fenitrothion TRIVIAL 23265500 A 123 130 benomyl TRIVIAL 23265500 A 382 389 benomyl TRIVIAL 23265500 A 39 44 ozone TRIVIAL 23265500 A 698 705 benomyl TRIVIAL 23265500 T 11 16 ozone TRIVIAL 23265503 A 1064 1076 anthocyanins FAMILY 23265503 A 237 246 phenolics FAMILY 23265503 A 301 312 flavan-3-ol FAMILY 23265503 A 323 334 anthocyanin FAMILY 23265503 A 450 471 hydroxycinnamic acids FAMILY 23265503 A 487 501 phenolic acids FAMILY 23265503 A 585 598 phenolic acid FAMILY 23265503 A 739 753 phenolic acids FAMILY 23265503 A 808 821 phenolic acid FAMILY 23265503 A 88 96 phenolic FAMILY 23265503 A 893 904 gallic acid TRIVIAL 23265503 A 990 1001 flavan-3-ol FAMILY 23265503 T 114 122 phenolic FAMILY 23265513 A 1149 1157 ethylene SYSTEMATIC 23265513 A 532 542 amino acid FAMILY 23265513 A 874 894 1-Methylcyclopropene SYSTEMATIC 23265513 A 896 901 1-MCP SYSTEMATIC 23265513 A 907 923 gibberellic acid TRIVIAL 23265513 A 925 930 GA(3) ABBREVIATION 23265513 A 969 977 ethylene SYSTEMATIC 23265513 T 130 150 1-methylcyclopropene SYSTEMATIC 23265513 T 155 171 gibberellic acid TRIVIAL 23265513 T 179 179 MULTIPLE 23265519 A 0 18 1-Deoxynojirimycin SYSTEMATIC 23265519 A 1036 1039 DNJ ABBREVIATION 23265519 A 1051 1077 2-amino-2-deoxy-D-mannitol SYSTEMATIC 23265519 A 1098 1101 DNJ ABBREVIATION 23265519 A 1126 1134 sorbitol TRIVIAL 23265519 A 1148 1151 DNJ ABBREVIATION 23265519 A 1332 1340 sorbitol TRIVIAL 23265519 A 1356 1359 DNJ ABBREVIATION 23265519 A 144 147 DNJ ABBREVIATION 23265519 A 1611 1614 DNJ ABBREVIATION 23265519 A 1696 1699 DNJ ABBREVIATION 23265519 A 20 23 DNJ ABBREVIATION 23265519 A 241 244 DNJ ABBREVIATION 23265519 A 400 403 DNJ ABBREVIATION 23265519 A 456 459 DNJ ABBREVIATION 23265519 A 514 517 DNJ ABBREVIATION 23265519 A 790 793 DNJ ABBREVIATION 23265519 A 913 916 DNJ ABBREVIATION 23265519 A 991 999 sorbitol TRIVIAL 23265519 T 42 60 1-deoxynojirimycin SYSTEMATIC 23265520 A 11 22 procyanidin FAMILY 23265520 A 48 55 glucose TRIVIAL 23265520 A 508 515 glucose TRIVIAL 23265520 A 528 537 palmitate TRIVIAL 23265520 A 593 600 glucose TRIVIAL 23265520 A 655 662 glucose TRIVIAL 23265520 A 676 685 palmitate TRIVIAL 23265520 T 11 22 procyanidin FAMILY 23265530 A 1076 1080 DAGs ABBREVIATION 23265530 A 1102 1105 DAG ABBREVIATION 23265530 A 1287 1291 DAGs ABBREVIATION 23265530 A 1305 1309 TAGs ABBREVIATION 23265530 A 1314 1318 DAGs ABBREVIATION 23265530 A 185 200 diacylglycerols FAMILY 23265530 A 202 206 DAGs ABBREVIATION 23265530 A 543 547 DAGs ABBREVIATION 23265530 A 62 78 triacylglycerols FAMILY 23265530 A 644 648 DAGs ABBREVIATION 23265530 A 764 768 DAGs ABBREVIATION 23265530 A 802 806 DAGs ABBREVIATION 23265530 A 83 98 diacylglycerols FAMILY 23265530 A 936 939 DAG ABBREVIATION 23265530 T 41 56 diacylglycerols FAMILY 23265535 A 139 149 Acrylamide TRIVIAL 23265535 A 15 31 vanadyl sulphate SYSTEMATIC 23265535 A 267 283 vanadyl sulphate SYSTEMATIC 23265535 A 285 292 VOSO(4) FORMULA 23265535 A 392 402 acrylamide TRIVIAL 23265535 A 467 483 vanadyl sulphate SYSTEMATIC 23265535 A 52 62 acrylamide TRIVIAL 23265535 A 590 602 L-asparagine TRIVIAL 23265535 A 607 616 D-glucose SYSTEMATIC 23265535 A 652 662 acrylamide TRIVIAL 23265535 A 725 741 vanadyl sulphate SYSTEMATIC 23265535 A 743 750 VOSO(4) FORMULA 23265535 A 794 800 VO(2+) FORMULA 23265535 A 804 814 asparagine TRIVIAL 23265535 A 903 913 acrylamide TRIVIAL 23265535 T 13 23 acrylamide TRIVIAL 23265535 T 37 45 vanadium SYSTEMATIC 23265536 A 101 104 CaF FORMULA 23265536 A 1044 1045 F FORMULA 23265536 A 1189 1190 F FORMULA 23265536 A 159 166 calcium SYSTEMATIC 23265536 A 183 191 graphite TRIVIAL 23265536 A 21 29 fluorine SYSTEMATIC 23265536 A 237 239 Ca FORMULA 23265536 A 248 256 graphite TRIVIAL 23265536 A 289 297 Fluorine SYSTEMATIC 23265536 A 498 499 F FORMULA 23265536 A 78 99 calcium mono-fluoride SYSTEMATIC 23265536 A 793 794 F FORMULA 23265536 A 961 962 F FORMULA 23265536 T 17 25 fluorine SYSTEMATIC 23265536 T 46 66 calcium-monofluoride SYSTEMATIC 23265540 A 139 143 NaCl FORMULA 23265540 A 145 148 KCl FORMULA 23265540 A 153 160 MgSO(4) FORMULA 23265540 A 732 737 amide FAMILY 23265540 A 954 973 aromatic amino acid FAMILY 23265543 A 233 240 alcohol FAMILY 23265543 A 241 246 ester FAMILY 23265543 A 372 377 Sugar FAMILY 23265543 A 422 430 nitrogen SYSTEMATIC 23265543 A 510 526 ammonium sulfate SYSTEMATIC 23265543 A 544 551 alcohol FAMILY 23265543 A 578 586 ammonium SYSTEMATIC 23265543 A 66 74 ammonium SYSTEMATIC 23265543 A 755 769 acetate esters FAMILY 23265543 A 796 804 ammonium SYSTEMATIC 23265543 A 843 854 acyl esters FAMILY 23265543 A 863 871 ammonium SYSTEMATIC 23265543 A 893 904 acyl esters FAMILY 23265543 A 90 95 sugar FAMILY 23265543 A 944 951 alcohol FAMILY 23265543 A 952 956 acyl FAMILY 23265543 A 982 986 acyl FAMILY 23265543 T 13 21 nitrogen SYSTEMATIC 23265543 T 57 65 alcohols FAMILY 23265543 T 66 72 esters FAMILY 23265874 A 130 139 serotonin TRIVIAL 23265874 A 260 271 Granisetron TRIVIAL 23265874 A 292 295 5HT SYSTEMATIC 23265874 A 30 70 5-hydroxytryptamine-tetramethylrhodamine SYSTEMATIC 23265874 A 357 366 serotonin TRIVIAL 23265874 A 378 381 5HT SYSTEMATIC 23265874 A 72 75 5HT SYSTEMATIC 23265874 A 82 97 indole nitrogen SYSTEMATIC 23265874 T 37 46 serotonin TRIVIAL 23265874 T 60 69 serotonin TRIVIAL 23265875 A 359 374 pyrrolopyridine SYSTEMATIC 23265875 A 379 394 pyrrolopyrazine SYSTEMATIC 23265875 A 97 100 ATP ABBREVIATION 23265876 A 283 296 2-deoxyribose SYSTEMATIC 23265876 A 433 444 3'-hydroxyl SYSTEMATIC 23265876 A 460 482 2-deoxyribonucleosides FAMILY 23265876 A 493 507 H-phosphonates FAMILY 23265876 A 519 538 3'-phenyl selenides FAMILY 23265876 A 550 582 saturated and unsaturated sugars MULTIPLE 23265876 A 617 621 ODNs FAMILY 23265876 A 629 633 ODNs FAMILY 23265876 A 671 696 C3'-dideoxyribonucleotide FAMILY 23265876 T 55 68 2-deoxyribose SYSTEMATIC 23265883 A 206 221 Nosokophic acid TRIVIAL 23265883 A 238 296 3-phosphoglycosyl-2-sesquiterpenyl dihydroxypropionic acid SYSTEMATIC 23265883 A 339 350 nosokomycin TRIVIAL 23265883 A 359 370 moenomycins FAMILY 23265883 A 41 56 nosokophic acid TRIVIAL 23265883 A 96 107 nosokomycin TRIVIAL 23265883 T 13 28 nosokophic acid TRIVIAL 23265883 T 58 69 moenomycins FAMILY 23265883 T 76 87 nosokomycin TRIVIAL 23265885 A 0 29 N-(Arylcyclopropyl)acetamides FAMILY 23265885 A 121 130 melatonin TRIVIAL 23265885 A 186 195 melatonin TRIVIAL 23265885 A 274 298 2-[(125)I]-iodomelatonin SYSTEMATIC 23265885 A 322 331 ethylenic SYSTEMATIC 23265885 A 335 346 cyclopropyl SYSTEMATIC 23265885 A 34 57 N-(arylvinyl)acetamides FAMILY 23265885 A 387 398 agomelatine TRIVIAL 23265885 A 400 408 Valdoxan TRIVIAL 23265885 A 430 441 agomelatine TRIVIAL 23265885 A 477 486 ethylenic SYSTEMATIC 23265885 A 524 535 cyclopropyl SYSTEMATIC 23265885 A 61 73 methyl ureas FAMILY 23265885 A 630 655 2,7-dimethoxy-naphtalenic SYSTEMATIC 23265885 T 118 127 melatonin TRIVIAL 23265885 T 17 46 N-(arylcyclopropyl)acetamides FAMILY 23265885 T 51 74 N-(arylvinyl)acetamides FAMILY 23265891 A 12 25 benzimidazole SYSTEMATIC 23265891 A 213 221 thiazole SYSTEMATIC 23265891 A 222 231 imidazole SYSTEMATIC 23265891 T 4 17 benzimidazole SYSTEMATIC 23265905 A 12 55 4,5-tetrahydropyrazolo[1,5-d][1,4]oxazepine SYSTEMATIC 23265905 T 30 121 2-methyl-4,5-substitutedbenzo[f]-3,3a,4,5-tetrahydro-pyrazolo[1,5-d][1,4]oxazepin-8(7H)-one FAMILY 23266123 A 15 39 triazole bisphosphonates FAMILY 23266123 A 219 227 triazole FAMILY 23266123 A 434 437 MTT ABBREVIATION 23266123 A 529 537 triazole FAMILY 23266123 A 545 559 geranylgeranyl TRIVIAL 23266123 A 646 656 isoprenoid FAMILY 23266123 T 0 8 Triazole FAMILY 23266269 A 0 16 Ganodermanondiol TRIVIAL 23266269 A 163 179 ganodermanondiol TRIVIAL 23266269 A 188 212 tert-butyl hydroperoxide SYSTEMATIC 23266269 A 214 219 t-BHP ABBREVIATION 23266269 A 245 261 Ganodermanondiol TRIVIAL 23266269 A 372 376 heme FAMILY 23266269 A 412 428 ganodermanondiol TRIVIAL 23266269 A 448 459 glutathione TRIVIAL 23266269 A 493 502 glutamine TRIVIAL 23266269 A 503 511 cysteine TRIVIAL 23266269 A 565 581 ganodermanondiol TRIVIAL 23266269 A 623 646 adenosine monophosphate SYSTEMATIC 23266269 A 724 730 Ca(2+) FORMULA 23266269 A 806 822 ganodermanondiol TRIVIAL 23266269 A 865 870 t-BHP ABBREVIATION 23266269 T 21 37 ganodermanondiol TRIVIAL 23266269 T 81 105 tert-butyl hydroperoxide SYSTEMATIC 23266270 A 1067 1071 DPEP ABBREVIATION 23266270 A 223 227 DPEP ABBREVIATION 23266270 A 296 308 nitric oxide SYSTEMATIC 23266270 A 401 403 NO FORMULA 23266270 A 408 426 prostaglandin E(2) TRIVIAL 23266270 A 428 434 PGE(2) ABBREVIATION 23266270 A 451 455 DPEP ABBREVIATION 23266270 A 50 91 trans-1,3-diphenyl-2,3-epoxypropane-1-one SYSTEMATIC 23266270 A 622 626 DPEP ABBREVIATION 23266270 A 636 638 NO FORMULA 23266270 A 643 649 PGE(2) ABBREVIATION 23266270 A 844 848 DPEP ABBREVIATION 23266270 A 922 926 DPEP ABBREVIATION 23266270 A 93 97 DPEP ABBREVIATION 23266270 T 29 70 trans-1,3-diphenyl-2,3-epoxypropane-1-one SYSTEMATIC 23266271 A 102 113 quinic acid TRIVIAL 23266271 A 1040 1054 phenolic acids FAMILY 23266271 A 118 134 chlorogenic acid TRIVIAL 23266271 A 264 278 phenolic acids FAMILY 23266271 A 573 584 quinic acid TRIVIAL 23266271 A 589 605 chlorogenic acid TRIVIAL 23266271 A 711 722 Quinic acid TRIVIAL 23266271 A 799 815 chlorogenic acid TRIVIAL 23266271 A 897 908 quinic acid TRIVIAL 23266271 A 913 929 chlorogenic acid TRIVIAL 23266271 T 23 31 phenolic FAMILY 23266271 T 43 70 chlorogenic and quinic acid MULTIPLE 23266428 A 1003 1007 GABA ABBREVIATION 23266428 A 1024 1028 mCPP ABBREVIATION 23266428 A 1029 1036 cocaine TRIVIAL 23266428 A 1037 1041 MDMA ABBREVIATION 23266428 A 1042 1045 MDA ABBREVIATION 23266428 A 1085 1089 GABA ABBREVIATION 23266428 A 1210 1217 cocaine TRIVIAL 23266428 A 1222 1226 mCPP ABBREVIATION 23266428 A 1266 1269 MDA ABBREVIATION 23266428 A 1275 1282 cocaine TRIVIAL 23266428 A 1286 1290 mCPP ABBREVIATION 23266428 A 1325 1329 MDMA ABBREVIATION 23266428 A 140 147 cocaine TRIVIAL 23266428 A 1480 1484 GABA ABBREVIATION 23266428 A 152 163 amphetamine TRIVIAL 23266428 A 1579 1583 GABA ABBREVIATION 23266428 A 1658 1666 dopamine TRIVIAL 23266428 A 1796 1800 GABA ABBREVIATION 23266428 A 186 219 3,4-methylenedioxymethamphetamine SYSTEMATIC 23266428 A 221 225 MDMA ABBREVIATION 23266428 A 257 264 ecstasy TRIVIAL 23266428 A 352 360 dopamine TRIVIAL 23266428 A 365 374 serotonin TRIVIAL 23266428 A 424 428 GABA ABBREVIATION 23266428 A 440 444 GABA ABBREVIATION 23266428 A 551 555 GABA ABBREVIATION 23266428 A 718 725 cocaine TRIVIAL 23266428 A 727 731 MDMA ABBREVIATION 23266428 A 733 762 3,4-methylenedioxyamphetamine SYSTEMATIC 23266428 A 764 767 MDA ABBREVIATION 23266428 A 773 800 meta-chlorophenylpiperazine SYSTEMATIC 23266428 A 802 806 mCPP ABBREVIATION 23266449 A 1014 1024 teniposide TRIVIAL 23266449 A 1337 1347 teniposide TRIVIAL 23266449 A 178 188 teniposide TRIVIAL 23266449 A 324 334 teniposide TRIVIAL 23266449 A 56 66 teniposide TRIVIAL 23266449 A 979 989 teniposide TRIVIAL 23266449 T 37 47 teniposide TRIVIAL 23266504 A 1029 1041 carbohydrate FAMILY 23266504 A 321 331 flavonoids FAMILY 23266504 A 346 354 Apigenin TRIVIAL 23266504 A 496 500 DPPH ABBREVIATION 23266504 A 502 506 ABTS ABBREVIATION 23266504 A 508 518 β-carotene TRIVIAL 23266504 A 538 540 Fe FORMULA 23266504 A 771 781 β-carotene TRIVIAL 23266504 A 861 869 n-hexane SYSTEMATIC 23266504 A 957 968 fatty acids FAMILY 23266504 A 973 982 vitamin E FAMILY 23266505 A 1007 1010 ALD ABBREVIATION 23266505 A 1069 1073 EGTA ABBREVIATION 23266505 A 1089 1098 calpeptin TRIVIAL 23266505 A 1194 1209 spironoclactone TRIVIAL 23266505 A 1258 1261 ALD ABBREVIATION 23266505 A 1279 1282 ALD ABBREVIATION 23266505 A 15 26 aldosterone TRIVIAL 23266505 A 216 219 ALD ABBREVIATION 23266505 A 28 31 ALD ABBREVIATION 23266505 A 280 312 ethylene glycol tetraacetic acid SYSTEMATIC 23266505 A 314 318 EGTA ABBREVIATION 23266505 A 330 339 calpeptin TRIVIAL 23266505 A 354 369 spironoclactone TRIVIAL 23266505 A 424 427 ALD ABBREVIATION 23266505 A 465 468 ALD ABBREVIATION 23266505 A 489 492 MTT ABBREVIATION 23266505 A 731 734 ALD ABBREVIATION 23266505 A 983 987 EGTA ABBREVIATION 23266505 T 128 139 aldosterone TRIVIAL 23266567 A 1074 1077 DHA ABBREVIATION 23266567 A 150 153 DHA ABBREVIATION 23266567 A 29 55 ω-3 long chain fatty acids FAMILY 23266567 A 320 358 long chain polyunsaturated fatty acids FAMILY 23266567 A 360 366 LCPUFA ABBREVIATION 23266567 A 376 379 DHA ABBREVIATION 23266567 A 514 517 DHA ABBREVIATION 23266567 A 66 86 docosahexaenoic acid SYSTEMATIC 23266567 A 676 682 LCPUFA ABBREVIATION 23266567 A 88 91 DHA ABBREVIATION 23266567 A 897 900 DHA ABBREVIATION 23266567 T 0 3 DHA ABBREVIATION 23266720 A 0 5 E-64d TRIVIAL 23266720 A 1223 1228 E-64d TRIVIAL 23266720 A 1271 1276 E-64d TRIVIAL 23266720 A 1543 1548 E-64d TRIVIAL 23266720 A 1711 1715 zinc SYSTEMATIC 23266720 A 185 190 E-64d TRIVIAL 23266720 A 282 292 penicillin FAMILY 23266720 A 349 359 penicillin FAMILY 23266720 A 509 514 E-64d TRIVIAL 23266720 A 570 575 E-64d TRIVIAL 23266720 A 819 824 E-64d TRIVIAL 23266720 T 134 144 penicillin FAMILY 23266720 T 96 101 E-64d TRIVIAL 23266728 A 111 125 anthraquinones FAMILY 23266728 A 1134 1139 rhein TRIVIAL 23266728 A 1164 1169 rhein TRIVIAL 23266728 A 136 142 emodin TRIVIAL 23266728 A 144 155 aloe-emodin TRIVIAL 23266728 A 157 162 rhein TRIVIAL 23266728 A 169 174 Rhein TRIVIAL 23266728 A 195 208 anthraquinone SYSTEMATIC 23266728 A 210 251 1, 3, 8-trihydroxy-6-methyl anthraquinone SYSTEMATIC 23266728 A 640 657 magnesium acetate SYSTEMATIC 23266728 A 658 666 methanol SYSTEMATIC 23266728 T 13 18 rhein TRIVIAL 23266730 A 1036 1050 theasaponin E1 TRIVIAL 23266730 A 1234 1242 saponins FAMILY 23266730 A 13 31 triterpene saponin FAMILY 23266730 A 234 241 saponin FAMILY 23266730 A 285 305 flavonoid glycosides FAMILY 23266730 A 431 445 theasaponin E1 TRIVIAL 23266730 A 451 465 theasaponin E2 TRIVIAL 23266730 A 471 485 theasaponin C1 TRIVIAL 23266730 A 491 505 assamsaponin C TRIVIAL 23266730 A 511 525 theasaponin H1 TRIVIAL 23266730 A 531 545 theasaponin A9 TRIVIAL 23266730 A 555 569 theasaponin A8 TRIVIAL 23266730 T 113 120 saponin FAMILY 23266730 T 30 43 triterpenoids FAMILY 23266734 A 194 198 (1)H FORMULA 23266734 A 203 208 (13)C FORMULA 23266734 A 4 29 2,5-disubstituted oxazole FAMILY 23266734 A 52 64 aspongopusin TRIVIAL 23266734 T 20 32 aspongopusin TRIVIAL 23267011 A 1017 1025 cytosine TRIVIAL 23267011 A 1116 1120 dATP ABBREVIATION 23267011 A 1145 1151 8-oxoG SYSTEMATIC 23267011 A 1194 1200 8-oxoG SYSTEMATIC 23267011 A 1276 1286 nucleotide FAMILY 23267011 A 1309 1319 syn-8-oxoG SYSTEMATIC 23267011 A 1435 1441 8-oxoG SYSTEMATIC 23267011 A 171 177 8-oxoG SYSTEMATIC 23267011 A 226 234 cytosine TRIVIAL 23267011 A 269 275 8-oxoG SYSTEMATIC 23267011 A 322 329 adenine TRIVIAL 23267011 A 351 361 syn-8-oxoG SYSTEMATIC 23267011 A 362 366 dAMP ABBREVIATION 23267011 A 523 529 8-oxoG SYSTEMATIC 23267011 A 55 90 8-oxo-7,8-dihydro-2'-deoxyguanosine SYSTEMATIC 23267011 A 576 596 anti- and syn-8-oxoG MULTIPLE 23267011 A 762 768 8-oxoG SYSTEMATIC 23267011 A 843 849 8-oxoG SYSTEMATIC 23267011 A 92 98 8-oxoG SYSTEMATIC 23267011 A 926 930 dCTP ABBREVIATION 23267011 A 978 989 anti-8-oxoG SYSTEMATIC 23267011 T 83 95 8-oxoguanine SYSTEMATIC 23267661 A 0 10 Tacrolimus TRIVIAL 23267661 A 108 112 PRED ABBREVIATION 23267661 A 1109 1113 PRED ABBREVIATION 23267661 A 1166 1169 TAC ABBREVIATION 23267661 A 12 15 TAC ABBREVIATION 23267661 A 1304 1308 PRED ABBREVIATION 23267661 A 1355 1358 TAC ABBREVIATION 23267661 A 246 249 TAC ABBREVIATION 23267661 A 343 346 TAC ABBREVIATION 23267661 A 430 433 TAC ABBREVIATION 23267661 A 435 439 PRED ABBREVIATION 23267661 A 672 676 PRED ABBREVIATION 23267661 A 704 707 TAC ABBREVIATION 23267661 A 762 766 PRED ABBREVIATION 23267661 A 791 794 TAC ABBREVIATION 23267661 A 96 106 prednisone TRIVIAL 23267661 A 981 984 TAC ABBREVIATION 23267661 T 130 140 tacrolimus TRIVIAL 23267661 T 92 102 prednisone TRIVIAL 23268337 A 1173 1181 Nile Red TRIVIAL 23268337 A 4 27 hydroxy-carboxylic acid FAMILY 23268337 A 649 658 L-lactate TRIVIAL 23268606 A 101 114 sesquiterpene FAMILY 23268606 A 11 56 dihydroagarofuran sesquiterpene polyol esters FAMILY 23268606 A 115 133 pyridine alkaloids FAMILY 23268606 A 303 307 (1)H FORMULA 23268606 A 308 312 (1)H FORMULA 23268606 A 454 466 nitric oxide SYSTEMATIC 23268606 A 58 76 triptersinines A-L MULTIPLE 23268606 T 18 31 sesquiterpene FAMILY 23268742 A 472 490 proanthocyanindins FAMILY 23268742 A 528 574 (2S)-4',5,7-trihydroxyflavan-(4β→8)-afzelechin SYSTEMATIC 23268742 A 583 632 (2S)-4',5,7-trihydroxyflavan-(4β→8)-epiafzelechin SYSTEMATIC 23268742 A 651 660 geranin B TRIVIAL 23268742 A 666 685 proanthocyanidin A2 TRIVIAL 23268742 A 695 714 proanthocyanidin A1 TRIVIAL 23268742 T 29 46 proanthocyanidins FAMILY 23270336 A 553 559 cobalt SYSTEMATIC 23270336 A 560 574 phthalocyanine TRIVIAL 23270336 A 751 757 cobalt SYSTEMATIC 23270336 A 758 772 phthalocyanine TRIVIAL 23270336 T 15 21 cobalt SYSTEMATIC 23270336 T 22 36 phthalocyanine TRIVIAL 23270378 A 117 127 vitamin B5 TRIVIAL 23270378 A 134 145 pantetheine TRIVIAL 23270378 A 147 163 Pantothenic acid TRIVIAL 23270378 A 212 222 coenzyme A TRIVIAL 23270378 A 281 291 fatty acid FAMILY 23270378 A 319 327 pyruvate TRIVIAL 23270378 A 340 351 citric acid TRIVIAL 23270378 A 373 384 pantetheine TRIVIAL 23270378 A 400 410 cysteamine TRIVIAL 23270378 A 761 772 pantetheine TRIVIAL 23270378 A 783 786 RR6 TRIVIAL 23270378 A 909 912 RR6 TRIVIAL 23270378 A 99 115 pantothenic acid TRIVIAL 23270514 A 103 111 graphene TRIVIAL 23270514 A 213 223 pyridinium SYSTEMATIC 23270514 A 230 238 pyridine SYSTEMATIC 23270514 A 245 252 cyanide SYSTEMATIC 23270514 A 263 268 amine SYSTEMATIC 23270514 A 274 283 nitrogens FAMILY 23270514 A 317 324 pyrrole SYSTEMATIC 23270514 A 330 338 nitrogen SYSTEMATIC 23270514 A 367 375 graphite TRIVIAL 23270514 A 381 389 nitrogen SYSTEMATIC 23270514 A 393 401 graphene TRIVIAL 23270514 A 443 451 nitrogen SYSTEMATIC 23270514 A 512 535 nitrogen-doped graphene TRIVIAL 23270514 A 658 674 N-doped graphene TRIVIAL 23270514 A 82 90 nitrogen SYSTEMATIC 23270514 T 110 118 graphene TRIVIAL 23270514 T 89 97 nitrogen SYSTEMATIC 23270871 A 1016 1030 n-butylbenzene SYSTEMATIC 23270871 A 1109 1112 MDA ABBREVIATION 23270871 A 1309 1317 hydroxyl SYSTEMATIC 23270871 A 1436 1439 MDA ABBREVIATION 23270871 A 1536 1539 MDA ABBREVIATION 23270871 A 1603 1611 n-hexane SYSTEMATIC 23270871 A 1613 1639 1,2,4-trimethylcyclohexane SYSTEMATIC 23270871 A 1641 1648 toluene TRIVIAL 23270871 A 1653 1667 n-butylbenzene SYSTEMATIC 23270871 A 198 204 oxygen SYSTEMATIC 23270871 A 240 248 hydroxyl SYSTEMATIC 23270871 A 258 260 OH FORMULA 23270871 A 286 301 malondialdehyde TRIVIAL 23270871 A 303 306 MDA ABBREVIATION 23270871 A 371 379 n-hexane SYSTEMATIC 23270871 A 381 389 n-octane SYSTEMATIC 23270871 A 391 398 toluene TRIVIAL 23270871 A 400 414 n-butylbenzene SYSTEMATIC 23270871 A 416 427 cyclohexane SYSTEMATIC 23270871 A 432 458 1,2,4-trimethylcyclohexane SYSTEMATIC 23270871 A 608 610 OH FORMULA 23270871 A 662 687 3,4-dihydroxybenzoic acid SYSTEMATIC 23270871 A 712 733 4-hydroxybenzoic acid SYSTEMATIC 23270871 A 864 867 MDA ABBREVIATION 23270994 A 0 22 1-Nitro-2-phenylethane SYSTEMATIC 23270994 A 1014 1032 tetraethylammonium SYSTEMATIC 23270994 A 1034 1047 glybenclamide TRIVIAL 23270994 A 1053 1068 4-aminopyridine SYSTEMATIC 23270994 A 1108 1130 1-nitro-2-phenylethane SYSTEMATIC 23270994 A 1147 1169 1-nitro-2-phenylethane SYSTEMATIC 23270994 A 1187 1230 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one SYSTEMATIC 23270994 A 1232 1235 ODQ ABBREVIATION 23270994 A 1278 1298 sodium nitroprusside SYSTEMATIC 23270994 A 1348 1357 guanylate TRIVIAL 23270994 A 1419 1441 1-nitro-2-phenylethane SYSTEMATIC 23270994 A 1475 1497 1-nitro-2-phenylethane SYSTEMATIC 23270994 A 1508 1544 cyclic guanosine 3',5'-monophosphate SYSTEMATIC 23270994 A 1546 1550 cGMP ABBREVIATION 23270994 A 1607 1610 ODQ ABBREVIATION 23270994 A 1627 1649 1-nitro-2-phenylethane SYSTEMATIC 23270994 A 1706 1715 guanylate TRIVIAL 23270994 A 1724 1728 cGMP ABBREVIATION 23270994 A 298 320 1-nitro-2-phenylethane SYSTEMATIC 23270994 A 380 402 1-nitro-2-phenylethane SYSTEMATIC 23270994 A 44 47 NO₂ FORMULA 23270994 A 485 518 L-N(G)-nitroarginine methyl ester SYSTEMATIC 23270994 A 520 526 L-NAME ABBREVIATION 23270994 A 536 548 nitric oxide SYSTEMATIC 23270994 A 627 639 indomethacin TRIVIAL 23270994 A 641 710 cis-N-(2-phenylcyclopentyl)-azacyclotridec-1-en-2-amine hydrochloride SYSTEMATIC 23270994 A 712 722 MDL-12330A IDENTIFIER 23270994 A 729 735 KT5720 IDENTIFIER 23270994 A 761 774 prostaglandin FAMILY 23270994 A 787 795 adenylyl TRIVIAL 23270994 A 840 854 methylene blue TRIVIAL 23270994 A 860 863 ODQ ABBREVIATION 23270994 A 872 881 guanylate TRIVIAL 23270994 A 939 961 1-nitro-2-phenylethane SYSTEMATIC 23270994 A 995 999 K(+) FORMULA 23270994 T 104 108 cGMP ABBREVIATION 23270994 T 28 50 1-nitro-2-phenylethane SYSTEMATIC 23270994 T 86 95 guanylate TRIVIAL 23271000 A 1085 1088 SDG ABBREVIATION 23271000 A 1274 1289 malondialdehyde TRIVIAL 23271000 A 1291 1294 MDA ABBREVIATION 23271000 A 1333 1343 superoxide TRIVIAL 23271000 A 1365 1376 glutathione TRIVIAL 23271000 A 1378 1381 GSH ABBREVIATION 23271000 A 1445 1456 cholesterol TRIVIAL 23271000 A 1468 1481 triglycerides FAMILY 23271000 A 1535 1538 SDG ABBREVIATION 23271000 A 1634 1637 SDG ABBREVIATION 23271000 A 1935 1938 STZ ABBREVIATION 23271000 A 370 402 Secoisolariciresinol diglucoside TRIVIAL 23271000 A 404 407 SDG ABBREVIATION 23271000 A 412 426 streptozotocin TRIVIAL 23271000 A 428 431 STZ ABBREVIATION 23271000 A 470 473 SDG ABBREVIATION 23271000 A 556 563 glucose TRIVIAL 23271000 A 688 699 tolbutamide TRIVIAL 23271000 A 768 771 SDG ABBREVIATION 23271000 A 826 833 glucose TRIVIAL 23271000 T 23 55 secoisolariciresinol diglucoside TRIVIAL 23271000 T 59 73 streptozotocin TRIVIAL 23271678 A 1004 1006 Se FORMULA 23271678 A 1072 1075 GRA ABBREVIATION 23271678 A 1117 1119 Se FORMULA 23271678 A 1303 1305 Se FORMULA 23271678 A 1339 1341 Se FORMULA 23271678 A 1402 1405 GRA ABBREVIATION 23271678 A 1435 1437 Se FORMULA 23271678 A 216 219 SFN ABBREVIATION 23271678 A 230 243 glucoraphanin TRIVIAL 23271678 A 245 248 GRA ABBREVIATION 23271678 A 310 312 Se FORMULA 23271678 A 326 337 glutathione TRIVIAL 23271678 A 33 45 sulforaphane TRIVIAL 23271678 A 435 437 Se FORMULA 23271678 A 442 445 GRA ABBREVIATION 23271678 A 47 50 SFN ABBREVIATION 23271678 A 575 577 Se FORMULA 23271678 A 582 585 GRA ABBREVIATION 23271678 A 663 665 Se FORMULA 23271678 A 685 687 Se FORMULA 23271678 A 754 756 Se FORMULA 23271678 A 796 798 Se FORMULA 23271678 A 857 859 Se FORMULA 23271678 A 912 914 Se FORMULA 23271678 A 929 932 GRA ABBREVIATION 23271678 T 11 19 selenium SYSTEMATIC 23271678 T 49 62 glucoraphanin TRIVIAL 23271732 A 1154 1165 amino acids FAMILY 23271732 A 1238 1239 C FORMULA 23271732 A 1602 1613 amino acids FAMILY 23271732 A 1621 1622 C FORMULA 23271732 A 353 354 C FORMULA 23271732 A 724 734 amino acid FAMILY 23271732 T 19 20 C FORMULA 23271732 T 30 41 amino acids FAMILY 23272784 A 33 52 Pb(m)Sb(2n)Te(m+3n) FAMILY 23272784 A 583 602 Pb(m)Sb(2n)Te(m+3n) FAMILY 23272784 A 739 743 PbTe FORMULA 23272784 A 746 756 Sb(2)Te(3) FORMULA 23272784 A 866 885 Pb(m)Sb(2n)Te(m+3n) FAMILY 23272784 T 45 49 PbTe FORMULA 23272784 T 50 56 Sb2Te3 FORMULA 23272784 T 65 84 Pb(m)Sb(2n)Te(m+3n) FAMILY 23273038 A 289 302 cinnamic acid TRIVIAL 23273038 A 483 496 cinnamic acid TRIVIAL 23273038 T 0 27 N-cinnamoylated chloroquine TRIVIAL 23273052 A 354 361 CoFe₂O₄ FORMULA 23273052 A 397 402 Fe₃O₄ FORMULA 23273052 A 422 428 NaZn₁₃ FORMULA 23273052 A 434 439 MgZn₂ FORMULA 23273052 A 445 452 CoFe₂O₄ FORMULA 23273052 A 454 459 Fe₃O₄ FORMULA 23273052 A 696 703 CoFe₂O₄ FORMULA 23273052 A 705 710 Fe₃O₄ FORMULA 23273052 A 853 859 NaZn₁₃ FORMULA 23273052 A 865 872 CoFe₂O₄ FORMULA 23273052 A 874 879 Fe₃O₄ FORMULA 23273052 T 57 64 CoFe₂O₄ FORMULA 23273052 T 66 71 Fe₃O₄ FORMULA 23273219 A 614 624 rifampicin TRIVIAL 23273219 A 70 124 N'-2-(4-Benzylpiperidin-/piperazin-1-yl)acylhydrazones FAMILY 23273219 T 54 107 N'-2-(4-benzylpiperidin-/piperazin-1-yl)acylhydrazone FAMILY 23273517 A 131 140 nilotinib TRIVIAL 23273517 A 219 234 trifluoromethyl SYSTEMATIC 23273517 A 22 37 trifluoromethyl SYSTEMATIC 23273517 A 267 275 fluorine SYSTEMATIC 23273517 A 282 288 methyl SYSTEMATIC 23273517 A 340 349 nilotinib TRIVIAL 23273517 A 472 481 nilotinib TRIVIAL 23273517 A 82 91 nilotinib TRIVIAL 23273517 T 73 82 nilotinib TRIVIAL 23273521 A 63 74 prolinamide TRIVIAL 23273751 A 0 13 Camptothecine TRIVIAL 23273751 A 147 150 CPT ABBREVIATION 23273751 A 15 26 Campothecin TRIVIAL 23273751 A 237 240 CPT ABBREVIATION 23273751 A 28 31 CPT ABBREVIATION 23273751 A 36 54 quinoline alkaloid FAMILY 23273751 A 439 442 CPT ABBREVIATION 23273751 A 584 587 CPT ABBREVIATION 23273751 A 589 602 9-methoxy CPT SYSTEMATIC 23273751 A 604 613 9-MeO-CPT SYSTEMATIC 23273751 A 619 633 10-hydroxy CPT SYSTEMATIC 23273751 A 635 644 10-OH-CPT SYSTEMATIC 23273751 A 801 804 CPT ABBREVIATION 23273751 A 806 815 9-MeO-CPT SYSTEMATIC 23273751 A 820 829 10-OH-CPT SYSTEMATIC 23273751 A 912 925 ethyl acetate SYSTEMATIC 23273751 T 80 93 camptothecine TRIVIAL 23273896 A 48 55 guanine TRIVIAL 23273896 A 56 66 nucleotide FAMILY 23274058 A 0 10 Jaceosidin TRIVIAL 23274058 A 1013 1023 jaceosidin TRIVIAL 23274058 A 1075 1085 jaceosidin TRIVIAL 23274058 A 1173 1180 PD98059 IDENTIFIER 23274058 A 1219 1229 jaceosidin TRIVIAL 23274058 A 1255 1265 jaceosidin TRIVIAL 23274058 A 14 23 flavonoid FAMILY 23274058 A 201 211 jaceosidin TRIVIAL 23274058 A 341 351 jaceosidin TRIVIAL 23274058 A 408 418 jaceosidin TRIVIAL 23274058 A 466 475 cisplatin TRIVIAL 23274058 A 524 534 jaceosidin TRIVIAL 23274058 A 617 626 cisplatin TRIVIAL 23274058 A 628 638 Jaceosidin TRIVIAL 23274058 A 799 809 jaceosidin TRIVIAL 23274058 A 887 897 jaceosidin TRIVIAL 23274058 T 0 10 Jaceosidin TRIVIAL 23274086 A 578 585 glucose TRIVIAL 23274086 A 586 592 carbon SYSTEMATIC 23274088 A 1118 1130 ptaquiloside TRIVIAL 23274088 A 1314 1318 zinc SYSTEMATIC 23274088 A 1370 1374 zinc SYSTEMATIC 23274088 A 1530 1534 zinc SYSTEMATIC 23274088 A 1560 1572 ptaquiloside TRIVIAL 23274088 A 1607 1615 selenium SYSTEMATIC 23274088 A 205 217 ptaquiloside TRIVIAL 23274088 A 259 267 selenium SYSTEMATIC 23274088 A 494 506 ptaquiloside TRIVIAL 23274088 A 526 534 selenium SYSTEMATIC 23274088 A 587 599 ptaquiloside TRIVIAL 23274088 A 677 685 selenium SYSTEMATIC 23274088 A 713 725 ptaquiloside TRIVIAL 23274088 T 0 12 Ptaquiloside TRIVIAL 23274088 T 103 111 selenium SYSTEMATIC 23274302 A 0 17 Indolylmaleimides FAMILY 23274302 A 1002 1008 indole SYSTEMATIC 23274302 A 215 221 PDA-66 IDENTIFIER 23274302 A 243 259 indolylmaleimide SYSTEMATIC 23274302 A 464 470 PDA-66 IDENTIFIER 23274302 A 538 544 PDA-66 IDENTIFIER 23274302 A 762 768 PDA-66 IDENTIFIER 23274302 A 795 801 PDA-66 IDENTIFIER 23274302 A 956 962 PDA-66 IDENTIFIER 23274302 T 24 40 indolylmaleimide SYSTEMATIC 23274539 A 1140 1149 rapamycin TRIVIAL 23274539 A 1172 1183 α-terpineol TRIVIAL 23274539 A 1269 1280 α-terpineol TRIVIAL 23274539 A 142 153 α-Terpineol TRIVIAL 23274539 A 159 170 monoterpene FAMILY 23274539 A 171 180 alcoholic FAMILY 23274539 A 351 362 α-terpineol TRIVIAL 23274539 A 391 394 AMP ABBREVIATION 23274539 A 432 438 sterol FAMILY 23274539 A 495 506 α-Terpineol TRIVIAL 23274539 A 583 594 α-Terpineol TRIVIAL 23274539 A 846 855 rapamycin TRIVIAL 23274539 A 939 950 α-terpineol TRIVIAL 23274539 A 952 963 α-Terpineol TRIVIAL 23274539 T 0 11 α-Terpineol TRIVIAL 23274539 T 56 59 AMP ABBREVIATION 23274539 T 81 87 sterol FAMILY 23274715 A 1061 1070 potassium SYSTEMATIC 23274715 A 480 489 potassium SYSTEMATIC 23274715 A 612 613 K FORMULA 23274715 A 64 70 carbon SYSTEMATIC 23274715 A 687 688 K FORMULA 23274715 T 105 114 potassium SYSTEMATIC 23274715 T 13 19 carbon SYSTEMATIC 23274766 A 0 10 Bile acids FAMILY 23274766 A 1084 1094 bile acids FAMILY 23274766 A 1300 1309 bile acid FAMILY 23274766 A 1343 1353 bile acids FAMILY 23274766 A 1363 1367 UDCA ABBREVIATION 23274766 A 1406 1416 bile acids FAMILY 23274766 A 1504 1514 bile acids FAMILY 23274766 A 155 165 bile acids FAMILY 23274766 A 286 296 bile acids FAMILY 23274766 A 492 502 Bile acids FAMILY 23274766 A 669 678 bile acid FAMILY 23274766 A 874 884 bile acids FAMILY 23274766 T 0 10 Bile acids FAMILY 23274770 A 1093 1104 mitragynine TRIVIAL 23274770 A 115 126 Mitragynine TRIVIAL 23274770 A 526 537 mitragynine TRIVIAL 23274770 A 713 724 mitragynine TRIVIAL 23274770 A 842 853 Mitragynine TRIVIAL 23274770 T 81 92 mitragynine TRIVIAL 23274771 A 1274 1277 DOX ABBREVIATION 23274771 A 228 239 Doxorubicin TRIVIAL 23274771 A 241 244 DOX ABBREVIATION 23274771 A 345 348 DOX ABBREVIATION 23274771 A 523 526 DOX ABBREVIATION 23274771 A 710 713 DOX ABBREVIATION 23274771 T 74 85 Doxorubicin TRIVIAL 23274777 A 293 302 spirostan TRIVIAL 23274777 A 310 320 ophiogenin TRIVIAL 23274777 A 350 360 spirostans FAMILY 23274777 A 384 407 sesquiterpene glycoside FAMILY 23274777 A 415 426 ophioside A TRIVIAL 23274777 A 456 477 monoterpene glycoside FAMILY 23274777 A 636 648 ophiopogonol TRIVIAL 23274887 A 949 956 glucose TRIVIAL 23274894 A 1016 1023 glucose TRIVIAL 23274894 A 1101 1108 Glucose TRIVIAL 23274894 A 1171 1178 calcium SYSTEMATIC 23274894 A 1347 1366 glucose-6-phosphate SYSTEMATIC 23274894 A 23 30 glucose TRIVIAL 23274894 A 298 305 glucose TRIVIAL 23274894 A 381 388 glucose TRIVIAL 23274894 A 624 631 glucose TRIVIAL 23274894 A 875 882 glucose TRIVIAL 23274894 T 37 44 Glucose TRIVIAL 23274908 A 1314 1321 glucose TRIVIAL 23274908 A 165 169 KATP FORMULA 23274908 A 275 279 KATP FORMULA 23274908 A 511 515 KATP FORMULA 23274908 A 564 573 diazoxide SYSTEMATIC 23274908 A 828 835 glucose TRIVIAL 23274908 A 837 846 Diazoxide TRIVIAL 23274908 A 865 876 tolbutamide TRIVIAL 23274908 A 976 983 glucose TRIVIAL 23275348 A 235 250 Naphthoquinones FAMILY 23275348 A 257 266 diospyrin TRIVIAL 23275348 A 271 286 7-methyljuglone SYSTEMATIC 23275348 A 580 581 N FORMULA 23275348 A 721 736 naphthoquinones FAMILY 23275348 T 19 28 diospyrin TRIVIAL 23275540 A 1065 1068 ClU ABBREVIATION 23275540 A 1152 1155 ClU ABBREVIATION 23275540 A 1161 1164 ClU ABBREVIATION 23275540 A 1410 1413 ClU ABBREVIATION 23275540 A 1420 1423 ClU ABBREVIATION 23275540 A 1586 1589 ClU ABBREVIATION 23275540 A 19 34 5-chlorouridine SYSTEMATIC 23275540 A 359 383 5-chloro-2'-deoxyuridine SYSTEMATIC 23275540 A 385 388 ClU ABBREVIATION 23275540 A 4 11 thymine TRIVIAL 23275540 A 729 732 ClU ABBREVIATION 23275540 A 903 906 ClU ABBREVIATION 23275540 A 943 946 ClU ABBREVIATION 23275540 T 37 51 5-chlorouracil SYSTEMATIC 23276137 A 60 75 N-acetyl lysine SYSTEMATIC 23276209 A 0 17 Thiosemicarbazone SYSTEMATIC 23276209 A 1049 1056 t-BuBpT ABBREVIATION 23276209 A 1130 1134 3-AP SYSTEMATIC 23276209 A 1152 1170 thiosemicarbazones FAMILY 23276209 A 151 201 3-aminopyridine-2-carboxaldehyde thiosemicarbazone SYSTEMATIC 23276209 A 203 207 3-AP SYSTEMATIC 23276209 A 308 312 3-AP SYSTEMATIC 23276209 A 387 390 BpT ABBREVIATION 23276209 A 43 80 2'-benzoylpyridine thiosemicarbazones FAMILY 23276209 A 495 501 phenyl SYSTEMATIC 23276209 A 509 513 RBpT FAMILY 23276209 A 522 532 Fe(III/II) FORMULA 23276209 A 663 667 RBpT FAMILY 23276209 A 774 777 BpT ABBREVIATION 23276209 A 82 85 BpT ABBREVIATION 23276209 A 871 878 t-BuBpT ABBREVIATION 23276209 A 948 952 3-AP SYSTEMATIC 23276209 T 0 54 Alkyl substituted 2'-benzoylpyridine thiosemicarbazone FAMILY 23276254 A 12 26 naphthyridinol SYSTEMATIC 23276254 A 1292 1306 naphthyridinol SYSTEMATIC 23276254 A 1437 1446 ascorbate TRIVIAL 23276254 A 1448 1464 N-acetylcysteine SYSTEMATIC 23276254 A 1470 1475 urate SYSTEMATIC 23276254 A 1493 1498 α-TOH ABBREVIATION 23276254 A 1579 1590 tocopherols FAMILY 23276254 A 1608 1624 naphthyiridinols FAMILY 23276254 A 1676 1691 naphthyridinols FAMILY 23276254 A 1725 1732 carbons FAMILY 23276254 A 1816 1821 α-TOH ABBREVIATION 23276254 A 329 339 tocopherol FAMILY 23276254 A 38 50 α-tocopherol TRIVIAL 23276254 A 387 402 naphthyridinols FAMILY 23276254 A 419 438 phosphatidylcholine FAMILY 23276254 A 52 57 α-TOH ABBREVIATION 23276254 A 525 545 boron dipyrromethene SYSTEMATIC 23276254 A 559 564 α-TOH ABBREVIATION 23276254 A 638 653 naphthyridinols FAMILY 23276254 A 735 742 peroxyl SYSTEMATIC 23276254 A 965 972 peroxyl SYSTEMATIC 23276254 T 70 84 naphthyridinol SYSTEMATIC 23276254 T 8 17 vitamin E FAMILY 23276728 A 107 128 N-acetylgalactosamine SYSTEMATIC 23276728 A 12 19 sulfate SYSTEMATIC 23276728 A 86 103 d-glucuronic acid TRIVIAL 23276728 T 46 53 sulfate SYSTEMATIC 23277103 A 1273 1283 glyphosate TRIVIAL 23277103 A 1288 1292 AMPA ABBREVIATION 23277103 A 1840 1850 glyphosate TRIVIAL 23277103 A 204 214 glyphosate TRIVIAL 23277103 A 2099 2109 glyphosate TRIVIAL 23277103 A 2114 2118 AMPA ABBREVIATION 23277103 A 2305 2315 glyphosate TRIVIAL 23277103 A 232 258 aminomethylphosphonic acid SYSTEMATIC 23277103 A 260 264 AMPA ABBREVIATION 23277103 A 381 391 glyphosate TRIVIAL 23277103 T 11 21 glyphosate TRIVIAL 23278282 A 1160 1170 tacrolimus TRIVIAL 23278282 A 1294 1304 tacrolimus TRIVIAL 23278282 A 27 37 tacrolimus TRIVIAL 23278282 A 448 458 nucleotide FAMILY 23278282 A 65 90 13-O-desmethyl tacrolimus SYSTEMATIC 23278282 A 665 675 tacrolimus TRIVIAL 23278282 A 945 955 tacrolimus TRIVIAL 23278282 A 95 120 15-O-desmethyl tacrolimus SYSTEMATIC 23278282 T 17 27 tacrolimus TRIVIAL 23279101 A 1033 1034 C FORMULA 23279101 A 1221 1230 histidine TRIVIAL 23279101 A 225 235 amino acid FAMILY 23279101 A 558 568 amino acid FAMILY 23279101 A 614 623 histidine TRIVIAL 23279101 A 721 724 ATP ABBREVIATION 23279101 A 744 753 histidine TRIVIAL 23279101 A 773 783 amino acid FAMILY 23279101 A 83 93 amino acid FAMILY 23279101 T 118 127 histidine TRIVIAL 23279849 A 1033 1038 morin TRIVIAL 23279849 A 1081 1086 morin TRIVIAL 23279849 A 1314 1325 thalidomide TRIVIAL 23279849 A 1330 1340 bortezomib TRIVIAL 23279849 A 137 142 morin TRIVIAL 23279849 A 1370 1375 morin TRIVIAL 23279849 A 1416 1425 flavonols FAMILY 23279849 A 144 175 3,5,7,2',4'-pentahydroxyflavone SYSTEMATIC 23279849 A 1457 1465 hydroxyl SYSTEMATIC 23279849 A 1547 1552 morin TRIVIAL 23279849 A 419 424 morin TRIVIAL 23279849 A 623 628 Morin TRIVIAL 23279849 A 820 825 morin TRIVIAL 23279849 A 885 893 tyrosine TRIVIAL 23279849 A 920 925 morin TRIVIAL 23279849 T 0 5 Morin TRIVIAL 23279849 T 21 29 tyrosine TRIVIAL 23279849 T 95 103 tyrosine TRIVIAL 23279941 A 178 180 Fe FORMULA 23279941 A 182 184 Ca FORMULA 23279941 A 186 188 Mg FORMULA 23279941 A 190 192 Zn FORMULA 23279941 A 194 196 Cu FORMULA 23279941 A 198 200 Na FORMULA 23279941 A 205 206 K FORMULA 23279941 T 29 31 Fe FORMULA 23279941 T 33 35 Ca FORMULA 23279941 T 37 39 Mg FORMULA 23279941 T 41 43 Zn FORMULA 23279941 T 45 47 Cu FORMULA 23279941 T 49 51 Na FORMULA 23279941 T 56 57 K FORMULA 23280515 A 109 116 silicon SYSTEMATIC 23280515 A 186 194 catechol TRIVIAL 23280515 A 213 220 silicon SYSTEMATIC 23280515 A 31 39 catechol TRIVIAL 23280515 A 435 442 lithium SYSTEMATIC 23280515 T 54 61 silicon SYSTEMATIC 23280515 T 85 92 lithium SYSTEMATIC 23280651 A 0 10 Coatline A TRIVIAL 23280651 A 19 35 α-epi-coatline A TRIVIAL 23280651 A 503 514 schoepfin A TRIVIAL 23280651 A 531 542 schoepfin D TRIVIAL 23280651 A 637 646 coatlines FAMILY 23280651 T 40 49 coatlines FAMILY 23280947 A 1076 1083 uranium SYSTEMATIC 23280947 A 1141 1148 uranium SYSTEMATIC 23280947 A 1255 1262 uranium SYSTEMATIC 23280947 A 1472 1479 uranium SYSTEMATIC 23280947 A 1602 1609 uranium SYSTEMATIC 23280947 A 1731 1738 uranium SYSTEMATIC 23280947 A 489 496 uranium SYSTEMATIC 23280947 A 498 499 U FORMULA 23280947 A 654 661 uranium SYSTEMATIC 23280947 T 123 130 uranium SYSTEMATIC 23280947 T 42 49 uranium SYSTEMATIC 23280986 A 185 192 leucine TRIVIAL 23280986 T 15 25 amino acid FAMILY 23281098 A 323 334 iridium-oxo SYSTEMATIC 23281098 A 714 716 Ir FORMULA 23281098 T 66 73 iridium SYSTEMATIC 23281267 A 295 298 SDS ABBREVIATION 23281296 A 118 124 Fe3 O4 FORMULA 23281296 A 289 295 Fe3 O4 FORMULA 23281296 A 29 35 silica TRIVIAL 23281296 A 297 301 SiO2 FORMULA 23281296 A 633 643 folic acid TRIVIAL 23281296 A 753 759 folate TRIVIAL 23281296 A 92 102 iron oxide SYSTEMATIC 23281296 T 106 111 Fe3O4 FORMULA 23281296 T 132 138 silica TRIVIAL 23281663 A 711 753 poly(ethylene glycol)-block-poly(l-lysine) FAMILY 23281663 A 755 765 PEG-b-PLys ABBREVIATION 23281663 A 771 824 poly(N-isopropylacrylamide)-block-poly(aspartic acid) FAMILY 23281663 A 826 839 PNIPAM-b-PAsp ABBREVIATION 23281663 A 995 1001 (125)I FORMULA 23281812 A 206 217 aldosterone TRIVIAL 23281812 A 242 250 estrogen FAMILY 23281812 A 304 315 aldosterone TRIVIAL 23281812 A 556 635 pyridinylmethyl substituted 1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-ones FAMILY 23281812 A 706 715 methylene SYSTEMATIC 23281812 T 0 28 Tetrahydropyrroloquinolinone SYSTEMATIC 23281812 T 63 74 aldosterone TRIVIAL 23282042 A 154 168 Mosher's ester TRIVIAL 23282042 A 27 43 brevipolides A-J FAMILY 23282042 A 317 330 brevipolide J TRIVIAL 23282042 A 397 432 6-heptyl-5,6-dihydro-2H-pyran-2-one SYSTEMATIC 23282042 A 458 470 cyclopropane SYSTEMATIC 23282042 A 485 497 brevipolides FAMILY 23282042 A 520 531 isoferuloyl TRIVIAL 23282042 A 553 571 p-methoxycinnamoyl SYSTEMATIC 23282042 A 640 670 6-heptyl-5,6-dihydro-α-pyrones FAMILY 23282042 A 798 807 (1)H-(1)H FORMULA 23282042 A 981 993 brevipolides FAMILY 23282042 T 54 66 brevipolides FAMILY 23282042 T 78 99 5,6-dihydro-α-pyrones FAMILY 23282091 A 12 24 WO2012081692 IDENTIFIER 23282091 A 600 608 pyrazole SYSTEMATIC 23282091 A 68 76 pyrazole SYSTEMATIC 23282091 A 732 742 suvorexant TRIVIAL 23282091 T 100 112 WO2012081692 IDENTIFIER 23282222 A 0 6 Silver SYSTEMATIC 23282222 A 1029 1031 Ag FORMULA 23282222 A 352 355 PEI ABBREVIATION 23282222 A 363 365 Ag FORMULA 23282222 A 44 60 polyethylenimine SYSTEMATIC 23282222 A 491 494 PEI ABBREVIATION 23282222 A 502 504 Ag FORMULA 23282222 A 62 65 PEI ABBREVIATION 23282222 A 723 726 PEI ABBREVIATION 23282222 A 772 774 Ag FORMULA 23282222 A 854 856 Ag FORMULA 23282222 T 65 81 polyethylenimine SYSTEMATIC 23282222 T 89 95 silver SYSTEMATIC 23282278 A 517 537 boron dipyrromethene SYSTEMATIC 23282278 A 539 545 BODIPY ABBREVIATION 23282278 A 554 560 BODIPY ABBREVIATION 23282278 A 944 950 BODIPY ABBREVIATION 23282998 A 0 7 Arsenic SYSTEMATIC 23282998 A 1119 1129 superoxide TRIVIAL 23282998 A 1201 1209 carbonyl FAMILY 23282998 A 1236 1243 arsenic SYSTEMATIC 23282998 A 1483 1490 arsenic SYSTEMATIC 23282998 A 1586 1593 arsenic SYSTEMATIC 23282998 A 1713 1720 arsenic SYSTEMATIC 23282998 A 182 207 deoxyuridine triphosphate SYSTEMATIC 23282998 A 367 374 arsenic SYSTEMATIC 23282998 A 472 485 ascorbic acid TRIVIAL 23282998 A 586 593 arsenic SYSTEMATIC 23282998 A 892 899 arsenic SYSTEMATIC 23282998 A 997 1004 arsenic SYSTEMATIC 23282998 T 20 27 arsenic SYSTEMATIC 23283976 A 1182 1188 Mg(2+) FORMULA 23283976 A 355 361 Mg(2+) FORMULA 23283976 A 411 417 Mg(2+) FORMULA 23283976 A 435 441 Mg(2+) FORMULA 23283976 A 480 490 aspartates FAMILY 23283976 A 756 762 Mg(2+) FORMULA 23283976 A 786 795 aspartate TRIVIAL 23283976 A 844 850 Mg(2+) FORMULA 23283976 A 94 104 nucleotide FAMILY 23286196 A 149 188 5-benzyl-3-phenyl-4,5-dihydroisoxazoles FAMILY 23286196 A 193 227 5-benzyl-3-phenyl-1,4,2-dioxazoles FAMILY 23286196 A 424 435 d-luciferin TRIVIAL 23286196 A 440 443 ATP ABBREVIATION 23286196 A 662 673 resveratrol TRIVIAL 23286196 A 870 881 resveratrol TRIVIAL 23286196 T 13 52 5-benzyl-3-phenyl-4,5-dihydroisoxazoles FAMILY 23286196 T 57 91 5-benzyl-3-phenyl-1,4,2-dioxazoles FAMILY 23286367 A 1040 1043 PCL ABBREVIATION 23286367 A 395 420 poly(methyl methacrylate) SYSTEMATIC 23286367 A 422 426 PMMA ABBREVIATION 23286367 A 474 486 benzophenone SYSTEMATIC 23286367 A 588 592 PMMA ABBREVIATION 23286367 A 624 631 acrylic SYSTEMATIC 23286367 A 685 689 PMMA ABBREVIATION 23286367 A 843 847 PMMA ABBREVIATION 23286367 A 85 91 quartz TRIVIAL 23286367 A 949 965 polycaprolactone SYSTEMATIC 23286367 A 967 970 PCL ABBREVIATION 23287076 A 1043 1055 flubendazole TRIVIAL 23287076 A 117 129 flubendazole TRIVIAL 23287076 A 378 390 flubendazole TRIVIAL 23287076 A 435 447 flubendazole TRIVIAL 23287076 A 449 460 Albendazole TRIVIAL 23287076 A 491 503 Flubendazole TRIVIAL 23287076 A 508 519 albendazole TRIVIAL 23287076 A 931 943 flubendazole TRIVIAL 23287076 T 15 28 benzimidazole SYSTEMATIC 23287076 T 47 59 flubendazole TRIVIAL 23287313 A 1189 1212 unsaturated fatty acids FAMILY 23287313 A 1214 1217 UFA ABBREVIATION 23287313 A 1230 1241 phytosterol FAMILY 23287313 A 1243 1255 β-sitosterol TRIVIAL 23287313 A 1257 1268 campesterol TRIVIAL 23287313 A 1274 1286 stigmasterol TRIVIAL 23287313 A 1359 1371 β-sitosterol TRIVIAL 23287313 A 1409 1421 phytosterone FAMILY 23287313 A 464 475 cholesterol TRIVIAL 23287313 A 509 520 cholesterol TRIVIAL 23287313 A 536 547 cholesterol TRIVIAL 23287313 A 564 576 triglyceride FAMILY 23287313 A 646 657 cholesterol TRIVIAL 23287313 A 672 681 bile acid FAMILY 23287313 A 819 828 carnitine TRIVIAL 23287313 A 879 890 cholesterol TRIVIAL 23287426 A 0 10 Perampanel TRIVIAL 23287426 A 1138 1148 perampanel TRIVIAL 23287426 A 1289 1299 Perampanel TRIVIAL 23287426 A 1443 1453 perampanel TRIVIAL 23287426 A 284 294 perampanel TRIVIAL 23287426 A 380 433 α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid SYSTEMATIC 23287426 A 435 439 AMPA ABBREVIATION 23287426 A 453 462 glutamate TRIVIAL 23287426 A 545 555 Perampanel TRIVIAL 23287426 A 720 730 Perampanel TRIVIAL 23287426 A 961 971 perampanel TRIVIAL 23287426 T 47 57 perampanel TRIVIAL 23287738 A 328 346 3,5-dimethylphenyl SYSTEMATIC 23287738 A 351 366 4-methoxyphenyl SYSTEMATIC 23287738 A 484 542 5-chloro-4-(4-alkoxyphenoxy)-2-(benzyl)pyridazin-3(2H)-one SYSTEMATIC 23287738 A 568 636 5-chloro-2-(9H-fluoren-9-yl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one SYSTEMATIC 23287738 A 641 649 CYM50769 IDENTIFIER 23287738 A 98 169 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one SYSTEMATIC 23288054 A 1029 1035 iodide SYSTEMATIC 23288054 A 1040 1046 iodide SYSTEMATIC 23288054 A 1089 1095 iodide SYSTEMATIC 23288054 A 1100 1106 iodide SYSTEMATIC 23288054 A 1145 1151 iodide SYSTEMATIC 23288054 A 1262 1277 thyroid hormone FAMILY 23288054 A 189 195 iodide SYSTEMATIC 23288054 A 360 366 iodide SYSTEMATIC 23288054 A 398 404 iodide SYSTEMATIC 23288054 A 414 420 iodide SYSTEMATIC 23288054 A 448 454 iodide SYSTEMATIC 23288054 A 472 478 Iodide SYSTEMATIC 23288054 A 636 642 iodide SYSTEMATIC 23288054 A 658 664 iodide SYSTEMATIC 23288054 A 729 744 thyroid hormone FAMILY 23288054 A 787 796 thyroxine TRIVIAL 23288054 A 842 858 triiodothyronine TRIVIAL 23288054 T 14 20 iodide SYSTEMATIC 23288142 A 1008 1018 wortmannin TRIVIAL 23288142 A 1029 1032 TPA ABBREVIATION 23288142 A 106 133 polyunsaturated fatty acids FAMILY 23288142 A 1091 1094 DHA ABBREVIATION 23288142 A 1194 1197 DHA ABBREVIATION 23288142 A 1201 1204 TPA ABBREVIATION 23288142 A 1306 1309 DHA ABBREVIATION 23288142 A 1367 1370 DHA ABBREVIATION 23288142 A 1451 1454 TPA ABBREVIATION 23288142 A 216 236 docosahexaenoic acid SYSTEMATIC 23288142 A 238 241 DHA ABBREVIATION 23288142 A 247 260 linoleic acid TRIVIAL 23288142 A 371 374 DHA ABBREVIATION 23288142 A 385 421 12-O-tetradecanoylphorbol-13-acetate SYSTEMATIC 23288142 A 423 426 TPA ABBREVIATION 23288142 A 463 466 TPA ABBREVIATION 23288142 A 553 556 DHA ABBREVIATION 23288142 A 685 692 PD98059 IDENTIFIER 23288142 A 702 712 wortmannin TRIVIAL 23288142 A 726 735 GF109203X IDENTIFIER 23288142 A 755 758 TPA ABBREVIATION 23288142 A 813 816 TPA ABBREVIATION 23288142 A 877 880 DHA ABBREVIATION 23288142 A 926 935 GF109203X IDENTIFIER 23288142 A 986 989 DHA ABBREVIATION 23288142 A 995 1002 PD98059 IDENTIFIER 23288142 T 108 144 12-O-tetradecanoylphorbol-13-acetate SYSTEMATIC 23288142 T 55 75 docosahexaenoic acid SYSTEMATIC 23288142 T 88 92 heme FAMILY 23288712 A 616 625 fullerene TRIVIAL 23288712 A 654 663 fullerene TRIVIAL 23288712 A 706 715 fullerene TRIVIAL 23288712 A 736 745 fullerene TRIVIAL 23288712 A 759 768 fullerene TRIVIAL 23288712 A 817 826 fullerene TRIVIAL 23288946 A 574 598 1,25-dihydroxyvitamin D₃ SYSTEMATIC 23288946 A 862 870 glycerol TRIVIAL 23288946 A 909 929 phosphatidylglycerol FAMILY 23288947 A 655 666 cholesterol TRIVIAL 23289502 A 0 13 Cyclic di-GMP TRIVIAL 23289502 A 15 23 c-di-GMP ABBREVIATION 23289502 A 202 210 c-di-GMP ABBREVIATION 23289502 A 319 327 c-di-GMP ABBREVIATION 23289502 A 389 397 c-di-GMP ABBREVIATION 23289502 A 569 577 c-di-GMP ABBREVIATION 23289502 A 634 642 c-di-GMP ABBREVIATION 23289502 A 856 864 c-di-GMP ABBREVIATION 23289502 T 41 54 cyclic di-GMP TRIVIAL 23289665 A 149 152 azo SYSTEMATIC 23289665 A 171 194 1-phenyl-azo-2-naphthol SYSTEMATIC 23289665 A 196 203 Sudan I TRIVIAL 23289665 A 256 263 Sudan I TRIVIAL 23289665 A 306 314 hydrogen SYSTEMATIC 23289665 A 381 384 C-H FORMULA 23289665 A 387 388 O FORMULA 23289665 A 389 397 hydrogen SYSTEMATIC 23289665 A 766 781 dichloromethane SYSTEMATIC 23289665 A 783 803 carbon tetrachloride SYSTEMATIC 23289665 A 809 819 chloroform TRIVIAL 23289665 A 836 843 hydrazo SYSTEMATIC 23289665 A 909 916 Sudan I TRIVIAL 23289665 T 11 18 hydrazo SYSTEMATIC 23289665 T 34 41 Sudan I TRIVIAL 23289665 T 42 45 azo SYSTEMATIC 23289665 T 7 10 azo SYSTEMATIC 23289770 A 122 127 diazo SYSTEMATIC 23289770 A 161 172 phosphonate SYSTEMATIC 23289770 A 270 297 cycloprop(en)ylphosphonates FAMILY 23289770 A 328 352 α-cyano diazophosphonate SYSTEMATIC 23289770 A 34 45 rhodium(II) SYSTEMATIC 23289770 A 357 373 Rh(2)(S-IBAZ)(4) FORMULA 23289770 A 421 451 phosphonic and carboxylic acid MULTIPLE 23289770 A 498 517 α-cyano diazo ester SYSTEMATIC 23289770 A 545 580 α-cyano cycloprop(en)ylcarboxylates FAMILY 23289770 A 674 686 cyanocarbene SYSTEMATIC 23289770 A 76 83 alkenes FAMILY 23289770 A 794 801 allenes FAMILY 23289770 A 85 92 alkynes FAMILY 23289770 A 909 932 alkylidenecyclopropanes FAMILY 23289770 A 98 105 allenes FAMILY 23289770 T 125 148 cyclopropylphosphonates FAMILY 23289770 T 153 176 alkylidenecyclopropanes FAMILY 23289770 T 16 28 Rh2(S-IBAZ)4 FORMULA 23289770 T 59 66 alkenes FAMILY 23289770 T 68 75 alkynes FAMILY 23289770 T 81 88 allenes FAMILY 23289972 A 1106 1109 Tyr FORMULA 23289972 A 1115 1118 His FORMULA 23289972 A 1124 1127 Ser FORMULA 23289972 A 1133 1136 His FORMULA 23289972 A 1201 1204 Tyr FORMULA 23289972 A 1210 1213 His FORMULA 23289972 A 1219 1222 Ser FORMULA 23289972 A 1231 1234 Tyr FORMULA 23289972 A 18 40 thiazolidine-2,4-dione SYSTEMATIC 23289972 A 209 213 (1)H FORMULA 23289972 A 215 220 (13)C FORMULA 23289972 A 45 60 barbituric acid TRIVIAL 23289972 A 720 727 glucose TRIVIAL 23289972 T 13 35 thiazolidine-2,4-dione SYSTEMATIC 23289972 T 36 56 biphenylcarbonitrile SYSTEMATIC 23290487 A 321 328 glucose TRIVIAL 23290487 A 467 476 palmatine TRIVIAL 23290487 A 544 551 glucose TRIVIAL 23290487 A 681 688 glucose TRIVIAL 23290487 A 733 742 palmatine TRIVIAL 23291036 A 1117 1126 ibuprofen TRIVIAL 23291036 A 304 317 hydroxypropyl SYSTEMATIC 23291036 A 345 353 caffeine TRIVIAL 23291036 A 415 422 glucose TRIVIAL 23291036 A 473 482 ibuprofen TRIVIAL 23291036 A 487 490 PEG ABBREVIATION 23291037 A 332 355 diltiazem hydrochloride SYSTEMATIC 23291037 A 527 550 diltiazem hydrochloride SYSTEMATIC 23291037 A 7 30 diltiazem hydrochloride SYSTEMATIC 23291046 A 1011 1017 t-AUCB ABBREVIATION 23291046 A 1071 1080 adamantyl SYSTEMATIC 23291046 A 1092 1096 urea TRIVIAL 23291046 A 1127 1133 phenyl SYSTEMATIC 23291046 A 1145 1149 urea TRIVIAL 23291046 A 1347 1351 TPPU ABBREVIATION 23291046 A 1453 1461 epoxides FAMILY 23291046 A 1513 1519 t-AUCB ABBREVIATION 23291046 A 1537 1543 phenyl SYSTEMATIC 23291046 A 1607 1616 adamantyl SYSTEMATIC 23291046 A 175 184 adamantyl SYSTEMATIC 23291046 A 196 200 urea TRIVIAL 23291046 A 285 294 adamantyl SYSTEMATIC 23291046 A 327 333 phenyl SYSTEMATIC 23291046 A 696 754 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea SYSTEMATIC 23291046 A 756 760 TPPU ABBREVIATION 23291046 A 8 15 epoxide SYSTEMATIC 23291046 A 918 927 adamantyl SYSTEMATIC 23291046 A 945 1009 trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid SYSTEMATIC 23291046 T 113 120 epoxide SYSTEMATIC 23291046 T 12 18 phenyl SYSTEMATIC 23291046 T 94 98 urea TRIVIAL 23291121 A 103 116 benzaldehydes FAMILY 23291121 A 12 76 N-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)thiosemicarbazide SYSTEMATIC 23291121 A 143 221 benzaldehyde N-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)thiosemicarbazones FAMILY 23291121 A 327 345 thiosemicarbazones FAMILY 23291121 A 383 387 (1)H FORMULA 23291121 A 393 398 (13)C FORMULA 23291121 A 457 475 thiosemicarbazones FAMILY 23291121 A 651 669 thiosemicarbazones FAMILY 23291121 A 720 724 DPPH ABBREVIATION 23291121 A 888 891 GSH ABBREVIATION 23291121 T 26 44 thiosemicarbazones FAMILY 23291121 T 62 75 benzaldehydes FAMILY 23291121 T 80 136 N-(tetra-O-acetyl-β-D-galactopyranosyl)thiosemicarbazide SYSTEMATIC 23291240 A 1296 1307 desmosterol TRIVIAL 23291240 A 1309 1320 cholesterol TRIVIAL 23291240 A 1325 1347 24S-hydroxycholesterol SYSTEMATIC 23291240 A 1410 1421 cholesterol TRIVIAL 23291240 A 1426 1448 24S-hydroxycholesterol SYSTEMATIC 23291240 A 1550 1561 cholesterol TRIVIAL 23291240 A 24 35 cholesterol TRIVIAL 23291240 A 377 388 cholesterol TRIVIAL 23291240 A 577 588 cholesterol TRIVIAL 23291240 A 594 605 cholesterol TRIVIAL 23291240 A 617 627 lanosterol TRIVIAL 23291240 A 629 640 lathosterol TRIVIAL 23291240 A 645 656 desmosterol TRIVIAL 23291240 A 666 677 cholesterol TRIVIAL 23291240 A 699 721 24S-hydroxycholesterol SYSTEMATIC 23291240 A 726 747 27-hydroxycholesterol SYSTEMATIC 23291240 A 871 882 desmosterol TRIVIAL 23291240 A 884 895 cholesterol TRIVIAL 23291240 A 900 922 24S-hydroxycholesterol SYSTEMATIC 23291240 A 948 970 24S-hydroxycholesterol SYSTEMATIC 23291240 T 27 38 cholesterol TRIVIAL 23291325 A 1048 1050 Pb FORMULA 23291325 A 179 189 Pb-acetate SYSTEMATIC 23291325 A 279 289 Pb-acetate SYSTEMATIC 23291325 A 362 374 co-enzymes Q FAMILY 23291325 A 408 419 glutathione TRIVIAL 23291325 A 572 582 Pb-acetate SYSTEMATIC 23291325 A 6 8 Pb FORMULA 23291325 A 868 870 Pb FORMULA 23291325 A 948 957 phenolics FAMILY 23291325 A 962 972 flavonoids FAMILY 23291326 A 655 664 α-thujone TRIVIAL 23291326 A 666 673 camphor TRIVIAL 23291326 A 675 682 borneol TRIVIAL 23291326 A 684 695 γ-muurolene TRIVIAL 23291326 A 700 708 sclareol TRIVIAL 23291333 A 138 150 alkyl esters FAMILY 23291333 A 200 211 gallic acid TRIVIAL 23291333 A 58 69 gallic acid TRIVIAL 23291333 A 78 83 ester FAMILY 23291333 T 0 12 Alkyl esters FAMILY 23291333 T 16 27 gallic acid TRIVIAL 23291401 A 1025 1036 nucleotides FAMILY 23291401 A 113 123 nucleotide FAMILY 23291401 A 1185 1195 nucleotide FAMILY 23291401 A 1299 1309 nucleotide FAMILY 23291401 A 1373 1383 nucleotide FAMILY 23291401 A 272 282 nucleotide FAMILY 23291401 A 341 351 amino acid FAMILY 23291401 A 579 589 nucleotide FAMILY 23291401 T 141 152 nucleotides FAMILY 23291401 T 70 88 3' ribonucleotides FAMILY 23291559 A 118 131 phenobarbital TRIVIAL 23291559 A 272 285 phenobarbital TRIVIAL 23291559 A 339 352 phenobarbital TRIVIAL 23291559 A 42 46 K(+) FORMULA 23291559 A 731 744 phenobarbital TRIVIAL 23291559 A 779 792 phenobarbital TRIVIAL 23291559 A 842 855 phenobarbital TRIVIAL 23291559 T 118 131 phenobarbital TRIVIAL 23291559 T 57 59 K+ FORMULA 23291560 A 0 11 Zearalenone TRIVIAL 23291560 A 1014 1026 progesterone TRIVIAL 23291560 A 1195 1198 ZEA ABBREVIATION 23291560 A 13 16 ZEA ABBREVIATION 23291560 A 1313 1316 ZEA ABBREVIATION 23291560 A 1388 1391 ZEA ABBREVIATION 23291560 A 1571 1574 ZEA ABBREVIATION 23291560 A 164 167 ZEA ABBREVIATION 23291560 A 352 355 ZEA ABBREVIATION 23291560 A 369 387 diethylstilbestrol SYSTEMATIC 23291560 A 476 479 ZEA ABBREVIATION 23291560 A 553 556 ZEA ABBREVIATION 23291560 A 876 879 ZEA ABBREVIATION 23291560 T 32 43 zearalenone TRIVIAL 23291713 A 1070 1081 chloroquine TRIVIAL 23291713 A 395 406 chloroquine TRIVIAL 23291713 A 449 467 hydroxychloroquine SYSTEMATIC 23291713 A 624 635 chloroquine TRIVIAL 23291713 A 885 896 chloroquine TRIVIAL 23292193 A 1016 1026 selenolate SYSTEMATIC 23292193 A 215 231 Au(18)(SePh)(14) FORMULA 23292193 A 288 313 Au(25)(SCH(2)CH(2)Ph)(18) FORMULA 23292193 A 319 331 selenophenol SYSTEMATIC 23292193 A 41 56 selenophenolate SYSTEMATIC 23292193 A 455 471 Au(18)(SePh)(14) FORMULA 23292193 A 512 528 Au(15)(SePh)(13) FORMULA 23292193 A 530 546 Au(19)(SePh)(15) FORMULA 23292193 A 551 567 Au(20)(SePh)(16) FORMULA 23292193 A 639 655 Au(18)(SePh)(14) FORMULA 23292193 A 67 83 Au(18)(SePh)(14) FORMULA 23292193 A 748 752 (1)H FORMULA 23292193 A 753 758 (13)C FORMULA 23292193 A 869 879 selenolate SYSTEMATIC 23292193 A 890 896 Au(18) FORMULA 23292193 T 13 23 selenolate SYSTEMATIC 23292193 T 34 48 Au18(SeC6H5)14 FORMULA 23292249 A 103 106 Cyt FORMULA 23292249 A 1034 1037 Hyp ABBREVIATION 23292249 A 1038 1041 Cyt FORMULA 23292249 A 1042 1045 Hyp ABBREVIATION 23292249 A 1047 1050 Cyt FORMULA 23292249 A 1056 1059 Hyp ABBREVIATION 23292249 A 1061 1064 Thy FORMULA 23292249 A 1065 1068 Hyp ABBREVIATION 23292249 A 1069 1072 Thy FORMULA 23292249 A 109 112 Hyp ABBREVIATION 23292249 A 1121 1124 Hyp ABBREVIATION 23292249 A 1125 1128 Hyp ABBREVIATION 23292249 A 1129 1132 Hyp ABBREVIATION 23292249 A 113 116 Thy FORMULA 23292249 A 1134 1137 Hyp ABBREVIATION 23292249 A 122 125 Hyp ABBREVIATION 23292249 A 127 130 Hyp ABBREVIATION 23292249 A 1308 1311 Hyp ABBREVIATION 23292249 A 1312 1315 Cyt FORMULA 23292249 A 1320 1323 Hyp ABBREVIATION 23292249 A 1325 1328 Thy FORMULA 23292249 A 1350 1353 Hyp ABBREVIATION 23292249 A 1354 1357 Hyp ABBREVIATION 23292249 A 1422 1425 Hyp ABBREVIATION 23292249 A 1427 1430 Cyt FORMULA 23292249 A 1433 1436 Hyp ABBREVIATION 23292249 A 1437 1440 Thy FORMULA 23292249 A 1443 1446 Hyp ABBREVIATION 23292249 A 1447 1450 Hyp ABBREVIATION 23292249 A 1455 1458 Hyp ABBREVIATION 23292249 A 1460 1463 Hyp ABBREVIATION 23292249 A 1480 1481 H FORMULA 23292249 A 1563 1566 C2H FORMULA 23292249 A 1567 1571 O2 H FORMULA 23292249 A 1584 1587 Hyp ABBREVIATION 23292249 A 1588 1591 Cyt FORMULA 23292249 A 1610 1612 O6 FORMULA 23292249 A 1612 1613 H FORMULA 23292249 A 1614 1616 O4 FORMULA 23292249 A 1617 1618 H FORMULA 23292249 A 1631 1634 Hyp ABBREVIATION 23292249 A 1636 1639 Thy FORMULA 23292249 A 50 53 Hyp ABBREVIATION 23292249 A 54 57 Cyt FORMULA 23292249 A 59 62 Hyp ABBREVIATION 23292249 A 64 67 Thy FORMULA 23292249 A 72 75 Hyp ABBREVIATION 23292249 A 76 79 Hyp ABBREVIATION 23292249 A 776 779 Hyp ABBREVIATION 23292249 A 780 783 Cyt FORMULA 23292249 A 788 791 Hyp ABBREVIATION 23292249 A 793 796 Thy FORMULA 23292249 A 849 852 Hyp ABBREVIATION 23292249 A 853 856 Hyp ABBREVIATION 23292249 A 98 101 Hyp ABBREVIATION 23292249 T 109 121 hypoxanthine TRIVIAL 23292302 A 0 4 Zinc SYSTEMATIC 23292302 A 1015 1022 calcium SYSTEMATIC 23292302 A 1056 1063 calcium SYSTEMATIC 23292302 A 1084 1091 calcium SYSTEMATIC 23292302 A 114 121 calcium SYSTEMATIC 23292302 A 1170 1174 zinc SYSTEMATIC 23292302 A 1187 1191 Zinc SYSTEMATIC 23292302 A 1215 1219 DTPA ABBREVIATION 23292302 A 1273 1280 calcium SYSTEMATIC 23292302 A 1406 1410 zinc SYSTEMATIC 23292302 A 1430 1437 calcium SYSTEMATIC 23292302 A 1517 1524 calcium SYSTEMATIC 23292302 A 256 260 zinc SYSTEMATIC 23292302 A 345 349 zinc SYSTEMATIC 23292302 A 370 374 zinc SYSTEMATIC 23292302 A 447 451 zinc SYSTEMATIC 23292302 A 488 494 Fluo-4 ABBREVIATION 23292302 A 51 81 diethylenetriaminepentaacetate SYSTEMATIC 23292302 A 520 527 Calcium SYSTEMATIC 23292302 A 631 638 calcium SYSTEMATIC 23292302 A 679 683 DTPA ABBREVIATION 23292302 A 685 689 Zinc SYSTEMATIC 23292302 A 712 719 calcium SYSTEMATIC 23292302 A 731 738 calcium SYSTEMATIC 23292302 A 83 87 DTPA ABBREVIATION 23292302 A 852 856 zinc SYSTEMATIC 23292302 A 861 868 calcium SYSTEMATIC 23292302 A 952 959 calcium SYSTEMATIC 23292302 A 972 984 thapsigargin TRIVIAL 23292302 T 0 4 Zinc SYSTEMATIC 23292302 T 52 56 zinc SYSTEMATIC 23292302 T 72 79 calcium SYSTEMATIC 23292321 A 12 29 1,8-naphthalimide SYSTEMATIC 23292321 A 702 719 1,8-naphthalimide SYSTEMATIC 23292321 A 746 763 1,8-naphthalimide SYSTEMATIC 23292321 A 799 804 -OCH3 FORMULA 23292321 A 809 817 -N(CH3)2 FORMULA 23292321 A 850 853 -CN FORMULA 23292321 A 857 863 -COCH3 FORMULA 23292321 A 875 901 2-(thiophen-2-yl)thiophene SYSTEMATIC 23292321 A 907 944 2,3-dihydrothieno[3,4-b][1, 4]dioxine SYSTEMATIC 23292321 A 950 975 2-phenyl-1,3,4-oxadiazole SYSTEMATIC 23292321 A 985 1011 benzo[c][1,2,5]thiadiazole SYSTEMATIC 23292321 T 68 85 1,8-naphthalimide SYSTEMATIC 23292791 A 0 14 Graphene oxide SYSTEMATIC 23292791 A 1026 1029 PEG ABBREVIATION 23292791 A 1030 1033 PEI ABBREVIATION 23292791 A 142 161 polyethylene glycol SYSTEMATIC 23292791 A 163 166 PEG ABBREVIATION 23292791 A 172 188 polyethylenimine SYSTEMATIC 23292791 A 190 193 PEI ABBREVIATION 23292791 A 231 236 amide FAMILY 23292791 A 330 333 PEG ABBREVIATION 23292791 A 334 337 PEI ABBREVIATION 23292791 A 381 384 PEI ABBREVIATION 23292791 A 396 399 PEI ABBREVIATION 23292791 A 434 437 PEG ABBREVIATION 23292791 A 438 441 PEI ABBREVIATION 23292791 A 619 622 PEG ABBREVIATION 23292791 A 623 626 PEI ABBREVIATION 23292791 A 937 940 PEG ABBREVIATION 23292791 A 941 944 PEI ABBREVIATION 23292791 T 0 19 Polyethylene Glycol FAMILY 23292791 T 24 40 Polyethylenimine FAMILY 23292791 T 66 80 Graphene Oxide SYSTEMATIC 23293126 A 1068 1070 Zn FORMULA 23293126 A 1072 1075 MDA ABBREVIATION 23293126 A 1120 1122 Zn FORMULA 23293126 A 230 241 cholesterol TRIVIAL 23293126 A 277 287 glutathion TRIVIAL 23293126 A 399 410 Cholesterol TRIVIAL 23293126 A 490 500 superoxide TRIVIAL 23293126 A 528 532 zinc SYSTEMATIC 23293126 A 534 536 Zn FORMULA 23293126 A 626 637 cholesterol TRIVIAL 23293126 A 694 709 malondialdehyde TRIVIAL 23293126 A 711 714 MDA ABBREVIATION 23293126 A 721 732 cholesterol TRIVIAL 23293126 A 764 766 Zn FORMULA 23293126 A 803 806 MDA ABBREVIATION 23293126 A 876 878 Zn FORMULA 23293126 A 981 984 MDA ABBREVIATION 23293126 A 989 1002 triglycerides FAMILY 23293132 A 229 235 silica TRIVIAL 23293132 A 237 245 asbestos FAMILY 23293133 A 1002 1003 P FORMULA 23293133 A 1005 1007 Mg FORMULA 23293133 A 1009 1011 Na FORMULA 23293133 A 1013 1015 Cl FORMULA 23293133 A 1017 1019 Zn FORMULA 23293133 A 1021 1023 Fe FORMULA 23293133 A 1025 1027 Ca FORMULA 23293133 A 1032 1034 Cu FORMULA 23293133 A 482 486 zinc SYSTEMATIC 23293133 A 488 490 Zn FORMULA 23293133 A 493 499 copper SYSTEMATIC 23293133 A 501 503 Cu FORMULA 23293133 A 506 510 iron SYSTEMATIC 23293133 A 512 514 Fe FORMULA 23293133 A 517 526 magnesium SYSTEMATIC 23293133 A 528 530 Mg FORMULA 23293133 A 533 540 calcium SYSTEMATIC 23293133 A 542 544 Ca FORMULA 23293133 A 547 556 potassium SYSTEMATIC 23293133 A 558 559 K FORMULA 23293133 A 562 570 chlorine SYSTEMATIC 23293133 A 572 574 Cl FORMULA 23293133 A 577 583 sodium SYSTEMATIC 23293133 A 585 587 Na FORMULA 23293133 A 593 603 phosphorus SYSTEMATIC 23293133 A 605 606 P FORMULA 23293133 A 999 1000 K FORMULA 23293134 A 494 511 hydrochloric acid SYSTEMATIC 23293134 A 513 516 HCl FORMULA 23293134 A 750 753 HCl FORMULA 23293834 A 282 287 Au₂Cd FORMULA 23293834 A 295 299 CdSe FORMULA 23293834 A 535 539 CdSe FORMULA 23293834 A 815 819 AuCd FORMULA 23293834 T 30 35 Au₂Cd FORMULA 23293834 T 42 46 CdSe FORMULA 23293839 A 0 10 Amino acid FAMILY 23293839 A 1936 1940 Emim ABBREVIATION 23293839 A 1942 1945 Gly FORMULA 23293839 A 2301 2311 amino acid FAMILY 23293839 A 2357 2358 H FORMULA 23293839 A 2469 2495 tetraalkylammonium halides FAMILY 23293839 A 370 381 amino acids FAMILY 23293839 A 443 453 amino acid FAMILY 23293839 A 796 823 1-ethyl-3-methylimidazolium SYSTEMATIC 23293839 A 826 830 Emim ABBREVIATION 23293839 A 839 849 amino acid FAMILY 23293839 A 867 874 glycine TRIVIAL 23293839 A 876 883 alanine TRIVIAL 23293839 A 885 891 valine TRIVIAL 23293839 A 893 900 leucine TRIVIAL 23293839 A 906 916 isoleucine TRIVIAL 23293839 T 62 72 amino acid FAMILY 23294008 A 0 11 Avermectins FAMILY 23294008 A 1048 1051 AVE ABBREVIATION 23294008 A 1057 1070 meilingmycins FAMILY 23294008 A 1130 1157 dihydroxy-ketone polyketide FAMILY 23294008 A 13 17 AVEs FAMILY 23294008 A 1338 1344 hexene SYSTEMATIC 23294008 A 1366 1375 macrolide FAMILY 23294008 A 1401 1420 hexahydrobenzofuran SYSTEMATIC 23294008 A 152 161 macrolide FAMILY 23294008 A 180 183 AVE ABBREVIATION 23294008 A 225 235 polyketide FAMILY 23294008 A 665 668 AVE ABBREVIATION 23294008 T 41 51 avermectin FAMILY 23294255 A 17 23 serine TRIVIAL 23294255 A 590 596 serine TRIVIAL 23294255 A 873 883 piperazine SYSTEMATIC 23294321 A 329 336 TUG-424 IDENTIFIER 23294321 A 4 19 free fatty acid FAMILY 23294321 A 650 657 glucose TRIVIAL 23294321 A 83 90 glucose TRIVIAL 23294321 T 36 51 free fatty acid FAMILY 23294333 A 1008 1012 DMSO ABBREVIATION 23294333 A 1058 1062 urea TRIVIAL 23294333 A 1063 1071 nitrogen SYSTEMATIC 23294333 A 1121 1128 iodogen TRIVIAL 23294333 A 1129 1133 DMSO ABBREVIATION 23294333 A 12 19 Iodogen TRIVIAL 23294333 A 1250 1257 iodogen TRIVIAL 23294333 A 1258 1262 DMSO ABBREVIATION 23294333 A 138 147 hypericin TRIVIAL 23294333 A 21 52 tetrachloro-diphenyl glycoluril SYSTEMATIC 23294333 A 231 238 iodogen TRIVIAL 23294333 A 239 243 DMSO ABBREVIATION 23294333 A 297 304 iodogen TRIVIAL 23294333 A 305 309 DMSO ABBREVIATION 23294333 A 402 409 iodogen TRIVIAL 23294333 A 410 414 DMSO ABBREVIATION 23294333 A 460 464 DMSO ABBREVIATION 23294333 A 635 642 iodogen TRIVIAL 23294333 A 643 647 DMSO ABBREVIATION 23294333 A 67 71 DMSO ABBREVIATION 23294333 A 73 92 dimethyl sulphoxide SYSTEMATIC 23294333 A 865 872 iodogen TRIVIAL 23294333 A 873 877 DMSO ABBREVIATION 23294333 A 991 998 iodogen TRIVIAL 23294333 A 999 1003 DMSO ABBREVIATION 23294333 T 100 119 dimethyl sulphoxide SYSTEMATIC 23294333 T 121 125 DMSO ABBREVIATION 23294333 T 45 76 tetrachloro-diphenyl glycoluril SYSTEMATIC 23294333 T 78 85 iodogen TRIVIAL 23294348 A 1026 1037 7-azaindole SYSTEMATIC 23294348 A 263 292 1H-pyrazolo[3,4-d]pyrimidines FAMILY 23294348 A 481 506 1H-pyrrolo[2,3-b]pyridine SYSTEMATIC 23294348 A 822 844 pyrrolo[2,3-b]pyridine SYSTEMATIC 23294348 T 51 103 1H-pyrrolo[2,3-b]- and 3H-imidazolo[4,5-b]-pyridines FAMILY 23294368 A 1387 1398 Paracetamol TRIVIAL 23295222 A 1176 1188 thio-NADP(+) SYSTEMATIC 23295222 A 1232 1239 NADP(+) ABBREVIATION 23295222 A 1244 1249 NADPH ABBREVIATION 23295222 A 1552 1555 Cys FORMULA 23295222 A 165 173 aldehyde SYSTEMATIC 23295222 A 23 48 10-formyltetrahydrofolate SYSTEMATIC 23295222 A 239 246 NADP(+) ABBREVIATION 23295222 A 282 291 aldehydes FAMILY 23295222 A 389 392 Cys FORMULA 23295222 A 400 403 Glu FORMULA 23295222 A 613 616 Cys FORMULA 23295222 A 628 635 alanine TRIVIAL 23295222 A 813 821 cysteine TRIVIAL 23295222 A 83 90 carboxy SYSTEMATIC 23295222 A 842 854 nicotinamide TRIVIAL 23295222 A 863 870 NADP(+) ABBREVIATION 23295222 A 991 994 Cys FORMULA 23295222 T 77 85 aldehyde SYSTEMATIC 23295227 A 103 112 tolrestat TRIVIAL 23295227 A 1133 1143 fidarestat TRIVIAL 23295227 A 1186 1196 fidarestat TRIVIAL 23295227 A 126 132 aldose FAMILY 23295227 A 1318 1321 Phe FORMULA 23295227 A 1326 1329 Phe FORMULA 23295227 A 1411 1414 Gln FORMULA 23295227 A 1431 1434 Ser FORMULA 23295227 A 1606 1609 Val ABBREVIATION 23295227 A 1629 1639 fidarestat TRIVIAL 23295227 A 166 181 carboxylic acid SYSTEMATIC 23295227 A 1776 1786 fidarestat TRIVIAL 23295227 A 278 288 fidarestat TRIVIAL 23295227 A 304 316 cyclic imide SYSTEMATIC 23295227 A 402 411 tolrestat TRIVIAL 23295227 A 425 435 fidarestat TRIVIAL 23295227 A 577 583 aldose FAMILY 23295227 A 616 624 aldehyde SYSTEMATIC 23295227 A 681 691 fidarestat TRIVIAL 23295227 A 779 782 Val ABBREVIATION 23295227 A 786 789 Leu FORMULA 23295227 A 853 863 fidarestat TRIVIAL 23295227 A 906 916 fidarestat TRIVIAL 23295227 A 91 98 NADP(+) ABBREVIATION 23295227 A 992 1002 fidarestat TRIVIAL 23295227 T 119 129 fidarestat TRIVIAL 23295227 T 69 76 NADP(+) ABBREVIATION 23295227 T 92 98 aldose FAMILY 23295228 A 0 9 Potassium SYSTEMATIC 23295228 A 1078 1088 amino acid FAMILY 23295228 A 1735 1744 potassium SYSTEMATIC 23295228 A 1814 1823 potassium SYSTEMATIC 23295228 A 55 63 aldehyde SYSTEMATIC 23295228 A 981 991 amino acid FAMILY 23295228 T 45 53 aldehyde SYSTEMATIC 23295712 A 108 114 TiO(2) FORMULA 23295712 A 179 185 TiO(2) FORMULA 23295712 A 347 353 TiO(2) FORMULA 23295712 A 540 546 TiO(2) FORMULA 23295712 A 685 693 hydroxyl SYSTEMATIC 23295712 A 722 728 TiO(2) FORMULA 23295712 A 859 865 TiO(2) FORMULA 23295712 A 90 106 titanium dioxide SYSTEMATIC 23295712 T 25 41 titanium dioxide SYSTEMATIC 23295712 T 43 47 TiO2 FORMULA 23296101 A 1079 1095 phthalate esters FAMILY 23296101 A 1136 1145 HC-030031 IDENTIFIER 23296101 A 1190 1197 menthol TRIVIAL 23296101 A 1201 1207 icilin TRIVIAL 23296101 A 1233 1249 phthalate esters FAMILY 23296101 A 1363 1367 FITC ABBREVIATION 23296101 A 175 201 fluorescein isothiocyanate TRIVIAL 23296101 A 203 207 FITC ABBREVIATION 23296101 A 250 266 phthalate esters FAMILY 23296101 A 278 295 dibutyl phthalate SYSTEMATIC 23296101 A 297 300 DBP ABBREVIATION 23296101 A 326 342 phthalate esters FAMILY 23296101 A 510 519 HC-030031 IDENTIFIER 23296101 A 581 584 DBP ABBREVIATION 23296101 A 601 617 phthalate esters FAMILY 23296101 A 639 655 phthalate esters FAMILY 23296101 A 746 750 FITC ABBREVIATION 23296101 A 771 778 menthol TRIVIAL 23296101 A 963 970 menthol TRIVIAL 23296101 A 975 981 icilin TRIVIAL 23296101 A 991 998 calcium SYSTEMATIC 23296101 T 64 80 phthalate esters FAMILY 23296103 A 1021 1024 PEI ABBREVIATION 23296103 A 1105 1111 oxygen SYSTEMATIC 23296103 A 172 188 Polyethylenimine FAMILY 23296103 A 190 193 PEI ABBREVIATION 23296103 A 342 369 primary and secondary amine MULTIPLE 23296103 A 411 414 PEI ABBREVIATION 23296103 A 415 419 PLGA ABBREVIATION 23296103 A 435 438 PEI ABBREVIATION 23296103 A 448 462 acetylated PEI ABBREVIATION 23296103 A 463 467 PLGA ABBREVIATION 23296103 A 483 488 AcPEI ABBREVIATION 23296103 A 992 995 PEI ABBREVIATION 23296103 T 20 23 PEI ABBREVIATION 23296103 T 73 96 polyethylenimine amines FAMILY 23296256 A 234 243 actinides FAMILY 23296256 A 254 261 Am(III) FORMULA 23296256 A 263 269 Th(IV) FORMULA 23296256 A 271 277 Pu(IV) FORMULA 23296256 A 279 284 Np(V) FORMULA 23296256 A 286 291 U(VI) FORMULA 23296256 A 29 43 graphene oxide SYSTEMATIC 23296256 A 321 327 Sr(II) FORMULA 23296256 A 329 336 Eu(III) FORMULA 23296256 A 341 348 Tc(VII) FORMULA 23296256 A 555 567 transuranium FAMILY 23296256 A 659 668 bentonite FAMILY 23296256 A 689 695 carbon SYSTEMATIC 23296256 T 0 14 Graphene oxide SYSTEMATIC 23296404 A 1002 1009 mercury SYSTEMATIC 23296404 A 1188 1195 mercury SYSTEMATIC 23296404 A 311 318 mercury SYSTEMATIC 23296404 A 329 342 methylmercury SYSTEMATIC 23296404 A 344 348 MeHg FORMULA 23296404 A 486 493 methane SYSTEMATIC 23296404 A 625 629 MeHg FORMULA 23296404 A 673 677 MeHg FORMULA 23296404 A 732 736 MeHg FORMULA 23296404 A 794 798 MeHg FORMULA 23296404 A 92 99 mercury SYSTEMATIC 23296404 T 21 28 mercury SYSTEMATIC 23296568 A 175 177 He FORMULA 23296568 A 178 181 C₆₀ TRIVIAL 23296568 A 225 227 He FORMULA 23296568 A 243 246 C₆₀ TRIVIAL 23296568 A 383 386 C₆₀ TRIVIAL 23296568 A 44 54 fullerenes FAMILY 23296568 A 501 510 fullerene TRIVIAL 23296568 A 597 599 He FORMULA 23296568 A 605 608 C₆₀ TRIVIAL 23296568 T 68 70 He FORMULA 23296568 T 71 74 C₆₀ TRIVIAL 23297161 A 1039 1042 RSV ABBREVIATION 23297161 A 1052 1055 RIF ABBREVIATION 23297161 A 1219 1222 RSV ABBREVIATION 23297161 A 1267 1270 RIF ABBREVIATION 23297161 A 294 304 amino acid FAMILY 23297161 A 662 689 estradiol-17β-d-glucuronide SYSTEMATIC 23297161 A 724 741 estrone-3-sulfate SYSTEMATIC 23297161 A 931 943 rosuvastatin TRIVIAL 23297161 A 945 948 RSV ABBREVIATION 23297161 A 962 972 rifampicin TRIVIAL 23297161 A 974 977 RIF ABBREVIATION 23297412 A 116 127 resveratrol TRIVIAL 23297412 A 161 167 NAD(+) ABBREVIATION 23297412 A 427 438 resveratrol TRIVIAL 23297412 A 575 588 phenylephrine TRIVIAL 23297412 A 645 656 resveratrol TRIVIAL 23297412 A 934 940 lysine TRIVIAL 23297412 T 0 11 Resveratrol TRIVIAL 23298241 A 315 319 (1)H FORMULA 23298241 A 324 329 (13)C FORMULA 23298241 A 342 347 (13)C FORMULA 23298241 A 348 352 (1)H FORMULA 23298258 A 1198 1202 atRA ABBREVIATION 23298258 A 1487 1491 atRA ABBREVIATION 23298258 A 1536 1540 atRA ABBREVIATION 23298258 A 194 198 atRA ABBREVIATION 23298258 A 329 333 atRA ABBREVIATION 23298258 A 558 562 atRA ABBREVIATION 23298258 A 65 88 all-trans retinoic acid TRIVIAL 23298258 A 658 667 histidine TRIVIAL 23298258 A 90 94 atRA ABBREVIATION 23298258 T 0 23 All-trans retinoic acid TRIVIAL 23298261 A 1156 1164 oxytocin TRIVIAL 23298261 A 1346 1354 oxytocin TRIVIAL 23298261 A 300 308 urethane TRIVIAL 23298261 A 401 409 oxytocin TRIVIAL 23298261 A 62 70 oxytocin TRIVIAL 23298261 A 625 636 vasopressin FAMILY 23298261 A 711 719 oxytocin TRIVIAL 23298261 A 922 930 oxytocin TRIVIAL 23298261 T 72 80 oxytocin TRIVIAL 23298277 A 143 150 proline TRIVIAL 23298277 A 228 229 N FORMULA 23298277 A 239 249 amino acid FAMILY 23298277 A 82 122 bicyclic octahydropyrrolo[1,2-a]pyrazine SYSTEMATIC 23298277 A 932 941 T-3256336 IDENTIFIER 23298277 T 144 151 proline TRIVIAL 23298277 T 92 123 octahydropyrrolo[1,2-a]pyrazine SYSTEMATIC 23298334 A 1045 1048 ATP ABBREVIATION 23298334 A 1064 1070 Hg(2+) FORMULA 23298334 A 107 113 silica TRIVIAL 23298334 A 1121 1127 Hg(2+) FORMULA 23298334 A 118 124 SiO(2) FORMULA 23298334 A 1344 1350 SiO(2) FORMULA 23298334 A 1630 1641 doxorubicin TRIVIAL 23298334 A 1650 1656 Mg(2+) FORMULA 23298334 A 1696 1699 ATP ABBREVIATION 23298334 A 1736 1742 Mg(2+) FORMULA 23298334 A 182 188 Mg(2+) FORMULA 23298334 A 193 199 Zn(2+) FORMULA 23298334 A 21 35 methylene blue TRIVIAL 23298334 A 248 254 Mg(2+) FORMULA 23298334 A 258 264 Zn(2+) FORMULA 23298334 A 464 470 Mg(2+) FORMULA 23298334 A 475 481 Zn(2+) FORMULA 23298334 A 48 56 thionine TRIVIAL 23298334 A 523 534 nucleotides FAMILY 23298334 A 772 797 adenosine-5'-triphosphate SYSTEMATIC 23298334 A 799 802 ATP ABBREVIATION 23298334 A 852 858 Hg(2+) FORMULA 23298334 A 953 959 Mg(2+) FORMULA 23298334 A 964 970 Zn(2+) FORMULA 23298334 T 17 21 SiO2 FORMULA 23298616 A 1059 1063 PLGA ABBREVIATION 23298616 A 1064 1067 PVA ABBREVIATION 23298616 A 1274 1287 dexamethasone TRIVIAL 23298616 A 1679 1692 dexamethasone TRIVIAL 23298616 A 1926 1930 PLGA ABBREVIATION 23298616 A 1943 1946 PVA ABBREVIATION 23298616 A 199 228 poly(lactic-co-glycolic) acid FAMILY 23298616 A 230 234 PLGA ABBREVIATION 23298616 A 261 280 poly(vinyl alcohol) SYSTEMATIC 23298616 A 27 34 glucose TRIVIAL 23298616 A 282 285 PVA ABBREVIATION 23298616 A 790 797 glucose TRIVIAL 23298616 A 841 845 PLGA ABBREVIATION 23298616 A 846 849 PVA ABBREVIATION 23298744 A 126 146 acetylaminochalcones FAMILY 23298744 A 227 241 sodium acetate SYSTEMATIC 23298744 A 246 257 acetic acid SYSTEMATIC 23298744 A 314 323 hydrazine SYSTEMATIC 23298744 A 334 380 3-(4-acetamidophenyl)-5-(aryl)-1-H-pyrazolines FAMILY 23298744 A 386 397 pyrazolines FAMILY 23298744 A 41 64 4-acetamidoacetophenone SYSTEMATIC 23298744 A 70 88 aromatic aldehydes FAMILY 23298744 T 39 49 pyrazolyne TRIVIAL 23298863 A 0 160 6-Ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide SYSTEMATIC 23298863 A 1065 1072 TAK-441 IDENTIFIER 23298863 A 162 169 TAK-441 IDENTIFIER 23298863 A 423 430 TAK-441 IDENTIFIER 23298863 A 674 681 TAK-441 IDENTIFIER 23298863 T 67 74 TAK-441 IDENTIFIER 23298867 A 418 427 potassium SYSTEMATIC 23299189 A 0 10 Ifosfamide TRIVIAL 23299189 A 1028 1031 IFO ABBREVIATION 23299189 A 1033 1036 NAC ABBREVIATION 23299189 A 1068 1071 ALA ABBREVIATION 23299189 A 1143 1146 IFO ABBREVIATION 23299189 A 12 15 IFO ABBREVIATION 23299189 A 1238 1241 ALA ABBREVIATION 23299189 A 1246 1249 NAC ABBREVIATION 23299189 A 1258 1261 IFO ABBREVIATION 23299189 A 211 214 IFO ABBREVIATION 23299189 A 450 453 IFO ABBREVIATION 23299189 A 537 554 alpha lipoic acid TRIVIAL 23299189 A 556 559 ALA ABBREVIATION 23299189 A 568 584 N-acetylcysteine SYSTEMATIC 23299189 A 586 589 NAC ABBREVIATION 23299189 A 690 693 IFO ABBREVIATION 23299189 A 723 726 IFO ABBREVIATION 23299189 A 729 732 ALA ABBREVIATION 23299189 A 766 769 IFO ABBREVIATION 23299189 A 772 775 NAC ABBREVIATION 23299189 A 813 828 malondialdehyde TRIVIAL 23299189 A 830 842 nitric oxide SYSTEMATIC 23299189 A 847 858 glutathione TRIVIAL 23299189 A 954 957 ALA ABBREVIATION 23299189 A 962 965 NAC ABBREVIATION 23299189 T 22 39 alpha lipoic acid TRIVIAL 23299189 T 47 63 N-acetylcysteine SYSTEMATIC 23299189 T 67 77 ifosfamide TRIVIAL 23299190 A 1022 1030 curcumin TRIVIAL 23299190 A 1052 1055 MDA ABBREVIATION 23299190 A 1114 1117 GSH ABBREVIATION 23299190 A 1230 1238 curcumin TRIVIAL 23299190 A 235 243 curcumin TRIVIAL 23299190 A 292 300 curcumin TRIVIAL 23299190 A 327 335 curcumin TRIVIAL 23299190 A 512 527 malondialdehyde TRIVIAL 23299190 A 529 532 MDA ABBREVIATION 23299190 A 535 545 superoxide TRIVIAL 23299190 A 567 578 glutathione TRIVIAL 23299190 A 580 583 GSH ABBREVIATION 23299190 A 60 68 curcumin TRIVIAL 23299190 A 782 797 2'-deoxyuridine SYSTEMATIC 23299190 A 799 814 5'-triphosphate SYSTEMATIC 23299190 A 922 930 curcumin TRIVIAL 23299190 T 58 66 curcumin TRIVIAL 23299756 A 1051 1058 tannins FAMILY 23299756 A 1074 1093 triterpene saponins FAMILY 23299756 A 1299 1306 tannins FAMILY 23299756 A 1311 1330 triterpene saponins FAMILY 23299756 A 257 264 tannins FAMILY 23299756 A 269 288 triterpene saponins FAMILY 23299756 A 40 47 tannins FAMILY 23299756 A 481 493 acetonitrile SYSTEMATIC 23299756 A 524 535 formic acid SYSTEMATIC 23299756 A 607 614 tannins FAMILY 23299756 A 616 627 gallic acid TRIVIAL 23299756 A 629 653 gallic acid methyl ester SYSTEMATIC 23299756 A 655 664 corilagin TRIVIAL 23299756 A 666 681 chebulagic acid TRIVIAL 23299756 A 683 718 1,2,3,6-tetra-O-galloyl-β-D-glucose SYSTEMATIC 23299756 A 720 732 ellagic acid TRIVIAL 23299756 A 734 749 chebulinic acid TRIVIAL 23299756 A 755 792 1,2,3,4,6-penta-O-galloyl-β-D-glucose SYSTEMATIC 23299756 A 802 821 triterpene saponins FAMILY 23299756 A 823 839 arjunglucoside-I TRIVIAL 23299756 A 841 859 arjunglucoside-III TRIVIAL 23299756 A 861 875 chebuloside II TRIVIAL 23299756 A 877 890 bellericoside TRIVIAL 23299756 A 892 901 arjunetin TRIVIAL 23299756 A 907 924 arjunglucoside-II TRIVIAL 23299756 T 51 58 tannins FAMILY 23299756 T 63 82 triterpene saponins FAMILY 23299759 A 365 397 (β-D-Glc)3 Yariv phenylglycoside SYSTEMATIC 23299759 A 601 633 (β-D-Glc)3 Yariv phenylglycoside SYSTEMATIC 23299759 A 682 714 (β-D-Glc)3 Yariv phenylglycoside SYSTEMATIC 23299759 A 742 768 fluorescein isothiocyanate TRIVIAL 23300006 A 1261 1268 ethanol SYSTEMATIC 23300006 A 1296 1303 ethanol SYSTEMATIC 23300006 A 1531 1538 ethanol SYSTEMATIC 23300006 A 439 446 ethanol SYSTEMATIC 23300006 A 596 652 3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium bromide SYSTEMATIC 23300006 A 660 667 glucose TRIVIAL 23300006 A 754 761 ethanol SYSTEMATIC 23300006 A 949 956 ethanol SYSTEMATIC 23300006 A 968 975 Ethanol SYSTEMATIC 23300006 T 33 40 ethanol SYSTEMATIC 23300078 A 0 8 Propofol TRIVIAL 23300078 A 1040 1051 amino acids FAMILY 23300078 A 1256 1264 Propofol TRIVIAL 23300078 A 1274 1285 [(3)H]AziPm SYSTEMATIC 23300078 A 128 147 γ-aminobutyric acid SYSTEMATIC 23300078 A 1312 1320 Propofol TRIVIAL 23300078 A 1331 1342 [(3)H]AziPm SYSTEMATIC 23300078 A 1555 1563 propofol TRIVIAL 23300078 A 222 235 acetylcholine SYSTEMATIC 23300078 A 278 286 propofol TRIVIAL 23300078 A 360 368 propofol TRIVIAL 23300078 A 370 428 2-isopropyl-5-[3-(trifluoromethyl)-3H-diazirin-3-yl]phenol SYSTEMATIC 23300078 A 430 435 AziPm ABBREVIATION 23300078 A 477 482 AziPm ABBREVIATION 23300078 A 542 550 propofol TRIVIAL 23300078 A 630 641 [(3)H]AziPm SYSTEMATIC 23300078 A 655 666 amino acids FAMILY 23300078 A 705 716 [(3)H]AziPm SYSTEMATIC 23300078 A 923 927 δPhe FORMULA 23300078 A 936 940 δCys FORMULA 23300078 T 100 108 propofol TRIVIAL 23300078 T 18 26 propofol TRIVIAL 23300078 T 56 69 acetylcholine SYSTEMATIC 23300339 A 1199 1202 Ser FORMULA 23300339 A 203 206 Thr FORMULA 23300339 A 214 217 Ser FORMULA 23300339 A 418 421 Ser FORMULA 23300339 A 769 772 Ser FORMULA 23300339 A 957 960 Ser FORMULA 23301560 A 160 172 carbodiimide SYSTEMATIC 23301560 A 394 397 MTT ABBREVIATION 23301560 A 827 837 amino acid FAMILY 23301560 A 866 876 amino acid FAMILY 23301560 A 94 104 amino acid FAMILY 23301560 T 0 10 Amino acid FAMILY 23301560 T 78 88 amino acid FAMILY 23301766 A 56 68 polyethylene SYSTEMATIC 23301766 A 80 92 carbon black TRIVIAL 23301766 T 25 37 polyethylene SYSTEMATIC 23301766 T 38 50 carbon black TRIVIAL 23301830 A 1299 1305 (S)-PR ABBREVIATION 23301830 A 1327 1333 (S)-PR ABBREVIATION 23301830 A 1473 1484 methacrylic TRIVIAL 23301830 A 1506 1512 (S)-PR ABBREVIATION 23301830 A 1521 1524 NMP ABBREVIATION 23301830 A 547 567 N-methyl pyrrolidone SYSTEMATIC 23301830 A 569 572 NMP ABBREVIATION 23301830 A 82 93 propranolol TRIVIAL 23301830 A 839 842 NMP ABBREVIATION 23301830 T 40 51 propranolol TRIVIAL 23301836 A 114 124 alkylamine FAMILY 23301836 A 1269 1279 decylamine SYSTEMATIC 23301836 A 1299 1307 graphene TRIVIAL 23301836 A 1471 1477 methyl SYSTEMATIC 23301836 A 1510 1515 amine SYSTEMATIC 23301836 A 165 173 graphene TRIVIAL 23301836 A 324 332 graphene TRIVIAL 23301836 A 590 598 graphene TRIVIAL 23301836 A 672 680 graphene TRIVIAL 23301836 A 689 694 alkyl FAMILY 23301836 A 796 802 methyl SYSTEMATIC 23301836 A 805 810 CH(3) FORMULA 23301836 A 815 820 amine SYSTEMATIC 23301836 A 823 828 NH(2) FORMULA 23301836 A 833 841 hydroxyl SYSTEMATIC 23301836 A 844 846 OH FORMULA 23301836 T 45 55 Alkylamine FAMILY 23301836 T 85 93 Graphene TRIVIAL 23301856 A 270 291 hydrazinonicotinamide SYSTEMATIC 23301856 A 293 298 HYNIC ABBREVIATION 23301856 A 302 309 Litorin TRIVIAL 23301856 A 311 318 (99m)Tc FORMULA 23301856 A 373 380 tricine TRIVIAL 23301856 A 385 414 ethylenediamine diacetic acid SYSTEMATIC 23301856 A 416 420 EDDA ABBREVIATION 23301856 A 525 533 cysteine TRIVIAL 23301856 A 583 611 (99m)Tc-EDDA-HYNIC-Q-Litorin SYSTEMATIC 23301856 A 616 647 (99m)Tc-tricine-HYNIC-Q-Litorin SYSTEMATIC 23301856 A 9 17 Bombesin TRIVIAL 23301856 T 23 59 (99m)Tc-EDDA/tricine-HYNIC-Q-Litorin MULTIPLE 23301860 A 0 6 Carbon SYSTEMATIC 23301860 A 1007 1028 poly(ethylene glycol) SYSTEMATIC 23301860 A 514 542 methoxypoly(ethylene glycol) FAMILY 23301860 A 731 752 poly(ethylene glycol) SYSTEMATIC 23301860 T 14 20 carbon SYSTEMATIC 23302584 A 143 162 2-Aminopyridin-3-ol SYSTEMATIC 23302584 A 18 27 guanidine TRIVIAL 23302584 A 184 207 thiophosphoryl chloride SYSTEMATIC 23302584 A 222 234 monochloride SYSTEMATIC 23302584 A 268 277 cyanamide SYSTEMATIC 23302584 A 306 315 cyanamine SYSTEMATIC 23302584 A 367 386 heterocyclic amines FAMILY 23302584 A 446 455 guanidine TRIVIAL 23302584 A 538 551 benzothiazole SYSTEMATIC 23302584 A 553 565 fluorophenyl SYSTEMATIC 23302584 A 571 582 piperazinyl SYSTEMATIC 23302584 T 19 43 phosphorylated guanidine TRIVIAL 23302584 T 61 70 cyanamide SYSTEMATIC 23302586 A 135 153 benzenesulfonamide SYSTEMATIC 23302586 A 207 227 4,7-dichloroquinolne SYSTEMATIC 23302586 A 330 341 Doxorubicin TRIVIAL 23302586 A 45 55 quinolines FAMILY 23302586 A 73 90 7-chloroquinoline SYSTEMATIC 23302586 A 844 860 phosphoinositide FAMILY 23302586 T 23 41 7-chloroquinolines FAMILY 23302586 T 73 91 benzenesulfonamide SYSTEMATIC 23302587 A 179 189 isocyanide SYSTEMATIC 23302587 A 40 56 α-acylaminoamido FAMILY 23302587 T 13 58 2-deoxy-2,3-didehydro-N-acetylneuraminic acid SYSTEMATIC 23302587 T 131 141 isocyanide SYSTEMATIC 23302587 T 81 97 α-acylaminoamido FAMILY 23302593 A 153 165 platycodon B TRIVIAL 23302593 A 167 262 3-O-β-D-glucopyranosyl-16-O-β-D-xylopyranosyl-2β,3β,16β,21β-tetrahydroxyolean-12-en-28-oic acid SYSTEMATIC 23302593 A 37 49 platycodon A TRIVIAL 23302593 A 51 147 3-O-β-D-glucopyranosyl-16-O-β-D-glucopyranosyl-2β,3β,16β,21β-tetrahydroxyolean-12-en-28-oic acid SYSTEMATIC 23302593 A 8 29 triterpenoid saponins FAMILY 23302593 T 8 29 triterpenoid saponins FAMILY 23302712 A 145 151 copper SYSTEMATIC 23302712 A 153 155 Cu FORMULA 23302712 A 158 165 cadmium SYSTEMATIC 23302712 A 167 169 Cd FORMULA 23302712 A 172 176 zinc SYSTEMATIC 23302712 A 178 180 Zn FORMULA 23302712 A 189 191 Pb FORMULA 23302712 A 194 200 nickel SYSTEMATIC 23302712 A 202 204 Ni FORMULA 23302712 A 207 211 iron SYSTEMATIC 23302712 A 213 215 Fe FORMULA 23302712 A 218 227 aluminium SYSTEMATIC 23302712 A 229 231 Al FORMULA 23302712 A 238 247 manganese SYSTEMATIC 23302712 A 249 251 Mn FORMULA 23302712 A 545 547 Cu FORMULA 23302712 A 549 551 Cd FORMULA 23302712 A 553 555 Zn FORMULA 23302712 A 557 559 Pb FORMULA 23302712 A 561 563 Ni FORMULA 23302712 A 565 567 Fe FORMULA 23302712 A 569 571 Al FORMULA 23302712 A 577 579 Mn FORMULA 23302712 A 844 846 Cu FORMULA 23302712 A 849 851 Cd FORMULA 23302712 A 854 856 Zn FORMULA 23302712 A 859 861 Pb FORMULA 23302712 A 864 866 Ni FORMULA 23302712 A 869 871 Al FORMULA 23302712 A 874 876 Fe FORMULA 23302712 A 879 881 Mn FORMULA 23302712 A 886 888 Cu FORMULA 23302712 A 891 893 Cd FORMULA 23302712 A 896 898 Zn FORMULA 23302712 A 901 903 Fe FORMULA 23302712 A 906 908 Pb FORMULA 23302712 A 911 913 Al FORMULA 23302712 A 916 918 Ni FORMULA 23302712 A 921 923 Mn FORMULA 23302712 A 962 964 Cu FORMULA 23303709 A 0 7 DPA-713 IDENTIFIER 23303709 A 1095 1102 DPA-713 IDENTIFIER 23303709 A 1255 1274 DPA-C(6)-(Gd)DOTAMA FORMULA 23303709 A 1476 1478 Gd FORMULA 23303709 A 407 426 DPA-C(6)-(Gd)DOTAMA FORMULA 23303709 A 509 516 DPA-713 IDENTIFIER 23303709 A 52 86 pyrazolo[1,5-a]pyrimidineacetamide SYSTEMATIC 23303709 A 522 539 Gd-DOTA monoamide SYSTEMATIC 23303709 A 546 550 DOTA ABBREVIATION 23303709 A 553 609 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid SYSTEMATIC 23303709 A 688 728 phenylpyrazolo[1,5-a]pyrimidineacetamide SYSTEMATIC 23303709 A 737 744 DPA-713 IDENTIFIER 23303709 A 761 767 carbon SYSTEMATIC 23303709 A 780 799 DPA-C(6)-(Gd)DOTAMA FORMULA 23303709 A 984 1003 DPA-C(6)-(Gd)DOTAMA FORMULA 23303709 T 41 43 Gd FORMULA 23303738 A 184 196 carbaboranes FAMILY 23303738 A 237 243 phenyl SYSTEMATIC 23303738 A 311 323 carbaboranyl FAMILY 23303738 A 355 380 2,3-disubstituted indoles FAMILY 23303738 A 406 418 carbaboranes FAMILY 23303738 A 446 479 2-carbaborane-3-phenyl-1H-indoles FAMILY 23303738 A 545 551 amides FAMILY 23303738 A 565 582 meta-carbaboranyl TRIVIAL 23303738 A 642 660 ortho-carbaboranyl TRIVIAL 23303738 T 0 33 2-Carbaborane-3-phenyl-1H-indoles FAMILY 23303790 A 105 111 uracil TRIVIAL 23303790 A 1072 1085 2-aminopurine SYSTEMATIC 23303790 A 234 240 uracil TRIVIAL 23303790 A 267 273 uracil TRIVIAL 23303790 A 411 417 uracil TRIVIAL 23303790 A 438 444 Uracil TRIVIAL 23303790 A 597 610 2-aminopurine SYSTEMATIC 23303790 A 740 746 uracil TRIVIAL 23303790 A 795 801 uracil TRIVIAL 23303790 A 929 940 amino acids FAMILY 23303790 T 98 104 uracil TRIVIAL 23305400 A 294 314 N-methyl-D-aspartate SYSTEMATIC 23305400 A 316 320 NMDA ABBREVIATION 23305400 A 981 990 monoamine FAMILY 23305503 A 0 9 Metformin TRIVIAL 23305503 A 1117 1126 metformin TRIVIAL 23305503 A 1132 1135 MPA ABBREVIATION 23305503 A 1204 1213 metformin TRIVIAL 23305503 A 1225 1233 estrogen FAMILY 23305503 A 1311 1323 progesterone TRIVIAL 23305503 A 235 262 medroxyprogesterone acetate TRIVIAL 23305503 A 264 267 MPA ABBREVIATION 23305503 A 274 283 metformin TRIVIAL 23305503 A 404 430 17 β Estradiol hemihydrate SYSTEMATIC 23305503 A 442 468 17 β Estradiol hemihydrate SYSTEMATIC 23305503 A 483 492 metformin TRIVIAL 23305503 A 505 531 17 β Estradiol hemihydrate SYSTEMATIC 23305503 A 546 549 MPA ABBREVIATION 23305503 A 786 795 estradiol TRIVIAL 23305503 A 938 947 Metformin TRIVIAL 23305503 A 952 963 MPA acetate SYSTEMATIC 23305503 T 43 53 metformine TRIVIAL 23305503 T 58 70 progesterone TRIVIAL 23305503 T 74 82 estrogen FAMILY 23305534 A 1020 1028 stilbene TRIVIAL 23305534 A 1104 1112 aldehyde SYSTEMATIC 23305534 A 1177 1192 carboxylic acid SYSTEMATIC 23305534 A 1200 1235 4-(1,3-benzoxazol-2-yl)benzoic acid SYSTEMATIC 23305534 A 13 45 4,4'-bis(2-benzoxazolyl)stilbene SYSTEMATIC 23305534 A 1352 1355 BBS ABBREVIATION 23305534 A 1445 1448 BBS ABBREVIATION 23305534 A 195 198 BBS ABBREVIATION 23305534 A 218 221 BBS ABBREVIATION 23305534 A 386 389 BBS ABBREVIATION 23305534 A 47 50 BBS ABBREVIATION 23305534 A 510 513 BBS ABBREVIATION 23305534 A 835 839 (1)H FORMULA 23305534 A 893 896 BBS ABBREVIATION 23305534 A 937 946 trans-BBS ABBREVIATION 23305534 T 75 107 4,4'-bis(2-benzoxazolyl)stilbene SYSTEMATIC 23305921 A 158 170 caffeic acid TRIVIAL 23305921 A 191 198 proline TRIVIAL 23305921 A 202 213 amino acids FAMILY 23305921 A 240 253 phenylalanine TRIVIAL 23305921 A 269 289 hydroxycinnamic acid SYSTEMATIC 23305921 A 28 65 caffeoyl-amino acidyl-hydroxamic acid FAMILY 23305921 A 291 294 HCA ABBREVIATION 23305921 A 337 365 phenylalanyl hydroxamic acid SYSTEMATIC 23305921 A 370 392 prolyl hydroxamic acid SYSTEMATIC 23305921 A 394 406 HCA-Phe-NHOH FORMULA 23305921 A 411 423 HCA-Pro-NHOH FORMULA 23305921 A 575 587 HCA-Phe-NHOH FORMULA 23305921 A 592 604 HCA-Pro-NHOH FORMULA 23305921 A 657 660 HCA ABBREVIATION 23305921 A 67 78 CA-Xaa-NHOH FAMILY 23305921 A 693 705 caffeic acid TRIVIAL 23305921 A 707 719 ferulic acid TRIVIAL 23305921 A 725 737 sinapic acid TRIVIAL 23305921 A 789 798 vitamin E FAMILY 23305921 A 809 815 Trolox TRIVIAL 23305921 A 846 858 caffeic acid TRIVIAL 23305921 A 863 875 sinapic acid TRIVIAL 23305921 T 41 70 hydroxycinnamoyl phenylalanyl SYSTEMATIC 23305921 T 71 93 prolyl hydroxamic acid SYSTEMATIC 23305949 A 358 387 ribonucleoside monophosphates FAMILY 23305949 A 389 394 rNMPs FAMILY 23305949 A 586 591 rNMPs FAMILY 23305949 A 626 630 rNMP ABBREVIATION 23305949 A 645 649 rNMP ABBREVIATION 23305949 A 797 801 rNMP ABBREVIATION 23305949 A 888 892 rNMP ABBREVIATION 23306025 A 1279 1289 diclofenac TRIVIAL 23306025 A 185 195 diclofenac TRIVIAL 23306025 T 72 82 diclofenac TRIVIAL 23306951 A 1125 1129 PhIP ABBREVIATION 23306951 A 1427 1431 PhIP ABBREVIATION 23306951 A 1479 1483 PhIP ABBREVIATION 23306951 A 287 315 heterocyclic aromatic amines FAMILY 23306951 A 317 321 HCAs ABBREVIATION 23306951 A 412 459 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine SYSTEMATIC 23306951 A 461 465 PhIP ABBREVIATION 23306951 A 495 498 HCA ABBREVIATION 23306951 A 654 658 PhIP ABBREVIATION 23306951 A 760 764 PhIP ABBREVIATION 23306951 A 904 914 (14)C-PhIP FORMULA 23306951 T 163 167 PhIP ABBREVIATION 23306951 T 196 200 PhIP ABBREVIATION 23306951 T 21 68 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine SYSTEMATIC 23306951 T 70 74 PhIP ABBREVIATION 23307232 A 1054 1062 warfarin TRIVIAL 23307232 A 1688 1696 warfarin TRIVIAL 23307232 A 405 413 warfarin TRIVIAL 23307232 A 498 506 warfarin TRIVIAL 23307232 A 54 62 warfarin TRIVIAL 23307232 A 610 618 warfarin TRIVIAL 23307232 T 0 8 Warfarin TRIVIAL 23307557 A 262 265 ADP ABBREVIATION 23307557 A 458 464 lysine TRIVIAL 23307694 A 1000 1008 hydrogen SYSTEMATIC 23307694 A 1029 1038 guanidino SYSTEMATIC 23307694 A 1056 1071 carbonyl oxygen SYSTEMATIC 23307694 A 182 222 trans-(4-guanidino)cyclohexylmethylamide SYSTEMATIC 23307694 A 224 228 GCMA ABBREVIATION 23307694 A 298 331 dichloro-substituted phenylacetyl FAMILY 23307694 A 434 438 GCMA ABBREVIATION 23307694 A 514 522 agmatine TRIVIAL 23307694 A 587 593 serine TRIVIAL 23307694 A 748 785 3,4-dichlorophenylacetyl-Lys-Lys-GCMA SYSTEMATIC 23307694 A 86 109 decarboxylated arginine TRIVIAL 23307694 A 910 916 phenyl SYSTEMATIC 23307694 A 933 943 cyclohexyl SYSTEMATIC 23307699 A 12 26 (+)-Usnic acid TRIVIAL 23307699 A 142 160 dihydroartemisinin SYSTEMATIC 23307699 A 386 396 artesunate TRIVIAL 23307788 A 145 154 rapamycin TRIVIAL 23307788 A 427 430 ATP ABBREVIATION 23307788 A 686 693 AZD8055 IDENTIFIER 23307788 A 707 710 ATP ABBREVIATION 23308013 A 1014 1018 TCDD ABBREVIATION 23308013 A 1114 1127 phenylephrine TRIVIAL 23308013 A 1138 1147 Melatonin TRIVIAL 23308013 A 1189 1193 TCDD ABBREVIATION 23308013 A 1237 1250 phenylephrine TRIVIAL 23308013 A 1261 1265 TCDD ABBREVIATION 23308013 A 1293 1308 malondialdehyde TRIVIAL 23308013 A 1337 1346 melatonin TRIVIAL 23308013 A 1377 1381 TCDD ABBREVIATION 23308013 A 1403 1414 glutathione TRIVIAL 23308013 A 1444 1453 melatonin TRIVIAL 23308013 A 1509 1513 TCDD ABBREVIATION 23308013 A 154 189 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23308013 A 1627 1636 melatonin TRIVIAL 23308013 A 1686 1690 TCDD ABBREVIATION 23308013 A 1745 1749 TCDD ABBREVIATION 23308013 A 191 195 TCDD ABBREVIATION 23308013 A 200 235 polychlorinated dibenzo-para-dioxin FAMILY 23308013 A 420 429 melatonin TRIVIAL 23308013 A 488 501 ethyl alcohol SYSTEMATIC 23308013 A 542 551 melatonin TRIVIAL 23308013 A 580 589 melatonin TRIVIAL 23308013 A 629 633 TCDD ABBREVIATION 23308013 A 664 668 TCDD ABBREVIATION 23308013 A 703 707 TCDD ABBREVIATION 23308013 A 710 719 melatonin TRIVIAL 23308013 A 736 740 TCDD ABBREVIATION 23308013 A 75 84 melatonin TRIVIAL 23308013 A 771 780 melatonin TRIVIAL 23308013 A 926 939 phenylephrine TRIVIAL 23308013 A 944 957 acetylcholine SYSTEMATIC 23308013 T 0 35 2,3,7,8-Tetrachlorodibenzo-p-dioxin SYSTEMATIC 23308013 T 84 93 melatonin TRIVIAL 23311415 A 182 195 canthin-6-one SYSTEMATIC 23311415 A 4 13 canthines FAMILY 23311415 A 505 514 canthines FAMILY 23311415 A 51 72 β-carboline alkaloids FAMILY 23311415 T 29 47 canthine alkaloids FAMILY 23311608 A 12 22 amino acid FAMILY 23311608 A 160 165 furan SYSTEMATIC 23311608 A 1817 1826 maleimide SYSTEMATIC 23311608 A 190 211 poly(ethylene glycol) SYSTEMATIC 23311608 A 1992 2001 maleimide SYSTEMATIC 23311608 A 213 216 PEG ABBREVIATION 23311608 A 320 325 thiol FAMILY 23311608 A 33 38 furan SYSTEMATIC 23311608 A 330 343 maleimide PEG TRIVIAL 23311608 A 426 435 maleimide SYSTEMATIC 23311608 A 552 561 maleimide SYSTEMATIC 23311608 A 918 923 furan SYSTEMATIC 23311608 A 972 981 maleimide SYSTEMATIC 23311608 T 47 68 poly(ethylene glycol) SYSTEMATIC 23311697 A 123 125 Au FORMULA 23311697 A 281 283 Au FORMULA 23311697 A 445 447 Au FORMULA 23311697 A 459 461 Au FORMULA 23311697 A 50 52 Au FORMULA 23311697 T 77 79 Au FORMULA 23311998 A 0 43 Poly(ferrocenyl(3-bromopropyl)methylsilane) FAMILY 23311998 A 201 206 amine SYSTEMATIC 23311998 A 273 280 silicon SYSTEMATIC 23311998 A 282 285 ITO ABBREVIATION 23311998 A 291 297 quartz TRIVIAL 23311998 A 48 68 poly(ethylene imine) FAMILY 23311998 A 749 771 poly(ferrocenylsilane) FAMILY 23311998 A 773 776 PFS ABBREVIATION 23311998 A 875 878 PFS ABBREVIATION 23311998 A 879 882 PEI ABBREVIATION 23311998 A 944 957 ascorbic acid TRIVIAL 23311998 A 962 979 hydrogen peroxide SYSTEMATIC 23312278 A 217 220 AMP ABBREVIATION 23312470 A 1003 1011 oxytocin TRIVIAL 23312470 A 1022 1031 disulfide SYSTEMATIC 23312470 A 1213 1224 glutathione TRIVIAL 23312470 A 709 720 vasopressin FAMILY 23312470 A 725 733 oxytocin TRIVIAL 23312470 A 987 998 Vasopressin FAMILY 23312472 A 193 206 2-aminobenzyl SYSTEMATIC 23312472 A 37 72 2,4-diaminopyrimidine-5-carboxamide SYSTEMATIC 23312472 A 99 115 2-Aminophenethyl SYSTEMATIC 23312472 T 17 52 2,4-diaminopyrimidine-5-carboxamide SYSTEMATIC 23312945 A 161 178 3-carboxylic acid SYSTEMATIC 23312945 A 182 195 ciprofloxacin TRIVIAL 23312945 A 204 213 oxaborole SYSTEMATIC 23312945 A 337 342 boron SYSTEMATIC 23312945 A 69 84 fluoroquinolone SYSTEMATIC 23312945 T 50 69 tricyclic oxaborole FAMILY 23312945 T 76 91 fluoroquinolone SYSTEMATIC 23313085 A 120 131 Vinclozolin TRIVIAL 23313085 A 223 234 Vinclozolin TRIVIAL 23313085 A 844 855 Vinclozolin TRIVIAL 23313085 T 0 11 Vinclozolin TRIVIAL 23313243 A 30 38 nicotine TRIVIAL 23313243 A 318 326 nicotine TRIVIAL 23313243 A 589 597 nicotine TRIVIAL 23313243 A 88 96 nicotine TRIVIAL 23313243 T 10 18 nicotine TRIVIAL 23313269 A 59 84 phenylpropanol glycosides FAMILY 23313269 A 86 98 rossicasides FAMILY 23313269 T 0 12 Triglyceride FAMILY 23313269 T 48 74 phenylpropanoid glycosides FAMILY 23313337 A 0 14 Hydroxytyrosol SYSTEMATIC 23313337 A 1014 1018 H2O2 FORMULA 23313337 A 1043 1046 HyT ABBREVIATION 23313337 A 133 136 HyT ABBREVIATION 23313337 A 16 19 HyT ABBREVIATION 23313337 A 26 36 polyphenol FAMILY 23313337 A 345 348 HyT ABBREVIATION 23313337 A 434 440 oxygen SYSTEMATIC 23313337 A 531 534 HyT ABBREVIATION 23313337 A 563 585 hydroxytyrosyl laurate TRIVIAL 23313337 A 839 843 H2O2 FORMULA 23313337 A 961 969 laur-HyT ABBREVIATION 23313337 T 27 41 hydroxytyrosol SYSTEMATIC 23313337 T 46 68 hydroxytyrosyl laurate TRIVIAL 23313339 A 1099 1101 Zn FORMULA 23313339 A 1171 1173 Zn FORMULA 23313339 A 1210 1212 Al FORMULA 23313339 A 177 186 aluminium SYSTEMATIC 23313339 A 188 190 Al FORMULA 23313339 A 282 291 aluminium SYSTEMATIC 23313339 A 301 305 zinc SYSTEMATIC 23313339 A 318 327 aluminium SYSTEMATIC 23313339 A 328 332 zinc SYSTEMATIC 23313339 A 342 351 Aluminium SYSTEMATIC 23313339 A 353 358 AlCl3 FORMULA 23313339 A 446 450 Zinc SYSTEMATIC 23313339 A 454 467 zinc sulphate SYSTEMATIC 23313339 A 615 626 cholesterol TRIVIAL 23313339 A 63 67 Zinc SYSTEMATIC 23313339 A 631 643 gangliosides FAMILY 23313339 A 69 71 Zn FORMULA 23313339 A 713 715 Al FORMULA 23313339 A 783 785 Zn FORMULA 23313339 A 820 822 Al FORMULA 23313339 A 894 900 dienes FAMILY 23313339 A 939 941 Zn FORMULA 23313339 A 965 967 Al FORMULA 23313339 T 0 4 Zinc SYSTEMATIC 23313339 T 24 33 aluminium SYSTEMATIC 23313557 A 1018 1024 GW4064 IDENTIFIER 23313557 A 102 115 dexamethasone TRIVIAL 23313557 A 117 129 prednisolone TRIVIAL 23313557 A 134 144 budesonide TRIVIAL 23313557 A 1376 1382 GW4064 IDENTIFIER 23313557 A 1415 1432 chenodeoxycholate TRIVIAL 23313557 A 1437 1443 GW4064 IDENTIFIER 23313557 A 177 187 bile acids FAMILY 23313557 A 397 409 deoxycholate SYSTEMATIC 23313557 A 924 930 GW4064 IDENTIFIER 23313557 T 118 127 bile acid FAMILY 23313610 A 19 32 mycotoxin T-2 TRIVIAL 23313610 A 293 302 T-2 toxin TRIVIAL 23313610 T 37 46 T-2 toxin TRIVIAL 23313620 A 125 139 hydroxytyrosol SYSTEMATIC 23313620 A 141 150 3,4-DHPEA SYSTEMATIC 23313620 A 156 186 3,4-dihydroxyphenethyl halides FAMILY 23313620 A 20 34 hydroxytyrosol SYSTEMATIC 23313620 A 235 243 catechol TRIVIAL 23313620 A 264 270 sulfur SYSTEMATIC 23313620 A 46 51 thiol FAMILY 23313620 A 479 488 3,4-DHPEA SYSTEMATIC 23313620 A 53 64 thioacetate SYSTEMATIC 23313620 A 540 554 hydroxytyrosol SYSTEMATIC 23313620 A 555 564 disulfide SYSTEMATIC 23313620 A 676 685 3,4-DHPEA SYSTEMATIC 23313620 A 69 78 disulfide SYSTEMATIC 23313620 A 711 725 hydroxytyrosol SYSTEMATIC 23313620 A 788 796 H(2)O(2) FORMULA 23313620 T 104 108 thio SYSTEMATIC 23313620 T 37 51 hydroxytyrosol SYSTEMATIC 23313622 A 439 452 acetaminophen TRIVIAL 23313622 A 463 470 lactose TRIVIAL 23313622 A 490 508 magnesium stearate SYSTEMATIC 23313622 A 630 643 acetaminophen TRIVIAL 23313622 A 665 672 lactose TRIVIAL 23313622 A 677 695 magnesium stearate SYSTEMATIC 23313622 A 973 986 acetaminophen TRIVIAL 23313623 A 0 9 Entecavir TRIVIAL 23313623 A 1023 1032 entecavir TRIVIAL 23313623 A 1122 1131 entecavir TRIVIAL 23313623 A 1158 1174 p-aminohippurate TRIVIAL 23313623 A 1176 1192 benzylpenicillin SYSTEMATIC 23313623 A 1194 1200 JBP485 IDENTIFIER 23313623 A 1206 1225 tetraethyl ammonium SYSTEMATIC 23313623 A 1271 1280 entecavir TRIVIAL 23313623 A 1368 1384 p-aminohippurate TRIVIAL 23313623 A 1386 1402 benzylpenicillin SYSTEMATIC 23313623 A 14 20 JBP485 IDENTIFIER 23313623 A 1408 1414 JBP485 IDENTIFIER 23313623 A 1438 1447 entecavir TRIVIAL 23313623 A 1557 1566 Entecavir TRIVIAL 23313623 A 1663 1672 entecavir TRIVIAL 23313623 A 1677 1683 JBP485 IDENTIFIER 23313623 A 191 200 entecavir TRIVIAL 23313623 A 24 33 dipeptide FAMILY 23313623 A 312 321 entecavir TRIVIAL 23313623 A 326 332 JBP485 IDENTIFIER 23313623 A 369 378 entecavir TRIVIAL 23313623 A 444 453 entecavir TRIVIAL 23313623 A 575 584 entecavir TRIVIAL 23313623 A 589 595 JBP485 IDENTIFIER 23313623 A 605 614 entecavir TRIVIAL 23313623 A 805 814 entecavir TRIVIAL 23313623 T 56 65 entecavir TRIVIAL 23313623 T 70 76 JBP485 IDENTIFIER 23313635 A 220 227 saponin FAMILY 23313635 A 304 314 barrigenol TRIVIAL 23313635 A 320 333 triterpenoids FAMILY 23313635 A 33 43 barrigenol TRIVIAL 23313635 A 49 64 triterpenenoids FAMILY 23313635 T 10 20 barrigenol TRIVIAL 23313635 T 26 39 triterpenoids FAMILY 23313637 A 161 173 nitric oxide SYSTEMATIC 23313637 A 174 178 cGMP ABBREVIATION 23313637 A 179 183 cAMP ABBREVIATION 23313637 A 502 511 quinoline SYSTEMATIC 23313637 A 60 64 cGMP ABBREVIATION 23313637 A 761 770 Quinoline SYSTEMATIC 23313637 T 13 22 quinoline SYSTEMATIC 23313663 A 1015 1018 BaP ABBREVIATION 23313663 A 1158 1161 BaP ABBREVIATION 23313663 A 346 378 polycyclic aromatic hydrocarbons FAMILY 23313663 A 380 384 PAHs ABBREVIATION 23313663 A 536 550 benzo[α]pyrene SYSTEMATIC 23313663 A 552 555 BaP ABBREVIATION 23313663 A 573 576 PAH ABBREVIATION 23313663 A 632 635 BaP ABBREVIATION 23313663 A 810 813 BaP ABBREVIATION 23313663 T 0 14 Benzo[α]pyrene SYSTEMATIC 23313711 A 0 9 Aldehydes FAMILY 23313711 A 1017 1028 glutathione TRIVIAL 23313711 A 1047 1058 glutathione TRIVIAL 23313711 A 1118 1126 aldehyde SYSTEMATIC 23313711 A 1140 1151 glutathione TRIVIAL 23313711 A 1196 1207 glutathione TRIVIAL 23313711 A 1269 1278 carnosine TRIVIAL 23313711 A 1331 1338 glucose TRIVIAL 23313711 A 1512 1521 carnosine TRIVIAL 23313711 A 1624 1633 aldehydes FAMILY 23313711 A 1646 1655 histamine TRIVIAL 23313711 A 1685 1694 carnosine TRIVIAL 23313711 A 1707 1716 histidine TRIVIAL 23313711 A 1822 1830 carbonyl FAMILY 23313711 A 266 275 aldehydes FAMILY 23313711 A 358 367 aldehydes FAMILY 23313711 A 436 442 thiols FAMILY 23313711 A 447 453 amines FAMILY 23313711 A 463 474 glutathione TRIVIAL 23313711 A 47 60 carbohydrates FAMILY 23313711 A 479 488 histidine TRIVIAL 23313711 A 501 510 Histidine TRIVIAL 23313711 A 714 722 aldehyde SYSTEMATIC 23313711 A 735 744 Histidine TRIVIAL 23313711 A 764 773 carnosine TRIVIAL 23313711 A 814 835 unsaturated aldehydes FAMILY 23313711 A 852 864 carbohydrate FAMILY 23313711 A 873 899 oxo- and hydroxy-aldehydes MULTIPLE 23313711 T 18 27 aldehydes FAMILY 23313711 T 31 40 histidine TRIVIAL 23313730 A 1035 1037 Mn FORMULA 23313730 A 1079 1090 amphetamine TRIVIAL 23313730 A 1181 1183 Mn FORMULA 23313730 A 1338 1340 Mn FORMULA 23313730 A 20 22 Mn FORMULA 23313730 A 251 253 Mn FORMULA 23313730 A 335 346 amphetamine TRIVIAL 23313730 A 382 390 dopamine TRIVIAL 23313730 A 455 457 Mn FORMULA 23313730 A 536 538 Mn FORMULA 23313730 A 705 707 Mn FORMULA 23313730 A 801 803 Mn FORMULA 23313730 A 826 828 Mn FORMULA 23313730 A 926 928 Mn FORMULA 23313730 T 14 23 manganese SYSTEMATIC 23313730 T 27 35 dopamine TRIVIAL 23313730 T 49 57 dopamine TRIVIAL 23313795 A 1084 1094 flavonoids FAMILY 23313795 A 126 136 flavonoids FAMILY 23313795 A 231 241 flavonoids FAMILY 23313795 A 288 320 3-hydroxyphloretin 6'-O-hexoside SYSTEMATIC 23313795 A 322 342 quercetin-7-hexoside SYSTEMATIC 23313795 A 34 44 flavonoids FAMILY 23313795 A 344 365 apigenin7-O-glucoside SYSTEMATIC 23313795 A 367 389 luteolin 7-O-glucoside SYSTEMATIC 23313795 A 391 415 apigenin 7-O-galactoside SYSTEMATIC 23313795 A 417 470 acacetin 7-O-(α-D-apio-furanosyl) (1→6)-β-d-glucoside SYSTEMATIC 23313795 A 472 504 3-hydroxy phloretin 6-O-hexoside SYSTEMATIC 23313795 A 506 528 luteolin-6-C-glucoside SYSTEMATIC 23313795 A 540 550 flavonoids FAMILY 23313795 A 595 605 superoxide TRIVIAL 23313795 A 671 676 rutin TRIVIAL 23313795 A 716 726 flavonoids FAMILY 23313795 A 763 767 DPPH ABBREVIATION 23313795 A 802 807 rutin TRIVIAL 23313795 A 830 835 rutin TRIVIAL 23313795 A 897 901 ABTS ABBREVIATION 23313795 A 946 956 flavonoids FAMILY 23313795 T 0 10 Flavonoids FAMILY 23313796 A 1121 1156 suffruticosols A (+95 vs -34) and B MULTIPLE 23313796 A 328 339 resveratrol TRIVIAL 23313796 A 359 370 resveratrol TRIVIAL 23313796 A 444 451 ethanol SYSTEMATIC 23313796 A 590 601 polyphenols FAMILY 23313796 A 603 618 suffruticosol A TRIVIAL 23313796 A 624 639 suffruticosol B TRIVIAL 23313796 A 645 662 trans-ε-viniferin TRIVIAL 23313796 A 672 686 trans-gnetin H TRIVIAL 23313796 A 798 815 Trans-ε-viniferin TRIVIAL 23313796 T 38 49 polyphenols FAMILY 23314046 A 154 177 thymidine monophosphate SYSTEMATIC 23314046 A 297 319 thymidine triphosphate SYSTEMATIC 23314047 A 12 34 N-methylthio-β-lactams FAMILY 23314047 A 143 155 polyphenolic FAMILY 23314047 A 179 187 β-lactam TRIVIAL 23314047 T 0 20 Monocyclic β-lactams FAMILY 23314047 T 77 102 N-methylthio-azetidinones FAMILY 23314053 A 326 376 1- and 12-Aryl substituted benzo[c]phenanthridines MULTIPLE 23314053 A 501 536 4- and 5-amino-1-phenylnaphthalenes MULTIPLE 23314053 A 595 618 benzo[c]phenanthridines FAMILY 23314053 A 628 669 4- and 5-substituted 1-phenylnaphthalenes MULTIPLE 23314053 T 34 75 4- and 5-substituted 1-phenylnaphthalenes MULTIPLE 23314054 A 412 429 2-hydroxypyridine SYSTEMATIC 23314054 A 609 667 N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide SYSTEMATIC 23314054 A 82 148 3-thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile SYSTEMATIC 23314054 T 63 124 N-substituted-5-(4-isopropylthiophenol)-2-hydroxynicotinamide FAMILY 23314104 A 812 820 graphene TRIVIAL 23314104 A 849 855 biotin TRIVIAL 23314320 A 157 162 oxime SYSTEMATIC 23314320 A 179 234 2-[(hydroxyimino)methyl]-1-methylpyridin-1-ium chloride SYSTEMATIC 23314320 A 1924 1929 oxime SYSTEMATIC 23314320 A 236 241 2-PAM SYSTEMATIC 23314320 A 339 407 1,1'-methylenebis{4-hydroxyiminomethyl}pyridinium dimethanesulfonate SYSTEMATIC 23314320 A 409 414 MMB-4 SYSTEMATIC 23314320 A 463 468 MMB-4 ABBREVIATION 23314320 A 587 592 oxime SYSTEMATIC 23314320 A 594 655 1,1'-trimethylenebis{4-hydroximinomethyl}pyridinium dibromide SYSTEMATIC 23314320 A 701 716 organophosphate FAMILY 23314320 A 717 743 diisopropylfluorophosphate SYSTEMATIC 23314320 A 9 15 oximes FAMILY 23314320 T 54 59 oxime SYSTEMATIC 23314320 T 60 65 TMB-4 IDENTIFIER 23314800 A 113 120 diamond TRIVIAL 23314800 A 247 254 diamond TRIVIAL 23314800 A 379 386 diamond TRIVIAL 23314913 A 368 379 lanthionine TRIVIAL 23314913 A 384 401 methyllanthionine SYSTEMATIC 23314913 T 59 70 lanthionine TRIVIAL 23315275 A 372 378 oxygen SYSTEMATIC 23315275 A 746 756 superoxide TRIVIAL 23315275 A 794 805 glutathione TRIVIAL 23315275 A 834 849 malondialdehyde TRIVIAL 23315275 A 851 854 MDA ABBREVIATION 23315275 A 977 980 MDA ABBREVIATION 23316003 A 30 41 Doxorubicin TRIVIAL 23316003 A 343 347 PLGA ABBREVIATION 23316003 A 352 355 Dox ABBREVIATION 23316003 A 43 46 Dox ABBREVIATION 23316003 A 470 473 Dox ABBREVIATION 23316003 A 506 510 PLGA ABBREVIATION 23316003 A 53 79 poly(lactide-co-glycolide) SYSTEMATIC 23316003 A 732 736 PLGA ABBREVIATION 23316003 A 749 752 Dox ABBREVIATION 23316003 A 81 85 PLGA ABBREVIATION 23316003 A 923 927 PLGA ABBREVIATION 23316003 A 940 943 Dox ABBREVIATION 23316003 T 35 46 doxorubicin TRIVIAL 23316003 T 52 78 poly(lactide-co-glycolide) SYSTEMATIC 23316685 A 485 491 copper SYSTEMATIC 23316685 A 69 75 copper SYSTEMATIC 23316685 A 911 917 copper SYSTEMATIC 23316748 A 114 125 vinblastine TRIVIAL 23316748 A 207 208 H FORMULA 23316748 A 390 401 vinblastine TRIVIAL 23316748 A 42 46 urea TRIVIAL 23316748 A 62 73 vinblastine TRIVIAL 23316748 T 18 29 vinblastine TRIVIAL 23316792 A 66 76 D-fructose TRIVIAL 23316792 A 699 705 sugars FAMILY 23316792 T 37 45 fructose TRIVIAL 23316943 A 175 181 carbon SYSTEMATIC 23316943 A 194 217 tetraethylorthosilicate SYSTEMATIC 23316943 A 219 223 TEOS ABBREVIATION 23316943 A 230 247 tributylphenyltin SYSTEMATIC 23316943 A 249 251 Sn FORMULA 23316943 A 302 332 poly(ethylene oxide-b-styrene) FAMILY 23316943 A 334 342 PEO-b-PS ABBREVIATION 23316943 A 380 382 Sn FORMULA 23316943 A 406 408 Sn FORMULA 23316943 A 476 478 Sn FORMULA 23316943 A 57 59 Sn FORMULA 23316943 A 651 658 lithium SYSTEMATIC 23316943 A 69 75 carbon SYSTEMATIC 23316943 A 76 82 silica TRIVIAL 23316943 T 21 24 tin SYSTEMATIC 23316943 T 34 40 carbon SYSTEMATIC 23316943 T 41 47 silica TRIVIAL 23316943 T 86 93 lithium SYSTEMATIC 23317008 A 257 270 acetylcholine SYSTEMATIC 23317031 A 124 126 Pt FORMULA 23317031 A 17 19 Pt FORMULA 23317031 A 246 248 Pt FORMULA 23317031 A 501 503 Pt FORMULA 23317031 A 546 560 graphene oxide SYSTEMATIC 23317031 A 578 580 Pt FORMULA 23317031 A 91 99 graphite TRIVIAL 23317031 T 10 12 Pt FORMULA 23317031 T 78 86 graphite TRIVIAL 23317098 A 1979 1986 glucose TRIVIAL 23317098 A 393 399 oxygen SYSTEMATIC 23317339 A 1301 1313 Ciplar LA 80 TRIVIAL 23317339 A 1634 1649 propranolol HCl FORMULA 23317339 A 165 180 propranolol HCl FORMULA 23317339 A 1745 1757 Ciplar LA 80 TRIVIAL 23317339 A 277 295 sodium bicarbonate SYSTEMATIC 23317339 T 106 121 propranolol HCl FORMULA 23317432 A 313 324 alkanethiol FAMILY 23317432 A 453 463 gold-thiol SYSTEMATIC 23317432 T 64 75 alkanethiol FAMILY 23317571 A 492 507 prostaglandin F FAMILY 23317571 A 787 798 dorzolamide TRIVIAL 23317571 T 56 71 prostaglandin F FAMILY 23318470 A 1419 1463 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine SYSTEMATIC 23318470 A 1465 1469 MPTP ABBREVIATION 23318470 A 1475 1485 probenecid TRIVIAL 23318470 A 1656 1660 MPTP ABBREVIATION 23318470 A 1665 1675 probenecid TRIVIAL 23318470 A 1774 1782 dopamine TRIVIAL 23318470 A 261 301 para-phenyl-substituted diindolylmethane FAMILY 23318470 A 613 659 1,1-bis(3'-indolyl)-1-(p-methoxyphenyl)methane SYSTEMATIC 23318470 A 670 707 1,1-bis(3'-indolyl)-1-(phenyl)methane SYSTEMATIC 23318470 A 709 755 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane SYSTEMATIC 23318470 A 770 815 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane SYSTEMATIC 23318470 T 81 122 para-phenyl substituted diindolylmethanes FAMILY 23318471 A 1024 1027 TES ABBREVIATION 23318471 A 1039 1049 superoxide TRIVIAL 23318471 A 1112 1115 TES ABBREVIATION 23318471 A 1151 1167 phosphoinositide FAMILY 23318471 A 1245 1253 androgen FAMILY 23318471 A 1304 1308 cGMP ABBREVIATION 23318471 A 146 155 androgens FAMILY 23318471 A 1485 1493 androgen FAMILY 23318471 A 1526 1529 TES ABBREVIATION 23318471 A 1576 1589 peroxynitrite SYSTEMATIC 23318471 A 1602 1610 xanthine TRIVIAL 23318471 A 1629 1639 superoxide TRIVIAL 23318471 A 1644 1646 NO FORMULA 23318471 A 1764 1772 androgen FAMILY 23318471 A 1827 1830 TES ABBREVIATION 23318471 A 1842 1846 cGMP ABBREVIATION 23318471 A 21 30 androgens FAMILY 23318471 A 246 258 testosterone TRIVIAL 23318471 A 260 263 TES ABBREVIATION 23318471 A 338 341 TES ABBREVIATION 23318471 A 521 524 TES ABBREVIATION 23318471 A 584 597 17β-estradiol SYSTEMATIC 23318471 A 599 618 Dichlorofluorescein SYSTEMATIC 23318471 A 636 649 nitrotyrosine SYSTEMATIC 23318471 A 688 691 TES ABBREVIATION 23318471 A 703 716 peroxynitrite SYSTEMATIC 23318471 A 785 788 TES ABBREVIATION 23318471 A 838 851 peroxynitrite SYSTEMATIC 23318471 A 867 870 TES ABBREVIATION 23318471 A 903 916 peroxynitrite SYSTEMATIC 23318471 A 935 945 superoxide TRIVIAL 23318471 A 950 961 nitic oxide SYSTEMATIC 23318471 A 968 976 xanthine TRIVIAL 23318471 T 0 13 Peroxynitrite SYSTEMATIC 23318471 T 23 35 testosterone TRIVIAL 23318553 A 101 108 sucrose TRIVIAL 23318553 A 113 140 4-hydroxyphenylboronic acid SYSTEMATIC 23318553 A 146 152 SBA-15 IDENTIFIER 23318553 A 153 159 silica TRIVIAL 23318553 A 170 178 Nitrogen SYSTEMATIC 23318553 A 19 38 boron-doped carbons FAMILY 23318553 A 454 455 B FORMULA 23318553 A 645 651 oxygen SYSTEMATIC 23318553 A 708 709 B FORMULA 23318553 T 19 38 boron-doped carbons FAMILY 23318553 T 78 84 oxygen SYSTEMATIC 23318644 A 1003 1010 alanine TRIVIAL 23318644 A 1215 1226 cholesterol TRIVIAL 23318644 A 985 996 cholesterol TRIVIAL 23318685 A 0 12 Peginesatide TRIVIAL 23318685 A 16 35 polyethylene glycol SYSTEMATIC 23318685 A 1732 1744 peginesatide TRIVIAL 23318685 A 307 319 peginesatide TRIVIAL 23318685 A 37 40 PEG ABBREVIATION 23318685 A 389 401 peginesatide TRIVIAL 23318685 A 528 540 peginesatide TRIVIAL 23318685 A 704 716 peginesatide TRIVIAL 23318685 T 0 12 Peginesatide TRIVIAL 23318728 A 1116 1124 nicotine TRIVIAL 23318728 A 1141 1153 nitric-oxide SYSTEMATIC 23318728 A 1198 1206 nicotine TRIVIAL 23318728 A 1343 1351 nicotine TRIVIAL 23318728 A 1356 1364 nicotine TRIVIAL 23318728 A 209 217 nicotine TRIVIAL 23318728 A 320 328 nicotine TRIVIAL 23318728 A 448 456 cotinine TRIVIAL 23318728 A 458 474 cotinine-N-oxide SYSTEMATIC 23318728 A 476 495 nicotine-1'-N-oxide SYSTEMATIC 23318728 A 499 523 trans-3'-hydroxycotinine SYSTEMATIC 23318728 A 592 600 Nicotine TRIVIAL 23318728 A 656 680 trans-3'-hydroxycotinine SYSTEMATIC 23318728 A 694 713 nicotine-1'-N-oxide SYSTEMATIC 23318728 T 11 19 nicotine TRIVIAL 23318949 A 1080 1091 fatty acids FAMILY 23318949 A 1204 1211 sulfide SYSTEMATIC 23318949 A 1216 1223 ammonia SYSTEMATIC 23318949 A 224 235 amino acids FAMILY 23318949 A 295 306 amino acids FAMILY 23318949 A 329 339 amino acid FAMILY 23318949 A 525 536 amino acids FAMILY 23318949 A 808 819 amino acids FAMILY 23318949 A 845 856 amino acids FAMILY 23318949 T 32 40 nitrogen SYSTEMATIC 23319419 A 113 117 K(+) FORMULA 23319419 A 1161 1172 amino acids FAMILY 23319419 A 1215 1218 ICA ABBREVIATION 23319419 A 1295 1298 ICA ABBREVIATION 23319419 A 1360 1363 ICA ABBREVIATION 23319419 A 1402 1405 ICA ABBREVIATION 23319419 A 165 170 ether SYSTEMATIC 23319419 A 185 189 K(+) FORMULA 23319419 A 252 262 ICA-105574 IDENTIFIER 23319419 A 264 267 ICA ABBREVIATION 23319419 A 272 309 3-nitro-N-[4-phenoxyphenyl]-benzamide SYSTEMATIC 23319419 A 385 388 ICA ABBREVIATION 23319419 A 646 649 ICA ABBREVIATION 23319419 A 703 706 ICA ABBREVIATION 23319419 A 80 85 ether SYSTEMATIC 23319419 A 836 839 ICA ABBREVIATION 23319419 A 982 985 ICA ABBREVIATION 23319419 T 0 10 ICA-105574 IDENTIFIER 23319419 T 113 122 potassium SYSTEMATIC 23319549 A 0 28 L-3,4-Dihydroxyphenylalanine SYSTEMATIC 23319549 A 153 159 L-DOPA ABBREVIATION 23319549 A 228 234 L-DOPA ABBREVIATION 23319549 A 30 36 L-DOPA ABBREVIATION 23319549 A 838 857 γ-aminobutyric acid SYSTEMATIC 23319549 A 859 863 GABA ABBREVIATION 23319549 A 872 881 adenosine TRIVIAL 23319549 T 20 26 L-DOPA ABBREVIATION 23321024 A 340 345 azide SYSTEMATIC 23321024 A 537 543 copper SYSTEMATIC 23321274 A 1093 1096 DXM ABBREVIATION 23321274 A 30 38 steroids FAMILY 23321274 A 459 472 dexamethasone TRIVIAL 23321274 A 474 477 DXM ABBREVIATION 23321274 A 598 602 PLGA ABBREVIATION 23321274 A 604 634 poly(d,l-lactide-co-glycolide) FAMILY 23321274 A 660 680 hydroxypropyl methyl SYSTEMATIC 23321274 A 703 706 DXM ABBREVIATION 23321274 A 887 890 DXM ABBREVIATION 23321274 T 35 48 dexamethasone TRIVIAL 23321687 A 1170 1182 theophylline TRIVIAL 23321687 A 1243 1251 caffeine TRIVIAL 23321687 A 1297 1309 theophylline TRIVIAL 23321687 A 1508 1520 theophylline TRIVIAL 23321687 A 1670 1678 caffeine TRIVIAL 23321687 A 1703 1715 theophylline TRIVIAL 23321687 A 1839 1847 caffeine TRIVIAL 23321687 A 184 192 dopamine TRIVIAL 23321687 A 1892 1904 theophylline TRIVIAL 23321687 A 1943 1951 caffeine TRIVIAL 23321687 A 2099 2107 caffeine TRIVIAL 23321687 A 2141 2153 theophylline TRIVIAL 23321687 A 27 35 caffeine TRIVIAL 23321687 A 287 298 haloperidol TRIVIAL 23321687 A 368 376 dopamine TRIVIAL 23321687 A 40 52 theophylline TRIVIAL 23321687 A 404 421 6-hydroxydopamine SYSTEMATIC 23321687 A 644 652 caffeine TRIVIAL 23321687 A 694 706 theophylline TRIVIAL 23321687 A 767 775 caffeine TRIVIAL 23321687 A 817 829 theophylline TRIVIAL 23321687 A 918 926 caffeine TRIVIAL 23321687 T 0 8 Caffeine TRIVIAL 23321687 T 47 59 theophylline TRIVIAL 23322473 A 1114 1116 As FORMULA 23322473 A 1277 1279 As FORMULA 23322473 A 129 136 arsenic SYSTEMATIC 23322473 A 26 33 arsenic SYSTEMATIC 23322473 A 347 349 As FORMULA 23322473 A 35 37 As FORMULA 23322473 A 401 417 ammonium acetate SYSTEMATIC 23322473 A 718 720 As FORMULA 23322473 A 791 793 As FORMULA 23322473 A 827 829 As FORMULA 23322473 A 951 958 Arsenic SYSTEMATIC 23322473 T 0 7 Arsenic SYSTEMATIC 23322906 A 31 41 nucleotide FAMILY 23323548 A 667 684 estrone-3-sulfate SYSTEMATIC 23323548 A 686 691 E-3-S SYSTEMATIC 23323548 A 697 713 taurocholic acid TRIVIAL 23323627 A 1003 1011 γ-CD-OEI ABBREVIATION 23323627 A 1042 1053 γ-CD-OEI-FA ABBREVIATION 23323627 A 108 114 folate TRIVIAL 23323627 A 1119 1128 disulfide SYSTEMATIC 23323627 A 1177 1191 γ-CD-OEI-SS-FA ABBREVIATION 23323627 A 17 23 folate TRIVIAL 23323627 A 371 385 γ-cyclodextrin TRIVIAL 23323627 A 387 391 γ-CD ABBREVIATION 23323627 A 411 428 oligoethylenimine FAMILY 23323627 A 430 433 OEI ABBREVIATION 23323627 A 445 455 folic acid TRIVIAL 23323627 A 486 495 disulfide SYSTEMATIC 23323627 A 585 599 γ-CD-OEI-SS-FA ABBREVIATION 23323627 A 727 741 γ-CD-OEI-SS-FA ABBREVIATION 23323627 A 77 83 folate TRIVIAL 23323627 A 979 995 polyethylenimine SYSTEMATIC 23323627 A 997 1000 PEI ABBREVIATION 23323627 T 0 10 Folic acid TRIVIAL 23323627 T 29 43 γ-cyclodextrin TRIVIAL 23323627 T 44 61 oligoethylenimine FAMILY 23323627 T 93 102 disulfide SYSTEMATIC 23323717 A 125 146 diterpenoid alkaloids FAMILY 23323717 A 34 46 kirinenine A TRIVIAL 23323717 A 6 32 C(18)-diterpenoid alkaloid FAMILY 23323717 T 0 21 Diterpenoid alkaloids FAMILY 23323802 A 152 165 ethyl acetate SYSTEMATIC 23323802 A 28 101 (R)-2-(2-(furan-2-yl)-oxoethyl)-octahydropyrrolo[1,2-a]pyrazine-1,4-dione SYSTEMATIC 23323802 A 6 26 2,5-diketopiperazine SYSTEMATIC 23323846 A 287 293 carbon SYSTEMATIC 23323846 A 993 1003 amino acid FAMILY 23323846 T 50 56 carbon SYSTEMATIC 23323861 A 37 95 7,3'-di-(γ,γ-dimethylallyloxy)-5-hydroxy-4'-methoxyflavone SYSTEMATIC 23323861 A 6 29 di-O-prenylated flavone TRIVIAL 23323861 T 6 29 di-O-prenylated flavone TRIVIAL 23323954 A 152 160 methanol SYSTEMATIC 23323954 A 18 53 lyciumtetraterpenic hexaarabinoside TRIVIAL 23323954 A 268 593 6-(1,1,5-trimethyl-5α-hydroxycyclohexanyl)-6'-(1',1',5'-trimethyl-2'β-hydroxycyclohexanyl)-9,13,9',13'-tetramethyloctadec-7,9,11,13,15,7',9',11',13'-nonene-5α-D-arabinopyranosyl(2a → 1b)-β-D-arabinopyranosyl-(2b → 1c)-β-D-arabinopyranosyl-2'-β-D-arabinopyranosyl-(2d → 1e)-α-D-arabinopyranosyl-(2e → 1f)-α-D-arabinopyranoside SYSTEMATIC 23323954 A 602 850 1(6),11(12),13(14),1'(6'),11'(12'),13'(14')-dodecahydro-β-caroten-4β,4'β-diol-4β-L-arabinopyranosyl-(2a → 1b)-β-L-arabinopyranosyl-(2b → 1c)-β-D-arabinopyranosido-4'β-L-arabinopyranosyl-(2d → 1e)-β-L-arabinopyranosyl-(2e → 1f)-β-D-arabinopyranoside SYSTEMATIC 23323954 A 62 91 tetraterpenyl hexaarabinoside TRIVIAL 23323954 T 4 27 tetraterpene glycosides FAMILY 23324405 A 0 89 (E)-2-(3-(3-((3-Bromophenyl)amino)-2-cyano-3-oxoprop-1-en-1-yl)-1H-indol-1-yl)acetic acid SYSTEMATIC 23324405 A 334 375 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole SYSTEMATIC 23324405 T 63 102 (E)-2-cyano-3-(1H-indol-3-yl)acrylamide SYSTEMATIC 23325361 A 514 522 Androgen FAMILY 23325368 A 1074 1078 5-HT SYSTEMATIC 23325368 A 1246 1257 sumatriptan TRIVIAL 23325368 A 1263 1267 5-HT SYSTEMATIC 23325368 A 363 374 sumatriptan TRIVIAL 23325368 A 512 523 sumatriptan TRIVIAL 23325368 A 627 638 sumatriptan TRIVIAL 23325368 A 763 774 Sumatriptan TRIVIAL 23325368 A 79 90 sumatriptan TRIVIAL 23325368 A 859 867 cortisol TRIVIAL 23325368 A 923 934 sumatriptan TRIVIAL 23325368 A 945 949 5-HT SYSTEMATIC 23325368 T 31 42 sumatriptan TRIVIAL 23325369 A 1036 1045 clozapine TRIVIAL 23325369 A 106 115 Clozapine TRIVIAL 23325369 A 1081 1090 clozapine TRIVIAL 23325369 A 1231 1240 clozapine TRIVIAL 23325369 A 1345 1354 clozapine TRIVIAL 23325369 A 19 31 triglyceride FAMILY 23325369 A 354 363 clozapine TRIVIAL 23325369 A 566 575 clozapine TRIVIAL 23325369 A 85 94 clozapine TRIVIAL 23325369 T 13 25 triglyceride FAMILY 23325369 T 74 83 clozapine TRIVIAL 23325491 A 116 152 3-amino-2-phenyl-1H-quinazolin-4-one SYSTEMATIC 23325491 A 12 79 3-[(4-substituted-benzylidene)-amino]-2-phenyl-3H-quinazolin-4-ones FAMILY 23325491 A 158 179 p-hydroxybenzaldehyde SYSTEMATIC 23325491 A 211 231 alkyl/benzyl halides MULTIPLE 23325491 A 247 264 phenacyl bromides FAMILY 23325491 A 546 607 3-[(4-butoxy-benzylidene)-amino]-2-phenyl-3H-quinazolin-4-one SYSTEMATIC 23325491 A 716 720 GABA ABBREVIATION 23325491 A 814 827 quinazolinone SYSTEMATIC 23325491 A 869 873 GABA ABBREVIATION 23325491 T 33 55 quinazolin-4-(3H)-ones FAMILY 23327465 A 511 530 methyl methacrylate SYSTEMATIC 23327465 A 531 545 butyl acrylate SYSTEMATIC 23327600 A 328 335 calcium SYSTEMATIC 23327600 A 353 360 calcium SYSTEMATIC 23327600 A 370 374 EDTA ABBREVIATION 23327600 A 480 484 NaOH FORMULA 23327600 A 773 777 EDTA ABBREVIATION 23327600 T 113 120 Calcium SYSTEMATIC 23327612 A 379 387 CH(3)ONO FORMULA 23327612 A 411 417 CH(3)O FORMULA 23327612 A 420 422 NO FORMULA 23327612 A 54 64 CH(3)NO(2) FORMULA 23327612 T 35 45 CH(3)NO(2) FORMULA 23327656 A 225 240 thiol-disulfide SYSTEMATIC 23327656 A 362 371 disulfide SYSTEMATIC 23327656 A 617 626 disulfide SYSTEMATIC 23327656 T 64 74 disulfides FAMILY 23327759 A 10 39 dibenzocyclooctadiene lignans FAMILY 23327759 A 41 55 marlignans M-S MULTIPLE 23327759 A 72 82 norlignans FAMILY 23327759 A 84 98 marphenols C-F MULTIPLE 23327759 T 0 29 Dibenzocyclooctadiene lignans FAMILY 23327759 T 34 44 norlignans FAMILY 23327779 A 1059 1074 [(3)H]-(+)-PHNO SYSTEMATIC 23327779 A 1298 1308 olanzapine TRIVIAL 23327779 A 1313 1324 haloperidol TRIVIAL 23327779 A 1354 1363 clozapine TRIVIAL 23327779 A 1434 1445 Risperidone TRIVIAL 23327779 A 153 161 dopamine TRIVIAL 23327779 A 28 70 [(3)H]-(+)-4-propyl-9-hydroxynaphthoxazine SYSTEMATIC 23327779 A 460 475 [(3)H]-(+)-PHNO SYSTEMATIC 23327779 A 72 87 [(3)H]-(+)-PHNO SYSTEMATIC 23327779 A 776 791 [(3)H]-(+)-PHNO SYSTEMATIC 23327779 A 873 888 [(3)H]-(+)-PHNO SYSTEMATIC 23327779 T 66 74 dopamine TRIVIAL 23327841 A 1177 1184 alcohol FAMILY 23327841 A 1282 1289 alcohol FAMILY 23327877 A 1067 1095 epigallocatechin 3-O-gallate SYSTEMATIC 23327877 A 1097 1101 EGCG ABBREVIATION 23327877 A 1178 1182 EGCG ABBREVIATION 23327877 A 1240 1244 EGCG ABBREVIATION 23327877 A 1349 1353 EGCG ABBREVIATION 23327877 A 1370 1379 quercetin TRIVIAL 23327877 A 200 210 Flavonoids FAMILY 23327877 A 229 238 catechins FAMILY 23327877 A 243 263 quercetin glycosides FAMILY 23327877 A 378 387 quercetin TRIVIAL 23327877 A 513 538 estradiol 17β-glucuronide SYSTEMATIC 23327877 A 540 557 estrone 3-sulfate SYSTEMATIC 23327877 A 563 593 dehydroepiandrosterone sulfate SYSTEMATIC 23327877 A 595 600 DHEAS ABBREVIATION 23327877 A 930 955 estradiol 17β-glucuronide SYSTEMATIC 23327877 T 103 112 quercetin TRIVIAL 23327877 T 62 90 epigallocatechin 3-O-gallate SYSTEMATIC 23327905 A 10 17 labdane TRIVIAL 23327905 A 23 35 diterpenoids FAMILY 23327905 A 37 55 vitextrifolins A-G MULTIPLE 23327905 T 0 7 Labdane TRIVIAL 23327905 T 13 25 diterpenoids FAMILY 23328125 A 1117 1120 Tyr FORMULA 23328125 A 1345 1348 Tyr FORMULA 23328125 A 175 183 tyramine TRIVIAL 23328125 A 188 191 Tyr FORMULA 23328125 A 238 241 Tyr FORMULA 23328125 A 256 273 hydrogen peroxide SYSTEMATIC 23328125 A 275 279 H2O2 FORMULA 23328125 A 339 342 Tyr FORMULA 23328125 A 402 406 H2O2 FORMULA 23328125 A 673 676 Tyr FORMULA 23328125 T 27 35 tyramine TRIVIAL 23329465 A 1483 1492 vitamin E FAMILY 23329465 A 1546 1558 pioglitazone TRIVIAL 23329465 A 539 554 free fatty acid FAMILY 23329465 A 918 925 alcohol FAMILY 23329466 A 0 27 Extended-release ranolazine TRIVIAL 23329466 A 1183 1196 ranolazine ER TRIVIAL 23329466 A 1277 1290 ranolazine ER TRIVIAL 23329466 A 182 188 sodium SYSTEMATIC 23329466 A 29 42 ranolazine ER TRIVIAL 23329466 A 314 327 ranolazine ER TRIVIAL 23329466 A 45 51 Ranexa TRIVIAL 23329466 A 559 572 ranolazine ER TRIVIAL 23329466 A 637 650 nitroglycerin SYSTEMATIC 23329466 A 824 837 ranolazine ER TRIVIAL 23329466 A 959 972 Ranolazine ER TRIVIAL 23329466 T 0 10 Ranolazine TRIVIAL 23329698 A 268 271 Ser FORMULA 23329698 A 272 275 Thr FORMULA 23330546 A 0 10 Bile acids FAMILY 23330546 A 132 142 androstane TRIVIAL 23330546 A 157 166 vitamin D FAMILY 23330546 A 230 237 glucose TRIVIAL 23330546 A 399 408 bile acid FAMILY 23330546 A 469 478 bile acid FAMILY 23330546 A 766 775 Bile-acid FAMILY 23330546 A 98 106 pregnane TRIVIAL 23330546 T 21 30 bile acid FAMILY 23330711 A 112 125 sodium iodide SYSTEMATIC 23330711 A 365 383 potassium fluoride SYSTEMATIC 23330726 A 167 186 poly(l-lactic acid) SYSTEMATIC 23330726 A 188 192 PLLA ABBREVIATION 23330726 A 531 534 PLL ABBREVIATION 23330726 A 81 95 poly(l-lysine) SYSTEMATIC 23330972 A 102 108 Zn(2+) FORMULA 23330972 A 110 116 Cd(2+) FORMULA 23330972 A 122 128 Hg(2+) FORMULA 23330972 A 179 203 3-mercaptopropionic acid SYSTEMATIC 23330972 A 66 92 group IIb transition-metal FAMILY 23330972 T 20 55 group IIb divalent transition-metal FAMILY 23330972 T 68 92 3-mercaptopropionic acid SYSTEMATIC 23331020 A 340 351 B(n)H(n)(-) FAMILY 23331020 A 352 370 polyhedral boranes FAMILY 23331020 A 37 45 B(6)H(y) FAMILY 23331020 A 395 406 B(6)H(3)(-) FORMULA 23331020 A 705 716 B(6)H(4)(-) FORMULA 23331020 A 751 759 hydrogen SYSTEMATIC 23331020 A 818 821 B-B FORMULA 23331020 A 966 971 boron SYSTEMATIC 23331020 T 31 37 B6H(y) FAMILY 23331067 A 1050 1054 MPTP ABBREVIATION 23331067 A 1158 1162 MPTP ABBREVIATION 23331067 A 1251 1255 MPTP ABBREVIATION 23331067 A 698 705 calcium SYSTEMATIC 23331067 A 936 940 MPTP ABBREVIATION 23331095 A 1013 1015 Cu FORMULA 23331095 A 1263 1277 copper sulfate SYSTEMATIC 23331095 A 1282 1298 copper hydroxide SYSTEMATIC 23331095 A 1822 1850 copper oxides and hydroxides MULTIPLE 23331095 A 1879 1885 sulfur SYSTEMATIC 23331095 A 2082 2090 enargite TRIVIAL 23331095 A 391 399 enargite TRIVIAL 23331095 A 505 513 enargite TRIVIAL 23331095 A 52 60 enargite TRIVIAL 23331095 A 589 597 enargite TRIVIAL 23331095 A 62 73 Cu(3)AsS(4) FORMULA 23331095 A 740 747 sulfide SYSTEMATIC 23331095 A 762 768 sulfur SYSTEMATIC 23331095 T 100 108 enargite TRIVIAL 23331245 A 1416 1422 Mn(3+) FORMULA 23331245 A 1565 1567 Mn FORMULA 23331245 A 223 236 NaMnGe(2)O(6) FORMULA 23331245 A 25 38 NaMnGe(2)O(6) FORMULA 23331245 A 467 471 Mn-O FORMULA 23331245 A 566 579 NaMnGe(2)O(6) FORMULA 23331245 A 591 599 pyroxene FAMILY 23331245 A 6 14 pyroxene FAMILY 23331245 A 742 750 pyroxene FAMILY 23331245 A 851 860 pyroxenes FAMILY 23331245 A 879 892 NaMnGe(2)O(6) FORMULA 23331245 T 65 73 pyroxene FAMILY 23331245 T 74 83 NaMnGe2O6 FORMULA 23332751 A 364 369 sugar FAMILY 23332751 A 370 379 phosphate SYSTEMATIC 23332751 A 665 668 Lys FORMULA 23332751 A 706 709 Lys FORMULA 23333176 A 210 222 nitric oxide SYSTEMATIC 23333573 A 365 369 DPPH ABBREVIATION 23333573 A 371 375 ABTS ABBREVIATION 23333573 A 380 384 AAPH ABBREVIATION 23333573 A 385 398 linoleic acid TRIVIAL 23333573 A 501 505 DPPH ABBREVIATION 23333576 A 1066 1073 glucose TRIVIAL 23333576 A 1099 1102 STZ ABBREVIATION 23333576 A 1137 1143 5'-AMP SYSTEMATIC 23333576 A 1248 1251 STZ ABBREVIATION 23333576 A 1382 1385 STZ ABBREVIATION 23333576 A 152 160 catechin TRIVIAL 23333576 A 167 179 procyanidins FAMILY 23333576 A 326 338 procyanidins FAMILY 23333576 A 56 63 glucose TRIVIAL 23333576 A 570 577 glucose TRIVIAL 23333576 A 609 639 cyclic adenosine monophosphate SYSTEMATIC 23333576 A 641 645 cAMP ABBREVIATION 23333576 A 647 660 dexamethasone TRIVIAL 23333576 A 720 732 streptozocin TRIVIAL 23333576 A 738 741 STZ ABBREVIATION 23333576 A 900 920 phosphoenol-pyruvate SYSTEMATIC 23333576 A 947 954 glucose TRIVIAL 23333576 T 10 22 procyanidins FAMILY 23333576 T 34 46 streptozocin TRIVIAL 23333577 A 0 10 Pinosylvin TRIVIAL 23333577 A 1320 1330 pinosylvin TRIVIAL 23333577 A 313 323 pinosylvin TRIVIAL 23333577 A 34 50 trans-stilbenoid TRIVIAL 23333577 A 383 393 Pinosylvin TRIVIAL 23333577 A 689 699 Pinosylvin TRIVIAL 23333577 A 860 876 phosphoinositide FAMILY 23333577 A 968 978 pinosylvin TRIVIAL 23333577 T 56 66 pinosylvin TRIVIAL 23333583 A 0 19 Picrosides I and II MULTIPLE 23333583 A 1084 1090 kutkin TRIVIAL 23333583 A 1152 1158 kutkin TRIVIAL 23333583 A 358 377 picrosides I and II MULTIPLE 23333583 A 452 458 kutkin TRIVIAL 23333583 A 473 492 picrosides I and II MULTIPLE 23333583 A 657 676 picrosides I and II MULTIPLE 23333583 A 823 842 picrosides I and II MULTIPLE 23333583 A 924 943 picrosides I and II MULTIPLE 23333583 T 40 59 picrosides I and II MULTIPLE 23333717 A 1098 1119 galloylated flavanols FAMILY 23333717 A 1133 1142 flavonols FAMILY 23333717 A 1251 1260 flavonols FAMILY 23333717 A 1298 1309 polyphenols FAMILY 23333717 A 557 569 polyphenolic FAMILY 23333790 A 1038 1046 quinones FAMILY 23333790 A 1048 1066 9,10-anthraquinone SYSTEMATIC 23333790 A 1076 1095 1,4-naphthroquinone SYSTEMATIC 23333790 A 199 205 oxygen SYSTEMATIC 23333790 A 283 291 quinones FAMILY 23333790 A 559 567 quinones FAMILY 23333790 A 742 762 aromatic hydrocarbon FAMILY 23333790 A 83 91 Quinones FAMILY 23333790 T 144 152 quinones FAMILY 23333897 A 1224 1230 silica TRIVIAL 23333897 A 1265 1271 silica TRIVIAL 23333897 A 1401 1407 silica TRIVIAL 23333897 A 530 536 Silica TRIVIAL 23333897 A 860 870 phalloidin TRIVIAL 23333897 A 871 876 TRITC ABBREVIATION 23333901 A 0 11 β-Lapachone TRIVIAL 23333901 A 115 122 NAD(P)H ABBREVIATION 23333901 A 123 130 quinone FAMILY 23333901 A 13 18 β-Lap ABBREVIATION 23333901 A 25 48 1,2-orthonaphthoquinone SYSTEMATIC 23333901 A 302 307 β-Lap ABBREVIATION 23333901 A 365 370 β-Lap ABBREVIATION 23333901 A 392 417 methylated-β-cyclodextrin TRIVIAL 23333901 A 418 431 poloxamer 407 TRIVIAL 23333901 A 447 452 β-Lap ABBREVIATION 23333901 A 918 923 β-Lap ABBREVIATION 23333901 T 32 43 β-Lapachone TRIVIAL 23333901 T 44 53 poloxamer FAMILY 23333998 A 1035 1040 oxide SYSTEMATIC 23333998 A 347 363 lanthanide oxide FAMILY 23333998 A 520 528 hydrogen SYSTEMATIC 23333998 T 29 34 oxide SYSTEMATIC 23334083 A 225 240 calcium oxalate SYSTEMATIC 23334083 A 245 259 hydroxyapatite TRIVIAL 23334083 A 261 276 Calcium oxalate SYSTEMATIC 23334083 A 341 355 hydroxyapatite TRIVIAL 23334083 A 426 440 hydroxyapatite TRIVIAL 23334083 A 640 654 hydroxyapatite TRIVIAL 23334090 A 145 151 carbon SYSTEMATIC 23334090 A 87 102 poly(acetylene) FAMILY 23334090 T 54 60 carbon SYSTEMATIC 23334403 A 1021 1033 atorvastatin TRIVIAL 23334403 A 1100 1122 o-hydroxy atorvastatin SYSTEMATIC 23334403 A 1276 1288 atorvastatin TRIVIAL 23334403 A 1331 1353 o-hydroxy atorvastatin SYSTEMATIC 23334403 A 137 147 almorexant TRIVIAL 23334403 A 1480 1490 almorexant TRIVIAL 23334403 A 1501 1512 simvastatin TRIVIAL 23334403 A 1577 1589 atorvastatin TRIVIAL 23334403 A 1711 1721 almorexant TRIVIAL 23334403 A 1727 1738 simvastatin TRIVIAL 23334403 A 1818 1830 atorvastatin TRIVIAL 23334403 A 268 278 almorexant TRIVIAL 23334403 A 381 392 simvastatin TRIVIAL 23334403 A 404 416 atorvastatin TRIVIAL 23334403 A 435 445 Almorexant TRIVIAL 23334403 A 473 484 simvastatin TRIVIAL 23334403 A 905 928 hydroxyacid simvastatin SYSTEMATIC 23334403 A 945 955 almorexant TRIVIAL 23334403 T 0 10 Almorexant TRIVIAL 23334403 T 105 116 simvastatin TRIVIAL 23334403 T 121 133 atorvastatin TRIVIAL 23334529 A 1006 1010 MnOx FORMULA 23334529 A 1304 1310 Carbon SYSTEMATIC 23334529 A 1487 1491 MnOx FORMULA 23334529 A 1530 1534 MnOx FORMULA 23334529 A 1535 1541 carbon SYSTEMATIC 23334529 A 1726 1732 carbon SYSTEMATIC 23334529 A 577 583 carbon SYSTEMATIC 23334529 A 698 713 manganese oxide SYSTEMATIC 23334529 A 715 719 MnOx FORMULA 23334529 A 807 811 MnOx FORMULA 23334529 A 812 813 C FORMULA 23334529 A 930 936 Carbon SYSTEMATIC 23334943 A 1453 1464 finasteride TRIVIAL 23334943 A 1468 1479 dutasteride TRIVIAL 23334943 A 81 92 finasteride TRIVIAL 23334943 A 97 108 dutasteride TRIVIAL 23335133 A 0 22 Fluocinolone acetonide TRIVIAL 23335133 A 1043 1065 Fluocinolone acetonide TRIVIAL 23335133 A 1277 1299 fluocinolone acetonide TRIVIAL 23335133 A 1424 1446 fluocinolone acetonide TRIVIAL 23335133 A 334 356 fluocinolone acetonide TRIVIAL 23335133 A 45 52 Iluvien TRIVIAL 23335133 A 509 531 fluocinolone acetonide TRIVIAL 23335133 A 87 101 corticosteroid TRIVIAL 23335133 A 874 896 fluocinolone acetonide TRIVIAL 23335133 T 0 22 Fluocinolone acetonide TRIVIAL 23335133 T 45 52 Iluvien TRIVIAL 23335392 A 1006 1033 2-aminoethoxydiphenylborane SYSTEMATIC 23335392 A 1059 1068 ryanodine TRIVIAL 23335392 A 107 111 K(+) FORMULA 23335392 A 1074 1101 inositol 1,4,5-triphosphate SYSTEMATIC 23335392 A 1112 1118 Ca(2+) FORMULA 23335392 A 113 114 K FORMULA 23335392 A 1132 1144 nitric oxide SYSTEMATIC 23335392 A 115 118 ATP ABBREVIATION 23335392 A 1164 1198 N(G)-nitro-l-arginine methyl ester SYSTEMATIC 23335392 A 1259 1263 DHPG ABBREVIATION 23335392 A 1320 1331 tolbutamide TRIVIAL 23335392 A 1459 1463 DHPG ABBREVIATION 23335392 A 1525 1526 K FORMULA 23335392 A 1527 1530 ATP ABBREVIATION 23335392 A 1544 1556 nitric oxide SYSTEMATIC 23335392 A 1628 1634 Ca(2+) FORMULA 23335392 A 1745 1746 K FORMULA 23335392 A 1747 1750 ATP ABBREVIATION 23335392 A 262 293 (RS)-3,5-dihydroxyphenylglycine SYSTEMATIC 23335392 A 28 34 Ca(2+) FORMULA 23335392 A 295 299 DHPG ABBREVIATION 23335392 A 325 334 glutamate TRIVIAL 23335392 A 370 371 K FORMULA 23335392 A 372 375 ATP ABBREVIATION 23335392 A 386 390 DHPG ABBREVIATION 23335392 A 50 70 N-methly-d-aspartate SYSTEMATIC 23335392 A 500 512 sulfonylurea FAMILY 23335392 A 519 530 tolbutamide TRIVIAL 23335392 A 624 625 K FORMULA 23335392 A 626 629 ATP ABBREVIATION 23335392 A 640 643 ATP ABBREVIATION 23335392 A 654 656 K+ FORMULA 23335392 A 687 691 DHPG ABBREVIATION 23335392 A 789 793 DHPG ABBREVIATION 23335392 A 832 850 cyclopiazonic acid TRIVIAL 23335392 A 855 867 thapsigargin TRIVIAL 23335392 A 884 892 caffeine TRIVIAL 23335392 A 93 96 ATP ABBREVIATION 23335392 A 943 949 Ca(2+) FORMULA 23335392 A 951 955 DHPG ABBREVIATION 23335392 A 992 1001 ryanodine TRIVIAL 23335392 T 21 22 K FORMULA 23335392 T 23 26 ATP ABBREVIATION 23335392 T 52 56 Ca2+ FORMULA 23335435 A 269 278 zeolite L TRIVIAL 23335435 A 302 316 aminosilicates FAMILY 23335435 A 379 384 COOH- FORMULA 23335435 A 386 393 NH(2) - FORMULA 23335435 A 395 413 polyethyleneglycol SYSTEMATIC 23335435 A 415 418 PEG ABBREVIATION 23335435 A 425 453 polyallylamine hydrochloride FAMILY 23335435 A 455 458 PAH ABBREVIATION 23335435 T 52 61 Zeolite L TRIVIAL 23335626 A 0 12 Okadaic acid TRIVIAL 23335626 A 1004 1014 19-epi-OKA SYSTEMATIC 23335626 A 1173 1176 OKA ABBREVIATION 23335626 A 1181 1198 dinophysistoxin-2 TRIVIAL 23335626 A 1234 1244 19-epi-OKA SYSTEMATIC 23335626 A 125 128 OKA ABBREVIATION 23335626 A 1328 1331 OKA ABBREVIATION 23335626 A 1336 1353 dinophysistoxin-2 TRIVIAL 23335626 A 138 148 19-epi-OKA SYSTEMATIC 23335626 A 14 17 OKA ABBREVIATION 23335626 A 1411 1421 19-epi-OKA SYSTEMATIC 23335626 A 1466 1469 OKA ABBREVIATION 23335626 A 270 273 OKA ABBREVIATION 23335626 A 284 294 19-epi-OKA SYSTEMATIC 23335626 A 299 302 OKA ABBREVIATION 23335626 A 476 486 19-epi-OKA SYSTEMATIC 23335626 A 548 551 OKA ABBREVIATION 23335626 A 567 584 dinophysistoxin-2 TRIVIAL 23335626 A 586 596 19-epi-OKA SYSTEMATIC 23335626 A 713 723 19-epi-OKA SYSTEMATIC 23335626 A 836 839 OKA ABBREVIATION 23335626 A 844 861 dinophysistoxin-2 TRIVIAL 23335626 A 889 899 19-epi-OKA SYSTEMATIC 23335626 A 964 974 19-epi-OKA SYSTEMATIC 23335626 A 991 994 OKA ABBREVIATION 23335626 T 75 94 19-Epi-okadaic acid SYSTEMATIC 23335627 A 1253 1261 acrolein TRIVIAL 23335627 A 1302 1310 acrolein TRIVIAL 23335627 A 483 491 acrolein TRIVIAL 23335627 A 508 516 aldehyde SYSTEMATIC 23335627 A 828 836 acrolein TRIVIAL 23335627 A 921 927 oxygen SYSTEMATIC 23335627 A 958 966 Acrolein TRIVIAL 23335627 T 120 128 acrolein TRIVIAL 23336063 A 317 335 gobichelin A and B MULTIPLE 23336063 A 506 517 gobichelins FAMILY 23336063 T 0 18 Gobichelin A and B MULTIPLE 23336064 A 1300 1303 ATP ABBREVIATION 23336064 A 790 793 ATP ABBREVIATION 23336064 A 820 829 histidine TRIVIAL 23336565 A 1017 1021 NMDA ABBREVIATION 23336565 A 1143 1148 LP 12 IDENTIFIER 23336565 A 1177 1181 NMDA ABBREVIATION 23336565 A 15 19 5-HT SYSTEMATIC 23336565 A 359 363 NMDA ABBREVIATION 23336565 A 397 401 NMDA ABBREVIATION 23336565 A 4 13 serotonin TRIVIAL 23336565 A 793 797 NMDA ABBREVIATION 23336565 A 966 971 LP 12 IDENTIFIER 23336565 A 991 996 LP 12 IDENTIFIER 23336565 T 0 19 5-Hydroxytryptamine SYSTEMATIC 23336565 T 60 64 NMDA ABBREVIATION 23336753 A 0 12 Dimolybdenum SYSTEMATIC 23336753 A 109 117 hydrogen SYSTEMATIC 23336753 A 167 177 CH(2)Cl(2) FORMULA 23336753 A 216 226 CH(2)Cl(2) FORMULA 23336753 A 311 320 Mo(2)(4+) FORMULA 23336753 A 61 67 lactam SYSTEMATIC 23336753 T 17 25 hydrogen SYSTEMATIC 23337530 A 0 8 Dipeptyl FAMILY 23337530 A 1170 1180 anagliptin TRIVIAL 23337530 A 1312 1322 anagliptin TRIVIAL 23337530 A 215 225 anagliptin TRIVIAL 23337530 A 258 268 anagliptin TRIVIAL 23337530 A 383 393 anagliptin TRIVIAL 23337530 A 523 532 oil red O TRIVIAL 23337530 A 588 595 glucose TRIVIAL 23337530 A 893 903 anagliptin TRIVIAL 23337530 A 984 994 anagliptin TRIVIAL 23337530 T 0 10 Anagliptin TRIVIAL 23337607 A 1002 1010 tyrosine TRIVIAL 23337607 A 1035 1043 dopamine TRIVIAL 23337607 A 1072 1075 BPA ABBREVIATION 23337607 A 1222 1225 BPA ABBREVIATION 23337607 A 1318 1326 dopamine TRIVIAL 23337607 A 1331 1340 serotonin TRIVIAL 23337607 A 1490 1493 BPA ABBREVIATION 23337607 A 1658 1661 BPA ABBREVIATION 23337607 A 17 28 bisphenol-A TRIVIAL 23337607 A 206 209 BPA ABBREVIATION 23337607 A 30 33 BPA ABBREVIATION 23337607 A 352 355 BPA ABBREVIATION 23337607 A 422 425 BPA ABBREVIATION 23337607 A 498 501 BPA ABBREVIATION 23337607 A 525 533 dopamine TRIVIAL 23337607 A 686 689 BPA ABBREVIATION 23337607 A 834 837 BPA ABBREVIATION 23337607 T 21 32 bisphenol A TRIVIAL 23337607 T 50 58 dopamine TRIVIAL 23339181 A 1188 1201 acetaminophen TRIVIAL 23339181 A 322 331 glutamate TRIVIAL 23339181 A 354 371 purine nucleoside TRIVIAL 23339181 A 393 399 malate TRIVIAL 23339181 A 622 635 acetaminophen TRIVIAL 23339181 A 71 78 alanine TRIVIAL 23339339 A 0 14 Graphene oxide SYSTEMATIC 23339339 A 1162 1168 carbon SYSTEMATIC 23339339 A 1209 1211 Al FORMULA 23339339 A 1213 1215 Cu FORMULA 23339339 A 1221 1226 steel TRIVIAL 23339339 A 129 148 chlorosulfonic acid SYSTEMATIC 23339339 A 1450 1456 carbon SYSTEMATIC 23339339 A 1500 1506 carbon SYSTEMATIC 23339339 A 50 66 reduced graphene TRIVIAL 23339339 A 613 629 reduced graphene TRIVIAL 23339339 A 819 827 graphene TRIVIAL 23339339 T 0 8 Graphene TRIVIAL 23339339 T 57 63 carbon SYSTEMATIC 23339625 A 204 230 dexamethasone 21-phosphate SYSTEMATIC 23339625 A 232 237 DEX-P ABBREVIATION 23339625 A 243 252 midazolam TRIVIAL 23339625 A 254 257 MDZ ABBREVIATION 23339625 A 336 341 DEX-P ABBREVIATION 23339625 A 471 476 DEX-P ABBREVIATION 23339625 A 534 539 DEX-P ABBREVIATION 23339625 A 635 640 DEX-P ABBREVIATION 23339625 A 762 767 DEX-P ABBREVIATION 23339625 A 807 812 DEX-P ABBREVIATION 23339625 A 936 941 DEX-P ABBREVIATION 23339625 T 105 118 dexamethasone TRIVIAL 23339629 A 154 166 dinucleotide FAMILY 23339629 A 254 261 thymine TRIVIAL 23339629 A 346 353 thymine TRIVIAL 23339629 A 494 501 thymine TRIVIAL 23339629 A 59 80 thymine-thymine (6-4) TRIVIAL 23339629 A 703 710 thymine TRIVIAL 23339629 A 893 914 thymine-thymine (6-4) TRIVIAL 23339629 T 40 61 thymine-thymine (6-4) TRIVIAL 23339682 A 467 475 caffeine TRIVIAL 23339682 A 477 490 chlorzoxazone SYSTEMATIC 23339682 A 492 503 tolbutamide TRIVIAL 23339682 A 505 515 metoprolol TRIVIAL 23339682 A 520 529 midazolam TRIVIAL 23339777 A 163 177 benzocamalexin TRIVIAL 23339777 A 66 75 camalexin TRIVIAL 23339777 T 21 30 camalexin TRIVIAL 23339855 A 1218 1228 Saxotoxins FAMILY 23339855 A 1240 1253 Trichothecene FAMILY 23339855 A 1863 1873 T(2) toxin TRIVIAL 23339884 A 1014 1026 sinapic acid TRIVIAL 23339884 A 214 228 phenolic acids FAMILY 23339884 A 230 249 protocatechuic acid TRIVIAL 23339884 A 251 272 p-hydroxybenzoic acid SYSTEMATIC 23339884 A 274 287 vanillic acid SYSTEMATIC 23339884 A 289 304 p-coumaric acid TRIVIAL 23339884 A 310 322 ferulic acid TRIVIAL 23339884 A 35 49 phenolic acids FAMILY 23339884 A 363 375 caffeic acid TRIVIAL 23339884 A 380 392 sinapic acid TRIVIAL 23339884 A 753 765 caffeic acid TRIVIAL 23339884 A 770 782 sinapic acid TRIVIAL 23339884 A 997 1009 caffeic acid TRIVIAL 23339884 T 29 43 phenolic acids FAMILY 23339967 A 0 10 Gentamicin FAMILY 23339967 A 1012 1023 3'-hydroxyl SYSTEMATIC 23339967 A 1031 1044 6-aminohexose SYSTEMATIC 23339967 A 1211 1225 aminoglycoside FAMILY 23339967 A 124 134 Gentamicin FAMILY 23339967 A 1265 1279 aminoglycoside FAMILY 23339967 A 147 158 3'-hydroxyl SYSTEMATIC 23339967 A 17 31 aminoglycoside FAMILY 23339967 A 314 325 gentamicins FAMILY 23339967 A 419 425 JI-20A IDENTIFIER 23339967 A 467 479 gentamicin C TRIVIAL 23339967 A 510 515 3'-OH SYSTEMATIC 23339967 A 573 583 gentamicin FAMILY 23339967 A 620 634 aminoglycoside FAMILY 23339967 A 825 836 Kanamycin A TRIVIAL 23339967 A 838 849 Kanamycin B TRIVIAL 23339967 A 851 861 Neomycin B TRIVIAL 23339967 A 866 874 Amikacin TRIVIAL 23339967 A 919 945 phosphorylated kanamycin B TRIVIAL 23339967 T 26 40 aminoglycoside FAMILY 23339967 T 63 73 gentamicin FAMILY 23340199 A 0 15 Fluoroquinolone FAMILY 23340199 A 1104 1108 CLFX ABBREVIATION 23340199 A 1124 1128 LOFX ABBREVIATION 23340199 A 1182 1186 CLFX ABBREVIATION 23340199 A 1202 1206 LOFX ABBREVIATION 23340199 A 1245 1249 CLFX ABBREVIATION 23340199 A 1271 1275 LOFX ABBREVIATION 23340199 A 1287 1291 CLFX ABBREVIATION 23340199 A 1316 1320 LOFX ABBREVIATION 23340199 A 496 509 clinafloxacin TRIVIAL 23340199 A 511 515 CLFX ABBREVIATION 23340199 A 521 533 lomefloxacin TRIVIAL 23340199 A 535 539 LOFX ABBREVIATION 23340199 A 614 618 CLFX ABBREVIATION 23340199 A 642 646 LOFX ABBREVIATION 23340199 T 100 115 fluoroquinolone SYSTEMATIC 23340251 A 376 380 cAMP ABBREVIATION 23340251 A 48 55 steroid FAMILY 23340251 A 578 582 cAMP ABBREVIATION 23340251 A 629 638 estradiol TRIVIAL 23340524 A 142 150 nitrogen SYSTEMATIC 23340524 A 206 214 graphite TRIVIAL 23340524 A 302 311 palladium SYSTEMATIC 23340524 A 382 390 nitrogen SYSTEMATIC 23340524 A 791 797 oxygen SYSTEMATIC 23340524 A 945 954 palladium SYSTEMATIC 23340524 T 0 9 Palladium SYSTEMATIC 23340524 T 37 45 nitrogen SYSTEMATIC 23340650 A 1095 1103 Nile Red TRIVIAL 23340650 A 958 979 glycerophosphocholine TRIVIAL 23340651 A 1032 1036 O(2) FORMULA 23340651 A 1106 1110 O(2) FORMULA 23340651 A 1283 1287 O(2) FORMULA 23340651 A 1330 1334 O(2) FORMULA 23340651 A 1365 1369 O(2) FORMULA 23340651 A 1420 1426 oxygen SYSTEMATIC 23340651 A 151 155 O(2) FORMULA 23340651 A 245 249 O(2) FORMULA 23340651 A 548 552 O(2) FORMULA 23340651 A 621 625 O(2) FORMULA 23340651 A 671 675 O(2) FORMULA 23340651 T 4 10 oxygen SYSTEMATIC 23340797 A 1104 1111 glucose TRIVIAL 23340797 A 31 38 glucose TRIVIAL 23340797 A 42 52 β-pyranose FAMILY 23340797 A 584 591 glucose TRIVIAL 23340797 A 638 646 fructose TRIVIAL 23340797 T 61 68 glucose TRIVIAL 23340887 A 1247 1260 triglycerides FAMILY 23340887 A 400 407 glucose TRIVIAL 23340887 A 614 625 cholesterol TRIVIAL 23340887 A 635 646 cholesterol TRIVIAL 23340887 A 653 666 triglycerides FAMILY 23340896 A 1092 1103 cholesterol TRIVIAL 23340896 A 1238 1251 triglycerides FAMILY 23340897 A 1017 1024 25(OH)D SYSTEMATIC 23340897 A 117 124 glucose TRIVIAL 23340897 A 1247 1254 25(OH)D SYSTEMATIC 23340897 A 1281 1288 glucose TRIVIAL 23340897 A 1338 1345 25(OH)D SYSTEMATIC 23340897 A 1495 1504 vitamin D FAMILY 23340897 A 224 231 25(OH)D SYSTEMATIC 23340897 A 333 340 25(OH)D SYSTEMATIC 23340897 A 35 54 25-hydroxyvitamin D SYSTEMATIC 23340897 A 482 489 glucose TRIVIAL 23340897 A 56 63 25[OH]D SYSTEMATIC 23340897 A 853 860 25(OH)D SYSTEMATIC 23340897 A 884 893 vitamin D FAMILY 23340897 T 0 19 25-Hydroxyvitamin D SYSTEMATIC 23340897 T 58 65 Glucose TRIVIAL 23340918 A 1147 1156 vitamin D FAMILY 23340918 A 1190 1199 vitamin D FAMILY 23340918 A 194 201 25(OH)D SYSTEMATIC 23340918 A 34 53 25-hydroxyvitamin D SYSTEMATIC 23340918 A 388 395 25(OH)D SYSTEMATIC 23340918 A 448 455 25(OH)D SYSTEMATIC 23340918 A 529 538 vitamin D FAMILY 23340918 A 55 62 25(OH)D SYSTEMATIC 23340918 A 696 703 25(OH)D SYSTEMATIC 23340918 A 831 840 vitamin D FAMILY 23340918 A 899 908 vitamin D FAMILY 23340918 T 6 25 25-hydroxyvitamin D SYSTEMATIC 23341167 A 1594 1604 primaquine TRIVIAL 23341167 A 834 844 enoyl acyl FAMILY 23341167 A 921 931 fatty acid FAMILY 23341167 T 14 24 fatty acid FAMILY 23341452 A 1194 1205 amino acids FAMILY 23341452 A 243 247 (1)H FORMULA 23341452 A 249 254 (13)C FORMULA 23341452 A 298 303 (13)C FORMULA 23341452 A 548 558 amino acid FAMILY 23341452 A 747 757 amino acid FAMILY 23341452 A 789 794 (13)C FORMULA 23341452 A 945 959 hydroxyproline SYSTEMATIC 23341452 A 964 978 proline prolyl TRIVIAL 23341452 T 69 79 amino acid FAMILY 23342998 A 529 539 nucleoside FAMILY 23342998 A 545 556 rilpivirine TRIVIAL 23342998 A 558 564 TMC278 IDENTIFIER 23342998 A 623 633 Nucleotide FAMILY 23342998 A 874 884 Nucleotide FAMILY 23343421 A 111 119 cryptand FAMILY 23343421 A 120 133 Kryptofix 222 TRIVIAL 23343421 A 138 149 crown ether FAMILY 23343421 A 1416 1420 K222 ABBREVIATION 23343421 A 150 160 18-Crown-6 SYSTEMATIC 23343421 A 1503 1507 18C6 SYSTEMATIC 23343421 A 43 65 sodium dodecyl sulfate SYSTEMATIC 23343421 A 67 70 SDS ABBREVIATION 23343421 A 673 676 SDS ABBREVIATION 23343421 A 782 785 SDS ABBREVIATION 23343421 A 868 871 SDS ABBREVIATION 23343596 A 1293 1297 AMPH ABBREVIATION 23343596 A 203 216 d-amphetamine TRIVIAL 23343596 A 218 222 AMPH ABBREVIATION 23343596 A 431 435 AMPH ABBREVIATION 23343596 A 982 993 amphetamine TRIVIAL 23343596 T 48 61 d-amphetamine TRIVIAL 23343761 A 1142 1147 Co₉S₈ FORMULA 23343761 A 1216 1221 Co₉S₈ FORMULA 23343761 A 502 542 transition-metal chalcogenide-alkylamine FAMILY 23343761 A 719 724 Co₉S₈ FORMULA 23343761 A 725 735 oleylamine SYSTEMATIC 23343761 A 737 742 Co₉S₈ FORMULA 23343761 A 935 940 Co₉S₈ FORMULA 23343761 A 956 966 oleylamine SYSTEMATIC 23343976 A 1045 1082 3-hydroxy-3-methylglutaryl coenzyme A SYSTEMATIC 23343976 A 800 806 sodium SYSTEMATIC 23344447 A 17 25 alcohols FAMILY 23344447 A 268 276 dioxygen SYSTEMATIC 23344447 A 29 45 carboxylic acids FAMILY 23344447 A 397 405 hydrogen SYSTEMATIC 23344447 A 425 434 ruthenium SYSTEMATIC 23344447 A 483 491 alcohols FAMILY 23344447 A 495 510 carboxylic acid SYSTEMATIC 23344447 A 668 684 carboxylic acids FAMILY 23344447 T 28 36 alcohols FAMILY 23344447 T 40 55 carboxylic acid SYSTEMATIC 23344447 T 66 68 H2 FORMULA 23344447 T 88 94 oxygen SYSTEMATIC 23344553 A 1113 1116 PCP ABBREVIATION 23344553 A 113 116 PCP ABBREVIATION 23344553 A 1259 1262 PCP ABBREVIATION 23344553 A 1311 1314 PCP ABBREVIATION 23344553 A 1411 1414 PCP ABBREVIATION 23344553 A 1580 1583 PCP ABBREVIATION 23344553 A 1612 1615 PCP ABBREVIATION 23344553 A 1677 1681 SACC ABBREVIATION 23344553 A 277 286 saccharin TRIVIAL 23344553 A 288 292 SACC ABBREVIATION 23344553 A 333 337 SACC ABBREVIATION 23344553 A 355 358 PCP ABBREVIATION 23344553 A 469 472 PCP ABBREVIATION 23344553 A 528 532 SACC ABBREVIATION 23344553 A 647 650 PCP ABBREVIATION 23344553 A 772 776 SACC ABBREVIATION 23344553 A 870 874 SACC ABBREVIATION 23344553 A 908 912 SACC ABBREVIATION 23344553 A 98 111 phencyclidine TRIVIAL 23344553 T 31 40 saccharin TRIVIAL 23344553 T 48 51 PCP ABBREVIATION 23344693 A 274 293 quinoidal thiophene SYSTEMATIC 23344693 A 489 508 quinoidal thiophene SYSTEMATIC 23344693 A 51 70 quinoidal thiophene SYSTEMATIC 23344693 A 593 612 quinoidal thiophene SYSTEMATIC 23344693 A 785 791 TiO(2) FORMULA 23344693 A 96 177 cyano-[5'-(4''-(N,N-dimethylamino)benzylidene)-5H-thiophen-2'-ylidene]acetic acid SYSTEMATIC 23344693 T 51 70 quinoidal thiophene SYSTEMATIC 23344821 A 1031 1042 cholesterol TRIVIAL 23344821 A 1116 1125 malathion TRIVIAL 23344821 A 229 237 malation TRIVIAL 23344821 A 330 344 malondialdhyde TRIVIAL 23344821 A 346 349 MDA ABBREVIATION 23344821 A 403 408 thiol FAMILY 23344821 A 472 482 superoxide TRIVIAL 23344821 A 594 603 malathion TRIVIAL 23344821 A 61 70 malathion TRIVIAL 23344821 A 711 720 aspartate TRIVIAL 23344821 A 748 755 alanine TRIVIAL 23344821 A 818 827 bilirubin TRIVIAL 23344821 A 829 839 creatinine TRIVIAL 23344821 A 840 844 urea TRIVIAL 23344821 A 849 858 acid uric TRIVIAL 23344821 A 901 913 triglyceride FAMILY 23344821 A 926 937 cholesterol TRIVIAL 23344821 A 968 979 cholesterol TRIVIAL 23344821 T 78 87 malathion TRIVIAL 23344822 A 748 755 benzene SYSTEMATIC 23344822 A 887 894 benzene SYSTEMATIC 23344822 A 89 96 benzene SYSTEMATIC 23344822 T 54 61 benzene SYSTEMATIC 23344927 A 1023 1025 Ag FORMULA 23344927 A 137 143 sodium SYSTEMATIC 23344927 A 145 147 Na FORMULA 23344927 A 153 160 calcium SYSTEMATIC 23344927 A 162 164 Ca FORMULA 23344927 A 29 35 silver SYSTEMATIC 23344927 A 296 316 polyvinylpyrrolidone SYSTEMATIC 23344927 A 334 336 Na FORMULA 23344927 A 379 384 AgNO3 FORMULA 23344927 A 403 405 Ca FORMULA 23344927 A 453 458 AgNO3 FORMULA 23344927 A 546 548 Na FORMULA 23344927 A 553 555 Ca FORMULA 23344927 A 590 598 cysteine TRIVIAL 23344927 A 621 626 AgNO3 FORMULA 23344927 A 651 653 Na FORMULA 23344927 A 678 680 Na FORMULA 23344927 A 731 733 Ca FORMULA 23344927 A 765 767 Ca FORMULA 23344927 A 852 857 AgNO3 FORMULA 23344927 A 877 885 cysteine TRIVIAL 23344927 A 890 892 Na FORMULA 23344927 A 897 899 Ca FORMULA 23344927 A 937 939 Na FORMULA 23344927 A 944 946 Ca FORMULA 23344927 A 976 984 cysteine TRIVIAL 23344927 T 14 20 sodium SYSTEMATIC 23344927 T 25 32 calcium SYSTEMATIC 23344927 T 61 67 silver SYSTEMATIC 23344956 A 1065 1076 brefeldin A TRIVIAL 23344956 A 650 665 Lys-Asp-Glu-Leu FORMULA 23344961 A 0 12 Camptothecin TRIVIAL 23344961 A 1293 1296 CPT ABBREVIATION 23344961 A 14 17 CPT ABBREVIATION 23344961 A 204 207 CPT ABBREVIATION 23344961 A 359 362 CPT ABBREVIATION 23344961 A 540 543 CPT ABBREVIATION 23344961 A 591 599 ICRF-187 IDENTIFIER 23344961 A 684 687 CPT ABBREVIATION 23344961 A 724 727 CPT ABBREVIATION 23344961 A 790 793 CPT ABBREVIATION 23344961 T 38 50 camptothecin TRIVIAL 23345166 A 228 240 melodamide A TRIVIAL 23345166 A 45 57 melodamide A TRIVIAL 23345166 A 555 565 superoxide TRIVIAL 23345166 A 69 83 phenolic amide FAMILY 23345166 A 697 707 superoxide TRIVIAL 23345166 A 824 836 melodamide A TRIVIAL 23345166 A 95 103 p-quinol TRIVIAL 23345166 T 27 39 melodamide A TRIVIAL 23345166 T 65 79 phenolic amide FAMILY 23345168 A 1064 1078 5-fluorouracil SYSTEMATIC 23345168 A 1231 1245 5-fluorouracil SYSTEMATIC 23345168 A 1776 1790 5-fluorouracil SYSTEMATIC 23345168 A 2164 2178 5-fluorouracil SYSTEMATIC 23345168 A 449 457 cysteine TRIVIAL 23345168 A 462 468 serine TRIVIAL 23345168 A 543 549 serine TRIVIAL 23345168 A 679 687 cysteine TRIVIAL 23345579 A 1053 1058 tabun TRIVIAL 23345579 A 1160 1180 Sp-tabun thiocholine TRIVIAL 23345579 A 1301 1321 Rp-tabun thiocholine TRIVIAL 23345579 A 1395 1396 O FORMULA 23345579 A 1440 1453 racemic tabun TRIVIAL 23345579 A 146 152 serine TRIVIAL 23345579 A 174 179 alkyl FAMILY 23345579 A 243 248 tabun TRIVIAL 23345579 A 32 37 tabun TRIVIAL 23345579 A 382 383 O FORMULA 23345579 A 4 19 phosphoramidate SYSTEMATIC 23345579 A 482 483 O FORMULA 23345579 A 523 555 tetraisopropyl pyrophosphoramide SYSTEMATIC 23345579 A 599 602 P-N FORMULA 23345579 A 639 642 P-N FORMULA 23345579 A 748 751 P-N FORMULA 23345579 A 760 765 tabun TRIVIAL 23345579 A 800 803 P-O FORMULA 23345579 A 880 881 O FORMULA 23345579 A 924 927 P-N FORMULA 23345579 A 958 986 Sp- and Rp-tabun thiocholine MULTIPLE 23345579 T 136 139 P-N FORMULA 23345579 T 55 71 Sp- and Rp-tabun MULTIPLE 23346866 A 222 231 quercetin TRIVIAL 23346866 A 276 281 amine SYSTEMATIC 23346866 A 357 366 quercetin TRIVIAL 23347038 A 1222 1225 M6P SYSTEMATIC 23347038 A 1281 1284 M6P SYSTEMATIC 23347038 A 1406 1418 carbohydrate FAMILY 23347038 A 208 211 M6P SYSTEMATIC 23347038 A 360 363 M6P SYSTEMATIC 23347038 A 4 7 M6P SYSTEMATIC 23347038 A 553 556 M6P SYSTEMATIC 23347038 A 772 775 M6P SYSTEMATIC 23347038 A 9 28 mannose 6-phosphate SYSTEMATIC 23347038 A 915 918 M6P SYSTEMATIC 23347038 A 929 932 M6P SYSTEMATIC 23347038 T 4 23 mannose 6-phosphate SYSTEMATIC 23347038 T 41 44 M6P SYSTEMATIC 23347049 A 143 150 thymine TRIVIAL 23347049 A 248 255 guanine TRIVIAL 23347049 A 282 289 guanine TRIVIAL 23347049 A 486 493 thymine TRIVIAL 23347049 T 51 58 thymine TRIVIAL 23347071 A 1210 1221 doxorubicin TRIVIAL 23347071 A 13 27 β-cyclodextrin TRIVIAL 23347071 A 178 192 β-cyclodextrin TRIVIAL 23347071 A 285 306 poly(ethylene glycol) SYSTEMATIC 23347071 A 474 495 poly(ethylene glycol) SYSTEMATIC 23347071 A 543 557 α-cyclodextrin TRIVIAL 23347071 A 663 668 (13)C FORMULA 23347071 A 706 720 β-cyclodextrin TRIVIAL 23347327 A 104 110 nickel SYSTEMATIC 23347327 A 123 138 bis-terpyridine TRIVIAL 23347327 A 25 27 Na FORMULA 23347327 A 28 43 montmorillonite TRIVIAL 23347327 T 28 43 montmorillonite TRIVIAL 23347396 A 104 138 dodecyl trimethyl ammonium bromide SYSTEMATIC 23347396 A 140 145 DoTAB ABBREVIATION 23347396 A 160 166 hexane SYSTEMATIC 23347396 A 692 697 DoTAB ABBREVIATION 23347396 T 128 134 hexane SYSTEMATIC 23347396 T 53 58 DoTAB ABBREVIATION 23347877 A 186 199 2-aminoindane SYSTEMATIC 23347877 A 269 274 5-IAI SYSTEMATIC 23347877 A 298 315 p-iodoamphetamine SYSTEMATIC 23347877 A 326 330 MDMA ABBREVIATION 23347877 A 68 87 5-iodo-2-aminoindan SYSTEMATIC 23347877 A 89 94 5-IAI SYSTEMATIC 23347877 T 0 19 5-Iodo-2-aminoindan SYSTEMATIC 23347877 T 102 106 MDMA ABBREVIATION 23347877 T 21 26 5-IAI SYSTEMATIC 23347952 A 290 298 morphine TRIVIAL 23347952 A 439 447 naloxone TRIVIAL 23347952 A 489 497 morphine TRIVIAL 23347952 A 543 550 phospho SYSTEMATIC 23347952 A 712 715 lys FORMULA 23347952 A 748 756 Morphine TRIVIAL 23347952 A 821 827 methyl SYSTEMATIC 23347952 A 828 831 CpG ABBREVIATION 23347952 A 861 864 Ser FORMULA 23347952 T 0 8 Morphine TRIVIAL 23347953 A 0 8 Dopamine TRIVIAL 23347953 A 308 314 l-dopa ABBREVIATION 23347953 A 316 324 dopamine TRIVIAL 23347953 A 355 362 cocaine TRIVIAL 23347953 A 387 393 6-OHDA SYSTEMATIC 23347953 A 447 453 6-OHDA SYSTEMATIC 23347953 A 485 493 SKF81297 IDENTIFIER 23347953 A 605 618 bromocriptine TRIVIAL 23347953 A 711 719 PD128907 IDENTIFIER 23347953 A 774 781 cocaine TRIVIAL 23347953 A 83 91 dopamine TRIVIAL 23347953 A 906 912 l-dopa ABBREVIATION 23347953 A 949 956 cocaine TRIVIAL 23347953 T 125 131 l-dopa ABBREVIATION 23347953 T 146 152 6-OHDA SYSTEMATIC 23347953 T 37 45 dopamine TRIVIAL 23347953 T 69 76 cocaine TRIVIAL 23347953 T 94 102 dopamine TRIVIAL 23348151 A 1120 1127 silicon SYSTEMATIC 23348151 A 318 325 silicon SYSTEMATIC 23348151 A 42 49 silicon SYSTEMATIC 23348151 A 651 658 silicon SYSTEMATIC 23348151 A 687 694 silicon SYSTEMATIC 23348151 A 77 84 silicon SYSTEMATIC 23348151 A 831 838 silicon SYSTEMATIC 23348151 T 44 51 silicon SYSTEMATIC 23348406 A 145 160 sodium selenite SYSTEMATIC 23348406 A 551 566 sodium selenite SYSTEMATIC 23348406 A 790 801 glutathione TRIVIAL 23348406 A 803 806 GSH ABBREVIATION 23348406 A 812 827 malondialdehyde TRIVIAL 23348406 A 829 832 MDA ABBREVIATION 23348406 A 904 911 nitrite SYSTEMATIC 23348406 A 954 962 selenite TRIVIAL 23348406 T 68 83 sodium selenite SYSTEMATIC 23348408 A 0 17 Patchouli alcohol TRIVIAL 23348408 T 30 47 patchouli alcohol TRIVIAL 23348497 A 1006 1014 cysteine TRIVIAL 23348497 A 1024 1027 Cys FORMULA 23348497 A 1241 1253 hypoxanthine TRIVIAL 23348497 A 1254 1261 guanine TRIVIAL 23348497 A 1330 1339 uric acid TRIVIAL 23348497 A 202 212 nucleotide FAMILY 23348497 A 303 312 uric acid TRIVIAL 23348497 A 84 93 uric acid TRIVIAL 23348842 A 555 567 kavalactones FAMILY 23348842 A 650 662 kavalactones FAMILY 23349208 A 1003 1009 (LTB)4 ABBREVIATION 23349208 A 1053 1057 TXB3 ABBREVIATION 23349208 A 1062 1066 LTB5 ABBREVIATION 23349208 A 109 112 DHA ABBREVIATION 23349208 A 1204 1207 EPA ABBREVIATION 23349208 A 1212 1215 DHA ABBREVIATION 23349208 A 1242 1262 mono- and trihydroxy MULTIPLE 23349208 A 1322 1331 resolvins FAMILY 23349208 A 1379 1382 EPA ABBREVIATION 23349208 A 1387 1390 DHA ABBREVIATION 23349208 A 297 307 fatty acid FAMILY 23349208 A 427 438 fatty acids FAMILY 23349208 A 444 447 DHA ABBREVIATION 23349208 A 481 484 EPA ABBREVIATION 23349208 A 55 76 eicosapentaenoic acid SYSTEMATIC 23349208 A 759 762 EPA ABBREVIATION 23349208 A 767 770 DHA ABBREVIATION 23349208 A 78 81 EPA ABBREVIATION 23349208 A 87 107 docosahexaenoic acid SYSTEMATIC 23349208 A 885 888 EPA ABBREVIATION 23349208 A 893 896 DHA ABBREVIATION 23349208 A 931 947 arachidonic acid TRIVIAL 23349208 A 964 977 thromboxane B NO CLASS 23349208 A 978 984 (TXB)2 ABBREVIATION 23349208 A 989 1002 leukotriene B NO CLASS 23349208 T 55 58 EPA ABBREVIATION 23349208 T 63 66 DHA ABBREVIATION 23349483 A 1163 1170 lactate FAMILY 23349483 A 1404 1411 lactate FAMILY 23349483 A 243 249 oxygen SYSTEMATIC 23349483 A 41 48 glucose TRIVIAL 23349483 A 417 423 tempol TRIVIAL 23349483 A 427 437 superoxide TRIVIAL 23349483 A 460 467 ebselen TRIVIAL 23349483 A 471 482 glutathione TRIVIAL 23349483 A 535 543 H(2)O(2) FORMULA 23349483 A 548 558 superoxide TRIVIAL 23349483 A 589 596 glucose TRIVIAL 23349483 A 612 615 ATP ABBREVIATION 23349483 A 657 664 Glucose TRIVIAL 23349483 A 756 763 glucose TRIVIAL 23349483 A 84 87 ATP ABBREVIATION 23349483 A 851 858 Lactate TRIVIAL 23349483 A 931 938 lactate FAMILY 23349483 A 976 983 lactate FAMILY 23349483 T 124 131 lactate FAMILY 23349483 T 22 28 oxygen SYSTEMATIC 23349488 A 315 322 glucose TRIVIAL 23349488 A 425 432 glucose TRIVIAL 23349490 A 1062 1069 glucose TRIVIAL 23349490 A 281 286 DHMEQ ABBREVIATION 23350530 A 0 4 PLGA ABBREVIATION 23350530 A 1181 1184 MTT ABBREVIATION 23350530 A 1270 1274 PLGA ABBREVIATION 23350530 A 1427 1435 curcumin TRIVIAL 23350530 A 315 323 curcumin TRIVIAL 23350530 A 332 336 PLGA ABBREVIATION 23350530 A 399 407 curcumin TRIVIAL 23350530 A 473 477 PLGA ABBREVIATION 23350530 A 650 654 PLGA ABBREVIATION 23350530 A 682 686 PLGA ABBREVIATION 23350530 A 734 742 curcumin TRIVIAL 23350530 A 998 1006 curcumin TRIVIAL 23350530 T 32 40 curcumin TRIVIAL 23350530 T 48 52 PLGA ABBREVIATION 23350706 A 872 932 N,N'-bis(n-octyl)-dicyanoperylene-3,4:9,10-bis dicarboximide SYSTEMATIC 23350710 A 567 576 xanthones FAMILY 23350710 A 581 591 flavonoids FAMILY 23350737 A 122 131 aldehydes FAMILY 23350737 A 62 73 oxazolidine SYSTEMATIC 23350737 A 78 90 thiazolidine SYSTEMATIC 23350847 A 37 53 pyrrolopyrazines FAMILY 23350847 T 0 16 Pyrrolopyrazines FAMILY 23350847 T 37 45 Tyrosine TRIVIAL 23350872 A 19 27 graphene TRIVIAL 23350872 A 586 594 hydrogen SYSTEMATIC 23350872 A 688 696 hydrogen SYSTEMATIC 23350872 T 32 40 graphene TRIVIAL 23351005 A 122 136 borylcopper(I) SYSTEMATIC 23351005 A 174 181 alkenes FAMILY 23351005 A 244 258 alkylcopper(I) FAMILY 23351005 A 274 280 halide FAMILY 23351005 A 32 47 alkenyl halides FAMILY 23351005 A 450 464 alkylboronates FAMILY 23351005 T 0 9 Copper(I) SYSTEMATIC 23351005 T 50 65 alkenyl halides FAMILY 23351136 A 1016 1023 steroid FAMILY 23351136 A 769 775 Sodium SYSTEMATIC 23351136 A 776 783 Glucose TRIVIAL 23351136 A 831 839 Tyrosine TRIVIAL 23351959 A 0 30 3,5,4'-Tri-O-acetylresveratrol SYSTEMATIC 23351959 A 104 107 RES ABBREVIATION 23351959 A 125 128 RES ABBREVIATION 23351959 A 242 247 TARES ABBREVIATION 23351959 A 252 255 RES ABBREVIATION 23351959 A 32 37 TARES ABBREVIATION 23351959 A 332 335 RES ABBREVIATION 23351959 A 356 361 TARES ABBREVIATION 23351959 A 479 484 TARES ABBREVIATION 23351959 A 620 625 TARES ABBREVIATION 23351959 A 629 632 RES ABBREVIATION 23351959 A 677 682 TARES ABBREVIATION 23351959 A 711 714 RES ABBREVIATION 23351959 A 72 80 hydroxyl SYSTEMATIC 23351959 A 777 780 RES ABBREVIATION 23351959 A 843 848 TARES ABBREVIATION 23351959 A 852 855 RES ABBREVIATION 23351959 A 877 880 RES ABBREVIATION 23351959 A 91 102 resveratrol TRIVIAL 23351959 T 61 72 resveratrol TRIVIAL 23351959 T 89 119 3,5,4'-tri-O-acetylresveratrol SYSTEMATIC 23352144 A 424 430 AA-861 TRIVIAL 23352144 A 435 447 parthenolide TRIVIAL 23352144 A 538 550 Parthenolide TRIVIAL 23352510 A 12 29 amino-pyrimidines FAMILY 23352510 A 204 223 1,2,3-benzotriazole SYSTEMATIC 23352510 T 119 138 1,2,3-benzotriazole SYSTEMATIC 23352510 T 15 31 amino-pyrimidine SYSTEMATIC 23352510 T 52 53 N FORMULA 23352512 A 201 204 Pyr FORMULA 23352512 A 25 31 O-acyl FAMILY 23352512 A 296 309 pyroglutamate TRIVIAL 23352512 A 326 329 Glu FORMULA 23352512 A 425 428 Pyr FORMULA 23352512 A 446 454 glutamyl TRIVIAL 23352512 A 523 526 Pyr FORMULA 23352512 A 640 653 pyroglutamate TRIVIAL 23352512 T 77 83 O-acyl FAMILY 23352690 A 1109 1121 testosterone TRIVIAL 23352690 A 1143 1152 estradiol TRIVIAL 23352843 A 103 111 fluorine SYSTEMATIC 23352843 A 121 129 fluorine SYSTEMATIC 23352843 A 376 392 perfluorocarbons FAMILY 23352843 A 557 572 perfluorocarbon SYSTEMATIC 23352843 T 0 15 Perfluorocarbon SYSTEMATIC 23352843 T 45 51 oxygen SYSTEMATIC 23352908 A 270 286 perfluoropentane SYSTEMATIC 23352908 A 288 292 PFC5 FORMULA 23352908 A 371 378 calcein TRIVIAL 23352908 A 431 437 folate TRIVIAL 23352908 A 446 450 PFC5 FORMULA 23352908 A 769 773 PFC5 FORMULA 23352908 A 788 794 folate TRIVIAL 23353004 A 226 239 acetaminophen TRIVIAL 23353004 A 241 245 APAP ABBREVIATION 23353004 A 314 334 carbon tetrachloride SYSTEMATIC 23353004 A 336 349 thioacetamide SYSTEMATIC 23353004 A 351 358 ethanol SYSTEMATIC 23353004 A 396 400 APAP ABBREVIATION 23353004 A 659 663 APAP ABBREVIATION 23353012 A 284 291 lactose TRIVIAL 23353012 A 293 302 trehalose TRIVIAL 23353012 A 485 494 trehalose TRIVIAL 23353655 A 18 30 triterpenoid FAMILY 23353655 A 39 56 sonhafouonic acid TRIVIAL 23353655 A 6 12 hopene TRIVIAL 23353655 T 0 17 Sonhafouonic acid TRIVIAL 23353655 T 50 56 hopene TRIVIAL 23353655 T 57 69 triterpenoid FAMILY 23353656 A 111 126 pestaloficiol S TRIVIAL 23353656 A 168 181 anofinic acid TRIVIAL 23353656 A 187 195 siccayne TRIVIAL 23353656 A 205 217 pyrenophorol TRIVIAL 23353656 A 400 417 secondary alcohol FAMILY 23353656 A 44 70 pestaloficiols Q (1) and R MULTIPLE 23353656 A 8 30 isoprenylated chromone TRIVIAL 23353656 A 88 98 benzofuran SYSTEMATIC 23353656 T 0 18 Pestaloficiols Q-S MULTIPLE 23353735 A 105 139 silathio/silasulfonyl acetic acids MULTIPLE 23353735 A 15 49 sila-substituted 1,3,4-oxadiazoles FAMILY 23353735 A 172 187 benzohydrazides FAMILY 23353735 A 207 229 phosphorus oxychloride SYSTEMATIC 23353735 A 238 272 sila-substituted 1,3,4-oxadiazoles FAMILY 23353735 A 440 448 sulfonyl SYSTEMATIC 23353735 A 461 498 bis(trimethylsilyl)-1,3,4-oxadiazoles FAMILY 23353735 A 580 587 sulphur SYSTEMATIC 23353735 A 600 637 bis(trimethylsilyl)-1,3,4-oxadiazoles FAMILY 23353735 T 40 121 2-((bis(trimethylsilyl)methylthio/methylsulfonyl)methyl)-5-aryl-1,3,4-oxadiazoles MULTIPLE 23353737 A 38 48 isoflavone FAMILY 23353737 T 59 69 isoflavone FAMILY 23353742 A 359 375 1,2,4-oxadiazole SYSTEMATIC 23353742 A 396 401 amide FAMILY 23353742 A 522 533 sulfonamide SYSTEMATIC 23353742 A 543 548 amide FAMILY 23353742 A 578 598 piperidyl-oxadiazole SYSTEMATIC 23353742 A 982 1006 piperidine-3-carboxamide SYSTEMATIC 23353742 T 29 50 piperidyl-oxadiazoles FAMILY 23353742 T 54 72 11β-hydroxysteroid FAMILY 23353745 A 322 327 alkyl FAMILY 23353745 A 42 81 (E)-4-aryl-4-oxo-2-butenoic acid amides FAMILY 23353745 T 0 39 (E)-4-Aryl-4-oxo-2-butenoic acid amides FAMILY 23353745 T 41 67 chalcone-aroylacrylic acid TRIVIAL 23353748 A 202 215 benzimidazole SYSTEMATIC 23353748 A 245 255 imidazolyl SYSTEMATIC 23353748 A 274 286 naphthylacyl FAMILY 23353748 A 290 307 4-methoxyphenacyl FAMILY 23353748 A 43 61 2-benzylbenzofuran SYSTEMATIC 23353748 A 509 518 cisplatin TRIVIAL 23353748 A 520 523 DDP ABBREVIATION 23353748 A 66 75 imidazole SYSTEMATIC 23353748 T 73 82 imidazole SYSTEMATIC 23353748 T 98 116 2-benzylbenzofuran SYSTEMATIC 23353754 A 411 421 geniposide TRIVIAL 23353754 A 642 652 geniposide TRIVIAL 23353754 T 89 99 geniposide TRIVIAL 23353806 A 1065 1073 Omniscan TRIVIAL 23353806 A 1188 1196 Omniscan TRIVIAL 23353806 A 1280 1283 Dox ABBREVIATION 23353806 A 1581 1591 gadolinium SYSTEMATIC 23353806 A 1829 1832 Dox ABBREVIATION 23353806 A 233 244 doxorubicin TRIVIAL 23353806 A 246 249 Dox ABBREVIATION 23353806 A 316 332 methacrylic acid TRIVIAL 23353806 A 334 337 MAA ABBREVIATION 23353806 A 343 357 polysorbate 80 TRIVIAL 23353806 A 359 364 PS 80 ABBREVIATION 23353806 A 410 445 diethylenetriaminepenta acetic acid SYSTEMATIC 23353806 A 447 451 DTPA ABBREVIATION 23353806 A 464 474 gadolinium SYSTEMATIC 23353806 A 555 566 doxorubicin TRIVIAL 23353806 A 588 592 PMAA ABBREVIATION 23353806 A 813 823 gadolinium SYSTEMATIC 23353806 A 894 896 Gd FORMULA 23353806 A 913 919 PolyGd SYSTEMATIC 23353806 A 926 928 Gd FORMULA 23353806 A 929 932 Dox ABBREVIATION 23353806 A 958 968 PolyGd-Dox SYSTEMATIC 23353808 A 1406 1409 CEL ABBREVIATION 23353808 A 1507 1513 silica TRIVIAL 23353808 A 1663 1666 CEL ABBREVIATION 23353808 A 250 260 Capmul MCM FAMILY 23353808 A 262 279 mono-diglycerides FAMILY 23353808 A 290 301 fatty acids FAMILY 23353808 A 307 313 silica TRIVIAL 23353808 A 329 336 Aerosil TRIVIAL 23353808 A 420 429 celecoxib TRIVIAL 23353808 A 431 434 CEL ABBREVIATION 23353808 A 65 71 silica TRIVIAL 23353808 A 679 685 Capmul FAMILY 23353808 A 871 874 CEL ABBREVIATION 23353808 T 0 6 Silica TRIVIAL 23353808 T 88 97 celecoxib TRIVIAL 23353902 A 1018 1022 CORT ABBREVIATION 23353902 A 1067 1070 FLU ABBREVIATION 23353902 A 1213 1216 FLU ABBREVIATION 23353902 A 1280 1284 CORT ABBREVIATION 23353902 A 1318 1321 FLU ABBREVIATION 23353902 A 1490 1493 FLU ABBREVIATION 23353902 A 1764 1767 FLU ABBREVIATION 23353902 A 392 402 fluoxetine TRIVIAL 23353902 A 404 407 FLU ABBREVIATION 23353902 A 480 483 FLU ABBREVIATION 23353902 A 695 709 corticosterone TRIVIAL 23353902 A 711 715 CORT ABBREVIATION 23353902 T 27 37 fluoxetine TRIVIAL 23354152 A 0 5 Boron SYSTEMATIC 23354152 A 1007 1019 mannitol BPA TRIVIAL 23354152 A 1126 1134 fructose TRIVIAL 23354152 A 1283 1291 mannitol TRIVIAL 23354152 A 1370 1373 BPA ABBREVIATION 23354152 A 148 153 boron SYSTEMATIC 23354152 A 335 343 fructose TRIVIAL 23354152 A 350 370 L-boronphenylalanine SYSTEMATIC 23354152 A 372 375 BPA ABBREVIATION 23354152 A 498 510 mannitol BPA TRIVIAL 23354152 A 548 560 mannitol BPA TRIVIAL 23354152 A 731 734 BPA ABBREVIATION 23354152 A 786 798 mannitol BPA TRIVIAL 23354152 A 863 866 BPA ABBREVIATION 23354152 T 39 66 boronphenylalanine mannitol SYSTEMATIC 23354152 T 83 88 boron SYSTEMATIC 23354378 A 0 8 Citrinin TRIVIAL 23354378 A 10 13 CIT ABBREVIATION 23354378 A 1093 1096 CIT ABBREVIATION 23354378 A 1116 1132 dihydrocitrinone SYSTEMATIC 23354378 A 1134 1140 HO-CIT ABBREVIATION 23354378 A 1240 1243 CIT ABBREVIATION 23354378 A 1259 1265 HO-CIT ABBREVIATION 23354378 A 1360 1363 CIT ABBREVIATION 23354378 A 1504 1507 CIT ABBREVIATION 23354378 A 1542 1545 OTA ABBREVIATION 23354378 A 1604 1607 CIT ABBREVIATION 23354378 A 163 166 CIT ABBREVIATION 23354378 A 1701 1707 HO-CIT ABBREVIATION 23354378 A 1769 1772 CIT ABBREVIATION 23354378 A 185 197 ochratoxin A TRIVIAL 23354378 A 1908 1911 CIT ABBREVIATION 23354378 A 199 202 OTA ABBREVIATION 23354378 A 333 336 OTA ABBREVIATION 23354378 A 346 349 CIT ABBREVIATION 23354378 A 411 414 CIT ABBREVIATION 23354378 A 601 604 CIT ABBREVIATION 23354378 A 886 889 CIT ABBREVIATION 23354378 T 24 32 citrinin TRIVIAL 23354393 A 1055 1059 DPPH ABBREVIATION 23354393 A 1132 1143 polyphenols FAMILY 23354393 A 19 30 fatty acids FAMILY 23354393 A 319 323 DPPH ABBREVIATION 23354393 A 32 39 sterols FAMILY 23354393 A 349 355 ferric SYSTEMATIC 23354393 A 390 397 ferrous SYSTEMATIC 23354393 A 474 481 sterols FAMILY 23354393 A 483 493 ergosterol TRIVIAL 23354393 A 644 655 polyphenols FAMILY 23354393 A 719 736 p-OH-benzoic acid SYSTEMATIC 23354393 A 738 760 p-OH-phenylacetic acid SYSTEMATIC 23354393 A 762 777 o-coumaric acid TRIVIAL 23354393 A 779 791 ferulic acid TRIVIAL 23354393 A 796 803 chrysin TRIVIAL 23354393 A 82 93 polyphenols FAMILY 23354393 A 822 839 triterpenic acids FAMILY 23354393 A 840 849 oleanolic TRIVIAL 23354393 A 854 861 ursolic TRIVIAL 23354393 A 954 961 ferrous SYSTEMATIC 23354393 A 98 112 terpenic acids FAMILY 23354531 A 1286 1295 memantine TRIVIAL 23354531 A 1344 1348 NMDA ABBREVIATION 23354531 A 1530 1534 NMDA ABBREVIATION 23354531 A 1586 1590 NMDA ABBREVIATION 23354531 A 185 189 NMDA ABBREVIATION 23354531 A 1901 1910 memantine TRIVIAL 23354531 A 201 210 memantine TRIVIAL 23354531 A 25 29 NMDA ABBREVIATION 23354531 A 354 363 memantine TRIVIAL 23354531 A 578 587 memantine TRIVIAL 23354531 A 763 772 memantine TRIVIAL 23354531 T 11 20 memantine TRIVIAL 23354545 A 1070 1078 selenium SYSTEMATIC 23354545 A 1294 1302 selenium SYSTEMATIC 23354545 A 1419 1427 selenium SYSTEMATIC 23354545 A 1535 1543 selenium SYSTEMATIC 23354545 A 1681 1689 selenium SYSTEMATIC 23354545 A 189 197 selenium SYSTEMATIC 23354545 A 301 309 selenium SYSTEMATIC 23354545 A 553 561 selenium SYSTEMATIC 23354545 T 23 31 selenium SYSTEMATIC 23354695 A 0 7 Cadmium SYSTEMATIC 23354695 A 1013 1015 Cd FORMULA 23354695 A 1020 1022 Zn FORMULA 23354695 A 1083 1085 Cd FORMULA 23354695 A 1090 1092 Zn FORMULA 23354695 A 1172 1174 Cd FORMULA 23354695 A 1178 1180 Zn FORMULA 23354695 A 17 21 zinc SYSTEMATIC 23354695 A 23 25 Zn FORMULA 23354695 A 386 388 Zn FORMULA 23354695 A 491 493 Cd FORMULA 23354695 A 548 550 Cd FORMULA 23354695 A 606 608 Cd FORMULA 23354695 A 613 615 Zn FORMULA 23354695 A 803 805 Cd FORMULA 23354695 A 861 863 Zn FORMULA 23354695 A 9 11 Cd FORMULA 23354695 A 931 933 Cd FORMULA 23354695 A 938 940 Zn FORMULA 23354695 T 53 60 cadmium SYSTEMATIC 23354695 T 65 69 zinc SYSTEMATIC 23355087 A 1110 1128 3-methylglutaconic SYSTEMATIC 23355087 A 123 145 3-methylglutaconyl-CoA SYSTEMATIC 23355087 A 1476 1494 3-methylglutaconic SYSTEMATIC 23355087 A 1830 1848 3-methylglutaconic SYSTEMATIC 23355087 A 203 210 leucine TRIVIAL 23355087 A 252 270 3-methylglutaconic SYSTEMATIC 23355087 A 30 53 3-methylglutaconic acid SYSTEMATIC 23355087 A 519 537 3-methylglutaconic SYSTEMATIC 23355087 A 703 721 3-methylglutaconic SYSTEMATIC 23355087 A 799 817 3-methylglutaconic SYSTEMATIC 23355087 A 905 923 3-methylglutaconic SYSTEMATIC 23355087 A 958 962 urea TRIVIAL 23355087 T 0 18 3-Methylglutaconic SYSTEMATIC 23355347 A 160 164 CuPc FORMULA 23355347 A 286 289 SO2 FORMULA 23355347 A 316 319 SO2 FORMULA 23355347 A 36 39 SO2 FORMULA 23355347 A 443 446 SO2 FORMULA 23355347 T 29 33 CuPc FORMULA 23355347 T 66 69 SO2 FORMULA 23355480 A 129 132 Gln FORMULA 23355480 A 133 136 Asn FORMULA 23355480 A 317 322 amide FAMILY 23355480 A 351 363 heteroarenes FAMILY 23355480 A 36 41 amide FAMILY 23355480 A 647 652 amide FAMILY 23355480 T 30 35 amide FAMILY 23355539 A 0 9 Lapatinib TRIVIAL 23355539 A 1105 1114 lapatinib TRIVIAL 23355539 A 1342 1351 lapatinib TRIVIAL 23355539 A 306 315 lapatinib TRIVIAL 23355539 A 447 456 lapatinib TRIVIAL 23355539 A 551 560 lapatinib TRIVIAL 23355539 A 747 756 lapatinib TRIVIAL 23355539 T 0 9 Lapatinib TRIVIAL 23355749 A 0 6 Carbon SYSTEMATIC 23355749 T 29 35 Carbon SYSTEMATIC 23356786 A 18 34 cyclopropylamide SYSTEMATIC 23356786 A 278 288 paclitaxel TRIVIAL 23356786 A 338 354 cyclopropylamide SYSTEMATIC 23356786 A 403 407 CA-4 ABBREVIATION 23356786 A 461 465 CA-4 ABBREVIATION 23356786 A 48 65 combretastatin-A4 TRIVIAL 23356786 A 67 71 CA-4 ABBREVIATION 23356786 T 24 40 cyclopropylamide SYSTEMATIC 23356786 T 54 71 combretastatin-A4 TRIVIAL 23356789 A 124 151 10-O-vanilloyltheviridoside SYSTEMATIC 23356789 A 157 192 6″-O-(trans-p-coumaroyl)-procumbide SYSTEMATIC 23356789 A 201 213 loganic acid TRIVIAL 23356789 A 25 36 rotunduside TRIVIAL 23356789 A 6 23 iridoid glycoside FAMILY 23356789 A 64 82 iridoid glycosides FAMILY 23356789 A 84 118 10-O-p-hydroxybenzoyltheviridoside SYSTEMATIC 23356789 T 6 23 iridoid glycoside FAMILY 23356826 A 101 132 6'-O-p-hydroxybenzoyl-gardoside SYSTEMATIC 23356826 A 152 170 iridoid glycosides FAMILY 23356826 A 20 95 2-methyl pyromeconic acid 3-O-β-d-glucopyranoside-6'-(O-4″-hydroxybenzoate) SYSTEMATIC 23356865 A 322 334 α-tocopherol TRIVIAL 23356865 A 339 359 α-tocopheryl acetate SYSTEMATIC 23356865 A 421 430 vitamin E FAMILY 23356865 A 505 514 vitamin E FAMILY 23356865 T 18 30 α-tocopherol TRIVIAL 23356865 T 35 55 α-tocopheryl acetate SYSTEMATIC 23356880 A 1112 1139 polyunsaturated fatty acids FAMILY 23356880 A 1153 1175 cis-cis-1,4-pentadiene SYSTEMATIC 23356880 A 1252 1268 trans-β-carotene TRIVIAL 23356880 A 1273 1285 xanthophylls FAMILY 23356880 A 1287 1293 lutein TRIVIAL 23356880 A 1295 1307 violaxanthin TRIVIAL 23356880 A 1309 1319 neoxanthin TRIVIAL 23356880 A 778 789 tocopherols FAMILY 23356880 A 794 806 tocotrienols FAMILY 23356880 A 833 844 oleocanthal TRIVIAL 23356880 A 846 856 p-HPEA-EDA ABBREVIATION 23357360 A 1134 1138 β-CD ABBREVIATION 23357360 A 121 129 p-cymene TRIVIAL 23357360 A 1370 1374 β-CD ABBREVIATION 23357360 A 1444 1448 β-CD ABBREVIATION 23357360 A 1507 1518 monoterpene FAMILY 23357360 A 1588 1592 β-CD ABBREVIATION 23357360 A 1645 1653 p-cymene TRIVIAL 23357360 A 220 232 monoterpenes FAMILY 23357360 A 299 307 p-cymene TRIVIAL 23357360 A 308 322 β-cyclodextrin TRIVIAL 23357360 A 324 328 β-CD ABBREVIATION 23357360 A 342 350 p-cymene TRIVIAL 23357360 A 466 477 monoterpene FAMILY 23357360 A 522 526 β-CD ABBREVIATION 23357360 A 64 72 p-cymene TRIVIAL 23357360 A 769 773 β-CD ABBREVIATION 23357360 A 784 795 acetic acid SYSTEMATIC 23357360 A 953 957 β-CD ABBREVIATION 23357360 T 15 23 p-cymene TRIVIAL 23357360 T 86 100 β-cyclodextrin TRIVIAL 23357416 A 1262 1269 DCFH-DA ABBREVIATION 23357416 A 184 222 dichloro-dihydro-fluorescein diacetate SYSTEMATIC 23357416 A 224 231 DCFH-DA ABBREVIATION 23357416 A 330 337 DCFH-DA ABBREVIATION 23357416 A 445 454 Rhodamine FAMILY 23357416 A 456 459 Rhd ABBREVIATION 23357416 A 483 489 silica TRIVIAL 23357416 A 491 495 SiO2 FORMULA 23357416 A 508 535 oleic acid coated magnetite TRIVIAL 23357416 A 538 543 Fe3O4 FORMULA 23357416 A 549 558 maghemite TRIVIAL 23357416 A 560 565 Fe2O3 FORMULA 23357416 A 567 577 iron oxide SYSTEMATIC 23357416 A 579 595 titanium dioxide SYSTEMATIC 23357416 A 597 601 TiO2 FORMULA 23357416 A 607 656 poly(ethylene oxide)-poly(lactide/glycolide) acid FAMILY 23357416 A 658 666 PLGA-PEO ABBREVIATION 23357416 T 0 38 Dichloro-dihydro-fluorescein diacetate SYSTEMATIC 23357416 T 40 47 DCFH-DA ABBREVIATION 23357567 A 1015 1027 formaldehyde SYSTEMATIC 23357567 A 1032 1040 acrolein TRIVIAL 23357567 A 1045 1059 benzo(a)pyrene SYSTEMATIC 23357567 A 1064 1082 di-hydroxybenzenes FAMILY 23357567 A 120 128 nicotine TRIVIAL 23357567 A 390 398 nicotine TRIVIAL 23357567 A 928 943 Nitrogen oxides FAMILY 23357567 A 948 953 amino FAMILY 23357567 A 958 965 nitroso SYSTEMATIC 23357977 A 1116 1123 calcium SYSTEMATIC 23357977 A 1239 1246 calcium SYSTEMATIC 23357977 A 137 144 calcium SYSTEMATIC 23357977 A 1459 1466 calcium SYSTEMATIC 23357977 A 1634 1641 calcium SYSTEMATIC 23357977 A 1694 1701 25(OH)D SYSTEMATIC 23357977 A 1848 1855 calcium SYSTEMATIC 23357977 A 272 279 calcium SYSTEMATIC 23357977 A 39 46 calcium SYSTEMATIC 23357977 A 664 671 calcium SYSTEMATIC 23357977 A 905 912 calcium SYSTEMATIC 23357977 T 30 37 calcium SYSTEMATIC 23358190 A 1059 1067 pyruvate TRIVIAL 23358190 A 1107 1115 dieldrin TRIVIAL 23358190 A 1207 1215 dieldrin TRIVIAL 23358190 A 360 368 dieldrin TRIVIAL 23358190 A 376 383 leucine TRIVIAL 23358190 A 488 498 amino acid FAMILY 23358190 A 49 57 dieldrin TRIVIAL 23358190 A 539 547 dieldrin TRIVIAL 23358190 A 596 603 leucine TRIVIAL 23358190 A 609 617 dieldrin TRIVIAL 23358190 A 679 686 leucine TRIVIAL 23358190 A 774 781 leucine TRIVIAL 23358190 A 803 811 dieldrin TRIVIAL 23358190 A 817 824 leucine TRIVIAL 23358190 A 864 872 dieldrin TRIVIAL 23358190 A 882 890 dieldrin TRIVIAL 23358190 A 903 913 amino acid FAMILY 23358190 T 35 43 dieldrin TRIVIAL 23358190 T 80 87 leucine TRIVIAL 23358193 A 1048 1050 Pb FORMULA 23358193 A 1152 1154 Pb FORMULA 23358193 A 1179 1181 Pb FORMULA 23358193 A 1324 1326 Pb FORMULA 23358193 A 1437 1439 Pb FORMULA 23358193 A 192 194 Pb FORMULA 23358193 A 539 549 monoamines FAMILY 23358193 A 610 621 amino acids FAMILY 23358193 A 685 687 Pb FORMULA 23358194 A 0 8 Atrazine TRIVIAL 23358194 A 1084 1092 atrazine TRIVIAL 23358194 A 1440 1448 atrazine TRIVIAL 23358194 A 1656 1664 atrazine TRIVIAL 23358194 A 379 387 atrazine TRIVIAL 23358194 A 527 535 atrazine TRIVIAL 23358194 A 682 690 atrazine TRIVIAL 23358194 A 852 860 atrazine TRIVIAL 23358194 A 959 967 atrazine TRIVIAL 23358194 T 50 58 atrazine TRIVIAL 23359363 A 1016 1023 glucose TRIVIAL 23359363 A 1365 1372 glucose TRIVIAL 23359363 A 231 238 glucose TRIVIAL 23359363 A 366 373 glucose TRIVIAL 23359363 A 416 423 glucose TRIVIAL 23359363 A 746 753 glucose TRIVIAL 23359363 A 890 897 glucose TRIVIAL 23359363 A 95 102 glucose TRIVIAL 23359363 T 17 24 Glucose TRIVIAL 23360104 A 117 133 phorbaketals A-C MULTIPLE 23360104 A 371 387 phorbaketals D-K MULTIPLE 23360104 A 399 409 spiroketal FAMILY 23360104 A 419 429 benzopyran SYSTEMATIC 23360104 A 445 458 phorbaketal A TRIVIAL 23360104 A 597 606 phorbin A TRIVIAL 23360104 A 696 708 phorbaketals FAMILY 23360104 A 83 99 sesterterpenoids FAMILY 23360104 T 10 26 sesterterpenoids FAMILY 23360109 A 312 323 cholesterol TRIVIAL 23360109 A 479 490 cholesterol TRIVIAL 23360143 A 245 254 aldehydes FAMILY 23360143 A 366 374 aldehyde SYSTEMATIC 23360143 A 579 588 aldehydes FAMILY 23360143 A 924 933 aldehydes FAMILY 23360143 T 41 50 aldehydes FAMILY 23360143 T 55 55 MULTIPLE 23360348 A 123 131 CNX-1351 IDENTIFIER 23360348 A 317 325 cysteine TRIVIAL 23360348 A 341 351 amino acid FAMILY 23360348 A 638 646 CNX-1220 IDENTIFIER 23360369 A 22 44 5,6,7-trimethoxyindole SYSTEMATIC 23360369 A 236 269 N-Methyl-5,6,7-trimethoxylindoles FAMILY 23360369 A 658 668 colchicine TRIVIAL 23360369 A 673 690 combretastatinA-4 TRIVIAL 23360369 T 50 83 N-Methyl-5,6,7-trimethoxylindoles FAMILY 23360430 A 0 11 Bisphenol A TRIVIAL 23360430 A 1071 1074 BPA ABBREVIATION 23360430 A 1120 1123 BPA ABBREVIATION 23360430 A 13 16 BPA ABBREVIATION 23360430 A 174 177 BPA ABBREVIATION 23360430 A 331 334 BPA ABBREVIATION 23360430 A 47 60 polycarbonate FAMILY 23360430 A 651 654 BPA ABBREVIATION 23360430 A 747 758 glutathione TRIVIAL 23360430 A 772 778 oxygen SYSTEMATIC 23360430 A 814 817 BPA ABBREVIATION 23360430 A 919 922 BPA ABBREVIATION 23360430 T 0 11 Bisphenol A TRIVIAL 23360449 A 1098 1112 organoselenium FAMILY 23360449 A 1226 1234 selenium SYSTEMATIC 23360449 A 14 22 selenium SYSTEMATIC 23360449 A 171 183 arylselenium FAMILY 23360449 A 194 208 benzeneselenol SYSTEMATIC 23360449 A 210 215 PhSeH FORMULA 23360449 A 218 237 dibenzyl diselenide SYSTEMATIC 23360449 A 239 244 DBDSe FORMULA 23360449 A 247 266 diphenyl diselenide SYSTEMATIC 23360449 A 268 273 DPDSe FORMULA 23360449 A 280 287 ebselen TRIVIAL 23360449 A 327 335 cysteine TRIVIAL 23360449 A 355 362 cystine TRIVIAL 23360449 A 368 375 glucose TRIVIAL 23360449 A 409 417 cysteine TRIVIAL 23360449 A 463 472 glutamate TRIVIAL 23360449 A 490 497 cystine TRIVIAL 23360449 A 498 507 glutamate TRIVIAL 23360449 A 592 599 cystine TRIVIAL 23360449 A 635 647 arylselenium FAMILY 23360449 A 843 851 cysteine TRIVIAL 23360449 A 879 884 DPDSe FORMULA 23360449 A 886 901 Sodium selenite SYSTEMATIC 23360449 A 903 910 Na2SeO3 FORMULA 23360449 A 913 929 selenomethionine SYSTEMATIC 23360449 A 931 936 SeMet FORMULA 23360449 A 939 955 seleno-l-cystine SYSTEMATIC 23360449 A 957 963 SeCySS FORMULA 23360449 A 970 993 Se-methylselenocysteine SYSTEMATIC 23360449 A 995 1002 MeSeCys FORMULA 23360449 T 0 14 Organoselenium FAMILY 23360449 T 84 92 cysteine TRIVIAL 23360537 A 314 324 tryptophan TRIVIAL 23360537 A 333 342 iron(III) SYSTEMATIC 23360537 A 352 374 hexadehydro-astechrome SYSTEMATIC 23360537 A 376 379 HAS ABBREVIATION 23360537 A 724 727 HAS ABBREVIATION 23360537 A 824 838 fumitremorgins FAMILY 23360537 T 42 51 iron(III) SYSTEMATIC 23361653 A 1449 1461 chalcogenide FAMILY 23361947 A 1222 1233 PI(4,5)P(2) SYSTEMATIC 23361947 A 1339 1350 PI(4,5)P(2) SYSTEMATIC 23361947 A 213 280 N(2)-(phenoxyacetyl)-N-[4-(1-piperidinylcarbonyl)benzyl]glycinamide SYSTEMATIC 23361947 A 322 361 phosphatidylinositol (4,5)-bisphosphate SYSTEMATIC 23361947 A 363 374 PI(4,5)P(2) SYSTEMATIC 23361947 A 716 814 2-(4-{[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]methyl})-1-piperazinyl)-N-(4-methylphenyl)acetamide SYSTEMATIC 23361947 A 820 899 3-(2-ethoxyphenyl)-5-[[4-(4-nitrophenyl)piperazin-1-yl]methyl]-1,2,4-oxadiazole SYSTEMATIC 23361947 A 910 999 N-[4-ethoxy-3-(1-piperidinylsulfonyl)phenyl]-2-(imidazo[2,1-b][1,3]thiazol-6-yl)acetamide SYSTEMATIC 23361947 T 80 119 phosphatidylinositol (4,5)-bisphosphate SYSTEMATIC 23362116 A 1106 1110 atRA ABBREVIATION 23362116 A 119 128 vitamin A FAMILY 23362116 A 130 137 retinol TRIVIAL 23362116 A 1308 1312 atRA ABBREVIATION 23362116 A 1365 1369 atRA ABBREVIATION 23362116 A 1579 1592 retinoic acid TRIVIAL 23362116 A 219 228 vitamin A FAMILY 23362116 A 282 305 all-trans retinoic acid TRIVIAL 23362116 A 307 311 atRA ABBREVIATION 23362116 A 320 324 atRA ABBREVIATION 23362116 A 454 458 atRA ABBREVIATION 23362116 A 549 557 retinoid FAMILY 23362116 A 61 68 retinol TRIVIAL 23362116 A 610 614 atRA ABBREVIATION 23362116 A 631 635 atRA ABBREVIATION 23362116 A 665 669 atRA ABBREVIATION 23362116 A 731 739 retinoid FAMILY 23362116 A 859 866 retinol TRIVIAL 23362116 A 9 16 retinol TRIVIAL 23362116 A 941 945 atRA ABBREVIATION 23362116 T 24 37 retinoic acid TRIVIAL 23362121 A 377 392 clovanemagnolol TRIVIAL 23362274 A 1155 1159 LSTc ABBREVIATION 23362274 A 1214 1218 LSTc ABBREVIATION 23362274 A 1388 1392 LSTc ABBREVIATION 23362274 A 482 493 sialic acid TRIVIAL 23362274 A 521 532 sialic acid TRIVIAL 23362274 A 722 749 sialylneolacto-N-tetraose c TRIVIAL 23362274 A 751 755 LSTc ABBREVIATION 23362274 A 758 762 LSTc ABBREVIATION 23362274 T 0 27 Sialylneolacto-N-tetraose c TRIVIAL 23362274 T 29 33 LSTc ABBREVIATION 23362800 A 107 113 alkene FAMILY 23362800 A 415 419 (1)H FORMULA 23362800 A 420 426 (29)Si FORMULA 23362800 A 462 467 (31)P FORMULA 23362800 A 607 613 propyl SYSTEMATIC 23362800 A 795 808 mesitylphenyl SYSTEMATIC 23362800 A 80 86 Ru-NHC FORMULA 23362800 A 894 903 phosphine SYSTEMATIC 23362800 T 95 108 Ru-NHC alkene FAMILY 23362838 A 1415 1418 LFP ABBREVIATION 23362838 A 29 51 lithium iron phosphate SYSTEMATIC 23362838 A 378 381 LFP ABBREVIATION 23362838 A 53 56 LFP ABBREVIATION 23362838 A 89 96 lithium SYSTEMATIC 23362838 T 39 46 LiFePO4 FORMULA 23363083 A 1213 1221 hydrogen SYSTEMATIC 23363083 A 242 264 amino or hydroxy acids MULTIPLE 23363083 A 295 307 kahalalide Y TRIVIAL 23363083 A 821 844 beta-hydroxy fatty acid FAMILY 23363083 T 39 51 kahalalide Y TRIVIAL 23363244 A 1023 1043 cyclopentane hydrate SYSTEMATIC 23363244 A 1254 1283 carboxylic and sulfonic acids MULTIPLE 23363244 A 193 204 hydrocarbon FAMILY 23363244 A 41 48 methane SYSTEMATIC 23363244 A 539 550 hydrocarbon FAMILY 23363244 A 675 695 cyclopentane hydrate SYSTEMATIC 23363244 A 738 750 cyclopentane SYSTEMATIC 23363244 A 913 933 cyclopentane hydrate SYSTEMATIC 23363244 A 978 990 cyclopentane SYSTEMATIC 23363244 T 64 84 cyclopentane hydrate SYSTEMATIC 23363530 A 1051 1060 T-2 toxin TRIVIAL 23363530 A 1221 1230 T-2 toxin TRIVIAL 23363530 A 1272 1281 T-2 toxin TRIVIAL 23363530 A 1321 1331 HT-2 toxin TRIVIAL 23363530 A 1367 1376 T-2 toxin TRIVIAL 23363530 A 1476 1485 T-2 toxin TRIVIAL 23363530 A 1637 1646 T-2 toxin TRIVIAL 23363530 A 187 196 T-2 toxin TRIVIAL 23363530 A 28 37 T-2 toxin TRIVIAL 23363530 A 395 404 T-2 toxin TRIVIAL 23363530 A 4 17 trichothecene FAMILY 23363530 A 474 483 T-2 toxin TRIVIAL 23363530 A 526 532 amines FAMILY 23363530 A 596 605 T-2 toxin TRIVIAL 23363530 A 859 868 T-2 toxin TRIVIAL 23363530 T 44 53 T-2 toxin TRIVIAL 23368645 A 1017 1021 ZnSe FORMULA 23368645 A 1119 1123 ZnSe FORMULA 23368645 A 1177 1181 ZnSe FORMULA 23368645 A 249 253 zinc SYSTEMATIC 23368645 A 256 258 Zn FORMULA 23368645 A 265 273 selenium SYSTEMATIC 23368645 A 276 278 Se FORMULA 23368645 A 407 409 Zn FORMULA 23368645 A 413 417 ZnSe FORMULA 23368645 A 455 457 Zn FORMULA 23368645 A 489 491 Se FORMULA 23368645 A 528 530 Zn FORMULA 23368645 A 57 70 zinc selenide SYSTEMATIC 23368645 A 72 76 ZnSe FORMULA 23368645 T 57 61 ZnSe FORMULA 23368743 A 0 4 Zinc SYSTEMATIC 23368743 A 1067 1071 zinc SYSTEMATIC 23368743 A 1145 1149 zinc SYSTEMATIC 23368743 A 128 132 zinc SYSTEMATIC 23368743 A 1297 1301 zinc SYSTEMATIC 23368743 A 1392 1396 zinc SYSTEMATIC 23368743 A 1486 1490 zinc SYSTEMATIC 23368743 A 150 154 zinc SYSTEMATIC 23368743 A 181 185 zinc SYSTEMATIC 23368743 A 229 233 zinc SYSTEMATIC 23368743 A 356 360 zinc SYSTEMATIC 23368743 A 429 433 zinc SYSTEMATIC 23368743 A 769 773 zinc SYSTEMATIC 23368743 A 833 837 zinc SYSTEMATIC 23368743 A 882 886 zinc SYSTEMATIC 23368743 A 926 930 zinc SYSTEMATIC 23368743 A 960 964 zinc SYSTEMATIC 23368743 T 0 4 Zinc SYSTEMATIC 23368853 A 290 293 ZnO FORMULA 23368853 A 402 405 ZnO FORMULA 23368853 A 416 430 ZnO-doped MnO2 FORMULA 23368853 A 462 468 carbon SYSTEMATIC 23368853 A 709 726 polyvinyl alcohol SYSTEMATIC 23368853 A 727 731 LiCl FORMULA 23368853 A 9 13 MnO2 FORMULA 23368853 T 13 16 ZnO FORMULA 23368901 A 1102 1119 choline octanoate SYSTEMATIC 23368901 A 1194 1208 choline oleate TRIVIAL 23368901 A 1794 1811 choline octanoate SYSTEMATIC 23368901 A 200 207 choline FAMILY 23368901 A 43 63 choline carboxylates FAMILY 23368901 A 563 570 choline FAMILY 23368901 A 594 599 alkyl FAMILY 23368901 A 620 625 alkyl FAMILY 23368901 A 64 70 ChC(m) FAMILY 23368901 A 695 702 choline FAMILY 23368901 A 714 718 C(8) FORMULA 23368901 A 723 728 C(10) FORMULA 23368901 A 744 761 choline octanoate SYSTEMATIC 23368901 A 76 81 alkyl FAMILY 23368901 A 766 783 choline decanoate SYSTEMATIC 23368901 A 796 801 C(18) FORMULA 23368901 A 839 853 choline oleate TRIVIAL 23368901 A 870 887 choline decanoate SYSTEMATIC 23368901 A 973 990 Choline octanoate SYSTEMATIC 23368901 T 69 88 choline carboxylate FAMILY 23369094 A 1026 1034 Tween-80 TRIVIAL 23369094 A 1092 1101 donepezil TRIVIAL 23369094 A 1259 1268 donepezil TRIVIAL 23369094 A 1276 1280 PLGA ABBREVIATION 23369094 A 1513 1522 donepezil TRIVIAL 23369094 A 177 186 Donepezil TRIVIAL 23369094 A 339 348 donepezil TRIVIAL 23369094 A 355 384 poly(lactic-co-glycolic acid) FAMILY 23369094 A 386 390 PLGA ABBREVIATION 23369094 A 468 472 PLGA ABBREVIATION 23369094 T 103 107 PLGA ABBREVIATION 23369094 T 86 95 donepezil TRIVIAL 23369536 A 241 251 nucleoside FAMILY 23369536 A 275 284 silatrane TRIVIAL 23369536 A 318 321 ACV ABBREVIATION 23369536 A 81 90 Acyclovir TRIVIAL 23369536 A 92 95 ACV ABBREVIATION 23369536 T 116 125 acyclovir TRIVIAL 23369536 T 127 130 ACV ABBREVIATION 23369536 T 39 49 nucleoside FAMILY 23369536 T 73 82 silatrane TRIVIAL 23370008 A 1032 1041 aspartate TRIVIAL 23370008 A 1063 1070 alanine TRIVIAL 23370008 A 1135 1144 ritodrine TRIVIAL 23370008 A 1241 1254 acetaminophen TRIVIAL 23370008 A 1256 1269 valproic acid TRIVIAL 23370008 A 1274 1283 metformin TRIVIAL 23370008 A 1318 1354 cyclic adenosine 3',5'-monophosphate SYSTEMATIC 23370008 A 1356 1360 cAMP ABBREVIATION 23370008 A 1406 1415 ritodrine TRIVIAL 23370008 A 150 159 ritodrine TRIVIAL 23370008 A 1743 1752 ritodrine TRIVIAL 23370008 A 20 29 ritodrine TRIVIAL 23370008 A 252 261 ritodrine TRIVIAL 23370008 A 428 437 ritodrine TRIVIAL 23370008 A 487 496 ritodrine TRIVIAL 23370008 A 597 606 Ritodrine TRIVIAL 23370008 A 664 671 steroid FAMILY 23370008 A 723 732 ritodrine TRIVIAL 23370008 A 845 854 ritodrine TRIVIAL 23370008 T 74 83 ritodrine TRIVIAL 23370290 A 1094 1098 NMDA ABBREVIATION 23370290 A 238 247 glutamate TRIVIAL 23370290 A 639 643 NMDA ABBREVIATION 23370290 A 711 715 AMPA ABBREVIATION 23370290 A 782 788 Ca(2+) FORMULA 23370290 T 25 32 calcium SYSTEMATIC 23371304 A 193 205 Methotrexate TRIVIAL 23371415 A 77 84 halogen FAMILY 23371415 A 85 91 quartz TRIVIAL 23371491 A 118 121 VPA ABBREVIATION 23371491 A 1243 1246 VAP ABBREVIATION 23371491 A 1335 1338 VPA ABBREVIATION 23371491 A 233 236 VPA ABBREVIATION 23371491 A 404 407 VPA ABBREVIATION 23371491 A 57 73 sodium valproate SYSTEMATIC 23371491 A 75 78 VPA ABBREVIATION 23371491 A 959 962 VPA ABBREVIATION 23371491 T 46 62 sodium valproate SYSTEMATIC 23371493 A 101 112 amphetamine TRIVIAL 23371493 A 11 22 Amphetamine TRIVIAL 23371493 A 1251 1262 amphetamine TRIVIAL 23371493 A 1294 1310 4-hydroxynonenal SYSTEMATIC 23371493 A 1331 1349 8-hydroxyguanosine SYSTEMATIC 23371493 A 1476 1487 amphetamine TRIVIAL 23371493 A 1745 1756 amphetamine TRIVIAL 23371493 A 283 294 amphetamine TRIVIAL 23371493 A 438 449 amphetamine TRIVIAL 23371493 A 617 628 amphetamine TRIVIAL 23371493 A 704 715 amphetamine TRIVIAL 23371493 A 991 1002 amphetamine TRIVIAL 23371493 T 25 36 amphetamine TRIVIAL 23371806 A 101 111 oroxylin A TRIVIAL 23371806 A 1035 1046 haloperidol TRIVIAL 23371806 A 1076 1085 baicalein TRIVIAL 23371806 A 1105 1109 GABA ABBREVIATION 23371806 A 1151 1161 oroxylin A TRIVIAL 23371806 A 1193 1208 methylphenidate SYSTEMATIC 23371806 A 1212 1220 dopamine TRIVIAL 23371806 A 1264 1278 norepinephrine TRIVIAL 23371806 A 1293 1304 atomoxetine TRIVIAL 23371806 A 1389 1399 oroxylin A TRIVIAL 23371806 A 1498 1502 GABA ABBREVIATION 23371806 A 1611 1621 oroxylin A TRIVIAL 23371806 A 361 371 oroxylin A TRIVIAL 23371806 A 393 397 GABA ABBREVIATION 23371806 A 50 69 γ-aminobutryic acid SYSTEMATIC 23371806 A 529 539 oroxylin A TRIVIAL 23371806 A 679 683 GABA ABBREVIATION 23371806 A 696 704 dopamine TRIVIAL 23371806 A 724 734 oroxylin A TRIVIAL 23371806 A 73 77 GABA ABBREVIATION 23371806 A 923 933 Oroxylin A TRIVIAL 23371806 T 0 10 Oroxylin A TRIVIAL 23371806 T 139 147 dopamine TRIVIAL 23371808 A 111 124 esfenvalerate TRIVIAL 23371808 A 130 139 triclosan TRIVIAL 23371808 A 96 109 picoxystrobin TRIVIAL 23371817 A 1578 1581 LT4 ABBREVIATION 23371817 A 263 276 levothyroxine TRIVIAL 23371817 A 278 281 LT4 ABBREVIATION 23371817 A 41 54 levothyroxine TRIVIAL 23371817 T 11 24 levothyroxine TRIVIAL 23372041 A 34 46 carbohydrate FAMILY 23372041 A 580 592 carbohydrate FAMILY 23373466 A 1090 1094 DMPC ABBREVIATION 23373466 A 1385 1389 DMPC ABBREVIATION 23373466 A 1462 1466 DMPC ABBREVIATION 23373649 A 1038 1042 BZDs FAMILY 23373649 A 1044 1057 neurosteroids FAMILY 23373649 A 1142 1146 GABA ABBREVIATION 23373649 A 1193 1203 topiramate TRIVIAL 23373649 A 1205 1209 TG41 IDENTIFIER 23373649 A 1211 1231 (+)- and (-)-borneol MULTIPLE 23373649 A 1233 1241 apigenin TRIVIAL 23373649 A 1247 1262 6-methylflavone SYSTEMATIC 23373649 A 1305 1309 GABA ABBREVIATION 23373649 A 1370 1374 GABA ABBREVIATION 23373649 A 176 180 GABA ABBREVIATION 23373649 A 25 29 GABA ABBREVIATION 23373649 A 4 23 γ-aminobutyric acid SYSTEMATIC 23373649 A 406 410 GABA ABBREVIATION 23373649 A 454 458 GABA ABBREVIATION 23373649 A 541 545 GABA ABBREVIATION 23373649 A 855 859 GABA ABBREVIATION 23373649 A 956 960 GABA ABBREVIATION 23373649 A 978 982 GABA ABBREVIATION 23373649 T 4 8 GABA ABBREVIATION 23373651 A 352 357 Taxol TRIVIAL 23373651 A 713 718 taxol TRIVIAL 23373651 A 79 84 taxol TRIVIAL 23373651 A 86 91 Taxol TRIVIAL 23373651 T 0 5 Taxol TRIVIAL 23373654 A 285 297 praziquantel TRIVIAL 23373654 A 380 387 emetine TRIVIAL 23373654 A 389 398 hydantoin TRIVIAL 23373654 A 400 411 nitrofurans FAMILY 23373654 A 413 423 lucanthone TRIVIAL 23373654 A 425 435 hycanthone TRIVIAL 23373654 A 437 448 oxamniquine TRIVIAL 23373654 A 465 481 organophosphates FAMILY 23373654 A 507 519 praziquantel TRIVIAL 23373751 A 145 165 poly(5-formylindole) FAMILY 23373751 A 167 172 P5FIn ABBREVIATION 23373751 A 245 259 5-formylindole SYSTEMATIC 23373751 A 261 265 5FIn SYSTEMATIC 23373751 A 386 394 aldehyde SYSTEMATIC 23373751 A 642 647 P5FIn ABBREVIATION 23373751 T 55 75 poly(5-formylindole) FAMILY 23373754 A 1242 1259 Cu2I2(MePyrPHOS)3 FORMULA 23373754 A 1718 1726 aluminum SYSTEMATIC 23373754 A 1731 1738 iridium SYSTEMATIC 23373754 A 1819 1823 Alq3 FORMULA 23373754 A 1828 1836 Ir(ppy)3 FORMULA 23373754 A 535 544 copper(I) SYSTEMATIC 23373754 T 58 64 copper SYSTEMATIC 23373756 A 321 337 L- and D-alanine MULTIPLE 23373756 A 366 387 Cα-deuterated alanine TRIVIAL 23373756 A 44 63 pyridoxal phosphate TRIVIAL 23373756 A 81 88 alanine TRIVIAL 23373756 A 860 867 alanine TRIVIAL 23373756 T 59 66 alanine TRIVIAL 23374349 A 696 697 N FORMULA 23374349 A 985 986 N FORMULA 23375059 A 1074 1081 25(OH)D SYSTEMATIC 23375059 A 1137 1150 1α,25(OH)(2)D SYSTEMATIC 23375059 A 1264 1277 1α,25(OH)(2)D SYSTEMATIC 23375059 A 1279 1286 25(OH)D SYSTEMATIC 23375059 A 1338 1345 25(OH)D SYSTEMATIC 23375059 A 1581 1588 25(OH)D SYSTEMATIC 23375059 A 1780 1787 25(OH)D SYSTEMATIC 23375059 A 1843 1856 1α,25(OH)(2)D SYSTEMATIC 23375059 A 493 506 1α,25(OH)(2)D SYSTEMATIC 23375059 A 580 589 vitamin D FAMILY 23375059 A 636 645 vitamin D FAMILY 23375059 A 70 94 1α,25-dihydroxyvitamin D SYSTEMATIC 23375059 A 755 762 25(OH)D SYSTEMATIC 23375059 A 873 886 1α,25(OH)(2)D SYSTEMATIC 23375059 A 936 945 vitamin D FAMILY 23375059 A 96 109 1α,25(OH)(2)D SYSTEMATIC 23375059 T 0 9 Vitamin D FAMILY 23375209 A 1440 1451 amino acids FAMILY 23375209 A 1509 1538 C4/Ci4, C3, C5 acylcarnitines MULTIPLE 23375209 A 1558 1569 amino acids FAMILY 23375209 A 556 563 glucose TRIVIAL 23375209 A 613 626 triglycerides FAMILY 23375209 T 15 26 amino acids FAMILY 23375227 A 12 33 C34-epi-C35-trifluoro SYSTEMATIC 23375227 A 181 232 C35-fluoro, C35-difluoro, and C35-trifluorosolamins MULTIPLE 23375227 A 264 268 NADH ABBREVIATION 23375227 A 269 279 ubiquinone FAMILY 23375227 A 359 365 methyl SYSTEMATIC 23375227 A 379 388 γ-lactone SYSTEMATIC 23375227 A 457 468 acetogenins FAMILY 23375227 A 47 54 solamin TRIVIAL 23375227 A 58 66 mono-THF FAMILY 23375227 A 79 89 acetogenin FAMILY 23375227 T 19 25 methyl SYSTEMATIC 23375227 T 39 48 γ-lactone SYSTEMATIC 23375227 T 69 80 acetogenins FAMILY 23375796 A 132 141 thiophene SYSTEMATIC 23375796 A 153 162 ketolides FAMILY 23375796 A 197 205 ketolide FAMILY 23375796 A 240 253 telithromycin TRIVIAL 23375796 A 26 33 9-oxime SYSTEMATIC 23375796 A 337 346 alkylides FAMILY 23375796 A 34 39 ether SYSTEMATIC 23375796 A 432 433 O FORMULA 23375796 A 44 53 ketolides FAMILY 23375796 A 505 514 macrolide FAMILY 23375796 A 532 546 clarithromycin TRIVIAL 23375796 A 567 568 O FORMULA 23375796 A 65 114 3-hydroxyl, 3-O-acyl and 3-O-alkyl clarithromycin MULTIPLE 23375796 A 703 712 alkylides FAMILY 23375796 A 810 824 clarithromycin TRIVIAL 23375796 A 833 842 alkylides FAMILY 23375796 T 40 47 9-oxime SYSTEMATIC 23375796 T 48 53 ether SYSTEMATIC 23375796 T 58 67 ketolides FAMILY 23375796 T 95 104 alkylides FAMILY 23376022 A 0 20 N-methyl-d-aspartate SYSTEMATIC 23376022 A 147 158 l-glutamate TRIVIAL 23376022 T 39 43 NMDA ABBREVIATION 23376091 A 0 7 Arsenic SYSTEMATIC 23376091 A 1007 1014 calcium SYSTEMATIC 23376091 A 1030 1037 calcium SYSTEMATIC 23376091 A 1168 1175 arsenic SYSTEMATIC 23376091 A 1221 1225 DMSA ABBREVIATION 23376091 A 1230 1237 MiADMSA ABBREVIATION 23376091 A 1310 1317 calcium SYSTEMATIC 23376091 A 1341 1348 arsenic SYSTEMATIC 23376091 A 1357 1364 calcium SYSTEMATIC 23376091 A 1376 1380 DMSA ABBREVIATION 23376091 A 1381 1388 MiADMSA ABBREVIATION 23376091 A 212 219 arsenic SYSTEMATIC 23376091 A 241 247 oxygen SYSTEMATIC 23376091 A 353 360 calcium SYSTEMATIC 23376091 A 390 397 calcium SYSTEMATIC 23376091 A 427 434 calcium SYSTEMATIC 23376091 A 451 458 arsenic SYSTEMATIC 23376091 A 539 546 arsenic SYSTEMATIC 23376091 A 673 680 arsenic SYSTEMATIC 23376091 A 739 741 NO FORMULA 23376091 A 746 753 calcium SYSTEMATIC 23376091 A 767 774 calcium SYSTEMATIC 23376091 T 0 7 Arsenic SYSTEMATIC 23376091 T 126 133 calcium SYSTEMATIC 23376091 T 53 57 Ca2+ FORMULA 23376120 A 1127 1136 gastrodin TRIVIAL 23376120 A 1245 1246 N FORMULA 23376120 A 1410 1419 gastrodin TRIVIAL 23376120 A 1491 1500 gastrodin TRIVIAL 23376120 A 23 32 gastrodin TRIVIAL 23376120 A 238 247 gastrodin TRIVIAL 23376120 A 385 394 gastrodin TRIVIAL 23376120 A 4 22 phenolic glucoside FAMILY 23376120 A 452 461 gastrodin TRIVIAL 23376120 A 630 642 nitric oxide SYSTEMATIC 23376120 A 799 808 gastrodin TRIVIAL 23376120 A 835 855 phosphatidylinositol TRIVIAL 23376120 A 924 934 wortmannin TRIVIAL 23376120 A 998 1007 gastrodin TRIVIAL 23376120 T 0 9 Gastrodin TRIVIAL 23376120 T 132 152 phosphatidylinositol TRIVIAL 23376121 A 1029 1033 HI-6 IDENTIFIER 23376121 A 1055 1065 phosphorus SYSTEMATIC 23376121 A 1074 1079 tabun TRIVIAL 23376121 A 1145 1148 Phe FORMULA 23376121 A 1156 1159 His FORMULA 23376121 A 1270 1274 HI-6 IDENTIFIER 23376121 A 1303 1313 cyclosarin TRIVIAL 23376121 A 1318 1328 Russian VX TRIVIAL 23376121 A 1357 1362 tabun TRIVIAL 23376121 A 150 156 serine TRIVIAL 23376121 A 188 194 oximes FAMILY 23376121 A 21 26 tabun TRIVIAL 23376121 A 28 38 cyclosarin TRIVIAL 23376121 A 295 300 oxime SYSTEMATIC 23376121 A 301 305 HI-6 IDENTIFIER 23376121 A 338 343 tabun TRIVIAL 23376121 A 394 404 cyclosarin TRIVIAL 23376121 A 409 419 Russian VX TRIVIAL 23376121 A 43 53 Russian VX TRIVIAL 23376121 A 497 501 HI-6 IDENTIFIER 23376121 A 590 600 cyclosarin TRIVIAL 23376121 A 605 615 Russian VX TRIVIAL 23376121 A 674 677 Phe FORMULA 23376121 A 685 688 His FORMULA 23376121 A 717 721 HI-6 IDENTIFIER 23376121 A 726 731 tabun TRIVIAL 23376121 A 892 896 HI-6 IDENTIFIER 23376121 A 906 911 tabun TRIVIAL 23376121 T 120 124 HI-6 IDENTIFIER 23376140 A 24 31 cadmium SYSTEMATIC 23376140 A 271 276 NADPH ABBREVIATION 23376140 A 341 348 Cadmium SYSTEMATIC 23376140 A 359 364 NADPH ABBREVIATION 23376140 A 483 491 tyrosine TRIVIAL 23376140 A 535 540 NADPH ABBREVIATION 23376140 A 603 609 serine TRIVIAL 23376140 A 719 721 Cd FORMULA 23376140 A 757 762 CdCl2 FORMULA 23376140 T 61 68 cadmium SYSTEMATIC 23376161 A 1092 1098 oxygen SYSTEMATIC 23376161 A 1152 1160 catalpol TRIVIAL 23376161 A 1230 1235 NADPH ABBREVIATION 23376161 A 1281 1289 catalpol TRIVIAL 23376161 A 1392 1400 catalpol TRIVIAL 23376161 A 411 419 catalpol TRIVIAL 23376161 A 524 532 Catalpol TRIVIAL 23376161 A 677 679 NO FORMULA 23376161 A 845 853 catalpol TRIVIAL 23376161 A 885 893 Catalpol TRIVIAL 23376161 T 0 8 Catalpol TRIVIAL 23376161 T 114 120 oxygen SYSTEMATIC 23376407 A 1129 1131 Ca FORMULA 23376407 A 1169 1171 Pb FORMULA 23376407 A 1256 1258 Pb FORMULA 23376407 A 1297 1299 Pb FORMULA 23376407 A 138 145 alcohol FAMILY 23376407 A 1462 1464 Pb FORMULA 23376407 A 1805 1807 Pb FORMULA 23376407 A 1855 1862 alcohol FAMILY 23376407 A 1904 1906 Pb FORMULA 23376407 A 28 35 ethanol SYSTEMATIC 23376407 A 479 498 25-hydroxyvitamin D SYSTEMATIC 23376407 A 503 526 1,25-dihydroxyvitamin D SYSTEMATIC 23376407 A 586 593 calcium SYSTEMATIC 23376407 A 596 598 Ca FORMULA 23376407 A 613 623 phosphorus SYSTEMATIC 23376407 A 697 699 Pb FORMULA 23376407 A 789 791 Ca FORMULA 23376407 A 79 81 Pb FORMULA 23376407 A 867 869 Pb FORMULA 23376407 A 926 928 Pb FORMULA 23376407 T 10 17 ethanol SYSTEMATIC 23376438 A 0 11 Zearalenone TRIVIAL 23376438 A 1079 1085 oxygen SYSTEMATIC 23376438 A 1124 1129 α-ZOL ABBREVIATION 23376438 A 1134 1139 β-ZOL ABBREVIATION 23376438 A 1228 1237 acteoside TRIVIAL 23376438 A 1243 1297 (E)-1-(3,4-dihydroxyphenethyl)-3-(4-hydroxystyryl)urea SYSTEMATIC 23376438 A 13 16 ZEN ABBREVIATION 23376438 A 1313 1316 ZEN ABBREVIATION 23376438 A 1430 1433 ZEN ABBREVIATION 23376438 A 1550 1553 ZEN ABBREVIATION 23376438 A 161 164 ZEN ABBREVIATION 23376438 A 1789 1792 ZEN ABBREVIATION 23376438 A 181 193 α-zearalenol TRIVIAL 23376438 A 195 200 α-ZOL ABBREVIATION 23376438 A 206 218 β-zearalenol TRIVIAL 23376438 A 220 225 β-ZOL ABBREVIATION 23376438 A 336 341 α-ZOL ABBREVIATION 23376438 A 345 350 β-ZOL ABBREVIATION 23376438 A 477 482 α-ZOL ABBREVIATION 23376438 A 487 492 β-ZOL ABBREVIATION 23376438 A 561 566 β-ZOL ABBREVIATION 23376438 A 630 635 α-ZOL ABBREVIATION 23376438 A 714 717 ZEN ABBREVIATION 23376438 A 950 951 N FORMULA 23376438 T 52 63 zearalenone TRIVIAL 23376438 T 76 88 α-zearalenol TRIVIAL 23376438 T 93 105 β-zearalenol TRIVIAL 23376440 A 0 7 Arsenic SYSTEMATIC 23376440 A 1008 1016 Arsenite SYSTEMATIC 23376440 A 1109 1118 melatonin TRIVIAL 23376440 A 1154 1186 DL-buthionine-(S, R)-sulfoximine SYSTEMATIC 23376440 A 1188 1191 BSO ABBREVIATION 23376440 A 1209 1231 gamma-glutamylcysteine SYSTEMATIC 23376440 A 1270 1273 GSH ABBREVIATION 23376440 A 1326 1334 arsenite SYSTEMATIC 23376440 A 142 149 arsenic SYSTEMATIC 23376440 A 210 217 arsenic SYSTEMATIC 23376440 A 274 281 arsenic SYSTEMATIC 23376440 A 28 34 oxygen SYSTEMATIC 23376440 A 364 371 arsenic SYSTEMATIC 23376440 A 530 545 sodium arsenite SYSTEMATIC 23376440 A 625 636 glutathione TRIVIAL 23376440 A 638 641 GSH ABBREVIATION 23376440 A 731 739 arsenite SYSTEMATIC 23376440 A 777 780 GSH ABBREVIATION 23376440 A 814 822 Arsenite SYSTEMATIC 23376440 A 949 957 arsenite SYSTEMATIC 23376440 T 0 15 Sodium arsenite SYSTEMATIC 23376440 T 126 132 oxygen SYSTEMATIC 23376476 A 0 12 8-Oxoguanine SYSTEMATIC 23376476 A 1174 1177 Cys FORMULA 23376476 A 416 437 8-hydroxydeoxyguanine SYSTEMATIC 23376476 A 439 445 8-OHdG SYSTEMATIC 23376476 A 705 711 8-OHdG SYSTEMATIC 23376476 A 745 748 Cys FORMULA 23376476 A 749 752 Cys FORMULA 23376476 A 794 800 8-OHdG SYSTEMATIC 23376476 A 837 840 Ser FORMULA 23376476 A 841 844 Ser FORMULA 23376476 A 930 936 8-OHdG SYSTEMATIC 23376478 A 403 425 lycorine hydrochloride SYSTEMATIC 23376478 T 0 22 Lycorine hydrochloride SYSTEMATIC 23376781 A 0 7 Cadmium SYSTEMATIC 23376781 A 1011 1018 cadmium SYSTEMATIC 23376781 A 1256 1263 cadmium SYSTEMATIC 23376781 A 223 230 cadmium SYSTEMATIC 23376781 A 261 278 δ-aminolevulinate SYSTEMATIC 23376781 A 292 297 δ-ALA SYSTEMATIC 23376781 A 405 410 δ-ALA SYSTEMATIC 23376781 A 435 442 cadmium SYSTEMATIC 23376781 A 564 571 cadmium SYSTEMATIC 23376781 A 672 681 catechins FAMILY 23376781 A 683 699 purine alkaloids FAMILY 23376781 A 704 715 gallic acid TRIVIAL 23376781 A 733 743 polyphenol FAMILY 23376781 A 910 917 phenols FAMILY 23376781 A 927 936 catechins FAMILY 23376781 A 947 956 catechins FAMILY 23376781 T 0 9 Catechins FAMILY 23376781 T 109 114 δ-ALA SYSTEMATIC 23376781 T 139 146 cadmium SYSTEMATIC 23376996 A 0 19 4-Nerolidylcatechol SYSTEMATIC 23376996 A 501 530 1,1-diphenyl-2-picrylhydrazyl SYSTEMATIC 23376996 A 532 536 DPPH ABBREVIATION 23376996 A 542 552 β-carotene TRIVIAL 23376996 T 0 19 4-Nerolidylcatechol SYSTEMATIC 23377117 A 1216 1225 flavonoid FAMILY 23377117 A 308 315 tannins FAMILY 23377117 A 317 325 saponins FAMILY 23377117 A 327 341 phenolic acids FAMILY 23377117 A 346 356 flavonoids FAMILY 23377117 A 440 462 apigenin 7-O-glucoside SYSTEMATIC 23377117 A 464 467 A7G SYSTEMATIC 23377117 A 472 481 flavonoid FAMILY 23377117 A 594 597 A7G SYSTEMATIC 23377117 A 628 650 ethyl methanesulfonate SYSTEMATIC 23377117 A 655 663 acridine TRIVIAL 23377117 A 722 734 sodium azide SYSTEMATIC 23377117 A 772 787 9-aminoacridine SYSTEMATIC 23377117 A 867 870 A7G SYSTEMATIC 23377117 T 15 24 flavonoid FAMILY 23377117 T 26 48 apigenin 7-O-glucoside SYSTEMATIC 23377119 A 520 532 chlorpyrifos TRIVIAL 23377119 A 534 546 cypermethrin TRIVIAL 23377119 A 548 558 dichlorvos TRIVIAL 23377119 A 560 585 glyphosate isopropylamine SYSTEMATIC 23377119 A 590 610 lambda cyhalomethrin FAMILY 23377119 A 673 698 glyphosate isopropylamine SYSTEMATIC 23377119 A 703 713 dichlorvos TRIVIAL 23377119 A 873 898 glyphosate isopropylamine SYSTEMATIC 23377119 A 903 913 dichlorvos TRIVIAL 23377542 A 181 194 retinoic acid TRIVIAL 23377699 A 0 11 Bisphenol A TRIVIAL 23377699 A 1061 1064 BPA ABBREVIATION 23377699 A 1168 1171 BPA ABBREVIATION 23377699 A 1273 1281 androgen FAMILY 23377699 A 13 16 BPA ABBREVIATION 23377699 A 1323 1326 BPA ABBREVIATION 23377699 A 1403 1406 BPA ABBREVIATION 23377699 A 179 182 BPA ABBREVIATION 23377699 A 334 337 BPA ABBREVIATION 23377699 A 669 672 BPA ABBREVIATION 23377699 A 724 727 BPA ABBREVIATION 23377699 A 767 770 BPA ABBREVIATION 23377699 A 96 99 BPA ABBREVIATION 23377699 T 20 31 bisphenol A TRIVIAL 23377699 T 50 59 thyroxine TRIVIAL 23377760 A 1711 1720 acyclovir TRIVIAL 23377760 A 1722 1731 aciclovir TRIVIAL 23377760 A 2182 2197 corticosteroids FAMILY 23377859 A 1162 1170 fipronil TRIVIAL 23377859 A 1176 1185 abamectin TRIVIAL 23377859 A 343 357 organochlorine FAMILY 23377859 A 388 404 organophosphates FAMILY 23377859 A 406 417 pyrethroids FAMILY 23377859 A 419 427 fipronil TRIVIAL 23377859 A 433 442 abamectin TRIVIAL 23377859 A 703 712 Abamectin TRIVIAL 23377859 A 714 722 fipronil TRIVIAL 23377859 A 728 739 pyrethroids FAMILY 23377859 A 748 760 cypermethrin TRIVIAL 23378624 A 1462 1474 prednisolone TRIVIAL 23378625 A 1306 1318 fructosamine SYSTEMATIC 23378625 A 1417 1429 fructosamine SYSTEMATIC 23378625 A 213 225 fructosamine SYSTEMATIC 23378625 A 343 355 fructosamine SYSTEMATIC 23379481 A 1008 1017 upamostat TRIVIAL 23379481 A 12 21 Upamostat TRIVIAL 23379481 A 23 31 Mesupron TRIVIAL 23379481 A 243 252 Upamostat TRIVIAL 23379481 A 377 386 Upamostat TRIVIAL 23379481 A 411 420 amidoxime SYSTEMATIC 23379481 A 428 442 hydroxyamidine SYSTEMATIC 23379481 A 491 497 WX-UK1 IDENTIFIER 23379481 A 552 561 upamostat TRIVIAL 23379481 A 58 64 serine TRIVIAL 23379481 A 591 597 WX-UK1 IDENTIFIER 23379481 A 639 649 molybdenum SYSTEMATIC 23379481 A 672 681 Amidoxime SYSTEMATIC 23379481 A 785 789 NADH ABBREVIATION 23379481 A 833 834 N FORMULA 23379481 A 993 994 N FORMULA 23379481 T 36 45 upamostat TRIVIAL 23379995 A 238 270 poly(3,4-ethylenedioxythiophene) SYSTEMATIC 23379995 A 271 293 poly(styrenesulfonate) FAMILY 23379995 A 295 300 PEDOT ABBREVIATION 23379995 A 301 304 PSS ABBREVIATION 23379995 A 391 402 polypyrrole FAMILY 23379995 A 404 407 Ppy ABBREVIATION 23379995 A 410 423 Ciprofloxacin TRIVIAL 23379995 A 424 437 hydrochloride FAMILY 23379995 A 439 444 Cipro ABBREVIATION 23379995 A 502 505 Ppy ABBREVIATION 23379995 A 532 537 Cipro ABBREVIATION 23379995 A 541 550 phosphate SYSTEMATIC 23379995 A 636 639 Ppy ABBREVIATION 23379995 A 640 645 Cipro ABBREVIATION 23379995 A 662 667 Cipro ABBREVIATION 23379995 A 926 931 Cipro ABBREVIATION 23379995 T 74 87 ciprofloxacin TRIVIAL 23379996 A 0 3 PEI ABBREVIATION 23379996 A 1266 1277 polylysines FAMILY 23379996 A 1367 1377 polylysine FAMILY 23379996 A 1431 1442 polylysines FAMILY 23379996 A 1645 1655 polylysine FAMILY 23379996 A 1831 1842 polylysines FAMILY 23379996 A 1960 1970 polylysine FAMILY 23379996 A 2040 2050 polylysine FAMILY 23379996 A 2249 2252 PEI ABBREVIATION 23379996 A 543 553 polylysine FAMILY 23379996 A 613 623 polylysine FAMILY 23379996 A 639 649 polylysine FAMILY 23379996 A 659 669 polylysine FAMILY 23379996 A 726 736 polylysine FAMILY 23379996 A 796 806 polylysine FAMILY 23379996 A 8 18 polylysine FAMILY 23379996 A 921 931 polylysine FAMILY 23379996 T 32 42 polylysine FAMILY 23379996 T 90 100 polylysine FAMILY 23380242 A 1108 1112 TiO2 FORMULA 23380242 A 1118 1122 TiO2 FORMULA 23380242 A 1342 1369 pyrrolidine dithiocarbamate SYSTEMATIC 23380242 A 1390 1414 epigallocatechin gallate TRIVIAL 23380242 A 1419 1427 apocynin TRIVIAL 23380242 A 1435 1443 LY294002 IDENTIFIER 23380242 A 1451 1458 PD98059 IDENTIFIER 23380242 A 1466 1474 SP600125 IDENTIFIER 23380242 A 1485 1493 SB203580 IDENTIFIER 23380242 A 1520 1524 TiO2 FORMULA 23380242 A 1595 1599 TiO2 FORMULA 23380242 A 323 331 titanium SYSTEMATIC 23380242 A 333 337 TiO2 FORMULA 23380242 A 528 532 TiO2 FORMULA 23380242 A 763 767 TiO2 FORMULA 23380242 A 894 898 TiO2 FORMULA 23380242 A 945 949 TiO2 FORMULA 23380242 T 0 16 Titanium dioxide SYSTEMATIC 23380376 A 101 131 unsaturated cyclohexenoic acid SYSTEMATIC 23380376 A 206 219 cinnamic acid TRIVIAL 23380376 A 62 72 chorismate TRIVIAL 23380376 A 76 89 isochorismate TRIVIAL 23380376 T 0 13 Cinnamic acid TRIVIAL 23380478 A 0 15 Carbon monoxide SYSTEMATIC 23380478 A 1096 1098 CO FORMULA 23380478 A 1178 1180 CO FORMULA 23380478 A 1305 1307 CO FORMULA 23380478 A 1532 1534 CO FORMULA 23380478 A 17 19 CO FORMULA 23380478 A 261 263 CO FORMULA 23380478 A 353 355 CO FORMULA 23380478 A 542 550 tartrate TRIVIAL 23380478 A 595 601 oxygen SYSTEMATIC 23380478 A 924 929 NADPH ABBREVIATION 23380478 A 981 983 CO FORMULA 23380478 A 985 987 CO FORMULA 23380478 T 0 15 Carbon monoxide SYSTEMATIC 23380989 A 25 32 kocurin TRIVIAL 23380989 A 348 358 amino acid FAMILY 23380989 A 436 444 PM181104 IDENTIFIER 23380989 A 450 457 Kocurin TRIVIAL 23380989 A 485 496 methicillin TRIVIAL 23380989 A 6 15 thiazolyl SYSTEMATIC 23380989 T 0 7 Kocurin TRIVIAL 23380989 T 100 109 thiazolyl SYSTEMATIC 23380989 T 31 39 PM181104 IDENTIFIER 23380989 T 49 60 methicillin TRIVIAL 23381061 A 110 120 Lewis acid FAMILY 23381061 A 158 165 anisole TRIVIAL 23381061 A 180 186 phenol SYSTEMATIC 23381061 A 34 41 anisole TRIVIAL 23381061 A 380 387 anisole TRIVIAL 23381061 A 45 51 phenol SYSTEMATIC 23381061 A 489 499 Lewis acid FAMILY 23381061 A 519 529 In(OTf)(3) FORMULA 23381061 A 547 553 phenol SYSTEMATIC 23381061 A 561 568 Anisole TRIVIAL 23381061 A 650 660 In(OTf)(3) FORMULA 23381061 A 705 712 anisole TRIVIAL 23381061 A 748 755 Anisole TRIVIAL 23381061 A 798 808 In(OTf)(3) FORMULA 23381061 A 925 935 In(OTf)(3) FORMULA 23381061 A 946 953 anisole TRIVIAL 23381061 A 968 974 phenol SYSTEMATIC 23381061 T 0 7 Anisole TRIVIAL 23381223 A 336 338 La FORMULA 23381223 A 345 350 C(82) TRIVIAL 23381223 A 352 357 La(2) FORMULA 23381223 A 363 368 C(80) TRIVIAL 23381223 A 374 380 Sc(3)N FORMULA 23381223 A 386 391 C(80) TRIVIAL 23381223 A 497 502 La(2) FORMULA 23381223 A 508 513 C(80) TRIVIAL 23381223 A 518 524 Sc(3)N FORMULA 23381223 A 530 535 C(80) TRIVIAL 23381223 A 749 754 La(2) FORMULA 23381223 A 760 765 C(80) TRIVIAL 23381223 A 969 974 La(2) FORMULA 23381223 A 980 985 C(80) TRIVIAL 23381223 T 57 74 metallofullerenes FAMILY 23381662 A 179 186 alanine TRIVIAL 23381662 A 29 38 pazopanib TRIVIAL 23381662 A 410 419 pazopanib TRIVIAL 23381662 T 65 74 pazopanib TRIVIAL 23381692 A 1091 1102 clopidogrel TRIVIAL 23381692 A 1316 1327 clopidogrel TRIVIAL 23381692 A 230 241 clopidogrel TRIVIAL 23381692 A 379 389 omeprazole TRIVIAL 23381692 A 394 406 lansoprazole TRIVIAL 23381692 A 460 463 ADP ABBREVIATION 23381692 A 638 649 clopidogrel TRIVIAL 23381692 A 72 83 clopidogrel TRIVIAL 23381692 A 880 891 clopidogrel TRIVIAL 23381692 T 0 11 Clopidogrel TRIVIAL 23381939 A 359 361 Si FORMULA 23381939 A 432 434 Si FORMULA 23381939 A 50 52 Si FORMULA 23381939 A 73 75 Si FORMULA 23381939 T 27 29 Si FORMULA 23381939 T 40 42 Si FORMULA 23382074 A 641 644 ZnF FORMULA 23382074 A 787 793 lysine TRIVIAL 23382074 A 835 841 lysine TRIVIAL 23382074 A 860 863 ZnF FORMULA 23382379 A 1039 1049 nucleotide FAMILY 23382379 A 1082 1114 N-methylanthraniloyl-nucleotides FAMILY 23382379 A 1132 1135 ATP ABBREVIATION 23382379 A 1280 1283 ATP ABBREVIATION 23382379 A 1586 1589 ATP ABBREVIATION 23382379 A 404 405 N FORMULA 23382381 A 1214 1215 N FORMULA 23382381 A 523 532 etoposide TRIVIAL 23382381 A 536 547 doxorubicin TRIVIAL 23383712 A 1011 1019 estrogen FAMILY 23383712 A 1300 1308 estrogen FAMILY 23383712 A 339 347 estrogen FAMILY 23383712 A 738 746 estrogen FAMILY 23383712 T 11 20 estrogens FAMILY 23383865 A 1007 1017 phosphines FAMILY 23383865 A 1044 1053 phosphine SYSTEMATIC 23383865 A 114 118 dppv ABBREVIATION 23383865 A 1152 1154 H1 FORMULA 23383865 A 121 140 cis-1,2-C2H2(PPh2)2 SYSTEMATIC 23383865 A 1240 1244 (1)H FORMULA 23383865 A 1249 1254 (31)P FORMULA 23383865 A 1296 1298 H1 FORMULA 23383865 A 1400 1402 Fe FORMULA 23383865 A 1434 1435 H FORMULA 23383865 A 1446 1454 Fe(II)-H FORMULA 23383865 A 1457 1462 Fe(I) FORMULA 23383865 A 1484 1491 hydride SYSTEMATIC 23383865 A 1497 1501 (1)H FORMULA 23383865 A 1539 1541 H1 FORMULA 23383865 A 1575 1577 H1 FORMULA 23383865 A 1587 1591 H(+) FORMULA 23383865 A 1611 1613 H2 FORMULA 23383865 A 1618 1625 [H1](+) FORMULA 23383865 A 1640 1644 D(+) FORMULA 23383865 A 1653 1655 D2 FORMULA 23383865 A 1669 1676 hydride SYSTEMATIC 23383865 A 1740 1747 hydride SYSTEMATIC 23383865 A 1793 1801 hydrogen SYSTEMATIC 23383865 A 18 24 diiron SYSTEMATIC 23383865 A 187 194 hydride SYSTEMATIC 23383865 A 195 202 [H1](+) FORMULA 23383865 A 209 230 decamethylcobaltocene SYSTEMATIC 23383865 A 25 32 hydrido SYSTEMATIC 23383865 A 270 272 H1 FORMULA 23383865 A 333 337 dppv ABBREVIATION 23383865 A 41 66 (μ-H)Fe2(pdt)(CO)2(dppv)2 FORMULA 23383865 A 419 426 Fe---Fe FORMULA 23383865 A 471 475 Fe-P FORMULA 23383865 A 515 519 Fe-H FORMULA 23383865 A 595 597 H1 FORMULA 23383865 A 69 71 H1 FORMULA 23383865 A 83 86 pdt ABBREVIATION 23383865 A 831 835 dppv ABBREVIATION 23383865 A 88 109 1,3-propanedithiolate SYSTEMATIC 23383865 A 916 920 dppv ABBREVIATION 23383865 A 961 966 (31)P FORMULA 23383865 T 29 43 diiron hydride SYSTEMATIC 23383865 T 70 77 hydride SYSTEMATIC 23383865 T 81 89 hydrogen SYSTEMATIC 23383985 A 103 107 PCBM ABBREVIATION 23383985 A 275 279 P3HT ABBREVIATION 23383985 A 280 284 PCBM ABBREVIATION 23383985 A 493 497 P3HT ABBREVIATION 23383985 A 498 502 PCBM ABBREVIATION 23383985 A 73 77 P3HT ABBREVIATION 23383985 A 746 750 PCBM ABBREVIATION 23383985 A 813 817 P3HT ABBREVIATION 23383985 A 866 870 PCBM ABBREVIATION 23383985 A 987 991 PCBM ABBREVIATION 23383985 T 64 68 P3HT ABBREVIATION 23383985 T 69 73 PCBM ABBREVIATION 23384061 A 164 176 Malonic acid TRIVIAL 23384061 A 317 329 malonic acid TRIVIAL 23384061 A 497 509 Malonic acid TRIVIAL 23384061 A 850 862 malonic acid TRIVIAL 23384061 T 20 32 malonic acid TRIVIAL 23384072 A 102 110 anilines FAMILY 23384072 A 1062 1063 N FORMULA 23384072 A 173 181 anilines FAMILY 23384072 A 348 349 N FORMULA 23384072 A 377 392 N-oxanilic acid TRIVIAL 23384072 A 575 583 anilines FAMILY 23384072 A 636 637 N FORMULA 23384072 A 751 759 N-acetyl SYSTEMATIC 23384072 A 835 843 N-acetyl SYSTEMATIC 23384072 A 847 862 N-oxanilic acid TRIVIAL 23384072 T 86 94 anilines FAMILY 23384278 A 452 460 aluminum SYSTEMATIC 23384278 A 489 509 polydimethylsiloxane SYSTEMATIC 23384278 A 511 515 PDMS ABBREVIATION 23384278 A 815 819 PDMS ABBREVIATION 23384287 A 1051 1061 amino acid FAMILY 23384287 A 1070 1073 Gly FORMULA 23384287 A 110 119 gentisate TRIVIAL 23384287 A 1221 1230 gentisate TRIVIAL 23384287 A 1235 1245 salicylate SYSTEMATIC 23384287 A 1282 1292 salicylate SYSTEMATIC 23384287 A 1340 1350 salicylate SYSTEMATIC 23384287 A 1414 1420 Fe(II) FORMULA 23384287 A 1491 1501 salicylate SYSTEMATIC 23384287 A 1516 1524 hydrogen SYSTEMATIC 23384287 A 1554 1557 Trp FORMULA 23384287 A 1565 1568 Asp FORMULA 23384287 A 161 170 gentisate TRIVIAL 23384287 A 172 193 2,5-dihydroxybenzoate SYSTEMATIC 23384287 A 4 14 salicylate SYSTEMATIC 23384287 A 589 600 salicylates FAMILY 23384287 A 718 727 gentisate TRIVIAL 23384287 A 729 751 1-hydroxy-2-naphthoate SYSTEMATIC 23384287 A 756 766 salicylate SYSTEMATIC 23384287 A 935 945 salicylate SYSTEMATIC 23384287 A 950 959 gentisate TRIVIAL 23384287 T 148 157 gentisate TRIVIAL 23384287 T 162 172 salicylate SYSTEMATIC 23384287 T 4 14 salicylate SYSTEMATIC 23384287 T 61 70 gentisate TRIVIAL 23384347 A 529 530 N FORMULA 23384347 A 775 776 C FORMULA 23384347 A 791 794 Gly FORMULA 23384347 A 828 829 C FORMULA 23384347 A 967 976 disulfide SYSTEMATIC 23384447 A 1195 1207 nitric oxide SYSTEMATIC 23384447 A 1247 1259 nitric oxide SYSTEMATIC 23384447 A 1261 1263 NO FORMULA 23384447 A 1394 1396 NO FORMULA 23384447 A 1481 1493 prostacyclin TRIVIAL 23384447 A 1530 1537 alcohol FAMILY 23384447 A 1831 1836 sugar FAMILY 23384447 A 1849 1856 ethanol SYSTEMATIC 23384447 A 407 412 sugar FAMILY 23384447 A 422 429 ethanol SYSTEMATIC 23384447 A 740 747 glucose TRIVIAL 23384447 A 805 812 ethanol SYSTEMATIC 23384447 T 162 167 sugar FAMILY 23384447 T 177 184 ethanol SYSTEMATIC 23385033 A 240 249 bleomycin FAMILY 23385033 A 267 276 cisplatin TRIVIAL 23385033 A 514 523 bleomycin FAMILY 23385033 A 528 537 cisplatin TRIVIAL 23385033 A 567 578 doxorubicin TRIVIAL 23385092 A 0 5 Azole FAMILY 23385092 A 151 165 1,2,4-triazole SYSTEMATIC 23385092 A 170 181 benzoxazole SYSTEMATIC 23385092 A 217 225 pyrazole SYSTEMATIC 23385092 A 342 343 C FORMULA 23385092 A 345 346 H FORMULA 23385092 A 348 349 N FORMULA 23385092 A 651 672 2,5-dichlorothiophene SYSTEMATIC 23385092 A 688 696 pyrazole SYSTEMATIC 23385092 A 710 718 triazole FAMILY 23385092 T 36 51 1,2,4-triazoles FAMILY 23385092 T 4 12 pyrazole SYSTEMATIC 23385092 T 56 68 benzoxazoles FAMILY 23385876 A 1010 1025 S-sulfocysteine SYSTEMATIC 23385876 A 102 118 transition metal FAMILY 23385876 A 1027 1037 RS-SO3(2-) FAMILY 23385876 A 1043 1046 Cys FORMULA 23385876 A 1095 1101 RS-SR' FAMILY 23385876 A 1113 1121 RS-S-SR' FAMILY 23385876 A 1144 1147 Cys FORMULA 23385876 A 1245 1248 Cys FORMULA 23385876 A 1414 1417 Cys FORMULA 23385876 A 1450 1458 cysteine TRIVIAL 23385876 A 209 226 transition metals FAMILY 23385876 A 251 258 sulfite SYSTEMATIC 23385876 A 280 298 di- and trisulfide MULTIPLE 23385876 A 314 320 RS-SR' FAMILY 23385876 A 332 340 RS-S-SR' FAMILY 23385876 A 38 44 sulfur SYSTEMATIC 23385876 A 436 455 chalcogen oxyanions FAMILY 23385876 A 456 464 selenite TRIVIAL 23385876 A 469 478 tellurite TRIVIAL 23385876 A 578 586 selenite TRIVIAL 23385876 A 588 596 SeO3(2-) FORMULA 23385876 A 601 610 tellurite TRIVIAL 23385876 A 612 620 TeO3(2-) FORMULA 23385876 A 656 666 disulfides FAMILY 23385876 A 671 688 selenotrisulfides FAMILY 23385876 A 692 710 tellurotrisulfides FAMILY 23385876 A 734 737 Cys FORMULA 23385876 A 744 747 Cys FORMULA 23385876 A 815 823 selenite TRIVIAL 23385876 A 850 859 tellurite TRIVIAL 23385876 A 943 946 Cys FORMULA 23385876 A 977 984 sulfite SYSTEMATIC 23385876 T 0 8 Selenite TRIVIAL 23385876 T 13 22 tellurite TRIVIAL 23385876 T 34 64 seleno- and tellurotrisulfides MULTIPLE 23385959 A 1021 1023 Mn FORMULA 23385959 A 1073 1089 F(2)-isoprostane FAMILY 23385959 A 1206 1208 Mn FORMULA 23385959 A 136 138 Mn FORMULA 23385959 A 1403 1409 Trolox TRIVIAL 23385959 A 1424 1426 Mn FORMULA 23385959 A 1506 1508 Mn FORMULA 23385959 A 1549 1565 F(2)-isoprostane FAMILY 23385959 A 1578 1584 Trolox TRIVIAL 23385959 A 1604 1606 Mn FORMULA 23385959 A 17 19 Mn FORMULA 23385959 A 1708 1710 Mn FORMULA 23385959 A 1934 1940 Trolox TRIVIAL 23385959 A 2015 2017 Mn FORMULA 23385959 A 309 311 Mn FORMULA 23385959 A 420 422 Mn FORMULA 23385959 A 551 553 Mn FORMULA 23385959 A 6 15 manganese SYSTEMATIC 23385959 A 906 908 Mn FORMULA 23385959 A 97 99 Mn FORMULA 23385959 T 0 9 Manganese SYSTEMATIC 23385959 T 108 114 Trolox TRIVIAL 23386248 A 1870 1880 irinotecan TRIVIAL 23386248 A 250 260 irinotecan TRIVIAL 23386248 A 26 29 UDP ABBREVIATION 23386248 A 335 345 folic acid TRIVIAL 23386248 A 347 357 leucovorin TRIVIAL 23386248 A 360 372 fluorouracil SYSTEMATIC 23386248 A 374 378 5-FU SYSTEMATIC 23386248 A 385 395 irinotecan TRIVIAL 23386248 A 397 406 camptosar TRIVIAL 23386248 A 70 80 irinotecan TRIVIAL 23386248 A 733 740 FOLFIRI TRIVIAL 23386248 T 141 155 5-fluorouracil SYSTEMATIC 23386248 T 156 166 irinotecan TRIVIAL 23386248 T 45 55 irinotecan TRIVIAL 23386387 A 0 6 ZnSnN2 FORMULA 23386387 T 63 69 ZnSnN2 FORMULA 23386394 A 158 165 d-block FAMILY 23386394 A 170 177 f-block FAMILY 23386417 A 0 8 Androgen FAMILY 23386417 A 1014 1022 androgen FAMILY 23386417 A 107 115 androgen FAMILY 23386417 A 1216 1224 androgen FAMILY 23386417 A 1546 1554 androgen FAMILY 23386417 A 188 196 androgen FAMILY 23386417 A 221 229 androgen FAMILY 23386417 A 332 340 androgen FAMILY 23386417 A 39 47 androgen FAMILY 23386417 A 456 464 androgen FAMILY 23386417 A 578 586 androgen FAMILY 23386417 A 870 878 androgen FAMILY 23386417 T 0 8 Androgen FAMILY 23386483 A 233 242 diterpene FAMILY 23386483 A 94 101 terpene FAMILY 23386483 T 49 58 diterpene FAMILY 23386596 A 0 15 Dexmedetomidine TRIVIAL 23386596 A 1377 1392 Dexmedetomidine TRIVIAL 23386596 A 1598 1613 dexmedetomidine TRIVIAL 23386596 A 1629 1636 alcohol FAMILY 23386596 A 1922 1941 γ-aminobutyric acid SYSTEMATIC 23386596 A 1985 2000 dexmedetomidine TRIVIAL 23386596 A 427 442 dexmedetomidine TRIVIAL 23386596 A 502 509 alcohol FAMILY 23386596 A 643 658 dexmedetomidine TRIVIAL 23386596 A 830 838 propofol TRIVIAL 23386596 A 932 947 dexmedetomidine TRIVIAL 23386596 T 54 69 dexmedetomidine TRIVIAL 23386609 A 11 18 guanine TRIVIAL 23386609 A 19 29 nucleotide FAMILY 23386609 A 63 66 ADP ABBREVIATION 23386609 T 105 115 Nucleotide FAMILY 23386609 T 17 27 Nucleotide FAMILY 23386609 T 9 16 Guanine TRIVIAL 23386609 T 97 104 Guanine TRIVIAL 23386703 A 1061 1070 GF-120918 IDENTIFIER 23386703 A 1204 1212 apixaban TRIVIAL 23386703 A 1383 1391 apixaban TRIVIAL 23386703 A 1491 1499 apixaban TRIVIAL 23386703 A 1572 1580 charcoal TRIVIAL 23386703 A 1688 1696 apixaban TRIVIAL 23386703 A 1769 1777 apixaban TRIVIAL 23386703 A 1972 1980 apixaban TRIVIAL 23386703 A 219 227 apixaban TRIVIAL 23386703 A 310 318 apixaban TRIVIAL 23386703 A 493 501 charcoal TRIVIAL 23386703 A 617 625 apixaban TRIVIAL 23386703 A 759 767 apixaban TRIVIAL 23386703 A 946 954 apixaban TRIVIAL 23386703 T 49 57 apixaban TRIVIAL 23387414 A 168 180 Organothiols FAMILY 23387414 A 17 35 sodium borohydride SYSTEMATIC 23387414 A 223 232 thiophene SYSTEMATIC 23387414 A 234 241 adenine TRIVIAL 23387414 A 243 252 rhodamine TRIVIAL 23387414 A 268 273 Br(-) FORMULA 23387414 A 278 282 I(-) FORMULA 23387414 A 300 303 PVP ABBREVIATION 23387414 A 305 329 poly(N-vinylpyrrolidone) FAMILY 23387414 A 431 438 hydride SYSTEMATIC 23387414 A 452 470 sodium borohydride SYSTEMATIC 23387414 A 47 59 organothiols FAMILY 23387414 A 515 527 organothiols FAMILY 23387414 A 551 563 organothiols FAMILY 23387414 A 612 630 Sodium borohydride SYSTEMATIC 23387414 T 60 78 sodium borohydride SYSTEMATIC 23387444 A 184 193 fullerene TRIVIAL 23387444 A 427 431 MoS2 FORMULA 23387444 A 436 441 MoSe2 FORMULA 23387444 A 599 603 MoS2 FORMULA 23387444 A 608 613 MoSe2 FORMULA 23387444 A 723 731 hydrogen SYSTEMATIC 23387444 T 13 17 MoS2 FORMULA 23387444 T 22 27 MoSe2 FORMULA 23387501 A 0 10 Nevirapine TRIVIAL 23387501 A 1036 1039 NVP ABBREVIATION 23387501 A 1126 1143 12-OH-NVP sulfate SYSTEMATIC 23387501 A 1170 1181 glutathione TRIVIAL 23387501 A 12 15 NVP ABBREVIATION 23387501 A 1210 1217 sulfate SYSTEMATIC 23387501 A 1304 1313 12-OH-NVP SYSTEMATIC 23387501 A 1425 1462 3'-phosphoadenosine-5'-phosphosulfate SYSTEMATIC 23387501 A 1464 1468 PAPS ABBREVIATION 23387501 A 1725 1728 NVP ABBREVIATION 23387501 A 1812 1815 NVP ABBREVIATION 23387501 A 1838 1855 12-OH-NVP sulfate SYSTEMATIC 23387501 A 1889 1892 NVP ABBREVIATION 23387501 A 255 258 NVP ABBREVIATION 23387501 A 271 280 12-OH-NVP SYSTEMATIC 23387501 A 374 383 12-OH-NVP SYSTEMATIC 23387501 A 392 408 benzylic sulfate SYSTEMATIC 23387501 A 466 469 NVP ABBREVIATION 23387501 A 473 482 12-OH-NVP SYSTEMATIC 23387501 A 489 496 sulfate SYSTEMATIC 23387501 A 637 640 NVP ABBREVIATION 23387501 T 0 10 Nevirapine TRIVIAL 23388040 A 591 610 polyethylene glycol SYSTEMATIC 23389043 A 101 105 GSSG ABBREVIATION 23389043 A 108 123 malondialdehyde TRIVIAL 23389043 A 1205 1213 8-oxo-dG SYSTEMATIC 23389043 A 125 128 MDA ABBREVIATION 23389043 A 153 188 8-oxo-7'8-dihydro-2'-deoxyguanosine SYSTEMATIC 23389043 A 190 198 8-oxo-dG SYSTEMATIC 23389043 A 326 334 8-oxo-dG SYSTEMATIC 23389043 A 67 95 reduced/oxidized glutathione MULTIPLE 23389043 A 718 721 MDA ABBREVIATION 23389043 A 726 734 8-oxo-dG SYSTEMATIC 23389043 A 772 775 GSH ABBREVIATION 23389043 A 810 814 GSSG ABBREVIATION 23389043 A 917 925 8-oxo-dG SYSTEMATIC 23389043 A 97 100 GSH ABBREVIATION 23389043 T 60 95 8-Oxo-7'8-dihydro-2'-deoxyguanosine SYSTEMATIC 23389043 T 97 105 8-oxo-dG SYSTEMATIC 23389092 A 1119 1133 ICZ glycosides FAMILY 23389092 A 149 153 ICZs FAMILY 23389092 A 21 24 ICZ ABBREVIATION 23389092 A 319 323 ICZs FAMILY 23389092 A 4 19 indolocarbazole SYSTEMATIC 23389092 A 414 417 FAD ABBREVIATION 23389092 A 460 463 ICZ ABBREVIATION 23389092 A 610 613 ICZ ABBREVIATION 23389092 A 646 651 sugar FAMILY 23389092 A 791 794 ICZ ABBREVIATION 23389092 A 971 974 ICZ ABBREVIATION 23389092 T 61 76 indolocarbazole SYSTEMATIC 23391154 A 1011 1021 N-halamine FAMILY 23391154 A 1116 1127 N-halamines FAMILY 23391154 A 14 33 N-halamine polymers FAMILY 23391154 A 396 406 N-halamine FAMILY 23391154 A 661 671 N-halamine FAMILY 23391154 A 680 681 N FORMULA 23391154 A 693 695 Cl FORMULA 23391154 A 699 701 Br FORMULA 23391154 A 705 706 I FORMULA 23391154 T 14 33 N-halamine polymers FAMILY 23391297 A 118 150 poly(acrylic acid)-b-polylactide FAMILY 23391297 A 152 165 P(AA)-b-P(LA) ABBREVIATION 23391297 A 610 623 P(AA)-b-P(LA) ABBREVIATION 23391307 A 13 20 CaFe2O4 FORMULA 23391307 A 21 28 ZnFe2O4 FORMULA 23391307 A 652 659 CaFe2O4 FORMULA 23391307 A 660 667 ZnFe2O4 FORMULA 23391307 T 48 55 CaFe2O4 FORMULA 23391307 T 56 63 ZnFe2O4 FORMULA 23391363 A 1323 1326 MTT ABBREVIATION 23391363 A 212 222 lovastatin TRIVIAL 23391363 A 531 539 nitrogen SYSTEMATIC 23391363 A 758 818 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide SYSTEMATIC 23391363 A 820 823 MTT ABBREVIATION 23391424 A 0 20 Dammarane Sapogenins FAMILY 23391424 A 101 104 PPD ABBREVIATION 23391424 A 1067 1070 PPD ABBREVIATION 23391424 A 1182 1185 PPT ABBREVIATION 23391424 A 1190 1193 PPD ABBREVIATION 23391424 A 1274 1277 PPT ABBREVIATION 23391424 A 1477 1480 PPT ABBREVIATION 23391424 A 149 161 ginsenosides FAMILY 23391424 A 353 356 PPT ABBREVIATION 23391424 A 361 364 PPD ABBREVIATION 23391424 A 52 68 protopanaxatriol TRIVIAL 23391424 A 553 556 PPT ABBREVIATION 23391424 A 561 564 PPD ABBREVIATION 23391424 A 628 631 PPT ABBREVIATION 23391424 A 70 73 PPT ABBREVIATION 23391424 A 763 766 PPD ABBREVIATION 23391424 A 84 99 protopanaxadiol TRIVIAL 23391424 A 879 882 PPD ABBREVIATION 23391424 A 887 890 PPT ABBREVIATION 23391424 A 975 978 PPT ABBREVIATION 23391424 T 102 117 protopanaxadiol TRIVIAL 23391424 T 59 79 dammarane sapogenins FAMILY 23391424 T 81 97 protopanaxatriol TRIVIAL 23391859 A 189 200 radioiodine SYSTEMATIC 23391859 A 369 380 radioiodine SYSTEMATIC 23391859 A 457 462 131-I FORMULA 23394107 A 414 423 disulfide SYSTEMATIC 23394107 A 485 496 glutathione TRIVIAL 23394107 A 586 597 glutathione TRIVIAL 23394107 A 753 763 Folic acid TRIVIAL 23394107 A 776 787 doxorubicin TRIVIAL 23394107 A 891 897 folate TRIVIAL 23394205 A 242 271 sulfonylmorpholinopyrimidines FAMILY 23394205 A 408 412 AZ20 IDENTIFIER 23394205 T 108 112 AZ20 IDENTIFIER 23394205 T 13 106 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole SYSTEMATIC 23394402 A 0 22 Poly(dimethylsiloxane) FAMILY 23394402 A 1345 1349 PDMS ABBREVIATION 23394402 A 1430 1434 PDMS ABBREVIATION 23394402 A 1509 1513 POSS ABBREVIATION 23394402 A 1544 1550 ethoxy SYSTEMATIC 23394402 A 1563 1570 methoxy SYSTEMATIC 23394402 A 1672 1680 nitrogen SYSTEMATIC 23394402 A 208 216 ammonium SYSTEMATIC 23394402 A 2345 2353 nitrogen SYSTEMATIC 23394402 A 24 28 PDMS ABBREVIATION 23394402 A 281 285 PDMS ABBREVIATION 23394402 A 403 407 PDMS ABBREVIATION 23394402 A 558 562 PDMS ABBREVIATION 23394402 A 610 618 ammonium SYSTEMATIC 23394402 A 659 667 ammonium SYSTEMATIC 23394402 A 683 719 polyhedral oligomeric silsesquioxane FAMILY 23394402 A 723 727 POSS ABBREVIATION 23394402 T 22 26 PDMS ABBREVIATION 23394402 T 56 64 ammonium SYSTEMATIC 23394702 A 390 398 platinum SYSTEMATIC 23394702 A 419 427 Platinum SYSTEMATIC 23394702 A 547 555 Platinum SYSTEMATIC 23394702 T 39 47 platinum SYSTEMATIC 23395003 A 47 53 lysine TRIVIAL 23395003 A 477 480 CpG ABBREVIATION 23395003 T 55 58 CpG ABBREVIATION 23395155 A 0 12 Nitric oxide SYSTEMATIC 23395155 A 14 16 NO FORMULA 23395155 A 193 195 NO FORMULA 23395155 A 297 302 NADPH ABBREVIATION 23395155 A 359 378 tetrahydrobiopterin SYSTEMATIC 23395155 A 380 383 BH4 FORMULA 23395155 A 421 424 BH4 FORMULA 23395155 A 437 443 oxygen SYSTEMATIC 23395155 A 46 48 NO FORMULA 23395155 A 469 471 NO FORMULA 23395155 A 512 522 superoxide TRIVIAL 23395155 A 578 580 NO FORMULA 23395155 A 899 908 nebivolol TRIVIAL 23395155 A 913 924 resveratrol TRIVIAL 23395155 T 26 28 NO FORMULA 23395163 A 163 164 O FORMULA 23395163 T 4 9 sugar FAMILY 23395634 A 1013 1019 HX0969 IDENTIFIER 23395634 A 102 110 propofol TRIVIAL 23395634 A 1061 1069 propofol TRIVIAL 23395634 A 175 181 HX0969 IDENTIFIER 23395634 A 245 251 HX0969 IDENTIFIER 23395634 A 297 305 propofol TRIVIAL 23395634 A 328 363 HX0969 disodium phosphate monoester SYSTEMATIC 23395634 A 33 41 propofol TRIVIAL 23395634 A 365 372 HX0969W IDENTIFIER 23395634 A 378 417 glycine ester trifluoroacetic acid salt SYSTEMATIC 23395634 A 419 427 HX101230 IDENTIFIER 23395634 A 510 517 Lusedra TRIVIAL 23395634 A 589 597 propofol TRIVIAL 23395634 A 634 640 HX0969 IDENTIFIER 23395634 A 797 804 HX0969W IDENTIFIER 23395634 A 834 841 Lusedra TRIVIAL 23395634 A 844 852 HX101230 IDENTIFIER 23395634 T 54 62 propofol TRIVIAL 23395653 A 211 218 pyrrole SYSTEMATIC 23395653 A 383 390 pyrrole SYSTEMATIC 23395653 A 436 456 piperidinyl nitrogen SYSTEMATIC 23395653 A 510 530 piperidinyl nitrogen SYSTEMATIC 23395653 A 556 562 biotin TRIVIAL 23395653 A 628 635 pyrrole SYSTEMATIC 23395653 T 36 43 pyrrole SYSTEMATIC 23395667 A 1007 1015 glycerol TRIVIAL 23395667 A 281 300 polyethylene glycol SYSTEMATIC 23395718 A 1074 1079 ozone TRIVIAL 23395718 A 1184 1188 AFB1 ABBREVIATION 23395718 A 1216 1221 ozone TRIVIAL 23395718 A 1227 1232 ozone TRIVIAL 23395718 A 125 130 ozone TRIVIAL 23395718 A 232 244 aflatoxin B1 TRIVIAL 23395718 A 246 250 AFB1 ABBREVIATION 23395718 A 25 34 aflatoxin FAMILY 23395718 A 281 286 ozone TRIVIAL 23395718 A 388 392 AFB1 ABBREVIATION 23395718 T 47 59 aflatoxin B1 TRIVIAL 23395825 A 0 14 1-Bromopropane SYSTEMATIC 23395825 A 1073 1076 GSH ABBREVIATION 23395825 A 1087 1089 SH FORMULA 23395825 A 1099 1102 GSH ABBREVIATION 23395825 A 1103 1107 GSSG ABBREVIATION 23395825 A 1209 1212 MDA ABBREVIATION 23395825 A 1220 1225 4-HNE SYSTEMATIC 23395825 A 1230 1233 MDA ABBREVIATION 23395825 A 1283 1287 1-BP SYSTEMATIC 23395825 A 1298 1301 GSH ABBREVIATION 23395825 A 1385 1389 1-BP SYSTEMATIC 23395825 A 1500 1504 1-BP SYSTEMATIC 23395825 A 16 20 1-BP SYSTEMATIC 23395825 A 244 248 1-BP SYSTEMATIC 23395825 A 375 379 1-BP SYSTEMATIC 23395825 A 41 46 ozone TRIVIAL 23395825 A 621 632 Glutathione TRIVIAL 23395825 A 634 637 GSH ABBREVIATION 23395825 A 640 660 oxidized glutathione TRIVIAL 23395825 A 662 666 GSSG ABBREVIATION 23395825 A 678 683 thiol FAMILY 23395825 A 691 693 SH FORMULA 23395825 A 704 707 GSH ABBREVIATION 23395825 A 727 730 GSH ABBREVIATION 23395825 A 743 746 GSH ABBREVIATION 23395825 A 763 778 malondialdehyde TRIVIAL 23395825 A 780 783 MDA ABBREVIATION 23395825 A 803 819 4-hydroxynonenal SYSTEMATIC 23395825 A 821 826 4-HNE SYSTEMATIC 23395825 A 832 835 MDA ABBREVIATION 23395825 A 936 940 1-BP SYSTEMATIC 23395825 T 13 29 4-hydroxynonenal SYSTEMATIC 23395825 T 139 153 1-bromopropane SYSTEMATIC 23395825 T 34 49 malondialdehyde TRIVIAL 23395899 A 674 684 α-amanitin TRIVIAL 23395899 A 688 701 actinomycin D TRIVIAL 23395915 A 1115 1123 rifampin TRIVIAL 23395915 A 1213 1221 rifampin TRIVIAL 23395915 A 209 217 rifampin TRIVIAL 23395915 A 453 461 rifampin TRIVIAL 23395915 A 581 590 verapamil TRIVIAL 23395915 A 632 640 rifampin TRIVIAL 23395915 A 735 743 rifampin TRIVIAL 23395915 A 806 814 rifampin TRIVIAL 23395915 A 852 860 rifampin TRIVIAL 23395915 A 875 882 digoxin TRIVIAL 23395915 A 934 942 rifampin TRIVIAL 23395915 A 991 998 digoxin TRIVIAL 23395915 T 29 37 rifampin TRIVIAL 23395916 A 0 15 Steroid hormone FAMILY 23395916 A 1040 1055 steroid hormone FAMILY 23395916 A 1161 1169 androgen FAMILY 23395916 T 37 45 androgen FAMILY 23396042 A 221 222 N FORMULA 23396042 A 266 267 C FORMULA 23396078 A 270 277 optovin TRIVIAL 23396078 A 403 410 optovin TRIVIAL 23396078 A 598 605 optovin TRIVIAL 23396078 A 616 623 Optovin TRIVIAL 23396078 A 715 723 cysteine TRIVIAL 23396078 A 772 779 optovin TRIVIAL 23396090 A 1052 1056 CDDP ABBREVIATION 23396090 A 1227 1231 CDDP ABBREVIATION 23396090 A 1242 1246 CDDP ABBREVIATION 23396090 A 1582 1586 CDDP ABBREVIATION 23396090 A 1630 1634 CDDP ABBREVIATION 23396090 A 219 223 CDDP ABBREVIATION 23396090 A 360 364 CDDP ABBREVIATION 23396090 A 38 47 cisplatin TRIVIAL 23396090 A 443 447 CDDP ABBREVIATION 23396090 A 49 53 CDDP ABBREVIATION 23396090 A 606 610 CDDP ABBREVIATION 23396090 A 65 69 CDDP ABBREVIATION 23396090 A 682 686 CDDP ABBREVIATION 23396090 A 862 866 CDDP ABBREVIATION 23396090 T 72 81 cisplatin TRIVIAL 23396144 A 1028 1031 CLS ABBREVIATION 23396144 A 1182 1185 CLS ABBREVIATION 23396144 A 454 462 buthanol SYSTEMATIC 23396144 A 467 479 ethylacetate SYSTEMATIC 23396144 A 497 505 methanol SYSTEMATIC 23396144 A 561 572 clerosterol TRIVIAL 23396144 A 574 577 CLS ABBREVIATION 23396144 A 744 756 nitric oxide SYSTEMATIC 23396144 A 835 838 CLS ABBREVIATION 23396144 A 923 939 prostaglandin E2 TRIVIAL 23396144 A 941 945 PGE2 ABBREVIATION 23396144 A 951 963 nitric oxide SYSTEMATIC 23396144 A 965 967 NO FORMULA 23396419 A 1137 1165 (-)-Epigallocatechin gallate TRIVIAL 23396419 A 1167 1180 cyclosporin A TRIVIAL 23396419 A 1182 1192 rifampicin TRIVIAL 23396419 A 1198 1209 telmisartan TRIVIAL 23396419 A 1233 1240 dioscin TRIVIAL 23396419 A 1302 1309 dioscin TRIVIAL 23396419 A 1481 1488 dioscin TRIVIAL 23396419 A 459 466 dioscin TRIVIAL 23396419 A 530 537 dioscin TRIVIAL 23396419 A 633 640 dioscin TRIVIAL 23396419 A 705 712 dioscin TRIVIAL 23396419 A 818 827 ibuprofen TRIVIAL 23396419 A 849 856 digoxin TRIVIAL 23396419 A 86 93 dioscin TRIVIAL 23396419 A 882 899 glycyrrhizic acid TRIVIAL 23396419 A 932 935 TEA ABBREVIATION 23396419 A 939 955 p-aminohippurate TRIVIAL 23396419 A 95 153 diosgenyl 2,4-di-O-a-L-rhamnopyranosyl-p-D-glucopyranoside SYSTEMATIC 23396419 A 967 974 dioscin TRIVIAL 23396419 T 80 87 dioscin TRIVIAL 23396446 A 1019 1027 arginine TRIVIAL 23396446 A 1183 1191 arginine TRIVIAL 23396446 A 562 577 protocatechuate TRIVIAL 23396446 A 721 736 protocatechuate TRIVIAL 23396446 A 747 755 phenolic FAMILY 23396446 A 820 835 protocatechuate TRIVIAL 23396446 A 987 1002 protocatechuate TRIVIAL 23396530 A 0 9 Arylamine FAMILY 23396530 A 1024 1033 arylamine FAMILY 23396530 A 299 308 arylamine FAMILY 23396530 A 376 389 ruthenium(II) SYSTEMATIC 23396530 A 649 658 arylamine FAMILY 23396530 A 741 750 arylamine FAMILY 23396530 A 777 783 iodide SYSTEMATIC 23396530 A 784 793 triiodide SYSTEMATIC 23396530 A 810 828 polypyridyl cobalt FAMILY 23396530 A 949 958 arylamine FAMILY 23396530 T 0 9 Arylamine FAMILY 23397052 A 1043 1052 monoamine FAMILY 23397052 A 1082 1096 norepinephrine TRIVIAL 23397052 A 198 206 Dopamine TRIVIAL 23397052 A 834 849 methylphenidate SYSTEMATIC 23397052 A 853 863 nisoxetine TRIVIAL 23397052 T 37 45 dopamine TRIVIAL 23397053 A 1197 1208 Risperidone TRIVIAL 23397053 A 1353 1364 Risperidone TRIVIAL 23397053 A 1470 1481 risperidone TRIVIAL 23397053 A 292 303 risperidone TRIVIAL 23397053 A 832 843 risperidone TRIVIAL 23397053 T 27 38 risperidone TRIVIAL 23397055 A 1023 1026 CPA ABBREVIATION 23397055 A 1070 1079 Adenosine TRIVIAL 23397055 A 1084 1087 CPA ABBREVIATION 23397055 A 1168 1172 DOCA ABBREVIATION 23397055 A 1205 1214 adenosine TRIVIAL 23397055 A 1219 1222 CPA ABBREVIATION 23397055 A 123 126 ATP ABBREVIATION 23397055 A 1283 1292 adenosine TRIVIAL 23397055 A 131 145 norepinephrine TRIVIAL 23397055 A 1310 1318 CGS21680 IDENTIFIER 23397055 A 1320 1339 C23H29N7O6.HCl.xH2O FORMULA 23397055 A 1505 1514 adenosine TRIVIAL 23397055 A 1621 1625 DOCA ABBREVIATION 23397055 A 1819 1823 DOCA ABBREVIATION 23397055 A 317 321 DOCA ABBREVIATION 23397055 A 333 342 Adenosine TRIVIAL 23397055 A 357 360 ATP ABBREVIATION 23397055 A 407 416 adenosine TRIVIAL 23397055 A 603 607 DOCA ABBREVIATION 23397055 A 61 88 deoxycorticosterone acetate SYSTEMATIC 23397055 A 850 858 tyrosine TRIVIAL 23397055 A 90 94 DOCA ABBREVIATION 23397055 A 981 990 Adenosine TRIVIAL 23397055 A 995 1021 N(6)-cyclopentyl-adenosine SYSTEMATIC 23397055 T 106 110 DOCA ABBREVIATION 23397055 T 35 44 adenosine TRIVIAL 23397359 A 162 171 C(60) (+) TRIVIAL 23397359 A 226 243 barium arachidate SYSTEMATIC 23397419 A 113 124 cholesterol TRIVIAL 23397419 A 1137 1148 cholesterol TRIVIAL 23397419 A 1212 1223 cholesterol TRIVIAL 23397419 A 278 289 cholesterol TRIVIAL 23397419 A 325 336 cholesterol TRIVIAL 23397419 A 443 454 cholesterol TRIVIAL 23397419 A 514 536 esterified cholesterol TRIVIAL 23397419 A 53 64 cholesterol TRIVIAL 23397419 A 706 717 cholesterol TRIVIAL 23397419 A 768 775 choline FAMILY 23397419 A 799 818 phosphatidylcholine FAMILY 23397419 A 828 842 sphingomyelins FAMILY 23397419 A 892 903 cholesterol TRIVIAL 23397419 A 956 967 cholesterol TRIVIAL 23397419 A 996 1007 cholesterol TRIVIAL 23397510 A 1005 1017 testosterone TRIVIAL 23397510 A 1095 1107 testosterone TRIVIAL 23397510 A 1201 1213 testosterone TRIVIAL 23397510 A 1328 1337 estradiol TRIVIAL 23397510 A 1486 1498 testosterone TRIVIAL 23397510 A 1563 1575 testosterone TRIVIAL 23397510 A 1663 1671 estrogen FAMILY 23397510 A 507 516 estradiol TRIVIAL 23397510 A 738 746 steroids FAMILY 23397510 A 914 923 estradiol TRIVIAL 23397510 A 931 943 testosterone TRIVIAL 23397510 T 18 26 steroids FAMILY 23397572 A 141 148 lithium SYSTEMATIC 23397572 A 149 155 sulfur SYSTEMATIC 23397572 A 254 261 lithium SYSTEMATIC 23397572 A 262 268 sulfur SYSTEMATIC 23397572 T 0 7 Lithium SYSTEMATIC 23397572 T 8 14 sulfur SYSTEMATIC 23397585 A 0 13 Iodothyronine TRIVIAL 23397585 A 1108 1143 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23397585 A 1145 1170 polychlorinated biphenyls FAMILY 23397585 A 1172 1188 propylthiouracil SYSTEMATIC 23397585 A 1190 1205 iodoacetic acid SYSTEMATIC 23397585 A 1207 1220 methylmercury SYSTEMATIC 23397585 A 1222 1233 β-estradiol TRIVIAL 23397585 A 1235 1246 methimazole TRIVIAL 23397585 A 1248 1268 3-methylcholanthrene SYSTEMATIC 23397585 A 1270 1283 aminotriazole SYSTEMATIC 23397585 A 1285 1295 amiodarone TRIVIAL 23397585 A 1297 1313 cadmium chloride SYSTEMATIC 23397585 A 1315 1325 dimethoate TRIVIAL 23397585 A 1327 1338 fenvalerate TRIVIAL 23397585 A 1340 1361 octylmethoxycinnamate SYSTEMATIC 23397585 A 1363 1376 iopanoic acid TRIVIAL 23397585 A 1378 1390 methoxychlor TRIVIAL 23397585 A 1396 1423 4-methylbenzylidene-camphor SYSTEMATIC 23397585 A 195 201 iodine SYSTEMATIC 23397585 A 216 225 thyroxine TRIVIAL 23397966 A 1647 1654 steroid FAMILY 23397966 A 192 199 steroid FAMILY 23397966 A 274 282 steroids FAMILY 23397966 A 493 506 dexamethasone TRIVIAL 23397966 A 823 836 dexamethasone TRIVIAL 23397966 A 838 847 lidocaine TRIVIAL 23397966 T 37 50 dexamethazone TRIVIAL 23398143 A 799 807 nitrogen SYSTEMATIC 23398172 A 0 8 Graphene TRIVIAL 23398172 A 203 211 graphene TRIVIAL 23398172 A 389 397 graphene TRIVIAL 23398172 T 75 83 graphene TRIVIAL 23398311 A 254 264 L-cysteine TRIVIAL 23398311 A 307 323 methacrylic acid TRIVIAL 23398311 A 368 379 Rhodamine B TRIVIAL 23398311 A 388 398 L-cysteine TRIVIAL 23398311 A 569 592 ferrocenecarboxaldehyde SYSTEMATIC 23398311 A 606 610 PMAA ABBREVIATION 23398311 A 63 69 silica TRIVIAL 23398311 A 822 826 SiO2 FORMULA 23398311 A 827 829 Au FORMULA 23398311 A 957 959 Au FORMULA 23398311 T 0 4 SiO2 FORMULA 23398311 T 5 7 Au FORMULA 23398496 A 569 576 glucose TRIVIAL 23398496 A 590 603 carbohydrates FAMILY 23398496 A 615 622 glucose TRIVIAL 23398658 A 102 108 nickel SYSTEMATIC 23399722 A 1034 1043 guanidino SYSTEMATIC 23399722 A 1076 1082 purine TRIVIAL 23399722 A 1148 1159 roscovitine TRIVIAL 23399722 A 117 127 olomoucine TRIVIAL 23399722 A 12 46 2,9-substituted 6-guanidinopurines FAMILY 23399722 A 132 143 roscovitine TRIVIAL 23399722 A 191 197 copper SYSTEMATIC 23399722 A 236 280 2-substituted 6-guanidino-9-isopropylpurines FAMILY 23399722 A 591 602 roscovitine TRIVIAL 23399722 A 828 849 (S)-6-guanidinopurine SYSTEMATIC 23399722 T 39 48 guanidino SYSTEMATIC 23399722 T 62 73 roscovitine TRIVIAL 23399882 A 1115 1123 agmatine TRIVIAL 23399882 A 1154 1161 ethanol SYSTEMATIC 23399882 A 1186 1197 imidazoline SYSTEMATIC 23399882 A 1243 1251 agmatine TRIVIAL 23399882 A 1276 1287 imidazoline SYSTEMATIC 23399882 A 1351 1358 ethanol SYSTEMATIC 23399882 A 152 163 imidazoline SYSTEMATIC 23399882 A 236 244 agmatine TRIVIAL 23399882 A 279 286 ethanol SYSTEMATIC 23399882 A 431 439 Agmatine TRIVIAL 23399882 A 45 53 agmatine TRIVIAL 23399882 A 492 499 ethanol SYSTEMATIC 23399882 A 553 561 efaroxan TRIVIAL 23399882 A 606 611 BU224 IDENTIFIER 23399882 A 637 645 agmatine TRIVIAL 23399882 A 672 679 ethanol SYSTEMATIC 23399882 A 737 742 2-BFI SYSTEMATIC 23399882 A 780 790 moxonidine TRIVIAL 23399882 A 87 94 ethanol SYSTEMATIC 23399882 A 895 903 agmatine TRIVIAL 23399882 A 933 940 ethanol SYSTEMATIC 23399882 A 946 954 Agmatine TRIVIAL 23399882 A 958 969 imidazoline SYSTEMATIC 23399882 T 0 8 Agmatine TRIVIAL 23399882 T 115 126 imidazoline SYSTEMATIC 23399882 T 58 65 ethanol SYSTEMATIC 23399949 A 0 7 Guanine TRIVIAL 23399949 A 545 549 K(+) FORMULA 23399949 A 783 794 nucleobases FAMILY 23399949 A 798 802 K(+) FORMULA 23399949 T 66 73 guanine TRIVIAL 23400365 A 109 125 Au(n)(PPh(3))(y) FAMILY 23400365 A 198 205 titania TRIVIAL 23400365 A 256 263 toluene TRIVIAL 23400365 A 351 353 Au FORMULA 23400365 A 465 476 phosphorous SYSTEMATIC 23400365 A 754 760 oxygen SYSTEMATIC 23400365 A 768 775 titania TRIVIAL 23400365 A 830 832 Au FORMULA 23400365 A 929 936 Au(101) FORMULA 23400365 T 84 91 titania TRIVIAL 23400739 A 0 9 Dovitinib TRIVIAL 23400739 A 1140 1149 dovitinib TRIVIAL 23400739 A 1232 1241 dovitinib TRIVIAL 23400739 A 1389 1398 dovitinib TRIVIAL 23400739 A 231 240 dovitinib TRIVIAL 23400739 A 297 306 dovitinib TRIVIAL 23400739 A 592 601 dovitinib TRIVIAL 23400739 A 707 716 dovitinib TRIVIAL 23400739 A 790 799 dovitinib TRIVIAL 23400739 T 92 101 dovitinib TRIVIAL 23400747 A 1040 1043 AML ABBREVIATION 23400747 A 106 109 LEX ABBREVIATION 23400747 A 1079 1087 β-lactam TRIVIAL 23400747 A 1130 1133 LEX ABBREVIATION 23400747 A 115 132 cefuroxime axetil TRIVIAL 23400747 A 1195 1203 β-lactam TRIVIAL 23400747 A 134 137 CXM ABBREVIATION 23400747 A 306 309 LEX ABBREVIATION 23400747 A 324 327 LEX ABBREVIATION 23400747 A 372 375 AML ABBREVIATION 23400747 A 382 385 CXM ABBREVIATION 23400747 A 404 407 CXM ABBREVIATION 23400747 A 452 455 AML ABBREVIATION 23400747 A 51 61 amlodipine TRIVIAL 23400747 A 63 66 AML ABBREVIATION 23400747 A 772 775 LEX ABBREVIATION 23400747 A 857 860 LEX ABBREVIATION 23400747 A 873 876 AML ABBREVIATION 23400747 A 94 104 cephalexin TRIVIAL 23400747 A 979 982 CXM ABBREVIATION 23400747 T 11 21 amlodipine TRIVIAL 23400747 T 53 63 cephalexin TRIVIAL 23400747 T 68 85 cefuroxime axetil TRIVIAL 23400749 A 1010 1018 imipenem TRIVIAL 23400749 A 1023 1032 meropenem TRIVIAL 23400749 A 1138 1147 β-lactams FAMILY 23400749 A 1149 1164 aminoglycosides FAMILY 23400749 A 1170 1186 fluoroquinolones FAMILY 23400749 A 1240 1250 carbapenem FAMILY 23400749 A 128 138 carbapenem FAMILY 23400749 A 1317 1325 imipenem TRIVIAL 23400749 A 1327 1336 meropenem TRIVIAL 23400749 A 1408 1416 imipenem TRIVIAL 23400749 A 1417 1427 cilastatin TRIVIAL 23400749 A 1432 1441 meropenem TRIVIAL 23400749 A 1459 1468 β-lactams FAMILY 23400749 A 1470 1485 aminoglycosides FAMILY 23400749 A 1491 1507 fluoroquinolones FAMILY 23400749 A 39 49 carbapenem FAMILY 23400749 A 411 419 imipenem TRIVIAL 23400749 A 420 430 cilastatin TRIVIAL 23400749 A 432 441 meropenem TRIVIAL 23400749 A 453 463 carbapenem FAMILY 23400749 A 497 505 imipenem TRIVIAL 23400749 A 616 626 carbapenem FAMILY 23400749 A 672 681 meropenem TRIVIAL 23400749 A 759 767 imipenem TRIVIAL 23400749 A 768 778 cilastatin TRIVIAL 23400749 A 780 789 meropenem TRIVIAL 23400749 A 801 811 carbapenem FAMILY 23400749 A 857 869 piperacillin TRIVIAL 23400749 A 870 880 tazobactam TRIVIAL 23400749 A 882 893 ceftazidime TRIVIAL 23400749 A 895 903 cefepime TRIVIAL 23400749 A 905 913 amikacin TRIVIAL 23400749 A 919 931 levofloxacin TRIVIAL 23400749 A 956 965 β-lactams FAMILY 23400749 A 967 982 aminoglycosides FAMILY 23400749 A 988 1004 fluoroquinolones FAMILY 23400749 T 20 30 carbapenem FAMILY 23400845 A 1417 1423 EHTeBB ABBREVIATION 23400845 A 1427 1433 BEHTBP ABBREVIATION 23400845 A 1564 1570 EHTeBB ABBREVIATION 23400845 A 1583 1589 BETHBP ABBREVIATION 23400845 A 496 522 bis(tribromophenoxy)ethane SYSTEMATIC 23400845 A 524 529 BTBPE ABBREVIATION 23400845 A 532 581 tetrabromobisphenol A bis(2,3-dibromopropyl ether SYSTEMATIC 23400845 A 583 588 TBBPA ABBREVIATION 23400845 A 589 593 DBPE ABBREVIATION 23400845 A 600 616 Firemaster BZ-54 TRIVIAL 23400845 A 650 686 bis(2-ethylhexyl)tetrabromophthalate SYSTEMATIC 23400845 A 688 694 BEHTBP ABBREVIATION 23400845 A 700 739 2-ethylhexyl-2,3,4,5-tetrabromobenzoate SYSTEMATIC 23400845 A 741 747 EHTeBB ABBREVIATION 23400845 A 949 954 BTBPE ABBREVIATION 23400845 A 956 961 TBBPA ABBREVIATION 23400845 A 962 966 DBPE ABBREVIATION 23400845 A 972 978 BEHTBP ABBREVIATION 23400899 A 0 30 Polybrominated diphenyl ethers FAMILY 23400899 A 160 165 PBDEs ABBREVIATION 23400899 A 296 327 pentabrominated diphenyl ethers FAMILY 23400899 A 32 37 PBDEs ABBREVIATION 23400964 A 1090 1110 dabigatran etexilate TRIVIAL 23400964 A 1146 1154 warfarin TRIVIAL 23400964 A 1320 1340 dabigatran etexilate TRIVIAL 23400964 A 1403 1423 dabigatran etexilate TRIVIAL 23400964 A 185 205 Dabigatran etexilate TRIVIAL 23400964 A 386 406 dabigatran etexilate TRIVIAL 23400964 A 489 509 dabigatran etexilate TRIVIAL 23400964 A 613 633 dabigatran etexilate TRIVIAL 23400964 A 723 743 dabigatran etexilate TRIVIAL 23400964 A 824 844 dabigatran etexilate TRIVIAL 23400964 A 976 986 creatinine TRIVIAL 23400964 T 21 41 dabigatran etexilate TRIVIAL 23401283 A 156 166 darapladib TRIVIAL 23401318 A 1171 1179 Cu oxide SYSTEMATIC 23401318 A 1206 1208 Cu FORMULA 23401318 A 126 132 copper SYSTEMATIC 23401318 A 134 136 Cu FORMULA 23401318 A 1361 1368 Cu(2) O FORMULA 23401318 A 1372 1375 CuO FORMULA 23401318 A 164 166 Si FORMULA 23401318 A 225 231 oxygen SYSTEMATIC 23401318 A 282 284 Cu FORMULA 23401318 A 320 328 Cu oxide SYSTEMATIC 23401318 A 476 478 Cu FORMULA 23401318 A 479 487 Cu oxide SYSTEMATIC 23401318 A 561 563 Cu FORMULA 23401318 A 660 662 Cu FORMULA 23401318 A 672 680 Cu oxide SYSTEMATIC 23401318 A 761 770 Cu oxides FAMILY 23401318 A 803 810 Cu(2) O FORMULA 23401318 A 815 818 CuO FORMULA 23401318 A 882 884 Cu FORMULA 23401318 A 900 908 Cu oxide SYSTEMATIC 23401318 A 969 971 Si FORMULA 23401318 T 8 20 Copper Oxide SYSTEMATIC 23401360 A 12 24 carbohydrate FAMILY 23401360 A 184 196 Carbohydrate FAMILY 23401360 A 523 535 carbohydrate FAMILY 23401360 A 573 587 β-galactosides FAMILY 23401360 T 8 20 Carbohydrate FAMILY 23401373 A 1046 1049 CB7 ABBREVIATION 23401373 A 1050 1053 CPT ABBREVIATION 23401373 A 1082 1100 quinoline nitrogen SYSTEMATIC 23401373 A 1104 1107 CPT ABBREVIATION 23401373 A 1145 1148 CB7 ABBREVIATION 23401373 A 1202 1205 CB7 ABBREVIATION 23401373 A 1281 1289 carbonyl FAMILY 23401373 A 131 146 cucurbit[7]uril TRIVIAL 23401373 A 1344 1347 CPT ABBREVIATION 23401373 A 1458 1462 NaCl FORMULA 23401373 A 148 151 CB7 ABBREVIATION 23401373 A 325 328 CB7 ABBREVIATION 23401373 A 329 332 CPT ABBREVIATION 23401373 A 400 403 CPT ABBREVIATION 23401373 A 565 568 CPT ABBREVIATION 23401373 A 593 607 β-cyclodextrin TRIVIAL 23401373 A 61 79 20(S)-camptothecin SYSTEMATIC 23401373 A 667 670 CB7 ABBREVIATION 23401373 A 710 718 carbonyl FAMILY 23401373 A 730 733 CB7 ABBREVIATION 23401373 A 81 84 CPT ABBREVIATION 23401373 A 954 957 CPT ABBREVIATION 23401373 T 65 77 camptothecin TRIVIAL 23401471 A 1404 1416 ketoconazole TRIVIAL 23401471 A 1669 1674 E2074 IDENTIFIER 23401471 A 287 292 E2074 IDENTIFIER 23401471 A 294 424 2-[(2R)-2-fluoro-3-{(3r)-[(3-fluorobenzyl)oxy]-8-azabicyclo[3.2.1]oct-8-yl}propyl]-4,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one SYSTEMATIC 23401471 A 435 441 sodium SYSTEMATIC 23401471 T 69 74 e2074 IDENTIFIER 23401471 T 84 90 sodium SYSTEMATIC 23401473 A 1056 1065 silybin B TRIVIAL 23401473 A 1122 1134 silychristin TRIVIAL 23401473 A 1213 1222 silybin A TRIVIAL 23401473 A 1228 1237 silybin B TRIVIAL 23401473 A 1285 1310 estradiol-17β-glucuronide SYSTEMATIC 23401473 A 1315 1327 rosuvastatin TRIVIAL 23401473 A 1637 1651 flavonolignans FAMILY 23401473 A 1797 1810 flavonolignan FAMILY 23401473 A 488 502 flavonolignans FAMILY 23401473 A 694 719 estradiol-17β-glucuronide SYSTEMATIC 23401473 A 748 765 estrone-3-sulfate SYSTEMATIC 23401473 A 813 827 flavonolignans FAMILY 23401473 A 994 1003 silybin A TRIVIAL 23401473 T 25 39 flavonolignans FAMILY 23402278 A 1038 1047 thiolates FAMILY 23402278 A 1049 1056 cyanide SYSTEMATIC 23402278 A 1062 1069 hydride SYSTEMATIC 23402278 A 1107 1112 nitro SYSTEMATIC 23402278 A 1168 1175 nitroso SYSTEMATIC 23402278 A 1251 1257 carbon SYSTEMATIC 23402278 A 1484 1497 nitroaromatic FAMILY 23402278 A 1526 1545 cysteine thiol(ate) SYSTEMATIC 23402278 A 1551 1558 hydride SYSTEMATIC 23402278 A 1627 1632 nitro SYSTEMATIC 23402278 A 1695 1702 nitroso SYSTEMATIC 23402278 A 183 196 Nitroaromatic FAMILY 23402278 A 218 241 1,3-benzothiazin-4-ones SYSTEMATIC 23402278 A 243 247 BTZs ABBREVIATION 23402278 A 348 355 nitroso SYSTEMATIC 23402278 A 373 377 BTZs ABBREVIATION 23402278 A 433 464 decaprenylphosphoryl-β-D-ribose SYSTEMATIC 23402278 A 618 622 BTZs ABBREVIATION 23402278 A 633 646 nitroaromatic FAMILY 23402278 A 722 729 carbons FAMILY 23402278 A 733 739 BTZ043 IDENTIFIER 23402278 A 752 765 nitroaromatic FAMILY 23402278 A 875 881 BTZ043 IDENTIFIER 23402278 A 901 914 nitroaromatic FAMILY 23402278 T 0 9 Thiolates FAMILY 23402278 T 48 54 BTZ043 IDENTIFIER 23402278 T 74 87 nitroaromatic FAMILY 23402300 A 0 7 Li-O(2) FORMULA 23402300 A 217 226 Li(2)O(2) FORMULA 23402300 A 253 262 Li(2)O(2) FORMULA 23402300 A 318 324 carbon SYSTEMATIC 23402300 A 438 444 K-O(2) FORMULA 23402300 A 473 477 K(+) FORMULA 23402300 A 494 501 O(2)(-) FORMULA 23402300 A 539 544 KO(2) FORMULA 23402300 A 635 639 O(2) FORMULA 23402300 A 640 647 O(2)(-) FORMULA 23402300 A 698 703 KO(2) FORMULA 23402300 A 932 944 metal-oxygen FAMILY 23402300 T 20 29 potassium SYSTEMATIC 23402300 T 30 36 oxygen SYSTEMATIC 23402300 T 54 74 potassium superoxide SYSTEMATIC 23402371 A 1189 1193 CDCF ABBREVIATION 23402371 A 542 545 ATP ABBREVIATION 23402371 A 566 604 5(6)-carboxy-2',7'-dichlorofluorescein SYSTEMATIC 23402371 A 606 610 CDCF ABBREVIATION 23402371 A 676 680 CDCF ABBREVIATION 23402371 A 804 817 benzbromarone TRIVIAL 23402371 A 822 828 MK-571 IDENTIFIER 23402432 A 107 117 meta-amino SYSTEMATIC 23402432 A 1109 1112 C═C FORMULA 23402432 A 1202 1208 m-ABDI ABBREVIATION 23402432 A 1212 1217 CD3CN FORMULA 23402432 A 1231 1236 CH3OH FORMULA 23402432 A 1241 1246 CD3OD FORMULA 23402432 A 1267 1275 hydrogen SYSTEMATIC 23402432 A 1635 1641 m-ABDI ABBREVIATION 23402432 A 1660 1668 carbonyl FAMILY 23402432 A 283 289 m-ABDI ABBREVIATION 23402432 A 293 298 CD3CN FORMULA 23402432 A 300 305 CH3OH FORMULA 23402432 A 311 316 CD3OD FORMULA 23402432 A 350 355 CD3CN FORMULA 23402432 A 466 472 m-ABDI ABBREVIATION 23402432 A 565 570 CH3OH FORMULA 23402432 A 693 699 m-ABDI ABBREVIATION 23402432 A 95 101 m-ABDI ABBREVIATION 23402432 T 11 19 hydrogen SYSTEMATIC 23402432 T 85 95 meta-amino SYSTEMATIC 23402628 A 1087 1101 tertiary amine SYSTEMATIC 23402628 A 217 253 secondary and tertiary linker amides MULTIPLE 23402628 A 23 39 ω-tertiary amine SYSTEMATIC 23402628 A 368 373 amide FAMILY 23402628 A 397 403 quartz TRIVIAL 23402628 A 445 536 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate methanaminium uronium SYSTEMATIC 23402628 A 538 542 HATU ABBREVIATION 23402628 A 55 60 thiol FAMILY 23402628 A 560 577 hydrogen peroxide SYSTEMATIC 23402628 A 647 656 phosphate SYSTEMATIC 23402628 A 716 730 Tertiary amine FAMILY 23402628 A 75 98 tertiary amine N-oxides FAMILY 23402628 A 807 830 tertiary amine N-oxides FAMILY 23402628 A 835 853 triethylene glycol SYSTEMATIC 23402628 A 947 968 dimethylamine N-oxide SYSTEMATIC 23402628 A 983 1004 ethyl secondary amide SYSTEMATIC 23402628 T 13 27 tertiary amine SYSTEMATIC 23402744 A 1047 1053 PCB180 ABBREVIATION 23402744 A 1180 1185 PCB74 ABBREVIATION 23402744 A 1189 1194 PCB95 ABBREVIATION 23402744 A 1285 1290 PCB74 ABBREVIATION 23402744 A 1295 1300 PCB95 ABBREVIATION 23402744 A 1389 1398 saccharin TRIVIAL 23402744 A 1746 1751 PCB52 ABBREVIATION 23402744 A 1781 1787 PCB180 ABBREVIATION 23402744 A 1856 1865 saccharin TRIVIAL 23402744 A 1978 1983 PCB74 ABBREVIATION 23402744 A 2021 2026 PCB95 ABBREVIATION 23402744 A 2037 2046 saccharin TRIVIAL 23402744 A 2205 2209 PCBs ABBREVIATION 23402744 A 2476 2480 PCBs ABBREVIATION 23402744 A 356 381 polychlorinated biphenyls FAMILY 23402744 A 383 387 PCBs ABBREVIATION 23402744 A 670 676 dioxin FAMILY 23402744 A 689 695 dioxin FAMILY 23402744 A 707 711 PCBs ABBREVIATION 23402744 A 744 751 steroid FAMILY 23402744 A 849 853 PCBs ABBREVIATION 23402744 A 983 988 PCB52 ABBREVIATION 23402744 T 117 123 dioxin FAMILY 23402744 T 129 133 PCBs ABBREVIATION 23402856 A 1069 1072 HEP ABBREVIATION 23402856 A 1077 1080 HCB ABBREVIATION 23402856 A 113 116 HCB ABBREVIATION 23402856 A 1131 1134 HEP ABBREVIATION 23402856 A 1139 1142 HCB ABBREVIATION 23402856 A 1291 1305 organochlorine FAMILY 23402856 A 1356 1370 organochlorine FAMILY 23402856 A 204 222 diethylnitrosamine SYSTEMATIC 23402856 A 224 227 DEN ABBREVIATION 23402856 A 311 314 HEP ABBREVIATION 23402856 A 329 332 HCB ABBREVIATION 23402856 A 47 61 organochlorine FAMILY 23402856 A 536 539 HEP ABBREVIATION 23402856 A 544 547 HCB ABBREVIATION 23402856 A 652 663 glutathione TRIVIAL 23402856 A 664 665 S FORMULA 23402856 A 73 83 heptachlor TRIVIAL 23402856 A 803 806 HEP ABBREVIATION 23402856 A 810 813 HCB ABBREVIATION 23402856 A 85 88 HEP ABBREVIATION 23402856 A 853 856 HEP ABBREVIATION 23402856 A 861 864 HCB ABBREVIATION 23402856 A 94 111 hexachlorobenzene SYSTEMATIC 23402856 T 20 34 organochlorine FAMILY 23402856 T 46 56 heptachlor TRIVIAL 23402856 T 61 78 hexachlorobenzene SYSTEMATIC 23402857 A 1281 1288 cadmium SYSTEMATIC 23402857 A 386 393 cadmium SYSTEMATIC 23402857 A 395 397 Cd FORMULA 23402857 A 400 407 arsenic SYSTEMATIC 23402857 A 409 411 As FORMULA 23402857 A 423 425 Pb FORMULA 23402857 A 489 496 Arsenic SYSTEMATIC 23402857 A 640 647 Arsenic SYSTEMATIC 23402857 A 762 769 Cadmium SYSTEMATIC 23402857 A 910 912 Cd FORMULA 23402857 A 931 933 Pb FORMULA 23402857 A 984 986 Pb FORMULA 23402857 A 991 993 Cd FORMULA 23402857 T 14 21 arsenic SYSTEMATIC 23402907 A 0 14 Diacylglycerol FAMILY 23402907 A 1235 1249 diacylglycerol FAMILY 23402907 A 16 19 DAG ABBREVIATION 23402907 A 305 319 diacylglycerol FAMILY 23402907 A 970 973 DAG ABBREVIATION 23402907 T 70 84 diacylglycerol FAMILY 23403015 A 1182 1185 FLT ABBREVIATION 23403015 A 1286 1289 GNP ABBREVIATION 23403015 A 1461 1464 FLT ABBREVIATION 23403015 A 175 182 Genipin TRIVIAL 23403015 A 184 187 GNP ABBREVIATION 23403015 A 550 553 FLT ABBREVIATION 23403015 A 83 92 flutamide TRIVIAL 23403015 A 871 874 GNP ABBREVIATION 23403015 A 94 97 FLT ABBREVIATION 23403015 T 93 102 flutamide TRIVIAL 23403085 A 12 34 mercaptoethylleonurine SYSTEMATIC 23403085 A 142 146 H2O2 FORMULA 23403085 A 375 379 H2O2 FORMULA 23403085 A 39 61 mercaptoethylguanidine SYSTEMATIC 23403085 T 27 49 mercaptoethylleonurine SYSTEMATIC 23403085 T 54 76 mercaptoethylguanidine SYSTEMATIC 23403085 T 88 105 hydrogen peroxide SYSTEMATIC 23403272 A 1053 1065 Paeoniflorin TRIVIAL 23403272 A 1161 1173 Paeoniflorin TRIVIAL 23403272 A 1264 1286 zinc protoporphyrin IX SYSTEMATIC 23403272 A 1288 1292 ZNPP ABBREVIATION 23403272 A 1342 1354 Paeoniflorin TRIVIAL 23403272 A 1435 1447 Paeoniflorin TRIVIAL 23403272 A 172 184 Paeoniflorin TRIVIAL 23403272 A 329 341 Paeoniflorin TRIVIAL 23403272 A 477 489 Paeoniflorin TRIVIAL 23403272 A 664 676 Paeoniflorin TRIVIAL 23403272 A 739 745 oxygen SYSTEMATIC 23403272 A 774 789 malondialdehyde TRIVIAL 23403272 A 791 794 MDA ABBREVIATION 23403272 A 800 807 lactate FAMILY 23403272 A 893 904 glutathione TRIVIAL 23403272 A 906 909 GSH ABBREVIATION 23403272 A 915 925 superoxide TRIVIAL 23403272 A 991 1003 Paeoniflorin TRIVIAL 23403272 T 0 12 Paeoniflorin TRIVIAL 23403272 T 145 149 heme FAMILY 23403471 A 310 317 glucose TRIVIAL 23404064 A 1513 1521 dopamine TRIVIAL 23404064 A 32 40 dopamine TRIVIAL 23404064 A 527 535 dopamine TRIVIAL 23404064 A 553 566 bromocriptine TRIVIAL 23404064 A 994 1007 bromocriptine TRIVIAL 23404093 A 1142 1152 Olanzapine TRIVIAL 23404093 A 1370 1380 gabapentin TRIVIAL 23404093 A 280 289 serotonin TRIVIAL 23404093 A 317 330 dexamethasone TRIVIAL 23404093 A 471 483 Palonosetron TRIVIAL 23404093 A 730 740 Aprepitant TRIVIAL 23404093 A 915 928 dexamethasone TRIVIAL 23404093 A 946 956 Rolapitant TRIVIAL 23404093 A 961 971 netupitant TRIVIAL 23404373 A 1083 1090 Nitroso SYSTEMATIC 23404373 A 1091 1096 oxime SYSTEMATIC 23404373 A 1133 1144 alkylamines FAMILY 23404373 A 1218 1219 N FORMULA 23404373 A 1234 1235 N FORMULA 23404373 A 1272 1293 primary hydroxylamine SYSTEMATIC 23404373 A 1310 1311 N FORMULA 23404373 A 1358 1365 nitrone SYSTEMATIC 23404373 A 1378 1379 N FORMULA 23404373 A 1394 1417 secondary hydroxylamine SYSTEMATIC 23404373 A 1454 1477 secondary hydroxylamine SYSTEMATIC 23404373 A 1516 1517 N FORMULA 23404373 A 1518 1531 hydroxylamine SYSTEMATIC 23404373 A 1552 1573 primary hydroxylamine SYSTEMATIC 23404373 A 1629 1638 lapatinib TRIVIAL 23404373 A 166 176 alkylamine FAMILY 23404373 A 1692 1699 nitroso SYSTEMATIC 23404373 A 1730 1753 secondary hydroxylamine SYSTEMATIC 23404373 A 1758 1765 nitrone SYSTEMATIC 23404373 A 1790 1791 N FORMULA 23404373 A 1812 1825 primary amine FAMILY 23404373 A 1838 1839 N FORMULA 23404373 A 268 275 ferrous SYSTEMATIC 23404373 A 276 280 heme FAMILY 23404373 A 281 285 iron SYSTEMATIC 23404373 A 380 387 ferrous SYSTEMATIC 23404373 A 388 392 iron SYSTEMATIC 23404373 A 503 507 heme FAMILY 23404373 A 508 512 iron SYSTEMATIC 23404373 A 528 550 potassium ferricyanide SYSTEMATIC 23404373 A 646 666 secondary alkylamine FAMILY 23404373 A 672 681 lapatinib TRIVIAL 23404373 A 711 720 lapatinib TRIVIAL 23404373 A 765 766 C FORMULA 23404373 A 782 783 N FORMULA 23404373 A 939 940 N FORMULA 23404373 A 953 960 nitroso SYSTEMATIC 23404373 A 961 966 oxime SYSTEMATIC 23404373 A 967 976 lapatinib TRIVIAL 23404373 T 122 129 Nitroso SYSTEMATIC 23404373 T 130 135 Oxime SYSTEMATIC 23404373 T 160 167 Nitrone SYSTEMATIC 23404373 T 45 54 Lapatinib TRIVIAL 23404680 A 0 11 Bisphenol A TRIVIAL 23404680 A 13 16 BPA ABBREVIATION 23404680 A 1589 1592 BPA ABBREVIATION 23404680 A 398 401 BPA ABBREVIATION 23404680 A 618 621 BPA ABBREVIATION 23404680 A 641 644 BPA ABBREVIATION 23404680 A 926 929 BPA ABBREVIATION 23404680 A 938 946 sulphate SYSTEMATIC 23404680 T 11 14 UDP ABBREVIATION 23404680 T 59 70 bisphenol A TRIVIAL 23404692 A 946 964 lambda-cyhalothrin TRIVIAL 23405013 A 158 166 tyrosine TRIVIAL 23405013 A 355 361 serine TRIVIAL 23405013 A 367 368 C FORMULA 23405013 A 468 471 Ser FORMULA 23405013 A 484 485 C FORMULA 23405013 A 618 621 Ser FORMULA 23405013 A 651 654 Ser FORMULA 23405013 A 663 670 alanine TRIVIAL 23405013 A 704 712 tyrosine TRIVIAL 23405013 A 848 851 Ser FORMULA 23405013 A 924 932 tyrosine TRIVIAL 23405013 A 977 980 Ser FORMULA 23405013 T 71 74 Ser FORMULA 23405965 A 246 256 indolizine SYSTEMATIC 23405965 T 0 10 Indolizine SYSTEMATIC 23405984 A 1014 1017 Pro FORMULA 23405984 A 161 170 disulfide SYSTEMATIC 23405984 A 198 250 cyclo S(1) ,S(9) Cys-Glu-Thr-Gly-Ala-Lys-Pro-His-Cys FORMULA 23405984 A 790 795 (1) H FORMULA 23405984 A 797 803 (13) C FORMULA 23405984 A 808 814 (15) N FORMULA 23405988 A 149 184 sodium dodecyl 6-benezene sulfonate SYSTEMATIC 23405988 A 186 191 LAS-6 ABBREVIATION 23405988 A 37 51 phenyl ethanol SYSTEMATIC 23405988 A 398 403 LAS-6 ABBREVIATION 23405988 A 61 69 linalool TRIVIAL 23405988 A 835 838 LAS ABBREVIATION 23405988 A 868 873 LAS-6 ABBREVIATION 23405988 A 908 913 LAS-4 SYSTEMATIC 23406025 A 1000 1017 hydrogen peroxide SYSTEMATIC 23406025 A 1019 1022 HPO ABBREVIATION 23406025 A 1085 1092 Fe (II) FORMULA 23406025 A 1159 1167 Fe (III) FORMULA 23406025 A 1249 1252 HPO ABBREVIATION 23406025 A 1326 1329 HPO ABBREVIATION 23406025 A 57 68 gallic acid TRIVIAL 23406025 A 640 646 oxygen SYSTEMATIC 23406025 A 670 681 semiquinone FAMILY 23406025 A 686 693 quinone FAMILY 23406025 A 727 733 oxygen SYSTEMATIC 23406025 A 788 794 Fe(2+) FORMULA 23406025 A 838 851 polyphenolics FAMILY 23406025 A 983 990 Fe (II) FORMULA 23406025 T 83 94 gallic acid TRIVIAL 23406025 T 9 22 polyphenolics FAMILY 23406315 A 1073 1074 N FORMULA 23406315 A 1080 1081 C FORMULA 23406315 A 166 175 methionyl TRIVIAL 23406315 A 217 220 Met FORMULA 23406315 A 231 246 azidonorleucine SYSTEMATIC 23406315 A 248 251 Anl ABBREVIATION 23406315 A 261 264 Met FORMULA 23406315 A 377 378 N FORMULA 23406315 A 384 385 C FORMULA 23406315 A 428 431 Anl ABBREVIATION 23406315 A 517 523 copper SYSTEMATIC 23406315 A 641 644 Anl ABBREVIATION 23406416 A 536 539 Tyr FORMULA 23406416 A 562 565 Tyr FORMULA 23406416 A 623 626 Tyr FORMULA 23406416 A 635 638 Phe FORMULA 23406484 A 1080 1090 tazobactam TRIVIAL 23406484 A 349 359 tazobactam TRIVIAL 23406484 A 506 516 isopentane SYSTEMATIC 23406484 A 547 555 nitrogen SYSTEMATIC 23406484 A 749 762 trans-enamine SYSTEMATIC 23406484 A 832 837 imine SYSTEMATIC 23406484 A 899 906 enamine SYSTEMATIC 23406484 A 947 953 imines FAMILY 23406484 A 980 988 enamines FAMILY 23406524 A 429 440 amino acids FAMILY 23406524 A 539 544 amino FAMILY 23406524 A 545 550 epoxy SYSTEMATIC 23406951 A 0 18 Lambda-cyhalothrin TRIVIAL 23406951 A 1012 1014 NO FORMULA 23406951 A 1255 1258 LTC ABBREVIATION 23406951 A 20 23 LTC ABBREVIATION 23406951 A 351 354 LTC ABBREVIATION 23406951 A 40 50 pyrethroid FAMILY 23406951 A 413 419 oxygen SYSTEMATIC 23406951 A 466 473 nitrite SYSTEMATIC 23406951 A 475 477 NO FORMULA 23406951 A 498 506 carbonyl FAMILY 23406951 A 524 539 malondialdehyde TRIVIAL 23406951 A 541 544 MDA ABBREVIATION 23406951 A 645 648 LTC ABBREVIATION 23406951 T 12 30 lambda-cyhalothrin TRIVIAL 23406951 T 44 54 pyrethroid FAMILY 23406951 T 75 81 oxygen SYSTEMATIC 23406956 A 1021 1030 vitamin E FAMILY 23406956 A 1097 1108 cholesterol TRIVIAL 23406956 A 1115 1128 triglycerides FAMILY 23406956 A 1160 1171 cholesterol TRIVIAL 23406956 A 1181 1203 17 beta hydroxysteroid FAMILY 23406956 A 1254 1269 malondialdehyde TRIVIAL 23406956 A 1271 1274 MDA ABBREVIATION 23406956 A 1342 1353 cholesterol TRIVIAL 23406956 A 1369 1381 testosterone TRIVIAL 23406956 A 1397 1408 ketosteroid FAMILY 23406956 A 1435 1440 thiol FAMILY 23406956 A 1445 1456 glutathione TRIVIAL 23406956 A 1457 1458 S FORMULA 23406956 A 1560 1580 l-carnitine TRIVIAL 23406956 A 1588 1597 vitamin E FAMILY 23406956 A 1639 1645 triton FAMILY 23406956 A 1753 1773 l-carnitine TRIVIAL 23406956 A 1778 1787 vitamin E FAMILY 23406956 A 249 258 Vitamin E FAMILY 23406956 A 263 283 l-carnitine TRIVIAL 23406956 A 345 359 Triton WR 1339 FAMILY 23406956 A 510 519 vitamin E FAMILY 23406956 A 524 544 l-carnitine TRIVIAL 23406956 A 656 665 vitamin E FAMILY 23406956 A 667 687 l-carnitine TRIVIAL 23406956 A 818 824 triton FAMILY 23406956 A 833 853 l-carnitine TRIVIAL 23406956 A 862 868 triton FAMILY 23406956 A 871 891 l-carnitine TRIVIAL 23406956 A 900 909 vitamin E FAMILY 23406956 A 918 924 triton FAMILY 23406956 A 927 936 vitamin E FAMILY 23406956 A 945 965 l-carnitine TRIVIAL 23406956 A 968 977 vitamin E FAMILY 23406956 A 989 995 triton FAMILY 23406956 A 998 1018 l-carnitine TRIVIAL 23406956 T 19 30 L-carnitine TRIVIAL 23406956 T 35 44 vitamin E FAMILY 23407584 A 11 19 graphite TRIVIAL 23407584 A 155 163 graphene TRIVIAL 23407584 A 36 44 graphene TRIVIAL 23407584 A 506 514 graphene TRIVIAL 23407584 T 35 43 graphite TRIVIAL 23407584 T 49 57 graphene TRIVIAL 23407783 A 1539 1548 SSR125543 IDENTIFIER 23407783 A 1550 1560 paroxetine TRIVIAL 23407783 A 1565 1578 D-cycloserine TRIVIAL 23407783 A 1652 1661 SSR125543 IDENTIFIER 23407783 A 479 488 SSR125543 IDENTIFIER 23407783 A 645 654 SSR125543 IDENTIFIER 23407783 A 685 689 5-HT SYSTEMATIC 23407783 A 710 720 paroxetine TRIVIAL 23407783 A 753 773 N-methyl-D-aspartate SYSTEMATIC 23407783 A 775 779 NMDA ABBREVIATION 23407783 A 799 812 D-cycloserine TRIVIAL 23407783 A 92 101 SSR125543 IDENTIFIER 23407783 T 140 150 paroxetine TRIVIAL 23407783 T 155 168 D-cycloserine TRIVIAL 23407783 T 31 40 SSR125543 IDENTIFIER 23408272 A 1009 1028 lup-20(29)-en-3-one SYSTEMATIC 23408272 A 1132 1151 lup-20(29)-en-3-one SYSTEMATIC 23408272 A 1428 1447 lup-20(29)-en-3-one SYSTEMATIC 23408272 A 1828 1841 ethyl acetate SYSTEMATIC 23408272 A 1874 1893 lup-20(29)-en-3-one SYSTEMATIC 23408272 A 284 303 lup-20(29)-en-3-one SYSTEMATIC 23408272 A 466 474 lupenone TRIVIAL 23408272 A 637 650 ethyl acetate SYSTEMATIC 23408272 A 882 895 ethyl acetate SYSTEMATIC 23408272 A 932 951 lup-20(29)-en-3-one SYSTEMATIC 23408272 T 0 8 Lupenone TRIVIAL 23409715 A 274 280 acetyl SYSTEMATIC 23409715 A 293 314 ε-N-acetylated lysine TRIVIAL 23409715 A 711 715 zinc SYSTEMATIC 23409715 A 814 824 amino acid FAMILY 23409721 A 46 49 ATP ABBREVIATION 23409919 A 14 24 moissanite TRIVIAL 23409919 A 74 89 ammonium iodide SYSTEMATIC 23409919 T 48 63 ammonium iodide SYSTEMATIC 23410043 A 143 156 6-Iodouridine SYSTEMATIC 23410043 A 195 221 orotidine 5'-monophosphate SYSTEMATIC 23410043 A 523 530 Uridine TRIVIAL 23410043 A 722 733 artemisinin TRIVIAL 23410043 A 738 750 azithromycin TRIVIAL 23410043 A 756 771 propionyl ester SYSTEMATIC 23410043 T 27 40 6-iodouridine SYSTEMATIC 23410068 A 101 113 acetonitrile SYSTEMATIC 23410068 A 115 118 ACN ABBREVIATION 23410068 A 130 135 HClO4 FORMULA 23410068 A 203 206 ACN ABBREVIATION 23410068 A 27 34 Au(111) FORMULA 23410068 A 432 452 4,4'-dibromobiphenyl SYSTEMATIC 23410068 A 50 91 4-bromobenzenediazonium tetrafluoroborate SYSTEMATIC 23410068 A 563 571 biphenyl SYSTEMATIC 23410068 A 93 96 BBD ABBREVIATION 23410068 T 19 28 diazonium SYSTEMATIC 23410068 T 38 45 Au(111) FORMULA 23410126 A 32 39 steroid FAMILY 23410126 A 372 380 androgen FAMILY 23410126 A 4 12 androgen FAMILY 23410126 A 762 770 androgen FAMILY 23410126 T 35 43 androgen FAMILY 23410129 A 734 742 androgen FAMILY 23410153 A 1036 1042 serine TRIVIAL 23410153 A 1043 1052 threonine TRIVIAL 23410153 A 1267 1270 ATP ABBREVIATION 23410153 A 195 201 serine TRIVIAL 23410153 A 202 211 threonine TRIVIAL 23410153 A 389 397 tyrosine TRIVIAL 23410161 A 1048 1060 rivastigmine TRIVIAL 23410161 A 1070 1079 monoamine FAMILY 23410161 A 1108 1118 rasagiline TRIVIAL 23410161 A 1297 1305 stilbene TRIVIAL 23410161 A 1394 1403 flavonoid FAMILY 23410161 A 1420 1431 resveratrol TRIVIAL 23410161 A 1443 1451 stilbene TRIVIAL 23410161 A 1698 1706 stilbene TRIVIAL 23410161 A 1816 1824 xanthine TRIVIAL 23410161 A 1917 1926 adenosine TRIVIAL 23410161 A 529 536 calcium SYSTEMATIC 23410161 A 555 559 NMDA ABBREVIATION 23410161 A 712 729 thiazolidinedione FAMILY 23410161 A 753 763 glitazones FAMILY 23410161 A 960 970 ladostigil TRIVIAL 23410191 A 1131 1143 acetonitrile SYSTEMATIC 23410191 A 127 137 Avobenzone TRIVIAL 23410191 A 142 154 acetonitrile SYSTEMATIC 23410191 A 221 225 keto SYSTEMATIC 23410191 A 266 270 enol SYSTEMATIC 23410191 A 279 291 acetonitrile SYSTEMATIC 23410191 A 353 357 keto SYSTEMATIC 23410191 A 409 413 keto SYSTEMATIC 23410191 A 421 425 enol SYSTEMATIC 23410191 A 475 479 keto SYSTEMATIC 23410191 A 51 55 enol SYSTEMATIC 23410191 A 549 553 keto SYSTEMATIC 23410191 A 60 64 keto SYSTEMATIC 23410191 A 600 604 enol SYSTEMATIC 23410191 A 664 676 acetonitrile SYSTEMATIC 23410191 A 716 724 alcohols FAMILY 23410191 A 74 113 4-tert-butyl-4'-methoxydibenzoylmethane SYSTEMATIC 23410191 A 919 923 keto SYSTEMATIC 23410191 A 931 935 enol SYSTEMATIC 23410191 T 48 87 4-tert-butyl-4'-methoxydibenzoylmethane SYSTEMATIC 23410191 T 92 104 acetonitrile SYSTEMATIC 23410221 A 1043 1051 ethephon TRIVIAL 23410221 A 1097 1118 cyclic oxaphosphetane SYSTEMATIC 23410221 A 1166 1191 2-hydroxyethylphosphonate SYSTEMATIC 23410221 A 1210 1213 Ser FORMULA 23410221 A 1240 1248 ethephon TRIVIAL 23410221 A 1264 1272 ethylene SYSTEMATIC 23410221 A 158 164 serine TRIVIAL 23410221 A 212 220 ethephon TRIVIAL 23410221 A 262 270 ethephon TRIVIAL 23410221 A 27 35 ethephon TRIVIAL 23410221 A 37 65 2-chloroethylphosphonic acid SYSTEMATIC 23410221 A 445 453 ethephon TRIVIAL 23410221 A 548 556 ethephon TRIVIAL 23410221 A 611 619 ethephon TRIVIAL 23410221 A 793 799 serine TRIVIAL 23410221 A 874 882 ethephon TRIVIAL 23410221 A 888 892 HPO3 FORMULA 23410221 T 41 49 ethephon TRIVIAL 23410250 A 1019 1026 glucose TRIVIAL 23410250 A 1086 1103 pentose phosphate FAMILY 23410250 A 1115 1134 6-aminonicotinamide SYSTEMATIC 23410250 A 1224 1232 pyruvate TRIVIAL 23410250 A 205 211 oxygen SYSTEMATIC 23410250 A 857 860 TCA ABBREVIATION 23410250 A 934 941 cyanide SYSTEMATIC 23410250 A 978 987 galactose TRIVIAL 23410538 A 1159 1167 nicotine TRIVIAL 23410538 A 133 141 nicotine TRIVIAL 23410538 A 1403 1411 nicotine TRIVIAL 23410538 A 1643 1651 nicotine TRIVIAL 23410538 A 2053 2061 nicotine TRIVIAL 23410538 A 2221 2229 nicotine TRIVIAL 23410538 A 282 290 nicotine TRIVIAL 23410538 A 642 650 nicotine TRIVIAL 23410538 A 930 938 nicotine TRIVIAL 23410538 T 36 44 nicotine TRIVIAL 23410587 A 275 282 cadmium SYSTEMATIC 23410587 A 38 45 cadmium SYSTEMATIC 23410587 T 33 40 cadmium SYSTEMATIC 23410589 A 1211 1230 hexavalent chromium SYSTEMATIC 23410589 A 1235 1241 nickel SYSTEMATIC 23410589 A 293 299 oxygen SYSTEMATIC 23410589 A 332 347 malondialdehyde TRIVIAL 23410589 A 349 352 MDA ABBREVIATION 23410589 A 430 450 potassium dichromate SYSTEMATIC 23410589 A 605 620 nickel chloride SYSTEMATIC 23410589 A 67 87 potassium dichromate SYSTEMATIC 23410589 A 778 781 MDA ABBREVIATION 23410589 A 881 888 Cr (VI) FORMULA 23410589 A 893 900 Ni (II) FORMULA 23410589 A 95 110 nickel chloride SYSTEMATIC 23410589 T 115 121 nickel SYSTEMATIC 23410589 T 91 110 hexavalent chromium SYSTEMATIC 23410798 A 172 174 Pd FORMULA 23410798 A 175 179 C-Cu FORMULA 23410798 A 259 327 1-(prop-2-ynyl)-1'H-spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione SYSTEMATIC 23410798 A 333 347 2-iodoanilides FAMILY 23410798 A 582 589 benzene SYSTEMATIC 23410798 A 598 626 1,2,3,4-tetrahydroquinazolin SYSTEMATIC 23410798 A 6 65 N-indolylmethyl substituted spiroindoline-3,2'-quinazolines FAMILY 23410798 A 725 727 NH FORMULA 23410798 A 743 751 sulfonyl SYSTEMATIC 23410798 A 781 782 H FORMULA 23410798 A 812 822 amino acid FAMILY 23410798 T 53 55 Pd FORMULA 23410798 T 56 57 C FORMULA 23410798 T 86 133 N-indolylmethyl spiroindoline-3,2'-quinazolines FAMILY 23410960 A 1033 1044 salinomycin TRIVIAL 23410960 A 1128 1139 salinomycin TRIVIAL 23410960 A 1309 1320 salinomycin TRIVIAL 23410960 A 194 205 salinomycin TRIVIAL 23410960 A 281 292 salinomycin TRIVIAL 23410960 A 345 356 salinomycin TRIVIAL 23410960 A 459 468 Oil Red O TRIVIAL 23410960 A 514 525 salinomycin TRIVIAL 23410960 A 549 610 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide SYSTEMATIC 23410960 A 613 616 MTT ABBREVIATION 23410960 A 799 810 salinomycin TRIVIAL 23410960 T 11 22 salinomycin TRIVIAL 23411170 A 1002 1014 trimethoprim TRIVIAL 23411170 A 1050 1063 sulphadiazine TRIVIAL 23411170 A 1068 1080 trimethoprim TRIVIAL 23411170 A 114 126 trimethoprim TRIVIAL 23411170 A 697 710 sulphadiazine TRIVIAL 23411170 A 715 727 trimethoprim TRIVIAL 23411170 A 810 822 Triton X-100 TRIVIAL 23411170 A 96 109 sulphadiazine TRIVIAL 23411170 A 984 997 sulphadiazine TRIVIAL 23411170 T 78 91 sulphadiazine TRIVIAL 23411170 T 96 108 trimethoprim TRIVIAL 23411171 A 360 362 NO FORMULA 23411171 A 560 570 superoxide TRIVIAL 23411171 A 592 603 glutathione TRIVIAL 23411171 A 672 683 acetic acid SYSTEMATIC 23411171 A 715 723 formalin TRIVIAL 23411172 A 34 45 procyanidin FAMILY 23411172 A 395 406 procyanidin FAMILY 23411172 A 6 16 polyphenol FAMILY 23411172 A 846 857 procyanidin FAMILY 23411172 A 937 948 polyphenols FAMILY 23411172 T 6 17 polyphenols FAMILY 23411174 A 25 27 Cd FORMULA 23411174 A 29 31 Cr FORMULA 23411174 A 33 35 Cu FORMULA 23411174 A 37 39 Fe FORMULA 23411174 A 41 43 Mn FORMULA 23411174 A 45 47 Ni FORMULA 23411174 A 49 51 Pb FORMULA 23411174 A 553 555 Cr FORMULA 23411174 A 56 58 Zn FORMULA 23411174 A 569 571 Cu FORMULA 23411174 A 585 587 Fe FORMULA 23411174 A 602 604 Mn FORMULA 23411174 A 618 620 Ni FORMULA 23411174 A 634 636 Pb FORMULA 23411174 A 653 655 Zn FORMULA 23411176 A 184 190 sugars FAMILY 23411176 A 197 202 sugar FAMILY 23411176 A 47 55 fructose TRIVIAL 23411176 A 741 748 glucose TRIVIAL 23411176 T 114 122 fructose TRIVIAL 23411179 A 24 34 polyphenol FAMILY 23411179 A 536 547 polyphenols FAMILY 23411187 A 1109 1119 flavonoids FAMILY 23411187 A 1121 1122 K FORMULA 23411187 A 1128 1129 P FORMULA 23411187 A 293 305 carbohydrate FAMILY 23411187 A 782 791 flavonoid FAMILY 23411187 A 875 885 flavonoids FAMILY 23411187 A 911 918 phenols FAMILY 23411190 A 511 526 pseudohypericin TRIVIAL 23411190 A 550 559 hypericin TRIVIAL 23411190 A 604 620 chlorogenic acid TRIVIAL 23411190 A 671 681 Hyperforin TRIVIAL 23411190 A 726 738 adhyperforin TRIVIAL 23411190 A 774 783 Hypericin TRIVIAL 23411190 A 788 803 pseudohypericin TRIVIAL 23411190 A 844 854 hyperforin TRIVIAL 23411190 A 856 868 adhyperforin TRIVIAL 23411190 A 874 890 chlorogenic acid TRIVIAL 23411207 A 1016 1020 DPPH ABBREVIATION 23411207 A 202 209 acetone SYSTEMATIC 23411207 A 319 332 Linoleic acid TRIVIAL 23411207 A 400 412 α-tocopherol TRIVIAL 23411207 A 464 468 DPPH ABBREVIATION 23411207 A 723 735 nitric oxide SYSTEMATIC 23411207 A 782 794 Nitric oxide SYSTEMATIC 23411207 A 796 798 NO FORMULA 23411207 A 804 820 prostaglandin E2 TRIVIAL 23411207 A 822 828 PGE(2) ABBREVIATION 23411207 A 962 971 phenolics FAMILY 23411218 A 1208 1213 amino FAMILY 23411218 A 1387 1392 amino FAMILY 23411221 A 140 146 niacin TRIVIAL 23411221 A 216 233 nicotinamide-d(4) SYSTEMATIC 23411221 A 394 408 nicotinic acid TRIVIAL 23411221 A 413 432 nicotinic acid-d(4) SYSTEMATIC 23411221 A 534 546 nicotinamide TRIVIAL 23411221 A 564 576 nicotinamide TRIVIAL 23411221 A 581 598 nicotinamide-d(4) SYSTEMATIC 23411221 A 870 876 niacin TRIVIAL 23411221 T 81 87 niacin TRIVIAL 23411222 A 135 138 LMN ABBREVIATION 23411222 A 376 383 HMG-CoA ABBREVIATION 23411222 A 45 57 thymoquinone TRIVIAL 23411222 A 67 75 limonene TRIVIAL 23411222 A 736 751 malondialdehyde TRIVIAL 23411222 A 77 80 LMN ABBREVIATION 23411222 A 824 827 LMN ABBREVIATION 23411222 T 44 56 thymoquinone TRIVIAL 23411222 T 61 69 limonene TRIVIAL 23411225 A 180 186 sodium SYSTEMATIC 23411225 A 453 466 hydroperoxide FAMILY 23411225 A 471 482 p-Anisidine TRIVIAL 23411225 A 545 558 hydroperoxide FAMILY 23411225 A 563 574 p-Anisidine TRIVIAL 23411225 A 618 624 sodium SYSTEMATIC 23411225 T 11 17 sodium SYSTEMATIC 23411226 A 0 16 Proanthocyanidin FAMILY 23411226 A 1135 1152 proanthocyanidins FAMILY 23411226 A 208 225 proanthocyanidins FAMILY 23411226 A 475 483 phenolic FAMILY 23411226 A 528 545 proanthocyanidins FAMILY 23411226 A 547 561 phenolic acids FAMILY 23411226 A 566 577 γ-oryzanols FAMILY 23411226 A 579 591 ferulic acid TRIVIAL 23411226 A 606 623 Proanthocyanidins FAMILY 23411226 A 817 828 amino acids FAMILY 23411226 A 867 876 vitamin E FAMILY 23411226 A 878 889 tocopherols FAMILY 23411226 A 894 906 tocotrienols FAMILY 23411226 A 984 993 phenolics FAMILY 23411226 T 98 115 proanthocyanidins FAMILY 23411228 A 1026 1029 HTy ABBREVIATION 23411228 A 111 114 HTy ABBREVIATION 23411228 A 252 255 HTy ABBREVIATION 23411228 A 259 265 HTy-Et FORMULA 23411228 A 33 59 hydroxytyrosyl ethyl ether SYSTEMATIC 23411228 A 392 395 HTy ABBREVIATION 23411228 A 400 406 HTy-Et FORMULA 23411228 A 541 544 HTy ABBREVIATION 23411228 A 549 555 HTy-Et FORMULA 23411228 A 61 67 HTy-Et FORMULA 23411228 A 744 755 polyphenols FAMILY 23411228 A 902 905 HTy ABBREVIATION 23411228 A 925 931 HTy-Et FORMULA 23411228 A 95 109 hydroxytyrosol SYSTEMATIC 23411228 A 993 999 HTy-Et FORMULA 23411228 T 0 26 Hydroxytyrosyl ethyl ether SYSTEMATIC 23411228 T 128 142 hydroxytyrosol SYSTEMATIC 23411237 A 0 15 Ethyl carbamate SYSTEMATIC 23411237 A 358 368 xanthydrol TRIVIAL 23411237 T 17 32 ethyl carbamate SYSTEMATIC 23411237 T 58 64 copper SYSTEMATIC 23411242 A 123 130 glucose TRIVIAL 23411242 A 474 481 glucose TRIVIAL 23411242 A 899 907 hydrogen SYSTEMATIC 23411243 A 209 215 tannin FAMILY 23411243 A 468 475 phenols FAMILY 23411243 A 59 67 phenolic FAMILY 23411243 A 626 637 flavan-3-ol FAMILY 23411243 A 642 658 polymeric phenol FAMILY 23411243 A 660 666 tannin FAMILY 23411243 T 91 99 phenolic FAMILY 23411246 A 220 224 iron SYSTEMATIC 23411246 A 266 270 zinc SYSTEMATIC 23411246 A 323 327 zinc SYSTEMATIC 23411246 A 496 509 iron sulphate SYSTEMATIC 23411246 A 565 569 zinc SYSTEMATIC 23411246 A 648 652 zinc SYSTEMATIC 23411246 A 745 758 zinc sulphate SYSTEMATIC 23411246 T 0 4 Iron SYSTEMATIC 23411246 T 9 13 zinc SYSTEMATIC 23411247 A 1051 1058 calcium SYSTEMATIC 23411247 A 185 189 Urea TRIVIAL 23411247 A 190 204 polyacrylamide SYSTEMATIC 23411247 A 875 882 CaCl(2) FORMULA 23411254 A 265 268 ETU ABBREVIATION 23411254 A 295 307 acetonitrile SYSTEMATIC 23411254 A 322 333 NH(3).H(2)0 FORMULA 23411254 A 65 81 ethylenethiourea SYSTEMATIC 23411254 A 83 86 ETU ABBREVIATION 23411254 A 848 851 ETU ABBREVIATION 23411254 A 924 927 ETU ABBREVIATION 23411254 T 33 49 ethylenethiourea SYSTEMATIC 23411256 A 301 304 His FORMULA 23411256 A 322 325 Glu FORMULA 23411256 A 349 352 Glu FORMULA 23411256 T 35 45 amino acid FAMILY 23411258 A 0 11 Secoiridoid FAMILY 23411258 A 255 266 dialdehydic SYSTEMATIC 23411258 A 275 304 decarboxymethyl elenolic acid SYSTEMATIC 23411258 A 315 329 hydroxytyrosol SYSTEMATIC 23411258 A 331 344 3,4-DHPEA-EDA SYSTEMATIC 23411258 A 471 484 3,4-DHPEA-EDA SYSTEMATIC 23411258 A 708 719 fatty acids FAMILY 23411258 T 20 33 3,4-DHPEA-EDA SYSTEMATIC 23411261 A 145 153 nitrogen SYSTEMATIC 23411261 A 273 281 nitrogen SYSTEMATIC 23411261 A 297 301 urea TRIVIAL 23411261 A 324 328 urea TRIVIAL 23411261 A 385 389 urea TRIVIAL 23411261 A 444 448 urea TRIVIAL 23411261 A 651 655 urea TRIVIAL 23411261 A 672 680 Geraniol TRIVIAL 23411261 A 682 690 geranial TRIVIAL 23411261 A 696 711 geranyl acetate SYSTEMATIC 23411261 A 804 808 urea TRIVIAL 23411261 A 844 852 geraniol TRIVIAL 23411261 A 857 865 geranial TRIVIAL 23411261 A 923 938 geranyl acetate SYSTEMATIC 23411261 A 989 993 urea TRIVIAL 23411261 T 26 30 urea TRIVIAL 23411262 A 420 424 NaCl FORMULA 23411262 A 528 536 mannitol TRIVIAL 23411262 A 619 623 NaCl FORMULA 23411262 A 690 694 NaCl FORMULA 23411264 A 149 156 trypsin TRIVIAL 23411264 A 546 553 α-amino SYSTEMATIC 23411267 A 154 162 Glycerol TRIVIAL 23411267 A 241 249 glycerol TRIVIAL 23411267 A 344 352 glycerol TRIVIAL 23411267 A 717 727 amino acid FAMILY 23411276 A 150 180 (-)-epigallocatechin-3-gallate TRIVIAL 23411276 A 60 80 vitexin-2-O-xyloside SYSTEMATIC 23411276 A 611 627 poly(ADP-ribose) SYSTEMATIC 23411276 A 659 665 Oxygen SYSTEMATIC 23411276 A 86 96 raphasatin TRIVIAL 23411276 A 98 141 4-methylsulphanyl-3-butenyl isothiocyanates FAMILY 23411276 T 0 20 Vitexin-2-O-xyloside SYSTEMATIC 23411276 T 22 32 raphasatin TRIVIAL 23411276 T 37 67 (-)-epigallocatechin-3-gallate TRIVIAL 23411278 A 1006 1020 phenolic acids FAMILY 23411278 A 303 318 (-)-epicatechin SYSTEMATIC 23411278 A 320 338 A-type procyanidin FAMILY 23411278 A 44 56 procyanidins FAMILY 23411278 A 453 465 procyanidins FAMILY 23411278 A 710 725 (-)-epicatechin SYSTEMATIC 23411278 T 36 54 A-type procyanidin FAMILY 23411279 A 245 252 acetone SYSTEMATIC 23411279 A 263 270 ethanol SYSTEMATIC 23411279 A 332 340 phenolic FAMILY 23411279 A 351 358 Acetone SYSTEMATIC 23411279 A 381 388 tannins FAMILY 23411279 A 522 526 DPPH ABBREVIATION 23411279 A 531 537 oxygen SYSTEMATIC 23411279 A 589 596 ethanol SYSTEMATIC 23411279 T 0 9 Phenolics FAMILY 23411282 A 648 656 phenolic FAMILY 23411282 A 743 751 phenolic FAMILY 23411282 T 37 46 phenolics FAMILY 23411285 A 98 105 lactose TRIVIAL 23411291 A 103 108 sugar FAMILY 23411291 A 163 168 sugar FAMILY 23411291 A 182 190 fructose TRIVIAL 23411291 A 210 217 glucose TRIVIAL 23411291 A 233 243 saccharose TRIVIAL 23411291 A 430 435 sugar FAMILY 23411291 A 488 493 (13)C FORMULA 23411291 A 494 499 (12)C FORMULA 23411291 A 689 694 sugar FAMILY 23411291 A 793 798 sugar FAMILY 23411291 A 812 817 sugar FAMILY 23411291 A 873 878 sugar FAMILY 23411291 A 982 987 sugar FAMILY 23411291 T 57 62 sugar FAMILY 23411291 T 75 78 13C FORMULA 23411291 T 79 82 12C FORMULA 23411292 A 1049 1060 lactic acid TRIVIAL 23411292 A 15 27 polyethylene SYSTEMATIC 23411292 A 35 52 calcium carbonate SYSTEMATIC 23411292 A 351 372 4-hydroxybenzoic acid SYSTEMATIC 23411292 A 377 391 methylene blue TRIVIAL 23411292 A 423 429 TiO(2) FORMULA 23411292 A 54 61 CaCO(3) FORMULA 23411292 A 79 85 TiO(2) FORMULA 23411292 A 870 877 CaCO(3) FORMULA 23411292 A 878 884 TiO(2) FORMULA 23411292 T 10 14 TiO2 FORMULA 23411295 A 369 404 oleic, linoleic, and palmitic acids MULTIPLE 23411295 A 528 563 oleic, linoleic, and palmitic acids MULTIPLE 23411295 A 594 623 stearic and unsaturated acids MULTIPLE 23411295 T 14 24 fatty acid FAMILY 23411298 A 1016 1026 sulfhydryl FAMILY 23411298 A 931 939 peroxide SYSTEMATIC 23411302 A 220 249 2,2-diphenyl-1-picrylhydrazyl SYSTEMATIC 23411302 A 251 255 DPPH ABBREVIATION 23411302 A 510 520 amino acid FAMILY 23411302 A 555 574 Tyr-Pro-Pro-Ala-Lys FORMULA 23411302 A 654 658 DPPH ABBREVIATION 23411302 A 668 676 hydroxyl SYSTEMATIC 23411302 A 690 700 superoxide TRIVIAL 23411302 A 834 847 linoleic acid TRIVIAL 23411302 A 964 974 amino acid FAMILY 23411302 A 985 988 Tyr FORMULA 23411302 A 993 996 Pro FORMULA 23411304 A 1207 1223 5-methylfurfural SYSTEMATIC 23411304 A 1225 1237 1(H)-pyrrole SYSTEMATIC 23411304 A 1239 1255 furfuryl alcohol TRIVIAL 23411304 A 1257 1286 1(H)-pyrrole-2-carboxaldehyde SYSTEMATIC 23411304 A 1288 1309 1-hydroxy-2-propanone SYSTEMATIC 23411304 A 1311 1333 dihydro-2(3H)-furanone SYSTEMATIC 23411304 A 1335 1362 5-methyl-(E)-2-hepten-4-one SYSTEMATIC 23411304 A 1364 1375 acetic acid SYSTEMATIC 23411304 A 1377 1385 pyridine SYSTEMATIC 23411304 A 1387 1395 furfural TRIVIAL 23411304 A 1397 1405 pyrazine SYSTEMATIC 23411304 A 1419 1434 alkyl-pyrazines FAMILY 23411304 A 1492 1508 5-methylfurfural SYSTEMATIC 23411304 A 1509 1529 2,5-dimethylpyrazine SYSTEMATIC 23411304 A 1531 1547 5-methylfurfural SYSTEMATIC 23411304 A 1548 1564 2-methylpyrazine SYSTEMATIC 23411304 A 1566 1586 2,5-dimethylpyrazine SYSTEMATIC 23411304 A 1587 1607 2,3-dimethylpyrazine SYSTEMATIC 23411308 A 0 18 Methionine sulfone SYSTEMATIC 23411308 A 288 308 methionine sulfoxide SYSTEMATIC 23411308 T 45 70 cyclolinopeptides J and K MULTIPLE 23411310 A 0 51 Polychlorinated dibenzo-p-dioxins and dibenzofurans MULTIPLE 23411310 A 102 109 DL-PCBs FAMILY 23411310 A 112 142 polybrominated diphenyl ethers FAMILY 23411310 A 144 149 PBDEs ABBREVIATION 23411310 A 156 173 hexachlorobenzene SYSTEMATIC 23411310 A 175 178 HCB ABBREVIATION 23411310 A 345 352 PCDD/Fs MULTIPLE 23411310 A 396 403 DL-PCBs FAMILY 23411310 A 447 452 PBDEs ABBREVIATION 23411310 A 493 496 HCB ABBREVIATION 23411310 A 53 60 PCDD/Fs MULTIPLE 23411310 A 63 100 dioxin-like polychlorinated biphenyls FAMILY 23411310 A 652 659 PCDD/Fs MULTIPLE 23411310 A 664 671 DL-PCBs FAMILY 23411310 A 782 787 PBDEs ABBREVIATION 23411310 A 940 943 HCB ABBREVIATION 23411310 T 18 25 PCDD/Fs MULTIPLE 23411310 T 27 43 dioxin-like PCBs FAMILY 23411310 T 45 50 PBDEs ABBREVIATION 23411310 T 56 73 hexachlorobenzene SYSTEMATIC 23411313 A 279 287 phenolic FAMILY 23411313 A 312 318 tannin FAMILY 23411313 A 343 354 anthocyanin FAMILY 23411313 T 101 109 phenolic FAMILY 23411319 A 1009 1021 anthocyanins FAMILY 23411319 A 1123 1132 flavonols FAMILY 23411319 A 405 416 anthocyanin FAMILY 23411319 A 421 429 flavonol TRIVIAL 23411319 A 726 735 flavonoid FAMILY 23411319 A 767 779 anthocyanins FAMILY 23411319 A 781 789 malvidin TRIVIAL 23411319 A 791 799 peonidin TRIVIAL 23411319 A 801 810 petunidin TRIVIAL 23411319 A 812 823 delphinidin TRIVIAL 23411319 A 828 836 cyanidin TRIVIAL 23411319 A 861 870 flavonols FAMILY 23411319 A 872 881 quercetin TRIVIAL 23411319 A 883 892 myricetin TRIVIAL 23411319 A 894 904 kaempherol TRIVIAL 23411319 A 906 916 laricitrin TRIVIAL 23411319 A 917 929 isorhamnetin TRIVIAL 23411319 A 934 944 syringetin TRIVIAL 23411319 T 13 23 flavonoids FAMILY 23411325 A 202 213 lanthanides FAMILY 23411325 A 485 496 lanthanides FAMILY 23411325 A 613 623 bentonites FAMILY 23411328 A 520 528 triolein TRIVIAL 23411329 A 0 23 Gamma-aminobutyric acid SYSTEMATIC 23411329 A 109 118 glutamate TRIVIAL 23411329 A 172 176 GABA ABBREVIATION 23411329 A 25 29 GABA ABBREVIATION 23411329 A 298 321 sodium dodecyl sulphate SYSTEMATIC 23411329 A 408 421 glutamic acid TRIVIAL 23411329 A 423 426 Glu FORMULA 23411329 A 48 58 amino acid FAMILY 23411329 A 482 488 Cu(2+) FORMULA 23411329 A 490 496 Fe(3+) FORMULA 23411329 A 498 504 Mg(2+) FORMULA 23411329 A 506 512 Ba(2+) FORMULA 23411329 A 514 528 aminoxyacetate SYSTEMATIC 23411329 A 530 534 EGTA ABBREVIATION 23411329 A 536 545 Na(2)EDTA FORMULA 23411329 A 547 557 l-cysteine TRIVIAL 23411329 A 562 582 beta-mercaptoethanol SYSTEMATIC 23411329 A 605 611 Ca(2+) FORMULA 23411329 A 753 763 amino-acid FAMILY 23411329 T 45 54 glutamate TRIVIAL 23411332 A 109 116 sucrose TRIVIAL 23411332 A 117 125 sorbitol TRIVIAL 23411332 A 133 137 SuSo ABBREVIATION 23411332 A 578 582 SuSo ABBREVIATION 23411338 A 214 230 organophosphorus FAMILY 23411338 A 331 340 omethoate TRIVIAL 23411338 A 342 349 phorate TRIVIAL 23411338 A 351 363 chlorpyrifos TRIVIAL 23411338 A 365 377 methidathion TRIVIAL 23411338 A 379 390 ethoprophos TRIVIAL 23411338 A 562 569 Dicofol TRIVIAL 23411338 A 627 637 pyrethroid FAMILY 23411339 A 1010 1021 anthocyanin FAMILY 23411339 A 1022 1028 ferric SYSTEMATIC 23411339 A 1047 1072 Ascorbic and lactic acids MULTIPLE 23411339 A 1089 1095 ferric SYSTEMATIC 23411339 A 1434 1452 ferric anthocyanin FAMILY 23411339 A 31 49 ferric anthocyanin FAMILY 23411339 A 406 412 ferric SYSTEMATIC 23411339 A 697 703 ferric SYSTEMATIC 23411339 T 40 58 ferric anthocyanin FAMILY 23411341 A 412 420 phenolic FAMILY 23411341 A 559 567 phenolic FAMILY 23411341 A 694 704 oleuropein TRIVIAL 23411341 A 835 845 polyphenol FAMILY 23411341 A 986 994 Phenolic FAMILY 23411341 T 54 62 phenolic FAMILY 23411599 A 1326 1329 PBO ABBREVIATION 23411599 A 519 532 thioacetamide SYSTEMATIC 23411599 A 534 537 TAA ABBREVIATION 23411599 A 540 552 fenbendazole TRIVIAL 23411599 A 558 571 methyleugenol SYSTEMATIC 23411599 A 618 636 piperonyl butoxide SYSTEMATIC 23411599 A 638 641 PBO ABBREVIATION 23411599 A 684 697 acetaminophen TRIVIAL 23411599 A 702 727 α-naphthyl isothiocyanate SYSTEMATIC 23411599 A 870 873 TAA ABBREVIATION 23411599 A 976 979 TAA ABBREVIATION 23411834 A 853 864 polystyrene SYSTEMATIC 23413358 A 1555 1564 Adenosine TRIVIAL 23413358 A 18 27 adenosine TRIVIAL 23413358 T 0 9 Adenosine TRIVIAL 23414067 A 0 38 Chlorocarbonylthio- and isothiocyanate MULTIPLE 23414067 A 1030 1035 argon SYSTEMATIC 23414067 A 1074 1083 ClC(O)SCN FORMULA 23414067 A 1087 1096 ClC(O)NCS FORMULA 23414067 A 109 111 Ar FORMULA 23414067 A 1161 1170 ClC(O)SCN FORMULA 23414067 A 1189 1194 argon SYSTEMATIC 23414067 A 1303 1308 He(I) FORMULA 23414067 A 1335 1344 ClC(O)SCN FORMULA 23414067 A 142 147 (13)C FORMULA 23414067 A 277 280 SCN FORMULA 23414067 A 307 310 C═O FORMULA 23414067 A 367 380 syn-ClC(O)SCN FORMULA 23414067 A 40 49 ClC(O)SCN FORMULA 23414067 A 466 475 ClC(O)SCN FORMULA 23414067 A 54 63 ClC(O)NCS FORMULA 23414067 A 698 707 ClC(O)NCS FORMULA 23414067 A 733 742 ClC(O)NCS FORMULA 23414067 A 925 934 ClC(O)NCS FORMULA 23414067 T 78 87 ClC(O)SCN FORMULA 23414067 T 92 101 ClC(O)NCS FORMULA 23414099 A 113 120 Au(111) FORMULA 23414099 A 214 225 octadecanol SYSTEMATIC 23414099 A 278 289 octadecanol SYSTEMATIC 23414099 A 304 310 BODIPY ABBREVIATION 23414099 A 357 368 octadecanol SYSTEMATIC 23414099 A 42 46 DOPC ABBREVIATION 23414099 A 92 103 octadecanol SYSTEMATIC 23414099 T 35 39 DOPC ABBREVIATION 23414099 T 58 69 octadecanol SYSTEMATIC 23414099 T 78 85 Au(111) FORMULA 23414292 A 1072 1076 DVSF ABBREVIATION 23414292 A 1152 1155 DAD ABBREVIATION 23414292 A 1157 1160 HN2 FORMULA 23414292 A 1166 1169 DEB ABBREVIATION 23414292 A 302 317 divinyl sulfone SYSTEMATIC 23414292 A 319 323 DVSF ABBREVIATION 23414292 A 520 524 DVSF ABBREVIATION 23414292 A 604 634 diethyl acetylenedicarboxylate SYSTEMATIC 23414292 A 636 639 DAD ABBREVIATION 23414292 A 64 73 disulfide SYSTEMATIC 23414292 A 642 657 mechlorethamine TRIVIAL 23414292 A 659 662 HN2 FORMULA 23414292 A 669 690 1,2,3,4-diepoxybutane SYSTEMATIC 23414292 A 692 695 DEB ABBREVIATION 23414292 A 811 815 DVSF ABBREVIATION 23414292 A 820 823 DAD ABBREVIATION 23414292 A 872 875 Cys FORMULA 23414381 A 161 171 amino acid FAMILY 23414381 A 338 348 amino acid FAMILY 23414381 A 34 45 amino acids FAMILY 23414381 A 385 396 amino acids FAMILY 23414381 A 441 451 amino acid FAMILY 23414381 A 598 609 amino acids FAMILY 23414381 A 777 787 amino acid FAMILY 23414381 T 73 84 amino acids FAMILY 23414431 A 1382 1391 n-alcohol FAMILY 23414431 A 621 631 n-acetates FAMILY 23414431 A 633 642 2-ketones FAMILY 23414431 A 644 654 n-nitriles FAMILY 23414431 A 660 670 n-alcohols FAMILY 23414804 A 116 125 histidine TRIVIAL 23414804 A 173 178 ester FAMILY 23414804 A 96 101 ester FAMILY 23414804 T 0 5 Ester SYSTEMATIC 23414804 T 22 31 histidine TRIVIAL 23414837 A 152 199 triazolo and imidazo dihydropyrazolopyrimidines MULTIPLE 23414837 A 222 261 Trifluoromethylcyclohexyl N(1) triazole SYSTEMATIC 23414837 A 24 74 amido and benzimidazole dihydropyrazolopyrimidines MULTIPLE 23414837 T 0 46 Triazolo and imidazo dihydropyrazolopyrimidine MULTIPLE 23414837 T 47 56 potassium SYSTEMATIC 23414838 A 175 228 4-phenyl-1-(quinuclidin-3-ylmethyl)quinolin-2(1H)-one SYSTEMATIC 23414838 A 401 421 4-fluoroquinuclidine SYSTEMATIC 23414838 A 459 471 quinuclidine TRIVIAL 23414838 A 73 82 quinolone FAMILY 23414838 A 96 109 acetylcholine SYSTEMATIC 23414838 T 31 40 quinolone FAMILY 23414838 T 54 67 acetylcholine SYSTEMATIC 23415228 A 714 721 calcium SYSTEMATIC 23415228 A 735 742 calcium SYSTEMATIC 23415228 A 968 975 calcium SYSTEMATIC 23415610 A 1027 1030 CBG ABBREVIATION 23415610 A 1227 1231 DNBS ABBREVIATION 23415610 A 1264 1267 CBG ABBREVIATION 23415610 A 1276 1288 nitric oxide SYSTEMATIC 23415610 A 1344 1354 Rimonabant TRIVIAL 23415610 A 1412 1415 CBG ABBREVIATION 23415610 A 1419 1431 nitric oxide SYSTEMATIC 23415610 A 1450 1458 SR144528 IDENTIFIER 23415610 A 1530 1533 CBG ABBREVIATION 23415610 A 1537 1549 nitric oxide SYSTEMATIC 23415610 A 1577 1580 CBG ABBREVIATION 23415610 A 1616 1628 nitric oxide SYSTEMATIC 23415610 A 1758 1761 CBG ABBREVIATION 23415610 A 260 272 cannabigerol TRIVIAL 23415610 A 274 277 CBG ABBREVIATION 23415610 A 421 450 dinitrobenzene sulphonic acid SYSTEMATIC 23415610 A 452 456 DNBS ABBREVIATION 23415610 A 721 733 nitric oxide SYSTEMATIC 23415610 A 807 811 CuZn FORMULA 23415610 A 812 822 superoxide TRIVIAL 23415610 A 967 979 nitric oxide SYSTEMATIC 23415610 T 60 72 cannabigerol TRIVIAL 23415904 A 0 18 11β-Hydroxysteroid FAMILY 23415904 A 103 110 11-keto SYSTEMATIC 23415904 A 1057 1069 7-oxysterols FAMILY 23415904 A 1178 1183 7βOHC SYSTEMATIC 23415904 A 1228 1242 corticosterone TRIVIAL 23415904 A 1263 1266 7KC SYSTEMATIC 23415904 A 1302 1326 11-dehydrocorticosterone SYSTEMATIC 23415904 A 1356 1368 7-oxysterols FAMILY 23415904 A 1401 1412 cholesterol TRIVIAL 23415904 A 1594 1599 7βOHC SYSTEMATIC 23415904 A 1604 1607 7KC SYSTEMATIC 23415904 A 1632 1635 7KC SYSTEMATIC 23415904 A 1648 1660 7-oxysterols FAMILY 23415904 A 1742 1754 7-oxysterols FAMILY 23415904 A 1824 1838 corticosteroid TRIVIAL 23415904 A 190 224 7β-hydroxy- and 7-keto-cholesterol MULTIPLE 23415904 A 226 231 7βOHC SYSTEMATIC 23415904 A 233 236 7KC SYSTEMATIC 23415904 A 436 439 7KC SYSTEMATIC 23415904 A 444 449 7βOHC SYSTEMATIC 23415904 A 523 533 oxysterols FAMILY 23415904 A 612 615 7KC SYSTEMATIC 23415904 A 620 625 7βOHC SYSTEMATIC 23415904 A 821 824 7KC SYSTEMATIC 23415904 A 825 830 7βOHC SYSTEMATIC 23415904 A 902 905 7KC SYSTEMATIC 23415904 A 906 911 7βOHC SYSTEMATIC 23415904 A 947 952 NADPH ABBREVIATION 23415904 A 996 1014 hexose-6-phosphate SYSTEMATIC 23415904 T 0 18 11β-Hydroxysteroid FAMILY 23415904 T 75 107 7-keto- and 7-hydroxy-oxysterols MULTIPLE 23416002 A 142 152 amino acid FAMILY 23416002 A 161 175 quinazolinones FAMILY 23416002 A 398 408 amino acid FAMILY 23416002 A 417 431 quinazolinones FAMILY 23416002 A 63 73 amino acid FAMILY 23416002 A 82 94 quinazolines FAMILY 23416002 T 0 10 Amino acid FAMILY 23416002 T 19 31 quinazolines FAMILY 23416005 A 224 234 Aza-BODIPY SYSTEMATIC 23416005 A 437 447 aza-BODIPY SYSTEMATIC 23416005 A 645 657 thioflavin T TRIVIAL 23416005 A 705 715 aza-BODIPY SYSTEMATIC 23416005 T 0 10 Aza-BODIPY SYSTEMATIC 23416039 A 1042 1052 lurasidone TRIVIAL 23416039 A 1167 1177 citalopram TRIVIAL 23416039 A 1213 1223 lurasidone TRIVIAL 23416039 A 1357 1367 lurasidone TRIVIAL 23416039 A 1543 1553 lurasidone TRIVIAL 23416039 A 312 321 serotonin TRIVIAL 23416039 A 542 552 Lurasidone TRIVIAL 23416039 A 735 745 lurasidone TRIVIAL 23416039 A 845 855 lurasidone TRIVIAL 23416039 T 11 21 lurasidone TRIVIAL 23416130 A 0 13 Dexamethasone TRIVIAL 23416130 A 15 18 Dex ABBREVIATION 23416130 A 209 212 Dex ABBREVIATION 23416130 A 284 287 Dex ABBREVIATION 23416130 A 366 369 Dex ABBREVIATION 23416130 A 596 599 Dex ABBREVIATION 23416130 A 653 656 Dex ABBREVIATION 23416130 A 825 828 Dex ABBREVIATION 23416130 T 0 13 Dexamethasone TRIVIAL 23416144 A 0 10 Cysteamine TRIVIAL 23416144 A 109 119 coenzyme A TRIVIAL 23416144 A 17 28 amino thiol SYSTEMATIC 23416144 A 198 208 cysteamine TRIVIAL 23416144 A 288 298 cysteamine TRIVIAL 23416144 A 340 347 cystine TRIVIAL 23416144 A 525 535 cysteamine TRIVIAL 23416144 A 55 66 HSCH2CH2NH2 FORMULA 23416144 A 735 745 cysteamine TRIVIAL 23416144 A 764 774 cysteamine TRIVIAL 23416144 A 82 92 cysteamine TRIVIAL 23416144 T 0 10 Cysteamine TRIVIAL 23416261 A 0 8 Amikacin TRIVIAL 23416261 A 1093 1101 amikacin TRIVIAL 23416261 A 1188 1203 aminoglycosides FAMILY 23416261 A 152 160 amikacin TRIVIAL 23416261 A 299 307 amikacin TRIVIAL 23416261 A 408 416 Amikacin TRIVIAL 23416261 A 639 647 amikacin TRIVIAL 23416261 A 797 807 superoxide TRIVIAL 23416261 A 844 855 glutathione TRIVIAL 23416261 A 893 901 amikacin TRIVIAL 23416261 A 93 108 aminoglycosides FAMILY 23416261 T 77 85 amikacin TRIVIAL 23416647 A 395 397 As FORMULA 23416647 A 399 401 Cu FORMULA 23416647 A 403 405 Ni FORMULA 23416647 A 410 412 Se FORMULA 23416647 A 433 435 Fe FORMULA 23416647 A 437 439 Co FORMULA 23416647 A 444 446 Pb FORMULA 23416648 A 1035 1046 glutathione TRIVIAL 23416648 A 1059 1062 GSH ABBREVIATION 23416648 A 460 470 fatty acid FAMILY 23416648 A 490 510 glycerol-3-phosphate SYSTEMATIC 23416648 A 646 657 cholesterol TRIVIAL 23416648 A 692 703 cholesterol TRIVIAL 23416648 A 723 734 cholesterol TRIVIAL 23416648 A 739 752 triglycerides FAMILY 23416648 A 901 916 malondialdehyde TRIVIAL 23416648 A 918 921 MDA ABBREVIATION 23416700 A 0 14 Angiotensin IV TRIVIAL 23416700 A 1034 1037 Val ABBREVIATION 23416700 A 1042 1045 Ile FORMULA 23416700 A 1050 1053 His FORMULA 23416700 A 1061 1064 Phe FORMULA 23416700 A 1082 1085 Ala FORMULA 23416700 A 1163 1166 Tyr FORMULA 23416700 A 1173 1176 Pro FORMULA 23416700 A 1256 1270 angiotensin IV TRIVIAL 23416700 A 1292 1308 divalinal-Ang IV TRIVIAL 23416700 A 1456 1470 angiotensin IV TRIVIAL 23416700 A 1563 1577 angiotensin IV TRIVIAL 23416700 A 1581 1597 divalinal-Ang IV TRIVIAL 23416700 A 16 57 Val(1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6) FORMULA 23416700 A 1639 1653 angiotensin IV TRIVIAL 23416700 A 1773 1787 angiotensin IV TRIVIAL 23416700 A 192 206 angiotensin IV TRIVIAL 23416700 A 361 372 hexapeptide FAMILY 23416700 A 436 450 angiotensin IV TRIVIAL 23416700 A 593 607 angiotensin IV TRIVIAL 23416700 A 819 833 angiotensin IV TRIVIAL 23416700 A 958 965 alanine TRIVIAL 23416700 A 978 992 angiotensin IV TRIVIAL 23416700 T 26 40 angiotensin IV TRIVIAL 23416701 A 356 365 phosphate SYSTEMATIC 23416798 A 1090 1094 DEXA ABBREVIATION 23416798 A 1329 1333 DEXA ABBREVIATION 23416798 A 1470 1474 DEXA ABBREVIATION 23416798 A 180 193 dexamethasone TRIVIAL 23416798 A 195 199 DEXA ABBREVIATION 23416798 A 2031 2044 dexamethasone TRIVIAL 23416798 A 525 533 creatine TRIVIAL 23416798 A 870 874 DEXA ABBREVIATION 23416798 T 0 13 Dexamethasone TRIVIAL 23416946 A 237 267 biotinylated trimethylpsoralen SYSTEMATIC 23417424 A 1422 1423 N FORMULA 23417652 A 1332 1336 PCBs ABBREVIATION 23417652 A 1510 1513 PCB ABBREVIATION 23417652 A 1622 1625 PCB ABBREVIATION 23417652 A 1849 1852 PCB ABBREVIATION 23417652 A 587 591 PCBs ABBREVIATION 23417652 A 617 621 PCBs ABBREVIATION 23417652 A 71 95 polychlorinated biphenyl FAMILY 23417652 A 97 100 PCB ABBREVIATION 23417652 T 55 79 polychlorinated biphenyl FAMILY 23417652 T 81 84 PCB ABBREVIATION 23417894 A 113 116 PSS ABBREVIATION 23417894 A 132 135 PSS ABBREVIATION 23417894 A 142 147 CaCO3 FORMULA 23417894 A 250 258 hydrogen SYSTEMATIC 23417894 A 312 315 PUA ABBREVIATION 23417894 A 320 323 PSS ABBREVIATION 23417894 A 40 70 aliphatic poly(urethane-amine) FAMILY 23417894 A 577 580 DOX ABBREVIATION 23417894 A 72 75 PUA ABBREVIATION 23417894 A 722 725 PUA ABBREVIATION 23417894 A 730 733 PSS ABBREVIATION 23417894 A 81 111 sodium poly(styrene sulfonate) FAMILY 23417894 A 864 867 PUA ABBREVIATION 23417894 T 81 111 Aliphatic Poly(urethane-amine) FAMILY 23417972 A 201 207 BaSnO3 FORMULA 23417972 A 223 229 BaSnO3 FORMULA 23417972 A 347 353 BaSnO3 FORMULA 23417972 A 36 46 perovskite TRIVIAL 23417972 A 47 53 BaSnO3 FORMULA 23417972 A 474 487 ternary oxide SYSTEMATIC 23417972 A 523 529 BaSnO3 FORMULA 23417972 A 602 606 TiO2 FORMULA 23417972 T 0 6 BaSnO3 FORMULA 23417972 T 7 17 perovskite TRIVIAL 23418013 A 14 28 graphene oxide SYSTEMATIC 23418013 T 14 28 Graphene Oxide SYSTEMATIC 23418022 A 142 165 heterocyclic terpenoids FAMILY 23418022 A 227 240 pyrophosphate SYSTEMATIC 23418022 A 50 58 squalene TRIVIAL 23418022 A 59 65 hopene TRIVIAL 23418022 T 13 36 heterocyclic terpenoids FAMILY 23418022 T 52 60 squalene TRIVIAL 23418022 T 61 67 hopene TRIVIAL 23418073 A 1033 1043 fullerenes FAMILY 23418073 A 1078 1082 TiO2 FORMULA 23418073 A 1122 1125 ZnO FORMULA 23418073 A 1252 1254 Ag FORMULA 23418073 A 1274 1278 TiO2 FORMULA 23418073 A 1337 1339 Ag FORMULA 23418073 A 1352 1356 TiO2 FORMULA 23418073 A 1373 1376 ZnO FORMULA 23418073 A 1430 1434 TiO2 FORMULA 23418073 A 648 650 Ag FORMULA 23418073 A 657 661 TiO2 FORMULA 23418073 A 669 672 ZnO FORMULA 23418073 A 674 680 carbon SYSTEMATIC 23418073 A 703 713 fullerenes FAMILY 23418073 A 969 971 Ag FORMULA 23418368 A 123 134 cholesterol TRIVIAL 23418368 A 710 721 cholesterol TRIVIAL 23418678 A 1104 1114 Evodiamine TRIVIAL 23418678 A 1119 1126 evodine TRIVIAL 23418678 A 1259 1269 evodiamine TRIVIAL 23418678 A 1274 1281 evodine TRIVIAL 23418678 A 145 155 evodiamine TRIVIAL 23418678 A 160 167 evodine TRIVIAL 23418678 A 263 271 n-hexane SYSTEMATIC 23418678 A 272 285 ethyl acetate SYSTEMATIC 23418678 A 425 433 methanol SYSTEMATIC 23418678 A 444 460 ammonium formate SYSTEMATIC 23418678 A 477 488 formic acid SYSTEMATIC 23418678 A 490 500 Evodiamine TRIVIAL 23418678 A 502 509 evodine TRIVIAL 23418678 A 515 528 glibenclamide TRIVIAL 23418678 A 686 696 evodiamine TRIVIAL 23418678 A 720 727 evodine TRIVIAL 23418678 A 840 850 evodiamine TRIVIAL 23418678 A 873 880 evodine TRIVIAL 23418678 A 936 946 evodiamine TRIVIAL 23418678 A 969 976 evodine TRIVIAL 23418678 T 30 40 evodiamine TRIVIAL 23418678 T 45 52 evodine TRIVIAL 23418739 A 37 50 ethyl acetate SYSTEMATIC 23418775 A 23 84 3β-(2-methoxy-oxalyloxy)-24-methylene-lanost-8-en-21-oic acid SYSTEMATIC 23418775 A 272 285 triterpenoids FAMILY 23418775 A 8 21 triterpenoids FAMILY 23418775 A 93 166 3β-(2-methoxy-oxalyloxy)-15α-hydroxy-24-methylene-lanost-8-en-21-oic acid SYSTEMATIC 23418775 T 8 21 triterpenoids FAMILY 23418898 A 10 20 norlignans FAMILY 23418898 A 134 147 ethyl acetate SYSTEMATIC 23418898 A 22 36 glechomols A-C MULTIPLE 23418898 A 283 297 Glechomols A-C MULTIPLE 23418898 A 313 323 norlignans FAMILY 23418898 A 530 538 H(2)O(2) FORMULA 23418898 A 90 105 4-ethylcatechol SYSTEMATIC 23418898 T 10 20 norlignans FAMILY 23419036 A 107 130 dodecylammonium bromide SYSTEMATIC 23419036 A 132 136 DTAB ABBREVIATION 23419036 A 240 243 SDS ABBREVIATION 23419036 A 244 248 DTAB ABBREVIATION 23419036 A 435 438 SDS ABBREVIATION 23419036 A 439 443 DTAB ABBREVIATION 23419036 A 65 86 sodium dodecylsulfate SYSTEMATIC 23419036 A 88 91 SDS ABBREVIATION 23419055 A 1075 1087 methacrylate TRIVIAL 23419055 A 1104 1116 methacrylate TRIVIAL 23419072 A 102 113 doxorubicin TRIVIAL 23419072 A 1083 1086 DOX ABBREVIATION 23419072 A 1134 1137 LAP ABBREVIATION 23419072 A 115 118 DOX ABBREVIATION 23419072 A 152 155 DOX ABBREVIATION 23419072 A 202 205 LAP ABBREVIATION 23419072 A 318 321 DOX ABBREVIATION 23419072 A 37 45 laponite TRIVIAL 23419072 A 437 440 DOX ABBREVIATION 23419072 A 446 449 LAP ABBREVIATION 23419072 A 450 453 DOX ABBREVIATION 23419072 A 47 50 LAP ABBREVIATION 23419072 A 485 488 DOX ABBREVIATION 23419072 A 643 646 LAP ABBREVIATION 23419072 A 647 650 DOX ABBREVIATION 23419072 A 812 815 DOX ABBREVIATION 23419072 A 833 836 DOX ABBREVIATION 23419072 A 941 944 LAP ABBREVIATION 23419072 A 945 948 DOX ABBREVIATION 23419072 A 977 980 DOX ABBREVIATION 23419072 T 0 8 Laponite TRIVIAL 23419072 T 48 59 Doxorubicin TRIVIAL 23419388 A 1388 1396 estrogen FAMILY 23419388 A 1520 1528 estrogen FAMILY 23419388 A 294 307 17β-estrodiol SYSTEMATIC 23419388 A 482 493 Fulvestrant TRIVIAL 23419388 A 495 506 ICI 182,780 IDENTIFIER 23419388 A 512 520 estrogen FAMILY 23419388 A 882 890 estrogen FAMILY 23419388 T 25 33 estrogen FAMILY 23419389 A 0 17 Dibutyl phthalate SYSTEMATIC 23419389 A 109 119 phthalates FAMILY 23419389 A 1129 1132 DBP ABBREVIATION 23419389 A 1208 1211 DBP ABBREVIATION 23419389 A 166 169 DBP ABBREVIATION 23419389 A 19 22 DBP ABBREVIATION 23419389 A 299 302 DBP ABBREVIATION 23419389 A 353 356 DBP ABBREVIATION 23419389 A 382 385 DBP ABBREVIATION 23419389 A 583 586 DBP ABBREVIATION 23419389 A 723 726 DBP ABBREVIATION 23419389 A 746 749 DBP ABBREVIATION 23419389 A 901 904 DBP ABBREVIATION 23419389 A 953 956 DBP ABBREVIATION 23419389 T 45 62 dibutyl phthalate SYSTEMATIC 23419484 A 0 8 Tyrosine TRIVIAL 23419484 A 126 134 tyrosine TRIVIAL 23419484 T 74 82 tyrosine TRIVIAL 23419536 A 1053 1056 NH2 FORMULA 23419536 A 1075 1078 PEG ABBREVIATION 23419536 A 580 599 polyethylene glycol SYSTEMATIC 23419536 A 601 604 PEG ABBREVIATION 23419536 A 627 632 amino FAMILY 23419536 A 645 648 NH2 FORMULA 23419536 A 674 682 carboxyl SYSTEMATIC 23419536 A 693 697 COOH FORMULA 23419536 A 699 715 cadmium selenide SYSTEMATIC 23419536 A 716 728 zinc sulfide SYSTEMATIC 23419536 A 943 947 COOH FORMULA 23419834 A 1322 1332 sulfhydryl FAMILY 23419834 A 1355 1379 α,β-unsaturated carbonyl FAMILY 23419834 A 1428 1433 hemin TRIVIAL 23419834 A 1460 1473 [Ru(CO)3Cl2]2 FORMULA 23419834 A 1477 1479 CO FORMULA 23419834 A 1531 1533 NO FORMULA 23419834 A 1684 1686 NO FORMULA 23419834 A 174 186 kavalactones FAMILY 23419834 A 1832 1834 NO FORMULA 23419834 A 1972 1974 NO FORMULA 23419834 A 342 353 kavalactone FAMILY 23419834 A 366 414 2',6'-dichloro-5-methoxymethyl-5,6-dehydrokawain SYSTEMATIC 23419834 A 698 700 NO FORMULA 23419834 A 898 902 heme FAMILY 23419834 T 2 13 kavalactone FAMILY 23419834 T 83 85 NO FORMULA 23420583 A 1090 1097 citrate FAMILY 23420583 A 1130 1132 Al FORMULA 23420583 A 1245 1247 Al FORMULA 23420583 A 1270 1279 phosphate SYSTEMATIC 23420583 A 1341 1343 Al FORMULA 23420583 A 1345 1346 P FORMULA 23420583 A 1351 1352 O FORMULA 23420583 A 1390 1399 phosphate SYSTEMATIC 23420583 A 1421 1433 borosilicate SYSTEMATIC 23420583 A 1508 1510 Al FORMULA 23420583 A 1519 1519 MULTIPLE 23420583 A 182 191 phosphate SYSTEMATIC 23420583 A 471 473 Al FORMULA 23420583 A 475 476 P FORMULA 23420583 A 481 482 O FORMULA 23420583 A 492 494 Si FORMULA 23420583 A 628 634 sulfur SYSTEMATIC 23420583 A 724 728 SiO2 FORMULA 23420583 A 80 89 phosphate SYSTEMATIC 23420583 A 813 815 Al FORMULA 23420583 A 820 822 Si FORMULA 23420583 A 911 913 Al FORMULA 23420583 A 918 920 Si FORMULA 23420583 A 924 936 borosilicate SYSTEMATIC 23420583 A 957 959 Al FORMULA 23420583 T 11 20 phosphate SYSTEMATIC 23420664 T 16 19 PEG ABBREVIATION 23420666 A 1098 1112 MgSO4 hydrates FAMILY 23420666 A 964 978 MgSO4 hydrates FAMILY 23420692 A 101 112 doxorubicin TRIVIAL 23420692 A 114 117 DOX ABBREVIATION 23420692 A 123 135 MPEG-b-PAMAM ABBREVIATION 23420692 A 160 169 hydrazone FAMILY 23420692 A 302 324 10-hydroxycamptothecin SYSTEMATIC 23420692 A 326 330 HCPT ABBREVIATION 23420692 A 52 68 MPEG-b-PAMAM-DOX ABBREVIATION 23420692 A 550 578 methyl thiazolyl tetrazolium SYSTEMATIC 23420692 A 580 583 MTT ABBREVIATION 23420692 A 641 645 HCPT ABBREVIATION 23420692 A 721 737 MPEG-b-PAMAM-DOX ABBREVIATION 23420692 A 753 757 HCPT ABBREVIATION 23420692 A 784 800 MPEG-b-PAMAM-DOX ABBREVIATION 23420692 A 805 809 HCPT ABBREVIATION 23420692 A 824 827 DOX ABBREVIATION 23420692 A 831 835 HCPT ABBREVIATION 23420692 T 15 37 10-Hydroxycamptothecin SYSTEMATIC 23420692 T 43 54 Doxorubicin TRIVIAL 23421589 A 594 605 pinostrobin TRIVIAL 23421589 A 609 618 flavanone TRIVIAL 23421589 A 762 770 chalcone FAMILY 23421589 A 772 781 flavanone TRIVIAL 23421589 A 786 793 flavone TRIVIAL 23421631 A 229 237 carbonyl FAMILY 23421864 A 0 12 Ginkgolide B TRIVIAL 23421864 A 1030 1037 lactone FAMILY 23421864 A 1041 1053 ginkgolide B TRIVIAL 23421864 A 1062 1073 carboxylate SYSTEMATIC 23421864 A 1206 1218 ginkgolide B TRIVIAL 23421864 A 1245 1252 lactone FAMILY 23421864 A 1258 1269 carboxylate SYSTEMATIC 23421864 A 204 211 lactone FAMILY 23421864 A 275 282 lactone FAMILY 23421864 A 289 295 GB-lac ABBREVIATION 23421864 A 31 38 lactone FAMILY 23421864 A 318 325 lactone FAMILY 23421864 A 330 341 carboxylate SYSTEMATIC 23421864 A 359 371 ginkgolide B TRIVIAL 23421864 A 444 456 ginkgolide B TRIVIAL 23421864 A 470 477 lactone FAMILY 23421864 A 560 572 ginkgolide B TRIVIAL 23421864 A 615 626 carboxylate SYSTEMATIC 23421864 A 690 696 GB-lac ABBREVIATION 23421864 A 797 804 lactone FAMILY 23421864 A 808 819 carboxylate SYSTEMATIC 23421864 A 883 890 lactone FAMILY 23421864 T 43 50 lactone FAMILY 23421864 T 58 69 carboxylate SYSTEMATIC 23421864 T 79 91 ginkgolide B TRIVIAL 23421872 A 121 128 TEMPONE ABBREVIATION 23421872 A 173 214 tris(o-phenylenedioxy)cyclotriphosphazene SYSTEMATIC 23421872 A 216 219 TPP ABBREVIATION 23421872 A 412 416 DTBN ABBREVIATION 23421872 A 42 61 di-t-butylnitroxide SYSTEMATIC 23421872 A 420 427 TEMPONE ABBREVIATION 23421872 A 452 455 TPP ABBREVIATION 23421872 A 559 563 DTBN ABBREVIATION 23421872 A 568 575 TEMPONE ABBREVIATION 23421872 A 63 67 DTBN ABBREVIATION 23421872 A 697 737 2,2,6,6-tetramethyl-1-piperidinyl-1-oxyl SYSTEMATIC 23421872 A 73 119 4-oxo-2,2,6,6-tetramethyl-1-piperidinyl-1-oxyl SYSTEMATIC 23421872 A 739 744 TEMPO ABBREVIATION 23421872 A 749 752 TPP ABBREVIATION 23421872 A 880 889 nitroxide SYSTEMATIC 23421872 A 970 973 TPP ABBREVIATION 23422352 A 122 125 ADP ABBREVIATION 23422352 A 289 295 biotin TRIVIAL 23423573 A 1149 1158 palmitate TRIVIAL 23423573 A 1207 1212 NADPH ABBREVIATION 23423573 A 174 183 palmitate TRIVIAL 23423573 A 218 223 NADPH ABBREVIATION 23423573 A 641 648 AMD3100 IDENTIFIER 23423573 A 735 744 palmitate TRIVIAL 23423573 A 897 911 streptozotocin TRIVIAL 23423573 T 62 71 palmitate TRIVIAL 23423713 A 1019 1024 V(5+) FORMULA 23423713 A 1173 1177 TCDD ABBREVIATION 23423713 A 1295 1300 V(5+) FORMULA 23423713 A 1320 1324 TCDD ABBREVIATION 23423713 A 1433 1437 TCDD ABBREVIATION 23423713 A 1539 1544 V(5+) FORMULA 23423713 A 232 237 V(5+) FORMULA 23423713 A 279 314 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23423713 A 316 320 TCDD ABBREVIATION 23423713 A 418 423 V(5+) FORMULA 23423713 A 474 478 TCDD ABBREVIATION 23423713 A 519 524 V(5+) FORMULA 23423713 A 650 655 V(5+) FORMULA 23423713 A 660 664 TCDD ABBREVIATION 23423713 A 666 671 V(5+) FORMULA 23423713 A 68 76 vanadium SYSTEMATIC 23423713 A 702 706 TCDD ABBREVIATION 23423713 A 78 83 V(5+) FORMULA 23423713 A 824 829 V(5+) FORMULA 23423713 A 844 848 TCDD ABBREVIATION 23423713 A 937 942 V(5+) FORMULA 23423713 A 971 975 TCDD ABBREVIATION 23423713 T 42 50 vanadium SYSTEMATIC 23423714 A 0 24 N-Phenyl-2-naphthylamine SYSTEMATIC 23423714 A 1002 1005 2NA SYSTEMATIC 23423714 A 1051 1054 2NA SYSTEMATIC 23423714 A 1109 1112 2NA SYSTEMATIC 23423714 A 1117 1121 P2NA SYSTEMATIC 23423714 A 1218 1222 P2NA SYSTEMATIC 23423714 A 1249 1252 2NA SYSTEMATIC 23423714 A 126 130 P2NA SYSTEMATIC 23423714 A 1312 1313 N FORMULA 23423714 A 1362 1365 2NA SYSTEMATIC 23423714 A 1413 1416 2NA SYSTEMATIC 23423714 A 1421 1425 P2NA SYSTEMATIC 23423714 A 1491 1495 P2NA SYSTEMATIC 23423714 A 1519 1522 2NA SYSTEMATIC 23423714 A 1553 1557 P2NA SYSTEMATIC 23423714 A 1604 1607 2NA SYSTEMATIC 23423714 A 166 181 2-naphthylamine SYSTEMATIC 23423714 A 1673 1677 P2NA SYSTEMATIC 23423714 A 183 186 2NA SYSTEMATIC 23423714 A 26 30 P2NA SYSTEMATIC 23423714 A 343 346 2NA SYSTEMATIC 23423714 A 389 393 P2NA SYSTEMATIC 23423714 A 410 413 2NA SYSTEMATIC 23423714 A 476 479 2NA SYSTEMATIC 23423714 A 542 545 2NA SYSTEMATIC 23423714 A 559 563 P2NA SYSTEMATIC 23423714 A 735 738 2NA SYSTEMATIC 23423714 A 744 748 P2NA SYSTEMATIC 23423714 A 854 857 2NA SYSTEMATIC 23423714 A 911 915 P2NA SYSTEMATIC 23423714 A 939 942 2NA SYSTEMATIC 23423714 A 966 969 2NA SYSTEMATIC 23423714 T 50 74 N-phenyl-2-naphthylamine SYSTEMATIC 23423714 T 91 106 2-naphthylamine SYSTEMATIC 23424204 A 103 108 epoxy SYSTEMATIC 23424204 A 1167 1179 testosterone TRIVIAL 23424204 A 1205 1212 glucose TRIVIAL 23424204 A 1254 1257 BPA ABBREVIATION 23424204 A 1329 1342 (14)C-glucose SYSTEMATIC 23424204 A 227 230 BPA ABBREVIATION 23424204 A 23 34 bisphenol-A TRIVIAL 23424204 A 36 39 BPA ABBREVIATION 23424204 A 460 467 glucose TRIVIAL 23424204 A 542 545 BPA ABBREVIATION 23424204 A 581 588 glucose TRIVIAL 23424204 A 773 776 BPA ABBREVIATION 23424204 A 921 928 glucose TRIVIAL 23424204 A 966 969 BPA ABBREVIATION 23424204 T 10 21 bisphenol-A TRIVIAL 23424204 T 57 64 glucose TRIVIAL 23424214 A 0 12 Artemisinins FAMILY 23424214 A 265 275 artesunate TRIVIAL 23424214 A 281 291 mefloquine TRIVIAL 23424214 T 24 34 artesunate TRIVIAL 23424214 T 39 49 mefloquine TRIVIAL 23424216 A 0 5 Rutin TRIVIAL 23424216 A 206 211 rutin TRIVIAL 23424216 A 229 234 rutin TRIVIAL 23424216 A 409 414 rutin TRIVIAL 23424216 A 569 574 rutin TRIVIAL 23424216 A 675 685 flavonoids FAMILY 23424216 A 826 843 hydrogen peroxide SYSTEMATIC 23424216 A 868 873 rutin TRIVIAL 23424996 A 182 195 ethyl acetate SYSTEMATIC 23425029 A 186 191 (18)O FORMULA 23425029 A 287 292 (13)C FORMULA 23425029 A 294 299 (15)N FORMULA 23425029 A 60 76 1,3,4-oxadiazole SYSTEMATIC 23425029 A 969 974 (14)N FORMULA 23425029 T 39 55 1,3,4-oxadiazole SYSTEMATIC 23425114 A 119 130 acetic acid SYSTEMATIC 23425114 A 149 158 glutamate TRIVIAL 23425114 A 164 172 formalin TRIVIAL 23425114 A 207 210 7MF SYSTEMATIC 23425114 A 333 336 7MF SYSTEMATIC 23425114 A 425 433 formalin TRIVIAL 23425114 A 545 554 glutamate TRIVIAL 23425114 A 576 579 7MF SYSTEMATIC 23425114 A 61 77 7-methoxyflavone SYSTEMATIC 23425114 A 640 643 7MF SYSTEMATIC 23425114 A 742 745 7MF SYSTEMATIC 23425114 A 79 82 7MF SYSTEMATIC 23425114 T 26 42 7-methoxyflavone SYSTEMATIC 23425332 A 0 16 Tetraarylmethane FAMILY 23425332 A 102 117 3,4,5-C6H2(OH)3 SYSTEMATIC 23425332 A 1090 1099 FA-Rh6G-1 ABBREVIATION 23425332 A 1215 1218 DOX ABBREVIATION 23425332 A 128 144 3,5-R2-4-C6H2NH2 SYSTEMATIC 23425332 A 158 161 iPr FORMULA 23425332 A 402 410 hydrogen SYSTEMATIC 23425332 A 45 55 pyrogallol TRIVIAL 23425332 A 64 71 aniline SYSTEMATIC 23425332 A 642 652 folic acid TRIVIAL 23425332 A 662 674 rhodamine 6G TRIVIAL 23425332 A 676 680 Rh6G ABBREVIATION 23425332 A 724 733 FA-Rh6G-1 ABBREVIATION 23425332 A 768 777 FA-Rh6G-1 ABBREVIATION 23425332 A 87 95 Ar2CAr'2 FORMULA 23425332 A 884 895 doxorubicin TRIVIAL 23425332 A 897 900 DOX ABBREVIATION 23425332 A 971 980 FA-Rh6G-1 ABBREVIATION 23425332 T 55 71 tetraarylmethane FAMILY 23426224 A 1090 1100 NdxFe1-xB8 FAMILY 23426224 A 168 176 Nd2Fe14B FORMULA 23426224 A 246 252 Nd(3+) FORMULA 23426224 A 279 287 Nd2Fe14B FORMULA 23426224 A 332 340 Nd2Fe14B FORMULA 23426224 A 424 431 Nd-Fe-B FORMULA 23426224 A 438 443 oxide SYSTEMATIC 23426224 A 52 60 Nd2Fe14B FORMULA 23426224 A 529 534 oxide SYSTEMATIC 23426224 A 538 542 CaH2 FORMULA 23426224 A 758 761 CaO FORMULA 23426224 A 960 962 Nd FORMULA 23426224 A 966 968 Fe FORMULA 23426224 T 47 55 Nd₂Fe₁₄B FORMULA 23426369 A 11 19 acyl-CoA ABBREVIATION 23426369 T 0 8 Acyl-CoA FAMILY 23426640 A 0 25 Epoxieicosatrienoic acids FAMILY 23426640 A 1197 1207 creatinine TRIVIAL 23426640 A 146 150 EETs ABBREVIATION 23426640 A 27 31 EETs ABBREVIATION 23426640 A 589 599 creatinine TRIVIAL 23426869 A 316 317 N FORMULA 23426869 A 338 350 acetyllysine SYSTEMATIC 23426869 A 81 93 acetyllysine SYSTEMATIC 23426869 T 28 29 N FORMULA 23426869 T 35 36 C FORMULA 23426869 T 58 70 acetyllysine SYSTEMATIC 23426956 A 1109 1118 rapamycin TRIVIAL 23426956 A 1130 1139 rapamycin TRIVIAL 23426956 A 1180 1189 Rapamycin TRIVIAL 23426956 A 1199 1211 rosuvastatin TRIVIAL 23426956 A 1293 1305 Rosuvastatin TRIVIAL 23426956 A 1430 1442 rosuvastatin TRIVIAL 23426956 A 1447 1456 rapamycin TRIVIAL 23426956 A 1524 1536 rosuvastatin TRIVIAL 23426956 A 1671 1683 rosuvastatin TRIVIAL 23426956 A 214 251 3-hydroxy-3-methylglutaryl coenzyme A SYSTEMATIC 23426956 A 289 299 isoprenoid FAMILY 23426956 A 390 402 rosuvastatin TRIVIAL 23426956 A 790 802 rosuvastatin TRIVIAL 23426956 A 963 975 Rosuvastatin TRIVIAL 23426956 T 24 36 Rosuvastatin TRIVIAL 23427008 A 21 26 PtCl2 FORMULA 23427008 A 214 225 enol esters FAMILY 23427008 A 241 254 cyclopentenyl SYSTEMATIC 23427008 A 45 54 1,6-enyne SYSTEMATIC 23427008 A 67 78 1,2-acyloxy SYSTEMATIC 23427008 T 0 5 PtCl2 FORMULA 23427008 T 108 136 All-Carbon 1,6-Enynyl Esters FAMILY 23427008 T 24 29 Enyne SYSTEMATIC 23427008 T 42 51 1,2 Ester FAMILY 23427019 A 208 210 Si FORMULA 23427019 A 211 215 SiO2 FORMULA 23427019 A 218 221 ITO ABBREVIATION 23427019 A 264 285 11-mercaptoundecanols FAMILY 23427019 A 392 394 Pt FORMULA 23427042 A 1024 1026 Cu FORMULA 23427042 A 411 413 Cu FORMULA 23427042 A 610 612 Cu FORMULA 23427042 A 727 729 Cu FORMULA 23427042 A 752 754 Cu FORMULA 23427042 A 76 78 Cu FORMULA 23427042 A 957 963 carbon SYSTEMATIC 23427042 T 17 23 copper SYSTEMATIC 23427167 A 100 114 ε-caprolactone SYSTEMATIC 23427167 A 66 88 trimethylene carbonate SYSTEMATIC 23427167 A 90 93 TMC ABBREVIATION 23427167 T 44 90 Poly(trimethylene carbonate-co-ε-caprolactone) FAMILY 23427187 A 179 193 glutaraldehyde TRIVIAL 23427187 A 529 537 methanol SYSTEMATIC 23427187 A 542 549 ethanol SYSTEMATIC 23427187 A 606 613 acetone SYSTEMATIC 23427187 A 615 632 isopropyl alcohol SYSTEMATIC 23427187 A 638 650 acetonitrile SYSTEMATIC 23427187 A 734 760 fluorescein-isothiocyanate SYSTEMATIC 23427187 A 762 766 FITC ABBREVIATION 23427814 A 444 510 N,N-diethyl-N-methyl-N-(2-methoxyethyl) ammonium tetrafluoroborate SYSTEMATIC 23427814 A 512 523 [DEME][BF4] FORMULA 23427814 A 864 875 [DEME][BF4] FORMULA 23427814 T 79 145 N,N-diethyl-N-methyl-N-(2-methoxyethyl) ammonium tetrafluoroborate SYSTEMATIC 23427996 A 50 56 phenyl SYSTEMATIC 23428306 A 1164 1171 glucose TRIVIAL 23428306 A 651 662 Cholesterol TRIVIAL 23428346 A 1008 1020 atorvastatin TRIVIAL 23428346 A 1040 1052 atorvastatin TRIVIAL 23428346 A 1080 1092 atorvastatin TRIVIAL 23428346 A 112 123 cholesterol TRIVIAL 23428346 A 1123 1135 atorvastatin TRIVIAL 23428346 A 1167 1179 nitric oxide SYSTEMATIC 23428346 A 1198 1208 superoxide TRIVIAL 23428346 A 1247 1252 NADPH ABBREVIATION 23428346 A 1324 1339 3-nitrotyrosine SYSTEMATIC 23428346 A 1374 1385 glutathione TRIVIAL 23428346 A 1386 1387 S FORMULA 23428346 A 1404 1412 xanthine TRIVIAL 23428346 A 1452 1464 atorvastatin TRIVIAL 23428346 A 1509 1517 carbonyl FAMILY 23428346 A 1522 1541 4-hydroxy-2-nonenal SYSTEMATIC 23428346 A 1625 1640 3-nitrotyrosine SYSTEMATIC 23428346 A 1738 1750 atorvastatin TRIVIAL 23428346 A 1836 1848 atorvastatin TRIVIAL 23428346 A 1945 1950 NADPH ABBREVIATION 23428346 A 1986 1996 superoxide TRIVIAL 23428346 A 236 247 cholesterol TRIVIAL 23428346 A 351 362 cholesterol TRIVIAL 23428346 A 37 74 3-hydroxy-3-methylglutaryl coenzyme A SYSTEMATIC 23428346 A 896 908 atorvastatin TRIVIAL 23428346 T 0 12 Atorvastatin TRIVIAL 23428385 A 594 614 acetylsalicylic acid SYSTEMATIC 23428385 A 630 633 ADP ABBREVIATION 23428385 A 666 677 clopidogrel TRIVIAL 23428385 A 694 703 prasugrel TRIVIAL 23428385 A 708 718 ticagrelor TRIVIAL 23428385 A 790 801 clopidogrel TRIVIAL 23428468 A 0 9 Oxysterol FAMILY 23428468 A 1571 1603 phosphatidylinositol-4-phosphate SYSTEMATIC 23428468 A 1618 1627 rapamycin TRIVIAL 23428468 A 1652 1660 nitrogen SYSTEMATIC 23428468 A 240 246 sterol FAMILY 23428468 A 72 78 sterol FAMILY 23428468 A 83 99 phosphoinositide FAMILY 23428468 T 0 9 Oxysterol FAMILY 23429041 A 0 18 Dihydroartemisinin SYSTEMATIC 23429041 A 1132 1135 DHA ABBREVIATION 23429041 A 20 23 DHA ABBREVIATION 23429041 A 266 269 DHA ABBREVIATION 23429041 A 408 411 DHA ABBREVIATION 23429041 A 415 418 PMA ABBREVIATION 23429041 A 447 450 DHA ABBREVIATION 23429041 A 478 481 PMA ABBREVIATION 23429041 A 511 515 PGE2 ABBREVIATION 23429041 A 57 68 artemisinin TRIVIAL 23429041 A 596 599 DHA ABBREVIATION 23429041 A 719 722 DHA ABBREVIATION 23429041 A 747 750 PMA ABBREVIATION 23429041 A 823 826 DHA ABBREVIATION 23429041 A 847 850 PMA ABBREVIATION 23429041 A 969 972 DHA ABBREVIATION 23429041 T 21 39 dihydroartemisinin SYSTEMATIC 23429041 T 48 61 phorbol ester FAMILY 23429042 A 0 11 Bisphenol A TRIVIAL 23429042 A 1064 1067 BPA ABBREVIATION 23429042 A 1156 1164 estrogen FAMILY 23429042 A 1235 1238 BPA ABBREVIATION 23429042 A 13 16 BPA ABBREVIATION 23429042 A 174 177 BPA ABBREVIATION 23429042 A 261 268 calcium SYSTEMATIC 23429042 A 337 340 BPA ABBREVIATION 23429042 A 562 565 BPA ABBREVIATION 23429042 A 601 614 17β-estradiol SYSTEMATIC 23429042 A 724 727 BPA ABBREVIATION 23429042 A 907 916 estrogens FAMILY 23429042 A 935 938 MPP ABBREVIATION 23429042 A 953 958 PHTPP ABBREVIATION 23429042 T 25 33 estrogen FAMILY 23429042 T 9 20 bisphenol A TRIVIAL 23429044 A 163 183 N-methyl-D-aspartate SYSTEMATIC 23429044 A 217 230 acetylcholine SYSTEMATIC 23429044 A 503 512 Eritrosin TRIVIAL 23429044 A 514 524 Ponceau 4R TRIVIAL 23429044 A 526 539 Allura Red AC TRIVIAL 23429044 A 541 558 Sunset Yellow FCF TRIVIAL 23429044 A 560 569 Tartrazin TRIVIAL 23429044 A 571 579 Amaranth TRIVIAL 23429044 A 581 595 Brilliant Blue TRIVIAL 23429044 A 597 605 Azorubin TRIVIAL 23429044 A 610 619 Indigotin TRIVIAL 23429061 A 1267 1277 creatinine TRIVIAL 23429061 A 1562 1572 creatinine TRIVIAL 23429061 A 225 234 uric acid TRIVIAL 23429061 A 244 252 N-acetyl SYSTEMATIC 23429061 A 992 1002 creatinine TRIVIAL 23429061 T 53 62 uric acid TRIVIAL 23429061 T 67 75 N-acetyl SYSTEMATIC 23430161 A 1047 1054 alcohol FAMILY 23430161 A 1371 1378 alcohol FAMILY 23430161 A 156 163 alcohol FAMILY 23430161 A 308 315 alcohol FAMILY 23430161 A 578 585 alcohol FAMILY 23430161 A 878 885 alcohol FAMILY 23430161 T 28 35 Alcohol SYSTEMATIC 23430162 A 1034 1041 ethanol SYSTEMATIC 23430162 A 1070 1083 [(35)S] GTPγS FORMULA 23430162 A 1181 1188 ethanol SYSTEMATIC 23430162 A 1213 1220 ethanol SYSTEMATIC 23430162 A 1255 1263 morphine TRIVIAL 23430162 A 1329 1337 morphine TRIVIAL 23430162 A 1341 1348 ethanol SYSTEMATIC 23430162 A 1523 1530 ethanol SYSTEMATIC 23430162 A 1565 1573 morphine TRIVIAL 23430162 A 242 249 ethanol SYSTEMATIC 23430162 A 328 335 ethanol SYSTEMATIC 23430162 A 419 427 morphine TRIVIAL 23430162 A 53 60 ethanol SYSTEMATIC 23430162 A 547 554 ethanol SYSTEMATIC 23430162 A 731 738 ethanol SYSTEMATIC 23430162 A 762 775 [(35)S] GTPγS FORMULA 23430162 A 851 859 morphine TRIVIAL 23430162 A 891 898 ethanol SYSTEMATIC 23430162 T 18 25 ethanol SYSTEMATIC 23430162 T 92 100 morphine TRIVIAL 23431112 A 0 7 ABT-384 IDENTIFIER 23431112 A 1106 1113 ABT-384 IDENTIFIER 23431112 A 1160 1167 ABT-384 IDENTIFIER 23431112 A 1230 1237 ABT-384 IDENTIFIER 23431112 A 1257 1269 ketoconazole TRIVIAL 23431112 A 1271 1280 A-1331480 IDENTIFIER 23431112 A 1324 1332 A-847082 IDENTIFIER 23431112 A 1561 1568 ABT-384 IDENTIFIER 23431112 A 1570 1579 A-1331480 IDENTIFIER 23431112 A 1585 1593 A-847082 IDENTIFIER 23431112 A 1602 1609 ABT-384 IDENTIFIER 23431112 A 1620 1632 ketoconazole TRIVIAL 23431112 A 1671 1678 ABT-384 IDENTIFIER 23431112 A 1731 1743 ketoconazole TRIVIAL 23431112 A 1765 1772 ABT-384 IDENTIFIER 23431112 A 1778 1790 ketoconazole TRIVIAL 23431112 A 186 204 11β-hydroxysteroid FAMILY 23431112 A 1943 1950 ABT-384 IDENTIFIER 23431112 A 235 242 ABT-384 IDENTIFIER 23431112 A 419 431 ketoconazole TRIVIAL 23431112 A 459 466 ABT-384 IDENTIFIER 23431112 A 499 508 A-1331480 IDENTIFIER 23431112 A 513 521 A-847082 IDENTIFIER 23431112 A 577 584 ABT-384 IDENTIFIER 23431112 A 609 621 ketoconazole TRIVIAL 23431112 A 623 630 ABT-384 IDENTIFIER 23431112 A 782 789 ABT-384 IDENTIFIER 23431112 A 831 843 ketoconazole TRIVIAL 23431112 A 875 884 A-1331480 IDENTIFIER 23431112 A 889 897 A-847082 IDENTIFIER 23431112 A 9 131 1-piperazineacetamide, N-[5-(aminocarbonyl) tricyclo[3.3.1.13,7]dec-2-yl]-α,α-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl] SYSTEMATIC 23431112 A 982 989 ABT-384 IDENTIFIER 23431112 T 10 22 Ketoconazole TRIVIAL 23431112 T 104 111 ABT-384 IDENTIFIER 23431112 T 54 72 11β-Hydroxysteroid FAMILY 23431964 A 134 150 sesquiterpenoids FAMILY 23431964 A 31 38 CHCl(3) FORMULA 23431964 A 39 43 MeOH FORMULA 23431964 T 8 24 sesquiterpenoids FAMILY 23432081 A 770 771 H FORMULA 23432081 A 774 776 H2 FORMULA 23432429 A 1014 1023 flavanone TRIVIAL 23432429 A 1025 1032 chrysin TRIVIAL 23432429 A 1034 1055 3-ethynylphenanthrene SYSTEMATIC 23432429 A 1057 1064 flavone TRIVIAL 23432429 A 1070 1086 7-hydroxyflavone SYSTEMATIC 23432429 A 112 119 flavone TRIVIAL 23432429 A 270 274 iron SYSTEMATIC 23432429 A 487 507 benzo[c]phenanthrene SYSTEMATIC 23432429 A 49 60 naphthalene SYSTEMATIC 23432429 A 509 521 fluoranthene SYSTEMATIC 23432429 A 523 560 2,3-dihydroxy-2,3-dihydrofluoranthene SYSTEMATIC 23432429 A 562 568 pyrene SYSTEMATIC 23432429 A 570 585 1-hydroxypyrene SYSTEMATIC 23432429 A 587 600 1-nitropyrene SYSTEMATIC 23432429 A 602 616 1-acetylpyrene SYSTEMATIC 23432429 A 618 632 2-acetylpyrene SYSTEMATIC 23432429 A 62 74 phenanthrene SYSTEMATIC 23432429 A 634 663 2,5,2',5'-tetrachlorobiphenyl SYSTEMATIC 23432429 A 665 681 7-hydroxyflavone SYSTEMATIC 23432429 A 683 690 chrysin TRIVIAL 23432429 A 696 704 galangin TRIVIAL 23432429 A 76 88 fluoranthene SYSTEMATIC 23432429 A 772 780 Coumarin TRIVIAL 23432429 A 848 879 2'-methoxy-5,7-dihydroxyflavone SYSTEMATIC 23432429 A 881 901 2-ethynylnaphthalene SYSTEMATIC 23432429 A 90 96 pyrene SYSTEMATIC 23432429 A 903 920 2'-methoxyflavone SYSTEMATIC 23432429 A 922 953 2-naphththalene propargyl ether SYSTEMATIC 23432429 A 955 967 acenaphthene TRIVIAL 23432429 A 969 983 acenaphthylene TRIVIAL 23432429 A 98 106 biphenyl SYSTEMATIC 23432429 A 985 996 naphthalene SYSTEMATIC 23432429 A 998 1012 1-acetylpyrene SYSTEMATIC 23432591 A 1034 1037 ATP ABBREVIATION 23432591 A 1237 1240 ATP ABBREVIATION 23432591 A 200 203 ATP ABBREVIATION 23432591 A 347 350 ATP ABBREVIATION 23432591 A 38 41 ATP ABBREVIATION 23432591 A 418 421 ATP ABBREVIATION 23432591 A 642 653 polyphenols FAMILY 23432591 A 673 676 ATP ABBREVIATION 23432591 A 922 925 ATP ABBREVIATION 23432591 T 0 3 ATP ABBREVIATION 23432683 A 29 61 transition metal dichalcogenides FAMILY 23432683 A 433 437 TMDs FAMILY 23432683 A 528 532 MoS2 FORMULA 23432683 A 537 541 WSe2 FORMULA 23432683 A 564 568 TMDs FAMILY 23432683 A 63 67 TMDs FAMILY 23432683 T 53 57 MoS2 FORMULA 23432683 T 62 66 WSe2 FORMULA 23433811 A 1221 1231 nucleotide FAMILY 23433811 A 264 274 nucleotide FAMILY 23433811 A 355 365 nucleotide FAMILY 23433811 A 455 460 6-4PP SYSTEMATIC 23433811 A 462 487 6,4 pyrimidine-pyrimidone SYSTEMATIC 23433811 A 497 501 BPDE ABBREVIATION 23433811 A 508 557 benzo(a)pyrene-trans-7,8-dihydrodiol-9,10-epoxide SYSTEMATIC 23433811 A 780 790 nucleotide FAMILY 23433811 A 919 929 nucleotide FAMILY 23433811 T 51 61 nucleotide FAMILY 23434029 A 24 56 5-aryl-3-acylpyridinyl-pyrazoles FAMILY 23434029 A 61 94 1-aryl-4-acylpyridinyl imidazoles FAMILY 23434029 T 38 63 pyrazole/imidazole amides MULTIPLE 23434418 A 132 218 4,5,6,7-tetrahydro-6-((5-substituted-1,3,4-oxadiazol-2-yl)methyl)thieno[2,3-c]pyridine FAMILY 23434418 A 14 24 zinc oxide SYSTEMATIC 23434418 A 29 45 titanium dioxide SYSTEMATIC 23434418 A 53 56 ZnO FORMULA 23434418 A 57 63 TiO(2) FORMULA 23434418 A 636 646 ampicillin TRIVIAL 23434418 A 648 661 ciprofloxacin TRIVIAL 23434418 A 666 676 miconazole TRIVIAL 23434418 A 769 787 2,6 dichlorophenyl SYSTEMATIC 23434418 A 803 817 4 fluorophenyl SYSTEMATIC 23434418 A 836 854 2,6 dichlorophenyl SYSTEMATIC 23434418 A 938 947 thiophene SYSTEMATIC 23434418 T 25 28 ZnO FORMULA 23434418 T 29 33 TiO2 FORMULA 23434418 T 67 153 4,5,6,7-tetrahydro-6-((5-substituted-1,3,4-oxadiazol-2-yl)methyl)thieno[2,3-c]pyridine FAMILY 23434419 A 173 180 guanide SYSTEMATIC 23434419 A 212 250 spermine and spermidine phenylguanides MULTIPLE 23434419 A 379 394 naphthylguanide SYSTEMATIC 23434419 A 414 424 polyamines FAMILY 23434419 A 425 435 spermidine TRIVIAL 23434419 A 440 448 spermine TRIVIAL 23434419 A 482 497 naphthylguanide SYSTEMATIC 23434419 A 538 569 spermine tris-1-naphthylguanide SYSTEMATIC 23434419 T 9 16 guanide SYSTEMATIC 23434639 A 12 21 linezolid TRIVIAL 23434639 A 27 51 oxazolidino-sulfonamides FAMILY 23434639 T 40 64 oxazolidino-sulfonamides FAMILY 23434640 A 101 114 ecteinascidin TRIVIAL 23434640 A 202 208 l-dopa ABBREVIATION 23434640 A 39 59 3-aryl acrylic amide FAMILY 23434640 A 524 550 3-thiophenyl acrylic amide SYSTEMATIC 23434640 A 90 100 saframycin TRIVIAL 23434640 T 129 135 l-dopa ABBREVIATION 23434640 T 30 50 3-aryl acrylic amide FAMILY 23434640 T 81 91 saframycin TRIVIAL 23434640 T 92 105 ecteinascidin TRIVIAL 23434647 A 835 845 phalloidin TRIVIAL 23434833 A 251 255 acyl FAMILY 23434833 A 853 857 acyl FAMILY 23434833 A 984 988 acyl FAMILY 23435124 A 1399 1403 iron SYSTEMATIC 23435124 A 296 300 iron SYSTEMATIC 23435124 A 372 376 iron SYSTEMATIC 23435124 A 378 383 FeSO4 FORMULA 23435124 A 414 420 oxygen SYSTEMATIC 23435124 A 511 522 glutathione TRIVIAL 23435124 A 611 615 Iron SYSTEMATIC 23435124 A 895 899 iron SYSTEMATIC 23435124 T 44 48 iron SYSTEMATIC 23435180 A 1062 1066 PFOA ABBREVIATION 23435180 A 1182 1186 PFOA ABBREVIATION 23435180 A 1217 1221 PFOA ABBREVIATION 23435180 A 1369 1373 PFOA ABBREVIATION 23435180 A 457 479 perfluorooctanoic acid SYSTEMATIC 23435180 A 481 485 PFOA ABBREVIATION 23435180 A 506 510 PFOA ABBREVIATION 23435180 A 670 674 PFOA ABBREVIATION 23435180 A 717 721 PFOA ABBREVIATION 23435180 A 897 901 PFOA ABBREVIATION 23435180 T 67 89 perfluorooctanoic acid SYSTEMATIC 23435216 A 0 7 Cuprate SYSTEMATIC 23435216 A 587 595 cuprates FAMILY 23435216 A 614 628 La1.9Sr0.1CuO4 FORMULA 23435216 A 870 886 La1.84Sr0.16CuO4 FORMULA 23435216 T 38 45 cuprate SYSTEMATIC 23435353 A 1367 1382 4-aminopyridine SYSTEMATIC 23435353 A 314 318 K(+) FORMULA 23435353 A 578 582 K(+) FORMULA 23435353 A 7 11 K(+) FORMULA 23435353 A 842 850 DAU-5884 IDENTIFIER 23435353 A 855 861 4-DAMP SYSTEMATIC 23435353 T 21 25 K(+) FORMULA 23435357 A 463 473 nucleotide FAMILY 23435357 A 701 709 tyrosine TRIVIAL 23435674 A 100 148 perylene-3,4,9,10-tetracarboxyl acid dianhydride SYSTEMATIC 23435674 A 1005 1008 KCl FORMULA 23435674 A 150 155 PTCDA ABBREVIATION 23435674 A 229 232 KCl FORMULA 23435674 A 264 269 PTCDA ABBREVIATION 23435674 A 992 997 PTCDA ABBREVIATION 23435674 T 29 34 PTCDA ABBREVIATION 23435674 T 52 55 KCl FORMULA 23435687 A 1352 1363 pralidoxime TRIVIAL 23435687 A 1365 1370 2-PAM SYSTEMATIC 23435687 A 1522 1538 organophosphorus FAMILY 23435687 A 234 246 chlorpyrifos TRIVIAL 23435687 A 505 517 chlorpyrifos TRIVIAL 23435687 A 616 628 chlorpyrifos TRIVIAL 23435687 A 885 897 chlorpyrifos TRIVIAL 23435687 T 111 123 chlorpyrifos TRIVIAL 23435944 A 0 10 Macelignan TRIVIAL 23435944 A 133 143 Macelignan TRIVIAL 23435944 A 460 470 macelignan TRIVIAL 23435944 T 34 44 macelignan TRIVIAL 23435964 A 102 123 Cobalt-protoporphyrin SYSTEMATIC 23435964 A 125 129 CoPP FORMULA 23435964 A 154 158 heme FAMILY 23435964 A 397 401 CoPP FORMULA 23435964 A 717 721 CoPP FORMULA 23435964 A 844 848 CoPP FORMULA 23435964 A 931 935 CoPP FORMULA 23435964 T 13 17 heme FAMILY 23436254 A 167 170 KOH FORMULA 23436254 A 6 12 carbon SYSTEMATIC 23436254 T 12 18 carbon SYSTEMATIC 23436258 A 1058 1067 Zanamivir TRIVIAL 23436258 A 1225 1234 Peramivir TRIVIAL 23436258 A 1361 1372 Laninamivir TRIVIAL 23436258 A 337 348 Oseltamivir TRIVIAL 23436258 A 377 388 carboxylate SYSTEMATIC 23436258 A 488 499 Oseltamivir TRIVIAL 23436258 A 532 555 oseltamivir carboxylate SYSTEMATIC 23436258 A 673 696 Oseltamivir carboxylate SYSTEMATIC 23436258 A 71 82 Oseltamivir TRIVIAL 23436258 A 801 811 probenecid TRIVIAL 23436258 A 857 868 oseltamivir TRIVIAL 23436258 A 897 906 peramivir TRIVIAL 23436258 A 937 946 zanamivir TRIVIAL 23436258 A 963 972 Zanamivir TRIVIAL 23436267 A 0 10 BMS-690514 IDENTIFIER 23436267 A 1026 1038 ketoconazole TRIVIAL 23436267 A 1184 1196 ketoconazole TRIVIAL 23436267 A 1284 1296 ketoconazole TRIVIAL 23436267 A 357 369 ketoconazole TRIVIAL 23436267 A 373 383 BMS-690514 IDENTIFIER 23436267 A 440 450 BMS-690514 IDENTIFIER 23436267 A 476 486 BMS-690514 IDENTIFIER 23436267 A 492 504 ketoconazole TRIVIAL 23436267 A 558 568 BMS-690514 IDENTIFIER 23436267 A 601 613 ketoconazole TRIVIAL 23436267 A 644 654 BMS-690514 IDENTIFIER 23436267 A 703 713 BMS-690514 IDENTIFIER 23436267 A 730 740 BMS-690514 IDENTIFIER 23436267 A 748 760 ketoconazole TRIVIAL 23436267 A 842 852 BMS-690514 IDENTIFIER 23436267 T 103 113 BMS-690514 IDENTIFIER 23436267 T 21 33 ketoconazole TRIVIAL 23436267 T 77 85 tyrosine TRIVIAL 23436305 A 16 33 organophosphorous FAMILY 23436305 A 216 232 organophosphates FAMILY 23436305 A 393 408 organophosphate FAMILY 23436305 T 57 72 organophosphate FAMILY 23436492 T 116 128 promethazine TRIVIAL 23436492 T 28 33 sugar FAMILY 23436571 A 1096 1100 PDMS ABBREVIATION 23436571 A 1162 1166 PDMS ABBREVIATION 23436571 A 172 176 PDMS ABBREVIATION 23436571 A 357 361 PDMS ABBREVIATION 23436571 A 48 70 poly(dimethylsiloxane) SYSTEMATIC 23436571 A 485 500 hexadecanethiol SYSTEMATIC 23436571 A 502 505 HDT ABBREVIATION 23436571 A 561 580 polyethylene glycol SYSTEMATIC 23436571 A 582 585 PEG ABBREVIATION 23436571 A 618 621 HDT ABBREVIATION 23436571 A 685 688 PEG ABBREVIATION 23436571 A 72 76 PDMS ABBREVIATION 23436571 A 758 762 PDMS ABBREVIATION 23436571 A 819 823 PDMS ABBREVIATION 23436571 A 867 871 PDMS ABBREVIATION 23436571 T 73 95 poly(dimethylsiloxane) SYSTEMATIC 23436650 A 1075 1083 androgen FAMILY 23436650 A 121 129 androgen FAMILY 23436650 A 172 181 androgens FAMILY 23436650 A 376 388 bicalutamide TRIVIAL 23436650 A 393 409 hydroxyflutamide TRIVIAL 23436650 A 492 500 androgen FAMILY 23436650 A 501 508 MDV3100 IDENTIFIER 23436650 A 524 531 MDV3100 IDENTIFIER 23436650 A 553 586 4-cyano-3-(trifluoromethyl)phenyl SYSTEMATIC 23436650 A 598 610 bicalutamide TRIVIAL 23436650 A 615 631 hydroxyflutamide TRIVIAL 23436650 A 758 791 4-cyano-3-(trifluoromethyl)phenyl SYSTEMATIC 23436650 T 29 37 androgen FAMILY 23436656 A 1069 1085 cyclophosphamide TRIVIAL 23436656 A 1090 1099 docetaxel TRIVIAL 23436656 A 1370 1373 CpG ABBREVIATION 23436656 A 1471 1493 5-aza-29-deoxycytidine SYSTEMATIC 23436656 A 565 581 propidium iodide TRIVIAL 23436656 A 612 618 oxygen SYSTEMATIC 23436656 A 851 860 Bisulfite SYSTEMATIC 23436656 T 127 134 Sulfate SYSTEMATIC 23436706 A 0 17 Combretastatin A1 TRIVIAL 23436706 A 1050 1053 CA1 ABBREVIATION 23436706 A 19 22 CA1 ABBREVIATION 23436706 A 248 265 combretastatin A4 TRIVIAL 23436706 A 267 270 CA4 ABBREVIATION 23436706 A 352 365 ortho-quinone TRIVIAL 23436706 A 444 463 3,4-diarylpyrazoles FAMILY 23436706 A 506 578 3-methoxy-6-[4-(3,4,5-trimethoxyphenyl)-1H-pyrazol-3-yl]benzene-1,2-diol SYSTEMATIC 23436706 A 54 64 colchicine TRIVIAL 23436706 A 677 692 combretastatins FAMILY 23436706 A 704 707 CA1 ABBREVIATION 23436706 A 709 712 CA4 ABBREVIATION 23436706 A 888 901 ortho-quinone TRIVIAL 23436706 A 921 929 pyrazole SYSTEMATIC 23436706 T 23 31 pyrazole SYSTEMATIC 23436706 T 45 62 combretastatin A1 TRIVIAL 23436749 A 1137 1142 PBDEs ABBREVIATION 23436749 A 1255 1260 PBDEs ABBREVIATION 23436749 A 633 663 polybrominated diphenyl ethers FAMILY 23436749 A 665 670 PBDEs ABBREVIATION 23436749 A 856 862 carbon SYSTEMATIC 23436749 A 892 900 hydroxyl SYSTEMATIC 23437929 A 145 169 alkyldimethylamine oxide FAMILY 23437929 A 171 177 CnDMAO FAMILY 23437929 A 310 316 Zn(2+) FORMULA 23437929 A 318 324 Ca(2+) FORMULA 23437929 A 326 332 Ba(2+) FORMULA 23437929 A 334 340 Al(3+) FORMULA 23437929 A 342 348 Fe(3+) FORMULA 23437929 A 350 356 La(3+) FORMULA 23437929 A 358 364 Eu(3+) FORMULA 23437929 A 370 376 Tb(3+) FORMULA 23437929 A 402 413 hydrocarbon FAMILY 23437929 A 418 430 fluorocarbon FAMILY 23437929 A 494 506 fluorocarbon FAMILY 23437929 A 527 538 hydrocarbon FAMILY 23437929 A 589 600 hydrocarbon FAMILY 23437929 A 672 684 fluorocarbon FAMILY 23437929 A 749 761 hydrocarbons FAMILY 23437929 A 976 982 CnDMAO FAMILY 23438015 A 175 182 diamond TRIVIAL 23438015 A 223 231 graphite TRIVIAL 23438015 A 259 267 graphene TRIVIAL 23438015 A 440 450 Kawazulite TRIVIAL 23438015 A 495 512 Bi2(Te,Se)2(Se,S) FORMULA 23438077 A 107 141 hexadecyltrimethylammonium bromide SYSTEMATIC 23438077 A 1096 1102 silica TRIVIAL 23438077 A 143 147 CTAB ABBREVIATION 23438077 A 153 175 sodium dodecyl sulfate SYSTEMATIC 23438077 A 177 180 SDS ABBREVIATION 23438077 A 197 213 polyethylenimine SYSTEMATIC 23438077 A 215 218 PEI ABBREVIATION 23438077 A 223 237 polyacrylamide SYSTEMATIC 23438077 A 239 243 PAAm ABBREVIATION 23438077 A 8 14 silica TRIVIAL 23438077 A 804 808 TMOS ABBREVIATION 23438077 A 900 906 silica TRIVIAL 23438077 T 44 50 silica TRIVIAL 23438471 A 727 743 aryl hydrocarbon FAMILY 23438501 A 1058 1065 cocaine TRIVIAL 23438501 A 1289 1296 cocaine TRIVIAL 23438501 A 156 163 cocaine TRIVIAL 23438501 A 174 181 cocaine TRIVIAL 23438501 A 418 425 cocaine TRIVIAL 23438501 A 460 467 cocaine TRIVIAL 23438501 A 502 509 cocaine TRIVIAL 23438501 A 60 67 cocaine TRIVIAL 23438501 T 125 132 cocaine TRIVIAL 23438501 T 38 45 cocaine TRIVIAL 23439383 A 580 584 NMDA ABBREVIATION 23439383 A 701 705 AMPA ABBREVIATION 23439383 A 767 771 AMPA ABBREVIATION 23439661 A 0 80 (S)-3-(Aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole SYSTEMATIC 23439661 A 105 110 boron SYSTEMATIC 23439661 A 1120 1130 GSK2251052 IDENTIFIER 23439661 A 1197 1205 propanol SYSTEMATIC 23439661 A 1238 1253 carboxylic acid SYSTEMATIC 23439661 A 157 163 leucyl TRIVIAL 23439661 A 1665 1681 4-methylpyrazole SYSTEMATIC 23439661 A 1712 1719 alcohol FAMILY 23439661 A 1767 1775 aldehyde SYSTEMATIC 23439661 A 347 364 [(14)C]GSK2251052 SYSTEMATIC 23439661 A 82 92 GSK2251052 IDENTIFIER 23439661 A 931 941 GSK2251052 IDENTIFIER 23439661 T 30 40 GSK2251052 IDENTIFIER 23439661 T 60 65 Boron SYSTEMATIC 23439872 A 1331 1337 carbon SYSTEMATIC 23439872 A 1410 1416 carbon SYSTEMATIC 23439872 A 1804 1810 carbon SYSTEMATIC 23439872 A 1854 1861 choline FAMILY 23439872 A 1867 1873 folate TRIVIAL 23439872 A 21 27 carbon SYSTEMATIC 23439872 A 229 235 carbon SYSTEMATIC 23439872 A 326 332 carbon SYSTEMATIC 23439872 A 500 507 choline FAMILY 23439872 A 513 519 folate TRIVIAL 23439872 A 604 610 carbon SYSTEMATIC 23439872 A 639 649 methionine TRIVIAL 23439872 A 682 695 cystathionine TRIVIAL 23439872 A 714 739 methylenetetrahydrofolate SYSTEMATIC 23439872 A 759 767 adenosyl TRIVIAL 23439872 A 795 820 methylenetetrahydrofolate SYSTEMATIC 23439872 T 101 107 folate TRIVIAL 23439872 T 38 44 carbon SYSTEMATIC 23439872 T 88 95 choline FAMILY 23440001 A 0 4 F-Ti FORMULA 23440001 A 138 155 ammonium fluoride SYSTEMATIC 23440001 A 172 176 NH4F FORMULA 23440001 A 235 237 Ti FORMULA 23440001 A 288 289 F FORMULA 23440001 A 303 310 zeolite TRIVIAL 23440001 A 351 353 Ti FORMULA 23440001 A 355 363 Fluorine SYSTEMATIC 23440001 A 418 425 zeolite TRIVIAL 23440001 A 44 52 fluorine SYSTEMATIC 23440001 A 483 485 Ti FORMULA 23440001 A 512 516 SiO3 FORMULA 23440001 A 517 519 2F FORMULA 23440001 A 524 528 SiO4 FORMULA 23440001 A 529 534 2F(-) FORMULA 23440001 A 565 569 SiO4 FORMULA 23440001 A 570 575 2F(-) FORMULA 23440001 A 585 589 F-Ti FORMULA 23440001 A 663 679 alkali chlorides FAMILY 23440001 A 68 70 Ti FORMULA 23440001 A 681 685 F-Ti FORMULA 23440001 A 705 709 SiO3 FORMULA 23440001 A 710 712 2F FORMULA 23440001 A 821 823 Ti FORMULA 23440001 T 61 69 fluorine SYSTEMATIC 23440001 T 87 101 titanosilicate SYSTEMATIC 23440015 A 1195 1197 Au FORMULA 23440015 A 248 250 Au FORMULA 23440015 A 840 842 Au FORMULA 23440581 A 773 785 conduritol F TRIVIAL 23440581 A 827 829 Si FORMULA 23440867 A 650 658 tyrosine TRIVIAL 23440867 A 678 687 gefitinib TRIVIAL 23440867 A 689 698 erlotinib TRIVIAL 23440867 A 700 709 lapatinib TRIVIAL 23440867 A 711 719 afatanib TRIVIAL 23440867 A 721 732 dacomitinib TRIVIAL 23440867 A 812 821 sorafenib TRIVIAL 23440867 A 823 832 sunitinib TRIVIAL 23440867 A 834 844 vandetanib TRIVIAL 23440867 A 910 930 phosphatidylinositol TRIVIAL 23440867 A 972 981 rapamycin TRIVIAL 23440918 A 0 6 Serine TRIVIAL 23440918 A 121 128 enamide SYSTEMATIC 23440918 A 170 181 nosiheptide TRIVIAL 23440918 A 45 48 Ser FORMULA 23440918 A 74 85 nosiheptide TRIVIAL 23440918 A 99 110 amino acids FAMILY 23440918 T 24 30 serine TRIVIAL 23440918 T 4 5 C FORMULA 23440918 T 65 76 nosiheptide TRIVIAL 23440928 A 1053 1062 carnosine TRIVIAL 23440928 A 1132 1140 hydrogen SYSTEMATIC 23440928 A 1265 1277 heptapeptide FAMILY 23440928 A 1297 1306 carnosine TRIVIAL 23440928 A 1362 1370 hydrogen SYSTEMATIC 23440928 A 1528 1537 carnosine TRIVIAL 23440928 A 1640 1648 hydrogen SYSTEMATIC 23440928 A 290 299 carnosine TRIVIAL 23440928 A 303 312 dipeptide FAMILY 23440928 A 416 428 thioflavin T TRIVIAL 23440928 A 466 475 carnosine TRIVIAL 23440928 A 620 629 carnosine TRIVIAL 23440928 A 951 960 carnosine TRIVIAL 23440928 T 0 9 Carnosine TRIVIAL 23440928 T 56 57 H FORMULA 23440974 A 111 117 copper SYSTEMATIC 23440974 A 26 31 oxide SYSTEMATIC 23440974 T 22 27 Oxide SYSTEMATIC 23441007 A 161 165 MoS2 FORMULA 23441007 A 68 72 MoS2 FORMULA 23441007 A 87 89 Si FORMULA 23441007 A 90 94 SiO2 FORMULA 23441007 T 50 54 MoS2 FORMULA 23441649 A 1104 1116 ampelopsin F TRIVIAL 23441649 A 1117 1125 pallidol TRIVIAL 23441649 A 122 132 stilbenoid FAMILY 23441649 A 24 36 ampelopsin F TRIVIAL 23441649 A 38 47 viniferin TRIVIAL 23441649 A 428 438 stilbenoid FAMILY 23441649 A 49 57 pallidol TRIVIAL 23441904 A 1034 1050 bile salts/acids MULTIPLE 23441904 A 1076 1092 bile salts/acids MULTIPLE 23441904 A 1136 1144 hydrogen SYSTEMATIC 23441904 A 1219 1235 bile salts/acids MULTIPLE 23441904 A 299 309 bile salts FAMILY 23441904 A 314 324 bile acids FAMILY 23441904 A 368 379 cyclohexane SYSTEMATIC 23441904 A 384 392 n-decane SYSTEMATIC 23441904 A 39 49 bile salts FAMILY 23441904 A 533 543 bile salts FAMILY 23441904 A 827 837 bile acids FAMILY 23441904 T 44 60 bile salts/acids MULTIPLE 23443358 A 82 87 sugar FAMILY 23443358 T 62 67 sugar FAMILY 23443488 A 236 242 amines FAMILY 23443488 A 27 33 amines FAMILY 23443488 A 297 303 amines FAMILY 23443488 A 545 551 amines FAMILY 23443488 A 613 619 amines FAMILY 23443488 T 36 42 amines FAMILY 23443753 A 179 188 sorafenib TRIVIAL 23443753 A 297 306 pazopanib TRIVIAL 23443753 A 474 483 sorafenib TRIVIAL 23443753 A 561 570 sorafenib TRIVIAL 23443753 A 676 685 sorafenib TRIVIAL 23443810 A 729 737 creatine TRIVIAL 23443810 A 834 842 creatine TRIVIAL 23444015 A 1331 1340 acetylene SYSTEMATIC 23444015 A 1353 1388 2-methyl-6-(phenylethynyl)-pyridine SYSTEMATIC 23444015 A 1426 1437 amino acids FAMILY 23444015 A 47 56 glutamate TRIVIAL 23444015 A 690 699 acetylene SYSTEMATIC 23444015 T 25 34 Glutamate TRIVIAL 23444138 A 206 213 steroid FAMILY 23444138 A 350 358 estrogen FAMILY 23444138 A 439 447 estrogen FAMILY 23444138 A 747 754 steroid FAMILY 23444138 T 69 77 estrogen FAMILY 23444282 A 1000 1008 Busulfan TRIVIAL 23444282 A 1186 1194 busulfan TRIVIAL 23444282 A 221 229 busulfan TRIVIAL 23444282 A 266 274 busulfan TRIVIAL 23444282 A 31 39 busulfan TRIVIAL 23444282 A 316 324 busulfan TRIVIAL 23444282 A 381 389 busulfan TRIVIAL 23444282 A 633 641 busulfan TRIVIAL 23444282 A 719 727 busulfan TRIVIAL 23444282 A 802 810 busulfan TRIVIAL 23444282 T 81 89 busulfan TRIVIAL 23444286 A 1248 1258 doxylamine TRIVIAL 23444286 A 1262 1265 PLP ABBREVIATION 23444286 A 20 30 doxylamine TRIVIAL 23444286 A 220 230 doxylamine TRIVIAL 23444286 A 231 241 pyridoxine TRIVIAL 23444286 A 31 41 pyridoxine TRIVIAL 23444286 A 341 351 doxylamine TRIVIAL 23444286 A 356 378 pyridoxal 5'-phosphate SYSTEMATIC 23444286 A 380 383 PLP ABBREVIATION 23444286 A 410 422 vitamin B(6) TRIVIAL 23444286 A 493 502 Diclectin TRIVIAL 23444286 A 710 719 Diclectin TRIVIAL 23444286 A 767 777 doxylamine TRIVIAL 23444286 A 9 18 Diclectin TRIVIAL 23444286 T 34 44 doxylamine TRIVIAL 23444286 T 45 55 pyridoxine TRIVIAL 23444300 A 1082 1085 ZnP FORMULA 23444300 A 110 112 Zn FORMULA 23444300 A 113 122 porphyrin FAMILY 23444300 A 1140 1143 NIE ABBREVIATION 23444300 A 1147 1149 Zn FORMULA 23444300 A 1150 1159 porphyrin FAMILY 23444300 A 1195 1202 corrole FAMILY 23444300 A 149 152 NIE ABBREVIATION 23444300 A 1548 1551 ZnP FORMULA 23444300 A 1704 1707 NIE ABBREVIATION 23444300 A 1708 1711 ZnP FORMULA 23444300 A 1722 1725 NIE ABBREVIATION 23444300 A 182 195 1,3-phenylene SYSTEMATIC 23444300 A 214 217 ZnP FORMULA 23444300 A 240 243 CC FORMULA 23444300 A 314 332 trans-A2 B-corrole FAMILY 23444300 A 348 353 imide SYSTEMATIC 23444300 A 400 431 meso-substituted A3 B-porphyrin FAMILY 23444300 A 50 74 meso-substituted corrole FAMILY 23444300 A 612 615 NIE ABBREVIATION 23444300 A 744 751 corrole FAMILY 23444300 A 79 99 1,8 naphthaleneimide SYSTEMATIC 23444300 A 928 931 ZnP FORMULA 23444300 A 963 966 NIE ABBREVIATION 23444300 T 29 52 porphyrin-imide-corrole FAMILY 23444334 A 109 112 BHT ABBREVIATION 23444334 A 131 155 ferric nitrilotriacetate SYSTEMATIC 23444334 A 157 163 Fe-NTA FORMULA 23444334 A 243 249 Fe-NTA FORMULA 23444334 A 265 274 ornithine TRIVIAL 23444334 A 320 328 carbonyl FAMILY 23444334 A 405 421 [(3)H] thymidine SYSTEMATIC 23444334 A 679 682 BHT ABBREVIATION 23444334 A 703 706 BHT ABBREVIATION 23444334 A 744 750 Fe-NTA FORMULA 23444334 A 81 107 butylated hydroxyl toluene SYSTEMATIC 23444334 T 21 45 butylated hydroxytoluene SYSTEMATIC 23444334 T 49 73 ferric nitrilotriacetate SYSTEMATIC 23444336 A 145 153 inositol TRIVIAL 23444336 A 878 885 calcein TRIVIAL 23444774 A 485 493 methanol SYSTEMATIC 23444774 A 498 513 phosphoric acid SYSTEMATIC 23444774 T 72 77 rhein TRIVIAL 23444774 T 78 88 diclofenac TRIVIAL 23444775 A 379 390 sibutramine TRIVIAL 23444775 A 478 489 sibutramine TRIVIAL 23444775 A 655 666 sibutramine TRIVIAL 23444775 T 24 35 sibutramine TRIVIAL 23444776 A 299 309 Phenacetin TRIVIAL 23444776 A 311 319 coumarin TRIVIAL 23444776 A 321 332 tolbutamide TRIVIAL 23444776 A 334 347 chlorzoxazone SYSTEMATIC 23444776 A 352 364 testosterone TRIVIAL 23444776 A 803 815 acetonitrile SYSTEMATIC 23444776 A 834 849 phosphoric acid SYSTEMATIC 23444776 T 109 122 chlorzoxazone SYSTEMATIC 23444776 T 124 136 testosterone TRIVIAL 23444776 T 74 84 phenacetin TRIVIAL 23444776 T 86 94 coumarin TRIVIAL 23444776 T 96 107 tolbutamide TRIVIAL 23444960 A 145 213 2,2',7,7'-tetrakis(N,N-di-p-methoxyphenylamine)-9,9'-spirobifluorene SYSTEMATIC 23444960 A 215 227 spiro-MeOTAD SYSTEMATIC 23444960 A 376 380 TiO2 FORMULA 23444960 A 426 430 ZrO2 FORMULA 23444960 A 781 793 spiro-MeOTAD SYSTEMATIC 23444960 A 870 874 TiO2 FORMULA 23444960 A 879 883 ZrO2 FORMULA 23444960 T 50 62 spiro-MeOTAD SYSTEMATIC 23444962 A 213 232 thiobarbituric-acid SYSTEMATIC 23444962 A 266 285 reduced glutathione TRIVIAL 23444962 A 636 647 doxorubicin TRIVIAL 23444963 A 1161 1172 cholesterol TRIVIAL 23444963 A 126 137 cholesterol TRIVIAL 23444963 A 631 638 glucose TRIVIAL 23444963 A 652 659 glucose TRIVIAL 23444963 A 667 678 cholesterol TRIVIAL 23444963 A 901 912 cholesterol TRIVIAL 23444964 A 1254 1268 corticosterone TRIVIAL 23444964 A 221 240 omega-3 fatty acids FAMILY 23444964 A 264 274 eicosanoid FAMILY 23444964 A 376 384 linalool TRIVIAL 23445346 A 247 268 dodecyl-β-D-maltoside SYSTEMATIC 23445346 A 270 273 DDM ABBREVIATION 23445346 A 286 313 lauryldimethylamine N-oxide SYSTEMATIC 23445346 A 315 319 LDAO ABBREVIATION 23445522 A 0 12 Almiramide C TRIVIAL 23445522 A 160 172 almiramide C TRIVIAL 23445522 A 541 552 almiramides FAMILY 23445522 A 927 938 almiramides FAMILY 23445522 T 41 51 Almiramide FAMILY 23445562 A 678 686 estrogen FAMILY 23445562 A 687 699 progesterone TRIVIAL 23446434 A 72 75 ZnO FORMULA 23446434 T 75 78 ZnO FORMULA 23446650 A 195 216 hydrazonoyl chlorides FAMILY 23446650 A 232 276 2-hydrazino-pyrido[2,3-d]pyrimidin-4(3H)-one SYSTEMATIC 23446650 A 292 301 aldehydes FAMILY 23446650 A 32 82 pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one SYSTEMATIC 23446650 A 99 189 7-(4-bromophenyl)-1,2-dihydro-5-(4-fluorophenyl)-2-thioxopyrido[2,3-d] pyrimidin-4(3H)-one SYSTEMATIC 23446650 T 13 64 pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones FAMILY 23448129 A 20 28 nitrogen SYSTEMATIC 23448129 A 307 311 H2O2 FORMULA 23448129 A 313 316 ·OH FORMULA 23448129 A 318 324 (-)OCl FORMULA 23448129 A 326 329 NO· FORMULA 23448129 A 335 340 O2(-) FORMULA 23448129 A 347 358 glutathione TRIVIAL 23448129 A 388 391 GSH ABBREVIATION 23448129 A 435 439 GSHs FAMILY 23448129 A 505 527 glutathione disulfides FAMILY 23448129 A 767 771 H2O2 FORMULA 23448129 A 9 15 oxygen SYSTEMATIC 23448129 T 0 11 Glutathione TRIVIAL 23448129 T 81 87 oxygen SYSTEMATIC 23448129 T 92 100 nitrogen SYSTEMATIC 23448165 A 1082 1090 graphene TRIVIAL 23448165 A 191 197 carbon SYSTEMATIC 23448165 A 222 230 graphene TRIVIAL 23448165 A 279 282 SiC FORMULA 23448165 A 355 363 graphene TRIVIAL 23448165 A 382 390 graphene TRIVIAL 23448165 A 534 542 graphene TRIVIAL 23448165 A 615 623 graphene TRIVIAL 23448165 A 673 675 Cu FORMULA 23448165 A 8 16 graphene TRIVIAL 23448165 A 961 969 graphene TRIVIAL 23448165 T 17 25 graphene TRIVIAL 23448281 A 0 31 Acyclic nucleoside phosphonates FAMILY 23448281 A 151 162 6-oxopurine SYSTEMATIC 23448281 A 255 286 2-(phosphonoethoxy)ethylguanine SYSTEMATIC 23448281 A 288 292 PEEG ABBREVIATION 23448281 A 33 37 ANPs FAMILY 23448281 A 352 356 ANPs FAMILY 23448281 A 397 408 phosphonate SYSTEMATIC 23448281 A 431 434 ANP ABBREVIATION 23448281 A 445 531 {[(2-[(Guanine-9H-yl)methyl]propane-1,3-diyl)bis(oxy)]bis(methylene)}diphosphonic acid SYSTEMATIC 23448281 A 54 65 6-oxopurine SYSTEMATIC 23448281 A 793 799 purine TRIVIAL 23448281 A 810 822 5'-phosphate SYSTEMATIC 23448281 A 834 847 pyrophosphate SYSTEMATIC 23448281 T 0 31 Acyclic nucleoside phosphonates FAMILY 23448281 T 52 63 phosphonate SYSTEMATIC 23448281 T 95 106 6-oxopurine SYSTEMATIC 23448346 A 0 8 Estrogen FAMILY 23448346 A 168 181 17β-estradiol SYSTEMATIC 23448346 A 779 790 ICI-182,780 IDENTIFIER 23448346 A 978 989 ICI-182,780 IDENTIFIER 23448346 T 19 27 estrogen FAMILY 23449200 A 200 213 acetaminophen TRIVIAL 23449200 A 215 227 indomethacin TRIVIAL 23449200 A 233 260 tri-O-methyl-β-cyclodextrin SYSTEMATIC 23449203 A 1077 1083 Ropion TRIVIAL 23449203 A 1085 1094 Primperan TRIVIAL 23449203 A 115 121 Ropion TRIVIAL 23449203 A 1172 1191 flurbiprofen axetil TRIVIAL 23449203 A 136 155 flurbiprofen axetil TRIVIAL 23449203 A 157 163 Ropion TRIVIAL 23449203 A 228 234 Ropion TRIVIAL 23449203 A 287 293 Ropion TRIVIAL 23449203 A 304 310 Gaster TRIVIAL 23449203 A 323 333 famotidine TRIVIAL 23449203 A 335 341 Gaster TRIVIAL 23449203 A 347 356 Primperan TRIVIAL 23449203 A 369 397 metoclopramide hydrochloride SYSTEMATIC 23449203 A 399 408 Primperan TRIVIAL 23449203 A 581 600 flurbiprofen axetil TRIVIAL 23449203 A 628 634 Ropion TRIVIAL 23449203 A 886 892 Ropion TRIVIAL 23449203 A 901 907 Ropion TRIVIAL 23449203 A 909 915 Gaster TRIVIAL 23449501 A 0 9 Potassium SYSTEMATIC 23449501 A 1012 1013 N FORMULA 23449501 A 11 15 K(+) FORMULA 23449501 A 1181 1185 K(+) FORMULA 23449501 A 1235 1239 K(+) FORMULA 23449501 A 133 137 K(+) FORMULA 23449501 A 1367 1373 Ca(2+) FORMULA 23449501 A 1398 1402 K(+) FORMULA 23449501 A 240 246 Ca(2+) FORMULA 23449501 A 308 314 Ca(2+) FORMULA 23449501 A 350 354 K(+) FORMULA 23449501 A 356 360 K(+) FORMULA 23449501 A 439 443 K(+) FORMULA 23449501 A 46 50 K(+) FORMULA 23449501 A 510 516 Ca(2+) FORMULA 23449501 A 584 590 Ca(2+) FORMULA 23449501 A 615 619 K(+) FORMULA 23449501 T 0 4 Ca2+ FORMULA 23449501 T 86 88 K+ FORMULA 23450708 A 263 278 oligothiophenes FAMILY 23450708 A 491 500 thiophene SYSTEMATIC 23450708 A 782 791 thiophene SYSTEMATIC 23450708 A 828 836 carboxyl SYSTEMATIC 23450708 T 23 38 oligothiophenes FAMILY 23450741 A 264 277 shikimic acid TRIVIAL 23450741 A 536 544 hydrogen SYSTEMATIC 23450827 A 383 397 Levonorgestrel TRIVIAL 23450827 A 715 729 levonorgestrel TRIVIAL 23450827 A 895 909 levonorgestrel TRIVIAL 23451853 A 1053 1055 HF FORMULA 23451853 A 1065 1069 Si-H FORMULA 23451853 A 1127 1137 1-dodecene SYSTEMATIC 23451853 A 1141 1158 10-bromo-1-decene SYSTEMATIC 23451853 A 117 119 Si FORMULA 23451853 A 1217 1219 Si FORMULA 23451853 A 1307 1314 dodecyl SYSTEMATIC 23451853 A 1454 1463 rhodamine TRIVIAL 23451853 A 236 238 Si FORMULA 23451853 A 270 272 Si FORMULA 23451853 A 377 390 silicon oxide SYSTEMATIC 23451853 A 461 463 Si FORMULA 23451853 A 512 518 octane SYSTEMATIC 23451853 A 580 597 hydrogen fluoride SYSTEMATIC 23451853 A 599 601 HF FORMULA 23451853 A 724 726 HF FORMULA 23451853 A 788 790 Si FORMULA 23451853 A 825 833 hydrogen SYSTEMATIC 23451853 A 846 850 Si-H FORMULA 23451853 A 923 929 octane SYSTEMATIC 23451853 A 978 982 Si-H FORMULA 23451853 T 84 91 silicon SYSTEMATIC 23452230 A 141 148 alkanes FAMILY 23452230 A 433 442 n-pentane SYSTEMATIC 23452230 T 65 74 n-Pentane SYSTEMATIC 23452271 A 1019 1023 Dopa ABBREVIATION 23452271 A 1024 1026 Ti FORMULA 23452271 A 1085 1089 Dopa ABBREVIATION 23452271 A 114 140 3,4-dihydroxyphenylalanine SYSTEMATIC 23452271 A 1323 1327 TiO2 FORMULA 23452271 A 1387 1391 Dopa ABBREVIATION 23452271 A 142 146 Dopa ABBREVIATION 23452271 A 166 170 Dopa ABBREVIATION 23452271 A 271 283 metal oxides FAMILY 23452271 A 285 293 Titanium SYSTEMATIC 23452271 A 369 373 TiO2 FORMULA 23452271 A 463 467 Dopa ABBREVIATION 23452271 A 471 475 TiO2 FORMULA 23452271 A 682 686 TiO2 FORMULA 23452271 A 794 798 TiO2 FORMULA 23452271 A 923 927 Dopa ABBREVIATION 23452271 A 967 971 Dopa ABBREVIATION 23452271 T 37 41 TiO2 FORMULA 23452431 A 1016 1022 oxygen SYSTEMATIC 23452431 A 704 710 oxygen SYSTEMATIC 23452431 T 40 46 Oxygen SYSTEMATIC 23452502 A 379 386 glucose TRIVIAL 23452502 A 402 412 fatty acid FAMILY 23452502 A 561 568 glucose TRIVIAL 23452502 A 572 582 fatty acid FAMILY 23453305 A 1361 1372 glutathione TRIVIAL 23453305 A 1374 1389 malondialdehyde TRIVIAL 23453305 A 1443 1450 ectoine TRIVIAL 23453305 A 228 235 Ectoine TRIVIAL 23453305 A 689 696 ectoine TRIVIAL 23453305 A 714 727 sulfasalazine TRIVIAL 23453305 A 825 859 2,4,6-trinitrobenzenesulfonic acid SYSTEMATIC 23453305 T 17 24 ectoine TRIVIAL 23453305 T 53 73 tetrahydropyrimidine SYSTEMATIC 23453306 A 1231 1237 thymol TRIVIAL 23453306 A 420 426 thymol TRIVIAL 23453306 A 680 686 thymol TRIVIAL 23453306 A 688 696 p-cymene TRIVIAL 23453306 A 698 709 γ-terpinene TRIVIAL 23453306 A 714 721 myrcene TRIVIAL 23454002 A 716 728 progesterone TRIVIAL 23454002 A 733 741 cortisol TRIVIAL 23454016 A 1302 1308 ferric SYSTEMATIC 23454016 A 1315 1321 Fe(3+) FORMULA 23454016 A 177 260 2-amino-4-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-6-aryl-4H-pyran-3-carbonitriles FAMILY 23454016 A 269 395 4,5-diamino-6-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-8-aryl-2-oxo-2,6-dihydrodipyrano [2,3-b:3,2-e]pyridine-3-carbonitriles FAMILY 23454016 A 404 498 4-amino-5-(5'-substituted 2'-phenyl-1H-indol-3-yl)-7-aryl-1H-pyrano[2,3-d]pyrimidin-2(5H)-ones FAMILY 23454016 A 507 605 4-amino-5-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-7-aryl-1H-pyrano[2,3-d]pyrimidin-2(5H)-thiones FAMILY 23454016 A 614 704 4-(5'-subtituted 2'-phenyl-1H-indol-3'-yl)-6-aryl-1,4-dihydropyrano[2,3-c]pyrazol-3-amines FAMILY 23454016 A 716 803 5-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-7-aryl-3H-pyrano[2,3-d]pyrimidin-4(5H)-ones FAMILY 23454016 A 80 86 indole SYSTEMATIC 23454016 T 19 101 2-amino-4-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-6-aryl-4H-pyran-3-carbonitrile FAMILY 23454135 A 1062 1067 VA441 IDENTIFIER 23454135 A 1072 1077 VA428 IDENTIFIER 23454135 A 1491 1496 VA441 IDENTIFIER 23454135 A 1501 1506 VA428 IDENTIFIER 23454135 A 548 597 1,5-diarylpyrrole-3-alkoxyethyl esters and ethers MULTIPLE 23454135 A 58 58 MULTIPLE 23454135 A 61 80 diaryl heterocycles FAMILY 23454135 A 630 668 1,5-diarylpyrrole-3-alkoxyethyl ethers FAMILY 23454135 A 670 675 VA441 IDENTIFIER 23454135 A 680 685 VA428 IDENTIFIER 23454135 A 756 765 celecoxib TRIVIAL 23454135 A 770 779 rofecoxib TRIVIAL 23454135 A 88 97 celecoxib TRIVIAL 23454135 A 99 108 rofecoxib TRIVIAL 23454144 A 429 435 oxygen SYSTEMATIC 23454145 A 1025 1042 7-ketocholesterol SYSTEMATIC 23454145 A 1086 1093 HMG-CoA ABBREVIATION 23454145 A 1119 1132 7-ketosterols FAMILY 23454145 A 1214 1231 7-ketocholesterol SYSTEMATIC 23454145 A 127 145 phytosterol oxides FAMILY 23454145 A 1441 1459 7-ketostigmasterol SYSTEMATIC 23454145 A 1487 1489 Ca FORMULA 23454145 A 1518 1524 HMGCoA TRIVIAL 23454145 A 1645 1657 7-ketosterol FAMILY 23454145 A 20 26 sterol FAMILY 23454145 A 358 369 cholesterol TRIVIAL 23454145 A 414 420 HMGCoA TRIVIAL 23454145 A 440 453 7-ketosterols FAMILY 23454145 A 455 467 stigmasterol TRIVIAL 23454145 A 468 479 cholesterol TRIVIAL 23454145 A 604 622 7-ketostigmasterol SYSTEMATIC 23454145 A 672 689 7-ketocholesterol SYSTEMATIC 23454145 A 765 778 7-ketosterols FAMILY 23454145 A 856 866 bradykinin TRIVIAL 23454145 A 915 933 7-ketostigmasterol SYSTEMATIC 23454145 A 98 116 cholesterol oxides FAMILY 23454145 T 112 124 7-ketosterol FAMILY 23454145 T 23 34 cholesterol TRIVIAL 23454146 A 1041 1042 N FORMULA 23454146 A 1078 1086 magnolol TRIVIAL 23454146 A 1180 1188 obovatol TRIVIAL 23454146 A 1213 1242 2,2-diphenyl-1-picrylhydrazyl SYSTEMATIC 23454146 A 1306 1312 oxygen SYSTEMATIC 23454146 A 1331 1340 glutamate TRIVIAL 23454146 A 1386 1394 obovatol TRIVIAL 23454146 A 1399 1407 honokiol TRIVIAL 23454146 A 148 156 Obovatol TRIVIAL 23454146 A 158 166 honokiol TRIVIAL 23454146 A 172 180 magnolol TRIVIAL 23454146 A 262 270 obovatol TRIVIAL 23454146 A 272 280 honokiol TRIVIAL 23454146 A 286 294 magnolol TRIVIAL 23454146 A 323 332 glutamate TRIVIAL 23454146 A 384 393 glutamate TRIVIAL 23454146 A 487 495 obovatol TRIVIAL 23454146 A 502 510 honokiol TRIVIAL 23454146 A 521 529 magnolol TRIVIAL 23454146 A 646 654 obovatol TRIVIAL 23454146 A 659 667 honokiol TRIVIAL 23454146 A 730 736 oxygen SYSTEMATIC 23454146 T 27 37 neolignans FAMILY 23454146 T 77 86 glutamate TRIVIAL 23454149 A 1023 1027 DMBT ABBREVIATION 23454149 A 1150 1154 DMBT ABBREVIATION 23454149 A 239 250 brartemicin TRIVIAL 23454149 A 374 378 DMBT ABBREVIATION 23454149 A 380 427 6,6'-bis (2,3-dimethoxybenzoyl)-a,a-d-trehalose SYSTEMATIC 23454149 A 501 505 DMBT ABBREVIATION 23454149 A 575 579 DMBT ABBREVIATION 23454149 A 646 649 MTT ABBREVIATION 23454149 A 713 717 DMBT ABBREVIATION 23454149 A 729 733 DMBT ABBREVIATION 23454149 A 829 833 DMBT ABBREVIATION 23454149 A 912 916 DMBT ABBREVIATION 23454149 T 43 47 DMBT ABBREVIATION 23454202 A 1058 1061 GSH ABBREVIATION 23454202 A 1304 1312 curcumin TRIVIAL 23454202 A 1368 1376 curcumin TRIVIAL 23454202 A 19 27 curcumin TRIVIAL 23454202 A 192 200 curcumin TRIVIAL 23454202 A 773 783 superoxide TRIVIAL 23454202 A 805 816 glutathione TRIVIAL 23454202 A 918 925 nitrite SYSTEMATIC 23454202 T 0 8 Curcumin TRIVIAL 23454217 A 1041 1046 11oxo SYSTEMATIC 23454217 A 1056 1070 pregnane(ene)s MULTIPLE 23454217 A 106 123 21-deoxycortisone SYSTEMATIC 23454217 A 1148 1149 C FORMULA 23454217 A 1254 1271 21-deoxycortisone SYSTEMATIC 23454217 A 1276 1285 cortisone TRIVIAL 23454217 A 1431 1441 6-hydroxyl SYSTEMATIC 23454217 A 1510 1527 21-deoxycortisone SYSTEMATIC 23454217 A 1716 1735 11oxo-pregnanetriol SYSTEMATIC 23454217 A 175 197 17-hydroxyprogesterone SYSTEMATIC 23454217 A 368 376 steroids FAMILY 23454217 A 452 459 steroid FAMILY 23454217 A 484 492 Cortisol TRIVIAL 23454217 A 53 69 21-deoxycortisol SYSTEMATIC 23454217 A 580 585 11oxo SYSTEMATIC 23454217 A 641 649 Steroids FAMILY 23454217 A 721 753 methyloxime-trimethylsilyl ether SYSTEMATIC 23454217 A 940 960 11oxo-pregnane(enes) MULTIPLE 23454217 A 95 100 11oxo SYSTEMATIC 23454217 T 0 8 Steroids FAMILY 23454217 T 121 136 11oxo-pregnanes FAMILY 23454217 T 141 156 11oxo-pregnenes FAMILY 23454417 A 1159 1166 glucose TRIVIAL 23454417 A 129 141 nitric oxide SYSTEMATIC 23454417 A 223 236 Peroxynitrite SYSTEMATIC 23454417 A 250 252 NO FORMULA 23454417 A 257 267 superoxide TRIVIAL 23454417 A 395 402 glucose TRIVIAL 23454417 A 750 757 glucose TRIVIAL 23454417 A 881 888 glucose TRIVIAL 23454417 A 893 906 peroxynitrite SYSTEMATIC 23454417 T 37 49 nitric oxide SYSTEMATIC 23454417 T 99 106 glucose TRIVIAL 23454527 A 419 435 N-acetylcysteine SYSTEMATIC 23454527 A 437 440 NAC ABBREVIATION 23454527 A 463 464 N FORMULA 23454527 A 498 506 SP600125 IDENTIFIER 23454528 A 1032 1037 MK801 IDENTIFIER 23454528 A 1039 1050 scopolamine TRIVIAL 23454528 A 425 445 N-methyl-d-aspartate SYSTEMATIC 23454528 A 466 471 MK801 IDENTIFIER 23454528 A 516 527 scopolamine TRIVIAL 23454528 A 902 908 SHA 68 IDENTIFIER 23454528 T 74 79 MK801 IDENTIFIER 23454528 T 81 92 scopolamine TRIVIAL 23454653 A 1009 1021 acetonitrile SYSTEMATIC 23454653 A 1106 1111 2M4MQ SYSTEMATIC 23454653 A 1143 1147 H2O2 FORMULA 23454653 A 1151 1154 H2O FORMULA 23454653 A 1165 1187 benzylic hydroperoxide SYSTEMATIC 23454653 A 1191 1198 alcohol FAMILY 23454653 A 1240 1243 GSH ABBREVIATION 23454653 A 1270 1278 cysteine TRIVIAL 23454653 A 1292 1295 Cys FORMULA 23454653 A 1354 1359 2M4MQ SYSTEMATIC 23454653 A 1397 1402 thiol FAMILY 23454653 A 1420 1424 thio SYSTEMATIC 23454653 A 1454 1459 2M4MP SYSTEMATIC 23454653 A 1594 1599 Amino SYSTEMATIC 23454653 A 1676 1681 2M4MQ SYSTEMATIC 23454653 A 1723 1729 lysine TRIVIAL 23454653 A 1733 1741 arginine TRIVIAL 23454653 A 1868 1890 sodium dodecyl sulfate SYSTEMATIC 23454653 A 1891 1903 tert-butanol SYSTEMATIC 23454653 A 1904 1914 chloroform TRIVIAL 23454653 A 498 515 hydrogen peroxide SYSTEMATIC 23454653 A 594 618 2-methoxy-4-methylphenol SYSTEMATIC 23454653 A 620 625 2M4MP SYSTEMATIC 23454653 A 867 872 (13)C FORMULA 23454653 A 943 948 2M4MP SYSTEMATIC 23454653 A 972 976 H2O2 FORMULA 23454653 T 65 94 2-methoxy-4-(¹³C)methylphenol SYSTEMATIC 23454828 A 1223 1234 terfenadine TRIVIAL 23454828 A 1348 1354 arenol TRIVIAL 23454828 A 1683 1689 phenol SYSTEMATIC 23454828 A 617 622 amine SYSTEMATIC 23454828 A 624 631 alcohol FAMILY 23454828 A 633 647 N- and S-oxide MULTIPLE 23454828 A 653 668 carboxylic acid SYSTEMATIC 23454828 A 927 942 carboxylic acid SYSTEMATIC 23454835 A 14 25 alternariol TRIVIAL 23454835 A 185 188 AOH FORMULA 23454835 A 263 266 AOH FORMULA 23454835 A 27 30 AOH FORMULA 23454835 A 605 608 AOH FORMULA 23454835 A 759 762 AOH FORMULA 23454835 T 0 11 Alternariol TRIVIAL 23454895 A 0 14 Graphene oxide SYSTEMATIC 23454895 A 111 115 PDEA ABBREVIATION 23454895 A 205 220 PDEA-grafted GO ABBREVIATION 23454895 A 222 229 GO-PDEA ABBREVIATION 23454895 A 439 443 PDEA ABBREVIATION 23454895 A 598 605 GO-PDEA ABBREVIATION 23454895 A 626 638 camptothecin TRIVIAL 23454895 A 640 643 CPT ABBREVIATION 23454895 A 68 109 poly(2-(diethylamino) ethyl methacrylate) FAMILY 23454895 A 700 703 CPT ABBREVIATION 23454895 A 818 825 GO-PDEA ABBREVIATION 23454895 A 886 897 GO-PDEA-CPT ABBREVIATION 23454895 A 998 1005 GO-PDEA ABBREVIATION 23454895 T 61 75 graphene oxide SYSTEMATIC 23455039 A 49 57 tyrosine TRIVIAL 23455039 A 739 749 amino-acid FAMILY 23455039 A 760 768 hydroxyl SYSTEMATIC 23455039 A 782 789 benzene SYSTEMATIC 23455039 T 67 75 tyrosine TRIVIAL 23455323 A 781 787 serine TRIVIAL 23455323 A 796 804 tyrosine TRIVIAL 23455461 A 1020 1026 silver SYSTEMATIC 23455461 A 1055 1057 Ag FORMULA 23455461 A 1251 1253 Ag FORMULA 23455461 A 228 230 Ag FORMULA 23455461 A 31 37 silver SYSTEMATIC 23455461 A 52 54 Ag FORMULA 23455461 A 609 611 Ag FORMULA 23455461 A 852 854 Ag FORMULA 23455461 A 945 951 silver SYSTEMATIC 23455461 T 7 13 silver SYSTEMATIC 23455597 A 1016 1029 d-amphetamine TRIVIAL 23455597 A 11 20 Histamine TRIVIAL 23455597 A 1148 1155 ABT-288 NO CLASS 23455597 A 1172 1183 amphetamine TRIVIAL 23455597 A 1316 1323 cocaine TRIVIAL 23455597 A 1415 1422 ABT-288 NO CLASS 23455597 A 1550 1557 ABT-288 NO CLASS 23455597 A 368 375 ABT-288 NO CLASS 23455597 A 516 523 ABT-288 NO CLASS 23455597 A 54 61 ABT-288 NO CLASS 23455597 A 653 664 amphetamine TRIVIAL 23455597 A 764 771 ABT-288 NO CLASS 23455597 A 849 856 ABT-288 NO CLASS 23455597 A 942 949 ABT-288 NO CLASS 23455597 T 37 44 ABT-288 NO CLASS 23455597 T 54 63 histamine TRIVIAL 23455732 A 222 229 silicon SYSTEMATIC 23456175 A 108 110 Na FORMULA 23456175 A 117 120 ZnO FORMULA 23456175 A 211 213 Ag FORMULA 23456175 A 256 258 Na FORMULA 23456175 A 265 268 ZnO FORMULA 23456175 A 279 281 Na FORMULA 23456175 A 94 96 Ag FORMULA 23456175 T 68 70 Ag FORMULA 23456175 T 89 91 Na FORMULA 23456175 T 98 101 ZnO FORMULA 23456813 A 1327 1334 carmine TRIVIAL 23456813 A 186 193 carmine TRIVIAL 23456813 A 562 569 carmine TRIVIAL 23456813 A 695 702 carmine TRIVIAL 23456813 A 951 958 carmine TRIVIAL 23457020 A 1116 1133 monofluoroacetate SYSTEMATIC 23457020 A 119 136 monofluoroacetate SYSTEMATIC 23457020 A 277 294 monofluoroacetate SYSTEMATIC 23457020 A 391 402 amino acids FAMILY 23457020 A 410 428 N-methyl-α-alanine SYSTEMATIC 23457020 A 430 448 N-methyl-β-alanine SYSTEMATIC 23457020 A 454 485 2,7-diaminooctan-1,8-dioic acid SYSTEMATIC 23457020 A 538 550 trigonelline TRIVIAL 23457020 A 678 680 1H FORMULA 23457020 A 757 768 amino acids FAMILY 23457020 T 24 41 monofluoroacetate SYSTEMATIC 23457020 T 8 19 amino acids FAMILY 23457090 A 140 145 Au-Ag FORMULA 23457090 A 210 212 Ag FORMULA 23457090 A 227 233 HAuCl4 FORMULA 23457090 A 273 275 Au FORMULA 23457090 A 323 329 HAuCl4 FORMULA 23457090 A 335 348 ascorbic acid TRIVIAL 23457090 A 371 373 Au FORMULA 23457090 A 425 431 HAuCl4 FORMULA 23457090 A 46 48 Au FORMULA 23457090 A 462 464 Au FORMULA 23457090 A 513 518 Au-Ag FORMULA 23457090 A 563 565 Au FORMULA 23457090 A 597 599 Au FORMULA 23457090 A 713 715 Au FORMULA 23457090 A 840 842 Ag FORMULA 23457090 A 880 885 Au-Ag FORMULA 23457090 T 110 116 Silver SYSTEMATIC 23457122 A 0 11 Bisphenol A TRIVIAL 23457122 A 1143 1146 BPA ABBREVIATION 23457122 A 13 16 BPA ABBREVIATION 23457122 A 1628 1631 BPA ABBREVIATION 23457122 A 432 440 estrogen FAMILY 23457122 A 475 478 BPA ABBREVIATION 23457122 A 503 511 estrogen FAMILY 23457122 A 619 622 BPA ABBREVIATION 23457122 A 80 83 BPA ABBREVIATION 23457122 A 828 831 BPA ABBREVIATION 23457122 A 857 874 ethinyl estradiol TRIVIAL 23457122 T 50 58 estrogen FAMILY 23457122 T 9 20 bisphenol a TRIVIAL 23458445 A 10 41 ethylenediaminetetraacetic acid SYSTEMATIC 23458445 A 117 155 ethylenediaminetetraacetic dianhydride SYSTEMATIC 23458445 A 157 162 EDTAD ABBREVIATION 23458445 A 43 47 EDTA ABBREVIATION 23458445 A 451 455 EDTA ABBREVIATION 23458445 A 729 733 EDTA ABBREVIATION 23458445 T 10 41 ethylenediaminetetraacetic Acid SYSTEMATIC 23458455 A 13 19 CdHgTe FORMULA 23458455 A 405 411 Cd(2+) FORMULA 23458455 A 415 421 Hg(2+) FORMULA 23458455 A 601 607 HTe(-) FORMULA 23458455 A 687 693 CdHgTe FORMULA 23458455 A 756 770 Cd0.21Hg0.79Te FORMULA 23458455 A 834 841 cadmium SYSTEMATIC 23458455 T 13 19 CdHgTe FORMULA 23458473 A 193 201 hydrogen SYSTEMATIC 23458473 A 232 240 hydroxyl SYSTEMATIC 23458473 A 598 613 phosphoric acid SYSTEMATIC 23458473 A 700 718 dimethyl sulfoxide SYSTEMATIC 23458473 A 724 741 dimethylformamide SYSTEMATIC 23458473 A 969 983 ethylene oxide SYSTEMATIC 23458473 A 984 999 epichlorohydrin TRIVIAL 23458473 T 56 71 phosphoric Acid SYSTEMATIC 23458581 A 1074 1085 amino acids FAMILY 23458581 A 300 311 amino acids FAMILY 23458581 A 455 466 amino acids FAMILY 23458581 A 53 64 amino acids FAMILY 23458581 A 670 673 Gly FORMULA 23458581 A 818 829 amino acids FAMILY 23458581 A 867 878 amino acids FAMILY 23458581 T 54 65 amino acids FAMILY 23458967 A 457 463 thiols FAMILY 23459067 A 102 114 polysiloxane FAMILY 23459067 A 190 198 paraffin FAMILY 23459067 A 378 388 n-eicosane SYSTEMATIC 23459067 A 412 435 polyhydromethylsiloxane FAMILY 23459067 A 500 512 polysiloxane FAMILY 23459067 A 546 556 silylvinyl SYSTEMATIC 23459067 A 561 567 alkoxy FAMILY 23459067 A 611 619 paraffin FAMILY 23459067 A 642 665 Pt(0) Karstedt catalyst TRIVIAL 23459067 A 763 775 polysiloxane FAMILY 23459067 A 77 87 n-eicosane SYSTEMATIC 23459067 A 847 854 silanol SYSTEMATIC 23459067 T 15 23 paraffin FAMILY 23459067 T 69 77 siloxane SYSTEMATIC 23459109 A 107 118 telmisartan TRIVIAL 23459109 A 1098 1104 oxygen SYSTEMATIC 23459109 A 1105 1113 nitrogen SYSTEMATIC 23459109 A 1119 1125 carbon SYSTEMATIC 23459109 A 1197 1200 TMS ABBREVIATION 23459109 A 120 123 TMS ABBREVIATION 23459109 A 1232 1235 TMS ABBREVIATION 23459109 A 1368 1371 TMS ABBREVIATION 23459109 A 1599 1602 TMS ABBREVIATION 23459109 A 272 275 TMS ABBREVIATION 23459109 A 560 563 TMS ABBREVIATION 23459109 A 743 746 TMS ABBREVIATION 23459109 T 58 69 telmisartan TRIVIAL 23459149 A 1011 1019 melamine TRIVIAL 23459149 A 1020 1029 uric acid TRIVIAL 23459149 A 1093 1101 melamine TRIVIAL 23459149 A 1163 1171 melamine TRIVIAL 23459149 A 1342 1350 melamine TRIVIAL 23459149 A 168 176 melamine TRIVIAL 23459149 A 614 622 melamine TRIVIAL 23459149 A 668 676 melamine TRIVIAL 23459149 A 871 879 melamine TRIVIAL 23459149 A 925 933 melamine TRIVIAL 23459149 T 79 87 melamine TRIVIAL 23459167 A 1051 1059 creatine TRIVIAL 23459167 A 1366 1381 methamphetamine TRIVIAL 23459167 A 1453 1464 amphetamine TRIVIAL 23459167 A 1590 1601 amphetamine TRIVIAL 23459167 A 1757 1768 amphetamine TRIVIAL 23459167 A 194 205 amphetamine TRIVIAL 23459167 A 297 308 amphetamine TRIVIAL 23459167 A 687 698 amphetamine TRIVIAL 23459167 A 840 851 amphetamine TRIVIAL 23459167 A 89 100 amphetamine TRIVIAL 23459167 A 995 1003 aldehyde SYSTEMATIC 23459167 T 111 122 amphetamine TRIVIAL 23459167 T 142 153 amphetamine TRIVIAL 23459442 A 1083 1086 Val ABBREVIATION 23459442 A 1087 1090 Val ABBREVIATION 23459442 A 13 14 O FORMULA 23459442 A 248 256 nicotine TRIVIAL 23459442 A 4 12 catechol TRIVIAL 23459442 A 428 436 nicotine TRIVIAL 23459442 A 478 484 valine TRIVIAL 23459442 A 486 489 Val ABBREVIATION 23459442 A 491 494 Val ABBREVIATION 23459442 A 519 529 methionine TRIVIAL 23459442 A 531 534 Met FORMULA 23459442 A 594 602 nicotine TRIVIAL 23459442 A 699 702 Val ABBREVIATION 23459442 A 703 706 Val ABBREVIATION 23459442 A 789 792 Val ABBREVIATION 23459442 A 793 796 Val ABBREVIATION 23459442 A 800 803 Met FORMULA 23459442 A 827 830 Val ABBREVIATION 23459442 A 831 834 Val ABBREVIATION 23459442 A 88 96 nicotine TRIVIAL 23459442 T 61 69 nicotine TRIVIAL 23460310 A 12 19 leucine TRIVIAL 23460310 A 3 11 arginine TRIVIAL 23460310 A 437 455 Lipofectamine 2000 TRIVIAL 23460363 A 333 350 polyglutamic acid FAMILY 23460363 A 378 381 PGA ABBREVIATION 23460363 A 574 580 folate TRIVIAL 23460363 T 23 40 Polyglutamic Acid FAMILY 23460404 A 220 250 Ni(II)-nitrilo(triacetic acid) SYSTEMATIC 23460404 A 260 288 poly(ethylene imine)-maltose FAMILY 23460404 A 290 299 Ni-NTA-DG FORMULA 23460404 A 357 360 His FORMULA 23460404 A 512 521 imidazole SYSTEMATIC 23460404 A 665 674 Ni-NTA-DG FORMULA 23460404 T 0 10 Ni(II)-NTA FORMULA 23460404 T 20 40 Poly(ethylene imine) FAMILY 23460473 A 12 19 halogen FAMILY 23460473 A 258 283 1,5-dichloroanthraquinone SYSTEMATIC 23460473 A 297 304 Au(111) FORMULA 23460473 A 316 318 Cl FORMULA 23460473 A 522 524 Cl FORMULA 23460473 A 527 528 H FORMULA 23460473 A 533 534 O FORMULA 23460473 A 537 538 H FORMULA 23460473 A 539 547 hydrogen SYSTEMATIC 23460473 A 587 589 Cl FORMULA 23460473 A 598 605 halogen FAMILY 23460473 A 70 72 Br FORMULA 23460473 A 705 707 Br FORMULA 23460473 A 713 714 I FORMULA 23460473 A 723 730 halogen FAMILY 23460473 A 738 740 Cl FORMULA 23460473 A 749 756 halogen FAMILY 23460473 A 77 78 I FORMULA 23460473 A 859 861 Cl FORMULA 23460473 T 15 17 cl FORMULA 23460473 T 20 21 h FORMULA 23460473 T 26 27 o FORMULA 23460473 T 30 31 h FORMULA 23460473 T 63 88 1,5-dichloroanthraquinone SYSTEMATIC 23460473 T 99 106 au(111) FORMULA 23461378 A 1000 1012 pitavastatin TRIVIAL 23461378 A 1027 1036 lopinavir TRIVIAL 23461378 A 755 772 estrone-3-sulfate SYSTEMATIC 23461378 A 933 943 olmesartan TRIVIAL 23461378 A 955 964 valsartan TRIVIAL 23461378 A 976 988 rosuvastatin TRIVIAL 23461585 A 1512 1518 Zn(2+) FORMULA 23461585 A 1523 1529 Mg(2+) FORMULA 23461585 A 1575 1581 Zn(2+) FORMULA 23461585 A 1604 1610 Mg(2+) FORMULA 23461585 A 1777 1783 Mg(2+) FORMULA 23461585 A 249 253 ZnAc FORMULA 23461585 A 254 257 PVA ABBREVIATION 23461585 A 262 266 MgAc FORMULA 23461585 A 267 271 ZnAc FORMULA 23461585 A 272 275 PVA ABBREVIATION 23461585 A 358 361 ZnO FORMULA 23461585 A 366 379 Mg(x)Zn(1-x)O FAMILY 23461585 A 449 466 magnesium acetate SYSTEMATIC 23461585 A 468 472 MgAc FORMULA 23461585 A 478 490 zinc acetate SYSTEMATIC 23461585 A 492 496 ZnAc FORMULA 23461585 A 503 522 poly(vinyl alcohol) SYSTEMATIC 23461585 A 52 65 Mg(x)Zn(1-x)O FAMILY 23461585 A 524 527 PVA ABBREVIATION 23461585 A 833 836 ZnO FORMULA 23461585 A 841 854 Mg(x)Zn(1-x)O FAMILY 23461585 A 98 104 Mg(2+) FORMULA 23461585 T 27 40 Mg(x)Zn(1-x)O FAMILY 23461585 T 56 60 Mg2+ FORMULA 23461648 A 441 451 amino acid FAMILY 23461648 A 468 476 fengycin FAMILY 23461648 A 486 496 fengycin C TRIVIAL 23461648 A 507 517 amino acid FAMILY 23461648 A 527 566 Glu-Orn-Tyr-Thr-Glu-Val-Pro-Gln-Thr-Ile FORMULA 23461648 A 614 624 fengycin B TRIVIAL 23461648 A 648 658 fengycin A TRIVIAL 23461648 A 685 705 β-hydroxy fatty acyl FAMILY 23461648 A 732 733 N FORMULA 23461648 A 750 761 decapeptide FAMILY 23461648 A 821 828 carbons FAMILY 23461648 A 834 835 C FORMULA 23461648 A 893 901 tyrosine TRIVIAL 23461648 A 960 964 acyl FAMILY 23461648 A 996 1010 cyclic lactone FAMILY 23461648 T 0 10 Fengycin C TRIVIAL 23461806 A 118 124 oxygen SYSTEMATIC 23461806 A 1197 1205 tyrosine TRIVIAL 23461806 A 471 479 tyrosine TRIVIAL 23461806 A 650 658 tyrosine TRIVIAL 23461806 A 823 831 tyrosine TRIVIAL 23461806 A 9 15 oxygen SYSTEMATIC 23461806 A 960 968 tyrosine TRIVIAL 23462211 A 103 147 6α,7α-diacetoxy-13-hydroxy-8(9),14-labdadien SYSTEMATIC 23462211 A 156 191 9-hydroxy-13(14)-labden-15,16-olide SYSTEMATIC 23462211 A 276 282 hexane SYSTEMATIC 23462211 A 28 64 13-hydroxy-5(10),14-halimadien-6-one SYSTEMATIC 23462211 A 376 388 diterpenoids FAMILY 23462211 A 546 550 (1)H FORMULA 23462211 A 589 600 diterpenoid FAMILY 23462211 A 6 26 halimane diterpenoid FAMILY 23462211 A 602 617 isoambreinolide TRIVIAL 23462211 A 81 101 labdane diterpenoids FAMILY 23462211 T 15 27 diterpenoids FAMILY 23462233 A 0 8 Aldehyde SYSTEMATIC 23462233 A 1019 1035 nitrosoguanidine SYSTEMATIC 23462233 A 1073 1081 tungsten SYSTEMATIC 23462233 A 1095 1106 hydralazine SYSTEMATIC 23462233 A 1152 1155 IMI ABBREVIATION 23462233 A 1192 1195 IMI ABBREVIATION 23462233 A 1237 1245 tungsten SYSTEMATIC 23462233 A 1247 1258 hydralazine SYSTEMATIC 23462233 A 1457 1460 IMI ABBREVIATION 23462233 A 1503 1506 IMI ABBREVIATION 23462233 A 1627 1630 IMI ABBREVIATION 23462233 A 1755 1768 neonicotinoid FAMILY 23462233 A 225 239 neonicotinoids FAMILY 23462233 A 299 309 nitroimino SYSTEMATIC 23462233 A 524 532 tungsten SYSTEMATIC 23462233 A 536 547 hydralazine SYSTEMATIC 23462233 A 764 772 tungsten SYSTEMATIC 23462233 A 786 797 hydralazine SYSTEMATIC 23462233 A 905 917 imidacloprid TRIVIAL 23462233 A 919 922 IMI ABBREVIATION 23462233 T 0 8 Aldehyde SYSTEMATIC 23462233 T 62 74 imidacloprid TRIVIAL 23462381 A 1271 1278 choline FAMILY 23462381 A 1400 1406 Fluo-4 ABBREVIATION 23462381 A 1410 1417 calcium SYSTEMATIC 23462381 A 1526 1533 calcium SYSTEMATIC 23462381 A 2077 2090 sphingomyelin FAMILY 23462381 A 2241 2248 calcium SYSTEMATIC 23462381 A 729 742 sphingomyelin FAMILY 23462381 A 782 802 ceramide 1-phosphate SYSTEMATIC 23462381 A 808 815 choline FAMILY 23462381 A 828 851 lysophosphatidylcholine FAMILY 23462381 A 864 885 lysophosphatidic acid TRIVIAL 23462381 A 891 898 choline FAMILY 23462381 A 937 956 phosphatidylcholine FAMILY 23462381 T 52 59 calcium SYSTEMATIC 23462506 A 1031 1037 lysine TRIVIAL 23462506 A 1585 1591 lysine TRIVIAL 23462506 A 16 22 lysine TRIVIAL 23462506 A 351 357 lysine TRIVIAL 23462506 A 392 400 arginine TRIVIAL 23462506 A 5 15 amino acid FAMILY 23462506 A 707 716 bile salt FAMILY 23462506 A 947 955 retinoid FAMILY 23462506 A 97 105 farnesyl TRIVIAL 23462506 T 40 46 lysine TRIVIAL 23462569 A 0 4 (1)H FORMULA 23462569 A 1019 1033 phosphocholine SYSTEMATIC 23462569 A 1058 1061 MAP ABBREVIATION 23462569 A 1093 1111 N-Acetyl-aspartate SYSTEMATIC 23462569 A 1186 1198 myo-inositol TRIVIAL 23462569 A 1255 1273 Tricarboxylic acid SYSTEMATIC 23462569 A 1311 1326 α-ketoglutarate TRIVIAL 23462569 A 1328 1337 succinate TRIVIAL 23462569 A 1339 1346 citrate FAMILY 23462569 A 1355 1365 methionine TRIVIAL 23462569 A 1425 1428 MAP ABBREVIATION 23462569 A 1454 1457 ADP ABBREVIATION 23462569 A 1521 1524 MAP ABBREVIATION 23462569 A 1777 1780 MAP ABBREVIATION 23462569 A 232 247 methamphetamine TRIVIAL 23462569 A 249 252 MAP ABBREVIATION 23462569 A 293 296 MAP ABBREVIATION 23462569 A 415 424 glutamate TRIVIAL 23462569 A 426 435 glutamine TRIVIAL 23462569 A 440 444 GABA ABBREVIATION 23462569 A 522 548 succinic acid semialdehyde SYSTEMATIC 23462569 A 574 578 GABA ABBREVIATION 23462569 A 633 642 serotonin TRIVIAL 23462569 A 695 703 dopamine TRIVIAL 23462569 A 744 747 MAP ABBREVIATION 23462569 A 759 770 Glutathione TRIVIAL 23462569 A 823 837 acetylcysteine SYSTEMATIC 23462569 A 875 882 taurine TRIVIAL 23462569 A 908 924 Homocysteic acid TRIVIAL 23462569 A 973 976 MAP ABBREVIATION 23462569 T 81 96 methamphetamine TRIVIAL 23462698 A 1297 1305 pregnane TRIVIAL 23462698 A 14 21 alcohol FAMILY 23462698 T 0 7 Alcohol SYSTEMATIC 23462812 A 11 16 Co3O4 FORMULA 23462812 A 166 171 Co3O4 FORMULA 23462812 A 300 307 lithium SYSTEMATIC 23462812 A 63 69 carbon SYSTEMATIC 23462812 A 783 788 Co3O4 FORMULA 23462812 T 11 16 Co3O4 FORMULA 23462812 T 39 45 carbon SYSTEMATIC 23462812 T 97 104 lithium SYSTEMATIC 23462886 A 1059 1066 glucose TRIVIAL 23462886 A 106 124 thiazolidinediones FAMILY 23462886 A 1104 1116 pioglitazone TRIVIAL 23462886 A 352 361 MSDC-0160 NO CLASS 23462886 A 389 405 pioglitazone HCl FORMULA 23462886 A 482 489 glucose TRIVIAL 23462886 A 600 609 MSDC-0160 NO CLASS 23462886 A 656 668 pioglitazone TRIVIAL 23462886 A 798 807 MSDC-0160 NO CLASS 23462886 A 906 915 MSDC-0160 NO CLASS 23462886 A 926 938 pioglitazone TRIVIAL 23462886 A 969 978 MSDC-0160 NO CLASS 23462886 T 37 46 MSDC-0160 NO CLASS 23463253 A 780 818 6-methoxy-N-(3-sulfopropyl)quinolinium SYSTEMATIC 23463253 A 820 823 SPQ ABBREVIATION 23463253 A 829 865 10-(3-sulfopropyl)acridinium betaine SYSTEMATIC 23463253 A 867 870 SAB ABBREVIATION 23463696 A 100 108 graphene TRIVIAL 23463696 A 163 171 graphene TRIVIAL 23463696 A 256 264 graphene TRIVIAL 23463696 A 26 32 carbon SYSTEMATIC 23463696 A 291 292 N FORMULA 23463696 A 312 320 graphene TRIVIAL 23463696 A 343 351 graphene TRIVIAL 23463696 A 44 47 ZnO FORMULA 23463696 A 51 54 ZnS FORMULA 23463696 A 6 14 graphite TRIVIAL 23463696 T 24 32 graphene TRIVIAL 23464637 A 475 492 polyacrylonitrile FAMILY 23464650 A 41 45 InAs FORMULA 23464650 A 46 56 InAs1-xSbx FAMILY 23464650 A 768 770 Sb FORMULA 23464650 A 80 82 Sb FORMULA 23464650 A 928 934 InAsSb FORMULA 23464650 A 965 967 Si FORMULA 23464650 T 35 41 InAsSb FORMULA 23464759 A 671 679 graphite TRIVIAL 23464759 A 685 689 mica TRIVIAL 23464881 A 121 129 graphene TRIVIAL 23464881 A 211 238 10,12-pentacosadiynoic acid SYSTEMATIC 23464881 A 240 244 PCDA ABBREVIATION 23464881 A 259 267 graphene TRIVIAL 23464881 A 357 362 oxide SYSTEMATIC 23464881 A 413 417 PCDA ABBREVIATION 23464881 A 536 544 graphene TRIVIAL 23464881 A 612 620 graphene TRIVIAL 23464881 A 644 654 zinc oxide SYSTEMATIC 23464881 A 659 666 alumina TRIVIAL 23464881 A 71 79 graphene TRIVIAL 23464881 A 748 752 PCDA ABBREVIATION 23464881 A 777 782 oxide SYSTEMATIC 23464881 T 44 49 Oxide SYSTEMATIC 23464881 T 68 76 Graphene TRIVIAL 23465061 A 149 162 ciliatamide A TRIVIAL 23465061 A 168 181 Ciliatamide D TRIVIAL 23465061 A 19 32 ciliatamide D TRIVIAL 23465061 A 215 223 N-Me-Phe FORMULA 23465061 A 239 250 N-Me-Met(O) FORMULA 23465061 A 337 348 amino acids FAMILY 23465061 T 108 121 Ciliatamide A TRIVIAL 23465061 T 13 26 Ciliatamide D TRIVIAL 23465613 A 287 296 disulfide SYSTEMATIC 23465613 A 448 453 hemin TRIVIAL 23465613 A 473 477 K(+) FORMULA 23465613 A 537 545 H(2)O(2) FORMULA 23465613 A 568 575 luminol TRIVIAL 23465613 A 79 88 disulfide SYSTEMATIC 23465614 A 143 159 diarylheptanoids FAMILY 23465614 A 176 184 methanol SYSTEMATIC 23465614 A 23 97 (5S)-hydroxy-1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl)-hepta-1E-en-3-one SYSTEMATIC 23465614 A 476 513 platyphyllonol-5-O-β-d-xylopyranoside SYSTEMATIC 23465614 A 6 21 diarylheptanoid FAMILY 23465614 A 726 738 troglitazone TRIVIAL 23465614 T 16 32 diarylheptanoids FAMILY 23466420 A 1088 1100 camptothecin TRIVIAL 23466420 A 1154 1163 Gimatecan TRIVIAL 23466420 A 1168 1180 camptothecin TRIVIAL 23466420 A 151 160 topotecan TRIVIAL 23466420 A 162 170 Hycantim TRIVIAL 23466420 A 1676 1688 Camptothecin TRIVIAL 23466420 A 176 185 gimatecan TRIVIAL 23466420 A 1806 1815 gimatecan TRIVIAL 23466420 A 187 193 ST1481 IDENTIFIER 23466420 A 212 222 irinotecan TRIVIAL 23466420 A 224 233 Camptosar TRIVIAL 23466420 A 271 276 SN-38 IDENTIFIER 23466420 A 322 334 camptothecin TRIVIAL 23466420 A 704 716 camptothecin TRIVIAL 23466420 A 808 817 gimatecan TRIVIAL 23466420 A 94 106 camptothecin TRIVIAL 23466420 A 993 1002 gimatecan TRIVIAL 23466420 T 0 9 Gimatecan TRIVIAL 23466420 T 20 32 camptothecin TRIVIAL 23468189 A 244 261 aryl sulfonamides FAMILY 23468189 A 780 799 benzenesulfonamides FAMILY 23468189 T 0 19 Benzenesulfonamides FAMILY 23468458 A 382 390 hydrogen SYSTEMATIC 23468458 A 49 56 vanadia TRIVIAL 23468458 T 0 8 Hydrogen SYSTEMATIC 23468458 T 25 32 vanadia TRIVIAL 23469681 A 0 9 Porphyrin FAMILY 23469681 A 1085 1094 porphyrin FAMILY 23469681 A 1121 1131 porphyrins FAMILY 23469681 A 1322 1331 porphyrin FAMILY 23469681 A 534 560 meso-tetraphenyl porphyrin SYSTEMATIC 23469681 A 593 602 4-hydroxy SYSTEMATIC 23469681 A 614 626 4-sulphonate SYSTEMATIC 23469681 A 628 637 4-carboxy SYSTEMATIC 23469681 A 653 673 4-trimethylanilinium SYSTEMATIC 23469681 A 856 866 porphyrins FAMILY 23469681 A 997 1005 Tween 80 TRIVIAL 23469681 T 97 111 meso-porphyrin FAMILY 23469757 A 1028 1032 PMAA ABBREVIATION 23469757 A 1119 1136 1,8-diaminooctane SYSTEMATIC 23469757 A 1200 1206 folate TRIVIAL 23469757 A 1449 1455 folate TRIVIAL 23469757 A 1640 1646 folate TRIVIAL 23469757 A 229 247 phenylboronic acid SYSTEMATIC 23469757 A 249 252 PBA ABBREVIATION 23469757 A 258 266 dopamine TRIVIAL 23469757 A 277 289 borate ester SYSTEMATIC 23469757 A 588 632 oligoethylene glycol methylether methacylate FAMILY 23469757 A 637 656 methyl acrylic acid SYSTEMATIC 23469757 A 658 678 POEGMEMA35-b-PMAA200 ABBREVIATION 23469757 A 683 702 POEGMEMA26-b-PMAA90 ABBREVIATION 23469757 A 709 717 platinum SYSTEMATIC 23469757 A 724 733 oxoplatin TRIVIAL 23469757 A 75 85 folic acid TRIVIAL 23469757 A 812 820 platinum SYSTEMATIC 23469757 A 866 874 platinum SYSTEMATIC 23469757 T 0 6 Folate TRIVIAL 23469757 T 45 63 Boronic Acid Ester SYSTEMATIC 23469757 T 75 83 Platinum SYSTEMATIC 23469759 A 278 285 Gd(III) FORMULA 23469759 A 389 402 glutamic acid TRIVIAL 23469759 A 478 485 Gd(III) FORMULA 23469759 T 53 55 Gd FORMULA 23469759 T 82 95 glutamic acid TRIVIAL 23470011 A 114 127 eudesmanolide TRIVIAL 23470011 A 129 189 1α-acetoxy-8α-hydroxy-2-oxo-eudesman-3,7(11)-dien-8,12-olide SYSTEMATIC 23470011 A 207 214 flavone TRIVIAL 23470011 A 21 86 1α-acetoxy-8α,9β-dihydroxy-2-oxo-eudesman-3,7(11)-dien-8,12-olide SYSTEMATIC 23470011 A 216 250 4',5,7-trihydroxy-6-methoxyflavone SYSTEMATIC 23470011 A 6 19 eudesmanolide TRIVIAL 23470011 T 6 27 sesquiterpene lactone FAMILY 23470073 A 930 938 bosentan TRIVIAL 23470077 A 0 27 Asymmetric Dimethylarginine TRIVIAL 23470077 A 1259 1263 ADMA ABBREVIATION 23470077 A 133 141 arginine TRIVIAL 23470077 A 1330 1334 ADMA ABBREVIATION 23470077 A 1376 1380 ADMA ABBREVIATION 23470077 A 162 170 arginine TRIVIAL 23470077 A 287 303 dimethylarginine SYSTEMATIC 23470077 A 29 33 ADMA ABBREVIATION 23470077 A 365 377 nitric oxide SYSTEMATIC 23470077 A 476 480 ADMA ABBREVIATION 23470077 A 534 536 NO FORMULA 23470077 A 65 77 nitric oxide SYSTEMATIC 23470077 A 697 701 ADMA ABBREVIATION 23470077 A 79 81 NO FORMULA 23470077 A 880 884 ADMA ABBREVIATION 23470077 A 95 99 ADMA ABBREVIATION 23470077 A 988 992 ADMA ABBREVIATION 23470077 T 0 27 Asymmetric Dimethylarginine TRIVIAL 23470077 T 29 33 ADMA ABBREVIATION 23470196 A 1113 1116 TGA ABBREVIATION 23470196 A 207 216 trimethyl SYSTEMATIC 23470196 A 233 247 carboxy-methyl SYSTEMATIC 23470196 A 277 294 thioglycolic acid SYSTEMATIC 23470196 A 296 299 TGA ABBREVIATION 23470196 A 330 333 TGA ABBREVIATION 23470196 A 361 364 TGA ABBREVIATION 23470196 A 408 411 TGA ABBREVIATION 23470196 A 709 712 TGA ABBREVIATION 23470196 A 787 813 fluorescein isothiocyanate TRIVIAL 23470196 A 815 819 FITC ABBREVIATION 23470196 A 887 890 TGA ABBREVIATION 23470196 T 9 26 thioglycolic Acid TRIVIAL 23470204 A 1118 1129 polylactide FAMILY 23470204 A 1134 1151 polyvinyl alcohol SYSTEMATIC 23470204 A 1376 1381 CaCO3 FORMULA 23470204 A 362 371 carbonate FAMILY 23470204 A 389 395 silver SYSTEMATIC 23470204 A 436 445 fullerene TRIVIAL 23470204 A 505 533 polyallylamine hydrochloride FAMILY 23470204 A 535 538 PAH ABBREVIATION 23470204 A 581 583 Ag FORMULA 23470204 A 621 627 silver SYSTEMATIC 23470204 A 695 700 CaCO3 FORMULA 23470204 A 701 704 PAH ABBREVIATION 23470204 A 716 718 Ag FORMULA 23470204 A 910 912 Ag FORMULA 23470204 A 945 947 Ag FORMULA 23470204 T 115 121 silver SYSTEMATIC 23470204 T 59 76 calcium carbonate SYSTEMATIC 23470325 A 15 22 calcium SYSTEMATIC 23470776 A 24 32 oxytocin TRIVIAL 23470776 A 61 71 nucleotide FAMILY 23470776 T 22 30 oxytocin TRIVIAL 23470866 A 0 10 Oroxylin A TRIVIAL 23470866 A 1093 1103 oroxylin A TRIVIAL 23470866 A 1170 1180 oroxylin A TRIVIAL 23470866 A 1243 1253 oroxylin A TRIVIAL 23470866 A 327 337 oroxylin A TRIVIAL 23470866 A 36 49 monoflavonoid FAMILY 23470866 A 377 387 oroxylin A TRIVIAL 23470866 A 499 509 oroxylin A TRIVIAL 23470866 A 635 645 oroxylin A TRIVIAL 23470866 A 899 909 oroxylin A TRIVIAL 23470866 A 911 932 NSC 109555 ditosylate IDENTIFIER 23470866 A 988 998 oroxylin A TRIVIAL 23470866 T 0 10 Oroxylin A TRIVIAL 23471121 A 1297 1300 MPH ABBREVIATION 23471121 A 240 255 methylphenidate SYSTEMATIC 23471121 A 257 260 MPH ABBREVIATION 23471121 A 447 450 MPH ABBREVIATION 23471121 A 484 487 MPH ABBREVIATION 23471121 T 107 110 MPH ABBREVIATION 23471121 T 85 100 methylphenidate SYSTEMATIC 23471352 A 0 16 Arsenic trioxide SYSTEMATIC 23471352 A 101 108 arsenic SYSTEMATIC 23471352 A 1060 1075 malondialdehyde TRIVIAL 23471352 A 1086 1092 oxygen SYSTEMATIC 23471352 A 1102 1125 8-hydroxydeoxyguanosine SYSTEMATIC 23471352 A 1133 1143 creatinine TRIVIAL 23471352 A 1151 1155 urea TRIVIAL 23471352 A 1156 1164 nitrogen SYSTEMATIC 23471352 A 1176 1183 arsenic SYSTEMATIC 23471352 A 1294 1299 As2O3 FORMULA 23471352 A 130 141 Resveratrol TRIVIAL 23471352 A 1346 1357 resveratrol TRIVIAL 23471352 A 1396 1402 oxygen SYSTEMATIC 23471352 A 1420 1425 As2O3 FORMULA 23471352 A 1500 1507 arsenic SYSTEMATIC 23471352 A 1541 1546 As2O3 FORMULA 23471352 A 158 170 polyphenolic FAMILY 23471352 A 1590 1601 resveratrol TRIVIAL 23471352 A 1719 1726 arsenic SYSTEMATIC 23471352 A 1740 1747 arsenic SYSTEMATIC 23471352 A 18 23 As2O3 FORMULA 23471352 A 207 212 As2O3 FORMULA 23471352 A 290 301 resveratrol TRIVIAL 23471352 A 305 310 As2O3 FORMULA 23471352 A 338 345 arsenic SYSTEMATIC 23471352 A 408 413 As2O3 FORMULA 23471352 A 433 444 resveratrol TRIVIAL 23471352 A 508 513 As2O3 FORMULA 23471352 A 644 651 arsenic SYSTEMATIC 23471352 A 724 731 arsenic SYSTEMATIC 23471352 A 751 762 resveratrol TRIVIAL 23471352 A 765 770 As2O3 FORMULA 23471352 A 800 811 glutathione TRIVIAL 23471352 A 838 848 superoxide TRIVIAL 23471352 A 881 892 glutathione TRIVIAL 23471352 A 896 916 oxidized glutathione TRIVIAL 23471352 A 928 935 arsenic SYSTEMATIC 23471352 A 974 992 methylated arsenic SYSTEMATIC 23471352 T 0 11 Resveratrol TRIVIAL 23471352 T 29 45 arsenic trioxide SYSTEMATIC 23471352 T 85 92 arsenic SYSTEMATIC 23471540 A 10 14 zinc SYSTEMATIC 23471540 A 1222 1226 zinc SYSTEMATIC 23471540 A 1374 1378 zinc SYSTEMATIC 23471540 A 364 368 zinc SYSTEMATIC 23471540 T 30 33 Cys FORMULA 23471540 T 35 38 His FORMULA 23471540 T 40 44 zinc SYSTEMATIC 23471741 A 0 9 Ritonavir TRIVIAL 23471741 A 161 170 ritonavir TRIVIAL 23471741 A 295 305 Cobicistat TRIVIAL 23471741 A 450 460 Cobicistat TRIVIAL 23471741 A 495 507 elvitegravir TRIVIAL 23471741 A 643 655 elvitegravir TRIVIAL 23471741 A 657 667 cobicistat TRIVIAL 23471741 A 669 682 emtricitabine TRIVIAL 23471741 A 688 697 tenofovir TRIVIAL 23471741 A 837 847 cobicistat TRIVIAL 23471741 A 945 955 Cobicistat TRIVIAL 23471741 T 0 10 Cobicistat TRIVIAL 23471964 A 241 247 oxygen SYSTEMATIC 23471964 A 320 335 cysteine thiols FAMILY 23471964 A 339 352 sulfenic acid SYSTEMATIC 23471964 A 372 380 cysteine TRIVIAL 23471964 A 521 529 cysteine TRIVIAL 23471964 A 729 744 cysteine thiols FAMILY 23471964 T 49 55 Oxygen SYSTEMATIC 23471964 T 89 97 CYSTEINE TRIVIAL 23472655 A 101 107 iodine SYSTEMATIC 23472655 A 1020 1026 iodine SYSTEMATIC 23472655 A 1099 1105 iodine SYSTEMATIC 23472655 A 1171 1177 iodine SYSTEMATIC 23472655 A 1284 1290 iodine SYSTEMATIC 23472655 A 1399 1405 iodine SYSTEMATIC 23472655 A 1475 1481 sodium SYSTEMATIC 23472655 A 1497 1503 iodine SYSTEMATIC 23472655 A 1600 1606 iodine SYSTEMATIC 23472655 A 1758 1764 iodine SYSTEMATIC 23472655 A 20 26 iodine SYSTEMATIC 23472655 A 2010 2016 iodine SYSTEMATIC 23472655 A 2076 2082 iodine SYSTEMATIC 23472655 A 2182 2188 sodium SYSTEMATIC 23472655 A 2266 2272 iodine SYSTEMATIC 23472655 A 356 362 iodine SYSTEMATIC 23472655 A 647 653 iodine SYSTEMATIC 23472655 A 68 83 thyroid hormone FAMILY 23472655 A 739 745 iodine SYSTEMATIC 23472655 A 778 784 iodine SYSTEMATIC 23472655 A 892 898 iodine SYSTEMATIC 23472655 A 939 945 iodine SYSTEMATIC 23472655 T 7 13 iodine SYSTEMATIC 23473032 A 117 132 α-ketoglutarate TRIVIAL 23473032 A 36 45 glutamine TRIVIAL 23473032 A 454 461 citrate FAMILY 23473032 A 507 514 acetate SYSTEMATIC 23473032 A 518 525 citrate FAMILY 23473032 A 567 574 citrate FAMILY 23473032 A 58 65 citrate FAMILY 23473032 A 655 662 citrate FAMILY 23473032 A 743 761 [(1-13)C]glutamine SYSTEMATIC 23473032 A 908 917 glutamine TRIVIAL 23473032 T 114 123 glutamine TRIVIAL 23473032 T 61 68 citrate FAMILY 23473036 A 593 603 fatty acid FAMILY 23473268 A 183 190 Au(III) FORMULA 23473268 A 213 219 HAuCl4 FORMULA 23473268 A 81 87 HAuCl4 FORMULA 23473372 A 143 151 Si2H6BH3 FORMULA 23473581 A 1132 1141 1-butanol SYSTEMATIC 23473581 A 1328 1337 1-butanol SYSTEMATIC 23473581 A 199 208 1-butanol SYSTEMATIC 23473581 A 26 35 1-butanol SYSTEMATIC 23473581 A 272 317 1-decyl-3-methyl-imidazolium tetracyanoborate SYSTEMATIC 23473581 A 331 334 tcb ABBREVIATION 23473581 A 341 387 4-decyl-4-methyl-morpholinium tetracyanoborate SYSTEMATIC 23473581 A 401 404 tcb ABBREVIATION 23473581 A 411 473 1-decyl-3-methyl-imidazolium bis(trifluoromethylsulfonyl)imide SYSTEMATIC 23473581 A 487 491 ntf2 ABBREVIATION 23473581 A 502 565 4-decyl-4-methyl-morpholinium bis(trifluoromethylsulfonyl)imide SYSTEMATIC 23473581 A 579 583 ntf2 ABBREVIATION 23473581 A 952 961 1-butanol SYSTEMATIC 23473581 A 976 985 1-butanol SYSTEMATIC 23473581 T 26 35 1-butanol SYSTEMATIC 23473803 A 1020 1024 cAMP ABBREVIATION 23473803 A 1054 1063 moexipril TRIVIAL 23473803 A 1100 1109 forskolin TRIVIAL 23473803 A 1136 1140 cAMP ABBREVIATION 23473803 A 1209 1218 moexipril TRIVIAL 23473803 A 1309 1313 cAMP ABBREVIATION 23473803 A 1364 1373 moexipril TRIVIAL 23473803 A 151 168 cyclic nucleotide FAMILY 23473803 A 187 222 cyclic 3'5' adenosine monophosphate SYSTEMATIC 23473803 A 224 228 cAMP ABBREVIATION 23473803 A 28 45 cyclic nucleotide FAMILY 23473803 A 655 664 moexipril TRIVIAL 23473803 A 692 703 angiotensin FAMILY 23473803 A 790 799 moexipril TRIVIAL 23473803 A 950 960 nucleotide FAMILY 23473803 T 45 54 moexipril TRIVIAL 23473803 T 79 83 cAMP ABBREVIATION 23473805 A 1004 1017 actinomycin D TRIVIAL 23473805 A 1032 1035 Rp1 TRIVIAL 23473805 A 1102 1105 Rp1 TRIVIAL 23473805 A 1129 1142 actinomycin D TRIVIAL 23473805 A 1246 1257 cholesterol TRIVIAL 23473805 A 1269 1272 Rp1 TRIVIAL 23473805 A 1324 1327 Rp1 TRIVIAL 23473805 A 1332 1345 actinomycin D TRIVIAL 23473805 A 138 141 ATP ABBREVIATION 23473805 A 1437 1440 Rp1 TRIVIAL 23473805 A 1446 1459 actinomycin D TRIVIAL 23473805 A 1461 1464 Rp1 TRIVIAL 23473805 A 1552 1563 doxorubicin TRIVIAL 23473805 A 357 368 cholesterol TRIVIAL 23473805 A 374 386 sphingolipid FAMILY 23473805 A 477 488 cholesterol TRIVIAL 23473805 A 544 555 cholesterol TRIVIAL 23473805 A 595 607 ginsenosides FAMILY 23473805 A 636 647 cholesterol TRIVIAL 23473805 A 694 697 Rp1 TRIVIAL 23473805 A 707 718 ginsenoside FAMILY 23473805 A 825 828 Rp1 TRIVIAL 23473805 A 870 881 doxorubicin TRIVIAL 23473805 A 885 898 rhodamine 123 TRIVIAL 23473805 A 931 942 doxorubicin TRIVIAL 23473805 A 960 963 Rp1 TRIVIAL 23473805 T 25 28 Rp1 TRIVIAL 23474029 A 210 231 poly(ethylene glycol) SYSTEMATIC 23474029 A 274 277 PEG ABBREVIATION 23474029 A 345 352 calcium SYSTEMATIC 23474029 A 357 366 phosphate SYSTEMATIC 23474029 A 465 468 PEG ABBREVIATION 23474029 A 519 522 PEG ABBREVIATION 23474029 T 65 76 doxorubicin TRIVIAL 23474171 A 1060 1066 5AzadC SYSTEMATIC 23474171 A 1108 1111 TSA ABBREVIATION 23474171 A 1168 1174 5AzadC SYSTEMATIC 23474171 A 1230 1236 5AzadC SYSTEMATIC 23474171 A 1349 1355 5AzadC SYSTEMATIC 23474171 A 5 17 progesterone TRIVIAL 23474171 A 576 598 5-aza-2'-deoxycytidine SYSTEMATIC 23474171 A 600 606 5AzadC SYSTEMATIC 23474171 A 646 660 trichostatin A TRIVIAL 23474171 A 662 665 TSA ABBREVIATION 23474171 A 819 825 5AzadC SYSTEMATIC 23474171 A 887 893 5AzadC SYSTEMATIC 23474171 A 997 1003 5AzadC SYSTEMATIC 23474171 T 73 85 progesterone TRIVIAL 23474269 A 1029 1036 suramin TRIVIAL 23474269 A 1254 1261 suramin TRIVIAL 23474269 A 1359 1366 Suramin TRIVIAL 23474269 A 1454 1461 suramin TRIVIAL 23474269 A 180 187 Suramin TRIVIAL 23474269 A 337 344 suramin TRIVIAL 23474269 A 41 48 suramin TRIVIAL 23474269 A 425 432 suramin TRIVIAL 23474269 A 52 79 polysulfonated naphthylurea FAMILY 23474269 A 568 575 suramin TRIVIAL 23474269 A 664 671 suramin TRIVIAL 23474269 A 686 693 suramin TRIVIAL 23474269 A 851 858 suramin TRIVIAL 23474269 A 923 930 suramin TRIVIAL 23474269 T 57 64 suramin TRIVIAL 23474317 A 1064 1067 FLX ABBREVIATION 23474317 A 1261 1264 FLX ABBREVIATION 23474317 A 159 169 fluoxetine TRIVIAL 23474317 A 171 174 FLX ABBREVIATION 23474317 A 189 198 serotonin TRIVIAL 23474317 A 302 305 FLX ABBREVIATION 23474317 A 471 474 FLX ABBREVIATION 23474317 A 534 537 FLX ABBREVIATION 23474317 A 722 732 fluoxetine TRIVIAL 23474317 A 980 983 FLX ABBREVIATION 23474317 T 44 54 fluoxetine TRIVIAL 23474318 A 1197 1210 carbohydrates FAMILY 23474318 A 1284 1290 oxygen SYSTEMATIC 23474318 A 1612 1622 superoxide TRIVIAL 23474318 A 510 520 glyphosate TRIVIAL 23474324 A 135 142 cadmium SYSTEMATIC 23474324 A 1417 1419 Cd FORMULA 23474324 A 144 146 Cd FORMULA 23474324 A 392 394 Cd FORMULA 23474324 A 409 411 Cd FORMULA 23474324 A 704 706 Cd FORMULA 23474324 T 94 101 cadmium SYSTEMATIC 23474589 A 177 184 glucose TRIVIAL 23474589 A 490 497 glucose TRIVIAL 23474593 A 141 152 Mn-doped Si FORMULA 23474593 A 180 190 fullerene- TRIVIAL 23474593 A 28 30 Mn FORMULA 23474593 A 31 38 Si14(+) FORMULA 23474593 A 343 345 Mn FORMULA 23474593 A 364 368 Si14 FORMULA 23474593 A 433 437 Si14 FORMULA 23474593 A 450 452 Mn FORMULA 23474593 A 468 470 Mn FORMULA 23474593 A 537 539 Mn FORMULA 23474593 A 657 659 Mn FORMULA 23474593 A 660 667 Si14(+) FORMULA 23474593 T 0 2 Mn FORMULA 23474593 T 20 30 fullerene- TRIVIAL 23474593 T 3 8 Si14+ FORMULA 23474593 T 54 61 silicon SYSTEMATIC 23474889 A 1112 1116 EtOH FORMULA 23474889 A 1125 1129 EtOH FORMULA 23474889 A 1236 1262 R-(alpha)-methyl-histamine SYSTEMATIC 23474889 A 1399 1403 EtOH FORMULA 23474889 A 1420 1424 EtOH FORMULA 23474889 A 145 152 alcohol FAMILY 23474889 A 1494 1503 histamine TRIVIAL 23474889 A 1637 1641 EtOH FORMULA 23474889 A 189 198 histamine TRIVIAL 23474889 A 336 343 ethanol SYSTEMATIC 23474889 A 345 349 EtOH FORMULA 23474889 A 372 376 EtOH FORMULA 23474889 A 442 446 EtOH FORMULA 23474889 A 448 457 saccharin TRIVIAL 23474889 A 463 470 quinine TRIVIAL 23474889 A 558 565 alcohol FAMILY 23474889 A 588 592 EtOH FORMULA 23474889 A 625 629 EtOH FORMULA 23474889 A 668 675 ethanol SYSTEMATIC 23474889 A 853 860 alcohol FAMILY 23474889 T 100 107 ethanol SYSTEMATIC 23474889 T 23 32 histamine TRIVIAL 23474889 T 76 83 alcohol FAMILY 23475371 A 1075 1078 ADR ABBREVIATION 23475371 A 1083 1085 Se FORMULA 23475371 A 1131 1134 ADR ABBREVIATION 23475371 A 1159 1161 Se FORMULA 23475371 A 1342 1352 adriamycin TRIVIAL 23475371 A 136 138 Se FORMULA 23475371 A 1360 1362 Se FORMULA 23475371 A 1403 1405 Se FORMULA 23475371 A 1429 1439 adriamycin TRIVIAL 23475371 A 147 150 ADR ABBREVIATION 23475371 A 1509 1511 Se FORMULA 23475371 A 1553 1563 adriamycin TRIVIAL 23475371 A 26 36 adriamycin TRIVIAL 23475371 A 340 351 glutathione TRIVIAL 23475371 A 38 41 ADR ABBREVIATION 23475371 A 429 432 ATP ABBREVIATION 23475371 A 443 452 potassium SYSTEMATIC 23475371 A 50 58 selenium SYSTEMATIC 23475371 A 60 62 Se FORMULA 23475371 A 659 662 ADR ABBREVIATION 23475371 A 666 668 Se FORMULA 23475371 A 792 795 ADR ABBREVIATION 23475371 A 800 802 Se FORMULA 23475371 A 947 950 ADR ABBREVIATION 23475371 A 954 956 Se FORMULA 23475371 T 0 8 Selenium SYSTEMATIC 23475371 T 101 110 Potassium SYSTEMATIC 23475371 T 20 30 Adriamycin TRIVIAL 23475371 T 87 90 ATP ABBREVIATION 23475431 A 1003 1010 digoxin TRIVIAL 23475431 A 984 992 warfarin TRIVIAL 23476712 A 724 731 adenine TRIVIAL 23476712 A 736 743 thymine TRIVIAL 23477486 A 249 259 iron oxide SYSTEMATIC 23477486 A 832 837 Na(+) FORMULA 23477486 A 839 843 K(+) FORMULA 23477486 A 845 851 Ca(2+) FORMULA 23477486 A 853 859 Cu(2+) FORMULA 23477486 A 865 871 Fe(3+) FORMULA 23477486 T 50 55 na(+) FORMULA 23477486 T 57 61 k(+) FORMULA 23477486 T 63 69 ca(2+) FORMULA 23477486 T 71 77 cu(2+) FORMULA 23477486 T 83 89 fe(3+) FORMULA 23477504 A 10 41 19-hydroxy steroidal glycosides FAMILY 23477504 A 124 139 junceelloside C TRIVIAL 23477504 A 391 396 sugar FAMILY 23477504 A 414 443 β-l- and β-d-arabinopyranoses MULTIPLE 23477504 A 470 496 thiocarbamoyl-thiazolidine SYSTEMATIC 23477504 A 51 69 junceellosides E-G MULTIPLE 23477504 A 532 551 d- and l-arabinoses MULTIPLE 23477504 A 590 605 junceelloside C TRIVIAL 23477504 A 731 750 β-l-arabinopyranose TRIVIAL 23477504 T 0 8 Steroids FAMILY 23477504 T 32 51 d- and l-Arabinoses MULTIPLE 23477570 A 1046 1060 dithiothreitol SYSTEMATIC 23477570 A 1062 1065 DTT ABBREVIATION 23477570 A 1083 1087 FITC ABBREVIATION 23477570 A 1110 1114 FITC ABBREVIATION 23477570 A 1300 1304 FITC ABBREVIATION 23477570 A 1430 1433 DTT ABBREVIATION 23477570 A 1454 1458 FITC ABBREVIATION 23477570 A 1529 1546 1,4-butanediamine SYSTEMATIC 23477570 A 1651 1654 MTT ABBREVIATION 23477570 A 176 193 PEG-P(HEMA-co-AC) ABBREVIATION 23477570 A 1831 1835 FITC ABBREVIATION 23477570 A 290 307 PEG-P(HEMA-co-AC) ABBREVIATION 23477570 A 599 608 phosphate SYSTEMATIC 23477570 A 627 636 disulfide SYSTEMATIC 23477570 A 727 736 cystamine TRIVIAL 23477570 A 768 784 cyclic carbonate SYSTEMATIC 23477570 A 93 174 poly(ethylene glycol)-b-poly(2-(hydroxyethyl) methacrylate-co-acryloyl carbonate) FAMILY 23478260 A 111 121 amino acid FAMILY 23478260 A 482 485 Ala FORMULA 23478260 A 492 495 Gly FORMULA 23478437 A 4 8 NAD+ ABBREVIATION 23478437 A 586 596 amino acid FAMILY 23478437 A 647 653 serine TRIVIAL 23478437 A 654 663 threonine TRIVIAL 23478437 A 682 694 ferrous iron SYSTEMATIC 23479080 A 1416 1419 AAP ABBREVIATION 23479080 A 167 180 Acetaminophen TRIVIAL 23479080 A 182 185 AAP ABBREVIATION 23479080 A 260 289 N-acetyl-p-benzoquinone-imine SYSTEMATIC 23479080 A 354 365 glutathione TRIVIAL 23479080 A 450 471 N-nitrosodiethylamine SYSTEMATIC 23479080 A 526 539 phenobarbital TRIVIAL 23479080 A 745 748 AAP ABBREVIATION 23479080 A 937 940 AAP ABBREVIATION 23479080 T 102 115 acetaminophen TRIVIAL 23479280 A 15 23 chlorine SYSTEMATIC 23479280 A 28 34 oxygen SYSTEMATIC 23479280 A 40 49 hydrazine SYSTEMATIC 23479280 A 63 72 hydrazine SYSTEMATIC 23479280 A 88 91 NO2 FORMULA 23479280 A 96 103 NO3 (-) FORMULA 23479280 T 65 71 oxygen SYSTEMATIC 23479280 T 77 86 hydrazine SYSTEMATIC 23479391 A 114 127 isoflavonoids FAMILY 23479391 A 140 154 3-arylcoumarin FAMILY 23479391 A 156 171 pterosonins A-F MULTIPLE 23479391 T 0 10 Flavonoids FAMILY 23479391 T 15 29 3-Arylcoumarin FAMILY 23479408 A 1038 1046 fibrates FAMILY 23479408 A 1050 1064 nicotinic acid TRIVIAL 23479408 A 1190 1203 triglycerides FAMILY 23479408 A 1277 1285 fibrates FAMILY 23479408 A 220 231 cholesterol TRIVIAL 23479408 A 340 352 triglyceride FAMILY 23479408 A 401 412 cholesterol TRIVIAL 23479408 A 537 547 fatty acid FAMILY 23479733 A 1011 1014 LNB ABBREVIATION 23479733 A 1019 1033 LNB-thiazoline SYSTEMATIC 23479733 A 1035 1061 Gal-β1,3-GlcNAc-thiazoline SYSTEMATIC 23479733 A 1090 1091 N FORMULA 23479733 A 1137 1138 C FORMULA 23479733 A 116 119 LNB ABBREVIATION 23479733 A 1211 1212 N FORMULA 23479733 A 1242 1243 N FORMULA 23479733 A 1334 1337 Gal ABBREVIATION 23479733 A 1372 1375 Gal ABBREVIATION 23479733 A 1451 1459 hydrogen SYSTEMATIC 23479733 A 1482 1491 hydroxyls FAMILY 23479733 A 1558 1561 LNB ABBREVIATION 23479733 A 1574 1580 GlcNAc FORMULA 23479733 A 1581 1586 sugar FAMILY 23479733 A 1595 1598 LNB ABBREVIATION 23479733 A 1657 1660 LNB ABBREVIATION 23479733 A 1661 1671 thiazoline SYSTEMATIC 23479733 A 1748 1749 N FORMULA 23479733 A 201 204 LNB ABBREVIATION 23479733 A 343 344 N FORMULA 23479733 A 413 416 LNB ABBREVIATION 23479733 A 545 546 N FORMULA 23479733 A 712 713 N FORMULA 23479733 A 751 765 monosaccharide FAMILY 23479733 A 766 772 GlcNAc FORMULA 23479733 A 82 97 lacto-N-biose I TRIVIAL 23479733 A 849 850 N FORMULA 23479733 A 946 947 N FORMULA 23479733 A 99 114 Gal-β1,3-GlcNAc SYSTEMATIC 23479733 T 60 61 N FORMULA 23480170 A 1005 1009 POPC ABBREVIATION 23480170 A 1015 1020 ozone TRIVIAL 23480170 A 1063 1072 palmitoyl TRIVIAL 23480170 A 1097 1106 palmitoyl TRIVIAL 23480170 A 1174 1180 oleoyl TRIVIAL 23480170 A 1225 1234 palmitoyl TRIVIAL 23480170 A 1374 1378 POPC ABBREVIATION 23480170 A 1399 1438 dipalmitoyl-sn-glycero-3-phosphocholine SYSTEMATIC 23480170 A 1440 1444 DPPC ABBREVIATION 23480170 A 1471 1475 DPPC ABBREVIATION 23480170 A 1576 1578 OH FORMULA 23480170 A 1656 1661 ozone TRIVIAL 23480170 A 240 245 ozone TRIVIAL 23480170 A 247 249 O3 FORMULA 23480170 A 385 433 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine SYSTEMATIC 23480170 A 435 439 POPC ABBREVIATION 23480170 A 446 451 ozone TRIVIAL 23480170 A 510 516 oleoyl TRIVIAL 23480170 A 527 531 POPC ABBREVIATION 23480170 A 785 791 oleoyl TRIVIAL 23480170 T 121 126 Ozone TRIVIAL 23480174 A 1007 1013 sodium SYSTEMATIC 23480174 A 1123 1130 [Li](+) FORMULA 23480174 A 1135 1142 [Na](+) FORMULA 23480174 A 121 130 [BMIM](+) ABBREVIATION 23480174 A 160 179 hexafluorophosphate SYSTEMATIC 23480174 A 181 189 [PF6](-) FORMULA 23480174 A 191 208 tetrafluoroborate SYSTEMATIC 23480174 A 210 218 [BF4](-) FORMULA 23480174 A 224 257 bis(trifluoromethylsulfonyl)imide SYSTEMATIC 23480174 A 259 268 [NTf2](-) FORMULA 23480174 A 308 315 lithium SYSTEMATIC 23480174 A 540 551 [BMIM][PF6] FORMULA 23480174 A 557 562 NaPF6 FORMULA 23480174 A 564 571 Lithium SYSTEMATIC 23480174 A 572 578 sodium SYSTEMATIC 23480174 A 92 119 1-butyl-3-methylimidazolium SYSTEMATIC 23480174 A 995 1002 lithium SYSTEMATIC 23480174 T 66 80 alkaline salts FAMILY 23480174 T 85 96 imidazolium SYSTEMATIC 23480625 A 1066 1074 ketamine TRIVIAL 23480625 A 322 330 ketamine TRIVIAL 23480625 A 38 46 ketamine TRIVIAL 23480625 A 432 440 ketamine TRIVIAL 23480625 A 560 568 ketamine TRIVIAL 23480625 A 755 763 ketamine TRIVIAL 23480625 A 803 811 ketamine TRIVIAL 23480625 A 913 921 ketamine TRIVIAL 23480625 T 20 28 Ketamine TRIVIAL 23480726 A 1006 1016 paclitaxel TRIVIAL 23480726 A 1094 1104 paclitaxel TRIVIAL 23480726 A 470 480 paclitaxel TRIVIAL 23480726 A 566 576 paclitaxel TRIVIAL 23480726 A 577 593 Oregon Green 488 TRIVIAL 23480726 A 696 706 paclitaxel TRIVIAL 23480726 A 794 804 paclitaxel TRIVIAL 23480726 A 891 901 paclitaxel TRIVIAL 23481635 A 135 143 guanines FAMILY 23481641 A 1149 1152 SIM ABBREVIATION 23481641 A 264 275 Simvastatin TRIVIAL 23481641 A 277 280 SIM ABBREVIATION 23481641 A 381 418 3-hydroxy-3-methylglutaryl-coenzyme A SYSTEMATIC 23481641 A 430 433 HMG ABBREVIATION 23481641 A 434 437 CoA ABBREVIATION 23481641 A 440 443 SIM ABBREVIATION 23481641 A 512 515 MTT ABBREVIATION 23481641 A 557 560 SIM ABBREVIATION 23481641 A 829 832 SIM ABBREVIATION 23481641 A 874 877 SIM ABBREVIATION 23481641 T 24 35 Simvastatin TRIVIAL 23481648 A 329 360 1-phenylbenzo[c]phenanthridines FAMILY 23481648 A 493 517 1,6-diphenylnaphthalenes FAMILY 23481648 A 667 691 1,6-diphenylnaphthalenes FAMILY 23481648 A 830 849 quaternary ammonium SYSTEMATIC 23481648 A 869 888 6-phenylnaphthalene SYSTEMATIC 23481648 A 942 961 Diphenylnaphthalene FAMILY 23481648 T 12 36 1,6-diphenylnaphthalenes FAMILY 23482393 A 1044 1050 5αghmC SYSTEMATIC 23482393 A 1105 1110 sugar FAMILY 23482393 A 21 44 5-hydroxymethylcytosine SYSTEMATIC 23482393 A 315 318 hmC ABBREVIATION 23482393 A 324 340 5-methylcytosine SYSTEMATIC 23482393 A 342 345 5mC SYSTEMATIC 23482393 A 351 359 cytosine TRIVIAL 23482393 A 46 50 5hmC SYSTEMATIC 23482393 A 598 606 cytosine TRIVIAL 23482393 A 668 677 cytosines FAMILY 23482393 A 727 735 cytosine TRIVIAL 23482393 A 882 902 5-β-glucosylated hmC SYSTEMATIC 23482393 A 904 910 5βghmC SYSTEMATIC 23482393 A 921 941 5-α-glucosylated hmC SYSTEMATIC 23482393 A 943 949 5αghmC SYSTEMATIC 23482393 A 996 1002 5βghmC SYSTEMATIC 23482393 T 24 47 5-hydroxymethylcytosine SYSTEMATIC 23483103 A 146 168 [Ru(phen)2(PAIDH)](2+) FORMULA 23483103 A 170 174 phen ABBREVIATION 23483103 A 177 196 1,10-phenanthroline SYSTEMATIC 23483103 A 201 222 [Ru(dmp)2(PAIDH)](2+) FORMULA 23483103 A 224 227 dmp ABBREVIATION 23483103 A 230 262 4,7-dimethyl-1,10-phenanthroline SYSTEMATIC 23483103 A 270 291 [Ru(dip)2(PAIDH)](2+) FORMULA 23483103 A 293 296 dip ABBREVIATION 23483103 A 299 331 4,7-diphenyl-1,10-phenanthroline SYSTEMATIC 23483103 A 41 62 [Ru(bpy)2(PAIDH)](2+) FORMULA 23483103 A 5 18 ruthenium(ii) SYSTEMATIC 23483103 A 64 67 bpy ABBREVIATION 23483103 A 70 85 2,2'-bipyridine SYSTEMATIC 23483103 A 87 92 PAIDH ABBREVIATION 23483103 A 95 141 2-pyridyl-1H-anthra[1,2-d]imidazole-6,11-dione SYSTEMATIC 23483103 T 68 81 ruthenium(ii) SYSTEMATIC 23484434 A 748 756 hydrogen SYSTEMATIC 23484493 A 56 77 chloronitrobenzamides FAMILY 23484493 A 79 83 CNBs FAMILY 23484493 T 16 37 Chloronitrobenzamides FAMILY 23484493 T 39 43 CNBs FAMILY 23484619 A 1027 1031 ODPA ABBREVIATION 23484619 A 1048 1050 Ga FORMULA 23484619 A 1070 1080 C17H35COOH FORMULA 23484619 A 108 117 C18H37NH2 FORMULA 23484619 A 1104 1106 Ga FORMULA 23484619 A 123 131 C18H37SH FORMULA 23484619 A 1282 1284 Ga FORMULA 23484619 A 1341 1345 ODPA ABBREVIATION 23484619 A 1388 1395 gallium SYSTEMATIC 23484619 A 1428 1432 ODPA ABBREVIATION 23484619 A 144 151 gallium SYSTEMATIC 23484619 A 1467 1475 hydrogen SYSTEMATIC 23484619 A 1498 1509 phosphonate SYSTEMATIC 23484619 A 1529 1534 oxide SYSTEMATIC 23484619 A 1613 1618 oxide SYSTEMATIC 23484619 A 1626 1633 gallium SYSTEMATIC 23484619 A 183 188 ozone TRIVIAL 23484619 A 303 308 ozone TRIVIAL 23484619 A 435 440 oxide SYSTEMATIC 23484619 A 46 58 hydrocarbons FAMILY 23484619 A 556 563 toluene TRIVIAL 23484619 A 634 641 gallium SYSTEMATIC 23484619 A 64 77 C18H37PO(OH)2 FORMULA 23484619 A 672 677 ozone TRIVIAL 23484619 A 686 693 gallium SYSTEMATIC 23484619 A 709 711 Ga FORMULA 23484619 A 728 732 ODPA ABBREVIATION 23484619 A 79 83 ODPA ABBREVIATION 23484619 A 820 824 ODPA ABBREVIATION 23484619 A 86 96 C17H35COOH FORMULA 23484619 A 874 886 acetonitrile SYSTEMATIC 23484619 A 98 106 C18H37OH FORMULA 23484619 T 34 46 Hydrocarbons FAMILY 23484619 T 58 65 Gallium SYSTEMATIC 23484668 A 10 26 diarylheptanoids FAMILY 23484668 A 170 225 (3S)-3-hydroxy-1,7-bis(4-hydroxyphenyl)-6E-hepten-5-one SYSTEMATIC 23484668 A 240 260 flavonoid glycosides FAMILY 23484668 A 262 341 3,7,3'-tri-O-methylquercetin-4'-O-β-d-apiofuranosyl-(1→2)-O-β-d-glucopyranoside SYSTEMATIC 23484668 A 28 91 (3S,5R)-3-hydroxy-5-methoxy-1,7-bis(4-hydroxyphenyl)-6E-heptene SYSTEMATIC 23484668 A 347 455 7,3'-di-O-methylquercetin-4'-O-β-d-glucopyranosyl-3-O-[6‴-(3-hydroxy-3-methylglutaroyl)]-α-d-glucopyranoside SYSTEMATIC 23484668 A 461 625 7,3'-di-O-methylquercetin-4'-O-β-d-glucopyranosyl-3-O-[(6'''''→5'''')-O-1'''''-(sinap-4-yl)-β-d-glucopyranosyl-6‴-(3-hydroxy-3-methylglutaroyl)]-α-d-glucopyranoside SYSTEMATIC 23484668 A 635 750 (2S)-5-hydroxy-7,3'-dimethoxyflavanone-4'-O-β-d-apiofuranosyl-(1→5)-O-β-d-apiofuranosyl-(1→2)-O-β-d-glucopyranoside SYSTEMATIC 23484668 A 97 160 (3S,5S)-3-hydroxy-5-methoxy-1,7-bis(4-hydroxyphenyl)-6E-heptene SYSTEMATIC 23484668 A 999 1015 (+)-Medioresinol TRIVIAL 23484668 T 0 16 Diarylheptanoids FAMILY 23484668 T 21 31 Flavonoids FAMILY 23484861 A 1219 1222 THF ABBREVIATION 23484861 A 1227 1237 chloroform TRIVIAL 23484861 A 377 381 zinc SYSTEMATIC 23484861 A 529 560 cethyltrimethylammonium bromide SYSTEMATIC 23484861 A 562 566 CTAB ABBREVIATION 23484861 A 769 797 acetato-benzimidazolato-zinc SYSTEMATIC 23484861 A 834 838 zinc SYSTEMATIC 23484861 A 866 873 acetate SYSTEMATIC 23484861 A 878 893 benzimidazolate SYSTEMATIC 23485017 A 105 140 transition metal dication complexes FAMILY 23485017 A 1266 1279 hydridomethyl SYSTEMATIC 23485017 A 20 27 methane SYSTEMATIC 23485017 A 209 216 methane SYSTEMATIC 23485017 A 304 327 [M(pyridine)2(CH4)](2+) FAMILY 23485017 A 47 54 methane SYSTEMATIC 23485017 A 502 519 transition metals FAMILY 23485017 A 595 612 transition metals FAMILY 23485017 A 636 643 methane SYSTEMATIC 23485017 A 668 691 [M(pyridine)2(CH4)](2+) FAMILY 23485017 A 751 753 Mn FORMULA 23485017 A 805 807 Fe FORMULA 23485017 A 811 813 Zn FORMULA 23485017 A 922 946 [Cr(pyridine)2(CH4)](2+) FORMULA 23485017 T 43 50 methane SYSTEMATIC 23485017 T 64 99 transition metal dication complexes FAMILY 23485046 A 0 24 Epigallocatechin gallate TRIVIAL 23485046 A 170 178 β-lactam TRIVIAL 23485046 A 195 207 tetracycline FAMILY 23485046 A 26 30 EGCG ABBREVIATION 23485046 A 278 282 EGCG ABBREVIATION 23485046 A 303 318 oxytetracycline SYSTEMATIC 23485046 A 408 420 erythromycin TRIVIAL 23485046 A 422 433 methicillin TRIVIAL 23485046 A 43 51 catechin TRIVIAL 23485046 A 438 450 tetracycline FAMILY 23485046 A 870 874 EGCG ABBREVIATION 23485046 A 888 903 oxytetracycline SYSTEMATIC 23485046 A 995 999 EGCG ABBREVIATION 23485046 T 28 52 epigallocatechin gallate TRIVIAL 23485046 T 57 72 oxytetracycline SYSTEMATIC 23485401 A 805 815 pyridazine SYSTEMATIC 23485401 A 822 830 pyridine SYSTEMATIC 23485401 T 40 50 pyridazine SYSTEMATIC 23485401 T 55 63 pyridine SYSTEMATIC 23485614 A 1033 1044 cholesterol TRIVIAL 23485614 A 1050 1063 triglycerides FAMILY 23485614 A 1095 1106 cholesterol TRIVIAL 23485614 A 1142 1153 cholesterol TRIVIAL 23485614 A 1189 1199 creatinine TRIVIAL 23485614 A 1204 1208 urea TRIVIAL 23485614 A 1294 1307 glibenclamide TRIVIAL 23485614 A 205 216 paracetamol TRIVIAL 23485614 A 246 253 alloxan TRIVIAL 23485614 A 493 500 alanine TRIVIAL 23485614 A 520 529 aspartate TRIVIAL 23485614 A 582 591 bilirubin TRIVIAL 23485614 A 637 647 superoxide TRIVIAL 23485614 A 687 698 glutathione TRIVIAL 23485614 A 700 703 GSH ABBREVIATION 23485614 A 708 719 glutathione TRIVIAL 23485614 A 790 801 paracetamol TRIVIAL 23485614 A 939 948 silymarin FAMILY 23485614 A 993 1000 glucose TRIVIAL 23485614 T 125 132 alloxan TRIVIAL 23485614 T 84 95 paracetamol TRIVIAL 23485653 A 1979 1982 BPA ABBREVIATION 23485653 A 37 48 bisphenol A TRIVIAL 23485653 A 428 431 BPA ABBREVIATION 23485653 A 50 53 BPA ABBREVIATION 23485653 T 105 116 bisphenol A TRIVIAL 23486920 A 123 128 amide FAMILY 23486920 A 136 216 (9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboximido)-4-ethylbenzene-1,2-diol SYSTEMATIC 23486920 A 256 267 glutathione TRIVIAL 23486920 A 269 272 GSH ABBREVIATION 23486920 A 275 308 nicotinamide adenine dinucleotide TRIVIAL 23486920 A 310 314 NADH ABBREVIATION 23486920 A 320 330 tryptophan TRIVIAL 23486920 A 332 335 Trp FORMULA 23486920 A 60 64 FePt FORMULA 23486920 A 678 681 GSH ABBREVIATION 23486920 A 683 687 NADH ABBREVIATION 23486920 A 692 695 Trp FORMULA 23486920 A 742 745 GSH ABBREVIATION 23486920 A 747 751 NADH ABBREVIATION 23486920 A 756 759 Trp FORMULA 23486920 T 136 147 glutathione TRIVIAL 23486920 T 149 182 nicotinamide adenine dinucleotide TRIVIAL 23486920 T 187 197 tryptophan TRIVIAL 23486920 T 29 33 FePt FORMULA 23486920 T 75 80 amide FAMILY 23488982 A 1051 1057 iodine SYSTEMATIC 23488982 A 33 39 iodine SYSTEMATIC 23488982 T 0 6 Iodine SYSTEMATIC 23489521 A 1090 1097 glucose TRIVIAL 23489622 A 130 142 amidinomycin TRIVIAL 23489622 A 192 212 methacryloyl anilide SYSTEMATIC 23489622 A 289 303 β-aminoamidine SYSTEMATIC 23489622 A 327 340 β-phenylamino SYSTEMATIC 23489622 A 451 458 amidine SYSTEMATIC 23489622 A 495 499 acyl FAMILY 23489622 A 518 531 β-phenylamino SYSTEMATIC 23489622 A 563 578 β-amidoamidines FAMILY 23489622 A 626 633 n-C8H17 FORMULA 23489622 A 637 645 n-C12H25 FORMULA 23489622 A 829 840 rimantadine TRIVIAL 23489622 A 9 68 racemic N-phenyl-substituted β-amidoamidines hydrochlorides FAMILY 23489622 T 116 128 amidinomycin TRIVIAL 23489622 T 36 72 N-phenyl-substituted β-amidoamidines FAMILY 23491640 A 1225 1232 alcohol FAMILY 23491640 A 837 838 N FORMULA 23491640 T 99 109 Alcoholics FAMILY 23492812 A 1208 1213 PBDDs FAMILY 23492812 A 1215 1220 PBDFs FAMILY 23492812 A 1239 1243 PBBs FAMILY 23492812 A 195 201 dioxin FAMILY 23492812 A 317 349 polybrominated dibenzo-p-dioxins FAMILY 23492812 A 351 356 PBDDs FAMILY 23492812 A 359 372 dibenzofurans FAMILY 23492812 A 374 379 PBDFs FAMILY 23492812 A 391 397 dioxin FAMILY 23492812 A 403 412 biphenyls FAMILY 23492812 A 417 421 PBBs FAMILY 23492812 A 500 506 dioxin FAMILY 23492812 T 0 32 Polybrominated Dibenzo-p-dioxins FAMILY 23492812 T 144 150 Dioxin FAMILY 23492812 T 34 39 PBDDs FAMILY 23492812 T 42 55 Dibenzofurans FAMILY 23492812 T 57 62 PBDFs FAMILY 23492812 T 68 77 Biphenyls FAMILY 23492812 T 79 83 PBBs FAMILY 23493259 A 226 233 glucose TRIVIAL 23493372 A 1004 1007 DEX ABBREVIATION 23493372 A 1101 1104 DEX ABBREVIATION 23493372 A 1183 1186 DEX ABBREVIATION 23493372 A 1324 1327 DEX ABBREVIATION 23493372 A 1451 1454 DEX ABBREVIATION 23493372 A 797 810 dexamethasone TRIVIAL 23493372 A 812 815 DEX ABBREVIATION 23493372 A 827 839 triglyceride FAMILY 23493372 A 906 909 DEX ABBREVIATION 23493372 T 0 13 Dexamethasone TRIVIAL 23493372 T 42 57 triacylglycerol FAMILY 23493568 A 1002 1010 tyrosine TRIVIAL 23493568 A 1091 1097 serine TRIVIAL 23493568 A 1268 1275 glucose TRIVIAL 23493568 A 483 490 glucose TRIVIAL 23493568 A 712 719 glucose TRIVIAL 23493568 A 815 822 glucose TRIVIAL 23494186 A 173 180 HMG-CoA ABBREVIATION 23494186 A 53 64 cholesterol TRIVIAL 23494186 A 584 593 ezetimibe TRIVIAL 23494186 A 595 604 bile acid FAMILY 23494186 A 621 629 fibrates FAMILY 23494186 T 4 15 Cholesterol TRIVIAL 23494481 A 1066 1073 ebselen TRIVIAL 23494481 A 1248 1259 glutathione TRIVIAL 23494481 A 126 132 oxygen SYSTEMATIC 23494481 A 1360 1371 glutathione TRIVIAL 23494481 A 14 25 glutathione TRIVIAL 23494481 A 323 334 glutathione TRIVIAL 23494481 A 485 488 GSH ABBREVIATION 23494481 A 559 570 glutathione TRIVIAL 23494481 A 583 614 L-buthionine-(S, R)-sulfoximine SYSTEMATIC 23494481 A 616 619 BSO ABBREVIATION 23494481 A 625 640 ethacrynic acid TRIVIAL 23494481 A 713 724 glutathione TRIVIAL 23494481 A 732 735 BSO ABBREVIATION 23494481 A 767 778 glutathione TRIVIAL 23494481 A 790 798 rotenone TRIVIAL 23494481 A 867 878 Glutathione TRIVIAL 23494481 A 892 895 BSO ABBREVIATION 23494481 T 87 98 glutathione TRIVIAL 23494524 A 1002 1003 H FORMULA 23494524 A 1018 1019 N FORMULA 23494524 A 1020 1023 H-N FORMULA 23494524 A 1028 1029 O FORMULA 23494524 A 1030 1033 H-C FORMULA 23494524 A 1144 1152 α-carbon SYSTEMATIC 23494524 A 1166 1176 dipeptides FAMILY 23494524 A 1206 1207 C FORMULA 23494524 A 1312 1320 α-carbon SYSTEMATIC 23494524 A 1420 1425 amide FAMILY 23494524 A 27 37 dipeptides FAMILY 23494524 A 278 288 dipeptides FAMILY 23494524 A 296 297 N FORMULA 23494524 A 307 321 selenocysteine TRIVIAL 23494524 A 353 354 C FORMULA 23494524 A 413 416 Ala FORMULA 23494524 A 418 421 Phe FORMULA 23494524 A 423 426 Glu FORMULA 23494524 A 428 431 Thr FORMULA 23494524 A 433 436 Asn FORMULA 23494524 A 438 441 Arg FORMULA 23494524 A 446 449 Sec FORMULA 23494524 A 561 571 dipeptides FAMILY 23494524 A 741 742 C FORMULA 23494524 A 875 883 α-carbon SYSTEMATIC 23494524 A 945 955 dipeptides FAMILY 23494524 T 13 23 dipeptides FAMILY 23494524 T 31 32 N FORMULA 23494524 T 42 56 selenocysteine TRIVIAL 23494938 A 17 31 nickel sulfide SYSTEMATIC 23494938 A 247 253 Ni3 S4 FORMULA 23494938 A 262 269 NiS1.03 FORMULA 23494938 A 323 330 lithium SYSTEMATIC 23494938 A 33 39 Ni3 S4 FORMULA 23494938 A 44 51 NiS1.03 FORMULA 23494938 A 72 95 nitrogen-doped graphene TRIVIAL 23494938 T 0 14 Nickel sulfide SYSTEMATIC 23494938 T 119 126 lithium SYSTEMATIC 23494938 T 15 38 nitrogen-doped graphene TRIVIAL 23495085 A 126 183 2-acetamide-3-methyl-3-nitrososulfanyl-N-aryl-butanamides FAMILY 23495085 A 189 198 p-methoxy SYSTEMATIC 23495085 A 200 208 o-chloro SYSTEMATIC 23495085 A 213 221 m-chloro SYSTEMATIC 23495085 A 31 36 (1) H FORMULA 23495085 A 41 47 (13) C FORMULA 23495085 A 71 121 2-acetamido-3-mercapto-3-methyl-N-aryl-butanamides FAMILY 23495085 T 0 5 (1) H FORMULA 23495085 T 10 16 (13) C FORMULA 23495085 T 33 83 2-acetamido-3-mercapto-3-methyl-N-aryl-butanamides FAMILY 23495085 T 88 144 2-acetamido-3-methyl-3-nitrososulfanyl-N-aryl-butanamide SYSTEMATIC 23495691 A 246 250 cAMP ABBREVIATION 23495691 A 4 8 cAMP ABBREVIATION 23495691 A 436 440 cAMP ABBREVIATION 23495691 A 472 476 cAMP ABBREVIATION 23495691 A 773 777 cAMP ABBREVIATION 23495691 T 50 60 cyclic AMP TRIVIAL 23495872 A 381 390 glutamine TRIVIAL 23495872 A 395 401 lysine TRIVIAL 23495872 A 557 563 lysine TRIVIAL 23495872 A 643 650 carboxy SYSTEMATIC 23495999 A 688 695 calcium SYSTEMATIC 23495999 A 774 781 calcium SYSTEMATIC 23496341 A 309 324 Didymellamide A TRIVIAL 23496341 A 367 372 azole FAMILY 23496341 A 41 59 didymellamides A-D MULTIPLE 23496341 A 9 39 4-hydroxy-2-pyridone alkaloids FAMILY 23496341 T 0 18 Pyridone Alkaloids FAMILY 23496341 T 112 117 Azole FAMILY 23497872 A 1012 1020 phenolic FAMILY 23497872 A 758 771 carbohydrates FAMILY 23497872 A 776 799 unsaturated fatty acids FAMILY 23497872 A 996 1007 tocopherols FAMILY 23497883 A 1006 1009 SOX ABBREVIATION 23497883 A 384 404 dimethylpolysiloxane FAMILY 23497883 A 406 409 SOX ABBREVIATION 23497883 A 448 451 SOP ABBREVIATION 23497883 A 541 544 GSH ABBREVIATION 23497883 A 560 563 GSH ABBREVIATION 23497883 A 564 568 GSSG ABBREVIATION 23497883 A 594 602 carbonyl FAMILY 23497883 A 665 670 NADPH ABBREVIATION 23497883 A 880 883 SOP ABBREVIATION 23497883 A 888 891 SOX ABBREVIATION 23497883 A 903 911 phenolic FAMILY 23497883 A 968 971 SOP ABBREVIATION 23497891 A 405 421 triacylglycerols FAMILY 23497891 A 423 427 TAGs ABBREVIATION 23497891 A 444 460 free fatty acids FAMILY 23497891 A 462 465 FFA ABBREVIATION 23497891 A 815 818 TAG ABBREVIATION 23497891 A 872 875 TAG ABBREVIATION 23497903 A 0 11 Calcium(II) SYSTEMATIC 23497903 A 1021 1028 hydroxy SYSTEMATIC 23497903 A 145 152 calcium SYSTEMATIC 23497903 A 205 216 calcium(II) SYSTEMATIC 23497903 A 30 39 palmitate TRIVIAL 23497903 A 41 47 Pal(-) ABBREVIATION 23497903 A 499 508 palmitate TRIVIAL 23497903 A 594 615 Ca(2+)][Pal(-)][OH(-) FORMULA 23497903 A 651 670 [Ca(2+)][Pal(-)](2) FORMULA 23497903 A 70 77 calcium SYSTEMATIC 23497903 A 717 728 Ca(OH)(Pal) FORMULA 23497903 A 760 780 Ca(Pal)2·Ca(OH)(Pal) FORMULA 23497903 A 956 964 Ca(Pal)2 FORMULA 23497903 T 0 25 Calcium hydroxy palmitate SYSTEMATIC 23497903 T 55 62 calcium SYSTEMATIC 23497903 T 80 89 palmitate TRIVIAL 23497904 A 1126 1134 phenolic FAMILY 23497904 A 326 334 phenolic FAMILY 23497904 A 896 915 flavonol glycosides FAMILY 23497904 A 920 941 hydroxycinnamic acids FAMILY 23497904 A 993 998 sugar FAMILY 23499503 A 354 376 pyrrolo[2,3-g]indazole SYSTEMATIC 23499503 A 562 565 ATP ABBREVIATION 23499503 A 67 89 pyrrolo[2,3-g]indazole SYSTEMATIC 23499503 T 18 41 pyrrolo[2,3-g]indazoles FAMILY 23499662 A 275 278 ATP ABBREVIATION 23499662 A 481 494 carbenoxolone TRIVIAL 23499662 A 496 506 mefloquine TRIVIAL 23499662 A 511 526 flufenamic acid TRIVIAL 23499662 A 785 793 chloride SYSTEMATIC 23499662 T 32 35 ATP ABBREVIATION 23499735 A 1004 1009 A-779 IDENTIFIER 23499735 A 1056 1064 PD123319 IDENTIFIER 23499735 A 1646 1651 A-779 IDENTIFIER 23499735 A 1656 1664 PD123319 IDENTIFIER 23499825 A 0 20 Steroidal glycosides FAMILY 23499825 A 542 566 5β-spirostanol glycoside FAMILY 23499825 A 577 587 cholestane TRIVIAL 23499825 A 706 734 (22R)-spirosolanol glycoside FAMILY 23499825 T 0 20 Steroidal glycosides FAMILY 23499927 A 213 217 K(+) FORMULA 23500059 A 1027 1038 simvastatin TRIVIAL 23500059 A 1363 1375 Alizarin red TRIVIAL 23500059 A 1391 1398 calcium SYSTEMATIC 23500059 A 643 680 poly(DL-lactic acid-co-glycolic acid) FAMILY 23500059 T 61 98 poly(dl-lactic acid-co-glycolic acid) FAMILY 23500116 A 1107 1118 Myritol 318 TRIVIAL 23500116 A 1119 1123 TPGS ABBREVIATION 23500116 A 1124 1132 Tween 80 TRIVIAL 23500116 A 1235 1246 Myritol 318 TRIVIAL 23500116 A 1247 1251 TPGS ABBREVIATION 23500116 A 1252 1260 Tween 80 TRIVIAL 23500116 A 1305 1316 fenofibrate TRIVIAL 23500116 A 1364 1375 fenofibrate TRIVIAL 23500116 A 395 406 fenofibrate TRIVIAL 23500116 A 781 792 fenofibrate TRIVIAL 23500116 A 912 919 V2(PO4) FORMULA 23500116 A 988 999 fenofibrate TRIVIAL 23500116 T 49 60 fenofibrate TRIVIAL 23500380 A 1003 1010 brucine TRIVIAL 23500380 A 1104 1111 brucine TRIVIAL 23500380 A 111 118 brucine TRIVIAL 23500380 A 1403 1410 brucine TRIVIAL 23500380 A 1564 1571 brucine TRIVIAL 23500380 A 21 28 brucine TRIVIAL 23500380 A 218 225 ethanol SYSTEMATIC 23500380 A 243 250 bruicne TRIVIAL 23500380 A 276 283 ethanol SYSTEMATIC 23500380 A 321 328 brucine TRIVIAL 23500380 A 483 490 brucine TRIVIAL 23500380 A 588 595 brucine TRIVIAL 23500380 A 679 686 Brucine TRIVIAL 23500380 A 836 843 brucine TRIVIAL 23500380 T 59 66 brucine TRIVIAL 23500382 A 1104 1111 glucose TRIVIAL 23500382 A 1170 1181 hematoxylin TRIVIAL 23500382 A 1182 1187 eosin FAMILY 23500382 A 1260 1271 methenamine TRIVIAL 23500382 A 1402 1413 kinsenoside TRIVIAL 23500382 A 1471 1482 kinsenoside TRIVIAL 23500382 A 178 189 kinsenoside TRIVIAL 23500382 A 199 206 glucose TRIVIAL 23500382 A 290 301 kinsenoside TRIVIAL 23500382 A 346 353 glucose TRIVIAL 23500382 A 358 369 cholesterol TRIVIAL 23500382 A 446 460 streptozotocin TRIVIAL 23500382 A 485 496 kinsenoside TRIVIAL 23500382 A 576 588 nitric oxide SYSTEMATIC 23500382 A 590 592 NO FORMULA 23500382 A 595 601 lactic TRIVIAL 23500382 A 623 633 superoxide TRIVIAL 23500382 A 738 745 glucose TRIVIAL 23500382 A 945 956 kinsenoside TRIVIAL 23500382 T 100 107 glucose TRIVIAL 23500382 T 38 49 kinsenoside TRIVIAL 23500386 A 284 299 d-galactosamine TRIVIAL 23500386 A 54 73 carbazole alkaloids FAMILY 23500386 A 9 28 carbazole alkaloids FAMILY 23500386 T 10 29 carbazole alkaloids FAMILY 23500387 A 1036 1044 curcumin TRIVIAL 23500387 A 1157 1165 curcumin TRIVIAL 23500387 A 1320 1328 curcumin TRIVIAL 23500387 A 1467 1475 curcumin TRIVIAL 23500387 A 322 335 dexamethasone TRIVIAL 23500387 A 350 358 curcumin TRIVIAL 23500387 A 588 599 hematoxylin TRIVIAL 23500387 A 604 609 eosin FAMILY 23500387 A 806 814 curcumin TRIVIAL 23500387 A 93 101 curcumin TRIVIAL 23500387 T 0 8 Curcumin TRIVIAL 23500490 A 1090 1094 zinc SYSTEMATIC 23500490 A 1164 1168 zinc SYSTEMATIC 23500490 A 1308 1312 zinc SYSTEMATIC 23500490 A 1421 1422 C FORMULA 23500490 A 1432 1436 zinc SYSTEMATIC 23500490 A 1498 1502 zinc SYSTEMATIC 23500490 A 379 380 C FORMULA 23500490 A 400 404 zinc SYSTEMATIC 23500490 A 459 463 zinc SYSTEMATIC 23500490 A 596 600 zinc SYSTEMATIC 23500490 A 641 642 C FORMULA 23500490 T 4 5 C FORMULA 23500536 A 1515 1527 l-amino acid FAMILY 23500536 A 887 890 KCl FORMULA 23500538 A 18 24 sterol FAMILY 23500538 A 29 38 oxysterol FAMILY 23500538 A 326 337 cholesterol TRIVIAL 23500538 A 342 353 desmosterol TRIVIAL 23500538 A 378 405 7- and 8-dehydrocholesterol MULTIPLE 23500538 A 413 440 7- and 8-dehydrodesmosterol MULTIPLE 23500538 A 513 523 oxysterols FAMILY 23500538 A 591 613 24S-hydroxycholesterol SYSTEMATIC 23500538 A 630 641 cholesterol TRIVIAL 23500538 A 700 711 cholesterol TRIVIAL 23500538 A 725 735 oxysterols FAMILY 23500538 A 789 809 7-dehydrocholesterol SYSTEMATIC 23500538 T 55 62 sterols FAMILY 23500538 T 67 77 oxysterols FAMILY 23500544 A 0 3 ATP ABBREVIATION 23500544 A 208 211 ATP ABBREVIATION 23500544 A 319 330 cholesterol TRIVIAL 23500544 A 382 392 Oxysterols FAMILY 23500544 A 413 424 cholesterol TRIVIAL 23500544 A 503 513 oxysterols FAMILY 23500544 A 517 528 cholesterol TRIVIAL 23500544 A 695 706 cholesterol TRIVIAL 23500544 A 711 720 oxysterol FAMILY 23500544 A 773 783 oxysterols FAMILY 23500544 T 26 29 ATP ABBREVIATION 23500544 T 64 74 oxysterols FAMILY 23500672 A 101 112 glutathione TRIVIAL 23500672 A 154 167 glutamic acid TRIVIAL 23500672 A 200 210 γ-glutamyl TRIVIAL 23500672 A 253 262 dipeptide FAMILY 23500672 A 422 435 glycylglycine TRIVIAL 23500672 A 474 485 glutathione TRIVIAL 23500672 A 691 716 γ-glutamyl-p-nitroanilide SYSTEMATIC 23500672 A 71 81 γ-glutamyl TRIVIAL 23500672 A 777 801 4-nitrobenzylglutathione SYSTEMATIC 23500672 A 813 841 2,4-dinitrophenylglutathione SYSTEMATIC 23500672 A 852 881 4-methylbiphenylylglutathione SYSTEMATIC 23500672 A 892 915 1-menaphthylglutathione SYSTEMATIC 23500672 A 930 960 9-methylanthracenylglutathione SYSTEMATIC 23500774 A 1234 1238 CCl4 FORMULA 23500774 A 165 173 puerarin TRIVIAL 23500774 A 221 225 CCl4 FORMULA 23500774 A 351 358 alanine TRIVIAL 23500774 A 383 392 aspartate TRIVIAL 23500774 A 423 432 bilirubin TRIVIAL 23500774 A 436 445 bilirubin TRIVIAL 23500774 A 607 611 CCl4 FORMULA 23500774 A 719 733 hydroxyproline SYSTEMATIC 23500774 A 735 738 Hyp ABBREVIATION 23500774 T 25 33 puerarin TRIVIAL 23500774 T 37 41 CCl4 FORMULA 23500779 A 1067 1071 HBCD ABBREVIATION 23500779 A 1073 1079 BDE-47 ABBREVIATION 23500779 A 1084 1088 TCDD ABBREVIATION 23500779 A 1105 1117 testosterone TRIVIAL 23500779 A 1133 1145 testosterone TRIVIAL 23500779 A 1146 1155 estradiol TRIVIAL 23500779 A 1225 1232 steroid FAMILY 23500779 A 180 202 Hexabromocyclododecane SYSTEMATIC 23500779 A 203 207 HBCD ABBREVIATION 23500779 A 209 243 2,2',4,4'-Tetrabromodiphenyl ether SYSTEMATIC 23500779 A 244 250 BDE-47 ABBREVIATION 23500779 A 252 285 2,2',4,4',5,5'-Hexachlorobiphenyl SYSTEMATIC 23500779 A 286 293 PCB-153 ABBREVIATION 23500779 A 295 329 2,3,7,8-Tetrachlorodibenzo-p-doxin SYSTEMATIC 23500779 A 330 334 TCDD ABBREVIATION 23500779 A 430 434 HBCD ABBREVIATION 23500779 A 452 458 BDE-47 ABBREVIATION 23500779 A 476 483 PCB-153 ABBREVIATION 23500779 A 501 505 TCDD ABBREVIATION 23500779 A 688 692 HBCD ABBREVIATION 23500779 A 808 814 BDE-47 ABBREVIATION 23500779 A 819 826 PCB-153 ABBREVIATION 23500779 A 929 936 PCB-153 ABBREVIATION 23500779 A 961 967 BDE-47 ABBREVIATION 23500779 A 969 973 HBCD ABBREVIATION 23500779 A 978 984 BDE-47 ABBREVIATION 23500779 T 105 109 TCDD ABBREVIATION 23500779 T 82 86 HBCD ABBREVIATION 23500779 T 88 94 BDE-47 ABBREVIATION 23500779 T 96 103 PCB-153 ABBREVIATION 23501055 A 35 48 gambogic acid TRIVIAL 23501055 A 717 723 prolyl TRIVIAL 23501055 A 758 764 oxygen SYSTEMATIC 23501055 T 0 13 Gambogic acid TRIVIAL 23501114 A 181 189 coumarin TRIVIAL 23501114 A 412 426 d-ribofuranose TRIVIAL 23501114 A 478 489 nucleosides FAMILY 23501114 A 48 61 benzimidazole SYSTEMATIC 23501114 A 62 70 coumarin TRIVIAL 23501114 A 722 735 benzimidazole SYSTEMATIC 23501114 A 737 745 coumarin TRIVIAL 23501114 A 751 763 ribofuranose TRIVIAL 23501114 A 89 108 β-d-ribofuranosides FAMILY 23501114 T 0 9 Coumarins FAMILY 23501114 T 29 43 benzimidazoles FAMILY 23501114 T 54 69 ribofuranosides FAMILY 23501490 A 0 18 Cylindrospermopsin TRIVIAL 23501490 A 1011 1021 superoxide TRIVIAL 23501490 A 1059 1082 gamma-glutamyl-cysteine TRIVIAL 23501490 A 1241 1244 CYN ABBREVIATION 23501490 A 1642 1645 CYN ABBREVIATION 23501490 A 20 23 CYN ABBREVIATION 23501490 A 260 263 CYN ABBREVIATION 23501490 A 298 309 glutathione TRIVIAL 23501490 A 334 337 CYN ABBREVIATION 23501490 A 504 507 CYN ABBREVIATION 23501490 A 572 583 l-carnitine TRIVIAL 23501490 A 666 669 CYN ABBREVIATION 23501490 A 674 683 deoxy-CYN SYSTEMATIC 23501490 A 702 705 CYN ABBREVIATION 23501490 A 918 937 reduced glutathione TRIVIAL 23501490 A 941 961 oxidised glutathione TRIVIAL 23501490 A 963 966 GSH ABBREVIATION 23501490 A 967 971 GSSG ABBREVIATION 23501490 A 996 1001 NADPH ABBREVIATION 23501490 T 23 34 l-carnitine TRIVIAL 23501490 T 43 61 cylindrospermopsin TRIVIAL 23503440 A 159 162 PHB ABBREVIATION 23503440 A 210 213 PHB ABBREVIATION 23503440 A 254 263 primidone TRIVIAL 23503440 A 337 346 primidone TRIVIAL 23503440 A 41 54 phenobarbital TRIVIAL 23503440 A 417 426 primidone TRIVIAL 23503440 A 487 490 PHB ABBREVIATION 23503440 A 512 521 primidone TRIVIAL 23503440 A 545 548 PHB ABBREVIATION 23503440 A 56 59 PHB ABBREVIATION 23503440 A 625 628 PHB ABBREVIATION 23503440 A 656 665 primidone TRIVIAL 23503440 T 19 28 primidone TRIVIAL 23503441 A 1540 1548 imatinib TRIVIAL 23503441 A 364 372 imatinib TRIVIAL 23503441 A 667 675 imatinib TRIVIAL 23503441 A 73 81 imatinib TRIVIAL 23503441 T 60 68 imatinib TRIVIAL 23503460 A 602 622 phosphatidylinositol TRIVIAL 23503470 A 159 163 TiO2 FORMULA 23503470 A 188 192 TiO2 FORMULA 23503470 A 2 6 TiO2 FORMULA 23503470 A 372 374 Li FORMULA 23503470 A 387 391 TiO2 FORMULA 23503470 A 468 470 Li FORMULA 23503470 T 45 49 TiO2 FORMULA 23503470 T 70 77 lithium SYSTEMATIC 23503611 A 594 601 lactate FAMILY 23503627 A 1178 1189 xanthohumol TRIVIAL 23503627 A 1191 1202 Xanthohumol TRIVIAL 23503627 A 136 147 xanthohumol TRIVIAL 23503627 A 1407 1418 xanthohumol TRIVIAL 23503627 A 273 284 xanthohumol TRIVIAL 23503627 A 29 40 xanthohumol TRIVIAL 23503627 A 568 578 12(S)-HETE SYSTEMATIC 23503627 A 664 675 xanthohumol TRIVIAL 23503627 A 764 775 Xanthohumol TRIVIAL 23503627 A 916 927 xanthohumol TRIVIAL 23503627 T 0 11 Xanthohumol TRIVIAL 23503780 A 238 247 histidine TRIVIAL 23503780 A 578 581 His FORMULA 23503780 A 608 611 His FORMULA 23503780 A 683 686 His FORMULA 23503780 A 762 765 His FORMULA 23503780 A 793 796 His FORMULA 23503780 A 833 836 His FORMULA 23503780 A 90 99 histidine TRIVIAL 23503780 A 958 967 histidine TRIVIAL 23503780 T 52 61 histidine TRIVIAL 23503967 A 1068 1075 glucose TRIVIAL 23503967 A 693 700 glucose TRIVIAL 23503967 A 749 756 glucose TRIVIAL 23504315 A 81 88 glucose TRIVIAL 23504628 A 186 199 polyglutamine FAMILY 23504628 A 201 206 polyQ ABBREVIATION 23504628 A 290 295 polyQ ABBREVIATION 23504628 A 329 334 polyQ ABBREVIATION 23504628 A 479 484 polyQ ABBREVIATION 23504628 A 589 594 polyQ ABBREVIATION 23504628 A 618 623 polyQ ABBREVIATION 23504628 A 733 738 polyQ ABBREVIATION 23504628 A 885 890 polyQ ABBREVIATION 23504628 T 107 120 Polyglutamine FAMILY 23504628 T 51 64 Polyglutamine FAMILY 23504855 A 165 173 zaleplon TRIVIAL 23504855 A 650 658 zaleplon TRIVIAL 23504855 A 72 80 zaleplon TRIVIAL 23504855 A 985 993 Zaleplon TRIVIAL 23504855 T 45 53 Zaleplon TRIVIAL 23505214 A 263 265 Fe FORMULA 23505214 A 53 59 BiFeO3 FORMULA 23505214 T 49 55 BiFeO3 FORMULA 23505636 A 0 6 Cobalt SYSTEMATIC 23505636 A 1027 1031 zinc SYSTEMATIC 23505636 A 1084 1088 zinc SYSTEMATIC 23505636 A 109 115 Cobalt SYSTEMATIC 23505636 A 1149 1155 cobalt SYSTEMATIC 23505636 A 1160 1164 zinc SYSTEMATIC 23505636 A 1280 1284 zinc SYSTEMATIC 23505636 A 1424 1430 cobalt SYSTEMATIC 23505636 A 1445 1449 zinc SYSTEMATIC 23505636 A 1584 1590 cobalt SYSTEMATIC 23505636 A 1595 1599 zinc SYSTEMATIC 23505636 A 291 297 cobalt SYSTEMATIC 23505636 A 308 322 CoCl(2)·6H(2)O FORMULA 23505636 A 410 416 Cobalt SYSTEMATIC 23505636 A 495 501 cobalt SYSTEMATIC 23505636 A 596 602 cobalt SYSTEMATIC 23505636 A 665 671 cobalt SYSTEMATIC 23505636 A 703 709 cobalt SYSTEMATIC 23505636 A 714 718 zinc SYSTEMATIC 23505636 A 939 945 cobalt SYSTEMATIC 23505636 T 0 15 Cobalt chloride SYSTEMATIC 23505636 T 111 115 zinc SYSTEMATIC 23505965 A 114 126 carbohydrate FAMILY 23505965 A 1347 1359 carbohydrate FAMILY 23505965 A 281 294 carbohydrates FAMILY 23505965 A 513 525 carbohydrate FAMILY 23505965 T 44 57 Carbohydrates FAMILY 23505966 A 252 282 poly(allylamine hydrochloride) SYSTEMATIC 23505966 A 284 287 PAH ABBREVIATION 23505966 A 305 323 poly(acrylic acid) SYSTEMATIC 23505966 A 325 328 PAA ABBREVIATION 23505966 A 367 399 4-(2-hydroxyethoxy) benzophenone SYSTEMATIC 23506002 A 66 78 isoxazolines FAMILY 23506120 A 100 108 nitrogen SYSTEMATIC 23506120 A 1014 1021 inosine TRIVIAL 23506120 A 1035 1049 8-oxoguanosine SYSTEMATIC 23506120 A 1068 1090 1,N(6)-ethenoadenosine SYSTEMATIC 23506120 A 114 121 halogen FAMILY 23506120 A 1347 1359 nitric oxide SYSTEMATIC 23506120 A 1417 1424 inosine TRIVIAL 23506120 A 1462 1474 nitric oxide SYSTEMATIC 23506120 A 1495 1511 N-methylarginine SYSTEMATIC 23506120 A 1556 1563 inosine TRIVIAL 23506120 A 1756 1765 adenosine TRIVIAL 23506120 A 1844 1850 oxygen SYSTEMATIC 23506120 A 1855 1863 nitrogen SYSTEMATIC 23506120 A 509 521 nitric oxide SYSTEMATIC 23506120 A 708 714 etheno SYSTEMATIC 23506120 A 92 98 oxygen SYSTEMATIC 23506120 A 975 985 nucleobase FAMILY 23506120 A 999 1009 xanthosine TRIVIAL 23506120 T 20 27 Inosine TRIVIAL 23506492 A 964 970 oxygen SYSTEMATIC 23506527 A 159 172 phenylalanine TRIVIAL 23506527 A 177 190 glutamic acid TRIVIAL 23506527 A 195 201 lysine TRIVIAL 23506783 A 163 180 bacosides A and B MULTIPLE 23506783 A 219 229 bacoside A TRIVIAL 23506783 A 267 275 saponins FAMILY 23506783 A 277 288 bacoside A3 TRIVIAL 23506783 A 294 307 bacopaside II TRIVIAL 23506783 A 313 328 bacopasaponin C TRIVIAL 23506783 A 341 352 jujobogenin TRIVIAL 23506783 A 451 463 bacopaside I TRIVIAL 23506783 A 481 489 saponins FAMILY 23506783 A 573 583 bacoside B TRIVIAL 23506783 A 830 847 bacosides A and B MULTIPLE 23506783 T 1 11 Bacoside B TRIVIAL 23507868 A 1225 1237 α-tocopherol TRIVIAL 23507868 A 1263 1278 malondialdehyde TRIVIAL 23508266 A 235 244 albuterol TRIVIAL 23508266 A 261 271 nucleotide FAMILY 23508295 A 1235 1241 copper SYSTEMATIC 23508295 A 1352 1358 copper SYSTEMATIC 23508295 A 996 1002 copper SYSTEMATIC 23508295 T 26 32 copper SYSTEMATIC 23508555 A 1019 1026 ethanol SYSTEMATIC 23508555 A 1144 1152 cortisol TRIVIAL 23508555 A 1211 1218 ethanol SYSTEMATIC 23508555 A 1311 1319 cortisol TRIVIAL 23508555 A 1353 1361 cortisol TRIVIAL 23508555 A 1392 1399 ethanol SYSTEMATIC 23508555 A 435 442 ethanol SYSTEMATIC 23508555 A 551 559 cortisol TRIVIAL 23508555 A 767 774 ethanol SYSTEMATIC 23508555 A 949 956 ethanol SYSTEMATIC 23508555 A 967 974 ethanol SYSTEMATIC 23508555 A 989 996 ethanol SYSTEMATIC 23508555 T 83 90 ethanol SYSTEMATIC 23508685 A 0 9 Serotonin TRIVIAL 23508685 A 1071 1076 TCB-2 IDENTIFIER 23508685 A 34 43 glutamate TRIVIAL 23508685 A 708 714 lysine TRIVIAL 23508685 A 855 861 lysine TRIVIAL 23508685 A 915 921 lysine TRIVIAL 23508718 A 0 6 DHEA-S ABBREVIATION 23508718 A 1059 1065 DHEA-S ABBREVIATION 23508718 A 1111 1117 DHEA-S ABBREVIATION 23508718 A 1251 1257 DHEA-S ABBREVIATION 23508718 A 1329 1335 DHEA-S ABBREVIATION 23508718 A 1340 1356 free fatty acids FAMILY 23508718 A 1402 1418 free fatty acids FAMILY 23508718 A 1469 1475 DHEA-S ABBREVIATION 23508718 A 28 35 steroid FAMILY 23508718 A 282 288 DHEA-S ABBREVIATION 23508718 A 346 362 free fatty acids FAMILY 23508718 A 474 480 DHEA-S ABBREVIATION 23508718 A 540 556 free fatty acids FAMILY 23508718 A 676 682 DHEA-S ABBREVIATION 23508718 A 716 722 DHEA-S ABBREVIATION 23508718 A 811 817 DHEA-S ABBREVIATION 23508718 A 93 99 DHEA-S ABBREVIATION 23508718 A 942 948 DHEA-S ABBREVIATION 23508718 A 953 969 free fatty acids FAMILY 23508718 T 16 46 Dehydroepiandrosterone Sulfate SYSTEMATIC 23508742 A 267 277 silica gel TRIVIAL 23508742 A 3 10 ethanol SYSTEMATIC 23508742 A 366 375 damulin A TRIVIAL 23508742 A 380 389 damulin B TRIVIAL 23508742 A 391 403 gypenoside L TRIVIAL 23508742 A 408 421 gypenoside LI TRIVIAL 23508742 A 494 497 MTT ABBREVIATION 23508742 A 630 638 hydroxyl SYSTEMATIC 23508742 T 0 9 Dammarane TRIVIAL 23508742 T 15 23 saponins FAMILY 23508744 A 35 53 aquilacallanes A-B MULTIPLE 23508744 A 375 387 ursolic acid TRIVIAL 23508744 A 396 420 5,7,4'-trimethoxyflavone SYSTEMATIC 23508744 A 8 33 tirucallane triterpenoids FAMILY 23508744 T 8 33 tirucallane triterpenoids FAMILY 23509003 A 0 8 Graphene TRIVIAL 23509003 A 1071 1079 graphene TRIVIAL 23509003 A 227 235 graphene TRIVIAL 23509003 A 271 279 graphene TRIVIAL 23509003 A 400 408 graphene TRIVIAL 23509003 A 496 504 graphene TRIVIAL 23509003 A 542 550 graphene TRIVIAL 23509003 A 581 589 graphene TRIVIAL 23509003 A 60 66 carbon SYSTEMATIC 23509003 A 618 626 chlorine SYSTEMATIC 23509003 A 726 734 chlorine SYSTEMATIC 23509003 A 818 826 graphene TRIVIAL 23509003 A 850 858 graphene TRIVIAL 23509003 A 986 994 chlorine SYSTEMATIC 23509003 T 79 87 graphene TRIVIAL 23509042 A 65 85 γ-hydroxyphosphonate SYSTEMATIC 23509611 A 103 106 MEP ABBREVIATION 23509611 A 156 171 bisphosphonates FAMILY 23509611 A 207 218 diphosphate SYSTEMATIC 23509611 A 238 252 Bisphosphonate SYSTEMATIC 23509611 A 367 370 MEP ABBREVIATION 23509611 T 80 96 cyclodiphosphate SYSTEMATIC 23510022 A 135 145 Scopoletin TRIVIAL 23510022 A 154 162 scopolin TRIVIAL 23510022 A 200 210 Scopoletin TRIVIAL 23510022 A 234 241 peroxyl SYSTEMATIC 23510022 A 336 344 scopolin TRIVIAL 23510022 A 570 576 oxygen SYSTEMATIC 23510022 A 595 605 superoxide TRIVIAL 23510022 T 0 10 Scopoletin TRIVIAL 23510022 T 149 155 Oxygen SYSTEMATIC 23510022 T 15 23 Scopolin TRIVIAL 23510074 A 30 37 1-ethyl SYSTEMATIC 23510074 A 40 47 1-butyl SYSTEMATIC 23510074 A 54 61 1-octyl SYSTEMATIC 23510074 A 64 128 1-alkyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl] imide FAMILY 23510074 A 860 937 1-ethyl- and 1-octyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl] imide MULTIPLE 23510074 T 89 152 1-Alkyl-3-methylimidazolium Bis[(trifluoromethyl)sulfonyl]imide FAMILY 23510370 A 912 925 sodium iodide SYSTEMATIC 23510510 A 142 144 Ag FORMULA 23510510 A 145 147 Au FORMULA 23510510 A 20 25 PAMAM ABBREVIATION 23510510 T 45 51 Silver SYSTEMATIC 23510527 A 1055 1064 aldehydes FAMILY 23510527 A 146 158 aqua-hydroxo SYSTEMATIC 23510527 A 159 168 (O2H3)(-) FORMULA 23510527 A 169 177 hydroxyl SYSTEMATIC 23510527 A 179 181 OH FORMULA 23510527 A 186 188 Sc FORMULA 23510527 A 432 468 [Sc3(3,5-DSB)2(μ-O2H3)(μ-OH)2(H2O)2] FORMULA 23510527 A 44 56 aqua-hydroxo SYSTEMATIC 23510527 A 483 491 (O2H3)Sc FORMULA 23510527 A 497 504 3,5-DSB SYSTEMATIC 23510527 A 507 530 3,5-disulfobenzoic acid SYSTEMATIC 23510527 A 602 630 [Sc3(3,5-DSB)2(μ-OH)3(H2O)4] FORMULA 23510527 A 65 74 (O2H3)(-) FORMULA 23510527 A 688 696 (O2H3)Sc FORMULA 23510527 A 771 797 [Sc3(3,5-DSB)(μ-OH)6(H2O)] FORMULA 23510527 A 812 841 [Sc(3,5-DSB)(Phen)(H2O)](H2O) FORMULA 23510527 A 868 870 OH FORMULA 23510527 A 882 889 H3O2(-) FORMULA 23510527 A 959 967 (O2H3)Sc FORMULA 23510527 T 0 4 H3O2 FORMULA 23510527 T 68 80 Aqua-Hydroxo SYSTEMATIC 23510527 T 81 89 Hydroxyl SYSTEMATIC 23511023 A 123 133 nucleotide FAMILY 23511023 A 323 344 benzofuranopyrimidone SYSTEMATIC 23511023 A 73 107 benzofurano[3,2-d]pyrimidine-2-one SYSTEMATIC 23511023 T 18 52 benzofurano[3,2-d]pyrimidin-2-ones FAMILY 23511023 T 76 86 nucleotide FAMILY 23511897 A 1241 1252 cholesterol TRIVIAL 23511897 A 310 325 steroid hormone FAMILY 23511897 A 414 417 ATP ABBREVIATION 23511897 A 477 488 cholesterol TRIVIAL 23511897 A 561 572 cholesterol TRIVIAL 23511897 A 63 74 cholesterol TRIVIAL 23511897 A 778 799 17-ketogenic steroids FAMILY 23511897 A 95 102 steroid FAMILY 23511897 T 40 51 cholesterol TRIVIAL 23512318 A 163 180 dimethylformamide SYSTEMATIC 23512318 A 209 225 thiol-disulphide SYSTEMATIC 23512318 A 392 421 thiolated poly(aspartic acid) FAMILY 23512318 A 605 615 disulphide SYSTEMATIC 23512318 A 72 91 poly(aspartic acid) SYSTEMATIC 23512318 T 25 35 Cysteamine TRIVIAL 23512318 T 45 64 Poly(aspartic acid) FAMILY 23512500 A 117 125 oregonin TRIVIAL 23512500 A 1184 1200 Diarylheptanoids FAMILY 23512500 A 131 146 platyphylloside TRIVIAL 23512500 A 1412 1422 amifostine TRIVIAL 23512500 A 152 165 rubranoside A TRIVIAL 23512500 A 171 184 rubranoside B TRIVIAL 23512500 A 190 202 hirsutanonol TRIVIAL 23512500 A 208 219 hirsutenone TRIVIAL 23512500 A 225 261 hirsutanonol-5-O-β-D-glucopyranoside SYSTEMATIC 23512500 A 267 304 platyphyllonol-5-O-β-D-xylopyranoside SYSTEMATIC 23512500 A 310 323 aceroside VII TRIVIAL 23512500 A 329 339 alnuside A TRIVIAL 23512500 A 346 356 alnuside B TRIVIAL 23512500 A 363 432 1,7-bis-(3,4-dihydoxyphenyl)-5-hydroxy-heptane-3-O-β-D-xylopyranoside SYSTEMATIC 23512500 A 439 523 (5S)-1-(4-hydroxyphenyl)-7-(3,4-dihydroxyphenyl)-5-O-β-D-glucopyranosyl-heptan-3-one SYSTEMATIC 23512500 A 534 632 (5S)-1,7-bis-(3,4-dihydroxyphenyl)-5-O-β-D-[6-(3,4-dimethoxycinnamoylglucopyranosyl)]-heptan-3-one SYSTEMATIC 23512500 A 650 666 diarylheptanoids FAMILY 23512500 A 99 115 diarylheptanoids FAMILY 23512500 T 0 16 Diarylheptanoids FAMILY 23512583 A 367 381 graphene oxide SYSTEMATIC 23512583 A 657 661 H2 S FORMULA 23512583 A 663 665 HI FORMULA 23512583 A 671 674 SO2 FORMULA 23512583 A 869 877 graphene TRIVIAL 23512583 T 23 37 Graphene Oxide SYSTEMATIC 23512910 A 1010 1013 PCL ABBREVIATION 23512910 A 1014 1019 β-TCP ABBREVIATION 23512910 A 217 220 PCL ABBREVIATION 23512910 A 221 226 β-TCP ABBREVIATION 23512910 A 376 379 MTT ABBREVIATION 23512910 A 493 496 PCL ABBREVIATION 23512910 A 497 502 β-TCP ABBREVIATION 23512910 A 545 548 PCL ABBREVIATION 23512910 A 549 554 β-TCP ABBREVIATION 23512910 A 590 593 PCL ABBREVIATION 23512910 A 594 599 β-TCP ABBREVIATION 23512910 A 61 64 PCL ABBREVIATION 23512910 A 65 70 β-TCP ABBREVIATION 23512910 A 666 669 PCL ABBREVIATION 23512910 A 670 675 β-TCP ABBREVIATION 23512910 T 79 95 Polycaprolactone FAMILY 23512910 T 96 118 β-Tricalcium Phosphate SYSTEMATIC 23514045 A 473 476 CO2 FORMULA 23514045 A 630 633 CO2 FORMULA 23514045 A 634 642 HCO3 (-) FORMULA 23514045 A 687 700 acetazolamide TRIVIAL 23514045 A 702 715 methazolamide TRIVIAL 23514045 A 717 727 topiramate TRIVIAL 23514045 A 729 739 zonisamide TRIVIAL 23514045 A 745 754 sulthiame TRIVIAL 23514045 A 803 806 CO2 FORMULA 23514379 A 1094 1104 kynurenine TRIVIAL 23514379 A 114 127 methoxyindole SYSTEMATIC 23514379 A 1205 1214 serotonin TRIVIAL 23514379 A 1227 1244 N-acetylserotonin SYSTEMATIC 23514379 A 1246 1249 NAS ABBREVIATION 23514379 A 1266 1274 tyrosine TRIVIAL 23514379 A 132 142 kynurenine TRIVIAL 23514379 A 144 147 KYN ABBREVIATION 23514379 A 1460 1471 indoleamine SYSTEMATIC 23514379 A 1528 1531 TRY ABBREVIATION 23514379 A 1534 1537 KYN ABBREVIATION 23514379 A 1550 1553 NAS ABBREVIATION 23514379 A 1558 1569 kynurenines FAMILY 23514379 A 161 171 tryptophan TRIVIAL 23514379 A 173 176 TRP ABBREVIATION 23514379 A 619 628 serotonin TRIVIAL 23514379 A 685 688 TRP ABBREVIATION 23514379 A 711 720 serotonin TRIVIAL 23514379 A 740 743 KYN ABBREVIATION 23514379 A 763 771 cortisol TRIVIAL 23514379 A 808 818 tryptophan TRIVIAL 23514379 A 865 868 TRP ABBREVIATION 23514379 A 871 874 KYN ABBREVIATION 23514379 A 926 929 KYN ABBREVIATION 23514379 T 0 9 Serotonin TRIVIAL 23514379 T 12 22 kynurenine TRIVIAL 23515291 A 1265 1285 phosphatidylinositol TRIVIAL 23515291 A 620 628 estrogen FAMILY 23515291 A 927 935 estrogen FAMILY 23515291 A 940 949 tamoxifen TRIVIAL 23515291 T 136 144 Estrogen FAMILY 23515494 A 1101 1110 serotonin TRIVIAL 23515494 A 1230 1239 serotonin TRIVIAL 23515494 A 219 228 serotonin TRIVIAL 23515494 A 50 65 methamphetamine TRIVIAL 23515494 A 815 824 serotonin TRIVIAL 23515494 A 870 880 tryptophan TRIVIAL 23515494 A 931 940 serotonin TRIVIAL 23515494 A 976 985 monoamine FAMILY 23515494 T 15 24 serotonin TRIVIAL 23515494 T 38 53 methamphetamine TRIVIAL 23515495 A 1133 1143 creatinine TRIVIAL 23515495 A 300 310 creatinine TRIVIAL 23515495 A 930 940 creatinine TRIVIAL 23515584 A 1279 1286 ethanol SYSTEMATIC 23515584 A 1557 1564 alcohol FAMILY 23515584 A 1678 1685 alcohol FAMILY 23515584 A 245 257 acetaldehyde SYSTEMATIC 23515584 A 389 396 ethanol SYSTEMATIC 23515584 A 414 426 acetaldehyde SYSTEMATIC 23515584 A 466 481 D-penicillamine TRIVIAL 23515584 A 620 627 alcohol FAMILY 23515584 A 666 673 ethanol SYSTEMATIC 23515584 T 12 27 D-penicillamine TRIVIAL 23515584 T 44 56 acetaldehyde SYSTEMATIC 23515584 T 85 92 alcohol FAMILY 23516047 A 1149 1153 NaCl FORMULA 23516047 A 1210 1213 Ag+ FORMULA 23516047 A 658 673 sodium chloride SYSTEMATIC 23516047 A 688 694 silver SYSTEMATIC 23516047 A 971 975 NaCl FORMULA 23516047 A 980 983 Ag+ FORMULA 23516047 T 10 16 silver SYSTEMATIC 23516047 T 21 25 NaCl FORMULA 23516330 A 1003 1004 N FORMULA 23516330 A 1010 1011 C FORMULA 23516330 A 1356 1357 C FORMULA 23516330 A 1454 1455 N FORMULA 23516330 A 390 394 cAMP ABBREVIATION 23516330 A 403 410 calcium SYSTEMATIC 23516963 A 148 188 7-amino-5-thio-thiazolo[4,5-d]pyrimidine SYSTEMATIC 23516963 A 364 372 leucinol TRIVIAL 23516963 A 443 451 α-methyl SYSTEMATIC 23516963 A 461 467 benzyl SYSTEMATIC 23516963 T 12 53 7-Amino-5-thio-thiazolo[4,5-d]pyrimidines FAMILY 23517464 A 689 693 CdSe FORMULA 23517464 A 73 77 CdSe FORMULA 23517464 T 62 66 CdSe FORMULA 23517501 A 104 159 3-alkylaminopyrido[4,3-e]-1,4,2-dithiazine 1,1-dioxides FAMILY 23517501 A 1134 1141 calcium SYSTEMATIC 23517501 A 1239 1241 NH FORMULA 23517501 A 1291 1293 NH FORMULA 23517501 A 1332 1369 benzo- and pyridothiadiazine dioxides MULTIPLE 23517501 A 291 294 ATP ABBREVIATION 23517501 A 305 314 potassium SYSTEMATIC 23517501 A 346 355 diazoxide SYSTEMATIC 23517501 A 360 423 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide SYSTEMATIC 23517501 A 39 99 3-alkyl/aralkyl/arylamino-1,4,2-benzodithiazine 1,1-dioxides MULTIPLE 23517501 A 509 526 1,2,4-thiadiazine SYSTEMATIC 23517501 A 548 564 1,4,2-dithiazine SYSTEMATIC 23517501 A 583 593 dithiazine FAMILY 23517501 A 690 708 1-phenylethylamino SYSTEMATIC 23517501 A 915 922 calcium SYSTEMATIC 23517501 A 957 1021 3-(1-phenylethyl)sulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxides FAMILY 23517501 T 0 41 1,4,2-Benzo/pyridodithiazine 1,1-Dioxides MULTIPLE 23517501 T 110 152 1,2,4-Benzo/pyridothiadiazine 1,1-Dioxides FAMILY 23517501 T 70 73 ATP ABBREVIATION 23517501 T 84 93 Potassium SYSTEMATIC 23517732 A 110 112 Fe FORMULA 23517732 A 1174 1195 3,3'-diindolylmethane SYSTEMATIC 23517732 A 185 207 3,3'-diindolylmethanes FAMILY 23517732 A 378 417 nitroaryl substituted diindolylmethanes FAMILY 23517732 A 39 61 3,3'-diindolylmethanes FAMILY 23517732 A 462 504 4-nitrophenyl linked 3,3'-diindolylmethane SYSTEMATIC 23517732 A 779 801 3,3'-diindolylmethanes FAMILY 23517732 A 79 81 Fe FORMULA 23517732 A 951 998 fluorophenyl substituted 3,3'-diindolylmethanes FAMILY 23517732 T 13 35 3,3'-diindolylmethanes FAMILY 23517733 A 1072 1081 cisplatin TRIVIAL 23517733 A 111 112 H FORMULA 23517733 A 114 117 CH3 FORMULA 23517733 A 119 121 Cl FORMULA 23517733 A 123 125 Br FORMULA 23517733 A 127 128 F FORMULA 23517733 A 130 133 CF3 FORMULA 23517733 A 135 139 SCH3 FORMULA 23517733 A 14 31 azaphenothiazines FAMILY 23517733 A 178 188 aminoalkyl FAMILY 23517733 A 236 250 diquinodithiin SYSTEMATIC 23517733 A 255 296 2,2'-dichloro-3,3'-diquinolinyl disulfide SYSTEMATIC 23517733 A 34 77 tetracyclic quino[3,2-b]benzo[1,4]thiazines FAMILY 23517733 A 364 383 6-dialkylaminoalkyl FAMILY 23517733 A 385 401 6-acylaminoalkyl FAMILY 23517733 A 406 424 sulfonylaminoalkyl FAMILY 23517733 T 63 94 quino[3,2-b]benzo[1,4]thiazines FAMILY 23517912 A 0 7 Fisetin TRIVIAL 23517912 A 1060 1067 Fisetin TRIVIAL 23517912 A 11 19 flavonol TRIVIAL 23517912 A 1154 1161 fisetin TRIVIAL 23517912 A 1196 1203 fisetin TRIVIAL 23517912 A 1267 1274 fisetin TRIVIAL 23517912 A 1335 1348 triglycerides FAMILY 23517912 A 1413 1420 Fisetin TRIVIAL 23517912 A 153 160 fisetin TRIVIAL 23517912 A 1581 1588 fisetin TRIVIAL 23517912 A 1750 1757 fisetin TRIVIAL 23517912 A 1857 1864 fisetin TRIVIAL 23517912 A 250 259 rapamycin TRIVIAL 23517912 A 386 393 fisetin TRIVIAL 23517912 A 565 572 Fisetin TRIVIAL 23517912 A 730 737 fisetin TRIVIAL 23517912 A 834 841 fisetin TRIVIAL 23517912 A 899 906 fisetin TRIVIAL 23517912 T 0 7 Fisetin TRIVIAL 23518229 A 1014 1020 lutein TRIVIAL 23518229 A 102 154 2,2'-Azobis (2-methylpropionamidine) dihydrochloride SYSTEMATIC 23518229 A 1039 1054 oxidized lutein TRIVIAL 23518229 A 1098 1102 AAPH ABBREVIATION 23518229 A 1114 1121 peroxyl SYSTEMATIC 23518229 A 1168 1175 polyene SYSTEMATIC 23518229 A 1185 1191 lutein TRIVIAL 23518229 A 156 160 AAPH ABBREVIATION 23518229 A 212 227 oxidized lutein TRIVIAL 23518229 A 259 265 Lutein TRIVIAL 23518229 A 280 284 AAPH ABBREVIATION 23518229 A 343 358 oxidized lutein TRIVIAL 23518229 A 35 41 lutein TRIVIAL 23518229 A 520 531 glutathione TRIVIAL 23518229 A 537 552 malondialdehyde TRIVIAL 23518229 A 561 565 AAPH ABBREVIATION 23518229 A 575 581 lutein TRIVIAL 23518229 A 627 631 H(+) FORMULA 23518229 A 632 635 H2O FORMULA 23518229 A 648 652 H(+) FORMULA 23518229 A 653 663 O2-C22H32O FORMULA 23518229 A 679 683 H(+) FORMULA 23518229 A 684 694 O2-C12H20O FORMULA 23518229 A 715 726 13-Z lutein SYSTEMATIC 23518229 A 728 743 13-Z zeaxanthin SYSTEMATIC 23518229 A 745 761 13'-Z zeaxanthin SYSTEMATIC 23518229 A 766 782 all-E zeaxanthin TRIVIAL 23518229 A 78 85 peroxyl SYSTEMATIC 23518229 A 820 835 oxidized lutein TRIVIAL 23518229 A 876 882 lutein TRIVIAL 23518229 A 899 914 Oxidized lutein TRIVIAL 23518229 A 984 995 glutathione TRIVIAL 23518229 T 102 154 2,2'-Azobis (2-methylpropionamidine) dihydrochloride SYSTEMATIC 23518229 T 204 210 lutein TRIVIAL 23518229 T 35 41 lutein TRIVIAL 23518229 T 78 85 peroxyl SYSTEMATIC 23518276 A 0 23 Tricyclic thiazoleamine FAMILY 23518276 A 238 275 4H-thiochromeno[4,3-d]thiazol-2-amine SYSTEMATIC 23518276 A 280 337 5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-d]thiazol-2-amine SYSTEMATIC 23518276 T 0 19 Tricyclic thiazoles FAMILY 23518299 A 1034 1040 6-OHDA SYSTEMATIC 23518299 A 1072 1075 SFN ABBREVIATION 23518299 A 1120 1131 glutathione TRIVIAL 23518299 A 1166 1177 glutathione TRIVIAL 23518299 A 1178 1179 S FORMULA 23518299 A 1196 1207 glutathione TRIVIAL 23518299 A 1328 1331 SFN ABBREVIATION 23518299 A 148 160 Sulforaphane TRIVIAL 23518299 A 162 165 SFN ABBREVIATION 23518299 A 399 402 SFN ABBREVIATION 23518299 A 475 492 6-hydroxydopamine SYSTEMATIC 23518299 A 494 500 6-OHDA SYSTEMATIC 23518299 A 544 547 SFN ABBREVIATION 23518299 A 633 639 6-OHDA SYSTEMATIC 23518299 A 657 663 6-OHDA SYSTEMATIC 23518299 A 751 754 SFN ABBREVIATION 23518299 A 779 782 SFN ABBREVIATION 23518299 A 793 799 6-OHDA SYSTEMATIC 23518299 A 985 988 SFN ABBREVIATION 23518299 T 26 38 sulforaphane TRIVIAL 23518299 T 42 59 6-hydroxydopamine SYSTEMATIC 23518319 A 150 156 silver SYSTEMATIC 23518319 A 295 315 formamido-pyrimidine SYSTEMATIC 23518319 A 683 689 oxygen SYSTEMATIC 23518319 T 87 93 silver SYSTEMATIC 23518471 A 1144 1155 gluthatione TRIVIAL 23518471 A 1156 1157 S FORMULA 23518471 A 1365 1368 ATP ABBREVIATION 23518471 A 1454 1458 NADH ABBREVIATION 23518471 A 1474 1483 succinate TRIVIAL 23518471 A 1499 1508 ubiquinol TRIVIAL 23518471 A 1558 1561 ATP ABBREVIATION 23518471 A 604 629 polychlorinated biphenyls FAMILY 23518471 A 631 635 PCBs ABBREVIATION 23518471 A 638 652 organochlorine FAMILY 23519015 A 1208 1225 4-aminothiophenol SYSTEMATIC 23519015 A 1230 1246 3-propanedithiol SYSTEMATIC 23519015 A 1262 1267 Zn3P2 FORMULA 23519015 A 206 220 zinc phosphide SYSTEMATIC 23519015 A 222 227 Zn3P2 FORMULA 23519015 A 233 248 zinc antimonide SYSTEMATIC 23519015 A 252 258 Zn4Sb3 FORMULA 23519015 A 315 320 Zn3P2 FORMULA 23519015 A 325 331 Zn4Sb3 FORMULA 23519015 A 435 445 phosphorus SYSTEMATIC 23519015 A 450 458 antimony SYSTEMATIC 23519015 A 506 510 zinc SYSTEMATIC 23519015 A 522 526 zinc SYSTEMATIC 23519015 A 678 683 Zn3P2 FORMULA 23519015 A 724 728 zinc SYSTEMATIC 23519015 T 55 60 Zn3P2 FORMULA 23519015 T 65 71 Zn4Sb3 FORMULA 23519077 A 1373 1379 serine TRIVIAL 23519077 A 1435 1441 serine TRIVIAL 23519149 A 0 11 Elisidepsin TRIVIAL 23519149 A 1008 1019 elisidepsin TRIVIAL 23519149 A 1226 1237 elisidepsin TRIVIAL 23519149 A 1243 1252 lapatinib TRIVIAL 23519149 A 1290 1294 5-FU SYSTEMATIC 23519149 A 1299 1310 oxaliplatin TRIVIAL 23519149 A 13 20 PM02734 IDENTIFIER 23519149 A 1387 1398 elisidepsin TRIVIAL 23519149 A 148 159 Elisidepsin TRIVIAL 23519149 A 22 29 Irvalec TRIVIAL 23519149 A 249 260 elisidepsin TRIVIAL 23519149 A 360 371 elisidepsin TRIVIAL 23519149 A 470 481 Elisidepsin TRIVIAL 23519149 A 674 685 elisidepsin TRIVIAL 23519149 A 84 96 Kahalalide F TRIVIAL 23519149 A 870 881 elisidepsin TRIVIAL 23519149 T 37 48 elisidepsin TRIVIAL 23519149 T 58 70 kahalalide f TRIVIAL 23519376 A 112 114 Au FORMULA 23519376 A 185 199 divinylbenzene SYSTEMATIC 23519376 A 506 526 poly(divinylbenzene) FAMILY 23519376 A 84 86 Si FORMULA 23519376 T 43 50 silicon SYSTEMATIC 23519470 A 1056 1065 menadione TRIVIAL 23519470 A 1069 1077 paraquat TRIVIAL 23519470 A 1093 1099 lysine TRIVIAL 23519470 A 1206 1215 threonine TRIVIAL 23519470 A 1273 1276 Thr FORMULA 23519470 A 1325 1328 Lys FORMULA 23519470 A 1372 1375 Thr FORMULA 23519470 A 1383 1386 Lys FORMULA 23519470 A 1495 1504 menadione TRIVIAL 23519470 A 1508 1516 paraquat TRIVIAL 23519470 A 500 506 oxygen SYSTEMATIC 23519470 A 754 764 superoxide TRIVIAL 23519470 A 776 785 menadione TRIVIAL 23519470 A 787 795 paraquat TRIVIAL 23519470 A 800 822 buthionine sulfoximine SYSTEMATIC 23519470 A 923 928 MG132 IDENTIFIER 23519470 T 65 71 Oxygen SYSTEMATIC 23519574 A 1139 1147 nicotine TRIVIAL 23519574 A 153 161 nicotine TRIVIAL 23519574 A 20 28 nicotine TRIVIAL 23519574 A 376 384 nicotine TRIVIAL 23519574 A 442 457 methamphetamine TRIVIAL 23519574 A 515 523 nicotine TRIVIAL 23519574 A 582 590 nicotine TRIVIAL 23519574 A 595 610 methamphetamine TRIVIAL 23519574 A 923 931 nicotine TRIVIAL 23519574 A 965 973 nicotine TRIVIAL 23519574 T 0 8 Nicotine TRIVIAL 23519574 T 43 58 methamphetamine TRIVIAL 23519822 A 1190 1200 acteosides FAMILY 23519822 A 1205 1215 irbesartan TRIVIAL 23519822 A 1261 1271 irbesartan TRIVIAL 23519822 A 142 152 irbesartan TRIVIAL 23519822 A 382 392 acteosides FAMILY 23519822 A 424 434 irbesartan TRIVIAL 23519822 A 481 491 irbesartan TRIVIAL 23519822 A 675 682 alanine TRIVIAL 23519822 A 701 710 aspartate TRIVIAL 23519822 A 73 83 acteosides FAMILY 23519822 T 137 147 Irbesartan TRIVIAL 23519822 T 73 83 Acteosides FAMILY 23519881 A 1038 1048 6-gingerol SYSTEMATIC 23519881 A 1073 1076 RGZ ABBREVIATION 23519881 A 120 133 rosiglitazone TRIVIAL 23519881 A 1270 1280 fatty acid FAMILY 23519881 A 1303 1313 fatty acid FAMILY 23519881 A 1334 1337 RGZ ABBREVIATION 23519881 A 135 138 RGZ ABBREVIATION 23519881 A 1389 1399 6-gingerol SYSTEMATIC 23519881 A 1424 1434 6-gingerol SYSTEMATIC 23519881 A 262 271 Oil-Red O TRIVIAL 23519881 A 275 278 RGZ ABBREVIATION 23519881 A 31 41 6-gingerol SYSTEMATIC 23519881 A 353 363 6-gingerol SYSTEMATIC 23519881 A 406 419 triglycerides FAMILY 23519881 A 43 97 (S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone SYSTEMATIC 23519881 A 705 715 6-gingerol SYSTEMATIC 23519881 A 817 820 RGZ ABBREVIATION 23519881 A 876 888 triglyceride FAMILY 23519881 A 913 916 RGZ ABBREVIATION 23519881 A 968 978 6-gingerol SYSTEMATIC 23519881 T 0 10 6-Gingerol SYSTEMATIC 23519881 T 20 33 Rosiglitazone TRIVIAL 23519952 A 717 726 alcoholic FAMILY 23520191 A 110 117 kaurene TRIVIAL 23520191 A 123 131 oridonin TRIVIAL 23520191 A 23 29 enmein TRIVIAL 23520191 A 35 51 14-O-diterpenoid FAMILY 23520191 A 388 398 paclitaxel TRIVIAL 23520191 A 809 820 diterpenoid FAMILY 23520191 T 50 56 enmein TRIVIAL 23520191 T 62 73 diterpenoid FAMILY 23520265 A 1086 1089 SUN ABBREVIATION 23520265 A 1303 1306 SUN ABBREVIATION 23520265 A 14 26 D-amino acid FAMILY 23520265 A 191 230 4H-furo[3,2-b]pyrrole-5-carboxylic acid SYSTEMATIC 23520265 A 232 235 SUN ABBREVIATION 23520265 A 312 315 SUN ABBREVIATION 23520265 A 516 519 SUN ABBREVIATION 23520265 A 731 739 D-serine TRIVIAL 23520265 T 29 41 D-AMINO ACID FAMILY 23521048 A 139 233 2-(5,7-diethyl-2-(4-(2-fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide SYSTEMATIC 23521048 A 348 366 pyrazolopyrimidine SYSTEMATIC 23521048 A 390 397 DPA-714 IDENTIFIER 23521048 A 419 430 fluorine-18 SYSTEMATIC 23521048 A 432 437 (18)F FORMULA 23521048 A 465 566 2-(5,7-diethyl-2-(4-(2-[(18)F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide SYSTEMATIC 23521048 A 568 573 (18)F FORMULA 23521048 A 648 653 (18)F FORMULA 23521048 A 77 114 5,6,7-substituted pyrazolopyrimidines FAMILY 23521048 T 50 87 5,6,7-Substituted Pyrazolopyrimidines FAMILY 23521163 A 141 157 botryosphaerin B TRIVIAL 23521163 A 166 175 LL-Z1271β IDENTIFIER 23521163 A 24 40 botryosphaerin F TRIVIAL 23521163 A 387 400 sesquiterpene FAMILY 23521163 A 85 135 13,14,15,16-tetranorlabd-7-ene-19,6b:12,17-diolide SYSTEMATIC 23521163 T 6 19 sesquiterpene FAMILY 23521216 A 118 140 C-methylated flavonols FAMILY 23521216 A 142 153 baeckeins A NO CLASS 23521216 A 169 186 6-methylquercetin SYSTEMATIC 23521216 A 195 237 6-methylquercetin-4'-O-β-d-glucopyranoside SYSTEMATIC 23521216 A 270 281 baeckeins C NO CLASS 23521216 A 59 70 biflavonoid FAMILY 23521216 A 80 90 baeckein E TRIVIAL 23521216 T 0 10 Baeckein E TRIVIAL 23521216 T 28 52 C-methylated biflavonoid FAMILY 23521495 A 115 134 Cys-Ala-Leu-Asn-Asn FORMULA 23521797 A 105 116 cholesterol TRIVIAL 23521797 A 450 460 oxysterols FAMILY 23521797 A 676 687 cholesterol TRIVIAL 23521797 A 792 801 oxysterol FAMILY 23521797 A 872 873 N FORMULA 23521797 A 883 889 sterol FAMILY 23521797 A 935 941 sterol FAMILY 23521797 T 108 114 sterol FAMILY 23521797 T 13 22 oxysterol FAMILY 23522793 A 456 457 C FORMULA 23522793 A 522 526 zinc SYSTEMATIC 23522793 A 782 786 H2O2 FORMULA 23522835 A 0 16 Poly(ADP-ribose) SYSTEMATIC 23522835 A 266 275 cisplatin TRIVIAL 23522835 A 505 514 cisplatin TRIVIAL 23522835 A 556 565 cisplatin TRIVIAL 23522835 A 670 686 poly(ADP-ribose) SYSTEMATIC 23522835 A 719 728 cisplatin TRIVIAL 23522835 T 111 120 cisplatin TRIVIAL 23522835 T 28 44 poly(ADP-ribose) SYSTEMATIC 23523101 A 1284 1288 HSYA ABBREVIATION 23523101 A 1324 1330 GW9662 IDENTIFIER 23523101 A 141 164 Hydroxysafflor yellow A SYSTEMATIC 23523101 A 1417 1421 HSYA ABBREVIATION 23523101 A 1507 1511 HSYA ABBREVIATION 23523101 A 166 170 HSYA ABBREVIATION 23523101 A 346 350 HSYA ABBREVIATION 23523101 A 419 423 CCl4 FORMULA 23523101 A 428 432 H2O2 FORMULA 23523101 A 557 561 HSYA ABBREVIATION 23523101 A 996 1000 HSYA ABBREVIATION 23523101 T 36 59 hydroxysafflor yellow A SYSTEMATIC 23523202 A 139 146 Xeljanz TRIVIAL 23523202 A 148 159 tofacitinib TRIVIAL 23523202 A 553 565 fostamatinib TRIVIAL 23523531 A 1217 1223 (125)I FORMULA 23523531 A 1342 1348 (125)I FORMULA 23523531 A 1733 1736 Lys FORMULA 23523531 A 1737 1740 Arg FORMULA 23523531 A 1757 1767 amino acid FAMILY 23523531 A 256 262 Ca(2+) FORMULA 23523531 A 273 277 K(+) FORMULA 23523531 A 82 86 K(+) FORMULA 23523531 T 30 34 K(+) FORMULA 23523547 A 1466 1474 glycerol TRIVIAL 23523547 A 1530 1538 glycerol TRIVIAL 23523547 A 1632 1640 glycerol TRIVIAL 23523547 A 1746 1754 glycerol TRIVIAL 23523547 A 1879 1887 glycerol TRIVIAL 23523547 A 1992 1995 BDP ABBREVIATION 23523547 A 258 285 beclomethasone dipropionate SYSTEMATIC 23523547 A 287 290 BDP ABBREVIATION 23523547 A 315 322 ethanol SYSTEMATIC 23523547 A 350 367 hydrofluoroalkane FAMILY 23523547 A 368 371 HFA ABBREVIATION 23523547 A 462 465 BDP ABBREVIATION 23523547 A 470 478 glycerol TRIVIAL 23523547 A 620 623 HFA ABBREVIATION 23523547 A 691 699 glycerol TRIVIAL 23523547 A 709 717 glycerol TRIVIAL 23523547 T 125 152 beclomethasone dipropionate SYSTEMATIC 23523547 T 179 187 glycerol TRIVIAL 23523661 A 1022 1031 bleomycin FAMILY 23523661 A 185 194 baicalein TRIVIAL 23523661 A 198 207 bleomycin FAMILY 23523661 A 381 390 bleomycin FAMILY 23523661 A 396 405 bleomycin FAMILY 23523661 A 477 486 baicalein TRIVIAL 23523661 A 524 533 baicalein TRIVIAL 23523661 A 544 558 hydroxyproline SYSTEMATIC 23523661 A 654 663 baicalein TRIVIAL 23523661 A 764 773 bleomycin FAMILY 23523661 A 792 801 baicalein TRIVIAL 23523661 A 851 860 baicalein TRIVIAL 23523661 A 862 871 Baicalein TRIVIAL 23523661 A 974 983 bleomycin FAMILY 23523661 A 998 1007 Baicalein TRIVIAL 23523661 T 0 9 Baicalein TRIVIAL 23523661 T 21 30 bleomycin FAMILY 23523830 A 1085 1111 epigallocatechin-3-gallate SYSTEMATIC 23523830 A 114 124 Flavonoids FAMILY 23523830 A 1317 1328 polyphenols FAMILY 23523830 A 310 319 quercetin TRIVIAL 23523830 A 324 350 epigallocatechin-3-gallate SYSTEMATIC 23523830 A 354 395 2-Dimyristoyl-sn-glycero-3-phosphocholine SYSTEMATIC 23523830 A 456 467 cholesterol TRIVIAL 23523830 A 475 482 Laurdan ABBREVIATION 23523830 A 660 670 flavonoids FAMILY 23523830 A 721 732 polyphenols FAMILY 23523830 A 852 863 cholesterol TRIVIAL 23523830 A 939 950 polyphenols FAMILY 23523830 A 984 993 Quercetin TRIVIAL 23523830 T 0 9 Quercetin TRIVIAL 23523830 T 14 40 epigallocatechin-3-gallate SYSTEMATIC 23523830 T 90 101 cholesterol TRIVIAL 23523831 A 1019 1025 oxygen SYSTEMATIC 23523831 A 1077 1083 DCF-DA ABBREVIATION 23523831 A 1218 1227 nerolidol TRIVIAL 23523831 A 211 224 (E)-nerolidol TRIVIAL 23523831 A 476 485 nerolidol TRIVIAL 23523831 A 600 609 nerolidol TRIVIAL 23523831 A 824 833 nerolidol TRIVIAL 23523831 A 853 863 superoxide TRIVIAL 23523831 A 936 945 nerolidol TRIVIAL 23523831 A 985 994 nerolidol TRIVIAL 23523831 T 88 97 nerolidol TRIVIAL 23523964 A 1156 1158 Zn FORMULA 23523964 A 1237 1239 Zn FORMULA 23523964 A 1357 1359 Zn FORMULA 23523964 A 197 199 Zn FORMULA 23523964 A 208 210 Zn FORMULA 23523964 A 243 245 Zn FORMULA 23523964 A 295 297 Zn FORMULA 23523964 A 305 307 Zn FORMULA 23523964 A 324 326 Zn FORMULA 23523964 A 390 392 Zn FORMULA 23523964 A 415 424 carnitine TRIVIAL 23523964 A 621 623 Zn FORMULA 23523964 A 72 74 Zn FORMULA 23523964 A 810 812 Zn FORMULA 23523964 A 968 970 Zn FORMULA 23523964 T 42 46 zinc SYSTEMATIC 23523964 T 48 50 Zn FORMULA 23524100 A 1134 1144 adriamycin TRIVIAL 23524100 A 1321 1331 adriamycin TRIVIAL 23524100 A 607 617 adriamycin TRIVIAL 23524100 T 121 131 adriamycin TRIVIAL 23524304 A 1089 1097 morphine TRIVIAL 23524304 A 1162 1170 Morphine TRIVIAL 23524304 A 1440 1451 [(3)H]DAMGO SYSTEMATIC 23524304 A 1665 1673 morphine TRIVIAL 23524304 A 29 37 morphine TRIVIAL 23524304 A 315 322 BD-1063 IDENTIFIER 23524304 A 324 331 BD-1047 IDENTIFIER 23524304 A 333 339 NE-100 IDENTIFIER 23524304 A 344 348 S1RA TRIVIAL 23524304 A 493 501 morphine TRIVIAL 23524304 A 598 606 morphine TRIVIAL 23524304 A 690 697 PRE-084 IDENTIFIER 23524304 A 736 744 morphine TRIVIAL 23524304 A 935 943 morphine TRIVIAL 23524304 T 16 24 morphine TRIVIAL 23524312 A 256 335 3-O-caffeoylquinic, 4-O-caffeoylquinic, 5-O-caffeoylquinic and rosmarinic acids MULTIPLE 23524312 A 341 349 luteolin TRIVIAL 23524312 A 354 365 pinocembrin TRIVIAL 23524312 A 373 380 ethanol SYSTEMATIC 23524312 A 459 467 phenolic FAMILY 23524312 A 543 549 Trolox TRIVIAL 23524312 A 583 589 oxygen SYSTEMATIC 23524312 A 619 625 Fe(2+) FORMULA 23524312 A 667 673 Fe(2+) FORMULA 23524312 A 866 872 Fe(2+) FORMULA 23524312 T 16 24 phenolic FAMILY 23524313 A 1079 1090 cholesterol TRIVIAL 23524313 A 1095 1104 bile acid FAMILY 23524313 A 180 187 fisetin TRIVIAL 23524313 A 199 210 cholesterol TRIVIAL 23524313 A 25 32 fisetin TRIVIAL 23524313 A 257 268 cholesterol TRIVIAL 23524313 A 309 320 cholesterol TRIVIAL 23524313 A 372 383 cholesterol TRIVIAL 23524313 A 392 403 cholesterol TRIVIAL 23524313 A 424 435 cholesterol TRIVIAL 23524313 A 48 59 cholesterol TRIVIAL 23524313 A 506 513 fisetin TRIVIAL 23524313 A 654 661 fisetin TRIVIAL 23524313 A 844 851 fisetin TRIVIAL 23524313 A 869 876 fisetin TRIVIAL 23524313 A 963 970 fisetin TRIVIAL 23524313 T 36 43 fisetin TRIVIAL 23524314 A 199 207 phenolic FAMILY 23524314 A 395 410 dicaffeoyl acid TRIVIAL 23524314 A 432 442 flavonoids FAMILY 23524314 A 455 464 quercetin TRIVIAL 23524314 A 466 476 kaempferol TRIVIAL 23524314 A 481 493 isorhamnetin TRIVIAL 23524314 A 586 633 isorhamnetin-3-O-rhmanoside-7,4'-di-O-glucoside SYSTEMATIC 23524314 A 638 672 quercetin-3-O-(2-pentosyl)hexoside SYSTEMATIC 23524314 A 839 854 dicaffeoyl acid TRIVIAL 23524314 A 937 946 monoamine FAMILY 23524314 T 0 8 Phenolic FAMILY 23524315 A 311 320 T-2 toxin TRIVIAL 23524315 A 526 535 T-2 toxin TRIVIAL 23524315 A 638 647 T-2 toxin TRIVIAL 23524315 T 4 17 mycotoxin T-2 TRIVIAL 23524663 A 1124 1128 (3)H FORMULA 23524663 A 1140 1144 (3)H FORMULA 23524663 A 1352 1356 (3)H FORMULA 23524663 A 137 141 (3)H FORMULA 23524663 A 1598 1609 nucleosides FAMILY 23524663 A 1735 1746 nucleosides FAMILY 23524663 A 228 230 Br FORMULA 23524663 A 231 235 (3)H FORMULA 23524663 A 403 407 (3)H FORMULA 23524663 A 941 945 (3)H FORMULA 23524663 T 47 49 3H FORMULA 23525200 A 135 138 ZnO FORMULA 23525200 A 204 207 ZnO FORMULA 23525200 A 316 320 CIGS ABBREVIATION 23525200 A 346 349 ZnO FORMULA 23525200 A 653 656 ZnO FORMULA 23525200 A 80 92 Cu(In,Ga)Se2 FORMULA 23525200 A 94 98 CIGS ABBREVIATION 23525200 T 54 66 Cu(In,Ga)Se2 FORMULA 23525200 T 84 87 ZnO FORMULA 23525524 A 1107 1116 MDL 11939 IDENTIFIER 23525524 A 1197 1200 DOI ABBREVIATION 23525524 A 130 150 N-methyl-D-aspartate SYSTEMATIC 23525524 A 1305 1310 TCB-2 IDENTIFIER 23525524 A 1360 1369 CP 809101 IDENTIFIER 23525524 A 1497 1505 ketamine TRIVIAL 23525524 A 306 332 Lysergic acid diethylamide SYSTEMATIC 23525524 A 334 337 LSD ABBREVIATION 23525524 A 343 374 2,5-dimethoxy-4-iodoamphetamine SYSTEMATIC 23525524 A 376 379 DOI ABBREVIATION 23525524 A 873 876 LSD ABBREVIATION 23525524 A 898 901 DOI ABBREVIATION 23526644 A 36 46 adamantane TRIVIAL 23527545 A 32 35 ADP ABBREVIATION 23527573 A 1315 1325 d-arginine TRIVIAL 23527573 A 47 53 serine TRIVIAL 23527573 A 648 654 serine TRIVIAL 23527573 A 819 839 4-amidinobenzylamide SYSTEMATIC 23527573 A 997 1037 sulfonylated 3-amindinophenylalanylamide SYSTEMATIC 23527573 T 78 84 serine TRIVIAL 23527578 A 21 29 graphene TRIVIAL 23527578 A 216 224 graphene TRIVIAL 23527578 A 872 880 graphene TRIVIAL 23527578 T 63 71 Graphene TRIVIAL 23527587 A 145 153 hydrogen SYSTEMATIC 23527587 A 322 332 nucleotide FAMILY 23527587 A 464 472 hydrogen SYSTEMATIC 23527663 A 106 114 chloride SYSTEMATIC 23527663 A 116 123 TTBC-Cl FORMULA 23527663 A 128 134 iodide SYSTEMATIC 23527663 A 148 154 TTBC-I FORMULA 23527663 A 358 365 TTBC-Cl FORMULA 23527663 A 37 100 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidacarbocyanine SYSTEMATIC 23527663 A 560 568 chloride SYSTEMATIC 23527663 A 579 585 iodide SYSTEMATIC 23527663 A 591 597 TTBC-I FORMULA 23527663 A 689 695 TTBC-I FORMULA 23527663 T 28 32 TTBC ABBREVIATION 23528295 A 0 9 Arvelexin TRIVIAL 23528295 A 106 128 indolyl-3-acetonitrile SYSTEMATIC 23528295 A 161 170 arvelexin TRIVIAL 23528295 A 224 226 NO FORMULA 23528295 A 231 235 PGE2 ABBREVIATION 23528295 A 287 310 indolyl-3-acetonitriles FAMILY 23528295 A 355 363 hydroxyl SYSTEMATIC 23528295 A 393 399 indole SYSTEMATIC 23528295 A 412 420 N-methyl SYSTEMATIC 23528295 A 458 460 NO FORMULA 23528295 A 465 469 PGE2 ABBREVIATION 23528295 A 510 519 arvelexin TRIVIAL 23528295 T 13 35 indolyl-3-acetonitrile SYSTEMATIC 23528295 T 80 92 nitric oxide SYSTEMATIC 23528295 T 97 101 PGE2 ABBREVIATION 23528299 A 254 262 bestatin TRIVIAL 23528299 A 274 279 LB-4b TRIVIAL 23528299 A 380 388 bestatin TRIVIAL 23528299 A 500 508 bestatin TRIVIAL 23528299 A 78 83 LB-4b TRIVIAL 23528299 T 52 57 LB-4b TRIVIAL 23528361 A 1317 1329 nitric oxide SYSTEMATIC 23528361 A 1331 1333 NO FORMULA 23528361 A 1764 1766 NO FORMULA 23528361 A 1785 1796 eicosanoids FAMILY 23528361 A 1799 1803 PGE2 ABBREVIATION 23528361 A 1808 1820 leukotrienes FAMILY 23528361 A 2154 2157 MTT ABBREVIATION 23528361 A 2245 2257 polyphenolic FAMILY 23528361 A 2259 2267 flavanol FAMILY 23528361 A 2272 2281 flavonoid FAMILY 23528361 A 593 595 NO FORMULA 23528361 A 915 917 NO FORMULA 23528361 A 919 923 PGE2 ABBREVIATION 23528361 T 81 92 eicosanoids FAMILY 23528361 T 95 107 leukotrienes FAMILY 23528610 A 1006 1013 ethanol SYSTEMATIC 23528610 A 1017 1025 morphine TRIVIAL 23528610 A 1037 1045 Diazepam TRIVIAL 23528610 A 1052 1059 ethanol SYSTEMATIC 23528610 A 1071 1079 morphine TRIVIAL 23528610 A 1153 1164 bicuculline TRIVIAL 23528610 A 1197 1206 phaclofen TRIVIAL 23528610 A 1289 1296 ethanol SYSTEMATIC 23528610 A 327 334 ethanol SYSTEMATIC 23528610 A 462 469 ethanol SYSTEMATIC 23528610 A 524 531 ethanol SYSTEMATIC 23528610 A 598 605 ethanol SYSTEMATIC 23528610 A 691 699 morphine TRIVIAL 23528610 A 732 737 DAMGO ABBREVIATION 23528610 A 742 750 morphine TRIVIAL 23528610 A 797 805 morphine TRIVIAL 23528610 A 873 884 bicuculline TRIVIAL 23528610 A 919 928 phaclofen TRIVIAL 23528610 T 12 20 Morphine TRIVIAL 23528610 T 44 51 Ethanol SYSTEMATIC 23528715 A 1305 1319 corticosterone TRIVIAL 23528715 A 450 464 corticosterone TRIVIAL 23528715 A 727 741 corticosterone TRIVIAL 23529014 A 20 32 20, 26-epoxy SYSTEMATIC 23529014 A 265 278 Hoduloside XI TRIVIAL 23529014 A 299 404 3-O-{β-d-glucopyranosyl(1→3)-[β-d-xylopyranosyl(1→2)]-α-l-arabinopyranosyl}-20, 26-epoxypseudojujubogenin SYSTEMATIC 23529014 A 406 420 Hoduloside XII TRIVIAL 23529014 A 439 554 3-O-{β-d-xylopyranose(1→2)glucopyranosyl(1→3)[rhamnopyranose(1→2)]β-d-glucopyranosyl}-20, 26-epoxypseudojujubogenin SYSTEMATIC 23529014 A 48 65 pseudojujubogenin TRIVIAL 23529014 A 67 80 hoduloside XI TRIVIAL 23529014 A 8 16 saponins FAMILY 23529014 A 89 103 hoduloside XII TRIVIAL 23529014 T 10 18 saponins FAMILY 23529014 T 22 34 20, 26-epoxy SYSTEMATIC 23529014 T 50 67 pseudojujubogenin TRIVIAL 23529015 A 1049 1053 HYDP ABBREVIATION 23529015 A 146 180 3,5-diprenyl-4-hydroxyacetophenone SYSTEMATIC 23529015 A 182 186 HYDP ABBREVIATION 23529015 A 322 334 encesanescin TRIVIAL 23529015 A 392 396 HYDP ABBREVIATION 23529015 A 571 575 HYDP ABBREVIATION 23529015 A 630 637 ethanol SYSTEMATIC 23529015 A 775 809 N(G)-nitro-l-arginine methyl ester SYSTEMATIC 23529015 A 811 823 indomethacin TRIVIAL 23529015 A 828 844 N-ethylmaleimide SYSTEMATIC 23529015 A 862 864 NO FORMULA 23529015 A 866 880 prostaglandins FAMILY 23529015 A 885 895 sulfhydryl FAMILY 23529015 T 58 92 3,5-diprenyl-4-hydroxyacetophenone SYSTEMATIC 23529067 A 1145 1148 MDA ABBREVIATION 23529067 A 1179 1181 Se FORMULA 23529067 A 1289 1291 Pb FORMULA 23529067 A 1299 1301 Se FORMULA 23529067 A 1389 1392 MDA ABBREVIATION 23529067 A 1469 1471 Se FORMULA 23529067 A 1577 1585 selenium SYSTEMATIC 23529067 A 20 22 Pb FORMULA 23529067 A 225 233 Selenium SYSTEMATIC 23529067 A 235 237 Se FORMULA 23529067 A 390 392 Se FORMULA 23529067 A 410 412 Pb FORMULA 23529067 A 550 562 lead acetate SYSTEMATIC 23529067 A 564 566 Pb FORMULA 23529067 A 574 576 Pb FORMULA 23529067 A 588 603 sodium selenite SYSTEMATIC 23529067 A 605 607 Se FORMULA 23529067 A 617 619 Pb FORMULA 23529067 A 628 630 Pb FORMULA 23529067 A 642 644 Se FORMULA 23529067 A 690 692 Pb FORMULA 23529067 A 700 702 Se FORMULA 23529067 A 842 849 lactate FAMILY 23529067 A 902 912 superoxide TRIVIAL 23529067 A 933 948 malondialdehyde TRIVIAL 23529067 A 950 953 MDA ABBREVIATION 23529067 A 998 1000 Pb FORMULA 23529067 T 14 29 sodium selenite SYSTEMATIC 23529381 A 1177 1185 nicotine TRIVIAL 23529381 A 472 480 nicotine TRIVIAL 23529381 A 485 500 methylphenidate SYSTEMATIC 23529473 A 1032 1035 Cys FORMULA 23529473 A 1145 1148 Cys FORMULA 23529473 A 1272 1275 Cys FORMULA 23529473 A 1304 1311 mercury SYSTEMATIC 23529473 A 162 169 mercury SYSTEMATIC 23529473 A 303 308 HgCl2 FORMULA 23529473 A 387 394 mercury SYSTEMATIC 23529473 A 570 573 Cys FORMULA 23529473 A 817 820 Cys FORMULA 23529473 A 856 859 Cys FORMULA 23529473 A 877 884 mercury SYSTEMATIC 23529473 T 33 40 mercury SYSTEMATIC 23529473 T 78 81 Cys FORMULA 23529650 A 1155 1157 Ag FORMULA 23529650 A 1158 1162 AgCl FORMULA 23529650 A 1349 1351 Ag FORMULA 23529650 A 1365 1369 AgCl FORMULA 23529650 A 1439 1441 Ag FORMULA 23529650 A 1462 1466 AgCl FORMULA 23529650 A 254 256 Ag FORMULA 23529650 A 257 261 AgCl FORMULA 23529650 A 367 369 Ag FORMULA 23529650 A 382 386 AgCl FORMULA 23529650 A 422 424 Ag FORMULA 23529650 A 63 65 Ag FORMULA 23529650 A 738 740 Cl FORMULA 23529650 A 81 85 AgCl FORMULA 23529650 A 816 818 Cl FORMULA 23529650 A 907 909 Cl FORMULA 23529650 T 52 54 Ag FORMULA 23529650 T 71 75 AgCl FORMULA 23529672 A 1010 1034 technetium pertechnetate SYSTEMATIC 23529672 A 1036 1045 (99m)TcO4 FORMULA 23529672 A 1050 1060 iodine-123 SYSTEMATIC 23529672 A 1062 1068 (123)I FORMULA 23529672 A 1179 1188 (99m)TcO4 FORMULA 23529672 A 1192 1198 (123)I FORMULA 23529672 A 1258 1270 (99m)Tc-MIBI FORMULA 23529672 A 1448 1460 (99m)Tc-MIBI FORMULA 23529672 A 358 370 (99m)Tc-MIBI FORMULA 23529672 A 494 506 (99m)Tc-MIBI FORMULA 23529672 A 64 76 (99m)Tc-MIBI FORMULA 23529672 A 765 777 (99m)Tc-MIBI FORMULA 23529672 T 26 38 (99m)Tc-MIBI FORMULA 23529860 A 121 132 sulfonamide SYSTEMATIC 23529860 A 168 200 methyl 2-isothiocyanato benzoate SYSTEMATIC 23529860 A 18 30 quinazolines FAMILY 23529860 A 310 320 ampicillin TRIVIAL 23529860 A 37 57 triazoloquinazolines FAMILY 23529860 A 68 87 triazinoquinazoline FAMILY 23529860 T 113 124 quinazoline SYSTEMATIC 23529860 T 69 81 sulfonamides FAMILY 23529904 A 1034 1045 haloperidol TRIVIAL 23529904 A 1281 1292 haloperidol TRIVIAL 23529904 A 1336 1347 haloperidol TRIVIAL 23529904 A 1416 1427 haloperidol TRIVIAL 23529904 A 1537 1548 haloperidol TRIVIAL 23529904 A 689 700 haloperidol TRIVIAL 23529904 A 855 866 haloperidol TRIVIAL 23530013 A 1556 1563 glucose TRIVIAL 23530013 A 1572 1579 glucose TRIVIAL 23530013 A 1663 1670 Glucose TRIVIAL 23530013 A 294 301 glucose TRIVIAL 23530013 A 784 791 Glucose TRIVIAL 23530057 A 1116 1119 Tyr FORMULA 23530057 A 212 220 tyrosine TRIVIAL 23530057 A 25 33 tyrosine TRIVIAL 23530057 A 286 299 phenylalanine TRIVIAL 23530057 A 357 360 Tyr FORMULA 23530057 A 369 372 Tyr FORMULA 23530057 A 586 595 tyrosines FAMILY 23530057 A 653 661 tyrosine TRIVIAL 23530057 A 674 677 Tyr FORMULA 23530057 A 903 906 Tyr FORMULA 23530595 A 444 449 allyl SYSTEMATIC 23530595 A 479 484 thiol FAMILY 23530815 A 156 163 butanol SYSTEMATIC 23530815 A 30 37 butanol SYSTEMATIC 23530815 T 43 52 n-Butanol SYSTEMATIC 23530834 A 18 35 (S)-phenylalanine TRIVIAL 23530834 A 281 318 cyclopropyl-substituted phenylalanine FAMILY 23530834 A 55 73 2-cyanopyrrolidine SYSTEMATIC 23530834 T 102 120 2-Cyanopyrrolidine SYSTEMATIC 23530834 T 65 82 (S)-Phenylalanine TRIVIAL 23531031 A 1082 1088 LBH589 IDENTIFIER 23531031 A 1382 1386 125I FORMULA 23531031 A 1450 1454 131I FORMULA 23531031 A 1548 1554 LBH589 IDENTIFIER 23531031 A 1754 1758 125I FORMULA 23531031 A 1827 1833 iodine SYSTEMATIC 23531031 A 1930 1934 131I FORMULA 23531031 A 2097 2108 radioiodine SYSTEMATIC 23531031 A 220 231 radioiodine SYSTEMATIC 23531031 A 419 430 radioiodine SYSTEMATIC 23531031 A 496 509 sodium iodide SYSTEMATIC 23531031 T 39 52 SODIUM IODIDE SYSTEMATIC 23531031 T 92 96 ¹³¹I FORMULA 23531416 A 0 30 Polybrominated diphenyl ethers FAMILY 23531416 A 1605 1616 6-OH-BDE-47 SYSTEMATIC 23531416 A 177 192 thyroid hormone FAMILY 23531416 A 1986 1993 OH-BDEs FAMILY 23531416 A 32 37 PBDEs ABBREVIATION 23531416 A 346 361 thyroid hormone FAMILY 23531416 A 447 453 OH-BDE FORMULA 23531416 A 72 90 hydroxylated PBDEs FAMILY 23531416 A 843 848 PBDEs ABBREVIATION 23531416 A 853 860 OH-BDEs FAMILY 23531416 A 92 99 OH-BDEs FAMILY 23531416 A 967 982 thyroid hormone FAMILY 23531416 T 145 151 OH-BDE FORMULA 23531416 T 51 66 thyroid hormone FAMILY 23531488 A 1091 1106 estrone sulfate SYSTEMATIC 23531488 A 1111 1123 rosuvastatin TRIVIAL 23531488 A 622 623 N FORMULA 23531488 A 633 644 amino acids FAMILY 23531488 A 750 751 N FORMULA 23532257 A 1278 1285 glucose TRIVIAL 23532331 A 397 405 tyrosine TRIVIAL 23532375 A 107 114 ecstasy TRIVIAL 23532375 A 1164 1171 ecstasy TRIVIAL 23532375 A 1333 1340 ecstasy TRIVIAL 23532375 A 342 349 ecstasy TRIVIAL 23532375 A 372 379 ecstasy TRIVIAL 23532375 A 403 410 ecstasy TRIVIAL 23532375 T 47 54 ecstasy TRIVIAL 23532445 A 1072 1082 Gentamicin FAMILY 23532445 A 1087 1092 G-418 IDENTIFIER 23532445 A 1376 1382 PTC124 IDENTIFIER 23532445 A 144 157 phenylalanine TRIVIAL 23532445 A 1542 1557 aminoglycosides FAMILY 23532445 A 1779 1792 phenylalanine TRIVIAL 23532445 A 442 456 aminoglycoside FAMILY 23532445 A 478 488 gentamicin FAMILY 23532445 A 493 498 G-418 IDENTIFIER 23532445 A 500 509 Geneticin TRIVIAL 23532445 A 595 609 aminoglycoside FAMILY 23532445 A 616 622 PTC124 IDENTIFIER 23532445 A 624 632 Ataluren TRIVIAL 23532445 A 767 782 aminoglycosides FAMILY 23532445 A 77 90 phenylalanine TRIVIAL 23532445 A 783 787 G418 IDENTIFIER 23532445 A 792 802 gentamicin FAMILY 23532445 A 808 814 PTC124 IDENTIFIER 23532445 T 25 38 phenylalanine TRIVIAL 23532445 T 82 97 aminoglycosides FAMILY 23532932 A 1008 1018 paclitaxel TRIVIAL 23532932 A 1023 1032 docetaxel TRIVIAL 23532932 A 1109 1112 PCN ABBREVIATION 23532932 A 1117 1126 docetaxel TRIVIAL 23532932 A 1311 1318 TCPOBOP TRIVIAL 23532932 A 908 937 pregnenolone-16α-carbonitrile SYSTEMATIC 23532932 A 939 942 PCN ABBREVIATION 23532932 A 999 1006 taxanes FAMILY 23532999 A 67 72 EtOAc FORMULA 23532999 T 0 26 O-heterocyclic embeurekols FAMILY 23533219 A 1235 1242 glucose TRIVIAL 23533219 A 878 890 triglyceride FAMILY 23534618 A 109 115 silica TRIVIAL 23534618 A 327 333 silica TRIVIAL 23534618 A 446 453 silanol SYSTEMATIC 23534618 A 462 470 ≡Si-O(-) FORMULA 23534618 T 52 57 oxide SYSTEMATIC 23534703 A 1021 1033 metallocenes FAMILY 23534703 A 235 237 He FORMULA 23534703 A 447 457 vanadocene TRIVIAL 23534703 A 471 482 nickelocene TRIVIAL 23534703 A 545 547 He FORMULA 23534703 A 65 77 metallocenes FAMILY 23534703 A 858 860 He FORMULA 23534703 A 939 941 Li FORMULA 23534703 A 960 962 He FORMULA 23534703 A 995 997 He FORMULA 23534703 T 115 125 vanadocene TRIVIAL 23534703 T 130 141 nickelocene TRIVIAL 23534703 T 71 83 metallocenes FAMILY 23534826 A 1231 1239 hydroxyl SYSTEMATIC 23534826 A 438 457 Poly(vinyl alcohol) FAMILY 23534826 A 459 462 PVA ABBREVIATION 23534826 A 59 78 poly(vinyl alcohol) SYSTEMATIC 23534826 A 690 693 PVA ABBREVIATION 23534826 T 46 65 Poly(vinyl alcohol) FAMILY 23534857 A 1050 1058 aldehyde SYSTEMATIC 23534857 A 1068 1075 epoxide SYSTEMATIC 23534857 A 1076 1084 aldehyde SYSTEMATIC 23534857 A 1160 1168 epoxides FAMILY 23534857 A 198 206 aldehyde SYSTEMATIC 23534857 A 374 383 aldehydes FAMILY 23534857 A 451 460 aldehydes FAMILY 23534857 A 779 788 aldehydes FAMILY 23534857 A 790 815 α,β-unsaturated aldehydes FAMILY 23534857 A 820 838 2,3-epoxyaldehydes FAMILY 23534857 A 886 895 aldehydes FAMILY 23534857 A 922 930 epoxides FAMILY 23534857 T 22 36 Epoxyaldehydes FAMILY 23535188 A 1074 1079 Diclo ABBREVIATION 23535188 A 1293 1296 PMA ABBREVIATION 23535188 A 1736 1739 ASA ABBREVIATION 23535188 A 1744 1749 Diclo ABBREVIATION 23535188 A 755 775 acetylsalicylic acid SYSTEMATIC 23535188 A 777 780 ASA ABBREVIATION 23535188 A 786 796 diclofenac TRIVIAL 23535188 A 798 803 Diclo ABBREVIATION 23535287 A 0 20 Cajaninstilbene acid TRIVIAL 23535287 A 1083 1086 CSA ABBREVIATION 23535287 A 1232 1235 CSA ABBREVIATION 23535287 A 22 25 CSA ABBREVIATION 23535287 A 304 307 CSA ABBREVIATION 23535287 A 408 414 oxygen SYSTEMATIC 23535287 A 434 438 H2O2 FORMULA 23535287 A 443 446 CSA ABBREVIATION 23535287 A 480 484 H2O2 FORMULA 23535287 A 492 495 CSA ABBREVIATION 23535287 A 596 599 CSA ABBREVIATION 23535287 A 811 814 CSA ABBREVIATION 23535287 A 874 878 heme FAMILY 23535287 A 899 906 NAD(P)H ABBREVIATION 23535287 A 907 914 quinone FAMILY 23535287 A 944 953 glutamate TRIVIAL 23535287 A 954 962 cysteine TRIVIAL 23535287 T 0 20 Cajaninstilbene acid TRIVIAL 23535287 T 22 25 CSA ABBREVIATION 23535329 A 52 71 carba-C-nucleosides FAMILY 23535329 T 48 60 C-nucleoside FAMILY 23535350 A 1036 1045 Asenapine TRIVIAL 23535350 A 1141 1150 Asenapine TRIVIAL 23535350 A 1289 1298 Asenapine TRIVIAL 23535350 A 302 311 Asenapine TRIVIAL 23535350 A 766 775 asenapine TRIVIAL 23535350 T 7 16 asenapine TRIVIAL 23536522 A 1082 1085 GSH ABBREVIATION 23536522 A 117 130 monocrotaline TRIVIAL 23536522 A 132 135 MCT ABBREVIATION 23536522 A 1356 1359 MCT ABBREVIATION 23536522 A 1537 1540 MCT ABBREVIATION 23536522 A 289 292 MCT ABBREVIATION 23536522 A 512 523 glutathione TRIVIAL 23536522 A 525 528 GSH ABBREVIATION 23536522 A 540 550 superoxide TRIVIAL 23536522 A 587 598 glutathione TRIVIAL 23536522 A 599 600 S FORMULA 23536522 A 755 758 MCT ABBREVIATION 23536522 A 803 806 MCT ABBREVIATION 23536522 A 866 869 MCT ABBREVIATION 23536522 A 923 926 GSH ABBREVIATION 23536522 T 36 49 monocrotaline TRIVIAL 23536973 A 1120 1131 ropivacaine TRIVIAL 23536973 A 1184 1195 ropivacaine TRIVIAL 23536973 A 1364 1375 ropivacaine TRIVIAL 23536973 A 212 216 NaCl FORMULA 23536973 A 223 234 ropivacaine TRIVIAL 23536973 A 243 254 ropivacaine TRIVIAL 23536973 A 544 555 ropivacaine TRIVIAL 23536973 A 69 80 ropivacaine TRIVIAL 23536973 A 774 785 ropivacaine TRIVIAL 23536973 A 877 885 pyruvate TRIVIAL 23536973 T 13 24 ropivacaine TRIVIAL 23537166 A 1253 1254 I FORMULA 23537166 A 206 207 I FORMULA 23537166 A 420 422 Cl FORMULA 23537166 A 707 708 I FORMULA 23537166 A 73 79 halide FAMILY 23537166 A 779 781 Cl FORMULA 23537166 A 88 89 I FORMULA 23537166 A 95 97 Cl FORMULA 23537166 A 953 954 I FORMULA 23537203 A 1046 1050 EGCG ABBREVIATION 23537203 A 1305 1309 EGCG ABBREVIATION 23537203 A 144 154 polyphenol FAMILY 23537203 A 155 183 (-)-epigallocatechin gallate TRIVIAL 23537203 A 185 189 EGCG ABBREVIATION 23537203 A 382 386 EGCG ABBREVIATION 23537203 A 525 529 EGCG ABBREVIATION 23537203 A 597 601 EGCG ABBREVIATION 23537203 A 781 785 EGCG ABBREVIATION 23537203 T 41 45 EGCG ABBREVIATION 23537377 A 175 176 C FORMULA 23537377 A 464 466 NO FORMULA 23537377 A 811 823 D-amino acid FAMILY 23537377 T 35 36 C FORMULA 23537388 A 1005 1013 arginine TRIVIAL 23537388 A 1051 1058 calcium SYSTEMATIC 23537388 A 118 123 Na(+) FORMULA 23537388 A 1188 1194 Ca(2+) FORMULA 23537388 A 1277 1283 Ca(2+) FORMULA 23537388 A 128 134 Ca(2+) FORMULA 23537388 A 1284 1289 Na(+) FORMULA 23537388 A 218 225 cyanide SYSTEMATIC 23537388 A 247 249 CN FORMULA 23537388 A 537 542 Na(+) FORMULA 23537388 A 547 553 Ca(2+) FORMULA 23537388 A 619 624 Na(+) FORMULA 23537388 A 680 685 Na(+) FORMULA 23537388 A 687 693 Ca(2+) FORMULA 23537388 A 746 751 amide FAMILY 23537388 A 801 812 carboxylate SYSTEMATIC 23537388 A 820 828 arginine TRIVIAL 23537388 A 860 866 heme a TRIVIAL 23537388 A 872 877 Na(+) FORMULA 23537388 A 922 927 amide FAMILY 23537388 A 937 943 heme a TRIVIAL 23537388 A 989 1000 carboxylate SYSTEMATIC 23537388 T 65 71 Sodium SYSTEMATIC 23537388 T 76 83 Calcium SYSTEMATIC 23537500 A 0 4 NMDA ABBREVIATION 23537500 A 1108 1117 Glutamate TRIVIAL 23537500 A 669 673 NMDA ABBREVIATION 23537500 A 856 860 NMDA ABBREVIATION 23537500 A 956 960 NMDA ABBREVIATION 23537500 T 0 4 NMDA ABBREVIATION 23537574 A 1062 1075 carbamazepine TRIVIAL 23537574 A 1080 1092 indomethacin TRIVIAL 23537574 A 1112 1123 amino acids FAMILY 23537574 A 1216 1227 amino acids FAMILY 23537574 A 1228 1236 arginine TRIVIAL 23537574 A 1238 1251 phenylalanine TRIVIAL 23537574 A 1253 1263 tryptophan TRIVIAL 23537574 A 1268 1276 tyrosine TRIVIAL 23537574 A 2028 2038 amino acid FAMILY 23537574 A 2142 2153 Amino acids FAMILY 23537574 A 889 900 amino acids FAMILY 23537574 T 0 11 Amino acids FAMILY 23537583 A 0 7 Mercury SYSTEMATIC 23537583 A 1057 1067 superoxide TRIVIAL 23537583 A 1191 1197 Hg(2+) FORMULA 23537583 A 1567 1573 Hg(2+) FORMULA 23537583 A 175 182 Mercury SYSTEMATIC 23537583 A 1816 1825 poly(Phe) FAMILY 23537583 A 1913 1919 Hg(2+) FORMULA 23537583 A 387 394 mercury SYSTEMATIC 23537583 A 484 491 mercury SYSTEMATIC 23537583 A 749 755 Hg(2+) FORMULA 23537583 A 786 792 Hg(2+) FORMULA 23537583 A 962 968 Hg(2+) FORMULA 23537583 T 86 93 mercury SYSTEMATIC 23537600 A 1006 1011 MC-YR ABBREVIATION 23537600 A 106 111 MC-RR ABBREVIATION 23537600 A 113 118 MC-LR ABBREVIATION 23537600 A 123 128 MC-YR ABBREVIATION 23537600 A 788 793 MC-LR ABBREVIATION 23537600 A 806 811 MC-LR ABBREVIATION 23537600 A 86 98 microcystins FAMILY 23537600 A 898 903 MC-RR ABBREVIATION 23537600 A 979 984 MC-RR ABBREVIATION 23537601 A 101 103 Cd FORMULA 23537601 A 1141 1143 Pb FORMULA 23537601 A 342 344 Hg FORMULA 23537601 A 350 352 Cd FORMULA 23537601 A 387 389 Cd FORMULA 23537601 A 538 540 Pb FORMULA 23537601 A 564 566 Hg FORMULA 23537601 A 595 597 Cd FORMULA 23537601 A 69 71 Pb FORMULA 23537601 A 74 81 mercury SYSTEMATIC 23537601 A 743 750 alcohol FAMILY 23537601 A 752 754 Hg FORMULA 23537601 A 793 795 Cd FORMULA 23537601 A 823 827 iron SYSTEMATIC 23537601 A 83 85 Hg FORMULA 23537601 A 92 99 cadmium SYSTEMATIC 23537601 A 982 984 Pb FORMULA 23537601 T 19 26 cadmium SYSTEMATIC 23537601 T 6 13 mercury SYSTEMATIC 23537890 A 1051 1057 d-GalN ABBREVIATION 23537890 A 1076 1085 Quercetin TRIVIAL 23537890 A 1235 1244 quercetin TRIVIAL 23537890 A 1398 1404 d-GalN ABBREVIATION 23537890 A 267 282 d-galactosamine TRIVIAL 23537890 A 284 290 d-GalN ABBREVIATION 23537890 A 368 377 quercetin TRIVIAL 23537890 A 396 402 d-GalN ABBREVIATION 23537890 A 502 508 d-GalN ABBREVIATION 23537890 A 676 685 Quercetin TRIVIAL 23537890 A 805 814 quercetin TRIVIAL 23537890 A 828 834 d-GalN ABBREVIATION 23537890 A 87 96 quercetin TRIVIAL 23537890 A 932 941 quercetin TRIVIAL 23537890 A 999 1007 nitrites FAMILY 23537890 T 100 109 quercetin TRIVIAL 23537890 T 158 173 d-galactosamine TRIVIAL 23537890 T 19 23 heme FAMILY 23537890 T 44 56 nitric oxide SYSTEMATIC 23538036 A 299 305 carbon SYSTEMATIC 23538115 A 108 118 adamantane TRIVIAL 23538115 A 127 137 adamantane TRIVIAL 23538115 T 13 23 adamantane TRIVIAL 23538201 A 1231 1235 iron SYSTEMATIC 23538201 A 1433 1442 Ezetimibe TRIVIAL 23538201 A 1459 1463 iron SYSTEMATIC 23538201 A 1549 1553 iron SYSTEMATIC 23538201 A 179 183 iron SYSTEMATIC 23538201 A 324 328 iron SYSTEMATIC 23538201 A 36 45 ezetimibe TRIVIAL 23538201 A 369 378 ezetimibe TRIVIAL 23538201 A 382 386 iron SYSTEMATIC 23538201 A 456 460 iron SYSTEMATIC 23538201 A 562 571 ezetimibe TRIVIAL 23538201 A 629 638 ezetimibe TRIVIAL 23538201 A 674 687 carbonyl iron SYSTEMATIC 23538201 A 734 743 ezetimibe TRIVIAL 23538201 A 765 778 carbonyl iron SYSTEMATIC 23538201 A 794 803 ezetimibe TRIVIAL 23538201 A 892 896 iron SYSTEMATIC 23538201 T 0 9 EZETIMIBE TRIVIAL 23538201 T 28 32 IRON SYSTEMATIC 23538867 A 1017 1030 mithracycin A TRIVIAL 23538867 A 1084 1088 MPP+ ABBREVIATION 23538867 A 117 121 MPP+ ABBREVIATION 23538867 A 1187 1190 ATX ABBREVIATION 23538867 A 1240 1243 ATX ABBREVIATION 23538867 A 1282 1286 MPP+ ABBREVIATION 23538867 A 222 226 MPP+ ABBREVIATION 23538867 A 26 37 astaxanthin TRIVIAL 23538867 A 268 271 MTT ABBREVIATION 23538867 A 323 326 ATX ABBREVIATION 23538867 A 39 42 ATX ABBREVIATION 23538867 A 432 436 NMDA ABBREVIATION 23538867 A 711 715 MPP+ ABBREVIATION 23538867 A 85 111 1-methyl-4-phenyl-pyridine SYSTEMATIC 23538867 A 855 858 ATX ABBREVIATION 23538867 A 863 867 MPP+ ABBREVIATION 23538867 A 980 984 MPP+ ABBREVIATION 23538867 T 0 11 Astaxanthin TRIVIAL 23538867 T 23 27 MPP+ ABBREVIATION 23539296 A 24 34 androstane TRIVIAL 23539296 A 502 512 anisomycin TRIVIAL 23539296 A 696 706 anisomycin TRIVIAL 23539296 A 769 779 anisomycin TRIVIAL 23539296 A 862 865 UDP ABBREVIATION 23539642 A 0 11 Amphetamine TRIVIAL 23539642 A 1004 1020 lisdexamfetamine TRIVIAL 23539642 A 1032 1045 d-amphetamine TRIVIAL 23539642 A 1103 1119 lisdexamfetamine TRIVIAL 23539642 A 416 427 amphetamine TRIVIAL 23539642 A 447 458 Amphetamine TRIVIAL 23539642 A 817 828 amphetamine TRIVIAL 23539642 A 840 856 lisdexamfetamine TRIVIAL 23539642 A 877 890 d-amphetamine TRIVIAL 23539642 T 0 11 Amphetamine TRIVIAL 23540648 A 359 367 cysteine TRIVIAL 23540648 A 71 79 indazole SYSTEMATIC 23540648 A 92 108 pyrrolopyrazines FAMILY 23540731 A 142 162 aryl pyrroloindoline FAMILY 23540731 A 2 8 copper SYSTEMATIC 23540731 A 317 340 (+)-naseseazine A and B MULTIPLE 23540731 A 32 42 tryptophan TRIVIAL 23540731 T 0 6 Copper SYSTEMATIC 23540731 T 49 59 tryptophan TRIVIAL 23540731 T 92 116 (+)-naseseazines a and B MULTIPLE 23540813 A 1036 1040 PLLA ABBREVIATION 23540813 A 177 180 PEG ABBREVIATION 23540813 A 268 278 chloroform TRIVIAL 23540813 A 280 287 toluene TRIVIAL 23540813 A 293 308 tetrahydrofuran SYSTEMATIC 23540813 A 320 323 PEG ABBREVIATION 23540813 A 353 363 chloroform TRIVIAL 23540813 A 379 394 poly(l-lactide) SYSTEMATIC 23540813 A 396 400 PLLA ABBREVIATION 23540813 A 402 412 chloroform TRIVIAL 23540813 A 442 445 PEG ABBREVIATION 23540813 A 475 479 PLLA ABBREVIATION 23540813 A 73 94 poly(ethylene glycol) SYSTEMATIC 23540813 A 853 856 PEG ABBREVIATION 23540813 A 894 898 PLLA ABBREVIATION 23540813 A 96 99 PEG ABBREVIATION 23540813 A 962 965 PEG ABBREVIATION 23540839 A 13 37 indole-6-carboxylic acid SYSTEMATIC 23540839 A 172 181 pepstatin FAMILY 23540839 A 230 252 3-indolepropionic acid SYSTEMATIC 23540839 A 505 514 pepstatin FAMILY 23540839 A 707 716 pepstatin FAMILY 23540839 A 869 878 pepstatin FAMILY 23541120 A 530 534 CdSe FORMULA 23541120 A 535 538 CdS FORMULA 23541120 A 590 594 CdSe FORMULA 23541120 A 599 602 CdS FORMULA 23541120 A 854 862 Hydrogen SYSTEMATIC 23541120 A 925 929 CdSe FORMULA 23541120 A 930 933 CdS FORMULA 23541215 A 1080 1089 diosmetin TRIVIAL 23541215 A 1095 1107 erythromycin TRIVIAL 23541215 A 1127 1136 Diosmetin TRIVIAL 23541215 A 1276 1285 diosmetin TRIVIAL 23541215 A 1316 1319 ATP ABBREVIATION 23541215 A 1412 1421 diosmetin TRIVIAL 23541215 A 235 245 Flavonoids FAMILY 23541215 A 25 36 methicillin TRIVIAL 23541215 A 373 380 Diosmin TRIVIAL 23541215 A 385 394 diosmetin TRIVIAL 23541215 A 407 417 flavonoids FAMILY 23541215 A 504 511 diosmin TRIVIAL 23541215 A 516 525 diosmetin TRIVIAL 23541215 A 635 643 pyruvate TRIVIAL 23541215 A 731 738 diosmin TRIVIAL 23541215 A 743 752 diosmetin TRIVIAL 23541215 A 885 894 diosmetin TRIVIAL 23541215 A 909 921 erythromycin TRIVIAL 23541215 T 179 187 pyruvate TRIVIAL 23541215 T 23 32 diosmetin TRIVIAL 23541215 T 38 50 erythromycin TRIVIAL 23541215 T 90 101 methicillin TRIVIAL 23541371 A 176 181 Na(+) FORMULA 23541371 A 270 275 Na(+) FORMULA 23541371 A 346 351 Na(+) FORMULA 23541371 A 754 761 lactate FAMILY 23541371 A 971 976 Na(+) FORMULA 23541371 T 92 98 Sodium SYSTEMATIC 23541434 A 1629 1638 carbachol TRIVIAL 23541434 A 504 507 ACh ABBREVIATION 23541434 A 512 515 KCl FORMULA 23541434 A 966 989 p-bromophenacyl bromide SYSTEMATIC 23541434 A 991 996 p-BPB ABBREVIATION 23541437 A 1174 1181 mercury SYSTEMATIC 23541437 A 1182 1190 selenium SYSTEMATIC 23541437 A 1322 1330 selenium SYSTEMATIC 23541437 A 136 143 mercury SYSTEMATIC 23541437 A 1366 1373 mercury SYSTEMATIC 23541437 A 180 188 selenium SYSTEMATIC 23541437 A 211 218 mercury SYSTEMATIC 23541437 A 275 283 selenium SYSTEMATIC 23541437 A 323 331 selenium SYSTEMATIC 23541437 A 332 339 mercury SYSTEMATIC 23541437 A 576 584 selenium SYSTEMATIC 23541437 A 585 592 mercury SYSTEMATIC 23541437 A 797 805 selenium SYSTEMATIC 23541437 A 80 88 selenium SYSTEMATIC 23541437 A 806 813 mercury SYSTEMATIC 23541437 A 857 864 mercury SYSTEMATIC 23541437 A 877 885 selenium SYSTEMATIC 23541437 A 89 96 mercury SYSTEMATIC 23541437 A 943 951 selenium SYSTEMATIC 23541437 A 952 959 mercury SYSTEMATIC 23541437 T 0 8 Selenium SYSTEMATIC 23541437 T 13 20 mercury SYSTEMATIC 23541671 A 230 243 2-deoxyribose SYSTEMATIC 23541671 A 282 290 fluorine SYSTEMATIC 23541671 A 318 331 2-deoxyribose SYSTEMATIC 23541671 A 482 516 2-fluoro-2-deoxyribose-1-phosphate SYSTEMATIC 23541671 A 521 559 2,2-difluoro-2-deoxyribose-1-phosphate SYSTEMATIC 23541671 A 54 91 2-fluoro-2-deoxyarabinose-1-phosphate SYSTEMATIC 23541671 A 673 711 2,2-difluoro-2-deoxyribose-1-phosphate SYSTEMATIC 23541671 A 96 134 2,2-difluoro-2-deoxyribose-1-phosphate SYSTEMATIC 23541671 T 51 85 2-fluoro-2-deoxyribose-1-phosphate SYSTEMATIC 23541671 T 90 128 2,2-difluoro-2-deoxyribose-1-phosphate SYSTEMATIC 23541843 A 1084 1101 tin mesoporphyrin SYSTEMATIC 23541843 A 1136 1140 MeHg FORMULA 23541843 A 1192 1196 TCDD ABBREVIATION 23541843 A 127 131 TCDD ABBREVIATION 23541843 A 1293 1297 MeHg FORMULA 23541843 A 1321 1325 TCDD ABBREVIATION 23541843 A 1386 1390 MeHg FORMULA 23541843 A 1405 1409 TCDD ABBREVIATION 23541843 A 1512 1516 MeHg FORMULA 23541843 A 273 286 methylmercury SYSTEMATIC 23541843 A 288 292 MeHg FORMULA 23541843 A 363 367 MeHg FORMULA 23541843 A 372 376 TCDD ABBREVIATION 23541843 A 40 57 mercuric chloride SYSTEMATIC 23541843 A 492 496 MeHg FORMULA 23541843 A 515 519 TCDD ABBREVIATION 23541843 A 59 65 Hg(2+) FORMULA 23541843 A 771 787 aryl hydrocarbon FAMILY 23541843 A 823 827 MeHg FORMULA 23541843 A 836 843 NAD(P)H ABBREVIATION 23541843 A 844 851 quinone FAMILY 23541843 A 936 940 MeHg FORMULA 23541843 A 998 1002 heme FAMILY 23541843 T 130 134 heme FAMILY 23541843 T 90 103 methylmercury SYSTEMATIC 23541893 A 536 537 C FORMULA 23541928 A 14 51 oligo(poly(ethylene glycol) fumarate) FAMILY 23541928 A 280 283 OPF ABBREVIATION 23541928 A 53 56 OPF ABBREVIATION 23541928 A 826 829 OPF ABBREVIATION 23541932 A 540 550 epimedin A TRIVIAL 23541932 A 552 562 epimedin B TRIVIAL 23541932 A 564 574 epimedin C TRIVIAL 23541932 A 579 586 icariin TRIVIAL 23541982 A 1021 1032 Cholesterol TRIVIAL 23541982 A 108 113 24OHC SYSTEMATIC 23541982 A 1099 1104 24OHC SYSTEMATIC 23541982 A 1187 1198 cholesterol TRIVIAL 23541982 A 1214 1219 24OHC SYSTEMATIC 23541982 A 1400 1405 27OHC SYSTEMATIC 23541982 A 1510 1515 24OHC SYSTEMATIC 23541982 A 1561 1571 oxysterols FAMILY 23541982 A 1630 1641 cholesterol TRIVIAL 23541982 A 18 29 cholesterol TRIVIAL 23541982 A 215 220 24OHC SYSTEMATIC 23541982 A 307 318 cholesterol TRIVIAL 23541982 A 564 569 24OHC SYSTEMATIC 23541982 A 616 621 24OHC SYSTEMATIC 23541982 A 67 78 cholesterol TRIVIAL 23541982 A 682 703 27-hydroxycholesterol SYSTEMATIC 23541982 A 705 710 27OHC SYSTEMATIC 23541982 A 808 818 oxysterols FAMILY 23541982 A 84 106 24S-hydroxycholesterol SYSTEMATIC 23541982 A 963 974 cholesterol TRIVIAL 23541982 T 48 58 oxysterols FAMILY 23542040 A 1034 1046 dexametasone TRIVIAL 23542040 A 711 718 nitrite SYSTEMATIC 23542040 A 719 726 nitrate SYSTEMATIC 23542147 A 1349 1353 PGE2 ABBREVIATION 23542147 A 2328 2331 Ser FORMULA 23542147 A 525 541 prostaglandin E2 TRIVIAL 23542147 A 543 547 PGE2 ABBREVIATION 23542147 T 0 7 Ethanol SYSTEMATIC 23542439 A 0 12 Progesterone TRIVIAL 23542439 A 1081 1093 progesterone TRIVIAL 23542439 A 1185 1201 Allopregnanolone TRIVIAL 23542439 A 1292 1298 5α-DHP SYSTEMATIC 23542439 A 1417 1433 Allopregnanolone TRIVIAL 23542439 A 1534 1542 Gabazine TRIVIAL 23542439 A 1686 1698 progestagens FAMILY 23542439 A 233 245 progesterone TRIVIAL 23542439 A 504 516 progesterone TRIVIAL 23542439 A 518 540 5α-dihydroprogesterone SYSTEMATIC 23542439 A 542 548 5α-DHP SYSTEMATIC 23542439 A 553 569 allopregnanolone TRIVIAL 23542439 A 571 600 3α, 5α-tetrahydroprogesterone SYSTEMATIC 23542439 A 697 709 Progesterone TRIVIAL 23542439 A 825 831 5α-DHP SYSTEMATIC 23542439 A 839 855 allopregnanolone TRIVIAL 23542439 A 877 888 finasteride TRIVIAL 23542439 A 961 973 progesterone TRIVIAL 23542439 T 19 27 steroids FAMILY 23542439 T 98 110 progesterone TRIVIAL 23542442 A 0 11 Hemopressin TRIVIAL 23542442 A 1197 1202 AM251 IDENTIFIER 23542442 A 1477 1488 hemopressin TRIVIAL 23542442 A 1668 1679 hemopressin TRIVIAL 23542442 A 388 399 hemopressin TRIVIAL 23542442 A 611 622 hemopressin TRIVIAL 23542442 A 657 663 oxygen SYSTEMATIC 23542442 A 839 850 hemopressin TRIVIAL 23542442 A 890 895 AM251 IDENTIFIER 23542442 A 90 101 Hemopressin TRIVIAL 23542442 A 952 963 hemopressin TRIVIAL 23542442 T 62 73 hemopressin TRIVIAL 23542578 A 122 128 GTX2,3 MULTIPLE 23542578 A 147 162 GTX2,3-aldehyde MULTIPLE 23542578 A 203 206 NH2 FORMULA 23542578 A 232 242 amino acid FAMILY 23542578 A 273 282 aldehydes FAMILY 23542578 A 320 335 GTX2,3-aldehyde MULTIPLE 23542578 A 367 382 GTX2,3-aldehyde MULTIPLE 23542578 A 849 855 GTX2,3 MULTIPLE 23542578 T 50 65 gonyautoxin 2,3 MULTIPLE 23542729 A 285 296 cholesterol TRIVIAL 23542729 A 524 533 oxysterol FAMILY 23542729 A 600 607 glucose TRIVIAL 23542729 A 987 998 cholesterol TRIVIAL 23542814 A 1277 1284 cocaine TRIVIAL 23542814 A 1289 1296 cocaine TRIVIAL 23542814 A 1297 1305 morphine TRIVIAL 23542814 A 271 278 cocaine TRIVIAL 23542814 A 396 403 cocaine TRIVIAL 23542814 A 411 419 morphine TRIVIAL 23542814 A 581 588 cocaine TRIVIAL 23542814 A 77 84 cocaine TRIVIAL 23542814 A 779 787 Morphine TRIVIAL 23542814 A 871 878 cocaine TRIVIAL 23542814 A 879 887 morphine TRIVIAL 23542814 A 911 918 cocaine TRIVIAL 23542814 A 94 101 Cocaine TRIVIAL 23542814 T 47 54 cocaine TRIVIAL 23542814 T 59 66 cocaine TRIVIAL 23542814 T 72 80 morphine TRIVIAL 23543012 A 1015 1026 heteronemin TRIVIAL 23543012 A 104 115 Heteronemin TRIVIAL 23543012 A 1044 1055 heteronemin TRIVIAL 23543012 A 1191 1202 heteronemin TRIVIAL 23543012 A 1262 1272 12(S)-HETE SYSTEMATIC 23543012 A 1455 1466 heteronemin TRIVIAL 23543012 A 1475 1486 heteronemin TRIVIAL 23543012 A 537 571 12(S)-Hydroxyeicosatetraenoic acid SYSTEMATIC 23543012 A 573 583 12(S)-HETE SYSTEMATIC 23543012 A 935 945 12(S)-HETE SYSTEMATIC 23543012 T 85 96 heteronemin TRIVIAL 23543412 A 1180 1200 phosphatidylinositol TRIVIAL 23543412 A 1220 1228 LY294002 IDENTIFIER 23543412 A 1256 1264 nicotine TRIVIAL 23543412 A 1389 1397 nicotine TRIVIAL 23543412 A 1502 1513 SB-277011-A IDENTIFIER 23543412 A 1544 1552 nicotine TRIVIAL 23543412 A 1719 1727 nicotine TRIVIAL 23543412 A 1831 1839 dopamine TRIVIAL 23543412 A 29 37 nicotine TRIVIAL 23543412 A 332 345 acetylcholine SYSTEMATIC 23543412 A 575 583 nicotine TRIVIAL 23543412 A 711 723 mecamylamine TRIVIAL 23543412 A 728 750 dihydro-β-erythroidine SYSTEMATIC 23543412 A 760 778 methyllycaconitine TRIVIAL 23543412 A 839 847 nicotine TRIVIAL 23543412 A 935 943 nicotine TRIVIAL 23543412 T 0 8 Nicotine TRIVIAL 23543412 T 92 100 Dopamine TRIVIAL 23543432 A 690 709 polyethylene glycol SYSTEMATIC 23543629 A 1004 1011 CX-4945 IDENTIFIER 23543629 A 136 143 CX-4945 IDENTIFIER 23543629 A 188 191 ATP ABBREVIATION 23543629 A 413 420 CX-4945 IDENTIFIER 23543629 A 445 452 CX-4945 IDENTIFIER 23543629 A 657 666 potassium SYSTEMATIC 23543629 A 693 700 CX-4945 IDENTIFIER 23543629 A 757 764 CX-4945 IDENTIFIER 23543629 T 50 57 CX-4945 IDENTIFIER 23543653 A 207 218 phthalazine TRIVIAL 23543653 A 6 34 4-(4-bromophenyl)phthalazine SYSTEMATIC 23543653 A 64 69 alkyl FAMILY 23543653 A 80 85 amine SYSTEMATIC 23543653 A 89 113 N-substituted piperazine FAMILY 23543653 T 6 39 4-substituted-2(1H)-phthalazinone FAMILY 23544460 A 1022 1028 nickel SYSTEMATIC 23544460 A 1033 1039 cobalt SYSTEMATIC 23544460 A 1062 1075 alkyl halides FAMILY 23544460 A 1081 1088 alkenes FAMILY 23544460 A 141 158 aliphatic halides FAMILY 23544460 A 18 31 alkyl halides FAMILY 23544460 A 293 305 aryl halides FAMILY 23544460 A 318 320 Ni FORMULA 23544460 A 326 328 Co FORMULA 23544460 A 37 44 alkenes FAMILY 23544460 A 410 417 alkenes FAMILY 23544460 A 443 456 alkyl halides FAMILY 23544460 A 511 518 alkenes FAMILY 23544460 A 640 642 Ni FORMULA 23544460 A 648 650 Co FORMULA 23544460 A 761 763 Ni FORMULA 23544460 A 769 771 Co FORMULA 23544460 A 794 807 alkyl halides FAMILY 23544460 A 811 818 alkenes FAMILY 23544460 T 0 6 Nickel SYSTEMATIC 23544460 T 11 17 Cobalt SYSTEMATIC 23544460 T 40 53 Alkyl Halides FAMILY 23544460 T 59 66 Alkenes FAMILY 23544604 A 0 10 Pyrazoline SYSTEMATIC 23544604 A 261 272 pyrazolines FAMILY 23544604 A 41 49 nitrogen SYSTEMATIC 23544604 A 465 476 pyrazolines FAMILY 23544604 A 575 585 pyrazoline SYSTEMATIC 23544604 T 0 11 Pyrazolines FAMILY 23544891 A 12 25 Levothyroxine TRIVIAL 23544891 A 2339 2352 levothyroxine TRIVIAL 23544891 A 265 278 levothyroxine TRIVIAL 23544891 A 664 677 levothyroxine TRIVIAL 23545134 A 0 12 Chlorpyrifos TRIVIAL 23545134 A 110 127 chlorpyrifos oxon TRIVIAL 23545134 A 1204 1207 CPF ABBREVIATION 23545134 A 14 17 CPF ABBREVIATION 23545134 A 1518 1521 CPF ABBREVIATION 23545134 A 25 40 organophosphate FAMILY 23545134 A 366 369 CPF ABBREVIATION 23545134 A 475 478 CPF ABBREVIATION 23545134 A 899 902 CPF ABBREVIATION 23545134 T 28 40 chlorpyrifos TRIVIAL 23545481 A 103 107 DEHP ABBREVIATION 23545481 A 1229 1233 DEHP ABBREVIATION 23545481 A 280 284 DEHP ABBREVIATION 23545481 A 513 517 MEHP ABBREVIATION 23545481 A 617 655 mono(2-ethyl-5-hydroxyhexyl) phthalate SYSTEMATIC 23545481 A 660 694 mono(2-ethyl-5-oxohexyl) phthalate SYSTEMATIC 23545481 A 933 946 phthalic acid TRIVIAL 23545481 T 46 72 Di(2-ethylhexyl) phthalate SYSTEMATIC 23545481 T 74 78 DEHP ABBREVIATION 23545560 A 1012 1016 RuO2 FORMULA 23545560 A 1210 1218 graphene TRIVIAL 23545560 A 216 224 graphene TRIVIAL 23545560 A 404 410 Nafion TRIVIAL 23545560 A 411 415 RuO2 FORMULA 23545560 A 518 522 RuO2 FORMULA 23545560 A 661 667 Nafion TRIVIAL 23545560 A 690 694 RuO2 FORMULA 23545560 T 63 71 graphene TRIVIAL 23545900 A 1031 1042 glutathione TRIVIAL 23545900 A 1058 1068 sulfhydryl FAMILY 23545900 A 908 923 malondialdehyde TRIVIAL 23545900 A 948 960 hyroperoxide SYSTEMATIC 23546009 A 1019 1027 chromone TRIVIAL 23546009 A 176 184 chromone TRIVIAL 23546009 A 280 288 chromone TRIVIAL 23546009 A 344 352 chromone TRIVIAL 23546009 A 452 479 3-amino-4-piperazinylphenyl SYSTEMATIC 23546009 A 501 509 chromone TRIVIAL 23546009 A 575 583 chromone TRIVIAL 23546009 A 613 654 2-(3-amino-4-piperazinylphenyl)-chromones FAMILY 23546009 A 67 75 chromone TRIVIAL 23546009 A 768 796 2-pyridinylpiperazinylphenyl SYSTEMATIC 23546009 A 833 841 chromone TRIVIAL 23546009 A 967 988 2-pyridinylpiperazine SYSTEMATIC 23546009 T 44 83 2-(3-Amino-4-piperazinylphenyl)chromone SYSTEMATIC 23546396 A 221 222 B FORMULA 23546396 A 497 498 B FORMULA 23546396 A 632 633 B FORMULA 23546396 A 66 71 boron SYSTEMATIC 23546396 A 73 74 B FORMULA 23546396 A 751 752 B FORMULA 23546396 A 908 909 B FORMULA 23546396 T 79 84 Boron SYSTEMATIC 23546599 A 1132 1136 cAMP ABBREVIATION 23546599 A 1331 1340 carbachol TRIVIAL 23546602 A 1183 1190 glucose TRIVIAL 23546602 A 1288 1295 glucose TRIVIAL 23546602 A 1305 1311 2-NBDG SYSTEMATIC 23546602 A 1593 1600 glucose TRIVIAL 23546602 A 173 181 estrogen FAMILY 23546602 A 186 193 glucose TRIVIAL 23546602 A 25 33 estrogen FAMILY 23546602 A 400 413 17β-estradiol SYSTEMATIC 23546602 A 500 507 glucose TRIVIAL 23546602 A 529 537 estrogen FAMILY 23546602 A 678 685 steroid FAMILY 23546602 A 780 793 17β-estradiol SYSTEMATIC 23546602 A 797 806 estradiol TRIVIAL 23546602 A 889 896 glucose TRIVIAL 23546602 A 909 916 glucose TRIVIAL 23546602 A 938 1002 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose SYSTEMATIC 23546602 T 0 13 17β-estradiol SYSTEMATIC 23546602 T 24 31 glucose TRIVIAL 23546614 A 1165 1177 triglyceride FAMILY 23546614 A 1234 1244 Fatty acid FAMILY 23546614 A 1261 1268 n3 PUFA ABBREVIATION 23546614 A 1611 1619 n-3 PUFA ABBREVIATION 23546614 A 1713 1726 triglycerides FAMILY 23546614 A 327 335 n-3 PUFA ABBREVIATION 23546614 A 414 435 eicosapentaenoic acid SYSTEMATIC 23546614 A 437 440 EPA ABBREVIATION 23546614 A 446 466 docosahexaenoic acid SYSTEMATIC 23546614 A 468 471 DHA ABBREVIATION 23546614 A 494 497 EPA ABBREVIATION 23546614 A 512 515 DHA ABBREVIATION 23546614 A 63 97 omega-3 polyunsaturated fatty acid FAMILY 23546614 A 911 919 n-3 PUFA ABBREVIATION 23546614 A 99 107 n-3 PUFA ABBREVIATION 23546614 T 19 50 n-3 polyunsaturated fatty acids FAMILY 23546876 A 1206 1207 C FORMULA 23546876 A 135 143 nitrogen SYSTEMATIC 23546876 A 1440 1449 oxo-acids FAMILY 23546876 A 1483 1497 cysteine thiol SYSTEMATIC 23546876 A 235 245 cyclic AMP TRIVIAL 23546876 A 426 434 cysteine TRIVIAL 23546876 A 794 800 serine TRIVIAL 23546876 A 809 810 C FORMULA 23546876 A 833 847 hexa-histidine TRIVIAL 23547729 A 135 145 aziridines FAMILY 23547729 A 337 342 (13)C FORMULA 23547729 A 60 71 triazolines FAMILY 23547729 T 50 60 Triazoline FAMILY 23547754 A 623 632 serotonin TRIVIAL 23547754 A 673 682 serotonin TRIVIAL 23547754 A 719 728 serotonin TRIVIAL 23547754 A 850 859 serotonin TRIVIAL 23547754 T 12 21 serotonin TRIVIAL 23547794 A 109 119 Nucleoside FAMILY 23547794 A 400 412 N-nucleoside FAMILY 23547794 A 463 475 C-nucleoside FAMILY 23547794 A 517 526 adenosine TRIVIAL 23547794 A 560 608 1'-cyano-2'-C-methyl 4-aza-7,9-dideaza adenosine SYSTEMATIC 23547794 A 656 669 monophosphate SYSTEMATIC 23547794 A 851 863 triphosphate SYSTEMATIC 23547794 A 930 937 GS-6620 IDENTIFIER 23547794 T 23 35 C-Nucleoside FAMILY 23547794 T 62 69 GS-6620 IDENTIFIER 23547843 A 127 161 (E)-3,4,3',5'-tetramethoxystilbene SYSTEMATIC 23547843 A 1373 1376 PMA ABBREVIATION 23547843 A 1433 1439 Trolox TRIVIAL 23547843 A 171 200 (E)-3,5,4'-trimethoxystilbene SYSTEMATIC 23547843 A 460 492 2,3,5,7-tetramethoxyphenanthrene SYSTEMATIC 23547843 A 76 85 stilbenes FAMILY 23547843 A 87 121 (Z)-3,4,3',5'-tetramethoxystilbene SYSTEMATIC 23547843 T 59 102 (Z)- and (E)-3,4,3',5'-Tetramethoxystilbene MULTIPLE 23548164 A 174 186 salvinorin A TRIVIAL 23548164 A 27 39 salvinorin A TRIVIAL 23548164 A 292 300 morphine TRIVIAL 23548164 A 4 26 neoclerodane diterpene FAMILY 23548164 A 468 480 salvinorin A TRIVIAL 23548164 T 0 13 Neoclerodanes FAMILY 23548202 A 1084 1092 tyrosine TRIVIAL 23548202 A 118 128 tryptophan TRIVIAL 23548202 A 204 220 veratryl alcohol TRIVIAL 23548202 A 270 274 H2O2 FORMULA 23548202 A 308 312 H2O2 FORMULA 23548202 A 329 333 H2O2 FORMULA 23548202 A 449 452 Tyr FORMULA 23548202 A 466 470 H2O2 FORMULA 23548202 A 497 500 Tyr FORMULA 23548202 A 628 631 Tyr FORMULA 23548202 A 640 643 Phe FORMULA 23548202 A 671 679 peroxide SYSTEMATIC 23548202 A 74 82 tyrosine TRIVIAL 23548202 A 753 761 tyrosine TRIVIAL 23548202 A 818 826 tyrosine TRIVIAL 23548202 A 84 87 Tyr FORMULA 23548202 A 861 882 dihydroxyphenyalanine SYSTEMATIC 23548202 A 894 898 H2O2 FORMULA 23548202 A 980 984 H2O2 FORMULA 23548202 T 15 23 tyrosine TRIVIAL 23548583 A 1159 1171 diterpenoids FAMILY 23548583 A 1197 1201 H2O2 FORMULA 23548583 A 1259 1262 MTT ABBREVIATION 23548583 A 1350 1362 diterpenoids FAMILY 23548583 A 1402 1406 H2O2 FORMULA 23548583 A 1460 1463 GSH ABBREVIATION 23548583 A 1464 1468 GSSG ABBREVIATION 23548583 A 1697 1709 diterpenoids FAMILY 23548583 A 1868 1872 H2O2 FORMULA 23548583 A 1997 2006 Andalusol TRIVIAL 23548583 A 2054 2066 diterpenoids FAMILY 23548583 A 345 357 Diterpenoids FAMILY 23548583 A 644 656 diterpenoids FAMILY 23548583 A 657 666 andalusol TRIVIAL 23548583 A 668 679 conchitriol TRIVIAL 23548583 A 684 696 lagascatriol TRIVIAL 23548583 A 750 754 H2O2 FORMULA 23548583 A 881 884 MTT ABBREVIATION 23548583 A 944 947 GSH ABBREVIATION 23548583 A 952 956 GSSG ABBREVIATION 23548583 T 43 55 diterpenoids FAMILY 23548702 A 1034 1039 AG490 TRIVIAL 23548702 A 1208 1213 AG490 TRIVIAL 23548702 A 1412 1427 prostaglandin E FAMILY 23548702 A 1501 1506 AG490 TRIVIAL 23548702 A 1641 1646 AG490 TRIVIAL 23548702 A 1799 1804 AG490 TRIVIAL 23548702 A 341 346 AG490 TRIVIAL 23548702 A 662 667 AG490 TRIVIAL 23548702 A 909 914 AG490 TRIVIAL 23548702 A 995 1000 AG490 TRIVIAL 23548702 T 32 37 AG490 TRIVIAL 23549262 A 1290 1306 phosphoinositide FAMILY 23549262 A 1461 1469 tyrosine TRIVIAL 23549262 A 1479 1487 tyrosine TRIVIAL 23549262 A 1613 1620 calcium SYSTEMATIC 23549262 A 1926 1934 tyrosine TRIVIAL 23549262 A 382 392 lipoxin A4 TRIVIAL 23549262 A 4 10 formyl SYSTEMATIC 23549262 A 700 709 resolvins FAMILY 23549262 A 975 984 adenylate TRIVIAL 23549262 T 50 56 formyl SYSTEMATIC 23549282 A 10 30 dolastane diterpenes FAMILY 23549282 A 66 82 perhydroazulenes FAMILY 23549282 T 49 59 Dolastanes FAMILY 23549331 A 1299 1309 eicosanoid FAMILY 23549331 A 204 215 eicosanoids FAMILY 23549331 A 98 114 arachidonic acid TRIVIAL 23549423 A 1037 1040 WO3 FORMULA 23549423 A 1056 1060 TiO2 FORMULA 23549423 A 1118 1120 Pt FORMULA 23549423 A 1121 1124 WO3 FORMULA 23549423 A 124 141 tungsten trioxide SYSTEMATIC 23549423 A 143 146 WO3 FORMULA 23549423 A 192 198 SBA-15 IDENTIFIER 23549423 A 213 219 carbon SYSTEMATIC 23549423 A 233 235 Pt FORMULA 23549423 A 279 284 W(6+) FORMULA 23549423 A 316 324 m-Pt-WO3 FORMULA 23549423 A 478 489 metal oxide FAMILY 23549423 A 586 594 m-Pt-WO3 FORMULA 23549423 A 754 762 m-Pt-WO3 FORMULA 23549423 A 834 842 m-Pt-WO3 FORMULA 23549423 A 85 93 platinum SYSTEMATIC 23549423 A 95 97 Pt FORMULA 23549423 T 56 58 Pt FORMULA 23549423 T 59 62 WO3 FORMULA 23549676 A 148 155 steroid FAMILY 23549676 A 212 220 steroids FAMILY 23549676 A 382 390 steroids FAMILY 23549676 T 19 26 Steroid FAMILY 23549733 A 139 147 hydrogen SYSTEMATIC 23550942 A 1015 1021 CoCrMo FORMULA 23550942 A 110 116 quartz TRIVIAL 23550942 A 17 23 CoCrMo FORMULA 23550942 A 726 728 Co FORMULA 23550942 A 730 732 Cr FORMULA 23550942 A 738 740 Mo FORMULA 23550942 A 796 798 Mo FORMULA 23550942 A 871 877 Mo(VI) FORMULA 23550942 T 17 27 molybdenum SYSTEMATIC 23551297 A 0 20 Aromatic amino acids FAMILY 23551297 A 298 312 Ac-Phe-Phe-NH2 FORMULA 23551297 A 319 333 Ac-Trp-Tyr-NH2 FORMULA 23551297 A 344 362 Ac-Phe-Phe-Phe-NH2 FORMULA 23551297 A 893 895 NH FORMULA 23551297 A 896 901 amide FAMILY 23552261 A 1040 1042 Pb FORMULA 23552261 A 1166 1168 Pb FORMULA 23552261 A 21 23 Pb FORMULA 23552261 A 26 33 cadmium SYSTEMATIC 23552261 A 325 327 Pb FORMULA 23552261 A 332 334 Cd FORMULA 23552261 A 35 37 Cd FORMULA 23552261 A 43 49 nickel SYSTEMATIC 23552261 A 51 53 Ni FORMULA 23552261 A 562 564 Pb FORMULA 23552261 A 566 568 Cd FORMULA 23552261 A 573 575 Ni FORMULA 23552261 A 696 698 Pb FORMULA 23552261 A 732 734 Cd FORMULA 23552261 A 765 767 Ni FORMULA 23552261 A 808 810 Ni FORMULA 23552261 A 888 890 Pb FORMULA 23552261 A 895 897 Cd FORMULA 23552261 A 927 929 Pb FORMULA 23552261 A 931 933 Cd FORMULA 23552261 A 938 940 Ni FORMULA 23552261 T 150 156 carbon SYSTEMATIC 23552261 T 33 40 cadmium SYSTEMATIC 23552261 T 45 51 nickel SYSTEMATIC 23552265 A 0 14 Benzo[a]pyrene SYSTEMATIC 23552265 A 101 105 PAHs ABBREVIATION 23552265 A 1106 1120 BaP t-7,8-diol SYSTEMATIC 23552265 A 1138 1142 NaN3 FORMULA 23552265 A 1159 1178 deuterated methanol SYSTEMATIC 23552265 A 1208 1214 oxygen SYSTEMATIC 23552265 A 1292 1306 hydroperoxides FAMILY 23552265 A 1334 1344 superoxide TRIVIAL 23552265 A 1440 1446 oxygen SYSTEMATIC 23552265 A 1451 1461 superoxide TRIVIAL 23552265 A 1520 1524 BPDE ABBREVIATION 23552265 A 16 19 BaP ABBREVIATION 23552265 A 170 174 PAHs ABBREVIATION 23552265 A 224 227 BaP ABBREVIATION 23552265 A 323 348 BaP trans-7,8-dihydrodiol SYSTEMATIC 23552265 A 350 364 BaP t-7,8-diol SYSTEMATIC 23552265 A 367 381 BaP t-4,5-diol SYSTEMATIC 23552265 A 383 398 BaP t-9,10-diol SYSTEMATIC 23552265 A 400 423 3-hydroxybenzo[a]pyrene SYSTEMATIC 23552265 A 425 433 3-OH-BaP SYSTEMATIC 23552265 A 436 456 BaP (7,10/8,9)tetrol SYSTEMATIC 23552265 A 462 482 BaP (7/8,9,10)tetrol SYSTEMATIC 23552265 A 509 512 BaP ABBREVIATION 23552265 A 514 522 3-OH-BaP SYSTEMATIC 23552265 A 524 538 BaP t-7,8-diol SYSTEMATIC 23552265 A 540 576 BaP trans-7,8-diol-anti-9,10-epoxide SYSTEMATIC 23552265 A 578 582 BPDE ABBREVIATION 23552265 A 589 609 BaP (7,10/8,9)tetrol SYSTEMATIC 23552265 A 67 99 polycyclic aromatic hydrocarbons FAMILY 23552265 A 879 895 methyl linoleate SYSTEMATIC 23552265 A 898 901 BaP ABBREVIATION 23552265 A 915 919 BPDE ABBREVIATION 23552265 A 939 943 PAHs ABBREVIATION 23552265 A 945 951 pyrene SYSTEMATIC 23552265 A 953 991 7,8,9,10-tetrahydro-BaP trans-7,8-diol SYSTEMATIC 23552265 A 997 1036 7,8,9,10-tetrahydro-BaP trans-9,10-diol SYSTEMATIC 23552265 T 24 38 benzo[a]pyrene SYSTEMATIC 23552265 T 88 94 oxygen SYSTEMATIC 23552828 A 153 162 phosphate SYSTEMATIC 23552828 A 177 198 poly(ethylene glycol) SYSTEMATIC 23552828 A 200 203 PEG ABBREVIATION 23552828 A 210 219 phosphate SYSTEMATIC 23552828 A 241 244 PEG ABBREVIATION 23552828 A 296 304 hydroxyl SYSTEMATIC 23552828 A 322 341 phosphoryl chloride SYSTEMATIC 23552828 A 562 568 Fe(3+) FORMULA 23552828 A 570 575 V(3+) FORMULA 23552828 A 577 583 Al(3+) FORMULA 23552828 A 585 591 Ti(3+) FORMULA 23552828 A 597 603 Ga(3+) FORMULA 23552828 A 813 819 Fe(3+) FORMULA 23552828 A 820 826 Fe(2+) FORMULA 23552828 A 880 889 phosphate SYSTEMATIC 23552828 T 20 41 poly(ethylene glycol) SYSTEMATIC 23552828 T 78 87 phosphate SYSTEMATIC 23552832 A 1024 1035 pentosidine TRIVIAL 23552832 A 1136 1147 pentosidine TRIVIAL 23552832 A 120 131 pentosidine TRIVIAL 23552832 A 1229 1240 pentosidine TRIVIAL 23552832 A 247 258 glutathione TRIVIAL 23552832 A 280 290 superoxide TRIVIAL 23552832 A 515 526 pentosidine TRIVIAL 23552832 A 717 728 pentosidine TRIVIAL 23552832 A 823 834 pentosidine TRIVIAL 23552832 A 989 1000 pentosidine TRIVIAL 23552832 T 60 71 Pentosidine TRIVIAL 23552851 A 1227 1234 dioscin TRIVIAL 23552851 A 1282 1289 Dioscin TRIVIAL 23552851 A 1400 1407 dioscin TRIVIAL 23552851 A 358 365 dioscin TRIVIAL 23552851 A 37 44 dioscin TRIVIAL 23552851 A 442 471 4'-6-diamidino-2-phenylindole SYSTEMATIC 23552851 A 615 622 dioscin TRIVIAL 23552851 A 715 722 dioscin TRIVIAL 23552851 A 827 841 bafilomycin A1 TRIVIAL 23552851 A 845 860 3-methyladenine SYSTEMATIC 23552851 A 950 957 dioscin TRIVIAL 23552851 T 0 7 Dioscin TRIVIAL 23552878 A 102 123 α-methylene-γ-lactone SYSTEMATIC 23552878 A 135 146 cembranoids FAMILY 23552878 A 148 220 (1R*,3R*, 4R*,14R*,7E,11E)-3,4-epoxycembra-7,11,15(17)-trien-16,14-olide SYSTEMATIC 23552878 A 226 306 (1R*,7S*,14S*,3E, 11E)-7-hydroperoxycembra-3,8(19),11,15(17)-tetraen-16,14-olide SYSTEMATIC 23552878 A 316 407 (1R*,7S*,14S*, 3E,11E)-18-acetoxy-7-hydroperoxycembra-3,8(19),11,15(17)-tetraen-16,14-olide SYSTEMATIC 23552878 T 28 39 Cembranoids FAMILY 23552907 A 1145 1156 risperidone TRIVIAL 23552907 A 1161 1173 aripiprazole TRIVIAL 23552907 A 1438 1449 ziprasidone TRIVIAL 23552907 A 1454 1466 paliperidone TRIVIAL 23552907 A 808 819 risperidone TRIVIAL 23552907 A 821 833 aripiprazole TRIVIAL 23552907 A 835 845 quetiapine TRIVIAL 23552907 A 847 858 ziprasidone TRIVIAL 23552907 A 860 870 olanzapine TRIVIAL 23552907 A 872 881 clozapine TRIVIAL 23552907 A 883 895 paliperidone TRIVIAL 23552907 A 897 908 iloperidone TRIVIAL 23552907 A 910 919 asenapine TRIVIAL 23552907 A 925 935 lurasidone TRIVIAL 23553601 A 221 231 colchicine TRIVIAL 23553601 A 821 831 colchicine TRIVIAL 23553601 A 837 845 steroids FAMILY 23553767 A 1020 1027 calcium SYSTEMATIC 23553997 A 445 452 ethanol SYSTEMATIC 23553997 A 601 608 ethanol SYSTEMATIC 23554049 A 0 11 Furanodiene TRIVIAL 23554049 A 13 16 FUR ABBREVIATION 23554049 A 233 236 FUR ABBREVIATION 23554049 A 242 252 paclitaxel TRIVIAL 23554049 A 254 257 TAX ABBREVIATION 23554049 A 31 40 terpenoid FAMILY 23554049 A 357 360 FUR ABBREVIATION 23554049 A 426 429 TAX ABBREVIATION 23554049 A 736 739 FUR ABBREVIATION 23554049 A 937 940 FUR ABBREVIATION 23554049 T 0 11 Furanodiene TRIVIAL 23554049 T 66 76 Paclitaxel TRIVIAL 23554071 A 352 359 calcium SYSTEMATIC 23554071 A 367 376 magnesium SYSTEMATIC 23554071 A 378 388 phosphorus SYSTEMATIC 23554071 A 390 398 selenium SYSTEMATIC 23554095 A 476 482 lysine TRIVIAL 23554095 T 88 94 lysine TRIVIAL 23554140 A 0 4 SiCN FORMULA 23554140 A 415 423 silazane TRIVIAL 23554140 A 428 440 polyethylene SYSTEMATIC 23554140 A 711 715 SiCN FORMULA 23554140 A 791 797 carbon SYSTEMATIC 23554140 T 0 4 SiCN FORMULA 23554140 T 6 10 SiCN FORMULA 23554268 A 0 8 Graphene TRIVIAL 23554268 A 168 176 graphene TRIVIAL 23554268 A 208 216 graphene TRIVIAL 23554268 A 441 449 graphene TRIVIAL 23554268 A 533 541 graphene TRIVIAL 23554268 A 679 687 graphene TRIVIAL 23554268 A 863 871 graphene TRIVIAL 23554268 T 0 8 Graphene TRIVIAL 23554268 T 70 78 Graphene TRIVIAL 23554268 T 83 91 Graphene TRIVIAL 23554292 A 196 206 S2 O3 (2-) FORMULA 23554292 A 242 247 Cu2 O FORMULA 23554292 A 429 436 Ni(OH)2 FORMULA 23554292 A 523 530 glucose TRIVIAL 23554292 A 82 89 Ni(OH)2 FORMULA 23554292 T 10 17 Ni(OH)2 FORMULA 23554292 T 71 78 Glucose TRIVIAL 23554450 A 112 125 levothyroxine TRIVIAL 23554450 A 1130 1143 levothyroxine TRIVIAL 23554450 A 1256 1269 levothyroxine TRIVIAL 23554450 A 542 555 levothyroxine TRIVIAL 23554450 A 616 629 levothyroxine TRIVIAL 23554450 A 705 718 levothyroxine TRIVIAL 23554450 A 947 956 thyroxine TRIVIAL 23554450 T 2 11 Thyroxine TRIVIAL 23554450 T 47 56 Thyroxine TRIVIAL 23554507 A 1003 1011 losartan TRIVIAL 23554507 A 1058 1065 U-73122 IDENTIFIER 23554507 A 1106 1134 2-aminoethoxydiphenyl borate SYSTEMATIC 23554507 A 1139 1167 inositol 1,4,5 trisphosphate SYSTEMATIC 23554507 A 188 191 UII ABBREVIATION 23554507 A 317 320 UII ABBREVIATION 23554507 A 40 52 urotensin II TRIVIAL 23554507 A 54 57 UII ABBREVIATION 23554507 A 967 975 urantide TRIVIAL 23554507 T 50 62 urotensin II TRIVIAL 23554574 A 256 272 glucosylceramide FAMILY 23554574 A 288 291 UDP ABBREVIATION 23554574 A 292 299 glucose TRIVIAL 23554574 A 300 308 ceramide FAMILY 23554574 A 825 828 UDP ABBREVIATION 23554574 A 829 836 glucose TRIVIAL 23554574 A 837 845 ceramide FAMILY 23554574 T 23 39 glucosylceramide FAMILY 23556333 A 153 156 BLA ABBREVIATION 23556333 A 77 94 bulleyaconitine A TRIVIAL 23556333 A 861 864 BLA ABBREVIATION 23556333 A 96 99 BLA ABBREVIATION 23556333 T 35 52 bulleyaconitine A TRIVIAL 23556340 A 0 17 Cyclic dipeptides FAMILY 23556340 A 1044 1063 polyethylene glycol SYSTEMATIC 23556340 A 1069 1079 folic acid TRIVIAL 23556340 A 1268 1278 folic acid TRIVIAL 23556340 A 129 143 Cyclo(His-Gly) FORMULA 23556340 A 1332 1338 folate TRIVIAL 23556340 A 1348 1362 cyclo(His-Ala) FORMULA 23556340 A 1387 1404 cyclic dipeptides FAMILY 23556340 A 148 162 cyclo(His-Ala) FORMULA 23556340 A 497 516 phosphatidylcholine FAMILY 23556340 A 535 554 phosphatidylcholine FAMILY 23556340 A 563 575 stearylamine SYSTEMATIC 23556340 A 577 593 alpha-tocopherol TRIVIAL 23556340 A 598 681 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] SYSTEMATIC 23556340 A 683 691 PEG-DSPE ABBREVIATION 23556340 A 696 748 folate-polyethylene glycol-cholesteryl hemisuccinate FAMILY 23556340 A 750 761 F-PEG-CHEMS ABBREVIATION 23556340 A 889 906 cyclic dipeptides FAMILY 23556340 A 936 942 folate TRIVIAL 23556340 T 49 66 cyclic dipeptides FAMILY 23556340 T 68 82 cyclo(His-Gly) FORMULA 23556340 T 87 101 cyclo(His-Ala) FORMULA 23556343 A 1162 1170 methanol SYSTEMATIC 23556343 A 1373 1381 methanol SYSTEMATIC 23556343 A 1587 1591 DPPH ABBREVIATION 23556343 A 1616 1624 methanol SYSTEMATIC 23556343 A 234 249 Dichloromethane SYSTEMATIC 23556343 A 251 259 methanol SYSTEMATIC 23556343 A 867 875 methanol SYSTEMATIC 23556438 A 160 164 HOCO FORMULA 23556438 A 169 173 DOCO FORMULA 23556438 A 67 71 HOCO FORMULA 23556438 T 30 43 Hydrocarboxyl SYSTEMATIC 23557033 A 282 311 1,1-diphenyl-2-picrylhydrazyl SYSTEMATIC 23557033 A 321 331 β-carotene TRIVIAL 23557033 A 332 345 linoleic acid TRIVIAL 23557033 A 440 450 flavonoids FAMILY 23557033 A 465 472 tannins FAMILY 23557092 A 181 207 P(MAGP-co-DMAEMA)-b-PPDSMA ABBREVIATION 23557092 A 242 331 poly((6-O-methacryloyl-1,2:3,4-di-O-isopropylidene-d-galactopyranose)-co-DMAEMA)-b-PPDSMA FAMILY 23557092 A 333 361 P(MAlpGP-co-DMAEMA)-b-PPDSMA ABBREVIATION 23557092 A 462 467 PDSMA ABBREVIATION 23557092 A 474 493 P(MAlpGP-co-DMAEMA) ABBREVIATION 23557092 A 49 179 poly(6-O-methacryloyl-d-galactopyranose-co-2-(N,N-dimethylaminoethyl) methacrylate)-b-poly(pyridyl disulfide ethyl methylacrylate) FAMILY 23557092 A 628 654 P(MAGP-co-DMAEMA)-b-PPDSMA ABBREVIATION 23557092 A 688 699 Doxorubicin TRIVIAL 23557092 A 701 704 DOX ABBREVIATION 23557092 A 731 757 P(MAGP-co-DMAEMA)-b-PPDSMA ABBREVIATION 23557092 A 802 813 glutathione TRIVIAL 23557092 A 815 818 GSH ABBREVIATION 23557092 A 851 860 galactose TRIVIAL 23557092 A 886 891 PMAGP ABBREVIATION 23557092 A 945 971 P(MAGP-co-DMAEMA)-b-PPDSMA ABBREVIATION 23557092 T 0 9 Galactose TRIVIAL 23557591 A 1263 1270 glucose TRIVIAL 23557591 A 1310 1317 glucose TRIVIAL 23557591 A 1388 1399 cholesterol TRIVIAL 23557591 A 541 548 glucose TRIVIAL 23557686 A 144 162 4-tert-octylphenol SYSTEMATIC 23557686 A 277 285 estrogen FAMILY 23557686 A 286 297 ICI 182,780 IDENTIFIER 23557686 A 369 377 estrogen FAMILY 23557686 A 750 754 cAMP ABBREVIATION 23557686 A 759 767 androgen FAMILY 23557686 T 31 39 estrogen FAMILY 23557686 T 5 23 4-tert-octylphenol SYSTEMATIC 23557706 A 1210 1215 NADPH ABBREVIATION 23557706 A 161 170 rapamycin TRIVIAL 23557706 A 282 289 glucose TRIVIAL 23557706 A 443 448 NADPH ABBREVIATION 23557706 A 498 507 rapamycin TRIVIAL 23557706 A 544 549 NADPH ABBREVIATION 23557706 A 874 879 NADPH ABBREVIATION 23557706 A 934 943 rapamycin TRIVIAL 23557746 A 15 23 hydrogen SYSTEMATIC 23557746 A 29 37 fluorine SYSTEMATIC 23557840 A 110 126 monoacylglycerol SYSTEMATIC 23557840 A 341 363 1,3,4-oxadiazol-2-ones FAMILY 23557840 A 72 88 fatty acid amide FAMILY 23557840 T 0 22 1,3,4-Oxadiazol-2-ones FAMILY 23557840 T 26 42 fatty-acid amide FAMILY 23557840 T 57 73 monoacylglycerol SYSTEMATIC 23557842 A 1275 1283 Carbopol TRIVIAL 23557842 A 557 565 Carbopol TRIVIAL 23557842 A 90 115 terbinafine hydrochloride SYSTEMATIC 23557842 T 97 122 terbinafine hydrochloride SYSTEMATIC 23557932 A 0 14 5-Fluorouracil SYSTEMATIC 23557932 A 1031 1035 5-FU SYSTEMATIC 23557932 A 1088 1092 5-FU SYSTEMATIC 23557932 A 1196 1200 5-FU SYSTEMATIC 23557932 A 1311 1315 5-FU SYSTEMATIC 23557932 A 1401 1405 5-FU SYSTEMATIC 23557932 A 16 20 5-FU SYSTEMATIC 23557932 A 339 343 5-FU SYSTEMATIC 23557932 A 568 572 5-FU SYSTEMATIC 23557932 A 739 743 5-FU SYSTEMATIC 23557932 A 901 905 5-FU SYSTEMATIC 23557932 T 20 34 5-fluorouracil SYSTEMATIC 23557989 A 813 823 nucleotide FAMILY 23557993 A 1109 1113 DPHD ABBREVIATION 23557993 A 1137 1145 estrogen FAMILY 23557993 A 1166 1175 ICI182780 IDENTIFIER 23557993 A 1201 1205 DPHD ABBREVIATION 23557993 A 1302 1306 DPHD ABBREVIATION 23557993 A 1403 1416 17β-estradiol SYSTEMATIC 23557993 A 1427 1431 DPHD ABBREVIATION 23557993 A 1533 1546 17β-estradiol SYSTEMATIC 23557993 A 1565 1569 DPHD ABBREVIATION 23557993 A 239 254 diarylheptanoid FAMILY 23557993 A 255 299 (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol SYSTEMATIC 23557993 A 301 305 DPHD ABBREVIATION 23557993 A 371 375 DPHD ABBREVIATION 23557993 A 454 458 DPHD ABBREVIATION 23557993 A 561 565 DPHD ABBREVIATION 23557993 A 578 591 17β-estradiol SYSTEMATIC 23557993 A 680 684 DPHD ABBREVIATION 23557993 A 715 719 DPHD ABBREVIATION 23557993 A 875 879 DPHD ABBREVIATION 23557993 A 969 973 DPHD ABBREVIATION 23557993 T 2 17 diarylheptanoid FAMILY 23557993 T 53 84 1,7-diphenyl-4,6-heptadien-3-ol SYSTEMATIC 23558202 A 105 110 EtOAc FORMULA 23558202 A 63 77 (-)-Palitantin TRIVIAL 23558202 A 9 22 cyclohexanone SYSTEMATIC 23558202 T 0 13 Cyclohexanone SYSTEMATIC 23558600 A 335 342 glucose TRIVIAL 23558678 A 81 88 luminal TRIVIAL 23558743 A 1219 1229 nucleotide FAMILY 23558743 A 1273 1283 nucleotide FAMILY 23558743 A 1316 1326 nucleotide FAMILY 23558743 A 161 171 guanosines FAMILY 23558743 A 912 922 nucleotide FAMILY 23559145 A 1134 1148 cyclosporine A TRIVIAL 23559145 A 1150 1153 CsA ABBREVIATION 23559145 A 1259 1262 CsA ABBREVIATION 23559483 A 1009 1030 7-iodo-7-deazaadenine SYSTEMATIC 23559483 A 1117 1123 7-iodo SYSTEMATIC 23559483 A 1128 1137 7-ethynyl SYSTEMATIC 23559483 A 1169 1225 2'-deoxy-2',2'-difluororibonucleoside 5'-O-triphosphates FAMILY 23559483 A 12 17 sugar FAMILY 23559483 A 164 168 aryl FAMILY 23559483 A 172 182 heteroaryl FAMILY 23559483 A 258 281 difluororibonucleosides FAMILY 23559483 A 337 359 6-chloro-7-deazapurine SYSTEMATIC 23559483 A 365 439 benzoyl-protected 2-deoxy-2,2-difluoro-D-erythro-pentofuranosyl-1-mesylate SYSTEMATIC 23559483 A 503 525 (het)arylboronic acids FAMILY 23559483 A 53 83 7-heteroaryl-7-deazaadenosines FAMILY 23559483 A 531 541 fluororibo SYSTEMATIC 23559483 A 579 588 palladium SYSTEMATIC 23559483 A 645 699 7-iodo-7-deazaadenine 2'-deoxy-2'-fluororibonucleoside SYSTEMATIC 23559483 A 708 730 (het)arylboronic acids FAMILY 23559483 A 815 832 arabinonucleoside FAMILY 23559483 A 85 151 2'-deoxy-2'-fluororibo- and 2'-deoxy-2',2'-difluororibonucleosides MULTIPLE 23559483 A 860 878 3'- and 5'-hydroxy MULTIPLE 23559483 A 993 1004 nucleosides FAMILY 23559483 T 133 160 7-(Het)aryl-7-deazaadenines FAMILY 23559483 T 53 119 2'-Deoxy-2',2'-difluororibo- and 2'-Deoxy-2'-fluororibonucleosides MULTIPLE 23560542 A 103 106 OTA ABBREVIATION 23560542 A 1056 1072 5'-monophosphate SYSTEMATIC 23560542 A 1130 1146 syn (nucleotide) FAMILY 23560542 A 1184 1193 phosphate SYSTEMATIC 23560542 A 1221 1226 amino FAMILY 23560542 A 1236 1243 guanine TRIVIAL 23560542 A 1348 1354 OTB-dG ABBREVIATION 23560542 A 1406 1414 cytosine TRIVIAL 23560542 A 1507 1517 nucleoside FAMILY 23560542 A 1522 1532 nucleotide FAMILY 23560542 A 191 201 nucleobase FAMILY 23560542 A 291 308 2'-deoxyguanosine SYSTEMATIC 23560542 A 359 369 nucleobase FAMILY 23560542 A 48 55 guanine TRIVIAL 23560542 A 501 504 OTA ABBREVIATION 23560542 A 548 558 nucleobase FAMILY 23560542 A 582 599 deoxyribose sugar TRIVIAL 23560542 A 657 660 C-C FORMULA 23560542 A 699 702 OTA ABBREVIATION 23560542 A 722 732 nucleoside FAMILY 23560542 A 817 820 OTA ABBREVIATION 23560542 A 865 866 H FORMULA 23560542 A 89 101 ochratoxin A TRIVIAL 23560542 A 904 912 hydrogen SYSTEMATIC 23560542 T 100 117 2'-Deoxyguanosine SYSTEMATIC 23560542 T 121 133 Ochratoxin A TRIVIAL 23560542 T 46 52 Carbon SYSTEMATIC 23560650 A 213 218 amino FAMILY 23560650 A 62 97 hexahydro-2H-pyrano[3,2-c]quinoline SYSTEMATIC 23560650 A 842 851 capsaicin TRIVIAL 23560650 A 856 864 formalin TRIVIAL 23560650 T 55 91 Hexahydro-2H-pyrano[3,2-c]quinolines FAMILY 23560689 A 36 53 mycoleptodiscin A TRIVIAL 23560689 A 380 386 indole SYSTEMATIC 23560689 A 387 395 terpenes FAMILY 23560689 A 436 453 Mycoleptodiscin B TRIVIAL 23560689 A 62 79 mycoleptodiscin B TRIVIAL 23560689 T 0 24 Mycoleptodiscins A and B MULTIPLE 23560747 A 591 602 polystyrene SYSTEMATIC 23560747 A 901 912 polystyrene SYSTEMATIC 23560913 A 120 126 oxygen SYSTEMATIC 23560913 A 18 20 Pt FORMULA 23560913 A 184 186 Pt FORMULA 23560913 A 327 329 Pt FORMULA 23560913 A 455 457 Pt FORMULA 23560913 A 581 583 Pt FORMULA 23560913 A 692 694 Pt FORMULA 23560913 T 56 58 Pt FORMULA 23560913 T 81 87 Oxygen SYSTEMATIC 23561070 A 1011 1023 anthocyanins FAMILY 23561070 A 177 188 anthocyanin FAMILY 23561070 A 283 287 DPPH ABBREVIATION 23561070 A 317 321 ABTS ABBREVIATION 23561070 A 370 376 oxygen SYSTEMATIC 23561070 A 4 16 anthocyanins FAMILY 23561070 A 426 437 anthocyanin FAMILY 23561070 A 519 531 anthocyanins FAMILY 23561070 A 636 658 cyanidin-3-O-glucoside SYSTEMATIC 23561070 A 660 682 peonidin-3-O-glucoside SYSTEMATIC 23561070 A 684 706 malvidin-3-O-glucoside SYSTEMATIC 23561070 A 708 731 petunidin-3-O-glucoside SYSTEMATIC 23561070 A 733 758 delphinidin-3-O-glucoside SYSTEMATIC 23561070 A 763 787 pelargonidin-3-glucoside SYSTEMATIC 23561070 A 83 86 TFA ABBREVIATION 23561070 A 854 876 Cyanidin-3-O-glucoside SYSTEMATIC 23561070 A 90 98 methanol SYSTEMATIC 23561070 A 913 924 anthocyanin FAMILY 23561070 T 103 115 anthocyanins FAMILY 23561070 T 24 36 anthocyanins FAMILY 23561073 A 146 156 salbutamol TRIVIAL 23561073 A 158 161 SAL ABBREVIATION 23561073 A 536 539 RAC ABBREVIATION 23561073 A 579 582 RAC ABBREVIATION 23561073 A 66 91 ractopamine hydrochloride SYSTEMATIC 23561073 A 762 765 RAC ABBREVIATION 23561073 A 93 96 RAC ABBREVIATION 23561073 T 86 97 ractopamine TRIVIAL 23561074 A 111 117 carbon SYSTEMATIC 23561074 A 359 399 acetic, citric, succinic and malic acids MULTIPLE 23561074 A 537 545 glycerol TRIVIAL 23561074 A 549 597 succinic, acetic, citric, malic and oxalic acids MULTIPLE 23561074 A 645 678 succinic, oxalic and acetic acids MULTIPLE 23561074 A 765 776 oxalic acid TRIVIAL 23561074 A 782 790 glycerol TRIVIAL 23561074 A 899 907 glycerol TRIVIAL 23561074 A 99 107 glycerol TRIVIAL 23561074 T 108 116 glycerol TRIVIAL 23561077 A 15 37 ethylene-vinyl alcohol SYSTEMATIC 23561077 A 49 53 EVOH FORMULA 23561077 A 66 75 flavonoid FAMILY 23561077 A 723 740 hydrogen peroxide SYSTEMATIC 23561078 A 112 122 flavonoids FAMILY 23561078 A 339 343 DPPH ABBREVIATION 23561078 A 345 349 ABTS ABBREVIATION 23561078 A 351 359 hydroxyl SYSTEMATIC 23561078 A 374 384 superoxide TRIVIAL 23561078 A 598 613 malondialdehyde TRIVIAL 23561078 A 625 635 superoxide TRIVIAL 23561078 A 650 661 glutathione TRIVIAL 23561078 A 729 740 glutathione TRIVIAL 23561078 A 799 803 CCl4 FORMULA 23561078 T 93 103 flavonoids FAMILY 23561083 A 1010 1018 phenolic FAMILY 23561083 A 116 124 phenolic FAMILY 23561083 A 1179 1187 phenolic FAMILY 23561083 A 1467 1475 phenolic FAMILY 23561083 A 1515 1523 phenolic FAMILY 23561083 A 212 219 alcohol FAMILY 23561083 A 35 43 phenolic FAMILY 23561083 A 395 403 phenolic FAMILY 23561083 A 460 468 phenolic FAMILY 23561083 A 502 515 linoleic acid TRIVIAL 23561083 A 516 526 β-carotene TRIVIAL 23561083 A 552 560 phenolic FAMILY 23561083 A 631 639 phenolic FAMILY 23561083 A 744 752 phenolic FAMILY 23561083 A 828 836 phenolic FAMILY 23561083 A 902 910 methanol SYSTEMATIC 23561083 A 930 938 phenolic FAMILY 23561083 T 50 58 phenolic FAMILY 23561088 A 104 133 delphinidin 3,5-O-diglucoside SYSTEMATIC 23561088 A 135 140 D3G5G SYSTEMATIC 23561088 A 146 188 delphinidin 3-O-sambubioside-5-O-glucoside SYSTEMATIC 23561088 A 190 195 D3S5G SYSTEMATIC 23561088 A 341 352 tetrazolium SYSTEMATIC 23561088 A 376 389 Hoechst 33342 TRIVIAL 23561088 A 441 446 D3G5G SYSTEMATIC 23561088 A 452 457 D3S5G SYSTEMATIC 23561088 A 530 536 oxygen SYSTEMATIC 23561088 A 567 644 5-(and-6)-chloromethyl-2,7-dichlorodihydro fluorescein diacetate acetyl ester MULTIPLE 23561088 A 646 656 CM-H2DCFDA ABBREVIATION 23561088 A 686 698 anthocyanins FAMILY 23561088 A 90 102 anthocyanins FAMILY 23561088 A 903 917 anthocyanidins FAMILY 23561088 T 56 77 delphinidin glycoside FAMILY 23561099 A 0 17 Indole-3-carbinol SYSTEMATIC 23561099 A 19 22 I3C SYSTEMATIC 23561099 A 235 248 carboxymethyl SYSTEMATIC 23561099 A 28 49 3,3'-diindolylmethane SYSTEMATIC 23561099 A 308 311 I3C SYSTEMATIC 23561099 A 316 319 DIM ABBREVIATION 23561099 A 51 54 DIM ABBREVIATION 23561099 A 612 615 I3C SYSTEMATIC 23561099 A 620 623 DIM ABBREVIATION 23561099 A 713 716 I3C SYSTEMATIC 23561099 A 721 724 DIM ABBREVIATION 23561099 A 905 908 I3C SYSTEMATIC 23561099 A 982 985 DIM ABBREVIATION 23561099 T 17 34 indole-3-carbinol SYSTEMATIC 23561099 T 39 60 3,3'-diindolylmethane SYSTEMATIC 23561099 T 69 82 carboxymethyl SYSTEMATIC 23561104 A 559 570 lactic acid TRIVIAL 23561107 A 1082 1087 Thiol SYSTEMATIC 23561107 A 1298 1304 silver SYSTEMATIC 23561107 A 1361 1367 silver SYSTEMATIC 23561107 A 298 304 silver SYSTEMATIC 23561107 A 351 357 Silver SYSTEMATIC 23561107 A 402 408 silver SYSTEMATIC 23561107 A 437 445 chloride SYSTEMATIC 23561107 A 485 500 silver chloride SYSTEMATIC 23561107 A 605 614 chlorides FAMILY 23561107 A 785 790 thiol FAMILY 23561107 A 821 827 silver SYSTEMATIC 23561107 A 835 848 methylsulphur SYSTEMATIC 23561107 A 9 15 silver SYSTEMATIC 23561107 T 18 24 silver SYSTEMATIC 23561108 A 1008 1015 tannins FAMILY 23561108 A 1043 1051 flavonol TRIVIAL 23561108 A 1078 1090 anthocyanins FAMILY 23561108 A 1177 1181 DPPH ABBREVIATION 23561108 A 1346 1355 phenolics FAMILY 23561108 A 1414 1426 polyphenolic FAMILY 23561108 A 1568 1593 3-O-(6″-O-galloyl)-hexose SYSTEMATIC 23561108 A 1609 1618 myricetin TRIVIAL 23561108 A 1620 1629 quercetin TRIVIAL 23561108 A 1631 1641 laricitrin TRIVIAL 23561108 A 1646 1658 isorhamnetin TRIVIAL 23561108 A 324 332 phenolic FAMILY 23561108 A 486 495 phenolics FAMILY 23561108 A 544 552 phenolic FAMILY 23561108 A 763 771 phenolic FAMILY 23561108 T 22 34 polyphenolic FAMILY 23561108 T 83 91 phenolic FAMILY 23561111 A 632 641 disulfide SYSTEMATIC 23561111 A 656 661 amide FAMILY 23561111 A 667 672 amide FAMILY 23561111 A 681 686 amide FAMILY 23561111 A 712 720 carboxyl SYSTEMATIC 23561112 A 0 9 Histamine TRIVIAL 23561112 A 11 21 putrescine TRIVIAL 23561112 A 168 171 UCA ABBREVIATION 23561112 A 22 32 cadaverine TRIVIAL 23561112 A 37 54 cis-urocanic acid TRIVIAL 23561112 A 376 385 trans-UCA ABBREVIATION 23561112 A 397 404 cis-UCA ABBREVIATION 23561112 A 419 429 cadaverine TRIVIAL 23561112 A 431 440 Histamine TRIVIAL 23561112 A 445 455 putrescine TRIVIAL 23561112 A 502 511 trans-UCA ABBREVIATION 23561112 A 56 59 UCA ABBREVIATION 23561112 A 674 683 trans-UCA ABBREVIATION 23561112 A 748 755 cis-UCA ABBREVIATION 23561112 A 858 867 Histamine TRIVIAL 23561112 A 869 879 putrescine TRIVIAL 23561112 A 884 894 cadaverine TRIVIAL 23561112 T 11 24 urocanic acid TRIVIAL 23561112 T 26 35 histamine TRIVIAL 23561112 T 37 47 putrescine TRIVIAL 23561112 T 52 62 cadaverine TRIVIAL 23561126 A 1003 1010 glucose TRIVIAL 23561126 A 114 121 glucose TRIVIAL 23561126 A 196 201 CaCl2 FORMULA 23561126 A 666 673 glucose TRIVIAL 23561126 T 101 113 polyhydroxyl SYSTEMATIC 23561129 A 1322 1326 MeIQ ABBREVIATION 23561129 A 134 153 heterocyclic amines FAMILY 23561129 A 1480 1485 MeIQx ABBREVIATION 23561129 A 1490 1497 Glu-P-1 TRIVIAL 23561129 A 1523 1527 HACs FAMILY 23561129 A 155 159 HCAs ABBREVIATION 23561129 A 434 438 HCAs ABBREVIATION 23561129 A 440 480 2-amino-3-methylimidazo-[4,5-f]quinoline SYSTEMATIC 23561129 A 487 531 2-amino-3,4-dimethylimidazo-[4,5-f]quinoline SYSTEMATIC 23561129 A 533 537 MeIQ ABBREVIATION 23561129 A 540 586 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline SYSTEMATIC 23561129 A 588 593 MeIQx ABBREVIATION 23561129 A 600 610 imidazoles FAMILY 23561129 A 611 660 2-amino-6-methyldipyrido-[1,2-a:3',2'-d]imidazole SYSTEMATIC 23561129 A 662 669 Glu-P-1 TRIVIAL 23561129 A 675 715 2-aminodipirydo-[1,2-a:3',2'-d]imidazole SYSTEMATIC 23561129 A 717 724 Glu-P-2 TRIVIAL 23561129 A 731 735 HCAs ABBREVIATION 23561129 A 805 809 MeIQ ABBREVIATION 23561129 A 850 855 MeIQx ABBREVIATION 23561129 A 860 867 Glu-P-1 TRIVIAL 23561129 A 894 901 Glu-P-2 TRIVIAL 23561129 A 931 935 HACs FAMILY 23561129 T 122 141 heterocyclic amines FAMILY 23561132 A 133 140 sterols FAMILY 23561132 A 175 181 sterol FAMILY 23561132 A 214 223 oxysterol FAMILY 23561132 A 32 39 sterols FAMILY 23561132 A 396 408 β-sitosterol TRIVIAL 23561132 A 447 453 oxygen SYSTEMATIC 23561132 A 554 564 silica gel TRIVIAL 23561132 A 737 749 β-sitosterol TRIVIAL 23561132 A 795 820 3β,3β'-disitosteryl ether SYSTEMATIC 23561132 A 996 1011 disteryl ethers FAMILY 23561132 T 83 95 β-sitosterol TRIVIAL 23561151 A 0 9 Phenolics FAMILY 23561151 A 118 129 anthocyanin FAMILY 23561151 A 234 245 anthocyanin FAMILY 23561151 A 420 431 anthocyanin FAMILY 23561151 A 459 471 anthocyanins FAMILY 23561151 A 568 580 anthocyanins FAMILY 23561151 A 758 770 anthocyanins FAMILY 23561151 A 772 797 cyanidin 3-O-sambubioside SYSTEMATIC 23561151 A 799 821 cyanidin 3-O-glucoside SYSTEMATIC 23561151 A 823 853 cyanidin 3-O-xylosylrutinoside SYSTEMATIC 23561151 A 859 882 cyanidin 3-O-rutinoside SYSTEMATIC 23561151 A 94 105 anthocyanin FAMILY 23561151 A 947 959 anthocyanins FAMILY 23561151 T 0 12 Anthocyanins FAMILY 23561153 A 1192 1196 H(1) FORMULA 23561153 A 164 168 NaOH FORMULA 23561153 A 173 176 KOH FORMULA 23561159 A 483 489 lutein TRIVIAL 23561159 A 494 504 zeaxanthin TRIVIAL 23561159 A 569 575 Lutein TRIVIAL 23561159 A 580 590 zeaxanthin TRIVIAL 23561159 A 665 675 zeaxanthin TRIVIAL 23561159 A 708 714 lutein TRIVIAL 23561159 A 834 838 DPPH ABBREVIATION 23561167 A 1017 1019 Al FORMULA 23561167 A 1021 1022 B FORMULA 23561167 A 1024 1026 Cu FORMULA 23561167 A 1028 1030 Fe FORMULA 23561167 A 1032 1033 P FORMULA 23561167 A 1035 1036 K FORMULA 23561167 A 1038 1040 Mn FORMULA 23561167 A 1042 1044 Ni FORMULA 23561167 A 1046 1048 Zn FORMULA 23561167 A 1103 1105 Ca FORMULA 23561167 A 1127 1129 Mg FORMULA 23561167 A 1374 1375 B FORMULA 23561167 A 1411 1413 Mg FORMULA 23561167 A 1545 1547 Mn FORMULA 23561167 A 1626 1628 Al FORMULA 23561167 A 21 23 Al FORMULA 23561167 A 25 26 B FORMULA 23561167 A 28 30 Cu FORMULA 23561167 A 32 34 Fe FORMULA 23561167 A 36 38 Mn FORMULA 23561167 A 40 42 Ni FORMULA 23561167 A 44 45 P FORMULA 23561167 A 451 453 Al FORMULA 23561167 A 47 49 Zn FORMULA 23561167 A 54 56 Ca FORMULA 23561167 A 58 59 K FORMULA 23561167 A 61 63 Mg FORMULA 23561167 A 707 709 Al FORMULA 23561167 A 823 825 Al FORMULA 23561167 A 827 829 Fe FORMULA 23561167 A 831 832 K FORMULA 23561167 A 834 836 Mn FORMULA 23561167 A 838 840 Ni FORMULA 23561167 A 842 844 Zn FORMULA 23561167 A 849 850 B FORMULA 23561167 A 852 854 Mg FORMULA 23561167 A 856 857 P FORMULA 23561167 A 913 915 Ca FORMULA 23561167 A 938 940 Cu FORMULA 23561167 A 945 946 P FORMULA 23561167 T 0 9 Aluminium SYSTEMATIC 23561168 A 1011 1017 ferric SYSTEMATIC 23561168 A 1049 1055 Trolox TRIVIAL 23561168 A 357 365 phenolic FAMILY 23561168 A 393 421 1,1-diphenyl-2-pireyhydrazyl SYSTEMATIC 23561168 A 454 462 hydroxyl SYSTEMATIC 23561168 A 550 558 naringin TRIVIAL 23561168 A 563 573 naringenin TRIVIAL 23561168 A 589 599 flavonoids FAMILY 23561168 A 733 744 cholesterol TRIVIAL 23561168 A 766 777 cholesterol TRIVIAL 23561168 A 800 809 bile acid FAMILY 23561168 A 942 951 phenolics FAMILY 23561180 A 124 135 vinblastine TRIVIAL 23561180 A 137 146 vindoline TRIVIAL 23561180 A 148 158 ajmalicine TRIVIAL 23561180 A 160 173 catharanthine TRIVIAL 23561180 A 179 191 vinleurosine TRIVIAL 23561180 A 574 585 vinblastine TRIVIAL 23561180 A 587 596 vindoline TRIVIAL 23561180 A 598 608 ajmalicine TRIVIAL 23561180 A 610 623 catharanthine TRIVIAL 23561180 A 629 641 vinleurosine TRIVIAL 23561186 A 146 157 amino acids FAMILY 23561186 A 167 173 valine TRIVIAL 23561186 A 23 64 E-(+)-S-(1-propenyl)-l-cysteine sulfoxide SYSTEMATIC 23561186 A 248 257 carbonyls FAMILY 23561186 A 325 338 cepathiolanes NO CLASS 23561186 A 343 351 l-valine TRIVIAL 23561186 A 375 388 cepathiolanes NO CLASS 23561186 A 444 456 formaldehyde SYSTEMATIC 23561186 A 587 707 2-(2-(1-(1-carboxy-2-methylpropyl)-3,4-dimethyl-1H-pyrrol-2-yl)methyl-3,4-dimethyl-1H-pyrrol-1-yl)-3-methylbutanoic acid SYSTEMATIC 23561193 A 1084 1091 phenols FAMILY 23561193 A 318 326 phenolic FAMILY 23561193 A 331 340 flavonoid FAMILY 23561193 A 523 552 1,1-diphenyl-2-picrylhydrazyl SYSTEMATIC 23561193 A 554 559 DPPH· ABBREVIATION 23561193 A 565 573 hydroxyl SYSTEMATIC 23561193 A 974 982 phenolic FAMILY 23561193 A 987 996 flavonoid FAMILY 23561200 A 139 149 fatty acid FAMILY 23561200 A 350 376 palmitic and stearic acids MULTIPLE 23561200 A 386 407 saturated fatty acids FAMILY 23561200 A 409 444 Oleic, linoleic and linolenic acids MULTIPLE 23561200 A 460 483 unsaturated fatty acids FAMILY 23561200 A 529 540 fatty acids FAMILY 23561200 A 739 749 Fatty acid FAMILY 23561200 T 0 10 Fatty acid FAMILY 23561202 A 129 133 TBHQ ABBREVIATION 23561202 A 200 206 silica TRIVIAL 23561202 A 243 249 silica TRIVIAL 23561202 A 283 315 (3-chloropropyl) trimethoxysilan SYSTEMATIC 23561202 A 320 336 polyethylenimine SYSTEMATIC 23561202 A 392 422 ethylene glycol dimethacrylate SYSTEMATIC 23561202 A 71 93 tert-butylhydroquinone SYSTEMATIC 23561202 A 837 841 TBHQ ABBREVIATION 23561202 A 95 99 TBHQ ABBREVIATION 23561202 T 0 22 Tert-butylhydroquinone SYSTEMATIC 23561205 A 0 8 Curcumin TRIVIAL 23561205 A 179 187 curcumin TRIVIAL 23561205 A 601 609 curcumin TRIVIAL 23561205 A 682 690 Curcumin TRIVIAL 23561205 A 828 836 curcumin TRIVIAL 23561205 A 954 962 curcumin TRIVIAL 23561205 T 0 8 Curcumin TRIVIAL 23561207 A 1443 1447 PAHs ABBREVIATION 23561207 A 1561 1565 PAHs ABBREVIATION 23561207 A 163 195 polycyclic aromatic hydrocarbons FAMILY 23561207 A 1638 1641 PAH ABBREVIATION 23561207 A 197 201 PAHs ABBREVIATION 23561207 A 444 448 PAHs ABBREVIATION 23561207 A 479 483 PAHs ABBREVIATION 23561207 A 789 799 silica gel TRIVIAL 23561207 A 804 812 florisil TRIVIAL 23561207 A 872 876 PAHs ABBREVIATION 23561207 T 78 110 polycyclic aromatic hydrocarbons FAMILY 23561210 A 1068 1075 glucose TRIVIAL 23561210 A 301 308 glucose TRIVIAL 23561210 A 312 323 glucosamine TRIVIAL 23561210 A 376 381 Sugar FAMILY 23561210 A 725 730 sugar FAMILY 23561210 A 954 965 Glucosamine TRIVIAL 23561210 T 57 68 glucosamine TRIVIAL 23561215 A 100 104 EGCG ABBREVIATION 23561215 A 210 214 EGCG ABBREVIATION 23561215 A 268 274 sugars FAMILY 23561215 A 370 376 sugars FAMILY 23561215 A 443 447 EGCG ABBREVIATION 23561215 A 544 550 sugars FAMILY 23561215 A 62 68 sugars FAMILY 23561215 A 625 627 O2 FORMULA 23561215 A 667 673 oxygen SYSTEMATIC 23561215 A 714 730 transition metal FAMILY 23561215 A 72 98 epigallocatechin-3-gallate SYSTEMATIC 23561215 A 808 814 sugars FAMILY 23561215 A 850 856 sugars FAMILY 23561215 A 918 924 sugars FAMILY 23561215 A 971 975 EGCG ABBREVIATION 23561215 T 14 24 saccharide FAMILY 23561215 T 44 70 epigallocatechin-3-gallate SYSTEMATIC 23561216 A 103 106 SSL ABBREVIATION 23561216 A 112 129 monoacylglycerols FAMILY 23561216 A 131 134 MAG ABBREVIATION 23561216 A 241 244 SSL ABBREVIATION 23561216 A 253 256 MAG ABBREVIATION 23561216 A 601 604 SSL ABBREVIATION 23561216 A 632 644 carbohydrate FAMILY 23561216 A 739 742 SSL ABBREVIATION 23561216 A 76 101 sodium stearoyl lactylate SYSTEMATIC 23561216 A 856 859 SSL ABBREVIATION 23561216 A 863 866 MAG ABBREVIATION 23561218 A 491 509 aflatoxins B and G MULTIPLE 23561218 A 519 537 cyclopiazonic acid TRIVIAL 23561218 A 539 542 CPA ABBREVIATION 23561218 A 852 862 aflatoxins FAMILY 23561218 A 867 870 CPA ABBREVIATION 23561221 A 135 146 citric acid TRIVIAL 23561221 A 787 793 esters FAMILY 23562061 A 0 9 Ostreol A TRIVIAL 23562061 A 185 196 polyhydroxy FAMILY 23562061 A 219 232 primary amino FAMILY 23562061 A 255 260 amide FAMILY 23562061 A 282 297 tetrahydropyran SYSTEMATIC 23562061 T 0 9 Ostreol A TRIVIAL 23562062 A 12 122 (S)-2-(2-(diethylamino)-5-(N-alkyl-N-sulfonamido)pyrimidin-4-ylamino)-3-(4-(carbamoyloxy)phenyl)propanoic acid FAMILY 23562062 T 0 27 Arylsulfonamide pyrimidines FAMILY 23562495 A 1035 1044 glutamate TRIVIAL 23562495 A 11 30 Citronellyl acetate TRIVIAL 23562495 A 1125 1128 CAT ABBREVIATION 23562495 A 1148 1151 CAT ABBREVIATION 23562495 A 1280 1283 CAT ABBREVIATION 23562495 A 1321 1330 capsaicin TRIVIAL 23562495 A 1344 1358 cinnamaldehyde TRIVIAL 23562495 A 1373 1380 menthol TRIVIAL 23562495 A 1420 1431 acetic acid SYSTEMATIC 23562495 A 1682 1685 CAT ABBREVIATION 23562495 A 1790 1793 CAT ABBREVIATION 23562495 A 1861 1870 glutamate TRIVIAL 23562495 A 1909 1912 CAT ABBREVIATION 23562495 A 32 35 CAT ABBREVIATION 23562495 A 328 331 CAT ABBREVIATION 23562495 A 345 356 acetic acid SYSTEMATIC 23562495 A 40 51 monoterpene FAMILY 23562495 A 441 450 glutamate TRIVIAL 23562495 A 455 463 formalin TRIVIAL 23562495 A 522 525 CAT ABBREVIATION 23562495 A 692 695 CAT ABBREVIATION 23562495 A 825 836 acetic acid SYSTEMATIC 23562495 A 926 934 formalin TRIVIAL 23562495 A 954 957 CAT ABBREVIATION 23562495 T 60 79 citronellyl acetate SYSTEMATIC 23562497 A 1146 1153 calcium SYSTEMATIC 23562497 A 1209 1222 acetylcholine SYSTEMATIC 23562497 A 348 355 calcium SYSTEMATIC 23562497 A 785 786 C FORMULA 23562497 T 207 208 C FORMULA 23562497 T 98 99 C FORMULA 23562533 A 0 55 Poly(N-isopropylacrylamide-co-N-hydroxyethylacrylamide) FAMILY 23562533 A 1348 1360 indomethacin TRIVIAL 23562533 A 515 523 hydroxyl SYSTEMATIC 23562533 A 536 550 glutaraldehyde TRIVIAL 23562533 A 57 78 poly(NIPAAm-co-HEAAm) FAMILY 23562533 A 814 826 indomethacin TRIVIAL 23562533 T 0 53 Poly(N-isopropylacrylamide-co-hydroxyethylacrylamide) FAMILY 23562535 A 1013 1023 mesalamine TRIVIAL 23562535 A 1102 1112 mesalamine TRIVIAL 23562535 A 491 504 carboxymethyl SYSTEMATIC 23562535 T 0 13 Carboxymethyl SYSTEMATIC 23562535 T 94 104 Mesalamine TRIVIAL 23562611 A 1058 1061 PEO ABBREVIATION 23562611 A 1094 1098 APAP ABBREVIATION 23562611 A 1099 1102 PEO ABBREVIATION 23562611 A 148 161 acetaminophen TRIVIAL 23562611 A 163 167 APAP ABBREVIATION 23562611 A 1698 1702 APAP ABBREVIATION 23562611 A 172 192 poly(ethylene oxide) SYSTEMATIC 23562611 A 1755 1758 PEO ABBREVIATION 23562611 A 1775 1779 APAP ABBREVIATION 23562611 A 194 197 PEO ABBREVIATION 23562611 A 248 252 APAP ABBREVIATION 23562611 A 253 256 PEO ABBREVIATION 23562611 A 311 314 PEO ABBREVIATION 23562611 A 332 336 APAP ABBREVIATION 23562611 A 341 344 PEO ABBREVIATION 23562611 A 438 442 APAP ABBREVIATION 23562611 A 443 446 PEO ABBREVIATION 23562611 A 489 493 APAP ABBREVIATION 23562611 A 623 627 APAP ABBREVIATION 23562611 A 631 634 PEO ABBREVIATION 23562611 A 730 733 PEO ABBREVIATION 23562611 A 772 776 APAP ABBREVIATION 23562611 A 808 812 APAP ABBREVIATION 23562611 A 908 911 PEO ABBREVIATION 23562611 A 943 947 APAP ABBREVIATION 23562611 T 19 39 poly(ethylene oxide) SYSTEMATIC 23562611 T 45 58 acetaminophen TRIVIAL 23562632 A 223 232 imidazole SYSTEMATIC 23562803 A 1953 1966 curculigoside FAMILY 23562928 A 1048 1061 dinitrophenyl SYSTEMATIC 23562928 A 1063 1066 DNP ABBREVIATION 23562928 A 188 204 prostaglandin D2 TRIVIAL 23562928 A 206 210 PGD2 ABBREVIATION 23562928 A 408 412 PGD2 ABBREVIATION 23562928 A 552 556 PGD2 ABBREVIATION 23562928 A 59 67 n-hexane SYSTEMATIC 23562928 T 136 152 prostaglandin D2 TRIVIAL 23562928 T 30 36 hexane SYSTEMATIC 23564313 A 1013 1024 vinblastine TRIVIAL 23564313 A 1263 1274 vinblastine TRIVIAL 23564313 A 1481 1492 vinblastine TRIVIAL 23564313 A 1590 1601 vinblastine TRIVIAL 23564313 A 429 440 vinblastine TRIVIAL 23564313 A 645 662 Poly (ADP-ribose) FAMILY 23564313 A 681 692 vinblastine TRIVIAL 23564313 A 780 786 oxygen SYSTEMATIC 23564313 A 825 831 Ca(2+) FORMULA 23564313 A 906 907 N FORMULA 23564313 A 970 978 inositol TRIVIAL 23564313 T 0 11 Vinblastine TRIVIAL 23564370 A 1061 1069 carbaryl TRIVIAL 23564370 A 1545 1553 carbaryl TRIVIAL 23564370 A 1587 1590 ATP ABBREVIATION 23564370 A 1918 1926 carbaryl TRIVIAL 23564370 A 682 690 carbaryl TRIVIAL 23564651 A 440 474 tris(4-(pyridin-4-yl)phenyl) amine SYSTEMATIC 23564651 A 56 68 fluorophenyl SYSTEMATIC 23564651 A 70 83 methoxyphenyl SYSTEMATIC 23564651 A 89 98 pyridinyl SYSTEMATIC 23564651 A 9 23 triphenylamine SYSTEMATIC 23564651 T 49 62 Triarylamines FAMILY 23566055 A 394 425 omega-3 and omega-6 fatty acids MULTIPLE 23566055 A 582 593 fatty acids FAMILY 23566055 A 983 992 phosphate SYSTEMATIC 23566055 T 61 72 Fatty Acids FAMILY 23566057 A 363 370 ethanol SYSTEMATIC 23566059 A 1108 1119 resveratrol TRIVIAL 23566059 A 1230 1242 anthocyanins FAMILY 23566059 A 255 267 anthocyanins FAMILY 23566059 A 337 349 anthocyanins FAMILY 23566059 A 413 424 anthocyanin FAMILY 23566059 A 462 491 1,1-diphenyl-2-picrylhydrazyl SYSTEMATIC 23566059 A 504 510 ferric SYSTEMATIC 23566059 A 549 560 resveratrol TRIVIAL 23566059 A 732 744 anthocyanins FAMILY 23566059 A 802 813 resveratrol TRIVIAL 23566059 A 815 826 Resveratrol TRIVIAL 23566059 A 9 20 Polyphenols FAMILY 23566059 T 85 97 anthocyanins FAMILY 23566197 A 18 37 ureido-sulfonamides FAMILY 23566197 A 66 89 aminobenzenesulfonamide SYSTEMATIC 23566197 A 95 116 alkyl/aryl isocyanate MULTIPLE 23566197 T 6 17 sulfonamide SYSTEMATIC 23566650 A 1073 1081 tyrosine TRIVIAL 23566650 A 1096 1116 phosphatidylinositol TRIVIAL 23566650 A 1170 1173 FFA ABBREVIATION 23566650 A 1303 1310 glucose TRIVIAL 23566650 A 1372 1375 TAG ABBREVIATION 23566650 A 1380 1391 cholesterol TRIVIAL 23566650 A 1438 1441 TAG ABBREVIATION 23566650 A 1547 1554 glucose TRIVIAL 23566650 A 1568 1571 FFA ABBREVIATION 23566650 A 1605 1608 TAG ABBREVIATION 23566650 A 212 219 glucose TRIVIAL 23566650 A 233 249 free fatty acids FAMILY 23566650 A 251 255 FFAs FAMILY 23566650 A 364 371 glucose TRIVIAL 23566650 A 385 395 oleic acid TRIVIAL 23566650 A 519 528 Oil-red O TRIVIAL 23566650 A 602 619 triacylglycerides FAMILY 23566650 A 621 624 TAG ABBREVIATION 23566650 A 630 641 cholesterol TRIVIAL 23566650 A 686 693 glucose TRIVIAL 23566650 A 844 851 glucose TRIVIAL 23566650 T 26 41 free fatty acid FAMILY 23566650 T 5 12 glucose TRIVIAL 23566885 A 1023 1033 dichlorvos TRIVIAL 23566885 A 1038 1050 deltamethrin TRIVIAL 23566885 A 1079 1086 lactate FAMILY 23566885 A 1088 1110 trimethylamine-N-oxide SYSTEMATIC 23566885 A 1112 1116 TMAO ABBREVIATION 23566885 A 1119 1126 choline FAMILY 23566885 A 1131 1138 alanine TRIVIAL 23566885 A 1260 1270 dichlorvos TRIVIAL 23566885 A 1275 1287 deltamethrin TRIVIAL 23566885 A 1325 1332 acetone SYSTEMATIC 23566885 A 1334 1337 DMG ABBREVIATION 23566885 A 137 147 dichlorvos TRIVIAL 23566885 A 1375 1379 TMAO ABBREVIATION 23566885 A 1381 1388 alanine TRIVIAL 23566885 A 1390 1397 choline FAMILY 23566885 A 1402 1409 acetone SYSTEMATIC 23566885 A 1479 1489 dichlorvos TRIVIAL 23566885 A 149 161 deltamethrin TRIVIAL 23566885 A 1493 1505 deltamethrin TRIVIAL 23566885 A 1571 1581 dichlorvos TRIVIAL 23566885 A 1583 1595 deltamethrin TRIVIAL 23566885 A 346 358 deltamethrin TRIVIAL 23566885 A 380 392 deltamethrin TRIVIAL 23566885 A 397 407 dichlorvos TRIVIAL 23566885 A 478 488 dichlorvos TRIVIAL 23566885 A 493 505 deltamethrin TRIVIAL 23566885 A 543 550 lactate FAMILY 23566885 A 552 565 dimethylamine SYSTEMATIC 23566885 A 567 568 N FORMULA 23566885 A 592 599 glycine TRIVIAL 23566885 A 654 664 dichlorvos TRIVIAL 23566885 A 668 680 deltamethrin TRIVIAL 23566885 A 729 739 dichlorvos TRIVIAL 23566885 A 763 770 lactate FAMILY 23566885 A 775 782 alanine TRIVIAL 23566885 A 801 816 dimethylglycine SYSTEMATIC 23566885 A 818 821 DMG ABBREVIATION 23566885 A 897 904 lactate FAMILY 23566885 A 961 973 deltamethrin TRIVIAL 23566885 T 0 4 (1)H FORMULA 23566885 T 100 110 dichlorvos TRIVIAL 23566885 T 112 124 deltamethrin TRIVIAL 23567033 A 1785 1796 sappanone A TRIVIAL 23567033 A 1798 1813 protosappanin E TRIVIAL 23567033 A 1818 1834 neoprotosappanin TRIVIAL 23567033 A 1934 1945 sappanone A TRIVIAL 23567033 A 1947 1962 protosappanin E TRIVIAL 23567033 A 1964 1980 neoprotosappanin TRIVIAL 23567033 A 767 770 CO2 FORMULA 23567036 A 748 752 salt TRIVIAL 23567036 A 770 789 hexavalent chromium SYSTEMATIC 23567036 A 876 889 iron chromite SYSTEMATIC 23567044 A 825 832 (111)In FORMULA 23567241 A 1082 1090 parabens FAMILY 23567241 A 1209 1214 alkyl FAMILY 23567241 A 137 145 estrogen FAMILY 23567241 A 174 182 androgen FAMILY 23567241 A 232 240 parabens FAMILY 23567241 A 343 351 parabens FAMILY 23567241 A 40 48 parabens FAMILY 23567241 A 407 415 parabens FAMILY 23567241 A 428 433 alkyl FAMILY 23567241 A 475 488 heptylparaben SYSTEMATIC 23567241 A 498 511 pentylparaben SYSTEMATIC 23567241 A 738 746 parabens FAMILY 23567241 A 903 915 butylparaben SYSTEMATIC 23567241 T 103 111 androgen FAMILY 23567241 T 52 60 parabens FAMILY 23567241 T 73 81 estrogen FAMILY 23567243 A 0 4 DICO ABBREVIATION 23567243 A 185 189 DICO ABBREVIATION 23567243 A 213 217 DICO ABBREVIATION 23567243 A 301 305 DICO ABBREVIATION 23567243 A 36 45 flavonoid FAMILY 23567243 A 430 434 DICO ABBREVIATION 23567243 A 680 684 DICO ABBREVIATION 23567243 A 712 716 DICO ABBREVIATION 23567243 A 830 834 DICO ABBREVIATION 23567243 T 0 4 DICO ABBREVIATION 23567243 T 33 42 flavonoid FAMILY 23567313 A 1029 1033 GABA ABBREVIATION 23567313 A 1483 1494 chloroquine TRIVIAL 23567313 A 170 181 chloroquine TRIVIAL 23567313 A 1757 1768 chloroquine TRIVIAL 23567313 A 20 31 chloroquine TRIVIAL 23567313 A 429 440 chloroquine TRIVIAL 23567313 T 0 11 Chloroquine TRIVIAL 23567949 A 12 29 thiazolidin-4-one SYSTEMATIC 23567949 A 257 274 thiazolidin-4-one SYSTEMATIC 23567949 A 279 294 thiazinan-4-one SYSTEMATIC 23567949 A 34 49 thiazinan-4-one SYSTEMATIC 23567949 A 479 494 thiazinan-4-one SYSTEMATIC 23567949 A 550 557 glucose TRIVIAL 23567949 T 0 17 Thiazolidin-4-one SYSTEMATIC 23567949 T 22 37 thiazinan-4-one SYSTEMATIC 23567949 T 63 76 rosiglitazone TRIVIAL 23567950 A 18 59 aliphatic amido-quaternary ammonium salts FAMILY 23567950 A 203 244 aliphatic amido-quaternary ammonium salts FAMILY 23567950 A 435 510 N,N-diethyl-N-(2-(N-methyltetradecanamido)ethyl)prop-2-en-1-aminium bromide SYSTEMATIC 23567950 T 45 86 aliphatic amido-quaternary ammonium salts FAMILY 23567961 A 15 23 tyrosine TRIVIAL 23567961 A 832 840 tyrosine TRIVIAL 23567962 A 128 140 hippeastrine TRIVIAL 23567962 A 20 30 lycorenine TRIVIAL 23567962 A 312 324 hippeastrine TRIVIAL 23567962 A 79 91 hippeastrine TRIVIAL 23567962 T 55 65 lycorenine TRIVIAL 23567998 A 0 10 Gabapentin TRIVIAL 23567998 A 1087 1097 gabapentin TRIVIAL 23567998 A 1253 1263 gabapentin TRIVIAL 23567998 A 1575 1585 Gabapentin TRIVIAL 23567998 A 1704 1714 gabapentin TRIVIAL 23567998 A 271 281 gabapentin TRIVIAL 23567998 A 521 544 radiolabeled gabapentin TRIVIAL 23567998 A 667 677 Gabapentin TRIVIAL 23567998 A 70 80 Gabapentin TRIVIAL 23567998 T 13 23 gabapentin TRIVIAL 23568451 A 24 28 CdSe FORMULA 23568451 A 29 32 CdS FORMULA 23568513 A 165 176 metal oxide FAMILY 23568513 A 72 83 metal oxide FAMILY 23568513 T 82 93 Metal Oxide FAMILY 23568577 A 1011 1018 sucrose TRIVIAL 23568577 A 1169 1176 sucrose TRIVIAL 23568577 A 1328 1335 sucrose TRIVIAL 23568577 A 1393 1402 sucralose TRIVIAL 23568577 A 590 597 sucrose TRIVIAL 23568577 A 683 690 sucrose TRIVIAL 23568577 A 835 844 sucralose TRIVIAL 23568856 A 131 139 dopamine TRIVIAL 23568856 A 1793 1801 dopamine TRIVIAL 23568856 A 340 347 cocaine TRIVIAL 23568856 A 36 42 sodium SYSTEMATIC 23568856 A 4 12 dopamine TRIVIAL 23568856 A 414 421 cocaine TRIVIAL 23568856 A 442 453 amphetamine TRIVIAL 23568856 A 496 505 monoamine FAMILY 23568856 A 644 652 dopamine TRIVIAL 23568856 A 750 758 dopamine TRIVIAL 23568856 A 852 859 cocaine TRIVIAL 23568856 A 996 1003 cocaine TRIVIAL 23568856 T 34 42 Dopamine TRIVIAL 23569205 A 0 8 Pyruvate TRIVIAL 23569205 A 1002 1010 pyruvate TRIVIAL 23569205 A 155 162 glucose TRIVIAL 23569205 A 341 349 pyruvate TRIVIAL 23569205 A 453 461 pyruvate TRIVIAL 23569205 A 715 730 monocarboxylate SYSTEMATIC 23569205 T 62 70 Pyruvate TRIVIAL 23570615 A 26 45 aristoyunnolins A-F MULTIPLE 23570615 A 749 756 PD98059 IDENTIFIER 23570615 A 79 98 7-O-ethyl madolin W SYSTEMATIC 23570615 A 8 24 sesquiterpenoids FAMILY 23570748 A 1072 1074 Se FORMULA 23570748 A 1118 1120 Se FORMULA 23570748 A 114 118 zinc SYSTEMATIC 23570748 A 120 122 Zn FORMULA 23570748 A 1206 1208 Se FORMULA 23570748 A 1263 1265 Se FORMULA 23570748 A 128 136 selenium SYSTEMATIC 23570748 A 1316 1318 Zn FORMULA 23570748 A 1358 1360 Se FORMULA 23570748 A 138 140 Se FORMULA 23570748 A 1393 1395 Zn FORMULA 23570748 A 1400 1402 Se FORMULA 23570748 A 1537 1539 Zn FORMULA 23570748 A 1544 1546 Se FORMULA 23570748 A 1618 1620 Zn FORMULA 23570748 A 1660 1662 Zn FORMULA 23570748 A 254 256 Zn FORMULA 23570748 A 261 263 Se FORMULA 23570748 A 350 352 Zn FORMULA 23570748 A 357 359 Se FORMULA 23570748 A 607 609 Zn FORMULA 23570748 A 614 616 Se FORMULA 23570748 A 730 732 Zn FORMULA 23570748 A 737 739 Se FORMULA 23570748 A 855 857 Zn FORMULA 23570748 A 947 949 Zn FORMULA 23570748 T 29 33 zinc SYSTEMATIC 23570748 T 38 46 selenium SYSTEMATIC 23570789 A 12 30 imidazopyridazines FAMILY 23570789 A 84 91 calcium SYSTEMATIC 23570789 T 12 30 imidazopyridazines FAMILY 23570789 T 92 99 calcium SYSTEMATIC 23570985 A 1257 1267 furosemide TRIVIAL 23570985 A 1368 1378 furosemide TRIVIAL 23570985 A 1492 1502 furosemide TRIVIAL 23570985 A 1504 1511 PVP K12 TRIVIAL 23570985 A 1516 1519 SDS ABBREVIATION 23570985 A 1652 1659 PVP K12 TRIVIAL 23570985 A 1664 1667 SDS ABBREVIATION 23570985 A 1694 1704 furosemide TRIVIAL 23570985 A 1815 1825 furosemide TRIVIAL 23570985 A 269 279 ingliforib TRIVIAL 23570985 A 281 291 furosemide TRIVIAL 23570985 A 296 305 celecoxib TRIVIAL 23570985 A 457 477 polyvinylpyrrolidone SYSTEMATIC 23570985 A 478 487 (PVP) K12 TRIVIAL 23570985 A 492 514 sodium dodecyl sulfate SYSTEMATIC 23570985 A 516 519 SDS ABBREVIATION 23570985 A 969 979 furosemide TRIVIAL 23570999 A 0 30 Polyhydroxy pregnane glycoside FAMILY 23570999 A 1038 1055 diclofenac sodium SYSTEMATIC 23570999 A 1112 1131 steroidal glycoside FAMILY 23570999 A 115 118 PPG ABBREVIATION 23570999 A 1151 1154 PPG ABBREVIATION 23570999 A 1385 1388 PPG ABBREVIATION 23570999 A 296 299 PPG ABBREVIATION 23570999 A 32 35 PPG ABBREVIATION 23570999 A 383 386 PPG ABBREVIATION 23570999 A 40 59 steroidal glycoside FAMILY 23570999 A 694 702 N-acetyl SYSTEMATIC 23570999 A 757 760 PPG ABBREVIATION 23570999 A 980 983 PPG ABBREVIATION 23570999 T 52 106 pentahydroxy-pregn-14-ol, 20-one-β-d-thevetopyranoside SYSTEMATIC 23571068 A 617 634 O(6)-alkylguanine FAMILY 23571068 A 735 745 nucleotide FAMILY 23571107 A 386 395 guanosine TRIVIAL 23571427 A 0 10 Ornidazole TRIVIAL 23571427 A 1137 1149 R-ornidazole TRIVIAL 23571427 A 1177 1189 S-ornidazole TRIVIAL 23571427 A 12 73 R,S-1-chloro-3-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ol SYSTEMATIC 23571427 A 1281 1293 R-ornidazole TRIVIAL 23571427 A 1326 1338 S-ornidazole TRIVIAL 23571427 A 1392 1411 S- and R-ornidazole MULTIPLE 23571427 A 1635 1645 ornidazole TRIVIAL 23571427 A 1735 1754 R- and S-ornidazole MULTIPLE 23571427 A 198 208 ornidazole TRIVIAL 23571427 A 417 435 racemic ornidazole TRIVIAL 23571427 A 538 548 ornidazole TRIVIAL 23571427 A 660 663 UDP ABBREVIATION 23571427 A 765 777 R-ornidazole TRIVIAL 23571427 A 803 815 S-ornidazole TRIVIAL 23571427 A 87 103 5-nitroimidazole SYSTEMATIC 23571427 A 907 920 niflumic acid TRIVIAL 23571427 A 925 937 flurbiprofen TRIVIAL 23571427 T 35 45 Ornidazole TRIVIAL 23571427 T 85 88 UDP ABBREVIATION 23571428 A 1031 1078 2-fluoro-N-methyl pyridinium p-toluenesulfonate SYSTEMATIC 23571428 A 1170 1187 N-methyl pyridine SYSTEMATIC 23571428 A 1189 1192 NMP ABBREVIATION 23571428 A 1355 1364 labetalol TRIVIAL 23571428 A 1366 1375 ezetimibe TRIVIAL 23571428 A 1377 1389 atorvastatin TRIVIAL 23571428 A 1394 1402 warfarin TRIVIAL 23571428 A 1494 1497 NMP ABBREVIATION 23571428 A 1693 1703 imipramine TRIVIAL 23571428 A 1707 1712 NADPH ABBREVIATION 23571428 A 191 199 quinones FAMILY 23571428 A 255 262 phenols FAMILY 23571428 A 266 276 arylamines FAMILY 23572393 A 113 121 diazepam TRIVIAL 23572393 A 126 140 phenobarbitone TRIVIAL 23572393 A 405 413 diazepam TRIVIAL 23572393 A 541 549 diazepam TRIVIAL 23572393 A 592 606 phenobarbitone TRIVIAL 23572393 A 735 743 diazepam TRIVIAL 23572393 A 748 762 phenobarbitone TRIVIAL 23572528 A 1407 1418 Brefeldin A TRIVIAL 23572528 A 732 751 mannose-6-phosphate SYSTEMATIC 23572528 A 787 788 C FORMULA 23572528 T 38 41 ADP ABBREVIATION 23573951 A 106 110 HQLG FAMILY 23573951 A 129 135 LiHQLG FORMULA 23573951 A 137 146 Zn(HQLG)2 FORMULA 23573951 A 152 161 Al(HQLG)3 FORMULA 23573951 A 36 41 Li(+) FORMULA 23573951 A 43 49 Zn(2+) FORMULA 23573951 A 55 61 Al(3+) FORMULA 23573951 A 652 690 (R,R)- or (S,S)-1,2-diaminocyclohexane MULTIPLE 23573951 A 66 104 quinolinol-functionalized l-glutamides FAMILY 23573951 A 708 717 Al(HQLG)3 FORMULA 23573951 A 766 772 LiHQLG FORMULA 23573951 A 842 851 Zn(HQLG)2 FORMULA 23573951 A 918 957 (R,R)- and (S,S)-1,2-diaminocyclohexane MULTIPLE 23573951 T 104 113 glutamide TRIVIAL 23573951 T 93 103 quinolinol TRIVIAL 23574017 A 1087 1098 doxorubicin TRIVIAL 23574017 A 1307 1318 doxorubicin TRIVIAL 23574017 A 1441 1452 doxorubicin TRIVIAL 23574017 A 1527 1535 estrogen FAMILY 23574017 A 199 219 17α-ethynylestradiol SYSTEMATIC 23574017 A 252 263 doxorubicin TRIVIAL 23574017 A 338 349 Doxorubicin TRIVIAL 23574017 A 66 74 estrogen FAMILY 23574017 A 706 717 doxorubicin TRIVIAL 23574017 A 839 850 doxorubicin TRIVIAL 23574017 A 891 904 hydrochloride FAMILY 23574017 A 997 1008 doxorubicin TRIVIAL 23574017 T 11 31 17α-ethynylestradiol SYSTEMATIC 23574017 T 152 163 doxorubicin TRIVIAL 23574017 T 79 90 doxorubicin TRIVIAL 23574336 A 13 25 nickel oxide SYSTEMATIC 23574336 A 195 197 CO FORMULA 23574336 A 234 244 NinOn+x(+) FAMILY 23574336 A 334 336 CO FORMULA 23574336 A 40 50 NinOn+x(+) FAMILY 23574336 A 408 410 CO FORMULA 23574336 A 566 568 CO FORMULA 23574336 A 604 614 NinOn+x(+) FAMILY 23574336 A 713 719 oxygen SYSTEMATIC 23574336 A 745 747 CO FORMULA 23574336 A 777 783 oxygen SYSTEMATIC 23574336 A 79 81 CO FORMULA 23574336 A 806 814 Ni6O7(+) FORMULA 23574336 A 819 827 Ni8O9(+) FORMULA 23574336 A 836 842 oxygen SYSTEMATIC 23574336 A 87 89 He FORMULA 23574336 T 13 15 CO FORMULA 23574336 T 19 31 Nickel Oxide SYSTEMATIC 23575975 A 1040 1045 sugar FAMILY 23575975 A 1046 1055 phosphate SYSTEMATIC 23575975 A 1056 1061 sugar FAMILY 23575975 A 14 23 phosphate SYSTEMATIC 23575975 A 8 13 sugar FAMILY 23575975 T 91 96 sugar FAMILY 23575975 T 97 106 phosphate SYSTEMATIC 23576019 A 2987 2999 methotrexate TRIVIAL 23576190 A 1045 1047 Cd FORMULA 23576190 A 1307 1309 Cd FORMULA 23576190 A 1596 1598 Cd FORMULA 23576190 A 934 936 Cd FORMULA 23576190 T 87 94 cadmium SYSTEMATIC 23576235 A 111 113 BN FORMULA 23576235 A 163 171 graphene TRIVIAL 23576235 A 174 176 BN FORMULA 23576235 A 253 261 graphene TRIVIAL 23576235 A 264 266 BN FORMULA 23576235 A 320 328 graphene TRIVIAL 23576235 A 329 333 SiO2 FORMULA 23576235 A 337 345 graphene TRIVIAL 23576235 A 363 365 BN FORMULA 23576235 A 414 422 graphene TRIVIAL 23576235 A 62 70 graphene TRIVIAL 23576235 A 94 107 boron nitride SYSTEMATIC 23576235 T 109 122 Boron Nitride SYSTEMATIC 23576235 T 27 35 Graphene TRIVIAL 23576235 T 77 85 Graphene TRIVIAL 23576432 A 1033 1040 choline FAMILY 23576432 A 1045 1074 dibutyroylphosphatidylcholine SYSTEMATIC 23576432 A 226 244 phosphatidylserine FAMILY 23576432 A 249 266 phosphoinositides FAMILY 23576432 A 343 362 phosphatidylcholine FAMILY 23576432 A 465 472 choline FAMILY 23576432 A 509 526 trimethylammonium SYSTEMATIC 23576432 A 717 733 quaternary amine FAMILY 23576432 A 806 826 phosphatidylinositol TRIVIAL 23576432 T 31 50 phosphatidylcholine FAMILY 23576475 A 274 282 dopamine TRIVIAL 23576475 A 307 320 ascorbic acid TRIVIAL 23576475 T 136 144 Dopamine TRIVIAL 23576475 T 174 187 Ascorbic Acid TRIVIAL 23578259 A 1008 1016 graphene TRIVIAL 23578259 A 1123 1128 ozone TRIVIAL 23578259 A 1167 1175 graphene TRIVIAL 23578259 A 156 161 ozone TRIVIAL 23578259 A 255 263 graphene TRIVIAL 23578259 A 316 324 graphene TRIVIAL 23578259 A 337 342 ozone TRIVIAL 23578259 A 355 360 ozone TRIVIAL 23578259 A 422 430 graphene TRIVIAL 23578259 A 45 53 graphene TRIVIAL 23578259 A 667 672 ozone TRIVIAL 23578259 A 673 690 oxidized graphene TRIVIAL 23578259 A 738 752 graphene oxide SYSTEMATIC 23578259 A 791 796 ozone TRIVIAL 23578259 A 838 846 graphene TRIVIAL 23578259 A 864 869 ozone TRIVIAL 23578259 A 901 906 ozone TRIVIAL 23578259 A 915 923 graphene TRIVIAL 23578259 T 48 56 Graphene TRIVIAL 23578259 T 60 65 Ozone TRIVIAL 23578341 A 1005 1012 glucose TRIVIAL 23578341 A 1136 1143 glucose TRIVIAL 23578341 A 1171 1178 glucose TRIVIAL 23578341 A 1209 1213 ADMA ABBREVIATION 23578341 A 1432 1436 ADMA ABBREVIATION 23578341 A 1577 1584 glucose TRIVIAL 23578341 A 1596 1600 ADMA ABBREVIATION 23578341 A 1605 1609 SDMA ABBREVIATION 23578341 A 1671 1678 glucose TRIVIAL 23578341 A 1693 1697 ADMA ABBREVIATION 23578341 A 1731 1738 glucose TRIVIAL 23578341 A 199 226 asymmetric dimethylarginine SYSTEMATIC 23578341 A 2107 2111 ADMA ABBREVIATION 23578341 A 228 232 ADMA ABBREVIATION 23578341 A 262 274 nitric oxide SYSTEMATIC 23578341 A 329 336 glucose TRIVIAL 23578341 A 616 620 ADMA ABBREVIATION 23578341 A 647 673 symmetric dimethylarginine SYSTEMATIC 23578341 A 67 79 nitric oxide SYSTEMATIC 23578341 A 675 679 SDMA ABBREVIATION 23578341 A 848 855 glucose TRIVIAL 23578341 A 874 881 glucose TRIVIAL 23578341 A 967 974 glucose TRIVIAL 23578341 T 0 27 Asymmetric dimethylarginine SYSTEMATIC 23578341 T 48 55 glucose TRIVIAL 23578390 A 0 15 Sodium fluoride SYSTEMATIC 23578390 A 1007 1010 NaF FORMULA 23578390 A 17 20 NaF FORMULA 23578390 A 256 259 NaF FORMULA 23578390 A 336 339 NaF FORMULA 23578390 A 465 468 NaF FORMULA 23578390 A 707 715 fluoride SYSTEMATIC 23578390 A 762 770 Fluoride SYSTEMATIC 23578390 A 866 874 fluoride SYSTEMATIC 23578390 T 0 15 Sodium fluoride SYSTEMATIC 23578391 A 1020 1039 tetraiiodothyronine SYSTEMATIC 23578391 A 1363 1368 PBDEs ABBREVIATION 23578391 A 254 259 PBDEs ABBREVIATION 23578391 A 287 307 2,2',4,4',5-pentaBDE SYSTEMATIC 23578391 A 30 60 polybrominated diphenyl ethers FAMILY 23578391 A 309 315 BDE-99 ABBREVIATION 23578391 A 366 372 BDE-99 ABBREVIATION 23578391 A 557 572 thyroid hormone FAMILY 23578391 A 62 67 PBDEs ABBREVIATION 23578391 A 791 797 BDE-99 ABBREVIATION 23578391 A 997 1013 triiodothyronine TRIVIAL 23578391 T 22 28 BDE-99 ABBREVIATION 23578391 T 75 90 thyroid hormone FAMILY 23578393 A 169 177 dopamine TRIVIAL 23578393 A 815 822 cocaine TRIVIAL 23578393 T 48 56 dopamine TRIVIAL 23578514 A 0 10 Anatoxin-a TRIVIAL 23578514 A 1001 1018 hydrogen peroxide SYSTEMATIC 23578514 A 111 124 acetylcholine SYSTEMATIC 23578514 A 1271 1288 hydrogen peroxide SYSTEMATIC 23578514 A 1315 1325 anatoxin-a TRIVIAL 23578514 A 1390 1403 chlorophyll a TRIVIAL 23578514 A 1485 1496 chlorophyll FAMILY 23578514 A 1615 1625 anatoxin-a TRIVIAL 23578514 A 1661 1671 anatoxin-a TRIVIAL 23578514 A 1855 1865 anatoxin-a TRIVIAL 23578514 A 351 361 Anatoxin-a TRIVIAL 23578514 A 569 579 anatoxin-a TRIVIAL 23578514 A 762 775 acetylcholine SYSTEMATIC 23578514 A 898 908 anatoxin-a TRIVIAL 23578514 T 52 62 anatoxin-a TRIVIAL 23578522 A 317 328 cholesterol TRIVIAL 23578522 A 670 681 cholesterol TRIVIAL 23578522 T 53 64 cholesterol TRIVIAL 23578608 A 1033 1039 stanol FAMILY 23578608 A 1104 1113 bile acid FAMILY 23578608 A 151 162 cholesterol TRIVIAL 23578608 A 186 197 cholesterol TRIVIAL 23578608 A 253 273 stanyl hemisuccinate FAMILY 23578608 A 293 318 stanyl sorbitol succinate FAMILY 23578608 A 367 378 cholesterol TRIVIAL 23578608 A 38 49 cholesterol TRIVIAL 23578608 A 407 418 cholesterol TRIVIAL 23578608 A 460 475 triacylglycerol FAMILY 23578608 A 505 516 cholesterol TRIVIAL 23578608 A 528 534 stanol FAMILY 23578608 A 563 574 cholesterol TRIVIAL 23578608 A 610 621 cholesterol TRIVIAL 23578608 A 652 672 stanyl hemisuccinate FAMILY 23578608 A 683 708 stanyl sorbitol succinate FAMILY 23578608 A 790 801 cholesterol TRIVIAL 23578608 A 85 91 stanol FAMILY 23578608 A 854 863 bile acid FAMILY 23578608 A 931 937 stanol FAMILY 23578608 A 996 1007 cholesterol TRIVIAL 23578608 T 14 20 stanol FAMILY 23578608 T 54 65 cholesterol TRIVIAL 23578613 A 173 180 zeranol TRIVIAL 23578613 A 182 191 taleranol TRIVIAL 23578613 A 197 216 diethylstilbesterol SYSTEMATIC 23578613 A 378 411 trans- and cis-diethylstilbestrol MULTIPLE 23578613 A 631 649 diethylstilbestrol SYSTEMATIC 23578613 T 54 61 zeranol TRIVIAL 23578613 T 66 84 diethylstilbestrol SYSTEMATIC 23578615 A 564 572 linalool TRIVIAL 23578615 A 574 587 β-damascenone TRIVIAL 23578615 A 589 604 ethyl hexanoate SYSTEMATIC 23578615 A 610 625 ethyl octanoate SYSTEMATIC 23578615 A 657 668 α-terpineol TRIVIAL 23578615 A 670 679 hotrienol TRIVIAL 23578615 A 681 692 nerol oxide SYSTEMATIC 23578615 A 694 721 furanic linalool oxides A/B MULTIPLE 23578615 A 726 736 rose oxide TRIVIAL 23578616 A 497 505 phenolic FAMILY 23578616 A 507 517 flavonoids FAMILY 23578616 A 522 537 tartaric esters FAMILY 23578616 A 743 750 alcohol FAMILY 23578620 A 1096 1104 catechin TRIVIAL 23578620 A 1205 1212 phenols FAMILY 23578620 A 1318 1324 phenol SYSTEMATIC 23578620 A 153 164 polyphenols FAMILY 23578620 A 202 218 oxidised phenols FAMILY 23578620 A 322 329 phenols FAMILY 23578620 A 343 354 epicatechin TRIVIAL 23578620 A 356 364 catechin TRIVIAL 23578620 A 544 552 catechin TRIVIAL 23578620 A 557 568 epicatechin TRIVIAL 23578620 A 760 768 catechin TRIVIAL 23578620 A 771 782 epicatechin TRIVIAL 23578620 A 794 800 phenol SYSTEMATIC 23578620 A 910 918 catechin TRIVIAL 23578620 A 930 941 epicatechin TRIVIAL 23578620 T 14 22 catechin TRIVIAL 23578620 T 27 38 epicatechin TRIVIAL 23578620 T 46 53 phenols FAMILY 23578628 A 100 103 ALT ABBREVIATION 23578628 A 106 114 tentoxin TRIVIAL 23578628 A 116 119 TEN ABBREVIATION 23578628 A 126 141 tenuazonic acid TRIVIAL 23578628 A 143 146 TeA ABBREVIATION 23578628 A 34 45 alternariol TRIVIAL 23578628 A 47 50 AOH FORMULA 23578628 A 53 81 alternariol monomethyl ether SYSTEMATIC 23578628 A 83 86 AME ABBREVIATION 23578628 A 883 886 AOH FORMULA 23578628 A 89 98 altenuene TRIVIAL 23578628 A 936 939 ALT ABBREVIATION 23578629 A 1006 1014 guaiacol TRIVIAL 23578629 A 1110 1117 eugenol TRIVIAL 23578629 A 1119 1127 vanillin TRIVIAL 23578629 A 471 478 phenols FAMILY 23578629 A 493 502 aldehydes FAMILY 23578629 A 504 511 phenols FAMILY 23578629 A 516 524 lactones FAMILY 23578629 A 938 946 Lactones FAMILY 23578629 A 994 1001 furanic FAMILY 23578637 A 1011 1027 selenomethionine SYSTEMATIC 23578637 A 1059 1067 selenium SYSTEMATIC 23578637 A 1182 1190 selenium SYSTEMATIC 23578637 A 1227 1235 selenium SYSTEMATIC 23578637 A 1342 1350 selenium SYSTEMATIC 23578637 A 1406 1414 selenium SYSTEMATIC 23578637 A 1444 1452 selenium SYSTEMATIC 23578637 A 1546 1554 selenium SYSTEMATIC 23578637 A 296 304 selenium SYSTEMATIC 23578637 A 344 352 Selenium SYSTEMATIC 23578637 A 36 44 selenium SYSTEMATIC 23578637 A 474 482 selenium SYSTEMATIC 23578637 A 508 510 Se FORMULA 23578637 A 557 565 selenium SYSTEMATIC 23578637 A 657 665 selenium SYSTEMATIC 23578637 A 775 783 selenium SYSTEMATIC 23578637 A 98 106 selenium SYSTEMATIC 23578637 A 980 988 selenium SYSTEMATIC 23578637 T 0 8 Selenium SYSTEMATIC 23578637 T 86 94 selenium SYSTEMATIC 23578638 A 227 229 Ca FORMULA 23578638 A 231 232 K FORMULA 23578638 A 234 236 Mg FORMULA 23578638 A 241 243 Na FORMULA 23578638 A 677 679 Al FORMULA 23578638 A 681 682 B FORMULA 23578638 A 684 686 Cd FORMULA 23578638 A 691 693 Co FORMULA 23578653 A 105 114 flavonols FAMILY 23578653 A 1068 1086 flavonol glycoside FAMILY 23578653 A 1088 1106 chakaflavonoside B TRIVIAL 23578653 A 1190 1200 oleic acid TRIVIAL 23578653 A 268 276 caffeine TRIVIAL 23578653 A 59 70 polyphenols FAMILY 23578653 A 733 744 polyphenols FAMILY 23578653 A 819 904 kaempferol 3-O-β-d-glucopyranosyl-(1→3)-α-l-rhamnopyranosyl-(1→6)-β-d-glucopyranoside SYSTEMATIC 23578653 A 82 91 catechins FAMILY 23578653 A 914 1001 kaempferol 3-O-β-d-glucopyranosyl-(1→3)-α-l-rhamnopyranosyl-(1→6)-β-d-galactopyranoside SYSTEMATIC 23578653 T 0 19 Flavonol glycosides FAMILY 23578653 T 109 120 polyphenols FAMILY 23578653 T 125 133 caffeine TRIVIAL 23578654 A 147 153 oxygen SYSTEMATIC 23578655 A 39 54 kresoxim methyl TRIVIAL 23578655 A 455 470 kresoxim methyl TRIVIAL 23578655 A 611 626 kresoxim methyl TRIVIAL 23578655 A 924 939 kresoxim methyl TRIVIAL 23578655 T 28 43 kresoxim methyl TRIVIAL 23578656 A 1061 1074 methyl esters FAMILY 23578656 A 1084 1100 methyl hexanoate SYSTEMATIC 23578656 A 1105 1121 methyl octanoate SYSTEMATIC 23578656 A 707 713 esters FAMILY 23578656 A 805 867 hexenyl, hexyl, 3-methylbutyl, butyl and 2-methylpropyl esters MULTIPLE 23578656 A 920 941 (Z)-3-hexenyl acetate SYSTEMATIC 23578658 A 144 152 lycopene TRIVIAL 23578658 A 154 164 β-carotene TRIVIAL 23579166 A 0 15 Montmorillonite TRIVIAL 23579166 A 1221 1229 Cloisite FAMILY 23579166 A 573 581 Cloisite FAMILY 23579166 A 583 586 Na+ FORMULA 23579166 A 607 615 Cloisite FAMILY 23579166 A 682 690 Cloisite FAMILY 23579166 A 986 997 glutathione TRIVIAL 23579178 A 1123 1126 MTT ABBREVIATION 23579178 A 1219 1226 glucose TRIVIAL 23579178 A 19 26 glucose TRIVIAL 23579178 A 322 325 MTT ABBREVIATION 23579178 A 332 346 [(14)C]glucose SYSTEMATIC 23579178 A 360 367 glucose TRIVIAL 23579178 A 393 400 glucose TRIVIAL 23579178 A 432 433 C FORMULA 23579178 A 50 61 sitagliptin TRIVIAL 23579178 A 67 76 metformin TRIVIAL 23579178 A 704 707 MTT ABBREVIATION 23579178 A 825 828 MTT ABBREVIATION 23579178 T 103 112 Metformin TRIVIAL 23579178 T 14 21 Glucose TRIVIAL 23579178 T 67 78 Sitagliptin TRIVIAL 23579428 A 110 122 Nitric oxide SYSTEMATIC 23579428 A 1123 1125 NO FORMULA 23579428 A 1130 1134 cGMP ABBREVIATION 23579428 A 1189 1196 cocaine TRIVIAL 23579428 A 1283 1290 cocaine TRIVIAL 23579428 A 1606 1610 cGMP ABBREVIATION 23579428 A 1702 1704 NO FORMULA 23579428 A 1709 1713 cGMP ABBREVIATION 23579428 A 1754 1761 cocaine TRIVIAL 23579428 A 190 197 cocaine TRIVIAL 23579428 A 20 27 cocaine TRIVIAL 23579428 A 242 254 nitric oxide SYSTEMATIC 23579428 A 271 273 NO FORMULA 23579428 A 282 290 guanylyl TRIVIAL 23579428 A 305 335 cyclic guanosine monophosphate SYSTEMATIC 23579428 A 337 341 cGMP ABBREVIATION 23579428 A 476 480 cGMP ABBREVIATION 23579428 A 845 852 cocaine TRIVIAL 23579428 A 905 914 glutamate TRIVIAL 23579428 T 53 60 cocaine TRIVIAL 23580152 A 1052 1056 (1)H FORMULA 23580152 A 1072 1080 n-C20H42 FORMULA 23580152 A 1081 1087 d-urea TRIVIAL 23580152 A 1164 1168 (1)H FORMULA 23580152 A 334 342 hydrogen SYSTEMATIC 23580152 A 379 387 n-alkane FAMILY 23580152 A 388 394 d-urea TRIVIAL 23580152 A 43 47 (1)H FORMULA 23580152 A 453 457 (1)H FORMULA 23580152 A 496 515 magnesium hydroxide SYSTEMATIC 23580152 A 520 530 adamantane TRIVIAL 23580152 A 692 696 (1)H FORMULA 23580152 A 767 777 adamantane TRIVIAL 23580152 A 849 856 Mg(OH)2 FORMULA 23580152 A 927 935 n-C20H42 FORMULA 23580152 A 936 942 d-urea TRIVIAL 23580152 T 56 60 (1)H FORMULA 23580372 A 152 160 graphite TRIVIAL 23580372 A 237 245 graphite TRIVIAL 23580372 A 270 278 graphene TRIVIAL 23580372 A 35 43 graphene TRIVIAL 23580372 A 380 388 graphene TRIVIAL 23580372 T 0 8 Graphene TRIVIAL 23580372 T 41 49 graphene TRIVIAL 23580374 A 0 8 Graphene TRIVIAL 23580374 A 318 326 graphene TRIVIAL 23580374 A 533 541 graphene TRIVIAL 23580374 T 94 102 graphene TRIVIAL 23580394 T 28 41 Squaraine Dye TRIVIAL 23580445 A 253 263 nucleotide FAMILY 23580445 A 670 679 NSC130813 IDENTIFIER 23580445 A 718 727 cisplatin TRIVIAL 23580445 A 732 743 mitomycin C TRIVIAL 23580458 A 100 107 Au(111) FORMULA 23580458 A 51 62 Fe14 (bta)6 FORMULA 23580644 A 1036 1041 MgADP FORMULA 23580644 A 1123 1128 MgADP FORMULA 23580644 A 1318 1321 ADP ABBREVIATION 23580644 A 714 717 His FORMULA 23580644 A 740 741 N FORMULA 23580644 A 906 916 nucleotide FAMILY 23581456 A 126 134 dilation NO CLASS 23581456 A 140 150 lumichrome TRIVIAL 23581456 A 156 165 curvulari NO CLASS 23581456 A 171 210 5,5'-oxy-dimethylene-bis(2-furaldehyde) SYSTEMATIC 23581456 A 216 224 chromone TRIVIAL 23581456 A 230 258 harman(1-methyl-β-carboline) SYSTEMATIC 23581456 A 24 83 4-(methoxymethyl)-7-methoxy-6-methyl-1(3H)-isobenzofuranone SYSTEMATIC 23581456 A 264 293 N9-methyl-1methyl-β-carboline SYSTEMATIC 23581456 A 6 22 isobenzofuranone SYSTEMATIC 23581456 T 6 22 isobenzofuranone SYSTEMATIC 23581551 A 229 253 (Aminoalkyl)fluoroindole FAMILY 23581551 A 359 368 serotonin TRIVIAL 23581551 A 507 520 3-alkylindole FAMILY 23581551 A 586 593 taurine TRIVIAL 23581551 A 65 82 hypochlorous acid TRIVIAL 23581551 A 683 695 fluoroindole SYSTEMATIC 23581551 A 716 723 carbons FAMILY 23581551 A 750 755 amide FAMILY 23581551 T 72 85 3-Alkylindole FAMILY 23581596 A 0 16 Sacchathridine A TRIVIAL 23581596 A 140 154 naphthoquinone FAMILY 23581596 A 174 189 acetylhydrazino SYSTEMATIC 23581596 A 311 327 prostaglandin E2 TRIVIAL 23581596 T 0 16 Sacchathridine A TRIVIAL 23581596 T 20 33 Prostaglandin FAMILY 23581848 A 253 260 ZYJ-34c IDENTIFIER 23581848 A 478 485 ZYJ-34v IDENTIFIER 23581848 A 53 75 tetrahydroisoquinoline SYSTEMATIC 23581848 A 82 97 hydroxamic acid SYSTEMATIC 23581848 A 837 841 SAHA ABBREVIATION 23581848 T 26 48 tetrahydroisoquinoline SYSTEMATIC 23581848 T 55 66 hydroxamate SYSTEMATIC 23581848 T 79 86 ZYJ-34v IDENTIFIER 23581876 A 101 110 ryanodine TRIVIAL 23581876 A 1033 1040 PCB 136 ABBREVIATION 23581876 A 1132 1139 PCB 136 ABBREVIATION 23581876 A 1190 1196 OH-PCB FORMULA 23581876 A 1408 1412 PCBs ABBREVIATION 23581876 A 160 164 PCBs ABBREVIATION 23581876 A 19 44 polychlorinated biphenyls FAMILY 23581876 A 265 268 PCB ABBREVIATION 23581876 A 336 340 PCBs ABBREVIATION 23581876 A 383 387 PCBs ABBREVIATION 23581876 A 46 50 PCBs ABBREVIATION 23581876 A 525 532 PCB 136 ABBREVIATION 23581876 A 60 67 PCB 136 ABBREVIATION 23581876 A 606 619 phenobarbital TRIVIAL 23581876 A 643 656 dexamethasone TRIVIAL 23581876 A 658 661 DEX ABBREVIATION 23581876 A 716 723 PCB 136 ABBREVIATION 23581876 A 835 851 hydroxylated PCB ABBREVIATION 23581876 A 853 859 OH-PCB FORMULA 23581876 A 916 922 OH-PCB FORMULA 23581876 A 978 981 DEX ABBREVIATION 23581876 T 110 123 dexamethasone TRIVIAL 23581876 T 14 47 2,2',3,3',6,6'-hexachlorobiphenyl SYSTEMATIC 23581876 T 49 56 PCB 136 ABBREVIATION 23581876 T 93 106 phenobarbital TRIVIAL 23581996 A 257 283 pentafluorophenyl acrylate SYSTEMATIC 23581996 A 285 289 PFPA ABBREVIATION 23581996 A 295 328 4-(trimethylsilyl) ethynylstyrene SYSTEMATIC 23581996 A 330 335 TMSES ABBREVIATION 23581996 A 375 382 silicon SYSTEMATIC 23581996 A 500 519 1-aminomethylpyrene SYSTEMATIC 23581996 A 521 524 AMP ABBREVIATION 23581996 A 530 548 5-azidofluorescein SYSTEMATIC 23581996 A 644 653 copper(I) SYSTEMATIC 23581996 A 664 670 alkyne FAMILY 23581996 A 671 676 azide SYSTEMATIC 23581996 A 763 768 TMSES ABBREVIATION 23581996 A 869 879 poly(PFPA) FAMILY 23581996 A 912 917 TMSES ABBREVIATION 23583259 A 0 11 Rilpivirine TRIVIAL 23583259 A 1270 1277 steroid FAMILY 23583259 A 1384 1395 Rilpivirine TRIVIAL 23583259 A 1397 1407 etravirine TRIVIAL 23583259 A 1413 1422 efavirenz TRIVIAL 23583259 A 1432 1442 nevirapine TRIVIAL 23583259 A 1446 1457 delavirdine TRIVIAL 23583259 A 1571 1581 nucleoside FAMILY 23583259 A 16 26 etravirine TRIVIAL 23583259 A 1647 1658 Rilpivirine TRIVIAL 23583259 A 1660 1670 etravirine TRIVIAL 23583259 A 1676 1685 efavirenz TRIVIAL 23583259 A 1695 1705 nevirapine TRIVIAL 23583259 A 1709 1720 delavirdine TRIVIAL 23583259 A 228 236 Pregnane TRIVIAL 23583259 A 440 451 rilpivirine TRIVIAL 23583259 A 456 466 etravirine TRIVIAL 23583259 A 53 63 nucleoside FAMILY 23583259 A 568 577 efavirenz TRIVIAL 23583259 A 579 589 nevirapine TRIVIAL 23583259 A 595 606 delavirdine TRIVIAL 23583259 A 639 649 nucleoside FAMILY 23583259 A 724 735 rilpivirine TRIVIAL 23583259 A 737 747 etravirine TRIVIAL 23583259 A 753 762 efavirenz TRIVIAL 23583259 A 772 782 nevirapine TRIVIAL 23583259 A 786 797 delavirdine TRIVIAL 23583259 A 884 895 rilpivirine TRIVIAL 23583259 A 897 907 etravirine TRIVIAL 23583259 A 913 922 efavirenz TRIVIAL 23583259 A 932 942 nevirapine TRIVIAL 23583259 A 946 957 delavirdine TRIVIAL 23583259 T 105 115 nucleoside FAMILY 23583259 T 17 25 pregnane TRIVIAL 23583259 T 40 51 rilpivirine TRIVIAL 23583259 T 56 66 etravirine TRIVIAL 23583485 A 232 243 Gypenosides FAMILY 23583485 A 368 379 gypenosides FAMILY 23583485 A 578 589 Gypenosides FAMILY 23583485 A 735 744 midazolam TRIVIAL 23583485 A 766 778 testosterone TRIVIAL 23583485 A 811 822 Gypenosides FAMILY 23583485 A 892 903 Gypenosides FAMILY 23583485 T 22 33 gypenosides FAMILY 23583510 A 127 132 THBDC ABBREVIATION 23583510 A 135 154 dihydropyrimidinone SYSTEMATIC 23583510 A 156 160 DHPM ABBREVIATION 23583510 A 25 43 tetrahydrocurcumin SYSTEMATIC 23583510 A 256 271 copper sulphate SYSTEMATIC 23583510 A 46 49 THC ABBREVIATION 23583510 A 463 473 THBDC-DHPM ABBREVIATION 23583510 A 53 80 tetrahydrodemethoxycurcumin SYSTEMATIC 23583510 A 602 614 galanthamine TRIVIAL 23583510 A 83 87 THDC ABBREVIATION 23583510 A 94 124 tetrahydrobisdemethoxycurcumin SYSTEMATIC 23583510 T 14 55 tetrahydrocurcuminoid dihydropyrimidinone SYSTEMATIC 23583511 A 152 155 MTX ABBREVIATION 23583511 A 30 42 methotrexate TRIVIAL 23583511 A 372 378 copper SYSTEMATIC 23583511 A 44 47 MTX ABBREVIATION 23583511 A 576 581 ester FAMILY 23583511 A 585 590 amide FAMILY 23583511 A 607 610 MTX ABBREVIATION 23583511 A 650 660 folic acid TRIVIAL 23583511 A 703 706 MTX ABBREVIATION 23583511 A 770 776 folate TRIVIAL 23583511 A 81 97 poly amido amine FAMILY 23583511 A 835 840 ester FAMILY 23583511 A 846 851 amide FAMILY 23583511 A 868 871 MTX ABBREVIATION 23583511 A 925 930 ester FAMILY 23583511 A 931 934 MTX ABBREVIATION 23583511 A 99 104 PAMAM ABBREVIATION 23583511 A 990 995 amide FAMILY 23583511 A 996 999 MTX ABBREVIATION 23583511 T 26 31 PAMAM ABBREVIATION 23583517 A 1311 1328 Na(+)/Ca(2+)-cAMP MULTIPLE 23583517 A 1464 1474 tryptophan TRIVIAL 23583517 A 1585 1595 tryptophan TRIVIAL 23583803 A 23 31 nitrogen SYSTEMATIC 23583806 A 1020 1022 NO FORMULA 23583806 A 1183 1190 allicin TRIVIAL 23583806 A 1299 1306 allicin TRIVIAL 23583806 A 683 685 NO FORMULA 23583806 A 805 812 allicin TRIVIAL 23583806 A 860 867 Allicin TRIVIAL 23583806 A 938 940 NO FORMULA 23583806 T 119 121 NO FORMULA 23583806 T 171 178 allicin TRIVIAL 23583883 A 1217 1227 superoxide TRIVIAL 23583883 A 1495 1505 superoxide TRIVIAL 23583883 A 1689 1705 Brilliant Blue G TRIVIAL 23583883 A 2139 2155 Brilliant Blue G TRIVIAL 23583883 A 605 608 ATP ABBREVIATION 23583883 A 795 805 superoxide TRIVIAL 23583884 A 0 35 2,3,7,8-Tetrachlorodibenzo-p-dioxin SYSTEMATIC 23583884 A 1043 1049 Ca(2+) FORMULA 23583884 A 1052 1058 Ca(2+) FORMULA 23583884 A 1072 1076 TCDD ABBREVIATION 23583884 A 1320 1324 TCDD ABBREVIATION 23583884 A 1345 1351 Ca(2+) FORMULA 23583884 A 1442 1446 TCDD ABBREVIATION 23583884 A 1574 1578 TCDD ABBREVIATION 23583884 A 1612 1618 Ca(2+) FORMULA 23583884 A 162 166 TCDD ABBREVIATION 23583884 A 320 324 TCDD ABBREVIATION 23583884 A 37 41 TCDD ABBREVIATION 23583884 A 468 472 TCDD ABBREVIATION 23583884 A 732 736 TCDD ABBREVIATION 23583884 A 812 818 Ca(2+) FORMULA 23583884 A 829 904 bis-(o-aminophenoxy) ethane-N,N,N',N'-tetra-acetic acid acetoxymethyl ester SYSTEMATIC 23583884 A 906 914 BAPTA-AM ABBREVIATION 23583884 A 920 930 nifedipine TRIVIAL 23583884 T 0 35 2,3,7,8-Tetrachlorodibenzo-p-dioxin SYSTEMATIC 23583884 T 102 109 calcium SYSTEMATIC 23583901 A 1273 1275 NO FORMULA 23583901 A 1636 1638 NO FORMULA 23583901 A 1708 1718 tryptophan TRIVIAL 23583901 A 1723 1733 flavonoids FAMILY 23583901 A 1745 1765 quercetin glycosides FAMILY 23583901 A 603 632 1,1-diphenyl-2-picrylhydrazyl SYSTEMATIC 23583901 A 660 666 oxygen SYSTEMATIC 23583901 A 903 916 phenylephrine TRIVIAL 23583931 A 1007 1013 Etd(+) ABBREVIATION 23583931 A 126 132 Ca(2+) FORMULA 23583931 A 1282 1285 ATP ABBREVIATION 23583931 A 1343 1346 Ser FORMULA 23583931 A 1351 1354 Thr FORMULA 23583931 A 1510 1513 ATP ABBREVIATION 23583931 A 1525 1532 glucose TRIVIAL 23583931 A 1546 1552 Ca(2+) FORMULA 23583931 A 220 223 ATP ABBREVIATION 23583931 A 407 422 dihydropyridine SYSTEMATIC 23583931 A 427 436 ryanodine TRIVIAL 23583931 A 542 550 ethidium TRIVIAL 23583931 A 552 558 Etd(+) ABBREVIATION 23583931 A 593 596 ATP ABBREVIATION 23583931 A 64 67 ATP ABBREVIATION 23583931 A 649 656 glucose TRIVIAL 23583931 A 692 698 2-NBDG SYSTEMATIC 23583931 A 714 721 glucose TRIVIAL 23583931 A 772 779 glucose TRIVIAL 23583931 A 994 997 ATP ABBREVIATION 23583931 T 4 7 ATP ABBREVIATION 23583933 A 1152 1160 nicotine TRIVIAL 23583933 A 119 132 acetylcholine SYSTEMATIC 23583933 A 1301 1310 adenosine TRIVIAL 23583933 A 1327 1335 nicotine TRIVIAL 23583933 A 1473 1481 nicotine TRIVIAL 23583933 A 1587 1596 adenosine TRIVIAL 23583933 A 1624 1632 nicotine TRIVIAL 23583933 A 164 172 nicotine TRIVIAL 23583933 A 1756 1764 nicotine TRIVIAL 23583933 A 301 310 adenosine TRIVIAL 23583933 A 37 46 adenosine TRIVIAL 23583933 A 439 447 nicotine TRIVIAL 23583933 A 562 570 cytisine TRIVIAL 23583933 A 581 600 [(125)I]epibatidine SYSTEMATIC 23583933 A 606 612 (125)I FORMULA 23583933 A 717 725 nicotine TRIVIAL 23583933 A 759 768 adenosine TRIVIAL 23583933 A 799 807 nicotine TRIVIAL 23583933 A 960 968 nicotine TRIVIAL 23583933 A 973 981 cotinine TRIVIAL 23583933 T 117 130 acetylcholine SYSTEMATIC 23583933 T 24 33 adenosine TRIVIAL 23583933 T 56 64 nicotine TRIVIAL 23584355 A 1020 1027 ethanol SYSTEMATIC 23584355 A 1082 1090 methanol SYSTEMATIC 23584355 A 1092 1104 acetaldehyde SYSTEMATIC 23584355 A 1110 1117 acetone SYSTEMATIC 23584355 A 1151 1158 ethanol SYSTEMATIC 23584355 A 12 20 Methanol SYSTEMATIC 23584355 A 1213 1221 methanol SYSTEMATIC 23584355 A 1238 1250 acetaldehyde SYSTEMATIC 23584355 A 1267 1274 acetone SYSTEMATIC 23584355 A 1297 1304 ethanol SYSTEMATIC 23584355 A 1345 1353 methanol SYSTEMATIC 23584355 A 1369 1381 acetaldehyde SYSTEMATIC 23584355 A 1397 1404 acetone SYSTEMATIC 23584355 A 1424 1431 ethanol SYSTEMATIC 23584355 A 22 34 acetaldehyde SYSTEMATIC 23584355 A 36 43 acetone SYSTEMATIC 23584355 A 379 386 ethanol SYSTEMATIC 23584355 A 388 396 methanol SYSTEMATIC 23584355 A 402 409 acetone SYSTEMATIC 23584355 A 49 56 ethanol SYSTEMATIC 23584355 A 679 695 sodium tungstate SYSTEMATIC 23584355 A 713 727 sulphuric acid SYSTEMATIC 23584355 A 827 847 dimethylpolysiloxane FAMILY 23584355 A 955 963 methanol SYSTEMATIC 23584355 A 965 977 acetaldehyde SYSTEMATIC 23584355 A 983 990 acetone SYSTEMATIC 23584355 T 30 38 methanol SYSTEMATIC 23584355 T 40 52 acetaldehyde SYSTEMATIC 23584355 T 54 61 acetone SYSTEMATIC 23584355 T 67 74 ethanol SYSTEMATIC 23584433 A 229 236 glucose TRIVIAL 23584433 A 256 263 glucose TRIVIAL 23584544 A 130 131 C FORMULA 23584544 A 186 196 eperezolid TRIVIAL 23584544 A 27 40 oxazolidinone SYSTEMATIC 23584544 A 335 344 linezolid TRIVIAL 23584544 A 399 412 thiocarbamate SYSTEMATIC 23584544 A 462 473 methicillin TRIVIAL 23584544 A 586 595 monoamine FAMILY 23584544 A 61 129 N-hydroxyacetyl-substituted [1,2,5]triazepane or [1,2,5]oxadiazepane MULTIPLE 23584544 T 111 130 [1,2,5]oxadiazepane SYSTEMATIC 23584544 T 131 132 C FORMULA 23584544 T 14 27 oxazolidinone SYSTEMATIC 23584544 T 47 62 N-hydroxyacetyl SYSTEMATIC 23584544 T 90 107 [1,2,5]triazepane SYSTEMATIC 23584554 A 1075 1076 C FORMULA 23584554 A 1113 1114 N FORMULA 23584554 A 1176 1187 amino acids FAMILY 23584554 A 882 883 N FORMULA 23584554 A 914 915 C FORMULA 23584554 T 102 112 amino acid FAMILY 23584844 A 0 5 Hemin TRIVIAL 23584844 A 1085 1098 ascorbic acid TRIVIAL 23584844 A 1122 1127 hemin TRIVIAL 23584844 A 1128 1132 iron SYSTEMATIC 23584844 A 1152 1156 iron SYSTEMATIC 23584844 A 1234 1241 calcium SYSTEMATIC 23584844 A 1258 1263 hemin TRIVIAL 23584844 A 1264 1268 iron SYSTEMATIC 23584844 A 1341 1348 calcium SYSTEMATIC 23584844 A 1425 1429 iron SYSTEMATIC 23584844 A 1532 1537 hemin TRIVIAL 23584844 A 1538 1542 iron SYSTEMATIC 23584844 A 1575 1579 iron SYSTEMATIC 23584844 A 1621 1626 hemin TRIVIAL 23584844 A 1627 1631 iron SYSTEMATIC 23584844 A 1728 1732 iron SYSTEMATIC 23584844 A 1759 1763 iron SYSTEMATIC 23584844 A 190 194 iron SYSTEMATIC 23584844 A 248 261 ascorbic acid TRIVIAL 23584844 A 267 274 calcium SYSTEMATIC 23584844 A 303 308 hemin TRIVIAL 23584844 A 466 472 (58)Fe FORMULA 23584844 A 490 495 hemin TRIVIAL 23584844 A 543 547 iron SYSTEMATIC 23584844 A 601 606 hemin TRIVIAL 23584844 A 607 611 iron SYSTEMATIC 23584844 A 653 657 iron SYSTEMATIC 23584844 A 68 72 heme FAMILY 23584844 A 7 46 iron (III) protoporphyrin chloride (IX) SYSTEMATIC 23584844 A 73 77 iron SYSTEMATIC 23584844 A 813 818 hemin TRIVIAL 23584844 A 819 823 iron SYSTEMATIC 23584844 A 859 863 iron SYSTEMATIC 23584844 A 96 100 iron SYSTEMATIC 23584844 T 124 128 Iron SYSTEMATIC 23584844 T 54 60 (58)Fe FORMULA 23584844 T 69 74 Hemin TRIVIAL 23585096 A 126 133 epoxide SYSTEMATIC 23585096 A 22 32 halohydrin FAMILY 23585096 A 232 259 ethyl (S)-3,4-epoxybutyrate SYSTEMATIC 23585096 A 283 318 ethyl (R)-4-cyano-3-hydroxybutyrate SYSTEMATIC 23585096 A 815 823 chloride SYSTEMATIC 23585096 A 828 855 ethyl (S)-3,4-epoxybutyrate SYSTEMATIC 23585096 A 864 899 ethyl (R)-4-cyano-3-hydroxybutyrate SYSTEMATIC 23585096 T 62 72 halohydrin FAMILY 23585307 A 154 161 glycine TRIVIAL 23585307 A 382 390 methanol SYSTEMATIC 23585307 A 8 13 Pt-Cu FORMULA 23585307 T 32 37 Pt-Cu FORMULA 23585307 T 60 67 Glycine TRIVIAL 23585555 A 125 135 creatinine TRIVIAL 23585555 A 148 163 Thyroid hormone FAMILY 23585555 A 187 197 creatinine TRIVIAL 23585555 A 561 580 para-aminohippurate SYSTEMATIC 23585555 A 631 641 creatinine TRIVIAL 23585555 A 776 782 sodium SYSTEMATIC 23586505 A 38 55 gold monofluoride SYSTEMATIC 23586505 A 57 60 AuF ABBREVIATION 23586505 T 94 97 AuF ABBREVIATION 23586585 A 0 8 Graphene TRIVIAL 23586585 A 1152 1160 graphene TRIVIAL 23586585 A 1284 1295 nucleobases FAMILY 23586585 A 1405 1413 graphene TRIVIAL 23586585 A 1468 1476 graphene TRIVIAL 23586585 A 1517 1528 nucleobases FAMILY 23586585 A 289 297 graphene TRIVIAL 23586585 A 483 491 graphene TRIVIAL 23586585 A 843 851 graphene TRIVIAL 23586585 A 896 904 graphene TRIVIAL 23586585 T 73 81 Graphene TRIVIAL 23587021 A 1726 1737 fatty acids FAMILY 23587021 A 182 189 calcium SYSTEMATIC 23587021 A 194 208 diacylglycerol FAMILY 23587021 A 402 409 glucose TRIVIAL 23587021 A 522 536 diacylglycerol FAMILY 23587424 A 0 12 Salvinorin A TRIVIAL 23587424 A 252 270 dicarboxylic ester SYSTEMATIC 23587424 A 279 291 salvinorin A TRIVIAL 23587424 A 463 477 Methyl malonyl SYSTEMATIC 23587424 T 32 50 dicarboxylic ester SYSTEMATIC 23587424 T 59 71 salvinorin A TRIVIAL 23587649 A 884 892 tyrosine TRIVIAL 23587837 A 270 286 N-methylpyrazole SYSTEMATIC 23587837 A 31 54 annonaceous acetogenins FAMILY 23587837 A 312 317 alkyl FAMILY 23587837 A 336 339 THF ABBREVIATION 23587837 A 399 404 Amide SYSTEMATIC 23587837 T 166 172 carbon SYSTEMATIC 23587837 T 187 190 THF ABBREVIATION 23587837 T 43 66 annonaceous acetogenins FAMILY 23587873 A 525 536 radioiodine SYSTEMATIC 23588092 A 1018 1025 ethanol SYSTEMATIC 23588092 A 1080 1083 GSH ABBREVIATION 23588092 A 1192 1202 piplartine TRIVIAL 23588092 A 1217 1221 H(+) FORMULA 23588092 A 1222 1226 K(+) FORMULA 23588092 A 1265 1275 piplartine TRIVIAL 23588092 A 1349 1361 pentagastrin TRIVIAL 23588092 A 1416 1425 piplatine TRIVIAL 23588092 A 1529 1532 GSH ABBREVIATION 23588092 A 251 266 dichloromethane SYSTEMATIC 23588092 A 322 332 piplartine TRIVIAL 23588092 A 479 486 ethanol SYSTEMATIC 23588092 A 514 525 glutathione TRIVIAL 23588092 A 527 530 GSH ABBREVIATION 23588092 A 630 634 H(+) FORMULA 23588092 A 635 639 K(+) FORMULA 23588092 A 931 941 piplartine TRIVIAL 23588092 T 47 62 dichloromethane SYSTEMATIC 23588092 T 76 86 piplartine TRIVIAL 23588305 A 1014 1024 nucleoside FAMILY 23588305 A 776 785 bile salt FAMILY 23588305 A 846 855 bile salt FAMILY 23588391 A 223 228 amino FAMILY 23588391 A 232 240 carboxyl SYSTEMATIC 23588391 A 27 37 amino acid FAMILY 23588391 A 308 314 carbon SYSTEMATIC 23588391 A 588 605 l-diphenylalanine SYSTEMATIC 23588559 A 1083 1095 azathioprine TRIVIAL 23588559 A 118 142 6-thioguanine nucleotide SYSTEMATIC 23588559 A 1209 1214 6-TGN SYSTEMATIC 23588559 A 1272 1283 allopurinol TRIVIAL 23588559 A 1294 1306 azathioprine TRIVIAL 23588559 A 1337 1348 allopurinol TRIVIAL 23588559 A 1359 1371 azathioprine TRIVIAL 23588559 A 1397 1402 6-TGN SYSTEMATIC 23588559 A 159 164 6-TGN SYSTEMATIC 23588559 A 1594 1598 MMPN ABBREVIATION 23588559 A 179 210 methylmercaptopurine nucleotide SYSTEMATIC 23588559 A 1823 1834 allopurinol TRIVIAL 23588559 A 1845 1857 azathioprine TRIVIAL 23588559 A 1937 1947 thiopurine TRIVIAL 23588559 A 1986 1998 azathioprine TRIVIAL 23588559 A 227 231 MMPN ABBREVIATION 23588559 A 277 288 allopurinol TRIVIAL 23588559 A 302 313 thiopurines FAMILY 23588559 A 424 435 allopurinol TRIVIAL 23588559 A 472 477 6-TGN SYSTEMATIC 23588559 A 522 534 azathioprine TRIVIAL 23588559 A 575 586 allopurinol TRIVIAL 23588559 A 607 619 azathioprine TRIVIAL 23588559 A 666 671 6-TGN SYSTEMATIC 23588559 A 738 742 MMPN ABBREVIATION 23588559 A 78 88 thiopurine TRIVIAL 23588559 A 826 833 alanine TRIVIAL 23588559 A 858 867 aspartate TRIVIAL 23588559 T 125 135 thiopurine TRIVIAL 23588559 T 4 15 allopurinol TRIVIAL 23588559 T 49 61 azathioprine TRIVIAL 23588565 A 103 128 4-hydroxycyclophosphamide SYSTEMATIC 23588565 A 130 133 HCY ABBREVIATION 23588565 A 299 302 HCY ABBREVIATION 23588565 A 470 473 HCY ABBREVIATION 23588565 A 61 77 cyclophosphamide TRIVIAL 23588565 A 774 783 aspartate TRIVIAL 23588565 T 40 56 cyclophosphamide TRIVIAL 23588836 A 148 160 PDPPT-alt-FN ABBREVIATION 23588836 A 2 22 diketopyrrolopyrrole FAMILY 23588836 A 24 27 DPP ABBREVIATION 23588836 A 258 270 PDPPT-alt-FN ABBREVIATION 23588836 A 34 44 fluorenone SYSTEMATIC 23588836 A 92 104 PDPPT-alt-FN ABBREVIATION 23588836 T 102 112 fluorenone SYSTEMATIC 23588836 T 81 101 diketopyrrolopyrrole FAMILY 23589405 A 1030 1038 atrazine TRIVIAL 23589405 A 1092 1095 SDS ABBREVIATION 23589405 A 1113 1121 atrazine TRIVIAL 23589405 A 1167 1174 ethanol SYSTEMATIC 23589405 A 1262 1265 SDS ABBREVIATION 23589405 A 1299 1307 atrazine TRIVIAL 23589405 A 183 205 sodium dodecyl sulfate SYSTEMATIC 23589405 A 207 210 SDS ABBREVIATION 23589405 A 213 221 atrazine TRIVIAL 23589405 A 291 298 Ethanol SYSTEMATIC 23589405 A 458 465 ethanol SYSTEMATIC 23589405 A 773 776 SDS ABBREVIATION 23589405 A 810 813 SDS ABBREVIATION 23589405 A 850 853 SDS ABBREVIATION 23589405 A 886 889 SDS ABBREVIATION 23589405 A 945 948 SDS ABBREVIATION 23589406 A 1100 1104 CAPE ABBREVIATION 23589406 A 1176 1180 CAPE ABBREVIATION 23589406 A 211 239 caffeic acid phenethyl ester SYSTEMATIC 23589406 A 23 64 1,1'dimethyl-bipyridilium 4,4'-dichloride SYSTEMATIC 23589406 A 241 245 CAPE ABBREVIATION 23589406 A 436 440 CAPE ABBREVIATION 23589406 A 655 659 CAPE ABBREVIATION 23589406 A 702 706 CAPE ABBREVIATION 23589406 A 752 756 CAPE ABBREVIATION 23589406 A 770 774 CAPE ABBREVIATION 23589406 A 849 861 haematoxylin TRIVIAL 23589406 A 866 871 eosin FAMILY 23589406 A 9 17 Paraquat TRIVIAL 23589406 T 22 50 caffeic acid phenethyl ester SYSTEMATIC 23589406 T 95 103 paraquat TRIVIAL 23589407 A 1227 1231 CCl4 FORMULA 23589407 A 136 156 carbon tetrachloride SYSTEMATIC 23589407 A 158 162 CCl4 FORMULA 23589407 A 374 378 NaCl FORMULA 23589407 A 384 402 dimethyl sulfoxide SYSTEMATIC 23589407 A 445 449 CCl4 FORMULA 23589407 A 525 529 CCl4 FORMULA 23589407 A 559 567 n-hexane SYSTEMATIC 23589407 A 689 693 CCl4 FORMULA 23589407 A 793 803 superoxide TRIVIAL 23589407 A 837 848 glutathione TRIVIAL 23589407 A 849 850 S FORMULA 23589407 A 864 875 glutathione TRIVIAL 23589407 A 888 899 glutathione TRIVIAL 23589407 A 915 926 glutathione TRIVIAL 23589407 A 973 992 thiobarbituric acid SYSTEMATIC 23589407 T 14 34 carbon tetrachloride SYSTEMATIC 23589407 T 69 77 n-hexane SYSTEMATIC 23590116 A 520 531 polystyrene SYSTEMATIC 23590116 A 535 548 polypropylene SYSTEMATIC 23590179 A 204 243 1,3,5-tris(pyridine-4-ylethynyl)benzene SYSTEMATIC 23590179 A 284 292 hydrogen SYSTEMATIC 23590179 A 302 303 H FORMULA 23590179 A 612 613 H FORMULA 23590179 A 965 973 graphite TRIVIAL 23590179 T 54 62 Hydrogen SYSTEMATIC 23590522 A 1000 1008 ethylene SYSTEMATIC 23590522 A 1012 1015 O H FORMULA 23590522 A 1031 1050 2-methyl-2-oxetanol SYSTEMATIC 23590522 A 1054 1056 OH FORMULA 23590522 A 1165 1177 cyclic ether FAMILY 23590522 A 1179 1198 2-methyl-2-oxetanol SYSTEMATIC 23590522 A 1244 1255 acetic acid SYSTEMATIC 23590522 A 1258 1266 ethylene SYSTEMATIC 23590522 A 1270 1272 OH FORMULA 23590522 A 1372 1384 1-buten-2-ol SYSTEMATIC 23590522 A 1386 1398 2-buten-2-ol SYSTEMATIC 23590522 A 1403 1406 HO2 FORMULA 23590522 A 1597 1616 2-methyl-2-oxetanol SYSTEMATIC 23590522 A 1619 1621 OH FORMULA 23590522 A 1634 1645 acetic acid SYSTEMATIC 23590522 A 1648 1656 ethylene SYSTEMATIC 23590522 A 1659 1661 OH FORMULA 23590522 A 1770 1778 butenols FAMILY 23590522 A 2098 2101 HO2 FORMULA 23590522 A 2113 2116 EMK ABBREVIATION 23590522 A 2130 2131 H FORMULA 23590522 A 2152 2155 HO2 FORMULA 23590522 A 2169 2172 EMK ABBREVIATION 23590522 A 68 87 ethyl methyl ketone SYSTEMATIC 23590522 A 89 92 EMK ABBREVIATION 23590522 A 917 929 1-buten-2-ol SYSTEMATIC 23590522 A 932 936 HÿO2 FORMULA 23590522 A 951 963 2-buten-2-ol SYSTEMATIC 23590522 A 966 970 HÿO2 FORMULA 23590522 A 986 997 acetic acid SYSTEMATIC 23590522 A 99 102 HO2 FORMULA 23590522 T 49 68 Ethyl Methyl Ketone SYSTEMATIC 23590522 T 74 77 HO2 FORMULA 23590644 A 0 22 12-Hydroxystearic acid SYSTEMATIC 23590644 A 197 203 12-HSA SYSTEMATIC 23590644 A 223 229 12-HSA SYSTEMATIC 23590644 A 230 243 acetronitrile SYSTEMATIC 23590644 A 24 30 12-HSA SYSTEMATIC 23590644 A 279 285 12-HSA SYSTEMATIC 23590644 A 305 311 12-HSA SYSTEMATIC 23590644 A 312 319 pentane SYSTEMATIC 23590644 A 396 408 acetonitrile SYSTEMATIC 23590644 A 508 514 12-HSA SYSTEMATIC 23590644 A 54 60 12-HSA SYSTEMATIC 23590644 A 61 74 acetronitrile SYSTEMATIC 23591113 A 13 32 γ-aminobutyric acid SYSTEMATIC 23591113 A 283 329 4-isobutyl-3-isopropylbicyclophosphorothionate SYSTEMATIC 23591113 A 331 336 PS-14 IDENTIFIER 23591113 A 34 38 GABA ABBREVIATION 23591113 A 455 460 PS-14 IDENTIFIER 23591113 A 46 54 chloride SYSTEMATIC 23591113 A 544 549 PS-14 IDENTIFIER 23591113 A 600 604 GABA ABBREVIATION 23591113 A 78 87 glutamate TRIVIAL 23591113 A 94 102 chloride SYSTEMATIC 23591113 T 114 118 GABA ABBREVIATION 23591113 T 125 133 chloride SYSTEMATIC 23591113 T 34 80 4-isobutyl-3-isopropylbicyclophosphorothionate SYSTEMATIC 23591116 A 110 179 3-O-descladinosyl-3-oxo-11-deoxy-10,11-epoxy-6-O-methylerythromycin A SYSTEMATIC 23591116 A 18 38 10-hydroxyl ketolide FAMILY 23591116 A 199 223 6-O-methylerythromycin A SYSTEMATIC 23591116 A 463 472 ketolides FAMILY 23591116 T 60 80 10-hydroxyl ketolide FAMILY 23591117 A 181 199 l- and d-arabinose MULTIPLE 23591117 A 23 58 pyrimidine deoxyapiothionucleosides FAMILY 23591117 A 346 356 nucleobase FAMILY 23591117 A 366 375 thiosugar FAMILY 23591117 T 44 79 pyrimidine deoxyapiothionucleosides FAMILY 23591579 A 1007 1014 arsenic SYSTEMATIC 23591579 A 1084 1091 arsenic SYSTEMATIC 23591579 A 1143 1150 arsenic SYSTEMATIC 23591579 A 250 257 arsenic SYSTEMATIC 23591579 A 378 384 NaAsO2 FORMULA 23591579 A 567 574 arsenic SYSTEMATIC 23591579 A 634 641 arsenic SYSTEMATIC 23591579 A 757 763 NaAsO2 FORMULA 23591579 A 793 802 melatonin TRIVIAL 23591579 A 854 861 arsenic SYSTEMATIC 23591579 T 106 113 arsenic SYSTEMATIC 23591845 A 103 113 phosphorus SYSTEMATIC 23591845 A 115 116 P FORMULA 23591845 A 1162 1163 P FORMULA 23591845 A 1318 1319 P FORMULA 23591845 A 214 215 P FORMULA 23591845 A 251 252 P FORMULA 23591845 A 296 305 phosphate SYSTEMATIC 23591845 A 370 371 P FORMULA 23591845 A 477 478 P FORMULA 23591845 A 600 601 P FORMULA 23591845 A 705 706 P FORMULA 23591845 A 760 761 P FORMULA 23591845 T 55 65 Phosphorus SYSTEMATIC 23592595 A 177 186 serotonin TRIVIAL 23592746 A 1029 1038 bile acid FAMILY 23592746 A 1056 1061 TUDCA ABBREVIATION 23592746 A 1131 1140 bile acid FAMILY 23592746 A 117 122 TUDCA ABBREVIATION 23592746 A 1239 1248 Bile acid FAMILY 23592746 A 1257 1262 TUDCA ABBREVIATION 23592746 A 1263 1267 UDCA ABBREVIATION 23592746 A 1312 1317 TUDCA ABBREVIATION 23592746 A 1442 1452 bile acids FAMILY 23592746 A 1591 1601 bile acids FAMILY 23592746 A 178 187 bile acid FAMILY 23592746 A 251 256 TUDCA ABBREVIATION 23592746 A 33 43 bile acids FAMILY 23592746 A 56 65 bile acid FAMILY 23592746 A 640 647 Glucose TRIVIAL 23592746 A 90 115 tauroursodeoxycholic acid TRIVIAL 23592746 A 911 918 glucose TRIVIAL 23592746 A 986 996 bile acids FAMILY 23592746 T 67 77 Bile Acids FAMILY 23594297 A 113 126 ascorbic acid TRIVIAL 23594297 A 127 134 citrate FAMILY 23594297 A 204 210 silver SYSTEMATIC 23594297 A 21 27 Silver SYSTEMATIC 23594297 A 241 252 gallic acid TRIVIAL 23594297 A 336 349 ascorbic acid TRIVIAL 23594297 A 354 361 citrate FAMILY 23594297 A 457 463 silver SYSTEMATIC 23594297 A 483 488 Ag(+) FORMULA 23594297 A 489 494 Ag(0) FORMULA 23594297 A 776 783 Citrate TRIVIAL 23594297 T 0 6 Silver SYSTEMATIC 23594303 A 1015 1018 VCM ABBREVIATION 23594303 A 1181 1184 VCM ABBREVIATION 23594303 A 281 291 vancomycin TRIVIAL 23594303 A 318 321 VCM ABBREVIATION 23594303 A 372 375 VCM ABBREVIATION 23594303 A 406 409 VCM ABBREVIATION 23594303 A 431 441 vancomycin TRIVIAL 23594303 A 541 544 VCM ABBREVIATION 23594303 A 627 630 VCM ABBREVIATION 23594303 A 663 673 vancomycin TRIVIAL 23594303 T 17 27 vancomycin TRIVIAL 23594303 T 39 44 acryl TRIVIAL 23594314 A 729 740 monoterpene FAMILY 23594314 A 745 771 sesquiterpene hydrocarbons FAMILY 23594314 A 773 796 Oxygenated monoterpenes FAMILY 23594999 A 221 227 oxygen SYSTEMATIC 23594999 A 232 240 nitrogen SYSTEMATIC 23594999 A 33 39 oxygen SYSTEMATIC 23595053 A 1029 1035 6dTalp SYSTEMATIC 23595053 A 1199 1200 O FORMULA 23595053 A 1274 1275 O FORMULA 23595053 A 1312 1318 6dTalp SYSTEMATIC 23595053 A 341 398 1,4'-bisphosphorylated β-(1→6)-linked d-GlcN disaccharide FAMILY 23595053 A 407 411 AraN FORMULA 23595053 A 561 562 O FORMULA 23595053 A 637 652 tetrasaccharide FAMILY 23595053 A 683 699 6-deoxy-l-talose SYSTEMATIC 23595053 A 701 707 6dTalp SYSTEMATIC 23595053 A 727 734 GalpNAc FORMULA 23595053 A 833 838 sugar FAMILY 23595053 A 906 912 6dTalp SYSTEMATIC 23595053 A 947 955 O-acetyl SYSTEMATIC 23595773 A 157 166 palbinone TRIVIAL 23595773 A 211 215 heme FAMILY 23595773 T 0 9 Palbinone TRIVIAL 23595773 T 80 84 Heme FAMILY 23596326 A 297 308 cholesterol TRIVIAL 23596326 A 543 554 cholesterol TRIVIAL 23597075 A 354 373 poly(β-amino ester) FAMILY 23597080 A 411 432 4-anilinoquinazolines FAMILY 23597080 A 433 442 lapatinib TRIVIAL 23597080 A 444 452 GW572016 IDENTIFIER 23597080 A 461 471 canertinib TRIVIAL 23597080 A 473 480 CI-1033 IDENTIFIER 23597080 A 730 751 4-anilinoquinazolines FAMILY 23597080 A 763 769 NEU617 IDENTIFIER 23597080 T 95 104 Lapatanib TRIVIAL 23597210 A 1208 1229 chlorinated ethylenes FAMILY 23597210 A 1273 1275 C4 FORMULA 23597210 A 1280 1282 C2 FORMULA 23597210 A 1353 1358 C4Cl4 FORMULA 23597210 A 1361 1366 C2Cl2 FORMULA 23597210 A 278 299 chlorinated ethylenes FAMILY 23597210 A 30 37 benzene SYSTEMATIC 23597210 A 301 307 CH2Cl2 FORMULA 23597210 A 309 314 C4Cl4 FORMULA 23597210 A 316 321 C4Cl6 FORMULA 23597210 A 327 331 C2H2 FORMULA 23597210 A 385 388 2C3 FORMULA 23597210 A 393 395 C4 FORMULA 23597210 A 396 398 C2 FORMULA 23597210 A 454 460 carbon SYSTEMATIC 23597210 A 478 483 C4Cl6 FORMULA 23597210 A 504 507 2C3 FORMULA 23597210 A 595 601 C2HCl3 FORMULA 23597210 A 611 613 C4 FORMULA 23597210 A 614 616 C2 FORMULA 23597210 A 68 99 dichloro- and trichloroethylene MULTIPLE 23597210 A 699 701 C3 FORMULA 23597210 A 716 722 carbon SYSTEMATIC 23597210 A 754 769 dichloromethane SYSTEMATIC 23597210 A 788 790 C3 FORMULA 23597210 A 822 839 perchlorinated C4 FORMULA 23597210 A 848 853 C4Cl5 FORMULA 23597210 A 855 860 C4Cl3 FORMULA 23597210 A 866 871 C4Cl4 FORMULA 23597210 A 877 882 C2Cl2 FORMULA 23597210 T 41 77 Unsaturated Chlorinated Hydrocarbons FAMILY 23597210 T 92 99 Benzene SYSTEMATIC 23597309 A 1142 1147 CH-01 IDENTIFIER 23597309 A 727 732 CH-01 IDENTIFIER 23597309 A 867 872 nitro SYSTEMATIC 23597309 T 0 5 CH-01 IDENTIFIER 23597444 A 110 126 sodium hydroxide SYSTEMATIC 23597449 A 120 141 1,2-dimethylhydrazine SYSTEMATIC 23597449 A 143 146 DMH ABBREVIATION 23597449 A 185 188 DMH ABBREVIATION 23597449 A 306 322 N-acetylcysteine SYSTEMATIC 23597449 A 324 327 NAC ABBREVIATION 23597449 A 699 702 NAC ABBREVIATION 23597449 T 49 66 dimethylhydrazine SYSTEMATIC 23597791 A 11 15 urea TRIVIAL 23597791 A 189 213 triazolothienopyrimidine SYSTEMATIC 23597791 A 296 313 1,1-difluoroethyl SYSTEMATIC 23597791 A 400 405 ethyl SYSTEMATIC 23597791 A 545 552 amidine SYSTEMATIC 23597791 A 560 569 thiophene SYSTEMATIC 23597791 T 0 55 1,1-Difluoroethyl-substituted triazolothienopyrimidines FAMILY 23597791 T 81 85 urea TRIVIAL 23598085 A 1085 1100 triacylglycerol FAMILY 23598085 A 1102 1105 TAG ABBREVIATION 23598085 A 1160 1167 glucose TRIVIAL 23598085 A 1317 1324 glucose TRIVIAL 23598085 A 1374 1377 TAG ABBREVIATION 23598085 A 1382 1389 glucose TRIVIAL 23598085 A 1480 1483 TAG ABBREVIATION 23598085 A 1489 1496 glucose TRIVIAL 23598085 A 1543 1550 glucose TRIVIAL 23598085 A 263 270 glucose TRIVIAL 23598085 A 522 529 glucose TRIVIAL 23598085 A 849 856 glucose TRIVIAL 23598085 A 894 901 glucose TRIVIAL 23598085 T 35 50 triacylglycerol FAMILY 23598085 T 56 63 glucose TRIVIAL 23599007 A 11 21 diterpenes FAMILY 23599007 A 277 286 abietanes FAMILY 23599007 A 29 43 decandrins A-K MULTIPLE 23599007 A 479 487 abietane TRIVIAL 23599007 A 492 503 podocarpane TRIVIAL 23599007 A 504 516 diterpenoids FAMILY 23599007 A 67 76 abietanes FAMILY 23599007 A 91 103 podocarpanes FAMILY 23599007 T 4 14 Diterpenes FAMILY 23599124 A 276 279 Mn6 FORMULA 23599124 A 366 373 Mn(III) FORMULA 23599124 A 639 642 Mn6 FORMULA 23599124 A 744 747 Mn6 FORMULA 23599124 A 76 79 Mn6 FORMULA 23599124 T 56 59 Mn6 FORMULA 23600364 A 169 171 Au FORMULA 23600364 A 83 85 Ag FORMULA 23600364 A 86 88 Au FORMULA 23600364 T 41 43 Ag FORMULA 23600364 T 44 46 Au FORMULA 23600402 A 238 245 octanol SYSTEMATIC 23600402 A 561 568 octanol SYSTEMATIC 23600526 A 1086 1089 Cy3 FAMILY 23600526 A 1136 1141 Cy5.5 FAMILY 23600526 A 1321 1324 Cy3 FAMILY 23600526 A 461 472 polystyrene SYSTEMATIC 23600526 A 671 677 quartz TRIVIAL 23600526 A 679 683 SiO2 FORMULA 23600526 A 688 695 silicon SYSTEMATIC 23600526 A 945 948 Cy3 FAMILY 23600526 A 953 958 Cy5.5 FAMILY 23600654 A 100 108 Eudragit TRIVIAL 23600654 A 315 319 NaCl FORMULA 23600654 A 321 325 NaBr FORMULA 23600654 A 330 336 KH2PO4 FORMULA 23600654 A 605 609 NaCl FORMULA 23600654 A 61 76 tolmetin sodium SYSTEMATIC 23600654 A 611 615 NaBr FORMULA 23600654 A 620 626 KH2PO4 FORMULA 23600654 A 974 982 Eudragit TRIVIAL 23600657 A 1256 1260 FITC ABBREVIATION 23600657 A 187 213 fluorescein isothiocyanate TRIVIAL 23600657 A 225 229 FITC ABBREVIATION 23600657 A 777 781 FITC ABBREVIATION 23600667 A 42 60 polyethyleneglycol SYSTEMATIC 23600667 A 612 653 Poly(2-(dimethylamino)ethyl methacrylate) FAMILY 23600682 A 31 55 ammopiptanosides A and B MULTIPLE 23600682 A 8 29 isoflavone glycosides FAMILY 23600682 A 89 93 EtOH FORMULA 23600698 A 361 383 sulfonated polyaniline FAMILY 23600698 A 385 389 SPAN ABBREVIATION 23600698 A 561 565 SPAN ABBREVIATION 23600698 T 0 22 Sulfonated Polyaniline FAMILY 23600789 A 10 40 sulfated triterpene glycosides FAMILY 23600789 A 152 243 3β-[(2-O-sulfo-β-d-xylopyranosyl)oxy]urs-12,19(29)-diene-28-oic acid 28-β-d-glucopyranoside SYSTEMATIC 23600789 A 249 336 3β-[(2-O-sulfo-β-d-xylopyranosyl)oxy]urs-12,19-diene-28-oic acid 28-β-d-glucopyranoside SYSTEMATIC 23600789 A 346 410 3β-[(2-O-sulfo-β-d-xylopyranosyl)oxy]urs-12,19-diene-28-oic acid SYSTEMATIC 23600789 A 42 61 asprellanosides C-E MULTIPLE 23600789 T 10 31 triterpene glycosides FAMILY 23601203 A 0 13 Catecholamine FAMILY 23601203 A 22 40 EDTA-bis(tyramide) SYSTEMATIC 23601203 A 293 303 amino acid FAMILY 23601203 A 313 316 Arg FORMULA 23601203 A 321 324 Arg FORMULA 23601203 A 332 335 Lys FORMULA 23601203 A 774 792 EDTA-bis(tyramide) SYSTEMATIC 23601203 A 806 814 (99m) Tc FORMULA 23601203 A 970 998 (99m) Tc- EDTA-bis(tyramide) SYSTEMATIC 23601203 T 47 60 catecholamine TRIVIAL 23601248 A 277 285 tyrosine TRIVIAL 23601248 A 918 930 lestaurtinib TRIVIAL 23601384 A 819 838 omega-3 fatty acids FAMILY 23601384 A 840 848 selenium SYSTEMATIC 23601384 A 850 857 taurine TRIVIAL 23601384 A 859 877 vitamins D and B12 MULTIPLE 23601384 T 43 54 fatty acids FAMILY 23601385 A 0 8 Caffeine TRIVIAL 23601385 A 125 133 caffeine TRIVIAL 23601385 A 225 233 caffeine TRIVIAL 23601385 A 353 361 caffeine TRIVIAL 23601385 A 494 502 caffeine TRIVIAL 23601385 A 707 715 caffeine TRIVIAL 23601385 A 762 770 caffeine TRIVIAL 23601385 A 860 868 caffeine TRIVIAL 23601385 T 10 18 caffeine TRIVIAL 23601399 A 326 335 vitamin C TRIVIAL 23601399 A 360 369 phenolics FAMILY 23601399 A 440 444 DPPH ABBREVIATION 23601399 A 651 663 phytosterols FAMILY 23601399 A 730 739 phenolics FAMILY 23601401 A 210 219 vitamin A FAMILY 23601401 A 343 352 vitamin A FAMILY 23601401 A 485 494 vitamin A FAMILY 23601401 A 548 555 retinol TRIVIAL 23601401 A 690 699 vitamin A FAMILY 23601401 A 759 768 vitamin A FAMILY 23601401 A 812 821 vitamin A FAMILY 23601401 T 51 60 vitamin A FAMILY 23601402 A 114 147 (6S)-5-methyltetrahydrofolic acid SYSTEMATIC 23601402 A 149 168 (6S)-5-CH3-H4PteGlu SYSTEMATIC 23601402 A 448 454 folate TRIVIAL 23601402 A 50 60 folic acid TRIVIAL 23601402 A 630 649 (6S)-5-CH3-H4PteGlu SYSTEMATIC 23601402 T 134 140 folate TRIVIAL 23601402 T 34 44 folic acid TRIVIAL 23601414 A 108 109 N FORMULA 23601414 A 251 252 N FORMULA 23601414 A 378 388 amino acid FAMILY 23601414 A 488 498 amino-acid FAMILY 23601414 A 599 607 nitrogen SYSTEMATIC 23601414 A 711 722 amino acids FAMILY 23601414 A 850 860 amino acid FAMILY 23601414 A 882 890 nitrogen SYSTEMATIC 23601414 A 930 941 amino acids FAMILY 23601414 A 98 106 nitrogen SYSTEMATIC 23601414 T 19 29 amino-acid FAMILY 23601414 T 6 14 nitrogen SYSTEMATIC 23601640 A 0 12 Actinorhodin TRIVIAL 23601640 A 101 104 BIQ ABBREVIATION 23601640 A 14 17 ACT ABBREVIATION 23601640 A 142 148 flavin FAMILY 23601640 A 193 196 ACT ABBREVIATION 23601640 A 269 275 flavin FAMILY 23601640 A 276 280 NADH ABBREVIATION 23601640 A 406 410 BIQs FAMILY 23601640 A 412 422 granaticin TRIVIAL 23601640 A 424 427 GRA ABBREVIATION 23601640 A 433 443 medermycin TRIVIAL 23601640 A 445 448 MED ABBREVIATION 23601640 A 485 494 alnumycin TRIVIAL 23601640 A 496 499 ALN ABBREVIATION 23601640 A 553 556 Gra ABBREVIATION 23601640 A 564 567 Med ABBREVIATION 23601640 A 648 651 Gra ABBREVIATION 23601640 A 695 704 p-quinone SYSTEMATIC 23601640 A 76 99 benzoisochromanequinone SYSTEMATIC 23601640 A 793 796 Med ABBREVIATION 23601640 A 817 826 p-quinone SYSTEMATIC 23601640 A 841 850 p-quinone SYSTEMATIC 23601640 A 866 869 BIQ ABBREVIATION 23601640 A 932 941 p-quinone SYSTEMATIC 23601640 A 955 958 ALN ABBREVIATION 23601640 T 90 102 actinorhodin TRIVIAL 23601708 A 41 63 pyrazole-4-acetic acid SYSTEMATIC 23601708 T 0 31 2-(1H-Pyrazol-4-yl)acetic acids FAMILY 23602152 A 110 114 5hmC SYSTEMATIC 23602152 A 117 133 5-formylcytosine SYSTEMATIC 23602152 A 135 138 5fC SYSTEMATIC 23602152 A 145 163 5-carboxylcytosine SYSTEMATIC 23602152 A 165 169 5caC SYSTEMATIC 23602152 A 172 175 5fC SYSTEMATIC 23602152 A 176 180 5caC SYSTEMATIC 23602152 A 234 243 cytosines FAMILY 23602152 A 247 254 thymine TRIVIAL 23602152 A 38 54 5-methylcytosine SYSTEMATIC 23602152 A 486 490 5hmC SYSTEMATIC 23602152 A 491 494 5fC SYSTEMATIC 23602152 A 495 499 5caC SYSTEMATIC 23602152 A 56 59 5mC SYSTEMATIC 23602152 A 630 633 5fC SYSTEMATIC 23602152 A 634 638 5caC SYSTEMATIC 23602152 A 801 804 5fC SYSTEMATIC 23602152 A 809 813 5caC SYSTEMATIC 23602152 A 85 108 5-hydroxymethylcytosine SYSTEMATIC 23602152 A 942 945 5mC SYSTEMATIC 23602152 T 52 68 5-Methylcytosine SYSTEMATIC 23602441 A 112 151 4-phenylpiperazine-1-carbothiohydrazide SYSTEMATIC 23602441 A 309 330 5-chloroindolin-2-one SYSTEMATIC 23602441 A 42 55 indolin-2-one SYSTEMATIC 23602441 A 429 435 phenyl SYSTEMATIC 23602441 A 461 471 piperazine SYSTEMATIC 23602441 A 763 772 Sunitinib TRIVIAL 23602441 A 777 790 indolin-2-one SYSTEMATIC 23602441 A 78 91 indolin-2-one SYSTEMATIC 23602441 T 46 77 piperazine-1-carbothiohydrazide SYSTEMATIC 23602441 T 93 106 indolin-2-one SYSTEMATIC 23602987 A 386 406 phosphatidylinositol TRIVIAL 23603004 A 1073 1086 malonaldehyde TRIVIAL 23603004 A 1091 1105 hydroxyproline SYSTEMATIC 23603004 A 1184 1187 GSH ABBREVIATION 23603004 A 1230 1238 naringin TRIVIAL 23603004 A 386 389 NAC ABBREVIATION 23603004 A 393 401 naringin TRIVIAL 23603004 A 498 501 NAC ABBREVIATION 23603004 A 50 58 naringin TRIVIAL 23603004 A 505 513 naringin TRIVIAL 23603004 A 67 75 paraquat TRIVIAL 23603004 A 712 720 naringin TRIVIAL 23603004 A 884 887 NAC ABBREVIATION 23603004 A 891 899 naringin TRIVIAL 23603004 A 942 950 naringin TRIVIAL 23603004 T 22 30 naringin TRIVIAL 23603004 T 39 47 paraquat TRIVIAL 23603147 A 0 7 Arsenic SYSTEMATIC 23603147 A 1332 1334 As FORMULA 23603147 A 1583 1590 arsenic SYSTEMATIC 23603147 A 265 272 arsenic SYSTEMATIC 23603147 A 379 386 arsenic SYSTEMATIC 23603147 A 392 397 As2O3 FORMULA 23603147 A 511 518 arsenic SYSTEMATIC 23603147 A 637 639 As FORMULA 23603147 A 9 11 As FORMULA 23603147 T 41 48 arsenic SYSTEMATIC 23603194 A 1040 1047 ethanol SYSTEMATIC 23603194 A 1182 1192 l-arginine TRIVIAL 23603194 A 1269 1276 ethanol SYSTEMATIC 23603194 A 1446 1469 l-arginine-nitric oxide SYSTEMATIC 23603194 A 471 478 ethanol SYSTEMATIC 23603194 A 709 716 ethanol SYSTEMATIC 23603194 A 805 816 acetic acid SYSTEMATIC 23603194 A 844 851 ethanol SYSTEMATIC 23603194 A 917 926 capsaicin TRIVIAL 23603194 A 951 960 glutamate TRIVIAL 23603194 T 64 71 ethanol SYSTEMATIC 23603202 A 143 152 glutamate TRIVIAL 23603202 A 192 201 glutamate TRIVIAL 23603202 A 284 293 glutamate TRIVIAL 23603382 A 0 7 Arsenic SYSTEMATIC 23603382 A 1091 1097 NaAsO2 FORMULA 23603382 A 1144 1151 Na2SeO3 FORMULA 23603382 A 234 242 selenium SYSTEMATIC 23603382 A 274 281 arsenic SYSTEMATIC 23603382 A 623 630 Na2SeO3 FORMULA 23603382 A 643 646 MDA ABBREVIATION 23603382 A 749 756 Na2SeO3 FORMULA 23603382 A 876 883 Na2SeO3 FORMULA 23603382 A 884 890 NaAsO2 FORMULA 23603382 A 9 11 As FORMULA 23603382 A 987 993 NaAsO2 FORMULA 23603382 T 136 143 arsenic SYSTEMATIC 23603382 T 22 30 selenium SYSTEMATIC 23603383 A 114 122 methanol SYSTEMATIC 23603383 A 276 284 phenolic FAMILY 23603383 A 447 456 flavonoid FAMILY 23603383 A 608 622 phenolic acids FAMILY 23603383 A 673 692 protocatechuic acid TRIVIAL 23603383 A 812 816 DPPH ABBREVIATION 23603383 A 828 831 TBA ABBREVIATION 23603616 A 1154 1200 imidazolyl substituted phenylene-benzothiazole FAMILY 23603616 A 254 302 amidino substituted-phenylene-bis-benzothyazoles FAMILY 23603616 A 29 56 phenylene-bisbenzothiazoles FAMILY 23603616 A 350 373 isophthaloyl dichloride SYSTEMATIC 23603616 A 381 405 terephthaloyl dichloride SYSTEMATIC 23603616 A 417 430 phthalic acid TRIVIAL 23603616 A 439 471 5-amidinium-2-aminobenzothiolate SYSTEMATIC 23603616 A 479 522 5-(imidazolinium-2-yl)-2-aminobenzothiolate SYSTEMATIC 23603616 A 6 13 amidino FAMILY 23603616 A 609 624 dihydrochloride SYSTEMATIC 23603616 A 679 682 HCl FORMULA 23603616 A 686 693 ethanol SYSTEMATIC 23603616 A 697 708 acetic acid SYSTEMATIC 23603616 A 882 935 diimidazolinyl substituted phenylene-bisbenzothiazole FAMILY 23603616 T 36 63 phenylene-bisbenzothiazoles FAMILY 23603856 A 255 263 graphene TRIVIAL 23603856 A 331 344 silicon oxide SYSTEMATIC 23603856 A 366 373 silicon SYSTEMATIC 23603856 A 641 649 graphene TRIVIAL 23603856 A 719 727 graphene TRIVIAL 23603856 A 99 107 graphene TRIVIAL 23603856 T 39 48 graphenes FAMILY 23603902 A 102 112 biliverdin TRIVIAL 23603902 A 1288 1295 methine SYSTEMATIC 23603902 A 1330 1337 methine SYSTEMATIC 23603902 A 1451 1454 Asp FORMULA 23603902 A 1486 1497 carboxylate SYSTEMATIC 23603902 A 1562 1570 carbonyl FAMILY 23603902 A 348 360 tetrapyrrole SYSTEMATIC 23603902 A 658 663 thiol FAMILY 23603902 A 678 681 Cys FORMULA 23603902 A 702 707 vinyl FAMILY 23603902 T 21 31 biliverdin TRIVIAL 23604005 A 146 156 graphdiyne TRIVIAL 23604005 A 205 215 graphdiyne TRIVIAL 23604005 A 520 530 graphdiyne TRIVIAL 23604005 A 639 649 graphdiyne TRIVIAL 23604005 A 708 716 graphene TRIVIAL 23604005 T 95 105 graphdiyne TRIVIAL 23604074 A 874 887 polyglutamine FAMILY 23604141 A 1038 1050 posaconazole TRIVIAL 23604141 A 1190 1196 azoles FAMILY 23604141 A 1261 1266 azole FAMILY 23604141 A 1321 1326 azole FAMILY 23604141 A 1514 1519 azole FAMILY 23604141 A 193 204 cholesterol TRIVIAL 23604141 A 286 292 azoles FAMILY 23604141 A 370 382 voriconazole TRIVIAL 23604141 A 387 399 clotrimazole TRIVIAL 23604141 A 458 470 posaconazole TRIVIAL 23604141 A 539 543 heme FAMILY 23604141 A 544 548 iron SYSTEMATIC 23604141 A 558 566 nitrogen SYSTEMATIC 23604141 A 588 593 azole FAMILY 23604141 A 61 67 azoles FAMILY 23604141 A 803 815 posaconazole TRIVIAL 23604141 A 866 878 posaconazole TRIVIAL 23604141 A 969 981 voriconazole TRIVIAL 23604141 A 986 998 clotrimazole TRIVIAL 23604141 T 11 17 Azoles FAMILY 23604141 T 71 82 Cholesterol TRIVIAL 23604334 A 1203 1210 U62,066 IDENTIFIER 23604334 A 1349 1356 U62,066 IDENTIFIER 23604334 A 411 418 U62,066 IDENTIFIER 23604334 A 599 606 U62,066 IDENTIFIER 23604334 A 636 645 saccharin TRIVIAL 23604334 A 672 681 saccharin TRIVIAL 23604334 A 896 903 U62,066 IDENTIFIER 23604336 A 1036 1051 Methylphenidate SYSTEMATIC 23604336 A 11 19 dopamine TRIVIAL 23604336 A 1127 1142 methylphenidate SYSTEMATIC 23604336 A 154 162 dopamine TRIVIAL 23604336 A 386 401 methylphenidate SYSTEMATIC 23604336 A 757 772 Methylphenidate SYSTEMATIC 23604336 A 876 884 pallidum SYSTEMATIC 23604336 A 913 928 Methylphenidate SYSTEMATIC 23604336 T 0 15 Methylphenidate SYSTEMATIC 23604490 A 657 663 Yb(3+) FORMULA 23604718 A 0 14 Sparstolonin B TRIVIAL 23604718 A 1020 1024 SsnB ABBREVIATION 23604718 A 1171 1175 SsnB ABBREVIATION 23604718 A 1236 1240 SsnB ABBREVIATION 23604718 A 158 162 SsnB ABBREVIATION 23604718 A 16 20 SsnB ABBREVIATION 23604718 A 28 39 isocoumarin TRIVIAL 23604718 A 393 397 SsnB ABBREVIATION 23604718 A 553 557 SsnB ABBREVIATION 23604718 A 904 908 SsnB ABBREVIATION 23604718 A 942 946 SsnB ABBREVIATION 23604718 T 0 14 Sparstolonin B TRIVIAL 23605691 A 1064 1073 oxycodone TRIVIAL 23605691 A 1278 1287 oxycodone TRIVIAL 23605691 A 1467 1477 rifampicin TRIVIAL 23605691 A 1498 1511 carbamazepine TRIVIAL 23605691 A 1586 1595 oxycodone TRIVIAL 23605691 A 1616 1624 morphine TRIVIAL 23605691 A 1718 1727 oxycodone TRIVIAL 23605691 A 1832 1840 morphine TRIVIAL 23605691 A 276 284 morphine TRIVIAL 23605691 A 304 313 Oxycodone TRIVIAL 23605691 A 38 47 oxycodone TRIVIAL 23605691 A 476 488 noroxycodone TRIVIAL 23605691 A 490 501 oxymorphone TRIVIAL 23605691 A 506 520 noroxymorphone TRIVIAL 23605691 A 522 531 Oxycodone TRIVIAL 23605691 A 85 93 morphine TRIVIAL 23605691 T 36 45 oxycodone TRIVIAL 23605692 A 1032 1041 rapamycin TRIVIAL 23605692 A 1057 1066 tamoxifen TRIVIAL 23605692 A 1385 1394 letrozole TRIVIAL 23605692 A 1407 1416 letrozole TRIVIAL 23605692 A 1598 1609 fulvestrant TRIVIAL 23605692 A 1686 1703 poly (ADP-ribose) SYSTEMATIC 23605692 A 1840 1852 progesterone TRIVIAL 23605692 A 943 951 estrogen FAMILY 23605693 A 1090 1100 vismodegib TRIVIAL 23606373 A 142 147 PEDOT ABBREVIATION 23606373 A 172 177 PEDOT ABBREVIATION 23606373 A 31 63 poly(3,4-ethylenedioxythiophene) SYSTEMATIC 23606373 A 64 86 poly(styrenesulfonate) FAMILY 23606373 A 7 22 ethylene glycol SYSTEMATIC 23606373 A 88 93 PEDOT ABBREVIATION 23606373 A 94 97 PSS ABBREVIATION 23606373 T 49 54 PEDOT ABBREVIATION 23606373 T 55 58 PSS ABBREVIATION 23606504 A 123 131 graphene TRIVIAL 23606504 A 149 155 Fe3 O4 FORMULA 23606504 A 188 196 graphene TRIVIAL 23606504 A 230 238 graphene TRIVIAL 23606504 A 257 263 Fe3 O4 FORMULA 23606504 A 265 273 graphene TRIVIAL 23606504 A 297 304 lithium SYSTEMATIC 23606504 A 31 37 Fe3 O4 FORMULA 23606504 A 54 68 graphene oxide SYSTEMATIC 23606504 T 3 11 Graphene TRIVIAL 23606504 T 53 59 Fe3 O4 FORMULA 23606504 T 85 92 Lithium SYSTEMATIC 23607283 A 1024 1028 dUTP ABBREVIATION 23607283 A 1111 1131 99m Tc pertechnetate SYSTEMATIC 23607283 A 1782 1802 99m Tc pertechnetate SYSTEMATIC 23607283 A 1999 2010 radioiodine SYSTEMATIC 23607283 A 49 60 radioiodine SYSTEMATIC 23607283 A 995 1011 deoxynucleotidyl FAMILY 23607283 T 72 83 Radioiodine SYSTEMATIC 23607697 A 162 175 Fampridine PR TRIVIAL 23607697 A 18 28 fampridine TRIVIAL 23607697 A 30 43 fampridine PR TRIVIAL 23607697 A 310 323 fampridine PR TRIVIAL 23607697 A 50 59 potassium SYSTEMATIC 23607697 T 49 59 Fampridine TRIVIAL 23607712 A 1160 1166 Ca(2+) FORMULA 23607712 A 1168 1172 H(+) FORMULA 23607712 A 1304 1310 Ca(2+) FORMULA 23607712 A 1335 1341 Ca(2+) FORMULA 23607712 A 1343 1347 H(+) FORMULA 23607712 A 15 21 Ca(2+) FORMULA 23607712 A 23 27 H(+) FORMULA 23607712 A 328 334 Ca(2+) FORMULA 23607712 A 413 420 calcium SYSTEMATIC 23607712 A 545 551 Ca(2+) FORMULA 23607712 A 553 557 H(+) FORMULA 23607712 A 581 587 Ca(2+) FORMULA 23607712 A 589 593 H(+) FORMULA 23607712 A 691 697 Ca(2+) FORMULA 23607712 A 736 740 H(+) FORMULA 23607712 A 756 767 bafilomycin FAMILY 23607712 A 778 785 calcium SYSTEMATIC 23607712 A 823 830 calcium SYSTEMATIC 23607712 A 896 902 Ca(2+) FORMULA 23607712 A 904 908 H(+) FORMULA 23607712 T 42 48 Ca(2+) FORMULA 23607712 T 50 54 H(+) FORMULA 23607891 A 1034 1042 apocynin TRIVIAL 23607891 A 1052 1056 iron SYSTEMATIC 23607891 A 1378 1387 magnetite TRIVIAL 23607891 A 19 28 magnetite TRIVIAL 23607891 A 305 314 magnetite TRIVIAL 23607891 A 455 465 superoxide TRIVIAL 23607891 A 578 581 GSH ABBREVIATION 23607891 A 630 639 magnetite TRIVIAL 23607891 A 885 904 diphenyleneiodonium TRIVIAL 23607891 A 906 909 DPI ABBREVIATION 23607891 A 914 919 NADPH ABBREVIATION 23607891 T 52 61 Magnetite TRIVIAL 23607932 A 195 230 p-hydroxybenzoic and cinnamic acids MULTIPLE 23607932 A 422 457 p-Hydroxybenzoic and cinnamic acids MULTIPLE 23607932 T 126 162 acetylated glucuronide methyl esters FAMILY 23607932 T 70 105 p-hydroxybenzoic and cinnamic acids MULTIPLE 23607964 A 0 12 Progesterone TRIVIAL 23607964 A 119 133 antiprogestins FAMILY 23607964 A 174 182 estrogen FAMILY 23607964 A 188 200 progesterone TRIVIAL 23607964 A 323 346 17-fluorinated steroids FAMILY 23607964 A 468 482 antiprogestins FAMILY 23607964 A 494 503 ZK230 211 IDENTIFIER 23607964 A 505 511 RU-486 IDENTIFIER 23607964 A 513 520 CDB2914 IDENTIFIER 23607964 A 522 529 CDB4124 IDENTIFIER 23607964 A 534 542 ORG33628 IDENTIFIER 23607964 A 717 722 EC304 IDENTIFIER 23607964 A 918 923 EC304 IDENTIFIER 23607964 A 98 110 progesterone TRIVIAL 23607964 T 53 76 17-fluorinated steroids FAMILY 23608020 A 1150 1154 urea TRIVIAL 23608020 A 1155 1163 nitrogen SYSTEMATIC 23608020 A 1174 1184 creatinine TRIVIAL 23608222 A 0 7 Glucose TRIVIAL 23608222 A 106 108 K+ FORMULA 23608222 A 1071 1079 atropine TRIVIAL 23608222 A 1080 1094 methyl nitrate SYSTEMATIC 23608222 A 1235 1247 carbohydrate FAMILY 23608222 A 1279 1286 glucose TRIVIAL 23608222 A 1395 1410 carbamylcholine SYSTEMATIC 23608222 A 289 296 glucose TRIVIAL 23608222 A 612 619 glucose TRIVIAL 23608222 A 723 735 carbohydrate FAMILY 23608222 A 908 920 carbohydrate FAMILY 23608222 A 92 95 ATP ABBREVIATION 23608535 A 1048 1055 calcium SYSTEMATIC 23608535 A 705 711 Ca(2+) FORMULA 23608635 A 1275 1280 hexyl SYSTEMATIC 23608635 A 1281 1286 butyl SYSTEMATIC 23608635 A 1287 1293 propyl SYSTEMATIC 23608635 A 1294 1300 methyl SYSTEMATIC 23608635 A 1429 1430 N FORMULA 23608635 A 326 334 O-methyl SYSTEMATIC 23608635 A 402 417 N,N,N-trimethyl SYSTEMATIC 23608635 A 437 458 N-propyl-(QuatPropyl) SYSTEMATIC 23608635 A 460 479 N-butyl-(QuatButyl) SYSTEMATIC 23608635 A 484 516 N-hexyl (QuatHexyl)-N,N-dimethyl SYSTEMATIC 23608635 A 85 92 N-alkyl FAMILY 23608635 A 877 886 QuatHexyl SYSTEMATIC 23608635 A 93 94 N FORMULA 23608635 T 0 1 N FORMULA 23608957 A 180 187 aspirin TRIVIAL 23608957 A 192 203 clopidogrel TRIVIAL 23609225 A 1006 1008 Xe FORMULA 23609225 A 1009 1011 Xe FORMULA 23609225 A 148 150 Ar FORMULA 23609225 A 151 153 Kr FORMULA 23609225 A 154 156 Xe FORMULA 23609225 A 18 23 noble FAMILY 23609225 A 237 250 Ar19Kr n Xe19 FAMILY 23609225 A 252 264 Ar19Kr19Xe n FAMILY 23609225 A 271 284 Ar n Kr19Xe19 FAMILY 23609225 A 490 492 Ar FORMULA 23609225 A 504 506 Kr FORMULA 23609225 A 511 513 Xe FORMULA 23609225 A 689 691 Ar FORMULA 23609225 A 692 694 Kr FORMULA 23609225 A 695 697 Xe FORMULA 23609225 A 847 849 Ar FORMULA 23609225 A 850 852 Kr FORMULA 23609225 A 853 855 Xe FORMULA 23609225 A 988 990 Ar FORMULA 23609225 A 991 993 Ar FORMULA 23609225 A 995 997 Ar FORMULA 23609225 A 998 1000 Kr FORMULA 23609225 T 40 45 noble FAMILY 23609771 A 1083 1095 [(35)S]GTPγS SYSTEMATIC 23609771 A 11 22 Venlafaxine TRIVIAL 23609771 A 1212 1223 venlafaxine TRIVIAL 23609771 A 1513 1524 venlafaxine TRIVIAL 23609771 A 401 405 5-HT SYSTEMATIC 23609771 A 42 51 serotonin TRIVIAL 23609771 A 56 69 noradrenaline TRIVIAL 23609771 A 813 824 venlafaxine TRIVIAL 23609771 A 982 993 venlafaxine TRIVIAL 23609771 T 75 86 venlafaxine TRIVIAL 23609961 A 344 362 2-aminoimidazolone SYSTEMATIC 23609961 A 404 418 glycocyamidine TRIVIAL 23609961 A 436 445 aldehydes FAMILY 23609961 A 55 76 polyandrocarpamines A NO CLASS 23609961 T 87 105 polyandrocarpamine FAMILY 23610058 A 1054 1061 glucose TRIVIAL 23610058 A 1105 1112 glucose TRIVIAL 23610058 A 1123 1137 streptozotocin TRIVIAL 23610082 A 271 281 creatinine TRIVIAL 23611293 A 676 690 norepinephrine TRIVIAL 23611293 A 761 776 dithiocarbamate SYSTEMATIC 23611309 A 1381 1389 fluoride SYSTEMATIC 23611309 A 471 479 fluoride SYSTEMATIC 23611309 T 42 69 Tm(3+)-Yb(3+) Doped β-NaYF4 FORMULA 23611476 A 114 117 SFN ABBREVIATION 23611476 A 1197 1216 polyethylene glycol SYSTEMATIC 23611476 A 1218 1221 PEG ABBREVIATION 23611476 A 1299 1302 SFN ABBREVIATION 23611476 A 1310 1313 PEG ABBREVIATION 23611476 A 1447 1450 SFN ABBREVIATION 23611476 A 18 30 Sulforaphane TRIVIAL 23611476 A 32 35 SFN ABBREVIATION 23611476 A 337 340 SFN ABBREVIATION 23611476 A 584 587 SFN ABBREVIATION 23611476 A 706 709 SFN ABBREVIATION 23611476 A 807 810 SFN ABBREVIATION 23611476 A 965 968 SFN ABBREVIATION 23611476 T 13 25 sulforaphane TRIVIAL 23611526 A 269 275 carbon SYSTEMATIC 23611526 A 352 371 polyethylene glycol SYSTEMATIC 23611526 A 373 376 PEG ABBREVIATION 23611526 A 504 507 PEG ABBREVIATION 23611526 T 25 31 carbon SYSTEMATIC 23611691 A 369 375 phenyl SYSTEMATIC 23611691 A 4 15 Asp-Phe-Gly FORMULA 23611691 A 465 482 N,N-dimethylamino SYSTEMATIC 23611691 A 608 625 N,N-dimethylamino SYSTEMATIC 23611691 T 49 60 Asp-Phe-Gly FORMULA 23611819 A 1120 1130 NTA-Fe(3+) FORMULA 23611819 A 1136 1147 metal oxide FAMILY 23611819 A 1149 1153 ZrO2 FORMULA 23611819 A 322 334 metal oxides FAMILY 23611819 A 336 340 TiO2 FORMULA 23611819 A 345 349 ZrO2 FORMULA 23611835 A 0 8 SB225002 IDENTIFIER 23611835 A 846 857 vinblastine TRIVIAL 23611835 A 902 910 SB265610 IDENTIFIER 23611835 A 951 959 SB225002 IDENTIFIER 23611835 T 50 58 SB225002 IDENTIFIER 23612420 A 1063 1073 wogonoside TRIVIAL 23612420 A 1219 1229 wogonoside TRIVIAL 23612420 A 234 244 wogonoside TRIVIAL 23612420 A 250 269 flavonoid glycoside FAMILY 23612420 A 337 347 wogonoside TRIVIAL 23612420 A 468 478 wogonoside TRIVIAL 23612420 A 487 499 nitric oxide SYSTEMATIC 23612420 A 501 503 NO FORMULA 23612420 A 506 522 prostaglandin E2 TRIVIAL 23612420 A 524 528 PGE2 ABBREVIATION 23612420 A 662 672 wogonoside TRIVIAL 23612420 A 705 717 nitric oxide SYSTEMATIC 23612420 A 823 833 Wogonoside TRIVIAL 23612420 A 921 923 NO FORMULA 23612420 A 928 932 PGE2 ABBREVIATION 23612420 T 0 10 Wogonoside TRIVIAL 23612854 A 1008 1016 dopamine TRIVIAL 23612854 A 1048 1055 cocaine TRIVIAL 23612854 A 11 19 Dopamine TRIVIAL 23612854 A 1111 1114 BZT ABBREVIATION 23612854 A 1127 1134 cocaine TRIVIAL 23612854 A 1197 1205 dopamine TRIVIAL 23612854 A 127 134 Cocaine TRIVIAL 23612854 A 1290 1297 cocaine TRIVIAL 23612854 A 1339 1342 BZT ABBREVIATION 23612854 A 1473 1480 cocaine TRIVIAL 23612854 A 1603 1606 BZT ABBREVIATION 23612854 A 1672 1679 cocaine TRIVIAL 23612854 A 333 344 benztropine TRIVIAL 23612854 A 346 349 BZT ABBREVIATION 23612854 A 554 562 dopamine TRIVIAL 23612854 A 608 615 cocaine TRIVIAL 23612854 A 625 628 BZT ABBREVIATION 23612854 A 642 644 Cl FORMULA 23612854 A 666 680 diphenyl-ether SYSTEMATIC 23612854 A 707 718 carboalkoxy FAMILY 23612854 A 758 765 tropane TRIVIAL 23612854 A 857 860 BZT ABBREVIATION 23612854 A 88 95 cocaine TRIVIAL 23612854 A 927 935 dopamine TRIVIAL 23612854 A 952 955 BZT ABBREVIATION 23612854 T 134 142 dopamine TRIVIAL 23612854 T 44 52 dopamine TRIVIAL 23612854 T 96 103 cocaine TRIVIAL 23613014 A 1088 1095 glucose TRIVIAL 23613014 A 1162 1171 tadalafil TRIVIAL 23613014 A 1237 1244 glucose TRIVIAL 23613014 A 1246 1253 glucose TRIVIAL 23613014 A 1277 1284 glucose TRIVIAL 23613014 A 1556 1563 glucose TRIVIAL 23613014 A 1616 1625 tadalafil TRIVIAL 23613014 A 215 222 glucose TRIVIAL 23613014 A 244 251 glucose TRIVIAL 23613014 A 302 309 glucose TRIVIAL 23613014 A 434 441 glucose TRIVIAL 23613014 A 455 462 glucose TRIVIAL 23613014 A 611 620 tadalafil TRIVIAL 23613014 A 707 714 glucose TRIVIAL 23613014 A 965 972 glucose TRIVIAL 23613014 T 40 47 Glucose TRIVIAL 23613149 A 1016 1026 creatinine TRIVIAL 23613149 A 1037 1041 urea TRIVIAL 23613149 A 1042 1050 nitrogen SYSTEMATIC 23613149 A 1052 1056 PbAc FORMULA 23613149 A 1085 1092 lactate FAMILY 23613149 A 1111 1115 NADP ABBREVIATION 23613149 A 1151 1157 malate TRIVIAL 23613149 A 1162 1181 glucose-6-phosphate SYSTEMATIC 23613149 A 1197 1204 glucose TRIVIAL 23613149 A 1220 1228 fructose TRIVIAL 23613149 A 1277 1281 PbAc FORMULA 23613149 A 1393 1403 superoxide TRIVIAL 23613149 A 1415 1426 glutathione TRIVIAL 23613149 A 1510 1522 carbohydrate FAMILY 23613149 A 1587 1591 PbAc FORMULA 23613149 A 1637 1641 PbAc FORMULA 23613149 A 1727 1731 PbAc FORMULA 23613149 A 377 392 ω-3 fatty acids FAMILY 23613149 A 397 404 lignans FAMILY 23613149 A 591 603 lead acetate SYSTEMATIC 23613149 A 605 609 PbAc FORMULA 23613149 A 725 737 lead acetate SYSTEMATIC 23613149 A 855 867 carbohydrate FAMILY 23613149 A 959 963 PbAc FORMULA 23613149 T 84 96 Carbohydrate FAMILY 23614400 A 112 118 Bi2Se3 FORMULA 23614400 T 103 109 Bi2Se3 FORMULA 23614462 A 199 274 ( - )-2-hydroxy-5-methoxybenzoic acid 2-O-β-d-(6-O-benzoyl)-glucopyranoside SYSTEMATIC 23614462 A 280 359 ( - )-4-hydroxy-3,5-dimethoxybenzoic acid 4-O-β-d-(6-O-benzoyl)-glucopyranoside SYSTEMATIC 23614462 A 365 446 ( - )-(E)-3,5-dimethoxyphenylpropenoic acid 4-O-β-d-(6-O-benzoyl)-glucopyranoside SYSTEMATIC 23614462 A 452 563 ( - )-(7S,8R)-(4-hydroxyphenylglycerol 9-O-β-d-[6-O-(E)-4-hydroxy-3,5-dimethoxyphenylpropenoyl]-glucopyranoside SYSTEMATIC 23614462 A 569 690 ( - )-(7S,8R)-(4-hydroxy-3-methoxyphenylglycerol 9-O-β-d-[6-O-(E)-4-hydroxy-3,5-dimethoxyphenylpropenoyl]-glucopyranoside SYSTEMATIC 23614462 A 700 829 ( - )-4-hydroxy-3-methoxyphenol β-d-{6-O-[4-O-(7S,8R)-(4-hydroxy-3-methoxyphenylglycerol-8-yl)-3-methoxybenzoyl]}-glucopyranoside SYSTEMATIC 23614462 T 0 19 Aromatic glycosides FAMILY 23614709 A 246 251 PEDOT ABBREVIATION 23614709 A 762 767 PEDOT ABBREVIATION 23614725 A 1185 1191 oxygen SYSTEMATIC 23614725 A 1201 1220 reduced glutathione TRIVIAL 23614725 A 1222 1225 GSH ABBREVIATION 23614725 A 1228 1231 GSH ABBREVIATION 23614725 A 1232 1233 S FORMULA 23614725 A 1277 1292 malondialdehyde TRIVIAL 23614725 A 1302 1310 carbonyl FAMILY 23614725 A 1315 1327 nitric oxide SYSTEMATIC 23614725 A 1329 1331 NO FORMULA 23614725 A 1397 1399 NO FORMULA 23614725 A 438 450 formaldehyde SYSTEMATIC 23614725 A 452 459 benzene SYSTEMATIC 23614725 A 461 468 toluene TRIVIAL 23614725 A 473 479 xylene FAMILY 23614725 A 923 950 8-hydroxy-2'-deoxyguanosine SYSTEMATIC 23615512 A 305 317 nitrobenzene SYSTEMATIC 23615512 A 322 340 1,4-dinitrobenzene SYSTEMATIC 23615512 A 408 415 toluene TRIVIAL 23615512 A 490 493 OPV ABBREVIATION 23615512 A 63 86 oligophenylene-vinylene FAMILY 23615512 A 640 643 OPV ABBREVIATION 23615512 A 88 91 OPV ABBREVIATION 23615707 A 1093 1096 NAC ABBREVIATION 23615707 A 1106 1109 NAC ABBREVIATION 23615707 A 1166 1180 organochlorine FAMILY 23615707 A 1245 1259 organochlorine FAMILY 23615707 A 1404 1407 NAC ABBREVIATION 23615707 A 1425 1428 DDT ABBREVIATION 23615707 A 257 273 N-Acetylcysteine SYSTEMATIC 23615707 A 275 278 NAC ABBREVIATION 23615707 A 30 61 dichlorodiphenyltrichloroethane SYSTEMATIC 23615707 A 4 18 organochlorine FAMILY 23615707 A 453 456 NAC ABBREVIATION 23615707 A 509 512 DDT ABBREVIATION 23615707 A 543 575 dichlorodiphenyldichloroethylene SYSTEMATIC 23615707 A 580 610 dichlorodiphenyldichloroethane SYSTEMATIC 23615707 A 63 66 DDT ABBREVIATION 23615707 A 743 749 oxygen SYSTEMATIC 23615707 A 992 995 NAC ABBREVIATION 23615707 T 19 35 N-acetylcysteine SYSTEMATIC 23615707 T 67 98 dichlorodiphenyltrichloroethane SYSTEMATIC 23616470 A 1152 1160 fluorene SYSTEMATIC 23616470 A 230 236 carbon SYSTEMATIC 23616470 A 281 299 (13) C-naphthalene SYSTEMATIC 23616470 A 303 318 (13) C-fluorene SYSTEMATIC 23616470 A 405 408 PAH ABBREVIATION 23616470 A 53 84 polycyclic aromatic hydrocarbon FAMILY 23616470 A 621 632 naphthalene SYSTEMATIC 23616470 A 671 677 (13) C FORMULA 23616470 A 756 767 naphthalene SYSTEMATIC 23616470 A 816 822 carbon SYSTEMATIC 23616470 A 826 829 PAH ABBREVIATION 23616470 A 86 89 PAH ABBREVIATION 23616470 A 889 897 fluorene SYSTEMATIC 23616470 A 941 952 naphthalene SYSTEMATIC 23616470 A 985 993 fluorene SYSTEMATIC 23616470 T 23 54 polycyclic aromatic hydrocarbon FAMILY 23616476 A 103 106 PEG ABBREVIATION 23616476 A 128 134 carbon SYSTEMATIC 23616476 A 208 219 doxorubicin TRIVIAL 23616476 A 221 224 DOX ABBREVIATION 23616476 A 335 338 DOX ABBREVIATION 23616476 A 339 342 PEG ABBREVIATION 23616476 A 451 454 DOX ABBREVIATION 23616476 A 567 570 DOX ABBREVIATION 23616476 A 571 574 PEG ABBREVIATION 23616476 A 58 68 folic acid TRIVIAL 23616476 A 80 101 poly(ethylene glycol) SYSTEMATIC 23616476 T 0 6 Folate TRIVIAL 23616476 T 18 21 PEG ABBREVIATION 23616476 T 39 45 Carbon SYSTEMATIC 23616476 T 82 93 Doxorubicin TRIVIAL 23617585 A 438 445 glucose TRIVIAL 23617585 A 574 580 carbon SYSTEMATIC 23617585 A 584 591 glucose TRIVIAL 23617585 A 785 792 glucose TRIVIAL 23617697 A 154 166 nitric oxide SYSTEMATIC 23617697 A 168 170 NO FORMULA 23617697 A 219 230 glutathione TRIVIAL 23617697 A 25 65 O(2)-(2,4-dinitrophenyl)diazeniumdiolate SYSTEMATIC 23617697 A 372 374 NO FORMULA 23617697 A 601 605 PABA ABBREVIATION 23617697 A 606 608 NO FORMULA 23617697 A 70 84 oleanolic acid TRIVIAL 23617697 T 21 61 O(2)-(2,4-Dinitrophenyl)diazeniumdiolate SYSTEMATIC 23617697 T 66 80 Oleanolic Acid TRIVIAL 23617697 T 99 111 Nitric Oxide SYSTEMATIC 23617758 A 1008 1012 TiO2 FORMULA 23617758 A 1092 1098 R-O-R' FAMILY 23617758 A 1119 1143 (saturated) hydrocarbons FAMILY 23617758 A 183 197 Au13/TiO2(110) FORMULA 23617758 A 206 214 methanol SYSTEMATIC 23617758 A 329 333 TiO2 FORMULA 23617758 A 391 395 O-Au FORMULA 23617758 A 418 425 methoxy SYSTEMATIC 23617758 A 616 617 C FORMULA 23617758 A 628 635 methoxy SYSTEMATIC 23617758 A 676 677 C FORMULA 23617758 A 688 695 methoxy SYSTEMATIC 23617758 A 743 746 O-C FORMULA 23617758 A 782 789 methoxy SYSTEMATIC 23617758 A 825 832 methoxy SYSTEMATIC 23617758 A 841 844 C-H FORMULA 23617758 A 870 876 oxygen SYSTEMATIC 23617758 T 60 68 methanol SYSTEMATIC 23617758 T 86 100 Au13/TiO2(110) FORMULA 23617821 A 491 497 oxygen SYSTEMATIC 23617821 A 828 844 N-Acetylcysteine SYSTEMATIC 23617821 A 982 1001 3-methylamphetamine SYSTEMATIC 23617821 T 0 7 Cadmium SYSTEMATIC 23619605 A 0 11 Naphthalene SYSTEMATIC 23619605 A 1332 1343 naphthalene SYSTEMATIC 23619605 A 298 309 naphthalene SYSTEMATIC 23619605 A 357 368 naphthalene SYSTEMATIC 23619605 A 621 639 5-phenyl-1-pentyne SYSTEMATIC 23619605 A 931 949 5-phenyl-1-pentyne SYSTEMATIC 23619605 A 970 981 naphthalene SYSTEMATIC 23619605 T 28 39 naphthalene SYSTEMATIC 23619606 A 1157 1161 DEHP ABBREVIATION 23619606 A 1198 1214 arachidonic acid TRIVIAL 23619606 A 1216 1232 α-linolenic acid TRIVIAL 23619606 A 1234 1250 palmitoleic acid TRIVIAL 23619606 A 124 134 fatty acid FAMILY 23619606 A 1255 1265 oleic acid TRIVIAL 23619606 A 1304 1308 DEHP ABBREVIATION 23619606 A 1493 1499 carbon SYSTEMATIC 23619606 A 1572 1576 DEHP ABBREVIATION 23619606 A 1663 1675 triglyceride FAMILY 23619606 A 21 47 di(2-ethylhexyl) phthalate SYSTEMATIC 23619606 A 395 399 DEHP ABBREVIATION 23619606 A 49 53 DEHP ABBREVIATION 23619606 A 513 572 n-3/n-6 polyunsaturated, saturated, and monounsaturated FAs MULTIPLE 23619606 A 746 759 linoleic acid TRIVIAL 23619606 A 76 88 triglyceride FAMILY 23619606 A 761 777 α-linolenic acid TRIVIAL 23619606 A 779 792 palmitic acid TRIVIAL 23619606 A 797 807 oleic acid TRIVIAL 23619606 A 892 896 DEHP ABBREVIATION 23619606 T 12 16 DEHP ABBREVIATION 23619606 T 32 42 fatty acid FAMILY 23619607 A 51 58 alcohol FAMILY 23619607 A 551 557 methyl SYSTEMATIC 23619607 A 558 561 CpG ABBREVIATION 23619607 T 12 18 methyl SYSTEMATIC 23619607 T 19 22 CpG ABBREVIATION 23620211 A 1236 1244 warfarin TRIVIAL 23620211 A 1248 1255 aspirin TRIVIAL 23620211 A 1512 1520 warfarin TRIVIAL 23620211 A 1618 1626 warfarin TRIVIAL 23620211 A 1856 1864 warfarin TRIVIAL 23620211 A 2094 2102 warfarin TRIVIAL 23620211 A 2104 2111 aspirin TRIVIAL 23620211 A 2117 2124 aspirin TRIVIAL 23620211 A 2130 2141 clopidogrel TRIVIAL 23620211 A 2177 2187 dabigatran TRIVIAL 23620211 A 2254 2262 warfarin TRIVIAL 23620211 A 2470 2478 warfarin TRIVIAL 23620211 A 2790 2798 warfarin TRIVIAL 23620211 A 2929 2937 warfarin TRIVIAL 23620211 A 2951 2959 warfarin TRIVIAL 23620211 A 3221 3231 dabigatran TRIVIAL 23620211 A 688 698 dabigatran TRIVIAL 23620211 A 738 748 Dabigatran TRIVIAL 23620211 A 918 928 dabigatran TRIVIAL 23620211 A 93 113 dabigatran etexilate TRIVIAL 23620211 A 998 1008 dabigatran TRIVIAL 23620211 T 0 10 Dabigatran TRIVIAL 23620263 A 168 172 zinc SYSTEMATIC 23620263 A 283 307 (R,R)-diaminocyclohexane SYSTEMATIC 23620263 A 321 326 furan SYSTEMATIC 23620263 A 34 58 (R,R)-diaminocyclohexane SYSTEMATIC 23620263 A 360 373 zinc chloride SYSTEMATIC 23620263 A 398 419 potassium carboxylate SYSTEMATIC 23620263 A 72 79 pyrrole SYSTEMATIC 23620263 A 81 86 furan SYSTEMATIC 23620263 A 91 98 benzene SYSTEMATIC 23620263 T 11 15 zinc SYSTEMATIC 23620263 T 45 52 ketones FAMILY 23620263 T 71 82 carboxylate SYSTEMATIC 23620485 A 1116 1127 telmisartan TRIVIAL 23620485 A 1132 1141 verapamil TRIVIAL 23620485 A 836 846 sertraline TRIVIAL 23620485 A 851 861 isradipine TRIVIAL 23620485 A 901 912 telmisartan TRIVIAL 23620485 A 917 926 verapamil TRIVIAL 23620485 A 946 957 telmisartan TRIVIAL 23620485 A 962 971 verapamil TRIVIAL 23620485 T 128 135 Digoxin TRIVIAL 23621148 A 1515 1519 mica TRIVIAL 23621420 A 211 241 biotinylated guanidinoneomycin TRIVIAL 23621420 A 243 253 biotinGNeo TRIVIAL 23621420 A 279 290 guanidinium SYSTEMATIC 23621420 A 420 430 biotinGNeo TRIVIAL 23621420 A 484 494 biotinGNeo TRIVIAL 23621420 A 602 612 biotinGNeo TRIVIAL 23621420 A 745 768 guanidinylated neomycin TRIVIAL 23621420 A 953 972 guanidinoglycosides FAMILY 23621491 A 1050 1052 Ag FORMULA 23621491 A 1395 1397 Ag FORMULA 23621491 A 1469 1471 Ag FORMULA 23621491 A 1598 1600 Ag FORMULA 23621491 A 1605 1607 Au FORMULA 23621491 A 1617 1619 Ag FORMULA 23621491 A 1678 1680 Ag FORMULA 23621491 A 1721 1723 Au FORMULA 23621491 A 330 336 silver SYSTEMATIC 23621491 A 352 354 Ag FORMULA 23621491 A 470 472 Ag FORMULA 23621491 A 500 502 Ag FORMULA 23621491 A 552 554 Ag FORMULA 23621491 A 618 628 amino acid FAMILY 23621491 A 636 637 C FORMULA 23621491 T 75 81 Silver SYSTEMATIC 23621521 A 0 7 Retinal TRIVIAL 23621521 T 49 56 retinal TRIVIAL 23621523 A 103 123 20'-deoxyvinblastine SYSTEMATIC 23621523 A 144 149 oxide SYSTEMATIC 23621523 A 25 42 N-oxide alkaloids FAMILY 23621523 A 44 68 17-desacetoxyvinblastine SYSTEMATIC 23621523 A 556 559 MTT ABBREVIATION 23621523 A 8 19 vinblastine TRIVIAL 23621523 A 89 94 oxide SYSTEMATIC 23621523 T 25 42 N-oxide alkaloids FAMILY 23621523 T 8 19 vinblastine TRIVIAL 23621567 A 117 123 lysine TRIVIAL 23621567 A 207 213 lysine TRIVIAL 23621567 A 222 225 Lys FORMULA 23621567 A 444 450 lysine TRIVIAL 23621567 A 654 657 ATP ABBREVIATION 23622980 A 200 225 2,3-disubstituted indoles FAMILY 23622980 T 30 55 2,3-disubstituted indoles FAMILY 23623492 A 21 71 ribo and 2'-β-C-methyl ribo Janus type nucleosides MULTIPLE 23623492 T 28 50 Janus type nucleosides FAMILY 23623752 A 1002 1009 codeine TRIVIAL 23623752 A 1024 1032 morphine TRIVIAL 23623752 A 1048 1055 codeine TRIVIAL 23623752 A 1180 1188 morphine TRIVIAL 23623752 A 1239 1247 morphine TRIVIAL 23623752 A 1251 1258 codeine TRIVIAL 23623752 A 1297 1305 morphine TRIVIAL 23623752 A 1339 1347 morphine TRIVIAL 23623752 A 1427 1435 morphine TRIVIAL 23623752 A 1460 1467 codeine TRIVIAL 23623752 A 1506 1513 codeine TRIVIAL 23623752 A 284 291 codeine TRIVIAL 23623752 A 306 314 morphine TRIVIAL 23623752 A 407 414 codeine TRIVIAL 23623752 A 509 520 propranolol TRIVIAL 23623752 A 529 540 propafenone TRIVIAL 23623752 A 787 794 codeine TRIVIAL 23623752 A 805 813 morphine TRIVIAL 23623752 A 833 841 morphine TRIVIAL 23623752 A 845 852 codeine TRIVIAL 23623820 A 1516 1556 ethyl 13(2) (S)-hydroxy-chlorophyllide a SYSTEMATIC 23623820 A 1597 1628 2-methyl-3-methoxyanthraquinone SYSTEMATIC 23623820 A 1634 1662 2-hydroxymethylanthraquinone SYSTEMATIC 23623820 A 1667 1698 2-hydroxy-3-methylanthraquinone SYSTEMATIC 23623820 A 1703 1740 2-hydroxymethy-1-hydroxyanthraquinone SYSTEMATIC 23623820 A 1745 1777 1-methoxy-2-hydroxyanthraquinone SYSTEMATIC 23623820 A 1782 1823 2-hydroxy-3-methyl-1-methoxyanthraquinone SYSTEMATIC 23623820 A 1829 1843 oleanolic acid TRIVIAL 23623820 A 1849 1861 ursolic acid TRIVIAL 23623820 A 1867 1879 stigmasterol TRIVIAL 23623820 A 1889 1904 docosanoic acid SYSTEMATIC 23623820 A 986 989 MTS ABBREVIATION 23623839 A 225 233 androgen FAMILY 23623839 A 270 286 N-acetylcysteine SYSTEMATIC 23623839 A 288 291 NAC ABBREVIATION 23623839 A 407 410 NAC ABBREVIATION 23623839 A 43 51 cysteine TRIVIAL 23623839 A 507 510 NAC ABBREVIATION 23623839 A 799 802 NAC ABBREVIATION 23623839 A 942 945 NAC ABBREVIATION 23623842 A 0 12 Cypermethrin TRIVIAL 23623842 A 1017 1028 glutathione TRIVIAL 23623842 A 1070 1082 cypermethrin TRIVIAL 23623842 A 1207 1219 cypermethrin TRIVIAL 23623842 A 323 334 glutathione TRIVIAL 23623842 A 34 44 pyrethroid FAMILY 23623842 A 354 364 superoxide TRIVIAL 23623842 A 402 413 glutathione TRIVIAL 23623842 A 437 448 glutathione TRIVIAL 23623842 A 471 490 glucose-6-phosphate SYSTEMATIC 23623842 A 546 557 glutathione TRIVIAL 23623842 A 606 615 vitamin E FAMILY 23623842 A 682 690 selenium SYSTEMATIC 23623842 A 768 779 glutathione TRIVIAL 23623842 A 835 847 cypermethrin TRIVIAL 23623842 A 952 963 glutathione TRIVIAL 23623842 A 984 994 superoxide TRIVIAL 23623842 T 42 54 cypermethrin TRIVIAL 23623845 A 1230 1236 silica TRIVIAL 23623845 A 1270 1276 oxygen SYSTEMATIC 23623845 A 1377 1395 dichlorofluorescin SYSTEMATIC 23623845 A 1397 1400 DCF ABBREVIATION 23623845 A 1549 1555 silica TRIVIAL 23623845 A 203 209 silica TRIVIAL 23623845 A 2049 2055 silica TRIVIAL 23623845 A 295 301 silica TRIVIAL 23623845 A 357 363 silica TRIVIAL 23623845 A 489 495 silica TRIVIAL 23623845 A 626 632 silica TRIVIAL 23623845 A 656 662 silica TRIVIAL 23623845 A 733 739 silica TRIVIAL 23623845 A 992 998 silica TRIVIAL 23623845 T 45 51 silica TRIVIAL 23624115 A 1081 1090 Carvacrol TRIVIAL 23624115 A 1095 1103 linalool TRIVIAL 23624115 A 1643 1652 Carvacrol TRIVIAL 23624115 A 1718 1726 linalool TRIVIAL 23624115 A 770 778 linalool TRIVIAL 23624115 A 783 792 carvacrol TRIVIAL 23624148 A 1012 1015 ATP ABBREVIATION 23624148 A 1032 1038 oxygen SYSTEMATIC 23624148 A 1066 1079 nitrotyrosine SYSTEMATIC 23624148 A 1106 1119 sciadopitysin TRIVIAL 23624148 A 1209 1222 sciadopitysin TRIVIAL 23624148 A 1252 1256 cAMP ABBREVIATION 23624148 A 1310 1321 antimycin A TRIVIAL 23624148 A 1352 1365 sciadopitysin TRIVIAL 23624148 A 137 150 sciadopitysin TRIVIAL 23624148 A 162 174 biflavonoids FAMILY 23624148 A 248 261 Sciadopitysin TRIVIAL 23624148 A 391 402 glutathione TRIVIAL 23624148 A 434 447 Sciadopitysin TRIVIAL 23624148 A 524 535 antimycin A TRIVIAL 23624148 A 625 638 sciadopitysin TRIVIAL 23624148 A 642 653 antimycin A TRIVIAL 23624148 A 733 744 antimycin A TRIVIAL 23624148 A 830 843 sciadopitysin TRIVIAL 23624148 A 853 864 antimycin A TRIVIAL 23624148 A 896 907 antimycin A TRIVIAL 23624148 A 988 1010 adenosine triphosphate SYSTEMATIC 23624148 T 0 13 Sciadopitysin TRIVIAL 23624290 A 1131 1141 Naltrexone TRIVIAL 23624290 A 1266 1277 naltrindole TRIVIAL 23624290 A 1304 1323 nor-binaltorphimine TRIVIAL 23624290 A 1388 1408 3,3-dibromoflavanone SYSTEMATIC 23624290 A 269 279 flavonoids FAMILY 23624290 A 354 374 3,3-dibromoflavanone SYSTEMATIC 23624290 A 393 402 flavonoid FAMILY 23624290 A 487 498 [(3)H]DAMGO SYSTEMATIC 23624290 A 531 540 Flavanone TRIVIAL 23624290 A 915 926 acetic acid SYSTEMATIC 23624290 A 962 970 formalin TRIVIAL 23624290 T 118 127 flavonoid FAMILY 23624290 T 128 148 3,3-dibromoflavanone SYSTEMATIC 23624290 T 43 53 flavonoids FAMILY 23624385 A 1181 1184 CYN ABBREVIATION 23624385 A 1407 1410 CYN ABBREVIATION 23624385 A 258 261 CYN ABBREVIATION 23624385 A 34 52 cylindrospermopsin TRIVIAL 23624385 A 374 377 CYN ABBREVIATION 23624385 A 54 57 CYN ABBREVIATION 23624385 A 583 586 CYN ABBREVIATION 23624385 T 31 49 cylindrospermopsin TRIVIAL 23624394 A 0 11 Zearalenone TRIVIAL 23624394 A 1267 1270 ZEA ABBREVIATION 23624394 A 13 16 ZEA ABBREVIATION 23624394 A 1416 1427 zearalenone TRIVIAL 23624394 A 533 536 ZEA ABBREVIATION 23624394 A 661 664 ZEA ABBREVIATION 23624394 A 78 90 mycoestrogen FAMILY 23624394 T 49 60 zearalenone TRIVIAL 23624809 A 191 199 nicotine TRIVIAL 23624809 A 41 49 nicotine TRIVIAL 23624809 A 426 434 nicotine TRIVIAL 23624809 A 753 761 nicotine TRIVIAL 23624809 A 870 878 nicotine TRIVIAL 23624809 T 23 31 nicotine TRIVIAL 23624852 A 1250 1275 dihydro-beta-erythroidine SYSTEMATIC 23624852 A 1299 1317 methyllycaconitine TRIVIAL 23624852 A 1349 1353 AP-5 IDENTIFIER 23624852 A 1607 1611 NMDA ABBREVIATION 23624852 A 18 26 dopamine TRIVIAL 23624852 A 418 438 N-methyl-D-aspartate SYSTEMATIC 23624852 A 493 506 acetylcholine SYSTEMATIC 23624852 A 831 835 AP-5 IDENTIFIER 23624852 A 879 883 NMDA ABBREVIATION 23624852 A 983 995 mecamylamine TRIVIAL 23624852 T 38 51 acetylcholine SYSTEMATIC 23624852 T 78 86 dopamine TRIVIAL 23625175 A 11 19 pyruvate TRIVIAL 23625695 A 533 535 Se FORMULA 23625695 A 611 613 Ba FORMULA 23625695 A 618 620 Ni FORMULA 23625695 A 779 781 Ni FORMULA 23625695 A 790 792 Co FORMULA 23625695 A 801 803 Se FORMULA 23625695 A 883 885 Ni FORMULA 23625695 A 894 896 Co FORMULA 23625695 A 905 907 Se FORMULA 23625813 A 1746 1756 creatinine TRIVIAL 23625813 A 433 443 creatinine TRIVIAL 23625813 A 511 521 creatinine TRIVIAL 23625813 T 50 60 Creatinine TRIVIAL 23625817 A 350 361 amino acids FAMILY 23625817 A 579 588 aminoacyl SYSTEMATIC 23625817 A 641 651 amino acid FAMILY 23625817 A 722 732 amino acid FAMILY 23625817 A 80 91 amino acids FAMILY 23625817 T 51 62 Amino Acids FAMILY 23625906 A 312 329 vitamins (A, C, E MULTIPLE 23625906 A 334 342 selenium SYSTEMATIC 23625907 A 1236 1244 carbamic SYSTEMATIC 23625907 A 143 153 pirimicarb TRIVIAL 23625907 T 0 10 Pirimicarb TRIVIAL 23625908 A 188 196 n-hexane SYSTEMATIC 23625908 A 201 204 Hex ABBREVIATION 23625908 A 207 217 chloroform TRIVIAL 23625908 A 222 227 CHCl3 FORMULA 23625908 A 233 246 ethyl acetate SYSTEMATIC 23625908 A 251 255 EtAc FORMULA 23625908 A 267 296 1,1-diphenyl,2-picrylhydrazyl SYSTEMATIC 23625908 A 359 363 EtAc FORMULA 23625908 A 403 406 Hex ABBREVIATION 23625908 A 411 416 CHCl3 FORMULA 23625908 A 424 428 EtAc FORMULA 23625908 A 604 607 Hex ABBREVIATION 23625908 A 612 617 CHCl3 FORMULA 23625908 A 625 629 EtAc FORMULA 23625908 A 806 810 EtAc FORMULA 23625908 T 0 29 1,1-Diphenyl,2-picrylhydrazyl SYSTEMATIC 23625910 A 0 15 Organophosphate FAMILY 23625910 A 481 497 organophosphorus FAMILY 23625910 A 592 608 organophosphorus FAMILY 23625910 T 136 151 organophosphate FAMILY 23625947 A 0 4 NMDA ABBREVIATION 23625947 A 110 137 N-hydroxypyrazole-5-glycine SYSTEMATIC 23625947 A 139 144 NHP5G SYSTEMATIC 23625947 A 176 185 glutamate TRIVIAL 23625947 A 261 265 NMDA ABBREVIATION 23625947 A 411 446 propyl- and ethyl-substituted NHP5G MULTIPLE 23625947 A 526 535 glutamate TRIVIAL 23625947 A 729 738 glutamate TRIVIAL 23625947 A 762 774 propyl-NHP5G SYSTEMATIC 23625947 A 829 833 AMPA ABBREVIATION 23625947 A 838 845 kainate TRIVIAL 23625947 A 926 931 NHP5G SYSTEMATIC 23625947 A 999 1004 amino FAMILY 23625947 T 51 60 Glutamate TRIVIAL 23625947 T 77 81 NMDA ABBREVIATION 23627252 A 1054 1058 PTFE ABBREVIATION 23627252 A 130 134 PTFE ABBREVIATION 23627252 A 29 48 trioxatriangulenium SYSTEMATIC 23627252 A 430 434 PTFE ABBREVIATION 23627252 A 594 599 alkyl FAMILY 23627252 T 114 118 PTFE ABBREVIATION 23627252 T 68 81 Triangulenium TRIVIAL 23627903 A 1115 1126 cholesterol TRIVIAL 23627903 A 1168 1179 cholesterol TRIVIAL 23627903 A 1611 1615 L-T4 ABBREVIATION 23628345 A 1141 1148 calcium SYSTEMATIC 23628345 A 162 193 R-2-amino-5-phosphonopentanoate SYSTEMATIC 23628345 A 1735 1739 NMDA ABBREVIATION 23628345 A 195 200 d-AP5 IDENTIFIER 23628345 A 1968 1972 NMDA ABBREVIATION 23628345 A 2170 2174 NMDA ABBREVIATION 23628345 A 477 486 glutamate TRIVIAL 23628345 A 992 996 NMDA ABBREVIATION 23628345 T 0 4 NMDA ABBREVIATION 23628454 A 1528 1535 glucose TRIVIAL 23628454 A 1607 1619 ferulic acid TRIVIAL 23628454 A 1787 1799 Ferulic acid TRIVIAL 23628454 A 1804 1809 rutin TRIVIAL 23628454 A 361 374 ethyl acetate SYSTEMATIC 23628592 A 0 11 Amphetamine TRIVIAL 23628592 A 1327 1338 amphetamine TRIVIAL 23628592 A 285 318 3,4-methylenedioxymethamphetamine SYSTEMATIC 23628592 A 320 324 MDMA ABBREVIATION 23628592 A 326 333 ecstasy TRIVIAL 23628592 A 369 381 amphetamines FAMILY 23628592 A 383 398 methamphetamine TRIVIAL 23628592 A 400 423 4-methylthyoamphetamine SYSTEMATIC 23628592 A 428 441 D-amphetamine TRIVIAL 23628592 A 726 738 amphetamines FAMILY 23628592 A 786 789 MTT ABBREVIATION 23628592 A 889 900 amphetamine TRIVIAL 23628592 T 21 32 amphetamine TRIVIAL 23628779 A 424 431 14-DACA ABBREVIATION 23628896 A 240 248 [S3]˙(-) FORMULA 23628896 A 28 36 [S3]˙(-) FORMULA 23628896 A 320 326 sulfur SYSTEMATIC 23628896 A 4 13 trisulfur SYSTEMATIC 23628896 A 747 755 [S3]˙(-) FORMULA 23628896 A 914 930 triatomic sulfur SYSTEMATIC 23628896 T 11 20 trisulfur SYSTEMATIC 23629517 A 1157 1161 urea TRIVIAL 23629669 A 143 152 magnetite TRIVIAL 23629669 A 214 230 ferrous chloride SYSTEMATIC 23629669 A 235 250 ferric chloride SYSTEMATIC 23629669 A 289 298 carbonate FAMILY 23629669 A 320 334 hydroxyapatite TRIVIAL 23629669 A 394 423 dicalcium phosphate dihydrate SYSTEMATIC 23629669 A 428 445 calcium carbonate SYSTEMATIC 23629669 A 475 484 magnetite TRIVIAL 23629669 A 517 526 magnetite TRIVIAL 23629669 A 567 581 hydroxyapatite TRIVIAL 23629669 A 621 630 magnetite TRIVIAL 23629669 A 63 72 magnetite TRIVIAL 23629669 A 631 645 hydroxyapatite TRIVIAL 23629669 A 695 704 magnetite TRIVIAL 23629669 A 73 87 hydroxyapatite TRIVIAL 23629669 A 881 890 magnetite TRIVIAL 23629669 A 912 921 magnetite TRIVIAL 23629669 T 30 39 Magnetite TRIVIAL 23629669 T 40 54 Hydroxyapatite TRIVIAL 23630169 A 108 117 fullerene TRIVIAL 23630169 A 192 195 C60 TRIVIAL 23630169 A 213 221 fluorene SYSTEMATIC 23630169 A 235 246 cyclopropyl SYSTEMATIC 23630169 A 394 397 C60 TRIVIAL 23630169 A 945 953 fluorene SYSTEMATIC 23630169 T 69 72 C60 TRIVIAL 23630181 A 119 122 MPC ABBREVIATION 23630181 A 252 255 MPC ABBREVIATION 23630181 A 260 274 vinylferrocene SYSTEMATIC 23630181 A 280 295 poly(MPC-co-VF) FAMILY 23630181 A 298 301 PMF ABBREVIATION 23630181 A 324 327 PMF ABBREVIATION 23630181 A 527 530 PMF ABBREVIATION 23630181 A 606 609 PMF ABBREVIATION 23630181 A 694 697 PMF ABBREVIATION 23630181 A 77 117 2-methacryloyloxyethyl phosphorylcholine SYSTEMATIC 23630454 A 1074 1081 glucose TRIVIAL 23630454 T 100 107 Glucose TRIVIAL 23631374 A 0 21 Milbemycins A3 and A4 MULTIPLE 23631374 A 493 501 hydrogen SYSTEMATIC 23631374 A 532 534 CH FORMULA 23631374 A 535 536 O FORMULA 23631374 A 542 550 hydrogen SYSTEMATIC 23631374 T 48 69 milbemycins A3 and A4 MULTIPLE 23631389 A 1009 1020 CMP-NCL-CA4 ABBREVIATION 23631389 A 284 297 aminoacrylate SYSTEMATIC 23631389 A 497 515 combretastatin A-4 TRIVIAL 23631389 A 517 520 CA4 ABBREVIATION 23631389 A 536 545 CMP-L-CA4 ABBREVIATION 23631389 A 547 550 CMP ABBREVIATION 23631389 A 552 567 dithiaporphyrin SYSTEMATIC 23631389 A 595 608 aminoacrylate SYSTEMATIC 23631389 A 664 677 aminoacrylate SYSTEMATIC 23631389 A 730 733 CA4 ABBREVIATION 23631389 A 755 760 CDCl3 FORMULA 23631389 A 900 903 CA4 ABBREVIATION 23631389 A 925 934 CMP-L-CA4 ABBREVIATION 23631389 T 55 72 Combretastain A-4 TRIVIAL 23631395 A 1817 1827 methionine TRIVIAL 23631395 A 26 36 methionine TRIVIAL 23631395 A 844 848 heme FAMILY 23631395 A 875 885 methionine TRIVIAL 23631395 T 52 62 Methionine TRIVIAL 23631402 A 1000 1006 Li2Sen FAMILY 23631402 A 1014 1020 Li2Se2 FORMULA 23631402 A 1026 1031 Li2Se FORMULA 23631402 A 1072 1077 Li2Se FORMULA 23631402 A 1093 1095 Se FORMULA 23631402 A 1104 1110 Li2Sen FAMILY 23631402 A 1269 1271 Li FORMULA 23631402 A 1272 1274 Se FORMULA 23631402 A 1285 1290 ether SYSTEMATIC 23631402 A 1350 1359 carbonate FAMILY 23631402 A 1384 1386 Li FORMULA 23631402 A 1387 1391 SeS2 FORMULA 23631402 A 1396 1398 Li FORMULA 23631402 A 1399 1403 SeS7 FORMULA 23631402 A 1411 1416 Li2Se FORMULA 23631402 A 1421 1425 Li2S FORMULA 23631402 A 1475 1477 Se FORMULA 23631402 A 312 316 SeSx FAMILY 23631402 A 317 323 carbon SYSTEMATIC 23631402 A 427 434 lithium SYSTEMATIC 23631402 A 446 451 ether SYSTEMATIC 23631402 A 626 628 Se FORMULA 23631402 A 721 723 Se FORMULA 23631402 A 89 96 lithium SYSTEMATIC 23631402 A 964 966 Se FORMULA 23631402 A 985 998 polyselenides FAMILY 23631402 T 28 30 Li FORMULA 23631402 T 31 35 SeSx FAMILY 23631425 A 280 283 Cs+ FORMULA 23631425 A 291 297 silica TRIVIAL 23631425 A 349 357 silanols FAMILY 23631425 A 45 51 silica TRIVIAL 23631425 A 508 511 Li+ FORMULA 23631425 A 516 519 Na+ FORMULA 23631425 A 608 616 silanols FAMILY 23631425 A 618 621 Cs+ FORMULA 23631425 A 860 866 oxides FAMILY 23631425 A 87 102 alkali-chloride FAMILY 23631425 T 70 76 Silica TRIVIAL 23631483 A 1004 1015 fluconazole TRIVIAL 23631483 A 1017 1029 Sedonans A-F MULTIPLE 23631483 A 1034 1050 ent-sandwicensin TRIVIAL 23631483 A 1254 1263 sedonan A TRIVIAL 23631483 A 1268 1284 ent-sandwicensin TRIVIAL 23631483 A 588 596 methanol SYSTEMATIC 23631483 A 659 672 isoflavonoids FAMILY 23631483 A 674 686 sedonans A-F MULTIPLE 23631483 A 700 713 but-2-enolide SYSTEMATIC 23631483 A 715 734 4'-O-methylpuerol A SYSTEMATIC 23631483 A 764 780 ent-sandwicensin TRIVIAL 23631483 T 46 59 Isoflavonoids FAMILY 23631496 A 1022 1024 Se FORMULA 23631496 A 1166 1168 Se FORMULA 23631496 A 1345 1347 Se FORMULA 23631496 A 1486 1488 Se FORMULA 23631496 A 1588 1590 Se FORMULA 23631496 A 328 330 Se FORMULA 23631496 A 388 390 Se FORMULA 23631496 A 477 479 Se FORMULA 23631496 A 566 568 Se FORMULA 23631496 A 60 68 selenium SYSTEMATIC 23631496 A 698 700 Se FORMULA 23631496 A 70 72 Se FORMULA 23631496 A 947 949 Se FORMULA 23631496 T 42 50 Selenium SYSTEMATIC 23631538 A 1057 1069 polyethylene SYSTEMATIC 23631672 A 104 116 chlorophylls FAMILY 23631672 A 118 122 Chls FAMILY 23631672 A 1212 1217 Chl a ABBREVIATION 23631672 A 1551 1556 Chl b ABBREVIATION 23631672 A 1605 1610 Chl b ABBREVIATION 23631672 A 1613 1618 Chl a ABBREVIATION 23631672 A 1892 1897 Chl b ABBREVIATION 23631672 A 1900 1905 Chl a ABBREVIATION 23631672 A 842 847 Chl a ABBREVIATION 23631672 A 972 977 Chl b ABBREVIATION 23631841 A 502 503 N FORMULA 23632085 A 1072 1081 histamine TRIVIAL 23632085 A 1181 1190 rottlerin TRIVIAL 23632085 A 1281 1290 rottlerin TRIVIAL 23632085 A 1401 1410 Rottlerin TRIVIAL 23632085 A 1515 1521 Ca(2+) FORMULA 23632085 A 1582 1591 rottlerin TRIVIAL 23632085 A 1712 1721 rottlerin TRIVIAL 23632085 A 206 215 Rottlerin TRIVIAL 23632085 A 445 454 rottlerin TRIVIAL 23632085 A 547 556 rottlerin TRIVIAL 23632085 A 597 606 rottlerin TRIVIAL 23632085 A 830 839 rottlerin TRIVIAL 23632085 A 928 937 rottlerin TRIVIAL 23632085 A 972 981 Rottlerin TRIVIAL 23632085 T 25 34 rottlerin TRIVIAL 23632905 A 1325 1328 STZ ABBREVIATION 23632905 A 256 270 streptozotocin TRIVIAL 23632905 A 272 275 STZ ABBREVIATION 23632905 A 652 655 STZ ABBREVIATION 23632905 T 38 52 Streptozotocin TRIVIAL 23634642 A 27 32 arene FAMILY 23634642 A 33 39 allene SYSTEMATIC 23634642 T 128 134 Carbon SYSTEMATIC 23634642 T 38 43 Arene FAMILY 23634642 T 44 50 Allene SYSTEMATIC 23634844 A 673 679 carbon SYSTEMATIC 23635319 A 1020 1023 ZnO FORMULA 23635319 A 321 323 Sb FORMULA 23635319 A 337 340 ZnO FORMULA 23635319 A 520 522 Sb FORMULA 23635319 A 665 667 Sb FORMULA 23635319 A 834 836 Sb FORMULA 23635319 A 850 853 ZnO FORMULA 23635319 T 44 47 ZnO FORMULA 23636129 A 706 719 polycarbonate FAMILY 23636270 A 1167 1173 Ca(2+) FORMULA 23636270 A 1273 1286 hydroperoxide FAMILY 23636270 A 1360 1369 vitamin E FAMILY 23636270 A 601 611 fatty acyl FAMILY 23636270 A 774 793 phosphatidylcholine FAMILY 23636270 A 797 821 phosphatidylethanolamine SYSTEMATIC 23636270 A 923 934 cardiolipin TRIVIAL 23636270 A 980 990 oleic acid TRIVIAL 23636447 A 1272 1280 Cortisol TRIVIAL 23636447 A 1517 1525 cortisol TRIVIAL 23636447 A 163 171 CORTISOL TRIVIAL 23636447 A 1643 1651 cortisol TRIVIAL 23636447 A 1753 1761 cortisol TRIVIAL 23636447 A 436 444 CORTISOL TRIVIAL 23636447 A 576 584 CORTISOL TRIVIAL 23636447 A 669 677 CORTISOL TRIVIAL 23636447 T 78 86 cortisol TRIVIAL 23636901 A 260 267 silicon SYSTEMATIC 23636901 A 3 7 TiO2 FORMULA 23637063 A 137 139 Si FORMULA 23637063 A 200 202 Si FORMULA 23637063 A 229 236 silicon SYSTEMATIC 23637063 A 79 81 Si FORMULA 23637063 T 121 128 Silicon SYSTEMATIC 23637063 T 70 77 Silicon SYSTEMATIC 23637063 T 9 16 Silicon SYSTEMATIC 23637074 A 476 485 pentacene SYSTEMATIC 23637074 A 511 514 C60 TRIVIAL 23638842 A 1050 1057 RS -GRA ABBREVIATION 23638842 A 1294 1301 RS -GRA ABBREVIATION 23638842 A 251 265 glucosinolates FAMILY 23638842 A 326 341 isothiocyanates FAMILY 23638842 A 425 444 (RS )-glucoraphanin TRIVIAL 23638842 A 555 562 RS -GRA ABBREVIATION 23638842 T 19 38 (RS )-glucoraphanin TRIVIAL 23639006 A 113 115 NO FORMULA 23639006 A 308 359 3α-2',2'-dimethylsuccinic acyl epi-aleuritolic acid FAMILY 23639006 A 470 472 NO FORMULA 23639006 A 565 567 NO FORMULA 23639006 A 8 28 epi-aleuritolic acid TRIVIAL 23639006 T 13 15 NO FORMULA 23639006 T 52 72 epi-aleuritolic acid TRIVIAL 23639103 A 206 229 glycosylated flavonoids FAMILY 23639103 A 326 418 3',5'-dimethoxymyricetin-3-O-β-d-xylopyranosyl-7-O-fucopyranosyl-(1 → 3)-β-d-glucopyranoside SYSTEMATIC 23639103 A 424 537 3'-methoxyquercetin-7-O-β-d-fucopyranosyl-(1 → 3)-β-d-glucopyranosyl-3-O-β-xylopyranosyl-(1 → 4)-β-xylopyranoside SYSTEMATIC 23639103 A 543 637 3'-methoxyquercetin-7-O-α-l-rhamnopyranosyl-3-O-α-arabinofuranosyl-(1 → 6)-β-d-glucopyranoside SYSTEMATIC 23639103 A 646 716 3',5'-dimethoxymyricetin-7-O-fucopyranosyl-(1 → 3)-β-d-glucopyranoside SYSTEMATIC 23639103 A 787 796 myricetin TRIVIAL 23639103 A 798 807 quercetin TRIVIAL 23639103 A 809 832 isorhamnetin glycosides FAMILY 23639103 A 841 855 phenolic acids FAMILY 23639103 A 860 866 esters FAMILY 23639115 A 170 191 16-deethylindanomycin SYSTEMATIC 23639115 A 197 222 iso-16-deethylindanomycin SYSTEMATIC 23639115 A 228 262 16-deethylindanomycin methyl ester SYSTEMATIC 23639115 A 271 309 iso-16-deethylindanomycin methyl ester SYSTEMATIC 23639115 A 411 422 indanomycin TRIVIAL 23639115 A 5 16 indanomycin TRIVIAL 23639115 T 0 11 Indanomycin TRIVIAL 23639187 A 1009 1033 2-deoxy-[(3)H]-d-glucose SYSTEMATIC 23639187 A 1035 1038 MTT ABBREVIATION 23639187 A 1043 1046 ATP ABBREVIATION 23639187 A 1104 1111 glucose TRIVIAL 23639187 A 1217 1249 phenylpyruvic acid-2-O-glucoside SYSTEMATIC 23639187 A 1254 1276 luteolin-7-O-glucoside SYSTEMATIC 23639187 A 1310 1317 glucose TRIVIAL 23639187 A 1353 1356 ATP ABBREVIATION 23639187 A 1423 1430 glucose TRIVIAL 23639187 A 1442 1445 ATP ABBREVIATION 23639187 A 1553 1562 palmitate TRIVIAL 23639187 A 1779 1786 glucose TRIVIAL 23639187 A 1819 1826 glucose TRIVIAL 23639187 A 1948 1957 palmitate TRIVIAL 23639187 A 20 36 free fatty acids FAMILY 23639187 A 218 225 glucose TRIVIAL 23639187 A 328 332 FFAs FAMILY 23639187 A 379 406 dihydrochalcone C-glucoside SYSTEMATIC 23639187 A 38 42 FFAs FAMILY 23639187 A 408 418 aspalathin TRIVIAL 23639187 A 58 84 saturated free fatty acids FAMILY 23639187 A 689 698 Palmitate TRIVIAL 23639187 A 758 768 aspalathin TRIVIAL 23639187 A 852 859 glucose TRIVIAL 23639187 A 93 102 palmitate TRIVIAL 23639187 A 947 954 Glucose TRIVIAL 23639187 T 16 25 palmitate TRIVIAL 23639190 A 1062 1072 chloroform TRIVIAL 23639190 A 1074 1087 ethyl acetate SYSTEMATIC 23639190 A 1089 1095 hexane SYSTEMATIC 23639190 A 1097 1104 ethanol SYSTEMATIC 23639190 A 1211 1217 hexane SYSTEMATIC 23639190 A 1222 1229 ethanol SYSTEMATIC 23639190 A 1357 1365 phenolic FAMILY 23639190 A 1383 1390 ethanol SYSTEMATIC 23639190 A 1437 1445 coumarin TRIVIAL 23639190 A 1459 1465 hexane SYSTEMATIC 23639190 A 734 742 Coumarin TRIVIAL 23639190 A 744 759 1,2-benzopyrone SYSTEMATIC 23639360 A 1000 1011 cholesterol TRIVIAL 23639360 A 1239 1245 sterol FAMILY 23639360 A 1345 1351 oxygen SYSTEMATIC 23639360 A 1364 1383 thiobarbituric acid SYSTEMATIC 23639360 A 1425 1435 superoxide TRIVIAL 23639360 A 1454 1473 reduced glutathione TRIVIAL 23639360 A 1474 1494 oxidized glutathione TRIVIAL 23639360 A 1637 1649 nitric oxide SYSTEMATIC 23639360 A 1688 1692 heme FAMILY 23639360 A 1767 1776 oil red O TRIVIAL 23639360 A 693 697 urea TRIVIAL 23639360 A 698 706 nitrogen SYSTEMATIC 23639360 A 708 718 creatinine TRIVIAL 23639360 A 720 730 creatinine TRIVIAL 23639360 A 777 789 triglyceride FAMILY 23639360 A 797 808 cholesterol TRIVIAL 23639360 A 825 835 fatty acid FAMILY 23639360 A 862 873 cholesterol TRIVIAL 23639360 A 908 919 cholesterol TRIVIAL 23639360 A 944 955 cholesterol TRIVIAL 23639360 A 977 989 triglyceride FAMILY 23639362 A 1033 1037 MPTP ABBREVIATION 23639362 A 1076 1084 dopamine TRIVIAL 23639362 A 1153 1175 17β-estradiol benzoate SYSTEMATIC 23639362 A 1317 1321 MPTP ABBREVIATION 23639362 A 1346 1350 MPTP ABBREVIATION 23639362 A 1690 1698 estrogen FAMILY 23639362 A 1759 1767 estrogen FAMILY 23639362 A 1795 1799 MPTP ABBREVIATION 23639362 A 277 285 estrogen FAMILY 23639362 A 361 369 estrogen FAMILY 23639362 A 506 514 estrogen FAMILY 23639362 A 628 636 dopamine TRIVIAL 23639362 A 656 664 tyrosine TRIVIAL 23639362 A 794 838 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine SYSTEMATIC 23639362 A 840 844 MPTP ABBREVIATION 23639362 T 134 142 estrogen FAMILY 23639362 T 28 72 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine SYSTEMATIC 23639451 A 1003 1006 RIF ABBREVIATION 23639451 A 1055 1063 titanium SYSTEMATIC 23639451 A 468 506 poly(D,L-lactic acid-co-glycolic acid) FAMILY 23639451 A 508 512 PLGA ABBREVIATION 23639451 A 547 559 fusidic acid TRIVIAL 23639451 A 573 579 sodium SYSTEMATIC 23639451 A 594 604 rifampicin TRIVIAL 23639451 A 606 609 RIF ABBREVIATION 23639451 A 880 891 methicillin TRIVIAL 23639451 T 0 12 Fusidic acid TRIVIAL 23639451 T 17 27 rifampicin TRIVIAL 23639451 T 38 42 PLGA ABBREVIATION 23639539 A 149 163 chloroformates FAMILY 23639539 A 199 218 potassium carbonate SYSTEMATIC 23639539 A 231 257 tetrabutylammonium bromide SYSTEMATIC 23639539 A 259 263 TBAB ABBREVIATION 23639539 A 336 340 (1)H FORMULA 23639539 A 342 347 (13)C FORMULA 23639539 A 386 390 (1)H FORMULA 23639539 A 44 76 piperidin-4-one oxime carbonates FAMILY 23639539 A 646 658 Streptomycin TRIVIAL 23639539 A 663 677 Amphotericin B TRIVIAL 23639539 A 82 132 1-methyl-3alkyl-2,6-diphenylpiperidin-4-one oximes FAMILY 23639539 T 63 124 1-methyl-3-alkyl-2,6-diphenylpiperidin-4-one oxime carbonates FAMILY 23639544 A 248 255 proline TRIVIAL 23639544 A 69 76 proline TRIVIAL 23639544 T 13 20 proline TRIVIAL 23639572 A 1147 1167 phosphatidylinositol TRIVIAL 23639572 A 1201 1211 wortmannin TRIVIAL 23639572 A 1324 1336 nitric oxide SYSTEMATIC 23639572 A 490 503 Linoleic acid TRIVIAL 23639572 A 538 553 free fatty acid FAMILY 23639572 A 622 641 deoxyribonucleotide FAMILY 23639572 A 663 688 deoxyuridine triphosphate SYSTEMATIC 23639572 A 772 789 poly (ADP-ribose) SYSTEMATIC 23639572 A 857 869 nitric oxide SYSTEMATIC 23639572 A 910 912 NO FORMULA 23639572 T 132 152 phosphatidylinositol TRIVIAL 23639572 T 60 75 free fatty acid FAMILY 23639586 A 0 10 Triptolide TRIVIAL 23639586 A 1206 1213 glucose TRIVIAL 23639586 A 1339 1346 glucose TRIVIAL 23639586 A 706 713 glucose TRIVIAL 23639586 A 878 885 glucose TRIVIAL 23639586 A 887 890 GSH ABBREVIATION 23639586 A 891 895 GSSG ABBREVIATION 23639586 A 903 910 glucose TRIVIAL 23639586 A 929 948 phosphoenolpyruvate SYSTEMATIC 23639586 T 76 86 triptolide TRIVIAL 23639626 A 1055 1071 aryl hydrocarbon FAMILY 23639626 A 1221 1225 TCDD ABBREVIATION 23639626 A 1266 1270 TCDD ABBREVIATION 23639626 A 1692 1698 dioxin FAMILY 23639626 A 1760 1764 TCDD ABBREVIATION 23639626 A 1884 1888 TCDD ABBREVIATION 23639626 A 192 196 TCDD ABBREVIATION 23639626 A 226 232 dioxin FAMILY 23639626 A 431 435 TCDD ABBREVIATION 23639626 A 58 93 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23639626 A 637 646 rapamycin TRIVIAL 23639626 A 704 708 TCDD ABBREVIATION 23639626 A 791 799 tyrosine TRIVIAL 23639626 A 883 887 TCDD ABBREVIATION 23639626 A 95 99 TCDD ABBREVIATION 23639626 T 0 4 TCDD ABBREVIATION 23639626 T 163 169 dioxin FAMILY 23639653 A 299 330 1,5-diarylpyrazol-3-carboxamide FAMILY 23639653 A 422 438 arachidonic acid TRIVIAL 23639653 A 514 547 1,5-Diarylpyrazole-3-carboxamides FAMILY 23639653 A 574 580 amines FAMILY 23639653 A 772 780 pyrazole SYSTEMATIC 23639653 T 0 8 Pyrazole SYSTEMATIC 23639653 T 38 54 arachidonic acid TRIVIAL 23639801 A 1121 1124 LPI ABBREVIATION 23639801 A 1224 1227 LPI ABBREVIATION 23639801 A 1337 1348 CID16020046 IDENTIFIER 23639801 A 330 341 CID16020046 IDENTIFIER 23639801 A 343 446 (4-[4-(3-hydroxyphenyl)-3-(4-methylphenyl)-6-oxo-1H,4H,5H,6H-pyrrolo [3,4-c] pyrazol-5-yl] benzoic acid SYSTEMATIC 23639801 A 47 71 lysophosphatidylinositol FAMILY 23639801 A 520 531 CID16020046 IDENTIFIER 23639801 A 681 684 LPI ABBREVIATION 23639801 A 694 698 Ca2+ FORMULA 23639801 A 73 76 LPI ABBREVIATION 23639801 A 848 859 CID16020046 IDENTIFIER 23639801 A 896 899 LPI ABBREVIATION 23639875 A 1026 1030 PGE2 ABBREVIATION 23639875 A 1205 1209 PGE2 ABBREVIATION 23639875 A 1236 1240 PGE2 ABBREVIATION 23639875 A 1353 1357 PGE2 ABBREVIATION 23639875 A 1653 1657 PGE2 ABBREVIATION 23639875 A 1806 1810 PGE2 ABBREVIATION 23639875 A 239 255 prostaglandin E2 TRIVIAL 23639875 A 257 261 PGE2 ABBREVIATION 23639875 A 697 701 PGE2 ABBREVIATION 23639875 T 0 16 Prostaglandin E2 TRIVIAL 23639947 A 263 266 ZnO FORMULA 23639947 A 6 9 ZnO FORMULA 23639947 A 79 82 CdS FORMULA 23639947 A 83 87 CdSe FORMULA 23639947 T 0 3 Zno FORMULA 23639947 T 40 43 CdS FORMULA 23639947 T 44 48 CdSe FORMULA 23640072 A 1070 1077 AZD1446 IDENTIFIER 23640072 A 1162 1170 nicotine TRIVIAL 23640072 A 1303 1311 nicotine TRIVIAL 23640072 A 1343 1350 AZD1446 IDENTIFIER 23640072 A 136 143 AZD1446 IDENTIFIER 23640072 A 1374 1381 AZD1446 IDENTIFIER 23640072 A 1566 1573 AZD1446 IDENTIFIER 23640072 A 175 188 acetylcholine SYSTEMATIC 23640072 A 352 359 AZD1446 IDENTIFIER 23640072 A 555 563 nicotine TRIVIAL 23640072 A 585 593 Nicotine TRIVIAL 23640072 A 638 645 AZD1446 IDENTIFIER 23640072 A 699 707 Nicotine TRIVIAL 23640072 A 732 739 AZD1446 IDENTIFIER 23640072 T 114 121 AZD1446 IDENTIFIER 23640072 T 123 130 TC-6683 IDENTIFIER 23640072 T 83 96 acetylcholine SYSTEMATIC 23640180 A 1136 1142 lysine TRIVIAL 23640180 A 1177 1180 Lys FORMULA 23640180 A 1185 1188 Lys FORMULA 23640180 A 1196 1199 Lys FORMULA 23640180 A 1287 1294 lysines FAMILY 23640180 A 1348 1355 lysines FAMILY 23640180 A 1373 1376 Lys FORMULA 23640180 A 1381 1384 Lys FORMULA 23640180 A 1392 1395 Lys FORMULA 23640180 A 1511 1514 Lys FORMULA 23640180 A 1519 1522 Lys FORMULA 23640180 A 1530 1533 Lys FORMULA 23640180 A 864 871 lysines FAMILY 23640180 A 902 910 arginine TRIVIAL 23640331 A 0 7 Steroid FAMILY 23640331 A 152 159 steroid FAMILY 23640331 A 363 375 progesterone TRIVIAL 23640331 T 0 12 Progesterone TRIVIAL 23640547 A 143 152 magnesium SYSTEMATIC 23640547 A 174 180 nickel SYSTEMATIC 23640547 A 324 332 chloride SYSTEMATIC 23640547 T 16 25 magnesium SYSTEMATIC 23640662 A 271 274 ZnO FORMULA 23640662 A 313 317 SiO2 FORMULA 23640662 A 55 58 ZnO FORMULA 23640662 A 587 590 ZnO FORMULA 23640662 A 69 74 MgZnO FORMULA 23640662 A 77 80 ZnO FORMULA 23640662 A 81 85 SiO2 FORMULA 23640662 A 88 90 Si FORMULA 23640662 T 56 61 MgZnO FORMULA 23640662 T 64 67 ZnO FORMULA 23640662 T 68 72 SiO2 FORMULA 23640662 T 75 77 Si FORMULA 23640687 A 1045 1058 prostaglandin FAMILY 23640687 A 1068 1079 epinephrine TRIVIAL 23640687 A 1081 1088 timolol TRIVIAL 23640687 A 630 648 thiazolidinediones FAMILY 23640687 A 803 813 fingolimod TRIVIAL 23640687 A 898 907 tamoxifen TRIVIAL 23640687 A 916 923 taxanes FAMILY 23640687 A 936 942 niacin TRIVIAL 23640814 A 7 26 Mn-doped iron oxide SYSTEMATIC 23640814 T 21 47 Manganese-Doped Iron Oxide SYSTEMATIC 23640846 A 200 206 oxygen SYSTEMATIC 23640846 A 232 241 graphenes FAMILY 23640846 A 298 307 graphenes FAMILY 23640846 A 344 350 helium SYSTEMATIC 23640846 T 0 6 Oxygen SYSTEMATIC 23640846 T 32 40 graphene TRIVIAL 23640862 A 1014 1017 ATP ABBREVIATION 23640862 A 1026 1029 NAD ABBREVIATION 23640862 A 1030 1034 NADH ABBREVIATION 23640862 A 1052 1064 nitric oxide SYSTEMATIC 23640862 A 1130 1133 Q10 ABBREVIATION 23640862 A 125 135 Nucleoside FAMILY 23640862 A 1601 1604 Q10 ABBREVIATION 23640862 A 1820 1823 Q10 ABBREVIATION 23640862 A 628 634 oxygen SYSTEMATIC 23640862 A 873 885 coenzyme Q10 TRIVIAL 23640862 A 887 890 Q10 ABBREVIATION 23640862 T 0 10 NUCLEOSIDE FAMILY 23640862 T 118 130 COENZYME Q10 TRIVIAL 23640894 A 595 601 serine TRIVIAL 23641914 A 1453 1467 toluidine blue TRIVIAL 23641914 A 342 351 polyester FAMILY 23641914 A 422 447 2-methylene-1,3-dioxepane SYSTEMATIC 23641914 A 452 473 glycidyl methacrylate TRIVIAL 23641914 A 669 699 epoxy-functionalized polyester FAMILY 23641914 T 139 149 polyesters FAMILY 23641914 T 20 45 2-methylene-1,3-dioxepane SYSTEMATIC 23641914 T 50 71 glycidyl methacrylate TRIVIAL 23641942 A 1057 1066 histidine TRIVIAL 23641942 A 119 128 histidine TRIVIAL 23641942 A 1416 1420 HPMA ABBREVIATION 23641942 A 276 309 N-(2-hydroxypropyl)methacrylamide SYSTEMATIC 23641942 A 311 315 HPMA ABBREVIATION 23641942 A 602 611 histidine TRIVIAL 23641942 A 824 833 histidine TRIVIAL 23641942 A 982 986 HPMA ABBREVIATION 23641942 T 13 22 histidine TRIVIAL 23641942 T 92 96 HPMA ABBREVIATION 23642037 A 294 300 Bi2Se3 FORMULA 23642037 A 978 984 Bi2Se3 FORMULA 23642037 T 68 74 Bi2Se3 FORMULA 23642478 A 12 31 benzenesulfonamides FAMILY 23642478 A 46 61 cyanoacrylamide SYSTEMATIC 23642478 A 620 625 azole FAMILY 23642478 A 700 712 sulfonamides FAMILY 23642478 A 72 83 tyrphostine TRIVIAL 23642478 T 31 50 Benzenesulfonamides FAMILY 23642478 T 65 80 cyanoacrylamide SYSTEMATIC 23643093 A 108 116 methanol SYSTEMATIC 23643093 A 1121 1135 5-fluorouracil SYSTEMATIC 23643093 A 1137 1141 5-FU SYSTEMATIC 23643093 A 1582 1586 5-FU SYSTEMATIC 23643093 A 1866 1895 benzophenanthridine alkaloids FAMILY 23643093 A 1900 1927 2-arylbenzofuran neolignans FAMILY 23643093 A 361 364 MTS ABBREVIATION 23643093 A 407 436 benzophenanthridine alkaloids FAMILY 23643093 A 454 483 dibenzyl butyrolactone lignan SYSTEMATIC 23643093 A 498 525 2-arylbenzofuran neolignans FAMILY 23643093 A 73 80 lignans FAMILY 23643093 T 31 65 benzophenanthridine-type alkaloids FAMILY 23643093 T 70 97 2-arylbenzofuran neolignans FAMILY 23643094 A 1094 1098 NDGA ABBREVIATION 23643094 A 247 251 NDGA ABBREVIATION 23643094 A 350 354 NDGA ABBREVIATION 23643094 A 423 427 NDGA ABBREVIATION 23643094 A 45 70 nordihydroguaiaretic acid TRIVIAL 23643094 A 600 604 NDGA ABBREVIATION 23643094 A 619 623 NDGA ABBREVIATION 23643094 A 625 629 NDGA ABBREVIATION 23643094 A 72 76 NDGA ABBREVIATION 23643094 A 881 885 NDGA ABBREVIATION 23643094 T 0 25 Nordihydroguaiaretic acid TRIVIAL 23643543 A 1013 1021 flavones FAMILY 23643543 A 112 120 flavones FAMILY 23643543 A 1242 1250 flavones FAMILY 23643543 A 1410 1420 liquiritin TRIVIAL 23643543 A 1434 1447 isoliquiritin TRIVIAL 23643543 A 1462 1476 liquiritigenin TRIVIAL 23643543 A 1490 1507 isoliquiritigenin TRIVIAL 23643543 A 1709 1719 liquiritin TRIVIAL 23643543 A 1721 1734 isoliquiritin TRIVIAL 23643543 A 1736 1750 liquiritigenin TRIVIAL 23643543 A 1752 1769 isoliquiritigenin TRIVIAL 23643543 A 1918 1931 Isoliquiritin TRIVIAL 23643543 A 2048 2065 Isoliquiritigenin TRIVIAL 23643543 A 2130 2144 Liquiritigenin TRIVIAL 23643543 A 221 229 flavones FAMILY 23643543 A 2342 2350 flavones FAMILY 23643543 A 348 356 flavones FAMILY 23643543 A 393 403 liquiritin TRIVIAL 23643543 A 405 418 isoliquiritin TRIVIAL 23643543 A 420 434 liquiritigenin TRIVIAL 23643543 A 436 453 isoliquiritigenin TRIVIAL 23643543 A 673 681 flavones FAMILY 23643543 A 737 745 flavones FAMILY 23643543 A 883 897 methanoic acid SYSTEMATIC 23643543 A 906 918 acetonitrile SYSTEMATIC 23643543 T 30 38 flavones FAMILY 23643699 A 1073 1081 nitriles FAMILY 23643699 A 1083 1095 benzonitrile SYSTEMATIC 23643699 A 1100 1137 α-cyclohexylidene benzeneacetonitrile SYSTEMATIC 23643699 A 115 123 nitriles FAMILY 23643699 A 1251 1259 nitriles FAMILY 23643699 A 250 258 nitriles FAMILY 23643699 A 266 274 nitriles FAMILY 23643699 A 572 580 nitriles FAMILY 23643699 A 617 630 Dodecanitrile SYSTEMATIC 23643699 A 635 678 2,2,3-trimethylcyclopent-3-enylacetonitrile SYSTEMATIC 23643699 A 788 807 citronellyl nitrile SYSTEMATIC 23643699 A 809 840 3-methyl-5-phenylpentanenitrile SYSTEMATIC 23643699 A 842 858 cinnamyl nitrile SYSTEMATIC 23643699 A 864 898 3-methyl-5-phenylpent-2-enenitrile SYSTEMATIC 23643699 A 93 100 nitrile SYSTEMATIC 23643699 A 996 1004 nitriles FAMILY 23643699 T 30 37 nitrile SYSTEMATIC 23643702 A 1038 1045 dodecyl SYSTEMATIC 23643702 A 1187 1193 ethers FAMILY 23643702 A 1210 1215 hexyl SYSTEMATIC 23643702 A 1259 1273 hydroxytyrosol SYSTEMATIC 23643702 A 141 147 ethers FAMILY 23643702 A 25 39 hydroxytyrosol SYSTEMATIC 23643702 A 306 311 ether SYSTEMATIC 23643702 A 325 330 ethyl SYSTEMATIC 23643702 A 332 337 butyl SYSTEMATIC 23643702 A 339 344 hexyl SYSTEMATIC 23643702 A 346 351 octyl SYSTEMATIC 23643702 A 356 363 dodecyl SYSTEMATIC 23643702 A 454 461 calcium SYSTEMATIC 23643702 A 470 484 thromboxane B2 TRIVIAL 23643702 A 486 490 TxB2 ABBREVIATION 23643702 A 500 524 6-keto-prostaglandin F1α SYSTEMATIC 23643702 A 526 538 6-keto-PGF1α SYSTEMATIC 23643702 A 544 552 nitrites FAMILY 23643702 A 555 563 nitrates FAMILY 23643702 A 595 604 peroxides FAMILY 23643702 A 643 662 reduced glutathione TRIVIAL 23643702 A 664 667 GSH ABBREVIATION 23643702 A 751 755 TxB2 ABBREVIATION 23643702 A 818 824 carbon SYSTEMATIC 23643702 A 861 866 hexyl SYSTEMATIC 23643702 A 886 893 nitrite SYSTEMATIC 23643702 A 913 916 GSH ABBREVIATION 23643702 A 974 986 6-keto-PGF1α SYSTEMATIC 23643702 T 0 26 Hydroxytyrosyl alkyl ether FAMILY 23643743 A 0 15 Methamphetamine TRIVIAL 23643743 A 1000 1010 ketoprofen TRIVIAL 23643743 A 1029 1033 Meth ABBREVIATION 23643743 A 109 113 5-HT SYSTEMATIC 23643743 A 1098 1106 SC-51089 IDENTIFIER 23643743 A 1132 1136 5-HT SYSTEMATIC 23643743 A 1169 1173 Meth ABBREVIATION 23643743 A 1299 1303 Meth ABBREVIATION 23643743 A 1331 1340 monoamine FAMILY 23643743 A 138 142 Meth ABBREVIATION 23643743 A 1493 1497 Meth ABBREVIATION 23643743 A 17 21 Meth ABBREVIATION 23643743 A 203 207 Meth ABBREVIATION 23643743 A 405 415 monoamines FAMILY 23643743 A 484 488 Meth ABBREVIATION 23643743 A 556 560 Meth ABBREVIATION 23643743 A 647 651 5-HT SYSTEMATIC 23643743 A 756 766 ketoprofen TRIVIAL 23643743 A 792 796 Meth ABBREVIATION 23643743 A 80 88 dopamine TRIVIAL 23643743 A 807 817 ketoprofen TRIVIAL 23643743 A 871 875 Meth ABBREVIATION 23643743 A 926 930 Meth ABBREVIATION 23643743 A 98 107 serotonin TRIVIAL 23643743 T 104 119 methamphetamine TRIVIAL 23643754 A 1131 1134 5HT SYSTEMATIC 23643754 A 1168 1173 ESCIT ABBREVIATION 23643754 A 1190 1194 5-HT SYSTEMATIC 23643754 A 124 133 serotonin TRIVIAL 23643754 A 1346 1350 5-HT SYSTEMATIC 23643754 A 135 139 5-HT SYSTEMATIC 23643754 A 299 303 5-HT SYSTEMATIC 23643754 A 351 363 escitalopram TRIVIAL 23643754 A 365 370 ESCIT ABBREVIATION 23643754 A 393 397 5-HT SYSTEMATIC 23643754 A 487 491 5-HT SYSTEMATIC 23643754 A 591 595 5-HT SYSTEMATIC 23643754 A 618 623 ESCIT ABBREVIATION 23643754 A 718 722 5-HT SYSTEMATIC 23643754 A 742 747 ESCIT ABBREVIATION 23643754 A 802 807 ESCIT ABBREVIATION 23643754 A 844 848 5-HT SYSTEMATIC 23643754 A 893 897 5-HT SYSTEMATIC 23643754 A 928 933 ESCIT ABBREVIATION 23643754 T 102 114 escitalopram TRIVIAL 23643754 T 59 68 serotonin TRIVIAL 23643799 A 0 8 Chromium SYSTEMATIC 23643799 A 1040 1048 chromium SYSTEMATIC 23643799 A 382 390 chromium SYSTEMATIC 23643799 A 597 605 chromium SYSTEMATIC 23643799 A 734 742 chromium SYSTEMATIC 23643799 A 851 859 chromium SYSTEMATIC 23643799 T 20 28 chromium SYSTEMATIC 23643845 A 108 123 brassinosteroid FAMILY 23643845 A 176 185 hecogenin TRIVIAL 23643845 A 231 239 carbonyl FAMILY 23643845 A 260 282 22,23-dioxocholestanic SYSTEMATIC 23643845 A 315 332 hecogenin acetate SYSTEMATIC 23643845 A 341 359 hecogenin tosylate SYSTEMATIC 23643845 A 37 58 pentacyclic steroidal FAMILY 23643845 A 507 529 22,23-dioxocholestanic SYSTEMATIC 23643845 A 566 574 carbonyl FAMILY 23643845 A 607 615 carbonyl FAMILY 23643845 A 635 664 20-epi-12,23-dihydroxy-22-oxo SYSTEMATIC 23643845 T 21 43 22,23-dioxocholestanic SYSTEMATIC 23643845 T 97 112 brassinosteroid FAMILY 23644191 A 188 197 copper(I) SYSTEMATIC 23644191 A 206 219 [CuCl(PPh3)L] FAMILY 23644191 A 276 285 copper(I) SYSTEMATIC 23644191 A 621 630 copper(I) SYSTEMATIC 23644191 A 8 29 copper(I) Schiff base FAMILY 23644191 T 127 136 copper(I) SYSTEMATIC 23644191 T 150 229 5-dimethyl-2-phenyl-4-[(pyridin-2-ylmethylene)-amino]-1,2-dihydro-pyrazol-3-one SYSTEMATIC 23644191 T 230 241 Schiff base FAMILY 23644197 A 161 168 ZSTK474 IDENTIFIER 23644197 A 222 235 4-Aminoalkoxy FAMILY 23644197 A 296 309 4-O(CH2)3NMe2 SYSTEMATIC 23644197 A 450 463 hydrochloride FAMILY 23644197 A 556 563 ZSTK474 IDENTIFIER 23644197 A 78 159 2-(difluoromethyl)-1-[4,6-di-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole SYSTEMATIC 23644197 T 138 218 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole SYSTEMATIC 23644197 T 220 227 ZSTK474 IDENTIFIER 23644197 T 45 65 phosphatidylinositol TRIVIAL 23644197 T 99 126 4-substituted benzimidazole FAMILY 23644202 A 129 158 2-methyl-5-nitro-1H-imidazole SYSTEMATIC 23644202 A 29 38 hydrazone FAMILY 23644202 A 310 323 acylhydrazone SYSTEMATIC 23644202 A 372 384 oxadiazoline SYSTEMATIC 23644202 A 488 501 acylhydrazone SYSTEMATIC 23644202 A 555 567 oxadiazoline SYSTEMATIC 23644202 A 592 595 MTT ABBREVIATION 23644202 A 76 88 oxadiazoline SYSTEMATIC 23644202 T 0 26 Nitroimidazolyl hydrazones FAMILY 23644202 T 70 88 1,3,4-oxadiazoline SYSTEMATIC 23644204 A 12 18 enmein TRIVIAL 23644204 A 24 35 diterpenoid FAMILY 23644204 A 278 286 oridonin TRIVIAL 23644204 A 365 370 Taxol TRIVIAL 23644204 A 73 80 kaurene TRIVIAL 23644204 A 98 106 oridonin TRIVIAL 23644204 T 0 6 Enmein TRIVIAL 23644204 T 12 23 diterpenoid FAMILY 23644204 T 45 52 kaurene TRIVIAL 23644204 T 58 66 oridonin TRIVIAL 23644911 A 299 307 Oxytocin TRIVIAL 23644911 T 25 33 oxytocin TRIVIAL 23645211 A 1048 1058 superoxide TRIVIAL 23645211 A 1070 1081 glutathione TRIVIAL 23645211 A 109 116 cadmium SYSTEMATIC 23645211 A 1162 1164 Cd FORMULA 23645211 A 118 120 Cd FORMULA 23645211 A 1204 1207 MDA ABBREVIATION 23645211 A 1397 1399 Cd FORMULA 23645211 A 1596 1598 Cd FORMULA 23645211 A 1786 1788 Cd FORMULA 23645211 A 1982 1984 Cd FORMULA 23645211 A 287 289 Cd FORMULA 23645211 A 302 304 Cd FORMULA 23645211 A 326 328 Cd FORMULA 23645211 A 376 392 cadmium chloride SYSTEMATIC 23645211 A 394 399 CdCl2 FORMULA 23645211 A 492 494 Cd FORMULA 23645211 A 617 619 Cd FORMULA 23645211 A 76 85 quercetin TRIVIAL 23645211 A 886 888 Cd FORMULA 23645211 A 921 923 Cd FORMULA 23645211 A 968 983 malondialdehyde TRIVIAL 23645211 A 985 988 MDA ABBREVIATION 23645211 T 21 28 cadmium SYSTEMATIC 23645211 T 8 17 quercetin TRIVIAL 23645360 A 1071 1082 norflurazon TRIVIAL 23645360 A 1386 1396 lincomycin TRIVIAL 23645360 A 398 408 lincomycin TRIVIAL 23645360 A 415 426 norflurazon TRIVIAL 23645360 A 973 983 lincomycin TRIVIAL 23645536 A 17 36 phenolic glycosides FAMILY 23645536 A 213 226 ethyl acetate SYSTEMATIC 23645536 A 227 236 n-butanol SYSTEMATIC 23645536 A 38 47 acteoside TRIVIAL 23645536 A 488 494 aldose FAMILY 23645536 A 49 61 eutigoside B TRIVIAL 23645536 A 529 538 acteoside TRIVIAL 23645536 A 63 75 isoacteoside TRIVIAL 23645536 A 678 687 quercetin TRIVIAL 23645536 A 764 773 acteoside TRIVIAL 23645536 A 77 82 rutin TRIVIAL 23645536 A 87 96 cornoside TRIVIAL 23645536 T 89 95 aldose FAMILY 23645677 A 1097 1102 KN-92 IDENTIFIER 23645677 A 1107 1110 H89 IDENTIFIER 23645677 A 1230 1237 calcium SYSTEMATIC 23645677 A 1250 1259 carbachol TRIVIAL 23645677 A 789 796 calcium SYSTEMATIC CHEMDNER_CORPUS_BIOCREATIVE_4/CHEMDNER_TEST/Readme.txt0000644002344200234200000001342112236175422022706 0ustar mkrallingerBioinfoUnixCHEMDNER task test data (Version 1.0 13-09-2013) ------------------------------------------------------------------------ This directory contains the CHEMDNER test set abstracts and annotations. 1) chemdner_abs_test.txt : Test set abstracts This file contains plain-text, UTF8-encoded PubMed abstracts in a tab-separated format with the following three columns: 1- Article identifier (PMID, PubMed identifier) 2- Title of the article 3- Abstract of the article The test set file consists in a set of 20,000 abstracts containing the 3000 test set abstracts in addition to a background collection of 17,000 random abstracts from PubMed. We added this background set to avoid any manual correction of the predictions. 2) chemdner_abs_test_pmid_label.txt This file contains the classification of the provided 20,000 abstracts  into the 3,000 test set abstracts and the background collection of 17,000 random abstracts from PubMed. Column 1 corresponds to the PMID of the abstract, and column 2 to the abstract label. If the abstract is labelled 'Y' it was part of the manually revised test set, if the label is 'N' it is part of the PubMed background collection. 3) Test data annotations: chemdner_ann_test_13-09-13.txt This file contains manually generated annotations of chemical entities of the test dataset. It consists of tab-separated fields containing: 1- Article identifier (PMID) 2- Type of text from which the annotation was derived (T: Title, A: Abstract) 3- Start offset 4- End offset 5- Text string of the entity mention 6- Type of chemical entity mention (ABBREVIATION,FAMILY,FORMULA,IDENTIFIERS,MULTIPLE,SYSTEMATIC,TRIVIAL) 4) Test data Gold Standard file for the Chemical document indexing (CDI) sub-task: cdi_ann_test_13-09-13.txt Given a set of documents, for this subtask, the participants were asked to return for each of them a ranked list of chemical entities described within each of these documents. It consists of tab-separated fields containing: 1- Article identifier (PMID) 2- Text string of the entity mention An example is shown below: 21723361 docosahexaenoic acid 21723361 docosahexaenoic acids 21723361 methylmercury 21838705 MonoCarboxylate 21838705 darunavir 21838705 ritonavir 21838705 saquinavir 5) Test data Gold Standard file for the Chemical entity mention recognition (CEM) sub-task: cem_ann_test_13-09-13.txt Given a set of documents, for this subtask, the participants had to return the start and end indices corresponding to all the chemical entities mentioned in this document. It consists of tab-separated columns containing: 1- Article identifier (PMID) 2- Offset string consisting in a triplet joined by the ':' character. You have to provide the text type (T: Title, A:Abstract), the start offset and the end offset. An example illustrating the format is shown below: 21723361 A:100:113 21723361 A:46:67 21723361 T:11:31 21723361 T:36:49 21838705 A:1070:1085 21838705 A:1419:1429 21838705 A:1434:1443 21838705 A:1765:1774 Additional comments ------------------- To evaluate the performance of your system we recommend you to use the BioCreative evaluation library scripts. You can also directly download it from the BioCreative Resources page at: http://www.biocreative.org/resources/biocreative-ii5/evaluation-library/ This webpage explains in detail how to install the library and how it works. For both of the tasks you should use the --INT evaluation option like shown below: bc-evaluate --INT prediction_file evaluation_file As the --INT option is chosen by default, you can also run this script without the argument: bc-evaluate prediction_file evaluation_file Example evaluation files for both subtasks were described above. A) Prediction format for the CDI subtask Please make sure that your predictions are compliant with the formatting information provided for the --INT option of the evaluation library (The webpage and the bc-evaluate -h and bc-evaluate -d option provide you with more details.) In short, you have to provide a tab-separated file with: 1- Article identifier 2- The chemical entity mention string 3- The rank of the chemical entity returned for this document 4- A confidence score Example cases are provided online in the CHEMDNER sample set (June 25, 2013) (http://www.biocreative.org/resources/corpora/bc-iv-chemdner-corpus/#bc-iv-chemdner-corpus:downloads) An example prediction for the sample set is shown below: 6780324 LHRH 1 0.9 6780324 FSH 2 0.857142857143 6780324 3H2O 3 0.75 6780324 (Bu)2cAMP 4 0.75 6780324 vitro 5 0.666666666667 6780324 plasminogen 6 0.5 6780324 ethylamide 7 0.5 6780324 beta-3H]testosterone 8 0.5 6780324 NIH-FSH-S13 9 0.5 6780324 D-Ser-(But),6 10 0.5 6780324 4-h 11 0.5 6780324 3-isobutyl-l-methylxanthine 12 0.5 2231607 thymidylate 1 0.666666666667 2231607 acid 2 0.666666666667 2231607 TS 3 0.666666666667 B) Prediction format for the CEM subtask Please make sure that your predictions are compliant with the formatting information provided for the --INT option of the evaluation library (The webpage and the bc-evaluate -h and bc-evaluate -d option provide you with more details.) In short, you have to provide a tab-separated file with: 1- Article identifier (PMID) 2- Offset string consisting in a triplet joined by the ':' character. You have to provide the text type (T: Title, A:Abstract), the start offset and the end offset. 3- The rank of the chemical entity returned for this document 4- A confidence score Example from the sample set (from June 25, 2013) is shown below: 6780324 A:104:107 1 0.5 6780324 A:1136:1147 2 0.5 6780324 A:1497:1500 3 0.5 6780324 A:162:167 4 0.5 6780324 A:17:21 5 0.5 6780324 A:319:330 6 0.5 6780324 A:448:452 7 0.5 CHEMDNER_CORPUS_BIOCREATIVE_4/CHEMDNER_TEST/cem_ann_test_13-09-13.txt0000644002344200234200000165732712236173707025152 0ustar mkrallingerBioinfoUnix21723361 A:100:113 21723361 A:46:67 21723361 T:11:31 21723361 T:36:49 21838705 A:1070:1085 21838705 A:1419:1429 21838705 A:1434:1443 21838705 A:1765:1774 22064666 A:112:124 22064666 A:1493:1503 22064666 A:168:170 22064666 A:278:288 22064666 A:50:60 22064666 A:651:661 22064666 T:12:24 22064666 T:83:93 22075688 A:1024:1026 22075688 A:1103:1106 22075688 A:1107:1110 22075688 A:1137:1148 22075688 A:1154:1165 22075688 A:1174:1180 22075688 A:1264:1275 22075688 A:1325:1327 22075688 A:1353:1364 22075688 A:1384:1387 22075688 A:232:250 22075688 A:252:255 22075688 A:258:269 22075688 A:430:433 22075688 A:447:465 22075688 A:467:473 22075688 A:64:74 22075688 A:736:739 22075688 A:740:743 22075688 A:755:757 22075688 A:830:833 22075688 A:900:911 22075688 A:98:109 22075688 T:27:36 22075688 T:79:97 22082826 A:1011:1022 22082826 A:1030:1040 22082826 A:1056:1067 22082826 A:1351:1355 22082826 A:794:802 22083351 A:1080:1083 22083351 A:1088:1092 22083351 A:1150:1159 22083351 A:175:188 22083351 A:190:193 22083351 A:199:230 22083351 A:232:236 22083351 A:509:512 22083351 A:517:521 22083351 A:649:652 22083351 A:657:661 22083351 A:799:802 22083351 A:807:811 22150026 A:181:192 22150026 A:194:202 22150026 A:204:212 22150026 A:214:220 22150026 A:222:229 22150026 A:231:245 22150026 A:247:252 22150026 A:254:265 22150026 A:270:284 22150026 A:290:303 22150026 A:321:342 22150026 A:344:375 22150026 A:380:392 22150026 A:479:491 22150026 A:510:539 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A:474:483 23443753 A:561:570 23443753 A:676:685 23443810 A:729:737 23443810 A:834:842 23444015 A:1331:1340 23444015 A:1353:1388 23444015 A:1426:1437 23444015 A:47:56 23444015 A:690:699 23444015 T:25:34 23444138 A:206:213 23444138 A:350:358 23444138 A:439:447 23444138 A:747:754 23444138 T:69:77 23444282 A:1000:1008 23444282 A:1186:1194 23444282 A:221:229 23444282 A:266:274 23444282 A:316:324 23444282 A:31:39 23444282 A:381:389 23444282 A:633:641 23444282 A:719:727 23444282 A:802:810 23444282 T:81:89 23444286 A:1248:1258 23444286 A:1262:1265 23444286 A:20:30 23444286 A:220:230 23444286 A:231:241 23444286 A:31:41 23444286 A:341:351 23444286 A:356:378 23444286 A:380:383 23444286 A:410:422 23444286 A:493:502 23444286 A:710:719 23444286 A:767:777 23444286 A:9:18 23444286 T:34:44 23444286 T:45:55 23444300 A:1082:1085 23444300 A:110:112 23444300 A:113:122 23444300 A:1140:1143 23444300 A:1147:1149 23444300 A:1150:1159 23444300 A:1195:1202 23444300 A:149:152 23444300 A:1548:1551 23444300 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23449501 A:0:9 23449501 A:1012:1013 23449501 A:1181:1185 23449501 A:11:15 23449501 A:1235:1239 23449501 A:133:137 23449501 A:1367:1373 23449501 A:1398:1402 23449501 A:240:246 23449501 A:308:314 23449501 A:350:354 23449501 A:356:360 23449501 A:439:443 23449501 A:46:50 23449501 A:510:516 23449501 A:584:590 23449501 A:615:619 23449501 T:0:4 23449501 T:86:88 23450708 A:263:278 23450708 A:491:500 23450708 A:782:791 23450708 A:828:836 23450708 T:23:38 23450741 A:264:277 23450741 A:536:544 23450827 A:383:397 23450827 A:715:729 23450827 A:895:909 23451853 A:1053:1055 23451853 A:1065:1069 23451853 A:1127:1137 23451853 A:1141:1158 23451853 A:117:119 23451853 A:1217:1219 23451853 A:1307:1314 23451853 A:1454:1463 23451853 A:236:238 23451853 A:270:272 23451853 A:377:390 23451853 A:461:463 23451853 A:512:518 23451853 A:580:597 23451853 A:599:601 23451853 A:724:726 23451853 A:788:790 23451853 A:825:833 23451853 A:846:850 23451853 A:923:929 23451853 A:978:982 23451853 T:84:91 23452230 A:141:148 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23641914 A:1453:1467 23641914 A:342:351 23641914 A:422:447 23641914 A:452:473 23641914 A:669:699 23641914 T:139:149 23641914 T:20:45 23641914 T:50:71 23641942 A:1057:1066 23641942 A:119:128 23641942 A:1416:1420 23641942 A:276:309 23641942 A:311:315 23641942 A:602:611 23641942 A:824:833 23641942 A:982:986 23641942 T:13:22 23641942 T:92:96 23642037 A:294:300 23642037 A:978:984 23642037 T:68:74 23642478 A:12:31 23642478 A:46:61 23642478 A:620:625 23642478 A:700:712 23642478 A:72:83 23642478 T:31:50 23642478 T:65:80 23643093 A:108:116 23643093 A:1121:1135 23643093 A:1137:1141 23643093 A:1582:1586 23643093 A:1866:1895 23643093 A:1900:1927 23643093 A:361:364 23643093 A:407:436 23643093 A:454:483 23643093 A:498:525 23643093 A:73:80 23643093 T:31:65 23643093 T:70:97 23643094 A:1094:1098 23643094 A:247:251 23643094 A:350:354 23643094 A:423:427 23643094 A:45:70 23643094 A:600:604 23643094 A:619:623 23643094 A:625:629 23643094 A:72:76 23643094 A:881:885 23643094 T:0:25 23643543 A:1013:1021 23643543 A:112:120 23643543 A:1242:1250 23643543 A:1410:1420 23643543 A:1434:1447 23643543 A:1462:1476 23643543 A:1490:1507 23643543 A:1709:1719 23643543 A:1721:1734 23643543 A:1736:1750 23643543 A:1752:1769 23643543 A:1918:1931 23643543 A:2048:2065 23643543 A:2130:2144 23643543 A:221:229 23643543 A:2342:2350 23643543 A:348:356 23643543 A:393:403 23643543 A:405:418 23643543 A:420:434 23643543 A:436:453 23643543 A:673:681 23643543 A:737:745 23643543 A:883:897 23643543 A:906:918 23643543 T:30:38 23643699 A:1073:1081 23643699 A:1083:1095 23643699 A:1100:1137 23643699 A:115:123 23643699 A:1251:1259 23643699 A:250:258 23643699 A:266:274 23643699 A:572:580 23643699 A:617:630 23643699 A:635:678 23643699 A:788:807 23643699 A:809:840 23643699 A:842:858 23643699 A:864:898 23643699 A:93:100 23643699 A:996:1004 23643699 T:30:37 23643702 A:1038:1045 23643702 A:1187:1193 23643702 A:1210:1215 23643702 A:1259:1273 23643702 A:141:147 23643702 A:25:39 23643702 A:306:311 23643702 A:325:330 23643702 A:332:337 23643702 A:339:344 23643702 A:346:351 23643702 A:356:363 23643702 A:454:461 23643702 A:470:484 23643702 A:486:490 23643702 A:500:524 23643702 A:526:538 23643702 A:544:552 23643702 A:555:563 23643702 A:595:604 23643702 A:643:662 23643702 A:664:667 23643702 A:751:755 23643702 A:818:824 23643702 A:861:866 23643702 A:886:893 23643702 A:913:916 23643702 A:974:986 23643702 T:0:26 23643743 A:0:15 23643743 A:1000:1010 23643743 A:1029:1033 23643743 A:1098:1106 23643743 A:109:113 23643743 A:1132:1136 23643743 A:1169:1173 23643743 A:1299:1303 23643743 A:1331:1340 23643743 A:138:142 23643743 A:1493:1497 23643743 A:17:21 23643743 A:203:207 23643743 A:405:415 23643743 A:484:488 23643743 A:556:560 23643743 A:647:651 23643743 A:756:766 23643743 A:792:796 23643743 A:807:817 23643743 A:80:88 23643743 A:871:875 23643743 A:926:930 23643743 A:98:107 23643743 T:104:119 23643754 A:1131:1134 23643754 A:1168:1173 23643754 A:1190:1194 23643754 A:124:133 23643754 A:1346:1350 23643754 A:135:139 23643754 A:299:303 23643754 A:351:363 23643754 A:365:370 23643754 A:393:397 23643754 A:487:491 23643754 A:591:595 23643754 A:618:623 23643754 A:718:722 23643754 A:742:747 23643754 A:802:807 23643754 A:844:848 23643754 A:893:897 23643754 A:928:933 23643754 T:102:114 23643754 T:59:68 23643799 A:0:8 23643799 A:1040:1048 23643799 A:382:390 23643799 A:597:605 23643799 A:734:742 23643799 A:851:859 23643799 T:20:28 23643845 A:108:123 23643845 A:176:185 23643845 A:231:239 23643845 A:260:282 23643845 A:315:332 23643845 A:341:359 23643845 A:37:58 23643845 A:507:529 23643845 A:566:574 23643845 A:607:615 23643845 A:635:664 23643845 T:21:43 23643845 T:97:112 23644191 A:188:197 23644191 A:206:219 23644191 A:276:285 23644191 A:621:630 23644191 A:8:29 23644191 T:127:136 23644191 T:150:229 23644191 T:230:241 23644197 A:161:168 23644197 A:222:235 23644197 A:296:309 23644197 A:450:463 23644197 A:556:563 23644197 A:78:159 23644197 T:138:218 23644197 T:220:227 23644197 T:45:65 23644197 T:99:126 23644202 A:129:158 23644202 A:29:38 23644202 A:310:323 23644202 A:372:384 23644202 A:488:501 23644202 A:555:567 23644202 A:592:595 23644202 A:76:88 23644202 T:0:26 23644202 T:70:88 23644204 A:12:18 23644204 A:24:35 23644204 A:278:286 23644204 A:365:370 23644204 A:73:80 23644204 A:98:106 23644204 T:0:6 23644204 T:12:23 23644204 T:45:52 23644204 T:58:66 23644911 A:299:307 23644911 T:25:33 23645211 A:1048:1058 23645211 A:1070:1081 23645211 A:109:116 23645211 A:1162:1164 23645211 A:118:120 23645211 A:1204:1207 23645211 A:1397:1399 23645211 A:1596:1598 23645211 A:1786:1788 23645211 A:1982:1984 23645211 A:287:289 23645211 A:302:304 23645211 A:326:328 23645211 A:376:392 23645211 A:394:399 23645211 A:492:494 23645211 A:617:619 23645211 A:76:85 23645211 A:886:888 23645211 A:921:923 23645211 A:968:983 23645211 A:985:988 23645211 T:21:28 23645211 T:8:17 23645360 A:1071:1082 23645360 A:1386:1396 23645360 A:398:408 23645360 A:415:426 23645360 A:973:983 23645536 A:17:36 23645536 A:213:226 23645536 A:227:236 23645536 A:38:47 23645536 A:488:494 23645536 A:49:61 23645536 A:529:538 23645536 A:63:75 23645536 A:678:687 23645536 A:764:773 23645536 A:77:82 23645536 A:87:96 23645536 T:89:95 23645677 A:1097:1102 23645677 A:1107:1110 23645677 A:1230:1237 23645677 A:1250:1259 23645677 A:789:796 CHEMDNER_CORPUS_BIOCREATIVE_4/CHEMDNER_TEST/cdi_ann_test_13-09-13.txt0000644002344200234200000112041412236173664025125 0ustar mkrallingerBioinfoUnix21723361 docosahexaenoic acid 21723361 docosahexaenoic acids 21723361 methylmercury 21838705 MonoCarboxylate 21838705 darunavir 21838705 ritonavir 21838705 saquinavir 22064666 NO 22064666 nitric oxide 22064666 sildenafil 22075688 (25)Mg(2+) 22075688 (25)MgPMC16 22075688 ADP 22075688 ATP 22075688 AlP 22075688 Bicarb 22075688 Mg 22075688 Sodium bicarbonate 22075688 aluminum phosphide 22075688 magnesium 22082826 dUTP 22082826 glutathione 22082826 ketamine 22082826 superoxide 22083351 PD-033299 22083351 SAHA 22083351 VPA 22083351 suberoylanilide hydroxamic acid 22083351 valproic acid 22150026 2,2-diphenyl-1-picrylhydrazyl 22150026 4-hydroxybenzoic acid 22150026 Trolox 22150026 betulin 22150026 betulinic acid 22150026 butylated hydroxyanisole 22150026 erythrodiol 22150026 gallic and protocatechuic acids 22150026 isocorilagin 22150026 lupeol 22150026 oleanolic acid 22150026 phenolic acid 22150026 triterpenes 22150026 uvaol 22150026 α-amyrin 22150026 β-amyrin 22155887 Trolox 22155887 fluoride 22173956 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine 22173956 2-amino-3-methylimidazo[4,5-f] quinoline 22173956 PhIP 22173956 heterocyclic amine 22173956 heterocyclic amines 22231567 amines 22233192 ALA 22233192 GLA 22233192 fatty acids 22233192 linoleic acid 22233192 linoleic and palmitic acids 22233192 oleic acid 22233192 α-tocopherol 22284538 carbohydrate 22284538 serine 22284538 threonine 22287617 Epicatechin 22287617 MDA 22287617 Nicotine 22287617 Vit E 22287617 Vitamin E 22287617 epicatechin 22287617 glutathione 22287617 malondialdhyde 22287617 nicotine 22287617 superoxide 22287617 vitamin E 22294440 Ni(2+) 22294440 malondialdehyde 22294440 nickel 22294440 oxygen 22294440 quercetin 22294440 trichostatin A 22301817 Cadmium 22301817 cadmium 22301817 graphite 22301817 nitric acid 22301817 perchloric acid 22304229 1,1,6,6-tetraphenylhexa-2,4-diyne-1,6-diol 22304229 hydrogen 22304229 patchouli alcohol 22317828 Brilliant blue 22317828 S 22317828 alanine 22317828 aspartate 22317828 bilirubin 22317828 carmoisine 22317828 creatinine 22317828 glutathione 22317828 propylene glycol 22317828 superoxide 22317828 tartrazine 22317828 trans-anethole 22317828 urea 22317828 vanillin 22320163 (22E,24R)-3β-hydroxy-ergosta-5,22-dien-7-one 22320163 (22E,24R)-6β-methoxyergosta-7,22-diene-3β,5α-diol 22320163 2',3'-diacetoxy-3,4,5',6',4″-pentahydroxy-p-terphenyl 22320163 3,4-dihydroxybenzoic acid 22320163 Steroids 22320163 benzoic acid 22320163 cerebroside 22320163 cerebroside B 22320163 ergosta-7,22-dien-3β-ol 22320163 ergosterol peroxide 22320163 methanol 22320163 methyl p-hydroxybenzoate 22320163 phenolic 22320163 phenolics 22320163 steroids 22323477 4-Thujanol 22323477 4-thujanol 22323477 MMC 22323477 bicyclic monoterpene alcohol 22323477 cyclophosphamide 22323477 mitomycin C 22323477 mitomycin-C 22323477 sabinene hydrate 22324400 Chlorogenic acid 22324400 chlorogenic acid 22324400 hyperoside 22324400 rutin 22324431 Bromotheoynic acid 22324431 brominated C(17) acetylenic acid 22324431 brominated acetylenic acid 22324431 bromotheoynic acid 22335791 Cyclo-(His,Leu) 22335791 cis-cyclo-(His,Leu) 22335791 cis-cyclo-(Leu,Tyr) 22335791 cis-cyclo-(Phe,Phe) 22335791 cis-cyclo-(Trp,Tyr) 22335791 cyclo-(His,Leu) 22335791 diketopiperazine 22335791 ethyl acetate 22335791 macrolactin A 22335791 tryptophane 22340730 leucine 22340730 phosphoinositide 22348279 4-terpineol 22348279 borneol 22348279 camphene 22348279 germacrene D 22348279 monoterpenoids 22348279 sesquiterpenoids 22348279 α-Thujone 22348279 β-caryophyllene 22348279 β-thujone 22349823 ATP 22349823 Met 22349823 Phe 22349823 erlotinib 22349823 gefitinib 22349823 tyrosine 22369145 5-FU 22369145 5-Fluorouracil 22369145 5-fluorouracil 22369145 Eudragit FS30D 22369145 Eudragit NE30D 22370636 GDC-0941 22370636 Trp 22370636 phosphoinositide 22370641 5-fluorouracil 22370641 Dox 22370641 Epi 22370641 anthracycline 22370641 cisplatin 22370641 doxorubicin 22370641 epirubicin 22376270 (+)-diayangambin 22376270 (+)-epi-magnolin 22376270 (E)-guggulsterone 22376270 (Z)-guggulsterone 22376270 (Z)-Δ(1,2) dehydroguggulsterone 22376270 acarbose 22376270 diasesartemin 22376270 epi-mukulin 22376270 gugglsterol I 22376270 methanol 22376270 n-hexane 22376270 Δ(6,7)dehydro-20-hydroxygugglsterone 22379948 6-desacetylnimbin 22379948 myricitrin 22379948 quercitrin 22400809 5-O-caffeoylshikimic acid 22400809 astilbin 22400809 chlorogenic acid 22400809 engeletin 22400809 isoengeletin 22400809 shikimic acid 22400809 syringic acid 22400809 taxifolin 22400809 trans-resveratrol 22401743 Progesterone 22401743 estradiol 22401743 estrogen 22401743 steroid 22401743 testosterone 22406206 2R,4R- isomer of 2-hydroxy-2-(indol-3-ylmethyl)-4-aminoglutaric acid 22406206 R, R-monatin 22406206 R,R-Monatin 22406206 R,R-monatin 22406206 arruva 22417089 2S*-(3-hydroxy-4-methoxyphenyl)-3R*-methyl-2H-[1,4]-dioxin [2,3]-chromen-7(3H)-one 22417089 3-hydroxy-1-(3-hydroxy-4-methoxyphenyl) propan-1-one 22417089 Grewialin 22417089 coumarinolignan 22417089 grewialin 22417089 lupeol 22417089 optivanin 22417089 stigmasterol 22417089 β-sitosterol 22422627 Berberine 22422627 SB203580 22422627 berberine 22430919 NO 22430919 nitric oxide 22439883 2-Hydroxy-4-methoxybenzaldehyde 22439883 docosane 22439883 heneicosane 22439883 tricosane 22450748 phospho 22473703 Hexane 22473703 Panaxynol 22473703 ginsenosides 22473703 methanol 22473703 panaxynol 22473703 polyacetylene 22473703 polyacetylenes 22473703 trypanothione 22473789 N-alkylamides 22473789 alkylamide 22473789 androgens 22473789 ethanol 22473789 fructose 22473789 testosterone 22484424 rapamycin 22491023 3-hydroxykynurenine 22491023 Glutamate 22491023 Xanthurenic acid 22491023 glutamate 22491023 kynurenine 22491023 tryptophan 22494023 metal oxide 22511564 arachidonic acid 22511564 histamine 22511564 p-cymene 22511564 phenol 22511564 thymol 22512576 C 22512576 N 22512576 N- t-Boc 22512576 N-formyl-L-methionyl-L-leucyl-Lphenylalanine 22512576 N-ureido 22512576 amino acid 22512576 fMLF 22512576 methyl-ester 22512576 superoxide 22512587 Thiazolidinedione 22512587 thiazolidinedione 22512587 thiazolidinediones 22512662 2α,24-diacetoxy-3β-hydroxyolean-12-en-28-oic acid 22512662 2α,3β,24-trihydroxyolean-12-en-28-oic acid 22512662 2α,3β-dihydroxyoleane-12-ene-28-oic acid 22512662 betulin 22512662 hyptatic acid-A 22512662 lupeol 22512662 maslinic acid 22512662 triterpenoid 22517576 1 H-[1,2,4]-oxadiazolole-[4,3-a] quinoxalin-10-one 22517576 Ca(2+) 22517576 Cinnamic acid 22517576 K(+) 22517576 KT5823 22517576 N(G) -nitro-l-arginine methyl ester 22517576 cGMP 22517576 cinnamic acid 22517576 cyclic guanosine monophosphate 22517576 methylene blue 22517576 nitric oxide 22517576 nitrite 22517576 phenylephrine 22517576 tetraethylammonium 22521336 prostaglandins 22521499 ACEA 22521499 AM281 22521499 CHPG 22521499 Glutamate 22521499 MTEP 22521499 VU0360172 22521499 glutamate 22532505 5' AMP 22532505 alanine 22532505 triglyceride 22533633 3',5-dihydroxy-3,4',5',7-tetramethoxy-flavone 22533633 8-oxo-pinoresinol 22533633 catechin 22533633 lignan 22533633 methanol 22533633 quercetin 22533633 quercetin-3-O-β-D-glucuronide 22533633 rutin 22538087 GABA 22546614 AMN082 22546614 GABA 22546614 Glutamate 22546614 cocaine 22546614 dopamine 22546614 ethanol 22546614 glutamate 22546614 heroin 22546614 pallidum 22546614 γ-aminobutyric acid 22566066 EGCG 22566066 Epigallocatechin gallate 22566066 Panaxadiol 22566066 catechin 22566066 epigallocatechin gallate 22566066 panaxadiol 22566066 sapogenin 22566066 saponins 22566106 cepharanthine 22566106 tetrahydropalmatine 22566106 xylopinine 22566158 streptozotocin 22566187 carbohydrate 22566187 ellagic acid 22566187 midazolam 22566187 polyphenol 22566187 polyphenols 22566187 quercetin 22566187 sugar 22566187 warfarin 22574728 cerebrosides 22574728 phenylethanoid glucoside 22574728 α-L-rhamnosyl (1 → 2)-β-D-glucose 22574752 drimenol 22574752 ethyl homovanillate 22574752 hydrocarbons 22574752 ketones 22574752 phenolic 22574752 terpenoids 22575576 17-α-ethynylestradiol 22575576 EE2 22575576 Oxygen 22575576 estrogen 22575576 oxygen 22575576 polyethylene glycol-4000 22578007 1α-acetoxy-5α, 7β-dihydroxycassa-11,13(15)-diene-16,12-lactone 22578007 cassane 22578007 diterpene 22580612 tyrosine 22585533 N 22585533 poly (ADP-ribose) 22585533 sesquiterpenol 22585533 β-Eudesmol 22585533 β-eudesmol 22594571 16-O-(β-D-glucopyranosyl)-3β,12β,16β,21α,22-pentahydroxy hopane 22594571 3-O-(β-D-xylopyranosyl)-spergulagenin A 22594571 glinoside C 22594571 saponin 22594571 spergulacin 22594571 spergulacin A 22594571 spergulin A 22594571 spergulin B 22594571 triterpene saponins 22594571 triterpenoid saponin 22607101 L-DOPA 22607101 PLGA 22607101 PVA 22607101 poly(D,L-lactide-co-glycolide) 22607101 polyvinyl alcohol 22609536 Fluoxetine 22609536 Glutamate 22609536 Ketamine 22609536 NMDA 22609536 fluoxetine 22609536 glutamate 22609536 ketamine 22609536 monoamine 22609536 serotonin 22610968 DADS 22610968 DPDS 22610968 allyl 22610968 diallyl disulfide 22610968 diallyl monosulfide 22610968 diallyl sulfides 22610968 diallyl tetrasulfide 22610968 diallyl trisulfide 22610968 dipropyl disulfide 22610968 dipropyl sulfides 22610968 dipropyl tetrasulfide 22610968 dipropyl trisulfide 22610968 sulfide 22624955 Flavonoids 22624955 bayarin 22624955 flavonoids 22624955 flavonol triglycoside 22624955 myricetin-3-O-[β-xylopyranosyl-(1-2)-α-rhamnopyranoside]-4'-O-α -rhamnopyranoside 22624955 saponins 22625220 H 22625220 flavonoid 22625220 flavonoids 22625220 phenolic 22634112 cAMP 22634112 corticosteroids 22634112 prostaglandin E(2) 22634361 5-HT 22634361 Glutamate 22634361 LSP1-2111 22634361 Lu AF21934 22634361 WAY100635 22634361 benzodiazepine 22634361 flumazenil 22634361 ritanserin 22634361 serotonin 22646908 menthone 22646908 piperitenone oxide 22646908 piperitone 22646908 piperitone oxide 22646908 pulegone 22648665 sulphorhodamine B 22659088 C 22659088 Ca 22659088 Glutamate 22659088 calcium 22659088 glutamate 22659090 (2R,4R)-APDC 22659090 Ca(2+) 22659090 DCG-IV 22659090 Glutamate 22659090 LY379268 22659090 LY541850 22659090 calcium 22659090 glutamate 22659408 Glutamate 22659408 Glycine 22659408 K(+) 22659408 KCl 22659408 LY341495 22659408 LY379268 22659408 N-acetylaspartyl-β-linked glutamate 22659408 N-acetylaspartylglutamate 22659408 NAAG 22659408 [(3)H]glycine 22659408 glutamate 22659408 glycine 22659408 β-NAAG 22659409 Glutamate 22659409 LY379268 22659409 METH 22659409 glutamate 22659409 methamphetamine 22676342 3-O-[β-D-apiofurarnosyl-(1-6)-β-D-glucopyranoxy]-6-hydroxy-p-cymene 22676342 4-[(6-O-(E)-caffeoyl)-β-D-glucopyranosyl]vanillic acid 22676342 ethanol 22676342 phenolic glycosides 22677456 cyclosarin 22677456 diisopropylfluorophosphate 22677456 methyl paraoxon 22677456 organophosphorus 22677456 paraoxon 22677456 sarin 22677456 soman 22677456 tabun 22678081 Vitamin C 22678081 hydrogen 22678081 hydroxyl 22678081 oxygen 22678081 vitamin C 22690946 Hyperinakin 22690946 phloroglucinol 22694056 cyanogenic glucosides 22694056 hydrogen cyanide 22695309 5-fluorocytosine 22695677 nucleotide 22705396 acetylcholine 22709946 (3)H-inositolmonophosphate 22709946 DHPG 22709946 Glutamate 22709946 MPEP 22709946 polyphosphoinositides 22713807 carboxyl 22713807 nucleotide 22717325 1-ethyl-3-methylimidazolium ethylsulfate 22717325 [EMIM][EtSO(4)] 22717325 alcohol 22717325 alcohols 22717325 aliphatic alcohols 22717325 imidazolium 22727823 GABA 22727823 γ-aminobutyric acid 22728760 Aripiprazole 22728760 atomoxetine 22728760 clonidine 22728760 pimozide 22728760 risperidone 22728760 serotonin 22728760 sulpiride 22728760 tiapride 22735770 atomoxetine 22735770 cocaine 22735770 galantamine 22735770 guanfacine 22735770 methamphetamine 22735770 methylphenidate 22735770 modafinil 22736379 L-NAME 22736379 Nitric Oxide 22736379 Pinosylvin 22736379 etoposide 22736379 nitric oxide 22736379 phenolic 22736379 pinosylvin 22744955 C21 H34 O3 22744955 DIME 22744955 Dihydroxy-Isosteviol Methyl Ester 22744955 Dihydroxy-isosteviol methyl ester 22749643 ATP 22749643 acetamide 22749643 benzodioxane 22749643 oxadiazole 22749842 MK-801 22749842 amphetamine 22750078 2-(6-chloropyridin-3-yl)-4-(2-methoxyethoxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl](imidazo[1,5-a]pyridin-1-yl)methanone 22750078 AMPA 22750078 MK-801 22750078 THPP-1 22750078 a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid 22750078 cAMP 22750078 cGMP 22750078 ketamine 22750412 Quetiapine 22750412 escitalopram 22750412 prazosin 22750412 quetiapine 22750412 serotonin 22752958 prednisolone 22752958 prednisone 22761049 Alloxan 22761049 Diosmetin Glycosides 22761049 acetone 22761049 alloxan 22761049 cholesterol 22761049 diosmetin 7-O-β-D-apiofuranoside 22761049 diosmetin 7-O-β-L-arabinofuranosyl (1 → 2) β-D-apiofuranoside 22761049 flavonoid 22761049 glucose 22761049 glutathione 22761049 superoxide 22761049 testosterone 22761049 triglycerides 22766107 glucose 22766107 metformin 22767283 ATP 22767283 CoQ(10) 22767283 PABA 22767283 coenzyme Q(10) 22767283 coenzyme Q10 22767283 para-aminobenzoic acid 22770610 Dasatinib 22770610 staurosporine 22770610 sunitinib 22776507 Nicotine 22776507 acetylcholine 22776507 nicotine 22776694 calcium 22788665 Anthocyanins 22788665 anthocyanin 22788665 anthocyanins 22788665 polyphenols 22796105 CPCCOEt 22796105 CPCOOEt 22796105 DHPG 22796105 GABA 22796105 Glutamate 22796105 MPEP 22796105 bicuculline 22796105 glutamate 22796337 AMP 22797669 2,7-dimethyl nitropyrene-4,5,9,10-tetraone 22797669 2-nitropyrene-4,5,9,10-tetraone 22797669 TDAE 22797669 tetrakis(dimethylamino)ethane 22797669 tetrakis(dimethylamino)ethene 22798247 androgen 22799538 3'-methylevenic acid 22799538 atranorin 22799538 baeomycesic acid 22799538 barbatinic acid 22799538 depsides 22799538 hypothamnolic acid 22799538 methyl 3'-methyllecanorate 22799538 squamatic acid 22799538 β-Orcinol 22799538 β-orcinol 22801296 AMPA 22801296 AMPAKINE 22801296 CX1739 22801296 CX1837 22801296 CX546 22801296 β-cyclodextrin 22812659 Androgen 22812659 androgen 22813462 Thienorphine 22813462 UDP 22813462 thienorphine 22818713 H2O2 22818713 Silibinin 22818713 flavonolignan 22818713 hydrogen peroxide 22818713 oxygen 22818713 phenylephrine 22818713 silibinin 22820555 Modafinil 22820555 modafinil 22820907 glutamate 22820932 estrogen 22820932 streptozotocin 22820932 sugar 22824189 5-HT 22824189 Egis-11150 22824189 Phencyclidine 22824189 chlorpromazine 22824189 clozapine 22824189 haloperidol 22824189 olanzapine 22824189 phencyclidine 22824189 risperidone 22824191 Propranolol 22824191 propranolol 22830980 BPB 22830980 BPB-glucuronide 22830980 BPB-sulfate 22830980 [(14)C]BPB 22830980 [14C]n-butyl-p-hydroxybenzoate 22830980 hydroxybenzoic acid 22830980 hydroxyhippuric acid 22830980 n-Butyl-p-hydroxybenzoate 22830980 n-butylparaben 22848037 Heme 22848037 heme 22859661 Se 22859661 Vitamin C 22859661 creatinine 22859661 glutathione 22859661 selenium 22859661 streptozotocin 22859661 urea 22859661 vitamin C 22859661 vitamin E 22863599 Dopamine 22863599 Rotigotine 22863599 dopamine 22863599 rotigotine 22867273 TAK-491 22867273 TAK-536 22867273 angiotensin II 22867273 ester 22867273 medoxomil 22867273 medoxomil alcohol 22867273 olmesartan medoxomil 22867529 4-anilinoquinazoline 22867529 6,7-dimethoxy-4-anilinoquinazoline 22867529 6-alkoxy 22867529 ATP 22867529 Asp 22867529 Cys 22867529 H 22867529 Met 22867529 N-H 22867529 Thr 22867529 aniline 22867529 anilino 22867529 ethylenediamine 22867529 phenyl 22867529 pyridinyl 22867529 quinazoline 22867529 tyrosine 22869589 deuterium 22869589 hydrogen 22871141 PEG 22871141 mono-, di- and triglycerides 22871141 polyethylene glycol 22878862 His 22878862 Tyr 22878862 zinc 22884520 Oxysterol 22884520 cholesterol 22884520 oxysterol 22884520 oxysterols 22884520 sterol 22884612 LSN2463359 22884612 MK-801 22884612 N-methyl-d-aspartate 22884612 NMDA 22884612 PCP 22884612 Ro 63-1908 22884612 SDZ 220,581 22884612 glutamate 22884612 phencyclidine 22884720 (7S)-3-tert-butyl-7-[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-A]pyridine 22884720 ADX47273 22884720 CDPPB 22884720 DHPG 22884720 LSN2463359 22884720 LSN2814617 22884720 MPEPy 22884720 N-(1-methylethyl)-5-(pyridin-4-ylethynyl)pyridine-2-carboxamide 22884720 N-methyl-d-aspartate 22884720 NMDA 22884720 SDZ 220,581 22884720 [³H]MPEP 22884720 glutamate 22885792 PEMA 22885792 TiO(2) 22885792 hydroxyl 22885792 oxygen 22885792 poly (ethylene-alt-maleic anhydride) 22885792 ·OH 22886720 1,25(OH)(2) D 22886720 1,25-dihydroxyvitamin D 22886720 25-hydroxyvitamin D 22886720 25OHD 22886720 Vitamin D 22886720 vitamin D 22887463 GaIn 22887463 Pb(2+) 22887463 crown-ether 22887463 crown-ether dithiol quaterthiophene 22887463 dithioester 22887463 dithiol 22887463 oligothiophene 22887720 Bisphosphonate 22887720 bisphosphonate 22887720 bisphosphonates 22889206 N-feruloyl serotonin 22889206 N-feruloyl serotonin-4'-O-β-D-glucopyranoside 22889206 N-isoferuloyl serotonin 22889206 N-isoferuloyl serotonin-3'-O-β-D-glucopyranoside 22889206 N-p-coumaroyl serotonin 22889206 N-p-methoxy cinnamoyl serotonin 22889206 O 22889206 serotonin 22889207 Sarglaucol 22889207 tetraterpenoids 22890749 aldehyde 22890749 ethyl 22890749 ethyl and ethyl 3-phenyl glycidate 22890749 ethylene 22890749 glycidic acid 22891925 2-phpy 22891925 3- and 4-phpy 22891925 C-H 22891925 [Ni(phpy)(m)](2+) 22891925 [NiCl(phpy)(2)](+) 22891925 [NiCl(phpy)(n)](+) 22891925 nickel(II) chloride 22891925 phenylpyridines 22891925 phpy 22893351 Hg 22893351 S 22893351 glutathione 22893351 mercury 22893354 KMnO(4) 22893354 KMnO4 22893354 Manganese 22893354 Mn 22893354 Mn(+2) 22893354 MnO4 (-) 22893354 Potassium permanganate 22893354 manganous 22893354 permanganate 22893354 potassium permanganate 22898212 CBDP 22898212 Cresyl saligenin phosphate 22898212 Glu 22898212 His 22898212 Ser 22898212 TCP 22898212 histidine 22898212 imidazole 22898212 l-histidine 22898212 lysine 22898212 nitrogen 22898212 o-cresol 22898212 o-hydroxybenzyl 22898212 saligenin 22898212 serine 22898212 tricresyl phosphate 22899726 HCH 22899726 Organochlorine 22899726 aldrin 22899726 dieldrin 22899726 endosulfan 22899726 hexachlorocyclohexane 22899726 op'-DDD 22899726 op'-DDE 22899726 op'-DDT 22899726 organochlorine 22899726 pp'-DDD 22899726 pp'-DDE 22899726 pp'-DDT 22899726 pp'-dichlorodiphenyldichloroethane 22899726 pp'-dichlorodiphenyldichloroethylene 22899726 pp'-dichlorodiphenyltrichloroethane 22899726 β-HCH 22899727 Mn 22899727 bilirubin 22899727 flavonoid 22899727 glutathione 22899727 manganese 22899727 manganese chloride 22899727 oxygen 22899727 sulfhydryl 22899727 superoxide 22899727 vitamin C 22899728 Cu 22899728 Superoxide 22899728 carbonyls 22899728 copper 22899728 ferric 22899728 glutathione 22899728 nitrate 22899728 nitrite 22899728 oxygen 22899728 saturated fatty acids 22899728 thiobarbituric acid 22899728 α-tocopherol 22902307 MTT 22902323 Fatty acids 22902323 arachidonic acid 22902323 fatty acid 22902323 fatty acids 22902329 Vitamin E 22902329 adenylyl 22902329 cyclic adenosine monophosphate 22902329 phosphotyrosine 22902329 somatostatin 22902329 tocopherol 22902329 tocopherols 22902329 vitamin E 22902329 vitamin-E 22902329 α-tocopherol 22906567 4-methylbenzilidene camphor 22906567 AVB 22906567 Avobenzone 22906567 MBC 22906567 OMC 22906567 avobenzone 22906567 octyl methoxycinnamate 22906567 vitamin A 22906567 vitamin A palmitate 22906570 SDS 22914798 CBiPES 22914798 GABA 22914798 NMDA 22914798 NaLac 22914798 THIIC 22914798 alprazolam 22914798 benzodiazepine 22914798 glutamate 22914798 glutamic acid 22914798 l-allyglycine 22914798 sodium lactate 22917842 fatty acid 22917842 glucose 22918703 LY294002 22918703 Phospho 22918703 SU5416 22918703 phospho 22921426 Ca(2+) 22921426 Pb(2+) 22921426 calcium 22921426 inositol-1,4,5-triphosphate 22921426 methionine choline 22921426 ryanodine 22921427 bufadienolide 22921427 bufadienolides 22921427 verapamil 22922038 NaP zeolite 22922038 NaP zeolites 22922246 Octanol 22923492 2,3,7,8-tetrachlorodibenzo-p-dioxin 22923492 Amino acid 22923492 amino acid 22923492 amino acids 22923492 aryl hydrocarbon 22923492 dioxin 22925550 SH 22925550 glucono-δ-lactone 22926046 Cys 22926046 amino acid 22926046 amino acids 22926699 aryl hydrocarbon 22929928 oil-red-O 22930682 Pb 22930682 Pb acetate 22930682 amino acids 22930682 monoamines 22931530 Cysteine 22931530 Serine 22931530 carbons 22931530 cysteine 22931530 serine 22931530 α-Amino-α´-Halomethylketones 22931530 α-Amino-α´-halomethylketones 22931533 Galantamine 22931533 Morphinans 22931533 acetylcholine 22931533 codeine 22931533 eseroline 22931533 galantamine 22931533 morphinan 22931535 TiO2 22933107 Manganese 22933107 cyclophosphamide 22933107 glucose 22933107 manganese 22933114 ATP 22933114 Ca(2+) 22933114 NAD(P)H 22933114 glucose 22935067 GCV 22935067 V-GCV 22935067 ganciclovir 22935067 mono-valyl ester 22935067 valganciclovir 22935616 Ser 22935616 phospho 22935616 phosphoinositide 22936354 calcium 22936354 chloride 22936354 hydroxyapatite 22936354 phosphatidylserine 22940465 ATP 22940465 Lipoic acid 22940465 Lyral 22940465 N-acetyl cysteine 22940465 glutathione 22940465 lilial 22940465 lipoic acid 22940465 lyral 22940465 oxygen 22940465 trolox 22940465 α,β-unsaturated aldehydes 22940466 N-acetyl-cysteine 22940466 NAC 22940466 Silver 22940466 oxygen 22941424 Glucose 22941424 carbohydrate 22941424 carbohydrates 22941424 cholesterol 22941424 glucose 22941424 triglycerides 22943130 (13)C6(15)N4 22943130 UDP 22943130 amino acid 22943130 arginine 22944045 DBP 22944045 DINP 22944045 DiNP 22944045 dibutyl phthalate 22944045 diisononyl phthalate 22944045 phthalate 22944069 Lithium 22944069 MG132 22944069 lithium 22944593 1,8-cineole 22944593 5-DSA 22944593 5-doxyl stearic acid 22944593 Terpenes 22944593 monoterpenes 22944593 nerolidol 22944593 sesquiterpene 22944593 terpenes 22944593 α-terpineol 22945792 cloxacillin 22945792 penicillins 22945792 warfarin 22946701 Danazol 22946701 GnRH 22946701 Levonorgestrel 22946701 progestogens 22946701 tranexamic acid 22949391 iron 22956307 cholesterol 22956307 creatinine 22956307 nitrogen 22956307 triglyceride 22956307 urea 22956627 ANIT 22956627 Bile acid 22956627 DPCPX 22956627 adenosine 22956627 alpha-naphthyl isothiocyanate 22956627 alpha-naphthylisothiocyanate 22956627 bile acid 22956627 bile acids 22960442 METH 22960442 Methamphetamine 22960442 nitric oxide 22960624 2-(hydroxyimino)-N-(2-(pyrrolidin-1-yl)ethyl)acetamide 22960624 2-PAM 22960624 2PAM 22960624 ACh 22960624 DAM 22960624 MINA 22960624 N-((1-(3-(2-((hydroxyimino)methyl)-1H-imidazol-1-yl)propyl)-1H-1,2,3-triazol-4-yl)methyl)benzamide 22960624 N-(2-(azepan-1-yl)ethyl)-2-(hydroxyimino)acetamide 22960624 Organophosphates 22960624 RS113A 22960624 RS113B 22960624 RS115A 22960624 RS150D 22960624 RS194B 22960624 RS41A 22960624 acetamide 22960624 acetylcholine 22960624 aldoximes 22960624 choline 22960624 cyclosarin 22960624 diacetylmonoxime 22960624 imidazole 22960624 monoisonitrosoacetone 22960624 oxime 22960624 oximes 22960624 phosphonate 22960624 phosphoramidate 22960624 phosphorate 22960624 phosphorus 22960624 quaternary pyridinium oxime 22960624 sarin 22960624 serine 22960624 tabun 22960624 tertiary amine 22960624 triazole 22961094 Cadmium 22961094 Cd 22961094 cadmium 22961094 cytochalasin D 22961094 zinc 22961427 PEH(+) 22961427 PEOH(-) 22961427 phosphatidylethanolamine 22963374 3'-hydroxy-4'-O-methylisoscutellarein 7-O-[6'″acetyl-β-D-allopyranosyl-(1 → 2)-6″-acetyl-β-D-glucopyranoside] 22963374 3'-hydroxy-4'-O-methylisoscutellarein 7-O-[6'″acetyl-β-D-allopyranosyl-(1 → 2)-β-D-glucopyranoside] 22963374 3'-hydroxy-isoscutellarein 7-O-[6'″acetyl-β-D-glucopyranosyl-(1 → 2)-β-D-glucopyranoside] 22963374 8-epi-loganin 22963374 acetyl harpagide 22963374 acetylated flavonoid glycosides 22963374 flavonoid 22963374 flavonoids 22963374 harpagide 22963374 iridoid glucosides 22963374 iridoids 22963552 AEOL 10113 22963552 AEOL 10150 22963552 M40419 22963552 N-acetyl-Lcysteine 22963552 N-acystelyn 22963552 aldehyde 22963552 alpha-lipoic acid 22963552 apocynin 22963552 carbocysteine lysine 22963552 carbonyl 22963552 catechins 22963552 curcumin 22963552 edaravone 22963552 erdosteine 22963552 ergothioneine 22963552 fudosteine 22963552 glutathione 22963552 hydrogen sulfide 22963552 lazaroids 22963552 lycopene 22963552 omega-3 fatty acids 22963552 polyphenols 22963552 porphyrins 22963552 quercetin sulforaphane 22963552 resveratrol 22963552 steroid 22963552 superoxide 22963552 thiol 22963552 tirilazad 22963552 tocotrienols 22963552 vitamin D 22963552 α-phenyl-N-tert-butyl nitrone 22969061 carbon 22974400 phenolics 22974400 terpenoids 22975162 coumarinolignoid alkaloids 22975162 coumarinolignoids 22975162 coumarins 22975162 indicumines A-B 22975162 indicumines C-D 22976785 phospho 22976785 pregnane 22976914 cortisol 22976914 glucose 22981993 5,5'-dithiobis-2-nitrobenzoic acid 22981993 cysteine 22981993 fluorescamine 22981993 lysine 22981993 thiol 22982445 LTD4 22982445 Leukotriene D4 22982445 Pranlukast 22982445 cysteinyl leukotriene 22982445 leukotriene D4 22982445 pranlukast 22983144 2-methyl-6-(phenylethynyl)-pyridine 22983144 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide 22983144 ADX47273 22983144 CDPPB 22983144 N-methyl-D-Aspartate 22983144 NMDA 22983144 dizocilpine 22983144 glutamate 22983144 phencyclidine 22983867 MSG 22983867 glucose 22983867 monosodium L-glutamate 22983867 tyrosine 22986338 Juvenile hormone 22986338 juvenile hormone 22988818 Deoxyglucose 22988818 Friedelin 22988818 MTT 22988818 Oil Red O 22988818 friedelin 22988818 glucose 22988818 lanosterol 22991163 alcohol 22991163 alendronate 22991447 S 22991447 nitric oxide 22996137 glucose 22996137 tyrosine 22996307 D-Orn 22996307 D-ornithine 22996307 L- and D-Orn 22996307 L- and D-amino acids 22996307 L-Orn 22996307 L-ornithine 22996307 Orn 22996307 Ornithine 22996307 Putrescine 22996307 S-adenosylmethionine 22996307 amino acids 22996307 nicotine 22996307 nicotinic alkaloids 22996307 ornithine 22996307 polyamines 22996307 spermidine 22996307 spermine 22997242 Fuc3Hex3HexNAc6 22997242 GalNAcβ1 → 4GlcNAc 22997242 LacdiNAc 22997242 N 22997242 N-linked fucosylated N,N'-diacetyllactosediamine 22997242 monofucosylated N,N'-diacetylhexosediamine 23000076 5-HT 23000076 AMPT 23000076 THC 23000076 WAY100635 23000076 catecholamine 23000076 catecholamines 23000076 pCPA 23000076 rimonabant 23000076 serotonin 23000076 Δ(9)-tetrahydrocannabinol 23001138 3,4-methylenedioxymethamphetamine 23001138 4-methylthioamphetamine 23001138 Ecstasy 23001138 MDMA 23001138 MTT 23001138 amphetamines 23001138 d-amphetamine 23001138 ecstasy 23001138 methamphetamine 23002036 12-O-tetradecanoylphorbol-13-acetate 23002036 AMP 23002036 Glucose 23002036 NH(2) 23002036 TPA 23002036 fatty acid 23002036 glucose 23007560 NaF 23007560 fluoride 23008503 PGE(2) 23008503 SC-560 23008503 celecoxib 23008503 cimetidine 23008503 ketorolac 23008503 meloxicam 23008503 prostaglandin E(2) 23009351 Epi 23009351 PAA 23009351 Plu 23009351 epirubicin 23009351 pluronic 23009351 poly(acrylic acid) 23009351 polyacrylic acid 23010104 steroid 23010392 Ca 23010392 Cd 23010392 Cr 23010392 Cu 23010392 Fe 23010392 Hg 23010392 Ni 23010392 Pb 23010392 Se 23010392 V 23010392 Zn 23010566 iodine 23014811 Lewis acids 23014811 N-heterocyclic carbenes 23014811 fluoride 23014811 fluorides 23014811 halides 23014811 metal and non-metal fluorides 23014811 metal/non-metal fluoride 23014811 oxide 23015541 Caffeine 23015541 caffeine 23015691 17β-estradiol 23015691 Androstanol 23015691 CITCO 23015691 TCPOBOP 23015691 androstane 23015691 androstenol 23015691 estrone 23015691 steroid 23016694 dopamine 23017387 Quercetin 23017387 glutathione 23017387 methionine sulfoxide 23017387 quercetin 23017387 quinone 23017387 tert-butyl hydroperoxide 23017391 Phenolic 23017391 Phenolic acids 23017391 benzoic acid 23017391 flavonoids 23017391 flavonols 23017391 hesperidin 23017391 phenolic acids 23017391 polyphenols 23017391 quercetrin 23017391 rutin 23017391 sugar 23017394 Betulinic acid 23017394 betulin 23017394 betulinic acid 23017395 DHA 23017395 EPA 23017395 HMG-CoA 23017395 cholesterol 23017395 triacylglycerols 23017397 2,6-dideoxyhexose-C-glycosyl flavones 23017397 C-dideoxyhexosyl flavones 23017397 apigenin-8-C-β-boivinopyranoside 23017397 apigenin-8-C-β-digitoxopyranoside 23017397 luteolin 23017397 luteolin-8-C-β-boivinopyranoside 23017397 luteolin-8-C-β-digitoxopyranosyl-4'-O-β-d-glucopyranoside 23017397 n-BuOH 23017397 n-butanol 23017402 NO 23017402 betulinic acid 23017402 carnosic acid 23017402 nitric oxide 23017402 triterpenic acids 23017408 Phenylalanine ammonia 23017408 ferulic acid 23017408 gallic acid 23017408 l-phe 23017408 l-phenylalanine 23017408 methanol 23017408 p-coumaric acid 23017408 phenolic 23017408 phenols 23017408 trans-cinnamic acid 23017409 2,4,6-trinitrobenzene sulphonic acid 23017409 TNBS 23017409 trinitrobenzene sulphonic acid 23017409 zingerone 23017413 5-cis-lycopene 23017413 9- and 13-cis-lycopene 23017413 caffeic 23017413 caffeic acid-O-glucoside 23017413 coumaric and ferulic acid-O-glucoside 23017413 flavanones 23017413 flavonols 23017413 hydroxycinnamic acids 23017413 polyphenol 23017413 α-carotene 23017415 Amino acid 23017415 amino acid 23017415 phytate 23017416 1-hexen-3-ol 23017416 1-octen-3-ol 23017416 1-penten-3-ol 23017416 3-undecen-2-one 23017416 Dimethyl sulphide 23017416 dimethyl sulphide 23017416 heptanal 23017416 hexanal 23017416 octanal 23017416 pentanal 23017418 DPPH 23017418 carvacrol 23017418 fumaric acid 23017421 cholesterol 23017421 ethyl behenate 23017421 fatty acid 23017421 fatty acids 23017421 triglycerides 23017422 Ba(2+) 23017422 Ca(2+) 23017422 D(2)O 23017422 H(2)O 23017422 Mg(2+) 23017422 Sr(2+) 23017422 alkaline earth metals 23017422 barium 23017422 calcium 23017422 sodium 23017422 strontium 23017424 lauric acid 23017424 lysine 23020803 1,25(OH)₂D₃ 23020803 1,25-dihydroxyvitamin D₃ 23020803 25(OH)D₃ 23020803 25-hydroxyvitamin D₃ 23020803 Vitamin D 23020803 calcium 23020803 vitamin D 23020803 vitamin D₃ 23022015 DCHP 23022015 DHP 23022015 Testosterone 23022015 di-n-hexyl phthalate 23022015 dicyclohexyl phthalate 23022323 acetylcholine 23023768 acetone 23023768 cobalt 23023768 graphene 23023768 isopropanol 23023768 poly(methyl methacrylate) 23027385 (η(7)-C(7)H(7))Zr(Y) 23027385 (η(7)-C(7)H(7))ZrCl(tmeda) 23027385 Zr(+iv) 23027385 allyl 23027385 amido 23027385 boratabenzene 23027385 cycloheptatrienyl 23027385 cycloheptatrienyl transition metal complexes 23027385 cycloheptatrienyl zirconium 23027385 cyclopentadienyl 23027385 imidazolin-2-iminato 23027385 pentadienyl 23027385 phospholyl 23028137 fructose 23028137 glucose 23030741 (14)C-labelled lesogaberan 23030741 (2R)-2-fluoro-3-hydroxyphosphonoyl-propanoic acid 23030741 3-hydroxyphosphonoyl-propanoic acid 23030741 3-hydroxypropyl-phosphinic acid 23030741 N 23030741 [(2R)-2-fluoro-3-guanidino-propyl]-phosphinic acid 23030741 [(2R)-3-acetamido-2-fluoropropyl]-phosphinic acid 23030741 [(2R)-3-amino-2-fluoropropyl]-phosphonic acid 23030741 alcohol 23030741 carboxylic acid 23030741 fluorine 23030741 lesogaberan 23030741 γ-aminobutyric acid 23030812 oxygen 23036451 PCBs 23036451 dioxins 23036451 polychlorinated biphenyls 23036454 cholesterol 23036454 glucose 23038767 biotin 23041113 Phlorotannin 23041113 butanol 23041257 DBDCT 23041257 Di-n-butyl-di-(4-chlorobenzohydroxamato) Tin (IV) 23041257 diorganotin (IV) 23041257 organotin (IV) 23041257 oxygen 23041257 propidium iodide 23042693 TPP 23042693 tris(o-phenylenedioxy)cyclotriphosphazene 23042762 carbohydrate 23042762 carbohydrates 23043184 BNZ 23043184 NADPH 23043184 benzphetamine 23043184 p-nitrophenol 23043184 tert-butyl hydroperoxide 23043462 Songaricalarins A-E 23043462 oplopane sesquiterpenes 23043462 oxygenated oplopane sesquiterpenes 23043462 songaricalarins A-E 23044046 Fumagillin 23044046 TNP-470 23044046 fumagillin 23044488 Amino acid 23044488 acyl 23044488 organophosphate 23044709 Tartrate 23047022 EDTA 23047022 GM6001 23047022 Proline 23047022 acetylcholine 23047022 atropine 23047022 batimastat 23047022 carbachol 23047022 muscarine 23047022 thiol 23047026 ACh 23047321 carbon 23051835 BPA 23051835 Bisphenol A 23051835 bisphenol A 23051835 ethinyl estradiol 23051835 steroid 23051890 alumina 23051890 hydrogen peroxide 23052036 Fenhexamid 23052036 Fludioxonil 23052036 actinomycin D 23052036 androgen 23052036 arylhydrocarbon 23052036 bicalutamide 23052036 cycloheximide 23052036 dihydrotestosterone 23052036 estradiol 23052036 estrogen 23052036 fenhexamid 23052036 fludioxonil 23052036 fulvestrant 23052036 phosphoinositide 23052036 α-napthoflavone 23052197 B[a]P 23052197 Benzo[a]pyrene 23052197 benzo[a]pyrene 23053786 malathion 23053787 O 23053787 S 23053787 caffeine 23053787 copper 23053787 ethoxyresorufin 23053787 glutathione 23053787 superoxide 23055538 acetaminophen 23055538 bisphenol A 23058474 estradiol 23061466 Acehytisine hydrochloride 23061466 Guangfu base A 23061466 K+ 23061466 Nef 23061466 O=C=N-C-C-C-N 23061466 ether 23061466 isoquinoline alkaloid 23061466 matrine 23061466 neferine 23061466 oxymatrine 23061466 quinolizidine alkaloids 23061466 sophocarpine 23061466 sophoridine 23061657 Piplartine 23061657 amide 23061657 piplartine 23061657 praziquantel 23063001 CO(2) 23063001 Cl 23063001 K(+) 23063001 Na 23063001 Na(+) 23063001 Pb 23063001 TMAO 23063001 ammonia 23063001 lactate 23063001 silver 23063001 urea 23063003 Cd 23063003 cadmium 23063003 glutathione 23063413 Vin 23063413 Vinblastine 23063413 tariquidar 23063595 AMP 23063595 polyphenols 23063671 BEA 23063671 FUS 23063671 beauvericin 23063671 enniatins A, A1, B and B1 23063671 fusaproliferin 23063746 pseudosaccharine 23063746 quinazoline 23063874 2-bromo-2-bromomethyl glutaronitrile 23063874 2-mercaptobenzothiazole 23063874 4-nitrobenzylbromide 23063874 MTT 23063874 ammonium hexachloroplatinate 23063874 benzaldehyde 23063874 cholorobenzene 23063874 cinnamaldehyde 23063874 cinnamyl alcohol 23063874 citral 23063874 diethylmaleate 23063874 diethylphtalate 23063874 dinitrochlorobenzene 23063874 diphenylmethane diisocyanate 23063874 eugenol 23063874 glutaraldehyde 23063874 glyoxal 23063874 hexamethylenediisocyanate 23063874 hydrobenzoic acid 23063874 isoeugenol 23063874 lactic acid 23063874 maleic anhydride 23063874 nickel sulfate 23063874 octanoic acid 23063874 oxazolone 23063874 p-phenylediamine 23063874 penicillin G 23063874 phenol 23063874 resorcinol 23063874 salicylic acid 23063874 sodium lauryl sulphate 23063874 sulfamic acid 23063874 tetramethylthiuram disulfide 23063874 trimellitic anhydride 23063876 DEHP 23063876 Di-(2-ethylhexyl)-phthalate 23063876 estrogen 23063876 phthalates 23063876 phthalic acid 23064031 AG1478 23064031 NFD 23064031 Naphtho[1,2-b]furan-4,5-dione 23064031 naphtho[1,2-b]furan-4,5-dione 23064031 phosphatidylinositol 23064031 wortmannin 23064475 25(OH)D 23064475 25-hydroxyvitamin D 23064475 Vitamin D 23064475 vitamin D 23065140 8-oxoguanine 23065140 Ca(2+) 23065140 Ketamine 23065140 L-Carnitine 23065140 L-carnitine 23065140 N-methyl-D-aspartate 23065140 NMDA 23065140 calcium 23065140 ketamine 23065140 oxygen 23065799 poly(D,L-lactide-co-glycolide) 23065799 β-Carotene 23065799 β-carotene 23066089 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid 23066089 BAPTA 23066089 C 23066089 Kainate 23066089 Ser 23066089 calcium 23066089 glutamate 23066089 kainate 23066089 lavendustin A 23066089 okadaic acid 23066089 phorbol 12-myristate,13-acetate 23066089 serines 23066089 tyrosine 23066091 1-[2-((3-carbamoyl-4-hydroxy)phenoxy)ethylamino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl)phenoxy]-2-propanol 23066091 4-[3-[(1,1-dimethylethyl)amino]2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one 23066091 CGP-12177 23066091 CGP-20712 23066091 N 23066091 S-propranolol 23066091 adenylyl 23066091 bisoprolol 23066091 isoproterenol 23066091 metoprolol 23066091 pindolol 23066091 timolol 23066093 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide 23066093 AM251 23066093 MG132 23066093 biarylpyrazole 23066093 estrogen 23066093 leptomycin B 23066093 phorbol ester 23066988 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide 23066988 AICAR 23066988 AMP 23066988 Metformin 23066988 adenosine monophosphate 23066988 compound C 23067059 TiO(2) 23067059 titanium 23068768 nandrolone decanoate 23068768 steroids 23069375 Rosi 23069375 Rosiglitazone 23069375 glucose 23069375 thiazolidinedione 23074026 PFOS 23074026 Perfluorooctane sulfonate 23074026 estradiol 23074026 estrogen 23074026 testosterone 23074026 thyroid hormone 23075005 Anagliptin 23075005 [(14)C]anagliptin 23075005 anagliptin 23075005 carboxylate 23075165 quartz 23075165 silver 23075165 thiophenol 23077183 Octreotide 23077183 octreotide 23077183 somatostatin 23079470 MLA 23079470 NS1738 23079470 PHA-543613 23079470 PNU-120596 23079470 acetylcholine 23079670 aza-dienes 23079670 nitrogen 23081760 acetone 23081760 dichloromethane 23081760 dichlorvos 23081760 diuron 23081760 endosulfan 23081760 glyphosate 23082005 aldosterone 23085120 B12H 23085120 Bis(12)-hupyridone 23085120 NMDA 23085120 acetylcholine 23085120 glutamate 23085120 huperzine A 23085120 pSer 23085120 phosphoinositide 23085190 MK-886 23085190 celecoxib 23085190 leukotriene (LT)B(4) 23085190 prostaglandin (PG)E(2) 23085367 Xanthohumol 23085367 xanthohumol 23085437 rapamycin 23085546 Soluplus 23085546 piroxicam 23085546 polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer 23086230 (+)- and (-)-coniine 23086230 (+)-coniine 23086230 (-)-Coniine 23086230 (-)-coniine 23086230 Coniine 23086230 acetylcholine 23086230 coniine 23086230 nicotine 23086230 piperidine alkaloid 23086230 pyridine alkaloid 23086461 2-O-sulfated 3,6 anhydro-α-D-galactose 23086461 2-O-sulfated-3,6-α-D-anhydrogalactose 23086461 disaccharide 23086461 disaccharides 23086461 neo-κ- and ι-carrabiose 23086748 Ag 23086748 Silver 23086748 lactate 23086748 silver 23086899 Ag(Cu) 23086899 Pt 23086899 ZrO(2) 23086899 oxide 23087260 E-prostanoid 23087260 GTP 23087260 GTPγS 23087260 PGE(2) 23087260 [(3)H]PGE(2) 23087260 guanosine 5[prime]-O-(3-thio)triphosphate 23087260 nucleotide 23087260 prostaglandin 23087260 prostaglandin E(2) 23087379 hydrogen 23089249 1-naphthyl methylcarbamate 23089249 Ca 23089249 Carbaryl 23089249 K 23089249 K(+) 23089249 Na 23089249 Na(+) 23089249 carbamate 23089249 carbaryl 23089249 cortisol 23089249 glucose 23089249 ouabain 23089249 phosphate 23089249 sevin 23090483 Cd 23090483 Zn 23090483 oxygen 23090483 zinc 23090647 Linaclotide 23090647 MM-419447 23090647 cGMP 23090647 cyclic guanosine-3',5'-monophosphate 23090647 disulfide 23090647 guanylate 23090647 linaclotide 23090712 La(III) 23090712 Lanthanum (III) 23090712 amino acid 23090712 glutamate 23090712 glutamine 23090712 lanthanum 23090712 nitrate 23090712 nitrogen 23091170 Diisocyanates 23091170 TDI 23091170 acetone 23091170 cyclophosphamide 23091170 isocyanate 23091170 methacholine 23091170 toluene-2,4-diisocyanate 23092130 PEO 23092130 PNIPAAM 23092130 PPO 23092130 poly(N-isopropylacrylamide) 23092130 poly(ethylene glycol) 23092130 poly(ethylene oxide) 23092130 poly(propylene oxide) 23092130 polyester 23092679 calcium 23092679 magnesium 23092759 2-BP 23092759 2-Bromopalmitate 23092759 2-bromopalmitate 23092759 NADPH 23092759 NO 23092759 nitric oxide 23092759 oxygen 23092918 rapamycin 23092918 serine 23092918 threonine 23092949 1,10-phenanthroline 23092949 2,2'-bipyridyl 23092949 Am(III) 23092949 Ca(II) 23092949 Cd(II) 23092949 Cu(II) 23092949 H 23092949 Hg(II) 23092949 Pb(II) 23092949 Phen 23092949 Zn(II) 23092949 alcohols 23092949 amides 23092949 anthracenyl 23092949 benzo 23092949 bpy 23092949 carboxylates 23092949 lanthanide(III) 23092949 oximes 23092949 phen 23092949 polypyridyl 23092949 pyridyl 23099431 (13)C(3)Ala-GHRP-6 23099431 GHRP-6 23099431 Growth Hormone-Releasing Peptide 6 23099431 His-(D-Trp)-Ala-Trp-(D-Phe)-Lys-NH(2,) 23100158 phosphatidylinositol 23100158 β-ionone 23100159 Iron 23100159 arsenic 23100159 hydrotalcite 23100159 iron 23101934 alkane 23101934 alkanedithiols 23101934 alkanes 23101934 alkoxydithiols 23101934 dithiolated oligoethers 23101934 oligoethers 23101934 oxygen 23102509 Asiatic acid 23102509 STZ 23102509 alanine 23102509 asiatic acid 23102509 aspartate 23102509 carbohydrate 23102509 fructose 23102509 glibenclamide 23102509 glucose 23102509 glucose-6-phosphate 23102509 pentacyclic triterpene 23102509 pyruvate 23102509 streptozotocin 23102509 triterpenoid 23103283 Mancozeb 23103283 Manganese 23103283 dopamine 23103283 manganese 23103283 serotonin 23103296 11-keto 23103296 11-keto-β-boswellic acid 23103296 3-acetyl-11-keto-β-boswellic acid 23103296 3-acetyl-α-boswellic acid 23103296 3-acetyl-β-boswellic acid 23103296 AKBA 23103296 Aα- and AβBA 23103296 AαBA 23103296 AβBA 23103296 KBA 23103296 boswellic acids 23103296 α-boswellic acid 23103296 αBA 23103296 β-boswellic acid 23103296 βBA 23103298 fagopyrin 23103298 naphthodianthrones 23103298 phenolic 23103347 Fenfluramine 23103347 Serotonin 23103347 fenfluramine 23103347 potassium chloride 23103347 serotonin 23103450 Arsenic trioxide 23103450 As(2)O(3) 23103450 K(+) 23103450 Matrine 23103450 ether 23103450 matrine 23103450 oxymatrine 23103450 potassium 23103562 Cisplatin 23103562 cisplatin 23103563 CpG 23103563 Ibandronate 23103563 aminobisphosphonates 23103563 bisphosphonates 23103563 farnesyl 23103563 farnesylpyrophosphate 23103563 geranylgeranyl-pyrophosphate 23103563 ibandronate 23103564 (15)N 23103564 (15)NH(4)(+) 23103564 Ornithine 23103564 PAGN 23103564 [2,5-(15)N]Ornithine 23103564 [2,5-(15)N]ornithine 23103564 amino acids 23103564 ammonia 23103564 glutamine 23103564 ornithine 23103564 ornithine phenylacetate 23103564 phenylacetate 23103564 phenylacetylglutamine 23103565 cAMP 23103565 hydrogen peroxide 23103565 oxygen 23103565 serine 23103613 Chloroacetic acid 23103613 N-acetylcysteine 23103613 NAC 23103613 SB203580 23103613 SP600125 23103613 acetic acid 23103613 glutathione 23103954 2-(β-d-glucopyranosyloxy)-1, 4-naphthoquinone 23103954 3-(4-hydroxy-3-methoxyphenyl)-triacontyl-(Z)-propenoate 23103954 3-(4-hyroxyphenyl)-triacontyl-(Z)-propenoate 23103954 4-hydroxy coumarine 23103954 7-hydroxy-4-methyl coumarin 23103954 lawsofructose 23103954 lawsorosemarinol 23103983 Al(OH)₃ 23103983 PLGA 23103983 aluminum hydroxide 23103983 calcium phosphate 23103983 poly(lactic-co-glycolic acid) 23103983 trehalose 23104136 Ca 23104136 N 23104136 N-Arachidonyl glycine 23104136 N-arachidonyl glycine 23104136 NAGly 23104136 adenylate 23104136 anandamide 23104136 calcium 23104136 cannabidiol 23104136 carboxylic 23104136 potassium 23104247 VPA 23104247 valproic acid 23104378 berberine 23104429 Arsenic 23104429 As(III) 23104429 As(V) 23104429 arsenic 23104429 dimethylarsinic acid 23104429 lactate 23104429 monomethylarsonic acid 23104429 phosphate 23104429 sodium arsenate 23104429 sodium arsenite 23104429 vitamin D(3) 23104969 EPH 23104969 Ethanol 23104969 d-MPH 23104969 dexmethylphenidate 23104969 dl-MPH 23104969 ethanol 23104969 l-EPH 23104969 l-MPH 23104969 l-ethylphenidate 23104969 methylphenidate 23104969 racemic methylphenidate 23108167 Fe₃O₄ 23108167 MTX 23108167 Methotrexate 23108167 methotrexate 23108167 polyglycerol 23108167 thiol-ene 23108801 graphene 23109293 BPA 23109293 Bisphenol A 23109293 ammonium 23109293 bisphenol A 23109293 nitrate 23109293 nitrite 23109293 nitrogen 23109429 N 23110439 2-arachidonoylglycerol 23111283 FITC 23111283 TSN 23111283 Toosendanin 23111283 propidium iodide 23111283 triterpenoid 23111828 BrdUrd 23111828 Griseofulvin 23111828 Wst-1 23111828 [3H]-thymidine 23111828 [3H]dT 23111828 griseofulvin 23111874 Tetrazolium bromide salt 23111874 TiO(2) 23111874 glutathione 23111874 lactate 23111874 malondialdehyde 23111874 oxygen 23111874 titanium dioxide 23115222 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene monoethanolate 23115222 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl) 23115222 MLA 23115222 N-(5-chloro-2-hydroxyphenyl)-N'-[2-chloro-5-(trifluoromethyl)phenyl 23115222 NS1738 23115222 PNU-120596 23115222 U0126 23115222 acetylcholine 23115222 choline 23115222 formalin 23116145 2,2'-biquinoline 23116145 N 23116145 cyclometallated iridium(III) 23116642 Platycodin D 23116642 alanine 23116642 aspartate 23116642 bilirubin 23116642 glutathione 23116642 malondialdehyde 23116642 nitric oxide 23116642 superoxide 23116642 triterpene saponin 23116938 Endosulfan 23116938 endosulfan 23116938 organochlorine 23116965 (-)-Epicatechin-3-gallate 23116965 (-)-epicatechin-3-gallate 23116965 Ca(2+) 23116965 ECG 23116965 K(+) 23116965 Na 23116965 Na(+) 23116965 polyphenol 23116965 sodium 23117572 I(-) 23117572 Na(+) 23117572 Radioiodine 23117572 SAHA 23117572 Sodium 23117572 iodide 23117572 radioiodine 23117572 valproic acid 23118328 candesartan 23118328 losartan 23118328 telmisartan 23118328 valsartan 23122062 Ethanol 23122062 carbon 23122062 carbon dioxide 23122062 glycerol 23122062 succinic acid 23122063 (1)H 23122063 (13)C 23122063 Sulforaphene 23122063 ethyl acetate 23122063 glucoraphenin 23122063 isothiocyanates 23122063 methanol 23122063 n-hexane 23122063 sulforaphene 23122075 cadmium 23122075 graphite 23122078 EDTA 23122078 Phenyl 23122078 SDS 23122078 Triton X-114 23122078 ammonium sulfate 23122078 ascorbic acid 23122078 catechol 23122078 citric acid 23122078 diphenols 23122078 glutathione 23122078 l-cysteine 23122080 gallic acid 23122087 CIP 23122087 Ciprofloxacin 23122087 DAN 23122087 ENR 23122087 FLU 23122087 NAL 23122087 OXO 23122087 SAR 23122087 acetonitrile 23122087 citrate 23122087 danofloxacin 23122087 enrofloxacin 23122087 flumequine 23122087 methanol 23122087 nalidixic acid 23122087 oxolinic acid 23122087 quinolone 23122087 quinolones 23122087 sarafloxacin 23122087 trifluoroacetic acid 23122091 Xylene 23122091 flavonoids 23122091 triterpenes 23122096 (1)H 23122096 1H 23122096 FAME 23122096 acylglycerol 23122096 fatty acid 23122096 fatty acid acyl 23122096 oleyl 23122096 polyunsaturated fatty acid 23122098 2-(2-hydroxy-5-(methoxycarbonyl) phenoxy)benzoic acid 23122098 2-(2-hydroxyl-5-(methoxycarbonyl) phenoxy) benzoic acid 23122098 3,4-dihydroxy benzoate 23122098 3,4-dihydroxyl benzoate 23122098 DPPH 23122098 butylated hydroxytoluene 23122098 ethyl shikimate 23122098 isolariciresinol 23122098 kaempferol 23122098 methanol 23122098 methyl shikimate 23122098 phenolic 23122098 stigmasterol 23122103 flavone-C-glycoside 23122103 flavone-C-glycosides 23122103 flavonoid-O-glycosides 23122103 polymethoxyflavones 23122109 Resveratrols 23122109 acetonitrile 23122109 ethyl acetate 23122109 methanol 23122109 resveratrol 23122109 resveratrols 23122119 5-O-caffeoylquinic acid 23122119 apigenin 23122119 carbohydrates 23122119 fatty acids 23122119 flavones 23122119 flavonoids 23122119 flavonols 23122119 oxalic, quinic, malic, citric and fumaric acids 23122119 phenolic 23122119 phenolic acids 23122119 tocopherols 23122123 Enniatins 23122123 deoxynivalenol 23122123 deoxynivalenol-3-glucoside 23122123 enniatins 23122123 enniatins A, A1, B and B1 23122125 4-HNE 23122125 Mn 23122125 dityrosine 23122125 lovastatin 23122125 oxygen 23122125 superoxide 23122133 ethanol 23122138 ABTS 23122138 CNBr 23122138 L-tyrosine 23122138 SDS 23122138 Sepharose 4B 23122138 Sulphanilamide 23122138 cyanogen bromide 23122138 sulphanilamide 23122148 flavonoids 23122148 luteolin O-acylhexoside 23122148 methanol 23122148 phenolic 23122148 phenolic acids 23122150 1-eicosanol 23122150 1-octadecanol 23122150 hydrocarbons 23122150 hydroxypalmitate monoesters 23122150 oleate 23122150 oleofin 23122150 palmitate 23122150 palmitate and oleate monoesters 23122150 paraffin 23122153 5-MTHF 23122153 Folates 23122153 [6S]-5-methyltetrahydrofolic acid 23122153 [6S]-5-methyltetrahydrofolic acid calcium 23122153 folates 23122156 amino acids 23122156 arginine 23122156 lysine 23122156 nitrogen 23122158 Chlorogenic acid 23122158 chlorogenic acid 23122158 phenolic 23122158 phlorizin 23122158 polyamide 23122158 polyphenols 23122159 GABA 23122159 Trolox 23122159 amino 23122159 phenolic 23122162 DPPH 23122162 Fucoxanthin 23122162 fucoxanthin 23122164 (23)Na 23122164 NaCl 23122164 sodium 23123250 Hup A 23123250 N-methyl-d-aspartate 23123250 NMDA 23123250 [+] and [-]-Hup A 23123250 [+] and [-]-Huperzine A 23123250 [+]-Hup A 23123250 [+]-Huperzine A 23123250 [-]-Hup A 23123250 [-]-Huperzine A 23123250 amino acid 23123250 soman 23123251 (RO)2P(O)X 23123251 Br 23123251 C6H5 23123251 CF3 23123251 COOEt 23123251 COOMe 23123251 Cl 23123251 Hal 23123251 OCH(CF3)R(1) 23123251 Organophosphorus 23123251 SCH(Hal)COOEt 23123251 SCH2Br 23123251 SCHCl2 23123251 alkyl 23123251 organophosphorus 23123251 serine 23123251 serines 23123253 Organophosphate 23123253 chlorpyrifos 23123253 diazinon 23123253 fluoride 23123253 organophosphate 23123253 organophosphorothioates 23123255 organophosphorus 23123257 polyglutamate 23123298 GEE 23123298 Helenalin 23123298 N-acetylcystine 23123298 NAC 23123298 glutathione ethyl ester 23123298 helenalin 23123298 oxygen 23123298 sesquiterpene lactone 23123425 alanine 23123425 aspartate 23123425 cholesterol 23123425 quercetin 23123425 triglycerides 23123646 ADP 23123646 ATP 23123646 K 23123646 potassium 23123677 tyrosine 23125001 Li 23125001 LiCoO(2) 23125001 lithium 23125180 2-chloro-1,3-butadiene 23125180 chloroprene 23125180 epoxides 23125180 glutathione 23125180 neoprene 23125180 β-Chloroprene 23125282 dehydroepiandrosterone 23125282 triazolam 23126604 PF127-PEI-FA 23126604 PP123 23126604 PTX 23126604 Pluronic 23126604 Pluronic F127-polyethylenimine-folate 23126604 Pluronic P123 23126604 ethanol 23126604 paclitaxel 23126604 verapamil 23127146 estrogen 23127602 (14)C-ethion 23127602 O,O-diethyl phosphorothioate 23127602 O-ethyl phosphorothioate 23127602 ethion 23127602 ethion dioxon 23127602 ethion monooxon 23127818 N-sulfonyl-3,7-dioxo-5β-cholan-24-amides 23127818 ursodeoxycholic acid 23127825 Ibuprofen Sodium 23127825 carbon dioxide 23127917 Ang-(1-7) 23127917 Angiotensin II 23127917 Angiotensin-(1-7) 23127917 NADPH 23127917 dUTP 23127917 deoxynucleotidyl 23127917 malondialdehyde 23127917 nitric oxide 23127917 superoxide 23128353 Glucosamine 23128353 glucosamine 23128353 heme 23128353 trypan blue 23129213 Crizotinib 23129213 Xalkori 23129213 crizotinib 23129213 midazolam 23129213 tyrosine 23129525 Arsenic 23129525 As 23129525 arsenic 23129525 arseno 23129525 arsenobetaine 23129525 arsenocholine 23129525 methyl-arsonate 23130659 1,2-dioleoyl-3-trimethylammonium-propane 23130659 Chol 23130659 DDAB 23130659 DDAB-PAMAM-G-4 23130659 DDAB-PAMAM-G4 23130659 DDAB-mPEG-G3 23130659 DDAB-mPEG-PAMAM-G4 23130659 DOPE 23130659 DOPE-PAMAM-G4 23130659 DOPE-mPEG-G3 23130659 DOPE-mPEG-PAMAM-G4 23130659 DOTAP 23130659 DOTAP-PAMAM-G4 23130659 DOTAP-mPEG-G3 23130659 DOTAP-mPEG-PAMAM-G4 23130659 PAMAM 23130659 PAMAM-G4 23130659 chol-PAMAM-G4 23130659 chol-mPEG-G3 23130659 chol-mPEG-PAMAM-G4 23130659 cholesterol 23130659 dioctadecyldimethylammoniumbromide 23130659 dioleoylphosphatidylethanolamine 23130659 mPEG-PAMAM 23130662 ATP 23130662 phosphoglycerate 23130662 pyruvate 23131042 D-glucuronic acid 23131042 glutathione 23131042 sulphate 23131800 P407 23131800 PEGylated and non-PEGylated octreotide 23131800 PEGylated octreotide 23131800 PVA 23131800 Poloxamer 23131800 Poloxamer 407 23131800 lactic acid 23131800 octreotide 23131800 polyvinyl alcohol 23131800 sodium bicarbonate 23134486 ATP 23134486 glucose-6-phosphate 23135544 GlcA 23135544 UDP 23135544 Xyl 23135544 glucuronic acid 23135544 sugars 23135544 uridine diphosphate 23135544 xylose 23137047 Mn(3)O(4) 23137047 MnO 23137047 Pt 23137047 Pt(II) 23137047 SiO(2) 23137047 hydrogen 23137047 manganese oxide 23137047 silica 23137047 silicate 23137955 Polydatin 23137955 fructose 23137955 polydatin 23137955 urate 23137955 uric acid 23137955 xanthine 23138334 Ca(2+) 23138334 Copper 23138334 Cu 23138334 Cu (2+) 23138334 Cu(2+) 23138334 H(+) 23138334 K(+) 23138334 Mg 23138334 Mg (2+) 23138334 Mg(2+) 23138334 Na(+) 23138334 copper 23138334 magnesium 23139010 1,2-diphytanoyl-sn-glycero-3-phosphocholine 23139010 DPhPC 23139010 L-α-PC 23139010 L-α-phosphatidylcholine 23139010 Teflon 23139010 cholesterol 23139010 gramicidin 23139010 sphingomyelin 23139074 C3'/C4'-hydroxy 23139074 Digitoxigenin 23139074 digitoxin 23139074 monosaccharide 23139074 palladium 23139074 α-L-/α-D-Glycoside 23139353 androgen 23139353 tyrosine 23139354 STZ 23139354 streptozotocin 23139355 fatty acids 23139355 glucose 23139355 triglycerides 23139356 estradiol 23139356 estrogen 23139356 glucose 23140136 2,2-diamino-oxazolone 23140136 2-amino-imidazolone 23140136 2-deoxyguanosine 23140136 8-OxodG 23140136 8-oxodG 23140136 guanidinohydantoin 23140136 guanine 23140136 oxygen 23140136 peroxynitrite 23140136 rose bengal 23140136 spiroiminodihydantoin 23141189 OH 23141189 TiO(2) 23141189 TiO2 23141189 platinum 23141189 titanium dioxide 23142211 NKA 23142211 neurokinin A 23142211 substance P 23142325 ABA 23142325 ATP 23142325 Abamectin 23142325 Ca(2+) 23142325 abamectin 23142325 adenine nucleotide 23142325 avermectins 23142325 glutamate 23142325 malate 23142325 oxygen 23142325 proadifen 23142325 succinate 23142425 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone 23142425 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone 23142425 His 23142425 NNAL 23142425 NNAL-Gluc 23142425 NNK 23142425 Tyr 23142425 UDP 23142425 nucleotide 23142506 K 23142506 K(+) 23142506 potassium 23142577 Bis-1 23142577 K252a 23142577 Na(3)VO(4) 23142710 NADPH 23142710 Superoxide 23142710 aspirin 23142710 diclofenac 23142710 diphenyleneiodonium 23142710 flufenamic acid 23142710 flurbiprofen 23142710 indomethacin 23142710 ketoprofen 23142710 meclofenamic acid 23142710 meloxicam 23142710 nicotinamide adenine dinucleotide phosphate 23142710 nimesulide 23142710 oxygen 23142710 phenylbutazone 23142710 piroxicam 23142710 superoxide 23142711 MG132 23142711 aldosterone 23142712 NADPH 23142712 Yuwen02f1 23142712 diphenylpyrazole 23142712 nitric oxide 23142712 oxygen 23142712 yuwen02f1 23142737 glucose 23142737 oxygen 23142791 2-bromoethylamine hydrobromide 23142791 n-phenylanthranilic acid 23142791 phenylbutazone 23143040 K(+) 23143040 NH(4)HCO(3) 23143040 Na 23143040 Na(+) 23143040 amm 23143040 ammonia 23143040 cortisol 23143040 sodium 23143040 urea 23143891 21-carboxy 23143891 21-nortriamcinolone acetonide 23143891 budesonide 23143891 flunisolide 23143891 fluticasone propionate 23143891 steroid 23143891 triamcinolone acetonide 23143891 Δ(6)-flunisolide 23143930 Au 23144004 Pt 23144004 TiO(2) 23144004 TiO2 23144238 DPA 23144238 GABA 23144238 NMDA 23144238 dipicrylamine 23144238 neurosteroids 23144238 sulfated neurosteroids 23145773 17β-hydroxysteroid 23145773 2,5-thiophene amide 23145773 2,5-thiophene amides 23145773 amide 23145773 anilides 23145773 estrogen 23145773 phenethylamides 23145773 phenyl 23146663 nucleotides 23146663 purine and pyrimidine nucleotides 23146748 estrogens 23146748 progesterone 23146748 prostaglandins 23146748 retinoic acid 23146754 N-methyl-d-aspartate 23146754 adenylate 23146754 arsenic 23146754 arsenite 23146756 3-alkylpyridinium salt 23146756 APS3 23146756 acetylcholine 23147375 PAH 23147375 PAHs 23147375 benzo[a]anthracene 23147375 benzo[a]pyrene 23147375 naphthalene 23147375 phenanthrene 23147375 polycyclic aromatic hydrocarbons 23147414 GABA 23147414 alcohol 23147414 ethanol 23147414 flurazepam 23147414 gaboxadol 23147414 zolpidem 23147417 Methylene Blue 23147417 NO 23147417 Nitric oxide 23147417 SB-408124 23147417 TCS OX2 29 23147417 guanylate 23147417 nitric oxide 23147680 CF(2)Cl(2) 23147680 CF(3)Cl 23147680 CF2Cl2 23147680 CF3Cl 23147680 CFCl(3) 23147680 CFCl3 23147680 CFCs 23147680 chlorofluorocarbons 23147807 carbon 23147869 PAH 23147869 PAHs 23147869 POM 23147869 carbon 23147869 polycyclic aromatic hydrocarbon 23147869 polycyclic aromatic hydrocarbons 23147869 polyoxymethylene 23148227 ADR 23148227 Lys 23148227 adriamycin 23148920 BAPTA-AM 23148920 H(2)S 23148920 Hydrogen sulfide 23148920 NO 23148920 NaHS 23148920 calcium 23148920 dantrolene 23148920 inositol 1,4,5-triphosphate 23148920 nitric oxide 23148920 phosphoserine 23148920 ryanodine 23148920 wortmannin 23148920 xestospongin C 23148988 1,2-dioleoyl-3-(trimethylammonium) propane 23148988 DOTAP 23148988 PEI 23148988 folate 23148988 folic acid 23148988 polyethylenimine 23149809 Ferulic acid 23149809 Fluoride 23149809 alanine 23149809 aspartate 23149809 bilirubin 23149809 ferulic acid 23149809 fluoride 23149809 gamma glutamyl 23149809 hydroperoxides 23149809 lactate 23149809 nitric oxide 23150213 ceftriaxone 23150213 ertapenem 23150213 flucloxacillin 23150213 teicoplanin 23150485 phosphoinositide 23150487 Obtusilactone B 23150487 butanolide 23150487 obtusilactone B 23150983 (1)H 23150983 (13)C 23150983 2-(substituted phenyl/benzyl-amino)-6-(4-chlorophenyl)-5-(methoxycarbonyl)-4-methyl-3,6-dihydropyrimidin-1-ium chlorides 23150983 MTT 23150983 hydrochloride 23152001 Ca 23152001 Cd 23152001 Cu 23152001 Fe 23152001 K 23152001 Mg 23152001 Mn 23152001 Se 23152001 Selenium 23152001 Zn 23152001 cadmium 23152001 selenium 23152124 CPT 23152124 phosphonate 23152124 silica 23153455 ATP 23153455 Vemurafenib 23153455 vemurafenib 23153547 5-flurouracil 23153547 mitomycin C 23153671 2,2-diphenyl-1-picrylhydrazyl 23153671 2,6-dimethoxyphenol 23153671 DPPH 23153671 NO 23153671 O(2)(·-) 23153671 OH 23153671 OH· 23153671 Trolox 23153671 cellobiose 23153671 ferulic acid 23153671 methoxylated phenolic 23153671 phenolic 23153671 sinapic acid 23153671 ·NO 23154302 glucose 23154302 heme 23154302 oxygen 23154302 progesterone 23154302 tyrosine 23154302 vitamin D 23154883 cholesterol 23154883 hydroxypropyl 23154883 triglycerides 23155049 N 23155049 rapamycin 23155202 MDA 23155202 Tween 80 23155202 artemether 23155202 artemisinin 23155202 glucose-6-phosphate 23155202 glutathione 23155202 lumefantrine 23155202 malondialdehyde 23157384 brilliant blue G 23157384 erythrosine B 23157384 methylene blue 23157624 acetylcholine 23157624 dopamine 23157624 glutamate 23157624 norepinephrine 23157624 serotonin 23157626 [(11)C]DASB 23157626 [(11)C]PHNO 23157626 amphetamine 23157626 dopamine 23157626 glutamate 23157626 serotonin 23157629 5-HT 23157629 C 23157629 Serotonin 23157629 catecholamines 23157629 serotonin 23157633 Gamma-aminobutyric-acid 23157633 N-Methyl-D-aspartic-acid 23157633 dopamine 23159329 METH 23159329 cAMP 23159329 methamphetamine 23159663 ACV 23159663 Acyclovir 23159663 TPP 23159663 tripolyphosphate 23159664 ISDN 23159664 N-succinyl 23159664 isosorbide dinitrate 23159708 mannitol 23159708 sucrose 23159708 trehalose 23159728 TCS 23159728 Triclosan 23159728 thyroid hormone 23159728 thyroxine 23159728 triclosan 23159884 organophosphorus 23159884 paraoxon 23159884 racemic sarin 23159884 soman 23159884 tabun 23159884 tryptophan 23159887 cAMP 23159914 (13)C 23159914 (13)C-FA 23159914 Formaldehyde 23159914 formaldehyde 23159985 myclobutanil 23159985 propiconazole 23159985 triadimefon 23159985 triazole 23159985 triazoles 23160090 HSYA 23160090 Hydroxysafflor yellow A 23160090 Hydroxysafflor yellow a 23160179 amino acid 23160179 lutein 23160179 β-carotene 23160270 La(2-x)Sr(x)CuO(4) 23160270 La(2-x)Sr(x)CuO4 23160270 copper oxides 23160434 nucleotides 23160820 MG-132 23160820 carbobenzoxy-Leu-Leu-leucinal 23160820 pregnane 23160820 rifampicin 23160931 C 23160931 C( n ) fullerene 23160931 C(59)TiH(2) 23160931 C(60) 23160931 C(60) fullerene 23160931 C(60)TiH(2) 23160931 C60 fullerene 23160931 H(2) 23160931 H2 23160931 Ti 23160931 TiH(2) 23160931 fullerene 23160931 hydrogen 23160941 N 23160941 N-formyl-Met-Leu-Phe-Ile-Ile-Lys-fluorescein isothiocyanate 23160941 Quin-C1 23160941 formyl 23160941 hexapeptide 23160941 nitrosylated pyrazolone 23160941 quinazolinone 23161216 RY796 23161216 glucose 23161216 potassium 23161216 somatostatin 23161368 ivermectin 23161369 1,3,5-trinitro-1,3,5-triazine 23161369 4-amino-2,6-dinitrotoluene 23161369 4A-DNT 23161369 RDX 23161427 Ilexpublesnins C-M 23161427 aldehyde 23161427 ilexpublesnins C-M 23161427 triterpene saponins 23161470 Si 23161470 SiO(2) 23161470 graphene 23161470 silicon nitride 23161531 Cl(-) 23161531 Coal 23161531 HCO 3(-) 23161531 SO 4(2-) 23161544 (-)-matairesinol 23161544 (-)-pluviatolide 23161544 (-)-podophyllotoxin 23161544 aryltetralin lignan 23161544 lignan 23161544 methylenedioxy 23161544 podophyllotoxin 23161550 (-)-2β-carbomethoxy-3β-(4-fluorophenyl) tropane 23161550 Ala 23161550 Asp 23161550 CFT 23161550 N 23161550 Ser 23161550 calcium 23161550 cocaine 23161550 dopamine 23161550 serine 23161550 zinc 23161584 C(10) to C(13) LABs 23161584 LAB 23161584 LABs 23161584 PAH 23161584 PAHs 23161584 aliphatic hydrocarbons 23161584 carbon 23161584 hydrocarbons 23161584 linear alkylbenzenes 23161584 n-C(15-35) 23161584 n-alkanes 23161584 polycyclic aromatic hydrocarbons 23161747 graphene 23161751 chlorate 23163352 (13)C 23163352 Alanine 23163352 alanine 23163352 amino acids 23163352 glycine 23163726 C 23163726 GTP 23163726 nucleotide 23163768 tyrosine 23164602 3α,22β-diacetoxy-7α-hydroxyl-5α-lanost-8,24E-dien-26-oic acid 23164602 GA-Mk 23164602 ganoderic acid 23164602 hydroxyl 23164602 methanol 23164617 AMPA 23164617 DNQX 23164617 GABA 23164617 NMDA 23164617 d-AP5 23164617 glutamate 23164617 kainate 23164617 muscimol 23164673 Cinobufagin 23164673 SB216367 23164673 cardenolidal steroid 23164673 cinobufagin 23165153 4-hydroxy-2-nonenal 23165153 4-oxo-2-nonenal 23165153 CDDP 23165153 Cisplatin 23165153 Z-Leu-Leu-Leu-al 23165153 aldehydes 23165153 cis-diamminedichloroplatinum 23165153 cisplatin 23165215 IRMOF-1 23165215 [Zn(4)O(CO(2)C(6)H(4)CO(2))(3)](n) 23165215 benzene 23165215 zinc 23165312 carbon 23165625 1,2-butadiene 23165625 1,3-butadiene 23165625 1,3-butadiene-phenyl 23165625 1,4-dihydronaphthalene 23165625 1-Methylindene 23165625 1-butyne 23165625 1-methylindene 23165625 1-phenyl-1-methylacetylene 23165625 2-butyne 23165625 C(10)H(10) 23165625 C(10)H(10)(+) 23165625 C(2)H(3) 23165625 C(4)H(6) 23165625 C(6)H(5) 23165625 C(8)H(8) 23165625 C(8)H(8)(+) 23165625 C(9)H(8) 23165625 C(9)H(8)(+) 23165625 CH(3) 23165625 CH(3)CCCH(3) 23165625 H 23165625 H(2)CCCH(CH(3)) 23165625 H(2)CCHCHCH(2) 23165625 HCCC(2)H(5) 23165625 hydrogen 23165625 indene 23165625 methyl 23165625 phenyl 23165625 phenylallene 23165625 styrene 23165625 trans-1,3-butadienylbenzene 23165625 vinyl 23165754 safranin O 23165754 tyrosine 23166317 7-hydroxy and 8,14-hydroxy EFV 23166317 8-hydroxy EFV 23166317 EFV 23166317 Efavirenz 23166317 efavirenz 23166320 Ala 23166320 Arg 23166320 C 23166320 N 23166320 N-O 23166320 O 23166320 amino acids 23166320 sulfate 23168113 MLA 23168113 PNU-120596 23168113 acetylcholine 23168113 donepezil 23168113 methyllycaconitine 23169263 1,2-diols 23169263 1H 23169263 CH 23169263 OH 23169263 benzene 23169263 butane-2,3-diols 23169263 cyclohexane-1,2-diols 23169263 ethane-1,2-diol 23169263 methylene 23169263 phenylethane-1,2-diol 23169263 propane-1,2-diol 23169263 tert-butylethane-1,2-diol 23169263 vicinal diols 23169689 Schaeffer's acid 23170960 glinides 23170960 glitazones 23170960 metformin 23170960 sulfonylureas 23171137 2,5-diketohexane 23171137 3,6-diketoheptanoyl-CoA 23171137 4-hydroxypentanoate 23171137 4-ketopentanoate 23171137 acetyl-CoA 23171137 calcium levulinate 23171137 carbon 23171137 carbons 23171137 cyclic CoA esters 23171137 cyclopentenyl 23171137 cyclopentenyl- and cyclopentadienyl-acyl-CoAs 23171137 ethanol 23171137 levulinate 23171137 levulinyl-CoA 23171137 lysine 23171137 methyl-pyrrolyl-acetyl-CoA 23171137 nitrogen 23171137 propionyl-CoA 23171137 pyrrolates 23171137 pyrrolyl 23171137 γ-diketo CoA ester 23171137 ε-nitrogen 23172657 perylene 23172777 furanopyrimidine 23172777 pyrazole 23172777 quinazoline 23174017 sugar 23174265 5-HT 23174265 CP55940 23174265 JTE-907 23174266 Polyphenols 23174266 polyphenols 23174754 androgen 23174754 estrogen 23174754 testosterone 23174758 cAMP 23174758 cGMP 23174758 cyclic-AMP 23175666 cortisol 23177254 chalcones 23177254 dihydropyrazolidines 23177254 miltefosine 23177254 pyrazolidines 23177254 terpenyl heterocycles 23177254 α and β ionone 23177257 flavanone 23177257 naringenin 23177786 TAzP 23177786 Triazoyl-phenyl 23177786 biaryl 23177786 jasmonate glucoside 23177786 triazoyl-phenyl 23177787 3-amino-thieno[2,3-b]pyridine-2-carboxamide 23177787 ACh 23177787 ML253 23177787 amphetamine 23177789 dammarane 23177789 saponins 23177789 triterpenes 23177789 tyrosine 23178164 CORT 23178164 corticosterone 23178255 25-OH-PPD 23178255 25-hydroxyprotopanaxadiol 23178255 MTT 23178255 amino acid 23178255 amino acids 23178255 ester 23178380 organophosphates 23178380 paraoxon 23178381 Aspidin PB 23178381 FITC 23178381 MTT 23178381 Ser 23178381 acridine orange 23178381 aspidin PB 23178381 phloroglucinol 23178381 propidium iodide 23178381 wortmannin 23178652 Erlotinib 23178652 MK-2206 23178652 erlotinib 23178652 forskolin 23178652 okadaic acid 23178652 phospho 23178655 Boldine 23178655 DHE 23178655 NAD(P)H 23178655 NO 23178655 STZ 23178655 [s]-2,9-dihydroxy-1,10-dimethoxyaporphine 23178655 acetylcholine 23178655 boldine 23178655 glucose 23178655 nitric oxide 23178655 nitrotyrosine 23178655 peroxynitrite 23178655 streptozotocin 23178655 superoxide 23178655 β-NAPDH 23178896 methyl methanesulfonate 23180160 ON123300 23180160 ON123x 23180160 ON123xx 23180340 13C 23180340 1H 23180340 2',4'-dihydroxy-4,6'-dimethoxy-3'(2''-hydroxybenzyl)dihydrochalcone 23180340 4,2',4'-trihydroxy-6'-methoxy-3'(2''-hydroxybenzyl)dihydrochalcone 23180340 C-benzylated dihydrochalcone 23180340 aromatic amide 23180340 aromatic esters 23180340 dihydrochalcone 23180340 flavonoid 23180651 AgNO3 23180651 H2O2 23180651 HF 23180651 KOH 23180651 NaOH 23180651 Si 23180651 alkali hydroxides 23180651 oxide 23180664 N-(3,5-dinitrobenzoyl)-L-leucine-n-propylamide 23180664 N-(3,5-dinitrobenzoyl)-S-leucine 23180664 organophosphonate 23180678 carbon 23180678 diamond 23180678 graphite 23180678 pipecolic acid 23180678 polysodium N-undecanoyl-L-leucylvanilate 23180678 polysodium N-undecanoyl-L-vanilate 23180678 porphyrins 23182090 2-aminooctahydrocyclopentalene-3a-carboxamide 23182090 2-aminooctahydrocyclopentalene-3a-carboxamides 23182463 amide hydrogens 23182463 amides 23182463 hydrogen 23182954 MDA 23182954 Ozone 23182954 ozone 23183423 silver 23183587 (2)H 23183587 2H 23183587 O-(2)H 23183772 Li 23183772 Si 23183772 lithium 23183772 silicon 23184152 lithium 23186244 1-(4-chlorophenyl)-3-phenylallyl 23186244 1-(4-chlorophenyl)-3-phenylallyl and 3-(4-chlorophenyl)-1-phenylallyl 4-nitrobenzoates 23186244 alcohols 23186244 allyl 23186244 allyl carboxylate 23186244 chiral 1,3-diarylallyl carboxylates 23186244 esters 23187064 oxygen 23187066 Cl(-) 23187066 ClO(4)(-) 23187066 DB15 23187066 Fe(0) 23187066 Fenton's reagent 23187066 H(2)CO(3) 23187066 H(2)O(2) 23187066 H(2)PO(4)(-) 23187066 NO(3)(-) 23187066 SO(4)(2-) 23187066 ZVI 23187066 Zero-valent iron 23187066 azo 23187066 direct blue 15 23187066 zero-valent iron 23187687 hydrogen 23187687 rapta-C 23188119 fluoride 23188828 phospho 23192842 H 23192842 N,N',N''-trihydroxyisocyanuric acid 23192842 N,N-dihydroxypyromellitimide 23192842 N-hydroxyphthalimide 23192842 NDHPI 23192842 NHPI 23192842 THICA 23192842 carbon 23192842 hydroxyimide 23192842 hydroxyimides 23193181 Resveratrol 23193181 glucose 23193181 resveratrol 23193186 glucose 23193255 nucleotide 23194503 MTT 23194503 retinoic acid 23194503 β-Cryptoxanthin 23194503 β-cryptoxanthin 23194508 Cr 23194508 In 23194508 tin dioxide 23194511 (+)-catechin 23194511 (-)-epicatechin 23194511 DPPH 23194511 caffeic acid 23194511 catechin 23194511 chlorogenic acid 23194511 flavonoid 23194511 flavonoids 23194511 gallic acid 23194511 phenolics 23194511 rutin 23194516 nitric oxide 23194519 hydroxychavicol 23194520 alkylresorcinols 23194520 folates 23194520 phenolic acids 23194520 sterols 23194520 tocols 23194527 carbohydrate 23194530 AMP 23194530 Ampicillin 23194530 CAP 23194530 CLO 23194530 DICLO 23194530 FFC 23194530 OXA 23194530 TAP 23194530 acetonitrile 23194530 ammonium acetate 23194530 amphenicol 23194530 chloramphenicol 23194530 cloxacillin 23194530 dicloxacillin 23194530 florfenicol 23194530 oxacillin 23194530 penicillin 23194530 penicillin G 23194530 penicillin V 23194530 thiamphenicol 23194536 Ginsenoside Re 23194536 digoxin 23194536 ginsenoside 23194536 ginsenoside F1 23194536 ginsenoside Re 23194536 ginsenoside Rg1 23194536 ginsenoside Rg2 23194536 ginsenosides 23194536 ginsenosides Re and Rg1 23194536 ginsenosides Rg2 and Rh1 23194536 ginsenosides Rh1 and F1 23194536 protopanaxatriol 23194538 1, 3, 6, 6'-tetra-feruloyl sucrose 23194538 1, 6, 6'-tri-feruloyl-3-p-coumaroyl sucrose 23194538 3, 6-di-p-coumaroyl-1, 6'-di-feruloyl sucrose 23194538 N-trans-feruloyltyramine 23194538 phenlypropanoid glycoside 23194538 quercetin-3-O-[β-D-xyloxyl-(1→2)-α-L-rhamnoside] 23194545 3-sophoroside-5-glucoside 23194545 anthocyanin 23194545 anthocyanins 23194545 caffeic acid 23194545 cyanidin 23194545 delphinidin-3,5-diglucoside 23194545 ferulic acid 23194545 p-hydroxybenzoic acid 23194545 peonidin 23194547 fructose 23194547 glucose 23194547 maltose 23194547 sucrose 23194547 sugar 23194547 sugars 23194554 lactic acid 23194554 tetrasaccharides 23194556 Co 23194556 Cr 23194556 Cu 23194556 Fe 23194556 Mn 23194556 Ni 23194556 Pb 23194556 Zn 23194558 Urea 23194561 C 23194561 N 23194561 O 23194561 S 23194562 melamine 23194565 Pyrrolizidine alkaloids 23194565 otonecine 23194565 pyrrolizidine alkaloids 23194565 retronecine 23194567 17β-estradiol 23194567 androgens 23194567 hydrocortisone 23194567 oestrogens 23194567 progestagens 23194567 progesterone 23194567 testosterone 23194824 Chrysin 23194824 DEN 23194824 Fe 23194824 Fe-NTA 23194824 Flavonoid 23194824 GSH 23194824 N-nitrosodiethylamine 23194824 PGE(2) 23194824 chrysin 23194824 creatinine 23194824 ferric nitrilotriacetate 23194824 flavonoid 23194824 glutathione 23194824 lactate 23194824 nitric oxide 23194824 nitrogen 23194824 ornithine 23194824 polyphenolic 23194824 prostaglandin E(2) 23194824 urea 23194826 Selenite 23194826 lanthanum hydroxide 23194826 selenite 23194826 sodium selenite 23194827 Cucurbitacin E 23194827 Cucurbitacins 23194827 Cucurbitacins I and D 23194827 MTT 23194827 UDP 23194827 cucurbitacin D 23194827 cucurbitacin E 23194827 cucurbitacin I 23194827 cucurbitacins 23194827 cucurbitacins E, D and I 23194827 cucurbitacins I and D 23194827 cucurbitacins I and E 23194827 cucurbitacins I, D and E 23194827 cucurbitacins I, D, E 23194827 cytochalasin D 23194827 glucuronide 23194827 sulfate 23195331 ATP 23197043 cAMP 23197374 Se 23197374 Selenium 23197374 amino acids 23197374 sodium selenate 23197374 sugar 23197648 BPA 23197648 Ba(2+) 23197648 Bisphenol A 23197648 Ca(2+) 23197648 R-C(CH(3))(2)-R 23197648 R-C(CH(3))(CH(2)CH(3))-R 23197648 bisphenolic 23197648 carbon 23197648 phenolic 23198917 bismuth 23199882 Nobiletin 23199882 PMFs 23199882 Polymethoxyflavones 23199882 nobiletin 23199882 polymethoxyflavones 23199990 Ni 23199990 Pb 23199990 aminothioazole 23199990 nickel 23199990 sulfonamide 23199991 Sitosterol 23199991 TG ester 23199991 ester 23199991 sitosterol 23199991 steradiene 23199991 sterol 23199991 triacylglycerol 23199991 triolein 23199994 cholesterol 23200002 fatty acid 23200243 Alexa Fluor 488 23200243 XAC 23200243 adenosine 23200245 Ala 23200245 Asp 23200245 C 23200245 CO 23200245 Galantamine 23200245 Gly 23200245 Ile 23200245 Leu 23200245 Lys 23200245 Phe 23200245 Val 23200245 azepine 23200245 galantamine 23200245 hydrogen 23200245 nitrogen 23200734 16-hydroxylated steroids O-TMS 23200734 2,17α-dimethyl-16ξ,17β-dihydroxy-5α-androst-1-en-3-one 23200734 2,17α-dimethyl-17β-hydroxy-5α-androst-1-en-3-one 23200734 2,17α-dimethyl-3α,16ξ,17β-trihydroxy-5α-androst-1-ene 23200734 methylstenbolone 23200734 steroid 23200734 steroids 23200734 testosterone 23200734 trimethylsilyl 23200736 Minocycline 23200736 NO 23200736 Tig 23200736 Tigecycline 23200736 glycylcycline 23200736 nitric oxide 23200736 tigecycline 23200945 NAD(+) 23200945 NADH 23200945 acetaldehyde 23200945 acrolein 23200945 alcohol 23200945 allyl alcohol 23200945 antimycin 23200945 dextrose 23200945 ethanol 23200945 glucose 23200945 pyrophosphate 23200945 zinc 23201310 carbamazepine 23201447 DON 23201447 OTA 23201447 ZEA 23201447 aflatoxins 23201447 deoxynivalenol 23201447 ochratoxin A 23201447 zearalenone 23202249 PBZ 23202249 Paclobutrazol 23202249 acetyl-CoA 23202249 androgen 23202249 cholesterol 23202249 fatty acid 23202249 free fatty acid 23202249 organochlorine 23202249 organophosphorus 23202249 paclobutrazol 23202249 stearoyl-CoA 23202249 triazole 23202249 triglyceride 23202888 4-nitrophenol 23202888 SnS(2) 23202888 SnS2 23202888 TiO(2) 23202888 TiO(2) (A or R) 23202888 TiO(2) (A) 23202888 TiO(2) (AR) 23202888 TiO(2) (R) 23202888 TiO2 23202888 anatase 23202888 methyl orange 23202888 phenols 23202888 rhodamine B 23202888 rutile 23204110 ATP 23204110 Ca(2+) 23204110 Na-arsenite 23204110 arsenic 23205533 2-hydroxy-6-(pentadec-8-enyl-10-hydroxy) benzoic acid 23205533 2-hydroxy-6-(pentadec-8-enyl-11-hydroxy-13-carbonyl) benzoic acid 23205533 D 23205533 GA (15:1) 23205533 H 23205533 deuterium 23205533 ginkgolic acid 23205533 ginkgolic acid (15:1) 23205533 glucuronide 23205533 hydrogen 23205533 mono-glucuronic acid 23205561 ZnO 23205561 silicon 23205610 histamine 23205610 modafinil 23205610 sulfinyl 23205610 sulfone 23205707 amino acid 23206862 benzimidazole 23206862 oxygen 23206991 Testosterone 23207249 benzodiazepine 23207249 benzodiazepines 23207249 diazepam 23207250 2,4,5-trimethoxycinnamic acids 23207250 3,4-dimethoxycinnamic 23207250 5-fluorouracil 23207250 Eugenol 23207250 benzene 23207250 caffeic 23207250 chlorogenic 23207250 cinnamic 23207250 eugenol 23207250 ferulic 23207250 ferulic and caffeic acids 23207250 p-coumaric 23207250 phenylpropanoids 23207251 23-methyl-6-O-desmethylauricepyrone 23207251 3-O-methylquercetin 23207251 ethanol 23207251 flavonols 23207251 quercetin 23207322 DOX 23207322 Doxorubicin hydrochloride 23207322 Fe3O4 23207322 PMAA 23207322 poly (methacrylic acid) 23207322 silica 23208951 PVA 23208951 poly(vinyl alcohol) 23208951 thiol 23208978 Alumina 23208978 TiO2 23208978 alumina 23208978 aluminium 23208978 phosphoric acid 23209193 antipyrine 23209193 caffeine 23209193 epiroprim 23209193 propafenone 23209193 theophylline 23209193 verapamil 23209194 ATP 23209194 midazolam 23209194 testosterone 23209282 deuterium 23209282 hydrogen 23209282 hydroxyl 23209282 methionine 23209282 valine 23210621 PVA 23210621 poly(vinyl alcohol) 23210706 2,2-dimethyl-1,3-benzodioxole-5-propanol 23210706 Catechol 23210706 DAGA 23210706 EVGE 23210706 FITC 23210706 MnO 23210706 N,N-diallyl glycidyl amine 23210706 OH 23210706 PEG 23210706 PEVGE 23210706 PGA 23210706 acetonide 23210706 catechol 23210706 epoxides 23210706 ethylene glycol vinyl glycidyl ether 23210706 ethylene oxide 23210706 fluoresceine isothiocyanate 23210706 metal oxide 23210706 poly(ethylene glycol vinyl glycidyl ether) 23210706 poly(ethylene glycol) 23210706 poly(glycidyl amine) 23210706 polyethers 23210706 primary amino 23210776 anthocyanins 23210776 aryl hydrocarbon 23210776 flavonoids 23210776 polyphenols 23210776 resveratrol 23210776 silibinin 23210778 Colchicine 23210778 Nitrogen 23210778 colchicine 23210781 eurabienol 23210781 phenolic 23210781 reserpine 23210781 terpenoids 23210781 thymol 23210783 Galanthamine 23210787 bacopasides 23210787 morphine 23210787 steroidal 23210849 Cantharidin 23210849 cantharidin 23210849 norcantharidin 23210849 norcantharimide 23211008 AgTCNQ 23211008 AuTTF 23211008 Zn(bix) 23211362 1-Nitrosocyclohexyl acetate 23211362 1-nitrosocyclohexyl acetate 23211362 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide 23211362 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F(2)(α) 23211362 ATP 23211362 Angeli's salt 23211362 Ca(2+) 23211362 GSH 23211362 HNO 23211362 K(+) 23211362 NCA 23211362 Nitroxyl 23211362 adenylyl 23211362 cGMP 23211362 glutathione 23211362 guanylyl 23211362 isopropylamine NONOate 23211362 nitric oxide 23211362 nitroxyl 23211362 thromboxane A(2) 23211426 Cholesterol 23211426 cholesterol 23211426 oxysterols 23211426 steroid 23211442 Caf 23211442 acarbose 23211442 amino acids 23211442 caffeine 23211442 ethanol 23211442 ethyl acetate 23211442 polyphenols 23211523 GnRH 23211523 N 23211524 GnRH 23211937 dopamine 23211937 fluoxetine 23211937 l-DOPA 23211937 noradrenaline 23211937 reboxetine 23211937 serotonin 23212108 5-HT 23212108 nitric oxide 23212306 Diazinon 23212306 N-methyl-D-aspartate 23212306 NMDA 23212306 calcium 23212306 cyclic AMP 23212306 diazinon 23212306 organophosphate 23212442 Cd 23212442 Cd(2+) 23212442 cadmium 23212742 1α,25(OH)2 D3 23212742 24R,25(OH)2 D3 23212742 25-hydroxyvitamin D3 23212742 25OHD3 23212742 4β,25(OH)2 D3 23212742 6',7'-dihydroxybergamottin 23212742 carbamazepine 23212742 hyperforin 23212742 monohydroxy 23212742 phenobarbital 23212742 rifampin 23212742 vitamin D 23212989 uranium 23214434 PEG 23214434 carbon 23214434 polyethylene glycol 23214511 Fatty acid 23214511 N-alkyl-O-arylcarbamates 23214511 [¹¹C]O-arylcarbamates 23214511 amide 23214511 carbamates 23214511 carbon-11 23214511 fatty acid 23214511 ¹¹C-carbonyl 23214931 CaCl(2) 23214931 NaCl 23214931 PGE 23214931 polyglycerol ester 23214953 15N 23214953 1H 23214953 N–H 23215021 FAM 23215021 PFP 23215021 fluorescein 23215021 graphene oxide 23215021 poly [(9,9-bis(6'-N,N,N-trimethylammonium)hexyl)-fluorenylene phenylene dibromide] 23215035 1,4-triazole 23215035 3-(acetylhydroxyamino)propyl phosphonic acid 23215035 FR900098 23215035 N 23215035 NH₂ 23215035 O 23215035 OH 23215035 amide 23215035 ether 23215035 fosmidomycin 23215035 phosphonate 23215035 urea 23215035 α-azido 23215035 α-carbon 23215155 Au 23215155 TiO(2) 23215155 boron-dipyrromethene 23215155 dinitrophenyl 23215155 sulfonate 23215155 titania 23215439 cholesterol 23215439 cholesteryl 23215439 vinyl ether 23215584 2,2,6,6-tetramethylpiperidinyl-1-oxyl 23215584 TEMPO 23215584 carbon 23218402 4'-OH 23218402 5,7-OH 23218402 Apigenin 23218402 NCF 23218402 ONPG 23218402 apigenin 23218402 cefepime 23218402 ceftazidime 23218402 cephalosporin 23218402 cephalosporins 23218402 clavulanic acid 23218402 crystal violet 23218402 flavonoids 23218402 flomoxef 23218402 imipenem 23218402 narigenin 23218402 naringenin 23218402 nitrocefin 23218402 o-nitrophenyl-β-D-galactoside 23218402 quercetin 23218602 1-[2-(N-Phenylbenzenesulfonamido)ethyl]-1H-1,2,3-triazole-4,5-dicarboxylic acid 23218602 PGE(2) 23218602 PGH(2) 23218602 Triton X-100 23218602 prostaglandin 23218602 prostaglandin E 23218602 sulfonamido-1,2,3-triazole-4,5-dicarboxylic 23218602 sulfonamido-1,2,3-triazole-4,5-dicarboxylic acid 23218715 4-aminothienopyridine 23218715 4-aminothienopyridines 23218950 5'-deoxynucleoside-triphosphate 23218950 dATP 23218950 dCTP 23218950 dGTP 23218950 dNTP 23218950 dNTPs 23218950 nucleoside diphosphate 23218950 rifampicin 23219002 ATP 23219002 K 23219002 K(+) 23219002 potassium 23219042 2,2'-biphenol 23219042 Achyrofuran 23219042 MC21-A 23219042 SYTOX Green 23219042 achyrofuran 23219042 dichloromethane 23219042 methicillin 23219042 vancomycin 23219337 Wogonin 23219337 wogonin 23219523 GSH 23219523 PEITC 23219523 Platinum 23219523 Pt 23219523 glutathione 23219523 platinum 23219523 β-phenylethyl isothiocyanate 23219524 FC131 23219524 MTSEA 23219524 cyclo(-D-Tyr(1)-Arg(2)-Arg(3)-Nal(4)-Gly(5)-) 23219524 cysteine 23219524 methanethiosulfonate-ethylammonium 23219701 2-arylboronic acids 23219701 2-arylvinylboronic acids 23219701 Alkenylboronic acids 23219701 alkenylboronic acids 23219701 esters 23219701 hydrogen peroxide 23219852 1,4-dioxane 23219852 Cholesterol 23219852 anisole 23219852 cholesterol 23219852 cyclohexanone 23219887 Asp 23219887 Cys 23219887 Met 23219887 Phe 23219887 Trp 23219887 aldehyde 23219887 amino acid 23219887 aminoaldehyde 23219887 arginine 23219887 carbonyl 23219887 carboxyl 23219887 carnitine 23219887 choline 23219887 hydroxyl 23219887 polyamine 23219887 ω-aminoaldehyde 23219887 ω-aminoaldehydes 23220104 HPMA 23220104 N-(2-hydroxypropyl)methacrylamide 23220104 ZnPP 23220104 oxygen 23220104 zinc protoporphyrin 23220105 HexPLA 23220105 Hexylsubstituted poly(lactic acid) 23220105 PLGA 23220105 Triptorelin 23220105 Triptorelin acetate 23220105 hexPLA 23220105 poly(lactic acid) 23220105 poly(lactic-co-glycolic acid) 23220105 triptorelin 23220107 man 23220107 mannose 23220294 dopamine 23220400 DCPG 23220400 MDCPG 23220410 Copper 23220410 K(+) 23220410 Na(+) 23220410 Organochlorines 23220410 aldrin 23220410 aluminum 23220410 chrome 23220410 dieldrin 23220410 endosulfan 23220410 heptachlor 23220410 heptachlor epoxide 23220410 iron 23220410 metolachlor 23220410 organochlorine 23220410 organochlorines 23220410 zinc 23220561 Equol 23220561 FLUT 23220561 GnRH 23220561 androgen 23220561 daidzein 23220561 equol 23220561 estrogen 23220561 flutamide 23220561 gonadotropin releasing hormone 23220561 isoflavone 23220587 NAD 23220587 Retinoic acid 23220587 aldehyde 23220587 retinal 23220587 retinoic acid 23220587 retinol 23220587 vitamin A 23220590 Cimetidine 23220590 NAD(+) 23220590 acetaldehyde 23220590 alcohol 23220590 aldehyde 23220590 cimetidine 23220590 ethanol 23220608 NO 23220608 nitric oxide 23220608 oxygen 23220608 phenolic 23220611 aluminiumneoaspergillin 23220611 aspergilliamide 23220611 aspergillic acid 23220611 ferrineoaspergillin 23220611 flavacol 23220611 neoaspergillic acid 23220611 ochratoxin A 23220611 ochratoxin A methyl ester 23220611 ochratoxin A n-butyl ester 23220611 ochratoxins 23220611 zirconium 23220611 zirconiumneoaspergillin 23220742 P505-15 23220742 PRT062607 23220742 fludarabine 23220742 tyrosine 23220748 TIC 23220748 Ticlopidine 23220748 bile acid 23220748 bile acids 23220748 diethylaminoethyl diphenylpropylacetate 23220748 glutathione 23220748 phosphatidylcholine 23220748 taurocholate 23220748 ticlopidine 23220749 Apomorphine 23220749 apomorphine 23220749 dopamine 23220749 morphine 23220749 serotonin 23221600 Stearoyl-CoA 23221600 carbohydrate 23221600 carbohydrates 23221600 stearoyl-CoA 23221600 sterol 23221600 thyroid hormone 23221600 triglyceride 23221636 nucleotide 23223176 Paroxetine 23223176 acetylcholine 23223176 glucose 23223176 oxygen 23223176 paroxetine 23223176 serotonin 23223176 sesamol 23223176 streptozotocin 23223191 Co(3)O(4) 23223191 Co(II) 23223191 Co(III) 23223191 Co(OH)(2) 23223191 CoOOH 23223191 CoSO(4) 23223191 H(2) 23223191 H(2)O(2) 23223191 cobalt oxide 23223191 γ-FeOOH 23223382 tungsten oxide salts 23223382 yttria 23223382 zirconia 23223407 amino acids 23223407 carbohydrates 23223407 glucose 23223407 steroid 23223414 H(2)O 23223414 NK1 23223414 NK7 23223414 TiO(2) 23223414 TiO2 23223414 aminophenyl acid 23223414 anatase (101) 23223414 oxide 23223450 4-hydroxyproline 23223450 disulfide 23223450 proline 23223517 3'-phosphoadenosine-5'-phosphosulfate 23223517 APAP 23223517 UDP 23223517 acetaminophen 23223523 copper 23223523 polycarbonate 23223523 rhodamine 6G 23223523 silver 23224299 carbon 23225148 silicon 23225329 1,12-diaminododecane 23225329 5-(4-aminobutyl)-2-thiopheneoctanamine 23225329 Arg 23225329 Gly 23225329 His 23225329 Leu 23225329 Lys 23225329 N12N 23225329 N4T8N 23225329 NMDA 23225329 Phe 23225329 Trp 23225329 Tyr 23225329 [(3) H]MK-801 23225329 amino acid 23225329 octanamine 23225329 phenylglycine 23225329 polyamine 23225329 polystyrene 23225329 spermine 23227815 2α,3β,15α,23-tetrahydroxyurs-12-en-28-oic acid 23227815 2α,3β,21β,23-tetrahydroxyurs-12-en-28-oic acid 23227815 2α,3β,23,30-tetrahydroxyurs-12-en-28-oic acid 23227815 2α,3β,23-trihydroxyurs-12-en-28, 30-dioic acid 23227815 Asiatic acid 23227815 asiatic acid 23227815 pentacyclic triterpene 23227928 MS(2) 23227928 Mo 23227928 W 23227928 graphene 23227928 h-BN 23227928 metal-disulfides 23227928 transition metal disulfides 23228175 (+)-argutoid A 23228175 (+)-incarvoid B 23228175 ( - )-incarvoid A 23228175 Terpenoids 23228175 incarvoid C 23228175 iridoids 23228175 monoterpenoid 23228182 Amino acid 23228182 amino acid 23228182 ethylene glycol 23228182 pSerMA 23228182 poly(ethylene glycol) 23228182 serine 23228182 zwitterionic poly(serine methacrylate) 23228444 (12)C 23228444 (13)C 23228444 17α-hydroxyprogesterone 23228444 Estrogens 23228444 carbon 23228444 desogestrel 23228444 estradiol 23228444 estrogen 23228444 estrogens 23228444 ethinylestradiol 23228444 pregnanediol 23228444 progesterone 23228695 NH₂ 23228695 amino acids 23228695 silicic acid 23228849 Dopamine 23228849 GLN 23228849 PCL 23228849 PEG 23228849 PEG-grafted PCL 23228849 PLGA 23228849 PLL 23228849 dopamine 23228849 glutamine 23228849 poly(ethylene glycol) 23228849 poly(lactic-co-glycolic acid) 23228849 poly(ε-caprolactone) 23228849 polylysine 23229134 As 23229134 Cd 23229134 Cr 23229134 Cu 23229134 Hg 23229134 Ni 23229134 Pb 23229134 Zn 23229135 CaCl2 23229135 Copper 23229135 Cu 23229135 calcium 23229135 carbon 23229135 copper 23229324 GO-Fc 23229324 ferrocene 23229324 graphene oxide 23229509 N 23229509 adenylyl 23229509 cAMP 23229512 VK2 23229512 VK2-2,3 epoxide 23229512 Vitamin K2 23229512 cysteine 23229512 menaquinone 23229518 1,2-dipalmitoyl-3-chloropropane-1,2-diol 23229518 3-MCPD 23229518 3-MCPD diester 23229518 3-MCPD fatty acid diesters 23229518 3-MCPD fatty acid esters 23229518 3-chloropropane-1,2-diol 23229518 fatty acid esters 23229954 L-phenylglycine 23229954 xanthones 23230132 Cannabinol 23230132 EtG 23230132 Ethanol 23230132 Ethyl glucuronide 23230132 UDP 23230132 cannabidiol 23230132 cannabinol 23230132 codeine 23230132 cotinine 23230132 ethanol 23230132 lorazepam 23230132 morphine 23230132 nicotine 23230132 oxazepam 23230213 Ethanol 23230213 alcohol 23230213 ethanol 23230213 glycine 23230213 strychnine 23230213 zinc 23230214 METH 23230214 Methamphetamine 23230214 Nitric oxide 23230214 dopamine 23230214 methamphetamine 23230214 nitric oxide 23230273 C 23230273 Ser 23231078 H2O 23231078 methyl orange 23231078 n-propanol 23231078 oleic acid 23231078 potassium ferricyanide 23231413 1-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)-4-morpholino-1H-pyrrole-2,5-dione 23231413 RI-1 23231413 RI-2 23231413 chloromaleimide 23231413 maleimide 23231413 thiol 23231492 amino acid 23231502 4-Hydroxynonenal 23231502 8-alkynyl-HNE 23231502 Cys 23231502 HNE 23231502 His 23231502 Lys 23231502 Pro 23231502 aldehydes 23231502 biotin 23231502 pSer 23231502 pThr 23231502 polyphenols 23231502 prolyl 23231586 iridoid glycoside 23231586 triterpenoid glycoside 23231808 Acetazolamide 23232447 6DBF7 23232447 Asp 23232447 C 23232447 DB16 23232447 DB21 23232447 DBF 23232447 Ile 23232447 Leu 23232447 Nle 23232447 Nva 23232447 Val 23232447 alanine 23232447 alkyl 23232447 carbohydrate 23232447 dibenzofuran 23232447 fluorescein isothiocyanate 23232447 lactose 23232447 lysines 23233343 PAH 23233343 PAHs 23233343 polycyclic aromatic hydrocarbon 23233534 Naloxone 23233534 naloxone 23233535 C 23233535 Met 23233535 N 23233535 Thr 23234496 Oxygen 23234496 oxygen 23234644 N'-amino 23234644 Novobiocin 23234644 amines 23234644 noviose 23234644 sugar 23237625 silica 23237625 silver 23237706 Cu 23237706 Diquat 23237706 S 23237706 Zn 23237706 diquat 23237706 diquat dibromide 23237706 glutathione 23237706 oxygen 23237706 retinoid 23237706 selenium 23237706 superoxide 23237836 Dopamine 23237836 aminothiazole 23237836 amphetamine 23237836 benzazepines 23237836 dopamine 23237840 3-(Benzylamino)pyrazine-2,5-dicarbonitrile 23237840 3-(benzylamino)-5-cyanopyrazine-2-carboxamides 23237840 3-(benzylamino)pyrazine-2,5-dicarbonitriles 23237840 4-NH(2) 23237840 benzylamino 23237840 phenyl 23237840 pyrazinamide 23237841 2'-Fluoro-6'-methylene-carbocyclic adenosine phosphoramidate 23237841 2'-fluoro 23237841 2'-fluoro-6'-methylene-carbocyclic adenosine 23237841 FMCA 23237841 FMCAP 23237841 carbocyclic 23237841 entecavir 23237841 hydrogen 23237841 lamivudine 23237841 monophosphate 23237841 phenylalanine 23238124 estrogen 23238275 BPA 23238275 Bisphenol A 23238275 epoxy 23238275 polycarbonate 23238275 thyroid hormone 23238275 thyroid hormones 23239534 H3O(+) 23239534 Mg(2+) 23239534 Mg(2+)(H2O)3 23239534 Mg(2+)(H2O)4 23239534 Mg(2+)(H2O)x 23239534 MgOH(+)(H2O) 23239534 hydrated magnesium 23239555 Boron 23239555 acyl 23239555 borinic acid 23239555 boronic 23239592 CdS 23239592 H2 23239592 Hydrogen 23239592 Titanate 23239592 titanate 23240691 amino acid 23240866 HPMA 23240866 N-(2-hydroxypropyl) methacrylamide 23240866 OEGMA 23240866 P(GMA) 23240866 P(GMA-TEPA)(50) 23240866 P(GMA-oligoamine) 23240866 P(HPMA) 23240866 P(OEGMA) 23240866 P(OEGMA)(15)-b-P(GMA-TEPA)(50) 23240866 PEHA 23240866 PEI 23240866 Polyethylenimine 23240866 TEPA 23240866 TREN 23240866 oligo(ethylene glycol) monomethyl ether methacrylate 23240866 oligoamine 23240866 oligoamines 23240866 pentaethylenehexamine 23240866 poly(glycidyl methacrylate) 23240866 tetraethylenepentamine 23240866 tris(2-aminoethyl)amine 23240892 APAP 23240892 PKAA 23240892 acetaminophen 23240892 alanine 23240892 poly(amidoamine) 23240892 poly(ketal amidoamine) 23240892 secondary amine 23241369 5'-Βenzylglycinyl-amiloride 23241369 5-Benzylglycinyl-amiloride 23241369 UCD38B 23241369 UCD74A 23241369 amiloride 23241369 glycinyl-amiloride 23241369 poly (ADP-ribose) 23241369 sodium 23241370 Polyazamacrocycles 23241370 polyazamacrocycles 23244065 S-adenosyl-L-methionine 23244065 SAM 23244065 methionine 23244212 silica 23244295 4-nitrophenyl chloroformate 23244295 NPC 23244295 arginine 23244295 aspartic acid 23244295 galactose 23244295 glycine 23244296 BF(4)(-) 23244296 NO(3)(-) 23244296 PF(6)(-) 23244296 SCN(-) 23244296 acetonitrile 23244296 tetraoxacalix[2]arene[2]triazine 23244296 triazine 23244580 phosphatidylinositol 3-OH 23244582 chalcones 23244582 flavonoid 23244684 methoxythiophene 23244684 thienopyrazine 23244684 thiophene 23246353 glucose 23246353 palmitate 23246355 3-(arylsulfonyl)spiroimidazolidine-2,4-diones 23246355 Spiroimidazolidine-2,4-dione 23246355 aldose 23246355 arylsulfonyl chlorides 23246355 norcamphor 23246355 spirobicycloimidazolidine-2,4-diones 23246355 spiroiminoimidazolidine-2,4-dione 23246435 ATP 23246459 nitric oxide 23246471 (18)F-FLT 23246471 3'-deoxy-3'-(18)F-fluorothymidine 23246471 PEG-b-PCL 23246471 Poly(ethylene glycol)-block-poly(ε-caprolactone) 23246471 cyclopamine 23246471 gossypol 23246471 paclitaxel 23246530 NMDA 23246530 calcium 23246619 Tacrolimus 23246619 tacrolimus 23246733 citrate 23246863 Cd 23246863 CdSe 23246863 ZnS 23246863 amine 23246863 carboxyl 23246863 nitrogen 23247057 17β estradiol 23247057 estrogen 23247074 Sn 23247074 Ti(0.5)Zr(0.25)Hf(0.25)NiSn 23247176 1,4-diiodotetrafluorobenzene 23247176 Halogen 23247176 bis(pyridyl urea) 23247176 bis(urea) 23247176 dimethylsulfoxide 23247176 halogen 23247176 hydrogen 23247176 methanol 23247176 pyridyl 23248200 E(2)17β-G 23248200 Rosuvastatin 23248200 estradiol 17β-d-glucuronide 23248200 gliclazide 23248200 glimepiride 23248200 glipizide 23248200 glyburide 23248200 metformin 23248200 pioglitazone 23248200 rosuvastatin 23248200 tolbutamide 23248200 troglitazone 23248975 Alexa 546 23248975 Rhodamine 6G 23248975 carbon 23249238 6OXY(Gly)(4) 23249238 6OXY(Gly)(4)OH 23249238 Amide 23249238 hydrocodone 23249238 maleimide 23249238 oxycodone 23249238 tetraglycine 23249238 thioether 23249274 4,4-benzenebiphenyldicarboxylic acid 23249274 BDPC 23249274 N(2) 23249274 NO(2) 23249274 NO2 23249274 UiO-66 23249274 UiO-67 23249274 Zirconium 23249274 Zr 23249274 nitrate 23249274 nitric and nitrous acids 23249274 nitrite 23249274 oxide 23250485 Androgens 23250485 androgen 23250485 androgens 23250485 oxygen 23250742 H(2)O(2) 23250742 H2O2 23250742 nitrogen 23250742 oxygen 23250746 C16 ceramide 23250746 Ceramides 23250746 Palmitate 23250746 ceramide 23250746 palmitate 23250746 saturated fatty acids 23250746 sphingolipid 23250746 sphingolipids 23252343 (1)H 23252343 (13)C 23252343 (19)F 23252343 2-benzoylmethylenequinoline difluoroborates 23252343 NBF(2)O 23252447 (BINAP)Pt(II) 23252447 CH(2)Cl(2) 23252447 HBC 23252447 HBC(Py)([(R)-Pt] 23252447 HBC(Py)([(R)-Pt]) 23252447 HBC(Py)([(S)-Pt]) 23252447 MeOH 23252447 Py 23252447 [(R)-Pt] 23252447 [(S)-Pt] 23252447 ether 23252447 ethylenediamine 23252447 hexa-peri-hexabenzocoronene 23252447 hexabenzocoronene 23252580 2,2'-azobis(2-amidinopropane) hydrochloride 23252580 AAPH 23252580 Amino Acid 23252580 Glucose 6-Phosphate 23252580 Met 23252580 Peroxyl 23252580 SDS 23252580 Trp 23252580 Tyr 23252580 carbonyl 23252580 carbonyls 23252580 dityrosine 23252580 glucose 6-phosphate 23252580 hydroperoxide 23252580 hydroperoxides 23252580 peroxyl 23252580 tryptophan 23252711 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile 23252711 5,6-dichlorobenzimidazone-1-β-d-ribofuranoside 23252711 C 23252711 DRB 23252745 5-nitro-8-hydroxyquinoline 23252745 nitroxoline 23252795 ATP 23252795 deforolimus 23252795 everolimus 23252795 rapamycin 23252795 sirolimus 23252795 temsirolimus 23252880 carbon 23253136 amino acids 23253172 17β-oestradiol 23253172 AVT 23253172 CORT 23253172 arginine vasopressin 23253172 arginine vasotocin 23253172 corticosterone 23253172 oestrogen 23253172 testosterone 23253260 DON 23253260 TBTO 23253260 deoxynivalenol 23253260 organotin 23253260 tributyltin oxide 23254551 1-C(10)H(9) 23254551 1-C(10)H(9)(+) 23254551 1-C10H9+ 23254551 2-C(10)H(9) 23254551 2-C(10)H(9)(+) 23254551 2-C10H9+ 23254551 Ar 23254551 C(10)H(8) 23254551 C(10)H(9) 23254551 C(10)H(9)(+) 23254551 Protonated naphthalene 23254551 hydronaphthyl 23254551 naphthalene 23254551 p-H(2) 23254551 para-hydrogen 23254551 protonated naphthalenes 23255551 E-3-S 23255551 bromsulphthalein 23255551 estrone-3-sulfate 23255551 methotrexate 23255551 rifampicin 23255551 taurocholate 23256441 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide 23256441 MTT 23256441 solar salts 23256472 (129)I 23256472 Iodine-129 23256532 Asp 23256532 Glycero-β-d-manno-heptose 7-Phosphate 23256532 aspartate 23256532 carbohydrate 23256532 d-glycero-β-d-manno-heptose 7-phosphate 23256532 heptose 23256532 nucleotide 23256622 5'-chloro-2, 3-didehydroindolo (2', 3': 2, 3) betulinic acid 23256622 5'-chloro-2, 3-didehydroindolo [2', 3': 2, 3] betulinic acid 23256622 DRF-4012 23256622 betulinic acid 23256622 lupane 23256622 triterpenes 23256623 NADPH 23256623 di-hydroxyl 23256623 luotonin A 23256623 mono-hydroxyl 23256623 quinazoline 23256623 quinolone 23256624 (14)C 23256725 GnRH 23256725 amino acid 23256725 gonadotrophin releasing hormone 23256725 testosterone 23256867 4,4'-diamino azobenzene 23256867 PMLG 23256867 Poly(γ-methyl-l-glutamate) 23256867 amide 23256867 ester 23256867 ethylene diamine 23256867 poly(γ-methyl l-glutamate) 23256867 quartz 23257216 retinoid 23257267 ATP 23257267 EGTA 23257267 Genipin 23257267 K 23257267 calcium 23257267 genipin 23257267 glucose 23257267 oxygen 23257267 wortmannin 23257906 FTO 23257906 carbon 23257906 fluorine-doped tin oxide 23257906 graphene 23258195 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine 23258195 C 23258195 MgCl(2)·6H(2)O 23258195 NaCl 23258195 Ozone 23258195 POPC 23258195 SOZ 23258195 aldehyde 23258195 carboxylic acid 23258195 ozone 23258195 phosphocholine 23258195 secondary ozonide 23258482 (TiO(2))(2)(Cu(2)O) 23258482 (TiO(2))(x)(Cu(2)O)(y) 23258482 (TiO2)x(Cu2O)y 23258482 Cu 23258482 Cu(2)O 23258482 Ti 23258482 TiO(2) 23258482 oxides 23259840 amine 23259841 C 23259841 N 23259841 O 23259841 S 23259841 halogens 23259935 (1)H 23259935 H(2)O(2) 23259935 HPA 23259935 PEG 23259935 PEG-HPA 23259935 hydroxyphenyl propionic acid 23259935 poly(ethylene glycol) 23260348 1-aryl-4-methyl[1,2,4]triazolo[4,3-a]quinoxalines 23260348 [1,2,4]triazolo[4,3-a]quinoxalines 23261424 Arachidonic Acid 23261591 8-OHdG 23261591 Paraquat 23261591 paraquat 23261671 Na selenite 23261671 Se 23261671 Se(IV) 23261671 chlorophyll a 23261671 chlorophylls 23261671 selenium 23261673 phytosterols 23261677 BHA 23261677 N-acetylcysteine 23261677 NAC 23261677 Nec-1 23261677 SKN 23261677 Shikonin 23261677 butylated hydroxyanisole 23261677 necrostatin-1 23261677 oxygen 23261680 3TC 23261680 AZT 23261680 Nucleoside 23261680 d4T 23261680 ddI 23261716 1-acenaphthenol 23261716 2-(4-chlorobenzylidene)cyclopentanol 23261716 2-(4-chlorobenzylidene)cyclopentanone 23261716 9-cis-retinaldehyde 23261716 CBCP-ol 23261716 CBCP-one 23261716 CBP-ol 23261716 CBP-one 23261716 NAD(+) 23261716 NADH 23261716 NADP(+) 23261716 NADPH 23261716 S-tetralol 23261716 cyclopentane 23261716 cyclopentanol 23261716 cyclopentanone 23261716 medroxyprogesterone acetate 23261716 ursodeoxycholic acid 23261758 OTA 23261758 Ochratoxin A 23261758 ochratoxin A 23261859 estradiol 23261859 progesterone 23261859 testosterone 23261865 5-bromo-2'-deoxyuridine 23261865 BrdU 23261865 BrdU(+) 23261865 ZM241385 23261865 adenosine 23261865 glucose 23261865 oxygen 23261866 BAY 73-6691 23261866 Caffeine 23261866 N(G)-nitro-l-arginine methyl ester 23261866 adenosine 23261866 cGMP 23261866 caffeine 23261866 dopamine 23261866 l-NAME 23261866 methylxanthines 23261866 nitric oxide 23261866 paraxanthine 23261866 theobromine 23261866 theophylline 23261990 TTX 23261990 tetrodotoxin 23262164 Biotin 23262164 DCX 23262164 PEG 23262164 Taxotere 23262164 biotin 23262164 docetaxel 23262164 poly(ethylene glycol) 23262269 3,4-dihydroxy-β-phenylethoxy-O-[β-d-apiofuranosyl-(1‴→6')-α-l-rhamnopyranosyl-(1″→3')-O-β-d-glucopyranoside] 23262269 MeOH 23262269 O-α-l-rhamnopyranosyl-(1″→3')-O-[β-d-apiofuranosyl-(1‴→6')] -4'-O-[(E)-caffeoyl]-d-glucopyranoside] 23262269 Phenylethanoid glycosides 23262269 acteoside 23262269 forsythoside B 23262269 n-BuOH 23262269 peiioside A(1)/A(2) 23262269 peiioside B 23262269 phenylethanoid glycosides 23262269 trisaccharide 23262271 (2S,3S)-2,3-trans-dihydromorin-7-O-β-d-glucoside 23262271 flavanol glucoside 23262271 oxyresveratrol 23262271 steppogenin 23262271 trans-dihydromorin 23262278 pepstatin 23262278 pepstatin A 23262663 polystyrene 23263985 CpG 23263985 phosphodiester 23263989 N 23263989 lysine 23263989 zinc 23264098 glatiramer acetate 23264447 estrone-3-sulfate 23264447 fexofenadine 23265459 GSH 23265459 MDA 23265459 Se 23265459 SeCl(2)O 23265459 Selenium chloride oxide 23265459 cyclophosphamide 23265459 glutathione 23265459 hydroxyl 23265459 malondialdehyde 23265459 selenium 23265459 superoxide 23265461 deoxynucleotidyl 23265461 deoxyuridine triphosphophate 23265477 SH 23265477 disulphide 23265477 sulfhydryl 23265485 α-naphthol 23265490 Menthol 23265490 eucalyptol 23265490 menthone 23265490 pulegone 23265490 β-CD 23265490 β-CDs 23265500 benomyl 23265500 fenitrothion 23265500 ozone 23265503 anthocyanin 23265503 anthocyanins 23265503 flavan-3-ol 23265503 gallic acid 23265503 hydroxycinnamic acids 23265503 phenolic 23265503 phenolic acid 23265503 phenolic acids 23265503 phenolics 23265513 1-MCP 23265513 1-Methylcyclopropene 23265513 1-methylcyclopropene 23265513 GA(3) 23265513 amino acid 23265513 ethylene 23265513 gibberellic acid 23265519 1-Deoxynojirimycin 23265519 1-deoxynojirimycin 23265519 2-amino-2-deoxy-D-mannitol 23265519 DNJ 23265519 sorbitol 23265520 glucose 23265520 palmitate 23265520 procyanidin 23265530 DAG 23265530 DAGs 23265530 TAGs 23265530 diacylglycerols 23265530 triacylglycerols 23265535 Acrylamide 23265535 D-glucose 23265535 L-asparagine 23265535 VO(2+) 23265535 VOSO(4) 23265535 acrylamide 23265535 asparagine 23265535 vanadium 23265535 vanadyl sulphate 23265536 Ca 23265536 CaF 23265536 F 23265536 Fluorine 23265536 calcium 23265536 calcium mono-fluoride 23265536 calcium-monofluoride 23265536 fluorine 23265536 graphite 23265540 KCl 23265540 MgSO(4) 23265540 NaCl 23265540 amide 23265540 aromatic amino acid 23265543 Sugar 23265543 acetate esters 23265543 acyl 23265543 acyl esters 23265543 alcohol 23265543 alcohols 23265543 ammonium 23265543 ammonium sulfate 23265543 ester 23265543 esters 23265543 nitrogen 23265543 sugar 23265874 5-hydroxytryptamine-tetramethylrhodamine 23265874 5HT 23265874 Granisetron 23265874 indole nitrogen 23265874 serotonin 23265875 ATP 23265875 pyrrolopyrazine 23265875 pyrrolopyridine 23265876 2-deoxyribonucleosides 23265876 2-deoxyribose 23265876 3'-hydroxyl 23265876 3'-phenyl selenides 23265876 C3'-dideoxyribonucleotide 23265876 H-phosphonates 23265876 ODNs 23265876 saturated and unsaturated sugars 23265883 3-phosphoglycosyl-2-sesquiterpenyl dihydroxypropionic acid 23265883 Nosokophic acid 23265883 moenomycins 23265883 nosokomycin 23265883 nosokophic acid 23265885 2,7-dimethoxy-naphtalenic 23265885 2-[(125)I]-iodomelatonin 23265885 N-(Arylcyclopropyl)acetamides 23265885 N-(arylcyclopropyl)acetamides 23265885 N-(arylvinyl)acetamides 23265885 Valdoxan 23265885 agomelatine 23265885 cyclopropyl 23265885 ethylenic 23265885 melatonin 23265885 methyl ureas 23265891 benzimidazole 23265891 imidazole 23265891 thiazole 23265905 2-methyl-4,5-substitutedbenzo[f]-3,3a,4,5-tetrahydro-pyrazolo[1,5-d][1,4]oxazepin-8(7H)-one 23265905 4,5-tetrahydropyrazolo[1,5-d][1,4]oxazepine 23266123 MTT 23266123 Triazole 23266123 geranylgeranyl 23266123 isoprenoid 23266123 triazole 23266123 triazole bisphosphonates 23266269 Ca(2+) 23266269 Ganodermanondiol 23266269 adenosine monophosphate 23266269 cysteine 23266269 ganodermanondiol 23266269 glutamine 23266269 glutathione 23266269 heme 23266269 t-BHP 23266269 tert-butyl hydroperoxide 23266270 DPEP 23266270 NO 23266270 PGE(2) 23266270 nitric oxide 23266270 prostaglandin E(2) 23266270 trans-1,3-diphenyl-2,3-epoxypropane-1-one 23266271 Quinic acid 23266271 chlorogenic acid 23266271 chlorogenic and quinic acid 23266271 phenolic 23266271 phenolic acids 23266271 quinic acid 23266428 3,4-methylenedioxyamphetamine 23266428 3,4-methylenedioxymethamphetamine 23266428 GABA 23266428 MDA 23266428 MDMA 23266428 amphetamine 23266428 cocaine 23266428 dopamine 23266428 ecstasy 23266428 mCPP 23266428 meta-chlorophenylpiperazine 23266428 serotonin 23266449 teniposide 23266504 ABTS 23266504 Apigenin 23266504 DPPH 23266504 Fe 23266504 carbohydrate 23266504 fatty acids 23266504 flavonoids 23266504 n-hexane 23266504 vitamin E 23266504 β-carotene 23266505 ALD 23266505 EGTA 23266505 MTT 23266505 aldosterone 23266505 calpeptin 23266505 ethylene glycol tetraacetic acid 23266505 spironoclactone 23266567 DHA 23266567 LCPUFA 23266567 docosahexaenoic acid 23266567 long chain polyunsaturated fatty acids 23266567 ω-3 long chain fatty acids 23266720 E-64d 23266720 penicillin 23266720 zinc 23266728 1, 3, 8-trihydroxy-6-methyl anthraquinone 23266728 Rhein 23266728 aloe-emodin 23266728 anthraquinone 23266728 anthraquinones 23266728 emodin 23266728 magnesium acetate 23266728 methanol 23266728 rhein 23266730 assamsaponin C 23266730 flavonoid glycosides 23266730 saponin 23266730 saponins 23266730 theasaponin A8 23266730 theasaponin A9 23266730 theasaponin C1 23266730 theasaponin E1 23266730 theasaponin E2 23266730 theasaponin H1 23266730 triterpene saponin 23266730 triterpenoids 23266734 (1)H 23266734 (13)C 23266734 2,5-disubstituted oxazole 23266734 aspongopusin 23267011 8-oxo-7,8-dihydro-2'-deoxyguanosine 23267011 8-oxoG 23267011 8-oxoguanine 23267011 adenine 23267011 anti- and syn-8-oxoG 23267011 anti-8-oxoG 23267011 cytosine 23267011 dAMP 23267011 dATP 23267011 dCTP 23267011 nucleotide 23267011 syn-8-oxoG 23267661 PRED 23267661 TAC 23267661 Tacrolimus 23267661 prednisone 23267661 tacrolimus 23268337 L-lactate 23268337 Nile Red 23268337 hydroxy-carboxylic acid 23268606 (1)H 23268606 dihydroagarofuran sesquiterpene polyol esters 23268606 nitric oxide 23268606 pyridine alkaloids 23268606 sesquiterpene 23268606 triptersinines A-L 23268742 (2S)-4',5,7-trihydroxyflavan-(4β→8)-afzelechin 23268742 (2S)-4',5,7-trihydroxyflavan-(4β→8)-epiafzelechin 23268742 geranin B 23268742 proanthocyanidin A1 23268742 proanthocyanidin A2 23268742 proanthocyanidins 23268742 proanthocyanindins 23270336 cobalt 23270336 phthalocyanine 23270378 Pantothenic acid 23270378 RR6 23270378 citric acid 23270378 coenzyme A 23270378 cysteamine 23270378 fatty acid 23270378 pantetheine 23270378 pantothenic acid 23270378 pyruvate 23270378 vitamin B5 23270514 N-doped graphene 23270514 amine 23270514 cyanide 23270514 graphene 23270514 graphite 23270514 nitrogen 23270514 nitrogen-doped graphene 23270514 nitrogens 23270514 pyridine 23270514 pyridinium 23270514 pyrrole 23270871 1,2,4-trimethylcyclohexane 23270871 3,4-dihydroxybenzoic acid 23270871 4-hydroxybenzoic acid 23270871 MDA 23270871 OH 23270871 cyclohexane 23270871 hydroxyl 23270871 malondialdehyde 23270871 n-butylbenzene 23270871 n-hexane 23270871 n-octane 23270871 oxygen 23270871 toluene 23270994 1-Nitro-2-phenylethane 23270994 1-nitro-2-phenylethane 23270994 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one 23270994 4-aminopyridine 23270994 K(+) 23270994 KT5720 23270994 L-N(G)-nitroarginine methyl ester 23270994 L-NAME 23270994 MDL-12330A 23270994 NO₂ 23270994 ODQ 23270994 adenylyl 23270994 cGMP 23270994 cis-N-(2-phenylcyclopentyl)-azacyclotridec-1-en-2-amine hydrochloride 23270994 cyclic guanosine 3',5'-monophosphate 23270994 glybenclamide 23270994 guanylate 23270994 indomethacin 23270994 methylene blue 23270994 nitric oxide 23270994 prostaglandin 23270994 sodium nitroprusside 23270994 tetraethylammonium 23271000 GSH 23271000 MDA 23271000 SDG 23271000 STZ 23271000 Secoisolariciresinol diglucoside 23271000 cholesterol 23271000 glucose 23271000 glutathione 23271000 malondialdehyde 23271000 secoisolariciresinol diglucoside 23271000 streptozotocin 23271000 superoxide 23271000 tolbutamide 23271000 triglycerides 23271678 GRA 23271678 SFN 23271678 Se 23271678 glucoraphanin 23271678 glutathione 23271678 selenium 23271678 sulforaphane 23271732 C 23271732 amino acid 23271732 amino acids 23272784 Pb(m)Sb(2n)Te(m+3n) 23272784 PbTe 23272784 Sb(2)Te(3) 23272784 Sb2Te3 23273038 N-cinnamoylated chloroquine 23273038 cinnamic acid 23273052 CoFe₂O₄ 23273052 Fe₃O₄ 23273052 MgZn₂ 23273052 NaZn₁₃ 23273219 N'-2-(4-Benzylpiperidin-/piperazin-1-yl)acylhydrazones 23273219 N'-2-(4-benzylpiperidin-/piperazin-1-yl)acylhydrazone 23273219 rifampicin 23273517 fluorine 23273517 methyl 23273517 nilotinib 23273517 trifluoromethyl 23273521 prolinamide 23273751 10-OH-CPT 23273751 10-hydroxy CPT 23273751 9-MeO-CPT 23273751 9-methoxy CPT 23273751 CPT 23273751 Campothecin 23273751 Camptothecine 23273751 camptothecine 23273751 ethyl acetate 23273751 quinoline alkaloid 23273896 guanine 23273896 nucleotide 23274058 Jaceosidin 23274058 PD98059 23274058 cisplatin 23274058 flavonoid 23274058 jaceosidin 23274086 carbon 23274086 glucose 23274088 Ptaquiloside 23274088 ptaquiloside 23274088 selenium 23274088 zinc 23274302 Indolylmaleimides 23274302 PDA-66 23274302 indole 23274302 indolylmaleimide 23274539 AMP 23274539 alcoholic 23274539 monoterpene 23274539 rapamycin 23274539 sterol 23274539 α-Terpineol 23274539 α-terpineol 23274715 K 23274715 carbon 23274715 potassium 23274766 Bile acids 23274766 UDCA 23274766 bile acid 23274766 bile acids 23274770 Mitragynine 23274770 mitragynine 23274771 DOX 23274771 Doxorubicin 23274777 monoterpene glycoside 23274777 ophiogenin 23274777 ophiopogonol 23274777 ophioside A 23274777 sesquiterpene glycoside 23274777 spirostan 23274777 spirostans 23274887 glucose 23274894 Glucose 23274894 calcium 23274894 glucose 23274894 glucose-6-phosphate 23274908 Diazoxide 23274908 KATP 23274908 diazoxide 23274908 glucose 23274908 tolbutamide 23275348 7-methyljuglone 23275348 N 23275348 Naphthoquinones 23275348 diospyrin 23275348 naphthoquinones 23275540 5-chloro-2'-deoxyuridine 23275540 5-chlorouracil 23275540 5-chlorouridine 23275540 ClU 23275540 thymine 23276137 N-acetyl lysine 23276209 2'-benzoylpyridine thiosemicarbazones 23276209 3-AP 23276209 3-aminopyridine-2-carboxaldehyde thiosemicarbazone 23276209 Alkyl substituted 2'-benzoylpyridine thiosemicarbazone 23276209 BpT 23276209 Fe(III/II) 23276209 RBpT 23276209 Thiosemicarbazone 23276209 phenyl 23276209 t-BuBpT 23276209 thiosemicarbazones 23276254 N-acetylcysteine 23276254 ascorbate 23276254 boron dipyrromethene 23276254 carbons 23276254 naphthyiridinols 23276254 naphthyridinol 23276254 naphthyridinols 23276254 peroxyl 23276254 phosphatidylcholine 23276254 tocopherol 23276254 tocopherols 23276254 urate 23276254 vitamin E 23276254 α-TOH 23276254 α-tocopherol 23276728 N-acetylgalactosamine 23276728 d-glucuronic acid 23276728 sulfate 23277103 AMPA 23277103 aminomethylphosphonic acid 23277103 glyphosate 23278282 13-O-desmethyl tacrolimus 23278282 15-O-desmethyl tacrolimus 23278282 nucleotide 23278282 tacrolimus 23279101 ATP 23279101 C 23279101 amino acid 23279101 histidine 23279849 3,5,7,2',4'-pentahydroxyflavone 23279849 Morin 23279849 bortezomib 23279849 flavonols 23279849 hydroxyl 23279849 morin 23279849 thalidomide 23279849 tyrosine 23279941 Ca 23279941 Cu 23279941 Fe 23279941 K 23279941 Mg 23279941 Na 23279941 Zn 23280515 catechol 23280515 lithium 23280515 silicon 23280651 Coatline A 23280651 coatlines 23280651 schoepfin A 23280651 schoepfin D 23280651 α-epi-coatline A 23280947 U 23280947 uranium 23280986 amino acid 23280986 leucine 23281098 Ir 23281098 iridium 23281098 iridium-oxo 23281267 SDS 23281296 Fe3 O4 23281296 Fe3O4 23281296 SiO2 23281296 folate 23281296 folic acid 23281296 iron oxide 23281296 silica 23281663 (125)I 23281663 PEG-b-PLys 23281663 PNIPAM-b-PAsp 23281663 poly(N-isopropylacrylamide)-block-poly(aspartic acid) 23281663 poly(ethylene glycol)-block-poly(l-lysine) 23281812 Tetrahydropyrroloquinolinone 23281812 aldosterone 23281812 estrogen 23281812 methylene 23281812 pyridinylmethyl substituted 1,2,5,6-tetrahydro-pyrrolo[3,2,1-ij]quinolin-4-ones 23282042 (1)H-(1)H 23282042 5,6-dihydro-α-pyrones 23282042 6-heptyl-5,6-dihydro-2H-pyran-2-one 23282042 6-heptyl-5,6-dihydro-α-pyrones 23282042 Mosher's ester 23282042 brevipolide J 23282042 brevipolides 23282042 brevipolides A-J 23282042 cyclopropane 23282042 isoferuloyl 23282042 p-methoxycinnamoyl 23282091 WO2012081692 23282091 pyrazole 23282091 suvorexant 23282222 Ag 23282222 PEI 23282222 Silver 23282222 polyethylenimine 23282222 silver 23282278 BODIPY 23282278 boron dipyrromethene 23282998 Arsenic 23282998 arsenic 23282998 ascorbic acid 23282998 carbonyl 23282998 deoxyuridine triphosphate 23282998 superoxide 23283976 Mg(2+) 23283976 aspartate 23283976 aspartates 23283976 nucleotide 23286196 5-benzyl-3-phenyl-1,4,2-dioxazoles 23286196 5-benzyl-3-phenyl-4,5-dihydroisoxazoles 23286196 ATP 23286196 d-luciferin 23286196 resveratrol 23286367 PCL 23286367 PMMA 23286367 acrylic 23286367 benzophenone 23286367 poly(methyl methacrylate) 23286367 polycaprolactone 23286367 quartz 23287076 Albendazole 23287076 Flubendazole 23287076 albendazole 23287076 benzimidazole 23287076 flubendazole 23287313 UFA 23287313 bile acid 23287313 campesterol 23287313 carnitine 23287313 cholesterol 23287313 phytosterol 23287313 phytosterone 23287313 stigmasterol 23287313 triglyceride 23287313 unsaturated fatty acids 23287313 β-sitosterol 23287426 AMPA 23287426 Perampanel 23287426 glutamate 23287426 perampanel 23287426 α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid 23287738 3,5-dimethylphenyl 23287738 4-methoxyphenyl 23287738 5-chloro-2-(3,5-dimethylphenyl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one 23287738 5-chloro-2-(9H-fluoren-9-yl)-4-(4-methoxyphenoxy)pyridazin-3(2H)-one 23287738 5-chloro-4-(4-alkoxyphenoxy)-2-(benzyl)pyridazin-3(2H)-one 23287738 CYM50769 23288054 Iodide 23288054 iodide 23288054 thyroid hormone 23288054 thyroxine 23288054 triiodothyronine 23288142 12-O-tetradecanoylphorbol-13-acetate 23288142 DHA 23288142 GF109203X 23288142 PD98059 23288142 TPA 23288142 docosahexaenoic acid 23288142 heme 23288142 linoleic acid 23288142 polyunsaturated fatty acids 23288142 wortmannin 23288712 fullerene 23288946 1,25-dihydroxyvitamin D₃ 23288946 glycerol 23288946 phosphatidylglycerol 23288947 cholesterol 23289502 Cyclic di-GMP 23289502 c-di-GMP 23289502 cyclic di-GMP 23289665 1-phenyl-azo-2-naphthol 23289665 C-H 23289665 O 23289665 Sudan I 23289665 azo 23289665 carbon tetrachloride 23289665 chloroform 23289665 dichloromethane 23289665 hydrazo 23289665 hydrogen 23289770 Rh(2)(S-IBAZ)(4) 23289770 Rh2(S-IBAZ)4 23289770 alkenes 23289770 alkylidenecyclopropanes 23289770 alkynes 23289770 allenes 23289770 cyanocarbene 23289770 cycloprop(en)ylphosphonates 23289770 cyclopropylphosphonates 23289770 diazo 23289770 phosphonate 23289770 phosphonic and carboxylic acid 23289770 rhodium(II) 23289770 α-cyano cycloprop(en)ylcarboxylates 23289770 α-cyano diazo ester 23289770 α-cyano diazophosphonate 23289972 (1)H 23289972 (13)C 23289972 His 23289972 Ser 23289972 Tyr 23289972 barbituric acid 23289972 biphenylcarbonitrile 23289972 glucose 23289972 thiazolidine-2,4-dione 23290487 glucose 23290487 palmatine 23291036 PEG 23291036 caffeine 23291036 glucose 23291036 hydroxypropyl 23291036 ibuprofen 23291037 diltiazem hydrochloride 23291046 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea 23291046 TPPU 23291046 adamantyl 23291046 epoxide 23291046 epoxides 23291046 phenyl 23291046 t-AUCB 23291046 trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid 23291046 urea 23291121 (1)H 23291121 (13)C 23291121 DPPH 23291121 GSH 23291121 N-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)thiosemicarbazide 23291121 N-(tetra-O-acetyl-β-D-galactopyranosyl)thiosemicarbazide 23291121 benzaldehyde N-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl)thiosemicarbazones 23291121 benzaldehydes 23291121 thiosemicarbazones 23291240 24S-hydroxycholesterol 23291240 27-hydroxycholesterol 23291240 cholesterol 23291240 desmosterol 23291240 lanosterol 23291240 lathosterol 23291325 Pb 23291325 Pb-acetate 23291325 co-enzymes Q 23291325 flavonoids 23291325 glutathione 23291325 phenolics 23291326 borneol 23291326 camphor 23291326 sclareol 23291326 α-thujone 23291326 γ-muurolene 23291333 Alkyl esters 23291333 alkyl esters 23291333 ester 23291333 gallic acid 23291401 3' ribonucleotides 23291401 amino acid 23291401 nucleotide 23291401 nucleotides 23291559 K(+) 23291559 K+ 23291559 phenobarbital 23291560 ZEA 23291560 Zearalenone 23291560 diethylstilbestrol 23291560 progesterone 23291560 zearalenone 23291713 chloroquine 23291713 hydroxychloroquine 23292193 (1)H 23292193 (13)C 23292193 Au(15)(SePh)(13) 23292193 Au(18) 23292193 Au(18)(SePh)(14) 23292193 Au(19)(SePh)(15) 23292193 Au(20)(SePh)(16) 23292193 Au(25)(SCH(2)CH(2)Ph)(18) 23292193 Au18(SeC6H5)14 23292193 selenolate 23292193 selenophenol 23292193 selenophenolate 23292249 C2H 23292249 Cyt 23292249 H 23292249 Hyp 23292249 O2 H 23292249 O4 23292249 O6 23292249 Thy 23292249 hypoxanthine 23292302 Calcium 23292302 DTPA 23292302 Fluo-4 23292302 Zinc 23292302 calcium 23292302 diethylenetriaminepentaacetate 23292302 thapsigargin 23292302 zinc 23292321 -CN 23292321 -COCH3 23292321 -N(CH3)2 23292321 -OCH3 23292321 1,8-naphthalimide 23292321 2,3-dihydrothieno[3,4-b][1, 4]dioxine 23292321 2-(thiophen-2-yl)thiophene 23292321 2-phenyl-1,3,4-oxadiazole 23292321 benzo[c][1,2,5]thiadiazole 23292791 Graphene Oxide 23292791 Graphene oxide 23292791 PEG 23292791 PEI 23292791 Polyethylene Glycol 23292791 Polyethylenimine 23292791 amide 23292791 polyethylene glycol 23292791 polyethylenimine 23293126 Cholesterol 23293126 MDA 23293126 Zn 23293126 cholesterol 23293126 glutathion 23293126 malondialdehyde 23293126 superoxide 23293126 triglycerides 23293126 zinc 23293132 asbestos 23293132 silica 23293133 Ca 23293133 Cl 23293133 Cu 23293133 Fe 23293133 K 23293133 Mg 23293133 Na 23293133 P 23293133 Zn 23293133 calcium 23293133 chlorine 23293133 copper 23293133 iron 23293133 magnesium 23293133 phosphorus 23293133 potassium 23293133 sodium 23293133 zinc 23293134 HCl 23293134 hydrochloric acid 23293834 AuCd 23293834 Au₂Cd 23293834 CdSe 23293839 1-ethyl-3-methylimidazolium 23293839 Amino acid 23293839 Emim 23293839 Gly 23293839 H 23293839 alanine 23293839 amino acid 23293839 amino acids 23293839 glycine 23293839 isoleucine 23293839 leucine 23293839 tetraalkylammonium halides 23293839 valine 23294008 AVE 23294008 AVEs 23294008 Avermectins 23294008 avermectin 23294008 dihydroxy-ketone polyketide 23294008 hexahydrobenzofuran 23294008 hexene 23294008 macrolide 23294008 meilingmycins 23294008 polyketide 23294255 piperazine 23294255 serine 23294321 TUG-424 23294321 free fatty acid 23294321 glucose 23294333 DMSO 23294333 Iodogen 23294333 dimethyl sulphoxide 23294333 hypericin 23294333 iodogen 23294333 nitrogen 23294333 tetrachloro-diphenyl glycoluril 23294333 urea 23294348 1H-pyrazolo[3,4-d]pyrimidines 23294348 1H-pyrrolo[2,3-b]- and 3H-imidazolo[4,5-b]-pyridines 23294348 1H-pyrrolo[2,3-b]pyridine 23294348 7-azaindole 23294348 pyrrolo[2,3-b]pyridine 23294368 Paracetamol 23295222 10-formyltetrahydrofolate 23295222 Cys 23295222 Glu 23295222 NADP(+) 23295222 NADPH 23295222 alanine 23295222 aldehyde 23295222 aldehydes 23295222 carboxy 23295222 cysteine 23295222 nicotinamide 23295222 thio-NADP(+) 23295227 Gln 23295227 Leu 23295227 NADP(+) 23295227 Phe 23295227 Ser 23295227 Val 23295227 aldehyde 23295227 aldose 23295227 carboxylic acid 23295227 cyclic imide 23295227 fidarestat 23295227 tolrestat 23295228 Potassium 23295228 aldehyde 23295228 amino acid 23295228 potassium 23295712 TiO(2) 23295712 TiO2 23295712 hydroxyl 23295712 titanium dioxide 23296101 DBP 23296101 FITC 23296101 HC-030031 23296101 calcium 23296101 dibutyl phthalate 23296101 fluorescein isothiocyanate 23296101 icilin 23296101 menthol 23296101 phthalate esters 23296103 AcPEI 23296103 PEI 23296103 PLGA 23296103 Polyethylenimine 23296103 acetylated PEI 23296103 oxygen 23296103 polyethylenimine amines 23296103 primary and secondary amine 23296256 Am(III) 23296256 Eu(III) 23296256 Graphene oxide 23296256 Np(V) 23296256 Pu(IV) 23296256 Sr(II) 23296256 Tc(VII) 23296256 Th(IV) 23296256 U(VI) 23296256 actinides 23296256 bentonite 23296256 carbon 23296256 graphene oxide 23296256 transuranium 23296404 MeHg 23296404 mercury 23296404 methane 23296404 methylmercury 23296568 C₆₀ 23296568 He 23296568 fullerene 23296568 fullerenes 23297161 RIF 23297161 RSV 23297161 amino acid 23297161 estradiol-17β-d-glucuronide 23297161 estrone-3-sulfate 23297161 rifampicin 23297161 rosuvastatin 23297412 NAD(+) 23297412 Resveratrol 23297412 lysine 23297412 phenylephrine 23297412 resveratrol 23298241 (1)H 23298241 (13)C 23298258 All-trans retinoic acid 23298258 all-trans retinoic acid 23298258 atRA 23298258 histidine 23298261 oxytocin 23298261 urethane 23298261 vasopressin 23298277 N 23298277 T-3256336 23298277 amino acid 23298277 bicyclic octahydropyrrolo[1,2-a]pyrazine 23298277 octahydropyrrolo[1,2-a]pyrazine 23298277 proline 23298334 ATP 23298334 Hg(2+) 23298334 Mg(2+) 23298334 SiO(2) 23298334 SiO2 23298334 Zn(2+) 23298334 adenosine-5'-triphosphate 23298334 doxorubicin 23298334 methylene blue 23298334 nucleotides 23298334 silica 23298334 thionine 23298616 PLGA 23298616 PVA 23298616 dexamethasone 23298616 glucose 23298616 poly(lactic-co-glycolic) acid 23298616 poly(vinyl alcohol) 23298744 3-(4-acetamidophenyl)-5-(aryl)-1-H-pyrazolines 23298744 4-acetamidoacetophenone 23298744 acetic acid 23298744 acetylaminochalcones 23298744 aromatic aldehydes 23298744 hydrazine 23298744 pyrazolines 23298744 pyrazolyne 23298744 sodium acetate 23298863 6-Ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide 23298863 TAK-441 23298867 potassium 23299189 ALA 23299189 IFO 23299189 Ifosfamide 23299189 N-acetylcysteine 23299189 NAC 23299189 alpha lipoic acid 23299189 glutathione 23299189 ifosfamide 23299189 malondialdehyde 23299189 nitric oxide 23299190 2'-deoxyuridine 23299190 5'-triphosphate 23299190 GSH 23299190 MDA 23299190 curcumin 23299190 glutathione 23299190 malondialdehyde 23299190 superoxide 23299756 1,2,3,4,6-penta-O-galloyl-β-D-glucose 23299756 1,2,3,6-tetra-O-galloyl-β-D-glucose 23299756 acetonitrile 23299756 arjunetin 23299756 arjunglucoside-I 23299756 arjunglucoside-II 23299756 arjunglucoside-III 23299756 bellericoside 23299756 chebulagic acid 23299756 chebulinic acid 23299756 chebuloside II 23299756 corilagin 23299756 ellagic acid 23299756 formic acid 23299756 gallic acid 23299756 gallic acid methyl ester 23299756 tannins 23299756 triterpene saponins 23299759 (β-D-Glc)3 Yariv phenylglycoside 23299759 fluorescein isothiocyanate 23300006 3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium bromide 23300006 Ethanol 23300006 ethanol 23300006 glucose 23300078 2-isopropyl-5-[3-(trifluoromethyl)-3H-diazirin-3-yl]phenol 23300078 AziPm 23300078 Propofol 23300078 [(3)H]AziPm 23300078 acetylcholine 23300078 amino acids 23300078 propofol 23300078 γ-aminobutyric acid 23300078 δCys 23300078 δPhe 23300339 Ser 23300339 Thr 23301560 Amino acid 23301560 MTT 23301560 amino acid 23301560 carbodiimide 23301766 carbon black 23301766 polyethylene 23301830 (S)-PR 23301830 N-methyl pyrrolidone 23301830 NMP 23301830 methacrylic 23301830 propranolol 23301836 Alkylamine 23301836 CH(3) 23301836 Graphene 23301836 NH(2) 23301836 OH 23301836 alkyl 23301836 alkylamine 23301836 amine 23301836 decylamine 23301836 graphene 23301836 hydroxyl 23301836 methyl 23301856 (99m)Tc 23301856 (99m)Tc-EDDA-HYNIC-Q-Litorin 23301856 (99m)Tc-EDDA/tricine-HYNIC-Q-Litorin 23301856 (99m)Tc-tricine-HYNIC-Q-Litorin 23301856 Bombesin 23301856 EDDA 23301856 HYNIC 23301856 Litorin 23301856 cysteine 23301856 ethylenediamine diacetic acid 23301856 hydrazinonicotinamide 23301856 tricine 23301860 Carbon 23301860 carbon 23301860 methoxypoly(ethylene glycol) 23301860 poly(ethylene glycol) 23302584 2-Aminopyridin-3-ol 23302584 benzothiazole 23302584 cyanamide 23302584 cyanamine 23302584 fluorophenyl 23302584 guanidine 23302584 heterocyclic amines 23302584 monochloride 23302584 phosphorylated guanidine 23302584 piperazinyl 23302584 thiophosphoryl chloride 23302586 4,7-dichloroquinolne 23302586 7-chloroquinoline 23302586 7-chloroquinolines 23302586 Doxorubicin 23302586 benzenesulfonamide 23302586 phosphoinositide 23302586 quinolines 23302587 2-deoxy-2,3-didehydro-N-acetylneuraminic acid 23302587 isocyanide 23302587 α-acylaminoamido 23302593 3-O-β-D-glucopyranosyl-16-O-β-D-glucopyranosyl-2β,3β,16β,21β-tetrahydroxyolean-12-en-28-oic acid 23302593 3-O-β-D-glucopyranosyl-16-O-β-D-xylopyranosyl-2β,3β,16β,21β-tetrahydroxyolean-12-en-28-oic acid 23302593 platycodon A 23302593 platycodon B 23302593 triterpenoid saponins 23302712 Al 23302712 Cd 23302712 Cu 23302712 Fe 23302712 Mn 23302712 Ni 23302712 Pb 23302712 Zn 23302712 aluminium 23302712 cadmium 23302712 copper 23302712 iron 23302712 manganese 23302712 nickel 23302712 zinc 23303709 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid 23303709 DOTA 23303709 DPA-713 23303709 DPA-C(6)-(Gd)DOTAMA 23303709 Gd 23303709 Gd-DOTA monoamide 23303709 carbon 23303709 phenylpyrazolo[1,5-a]pyrimidineacetamide 23303709 pyrazolo[1,5-a]pyrimidineacetamide 23303738 2,3-disubstituted indoles 23303738 2-Carbaborane-3-phenyl-1H-indoles 23303738 2-carbaborane-3-phenyl-1H-indoles 23303738 amides 23303738 carbaboranes 23303738 carbaboranyl 23303738 meta-carbaboranyl 23303738 ortho-carbaboranyl 23303738 phenyl 23303790 2-aminopurine 23303790 Uracil 23303790 amino acids 23303790 uracil 23305400 N-methyl-D-aspartate 23305400 NMDA 23305400 monoamine 23305503 17 β Estradiol hemihydrate 23305503 MPA 23305503 MPA acetate 23305503 Metformin 23305503 estradiol 23305503 estrogen 23305503 medroxyprogesterone acetate 23305503 metformin 23305503 metformine 23305503 progesterone 23305534 (1)H 23305534 4,4'-bis(2-benzoxazolyl)stilbene 23305534 4-(1,3-benzoxazol-2-yl)benzoic acid 23305534 BBS 23305534 aldehyde 23305534 carboxylic acid 23305534 stilbene 23305534 trans-BBS 23305921 CA-Xaa-NHOH 23305921 HCA 23305921 HCA-Phe-NHOH 23305921 HCA-Pro-NHOH 23305921 Trolox 23305921 amino acids 23305921 caffeic acid 23305921 caffeoyl-amino acidyl-hydroxamic acid 23305921 ferulic acid 23305921 hydroxycinnamic acid 23305921 hydroxycinnamoyl phenylalanyl 23305921 phenylalanine 23305921 phenylalanyl hydroxamic acid 23305921 proline 23305921 prolyl hydroxamic acid 23305921 sinapic acid 23305921 vitamin E 23305949 rNMP 23305949 rNMPs 23305949 ribonucleoside monophosphates 23306025 diclofenac 23306951 (14)C-PhIP 23306951 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine 23306951 HCA 23306951 HCAs 23306951 PhIP 23306951 heterocyclic aromatic amines 23307232 Warfarin 23307232 warfarin 23307557 ADP 23307557 lysine 23307694 3,4-dichlorophenylacetyl-Lys-Lys-GCMA 23307694 GCMA 23307694 agmatine 23307694 carbonyl oxygen 23307694 cyclohexyl 23307694 decarboxylated arginine 23307694 dichloro-substituted phenylacetyl 23307694 guanidino 23307694 hydrogen 23307694 phenyl 23307694 serine 23307694 trans-(4-guanidino)cyclohexylmethylamide 23307699 (+)-Usnic acid 23307699 artesunate 23307699 dihydroartemisinin 23307788 ATP 23307788 AZD8055 23307788 rapamycin 23308013 2,3,7,8-Tetrachlorodibenzo-p-dioxin 23308013 2,3,7,8-tetrachlorodibenzo-p-dioxin 23308013 Melatonin 23308013 TCDD 23308013 acetylcholine 23308013 ethyl alcohol 23308013 glutathione 23308013 malondialdehyde 23308013 melatonin 23308013 phenylephrine 23308013 polychlorinated dibenzo-para-dioxin 23311415 canthin-6-one 23311415 canthine alkaloids 23311415 canthines 23311415 β-carboline alkaloids 23311608 PEG 23311608 amino acid 23311608 furan 23311608 maleimide 23311608 maleimide PEG 23311608 poly(ethylene glycol) 23311608 thiol 23311697 Au 23311998 ITO 23311998 PEI 23311998 PFS 23311998 Poly(ferrocenyl(3-bromopropyl)methylsilane) 23311998 amine 23311998 ascorbic acid 23311998 hydrogen peroxide 23311998 poly(ethylene imine) 23311998 poly(ferrocenylsilane) 23311998 quartz 23311998 silicon 23312278 AMP 23312470 Vasopressin 23312470 disulfide 23312470 glutathione 23312470 oxytocin 23312470 vasopressin 23312472 2,4-diaminopyrimidine-5-carboxamide 23312472 2-Aminophenethyl 23312472 2-aminobenzyl 23312945 3-carboxylic acid 23312945 boron 23312945 ciprofloxacin 23312945 fluoroquinolone 23312945 oxaborole 23312945 tricyclic oxaborole 23313085 Vinclozolin 23313243 nicotine 23313269 Triglyceride 23313269 phenylpropanoid glycosides 23313269 phenylpropanol glycosides 23313269 rossicasides 23313337 H2O2 23313337 HyT 23313337 Hydroxytyrosol 23313337 hydroxytyrosol 23313337 hydroxytyrosyl laurate 23313337 laur-HyT 23313337 oxygen 23313337 polyphenol 23313339 Al 23313339 AlCl3 23313339 Aluminium 23313339 Zinc 23313339 Zn 23313339 aluminium 23313339 cholesterol 23313339 dienes 23313339 gangliosides 23313339 zinc 23313339 zinc sulphate 23313557 GW4064 23313557 bile acid 23313557 bile acids 23313557 budesonide 23313557 chenodeoxycholate 23313557 deoxycholate 23313557 dexamethasone 23313557 prednisolone 23313610 T-2 toxin 23313610 mycotoxin T-2 23313620 3,4-DHPEA 23313620 3,4-dihydroxyphenethyl halides 23313620 H(2)O(2) 23313620 catechol 23313620 disulfide 23313620 hydroxytyrosol 23313620 sulfur 23313620 thio 23313620 thioacetate 23313620 thiol 23313622 acetaminophen 23313622 lactose 23313622 magnesium stearate 23313623 Entecavir 23313623 JBP485 23313623 benzylpenicillin 23313623 dipeptide 23313623 entecavir 23313623 p-aminohippurate 23313623 tetraethyl ammonium 23313635 barrigenol 23313635 saponin 23313635 triterpenenoids 23313635 triterpenoids 23313637 Quinoline 23313637 cAMP 23313637 cGMP 23313637 nitric oxide 23313637 quinoline 23313663 BaP 23313663 Benzo[α]pyrene 23313663 PAH 23313663 PAHs 23313663 benzo[α]pyrene 23313663 polycyclic aromatic hydrocarbons 23313711 Aldehydes 23313711 Histidine 23313711 aldehyde 23313711 aldehydes 23313711 amines 23313711 carbohydrate 23313711 carbohydrates 23313711 carbonyl 23313711 carnosine 23313711 glucose 23313711 glutathione 23313711 histamine 23313711 histidine 23313711 oxo- and hydroxy-aldehydes 23313711 thiols 23313711 unsaturated aldehydes 23313730 Mn 23313730 amphetamine 23313730 dopamine 23313730 manganese 23313795 3-hydroxy phloretin 6-O-hexoside 23313795 3-hydroxyphloretin 6'-O-hexoside 23313795 ABTS 23313795 DPPH 23313795 Flavonoids 23313795 acacetin 7-O-(α-D-apio-furanosyl) (1→6)-β-d-glucoside 23313795 apigenin 7-O-galactoside 23313795 apigenin7-O-glucoside 23313795 flavonoids 23313795 luteolin 7-O-glucoside 23313795 luteolin-6-C-glucoside 23313795 quercetin-7-hexoside 23313795 rutin 23313795 superoxide 23313796 Trans-ε-viniferin 23313796 ethanol 23313796 polyphenols 23313796 resveratrol 23313796 suffruticosol A 23313796 suffruticosol B 23313796 suffruticosols A (+95 vs -34) and B 23313796 trans-gnetin H 23313796 trans-ε-viniferin 23314046 thymidine monophosphate 23314046 thymidine triphosphate 23314047 Monocyclic β-lactams 23314047 N-methylthio-azetidinones 23314047 N-methylthio-β-lactams 23314047 polyphenolic 23314047 β-lactam 23314053 1- and 12-Aryl substituted benzo[c]phenanthridines 23314053 4- and 5-amino-1-phenylnaphthalenes 23314053 4- and 5-substituted 1-phenylnaphthalenes 23314053 benzo[c]phenanthridines 23314054 2-hydroxypyridine 23314054 3-thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile 23314054 N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide 23314054 N-substituted-5-(4-isopropylthiophenol)-2-hydroxynicotinamide 23314104 biotin 23314104 graphene 23314320 1,1'-methylenebis{4-hydroxyiminomethyl}pyridinium dimethanesulfonate 23314320 1,1'-trimethylenebis{4-hydroximinomethyl}pyridinium dibromide 23314320 2-PAM 23314320 2-[(hydroxyimino)methyl]-1-methylpyridin-1-ium chloride 23314320 MMB-4 23314320 TMB-4 23314320 diisopropylfluorophosphate 23314320 organophosphate 23314320 oxime 23314320 oximes 23314800 diamond 23314913 lanthionine 23314913 methyllanthionine 23315275 MDA 23315275 glutathione 23315275 malondialdehyde 23315275 oxygen 23315275 superoxide 23316003 Dox 23316003 Doxorubicin 23316003 PLGA 23316003 doxorubicin 23316003 poly(lactide-co-glycolide) 23316685 copper 23316748 H 23316748 urea 23316748 vinblastine 23316792 D-fructose 23316792 fructose 23316792 sugars 23316943 PEO-b-PS 23316943 Sn 23316943 TEOS 23316943 carbon 23316943 lithium 23316943 poly(ethylene oxide-b-styrene) 23316943 silica 23316943 tetraethylorthosilicate 23316943 tin 23316943 tributylphenyltin 23317008 acetylcholine 23317031 Pt 23317031 graphene oxide 23317031 graphite 23317098 glucose 23317098 oxygen 23317339 Ciplar LA 80 23317339 propranolol HCl 23317339 sodium bicarbonate 23317432 alkanethiol 23317432 gold-thiol 23317571 dorzolamide 23317571 prostaglandin F 23318470 1,1-bis(3'-indolyl)-1-(p-chlorophenyl)methane 23318470 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane 23318470 1,1-bis(3'-indolyl)-1-(p-methoxyphenyl)methane 23318470 1,1-bis(3'-indolyl)-1-(phenyl)methane 23318470 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 23318470 MPTP 23318470 dopamine 23318470 para-phenyl substituted diindolylmethanes 23318470 para-phenyl-substituted diindolylmethane 23318470 probenecid 23318471 17β-estradiol 23318471 Dichlorofluorescein 23318471 NO 23318471 Peroxynitrite 23318471 TES 23318471 androgen 23318471 androgens 23318471 cGMP 23318471 nitic oxide 23318471 nitrotyrosine 23318471 peroxynitrite 23318471 phosphoinositide 23318471 superoxide 23318471 testosterone 23318471 xanthine 23318553 4-hydroxyphenylboronic acid 23318553 B 23318553 Nitrogen 23318553 SBA-15 23318553 boron-doped carbons 23318553 oxygen 23318553 silica 23318553 sucrose 23318644 alanine 23318644 cholesterol 23318685 PEG 23318685 Peginesatide 23318685 peginesatide 23318685 polyethylene glycol 23318728 Nicotine 23318728 cotinine 23318728 cotinine-N-oxide 23318728 nicotine 23318728 nicotine-1'-N-oxide 23318728 nitric-oxide 23318728 trans-3'-hydroxycotinine 23318949 amino acid 23318949 amino acids 23318949 ammonia 23318949 fatty acids 23318949 nitrogen 23318949 sulfide 23319419 3-nitro-N-[4-phenoxyphenyl]-benzamide 23319419 ICA 23319419 ICA-105574 23319419 K(+) 23319419 amino acids 23319419 ether 23319419 potassium 23319549 GABA 23319549 L-3,4-Dihydroxyphenylalanine 23319549 L-DOPA 23319549 adenosine 23319549 γ-aminobutyric acid 23321024 azide 23321024 copper 23321274 DXM 23321274 PLGA 23321274 dexamethasone 23321274 hydroxypropyl methyl 23321274 poly(d,l-lactide-co-glycolide) 23321274 steroids 23321687 6-hydroxydopamine 23321687 Caffeine 23321687 caffeine 23321687 dopamine 23321687 haloperidol 23321687 theophylline 23322473 Arsenic 23322473 As 23322473 ammonium acetate 23322473 arsenic 23322906 nucleotide 23323548 E-3-S 23323548 estrone-3-sulfate 23323548 taurocholic acid 23323627 Folic acid 23323627 OEI 23323627 PEI 23323627 disulfide 23323627 folate 23323627 folic acid 23323627 oligoethylenimine 23323627 polyethylenimine 23323627 γ-CD 23323627 γ-CD-OEI 23323627 γ-CD-OEI-FA 23323627 γ-CD-OEI-SS-FA 23323627 γ-cyclodextrin 23323717 C(18)-diterpenoid alkaloid 23323717 Diterpenoid alkaloids 23323717 diterpenoid alkaloids 23323717 kirinenine A 23323802 (R)-2-(2-(furan-2-yl)-oxoethyl)-octahydropyrrolo[1,2-a]pyrazine-1,4-dione 23323802 2,5-diketopiperazine 23323802 ethyl acetate 23323846 amino acid 23323846 carbon 23323861 7,3'-di-(γ,γ-dimethylallyloxy)-5-hydroxy-4'-methoxyflavone 23323861 di-O-prenylated flavone 23323954 1(6),11(12),13(14),1'(6'),11'(12'),13'(14')-dodecahydro-β-caroten-4β,4'β-diol-4β-L-arabinopyranosyl-(2a → 1b)-β-L-arabinopyranosyl-(2b → 1c)-β-D-arabinopyranosido-4'β-L-arabinopyranosyl-(2d → 1e)-β-L-arabinopyranosyl-(2e → 1f)-β-D-arabinopyranoside 23323954 6-(1,1,5-trimethyl-5α-hydroxycyclohexanyl)-6'-(1',1',5'-trimethyl-2'β-hydroxycyclohexanyl)-9,13,9',13'-tetramethyloctadec-7,9,11,13,15,7',9',11',13'-nonene-5α-D-arabinopyranosyl(2a → 1b)-β-D-arabinopyranosyl-(2b → 1c)-β-D-arabinopyranosyl-2'-β-D-arabinopyranosyl-(2d → 1e)-α-D-arabinopyranosyl-(2e → 1f)-α-D-arabinopyranoside 23323954 lyciumtetraterpenic hexaarabinoside 23323954 methanol 23323954 tetraterpene glycosides 23323954 tetraterpenyl hexaarabinoside 23324405 (E)-2-(3-(3-((3-Bromophenyl)amino)-2-cyano-3-oxoprop-1-en-1-yl)-1H-indol-1-yl)acetic acid 23324405 (E)-2-cyano-3-(1H-indol-3-yl)acrylamide 23324405 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 23325361 Androgen 23325368 5-HT 23325368 Sumatriptan 23325368 cortisol 23325368 sumatriptan 23325369 Clozapine 23325369 clozapine 23325369 triglyceride 23325491 3-[(4-butoxy-benzylidene)-amino]-2-phenyl-3H-quinazolin-4-one 23325491 3-[(4-substituted-benzylidene)-amino]-2-phenyl-3H-quinazolin-4-ones 23325491 3-amino-2-phenyl-1H-quinazolin-4-one 23325491 GABA 23325491 alkyl/benzyl halides 23325491 p-hydroxybenzaldehyde 23325491 phenacyl bromides 23325491 quinazolin-4-(3H)-ones 23325491 quinazolinone 23327465 butyl acrylate 23327465 methyl methacrylate 23327600 Calcium 23327600 EDTA 23327600 NaOH 23327600 calcium 23327612 CH(3)NO(2) 23327612 CH(3)O 23327612 CH(3)ONO 23327612 NO 23327656 disulfide 23327656 disulfides 23327656 thiol-disulfide 23327759 Dibenzocyclooctadiene lignans 23327759 dibenzocyclooctadiene lignans 23327759 marlignans M-S 23327759 marphenols C-F 23327759 norlignans 23327779 Risperidone 23327779 [(3)H]-(+)-4-propyl-9-hydroxynaphthoxazine 23327779 [(3)H]-(+)-PHNO 23327779 clozapine 23327779 dopamine 23327779 haloperidol 23327779 olanzapine 23327841 alcohol 23327877 DHEAS 23327877 EGCG 23327877 Flavonoids 23327877 catechins 23327877 dehydroepiandrosterone sulfate 23327877 epigallocatechin 3-O-gallate 23327877 estradiol 17β-glucuronide 23327877 estrone 3-sulfate 23327877 quercetin 23327877 quercetin glycosides 23327905 Labdane 23327905 diterpenoids 23327905 labdane 23327905 vitextrifolins A-G 23328125 H2O2 23328125 Tyr 23328125 hydrogen peroxide 23328125 tyramine 23329465 alcohol 23329465 free fatty acid 23329465 pioglitazone 23329465 vitamin E 23329466 Extended-release ranolazine 23329466 Ranexa 23329466 Ranolazine 23329466 Ranolazine ER 23329466 nitroglycerin 23329466 ranolazine ER 23329466 sodium 23329698 Ser 23329698 Thr 23330546 Bile acids 23330546 Bile-acid 23330546 androstane 23330546 bile acid 23330546 glucose 23330546 pregnane 23330546 vitamin D 23330711 potassium fluoride 23330711 sodium iodide 23330726 PLL 23330726 PLLA 23330726 poly(l-lactic acid) 23330726 poly(l-lysine) 23330972 3-mercaptopropionic acid 23330972 Cd(2+) 23330972 Hg(2+) 23330972 Zn(2+) 23330972 group IIb divalent transition-metal 23330972 group IIb transition-metal 23331020 B(6)H(3)(-) 23331020 B(6)H(4)(-) 23331020 B(6)H(y) 23331020 B(n)H(n)(-) 23331020 B-B 23331020 B6H(y) 23331020 boron 23331020 hydrogen 23331020 polyhedral boranes 23331067 MPTP 23331067 calcium 23331095 Cu 23331095 Cu(3)AsS(4) 23331095 copper hydroxide 23331095 copper oxides and hydroxides 23331095 copper sulfate 23331095 enargite 23331095 sulfide 23331095 sulfur 23331245 Mn 23331245 Mn(3+) 23331245 Mn-O 23331245 NaMnGe(2)O(6) 23331245 NaMnGe2O6 23331245 pyroxene 23331245 pyroxenes 23332751 Lys 23332751 phosphate 23332751 sugar 23333176 nitric oxide 23333573 AAPH 23333573 ABTS 23333573 DPPH 23333573 linoleic acid 23333576 5'-AMP 23333576 STZ 23333576 cAMP 23333576 catechin 23333576 cyclic adenosine monophosphate 23333576 dexamethasone 23333576 glucose 23333576 phosphoenol-pyruvate 23333576 procyanidins 23333576 streptozocin 23333577 Pinosylvin 23333577 phosphoinositide 23333577 pinosylvin 23333577 trans-stilbenoid 23333583 Picrosides I and II 23333583 kutkin 23333583 picrosides I and II 23333717 flavonols 23333717 galloylated flavanols 23333717 polyphenolic 23333717 polyphenols 23333790 1,4-naphthroquinone 23333790 9,10-anthraquinone 23333790 Quinones 23333790 aromatic hydrocarbon 23333790 oxygen 23333790 quinones 23333897 Silica 23333897 TRITC 23333897 phalloidin 23333897 silica 23333901 1,2-orthonaphthoquinone 23333901 NAD(P)H 23333901 methylated-β-cyclodextrin 23333901 poloxamer 23333901 poloxamer 407 23333901 quinone 23333901 β-Lap 23333901 β-Lapachone 23333998 hydrogen 23333998 lanthanide oxide 23333998 oxide 23334083 Calcium oxalate 23334083 calcium oxalate 23334083 hydroxyapatite 23334090 carbon 23334090 poly(acetylene) 23334403 Almorexant 23334403 almorexant 23334403 atorvastatin 23334403 hydroxyacid simvastatin 23334403 o-hydroxy atorvastatin 23334403 simvastatin 23334529 C 23334529 Carbon 23334529 MnOx 23334529 carbon 23334529 manganese oxide 23334943 dutasteride 23334943 finasteride 23335133 Fluocinolone acetonide 23335133 Iluvien 23335133 corticosteroid 23335133 fluocinolone acetonide 23335392 (RS)-3,5-dihydroxyphenylglycine 23335392 2-aminoethoxydiphenylborane 23335392 ATP 23335392 Ca(2+) 23335392 Ca2+ 23335392 DHPG 23335392 K 23335392 K(+) 23335392 K+ 23335392 N(G)-nitro-l-arginine methyl ester 23335392 N-methly-d-aspartate 23335392 caffeine 23335392 cyclopiazonic acid 23335392 glutamate 23335392 inositol 1,4,5-triphosphate 23335392 nitric oxide 23335392 ryanodine 23335392 sulfonylurea 23335392 thapsigargin 23335392 tolbutamide 23335435 COOH- 23335435 NH(2) - 23335435 PAH 23335435 PEG 23335435 Zeolite L 23335435 aminosilicates 23335435 polyallylamine hydrochloride 23335435 polyethyleneglycol 23335435 zeolite L 23335626 19-Epi-okadaic acid 23335626 19-epi-OKA 23335626 OKA 23335626 Okadaic acid 23335626 dinophysistoxin-2 23335627 Acrolein 23335627 acrolein 23335627 aldehyde 23335627 oxygen 23336063 Gobichelin A and B 23336063 gobichelin A and B 23336063 gobichelins 23336064 ATP 23336064 histidine 23336565 5-HT 23336565 5-Hydroxytryptamine 23336565 LP 12 23336565 NMDA 23336565 serotonin 23336753 CH(2)Cl(2) 23336753 Dimolybdenum 23336753 Mo(2)(4+) 23336753 hydrogen 23336753 lactam 23337530 Anagliptin 23337530 Dipeptyl 23337530 anagliptin 23337530 glucose 23337530 oil red O 23337607 BPA 23337607 bisphenol A 23337607 bisphenol-A 23337607 dopamine 23337607 serotonin 23337607 tyrosine 23339181 acetaminophen 23339181 alanine 23339181 glutamate 23339181 malate 23339181 purine nucleoside 23339339 Al 23339339 Cu 23339339 Graphene 23339339 Graphene oxide 23339339 carbon 23339339 chlorosulfonic acid 23339339 graphene 23339339 reduced graphene 23339339 steel 23339625 DEX-P 23339625 MDZ 23339625 dexamethasone 23339625 dexamethasone 21-phosphate 23339625 midazolam 23339629 dinucleotide 23339629 thymine 23339629 thymine-thymine (6-4) 23339682 caffeine 23339682 chlorzoxazone 23339682 metoprolol 23339682 midazolam 23339682 tolbutamide 23339777 benzocamalexin 23339777 camalexin 23339855 Saxotoxins 23339855 T(2) toxin 23339855 Trichothecene 23339884 caffeic acid 23339884 ferulic acid 23339884 p-coumaric acid 23339884 p-hydroxybenzoic acid 23339884 phenolic acids 23339884 protocatechuic acid 23339884 sinapic acid 23339884 vanillic acid 23339967 3'-OH 23339967 3'-hydroxyl 23339967 6-aminohexose 23339967 Amikacin 23339967 Gentamicin 23339967 JI-20A 23339967 Kanamycin A 23339967 Kanamycin B 23339967 Neomycin B 23339967 aminoglycoside 23339967 gentamicin 23339967 gentamicin C 23339967 gentamicins 23339967 phosphorylated kanamycin B 23340199 CLFX 23340199 Fluoroquinolone 23340199 LOFX 23340199 clinafloxacin 23340199 fluoroquinolone 23340199 lomefloxacin 23340251 cAMP 23340251 estradiol 23340251 steroid 23340524 Palladium 23340524 graphite 23340524 nitrogen 23340524 oxygen 23340524 palladium 23340650 Nile Red 23340650 glycerophosphocholine 23340651 O(2) 23340651 oxygen 23340797 fructose 23340797 glucose 23340797 β-pyranose 23340887 cholesterol 23340887 glucose 23340887 triglycerides 23340896 cholesterol 23340896 triglycerides 23340897 25(OH)D 23340897 25-Hydroxyvitamin D 23340897 25-hydroxyvitamin D 23340897 25[OH]D 23340897 Glucose 23340897 glucose 23340897 vitamin D 23340918 25(OH)D 23340918 25-hydroxyvitamin D 23340918 vitamin D 23341167 enoyl acyl 23341167 fatty acid 23341167 primaquine 23341452 (1)H 23341452 (13)C 23341452 amino acid 23341452 amino acids 23341452 hydroxyproline 23341452 proline prolyl 23342998 Nucleotide 23342998 TMC278 23342998 nucleoside 23342998 rilpivirine 23343421 18-Crown-6 23343421 18C6 23343421 K222 23343421 Kryptofix 222 23343421 SDS 23343421 crown ether 23343421 cryptand 23343421 sodium dodecyl sulfate 23343596 AMPH 23343596 amphetamine 23343596 d-amphetamine 23343761 Co₉S₈ 23343761 oleylamine 23343761 transition-metal chalcogenide-alkylamine 23343976 3-hydroxy-3-methylglutaryl coenzyme A 23343976 sodium 23344447 H2 23344447 alcohols 23344447 carboxylic acid 23344447 carboxylic acids 23344447 dioxygen 23344447 hydrogen 23344447 oxygen 23344447 ruthenium 23344553 PCP 23344553 SACC 23344553 phencyclidine 23344553 saccharin 23344693 TiO(2) 23344693 cyano-[5'-(4''-(N,N-dimethylamino)benzylidene)-5H-thiophen-2'-ylidene]acetic acid 23344693 quinoidal thiophene 23344821 MDA 23344821 acid uric 23344821 alanine 23344821 aspartate 23344821 bilirubin 23344821 cholesterol 23344821 creatinine 23344821 malathion 23344821 malation 23344821 malondialdhyde 23344821 superoxide 23344821 thiol 23344821 triglyceride 23344821 urea 23344822 benzene 23344927 Ag 23344927 AgNO3 23344927 Ca 23344927 Na 23344927 calcium 23344927 cysteine 23344927 polyvinylpyrrolidone 23344927 silver 23344927 sodium 23344956 Lys-Asp-Glu-Leu 23344956 brefeldin A 23344961 CPT 23344961 Camptothecin 23344961 ICRF-187 23344961 camptothecin 23345166 melodamide A 23345166 p-quinol 23345166 phenolic amide 23345166 superoxide 23345168 5-fluorouracil 23345168 cysteine 23345168 serine 23345579 O 23345579 P-N 23345579 P-O 23345579 Rp-tabun thiocholine 23345579 Sp- and Rp-tabun 23345579 Sp- and Rp-tabun thiocholine 23345579 Sp-tabun thiocholine 23345579 alkyl 23345579 phosphoramidate 23345579 racemic tabun 23345579 serine 23345579 tabun 23345579 tetraisopropyl pyrophosphoramide 23346866 amine 23346866 quercetin 23347038 M6P 23347038 carbohydrate 23347038 mannose 6-phosphate 23347049 guanine 23347049 thymine 23347071 (13)C 23347071 doxorubicin 23347071 poly(ethylene glycol) 23347071 α-cyclodextrin 23347071 β-cyclodextrin 23347327 Na 23347327 bis-terpyridine 23347327 montmorillonite 23347327 nickel 23347396 DoTAB 23347396 dodecyl trimethyl ammonium bromide 23347396 hexane 23347877 2-aminoindane 23347877 5-IAI 23347877 5-Iodo-2-aminoindan 23347877 5-iodo-2-aminoindan 23347877 MDMA 23347877 p-iodoamphetamine 23347952 CpG 23347952 Morphine 23347952 Ser 23347952 lys 23347952 methyl 23347952 morphine 23347952 naloxone 23347952 phospho 23347953 6-OHDA 23347953 Dopamine 23347953 PD128907 23347953 SKF81297 23347953 bromocriptine 23347953 cocaine 23347953 dopamine 23347953 l-dopa 23348151 silicon 23348406 GSH 23348406 MDA 23348406 glutathione 23348406 malondialdehyde 23348406 nitrite 23348406 selenite 23348406 sodium selenite 23348408 Patchouli alcohol 23348408 patchouli alcohol 23348497 Cys 23348497 cysteine 23348497 guanine 23348497 hypoxanthine 23348497 nucleotide 23348497 uric acid 23348842 kavalactones 23349208 (LTB)4 23349208 (TXB)2 23349208 DHA 23349208 EPA 23349208 LTB5 23349208 TXB3 23349208 arachidonic acid 23349208 docosahexaenoic acid 23349208 eicosapentaenoic acid 23349208 fatty acid 23349208 fatty acids 23349208 leukotriene B 23349208 mono- and trihydroxy 23349208 resolvins 23349208 thromboxane B 23349483 ATP 23349483 Glucose 23349483 H(2)O(2) 23349483 Lactate 23349483 ebselen 23349483 glucose 23349483 glutathione 23349483 lactate 23349483 oxygen 23349483 superoxide 23349483 tempol 23349488 glucose 23349490 DHMEQ 23349490 glucose 23350530 MTT 23350530 PLGA 23350530 curcumin 23350706 N,N'-bis(n-octyl)-dicyanoperylene-3,4:9,10-bis dicarboximide 23350710 flavonoids 23350710 xanthones 23350737 aldehydes 23350737 oxazolidine 23350737 thiazolidine 23350847 Pyrrolopyrazines 23350847 Tyrosine 23350847 pyrrolopyrazines 23350872 graphene 23350872 hydrogen 23351005 Copper(I) 23351005 alkenes 23351005 alkenyl halides 23351005 alkylboronates 23351005 alkylcopper(I) 23351005 borylcopper(I) 23351005 halide 23351136 Glucose 23351136 Sodium 23351136 Tyrosine 23351136 steroid 23351959 3,5,4'-Tri-O-acetylresveratrol 23351959 3,5,4'-tri-O-acetylresveratrol 23351959 RES 23351959 TARES 23351959 hydroxyl 23351959 resveratrol 23352144 AA-861 23352144 Parthenolide 23352144 parthenolide 23352510 1,2,3-benzotriazole 23352510 N 23352510 amino-pyrimidine 23352510 amino-pyrimidines 23352512 Glu 23352512 O-acyl 23352512 Pyr 23352512 glutamyl 23352512 pyroglutamate 23352690 estradiol 23352690 testosterone 23352843 Perfluorocarbon 23352843 fluorine 23352843 oxygen 23352843 perfluorocarbon 23352843 perfluorocarbons 23352908 PFC5 23352908 calcein 23352908 folate 23352908 perfluoropentane 23353004 APAP 23353004 acetaminophen 23353004 carbon tetrachloride 23353004 ethanol 23353004 thioacetamide 23353012 lactose 23353012 trehalose 23353655 Sonhafouonic acid 23353655 hopene 23353655 sonhafouonic acid 23353655 triterpenoid 23353656 Pestaloficiols Q-S 23353656 anofinic acid 23353656 benzofuran 23353656 isoprenylated chromone 23353656 pestaloficiol S 23353656 pestaloficiols Q (1) and R 23353656 pyrenophorol 23353656 secondary alcohol 23353656 siccayne 23353735 2-((bis(trimethylsilyl)methylthio/methylsulfonyl)methyl)-5-aryl-1,3,4-oxadiazoles 23353735 benzohydrazides 23353735 bis(trimethylsilyl)-1,3,4-oxadiazoles 23353735 phosphorus oxychloride 23353735 sila-substituted 1,3,4-oxadiazoles 23353735 silathio/silasulfonyl acetic acids 23353735 sulfonyl 23353735 sulphur 23353737 isoflavone 23353742 1,2,4-oxadiazole 23353742 11β-hydroxysteroid 23353742 amide 23353742 piperidine-3-carboxamide 23353742 piperidyl-oxadiazole 23353742 piperidyl-oxadiazoles 23353742 sulfonamide 23353745 (E)-4-Aryl-4-oxo-2-butenoic acid amides 23353745 (E)-4-aryl-4-oxo-2-butenoic acid amides 23353745 alkyl 23353745 chalcone-aroylacrylic acid 23353748 2-benzylbenzofuran 23353748 4-methoxyphenacyl 23353748 DDP 23353748 benzimidazole 23353748 cisplatin 23353748 imidazole 23353748 imidazolyl 23353748 naphthylacyl 23353754 geniposide 23353806 DTPA 23353806 Dox 23353806 Gd 23353806 MAA 23353806 Omniscan 23353806 PMAA 23353806 PS 80 23353806 PolyGd 23353806 PolyGd-Dox 23353806 diethylenetriaminepenta acetic acid 23353806 doxorubicin 23353806 gadolinium 23353806 methacrylic acid 23353806 polysorbate 80 23353808 Aerosil 23353808 CEL 23353808 Capmul 23353808 Capmul MCM 23353808 Silica 23353808 celecoxib 23353808 fatty acids 23353808 mono-diglycerides 23353808 silica 23353902 CORT 23353902 FLU 23353902 corticosterone 23353902 fluoxetine 23354152 BPA 23354152 Boron 23354152 L-boronphenylalanine 23354152 boron 23354152 boronphenylalanine mannitol 23354152 fructose 23354152 mannitol 23354152 mannitol BPA 23354378 CIT 23354378 Citrinin 23354378 HO-CIT 23354378 OTA 23354378 citrinin 23354378 dihydrocitrinone 23354378 ochratoxin A 23354393 DPPH 23354393 chrysin 23354393 ergosterol 23354393 fatty acids 23354393 ferric 23354393 ferrous 23354393 ferulic acid 23354393 o-coumaric acid 23354393 oleanolic 23354393 p-OH-benzoic acid 23354393 p-OH-phenylacetic acid 23354393 polyphenols 23354393 sterols 23354393 terpenic acids 23354393 triterpenic acids 23354393 ursolic 23354531 NMDA 23354531 memantine 23354545 selenium 23354695 Cadmium 23354695 Cd 23354695 Zn 23354695 cadmium 23354695 zinc 23355087 3-Methylglutaconic 23355087 3-methylglutaconic 23355087 3-methylglutaconic acid 23355087 3-methylglutaconyl-CoA 23355087 leucine 23355087 urea 23355347 CuPc 23355347 SO2 23355480 Asn 23355480 Gln 23355480 amide 23355480 heteroarenes 23355539 Lapatinib 23355539 lapatinib 23355749 Carbon 23356786 CA-4 23356786 combretastatin-A4 23356786 cyclopropylamide 23356786 paclitaxel 23356789 10-O-p-hydroxybenzoyltheviridoside 23356789 10-O-vanilloyltheviridoside 23356789 6″-O-(trans-p-coumaroyl)-procumbide 23356789 iridoid glycoside 23356789 iridoid glycosides 23356789 loganic acid 23356789 rotunduside 23356826 2-methyl pyromeconic acid 3-O-β-d-glucopyranoside-6'-(O-4″-hydroxybenzoate) 23356826 6'-O-p-hydroxybenzoyl-gardoside 23356826 iridoid glycosides 23356865 vitamin E 23356865 α-tocopherol 23356865 α-tocopheryl acetate 23356880 cis-cis-1,4-pentadiene 23356880 lutein 23356880 neoxanthin 23356880 oleocanthal 23356880 p-HPEA-EDA 23356880 polyunsaturated fatty acids 23356880 tocopherols 23356880 tocotrienols 23356880 trans-β-carotene 23356880 violaxanthin 23356880 xanthophylls 23357360 acetic acid 23357360 monoterpene 23357360 monoterpenes 23357360 p-cymene 23357360 β-CD 23357360 β-cyclodextrin 23357416 DCFH-DA 23357416 Dichloro-dihydro-fluorescein diacetate 23357416 Fe2O3 23357416 Fe3O4 23357416 PLGA-PEO 23357416 Rhd 23357416 Rhodamine 23357416 SiO2 23357416 TiO2 23357416 dichloro-dihydro-fluorescein diacetate 23357416 iron oxide 23357416 maghemite 23357416 oleic acid coated magnetite 23357416 poly(ethylene oxide)-poly(lactide/glycolide) acid 23357416 silica 23357416 titanium dioxide 23357567 Nitrogen oxides 23357567 acrolein 23357567 amino 23357567 benzo(a)pyrene 23357567 di-hydroxybenzenes 23357567 formaldehyde 23357567 nicotine 23357567 nitroso 23357977 25(OH)D 23357977 calcium 23358190 amino acid 23358190 dieldrin 23358190 leucine 23358190 pyruvate 23358193 Pb 23358193 amino acids 23358193 monoamines 23358194 Atrazine 23358194 atrazine 23359363 Glucose 23359363 glucose 23360104 benzopyran 23360104 phorbaketal A 23360104 phorbaketals 23360104 phorbaketals A-C 23360104 phorbaketals D-K 23360104 phorbin A 23360104 sesterterpenoids 23360104 spiroketal 23360109 cholesterol 23360143 aldehyde 23360143 aldehydes 23360348 CNX-1220 23360348 CNX-1351 23360348 amino acid 23360348 cysteine 23360369 5,6,7-trimethoxyindole 23360369 N-Methyl-5,6,7-trimethoxylindoles 23360369 colchicine 23360369 combretastatinA-4 23360430 BPA 23360430 Bisphenol A 23360430 glutathione 23360430 oxygen 23360430 polycarbonate 23360449 DBDSe 23360449 DPDSe 23360449 MeSeCys 23360449 Na2SeO3 23360449 Organoselenium 23360449 PhSeH 23360449 Se-methylselenocysteine 23360449 SeCySS 23360449 SeMet 23360449 Sodium selenite 23360449 arylselenium 23360449 benzeneselenol 23360449 cysteine 23360449 cystine 23360449 dibenzyl diselenide 23360449 diphenyl diselenide 23360449 ebselen 23360449 glucose 23360449 glutamate 23360449 organoselenium 23360449 selenium 23360449 seleno-l-cystine 23360449 selenomethionine 23360537 HAS 23360537 fumitremorgins 23360537 hexadehydro-astechrome 23360537 iron(III) 23360537 tryptophan 23361653 chalcogenide 23361947 2-(4-{[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]methyl})-1-piperazinyl)-N-(4-methylphenyl)acetamide 23361947 3-(2-ethoxyphenyl)-5-[[4-(4-nitrophenyl)piperazin-1-yl]methyl]-1,2,4-oxadiazole 23361947 N(2)-(phenoxyacetyl)-N-[4-(1-piperidinylcarbonyl)benzyl]glycinamide 23361947 N-[4-ethoxy-3-(1-piperidinylsulfonyl)phenyl]-2-(imidazo[2,1-b][1,3]thiazol-6-yl)acetamide 23361947 PI(4,5)P(2) 23361947 phosphatidylinositol (4,5)-bisphosphate 23362116 all-trans retinoic acid 23362116 atRA 23362116 retinoic acid 23362116 retinoid 23362116 retinol 23362116 vitamin A 23362121 clovanemagnolol 23362274 LSTc 23362274 Sialylneolacto-N-tetraose c 23362274 sialic acid 23362274 sialylneolacto-N-tetraose c 23362800 (1)H 23362800 (29)Si 23362800 (31)P 23362800 Ru-NHC 23362800 Ru-NHC alkene 23362800 alkene 23362800 mesitylphenyl 23362800 phosphine 23362800 propyl 23362838 LFP 23362838 LiFePO4 23362838 lithium 23362838 lithium iron phosphate 23363083 amino or hydroxy acids 23363083 beta-hydroxy fatty acid 23363083 hydrogen 23363083 kahalalide Y 23363244 carboxylic and sulfonic acids 23363244 cyclopentane 23363244 cyclopentane hydrate 23363244 hydrocarbon 23363244 methane 23363530 HT-2 toxin 23363530 T-2 toxin 23363530 amines 23363530 trichothecene 23368645 Se 23368645 Zn 23368645 ZnSe 23368645 selenium 23368645 zinc 23368645 zinc selenide 23368743 Zinc 23368743 zinc 23368853 LiCl 23368853 MnO2 23368853 ZnO 23368853 ZnO-doped MnO2 23368853 carbon 23368853 polyvinyl alcohol 23368901 C(10) 23368901 C(18) 23368901 C(8) 23368901 ChC(m) 23368901 Choline octanoate 23368901 alkyl 23368901 choline 23368901 choline carboxylate 23368901 choline carboxylates 23368901 choline decanoate 23368901 choline octanoate 23368901 choline oleate 23369094 Donepezil 23369094 PLGA 23369094 Tween-80 23369094 donepezil 23369094 poly(lactic-co-glycolic acid) 23369536 ACV 23369536 Acyclovir 23369536 acyclovir 23369536 nucleoside 23369536 silatrane 23370008 Ritodrine 23370008 acetaminophen 23370008 alanine 23370008 aspartate 23370008 cAMP 23370008 cyclic adenosine 3',5'-monophosphate 23370008 metformin 23370008 ritodrine 23370008 steroid 23370008 valproic acid 23370290 AMPA 23370290 Ca(2+) 23370290 NMDA 23370290 calcium 23370290 glutamate 23371304 Methotrexate 23371415 halogen 23371415 quartz 23371491 VAP 23371491 VPA 23371491 sodium valproate 23371493 4-hydroxynonenal 23371493 8-hydroxyguanosine 23371493 Amphetamine 23371493 amphetamine 23371806 GABA 23371806 Oroxylin A 23371806 atomoxetine 23371806 baicalein 23371806 dopamine 23371806 haloperidol 23371806 methylphenidate 23371806 norepinephrine 23371806 oroxylin A 23371806 γ-aminobutryic acid 23371808 esfenvalerate 23371808 picoxystrobin 23371808 triclosan 23371817 LT4 23371817 levothyroxine 23372041 carbohydrate 23373466 DMPC 23373649 (+)- and (-)-borneol 23373649 6-methylflavone 23373649 BZDs 23373649 GABA 23373649 TG41 23373649 apigenin 23373649 neurosteroids 23373649 topiramate 23373649 γ-aminobutyric acid 23373651 Taxol 23373651 taxol 23373654 emetine 23373654 hycanthone 23373654 hydantoin 23373654 lucanthone 23373654 nitrofurans 23373654 organophosphates 23373654 oxamniquine 23373654 praziquantel 23373751 5-formylindole 23373751 5FIn 23373751 P5FIn 23373751 aldehyde 23373751 poly(5-formylindole) 23373754 Alq3 23373754 Cu2I2(MePyrPHOS)3 23373754 Ir(ppy)3 23373754 aluminum 23373754 copper 23373754 copper(I) 23373754 iridium 23373756 Cα-deuterated alanine 23373756 L- and D-alanine 23373756 alanine 23373756 pyridoxal phosphate 23374349 N 23375059 1α,25(OH)(2)D 23375059 1α,25-dihydroxyvitamin D 23375059 25(OH)D 23375059 Vitamin D 23375059 vitamin D 23375209 C4/Ci4, C3, C5 acylcarnitines 23375209 amino acids 23375209 glucose 23375209 triglycerides 23375227 C34-epi-C35-trifluoro 23375227 C35-fluoro, C35-difluoro, and C35-trifluorosolamins 23375227 NADH 23375227 acetogenin 23375227 acetogenins 23375227 methyl 23375227 mono-THF 23375227 solamin 23375227 ubiquinone 23375227 γ-lactone 23375796 3-hydroxyl, 3-O-acyl and 3-O-alkyl clarithromycin 23375796 9-oxime 23375796 O 23375796 alkylides 23375796 clarithromycin 23375796 ether 23375796 ketolide 23375796 ketolides 23375796 macrolide 23375796 telithromycin 23375796 thiophene 23376022 N-methyl-d-aspartate 23376022 NMDA 23376022 l-glutamate 23376091 Arsenic 23376091 Ca2+ 23376091 DMSA 23376091 MiADMSA 23376091 NO 23376091 arsenic 23376091 calcium 23376091 oxygen 23376120 Gastrodin 23376120 N 23376120 gastrodin 23376120 nitric oxide 23376120 phenolic glucoside 23376120 phosphatidylinositol 23376120 wortmannin 23376121 HI-6 23376121 His 23376121 Phe 23376121 Russian VX 23376121 cyclosarin 23376121 oxime 23376121 oximes 23376121 phosphorus 23376121 serine 23376121 tabun 23376140 Cadmium 23376140 Cd 23376140 CdCl2 23376140 NADPH 23376140 cadmium 23376140 serine 23376140 tyrosine 23376161 Catalpol 23376161 NADPH 23376161 NO 23376161 catalpol 23376161 oxygen 23376407 1,25-dihydroxyvitamin D 23376407 25-hydroxyvitamin D 23376407 Ca 23376407 Pb 23376407 alcohol 23376407 calcium 23376407 ethanol 23376407 phosphorus 23376438 (E)-1-(3,4-dihydroxyphenethyl)-3-(4-hydroxystyryl)urea 23376438 N 23376438 ZEN 23376438 Zearalenone 23376438 acteoside 23376438 oxygen 23376438 zearalenone 23376438 α-ZOL 23376438 α-zearalenol 23376438 β-ZOL 23376438 β-zearalenol 23376440 Arsenic 23376440 Arsenite 23376440 BSO 23376440 DL-buthionine-(S, R)-sulfoximine 23376440 GSH 23376440 Sodium arsenite 23376440 arsenic 23376440 arsenite 23376440 gamma-glutamylcysteine 23376440 glutathione 23376440 melatonin 23376440 oxygen 23376440 sodium arsenite 23376476 8-OHdG 23376476 8-Oxoguanine 23376476 8-hydroxydeoxyguanine 23376476 Cys 23376476 Ser 23376478 Lycorine hydrochloride 23376478 lycorine hydrochloride 23376781 Cadmium 23376781 Catechins 23376781 cadmium 23376781 catechins 23376781 gallic acid 23376781 phenols 23376781 polyphenol 23376781 purine alkaloids 23376781 δ-ALA 23376781 δ-aminolevulinate 23376996 1,1-diphenyl-2-picrylhydrazyl 23376996 4-Nerolidylcatechol 23376996 DPPH 23376996 β-carotene 23377117 9-aminoacridine 23377117 A7G 23377117 acridine 23377117 apigenin 7-O-glucoside 23377117 ethyl methanesulfonate 23377117 flavonoid 23377117 flavonoids 23377117 phenolic acids 23377117 saponins 23377117 sodium azide 23377117 tannins 23377119 chlorpyrifos 23377119 cypermethrin 23377119 dichlorvos 23377119 glyphosate isopropylamine 23377119 lambda cyhalomethrin 23377542 retinoic acid 23377699 BPA 23377699 Bisphenol A 23377699 androgen 23377699 bisphenol A 23377699 thyroxine 23377760 aciclovir 23377760 acyclovir 23377760 corticosteroids 23377859 Abamectin 23377859 abamectin 23377859 cypermethrin 23377859 fipronil 23377859 organochlorine 23377859 organophosphates 23377859 pyrethroids 23378624 prednisolone 23378625 fructosamine 23379481 Amidoxime 23379481 Mesupron 23379481 N 23379481 NADH 23379481 Upamostat 23379481 WX-UK1 23379481 amidoxime 23379481 hydroxyamidine 23379481 molybdenum 23379481 serine 23379481 upamostat 23379995 Cipro 23379995 Ciprofloxacin 23379995 PEDOT 23379995 PSS 23379995 Ppy 23379995 ciprofloxacin 23379995 hydrochloride 23379995 phosphate 23379995 poly(3,4-ethylenedioxythiophene) 23379995 poly(styrenesulfonate) 23379995 polypyrrole 23379996 PEI 23379996 polylysine 23379996 polylysines 23380242 LY294002 23380242 PD98059 23380242 SB203580 23380242 SP600125 23380242 TiO2 23380242 Titanium dioxide 23380242 apocynin 23380242 epigallocatechin gallate 23380242 pyrrolidine dithiocarbamate 23380242 titanium 23380376 Cinnamic acid 23380376 chorismate 23380376 cinnamic acid 23380376 isochorismate 23380376 unsaturated cyclohexenoic acid 23380478 CO 23380478 Carbon monoxide 23380478 NADPH 23380478 oxygen 23380478 tartrate 23380989 Kocurin 23380989 PM181104 23380989 amino acid 23380989 kocurin 23380989 methicillin 23380989 thiazolyl 23381061 Anisole 23381061 In(OTf)(3) 23381061 Lewis acid 23381061 anisole 23381061 phenol 23381223 C(80) 23381223 C(82) 23381223 La 23381223 La(2) 23381223 Sc(3)N 23381223 metallofullerenes 23381662 alanine 23381662 pazopanib 23381692 ADP 23381692 Clopidogrel 23381692 clopidogrel 23381692 lansoprazole 23381692 omeprazole 23381939 Si 23382074 ZnF 23382074 lysine 23382379 ATP 23382379 N 23382379 N-methylanthraniloyl-nucleotides 23382379 nucleotide 23382381 N 23382381 doxorubicin 23382381 etoposide 23383712 estrogen 23383712 estrogens 23383865 (1)H 23383865 (31)P 23383865 (μ-H)Fe2(pdt)(CO)2(dppv)2 23383865 1,3-propanedithiolate 23383865 D(+) 23383865 D2 23383865 Fe 23383865 Fe(I) 23383865 Fe(II)-H 23383865 Fe---Fe 23383865 Fe-H 23383865 Fe-P 23383865 H 23383865 H(+) 23383865 H1 23383865 H2 23383865 [H1](+) 23383865 cis-1,2-C2H2(PPh2)2 23383865 decamethylcobaltocene 23383865 diiron 23383865 diiron hydride 23383865 dppv 23383865 hydride 23383865 hydrido 23383865 hydrogen 23383865 pdt 23383865 phosphine 23383865 phosphines 23383985 P3HT 23383985 PCBM 23384061 Malonic acid 23384061 malonic acid 23384072 N 23384072 N-acetyl 23384072 N-oxanilic acid 23384072 anilines 23384278 PDMS 23384278 aluminum 23384278 polydimethylsiloxane 23384287 1-hydroxy-2-naphthoate 23384287 2,5-dihydroxybenzoate 23384287 Asp 23384287 Fe(II) 23384287 Gly 23384287 Trp 23384287 amino acid 23384287 gentisate 23384287 hydrogen 23384287 salicylate 23384287 salicylates 23384347 C 23384347 Gly 23384347 N 23384347 disulfide 23384447 NO 23384447 alcohol 23384447 ethanol 23384447 glucose 23384447 nitric oxide 23384447 prostacyclin 23384447 sugar 23385033 bleomycin 23385033 cisplatin 23385033 doxorubicin 23385092 1,2,4-triazole 23385092 1,2,4-triazoles 23385092 2,5-dichlorothiophene 23385092 Azole 23385092 C 23385092 H 23385092 N 23385092 benzoxazole 23385092 benzoxazoles 23385092 pyrazole 23385092 triazole 23385876 Cys 23385876 RS-S-SR' 23385876 RS-SO3(2-) 23385876 RS-SR' 23385876 S-sulfocysteine 23385876 SeO3(2-) 23385876 Selenite 23385876 TeO3(2-) 23385876 chalcogen oxyanions 23385876 cysteine 23385876 di- and trisulfide 23385876 disulfides 23385876 selenite 23385876 seleno- and tellurotrisulfides 23385876 selenotrisulfides 23385876 sulfite 23385876 sulfur 23385876 tellurite 23385876 tellurotrisulfides 23385876 transition metal 23385876 transition metals 23385959 F(2)-isoprostane 23385959 Manganese 23385959 Mn 23385959 Trolox 23385959 manganese 23386248 5-FU 23386248 5-fluorouracil 23386248 FOLFIRI 23386248 UDP 23386248 camptosar 23386248 fluorouracil 23386248 folic acid 23386248 irinotecan 23386248 leucovorin 23386387 ZnSnN2 23386394 d-block 23386394 f-block 23386417 Androgen 23386417 androgen 23386483 diterpene 23386483 terpene 23386596 Dexmedetomidine 23386596 alcohol 23386596 dexmedetomidine 23386596 propofol 23386596 γ-aminobutyric acid 23386609 ADP 23386609 Guanine 23386609 Nucleotide 23386609 guanine 23386609 nucleotide 23386703 GF-120918 23386703 apixaban 23386703 charcoal 23387414 Br(-) 23387414 I(-) 23387414 Organothiols 23387414 PVP 23387414 Sodium borohydride 23387414 adenine 23387414 hydride 23387414 organothiols 23387414 poly(N-vinylpyrrolidone) 23387414 rhodamine 23387414 sodium borohydride 23387414 thiophene 23387444 MoS2 23387444 MoSe2 23387444 fullerene 23387444 hydrogen 23387501 12-OH-NVP 23387501 12-OH-NVP sulfate 23387501 3'-phosphoadenosine-5'-phosphosulfate 23387501 NVP 23387501 Nevirapine 23387501 PAPS 23387501 benzylic sulfate 23387501 glutathione 23387501 sulfate 23388040 polyethylene glycol 23389043 8-Oxo-7'8-dihydro-2'-deoxyguanosine 23389043 8-oxo-7'8-dihydro-2'-deoxyguanosine 23389043 8-oxo-dG 23389043 GSH 23389043 GSSG 23389043 MDA 23389043 malondialdehyde 23389043 reduced/oxidized glutathione 23389092 FAD 23389092 ICZ 23389092 ICZ glycosides 23389092 ICZs 23389092 indolocarbazole 23389092 sugar 23391154 Br 23391154 Cl 23391154 I 23391154 N 23391154 N-halamine 23391154 N-halamine polymers 23391154 N-halamines 23391297 P(AA)-b-P(LA) 23391297 poly(acrylic acid)-b-polylactide 23391307 CaFe2O4 23391307 ZnFe2O4 23391363 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide 23391363 MTT 23391363 lovastatin 23391363 nitrogen 23391424 Dammarane Sapogenins 23391424 PPD 23391424 PPT 23391424 dammarane sapogenins 23391424 ginsenosides 23391424 protopanaxadiol 23391424 protopanaxatriol 23391859 131-I 23391859 radioiodine 23394107 Folic acid 23394107 disulfide 23394107 doxorubicin 23394107 folate 23394107 glutathione 23394205 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole 23394205 AZ20 23394205 sulfonylmorpholinopyrimidines 23394402 PDMS 23394402 POSS 23394402 Poly(dimethylsiloxane) 23394402 ammonium 23394402 ethoxy 23394402 methoxy 23394402 nitrogen 23394402 polyhedral oligomeric silsesquioxane 23394702 Platinum 23394702 platinum 23395003 CpG 23395003 lysine 23395155 BH4 23395155 NADPH 23395155 NO 23395155 Nitric oxide 23395155 nebivolol 23395155 oxygen 23395155 resveratrol 23395155 superoxide 23395155 tetrahydrobiopterin 23395163 O 23395163 sugar 23395634 HX0969 23395634 HX0969 disodium phosphate monoester 23395634 HX0969W 23395634 HX101230 23395634 Lusedra 23395634 glycine ester trifluoroacetic acid salt 23395634 propofol 23395653 biotin 23395653 piperidinyl nitrogen 23395653 pyrrole 23395667 glycerol 23395667 polyethylene glycol 23395718 AFB1 23395718 aflatoxin 23395718 aflatoxin B1 23395718 ozone 23395825 1-BP 23395825 1-Bromopropane 23395825 1-bromopropane 23395825 4-HNE 23395825 4-hydroxynonenal 23395825 GSH 23395825 GSSG 23395825 Glutathione 23395825 MDA 23395825 SH 23395825 malondialdehyde 23395825 oxidized glutathione 23395825 ozone 23395825 thiol 23395899 actinomycin D 23395899 α-amanitin 23395915 digoxin 23395915 rifampin 23395915 verapamil 23395916 Steroid hormone 23395916 androgen 23395916 steroid hormone 23396042 C 23396042 N 23396078 Optovin 23396078 cysteine 23396078 optovin 23396090 CDDP 23396090 cisplatin 23396144 CLS 23396144 NO 23396144 PGE2 23396144 buthanol 23396144 clerosterol 23396144 ethylacetate 23396144 methanol 23396144 nitric oxide 23396144 prostaglandin E2 23396419 (-)-Epigallocatechin gallate 23396419 TEA 23396419 cyclosporin A 23396419 digoxin 23396419 dioscin 23396419 diosgenyl 2,4-di-O-a-L-rhamnopyranosyl-p-D-glucopyranoside 23396419 glycyrrhizic acid 23396419 ibuprofen 23396419 p-aminohippurate 23396419 rifampicin 23396419 telmisartan 23396446 arginine 23396446 phenolic 23396446 protocatechuate 23396530 Arylamine 23396530 arylamine 23396530 iodide 23396530 polypyridyl cobalt 23396530 ruthenium(II) 23396530 triiodide 23397052 Dopamine 23397052 dopamine 23397052 methylphenidate 23397052 monoamine 23397052 nisoxetine 23397052 norepinephrine 23397053 Risperidone 23397053 risperidone 23397055 ATP 23397055 Adenosine 23397055 C23H29N7O6.HCl.xH2O 23397055 CGS21680 23397055 CPA 23397055 DOCA 23397055 N(6)-cyclopentyl-adenosine 23397055 adenosine 23397055 deoxycorticosterone acetate 23397055 norepinephrine 23397055 tyrosine 23397359 C(60) (+) 23397359 barium arachidate 23397419 cholesterol 23397419 choline 23397419 esterified cholesterol 23397419 phosphatidylcholine 23397419 sphingomyelins 23397510 estradiol 23397510 estrogen 23397510 steroids 23397510 testosterone 23397572 Lithium 23397572 lithium 23397572 sulfur 23397585 2,3,7,8-tetrachlorodibenzo-p-dioxin 23397585 3-methylcholanthrene 23397585 4-methylbenzylidene-camphor 23397585 Iodothyronine 23397585 aminotriazole 23397585 amiodarone 23397585 cadmium chloride 23397585 dimethoate 23397585 fenvalerate 23397585 iodine 23397585 iodoacetic acid 23397585 iopanoic acid 23397585 methimazole 23397585 methoxychlor 23397585 methylmercury 23397585 octylmethoxycinnamate 23397585 polychlorinated biphenyls 23397585 propylthiouracil 23397585 thyroxine 23397585 β-estradiol 23397966 dexamethasone 23397966 dexamethazone 23397966 lidocaine 23397966 steroid 23397966 steroids 23398143 nitrogen 23398172 Graphene 23398172 graphene 23398311 Au 23398311 L-cysteine 23398311 PMAA 23398311 Rhodamine B 23398311 SiO2 23398311 ferrocenecarboxaldehyde 23398311 methacrylic acid 23398311 silica 23398496 carbohydrates 23398496 glucose 23398658 nickel 23399722 (S)-6-guanidinopurine 23399722 2,9-substituted 6-guanidinopurines 23399722 2-substituted 6-guanidino-9-isopropylpurines 23399722 copper 23399722 guanidino 23399722 olomoucine 23399722 purine 23399722 roscovitine 23399882 2-BFI 23399882 Agmatine 23399882 BU224 23399882 agmatine 23399882 efaroxan 23399882 ethanol 23399882 imidazoline 23399882 moxonidine 23399949 Guanine 23399949 K(+) 23399949 guanine 23399949 nucleobases 23400365 Au 23400365 Au(101) 23400365 Au(n)(PPh(3))(y) 23400365 oxygen 23400365 phosphorous 23400365 titania 23400365 toluene 23400739 Dovitinib 23400739 dovitinib 23400747 AML 23400747 CXM 23400747 LEX 23400747 amlodipine 23400747 cefuroxime axetil 23400747 cephalexin 23400747 β-lactam 23400749 amikacin 23400749 aminoglycosides 23400749 carbapenem 23400749 cefepime 23400749 ceftazidime 23400749 cilastatin 23400749 fluoroquinolones 23400749 imipenem 23400749 levofloxacin 23400749 meropenem 23400749 piperacillin 23400749 tazobactam 23400749 β-lactams 23400845 2-ethylhexyl-2,3,4,5-tetrabromobenzoate 23400845 BEHTBP 23400845 BETHBP 23400845 BTBPE 23400845 DBPE 23400845 EHTeBB 23400845 Firemaster BZ-54 23400845 TBBPA 23400845 bis(2-ethylhexyl)tetrabromophthalate 23400845 bis(tribromophenoxy)ethane 23400845 tetrabromobisphenol A bis(2,3-dibromopropyl ether 23400899 PBDEs 23400899 Polybrominated diphenyl ethers 23400899 pentabrominated diphenyl ethers 23400964 Dabigatran etexilate 23400964 creatinine 23400964 dabigatran etexilate 23400964 warfarin 23401283 darapladib 23401318 Copper Oxide 23401318 Cu 23401318 Cu oxide 23401318 Cu oxides 23401318 Cu(2) O 23401318 CuO 23401318 Si 23401318 copper 23401318 oxygen 23401360 Carbohydrate 23401360 carbohydrate 23401360 β-galactosides 23401373 20(S)-camptothecin 23401373 CB7 23401373 CPT 23401373 NaCl 23401373 camptothecin 23401373 carbonyl 23401373 cucurbit[7]uril 23401373 quinoline nitrogen 23401373 β-cyclodextrin 23401471 2-[(2R)-2-fluoro-3-{(3r)-[(3-fluorobenzyl)oxy]-8-azabicyclo[3.2.1]oct-8-yl}propyl]-4,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one 23401471 E2074 23401471 e2074 23401471 ketoconazole 23401471 sodium 23401473 estradiol-17β-glucuronide 23401473 estrone-3-sulfate 23401473 flavonolignan 23401473 flavonolignans 23401473 rosuvastatin 23401473 silybin A 23401473 silybin B 23401473 silychristin 23402278 1,3-benzothiazin-4-ones 23402278 BTZ043 23402278 BTZs 23402278 Nitroaromatic 23402278 Thiolates 23402278 carbon 23402278 carbons 23402278 cyanide 23402278 cysteine thiol(ate) 23402278 decaprenylphosphoryl-β-D-ribose 23402278 hydride 23402278 nitro 23402278 nitroaromatic 23402278 nitroso 23402278 thiolates 23402300 K(+) 23402300 K-O(2) 23402300 KO(2) 23402300 Li(2)O(2) 23402300 Li-O(2) 23402300 O(2) 23402300 O(2)(-) 23402300 carbon 23402300 metal-oxygen 23402300 oxygen 23402300 potassium 23402300 potassium superoxide 23402371 5(6)-carboxy-2',7'-dichlorofluorescein 23402371 ATP 23402371 CDCF 23402371 MK-571 23402371 benzbromarone 23402432 CD3CN 23402432 CD3OD 23402432 CH3OH 23402432 C═C 23402432 carbonyl 23402432 hydrogen 23402432 m-ABDI 23402432 meta-amino 23402628 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate methanaminium uronium 23402628 HATU 23402628 Tertiary amine 23402628 amide 23402628 dimethylamine N-oxide 23402628 ethyl secondary amide 23402628 hydrogen peroxide 23402628 phosphate 23402628 quartz 23402628 secondary and tertiary linker amides 23402628 tertiary amine 23402628 tertiary amine N-oxides 23402628 thiol 23402628 triethylene glycol 23402628 ω-tertiary amine 23402744 PCB180 23402744 PCB52 23402744 PCB74 23402744 PCB95 23402744 PCBs 23402744 dioxin 23402744 polychlorinated biphenyls 23402744 saccharin 23402744 steroid 23402856 DEN 23402856 HCB 23402856 HEP 23402856 S 23402856 diethylnitrosamine 23402856 glutathione 23402856 heptachlor 23402856 hexachlorobenzene 23402856 organochlorine 23402857 Arsenic 23402857 As 23402857 Cadmium 23402857 Cd 23402857 Pb 23402857 arsenic 23402857 cadmium 23402907 DAG 23402907 Diacylglycerol 23402907 diacylglycerol 23403015 FLT 23403015 GNP 23403015 Genipin 23403015 flutamide 23403085 H2O2 23403085 hydrogen peroxide 23403085 mercaptoethylguanidine 23403085 mercaptoethylleonurine 23403272 GSH 23403272 MDA 23403272 Paeoniflorin 23403272 ZNPP 23403272 glutathione 23403272 heme 23403272 lactate 23403272 malondialdehyde 23403272 oxygen 23403272 superoxide 23403272 zinc protoporphyrin IX 23403471 glucose 23404064 bromocriptine 23404064 dopamine 23404093 Aprepitant 23404093 Olanzapine 23404093 Palonosetron 23404093 Rolapitant 23404093 dexamethasone 23404093 gabapentin 23404093 netupitant 23404093 serotonin 23404373 C 23404373 Lapatinib 23404373 N 23404373 Nitrone 23404373 Nitroso 23404373 Oxime 23404373 alkylamine 23404373 alkylamines 23404373 ferrous 23404373 heme 23404373 hydroxylamine 23404373 iron 23404373 lapatinib 23404373 nitrone 23404373 nitroso 23404373 oxime 23404373 potassium ferricyanide 23404373 primary amine 23404373 primary hydroxylamine 23404373 secondary alkylamine 23404373 secondary hydroxylamine 23404680 BPA 23404680 Bisphenol A 23404680 UDP 23404680 bisphenol A 23404680 sulphate 23404692 lambda-cyhalothrin 23405013 C 23405013 Ser 23405013 alanine 23405013 serine 23405013 tyrosine 23405965 Indolizine 23405965 indolizine 23405984 (1) H 23405984 (13) C 23405984 (15) N 23405984 Pro 23405984 cyclo S(1) ,S(9) Cys-Glu-Thr-Gly-Ala-Lys-Pro-His-Cys 23405984 disulfide 23405988 LAS 23405988 LAS-4 23405988 LAS-6 23405988 linalool 23405988 phenyl ethanol 23405988 sodium dodecyl 6-benezene sulfonate 23406025 Fe (II) 23406025 Fe (III) 23406025 Fe(2+) 23406025 HPO 23406025 gallic acid 23406025 hydrogen peroxide 23406025 oxygen 23406025 polyphenolics 23406025 quinone 23406025 semiquinone 23406315 Anl 23406315 C 23406315 Met 23406315 N 23406315 azidonorleucine 23406315 copper 23406315 methionyl 23406416 Phe 23406416 Tyr 23406484 enamine 23406484 enamines 23406484 imine 23406484 imines 23406484 isopentane 23406484 nitrogen 23406484 tazobactam 23406484 trans-enamine 23406524 amino 23406524 amino acids 23406524 epoxy 23406951 LTC 23406951 Lambda-cyhalothrin 23406951 MDA 23406951 NO 23406951 carbonyl 23406951 lambda-cyhalothrin 23406951 malondialdehyde 23406951 nitrite 23406951 oxygen 23406951 pyrethroid 23406956 17 beta hydroxysteroid 23406956 l-carnitine 23406956 L-carnitine 23406956 MDA 23406956 S 23406956 Triton WR 1339 23406956 Vitamin E 23406956 cholesterol 23406956 glutathione 23406956 ketosteroid 23406956 malondialdehyde 23406956 testosterone 23406956 thiol 23406956 triglycerides 23406956 triton 23406956 vitamin E 23407584 graphene 23407584 graphite 23407783 5-HT 23407783 D-cycloserine 23407783 N-methyl-D-aspartate 23407783 NMDA 23407783 SSR125543 23407783 paroxetine 23408272 Lupenone 23408272 ethyl acetate 23408272 lup-20(29)-en-3-one 23408272 lupenone 23409715 acetyl 23409715 amino acid 23409715 zinc 23409715 ε-N-acetylated lysine 23409721 ATP 23409919 ammonium iodide 23409919 moissanite 23410043 6-Iodouridine 23410043 6-iodouridine 23410043 Uridine 23410043 artemisinin 23410043 azithromycin 23410043 orotidine 5'-monophosphate 23410043 propionyl ester 23410068 4,4'-dibromobiphenyl 23410068 4-bromobenzenediazonium tetrafluoroborate 23410068 ACN 23410068 Au(111) 23410068 BBD 23410068 HClO4 23410068 acetonitrile 23410068 biphenyl 23410068 diazonium 23410126 androgen 23410126 steroid 23410129 androgen 23410153 ATP 23410153 serine 23410153 threonine 23410153 tyrosine 23410161 NMDA 23410161 adenosine 23410161 calcium 23410161 flavonoid 23410161 glitazones 23410161 ladostigil 23410161 monoamine 23410161 rasagiline 23410161 resveratrol 23410161 rivastigmine 23410161 stilbene 23410161 thiazolidinedione 23410161 xanthine 23410191 4-tert-butyl-4'-methoxydibenzoylmethane 23410191 Avobenzone 23410191 acetonitrile 23410191 alcohols 23410191 enol 23410191 keto 23410221 2-chloroethylphosphonic acid 23410221 2-hydroxyethylphosphonate 23410221 HPO3 23410221 Ser 23410221 cyclic oxaphosphetane 23410221 ethephon 23410221 ethylene 23410221 serine 23410250 6-aminonicotinamide 23410250 TCA 23410250 cyanide 23410250 galactose 23410250 glucose 23410250 oxygen 23410250 pentose phosphate 23410250 pyruvate 23410538 nicotine 23410587 cadmium 23410589 Cr (VI) 23410589 MDA 23410589 Ni (II) 23410589 hexavalent chromium 23410589 malondialdehyde 23410589 nickel 23410589 nickel chloride 23410589 oxygen 23410589 potassium dichromate 23410798 1,2,3,4-tetrahydroquinazolin 23410798 1-(prop-2-ynyl)-1'H-spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione 23410798 2-iodoanilides 23410798 C 23410798 C-Cu 23410798 H 23410798 N-indolylmethyl spiroindoline-3,2'-quinazolines 23410798 N-indolylmethyl substituted spiroindoline-3,2'-quinazolines 23410798 NH 23410798 Pd 23410798 amino acid 23410798 benzene 23410798 sulfonyl 23410960 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide 23410960 MTT 23410960 Oil Red O 23410960 salinomycin 23411170 Triton X-100 23411170 sulphadiazine 23411170 trimethoprim 23411171 NO 23411171 acetic acid 23411171 formalin 23411171 glutathione 23411171 superoxide 23411172 polyphenol 23411172 polyphenols 23411172 procyanidin 23411174 Cd 23411174 Cr 23411174 Cu 23411174 Fe 23411174 Mn 23411174 Ni 23411174 Pb 23411174 Zn 23411176 fructose 23411176 glucose 23411176 sugar 23411176 sugars 23411179 polyphenol 23411179 polyphenols 23411187 K 23411187 P 23411187 carbohydrate 23411187 flavonoid 23411187 flavonoids 23411187 phenols 23411190 Hyperforin 23411190 Hypericin 23411190 adhyperforin 23411190 chlorogenic acid 23411190 hyperforin 23411190 hypericin 23411190 pseudohypericin 23411207 DPPH 23411207 Linoleic acid 23411207 NO 23411207 Nitric oxide 23411207 PGE(2) 23411207 acetone 23411207 nitric oxide 23411207 phenolics 23411207 prostaglandin E2 23411207 α-tocopherol 23411218 amino 23411221 niacin 23411221 nicotinamide 23411221 nicotinamide-d(4) 23411221 nicotinic acid 23411221 nicotinic acid-d(4) 23411222 HMG-CoA 23411222 LMN 23411222 limonene 23411222 malondialdehyde 23411222 thymoquinone 23411225 hydroperoxide 23411225 p-Anisidine 23411225 sodium 23411226 Proanthocyanidin 23411226 Proanthocyanidins 23411226 amino acids 23411226 ferulic acid 23411226 phenolic 23411226 phenolic acids 23411226 phenolics 23411226 proanthocyanidins 23411226 tocopherols 23411226 tocotrienols 23411226 vitamin E 23411226 γ-oryzanols 23411228 HTy 23411228 HTy-Et 23411228 Hydroxytyrosyl ethyl ether 23411228 hydroxytyrosol 23411228 hydroxytyrosyl ethyl ether 23411228 polyphenols 23411237 Ethyl carbamate 23411237 copper 23411237 ethyl carbamate 23411237 xanthydrol 23411242 glucose 23411242 hydrogen 23411243 flavan-3-ol 23411243 phenolic 23411243 phenols 23411243 polymeric phenol 23411243 tannin 23411246 Iron 23411246 iron 23411246 iron sulphate 23411246 zinc 23411246 zinc sulphate 23411247 CaCl(2) 23411247 Urea 23411247 calcium 23411247 polyacrylamide 23411254 ETU 23411254 NH(3).H(2)0 23411254 acetonitrile 23411254 ethylenethiourea 23411256 Glu 23411256 His 23411256 amino acid 23411258 3,4-DHPEA-EDA 23411258 Secoiridoid 23411258 decarboxymethyl elenolic acid 23411258 dialdehydic 23411258 fatty acids 23411258 hydroxytyrosol 23411261 Geraniol 23411261 geranial 23411261 geraniol 23411261 geranyl acetate 23411261 nitrogen 23411261 urea 23411262 NaCl 23411262 mannitol 23411264 trypsin 23411264 α-amino 23411267 Glycerol 23411267 amino acid 23411267 glycerol 23411276 (-)-epigallocatechin-3-gallate 23411276 4-methylsulphanyl-3-butenyl isothiocyanates 23411276 Oxygen 23411276 Vitexin-2-O-xyloside 23411276 poly(ADP-ribose) 23411276 raphasatin 23411276 vitexin-2-O-xyloside 23411278 (-)-epicatechin 23411278 A-type procyanidin 23411278 phenolic acids 23411278 procyanidins 23411279 Acetone 23411279 DPPH 23411279 Phenolics 23411279 acetone 23411279 ethanol 23411279 oxygen 23411279 phenolic 23411279 tannins 23411282 phenolic 23411282 phenolics 23411285 lactose 23411291 (12)C 23411291 (13)C 23411291 12C 23411291 13C 23411291 fructose 23411291 glucose 23411291 saccharose 23411291 sugar 23411292 4-hydroxybenzoic acid 23411292 CaCO(3) 23411292 TiO(2) 23411292 TiO2 23411292 calcium carbonate 23411292 lactic acid 23411292 methylene blue 23411292 polyethylene 23411295 fatty acid 23411295 oleic, linoleic, and palmitic acids 23411295 stearic and unsaturated acids 23411298 peroxide 23411298 sulfhydryl 23411302 2,2-diphenyl-1-picrylhydrazyl 23411302 DPPH 23411302 Pro 23411302 Tyr 23411302 Tyr-Pro-Pro-Ala-Lys 23411302 amino acid 23411302 hydroxyl 23411302 linoleic acid 23411302 superoxide 23411304 1(H)-pyrrole 23411304 1(H)-pyrrole-2-carboxaldehyde 23411304 1-hydroxy-2-propanone 23411304 2,3-dimethylpyrazine 23411304 2,5-dimethylpyrazine 23411304 2-methylpyrazine 23411304 5-methyl-(E)-2-hepten-4-one 23411304 5-methylfurfural 23411304 acetic acid 23411304 alkyl-pyrazines 23411304 dihydro-2(3H)-furanone 23411304 furfural 23411304 furfuryl alcohol 23411304 pyrazine 23411304 pyridine 23411308 Methionine sulfone 23411308 cyclolinopeptides J and K 23411308 methionine sulfoxide 23411310 DL-PCBs 23411310 HCB 23411310 PBDEs 23411310 PCDD/Fs 23411310 Polychlorinated dibenzo-p-dioxins and dibenzofurans 23411310 dioxin-like PCBs 23411310 dioxin-like polychlorinated biphenyls 23411310 hexachlorobenzene 23411310 polybrominated diphenyl ethers 23411313 anthocyanin 23411313 phenolic 23411313 tannin 23411319 anthocyanin 23411319 anthocyanins 23411319 cyanidin 23411319 delphinidin 23411319 flavonoid 23411319 flavonoids 23411319 flavonol 23411319 flavonols 23411319 isorhamnetin 23411319 kaempherol 23411319 laricitrin 23411319 malvidin 23411319 myricetin 23411319 peonidin 23411319 petunidin 23411319 quercetin 23411319 syringetin 23411325 bentonites 23411325 lanthanides 23411328 triolein 23411329 Ba(2+) 23411329 Ca(2+) 23411329 Cu(2+) 23411329 EGTA 23411329 Fe(3+) 23411329 GABA 23411329 Gamma-aminobutyric acid 23411329 Glu 23411329 Mg(2+) 23411329 Na(2)EDTA 23411329 amino acid 23411329 amino-acid 23411329 aminoxyacetate 23411329 beta-mercaptoethanol 23411329 glutamate 23411329 glutamic acid 23411329 l-cysteine 23411329 sodium dodecyl sulphate 23411332 SuSo 23411332 sorbitol 23411332 sucrose 23411338 Dicofol 23411338 chlorpyrifos 23411338 ethoprophos 23411338 methidathion 23411338 omethoate 23411338 organophosphorus 23411338 phorate 23411338 pyrethroid 23411339 Ascorbic and lactic acids 23411339 anthocyanin 23411339 ferric 23411339 ferric anthocyanin 23411341 Phenolic 23411341 oleuropein 23411341 phenolic 23411341 polyphenol 23411599 PBO 23411599 TAA 23411599 acetaminophen 23411599 fenbendazole 23411599 methyleugenol 23411599 piperonyl butoxide 23411599 thioacetamide 23411599 α-naphthyl isothiocyanate 23411834 polystyrene 23413358 Adenosine 23413358 adenosine 23414067 (13)C 23414067 Ar 23414067 Chlorocarbonylthio- and isothiocyanate 23414067 ClC(O)NCS 23414067 ClC(O)SCN 23414067 C═O 23414067 He(I) 23414067 SCN 23414067 argon 23414067 syn-ClC(O)SCN 23414099 Au(111) 23414099 BODIPY 23414099 DOPC 23414099 octadecanol 23414292 1,2,3,4-diepoxybutane 23414292 Cys 23414292 DAD 23414292 DEB 23414292 DVSF 23414292 HN2 23414292 diethyl acetylenedicarboxylate 23414292 disulfide 23414292 divinyl sulfone 23414292 mechlorethamine 23414381 amino acid 23414381 amino acids 23414431 2-ketones 23414431 n-acetates 23414431 n-alcohol 23414431 n-alcohols 23414431 n-nitriles 23414804 Ester 23414804 ester 23414804 histidine 23414837 Triazolo and imidazo dihydropyrazolopyrimidine 23414837 Trifluoromethylcyclohexyl N(1) triazole 23414837 amido and benzimidazole dihydropyrazolopyrimidines 23414837 potassium 23414837 triazolo and imidazo dihydropyrazolopyrimidines 23414838 4-fluoroquinuclidine 23414838 4-phenyl-1-(quinuclidin-3-ylmethyl)quinolin-2(1H)-one 23414838 acetylcholine 23414838 quinolone 23414838 quinuclidine 23415228 calcium 23415610 CBG 23415610 CuZn 23415610 DNBS 23415610 Rimonabant 23415610 SR144528 23415610 cannabigerol 23415610 dinitrobenzene sulphonic acid 23415610 nitric oxide 23415610 superoxide 23415904 11-dehydrocorticosterone 23415904 11-keto 23415904 11β-Hydroxysteroid 23415904 7-keto- and 7-hydroxy-oxysterols 23415904 7-oxysterols 23415904 7KC 23415904 7β-hydroxy- and 7-keto-cholesterol 23415904 7βOHC 23415904 NADPH 23415904 cholesterol 23415904 corticosteroid 23415904 corticosterone 23415904 hexose-6-phosphate 23415904 oxysterols 23416002 Amino acid 23416002 amino acid 23416002 quinazolines 23416002 quinazolinones 23416005 Aza-BODIPY 23416005 aza-BODIPY 23416005 thioflavin T 23416039 Lurasidone 23416039 citalopram 23416039 lurasidone 23416039 serotonin 23416130 Dex 23416130 Dexamethasone 23416144 Cysteamine 23416144 HSCH2CH2NH2 23416144 amino thiol 23416144 coenzyme A 23416144 cysteamine 23416144 cystine 23416261 Amikacin 23416261 amikacin 23416261 aminoglycosides 23416261 glutathione 23416261 superoxide 23416647 As 23416647 Co 23416647 Cu 23416647 Fe 23416647 Ni 23416647 Pb 23416647 Se 23416648 GSH 23416648 MDA 23416648 cholesterol 23416648 fatty acid 23416648 glutathione 23416648 glycerol-3-phosphate 23416648 malondialdehyde 23416648 triglycerides 23416700 Ala 23416700 Angiotensin IV 23416700 His 23416700 Ile 23416700 Phe 23416700 Pro 23416700 Tyr 23416700 Val 23416700 Val(1)-Tyr(2)-Ile(3)-His(4)-Pro(5)-Phe(6) 23416700 alanine 23416700 angiotensin IV 23416700 divalinal-Ang IV 23416700 hexapeptide 23416701 phosphate 23416798 DEXA 23416798 Dexamethasone 23416798 creatine 23416798 dexamethasone 23416946 biotinylated trimethylpsoralen 23417424 N 23417652 PCB 23417652 PCBs 23417652 polychlorinated biphenyl 23417894 Aliphatic Poly(urethane-amine) 23417894 CaCO3 23417894 DOX 23417894 PSS 23417894 PUA 23417894 aliphatic poly(urethane-amine) 23417894 hydrogen 23417894 sodium poly(styrene sulfonate) 23417972 BaSnO3 23417972 TiO2 23417972 perovskite 23417972 ternary oxide 23418013 Graphene Oxide 23418013 graphene oxide 23418022 heterocyclic terpenoids 23418022 hopene 23418022 pyrophosphate 23418022 squalene 23418073 Ag 23418073 TiO2 23418073 ZnO 23418073 carbon 23418073 fullerenes 23418368 cholesterol 23418678 Evodiamine 23418678 ammonium formate 23418678 ethyl acetate 23418678 evodiamine 23418678 evodine 23418678 formic acid 23418678 glibenclamide 23418678 methanol 23418678 n-hexane 23418739 ethyl acetate 23418775 3β-(2-methoxy-oxalyloxy)-15α-hydroxy-24-methylene-lanost-8-en-21-oic acid 23418775 3β-(2-methoxy-oxalyloxy)-24-methylene-lanost-8-en-21-oic acid 23418775 triterpenoids 23418898 4-ethylcatechol 23418898 Glechomols A-C 23418898 H(2)O(2) 23418898 ethyl acetate 23418898 glechomols A-C 23418898 norlignans 23419036 DTAB 23419036 SDS 23419036 dodecylammonium bromide 23419036 sodium dodecylsulfate 23419055 methacrylate 23419072 DOX 23419072 Doxorubicin 23419072 LAP 23419072 Laponite 23419072 doxorubicin 23419072 laponite 23419388 17β-estrodiol 23419388 Fulvestrant 23419388 ICI 182,780 23419388 estrogen 23419389 DBP 23419389 Dibutyl phthalate 23419389 dibutyl phthalate 23419389 phthalates 23419484 Tyrosine 23419484 tyrosine 23419536 COOH 23419536 NH2 23419536 PEG 23419536 amino 23419536 cadmium selenide 23419536 carboxyl 23419536 polyethylene glycol 23419536 zinc sulfide 23419834 2',6'-dichloro-5-methoxymethyl-5,6-dehydrokawain 23419834 CO 23419834 NO 23419834 [Ru(CO)3Cl2]2 23419834 heme 23419834 hemin 23419834 kavalactone 23419834 kavalactones 23419834 sulfhydryl 23419834 α,β-unsaturated carbonyl 23420583 Al 23420583 O 23420583 P 23420583 Si 23420583 SiO2 23420583 borosilicate 23420583 citrate 23420583 phosphate 23420583 sulfur 23420664 PEG 23420666 MgSO4 hydrates 23420692 10-Hydroxycamptothecin 23420692 10-hydroxycamptothecin 23420692 DOX 23420692 Doxorubicin 23420692 HCPT 23420692 MPEG-b-PAMAM 23420692 MPEG-b-PAMAM-DOX 23420692 MTT 23420692 doxorubicin 23420692 hydrazone 23420692 methyl thiazolyl tetrazolium 23421589 chalcone 23421589 flavanone 23421589 flavone 23421589 pinostrobin 23421631 carbonyl 23421864 GB-lac 23421864 Ginkgolide B 23421864 carboxylate 23421864 ginkgolide B 23421864 lactone 23421872 2,2,6,6-tetramethyl-1-piperidinyl-1-oxyl 23421872 4-oxo-2,2,6,6-tetramethyl-1-piperidinyl-1-oxyl 23421872 DTBN 23421872 TEMPO 23421872 TEMPONE 23421872 TPP 23421872 di-t-butylnitroxide 23421872 nitroxide 23421872 tris(o-phenylenedioxy)cyclotriphosphazene 23422352 ADP 23422352 biotin 23423573 AMD3100 23423573 NADPH 23423573 palmitate 23423573 streptozotocin 23423713 2,3,7,8-tetrachlorodibenzo-p-dioxin 23423713 TCDD 23423713 V(5+) 23423713 vanadium 23423714 2-naphthylamine 23423714 2NA 23423714 N 23423714 N-Phenyl-2-naphthylamine 23423714 N-phenyl-2-naphthylamine 23423714 P2NA 23424204 (14)C-glucose 23424204 BPA 23424204 bisphenol-A 23424204 epoxy 23424204 glucose 23424204 testosterone 23424214 Artemisinins 23424214 artesunate 23424214 mefloquine 23424216 Rutin 23424216 flavonoids 23424216 hydrogen peroxide 23424216 rutin 23424996 ethyl acetate 23425029 (13)C 23425029 (14)N 23425029 (15)N 23425029 (18)O 23425029 1,3,4-oxadiazole 23425114 7-methoxyflavone 23425114 7MF 23425114 acetic acid 23425114 formalin 23425114 glutamate 23425332 3,4,5-C6H2(OH)3 23425332 3,5-R2-4-C6H2NH2 23425332 Ar2CAr'2 23425332 DOX 23425332 FA-Rh6G-1 23425332 Rh6G 23425332 Tetraarylmethane 23425332 aniline 23425332 doxorubicin 23425332 folic acid 23425332 hydrogen 23425332 iPr 23425332 pyrogallol 23425332 rhodamine 6G 23425332 tetraarylmethane 23426224 CaH2 23426224 CaO 23426224 Fe 23426224 Nd 23426224 Nd(3+) 23426224 Nd-Fe-B 23426224 Nd2Fe14B 23426224 NdxFe1-xB8 23426224 Nd₂Fe₁₄B 23426224 oxide 23426369 Acyl-CoA 23426369 acyl-CoA 23426640 EETs 23426640 Epoxieicosatrienoic acids 23426640 creatinine 23426869 C 23426869 N 23426869 acetyllysine 23426956 3-hydroxy-3-methylglutaryl coenzyme A 23426956 Rapamycin 23426956 Rosuvastatin 23426956 isoprenoid 23426956 rapamycin 23426956 rosuvastatin 23427008 1,2 Ester 23427008 1,2-acyloxy 23427008 1,6-enyne 23427008 All-Carbon 1,6-Enynyl Esters 23427008 Enyne 23427008 PtCl2 23427008 cyclopentenyl 23427008 enol esters 23427019 11-mercaptoundecanols 23427019 ITO 23427019 Pt 23427019 Si 23427019 SiO2 23427042 Cu 23427042 carbon 23427042 copper 23427167 Poly(trimethylene carbonate-co-ε-caprolactone) 23427167 TMC 23427167 trimethylene carbonate 23427167 ε-caprolactone 23427187 FITC 23427187 acetone 23427187 acetonitrile 23427187 ethanol 23427187 fluorescein-isothiocyanate 23427187 glutaraldehyde 23427187 isopropyl alcohol 23427187 methanol 23427814 N,N-diethyl-N-methyl-N-(2-methoxyethyl) ammonium tetrafluoroborate 23427814 [DEME][BF4] 23427996 phenyl 23428306 Cholesterol 23428306 glucose 23428346 3-hydroxy-3-methylglutaryl coenzyme A 23428346 3-nitrotyrosine 23428346 4-hydroxy-2-nonenal 23428346 Atorvastatin 23428346 NADPH 23428346 S 23428346 atorvastatin 23428346 carbonyl 23428346 cholesterol 23428346 glutathione 23428346 nitric oxide 23428346 superoxide 23428346 xanthine 23428385 ADP 23428385 acetylsalicylic acid 23428385 clopidogrel 23428385 prasugrel 23428385 ticagrelor 23428468 Oxysterol 23428468 nitrogen 23428468 phosphatidylinositol-4-phosphate 23428468 phosphoinositide 23428468 rapamycin 23428468 sterol 23429041 DHA 23429041 Dihydroartemisinin 23429041 PGE2 23429041 PMA 23429041 artemisinin 23429041 dihydroartemisinin 23429041 phorbol ester 23429042 17β-estradiol 23429042 BPA 23429042 Bisphenol A 23429042 MPP 23429042 PHTPP 23429042 bisphenol A 23429042 calcium 23429042 estrogen 23429042 estrogens 23429044 Allura Red AC 23429044 Amaranth 23429044 Azorubin 23429044 Brilliant Blue 23429044 Eritrosin 23429044 Indigotin 23429044 N-methyl-D-aspartate 23429044 Ponceau 4R 23429044 Sunset Yellow FCF 23429044 Tartrazin 23429044 acetylcholine 23429061 N-acetyl 23429061 creatinine 23429061 uric acid 23430161 Alcohol 23430161 alcohol 23430162 [(35)S] GTPγS 23430162 ethanol 23430162 morphine 23431112 1-piperazineacetamide, N-[5-(aminocarbonyl) tricyclo[3.3.1.13,7]dec-2-yl]-α,α-dimethyl-4-[5-(trifluoromethyl)-2-pyridinyl] 23431112 11β-Hydroxysteroid 23431112 11β-hydroxysteroid 23431112 A-1331480 23431112 A-847082 23431112 ABT-384 23431112 Ketoconazole 23431112 ketoconazole 23431964 CHCl(3) 23431964 MeOH 23431964 sesquiterpenoids 23432081 H 23432081 H2 23432429 1-acetylpyrene 23432429 1-hydroxypyrene 23432429 1-nitropyrene 23432429 2'-methoxy-5,7-dihydroxyflavone 23432429 2'-methoxyflavone 23432429 2,3-dihydroxy-2,3-dihydrofluoranthene 23432429 2,5,2',5'-tetrachlorobiphenyl 23432429 2-acetylpyrene 23432429 2-ethynylnaphthalene 23432429 2-naphththalene propargyl ether 23432429 3-ethynylphenanthrene 23432429 7-hydroxyflavone 23432429 Coumarin 23432429 acenaphthene 23432429 acenaphthylene 23432429 benzo[c]phenanthrene 23432429 biphenyl 23432429 chrysin 23432429 flavanone 23432429 flavone 23432429 fluoranthene 23432429 galangin 23432429 iron 23432429 naphthalene 23432429 phenanthrene 23432429 pyrene 23432591 ATP 23432591 polyphenols 23432683 MoS2 23432683 TMDs 23432683 WSe2 23432683 transition metal dichalcogenides 23433811 6,4 pyrimidine-pyrimidone 23433811 6-4PP 23433811 BPDE 23433811 benzo(a)pyrene-trans-7,8-dihydrodiol-9,10-epoxide 23433811 nucleotide 23434029 1-aryl-4-acylpyridinyl imidazoles 23434029 5-aryl-3-acylpyridinyl-pyrazoles 23434029 pyrazole/imidazole amides 23434418 2,6 dichlorophenyl 23434418 4 fluorophenyl 23434418 4,5,6,7-tetrahydro-6-((5-substituted-1,3,4-oxadiazol-2-yl)methyl)thieno[2,3-c]pyridine 23434418 TiO(2) 23434418 TiO2 23434418 ZnO 23434418 ampicillin 23434418 ciprofloxacin 23434418 miconazole 23434418 thiophene 23434418 titanium dioxide 23434418 zinc oxide 23434419 guanide 23434419 naphthylguanide 23434419 polyamines 23434419 spermidine 23434419 spermine 23434419 spermine and spermidine phenylguanides 23434419 spermine tris-1-naphthylguanide 23434639 linezolid 23434639 oxazolidino-sulfonamides 23434640 3-aryl acrylic amide 23434640 3-thiophenyl acrylic amide 23434640 ecteinascidin 23434640 l-dopa 23434640 saframycin 23434647 phalloidin 23434833 acyl 23435124 FeSO4 23435124 Iron 23435124 glutathione 23435124 iron 23435124 oxygen 23435180 PFOA 23435180 perfluorooctanoic acid 23435216 Cuprate 23435216 La1.84Sr0.16CuO4 23435216 La1.9Sr0.1CuO4 23435216 cuprate 23435216 cuprates 23435353 4-DAMP 23435353 4-aminopyridine 23435353 DAU-5884 23435353 K(+) 23435357 nucleotide 23435357 tyrosine 23435674 KCl 23435674 PTCDA 23435674 perylene-3,4,9,10-tetracarboxyl acid dianhydride 23435687 2-PAM 23435687 chlorpyrifos 23435687 organophosphorus 23435687 pralidoxime 23435944 Macelignan 23435944 macelignan 23435964 CoPP 23435964 Cobalt-protoporphyrin 23435964 heme 23436254 KOH 23436254 carbon 23436258 Laninamivir 23436258 Oseltamivir 23436258 Oseltamivir carboxylate 23436258 Peramivir 23436258 Zanamivir 23436258 carboxylate 23436258 oseltamivir 23436258 oseltamivir carboxylate 23436258 peramivir 23436258 probenecid 23436258 zanamivir 23436267 BMS-690514 23436267 ketoconazole 23436267 tyrosine 23436305 organophosphate 23436305 organophosphates 23436305 organophosphorous 23436492 promethazine 23436492 sugar 23436571 HDT 23436571 PDMS 23436571 PEG 23436571 hexadecanethiol 23436571 poly(dimethylsiloxane) 23436571 polyethylene glycol 23436650 4-cyano-3-(trifluoromethyl)phenyl 23436650 MDV3100 23436650 androgen 23436650 androgens 23436650 bicalutamide 23436650 hydroxyflutamide 23436656 5-aza-29-deoxycytidine 23436656 Bisulfite 23436656 CpG 23436656 Sulfate 23436656 cyclophosphamide 23436656 docetaxel 23436656 oxygen 23436656 propidium iodide 23436706 3,4-diarylpyrazoles 23436706 3-methoxy-6-[4-(3,4,5-trimethoxyphenyl)-1H-pyrazol-3-yl]benzene-1,2-diol 23436706 CA1 23436706 CA4 23436706 Combretastatin A1 23436706 colchicine 23436706 combretastatin A1 23436706 combretastatin A4 23436706 combretastatins 23436706 ortho-quinone 23436706 pyrazole 23436749 PBDEs 23436749 carbon 23436749 hydroxyl 23436749 polybrominated diphenyl ethers 23437929 Al(3+) 23437929 Ba(2+) 23437929 Ca(2+) 23437929 CnDMAO 23437929 Eu(3+) 23437929 Fe(3+) 23437929 La(3+) 23437929 Tb(3+) 23437929 Zn(2+) 23437929 alkyldimethylamine oxide 23437929 fluorocarbon 23437929 hydrocarbon 23437929 hydrocarbons 23438015 Bi2(Te,Se)2(Se,S) 23438015 Kawazulite 23438015 diamond 23438015 graphene 23438015 graphite 23438077 CTAB 23438077 PAAm 23438077 PEI 23438077 SDS 23438077 TMOS 23438077 hexadecyltrimethylammonium bromide 23438077 polyacrylamide 23438077 polyethylenimine 23438077 silica 23438077 sodium dodecyl sulfate 23438471 aryl hydrocarbon 23438501 cocaine 23439383 AMPA 23439383 NMDA 23439661 (S)-3-(Aminomethyl)-7-(3-hydroxypropoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole 23439661 4-methylpyrazole 23439661 Boron 23439661 GSK2251052 23439661 [(14)C]GSK2251052 23439661 alcohol 23439661 aldehyde 23439661 boron 23439661 carboxylic acid 23439661 leucyl 23439661 propanol 23439872 adenosyl 23439872 carbon 23439872 choline 23439872 cystathionine 23439872 folate 23439872 methionine 23439872 methylenetetrahydrofolate 23440001 2F 23440001 2F(-) 23440001 F 23440001 F-Ti 23440001 Fluorine 23440001 NH4F 23440001 SiO3 23440001 SiO4 23440001 Ti 23440001 alkali chlorides 23440001 ammonium fluoride 23440001 fluorine 23440001 titanosilicate 23440001 zeolite 23440015 Au 23440581 Si 23440581 conduritol F 23440867 afatanib 23440867 dacomitinib 23440867 erlotinib 23440867 gefitinib 23440867 lapatinib 23440867 phosphatidylinositol 23440867 rapamycin 23440867 sorafenib 23440867 sunitinib 23440867 tyrosine 23440867 vandetanib 23440918 C 23440918 Ser 23440918 Serine 23440918 amino acids 23440918 enamide 23440918 nosiheptide 23440918 serine 23440928 Carnosine 23440928 H 23440928 carnosine 23440928 dipeptide 23440928 heptapeptide 23440928 hydrogen 23440928 thioflavin T 23440974 Oxide 23440974 copper 23440974 oxide 23441007 MoS2 23441007 Si 23441007 SiO2 23441649 ampelopsin F 23441649 pallidol 23441649 stilbenoid 23441649 viniferin 23441904 bile acids 23441904 bile salts 23441904 bile salts/acids 23441904 cyclohexane 23441904 hydrogen 23441904 n-decane 23443358 sugar 23443488 amines 23443753 pazopanib 23443753 sorafenib 23443810 creatine 23444015 2-methyl-6-(phenylethynyl)-pyridine 23444015 Glutamate 23444015 acetylene 23444015 amino acids 23444015 glutamate 23444138 estrogen 23444138 steroid 23444282 Busulfan 23444282 busulfan 23444286 Diclectin 23444286 PLP 23444286 doxylamine 23444286 pyridoxal 5'-phosphate 23444286 pyridoxine 23444286 vitamin B(6) 23444300 1,3-phenylene 23444300 1,8 naphthaleneimide 23444300 CC 23444300 NIE 23444300 Zn 23444300 ZnP 23444300 corrole 23444300 imide 23444300 meso-substituted A3 B-porphyrin 23444300 meso-substituted corrole 23444300 porphyrin 23444300 porphyrin-imide-corrole 23444300 trans-A2 B-corrole 23444334 BHT 23444334 Fe-NTA 23444334 [(3)H] thymidine 23444334 butylated hydroxyl toluene 23444334 butylated hydroxytoluene 23444334 carbonyl 23444334 ferric nitrilotriacetate 23444334 ornithine 23444336 calcein 23444336 inositol 23444774 diclofenac 23444774 methanol 23444774 phosphoric acid 23444774 rhein 23444775 sibutramine 23444776 Phenacetin 23444776 acetonitrile 23444776 chlorzoxazone 23444776 coumarin 23444776 phenacetin 23444776 phosphoric acid 23444776 testosterone 23444776 tolbutamide 23444960 2,2',7,7'-tetrakis(N,N-di-p-methoxyphenylamine)-9,9'-spirobifluorene 23444960 TiO2 23444960 ZrO2 23444960 spiro-MeOTAD 23444962 doxorubicin 23444962 reduced glutathione 23444962 thiobarbituric-acid 23444963 cholesterol 23444963 glucose 23444964 corticosterone 23444964 eicosanoid 23444964 linalool 23444964 omega-3 fatty acids 23445346 DDM 23445346 LDAO 23445346 dodecyl-β-D-maltoside 23445346 lauryldimethylamine N-oxide 23445522 Almiramide 23445522 Almiramide C 23445522 almiramide C 23445522 almiramides 23445562 estrogen 23445562 progesterone 23446434 ZnO 23446650 2-hydrazino-pyrido[2,3-d]pyrimidin-4(3H)-one 23446650 7-(4-bromophenyl)-1,2-dihydro-5-(4-fluorophenyl)-2-thioxopyrido[2,3-d] pyrimidin-4(3H)-one 23446650 aldehydes 23446650 hydrazonoyl chlorides 23446650 pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-one 23446650 pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones 23448129 (-)OCl 23448129 GSH 23448129 GSHs 23448129 Glutathione 23448129 H2O2 23448129 NO· 23448129 O2(-) 23448129 glutathione 23448129 glutathione disulfides 23448129 nitrogen 23448129 oxygen 23448129 ·OH 23448165 Cu 23448165 SiC 23448165 carbon 23448165 graphene 23448281 2-(phosphonoethoxy)ethylguanine 23448281 5'-phosphate 23448281 6-oxopurine 23448281 ANP 23448281 ANPs 23448281 Acyclic nucleoside phosphonates 23448281 PEEG 23448281 phosphonate 23448281 purine 23448281 pyrophosphate 23448281 {[(2-[(Guanine-9H-yl)methyl]propane-1,3-diyl)bis(oxy)]bis(methylene)}diphosphonic acid 23448346 17β-estradiol 23448346 Estrogen 23448346 ICI-182,780 23448346 estrogen 23449200 acetaminophen 23449200 indomethacin 23449200 tri-O-methyl-β-cyclodextrin 23449203 Gaster 23449203 Primperan 23449203 Ropion 23449203 famotidine 23449203 flurbiprofen axetil 23449203 metoclopramide hydrochloride 23449501 Ca(2+) 23449501 Ca2+ 23449501 K(+) 23449501 K+ 23449501 N 23449501 Potassium 23450708 carboxyl 23450708 oligothiophenes 23450708 thiophene 23450741 hydrogen 23450741 shikimic acid 23450827 Levonorgestrel 23450827 levonorgestrel 23451853 1-dodecene 23451853 10-bromo-1-decene 23451853 HF 23451853 Si 23451853 Si-H 23451853 dodecyl 23451853 hydrogen 23451853 hydrogen fluoride 23451853 octane 23451853 rhodamine 23451853 silicon 23451853 silicon oxide 23452230 alkanes 23452230 n-Pentane 23452230 n-pentane 23452271 3,4-dihydroxyphenylalanine 23452271 Dopa 23452271 Ti 23452271 TiO2 23452271 Titanium 23452271 metal oxides 23452431 Oxygen 23452431 oxygen 23452502 fatty acid 23452502 glucose 23453305 2,4,6-trinitrobenzenesulfonic acid 23453305 Ectoine 23453305 ectoine 23453305 glutathione 23453305 malondialdehyde 23453305 sulfasalazine 23453305 tetrahydropyrimidine 23453306 myrcene 23453306 p-cymene 23453306 thymol 23453306 γ-terpinene 23454002 cortisol 23454002 progesterone 23454016 2-amino-4-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-6-aryl-4H-pyran-3-carbonitrile 23454016 2-amino-4-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-6-aryl-4H-pyran-3-carbonitriles 23454016 4,5-diamino-6-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-8-aryl-2-oxo-2,6-dihydrodipyrano [2,3-b:3,2-e]pyridine-3-carbonitriles 23454016 4-(5'-subtituted 2'-phenyl-1H-indol-3'-yl)-6-aryl-1,4-dihydropyrano[2,3-c]pyrazol-3-amines 23454016 4-amino-5-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-7-aryl-1H-pyrano[2,3-d]pyrimidin-2(5H)-thiones 23454016 4-amino-5-(5'-substituted 2'-phenyl-1H-indol-3-yl)-7-aryl-1H-pyrano[2,3-d]pyrimidin-2(5H)-ones 23454016 5-(5'-substituted 2'-phenyl-1H-indol-3'-yl)-7-aryl-3H-pyrano[2,3-d]pyrimidin-4(5H)-ones 23454016 Fe(3+) 23454016 ferric 23454016 indole 23454135 1,5-diarylpyrrole-3-alkoxyethyl esters and ethers 23454135 1,5-diarylpyrrole-3-alkoxyethyl ethers 23454135 VA428 23454135 VA441 23454135 celecoxib 23454135 diaryl heterocycles 23454135 rofecoxib 23454144 oxygen 23454145 7-ketocholesterol 23454145 7-ketosterol 23454145 7-ketosterols 23454145 7-ketostigmasterol 23454145 Ca 23454145 HMG-CoA 23454145 HMGCoA 23454145 bradykinin 23454145 cholesterol 23454145 cholesterol oxides 23454145 phytosterol oxides 23454145 sterol 23454145 stigmasterol 23454146 2,2-diphenyl-1-picrylhydrazyl 23454146 N 23454146 Obovatol 23454146 glutamate 23454146 honokiol 23454146 magnolol 23454146 neolignans 23454146 obovatol 23454146 oxygen 23454149 6,6'-bis (2,3-dimethoxybenzoyl)-a,a-d-trehalose 23454149 DMBT 23454149 MTT 23454149 brartemicin 23454202 Curcumin 23454202 GSH 23454202 curcumin 23454202 glutathione 23454202 nitrite 23454202 superoxide 23454217 11oxo 23454217 11oxo-pregnane(enes) 23454217 11oxo-pregnanes 23454217 11oxo-pregnanetriol 23454217 11oxo-pregnenes 23454217 17-hydroxyprogesterone 23454217 21-deoxycortisol 23454217 21-deoxycortisone 23454217 6-hydroxyl 23454217 C 23454217 Cortisol 23454217 Steroids 23454217 cortisone 23454217 methyloxime-trimethylsilyl ether 23454217 pregnane(ene)s 23454217 steroid 23454217 steroids 23454417 NO 23454417 Peroxynitrite 23454417 glucose 23454417 nitric oxide 23454417 peroxynitrite 23454417 superoxide 23454527 N 23454527 N-acetylcysteine 23454527 NAC 23454527 SP600125 23454528 MK801 23454528 N-methyl-d-aspartate 23454528 SHA 68 23454528 scopolamine 23454653 (13)C 23454653 2-methoxy-4-(¹³C)methylphenol 23454653 2-methoxy-4-methylphenol 23454653 2M4MP 23454653 2M4MQ 23454653 Amino 23454653 Cys 23454653 GSH 23454653 H2O 23454653 H2O2 23454653 acetonitrile 23454653 alcohol 23454653 arginine 23454653 benzylic hydroperoxide 23454653 chloroform 23454653 cysteine 23454653 hydrogen peroxide 23454653 lysine 23454653 sodium dodecyl sulfate 23454653 tert-butanol 23454653 thio 23454653 thiol 23454828 N- and S-oxide 23454828 alcohol 23454828 amine 23454828 arenol 23454828 carboxylic acid 23454828 phenol 23454828 terfenadine 23454835 AOH 23454835 Alternariol 23454835 alternariol 23454895 CPT 23454895 GO-PDEA 23454895 GO-PDEA-CPT 23454895 Graphene oxide 23454895 PDEA 23454895 PDEA-grafted GO 23454895 camptothecin 23454895 graphene oxide 23454895 poly(2-(diethylamino) ethyl methacrylate) 23455039 amino-acid 23455039 benzene 23455039 hydroxyl 23455039 tyrosine 23455323 serine 23455323 tyrosine 23455461 Ag 23455461 silver 23455597 ABT-288 23455597 Histamine 23455597 amphetamine 23455597 cocaine 23455597 d-amphetamine 23455597 histamine 23455732 silicon 23456175 Ag 23456175 Na 23456175 ZnO 23456813 carmine 23457020 1H 23457020 2,7-diaminooctan-1,8-dioic acid 23457020 N-methyl-α-alanine 23457020 N-methyl-β-alanine 23457020 amino acids 23457020 monofluoroacetate 23457020 trigonelline 23457090 Ag 23457090 Au 23457090 Au-Ag 23457090 HAuCl4 23457090 Silver 23457090 ascorbic acid 23457122 BPA 23457122 Bisphenol A 23457122 bisphenol a 23457122 estrogen 23457122 ethinyl estradiol 23458445 EDTA 23458445 EDTAD 23458445 ethylenediaminetetraacetic Acid 23458445 ethylenediaminetetraacetic acid 23458445 ethylenediaminetetraacetic dianhydride 23458455 Cd(2+) 23458455 Cd0.21Hg0.79Te 23458455 CdHgTe 23458455 HTe(-) 23458455 Hg(2+) 23458455 cadmium 23458473 dimethyl sulfoxide 23458473 dimethylformamide 23458473 epichlorohydrin 23458473 ethylene oxide 23458473 hydrogen 23458473 hydroxyl 23458473 phosphoric Acid 23458473 phosphoric acid 23458581 Gly 23458581 amino acids 23458967 thiols 23459067 Pt(0) Karstedt catalyst 23459067 alkoxy 23459067 n-eicosane 23459067 paraffin 23459067 polyhydromethylsiloxane 23459067 polysiloxane 23459067 silanol 23459067 siloxane 23459067 silylvinyl 23459109 TMS 23459109 carbon 23459109 nitrogen 23459109 oxygen 23459109 telmisartan 23459149 melamine 23459149 uric acid 23459167 aldehyde 23459167 amphetamine 23459167 creatine 23459167 methamphetamine 23459442 Met 23459442 O 23459442 Val 23459442 catechol 23459442 methionine 23459442 nicotine 23459442 valine 23460310 Lipofectamine 2000 23460310 arginine 23460310 leucine 23460363 PGA 23460363 Polyglutamic Acid 23460363 folate 23460363 polyglutamic acid 23460404 His 23460404 Ni(II)-NTA 23460404 Ni(II)-nitrilo(triacetic acid) 23460404 Ni-NTA-DG 23460404 Poly(ethylene imine) 23460404 imidazole 23460404 poly(ethylene imine)-maltose 23460473 1,5-dichloroanthraquinone 23460473 Au(111) 23460473 Br 23460473 Cl 23460473 H 23460473 I 23460473 O 23460473 au(111) 23460473 cl 23460473 h 23460473 halogen 23460473 hydrogen 23460473 o 23461378 estrone-3-sulfate 23461378 lopinavir 23461378 olmesartan 23461378 pitavastatin 23461378 rosuvastatin 23461378 valsartan 23461585 Mg(2+) 23461585 Mg(x)Zn(1-x)O 23461585 Mg2+ 23461585 MgAc 23461585 PVA 23461585 Zn(2+) 23461585 ZnAc 23461585 ZnO 23461585 magnesium acetate 23461585 poly(vinyl alcohol) 23461585 zinc acetate 23461648 C 23461648 Fengycin C 23461648 Glu-Orn-Tyr-Thr-Glu-Val-Pro-Gln-Thr-Ile 23461648 N 23461648 acyl 23461648 amino acid 23461648 carbons 23461648 cyclic lactone 23461648 decapeptide 23461648 fengycin 23461648 fengycin A 23461648 fengycin B 23461648 fengycin C 23461648 tyrosine 23461648 β-hydroxy fatty acyl 23461806 oxygen 23461806 tyrosine 23462211 (1)H 23462211 13-hydroxy-5(10),14-halimadien-6-one 23462211 6α,7α-diacetoxy-13-hydroxy-8(9),14-labdadien 23462211 9-hydroxy-13(14)-labden-15,16-olide 23462211 diterpenoid 23462211 diterpenoids 23462211 halimane diterpenoid 23462211 hexane 23462211 isoambreinolide 23462211 labdane diterpenoids 23462233 Aldehyde 23462233 IMI 23462233 hydralazine 23462233 imidacloprid 23462233 neonicotinoid 23462233 neonicotinoids 23462233 nitroimino 23462233 nitrosoguanidine 23462233 tungsten 23462381 Fluo-4 23462381 calcium 23462381 ceramide 1-phosphate 23462381 choline 23462381 lysophosphatidic acid 23462381 lysophosphatidylcholine 23462381 phosphatidylcholine 23462381 sphingomyelin 23462506 amino acid 23462506 arginine 23462506 bile salt 23462506 farnesyl 23462506 lysine 23462506 retinoid 23462569 (1)H 23462569 ADP 23462569 GABA 23462569 Glutathione 23462569 Homocysteic acid 23462569 MAP 23462569 N-Acetyl-aspartate 23462569 Tricarboxylic acid 23462569 acetylcysteine 23462569 citrate 23462569 dopamine 23462569 glutamate 23462569 glutamine 23462569 methamphetamine 23462569 methionine 23462569 myo-inositol 23462569 phosphocholine 23462569 serotonin 23462569 succinate 23462569 succinic acid semialdehyde 23462569 taurine 23462569 α-ketoglutarate 23462698 Alcohol 23462698 alcohol 23462698 pregnane 23462812 Co3O4 23462812 carbon 23462812 lithium 23462886 MSDC-0160 23462886 glucose 23462886 pioglitazone 23462886 pioglitazone HCl 23462886 thiazolidinediones 23463253 10-(3-sulfopropyl)acridinium betaine 23463253 6-methoxy-N-(3-sulfopropyl)quinolinium 23463253 SAB 23463253 SPQ 23463696 N 23463696 ZnO 23463696 ZnS 23463696 carbon 23463696 graphene 23463696 graphite 23464637 polyacrylonitrile 23464650 InAs 23464650 InAs1-xSbx 23464650 InAsSb 23464650 Sb 23464650 Si 23464759 graphite 23464759 mica 23464881 10,12-pentacosadiynoic acid 23464881 Graphene 23464881 Oxide 23464881 PCDA 23464881 alumina 23464881 graphene 23464881 oxide 23464881 zinc oxide 23465061 Ciliatamide A 23465061 Ciliatamide D 23465061 N-Me-Met(O) 23465061 N-Me-Phe 23465061 amino acids 23465061 ciliatamide A 23465061 ciliatamide D 23465613 H(2)O(2) 23465613 K(+) 23465613 disulfide 23465613 hemin 23465613 luminol 23465614 (5S)-hydroxy-1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl)-hepta-1E-en-3-one 23465614 diarylheptanoid 23465614 diarylheptanoids 23465614 methanol 23465614 platyphyllonol-5-O-β-d-xylopyranoside 23465614 troglitazone 23466420 Camptosar 23466420 Camptothecin 23466420 Gimatecan 23466420 Hycantim 23466420 SN-38 23466420 ST1481 23466420 camptothecin 23466420 gimatecan 23466420 irinotecan 23466420 topotecan 23468189 Benzenesulfonamides 23468189 aryl sulfonamides 23468189 benzenesulfonamides 23468458 Hydrogen 23468458 hydrogen 23468458 vanadia 23469681 4-carboxy 23469681 4-hydroxy 23469681 4-sulphonate 23469681 4-trimethylanilinium 23469681 Porphyrin 23469681 Tween 80 23469681 meso-porphyrin 23469681 meso-tetraphenyl porphyrin 23469681 porphyrin 23469681 porphyrins 23469757 1,8-diaminooctane 23469757 Boronic Acid Ester 23469757 Folate 23469757 PBA 23469757 PMAA 23469757 POEGMEMA26-b-PMAA90 23469757 POEGMEMA35-b-PMAA200 23469757 Platinum 23469757 borate ester 23469757 dopamine 23469757 folate 23469757 folic acid 23469757 methyl acrylic acid 23469757 oligoethylene glycol methylether methacylate 23469757 oxoplatin 23469757 phenylboronic acid 23469757 platinum 23469759 Gd 23469759 Gd(III) 23469759 glutamic acid 23470011 1α-acetoxy-8α,9β-dihydroxy-2-oxo-eudesman-3,7(11)-dien-8,12-olide 23470011 1α-acetoxy-8α-hydroxy-2-oxo-eudesman-3,7(11)-dien-8,12-olide 23470011 4',5,7-trihydroxy-6-methoxyflavone 23470011 eudesmanolide 23470011 flavone 23470011 sesquiterpene lactone 23470073 bosentan 23470077 ADMA 23470077 Asymmetric Dimethylarginine 23470077 NO 23470077 arginine 23470077 dimethylarginine 23470077 nitric oxide 23470196 FITC 23470196 TGA 23470196 carboxy-methyl 23470196 fluorescein isothiocyanate 23470196 thioglycolic Acid 23470196 thioglycolic acid 23470196 trimethyl 23470204 Ag 23470204 CaCO3 23470204 PAH 23470204 calcium carbonate 23470204 carbonate 23470204 fullerene 23470204 polyallylamine hydrochloride 23470204 polylactide 23470204 polyvinyl alcohol 23470204 silver 23470325 calcium 23470776 nucleotide 23470776 oxytocin 23470866 NSC 109555 ditosylate 23470866 Oroxylin A 23470866 monoflavonoid 23470866 oroxylin A 23471121 MPH 23471121 methylphenidate 23471352 8-hydroxydeoxyguanosine 23471352 Arsenic trioxide 23471352 As2O3 23471352 Resveratrol 23471352 arsenic 23471352 arsenic trioxide 23471352 creatinine 23471352 glutathione 23471352 malondialdehyde 23471352 methylated arsenic 23471352 nitrogen 23471352 oxidized glutathione 23471352 oxygen 23471352 polyphenolic 23471352 resveratrol 23471352 superoxide 23471352 urea 23471540 Cys 23471540 His 23471540 zinc 23471741 Cobicistat 23471741 Ritonavir 23471741 cobicistat 23471741 elvitegravir 23471741 emtricitabine 23471741 ritonavir 23471741 tenofovir 23471964 CYSTEINE 23471964 Oxygen 23471964 cysteine 23471964 cysteine thiols 23471964 oxygen 23471964 sulfenic acid 23472655 iodine 23472655 sodium 23472655 thyroid hormone 23473032 [(1-13)C]glutamine 23473032 acetate 23473032 citrate 23473032 glutamine 23473032 α-ketoglutarate 23473036 fatty acid 23473268 Au(III) 23473268 HAuCl4 23473372 Si2H6BH3 23473581 1-butanol 23473581 1-decyl-3-methyl-imidazolium bis(trifluoromethylsulfonyl)imide 23473581 1-decyl-3-methyl-imidazolium tetracyanoborate 23473581 4-decyl-4-methyl-morpholinium bis(trifluoromethylsulfonyl)imide 23473581 4-decyl-4-methyl-morpholinium tetracyanoborate 23473581 ntf2 23473581 tcb 23473803 angiotensin 23473803 cAMP 23473803 cyclic 3'5' adenosine monophosphate 23473803 cyclic nucleotide 23473803 forskolin 23473803 moexipril 23473803 nucleotide 23473805 ATP 23473805 Rp1 23473805 actinomycin D 23473805 cholesterol 23473805 doxorubicin 23473805 ginsenoside 23473805 ginsenosides 23473805 rhodamine 123 23473805 sphingolipid 23474029 PEG 23474029 calcium 23474029 doxorubicin 23474029 phosphate 23474029 poly(ethylene glycol) 23474171 5-aza-2'-deoxycytidine 23474171 5AzadC 23474171 TSA 23474171 progesterone 23474171 trichostatin A 23474269 Suramin 23474269 polysulfonated naphthylurea 23474269 suramin 23474317 FLX 23474317 fluoxetine 23474317 serotonin 23474318 carbohydrates 23474318 glyphosate 23474318 oxygen 23474318 superoxide 23474324 Cd 23474324 cadmium 23474589 glucose 23474593 Mn 23474593 Mn-doped Si 23474593 Si14 23474593 Si14(+) 23474593 Si14+ 23474593 fullerene- 23474593 silicon 23474889 EtOH 23474889 R-(alpha)-methyl-histamine 23474889 alcohol 23474889 ethanol 23474889 histamine 23474889 quinine 23474889 saccharin 23475371 ADR 23475371 ATP 23475371 Adriamycin 23475371 Potassium 23475371 Se 23475371 Selenium 23475371 adriamycin 23475371 glutathione 23475371 potassium 23475371 selenium 23475431 digoxin 23475431 warfarin 23476712 adenine 23476712 thymine 23477486 Ca(2+) 23477486 Cu(2+) 23477486 Fe(3+) 23477486 K(+) 23477486 Na(+) 23477486 ca(2+) 23477486 cu(2+) 23477486 fe(3+) 23477486 iron oxide 23477486 k(+) 23477486 na(+) 23477504 19-hydroxy steroidal glycosides 23477504 Steroids 23477504 d- and l-Arabinoses 23477504 d- and l-arabinoses 23477504 junceelloside C 23477504 junceellosides E-G 23477504 sugar 23477504 thiocarbamoyl-thiazolidine 23477504 β-l- and β-d-arabinopyranoses 23477504 β-l-arabinopyranose 23477570 1,4-butanediamine 23477570 DTT 23477570 FITC 23477570 MTT 23477570 PEG-P(HEMA-co-AC) 23477570 cyclic carbonate 23477570 cystamine 23477570 disulfide 23477570 dithiothreitol 23477570 phosphate 23477570 poly(ethylene glycol)-b-poly(2-(hydroxyethyl) methacrylate-co-acryloyl carbonate) 23478260 Ala 23478260 Gly 23478260 amino acid 23478437 NAD+ 23478437 amino acid 23478437 ferrous iron 23478437 serine 23478437 threonine 23479080 AAP 23479080 Acetaminophen 23479080 N-acetyl-p-benzoquinone-imine 23479080 N-nitrosodiethylamine 23479080 acetaminophen 23479080 glutathione 23479080 phenobarbital 23479280 NO2 23479280 NO3 (-) 23479280 chlorine 23479280 hydrazine 23479280 oxygen 23479391 3-Arylcoumarin 23479391 3-arylcoumarin 23479391 Flavonoids 23479391 isoflavonoids 23479391 pterosonins A-F 23479408 cholesterol 23479408 fatty acid 23479408 fibrates 23479408 nicotinic acid 23479408 triglyceride 23479408 triglycerides 23479733 C 23479733 Gal 23479733 Gal-β1,3-GlcNAc 23479733 Gal-β1,3-GlcNAc-thiazoline 23479733 GlcNAc 23479733 LNB 23479733 LNB-thiazoline 23479733 N 23479733 hydrogen 23479733 hydroxyls 23479733 lacto-N-biose I 23479733 monosaccharide 23479733 sugar 23479733 thiazoline 23480170 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine 23480170 DPPC 23480170 O3 23480170 OH 23480170 Ozone 23480170 POPC 23480170 dipalmitoyl-sn-glycero-3-phosphocholine 23480170 oleoyl 23480170 ozone 23480170 palmitoyl 23480174 1-butyl-3-methylimidazolium 23480174 Lithium 23480174 NaPF6 23480174 [BF4](-) 23480174 [BMIM](+) 23480174 [BMIM][PF6] 23480174 [Li](+) 23480174 [NTf2](-) 23480174 [Na](+) 23480174 [PF6](-) 23480174 alkaline salts 23480174 bis(trifluoromethylsulfonyl)imide 23480174 hexafluorophosphate 23480174 imidazolium 23480174 lithium 23480174 sodium 23480174 tetrafluoroborate 23480625 Ketamine 23480625 ketamine 23480726 Oregon Green 488 23480726 paclitaxel 23481635 guanines 23481641 3-hydroxy-3-methylglutaryl-coenzyme A 23481641 CoA 23481641 HMG 23481641 MTT 23481641 SIM 23481641 Simvastatin 23481648 1,6-diphenylnaphthalenes 23481648 1-phenylbenzo[c]phenanthridines 23481648 6-phenylnaphthalene 23481648 Diphenylnaphthalene 23481648 quaternary ammonium 23482393 5-hydroxymethylcytosine 23482393 5-methylcytosine 23482393 5-α-glucosylated hmC 23482393 5-β-glucosylated hmC 23482393 5hmC 23482393 5mC 23482393 5αghmC 23482393 5βghmC 23482393 cytosine 23482393 cytosines 23482393 hmC 23482393 sugar 23483103 1,10-phenanthroline 23483103 2,2'-bipyridine 23483103 2-pyridyl-1H-anthra[1,2-d]imidazole-6,11-dione 23483103 4,7-dimethyl-1,10-phenanthroline 23483103 4,7-diphenyl-1,10-phenanthroline 23483103 PAIDH 23483103 [Ru(bpy)2(PAIDH)](2+) 23483103 [Ru(dip)2(PAIDH)](2+) 23483103 [Ru(dmp)2(PAIDH)](2+) 23483103 [Ru(phen)2(PAIDH)](2+) 23483103 bpy 23483103 dip 23483103 dmp 23483103 phen 23483103 ruthenium(ii) 23484434 hydrogen 23484493 CNBs 23484493 Chloronitrobenzamides 23484493 chloronitrobenzamides 23484619 C17H35COOH 23484619 C18H37NH2 23484619 C18H37OH 23484619 C18H37PO(OH)2 23484619 C18H37SH 23484619 Ga 23484619 Gallium 23484619 Hydrocarbons 23484619 ODPA 23484619 acetonitrile 23484619 gallium 23484619 hydrocarbons 23484619 hydrogen 23484619 oxide 23484619 ozone 23484619 phosphonate 23484619 toluene 23484668 (+)-Medioresinol 23484668 (2S)-5-hydroxy-7,3'-dimethoxyflavanone-4'-O-β-d-apiofuranosyl-(1→5)-O-β-d-apiofuranosyl-(1→2)-O-β-d-glucopyranoside 23484668 (3S)-3-hydroxy-1,7-bis(4-hydroxyphenyl)-6E-hepten-5-one 23484668 (3S,5R)-3-hydroxy-5-methoxy-1,7-bis(4-hydroxyphenyl)-6E-heptene 23484668 (3S,5S)-3-hydroxy-5-methoxy-1,7-bis(4-hydroxyphenyl)-6E-heptene 23484668 3,7,3'-tri-O-methylquercetin-4'-O-β-d-apiofuranosyl-(1→2)-O-β-d-glucopyranoside 23484668 7,3'-di-O-methylquercetin-4'-O-β-d-glucopyranosyl-3-O-[(6'''''→5'''')-O-1'''''-(sinap-4-yl)-β-d-glucopyranosyl-6‴-(3-hydroxy-3-methylglutaroyl)]-α-d-glucopyranoside 23484668 7,3'-di-O-methylquercetin-4'-O-β-d-glucopyranosyl-3-O-[6‴-(3-hydroxy-3-methylglutaroyl)]-α-d-glucopyranoside 23484668 Diarylheptanoids 23484668 Flavonoids 23484668 diarylheptanoids 23484668 flavonoid glycosides 23484861 CTAB 23484861 THF 23484861 acetate 23484861 acetato-benzimidazolato-zinc 23484861 benzimidazolate 23484861 cethyltrimethylammonium bromide 23484861 chloroform 23484861 zinc 23485017 Fe 23485017 Mn 23485017 Zn 23485017 [Cr(pyridine)2(CH4)](2+) 23485017 [M(pyridine)2(CH4)](2+) 23485017 hydridomethyl 23485017 methane 23485017 transition metal dication complexes 23485017 transition metals 23485046 EGCG 23485046 Epigallocatechin gallate 23485046 catechin 23485046 epigallocatechin gallate 23485046 erythromycin 23485046 methicillin 23485046 oxytetracycline 23485046 tetracycline 23485046 β-lactam 23485401 pyridazine 23485401 pyridine 23485614 GSH 23485614 alanine 23485614 alloxan 23485614 aspartate 23485614 bilirubin 23485614 cholesterol 23485614 creatinine 23485614 glibenclamide 23485614 glucose 23485614 glutathione 23485614 paracetamol 23485614 silymarin 23485614 superoxide 23485614 triglycerides 23485614 urea 23485653 BPA 23485653 bisphenol A 23486920 (9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboximido)-4-ethylbenzene-1,2-diol 23486920 FePt 23486920 GSH 23486920 NADH 23486920 Trp 23486920 amide 23486920 glutathione 23486920 nicotinamide adenine dinucleotide 23486920 tryptophan 23488982 Iodine 23488982 iodine 23489521 glucose 23489622 N-phenyl-substituted β-amidoamidines 23489622 acyl 23489622 amidine 23489622 amidinomycin 23489622 methacryloyl anilide 23489622 n-C12H25 23489622 n-C8H17 23489622 racemic N-phenyl-substituted β-amidoamidines hydrochlorides 23489622 rimantadine 23489622 β-amidoamidines 23489622 β-aminoamidine 23489622 β-phenylamino 23491640 Alcoholics 23491640 N 23491640 alcohol 23492812 Biphenyls 23492812 Dibenzofurans 23492812 Dioxin 23492812 PBBs 23492812 PBDDs 23492812 PBDFs 23492812 Polybrominated Dibenzo-p-dioxins 23492812 biphenyls 23492812 dibenzofurans 23492812 dioxin 23492812 polybrominated dibenzo-p-dioxins 23493259 glucose 23493372 DEX 23493372 Dexamethasone 23493372 dexamethasone 23493372 triacylglycerol 23493372 triglyceride 23493568 glucose 23493568 serine 23493568 tyrosine 23494186 Cholesterol 23494186 HMG-CoA 23494186 bile acid 23494186 cholesterol 23494186 ezetimibe 23494186 fibrates 23494481 BSO 23494481 GSH 23494481 Glutathione 23494481 L-buthionine-(S, R)-sulfoximine 23494481 ebselen 23494481 ethacrynic acid 23494481 glutathione 23494481 oxygen 23494481 rotenone 23494524 Ala 23494524 Arg 23494524 Asn 23494524 C 23494524 Glu 23494524 H 23494524 H-C 23494524 H-N 23494524 N 23494524 O 23494524 Phe 23494524 Sec 23494524 Thr 23494524 amide 23494524 dipeptides 23494524 selenocysteine 23494524 α-carbon 23494938 Ni3 S4 23494938 NiS1.03 23494938 Nickel sulfide 23494938 lithium 23494938 nickel sulfide 23494938 nitrogen-doped graphene 23495085 (1) H 23495085 (13) C 23495085 2-acetamide-3-methyl-3-nitrososulfanyl-N-aryl-butanamides 23495085 2-acetamido-3-mercapto-3-methyl-N-aryl-butanamides 23495085 2-acetamido-3-methyl-3-nitrososulfanyl-N-aryl-butanamide 23495085 m-chloro 23495085 o-chloro 23495085 p-methoxy 23495691 cAMP 23495691 cyclic AMP 23495872 carboxy 23495872 glutamine 23495872 lysine 23495999 calcium 23496341 4-hydroxy-2-pyridone alkaloids 23496341 Azole 23496341 Didymellamide A 23496341 Pyridone Alkaloids 23496341 azole 23496341 didymellamides A-D 23497872 carbohydrates 23497872 phenolic 23497872 tocopherols 23497872 unsaturated fatty acids 23497883 GSH 23497883 GSSG 23497883 NADPH 23497883 SOP 23497883 SOX 23497883 carbonyl 23497883 dimethylpolysiloxane 23497883 phenolic 23497891 FFA 23497891 TAG 23497891 TAGs 23497891 free fatty acids 23497891 triacylglycerols 23497903 Ca(2+)][Pal(-)][OH(-) 23497903 Ca(OH)(Pal) 23497903 Ca(Pal)2 23497903 Ca(Pal)2·Ca(OH)(Pal) 23497903 Calcium hydroxy palmitate 23497903 Calcium(II) 23497903 Pal(-) 23497903 [Ca(2+)][Pal(-)](2) 23497903 calcium 23497903 calcium(II) 23497903 hydroxy 23497903 palmitate 23497904 flavonol glycosides 23497904 hydroxycinnamic acids 23497904 phenolic 23497904 sugar 23499503 ATP 23499503 pyrrolo[2,3-g]indazole 23499503 pyrrolo[2,3-g]indazoles 23499662 ATP 23499662 carbenoxolone 23499662 chloride 23499662 flufenamic acid 23499662 mefloquine 23499735 A-779 23499735 PD123319 23499825 (22R)-spirosolanol glycoside 23499825 5β-spirostanol glycoside 23499825 Steroidal glycosides 23499825 cholestane 23499927 K(+) 23500059 Alizarin red 23500059 calcium 23500059 poly(DL-lactic acid-co-glycolic acid) 23500059 poly(dl-lactic acid-co-glycolic acid) 23500059 simvastatin 23500116 Myritol 318 23500116 TPGS 23500116 Tween 80 23500116 V2(PO4) 23500116 fenofibrate 23500380 Brucine 23500380 brucine 23500380 bruicne 23500380 ethanol 23500382 NO 23500382 cholesterol 23500382 eosin 23500382 glucose 23500382 hematoxylin 23500382 kinsenoside 23500382 lactic 23500382 methenamine 23500382 nitric oxide 23500382 streptozotocin 23500382 superoxide 23500386 carbazole alkaloids 23500386 d-galactosamine 23500387 Curcumin 23500387 curcumin 23500387 dexamethasone 23500387 eosin 23500387 hematoxylin 23500490 C 23500490 zinc 23500536 KCl 23500536 l-amino acid 23500538 24S-hydroxycholesterol 23500538 7- and 8-dehydrocholesterol 23500538 7- and 8-dehydrodesmosterol 23500538 7-dehydrocholesterol 23500538 cholesterol 23500538 desmosterol 23500538 oxysterol 23500538 oxysterols 23500538 sterol 23500538 sterols 23500544 ATP 23500544 Oxysterols 23500544 cholesterol 23500544 oxysterol 23500544 oxysterols 23500672 1-menaphthylglutathione 23500672 2,4-dinitrophenylglutathione 23500672 4-methylbiphenylylglutathione 23500672 4-nitrobenzylglutathione 23500672 9-methylanthracenylglutathione 23500672 dipeptide 23500672 glutamic acid 23500672 glutathione 23500672 glycylglycine 23500672 γ-glutamyl 23500672 γ-glutamyl-p-nitroanilide 23500774 CCl4 23500774 Hyp 23500774 alanine 23500774 aspartate 23500774 bilirubin 23500774 hydroxyproline 23500774 puerarin 23500779 2,2',4,4',5,5'-Hexachlorobiphenyl 23500779 2,2',4,4'-Tetrabromodiphenyl ether 23500779 2,3,7,8-Tetrachlorodibenzo-p-doxin 23500779 BDE-47 23500779 HBCD 23500779 Hexabromocyclododecane 23500779 PCB-153 23500779 TCDD 23500779 estradiol 23500779 steroid 23500779 testosterone 23501055 Gambogic acid 23501055 gambogic acid 23501055 oxygen 23501055 prolyl 23501114 Coumarins 23501114 benzimidazole 23501114 benzimidazoles 23501114 coumarin 23501114 d-ribofuranose 23501114 nucleosides 23501114 ribofuranose 23501114 ribofuranosides 23501114 β-d-ribofuranosides 23501490 CYN 23501490 Cylindrospermopsin 23501490 GSH 23501490 GSSG 23501490 NADPH 23501490 cylindrospermopsin 23501490 deoxy-CYN 23501490 gamma-glutamyl-cysteine 23501490 glutathione 23501490 l-carnitine 23501490 oxidised glutathione 23501490 reduced glutathione 23501490 superoxide 23503440 PHB 23503440 phenobarbital 23503440 primidone 23503441 imatinib 23503460 phosphatidylinositol 23503470 Li 23503470 TiO2 23503470 lithium 23503611 lactate 23503627 12(S)-HETE 23503627 Xanthohumol 23503627 xanthohumol 23503780 His 23503780 histidine 23503967 glucose 23504315 glucose 23504628 Polyglutamine 23504628 polyQ 23504628 polyglutamine 23504855 Zaleplon 23504855 zaleplon 23505214 BiFeO3 23505214 Fe 23505636 CoCl(2)·6H(2)O 23505636 Cobalt 23505636 Cobalt chloride 23505636 cobalt 23505636 zinc 23505965 Carbohydrates 23505965 carbohydrate 23505965 carbohydrates 23505966 4-(2-hydroxyethoxy) benzophenone 23505966 PAA 23505966 PAH 23505966 poly(acrylic acid) 23505966 poly(allylamine hydrochloride) 23506002 isoxazolines 23506120 1,N(6)-ethenoadenosine 23506120 8-oxoguanosine 23506120 Inosine 23506120 N-methylarginine 23506120 adenosine 23506120 etheno 23506120 halogen 23506120 inosine 23506120 nitric oxide 23506120 nitrogen 23506120 nucleobase 23506120 oxygen 23506120 xanthosine 23506492 oxygen 23506527 glutamic acid 23506527 lysine 23506527 phenylalanine 23506783 Bacoside B 23506783 bacopasaponin C 23506783 bacopaside I 23506783 bacopaside II 23506783 bacoside A 23506783 bacoside A3 23506783 bacoside B 23506783 bacosides A and B 23506783 jujobogenin 23506783 saponins 23507868 malondialdehyde 23507868 α-tocopherol 23508266 albuterol 23508266 nucleotide 23508295 copper 23508555 cortisol 23508555 ethanol 23508685 Serotonin 23508685 TCB-2 23508685 glutamate 23508685 lysine 23508718 DHEA-S 23508718 Dehydroepiandrosterone Sulfate 23508718 free fatty acids 23508718 steroid 23508742 Dammarane 23508742 MTT 23508742 damulin A 23508742 damulin B 23508742 ethanol 23508742 gypenoside L 23508742 gypenoside LI 23508742 hydroxyl 23508742 saponins 23508742 silica gel 23508744 5,7,4'-trimethoxyflavone 23508744 aquilacallanes A-B 23508744 tirucallane triterpenoids 23508744 ursolic acid 23509003 Graphene 23509003 carbon 23509003 chlorine 23509003 graphene 23509042 γ-hydroxyphosphonate 23509611 Bisphosphonate 23509611 MEP 23509611 bisphosphonates 23509611 cyclodiphosphate 23509611 diphosphate 23510022 Oxygen 23510022 Scopoletin 23510022 Scopolin 23510022 oxygen 23510022 peroxyl 23510022 scopolin 23510022 superoxide 23510074 1-Alkyl-3-methylimidazolium Bis[(trifluoromethyl)sulfonyl]imide 23510074 1-alkyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl] imide 23510074 1-butyl 23510074 1-ethyl 23510074 1-ethyl- and 1-octyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl] imide 23510074 1-octyl 23510370 sodium iodide 23510510 Ag 23510510 Au 23510510 PAMAM 23510510 Silver 23510527 (O2H3)(-) 23510527 (O2H3)Sc 23510527 3,5-DSB 23510527 3,5-disulfobenzoic acid 23510527 Aqua-Hydroxo 23510527 H3O2 23510527 H3O2(-) 23510527 Hydroxyl 23510527 OH 23510527 Sc 23510527 [Sc(3,5-DSB)(Phen)(H2O)](H2O) 23510527 [Sc3(3,5-DSB)(μ-OH)6(H2O)] 23510527 [Sc3(3,5-DSB)2(μ-O2H3)(μ-OH)2(H2O)2] 23510527 [Sc3(3,5-DSB)2(μ-OH)3(H2O)4] 23510527 aldehydes 23510527 aqua-hydroxo 23510527 hydroxyl 23511023 benzofurano[3,2-d]pyrimidin-2-ones 23511023 benzofurano[3,2-d]pyrimidine-2-one 23511023 benzofuranopyrimidone 23511023 nucleotide 23511897 17-ketogenic steroids 23511897 ATP 23511897 cholesterol 23511897 steroid 23511897 steroid hormone 23512318 Cysteamine 23512318 Poly(aspartic acid) 23512318 dimethylformamide 23512318 disulphide 23512318 poly(aspartic acid) 23512318 thiol-disulphide 23512318 thiolated poly(aspartic acid) 23512500 (5S)-1,7-bis-(3,4-dihydroxyphenyl)-5-O-β-D-[6-(3,4-dimethoxycinnamoylglucopyranosyl)]-heptan-3-one 23512500 (5S)-1-(4-hydroxyphenyl)-7-(3,4-dihydroxyphenyl)-5-O-β-D-glucopyranosyl-heptan-3-one 23512500 1,7-bis-(3,4-dihydoxyphenyl)-5-hydroxy-heptane-3-O-β-D-xylopyranoside 23512500 Diarylheptanoids 23512500 aceroside VII 23512500 alnuside A 23512500 alnuside B 23512500 amifostine 23512500 diarylheptanoids 23512500 hirsutanonol 23512500 hirsutanonol-5-O-β-D-glucopyranoside 23512500 hirsutenone 23512500 oregonin 23512500 platyphyllonol-5-O-β-D-xylopyranoside 23512500 platyphylloside 23512500 rubranoside A 23512500 rubranoside B 23512583 Graphene Oxide 23512583 H2 S 23512583 HI 23512583 SO2 23512583 graphene 23512583 graphene oxide 23512910 MTT 23512910 PCL 23512910 Polycaprolactone 23512910 β-TCP 23512910 β-Tricalcium Phosphate 23514045 CO2 23514045 HCO3 (-) 23514045 acetazolamide 23514045 methazolamide 23514045 sulthiame 23514045 topiramate 23514045 zonisamide 23514379 KYN 23514379 N-acetylserotonin 23514379 NAS 23514379 Serotonin 23514379 TRP 23514379 TRY 23514379 cortisol 23514379 indoleamine 23514379 kynurenine 23514379 kynurenines 23514379 methoxyindole 23514379 serotonin 23514379 tryptophan 23514379 tyrosine 23515291 Estrogen 23515291 estrogen 23515291 phosphatidylinositol 23515291 tamoxifen 23515494 methamphetamine 23515494 monoamine 23515494 serotonin 23515494 tryptophan 23515495 creatinine 23515584 D-penicillamine 23515584 acetaldehyde 23515584 alcohol 23515584 ethanol 23516047 Ag+ 23516047 NaCl 23516047 silver 23516047 sodium chloride 23516330 C 23516330 N 23516330 cAMP 23516330 calcium 23516963 7-Amino-5-thio-thiazolo[4,5-d]pyrimidines 23516963 7-amino-5-thio-thiazolo[4,5-d]pyrimidine 23516963 benzyl 23516963 leucinol 23516963 α-methyl 23517464 CdSe 23517501 1,2,4-Benzo/pyridothiadiazine 1,1-Dioxides 23517501 1,2,4-thiadiazine 23517501 1,4,2-Benzo/pyridodithiazine 1,1-Dioxides 23517501 1,4,2-dithiazine 23517501 1-phenylethylamino 23517501 3-(1-phenylethyl)sulfanyl-4H-1,2,4-benzothiadiazine 1,1-dioxides 23517501 3-alkyl/aralkyl/arylamino-1,4,2-benzodithiazine 1,1-dioxides 23517501 3-alkylaminopyrido[4,3-e]-1,4,2-dithiazine 1,1-dioxides 23517501 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide 23517501 ATP 23517501 NH 23517501 Potassium 23517501 benzo- and pyridothiadiazine dioxides 23517501 calcium 23517501 diazoxide 23517501 dithiazine 23517501 potassium 23517732 3,3'-diindolylmethane 23517732 3,3'-diindolylmethanes 23517732 4-nitrophenyl linked 3,3'-diindolylmethane 23517732 Fe 23517732 fluorophenyl substituted 3,3'-diindolylmethanes 23517732 nitroaryl substituted diindolylmethanes 23517733 2,2'-dichloro-3,3'-diquinolinyl disulfide 23517733 6-acylaminoalkyl 23517733 6-dialkylaminoalkyl 23517733 Br 23517733 CF3 23517733 CH3 23517733 Cl 23517733 F 23517733 H 23517733 SCH3 23517733 aminoalkyl 23517733 azaphenothiazines 23517733 cisplatin 23517733 diquinodithiin 23517733 quino[3,2-b]benzo[1,4]thiazines 23517733 sulfonylaminoalkyl 23517733 tetracyclic quino[3,2-b]benzo[1,4]thiazines 23517912 Fisetin 23517912 fisetin 23517912 flavonol 23517912 rapamycin 23517912 triglycerides 23518229 13'-Z zeaxanthin 23518229 13-Z lutein 23518229 13-Z zeaxanthin 23518229 2,2'-Azobis (2-methylpropionamidine) dihydrochloride 23518229 AAPH 23518229 H(+) 23518229 H2O 23518229 Lutein 23518229 O2-C12H20O 23518229 O2-C22H32O 23518229 Oxidized lutein 23518229 all-E zeaxanthin 23518229 glutathione 23518229 lutein 23518229 malondialdehyde 23518229 oxidized lutein 23518229 peroxyl 23518229 polyene 23518276 4H-thiochromeno[4,3-d]thiazol-2-amine 23518276 5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-d]thiazol-2-amine 23518276 Tricyclic thiazoleamine 23518276 Tricyclic thiazoles 23518299 6-OHDA 23518299 6-hydroxydopamine 23518299 S 23518299 SFN 23518299 Sulforaphane 23518299 glutathione 23518299 sulforaphane 23518319 formamido-pyrimidine 23518319 oxygen 23518319 silver 23518471 ATP 23518471 NADH 23518471 PCBs 23518471 S 23518471 gluthatione 23518471 organochlorine 23518471 polychlorinated biphenyls 23518471 succinate 23518471 ubiquinol 23519015 3-propanedithiol 23519015 4-aminothiophenol 23519015 Zn3P2 23519015 Zn4Sb3 23519015 antimony 23519015 phosphorus 23519015 zinc 23519015 zinc antimonide 23519015 zinc phosphide 23519077 serine 23519149 5-FU 23519149 Elisidepsin 23519149 Irvalec 23519149 Kahalalide F 23519149 PM02734 23519149 elisidepsin 23519149 kahalalide f 23519149 lapatinib 23519149 oxaliplatin 23519376 Au 23519376 Si 23519376 divinylbenzene 23519376 poly(divinylbenzene) 23519376 silicon 23519470 Lys 23519470 MG132 23519470 Oxygen 23519470 Thr 23519470 buthionine sulfoximine 23519470 lysine 23519470 menadione 23519470 oxygen 23519470 paraquat 23519470 superoxide 23519470 threonine 23519574 Nicotine 23519574 methamphetamine 23519574 nicotine 23519822 Acteosides 23519822 Irbesartan 23519822 acteosides 23519822 alanine 23519822 aspartate 23519822 irbesartan 23519881 (S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone 23519881 6-Gingerol 23519881 6-gingerol 23519881 Oil-Red O 23519881 RGZ 23519881 Rosiglitazone 23519881 fatty acid 23519881 rosiglitazone 23519881 triglyceride 23519881 triglycerides 23519952 alcoholic 23520191 14-O-diterpenoid 23520191 diterpenoid 23520191 enmein 23520191 kaurene 23520191 oridonin 23520191 paclitaxel 23520265 4H-furo[3,2-b]pyrrole-5-carboxylic acid 23520265 D-AMINO ACID 23520265 D-amino acid 23520265 D-serine 23520265 SUN 23521048 (18)F 23521048 2-(5,7-diethyl-2-(4-(2-[(18)F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide 23521048 2-(5,7-diethyl-2-(4-(2-fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide 23521048 5,6,7-Substituted Pyrazolopyrimidines 23521048 5,6,7-substituted pyrazolopyrimidines 23521048 DPA-714 23521048 fluorine-18 23521048 pyrazolopyrimidine 23521163 13,14,15,16-tetranorlabd-7-ene-19,6b:12,17-diolide 23521163 LL-Z1271β 23521163 botryosphaerin B 23521163 botryosphaerin F 23521163 sesquiterpene 23521216 6-methylquercetin 23521216 6-methylquercetin-4'-O-β-d-glucopyranoside 23521216 Baeckein E 23521216 C-methylated biflavonoid 23521216 C-methylated flavonols 23521216 baeckein E 23521216 baeckeins A 23521216 baeckeins C 23521216 biflavonoid 23521495 Cys-Ala-Leu-Asn-Asn 23521797 N 23521797 cholesterol 23521797 oxysterol 23521797 oxysterols 23521797 sterol 23522793 C 23522793 H2O2 23522793 zinc 23522835 Poly(ADP-ribose) 23522835 cisplatin 23522835 poly(ADP-ribose) 23523101 CCl4 23523101 GW9662 23523101 H2O2 23523101 HSYA 23523101 Hydroxysafflor yellow A 23523101 hydroxysafflor yellow A 23523202 Xeljanz 23523202 fostamatinib 23523202 tofacitinib 23523531 (125)I 23523531 Arg 23523531 Ca(2+) 23523531 K(+) 23523531 Lys 23523531 amino acid 23523547 BDP 23523547 HFA 23523547 beclomethasone dipropionate 23523547 ethanol 23523547 glycerol 23523547 hydrofluoroalkane 23523661 Baicalein 23523661 baicalein 23523661 bleomycin 23523661 hydroxyproline 23523830 2-Dimyristoyl-sn-glycero-3-phosphocholine 23523830 Flavonoids 23523830 Laurdan 23523830 Quercetin 23523830 cholesterol 23523830 epigallocatechin-3-gallate 23523830 flavonoids 23523830 polyphenols 23523830 quercetin 23523831 (E)-nerolidol 23523831 DCF-DA 23523831 nerolidol 23523831 oxygen 23523831 superoxide 23523964 Zn 23523964 carnitine 23523964 zinc 23524100 adriamycin 23524304 BD-1047 23524304 BD-1063 23524304 Morphine 23524304 NE-100 23524304 PRE-084 23524304 S1RA 23524304 [(3)H]DAMGO 23524304 morphine 23524312 3-O-caffeoylquinic, 4-O-caffeoylquinic, 5-O-caffeoylquinic and rosmarinic acids 23524312 Fe(2+) 23524312 Trolox 23524312 ethanol 23524312 luteolin 23524312 oxygen 23524312 phenolic 23524312 pinocembrin 23524313 bile acid 23524313 cholesterol 23524313 fisetin 23524314 Phenolic 23524314 dicaffeoyl acid 23524314 flavonoids 23524314 isorhamnetin 23524314 isorhamnetin-3-O-rhmanoside-7,4'-di-O-glucoside 23524314 kaempferol 23524314 monoamine 23524314 phenolic 23524314 quercetin 23524314 quercetin-3-O-(2-pentosyl)hexoside 23524315 T-2 toxin 23524315 mycotoxin T-2 23524663 (3)H 23524663 3H 23524663 Br 23524663 nucleosides 23525200 CIGS 23525200 Cu(In,Ga)Se2 23525200 ZnO 23525524 2,5-dimethoxy-4-iodoamphetamine 23525524 CP 809101 23525524 DOI 23525524 LSD 23525524 Lysergic acid diethylamide 23525524 MDL 11939 23525524 N-methyl-D-aspartate 23525524 TCB-2 23525524 ketamine 23526644 adamantane 23527545 ADP 23527573 4-amidinobenzylamide 23527573 d-arginine 23527573 serine 23527573 sulfonylated 3-amindinophenylalanylamide 23527578 Graphene 23527578 graphene 23527587 hydrogen 23527587 nucleotide 23527663 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidacarbocyanine 23527663 TTBC 23527663 TTBC-Cl 23527663 TTBC-I 23527663 chloride 23527663 iodide 23528295 Arvelexin 23528295 N-methyl 23528295 NO 23528295 PGE2 23528295 arvelexin 23528295 hydroxyl 23528295 indole 23528295 indolyl-3-acetonitrile 23528295 indolyl-3-acetonitriles 23528295 nitric oxide 23528299 LB-4b 23528299 bestatin 23528361 MTT 23528361 NO 23528361 PGE2 23528361 eicosanoids 23528361 flavanol 23528361 flavonoid 23528361 leukotrienes 23528361 nitric oxide 23528361 polyphenolic 23528610 DAMGO 23528610 Diazepam 23528610 Ethanol 23528610 Morphine 23528610 bicuculline 23528610 ethanol 23528610 morphine 23528610 phaclofen 23528715 corticosterone 23529014 20, 26-epoxy 23529014 3-O-{β-d-glucopyranosyl(1→3)-[β-d-xylopyranosyl(1→2)]-α-l-arabinopyranosyl}-20, 26-epoxypseudojujubogenin 23529014 3-O-{β-d-xylopyranose(1→2)glucopyranosyl(1→3)[rhamnopyranose(1→2)]β-d-glucopyranosyl}-20, 26-epoxypseudojujubogenin 23529014 Hoduloside XI 23529014 Hoduloside XII 23529014 hoduloside XI 23529014 hoduloside XII 23529014 pseudojujubogenin 23529014 saponins 23529015 3,5-diprenyl-4-hydroxyacetophenone 23529015 HYDP 23529015 N(G)-nitro-l-arginine methyl ester 23529015 N-ethylmaleimide 23529015 NO 23529015 encesanescin 23529015 ethanol 23529015 indomethacin 23529015 prostaglandins 23529015 sulfhydryl 23529067 MDA 23529067 Pb 23529067 Se 23529067 Selenium 23529067 lactate 23529067 lead acetate 23529067 malondialdehyde 23529067 selenium 23529067 sodium selenite 23529067 superoxide 23529381 methylphenidate 23529381 nicotine 23529473 Cys 23529473 HgCl2 23529473 mercury 23529650 Ag 23529650 AgCl 23529650 Cl 23529672 (123)I 23529672 (99m)Tc-MIBI 23529672 (99m)TcO4 23529672 iodine-123 23529672 technetium pertechnetate 23529860 ampicillin 23529860 methyl 2-isothiocyanato benzoate 23529860 quinazoline 23529860 quinazolines 23529860 sulfonamide 23529860 sulfonamides 23529860 triazinoquinazoline 23529860 triazoloquinazolines 23529904 haloperidol 23530013 Glucose 23530013 glucose 23530057 Tyr 23530057 phenylalanine 23530057 tyrosine 23530057 tyrosines 23530595 allyl 23530595 thiol 23530815 butanol 23530815 n-Butanol 23530834 (S)-Phenylalanine 23530834 (S)-phenylalanine 23530834 2-Cyanopyrrolidine 23530834 2-cyanopyrrolidine 23530834 cyclopropyl-substituted phenylalanine 23531031 125I 23531031 131I 23531031 LBH589 23531031 SODIUM IODIDE 23531031 iodine 23531031 radioiodine 23531031 sodium iodide 23531031 ¹³¹I 23531416 6-OH-BDE-47 23531416 OH-BDE 23531416 OH-BDEs 23531416 PBDEs 23531416 Polybrominated diphenyl ethers 23531416 hydroxylated PBDEs 23531416 thyroid hormone 23531488 N 23531488 amino acids 23531488 estrone sulfate 23531488 rosuvastatin 23532257 glucose 23532331 tyrosine 23532375 ecstasy 23532445 Ataluren 23532445 G-418 23532445 G418 23532445 Geneticin 23532445 Gentamicin 23532445 PTC124 23532445 aminoglycoside 23532445 aminoglycosides 23532445 gentamicin 23532445 phenylalanine 23532932 PCN 23532932 TCPOBOP 23532932 docetaxel 23532932 paclitaxel 23532932 pregnenolone-16α-carbonitrile 23532932 taxanes 23532999 EtOAc 23532999 O-heterocyclic embeurekols 23533219 glucose 23533219 triglyceride 23534618 oxide 23534618 silanol 23534618 silica 23534618 ≡Si-O(-) 23534703 He 23534703 Li 23534703 metallocenes 23534703 nickelocene 23534703 vanadocene 23534826 PVA 23534826 Poly(vinyl alcohol) 23534826 hydroxyl 23534826 poly(vinyl alcohol) 23534857 2,3-epoxyaldehydes 23534857 Epoxyaldehydes 23534857 aldehyde 23534857 aldehydes 23534857 epoxide 23534857 epoxides 23534857 α,β-unsaturated aldehydes 23535188 ASA 23535188 Diclo 23535188 PMA 23535188 acetylsalicylic acid 23535188 diclofenac 23535287 CSA 23535287 Cajaninstilbene acid 23535287 H2O2 23535287 NAD(P)H 23535287 cysteine 23535287 glutamate 23535287 heme 23535287 oxygen 23535287 quinone 23535329 C-nucleoside 23535329 carba-C-nucleosides 23535350 Asenapine 23535350 asenapine 23536522 GSH 23536522 MCT 23536522 S 23536522 glutathione 23536522 monocrotaline 23536522 superoxide 23536973 NaCl 23536973 pyruvate 23536973 ropivacaine 23537166 Cl 23537166 I 23537166 halide 23537203 (-)-epigallocatechin gallate 23537203 EGCG 23537203 polyphenol 23537377 C 23537377 D-amino acid 23537377 NO 23537388 CN 23537388 Ca(2+) 23537388 Calcium 23537388 Na(+) 23537388 Sodium 23537388 amide 23537388 arginine 23537388 calcium 23537388 carboxylate 23537388 cyanide 23537388 heme a 23537500 Glutamate 23537500 NMDA 23537574 Amino acids 23537574 amino acid 23537574 amino acids 23537574 arginine 23537574 carbamazepine 23537574 indomethacin 23537574 phenylalanine 23537574 tryptophan 23537574 tyrosine 23537583 Hg(2+) 23537583 Mercury 23537583 mercury 23537583 poly(Phe) 23537583 superoxide 23537600 MC-LR 23537600 MC-RR 23537600 MC-YR 23537600 microcystins 23537601 Cd 23537601 Hg 23537601 Pb 23537601 alcohol 23537601 cadmium 23537601 iron 23537601 mercury 23537890 Quercetin 23537890 d-GalN 23537890 d-galactosamine 23537890 heme 23537890 nitric oxide 23537890 nitrites 23537890 quercetin 23538036 carbon 23538115 adamantane 23538201 EZETIMIBE 23538201 Ezetimibe 23538201 IRON 23538201 carbonyl iron 23538201 ezetimibe 23538201 iron 23538867 1-methyl-4-phenyl-pyridine 23538867 ATX 23538867 Astaxanthin 23538867 MPP+ 23538867 MTT 23538867 NMDA 23538867 astaxanthin 23538867 mithracycin A 23539296 UDP 23539296 androstane 23539296 anisomycin 23539642 Amphetamine 23539642 amphetamine 23539642 d-amphetamine 23539642 lisdexamfetamine 23540648 cysteine 23540648 indazole 23540648 pyrrolopyrazines 23540731 (+)-naseseazine A and B 23540731 (+)-naseseazines a and B 23540731 Copper 23540731 aryl pyrroloindoline 23540731 copper 23540731 tryptophan 23540813 PEG 23540813 PLLA 23540813 chloroform 23540813 poly(ethylene glycol) 23540813 poly(l-lactide) 23540813 tetrahydrofuran 23540813 toluene 23540839 3-indolepropionic acid 23540839 indole-6-carboxylic acid 23540839 pepstatin 23541120 CdS 23541120 CdSe 23541120 Hydrogen 23541215 ATP 23541215 Diosmetin 23541215 Diosmin 23541215 Flavonoids 23541215 diosmetin 23541215 diosmin 23541215 erythromycin 23541215 flavonoids 23541215 methicillin 23541215 pyruvate 23541371 Na(+) 23541371 Sodium 23541371 lactate 23541434 ACh 23541434 KCl 23541434 carbachol 23541434 p-BPB 23541434 p-bromophenacyl bromide 23541437 Selenium 23541437 mercury 23541437 selenium 23541671 2,2-difluoro-2-deoxyribose-1-phosphate 23541671 2-deoxyribose 23541671 2-fluoro-2-deoxyarabinose-1-phosphate 23541671 2-fluoro-2-deoxyribose-1-phosphate 23541671 fluorine 23541843 Hg(2+) 23541843 MeHg 23541843 NAD(P)H 23541843 TCDD 23541843 aryl hydrocarbon 23541843 heme 23541843 mercuric chloride 23541843 methylmercury 23541843 quinone 23541843 tin mesoporphyrin 23541893 C 23541928 OPF 23541928 oligo(poly(ethylene glycol) fumarate) 23541932 epimedin A 23541932 epimedin B 23541932 epimedin C 23541932 icariin 23541982 24OHC 23541982 24S-hydroxycholesterol 23541982 27-hydroxycholesterol 23541982 27OHC 23541982 Cholesterol 23541982 cholesterol 23541982 oxysterols 23542040 dexametasone 23542040 nitrate 23542040 nitrite 23542147 Ethanol 23542147 PGE2 23542147 Ser 23542147 prostaglandin E2 23542439 3α, 5α-tetrahydroprogesterone 23542439 5α-DHP 23542439 5α-dihydroprogesterone 23542439 Allopregnanolone 23542439 Gabazine 23542439 Progesterone 23542439 allopregnanolone 23542439 finasteride 23542439 progestagens 23542439 progesterone 23542439 steroids 23542442 AM251 23542442 Hemopressin 23542442 hemopressin 23542442 oxygen 23542578 GTX2,3 23542578 GTX2,3-aldehyde 23542578 NH2 23542578 aldehydes 23542578 amino acid 23542578 gonyautoxin 2,3 23542729 cholesterol 23542729 glucose 23542729 oxysterol 23542814 Cocaine 23542814 Morphine 23542814 cocaine 23542814 morphine 23543012 12(S)-HETE 23543012 12(S)-Hydroxyeicosatetraenoic acid 23543012 Heteronemin 23543012 heteronemin 23543412 Dopamine 23543412 LY294002 23543412 Nicotine 23543412 SB-277011-A 23543412 acetylcholine 23543412 dihydro-β-erythroidine 23543412 dopamine 23543412 mecamylamine 23543412 methyllycaconitine 23543412 nicotine 23543412 phosphatidylinositol 23543432 polyethylene glycol 23543629 ATP 23543629 CX-4945 23543629 potassium 23543653 4-(4-bromophenyl)phthalazine 23543653 4-substituted-2(1H)-phthalazinone 23543653 N-substituted piperazine 23543653 alkyl 23543653 amine 23543653 phthalazine 23544460 Alkenes 23544460 Alkyl Halides 23544460 Co 23544460 Cobalt 23544460 Ni 23544460 Nickel 23544460 aliphatic halides 23544460 alkenes 23544460 alkyl halides 23544460 aryl halides 23544460 cobalt 23544460 nickel 23544604 Pyrazoline 23544604 Pyrazolines 23544604 nitrogen 23544604 pyrazoline 23544604 pyrazolines 23544891 Levothyroxine 23544891 levothyroxine 23545134 CPF 23545134 Chlorpyrifos 23545134 chlorpyrifos 23545134 chlorpyrifos oxon 23545134 organophosphate 23545481 DEHP 23545481 Di(2-ethylhexyl) phthalate 23545481 MEHP 23545481 mono(2-ethyl-5-hydroxyhexyl) phthalate 23545481 mono(2-ethyl-5-oxohexyl) phthalate 23545481 phthalic acid 23545560 Nafion 23545560 RuO2 23545560 graphene 23545900 glutathione 23545900 hyroperoxide 23545900 malondialdehyde 23545900 sulfhydryl 23546009 2-(3-Amino-4-piperazinylphenyl)chromone 23546009 2-(3-amino-4-piperazinylphenyl)-chromones 23546009 2-pyridinylpiperazine 23546009 2-pyridinylpiperazinylphenyl 23546009 3-amino-4-piperazinylphenyl 23546009 chromone 23546396 B 23546396 Boron 23546396 boron 23546599 cAMP 23546599 carbachol 23546602 17β-estradiol 23546602 2-NBDG 23546602 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose 23546602 estradiol 23546602 estrogen 23546602 glucose 23546602 steroid 23546614 DHA 23546614 EPA 23546614 Fatty acid 23546614 docosahexaenoic acid 23546614 eicosapentaenoic acid 23546614 n-3 PUFA 23546614 n-3 polyunsaturated fatty acids 23546614 n3 PUFA 23546614 omega-3 polyunsaturated fatty acid 23546614 triglyceride 23546614 triglycerides 23546876 C 23546876 cyclic AMP 23546876 cysteine 23546876 cysteine thiol 23546876 hexa-histidine 23546876 nitrogen 23546876 oxo-acids 23546876 serine 23547729 (13)C 23547729 Triazoline 23547729 aziridines 23547729 triazolines 23547754 serotonin 23547794 1'-cyano-2'-C-methyl 4-aza-7,9-dideaza adenosine 23547794 C-Nucleoside 23547794 C-nucleoside 23547794 GS-6620 23547794 N-nucleoside 23547794 Nucleoside 23547794 adenosine 23547794 monophosphate 23547794 triphosphate 23547843 (E)-3,4,3',5'-tetramethoxystilbene 23547843 (E)-3,5,4'-trimethoxystilbene 23547843 (Z)- and (E)-3,4,3',5'-Tetramethoxystilbene 23547843 (Z)-3,4,3',5'-tetramethoxystilbene 23547843 2,3,5,7-tetramethoxyphenanthrene 23547843 PMA 23547843 Trolox 23547843 stilbenes 23548164 Neoclerodanes 23548164 morphine 23548164 neoclerodane diterpene 23548164 salvinorin A 23548202 H2O2 23548202 Phe 23548202 Tyr 23548202 dihydroxyphenyalanine 23548202 peroxide 23548202 tryptophan 23548202 tyrosine 23548202 veratryl alcohol 23548583 Andalusol 23548583 Diterpenoids 23548583 GSH 23548583 GSSG 23548583 H2O2 23548583 MTT 23548583 andalusol 23548583 conchitriol 23548583 diterpenoids 23548583 lagascatriol 23548702 AG490 23548702 prostaglandin E 23549262 adenylate 23549262 calcium 23549262 formyl 23549262 lipoxin A4 23549262 phosphoinositide 23549262 resolvins 23549262 tyrosine 23549282 Dolastanes 23549282 dolastane diterpenes 23549282 perhydroazulenes 23549331 arachidonic acid 23549331 eicosanoid 23549331 eicosanoids 23549423 Pt 23549423 SBA-15 23549423 TiO2 23549423 W(6+) 23549423 WO3 23549423 carbon 23549423 m-Pt-WO3 23549423 metal oxide 23549423 platinum 23549423 tungsten trioxide 23549676 Steroid 23549676 steroid 23549676 steroids 23549733 hydrogen 23550942 Co 23550942 CoCrMo 23550942 Cr 23550942 Mo 23550942 Mo(VI) 23550942 molybdenum 23550942 quartz 23551297 Ac-Phe-Phe-NH2 23551297 Ac-Phe-Phe-Phe-NH2 23551297 Ac-Trp-Tyr-NH2 23551297 Aromatic amino acids 23551297 NH 23551297 amide 23552261 Cd 23552261 Ni 23552261 Pb 23552261 cadmium 23552261 carbon 23552261 nickel 23552265 3-OH-BaP 23552265 3-hydroxybenzo[a]pyrene 23552265 7,8,9,10-tetrahydro-BaP trans-7,8-diol 23552265 7,8,9,10-tetrahydro-BaP trans-9,10-diol 23552265 BPDE 23552265 BaP 23552265 BaP (7,10/8,9)tetrol 23552265 BaP (7/8,9,10)tetrol 23552265 BaP t-4,5-diol 23552265 BaP t-7,8-diol 23552265 BaP t-9,10-diol 23552265 BaP trans-7,8-dihydrodiol 23552265 BaP trans-7,8-diol-anti-9,10-epoxide 23552265 Benzo[a]pyrene 23552265 NaN3 23552265 PAHs 23552265 benzo[a]pyrene 23552265 deuterated methanol 23552265 hydroperoxides 23552265 methyl linoleate 23552265 oxygen 23552265 polycyclic aromatic hydrocarbons 23552265 pyrene 23552265 superoxide 23552828 Al(3+) 23552828 Fe(2+) 23552828 Fe(3+) 23552828 Ga(3+) 23552828 PEG 23552828 Ti(3+) 23552828 V(3+) 23552828 hydroxyl 23552828 phosphate 23552828 phosphoryl chloride 23552828 poly(ethylene glycol) 23552832 Pentosidine 23552832 glutathione 23552832 pentosidine 23552832 superoxide 23552851 3-methyladenine 23552851 4'-6-diamidino-2-phenylindole 23552851 Dioscin 23552851 bafilomycin A1 23552851 dioscin 23552878 (1R*,3R*, 4R*,14R*,7E,11E)-3,4-epoxycembra-7,11,15(17)-trien-16,14-olide 23552878 (1R*,7S*,14S*, 3E,11E)-18-acetoxy-7-hydroperoxycembra-3,8(19),11,15(17)-tetraen-16,14-olide 23552878 (1R*,7S*,14S*,3E, 11E)-7-hydroperoxycembra-3,8(19),11,15(17)-tetraen-16,14-olide 23552878 Cembranoids 23552878 cembranoids 23552878 α-methylene-γ-lactone 23552907 aripiprazole 23552907 asenapine 23552907 clozapine 23552907 iloperidone 23552907 lurasidone 23552907 olanzapine 23552907 paliperidone 23552907 quetiapine 23552907 risperidone 23552907 ziprasidone 23553601 colchicine 23553601 steroids 23553767 calcium 23553997 ethanol 23554049 FUR 23554049 Furanodiene 23554049 Paclitaxel 23554049 TAX 23554049 paclitaxel 23554049 terpenoid 23554071 calcium 23554071 magnesium 23554071 phosphorus 23554071 selenium 23554095 lysine 23554140 SiCN 23554140 carbon 23554140 polyethylene 23554140 silazane 23554268 Graphene 23554268 graphene 23554292 Cu2 O 23554292 Glucose 23554292 Ni(OH)2 23554292 S2 O3 (2-) 23554292 glucose 23554450 Thyroxine 23554450 levothyroxine 23554450 thyroxine 23554507 2-aminoethoxydiphenyl borate 23554507 U-73122 23554507 UII 23554507 inositol 1,4,5 trisphosphate 23554507 losartan 23554507 urantide 23554507 urotensin II 23554574 UDP 23554574 ceramide 23554574 glucose 23554574 glucosylceramide 23556333 BLA 23556333 bulleyaconitine A 23556340 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] 23556340 Cyclic dipeptides 23556340 Cyclo(His-Gly) 23556340 F-PEG-CHEMS 23556340 PEG-DSPE 23556340 alpha-tocopherol 23556340 cyclic dipeptides 23556340 cyclo(His-Ala) 23556340 cyclo(His-Gly) 23556340 folate 23556340 folate-polyethylene glycol-cholesteryl hemisuccinate 23556340 folic acid 23556340 phosphatidylcholine 23556340 polyethylene glycol 23556340 stearylamine 23556343 DPPH 23556343 Dichloromethane 23556343 methanol 23556438 DOCO 23556438 HOCO 23556438 Hydrocarboxyl 23557033 1,1-diphenyl-2-picrylhydrazyl 23557033 flavonoids 23557033 linoleic acid 23557033 tannins 23557033 β-carotene 23557092 DOX 23557092 Doxorubicin 23557092 GSH 23557092 Galactose 23557092 P(MAGP-co-DMAEMA)-b-PPDSMA 23557092 P(MAlpGP-co-DMAEMA) 23557092 P(MAlpGP-co-DMAEMA)-b-PPDSMA 23557092 PDSMA 23557092 PMAGP 23557092 galactose 23557092 glutathione 23557092 poly((6-O-methacryloyl-1,2:3,4-di-O-isopropylidene-d-galactopyranose)-co-DMAEMA)-b-PPDSMA 23557092 poly(6-O-methacryloyl-d-galactopyranose-co-2-(N,N-dimethylaminoethyl) methacrylate)-b-poly(pyridyl disulfide ethyl methylacrylate) 23557591 cholesterol 23557591 glucose 23557686 4-tert-octylphenol 23557686 ICI 182,780 23557686 androgen 23557686 cAMP 23557686 estrogen 23557706 NADPH 23557706 glucose 23557706 rapamycin 23557746 fluorine 23557746 hydrogen 23557840 1,3,4-Oxadiazol-2-ones 23557840 1,3,4-oxadiazol-2-ones 23557840 fatty acid amide 23557840 fatty-acid amide 23557840 monoacylglycerol 23557842 Carbopol 23557842 terbinafine hydrochloride 23557932 5-FU 23557932 5-Fluorouracil 23557932 5-fluorouracil 23557989 nucleotide 23557993 (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol 23557993 1,7-diphenyl-4,6-heptadien-3-ol 23557993 17β-estradiol 23557993 DPHD 23557993 ICI182780 23557993 diarylheptanoid 23557993 estrogen 23558202 (-)-Palitantin 23558202 Cyclohexanone 23558202 EtOAc 23558202 cyclohexanone 23558600 glucose 23558678 luminal 23558743 guanosines 23558743 nucleotide 23559145 CsA 23559145 cyclosporine A 23559483 (het)arylboronic acids 23559483 2'-Deoxy-2',2'-difluororibo- and 2'-Deoxy-2'-fluororibonucleosides 23559483 2'-deoxy-2',2'-difluororibonucleoside 5'-O-triphosphates 23559483 2'-deoxy-2'-fluororibo- and 2'-deoxy-2',2'-difluororibonucleosides 23559483 3'- and 5'-hydroxy 23559483 6-chloro-7-deazapurine 23559483 7-(Het)aryl-7-deazaadenines 23559483 7-ethynyl 23559483 7-heteroaryl-7-deazaadenosines 23559483 7-iodo 23559483 7-iodo-7-deazaadenine 23559483 7-iodo-7-deazaadenine 2'-deoxy-2'-fluororibonucleoside 23559483 arabinonucleoside 23559483 aryl 23559483 benzoyl-protected 2-deoxy-2,2-difluoro-D-erythro-pentofuranosyl-1-mesylate 23559483 difluororibonucleosides 23559483 fluororibo 23559483 heteroaryl 23559483 nucleosides 23559483 palladium 23559483 sugar 23560542 2'-Deoxyguanosine 23560542 2'-deoxyguanosine 23560542 5'-monophosphate 23560542 C-C 23560542 Carbon 23560542 H 23560542 OTA 23560542 OTB-dG 23560542 Ochratoxin A 23560542 amino 23560542 cytosine 23560542 deoxyribose sugar 23560542 guanine 23560542 hydrogen 23560542 nucleobase 23560542 nucleoside 23560542 nucleotide 23560542 ochratoxin A 23560542 phosphate 23560542 syn (nucleotide) 23560650 Hexahydro-2H-pyrano[3,2-c]quinolines 23560650 amino 23560650 capsaicin 23560650 formalin 23560650 hexahydro-2H-pyrano[3,2-c]quinoline 23560689 Mycoleptodiscin B 23560689 Mycoleptodiscins A and B 23560689 indole 23560689 mycoleptodiscin A 23560689 mycoleptodiscin B 23560689 terpenes 23560747 polystyrene 23560913 Oxygen 23560913 Pt 23560913 oxygen 23561070 ABTS 23561070 Cyanidin-3-O-glucoside 23561070 DPPH 23561070 TFA 23561070 anthocyanin 23561070 anthocyanins 23561070 cyanidin-3-O-glucoside 23561070 delphinidin-3-O-glucoside 23561070 malvidin-3-O-glucoside 23561070 methanol 23561070 oxygen 23561070 pelargonidin-3-glucoside 23561070 peonidin-3-O-glucoside 23561070 petunidin-3-O-glucoside 23561073 RAC 23561073 SAL 23561073 ractopamine 23561073 ractopamine hydrochloride 23561073 salbutamol 23561074 acetic, citric, succinic and malic acids 23561074 carbon 23561074 glycerol 23561074 oxalic acid 23561074 succinic, acetic, citric, malic and oxalic acids 23561074 succinic, oxalic and acetic acids 23561077 EVOH 23561077 ethylene-vinyl alcohol 23561077 flavonoid 23561077 hydrogen peroxide 23561078 ABTS 23561078 CCl4 23561078 DPPH 23561078 flavonoids 23561078 glutathione 23561078 hydroxyl 23561078 malondialdehyde 23561078 superoxide 23561083 alcohol 23561083 linoleic acid 23561083 methanol 23561083 phenolic 23561083 β-carotene 23561088 5-(and-6)-chloromethyl-2,7-dichlorodihydro fluorescein diacetate acetyl ester 23561088 CM-H2DCFDA 23561088 D3G5G 23561088 D3S5G 23561088 Hoechst 33342 23561088 anthocyanidins 23561088 anthocyanins 23561088 delphinidin 3,5-O-diglucoside 23561088 delphinidin 3-O-sambubioside-5-O-glucoside 23561088 delphinidin glycoside 23561088 oxygen 23561088 tetrazolium 23561099 3,3'-diindolylmethane 23561099 DIM 23561099 I3C 23561099 Indole-3-carbinol 23561099 carboxymethyl 23561099 indole-3-carbinol 23561104 lactic acid 23561107 Silver 23561107 Thiol 23561107 chloride 23561107 chlorides 23561107 methylsulphur 23561107 silver 23561107 silver chloride 23561107 thiol 23561108 3-O-(6″-O-galloyl)-hexose 23561108 DPPH 23561108 anthocyanins 23561108 flavonol 23561108 isorhamnetin 23561108 laricitrin 23561108 myricetin 23561108 phenolic 23561108 phenolics 23561108 polyphenolic 23561108 quercetin 23561108 tannins 23561111 amide 23561111 carboxyl 23561111 disulfide 23561112 Histamine 23561112 UCA 23561112 cadaverine 23561112 cis-UCA 23561112 cis-urocanic acid 23561112 histamine 23561112 putrescine 23561112 trans-UCA 23561112 urocanic acid 23561126 CaCl2 23561126 glucose 23561126 polyhydroxyl 23561129 2-amino-3,4-dimethylimidazo-[4,5-f]quinoline 23561129 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline 23561129 2-amino-3-methylimidazo-[4,5-f]quinoline 23561129 2-amino-6-methyldipyrido-[1,2-a:3',2'-d]imidazole 23561129 2-aminodipirydo-[1,2-a:3',2'-d]imidazole 23561129 Glu-P-1 23561129 Glu-P-2 23561129 HACs 23561129 HCAs 23561129 MeIQ 23561129 MeIQx 23561129 heterocyclic amines 23561129 imidazoles 23561132 3β,3β'-disitosteryl ether 23561132 disteryl ethers 23561132 oxygen 23561132 oxysterol 23561132 silica gel 23561132 sterol 23561132 sterols 23561132 β-sitosterol 23561151 Anthocyanins 23561151 Phenolics 23561151 anthocyanin 23561151 anthocyanins 23561151 cyanidin 3-O-glucoside 23561151 cyanidin 3-O-rutinoside 23561151 cyanidin 3-O-sambubioside 23561151 cyanidin 3-O-xylosylrutinoside 23561153 H(1) 23561153 KOH 23561153 NaOH 23561159 DPPH 23561159 Lutein 23561159 lutein 23561159 zeaxanthin 23561167 Al 23561167 Aluminium 23561167 B 23561167 Ca 23561167 Cu 23561167 Fe 23561167 K 23561167 Mg 23561167 Mn 23561167 Ni 23561167 P 23561167 Zn 23561168 1,1-diphenyl-2-pireyhydrazyl 23561168 Trolox 23561168 bile acid 23561168 cholesterol 23561168 ferric 23561168 flavonoids 23561168 hydroxyl 23561168 naringenin 23561168 naringin 23561168 phenolic 23561168 phenolics 23561180 ajmalicine 23561180 catharanthine 23561180 vinblastine 23561180 vindoline 23561180 vinleurosine 23561186 2-(2-(1-(1-carboxy-2-methylpropyl)-3,4-dimethyl-1H-pyrrol-2-yl)methyl-3,4-dimethyl-1H-pyrrol-1-yl)-3-methylbutanoic acid 23561186 E-(+)-S-(1-propenyl)-l-cysteine sulfoxide 23561186 amino acids 23561186 carbonyls 23561186 cepathiolanes 23561186 formaldehyde 23561186 l-valine 23561186 valine 23561193 1,1-diphenyl-2-picrylhydrazyl 23561193 DPPH· 23561193 flavonoid 23561193 hydroxyl 23561193 phenolic 23561193 phenols 23561200 Fatty acid 23561200 Oleic, linoleic and linolenic acids 23561200 fatty acid 23561200 fatty acids 23561200 palmitic and stearic acids 23561200 saturated fatty acids 23561200 unsaturated fatty acids 23561202 (3-chloropropyl) trimethoxysilan 23561202 TBHQ 23561202 Tert-butylhydroquinone 23561202 ethylene glycol dimethacrylate 23561202 polyethylenimine 23561202 silica 23561202 tert-butylhydroquinone 23561205 Curcumin 23561205 curcumin 23561207 PAH 23561207 PAHs 23561207 florisil 23561207 polycyclic aromatic hydrocarbons 23561207 silica gel 23561210 Glucosamine 23561210 Sugar 23561210 glucosamine 23561210 glucose 23561210 sugar 23561215 EGCG 23561215 O2 23561215 epigallocatechin-3-gallate 23561215 oxygen 23561215 saccharide 23561215 sugars 23561215 transition metal 23561216 MAG 23561216 SSL 23561216 carbohydrate 23561216 monoacylglycerols 23561216 sodium stearoyl lactylate 23561218 CPA 23561218 aflatoxins 23561218 aflatoxins B and G 23561218 cyclopiazonic acid 23561221 citric acid 23561221 esters 23562061 Ostreol A 23562061 amide 23562061 polyhydroxy 23562061 primary amino 23562061 tetrahydropyran 23562062 (S)-2-(2-(diethylamino)-5-(N-alkyl-N-sulfonamido)pyrimidin-4-ylamino)-3-(4-(carbamoyloxy)phenyl)propanoic acid 23562062 Arylsulfonamide pyrimidines 23562495 CAT 23562495 Citronellyl acetate 23562495 acetic acid 23562495 capsaicin 23562495 cinnamaldehyde 23562495 citronellyl acetate 23562495 formalin 23562495 glutamate 23562495 menthol 23562495 monoterpene 23562497 C 23562497 acetylcholine 23562497 calcium 23562533 Poly(N-isopropylacrylamide-co-N-hydroxyethylacrylamide) 23562533 Poly(N-isopropylacrylamide-co-hydroxyethylacrylamide) 23562533 glutaraldehyde 23562533 hydroxyl 23562533 indomethacin 23562533 poly(NIPAAm-co-HEAAm) 23562535 Carboxymethyl 23562535 Mesalamine 23562535 carboxymethyl 23562535 mesalamine 23562611 APAP 23562611 PEO 23562611 acetaminophen 23562611 poly(ethylene oxide) 23562632 imidazole 23562803 curculigoside 23562928 DNP 23562928 PGD2 23562928 dinitrophenyl 23562928 hexane 23562928 n-hexane 23562928 prostaglandin D2 23564313 Ca(2+) 23564313 N 23564313 Poly (ADP-ribose) 23564313 Vinblastine 23564313 inositol 23564313 oxygen 23564313 vinblastine 23564370 ATP 23564370 carbaryl 23564651 Triarylamines 23564651 fluorophenyl 23564651 methoxyphenyl 23564651 pyridinyl 23564651 triphenylamine 23564651 tris(4-(pyridin-4-yl)phenyl) amine 23566055 Fatty Acids 23566055 fatty acids 23566055 omega-3 and omega-6 fatty acids 23566055 phosphate 23566057 ethanol 23566059 1,1-diphenyl-2-picrylhydrazyl 23566059 Polyphenols 23566059 Resveratrol 23566059 anthocyanin 23566059 anthocyanins 23566059 ferric 23566059 resveratrol 23566197 alkyl/aryl isocyanate 23566197 aminobenzenesulfonamide 23566197 sulfonamide 23566197 ureido-sulfonamides 23566650 FFA 23566650 FFAs 23566650 Oil-red O 23566650 TAG 23566650 cholesterol 23566650 free fatty acid 23566650 free fatty acids 23566650 glucose 23566650 oleic acid 23566650 phosphatidylinositol 23566650 triacylglycerides 23566650 tyrosine 23566885 (1)H 23566885 DMG 23566885 N 23566885 TMAO 23566885 acetone 23566885 alanine 23566885 choline 23566885 deltamethrin 23566885 dichlorvos 23566885 dimethylamine 23566885 dimethylglycine 23566885 glycine 23566885 lactate 23566885 trimethylamine-N-oxide 23567033 CO2 23567033 neoprotosappanin 23567033 protosappanin E 23567033 sappanone A 23567036 hexavalent chromium 23567036 iron chromite 23567036 salt 23567044 (111)In 23567241 alkyl 23567241 androgen 23567241 butylparaben 23567241 estrogen 23567241 heptylparaben 23567241 parabens 23567241 pentylparaben 23567243 DICO 23567243 flavonoid 23567313 Chloroquine 23567313 GABA 23567313 chloroquine 23567949 Thiazolidin-4-one 23567949 glucose 23567949 rosiglitazone 23567949 thiazinan-4-one 23567949 thiazolidin-4-one 23567950 N,N-diethyl-N-(2-(N-methyltetradecanamido)ethyl)prop-2-en-1-aminium bromide 23567950 aliphatic amido-quaternary ammonium salts 23567961 tyrosine 23567962 hippeastrine 23567962 lycorenine 23567998 Gabapentin 23567998 gabapentin 23567998 radiolabeled gabapentin 23568451 CdS 23568451 CdSe 23568513 Metal Oxide 23568513 metal oxide 23568577 sucralose 23568577 sucrose 23568856 Dopamine 23568856 amphetamine 23568856 cocaine 23568856 dopamine 23568856 monoamine 23568856 sodium 23569205 Pyruvate 23569205 glucose 23569205 monocarboxylate 23569205 pyruvate 23570615 7-O-ethyl madolin W 23570615 PD98059 23570615 aristoyunnolins A-F 23570615 sesquiterpenoids 23570748 Se 23570748 Zn 23570748 selenium 23570748 zinc 23570789 calcium 23570789 imidazopyridazines 23570985 (PVP) K12 23570985 PVP K12 23570985 SDS 23570985 celecoxib 23570985 furosemide 23570985 ingliforib 23570985 polyvinylpyrrolidone 23570985 sodium dodecyl sulfate 23570999 N-acetyl 23570999 PPG 23570999 Polyhydroxy pregnane glycoside 23570999 diclofenac sodium 23570999 pentahydroxy-pregn-14-ol, 20-one-β-d-thevetopyranoside 23570999 steroidal glycoside 23571068 O(6)-alkylguanine 23571068 nucleotide 23571107 guanosine 23571427 5-nitroimidazole 23571427 Ornidazole 23571427 R,S-1-chloro-3-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ol 23571427 R- and S-ornidazole 23571427 R-ornidazole 23571427 S- and R-ornidazole 23571427 S-ornidazole 23571427 UDP 23571427 flurbiprofen 23571427 niflumic acid 23571427 ornidazole 23571427 racemic ornidazole 23571428 2-fluoro-N-methyl pyridinium p-toluenesulfonate 23571428 N-methyl pyridine 23571428 NADPH 23571428 NMP 23571428 arylamines 23571428 atorvastatin 23571428 ezetimibe 23571428 imipramine 23571428 labetalol 23571428 phenols 23571428 quinones 23571428 warfarin 23572393 diazepam 23572393 phenobarbitone 23572528 ADP 23572528 Brefeldin A 23572528 C 23572528 mannose-6-phosphate 23573951 (R,R)- and (S,S)-1,2-diaminocyclohexane 23573951 (R,R)- or (S,S)-1,2-diaminocyclohexane 23573951 Al(3+) 23573951 Al(HQLG)3 23573951 HQLG 23573951 Li(+) 23573951 LiHQLG 23573951 Zn(2+) 23573951 Zn(HQLG)2 23573951 glutamide 23573951 quinolinol 23573951 quinolinol-functionalized l-glutamides 23574017 17α-ethynylestradiol 23574017 Doxorubicin 23574017 doxorubicin 23574017 estrogen 23574017 hydrochloride 23574336 CO 23574336 He 23574336 Ni6O7(+) 23574336 Ni8O9(+) 23574336 Nickel Oxide 23574336 NinOn+x(+) 23574336 nickel oxide 23574336 oxygen 23575975 phosphate 23575975 sugar 23576019 methotrexate 23576190 Cd 23576190 cadmium 23576235 BN 23576235 Boron Nitride 23576235 Graphene 23576235 SiO2 23576235 boron nitride 23576235 graphene 23576432 choline 23576432 dibutyroylphosphatidylcholine 23576432 phosphatidylcholine 23576432 phosphatidylinositol 23576432 phosphatidylserine 23576432 phosphoinositides 23576432 quaternary amine 23576432 trimethylammonium 23576475 Ascorbic Acid 23576475 Dopamine 23576475 ascorbic acid 23576475 dopamine 23578259 Graphene 23578259 Ozone 23578259 graphene 23578259 graphene oxide 23578259 oxidized graphene 23578259 ozone 23578341 ADMA 23578341 Asymmetric dimethylarginine 23578341 SDMA 23578341 asymmetric dimethylarginine 23578341 glucose 23578341 nitric oxide 23578341 symmetric dimethylarginine 23578390 Fluoride 23578390 NaF 23578390 Sodium fluoride 23578390 fluoride 23578391 2,2',4,4',5-pentaBDE 23578391 BDE-99 23578391 PBDEs 23578391 polybrominated diphenyl ethers 23578391 tetraiiodothyronine 23578391 thyroid hormone 23578391 triiodothyronine 23578393 cocaine 23578393 dopamine 23578514 Anatoxin-a 23578514 acetylcholine 23578514 anatoxin-a 23578514 chlorophyll 23578514 chlorophyll a 23578514 hydrogen peroxide 23578522 cholesterol 23578608 bile acid 23578608 cholesterol 23578608 stanol 23578608 stanyl hemisuccinate 23578608 stanyl sorbitol succinate 23578608 triacylglycerol 23578613 diethylstilbesterol 23578613 diethylstilbestrol 23578613 taleranol 23578613 trans- and cis-diethylstilbestrol 23578613 zeranol 23578615 ethyl hexanoate 23578615 ethyl octanoate 23578615 furanic linalool oxides A/B 23578615 hotrienol 23578615 linalool 23578615 nerol oxide 23578615 rose oxide 23578615 α-terpineol 23578615 β-damascenone 23578616 alcohol 23578616 flavonoids 23578616 phenolic 23578616 tartaric esters 23578620 catechin 23578620 epicatechin 23578620 oxidised phenols 23578620 phenol 23578620 phenols 23578620 polyphenols 23578628 ALT 23578628 AME 23578628 AOH 23578628 TEN 23578628 TeA 23578628 altenuene 23578628 alternariol 23578628 alternariol monomethyl ether 23578628 tentoxin 23578628 tenuazonic acid 23578629 Lactones 23578629 aldehydes 23578629 eugenol 23578629 furanic 23578629 guaiacol 23578629 lactones 23578629 phenols 23578629 vanillin 23578637 Se 23578637 Selenium 23578637 selenium 23578637 selenomethionine 23578638 Al 23578638 B 23578638 Ca 23578638 Cd 23578638 Co 23578638 K 23578638 Mg 23578638 Na 23578653 Flavonol glycosides 23578653 caffeine 23578653 catechins 23578653 chakaflavonoside B 23578653 flavonol glycoside 23578653 flavonols 23578653 kaempferol 3-O-β-d-glucopyranosyl-(1→3)-α-l-rhamnopyranosyl-(1→6)-β-d-galactopyranoside 23578653 kaempferol 3-O-β-d-glucopyranosyl-(1→3)-α-l-rhamnopyranosyl-(1→6)-β-d-glucopyranoside 23578653 oleic acid 23578653 polyphenols 23578654 oxygen 23578655 kresoxim methyl 23578656 (Z)-3-hexenyl acetate 23578656 esters 23578656 hexenyl, hexyl, 3-methylbutyl, butyl and 2-methylpropyl esters 23578656 methyl esters 23578656 methyl hexanoate 23578656 methyl octanoate 23578658 lycopene 23578658 β-carotene 23579166 Cloisite 23579166 Montmorillonite 23579166 Na+ 23579166 glutathione 23579178 C 23579178 Glucose 23579178 MTT 23579178 Metformin 23579178 Sitagliptin 23579178 [(14)C]glucose 23579178 glucose 23579178 metformin 23579178 sitagliptin 23579428 NO 23579428 Nitric oxide 23579428 cGMP 23579428 cocaine 23579428 cyclic guanosine monophosphate 23579428 glutamate 23579428 guanylyl 23579428 nitric oxide 23580152 (1)H 23580152 Mg(OH)2 23580152 adamantane 23580152 d-urea 23580152 hydrogen 23580152 magnesium hydroxide 23580152 n-C20H42 23580152 n-alkane 23580372 Graphene 23580372 graphene 23580372 graphite 23580374 Graphene 23580374 graphene 23580394 Squaraine Dye 23580445 NSC130813 23580445 cisplatin 23580445 mitomycin C 23580445 nucleotide 23580458 Au(111) 23580458 Fe14 (bta)6 23580644 ADP 23580644 His 23580644 MgADP 23580644 N 23580644 nucleotide 23581456 4-(methoxymethyl)-7-methoxy-6-methyl-1(3H)-isobenzofuranone 23581456 5,5'-oxy-dimethylene-bis(2-furaldehyde) 23581456 N9-methyl-1methyl-β-carboline 23581456 chromone 23581456 curvulari 23581456 dilation 23581456 harman(1-methyl-β-carboline) 23581456 isobenzofuranone 23581456 lumichrome 23581551 (Aminoalkyl)fluoroindole 23581551 3-Alkylindole 23581551 3-alkylindole 23581551 amide 23581551 carbons 23581551 fluoroindole 23581551 hypochlorous acid 23581551 serotonin 23581551 taurine 23581596 Prostaglandin 23581596 Sacchathridine A 23581596 acetylhydrazino 23581596 naphthoquinone 23581596 prostaglandin E2 23581848 SAHA 23581848 ZYJ-34c 23581848 ZYJ-34v 23581848 hydroxamate 23581848 hydroxamic acid 23581848 tetrahydroisoquinoline 23581876 2,2',3,3',6,6'-hexachlorobiphenyl 23581876 DEX 23581876 OH-PCB 23581876 PCB 23581876 PCB 136 23581876 PCBs 23581876 dexamethasone 23581876 hydroxylated PCB 23581876 phenobarbital 23581876 polychlorinated biphenyls 23581876 ryanodine 23581996 1-aminomethylpyrene 23581996 4-(trimethylsilyl) ethynylstyrene 23581996 5-azidofluorescein 23581996 AMP 23581996 PFPA 23581996 TMSES 23581996 alkyne 23581996 azide 23581996 copper(I) 23581996 pentafluorophenyl acrylate 23581996 poly(PFPA) 23581996 silicon 23583259 Pregnane 23583259 Rilpivirine 23583259 delavirdine 23583259 efavirenz 23583259 etravirine 23583259 nevirapine 23583259 nucleoside 23583259 pregnane 23583259 rilpivirine 23583259 steroid 23583485 Gypenosides 23583485 gypenosides 23583485 midazolam 23583485 testosterone 23583510 DHPM 23583510 THBDC 23583510 THBDC-DHPM 23583510 THC 23583510 THDC 23583510 copper sulphate 23583510 dihydropyrimidinone 23583510 galanthamine 23583510 tetrahydrobisdemethoxycurcumin 23583510 tetrahydrocurcumin 23583510 tetrahydrocurcuminoid dihydropyrimidinone 23583510 tetrahydrodemethoxycurcumin 23583511 MTX 23583511 PAMAM 23583511 amide 23583511 copper 23583511 ester 23583511 folate 23583511 folic acid 23583511 methotrexate 23583511 poly amido amine 23583517 Na(+)/Ca(2+)-cAMP 23583517 tryptophan 23583803 nitrogen 23583806 Allicin 23583806 NO 23583806 allicin 23583883 ATP 23583883 Brilliant Blue G 23583883 superoxide 23583884 2,3,7,8-Tetrachlorodibenzo-p-dioxin 23583884 BAPTA-AM 23583884 Ca(2+) 23583884 TCDD 23583884 bis-(o-aminophenoxy) ethane-N,N,N',N'-tetra-acetic acid acetoxymethyl ester 23583884 calcium 23583884 nifedipine 23583901 1,1-diphenyl-2-picrylhydrazyl 23583901 NO 23583901 flavonoids 23583901 oxygen 23583901 phenylephrine 23583901 quercetin glycosides 23583901 tryptophan 23583931 2-NBDG 23583931 ATP 23583931 Ca(2+) 23583931 Etd(+) 23583931 Ser 23583931 Thr 23583931 dihydropyridine 23583931 ethidium 23583931 glucose 23583931 ryanodine 23583933 (125)I 23583933 [(125)I]epibatidine 23583933 acetylcholine 23583933 adenosine 23583933 cotinine 23583933 cytisine 23583933 nicotine 23584355 Methanol 23584355 acetaldehyde 23584355 acetone 23584355 dimethylpolysiloxane 23584355 ethanol 23584355 methanol 23584355 sodium tungstate 23584355 sulphuric acid 23584433 glucose 23584544 C 23584544 N-hydroxyacetyl 23584544 N-hydroxyacetyl-substituted [1,2,5]triazepane or [1,2,5]oxadiazepane 23584544 [1,2,5]oxadiazepane 23584544 [1,2,5]triazepane 23584544 eperezolid 23584544 linezolid 23584544 methicillin 23584544 monoamine 23584544 oxazolidinone 23584544 thiocarbamate 23584554 C 23584554 N 23584554 amino acid 23584554 amino acids 23584844 (58)Fe 23584844 Hemin 23584844 Iron 23584844 ascorbic acid 23584844 calcium 23584844 heme 23584844 hemin 23584844 iron 23584844 iron (III) protoporphyrin chloride (IX) 23585096 chloride 23585096 epoxide 23585096 ethyl (R)-4-cyano-3-hydroxybutyrate 23585096 ethyl (S)-3,4-epoxybutyrate 23585096 halohydrin 23585307 Glycine 23585307 Pt-Cu 23585307 glycine 23585307 methanol 23585555 Thyroid hormone 23585555 creatinine 23585555 para-aminohippurate 23585555 sodium 23586505 AuF 23586505 gold monofluoride 23586585 Graphene 23586585 graphene 23586585 nucleobases 23587021 calcium 23587021 diacylglycerol 23587021 fatty acids 23587021 glucose 23587424 Methyl malonyl 23587424 Salvinorin A 23587424 dicarboxylic ester 23587424 salvinorin A 23587649 tyrosine 23587837 Amide 23587837 N-methylpyrazole 23587837 THF 23587837 alkyl 23587837 annonaceous acetogenins 23587837 carbon 23587873 radioiodine 23588092 GSH 23588092 H(+) 23588092 K(+) 23588092 dichloromethane 23588092 ethanol 23588092 glutathione 23588092 pentagastrin 23588092 piplartine 23588092 piplatine 23588305 bile salt 23588305 nucleoside 23588391 amino 23588391 amino acid 23588391 carbon 23588391 carboxyl 23588391 l-diphenylalanine 23588559 6-TGN 23588559 6-thioguanine nucleotide 23588559 MMPN 23588559 alanine 23588559 allopurinol 23588559 aspartate 23588559 azathioprine 23588559 methylmercaptopurine nucleotide 23588559 thiopurine 23588559 thiopurines 23588565 4-hydroxycyclophosphamide 23588565 HCY 23588565 aspartate 23588565 cyclophosphamide 23588836 DPP 23588836 PDPPT-alt-FN 23588836 diketopyrrolopyrrole 23588836 fluorenone 23589405 Ethanol 23589405 SDS 23589405 atrazine 23589405 ethanol 23589405 sodium dodecyl sulfate 23589406 1,1'dimethyl-bipyridilium 4,4'-dichloride 23589406 CAPE 23589406 Paraquat 23589406 caffeic acid phenethyl ester 23589406 eosin 23589406 haematoxylin 23589406 paraquat 23589407 CCl4 23589407 NaCl 23589407 S 23589407 carbon tetrachloride 23589407 dimethyl sulfoxide 23589407 glutathione 23589407 n-hexane 23589407 superoxide 23589407 thiobarbituric acid 23590116 polypropylene 23590116 polystyrene 23590179 1,3,5-tris(pyridine-4-ylethynyl)benzene 23590179 H 23590179 Hydrogen 23590179 graphite 23590179 hydrogen 23590522 1-buten-2-ol 23590522 2-buten-2-ol 23590522 2-methyl-2-oxetanol 23590522 EMK 23590522 Ethyl Methyl Ketone 23590522 H 23590522 HO2 23590522 HÿO2 23590522 O H 23590522 OH 23590522 acetic acid 23590522 butenols 23590522 cyclic ether 23590522 ethyl methyl ketone 23590522 ethylene 23590644 12-HSA 23590644 12-Hydroxystearic acid 23590644 acetonitrile 23590644 acetronitrile 23590644 pentane 23591113 4-isobutyl-3-isopropylbicyclophosphorothionate 23591113 GABA 23591113 PS-14 23591113 chloride 23591113 glutamate 23591113 γ-aminobutyric acid 23591116 10-hydroxyl ketolide 23591116 3-O-descladinosyl-3-oxo-11-deoxy-10,11-epoxy-6-O-methylerythromycin A 23591116 6-O-methylerythromycin A 23591116 ketolides 23591117 l- and d-arabinose 23591117 nucleobase 23591117 pyrimidine deoxyapiothionucleosides 23591117 thiosugar 23591579 NaAsO2 23591579 arsenic 23591579 melatonin 23591845 P 23591845 Phosphorus 23591845 phosphate 23591845 phosphorus 23592595 serotonin 23592746 Bile Acids 23592746 Bile acid 23592746 Glucose 23592746 TUDCA 23592746 UDCA 23592746 bile acid 23592746 bile acids 23592746 glucose 23592746 tauroursodeoxycholic acid 23594297 Ag(+) 23594297 Ag(0) 23594297 Citrate 23594297 Silver 23594297 ascorbic acid 23594297 citrate 23594297 gallic acid 23594297 silver 23594303 VCM 23594303 acryl 23594303 vancomycin 23594314 Oxygenated monoterpenes 23594314 monoterpene 23594314 sesquiterpene hydrocarbons 23594999 nitrogen 23594999 oxygen 23595053 1,4'-bisphosphorylated β-(1→6)-linked d-GlcN disaccharide 23595053 6-deoxy-l-talose 23595053 6dTalp 23595053 AraN 23595053 GalpNAc 23595053 O 23595053 O-acetyl 23595053 sugar 23595053 tetrasaccharide 23595773 Heme 23595773 Palbinone 23595773 heme 23595773 palbinone 23596326 cholesterol 23597075 poly(β-amino ester) 23597080 4-anilinoquinazolines 23597080 CI-1033 23597080 GW572016 23597080 Lapatanib 23597080 NEU617 23597080 canertinib 23597080 lapatinib 23597210 2C3 23597210 Benzene 23597210 C2 23597210 C2Cl2 23597210 C2H2 23597210 C2HCl3 23597210 C3 23597210 C4 23597210 C4Cl3 23597210 C4Cl4 23597210 C4Cl5 23597210 C4Cl6 23597210 CH2Cl2 23597210 Unsaturated Chlorinated Hydrocarbons 23597210 benzene 23597210 carbon 23597210 chlorinated ethylenes 23597210 dichloro- and trichloroethylene 23597210 dichloromethane 23597210 perchlorinated C4 23597309 CH-01 23597309 nitro 23597444 sodium hydroxide 23597449 1,2-dimethylhydrazine 23597449 DMH 23597449 N-acetylcysteine 23597449 NAC 23597449 dimethylhydrazine 23597791 1,1-Difluoroethyl-substituted triazolothienopyrimidines 23597791 1,1-difluoroethyl 23597791 amidine 23597791 ethyl 23597791 thiophene 23597791 triazolothienopyrimidine 23597791 urea 23598085 TAG 23598085 glucose 23598085 triacylglycerol 23599007 Diterpenes 23599007 abietane 23599007 abietanes 23599007 decandrins A-K 23599007 diterpenes 23599007 diterpenoids 23599007 podocarpane 23599007 podocarpanes 23599124 Mn(III) 23599124 Mn6 23600364 Ag 23600364 Au 23600402 octanol 23600526 Cy3 23600526 Cy5.5 23600526 SiO2 23600526 polystyrene 23600526 quartz 23600526 silicon 23600654 Eudragit 23600654 KH2PO4 23600654 NaBr 23600654 NaCl 23600654 tolmetin sodium 23600657 FITC 23600657 fluorescein isothiocyanate 23600667 Poly(2-(dimethylamino)ethyl methacrylate) 23600667 polyethyleneglycol 23600682 EtOH 23600682 ammopiptanosides A and B 23600682 isoflavone glycosides 23600698 SPAN 23600698 Sulfonated Polyaniline 23600698 sulfonated polyaniline 23600789 3β-[(2-O-sulfo-β-d-xylopyranosyl)oxy]urs-12,19(29)-diene-28-oic acid 28-β-d-glucopyranoside 23600789 3β-[(2-O-sulfo-β-d-xylopyranosyl)oxy]urs-12,19-diene-28-oic acid 23600789 3β-[(2-O-sulfo-β-d-xylopyranosyl)oxy]urs-12,19-diene-28-oic acid 28-β-d-glucopyranoside 23600789 asprellanosides C-E 23600789 sulfated triterpene glycosides 23600789 triterpene glycosides 23601203 (99m) Tc 23601203 (99m) Tc- EDTA-bis(tyramide) 23601203 Arg 23601203 Catecholamine 23601203 EDTA-bis(tyramide) 23601203 Lys 23601203 amino acid 23601203 catecholamine 23601248 lestaurtinib 23601248 tyrosine 23601384 fatty acids 23601384 omega-3 fatty acids 23601384 selenium 23601384 taurine 23601384 vitamins D and B12 23601385 Caffeine 23601385 caffeine 23601399 DPPH 23601399 phenolics 23601399 phytosterols 23601399 vitamin C 23601401 retinol 23601401 vitamin A 23601402 (6S)-5-CH3-H4PteGlu 23601402 (6S)-5-methyltetrahydrofolic acid 23601402 folate 23601402 folic acid 23601414 N 23601414 amino acid 23601414 amino acids 23601414 amino-acid 23601414 nitrogen 23601640 ACT 23601640 ALN 23601640 Actinorhodin 23601640 BIQ 23601640 BIQs 23601640 GRA 23601640 Gra 23601640 MED 23601640 Med 23601640 NADH 23601640 actinorhodin 23601640 alnumycin 23601640 benzoisochromanequinone 23601640 flavin 23601640 granaticin 23601640 medermycin 23601640 p-quinone 23601708 2-(1H-Pyrazol-4-yl)acetic acids 23601708 pyrazole-4-acetic acid 23602152 5-Methylcytosine 23602152 5-carboxylcytosine 23602152 5-formylcytosine 23602152 5-hydroxymethylcytosine 23602152 5-methylcytosine 23602152 5caC 23602152 5fC 23602152 5hmC 23602152 5mC 23602152 cytosines 23602152 thymine 23602441 4-phenylpiperazine-1-carbothiohydrazide 23602441 5-chloroindolin-2-one 23602441 Sunitinib 23602441 indolin-2-one 23602441 phenyl 23602441 piperazine 23602441 piperazine-1-carbothiohydrazide 23602987 phosphatidylinositol 23603004 GSH 23603004 NAC 23603004 hydroxyproline 23603004 malonaldehyde 23603004 naringin 23603004 paraquat 23603147 Arsenic 23603147 As 23603147 As2O3 23603147 arsenic 23603194 acetic acid 23603194 capsaicin 23603194 ethanol 23603194 glutamate 23603194 l-arginine 23603194 l-arginine-nitric oxide 23603202 glutamate 23603382 Arsenic 23603382 As 23603382 MDA 23603382 Na2SeO3 23603382 NaAsO2 23603382 arsenic 23603382 selenium 23603383 DPPH 23603383 TBA 23603383 flavonoid 23603383 methanol 23603383 phenolic 23603383 phenolic acids 23603383 protocatechuic acid 23603616 5-(imidazolinium-2-yl)-2-aminobenzothiolate 23603616 5-amidinium-2-aminobenzothiolate 23603616 HCl 23603616 acetic acid 23603616 amidino 23603616 amidino substituted-phenylene-bis-benzothyazoles 23603616 dihydrochloride 23603616 diimidazolinyl substituted phenylene-bisbenzothiazole 23603616 ethanol 23603616 imidazolyl substituted phenylene-benzothiazole 23603616 isophthaloyl dichloride 23603616 phenylene-bisbenzothiazoles 23603616 phthalic acid 23603616 terephthaloyl dichloride 23603856 graphene 23603856 graphenes 23603856 silicon 23603856 silicon oxide 23603902 Asp 23603902 Cys 23603902 biliverdin 23603902 carbonyl 23603902 carboxylate 23603902 methine 23603902 tetrapyrrole 23603902 thiol 23603902 vinyl 23604005 graphdiyne 23604005 graphene 23604074 polyglutamine 23604141 Azoles 23604141 Cholesterol 23604141 azole 23604141 azoles 23604141 cholesterol 23604141 clotrimazole 23604141 heme 23604141 iron 23604141 nitrogen 23604141 posaconazole 23604141 voriconazole 23604334 U62,066 23604334 saccharin 23604336 Methylphenidate 23604336 dopamine 23604336 methylphenidate 23604336 pallidum 23604490 Yb(3+) 23604718 Sparstolonin B 23604718 SsnB 23604718 isocoumarin 23605691 Oxycodone 23605691 carbamazepine 23605691 morphine 23605691 noroxycodone 23605691 noroxymorphone 23605691 oxycodone 23605691 oxymorphone 23605691 rifampicin 23605692 estrogen 23605692 fulvestrant 23605692 letrozole 23605692 poly (ADP-ribose) 23605692 progesterone 23605692 rapamycin 23605692 tamoxifen 23605693 vismodegib 23606373 PEDOT 23606373 PSS 23606373 ethylene glycol 23606373 poly(3,4-ethylenedioxythiophene) 23606373 poly(styrenesulfonate) 23606504 Fe3 O4 23606504 Graphene 23606504 Lithium 23606504 graphene 23606504 graphene oxide 23606504 lithium 23607283 99m Tc pertechnetate 23607283 Radioiodine 23607283 dUTP 23607283 deoxynucleotidyl 23607283 radioiodine 23607697 Fampridine 23607697 Fampridine PR 23607697 fampridine 23607697 fampridine PR 23607697 potassium 23607712 Ca(2+) 23607712 H(+) 23607712 bafilomycin 23607712 calcium 23607891 DPI 23607891 GSH 23607891 Magnetite 23607891 NADPH 23607891 apocynin 23607891 diphenyleneiodonium 23607891 iron 23607891 magnetite 23607891 superoxide 23607932 acetylated glucuronide methyl esters 23607932 p-Hydroxybenzoic and cinnamic acids 23607932 p-hydroxybenzoic and cinnamic acids 23607964 17-fluorinated steroids 23607964 CDB2914 23607964 CDB4124 23607964 EC304 23607964 ORG33628 23607964 Progesterone 23607964 RU-486 23607964 ZK230 211 23607964 antiprogestins 23607964 estrogen 23607964 progesterone 23608020 creatinine 23608020 nitrogen 23608020 urea 23608222 ATP 23608222 Glucose 23608222 K+ 23608222 atropine 23608222 carbamylcholine 23608222 carbohydrate 23608222 glucose 23608222 methyl nitrate 23608535 Ca(2+) 23608535 calcium 23608635 N 23608635 N,N,N-trimethyl 23608635 N-alkyl 23608635 N-butyl-(QuatButyl) 23608635 N-hexyl (QuatHexyl)-N,N-dimethyl 23608635 N-propyl-(QuatPropyl) 23608635 O-methyl 23608635 QuatHexyl 23608635 butyl 23608635 hexyl 23608635 methyl 23608635 propyl 23608957 aspirin 23608957 clopidogrel 23609225 Ar 23609225 Ar n Kr19Xe19 23609225 Ar19Kr n Xe19 23609225 Ar19Kr19Xe n 23609225 Kr 23609225 Xe 23609225 noble 23609771 5-HT 23609771 Venlafaxine 23609771 [(35)S]GTPγS 23609771 noradrenaline 23609771 serotonin 23609771 venlafaxine 23609961 2-aminoimidazolone 23609961 aldehydes 23609961 glycocyamidine 23609961 polyandrocarpamine 23609961 polyandrocarpamines A 23610058 glucose 23610058 streptozotocin 23610082 creatinine 23611293 dithiocarbamate 23611293 norepinephrine 23611309 Tm(3+)-Yb(3+) Doped β-NaYF4 23611309 fluoride 23611476 PEG 23611476 SFN 23611476 Sulforaphane 23611476 polyethylene glycol 23611476 sulforaphane 23611526 PEG 23611526 carbon 23611526 polyethylene glycol 23611691 Asp-Phe-Gly 23611691 N,N-dimethylamino 23611691 phenyl 23611819 NTA-Fe(3+) 23611819 TiO2 23611819 ZrO2 23611819 metal oxide 23611819 metal oxides 23611835 SB225002 23611835 SB265610 23611835 vinblastine 23612420 NO 23612420 PGE2 23612420 Wogonoside 23612420 flavonoid glycoside 23612420 nitric oxide 23612420 prostaglandin E2 23612420 wogonoside 23612854 BZT 23612854 Cl 23612854 Cocaine 23612854 Dopamine 23612854 benztropine 23612854 carboalkoxy 23612854 cocaine 23612854 diphenyl-ether 23612854 dopamine 23612854 tropane 23613014 Glucose 23613014 glucose 23613014 tadalafil 23613149 Carbohydrate 23613149 NADP 23613149 PbAc 23613149 carbohydrate 23613149 creatinine 23613149 fructose 23613149 glucose 23613149 glucose-6-phosphate 23613149 glutathione 23613149 lactate 23613149 lead acetate 23613149 lignans 23613149 malate 23613149 nitrogen 23613149 superoxide 23613149 urea 23613149 ω-3 fatty acids 23614400 Bi2Se3 23614462 ( - )-(7S,8R)-(4-hydroxy-3-methoxyphenylglycerol 9-O-β-d-[6-O-(E)-4-hydroxy-3,5-dimethoxyphenylpropenoyl]-glucopyranoside 23614462 ( - )-(7S,8R)-(4-hydroxyphenylglycerol 9-O-β-d-[6-O-(E)-4-hydroxy-3,5-dimethoxyphenylpropenoyl]-glucopyranoside 23614462 ( - )-(E)-3,5-dimethoxyphenylpropenoic acid 4-O-β-d-(6-O-benzoyl)-glucopyranoside 23614462 ( - )-2-hydroxy-5-methoxybenzoic acid 2-O-β-d-(6-O-benzoyl)-glucopyranoside 23614462 ( - )-4-hydroxy-3,5-dimethoxybenzoic acid 4-O-β-d-(6-O-benzoyl)-glucopyranoside 23614462 ( - )-4-hydroxy-3-methoxyphenol β-d-{6-O-[4-O-(7S,8R)-(4-hydroxy-3-methoxyphenylglycerol-8-yl)-3-methoxybenzoyl]}-glucopyranoside 23614462 Aromatic glycosides 23614709 PEDOT 23614725 8-hydroxy-2'-deoxyguanosine 23614725 GSH 23614725 NO 23614725 S 23614725 benzene 23614725 carbonyl 23614725 formaldehyde 23614725 malondialdehyde 23614725 nitric oxide 23614725 oxygen 23614725 reduced glutathione 23614725 toluene 23614725 xylene 23615512 1,4-dinitrobenzene 23615512 OPV 23615512 nitrobenzene 23615512 oligophenylene-vinylene 23615512 toluene 23615707 DDT 23615707 N-Acetylcysteine 23615707 N-acetylcysteine 23615707 NAC 23615707 dichlorodiphenyldichloroethane 23615707 dichlorodiphenyldichloroethylene 23615707 dichlorodiphenyltrichloroethane 23615707 organochlorine 23615707 oxygen 23616470 (13) C 23616470 (13) C-fluorene 23616470 (13) C-naphthalene 23616470 PAH 23616470 carbon 23616470 fluorene 23616470 naphthalene 23616470 polycyclic aromatic hydrocarbon 23616476 Carbon 23616476 DOX 23616476 Doxorubicin 23616476 Folate 23616476 PEG 23616476 carbon 23616476 doxorubicin 23616476 folic acid 23616476 poly(ethylene glycol) 23617585 carbon 23617585 glucose 23617697 NO 23617697 Nitric Oxide 23617697 O(2)-(2,4-Dinitrophenyl)diazeniumdiolate 23617697 O(2)-(2,4-dinitrophenyl)diazeniumdiolate 23617697 Oleanolic Acid 23617697 PABA 23617697 glutathione 23617697 nitric oxide 23617697 oleanolic acid 23617758 (saturated) hydrocarbons 23617758 Au13/TiO2(110) 23617758 C 23617758 C-H 23617758 O-Au 23617758 O-C 23617758 R-O-R' 23617758 TiO2 23617758 methanol 23617758 methoxy 23617758 oxygen 23617821 3-methylamphetamine 23617821 Cadmium 23617821 N-Acetylcysteine 23617821 oxygen 23619605 5-phenyl-1-pentyne 23619605 Naphthalene 23619605 naphthalene 23619606 DEHP 23619606 arachidonic acid 23619606 carbon 23619606 di(2-ethylhexyl) phthalate 23619606 fatty acid 23619606 linoleic acid 23619606 n-3/n-6 polyunsaturated, saturated, and monounsaturated FAs 23619606 oleic acid 23619606 palmitic acid 23619606 palmitoleic acid 23619606 triglyceride 23619606 α-linolenic acid 23619607 CpG 23619607 alcohol 23619607 methyl 23620211 Dabigatran 23620211 aspirin 23620211 clopidogrel 23620211 dabigatran 23620211 dabigatran etexilate 23620211 warfarin 23620263 (R,R)-diaminocyclohexane 23620263 benzene 23620263 carboxylate 23620263 furan 23620263 ketones 23620263 potassium carboxylate 23620263 pyrrole 23620263 zinc 23620263 zinc chloride 23620485 Digoxin 23620485 isradipine 23620485 sertraline 23620485 telmisartan 23620485 verapamil 23621148 mica 23621420 biotinGNeo 23621420 biotinylated guanidinoneomycin 23621420 guanidinium 23621420 guanidinoglycosides 23621420 guanidinylated neomycin 23621491 Ag 23621491 Au 23621491 C 23621491 Silver 23621491 amino acid 23621491 silver 23621521 Retinal 23621521 retinal 23621523 17-desacetoxyvinblastine 23621523 20'-deoxyvinblastine 23621523 MTT 23621523 N-oxide alkaloids 23621523 oxide 23621523 vinblastine 23621567 ATP 23621567 Lys 23621567 lysine 23622980 2,3-disubstituted indoles 23623492 Janus type nucleosides 23623492 ribo and 2'-β-C-methyl ribo Janus type nucleosides 23623752 codeine 23623752 morphine 23623752 propafenone 23623752 propranolol 23623820 1-methoxy-2-hydroxyanthraquinone 23623820 2-hydroxy-3-methyl-1-methoxyanthraquinone 23623820 2-hydroxy-3-methylanthraquinone 23623820 2-hydroxymethy-1-hydroxyanthraquinone 23623820 2-hydroxymethylanthraquinone 23623820 2-methyl-3-methoxyanthraquinone 23623820 MTS 23623820 docosanoic acid 23623820 ethyl 13(2) (S)-hydroxy-chlorophyllide a 23623820 oleanolic acid 23623820 stigmasterol 23623820 ursolic acid 23623839 N-acetylcysteine 23623839 NAC 23623839 androgen 23623839 cysteine 23623842 Cypermethrin 23623842 cypermethrin 23623842 glucose-6-phosphate 23623842 glutathione 23623842 pyrethroid 23623842 selenium 23623842 superoxide 23623842 vitamin E 23623845 DCF 23623845 dichlorofluorescin 23623845 oxygen 23623845 silica 23624115 Carvacrol 23624115 carvacrol 23624115 linalool 23624148 ATP 23624148 Sciadopitysin 23624148 adenosine triphosphate 23624148 antimycin A 23624148 biflavonoids 23624148 cAMP 23624148 glutathione 23624148 nitrotyrosine 23624148 oxygen 23624148 sciadopitysin 23624290 3,3-dibromoflavanone 23624290 Flavanone 23624290 Naltrexone 23624290 [(3)H]DAMGO 23624290 acetic acid 23624290 flavonoid 23624290 flavonoids 23624290 formalin 23624290 naltrindole 23624290 nor-binaltorphimine 23624385 CYN 23624385 cylindrospermopsin 23624394 ZEA 23624394 Zearalenone 23624394 mycoestrogen 23624394 zearalenone 23624809 nicotine 23624852 AP-5 23624852 N-methyl-D-aspartate 23624852 NMDA 23624852 acetylcholine 23624852 dihydro-beta-erythroidine 23624852 dopamine 23624852 mecamylamine 23624852 methyllycaconitine 23625175 pyruvate 23625695 Ba 23625695 Co 23625695 Ni 23625695 Se 23625813 Creatinine 23625813 creatinine 23625817 Amino Acids 23625817 amino acid 23625817 amino acids 23625817 aminoacyl 23625906 selenium 23625906 vitamins (A, C, E 23625907 Pirimicarb 23625907 carbamic 23625907 pirimicarb 23625908 1,1-Diphenyl,2-picrylhydrazyl 23625908 1,1-diphenyl,2-picrylhydrazyl 23625908 CHCl3 23625908 EtAc 23625908 Hex 23625908 chloroform 23625908 ethyl acetate 23625908 n-hexane 23625910 Organophosphate 23625910 organophosphate 23625910 organophosphorus 23625947 AMPA 23625947 Glutamate 23625947 N-hydroxypyrazole-5-glycine 23625947 NHP5G 23625947 NMDA 23625947 amino 23625947 glutamate 23625947 kainate 23625947 propyl- and ethyl-substituted NHP5G 23625947 propyl-NHP5G 23627252 PTFE 23627252 Triangulenium 23627252 alkyl 23627252 trioxatriangulenium 23627903 L-T4 23627903 cholesterol 23628345 NMDA 23628345 R-2-amino-5-phosphonopentanoate 23628345 calcium 23628345 d-AP5 23628345 glutamate 23628454 Ferulic acid 23628454 ethyl acetate 23628454 ferulic acid 23628454 glucose 23628454 rutin 23628592 3,4-methylenedioxymethamphetamine 23628592 4-methylthyoamphetamine 23628592 Amphetamine 23628592 D-amphetamine 23628592 MDMA 23628592 MTT 23628592 amphetamine 23628592 amphetamines 23628592 ecstasy 23628592 methamphetamine 23628779 14-DACA 23628896 [S3]˙(-) 23628896 sulfur 23628896 triatomic sulfur 23628896 trisulfur 23629517 urea 23629669 Hydroxyapatite 23629669 Magnetite 23629669 calcium carbonate 23629669 carbonate 23629669 dicalcium phosphate dihydrate 23629669 ferric chloride 23629669 ferrous chloride 23629669 hydroxyapatite 23629669 magnetite 23630169 C60 23630169 cyclopropyl 23630169 fluorene 23630169 fullerene 23630181 2-methacryloyloxyethyl phosphorylcholine 23630181 MPC 23630181 PMF 23630181 poly(MPC-co-VF) 23630181 vinylferrocene 23630454 Glucose 23630454 glucose 23631374 CH 23631374 Milbemycins A3 and A4 23631374 O 23631374 hydrogen 23631374 milbemycins A3 and A4 23631389 CA4 23631389 CDCl3 23631389 CMP 23631389 CMP-L-CA4 23631389 CMP-NCL-CA4 23631389 Combretastain A-4 23631389 aminoacrylate 23631389 combretastatin A-4 23631389 dithiaporphyrin 23631395 Methionine 23631395 heme 23631395 methionine 23631402 Li 23631402 Li2S 23631402 Li2Se 23631402 Li2Se2 23631402 Li2Sen 23631402 Se 23631402 SeS2 23631402 SeS7 23631402 SeSx 23631402 carbon 23631402 carbonate 23631402 ether 23631402 lithium 23631402 polyselenides 23631425 Cs+ 23631425 Li+ 23631425 Na+ 23631425 Silica 23631425 alkali-chloride 23631425 oxides 23631425 silanols 23631425 silica 23631483 4'-O-methylpuerol A 23631483 Isoflavonoids 23631483 Sedonans A-F 23631483 but-2-enolide 23631483 ent-sandwicensin 23631483 fluconazole 23631483 isoflavonoids 23631483 methanol 23631483 sedonan A 23631483 sedonans A-F 23631496 Se 23631496 Selenium 23631496 selenium 23631538 polyethylene 23631672 Chl a 23631672 Chl b 23631672 Chls 23631672 chlorophylls 23631841 N 23632085 Ca(2+) 23632085 Rottlerin 23632085 histamine 23632085 rottlerin 23632905 STZ 23632905 Streptozotocin 23632905 streptozotocin 23634642 Allene 23634642 Arene 23634642 Carbon 23634642 allene 23634642 arene 23634844 carbon 23635319 Sb 23635319 ZnO 23636129 polycarbonate 23636270 Ca(2+) 23636270 cardiolipin 23636270 fatty acyl 23636270 hydroperoxide 23636270 oleic acid 23636270 phosphatidylcholine 23636270 phosphatidylethanolamine 23636270 vitamin E 23636447 CORTISOL 23636447 Cortisol 23636447 cortisol 23636901 TiO2 23636901 silicon 23637063 Si 23637063 Silicon 23637063 silicon 23637074 C60 23637074 pentacene 23638842 (RS )-glucoraphanin 23638842 RS -GRA 23638842 glucosinolates 23638842 isothiocyanates 23639006 3α-2',2'-dimethylsuccinic acyl epi-aleuritolic acid 23639006 NO 23639006 epi-aleuritolic acid 23639103 3',5'-dimethoxymyricetin-3-O-β-d-xylopyranosyl-7-O-fucopyranosyl-(1 → 3)-β-d-glucopyranoside 23639103 3',5'-dimethoxymyricetin-7-O-fucopyranosyl-(1 → 3)-β-d-glucopyranoside 23639103 3'-methoxyquercetin-7-O-α-l-rhamnopyranosyl-3-O-α-arabinofuranosyl-(1 → 6)-β-d-glucopyranoside 23639103 3'-methoxyquercetin-7-O-β-d-fucopyranosyl-(1 → 3)-β-d-glucopyranosyl-3-O-β-xylopyranosyl-(1 → 4)-β-xylopyranoside 23639103 esters 23639103 glycosylated flavonoids 23639103 isorhamnetin glycosides 23639103 myricetin 23639103 phenolic acids 23639103 quercetin 23639115 16-deethylindanomycin 23639115 16-deethylindanomycin methyl ester 23639115 Indanomycin 23639115 indanomycin 23639115 iso-16-deethylindanomycin 23639115 iso-16-deethylindanomycin methyl ester 23639187 2-deoxy-[(3)H]-d-glucose 23639187 ATP 23639187 FFAs 23639187 Glucose 23639187 MTT 23639187 Palmitate 23639187 aspalathin 23639187 dihydrochalcone C-glucoside 23639187 free fatty acids 23639187 glucose 23639187 luteolin-7-O-glucoside 23639187 palmitate 23639187 phenylpyruvic acid-2-O-glucoside 23639187 saturated free fatty acids 23639190 1,2-benzopyrone 23639190 Coumarin 23639190 chloroform 23639190 coumarin 23639190 ethanol 23639190 ethyl acetate 23639190 hexane 23639190 phenolic 23639360 cholesterol 23639360 creatinine 23639360 fatty acid 23639360 heme 23639360 nitric oxide 23639360 nitrogen 23639360 oil red O 23639360 oxidized glutathione 23639360 oxygen 23639360 reduced glutathione 23639360 sterol 23639360 superoxide 23639360 thiobarbituric acid 23639360 triglyceride 23639360 urea 23639362 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 23639362 17β-estradiol benzoate 23639362 MPTP 23639362 dopamine 23639362 estrogen 23639362 tyrosine 23639451 Fusidic acid 23639451 PLGA 23639451 RIF 23639451 fusidic acid 23639451 methicillin 23639451 poly(D,L-lactic acid-co-glycolic acid) 23639451 rifampicin 23639451 sodium 23639451 titanium 23639539 (1)H 23639539 (13)C 23639539 1-methyl-3-alkyl-2,6-diphenylpiperidin-4-one oxime carbonates 23639539 1-methyl-3alkyl-2,6-diphenylpiperidin-4-one oximes 23639539 Amphotericin B 23639539 Streptomycin 23639539 TBAB 23639539 chloroformates 23639539 piperidin-4-one oxime carbonates 23639539 potassium carbonate 23639539 tetrabutylammonium bromide 23639544 proline 23639572 Linoleic acid 23639572 NO 23639572 deoxyribonucleotide 23639572 deoxyuridine triphosphate 23639572 free fatty acid 23639572 nitric oxide 23639572 phosphatidylinositol 23639572 poly (ADP-ribose) 23639572 wortmannin 23639586 GSH 23639586 GSSG 23639586 Triptolide 23639586 glucose 23639586 phosphoenolpyruvate 23639586 triptolide 23639626 2,3,7,8-tetrachlorodibenzo-p-dioxin 23639626 TCDD 23639626 aryl hydrocarbon 23639626 dioxin 23639626 rapamycin 23639626 tyrosine 23639653 1,5-Diarylpyrazole-3-carboxamides 23639653 1,5-diarylpyrazol-3-carboxamide 23639653 Pyrazole 23639653 amines 23639653 arachidonic acid 23639653 pyrazole 23639801 (4-[4-(3-hydroxyphenyl)-3-(4-methylphenyl)-6-oxo-1H,4H,5H,6H-pyrrolo [3,4-c] pyrazol-5-yl] benzoic acid 23639801 CID16020046 23639801 Ca2+ 23639801 LPI 23639801 lysophosphatidylinositol 23639875 PGE2 23639875 Prostaglandin E2 23639875 prostaglandin E2 23639947 CdS 23639947 CdSe 23639947 ZnO 23639947 Zno 23640072 AZD1446 23640072 Nicotine 23640072 TC-6683 23640072 acetylcholine 23640072 nicotine 23640180 Lys 23640180 arginine 23640180 lysine 23640180 lysines 23640331 Progesterone 23640331 Steroid 23640331 progesterone 23640331 steroid 23640547 chloride 23640547 magnesium 23640547 nickel 23640662 MgZnO 23640662 Si 23640662 SiO2 23640662 ZnO 23640687 epinephrine 23640687 fingolimod 23640687 niacin 23640687 prostaglandin 23640687 tamoxifen 23640687 taxanes 23640687 thiazolidinediones 23640687 timolol 23640814 Manganese-Doped Iron Oxide 23640814 Mn-doped iron oxide 23640846 Oxygen 23640846 graphene 23640846 graphenes 23640846 helium 23640846 oxygen 23640862 ATP 23640862 COENZYME Q10 23640862 NAD 23640862 NADH 23640862 NUCLEOSIDE 23640862 Nucleoside 23640862 Q10 23640862 coenzyme Q10 23640862 nitric oxide 23640862 oxygen 23640894 serine 23641914 2-methylene-1,3-dioxepane 23641914 epoxy-functionalized polyester 23641914 glycidyl methacrylate 23641914 polyester 23641914 polyesters 23641914 toluidine blue 23641942 HPMA 23641942 N-(2-hydroxypropyl)methacrylamide 23641942 histidine 23642037 Bi2Se3 23642478 Benzenesulfonamides 23642478 azole 23642478 benzenesulfonamides 23642478 cyanoacrylamide 23642478 sulfonamides 23642478 tyrphostine 23643093 2-arylbenzofuran neolignans 23643093 5-FU 23643093 5-fluorouracil 23643093 MTS 23643093 benzophenanthridine alkaloids 23643093 benzophenanthridine-type alkaloids 23643093 dibenzyl butyrolactone lignan 23643093 lignans 23643093 methanol 23643094 NDGA 23643094 Nordihydroguaiaretic acid 23643094 nordihydroguaiaretic acid 23643543 Isoliquiritigenin 23643543 Isoliquiritin 23643543 Liquiritigenin 23643543 acetonitrile 23643543 flavones 23643543 isoliquiritigenin 23643543 isoliquiritin 23643543 liquiritigenin 23643543 liquiritin 23643543 methanoic acid 23643699 2,2,3-trimethylcyclopent-3-enylacetonitrile 23643699 3-methyl-5-phenylpent-2-enenitrile 23643699 3-methyl-5-phenylpentanenitrile 23643699 Dodecanitrile 23643699 benzonitrile 23643699 cinnamyl nitrile 23643699 citronellyl nitrile 23643699 nitrile 23643699 nitriles 23643699 α-cyclohexylidene benzeneacetonitrile 23643702 6-keto-PGF1α 23643702 6-keto-prostaglandin F1α 23643702 GSH 23643702 Hydroxytyrosyl alkyl ether 23643702 TxB2 23643702 butyl 23643702 calcium 23643702 carbon 23643702 dodecyl 23643702 ether 23643702 ethers 23643702 ethyl 23643702 hexyl 23643702 hydroxytyrosol 23643702 nitrates 23643702 nitrite 23643702 nitrites 23643702 octyl 23643702 peroxides 23643702 reduced glutathione 23643702 thromboxane B2 23643743 5-HT 23643743 Meth 23643743 Methamphetamine 23643743 SC-51089 23643743 dopamine 23643743 ketoprofen 23643743 methamphetamine 23643743 monoamine 23643743 monoamines 23643743 serotonin 23643754 5-HT 23643754 5HT 23643754 ESCIT 23643754 escitalopram 23643754 serotonin 23643799 Chromium 23643799 chromium 23643845 20-epi-12,23-dihydroxy-22-oxo 23643845 22,23-dioxocholestanic 23643845 brassinosteroid 23643845 carbonyl 23643845 hecogenin 23643845 hecogenin acetate 23643845 hecogenin tosylate 23643845 pentacyclic steroidal 23644191 5-dimethyl-2-phenyl-4-[(pyridin-2-ylmethylene)-amino]-1,2-dihydro-pyrazol-3-one 23644191 Schiff base 23644191 [CuCl(PPh3)L] 23644191 copper(I) 23644191 copper(I) Schiff base 23644197 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole 23644197 2-(difluoromethyl)-1-[4,6-di-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole 23644197 4-Aminoalkoxy 23644197 4-O(CH2)3NMe2 23644197 4-substituted benzimidazole 23644197 ZSTK474 23644197 hydrochloride 23644197 phosphatidylinositol 23644202 1,3,4-oxadiazoline 23644202 2-methyl-5-nitro-1H-imidazole 23644202 MTT 23644202 Nitroimidazolyl hydrazones 23644202 acylhydrazone 23644202 hydrazone 23644202 oxadiazoline 23644204 Enmein 23644204 Taxol 23644204 diterpenoid 23644204 enmein 23644204 kaurene 23644204 oridonin 23644911 Oxytocin 23644911 oxytocin 23645211 Cd 23645211 CdCl2 23645211 MDA 23645211 cadmium 23645211 cadmium chloride 23645211 glutathione 23645211 malondialdehyde 23645211 quercetin 23645211 superoxide 23645360 lincomycin 23645360 norflurazon 23645536 acteoside 23645536 aldose 23645536 cornoside 23645536 ethyl acetate 23645536 eutigoside B 23645536 isoacteoside 23645536 n-butanol 23645536 phenolic glycosides 23645536 quercetin 23645536 rutin 23645677 H89 23645677 KN-92 23645677 calcium 23645677 carbachol 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CHEMDNER_CORPUS_BIOCREATIVE_4/CHEMDNER_DEVELOPMENT/0000755002344200234200000000000012551146051021746 5ustar mkrallingerBioinfoUnixCHEMDNER_CORPUS_BIOCREATIVE_4/CHEMDNER_DEVELOPMENT/chemdner_ann_development_13-08-18.txt0000644002344200234200000434340312204144615030522 0ustar mkrallingerBioinfoUnix22006095 A 285 294 serotonin TRIVIAL 22006095 A 498 512 venlafaxine XR TRIVIAL 22006095 A 622 636 venlafaxine XR TRIVIAL 22006095 T 0 9 Serotonin TRIVIAL 22006095 T 79 93 venlafaxine XR TRIVIAL 22056334 A 1002 1010 p,p'-DDE SYSTEMATIC 22056334 A 1016 1029 methylmercury SYSTEMATIC 22056334 A 1173 1203 polybrominated diphenyl ethers FAMILY 22056334 A 391 404 methylmercury SYSTEMATIC 22056334 A 824 856 dichlorodiphenyldichloroethylene SYSTEMATIC 22056334 A 858 866 p,p'-DDE SYSTEMATIC 22056334 A 938 945 dioxins FAMILY 22056334 A 950 956 furans FAMILY 22056334 A 958 962 PCDD ABBREVIATION 22056334 A 968 993 polychlorinated biphenyls FAMILY 22056334 A 995 999 PCBs ABBREVIATION 22079313 A 107 120 methylmercury SYSTEMATIC 22079313 A 1159 1162 DHA ABBREVIATION 22079313 A 1212 1216 MeHg FORMULA 22079313 A 122 126 MeHg FORMULA 22079313 A 20 43 N3-docosahexaenoic acid SYSTEMATIC 22079313 A 321 324 DHA ABBREVIATION 22079313 A 376 379 DHA ABBREVIATION 22079313 A 493 497 MeHg FORMULA 22079313 A 54 57 DHA ABBREVIATION 22079313 A 698 702 MeHg FORMULA 22079313 A 707 710 DHA ABBREVIATION 22079313 A 848 852 MeHg FORMULA 22079313 A 903 906 DHA ABBREVIATION 22082827 A 1076 1093 hydrogen peroxide SYSTEMATIC 22082827 A 1098 1113 malondialdehyde TRIVIAL 22082827 A 1130 1141 glutathione TRIVIAL 22082827 A 420 422 Zn FORMULA 22082827 A 425 427 Fe FORMULA 22082827 A 430 432 Pb FORMULA 22082827 A 435 437 Cu FORMULA 22082827 A 440 442 Ni FORMULA 22082827 A 508 510 Fe FORMULA 22082827 A 513 515 Pb FORMULA 22082827 A 517 519 Zn FORMULA 22082827 A 528 530 Cu FORMULA 22082827 A 535 537 Ni FORMULA 22082827 A 570 572 Ni FORMULA 22082827 A 575 577 Zn FORMULA 22082827 A 580 582 Fe FORMULA 22082827 A 585 587 Cu FORMULA 22082827 A 590 592 Pb FORMULA 22082827 A 604 606 Ni FORMULA 22082827 A 609 611 Cu FORMULA 22082827 A 614 616 Pb FORMULA 22082827 A 619 621 Zn FORMULA 22082827 A 624 626 Fe FORMULA 22082827 A 699 703 iron SYSTEMATIC 22082827 A 728 732 zinc SYSTEMATIC 22082827 A 786 792 copper SYSTEMATIC 22082827 A 817 823 nickel SYSTEMATIC 22082827 A 910 920 superoxide TRIVIAL 22082827 A 942 953 glutathione TRIVIAL 22082827 A 954 955 S FORMULA 22082827 A 972 983 glutathione TRIVIAL 22236017 A 297 305 linalool TRIVIAL 22236017 A 382 390 linalool TRIVIAL 22236017 A 395 404 terpineol TRIVIAL 22236093 A 197 219 3-methylthio-1-propene SYSTEMATIC 22239172 A 159 167 clavatol TRIVIAL 22239172 A 171 195 dimethylated tetraketide FAMILY 22239172 A 318 332 tetronic acids FAMILY 22239172 A 334 350 viridicatic acid TRIVIAL 22239172 A 355 370 terrestric acid TRIVIAL 22239172 A 381 394 ethyl acetate SYSTEMATIC 22239172 A 399 408 n-butanol SYSTEMATIC 22239172 A 591 605 tetronic acids FAMILY 22239172 A 721 735 tetronic acids FAMILY 22239172 T 0 10 Diclavatol TRIVIAL 22239172 T 15 29 tetronic acids FAMILY 22273350 A 216 230 sesquiterpenes FAMILY 22273350 A 241 253 monoterpenes FAMILY 22273350 A 266 277 triterpenes FAMILY 22273350 A 323 338 β-caryophyllene TRIVIAL 22273350 A 349 358 α-cadinol TRIVIAL 22273350 A 369 386 8S,13-cedran-diol SYSTEMATIC 22273350 A 396 407 α-terpineol TRIVIAL 22273350 A 417 427 β-eudesmol TRIVIAL 22273350 A 437 456 caryophyllene oxide SYSTEMATIC 22273350 A 469 490 ethyl iso-allocholate SYSTEMATIC 22273350 A 510 520 β-cubebene TRIVIAL 22273350 A 522 532 γ-cadinene TRIVIAL 22273350 A 534 541 cubenol TRIVIAL 22273350 A 543 553 1,8-cineol TRIVIAL 22273350 A 555 563 o-cymene TRIVIAL 22273350 A 565 575 curcumenol TRIVIAL 22273350 A 577 588 spathulenol TRIVIAL 22273350 A 590 600 friedeline TRIVIAL 22273350 A 605 617 β-sitosterol TRIVIAL 22273350 A 710 739 1,1-diphenyl-2-picrylhydrazyl SYSTEMATIC 22301814 A 1042 1049 arsenic SYSTEMATIC 22301814 A 140 147 arsenic SYSTEMATIC 22301814 A 149 155 NaAsO2 FORMULA 22301814 A 261 268 arsenic SYSTEMATIC 22301814 A 358 365 alanine TRIVIAL 22301814 A 384 393 aspartate TRIVIAL 22301814 A 458 467 bilirubin TRIVIAL 22301814 A 469 480 cholesterol TRIVIAL 22301814 A 482 486 urea TRIVIAL 22301814 A 491 501 creatinine TRIVIAL 22301814 A 634 641 arsenic SYSTEMATIC 22301814 A 709 728 thiobarbituric acid SYSTEMATIC 22301814 A 879 886 arsenic SYSTEMATIC 22301814 T 29 36 arsenic SYSTEMATIC 22301815 A 1089 1099 endosulfan TRIVIAL 22301815 A 15 25 endosulfan TRIVIAL 22301815 A 30 44 organochlorine FAMILY 22301815 A 491 501 endosulfan TRIVIAL 22301815 A 631 641 endosulfan TRIVIAL 22301815 A 643 650 Glucose TRIVIAL 22301815 A 755 762 Glucose TRIVIAL 22301815 A 774 785 glutathione TRIVIAL 22301815 A 786 787 S FORMULA 22301815 A 967 975 Cortisol TRIVIAL 22301815 T 11 23 carbohydrate FAMILY 22301815 T 154 164 endosulfan TRIVIAL 22301815 T 65 73 cortisol TRIVIAL 22312035 A 241 245 AFM1 ABBREVIATION 22312035 A 329 333 AFM1 ABBREVIATION 22312035 A 38 50 aflatoxin M1 TRIVIAL 22312035 A 500 504 AFM1 ABBREVIATION 22312035 A 52 56 AFM1 ABBREVIATION 22312035 A 680 684 AFM1 ABBREVIATION 22312035 A 893 897 AFM1 ABBREVIATION 22312035 T 17 29 aflatoxin M1 TRIVIAL 22313530 A 1103 1116 phencyclidine TRIVIAL 22313530 A 1120 1131 amphetamine TRIVIAL 22313530 A 1167 1181 [(3)H]LY459477 SYSTEMATIC 22313530 A 1703 1717 [(3)H]LY459477 SYSTEMATIC 22313530 A 1936 1945 Glutamate TRIVIAL 22313530 A 22 31 glutamate TRIVIAL 22313530 A 306 364 2-amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid SYSTEMATIC 22313530 A 307 364 -amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid SYSTEMATIC 22313530 A 366 374 LY459477 IDENTIFIER 22313530 A 526 534 LY459477 IDENTIFIER 22313530 A 651 659 LY459477 IDENTIFIER 22313530 A 781 790 glutamate TRIVIAL 22313530 A 890 899 glutamate TRIVIAL 22313530 A 990 998 LY459477 IDENTIFIER 22313530 T 33 42 glutamate TRIVIAL 22313530 T 82 94 [³H]LY459477 SYSTEMATIC 22335586 A 1131 1142 risperidone TRIVIAL 22335586 A 1206 1217 risperidone TRIVIAL 22335586 A 1298 1309 risperidone TRIVIAL 22335586 A 1587 1598 risperidone TRIVIAL 22335586 A 194 205 risperidone TRIVIAL 22335586 A 21 32 risperidone TRIVIAL 22335586 A 333 348 eudragit RL 100 FAMILY 22335586 A 353 368 eudragit RS 100 FAMILY 22335586 A 558 569 risperidone TRIVIAL 22335586 A 759 770 risperidone TRIVIAL 22335586 A 776 783 ERL 100 FAMILY 22335586 A 788 795 ERS 100 FAMILY 22335586 T 79 90 risperidone TRIVIAL 22348222 A 249 271 Trans-3(10)-caren-4-ol SYSTEMATIC 22348222 A 281 297 artemisia ketone TRIVIAL 22348222 A 307 318 1,8-cineole SYSTEMATIC 22348222 A 328 338 δ-selinene TRIVIAL 22348222 A 351 359 α-pinene TRIVIAL 22348222 A 404 416 monoterpenes FAMILY 22348222 A 464 490 sesquiterpene hydrocarbons FAMILY 22348222 A 500 524 monoterpene hydrocarbons FAMILY 22348951 A 1033 1044 glutathione TRIVIAL 22348951 A 1068 1079 reduced GSH ABBREVIATION 22348951 A 1080 1093 oxidized GSSG ABBREVIATION 22348951 A 1870 1873 GSH ABBREVIATION 22348951 A 1874 1878 GSSG ABBREVIATION 22348951 A 499 505 oxygen SYSTEMATIC 22348951 A 576 586 superoxide TRIVIAL 22352409 A 115 128 glucoraphanin TRIVIAL 22352409 A 163 175 sulforaphane TRIVIAL 22352409 A 487 500 glucoraphanin TRIVIAL 22352409 A 505 517 sulforaphane TRIVIAL 22352409 A 636 649 glucoraphanin TRIVIAL 22352409 T 30 43 glucoraphanin TRIVIAL 22352409 T 48 60 sulforaphane TRIVIAL 22360570 A 0 3 Ser FORMULA 22360570 A 4 7 Thr FORMULA 22364642 A 149 166 calcium carbonate SYSTEMATIC 22364642 A 167 175 dextrose TRIVIAL 22364642 A 218 226 dextrose TRIVIAL 22364642 A 260 277 calcium carbonate SYSTEMATIC 22364642 A 327 337 chloroform TRIVIAL 22364642 A 478 486 serratin TRIVIAL 22364642 T 0 8 Serratin TRIVIAL 22372659 A 270 279 harpagide TRIVIAL 22372659 A 281 302 7-β-hydroxy-harpagide SYSTEMATIC 22372659 A 304 310 ajugol TRIVIAL 22372659 A 312 332 5-allosyloxy-aucubin SYSTEMATIC 22372659 A 334 346 verbascoside TRIVIAL 22372659 A 386 393 arbutin TRIVIAL 22372865 A 0 23 Metformin hydrochloride SYSTEMATIC 22372865 A 1144 1151 glucose TRIVIAL 22372865 A 1311 1318 glucose TRIVIAL 22372865 A 32 41 biguanide TRIVIAL 22372865 T 75 98 metformin hydrochloride SYSTEMATIC 22381584 A 1123 1127 MCPG ABBREVIATION 22381584 A 1136 1140 CHPG ABBREVIATION 22381584 A 1205 1209 MTEP ABBREVIATION 22381584 A 1222 1228 Ca(2+) FORMULA 22381584 A 1256 1260 CHPG ABBREVIATION 22381584 A 1292 1298 Ca(2+) FORMULA 22381584 A 1304 1307 CPA ABBREVIATION 22381584 A 1308 1320 thapsigargin TRIVIAL 22381584 A 1381 1385 CHPG ABBREVIATION 22381584 A 1438 1441 TEA ABBREVIATION 22381584 A 1452 1461 potassium SYSTEMATIC 22381584 A 1498 1504 Ca(2+) FORMULA 22381584 A 1515 1524 potassium SYSTEMATIC 22381584 A 1571 1575 CHPG ABBREVIATION 22381584 A 1632 1636 CHPG ABBREVIATION 22381584 A 2047 2056 glutamate TRIVIAL 22381584 A 2317 2326 glutamate TRIVIAL 22381584 A 2403 2412 glutamate TRIVIAL 22381584 A 2532 2541 Glutamate TRIVIAL 22381584 A 391 400 Glutamate TRIVIAL 22381584 A 508 517 glutamate TRIVIAL 22381584 A 578 587 glutamate TRIVIAL 22381584 A 755 761 Ca(2+) FORMULA 22381584 A 924 928 CHPG ABBREVIATION 22381584 A 974 982 LY379268 IDENTIFIER 22381584 A 999 1002 TTX ABBREVIATION 22381584 T 64 73 glutamate TRIVIAL 22391562 A 317 322 AR323 NO CLASS 22391562 A 327 332 AR678 NO CLASS 22400496 A 150 158 steroids FAMILY 22400496 A 170 179 bibenzyls FAMILY 22400496 A 192 201 flavonoid FAMILY 22400496 A 214 223 terpenoid FAMILY 22400496 A 298 307 bibenzyls FAMILY 22400496 A 368 377 bibenzyls FAMILY 22401710 A 1174 1184 ketoprofen TRIVIAL 22401710 A 1287 1297 ketoprofen TRIVIAL 22401710 A 1416 1420 PVPP ABBREVIATION 22401710 A 1566 1576 ketoprofen TRIVIAL 22401710 A 309 319 Ketoprofen TRIVIAL 22401710 A 466 476 ketoprofen TRIVIAL 22401710 A 563 573 ketoprofen TRIVIAL 22401710 A 655 670 Eudragit RS-30D TRIVIAL 22401710 A 688 691 PEG ABBREVIATION 22401710 A 688 696 PEG 6000 TRIVIAL 22401710 A 896 903 lactose TRIVIAL 22401710 A 905 913 mannitol TRIVIAL 22401710 A 951 971 polyvinylpyrrolidone SYSTEMATIC 22401710 A 973 977 PVPP ABBREVIATION 22401710 T 49 59 ketoprofen TRIVIAL 22410775 A 29 37 tyrosine TRIVIAL 22410775 T 13 21 tyrosine TRIVIAL 22410778 A 1014 1036 adenosine triphosphate SYSTEMATIC 22410778 A 1038 1041 ATP ABBREVIATION 22410778 A 1109 1115 oxygen SYSTEMATIC 22410778 A 1409 1416 glucose TRIVIAL 22410778 A 1591 1594 ATP ABBREVIATION 22410778 A 332 339 glucose TRIVIAL 22410778 A 537 567 cyclic adenosine monophosphate SYSTEMATIC 22410778 A 568 572 cAMP ABBREVIATION 22410778 A 599 603 cAMP ABBREVIATION 22410778 A 709 713 cAMP ABBREVIATION 22410778 A 869 878 forskolin TRIVIAL 22410778 A 950 957 glucose TRIVIAL 22410778 T 65 69 cAMP ABBREVIATION 22410778 T 86 95 forskolin TRIVIAL 22424051 A 141 150 chromones FAMILY 22424051 A 152 165 anthraquinone SYSTEMATIC 22424051 A 16 75 5,7-dihydroxy-2 -(hydroxymethyl)-6,8-dimethyl-chromen-4-one SYSTEMATIC 22424051 A 167 177 flavonoids FAMILY 22424051 A 179 199 flavonoid glycosides FAMILY 22424051 A 201 208 benzene SYSTEMATIC 22424051 A 222 235 ellagic acids FAMILY 22424051 A 240 248 terpenes FAMILY 22424051 A 6 14 chromone TRIVIAL 22424051 A 83 95 melachromone TRIVIAL 22424051 T 6 14 chromone TRIVIAL 22426233 A 1167 1176 histamine TRIVIAL 22426233 A 1184 1191 calcium SYSTEMATIC 22426233 A 13 22 glutamate TRIVIAL 22426233 A 1312 1319 calcium SYSTEMATIC 22426233 A 1652 1661 Glutamate TRIVIAL 22426233 A 379 388 histamine TRIVIAL 22426233 A 410 419 glutamate TRIVIAL 22426233 A 430 437 calcium SYSTEMATIC 22426233 A 585 592 calcium SYSTEMATIC 22426233 A 617 626 glutamate TRIVIAL 22426233 A 683 692 histamine TRIVIAL 22426233 A 746 755 histamine TRIVIAL 22426233 A 867 871 cAMP ABBREVIATION 22429027 A 17 38 triterpenoid saponins FAMILY 22429027 A 188 365 3-O-β-D-glucopyranosyl (1→6)-[β-D-glucopyranosyl (1→2)]-β-D-glucopyranosyl, 28-O-β-D-glucopyranosyl (1→6)-[α-L-rhamnopyranosyl (1→2)]-β-D-glucopyranosyl 16-deoxybarringtogenol C SYSTEMATIC 22429027 A 374 523 3-O-β-D-glucopyranosyl (1→6)-[β-D-glucopyranosyl (1→2)]-β-D-glucopyranosyl, 28-O-β-D-glucopyranosyl (1→6)-β-D-glucopyranosyl 16-deoxybarringtogenol C SYSTEMATIC 22429027 A 40 56 xanthohuskisides FAMILY 22429027 A 8 16 oleanane TRIVIAL 22429027 T 8 29 triterpenoid saponins FAMILY 22430206 A 685 693 tyrosine TRIVIAL 22438091 A 0 10 Sinensetin TRIVIAL 22438091 A 124 134 sinensetin TRIVIAL 22438091 A 184 194 Sinensetin TRIVIAL 22438091 A 21 45 polymethoxylated flavone TRIVIAL 22438091 A 223 229 sterol FAMILY 22438091 A 355 365 sinensetin TRIVIAL 22438091 A 486 490 cAMP ABBREVIATION 22438091 A 529 539 sinensetin TRIVIAL 22438091 A 569 576 glucose TRIVIAL 22438091 A 670 680 sinensetin TRIVIAL 22438091 A 714 717 AMP ABBREVIATION 22438091 A 754 764 acetyl-CoA SYSTEMATIC 22438091 A 817 826 carnitine TRIVIAL 22438091 A 868 878 sinensetin TRIVIAL 22438091 A 980 990 sinensetin TRIVIAL 22438091 T 11 21 sinensetin TRIVIAL 22438103 A 381 388 ethanol SYSTEMATIC 22439867 A 0 6 Aceton SYSTEMATIC 22439867 A 127 139 diterpenoids FAMILY 22439867 A 183 215 pentacyclic myrisinane polyester FAMILY 22439867 A 229 289 3,5,10-O-triacetyl-8-O-isobutanoyl-14-O-benzoylcyclomyrsinol SYSTEMATIC 22439867 A 295 357 3,5,10,14-O-tetraacetyl-8-O-(2'-methyl butanoyl)-cyclomyrsinol SYSTEMATIC 22439867 A 366 417 3,5,10,14-O-tetracetyl-8-O-isobutanoylcyclomyrsinol SYSTEMATIC 22439867 A 463 468 (13)C FORMULA 22439867 A 474 478 (1)H FORMULA 22439867 A 8 18 chloroform TRIVIAL 22439867 T 22 46 cyclomyrsinol diterpenes FAMILY 22440717 A 372 385 17β-estradiol SYSTEMATIC 22440717 A 407 415 estrogen FAMILY 22440717 A 770 778 estrogen FAMILY 22443216 A 290 301 Monoterpene FAMILY 22443216 A 319 345 sesquiterpene hydrocarbons FAMILY 22443216 A 408 416 α-pinene TRIVIAL 22443216 A 429 441 germacrene D TRIVIAL 22443216 A 455 465 δ-3-carene SYSTEMATIC 22443216 A 480 490 γ-cadinene TRIVIAL 22443216 A 761 769 α-pinene TRIVIAL 22443216 A 771 783 germacrene D TRIVIAL 22443216 A 785 795 δ-3-carene SYSTEMATIC 22443216 A 800 810 γ-cadinene TRIVIAL 22443683 A 72 75 Ser FORMULA 22443683 A 76 79 Thr FORMULA 22443683 A 819 842 leucine carboxyl methyl SYSTEMATIC 22443683 A 871 877 methyl SYSTEMATIC 22443683 A 925 934 rapamycin TRIVIAL 22447662 A 1079 1086 alanine TRIVIAL 22447662 A 1107 1116 aspartate TRIVIAL 22447662 A 1178 1188 creatinine TRIVIAL 22447662 A 1196 1207 cholesterol TRIVIAL 22447662 A 1209 1222 urea nitrogen SYSTEMATIC 22447662 A 1227 1234 glucose TRIVIAL 22447662 A 308 321 Ascorbic acid TRIVIAL 22447662 A 431 442 glutathione TRIVIAL 22447662 A 461 480 reduced glutathione TRIVIAL 22447662 A 482 485 GSH ABBREVIATION 22447662 A 488 499 glutathione TRIVIAL 22447662 A 517 527 superoxide TRIVIAL 22447662 A 705 717 nitric oxide SYSTEMATIC 22447662 A 881 894 acetylcholine SYSTEMATIC 22447662 A 896 899 ACh ABBREVIATION 22447684 A 1362 1371 quercetin TRIVIAL 22447684 A 288 297 Quercetin TRIVIAL 22447684 A 549 560 cholesterol TRIVIAL 22447684 A 562 574 triglyceride FAMILY 22447684 A 580 599 thiobarbituric acid SYSTEMATIC 22447684 A 67 76 quercetin TRIVIAL 22447684 A 808 817 quercetin TRIVIAL 22447684 A 862 871 quercetin TRIVIAL 22447684 A 949 958 Quercetin TRIVIAL 22447684 T 0 9 Quercetin TRIVIAL 22451331 A 1018 1024 Triton TRIVIAL 22451331 A 1026 1034 fructose TRIVIAL 22451331 A 1039 1046 ethanol SYSTEMATIC 22451331 A 406 415 tyloxapol FAMILY 22451331 A 417 425 fructose TRIVIAL 22451331 A 430 437 ethanol SYSTEMATIC 22451331 A 468 481 Triton WR1339 TRIVIAL 22451331 A 514 527 triglycerides FAMILY 22451331 A 612 620 fructose TRIVIAL 22451331 A 728 735 ethanol SYSTEMATIC 22455790 A 37 51 sarmentosamide TRIVIAL 22455790 T 0 14 Sarmentosamide TRIVIAL 22455790 T 24 37 hexadienamide SYSTEMATIC 22455986 A 186 198 polyphenolic FAMILY 22455986 A 278 290 polyphenolic FAMILY 22455986 A 339 346 sterols FAMILY 22455986 A 360 372 γ-sitosterol TRIVIAL 22455986 A 542 545 MTT ABBREVIATION 22456000 A 0 12 Diphysidione TRIVIAL 22456000 A 181 220 4-(4-hydroxy-phenyl)-3H-pyran-2,6-dione SYSTEMATIC 22456000 A 24 49 p-hydroxyphenyl anhydride SYSTEMATIC 22456000 A 55 62 vitexin TRIVIAL 22456000 T 15 40 p-hydroxyphenyl anhydride SYSTEMATIC 22465815 A 1222 1231 glutamate TRIVIAL 22465815 A 1236 1244 dopamine TRIVIAL 22465815 A 1578 1587 Glutamate TRIVIAL 22465815 A 378 387 glutamate TRIVIAL 22465815 A 392 400 dopamine TRIVIAL 22465815 A 741 750 glutamate TRIVIAL 22472136 A 14 20 copper SYSTEMATIC 22472136 A 22 28 nickel SYSTEMATIC 22472136 A 351 358 arsenic SYSTEMATIC 22472136 A 36 43 cadmium SYSTEMATIC 22472136 A 45 52 arsenic SYSTEMATIC 22472136 A 515 522 cadmium SYSTEMATIC 22472136 A 54 62 chromium SYSTEMATIC 22472136 A 67 75 vanadium SYSTEMATIC 22475036 A 103 115 xantoquinone TRIVIAL 22475036 A 117 164 5α,6α-dimethoxy-7,11,14-trioxoabieta-8,12-diene SYSTEMATIC 22475036 A 180 201 oleanene triterpenoid FAMILY 22475036 A 209 236 1β,3β-dihydroxy-12-oleanene SYSTEMATIC 22475036 A 277 286 terpenoid FAMILY 22475036 A 386 390 (1)H FORMULA 22475036 A 396 401 (13)C FORMULA 22475036 A 461 462 H FORMULA 22475036 A 463 464 H FORMULA 22475036 A 81 101 abietane diterpenoid FAMILY 22475036 A 9 19 chloroform TRIVIAL 22475036 T 6 26 abietane diterpenoid FAMILY 22475047 A 26 37 monoterpene FAMILY 22475047 A 6 11 amide FAMILY 22475047 T 22 33 monoterpene FAMILY 22475047 T 6 11 amide FAMILY 22480349 A 118 155 lup-12, 20(29)-dien-3β-ol-26-oic acid SYSTEMATIC 22480349 A 157 177 moruslupenoic acid B TRIVIAL 22480349 A 16 41 pentacyclic triterpenoids FAMILY 22480349 A 183 213 lanst-5, 24-dien-3β-yl acetate SYSTEMATIC 22480349 A 215 238 moruslanosteryl acetate SYSTEMATIC 22480349 A 294 310 α-amyrin acetate SYSTEMATIC 22480349 A 312 340 β-amyrin-β-D-glucopyranoside TRIVIAL 22480349 A 345 359 betulinic acid TRIVIAL 22480349 A 4 10 lupeol TRIVIAL 22480349 A 59 90 lup-20(29)-en-3β-ol-27-oic acid SYSTEMATIC 22480349 A 92 112 moruslupenoic acid A TRIVIAL 22480349 T 4 17 triterpenoids FAMILY 22491024 A 1064 1081 6-hydroxydopamine SYSTEMATIC 22491024 A 1129 1139 Lu AF21934 IDENTIFIER 22491024 A 1223 1233 Lu AF21934 IDENTIFIER 22491024 A 1275 1281 l-DOPA ABBREVIATION 22491024 A 1486 1496 Lu AF21934 IDENTIFIER 22491024 A 156 164 dopamine TRIVIAL 22491024 A 1576 1583 calcium SYSTEMATIC 22491024 A 1728 1734 l-DOPA ABBREVIATION 22491024 A 1782 1788 l-DOPA ABBREVIATION 22491024 A 1815 1821 l-DOPA ABBREVIATION 22491024 A 2008 2017 Glutamate TRIVIAL 22491024 A 23 32 glutamate TRIVIAL 22491024 A 447 453 l-DOPA ABBREVIATION 22491024 A 490 496 l-DOPA ABBREVIATION 22491024 A 599 609 Lu AF21934 IDENTIFIER 22491024 A 779 789 Lu AF21934 IDENTIFIER 22491024 A 913 922 LSP1-2111 IDENTIFIER 22491024 A 939 949 Lu AF21934 IDENTIFIER 22491024 A 996 1007 haloperidol TRIVIAL 22491024 T 16 22 L-DOPA ABBREVIATION 22491024 T 81 90 glutamate TRIVIAL 22493952 A 1010 1034 aleuritolic acid acetate TRIVIAL 22493952 A 117 132 carboxylic acid SYSTEMATIC 22493952 A 1270 1290 3-oxo-taraxer-14-ene SYSTEMATIC 22493952 A 1294 1304 taraxerone TRIVIAL 22493952 A 1309 1321 β-sitosterol TRIVIAL 22493952 A 1330 1342 stigmasterol TRIVIAL 22493952 A 270 310 2α,3α-dihydroxytaraxer-14-en-28-oic acid SYSTEMATIC 22493952 A 333 372 2α,3α-diacetyltaraxer-14-en-28-oic acid SYSTEMATIC 22493952 A 378 438 2α,3α-di-O-carbonyl-2α,3α-dihydroxytaraxer-14-en-28-oic acid SYSTEMATIC 22493952 A 447 489 2α,3α-dipropionyltaraxer-14-en-28-oic acid SYSTEMATIC 22493952 A 565 600 3β-hydroxytaraxer-14-en-28-oic acid SYSTEMATIC 22493952 A 6 30 pentacyclic triterpenoid FAMILY 22493952 A 604 620 aleuritolic acid TRIVIAL 22493952 A 70 84 taraxer-14-ene TRIVIAL 22493952 A 722 736 maprounic acid TRIVIAL 22493952 A 742 758 aleuritolic acid TRIVIAL 22493952 A 789 803 maprounic acid TRIVIAL 22493952 A 832 862 p-bromobenzyl acetylmaprounate SYSTEMATIC 22493952 A 900 935 3α-hydroxytaraxer-14-en-28-oic acid SYSTEMATIC 22493952 A 939 958 isoaleuritolic acid TRIVIAL 22493952 A 964 1006 3α-acetyltaraxer-14-en-28-oic acid acetate SYSTEMATIC 22493952 T 4 17 triterpenoids FAMILY 22494026 A 105 115 flavonoids FAMILY 22494026 A 117 129 rhamnocitrin TRIVIAL 22494026 A 135 145 pratensein TRIVIAL 22494026 A 151 195 (3R)-7,3'-dihydroxy-2',4'-dimethoxyisoflavan SYSTEMATIC 22494026 A 201 245 (3R)-7,2'-dihydroxy-3',4'-dimethoxyisoflavan SYSTEMATIC 22494026 A 254 271 isoliquiritigenin TRIVIAL 22494026 A 26 74 3-O-rhamnocitrin-6-O-benzoyl-β-D-glucopyranoside SYSTEMATIC 22494026 A 6 24 acylated flavonoid FAMILY 22494026 T 6 14 flavonol TRIVIAL 22495969 A 0 17 Phytoecdysteroids FAMILY 22495969 A 130 148 20-hydroxyecdysone SYSTEMATIC 22495969 A 183 200 phytoecdysteroids FAMILY 22495969 T 23 41 20-hydroxyecdysone SYSTEMATIC 22499272 A 274 281 glucose TRIVIAL 22499272 A 359 371 carbohydrate FAMILY 22499272 A 375 389 streptozotocin TRIVIAL 22499272 A 391 394 STZ ABBREVIATION 22499272 A 558 565 glucose TRIVIAL 22499272 A 567 578 cholesterol TRIVIAL 22499272 A 580 593 triglycerides FAMILY 22499272 A 684 687 STZ ABBREVIATION 22499272 A 813 832 glucose-6 phosphate SYSTEMATIC 22499272 A 863 866 STZ ABBREVIATION 22499272 T 97 111 streptozotocin TRIVIAL 22503097 A 1329 1337 nitrogen SYSTEMATIC 22503097 A 289 301 Griseofulvin TRIVIAL 22503097 A 306 314 Naproxen TRIVIAL 22503097 A 899 912 hydroxypropyl SYSTEMATIC 22503097 A 927 948 sodium lauryl sulfate SYSTEMATIC 22508482 A 1501 1509 H(2)O(2) FORMULA 22508482 A 242 250 H(2)O(2) FORMULA 22508482 A 859 867 H(2)O(2) FORMULA 22511240 A 191 217 fluorescein isothiocyanate TRIVIAL 22511240 A 356 358 NO FORMULA 22511240 A 406 418 nitric oxide SYSTEMATIC 22511240 A 573 579 oxygen SYSTEMATIC 22511286 A 217 228 polyphenols FAMILY 22511286 A 233 242 xanthines FAMILY 22511286 A 350 356 oxygen SYSTEMATIC 22511286 A 607 624 hydrogen peroxide SYSTEMATIC 22511286 A 695 712 hydrogen peroxide SYSTEMATIC 22511286 A 753 769 chlorogenic acid TRIVIAL 22511286 A 774 782 caffeine TRIVIAL 22511286 T 119 127 phenolic FAMILY 22511286 T 132 140 xanthine TRIVIAL 22511286 T 14 31 hydrogen peroxide SYSTEMATIC 22511336 A 457 464 glucose TRIVIAL 22511336 A 555 566 hematoxylin TRIVIAL 22511336 A 567 572 eosin FAMILY 22511336 A 656 663 glucose TRIVIAL 22511336 A 736 743 glucose TRIVIAL 22511336 A 912 919 glucose TRIVIAL 22519721 A 388 421 poly (ethylene glycol) diacrylate FAMILY 22519721 A 833 844 rhodamine B TRIVIAL 22519721 A 956 967 rhodamine B TRIVIAL 22521210 A 143 151 estrogen FAMILY 22521210 A 1659 1668 estrogens FAMILY 22521210 A 335 344 estrogens FAMILY 22521210 A 578 586 estrogen FAMILY 22521210 A 952 961 estrogens FAMILY 22521210 T 11 20 estradiol TRIVIAL 22524504 A 1044 1055 fenofibrate TRIVIAL 22524504 A 1251 1262 fenofibrate TRIVIAL 22524504 A 174 185 fenofibrate TRIVIAL 22524504 A 399 410 fenofibrate TRIVIAL 22524504 A 505 511 sugars FAMILY 22524504 A 557 568 fenofibrate TRIVIAL 22524504 A 722 733 Fenofibrate TRIVIAL 22524504 A 851 871 polyvinylpyrrolidone SYSTEMATIC 22524504 A 881 899 amino methacrylate SYSTEMATIC 22524504 A 955 966 fenofibrate TRIVIAL 22525271 A 460 468 tyrosine TRIVIAL 22525272 A 1472 1475 ATP ABBREVIATION 22525272 A 1480 1487 lactate FAMILY 22531751 A 1453 1461 LY541850 IDENTIFIER 22531751 A 1488 1496 LY395756 IDENTIFIER 22531751 A 1517 1525 LY541850 IDENTIFIER 22531751 A 1694 1703 Glutamate TRIVIAL 22531751 A 22 31 glutamate TRIVIAL 22531751 A 818 826 LY341495 IDENTIFIER 22531751 A 888 896 LY395756 IDENTIFIER 22532499 A 28 35 glucose TRIVIAL 22532499 A 362 423 2-(n-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose SYSTEMATIC 22532499 A 478 485 Glucose TRIVIAL 22532499 A 567 574 glucose TRIVIAL 22532499 A 714 724 Vescalagin TRIVIAL 22532499 A 844 851 glucose TRIVIAL 22532499 A 945 955 vescalagin TRIVIAL 22532499 T 67 128 2-(n-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose SYSTEMATIC 22537580 A 13 35 enolic acyl phragmalin FAMILY 22537580 A 41 61 limonoid orthoesters FAMILY 22537580 A 63 79 chukvelutilide G TRIVIAL 22537580 A 88 100 chukrasine F TRIVIAL 22537580 T 13 35 enolic acyl phragmalin FAMILY 22537580 T 41 50 limonoids FAMILY 22548320 A 108 121 δ-tocotrienol TRIVIAL 22548320 A 123 144 1,7-dihydroxyxanthone SYSTEMATIC 22548320 A 149 162 globuxanthone TRIVIAL 22548320 A 16 33 calothorexanthone TRIVIAL 22548320 A 419 423 DPPH ABBREVIATION 22548320 A 6 14 xanthone TRIVIAL 22548320 A 71 80 garbogiol TRIVIAL 22548320 A 82 106 1,4,8-trihydroxyxanthone SYSTEMATIC 22548320 T 6 14 xanthone TRIVIAL 22553909 A 1010 1024 β-cyclodextrin TRIVIAL 22553909 A 1026 1030 β-CD ABBREVIATION 22553909 A 1036 1053 HP-β-cyclodextrin TRIVIAL 22553909 A 1055 1062 HP-β-CD ABBREVIATION 22553909 A 1203 1209 ITRDNT ABBREVIATION 22553909 A 1214 1221 HP-β-CD ABBREVIATION 22553909 A 1273 1276 ITR ABBREVIATION 22553909 A 1406 1412 ITRDNT ABBREVIATION 22553909 A 1493 1496 ITR ABBREVIATION 22553909 A 1512 1515 ITR ABBREVIATION 22553909 A 23 35 itraconazole TRIVIAL 22553909 A 244 268 itraconazolium dinitrate SYSTEMATIC 22553909 A 275 281 ITRDNT ABBREVIATION 22553909 A 37 40 ITR ABBREVIATION 22553909 A 516 522 ITRDNT ABBREVIATION 22553909 A 534 537 ITR ABBREVIATION 22553909 A 721 724 ITR ABBREVIATION 22553909 A 843 849 ITRDNT ABBREVIATION 22553909 A 893 896 ITR ABBREVIATION 22553909 A 971 974 ITR ABBREVIATION 22553909 A 979 985 ITRDNT ABBREVIATION 22553909 T 70 94 itraconazolium dinitrate SYSTEMATIC 22554350 A 143 152 Vitamin E FAMILY 22554350 A 547 556 vitamin E FAMILY 22554350 A 573 586 triglycerides FAMILY 22554350 A 739 748 vitamin E FAMILY 22554350 T 1 10 Vitamin E FAMILY 22564440 A 1523 1539 5-methylcytosine SYSTEMATIC 22564440 A 1544 1567 5-hydroxymethylcytosine SYSTEMATIC 22564440 A 1580 1583 CpG ABBREVIATION 22564440 A 1926 1939 valproic acid TRIVIAL 22564440 A 1977 1986 clozapine TRIVIAL 22564440 A 262 275 glutamic acid TRIVIAL 22564442 A 1004 1015 MDL-12,330A IDENTIFIER 22564442 A 1024 1034 [(3)H]GABA FORMULA 22564442 A 1051 1060 8-Br-cAMP SYSTEMATIC 22564442 A 1072 1078 AMN082 IDENTIFIER 22564442 A 1128 1139 (-)baclofen TRIVIAL 22564442 A 1164 1168 GABA ABBREVIATION 22564442 A 1183 1259 3-[[(3,4-Dichlorophenyl)methyl]amino]propyl] diethoxymethyl) phosphinic acid SYSTEMATIC 22564442 A 1261 1269 CGP52432 IDENTIFIER 22564442 A 1284 1295 (-)baclofen TRIVIAL 22564442 A 1318 1322 GABA ABBREVIATION 22564442 A 1353 1358 MMPIP ABBREVIATION 22564442 A 1373 1382 forskolin TRIVIAL 22564442 A 1390 1400 [(3)H]GABA FORMULA 22564442 A 1424 1430 AMN082 IDENTIFIER 22564442 A 1434 1445 (-)baclofen TRIVIAL 22564442 A 1698 1702 GABA ABBREVIATION 22564442 A 1740 1744 GABA ABBREVIATION 22564442 A 1922 1926 GABA ABBREVIATION 22564442 A 2013 2017 GABA ABBREVIATION 22564442 A 206 233 [(3)H]D-γ-aminobutyric acid SYSTEMATIC 22564442 A 235 245 [(3)H]GABA FORMULA 22564442 A 288 291 KCl FORMULA 22564442 A 297 301 K(+) FORMULA 22564442 A 309 319 [(3)H]GABA FORMULA 22564442 A 374 427 N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride SYSTEMATIC 22564442 A 429 435 AMN082 IDENTIFIER 22564442 A 501 538 l-(+)-2-amino-4-phosphonobutyric acid SYSTEMATIC 22564442 A 540 547 (l)-AP4 IDENTIFIER 22564442 A 588 618 (S)-3,4-dicarboxyphenylglycine SYSTEMATIC 22564442 A 620 632 (S)-3,4-DCPG SYSTEMATIC 22564442 A 662 668 AMN082 IDENTIFIER 22564442 A 67 76 glutamate TRIVIAL 22564442 A 673 680 (l)-AP4 IDENTIFIER 22564442 A 761 853 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one hydrochloride SYSTEMATIC 22564442 A 855 860 MMPIP ABBREVIATION 22564442 A 863 869 AMN082 IDENTIFIER 22564442 A 890 895 MMPIP ABBREVIATION 22564442 A 917 921 K(+) FORMULA 22564442 A 951 955 GABA ABBREVIATION 22564442 A 957 963 AMN082 IDENTIFIER 22564442 T 36 40 GABA ABBREVIATION 22577972 A 136 160 pentacyclic triterpenene FAMILY 22577972 A 245 268 pentacyclic triterpenes FAMILY 22577972 A 433 440 ethanol SYSTEMATIC 22577972 A 604 626 pentacyclic triterpene FAMILY 22577972 A 66 89 pentacyclic triterpenes FAMILY 22577972 A 698 721 pentacyclic triterpenes FAMILY 22577972 A 798 805 ethanol SYSTEMATIC 22577972 T 27 49 pentacyclic triterpene FAMILY 22578098 A 1040 1050 amino acid FAMILY 22578098 A 1153 1160 alanine TRIVIAL 22578098 A 218 224 Ca(2+) FORMULA 22578098 A 43 49 Ca(2+) FORMULA 22578098 A 576 582 Ca(2+) FORMULA 22578098 A 861 867 Ca(2+) FORMULA 22578098 A 981 988 alanine TRIVIAL 22581512 A 493 501 α-pinene TRIVIAL 22581512 A 503 511 p-cymene TRIVIAL 22581512 A 513 524 1,8-cineole SYSTEMATIC 22581512 A 530 538 limonene TRIVIAL 22581512 A 703 711 α-pinene TRIVIAL 22581512 A 905 913 α-pinene TRIVIAL 22581512 A 953 964 1,8-cineole SYSTEMATIC 22585412 A 0 15 p-Coumaric acid TRIVIAL 22585412 A 19 26 hydroxy SYSTEMATIC 22585412 A 207 222 p-coumaric acid TRIVIAL 22585412 A 306 321 p-coumaric acid TRIVIAL 22585412 A 41 54 cinnamic acid TRIVIAL 22585412 A 473 488 p-coumaric acid TRIVIAL 22585412 A 659 674 p-coumaric acid TRIVIAL 22585412 A 815 830 p-coumaric acid TRIVIAL 22585412 A 951 966 p-coumaric acid TRIVIAL 22585412 T 26 41 p-coumaric acid TRIVIAL 22591127 A 336 344 methanol SYSTEMATIC 22591127 A 345 355 chloroform TRIVIAL 22591127 A 36 46 fatty acid FAMILY 22591127 A 394 410 FA methyl esters FAMILY 22591127 A 412 416 FAME ABBREVIATION 22591127 A 435 439 FAME ABBREVIATION 22591127 A 625 633 palmitic TRIVIAL 22591127 A 635 640 C16:0 FORMULA 22591127 A 646 654 myristic TRIVIAL 22591127 A 656 661 C14:0 FORMULA 22591127 A 670 675 oleic TRIVIAL 22591127 A 677 682 C18:1 FORMULA 22591127 A 705 725 monounsaturated acid FAMILY 22591127 A 750 761 linoleic FA TRIVIAL 22591127 A 763 768 C18:2 FORMULA 22591127 A 779 790 α-linolenic TRIVIAL 22591127 A 792 797 C18:3 FORMULA 22591127 A 807 823 eicosapentaenoic SYSTEMATIC 22591127 A 955 956 H FORMULA 22591127 T 0 10 Fatty acid FAMILY 22591175 A 133 141 puerarin TRIVIAL 22591175 A 205 213 puerarin TRIVIAL 22591175 A 218 248 2-hydroxypropyl-β-cyclodextrin SYSTEMATIC 22591175 A 250 254 HPCD ABBREVIATION 22591175 A 347 351 HPCD ABBREVIATION 22591175 A 792 800 puerarin TRIVIAL 22591175 T 49 57 puerarin TRIVIAL 22607130 A 1067 1075 apigenin TRIVIAL 22607130 A 1144 1152 apigenin TRIVIAL 22607130 A 178 186 apigenin TRIVIAL 22607130 A 317 325 apigenin TRIVIAL 22607130 A 478 488 Transcutol TRIVIAL 22607130 A 502 509 Capryol TRIVIAL 22607130 A 545 553 apigenin TRIVIAL 22607130 A 623 631 apigenin TRIVIAL 22607130 A 663 671 Apigenin TRIVIAL 22607130 A 944 952 apigenin TRIVIAL 22607130 T 74 82 apigenin TRIVIAL 22610748 A 1059 1069 superoxide TRIVIAL 22610748 A 1118 1129 glutathione TRIVIAL 22610748 A 1392 1395 SCH ABBREVIATION 22610748 A 222 229 sesamin TRIVIAL 22610748 A 251 254 SCH ABBREVIATION 22610748 A 316 323 alanine TRIVIAL 22610748 A 350 359 aspartate TRIVIAL 22610748 A 407 410 SCH ABBREVIATION 22610748 A 519 522 SCH ABBREVIATION 22610748 A 542 551 bilirubin TRIVIAL 22610748 A 560 569 bilirubin TRIVIAL 22610748 A 618 629 glutathione TRIVIAL 22610748 A 642 653 glutathione TRIVIAL 22610748 A 789 792 SCH ABBREVIATION 22610748 A 871 880 bilirubin TRIVIAL 22610748 A 892 901 bilirubin TRIVIAL 22610748 A 913 916 SCH ABBREVIATION 22610748 A 993 1012 thiobarbituric acid SYSTEMATIC 22610748 T 88 95 sesamin TRIVIAL 22614004 A 1046 1049 DCA ABBREVIATION 22614004 A 1109 1124 α-ketoglutarate TRIVIAL 22614004 A 1213 1221 H(2)O(2) FORMULA 22614004 A 1775 1783 pyruvate TRIVIAL 22614004 A 375 383 pyruvate TRIVIAL 22614004 A 411 426 dichloroacetate SYSTEMATIC 22614004 A 428 431 DCA ABBREVIATION 22614004 A 443 450 glucose TRIVIAL 22614004 A 542 545 DCA ABBREVIATION 22614004 A 62 69 glucose TRIVIAL 22614004 A 908 914 prolyl TRIVIAL 22614004 A 976 979 DCA ABBREVIATION 22614014 A 296 304 cysteine TRIVIAL 22616839 A 1018 1026 Tween 20 TRIVIAL 22616839 A 1198 1206 Tween 20 TRIVIAL 22616839 A 1455 1475 Atorvastatin calcium SYSTEMATIC 22616839 A 147 167 Atorvastatin calcium SYSTEMATIC 22616839 A 215 235 Atorvastatin calcium SYSTEMATIC 22616839 A 327 335 Tween 20 TRIVIAL 22616839 A 337 345 Tween 60 TRIVIAL 22616839 A 347 355 Tween 80 TRIVIAL 22616839 A 731 739 Tween 20 TRIVIAL 22616839 A 742 750 Tween 60 TRIVIAL 22616839 A 753 761 Tween 80 TRIVIAL 22616933 A 0 11 Astaxanthin TRIVIAL 22616933 A 13 21 C40H52O4 FORMULA 22616933 A 368 379 astaxanthin TRIVIAL 22616933 A 503 514 astaxanthin TRIVIAL 22616933 A 533 544 astaxanthin TRIVIAL 22616933 A 768 779 astaxanthin TRIVIAL 22616933 A 887 898 astaxanthin TRIVIAL 22616933 T 25 36 astaxanthin TRIVIAL 22619007 A 0 9 Silibinin TRIVIAL 22619007 A 13 22 flavonoid FAMILY 22619007 A 209 218 Silibinin TRIVIAL 22619007 A 321 330 Silibinin TRIVIAL 22619007 A 483 492 Silibinin TRIVIAL 22619007 A 584 593 Silibinin TRIVIAL 22619007 A 660 669 Silibinin TRIVIAL 22619007 A 757 766 Silibinin TRIVIAL 22619007 A 872 881 Silibinin TRIVIAL 22619007 T 0 9 Silibinin TRIVIAL 22640596 A 124 186 5-[(α-D-galactopyranosyloxy) methyl]-1H-pyrrole-2-carbaldehyde SYSTEMATIC 22640596 A 195 243 6-[(α-D-galactopyranosyloxy) methyl]-3-pyridinol SYSTEMATIC 22640596 A 379 388 galactose TRIVIAL 22640596 A 437 444 pyrrole SYSTEMATIC 22640596 A 449 458 pyridinol SYSTEMATIC 22640596 A 8 29 alkaloid galactosides FAMILY 22640596 T 8 29 alkaloid galactosides FAMILY 22640631 A 1158 1167 Glutamate TRIVIAL 22640631 A 548 557 glutamate TRIVIAL 22640631 A 988 996 ketamine TRIVIAL 22646532 A 1075 1082 glucose TRIVIAL 22646532 A 594 601 glucose TRIVIAL 22664304 A 1141 1147 l-DOPA ABBREVIATION 22664304 A 1387 1396 Glutamate TRIVIAL 22664304 A 476 485 glutamate TRIVIAL 22664304 A 715 724 glutamate TRIVIAL 22664304 T 37 46 glutamate TRIVIAL 22690834 A 1453 1461 adefovir TRIVIAL 22690834 A 1577 1585 adefovir TRIVIAL 22690834 A 159 177 adefovir dipivoxil TRIVIAL 22690834 A 186 196 nucleoside FAMILY 22690834 T 48 66 adefovir dipivoxil TRIVIAL 22691039 A 19 71 2,3,6-tribromo-4,5-dihydroxybenzyl methyl sulphoxide SYSTEMATIC 22691039 A 244 255 bromophenol SYSTEMATIC 22691039 A 6 17 bromophenol SYSTEMATIC 22691039 A 95 99 EtOH FORMULA 22691039 T 6 35 bromobenzyl methyl sulphoxide SYSTEMATIC 22691108 A 128 141 ethyl acetate SYSTEMATIC 22691108 A 225 254 hydroxy-phenyl-ethyl alcohols FAMILY 22691108 A 256 272 hydroxyl-tyrosol SYSTEMATIC 22691108 A 277 284 tyrosol TRIVIAL 22691108 A 352 363 flavonoidic FAMILY 22691108 A 374 387 aromadendrine TRIVIAL 22691108 A 391 406 dihydroflavonol SYSTEMATIC 22691108 A 469 482 aromadendrine TRIVIAL 22691108 A 529 542 aromadendrine TRIVIAL 22691108 A 594 607 aromadendrine TRIVIAL 22691108 A 756 769 aromadendrine TRIVIAL 22691108 T 0 13 Aromadendrine TRIVIAL 22691108 T 38 47 flavonoid FAMILY 22694127 A 1004 1013 ibuprofen TRIVIAL 22694127 A 1053 1062 ibuprofen TRIVIAL 22694127 A 1089 1098 ibuprofen TRIVIAL 22694127 A 113 122 ibuprofen TRIVIAL 22694127 A 1189 1198 ibuprofen TRIVIAL 22694127 A 1221 1230 ibuprofen TRIVIAL 22694127 A 1272 1281 ibuprofen TRIVIAL 22694127 A 1378 1387 ibuprofen TRIVIAL 22694127 A 1418 1427 ibuprofen TRIVIAL 22694127 A 337 346 ibuprofen TRIVIAL 22694127 A 417 422 OH(-) FORMULA 22694127 A 448 457 Ibuprofen TRIVIAL 22694127 A 807 816 ibuprofen TRIVIAL 22694127 A 932 941 ibuprofen TRIVIAL 22694127 T 0 9 Ibuprofen TRIVIAL 22697341 A 1051 1059 Carbomer FAMILY 22697341 A 1417 1427 diflunisal TRIVIAL 22697341 A 251 264 butyl lactate SYSTEMATIC 22697341 A 266 270 Brij TRIVIAL 22697341 A 278 288 Transcutol TRIVIAL 22697341 A 423 436 butyl lactate SYSTEMATIC 22697341 A 920 928 Carbomer FAMILY 22697341 A 97 107 diflunisal TRIVIAL 22697341 T 57 67 diflunisal TRIVIAL 22703292 A 101 105 ABTS ABBREVIATION 22703292 A 146 156 β-carotene TRIVIAL 22703292 A 810 823 linoleic acid TRIVIAL 22703292 A 909 915 phenol SYSTEMATIC 22703292 A 92 96 DPPH ABBREVIATION 22703292 A 920 929 flavonoid FAMILY 22703341 A 112 129 feroniellides C-E MULTIPLE 22703341 A 232 245 triterpenoids FAMILY 22703341 A 256 277 feroniellides D and E MULTIPLE 22703341 A 423 440 feroniellides A-C MULTIPLE 22703341 A 512 523 isovalerate TRIVIAL 22703341 A 534 555 feroniellides D and E MULTIPLE 22703341 A 77 105 apotirucallane triterpenoids FAMILY 22703341 T 0 17 Feroniellides C-E MULTIPLE 22703341 T 23 51 apotirucallane triterpenoids FAMILY 22705273 A 44 52 chloride SYSTEMATIC 22705273 T 7 15 chloride SYSTEMATIC 22708546 A 0 19 Garcinielliptone FC TRIVIAL 22708546 A 21 24 GFC ABBREVIATION 22708546 A 320 323 GFC ABBREVIATION 22708546 A 37 60 prenylated benzophenone SYSTEMATIC 22708546 A 391 425 polyisoprenylated benzophenone GFC FAMILY 22708583 A 207 211 DPPH ABBREVIATION 22708583 A 213 217 ABTS ABBREVIATION 22708583 A 306 308 1H FORMULA 22708583 A 310 313 13C FORMULA 22708583 A 34 42 flavones FAMILY 22708583 A 407 415 Flavones FAMILY 22708583 A 473 477 DPPH ABBREVIATION 22708583 A 560 564 ABTS ABBREVIATION 22708583 A 627 635 luteolin TRIVIAL 22708583 A 672 687 ortho-dihydroxy SYSTEMATIC 22708583 A 708 715 flavone TRIVIAL 22708583 T 6 32 acylated flavone glycoside FAMILY 22708620 A 304 328 butylated hydroxytoluene SYSTEMATIC 22708620 A 330 333 BHT ABBREVIATION 22708620 A 345 351 phytol TRIVIAL 22708620 A 362 377 α-caryophyllene TRIVIAL 22708620 A 388 397 δ-elemene TRIVIAL 22708620 A 408 423 β-caryophyllene TRIVIAL 22708620 A 433 442 γ-elemene TRIVIAL 22708620 A 455 467 germacrene D TRIVIAL 22708620 A 586 615 1,1-diphenyl-2-picrylhydrazyl SYSTEMATIC 22708620 A 734 737 BHT ABBREVIATION 22708620 A 786 792 hexane SYSTEMATIC 22708639 A 233 246 acetylcholine SYSTEMATIC 22708639 A 272 280 oxytocin TRIVIAL 22708639 A 309 325 prostaglandin E2 TRIVIAL 22708639 A 327 331 PGE2 ABBREVIATION 22708639 A 554 567 acetylcholine SYSTEMATIC 22708639 A 569 577 oxytocin TRIVIAL 22708639 A 582 586 PGE2 ABBREVIATION 22708657 A 287 290 13C FORMULA 22708657 A 31 53 1β-methoxycaryol-9-one SYSTEMATIC 22708657 A 6 29 caryolane sesquiterpene FAMILY 22708657 T 6 29 caryolane sesquiterpene FAMILY 22708724 A 478 536 2-methyl-5 -(3'-methyl-but-2'-enyloxy)-[1,4]naphthoquinone SYSTEMATIC 22708724 A 544 568 prenyloxy-naphthoquinone SYSTEMATIC 22708724 A 797 808 miltefosine TRIVIAL 22708724 T 19 43 prenyloxy-naphthoquinone SYSTEMATIC 22712554 A 171 186 tsukubachelin B TRIVIAL 22712554 A 20 35 tsukubachelin B TRIVIAL 22712554 A 329 344 tsukubachelin B TRIVIAL 22712554 A 368 379 amino acids FAMILY 22712554 A 400 406 serine TRIVIAL 22712554 A 425 434 ornithine TRIVIAL 22712554 A 436 478 N-α-methyl-N-δ-hydroxy-N-δ-formylornithine SYSTEMATIC 22712554 A 480 511 N-α-methyl-N-δ-hydroxyornithine SYSTEMATIC 22712554 A 517 542 cyclic N-hydroxyornithine SYSTEMATIC 22712554 A 62 66 iron SYSTEMATIC 22712554 T 57 72 tsukubachelin B TRIVIAL 22717743 A 620 632 triglyceride FAMILY 22718571 A 114 126 swertiamarin TRIVIAL 22718571 A 160 170 Gentianine TRIVIAL 22718571 A 198 210 swertiamarin TRIVIAL 22718571 A 340 352 swertiamarin TRIVIAL 22718571 A 363 373 gentianine TRIVIAL 22718571 A 375 387 Swertiamarin TRIVIAL 22718571 A 54 66 swertiamarin TRIVIAL 22718571 A 601 611 gentianine TRIVIAL 22718571 A 834 846 swertiamarin TRIVIAL 22718571 A 857 867 gentianine TRIVIAL 22718571 A 893 905 swertiamarin TRIVIAL 22718571 T 26 38 Swertiamarin TRIVIAL 22718571 T 71 81 Gentianine TRIVIAL 22719017 A 1134 1137 Ser FORMULA 22719017 A 126 146 N-methyl-D-aspartate SYSTEMATIC 22719017 A 1302 1311 LSL 60101 IDENTIFIER 22719017 A 1317 1326 imidazole SYSTEMATIC 22719017 A 1339 1344 2-BFI SYSTEMATIC 22719017 A 1350 1358 idazoxan TRIVIAL 22719017 A 148 152 NMDA ABBREVIATION 22719017 A 15 26 imidazoline SYSTEMATIC 22719017 A 1519 1530 imidazoline SYSTEMATIC 22719017 A 232 243 imidazoline SYSTEMATIC 22719017 A 281 303 2-styryl-2-imidazoline SYSTEMATIC 22719017 A 305 314 LSL 61122 IDENTIFIER 22719017 A 317 349 2-(2-benzofuranyl)-2-imidazoline SYSTEMATIC 22719017 A 351 356 2-BFI SYSTEMATIC 22719017 A 359 411 2-(4,5-dihydroimidazol-2-yl) quinoline hydrochloride SYSTEMATIC 22719017 A 413 419 BU-224 IDENTIFIER 22719017 A 441 449 idazoxan TRIVIAL 22719017 A 554 563 LSL 61122 IDENTIFIER 22719017 A 687 695 idazoxan TRIVIAL 22719017 A 760 771 imidazoline SYSTEMATIC 22719017 T 36 47 imidazoline SYSTEMATIC 22720714 A 122 130 lyciumin TRIVIAL 22720714 A 302 306 (1)H FORMULA 22720714 A 307 311 (1)H FORMULA 22720714 T 23 29 lignan FAMILY 22720714 T 6 17 furolactone FAMILY 22722027 A 1034 1044 MDL 11,939 IDENTIFIER 22722027 A 1166 1171 TCB-2 IDENTIFIER 22722027 A 1291 1296 TCB-2 IDENTIFIER 22722027 A 1522 1527 TCB-2 IDENTIFIER 22722027 A 340 349 Serotonin TRIVIAL 22722027 A 431 440 serotonin TRIVIAL 22722027 A 839 844 TCB-2 IDENTIFIER 22722027 T 15 24 serotonin TRIVIAL 22722028 A 1393 1406 valproic acid TRIVIAL 22722028 A 1452 1458 AMN082 IDENTIFIER 22722028 A 1473 1482 glutamate TRIVIAL 22722028 A 1518 1524 MS-275 IDENTIFIER 22722028 A 1528 1532 PEPA ABBREVIATION 22722028 A 1534 1538 AMPA ABBREVIATION 22722028 A 583 596 d-cycloserine TRIVIAL 22722028 A 598 618 N-methly-d-aspartate SYSTEMATIC 22722028 A 639 645 MS-275 IDENTIFIER 22722774 A 1049 1053 NaCl FORMULA 22722774 A 1212 1216 NaCl FORMULA 22722774 A 18 32 salicylic acid TRIVIAL 22722774 A 319 323 NaCl FORMULA 22722774 A 453 463 superoxide TRIVIAL 22722774 T 62 76 salicylic acid TRIVIAL 22725249 A 204 208 PLGA ABBREVIATION 22725249 A 253 257 PLGA ABBREVIATION 22725249 A 259 263 PLGA ABBREVIATION 22725249 A 29 60 Poly-(lactide-co-glycolic acid) FAMILY 22725249 A 304 308 PLGA ABBREVIATION 22725249 A 62 66 PLGA ABBREVIATION 22725249 A 786 790 PLGA ABBREVIATION 22725249 A 856 860 PLGA ABBREVIATION 22725249 T 50 54 PLGA ABBREVIATION 22732147 A 0 8 Melamine TRIVIAL 22732147 A 161 169 melamine TRIVIAL 22732147 A 228 236 melamine TRIVIAL 22732147 A 365 373 melamine TRIVIAL 22732147 A 559 567 melamine TRIVIAL 22732147 A 734 742 melamine TRIVIAL 22732147 A 835 843 melamine TRIVIAL 22732147 T 0 8 Melamine TRIVIAL 22732440 A 231 235 GABA ABBREVIATION 22732440 A 304 308 GABA ABBREVIATION 22732440 A 524 528 GABA ABBREVIATION 22732440 A 762 853 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one SYSTEMATIC 22732440 A 871 914 methyl 3,5-diphenylpyridazine-4-carboxylate SYSTEMATIC 22732440 A 961 980 γ-aminobutyric acid SYSTEMATIC 22732440 A 984 988 GABA ABBREVIATION 22732440 T 10 14 GABA ABBREVIATION 22736625 A 950 958 estrogen FAMILY 22749926 A 1266 1274 nicotine TRIVIAL 22749926 A 1356 1364 nicotine TRIVIAL 22749926 A 1400 1413 acetylcholine SYSTEMATIC 22749926 A 1630 1643 acetylcholine SYSTEMATIC 22749926 A 265 278 acetylcholine SYSTEMATIC 22749926 A 606 614 nicotine TRIVIAL 22749926 A 729 737 nicotine TRIVIAL 22749926 A 859 867 nicotine TRIVIAL 22749926 T 0 8 Nicotine TRIVIAL 22757667 A 1008 1016 p-cymene TRIVIAL 22757667 A 629 637 Geraniol TRIVIAL 22757667 A 639 648 α-cedrene TRIVIAL 22757667 A 653 661 p-cymene TRIVIAL 22757667 A 702 710 Geraniol TRIVIAL 22757667 A 774 783 α-cedrene TRIVIAL 22761031 A 1034 1041 phospho SYSTEMATIC 22761031 A 1104 1107 AUR ABBREVIATION 22761031 A 29 38 auraptene TRIVIAL 22761031 A 40 60 7-geranyloxycoumarin SYSTEMATIC 22761031 A 448 451 AUR ABBREVIATION 22761031 A 62 65 AUR ABBREVIATION 22761031 A 650 653 AUR ABBREVIATION 22761031 A 70 88 geranyloxycoumarin SYSTEMATIC 22761031 A 864 867 AUR ABBREVIATION 22761031 T 0 9 Auraptene TRIVIAL 22761042 A 289 297 methanol SYSTEMATIC 22761042 A 299 303 MeOH FORMULA 22761042 A 373 377 MeOH FORMULA 22761042 A 402 410 n-hexane SYSTEMATIC 22761042 A 415 425 chloroform TRIVIAL 22761042 A 427 432 CHCl3 FORMULA 22761042 A 445 449 MeOH FORMULA 22761042 A 451 459 n-hexane SYSTEMATIC 22761042 A 464 469 CHCl3 FORMULA 22761042 A 627 630 MTT ABBREVIATION 22761042 A 718 746 2,2-diphenyl-1-picryhydrazyl SYSTEMATIC 22761042 A 748 752 DPPH ABBREVIATION 22761042 A 768 772 DPPH ABBREVIATION 22761042 A 784 788 MeOH FORMULA 22765351 A 0 16 Thioxodipeptides FAMILY 22765351 A 1026 1041 ammonium cation SYSTEMATIC 22765351 A 1193 1194 N FORMULA 22765351 A 1204 1212 ammonium SYSTEMATIC 22765351 A 1237 1259 thioenol anion-radical SYSTEMATIC 22765351 A 1274 1288 aminothioketyl SYSTEMATIC 22765351 A 128 139 thioxoamide SYSTEMATIC 22765351 A 1402 1408 N-C(α) FORMULA 22765351 A 1664 1672 hydrogen SYSTEMATIC 22765351 A 1685 1688 GtK ABBREVIATION 22765351 A 1691 1693 2H FORMULA 22765351 A 17 29 Gly-thio-Lys SYSTEMATIC 22765351 A 1869 1870 N FORMULA 22765351 A 1884 1890 lysine TRIVIAL 22765351 A 1891 1899 ammonium SYSTEMATIC 22765351 A 1929 1937 hydrogen SYSTEMATIC 22765351 A 227 230 GtK ABBREVIATION 22765351 A 233 235 2H FORMULA 22765351 A 243 246 AtK ABBREVIATION 22765351 A 249 251 2H FORMULA 22765351 A 263 266 AtR ABBREVIATION 22765351 A 269 271 2H FORMULA 22765351 A 31 34 GtK ABBREVIATION 22765351 A 349 375 fluoranthene anion-radical SYSTEMATIC 22765351 A 37 49 Ala-thio-Lys SYSTEMATIC 22765351 A 478 486 hydrogen SYSTEMATIC 22765351 A 51 54 AtK ABBREVIATION 22765351 A 61 73 Ala-thio-Arg SYSTEMATIC 22765351 A 672 675 GtK ABBREVIATION 22765351 A 678 680 2H FORMULA 22765351 A 688 691 AtK ABBREVIATION 22765351 A 694 696 2H FORMULA 22765351 A 708 711 AtR ABBREVIATION 22765351 A 714 716 2H FORMULA 22765351 A 75 78 AtR ABBREVIATION 22765351 A 903 906 GtK ABBREVIATION 22765351 A 909 911 2H FORMULA 22765351 A 919 922 AtK ABBREVIATION 22765351 A 925 927 2H FORMULA 22765351 A 93 98 amide FAMILY 22765351 A 939 942 AtR ABBREVIATION 22765351 A 945 947 2H FORMULA 22765351 A 999 1021 thioenol anion-radical SYSTEMATIC 22765351 T 55 66 thioxoamide SYSTEMATIC 22766391 A 174 187 acetylcholine SYSTEMATIC 22766391 A 215 227 JNJ-39393406 IDENTIFIER 22766391 A 376 388 JNJ-39393406 IDENTIFIER 22766391 A 478 490 JNJ-39393406 IDENTIFIER 22788802 A 1011 1015 H(+) FORMULA 22788802 A 1044 1048 D(+) FORMULA 22788802 A 110 116 HOD(+) FORMULA 22788802 A 1107 1113 HOD(+) FORMULA 22788802 A 12 18 HOD(+) FORMULA 22788802 A 1319 1320 H FORMULA 22788802 A 1324 1325 D FORMULA 22788802 A 1500 1507 HOCO(+) FORMULA 22788802 A 1510 1511 D FORMULA 22788802 A 1516 1523 DOCO(+) FORMULA 22788802 A 1526 1527 H FORMULA 22788802 A 213 215 OH FORMULA 22788802 A 24 26 CO FORMULA 22788802 A 263 265 OD FORMULA 22788802 A 457 465 deuteron SYSTEMATIC 22788802 A 487 493 HCO(+) FORMULA 22788802 A 498 504 DCO(+) FORMULA 22788802 A 559 565 HCO(+) FORMULA 22788802 A 570 576 DCO(+) FORMULA 22788802 A 643 649 HOD(+) FORMULA 22788802 A 758 764 HCO(+) FORMULA 22788802 A 769 775 DCO(+) FORMULA 22788802 A 822 828 HOD(+) FORMULA 22788802 A 866 868 OH FORMULA 22788802 A 872 874 OD FORMULA 22788802 A 898 902 H(+) FORMULA 22788802 A 906 910 D(+) FORMULA 22788802 A 948 952 D(+) FORMULA 22788802 A 956 960 H(+) FORMULA 22788802 T 109 111 CO FORMULA 22788802 T 62 70 deuteron SYSTEMATIC 22788802 T 99 103 HOD+ FORMULA 22790339 A 1024 1025 N FORMULA 22790339 A 1035 1050 ethylenediamine SYSTEMATIC 22790339 A 1054 1058 urea TRIVIAL 22790339 A 133 163 1,3-dimethyl-2-imidazolidinone SYSTEMATIC 22790339 A 1603 1606 DMI ABBREVIATION 22790339 A 165 168 DMI ABBREVIATION 22790339 A 1679 1694 imidazolidinone SYSTEMATIC 22790339 A 1719 1723 urea TRIVIAL 22790339 A 182 186 urea TRIVIAL 22790339 A 303 310 ammonia SYSTEMATIC 22790339 A 331 333 NH FORMULA 22790339 A 343 366 dimethylethylenediamine SYSTEMATIC 22790339 A 368 373 DMEDA ABBREVIATION 22790339 A 393 399 carbon SYSTEMATIC 22790339 A 408 412 urea TRIVIAL 22790339 A 431 434 NH3 FORMULA 22790339 A 475 495 CH3NHC2H4N(CH3)CONH2 FORMULA 22790339 A 564 581 secondary ammonia FAMILY 22790339 A 633 640 ammonia SYSTEMATIC 22790339 T 108 112 urea TRIVIAL 22790339 T 74 104 1,3-dimethyl-2-imidazolidinone SYSTEMATIC 22796110 A 518 531 acetylcholine SYSTEMATIC 22796110 A 613 626 acetylcholine SYSTEMATIC 22796428 A 1092 1101 AHN 2-005 IDENTIFIER 22796428 A 1204 1213 AHN 2-005 IDENTIFIER 22796428 A 1438 1449 benztropine TRIVIAL 22796428 A 1734 1743 AHN 2-005 IDENTIFIER 22796428 A 189 203 norepinephrine TRIVIAL 22796428 A 213 221 dopamine TRIVIAL 22796428 A 319 330 benztropine TRIVIAL 22796428 A 593 604 benztropine TRIVIAL 22796428 A 613 622 AHN 2-005 IDENTIFIER 22796428 A 783 792 AHN 2-005 IDENTIFIER 22796428 T 12 20 dopamine TRIVIAL 22796429 A 0 4 NMDA ABBREVIATION 22796429 T 4 8 NMDA ABBREVIATION 22798249 A 474 481 glucose TRIVIAL 22800435 A 475 479 CdSe FORMULA 22800435 A 480 483 ZnS FORMULA 22800435 A 687 695 wurtzite TRIVIAL 22800435 A 699 703 NiAs FORMULA 22800435 T 64 68 CdSe FORMULA 22800435 T 69 72 ZnS FORMULA 22809709 A 0 8 Dopamine TRIVIAL 22809709 A 1018 1026 nicotine TRIVIAL 22809709 A 1122 1130 nicotine TRIVIAL 22809709 A 1177 1189 mecamylamine TRIVIAL 22809709 A 1223 1241 methyllycaconitine TRIVIAL 22809709 A 1245 1254 WAY100635 IDENTIFIER 22809709 A 1296 1330 dihydro-β-erythroidinehydrobromide SYSTEMATIC 22809709 A 1332 1336 DHβE ABBREVIATION 22809709 A 1398 1406 nicotine TRIVIAL 22809709 A 1488 1497 8-OH-DPAT SYSTEMATIC 22809709 A 1614 1623 WAY100635 IDENTIFIER 22809709 A 1658 1666 nicotine TRIVIAL 22809709 A 478 486 nicotine TRIVIAL 22809709 A 619 628 serotonin TRIVIAL 22809709 A 75 83 dopamine TRIVIAL 22809709 A 752 760 nicotine TRIVIAL 22809709 A 767 775 nicotine TRIVIAL 22809709 A 843 856 acetylcholine SYSTEMATIC 22809709 A 884 896 mecamylamine TRIVIAL 22809709 A 923 932 WAY100635 IDENTIFIER 22809709 A 971 979 nicotine TRIVIAL 22809709 T 114 122 nicotine TRIVIAL 22809709 T 76 84 dopamine TRIVIAL 22812637 A 21 31 diterpenes FAMILY 22812637 A 33 49 Caesalpinolide F TRIVIAL 22812637 A 58 74 Caesalpinolide G TRIVIAL 22812637 A 8 15 cassane TRIVIAL 22812637 T 8 18 diterpenes FAMILY 22813627 A 262 284 Monoisononyl phthalate SYSTEMATIC 22813627 A 286 290 MiNP ABBREVIATION 22813627 A 293 325 mono(carboxy-isooctyl) phthalate SYSTEMATIC 22813627 A 327 332 MCiOP ABBREVIATION 22813627 A 335 368 mono(hydroxyl-isononyl) phthalate SYSTEMATIC 22813627 A 370 375 MHiNP ABBREVIATION 22813627 A 378 406 mono(oxo-isononyl) phthalate SYSTEMATIC 22813627 A 408 413 MOiNP ABBREVIATION 22813627 A 420 454 monoisononyl phthalate glucuronide SYSTEMATIC 22813627 A 456 462 MiNP-G ABBREVIATION 22813627 A 500 505 MCiOP ABBREVIATION 22813627 A 564 568 MiNP ABBREVIATION 22813627 A 570 575 MHiNP ABBREVIATION 22813627 A 577 582 MOiNP ABBREVIATION 22813627 A 588 594 MiNP-G ABBREVIATION 22813627 A 65 85 diisononyl phthalate SYSTEMATIC 22813627 A 652 664 Testosterone TRIVIAL 22813627 A 87 91 DiNP ABBREVIATION 22813627 A 937 949 testosterone TRIVIAL 22813627 T 15 36 diiosononyl phthalate SYSTEMATIC 22815312 A 1168 1181 carbamazepine TRIVIAL 22815312 A 1186 1194 rifampin TRIVIAL 22815312 A 1196 1205 estradiol TRIVIAL 22815312 A 1256 1264 rifampin TRIVIAL 22815312 A 1269 1282 carbamazepine TRIVIAL 22815312 A 1348 1357 estradiol TRIVIAL 22815312 A 1515 1524 methadone TRIVIAL 22815312 A 426 435 estradiol TRIVIAL 22815312 A 445 454 estradiol TRIVIAL 22815312 A 555 564 estradiol TRIVIAL 22815312 A 704 713 estradiol TRIVIAL 22815312 A 775 784 bupropion TRIVIAL 22815312 A 924 933 estradiol TRIVIAL 22815312 T 111 120 methadone TRIVIAL 22815312 T 47 56 estradiol TRIVIAL 22820274 A 165 176 Cholesterol TRIVIAL 22830954 A 1062 1073 sibutramine TRIVIAL 22830954 A 1079 1093 clarithromycin TRIVIAL 22830954 A 1126 1137 sibutramine TRIVIAL 22830954 A 1254 1265 sibutramine TRIVIAL 22830954 A 25 36 sibutramine TRIVIAL 22830954 A 267 278 clopidogrel TRIVIAL 22830954 A 282 296 clarithromycin TRIVIAL 22830954 A 320 331 clopidogrel TRIVIAL 22830954 A 336 350 clarithromycin TRIVIAL 22830954 A 416 427 sibutramine TRIVIAL 22830954 A 481 495 clarithromycin TRIVIAL 22830954 A 565 576 sibutramine TRIVIAL 22830954 A 631 642 clopidogrel TRIVIAL 22830954 A 683 697 clarithromycin TRIVIAL 22830954 A 750 761 clopidogrel TRIVIAL 22830954 A 880 891 sibutramine TRIVIAL 22830954 A 94 105 sibutramine TRIVIAL 22830954 A 979 990 clopidogrel TRIVIAL 22830954 T 11 22 clopidogrel TRIVIAL 22830954 T 27 41 clarithromycin TRIVIAL 22830954 T 64 75 sibutramine TRIVIAL 22835278 A 1255 1267 testosterone TRIVIAL 22835278 A 140 152 testosterone TRIVIAL 22835278 A 373 381 androgen FAMILY 22835278 A 504 516 testosterone TRIVIAL 22835278 A 546 554 androgen FAMILY 22835278 A 653 658 DHEAS ABBREVIATION 22837389 A 1104 1112 estrogen FAMILY 22837389 A 1117 1129 progesterone TRIVIAL 22837389 A 306 314 estrogen FAMILY 22837389 A 319 331 progesterone TRIVIAL 22837389 A 454 463 estradiol TRIVIAL 22837389 A 468 480 progesterone TRIVIAL 22837389 A 593 602 estradiol TRIVIAL 22837389 A 659 671 progesterone TRIVIAL 22837389 A 915 924 Estradiol TRIVIAL 22837389 T 62 71 estradiol TRIVIAL 22837389 T 76 88 progesterone TRIVIAL 22847135 A 1049 1057 naringin TRIVIAL 22847135 A 1215 1223 naringin TRIVIAL 22847135 A 1324 1332 naringin TRIVIAL 22847135 A 186 195 flavonoid FAMILY 22847135 A 366 374 naringin TRIVIAL 22847135 A 512 520 naringin TRIVIAL 22847135 A 616 619 MTT ABBREVIATION 22847135 A 761 769 Naringin TRIVIAL 22847135 T 0 8 Naringin TRIVIAL 22849377 A 1143 1148 Na(+) FORMULA 22849377 A 1160 1162 Na FORMULA 22851333 A 1042 1050 cortisol TRIVIAL 22851333 A 1611 1619 cortisol TRIVIAL 22851333 A 664 673 adenosine TRIVIAL 22854821 A 121 127 carbon SYSTEMATIC 22854821 T 85 91 carbon SYSTEMATIC 22856387 A 1019 1027 TM-25659 IDENTIFIER 22856387 A 1132 1140 TM-25659 IDENTIFIER 22856387 A 1247 1255 TM-25659 IDENTIFIER 22856387 A 644 652 TM-25659 IDENTIFIER 22856387 A 69 77 TM-25659 IDENTIFIER 22856387 A 819 827 TM-25659 IDENTIFIER 22856387 A 933 941 TM-25659 IDENTIFIER 22856387 T 60 68 TM-25659 IDENTIFIER 22864625 A 1054 1057 INH ABBREVIATION 22864625 A 1061 1062 B FORMULA 22864625 A 1134 1137 INH ABBREVIATION 22864625 A 350 359 isoniazid TRIVIAL 22864625 A 361 364 INH ABBREVIATION 22864625 A 574 579 boron SYSTEMATIC 22864625 A 610 613 INH ABBREVIATION 22864625 A 69 75 carbon SYSTEMATIC 22864625 A 893 896 INH ABBREVIATION 22864625 A 905 906 B FORMULA 22864625 T 103 109 carbon SYSTEMATIC 22864625 T 55 64 isoniazid TRIVIAL 22864625 T 83 84 B FORMULA 22864849 A 0 7 Chrysin TRIVIAL 22864849 A 1006 1014 apigenin TRIVIAL 22864849 A 1020 1028 luteolin TRIVIAL 22864849 A 1313 1320 chrysin TRIVIAL 22864849 A 1413 1420 chrysin TRIVIAL 22864849 A 1422 1430 apigenin TRIVIAL 22864849 A 1436 1444 luteolin TRIVIAL 22864849 A 1453 1457 tBHP ABBREVIATION 22864849 A 156 163 chrysin TRIVIAL 22864849 A 165 173 apigenin TRIVIAL 22864849 A 179 187 luteolin TRIVIAL 22864849 A 196 220 tert-butyl hydroperoxide SYSTEMATIC 22864849 A 222 226 tBHP ABBREVIATION 22864849 A 23 31 luteolin TRIVIAL 22864849 A 318 325 Chrysin TRIVIAL 22864849 A 327 335 apigenin TRIVIAL 22864849 A 341 349 luteolin TRIVIAL 22864849 A 36 44 flavones FAMILY 22864849 A 406 410 heme FAMILY 22864849 A 434 443 glutamate TRIVIAL 22864849 A 444 452 cysteine TRIVIAL 22864849 A 543 554 glutathione TRIVIAL 22864849 A 556 559 GSH ABBREVIATION 22864849 A 586 589 GSH ABBREVIATION 22864849 A 593 605 oxidized GSH ABBREVIATION 22864849 A 635 642 chrysin TRIVIAL 22864849 A 720 723 GSH ABBREVIATION 22864849 A 751 757 oxygen SYSTEMATIC 22864849 A 76 84 hydroxyl SYSTEMATIC 22864849 A 788 792 tBHP ABBREVIATION 22864849 A 829 836 chrysin TRIVIAL 22864849 A 838 846 apigenin TRIVIAL 22864849 A 852 860 luteolin TRIVIAL 22864849 A 9 17 apigenin TRIVIAL 22864849 A 926 952 l-buthionine-S-sulfoximine SYSTEMATIC 22864849 A 976 995 zinc protoporphyrin SYSTEMATIC 22864849 A 997 1004 Chrysin TRIVIAL 22864849 T 122 126 heme FAMILY 22864849 T 14 21 chrysin TRIVIAL 22864849 T 143 152 glutamate TRIVIAL 22864849 T 153 161 cysteine TRIVIAL 22864849 T 23 31 apigenin TRIVIAL 22864849 T 37 45 luteolin TRIVIAL 22867272 A 219 230 propranolol TRIVIAL 22867272 A 240 252 flurbiprofen TRIVIAL 22867272 T 51 62 propranolol TRIVIAL 22867272 T 67 79 flurbiprofen TRIVIAL 22871218 A 135 147 ginsenosides FAMILY 22871218 A 344 350 KH2PO4 FORMULA 22871218 A 426 438 ginsenosides FAMILY 22871218 T 20 32 ginsenosides FAMILY 22872142 A 108 116 amalgams FAMILY 22872142 A 1165 1173 amalgams FAMILY 22872142 A 149 162 methacrylates FAMILY 22872142 A 169 171 Hg FORMULA 22872142 A 726 734 amalgams FAMILY 22872142 A 985 992 alcohol FAMILY 22872142 A 99 101 Hg FORMULA 22872606 A 1116 1131 malondialdehyde TRIVIAL 22872606 A 1275 1286 glutathione TRIVIAL 22872606 A 132 144 thymoquinone TRIVIAL 22872606 A 1343 1353 superoxide TRIVIAL 22872606 T 46 58 thymoquinone TRIVIAL 22876784 A 1221 1224 MEG ABBREVIATION 22876784 A 134 137 MEG ABBREVIATION 22876784 A 18 21 MEG ABBREVIATION 22876784 A 265 268 MEG ABBREVIATION 22876784 A 3 16 Methyleugenol TRIVIAL 22876784 A 439 442 MEG ABBREVIATION 22876784 A 550 553 MEG ABBREVIATION 22876784 A 631 634 MEG ABBREVIATION 22876784 A 846 849 MEG ABBREVIATION 22876784 A 940 943 MEG ABBREVIATION 22876784 T 18 31 methyleugenol SYSTEMATIC 22876943 A 0 9 Chalcones FAMILY 22876943 A 11 39 1, 3-Diphenyl-2-propen-1-one SYSTEMATIC 22876943 A 129 139 flavonoids FAMILY 22876943 A 144 157 isoflavonoids FAMILY 22876943 A 174 183 chalcones FAMILY 22876943 A 223 232 chalcones FAMILY 22876943 A 530 539 chalcones FAMILY 22876943 A 661 669 chalcone FAMILY 22876943 A 68 74 carbon SYSTEMATIC 22876943 A 707 716 chalcones FAMILY 22876943 A 740 744 heme FAMILY 22876943 A 75 100 α, β-unsaturated carbonyl FAMILY 22876943 A 808 820 nitric oxide SYSTEMATIC 22876943 A 822 824 NO FORMULA 22876943 T 28 56 1, 3-diphenyl-2-propen-1-one SYSTEMATIC 22876949 A 0 9 Chalcones FAMILY 22876949 A 229 238 chalcones FAMILY 22876949 A 329 338 chalcones FAMILY 22876949 A 39 51 polyphenolic FAMILY 22876949 A 79 89 flavonoids FAMILY 22876949 A 850 859 chalcones FAMILY 22876949 T 0 9 Chalcones FAMILY 22876953 A 1003 1006 NAD ABBREVIATION 22876953 A 1115 1137 2'-O-acetyl-ADP-ribose SYSTEMATIC 22876953 A 1139 1149 2'-O-AADPR SYSTEMATIC 22876953 A 156 162 acetyl SYSTEMATIC 22876953 A 195 211 Nε-acetyl-lysine SYSTEMATIC 22876953 A 876 881 amide FAMILY 22876953 A 929 941 nicotinamide TRIVIAL 22876953 A 956 991 β-nicotinamide adenine dinucleotide TRIVIAL 22876953 A 993 998 β-NAD ABBREVIATION 22878908 A 0 18 Thiazolidinediones FAMILY 22878908 A 1149 1152 TZD ABBREVIATION 22878908 A 115 119 TZDs FAMILY 22878908 A 127 135 estrogen FAMILY 22878908 A 20 24 TZDs FAMILY 22878908 A 254 258 TZDs FAMILY 22878908 A 420 423 TZD ABBREVIATION 22878908 A 594 606 testosterone TRIVIAL 22878908 A 608 620 pioglitazone TRIVIAL 22878908 A 624 637 rosiglitazone TRIVIAL 22878908 A 744 748 TZDs FAMILY 22878908 A 759 768 estradiol TRIVIAL 22878908 A 830 834 TZDs FAMILY 22878908 A 880 890 oleic acid TRIVIAL 22878908 A 899 903 TZDs FAMILY 22878908 T 0 18 Thiazolidinediones FAMILY 22878908 T 20 24 TZDs FAMILY 22878908 T 90 93 TZD ABBREVIATION 22883213 A 200 209 alloferon TRIVIAL 22883213 A 239 248 alloferon TRIVIAL 22883213 A 302 303 N FORMULA 22883213 A 308 309 C FORMULA 22883213 A 325 326 N FORMULA 22883213 A 364 414 Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-His-Gly-OH FORMULA 22883213 A 429 432 Phe FORMULA 22883213 A 439 442 Tyr FORMULA 22883213 A 449 452 Trp FORMULA 22883213 A 469 478 Phe(p-Cl) FORMULA 22883213 A 489 499 Phe(p-OMe) FORMULA 22883213 A 694 710 [3-13]-alloferon TRIVIAL 22883213 A 88 97 alloferon TRIVIAL 22883213 A 99 155 H-His-Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-His-Gly-OH FORMULA 22883213 T 4 13 alloferon TRIVIAL 22884111 A 151 154 ZnO FORMULA 22884111 A 159 161 Zn FORMULA 22884111 A 168 184 sodium hydroxide SYSTEMATIC 22884111 A 189 205 ammonia solution SYSTEMATIC 22884111 A 34 37 ZnO FORMULA 22884111 A 391 394 ZnO FORMULA 22884111 A 538 541 ZnO FORMULA 22884111 A 54 57 ZnO FORMULA 22884111 A 639 642 ZnO FORMULA 22884111 A 705 708 ZnO FORMULA 22884111 T 39 42 ZnO FORMULA 22884611 A 31 42 amphetamine TRIVIAL 22884611 A 66 74 Adderall TRIVIAL 22884611 T 62 73 amphetamine TRIVIAL 22887780 A 12 31 25-hydroxyvitamin D SYSTEMATIC 22887780 A 1229 1235 25-OHD SYSTEMATIC 22887780 A 1291 1297 25-OHD SYSTEMATIC 22887780 A 1343 1349 lysine TRIVIAL 22887780 A 1354 1363 threonine TRIVIAL 22887780 A 1413 1419 25-OHD SYSTEMATIC 22887780 A 1536 1542 25-OHD SYSTEMATIC 22887780 A 1579 1585 25-OHD SYSTEMATIC 22887780 A 1800 1806 25-OHD SYSTEMATIC 22887780 A 1858 1864 25-OHD SYSTEMATIC 22887780 A 236 245 vitamin D FAMILY 22887780 A 312 318 25-OHD SYSTEMATIC 22887780 A 33 39 25-OHD SYSTEMATIC 22887780 A 416 425 vitamin D FAMILY 22887780 A 468 474 25-OHD SYSTEMATIC 22887780 A 517 527 nucleotide FAMILY 22887780 A 855 861 25-OHD SYSTEMATIC 22887780 T 0 9 Vitamin D FAMILY 22887780 T 50 69 25-hydroxyvitamin D SYSTEMATIC 22889582 A 101 116 propylene oxide SYSTEMATIC 22889582 A 149 156 guanine TRIVIAL 22889582 A 564 569 epoxy SYSTEMATIC 22889582 T 107 122 propylene oxide SYSTEMATIC 22898566 A 1026 1029 DHA ABBREVIATION 22898566 A 1034 1037 EPA ABBREVIATION 22898566 A 186 199 hydroperoxide FAMILY 22898566 A 288 300 Omega-3 PUFA FAMILY 22898566 A 48 83 omega-3 polyunsaturated fatty acids FAMILY 22898566 A 618 638 docosahexaenoic acid SYSTEMATIC 22898566 A 640 643 DHA ABBREVIATION 22898566 A 649 670 eicosapentaenoic acid SYSTEMATIC 22898566 A 672 675 EPA ABBREVIATION 22898566 A 85 90 PUFAs ABBREVIATION 22898566 A 862 865 DHA ABBREVIATION 22898566 A 870 873 EPA ABBREVIATION 22898566 A 967 970 DHA ABBREVIATION 22898566 A 975 978 EPA ABBREVIATION 22898566 T 23 58 omega-3 polyunsaturated fatty acids FAMILY 22899102 A 1002 1006 BPDE ABBREVIATION 22899102 A 122 136 benzo[a]pyrene SYSTEMATIC 22899102 A 1249 1265 BPDE glutathione TRIVIAL 22899102 A 1454 1470 BPDE glutathione TRIVIAL 22899102 A 1522 1526 BPDE ABBREVIATION 22899102 A 1545 1556 glutathione TRIVIAL 22899102 A 273 283 BP phenols FAMILY 22899102 A 348 356 sulfates FAMILY 22899102 A 484 515 BP-7,8-dihydrodiol-9,10-epoxide SYSTEMATIC 22899102 A 517 521 BPDE ABBREVIATION 22899102 A 544 555 glutathione TRIVIAL 22899102 A 589 600 glutathione TRIVIAL 22899102 A 601 602 S FORMULA 22899102 A 772 776 BPDE ABBREVIATION 22899102 A 809 820 glutathione TRIVIAL 22899102 A 871 882 glutathione TRIVIAL 22899102 A 976 987 glutathione TRIVIAL 22899102 T 131 145 benzo[a]pyrene SYSTEMATIC 22899102 T 78 89 glutathione TRIVIAL 22901687 A 1006 1016 oleuropein TRIVIAL 22901687 A 1145 1157 testosterone TRIVIAL 22901687 A 1295 1305 oleuropein TRIVIAL 22901687 A 138 150 testosterone TRIVIAL 22901687 A 1403 1413 oleuropein TRIVIAL 22901687 A 15 25 oleuropein TRIVIAL 22901687 A 1500 1513 noradrenaline TRIVIAL 22901687 A 1529 1541 testosterone TRIVIAL 22901687 A 1571 1585 corticosterone TRIVIAL 22901687 A 162 176 corticosterone TRIVIAL 22901687 A 29 37 phenolic FAMILY 22901687 A 372 382 oleuropein TRIVIAL 22901687 A 414 426 testosterone TRIVIAL 22901687 A 487 501 corticosterone TRIVIAL 22901687 A 569 579 oleuropein TRIVIAL 22901687 A 620 630 oleuropein TRIVIAL 22901687 A 644 657 noradrenaline TRIVIAL 22901687 A 665 673 nitrogen SYSTEMATIC 22901687 A 775 785 oleuropein TRIVIAL 22901687 A 848 858 oleuropein TRIVIAL 22901687 A 908 918 oleuropein TRIVIAL 22901687 A 937 945 phenolic FAMILY 22901687 T 0 10 Oleuropein TRIVIAL 22901687 T 115 129 corticosterone TRIVIAL 22901687 T 45 58 noradrenaline TRIVIAL 22901687 T 74 86 testosterone TRIVIAL 22902308 A 506 517 pravastatin TRIVIAL 22902308 A 577 586 metformin TRIVIAL 22905673 A 257 270 aminophylline TRIVIAL 22905673 A 284 292 Carbopol TRIVIAL 22905673 A 393 403 Aminofilin TRIVIAL 22905673 A 453 465 Phyllocontin TRIVIAL 22910795 A 0 7 Mercury SYSTEMATIC 22910795 A 1002 1008 Hg(2+) FORMULA 22910795 A 1177 1183 Hg(2+) FORMULA 22910795 A 1296 1302 Hg(2+) FORMULA 22910795 A 346 354 mercuric SYSTEMATIC 22910795 A 356 362 Hg(2+) FORMULA 22910795 A 374 380 Pb(2+) FORMULA 22910795 A 412 424 Pb(NO(3))(2) FORMULA 22910795 A 493 500 HgCl(2) FORMULA 22910795 A 614 620 Hg(2+) FORMULA 22910795 A 638 644 oxygen SYSTEMATIC 22910795 A 748 764 Dihydrorhodamine SYSTEMATIC 22910795 A 769 782 Rhodamine-123 TRIVIAL 22910795 A 814 830 N-acetylcysteine SYSTEMATIC 22910795 A 871 877 Hg(2+) FORMULA 22910795 T 19 27 mercuric SYSTEMATIC 22918489 A 522 525 ADP ABBREVIATION 22918489 A 871 875 zinc SYSTEMATIC 22922115 A 0 16 Organophosphorus FAMILY 22922115 A 164 170 oximes FAMILY 22922115 A 323 329 oximes FAMILY 22922115 A 513 518 soman TRIVIAL 22922115 A 99 105 serine TRIVIAL 22926007 A 1131 1142 glutathione TRIVIAL 22926007 A 1143 1144 S FORMULA 22926007 A 33 49 organophosphorus FAMILY 22926007 A 350 363 acetylcholine SYSTEMATIC 22926007 A 59 74 methylcarbamate SYSTEMATIC 22926007 A 644 654 amino acid FAMILY 22931187 A 1150 1161 di-cysteine TRIVIAL 22931187 A 1192 1198 PTZ601 IDENTIFIER 22931187 A 1364 1370 PTZ601 IDENTIFIER 22931187 A 247 253 PTZ601 IDENTIFIER 22931187 A 575 581 PTZ601 IDENTIFIER 22931187 A 67 78 [14C]PTZ601 SYSTEMATIC 22931187 A 670 676 PTZ601 IDENTIFIER 22931187 T 30 41 [¹⁴C]PTZ601 SYSTEMATIC 22935038 A 1021 1025 CORT ABBREVIATION 22935038 A 1490 1494 CORT ABBREVIATION 22935038 A 1619 1623 CORT ABBREVIATION 22935038 A 1880 1884 CORT ABBREVIATION 22935038 A 2022 2026 CORT ABBREVIATION 22935038 A 350 364 corticosterone TRIVIAL 22935038 A 366 370 CORT ABBREVIATION 22935038 A 698 702 CORT ABBREVIATION 22935038 T 11 25 corticosterone TRIVIAL 22935511 A 138 145 cocaine TRIVIAL 22935511 A 179 186 cocaine TRIVIAL 22935511 A 296 303 cocaine TRIVIAL 22935511 A 442 449 cocaine TRIVIAL 22935511 A 57 64 cocaine TRIVIAL 22935511 A 620 627 cocaine TRIVIAL 22935511 T 16 23 cocaine TRIVIAL 22935511 T 59 66 cocaine TRIVIAL 22935511 T 88 95 cocaine TRIVIAL 22935610 A 431 437 prolyl TRIVIAL 22935610 A 810 813 Ser FORMULA 22935610 T 4 10 prolyl TRIVIAL 22936348 A 117 121 COOX FAMILY 22936348 A 125 126 H FORMULA 22936348 A 128 131 CH3 FORMULA 22936348 A 133 139 CH2NH2 FORMULA 22936348 A 141 146 CH3Ph FORMULA 22936348 A 148 154 CH2NO2 FORMULA 22936348 A 160 165 CH2CN FORMULA 22936348 A 46 52 carbon SYSTEMATIC 22936348 A 516 522 CH2NO2 FORMULA 22936348 A 524 529 CH2CN FORMULA 22936348 A 531 532 H FORMULA 22936348 A 534 539 CH2Ph FORMULA 22936348 A 541 544 CH3 FORMULA 22936348 A 546 552 CH2NH2 FORMULA 22936348 A 675 676 H FORMULA 22936348 A 775 781 CH2NO2 FORMULA 22936348 A 787 792 CH2CN FORMULA 22936348 A 83 93 carboxylic SYSTEMATIC 22936348 T 0 6 Carbon SYSTEMATIC 22936348 T 39 49 carboxylic SYSTEMATIC 22939001 A 140 150 kojic acid TRIVIAL 22939001 A 152 165 malononitrile TRIVIAL 22939001 A 171 189 aromatic aldehydes FAMILY 22939001 A 45 97 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile SYSTEMATIC 22939001 A 562 578 transition metal FAMILY 22939001 T 41 93 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile SYSTEMATIC 22939899 A 144 151 retinal TRIVIAL 22939899 T 35 42 retinal TRIVIAL 22940000 A 185 194 adenosine TRIVIAL 22940000 A 239 248 adenosine TRIVIAL 22940000 A 25 34 adenosine TRIVIAL 22940000 A 339 348 adenosine TRIVIAL 22940000 T 0 9 Adenosine TRIVIAL 22940001 A 245 251 methyl SYSTEMATIC 22940001 A 252 255 CpG ABBREVIATION 22940575 A 730 747 pentylenetetrazol TRIVIAL 22940575 A 749 760 kainic acid TRIVIAL 22940575 A 762 773 pilocarpine TRIVIAL 22948775 A 649 656 glucose TRIVIAL 22948803 A 1173 1174 N FORMULA 22948803 A 835 850 2-aminopyridine SYSTEMATIC 22951949 A 0 16 Dithiocarbamates FAMILY 22951949 A 1339 1344 DEDTC ABBREVIATION 22951949 A 1370 1376 copper SYSTEMATIC 22951949 A 145 161 dithiocarbamates FAMILY 22951949 A 1467 1472 DEDTC ABBREVIATION 22951949 A 1549 1555 copper SYSTEMATIC 22951949 A 1643 1649 copper SYSTEMATIC 22951949 A 1675 1680 DEDTC ABBREVIATION 22951949 A 1744 1750 copper SYSTEMATIC 22951949 A 1834 1839 DEDTC ABBREVIATION 22951949 A 1865 1871 copper SYSTEMATIC 22951949 A 21 29 nitrogen SYSTEMATIC 22951949 A 264 270 copper SYSTEMATIC 22951949 A 332 358 N,N-diethyldithiocarbamate SYSTEMATIC 22951949 A 35 41 sulfur SYSTEMATIC 22951949 A 360 365 DEDTC ABBREVIATION 22951949 A 442 448 copper SYSTEMATIC 22951949 A 456 461 DEDTC ABBREVIATION 22951949 A 518 526 Cu-DEDTC FORMULA 22951949 A 694 700 copper SYSTEMATIC 22951949 A 733 738 DEDTC ABBREVIATION 22951949 A 801 806 DEDTC ABBREVIATION 22951949 A 919 931 DEDTC-copper SYSTEMATIC 22951949 T 0 22 Diethyldithiocarbamate SYSTEMATIC 22951949 T 93 99 copper SYSTEMATIC 22954533 A 0 6 Silver SYSTEMATIC 22954533 A 1191 1197 Silver SYSTEMATIC 22954533 A 409 416 citrate FAMILY 22954533 A 601 607 silver SYSTEMATIC 22954533 A 766 777 Neutral red TRIVIAL 22954533 A 894 900 silver SYSTEMATIC 22954533 T 0 6 Silver SYSTEMATIC 22956628 A 1071 1078 arsenic SYSTEMATIC 22956628 A 1095 1104 Bisulfite SYSTEMATIC 22956628 A 1451 1458 arsenic SYSTEMATIC 22956628 A 1537 1544 arsenic SYSTEMATIC 22956628 A 182 189 arsenic SYSTEMATIC 22956628 A 337 344 arsenic SYSTEMATIC 22956628 A 468 475 arsenic SYSTEMATIC 22956628 A 565 571 methyl SYSTEMATIC 22956628 A 701 709 NaAsO(2) FORMULA 22956628 A 718 725 arsenic SYSTEMATIC 22956628 A 9 16 arsenic SYSTEMATIC 22956628 A 94 101 Arsenic SYSTEMATIC 22956628 T 80 87 arsenic SYSTEMATIC 22956632 A 1622 1630 GDC-0152 IDENTIFIER 22956632 A 211 219 GDC-0152 IDENTIFIER 22956632 A 314 322 GDC-0152 IDENTIFIER 22956632 A 845 853 GDC-0152 IDENTIFIER 22956632 T 50 58 GDC-0152 IDENTIFIER 22961095 A 1003 1010 nitrite SYSTEMATIC 22961095 A 1011 1018 nitrate SYSTEMATIC 22961095 A 1103 1111 acrolein TRIVIAL 22961095 A 1177 1185 acrolein TRIVIAL 22961095 A 123 131 Acrolein TRIVIAL 22961095 A 1245 1254 RO32-0432 IDENTIFIER 22961095 A 1304 1312 acrolein TRIVIAL 22961095 A 161 177 cyclophosphamide TRIVIAL 22961095 A 1613 1621 acrolein TRIVIAL 22961095 A 1699 1701 NO FORMULA 22961095 A 1740 1748 acrolein TRIVIAL 22961095 A 1876 1892 cyclophosphamide TRIVIAL 22961095 A 267 275 acrolein TRIVIAL 22961095 A 382 390 Acrolein TRIVIAL 22961095 A 549 557 Acrolein TRIVIAL 22961095 A 68 84 cyclophosphamide TRIVIAL 22961095 A 689 701 nitric oxide SYSTEMATIC 22961095 A 703 705 NO FORMULA 22961095 A 788 796 acrolein TRIVIAL 22961095 A 825 833 acrolein TRIVIAL 22961095 A 871 878 nitrite SYSTEMATIC 22961095 A 879 886 nitrate SYSTEMATIC 22961095 A 984 992 acrolein TRIVIAL 22961095 T 144 152 acrolein TRIVIAL 22961095 T 178 194 cyclophosphamide TRIVIAL 22961095 T 39 51 nitric oxide SYSTEMATIC 22963497 A 219 250 gonadotrophin-releasing hormone TRIVIAL 22963497 A 252 256 GnRH ABBREVIATION 22963497 A 396 405 phoenixin NO CLASS 22963497 A 492 496 GnRH ABBREVIATION 22963497 A 575 584 phoenixin NO CLASS 22963497 A 686 690 GnRH ABBREVIATION 22963497 A 729 738 Phoenixin NO CLASS 22963497 T 30 39 phoenixin NO CLASS 22965581 A 0 6 Carbon SYSTEMATIC 22965581 A 240 245 oxide SYSTEMATIC 22965581 A 37 42 oxide SYSTEMATIC 22965581 A 410 415 oxide SYSTEMATIC 22965581 A 464 470 TiO(2) FORMULA 22965581 A 577 583 TiO(2) FORMULA 22965581 A 641 646 oxide SYSTEMATIC 22965581 A 780 786 TiO(2) FORMULA 22965581 T 19 25 carbon SYSTEMATIC 22965581 T 35 42 titania TRIVIAL 22966073 A 0 9 Cysteines FAMILY 22966073 A 1076 1084 cysteine TRIVIAL 22966073 A 1095 1105 glutamates FAMILY 22966073 A 1116 1124 cysteine TRIVIAL 22966073 A 125 134 disulfide SYSTEMATIC 22966073 A 183 192 cysteines FAMILY 22966073 A 280 289 cysteines FAMILY 22966073 A 343 349 serine TRIVIAL 22966073 A 539 547 tyrosine TRIVIAL 22966073 A 571 579 cysteine TRIVIAL 22966073 A 736 745 cysteines FAMILY 22966073 A 772 780 cysteine TRIVIAL 22966073 A 840 846 Lysine TRIVIAL 22966073 A 863 872 glutamate TRIVIAL 22966073 A 888 897 glutamate TRIVIAL 22966073 T 9 18 cysteines FAMILY 22967140 A 114 124 oestradiol TRIVIAL 22967140 A 1223 1232 oestrogen FAMILY 22967140 A 18 30 nitric oxide SYSTEMATIC 22967140 A 248 253 NADPH ABBREVIATION 22967140 A 277 287 oestradiol TRIVIAL 22967140 A 373 382 oestrogen FAMILY 22967140 A 535 545 oestradiol TRIVIAL 22967140 A 571 574 PPT ABBREVIATION 22967140 A 576 630 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol SYSTEMATIC 22967140 A 657 660 DPN ABBREVIATION 22967140 A 662 700 2,3-bis(4-hydroxyphenyl)-propionitrile SYSTEMATIC 22967140 A 70 75 NADPH ABBREVIATION 22967140 A 730 733 MPP ABBREVIATION 22967140 A 735 801 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol SYSTEMATIC 22967140 A 803 830 1H-pyrazole dihydrochloride SYSTEMATIC 22967140 A 862 867 PHTPP ABBREVIATION 22967140 A 869 941 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol SYSTEMATIC 22967140 A 958 963 NADPH ABBREVIATION 22967140 T 49 54 NADPH ABBREVIATION 22967140 T 8 17 oestrogen FAMILY 22968082 A 1028 1032 AMPH ABBREVIATION 22968082 A 1210 1214 AMPH ABBREVIATION 22968082 A 1305 1309 AMPH ABBREVIATION 22968082 A 1609 1613 AMPH ABBREVIATION 22968082 A 1666 1670 AMPH ABBREVIATION 22968082 A 1775 1779 AMPH ABBREVIATION 22968082 A 911 924 d-amphetamine TRIVIAL 22968082 A 926 930 AMPH ABBREVIATION 22972752 A 0 8 Estrogen FAMILY 22972752 A 109 118 estradiol TRIVIAL 22972752 A 1398 1406 estrogen FAMILY 22972752 T 0 8 Estrogen FAMILY 22974972 A 1082 1105 Adenosine-monophosphate SYSTEMATIC 22974972 A 1142 1152 acetyl-CoA SYSTEMATIC 22974972 A 1249 1256 HMG-CoA ABBREVIATION 22974972 A 868 879 cholesterol TRIVIAL 22974972 A 908 919 cholesterol TRIVIAL 22974972 A 982 993 cholesterol TRIVIAL 22977165 A 1049 1051 Gd FORMULA 22977165 A 1070 1081 Gadodiamide TRIVIAL 22977165 A 114 124 gadolinium SYSTEMATIC 22977165 A 1189 1196 adenine TRIVIAL 22977165 A 1288 1299 gadodiamide TRIVIAL 22977165 A 1301 1314 gadopentetate TRIVIAL 22977165 A 1320 1330 gadobenate TRIVIAL 22977165 A 1438 1440 Gd FORMULA 22977165 A 1461 1471 gadobenate TRIVIAL 22977165 A 1510 1521 Gadodiamide TRIVIAL 22977165 A 1650 1661 gadodiamide TRIVIAL 22977165 A 1667 1680 gadopentetate TRIVIAL 22977165 A 400 407 adenine TRIVIAL 22977165 A 552 563 gadodiamide TRIVIAL 22977165 A 684 694 gadoterate TRIVIAL 22977165 A 696 706 gadobutrol TRIVIAL 22977165 A 708 718 gadobenate TRIVIAL 22977165 A 720 733 gadopentetate TRIVIAL 22977165 A 739 750 gadodiamide TRIVIAL 22977165 A 784 791 adenine TRIVIAL 22977165 A 898 900 Gd FORMULA 22977165 T 102 109 adenine TRIVIAL 22977167 A 1317 1321 O(3) FORMULA 22977167 A 1576 1580 O(3) FORMULA 22977167 A 1769 1773 O(3) FORMULA 22977167 A 445 450 ozone TRIVIAL 22977167 A 452 456 O(3) FORMULA 22977167 A 841 845 O(3) FORMULA 22977167 A 855 859 O(3) FORMULA 22977167 A 876 888 carbon black TRIVIAL 22977167 A 904 908 O(3) FORMULA 22977167 T 11 16 ozone TRIVIAL 22981459 A 1367 1375 atropine TRIVIAL 22981459 A 1377 1385 diazepam TRIVIAL 22981459 A 1390 1394 HI-6 IDENTIFIER 22981459 A 364 369 oxime SYSTEMATIC 22981459 A 683 688 oxime SYSTEMATIC 22981459 A 7 24 organophosphorous FAMILY 22981796 A 585 591 copper SYSTEMATIC 22981796 A 593 595 Cu FORMULA 22981796 A 749 751 Cu FORMULA 22981796 A 850 852 Cu FORMULA 22981796 A 944 951 lactate FAMILY 22981796 A 990 996 oxygen SYSTEMATIC 22982007 A 151 170 potassium hydroxide SYSTEMATIC 22982007 A 175 196 manganese(II) nitrate SYSTEMATIC 22982007 A 26 49 trimanganese tetraoxide SYSTEMATIC 22982007 A 51 60 Mn(3)O(4) FORMULA 22982007 T 58 63 Mn3O4 FORMULA 22982218 A 154 158 PJ34 IDENTIFIER 22982218 A 264 268 PJ34 IDENTIFIER 22982218 A 368 380 radio-iodine SYSTEMATIC 22982218 A 482 486 PJ34 IDENTIFIER 22982218 A 643 647 PJ34 IDENTIFIER 22982218 A 65 78 sodium iodide SYSTEMATIC 22982218 T 19 23 PJ34 IDENTIFIER 22982248 A 1146 1150 NMDA ABBREVIATION 22982248 A 1155 1161 MK-801 IDENTIFIER 22982248 A 1209 1213 NMDA ABBREVIATION 22982248 A 1510 1514 NMDA ABBREVIATION 22982248 A 502 506 NMDA ABBREVIATION 22982248 T 0 4 NMDA ABBREVIATION 22982479 A 1340 1350 fluoxetine TRIVIAL 22982479 A 1427 1438 mirtazapine TRIVIAL 22982479 A 345 358 noradrenaline TRIVIAL 22982479 A 521 530 guanidine TRIVIAL 22982479 A 535 553 2-aminoimidazoline SYSTEMATIC 22982479 A 681 694 noradrenaline TRIVIAL 22982569 A 656 664 Tyrosine TRIVIAL 22982776 A 116 132 organophosphorus FAMILY 22982776 A 472 481 histidine TRIVIAL 22985736 A 0 26 Di-2-ethyl hexyl phthalate SYSTEMATIC 22985736 A 28 32 DEHP ABBREVIATION 22985736 A 302 306 DEHP ABBREVIATION 22985736 A 548 552 DEHP ABBREVIATION 22985736 A 583 587 DEHP ABBREVIATION 22985736 A 647 651 DEHP ABBREVIATION 22985736 A 865 869 DEHP ABBREVIATION 22985736 A 978 982 DEHP ABBREVIATION 22985736 T 0 26 Di 2-ethyl hexyl phthalate SYSTEMATIC 22986488 A 1041 1053 1,25(OH)(2)D SYSTEMATIC 22986488 A 142 151 phosphate SYSTEMATIC 22986488 A 1445 1457 1,25(OH)(2)D SYSTEMATIC 22986488 A 1550 1562 1,25(OH)(2)D SYSTEMATIC 22986488 A 159 168 phosphate SYSTEMATIC 22986488 A 1605 1617 1,25(OH)(2)D SYSTEMATIC 22986488 A 173 196 1,25-dihydroxyvitamin D SYSTEMATIC 22986488 A 198 210 1,25(OH)(2)D SYSTEMATIC 22986488 A 310 319 phosphate SYSTEMATIC 22986488 A 387 396 vitamin D FAMILY 22986488 A 506 515 vitamin D FAMILY 22986488 A 757 764 calcium SYSTEMATIC 22986488 A 766 775 phosphate SYSTEMATIC 22986488 A 82 91 phosphate SYSTEMATIC 22986488 A 909 937 Twenty five-hydroxyvitamin D SYSTEMATIC 22986488 A 939 946 25(OH)D SYSTEMATIC 22986488 T 24 36 1,25(OH)(2)D SYSTEMATIC 22986947 A 0 13 Acetaminophen TRIVIAL 22986947 A 1141 1148 A438079 IDENTIFIER 22986947 A 1174 1177 GSH ABBREVIATION 22986947 A 1450 1457 A438079 IDENTIFIER 22986947 A 15 19 APAP ABBREVIATION 22986947 A 1508 1532 tert-butyl hydroperoxide SYSTEMATIC 22986947 A 1537 1540 GSH ABBREVIATION 22986947 A 1561 1568 A438079 IDENTIFIER 22986947 A 1657 1664 A438079 IDENTIFIER 22986947 A 1673 1677 APAP ABBREVIATION 22986947 A 351 358 A438079 IDENTIFIER 22986947 A 376 380 APAP ABBREVIATION 22986947 A 546 553 A438079 IDENTIFIER 22986947 A 653 657 APAP ABBREVIATION 22986947 A 674 681 A438079 IDENTIFIER 22986947 A 707 710 GSH ABBREVIATION 22986947 A 754 755 N FORMULA 22986947 A 870 874 APAP ABBREVIATION 22986947 A 891 895 APAP ABBREVIATION 22986947 A 909 912 GSH ABBREVIATION 22986947 T 56 69 acetaminophen TRIVIAL 22987483 A 315 321 carbon SYSTEMATIC 22987483 A 98 104 carbon SYSTEMATIC 22987483 T 32 38 carbon SYSTEMATIC 22987605 A 14 20 carbon SYSTEMATIC 22987605 A 48 59 polystyrene SYSTEMATIC 22987605 T 34 40 carbon SYSTEMATIC 22989414 A 0 12 Withaferin A TRIVIAL 22989414 A 1046 1058 withaferin A TRIVIAL 22989414 A 1111 1121 withaferin TRIVIAL 22989414 A 1152 1158 Ca(2+) FORMULA 22989414 A 1197 1205 ceramide FAMILY 22989414 A 1267 1279 Withaferin A TRIVIAL 22989414 A 1366 1372 Ca(2+) FORMULA 22989414 A 138 150 Withaferin A TRIVIAL 22989414 A 1382 1391 amiloride TRIVIAL 22989414 A 1413 1432 N-acetyl-l-cysteine SYSTEMATIC 22989414 A 1455 1467 withaferin A TRIVIAL 22989414 A 1534 1546 withaferin A TRIVIAL 22989414 A 16 28 triterpenoid FAMILY 22989414 A 441 459 phosphatidylserine FAMILY 22989414 A 542 548 Ca(2+) FORMULA 22989414 A 559 565 Ca(2+) FORMULA 22989414 A 612 618 Ca(2+) FORMULA 22989414 A 646 654 ceramide FAMILY 22989414 A 672 675 ATP ABBREVIATION 22989414 A 723 735 withaferin A TRIVIAL 22989414 A 770 776 Ca(2+) FORMULA 22989414 A 800 805 Fluo3 TRIVIAL 22989414 A 854 872 phosphatidylserine FAMILY 22989414 A 963 968 DCFDA ABBREVIATION 22989414 A 986 994 ceramide FAMILY 22989414 T 0 12 Withaferin A TRIVIAL 22989414 T 24 28 Ca2+ FORMULA 22989414 T 36 44 ceramide FAMILY 22989504 A 2015 2023 curcumin TRIVIAL 22989504 A 2028 2039 resveratrol TRIVIAL 22989775 A 1116 1126 carbamates FAMILY 22989775 A 253 263 carbamates FAMILY 22989775 A 316 325 carbamate FAMILY 22989775 A 347 356 carbamate FAMILY 22989775 A 4 14 carbamates FAMILY 22989775 A 488 497 carbamate FAMILY 22989775 A 684 693 carbamate FAMILY 22989775 A 965 975 carbamates FAMILY 22989775 T 0 21 Aryl methylcarbamates FAMILY 22989775 T 69 78 carbamate FAMILY 22991293 A 148 152 zinc SYSTEMATIC 22991293 A 181 190 phosphate SYSTEMATIC 22991293 A 47 56 phosphate SYSTEMATIC 22991293 A 519 525 serine TRIVIAL 22991293 A 531 540 aspartate TRIVIAL 22991293 A 710 711 N FORMULA 22992332 A 1029 1032 VPA ABBREVIATION 22992332 A 106 119 valproic acid TRIVIAL 22992332 A 1142 1145 DCS ABBREVIATION 22992332 A 121 124 VPA ABBREVIATION 22992332 A 1220 1223 DCS ABBREVIATION 22992332 A 1228 1231 VPA ABBREVIATION 22992332 A 21 34 D-cycloserine TRIVIAL 22992332 A 286 289 DCS ABBREVIATION 22992332 A 303 306 VPA ABBREVIATION 22992332 A 36 39 DCS ABBREVIATION 22992332 A 45 75 N-methyl-D-aspartate glutamate SYSTEMATIC 22992332 A 956 959 DCS ABBREVIATION 22992332 A 964 967 VPA ABBREVIATION 22992332 T 0 13 Valproic acid TRIVIAL 22992332 T 22 35 D-cycloserine TRIVIAL 22992376 A 1220 1228 caffeine TRIVIAL 22992376 A 353 361 caffeine TRIVIAL 22992376 A 39 47 caffeine TRIVIAL 22992376 A 440 448 caffeine TRIVIAL 22992376 A 864 872 caffeine TRIVIAL 22992376 A 929 937 caffeine TRIVIAL 22992376 T 17 25 caffeine TRIVIAL 22995439 A 1082 1091 Fe(3)O(4) FORMULA 22995439 A 1298 1307 Fe(3)O(4) FORMULA 22995439 A 1513 1522 Fe(3)O(4) FORMULA 22995439 A 349 358 Fe(3)O(4) FORMULA 22995439 A 35 45 iron oxide SYSTEMATIC 22995439 A 470 479 Fe(3)O(4) FORMULA 22995439 A 582 591 Fe(3)O(4) FORMULA 22995439 A 61 70 Fe(3)O(4) FORMULA 22995439 A 740 749 Fe(3)O(4) FORMULA 22995439 A 806 815 Fe(3)O(4) FORMULA 22995439 A 848 857 Fe(3)O(4) FORMULA 22995439 T 24 34 iron oxide SYSTEMATIC 22995584 A 0 11 Epothilones FAMILY 22995584 A 1022 1038 N-acetylcysteine SYSTEMATIC 22995584 A 1040 1043 NAC ABBREVIATION 22995584 A 1119 1124 Epo A ABBREVIATION 22995584 A 1129 1134 Epo B ABBREVIATION 22995584 A 1252 1255 PTX ABBREVIATION 22995584 A 1272 1283 Epothilones FAMILY 22995584 A 136 148 epothilone A TRIVIAL 22995584 A 1393 1396 NAC ABBREVIATION 22995584 A 1442 1452 epothilone FAMILY 22995584 A 150 155 Epo A ABBREVIATION 22995584 A 1603 1614 epothilones FAMILY 22995584 A 161 173 epothilone B TRIVIAL 22995584 A 1630 1640 paclitaxel TRIVIAL 22995584 A 175 180 Epo B ABBREVIATION 22995584 A 231 241 paclitaxel TRIVIAL 22995584 A 243 246 PTX ABBREVIATION 22995584 A 259 265 taxane FAMILY 22995584 A 416 429 Hoechst 33258 TRIVIAL 22995584 A 434 450 propidium iodide TRIVIAL 22995584 A 514 520 oxygen SYSTEMATIC 22995584 A 609 614 Epo A ABBREVIATION 22995584 A 616 621 Epo B ABBREVIATION 22995584 A 626 629 PTX ABBREVIATION 22995584 A 679 689 DCFH(2)-DA ABBREVIATION 22995584 A 691 733 2',7'-dichlorodihydrofluorescein diacetate SYSTEMATIC 22995584 A 739 743 JC-1 IDENTIFIER 22995584 A 745 811 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine SYSTEMATIC 22995584 A 75 82 taxanes FAMILY 22995584 A 872 875 MTT ABBREVIATION 22995584 A 877 937 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide SYSTEMATIC 22995584 T 82 100 epothilone A and B MULTIPLE 22998221 A 333 339 span20 TRIVIAL 22998221 A 341 347 span40 TRIVIAL 22998221 A 349 355 span60 TRIVIAL 22998221 A 361 367 span80 TRIVIAL 22998221 A 373 384 cholesterol TRIVIAL 22998221 A 419 435 dicetylphosphate SYSTEMATIC 22998221 A 669 679 isradipine TRIVIAL 22998221 A 82 92 isradipine TRIVIAL 22998221 T 33 43 isradipine TRIVIAL 22998295 A 1009 1025 propylene glycol SYSTEMATIC 22998295 A 1143 1146 MTX ABBREVIATION 22998295 A 1156 1159 MTX ABBREVIATION 22998295 A 1160 1164 β-CD ABBREVIATION 22998295 A 1365 1368 MTX ABBREVIATION 22998295 A 1378 1381 MTX ABBREVIATION 22998295 A 1382 1386 β-CD ABBREVIATION 22998295 A 1442 1446 β-CD ABBREVIATION 22998295 A 1533 1536 MTX ABBREVIATION 22998295 A 1588 1591 MTX ABBREVIATION 22998295 A 542 545 MTX ABBREVIATION 22998295 A 546 550 β-CD ABBREVIATION 22998295 A 58 70 methotrexate TRIVIAL 22998295 A 603 606 MTX ABBREVIATION 22998295 A 690 693 MTX ABBREVIATION 22998295 A 72 75 MTX ABBREVIATION 22998295 A 800 803 MTX ABBREVIATION 22998295 A 804 808 β-CD ABBREVIATION 22998295 A 82 96 β-cyclodextrin TRIVIAL 22998295 A 98 102 β-CD ABBREVIATION 22998295 A 981 993 ethyl oleate SYSTEMATIC 22998295 A 995 1003 tween 80 FAMILY 22998295 T 15 29 β-cyclodextrin TRIVIAL 22998295 T 151 163 methotrexate TRIVIAL 23000249 A 1402 1410 cysteine TRIVIAL 23000249 A 1760 1763 Met FORMULA 23000249 A 1775 1778 Met FORMULA 23000249 A 1816 1819 Met FORMULA 23000249 A 1876 1880 zinc SYSTEMATIC 23000249 A 1889 1899 histidines FAMILY 23000445 A 1234 1244 wogonoside TRIVIAL 23000445 A 215 225 wogonoside TRIVIAL 23000445 A 293 303 wogonoside TRIVIAL 23000445 A 40 50 wogonoside TRIVIAL 23000445 A 520 530 wogonoside TRIVIAL 23000445 A 64 73 flavonoid FAMILY 23000445 A 695 705 wogonoside TRIVIAL 23000445 A 767 777 wogonoside TRIVIAL 23000445 A 893 903 wogonoside TRIVIAL 23000445 A 923 933 Wogonoside TRIVIAL 23000445 A 988 997 rapamycin TRIVIAL 23000445 T 0 10 Wogonoside TRIVIAL 23000446 A 1049 1065 chlorogenic acid TRIVIAL 23000446 A 1167 1177 nucleotide FAMILY 23000446 A 1308 1316 phenolic FAMILY 23000446 A 558 566 phenolic FAMILY 23000446 A 759 768 quercetin TRIVIAL 23000446 A 773 778 rutin TRIVIAL 23000446 A 923 946 methyl-methanesulfonate SYSTEMATIC 23001363 A 206 214 hydrogen SYSTEMATIC 23001363 A 335 343 hydrogen SYSTEMATIC 23001363 A 51 55 NaCl FORMULA 23001363 T 38 42 NaCl FORMULA 23003213 A 115 120 Fe3O4 FORMULA 23003213 A 495 500 Fe3O4 FORMULA 23008095 A 1203 1214 radioiodine SYSTEMATIC 23008095 A 815 826 radioiodine SYSTEMATIC 23010360 A 1014 1019 GS967 IDENTIFIER 23010360 A 1083 1088 GS967 IDENTIFIER 23010360 A 114 121 calcium SYSTEMATIC 23010360 A 1195 1197 Na FORMULA 23010360 A 1225 1227 Kr FORMULA 23010360 A 1239 1245 E-4031 IDENTIFIER 23010360 A 1291 1296 GS967 IDENTIFIER 23010360 A 1351 1362 methoxamine TRIVIAL 23010360 A 1363 1372 clofilium TRIVIAL 23010360 A 1418 1423 GS967 IDENTIFIER 23010360 A 1471 1473 Na FORMULA 23010360 A 1503 1513 flecainide TRIVIAL 23010360 A 1517 1527 ranolazine TRIVIAL 23010360 A 1590 1595 GS967 IDENTIFIER 23010360 A 1660 1665 GS967 IDENTIFIER 23010360 A 1695 1697 Na FORMULA 23010360 A 1712 1717 GS967 IDENTIFIER 23010360 A 1748 1750 Na FORMULA 23010360 A 215 217 Na FORMULA 23010360 A 27 33 sodium SYSTEMATIC 23010360 A 283 288 GS967 IDENTIFIER 23010360 A 290 371 6-[4-(trifluoromethoxy)phenyl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine SYSTEMATIC 23010360 A 417 419 Na FORMULA 23010360 A 50 52 Na FORMULA 23010360 A 509 514 GS967 IDENTIFIER 23010360 A 632 637 GS967 IDENTIFIER 23010360 A 742 747 GS967 IDENTIFIER 23010360 A 808 810 Na FORMULA 23010360 A 930 932 Na FORMULA 23010360 A 937 942 GS967 IDENTIFIER 23010360 A 97 103 sodium SYSTEMATIC 23010360 T 57 63 sodium SYSTEMATIC 23010565 A 1316 1319 PEI ABBREVIATION 23010565 A 1364 1367 OAM ABBREVIATION 23010565 A 1525 1551 glyceraldehyde 3-phosphate SYSTEMATIC 23010565 A 801 817 polyethylenimine SYSTEMATIC 23010565 A 819 822 PEI ABBREVIATION 23010565 A 846 856 oleylamine SYSTEMATIC 23010565 A 858 861 OAM ABBREVIATION 23010565 A 877 886 monoolein TRIVIAL 23010670 A 1123 1137 methylchavicol SYSTEMATIC 23010670 A 258 275 sodium dichromate SYSTEMATIC 23010670 A 351 367 ethidium bromide SYSTEMATIC 23010670 A 695 702 alanine TRIVIAL 23010670 A 730 739 aspartate TRIVIAL 23010670 A 829 840 hematoxylin TRIVIAL 23010670 A 845 850 eosin FAMILY 23014761 A 1048 1057 erlotinib TRIVIAL 23014761 A 1118 1127 elacridar TRIVIAL 23014761 A 1151 1160 erlotinib TRIVIAL 23014761 A 512 521 erlotinib TRIVIAL 23014761 A 620 629 erlotinib TRIVIAL 23014761 A 728 737 elacridar TRIVIAL 23014761 A 772 781 erlotinib TRIVIAL 23014761 A 810 819 erlotinib TRIVIAL 23017390 A 0 8 Phenolic FAMILY 23017390 A 204 215 Gallic acid TRIVIAL 23017390 A 220 234 p-cumaric acid TRIVIAL 23017390 A 328 339 gallic acid TRIVIAL 23017390 A 341 355 p-cumaric acid TRIVIAL 23017390 A 357 385 sinapinic and apigenin acids MULTIPLE 23017390 A 423 437 Hydroxytyrosol SYSTEMATIC 23017390 A 439 444 rutin TRIVIAL 23017390 A 446 456 oleoropein TRIVIAL 23017390 A 458 466 luteolin TRIVIAL 23017390 A 468 475 tyrosol TRIVIAL 23017390 A 477 489 vanilic acid TRIVIAL 23017390 A 494 505 gallic acid TRIVIAL 23017390 A 574 581 tyrasol TRIVIAL 23017390 A 625 633 Luteolin TRIVIAL 23017390 A 738 788 syringic, p-cumaric, chlorogenic and ferulic acids MULTIPLE 23017390 A 790 803 Vanillic acid TRIVIAL 23017390 T 0 9 Phenolics FAMILY 23017392 A 336 345 phenolics FAMILY 23017392 A 347 356 vitamin C TRIVIAL 23017392 A 380 391 anthocyanin FAMILY 23017392 A 850 859 phenolics FAMILY 23017392 A 882 891 vitamin C TRIVIAL 23017392 A 927 938 anthocyanin FAMILY 23017398 A 264 276 ochratoxin A TRIVIAL 23017398 A 307 319 Ochratoxin A TRIVIAL 23017398 A 452 464 ochratoxin A TRIVIAL 23017398 A 523 535 ochratoxin A TRIVIAL 23017398 A 648 660 ochratoxin A TRIVIAL 23017398 A 83 95 ochratoxin A TRIVIAL 23017398 A 902 914 ochratoxin A TRIVIAL 23017398 T 14 26 ochratoxin A TRIVIAL 23017405 A 568 579 amino acids FAMILY 23017405 A 784 805 2-methyl-3-furanthiol SYSTEMATIC 23017405 A 807 837 bis(2-methyl-3-furyl)disulfide SYSTEMATIC 23017407 A 1093 1103 flumazenil TRIVIAL 23017407 A 1107 1111 GABA ABBREVIATION 23017407 A 1115 1118 BZD ABBREVIATION 23017407 A 1209 1222 pentobarbital TRIVIAL 23017407 A 254 264 flavonoids FAMILY 23017407 A 463 470 ethanol SYSTEMATIC 23017407 A 688 701 pentobarbital TRIVIAL 23017407 A 774 787 ethyl acetate SYSTEMATIC 23017407 A 868 877 flavonoid FAMILY 23017407 A 962 966 GABA ABBREVIATION 23017407 A 970 984 benzodiazepine FAMILY 23017407 A 986 989 BZD ABBREVIATION 23017407 T 30 37 ethanol SYSTEMATIC 23017407 T 58 71 pentobarbital TRIVIAL 23017411 A 1093 1098 rutin TRIVIAL 23017411 A 113 117 β-CD ABBREVIATION 23017411 A 120 152 (2-hydroxypropyl)-α-cyclodextrin SYSTEMATIC 23017411 A 154 161 HP-α-CD ABBREVIATION 23017411 A 164 196 (2-hydroxypropyl)-β-cyclodextrin SYSTEMATIC 23017411 A 198 205 HP-β-CD ABBREVIATION 23017411 A 211 243 (2-hydroxypropyl)-γ-cyclodextrin SYSTEMATIC 23017411 A 245 252 HP-γ-CD ABBREVIATION 23017411 A 336 341 rutin TRIVIAL 23017411 A 411 416 rutin TRIVIAL 23017411 A 468 475 HP-α-CD ABBREVIATION 23017411 A 477 481 β-CD ABBREVIATION 23017411 A 483 490 HP-β-CD ABBREVIATION 23017411 A 495 502 HP-γ-CD ABBREVIATION 23017411 A 530 537 HP-γ-CD ABBREVIATION 23017411 A 542 549 HP-β-CD ABBREVIATION 23017411 A 60 65 rutin TRIVIAL 23017411 A 600 604 β-CD ABBREVIATION 23017411 A 609 616 HP-α-CD ABBREVIATION 23017411 A 674 679 rutin TRIVIAL 23017411 A 685 692 HP-β-CD ABBREVIATION 23017411 A 830 834 (1)H FORMULA 23017411 A 872 877 rutin TRIVIAL 23017411 A 952 959 HP-β-CD ABBREVIATION 23017411 A 97 111 β-cyclodextrin TRIVIAL 23017411 T 102 107 rutin TRIVIAL 23017419 A 245 251 oxygen SYSTEMATIC 23017419 A 514 520 oxygen SYSTEMATIC 23017419 A 627 633 oxygen SYSTEMATIC 23017419 A 794 800 oxygen SYSTEMATIC 23017419 A 8 14 oxygen SYSTEMATIC 23017419 A 91 97 oxygen SYSTEMATIC 23017419 A 981 987 oxygen SYSTEMATIC 23017419 T 12 18 oxygen SYSTEMATIC 23017425 A 905 915 flavanones FAMILY 23017425 A 917 925 flavones FAMILY 23017425 A 927 952 polymethoxylated flavones FAMILY 23017425 A 957 966 scoparone TRIVIAL 23019138 A 1076 1086 furosemide TRIVIAL 23019138 A 1101 1181 trans-(-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide SYSTEMATIC 23019138 A 1183 1190 U50-488 IDENTIFIER 23019138 A 1193 1207 Methanandamide TRIVIAL 23019138 A 1283 1289 AM1241 IDENTIFIER 23019138 A 1291 1353 1-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole SYSTEMATIC 23019138 A 1360 1370 anandamide TRIVIAL 23019138 A 1391 1396 AM404 IDENTIFIER 23019138 A 1420 1430 rimonabant TRIVIAL 23019138 A 1522 1528 AM4054 IDENTIFIER 23019138 A 1683 1693 rimonabant TRIVIAL 23019138 A 1710 1719 vanilloid FAMILY 23019138 A 1747 1758 capsazepine TRIVIAL 23019138 A 1784 1794 WIN 55,212 IDENTIFIER 23019138 A 1829 1834 AM630 IDENTIFIER 23019138 A 1836 1922 (6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl) methanone) SYSTEMATIC 23019138 A 499 524 Δ(9)-tetrahydrocannabinol SYSTEMATIC 23019138 A 526 536 WIN 55,212 IDENTIFIER 23019138 A 538 659 R-(1)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate SYSTEMATIC 23019138 A 662 668 AM2389 IDENTIFIER 23019138 A 670 726 9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol SYSTEMATIC 23019138 A 733 739 AM4054 IDENTIFIER 23019138 A 741 795 9β-(hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol SYSTEMATIC 23020786 A 1178 1188 nabumetone TRIVIAL 23020786 A 128 158 6-methoxy-2-naphtylacetic acid SYSTEMATIC 23020786 A 1324 1332 carbonyl FAMILY 23020786 A 1365 1375 nabumetone TRIVIAL 23020786 A 3 13 Nabumetone TRIVIAL 23020786 A 306 314 carbonyl FAMILY 23020786 A 373 383 nabumetone TRIVIAL 23020786 A 499 509 nabumetone TRIVIAL 23020786 A 560 568 carbonyl FAMILY 23020786 A 671 679 carbonyl FAMILY 23020786 A 693 703 nabumetone TRIVIAL 23020786 A 813 821 carbonyl FAMILY 23020786 A 886 896 nabumetone TRIVIAL 23020786 A 959 969 nabumetone TRIVIAL 23020786 T 111 121 nabumetone TRIVIAL 23020786 T 8 16 carbonyl FAMILY 23020787 A 1069 1081 gemifloxacin TRIVIAL 23020787 A 173 185 gemifloxacin TRIVIAL 23020787 A 33 54 gemifloxacin mesylate TRIVIAL 23020787 A 562 567 MK571 IDENTIFIER 23020787 A 579 584 Ko143 IDENTIFIER 23020787 A 794 803 verapamil TRIVIAL 23020787 A 808 813 Ko143 IDENTIFIER 23020787 A 840 845 MK571 IDENTIFIER 23020787 A 932 937 Ko143 IDENTIFIER 23020787 A 951 956 MK571 IDENTIFIER 23020787 A 972 981 verapamil TRIVIAL 23020787 T 13 25 gemifloxacin TRIVIAL 23020787 T 44 53 quinolone FAMILY 23020788 A 1004 1023 abiraterone sulfate SYSTEMATIC 23020788 A 1028 1055 N-oxide abiraterone sulfate SYSTEMATIC 23020788 A 1099 1126 N-oxide abiraterone sulfate SYSTEMATIC 23020788 A 1211 1222 abiraterone TRIVIAL 23020788 A 28 53 (14)C-abiraterone acetate SYSTEMATIC 23020788 A 306 317 abiraterone TRIVIAL 23020788 A 523 534 abiraterone TRIVIAL 23020788 A 73 84 abiraterone TRIVIAL 23020788 A 872 883 abiraterone TRIVIAL 23020788 T 58 89 14C-labeled abiraterone acetate SYSTEMATIC 23022048 A 1062 1066 GABA ABBREVIATION 23022048 A 1093 1096 LAG ABBREVIATION 23022048 A 1216 1219 LAG ABBREVIATION 23022048 A 1334 1338 GABA ABBREVIATION 23022048 A 1452 1456 GABA ABBREVIATION 23022048 A 1493 1497 GABA ABBREVIATION 23022048 A 1557 1561 GABA ABBREVIATION 23022048 A 234 253 γ-aminobutyric acid SYSTEMATIC 23022048 A 255 259 GABA ABBREVIATION 23022048 A 421 425 GABA ABBREVIATION 23022048 A 443 456 glutamic acid TRIVIAL 23022048 A 529 533 GABA ABBREVIATION 23022048 A 594 598 GABA ABBREVIATION 23022048 A 717 721 GABA ABBREVIATION 23022048 A 737 751 l-allylglycine TRIVIAL 23022048 A 753 756 LAG ABBREVIATION 23022048 T 14 18 GABA ABBREVIATION 23022271 A 0 8 Cytisine TRIVIAL 23022271 A 10 13 CYT ABBREVIATION 23022271 A 235 238 CYT ABBREVIATION 23022271 A 285 305 N-methyl-d-aspartate SYSTEMATIC 23022271 A 307 311 NMDA ABBREVIATION 23022271 A 335 338 CYT ABBREVIATION 23022271 A 438 442 NMDA ABBREVIATION 23022271 A 480 483 CYT ABBREVIATION 23022271 A 542 546 NMDA ABBREVIATION 23022271 A 583 589 Ca(2+) FORMULA 23022271 A 659 662 CYT ABBREVIATION 23022271 A 725 729 NMDA ABBREVIATION 23022271 A 755 759 NMDA ABBREVIATION 23022271 A 814 818 NMDA ABBREVIATION 23022271 A 858 861 CYT ABBREVIATION 23022271 A 954 958 NMDA ABBREVIATION 23022271 T 0 8 Cytisine TRIVIAL 23022271 T 101 105 NMDA ABBREVIATION 23022324 A 0 7 Arsenic SYSTEMATIC 23022324 A 1085 1093 NaAsO(2) FORMULA 23022324 A 1103 1111 NaAsO(2) FORMULA 23022324 A 1164 1172 NaAsO(2) FORMULA 23022324 A 1224 1232 NaAsO(2) FORMULA 23022324 A 1617 1625 NaAsO(2) FORMULA 23022324 A 341 356 sodium arsenite SYSTEMATIC 23022324 A 358 366 NaAsO(2) FORMULA 23022324 A 617 625 NaAsO(2) FORMULA 23022324 A 901 909 NaAsO(2) FORMULA 23022324 A 962 970 NaAsO(2) FORMULA 23022324 T 82 97 sodium arsenite SYSTEMATIC 23024204 A 0 20 Triethylenetetramine SYSTEMATIC 23024204 A 1103 1107 TETA ABBREVIATION 23024204 A 1112 1120 SpmTrien TRIVIAL 23024204 A 1154 1158 TETA ABBREVIATION 23024204 A 1168 1176 SpmTrien TRIVIAL 23024204 A 139 148 polyamine FAMILY 23024204 A 149 159 spermidine TRIVIAL 23024204 A 185 189 TETA ABBREVIATION 23024204 A 217 226 polyamine FAMILY 23024204 A 22 26 TETA ABBREVIATION 23024204 A 244 254 spermidine TRIVIAL 23024204 A 255 263 spermine TRIVIAL 23024204 A 28 35 Syprine TRIVIAL 23024204 A 302 312 thialysine SYSTEMATIC 23024204 A 398 402 TETA ABBREVIATION 23024204 A 516 520 TETA ABBREVIATION 23024204 A 815 819 TETA ABBREVIATION 23024204 A 841 874 1,12-diamino-3,6,9-triazadodecane SYSTEMATIC 23024204 A 875 883 SpmTrien TRIVIAL 23024204 A 90 96 copper SYSTEMATIC 23024204 A 905 913 spermine TRIVIAL 23024204 T 127 137 thialysine SYSTEMATIC 23024204 T 14 34 triethylenetetramine SYSTEMATIC 23024204 T 39 72 1,12-diamino-3,6,9-triazadodecane SYSTEMATIC 23024204 T 80 90 spermidine TRIVIAL 23024204 T 91 99 spermine TRIVIAL 23025634 A 110 112 Ag FORMULA 23025634 A 29 33 CdSe FORMULA 23025634 A 773 777 CdSe FORMULA 23026138 A 1192 1207 methamphetamine TRIVIAL 23026138 A 1303 1318 methamphetamine TRIVIAL 23026138 A 1364 1379 methamphetamine TRIVIAL 23026138 A 1574 1589 methamphetamine TRIVIAL 23026138 A 229 237 phenolic FAMILY 23026138 A 285 300 hydroxysteroids FAMILY 23026138 A 316 325 alcoholic FAMILY 23026138 A 424 439 methamphetamine TRIVIAL 23026138 T 0 15 Methamphetamine TRIVIAL 23030793 A 587 596 polyamine FAMILY 23036111 A 159 163 (1)H FORMULA 23036111 A 168 173 (13)C FORMULA 23036111 A 21 33 acetophenone TRIVIAL 23036111 A 496 505 hymexazol TRIVIAL 23036111 A 62 67 alkyl FAMILY 23036111 A 71 77 benzyl SYSTEMATIC 23036111 A 776 789 acetophenones FAMILY 23036111 T 88 100 acetophenone TRIVIAL 23036330 A 1102 1110 formalin TRIVIAL 23036330 A 180 188 tyrosine TRIVIAL 23040268 A 852 853 C FORMULA 23041041 A 256 315 5-(5-Phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one SYSTEMATIC 23041041 A 539 637 4-((5Z)-5-{[5-(4-bromophenyl)-2-furyl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)butanoic acid SYSTEMATIC 23041041 A 642 740 6-((5Z)-5-{[5-(4-bromophenyl)-2-furyl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)hexanoic acid SYSTEMATIC 23041041 A 829 888 5-(5-Phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one SYSTEMATIC 23041042 A 225 230 soman TRIVIAL 23041042 A 482 498 organophosphorus FAMILY 23041042 A 58 74 organophosphorus FAMILY 23041042 T 72 88 organophosphorus FAMILY 23041232 A 188 198 fatty acid FAMILY 23042952 A 0 11 Resveratrol TRIVIAL 23042952 A 1027 1030 RSV ABBREVIATION 23042952 A 1071 1074 RSV ABBREVIATION 23042952 A 1079 1086 4'G-RSV SYSTEMATIC 23042952 A 1096 1102 3G-RSV SYSTEMATIC 23042952 A 1206 1209 RSV ABBREVIATION 23042952 A 1214 1221 4'G-RSV SYSTEMATIC 23042952 A 125 128 RSV ABBREVIATION 23042952 A 1262 1268 3G-RSV SYSTEMATIC 23042952 A 1278 1281 RSV ABBREVIATION 23042952 A 13 44 trans-3,5,4'-trihydroxystilbene SYSTEMATIC 23042952 A 1390 1397 4'G-RSV SYSTEMATIC 23042952 A 1415 1422 4'G-RSV SYSTEMATIC 23042952 A 1461 1464 RSV ABBREVIATION 23042952 A 1538 1544 3G-RSV SYSTEMATIC 23042952 A 155 161 NAD(+) ABBREVIATION 23042952 A 1567 1574 4'G-RSV SYSTEMATIC 23042952 A 1587 1590 RSV ABBREVIATION 23042952 A 289 299 superoxide TRIVIAL 23042952 A 46 49 RSV ABBREVIATION 23042952 A 476 479 RSV ABBREVIATION 23042952 A 488 501 glycosyl RSVs FAMILY 23042952 A 503 532 resveratrol-3-O-β-d-glucoside SYSTEMATIC 23042952 A 534 540 3G-RSV SYSTEMATIC 23042952 A 542 551 polydatin TRIVIAL 23042952 A 552 558 piceid TRIVIAL 23042952 A 564 594 resveratrol-4'-O-β-d-glucoside SYSTEMATIC 23042952 A 596 603 4'G-RSV SYSTEMATIC 23042952 A 62 72 polyphenol FAMILY 23042952 A 671 700 2,2-diphenyl-1-picrylhydrazyl SYSTEMATIC 23042952 A 756 762 3G-RSV SYSTEMATIC 23042952 A 789 792 RSV ABBREVIATION 23042952 A 839 846 4'G-RSV SYSTEMATIC 23042952 A 876 879 RSV ABBREVIATION 23042952 A 890 897 4'G-RSV SYSTEMATIC 23042952 A 907 913 3G-RSV SYSTEMATIC 23042952 T 45 56 resveratrol TRIVIAL 23042952 T 57 101 (trans-3,5,4'-trihydroxystilbene) glucosides SYSTEMATIC 23043183 A 1041 1051 vilanterol TRIVIAL 23043183 A 1271 1281 vilanterol TRIVIAL 23043183 A 220 230 vilanterol TRIVIAL 23043183 A 34 44 vilanterol TRIVIAL 23043183 A 398 415 [(14)C]vilanterol SYSTEMATIC 23043183 A 519 529 vilanterol TRIVIAL 23043183 A 685 686 O FORMULA 23043183 A 753 763 Vilanterol TRIVIAL 23043183 A 946 947 O FORMULA 23043183 T 30 40 vilanterol TRIVIAL 23044094 A 1031 1043 benzophenone SYSTEMATIC 23044094 A 1045 1115 4-ter-butyl-4-methoxy-dibenzoylmethane, 2-ethylexyl-p-methoxycinnamate SYSTEMATIC 23044094 A 1117 1127 ketoprofen TRIVIAL 23044094 A 1129 1144 6-methylcumarin SYSTEMATIC 23044094 A 1180 1199 4-aminobenzoic acid SYSTEMATIC 23044094 A 1201 1215 chlorpromazine TRIVIAL 23044094 A 1217 1229 promethazine TRIVIAL 23044094 A 1248 1256 acridine TRIVIAL 23044094 A 1258 1267 ibuprofen TRIVIAL 23044094 A 1269 1286 8-methoxypsoralen SYSTEMATIC 23044094 A 1288 1301 retinoic acid TRIVIAL 23044094 A 1328 1339 lactic acid TRIVIAL 23044094 A 1341 1344 SDS ABBREVIATION 23044094 A 1349 1366 p-phenilendiamine SYSTEMATIC 23044094 A 1454 1457 MTT ABBREVIATION 23044094 A 815 830 chloropromazine SYSTEMATIC 23044908 A 1261 1276 Zoledronic acid TRIVIAL 23044908 A 1649 1664 zoledronic acid TRIVIAL 23044908 A 1900 1915 zoledronic acid TRIVIAL 23044908 A 724 739 zoledronic acid TRIVIAL 23044908 T 45 60 zoledronic acid TRIVIAL 23044992 A 1289 1297 tartrate TRIVIAL 23046379 A 1014 1020 PGE(2) ABBREVIATION 23046379 A 1822 1828 PGE(2) ABBREVIATION 23046379 A 994 1012 prostaglandin E(2) TRIVIAL 23046389 A 1015 1025 zoniporide TRIVIAL 23046389 A 190 200 zoniporide TRIVIAL 23046389 A 3 11 Aldehyde SYSTEMATIC 23046389 A 531 541 zoniporide TRIVIAL 23046389 A 545 560 2-oxozoniporide SYSTEMATIC 23046389 A 644 654 zoniporide TRIVIAL 23046389 A 740 750 zoniporide TRIVIAL 23046389 A 783 793 zoniporide TRIVIAL 23046389 T 44 54 zoniporide TRIVIAL 23046389 T 58 66 aldehyde SYSTEMATIC 23046524 A 1298 1306 paraoxon TRIVIAL 23046524 A 1515 1523 paraoxon TRIVIAL 23046524 A 461 469 paraoxon TRIVIAL 23046524 A 6 14 paraoxon TRIVIAL 23046524 A 757 765 paraoxon TRIVIAL 23046524 A 912 920 paraoxon TRIVIAL 23046524 T 75 83 paraoxon TRIVIAL 23047462 A 194 200 TiO(2) FORMULA 23047462 A 297 321 fluorine-doped tin oxide SYSTEMATIC 23047462 A 323 326 FTO ABBREVIATION 23047462 A 64 70 TiO(2) FORMULA 23047462 A 651 654 FTO ABBREVIATION 23047462 A 676 682 TiO(2) FORMULA 23047462 A 732 738 TiO(2) FORMULA 23047462 A 752 755 FTO ABBREVIATION 23047462 A 783 789 TiO(2) FORMULA 23047462 A 983 990 TiCl(4) FORMULA 23047462 T 20 24 TiO2 FORMULA 23047828 A 1001 1012 aldosterone TRIVIAL 23047828 A 1017 1025 cortisol TRIVIAL 23047828 A 1128 1139 aldosterone TRIVIAL 23047828 A 1144 1152 cortisol TRIVIAL 23047828 A 504 511 glucose TRIVIAL 23047828 A 641 652 aldosterone TRIVIAL 23047828 A 657 665 cortisol TRIVIAL 23047828 A 731 738 glucose TRIVIAL 23047828 A 74 85 aldosterone TRIVIAL 23047828 A 782 789 glucose TRIVIAL 23047828 A 90 98 cortisol TRIVIAL 23047828 T 114 122 cortisol TRIVIAL 23047828 T 127 138 aldosterone TRIVIAL 23047828 T 69 76 glucose TRIVIAL 23048186 A 578 587 BIM-22493 NO CLASS 23048186 A 591 597 RM-493 NO CLASS 23048186 A 853 860 glucose TRIVIAL 23048186 A 947 956 BIM-22493 NO CLASS 23048186 A 996 1005 LY2112688 NO CLASS 23052058 A 10 20 fatty acid FAMILY 23052058 T 10 20 fatty acid FAMILY 23052190 A 0 5 Sarin TRIVIAL 23052190 A 1041 1044 MDZ ABBREVIATION 23052190 A 1049 1052 CRM ABBREVIATION 23052190 A 1265 1268 MGS ABBREVIATION 23052190 A 1298 1303 sarin TRIVIAL 23052190 A 1411 1414 MGS ABBREVIATION 23052190 A 1477 1482 sarin TRIVIAL 23052190 A 16 31 organophosphate FAMILY 23052190 A 221 238 Magnesium sulfate SYSTEMATIC 23052190 A 240 243 MGS ABBREVIATION 23052190 A 343 350 kainate TRIVIAL 23052190 A 372 389 Magnesium sulfate SYSTEMATIC 23052190 A 518 527 midazolam TRIVIAL 23052190 A 529 532 MDZ ABBREVIATION 23052190 A 538 548 caramiphen TRIVIAL 23052190 A 550 553 CRM ABBREVIATION 23052190 A 598 603 sarin TRIVIAL 23052190 A 652 657 oxime SYSTEMATIC 23052190 A 658 662 TMB4 TRIVIAL 23052190 A 667 675 atropine TRIVIAL 23052190 A 744 747 MGS ABBREVIATION 23052190 A 749 752 CRM ABBREVIATION 23052190 A 757 760 MDZ ABBREVIATION 23052190 A 974 977 MGS ABBREVIATION 23052190 T 0 17 Magnesium sulfate SYSTEMATIC 23052190 T 36 41 sarin TRIVIAL 23052191 A 0 8 Melamine TRIVIAL 23052191 A 1004 1008 urea TRIVIAL 23052191 A 1009 1017 nitrogen SYSTEMATIC 23052191 A 1022 1032 creatinine TRIVIAL 23052191 A 183 191 melamine TRIVIAL 23052191 A 1970 1978 melamine TRIVIAL 23052191 A 2127 2135 melamine TRIVIAL 23052191 A 2211 2219 melamine TRIVIAL 23052191 A 2395 2402 alanine TRIVIAL 23052191 A 272 280 melamine TRIVIAL 23052191 A 396 404 melamine TRIVIAL 23052191 A 817 825 melamine TRIVIAL 23052191 T 37 45 melamine TRIVIAL 23053666 A 1209 1215 copper SYSTEMATIC 23053666 A 1217 1219 Cu FORMULA 23053666 A 1228 1230 Cu FORMULA 23053666 A 1243 1245 Cu FORMULA 23053666 A 1307 1309 Cu FORMULA 23053666 A 1438 1444 l-DOPA ABBREVIATION 23053666 A 1601 1603 Cu FORMULA 23053666 A 305 314 cisplatin TRIVIAL 23053666 A 764 772 platinum SYSTEMATIC 23053666 A 774 776 Pt FORMULA 23053666 A 786 788 Pt FORMULA 23053666 A 880 886 copper SYSTEMATIC 23053666 T 102 111 cisplatin TRIVIAL 23053666 T 48 57 cisplatin TRIVIAL 23053666 T 91 97 copper SYSTEMATIC 23054066 A 1058 1067 serotonin TRIVIAL 23054066 A 1090 1099 serotonin TRIVIAL 23054066 A 1127 1131 MDMA ABBREVIATION 23054066 A 155 164 serotonin TRIVIAL 23054066 A 215 224 serotonin TRIVIAL 23054066 A 260 269 serotonin TRIVIAL 23054066 A 302 306 MDMA ABBREVIATION 23054066 A 367 376 serotonin TRIVIAL 23054066 A 574 584 tryptophan TRIVIAL 23054066 A 59 93 3,4- methylenedioxymethamphetamine SYSTEMATIC 23054066 A 659 668 serotonin TRIVIAL 23054066 A 741 745 MDMA ABBREVIATION 23054066 A 779 789 tryptophan TRIVIAL 23054066 A 827 836 serotonin TRIVIAL 23054066 A 895 904 serotonin TRIVIAL 23054066 A 934 943 serotonin TRIVIAL 23054066 A 95 99 MDMA ABBREVIATION 23054066 A 996 1000 MDMA ABBREVIATION 23054066 T 20 29 serotonin TRIVIAL 23054066 T 90 94 MDMA ABBREVIATION 23055445 A 149 151 Al FORMULA 23055445 A 152 154 Pd FORMULA 23055445 A 199 201 Pd FORMULA 23055445 A 223 225 Al FORMULA 23055445 A 284 292 hydrogen SYSTEMATIC 23055445 A 339 341 Al FORMULA 23055445 A 396 402 oxygen SYSTEMATIC 23055445 A 443 445 Pd FORMULA 23055445 A 457 474 hydrogen peroxide SYSTEMATIC 23055540 A 1050 1058 INO-8875 IDENTIFIER 23055540 A 1144 1152 INO-8875 IDENTIFIER 23055540 A 1170 1177 CVT-510 IDENTIFIER 23055540 A 1343 1350 CVT-510 IDENTIFIER 23055540 A 1368 1376 INO-8875 IDENTIFIER 23055540 A 1420 1428 INO-8875 IDENTIFIER 23055540 A 1529 1536 CVT-510 IDENTIFIER 23055540 A 1561 1569 INO-8875 IDENTIFIER 23055540 A 1642 1650 INO-8875 IDENTIFIER 23055540 A 1737 1744 CVT-510 IDENTIFIER 23055540 A 298 306 INO-8875 IDENTIFIER 23055540 A 377 426 N-[3(R)-tetrahydrofuranyl]-6-aminopurine riboside SYSTEMATIC 23055540 A 428 435 CVT-510 IDENTIFIER 23055540 A 44 53 adenosine TRIVIAL 23055540 A 692 700 INO-8875 IDENTIFIER 23055540 A 798 806 INO-8875 IDENTIFIER 23055540 A 903 911 INO-8875 IDENTIFIER 23055540 T 0 8 INO-8875 IDENTIFIER 23055540 T 32 41 adenosine TRIVIAL 23058251 A 1398 1410 imidacloprid TRIVIAL 23058251 A 1426 1431 NADPH ABBREVIATION 23058251 A 1479 1491 imidacloprid TRIVIAL 23058251 A 154 169 organochlorines FAMILY 23058251 A 1658 1670 imidacloprid TRIVIAL 23058251 A 171 187 organophosphates FAMILY 23058251 A 1731 1743 imidacloprid TRIVIAL 23058251 A 1803 1815 imidacloprid TRIVIAL 23058251 A 189 199 carbamates FAMILY 23058251 A 204 215 pyrethroids FAMILY 23058251 A 2051 2063 imidacloprid TRIVIAL 23058251 A 490 502 imidacloprid TRIVIAL 23058251 A 623 635 imidacloprid TRIVIAL 23058251 A 763 774 pyrethroids FAMILY 23058251 A 776 792 organophosphates FAMILY 23058251 A 797 807 carbamates FAMILY 23058251 T 90 102 imidacloprid TRIVIAL 23059508 A 0 8 Aluminum SYSTEMATIC 23059508 A 10 12 Al FORMULA 23059508 A 1146 1153 AlCl(3) FORMULA 23059508 A 1274 1281 AlCl(3) FORMULA 23059508 A 246 248 Al FORMULA 23059508 A 320 340 aluminum trichloride SYSTEMATIC 23059508 A 342 349 AlCl(3) FORMULA 23059508 A 518 525 AlCl(3) FORMULA 23059508 A 622 624 Al FORMULA 23059508 A 743 748 NADPH ABBREVIATION 23059508 A 778 788 aminopyrin TRIVIAL 23059508 A 789 790 N FORMULA 23059508 A 823 824 N FORMULA 23059508 A 848 855 aniline SYSTEMATIC 23059508 A 959 961 Al FORMULA 23059508 T 34 54 aluminum trichloride SYSTEMATIC 23059509 A 18 20 Pb FORMULA 23059509 A 183 185 Pb FORMULA 23059509 A 190 192 Cd FORMULA 23059509 A 22 24 Cd FORMULA 23059509 A 272 274 Pb FORMULA 23059509 A 397 399 Pb FORMULA 23059509 A 404 406 Cd FORMULA 23059509 T 65 69 zinc SYSTEMATIC 23059538 A 1902 1910 d-alanyl TRIVIAL 23059538 A 1915 1923 glycosyl SYSTEMATIC 23059655 A 1065 1073 graphene TRIVIAL 23059655 A 114 136 reduced graphene oxide SYSTEMATIC 23059655 A 1229 1237 graphene TRIVIAL 23059655 A 1265 1273 graphene TRIVIAL 23059655 A 138 141 RGO ABBREVIATION 23059655 A 1562 1570 graphene TRIVIAL 23059655 A 319 327 graphene TRIVIAL 23059655 A 56 64 graphene TRIVIAL 23059655 A 572 580 graphene TRIVIAL 23059655 A 775 783 graphene TRIVIAL 23059655 A 806 814 graphene TRIVIAL 23059655 A 93 107 graphene oxide SYSTEMATIC 23059655 T 5 13 graphene TRIVIAL 23059794 A 0 29 Perfluorooctane sulfonic acid SYSTEMATIC 23059794 A 1046 1050 PFOS ABBREVIATION 23059794 A 1231 1235 PFOS ABBREVIATION 23059794 A 1396 1400 PFOS ABBREVIATION 23059794 A 1459 1463 PFOS ABBREVIATION 23059794 A 162 166 PFOS ABBREVIATION 23059794 A 1677 1681 PFOS ABBREVIATION 23059794 A 289 293 PFOS ABBREVIATION 23059794 A 31 35 PFOS ABBREVIATION 23059794 A 366 370 PFOS ABBREVIATION 23059794 A 449 453 PFOS ABBREVIATION 23059794 A 803 807 PFOS ABBREVIATION 23059794 T 8 12 PFOS ABBREVIATION 23060276 A 1082 1113 polycyclic aromatic hydrocarbon FAMILY 23060276 A 1164 1171 cadmium SYSTEMATIC 23060276 A 1173 1181 chromium SYSTEMATIC 23060276 A 1183 1189 copper SYSTEMATIC 23060276 A 1191 1197 nickel SYSTEMATIC 23060276 A 1205 1211 silver SYSTEMATIC 23060276 A 1213 1217 zinc SYSTEMATIC 23060409 A 0 21 1,3-Dimethylamylamine SYSTEMATIC 23060409 A 1009 1013 DMAA ABBREVIATION 23060409 A 1043 1051 caffeine TRIVIAL 23060409 A 156 160 DMAA ABBREVIATION 23060409 A 206 210 DMAA ABBREVIATION 23060409 A 23 27 DMAA ABBREVIATION 23060409 A 899 907 charcoal TRIVIAL 23060409 T 13 34 1,3-dimethylamylamine SYSTEMATIC 23060411 A 1043 1052 phosphate SYSTEMATIC 23060411 A 1192 1201 NaH2PO(4) FORMULA 23060411 A 1216 1225 Na2HPO(4) FORMULA 23060411 A 1227 1241 monophosphates FAMILY 23060411 A 1294 1299 PO(4) FORMULA 23060411 A 1383 1403 sodium metaphosphate SYSTEMATIC 23060411 A 1405 1421 (NaPO(3))6 • H2O FORMULA 23060411 A 1502 1505 PO4 FORMULA 23060411 A 1603 1619 (NaPO(3))6 • H2O FORMULA 23060411 A 1660 1663 PO4 FORMULA 23060411 A 362 372 phosphates FAMILY 23060411 A 388 402 polyphosphates FAMILY 23060411 A 422 432 phosphates FAMILY 23060411 A 466 480 pyrophosphates FAMILY 23060411 A 569 583 Polyphosphates FAMILY 23060411 A 778 792 polyphosphates FAMILY 23060411 A 832 846 monophosphates FAMILY 23060411 A 926 940 monophosphates FAMILY 23060411 T 63 73 phosphates FAMILY 23060524 A 1071 1082 cholesterol TRIVIAL 23060524 A 1087 1100 triglycerides FAMILY 23060524 A 1537 1548 cholesterol TRIVIAL 23060524 A 1553 1565 triglyceride FAMILY 23060524 A 532 546 streptozotocin TRIVIAL 23061622 A 0 8 Platinum SYSTEMATIC 23061622 A 268 277 estradiol TRIVIAL 23061622 A 27 36 cisplatin TRIVIAL 23061622 A 285 293 platinum SYSTEMATIC 23061622 A 41 51 caboplatin TRIVIAL 23061622 A 445 454 estradiol TRIVIAL 23061622 A 462 470 platinum SYSTEMATIC 23061622 T 50 59 estradiol TRIVIAL 23061622 T 67 75 platinum SYSTEMATIC 23061623 A 246 257 polyphenols FAMILY 23061623 A 259 269 flavonoids FAMILY 23061623 A 271 280 xanthones FAMILY 23061623 A 282 291 coumarins FAMILY 23061623 A 297 310 ellagitannins FAMILY 23063623 A 135 147 bicalutamide TRIVIAL 23063623 A 149 152 BIC ABBREVIATION 23063623 A 244 247 BIC ABBREVIATION 23063623 A 271 278 MDV3100 IDENTIFIER 23063623 A 288 300 Enzalutamide TRIVIAL 23063623 A 34 43 androgens FAMILY 23063623 A 414 422 androgen FAMILY 23063623 A 836 839 BIC ABBREVIATION 23063623 T 107 119 Enzalutamide TRIVIAL 23063623 T 44 56 bicalutamide TRIVIAL 23063623 T 98 105 MDV3100 IDENTIFIER 23063689 A 0 15 Benzodiazepines FAMILY 23063689 A 1045 1053 diazepam TRIVIAL 23063689 A 1361 1369 diazepam TRIVIAL 23063689 A 1418 1433 benzodiazepines FAMILY 23063689 A 148 163 benzodiazepines FAMILY 23063689 A 379 394 benzodiazepines FAMILY 23063689 A 740 748 diazepam TRIVIAL 23063689 A 938 946 diazepam TRIVIAL 23063689 T 61 69 diazepam TRIVIAL 23063782 A 0 6 Oxygen SYSTEMATIC 23063782 A 1321 1327 oxygen SYSTEMATIC 23063782 A 1402 1408 oxygen SYSTEMATIC 23063782 A 1487 1493 oxygen SYSTEMATIC 23063782 A 155 161 oxygen SYSTEMATIC 23063782 A 256 262 oxygen SYSTEMATIC 23063782 A 513 519 oxygen SYSTEMATIC 23063782 A 535 541 oxygen SYSTEMATIC 23063782 A 561 567 oxygen SYSTEMATIC 23063782 A 767 773 oxygen SYSTEMATIC 23063782 T 12 18 oxygen SYSTEMATIC 23064325 A 1081 1085 ITRA ABBREVIATION 23064325 A 1138 1149 polysorbate FAMILY 23064325 A 1138 1152 polysorbate 80 TRIVIAL 23064325 A 1191 1195 ITRA ABBREVIATION 23064325 A 1832 1836 ITRA ABBREVIATION 23064325 A 315 326 tobramycine TRIVIAL 23064325 A 629 641 itraconazole TRIVIAL 23064325 A 643 647 ITRA ABBREVIATION 23064325 A 758 762 ITRA ABBREVIATION 23064325 A 887 891 ITRA ABBREVIATION 23064325 T 30 42 itraconazole TRIVIAL 23064722 A 0 9 Adenosine TRIVIAL 23064722 A 1039 1042 ATP ABBREVIATION 23064722 A 1095 1104 adenosine TRIVIAL 23064722 A 143 152 Adenosine TRIVIAL 23064722 A 211 221 nucleoside FAMILY 23064722 A 250 259 adenosine TRIVIAL 23064722 A 285 294 Adenosine TRIVIAL 23064722 A 335 344 adenosine TRIVIAL 23064722 A 376 379 ATP ABBREVIATION 23064722 A 413 416 ATP ABBREVIATION 23064722 A 446 449 ATP ABBREVIATION 23064722 A 461 480 adenine nucleotides FAMILY 23064722 A 483 492 adenosine TRIVIAL 23064722 A 501 510 adenosine TRIVIAL 23064722 A 522 531 adenosine TRIVIAL 23064722 A 678 687 adenosine TRIVIAL 23064722 A 774 783 adenosine TRIVIAL 23064722 A 908 918 nucleoside FAMILY 23064722 T 14 23 adenosine TRIVIAL 23065141 A 1006 1010 DCPA ABBREVIATION 23065141 A 1043 1062 3,4-dichloroaniline SYSTEMATIC 23065141 A 1064 1067 DCA ABBREVIATION 23065141 A 1099 1102 DCA ABBREVIATION 23065141 A 1130 1159 6-hydroxy-3,4-dichloroaniline SYSTEMATIC 23065141 A 1161 1168 6OH-DCA SYSTEMATIC 23065141 A 1174 1203 N-hydroxy-3,4-dichloroaniline SYSTEMATIC 23065141 A 1205 1212 NOH-DCA SYSTEMATIC 23065141 A 1273 1277 DCPA ABBREVIATION 23065141 A 1373 1377 DCPA ABBREVIATION 23065141 A 1454 1462 fluorine SYSTEMATIC 23065141 A 1474 1478 DCPA ABBREVIATION 23065141 A 1483 1486 DCA ABBREVIATION 23065141 A 1539 1547 chlorine SYSTEMATIC 23065141 A 1637 1641 DCPA ABBREVIATION 23065141 A 1646 1649 DCA ABBREVIATION 23065141 A 1730 1737 calcium SYSTEMATIC 23065141 A 1767 1774 6OH-DCA SYSTEMATIC 23065141 A 1779 1786 NOH-DCA SYSTEMATIC 23065141 A 1849 1856 calcium SYSTEMATIC 23065141 A 1873 1882 chlorines FAMILY 23065141 A 1886 1890 DCPA ABBREVIATION 23065141 A 1895 1898 DCA ABBREVIATION 23065141 A 1921 1930 fluorines FAMILY 23065141 A 1997 2001 DCPA ABBREVIATION 23065141 A 2067 2076 chlorines FAMILY 23065141 A 448 456 Propanil TRIVIAL 23065141 A 458 484 3,4-dichloropropionanilide SYSTEMATIC 23065141 A 486 490 DCPA ABBREVIATION 23065141 A 646 650 DCPA ABBREVIATION 23065141 A 884 910 3,4-dichloropropionanalide SYSTEMATIC 23065141 T 105 112 calcium SYSTEMATIC 23065141 T 131 138 calcium SYSTEMATIC 23065141 T 20 29 N-hydroxy SYSTEMATIC 23065141 T 34 43 6-hydroxy SYSTEMATIC 23065141 T 59 85 3,4-dichloropropionanilide SYSTEMATIC 23065531 A 0 14 [(18)F]DPA-714 SYSTEMATIC 23065531 A 1026 1035 O-deethyl SYSTEMATIC 23065531 A 1037 1045 hydroxyl SYSTEMATIC 23065531 A 1051 1060 N-deethyl SYSTEMATIC 23065531 A 1091 1098 DPA-714 IDENTIFIER 23065531 A 1245 1260 carboxylic acid SYSTEMATIC 23065531 A 1325 1326 O FORMULA 23065531 A 1377 1401 [(18)F]fluoroacetic acid SYSTEMATIC 23065531 A 16 115 N,N-diethyl-2-(2-(4-(2[(18)F]-fluoroethoxy)phenyl)5,7dimethylpyrazolo[1,5a]pyrimidin-3-yl)acetamide SYSTEMATIC 23065531 A 1604 1618 [(18)F]DPA-714 SYSTEMATIC 23065531 A 1696 1710 [(18)F]DPA-714 SYSTEMATIC 23065531 A 1759 1773 [(18)F]deethyl SYSTEMATIC 23065531 A 1775 1790 [(18)F]hydroxyl SYSTEMATIC 23065531 A 1796 1818 [(18)F]carboxylic acid SYSTEMATIC 23065531 A 1834 1848 [(18)F]DPA-714 SYSTEMATIC 23065531 A 371 385 [(18)F]DPA-714 SYSTEMATIC 23065531 A 592 606 [(18)F]DPA-714 SYSTEMATIC 23065531 T 33 47 [(18)F]DPA-714 SYSTEMATIC 23065592 A 193 202 vitamin D FAMILY 23065592 T 21 30 vitamin D FAMILY 23066870 A 667 674 alanine TRIVIAL 23066870 T 61 68 alanine TRIVIAL 23066996 A 299 309 amino acid FAMILY 23066996 A 345 352 alanine TRIVIAL 23066996 A 366 376 amino acid FAMILY 23066996 A 644 654 amino acid FAMILY 23066996 A 679 690 amino acids FAMILY 23066996 T 0 7 Alanine TRIVIAL 23072367 A 222 239 phosphoamino acid SYSTEMATIC 23072367 A 450 487 phosphatidylinositol 4,5-bisphosphate TRIVIAL 23072367 A 489 500 PI(4,5)P(2) SYSTEMATIC 23072367 A 566 577 PI(4,5)P(2) SYSTEMATIC 23072367 A 676 687 PI(4,5)P(2) SYSTEMATIC 23072941 A 0 9 Acyclovir TRIVIAL 23072941 A 1038 1047 acyclovir TRIVIAL 23072941 A 483 578 O-2,O-3 permethylated O-6 alkylthio- and perfluoroalkyl-propanethio-amphiphilic β-cyclodextrins MULTIPLE 23072941 A 725 734 acyclovir TRIVIAL 23072941 A 798 812 β-cyclodextrin TRIVIAL 23072941 T 143 152 acyclovir TRIVIAL 23073075 A 0 10 Fingolimod TRIVIAL 23073075 A 1038 1042 W146 IDENTIFIER 23073075 A 1118 1138 phosphatidylinositol TRIVIAL 23073075 A 1176 1182 FTY720 IDENTIFIER 23073075 A 1187 1195 FTY720-P IDENTIFIER 23073075 A 12 18 FTY720 IDENTIFIER 23073075 A 124 147 sphingosine-1-phosphate SYSTEMATIC 23073075 A 1335 1341 FTY720 IDENTIFIER 23073075 A 385 391 FTY720 IDENTIFIER 23073075 A 498 504 FTY720 IDENTIFIER 23073075 A 529 537 FTY720-P IDENTIFIER 23073075 A 543 566 sphingosine-1-phosphate SYSTEMATIC 23073075 A 568 571 S1P ABBREVIATION 23073075 A 743 763 N-methyl-d-aspartate SYSTEMATIC 23073075 A 765 769 NMDA ABBREVIATION 23073075 A 827 833 FTY720 IDENTIFIER 23073075 A 835 843 FTY720-P IDENTIFIER 23073075 A 849 852 S1P ABBREVIATION 23073075 A 912 916 NMDA ABBREVIATION 23073075 T 0 10 Fingolimod TRIVIAL 23074095 A 449 452 PEG ABBREVIATION 23076766 A 116 122 silica TRIVIAL 23076766 A 603 628 doxorubicin hydrochloride SYSTEMATIC 23076766 A 630 633 Dox ABBREVIATION 23076766 A 701 704 Dox ABBREVIATION 23076766 A 773 776 Dox ABBREVIATION 23076766 A 781 784 Dox ABBREVIATION 23076766 T 36 42 silica TRIVIAL 23078954 A 1258 1261 DON ABBREVIATION 23078954 A 1297 1303 carbon SYSTEMATIC 23078954 A 1359 1362 DON ABBREVIATION 23078954 A 1419 1426 tylosin TRIVIAL 23078954 A 1501 1510 macrolide FAMILY 23078954 A 1526 1535 bentonite FAMILY 23078954 A 1553 1562 bentonite FAMILY 23078954 A 1596 1603 tylosin TRIVIAL 23078954 A 1660 1667 tylosin TRIVIAL 23078954 A 1671 1680 bentonite FAMILY 23078954 A 1722 1731 bentonite FAMILY 23078954 A 1736 1743 tylosin TRIVIAL 23078954 A 1849 1856 tylosin TRIVIAL 23078954 A 327 334 tylosin TRIVIAL 23078954 A 393 399 carbon SYSTEMATIC 23078954 A 404 413 bentonite FAMILY 23078954 A 557 560 DON ABBREVIATION 23078954 A 565 572 tylosin TRIVIAL 23078954 A 745 756 neutral red TRIVIAL 23078954 A 811 817 carbon SYSTEMATIC 23078954 A 836 839 DON ABBREVIATION 23078954 A 894 897 DON ABBREVIATION 23078954 A 963 966 DON ABBREVIATION 23079545 A 1022 1025 ARG FORMULA 23079545 A 1188 1196 arginine TRIVIAL 23079545 A 172 180 arginine TRIVIAL 23079545 A 313 321 arginine TRIVIAL 23079545 A 4 12 arginine TRIVIAL 23079545 A 448 456 arginine TRIVIAL 23079545 A 678 681 ARG FORMULA 23079545 A 957 960 ARG FORMULA 23079545 T 4 12 arginine TRIVIAL 23080299 A 166 186 (E)-α-bromoacrylates FAMILY 23080299 A 274 323 methyl bis(2,2,2-trifluoroethoxy)phosphonoacetate SYSTEMATIC 23080299 A 54 108 methyl bis(2,2,2-trifluoroethoxy)bromophosphonoacetate SYSTEMATIC 23080299 T 117 137 (E)-α-bromoacrylates FAMILY 23080299 T 24 79 methyl bis(2,2,2-trifluoroethoxy)-bromophosphonoacetate SYSTEMATIC 23080535 A 123 124 H FORMULA 23080535 A 125 131 TiO(2) FORMULA 23080535 A 133 134 C FORMULA 23080535 A 61 62 H FORMULA 23080535 A 63 69 TiO(2) FORMULA 23080535 A 71 77 MnO(2) FORMULA 23080535 T 0 1 H FORMULA 23080535 T 10 16 MnO(2) FORMULA 23080535 T 19 20 H FORMULA 23080535 T 2 8 TiO(2) FORMULA 23080535 T 21 27 TiO(2) FORMULA 23080535 T 29 30 C FORMULA 23084046 A 1009 1015 TiO(2) FORMULA 23084046 A 1149 1155 TiO(2) FORMULA 23084046 A 1186 1191 Na(+) FORMULA 23084046 A 1191 1195 K(+) FORMULA 23084046 A 1251 1262 glutathione TRIVIAL 23084046 A 1264 1267 GSH ABBREVIATION 23084046 A 1340 1346 TiO(2) FORMULA 23084046 A 1395 1401 TiO(2) FORMULA 23084046 A 151 157 TiO(2) FORMULA 23084046 A 1723 1729 TiO(2) FORMULA 23084046 A 1855 1861 TiO(2) FORMULA 23084046 A 281 287 TiO(2) FORMULA 23084046 A 289 295 TiO(2) FORMULA 23084046 A 321 327 TiO(2) FORMULA 23084046 A 623 629 TiO(2) FORMULA 23084046 A 66 82 titanium dioxide SYSTEMATIC 23084046 A 690 692 Ti FORMULA 23084046 A 773 779 TiO(2) FORMULA 23084046 A 792 798 TiO(2) FORMULA 23084046 A 98 104 TiO(2) FORMULA 23084046 T 22 38 titanium dioxide SYSTEMATIC 23084047 A 1228 1233 MC-LR ABBREVIATION 23084047 A 1405 1417 microcystins FAMILY 23084047 A 280 285 MC-LR ABBREVIATION 23084047 A 36 50 microcystin-LR TRIVIAL 23084047 A 486 491 MC-LR ABBREVIATION 23084047 A 511 517 oxygen SYSTEMATIC 23084047 A 52 57 MC-LR ABBREVIATION 23084047 A 541 556 malondialdehyde TRIVIAL 23084047 A 617 628 glutathione TRIVIAL 23084047 A 629 630 S FORMULA 23084047 A 657 668 glutathione TRIVIAL 23084047 A 731 741 superoxide TRIVIAL 23084047 T 17 31 microcystin-LR TRIVIAL 23084158 A 126 143 magnesium nitrate SYSTEMATIC 23084158 A 14 33 magnesium hydroxide SYSTEMATIC 23084158 A 148 167 potassium hydroxide SYSTEMATIC 23084158 A 301 310 Mg(OH)(2) FORMULA 23084158 T 70 89 magnesium hydroxide SYSTEMATIC 23085095 A 1038 1065 1-(2-pyrimidinyl)piperazine SYSTEMATIC 23085095 A 1070 1089 6'-hydroxybuspirone SYSTEMATIC 23085095 A 171 181 paclitaxel TRIVIAL 23085095 A 183 192 Aconitine TRIVIAL 23085095 A 523 532 buspirone TRIVIAL 23085095 A 588 597 buspirone TRIVIAL 23085095 A 730 739 buspirone TRIVIAL 23085095 A 769 778 Buspirone TRIVIAL 23085095 A 805 832 1-(2-pyrimidinyl)piperazine SYSTEMATIC 23085095 A 837 856 6'-hydroxybuspirone SYSTEMATIC 23085095 T 242 251 buspirone TRIVIAL 23085095 T 29 38 aconitine TRIVIAL 23085121 A 848 863 organophosphate FAMILY 23085122 A 13 30 organophosphorous FAMILY 23085122 A 1304 1307 IPA ABBREVIATION 23085122 A 140 146 oximes FAMILY 23085122 A 148 156 atropine TRIVIAL 23085122 A 161 169 diazepam TRIVIAL 23085122 A 487 496 carbamate FAMILY 23085122 A 498 512 pyridostigmine TRIVIAL 23085122 A 516 529 physostigmine TRIVIAL 23085122 A 551 563 procyclidine TRIVIAL 23085122 A 567 578 scopolamine TRIVIAL 23085122 A 641 652 scopolamine TRIVIAL 23085295 A 588 604 propidium iodide TRIVIAL 23085295 A 614 660 4',6'-diamidino-2-phenylindole dihydrochloride SYSTEMATIC 23085295 A 662 666 DAPI ABBREVIATION 23085331 A 0 11 Telmisartan TRIVIAL 23085331 A 1130 1133 TLM ABBREVIATION 23085331 A 1239 1242 TLM ABBREVIATION 23085331 A 13 16 TLM ABBREVIATION 23085331 A 1338 1349 telmisartan TRIVIAL 23085331 A 286 289 TLM ABBREVIATION 23085331 A 754 757 TLM ABBREVIATION 23085331 A 766 769 HCl FORMULA 23085331 A 863 866 TLM ABBREVIATION 23085331 T 34 45 telmisartan TRIVIAL 23085382 A 0 11 Minocycline TRIVIAL 23085382 A 1125 1136 minocycline TRIVIAL 23085382 A 51 63 tetracycline FAMILY 23085382 A 793 804 minocycline TRIVIAL 23085382 T 48 59 minocycline TRIVIAL 23085436 A 1393 1400 glucose TRIVIAL 23085436 A 1473 1480 glucose TRIVIAL 23085436 A 399 410 cholesterol TRIVIAL 23085436 A 516 523 glucose TRIVIAL 23085436 A 587 594 glucose TRIVIAL 23085436 A 735 750 triacylglycerol FAMILY 23085522 A 1175 1182 PCB-153 ABBREVIATION 23085522 A 1676 1683 PCB-153 ABBREVIATION 23085522 A 443 471 polychlorinated biphenyl-153 TRIVIAL 23085522 A 473 480 PCB-153 ABBREVIATION 23085522 A 483 515 dichlorodiphenyldichloroethylene SYSTEMATIC 23085522 A 517 520 DDE ABBREVIATION 23085522 A 526 543 hexachlorobenzene SYSTEMATIC 23085522 A 545 548 HCB ABBREVIATION 23085522 A 944 951 PCB-153 ABBREVIATION 23085522 A 953 956 DDE ABBREVIATION 23085522 A 961 964 HCB ABBREVIATION 23086037 A 1011 1031 monosodium uric acid SYSTEMATIC 23086037 A 1066 1072 oxygen SYSTEMATIC 23086037 A 1190 1199 metformin TRIVIAL 23086037 A 1299 1302 AMP ABBREVIATION 23086037 A 1513 1522 metformin TRIVIAL 23086037 A 57 67 nucleotide FAMILY 23086037 A 925 928 ATP ABBREVIATION 23086037 A 967 978 fatty acids FAMILY 23086141 A 1097 1101 CORT ABBREVIATION 23086141 A 386 400 corticosterone TRIVIAL 23086141 A 402 406 CORT ABBREVIATION 23086141 A 716 720 CORT ABBREVIATION 23086141 A 808 812 CORT ABBREVIATION 23086141 A 938 942 CORT ABBREVIATION 23086182 A 1009 1012 DDD ABBREVIATION 23086182 A 1182 1185 DDT ABBREVIATION 23086182 A 1195 1198 DDT ABBREVIATION 23086182 A 1203 1206 DDD ABBREVIATION 23086182 A 157 167 permethrin TRIVIAL 23086182 A 172 203 dichlorodiphenyltrichloroethane SYSTEMATIC 23086182 A 205 208 DDT ABBREVIATION 23086182 A 515 535 polydimethylsiloxane SYSTEMATIC 23086182 A 856 866 permethrin TRIVIAL 23086182 A 970 973 DDT ABBREVIATION 23086182 A 977 1007 dichlorodiphenyldichloroethane SYSTEMATIC 23086182 T 42 52 permethrin TRIVIAL 23086182 T 57 60 DDT ABBREVIATION 23086747 A 1026 1030 iron SYSTEMATIC 23086747 A 1048 1052 iron SYSTEMATIC 23086747 A 1106 1110 iron SYSTEMATIC 23086747 A 1249 1253 iron SYSTEMATIC 23086747 A 1357 1361 iron SYSTEMATIC 23086747 A 1749 1753 iron SYSTEMATIC 23086747 A 1790 1794 iron SYSTEMATIC 23086747 A 1848 1852 iron SYSTEMATIC 23086747 A 240 244 iron SYSTEMATIC 23086747 A 322 326 iron SYSTEMATIC 23086747 A 397 401 iron SYSTEMATIC 23086747 A 42 69 2,3-dimercaptosuccinic acid SYSTEMATIC 23086747 A 506 510 iron SYSTEMATIC 23086747 A 610 614 iron SYSTEMATIC 23086747 A 629 644 desferrioxamine TRIVIAL 23086747 A 77 86 Fe(3)O(4) FORMULA 23086747 A 823 828 irons FAMILY 23086747 A 902 906 iron SYSTEMATIC 23086747 A 930 934 iron SYSTEMATIC 23086747 A 968 972 iron SYSTEMATIC 23086747 T 11 15 DMSA ABBREVIATION 23086747 T 23 28 Fe3O4 FORMULA 23086747 T 84 88 iron SYSTEMATIC 23089045 A 466 474 tyrosine TRIVIAL 23089153 A 118 124 oxygen SYSTEMATIC 23089153 A 363 371 cysteine TRIVIAL 23089153 A 372 377 thiol FAMILY 23089211 A 1041 1052 cholesterol TRIVIAL 23089211 A 144 161 Cholesteryl ester SYSTEMATIC 23089211 A 277 288 cholesterol TRIVIAL 23089211 A 371 386 triacylglycerol FAMILY 23089211 A 572 586 corticosterone TRIVIAL 23089211 A 609 621 progesterone TRIVIAL 23089211 A 667 679 testosterone TRIVIAL 23089211 A 746 757 cholesterol TRIVIAL 23089211 A 872 883 cholesterol TRIVIAL 23089211 T 0 17 Cholesterol ester SYSTEMATIC 23089250 A 0 8 Selenium SYSTEMATIC 23089250 A 10 12 Se FORMULA 23089250 A 1148 1150 Se FORMULA 23089250 A 1155 1157 Hg FORMULA 23089250 A 117 119 Se FORMULA 23089250 A 1222 1227 SeMet FORMULA 23089250 A 1232 1236 MeHg FORMULA 23089250 A 1297 1299 Se FORMULA 23089250 A 1304 1306 Hg FORMULA 23089250 A 1318 1320 Se FORMULA 23089250 A 1364 1366 Se FORMULA 23089250 A 1371 1373 Hg FORMULA 23089250 A 1456 1458 Se FORMULA 23089250 A 1514 1516 Se FORMULA 23089250 A 1545 1547 Se FORMULA 23089250 A 161 163 Hg FORMULA 23089250 A 1670 1672 Hg FORMULA 23089250 A 1779 1781 Hg FORMULA 23089250 A 18 25 mercury SYSTEMATIC 23089250 A 1862 1867 SeMet FORMULA 23089250 A 1869 1871 Se FORMULA 23089250 A 1876 1878 Hg FORMULA 23089250 A 1909 1911 Se FORMULA 23089250 A 1912 1914 Hg FORMULA 23089250 A 2011 2013 Se FORMULA 23089250 A 2018 2020 Hg FORMULA 23089250 A 2096 2101 SeMet FORMULA 23089250 A 2117 2119 Hg FORMULA 23089250 A 2150 2152 Se FORMULA 23089250 A 2218 2220 Se FORMULA 23089250 A 2221 2223 Hg FORMULA 23089250 A 227 229 Se FORMULA 23089250 A 238 240 Hg FORMULA 23089250 A 2476 2481 SeMet FORMULA 23089250 A 2486 2490 MeHg FORMULA 23089250 A 27 29 Hg FORMULA 23089250 A 521 523 Se FORMULA 23089250 A 528 530 Hg FORMULA 23089250 A 694 702 Selenium SYSTEMATIC 23089250 A 707 709 Hg FORMULA 23089250 A 727 745 L-selenomethionine TRIVIAL 23089250 A 747 752 SeMet FORMULA 23089250 A 758 771 methylmercury SYSTEMATIC 23089250 A 773 777 MeHg FORMULA 23089250 A 880 885 SeMet FORMULA 23089250 A 894 896 Se FORMULA 23089250 A 918 922 MeHg FORMULA 23089250 A 931 933 Hg FORMULA 23089250 A 964 966 Se FORMULA 23089250 A 967 969 Hg FORMULA 23089250 A 978 980 Se FORMULA 23089250 T 27 43 selenomethionine SYSTEMATIC 23089250 T 48 61 methylmercury SYSTEMATIC 23090760 A 308 316 α-MoO(3) FORMULA 23090760 A 67 75 α-MoO(3) FORMULA 23090760 T 68 84 molybdenum oxide SYSTEMATIC 23090793 A 143 149 carbon SYSTEMATIC 23090793 A 330 336 carbon SYSTEMATIC 23090793 T 44 50 carbon SYSTEMATIC 23091168 A 419 429 diclofenac TRIVIAL 23091168 A 431 443 indomethacin TRIVIAL 23091168 A 448 456 naproxen TRIVIAL 23091188 A 1077 1080 LPV ABBREVIATION 23091188 A 1137 1146 [(3)H]TCA SYSTEMATIC 23091188 A 1194 1197 LPV ABBREVIATION 23091188 A 1202 1205 RTV ABBREVIATION 23091188 A 1229 1232 LPV ABBREVIATION 23091188 A 1236 1239 LPV ABBREVIATION 23091188 A 1244 1247 RTV ABBREVIATION 23091188 A 1291 1300 [(3)H]TCA SYSTEMATIC 23091188 A 1304 1315 [(14)C]CDCA SYSTEMATIC 23091188 A 1346 1349 LPV ABBREVIATION 23091188 A 1359 1362 RTV ABBREVIATION 23091188 A 1375 1378 LPV ABBREVIATION 23091188 A 1470 1480 bile acids FAMILY 23091188 A 1482 1485 TCA ABBREVIATION 23091188 A 1487 1503 glycocholic acid TRIVIAL 23091188 A 1505 1531 taurochenodeoxycholic acid TRIVIAL 23091188 A 1533 1559 glycochenodeoxycholic acid TRIVIAL 23091188 A 1565 1589 α/β-tauromuricholic acid MULTIPLE 23091188 A 1629 1639 bile acids FAMILY 23091188 A 18 27 bile salt FAMILY 23091188 A 195 204 lopinavir TRIVIAL 23091188 A 206 209 LPV ABBREVIATION 23091188 A 215 224 ritonavir TRIVIAL 23091188 A 226 229 RTV ABBREVIATION 23091188 A 290 293 LPV ABBREVIATION 23091188 A 298 301 RTV ABBREVIATION 23091188 A 323 326 LPV ABBREVIATION 23091188 A 356 365 bile acid FAMILY 23091188 A 392 401 bile acid FAMILY 23091188 A 471 474 LPV ABBREVIATION 23091188 A 476 479 RTV ABBREVIATION 23091188 A 485 488 LPV ABBREVIATION 23091188 A 536 558 [(3)H]taurocholic acid SYSTEMATIC 23091188 A 560 563 TCA ABBREVIATION 23091188 A 569 597 [(14)C]chenodeoxycholic acid SYSTEMATIC 23091188 A 599 603 CDCA ABBREVIATION 23091188 A 695 702 Lactate TRIVIAL 23091188 A 721 724 ATP ABBREVIATION 23091188 A 777 780 LPV ABBREVIATION 23091188 A 785 788 RTV ABBREVIATION 23091188 A 812 815 LPV ABBREVIATION 23091188 A 853 856 RTV ABBREVIATION 23091188 A 87 97 bile acids FAMILY 23091188 A 882 891 [(3)H]TCA SYSTEMATIC 23091188 A 953 956 LPV ABBREVIATION 23091188 A 983 992 [(3)H]TCA SYSTEMATIC 23091188 T 12 21 lopinavir TRIVIAL 23091188 T 26 35 ritonavir TRIVIAL 23091188 T 67 76 bile acid FAMILY 23092225 A 1000 1006 TiO(2) FORMULA 23092225 A 1080 1088 silicone FAMILY 23092225 A 1192 1196 PDMS ABBREVIATION 23092225 A 1489 1495 TiO(2) FORMULA 23092225 A 1546 1554 silicone FAMILY 23092225 A 1643 1649 TiO(2) FORMULA 23092225 A 1650 1658 silicone FAMILY 23092225 A 955 978 poly(dimethyl siloxane) FAMILY 23092225 A 980 984 PDMS ABBREVIATION 23092304 A 108 148 poly(2-(dimethylamino)ethylmethacrylate) FAMILY 23092304 A 150 157 PDMAEMA ABBREVIATION 23092304 A 283 290 PDMAEMA ABBREVIATION 23092304 A 842 849 PDMAEMA ABBREVIATION 23092880 A 1489 1496 glucose TRIVIAL 23092880 A 436 445 rapamycin TRIVIAL 23092880 A 50 59 rapamycin TRIVIAL 23092880 A 850 857 glucose TRIVIAL 23093023 A 1385 1394 OSU-03012 IDENTIFIER 23093023 A 1396 1484 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}-acetamide SYSTEMATIC 23093023 A 665 669 O(2) FORMULA 23093023 A 673 678 CO(2) FORMULA 23093023 A 686 690 O(2) FORMULA 23093023 A 694 699 CO(2) FORMULA 23093024 A 0 13 Acetaminophen TRIVIAL 23093024 A 1072 1083 sulfhydryls FAMILY 23093024 A 1152 1162 sulfhydryl FAMILY 23093024 A 1240 1244 APAP ABBREVIATION 23093024 A 1289 1299 sulfhydryl FAMILY 23093024 A 1449 1477 tris(2-carboxyethy)phosphine SYSTEMATIC 23093024 A 1485 1494 maleimide SYSTEMATIC 23093024 A 15 19 APAP ABBREVIATION 23093024 A 155 165 sulfhydryl FAMILY 23093024 A 1557 1567 sulfhydryl FAMILY 23093024 A 1682 1686 APAP ABBREVIATION 23093024 A 244 254 sulfhydryl FAMILY 23093024 A 336 340 APAP ABBREVIATION 23093024 A 381 388 alanine TRIVIAL 23093024 A 434 445 glutathione TRIVIAL 23093024 A 497 508 sulfhydryls FAMILY 23093024 A 569 578 maleimide SYSTEMATIC 23093024 A 633 636 SDS ABBREVIATION 23093024 A 637 651 polyacrylamide SYSTEMATIC 23093024 A 688 698 sulfhydryl FAMILY 23093024 A 772 776 APAP ABBREVIATION 23093024 A 900 910 sulfhydryl FAMILY 23093024 A 959 968 maleimide SYSTEMATIC 23093024 T 20 30 sulfhydryl FAMILY 23093024 T 47 60 acetaminophen TRIVIAL 23093494 A 0 7 Ethanol SYSTEMATIC 23093494 A 103 109 Ca(2+) FORMULA 23093494 A 1054 1058 K(+) FORMULA 23093494 A 1068 1069 K FORMULA 23093494 A 1160 1167 ethanol SYSTEMATIC 23093494 A 1222 1223 N FORMULA 23093494 A 129 133 K(+) FORMULA 23093494 A 1300 1307 ethanol SYSTEMATIC 23093494 A 1390 1391 K FORMULA 23093494 A 1486 1493 ethanol SYSTEMATIC 23093494 A 1532 1538 Ca(2+) FORMULA 23093494 A 1576 1580 K(+) FORMULA 23093494 A 1620 1621 K FORMULA 23093494 A 1707 1714 ethanol SYSTEMATIC 23093494 A 220 227 Ethanol SYSTEMATIC 23093494 A 389 396 ethanol SYSTEMATIC 23093494 A 432 439 ethanol SYSTEMATIC 23093494 A 520 527 Ethanol SYSTEMATIC 23093494 A 587 593 Ca(2+) FORMULA 23093494 A 63 70 alcohol FAMILY 23093494 A 697 704 ethanol SYSTEMATIC 23093494 A 752 757 Na(+) FORMULA 23093494 A 758 763 Cl(-) FORMULA 23093494 A 777 781 H(+) FORMULA 23093494 A 874 875 N FORMULA 23093494 T 49 56 ethanol SYSTEMATIC 23093496 A 1034 1037 ATP ABBREVIATION 23093496 A 1234 1255 N-Methyl-anthraniloyl SYSTEMATIC 23093496 A 1276 1281 3'-OH SYSTEMATIC 23093496 A 1289 1303 2'-deoxyribose SYSTEMATIC 23093496 A 1333 1336 ATP ABBREVIATION 23093496 A 1356 1359 ADP ABBREVIATION 23093496 A 1556 1559 ADP ABBREVIATION 23093496 A 1564 1567 ATP ABBREVIATION 23093496 A 1575 1578 ATP ABBREVIATION 23093496 A 1676 1679 ATP ABBREVIATION 23093496 A 1714 1717 ATP ABBREVIATION 23093496 A 181 192 clopidogrel TRIVIAL 23093496 A 4 7 ADP ABBREVIATION 23093496 A 639 645 purine TRIVIAL 23093496 A 776 779 ATP ABBREVIATION 23093496 A 784 787 ATP ABBREVIATION 23093496 A 852 870 2-(methylthio)-ADP SYSTEMATIC 23093496 A 873 891 2-(methylthio)-ATP SYSTEMATIC 23093496 A 894 897 ADP ABBREVIATION 23093496 A 900 903 ATP ABBREVIATION 23093496 T 101 104 ADP ABBREVIATION 23095245 A 425 434 clozapine TRIVIAL 23095245 A 438 448 olanzapine TRIVIAL 23095245 A 466 478 aripiprazole TRIVIAL 23095245 A 482 493 amisulpride TRIVIAL 23097088 A 1098 1103 CdCl₂ FORMULA 23097088 A 790 798 tyrosine TRIVIAL 23097088 A 842 847 CdCl₂ FORMULA 23097213 A 729 736 ADL5859 IDENTIFIER 23098878 A 16 29 anthraquinone SYSTEMATIC 23098878 A 43 55 bulgareone A TRIVIAL 23098878 A 63 75 bulgareone B TRIVIAL 23098878 T 8 21 anthraquinone SYSTEMATIC 23099319 A 1076 1079 DOM ABBREVIATION 23099319 A 1251 1254 DOM ABBREVIATION 23099319 A 1384 1387 DOM ABBREVIATION 23099319 A 1440 1443 DOM ABBREVIATION 23099319 A 1569 1572 DOM ABBREVIATION 23099319 A 157 160 DOM ABBREVIATION 23099319 A 249 252 DOM ABBREVIATION 23099319 A 328 331 DOM ABBREVIATION 23099319 A 437 440 DOM ABBREVIATION 23099319 A 605 608 DOM ABBREVIATION 23099319 A 66 77 domoic acid TRIVIAL 23099319 A 750 753 DOM ABBREVIATION 23099319 A 79 82 DOM ABBREVIATION 23099319 A 824 827 DOM ABBREVIATION 23099319 A 903 922 phosphorylated cAMP ABBREVIATION 23099319 T 40 51 domoic acid TRIVIAL 23099502 A 1035 1049 deoxynivalenol TRIVIAL 23099502 A 1051 1060 T-2 toxin TRIVIAL 23099502 A 1065 1076 zearalenone TRIVIAL 23099502 A 1148 1162 deoxynivalenol TRIVIAL 23099502 A 1164 1173 T-2 toxin TRIVIAL 23099502 A 1178 1189 zearalenone TRIVIAL 23099502 A 1230 1239 T-2 toxin TRIVIAL 23099502 A 1301 1315 deoxynivalenol TRIVIAL 23099502 A 1330 1341 zearalenone TRIVIAL 23099502 A 353 367 deoxynivalenol TRIVIAL 23099502 A 369 372 T-2 TRIVIAL 23099502 A 377 388 zearalenone TRIVIAL 23099502 A 488 502 deoxynivalenol TRIVIAL 23099502 A 549 558 T-2 toxin TRIVIAL 23099502 A 580 591 zearalenone TRIVIAL 23099502 A 788 802 Deoxynivalenol TRIVIAL 23099502 A 856 867 zearalenone TRIVIAL 23099502 A 872 875 T-2 TRIVIAL 23099502 T 57 71 deoxynivalenol TRIVIAL 23099502 T 73 82 T-2 toxin TRIVIAL 23099502 T 87 98 zearalenone TRIVIAL 23099503 A 1008 1015 lactate FAMILY 23099503 A 114 117 PMF ABBREVIATION 23099503 A 1199 1202 PMF ABBREVIATION 23099503 A 1272 1275 PMF ABBREVIATION 23099503 A 248 259 cholesterol TRIVIAL 23099503 A 289 292 PMF ABBREVIATION 23099503 A 364 367 PMF ABBREVIATION 23099503 A 421 430 aspartate TRIVIAL 23099503 A 659 665 niacin TRIVIAL 23099503 A 669 672 PMF ABBREVIATION 23099503 A 740 750 creatinine TRIVIAL 23099503 A 754 758 urea TRIVIAL 23099503 A 787 796 bilirubin TRIVIAL 23099503 A 79 104 polymethoxylated flavones FAMILY 23099503 A 917 920 PMF ABBREVIATION 23099503 A 988 996 creatine TRIVIAL 23099503 T 12 37 polymethoxylated flavones FAMILY 23100157 A 0 12 Formaldehyde SYSTEMATIC 23100157 T 90 102 formaldehyde SYSTEMATIC 23103224 A 0 9 Cisplatin TRIVIAL 23103224 A 139 148 cisplatin TRIVIAL 23103224 A 236 245 cisplatin TRIVIAL 23103224 A 627 636 cisplatin TRIVIAL 23103224 T 37 46 cisplatin TRIVIAL 23103330 A 823 830 steroid FAMILY 23103330 A 835 843 estrogen FAMILY 23103351 A 1488 1497 d-glucose TRIVIAL 23103351 A 1502 1511 l-leucine TRIVIAL 23103351 A 1744 1756 testosterone TRIVIAL 23103351 A 1761 1770 midazolam TRIVIAL 23103351 A 850 862 testosterone TRIVIAL 23103351 A 867 876 midazolam TRIVIAL 23103446 A 1032 1044 daunorubicin TRIVIAL 23103446 A 1046 1049 DNR ABBREVIATION 23103446 A 1153 1162 nilotinib TRIVIAL 23103446 A 1216 1219 DNR ABBREVIATION 23103446 A 1307 1316 nilotinib TRIVIAL 23103446 A 143 146 Dox ABBREVIATION 23103446 A 312 315 Dox ABBREVIATION 23103446 A 560 563 Dox ABBREVIATION 23103446 A 647 656 nilotinib TRIVIAL 23103446 A 802 805 Dox ABBREVIATION 23103446 A 815 824 nilotinib TRIVIAL 23103446 A 82 91 nilotinib TRIVIAL 23103446 A 951 960 nilotinib TRIVIAL 23103446 T 41 50 nilotinib TRIVIAL 23103566 A 1091 1098 HFCS-55 TRIVIAL 23103566 A 1146 1152 GW0742 IDENTIFIER 23103566 A 1227 1233 GW0742 IDENTIFIER 23103566 A 1330 1337 HFCS-55 TRIVIAL 23103566 A 287 292 sugar FAMILY 23103566 A 35 42 HFCS-55 TRIVIAL 23103566 A 406 413 HFCS-55 TRIVIAL 23103566 A 548 554 GW0742 IDENTIFIER 23103566 A 601 608 HFCS-55 TRIVIAL 23103566 A 712 719 HFCS-55 TRIVIAL 23103566 A 869 876 HFCS-55 TRIVIAL 23103566 A 9 33 high-fructose corn syrup TRIVIAL 23103566 A 915 925 nucleotide FAMILY 23103566 A 945 952 leucine TRIVIAL 23103566 T 55 62 HFCS-55 TRIVIAL 23103569 A 0 16 Hydrogen sulfide SYSTEMATIC 23103569 A 1057 1069 NOSH-aspirin FORMULA 23103569 A 1089 1091 NO FORMULA 23103569 A 1096 1099 H2S FORMULA 23103569 A 18 21 H2S FORMULA 23103569 A 310 313 H2S FORMULA 23103569 A 332 344 nitric oxide SYSTEMATIC 23103569 A 346 348 NO FORMULA 23103569 A 354 369 carbon monoxide SYSTEMATIC 23103569 A 371 373 CO FORMULA 23103569 A 492 495 H2S FORMULA 23103569 A 584 587 H2S FORMULA 23103569 A 669 681 sulforaphane TRIVIAL 23103569 A 683 689 erucin TRIVIAL 23103569 A 695 701 iberin TRIVIAL 23103569 A 717 720 H2S FORMULA 23103569 A 746 753 GYY4137 IDENTIFIER 23103569 A 755 763 cysteine TRIVIAL 23103569 A 773 790 S-propyl cysteine SYSTEMATIC 23103569 A 792 808 S-allyl cysteine SYSTEMATIC 23103569 A 810 830 S-propargyl cysteine SYSTEMATIC 23103569 A 836 853 N-acetyl cysteine SYSTEMATIC 23103569 A 855 869 Dithiolethione FAMILY 23103569 A 912 918 L-DOPA ABBREVIATION 23103569 A 920 930 sildenafil TRIVIAL 23103569 A 932 939 aspirin TRIVIAL 23103569 A 941 951 diclofenac TRIVIAL 23103569 A 953 961 naproxen TRIVIAL 23103569 A 963 972 ibuprofen TRIVIAL 23103569 A 974 986 indomethacin TRIVIAL 23103569 A 992 1002 mesalamine TRIVIAL 23103569 T 37 53 hydrogen sulfide SYSTEMATIC 23103569 T 58 74 hydrogen sulfide SYSTEMATIC 23103600 A 944 947 NAD ABBREVIATION 23103600 A 959 963 NADP ABBREVIATION 23104246 A 10 17 arsenic SYSTEMATIC 23104246 A 1046 1053 arsenic SYSTEMATIC 23104246 A 1190 1197 arsenic SYSTEMATIC 23104246 A 1277 1284 arsenic SYSTEMATIC 23104246 A 221 228 arsenic SYSTEMATIC 23104246 A 430 437 arsenic SYSTEMATIC 23104246 A 449 457 arsenite SYSTEMATIC 23104246 A 459 466 As(III) FORMULA 23104246 A 472 480 arsenate SYSTEMATIC 23104246 A 482 487 As(V) FORMULA 23104246 A 762 769 arsenic SYSTEMATIC 23104246 T 30 37 arsenic SYSTEMATIC 23106203 A 1075 1084 phosphate SYSTEMATIC 23106203 A 1397 1405 nitrogen SYSTEMATIC 23106203 A 1556 1564 nitrogen SYSTEMATIC 23106203 A 1782 1791 glutamate TRIVIAL 23106203 A 250 259 glutamate TRIVIAL 23107818 A 102 113 doxorubicin TRIVIAL 23107818 A 1024 1033 rapamycin TRIVIAL 23107818 A 1074 1077 DXR ABBREVIATION 23107818 A 115 118 DXR ABBREVIATION 23107818 A 1503 1512 rapamycin TRIVIAL 23107818 A 1554 1557 DXR ABBREVIATION 23107818 A 181 192 doxorubicin TRIVIAL 23107818 A 302 305 DXR ABBREVIATION 23107818 A 329 335 oxygen SYSTEMATIC 23107818 A 438 452 bafilomycin A1 TRIVIAL 23107818 A 485 494 rapamycin TRIVIAL 23107818 A 534 537 DXR ABBREVIATION 23107818 A 591 600 rapamycin TRIVIAL 23107818 A 620 623 DXR ABBREVIATION 23107818 A 685 688 DXR ABBREVIATION 23107818 T 56 67 doxorubicin TRIVIAL 23108036 A 0 7 Arsenic SYSTEMATIC 23108036 A 1101 1108 arsenic SYSTEMATIC 23108036 A 166 173 arsenic SYSTEMATIC 23108036 A 272 279 arsenic SYSTEMATIC 23108036 A 334 341 arsenic SYSTEMATIC 23108036 A 423 430 Arsenic SYSTEMATIC 23108036 A 646 656 fatty acid FAMILY 23108036 A 684 691 Arsenic SYSTEMATIC 23108036 A 837 849 troglitazone TRIVIAL 23108036 A 895 902 arsenic SYSTEMATIC 23108036 A 993 1000 arsenic SYSTEMATIC 23108036 T 0 7 Arsenic SYSTEMATIC 23108606 A 199 265 1,8-di((R)-α-methylnaphthyl)-1,3,6,8,10,13-hexaazacyclotetradecane SYSTEMATIC 23108606 A 432 442 nickel(II) SYSTEMATIC 23108606 A 463 500 [Ni(L(R,R))](3) [C(6)H(3)(COO)(3)](2) FAMILY 23108606 A 48 71 [Ni(L(R,R))](ClO(4))(2) FAMILY 23108606 A 576 607 1,3,5-benzenetricarboxylic acid SYSTEMATIC 23108606 A 609 616 BTC(3-) ABBREVIATION 23108606 A 643 665 rac-1,1'-bi-2-naphthol SYSTEMATIC 23108606 A 670 710 rac-2,2,2-trifluoro-1-(9-anthryl)ethanol SYSTEMATIC 23108606 A 8 26 nickel(II) hexaaza SYSTEMATIC 23108606 A 833 843 Binaphthol SYSTEMATIC 23108606 T 36 46 nickel(II) SYSTEMATIC 23108606 T 72 97 (R)-naphthylethyleneamine SYSTEMATIC 23108727 A 174 183 Ga(In)NAs FORMULA 23108727 T 50 59 Ga(In)NAs FORMULA 23108979 A 0 13 Ethyl acetate SYSTEMATIC 23108979 A 15 30 ethyl ethanoate SYSTEMATIC 23108979 A 184 197 ethyl acetate SYSTEMATIC 23108979 T 0 13 Ethyl acetate SYSTEMATIC 23109258 A 1010 1027 pentachlorophenol SYSTEMATIC 23109258 A 606 617 isoproturon TRIVIAL 23109258 A 619 637 metsulfuron-methyl SYSTEMATIC 23109258 A 643 660 pentachlorophenol SYSTEMATIC 23109258 A 789 807 metsulfuron-methyl SYSTEMATIC 23109258 A 897 908 isoproturon TRIVIAL 23109425 A 197 198 C FORMULA 23110414 A 74 83 modafinil TRIVIAL 23110812 A 1026 1030 EDTA ABBREVIATION 23111348 A 0 6 Thymol TRIVIAL 23111348 A 1097 1108 Rhodamine6G TRIVIAL 23111348 A 1110 1113 R6G ABBREVIATION 23111348 A 1131 1144 Hoechst 33342 TRIVIAL 23111348 A 1263 1270 glucose TRIVIAL 23111348 A 1339 1342 FLC ABBREVIATION 23111348 A 1367 1374 glucose TRIVIAL 23111348 A 1391 1403 monoterpenes FAMILY 23111348 A 1571 1583 monoterpenes FAMILY 23111348 A 1605 1608 FLC ABBREVIATION 23111348 A 1687 1690 FLC ABBREVIATION 23111348 A 17 26 carvacrol TRIVIAL 23111348 A 1763 1766 THY ABBREVIATION 23111348 A 1771 1775 CARV ABBREVIATION 23111348 A 274 286 monoterpenes FAMILY 23111348 A 28 32 CARV ABBREVIATION 23111348 A 292 297 azole FAMILY 23111348 A 310 321 fluconazole TRIVIAL 23111348 A 337 343 azoles FAMILY 23111348 A 675 687 monoterpenes FAMILY 23111348 A 692 695 FLC ABBREVIATION 23111348 A 727 730 FLC ABBREVIATION 23111348 A 753 756 FLC ABBREVIATION 23111348 A 8 11 THY ABBREVIATION 23111348 A 829 832 THY ABBREVIATION 23111348 A 833 836 FLC ABBREVIATION 23111348 A 841 845 CARV ABBREVIATION 23111348 A 846 849 FLC ABBREVIATION 23111348 T 106 117 fluconazole TRIVIAL 23111348 T 88 100 monoterpenes FAMILY 23111803 A 1076 1088 imidacloprid TRIVIAL 23111803 A 1106 1112 thiram TRIVIAL 23111803 A 1300 1312 imidacloprid TRIVIAL 23111803 A 1317 1323 thiram TRIVIAL 23111803 A 1581 1593 imidacloprid TRIVIAL 23111803 A 1598 1612 difenoconazole TRIVIAL 23111803 A 1668 1674 thiram TRIVIAL 23111803 A 1679 1691 imidacloprid TRIVIAL 23111803 A 457 471 difenoconazole TRIVIAL 23111803 A 485 491 thiram TRIVIAL 23111803 A 507 519 imidacloprid TRIVIAL 23111803 A 932 938 Thiram TRIVIAL 23111803 A 943 955 imidacloprid TRIVIAL 23111803 T 110 124 difenoconazole TRIVIAL 23111803 T 85 97 imidacloprid TRIVIAL 23111803 T 99 105 thiram TRIVIAL 23111876 A 1020 1025 DPCPX ABBREVIATION 23111876 A 1065 1078 amitriptyline TRIVIAL 23111876 A 1136 1141 DPCPX ABBREVIATION 23111876 A 1170 1183 amitriptyline TRIVIAL 23111876 A 1266 1275 adenosine TRIVIAL 23111876 A 1347 1360 amitriptyline TRIVIAL 23111876 A 1469 1482 amitriptyline TRIVIAL 23111876 A 201 214 amitriptyline TRIVIAL 23111876 A 28 37 adenosine TRIVIAL 23111876 A 298 307 adenosine TRIVIAL 23111876 A 325 359 8-cyclopentyl-1,3-dipropylxanthine SYSTEMATIC 23111876 A 361 366 DPCPX ABBREVIATION 23111876 A 392 401 adenosine TRIVIAL 23111876 A 429 456 8-(3-chlorostyryl) caffeine SYSTEMATIC 23111876 A 475 488 amitriptyline TRIVIAL 23111876 A 51 64 amitriptyline TRIVIAL 23111876 A 694 707 Amitriptyline TRIVIAL 23111876 A 810 823 amitriptyline TRIVIAL 23111876 A 838 851 Amitriptyline TRIVIAL 23111876 A 912 917 DPCPX ABBREVIATION 23111876 A 952 965 amitriptyline TRIVIAL 23111876 T 12 21 adenosine TRIVIAL 23111876 T 35 48 amitriptyline TRIVIAL 23111877 A 0 10 Duloxetine TRIVIAL 23111877 A 16 25 serotonin TRIVIAL 23111877 A 182 192 duloxetine TRIVIAL 23111877 A 284 294 duloxetine TRIVIAL 23111877 A 30 44 norepinephrine TRIVIAL 23111877 T 13 23 duloxetine TRIVIAL 23111881 A 0 13 Thioacetamide SYSTEMATIC 23111881 A 1170 1173 TAA ABBREVIATION 23111881 A 1209 1212 TAA ABBREVIATION 23111881 A 133 136 TAA ABBREVIATION 23111881 A 15 18 TAA ABBREVIATION 23111881 A 297 300 TAA ABBREVIATION 23111881 A 317 320 TAA ABBREVIATION 23111881 A 339 342 TAA ABBREVIATION 23111881 A 365 368 TAA ABBREVIATION 23111881 A 401 404 TAA ABBREVIATION 23111881 A 458 461 TAA ABBREVIATION 23111881 A 476 479 TAA ABBREVIATION 23111881 A 498 501 TAA ABBREVIATION 23111881 A 588 591 TAA ABBREVIATION 23111881 A 673 676 TAA ABBREVIATION 23111881 A 707 710 TAA ABBREVIATION 23111881 A 964 967 TAA ABBREVIATION 23111881 T 21 34 thioacetamide SYSTEMATIC 23111886 A 0 9 Cisplatin TRIVIAL 23111886 A 11 15 Cisp ABBREVIATION 23111886 A 1152 1156 Cisp ABBREVIATION 23111886 A 350 354 Cisp ABBREVIATION 23111886 A 486 490 Cisp ABBREVIATION 23111886 A 515 519 Cisp ABBREVIATION 23111886 A 608 612 Cisp ABBREVIATION 23111886 A 769 779 creatinine TRIVIAL 23111886 A 787 791 urea TRIVIAL 23111886 A 792 800 nitrogen SYSTEMATIC 23111886 A 802 809 alanine TRIVIAL 23111886 A 828 837 aspartate TRIVIAL 23111886 A 902 911 bilirubin TRIVIAL 23111886 A 91 95 Cisp ABBREVIATION 23111886 A 927 936 bilirubin TRIVIAL 23111886 A 997 1001 Cisp ABBREVIATION 23111886 T 66 75 cisplatin TRIVIAL 23111950 A 0 9 Magnesium SYSTEMATIC 23111950 A 11 13 Mg FORMULA 23111950 A 1103 1105 Mg FORMULA 23111950 A 1244 1246 Mg FORMULA 23111950 A 1352 1354 Mg FORMULA 23111950 A 1466 1468 Mg FORMULA 23111950 A 226 228 Mg FORMULA 23111950 A 514 516 Mg FORMULA 23111950 A 605 607 Mg FORMULA 23111950 A 649 652 MgO FORMULA 23111950 A 746 748 Mg FORMULA 23111950 A 845 847 Mg FORMULA 23111950 A 887 889 Mg FORMULA 23111950 T 41 50 magnesium SYSTEMATIC 23115221 A 1153 1161 nicotine TRIVIAL 23115221 A 1260 1268 nicotine TRIVIAL 23115221 A 1273 1281 cotinine TRIVIAL 23115221 A 1344 1352 cotinine TRIVIAL 23115221 A 137 145 nicotine TRIVIAL 23115221 A 1535 1543 nicotine TRIVIAL 23115221 A 20 28 nicotine TRIVIAL 23115221 A 212 226 sodium sulfate SYSTEMATIC 23115221 A 290 298 cotinine TRIVIAL 23115221 A 322 330 nicotine TRIVIAL 23115221 A 692 700 nicotine TRIVIAL 23115221 A 705 713 cotinine TRIVIAL 23115221 A 847 855 nicotine TRIVIAL 23115221 A 860 868 cotinine TRIVIAL 23115221 A 948 956 nicotine TRIVIAL 23115221 T 32 40 nicotine TRIVIAL 23117151 A 112 116 TCDD ABBREVIATION 23117151 A 119 123 TCDD ABBREVIATION 23117151 A 141 157 aryl hydrocarbon FAMILY 23117151 A 199 207 androgen FAMILY 23117151 A 348 352 TCDD ABBREVIATION 23117151 A 425 447 5α-dihydrotestosterone SYSTEMATIC 23117151 A 588 592 TCDD ABBREVIATION 23117151 A 637 641 TCDD ABBREVIATION 23117151 A 733 737 TCDD ABBREVIATION 23117151 A 75 110 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23117151 A 804 808 TCDD ABBREVIATION 23117151 A 896 900 TCDD ABBREVIATION 23117151 T 0 8 Androgen FAMILY 23117151 T 59 94 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23117207 A 1377 1385 hydrogen SYSTEMATIC 23118486 A 843 850 sulfate SYSTEMATIC 23121886 A 1188 1190 Pb FORMULA 23121886 A 345 347 Ag FORMULA 23121886 A 349 351 As FORMULA 23121886 A 353 355 Cd FORMULA 23121886 A 357 359 Cu FORMULA 23121886 A 361 363 Pb FORMULA 23121886 A 368 370 Zn FORMULA 23122065 A 418 424 Ca(2+) FORMULA 23122065 A 522 529 calcium SYSTEMATIC 23122065 A 540 546 A23187 IDENTIFIER 23122065 A 674 694 phosphatidylinositol TRIVIAL 23122067 A 1020 1027 phenols FAMILY 23122067 A 16 23 phenols FAMILY 23122067 A 250 264 anthraquinones FAMILY 23122067 A 299 311 chrysophanol TRIVIAL 23122067 A 341 347 emodin TRIVIAL 23122067 A 379 387 physcion TRIVIAL 23122067 A 581 589 phenolic FAMILY 23122067 A 594 603 flavonoid FAMILY 23122067 A 995 1009 anthraquinones FAMILY 23122067 T 0 13 Anthraquinone SYSTEMATIC 23122070 A 117 138 4-hydroxybenzaldehyde SYSTEMATIC 23122070 A 140 164 myricetin-3-O-rhamnoside SYSTEMATIC 23122070 A 166 190 europetin-3-O-rhamnoside SYSTEMATIC 23122070 A 192 201 phloretin TRIVIAL 23122070 A 203 215 myrigalone-G TRIVIAL 23122070 A 220 232 myrigalone-B TRIVIAL 23122070 A 455 462 glucose TRIVIAL 23122070 A 550 574 myricetin-3-O-rhamnoside SYSTEMATIC 23122070 A 579 603 europetin-3-O-rhamnoside SYSTEMATIC 23122070 A 740 753 rosiglitazone TRIVIAL 23122070 A 826 832 2-NBDG SYSTEMATIC 23122070 T 100 106 2-NBDG SYSTEMATIC 23122072 A 12 20 phenolic FAMILY 23122072 A 581 589 phenolic FAMILY 23122072 A 744 752 phenolic FAMILY 23122072 T 79 87 phenolic FAMILY 23122079 A 0 9 Phillyrin TRIVIAL 23122079 A 1092 1101 phillyrin TRIVIAL 23122079 A 227 236 phillyrin TRIVIAL 23122079 A 263 270 glucose TRIVIAL 23122079 A 340 349 phillyrin TRIVIAL 23122079 A 366 373 glucose TRIVIAL 23122079 A 417 426 Phillyrin TRIVIAL 23122079 A 451 458 glucose TRIVIAL 23122079 A 467 477 fatty acid FAMILY 23122079 A 518 524 sterol FAMILY 23122079 A 623 626 AMP ABBREVIATION 23122079 A 669 679 compound C TRIVIAL 23122079 A 751 760 phillyrin TRIVIAL 23122079 A 858 867 phillyrin TRIVIAL 23122079 A 946 955 phillyrin TRIVIAL 23122079 T 0 9 Phillyrin TRIVIAL 23122079 T 119 122 AMP ABBREVIATION 23122079 T 26 33 glucose TRIVIAL 23122081 A 1161 1169 lycopene TRIVIAL 23122081 A 538 546 lycopene TRIVIAL 23122081 A 670 678 lycopene TRIVIAL 23122094 A 800 808 linalool TRIVIAL 23122094 A 810 823 terpinen-4-ol SYSTEMATIC 23122094 A 828 839 α-terpineol TRIVIAL 23122094 A 945 961 terpene alcohols FAMILY 23122099 A 205 219 vitamin (B(9)) TRIVIAL 23122099 A 263 277 salicylic acid TRIVIAL 23122099 A 334 341 folates FAMILY 23122099 A 344 368 5-methyltetrahydrofolate SYSTEMATIC 23122099 A 370 394 5-formyltetrahydrofolate SYSTEMATIC 23122099 A 399 424 10-formyltetrahydrofolate SYSTEMATIC 23122099 A 99 113 salicylic acid TRIVIAL 23122099 T 0 14 Salicylic acid TRIVIAL 23122100 A 1140 1156 dimethylsiloxane SYSTEMATIC 23122100 A 147 158 fatty acids FAMILY 23122100 A 205 216 eicosanoids FAMILY 23122100 A 461 472 eicosanoids FAMILY 23122100 A 739 750 eicosanoids FAMILY 23122100 A 881 908 hydroxyoctadecadienoic acid SYSTEMATIC 23122100 A 910 914 HODE ABBREVIATION 23122100 A 998 1002 HODE ABBREVIATION 23122100 T 105 116 fatty acids FAMILY 23122102 A 559 578 phenolic glycosides FAMILY 23122102 A 594 619 phenylpropanoid glucoside SYSTEMATIC 23122102 A 621 629 saponins FAMILY 23122102 A 635 646 fatty acids FAMILY 23122102 A 838 848 β-carotene TRIVIAL 23122102 A 850 861 fatty acids FAMILY 23122102 A 863 876 ascorbic acid TRIVIAL 23122102 A 999 1007 phenolic FAMILY 23122111 A 1118 1126 neferine TRIVIAL 23122111 A 120 128 Neferine TRIVIAL 23122111 A 1212 1220 neferine TRIVIAL 23122111 A 359 366 calcium SYSTEMATIC 23122111 A 375 381 Ca(2+) FORMULA 23122111 A 497 503 oxygen SYSTEMATIC 23122111 A 542 550 neferine TRIVIAL 23122111 A 598 609 glutathione TRIVIAL 23122111 A 669 675 Ca(2+) FORMULA 23122111 A 710 718 neferine TRIVIAL 23122111 T 0 8 Neferine TRIVIAL 23122111 T 26 32 oxygen SYSTEMATIC 23122115 A 15 24 lactulose TRIVIAL 23122115 A 187 195 fructose TRIVIAL 23122115 A 200 209 lactulose TRIVIAL 23122115 A 247 256 galactose TRIVIAL 23122115 A 258 265 glucose TRIVIAL 23122115 A 270 278 fructose TRIVIAL 23122115 A 345 352 lactose TRIVIAL 23122115 A 395 404 lactulose TRIVIAL 23122115 A 416 425 Galactose TRIVIAL 23122115 A 430 438 fructose TRIVIAL 23122115 A 45 52 lactose TRIVIAL 23122115 A 472 479 glucose TRIVIAL 23122115 A 543 552 galactose TRIVIAL 23122115 A 557 564 glucose TRIVIAL 23122115 A 720 729 lactulose TRIVIAL 23122115 A 817 826 Lactulose TRIVIAL 23122115 A 904 913 lactulose TRIVIAL 23122115 T 34 43 lactulose TRIVIAL 23122115 T 54 61 lactose TRIVIAL 23122120 A 1006 1012 Neu5Ac SYSTEMATIC 23122120 A 1181 1187 Neu5Ac SYSTEMATIC 23122120 A 67 78 sialic acid TRIVIAL 23122120 A 80 86 Neu5Ac SYSTEMATIC 23122120 T 17 28 sialic acid TRIVIAL 23122121 A 1021 1035 betulinic acid TRIVIAL 23122121 A 1130 1147 triterpenic acids FAMILY 23122121 A 1387 1404 triterpenic acids FAMILY 23122121 A 18 46 triterpene pentacyclic acids FAMILY 23122121 A 200 259 betulinic, corosolic, maslinic, oleanolic and ursolic acids MULTIPLE 23122121 A 551 565 corosolic acid TRIVIAL 23122121 A 708 722 oleanolic acid TRIVIAL 23122121 A 806 813 ursolic TRIVIAL 23122121 A 970 983 maslinic acid TRIVIAL 23122121 T 43 101 betulinic, corosolic, maslinic, oleanolic and ursolic acid MULTIPLE 23122126 A 898 907 bile salt FAMILY 23122134 A 167 179 polydextrose FAMILY 23122134 A 655 667 polydextrose FAMILY 23122143 A 244 254 fatty acid FAMILY 23122143 A 270 281 p-anisidine SYSTEMATIC 23122143 A 314 324 fatty acid FAMILY 23122143 A 861 888 polyunsaturated fatty acids FAMILY 23122147 A 741 776 tetrahydroaldosterone-3-glucuronide SYSTEMATIC 23122147 A 778 801 cortolone-3-glucuronide SYSTEMATIC 23122147 A 803 827 testosterone-glucuronide SYSTEMATIC 23122147 A 832 854 17-hydroxyprogesterone SYSTEMATIC 23122147 A 879 886 steroid FAMILY 23122147 T 72 79 steroid FAMILY 23122151 A 1007 1017 myricitrin TRIVIAL 23122151 A 1074 1084 flavonoids FAMILY 23122151 A 197 203 aldose FAMILY 23122151 A 224 232 methanol SYSTEMATIC 23122151 A 457 470 ethyl acetate SYSTEMATIC 23122151 A 472 477 EtOAc FORMULA 23122151 A 573 578 EtOAc FORMULA 23122151 A 624 634 flavonoids FAMILY 23122151 A 687 697 kaempferol TRIVIAL 23122151 A 703 710 afzelin TRIVIAL 23122151 A 716 725 quercetin TRIVIAL 23122151 A 731 741 quercitrin TRIVIAL 23122151 A 747 756 myricetin TRIVIAL 23122151 A 765 775 myricitrin TRIVIAL 23122151 A 957 967 flavonoids FAMILY 23122151 A 988 998 quercitrin TRIVIAL 23122151 T 142 148 aldose FAMILY 23122151 T 18 28 flavonoids FAMILY 23122151 T 33 54 flavonoid rhamnosides FAMILY 23122157 A 0 11 Gallic acid TRIVIAL 23122157 A 340 351 gallic acid TRIVIAL 23122157 A 468 479 gallic acid TRIVIAL 23122157 A 695 706 gallic acid TRIVIAL 23122157 A 734 764 1,1'-diphenyl-2-picrylhydrazyl SYSTEMATIC 23122157 A 766 770 DPPH ABBREVIATION 23122157 A 794 805 gallic acid TRIVIAL 23122157 T 130 141 gallic acid TRIVIAL 23122161 A 1067 1073 PGE(2) ABBREVIATION 23122161 A 1166 1172 hexane SYSTEMATIC 23122161 A 535 547 nitric oxide SYSTEMATIC 23122161 A 616 628 nitric oxide SYSTEMATIC 23122161 A 630 632 NO FORMULA 23122161 A 635 653 prostaglandin E(2) TRIVIAL 23122161 A 655 661 PGE(2) ABBREVIATION 23122161 A 753 761 methanol SYSTEMATIC 23122161 A 790 796 hexane SYSTEMATIC 23122161 A 814 816 NO FORMULA 23122161 A 891 899 methanol SYSTEMATIC 23122161 A 916 922 hexane SYSTEMATIC 23122166 A 130 137 ethanol SYSTEMATIC 23122166 A 307 319 trigycerides FAMILY 23122166 A 628 631 AMP ABBREVIATION 23122166 A 709 719 acetyl-CoA SYSTEMATIC 23122166 A 765 774 carnitine TRIVIAL 23122166 A 775 784 palmitoyl TRIVIAL 23122166 A 867 877 fatty acid FAMILY 23122331 A 1167 1172 (15)N FORMULA 23122331 A 1240 1245 sugar FAMILY 23122331 A 1266 1271 sugar FAMILY 23122331 A 1312 1319 lactose TRIVIAL 23122331 A 139 144 sugar FAMILY 23122331 A 1391 1396 sugar FAMILY 23122331 A 1437 1442 sugar FAMILY 23122331 A 1596 1601 sugar FAMILY 23122331 A 1632 1637 sugar FAMILY 23122331 A 1718 1723 sugar FAMILY 23122331 A 212 217 sugar FAMILY 23122331 A 346 351 sugar FAMILY 23122331 A 399 404 sugar FAMILY 23122331 A 4 5 C FORMULA 23122331 A 480 485 sugar FAMILY 23122331 A 578 585 lactose TRIVIAL 23122331 A 641 646 sugar FAMILY 23122331 A 664 671 lactose TRIVIAL 23122331 A 710 715 sugar FAMILY 23122331 A 733 740 lactose TRIVIAL 23122331 A 818 823 sugar FAMILY 23122331 A 849 854 (15)N FORMULA 23122331 A 901 906 sugar FAMILY 23122331 A 926 933 lactose TRIVIAL 23122331 A 982 987 sugar FAMILY 23122331 T 34 35 C FORMULA 23123224 A 556 563 ethanol SYSTEMATIC 23123224 A 839 848 berberine TRIVIAL 23123224 A 854 863 palmatine TRIVIAL 23123224 A 868 880 jatrorrhizin TRIVIAL 23123225 A 153 162 β-Asarone TRIVIAL 23123225 A 307 316 β-asarone TRIVIAL 23123225 A 401 410 β-Asarone TRIVIAL 23123225 A 585 594 β-asarone TRIVIAL 23123225 A 626 636 ergosterol TRIVIAL 23123225 A 679 688 β-asarone TRIVIAL 23123225 A 75 84 β-asarone TRIVIAL 23123225 A 774 783 β-asarone TRIVIAL 23123225 T 0 9 β-Asarone TRIVIAL 23123225 T 104 114 ergosterol TRIVIAL 23123249 A 1005 1010 sarin TRIVIAL 23123249 A 1069 1074 oxime SYSTEMATIC 23123249 A 1401 1407 oximes FAMILY 23123249 A 1425 1430 sarin TRIVIAL 23123249 A 1441 1445 NIMP ABBREVIATION 23123249 A 145 150 oxime SYSTEMATIC 23123249 A 1508 1513 oxime SYSTEMATIC 23123249 A 1594 1600 oximes FAMILY 23123249 A 1624 1630 oximes FAMILY 23123249 A 361 391 phenoxyalkyl pyridinium oximes FAMILY 23123249 A 45 60 organophosphate FAMILY 23123249 A 458 464 oximes FAMILY 23123249 A 510 516 oximes FAMILY 23123249 A 610 615 sarin TRIVIAL 23123249 A 617 657 phthalimidyl isopropyl methylphosphonate SYSTEMATIC 23123249 A 659 663 PIMP ABBREVIATION 23123249 A 673 708 nitrophenyl ethyl methylphosphonate SYSTEMATIC 23123249 A 710 714 NEMP ABBREVIATION 23123249 A 721 727 oximes FAMILY 23123249 A 861 866 oxime SYSTEMATIC 23123249 A 958 997 nitrophenyl isopropyl methylphosphonate SYSTEMATIC 23123249 A 999 1003 NIMP ABBREVIATION 23123249 T 35 40 oxime SYSTEMATIC 23123662 A 1004 1008 zinc SYSTEMATIC 23123662 A 1091 1099 platinum SYSTEMATIC 23123662 A 1125 1136 oxaliplatin TRIVIAL 23123662 A 1159 1170 oxaliplatin TRIVIAL 23123662 A 1205 1213 platinum SYSTEMATIC 23123662 A 1275 1286 oxaliplatin TRIVIAL 23123662 A 1359 1365 copper SYSTEMATIC 23123662 A 140 146 copper SYSTEMATIC 23123662 A 1426 1432 copper SYSTEMATIC 23123662 A 1437 1445 platinum SYSTEMATIC 23123662 A 1557 1563 copper SYSTEMATIC 23123662 A 1633 1639 copper SYSTEMATIC 23123662 A 1691 1702 oxaliplatin TRIVIAL 23123662 A 217 223 copper SYSTEMATIC 23123662 A 275 281 copper SYSTEMATIC 23123662 A 286 294 platinum SYSTEMATIC 23123662 A 409 415 copper SYSTEMATIC 23123662 A 420 428 platinum SYSTEMATIC 23123662 A 51 59 platinum SYSTEMATIC 23123662 A 544 550 copper SYSTEMATIC 23123662 A 552 563 oxaliplatin TRIVIAL 23123662 A 565 574 cisplatin TRIVIAL 23123662 A 579 590 carboplatin TRIVIAL 23123662 A 823 829 copper SYSTEMATIC 23123662 A 853 859 copper SYSTEMATIC 23123662 A 884 890 copper SYSTEMATIC 23123662 A 993 999 silver SYSTEMATIC 23123662 T 56 62 copper SYSTEMATIC 23123662 T 67 75 platinum SYSTEMATIC 23123664 A 0 9 Tamoxifen TRIVIAL 23123664 A 1011 1029 γ-glutamylcysteine SYSTEMATIC 23123664 A 11 14 TAM ABBREVIATION 23123664 A 1124 1130 sulfur SYSTEMATIC 23123664 A 1131 1141 amino acid FAMILY 23123664 A 1246 1252 sulfur SYSTEMATIC 23123664 A 1253 1263 amino acid FAMILY 23123664 A 1289 1297 cysteine TRIVIAL 23123664 A 1313 1325 homocysteine TRIVIAL 23123664 A 1330 1333 GSH ABBREVIATION 23123664 A 1349 1357 cysteine TRIVIAL 23123664 A 1377 1397 S-adenosylmethionine TRIVIAL 23123664 A 1398 1420 S-adenosylhomocysteine TRIVIAL 23123664 A 1591 1601 methionine TRIVIAL 23123664 A 1630 1652 S-adenosylhomocysteine TRIVIAL 23123664 A 1738 1746 cysteine TRIVIAL 23123664 A 175 181 sulfur SYSTEMATIC 23123664 A 1776 1779 GSH ABBREVIATION 23123664 A 1784 1791 taurine TRIVIAL 23123664 A 182 192 amino acid FAMILY 23123664 A 1828 1836 cysteine TRIVIAL 23123664 A 300 306 sulfur SYSTEMATIC 23123664 A 307 317 amino acid FAMILY 23123664 A 334 344 methionine TRIVIAL 23123664 A 348 355 taurine TRIVIAL 23123664 A 359 370 glutathione TRIVIAL 23123664 A 372 375 GSH ABBREVIATION 23123664 A 402 405 TAM ABBREVIATION 23123664 A 547 557 methionine TRIVIAL 23123664 A 561 569 cysteine TRIVIAL 23123664 A 588 596 cysteine TRIVIAL 23123664 A 600 603 GSH ABBREVIATION 23123664 A 608 615 taurine TRIVIAL 23123664 A 617 625 Cysteine TRIVIAL 23123664 A 739 742 GSH ABBREVIATION 23123664 A 744 755 hypotaurine TRIVIAL 23123664 A 761 768 taurine TRIVIAL 23123664 A 872 880 cysteine TRIVIAL 23123664 A 910 926 propargylglycine SYSTEMATIC 23123664 A 939 952 cystathionine TRIVIAL 23123664 A 94 104 methionine TRIVIAL 23123664 A 976 998 buthionine sulfoximine SYSTEMATIC 23123664 T 13 21 cysteine TRIVIAL 23123664 T 37 46 tamoxifen TRIVIAL 23123771 A 1010 1018 nitrogen SYSTEMATIC 23123771 A 1022 1025 His FORMULA 23123771 A 1034 1040 oxygen SYSTEMATIC 23123771 A 1044 1047 Ser FORMULA 23123771 A 233 240 leucine TRIVIAL 23123771 A 248 255 proline TRIVIAL 23123771 A 963 971 nitrogen SYSTEMATIC 23123771 A 975 978 His FORMULA 23123771 A 987 993 oxygen SYSTEMATIC 23123771 A 997 1000 Glu FORMULA 23124594 A 1157 1167 stevioside TRIVIAL 23124594 A 1172 1186 rebaudioside A TRIVIAL 23124594 A 121 131 stevioside TRIVIAL 23124594 A 136 150 rebaudioside A TRIVIAL 23124594 A 281 299 steviol glycosides FAMILY 23124594 A 331 341 stevioside TRIVIAL 23124594 A 346 360 rebaudioside A TRIVIAL 23124594 A 382 399 steviol glycoside FAMILY 23124594 A 525 535 stevioside TRIVIAL 23124594 A 539 553 rebaudioside A TRIVIAL 23124594 A 789 799 stevioside TRIVIAL 23124594 A 804 818 rebaudioside A TRIVIAL 23124594 A 94 112 steviol glycosides FAMILY 23124594 A 941 951 stevioside TRIVIAL 23124594 A 956 970 rebaudioside A TRIVIAL 23124594 T 25 35 stevioside TRIVIAL 23124594 T 40 54 rebaudioside A TRIVIAL 23125284 A 152 158 oxygen SYSTEMATIC 23126422 A 18 40 2-amino-4-arylthiazole FAMILY 23126422 T 0 22 2-Amino-4-arylthiazole FAMILY 23126495 A 286 294 sclareol TRIVIAL 23126495 A 296 308 β-sitosterol TRIVIAL 23126495 A 310 320 salvigenin TRIVIAL 23126495 A 322 336 oleanolic acid TRIVIAL 23126495 A 341 353 ursolic acid TRIVIAL 23126495 A 4 19 dichloromethane SYSTEMATIC 23126495 A 406 410 DPPH ABBREVIATION 23126495 A 686 694 sclareol TRIVIAL 23126495 A 779 806 oleanolic and ursolic acids MULTIPLE 23127499 A 1012 1018 8-oxoG SYSTEMATIC 23127499 A 1260 1266 8-oxoG SYSTEMATIC 23127499 A 1558 1573 5-hydroxyuracil SYSTEMATIC 23127499 A 1733 1739 8-oxoG SYSTEMATIC 23127499 A 322 334 8-oxoguanine SYSTEMATIC 23127499 A 336 342 8-oxoG SYSTEMATIC 23127499 A 398 410 8-oxoguanine SYSTEMATIC 23127499 A 698 704 8-oxoG SYSTEMATIC 23127499 T 19 31 8-oxoguanine SYSTEMATIC 23127540 A 0 6 Sulfur SYSTEMATIC 23127540 A 1025 1029 O(2) FORMULA 23127540 A 1061 1066 SO(2) FORMULA 23127540 A 1100 1106 sulfur SYSTEMATIC 23127540 A 1197 1203 sulfur SYSTEMATIC 23127540 A 1204 1218 sulfurous acid SYSTEMATIC 23127540 A 1257 1262 SO(2) FORMULA 23127540 A 813 819 sulfur SYSTEMATIC 23127540 T 0 6 Sulfur SYSTEMATIC 23127567 A 145 154 Oleandrin TRIVIAL 23127567 A 493 496 AZT ABBREVIATION 23127567 A 661 670 oleandrin TRIVIAL 23127567 A 950 959 oleandrin TRIVIAL 23127567 T 42 51 oleandrin TRIVIAL 23127600 A 1012 1023 polyphenols FAMILY 23127600 A 107 118 polyphenols FAMILY 23127600 A 191 205 streptozotocin TRIVIAL 23127600 A 233 238 sugar FAMILY 23127600 A 345 352 glucose TRIVIAL 23127600 A 380 387 glucose TRIVIAL 23127600 A 435 452 dimethyldiguanide SYSTEMATIC 23127600 A 573 580 glucose TRIVIAL 23127600 T 30 41 polyphenols FAMILY 23127600 T 50 53 STZ ABBREVIATION 23127820 A 176 183 ethanol SYSTEMATIC 23127820 A 40 56 stauntosides C-K MULTIPLE 23127820 A 9 29 steroidal glycosides FAMILY 23127820 T 9 29 steroidal glycosides FAMILY 23127916 A 115 123 tyrosine TRIVIAL 23127916 A 1650 1658 imatinib TRIVIAL 23127916 A 266 274 imatinib TRIVIAL 23127916 A 458 466 imatinib TRIVIAL 23127916 A 868 876 imatinib TRIVIAL 23127916 A 93 101 imatinib TRIVIAL 23127916 A 938 946 imatinib TRIVIAL 23127916 T 164 172 imatinib TRIVIAL 23129783 A 0 6 Sulfur SYSTEMATIC 23129783 A 1089 1105 propidium iodide TRIVIAL 23129783 T 75 81 sulfur SYSTEMATIC 23129806 A 113 120 glucose TRIVIAL 23129806 A 321 328 glucose TRIVIAL 23129806 A 36 42 NAD(+) ABBREVIATION 23129806 A 830 841 fatty acids FAMILY 23130977 A 160 168 tyrosine TRIVIAL 23131595 A 1155 1164 adenosine TRIVIAL 23131595 A 1177 1186 Adenosine TRIVIAL 23131595 A 1338 1341 ATP ABBREVIATION 23132629 A 16 26 enaminones FAMILY 23132629 A 197 202 (15)N FORMULA 23132629 A 32 66 3-amino-2-cyanopent-2-enedinitrile SYSTEMATIC 23132629 T 102 112 enaminones FAMILY 23132629 T 134 137 15N FORMULA 23132866 A 1217 1225 androgen FAMILY 23132866 A 4 12 androgen FAMILY 23132866 A 536 539 Ser FORMULA 23132866 A 645 653 androgen FAMILY 23132866 A 711 714 Thr FORMULA 23132866 A 723 726 Ser FORMULA 23132866 A 813 816 Thr FORMULA 23132866 A 839 842 Ser FORMULA 23132866 T 85 93 androgen FAMILY 23132909 A 1033 1044 cholesterol TRIVIAL 23132909 A 536 547 cholesterol TRIVIAL 23132909 A 552 564 triglyceride FAMILY 23134558 A 1001 1004 LNG ABBREVIATION 23134558 A 114 117 LNG ABBREVIATION 23134558 A 423 426 LNG ABBREVIATION 23134558 A 503 506 LNG ABBREVIATION 23134558 A 68 82 levonorgestrel TRIVIAL 23134558 T 16 30 levonorgestrel TRIVIAL 23134558 T 52 55 LNG ABBREVIATION 23135241 A 1167 1175 idazoxan TRIVIAL 23135241 A 1180 1191 agomelatine TRIVIAL 23135241 A 1348 1359 sibutramine TRIVIAL 23135241 A 1368 1378 fluoxetine TRIVIAL 23135241 A 1390 1400 paroxetine TRIVIAL 23135241 A 1566 1579 noradrenaline TRIVIAL 23135241 A 192 201 Serotonin TRIVIAL 23135241 A 382 391 monoamine FAMILY 23135241 A 576 584 idazoxan TRIVIAL 23135241 A 611 622 agomelatine TRIVIAL 23135241 A 653 666 noradrenaline TRIVIAL 23135241 A 67 80 catecholamine TRIVIAL 23135241 A 766 777 venlafaxine TRIVIAL 23135241 A 781 790 serotonin TRIVIAL 23135241 A 795 808 noradrenaline TRIVIAL 23135241 A 844 853 bupropion TRIVIAL 23135241 A 855 863 dopamine TRIVIAL 23135241 A 868 881 noradrenaline TRIVIAL 23135241 A 904 915 Sibutramine TRIVIAL 23135241 T 37 46 monoamine FAMILY 23135549 A 0 7 Cadmium SYSTEMATIC 23135549 A 1014 1016 Cd FORMULA 23135549 A 1110 1112 Cd FORMULA 23135549 A 1156 1161 CdCl₂ FORMULA 23135549 A 1198 1200 Cd FORMULA 23135549 A 1206 1208 Cd FORMULA 23135549 A 1228 1231 EE₂ ABBREVIATION 23135549 A 1349 1351 Cd FORMULA 23135549 A 1367 1370 EE₂ ABBREVIATION 23135549 A 1399 1401 Cd FORMULA 23135549 A 141 149 estrogen FAMILY 23135549 A 1421 1423 Cd FORMULA 23135549 A 1487 1496 estrogens FAMILY 23135549 A 1630 1632 Cd FORMULA 23135549 A 1638 1646 estrogen FAMILY 23135549 A 223 225 Cd FORMULA 23135549 A 256 264 estrogen FAMILY 23135549 A 319 321 Cd FORMULA 23135549 A 326 351 17-alpha-ethinylestradiol SYSTEMATIC 23135549 A 353 356 EE₂ ABBREVIATION 23135549 A 39 47 estrogen FAMILY 23135549 A 594 599 CdCl₂ FORMULA 23135549 A 617 619 Cd FORMULA 23135549 A 642 645 EE2 ABBREVIATION 23135549 A 66 82 aryl hydrocarbon FAMILY 23135549 A 694 696 Cd FORMULA 23135549 A 788 796 estrogen FAMILY 23135549 A 852 855 EE₂ ABBREVIATION 23135549 A 9 11 Cd FORMULA 23135549 A 931 933 Cd FORMULA 23135549 T 110 127 ethinyl-estradiol SYSTEMATIC 23135549 T 19 26 cadmium SYSTEMATIC 23136062 A 1000 1004 NOPO ABBREVIATION 23136062 A 103 114 (68) Ga(3+) FORMULA 23136062 A 1047 1051 NOTA ABBREVIATION 23136062 A 1195 1201 Ga(3+) FORMULA 23136062 A 1246 1253 (68) Ga FORMULA 23136062 A 1329 1336 (68) Ge FORMULA 23136062 A 1454 1461 (68) Ge FORMULA 23136062 A 1481 1488 (68) Ga FORMULA 23136062 A 159 166 (68) Ga FORMULA 23136062 A 179 223 1,4,7-triazacyclononane-1,4,7-triacetic acid SYSTEMATIC 23136062 A 225 229 NOTA ABBREVIATION 23136062 A 232 288 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid SYSTEMATIC 23136062 A 27 33 Zn(2+) FORMULA 23136062 A 290 294 DOTA ABBREVIATION 23136062 A 297 371 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid]) SYSTEMATIC 23136062 A 36 42 Cu(2+) FORMULA 23136062 A 373 377 TRAP ABBREVIATION 23136062 A 384 497 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] SYSTEMATIC 23136062 A 45 51 Fe(3+) FORMULA 23136062 A 499 503 NOPO ABBREVIATION 23136062 A 54 60 Al(3+) FORMULA 23136062 A 627 634 (68) Ga FORMULA 23136062 A 63 69 Ti(IV) FORMULA 23136062 A 654 665 carboxylate SYSTEMATIC 23136062 A 681 685 NOTA ABBREVIATION 23136062 A 690 694 DOTA ABBREVIATION 23136062 A 76 82 Sn(IV) FORMULA 23136062 A 768 779 phosphinate SYSTEMATIC 23136062 A 795 799 TRAP ABBREVIATION 23136062 A 804 808 NOPO ABBREVIATION 23136062 A 862 868 Zn(II) FORMULA 23136062 A 874 885 (68) Ga(3+) FORMULA 23136062 A 926 932 (31) P FORMULA 23136062 A 951 958 (68) Ga FORMULA 23136062 A 971 977 Zn(II) FORMULA 23136062 A 991 995 TRAP ABBREVIATION 23136062 T 7 13 (68)Ga FORMULA 23136062 T 88 94 (68)Ge FORMULA 23136062 T 95 101 (68)Ga FORMULA 23136129 A 189 199 nucleotide FAMILY 23137956 A 0 8 Selenium SYSTEMATIC 23137956 A 1001 1002 S FORMULA 23137956 A 1031 1035 EGCG ABBREVIATION 23137956 A 117 143 epigallocatechin-3-gallate SYSTEMATIC 23137956 A 1176 1184 selenium SYSTEMATIC 23137956 A 1189 1193 EGCG ABBREVIATION 23137956 A 1307 1315 selenium SYSTEMATIC 23137956 A 145 149 EGCG ABBREVIATION 23137956 A 189 198 catechins FAMILY 23137956 A 336 340 EGCG ABBREVIATION 23137956 A 358 373 sodium selenite SYSTEMATIC 23137956 A 445 453 selenite TRIVIAL 23137956 A 497 499 Se FORMULA 23137956 A 608 616 selenite TRIVIAL 23137956 A 639 643 EGCG ABBREVIATION 23137956 A 802 806 EGCG ABBREVIATION 23137956 A 807 815 selenite TRIVIAL 23137956 A 863 871 selenium SYSTEMATIC 23137956 A 930 938 selenite TRIVIAL 23137956 A 989 1000 glutathione TRIVIAL 23137956 T 10 25 sodium selenite SYSTEMATIC 23137956 T 109 135 epigallocatechin-3-gallate SYSTEMATIC 23141426 A 568 581 Hoechst 33258 TRIVIAL 23141427 A 1287 1291 5-HT SYSTEMATIC 23141427 A 1398 1402 5-HT SYSTEMATIC 23141427 A 1561 1565 5-HT SYSTEMATIC 23141427 A 1682 1684 NO FORMULA 23141427 A 2023 2027 5-HT SYSTEMATIC 23141427 A 2032 2034 NO FORMULA 23141427 A 753 765 nitric oxide SYSTEMATIC 23141427 A 767 769 NO FORMULA 23141427 A 789 808 5-hydroxytryptamine SYSTEMATIC 23141427 A 810 814 5-HT SYSTEMATIC 23141427 A 966 978 acetonitrile SYSTEMATIC 23141427 A 989 1004 phosphoric acid SYSTEMATIC 23141427 T 106 110 5-HT SYSTEMATIC 23141427 T 115 117 NO FORMULA 23142073 A 0 9 Saxitoxin TRIVIAL 23142073 A 1084 1087 STX ABBREVIATION 23142073 A 11 14 STX ABBREVIATION 23142073 A 1594 1597 STX ABBREVIATION 23142073 A 1723 1726 STX ABBREVIATION 23142073 A 890 893 STX ABBREVIATION 23142073 A 959 962 STX ABBREVIATION 23142073 T 29 38 saxitoxin TRIVIAL 23142104 A 679 686 retinal TRIVIAL 23142104 T 34 41 retinal TRIVIAL 23142105 A 162 168 oxygen SYSTEMATIC 23142105 A 575 581 oxygen SYSTEMATIC 23142327 A 1030 1049 11-Ketotestosterone SYSTEMATIC 23142327 A 1051 1056 11-kT SYSTEMATIC 23142327 A 1149 1158 androgens FAMILY 23142327 A 1160 1165 11-kT SYSTEMATIC 23142327 A 1267 1272 11-kT SYSTEMATIC 23142327 A 1373 1381 androgen FAMILY 23142327 A 277 285 androgen FAMILY 23142327 A 433 441 androgen FAMILY 23142327 T 14 22 androgen FAMILY 23142505 A 517 521 PGE2 ABBREVIATION 23142505 A 628 640 nitric oxide SYSTEMATIC 23142507 A 357 367 nucleotide FAMILY 23142507 A 450 460 amino acid FAMILY 23142507 A 801 804 Lys FORMULA 23142507 A 807 810 His FORMULA 23142507 A 819 822 Cys FORMULA 23142507 A 825 828 Asp FORMULA 23142507 A 841 844 Ala FORMULA 23142507 A 847 850 Phe FORMULA 23142507 A 935 938 Glu FORMULA 23142507 A 941 944 Lys FORMULA 23142507 A 959 962 Lys FORMULA 23142507 A 965 968 Asn FORMULA 23142547 A 1086 1087 C FORMULA 23142547 A 1100 1110 amino acid FAMILY 23142547 A 1272 1273 C FORMULA 23142547 A 311 315 dCMP ABBREVIATION 23142547 A 608 609 C FORMULA 23142547 A 642 643 N FORMULA 23142547 A 814 834 1,N(6)-ethenoadenine SYSTEMATIC 23142547 A 922 926 dCMP ABBREVIATION 23142559 A 1129 1140 pilocarpine TRIVIAL 23142559 A 1271 1274 ACh ABBREVIATION 23142559 A 1544 1547 ACh ABBREVIATION 23142559 A 255 268 acetylcholine SYSTEMATIC 23142559 A 270 273 ACh ABBREVIATION 23142559 A 486 489 ACh ABBREVIATION 23142559 A 618 628 tiotropium TRIVIAL 23142559 A 652 658 4-DAMP SYSTEMATIC 23142559 A 699 710 pilocarpine TRIVIAL 23142559 A 744 757 physostigmine TRIVIAL 23142559 A 804 807 ACh ABBREVIATION 23142559 A 936 947 pilocarpine TRIVIAL 23142559 A 952 965 physostigmine TRIVIAL 23142599 A 1188 1200 2,3,7,8-TCDD SYSTEMATIC 23142599 A 1253 1265 2,3,7,8-TCDD SYSTEMATIC 23142599 A 396 412 aryl hydrocarbon FAMILY 23142599 A 434 440 dioxin FAMILY 23142599 A 454 462 estrogen FAMILY 23142599 A 687 707 17α-ethynylestradiol SYSTEMATIC 23142599 A 709 712 EE2 ABBREVIATION 23142599 A 835 838 EE2 ABBREVIATION 23142599 A 868 903 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23142599 A 905 917 2,3,7,8-TCDD SYSTEMATIC 23142599 A 922 959 1,2,3,7,8-pentachlorodibenzo-p-dioxin SYSTEMATIC 23142599 A 974 977 EE2 ABBREVIATION 23142599 T 45 80 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23142599 T 96 112 aryl hydrocarbon FAMILY 23142789 A 0 11 Octylphenol TRIVIAL 23142789 A 1102 1122 17α-ethynylestradiol SYSTEMATIC 23142789 A 1143 1146 BPA ABBREVIATION 23142789 A 1324 1326 Ca FORMULA 23142789 A 135 146 Bisphenol A TRIVIAL 23142789 A 1383 1386 BPA ABBREVIATION 23142789 A 1413 1415 Ca FORMULA 23142789 A 148 151 BPA ABBREVIATION 23142789 A 1525 1528 BPA ABBREVIATION 23142789 A 1579 1582 BPA ABBREVIATION 23142789 A 1657 1660 BPA ABBREVIATION 23142789 A 1746 1749 BPA ABBREVIATION 23142789 A 1839 1842 BPA ABBREVIATION 23142789 A 1893 1895 Ca FORMULA 23142789 A 196 202 phenol SYSTEMATIC 23142789 A 1968 1970 Ca FORMULA 23142789 A 238 251 polycarbonate FAMILY 23142789 A 264 269 epoxy SYSTEMATIC 23142789 A 316 319 BPA ABBREVIATION 23142789 A 412 419 calcium SYSTEMATIC 23142789 A 421 423 Ca FORMULA 23142789 A 47 70 alkylphenol ethoxylates FAMILY 23142789 A 481 484 BPA ABBREVIATION 23142789 A 488 490 Ca FORMULA 23142789 A 529 531 Ca FORMULA 23142789 A 640 642 Ca FORMULA 23142789 A 684 693 vitamin D FAMILY 23142789 A 704 706 Ca FORMULA 23142789 A 932 934 Ca FORMULA 23142789 A 966 968 Ca FORMULA 23142789 T 11 22 octylphenol SYSTEMATIC 23142789 T 27 38 bisphenol A TRIVIAL 23142789 T 60 67 calcium SYSTEMATIC 23142844 A 1032 1036 POPC ABBREVIATION 23142844 A 1054 1058 POPC ABBREVIATION 23142844 A 1062 1066 CHOL ABBREVIATION 23142844 A 1127 1133 quartz TRIVIAL 23142844 A 1211 1221 phosphorus SYSTEMATIC 23142844 A 1471 1481 Tetracaine TRIVIAL 23142844 A 1520 1529 lidocaine TRIVIAL 23142844 A 1564 1568 POPC ABBREVIATION 23142844 A 1602 1610 propofol TRIVIAL 23142844 A 1745 1749 DMPC ABBREVIATION 23142844 A 729 733 POPC ABBREVIATION 23142844 A 735 748 sphingomyelin FAMILY 23142844 A 753 764 cholesterol TRIVIAL 23142844 A 869 879 tetracaine TRIVIAL 23142844 A 884 893 lidocaine TRIVIAL 23142844 A 923 931 propofol TRIVIAL 23142844 A 961 972 cholesterol TRIVIAL 23143037 A 1043 1046 IBU ABBREVIATION 23143037 A 1122 1125 IBU ABBREVIATION 23143037 A 1191 1207 arachidonic acid TRIVIAL 23143037 A 1381 1392 glutathione TRIVIAL 23143037 A 1393 1394 S FORMULA 23143037 A 1491 1494 IBU ABBREVIATION 23143037 A 1664 1667 IBU ABBREVIATION 23143037 A 268 277 ibuprofen TRIVIAL 23143037 A 279 282 IBU ABBREVIATION 23143037 A 495 505 superoxide TRIVIAL 23143037 A 639 642 IBU ABBREVIATION 23143037 A 761 764 IBU ABBREVIATION 23143037 A 900 903 IBU ABBREVIATION 23143037 T 97 106 ibuprofen TRIVIAL 23143415 A 277 281 O(2) FORMULA 23143415 A 426 430 O(2) FORMULA 23143415 A 448 452 O(2) FORMULA 23143415 A 466 470 NiFe FORMULA 23143415 A 81 92 nickel-iron SYSTEMATIC 23143415 A 94 98 NiFe FORMULA 23143415 T 0 2 O2 FORMULA 23143415 T 51 55 NiFe FORMULA 23143619 A 714 727 acetaminophen TRIVIAL 23143619 A 732 742 diclofenac TRIVIAL 23143619 A 921 934 trovafloxacin TRIVIAL 23143802 A 1493 1501 Alachlor TRIVIAL 23143802 A 733 745 testosterone TRIVIAL 23143803 A 255 261 pyrene SYSTEMATIC 23143803 A 511 517 pyrene SYSTEMATIC 23143803 A 613 619 pyrene SYSTEMATIC 23143803 A 692 698 pyrene SYSTEMATIC 23143803 A 903 909 pyrene SYSTEMATIC 23143803 T 11 17 pyrene SYSTEMATIC 23143912 A 133 140 zeolite TRIVIAL 23143912 A 312 327 aluminosilicate TRIVIAL 23143912 A 442 449 zeolite TRIVIAL 23143912 A 474 482 silicate FAMILY 23143912 A 520 522 Al FORMULA 23143912 A 529 531 Ti FORMULA 23143912 A 533 535 Fe FORMULA 23143912 A 677 685 zeolites FAMILY 23143912 T 106 114 zeolites FAMILY 23143912 T 16 31 aluminosilicate TRIVIAL 23143926 A 111 120 Phortress TRIVIAL 23143926 A 1475 1485 NSC 710305 IDENTIFIER 23143926 A 1636 1646 NSC 710305 IDENTIFIER 23143926 A 21 96 2-[4-amino-3-methylphenyl]-5-fluorobenzothiazole lysylamide dihydrochloride SYSTEMATIC 23143926 A 448 458 NSC 710305 IDENTIFIER 23143926 A 681 691 NSC 710305 IDENTIFIER 23143926 A 877 887 NSC 710305 IDENTIFIER 23143926 A 985 995 NSC 710305 IDENTIFIER 23143926 A 99 109 NSC 710305 IDENTIFIER 23143926 T 127 137 NSC 710305 IDENTIFIER 23143926 T 139 148 Phortress TRIVIAL 23143926 T 50 125 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole lysylamide dihydrochloride SYSTEMATIC 23145944 A 692 704 polyarginine FAMILY 23146664 A 0 10 Mesalamine TRIVIAL 23146664 A 12 17 5-ASA SYSTEMATIC 23146664 A 1284 1289 5-ASA SYSTEMATIC 23146664 A 1381 1391 mesalamine TRIVIAL 23146664 A 1512 1517 5-ASA SYSTEMATIC 23146664 A 1686 1691 5-ASA SYSTEMATIC 23146664 A 203 208 5-ASA SYSTEMATIC 23146664 A 400 405 5-ASA SYSTEMATIC 23146664 A 519 524 5-ASA SYSTEMATIC 23146664 A 653 658 5-ASA SYSTEMATIC 23146664 A 759 764 5-ASA SYSTEMATIC 23146664 A 834 839 5-ASA SYSTEMATIC 23146664 A 858 863 5-ASA SYSTEMATIC 23146664 A 982 987 5-ASA SYSTEMATIC 23146664 T 0 10 Mesalamine TRIVIAL 23146691 A 191 215 Emodin-6-O-β-D-glucoside SYSTEMATIC 23146691 T 0 24 Emodin-6-O-β-D-glucoside SYSTEMATIC 23146695 A 1018 1030 nitric oxide SYSTEMATIC 23146695 A 1102 1110 puerarin TRIVIAL 23146695 A 1151 1157 CCl(4) FORMULA 23146695 A 192 212 carbon tetrachloride SYSTEMATIC 23146695 A 214 220 CCl(4) FORMULA 23146695 A 322 329 alanine TRIVIAL 23146695 A 354 363 aspartate TRIVIAL 23146695 A 61 69 puerarin TRIVIAL 23146695 A 706 716 superoxide TRIVIAL 23146695 A 768 783 malondialdehyde TRIVIAL 23146695 A 785 788 MDA ABBREVIATION 23146695 A 89 101 isoflavonoid FAMILY 23146695 T 0 8 Puerarin TRIVIAL 23146695 T 43 47 CCl4 FORMULA 23146698 A 102 122 carbon tetrachloride SYSTEMATIC 23146698 A 1183 1192 sweroside TRIVIAL 23146698 A 1194 1206 swertiamarin TRIVIAL 23146698 A 1211 1223 gentiopicrin TRIVIAL 23146698 A 153 161 Methanol SYSTEMATIC 23146698 A 360 366 CCl(4) FORMULA 23146698 A 479 485 CCl(4) FORMULA 23146698 A 601 610 bilirubin TRIVIAL 23146698 A 744 754 superoxide TRIVIAL 23146698 A 769 788 reduced glutathione TRIVIAL 23146698 A 843 858 malondialdehyde TRIVIAL 23146698 A 875 881 CCl(4) FORMULA 23146698 A 976 982 CCl(4) FORMULA 23146698 T 69 89 carbon tetrachloride SYSTEMATIC 23146750 A 1127 1133 PCB126 TRIVIAL 23146750 A 1169 1174 BDE47 IDENTIFIER 23146750 A 1179 1185 PCB153 TRIVIAL 23146750 A 1320 1323 BPA ABBREVIATION 23146750 A 1328 1332 PFOA ABBREVIATION 23146750 A 425 431 dioxin FAMILY 23146750 A 437 461 polychlorinated biphenyl FAMILY 23146750 A 463 469 PCB126 TRIVIAL 23146750 A 483 489 dioxin FAMILY 23146750 A 495 519 polychlorinated biphenyl FAMILY 23146750 A 521 527 PCB153 TRIVIAL 23146750 A 566 571 BDE47 IDENTIFIER 23146750 A 582 607 perfluorinated alkyl acid FAMILY 23146750 A 609 613 PFOA ABBREVIATION 23146750 A 624 633 bisphenol TRIVIAL 23146750 A 635 638 BPA ABBREVIATION 23146750 A 879 885 PCB126 TRIVIAL 23146750 A 907 913 PCB153 TRIVIAL 23146750 A 918 923 BDE47 IDENTIFIER 23146750 A 929 933 PFOA ABBREVIATION 23146750 A 938 941 BPA ABBREVIATION 23146755 A 0 9 Carvacrol TRIVIAL 23146755 A 1015 1024 carvacrol TRIVIAL 23146755 A 1034 1040 Ca(2+) FORMULA 23146755 A 1051 1060 Carvacrol TRIVIAL 23146755 A 1125 1131 Ca(2+) FORMULA 23146755 A 1150 1158 BAPTA-AM ABBREVIATION 23146755 A 1160 1236 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester SYSTEMATIC 23146755 A 1239 1248 Carvacrol TRIVIAL 23146755 A 1294 1300 oxygen SYSTEMATIC 23146755 A 1340 1349 carvacrol TRIVIAL 23146755 A 1361 1367 Ca(2+) FORMULA 23146755 A 1403 1409 Ca(2+) FORMULA 23146755 A 1453 1459 Ca(2+) FORMULA 23146755 A 1504 1510 Ca(2+) FORMULA 23146755 A 1521 1530 Carvacrol TRIVIAL 23146755 A 180 189 carvacrol TRIVIAL 23146755 A 198 204 Ca(2+) FORMULA 23146755 A 290 299 carvacrol TRIVIAL 23146755 A 318 324 Ca(2+) FORMULA 23146755 A 342 348 Ca(2+) FORMULA 23146755 A 416 425 Carvacrol TRIVIAL 23146755 A 437 443 Ca(2+) FORMULA 23146755 A 508 514 Ca(2+) FORMULA 23146755 A 516 525 Carvacrol TRIVIAL 23146755 A 534 540 Ca(2+) FORMULA 23146755 A 581 587 Ca(2+) FORMULA 23146755 A 686 692 Ca(2+) FORMULA 23146755 A 748 754 Ca(2+) FORMULA 23146755 A 770 782 thapsigargin TRIVIAL 23146755 A 791 820 2,5-di-tert-butylhydroquinone SYSTEMATIC 23146755 A 822 825 BHQ ABBREVIATION 23146755 A 837 846 carvacrol TRIVIAL 23146755 A 856 862 Ca(2+) FORMULA 23146755 A 86 92 Ca(2+) FORMULA 23146755 A 901 910 carvacrol TRIVIAL 23146755 A 927 930 BHQ ABBREVIATION 23146755 A 940 946 Ca(2+) FORMULA 23146755 A 998 1004 U73122 IDENTIFIER 23146755 T 17 26 carvacrol TRIVIAL 23146755 T 35 39 Ca2+ FORMULA 23146755 T 56 60 Ca2+ FORMULA 23146758 A 110 121 6-OH-BDE-47 SYSTEMATIC 23146758 A 208 223 androstenedione TRIVIAL 23146758 A 228 240 testosterone TRIVIAL 23146758 A 272 281 estradiol TRIVIAL 23146758 A 339 348 estradiol TRIVIAL 23146758 A 461 480 dibenzylfluorescein SYSTEMATIC 23146758 A 569 581 testosterone TRIVIAL 23146758 A 585 594 estradiol TRIVIAL 23146758 A 61 80 hydroxylated BDE-47 TRIVIAL 23146758 A 610 621 5-OH-BDE-47 SYSTEMATIC 23146758 A 626 637 6-OH-BDE-47 SYSTEMATIC 23146758 A 692 702 CGS 16949A IDENTIFIER 23146758 A 751 760 estradiol TRIVIAL 23146758 A 94 105 5-OH-BDE-47 SYSTEMATIC 23146758 T 102 111 estradiol TRIVIAL 23146758 T 4 38 2,2',4,4'-tetrabromodiphenyl ether SYSTEMATIC 23146758 T 64 75 5-OH-BDE-47 SYSTEMATIC 23146758 T 80 91 6-OH-BDE-47 SYSTEMATIC 23146761 A 0 24 Epigallocatechin gallate TRIVIAL 23146761 A 1009 1018 bile acid FAMILY 23146761 A 1103 1131 7α-hydroxy-4-cholesten-3-one SYSTEMATIC 23146761 A 1146 1150 EGCG ABBREVIATION 23146761 A 1180 1189 bile acid FAMILY 23146761 A 1279 1283 EGCG ABBREVIATION 23146761 A 1308 1324 ethinylestradiol SYSTEMATIC 23146761 A 1448 1452 EGCG ABBREVIATION 23146761 A 1469 1478 bile acid FAMILY 23146761 A 1598 1607 bile acid FAMILY 23146761 A 1697 1701 EGCG ABBREVIATION 23146761 A 26 30 EGCG ABBREVIATION 23146761 A 278 282 EGCG ABBREVIATION 23146761 A 300 309 bile acid FAMILY 23146761 A 353 357 EGCG ABBREVIATION 23146761 A 442 451 bile acid FAMILY 23146761 A 482 486 EGCG ABBREVIATION 23146761 A 515 526 glutathione TRIVIAL 23146761 A 579 590 glutathione TRIVIAL 23146761 A 743 747 EGCG ABBREVIATION 23146761 A 783 792 bile acid FAMILY 23146761 A 863 872 bile acid FAMILY 23146761 A 934 943 bile acid FAMILY 23146761 A 994 998 EGCG ABBREVIATION 23146761 T 22 46 epigallocatechin gallate TRIVIAL 23147004 A 1013 1019 methyl SYSTEMATIC 23147004 A 379 393 phosphodiester SYSTEMATIC 23147004 A 610 617 adenine TRIVIAL 23147004 T 82 88 methyl SYSTEMATIC 23147033 A 1095 1103 butyrate SYSTEMATIC 23147033 A 1265 1277 carbohydrate FAMILY 23147033 A 1323 1334 lactic acid TRIVIAL 23147033 A 154 167 carbohydrates FAMILY 23147033 A 781 794 carbohydrates FAMILY 23147033 A 842 853 fatty acids FAMILY 23147033 A 911 918 acetate SYSTEMATIC 23147033 A 920 930 propionate SYSTEMATIC 23147033 A 935 943 butyrate SYSTEMATIC 23147639 A 1175 1184 (19Z)-HCA ABBREVIATION 23147639 A 186 207 (19Z)-Halichondramide TRIVIAL 23147639 A 209 218 (19Z)-HCA ABBREVIATION 23147639 A 229 240 trisoxazole SYSTEMATIC 23147639 A 5 12 oxazole SYSTEMATIC 23147639 A 507 516 (19Z)-HCA ABBREVIATION 23147639 A 550 559 (19Z)-HCA ABBREVIATION 23147639 A 837 846 (19Z)-HCA ABBREVIATION 23147639 A 983 992 (19Z)-HCA ABBREVIATION 23147639 T 29 50 (19Z)-halichondramide TRIVIAL 23147692 A 219 240 acetylphenylhydrazine SYSTEMATIC 23147987 A 1096 1099 PCB ABBREVIATION 23147987 A 1506 1509 PCB ABBREVIATION 23147987 A 303 306 PCB ABBREVIATION 23147987 A 42 67 polychlorinated biphenyls FAMILY 23147987 A 644 647 PCB ABBREVIATION 23147987 A 69 73 PCBs ABBREVIATION 23147987 A 894 897 PCB ABBREVIATION 23147987 T 53 77 polychlorinated biphenyl FAMILY 23148024 A 1143 1147 BPDE ABBREVIATION 23148024 A 155 188 (+)-anti-BP-7,8-diol-9,10-epoxide SYSTEMATIC 23148024 A 190 194 BPDE ABBREVIATION 23148024 A 261 265 PAHs ABBREVIATION 23148024 A 37 40 PAH ABBREVIATION 23148024 A 4 35 polycyclic aromatic hydrocarbon FAMILY 23148024 A 42 56 benzo[a]pyrene SYSTEMATIC 23148024 T 74 88 benzo[a]pyrene SYSTEMATIC 23149118 A 0 8 Atrazine TRIVIAL 23149118 A 1272 1280 atrazine TRIVIAL 23149118 A 1613 1621 atrazine TRIVIAL 23149118 A 1701 1714 plastoquinone TRIVIAL 23149118 A 1786 1794 atrazine TRIVIAL 23149118 A 1889 1897 atrazine TRIVIAL 23149118 A 1952 1960 quinones FAMILY 23149118 A 330 338 atrazine TRIVIAL 23149118 A 390 398 atrazine TRIVIAL 23149118 A 580 588 atrazine TRIVIAL 23149118 A 736 744 atrazine TRIVIAL 23149118 A 795 803 Atrazine TRIVIAL 23149118 T 91 99 atrazine TRIVIAL 23149657 A 1039 1051 sulfonylurea FAMILY 23149657 A 1334 1347 sulfonylureas FAMILY 23149657 A 630 637 glucose TRIVIAL 23149657 T 41 53 sulfonylurea FAMILY 23150067 A 109 191 N(3),N(11)-bis(2-hydroxyethyl)-14-aryl-14H-dibenzo[a,j]xanthene-3,11-dimethanamine FAMILY 23150067 A 18 101 N(3),N(11)-bis(2-hydroxyethyl)-14-aryl-14H-dibenzo[a,j]xanthenes-3,11-dicarboxamide FAMILY 23150067 A 228 284 14-aryl-14H-dibenzo[a,j]xanthenes-3,11-dicarboxylic acid FAMILY 23150067 A 354 358 (1)H FORMULA 23150067 A 364 369 (13)C FORMULA 23150067 A 798 809 carboxamide SYSTEMATIC 23150067 A 999 1008 As(2)O(3) FORMULA 23150067 T 45 128 N(3),N(11)-bis(2-hydroxyethyl)-14-aryl-14H-dibenzo[a,j]xanthenes-3,11-dicarboxamide FAMILY 23150210 A 418 424 XR9576 IDENTIFIER 23150210 A 426 436 tariquidar TRIVIAL 23150210 A 648 661 Hoechst 33342 TRIVIAL 23150226 A 16 19 S-S FORMULA 23150226 A 97 106 disulfide SYSTEMATIC 23150226 T 47 56 disulfide SYSTEMATIC 23150428 A 1050 1063 retinoic acid TRIVIAL 23150428 A 1116 1129 retinoic acid TRIVIAL 23150428 A 1519 1532 retinoic acid TRIVIAL 23150428 A 655 666 dextrorphan TRIVIAL 23150428 A 682 698 dextromethorphan TRIVIAL 23150428 A 893 906 retinoic acid TRIVIAL 23150493 A 1157 1173 N-acetylcysteine SYSTEMATIC 23150493 A 508 519 fatty acids FAMILY 23150493 A 797 807 fatty acid FAMILY 23150493 T 18 28 fatty acid FAMILY 23150495 A 1082 1089 glucose TRIVIAL 23150495 A 1145 1152 glucose TRIVIAL 23150495 A 1369 1376 glucose TRIVIAL 23150495 A 1727 1734 glucose TRIVIAL 23150999 A 1105 1116 cholesterol TRIVIAL 23150999 A 162 181 glycerophospholipid FAMILY 23150999 A 858 871 sphingolipids FAMILY 23151001 A 131 132 C FORMULA 23151002 A 299 310 cholesterol TRIVIAL 23151002 A 315 328 sphingolipids FAMILY 23151002 A 406 417 Cholesterol TRIVIAL 23151002 A 422 435 sphingolipids FAMILY 23151002 A 666 675 serotonin TRIVIAL 23151002 T 35 44 serotonin TRIVIAL 23151004 A 110 133 palmytoilated aminoacid FAMILY 23151004 A 1174 1185 cholesterol TRIVIAL 23151004 A 197 208 cholesterol TRIVIAL 23151004 A 265 276 cholesterol TRIVIAL 23152189 A 1004 1007 GSH ABBREVIATION 23152189 A 1008 1029 glutathione disulfide SYSTEMATIC 23152189 A 1054 1058 TCDD ABBREVIATION 23152189 A 1179 1182 ATP ABBREVIATION 23152189 A 1236 1242 oxygen SYSTEMATIC 23152189 A 1258 1275 hydrogen peroxide SYSTEMATIC 23152189 A 1277 1293 Aryl hydrocarbon FAMILY 23152189 A 1365 1369 TCDD ABBREVIATION 23152189 A 1402 1405 ATP ABBREVIATION 23152189 A 1555 1559 TCDD ABBREVIATION 23152189 A 1675 1679 TCDD ABBREVIATION 23152189 A 228 232 TCDD ABBREVIATION 23152189 A 357 361 TCDD ABBREVIATION 23152189 A 515 523 ceramide FAMILY 23152189 A 52 87 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23152189 A 600 609 ceramides FAMILY 23152189 A 628 632 TCDD ABBREVIATION 23152189 A 656 665 ceramides FAMILY 23152189 A 674 685 fatty acids FAMILY 23152189 A 687 691 TCDD ABBREVIATION 23152189 A 724 731 glucose TRIVIAL 23152189 A 854 862 pyruvate TRIVIAL 23152189 A 864 868 NADH ABBREVIATION 23152189 A 89 93 TCDD ABBREVIATION 23152189 A 923 929 NAD(+) ABBREVIATION 23152189 A 959 970 glutathione TRIVIAL 23152189 A 972 975 GSH ABBREVIATION 23152189 T 0 35 2,3,7,8-Tetrachlorodibenzo-p-dioxin SYSTEMATIC 23152189 T 68 74 oxygen SYSTEMATIC 23152191 A 0 25 Δ(9)-tetrahydrocannabinol SYSTEMATIC 23152191 A 1162 1170 Δ(9)-THC SYSTEMATIC 23152191 A 1399 1407 Δ(9)-THC SYSTEMATIC 23152191 A 1538 1546 Δ(9)-THC SYSTEMATIC 23152191 A 1649 1657 Δ(9)-THC SYSTEMATIC 23152191 A 27 35 Δ(9)-THC SYSTEMATIC 23152191 A 491 499 Δ(9)-THC SYSTEMATIC 23152191 A 559 567 Δ(9)-THC SYSTEMATIC 23152191 A 639 647 Δ(9)-THC SYSTEMATIC 23152191 A 762 770 Δ(9)-THC SYSTEMATIC 23152191 T 0 23 Δ9-tetrahydrocannabinol SYSTEMATIC 23152439 A 1170 1179 vitamin D FAMILY 23152439 A 1537 1544 calcium SYSTEMATIC 23152439 A 1576 1583 calcium SYSTEMATIC 23152439 A 1636 1645 vitamin D FAMILY 23152439 A 1670 1679 magnesium SYSTEMATIC 23152439 A 1867 1882 bisphosphonates FAMILY 23152439 A 702 709 calcium SYSTEMATIC 23153618 A 1059 1070 fatty acids FAMILY 23153618 A 167 179 stearic acid TRIVIAL 23153618 A 181 190 poloxamer FAMILY 23153618 A 195 214 polyethylene glycol SYSTEMATIC 23153618 A 353 365 stearic acid TRIVIAL 23153618 A 367 376 poloxamer FAMILY 23153618 A 381 400 polyethylene glycol SYSTEMATIC 23153618 A 66 75 lopinavir TRIVIAL 23153618 A 919 928 lopinavir TRIVIAL 23153618 A 963 972 lopinavir TRIVIAL 23153618 T 51 60 lopinavir TRIVIAL 23153668 A 1057 1060 PLL ABBREVIATION 23153668 A 1159 1162 PLL ABBREVIATION 23153668 A 220 233 poly-L-lysine SYSTEMATIC 23153668 A 235 238 PLL ABBREVIATION 23153668 A 474 484 coumarin-6 TRIVIAL 23153668 A 571 574 PLL ABBREVIATION 23153668 A 677 680 PLL ABBREVIATION 23153668 T 52 65 poly-L-lysine SYSTEMATIC 23154194 A 1151 1156 l-Pro FORMULA 23154194 A 1275 1280 l-Pro FORMULA 23154194 A 1396 1401 l-Pro FORMULA 23154194 A 165 176 amino acids FAMILY 23154194 A 178 185 proline TRIVIAL 23154194 A 187 196 sarcosine TRIVIAL 23154194 A 198 205 alanine TRIVIAL 23154194 A 207 216 β-alanine TRIVIAL 23154194 A 222 229 glycine TRIVIAL 23154194 A 284 289 ester FAMILY 23154194 A 445 452 proline TRIVIAL 23154194 A 464 469 l-Pro FORMULA 23154194 A 604 609 Azone TRIVIAL 23154194 A 611 616 DDAIP ABBREVIATION 23154194 A 618 622 DDAK ABBREVIATION 23154194 A 628 642 Transkarbam 12 TRIVIAL 23154194 A 679 684 l-Pro FORMULA 23154194 A 713 729 propylene glycol SYSTEMATIC 23154194 A 762 767 l-Pro FORMULA 23154194 A 880 885 l-Pro FORMULA 23154194 T 0 10 Amino acid FAMILY 23154533 A 0 16 Propylthiouracil SYSTEMATIC 23154533 A 1089 1092 PTU ABBREVIATION 23154533 A 1154 1157 MMI ABBREVIATION 23154533 A 1161 1164 PTU ABBREVIATION 23154533 A 1233 1236 PTU ABBREVIATION 23154533 A 165 176 methimazole TRIVIAL 23154533 A 178 181 MMI ABBREVIATION 23154533 A 18 21 PTU ABBREVIATION 23154533 A 237 240 PTU ABBREVIATION 23154533 A 413 416 MMI ABBREVIATION 23154533 A 605 608 PTU ABBREVIATION 23154533 A 715 718 PTU ABBREVIATION 23154533 A 819 822 PTU ABBREVIATION 23154533 A 875 878 PTU ABBREVIATION 23154533 A 950 953 PTU ABBREVIATION 23154533 T 117 133 propylthiouracil SYSTEMATIC 23154533 T 89 100 methimazole TRIVIAL 23157419 A 753 760 CaCO(3) FORMULA 23157419 A 765 773 CaHPO(4) FORMULA 23157419 A 777 784 calcium SYSTEMATIC 23157419 A 825 832 CaCO(3) FORMULA 23157419 A 923 931 CaHPO(4) FORMULA 23157419 A 995 1003 CaHPO(4) FORMULA 23157625 A 252 260 dopamine TRIVIAL 23157625 A 262 271 glutamate TRIVIAL 23157625 A 273 282 serotonin TRIVIAL 23157625 A 287 291 GABA ABBREVIATION 23157625 A 862 871 clozapine TRIVIAL 23157625 A 912 923 risperidone TRIVIAL 23157627 A 184 193 serotonin TRIVIAL 23157627 A 195 199 5-HT SYSTEMATIC 23157627 A 272 276 5-HT SYSTEMATIC 23157627 A 300 304 5-HT SYSTEMATIC 23157627 A 489 493 5-HT SYSTEMATIC 23157627 A 571 579 dopamine TRIVIAL 23157627 A 581 590 glutamate TRIVIAL 23157627 A 596 619 gamma-aminobutyric acid SYSTEMATIC 23157627 A 866 870 5-HT SYSTEMATIC 23157627 T 23 32 serotonin TRIVIAL 23157632 A 47 55 dopamine TRIVIAL 23157632 A 588 592 DOPA ABBREVIATION 23157632 A 747 755 dopamine TRIVIAL 23157632 T 18 26 dopamine TRIVIAL 23157634 A 1058 1067 glutamate TRIVIAL 23157634 A 1377 1381 (1)H FORMULA 23157634 A 169 186 N-acetylaspartate SYSTEMATIC 23157634 A 188 191 NAA ABBREVIATION 23157634 A 194 201 choline FAMILY 23157634 A 230 242 myo-inositol TRIVIAL 23157634 A 252 261 glutamate TRIVIAL 23157634 A 263 266 Glu FORMULA 23157634 A 269 278 glutamine TRIVIAL 23157634 A 280 283 Gln FORMULA 23157634 A 289 293 GABA ABBREVIATION 23157634 A 335 339 (1)H FORMULA 23157634 A 40 44 (1)H FORMULA 23157634 A 539 543 (1)H FORMULA 23157634 A 770 773 NAA ABBREVIATION 23157634 A 857 860 NAA ABBREVIATION 23159330 A 1111 1120 rapamycin TRIVIAL 23159330 A 1249 1258 rapamycin TRIVIAL 23159330 A 1337 1346 rapamycin TRIVIAL 23159330 A 410 419 Rapamycin TRIVIAL 23159330 A 815 824 rapamycin TRIVIAL 23159330 A 890 899 Rapamycin TRIVIAL 23159330 T 39 48 rapamycin TRIVIAL 23159502 A 679 685 oxygen SYSTEMATIC 23159668 A 48 61 hydroxypropyl SYSTEMATIC 23159668 A 9 14 ethyl SYSTEMATIC 23159668 T 72 91 ethyl-hydroxypropyl SYSTEMATIC 23159791 A 1079 1089 bradykinin TRIVIAL 23159885 A 108 117 NAD(P)(+) ABBREVIATION 23159885 A 168 177 aldehydes FAMILY 23159885 A 201 217 carboxylic acids FAMILY 23159885 A 312 320 aldehyde SYSTEMATIC 23159885 A 4 12 aldehyde SYSTEMATIC 23159885 A 61 106 nicotinamide adenine dinucleotide (phosphate) SYSTEMATIC 23159885 A 634 642 aldehyde SYSTEMATIC 23159885 A 781 789 Aldehyde SYSTEMATIC 23159885 T 0 8 Aldehyde SYSTEMATIC 23159886 A 1035 1045 superoxide TRIVIAL 23159886 A 1060 1071 glutathione TRIVIAL 23159886 A 1096 1099 GSH ABBREVIATION 23159886 A 1124 1127 NAC ABBREVIATION 23159886 A 116 133 N-acetyl cysteine SYSTEMATIC 23159886 A 135 138 NAC ABBREVIATION 23159886 A 143 154 glutathione TRIVIAL 23159886 A 1436 1439 NAC ABBREVIATION 23159886 A 1535 1538 NAC ABBREVIATION 23159886 A 1547 1558 glutathione TRIVIAL 23159886 A 156 159 GSH ABBREVIATION 23159886 A 1637 1640 NAC ABBREVIATION 23159886 A 338 341 NAC ABBREVIATION 23159886 A 442 449 alanine TRIVIAL 23159886 A 475 484 aspartate TRIVIAL 23159886 A 519 528 bilirubin TRIVIAL 23159886 A 659 670 glutathione TRIVIAL 23159886 A 671 672 S FORMULA 23159886 A 734 746 nitric oxide SYSTEMATIC 23159886 A 83 91 paraquat TRIVIAL 23159886 A 904 907 NAC ABBREVIATION 23159886 A 956 965 bilirubin TRIVIAL 23159886 A 990 997 nitrite SYSTEMATIC 23159886 T 111 119 paraquat TRIVIAL 23159886 T 40 57 N-acetyl cysteine SYSTEMATIC 23159986 A 1067 1084 potassium bromate SYSTEMATIC 23159986 A 1140 1150 D-limonene TRIVIAL 23159986 A 1227 1244 potassium bromate SYSTEMATIC 23159986 A 1381 1391 D-limonene TRIVIAL 23159986 A 1492 1502 creatinine TRIVIAL 23159986 A 1757 1767 D-limonene TRIVIAL 23159986 A 439 449 2-propanol SYSTEMATIC 23159986 A 453 463 D-limonene TRIVIAL 23159986 A 515 525 creatinine TRIVIAL 23159986 A 636 653 potassium bromate SYSTEMATIC 23159986 A 723 733 D-limonene TRIVIAL 23159986 A 822 832 D-limonene TRIVIAL 23159986 A 999 1009 2-propanol SYSTEMATIC 23160480 A 1103 1111 tyrosine TRIVIAL 23160480 A 1182 1190 tyrosine TRIVIAL 23160480 A 245 252 alanine TRIVIAL 23160480 A 256 263 proline TRIVIAL 23160480 A 563 573 amino acid FAMILY 23160480 A 667 677 nucleotide FAMILY 23160480 A 710 722 phenyalanine TRIVIAL 23160480 A 730 736 serine TRIVIAL 23160481 A 108 128 phosphatidylinositol TRIVIAL 23160481 A 952 956 cAMP ABBREVIATION 23160481 A 99 103 cAMP ABBREVIATION 23160530 A 1097 1104 glucose TRIVIAL 23160530 A 1230 1237 glucose TRIVIAL 23160530 A 13 20 glucose TRIVIAL 23160530 A 1317 1324 glucose TRIVIAL 23160530 A 1419 1426 glucose TRIVIAL 23160530 A 185 193 Diazepam TRIVIAL 23160530 A 444 451 glucose TRIVIAL 23160530 A 525 532 glucose TRIVIAL 23160530 A 630 637 glucose TRIVIAL 23160530 A 785 792 glucose TRIVIAL 23160530 A 91 98 glucose TRIVIAL 23160530 A 995 1002 glucose TRIVIAL 23160530 T 27 34 glucose TRIVIAL 23161062 A 510 518 carboxyl SYSTEMATIC 23161484 A 1132 1138 LC-95A TRIVIAL 23161484 A 381 406 PHOS-CHEK 259F and LC-95A MULTIPLE 23161484 A 732 736 259F TRIVIAL 23161484 A 741 747 LC-95A TRIVIAL 23161484 A 959 963 259F TRIVIAL 23161512 A 706 714 selenium SYSTEMATIC 23161512 A 791 797 oxygen SYSTEMATIC 23161521 A 189 191 Si FORMULA 23161521 A 59 61 Hg FORMULA 23161521 A 64 71 styrene TRIVIAL 23161521 A 72 74 Si FORMULA 23161581 A 386 388 Ag FORMULA 23161581 A 59 72 Ag-doped PbSe FORMULA 23161581 T 13 19 silver SYSTEMATIC 23161581 T 66 70 PbSe FORMULA 23161646 A 0 8 Graphene TRIVIAL 23161646 A 252 260 graphene TRIVIAL 23161646 A 628 636 graphene TRIVIAL 23161646 A 702 712 nucleotide FAMILY 23161646 A 71 77 carbon SYSTEMATIC 23161646 A 847 855 graphene TRIVIAL 23161646 T 61 69 graphene TRIVIAL 23161646 T 74 88 graphene oxide SYSTEMATIC 23161844 A 259 268 histamine TRIVIAL 23161868 A 1334 1348 corticosterone TRIVIAL 23161868 A 1612 1626 corticosterone TRIVIAL 23161873 A 1065 1072 glucose TRIVIAL 23161873 A 1242 1250 fructose TRIVIAL 23161873 A 1305 1314 uric acid TRIVIAL 23161873 A 1316 1323 alanine TRIVIAL 23161873 A 1342 1351 aspartate TRIVIAL 23161873 A 1434 1442 fructose TRIVIAL 23161873 A 1508 1516 fructose TRIVIAL 23161873 A 1597 1605 fructose TRIVIAL 23161873 A 206 211 sugar FAMILY 23161873 A 292 307 monosaccharides FAMILY 23161873 A 392 404 carbohydrate FAMILY 23161873 A 647 655 fructose TRIVIAL 23161873 A 712 724 triglyceride FAMILY 23161873 A 838 846 fructose TRIVIAL 23161873 A 971 983 triglyceride FAMILY 23161873 T 16 28 carbohydrate FAMILY 23161873 T 70 78 fructose TRIVIAL 23163337 A 0 4 Iron SYSTEMATIC 23163337 A 1106 1113 nitrate SYSTEMATIC 23163337 A 1151 1158 nitrite SYSTEMATIC 23163337 A 1238 1242 iron SYSTEMATIC 23163337 A 1462 1466 iron SYSTEMATIC 23163337 A 162 166 iron SYSTEMATIC 23163337 A 277 281 iron SYSTEMATIC 23163337 A 457 461 iron SYSTEMATIC 23163337 A 754 758 iron SYSTEMATIC 23163337 T 60 64 iron SYSTEMATIC 23164616 A 1176 1183 ethanol SYSTEMATIC 23164616 A 1285 1292 ethanol SYSTEMATIC 23164616 A 1577 1584 ethanol SYSTEMATIC 23164616 A 1729 1736 ethanol SYSTEMATIC 23164616 A 216 223 ethanol SYSTEMATIC 23164616 A 337 344 ethanol SYSTEMATIC 23164616 A 848 855 ethanol SYSTEMATIC 23164616 A 918 925 ethanol SYSTEMATIC 23164616 T 65 72 ethanol SYSTEMATIC 23164618 A 0 8 Dopamine TRIVIAL 23164618 A 1022 1030 morphine TRIVIAL 23164618 A 1216 1226 cyclic-AMP TRIVIAL 23164618 A 1228 1232 cAMP ABBREVIATION 23164618 A 1299 1303 cAMP ABBREVIATION 23164618 A 968 976 morphine TRIVIAL 23164618 T 165 175 cyclic-AMP TRIVIAL 23164618 T 28 36 dopamine TRIVIAL 23164619 A 0 7 Glucose TRIVIAL 23164619 A 1070 1073 MLA ABBREVIATION 23164619 A 1077 1081 DHβE ABBREVIATION 23164619 A 1202 1209 glucose TRIVIAL 23164619 A 1219 1223 DHβE ABBREVIATION 23164619 A 1233 1236 MLA ABBREVIATION 23164619 A 130 137 glucose TRIVIAL 23164619 A 1415 1418 MLA ABBREVIATION 23164619 A 1423 1427 DHβE ABBREVIATION 23164619 A 1471 1478 glucose TRIVIAL 23164619 A 1488 1492 DHβE ABBREVIATION 23164619 A 1502 1505 MLA ABBREVIATION 23164619 A 1545 1552 glucose TRIVIAL 23164619 A 1566 1570 DHβE ABBREVIATION 23164619 A 1580 1583 MLA ABBREVIATION 23164619 A 1748 1755 glucose TRIVIAL 23164619 A 221 234 acetylcholine SYSTEMATIC 23164619 A 276 289 acetylcholine SYSTEMATIC 23164619 A 360 367 glucose TRIVIAL 23164619 A 423 436 acetylcholine SYSTEMATIC 23164619 A 521 528 glucose TRIVIAL 23164619 A 604 622 methyllycaconitine TRIVIAL 23164619 A 624 627 MLA ABBREVIATION 23164619 A 632 657 dihydro-beta-erythroidine SYSTEMATIC 23164619 A 659 663 DHβE ABBREVIATION 23164619 A 892 899 glucose TRIVIAL 23164619 A 982 986 DHβE ABBREVIATION 23164619 T 0 7 Glucose TRIVIAL 23164713 A 121 126 NA255 IDENTIFIER 23164713 A 269 274 NA255 IDENTIFIER 23164713 A 335 340 NA255 IDENTIFIER 23164713 A 411 416 NA255 IDENTIFIER 23164713 T 106 111 NA255 IDENTIFIER 23164921 A 1062 1070 catalpol TRIVIAL 23164921 A 1253 1261 catalpol TRIVIAL 23164921 A 202 210 catalpol TRIVIAL 23164921 A 277 285 catalpol TRIVIAL 23164921 A 449 457 catalpol TRIVIAL 23164921 A 525 533 catalpol TRIVIAL 23164921 A 618 620 NO FORMULA 23164921 A 688 696 catalpol TRIVIAL 23164921 A 751 759 catalpol TRIVIAL 23164921 A 930 938 catalpol TRIVIAL 23164921 T 0 8 Catalpol TRIVIAL 23164932 A 0 21 3-Nitropropionic acid SYSTEMATIC 23164932 A 1015 1019 3-NP SYSTEMATIC 23164932 A 1078 1082 3-NP SYSTEMATIC 23164932 A 1199 1203 3-NP SYSTEMATIC 23164932 A 1227 1231 3-NP SYSTEMATIC 23164932 A 1236 1240 3-NP SYSTEMATIC 23164932 A 1294 1298 3-NP SYSTEMATIC 23164932 A 1338 1342 3-NP SYSTEMATIC 23164932 A 1502 1506 3-NP SYSTEMATIC 23164932 A 23 27 3-NP SYSTEMATIC 23164932 A 292 296 3-NP SYSTEMATIC 23164932 A 439 443 3-NP SYSTEMATIC 23164932 A 539 543 3-NP SYSTEMATIC 23164932 A 621 625 3-NP SYSTEMATIC 23164932 A 649 653 3-NP SYSTEMATIC 23164932 A 701 705 3-NP SYSTEMATIC 23164932 A 962 966 3-NP SYSTEMATIC 23164932 T 37 58 3-nitropropionic acid SYSTEMATIC 23164985 A 26 41 3-cyanopyridine SYSTEMATIC 23164985 T 58 73 3-cyanopyridine SYSTEMATIC 23165154 A 1021 1027 sodium SYSTEMATIC 23165154 A 130 140 Rotigotine TRIVIAL 23165154 A 150 158 ergoline TRIVIAL 23165154 A 174 182 dopamine TRIVIAL 23165154 A 252 262 rotigotine TRIVIAL 23165154 A 339 365 poly(lactide-co-glycolide) SYSTEMATIC 23165154 A 787 795 dopamine TRIVIAL 23165154 A 842 852 rotigotine TRIVIAL 23165154 A 968 994 poly(lactide-co-glycolide) SYSTEMATIC 23165154 T 55 65 rotigotine TRIVIAL 23165155 A 1089 1092 DDT ABBREVIATION 23165155 A 1097 1105 dieldrin TRIVIAL 23165155 A 1159 1162 DDT ABBREVIATION 23165155 A 1163 1171 dieldrin TRIVIAL 23165155 A 491 494 MTT ABBREVIATION 23165155 A 499 510 neutral red TRIVIAL 23165155 A 816 847 dichlorodiphenyltrichloroethane SYSTEMATIC 23165155 A 849 852 DDT ABBREVIATION 23165155 A 858 866 dieldrin TRIVIAL 23165858 A 421 426 CoCl2 FORMULA 23165858 A 431 436 CaCl2 FORMULA 23165858 A 52 53 N FORMULA 23165858 A 578 580 Co FORMULA 23165858 A 582 583 P FORMULA 23165858 A 588 590 Ca FORMULA 23165858 A 63 74 amino acids FAMILY 23166012 A 0 32 Sodium dodecyl benzene sulfonate SYSTEMATIC 23166012 A 1035 1039 SDBS ABBREVIATION 23166012 A 1044 1048 CTAC ABBREVIATION 23166012 A 1146 1150 SDBS ABBREVIATION 23166012 A 1410 1414 SDBS ABBREVIATION 23166012 A 1432 1436 CTAC ABBREVIATION 23166012 A 1506 1510 SDBS ABBREVIATION 23166012 A 1528 1532 CTAC ABBREVIATION 23166012 A 34 38 SDBS ABBREVIATION 23166012 A 357 361 SDBS ABBREVIATION 23166012 A 363 367 CTAC ABBREVIATION 23166012 A 424 434 β-carotene TRIVIAL 23166012 A 44 77 cetyl trimethyl ammonium chloride SYSTEMATIC 23166012 A 477 487 superoxide TRIVIAL 23166012 A 548 552 SDBS ABBREVIATION 23166012 A 604 608 CTAC ABBREVIATION 23166012 A 677 687 β-carotene TRIVIAL 23166012 A 760 764 CTAC ABBREVIATION 23166012 A 79 83 CTAC ABBREVIATION 23166012 A 866 870 SDBS ABBREVIATION 23167526 A 170 179 xanthones FAMILY 23167526 A 189 202 gambogic acid TRIVIAL 23167526 A 729 742 gambogic acid TRIVIAL 23167526 A 88 103 hydroxyxanthone SYSTEMATIC 23167526 T 9 18 xanthones FAMILY 23167531 A 1058 1067 darexaban TRIVIAL 23167531 A 1110 1130 N-demethyl darexaban SYSTEMATIC 23167531 A 1239 1248 darexaban TRIVIAL 23167531 A 1314 1317 UDP ABBREVIATION 23167531 A 163 187 [(14)C]darexaban maleate SYSTEMATIC 23167531 A 242 258 [(14)C]Darexaban SYSTEMATIC 23167531 A 391 412 darexaban glucuronide TRIVIAL 23167531 A 47 56 darexaban TRIVIAL 23167531 A 474 483 darexaban TRIVIAL 23167531 A 58 63 YM150 IDENTIFIER 23167531 A 881 889 N-oxides FAMILY 23167531 T 40 49 darexaban TRIVIAL 23167531 T 51 56 YM150 IDENTIFIER 23167767 A 162 183 poly(ethylene glycol) SYSTEMATIC 23167767 A 505 516 polystyrene SYSTEMATIC 23167767 T 109 139 poly(ethylene glycol) acrylate FAMILY 23167812 A 14 42 8,8-dialkyldihydroberberines FAMILY 23167812 A 268 304 8,8-diethyldihydroberberine chloride SYSTEMATIC 23167812 A 422 442 8,8-dialkylcanadines FAMILY 23167812 A 44 52 8,8-DDBs FAMILY 23167812 A 487 495 8,8-DDBs FAMILY 23167812 A 615 623 8,8-DDBs FAMILY 23167812 A 708 719 poly(dA·dT) FAMILY 23167812 A 734 742 8,8-DDBs FAMILY 23167812 A 835 872 8,8-dimethyldihydroberberine chloride SYSTEMATIC 23167812 T 0 28 8,8-dialkyldihydroberberines FAMILY 23168114 A 0 15 Benzodiazepines FAMILY 23168114 A 1086 1089 BDZ ABBREVIATION 23168114 A 1142 1145 STP ABBREVIATION 23168114 A 1205 1208 DZP ABBREVIATION 23168114 A 1273 1276 STP ABBREVIATION 23168114 A 1414 1417 STP ABBREVIATION 23168114 A 1517 1520 STP ABBREVIATION 23168114 A 17 21 BZDs FAMILY 23168114 A 174 177 BZD ABBREVIATION 23168114 A 227 238 Stiripentol TRIVIAL 23168114 A 240 243 STP ABBREVIATION 23168114 A 351 354 STP ABBREVIATION 23168114 A 442 445 STP ABBREVIATION 23168114 A 598 601 STP ABBREVIATION 23168114 A 606 614 diazepam TRIVIAL 23168114 A 616 619 DZP ABBREVIATION 23168114 A 638 641 BZD ABBREVIATION 23168114 A 736 739 STP ABBREVIATION 23168114 A 824 827 DZP ABBREVIATION 23168114 A 956 959 STP ABBREVIATION 23168114 A 97 100 BZD ABBREVIATION 23168114 T 0 11 Stiripentol TRIVIAL 23168114 T 83 97 benzodiazepine FAMILY 23168115 A 1027 1031 5-HT SYSTEMATIC 23168115 A 1134 1141 GTP-γ-S ABBREVIATION 23168115 A 1279 1288 glutamate TRIVIAL 23168115 A 1327 1331 5-HT SYSTEMATIC 23168115 A 235 239 5-HT SYSTEMATIC 23168115 A 29 33 5-HT SYSTEMATIC 23168115 A 330 339 glutamate TRIVIAL 23168115 A 354 358 5-HT SYSTEMATIC 23168115 A 466 470 5-HT SYSTEMATIC 23168115 A 835 839 GABA ABBREVIATION 23168115 A 844 848 5-HT SYSTEMATIC 23168115 A 919 923 5-HT SYSTEMATIC 23168115 T 14 23 serotonin TRIVIAL 23168115 T 25 29 5-HT SYSTEMATIC 23168115 T 62 71 glutamate TRIVIAL 23169608 A 0 18 3-n-Butylphthalide SYSTEMATIC 23169608 A 1248 1262 11-hydroxy-NBP SYSTEMATIC 23169608 A 1279 1293 11-hydroxy-NBP SYSTEMATIC 23169608 A 1369 1376 alcohol FAMILY 23169608 A 1396 1404 aldehyde SYSTEMATIC 23169608 A 1553 1576 phthalide-3-acetic acid SYSTEMATIC 23169608 A 1639 1642 NBP ABBREVIATION 23169608 A 194 197 NBP ABBREVIATION 23169608 A 20 23 NBP ABBREVIATION 23169608 A 285 288 NBP ABBREVIATION 23169608 A 359 362 NBP ABBREVIATION 23169608 A 480 485 alkyl FAMILY 23169608 A 514 537 3-, ω-1-, and ω-carbons MULTIPLE 23169608 A 644 659 NBP-11-oic acid SYSTEMATIC 23169608 A 734 745 10-Keto-NBP SYSTEMATIC 23169608 A 752 765 3-hydroxy-NBP SYSTEMATIC 23169608 A 774 788 10-hydroxy-NBP SYSTEMATIC 23169608 A 944 947 NBP ABBREVIATION 23169608 T 104 111 alcohol FAMILY 23169608 T 35 53 3-n-butylphthalide SYSTEMATIC 23169608 T 55 58 NBP ABBREVIATION 23169609 A 109 116 glucose TRIVIAL 23169609 A 1254 1277 des-ethyl ertugliflozin SYSTEMATIC 23169609 A 1355 1368 ertugliflozin TRIVIAL 23169609 A 180 201 [(14)C]-ertugliflozin SYSTEMATIC 23169609 A 19 32 ertugliflozin TRIVIAL 23169609 A 34 45 PF-04971729 IDENTIFIER 23169609 A 451 464 ertugliflozin TRIVIAL 23169609 A 579 592 ertugliflozin TRIVIAL 23169609 A 778 786 hydroxyl SYSTEMATIC 23169609 A 92 98 sodium SYSTEMATIC 23169609 A 996 1040 ertugliflozin -4-O-β- and -3-O-β-glucuronide SYSTEMATIC 23169609 T 70 83 ertugliflozin TRIVIAL 23169609 T 85 96 PF-04971729 IDENTIFIER 23169610 A 0 20 3-Methylcholanthrene SYSTEMATIC 23169610 A 51 67 aryl hydrocarbon FAMILY 23169610 A 546 551 NADPH ABBREVIATION 23169610 T 140 160 3-methylcholanthrene SYSTEMATIC 23170792 A 1213 1223 ticagrelor TRIVIAL 23170792 A 1228 1237 prasugrel TRIVIAL 23170792 A 1301 1308 aspirin TRIVIAL 23170792 A 1316 1327 clopidogrel TRIVIAL 23170792 A 1477 1492 thienopyridines FAMILY 23170792 A 337 344 aspirin TRIVIAL 23170792 A 349 364 thienopyridines FAMILY 23170792 A 996 1004 warfarin TRIVIAL 23170957 A 504 514 acetyl-CoA SYSTEMATIC 23170957 A 615 626 malonyl-CoA TRIVIAL 23170957 A 982 992 fatty acid FAMILY 23170957 T 20 30 fatty acid FAMILY 23171424 A 1148 1154 phenol SYSTEMATIC 23171424 A 1156 1159 SDS ABBREVIATION 23171424 A 125 129 iron SYSTEMATIC 23171424 A 158 165 propane SYSTEMATIC 23171424 A 170 176 phenol SYSTEMATIC 23171424 A 583 589 phenol SYSTEMATIC 23171424 A 670 673 SDS ABBREVIATION 23171424 A 894 904 amino acid FAMILY 23171424 T 28 32 iron SYSTEMATIC 23171962 A 104 106 Cu FORMULA 23171962 A 134 137 CuO FORMULA 23171962 A 196 203 lithium SYSTEMATIC 23171962 A 303 315 carbon black TRIVIAL 23171962 A 70 73 CuO FORMULA 23171962 T 59 62 CuO FORMULA 23171962 T 82 84 Cu FORMULA 23172156 A 151 157 silica TRIVIAL 23172156 A 682 688 silica TRIVIAL 23172156 A 83 92 zirconium FAMILY 23172726 A 18 26 FR901464 IDENTIFIER 23172726 A 215 227 meayamycin B TRIVIAL 23172726 A 41 53 herboxidiene TRIVIAL 23172734 A 0 9 Fullerene TRIVIAL 23172734 A 1005 1008 PCB ABBREVIATION 23172734 A 1214 1220 nC(60) FAMILY 23172734 A 1268 1274 nC(60) FAMILY 23172734 A 1367 1370 PCB ABBREVIATION 23172734 A 1484 1490 nC(60) FAMILY 23172734 A 25 31 nC(60) FAMILY 23172734 A 258 264 nC(60) FAMILY 23172734 A 307 313 nC(60) FAMILY 23172734 A 364 370 nC(60) FAMILY 23172734 A 410 417 toluene TRIVIAL 23172734 A 536 541 C(60) TRIVIAL 23172734 A 545 552 toluene TRIVIAL 23172734 A 556 562 nC(60) FAMILY 23172734 A 871 877 nC(60) FAMILY 23172734 A 934 940 nC(60) FAMILY 23172734 A 969 1003 2,2',5,5'-polychlorinated biphenyl SYSTEMATIC 23172734 T 107 111 nC60 FAMILY 23172734 T 37 46 fullerene TRIVIAL 23172734 T 62 66 nC60 FAMILY 23173549 A 371 387 aryl hydrocarbon FAMILY 23173549 A 56 66 androstane TRIVIAL 23174031 A 246 255 androgens FAMILY 23174031 A 694 709 androstenedione TRIVIAL 23174031 T 71 80 androgens FAMILY 23174144 A 1321 1328 CuSO(4) FORMULA 23174144 A 1333 1335 Cu FORMULA 23174144 A 1451 1453 Cu FORMULA 23174144 A 1549 1556 CuSO(4) FORMULA 23174144 A 1614 1621 CuSO(4) FORMULA 23174144 A 22 28 copper SYSTEMATIC 23174144 A 293 295 Cu FORMULA 23174144 A 337 339 Cu FORMULA 23174144 A 344 351 CuSO(4) FORMULA 23174144 A 356 358 Cu FORMULA 23174144 A 586 588 Cu FORMULA 23174144 A 626 633 CuSO(4) FORMULA 23174144 A 94 100 copper SYSTEMATIC 23174144 T 40 46 copper SYSTEMATIC 23174144 T 65 80 copper sulphate SYSTEMATIC 23174340 A 0 10 BMS-763534 IDENTIFIER 23174340 A 1040 1044 TBOB ABBREVIATION 23174340 A 1057 1061 GABA ABBREVIATION 23174340 A 1114 1118 GABA ABBREVIATION 23174340 A 1274 1284 BMS-790318 IDENTIFIER 23174340 A 1294 1298 TBOB ABBREVIATION 23174340 A 1311 1315 GABA ABBREVIATION 23174340 A 1386 1390 GABA ABBREVIATION 23174340 A 173 177 cAMP ABBREVIATION 23174340 A 204 214 BMS-763534 IDENTIFIER 23174340 A 247 253 (125)I FORMULA 23174340 A 375 385 BMS-763534 IDENTIFIER 23174340 A 648 658 BMS-763534 IDENTIFIER 23174340 A 861 871 BMS-763534 IDENTIFIER 23174340 A 922 938 chlordiazepoxide TRIVIAL 23174340 A 954 964 BMS-790318 IDENTIFIER 23174340 A 970 971 O FORMULA 23174340 A 999 1009 BMS-763534 IDENTIFIER 23174340 T 79 89 BMS-763534 IDENTIFIER 23174518 A 309 319 polyphenol FAMILY 23174518 A 329 358 2,2-diphenyl-1-picrylhydrazyl SYSTEMATIC 23174518 A 427 437 superoxide TRIVIAL 23174748 A 1153 1158 R-123 ABBREVIATION 23174748 A 1193 1198 R-123 ABBREVIATION 23174748 A 186 199 anthraquinone SYSTEMATIC 23174748 A 499 512 rhodamine-123 TRIVIAL 23174748 A 514 519 R-123 ABBREVIATION 23174748 A 665 679 anthraquinones FAMILY 23174748 A 736 738 NO FORMULA 23174748 A 799 811 nitric oxide SYSTEMATIC 23174748 A 884 902 prostaglandin E(2) TRIVIAL 23174748 A 904 910 PGE(2) ABBREVIATION 23174748 A 964 970 Emodin TRIVIAL 23174748 T 32 46 anthraquinones FAMILY 23175103 A 1000 1009 Co(3)O(4) FORMULA 23175103 A 1084 1086 CO FORMULA 23175103 A 1143 1144 O FORMULA 23175103 A 1173 1179 Co(3+) FORMULA 23175103 A 1200 1206 Co(2+) FORMULA 23175103 A 1216 1217 O FORMULA 23175103 A 1226 1232 Co(3+) FORMULA 23175103 A 1267 1269 CO FORMULA 23175103 A 1283 1292 Co(3)O(4) FORMULA 23175103 A 1357 1363 Co(3+) FORMULA 23175103 A 1367 1368 O FORMULA 23175103 A 248 250 CO FORMULA 23175103 A 26 28 CO FORMULA 23175103 A 459 461 CO FORMULA 23175103 A 46 55 Co(3)O(4) FORMULA 23175103 A 502 508 oxygen SYSTEMATIC 23175103 A 516 517 O FORMULA 23175103 A 522 523 O FORMULA 23175103 A 537 542 CO(2) FORMULA 23175103 A 643 647 O(2) FORMULA 23175103 A 66 75 Co(3)O(4) FORMULA 23175103 A 660 662 CO FORMULA 23175103 A 736 738 CO FORMULA 23175103 A 747 752 CO(2) FORMULA 23175103 A 754 758 O(2) FORMULA 23175103 A 762 764 CO FORMULA 23175103 A 768 773 CO(2) FORMULA 23175103 A 777 778 O FORMULA 23175103 A 806 808 CO FORMULA 23175103 A 883 885 CO FORMULA 23175103 A 917 926 Co(3)O(4) FORMULA 23175103 A 944 953 Co(3)O(4) FORMULA 23175103 A 972 981 Co(3)O(4) FORMULA 23175103 T 25 27 CO FORMULA 23175103 T 41 46 Co3O4 FORMULA 23177260 A 1257 1269 trimethyltin SYSTEMATIC 23177260 A 175 187 trimethyltin SYSTEMATIC 23177260 A 189 192 TMT ABBREVIATION 23177260 A 395 407 Trimethyltin SYSTEMATIC 23177260 A 481 484 TMT ABBREVIATION 23177260 A 601 610 serotonin TRIVIAL 23177260 A 615 628 acetylcholine SYSTEMATIC 23177260 A 733 736 MDA ABBREVIATION 23177260 A 773 776 GSH ABBREVIATION 23177260 A 778 782 GSSH ABBREVIATION 23177260 A 795 806 glutathione TRIVIAL 23177260 A 821 831 Superoxide TRIVIAL 23177260 A 867 870 TMT ABBREVIATION 23177260 A 987 999 trimethyltin SYSTEMATIC 23177260 T 100 112 trimethyltin SYSTEMATIC 23177536 A 1008 1011 VPA ABBREVIATION 23177536 A 1247 1250 VPA ABBREVIATION 23177536 A 1295 1306 fatty acids FAMILY 23177536 A 1426 1429 VPA ABBREVIATION 23177536 A 17 29 triglyceride FAMILY 23177536 A 178 189 fatty acids FAMILY 23177536 A 220 231 fatty acids FAMILY 23177536 A 339 348 Valproate TRIVIAL 23177536 A 350 353 VPA ABBREVIATION 23177536 A 392 403 fatty acids FAMILY 23177536 A 683 694 fatty acids FAMILY 23177536 A 855 858 VPA ABBREVIATION 23177536 T 58 69 fatty acids FAMILY 23178198 A 1095 1104 etazolate TRIVIAL 23178198 A 532 541 etazolate TRIVIAL 23178198 A 718 727 etazolate TRIVIAL 23178198 T 0 9 Etazolate TRIVIAL 23178257 A 117 133 1α,25(OH)(2)D(3) SYSTEMATIC 23178257 A 1174 1183 vitamin D FAMILY 23178257 A 140 147 calcium SYSTEMATIC 23178257 A 152 162 phosphorus SYSTEMATIC 23178257 A 248 264 1α,25(OH)(2)D(3) SYSTEMATIC 23178257 A 372 388 1α,25(OH)(2)D(3) SYSTEMATIC 23178257 A 430 439 vitamin D FAMILY 23178257 A 522 531 vitamin D FAMILY 23178257 A 77 86 vitamin D FAMILY 23178257 A 88 115 1α,25-dihydroxyvitamin D(3) SYSTEMATIC 23178257 T 0 9 Vitamin D FAMILY 23178323 A 1112 1118 serine TRIVIAL 23178323 A 13 19 serine TRIVIAL 23178323 A 1535 1541 serine TRIVIAL 23178323 A 551 557 serine TRIVIAL 23178323 A 834 835 N FORMULA 23178323 A 952 953 N FORMULA 23178323 T 51 57 serine TRIVIAL 23178441 A 1035 1045 cefadroxil TRIVIAL 23178441 A 1128 1138 quetiapine TRIVIAL 23178441 A 855 878 citric and lactic acids MULTIPLE 23178632 A 1042 1052 amiodarone TRIVIAL 23178632 A 1147 1157 amiodarone TRIVIAL 23178632 A 1203 1213 amiodarone TRIVIAL 23178632 A 1278 1288 amiodarone TRIVIAL 23178632 A 296 306 amiodarone TRIVIAL 23178632 A 484 494 amiodarone TRIVIAL 23178632 A 624 634 amiodarone TRIVIAL 23178632 A 876 886 amiodarone TRIVIAL 23178632 T 123 133 amiodarone TRIVIAL 23178632 T 55 65 amiodarone TRIVIAL 23178651 A 277 294 diallyl disulfide SYSTEMATIC 23178651 T 15 32 diallyl disulfide SYSTEMATIC 23178681 A 265 271 oxygen SYSTEMATIC 23178681 A 453 461 H(2)O(2) FORMULA 23178681 A 721 729 H(2)O(2) FORMULA 23178950 A 102 113 doxorubicin TRIVIAL 23178950 A 1095 1098 DOX ABBREVIATION 23178950 A 1103 1107 DTXL ABBREVIATION 23178950 A 115 118 DOX ABBREVIATION 23178950 A 1363 1367 DTXL ABBREVIATION 23178950 A 1372 1375 DOX ABBREVIATION 23178950 A 1536 1540 DTXL ABBREVIATION 23178950 A 1544 1547 DOX ABBREVIATION 23178950 A 1719 1723 HPMA ABBREVIATION 23178950 A 201 204 PBS ABBREVIATION 23178950 A 205 209 PBDL ABBREVIATION 23178950 A 211 259 poly(butylene succinate-co-butylene dilinoleate) FAMILY 23178950 A 265 269 HPMA ABBREVIATION 23178950 A 288 321 N-(2-hydroxypropyl)methacrylamide SYSTEMATIC 23178950 A 389 400 cholesterol TRIVIAL 23178950 A 628 633 PHPMA ABBREVIATION 23178950 A 759 768 docetaxel TRIVIAL 23178950 A 770 774 DTXL ABBREVIATION 23178950 A 81 90 docetaxel TRIVIAL 23178950 A 812 815 PBS ABBREVIATION 23178950 A 816 820 PBDL ABBREVIATION 23178950 A 863 888 doxorubicin hydrochloride SYSTEMATIC 23178950 A 890 897 DOX·HCl FORMULA 23178950 A 92 96 DTXL ABBREVIATION 23178950 A 941 946 PHPMA ABBREVIATION 23178950 A 967 976 hydrazone FAMILY 23178950 T 122 131 polyester FAMILY 23178950 T 85 89 HPMA ABBREVIATION 23179349 A 108 116 fructose TRIVIAL 23179349 A 1093 1105 nitric oxide SYSTEMATIC 23179349 A 1191 1195 iron SYSTEMATIC 23179349 A 1277 1281 iron SYSTEMATIC 23179349 A 1314 1318 zinc SYSTEMATIC 23179349 A 1320 1326 copper SYSTEMATIC 23179349 A 1332 1339 calcium SYSTEMATIC 23179349 A 1387 1399 nitric oxide SYSTEMATIC 23179349 A 1429 1433 iron SYSTEMATIC 23179349 A 144 148 iron SYSTEMATIC 23179349 A 1440 1448 fructose TRIVIAL 23179349 A 1492 1496 zinc SYSTEMATIC 23179349 A 1498 1504 copper SYSTEMATIC 23179349 A 1510 1517 calcium SYSTEMATIC 23179349 A 289 297 fructose TRIVIAL 23179349 A 381 385 iron SYSTEMATIC 23179349 A 578 590 nitric oxide SYSTEMATIC 23179349 A 596 600 iron SYSTEMATIC 23179349 A 620 624 iron SYSTEMATIC 23179349 A 626 630 zinc SYSTEMATIC 23179349 A 632 638 copper SYSTEMATIC 23179349 A 644 651 calcium SYSTEMATIC 23179349 A 889 893 iron SYSTEMATIC 23179349 A 914 918 zinc SYSTEMATIC 23179349 A 923 929 copper SYSTEMATIC 23179349 A 983 990 calcium SYSTEMATIC 23179349 T 0 4 Iron SYSTEMATIC 23179349 T 83 91 fructose TRIVIAL 23179350 T 34 46 lead acetate SYSTEMATIC 23179409 A 1018 1026 Atrazine TRIVIAL 23179409 A 115 123 atrazine TRIVIAL 23179409 A 1262 1270 atrazine TRIVIAL 23179409 A 1631 1639 atrazine TRIVIAL 23179409 A 634 642 atrazine TRIVIAL 23179409 A 705 713 atrazine TRIVIAL 23179409 A 722 735 chlorophyll a TRIVIAL 23179409 A 737 742 Chl a ABBREVIATION 23179409 A 786 794 atrazine TRIVIAL 23179409 A 903 911 nitrogen SYSTEMATIC 23179409 A 942 947 Chl a ABBREVIATION 23179409 A 959 969 phosphorus SYSTEMATIC 23179409 T 37 45 atrazine TRIVIAL 23179753 A 1264 1268 MeHg FORMULA 23179753 A 1650 1653 VPA ABBREVIATION 23179753 A 1658 1662 MeHg FORMULA 23179753 A 674 687 Valproic acid TRIVIAL 23179753 A 689 692 VPA ABBREVIATION 23179753 A 698 711 methylmercury SYSTEMATIC 23179753 A 713 717 MeHg FORMULA 23179775 A 1013 1021 cortisol TRIVIAL 23179775 A 1059 1073 hydrocortisone TRIVIAL 23179775 A 122 130 cortisol TRIVIAL 23179775 A 435 444 androgens FAMILY 23179775 A 747 755 cortisol TRIVIAL 23179775 A 884 898 hydrocortisone TRIVIAL 23179775 A 902 919 cortisone acetate SYSTEMATIC 23180341 A 112 117 EtOAc FORMULA 23180341 A 23 37 amauroamoienin TRIVIAL 23180449 A 103 108 GeSe2 FORMULA 23180449 A 233 237 CdSe FORMULA 23180449 T 31 36 GeSe2 FORMULA 23180684 A 0 14 Methyl mercury SYSTEMATIC 23180684 A 1166 1170 MeHg FORMULA 23180684 A 16 20 MeHg FORMULA 23180684 A 206 210 MeHg FORMULA 23180684 A 302 306 MeHg FORMULA 23180684 A 489 493 MeHg FORMULA 23180684 A 678 682 MeHg FORMULA 23180684 A 780 784 MeHg FORMULA 23180684 A 809 813 MeHg FORMULA 23180684 T 64 71 mercury SYSTEMATIC 23180691 A 718 737 polyethylene glycol SYSTEMATIC 23180693 A 128 153 Bi(3) Fe(2) Mn(2) O(10+δ) FORMULA 23180693 A 449 459 perovskite TRIVIAL 23180693 A 460 467 BiRO(3) FAMILY 23180693 A 473 475 Cr FORMULA 23180693 A 477 479 Mn FORMULA 23180693 A 48 56 BiFeO(3) FORMULA 23180693 A 481 483 Fe FORMULA 23180693 A 485 487 Co FORMULA 23180693 A 489 491 Ni FORMULA 23180693 A 61 69 BiMnO(3) FORMULA 23180693 T 61 68 bismuth SYSTEMATIC 23182087 A 0 13 Benzothiazole SYSTEMATIC 23182087 A 101 107 NK0148 IDENTIFIER 23182087 A 18 31 benzimidazole SYSTEMATIC 23182087 A 253 264 thalidomide TRIVIAL 23182087 A 368 373 NK037 IDENTIFIER 23182087 A 375 380 NK041 IDENTIFIER 23182087 A 385 390 NK042 IDENTIFIER 23182087 A 43 54 phthalimide TRIVIAL 23182087 A 494 498 NKTA TRIVIAL 23182087 A 622 629 NK0139A IDENTIFIER 23182087 A 634 640 NK0148 IDENTIFIER 23182087 A 665 669 NKTA TRIVIAL 23182087 A 68 73 NK037 IDENTIFIER 23182087 A 75 80 NK041 IDENTIFIER 23182087 A 82 87 NK042 IDENTIFIER 23182087 A 89 96 NK0139A IDENTIFIER 23182087 T 42 55 benzothiazole SYSTEMATIC 23182087 T 57 70 benzimidazole SYSTEMATIC 23182087 T 82 93 phthalimide TRIVIAL 23182739 A 103 117 phenolic acids FAMILY 23182739 A 119 126 tannins FAMILY 23182739 A 131 141 flavonoids FAMILY 23182739 A 679 687 phenolic FAMILY 23182766 A 1023 1034 cholesterol TRIVIAL 23182766 A 1161 1172 cholesterol TRIVIAL 23182766 A 1283 1294 cholesterol TRIVIAL 23182766 A 1326 1334 creatine TRIVIAL 23182766 A 289 296 carboxy SYSTEMATIC 23182766 A 354 365 cholesterol TRIVIAL 23182766 A 390 400 amino acid FAMILY 23182766 A 461 472 cholesterol TRIVIAL 23182766 A 70 81 cholesterol TRIVIAL 23182766 A 750 761 cholesterol TRIVIAL 23182766 A 900 911 cholesterol TRIVIAL 23182766 A 951 962 cholesterol TRIVIAL 23182766 T 62 73 cholesterol TRIVIAL 23182766 T 98 108 amino acid FAMILY 23182946 A 1051 1060 (PhTe)(2) FORMULA 23182946 A 1202 1217 [(3)H]glutamate SYSTEMATIC 23182946 A 1286 1289 Ser FORMULA 23182946 A 1311 1320 (PhTe)(2) FORMULA 23182946 A 1412 1421 (PhTe)(2) FORMULA 23182946 A 1856 1865 glutamate TRIVIAL 23182946 A 2006 2015 (PhTe)(2) FORMULA 23182946 A 574 578 cAMP ABBREVIATION 23182946 A 68 88 diphenyl ditelluride SYSTEMATIC 23182946 A 703 712 (PhTe)(2) FORMULA 23182946 A 813 822 (PhTe)(2) FORMULA 23182946 A 877 893 propidium iodide TRIVIAL 23182946 A 89 98 (PhTe)(2) FORMULA 23182946 T 125 145 diphenyl ditelluride SYSTEMATIC 23183177 A 1032 1041 digitonin TRIVIAL 23183177 A 1104 1105 C FORMULA 23183177 A 1357 1358 N FORMULA 23183177 A 137 155 11β-hydroxysteroid FAMILY 23183177 A 1526 1545 glucose-6-phosphate SYSTEMATIC 23183177 A 1570 1575 NADPH ABBREVIATION 23183177 A 263 282 pyridine nucleotide FAMILY 23183177 A 428 446 hexose-6-phosphate SYSTEMATIC 23183177 A 484 527 nicotinamide adenine dinucleotide phosphate SYSTEMATIC 23183177 A 529 534 NADPH ABBREVIATION 23183177 A 54 72 17β-hydroxysteroid SYSTEMATIC 23183177 A 696 720 Δ4-androstene-3,17-dione SYSTEMATIC 23183177 A 807 825 hexose-6-phosphate SYSTEMATIC 23183177 A 867 886 glucose-6-phosphate SYSTEMATIC 23183177 A 967 972 NADPH ABBREVIATION 23183177 T 105 124 glucose-6-phosphate SYSTEMATIC 23183177 T 22 40 17β-hydroxysteroid SYSTEMATIC 23183177 T 86 91 NADPH ABBREVIATION 23183374 A 1282 1290 cytosine TRIVIAL 23183374 A 189 197 cytosine TRIVIAL 23183374 A 19 27 cytidine TRIVIAL 23183374 A 201 207 uracil TRIVIAL 23183374 A 961 962 C FORMULA 23183374 T 74 82 cytidine TRIVIAL 23183543 A 115 124 hydrazone FAMILY 23183543 A 164 173 hydrazone FAMILY 23183543 A 189 219 2-hydrazinyl-1,3,4-thiadiazole SYSTEMATIC 23183543 A 342 358 arachidonic acid TRIVIAL 23183543 A 363 366 ADP ABBREVIATION 23183543 T 62 74 Schiff bases FAMILY 23183543 T 88 118 2-hydrazinyl-1,3,4-thiadiazole SYSTEMATIC 23183624 A 1040 1048 aluminum SYSTEMATIC 23184149 A 1057 1065 dopamine TRIVIAL 23184149 A 1096 1102 Ca(2+) FORMULA 23184149 A 1539 1545 Ca(2+) FORMULA 23184149 A 1624 1630 oxygen SYSTEMATIC 23184149 A 219 229 nucleotide FAMILY 23184149 T 146 154 dopamine TRIVIAL 23184572 A 813 821 hydrogen SYSTEMATIC 23184572 A 888 896 hydrogen SYSTEMATIC 23185042 A 1063 1067 6-MI SYSTEMATIC 23185042 A 1261 1265 6-MI SYSTEMATIC 23185042 A 233 257 6-methyl isoxanthopterin SYSTEMATIC 23185042 A 259 263 6-MI SYSTEMATIC 23185042 A 292 299 guanine TRIVIAL 23185042 A 756 760 6-MI SYSTEMATIC 23185042 T 107 114 guanine TRIVIAL 23185042 T 33 57 6-methyl isoxanthopterin SYSTEMATIC 23186033 A 1491 1494 RAI ABBREVIATION 23186033 A 159 169 Romidepsin TRIVIAL 23186033 A 1700 1703 RAI ABBREVIATION 23186033 A 1736 1746 romidepsin TRIVIAL 23186033 A 354 367 sodium iodide SYSTEMATIC 23186033 A 433 439 iodine SYSTEMATIC 23186033 A 465 468 RAI ABBREVIATION 23186033 A 47 65 radioactive iodine SYSTEMATIC 23186033 A 600 603 RAI ABBREVIATION 23186033 A 67 70 RAI ABBREVIATION 23186033 A 809 819 Romidepsin TRIVIAL 23186033 A 970 973 RAI ABBREVIATION 23186033 T 14 24 romidepsin TRIVIAL 23186033 T 51 69 radioactive iodine SYSTEMATIC 23186033 T 82 100 radioactive iodine SYSTEMATIC 23186588 A 1052 1059 A317491 IDENTIFIER 23186588 A 1297 1304 αβmeATP ABBREVIATION 23186588 A 1502 1509 αβmeATP ABBREVIATION 23186588 A 1571 1577 PGE(2) ABBREVIATION 23186588 A 210 228 prostaglandin E(2) TRIVIAL 23186588 A 248 254 amines FAMILY 23186588 A 500 518 prostaglandin E(2) TRIVIAL 23186588 A 538 543 amine SYSTEMATIC 23186588 A 603 610 A317491 IDENTIFIER 23186588 A 684 697 dexamethasone TRIVIAL 23186588 A 830 836 PGE(2) ABBREVIATION 23186588 A 851 859 dopamine TRIVIAL 23186588 A 950 957 αβmeATP ABBREVIATION 23186588 A 994 1007 dexamethasone TRIVIAL 23186588 T 113 119 amines FAMILY 23186588 T 78 92 prostaglandins FAMILY 23187065 A 1195 1199 FAAS ABBREVIATION 23187065 A 159 182 fatty acid alkyl esters FAMILY 23187065 A 184 188 FAAS ABBREVIATION 23187065 A 535 539 FAAS ABBREVIATION 23187065 A 945 949 FAAS ABBREVIATION 23187618 A 105 112 silicas TRIVIAL 23187618 A 114 120 MCM-41 IDENTIFIER 23187618 A 122 128 MCM-48 TRIVIAL 23187618 A 130 136 SBA-15 IDENTIFIER 23187618 A 141 147 SBA-16 TRIVIAL 23187618 A 176 182 MCM-41 IDENTIFIER 23187618 A 190 196 ethene SYSTEMATIC 23187618 A 205 208 PMO ABBREVIATION 23187618 A 286 292 silica TRIVIAL 23187618 A 294 303 Nucleosil TRIVIAL 23187618 A 352 360 silanols FAMILY 23187618 A 379 407 geminal and vicinal silanols MULTIPLE 23187618 A 486 493 silanol SYSTEMATIC 23187618 A 51 58 silanol SYSTEMATIC 23187618 A 530 537 silanol SYSTEMATIC 23187618 A 608 615 silanes FAMILY 23187618 A 640 647 silicas TRIVIAL 23187618 A 708 711 PMO ABBREVIATION 23187618 A 756 763 silanol SYSTEMATIC 23187618 A 802 810 silanols FAMILY 23187618 A 871 879 silanes. FAMILY 23187618 T 122 130 silanols FAMILY 23187618 T 18 25 silanol SYSTEMATIC 23187618 T 71 78 silicas TRIVIAL 23187618 T 83 96 organosilicas FAMILY 23187874 A 1028 1045 pristine graphene TRIVIAL 23187874 A 136 144 graphene TRIVIAL 23187874 A 273 281 graphene TRIVIAL 23187874 A 41 49 graphene TRIVIAL 23187874 A 686 694 graphene TRIVIAL 23187874 T 102 110 graphene TRIVIAL 23188391 A 141 148 glucose TRIVIAL 23188391 A 210 217 glucose TRIVIAL 23188391 A 50 57 glucose TRIVIAL 23188391 A 925 932 glucose TRIVIAL 23188717 A 474 493 naphthalene diimide SYSTEMATIC 23188717 T 52 71 naphthalene diimide SYSTEMATIC 23188819 A 53 57 zinc SYSTEMATIC 23190031 A 0 10 Mangiferin TRIVIAL 23190031 A 229 239 Mangiferin TRIVIAL 23190031 A 30 40 polyphenol FAMILY 23190031 A 407 417 Mangiferin TRIVIAL 23190031 A 44 62 C-glycosylxanthone FAMILY 23190031 A 511 521 mangiferin TRIVIAL 23190031 A 537 554 aromatic hydroxyl FAMILY 23190031 A 623 633 Mangiferin TRIVIAL 23190031 A 655 659 iron SYSTEMATIC 23190031 A 709 717 hydroxyl SYSTEMATIC 23190031 A 855 865 mangiferin TRIVIAL 23190031 T 0 10 Mangiferin TRIVIAL 23190031 T 25 35 xanthonoid TRIVIAL 23190033 A 1033 1047 carbon dioxide SYSTEMATIC 23190033 A 1176 1182 phenyl SYSTEMATIC 23190033 A 1193 1199 phenol SYSTEMATIC 23190033 A 1270 1275 CO(2) FORMULA 23190033 A 1382 1388 phenol SYSTEMATIC 23190033 A 1401 1406 CO(2) FORMULA 23190033 A 1510 1518 phenolic FAMILY 23190033 A 1664 1672 phenolic FAMILY 23190033 A 1718 1726 phenolic FAMILY 23190033 A 2088 2096 phenolic FAMILY 23190033 A 480 489 phenolics FAMILY 23190033 A 494 504 flavonoids FAMILY 23190033 A 737 751 carbon dioxide SYSTEMATIC 23190033 A 753 758 CO(2) FORMULA 23190033 A 763 774 bicarbonate SYSTEMATIC 23190033 A 776 784 HCO(3) - FORMULA 23190033 A 823 831 HCO(3) - FORMULA 23190033 A 869 874 CO(2) FORMULA 23190033 T 0 8 Phenolic FAMILY 23190035 A 0 9 Quinoline SYSTEMATIC 23190035 A 169 178 quinoline SYSTEMATIC 23190035 T 30 39 quinoline SYSTEMATIC 23190093 A 137 155 N-carboxyanhydride SYSTEMATIC 23190093 A 157 160 NCA ABBREVIATION 23190093 A 196 210 PEG2000-Tyr(6) FORMULA 23190093 A 34 55 poly(ethylene glycol) SYSTEMATIC 23190093 A 57 60 PEG ABBREVIATION 23190093 A 583 591 tyrosine TRIVIAL 23190093 A 69 84 oligo(tyrosine) FAMILY 23190093 T 71 86 (oligo)tyrosine FAMILY 23190297 A 1006 1026 3-methylcholanthrene SYSTEMATIC 23190297 A 1032 1045 phenobarbital TRIVIAL 23190297 A 1147 1151 BP-3 ABBREVIATION 23190297 A 136 141 NADPH ABBREVIATION 23190297 A 174 209 2,5-dihydroxy-4-methoxybenzophenone SYSTEMATIC 23190297 A 211 220 5-OH-BP-3 SYSTEMATIC 23190297 A 24 55 2-hydroxy-4-methoxybenzophenone SYSTEMATIC 23190297 A 265 269 BP-3 ABBREVIATION 23190297 A 303 328 2,4-dihydroxybenzophenone SYSTEMATIC 23190297 A 330 341 2,4-diOH-BP SYSTEMATIC 23190297 A 399 403 BP-3 ABBREVIATION 23190297 A 447 456 5-OH-BP-3 SYSTEMATIC 23190297 A 503 514 2,4-diOH-BP SYSTEMATIC 23190297 A 550 559 5-OH-BP-3 SYSTEMATIC 23190297 A 57 61 BP-3 ABBREVIATION 23190297 A 577 586 SKF 525-A IDENTIFIER 23190297 A 591 603 ketoconazole TRIVIAL 23190297 A 619 628 quinidine TRIVIAL 23190297 A 633 647 sulfaphenazole TRIVIAL 23190297 A 680 691 2,4-diOH-BP SYSTEMATIC 23190297 A 709 718 SKF 525-A IDENTIFIER 23190297 A 720 732 ketoconazole TRIVIAL 23190297 A 737 753 α-naphthoflavone TRIVIAL 23190297 A 769 783 sulfaphenazole TRIVIAL 23190297 A 8 22 benzophenone-3 TRIVIAL 23190297 A 819 828 5-OH-BP-3 SYSTEMATIC 23190297 A 865 878 dexamethasone TRIVIAL 23190297 A 881 894 phenobarbital TRIVIAL 23190297 A 900 920 3-methylcholanthrene SYSTEMATIC 23190297 A 958 969 2,4-diOH-BP SYSTEMATIC 23190297 T 0 35 2,5-Dihydroxy-4-methoxybenzophenone SYSTEMATIC 23190297 T 74 88 benzophenone-3 TRIVIAL 23192339 A 141 148 glucose TRIVIAL 23192347 A 155 164 disulfide SYSTEMATIC 23192347 A 290 299 cysteines FAMILY 23192347 A 321 330 disulfide SYSTEMATIC 23192347 T 37 46 disulfide SYSTEMATIC 23192350 A 87 100 carbohydrates FAMILY 23192350 A 949 950 N FORMULA 23192785 A 15 38 chiral β-amino alcohols FAMILY 23192785 A 188 204 β-amino alcohols FAMILY 23192785 A 252 263 amino acids FAMILY 23192785 A 315 320 aldol FAMILY 23192785 A 350 357 ketones FAMILY 23192785 A 362 380 aromatic aldehydes FAMILY 23192785 A 388 393 aldol FAMILY 23192785 A 432 449 β-hydroxy ketones FAMILY 23192785 A 492 512 (S)-2-phenylglycinol SYSTEMATIC 23192785 A 517 529 Triton X-100 TRIVIAL 23192785 A 73 78 aldol FAMILY 23192785 T 28 43 β-amino alcohol FAMILY 23192785 T 72 77 aldol FAMILY 23194076 A 392 400 Orlistat TRIVIAL 23194076 A 525 534 androgens FAMILY 23194076 A 573 580 glucose TRIVIAL 23194076 A 617 625 Androgen FAMILY 23194076 A 818 830 Testosterone TRIVIAL 23194076 A 82 90 Orlistat TRIVIAL 23194076 A 992 1000 Orlistat TRIVIAL 23194076 T 28 36 Orlistat TRIVIAL 23194156 A 1208 1218 Safranin-O TRIVIAL 23194156 A 894 903 sulfonate SYSTEMATIC 23194156 A 905 916 carboxylate SYSTEMATIC 23194156 A 922 930 hydroxyl SYSTEMATIC 23194280 A 13 21 graphene TRIVIAL 23194280 A 252 260 hydrogen SYSTEMATIC 23194280 A 601 609 hydrogen SYSTEMATIC 23194280 A 703 711 hydrogen SYSTEMATIC 23194280 A 759 765 carbon SYSTEMATIC 23194280 T 51 59 graphene TRIVIAL 23194408 A 1047 1054 cocaine TRIVIAL 23194408 A 1060 1071 amphetamine TRIVIAL 23194408 A 1816 1824 dopamine TRIVIAL 23194506 A 316 319 SDS ABBREVIATION 23194513 A 1026 1036 polyphenol FAMILY 23194513 A 1067 1077 polyphenol FAMILY 23194513 A 131 142 polyphenols FAMILY 23194513 A 1326 1337 polyphenols FAMILY 23194513 A 18 24 carbon SYSTEMATIC 23194513 A 388 433 gallic, caffeic, ferulic and p-coumaric acids MULTIPLE 23194513 A 445 452 acetate SYSTEMATIC 23194513 A 485 489 NaCl FORMULA 23194513 A 532 549 polyethyleneimine SYSTEMATIC 23194513 A 551 554 PEI ABBREVIATION 23194513 A 70 76 carbon SYSTEMATIC 23194513 A 731 741 polyphenol FAMILY 23194513 T 18 29 polyphenols FAMILY 23194513 T 94 100 carbon SYSTEMATIC 23194514 A 573 583 lactokinin TRIVIAL 23194515 A 407 418 amino acids FAMILY 23194515 A 73 83 amino acid FAMILY 23194515 T 141 152 amino acids FAMILY 23194529 A 210 220 D-fagomine TRIVIAL 23194529 A 429 439 D-fagomine TRIVIAL 23194529 A 668 678 D-fagomine TRIVIAL 23194529 A 70 80 D-fagomine TRIVIAL 23194529 A 881 891 D-fagomine TRIVIAL 23194529 T 16 26 D-fagomine TRIVIAL 23194532 A 1023 1029 CCl(4) FORMULA 23194532 A 129 149 carbon tetrachloride SYSTEMATIC 23194532 A 151 157 CCl(4) FORMULA 23194532 A 357 376 thiobarbituric acid SYSTEMATIC 23194532 A 417 426 carbonyls FAMILY 23194532 A 490 496 CCl(4) FORMULA 23194532 A 620 631 glutathione TRIVIAL 23194532 A 644 647 GSH ABBREVIATION 23194532 A 656 667 glutathione TRIVIAL 23194532 A 679 682 GSH ABBREVIATION 23194532 A 773 779 CCl(4) FORMULA 23194532 A 834 848 hydroxyproline SYSTEMATIC 23194534 A 802 811 carbonyls FAMILY 23194537 A 110 123 angiotensin I TRIVIAL 23194537 A 176 177 C FORMULA 23194537 A 548 549 C FORMULA 23194537 A 679 680 C FORMULA 23194537 A 940 951 amino acids FAMILY 23194537 A 960 967 sulphur SYSTEMATIC 23194537 A 979 990 amino acids FAMILY 23194537 T 22 35 angiotensin I TRIVIAL 23194541 A 1102 1110 Caffeine TRIVIAL 23194541 A 1483 1494 anthocyanin FAMILY 23194541 A 1542 1564 Cyanidin-3-O-glucoside SYSTEMATIC 23194541 A 1573 1584 anthocyanin FAMILY 23194541 A 1663 1672 catechins FAMILY 23194541 A 1927 1936 flavonoid FAMILY 23194541 A 233 244 polyphenols FAMILY 23194541 A 270 278 catechin TRIVIAL 23194541 A 345 353 phenolic FAMILY 23194541 A 407 429 Folin-Ciocalteu phenol TRIVIAL 23194541 A 439 447 Catechin TRIVIAL 23194541 A 630 658 2,2'-diphenyl picrylhydrazyl SYSTEMATIC 23194541 A 660 664 DPPH ABBREVIATION 23194541 A 717 725 catechin TRIVIAL 23194541 A 914 922 catechin TRIVIAL 23194541 T 19 27 catechin TRIVIAL 23194541 T 6 17 polyphenols FAMILY 23194542 A 1071 1075 6-BA SYSTEMATIC 23194542 A 109 122 thiabendazole TRIVIAL 23194542 A 1144 1155 carbendazim TRIVIAL 23194542 A 1157 1170 thiabendazole TRIVIAL 23194542 A 1176 1180 6-BA SYSTEMATIC 23194542 A 133 153 6-benzyl aminopurine SYSTEMATIC 23194542 A 155 159 6-BA SYSTEMATIC 23194542 A 210 222 acetonitrile SYSTEMATIC 23194542 A 91 102 carbendazim TRIVIAL 23194548 A 114 121 ethanol SYSTEMATIC 23194548 A 581 641 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide SYSTEMATIC 23194548 A 643 646 MTT ABBREVIATION 23194548 A 762 773 uronic acid FAMILY 23194548 A 807 822 monosaccharides FAMILY 23194548 A 834 841 glucose TRIVIAL 23194548 A 843 851 rhamnose TRIVIAL 23194548 A 853 862 arabinose TRIVIAL 23194548 A 864 870 xylose TRIVIAL 23194548 A 872 879 mannose TRIVIAL 23194548 A 884 893 galactose TRIVIAL 23194828 A 1073 1086 D-amphetamine TRIVIAL 23194828 A 1173 1176 CPF ABBREVIATION 23194828 A 1188 1191 CPF ABBREVIATION 23194828 A 1233 1241 dopamine TRIVIAL 23194828 A 1296 1319 gamma-aminobutyric acid SYSTEMATIC 23194828 A 1321 1325 GABA ABBREVIATION 23194828 A 1331 1340 glutamate TRIVIAL 23194828 A 1416 1419 CPF ABBREVIATION 23194828 A 1539 1549 amino acid FAMILY 23194828 A 267 282 organophosphate FAMILY 23194828 A 288 300 chlorpyrifos TRIVIAL 23194828 A 302 305 CPF ABBREVIATION 23194828 A 482 485 CPF ABBREVIATION 23194828 A 694 707 d-amphetamine TRIVIAL 23194828 A 709 719 quinpirole TRIVIAL 23194828 A 721 732 dizocilpine TRIVIAL 23194828 A 734 740 MK-801 IDENTIFIER 23194828 A 745 755 ketanserin TRIVIAL 23194828 A 809 819 monoamines FAMILY 23194828 A 824 835 amino acids FAMILY 23194828 A 884 887 CPF ABBREVIATION 23194828 T 77 89 Chlorpyrifos TRIVIAL 23195733 A 13 53 5-, 6- and 8-(4-aminobutyloxy)quinolines MULTIPLE 23195733 A 165 182 hydroxyquinolines FAMILY 23195733 A 220 227 rhodium SYSTEMATIC 23195733 A 307 317 quinolines FAMILY 23195733 A 380 391 chloroquine TRIVIAL 23195733 A 495 506 chloroquine TRIVIAL 23195733 A 63 69 oxygen SYSTEMATIC 23195733 A 89 126 4- and 8-(4-aminobutylamino)quinoline MULTIPLE 23195733 T 49 76 (4-aminobutyloxy)quinolines FAMILY 23195751 A 33 41 estrogen FAMILY 23195751 A 936 949 17β-estradiol SYSTEMATIC 23195751 T 48 57 estradiol TRIVIAL 23195959 A 207 214 phospho SYSTEMATIC 23195959 T 34 41 phospho SYSTEMATIC 23196670 A 120 124 PCBs ABBREVIATION 23196670 A 1313 1317 TCDD ABBREVIATION 23196670 A 215 231 aryl hydrocarbon FAMILY 23196670 A 40 75 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23196670 A 526 533 PCB 126 TRIVIAL 23196670 A 77 81 TCDD ABBREVIATION 23196670 A 93 118 polychlorinated biphenyls FAMILY 23197401 A 112 117 C(60) TRIVIAL 23197401 A 174 179 C(60) TRIVIAL 23197401 A 24 43 poly(vinyl alcohol) SYSTEMATIC 23197401 A 44 49 C(60) TRIVIAL 23197401 A 451 459 hydroxyl SYSTEMATIC 23197401 A 54 111 poly{[poly(ethylene glycol) acrylate]-co-(vinyl acetate)} SYSTEMATIC 23197401 A 644 689 poly[(N-vinylpyrrolidone)-co-(vinyl acetate)] SYSTEMATIC 23197401 A 690 695 C(60) TRIVIAL 23197401 A 730 738 hydroxyl SYSTEMATIC 23197401 T 63 68 c(60) TRIVIAL 23197647 A 1232 1244 methotrexate TRIVIAL 23197647 A 1246 1249 MTX ABBREVIATION 23197647 A 1325 1334 [(3)H]MTX SYSTEMATIC 23197647 A 1387 1390 MTX ABBREVIATION 23197647 A 1450 1459 etoposide TRIVIAL 23197647 A 1524 1527 MTX ABBREVIATION 23197647 A 933 942 etoposide TRIVIAL 23197647 A 956 961 MK571 IDENTIFIER 23197647 T 102 114 methotrexate TRIVIAL 23197647 T 47 56 Etoposide TRIVIAL 23197773 A 1072 1080 SKF82958 IDENTIFIER 23197773 A 1083 1177 (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride SYSTEMATIC 23197773 A 1179 1187 SCH23390 IDENTIFIER 23197773 A 1190 1261 (6aR)-5,6,6a,7-tetrahydro-6-propyl-4H-dibenzo[de,g]quinoline-10,11-diol SYSTEMATIC 23197773 A 1263 1272 R-(-)-NPA ABBREVIATION 23197773 A 1275 1286 haloperidol TRIVIAL 23197773 A 1300 1308 morphine TRIVIAL 23197773 A 1310 1320 naltrexone TRIVIAL 23197773 A 1539 1544 AM411 IDENTIFIER 23197773 A 1615 1625 naltrexone TRIVIAL 23197773 A 1786 1791 AM411 IDENTIFIER 23197773 A 1793 1807 methanandamide TRIVIAL 23197773 A 1823 1829 AM4054 IDENTIFIER 23197773 A 1831 1842 WIN55,212.2 IDENTIFIER 23197773 A 1844 1852 Δ(9)-THC SYSTEMATIC 23197773 A 1979 1988 SR141716A IDENTIFIER 23197773 A 1993 1999 AM4113 IDENTIFIER 23197773 A 2099 2114 methamphetamine TRIVIAL 23197773 A 2139 2148 R-(-)-NPA ABBREVIATION 23197773 A 2651 2666 methamphetamine TRIVIAL 23197773 A 2671 2680 R-(-)-NPA ABBREVIATION 23197773 A 299 384 (6aR,10aR)-3-(1-adamantyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydrobenzo[c]chromen-1-ol SYSTEMATIC 23197773 A 386 391 AM411 IDENTIFIER 23197773 A 394 448 9β-(hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol SYSTEMATIC 23197773 A 450 456 AM4054 IDENTIFIER 23197773 A 459 580 R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate SYSTEMATIC 23197773 A 582 593 WIN55,212.2 IDENTIFIER 23197773 A 596 621 Δ(9)-tetrahydrocannabinol SYSTEMATIC 23197773 A 623 631 Δ(9)-THC SYSTEMATIC 23197773 A 634 696 (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide (methanandamide) SYSTEMATIC 23197773 A 718 814 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide SYSTEMATIC 23197773 A 816 825 SR141716A IDENTIFIER 23197773 A 828 922 5-(4-alkylphenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide FAMILY 23197773 A 924 930 AM4113 IDENTIFIER 23197773 A 938 946 dopamine TRIVIAL 23197773 A 961 976 methamphetamine TRIVIAL 23197773 A 978 1070 (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide SYSTEMATIC 23198782 A 154 161 sucrose TRIVIAL 23198782 A 215 222 sucrose TRIVIAL 23199199 A 168 176 dithiols FAMILY 23199985 A 394 403 manganese SYSTEMATIC 23199985 A 518 532 Polyacrylamide FAMILY 23199985 A 611 625 polyacrylamide SYSTEMATIC 23199985 A 711 725 polyacrylamide SYSTEMATIC 23199987 A 358 364 amines FAMILY 23199987 A 366 376 putrescine TRIVIAL 23199987 A 378 388 cadaverine TRIVIAL 23199987 A 390 400 spermidine TRIVIAL 23199987 A 402 410 spermine TRIVIAL 23199987 A 412 421 histamine TRIVIAL 23199987 A 423 431 tyramine TRIVIAL 23199987 A 433 443 tryptamine TRIVIAL 23199987 A 448 464 phenylethylamine SYSTEMATIC 23199987 A 483 493 Putrescine TRIVIAL 23199987 A 495 505 cadaverine TRIVIAL 23199987 A 510 518 tyramine TRIVIAL 23199987 A 690 696 amines FAMILY 23199987 A 698 708 Polyamines FAMILY 23199987 A 709 719 spermidine TRIVIAL 23199987 A 724 732 spermine TRIVIAL 23199987 A 840 850 Tryptamine TRIVIAL 23199987 A 852 868 phenylethylamine SYSTEMATIC 23199987 A 873 882 histamine TRIVIAL 23199987 T 46 52 amines FAMILY 23199989 A 372 388 (Z)-3-hexen-1-ol SYSTEMATIC 23199989 A 393 400 hexanol SYSTEMATIC 23199989 A 660 675 2-phenylethanol SYSTEMATIC 23199989 A 677 690 β-damascenone TRIVIAL 23199989 A 692 700 vanillin TRIVIAL 23199989 A 705 742 2,5-dimethyl-4-hydroxy-3(2H)-furanone SYSTEMATIC 23199989 A 744 748 DMHF ABBREVIATION 23199989 A 779 783 DMHF ABBREVIATION 23199996 A 102 103 S FORMULA 23199996 A 105 107 Mg FORMULA 23199996 A 109 111 Ca FORMULA 23199996 A 113 115 Zn FORMULA 23199996 A 117 119 Cu FORMULA 23199996 A 121 123 Fe FORMULA 23199996 A 125 127 Mn FORMULA 23199996 A 133 135 Se FORMULA 23199996 A 162 164 Hg FORMULA 23199996 A 165 169 MeHg FORMULA 23199996 A 171 173 Cd FORMULA 23199996 A 175 177 Pb FORMULA 23199996 A 183 185 As FORMULA 23199996 A 197 203 silver SYSTEMATIC 23199996 A 23 33 fatty acid FAMILY 23199996 A 368 379 cholesterol TRIVIAL 23199996 A 43 54 cholesterol TRIVIAL 23199996 A 434 461 Polyunsaturated fatty acids FAMILY 23199996 A 463 467 PUFA ABBREVIATION 23199996 A 500 511 fatty acids FAMILY 23199996 A 56 67 α-tocoferol TRIVIAL 23199996 A 633 635 Se FORMULA 23199996 A 753 759 silver SYSTEMATIC 23199996 A 810 817 mercury SYSTEMATIC 23199996 A 91 92 K FORMULA 23199996 A 94 96 Na FORMULA 23199996 A 98 100 Cl FORMULA 23199998 A 329 341 acetonitrile SYSTEMATIC 23199998 A 377 388 formic acid SYSTEMATIC 23199998 A 412 415 GCB ABBREVIATION 23199998 A 617 622 Amide SYSTEMATIC 23199998 A 912 915 STX ABBREVIATION 23200254 A 12 60 4-azaindole oxoacetic acid piperazine benzamides FAMILY 23200254 A 214 224 BMS-378806 IDENTIFIER 23200254 A 299 310 4-azaindole SYSTEMATIC 23200254 T 95 106 4-azaindole SYSTEMATIC 23200255 A 0 104 (-)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one SYSTEMATIC 23200255 A 106 114 KCA-1490 IDENTIFIER 23200255 A 234 235 N FORMULA 23200255 A 254 266 pyridazinone SYSTEMATIC 23200255 A 357 394 6-aryl-4,5-dihydropyridazin-3(2H)-one FAMILY 23200255 A 412 413 N FORMULA 23200255 A 531 550 dihydropyridazinone SYSTEMATIC 23200255 A 612 634 4,4-dimethylpyrazolone SYSTEMATIC 23200255 A 657 673 pyrazolopyridine SYSTEMATIC 23200255 A 800 809 histamine TRIVIAL 23200732 A 0 9 Estrogens FAMILY 23200732 A 1259 1268 estrogens FAMILY 23200732 A 1282 1290 estrogen FAMILY 23200732 A 211 219 estrogen FAMILY 23200732 A 267 275 estrogen FAMILY 23200732 A 585 593 estrogen FAMILY 23200732 A 802 809 steroid FAMILY 23200732 T 79 87 estrogen FAMILY 23200735 A 1014 1024 cyclic-AMP TRIVIAL 23200735 A 1090 1100 cyclic-AMP TRIVIAL 23200735 A 1139 1142 ATZ ABBREVIATION 23200735 A 1203 1206 ATZ ABBREVIATION 23200735 A 1307 1317 cyclic-AMP TRIVIAL 23200735 A 251 268 3β-hydroxysteroid FAMILY 23200735 A 33 42 quercetin TRIVIAL 23200735 A 381 389 androgen FAMILY 23200735 A 405 413 estrogen FAMILY 23200735 A 554 557 ATZ ABBREVIATION 23200735 A 634 637 ATZ ABBREVIATION 23200735 A 670 679 quercetin TRIVIAL 23200735 A 80 88 atrazine TRIVIAL 23200735 A 90 93 ATZ ABBREVIATION 23200735 A 935 945 cyclic-AMP TRIVIAL 23200735 T 11 20 quercetin TRIVIAL 23200735 T 114 122 atrazine TRIVIAL 23200888 A 0 8 Thiazole SYSTEMATIC 23200888 A 1201 1209 thiazole SYSTEMATIC 23200888 A 1210 1212 Zn FORMULA 23200888 A 210 218 thiazole SYSTEMATIC 23200888 A 219 221 Zn FORMULA 23200888 A 400 408 thiazole SYSTEMATIC 23200888 A 409 411 Zn FORMULA 23200888 A 709 717 thiazole SYSTEMATIC 23200888 A 718 720 Zn FORMULA 23200888 A 86 97 thiadiazole SYSTEMATIC 23200888 A 9 11 Zn FORMULA 23200888 T 32 40 thiazole SYSTEMATIC 23200888 T 41 43 Zn FORMULA 23200942 A 1122 1127 soman TRIVIAL 23200942 A 1129 1134 tabun TRIVIAL 23200942 A 1167 1172 sarin TRIVIAL 23200942 A 151 156 sarin TRIVIAL 23200942 A 158 163 soman TRIVIAL 23200942 A 165 170 tabun TRIVIAL 23200942 A 841 846 sarin TRIVIAL 23200942 A 848 853 soman TRIVIAL 23200942 A 855 860 tabun TRIVIAL 23200942 A 92 107 organophosphate FAMILY 23200942 T 108 123 organophosphate FAMILY 23200943 A 1037 1062 3-keto and 20-ketosteroid MULTIPLE 23200943 A 1146 1164 20α-hydroxysteroid FAMILY 23200943 A 1530 1542 progesterone TRIVIAL 23200943 A 1601 1613 progesterone TRIVIAL 23200943 A 1845 1857 progesterone TRIVIAL 23200943 A 189 201 progesterone TRIVIAL 23200943 A 1907 1919 progesterone TRIVIAL 23200943 A 231 243 progesterone TRIVIAL 23200943 A 564 576 progesterone TRIVIAL 23200943 A 682 699 3β-hydroxysteroid FAMILY 23200943 A 714 725 ketosteroid FAMILY 23200943 A 998 1010 progesterone TRIVIAL 23200943 T 40 52 progesterone TRIVIAL 23200944 A 19 26 alcohol FAMILY 23200944 A 817 819 Zn FORMULA 23200944 T 37 44 alcohol FAMILY 23201051 A 119 166 stearoyl-PEG-poly-sulfadimethoxine methacrylate FAMILY 23201051 A 1304 1315 fluorescein TRIVIAL 23201051 A 1325 1345 stearoyl-PEG-polySDM ABBREVIATION 23201051 A 1579 1590 fluorescein TRIVIAL 23201051 A 1600 1620 stearoyl-PEG-polySDM ABBREVIATION 23201051 A 1665 1675 paclitaxel TRIVIAL 23201051 A 168 188 stearoyl-PEG-polySDM ABBREVIATION 23201051 A 1683 1703 stearoyl-PEG-polySDM ABBREVIATION 23201051 A 1838 1848 paclitaxel TRIVIAL 23201051 A 282 302 Stearoyl-PEG-polySDM ABBREVIATION 23201051 A 375 404 sulfadimethoxine methacrylate TRIVIAL 23201051 A 440 445 amino FAMILY 23201051 A 463 479 stearoyl-PEG-NH2 FORMULA 23201051 A 515 535 stearoyl-PEG-polySDM ABBREVIATION 23201051 A 573 603 methacryloyl sulfadimethoxines FAMILY 23201051 A 672 692 stearoyl-PEG-polySDM ABBREVIATION 23201051 A 985 993 Brij-700 TRIVIAL 23201092 A 0 32 Gonadotrophin-inhibitory hormone TRIVIAL 23201092 A 1091 1095 GnIH ABBREVIATION 23201092 A 1157 1161 GnIH ABBREVIATION 23201092 A 34 38 GnIH ABBREVIATION 23201092 A 526 530 GnIH ABBREVIATION 23201092 A 728 732 GnIH ABBREVIATION 23201092 A 799 803 GnIH ABBREVIATION 23201092 A 819 823 GnIH ABBREVIATION 23201092 A 893 897 GnIH ABBREVIATION 23201092 A 957 961 GnIH ABBREVIATION 23201092 A 969 973 GnIH ABBREVIATION 23201092 T 59 63 GnIH ABBREVIATION 23201179 A 1012 1015 AVT ABBREVIATION 23201179 A 104 107 AVT ABBREVIATION 23201179 A 1161 1164 AVT ABBREVIATION 23201179 A 137 157 arginine vasopressin TRIVIAL 23201179 A 1519 1522 AVT ABBREVIATION 23201179 A 159 162 AVP ABBREVIATION 23201179 A 1718 1721 AVT ABBREVIATION 23201179 A 1722 1725 AVP ABBREVIATION 23201179 A 182 185 AVT ABBREVIATION 23201179 A 186 189 AVP ABBREVIATION 23201179 A 343 346 AVT ABBREVIATION 23201179 A 347 350 AVP ABBREVIATION 23201179 A 496 499 AVT ABBREVIATION 23201179 A 794 797 AVT ABBREVIATION 23201179 A 84 102 arginine vasotocin TRIVIAL 23201179 T 51 60 vasotocin TRIVIAL 23201180 A 0 10 Fenamiphos TRIVIAL 23201180 A 1086 1096 fenamiphos TRIVIAL 23201180 A 12 63 ethyl 4-methylthio-m-tolyl isopropylphosphoramidate SYSTEMATIC 23201180 A 1298 1314 organophosphorus FAMILY 23201180 A 279 295 organophosphorus FAMILY 23201180 A 364 374 fenamiphos TRIVIAL 23201180 A 435 441 hexane SYSTEMATIC 23201180 A 442 449 ethanol SYSTEMATIC 23201180 A 78 94 organophosphorus FAMILY 23201180 A 878 892 (+)-fenamiphos TRIVIAL 23201180 A 928 942 (-)-fenamiphos TRIVIAL 23201180 A 962 968 Ca(2+) FORMULA 23201180 T 0 10 Fenamiphos TRIVIAL 23201337 A 1013 1021 oxytocin TRIVIAL 23201337 A 1192 1200 oxytocin TRIVIAL 23201337 A 1324 1332 oxytocin TRIVIAL 23201337 A 1482 1490 oxytocin TRIVIAL 23201337 A 158 166 Oxytocin TRIVIAL 23201337 A 17 25 oxytocin TRIVIAL 23201337 A 382 390 oxytocin TRIVIAL 23201337 A 684 692 oxytocin TRIVIAL 23201337 A 792 800 oxytocin TRIVIAL 23201337 A 891 899 oxytocin TRIVIAL 23201337 A 943 951 estrogen FAMILY 23201337 A 953 965 progesterone TRIVIAL 23201337 T 15 23 oxytocin TRIVIAL 23201371 A 1005 1016 Vitamin B12 TRIVIAL 23201371 A 1055 1058 NOR ABBREVIATION 23201371 A 1062 1065 NLX ABBREVIATION 23201371 A 1076 1086 Vitamins B FAMILY 23201371 A 1139 1142 NLX ABBREVIATION 23201371 A 1146 1149 NOR ABBREVIATION 23201371 A 1178 1188 Vitamin B1 TRIVIAL 23201371 A 123 127 MNNG ABBREVIATION 23201371 A 1249 1253 MNNG ABBREVIATION 23201371 A 1257 1261 ENNG ABBREVIATION 23201371 A 130 164 ethyl-N-nitro-N'- nitrosoguanidine SYSTEMATIC 23201371 A 1304 1314 vitamins B FAMILY 23201371 A 166 170 ENNG ABBREVIATION 23201371 A 193 210 2-aminoanthracene SYSTEMATIC 23201371 A 212 215 2AA SYSTEMATIC 23201371 A 221 244 2-acetyl-amino-fluorene SYSTEMATIC 23201371 A 246 249 2AF SYSTEMATIC 23201371 A 282 293 norfloxacin TRIVIAL 23201371 A 295 298 NOR ABBREVIATION 23201371 A 304 318 nalidixic acid TRIVIAL 23201371 A 320 323 NLX ABBREVIATION 23201371 A 36 46 vitamins B FAMILY 23201371 A 439 442 NOR ABBREVIATION 23201371 A 457 460 NLX ABBREVIATION 23201371 A 486 496 Vitamin B1 TRIVIAL 23201371 A 535 539 MNNG ABBREVIATION 23201371 A 552 556 ENNG ABBREVIATION 23201371 A 737 740 NOR ABBREVIATION 23201371 A 744 747 NLX ABBREVIATION 23201371 A 787 805 vitamins B1 and B6 MULTIPLE 23201371 A 854 857 NOR ABBREVIATION 23201371 A 871 874 NLX ABBREVIATION 23201371 A 88 121 methyl-N-nitro-N-nitrosoguanidine SYSTEMATIC 23201371 T 28 51 vitamins B1, B6 and B12 MULTIPLE 23201441 A 1236 1240 OFLX ABBREVIATION 23201441 A 160 169 ofloxacin TRIVIAL 23201441 A 171 175 OFLX ABBREVIATION 23201441 A 224 228 OFLX ABBREVIATION 23201441 A 557 570 prostaglandin FAMILY 23201441 T 80 89 quinolone FAMILY 23201452 A 74 81 ethanol SYSTEMATIC 23201622 A 1263 1266 PEI ABBREVIATION 23201622 A 1278 1281 PEI ABBREVIATION 23201622 A 141 158 Polyethyleneimine FAMILY 23201622 A 160 163 PEI ABBREVIATION 23201622 A 300 303 PEI ABBREVIATION 23201622 T 169 186 polyethyleneimine SYSTEMATIC 23201927 A 1083 1088 Sal B ABBREVIATION 23201927 A 1159 1162 ATO ABBREVIATION 23201927 A 1286 1291 Sal B ABBREVIATION 23201927 A 1352 1355 ATO ABBREVIATION 23201927 A 20 36 arsenic trioxide SYSTEMATIC 23201927 A 272 290 salvianolic acid B TRIVIAL 23201927 A 292 297 Sal B ABBREVIATION 23201927 A 351 356 Sal B ABBREVIATION 23201927 A 374 377 ATO ABBREVIATION 23201927 A 38 41 ATO ABBREVIATION 23201927 A 421 424 MTT ABBREVIATION 23201927 A 505 518 Hoechst 33342 TRIVIAL 23201927 A 546 551 Sal B ABBREVIATION 23201927 A 607 610 ATO ABBREVIATION 23201927 A 769 777 LY294002 IDENTIFIER 23201927 A 826 831 Sal B ABBREVIATION 23201927 A 840 843 ATO ABBREVIATION 23201927 A 933 938 Sal B ABBREVIATION 23201927 T 27 45 salvianolic acid B TRIVIAL 23201927 T 54 70 arsenic trioxide SYSTEMATIC 23202134 A 1101 1103 Pb FORMULA 23202134 A 1253 1256 MDA ABBREVIATION 23202134 A 1328 1341 jasmonic acid TRIVIAL 23202134 A 265 267 Pb FORMULA 23202134 A 380 382 Pb FORMULA 23202134 A 467 469 Pb FORMULA 23202134 A 539 541 Pb FORMULA 23202134 A 589 591 Pb FORMULA 23202134 A 67 69 Pb FORMULA 23202134 A 975 985 superoxide TRIVIAL 23202371 A 186 194 graphene TRIVIAL 23202371 A 206 212 MoS(2) FORMULA 23202371 A 46 54 graphene TRIVIAL 23202371 A 538 544 MoS(2) FORMULA 23202371 A 59 91 transition-metal dichalcogenides FAMILY 23202371 T 34 38 MoS2 FORMULA 23202372 A 1062 1069 lithium SYSTEMATIC 23202372 A 1073 1079 sodium SYSTEMATIC 23202372 A 118 124 oxygen SYSTEMATIC 23202372 A 263 269 oxygen SYSTEMATIC 23202372 A 286 292 oxides FAMILY 23202372 A 403 410 Li-O(2) FORMULA 23202372 A 430 439 carbonate FAMILY 23202372 A 463 472 Li(2)O(2) FORMULA 23202372 A 625 632 Li-O(2) FORMULA 23202372 A 726 733 Na-O(2) FORMULA 23202372 A 869 875 carbon SYSTEMATIC 23202372 A 923 940 sodium superoxide SYSTEMATIC 23202372 A 942 948 NaO(2) FORMULA 23202372 T 32 49 sodium superoxide SYSTEMATIC 23202372 T 51 55 NaO2 FORMULA 23202442 A 106 112 Cu(II) FORMULA 23202442 A 12 17 (13)C FORMULA 23202442 A 533 539 Cu(II) FORMULA 23202442 A 764 769 (13)C FORMULA 23202442 A 983 988 (13)C FORMULA 23202442 T 28 31 13C FORMULA 23202846 A 1021 1024 Cys FORMULA 23202846 A 1202 1205 Cbz ABBREVIATION 23202846 A 1211 1213 CN FORMULA 23202846 A 1480 1487 nitrile SYSTEMATIC 23202846 A 327 334 nitrile SYSTEMATIC 23202846 A 382 383 N FORMULA 23202846 A 666 673 nitrile SYSTEMATIC 23202846 A 764 767 Cbz ABBREVIATION 23202846 A 773 775 CN FORMULA 23202846 A 784 785 N FORMULA 23202846 A 795 809 carbobenzyloxy SYSTEMATIC 23202846 A 941 948 nitrile SYSTEMATIC 23202846 T 51 58 nitrile SYSTEMATIC 23202847 A 111 117 sodium SYSTEMATIC 23202847 A 14 22 chalcone FAMILY 23202847 A 170 187 chalcone sulfides FAMILY 23202847 A 193 199 m-CPBA ABBREVIATION 23202847 A 232 240 sulfones FAMILY 23202847 A 245 255 bisulfones FAMILY 23202847 A 29 36 sulfone SYSTEMATIC 23202847 A 41 50 bisulfone SYSTEMATIC 23202847 A 645 659 Amphotericin-B TRIVIAL 23202847 A 664 672 Nystatin TRIVIAL 23202847 A 86 94 chalcone FAMILY 23202847 A 880 890 Ampicillin TRIVIAL 23202847 A 895 904 Kanamycin TRIVIAL 23202847 A 96 106 thiophenol SYSTEMATIC 23202847 T 62 70 chalcone FAMILY 23202847 T 77 85 sulfones FAMILY 23202847 T 90 100 bisulfones FAMILY 23202848 A 12 72 (E)-5-alkoxy-3-(3-phenyl-3-oxoprop-1-enyl)-4H-chromen-4-ones FAMILY 23202848 A 217 226 Propenone SYSTEMATIC 23202848 A 299 309 isoflavone FAMILY 23202848 A 316 324 chalcone FAMILY 23202848 A 674 682 hydroxyl SYSTEMATIC 23202848 A 692 707 allylic alcohol SYSTEMATIC 23202848 A 796 802 phenyl SYSTEMATIC 23202848 A 81 145 (E)-5-alkoxy-3-(3-hydroxy-3-phenylprop-1-enyl)-4H-chromen-4-ones FAMILY 23202848 A 882 890 hydrogen SYSTEMATIC 23202848 A 911 919 hydroxyl SYSTEMATIC 23202848 A 929 944 allylic alcohol SYSTEMATIC 23202848 T 24 34 chromenone TRIVIAL 23202851 A 12 51 9-O-(3-aryl-2-propargyl)oxime ketolides FAMILY 23202851 A 268 282 clarithromycin TRIVIAL 23202851 A 287 299 azithromycin TRIVIAL 23202851 A 320 333 4-isoquinolyl SYSTEMATIC 23202851 A 471 482 methicillin TRIVIAL 23202851 A 519 530 methicillin TRIVIAL 23202851 A 586 592 propyl SYSTEMATIC 23202851 A 666 674 propynyl SYSTEMATIC 23202851 A 679 687 propenyl SYSTEMATIC 23202851 T 49 117 14-membered 9-O-(3-arylalkyl) oxime 11,12-cyclic carbonate ketolides FAMILY 23202852 A 1019 1111 (E)-2-methyl-N'-(4-phenyl-3-furoxanylmethylidene)-4H-imidazo[1,2-a]pyridine-3-carbohydrazide SYSTEMATIC 23202852 A 1235 1308 (E)-N'-(5-benzofuroxanylmethylidene)benzo[d][1,3]dioxole-5-carbohydrazide SYSTEMATIC 23202852 A 1316 1394 (E)-N'-(4-hydroxy-3-methoxyphenylmethylidene)-3-methylfuroxan-4-carbohydrazide SYSTEMATIC 23202852 A 228 243 N-Acylhydrazone SYSTEMATIC 23202852 A 381 388 furoxan TRIVIAL 23202852 A 530 556 furoxanyl N-acylhydrazones FAMILY 23202852 A 817 863 N'-(4-phenyl-3-furoxanylmethylidene)isoniazide SYSTEMATIC 23202852 A 963 972 isoniazid TRIVIAL 23202852 A 993 1018 Furoxanyl N-acylhydrazone SYSTEMATIC 23202852 T 7 32 furoxanyl N-acylhydrazone SYSTEMATIC 23202986 A 18 25 (1)H(N) FORMULA 23202986 A 357 365 hydrogen SYSTEMATIC 23202986 A 502 510 hydrogen SYSTEMATIC 23202986 A 601 608 (1)H(N) FORMULA 23202986 A 708 716 hydrogen SYSTEMATIC 23202986 A 787 795 hydrogen SYSTEMATIC 23202986 T 103 106 O=C FORMULA 23202986 T 107 115 hydrogen SYSTEMATIC 23202986 T 18 23 ¹H(N) FORMULA 23202986 T 97 100 N-H FORMULA 23203941 A 140 153 vitamin B(12) TRIVIAL 23203941 A 319 332 vitamin B(12) TRIVIAL 23203941 T 52 65 vitamin-B(12) TRIVIAL 23204111 A 1020 1024 TCDD ABBREVIATION 23204111 A 1070 1074 TCDD ABBREVIATION 23204111 A 1082 1098 aryl hydrocarbon FAMILY 23204111 A 1179 1183 TCDD ABBREVIATION 23204111 A 132 167 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23204111 A 1337 1341 TCDD ABBREVIATION 23204111 A 1548 1552 TCDD ABBREVIATION 23204111 A 1678 1682 TCDD ABBREVIATION 23204111 A 169 173 TCDD ABBREVIATION 23204111 A 277 281 TCDD ABBREVIATION 23204111 A 459 463 TCDD ABBREVIATION 23204111 A 721 725 TCDD ABBREVIATION 23204111 A 761 765 TCDD ABBREVIATION 23204111 T 0 4 TCDD ABBREVIATION 23204517 A 1127 1133 Ca(2+) FORMULA 23204517 A 129 135 Ca(2+) FORMULA 23204517 A 241 247 Ca(2+) FORMULA 23204517 A 285 291 Ca(2+) FORMULA 23204517 A 333 339 Ca(2+) FORMULA 23204517 A 385 391 Ca(2+) FORMULA 23204517 A 473 479 Ca(2+) FORMULA 23204517 A 551 557 Ca(2+) FORMULA 23204517 A 630 633 ATP ABBREVIATION 23204517 A 642 648 Ca(2+) FORMULA 23204517 A 739 742 ATP ABBREVIATION 23204517 A 774 780 Ca(2+) FORMULA 23204517 A 881 887 Ca(2+) FORMULA 23204517 A 933 936 ATP ABBREVIATION 23204517 A 945 951 Ca(2+) FORMULA 23204517 T 53 56 ATP ABBREVIATION 23204517 T 65 69 Ca2+ FORMULA 23205514 A 1000 1020 9-hydroxyrisperidone SYSTEMATIC 23205514 A 1358 1369 risperidone TRIVIAL 23205514 A 1374 1394 9-hydroxyrisperidone SYSTEMATIC 23205514 A 365 376 risperidone TRIVIAL 23205514 A 404 424 9-hydroxyrisperidone SYSTEMATIC 23205514 A 472 483 risperidone TRIVIAL 23205514 A 488 508 9-hydroxyrisperidone SYSTEMATIC 23205514 A 595 606 risperidone TRIVIAL 23205514 A 693 713 9-hydroxyrisperidone SYSTEMATIC 23205514 A 957 968 risperidone TRIVIAL 23205514 A 984 995 risperidone TRIVIAL 23205514 T 116 136 9-hydroxyrisperidone SYSTEMATIC 23205514 T 78 89 risperidone TRIVIAL 23205567 A 387 399 Nitric Oxide SYSTEMATIC 23205584 A 139 157 perfluoropolyether FAMILY 23205584 T 6 24 perfluoropolyether FAMILY 23205634 A 1130 1141 cholesterol TRIVIAL 23205634 A 1146 1156 bile acids FAMILY 23205634 A 701 712 cholesterol TRIVIAL 23205634 A 748 758 bile acids FAMILY 23205634 A 861 872 cholesterol TRIVIAL 23205634 A 924 935 cholesterol TRIVIAL 23205634 A 951 961 Bile acids FAMILY 23205634 T 34 45 cholesterol TRIVIAL 23205634 T 50 60 bile acids FAMILY 23205668 A 27 30 InP FORMULA 23205668 A 288 296 wurtzite TRIVIAL 23205668 A 297 308 zinc-blende SYSTEMATIC 23205668 A 371 377 indium SYSTEMATIC 23205668 T 46 49 InP FORMULA 23205727 A 47 71 Pb(Zr(0.52)Ti(0.48))O(3) FORMULA 23205727 A 73 76 PZT ABBREVIATION 23205740 A 1058 1063 sarin TRIVIAL 23205740 A 1186 1195 potassium SYSTEMATIC 23205740 A 1219 1226 calcium SYSTEMATIC 23205740 A 1228 1233 sarin TRIVIAL 23205740 A 1321 1326 sarin TRIVIAL 23205740 A 1359 1364 sarin TRIVIAL 23205740 A 1408 1434 dimethyl methylphosphonate SYSTEMATIC 23205740 A 287 292 sarin TRIVIAL 23205740 A 366 371 sarin TRIVIAL 23205740 A 470 476 Nafion TRIVIAL 23205740 A 478 500 sulfonated polystyrene FAMILY 23205740 A 502 505 sPS ABBREVIATION 23205740 A 557 560 sPS ABBREVIATION 23205740 A 561 571 polyolefin FAMILY 23205740 A 601 604 sPS ABBREVIATION 23205740 A 605 617 polyethylene SYSTEMATIC 23205740 A 643 648 sarin TRIVIAL 23205740 A 732 747 hydrated Nafion FAMILY 23205740 A 775 787 hydrated sPS ABBREVIATION 23205740 A 860 865 sarin TRIVIAL 23205740 A 965 970 sarin TRIVIAL 23205740 T 16 21 sarin TRIVIAL 23206276 A 1003 1006 RdB ABBREVIATION 23206276 A 1087 1090 RdB ABBREVIATION 23206276 A 1131 1133 Ag FORMULA 23206276 A 1137 1139 Au FORMULA 23206276 A 1238 1241 RdB ABBREVIATION 23206276 A 1267 1276 Fe(3)O(4) FORMULA 23206276 A 1277 1279 Ag FORMULA 23206276 A 1294 1297 RdB ABBREVIATION 23206276 A 305 307 Au FORMULA 23206276 A 497 499 Ag FORMULA 23206276 A 652 661 Fe(3)O(4) FORMULA 23206276 A 662 664 Ag FORMULA 23206276 A 665 671 SiO(2) FORMULA 23206276 A 672 674 Au FORMULA 23206276 A 743 745 Ag FORMULA 23206276 A 749 751 Au FORMULA 23206276 A 883 892 Fe(3)O(4) FORMULA 23206276 A 893 895 Ag FORMULA 23206276 A 896 902 SiO(2) FORMULA 23206276 A 903 905 Au FORMULA 23206276 A 990 1001 Rhodamine-b TRIVIAL 23206276 T 16 21 Fe3O4 FORMULA 23206276 T 22 24 Ag FORMULA 23206276 T 25 29 SiO2 FORMULA 23206276 T 30 32 Au FORMULA 23206310 A 421 436 corticosteroids FAMILY 23206310 A 443 460 mycophenolic acid TRIVIAL 23206865 A 113 126 naphthalimide FAMILY 23206865 A 163 177 naphthalimides FAMILY 23206865 A 189 198 propargyl SYSTEMATIC 23206865 A 434 439 imide SYSTEMATIC 23206865 A 555 568 naphthalimide FAMILY 23206865 A 682 695 naphthalimide FAMILY 23206865 A 796 805 propargyl SYSTEMATIC 23206865 A 824 838 naphthalimides FAMILY 23206865 T 34 48 naphthalimides FAMILY 23206867 A 18 28 benzamides FAMILY 23206867 T 44 54 benzamides FAMILY 23207055 A 1077 1080 DMP ABBREVIATION 23207055 A 1093 1127 hydroxylated monomethyl phthalates FAMILY 23207055 A 1132 1158 hydroxylated phthalic acid TRIVIAL 23207055 A 259 262 DMP ABBREVIATION 23207055 A 310 327 hydrogen peroxide SYSTEMATIC 23207055 A 405 408 DMP ABBREVIATION 23207055 A 532 535 DMP ABBREVIATION 23207055 A 57 75 dimethyl phthalate SYSTEMATIC 23207055 A 725 742 hydrogen peroxide SYSTEMATIC 23207055 A 77 80 DMP ABBREVIATION 23207055 A 921 924 DMP ABBREVIATION 23207055 T 41 59 dimethyl phthalate SYSTEMATIC 23207056 A 121 129 hydroxyl SYSTEMATIC 23207056 A 162 176 salicylic acid TRIVIAL 23207056 A 538 552 salicylic acid TRIVIAL 23207056 A 678 686 hydroxyl SYSTEMATIC 23207056 A 852 873 dihydroxybenzoic acid SYSTEMATIC 23207056 A 881 885 DHBA ABBREVIATION 23207056 T 119 133 salicylic acid TRIVIAL 23207056 T 14 22 hydroxyl SYSTEMATIC 23207323 A 1200 1211 apomorphine TRIVIAL 23207323 A 200 211 apomorphine TRIVIAL 23207323 A 232 243 apomorphine TRIVIAL 23207323 A 531 542 apomorphine TRIVIAL 23207323 A 690 701 apomorphine TRIVIAL 23207323 T 54 65 apomorphine TRIVIAL 23207409 A 1523 1532 coumarins FAMILY 23207409 A 666 675 chromones FAMILY 23207409 A 677 686 coumarins FAMILY 23207409 A 688 697 chalcones FAMILY 23207409 A 699 718 thiazolylhydrazones FAMILY 23207679 A 175 194 triterpene saponins FAMILY 23207679 A 216 232 lignan glycoside FAMILY 23207679 A 315 323 saponins FAMILY 23207679 A 387 398 epicatechin TRIVIAL 23207679 T 0 19 Triterpene saponins FAMILY 23208411 A 107 121 graphene oxide SYSTEMATIC 23208411 T 86 94 graphene TRIVIAL 23208787 A 177 183 (19) F FORMULA 23208787 A 205 211 (18) F FORMULA 23208822 A 113 126 tartaric acid TRIVIAL 23208822 A 191 209 bis(dimethylamide) SYSTEMATIC 23208822 A 218 231 tartaric acid TRIVIAL 23208822 A 23 52 polyhydroxy caprolactam amide SYSTEMATIC 23208822 A 233 245 Zn(BH(4))(2) FORMULA 23208822 A 70 81 bengamide E TRIVIAL 23208822 T 35 50 (-)-bengamide E TRIVIAL 23208955 A 622 628 silica TRIVIAL 23208955 A 727 737 nucleotide FAMILY 23208955 A 774 777 GDP ABBREVIATION 23208955 A 783 786 GTP ABBREVIATION 23208955 A 925 935 nucleotide FAMILY 23209285 A 359 362 Arg FORMULA 23210482 A 514 526 fusicoccin A TRIVIAL 23210639 A 115 122 PNIPAAm ABBREVIATION 23210639 A 135 161 poly-N-isopropylacrylamide SYSTEMATIC 23210639 A 401 408 PNIMAAm ABBREVIATION 23210639 A 793 800 PNIPAAm ABBREVIATION 23210639 A 819 826 PNIPAAm ABBREVIATION 23210639 A 886 893 PNIPAAm ABBREVIATION 23210639 T 39 46 PNIPAAm ABBREVIATION 23210742 A 1211 1215 OHAC ABBREVIATION 23210742 A 1216 1225 trans-ACA TRIVIAL 23210742 A 1378 1382 OHAC ABBREVIATION 23210742 A 1387 1394 cis-ACA TRIVIAL 23210742 A 1636 1645 trans-ACA TRIVIAL 23210742 A 1650 1657 cis-ACA TRIVIAL 23210742 A 1673 1677 (1)H FORMULA 23210742 A 442 491 oleyl bis(2-hydroxyethyl)methyl ammonium chloride SYSTEMATIC 23210742 A 493 497 OHAC ABBREVIATION 23210742 A 515 521 sodium SYSTEMATIC 23210742 A 530 554 4-phenylazo benzoic acid SYSTEMATIC 23210742 A 556 559 ACA ABBREVIATION 23210742 A 579 582 ACA ABBREVIATION 23210742 A 619 623 OHAC ABBREVIATION 23210742 A 624 627 ACA ABBREVIATION 23210742 A 797 806 trans-ACA TRIVIAL 23210742 A 823 830 cis-ACA TRIVIAL 23210774 A 234 237 ATP ABBREVIATION 23210774 A 288 295 CX-4945 IDENTIFIER 23210774 A 502 505 ATP ABBREVIATION 23210774 A 529 532 ATP ABBREVIATION 23210777 A 0 5 Taxol TRIVIAL 23210777 A 1006 1022 methyl jasmonate SYSTEMATIC 23210777 A 1146 1152 taxane FAMILY 23210777 A 1304 1310 taxane FAMILY 23210777 A 1520 1526 taxane FAMILY 23210777 A 1611 1621 paclitaxel TRIVIAL 23210777 A 272 279 Taxanes FAMILY 23210777 A 474 481 taxanes FAMILY 23210777 A 7 17 paclitaxel TRIVIAL 23210777 A 803 813 paclitaxel TRIVIAL 23210777 A 932 939 taxanes FAMILY 23210777 T 107 117 paclitaxel TRIVIAL 23210780 A 0 25 Pentacyclic triterpenoids FAMILY 23210780 A 379 404 pentacyclic triterpenoids FAMILY 23210780 A 40 48 oleanane TRIVIAL 23210780 A 414 428 oleanolic acid TRIVIAL 23210780 A 430 442 glycyrrhizin TRIVIAL 23210780 A 444 463 glycyrrhetinic acid TRIVIAL 23210780 A 465 477 ursolic acid TRIVIAL 23210780 A 479 486 betulin TRIVIAL 23210780 A 488 502 betulinic acid TRIVIAL 23210780 A 50 56 ursane TRIVIAL 23210780 A 507 513 lupeol TRIVIAL 23210780 A 581 588 glucose TRIVIAL 23210780 A 601 608 glucose TRIVIAL 23210780 A 61 67 lupane TRIVIAL 23210780 A 719 742 pentacyclic triterpenes FAMILY 23210780 T 4 29 pentacyclic triterpenoids FAMILY 23210786 A 1145 1156 resveratrol TRIVIAL 23210786 A 1161 1173 thymoquinone TRIVIAL 23210786 A 1262 1277 cinnamtannin B1 TRIVIAL 23210786 A 1282 1288 crocin TRIVIAL 23210852 A 345 360 cyclohexylidene SYSTEMATIC 23210852 A 61 83 dicaffeoylquinic acids FAMILY 23210852 A 614 624 digalloyls FAMILY 23210852 A 85 90 DCQAs FAMILY 23210852 T 45 76 dicaffeoyl and digalloyl esters MULTIPLE 23210852 T 80 91 quinic acid TRIVIAL 23210854 A 518 524 methyl SYSTEMATIC 23210854 A 547 553 lysine TRIVIAL 23211363 A 0 8 Dopamine TRIVIAL 23211363 A 1022 1025 ARI ABBREVIATION 23211363 A 1030 1034 ETIC ABBREVIATION 23211363 A 1063 1070 cocaine TRIVIAL 23211363 A 1087 1094 (-)-NPA ABBREVIATION 23211363 A 1126 1133 cocaine TRIVIAL 23211363 A 1144 1151 cocaine TRIVIAL 23211363 A 1301 1304 ARI ABBREVIATION 23211363 A 1314 1321 (-)-NPA ABBREVIATION 23211363 A 1333 1340 cocaine TRIVIAL 23211363 A 1377 1384 (-)-NPA ABBREVIATION 23211363 A 1394 1397 ARI ABBREVIATION 23211363 A 1463 1470 cocaine TRIVIAL 23211363 A 1491 1494 ARI ABBREVIATION 23211363 A 1745 1752 cocaine TRIVIAL 23211363 A 1844 1851 cocaine TRIVIAL 23211363 A 281 288 cocaine TRIVIAL 23211363 A 516 541 R(-)-norpropylapomorphine TRIVIAL 23211363 A 543 550 (-)-NPA ABBREVIATION 23211363 A 574 586 aripiprazole TRIVIAL 23211363 A 588 591 ARI ABBREVIATION 23211363 A 609 620 eticlopride TRIVIAL 23211363 A 622 626 ETIC ABBREVIATION 23211363 A 684 691 cocaine TRIVIAL 23211363 A 705 712 cocaine TRIVIAL 23211363 A 741 748 cocaine TRIVIAL 23211363 A 80 87 cocaine TRIVIAL 23211363 A 853 860 (-)-NPA ABBREVIATION 23211363 A 919 922 ARI ABBREVIATION 23211363 A 936 939 ARI ABBREVIATION 23211363 A 944 951 (-)-NPA ABBREVIATION 23211363 A 969 976 cocaine TRIVIAL 23211363 T 11 19 dopamine TRIVIAL 23211363 T 51 58 cocaine TRIVIAL 23211441 A 264 274 quercitrin TRIVIAL 23211441 A 285 292 afzelin TRIVIAL 23211441 A 308 332 tert-butyl hydroperoxide SYSTEMATIC 23211441 A 334 339 t-BHP ABBREVIATION 23211441 A 543 548 t-BHP ABBREVIATION 23211441 A 611 618 alanine TRIVIAL 23211441 A 623 632 aspartate TRIVIAL 23211441 A 665 676 glutathione TRIVIAL 23211441 A 915 920 t-BHP ABBREVIATION 23211441 T 74 98 tert-butyl hydroperoxide SYSTEMATIC 23211707 A 0 8 Estrogen FAMILY 23211707 A 151 160 estrogens FAMILY 23211707 A 344 351 steroid FAMILY 23211707 A 568 589 propyl pyrazole triol SYSTEMATIC 23211707 A 717 726 estrogens FAMILY 23211707 A 920 928 estrogen FAMILY 23211707 T 0 7 Steroid FAMILY 23212047 A 1186 1189 ADP ABBREVIATION 23212047 A 1282 1285 ADP ABBREVIATION 23212047 A 1368 1378 nucleoside FAMILY 23212047 A 154 157 ADP ABBREVIATION 23212047 A 223 226 ADP ABBREVIATION 23212047 A 312 321 guanosine TRIVIAL 23212047 A 326 332 NAD(+) ABBREVIATION 23212047 A 369 400 N(2)-(ADP-ribos-1-yl)-guanosine SYSTEMATIC 23212047 A 402 410 (ar2)Guo ABBREVIATION 23212047 A 471 474 ADP ABBREVIATION 23212047 A 486 500 deoxyguanosine SYSTEMATIC 23212047 A 502 505 GMP ABBREVIATION 23212047 A 507 511 dGMP ABBREVIATION 23212047 A 513 516 GTP ABBREVIATION 23212047 A 518 522 dGTP ABBREVIATION 23212047 A 528 538 cyclic GMP TRIVIAL 23212047 A 622 625 ADP ABBREVIATION 23212047 A 739 742 ADP ABBREVIATION 23212047 A 891 894 ADP ABBREVIATION 23212047 A 911 920 guanosine TRIVIAL 23212047 A 925 948 guanine mononucleotides FAMILY 23212047 A 985 988 ADP ABBREVIATION 23212047 T 0 3 ADP ABBREVIATION 23212047 T 20 29 guanosine TRIVIAL 23212107 A 0 9 Vitamin K FAMILY 23212107 A 229 239 dabigatran TRIVIAL 23212107 A 241 252 rivaroxaban TRIVIAL 23212107 A 258 266 apixaban TRIVIAL 23212107 A 447 455 warfarin TRIVIAL 23212107 A 521 529 warfarin TRIVIAL 23212238 A 103 105 NO FORMULA 23212238 A 546 554 hydrogen SYSTEMATIC 23212238 A 61 68 CH(2)XO FAMILY 23212238 A 74 75 F FORMULA 23212238 A 77 79 Cl FORMULA 23212238 A 81 83 Br FORMULA 23212238 T 37 42 CH2XO FAMILY 23212238 T 48 49 F FORMULA 23212238 T 51 53 Cl FORMULA 23212238 T 55 57 Br FORMULA 23212238 T 77 79 NO FORMULA 23212912 A 792 795 Val ABBREVIATION 23212963 A 0 6 Carbon SYSTEMATIC 23212963 A 1117 1120 SDS ABBREVIATION 23212963 A 1178 1181 SDS ABBREVIATION 23212963 A 1462 1468 carbon SYSTEMATIC 23212963 A 1519 1525 carbon SYSTEMATIC 23212963 A 304 316 phenanthrene SYSTEMATIC 23212963 A 318 328 2-naphthol SYSTEMATIC 23212963 A 334 349 1-naphthylamine SYSTEMATIC 23212963 A 429 435 carbon SYSTEMATIC 23212963 A 507 529 sodium dodecyl sulfate SYSTEMATIC 23212963 A 531 534 SDS ABBREVIATION 23212963 A 852 862 Lewis acid FAMILY 23212963 A 934 937 SDS ABBREVIATION 23212963 A 950 953 SDS ABBREVIATION 23212963 T 14 26 phenanthrene SYSTEMATIC 23212963 T 28 38 2-naphthol SYSTEMATIC 23212963 T 44 59 1-naphthylamine SYSTEMATIC 23212963 T 94 100 carbon SYSTEMATIC 23212976 A 150 183 polychlorinated dibenzo-p-dioxins FAMILY 23212976 A 1542 1549 dioxins FAMILY 23212976 A 1554 1558 PCBs ABBREVIATION 23212976 A 188 213 polychlorinated biphenyls FAMILY 23212976 A 215 219 PCBs ABBREVIATION 23212976 A 380 394 organochlorine FAMILY 23213044 A 101 123 reduced graphene oxide SYSTEMATIC 23213044 A 125 128 RGO ABBREVIATION 23213044 A 330 333 RGO ABBREVIATION 23213044 T 0 22 Reduced graphene oxide SYSTEMATIC 23213199 A 0 13 17β-Estradiol SYSTEMATIC 23213199 A 1011 1021 superoxide TRIVIAL 23213199 A 193 201 H(2)O(2) FORMULA 23213199 A 271 279 estrogen FAMILY 23213199 A 489 496 calcein TRIVIAL 23213199 A 497 515 acetoxymethylester SYSTEMATIC 23213199 A 516 522 cobalt SYSTEMATIC 23213199 A 637 645 H(2)O(2) FORMULA 23213199 A 738 746 H(2)O(2) FORMULA 23213199 A 825 832 steroid FAMILY 23213199 T 0 9 Estradiol TRIVIAL 23214973 A 1138 1149 alkynyl PVA FAMILY 23214973 A 119 130 sialic acid TRIVIAL 23214973 A 15 40 alkynyl polyvinyl alcohol FAMILY 23214973 A 341 344 PVA ABBREVIATION 23214973 A 572 575 PVA ABBREVIATION 23214973 A 64 67 PVA ABBREVIATION 23214973 A 928 933 azide SYSTEMATIC 23214973 A 960 971 alkynyl PVA FAMILY 23214973 T 30 37 alkynyl FAMILY 23215039 A 24 32 cysteine TRIVIAL 23215051 A 116 124 fluorine SYSTEMATIC 23215051 A 148 152 ZnSe FORMULA 23215051 A 153 159 ZnMgSe FORMULA 23215051 T 53 61 fluorine SYSTEMATIC 23215051 T 73 77 ZnSe FORMULA 23216107 A 1155 1163 phenolic FAMILY 23216107 A 152 164 carbohydrate FAMILY 23216107 A 926 931 (•)OH FORMULA 23216107 A 954 960 Fe(2+) FORMULA 23216107 A 998 1004 Fe(2+) FORMULA 23218401 A 230 241 polyphenols FAMILY 23218401 A 252 267 dihydrochalcone SYSTEMATIC 23218401 A 269 279 aspalathin TRIVIAL 23218401 A 450 457 glucose TRIVIAL 23218401 A 659 669 aspalathin TRIVIAL 23218401 A 747 757 superoxide TRIVIAL 23218401 A 783 790 juglone TRIVIAL 23218401 A 797 807 aspalathin TRIVIAL 23218401 A 928 938 aspalathin TRIVIAL 23218401 T 23 33 aspalathin TRIVIAL 23218718 A 18 30 monocarbonyl SYSTEMATIC 23218718 A 298 309 doxorubicin TRIVIAL 23218718 A 44 52 curcumin TRIVIAL 23218718 T 64 76 monocarbonyl SYSTEMATIC 23218718 T 90 98 curcumin TRIVIAL 23219324 A 0 12 Metachromins FAMILY 23219324 A 115 131 metachromins L-Q MULTIPLE 23219324 A 139 163 sesquiterpenoid quinones FAMILY 23219324 A 172 182 amino acid FAMILY 23219324 A 239 251 metachromins FAMILY 23219324 A 287 295 tyrosine TRIVIAL 23219324 A 29 53 sesquiterpenoid quinones FAMILY 23219324 A 426 442 metachromins L-Q MULTIPLE 23219324 T 22 38 metachromins L-Q MULTIPLE 23219324 T 80 88 tyrosine TRIVIAL 23219338 A 1037 1044 glucose TRIVIAL 23219338 A 390 404 streptozotocin TRIVIAL 23219338 A 556 563 glucose TRIVIAL 23219338 A 860 867 glucose TRIVIAL 23219338 A 881 893 triglyceride FAMILY 23219338 T 83 97 streptozotocin TRIVIAL 23219593 A 494 512 4-tert-octylphenol SYSTEMATIC 23219593 A 713 716 MTT ABBREVIATION 23219593 A 91 98 steroid FAMILY 23219593 T 0 18 4-tert-Octylphenol SYSTEMATIC 23219593 T 142 150 estrogen FAMILY 23219683 A 1087 1089 Fe FORMULA 23219683 A 1164 1166 Pb FORMULA 23219683 A 1204 1206 Pb FORMULA 23219683 A 1215 1217 Fe FORMULA 23219683 A 170 172 Pb FORMULA 23219683 A 186 188 Fe FORMULA 23219683 A 239 241 Fe FORMULA 23219683 A 27 29 Pb FORMULA 23219683 A 333 335 Pb FORMULA 23219683 A 349 351 Fe FORMULA 23219683 A 35 39 iron SYSTEMATIC 23219683 A 41 43 Fe FORMULA 23219683 A 480 482 Pb FORMULA 23219683 A 539 541 Fe FORMULA 23219683 A 782 784 Pb FORMULA 23219683 A 808 810 Fe FORMULA 23219683 A 982 984 Pb FORMULA 23219702 A 134 148 (+)-sattabacin TRIVIAL 23219702 A 309 323 (+)-sattabacin TRIVIAL 23219702 A 46 60 (+)-sattabacin TRIVIAL 23219702 A 528 538 sattabacin TRIVIAL 23219702 A 590 604 (+)-sattabacin TRIVIAL 23219702 T 22 36 (+)-sattabacin TRIVIAL 23219925 A 0 10 Kynurenine TRIVIAL 23219925 A 111 121 tryptophan TRIVIAL 23219925 A 1178 1188 tryptophan TRIVIAL 23219925 A 1337 1356 3-hydroxykynurenine SYSTEMATIC 23219925 A 519 538 3-Hydroxykynurenine SYSTEMATIC 23219925 A 819 838 3-hydroxykynurenine SYSTEMATIC 23219925 T 0 19 3-Hydroxykynurenine SYSTEMATIC 23219934 A 0 8 N-formyl SYSTEMATIC 23219934 A 405 423 ureidopropanamides FAMILY 23219934 A 465 473 PD168368 IDENTIFIER 23219934 A 474 482 PD176252 IDENTIFIER 23219934 A 601 648 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones FAMILY 23219934 A 746 763 ureidopropanamide SYSTEMATIC 23219934 A 816 822 Ca(2+) FORMULA 23219934 T 0 56 3-(1H-indol-3-yl)-2-[3-(4-nitrophenyl)ureido]propanamide SYSTEMATIC 23219934 T 80 86 formyl SYSTEMATIC 23220035 A 0 6 Esters FAMILY 23220035 A 10 23 phthalic acid TRIVIAL 23220035 A 1029 1045 aryl hydrocarbon FAMILY 23220035 A 1092 1102 phthalates FAMILY 23220035 A 1116 1120 DEHP ABBREVIATION 23220035 A 1121 1124 DEP ABBREVIATION 23220035 A 1125 1128 BBP ABBREVIATION 23220035 A 1129 1132 DBP ABBREVIATION 23220035 A 1238 1248 phthalates FAMILY 23220035 A 1257 1266 phthalate FAMILY 23220035 A 1322 1332 phthalates FAMILY 23220035 A 390 417 di-(2-ethy hexyl) phthalate SYSTEMATIC 23220035 A 419 423 DEHP ABBREVIATION 23220035 A 426 443 diethyl phthalate SYSTEMATIC 23220035 A 445 448 DEP ABBREVIATION 23220035 A 451 468 dibutyl phthalate SYSTEMATIC 23220035 A 470 473 DBP ABBREVIATION 23220035 A 479 501 benzyl butyl phthalate SYSTEMATIC 23220035 A 503 506 BBP ABBREVIATION 23220035 A 628 632 DEHP ABBREVIATION 23220035 A 637 640 DEP ABBREVIATION 23220035 A 673 676 DBP ABBREVIATION 23220035 A 681 684 BBP ABBREVIATION 23220035 A 733 737 DEHP ABBREVIATION 23220035 A 742 745 DEP ABBREVIATION 23220035 A 760 769 estradiol TRIVIAL 23220035 A 854 861 steroid FAMILY 23220035 A 948 956 estrogen FAMILY 23220035 A 976 986 phthalates FAMILY 23220035 T 21 31 phthalates FAMILY 23220037 A 1009 1021 [³H]-choline FAMILY 23220037 A 1045 1048 DOX ABBREVIATION 23220037 A 1358 1361 DOX ABBREVIATION 23220037 A 1393 1400 choline FAMILY 23220037 A 1493 1496 DOX ABBREVIATION 23220037 A 1592 1599 choline FAMILY 23220037 A 317 325 paraquat TRIVIAL 23220037 A 551 562 doxorubicin TRIVIAL 23220037 A 564 567 DOX ABBREVIATION 23220037 A 57 60 ATP ABBREVIATION 23220037 A 781 784 MTT ABBREVIATION 23220037 A 912 915 DOX ABBREVIATION 23220037 A 937 944 choline FAMILY 23220037 T 0 11 Doxorubicin TRIVIAL 23220037 T 22 30 paraquat TRIVIAL 23220041 A 1048 1080 Capreomycin oleate and linoleate MULTIPLE 23220041 A 1109 1128 capreomycin sulfate SYSTEMATIC 23220041 A 1160 1182 capreomycin linolenate TRIVIAL 23220041 A 1356 1374 capreomycin oleate TRIVIAL 23220041 A 1447 1465 capreomycin oleate TRIVIAL 23220041 A 173 184 capreomycin TRIVIAL 23220041 A 434 445 Capreomycin TRIVIAL 23220041 A 498 504 oleate TRIVIAL 23220041 A 506 515 linoleate TRIVIAL 23220041 A 521 531 linolenate TRIVIAL 23220041 A 731 749 capreomycin oleate TRIVIAL 23220041 A 859 895 capreomycin linoleate and linolenate MULTIPLE 23220041 T 0 11 Capreomycin TRIVIAL 23220145 A 395 405 superoxide TRIVIAL 23220145 A 474 482 phenolic FAMILY 23220145 A 586 592 phenol SYSTEMATIC 23220145 A 623 635 pyrocatechol TRIVIAL 23220145 A 64 71 acetone SYSTEMATIC 23220145 A 806 819 physodic acid TRIVIAL 23220145 A 933 936 MTT ABBREVIATION 23220290 A 1045 1048 SDC ABBREVIATION 23220290 A 1305 1315 bile salts FAMILY 23220290 A 208 211 MTT ABBREVIATION 23220290 A 359 363 FITC ABBREVIATION 23220290 A 584 603 sodium deoxycholate SYSTEMATIC 23220290 A 59 68 bile salt FAMILY 23220290 A 605 608 SDC ABBREVIATION 23220290 A 692 695 SDC ABBREVIATION 23220290 A 735 738 SDC ABBREVIATION 23220290 T 58 68 bile salts FAMILY 23220340 A 197 210 l-polylactide FAMILY 23220340 A 212 225 d-polylactide FAMILY 23220340 A 237 254 polyglycolic acid FAMILY 23220340 A 256 275 polyethylene glycol SYSTEMATIC 23220340 A 291 305 Cyclosporine A TRIVIAL 23220489 A 1195 1200 H(2)O FORMULA 23220512 A 139 153 polyacetylenes FAMILY 23220512 A 172 186 polyacetylenes FAMILY 23220512 A 285 298 polyacetylene SYSTEMATIC 23220512 A 299 318 gymnasterkoreayne B TRIVIAL 23220512 A 320 323 GKB ABBREVIATION 23220512 A 509 512 GKB ABBREVIATION 23220512 A 520 523 GKB ABBREVIATION 23220512 A 544 551 ethanol SYSTEMATIC 23220512 A 708 714 sodium SYSTEMATIC 23220512 A 715 727 azoxymethane SYSTEMATIC 23220512 A 745 748 GKB ABBREVIATION 23220512 A 850 853 GKB ABBREVIATION 23220512 T 2 15 polyacetylene SYSTEMATIC 23220609 A 0 13 Benzylparaben SYSTEMATIC 23220609 A 1008 1011 BzP ABBREVIATION 23220609 A 1086 1099 17β-estradiol SYSTEMATIC 23220609 A 15 18 BzP ABBREVIATION 23220609 A 311 314 BzP ABBREVIATION 23220609 A 452 455 BzP ABBREVIATION 23220609 A 505 513 estrogen FAMILY 23220609 A 663 666 BzP ABBREVIATION 23220609 A 768 771 BzP ABBREVIATION 23220609 A 874 877 BzP ABBREVIATION 23220609 A 927 935 parabens FAMILY 23220609 A 997 1000 BzP ABBREVIATION 23220609 T 26 39 benzylparaben SYSTEMATIC 23220614 A 0 11 Isoorientin TRIVIAL 23220614 A 1006 1014 SP600125 IDENTIFIER 23220614 A 1037 1045 SB203580 IDENTIFIER 23220614 A 1127 1130 ISO ABBREVIATION 23220614 A 1164 1167 NAC ABBREVIATION 23220614 A 1210 1213 ISO ABBREVIATION 23220614 A 1236 1239 NAC ABBREVIATION 23220614 A 13 16 ISO ABBREVIATION 23220614 A 1314 1317 ISO ABBREVIATION 23220614 A 1370 1373 ISO ABBREVIATION 23220614 A 1500 1503 ISO ABBREVIATION 23220614 A 1656 1659 ISO ABBREVIATION 23220614 A 185 188 ISO ABBREVIATION 23220614 A 27 36 4261-42-1 IDENTIFIER 23220614 A 336 339 ISO ABBREVIATION 23220614 A 429 432 ISO ABBREVIATION 23220614 A 43 52 flavonoid FAMILY 23220614 A 556 559 ISO ABBREVIATION 23220614 A 659 662 ISO ABBREVIATION 23220614 A 700 703 ISO ABBREVIATION 23220614 A 822 827 U0126 IDENTIFIER 23220614 A 877 880 ISO ABBREVIATION 23220614 T 77 88 isoorientin TRIVIAL 23220616 A 1031 1041 methionine TRIVIAL 23220616 A 1078 1090 homocysteine TRIVIAL 23220616 A 1110 1121 Glutathione TRIVIAL 23220616 A 112 129 sulfur amino acid FAMILY 23220616 A 1175 1193 γ-glutamylcysteine SYSTEMATIC 23220616 A 1233 1244 hypotaurine TRIVIAL 23220616 A 1290 1298 cysteine TRIVIAL 23220616 A 179 189 methionine TRIVIAL 23220616 A 269 281 homocysteine TRIVIAL 23220616 A 339 349 methionine TRIVIAL 23220616 A 377 383 sulfur SYSTEMATIC 23220616 A 395 405 methionine TRIVIAL 23220616 A 429 449 S-adenosylmethionine TRIVIAL 23220616 A 451 463 homocysteine TRIVIAL 23220616 A 465 473 cysteine TRIVIAL 23220616 A 479 490 hypotaurine TRIVIAL 23220616 A 525 547 S-adenosylhomocysteine TRIVIAL 23220616 A 549 559 putrescine TRIVIAL 23220616 A 565 575 spermidine TRIVIAL 23220616 A 640 650 methionine TRIVIAL 23220616 A 681 701 S-adenosylmethionine TRIVIAL 23220616 A 790 799 polyamine FAMILY 23220616 A 84 102 sulfur amino acids FAMILY 23220616 A 849 859 methionine TRIVIAL 23220616 A 919 939 S-adenosylmethionine TRIVIAL 23220616 A 951 963 homocysteine TRIVIAL 23220616 T 22 40 sulfur amino acids FAMILY 23220618 A 103 113 hyperoside TRIVIAL 23220618 A 1079 1082 IMG ABBREVIATION 23220618 A 1194 1197 IMG ABBREVIATION 23220618 A 1225 1235 hyperoside TRIVIAL 23220618 A 1305 1312 methoxy SYSTEMATIC 23220618 A 1322 1325 IMG ABBREVIATION 23220618 A 1327 1330 IMG ABBREVIATION 23220618 A 1335 1345 hyperoside TRIVIAL 23220618 A 64 92 isorhamnetin-3-O-galactoside SYSTEMATIC 23220618 A 653 656 IMG ABBREVIATION 23220618 A 661 671 hyperoside TRIVIAL 23220618 A 778 781 IMG ABBREVIATION 23220618 A 785 795 hyperoside TRIVIAL 23220618 A 94 97 IMG ABBREVIATION 23220618 A 980 983 IMG ABBREVIATION 23220618 A 988 998 hyperoside TRIVIAL 23220618 T 49 77 isorhamnetin-3-O-galactoside SYSTEMATIC 23220618 T 82 92 hyperoside TRIVIAL 23220641 A 119 122 AcK ABBREVIATION 23220641 A 74 80 NAD(+) ABBREVIATION 23220641 A 99 117 N(ε)-acetyl-lysine SYSTEMATIC 23223020 A 12 19 glucose TRIVIAL 23223020 A 206 213 glucose TRIVIAL 23223020 A 398 406 fructose TRIVIAL 23223020 A 487 494 glucose TRIVIAL 23223020 A 541 548 glucose TRIVIAL 23223020 A 576 583 glucose TRIVIAL 23223020 T 74 82 fructose TRIVIAL 23223020 T 8 15 glucose TRIVIAL 23223125 A 767 781 phthalocyanine TRIVIAL 23223125 A 782 791 fullerene TRIVIAL 23223125 A 836 850 phthalocyanine TRIVIAL 23223177 A 1056 1065 metformin TRIVIAL 23223177 A 501 508 glucose TRIVIAL 23223177 A 577 584 glucose TRIVIAL 23223177 A 622 625 NH2 FORMULA 23223177 A 916 923 glucose TRIVIAL 23223177 A 95 98 AMP ABBREVIATION 23223499 A 1044 1052 cortisol TRIVIAL 23223499 A 129 138 estrogens FAMILY 23223499 A 150 163 17β-estradiol SYSTEMATIC 23223499 A 166 174 cortisol TRIVIAL 23223499 A 180 192 progesterone TRIVIAL 23223499 A 789 797 estrogen FAMILY 23223499 A 836 844 cortisol TRIVIAL 23223499 A 969 977 cortisol TRIVIAL 23223802 A 102 108 silver SYSTEMATIC 23223802 A 378 384 Cu(2+) FORMULA 23223802 A 443 449 Cu(2+) FORMULA 23223802 A 530 536 silver SYSTEMATIC 23223802 A 541 547 copper SYSTEMATIC 23223802 A 65 71 copper SYSTEMATIC 23223802 T 27 33 copper SYSTEMATIC 23225346 A 24 47 2-Phenoxy-nicotinamides FAMILY 23225346 T 0 23 2-Phenoxy-nicotinamides FAMILY 23225346 T 51 60 bile acid FAMILY 23225753 A 855 867 gangliosides FAMILY 23225753 T 10 21 ganglioside TRIVIAL 23228341 A 1039 1049 organotins FAMILY 23228341 A 233 243 organotins FAMILY 23228341 A 245 255 Organotins FAMILY 23228341 A 404 413 organotin FAMILY 23228341 A 623 633 organotins FAMILY 23228341 A 682 691 organotin FAMILY 23228341 A 714 726 triorganotin FAMILY 23228341 A 736 747 tributyltin SYSTEMATIC 23228341 A 861 873 triorganotin FAMILY 23228341 T 0 10 Organotins FAMILY 23228472 A 14 20 uracil TRIVIAL 23228472 A 86 92 uracil TRIVIAL 23228472 T 54 60 uracil TRIVIAL 23228886 A 0 22 Tetrahydropapaveroline SYSTEMATIC 23228886 A 1036 1039 THP ABBREVIATION 23228886 A 1143 1146 THP ABBREVIATION 23228886 A 1251 1254 THP ABBREVIATION 23228886 A 1342 1345 THP ABBREVIATION 23228886 A 136 142 l-DOPA ABBREVIATION 23228886 A 24 27 THP ABBREVIATION 23228886 A 255 258 THP ABBREVIATION 23228886 A 302 305 THP ABBREVIATION 23228886 A 356 359 THP ABBREVIATION 23228886 A 400 408 carbonyl FAMILY 23228886 A 423 433 dityrosine TRIVIAL 23228886 A 455 458 THP ABBREVIATION 23228886 A 512 515 THP ABBREVIATION 23228886 A 599 602 THP ABBREVIATION 23228886 A 676 682 oxygen SYSTEMATIC 23228886 A 703 706 THP ABBREVIATION 23228886 A 737 747 amino acid FAMILY 23228886 A 758 767 glutamate TRIVIAL 23228886 A 769 776 proline TRIVIAL 23228886 A 781 787 lysine TRIVIAL 23228886 A 874 880 copper SYSTEMATIC 23228886 A 889 892 THP ABBREVIATION 23228886 A 947 950 THP ABBREVIATION 23228886 A 952 958 copper SYSTEMATIC 23228886 T 102 124 tetrahydropapaveroline SYSTEMATIC 23228886 T 81 89 catechol TRIVIAL 23229056 A 18 50 11,4″-disubstituted azithromycin FAMILY 23229056 A 215 227 erythromycin TRIVIAL 23229056 A 330 342 erythromycin TRIVIAL 23229056 A 381 395 erythromycin A TRIVIAL 23229056 A 397 411 clarithromycin TRIVIAL 23229056 A 415 427 azithromycin TRIVIAL 23229056 A 693 705 erythromycin TRIVIAL 23229056 A 857 874 3,5-dinitrophenyl SYSTEMATIC 23229056 A 896 904 bisamide SYSTEMATIC 23229056 T 128 140 erythromycin TRIVIAL 23229056 T 48 80 11,4″-disubstituted azithromycin FAMILY 23229057 A 1035 1066 {[H(2)B(tz(NO2))(2)]Cu[PCN]}(n) FAMILY 23229057 A 1098 1118 bis(triazolyl)borate SYSTEMATIC 23229057 A 1127 1130 PCN ABBREVIATION 23229057 A 1162 1165 PCN ABBREVIATION 23229057 A 118 141 poly(pyrazolyl)methanes FAMILY 23229057 A 1287 1290 PCN ABBREVIATION 23229057 A 1396 1399 MTT ABBREVIATION 23229057 A 148 178 tertiary monodentate phosphine SYSTEMATIC 23229057 A 1571 1580 cisplatin TRIVIAL 23229057 A 1668 1674 Copper SYSTEMATIC 23229057 A 1751 1760 cisplatin TRIVIAL 23229057 A 180 183 PTA ABBREVIATION 23229057 A 186 218 1,3,5-triaza-7-phosphaadamantane SYSTEMATIC 23229057 A 220 223 PCN ABBREVIATION 23229057 A 226 251 tris(cyanoethyl)phosphine SYSTEMATIC 23229057 A 29 38 copper(I) SYSTEMATIC 23229057 A 421 426 (31)P FORMULA 23229057 A 431 435 (1)H FORMULA 23229057 A 478 479 N FORMULA 23229057 A 480 481 N FORMULA 23229057 A 51 72 [Cu(CH(3)CN)(4)]BF(4) FORMULA 23229057 A 520 530 phosphines FAMILY 23229057 A 575 576 N FORMULA 23229057 A 577 578 N FORMULA 23229057 A 579 580 O FORMULA 23229057 A 585 586 N FORMULA 23229057 A 587 588 N FORMULA 23229057 A 589 590 N FORMULA 23229057 A 630 639 phosphine SYSTEMATIC 23229057 A 74 78 CuCl FORMULA 23229057 A 96 114 bis(azolyl)borates FAMILY 23229057 T 20 61 phosphine/scorpionate copper(I) complexes MULTIPLE 23229136 A 1026 1028 Cr FORMULA 23229136 A 1058 1060 Ni FORMULA 23229136 A 1391 1399 platinum SYSTEMATIC 23229136 A 29 37 platinum SYSTEMATIC 23229136 T 54 62 platinum SYSTEMATIC 23229141 A 181 188 cystine TRIVIAL 23229141 A 379 386 cystine TRIVIAL 23229141 A 41 50 disulfide SYSTEMATIC 23229141 T 35 42 cystine TRIVIAL 23229510 A 1008 1012 E235 IDENTIFIER 23229510 A 1045 1049 E235 IDENTIFIER 23229510 A 1158 1162 E235 IDENTIFIER 23229510 A 1304 1308 E235 IDENTIFIER 23229510 A 1325 1329 E235 IDENTIFIER 23229510 A 1435 1439 E235 IDENTIFIER 23229510 A 1519 1522 Ser FORMULA 23229510 A 1609 1613 E235 IDENTIFIER 23229510 A 1810 1814 E235 IDENTIFIER 23229510 A 342 352 amino acid FAMILY 23229510 A 640 644 E235 IDENTIFIER 23229510 A 645 739 (N-(1-benzyl-piperidin-4-yl)-2-(4-fluoro-phenyl)-benzo[d]imidazo[2,1-b]thiazole-7-carboxamide) SYSTEMATIC 23229510 A 646 738 N-(1-benzyl-piperidin-4-yl)-2-(4-fluoro-phenyl)-benzo[d]imidazo[2,1-b]thiazole-7-carboxamide SYSTEMATIC 23229556 A 1173 1179 xylose TRIVIAL 23229556 A 1454 1457 Gln FORMULA 23229556 A 191 203 carbohydrate FAMILY 23229556 A 32 38 carbon SYSTEMATIC 23229556 A 464 475 α1,6-xylose SYSTEMATIC 23229556 T 31 43 carbohydrate FAMILY 23230133 A 1049 1061 danofloxacin TRIVIAL 23230133 A 11 33 adenosine triphosphate SYSTEMATIC 23230133 A 590 602 danofloxacin TRIVIAL 23230133 A 652 664 Danofloxacin TRIVIAL 23230133 A 928 940 danofloxacin TRIVIAL 23230133 T 11 14 ATP ABBREVIATION 23230133 T 139 151 danofloxacin TRIVIAL 23230905 A 1187 1189 Au FORMULA 23230905 A 1244 1246 Au FORMULA 23230905 A 279 281 Au FORMULA 23230905 A 380 383 PLA ABBREVIATION 23230905 A 390 393 PEG ABBREVIATION 23230905 A 401 404 PLA ABBREVIATION 23230905 A 466 468 Au FORMULA 23230905 A 730 732 Au FORMULA 23230905 A 776 778 Au FORMULA 23230905 A 823 825 Au FORMULA 23231351 A 151 161 porphyrins FAMILY 23231351 A 278 287 porphyrin FAMILY 23231351 A 455 464 porphyrin FAMILY 23231351 A 599 608 porphyrin FAMILY 23231351 T 0 9 Porphyrin FAMILY 23231410 A 326 339 sulfonic-acid SYSTEMATIC 23231410 A 426 435 hydronium SYSTEMATIC 23231410 A 546 554 hydrogen SYSTEMATIC 23231410 A 587 596 hydronium SYSTEMATIC 23231410 A 751 760 sulfonate SYSTEMATIC 23231410 A 805 813 hydrogen SYSTEMATIC 23231410 A 905 918 sulfonic acid SYSTEMATIC 23231420 A 1070 1075 PMPTS ABBREVIATION 23231420 A 1255 1260 PMPTS ABBREVIATION 23231420 A 1300 1305 PMPTS ABBREVIATION 23231420 A 1353 1356 PSQ ABBREVIATION 23231420 A 1501 1506 PMPTS ABBREVIATION 23231420 A 1572 1575 PSQ ABBREVIATION 23231420 A 1805 1810 PMPTS ABBREVIATION 23231420 A 181 184 PSQ ABBREVIATION 23231420 A 25 36 polystyrene SYSTEMATIC 23231420 A 252 289 γ-methacryloxypropyl trimethoxysilane SYSTEMATIC 23231420 A 291 295 MPTS ABBREVIATION 23231420 A 300 307 ethanol SYSTEMATIC 23231420 A 346 367 methacryloxypropylene SYSTEMATIC 23231420 A 37 55 polysilsesquioxane FAMILY 23231420 A 383 386 PSQ ABBREVIATION 23231420 A 388 393 PMPTS ABBREVIATION 23231420 A 446 453 styrene TRIVIAL 23231420 A 475 478 PSQ ABBREVIATION 23231420 A 60 63 PSQ ABBREVIATION 23231420 A 705 710 PMPTS ABBREVIATION 23231420 T 123 166 poly(γ-methacryloxypropyl trimethoxysilane) FAMILY 23231420 T 13 24 polystyrene SYSTEMATIC 23231420 T 25 43 polysilsesquioxane FAMILY 23232060 A 33 63 4-phenyl-2-phenylaminopyridine SYSTEMATIC 23232060 T 13 43 4-phenyl-2-phenylaminopyridine SYSTEMATIC 23232079 A 1096 1106 citalopram TRIVIAL 23232079 A 189 199 citalopram TRIVIAL 23232079 A 344 354 citalopram TRIVIAL 23232079 A 74 84 citalopram TRIVIAL 23232079 A 963 973 citalopram TRIVIAL 23232079 T 0 10 Citalopram TRIVIAL 23232123 A 672 682 amino acid FAMILY 23232323 A 200 255 3β, 4α-dihydroxy-1-(3-phenylpropanoyl)-piperidine-2-one SYSTEMATIC 23232323 A 264 323 (2E, 4E, 14Z)-6-hydroxyl-N-isobutyleicosa-2,4,14-trienamide SYSTEMATIC 23232323 T 4 19 amide alkaloids FAMILY 23232711 A 275 285 porphyrins FAMILY 23232711 A 312 322 porphyrins FAMILY 23232711 A 472 482 porphyrins FAMILY 23232711 A 667 677 porphyrins FAMILY 23232711 A 90 99 porphyrin FAMILY 23232711 T 33 43 porphyrins FAMILY 23233324 A 0 14 Chlorothalonil TRIVIAL 23233324 A 1259 1273 chlorothalonil TRIVIAL 23233324 A 1552 1566 chlorothalonil TRIVIAL 23233324 A 318 332 Chlorothalonil TRIVIAL 23233324 A 479 493 chlorothalonil TRIVIAL 23233324 T 24 38 chlorothalonil TRIVIAL 23234271 A 196 210 diazatricyclic FAMILY 23234271 A 39 76 2,6-diazatricyclo[3.3.1.1∼3,7∼]decane SYSTEMATIC 23234271 A 467 500 3-oxa-7-aza-bicyclo[3.3.1]nonanes FAMILY 23234271 A 518 527 carbamate FAMILY 23234271 A 545 558 diazatricylic FAMILY 23234271 T 24 43 diazatricyclodecane SYSTEMATIC 23234434 A 1012 1020 pyridine SYSTEMATIC 23234434 A 1104 1108 PPCA ABBREVIATION 23234434 A 1130 1140 Pd acetate SYSTEMATIC 23234434 A 1332 1355 dimethylethynylcarbinol SYSTEMATIC 23234434 A 1357 1361 DMEC ABBREVIATION 23234434 A 1366 1387 dimethylvinylcarbinol SYSTEMATIC 23234434 A 1428 1431 LLA ABBREVIATION 23234434 A 1502 1506 DMEC ABBREVIATION 23234434 A 170 210 linolenic (LLA) and linoleic (LEA) acids MULTIPLE 23234434 A 214 222 pyridine SYSTEMATIC 23234434 A 240 274 6-methylpyridine-2-carboxylic acid SYSTEMATIC 23234434 A 276 293 isonicotinic acid SYSTEMATIC 23234434 A 295 318 3-hydroxypicolinic acid SYSTEMATIC 23234434 A 324 366 6-(1-piperidinyl)pyridine-3-carboxlic acid SYSTEMATIC 23234434 A 368 372 PPCA ABBREVIATION 23234434 A 53 63 iron oxide SYSTEMATIC 23234434 A 612 615 LLA ABBREVIATION 23234434 A 620 623 LEA ABBREVIATION 23234434 A 643 653 iron oxide SYSTEMATIC 23234434 A 702 740 bis(acetonitrile)dichloropalladium(II) SYSTEMATIC 23234434 A 873 881 pyridine SYSTEMATIC 23234434 A 907 911 PPCA ABBREVIATION 23234434 A 921 922 N FORMULA 23234434 T 34 44 iron oxide SYSTEMATIC 23235156 A 1577 1583 Ca(2+) FORMULA 23235156 A 178 185 calcium SYSTEMATIC 23235690 A 104 106 Fe FORMULA 23235690 A 1089 1091 Si FORMULA 23235690 A 1092 1094 Fe FORMULA 23235690 A 148 150 Li FORMULA 23235690 A 22 24 Si FORMULA 23235690 A 25 27 Fe FORMULA 23235690 A 274 276 Fe FORMULA 23235690 A 360 362 Li FORMULA 23235690 A 476 478 Fe FORMULA 23235690 A 604 606 Si FORMULA 23235690 A 69 76 silicon SYSTEMATIC 23235690 A 866 868 Ti FORMULA 23235690 A 927 929 Si FORMULA 23235690 A 930 932 Fe FORMULA 23235690 A 956 958 Fe FORMULA 23235690 T 56 58 Si FORMULA 23235690 T 59 61 Fe FORMULA 23235690 T 81 88 lithium SYSTEMATIC 23235923 A 637 646 potassium SYSTEMATIC 23235923 A 676 683 calcium SYSTEMATIC 23235923 A 889 919 cyclic adenosine monophosphate SYSTEMATIC 23237384 A 142 152 amino acid FAMILY 23237384 A 4 16 sulfonylurea FAMILY 23237384 A 435 448 sulfonylureas FAMILY 23237384 A 550 622 ethyl 2-(N-((4-iodo-6-methoxypyrimidin-2-yl)carbamoyl)sulfamoyl)benzoate SYSTEMATIC 23237384 A 756 769 sulfonylureas FAMILY 23237384 T 0 13 Sulfonylureas FAMILY 23237450 A 481 488 calcium SYSTEMATIC 23237450 A 493 502 phosphate SYSTEMATIC 23237450 A 675 681 Ca(2+) FORMULA 23237450 A 714 720 Ca(2+) FORMULA 23237450 T 0 7 Calcium SYSTEMATIC 23237733 A 0 17 Isoliquiritigenin TRIVIAL 23237733 A 1203 1220 isoliquiritigenin TRIVIAL 23237733 A 1307 1324 isoliquiritigenin TRIVIAL 23237733 A 155 158 UDP ABBREVIATION 23237733 A 267 284 isoliquiritigenin TRIVIAL 23237733 A 426 447 4-methylumbelliferone SYSTEMATIC 23237733 A 44 52 chalcone FAMILY 23237733 A 449 453 4-MU SYSTEMATIC 23237733 A 533 550 isoliquiritigenin TRIVIAL 23237733 A 826 843 isoliquiritigenin TRIVIAL 23237733 A 966 983 isoliquiritigenin TRIVIAL 23237733 T 0 17 Isoliquiritigenin TRIVIAL 23237733 T 120 141 4-methylumbelliferone SYSTEMATIC 23237733 T 143 147 4-MU SYSTEMATIC 23237733 T 68 71 UDP ABBREVIATION 23237835 A 120 127 epoxide SYSTEMATIC 23237835 A 166 191 epoxyeicosatrienoic acids FAMILY 23237835 A 19 24 amide FAMILY 23237835 A 193 197 EETs ABBREVIATION 23237835 A 29 33 urea TRIVIAL 23237835 A 56 63 epoxide SYSTEMATIC 23237835 T 49 59 piperidine SYSTEMATIC 23237835 T 72 76 urea TRIVIAL 23237835 T 85 92 epoxide SYSTEMATIC 23237860 A 1495 1498 CoA ABBREVIATION 23237860 A 186 195 aldehydes FAMILY 23237860 A 319 343 4-hydroxy-2-ketovalerate SYSTEMATIC 23237860 A 363 375 acetaldehyde SYSTEMATIC 23237860 A 37 45 aldehyde SYSTEMATIC 23237860 A 546 549 CoA ABBREVIATION 23237860 A 807 819 acetaldehyde SYSTEMATIC 23237860 A 849 873 4-hydroxy-2-ketovalerate SYSTEMATIC 23237860 A 888 898 acetyl-CoA SYSTEMATIC 23237860 A 991 999 aldehyde SYSTEMATIC 23237860 T 46 58 acetaldehyde SYSTEMATIC 23238103 A 0 8 Estrogen FAMILY 23238103 A 1254 1263 estradiol TRIVIAL 23238103 A 1268 1280 testosterone TRIVIAL 23238103 A 1621 1629 estrogen FAMILY 23238103 A 288 296 estrogen FAMILY 23238103 A 445 453 estrogen FAMILY 23238103 A 496 503 steroid FAMILY 23238103 A 515 523 androgen FAMILY 23238103 A 540 554 corticosterone TRIVIAL 23238103 A 697 710 17β-estradiol SYSTEMATIC 23238103 A 712 724 testosterone TRIVIAL 23238103 A 729 743 corticosterone TRIVIAL 23238103 T 59 66 steroid FAMILY 23238226 A 160 162 Si FORMULA 23238226 A 223 230 ammonia SYSTEMATIC 23238226 A 365 369 SiGe FORMULA 23238226 A 370 372 Si FORMULA 23238226 A 373 375 Cr FORMULA 23238226 A 47 51 SiGe FORMULA 23238226 A 52 54 Si FORMULA 23238226 A 55 57 Cr FORMULA 23238226 A 707 709 Si FORMULA 23238226 A 81 83 Si FORMULA 23238226 T 25 29 SiGe FORMULA 23238226 T 30 32 Si FORMULA 23238226 T 33 35 Cr FORMULA 23238226 T 50 52 Si FORMULA 23238299 A 1013 1024 chelidonine TRIVIAL 23238299 A 1240 1251 chelidonine TRIVIAL 23238299 A 1434 1445 chelidonine TRIVIAL 23238299 A 161 172 chelidonine TRIVIAL 23238299 A 236 287 protoberberine and benzo[c]phenanthridine alkaloids MULTIPLE 23238299 A 461 472 Chelidonine TRIVIAL 23238299 A 608 619 doxorubicin TRIVIAL 23238299 A 645 656 chelidonine TRIVIAL 23238299 A 889 908 phosphatidyl serine FAMILY 23238299 T 54 65 chelidonine TRIVIAL 23238642 A 1052 1058 As(3+) FORMULA 23238642 A 1063 1069 As(5+) FORMULA 23238642 A 11 18 arsenic SYSTEMATIC 23238642 A 1112 1120 Arsenate SYSTEMATIC 23238642 A 1219 1227 arsenite SYSTEMATIC 23238642 A 1653 1659 As(5+) FORMULA 23238642 A 1694 1702 arsenate SYSTEMATIC 23238642 A 1748 1754 As(3+) FORMULA 23238642 A 176 183 arsenic SYSTEMATIC 23238642 A 20 22 As FORMULA 23238642 A 352 359 arsenic SYSTEMATIC 23238642 A 413 419 As(3+) FORMULA 23238642 A 469 471 As FORMULA 23238642 A 519 525 Cu(2+) FORMULA 23238642 A 527 533 Cr(2+) FORMULA 23238642 A 535 541 Ni(2+) FORMULA 23238642 A 574 582 arsenate SYSTEMATIC 23238642 A 60 67 arsenic SYSTEMATIC 23238642 A 672 680 arsenite SYSTEMATIC 23238642 T 20 27 arsenic SYSTEMATIC 23238642 T 52 59 arsenic SYSTEMATIC 23238784 A 1054 1064 bile acids FAMILY 23238784 A 1172 1182 bile salts FAMILY 23238784 A 1334 1338 DMSO ABBREVIATION 23238784 A 221 238 dimethylsulfoxide SYSTEMATIC 23238784 A 240 244 DMSO ABBREVIATION 23238784 A 563 567 DMSO ABBREVIATION 23238784 A 825 828 UDP ABBREVIATION 23238784 A 967 977 rifampicin TRIVIAL 23238784 T 116 134 dimethyl sulfoxide SYSTEMATIC 23238784 T 40 49 bile acid FAMILY 23239458 A 90 127 4-N,N-dimethylamino-1,8-naphthalimide SYSTEMATIC 23239550 A 12 56 17,17-dialkyl-3,14-diaryltetrabenzofluorenes FAMILY 23239550 A 1259 1262 THF ABBREVIATION 23239550 A 153 165 3,14-dibromo FAMILY 23239550 A 481 499 bis(p-nitrophenyl) SYSTEMATIC 23239550 A 833 848 tetrahydrofuran SYSTEMATIC 23239550 A 850 853 THF ABBREVIATION 23239550 T 0 66 3,14-Bis(p-nitrophenyl)-17,17-dipentyltetrabenzo[a,c,g,i]-fluorene SYSTEMATIC 23239602 A 22 27 FePO4 FORMULA 23239602 A 335 340 FePO4 FORMULA 23239602 A 391 393 Li FORMULA 23239602 T 38 43 FePO4 FORMULA 23239629 A 391 433 N-[3-(dimethylamino)propyl] methacrylamide SYSTEMATIC 23239629 A 435 441 DMAPMA ABBREVIATION 23240979 A 107 133 poly(phenylene ethynylene) FAMILY 23240979 A 1219 1223 OPEs FAMILY 23240979 A 135 138 PPE ABBREVIATION 23240979 A 1362 1368 oxygen SYSTEMATIC 23240979 A 1393 1399 oxygen SYSTEMATIC 23240979 A 1434 1437 OPE ABBREVIATION 23240979 A 194 221 oligo-phenylene ethynylenes FAMILY 23240979 A 223 227 OPEs FAMILY 23240979 A 305 308 OPE ABBREVIATION 23240979 A 609 612 OPE ABBREVIATION 23240979 A 749 752 OPE ABBREVIATION 23240979 A 997 1001 OPEs FAMILY 23240995 A 1107 1113 InGaAs FORMULA 23240995 A 1153 1160 silicon SYSTEMATIC 23240995 A 1329 1336 silicon SYSTEMATIC 23240995 A 1374 1380 SiN(x) FAMILY 23240995 A 1382 1388 SiO(2) FORMULA 23240995 A 1393 1399 SiO(2) FORMULA 23240995 A 1400 1402 Si FORMULA 23240995 A 1426 1430 GaAs FORMULA 23240995 A 1479 1495 In(0.2)Ga(0.8)As FORMULA 23240995 A 220 227 silicon SYSTEMATIC 23240995 A 522 524 Al FORMULA 23240995 A 525 527 In FORMULA 23240995 A 528 532 GaAs FORMULA 23240995 A 555 562 silicon SYSTEMATIC 23240995 A 67 69 Si FORMULA 23240995 A 746 752 InGaAs FORMULA 23240995 A 753 757 GaAs FORMULA 23240995 A 910 918 wurtzite TRIVIAL 23240995 T 71 78 silicon SYSTEMATIC 23241082 A 1073 1087 ammonium salts FAMILY 23241082 A 1186 1194 PF(6)(-) FORMULA 23241082 A 160 207 1-butyl-3-methylimidazolium hexafluorophosphate SYSTEMATIC 23241082 A 209 223 [C(4)mim]PF(6) FORMULA 23241082 A 248 253 (31)P FORMULA 23241082 A 31 50 hexafluorophosphate SYSTEMATIC 23241082 A 342 350 PF(6)(-) FORMULA 23241082 A 58 66 PF(6)(-) FORMULA 23241082 A 628 636 PF(6)(-) FORMULA 23241082 A 898 906 PF(6)(-) FORMULA 23241082 A 972 980 PF(6)(-) FORMULA 23241082 T 101 148 1-butyl-3-methylimidazolium hexafluorophosphate SYSTEMATIC 23241082 T 163 166 31P FORMULA 23241082 T 50 56 PF6(-) FORMULA 23243006 A 1258 1271 methylmercury SYSTEMATIC 23243006 A 1276 1287 flusilazole TRIVIAL 23243006 A 1349 1362 Valproic acid TRIVIAL 23244033 A 113 119 MnO(2) FORMULA 23244033 A 12 18 carbon SYSTEMATIC 23244033 A 89 91 Pd FORMULA 23244162 A 103 114 polystyrene SYSTEMATIC 23244162 A 139 162 poly(vinyl pyrrolidone) FAMILY 23244162 A 164 167 PVP ABBREVIATION 23244162 A 172 179 PS(PVP) ABBREVIATION 23244162 A 303 311 hydrogen SYSTEMATIC 23244162 A 340 343 PAA ABBREVIATION 23244162 A 348 351 PVP ABBREVIATION 23244162 A 371 378 PS(PAA) ABBREVIATION 23244162 A 384 391 PS(PVP) ABBREVIATION 23244162 A 42 60 poly(acrylic acid) SYSTEMATIC 23244162 A 422 425 PVP ABBREVIATION 23244162 A 447 454 PS(PAA) ABBREVIATION 23244162 A 564 589 poly(methyl methacrylate) SYSTEMATIC 23244162 A 6 17 polystyrene SYSTEMATIC 23244162 A 614 617 PAA ABBREVIATION 23244162 A 62 65 PAA ABBREVIATION 23244162 A 621 630 PMMA(PAA) ABBREVIATION 23244162 A 638 645 PS(PVP) ABBREVIATION 23244162 A 70 77 PS(PAA) ABBREVIATION 23244162 A 711 720 PMMA(PAA) ABBREVIATION 23244162 A 728 735 PS(PVP) ABBREVIATION 23244162 A 940 948 hydrogen SYSTEMATIC 23244162 T 91 99 hydrogen SYSTEMATIC 23244292 A 1085 1086 B FORMULA 23244292 A 1090 1091 O FORMULA 23244292 A 20 28 graphene TRIVIAL 23244292 A 246 254 graphene TRIVIAL 23244292 A 286 287 B FORMULA 23244292 A 309 315 borane SYSTEMATIC 23244292 A 324 338 graphene oxide SYSTEMATIC 23244292 A 340 341 B FORMULA 23244292 A 345 346 O FORMULA 23244292 A 400 414 graphene oxide SYSTEMATIC 23244292 A 420 426 borane SYSTEMATIC 23244292 A 427 442 tetrahydrofuran SYSTEMATIC 23244292 A 567 583 B-doped graphene TRIVIAL 23244292 A 640 656 B-doped graphene TRIVIAL 23244292 A 691 692 B FORMULA 23244292 A 696 697 O FORMULA 23244292 A 932 938 carbon SYSTEMATIC 23244292 T 14 30 B-doped graphene TRIVIAL 23244594 A 1118 1122 (1)H FORMULA 23244594 A 124 138 C(12)φ(2)C(12) FORMULA 23244594 A 286 337 O,O'-bis(sodium 2-dodecylcarboxylate)-p-benzenediol SYSTEMATIC 23244594 A 339 350 C(12)φC(12) FORMULA 23244594 A 388 394 phenyl SYSTEMATIC 23244594 A 539 553 C(12)φ(2)C(12) FORMULA 23244594 A 54 107 O,O'-bis(sodium 2-dodecylcarboxylate)-p-dibenzenediol SYSTEMATIC 23244594 A 564 575 C(12)φC(12) FORMULA 23244594 A 739 753 C(12)φ(2)C(12) FORMULA 23244594 A 817 831 C(12)φ(2)C(12) FORMULA 23244594 A 845 850 alkyl FAMILY 23244594 T 33 44 carboxylate SYSTEMATIC 23244629 A 250 254 AIBN ABBREVIATION 23244629 A 309 348 2-aminoethyl methacrylate hydrochloride SYSTEMATIC 23244629 A 350 354 AEMA ABBREVIATION 23244629 A 356 377 N-isopropylacrylamide SYSTEMATIC 23244629 A 379 385 NIPAAM ABBREVIATION 23244629 A 639 657 ammonium hydroxide SYSTEMATIC 23244683 A 1146 1154 graphene TRIVIAL 23244683 A 1206 1214 graphene TRIVIAL 23244683 A 1359 1367 graphene TRIVIAL 23244683 A 159 167 graphene TRIVIAL 23244683 A 168 174 SiO(2) FORMULA 23244683 A 175 177 Si FORMULA 23244683 A 286 294 graphene TRIVIAL 23244683 A 295 301 SiO(2) FORMULA 23244683 A 302 304 Si FORMULA 23244683 A 407 415 graphene TRIVIAL 23244683 A 503 509 SiO(2) FORMULA 23244683 A 768 774 SiO(2) FORMULA 23244683 A 95 103 graphene TRIVIAL 23244683 A 973 979 SiO(2) FORMULA 23244683 T 48 56 graphene TRIVIAL 23244683 T 57 62 oxide SYSTEMATIC 23245513 A 18 61 N-methoxycarbonyl-2-amino-1,8-naphthyridine SYSTEMATIC 23245513 A 222 230 hydrogen SYSTEMATIC 23245513 A 249 256 guanine TRIVIAL 23245513 A 258 262 MCND ABBREVIATION 23245513 A 279 286 guanine TRIVIAL 23245513 A 287 294 guanine TRIVIAL 23245513 A 315 322 adenine TRIVIAL 23245513 A 323 330 adenine TRIVIAL 23245513 A 560 564 MCND ABBREVIATION 23245513 A 600 604 MCND ABBREVIATION 23245513 A 63 67 MCND ABBREVIATION 23245513 A 638 653 methylcarbamate SYSTEMATIC 23245513 T 18 61 N-methoxycarbonyl-2-amino-1,8-naphthyridine SYSTEMATIC 23245515 A 191 196 amide FAMILY 23245515 A 49 71 methyl naphthyridinone SYSTEMATIC 23245515 A 498 507 GSK364735 IDENTIFIER 23245515 T 0 15 Naphthyridinone TRIVIAL 23245515 T 105 110 amide FAMILY 23245515 T 17 20 NTD ABBREVIATION 23245515 T 58 64 methyl SYSTEMATIC 23245695 A 0 9 Cisplatin TRIVIAL 23245695 A 206 214 guanines FAMILY 23245695 A 272 282 nucleotide FAMILY 23245695 A 352 361 cisplatin TRIVIAL 23245695 A 664 673 cisplatin TRIVIAL 23245695 A 795 804 cisplatin TRIVIAL 23245695 A 970 979 cisplatin TRIVIAL 23245695 T 35 45 nucleotide FAMILY 23245695 T 74 83 cisplatin TRIVIAL 23246460 A 251 271 glufosinate ammonium SYSTEMATIC 23246469 A 274 281 Gd-DTPA FORMULA 23246469 A 283 291 Gd-BOPTA FORMULA 23246469 A 293 300 Gd-DOTA FORMULA 23246469 A 302 312 Gd-BT-DO3A FORMULA 23246469 A 314 325 Gd-DTPA-BMA FORMULA 23246469 A 331 341 Gd-HP-DO3A FORMULA 23246469 A 443 486 1,2-dipalmitoyl-sn-glycero-3-phosphocholine SYSTEMATIC 23246469 A 487 529 1,2-distearoyl-sn-glycero-3-phosphocholine SYSTEMATIC 23246469 A 530 576 1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol SYSTEMATIC 23246469 A 601 608 DPPG(2) ABBREVIATION 23246469 T 10 12 Gd FORMULA 23246469 T 74 96 phosphatidyldiglycerol TRIVIAL 23246481 A 0 7 Wogonin TRIVIAL 23246481 A 190 197 wogonin TRIVIAL 23246481 A 292 299 wogonin TRIVIAL 23246481 A 303 307 H2O2 FORMULA 23246481 A 31 44 monoflavonoid FAMILY 23246481 A 404 411 wogonin TRIVIAL 23246481 A 429 433 H2O2 FORMULA 23246481 A 610 617 wogonin TRIVIAL 23246481 A 628 632 H2O2 FORMULA 23246481 A 769 776 wogonin TRIVIAL 23246481 A 787 797 anisomycin TRIVIAL 23246481 A 892 899 wogonin TRIVIAL 23246481 A 914 918 H2O2 FORMULA 23246481 T 0 7 Wogonin TRIVIAL 23246481 T 17 21 H2O2 FORMULA 23246578 A 697 710 dexamethasone TRIVIAL 23246578 A 712 720 zileuton TRIVIAL 23246578 A 724 728 Boc2 FORMULA 23246578 A 756 762 formyl SYSTEMATIC 23246578 A 796 808 indomethacin TRIVIAL 23246611 A 228 232 DMSO ABBREVIATION 23246611 A 252 258 NaHCO3 FORMULA 23246611 A 395 412 Hydrogen peroxide SYSTEMATIC 23246611 A 692 696 H2O2 FORMULA 23246611 T 119 123 DMSO ABBREVIATION 23246611 T 128 134 NaHCO3 FORMULA 23246732 A 1000 1002 Pb FORMULA 23246732 A 1156 1158 Pb FORMULA 23246732 A 1234 1236 Pb FORMULA 23246732 A 32 34 Pb FORMULA 23246732 A 386 401 methyl cytosine SYSTEMATIC 23246732 A 474 476 Pb FORMULA 23246732 A 600 610 Pb acetate SYSTEMATIC 23246732 A 774 776 Pb FORMULA 23246732 T 85 100 methyl cytosine SYSTEMATIC 23246797 A 1342 1351 Tandemact TRIVIAL 23246797 A 1374 1379 Inegy TRIVIAL 23246797 A 1490 1502 pioglitazone TRIVIAL 23246797 A 1917 1929 pioglitazone TRIVIAL 23246797 A 1930 1941 glimepiride TRIVIAL 23246797 A 2025 2037 pioglitazone TRIVIAL 23246797 A 2052 2063 glimepiride TRIVIAL 23246797 A 2106 2115 ezetimibe TRIVIAL 23246797 A 2124 2135 simvastatin TRIVIAL 23246797 A 2163 2172 ezetimibe TRIVIAL 23246797 A 2173 2184 simvastatin TRIVIAL 23246797 A 2244 2253 ezetimibe TRIVIAL 23246797 A 2262 2273 simvastatin TRIVIAL 23246797 A 2628 2635 HP-β-CD ABBREVIATION 23246797 A 2640 2648 Soluplus TRIVIAL 23246797 A 491 502 glimepiride TRIVIAL 23246797 A 521 533 pioglitazone TRIVIAL 23246797 A 582 593 simvastatin TRIVIAL 23246797 A 598 607 ezetimibe TRIVIAL 23246797 A 754 782 hydroxypropyl-β-cyclodextrin SYSTEMATIC 23246797 A 784 791 HP-β-CD ABBREVIATION 23246797 A 822 830 Soluplus TRIVIAL 23246797 A 860 881 polyvinyl caprolactam SYSTEMATIC 23246797 A 884 901 polyvinyl acetate SYSTEMATIC 23246797 A 904 923 polyethylene glycol SYSTEMATIC 23246797 A 986 993 HP-β-CD ABBREVIATION 23246797 A 998 1006 Soluplus TRIVIAL 23246797 T 110 122 pioglitazone TRIVIAL 23246797 T 123 134 glimepiride TRIVIAL 23246797 T 139 148 ezetimibe TRIVIAL 23246797 T 149 160 simvastatin TRIVIAL 23246798 A 1058 1065 camphor TRIVIAL 23246798 A 1187 1194 camphor TRIVIAL 23246798 A 390 393 PEO ABBREVIATION 23246798 A 562 565 PEO ABBREVIATION 23246798 A 610 613 PEO ABBREVIATION 23246798 A 716 719 PEO ABBREVIATION 23246798 A 721 728 Camphor TRIVIAL 23246798 A 831 838 Camphor TRIVIAL 23246798 A 92 101 metformin TRIVIAL 23246798 T 45 54 metformin TRIVIAL 23247008 A 110 119 aldehydes FAMILY 23247008 A 246 258 acetaldehyde SYSTEMATIC 23247008 A 441 451 amino acid FAMILY 23247008 A 76 88 acetaldehyde SYSTEMATIC 23247048 A 846 857 aldosterone TRIVIAL 23247407 A 124 126 Au FORMULA 23247407 A 36 38 CO FORMULA 23247407 A 378 380 CO FORMULA 23247407 A 909 911 CO FORMULA 23247407 T 74 76 CO FORMULA 23247407 T 82 84 Au FORMULA 23247471 A 293 299 TiO(2) FORMULA 23247471 A 358 364 TiO(2) FORMULA 23247471 A 498 503 Ga(+) FORMULA 23247471 A 510 516 TiO(2) FORMULA 23247471 A 665 670 Ga(+) FORMULA 23247471 A 7 13 TiO(2) FORMULA 23247471 A 821 826 Ga(+) FORMULA 23247471 T 40 44 TiO2 FORMULA 23247545 A 571 573 Hg FORMULA 23247545 A 575 577 Cd FORMULA 23247545 A 579 581 Pb FORMULA 23247545 A 583 585 Cu FORMULA 23247545 A 587 589 Zn FORMULA 23247545 A 591 593 Ni FORMULA 23247545 A 595 597 Cr FORMULA 23247545 A 599 601 As FORMULA 23247545 A 606 608 Se FORMULA 23247545 A 611 615 PCBs ABBREVIATION 23247545 A 647 651 DDTs FAMILY 23247722 A 1389 1397 hydrogen SYSTEMATIC 23247722 A 1463 1471 hydrogen SYSTEMATIC 23247722 A 1508 1518 chloroform TRIVIAL 23247722 A 167 175 methanol SYSTEMATIC 23247722 A 1705 1721 methyl mandelate SYSTEMATIC 23247722 A 177 186 MeOH-d(4) FORMULA 23247722 A 189 207 dimethyl sulfoxide SYSTEMATIC 23247722 A 209 218 DMSO-d(6) ABBREVIATION 23247722 A 225 235 chloroform TRIVIAL 23247722 A 237 244 CDCl(3) FORMULA 23247722 A 80 96 methyl mandelate SYSTEMATIC 23247722 A 885 901 methyl mandelate SYSTEMATIC 23247722 A 958 966 hydrogen SYSTEMATIC 23247722 T 27 43 methyl mandelate SYSTEMATIC 23247722 T 47 55 methanol SYSTEMATIC 23247722 T 57 75 dimethyl sulfoxide SYSTEMATIC 23247722 T 81 91 chloroform TRIVIAL 23248329 A 0 18 Glycosphingolipids FAMILY 23248329 A 936 949 sphingomyelin FAMILY 23248329 A 955 966 cholesterol TRIVIAL 23248329 T 27 44 glycosphingolipid FAMILY 23249265 A 1190 1197 silicon SYSTEMATIC 23249265 A 136 144 graphene TRIVIAL 23249265 A 150 156 carbon SYSTEMATIC 23249265 A 598 605 silicon SYSTEMATIC 23249265 A 960 967 silicon SYSTEMATIC 23249265 T 44 51 silicon SYSTEMATIC 23249276 A 207 225 flavone glycosides FAMILY 23249276 A 238 245 diosmin TRIVIAL 23249276 A 266 280 citroflavonoid FAMILY 23249276 A 411 439 3-bromo- and 3-chlorodiosmin MULTIPLE 23249276 T 39 57 flavone glycosides FAMILY 23249300 A 572 585 sulfonic acid SYSTEMATIC 23249300 A 715 740 poly(tetrafluoroethylene) FAMILY 23249300 T 47 69 perfluorosulfonic acid SYSTEMATIC 23249384 A 1057 1062 HEPES ABBREVIATION 23249384 A 1101 1104 THF ABBREVIATION 23249384 A 1124 1129 HEPES ABBREVIATION 23249384 A 1151 1154 THF ABBREVIATION 23249384 A 129 134 HEPES ABBREVIATION 23249384 A 1358 1361 THF ABBREVIATION 23249384 A 163 178 tetrahydrofuran SYSTEMATIC 23249384 A 180 183 THF ABBREVIATION 23249384 A 186 224 1,3-dioxolane, 1,4-dioxane, 1-propanol SYSTEMATIC 23249384 A 226 236 2-propanol SYSTEMATIC 23249384 A 238 250 tert-butanol SYSTEMATIC 23249384 A 252 264 acetonitrile SYSTEMATIC 23249384 A 269 276 acetone SYSTEMATIC 23249384 A 473 478 HEPES ABBREVIATION 23249384 A 595 600 HEPES ABBREVIATION 23249384 A 611 614 THF ABBREVIATION 23249384 A 759 764 HEPES ABBREVIATION 23249384 A 77 127 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid SYSTEMATIC 23249384 A 934 939 HEPES ABBREVIATION 23249384 A 948 951 THF ABBREVIATION 23249538 A 497 507 amino acid FAMILY 23249624 A 114 120 serine TRIVIAL 23249624 A 1158 1168 dabrafenib TRIVIAL 23249624 A 121 130 threonine TRIVIAL 23249624 A 1279 1289 Dabrafenib TRIVIAL 23249624 A 1527 1538 vemurafenib TRIVIAL 23249624 A 1571 1581 dabrafenib TRIVIAL 23249624 A 1655 1665 dabrafenib TRIVIAL 23249624 A 213 219 valine TRIVIAL 23249624 A 227 240 glutamic acid TRIVIAL 23249624 A 338 348 dabrafenib TRIVIAL 23249624 A 433 443 dabrafenib TRIVIAL 23249624 A 544 554 dabrafenib TRIVIAL 23249624 A 819 829 dabrafenib TRIVIAL 23249624 T 40 49 threonine TRIVIAL 23249624 T 88 98 dabrafenib TRIVIAL 23249625 A 1335 1342 glucose TRIVIAL 23249625 A 143 149 oxygen SYSTEMATIC 23249625 A 1666 1673 glucose TRIVIAL 23249625 A 221 228 glucose TRIVIAL 23249625 A 419 426 glucose TRIVIAL 23249625 A 459 465 oxygen SYSTEMATIC 23249625 A 545 552 glucose TRIVIAL 23249625 A 630 637 glucose TRIVIAL 23249625 A 973 980 glucose TRIVIAL 23249625 T 108 115 glucose TRIVIAL 23249626 A 1118 1125 sulfate SYSTEMATIC 23249751 A 313 324 2'-O-methyl SYSTEMATIC 23250808 A 267 276 esculetin TRIVIAL 23250808 A 39 48 esculetin TRIVIAL 23250808 A 468 475 ethanol SYSTEMATIC 23250808 A 495 508 decenoic acid SYSTEMATIC 23250808 A 50 71 6,7-dihydroxycoumarin SYSTEMATIC 23250808 A 510 520 oleic acid TRIVIAL 23250808 A 522 536 R-(+)-limonene TRIVIAL 23250808 A 542 553 laurocapram TRIVIAL 23250808 A 555 560 Azone TRIVIAL 23250808 A 570 577 ethanol SYSTEMATIC 23250808 A 625 635 oleic acid TRIVIAL 23250808 A 639 650 laurocapram TRIVIAL 23250808 A 723 732 esculetin TRIVIAL 23250808 A 781 792 laurocapram TRIVIAL 23250808 A 845 854 esculetin TRIVIAL 23250808 T 41 50 esculetin TRIVIAL 23252553 A 214 224 ampicillin TRIVIAL 23252553 A 225 236 clavulanate TRIVIAL 23252553 A 275 278 Lys FORMULA 23252553 A 390 393 Arg FORMULA 23252553 A 418 428 ampicillin TRIVIAL 23252553 A 429 440 clavulanate TRIVIAL 23252553 A 494 497 Arg FORMULA 23252553 A 506 509 Ser FORMULA 23252553 A 544 547 Ser FORMULA 23252553 A 591 602 clavulanate TRIVIAL 23252553 A 626 638 boronic acid SYSTEMATIC 23252553 A 712 722 ampicillin TRIVIAL 23252553 A 801 811 ampicillin TRIVIAL 23252553 A 843 851 hydrogen SYSTEMATIC 23252553 A 932 935 Ser FORMULA 23252553 A 944 947 Lys FORMULA 23252553 A 961 969 hydrogen SYSTEMATIC 23252553 T 120 130 sulfhydryl FAMILY 23252553 T 32 44 boronic acid SYSTEMATIC 23252553 T 94 109 clavulanic acid TRIVIAL 23252613 A 513 522 LiFePO(4) FORMULA 23252613 A 809 811 Li FORMULA 23252613 T 121 123 Li FORMULA 23252799 A 144 153 PS-b-P4VP ABBREVIATION 23252846 A 251 255 YBCO ABBREVIATION 23252846 A 33 48 YBa(2)Cu(3)O(7) FORMULA 23252846 A 362 366 YBCO ABBREVIATION 23252846 A 50 54 YBCO ABBREVIATION 23252846 A 594 596 Au FORMULA 23252950 A 121 129 Busulfan TRIVIAL 23252950 A 139 155 cyclophosphamide TRIVIAL 23252950 A 386 394 aldehyde SYSTEMATIC 23252950 A 569 580 glutathione TRIVIAL 23252950 A 581 582 S FORMULA 23252950 A 715 724 melphalan TRIVIAL 23252950 A 733 745 chlorambucil TRIVIAL 23252950 T 28 36 busulfan TRIVIAL 23252950 T 37 53 cyclophosphamide TRIVIAL 23253427 A 0 15 Carbon monoxide SYSTEMATIC 23253427 A 1115 1123 CORM-319 IDENTIFIER 23253427 A 1163 1165 CO FORMULA 23253427 A 1365 1379 iron carbonyls FAMILY 23253427 A 140 142 CO FORMULA 23253427 A 1462 1464 CO FORMULA 23253427 A 1543 1545 CO FORMULA 23253427 A 269 271 CO FORMULA 23253427 A 37 39 CO FORMULA 23253427 A 381 401 iron-allyl carbonyls FAMILY 23253427 A 438 440 CO FORMULA 23253427 A 478 486 CORM-307 IDENTIFIER 23253427 A 488 496 CORM-308 IDENTIFIER 23253427 A 501 509 CORM-314 IDENTIFIER 23253427 A 527 544 dimethylsulfoxide SYSTEMATIC 23253427 A 546 550 DMSO ABBREVIATION 23253427 A 575 583 CORM-319 IDENTIFIER 23253427 A 60 82 organometallo carbonyl FAMILY 23253427 A 628 641 iron-carbonyl SYSTEMATIC 23253427 A 647 673 hydrogen tetrafluoroborate SYSTEMATIC 23253427 A 730 732 CO FORMULA 23253427 A 734 736 CO FORMULA 23253427 A 752 756 DMSO ABBREVIATION 23253427 A 886 900 iron carbonyls FAMILY 23253427 A 912 916 DMSO ABBREVIATION 23253427 A 926 928 CO FORMULA 23253427 T 39 51 nitric oxide SYSTEMATIC 23253427 T 74 78 iron SYSTEMATIC 23253427 T 90 105 carbon monoxide SYSTEMATIC 23254197 A 213 221 androgen FAMILY 23254197 A 323 332 estrogens FAMILY 23254197 A 574 583 estrogens FAMILY 23254197 A 640 649 estradiol TRIVIAL 23254197 A 8 15 steroid FAMILY 23254197 T 0 9 Estradiol TRIVIAL 23254197 T 55 63 androgen FAMILY 23254198 A 1179 1191 progesterone TRIVIAL 23254198 A 125 133 estrogen FAMILY 23254198 A 1252 1255 BZA ABBREVIATION 23254198 A 1312 1320 estrogen FAMILY 23254198 A 1476 1479 BZA ABBREVIATION 23254198 A 1513 1516 BZA ABBREVIATION 23254198 A 171 179 estrogen FAMILY 23254198 A 295 306 progestogen FAMILY 23254198 A 323 335 bazedoxifene TRIVIAL 23254198 A 337 340 BZA ABBREVIATION 23254198 A 358 367 estrogens FAMILY 23254198 A 533 542 estradiol TRIVIAL 23254198 A 88 96 estrogen FAMILY 23254198 A 983 986 BZA ABBREVIATION 23254198 T 24 36 bazedoxifene TRIVIAL 23254198 T 55 63 estrogen FAMILY 23254253 A 1138 1145 AgVO(3) FORMULA 23254253 A 1189 1196 lithium SYSTEMATIC 23254253 A 1265 1267 Ag FORMULA 23254253 A 167 174 lithium SYSTEMATIC 23254253 A 259 280 silver vanadium oxide SYSTEMATIC 23254253 A 284 291 AgVO(3) FORMULA 23254253 A 325 327 Ag FORMULA 23254253 A 359 365 carbon SYSTEMATIC 23254253 A 436 438 Ag FORMULA 23254253 A 541 548 AgVO(3) FORMULA 23254253 A 616 618 Ag FORMULA 23254253 A 790 797 AgVO(3) FORMULA 23254253 T 101 108 lithium SYSTEMATIC 23254253 T 47 68 silver vanadium oxide SYSTEMATIC 23254341 A 904 910 Ca(2+) FORMULA 23254341 A 921 922 N FORMULA 23254573 A 104 110 7-DCCA SYSTEMATIC 23254573 A 121 124 AOT ABBREVIATION 23254573 A 125 134 isooctane SYSTEMATIC 23254573 A 333 339 7-DCCA SYSTEMATIC 23254573 A 357 360 AOT ABBREVIATION 23254573 A 361 370 isooctane SYSTEMATIC 23254573 A 55 102 7-(N,N'-diethylamino)coumarin-3-carboxylic acid SYSTEMATIC 23254573 A 645 651 7-DCCA SYSTEMATIC 23254573 A 779 785 7-DCCA SYSTEMATIC 23254573 A 941 947 7-DCCA SYSTEMATIC 23254573 T 20 67 7-(N,N'-diethylamino)coumarin-3-carboxylic acid SYSTEMATIC 23254573 T 77 80 AOT ABBREVIATION 23254573 T 81 90 isooctane SYSTEMATIC 23255101 A 107 114 silicon SYSTEMATIC 23255101 T 77 84 silicon SYSTEMATIC 23255236 A 0 1 N FORMULA 23255236 A 166 167 N FORMULA 23255236 A 264 265 N FORMULA 23255236 A 423 424 N FORMULA 23255236 A 592 593 N FORMULA 23255236 T 39 40 N FORMULA 23255254 A 203 227 2-aminoethylmethacrylate SYSTEMATIC 23255254 A 25 33 ammonium SYSTEMATIC 23255254 A 359 368 cyanamide SYSTEMATIC 23255254 A 39 48 guanidine TRIVIAL 23255254 T 47 77 poly(2-aminoethylmethacrylate) FAMILY 23255426 A 1089 1097 selenium SYSTEMATIC 23255426 A 1375 1383 selenium SYSTEMATIC 23255426 A 472 476 (1)H FORMULA 23255426 A 632 640 selenium SYSTEMATIC 23255426 A 680 688 selenium SYSTEMATIC 23255426 A 807 815 selenium SYSTEMATIC 23255426 A 920 928 selenium SYSTEMATIC 23256440 A 1437 1448 polystyrene SYSTEMATIC 23256440 A 217 227 norbornene TRIVIAL 23256440 A 401 412 polystyrene SYSTEMATIC 23256440 A 940 951 polystyrene SYSTEMATIC 23256525 A 111 117 silver SYSTEMATIC 23256525 A 296 309 Ag(55)-SCH(3) FORMULA 23256525 A 488 493 thiol FAMILY 23256525 A 52 64 methyl-thiol SYSTEMATIC 23256525 A 638 644 Ag(55) FORMULA 23256525 A 674 680 SCH(3) FORMULA 23256525 A 761 767 Ag(55) FORMULA 23256525 T 35 39 SCH3 FORMULA 23256525 T 60 64 Ag55 FORMULA 23256531 A 1009 1016 benzene SYSTEMATIC 23256531 A 1208 1213 C(60) TRIVIAL 23256531 A 1320 1329 fullerene TRIVIAL 23256531 A 137 142 C(60) TRIVIAL 23256531 A 1455 1460 C(60) TRIVIAL 23256531 A 1488 1493 C(60) TRIVIAL 23256531 A 1521 1526 C(60) TRIVIAL 23256531 A 1559 1568 C(12)G(2) FORMULA 23256531 A 1569 1576 butanol SYSTEMATIC 23256531 A 1689 1698 C(12)G(2) FORMULA 23256531 A 1795 1800 C(60) TRIVIAL 23256531 A 1858 1888 cetyltrimethylammonium bromide SYSTEMATIC 23256531 A 1890 1894 CTAB ABBREVIATION 23256531 A 1900 1931 cetyltrimethylammonium chloride SYSTEMATIC 23256531 A 1933 1937 CTAC ABBREVIATION 23256531 A 1940 1945 C(60) TRIVIAL 23256531 A 1974 1978 CTAB ABBREVIATION 23256531 A 1989 1993 CTAC ABBREVIATION 23256531 A 2132 2137 C(60) TRIVIAL 23256531 A 2270 2275 C(60) TRIVIAL 23256531 A 2349 2358 fullerene TRIVIAL 23256531 A 260 267 butanol SYSTEMATIC 23256531 A 297 302 C(60) TRIVIAL 23256531 A 306 313 benzene SYSTEMATIC 23256531 A 436 441 C(60) TRIVIAL 23256531 A 513 518 C(60) TRIVIAL 23256531 A 54 63 fullerene TRIVIAL 23256531 A 619 626 butanol SYSTEMATIC 23256531 A 627 634 benzene SYSTEMATIC 23256531 A 647 652 C(60) TRIVIAL 23256531 A 65 70 C(60) TRIVIAL 23256531 A 681 686 C(60) TRIVIAL 23256531 A 851 856 C(60) TRIVIAL 23256531 A 938 960 diglycerol monolaurate TRIVIAL 23256531 A 962 971 C(12)G(2) FORMULA 23256531 A 996 1003 butanol SYSTEMATIC 23256531 T 32 41 Fullerene TRIVIAL 23256531 T 43 48 C(60) TRIVIAL 23256625 A 1023 1033 GSK1292263 IDENTIFIER 23256625 A 1090 1101 simvastatin TRIVIAL 23256625 A 1174 1184 GSK1292263 IDENTIFIER 23256625 A 1218 1229 simvastatin TRIVIAL 23256625 A 1234 1245 rosuvastain TRIVIAL 23256625 A 134 145 simvastatin TRIVIAL 23256625 A 1352 1362 GSK1292263 IDENTIFIER 23256625 A 150 162 rosuvastatin TRIVIAL 23256625 A 247 257 GSK1292263 IDENTIFIER 23256625 A 324 334 GSK1292263 IDENTIFIER 23256625 A 382 393 simvastatin TRIVIAL 23256625 A 418 430 rosuvastatin TRIVIAL 23256625 A 465 475 GSK1292263 IDENTIFIER 23256625 A 60 70 GSK1292263 IDENTIFIER 23256625 A 609 619 GSK1292263 IDENTIFIER 23256625 A 766 777 simvastatin TRIVIAL 23256625 A 825 837 rosuvastatin TRIVIAL 23256625 A 921 931 GSK1292263 IDENTIFIER 23256625 T 35 45 GSK1292263 IDENTIFIER 23256708 A 155 171 allylic alcohols FAMILY 23256708 A 176 209 potassium alkenyltrifluoroborates FAMILY 23256708 A 21 23 Ir FORMULA 23256708 A 307 320 Ir-(P,olefin) FAMILY 23256708 A 373 383 1,4-dienes FAMILY 23256708 A 387 394 trienes FAMILY 23256708 A 446 456 (-)-nyasol TRIVIAL 23256708 A 461 478 (-)-hinokiresinol TRIVIAL 23256708 A 72 94 vinyl trifluoroborates FAMILY 23256708 T 0 7 Iridium SYSTEMATIC 23257178 A 1001 1008 steroid FAMILY 23257178 A 121 128 steroid FAMILY 23257178 A 1219 1226 steroid FAMILY 23257178 A 1271 1278 steroid FAMILY 23257178 A 1317 1324 steroid FAMILY 23257178 A 1342 1352 ergosterol TRIVIAL 23257178 A 1450 1456 sterol FAMILY 23257178 A 1507 1514 steroid FAMILY 23257178 A 1600 1610 tryptophan TRIVIAL 23257178 A 185 192 steroid FAMILY 23257178 A 262 269 Steroid FAMILY 23257178 A 536 551 androstenedione TRIVIAL 23257178 A 556 568 testosterone TRIVIAL 23257178 A 651 659 steroids FAMILY 23257178 A 749 756 steroid FAMILY 23257178 A 910 917 steroid FAMILY 23257178 T 0 7 Steroid FAMILY 23257312 A 1005 1013 ADX71743 IDENTIFIER 23257312 A 1211 1219 ADX71743 IDENTIFIER 23257312 A 1248 1259 amphetamine TRIVIAL 23257312 A 13 22 glutamate TRIVIAL 23257312 A 1320 1351 2,5-dimethoxy-4-iodoamphetamine SYSTEMATIC 23257312 A 1516 1524 ADX71743 IDENTIFIER 23257312 A 1697 1705 ADX71743 IDENTIFIER 23257312 A 316 386 (+)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d]oxazol-4(5H)-one SYSTEMATIC 23257312 A 388 396 ADX71743 IDENTIFIER 23257312 A 532 569 L-(+)-2-amino-4-phosphonobutyric acid SYSTEMATIC 23257312 A 673 681 ADX71743 IDENTIFIER 23257312 A 877 885 ADX71743 IDENTIFIER 23257312 T 0 8 ADX71743 IDENTIFIER 23257312 T 79 88 glutamate TRIVIAL 23257627 A 52 117 6-amino-4-(2,4-dimethoxyphenyl)-[1,2]dithiolo[4,3-b]pyrrol-5-ones FAMILY 23257627 A 549 565 cyclophosphamide TRIVIAL 23257627 T 25 90 6-amino-4-(2,4-dimethoxyphenyl)-[1,2]dithiolo[4,3-b]pyrrol-5-ones FAMILY 23257735 A 127 135 cortisol TRIVIAL 23257735 A 89 100 aldosterone TRIVIAL 23257735 T 55 66 aldosterone TRIVIAL 23257777 A 51 59 graphene TRIVIAL 23257777 A 63 71 graphane TRIVIAL 23257777 A 880 888 graphene TRIVIAL 23257777 A 889 897 graphane TRIVIAL 23257777 A 924 932 hydrogen SYSTEMATIC 23257777 A 980 988 hydrogen SYSTEMATIC 23257777 T 61 69 graphene TRIVIAL 23257777 T 73 81 graphane TRIVIAL 23258121 A 109 114 44BPY SYSTEMATIC 23258121 A 497 502 44BPY SYSTEMATIC 23258121 A 602 610 pyridine SYSTEMATIC 23258121 A 90 107 (4,4')-bipyridine SYSTEMATIC 23258121 T 0 17 (4,4')-Bipyridine SYSTEMATIC 23258548 A 1014 1020 25HC3S SYSTEMATIC 23258548 A 1162 1172 fatty acid FAMILY 23258548 A 1183 1193 acetyl-CoA SYSTEMATIC 23258548 A 1213 1233 glycerol-3-phosphate SYSTEMATIC 23258548 A 1264 1270 25HC3S SYSTEMATIC 23258548 A 1412 1419 glucose TRIVIAL 23258548 A 1474 1480 25HC3S SYSTEMATIC 23258548 A 1571 1577 25HC3S SYSTEMATIC 23258548 A 319 330 cholesterol TRIVIAL 23258548 A 343 375 5-cholesten-3β,25-diol 3-sulfate SYSTEMATIC 23258548 A 377 383 25HC3S SYSTEMATIC 23258548 A 549 555 25HC3S SYSTEMATIC 23258548 A 697 703 25HC3S SYSTEMATIC 23258548 A 859 865 25HC3S SYSTEMATIC 23258548 T 0 32 5-cholesten-3β,25-diol 3-sulfate SYSTEMATIC 23258566 A 1040 1046 oxygen SYSTEMATIC 23258566 A 1116 1119 YSZ ABBREVIATION 23258566 A 1215 1218 YSZ ABBREVIATION 23258566 A 1391 1394 YSZ ABBREVIATION 23258566 A 186 194 Y(2)O(3) FORMULA 23258566 A 206 212 ZrO(2) FORMULA 23258566 A 214 217 YSZ ABBREVIATION 23258566 A 651 656 (18)O FORMULA 23258566 A 700 703 YSZ ABBREVIATION 23258566 A 704 712 Y(2)O(3) FORMULA 23258566 A 817 826 Al(2)O(3) FORMULA 23258566 T 0 6 Oxygen SYSTEMATIC 23258566 T 53 57 Y2O3 FORMULA 23258566 T 58 61 YSZ ABBREVIATION 23259487 A 1000 1024 [Fe(III)(tpp)(ImH)(2)]Cl FORMULA 23259487 A 1026 1029 tpp ABBREVIATION 23259487 A 1032 1057 meso-tetraphenylporphyrin SYSTEMATIC 23259487 A 1070 1076 Fe(II) FORMULA 23259487 A 1083 1089 Fe(II) FORMULA 23259487 A 1100 1107 Fe(III) FORMULA 23259487 A 1230 1237 oxy-pfp SYSTEMATIC 23259487 A 1243 1245 Fe FORMULA 23259487 A 1246 1250 O(2) FORMULA 23259487 A 1251 1254 pfp ABBREVIATION 23259487 A 1359 1363 O(2) FORMULA 23259487 A 1373 1377 iron SYSTEMATIC 23259487 A 232 241 porphyrin FAMILY 23259487 A 32 34 Fe FORMULA 23259487 A 35 39 O(2) FORMULA 23259487 A 358 362 iron SYSTEMATIC 23259487 A 538 542 iron SYSTEMATIC 23259487 A 561 563 Fe FORMULA 23259487 A 564 568 O(2) FORMULA 23259487 A 569 573 heme FAMILY 23259487 A 582 603 [Fe(pfp)(1-MeIm)O(2)] FORMULA 23259487 A 605 608 pfp ABBREVIATION 23259487 A 611 633 picket fence porphyrin FAMILY 23259487 A 638 685 meso-tetra(α,α,α,α-o-pivalamidophenyl)porphyrin SYSTEMATIC 23259487 A 689 695 TpivPP ABBREVIATION 23259487 A 901 922 [Fe(pfp)(1-MeIm)O(2)] FORMULA 23259487 A 955 979 [Fe(II)(pfp)(1-MeIm)(2)] FORMULA 23259487 A 981 994 [Fe(II)(pfp)] FORMULA 23259487 T 0 4 Iron SYSTEMATIC 23259487 T 102 104 O2 FORMULA 23259487 T 62 71 porphyrin FAMILY 23259487 T 99 101 Fe FORMULA 23259533 A 214 216 Si FORMULA 23259533 A 238 246 graphene TRIVIAL 23259533 A 495 497 Si FORMULA 23259533 A 559 561 Si FORMULA 23259533 T 71 79 Graphene TRIVIAL 23259708 A 1320 1326 silver SYSTEMATIC 23259708 A 1569 1575 silver SYSTEMATIC 23259708 T 55 57 Au FORMULA 23259708 T 62 64 Ag FORMULA 23259819 A 109 115 SnO(2) FORMULA 23259819 A 211 225 graphene oxide SYSTEMATIC 23259819 A 249 255 Sn(2+) FORMULA 23259819 A 280 282 Pd FORMULA 23259819 A 286 288 Pt FORMULA 23259819 A 335 349 graphene oxide SYSTEMATIC 23259819 A 34 41 alcohol FAMILY 23259819 A 360 374 graphene oxide SYSTEMATIC 23259819 A 390 398 graphene TRIVIAL 23259819 A 417 424 NaBH(4) FORMULA 23259819 A 444 450 carbon SYSTEMATIC 23259819 A 458 471 Vulcan XC-72R TRIVIAL 23259819 A 483 485 Pd FORMULA 23259819 A 490 492 Pt FORMULA 23259819 A 508 516 graphene TRIVIAL 23259819 A 517 519 Pd FORMULA 23259819 A 524 526 Pt FORMULA 23259819 A 54 62 graphene TRIVIAL 23259819 A 610 617 alcohol FAMILY 23259819 A 63 65 Pd FORMULA 23259819 A 668 674 SnO(2) FORMULA 23259819 A 70 78 graphene TRIVIAL 23259819 A 79 81 Pt FORMULA 23259819 T 108 115 alcohol FAMILY 23259819 T 34 42 graphene TRIVIAL 23259819 T 43 45 Pd FORMULA 23259819 T 47 49 Pt FORMULA 23259848 A 388 391 C-H FORMULA 23259848 A 447 460 polypropylene SYSTEMATIC 23259848 A 473 476 C-H FORMULA 23259848 A 557 567 bromoalkyl FAMILY 23259848 A 599 634 2-(dimethylamino)ethyl methacrylate SYSTEMATIC 23259848 A 636 642 DMAEMA ABBREVIATION 23259848 A 648 669 glycidyl methacrylate TRIVIAL 23259848 A 671 674 GMA ABBREVIATION 23259848 A 733 742 P(DMAEMA) ABBREVIATION 23259848 A 754 760 P(GMA) ABBREVIATION 23259848 A 772 777 epoxy SYSTEMATIC 23259848 A 792 798 P(GMA) ABBREVIATION 23259848 A 867 876 P(DMAEMA) ABBREVIATION 23260346 A 338 348 darapladib TRIVIAL 23260346 A 460 470 darapladib TRIVIAL 23260346 A 528 534 serine TRIVIAL 23260346 A 764 774 darapladib TRIVIAL 23260346 A 818 827 carbamate FAMILY 23260350 A 0 12 Leukotrienes FAMILY 23260350 A 206 212 LTA(4) ABBREVIATION 23260350 A 216 222 LTB(4) ABBREVIATION 23260350 A 224 230 LTB(4) ABBREVIATION 23260350 A 338 349 benzofurans FAMILY 23260350 A 377 387 benzofuran SYSTEMATIC 23260350 A 444 450 LTB(4) ABBREVIATION 23260350 A 532 542 Benzofuran SYSTEMATIC 23260350 A 92 108 Leukotriene A(4) TRIVIAL 23260350 T 18 28 benzofuran SYSTEMATIC 23260350 T 65 81 leukotriene A(4) TRIVIAL 23261051 A 1375 1399 methyl methane sulfonate SYSTEMATIC 23261051 A 1401 1404 MMS ABBREVIATION 23261051 A 1531 1534 MMS ABBREVIATION 23261051 A 1665 1668 MMS ABBREVIATION 23261423 A 0 8 Nicotine TRIVIAL 23261423 A 10 13 NIC ABBREVIATION 23261423 A 1142 1166 [(3)H]methyllycaconitine SYSTEMATIC 23261423 A 1202 1205 NIC ABBREVIATION 23261423 A 1206 1210 MDMA ABBREVIATION 23261423 A 1267 1271 MDMA ABBREVIATION 23261423 A 128 141 acetylcholine SYSTEMATIC 23261423 A 1313 1316 NIC ABBREVIATION 23261423 A 1385 1389 MDMA ABBREVIATION 23261423 A 1838 1846 nicotine TRIVIAL 23261423 A 1872 1876 MDMA ABBREVIATION 23261423 A 273 307 3,4-methylenedioxy-methamphetamine SYSTEMATIC 23261423 A 309 313 MDMA ABBREVIATION 23261423 A 406 410 MDMA ABBREVIATION 23261423 A 530 534 MDMA ABBREVIATION 23261423 A 589 592 NIC ABBREVIATION 23261423 A 625 634 serotonin TRIVIAL 23261423 A 658 662 MDMA ABBREVIATION 23261423 A 696 712 [(3)H]paroxetine SYSTEMATIC 23261423 A 846 849 NIC ABBREVIATION 23261423 A 877 880 NIC ABBREVIATION 23261423 A 885 889 MDMA ABBREVIATION 23261423 A 928 945 [(3)H]epibatidine SYSTEMATIC 23261423 T 0 34 3,4-Methylenedioxy-methamphetamine SYSTEMATIC 23261423 T 155 163 nicotine TRIVIAL 23261526 A 1002 1018 methyl parathion TRIVIAL 23261526 A 1048 1053 thiol FAMILY 23261526 A 1085 1109 2-hydroxyethyl disulfide SYSTEMATIC 23261526 A 1111 1117 2-HEDS SYSTEMATIC 23261526 A 1134 1150 4-hydroxynonenal SYSTEMATIC 23261526 A 1152 1155 HNE ABBREVIATION 23261526 A 1166 1174 aldehyde SYSTEMATIC 23261526 A 1262 1265 HNE ABBREVIATION 23261526 A 1377 1380 HNE ABBREVIATION 23261526 A 16 17 S FORMULA 23261526 A 4 15 glutathione TRIVIAL 23261526 A 414 425 amino acids FAMILY 23261526 A 550 561 amino acids FAMILY 23261526 T 50 61 glutathione TRIVIAL 23261526 T 62 63 S FORMULA 23261589 A 0 10 Salsolinol TRIVIAL 23261589 A 1034 1037 SAL ABBREVIATION 23261589 A 1142 1145 SAL ABBREVIATION 23261589 A 12 15 SAL ABBREVIATION 23261589 A 1367 1370 Sal ABBREVIATION 23261589 A 139 183 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine SYSTEMATIC 23261589 A 1679 1682 SAL ABBREVIATION 23261589 A 1749 1757 LY294002 IDENTIFIER 23261589 A 1826 1829 SAL ABBREVIATION 23261589 A 185 189 MPTP ABBREVIATION 23261589 A 20 41 catechol isoquinoline FAMILY 23261589 A 305 308 SAL ABBREVIATION 23261589 A 483 486 SAL ABBREVIATION 23261589 A 832 835 SAL ABBREVIATION 23261589 T 0 10 Salsolinol TRIVIAL 23261643 A 1012 1026 benzo(a)pyrene SYSTEMATIC 23261643 A 1028 1041 valproic acid TRIVIAL 23261643 A 1073 1085 aflatoxin B1 TRIVIAL 23261643 A 1150 1163 cycloheximide TRIVIAL 23261643 A 1165 1187 sodium lauryl sulphate SYSTEMATIC 23261643 A 1189 1218 atropine sulphate monohydrate SYSTEMATIC 23261643 A 1220 1240 acetylsalicylic acid SYSTEMATIC 23261643 A 678 689 Neutral Red TRIVIAL 23261672 A 214 234 glufosinate ammonium SYSTEMATIC 23261672 A 544 564 glufosinate ammonium SYSTEMATIC 23261678 A 1021 1031 oleuropein TRIVIAL 23261678 A 1188 1198 oleuropein TRIVIAL 23261678 A 1271 1281 oleuropein TRIVIAL 23261678 A 502 512 oleuropein TRIVIAL 23261678 A 620 630 oleuropein TRIVIAL 23261678 A 878 888 oleuropein TRIVIAL 23261678 T 10 20 oleuropein TRIVIAL 23261679 A 1147 1158 monotropein TRIVIAL 23261679 A 249 260 monotropein TRIVIAL 23261679 A 32 43 monotropein TRIVIAL 23261679 A 339 345 sodium SYSTEMATIC 23261679 A 381 392 Monotropein TRIVIAL 23261679 A 443 455 nitric oxide SYSTEMATIC 23261679 A 617 628 monotropein TRIVIAL 23261679 A 726 737 monotropein TRIVIAL 23261679 A 894 905 monotropein TRIVIAL 23261679 T 0 11 Monotropein TRIVIAL 23261679 T 142 148 sodium SYSTEMATIC 23261757 A 1086 1095 vitamin D FAMILY 23261757 A 1365 1375 gentamicin FAMILY 23261757 A 655 662 nitrate SYSTEMATIC 23261757 A 756 766 gentamicin FAMILY 23261757 A 889 899 gentamicin FAMILY 23261757 T 113 123 gentamicin FAMILY 23262028 A 304 318 streptozotocin TRIVIAL 23262035 A 116 136 2-aminobenzothiazole SYSTEMATIC 23262035 A 141 189 1-aryl-3,3-bis- (methylsulfanyl)-2-propen-1-ones FAMILY 23262035 A 230 244 sodium hydride SYSTEMATIC 23262035 A 248 251 THF ABBREVIATION 23262035 A 30 85 (E)-3-(Benzo [d]thiazol-2-ylamino)phenylprop-2-en-1-one SYSTEMATIC 23262035 A 332 336 (1)H FORMULA 23262035 A 342 347 (13)C FORMULA 23262035 A 471 526 (E)-3-(Benzo [d]thiazol-2-ylamino)phenylprop-2-en-1-one SYSTEMATIC 23262035 T 70 126 (E)-3-(Benzo [d]thiazol-2-ylamino) phenylprop-2-en-1-one SYSTEMATIC 23262161 A 914 933 poly(vinyl alcohol) SYSTEMATIC 23262161 A 935 938 PVA ABBREVIATION 23262161 A 944 965 poly(ethylene glycol) SYSTEMATIC 23262161 A 967 970 PEG ABBREVIATION 23262201 A 1006 1009 PTX ABBREVIATION 23262201 A 1019 1022 PTX ABBREVIATION 23262201 A 1061 1064 PTX ABBREVIATION 23262201 A 1124 1127 PTX ABBREVIATION 23262201 A 1134 1137 PTX ABBREVIATION 23262201 A 1211 1214 PTX ABBREVIATION 23262201 A 1226 1229 PTX ABBREVIATION 23262201 A 1236 1239 PTX ABBREVIATION 23262201 A 1384 1387 PTX ABBREVIATION 23262201 A 1443 1446 PTX ABBREVIATION 23262201 A 1472 1475 PTX ABBREVIATION 23262201 A 1581 1584 PTX ABBREVIATION 23262201 A 1621 1624 PTX ABBREVIATION 23262201 A 1693 1696 PTX ABBREVIATION 23262201 A 1704 1707 PTX ABBREVIATION 23262201 A 1730 1733 PTX ABBREVIATION 23262201 A 1781 1784 PTX ABBREVIATION 23262201 A 1870 1873 PTX ABBREVIATION 23262201 A 189 199 paclitaxel TRIVIAL 23262201 A 201 204 PTX ABBREVIATION 23262201 A 557 560 PTX ABBREVIATION 23262201 A 605 638 N-(2-hydroxypropyl)methacrylamide SYSTEMATIC 23262201 A 639 643 HPMA ABBREVIATION 23262201 A 655 658 PTX ABBREVIATION 23262201 A 673 676 PTX ABBREVIATION 23262201 A 951 954 PTX ABBREVIATION 23262201 A 956 960 HPMA ABBREVIATION 23262201 A 971 974 PTX ABBREVIATION 23262201 T 120 130 paclitaxel TRIVIAL 23262201 T 64 68 HPMA ABBREVIATION 23262268 A 131 165 C(22)-steroidal lactone glycosides FAMILY 23262268 A 213 231 chonglouoside SL-7 TRIVIAL 23262268 A 240 258 chonglouoside SL-8 TRIVIAL 23262268 A 435 469 C(22)-steroidal lactone glycosides FAMILY 23262268 T 0 34 C(22)-steroidal lactone glycosides FAMILY 23262392 A 0 8 Caffeine TRIVIAL 23262392 A 1034 1047 chelerythrine TRIVIAL 23262392 A 1052 1065 staurosporine TRIVIAL 23262392 A 110 118 caffeine TRIVIAL 23262392 A 1184 1192 caffeine TRIVIAL 23262392 A 1213 1221 caffeine TRIVIAL 23262392 A 1252 1262 wortmannin TRIVIAL 23262392 A 136 145 Glutamate TRIVIAL 23262392 A 1381 1391 wortmannin TRIVIAL 23262392 A 1393 1401 caffeine TRIVIAL 23262392 A 1407 1417 wortmannin TRIVIAL 23262392 A 1418 1426 caffeine TRIVIAL 23262392 A 1464 1472 caffeine TRIVIAL 23262392 A 1527 1535 caffeine TRIVIAL 23262392 A 213 222 glutamate TRIVIAL 23262392 A 296 306 amino acid FAMILY 23262392 A 387 395 caffeine TRIVIAL 23262392 A 577 588 l-Glutamate TRIVIAL 23262392 A 678 686 Caffeine TRIVIAL 23262392 A 740 748 Caffeine TRIVIAL 23262392 A 837 846 glutamate TRIVIAL 23262392 A 879 910 phorbol-12-myristate-13-acetate SYSTEMATIC 23262392 A 912 915 PMA ABBREVIATION 23262392 A 950 958 caffeine TRIVIAL 23262392 A 960 963 PMA ABBREVIATION 23262392 T 0 8 Caffeine TRIVIAL 23262392 T 47 56 glutamate TRIVIAL 23262562 A 138 146 platinum SYSTEMATIC 23262562 A 227 244 [C(4)mim][NTf(2)] ABBREVIATION 23262562 A 246 265 [C(4)mpyrr][NTf(2)] ABBREVIATION 23262562 A 267 281 [C(4)mim][OTf] ABBREVIATION 23262562 A 286 302 [C(4)mim][BF(4)] FORMULA 23262562 A 311 313 Ag FORMULA 23262562 A 314 319 Ag(+) FORMULA 23262562 A 33 45 benzoic acid SYSTEMATIC 23262562 A 440 452 benzoic acid SYSTEMATIC 23262562 A 489 493 H(+) FORMULA 23262562 A 522 530 hydrogen SYSTEMATIC 23262562 A 558 559 H FORMULA 23262562 A 596 608 benzoic acid SYSTEMATIC 23262562 A 685 716 bis(benzyloxycarbonyl)-l-lysine SYSTEMATIC 23262562 A 77 85 hydrogen SYSTEMATIC 23262562 A 87 91 H(2) FORMULA 23262562 T 24 36 benzoic acid SYSTEMATIC 23262562 T 75 83 hydrogen SYSTEMATIC 23262562 T 89 97 platinum SYSTEMATIC 23263362 A 1013 1015 Fe FORMULA 23263362 A 1149 1150 S FORMULA 23263362 A 487 492 Fe2S2 FORMULA 23263362 A 499 504 Fe3S4 FORMULA 23263362 A 514 519 Fe4S4 FORMULA 23263362 A 687 689 Fe FORMULA 23263362 A 694 695 S FORMULA 23263362 A 72 77 Fe2S2 FORMULA 23263362 A 79 84 Fe3S4 FORMULA 23263362 A 794 796 Fe FORMULA 23263362 A 89 94 Fe4S4 FORMULA 23263362 T 74 79 Fe₂S₂ FORMULA 23263362 T 84 89 Fe₃S₄ FORMULA 23263362 T 97 102 Fe₄S₄ FORMULA 23263864 A 493 494 C FORMULA 23263984 A 240 250 fatty acid FAMILY 23263984 A 588 598 amino acid FAMILY 23263984 T 104 114 fatty acid FAMILY 23264019 A 526 533 lindane TRIVIAL 23264019 A 535 544 gamma-HCH TRIVIAL 23264019 A 562 569 lindane TRIVIAL 23264019 A 832 839 Lindane TRIVIAL 23264019 T 80 87 lindane TRIVIAL 23264448 A 1062 1074 valacyclovir TRIVIAL 23264448 A 1145 1157 Valacyclovir TRIVIAL 23264448 A 1208 1223 glycylsarcosine TRIVIAL 23264448 A 1232 1261 aminocephalosporin cefadroxil SYSTEMATIC 23264448 A 1278 1289 amino acids FAMILY 23264448 A 1290 1298 l-valine TRIVIAL 23264448 A 1302 1313 l-histidine TRIVIAL 23264448 A 1332 1348 p-aminohippurate TRIVIAL 23264448 A 1370 1388 tetraethylammonium SYSTEMATIC 23264448 A 1490 1502 valacyclovir TRIVIAL 23264448 A 152 164 valacyclovir TRIVIAL 23264448 A 1691 1703 valacyclovir TRIVIAL 23264448 A 205 214 acyclovir TRIVIAL 23264448 A 350 368 [(3)H]valacyclovir SYSTEMATIC 23264448 A 407 416 Acyclovir TRIVIAL 23264448 A 492 504 valacyclovir TRIVIAL 23264448 A 543 555 valacyclovir TRIVIAL 23264448 A 704 716 Valacyclovir TRIVIAL 23264448 A 969 981 Valacyclovir TRIVIAL 23264448 T 72 84 valacyclovir TRIVIAL 23265191 A 0 11 Iron-sulfur SYSTEMATIC 23265191 A 1031 1035 Fe-S FORMULA 23265191 A 1150 1154 Fe-S FORMULA 23265191 A 13 17 Fe-S FORMULA 23265191 A 148 159 iron-sulfur SYSTEMATIC 23265191 A 202 213 iron-sulfur SYSTEMATIC 23265191 A 288 292 Fe-S FORMULA 23265191 A 343 351 cysteine TRIVIAL 23265191 A 656 660 iron SYSTEMATIC 23265191 A 704 712 cysteine TRIVIAL 23265191 A 794 798 iron SYSTEMATIC 23265191 A 803 813 L-cysteine TRIVIAL 23265191 A 819 828 Fe(4)S(4) FORMULA 23265191 A 97 101 Fe-S FORMULA 23265191 T 28 34 sulfur SYSTEMATIC 23265191 T 50 54 iron SYSTEMATIC 23265191 T 76 81 Fe4S4 FORMULA 23265312 A 193 200 silicon SYSTEMATIC 23265312 A 9 16 silicon SYSTEMATIC 23265447 A 185 187 Na FORMULA 23265447 A 189 190 K FORMULA 23265447 A 192 194 Ca FORMULA 23265447 A 217 219 Mn FORMULA 23265447 A 442 448 sodium SYSTEMATIC 23265447 A 515 516 K FORMULA 23265447 A 521 523 Ca FORMULA 23265447 A 540 542 Na FORMULA 23265447 A 547 549 Ca FORMULA 23265447 A 668 669 K FORMULA 23265447 A 69 73 NaCl FORMULA 23265447 A 75 78 KCl FORMULA 23265447 A 84 91 CaCl(2) FORMULA 23265448 A 170 179 triiodide SYSTEMATIC 23265448 A 232 241 triiodide SYSTEMATIC 23265448 A 360 379 potassium triiodide SYSTEMATIC 23265448 A 39 47 platinum SYSTEMATIC 23265448 A 416 425 triiodide SYSTEMATIC 23265448 A 494 503 triiodide SYSTEMATIC 23265448 A 565 573 platinum SYSTEMATIC 23265448 T 54 62 platinum SYSTEMATIC 23265450 A 312 329 hydrogen peroxide SYSTEMATIC 23265450 A 348 352 urea TRIVIAL 23265450 A 888 892 urea TRIVIAL 23265450 A 897 914 hydrogen peroxide SYSTEMATIC 23265451 A 693 708 β-cryptoxanthin TRIVIAL 23265451 A 809 814 epoxy SYSTEMATIC 23265451 A 815 823 furanoxy SYSTEMATIC 23265451 A 841 853 violaxanthin TRIVIAL 23265451 A 858 872 antheraxanthin TRIVIAL 23265454 A 0 9 Myricetin TRIVIAL 23265454 A 1075 1084 myricetin TRIVIAL 23265454 A 1109 1119 myricitrin TRIVIAL 23265454 A 1193 1202 flavonoid FAMILY 23265454 A 1306 1315 myricetin TRIVIAL 23265454 A 1345 1355 myricitrin TRIVIAL 23265454 A 14 24 myricitrin TRIVIAL 23265454 A 380 389 myricetin TRIVIAL 23265454 A 391 401 myricitrin TRIVIAL 23265454 A 403 412 quercetin TRIVIAL 23265454 A 417 427 quercitrin TRIVIAL 23265454 A 433 436 MTT ABBREVIATION 23265454 A 458 467 myricetin TRIVIAL 23265454 A 49 59 flavonoids FAMILY 23265454 A 545 555 myricitrin TRIVIAL 23265454 A 572 582 quercitrin TRIVIAL 23265454 A 692 701 myricetin TRIVIAL 23265454 A 731 741 myricitrin TRIVIAL 23265454 A 822 832 flavonoids FAMILY 23265454 A 892 907 acridine orange TRIVIAL 23265454 A 931 935 FITC ABBREVIATION 23265454 A 978 987 myricetin TRIVIAL 23265454 A 992 1002 myricitrin TRIVIAL 23265454 T 49 59 flavonoids FAMILY 23265455 A 100 111 Penconazole TRIVIAL 23265455 A 113 124 Procymidone TRIVIAL 23265455 A 126 135 Iprodione TRIVIAL 23265455 A 137 151 Bromopropylate TRIVIAL 23265455 A 156 174 Lambda-Cyhalothrin TRIVIAL 23265455 A 541 549 florosil TRIVIAL 23265455 A 701 712 cyclohexane SYSTEMATIC 23265455 A 713 726 ethyl acetate SYSTEMATIC 23265455 A 763 771 florosil TRIVIAL 23265455 A 86 98 Chlorpyrifos TRIVIAL 23265457 A 511 522 amino acids FAMILY 23265457 A 536 547 nucleotides FAMILY 23265457 A 877 896 γ-aminobutyric acid SYSTEMATIC 23265457 A 901 914 ergothioneine TRIVIAL 23265460 A 18 32 deoxynivalenol TRIVIAL 23265460 A 244 247 DON ABBREVIATION 23265460 A 270 273 DON ABBREVIATION 23265460 A 34 37 DON ABBREVIATION 23265460 A 366 369 DON ABBREVIATION 23265460 A 502 505 DON ABBREVIATION 23265460 A 899 902 DON ABBREVIATION 23265460 A 927 930 DON ABBREVIATION 23265460 T 22 36 deoxynivalenol TRIVIAL 23265463 A 1008 1011 DHS ABBREVIATION 23265463 A 1036 1042 CCl(4) FORMULA 23265463 A 121 127 CCl(4) FORMULA 23265463 A 177 180 DHS ABBREVIATION 23265463 A 226 235 aspartate TRIVIAL 23265463 A 254 261 alanine TRIVIAL 23265463 A 312 318 CCl(4) FORMULA 23265463 A 358 361 DHS ABBREVIATION 23265463 A 469 475 CCl(4) FORMULA 23265463 A 569 579 superoxide TRIVIAL 23265463 A 601 612 glutathione TRIVIAL 23265463 A 654 660 CCl(4) FORMULA 23265463 A 66 84 2,3-dehydrosilybin SYSTEMATIC 23265463 A 708 711 DHS ABBREVIATION 23265463 A 760 772 nitric oxide SYSTEMATIC 23265463 A 830 836 CCl(4) FORMULA 23265463 A 86 89 DHS ABBREVIATION 23265463 A 865 868 DHS ABBREVIATION 23265463 A 935 941 CCl(4) FORMULA 23265463 A 99 119 carbon tetrachloride SYSTEMATIC 23265463 T 27 45 2,3-dehydrosilybin SYSTEMATIC 23265463 T 49 69 carbon tetrachloride SYSTEMATIC 23265464 A 1306 1316 superoxide TRIVIAL 23265464 A 164 168 ABTS ABBREVIATION 23265464 A 178 232 2,2'-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) SYSTEMATIC 23265464 A 400 407 ABTS(+) ABBREVIATION 23265464 A 426 432 Trolox TRIVIAL 23265464 A 434 487 6-hydroxy-2,5,7,8-tetramethychroman-2-carboxylic acid SYSTEMATIC 23265464 A 599 605 Trolox TRIVIAL 23265465 A 1038 1046 daidzein TRIVIAL 23265465 A 1064 1073 genistein TRIVIAL 23265465 A 143 156 isoflavonoids FAMILY 23265465 A 283 291 daidzein TRIVIAL 23265465 A 295 316 O-desmethylangolensin TRIVIAL 23265465 A 332 365 2-(4-hydroxyphenyl)propionic acid SYSTEMATIC 23265465 A 371 380 genistein TRIVIAL 23265465 A 4 17 isoflavonoids FAMILY 23265465 A 421 454 2-(4-hydroxyphenyl)propionic acid SYSTEMATIC 23265465 A 585 622 (S)-2-(4-hydroxyphenyl)propionic acid SYSTEMATIC 23265465 A 628 649 (S)-2-phenylpropionic SYSTEMATIC 23265465 A 805 811 2-HPPA SYSTEMATIC 23265465 A 885 894 genistein TRIVIAL 23265465 A 924 945 O-desmethylangolensin TRIVIAL 23265465 A 987 1000 isoflavonoids FAMILY 23265465 T 14 23 genistein TRIVIAL 23265468 A 145 155 flavonoids FAMILY 23265468 A 162 176 phenolic acids FAMILY 23265468 A 310 318 methanol SYSTEMATIC 23265468 A 332 343 acetic acid SYSTEMATIC 23265468 T 26 36 flavonoids FAMILY 23265468 T 41 55 phenolic acids FAMILY 23265471 A 357 370 glucovanillin TRIVIAL 23265471 A 839 847 vanillin TRIVIAL 23265471 A 861 884 4-hydroxybenzyl alcohol SYSTEMATIC 23265471 A 902 916 anisyl alcohol TRIVIAL 23265471 T 116 125 phenolics FAMILY 23265472 A 1093 1102 potassium SYSTEMATIC 23265472 A 1134 1141 calcium SYSTEMATIC 23265472 A 1171 1177 sodium SYSTEMATIC 23265472 A 1211 1220 magnesium SYSTEMATIC 23265472 A 1257 1268 phosphorous SYSTEMATIC 23265472 A 1297 1306 Manganese SYSTEMATIC 23265472 A 1311 1317 copper SYSTEMATIC 23265472 A 1371 1375 iron SYSTEMATIC 23265472 A 1380 1384 zinc SYSTEMATIC 23265472 A 1540 1553 carbohydrates FAMILY 23265472 A 1592 1599 calcium SYSTEMATIC 23265472 A 1601 1610 potassium SYSTEMATIC 23265472 A 1612 1618 sodium SYSTEMATIC 23265472 A 1620 1631 phosphorous SYSTEMATIC 23265472 A 1633 1639 copper SYSTEMATIC 23265472 A 1641 1645 iron SYSTEMATIC 23265472 A 1647 1656 Vitamin C TRIVIAL 23265472 A 1661 1665 zinc SYSTEMATIC 23265472 A 838 850 carbohydrate FAMILY 23265472 A 908 917 vitamin C TRIVIAL 23265473 A 114 131 isoliquiritigenin TRIVIAL 23265473 A 138 148 liquiritin TRIVIAL 23265473 A 158 175 glycyrrhizic acid TRIVIAL 23265473 A 289 324 1-butyl-3-methylimidazolium bromide SYSTEMATIC 23265473 T 45 62 isoliquiritigenin TRIVIAL 23265473 T 64 74 liquiritin TRIVIAL 23265473 T 80 97 glycyrrhizic acid TRIVIAL 23265474 A 1085 1089 PhIP ABBREVIATION 23265474 A 110 114 PhIP ABBREVIATION 23265474 A 1157 1170 phenylalanine TRIVIAL 23265474 A 1174 1192 phenylacetaldehyde SYSTEMATIC 23265474 A 1224 1232 carbonyl FAMILY 23265474 A 124 134 creatinine TRIVIAL 23265474 A 1287 1300 phenylalanine TRIVIAL 23265474 A 135 148 phenylalanine TRIVIAL 23265474 A 1353 1357 PhIP ABBREVIATION 23265474 A 150 153 CRN ABBREVIATION 23265474 A 154 157 Phe FORMULA 23265474 A 163 173 creatinine TRIVIAL 23265474 A 174 187 phenylalanine TRIVIAL 23265474 A 188 203 4-oxo-2-nonenal SYSTEMATIC 23265474 A 205 208 CRN ABBREVIATION 23265474 A 209 212 Phe FORMULA 23265474 A 286 295 carbonyls FAMILY 23265474 A 307 311 PhIP ABBREVIATION 23265474 A 332 336 PhIP ABBREVIATION 23265474 A 372 375 CRN ABBREVIATION 23265474 A 376 379 Phe FORMULA 23265474 A 460 464 PhIP ABBREVIATION 23265474 A 61 108 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine SYSTEMATIC 23265474 A 701 705 PhIP ABBREVIATION 23265474 A 742 746 PhIP ABBREVIATION 23265474 A 778 781 CRN ABBREVIATION 23265474 A 782 785 Phe FORMULA 23265474 A 790 793 CRN ABBREVIATION 23265474 A 794 797 Phe FORMULA 23265474 A 830 840 creatinine TRIVIAL 23265474 A 856 869 phenylalanine TRIVIAL 23265474 A 904 910 oxygen SYSTEMATIC 23265474 A 994 1001 ammonia SYSTEMATIC 23265474 T 112 122 creatinine TRIVIAL 23265474 T 123 136 phenylalanine TRIVIAL 23265474 T 137 152 4-oxo-2-nonenal SYSTEMATIC 23265474 T 25 72 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine SYSTEMATIC 23265474 T 74 78 PhIP ABBREVIATION 23265474 T 83 93 creatinine TRIVIAL 23265474 T 94 107 phenylalanine TRIVIAL 23265484 A 403 415 n-heptadecan SYSTEMATIC 23265484 A 704 715 E-β-ocimene TRIVIAL 23265484 A 752 760 α-pinene TRIVIAL 23265484 A 770 780 n-heptanol SYSTEMATIC 23265484 A 790 804 β-phellanderne TRIVIAL 23265484 A 817 825 linalool TRIVIAL 23265489 A 693 731 9,10-epoxy-18-hydroxyoctadecanoic acid SYSTEMATIC 23265494 A 1008 1016 1,5-DCQA SYSTEMATIC 23265494 A 198 217 caffeoylquinic acid TRIVIAL 23265494 A 337 348 acetic acid SYSTEMATIC 23265494 A 362 374 acetonitrile SYSTEMATIC 23265494 A 709 725 chlorogenic acid TRIVIAL 23265494 A 727 732 5-CQA SYSTEMATIC 23265494 A 738 763 1,5-dicaffeoylquinic acid SYSTEMATIC 23265494 A 765 773 1,5-DCQA SYSTEMATIC 23265494 A 874 879 5-CQA SYSTEMATIC 23265494 A 976 981 5-CQA SYSTEMATIC 23265494 T 17 32 caffeoyl esters FAMILY 23265496 A 1000 1017 diethylaminoethyl SYSTEMATIC 23265496 A 1147 1155 Tris-HCl SYSTEMATIC 23265505 A 393 397 DPPH ABBREVIATION 23265505 A 663 677 phenolic acids FAMILY 23265505 A 699 724 caffeic and benzoic acids MULTIPLE 23265505 A 730 740 flavonoids FAMILY 23265505 A 971 979 methanol SYSTEMATIC 23265505 A 990 997 ethanol SYSTEMATIC 23265509 A 0 9 Punicalin TRIVIAL 23265509 A 1028 1037 punicalin TRIVIAL 23265509 A 160 169 punicalin TRIVIAL 23265509 A 302 310 methanol SYSTEMATIC 23265509 A 326 329 TFA ABBREVIATION 23265509 A 463 472 punicalin TRIVIAL 23265509 A 519 530 gallic acid TRIVIAL 23265509 A 721 730 punicalin TRIVIAL 23265509 A 746 757 punicalagin TRIVIAL 23265509 A 795 804 punicalin TRIVIAL 23265509 A 922 931 punicalin TRIVIAL 23265509 A 963 969 tannin FAMILY 23265509 T 73 82 punicalin TRIVIAL 23265510 A 1013 1020 retinol TRIVIAL 23265510 A 1025 1038 retinoic acid TRIVIAL 23265510 A 1108 1116 Retinoid FAMILY 23265510 A 1240 1249 retinoids FAMILY 23265510 A 21 28 retinol TRIVIAL 23265510 A 267 274 retinol TRIVIAL 23265510 A 279 292 retinoic acid TRIVIAL 23265510 A 33 46 retinoic acid TRIVIAL 23265510 A 347 355 retinoid FAMILY 23265510 A 447 456 retinoids FAMILY 23265510 A 552 559 retinol TRIVIAL 23265510 A 605 612 retinol TRIVIAL 23265510 A 658 671 retinoic acid TRIVIAL 23265510 A 716 729 retinoic acid TRIVIAL 23265510 A 789 796 retinol TRIVIAL 23265510 A 900 913 retinoic acid TRIVIAL 23265510 T 11 20 vitamin A FAMILY 23265511 A 248 254 Lutein TRIVIAL 23265511 A 313 325 α-tocopherol TRIVIAL 23265511 A 477 488 tocopherols FAMILY 23265511 A 555 561 oxygen SYSTEMATIC 23265511 A 563 571 hydroxyl SYSTEMATIC 23265511 A 577 585 ABTS(·+) ABBREVIATION 23265511 A 835 843 ABTS(·+) ABBREVIATION 23265511 A 953 961 hydroxyl SYSTEMATIC 23265515 A 1058 1065 arsenic SYSTEMATIC 23265515 A 241 249 arsenite SYSTEMATIC 23265515 A 259 266 As(III) FORMULA 23265515 A 299 328 sodium diethyldithiocarbamate SYSTEMATIC 23265515 A 330 334 DDTC ABBREVIATION 23265515 A 373 420 1-octyl-3-methylimidazolium hexafluorophosphate SYSTEMATIC 23265515 A 422 438 [C(8)mim][PF(6)] FORMULA 23265515 A 545 552 As(III) FORMULA 23265515 A 63 70 arsenic SYSTEMATIC 23265515 A 662 667 As(V) FORMULA 23265515 A 722 729 arsenic SYSTEMATIC 23265515 A 734 741 As(III) FORMULA 23265515 A 772 779 arsenic SYSTEMATIC 23265515 A 821 835 organo-arsenic FAMILY 23265515 A 896 903 As(III) FORMULA 23265515 T 0 7 Arsenic SYSTEMATIC 23265516 A 1041 1049 flavones FAMILY 23265516 A 146 154 flavones FAMILY 23265516 A 257 269 anthocyanins FAMILY 23265516 A 33 45 anthocyanins FAMILY 23265516 A 51 59 flavones FAMILY 23265516 A 601 624 cyanidin quinoidal base TRIVIAL 23265516 A 625 633 baicalin TRIVIAL 23265516 A 686 694 hydrogen SYSTEMATIC 23265516 A 957 969 anthocyanins FAMILY 23265516 T 17 28 anthocyanin FAMILY 23265516 T 42 49 flavone TRIVIAL 23265522 A 596 602 phenol SYSTEMATIC 23265522 A 701 715 salicylic acid TRIVIAL 23265522 T 102 116 salicylic acid TRIVIAL 23265523 A 1098 1104 oxygen SYSTEMATIC 23265523 A 1298 1306 phenolic FAMILY 23265523 A 1325 1337 anthocyanins FAMILY 23265523 A 1376 1384 phenolic FAMILY 23265523 A 251 259 phenolic FAMILY 23265523 A 403 411 Phenolic FAMILY 23265523 A 782 799 sulphorhodamine B TRIVIAL 23265523 A 852 860 phenolic FAMILY 23265524 A 1067 1072 sugar FAMILY 23265524 A 1173 1178 sugar FAMILY 23265524 A 1247 1253 tannin FAMILY 23265524 A 153 163 bisulphite SYSTEMATIC 23265524 A 186 191 sugar FAMILY 23265524 A 237 243 tannin FAMILY 23265524 A 308 316 hydrogen SYSTEMATIC 23265524 A 333 337 urea TRIVIAL 23265524 A 357 363 tannin FAMILY 23265524 A 36 41 sugar FAMILY 23265524 A 428 433 sugar FAMILY 23265524 A 493 499 tannin FAMILY 23265524 A 549 555 tannin FAMILY 23265524 A 72 78 tannin FAMILY 23265524 A 770 776 tannin FAMILY 23265524 A 807 814 glucose TRIVIAL 23265524 A 819 826 sucrose TRIVIAL 23265524 A 858 863 sugar FAMILY 23265524 A 896 906 bisulphite SYSTEMATIC 23265524 A 965 970 sugar FAMILY 23265524 A 988 994 tannin FAMILY 23265524 T 0 7 Glucose TRIVIAL 23265524 T 109 116 glucose TRIVIAL 23265524 T 121 128 sucrose TRIVIAL 23265524 T 144 154 bisulphite SYSTEMATIC 23265524 T 22 29 sucrose TRIVIAL 23265524 T 65 71 tannin FAMILY 23265524 T 9 17 fructose TRIVIAL 23265528 A 328 335 glucose TRIVIAL 23265528 A 337 346 galactose TRIVIAL 23265528 A 348 355 lactose TRIVIAL 23265528 A 357 365 fructose TRIVIAL 23265528 A 367 373 ribose TRIVIAL 23265528 A 378 387 arabinose TRIVIAL 23265528 A 574 587 carbohydrates FAMILY 23265528 A 589 595 Ribose TRIVIAL 23265528 A 696 709 anhydroribose TRIVIAL 23265528 A 870 899 1,1-diphenyl-2-picrylhydrazyl SYSTEMATIC 23265528 A 901 905 DPPH ABBREVIATION 23265528 A 951 955 iron SYSTEMATIC 23265532 A 275 280 sugar FAMILY 23265532 A 293 304 citric acid TRIVIAL 23265532 A 40 48 fructose TRIVIAL 23265532 A 523 539 isobutyl acetate SYSTEMATIC 23265532 A 53 65 isomaltulose TRIVIAL 23265532 A 541 555 butyl butyrate SYSTEMATIC 23265532 A 557 577 3-hexen-1-yl acetate SYSTEMATIC 23265532 A 581 592 propan-2-ol SYSTEMATIC 23265532 A 680 686 esters FAMILY 23265532 A 691 699 alcohols FAMILY 23265532 A 750 756 furans FAMILY 23265532 A 758 766 furfural TRIVIAL 23265532 A 768 782 2-acetylfurane SYSTEMATIC 23265532 A 77 84 sucrose TRIVIAL 23265532 A 784 801 5-methyl furfural SYSTEMATIC 23265532 A 803 813 mesifurane TRIVIAL 23265532 A 819 828 aldehydes FAMILY 23265532 A 830 837 octanal SYSTEMATIC 23265532 A 839 846 nonanal SYSTEMATIC 23265532 A 848 855 decanal SYSTEMATIC 23265532 A 860 872 benzaldeyhde SYSTEMATIC 23265532 A 915 922 sucrose TRIVIAL 23265532 A 923 935 isomaltulose TRIVIAL 23265532 A 979 990 citric acid TRIVIAL 23265532 T 80 92 isomaltulose TRIVIAL 23265534 A 392 396 ABTS ABBREVIATION 23265534 A 530 537 ethanol SYSTEMATIC 23265534 A 577 584 ABTS(+) ABBREVIATION 23265534 A 723 730 ABTS(+) ABBREVIATION 23265534 T 16 35 ABTS radical cation ABBREVIATION 23265537 A 139 148 histidine TRIVIAL 23265537 A 159 165 lysine TRIVIAL 23265537 A 26 32 amines FAMILY 23265537 A 274 280 amines FAMILY 23265537 A 356 365 histamine TRIVIAL 23265537 A 383 392 histidine TRIVIAL 23265537 A 443 451 tyramine TRIVIAL 23265537 A 543 548 amine SYSTEMATIC 23265537 A 715 724 histamine TRIVIAL 23265537 A 873 879 amines FAMILY 23265537 A 892 901 histamine TRIVIAL 23265537 A 907 915 tyramine TRIVIAL 23265537 T 9 15 amines FAMILY 23265539 A 1009 1028 Aliphatic aldehydes FAMILY 23265539 A 1037 1044 hexanal SYSTEMATIC 23265539 A 1046 1059 (E)-2-octenal SYSTEMATIC 23265539 A 1065 1072 nonanal SYSTEMATIC 23265539 A 1260 1268 peroxide SYSTEMATIC 23265539 A 1296 1315 aliphatic aldehydes FAMILY 23265539 A 1455 1462 hexanal SYSTEMATIC 23265539 A 1467 1474 nonanal SYSTEMATIC 23265539 A 1566 1574 peroxide SYSTEMATIC 23265539 A 627 635 peroxide SYSTEMATIC 23265539 A 928 937 aldehydes FAMILY 23265539 A 939 947 alcohols FAMILY 23265539 A 953 962 pyrazines FAMILY 23265872 A 16 35 triazole acetamides FAMILY 23265872 A 282 291 milrinone TRIVIAL 23265872 A 304 322 triazole acetamide SYSTEMATIC 23265872 A 404 413 milrinone TRIVIAL 23265872 T 17 36 triazole acetamides FAMILY 23265873 A 149 259 N(4)-(5-(2/3/4-substituted-phenyl)-1,3,4-oxadiazol-2-yl)-N(1)-(3,7-dimethylocta-3,6-dienylidene)-semicarbazide FAMILY 23265873 A 20 144 N(4)-(5-(2/3/4-substituted-phenyl)-1,3,4-oxadiazol-2-yl)-N(1)-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enylidene)semicarbazide FAMILY 23265873 A 472 490 pentylenetrtrazole TRIVIAL 23265873 A 516 526 strychnine TRIVIAL 23265873 A 657 661 GABA ABBREVIATION 23265873 T 107 121 semicarbazones FAMILY 23265873 T 19 25 citral TRIVIAL 23265873 T 32 67 2,5-disubstituted-1,3,4-oxadiazoles FAMILY 23265873 T 6 14 limonene TRIVIAL 23265878 A 107 118 isocytosine TRIVIAL 23265878 A 85 93 xanthine TRIVIAL 23265878 T 21 32 isocytosine TRIVIAL 23265878 T 41 49 xanthine TRIVIAL 23265884 A 155 185 1,14-sperminedihomovanillamide SYSTEMATIC 23265884 A 187 198 orthidine F TRIVIAL 23265884 A 383 391 spermine TRIVIAL 23265884 A 392 401 polyamine FAMILY 23265884 A 486 529 1,14-spermine-di-(2-hydroxyphenylacetamide) SYSTEMATIC 23265884 A 677 703 phenylacetamido-polyamines FAMILY 23265884 T 70 101 1,14-sperminediphenylacetamides FAMILY 23265889 A 138 144 phenol SYSTEMATIC 23265889 A 252 267 aminopyrimidine SYSTEMATIC 23265889 A 303 309 phenol SYSTEMATIC 23265889 A 347 355 hydrogen SYSTEMATIC 23265889 A 375 390 aminopyrimidine SYSTEMATIC 23265889 A 413 428 aminopyrimidine SYSTEMATIC 23265889 T 114 136 phenol glucuronic acid SYSTEMATIC 23265889 T 23 47 dihydropyrrolopyrimidine SYSTEMATIC 23265893 A 1234 1240 (125)I FORMULA 23265893 A 1241 1244 Tyr FORMULA 23265893 A 1404 1410 (125)I FORMULA 23265893 A 571 579 bombesin TRIVIAL 23265895 A 268 273 ST-37 IDENTIFIER 23265895 A 288 301 benzimidazole SYSTEMATIC 23265895 A 423 429 phenyl SYSTEMATIC 23265895 A 440 451 methylamino SYSTEMATIC 23265895 A 483 496 benzimidazole SYSTEMATIC 23265895 A 615 628 benzimidazole SYSTEMATIC 23265895 A 840 846 ST-193 IDENTIFIER 23265895 T 87 100 benzimidazole SYSTEMATIC 23266309 A 290 296 Ca(2+) FORMULA 23266309 A 423 430 calcium SYSTEMATIC 23266309 A 696 703 calcium SYSTEMATIC 23266310 A 1042 1049 nitrate SYSTEMATIC 23266310 A 988 995 cyanide SYSTEMATIC 23266491 A 1069 1078 phosphate SYSTEMATIC 23266491 A 1153 1162 phosphate SYSTEMATIC 23266491 A 337 346 phosphate SYSTEMATIC 23266491 A 663 676 retinoic acid TRIVIAL 23266491 A 728 735 retinol TRIVIAL 23266491 T 0 7 Retinol FAMILY 23266503 A 0 9 Baicalein TRIVIAL 23266503 A 1186 1195 baicalein TRIVIAL 23266503 A 1247 1256 baicalein TRIVIAL 23266503 A 226 235 baicalein TRIVIAL 23266503 A 25 34 flavonoid FAMILY 23266503 A 280 289 baicalein TRIVIAL 23266503 A 352 361 baicalein TRIVIAL 23266503 A 468 477 baicalein TRIVIAL 23266503 A 753 762 baicalein TRIVIAL 23266503 A 794 803 baicalein TRIVIAL 23266503 A 931 940 baicalein TRIVIAL 23266503 T 11 20 baicalein TRIVIAL 23266665 A 0 32 Tri-and diorganotin(IV) orotates FAMILY 23266665 A 104 109 n-Oct FORMULA 23266665 A 114 116 Ph FORMULA 23266665 A 118 127 H(2)Or(-) FORMULA 23266665 A 143 154 orotic acid TRIVIAL 23266665 A 156 162 H(3)Or FORMULA 23266665 A 166 180 n-Bu(2)Sn(HOr) FORMULA 23266665 A 287 301 R(3)Sn(H(2)Or) FAMILY 23266665 A 306 323 R(2)Sn(H(2)Or)(2) FAMILY 23266665 A 416 430 n-Bu(2)Sn(HOr) FORMULA 23266665 A 53 70 R(n)Sn(H(2)Or)(m) FAMILY 23266665 A 649 670 n-Oct(2)Sn(H(2)Or)(2) FORMULA 23266665 A 94 96 Me FORMULA 23266665 A 98 102 n-Bu FORMULA 23266665 T 0 24 Tri- and diorganotin(IV) MULTIPLE 23266665 T 61 72 orotic acid TRIVIAL 23266726 A 0 15 Isothiocyanates FAMILY 23266726 A 1120 1123 ITC ABBREVIATION 23266726 A 1282 1285 ITC ABBREVIATION 23266726 A 17 21 ITCs FAMILY 23266726 A 175 179 ITCs FAMILY 23266726 A 263 266 ITC ABBREVIATION 23266726 A 349 352 ITC ABBREVIATION 23266726 A 503 506 ITC ABBREVIATION 23266726 A 606 609 ITC ABBREVIATION 23266726 A 735 751 mercapturic acid TRIVIAL 23266726 A 985 988 ITC ABBREVIATION 23266726 T 33 48 isothiocyanates FAMILY 23266726 T 56 69 glucosinolate FAMILY 23266733 A 1043 1053 cytarabine TRIVIAL 23266733 A 169 179 cytarabine TRIVIAL 23266733 A 470 480 cytarabine TRIVIAL 23266733 A 954 964 cytarabine TRIVIAL 23266735 A 235 241 sterol FAMILY 23266735 A 425 436 phytosterol FAMILY 23266735 A 43 50 sterols FAMILY 23266735 A 52 72 trihydroxysitosterol SYSTEMATIC 23266735 A 81 110 5α,6β,7α-7α-acetoxysitosterol SYSTEMATIC 23266735 A 9 16 sterols FAMILY 23266735 T 53 64 phytosterol FAMILY 23267008 A 1002 1014 ellagic acid TRIVIAL 23267008 A 1081 1088 suramin TRIVIAL 23267008 A 1093 1104 doxorubicin TRIVIAL 23267008 A 1134 1157 nucleotide triphosphate FAMILY 23267008 A 977 984 suramin TRIVIAL 23267008 A 986 997 doxorubicin TRIVIAL 23267767 A 24 59 ortho-carboranylphenoxyacetanilides FAMILY 23267767 A 422 425 MTT ABBREVIATION 23267767 A 709 715 malate TRIVIAL 23267767 A 897 900 ETB ABBREVIATION 23267767 T 71 86 ortho-carborane TRIVIAL 23267840 A 1117 1125 curcumin TRIVIAL 23267840 A 1142 1151 glutamate TRIVIAL 23267840 A 147 155 curcumin TRIVIAL 23267840 A 159 168 glutamate TRIVIAL 23267840 A 215 229 streptozotocin TRIVIAL 23267840 A 322 331 glutamate TRIVIAL 23267840 A 378 387 glutamate TRIVIAL 23267840 A 451 500 α-amino-3-hydroxy-5-methyl-4-isoxazole propionate SYSTEMATIC 23267840 A 505 525 N-methyl-D-aspartate SYSTEMATIC 23267840 A 606 617 glutathione TRIVIAL 23267840 A 738 747 glutamate TRIVIAL 23267840 A 748 757 aspartate TRIVIAL 23267840 A 793 802 glutamate TRIVIAL 23267840 A 993 1001 Curcumin TRIVIAL 23267840 T 0 4 NMDA ABBREVIATION 23267840 T 130 138 curcumin TRIVIAL 23267840 T 69 83 streptozotocin TRIVIAL 23267840 T 9 13 AMPA ABBREVIATION 23268106 A 0 7 Neu2000 IDENTIFIER 23268106 A 1016 1040 tert-butyl hydroperoxide SYSTEMATIC 23268106 A 1123 1130 Neu2000 IDENTIFIER 23268106 A 1295 1302 Neu2000 IDENTIFIER 23268106 A 1490 1497 Neu2000 IDENTIFIER 23268106 A 1577 1584 phenoxy SYSTEMATIC 23268106 A 165 185 N-methyl-d-aspartate SYSTEMATIC 23268106 A 308 315 Neu2000 IDENTIFIER 23268106 A 347 353 oxygen SYSTEMATIC 23268106 A 375 383 nitrogen SYSTEMATIC 23268106 A 532 539 Neu2000 IDENTIFIER 23268106 A 576 586 superoxide TRIVIAL 23268106 A 588 600 nitric oxide SYSTEMATIC 23268106 A 606 614 hydroxyl SYSTEMATIC 23268106 A 651 664 peroxynitrite SYSTEMATIC 23268106 A 696 703 Neu2000 IDENTIFIER 23268106 A 735 752 hydrogen peroxide SYSTEMATIC 23268106 A 770 779 antimycin FAMILY 23268106 A 804 811 Neu2000 IDENTIFIER 23268106 A 834 842 hydroxyl SYSTEMATIC 23268106 A 865 884 iron(III)-ascorbate SYSTEMATIC 23268106 A 9 84 2-hydroxy-5-(2,3,5,6-tetrafluoro-4 trifluoromethylbenzylamino) benzoic acid SYSTEMATIC 23268106 A 902 910 carbonyl FAMILY 23268106 A 933 941 hydroxyl SYSTEMATIC 23268106 A 955 968 peroxynitrite SYSTEMATIC 23268106 A 984 995 glutathione TRIVIAL 23268106 T 26 33 Neu2000 IDENTIFIER 23268441 A 124 134 nucleotide FAMILY 23268441 A 595 604 Bisulfite SYSTEMATIC 23268441 A 728 737 bisulfite SYSTEMATIC 23268441 A 74 83 bisulfite SYSTEMATIC 23268441 T 58 67 bisulfite SYSTEMATIC 23268549 A 0 7 Ethanol SYSTEMATIC 23268549 A 1168 1181 cyclosporin A TRIVIAL 23268549 A 1186 1199 nortriptyline TRIVIAL 23268549 A 1216 1223 ethanol SYSTEMATIC 23268549 A 1259 1266 ethanol SYSTEMATIC 23268549 A 1345 1352 ethanol SYSTEMATIC 23268549 A 228 235 ethanol SYSTEMATIC 23268549 A 348 355 ethanol SYSTEMATIC 23268549 A 425 431 oxygen SYSTEMATIC 23268549 A 513 520 ethanol SYSTEMATIC 23268549 A 637 643 oxygen SYSTEMATIC 23268549 A 691 699 H(2)O(2) FORMULA 23268549 A 785 792 ethanol SYSTEMATIC 23268549 A 974 981 Ethanol SYSTEMATIC 23268549 T 62 69 Ethanol SYSTEMATIC 23268987 A 175 184 glutamate TRIVIAL 23268987 A 216 223 MGS0028 IDENTIFIER 23268987 A 43 52 glutamate TRIVIAL 23268987 A 577 584 MGS0028 IDENTIFIER 23268987 A 609 616 MGS0028 IDENTIFIER 23268987 A 786 793 MGS0028 IDENTIFIER 23268987 T 27 36 glutamate TRIVIAL 23268987 T 58 65 MGS0028 IDENTIFIER 23270282 A 0 11 Crambescins FAMILY 23270282 A 1017 1024 CrambC1 ABBREVIATION 23270282 A 1029 1037 Cramb816 ABBREVIATION 23270282 A 1056 1061 Na(+) FORMULA 23270282 A 1086 1094 Cramb816 ABBREVIATION 23270282 A 1113 1119 Ca(2+) FORMULA 23270282 A 1128 1136 NcrambA2 ABBREVIATION 23270282 A 1175 1183 Cramb816 ABBREVIATION 23270282 A 1187 1194 calcium SYSTEMATIC 23270282 A 1316 1322 Ca(2+) FORMULA 23270282 A 1364 1372 Cramb816 ABBREVIATION 23270282 A 1427 1434 calcium SYSTEMATIC 23270282 A 1468 1476 Cramb816 ABBREVIATION 23270282 A 1500 1519 guanidine alkaloids FAMILY 23270282 A 1578 1589 crambescins FAMILY 23270282 A 16 29 crambescidins FAMILY 23270282 A 1614 1623 potassium SYSTEMATIC 23270282 A 1640 1648 Cramb816 ABBREVIATION 23270282 A 1674 1681 calcium SYSTEMATIC 23270282 A 1720 1730 nifedipine TRIVIAL 23270282 A 1756 1764 Cramb816 ABBREVIATION 23270282 A 1783 1785 Ca FORMULA 23270282 A 1793 1795 Na FORMULA 23270282 A 2057 2067 crambescin FAMILY 23270282 A 207 223 crambescidin 816 TRIVIAL 23270282 A 2072 2084 crambescidin FAMILY 23270282 A 2112 2118 sodium SYSTEMATIC 23270282 A 2120 2129 potassium SYSTEMATIC 23270282 A 2135 2142 calcium SYSTEMATIC 23270282 A 225 233 Cramb816 ABBREVIATION 23270282 A 242 249 calcium SYSTEMATIC 23270282 A 422 430 Cramb816 ABBREVIATION 23270282 A 460 470 crambescin FAMILY 23270282 A 479 495 norcrambescin A2 TRIVIAL 23270282 A 497 505 NcrambA2 ABBREVIATION 23270282 A 50 69 guanidine alkaloids FAMILY 23270282 A 508 521 crambescin A2 TRIVIAL 23270282 A 523 530 CrambA2 ABBREVIATION 23270282 A 537 550 crambescin C1 TRIVIAL 23270282 A 552 559 CrambC1 ABBREVIATION 23270282 A 617 623 sodium SYSTEMATIC 23270282 A 625 634 potassium SYSTEMATIC 23270282 A 640 647 calcium SYSTEMATIC 23270282 A 707 713 sodium SYSTEMATIC 23270282 A 715 724 potassium SYSTEMATIC 23270282 A 730 737 calcium SYSTEMATIC 23270282 A 773 792 guanidine alkaloids FAMILY 23270282 A 885 896 crambescins FAMILY 23270282 A 907 911 K(+) FORMULA 23270282 A 949 957 NcrambA2 ABBREVIATION 23270282 A 960 967 CrambC1 ABBREVIATION 23270282 A 970 977 CrambA2 ABBREVIATION 23270282 A 985 993 Cramb816 ABBREVIATION 23270282 T 40 56 Crambescidin 816 TRIVIAL 23270282 T 74 80 Sodium SYSTEMATIC 23270282 T 82 91 Potassium SYSTEMATIC 23270282 T 96 103 Calcium SYSTEMATIC 23270326 A 117 135 Cylindrospermopsin TRIVIAL 23270326 A 137 140 CYN ABBREVIATION 23270326 A 312 323 glutathione TRIVIAL 23270326 A 387 405 cylindrospermopsin TRIVIAL 23270326 A 507 510 CYN ABBREVIATION 23270326 A 565 571 oxygen SYSTEMATIC 23270326 A 760 778 cylindrospermopsin TRIVIAL 23270326 T 61 79 cylindrospermopsin TRIVIAL 23270387 A 149 156 mesityl TRIVIAL 23270565 A 0 14 Licochalcone A TRIVIAL 23270565 A 197 206 chalcones FAMILY 23270565 A 208 219 medicagenin TRIVIAL 23270565 A 229 240 munchiwarin TRIVIAL 23270565 A 364 373 chalcones FAMILY 23270565 A 599 608 chalcones FAMILY 23270565 T 67 76 chalcones FAMILY 23270593 A 236 246 amino acid FAMILY 23270593 A 519 525 methyl SYSTEMATIC 23270805 A 17 25 oxytocin TRIVIAL 23270805 A 494 501 glucose TRIVIAL 23270805 A 54 64 anorexigen FAMILY 23270805 A 541 549 oxytocin TRIVIAL 23270805 A 677 685 oxytocin TRIVIAL 23270805 A 891 899 oxytocin TRIVIAL 23270805 T 60 68 oxytocin TRIVIAL 23270965 A 0 19 Safrole-2',3'-oxide SYSTEMATIC 23270965 A 1157 1160 SFO ABBREVIATION 23270965 A 1322 1325 SFO ABBREVIATION 23270965 A 1350 1353 SFO ABBREVIATION 23270965 A 21 24 SFO ABBREVIATION 23270965 A 310 313 SFO ABBREVIATION 23270965 A 568 571 SFO ABBREVIATION 23270965 A 67 74 safrole TRIVIAL 23270965 A 742 745 SFO ABBREVIATION 23270965 A 747 750 SFO ABBREVIATION 23270965 A 76 110 4-allyl-1, 2-methylenedioxybenzene SYSTEMATIC 23270965 A 808 811 SFO ABBREVIATION 23270965 A 978 981 SFO ABBREVIATION 23270965 T 0 19 Safrole-2',3'-oxide SYSTEMATIC 23270990 A 0 6 Valine TRIVIAL 23270990 A 104 117 phenylalanine TRIVIAL 23270990 A 204 207 TEA ABBREVIATION 23270990 A 241 254 phenylalanine TRIVIAL 23270990 A 311 324 phenylalanine TRIVIAL 23270990 A 382 395 phenylalanine TRIVIAL 23270990 A 475 481 valine TRIVIAL 23270990 A 509 516 alanine TRIVIAL 23270990 A 613 620 alanine TRIVIAL 23270990 A 735 738 TEA ABBREVIATION 23270990 A 91 98 alanine TRIVIAL 23270990 T 137 144 calcium SYSTEMATIC 23270990 T 155 164 potassium SYSTEMATIC 23270990 T 31 49 tetraethylammonium SYSTEMATIC 23271001 A 1091 1099 curcumin TRIVIAL 23271001 A 1362 1370 curcumin TRIVIAL 23271001 A 205 213 curcumin TRIVIAL 23271001 A 22 30 curcumin TRIVIAL 23271001 A 370 378 Curcumin TRIVIAL 23271001 A 563 571 Curcumin TRIVIAL 23271001 A 835 843 curcumin TRIVIAL 23271001 T 0 8 Curcumin TRIVIAL 23271002 A 102 105 CAN ABBREVIATION 23271002 A 163 166 CAN ABBREVIATION 23271002 A 209 211 NO FORMULA 23271002 A 302 305 CAN ABBREVIATION 23271002 A 382 385 CAN ABBREVIATION 23271002 A 591 594 CAN ABBREVIATION 23271002 A 67 100 4-methoxy-5- hydroxycanthin-6-one SYSTEMATIC 23271002 T 50 83 4-methoxy-5- hydroxycanthin-6-one SYSTEMATIC 23271679 A 0 4 Iron SYSTEMATIC 23271679 A 1053 1057 iron SYSTEMATIC 23271679 A 1067 1084 ferrous gluconate SYSTEMATIC 23271679 A 1101 1108 glycine TRIVIAL 23271679 A 1154 1158 iron SYSTEMATIC 23271679 A 1178 1182 iron SYSTEMATIC 23271679 A 206 210 iron SYSTEMATIC 23271679 A 280 297 ferrous gluconate SYSTEMATIC 23271679 A 314 321 glycine TRIVIAL 23271679 A 362 366 zinc SYSTEMATIC 23271679 A 372 376 iron SYSTEMATIC 23271679 A 456 460 zinc SYSTEMATIC 23271679 A 514 531 ferrous ascorbate SYSTEMATIC 23271679 A 574 584 radio iron SYSTEMATIC 23271679 A 586 592 (55)Fe FORMULA 23271679 A 597 603 (59)Fe FORMULA 23271679 A 698 702 iron SYSTEMATIC 23271679 A 744 748 iron SYSTEMATIC 23271679 A 854 858 Iron SYSTEMATIC 23271679 A 87 91 iron SYSTEMATIC 23271679 A 906 908 Ca FORMULA 23271679 A 913 915 Zn FORMULA 23271679 A 950 952 Zn FORMULA 23271679 T 30 47 ferrous gluconate SYSTEMATIC 23271679 T 53 60 glycine TRIVIAL 23271679 T 93 97 iron SYSTEMATIC 23273260 A 1006 1014 carbonyl FAMILY 23273260 A 1024 1031 guanine TRIVIAL 23273260 A 1050 1053 C═O FORMULA 23273260 A 1076 1102 cis-[Pt(NH(3))(2)(G)Cl](+) FORMULA 23273260 A 1173 1176 C═O FORMULA 23273260 A 1224 1226 CO FORMULA 23273260 A 1235 1242 guanine TRIVIAL 23273260 A 1287 1295 hydrogen SYSTEMATIC 23273260 A 1326 1352 cis-[Pt(NH(3))(2)(A)Cl](+) FORMULA 23273260 A 137 144 adenine TRIVIAL 23273260 A 1408 1413 PtAN3 FORMULA 23273260 A 1418 1423 PtAN1 FORMULA 23273260 A 1431 1433 Pt FORMULA 23273260 A 1480 1487 adenine TRIVIAL 23273260 A 154 161 guanine TRIVIAL 23273260 A 380 406 cis-[Pt(NH(3))(2)(G)Cl](+) FORMULA 23273260 A 411 437 cis-[Pt(NH(3))(2)(A)Cl](+) FORMULA 23273260 A 451 460 cisplatin TRIVIAL 23273260 A 499 514 carbonyl oxygen SYSTEMATIC 23273260 A 522 524 O6 FORMULA 23273260 A 530 537 guanine TRIVIAL 23273260 A 575 582 adenine TRIVIAL 23273260 A 62 88 cis-[Pt(NH(3))(2)(G)Cl](+) FORMULA 23273260 A 654 661 adenine TRIVIAL 23273260 A 788 814 cis-[Pt(NH(3))(2)(G)Cl](+) FORMULA 23273260 A 852 854 Pt FORMULA 23273260 A 882 889 guanine TRIVIAL 23273260 A 925 933 hydrogen SYSTEMATIC 23273260 A 93 119 cis-[Pt(NH(3))(2)(A)Cl](+) FORMULA 23273260 A 964 972 hydrogen SYSTEMATIC 23273260 A 985 990 NH(3) FORMULA 23273260 T 15 24 cisplatin TRIVIAL 23273260 T 30 37 adenine TRIVIAL 23273260 T 42 49 guanine TRIVIAL 23273506 A 1244 1254 amino acid FAMILY 23273506 A 131 142 alkylpurine FAMILY 23273506 A 1428 1434 serine TRIVIAL 23273506 A 417 441 N3- and N7-alkylguanines MULTIPLE 23273506 A 446 466 1,N(6)-ethenoadenine SYSTEMATIC 23273506 A 530 541 alkylpurine FAMILY 23273895 A 42 48 Ca(2+) FORMULA 23273895 A 917 923 Ca(2+) FORMULA 23273999 A 1029 1069 3,4-methylenedioxy-α-ethylphenethylamine SYSTEMATIC 23273999 A 1071 1078 3,4-BDB SYSTEMATIC 23273999 A 1098 1129 2,5-dimethoxy-4-iodoamphetamine SYSTEMATIC 23273999 A 1131 1134 DOI ABBREVIATION 23273999 A 1157 1165 glaucine TRIVIAL 23273999 A 1189 1224 N-iso-propyl-1,2-diphenylethylamine SYSTEMATIC 23273999 A 1226 1231 NPDPA ABBREVIATION 23273999 A 1238 1280 N-(1-phenylcyclohexyl)-3-ethoxypropanamine SYSTEMATIC 23273999 A 1282 1287 PCEPA ABBREVIATION 23273999 A 1347 1356 verapamil TRIVIAL 23273999 A 1360 1370 sertraline TRIVIAL 23273999 A 939 949 sertraline TRIVIAL 23273999 A 954 963 verapamil TRIVIAL 23274087 A 0 17 6-Hydroxydopamine SYSTEMATIC 23274087 A 1207 1213 6-OHDA SYSTEMATIC 23274087 A 19 25 6-OHDA SYSTEMATIC 23274087 A 245 251 6-OHDA SYSTEMATIC 23274087 A 394 400 6-OHDA SYSTEMATIC 23274087 A 764 770 6-OHDA SYSTEMATIC 23274087 T 0 6 6-OHDA SYSTEMATIC 23274345 A 1719 1724 β-TCP ABBREVIATION 23274345 A 2068 2081 dexamethasone TRIVIAL 23274345 A 2239 2244 β-TCP ABBREVIATION 23274345 A 631 644 dexamethasone TRIVIAL 23274345 A 699 724 beta-tricalcium phosphate SYSTEMATIC 23274345 A 726 731 β-TCP ABBREVIATION 23274345 A 977 990 dexamethasone TRIVIAL 23274345 T 143 156 dexamethasone TRIVIAL 23274345 T 161 186 beta-tricalcium phosphate SYSTEMATIC 23274394 A 1033 1046 methapyrilene TRIVIAL 23274394 A 1124 1137 methapyrilene TRIVIAL 23274394 A 1467 1480 methapyrilene TRIVIAL 23274394 A 274 287 methapyrilene TRIVIAL 23274394 A 654 667 methapyrilene TRIVIAL 23274394 A 799 812 methapyrilene TRIVIAL 23274413 A 0 13 Gambogic acid TRIVIAL 23274413 A 1056 1065 potassium SYSTEMATIC 23274413 A 1108 1114 oxygen SYSTEMATIC 23274413 A 914 921 steroid FAMILY 23274413 T 42 55 gambogic acid TRIVIAL 23274570 A 18 30 spirolactone SYSTEMATIC 23274570 A 36 47 diterpenoid FAMILY 23274570 A 556 568 spirolactone SYSTEMATIC 23274570 A 574 585 diterpenoid FAMILY 23274570 A 601 609 oridonin TRIVIAL 23274570 A 63 71 oridonin TRIVIAL 23274570 T 13 25 spirolactone SYSTEMATIC 23274570 T 31 42 diterpenoid FAMILY 23274570 T 60 67 kaurene TRIVIAL 23274570 T 73 81 oridonin TRIVIAL 23274698 A 1029 1037 androgen FAMILY 23274698 A 1048 1070 dehydroepiandrosterone TRIVIAL 23274698 A 1072 1076 DHEA ABBREVIATION 23274698 A 1372 1380 steroids FAMILY 23274698 A 635 642 steroid FAMILY 23274698 A 853 865 testosterone TRIVIAL 23274698 A 910 922 testosterone TRIVIAL 23274698 A 927 936 estradiol TRIVIAL 23274714 A 0 14 Trichothecenes FAMILY 23274714 A 1006 1020 trichothecenes FAMILY 23274714 A 1223 1236 trichothecene FAMILY 23274714 A 1297 1311 trichothecenes FAMILY 23274714 A 1454 1468 Trichothecenes FAMILY 23274714 A 19 45 sesquiterpenoid mycotoxins FAMILY 23274714 A 191 205 Trichothecenes FAMILY 23274714 A 445 459 trichothecenes FAMILY 23274714 A 604 618 trichothecenes FAMILY 23274714 A 755 769 trichothecenes FAMILY 23274714 A 956 969 trichothecene FAMILY 23274714 T 0 13 Trichothecene FAMILY 23274767 A 1105 1116 cholesterol TRIVIAL 23274767 A 1231 1242 cholesterol TRIVIAL 23274767 A 496 507 polystyrene SYSTEMATIC 23274767 A 57 68 polystyrene SYSTEMATIC 23274767 T 55 66 cholesterol TRIVIAL 23274889 A 1207 1215 butyrate SYSTEMATIC 23274889 A 614 621 lactate FAMILY 23274889 A 636 644 butyrate SYSTEMATIC 23274893 A 1010 1019 glutamate TRIVIAL 23274893 A 1119 1128 glutamine TRIVIAL 23274893 A 1255 1262 glucose TRIVIAL 23274893 A 1317 1324 glucose TRIVIAL 23274893 A 1430 1439 glutamate TRIVIAL 23274893 A 1440 1449 glutamine TRIVIAL 23274893 A 224 231 glucose TRIVIAL 23274893 A 435 444 glutamine TRIVIAL 23274893 A 445 454 glutamate TRIVIAL 23274893 A 534 541 glucose TRIVIAL 23274893 T 119 128 glutamine TRIVIAL 23274893 T 129 138 glutamate TRIVIAL 23274898 A 1104 1112 AS605240 IDENTIFIER 23274898 A 1114 1117 ATP ABBREVIATION 23274898 A 1351 1354 ATP ABBREVIATION 23274898 A 1366 1372 2-NBDG SYSTEMATIC 23274898 A 139 142 ATP ABBREVIATION 23274898 A 1488 1491 ATP ABBREVIATION 23274898 A 16 23 glucose TRIVIAL 23274898 A 294 301 glucose TRIVIAL 23274898 A 334 337 ATP ABBREVIATION 23274898 A 378 391 2-NBD-Glucose SYSTEMATIC 23274898 A 393 399 2-NBDG SYSTEMATIC 23274898 A 465 468 ATP ABBREVIATION 23274898 A 479 485 2-NBDG SYSTEMATIC 23274898 A 511 530 adenosine-phosphate SYSTEMATIC 23274898 A 580 587 suramin TRIVIAL 23274898 A 648 651 ATP ABBREVIATION 23274898 A 729 736 suramin TRIVIAL 23274898 A 748 751 ATP ABBREVIATION 23274898 A 887 890 ATP ABBREVIATION 23274898 A 901 907 2-NBDG SYSTEMATIC 23274898 A 940 943 ATP ABBREVIATION 23274898 A 954 960 2-NBDG SYSTEMATIC 23274898 T 27 30 ATP ABBREVIATION 23274898 T 67 74 Glucose TRIVIAL 23274907 A 423 430 glucose TRIVIAL 23274909 A 251 264 sulfonylureas FAMILY 23274909 A 318 325 glucose TRIVIAL 23274909 A 700 707 glucose TRIVIAL 23274909 A 837 846 carbachol TRIVIAL 23274916 A 1003 1007 TiO2 FORMULA 23274916 A 146 162 titanium dioxide SYSTEMATIC 23274916 A 164 168 TiO2 FORMULA 23274916 A 464 468 TiO2 FORMULA 23274916 A 631 635 TiO2 FORMULA 23274916 A 730 742 polyacrylate FAMILY 23274916 A 755 759 TiO2 FORMULA 23274916 A 931 943 polyacrylate FAMILY 23274916 A 956 960 TiO2 FORMULA 23274916 T 50 66 titanium dioxide SYSTEMATIC 23274916 T 68 72 TiO2 FORMULA 23274950 A 1086 1096 mesalamine TRIVIAL 23274950 A 133 143 mesalamine TRIVIAL 23274950 A 1600 1610 mesalamine TRIVIAL 23274950 A 317 327 mesalamine TRIVIAL 23274950 A 335 340 BaSO4 FORMULA 23274950 T 97 107 mesalamine TRIVIAL 23275067 A 0 4 GABA ABBREVIATION 23275067 A 1031 1035 GABA ABBREVIATION 23275067 A 1067 1123 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol SYSTEMATIC 23275067 A 1125 1132 CGP7930 IDENTIFIER 23275067 A 1167 1175 rac-BHFF ABBREVIATION 23275067 A 1244 1248 GABA ABBREVIATION 23275067 A 1265 1269 GABA ABBREVIATION 23275067 A 1332 1340 rac-BHFF ABBREVIATION 23275067 A 1389 1397 baclofen TRIVIAL 23275067 A 1410 1413 GHB ABBREVIATION 23275067 A 1464 1468 GABA ABBREVIATION 23275067 A 1531 1535 GABA ABBREVIATION 23275067 A 1619 1623 GABA ABBREVIATION 23275067 A 1706 1721 benzodiazepines FAMILY 23275067 A 1723 1730 alcohol FAMILY 23275067 A 1732 1739 cocaine TRIVIAL 23275067 A 1745 1753 nicotine TRIVIAL 23275067 A 176 180 GABA ABBREVIATION 23275067 A 1781 1789 rac-BHFF ABBREVIATION 23275067 A 1810 1818 baclofen TRIVIAL 23275067 A 1830 1833 GHB ABBREVIATION 23275067 A 1897 1901 GABA ABBREVIATION 23275067 A 1940 1948 baclofen TRIVIAL 23275067 A 1953 1956 GHB ABBREVIATION 23275067 A 390 394 GABA ABBREVIATION 23275067 A 426 497 (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one SYSTEMATIC 23275067 A 499 507 rac-BHFF ABBREVIATION 23275067 A 566 574 rac-BHFF ABBREVIATION 23275067 A 600 604 GABA ABBREVIATION 23275067 A 626 634 baclofen TRIVIAL 23275067 A 639 656 γ-hydroxybutyrate SYSTEMATIC 23275067 A 658 661 GHB ABBREVIATION 23275067 A 671 679 diazepam TRIVIAL 23275067 A 692 699 alcohol FAMILY 23275067 A 701 708 cocaine TRIVIAL 23275067 A 714 722 nicotine TRIVIAL 23275067 A 788 792 GABA ABBREVIATION 23275067 A 865 873 rac-BHFF ABBREVIATION 23275067 A 902 906 GABA ABBREVIATION 23275067 A 930 975 3-aminopropyl (diethoxymethyl)phosphinic acid SYSTEMATIC 23275067 A 977 985 CGP35348 IDENTIFIER 23275067 T 73 81 rac-BHFF ABBREVIATION 23275112 A 1090 1102 levofloxacin TRIVIAL 23275112 A 385 391 silica TRIVIAL 23275112 A 749 756 calcium SYSTEMATIC 23275112 A 812 819 ethanol SYSTEMATIC 23275112 A 836 843 silanol SYSTEMATIC 23275112 A 986 998 levofloxacin TRIVIAL 23275112 T 21 33 levofloxacin TRIVIAL 23275442 A 747 755 carboxyl SYSTEMATIC 23275442 A 760 765 amino FAMILY 23275442 A 815 826 amino acids FAMILY 23275471 A 1427 1434 calcein TRIVIAL 23275571 A 849 858 magnesium SYSTEMATIC 23276134 A 232 242 pyrimidine SYSTEMATIC 23276134 A 255 266 quinazoline SYSTEMATIC 23276134 A 285 308 quinazolinone alkaloids FAMILY 23276134 A 414 419 benzo SYSTEMATIC 23276134 A 434 447 quinazolinone SYSTEMATIC 23276134 A 73 104 polycyclic 4(3H)-quinazolinones FAMILY 23276134 T 63 83 4(3H)-quinazolinones FAMILY 23276150 A 1009 1014 amino FAMILY 23276150 A 1056 1061 amino FAMILY 23276150 A 1126 1131 amino FAMILY 23276150 A 1215 1219 PMMA ABBREVIATION 23276150 A 1274 1277 Boc ABBREVIATION 23276150 A 1349 1354 amino FAMILY 23276150 A 135 140 amino FAMILY 23276150 A 1415 1420 amino FAMILY 23276150 A 153 161 hydroxyl SYSTEMATIC 23276150 A 307 312 amino FAMILY 23276150 A 385 397 methacrylate TRIVIAL 23276150 A 453 472 methyl methacrylate SYSTEMATIC 23276150 A 477 502 2-aminoethyl methacrylate SYSTEMATIC 23276150 A 562 567 amino FAMILY 23276150 A 614 639 poly(methyl methacrylate) SYSTEMATIC 23276150 A 641 645 PMMA ABBREVIATION 23276150 A 795 800 amino FAMILY 23276150 A 860 865 amino FAMILY 23276150 A 934 952 p-Toluenesulfonate SYSTEMATIC 23276150 A 969 988 tert-butoxycarbonyl SYSTEMATIC 23276150 A 990 993 Boc ABBREVIATION 23276150 T 11 16 amino FAMILY 23276150 T 71 83 methacrylate TRIVIAL 23276229 A 152 167 2-butoxyethanol SYSTEMATIC 23276229 A 35 49 crystal violet TRIVIAL 23276229 T 28 42 crystal violet TRIVIAL 23276229 T 48 57 hydroxide SYSTEMATIC 23276229 T 90 105 2-butoxyethanol SYSTEMATIC 23276631 A 243 255 progesterone TRIVIAL 23277288 A 1059 1067 pregnane TRIVIAL 23277288 A 665 673 pregnane TRIVIAL 23277288 A 788 797 erlotinib TRIVIAL 23277288 A 799 808 gefitinib TRIVIAL 23277288 A 810 819 nilotinib TRIVIAL 23277288 A 821 830 sorafenib TRIVIAL 23277288 A 83 91 tyrosine TRIVIAL 23277288 A 832 842 vandetanib TRIVIAL 23277288 T 56 64 tyrosine TRIVIAL 23277289 A 1186 1194 mannitol TRIVIAL 23277289 A 1196 1205 trehalose TRIVIAL 23277289 A 1239 1247 mannitol TRIVIAL 23277289 A 1329 1338 trehalose TRIVIAL 23277289 A 1455 1463 mannitol TRIVIAL 23277289 A 1568 1577 trehalose TRIVIAL 23277289 A 1652 1661 trehalose TRIVIAL 23277289 A 1865 1868 AHL ABBREVIATION 23277289 A 275 298 acyl-homoserine lactone FAMILY 23277289 A 300 303 AHL ABBREVIATION 23277289 A 902 910 mannitol TRIVIAL 23277289 A 912 921 trehalose TRIVIAL 23277289 T 43 66 acyl-homoserine-lactone FAMILY 23277358 A 260 266 lysine TRIVIAL 23277358 A 519 530 polyproline FAMILY 23277358 A 764 772 fMet-Lys FORMULA 23277358 A 77 89 (R)-β-lysine TRIVIAL 23277358 A 776 784 fMet-Phe FORMULA 23277358 A 906 924 hydroxyl-(β)-lysyl SYSTEMATIC 23277358 A 951 960 puromycin TRIVIAL 23277358 T 0 12 (R)-β-lysine TRIVIAL 23278281 A 104 115 glutathione TRIVIAL 23278281 A 12 19 Toluene TRIVIAL 23278281 A 135 190 benzylmercapturic, o-, m- and p-toluylmercapturic acids MULTIPLE 23278281 A 192 195 MAs MULTIPLE 23278281 A 21 24 TOL ABBREVIATION 23278281 A 249 252 TOL ABBREVIATION 23278281 A 317 320 MAs FAMILY 23278281 A 354 357 TOL ABBREVIATION 23278281 A 427 430 TOL ABBREVIATION 23278281 A 448 451 TOL ABBREVIATION 23278281 A 462 465 Tol ABBREVIATION 23278281 A 482 495 hippuric acid TRIVIAL 23278281 A 505 513 o-cresol TRIVIAL 23278281 A 515 519 oCre ABBREVIATION 23278281 A 609 612 TOL ABBREVIATION 23278281 A 628 631 Tol ABBREVIATION 23278281 A 686 689 TOL ABBREVIATION 23278281 A 803 806 MAs FAMILY 23278281 A 831 834 Tol ABBREVIATION 23278281 A 873 876 Tol ABBREVIATION 23278281 A 884 887 MAs FAMILY 23278281 A 917 921 oCre ABBREVIATION 23278281 A 965 968 TOL ABBREVIATION 23278281 T 115 123 o-cresol TRIVIAL 23278281 T 134 141 toluene TRIVIAL 23278281 T 14 21 toluene TRIVIAL 23278281 T 40 57 mercapturic acids FAMILY 23278281 T 97 110 hippuric acid TRIVIAL 23278394 A 0 8 Estrogen FAMILY 23278394 A 1076 1087 Fulvestrant TRIVIAL 23278394 A 1225 1234 tamoxifen TRIVIAL 23278394 A 1242 1250 estrogen FAMILY 23278394 A 1557 1566 tamoxifen TRIVIAL 23278394 A 540 548 estrogen FAMILY 23278394 A 701 731 gonadotropin-releasing hormone TRIVIAL 23278394 A 849 858 Tamoxifen TRIVIAL 23278394 T 13 21 estrogen FAMILY 23278396 A 112 120 estrogen FAMILY 23278396 A 136 148 progesterone TRIVIAL 23278396 A 903 912 cisplatin TRIVIAL 23278396 A 914 930 cyclophosphamide TRIVIAL 23278396 A 957 974 poly (ADP-ribose) SYSTEMATIC 23278396 A 998 1005 Tyrosin TRIVIAL 23278403 A 0 8 Androgen FAMILY 23278403 A 230 242 Bicalutamide TRIVIAL 23278403 A 268 280 Enzalutamide TRIVIAL 23278403 T 24 32 androgen FAMILY 23279865 A 12 45 anthra[1,2-d]imidazole-6,11-dione SYSTEMATIC 23279865 T 58 91 anthra[1,2-d]imidazole-6,11-dione SYSTEMATIC 23279867 A 114 133 1,4-naphthoquinones FAMILY 23279867 A 339 404 2-((8E,11Z)-heptadeca-8,11-dienyl)-3-hydroxynaphthalene-1,4-dione SYSTEMATIC 23279867 T 75 94 1,4-naphthoquinones FAMILY 23279930 A 112 128 benzylpiperazine SYSTEMATIC 23279930 A 14 47 [1,2,4]triazolo[3,4-a]phthalazine SYSTEMATIC 23279930 A 381 390 milrinone TRIVIAL 23279930 A 396 468 6-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)tetrazolo[5,1-a]phthalazine SYSTEMATIC 23279930 A 52 79 tetrazolo[5,1-a]phthalazine SYSTEMATIC 23279930 A 572 581 milrinone TRIVIAL 23279930 T 137 153 Benzylpiperazine SYSTEMATIC 23279930 T 39 72 [1,2,4]Triazolo[3,4-a]phthalazine SYSTEMATIC 23279930 T 77 104 Tetrazolo[5,1-a]phthalazine SYSTEMATIC 23280488 A 1008 1011 TBA ABBREVIATION 23280488 A 1063 1069 carbon SYSTEMATIC 23280488 A 1188 1191 TBA ABBREVIATION 23280488 A 1220 1223 TBA ABBREVIATION 23280488 A 1611 1617 carbon SYSTEMATIC 23280488 A 1622 1630 nitrogen SYSTEMATIC 23280488 A 1723 1736 Chlorophyll-a TRIVIAL 23280488 A 1808 1811 TBA ABBREVIATION 23280488 A 1957 1963 carbon SYSTEMATIC 23280488 A 1964 1972 nitrogen SYSTEMATIC 23280488 A 1974 1975 C FORMULA 23280488 A 1976 1977 N FORMULA 23280488 A 198 201 TBA ABBREVIATION 23280488 A 1983 1994 chlorophyll FAMILY 23280488 A 1995 2001 carbon SYSTEMATIC 23280488 A 2003 2006 Chl ABBREVIATION 23280488 A 2007 2008 C FORMULA 23280488 A 2022 2023 C FORMULA 23280488 A 2024 2025 N FORMULA 23280488 A 2109 2112 Chl ABBREVIATION 23280488 A 2113 2114 C FORMULA 23280488 A 2167 2170 TBA ABBREVIATION 23280488 A 2374 2381 Nitrate SYSTEMATIC 23280488 A 2386 2395 phosphate SYSTEMATIC 23280488 A 24 38 terbuthylazine TRIVIAL 23280488 A 2446 2449 TBA ABBREVIATION 23280488 A 2496 2503 nitrate SYSTEMATIC 23280488 A 2782 2796 terbuthylazine TRIVIAL 23280488 A 40 43 TBA ABBREVIATION 23280488 A 708 722 terbuthylazine TRIVIAL 23280488 A 919 922 TBA ABBREVIATION 23280488 T 34 48 terbuthylazine TRIVIAL 23280489 A 1035 1046 dutasteride TRIVIAL 23280489 A 1077 1092 steroid hormone FAMILY 23280489 A 1184 1195 dutasteride TRIVIAL 23280489 A 1252 1263 dutasteride TRIVIAL 23280489 A 1721 1732 dutasteride TRIVIAL 23280489 A 530 541 dutasteride TRIVIAL 23280489 A 783 795 testosterone TRIVIAL 23280489 A 801 820 dihydrotestosterone SYSTEMATIC 23280489 A 822 825 DHT ABBREVIATION 23280489 T 97 108 dutasteride TRIVIAL 23280672 A 1008 1021 methylmercury SYSTEMATIC 23280672 A 1224 1231 mercury SYSTEMATIC 23280672 A 1295 1302 mercury SYSTEMATIC 23280672 A 142 149 mercury SYSTEMATIC 23280672 A 246 253 mercury SYSTEMATIC 23280672 A 294 301 mercury SYSTEMATIC 23280672 A 363 370 mercury SYSTEMATIC 23280672 A 453 460 mercury SYSTEMATIC 23280672 A 577 584 mercury SYSTEMATIC 23280672 A 717 724 mercury SYSTEMATIC 23280672 T 69 76 mercury SYSTEMATIC 23280691 A 1082 1099 4-iso-nonylphenol SYSTEMATIC 23280691 A 114 122 estrogen FAMILY 23280691 A 345 361 ethinylestradiol SYSTEMATIC 23280691 A 510 524 4-nonylphenols FAMILY 23280691 A 537 556 steroidal estrogens FAMILY 23280691 A 640 657 4-iso-nonylphenol SYSTEMATIC 23280691 A 662 669 estrone TRIVIAL 23280691 A 900 918 4-iso-nonylphenols FAMILY 23280809 A 0 13 Amitriptyline TRIVIAL 23280809 A 1280 1293 amitriptyline TRIVIAL 23280809 A 1314 1327 nortriptyline TRIVIAL 23280809 A 1372 1385 nortriptyline TRIVIAL 23280809 A 1461 1474 nortriptyline TRIVIAL 23280809 A 1552 1565 amitriptyline TRIVIAL 23280809 A 1753 1766 nortriptyline TRIVIAL 23280809 A 18 31 nortriptyline TRIVIAL 23280809 A 415 428 amitriptyline TRIVIAL 23280809 A 572 595 Tritiated amitriptyline TRIVIAL 23280809 A 687 692 (3) H FORMULA 23280809 A 920 933 Nortriptyline TRIVIAL 23280809 A 935 960 N-desmethyl amitriptyline SYSTEMATIC 23280809 A 966 987 amitriptyline-N-oxide SYSTEMATIC 23280809 T 50 63 amitriptyline TRIVIAL 23280809 T 68 81 nortriptyline TRIVIAL 23280831 A 114 118 MeHg FORMULA 23280831 A 356 363 mercury SYSTEMATIC 23280831 A 897 901 MeHg FORMULA 23280831 A 99 112 methylmercury SYSTEMATIC 23280831 T 0 7 Mercury SYSTEMATIC 23281020 A 162 170 hydrogen SYSTEMATIC 23281020 A 2 8 carbon SYSTEMATIC 23281020 T 2 8 carbon SYSTEMATIC 23281044 A 132 153 benzo[e]pyridoindoles FAMILY 23281044 A 155 159 BePI ABBREVIATION 23281044 A 302 306 BePI ABBREVIATION 23281044 A 469 485 Tetracyclic BePI ABBREVIATION 23281044 A 569 572 oxo SYSTEMATIC 23281044 A 586 594 pyridine SYSTEMATIC 23281044 A 674 697 benzo[e]pyridoindolones FAMILY 23281044 A 854 858 BePI ABBREVIATION 23281044 T 13 36 benzo[e]pyridoindolones FAMILY 23281180 A 131 143 camptothecin TRIVIAL 23281180 A 267 340 N-arylsulfonyl-(R)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ester FAMILY 23281180 A 33 80 (20S)-10-(3-aminopropyloxy)-7-ethylcamptothecin SYSTEMATIC 23281180 A 399 478 ethyl-(S)-2-acyloxy-2-(6-cyano-5-oxo-1,2,3,5-tetrahydroindolizin-7-yl)butanoate FAMILY 23281180 A 584 591 acetone SYSTEMATIC 23281180 A 82 88 T-2513 IDENTIFIER 23281180 T 100 112 camptothecin TRIVIAL 23281180 T 23 70 (20S)-10-(3-aminopropyloxy)-7-ethylcamptothecin SYSTEMATIC 23281275 A 606 624 poly(ethylenimine) FAMILY 23281275 A 625 628 PEI ABBREVIATION 23281657 A 0 10 Chloroform SYSTEMATIC 23281657 A 11 18 acetone SYSTEMATIC 23281657 A 119 132 diterpenoidal FAMILY 23281657 A 198 211 cyclomyrsinol TRIVIAL 23281657 A 217 227 diterpenes FAMILY 23281657 A 290 294 (1)H FORMULA 23281657 A 299 304 (13)C FORMULA 23281657 T 4 28 cyclomyrsinol diterpenes FAMILY 23281661 A 244 250 silica TRIVIAL 23281661 A 714 720 silica TRIVIAL 23281892 A 284 313 5-nitro-2-furancarboxylamides FAMILY 23281892 A 382 392 nifurtimox TRIVIAL 23281892 A 53 63 nifurtimox TRIVIAL 23281892 A 565 575 nifurtimox TRIVIAL 23281892 A 64 76 eflornithine TRIVIAL 23281892 A 688 717 5-nitro-2-furancarboxylamides FAMILY 23281892 A 807 817 nifurtimox TRIVIAL 23281892 T 11 40 5-nitro-2-furancarboxylamides FAMILY 23281965 A 1388 1395 calcium SYSTEMATIC 23281965 A 1397 1406 phosphate SYSTEMATIC 23281965 A 1408 1419 cholesterol TRIVIAL 23281965 A 1425 1437 triglyceride FAMILY 23281965 A 1696 1707 cholesterol TRIVIAL 23281965 A 1713 1725 triglyceride FAMILY 23281965 A 192 207 thyroid hormone FAMILY 23281965 A 610 621 L-thyroxine TRIVIAL 23281965 T 0 15 Thyroid hormone FAMILY 23282011 A 242 251 thioether SYSTEMATIC 23282011 A 274 282 cysteine TRIVIAL 23282011 A 291 294 Cys FORMULA 23282011 A 305 313 α-carbon SYSTEMATIC 23282011 A 321 331 methionine TRIVIAL 23282011 A 340 343 Met FORMULA 23282011 A 416 422 4Fe-4S FORMULA 23282011 A 452 455 SAM ABBREVIATION 23282011 A 702 711 thioether SYSTEMATIC 23282011 A 758 769 amino acids FAMILY 23282011 A 843 852 thioether SYSTEMATIC 23282011 T 5 11 4Fe-4S FORMULA 23282011 T 66 75 thioether SYSTEMATIC 23282065 A 1042 1052 flavonoids FAMILY 23282065 A 1106 1116 flavonoids FAMILY 23282065 A 1170 1181 amino acids FAMILY 23282065 A 12 22 Flavonoids FAMILY 23282065 A 1231 1240 Quercetin TRIVIAL 23282065 A 1242 1251 myricetin TRIVIAL 23282065 A 1256 1265 genistein TRIVIAL 23282065 A 1364 1387 glycosylated flavonoids FAMILY 23282065 A 1510 1515 sugar FAMILY 23282065 A 300 308 aldehyde SYSTEMATIC 23282065 A 38 50 polyphenolic FAMILY 23282065 A 474 484 flavonoids FAMILY 23282065 A 657 667 flavonoids FAMILY 23282065 T 37 45 aldehyde SYSTEMATIC 23282065 T 68 78 flavonoids FAMILY 23282083 A 119 126 ethanol SYSTEMATIC 23282083 A 48 57 aaptamine TRIVIAL 23282083 A 9 18 aaptamine TRIVIAL 23282083 T 0 9 Aaptamine TRIVIAL 23283546 A 230 238 hydrogen SYSTEMATIC 23283546 A 279 281 OH FORMULA 23283546 A 282 290 phenolic FAMILY 23283546 A 361 369 hydrogen SYSTEMATIC 23283546 A 444 452 hydrogen SYSTEMATIC 23283546 A 51 60 quercetin TRIVIAL 23283546 A 557 565 hydrogen SYSTEMATIC 23283546 A 79 88 taxifolin TRIVIAL 23283546 A 860 868 hydrogen SYSTEMATIC 23283546 A 90 106 dihydroquercetin SYSTEMATIC 23283546 T 43 52 taxifolin TRIVIAL 23283546 T 7 16 quercetin TRIVIAL 23286284 A 808 818 irinotecan TRIVIAL 23286284 A 820 826 CPT-11 IDENTIFIER 23286606 A 1124 1130 oxygen SYSTEMATIC 23286606 A 1242 1248 oxygen SYSTEMATIC 23286606 A 142 156 Ru(bpy)(2)phen FORMULA 23286606 A 163 166 bpy ABBREVIATION 23286606 A 168 182 2,2'-bipyridyl SYSTEMATIC 23286606 A 184 188 phen ABBREVIATION 23286606 A 190 202 phenathrolin SYSTEMATIC 23286606 A 257 282 ruthenium(II) polypyridyl FAMILY 23286606 A 334 340 silica TRIVIAL 23286606 A 69 75 oxygen SYSTEMATIC 23286606 A 912 918 oxygen SYSTEMATIC 23286606 T 127 133 oxygen SYSTEMATIC 23287046 A 437 504 5-(and 6-)-chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate MULTIPLE 23287046 A 45 51 oxygen SYSTEMATIC 23287046 A 506 518 acetyl ester SYSTEMATIC 23287046 A 520 530 CM-H2DCFDA ABBREVIATION 23287412 A 1020 1026 Ca(2+) FORMULA 23287412 A 1061 1067 Ca(2+) FORMULA 23287412 A 1138 1144 Ca(2+) FORMULA 23287412 A 174 181 calcium SYSTEMATIC 23287412 A 416 422 Ca(2+) FORMULA 23287412 T 21 28 calcium SYSTEMATIC 23287539 A 1159 1178 trans-hinokiresinol TRIVIAL 23287539 A 1296 1310 hinokiresinols FAMILY 23287539 A 1430 1449 trans-hinokiresinol TRIVIAL 23287539 A 1482 1495 nitrotyrosine SYSTEMATIC 23287539 A 1552 1566 hinokiresinols FAMILY 23287539 A 1829 1843 hinokiresinols FAMILY 23287539 A 1917 1931 hinokiresinols FAMILY 23287539 A 261 278 Cis-hinokiresinol TRIVIAL 23287539 A 302 317 phenylpropanoid SYSTEMATIC 23287539 A 390 398 estrogen FAMILY 23287539 A 479 508 trans- and cis-hinokiresinols MULTIPLE 23287539 A 577 581 DPPH ABBREVIATION 23287539 A 675 694 trans-hinokiresinol TRIVIAL 23287539 A 775 781 oxygen SYSTEMATIC 23287539 A 782 789 glucose TRIVIAL 23287539 A 937 939 Cu FORMULA 23287539 A 940 942 Zn FORMULA 23287539 A 959 978 trans-hinokiresinol TRIVIAL 23287539 A 999 1016 cis-hinokiresinol TRIVIAL 23287539 T 67 96 trans- and cis-hinokiresinols MULTIPLE 23287708 A 0 17 Sunset yellow FCF TRIVIAL 23287708 T 0 17 Sunset yellow FCF TRIVIAL 23287726 A 232 233 N FORMULA 23287726 A 397 398 N FORMULA 23287726 A 616 626 amino acid FAMILY 23287726 A 688 698 amino acid FAMILY 23287726 A 721 729 cysteine TRIVIAL 23287726 A 907 917 nucleotide FAMILY 23287727 A 108 116 saponins FAMILY 23287727 A 118 125 lignans FAMILY 23287727 A 127 145 spermine alkaloids FAMILY 23287727 A 147 157 flavonoids FAMILY 23287727 A 159 177 glycosides phenols FAMILY 23287727 A 182 192 pyridoxine TRIVIAL 23287737 A 282 294 thiocarbonyl SYSTEMATIC 23287737 A 31 56 2'-deoxy-6-thioguanosines FAMILY 23287737 A 368 373 sugar FAMILY 23287737 A 542 548 s(6)Gs FAMILY 23287737 A 553 559 s(4)Ts FAMILY 23287737 A 58 64 s(6)Gs FAMILY 23287737 A 70 86 4-thiothymidines FAMILY 23287737 A 88 94 s(4)Ts FAMILY 23287737 T 131 143 thiocarbonyl SYSTEMATIC 23288051 A 1002 1020 O(6)-methylguanine SYSTEMATIC 23288051 A 1022 1029 O(6)MeG FORMULA 23288051 A 1053 1060 O(6)MeG FORMULA 23288051 A 1132 1135 MNU ABBREVIATION 23288051 A 186 192 methyl SYSTEMATIC 23288051 A 198 219 ethylmethanesulfonate SYSTEMATIC 23288051 A 224 241 methylnitrosourea SYSTEMATIC 23288051 A 243 246 MNU ABBREVIATION 23288051 A 252 268 ethylnitrosourea SYSTEMATIC 23288051 A 489 492 MNU ABBREVIATION 23288051 A 622 625 MNU ABBREVIATION 23288051 A 709 712 MNU ABBREVIATION 23288051 A 865 877 hypoxanthine TRIVIAL 23288051 A 879 886 guanine TRIVIAL 23288053 A 1082 1088 iodine SYSTEMATIC 23288053 A 1153 1159 iodine SYSTEMATIC 23288053 A 1239 1245 iodine SYSTEMATIC 23288053 A 1577 1583 iodine SYSTEMATIC 23288053 A 370 376 iodine SYSTEMATIC 23288053 A 468 474 iodine SYSTEMATIC 23288053 A 529 545 potassium iodate SYSTEMATIC 23288053 A 594 600 iodine SYSTEMATIC 23288053 A 64 70 iodine SYSTEMATIC 23288053 A 644 650 iodine SYSTEMATIC 23288053 A 692 698 iodine SYSTEMATIC 23288053 T 28 34 iodine SYSTEMATIC 23288144 A 0 9 Sunitinib TRIVIAL 23288144 A 11 14 SUN ABBREVIATION 23288144 A 1143 1146 SUN ABBREVIATION 23288144 A 1277 1280 SUN ABBREVIATION 23288144 A 1408 1411 SUN ABBREVIATION 23288144 A 1522 1525 SUN ABBREVIATION 23288144 A 194 197 SUN ABBREVIATION 23288144 A 406 409 SUN ABBREVIATION 23288144 A 45 53 tyrosine TRIVIAL 23288144 A 551 554 SUN ABBREVIATION 23288144 A 691 694 SUN ABBREVIATION 23288144 A 752 765 actinomycin D TRIVIAL 23288144 A 781 784 SUN ABBREVIATION 23288144 A 846 849 SUN ABBREVIATION 23288144 A 910 926 aryl hydrocarbon FAMILY 23288144 T 0 9 Sunitinib TRIVIAL 23288144 T 13 21 tyrosine TRIVIAL 23288144 T 134 150 aryl hydrocarbon FAMILY 23288505 A 1004 1015 sulfadoxine TRIVIAL 23288505 A 1031 1044 pyrimethamine TRIVIAL 23288505 A 1059 1069 mefloquine TRIVIAL 23288505 A 1091 1102 piperaquine TRIVIAL 23288505 A 408 419 artemisinin TRIVIAL 23288505 A 911 922 artemisinin TRIVIAL 23288505 A 947 959 lumefantrine TRIVIAL 23288505 A 976 987 amodiaquine TRIVIAL 23288505 T 27 38 artemisinin TRIVIAL 23288505 T 79 90 artemisinin TRIVIAL 23288867 A 1041 1047 methyl SYSTEMATIC 23288867 A 1063 1071 hydroxyl SYSTEMATIC 23288867 A 1120 1129 estrogens FAMILY 23288867 A 1150 1159 estradiol TRIVIAL 23288867 A 1256 1260 3-OH SYSTEMATIC 23288867 A 1316 1321 17-OH SYSTEMATIC 23288867 A 1393 1398 17-OH SYSTEMATIC 23288867 A 1403 1407 3-OH SYSTEMATIC 23288867 A 1411 1427 13-espiestradiol SYSTEMATIC 23288867 A 1498 1502 3-OH SYSTEMATIC 23288867 A 1518 1527 estrogens FAMILY 23288867 A 1597 1606 hydroxyls FAMILY 23288867 A 1625 1632 steroid FAMILY 23288867 A 1625 1641 steroid hormones FAMILY 23288867 A 209 213 3-OH SYSTEMATIC 23288867 A 227 235 estriols FAMILY 23288867 A 23 30 estriol TRIVIAL 23288867 A 315 320 16-OH SYSTEMATIC 23288867 A 32 45 16-epiestriol SYSTEMATIC 23288867 A 324 331 estriol TRIVIAL 23288867 A 336 349 16-epiestriol SYSTEMATIC 23288867 A 359 364 17-OH SYSTEMATIC 23288867 A 368 381 17-epiestriol SYSTEMATIC 23288867 A 419 424 17-OH SYSTEMATIC 23288867 A 488 497 estrogens FAMILY 23288867 A 51 64 17-epiestriol SYSTEMATIC 23288867 A 536 544 estriols FAMILY 23288867 A 78 81 UDP ABBREVIATION 23288867 A 781 788 estriol TRIVIAL 23288867 A 793 806 17-epiestriol SYSTEMATIC 23288867 A 859 872 16-epiestriol SYSTEMATIC 23288867 A 907 914 estriol TRIVIAL 23288867 A 962 977 13-epiestradiol SYSTEMATIC 23288867 A 991 1000 estradiol TRIVIAL 23288867 T 103 110 estriol TRIVIAL 23288867 T 112 125 16-epiestriol SYSTEMATIC 23288867 T 127 140 17-epiestriol SYSTEMATIC 23288867 T 146 161 13-epiestradiol SYSTEMATIC 23288867 T 48 51 UDP ABBREVIATION 23289503 A 0 7 Sudan I TRIVIAL 23289503 A 1118 1125 Sudan I TRIVIAL 23289503 A 1270 1277 Sudan I TRIVIAL 23289503 A 1464 1471 Sudan I TRIVIAL 23289503 A 1529 1536 Sudan I TRIVIAL 23289503 A 1716 1723 Sudan I TRIVIAL 23289503 A 1767 1774 Sudan I TRIVIAL 23289503 A 1825 1828 azo SYSTEMATIC 23289503 A 208 215 Sudan I TRIVIAL 23289503 A 454 461 Sudan I TRIVIAL 23289503 A 492 499 Sudan I TRIVIAL 23289503 A 637 642 NADPH ABBREVIATION 23289503 A 663 670 NAD(P)H ABBREVIATION 23289503 A 671 678 quinone FAMILY 23289503 A 815 822 Sudan I TRIVIAL 23289503 A 9 38 1-phenylazo-2-hydroxynaphthol SYSTEMATIC 23289503 A 986 993 Sudan I TRIVIAL 23289503 T 168 171 azo SYSTEMATIC 23289503 T 176 198 1-phenylazo-2-naphthol SYSTEMATIC 23289503 T 200 207 Sudan I TRIVIAL 23289503 T 45 52 NAD(P)H ABBREVIATION 23289503 T 53 60 quinone FAMILY 23289528 A 1013 1022 porphyrin FAMILY 23289528 A 1031 1035 heme FAMILY 23289528 A 1086 1089 Phe FORMULA 23289528 A 1131 1135 heme FAMILY 23289528 A 1206 1209 Phe FORMULA 23289528 A 1342 1346 heme FAMILY 23289528 A 240 244 heme FAMILY 23289528 A 394 398 heme FAMILY 23289528 A 427 430 His FORMULA 23289528 A 458 462 iron SYSTEMATIC 23289528 A 530 534 heme FAMILY 23289528 A 570 582 Thioflavin T TRIVIAL 23289528 A 703 707 iron SYSTEMATIC 23289528 A 809 813 heme FAMILY 23289528 A 963 967 heme FAMILY 23289528 A 971 985 protoporphyrin FAMILY 23289528 T 27 31 iron SYSTEMATIC 23289528 T 47 56 porphyrin FAMILY 23289528 T 65 69 heme FAMILY 23289528 T 84 88 heme FAMILY 23289788 A 164 175 cholesterol TRIVIAL 23289788 A 531 542 doxorubicin TRIVIAL 23289802 A 137 147 superoxide TRIVIAL 23289802 A 24 30 silica TRIVIAL 23289802 A 346 352 silica TRIVIAL 23289802 A 490 492 Cu FORMULA 23289802 A 493 495 Zn FORMULA 23289802 A 496 506 superoxide TRIVIAL 23289802 A 590 596 oxygen SYSTEMATIC 23289802 A 691 693 Cu FORMULA 23289802 A 694 696 Zn FORMULA 23289802 A 921 923 Ni FORMULA 23289802 T 69 75 silica TRIVIAL 23289802 T 91 101 superoxide TRIVIAL 23289830 A 566 569 Glu FORMULA 23289830 A 625 628 Glu FORMULA 23289830 A 704 716 [³H]CP55,940 SYSTEMATIC 23289830 A 738 742 GABA ABBREVIATION 23289830 A 969 974 HU210 IDENTIFIER 23289830 A 986 999 [(35) S]GTPγS SYSTEMATIC 23289851 A 375 395 phosphatidylinositol TRIVIAL 23289851 A 469 489 phosphatidylinositol TRIVIAL 23289851 A 495 527 phosphatidylinositol 3-phosphate SYSTEMATIC 23289851 A 529 561 Phosphatidylinositol 3-phosphate SYSTEMATIC 23289851 A 849 881 phosphatidylinositol 3-phosphate SYSTEMATIC 23289851 T 10 30 phosphatidylinositol TRIVIAL 23289851 T 66 74 PtdIns3P SYSTEMATIC 23290048 A 18 26 pyrazole SYSTEMATIC 23290048 A 213 217 (1)H FORMULA 23290048 A 218 222 (1)H FORMULA 23290048 A 229 233 (1)H FORMULA 23290048 A 234 239 (13)C FORMULA 23290048 A 249 253 (1)H FORMULA 23290048 A 254 259 (13)C FORMULA 23290048 A 38 51 benzophenones FAMILY 23290048 A 96 144 1-methyl-5-(2,4,6-trimethoxy-phenyl)-1H-pyrazole SYSTEMATIC 23290048 T 71 79 pyrazole SYSTEMATIC 23290048 T 91 104 benzophenones FAMILY 23290051 A 123 129 GUT-70 TRIVIAL 23290051 A 27 33 GUT-70 TRIVIAL 23290051 A 356 362 GUT-70 TRIVIAL 23290051 T 37 55 tricyclic coumarin TRIVIAL 23290051 T 56 62 GUT-70 TRIVIAL 23291047 A 1041 1051 acebutolol TRIVIAL 23291047 A 19 30 propranolol TRIVIAL 23291047 A 227 247 phosphatidylcholines FAMILY 23291047 A 35 45 acebutolol TRIVIAL 23291047 A 664 675 hydrocarbon FAMILY 23291047 A 777 788 propranolol TRIVIAL 23291047 A 793 803 acebutolol TRIVIAL 23291047 A 955 966 propranolol TRIVIAL 23291047 T 76 87 propranolol TRIVIAL 23291047 T 92 102 acebutolol TRIVIAL 23291050 A 1123 1126 AZM ABBREVIATION 23291050 A 1231 1234 AZM ABBREVIATION 23291050 A 1235 1238 CPF ABBREVIATION 23291050 A 1659 1662 AZM ABBREVIATION 23291050 A 1663 1666 CPF ABBREVIATION 23291050 A 1726 1729 CPF ABBREVIATION 23291050 A 1730 1733 CPF ABBREVIATION 23291050 A 1855 1871 organophosphorus FAMILY 23291050 A 2040 2043 OPs FAMILY 23291050 A 344 360 organophosphorus FAMILY 23291050 A 372 387 azinphos-methyl TRIVIAL 23291050 A 389 392 AZM ABBREVIATION 23291050 A 398 410 chlorpyrifos TRIVIAL 23291050 A 412 415 CPF ABBREVIATION 23291050 A 491 494 AZM ABBREVIATION 23291050 A 499 502 CPF ABBREVIATION 23291050 A 668 685 acetylthiocholine SYSTEMATIC 23291050 A 751 772 p-nitrophenyl acetate SYSTEMATIC 23291050 A 774 796 p-nitrophenyl butyrate SYSTEMATIC 23291050 A 798 823 1- and 2-naphthyl acetate MULTIPLE 23291050 A 865 868 CPF ABBREVIATION 23291050 A 918 921 AZM ABBREVIATION 23291050 T 101 116 azinphos-methyl TRIVIAL 23291050 T 121 133 chlorpyrifos TRIVIAL 23291323 A 1000 1004 F(-) FORMULA 23291323 A 1005 1010 OH(-) FORMULA 23291323 A 1115 1120 Cl(-) FORMULA 23291323 A 1244 1252 fluoride SYSTEMATIC 23291323 A 1356 1364 fluoride SYSTEMATIC 23291323 A 204 212 fluoride SYSTEMATIC 23291323 A 270 278 fluoride SYSTEMATIC 23291323 A 39 47 fluoride SYSTEMATIC 23291323 A 549 557 fluoride SYSTEMATIC 23291323 A 842 850 fluoride SYSTEMATIC 23291323 A 971 975 F(-) FORMULA 23291323 A 976 980 H(+) FORMULA 23291323 T 42 50 fluoride SYSTEMATIC 23291341 A 117 124 glucose TRIVIAL 23291341 A 259 264 D-Phe FORMULA 23291341 A 269 274 β-Ala FORMULA 23291341 A 279 282 Phe FORMULA 23291341 A 287 290 Nle FORMULA 23291341 A 295 303 bombesin TRIVIAL 23291341 A 348 355 glucose TRIVIAL 23291341 A 47 54 glucose TRIVIAL 23291341 A 766 773 glucose TRIVIAL 23291341 A 856 866 Wortmannin TRIVIAL 23291341 A 871 878 PD98059 IDENTIFIER 23291341 A 888 897 rapamycin TRIVIAL 23291341 A 947 954 glucose TRIVIAL 23291341 A 999 1006 glucose TRIVIAL 23291341 T 0 8 Bombesin TRIVIAL 23291558 A 1013 1016 FSK ABBREVIATION 23291558 A 1037 1073 phorbol 12-tetradecanoate 13-acetate SYSTEMATIC 23291558 A 1234 1237 BNF ABBREVIATION 23291558 A 1241 1244 FSK ABBREVIATION 23291558 A 203 219 aryl hydrocarbon FAMILY 23291558 A 243 279 2,3,7,8- tetrachlorodibenzo-p-dioxin SYSTEMATIC 23291558 A 448 464 β-naphthoflavone TRIVIAL 23291558 A 466 469 BNF ABBREVIATION 23291558 A 629 632 BNF ABBREVIATION 23291558 A 651 654 BNF ABBREVIATION 23291558 A 755 758 BNF ABBREVIATION 23291558 A 767 776 forskolin TRIVIAL 23291558 A 778 781 FSK ABBREVIATION 23291558 A 864 867 BNF ABBREVIATION 23291558 A 882 885 FSK ABBREVIATION 23291558 A 924 928 cAMP ABBREVIATION 23291558 T 0 16 Aryl hydrocarbon FAMILY 23291595 A 114 125 cholic acid TRIVIAL 23291595 A 127 139 etienic acid TRIVIAL 23291595 A 141 148 estrone TRIVIAL 23291595 A 156 161 Cu(I) FORMULA 23291595 A 209 216 Steroid FAMILY 23291595 A 295 342 2,6-bis((1H-1,2,3-triazol-1-yl)-methyl)pyridine SYSTEMATIC 23291595 T 51 58 steroid FAMILY 23291595 T 94 101 steroid FAMILY 23292158 A 1194 1197 PRG ABBREVIATION 23292158 A 1489 1492 PRG ABBREVIATION 23292158 A 1530 1533 PRG ABBREVIATION 23292158 A 1784 1787 PRG ABBREVIATION 23292158 A 21 24 PRG ABBREVIATION 23292158 A 314 317 PRG ABBREVIATION 23292158 A 445 448 PRG ABBREVIATION 23292158 A 567 570 PRG ABBREVIATION 23292158 A 859 862 PRG ABBREVIATION 23292158 A 9 19 Pregabalin TRIVIAL 23292158 A 978 981 PRG ABBREVIATION 23292158 T 0 10 Pregabalin TRIVIAL 23292170 A 236 243 glucose TRIVIAL 23292170 A 40 47 glucose TRIVIAL 23292170 A 484 491 glucose TRIVIAL 23292170 A 812 819 glucose TRIVIAL 23292170 T 82 89 glucose TRIVIAL 23292655 A 255 266 amino acids FAMILY 23292655 A 689 690 N FORMULA 23292655 A 710 730 N-methyl-D-aspartate SYSTEMATIC 23292747 A 163 169 silver SYSTEMATIC 23292747 A 318 324 silver SYSTEMATIC 23292747 A 34 40 silver SYSTEMATIC 23292747 A 508 513 Ag(+) FORMULA 23292747 A 702 708 silver SYSTEMATIC 23292747 T 30 36 Silver SYSTEMATIC 23292798 A 101 111 4-Me-UAB30 SYSTEMATIC 23292798 A 1011 1016 UAB30 IDENTIFIER 23292798 A 1081 1094 retinoic acid TRIVIAL 23292798 A 1107 1116 vitamin D FAMILY 23292798 A 1163 1168 UAB30 IDENTIFIER 23292798 A 1231 1247 aryl hydrocarbon FAMILY 23292798 A 1347 1352 UAB30 IDENTIFIER 23292798 A 1391 1413 dimethylbenzanthracene SYSTEMATIC 23292798 A 1415 1419 DMBA ABBREVIATION 23292798 A 1471 1475 DMBA ABBREVIATION 23292798 A 1632 1641 Targretin TRIVIAL 23292798 A 175 178 TRG ABBREVIATION 23292798 A 183 193 4-Me-UAB30 SYSTEMATIC 23292798 A 21 29 retinoid FAMILY 23292798 A 222 234 triglyceride FAMILY 23292798 A 57 66 Targretin TRIVIAL 23292798 A 68 71 TRG ABBREVIATION 23292798 A 74 79 UAB30 IDENTIFIER 23292798 A 816 819 TRG ABBREVIATION 23292798 A 822 832 4-Me-UAB30 SYSTEMATIC 23292798 A 835 840 UAB30 IDENTIFIER 23292798 A 85 99 4-methyl-UAB30 SYSTEMATIC 23292798 A 943 956 triglycerides FAMILY 23292798 A 983 986 TRG ABBREVIATION 23292798 A 991 1001 4-Me-UAB30 SYSTEMATIC 23292798 T 105 114 Targretin TRIVIAL 23292798 T 116 126 Bexarotene TRIVIAL 23292798 T 78 83 UAB30 IDENTIFIER 23292798 T 85 99 4-methyl-UAB30 SYSTEMATIC 23293024 A 20 26 serine TRIVIAL 23293024 A 27 36 threonine TRIVIAL 23293106 A 111 114 PCB ABBREVIATION 23293106 A 1149 1153 PCBs ABBREVIATION 23293106 A 1204 1208 PCBs ABBREVIATION 23293106 A 1304 1308 PCBs ABBREVIATION 23293106 A 299 303 PCBs ABBREVIATION 23293106 A 570 574 PCBs ABBREVIATION 23293106 A 611 615 PCBs ABBREVIATION 23293106 A 779 783 PCBs ABBREVIATION 23293106 A 85 109 polychlorinated biphenyl FAMILY 23293106 A 858 862 PCBs ABBREVIATION 23293106 A 941 945 PCBs ABBREVIATION 23293129 A 1226 1262 N-methyl-N'-nitro-N-nitrosoguanidine SYSTEMATIC 23293129 A 1264 1271 acridin TRIVIAL 23293129 A 1276 1285 aflatoxin FAMILY 23293129 A 523 532 aflatoxin FAMILY 23293129 A 60 68 methanol SYSTEMATIC 23293129 A 709 723 aflatoxin B(1) TRIVIAL 23293129 A 765 780 malondialdehyde TRIVIAL 23293129 A 811 821 superoxide TRIVIAL 23293129 A 833 844 glutathione TRIVIAL 23293129 A 849 860 glutathione TRIVIAL 23293129 A 896 905 aflatoxin FAMILY 23293130 A 1013 1028 malondialdehyde TRIVIAL 23293130 A 1039 1052 hydroperoxide FAMILY 23293130 A 1056 1061 trona TRIVIAL 23293130 A 1178 1183 trona TRIVIAL 23293130 A 15 20 trona TRIVIAL 23293130 A 22 26 Kaun TRIVIAL 23293130 A 354 359 trona TRIVIAL 23293130 A 470 475 trona TRIVIAL 23293130 A 791 801 superoxide TRIVIAL 23293130 A 823 834 glutathione TRIVIAL 23293130 A 847 858 glutathione TRIVIAL 23293130 A 887 906 reduced glutathione TRIVIAL 23293130 A 908 924 vitamins C and E MULTIPLE 23293130 T 11 16 trona TRIVIAL 23293300 A 1009 1017 rifampin TRIVIAL 23293300 A 1029 1039 telaprevir TRIVIAL 23293300 A 1042 1045 BOC ABBREVIATION 23293300 A 1149 1155 sodium SYSTEMATIC 23293300 A 1156 1168 taurocholate TRIVIAL 23293300 A 1224 1227 BOC ABBREVIATION 23293300 A 1467 1470 BOC ABBREVIATION 23293300 A 196 199 BOC ABBREVIATION 23293300 A 25 35 boceprevir TRIVIAL 23293300 A 37 40 BOC ABBREVIATION 23293300 A 425 428 UDP ABBREVIATION 23293300 A 467 470 BOC ABBREVIATION 23293300 A 760 763 BOC ABBREVIATION 23293300 A 848 860 pitavastatin TRIVIAL 23293300 A 900 912 atorvastatin TRIVIAL 23293300 A 940 943 BOC ABBREVIATION 23293300 A 986 998 ketoconazole TRIVIAL 23293300 T 58 68 boceprevir TRIVIAL 23294363 A 1120 1128 CNV97101 IDENTIFIER 23294363 A 133 148 fluoroquinolone SYSTEMATIC 23294363 A 150 158 CNV97101 IDENTIFIER 23294363 T 66 81 fluoroquinolone SYSTEMATIC 23294378 A 10 40 ent-eudesmane sesquiterpenoids FAMILY 23294378 A 110 145 polyoxygenated benzofuran-3(2H)-one FAMILY 23294378 A 153 165 arundinone B TRIVIAL 23294378 A 42 56 arundinols A-C MULTIPLE 23294378 A 445 447 Cu FORMULA 23294378 A 488 505 tertiary alcohols FAMILY 23294378 A 584 604 [Rh(2)(OCOCF(3))(4)] FORMULA 23294378 A 585 603 Rh(2)(OCOCF(3))(4) FORMULA 23294378 A 616 628 Arundinone B TRIVIAL 23294378 A 662 682 benzofuran-3(2H)-one SYSTEMATIC 23294378 A 68 84 isochroman-1-one SYSTEMATIC 23294378 A 86 98 arundinone A TRIVIAL 23294378 T 0 14 Arundinols A-C MULTIPLE 23294378 T 19 38 arundinones A and B MULTIPLE 23294700 A 22 30 tyrosine TRIVIAL 23294700 T 35 43 tyrosine TRIVIAL 23295225 A 0 8 Carbonyl SYSTEMATIC 23295225 A 1069 1078 disulfide SYSTEMATIC 23295225 A 1104 1107 Cys FORMULA 23295225 A 1116 1119 Cys FORMULA 23295225 A 1169 1178 cysteines FAMILY 23295225 A 1283 1287 GSNO ABBREVIATION 23295225 A 1372 1376 GSNO ABBREVIATION 23295225 A 1440 1449 menadione TRIVIAL 23295225 A 1451 1468 4-benzoylpyridine SYSTEMATIC 23295225 A 1470 1485 2,3-hexanedione SYSTEMATIC 23295225 A 1487 1499 daunorubicin TRIVIAL 23295225 A 1504 1522 1,4-naphthoquinone SYSTEMATIC 23295225 A 1599 1609 1,2-diketo SYSTEMATIC 23295225 A 1637 1655 1,2-naphthoquinone SYSTEMATIC 23295225 A 1657 1681 9,10-phenanthrenequinone SYSTEMATIC 23295225 A 1683 1689 isatin TRIVIAL 23295225 A 1703 1727 9,10-phenanthrenequinone SYSTEMATIC 23295225 A 1902 1906 GSNO ABBREVIATION 23295225 A 1940 1948 cysteine TRIVIAL 23295225 A 2087 2090 Cys FORMULA 23295225 A 2102 2105 Cys FORMULA 23295225 A 263 283 S-Nitrosoglutathione SYSTEMATIC 23295225 A 285 289 GSNO ABBREVIATION 23295225 A 427 431 GSNO ABBREVIATION 23295225 A 635 639 GSNO ABBREVIATION 23295225 A 896 900 GSNO ABBREVIATION 23295225 A 925 944 S-glutathionylation SYSTEMATIC 23295225 A 94 99 NADPH ABBREVIATION 23295225 A 948 957 cysteines FAMILY 23295225 T 0 20 S-nitrosoglutathione SYSTEMATIC 23295225 T 41 49 cysteine TRIVIAL 23295225 T 68 76 carbonyl FAMILY 23295323 A 115 127 carbon black TRIVIAL 23295323 A 133 142 Printex90 TRIVIAL 23295323 A 312 321 Printex90 TRIVIAL 23295323 A 686 690 TiO2 FORMULA 23295323 A 77 93 titanium dioxide SYSTEMATIC 23295323 A 878 882 TiO2 FORMULA 23295323 A 948 957 Printex90 TRIVIAL 23295323 A 95 99 TiO2 FORMULA 23295385 A 0 8 SKF83959 IDENTIFIER 23295385 A 10 94 3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine SYSTEMATIC 23295385 A 1000 1074 (+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide SYSTEMATIC 23295385 A 109 117 dopamine TRIVIAL 23295385 A 1263 1293 (3)H-1,3-di(2-tolyl)-guanidine SYSTEMATIC 23295385 A 1295 1303 (3)H-DTG SYSTEMATIC 23295385 A 1379 1387 SKF83959 IDENTIFIER 23295385 A 241 246 Na(+) FORMULA 23295385 A 285 294 glutamate TRIVIAL 23295385 A 428 436 SKF83959 IDENTIFIER 23295385 A 489 497 SKF83959 IDENTIFIER 23295385 A 535 554 (3)H(+)-pentazocine SYSTEMATIC 23295385 A 671 688 (3)H-progesterone SYSTEMATIC 23295385 A 853 861 SKF83959 IDENTIFIER 23295385 A 879 887 SCH22390 IDENTIFIER 23295385 A 889 984 (R)-(1)-7-chloro-8- hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride SYSTEMATIC 23295385 A 990 998 SKF38393 IDENTIFIER 23295385 T 0 8 SKF83959 IDENTIFIER 23295386 A 109 119 fatty acid FAMILY 23295386 A 1229 1278 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine SYSTEMATIC 23295386 A 1519 1527 WY14,643 IDENTIFIER 23295386 A 782 837 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid SYSTEMATIC 23295386 A 839 847 WY14,643 IDENTIFIER 23295386 A 999 1007 WY14,643 IDENTIFIER 23295645 A 1141 1161 prednisolone acetate SYSTEMATIC 23295645 A 193 223 Poly(d,l-lactide-co-glycolide) FAMILY 23295645 A 225 229 PLGA ABBREVIATION 23295645 A 56 79 triamcinolone acetonide TRIVIAL 23295645 A 804 806 NO FORMULA 23295645 A 808 812 PGE2 ABBREVIATION 23295645 T 0 33 Polymeric triamcinolone acetonide FAMILY 23295645 T 10 33 triamcinolone acetonide TRIVIAL 23295732 A 119 127 ferrites FAMILY 23295732 A 133 143 cobaltites FAMILY 23295732 A 151 161 perovskite TRIVIAL 23295732 A 602 608 oxygen SYSTEMATIC 23295732 A 655 682 Strontium doped perovskites FAMILY 23295732 A 753 764 perovskites FAMILY 23295732 A 97 117 lanthanum manganites FAMILY 23295732 A 989 995 oxygen SYSTEMATIC 23295732 T 72 82 perovskite TRIVIAL 23296027 A 456 467 corannulene TRIVIAL 23296027 A 478 486 sumanene TRIVIAL 23296027 A 665 675 C(36)H(12) FORMULA 23296098 A 0 12 Ochratoxin A TRIVIAL 23296098 A 1047 1056 estradiol TRIVIAL 23296098 A 14 17 OTA ABBREVIATION 23296098 A 1447 1454 steroid FAMILY 23296098 A 1463 1472 estradiol TRIVIAL 23296098 A 270 273 OTA ABBREVIATION 23296098 A 298 301 OTA ABBREVIATION 23296098 A 395 404 oestrogen FAMILY 23296098 A 406 414 androgen FAMILY 23296098 A 416 427 progestagen FAMILY 23296098 A 629 632 MTT ABBREVIATION 23296098 A 634 668 thiazolyl blue tetrazolium bromide SYSTEMATIC 23296098 T 32 44 ochratoxin A TRIVIAL 23296104 A 0 8 Morphine TRIVIAL 23296104 A 1162 1170 morphine TRIVIAL 23296104 A 1311 1314 CO₂ FORMULA 23296104 A 1433 1441 morphine TRIVIAL 23296104 A 1539 1547 morphine TRIVIAL 23296104 A 1625 1633 morphine TRIVIAL 23296104 A 168 176 morphine TRIVIAL 23296104 A 1737 1745 morphine TRIVIAL 23296104 A 1778 1786 morphine TRIVIAL 23296104 A 1908 1916 morphine TRIVIAL 23296104 A 398 406 morphine TRIVIAL 23296104 A 763 771 Morphine TRIVIAL 23296104 A 993 1001 morphine TRIVIAL 23296104 T 27 35 morphine TRIVIAL 23296142 A 1012 1021 estradiol TRIVIAL 23296142 A 1205 1216 ICI 182,780 IDENTIFIER 23296142 A 1270 1289 bisindolylmaleimide TRIVIAL 23296142 A 1291 1294 BIS FAMILY 23296142 A 1354 1363 estradiol TRIVIAL 23296142 A 1534 1543 estradiol TRIVIAL 23296142 A 37 46 estradiol TRIVIAL 23296142 A 74 82 estrogen FAMILY 23296142 A 972 981 estradiol TRIVIAL 23296142 T 19 28 estradiol TRIVIAL 23296276 A 20 33 borotellurite SYSTEMATIC 23296276 A 53 62 manganese SYSTEMATIC 23296276 A 63 104 (1-x) [(B(2)O(3))(0.3)(TeO(2))(0.7)]-xMnO FAMILY 23296276 A 685 694 manganese SYSTEMATIC 23296276 A 753 768 manganese oxide SYSTEMATIC 23296276 A 803 809 TeO(4) FORMULA 23296276 A 844 850 oxygen SYSTEMATIC 23296276 A 859 865 TeO(3) FORMULA 23296276 A 902 908 oxygen SYSTEMATIC 23296276 T 54 67 borotellurite SYSTEMATIC 23296276 T 85 94 manganese SYSTEMATIC 23296904 A 1041 1052 Resveratrol TRIVIAL 23296904 A 1077 1084 CaCl(2) FORMULA 23296904 A 1090 1108 potassium chloride SYSTEMATIC 23296904 A 1139 1141 Ca FORMULA 23296904 A 1192 1203 resveratrol TRIVIAL 23296904 A 1261 1267 Ca(2+) FORMULA 23296904 A 1284 1290 Ca(2+) FORMULA 23296904 A 1352 1363 resveratrol TRIVIAL 23296904 A 1458 1469 resveratrol TRIVIAL 23296904 A 192 206 norepinephrine TRIVIAL 23296904 A 213 238 adenosine 5'-triphosphate SYSTEMATIC 23296904 A 240 243 ATP ABBREVIATION 23296904 A 251 255 K(+) FORMULA 23296904 A 272 288 calcium chloride SYSTEMATIC 23296904 A 290 297 CaCl(2) FORMULA 23296904 A 303 309 Ca(2+) FORMULA 23296904 A 31 42 resveratrol TRIVIAL 23296904 A 325 329 K(+) FORMULA 23296904 A 332 338 Ca(2+) FORMULA 23296904 A 406 417 resveratrol TRIVIAL 23296904 A 425 431 NS1619 IDENTIFIER 23296904 A 457 464 calcium SYSTEMATIC 23296904 A 479 481 Ca FORMULA 23296904 A 535 546 resveratrol TRIVIAL 23296904 A 554 557 ATP ABBREVIATION 23296904 A 604 606 Ca FORMULA 23296904 A 648 659 resveratrol TRIVIAL 23296904 A 740 741 K FORMULA 23296904 A 742 744 Ca FORMULA 23296904 A 773 776 ATP ABBREVIATION 23296904 A 800 804 K(+) FORMULA 23296904 A 844 855 resveratrol TRIVIAL 23296904 A 884 888 K(+) FORMULA 23296904 A 911 922 resveratrol TRIVIAL 23296904 A 997 1008 resveratrol TRIVIAL 23296904 T 15 25 Polyphenol FAMILY 23296904 T 26 37 Resveratrol TRIVIAL 23296904 T 86 100 Norepinephrine TRIVIAL 23297162 A 1017 1028 atipamezole TRIVIAL 23297162 A 1145 1164 5-hydroxytryptamine SYSTEMATIC 23297162 A 1182 1277 (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride SYSTEMATIC 23297162 A 1308 1319 milnacipran TRIVIAL 23297162 A 1499 1510 milnacipran TRIVIAL 23297162 A 1569 1577 naloxone TRIVIAL 23297162 A 1633 1644 milnacipran TRIVIAL 23297162 A 1952 1963 milnacipran TRIVIAL 23297162 A 282 291 monoamine FAMILY 23297162 A 472 494 monosodium iodoacetate SYSTEMATIC 23297162 A 563 572 serotonin TRIVIAL 23297162 A 573 586 noradrenaline TRIVIAL 23297162 A 606 617 milnacipran TRIVIAL 23297162 A 708 719 milnacipran TRIVIAL 23297162 A 956 967 atipamezole TRIVIAL 23297162 T 30 41 milnacipran TRIVIAL 23297162 T 49 71 monosodium iodoacetate SYSTEMATIC 23297245 A 0 7 Mercury SYSTEMATIC 23297245 A 1146 1153 mercury SYSTEMATIC 23297245 A 1264 1271 mercury SYSTEMATIC 23297245 A 1314 1321 mercury SYSTEMATIC 23297245 A 1400 1407 mercury SYSTEMATIC 23297245 A 143 150 mercury SYSTEMATIC 23297245 A 286 293 mercury SYSTEMATIC 23297245 A 348 355 mercury SYSTEMATIC 23297245 A 582 589 mercury SYSTEMATIC 23297245 A 704 711 mercury SYSTEMATIC 23297245 A 83 90 mercury SYSTEMATIC 23297245 A 874 881 mercury SYSTEMATIC 23297245 A 914 921 mercury SYSTEMATIC 23297245 A 981 988 mercury SYSTEMATIC 23297245 T 11 18 mercury SYSTEMATIC 23297250 A 1005 1012 sulfate SYSTEMATIC 23297250 A 1017 1025 chloride SYSTEMATIC 23297250 A 1058 1065 nitrate SYSTEMATIC 23297250 A 1119 1125 Ca(2+) FORMULA 23297250 A 1245 1247 Ni FORMULA 23297250 A 1311 1317 Ni(2+) FORMULA 23297250 A 135 137 Ni FORMULA 23297250 A 1493 1495 Ni FORMULA 23297250 A 168 170 Ni FORMULA 23297250 A 197 203 Ni(2+) FORMULA 23297250 A 229 231 Ni FORMULA 23297250 A 334 336 Ni FORMULA 23297250 A 37 43 Ca(2+) FORMULA 23297250 A 46 52 Mg(2+) FORMULA 23297250 A 55 60 Na(+) FORMULA 23297250 A 551 553 Ni FORMULA 23297250 A 601 603 Ni FORMULA 23297250 A 63 67 K(+) FORMULA 23297250 A 691 697 Ca(2+) FORMULA 23297250 A 702 708 Mg(2+) FORMULA 23297250 A 710 717 sulfate SYSTEMATIC 23297250 A 73 75 Ni FORMULA 23297250 A 769 771 Ni FORMULA 23297250 A 802 804 Ca FORMULA 23297250 A 808 810 Mg FORMULA 23297250 A 840 842 Ni FORMULA 23297250 A 889 891 Ca FORMULA 23297250 A 893 900 sulfate SYSTEMATIC 23297250 A 902 910 chloride SYSTEMATIC 23297250 A 915 922 nitrate SYSTEMATIC 23297250 A 990 992 Ni FORMULA 23297250 T 177 179 Ni FORMULA 23297250 T 25 31 Ca(2+) FORMULA 23297250 T 34 40 Mg(2+) FORMULA 23297250 T 43 48 Na(+) FORMULA 23297250 T 51 55 K(+) FORMULA 23297250 T 70 76 SO 42- FORMULA 23297250 T 78 83 Cl(-) FORMULA 23297250 T 86 91 NO 3- FORMULA 23297250 T 96 98 Ni FORMULA 23297362 A 304 336 phosphatidylinositol 3-phosphate SYSTEMATIC 23297362 A 338 346 PtdIns3P SYSTEMATIC 23297362 A 352 365 PtdIns(3,5)P2 SYSTEMATIC 23297676 A 538 548 flavonoids FAMILY 23297676 A 555 567 scutellarein TRIVIAL 23297676 A 581 596 phenylethanoids FAMILY 23297676 A 603 615 verbascoside TRIVIAL 23297676 A 621 629 iridoids FAMILY 23297676 A 636 647 melittoside TRIVIAL 23297676 A 652 672 5-allosyloxy-aucubin SYSTEMATIC 23297676 A 696 703 siderol TRIVIAL 23297676 A 841 849 iridoids FAMILY 23297714 A 1045 1057 testosterone TRIVIAL 23297714 A 1237 1244 alcohol FAMILY 23297714 A 432 439 ethanol SYSTEMATIC 23297714 A 978 982 dUTP ABBREVIATION 23297716 A 327 348 phenolic monoterpenes FAMILY 23297716 A 366 372 thymol TRIVIAL 23297716 A 389 398 carvacrol TRIVIAL 23297716 A 492 498 thymol TRIVIAL 23297716 A 509 518 carvacrol TRIVIAL 23297716 T 71 92 phenolic monoterpenes FAMILY 23297831 A 1096 1106 anthracene SYSTEMATIC 23297831 A 1107 1113 pyrene SYSTEMATIC 23297831 A 1123 1134 naphthalene SYSTEMATIC 23297831 A 1257 1273 poly(aryl ether) FAMILY 23297831 A 454 464 anthracene SYSTEMATIC 23297831 A 469 475 pyrene SYSTEMATIC 23297831 A 6 22 poly(aryl ether) FAMILY 23297831 A 91 102 naphthalene SYSTEMATIC 23297831 T 46 57 naphthalene SYSTEMATIC 23297831 T 69 85 poly(aryl ether) FAMILY 23297842 A 12 21 α-glucose TRIVIAL 23297842 A 775 784 α-glucose TRIVIAL 23297842 T 42 49 glucose TRIVIAL 23298136 A 347 354 luminol TRIVIAL 23298136 A 375 400 meso-tetraphenylporphyrin SYSTEMATIC 23298136 A 472 497 meso-tetraphenylporphyrin SYSTEMATIC 23298136 A 525 532 luminol TRIVIAL 23298136 A 914 921 luminol TRIVIAL 23298136 A 953 978 meso-tetraphenylporphyrin SYSTEMATIC 23298136 T 0 7 Luminol TRIVIAL 23298136 T 35 60 meso-tetraphenylporphyrin SYSTEMATIC 23298138 A 654 658 iodo SYSTEMATIC 23298139 A 122 128 silver SYSTEMATIC 23298139 T 0 6 Silver SYSTEMATIC 23298236 A 0 8 GRL-0519 IDENTIFIER 23298236 A 101 109 tris-THF SYSTEMATIC 23298236 A 755 763 hydrogen SYSTEMATIC 23298236 A 79 99 tris-tetrahydrofuran SYSTEMATIC 23298236 A 833 841 carbonyl FAMILY 23298236 A 842 848 oxygen SYSTEMATIC 23298236 A 953 961 tris-THF SYSTEMATIC 23298236 T 61 69 GRL-0519 IDENTIFIER 23298236 T 9 29 tris-tetrahydrofuran SYSTEMATIC 23298292 A 298 308 amino acid FAMILY 23298292 A 329 339 D,L-valine TRIVIAL 23298292 A 703 714 polysorbate FAMILY 23298292 A 718 732 sorbitan ester TRIVIAL 23298577 A 1013 1016 PPI ABBREVIATION 23298577 A 103 114 sialic acid TRIVIAL 23298577 A 1180 1192 carbohydrate FAMILY 23298577 A 126 159 mannosylated poly(propyleneimine) FAMILY 23298577 A 1525 1528 ZDV ABBREVIATION 23298577 A 161 164 PPI ABBREVIATION 23298577 A 211 214 PPI ABBREVIATION 23298577 A 227 238 sialic acid TRIVIAL 23298577 A 250 253 PPI ABBREVIATION 23298577 A 273 280 mannose TRIVIAL 23298577 A 292 295 PPI ABBREVIATION 23298577 A 342 353 sialic acid TRIVIAL 23298577 A 365 381 mannosylated PPI ABBREVIATION 23298577 A 378 381 PPI ABBREVIATION 23298577 A 449 453 (1)H FORMULA 23298577 A 707 710 PPI ABBREVIATION 23298577 A 760 763 ZDV ABBREVIATION 23298577 A 82 92 zidovudine TRIVIAL 23298577 A 94 97 ZDV ABBREVIATION 23298577 A 944 947 ZDV ABBREVIATION 23298577 T 55 65 zidovudine TRIVIAL 23298577 T 73 84 sialic acid TRIVIAL 23298577 T 96 129 mannosylated poly(propyleneimine) FAMILY 23298578 A 1085 1096 cholesterol TRIVIAL 23298578 A 1340 1350 lamivudine TRIVIAL 23298578 A 356 366 lamivudine TRIVIAL 23298578 A 368 392 deoxycytidine nucleoside TRIVIAL 23298578 T 0 10 Lamivudine TRIVIAL 23298613 A 1018 1022 ZnPc FORMULA 23298613 A 1023 1026 DTX ABBREVIATION 23298613 A 1144 1148 ZnPc FORMULA 23298613 A 1187 1191 ZnPc FORMULA 23298613 A 1238 1241 DTX ABBREVIATION 23298613 A 1263 1267 ZnPc FORMULA 23298613 A 1313 1319 oxygen SYSTEMATIC 23298613 A 1349 1353 ZnPc FORMULA 23298613 A 1430 1434 ZnPc FORMULA 23298613 A 1723 1727 ZnPc FORMULA 23298613 A 1728 1731 DTX ABBREVIATION 23298613 A 1798 1801 DTX ABBREVIATION 23298613 A 1842 1845 DTX ABBREVIATION 23298613 A 1850 1854 ZnPc FORMULA 23298613 A 1887 1891 ZnPc FORMULA 23298613 A 1892 1895 DTX ABBREVIATION 23298613 A 1922 1925 DTX ABBREVIATION 23298613 A 2041 2044 PEO ABBREVIATION 23298613 A 2045 2048 PCL ABBREVIATION 23298613 A 297 306 docetaxel TRIVIAL 23298613 A 308 311 DTX ABBREVIATION 23298613 A 355 359 zinc SYSTEMATIC 23298613 A 360 374 phthalocyanine TRIVIAL 23298613 A 376 380 ZnPc FORMULA 23298613 A 539 559 poly(ε-caprolactone) FAMILY 23298613 A 561 564 PCL ABBREVIATION 23298613 A 572 592 poly(ethylene oxide) SYSTEMATIC 23298613 A 594 597 PEO ABBREVIATION 23298613 A 689 692 DTX ABBREVIATION 23298613 A 697 701 ZnPc FORMULA 23298613 T 60 69 docetaxel TRIVIAL 23298613 T 74 80 Zn(II) FORMULA 23298613 T 81 95 phthalocyanine TRIVIAL 23298614 A 1048 1051 PEI ABBREVIATION 23298614 A 1108 1111 PEI ABBREVIATION 23298614 A 1195 1198 PEI ABBREVIATION 23298614 A 1203 1206 PEI ABBREVIATION 23298614 A 1233 1246 primary amine FAMILY 23298614 A 1276 1279 PEI ABBREVIATION 23298614 A 1344 1353 acyclovir TRIVIAL 23298614 A 1358 1361 PEI ABBREVIATION 23298614 A 1439 1453 polyallylamine FAMILY 23298614 A 1571 1574 PEI ABBREVIATION 23298614 A 1603 1606 PEI ABBREVIATION 23298614 A 1670 1684 primary amines FAMILY 23298614 A 1749 1777 secondary and tertiary amine MULTIPLE 23298614 A 1790 1793 PEI ABBREVIATION 23298614 A 236 252 polyethylenimine SYSTEMATIC 23298614 A 254 257 PEI ABBREVIATION 23298614 A 375 378 PEI ABBREVIATION 23298614 A 433 443 oleic acid TRIVIAL 23298614 A 455 458 PEI ABBREVIATION 23298614 A 580 584 PEIs ABBREVIATION 23298614 A 611 624 primary amine FAMILY 23298614 A 650 668 ethylene carbonate SYSTEMATIC 23298614 A 684 698 polyallylamine FAMILY 23298614 A 709 718 polyamine FAMILY 23298614 A 733 747 primary amines FAMILY 23298614 A 908 911 PEI ABBREVIATION 23298614 T 0 16 Polyethylenimine FAMILY 23298614 T 71 84 primary amine FAMILY 23298622 A 1147 1157 nimodipine TRIVIAL 23298622 A 529 539 nimodipine TRIVIAL 23298622 A 62 72 nimodipine TRIVIAL 23298622 A 657 667 nimodipine TRIVIAL 23298622 A 80 84 PLGA ABBREVIATION 23298622 T 16 26 nimodipine TRIVIAL 23298677 A 1026 1034 SB203580 IDENTIFIER 23298677 A 1046 1054 SP600125 IDENTIFIER 23298677 A 1056 1063 PD98059 IDENTIFIER 23298677 A 1069 1077 LY294002 IDENTIFIER 23298677 A 1190 1200 creatinine TRIVIAL 23298677 A 136 140 heme FAMILY 23298677 A 239 246 ethanol SYSTEMATIC 23298677 T 61 68 ethanol SYSTEMATIC 23298694 A 1018 1021 DON ABBREVIATION 23298694 A 1085 1088 DON ABBREVIATION 23298694 A 1185 1188 DON ABBREVIATION 23298694 A 1442 1445 DON ABBREVIATION 23298694 A 186 189 DON ABBREVIATION 23298694 A 33 47 deoxynivalenol TRIVIAL 23298694 A 434 437 DON ABBREVIATION 23298694 A 49 52 DON ABBREVIATION 23298694 A 506 509 DON ABBREVIATION 23298694 A 968 971 DON ABBREVIATION 23298694 T 100 114 deoxynivalenol TRIVIAL 23298698 A 0 16 Prostaglandin E2 TRIVIAL 23298698 A 1191 1195 PGE2 ABBREVIATION 23298698 A 1440 1444 PGE2 ABBREVIATION 23298698 A 210 214 PGE2 ABBREVIATION 23298698 A 333 337 PGE2 ABBREVIATION 23298698 A 707 711 PGE2 ABBREVIATION 23298698 A 913 917 PGE2 ABBREVIATION 23298698 T 21 37 prostaglandin E2 TRIVIAL 23298809 A 14 24 nucleoside FAMILY 23298809 A 256 261 ethyl SYSTEMATIC 23298809 A 266 275 isopropyl SYSTEMATIC 23298809 T 16 30 benzyloxazoles FAMILY 23298809 T 38 48 nucleoside FAMILY 23298862 A 112 121 Methadone TRIVIAL 23298862 A 1154 1167 R- and S-EDDP MULTIPLE 23298862 A 1183 1200 racemic methadone TRIVIAL 23298862 A 1252 1270 R- and S-methadone MULTIPLE 23298862 A 1347 1360 S>R-methadone MULTIPLE 23298862 A 1461 1470 methadone TRIVIAL 23298862 A 1471 1472 N FORMULA 23298862 A 1506 1515 methadone TRIVIAL 23298862 A 1516 1517 N FORMULA 23298862 A 164 165 N FORMULA 23298862 A 1684 1693 methadone TRIVIAL 23298862 A 1694 1695 N FORMULA 23298862 A 1797 1806 methadone TRIVIAL 23298862 A 183 227 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine SYSTEMATIC 23298862 A 229 233 EDDP ABBREVIATION 23298862 A 23 32 methadone TRIVIAL 23298862 A 355 364 methadone TRIVIAL 23298862 A 504 513 methadone TRIVIAL 23298862 A 514 515 N FORMULA 23298862 A 575 584 Methadone TRIVIAL 23298862 A 609 610 N FORMULA 23298862 A 795 804 methadone TRIVIAL 23298862 A 816 817 N FORMULA 23298862 A 940 949 methadone TRIVIAL 23298862 T 0 9 Methadone TRIVIAL 23298862 T 10 11 N FORMULA 23299080 A 35 45 androstane TRIVIAL 23299080 A 62 70 pregnane TRIVIAL 23299080 A 92 101 vitamin D FAMILY 23299193 A 1090 1102 cypermethrin TRIVIAL 23299193 A 1107 1124 alphacypermethrin TRIVIAL 23299193 A 1372 1382 pyrethroid FAMILY 23299193 A 264 276 cypermethrin TRIVIAL 23299193 A 279 297 piperonyl butoxide SYSTEMATIC 23299193 A 299 302 PBO ABBREVIATION 23299193 A 314 331 alphacypermethrin TRIVIAL 23299193 A 334 337 PBO ABBREVIATION 23299193 A 348 360 deltamethrin TRIVIAL 23299193 A 363 366 PBO ABBREVIATION 23299193 A 377 389 cypermethrin TRIVIAL 23299193 A 392 395 PBO ABBREVIATION 23299193 A 398 410 tetramethrin TRIVIAL 23299193 A 421 438 alphacypermethrin TRIVIAL 23299193 A 441 444 PBO ABBREVIATION 23299193 A 447 459 tetramethrin TRIVIAL 23299193 A 474 486 deltamethrin TRIVIAL 23299193 A 489 492 PBO ABBREVIATION 23299193 A 760 772 cypermethrin TRIVIAL 23299193 A 777 794 alphacypermethrin TRIVIAL 23299193 T 61 72 pyrethroids FAMILY 23299193 T 74 92 piperonyl butoxide SYSTEMATIC 23299193 T 98 110 tetramethrin TRIVIAL 23300130 A 22 25 PEI ABBREVIATION 23300130 A 4 20 polyethylenimine SYSTEMATIC 23300130 A 82 119 Tris(hydroxymethyl) acrylamidomethane SYSTEMATIC 23300130 T 17 25 Hydroxyl SYSTEMATIC 23300130 T 35 51 Polyethylenimine FAMILY 23300287 A 1143 1150 glucose TRIVIAL 23300287 A 1629 1636 glucose TRIVIAL 23300287 A 511 518 glucose TRIVIAL 23300287 A 816 823 glucose TRIVIAL 23301582 A 514 520 quartz TRIVIAL 23301592 A 1100 1113 dihydrofolate SYSTEMATIC 23301592 A 120 131 guanidinium SYSTEMATIC 23301592 A 136 156 2-aminoimidazolinium SYSTEMATIC 23301592 A 205 215 aminoalkyl FAMILY 23301592 A 349 359 aminoalkyl FAMILY 23301592 A 580 590 aminoalkyl FAMILY 23301592 A 734 735 O FORMULA 23301592 T 0 10 Aminoalkyl FAMILY 23301592 T 26 35 guanidine TRIVIAL 23301655 A 365 366 C FORMULA 23301655 A 414 420 Phenyl SYSTEMATIC 23301655 A 422 428 propyl SYSTEMATIC 23301655 A 434 438 amyl SYSTEMATIC 23301655 A 485 504 polyethylene glycol SYSTEMATIC 23301655 A 506 509 PEG ABBREVIATION 23301655 A 535 541 propyl SYSTEMATIC 23301655 A 546 550 amyl SYSTEMATIC 23301655 A 622 628 phenyl SYSTEMATIC 23301655 A 650 653 PEG ABBREVIATION 23301655 A 720 721 C FORMULA 23301655 A 859 862 PEG ABBREVIATION 23301655 A 883 886 PEG ABBREVIATION 23301655 T 0 6 Phenyl SYSTEMATIC 23301655 T 28 31 PEG ABBREVIATION 23301655 T 70 71 C FORMULA 23301838 A 189 197 graphene TRIVIAL 23301838 A 467 475 graphene TRIVIAL 23301838 A 532 545 boron nitride SYSTEMATIC 23301838 A 777 785 graphene TRIVIAL 23301838 A 886 894 graphene TRIVIAL 23301838 A 908 912 SiO₂ FORMULA 23301838 A 925 933 Graphene TRIVIAL 23301838 T 54 62 graphene TRIVIAL 23301838 T 77 90 boron nitride SYSTEMATIC 23301897 A 1011 1020 rocaglaol TRIVIAL 23301897 A 1289 1303 perviridicin B TRIVIAL 23301897 A 1321 1330 rocaglate TRIVIAL 23301897 A 133 158 cycloartane triterpenoids FAMILY 23301897 A 1368 1381 sesquiterpene FAMILY 23301897 A 1383 1406 2-oxaisodauc-5-en-12-al SYSTEMATIC 23301897 A 249 259 chloroform TRIVIAL 23301897 A 291 299 methanol SYSTEMATIC 23301897 A 35 58 cyclopenta[b]benzopyran SYSTEMATIC 23301897 A 780 784 diol SYSTEMATIC 23301897 A 825 850 dimolybdenum tetraacetate SYSTEMATIC 23301897 A 83 106 cyclopenta[b]benzofuran SYSTEMATIC 23301897 A 852 861 Mo2(AcO)4 FORMULA 23301897 A 913 922 rocaglate TRIVIAL 23301897 T 10 21 flavaglines FAMILY 23302007 A 228 246 organic carbonates FAMILY 23302007 A 261 269 epoxides FAMILY 23302007 A 274 279 CO(2) FORMULA 23302007 A 3 11 aluminum SYSTEMATIC 23302007 A 32 50 amino triphenolate SYSTEMATIC 23302007 T 11 19 aluminum SYSTEMATIC 23302007 T 68 86 organic carbonates FAMILY 23302590 A 440 450 L-tyrosine TRIVIAL 23302590 A 452 455 Tyr FORMULA 23302590 A 461 471 amino acid FAMILY 23302590 A 495 503 hydroxyl SYSTEMATIC 23302590 A 604 607 Tyr FORMULA 23302590 A 650 668 N-(3-oxobutyl)-Tyr SYSTEMATIC 23302590 A 699 711 N-acetyl-Tyr SYSTEMATIC 23302590 A 716 728 O-acetyl-Tyr SYSTEMATIC 23302590 A 768 771 Tyr FORMULA 23302590 A 777 796 methyl vinyl ketone SYSTEMATIC 23302590 A 801 817 acetic anhydride SYSTEMATIC 23302590 A 858 877 methyl vinyl ketone SYSTEMATIC 23302590 A 882 898 acetic anhydride SYSTEMATIC 23302590 A 997 1000 Tyr FORMULA 23302592 A 40 60 schisphenlignans A-E MULTIPLE 23302592 A 9 38 dibenzocyclooctadiene lignans FAMILY 23302592 T 0 20 Schisphenlignans A-E MULTIPLE 23302592 T 31 60 dibenzocyclooctadiene lignans FAMILY 23303199 A 402 410 hydrogen SYSTEMATIC 23303199 A 538 546 hydrogen SYSTEMATIC 23303199 A 631 639 hydrogen SYSTEMATIC 23303199 T 75 83 hydrogen SYSTEMATIC 23303207 A 1089 1093 H2O2 FORMULA 23303207 A 1322 1326 H2O2 FORMULA 23303207 A 1425 1429 H2O2 FORMULA 23303207 A 1580 1591 indoleamine SYSTEMATIC 23303207 A 1619 1629 tryptophan TRIVIAL 23303207 A 291 301 tryptophan TRIVIAL 23303207 A 314 325 indoleamine SYSTEMATIC 23303207 A 526 536 tryptophan TRIVIAL 23303207 A 538 548 kynurenine TRIVIAL 23303207 A 554 573 5-hydroxytryptamine SYSTEMATIC 23303207 A 575 579 5-HT SYSTEMATIC 23303207 A 845 855 kynurenine TRIVIAL 23303207 A 941 945 5-HT SYSTEMATIC 23303207 A 954 958 H2O2 FORMULA 23303207 T 33 44 indoleamine SYSTEMATIC 23303207 T 72 82 tryptophan TRIVIAL 23303314 A 107 109 Pt FORMULA 23303314 A 191 197 oxygen SYSTEMATIC 23303314 T 14 16 Pt FORMULA 23303314 T 50 55 oxide SYSTEMATIC 23303365 A 111 113 Au FORMULA 23303365 A 114 120 SiO(2) FORMULA 23303365 A 167 181 benzyl alcohol SYSTEMATIC 23303365 A 225 245 polyvinylpyrrolidone SYSTEMATIC 23303365 A 253 255 Au FORMULA 23303365 A 256 262 SiO(2) FORMULA 23303365 A 293 305 benzaldehyde SYSTEMATIC 23303469 A 154 159 FeGaB FORMULA 23303469 A 160 166 PZN-PT ABBREVIATION 23303469 A 326 332 PZN-PT ABBREVIATION 23303575 A 0 7 Halogen FAMILY 23303575 A 1145 1152 halogen FAMILY 23303575 A 1157 1165 hydrogen SYSTEMATIC 23303575 A 1249 1257 halogens FAMILY 23303575 A 1439 1446 halogen FAMILY 23303575 A 462 469 halogen FAMILY 23303575 A 620 627 halogen FAMILY 23303575 A 685 692 halogen FAMILY 23303575 A 746 753 halogen FAMILY 23303575 A 932 939 halogen FAMILY 23303575 T 0 7 Halogen FAMILY 23303713 A 611 617 prolyl TRIVIAL 23303717 A 152 158 cyclam TRIVIAL 23303717 A 182 195 naphthalimide FAMILY 23303717 A 232 240 zinc(II) SYSTEMATIC 23303717 A 293 299 biotin TRIVIAL 23303717 A 326 338 bis-triazole SYSTEMATIC 23303717 A 492 502 copper(II) SYSTEMATIC 23303717 A 507 515 zinc(II) SYSTEMATIC 23303717 A 521 529 zinc(II) SYSTEMATIC 23303717 A 824 830 biotin TRIVIAL 23303717 A 84 90 biotin TRIVIAL 23303727 A 163 172 aldehydes FAMILY 23303727 A 187 199 acetaldehyde SYSTEMATIC 23303727 A 203 210 octanal SYSTEMATIC 23303727 A 215 235 trans-β-nitrostyrene SYSTEMATIC 23303727 A 284 288 4-OT SYSTEMATIC 23303727 A 327 343 γ-nitroaldehydes FAMILY 23303727 A 38 45 proline TRIVIAL 23303727 A 59 75 4-oxalocrotonate SYSTEMATIC 23303727 A 89 93 4-OT SYSTEMATIC 23303727 T 104 111 proline TRIVIAL 23303727 T 125 141 4-oxalocrotonate SYSTEMATIC 23303727 T 69 78 aldehydes FAMILY 23303727 T 82 96 β-nitrostyrene SYSTEMATIC 23303733 A 137 144 AlMeImF FORMULA 23303733 A 287 291 F(-) FORMULA 23303733 A 30 38 fluoride SYSTEMATIC 23303733 A 329 334 ester FAMILY 23303733 A 377 384 AlMeImF FORMULA 23303733 A 385 389 DMSO ABBREVIATION 23303733 A 466 502 1-allyl-3-methylimidazolium chloride SYSTEMATIC 23303733 A 558 583 carboxylic acid anhydride SYSTEMATIC 23303733 A 618 631 acyl fluoride FAMILY 23303733 A 713 717 DMSO ABBREVIATION 23303733 A 99 135 1-allyl-3-methylimidazolium fluoride SYSTEMATIC 23303733 T 169 205 1-allyl-3-methylimidazolium fluoride SYSTEMATIC 23303733 T 206 210 DMSO ABBREVIATION 23303733 T 55 63 fluoride SYSTEMATIC 23305495 A 119 131 laurolitsine TRIVIAL 23305495 A 149 158 aporphine FAMILY 23305495 A 197 216 N-propylnorglaucine SYSTEMATIC 23305495 A 226 231 H2SO4 FORMULA 23305495 A 267 300 11-sulfonyl-1,11-anhydroaporphine SYSTEMATIC 23305495 A 314 333 N-formylnorglaucine SYSTEMATIC 23305495 A 348 353 H2SO4 FORMULA 23305495 A 376 391 9-sulfonyl-seco SYSTEMATIC 23305495 A 4 5 N FORMULA 23305495 A 40 53 thaliporphine TRIVIAL 23305495 A 445 450 H2SO4 FORMULA 23305495 A 521 536 (±)-wilsonirine TRIVIAL 23305495 A 538 542 (1)H FORMULA 23305495 A 687 700 Thaliporphine TRIVIAL 23305495 A 894 895 N FORMULA 23305495 T 41 54 thaliporphine TRIVIAL 23305495 T 55 56 N FORMULA 23305513 A 113 126 Bioglass 45S5 TRIVIAL 23305513 A 1451 1456 Na(+) FORMULA 23305513 A 1457 1461 H(+) FORMULA 23305513 A 35 59 hydroxycarbonate apatite SYSTEMATIC 23305513 A 459 476 poly(D,L-lactide) SYSTEMATIC 23305513 A 478 483 PDLLA ABBREVIATION 23305513 T 27 40 Bioglass 45S5 TRIVIAL 23305550 A 213 219 silver SYSTEMATIC 23305709 A 0 9 LY2090314 IDENTIFIER 23305709 A 11 153 3-[9-fluoro-2-(piperidin-1-ylcarbonyl)-1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl]-4-imidazo[1,2-a]pyridin-3-yl-1H-pyrrole-2,5-dione SYSTEMATIC 23305709 A 1111 1120 LY2090314 IDENTIFIER 23305709 A 1438 1459 LY2090314 glucuronide IDENTIFIER 23305709 A 1704 1713 LY2090314 IDENTIFIER 23305709 A 295 311 [(14)C]LY2090314 SYSTEMATIC 23305709 A 374 383 LY2090314 IDENTIFIER 23305709 A 711 720 LY2090314 IDENTIFIER 23305709 T 88 97 LY2090314 IDENTIFIER 23305776 A 10 18 phenolic FAMILY 23305776 A 301 360 2-(2'-methoxy-4'-hydroxy)-aryl-3-methy-6-hydroxy-benzofuran SYSTEMATIC 23305776 A 366 431 (2S)-6,7-(2,2-dimethyldihydropyrano)-8-prenyl-4'-hydroxyflavanone SYSTEMATIC 23305776 A 441 475 6-prenyl-7,3',4'-trihydroxyflavone SYSTEMATIC 23305776 A 552 556 ABTS ABBREVIATION 23305776 T 10 18 phenolic FAMILY 23305850 A 1062 1074 sulforaphane TRIVIAL 23305850 A 1076 1098 tert-butylhydroquinone SYSTEMATIC 23305850 A 1100 1117 cinnamic aldehyde TRIVIAL 23305850 A 1123 1140 hydrogen peroxide SYSTEMATIC 23305850 A 1734 1746 sulforaphane TRIVIAL 23305850 A 1861 1873 sulforaphane TRIVIAL 23305919 A 452 458 oxygen SYSTEMATIC 23305919 A 479 485 oxygen SYSTEMATIC 23305919 A 708 719 glutathione TRIVIAL 23305919 A 739 750 glutathione TRIVIAL 23305919 A 751 752 S FORMULA 23305919 A 803 808 thiol FAMILY 23305919 T 66 99 3,5-bis(benzylidene)-4-piperidone SYSTEMATIC 23305994 A 109 117 apigenin TRIVIAL 23305994 A 136 145 flavonoid FAMILY 23305994 T 15 23 apigenin TRIVIAL 23306105 A 0 37 Tris(1,3-dichloro-2-propyl) phosphate SYSTEMATIC 23306105 A 1312 1317 TDCPP ABBREVIATION 23306105 A 1433 1436 TPP ABBREVIATION 23306105 A 1573 1578 TDCPP ABBREVIATION 23306105 A 1664 1667 TPP ABBREVIATION 23306105 A 1717 1722 TDCPP ABBREVIATION 23306105 A 1727 1730 TPP ABBREVIATION 23306105 A 1853 1858 TDCPP ABBREVIATION 23306105 A 330 335 TDCPP ABBREVIATION 23306105 A 340 343 TPP ABBREVIATION 23306105 A 39 44 TDCPP ABBREVIATION 23306105 A 455 460 TDCPP ABBREVIATION 23306105 A 464 467 TPP ABBREVIATION 23306105 A 50 69 triphenyl phosphate SYSTEMATIC 23306105 A 629 634 TDCPP ABBREVIATION 23306105 A 653 656 TPP ABBREVIATION 23306105 A 71 74 TPP ABBREVIATION 23306105 A 765 781 aryl hydrocarbon FAMILY 23306105 A 889 904 thyroid hormone FAMILY 23306105 T 11 48 tris(1,3-dichloro-2-propyl) phosphate SYSTEMATIC 23306105 T 53 72 triphenyl phosphate SYSTEMATIC 23306106 A 0 11 Fatty acids FAMILY 23306106 A 1023 1032 PO(4)(3-) FORMULA 23306106 A 1055 1064 PO(4)(3-) FORMULA 23306106 A 1079 1081 Cd FORMULA 23306106 A 115 126 hydrocarbon FAMILY 23306106 A 1161 1166 PUFAs ABBREVIATION 23306106 A 1191 1200 PO(4)(3-) FORMULA 23306106 A 1262 1267 PUFAs ABBREVIATION 23306106 A 1269 1276 acetone SYSTEMATIC 23306106 A 1332 1341 phosphate SYSTEMATIC 23306106 A 1397 1400 TAG ABBREVIATION 23306106 A 1454 1458 MUFA ABBREVIATION 23306106 A 1463 1467 SAFA ABBREVIATION 23306106 A 1475 1479 SAFA ABBREVIATION 23306106 A 1543 1545 Cd FORMULA 23306106 A 1566 1575 PO(4)(3-) FORMULA 23306106 A 1628 1637 PO(4)(3-) FORMULA 23306106 A 1653 1655 Cd FORMULA 23306106 A 1814 1823 PO(4)(3-) FORMULA 23306106 A 1839 1841 Cd FORMULA 23306106 A 292 299 cadmium SYSTEMATIC 23306106 A 328 330 Cd FORMULA 23306106 A 351 361 fatty acid FAMILY 23306106 A 424 433 phosphate SYSTEMATIC 23306106 A 435 444 PO(4)(3-) FORMULA 23306106 A 505 514 PO(4)(3-) FORMULA 23306106 A 530 532 Cd FORMULA 23306106 A 565 580 triacylglycerol FAMILY 23306106 A 582 585 TAG ABBREVIATION 23306106 A 637 647 Fatty acid FAMILY 23306106 A 725 727 Cd FORMULA 23306106 A 739 748 PO(4)(3-) FORMULA 23306106 A 772 781 PO(4)(3-) FORMULA 23306106 A 797 799 Cd FORMULA 23306106 A 834 854 saturated fatty acid FAMILY 23306106 A 856 860 SAFA ABBREVIATION 23306106 A 866 884 monounsaturated FA ABBREVIATION 23306106 A 886 890 MUFA ABBREVIATION 23306106 A 914 932 polyunsaturated FA ABBREVIATION 23306106 A 934 938 PUFA ABBREVIATION 23306106 A 944 951 ω3 PUFA ABBREVIATION 23306106 A 957 961 PUFA ABBREVIATION 23306106 A 962 966 SAFA ABBREVIATION 23306106 T 86 93 cadmium SYSTEMATIC 23306106 T 98 107 phosphate SYSTEMATIC 23306206 A 243 247 H(+) FORMULA 23306206 A 308 312 H(+) FORMULA 23306206 A 65 69 NADH ABBREVIATION 23306206 A 662 666 NADH ABBREVIATION 23306206 A 667 673 NAD(+) ABBREVIATION 23306206 A 678 687 ubiquinol TRIVIAL 23306206 A 688 698 ubiquinone FAMILY 23306206 A 89 99 ubiquinone FAMILY 23306206 A 935 939 H(+) FORMULA 23306788 A 1127 1130 GSH ABBREVIATION 23306788 A 132 144 caffeic acid TRIVIAL 23306788 A 151 166 rosmarinic acid TRIVIAL 23306788 A 353 368 rosmarinic acid TRIVIAL 23306788 A 496 520 tert-butyl hydroperoxide SYSTEMATIC 23306788 A 626 635 aspartate TRIVIAL 23306788 A 654 661 alanine TRIVIAL 23306788 A 680 700 oxidized glutathione TRIVIAL 23306788 A 784 795 glutathione TRIVIAL 23306788 A 811 821 superoxide TRIVIAL 23306788 A 977 988 glutathione TRIVIAL 23306788 T 105 110 t-BHP ABBREVIATION 23306788 T 24 36 caffeic acid TRIVIAL 23306788 T 41 56 rosmarinic acid TRIVIAL 23306944 A 1139 1158 sodium metasilicate SYSTEMATIC 23306944 A 1331 1350 sodium metasilicate SYSTEMATIC 23306944 A 1428 1430 Si FORMULA 23306944 A 161 163 Si FORMULA 23306944 A 223 225 Si FORMULA 23306944 A 351 353 Si FORMULA 23306944 A 44 51 silicon SYSTEMATIC 23306944 A 463 482 sodium metasilicate SYSTEMATIC 23306944 A 53 55 Si FORMULA 23306944 A 532 534 Si FORMULA 23306944 A 578 597 sodium metasilicate SYSTEMATIC 23306944 A 734 753 sodium metasilicate SYSTEMATIC 23306944 A 880 894 Alizarin Red S TRIVIAL 23306944 A 950 969 sodium metasilicate SYSTEMATIC 23306944 T 11 18 silicon SYSTEMATIC 23307549 A 1459 1470 Ruxolitinib TRIVIAL 23307549 A 1707 1718 ruxolitinib TRIVIAL 23307549 A 1821 1832 ruxolitinib TRIVIAL 23307549 A 1965 1976 ruxolitinib TRIVIAL 23307549 A 2133 2144 ruxolitinib TRIVIAL 23307549 T 0 11 Ruxolitinib TRIVIAL 23307703 A 195 197 Si FORMULA 23307703 A 242 247 octyl SYSTEMATIC 23307703 A 250 271 (trimethylsilyl)vinyl SYSTEMATIC 23307703 A 278 291 2-phenylvinyl SYSTEMATIC 23307703 A 299 301 Si FORMULA 23307703 A 439 444 octyl SYSTEMATIC 23307703 A 452 454 Si FORMULA 23307703 A 471 484 2-phenylvinyl SYSTEMATIC 23307703 A 492 494 Si FORMULA 23307703 A 56 63 silicon SYSTEMATIC 23307703 A 817 819 Si FORMULA 23307703 A 872 874 Si FORMULA 23307703 T 29 31 Si FORMULA 23311288 A 0 17 O(6)-Alkylguanine FAMILY 23311288 A 121 128 guanine TRIVIAL 23311288 T 104 145 6-(benzyloxy)-2-(aryldiazenyl)-9H-purines FAMILY 23311288 T 161 177 O6-benzylguanine SYSTEMATIC 23311288 T 18 33 O6-alkylguanine FAMILY 23311400 A 169 177 PS-b-PAA ABBREVIATION 23311400 A 181 184 DMF ABBREVIATION 23311400 A 185 192 dioxane SYSTEMATIC 23311471 A 1012 1015 PEG ABBREVIATION 23311471 A 1148 1157 galactose TRIVIAL 23311471 A 119 127 PEG-PPLG ABBREVIATION 23311471 A 130 135 (13)C FORMULA 23311471 A 60 117 poly(ethylene glycol)-block-poly(γ-propargyl-l-glutamate) FAMILY 23311471 A 827 834 alkynyl FAMILY 23311471 A 854 862 PEG-PPLG ABBREVIATION 23311471 A 924 929 azide SYSTEMATIC 23311471 A 968 974 biotin TRIVIAL 23311471 A 979 988 galactose TRIVIAL 23311532 A 0 8 Dopamine TRIVIAL 23311532 A 1102 1105 PDA ABBREVIATION 23311532 A 1212 1215 PDA ABBREVIATION 23311532 A 1371 1374 PDA ABBREVIATION 23311532 A 252 264 polydopamine TRIVIAL 23311532 A 266 269 PDA ABBREVIATION 23311532 A 482 485 PDA ABBREVIATION 23311532 A 509 529 polydimethylsiloxane SYSTEMATIC 23311532 A 531 535 PDMS ABBREVIATION 23311532 A 542 547 epoxy SYSTEMATIC 23311532 A 563 566 PDA ABBREVIATION 23311532 T 54 66 polydopamine TRIVIAL 23311883 A 627 637 hexadecane SYSTEMATIC 23311883 A 642 650 dodecane SYSTEMATIC 23311976 A 0 9 Coumarins FAMILY 23311976 A 132 142 coumestans FAMILY 23311976 A 14 24 coumestans FAMILY 23311976 A 269 278 coumarins FAMILY 23311976 A 307 317 coumestans FAMILY 23311976 A 499 507 coumarin TRIVIAL 23311976 A 512 522 neoflavone TRIVIAL 23311976 A 699 732 6,8-diallyl-5,7-dihydroxycoumarin SYSTEMATIC 23311976 A 794 807 floroglucinol TRIVIAL 23311976 A 901 910 coumestan TRIVIAL 23311976 A 911 917 LQB-34 IDENTIFIER 23311976 T 14 22 Coumarin TRIVIAL 23311976 T 27 37 Neoflavone TRIVIAL 23312283 A 12 34 trimethylamine-N-oxide SYSTEMATIC 23312283 A 160 164 TMAO ABBREVIATION 23312283 A 197 203 flavin FAMILY 23312283 A 258 272 trimethylamine SYSTEMATIC 23312283 A 274 277 TMA ABBREVIATION 23312283 A 317 324 choline FAMILY 23312283 A 329 333 TMAO ABBREVIATION 23312283 A 36 40 TMAO ABBREVIATION 23312283 A 474 478 TMAO ABBREVIATION 23312283 A 517 521 TMAO ABBREVIATION 23312283 A 701 710 androgens FAMILY 23312283 A 750 760 bile acids FAMILY 23312283 A 824 833 bile acid FAMILY 23312283 A 953 957 TMAO ABBREVIATION 23312283 A 992 996 TMAO ABBREVIATION 23312283 T 0 22 Trimethylamine-N-oxide SYSTEMATIC 23312474 A 0 47 N-Acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine FAMILY 23312474 A 410 421 ethyl ester SYSTEMATIC 23312474 A 716 763 N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine FAMILY 23312474 A 857 868 Ethyl ester SYSTEMATIC 23312474 A 99 123 2,6-dichlorobenzoylamine SYSTEMATIC 23312474 T 110 116 esters FAMILY 23312474 T 18 65 N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine FAMILY 23313270 A 16 26 terpenoids FAMILY 23313270 A 28 48 tricycloalternarenes FAMILY 23313270 A 321 324 TCA ABBREVIATION 23313270 A 422 425 TCA ABBREVIATION 23313270 A 50 54 TCAs FAMILY 23313270 A 91 111 tricycloalternarenes FAMILY 23313270 T 0 24 Tricycloalternarenes F-H MULTIPLE 23313270 T 42 52 terpenoids FAMILY 23313271 A 10 35 cycloartane triterpenoids FAMILY 23313271 A 282 298 Aphagrandinoid A TRIVIAL 23313271 A 306 334 29-nor-cycloart triterpenoid SYSTEMATIC 23313271 A 37 56 aphagrandinoids A-C MULTIPLE 23313271 A 395 411 aphagrandinoid C TRIVIAL 23313271 A 421 440 pentnortriterpenoid FAMILY 23313271 A 91 107 aphagrandinoid D TRIVIAL 23313271 T 0 19 Aphagrandinoids A-D MULTIPLE 23313271 T 21 46 cycloartane triterpenoids FAMILY 23313336 A 0 9 Estradiol TRIVIAL 23313336 A 110 117 estriol TRIVIAL 23313336 A 164 176 progesterone TRIVIAL 23313336 A 178 190 testosterone TRIVIAL 23313336 A 192 200 cortisol TRIVIAL 23313336 A 205 216 aldosterone TRIVIAL 23313336 A 255 261 ketone SYSTEMATIC 23313336 A 285 291 methyl SYSTEMATIC 23313336 A 331 339 estrogen FAMILY 23313336 A 435 443 steroids FAMILY 23313336 A 455 474 Δ(5)-androstenediol SYSTEMATIC 23313336 A 476 493 5α-androstanediol SYSTEMATIC 23313336 A 498 519 27-hydroxycholesterol SYSTEMATIC 23313336 A 564 575 3β-hydroxyl SYSTEMATIC 23313336 A 586 592 methyl SYSTEMATIC 23313336 A 656 664 estrogen FAMILY 23313336 A 711 719 estrogen FAMILY 23313336 A 897 906 estrogens FAMILY 23313336 A 963 971 steroids FAMILY 23313336 A 98 105 estrone TRIVIAL 23313336 T 27 36 estrogens FAMILY 23313338 A 100 111 bisphenol-A TRIVIAL 23313338 A 113 116 BPA ABBREVIATION 23313338 A 1137 1140 BPA ABBREVIATION 23313338 A 386 389 BPA ABBREVIATION 23313338 A 494 497 BPA ABBREVIATION 23313338 A 768 771 BPA ABBREVIATION 23313338 A 87 95 steroids FAMILY 23313338 A 881 889 steroids FAMILY 23313338 T 97 108 bisphenol-A TRIVIAL 23313345 A 477 500 3,5,3'-triiodothyronine SYSTEMATIC 23313345 A 928 940 nitric oxide SYSTEMATIC 23313377 A 421 433 nitric oxide SYSTEMATIC 23313378 A 1004 1017 (-)-xanthatin TRIVIAL 23313378 A 1196 1215 N-acetyl-l-cysteine SYSTEMATIC 23313378 A 1290 1303 (-)-xanthatin TRIVIAL 23313378 A 29 42 (-)-xanthatin TRIVIAL 23313378 A 588 601 (-)-xanthatin TRIVIAL 23313378 A 634 647 (-)-xanthatin TRIVIAL 23313378 A 66 78 xanthanolide FAMILY 23313378 A 735 748 (-)-xanthatin TRIVIAL 23313378 A 845 851 oxygen SYSTEMATIC 23313378 T 0 13 (-)-Xanthatin TRIVIAL 23313378 T 150 156 oxygen SYSTEMATIC 23313609 A 1051 1100 malvidin 3-O-p-coumaroyl-rutinoside-5-O-glucoside SYSTEMATIC 23313609 A 1105 1155 petunidin 3-O-p-coumaroyl-rutinoside-5-O-glucoside SYSTEMATIC 23313609 A 164 176 anthocyanins FAMILY 23313609 A 261 273 anthocyanins FAMILY 23313609 A 442 454 Anthocyanins FAMILY 23313609 A 737 741 DPPH ABBREVIATION 23313609 A 896 908 anthocyanins FAMILY 23313632 A 211 219 aldehyde SYSTEMATIC 23313632 A 233 246 ethyl lactate SYSTEMATIC 23313632 A 28 46 8,4'-oxyneolignans FAMILY 23313632 A 47 58 (-)-virolin TRIVIAL 23313632 A 60 76 (-)-surinamensin TRIVIAL 23313632 T 56 74 8,4'-oxyneolignans FAMILY 23313632 T 75 82 virolin TRIVIAL 23313632 T 84 96 surinamensin TRIVIAL 23313633 A 165 179 glutaraldehyde TRIVIAL 23313633 A 313 323 Bacitracin TRIVIAL 23313633 A 328 347 sodium taurocholate SYSTEMATIC 23313633 A 508 517 phosphate SYSTEMATIC 23313633 A 544 547 HCl FORMULA 23313633 A 591 601 bacitracin TRIVIAL 23313633 A 724 734 bacitracin TRIVIAL 23313794 A 0 50 2-Amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine SYSTEMATIC 23313794 A 1063 1067 PhIP ABBREVIATION 23313794 A 107 111 HCAs ABBREVIATION 23313794 A 1244 1248 PhIP ABBREVIATION 23313794 A 207 211 PhIP ABBREVIATION 23313794 A 254 258 PhIP ABBREVIATION 23313794 A 415 419 PhIP ABBREVIATION 23313794 A 485 489 PhIP ABBREVIATION 23313794 A 52 56 PhIP ABBREVIATION 23313794 A 534 544 superoxide TRIVIAL 23313794 A 699 703 PhIP ABBREVIATION 23313794 A 705 720 malondialdehyde TRIVIAL 23313794 A 722 725 MDA ABBREVIATION 23313794 A 745 753 carbonyl FAMILY 23313794 A 86 105 heterocyclic amines FAMILY 23313794 A 873 877 PhIP ABBREVIATION 23313794 T 11 61 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine SYSTEMATIC 23313794 T 63 67 PhIP ABBREVIATION 23314050 A 0 10 α-Santonin TRIVIAL 23314050 A 145 155 aryl azide FAMILY 23314050 A 162 194 propargylated α-desmotrosantonin TRIVIAL 23314050 A 33 48 1,2,3-triazoles FAMILY 23314050 A 398 408 α-santonin TRIVIAL 23314050 A 410 418 Triazole FAMILY 23314050 A 69 81 Azide-Alkyne FAMILY 23314050 A 709 717 triazole FAMILY 23314050 T 65 75 α-santonin TRIVIAL 23314050 T 84 99 1,2,3-triazoles FAMILY 23314275 A 0 11 Tributyltin SYSTEMATIC 23314275 A 1057 1077 N-methyl-D-aspartate SYSTEMATIC 23314275 A 1089 1141 a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid SYSTEMATIC 23314275 A 1164 1170 Ca(2+) FORMULA 23314275 A 1215 1245 cyclic adenosine monophosphate SYSTEMATIC 23314275 A 13 16 TBT ABBREVIATION 23314275 A 1311 1314 TBT ABBREVIATION 23314275 A 159 162 TBT ABBREVIATION 23314275 A 279 282 TBT ABBREVIATION 23314275 A 424 427 TBT ABBREVIATION 23314275 A 490 498 Dopamine TRIVIAL 23314275 A 569 588 5-hydroxytryptamine SYSTEMATIC 23314275 A 593 607 norepinephrine TRIVIAL 23314275 A 646 649 TBT ABBREVIATION 23314275 A 709 717 dopamine TRIVIAL 23314275 A 875 878 TBT ABBREVIATION 23314275 A 912 922 amino acid FAMILY 23314275 A 952 961 glutamate TRIVIAL 23314275 T 0 11 Tributyltin SYSTEMATIC 23314308 A 1033 1038 2-APB SYSTEMATIC 23314308 A 1098 1106 caffeine TRIVIAL 23314308 A 1217 1223 Ca(2+) FORMULA 23314308 A 1336 1342 Ca(2+) FORMULA 23314308 A 1407 1413 Ca(2+) FORMULA 23314308 A 143 149 Ca(2+) FORMULA 23314308 A 1430 1436 Ca(2+) FORMULA 23314308 A 1567 1573 Ca(2+) FORMULA 23314308 A 259 272 phenylephrine TRIVIAL 23314308 A 325 335 nifedipine TRIVIAL 23314308 A 350 368 tetraethylammonium SYSTEMATIC 23314308 A 370 373 TEA ABBREVIATION 23314308 A 406 416 BAY K 8644 IDENTIFIER 23314308 A 478 484 Ca(2+) FORMULA 23314308 A 580 592 Tetrodotoxin TRIVIAL 23314308 A 604 613 capsaicin TRIVIAL 23314308 A 75 81 Ca(2+) FORMULA 23314308 A 863 873 BAY K 8644 IDENTIFIER 23314308 A 906 916 nifedipine TRIVIAL 23314308 A 983 1004 Inositol triphosphate TRIVIAL 23314308 T 108 115 calcium SYSTEMATIC 23315091 A 11 28 Pentachlorophenol SYSTEMATIC 23315091 A 1499 1502 PCP ABBREVIATION 23315091 A 1616 1619 PCP ABBREVIATION 23315091 A 1735 1738 PCP ABBREVIATION 23315091 A 30 33 PCP ABBREVIATION 23315091 A 300 303 PCP ABBREVIATION 23315091 A 430 433 PCP ABBREVIATION 23315091 A 800 803 PCP ABBREVIATION 23315091 T 25 42 pentachlorophenol SYSTEMATIC 23315277 A 1239 1245 SiO(2) FORMULA 23315277 A 1277 1283 SiO(2) FORMULA 23315277 A 198 204 SiO(2) FORMULA 23315277 A 24 30 silica TRIVIAL 23315277 A 338 344 SiO(2) FORMULA 23315277 A 434 440 SiO(2) FORMULA 23315277 A 46 52 SiO(2) FORMULA 23315277 A 582 641 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide SYSTEMATIC 23315277 A 647 654 lactate FAMILY 23315277 A 685 691 SiO(2) FORMULA 23315277 A 793 804 glutathione TRIVIAL 23315277 A 831 837 oxygen SYSTEMATIC 23315277 A 992 998 SiO(2) FORMULA 23315277 T 0 6 Silica TRIVIAL 23315522 A 1082 1088 Mn(2+) FORMULA 23315522 A 1111 1115 H2O2 FORMULA 23315522 A 1173 1182 succinate TRIVIAL 23315522 A 1218 1224 malate TRIVIAL 23315522 A 1229 1238 glutamate TRIVIAL 23315522 A 1257 1261 H2O2 FORMULA 23315522 A 1292 1298 Mn(2+) FORMULA 23315522 A 1317 1326 succinate TRIVIAL 23315522 A 1337 1343 Mn(2+) FORMULA 23315522 A 1366 1370 H2O2 FORMULA 23315522 A 1539 1545 Mn(2+) FORMULA 23315522 A 1554 1558 H2O2 FORMULA 23315522 A 1635 1637 Mn FORMULA 23315522 A 218 220 Mn FORMULA 23315522 A 275 286 divalent Mn FORMULA 23315522 A 288 294 Mn(2+) FORMULA 23315522 A 32 41 manganese SYSTEMATIC 23315522 A 346 363 hydrogen peroxide SYSTEMATIC 23315522 A 365 369 H2O2 FORMULA 23315522 A 423 429 Mn(2+) FORMULA 23315522 A 43 45 Mn FORMULA 23315522 A 538 544 Mn(2+) FORMULA 23315522 A 553 557 H2O2 FORMULA 23315522 A 628 634 Mn(2+) FORMULA 23315522 A 644 700 divalent copper, cadmium, nickel, cobalt, zinc, and iron MULTIPLE 23315522 A 738 742 H2O2 FORMULA 23315522 A 837 843 Mn(2+) FORMULA 23315522 A 880 884 H2O2 FORMULA 23315522 T 100 117 hydrogen peroxide SYSTEMATIC 23315522 T 73 91 divalent manganese SYSTEMATIC 23315586 A 1374 1381 calcium SYSTEMATIC 23315586 A 600 606 Ca(2+) FORMULA 23315586 A 694 697 ATP ABBREVIATION 23315644 A 236 252 arachidonic acid TRIVIAL 23315644 A 259 272 linoleic acid TRIVIAL 23315644 A 790 798 epoxides FAMILY 23315644 A 803 810 hydroxy SYSTEMATIC 23316011 A 329 387 poly(ethylene glycol)-poly(serinol hexamethylene urethane) FAMILY 23316011 A 389 393 ESHU ABBREVIATION 23316011 A 490 494 ESHU ABBREVIATION 23316011 A 638 642 ESHU ABBREVIATION 23316011 A 685 689 ESHU ABBREVIATION 23316015 T 84 88 iron SYSTEMATIC 23316053 A 122 130 tyrosine TRIVIAL 23316053 A 450 458 imatinib TRIVIAL 23316053 A 50 58 tyrosine TRIVIAL 23316864 A 57 62 CO(2) FORMULA 23316864 A 861 873 manoyl oxide TRIVIAL 23316864 A 875 888 trans-totarol TRIVIAL 23316864 A 893 905 α-acoradiene TRIVIAL 23316933 A 1032 1042 nucleoside FAMILY 23316933 A 1076 1085 adenosine TRIVIAL 23316933 A 1512 1521 adenosine TRIVIAL 23316933 A 1668 1677 adenosine TRIVIAL 23316933 A 611 620 adenosine TRIVIAL 23316933 A 716 726 nucleoside FAMILY 23316933 A 766 769 ATP ABBREVIATION 23316933 A 774 784 cyclic AMP TRIVIAL 23316933 A 864 874 nucleoside FAMILY 23316933 A 903 912 adenosine TRIVIAL 23316933 T 10 19 adenosine TRIVIAL 23316963 A 1530 1534 zinc SYSTEMATIC 23316963 A 1546 1557 doxycycline TRIVIAL 23316963 A 1559 1569 batimastat TRIVIAL 23316963 A 1574 1584 marimastat TRIVIAL 23317013 A 178 195 solphenazines A-F MULTIPLE 23317013 A 285 294 rhamnosyl TRIVIAL 23317013 A 307 314 paraben FAMILY 23317013 A 382 410 N-methyl-p-aminobenzoic acid SYSTEMATIC 23317013 T 0 17 Solphenazines A-F MULTIPLE 23317013 T 19 42 glycosylated phenazines FAMILY 23317099 A 112 123 spiroacetal FAMILY 23317099 A 263 278 tetrahydrofuran SYSTEMATIC 23317099 A 527 538 spiroacetal FAMILY 23317099 A 92 107 tetrahydrofuran SYSTEMATIC 23317099 T 76 91 tetrahydrofuran SYSTEMATIC 23317099 T 96 107 spiroacetal FAMILY 23317164 A 0 6 Oxygen SYSTEMATIC 23317164 A 1052 1056 O(2) FORMULA 23317164 A 1118 1122 O(2) FORMULA 23317164 A 1342 1346 O(2) FORMULA 23317164 A 1427 1431 O(2) FORMULA 23317164 A 1568 1572 O(2) FORMULA 23317164 A 46 50 O(2) FORMULA 23317164 A 482 486 O(2) FORMULA 23317164 A 673 677 O(2) FORMULA 23317164 A 707 711 O(2) FORMULA 23317164 A 775 779 O(2) FORMULA 23317164 A 8 12 O(2) FORMULA 23317164 T 4 10 oxygen SYSTEMATIC 23317165 A 1113 1122 imidazole SYSTEMATIC 23317165 A 1207 1216 imidazole SYSTEMATIC 23317165 A 1284 1293 imidazole SYSTEMATIC 23317165 A 800 809 imidazole SYSTEMATIC 23317165 A 865 868 ATP ABBREVIATION 23317165 A 927 936 imidazole SYSTEMATIC 23317165 T 90 99 Imidazole SYSTEMATIC 23317370 A 1273 1277 H(2) FORMULA 23317370 A 1349 1351 Pt FORMULA 23317370 A 1352 1354 Ir FORMULA 23317370 A 208 216 thiolate SYSTEMATIC 23317370 A 251 256 thiol FAMILY 23317370 A 320 322 Au FORMULA 23317370 A 363 371 thiolate SYSTEMATIC 23317370 A 486 494 thiolate SYSTEMATIC 23317370 A 60 62 Au FORMULA 23317370 A 663 671 thiolate SYSTEMATIC 23317370 A 818 822 H(2) FORMULA 23317370 A 95 100 thiol FAMILY 23317370 A 985 989 H(2) FORMULA 23317370 T 20 29 thiolates FAMILY 23317570 A 65 80 carboxylic acid SYSTEMATIC 23317570 A 96 117 pyridine-carboxamides FAMILY 23317570 T 23 43 pyridine-carboxamide SYSTEMATIC 23318354 A 286 295 graphitic TRIVIAL 23318431 A 709 717 tyrosine TRIVIAL 23318431 A 918 924 oxygen SYSTEMATIC 23318598 A 1012 1019 glucose TRIVIAL 23318598 A 1077 1084 glucose TRIVIAL 23318598 A 117 124 glucose TRIVIAL 23318598 A 1239 1252 catecholamine TRIVIAL 23318598 A 1533 1540 glucose TRIVIAL 23318598 A 1653 1660 glucose TRIVIAL 23318598 A 257 264 glucose TRIVIAL 23318598 A 367 374 glucose TRIVIAL 23318598 A 49 56 glucose TRIVIAL 23318598 A 565 572 glucose TRIVIAL 23318598 A 785 792 glucose TRIVIAL 23318598 A 851 858 glucose TRIVIAL 23318598 A 884 891 glucose TRIVIAL 23318598 T 109 116 glucose TRIVIAL 23318598 T 56 63 glucose TRIVIAL 23318726 A 108 114 Butein TRIVIAL 23318726 A 1085 1088 NH2 FORMULA 23318726 A 1134 1140 butein TRIVIAL 23318726 A 1170 1176 butein TRIVIAL 23318726 A 124 134 polyphenol FAMILY 23318726 A 1253 1259 butein TRIVIAL 23318726 A 202 208 oxygen SYSTEMATIC 23318726 A 338 344 butein TRIVIAL 23318726 A 381 398 hydrogen peroxide SYSTEMATIC 23318726 A 400 404 H2O2 FORMULA 23318726 A 433 437 H2O2 FORMULA 23318726 A 535 539 H2O2 FORMULA 23318726 A 615 621 butein TRIVIAL 23318726 A 662 668 Butein TRIVIAL 23318726 A 684 688 heme FAMILY 23318726 A 757 763 butein TRIVIAL 23318726 A 825 829 H2O2 FORMULA 23318726 A 882 888 butein TRIVIAL 23318726 T 0 6 Butein TRIVIAL 23318726 T 45 62 hydrogen peroxide SYSTEMATIC 23318731 A 1040 1043 BaP ABBREVIATION 23318731 A 1227 1229 Pb FORMULA 23318731 A 1233 1236 BaP ABBREVIATION 23318731 A 238 240 Pb FORMULA 23318731 A 245 248 BaP ABBREVIATION 23318731 A 320 322 Pb FORMULA 23318731 A 327 330 BaP ABBREVIATION 23318731 A 39 41 Pb FORMULA 23318731 A 47 61 benzo[a]pyrene SYSTEMATIC 23318731 A 483 485 Pb FORMULA 23318731 A 490 493 BaP ABBREVIATION 23318731 A 562 564 Pb FORMULA 23318731 A 568 571 BaP ABBREVIATION 23318731 A 63 66 BaP ABBREVIATION 23318731 A 650 678 8-epi-prostaglandin F2 alpha SYSTEMATIC 23318731 A 680 691 8-epi-PGF2a SYSTEMATIC 23318731 A 698 713 3-nitrotyrosine SYSTEMATIC 23318731 A 715 719 3-NT SYSTEMATIC 23318731 A 722 724 Pb FORMULA 23318731 A 729 732 BaP ABBREVIATION 23318731 A 877 881 3-NT SYSTEMATIC 23318731 A 932 943 8-Epi-PGF2a SYSTEMATIC 23318731 A 997 999 Pb FORMULA 23318731 T 103 117 benzo[a]pyrene SYSTEMATIC 23318833 A 1020 1043 8-hydroxydeoxyguanosine SYSTEMATIC 23318833 A 1111 1130 4-hydroxy-2-nonenal SYSTEMATIC 23318833 A 1280 1283 TAA ABBREVIATION 23318833 A 1408 1411 TAA ABBREVIATION 23318833 A 169 189 N-diethylnitrosamine SYSTEMATIC 23318833 A 204 217 thioacetamide SYSTEMATIC 23318833 A 219 222 TAA ABBREVIATION 23318833 A 499 502 TAA ABBREVIATION 23318833 A 536 547 glutathione TRIVIAL 23318833 A 548 549 S FORMULA 23318833 A 63 76 isoquercitrin TRIVIAL 23318833 A 757 760 TAA ABBREVIATION 23318833 A 824 828 heme FAMILY 23318833 A 977 996 thiobarbituric acid SYSTEMATIC 23318833 T 33 46 isoquercitrin TRIVIAL 23318833 T 94 107 thioacetamide SYSTEMATIC 23319077 A 0 11 Ciguatoxins FAMILY 23319077 A 16 22 sodium SYSTEMATIC 23319077 A 163 173 ciguatoxin TRIVIAL 23319077 A 176 181 CTX-1 ABBREVIATION 23319077 A 234 239 CTX-1 ABBREVIATION 23319077 A 266 276 ciguatoxin TRIVIAL 23319077 A 439 449 ciguatoxin TRIVIAL 23319077 A 601 611 Ciguatoxin TRIVIAL 23319077 A 848 853 CTX-1 ABBREVIATION 23319077 A 999 1004 CTX-1 ABBREVIATION 23319077 T 69 79 ciguatoxin TRIVIAL 23319077 T 82 87 CTX-1 ABBREVIATION 23319147 A 1003 1008 C(60) TRIVIAL 23319147 A 1123 1128 C(60) TRIVIAL 23319147 A 1235 1240 C(60) TRIVIAL 23319147 A 323 328 C(60) TRIVIAL 23319147 A 409 414 C(60) TRIVIAL 23319147 A 515 520 C(60) TRIVIAL 23319147 A 809 814 C(60) TRIVIAL 23319147 A 84 89 C(60) TRIVIAL 23319147 T 74 77 C60 TRIVIAL 23319166 A 90 94 PDMS ABBREVIATION 23319588 A 114 115 N FORMULA 23319588 A 171 182 amino acids FAMILY 23319588 A 483 494 amino acids FAMILY 23319588 A 683 695 leptomycin B TRIVIAL 23319588 A 83 96 polyglutamine FAMILY 23319588 T 3 4 N FORMULA 23320465 A 1127 1129 Au FORMULA 23320465 A 386 388 Au FORMULA 23320465 A 986 988 Au FORMULA 23320542 A 701 702 C FORMULA 23320732 A 10 19 manganese SYSTEMATIC 23320732 A 100 110 fosfomycin TRIVIAL 23320732 A 125 136 glutathione TRIVIAL 23320732 A 1366 1373 epoxide SYSTEMATIC 23320732 A 138 141 GSH ABBREVIATION 23320732 A 1489 1492 GSH ABBREVIATION 23320732 A 1601 1604 GSH ABBREVIATION 23320732 A 53 59 Mn(2+) FORMULA 23320732 A 601 612 glutathione TRIVIAL 23320732 A 729 738 GSH thiol SYSTEMATIC 23320732 A 752 755 Tyr FORMULA 23320732 A 795 807 GSH thiolate SYSTEMATIC 23320732 A 819 826 epoxide SYSTEMATIC 23320732 A 926 932 Mn(2+) FORMULA 23320732 A 957 967 Lewis acid FAMILY 23320732 T 57 67 fosfomycin TRIVIAL 23320893 A 103 111 graphene TRIVIAL 23320893 A 1031 1037 carbon SYSTEMATIC 23320893 A 1048 1056 graphite TRIVIAL 23320893 A 1309 1317 graphene TRIVIAL 23320893 A 1456 1464 graphene TRIVIAL 23320893 A 175 183 graphene TRIVIAL 23320893 A 293 301 graphite TRIVIAL 23320893 A 374 382 graphene TRIVIAL 23320893 A 455 463 graphite TRIVIAL 23320893 A 796 804 graphene TRIVIAL 23320893 A 963 971 graphite TRIVIAL 23320893 A 983 991 graphene TRIVIAL 23320893 T 38 46 graphene TRIVIAL 23321074 A 435 444 tamoxifen TRIVIAL 23321159 A 0 8 Morphine TRIVIAL 23321216 A 1045 1052 glucose TRIVIAL 23321216 A 107 114 glucose TRIVIAL 23321216 A 1197 1204 glucose TRIVIAL 23321216 A 1644 1651 glucose TRIVIAL 23321216 A 447 454 glucose TRIVIAL 23321216 A 636 643 glucose TRIVIAL 23321216 A 743 750 glucose TRIVIAL 23321216 A 938 945 glucose TRIVIAL 23321216 T 39 46 Glucose TRIVIAL 23321259 A 27 73 7-alkyloxy-4,5-dihydro-imidazo[1,2-a]quinoline FAMILY 23321259 A 309 356 7-heptyloxy-4,5-dihydro-imidazo[1,2-a]quinoline SYSTEMATIC 23321259 A 535 548 ciprofloxacin TRIVIAL 23321259 A 553 564 amoxicillin TRIVIAL 23321259 T 54 100 7-alkyloxy-4,5-dihydro-imidazo[1,2-a]quinoline FAMILY 23321396 A 515 523 Androgen FAMILY 23321560 A 119 132 isoproterenol TRIVIAL 23321560 A 134 137 ISO ABBREVIATION 23321560 A 257 260 ISO ABBREVIATION 23321560 A 337 345 creatine TRIVIAL 23321560 A 357 364 lactate FAMILY 23321560 A 38 71 N,α-L-rhamnopyranosyl vincosamide SYSTEMATIC 23321560 A 383 392 glutamate TRIVIAL 23321560 A 393 401 pyruvate TRIVIAL 23321560 A 675 678 ISO ABBREVIATION 23321560 A 808 839 tri-phenyl tetrazolium chloride SYSTEMATIC 23321560 A 841 844 TTC ABBREVIATION 23321560 T 133 146 isoproterenol TRIVIAL 23321560 T 30 63 N,α-L-rhamnopyranosyl vincosamide SYSTEMATIC 23321560 T 68 83 indole alkaloid FAMILY 23321564 A 198 208 hydrazones FAMILY 23321564 A 210 230 (thio)semicarbazones FAMILY 23321564 A 236 261 oximes of indenoindolones FAMILY 23321564 A 267 281 indenoindolols FAMILY 23321564 A 487 502 indenoindolones FAMILY 23321564 A 597 611 indenoindolone SYSTEMATIC 23321564 A 673 682 etoposide TRIVIAL 23321564 A 687 701 5-fluorouracil SYSTEMATIC 23321564 A 773 788 indenoindolones FAMILY 23321564 A 87 101 indenoindolone SYSTEMATIC 23321564 T 0 14 Indenoindolone SYSTEMATIC 23321689 A 1073 1083 PNU-282987 IDENTIFIER 23321689 A 1252 1262 WAY-100135 IDENTIFIER 23321689 A 1299 1317 methyllycaconitine TRIVIAL 23321689 A 1377 1387 PNU-282987 IDENTIFIER 23321689 A 17 30 acetylcholine SYSTEMATIC 23321689 A 292 300 nicotine TRIVIAL 23321689 A 490 500 PNU-282987 IDENTIFIER 23321689 A 511 521 PNU-120596 IDENTIFIER 23321689 A 669 679 PNU-282987 IDENTIFIER 23321689 A 684 694 PNU-120596 IDENTIFIER 23321689 A 818 829 scopolamine TRIVIAL 23321689 A 846 856 PNU-120596 IDENTIFIER 23321689 A 861 871 PNU-282987 IDENTIFIER 23321689 A 960 970 PNU-120596 IDENTIFIER 23322166 A 1401 1404 LPA ABBREVIATION 23322166 A 163 166 LPA ABBREVIATION 23322166 A 318 321 LPA ABBREVIATION 23322166 A 39 60 lysophosphatidic acid TRIVIAL 23322166 A 62 65 LPA ABBREVIATION 23322284 A 1055 1062 calcium SYSTEMATIC 23322284 A 1084 1093 manganese SYSTEMATIC 23322284 A 1234 1243 magnesium SYSTEMATIC 23322284 A 1248 1256 chromium SYSTEMATIC 23322284 A 1301 1305 zinc SYSTEMATIC 23322284 A 1310 1316 copper SYSTEMATIC 23322284 A 1348 1355 calcium SYSTEMATIC 23322284 A 1371 1380 manganese SYSTEMATIC 23322284 A 149 155 copper SYSTEMATIC 23322284 A 157 166 magnesium SYSTEMATIC 23322284 A 1591 1600 magnesium SYSTEMATIC 23322284 A 1627 1635 chromium SYSTEMATIC 23322284 A 168 172 zinc SYSTEMATIC 23322284 A 174 183 manganese SYSTEMATIC 23322284 A 185 193 chromium SYSTEMATIC 23322284 A 199 206 calcium SYSTEMATIC 23322284 A 704 716 testosterone TRIVIAL 23322284 A 727 734 glucose TRIVIAL 23322284 A 798 810 testosterone TRIVIAL 23322418 A 124 153 heptaprenylglyceryl phosphate SYSTEMATIC 23322418 A 159 182 heptaprenyl diphosphate SYSTEMATIC 23322418 A 187 207 glycerol-1-phosphate SYSTEMATIC 23322418 A 26 42 triose phosphate FAMILY 23322537 A 222 235 acetylcholine SYSTEMATIC 23322558 A 0 14 Perfluoroalkyl FAMILY 23322558 A 1188 1195 alanine TRIVIAL 23322558 A 1241 1251 creatinine TRIVIAL 23322558 A 1253 1263 phosphorus SYSTEMATIC 23322558 A 1319 1330 cholesterol TRIVIAL 23322558 A 1339 1349 creatinine TRIVIAL 23322558 A 335 356 perfluorocarboxylates FAMILY 23322558 A 359 384 perfluoroalkyl sulfonates FAMILY 23322558 A 386 411 perfluorooctane sulfonate SYSTEMATIC 23322558 A 413 435 perfluorooctanoic acid SYSTEMATIC 23322558 A 441 463 perfluorodecanoic acid SYSTEMATIC 23322558 T 21 35 perfluoroalkyl FAMILY 23322586 A 129 137 aluminum SYSTEMATIC 23322586 A 142 150 titanium SYSTEMATIC 23322586 A 42 58 titanium dioxide SYSTEMATIC 23322633 A 1043 1058 lactam carbonyl SYSTEMATIC 23322633 A 111 126 carboxylic acid SYSTEMATIC 23322633 A 1165 1175 α-ammonium SYSTEMATIC 23322633 A 1298 1306 anilines FAMILY 23322633 A 1308 1315 isatins FAMILY 23322633 A 1319 1337 anthranilic esters FAMILY 23322633 A 1429 1438 glutamate TRIVIAL 23322633 A 17 30 α-amino acids FAMILY 23322633 A 177 189 α-amino acid FAMILY 23322633 A 375 388 α-amino acids FAMILY 23322633 A 404 429 quinoxaline-2,4(1H)-dione SYSTEMATIC 23322633 A 431 456 quinoxaline-2,3(1H)-dione SYSTEMATIC 23322633 A 461 479 quinolin-2(1H)-one SYSTEMATIC 23322633 A 481 493 azagrevellin TRIVIAL 23322633 A 498 505 azepine SYSTEMATIC 23322633 A 619 632 α-amino acids FAMILY 23322633 A 70 83 α-carboxylate SYSTEMATIC 23322633 A 877 890 α-amino acids FAMILY 23322633 A 982 997 lactam carbonyl SYSTEMATIC 23322633 T 45 58 α-amino acids FAMILY 23322676 A 1123 1130 glucose TRIVIAL 23322676 A 1155 1162 glucose TRIVIAL 23322676 A 1856 1863 glucose TRIVIAL 23322676 A 2025 2032 glucose TRIVIAL 23322676 A 340 347 glucose TRIVIAL 23322676 A 536 547 alendronate TRIVIAL 23322676 A 602 617 Zoledronic Acid TRIVIAL 23322676 A 679 694 zoledronic acid TRIVIAL 23322676 A 841 848 glucose TRIVIAL 23322676 T 39 46 glucose TRIVIAL 23322677 A 0 6 Carbon SYSTEMATIC 23322677 A 127 134 Silicon SYSTEMATIC 23322677 A 16 23 silicon SYSTEMATIC 23322677 A 205 216 polyaniline SYSTEMATIC 23322677 A 417 428 polyaniline SYSTEMATIC 23322677 A 442 449 silicon SYSTEMATIC 23322677 A 481 487 carbon SYSTEMATIC 23322677 A 666 672 carbon SYSTEMATIC 23322677 A 774 781 silicon SYSTEMATIC 23322677 A 791 797 carbon SYSTEMATIC 23322677 A 813 830 hydrofluoric acid SYSTEMATIC 23322677 A 854 870 thionyl chloride SYSTEMATIC 23322677 T 14 20 carbon SYSTEMATIC 23322677 T 30 41 polyaniline SYSTEMATIC 23322677 T 44 51 silicon SYSTEMATIC 23322705 A 1005 1030 inositol hexakisphosphate SYSTEMATIC 23322705 A 1348 1370 inositol polyphosphate FAMILY 23322705 A 1523 1546 inositol polyphosphates FAMILY 23322705 A 524 546 inositol polyphosphate FAMILY 23322705 A 714 736 inositol polyphosphate FAMILY 23322705 A 792 817 inositol hexakisphosphate SYSTEMATIC 23322705 A 846 869 inositol pyrophosphates FAMILY 23322705 T 60 82 inositol polyphosphate FAMILY 23322769 A 140 151 cholesterol TRIVIAL 23322769 A 1594 1605 manumycin A TRIVIAL 23322769 A 1708 1725 cholesterol ester FAMILY 23322769 A 18 29 cholesterol TRIVIAL 23322769 A 402 413 cholesterol TRIVIAL 23322769 A 551 562 cholesterol TRIVIAL 23323521 A 785 786 H FORMULA 23323521 A 826 827 N FORMULA 23323521 A 910 925 bis(aryl) ether FAMILY 23323521 A 926 927 C FORMULA 23323521 A 961 970 dipeptide FAMILY 23323521 T 20 23 ATP ABBREVIATION 23323600 A 104 178 1,2,4,21,18,19-hexadehydro-4-demethyl-3,17-epoxy-7,20(2H,19H)-cyclovobasan SYSTEMATIC 23323600 A 186 271 1,2,18,19-tetradehydro-4-demethyl-4-formaldehyde-3,17-epoxy-7,20(2H,19H)-cyclovobasan SYSTEMATIC 23323600 A 26 96 1,2,18,19-tetradehydro-4-demethyl-3,17-epoxy-7,20(2H,19H)-cyclovobasan SYSTEMATIC 23323600 A 283 363 1,2,4,21,18,19-hexadehydro-4-demethyl-4-oxy-3,17-epoxy-7,20(2H,19H)-cyclovobasan SYSTEMATIC 23323600 A 388 398 chloroform TRIVIAL 23323600 A 410 417 koumine TRIVIAL 23323600 A 433 446 phenobarbital TRIVIAL 23323600 A 634 641 koumine TRIVIAL 23323600 A 689 696 koumine TRIVIAL 23323600 T 9 16 koumine TRIVIAL 23323640 A 1035 1051 Ge(8)Sb(2)Te(11) FORMULA 23323640 A 1056 1071 Ge(3)Sb(2)Te(6) FORMULA 23323640 A 184 190 GeSbTe FORMULA 23323640 A 337 339 Sb FORMULA 23323640 A 493 509 Ge(8)Sb(2)Te(11) FORMULA 23323640 A 511 526 Ge(3)Sb(2)Te(6) FORMULA 23323640 A 528 543 Ge(3)Sb(8)Te(6) FORMULA 23323640 A 549 564 Ge(2)Sb(7)Te(4) FORMULA 23323640 A 610 625 Ge(3)Sb(2)Te(6) FORMULA 23323640 A 744 759 Ge(3)Sb(8)Te(6) FORMULA 23323640 A 764 779 Ge(2)Sb(7)Te(4) FORMULA 23323640 A 817 823 3Sb(2) FORMULA 23323640 A 848 863 Ge(3)Sb(2)Te(6) FORMULA 23323640 A 868 883 Ge(2)Sb(1)Te(4) FORMULA 23323640 T 16 22 GeSbTe FORMULA 23323647 A 17 54 6-(5-acetyl-2-methoxyphenyl)-apigenin SYSTEMATIC 23323647 A 6 15 flavonoid FAMILY 23323647 T 21 29 6-phenyl SYSTEMATIC 23323647 T 6 15 flavonoid FAMILY 23323712 A 0 23 All-trans retinoic acid TRIVIAL 23323712 T 35 48 retinoic acid TRIVIAL 23323808 A 361 375 In(x)Ga(1-x)As FAMILY 23323808 A 429 443 In(x)Ga(1-x)As FAMILY 23323808 A 517 521 GaAs FORMULA 23323808 A 541 555 In(x)Ga(1-x)As FAMILY 23323808 A 733 735 Au FORMULA 23323808 A 80 94 In(x)Ga(1-x)As FAMILY 23323808 A 948 950 Au FORMULA 23323808 T 28 30 Au FORMULA 23323808 T 52 58 InGaAs FORMULA 23323839 A 17 35 6-hydroxy-7-methyl SYSTEMATIC 23323839 A 189 228 3,5-dimethoxy-4-methylhomophthalic acid SYSTEMATIC 23323839 A 238 256 cinnamoyl chloride SYSTEMATIC 23323839 A 313 355 6,8-dihydroxy-7-methyl-3-styrylisocoumarin SYSTEMATIC 23323839 A 375 386 isocoumarin TRIVIAL 23323839 A 390 399 keto acid FAMILY 23323839 A 450 462 hydroxy acid FAMILY 23323839 A 46 54 typharin TRIVIAL 23323839 A 483 545 ( ± )-6,8-dimethoxy-3-(4-methoxyphenyl)-3,4-dihydroisocoumarin SYSTEMATIC 23323839 A 56 99 8-dihydroxy-3-styryl-3,4-dihydroisocoumarin SYSTEMATIC 23323839 A 595 612 aluminum chloride SYSTEMATIC 23323839 A 613 625 ethane thiol SYSTEMATIC 23323839 A 646 657 isocoumarin TRIVIAL 23323839 A 810 822 levofloxacin TRIVIAL 23323839 T 42 50 typharin TRIVIAL 23323839 T 59 113 6,8-dihydroxy-7-methyl-3-styryl-3,4-dihydroisocoumarin SYSTEMATIC 23323873 A 1051 1069 methylprednisolone SYSTEMATIC 23323873 A 302 316 corticosteroid TRIVIAL 23323873 A 318 336 methylprednisolone SYSTEMATIC 23323873 A 66 81 corticosteroids FAMILY 23323873 A 786 803 Polyvinyl-alcohol FAMILY 23323873 A 805 808 PVA ABBREVIATION 23323873 A 933 940 acetone SYSTEMATIC 23323873 A 942 957 dichloromethane SYSTEMATIC 23323873 A 965 993 polyD,L-lactide-co-glycolide FAMILY 23323873 A 995 999 PLGA ABBREVIATION 23323873 T 52 70 methylprednisolone SYSTEMATIC 23323890 A 0 17 Fasciospyrinadine TRIVIAL 23323890 A 113 132 monocyclicfarnesane TRIVIAL 23323890 A 154 173 3-methylenepyridine SYSTEMATIC 23323890 A 31 44 sesquiterpene FAMILY 23323890 A 45 62 pyridine alkaloid FAMILY 23323890 T 0 17 Fasciospyrinadine TRIVIAL 23323890 T 27 40 sesquiterpene FAMILY 23323890 T 41 58 pyridine alkaloid FAMILY 23323975 A 326 331 CO(2) FORMULA 23323975 A 51 54 OCS FORMULA 23323975 A 530 533 OCS FORMULA 23323975 A 55 60 CO(2) FORMULA 23323975 A 669 672 OCS FORMULA 23323975 A 673 678 CO(2) FORMULA 23323975 A 95 100 CO(2) FORMULA 23323975 T 66 69 OCS FORMULA 23323975 T 70 75 CO(2) FORMULA 23323975 T 91 96 CO(2) FORMULA 23324033 A 0 9 Aglinin A TRIVIAL 23324033 A 202 211 acetonide SYSTEMATIC 23324033 A 311 316 (13)C FORMULA 23324033 A 388 393 (13)C FORMULA 23324033 A 45 108 20S,24-epoxy-24,25-dihydroxy-3,4-secodammar-4(28)-en-3-oic acid SYSTEMATIC 23324033 T 18 27 aglinin A TRIVIAL 23324406 A 140 164 inosine 5'-monophosphate SYSTEMATIC 23324406 A 209 228 guanine nucleotides FAMILY 23324406 A 250 306 N-aryl-3,4-dihydro-3-methyl-4-oxo-1-phthalazineacetamide FAMILY 23324406 A 449 462 phthalazinone TRIVIAL 23324406 A 510 525 benzofuranamide FAMILY 23324406 T 0 13 Phthalazinone TRIVIAL 23324406 T 28 52 inosine-5'-monophosphate SYSTEMATIC 23325363 A 1004 1016 carbohydrate FAMILY 23325363 A 493 501 dextrose TRIVIAL 23325363 A 554 561 glucose TRIVIAL 23325363 A 563 570 glucose TRIVIAL 23325363 A 598 609 cholesterol TRIVIAL 23325363 A 614 626 triglyceride FAMILY 23325363 A 914 921 glucose TRIVIAL 23325363 T 23 36 carbohydrates FAMILY 23325370 A 1093 1100 alcohol FAMILY 23325370 A 1146 1153 alcohol FAMILY 23325370 A 122 129 alcohol FAMILY 23325370 A 1261 1268 alcohol FAMILY 23325370 A 186 193 alcohol FAMILY 23325370 A 209 216 alcohol FAMILY 23325370 A 296 303 alcohol FAMILY 23325370 A 409 416 Alcohol SYSTEMATIC 23325370 A 501 508 alcohol FAMILY 23325370 A 529 536 alcohol FAMILY 23325370 A 625 632 alcohol FAMILY 23325370 A 681 688 alcohol FAMILY 23325370 A 753 760 alcohol FAMILY 23325370 A 842 849 alcohol FAMILY 23325370 A 944 951 alcohol FAMILY 23325370 T 23 30 alcohol FAMILY 23325372 A 1029 1036 alcohol FAMILY 23325372 A 1070 1082 aripiprazole TRIVIAL 23325372 A 1085 1097 escitalopram TRIVIAL 23325372 A 1171 1183 escitalopram TRIVIAL 23325372 A 1329 1336 alcohol FAMILY 23325372 A 1380 1392 aripiprazole TRIVIAL 23325372 A 1395 1407 escitalopram TRIVIAL 23325372 A 1516 1523 alcohol FAMILY 23325372 A 1622 1629 alcohol FAMILY 23325372 A 1674 1686 aripiprazole TRIVIAL 23325372 A 1758 1765 alcohol FAMILY 23325372 A 209 221 escitalopram TRIVIAL 23325372 A 227 239 aripiprazole TRIVIAL 23325372 A 304 311 alcohol FAMILY 23325372 A 370 377 alcohol FAMILY 23325372 A 449 461 escitalopram TRIVIAL 23325372 A 525 532 alcohol FAMILY 23325372 A 589 601 aripiprazole TRIVIAL 23325372 A 604 616 escitalopram TRIVIAL 23325372 A 624 636 escitalopram TRIVIAL 23325372 A 736 743 alcohol FAMILY 23325372 A 82 89 alcohol FAMILY 23325372 A 915 927 aripiprazole TRIVIAL 23325372 A 930 942 escitalopram TRIVIAL 23325372 A 947 959 escitalopram TRIVIAL 23325372 T 107 114 alcohol FAMILY 23325372 T 11 23 aripiprazole TRIVIAL 23325372 T 37 49 escitalopram TRIVIAL 23325437 A 1176 1186 losmapimod TRIVIAL 23325437 A 1595 1605 losmapimod TRIVIAL 23325437 A 263 273 Losmapimod TRIVIAL 23325437 A 487 497 losmapimod TRIVIAL 23325437 A 56 66 losmapimod TRIVIAL 23325437 A 637 647 losmapimod TRIVIAL 23325437 A 776 786 losmapimod TRIVIAL 23325437 A 877 887 losmapimod TRIVIAL 23325437 T 0 10 Losmapimod TRIVIAL 23325562 A 1011 1021 compound C TRIVIAL 23325562 A 1041 1049 SB216763 IDENTIFIER 23325562 A 1105 1117 ursolic acid TRIVIAL 23325562 A 1169 1174 MG132 IDENTIFIER 23325562 A 1269 1281 ursolic acid TRIVIAL 23325562 A 1333 1345 ursolic acid TRIVIAL 23325562 A 158 161 AMP ABBREVIATION 23325562 A 327 339 Ursolic acid TRIVIAL 23325562 A 33 45 ursolic acid TRIVIAL 23325562 A 426 434 ethidium TRIVIAL 23325562 A 501 505 dUTP ABBREVIATION 23325562 A 600 615 poly-ADP-ribose FAMILY 23325562 A 752 764 ursolic acid TRIVIAL 23325562 A 890 896 serine TRIVIAL 23325562 A 908 920 ursolic acid TRIVIAL 23325562 T 102 114 Ursolic Acid TRIVIAL 23325562 T 14 17 AMP ABBREVIATION 23325700 A 113 133 6-nitrobenzothiazole SYSTEMATIC 23325700 A 1167 1175 hydrogen SYSTEMATIC 23325700 A 1217 1237 6-nitrobenzothiazole SYSTEMATIC 23325700 A 142 156 semicarbazones FAMILY 23325700 A 1523 1537 semicarbazones FAMILY 23325700 A 766 845 1-[(4-Chlorophenyl)(phenyl)methylene]-4-(6-nitrobenzothiazol-2-yl)semicarbazide SYSTEMATIC 23325700 T 120 134 semicarbazones FAMILY 23325700 T 91 111 6-nitrobenzothiazole SYSTEMATIC 23325847 A 1148 1151 GTP ABBREVIATION 23325847 A 503 525 guanosine triphosphate SYSTEMATIC 23325847 A 527 530 GTP ABBREVIATION 23325847 A 704 705 C FORMULA 23327103 A 1020 1025 amine SYSTEMATIC 23327103 A 1178 1184 carbon SYSTEMATIC 23327103 A 43 49 carbon SYSTEMATIC 23327103 A 537 543 carbon SYSTEMATIC 23327103 A 569 584 carboxylic acid SYSTEMATIC 23327103 A 73 81 graphene TRIVIAL 23327103 A 785 790 NH(3) FORMULA 23327103 T 40 46 carbon SYSTEMATIC 23327358 A 143 167 styrene-isoprene-styrene TRIVIAL 23327358 A 169 172 SIS ABBREVIATION 23327358 A 319 322 SIS ABBREVIATION 23327358 A 481 498 methyl salicylate SYSTEMATIC 23327358 A 772 775 SIS ABBREVIATION 23327358 A 952 955 SIS ABBREVIATION 23327445 A 135 143 graphene TRIVIAL 23327445 A 238 246 graphene TRIVIAL 23327445 A 279 287 graphene TRIVIAL 23327445 A 681 689 graphene TRIVIAL 23327445 A 883 891 graphene TRIVIAL 23327445 A 903 910 silicon SYSTEMATIC 23327445 T 95 103 graphene TRIVIAL 23327533 A 108 122 [(14)C]ABT-107 SYSTEMATIC 23327533 A 1094 1101 ABT-107 IDENTIFIER 23327533 A 1274 1281 ABT-107 IDENTIFIER 23327533 A 206 213 ABT-107 IDENTIFIER 23327533 A 26 33 ABT-107 IDENTIFIER 23327533 A 314 321 ABT-107 IDENTIFIER 23327533 A 342 350 nitrogen SYSTEMATIC 23327533 A 354 366 quinuclidine TRIVIAL 23327533 A 419 425 indole SYSTEMATIC 23327533 A 471 472 N FORMULA 23327533 A 590 596 indole SYSTEMATIC 23327533 A 619 626 ABT-107 IDENTIFIER 23327533 T 62 75 acetylcholine SYSTEMATIC 23327546 A 689 695 sulfur SYSTEMATIC 23327546 A 747 768 tetrathienoanthracene SYSTEMATIC 23327546 A 785 794 pentacene SYSTEMATIC 23327546 A 802 809 Ni(111) FORMULA 23327546 T 32 53 tetrathienoanthracene SYSTEMATIC 23327546 T 59 68 pentacene SYSTEMATIC 23327546 T 72 79 Ni(111) FORMULA 23327588 A 1267 1276 androgens FAMILY 23327588 A 684 693 androgens FAMILY 23327588 A 698 707 estradiol TRIVIAL 23327588 A 967 975 androgen FAMILY 23327691 A 207 216 CJ-15,208 IDENTIFIER 23327691 A 383 392 CJ-15,208 IDENTIFIER 23327691 A 4 28 macrocyclic tetrapeptide FAMILY 23327691 A 413 420 cocaine TRIVIAL 23327691 A 45 54 CJ-15,208 IDENTIFIER 23327691 A 471 478 cocaine TRIVIAL 23327691 A 56 80 cyclo[Phe-d-Pro-Phe-Trp] TRIVIAL 23327691 A 582 591 CJ-15,208 IDENTIFIER 23327691 T 110 117 cocaine TRIVIAL 23327691 T 40 49 CJ-15,208 IDENTIFIER 23327722 A 215 222 carboxy SYSTEMATIC 23327722 A 232 238 lysine TRIVIAL 23327735 A 224 231 embelin TRIVIAL 23327735 A 33 40 embelin TRIVIAL 23327735 A 365 372 Embelin TRIVIAL 23327735 A 568 582 hydroxyproline SYSTEMATIC 23327735 A 584 594 hexosamine FAMILY 23327735 A 648 651 STZ ABBREVIATION 23327735 A 67 81 streptozotocin TRIVIAL 23327735 A 700 707 embelin TRIVIAL 23327735 A 730 744 hydroxyproline SYSTEMATIC 23327735 A 746 756 hexosamine FAMILY 23327735 A 83 86 STZ ABBREVIATION 23327735 A 857 864 Embelin TRIVIAL 23327735 A 985 992 embelin TRIVIAL 23327735 T 0 7 Embelin TRIVIAL 23327832 A 27 37 diterpenes FAMILY 23327832 A 51 67 sikkimenoids A-D MULTIPLE 23327832 A 9 21 jatropholane TRIVIAL 23327832 T 0 12 Jatropholane TRIVIAL 23327832 T 18 28 diterpenes FAMILY 23328624 A 240 241 C FORMULA 23328624 A 374 375 C FORMULA 23328895 A 1420 1429 estrogens FAMILY 23328895 A 1431 1443 progesterone TRIVIAL 23331575 A 0 11 Mithramycin TRIVIAL 23331575 A 1120 1134 mithramycin SK TRIVIAL 23331575 A 1200 1214 mithramycin SA TRIVIAL 23331575 A 13 16 MTM ABBREVIATION 23331575 A 150 161 mithramycin TRIVIAL 23331575 A 306 320 Mithramycin SA TRIVIAL 23331575 A 415 426 mithramycin TRIVIAL 23331575 A 437 451 mithramycin SK TRIVIAL 23331575 A 456 471 mithramycin SDK TRIVIAL 23331575 A 473 487 Mithramycin SA TRIVIAL 23331575 A 537 548 mithramycin TRIVIAL 23331575 A 572 578 carbon SYSTEMATIC 23331575 A 622 637 carboxylic acid SYSTEMATIC 23331575 A 709 718 phosphate SYSTEMATIC 23331575 A 731 742 mithramycin TRIVIAL 23331575 A 876 891 carboxylic acid SYSTEMATIC 23331575 A 945 954 phosphate SYSTEMATIC 23331575 T 15 29 Mithramycin SA TRIVIAL 23331859 A 1167 1173 sodium SYSTEMATIC 23331859 A 1281 1290 Vasotocin TRIVIAL 23331859 A 1299 1305 sodium SYSTEMATIC 23331859 A 273 277 NaCl FORMULA 23331859 A 318 326 Oxytocin TRIVIAL 23331859 A 622 630 Oxytocin TRIVIAL 23331859 A 646 655 vasotocin TRIVIAL 23331859 A 660 668 oxytocin TRIVIAL 23331859 A 861 869 oxytocin TRIVIAL 23331859 T 0 8 Oxytocin TRIVIAL 23332447 A 1117 1123 sterol FAMILY 23332447 A 1162 1176 diacylglycerol FAMILY 23332447 A 1199 1209 fatty acid FAMILY 23332447 A 30 42 testosterone TRIVIAL 23332447 A 774 786 triglyceride FAMILY 23332447 A 969 981 triglyceride FAMILY 23332447 T 0 12 Testosterone TRIVIAL 23332447 T 57 70 triglycerides FAMILY 23333175 A 510 517 aspirin TRIVIAL 23333175 A 522 530 warfarin TRIVIAL 23333184 A 113 122 potassium SYSTEMATIC 23333184 A 18 29 aldosterone TRIVIAL 23333184 A 208 219 aldosterone TRIVIAL 23333184 A 502 516 spironolactone TRIVIAL 23333184 A 521 531 eplerenone TRIVIAL 23333184 A 89 95 sodium SYSTEMATIC 23333208 A 12 35 tetrahydroisoquinolines FAMILY 23333305 A 667 668 N FORMULA 23333305 A 678 685 phospho SYSTEMATIC 23333424 A 0 6 Silver SYSTEMATIC 23333424 A 1144 1146 Ag FORMULA 23333424 A 1188 1205 hydrogen peroxide SYSTEMATIC 23333424 A 1207 1211 H2O2 FORMULA 23333424 A 1284 1288 H2O2 FORMULA 23333424 A 1292 1294 Ag FORMULA 23333424 A 1318 1320 Ag FORMULA 23333424 A 1383 1387 H2O2 FORMULA 23333424 A 1398 1400 Ag FORMULA 23333424 A 171 173 Ag FORMULA 23333424 A 298 303 AgNO3 FORMULA 23333424 A 362 364 Ag FORMULA 23333424 A 425 431 oxygen SYSTEMATIC 23333424 A 525 527 Ag FORMULA 23333424 A 597 599 Ag FORMULA 23333424 A 705 707 Ag FORMULA 23333424 A 8 10 Ag FORMULA 23333424 A 863 865 Ag FORMULA 23333424 A 966 968 Ag FORMULA 23333424 A 993 999 oxygen SYSTEMATIC 23333424 T 140 154 silver nitrate SYSTEMATIC 23333503 A 1006 1009 ODQ ABBREVIATION 23333503 A 1047 1051 K(+) FORMULA 23333503 A 1066 1069 TEA ABBREVIATION 23333503 A 1103 1106 ODQ ABBREVIATION 23333503 A 1111 1114 TEA ABBREVIATION 23333503 A 112 114 NO FORMULA 23333503 A 1155 1160 RuBPY FORMULA 23333503 A 1215 1226 4-Di-ANNEPS SYSTEMATIC 23333503 A 1245 1250 RuBPY FORMULA 23333503 A 1354 1356 NO FORMULA 23333503 A 1380 1385 RuBPY FORMULA 23333503 A 1435 1439 K(+) FORMULA 23333503 A 1462 1465 TEA ABBREVIATION 23333503 A 1532 1534 NO FORMULA 23333503 A 1553 1558 RuBPY FORMULA 23333503 A 1590 1594 K(+) FORMULA 23333503 A 214 216 NO FORMULA 23333503 A 237 242 RuBPY FORMULA 23333503 A 258 260 NO FORMULA 23333503 A 275 295 sodium nitroprusside SYSTEMATIC 23333503 A 297 300 SNP ABBREVIATION 23333503 A 384 392 guanylyl TRIVIAL 23333503 A 4 36 cis-[Ru(bpy)(2)(py)NO(2)](PF(6)) FORMULA 23333503 A 408 412 K(+) FORMULA 23333503 A 45 50 RuBPY FORMULA 23333503 A 494 496 NO FORMULA 23333503 A 527 529 NO FORMULA 23333503 A 543 548 RuBPY FORMULA 23333503 A 69 81 nitric oxide SYSTEMATIC 23333503 A 717 721 K(+) FORMULA 23333503 A 758 760 NO FORMULA 23333503 A 775 780 RuBPY FORMULA 23333503 A 797 799 NO FORMULA 23333503 A 814 817 SNP ABBREVIATION 23333503 A 819 824 RuBPY FORMULA 23333503 A 83 85 NO FORMULA 23333503 A 839 851 radicalar NO FORMULA 23333503 A 859 862 SNP ABBREVIATION 23333503 A 877 882 NO(-) FORMULA 23333503 A 887 889 NO FORMULA 23333503 A 930 935 RuBPY FORMULA 23333503 T 0 12 Nitric oxide SYSTEMATIC 23333503 T 39 44 RuBPY FORMULA 23333640 A 101 109 arsenite SYSTEMATIC 23333640 A 1062 1065 BaP ABBREVIATION 23333640 A 1203 1211 arsenite SYSTEMATIC 23333640 A 1225 1228 BaP ABBREVIATION 23333640 A 18 32 benzo(a)pyrene SYSTEMATIC 23333640 A 312 320 arsenite SYSTEMATIC 23333640 A 34 37 BaP ABBREVIATION 23333640 A 486 494 arsenite SYSTEMATIC 23333640 A 5 13 arsenite SYSTEMATIC 23333640 A 500 503 BaP ABBREVIATION 23333640 A 650 658 arsenite SYSTEMATIC 23333640 A 772 775 BaP ABBREVIATION 23333640 A 823 831 arsenite SYSTEMATIC 23333640 A 907 910 BaP ABBREVIATION 23333640 A 965 973 arsenite SYSTEMATIC 23333640 T 101 115 benzo(a)pyrene SYSTEMATIC 23333640 T 89 97 arsenite SYSTEMATIC 23333907 A 1000 1016 cryptotanshinone TRIVIAL 23333907 A 1020 1039 dihydrotanshinone I TRIVIAL 23333907 A 1220 1228 propofol TRIVIAL 23333907 A 1284 1303 dihydrotanshinone I TRIVIAL 23333907 A 1308 1324 cryptotanshinone TRIVIAL 23333907 A 1389 1397 propofol TRIVIAL 23333907 A 1435 1454 dihydrotanshinone I TRIVIAL 23333907 A 1459 1475 cryptotanshinone TRIVIAL 23333907 A 1516 1524 propofol TRIVIAL 23333907 A 220 223 UDP ABBREVIATION 23333907 A 427 443 cryptotanshinone TRIVIAL 23333907 A 448 467 dihydrotanshinone I TRIVIAL 23333907 A 497 505 propofol TRIVIAL 23333907 A 620 636 cryptotanshinone TRIVIAL 23333907 A 641 660 dihydrotanshinone I TRIVIAL 23333907 A 719 727 propofol TRIVIAL 23333907 A 866 882 cryptotanshinone TRIVIAL 23333907 A 887 906 dihydrotanshinone I TRIVIAL 23333907 T 0 16 Cryptotanshinone TRIVIAL 23333907 T 113 121 propofol TRIVIAL 23333907 T 21 40 dihydrotanshinone I TRIVIAL 23334349 A 1003 1006 H-N FORMULA 23334349 A 1011 1012 O FORMULA 23334349 A 1015 1018 H-C FORMULA 23334349 A 1181 1191 dipeptides FAMILY 23334349 A 13 23 dipeptides FAMILY 23334349 A 199 209 dipeptides FAMILY 23334349 A 35 46 pyrrolysine TRIVIAL 23334349 A 426 427 C FORMULA 23334349 A 560 568 α-carbon SYSTEMATIC 23334349 A 630 640 dipeptides FAMILY 23334349 A 67 68 N FORMULA 23334349 A 738 748 dipeptides FAMILY 23334349 A 802 803 C FORMULA 23334349 A 901 909 α-carbon SYSTEMATIC 23334349 A 974 975 H FORMULA 23334349 A 990 991 O FORMULA 23334349 A 994 997 H-N FORMULA 23334349 A 999 1000 N FORMULA 23334349 T 18 27 dipeptide FAMILY 23334349 T 50 61 pyrrolysine TRIVIAL 23334349 T 65 66 N FORMULA 23334800 A 105 122 cadmium telluride SYSTEMATIC 23334800 A 124 128 CdTe FORMULA 23334800 A 301 305 CdTe FORMULA 23334800 A 337 341 CdTe FORMULA 23334800 A 395 399 CdTe FORMULA 23334800 A 431 433 Te FORMULA 23334800 A 447 449 Cd FORMULA 23334800 A 454 456 Cd FORMULA 23334800 A 470 472 Cd FORMULA 23334800 A 474 478 CdTe FORMULA 23334800 A 724 728 CdTe FORMULA 23334800 A 75 81 carbon SYSTEMATIC 23334800 A 809 811 Cd FORMULA 23334800 A 817 821 CdTe FORMULA 23334800 T 29 33 CdTe FORMULA 23334855 A 446 460 salicylic acid TRIVIAL 23334855 A 462 478 methyl jasmonate SYSTEMATIC 23334855 A 480 493 abscisic acid TRIVIAL 23334864 A 0 4 Iron SYSTEMATIC 23334864 A 1099 1103 iron SYSTEMATIC 23334864 A 117 121 iron SYSTEMATIC 23334864 A 1217 1221 iron SYSTEMATIC 23334864 A 250 254 iron SYSTEMATIC 23334864 A 391 414 ferric ammonium citrate SYSTEMATIC 23334864 A 429 435 ferric SYSTEMATIC 23334864 A 455 459 iron SYSTEMATIC 23334864 A 525 531 oxygen SYSTEMATIC 23334864 A 563 595 2,7-dichlorofluorescin diacetate SYSTEMATIC 23334864 A 770 774 iron SYSTEMATIC 23334864 A 826 830 iron SYSTEMATIC 23334864 T 0 4 Iron SYSTEMATIC 23335025 A 116 124 estrogen FAMILY 23335025 A 19 27 estrogen FAMILY 23335025 A 318 326 estrogen FAMILY 23335025 T 52 60 estrogen FAMILY 23335030 A 118 121 ZnO FORMULA 23335030 A 22 27 FePt3 FORMULA 23335030 A 363 365 Fe FORMULA 23335030 T 35 38 ZnO FORMULA 23335030 T 59 64 FePt3 FORMULA 23335106 T 83 86 azo SYSTEMATIC 23335346 A 1123 1135 hexaconazole TRIVIAL 23335346 A 1558 1570 hexaconazole TRIVIAL 23335346 A 179 191 Hexaconazole TRIVIAL 23335346 A 519 531 hexaconazole TRIVIAL 23335346 A 680 692 acetonitrile SYSTEMATIC 23335346 A 698 714 ammonium acetate SYSTEMATIC 23335346 A 999 1015 rac-hexaconazole TRIVIAL 23335346 T 43 51 triazole FAMILY 23335346 T 62 74 hexaconazole TRIVIAL 23335398 A 1221 1222 O FORMULA 23335398 A 1290 1306 dimethylarginine SYSTEMATIC 23335398 A 257 265 O-GlcNAc FORMULA 23335398 A 267 268 O FORMULA 23335398 A 276 295 N-acetylglucosamine SYSTEMATIC 23335398 A 475 483 O-GlcNAc FORMULA 23335398 A 592 600 O-GlcNAc FORMULA 23335398 A 866 867 O FORMULA 23335398 A 990 998 O-GlcNAc FORMULA 23335398 T 137 138 O FORMULA 23335398 T 88 96 O-GlcNAc FORMULA 23335817 A 0 3 ZnO FORMULA 23335817 A 136 148 formaldehyde SYSTEMATIC 23335817 A 27 35 methanol SYSTEMATIC 23335817 A 318 330 formaldehyde SYSTEMATIC 23335817 A 335 343 methanol SYSTEMATIC 23335817 A 349 352 ZnO FORMULA 23335817 A 360 365 CO(2) FORMULA 23335817 A 423 427 ZnPd FORMULA 23335817 A 48 60 formaldehyde SYSTEMATIC 23335817 A 489 493 ZnPd FORMULA 23335817 A 508 512 ZnPd FORMULA 23335817 A 513 516 ZnO FORMULA 23335817 A 540 552 formaldehyde SYSTEMATIC 23335817 A 568 576 methanol SYSTEMATIC 23335817 A 594 599 CO(2) FORMULA 23335817 A 650 654 ZnPd FORMULA 23335817 A 659 662 ZnO FORMULA 23335817 A 673 677 ZnPd FORMULA 23335817 A 712 717 CO(2) FORMULA 23335817 A 746 749 ZnO FORMULA 23335817 A 763 775 formaldehyde SYSTEMATIC 23335817 A 805 810 CO(2) FORMULA 23335817 A 96 104 methanol SYSTEMATIC 23335817 T 0 3 ZnO FORMULA 23335817 T 9 14 CO(2) FORMULA 23336435 A 23 58 (17Z,20Z)-hexacosa-17,20-dien-9-one SYSTEMATIC 23336435 A 76 94 bisindole alkaloid FAMILY 23336435 A 96 105 gangenoid TRIVIAL 23336441 A 1109 1111 Li FORMULA 23336441 A 1194 1196 Li FORMULA 23336441 A 1293 1295 Li FORMULA 23336441 A 132 134 Li FORMULA 23336441 A 38 40 Li FORMULA 23336441 A 395 420 LiNi(1/3)Co(1/3)Mn(1/3)O₂ FORMULA 23336441 A 62 87 LiNi(1/3)Co(1/3)Mn(1/3)O₂ FORMULA 23336441 T 21 28 lithium SYSTEMATIC 23336441 T 82 89 lithium SYSTEMATIC 23337041 A 1022 1036 polyphosphates FAMILY 23337041 A 1038 1044 PolyP5 ABBREVIATION 23337041 A 1049 1056 PolyP65 ABBREVIATION 23337041 A 1058 1072 polyphosphates FAMILY 23337041 A 1085 1094 phosphate SYSTEMATIC 23337041 A 1253 1271 β-glycerophosphate SYSTEMATIC 23337041 A 1285 1294 phosphate SYSTEMATIC 23337041 A 1340 1346 PolyP5 ABBREVIATION 23337041 A 1350 1357 PolyP65 ABBREVIATION 23337041 A 1483 1497 polyphosphates FAMILY 23337041 A 177 186 phosphate SYSTEMATIC 23337041 A 1814 1820 PolyP5 ABBREVIATION 23337041 A 1825 1832 PolyP65 ABBREVIATION 23337041 A 1852 1866 hydroxyapatite TRIVIAL 23337041 A 1988 1994 PolyPs FAMILY 23337041 A 2060 2074 polyphosphates FAMILY 23337041 A 2148 2162 polyphosphates FAMILY 23337041 A 2278 2291 pyrophosphate SYSTEMATIC 23337041 A 229 243 polyphosphates FAMILY 23337041 A 2293 2296 PPi ABBREVIATION 23337041 A 2325 2343 β-glycerophosphate SYSTEMATIC 23337041 A 2390 2404 polyphosphates FAMILY 23337041 A 2481 2494 pyrophosphate SYSTEMATIC 23337041 A 2564 2573 phosphate SYSTEMATIC 23337041 A 258 273 orthophosphates FAMILY 23337041 A 2643 2657 polyphosphates FAMILY 23337041 A 284 300 phosphoanhydride SYSTEMATIC 23337041 A 337 352 orthophosphates FAMILY 23337041 A 376 390 polyphosphates FAMILY 23337041 A 42 51 phosphate SYSTEMATIC 23337041 A 574 588 polyphosphates FAMILY 23337041 A 75 84 phosphate SYSTEMATIC 23337041 T 0 14 Polyphosphates FAMILY 23337256 A 1002 1010 ketamine TRIVIAL 23337256 A 1123 1131 estrogen FAMILY 23337256 A 1136 1148 progesterone TRIVIAL 23337256 A 1264 1272 ketamine TRIVIAL 23337256 A 1337 1346 rapamycin TRIVIAL 23337256 A 1493 1501 ketamine TRIVIAL 23337256 A 1606 1614 ketamine TRIVIAL 23337256 A 394 402 ketamine TRIVIAL 23337256 A 407 427 N-methyl d-aspartate SYSTEMATIC 23337256 A 663 671 ketamine TRIVIAL 23337256 A 770 778 ketamine TRIVIAL 23337256 A 877 885 ketamine TRIVIAL 23337256 T 54 62 ketamine TRIVIAL 23337257 A 1033 1046 d-amphetamine TRIVIAL 23337257 A 1462 1475 d-amphetamine TRIVIAL 23337257 A 1609 1617 dopamine TRIVIAL 23337257 A 310 323 d-amphetamine TRIVIAL 23337257 A 34 42 dopamine TRIVIAL 23337257 A 517 525 dopamine TRIVIAL 23337257 A 852 860 dopamine TRIVIAL 23337257 T 61 69 dopamine TRIVIAL 23337567 A 0 16 Arsenic trioxide SYSTEMATIC 23337567 A 1057 1060 ATO ABBREVIATION 23337567 A 163 166 ATO ABBREVIATION 23337567 A 18 21 ATO ABBREVIATION 23337567 A 319 322 ATO ABBREVIATION 23337567 A 72 79 arsenic SYSTEMATIC 23337567 T 24 40 arsenic trioxide SYSTEMATIC 23337568 A 1010 1014 LiCl FORMULA 23337568 A 1019 1028 SB-415286 IDENTIFIER 23337568 A 471 488 3-hydroxychromone SYSTEMATIC 23337568 A 497 522 isothiazolidine-1,1-dione SYSTEMATIC 23337568 T 24 41 3-hydroxychromone SYSTEMATIC 23337597 A 22 25 POM ABBREVIATION 23337597 A 357 360 POM ABBREVIATION 23337597 A 437 442 amine SYSTEMATIC 23337597 A 5 20 polyoxometalate FAMILY 23337597 A 686 689 POM ABBREVIATION 23337597 A 819 822 POM ABBREVIATION 23337597 T 0 15 Polyoxometalate FAMILY 23337598 A 12 26 naphthoquinone FAMILY 23337598 A 272 285 aryl chloride FAMILY 23337598 A 286 293 aniline SYSTEMATIC 23337598 A 333 347 naphthoquinone FAMILY 23337598 T 6 20 naphthoquinone FAMILY 23337602 A 1013 1019 HT1171 IDENTIFIER 23337602 A 160 166 HT1171 IDENTIFIER 23337602 A 21 37 oxathiazol-2-one SYSTEMATIC 23337602 A 308 324 oxathiazol-2-one SYSTEMATIC 23337602 A 335 359 3H-1,2,4-dithiazol-3-one SYSTEMATIC 23337602 A 378 400 1,3,4-oxathiazol-2-one SYSTEMATIC 23337602 A 724 748 3H-1,2,4-dithiazol-3-one SYSTEMATIC 23337602 A 949 952 MTT ABBREVIATION 23337602 T 0 24 3H-1,2,4-Dithiazol-3-one SYSTEMATIC 23337911 A 357 365 atrazine TRIVIAL 23337911 A 367 370 ATR ABBREVIATION 23337911 A 373 391 diethylstilbestrol SYSTEMATIC 23337911 A 393 396 DES ABBREVIATION 23337911 A 399 415 para-nonylphenol SYSTEMATIC 23337911 A 417 421 p-NP ABBREVIATION 23337911 A 424 435 resveratrol TRIVIAL 23337911 A 437 440 RES ABBREVIATION 23337911 A 446 460 17 β-estradiol SYSTEMATIC 23337911 A 844 847 ATR ABBREVIATION 23337911 A 951 954 ATR ABBREVIATION 23337911 A 956 959 DES ABBREVIATION 23337911 A 961 965 p-NP ABBREVIATION 23337911 A 970 973 RES ABBREVIATION 23337911 T 86 99 17β-estradiol SYSTEMATIC 23338044 A 157 173 [W(10)O(32)](5-) FORMULA 23338044 A 219 235 [W(10)O(32)](6-) FORMULA 23338044 A 24 40 [W(10)O(32)](4-) FORMULA 23338044 T 54 64 [W10O32]4- FORMULA 23338539 A 257 267 bortezomib TRIVIAL 23338539 A 269 276 Velcade TRIVIAL 23338539 A 30 40 bortezomib TRIVIAL 23338539 A 390 400 bortezomib TRIVIAL 23338539 A 432 442 bortezomib TRIVIAL 23338539 A 662 672 bortezomib TRIVIAL 23338539 A 854 864 bortezomib TRIVIAL 23338539 A 879 889 bortezomib TRIVIAL 23338539 T 13 23 bortezomib TRIVIAL 23338843 A 106 122 indium tin oxide SYSTEMATIC 23338843 A 124 127 ITO ABBREVIATION 23338843 A 307 309 Au FORMULA 23338843 A 418 421 ITO ABBREVIATION 23338843 A 84 86 Au FORMULA 23339052 A 104 107 DOX ABBREVIATION 23339052 A 242 247 thiol FAMILY 23339052 A 40 73 N-(2-hydroxypropyl)methacrylamide SYSTEMATIC 23339052 A 512 516 HPMA ABBREVIATION 23339052 A 527 530 DOX ABBREVIATION 23339052 A 75 79 HPMA ABBREVIATION 23339052 A 91 102 doxorubicin TRIVIAL 23339052 T 51 55 HPMA ABBREVIATION 23339052 T 66 77 doxorubicin TRIVIAL 23339076 A 0 16 Metal-pernitride FAMILY 23339076 A 252 263 pernitrides FAMILY 23339076 A 308 310 Ca FORMULA 23339076 A 312 314 Sr FORMULA 23339076 A 316 318 Ba FORMULA 23339076 A 320 322 La FORMULA 23339076 A 328 330 Ti FORMULA 23339076 A 792 796 TiN2 FORMULA 23339076 A 841 845 TiN2 FORMULA 23339076 T 31 41 pernitride SYSTEMATIC 23339076 T 42 45 MN2 FAMILY 23339076 T 59 61 Ca FORMULA 23339076 T 63 65 Sr FORMULA 23339076 T 67 69 Ba FORMULA 23339076 T 71 73 La FORMULA 23339076 T 79 81 Ti FORMULA 23339663 A 0 22 Tri-o-cresyl-phosphate SYSTEMATIC 23339663 A 1005 1009 CBDP ABBREVIATION 23339663 A 1065 1074 H(2)(16)O FORMULA 23339663 A 1078 1087 H(2)(18)O FORMULA 23339663 A 1405 1410 oxime SYSTEMATIC 23339663 A 155 159 TOCP ABBREVIATION 23339663 A 1559 1563 CBDP ABBREVIATION 23339663 A 178 204 cresyl saligenin phosphate SYSTEMATIC 23339663 A 206 210 CBDP ABBREVIATION 23339663 A 24 28 TOCP ABBREVIATION 23339663 A 522 526 CBDP ABBREVIATION 23339663 A 646 650 CBDP ABBREVIATION 23339663 A 778 782 CBDP ABBREVIATION 23339663 A 960 963 Phe FORMULA 23339663 T 34 49 organophosphate FAMILY 23339663 T 50 54 CBDP ABBREVIATION 23339742 A 961 964 ATP ABBREVIATION 23339744 A 11 27 Triiodothyronine SYSTEMATIC 23339744 A 1573 1588 thyroid hormone FAMILY 23339744 A 1882 1898 thyroid hormones FAMILY 23339744 A 1943 1958 thyroid hormone FAMILY 23339744 A 223 238 thyroid hormone FAMILY 23339744 T 0 15 Thyroid hormone FAMILY 23339830 A 1115 1121 SiO(2) FORMULA 23339830 A 1132 1140 graphene TRIVIAL 23339830 A 1238 1246 graphene TRIVIAL 23339830 A 156 164 graphene TRIVIAL 23339830 A 1998 2006 graphene TRIVIAL 23339830 A 22 30 graphene TRIVIAL 23339830 A 249 257 graphene TRIVIAL 23339830 A 567 589 phenyl-diazonium salts FAMILY 23339830 T 45 53 graphene TRIVIAL 23339966 A 18 98 5-((1-aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones FAMILY 23339966 A 509 510 N FORMULA 23339966 A 511 520 naphthoyl SYSTEMATIC 23339966 A 938 946 hydrogen SYSTEMATIC 23339966 T 0 80 5-((1-Aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones FAMILY 23340093 A 1015 1022 furanic FAMILY 23340093 A 108 113 furan SYSTEMATIC 23340093 A 115 125 2-furfural SYSTEMATIC 23340093 A 127 143 furfuryl alcohol TRIVIAL 23340093 A 145 158 2-pentylfuran SYSTEMATIC 23340093 A 160 183 5-hydroxymethylfurfural SYSTEMATIC 23340093 A 266 273 furanic FAMILY 23340093 A 389 396 furanic FAMILY 23340093 A 590 597 furanic FAMILY 23340093 A 826 833 furanic FAMILY 23340093 A 89 96 furanic FAMILY 23340093 T 45 52 furanic FAMILY 23340252 A 1160 1164 Cort ABBREVIATION 23340252 A 1326 1343 acetyl-coenzyme A SYSTEMATIC 23340252 A 1657 1661 Cort ABBREVIATION 23340252 A 241 256 phenylsulfamide SYSTEMATIC 23340252 A 267 279 tolylfluanid TRIVIAL 23340252 A 623 637 corticosterone TRIVIAL 23340252 A 639 643 Cort ABBREVIATION 23340252 A 731 737 serine TRIVIAL 23340252 A 905 912 leucine TRIVIAL 23340252 A 958 962 Cort ABBREVIATION 23340252 T 34 46 tolylfluanid TRIVIAL 23340305 A 125 131 oxygen SYSTEMATIC 23340305 A 298 323 polychlorinated biphenyls FAMILY 23340305 A 442 474 2,7-dichlorofluorescin diacetate SYSTEMATIC 23340305 A 476 483 DCFH-DA ABBREVIATION 23340305 A 493 504 trypan blue TRIVIAL 23340305 A 631 655 perfluorooctyl sulfonate SYSTEMATIC 23340305 A 657 661 PFOS ABBREVIATION 23340305 A 664 693 perfluorooctane sulfonylamide SYSTEMATIC 23340305 A 695 700 PFOSA ABBREVIATION 23340305 A 710 731 fluorotelomer alcohol FAMILY 23340305 A 732 763 1H, 1H, 2H, 2H-perfluorodecanol SYSTEMATIC 23340305 A 765 773 FTOH 8:2 ABBREVIATION 23340305 A 858 862 PFOS ABBREVIATION 23340305 A 864 886 perfluorooctanoic acid SYSTEMATIC 23340305 A 888 892 PFOA ABBREVIATION 23340305 A 898 903 PFOSA ABBREVIATION 23340305 T 73 79 oxygen SYSTEMATIC 23340494 A 1032 1039 Carboxy SYSTEMATIC 23340494 A 1064 1075 amino acids FAMILY 23340494 A 316 323 cystine TRIVIAL 23340494 A 680 681 C FORMULA 23340653 A 1080 1083 GGA ABBREVIATION 23340653 A 119 122 GGA ABBREVIATION 23340653 A 1210 1213 GGA ABBREVIATION 23340653 A 130 152 acyclic polyisoprenoid FAMILY 23340653 A 1352 1355 GGA ABBREVIATION 23340653 A 1399 1402 GGA ABBREVIATION 23340653 A 1446 1449 Ser FORMULA 23340653 A 1450 1454 Ther FORMULA 23340653 A 1542 1545 GGA ABBREVIATION 23340653 A 1547 1550 GGA ABBREVIATION 23340653 A 462 465 GGA ABBREVIATION 23340653 A 522 525 GGA ABBREVIATION 23340653 A 562 565 GGA ABBREVIATION 23340653 A 706 717 hematoxylin TRIVIAL 23340653 A 722 727 eosin FAMILY 23340653 A 780 784 dUTP ABBREVIATION 23340653 A 828 834 oxygen SYSTEMATIC 23340653 A 96 117 Geranylgeranylacetone TRIVIAL 23340670 A 1060 1065 (13)C FORMULA 23340670 A 197 210 L-polylactide FAMILY 23340670 A 514 520 α-PLLA ABBREVIATION 23340670 A 848 853 (13)C FORMULA 23340670 T 23 40 α-poly(L-lactide) FAMILY 23340689 A 447 455 aluminum SYSTEMATIC 23340689 A 522 530 Al(3)(-) FORMULA 23340689 A 576 584 Al(4)(-) FORMULA 23340689 A 77 85 Al(n)(-) FAMILY 23340689 T 31 39 aluminum SYSTEMATIC 23341183 A 1091 1096 FK506 IDENTIFIER 23341183 A 140 143 MTX ABBREVIATION 23341183 A 402 411 tamoxifen TRIVIAL 23341183 A 413 422 reversine TRIVIAL 23341183 A 428 433 FK506 IDENTIFIER 23341183 A 457 466 acetylene SYSTEMATIC 23341183 A 47 50 MTX ABBREVIATION 23341183 A 592 595 MTX ABBREVIATION 23341183 A 67 72 azide SYSTEMATIC 23341183 A 798 801 MTX ABBREVIATION 23341183 A 915 920 FK506 IDENTIFIER 23341183 A 980 985 FK506 IDENTIFIER 23341183 T 14 17 MTX ABBREVIATION 23341191 A 1071 1079 vanadium SYSTEMATIC 23341191 A 185 200 silver vanadate SYSTEMATIC 23341191 A 225 231 silver SYSTEMATIC 23341191 A 413 419 silver SYSTEMATIC 23341191 A 424 432 vanadium SYSTEMATIC 23341191 A 635 641 silver SYSTEMATIC 23341191 A 773 788 Silver vanadate SYSTEMATIC 23341191 A 814 820 silver SYSTEMATIC 23341191 A 896 902 silver SYSTEMATIC 23341191 A 959 965 silver SYSTEMATIC 23341191 T 12 18 silver SYSTEMATIC 23341191 T 23 31 vanadium SYSTEMATIC 23341191 T 59 74 silver vanadate SYSTEMATIC 23341196 A 649 652 Lys FORMULA 23341212 A 1009 1073 3,3,5,5,8,8-hexamethyl-7-oxabicyclo[4.3.0]non-1(6)-ene-2,4-dione SYSTEMATIC 23341212 A 230 236 (13) C FORMULA 23341212 A 290 302 monoterpenes FAMILY 23341212 A 304 312 α-pinene TRIVIAL 23341212 A 330 341 1,8-cineole SYSTEMATIC 23341212 A 429 445 myrtenyl acetate SYSTEMATIC 23341212 A 760 768 α-pinene TRIVIAL 23341212 A 770 778 linalool TRIVIAL 23341212 A 784 799 linalyl acetate SYSTEMATIC 23341212 A 865 873 α-pinene TRIVIAL 23341212 A 878 889 1,8-cineole SYSTEMATIC 23341212 A 957 968 1,8-cineole SYSTEMATIC 23341212 A 973 981 limonene TRIVIAL 23341241 A 1035 1039 MeHg FORMULA 23341241 A 1122 1124 Hg FORMULA 23341241 A 1185 1187 Hg FORMULA 23341241 A 228 232 MeHg FORMULA 23341241 A 23 27 MeHg FORMULA 23341241 A 289 293 MeHg FORMULA 23341241 A 423 427 MeHg FORMULA 23341241 A 561 565 MeHg FORMULA 23341241 A 605 612 Mercury SYSTEMATIC 23341241 A 674 676 Hg FORMULA 23341241 A 780 784 MeHg FORMULA 23341241 A 8 21 methylmercury SYSTEMATIC 23341241 A 870 874 MeHg FORMULA 23341241 T 24 37 methylmercury SYSTEMATIC 23341458 A 1027 1030 Arg FORMULA 23341458 A 1036 1039 Lys FORMULA 23341458 A 1122 1123 N FORMULA 23341458 A 1141 1144 Arg FORMULA 23341458 A 1150 1153 Lys FORMULA 23341458 A 762 763 N FORMULA 23341458 A 893 896 Arg FORMULA 23341458 A 902 905 Gln FORMULA 23341458 A 931 932 N FORMULA 23343190 A 105 117 BaFe(2)As(2) FORMULA 23343190 A 169 193 Ba(Fe(1-x)Co(x))(2)As(2) FAMILY 23343190 A 195 218 BaFe(2)(As(1-x)P(x))(2) FAMILY 23343190 A 224 245 Ba(1-x)K(x)Fe(2)As(2) FAMILY 23343190 A 33 37 iron SYSTEMATIC 23343190 T 134 142 BaFe2As2 FORMULA 23343190 T 59 73 iron arsenides FAMILY 23343308 A 550 559 ibuprofen TRIVIAL 23343308 A 606 616 ibuprophen TRIVIAL 23343308 A 711 720 ibuprofen TRIVIAL 23343308 A 945 954 ibuprofen TRIVIAL 23343346 A 1005 1021 [Co(II)(ChH)](+) FORMULA 23343346 A 102 110 dioxygen SYSTEMATIC 23343346 A 1081 1099 [Co(III)(ChH)](2+) FORMULA 23343346 A 1103 1112 ferrocene TRIVIAL 23343346 A 112 116 O(2) FORMULA 23343346 A 1143 1150 HClO(4) FORMULA 23343346 A 1192 1208 [Co(III)(Ch)](+) FORMULA 23343346 A 1282 1289 HClO(4) FORMULA 23343346 A 1316 1332 [Co(III)(Ch)](+) FORMULA 23343346 A 1359 1375 [Co(III)(Ch)](+) FORMULA 23343346 A 1446 1464 [Co(III)(ChH)](2+) FORMULA 23343346 A 146 155 ferrocene TRIVIAL 23343346 A 1499 1503 O(2) FORMULA 23343346 A 1556 1573 [Co(III)(OEP)](+) FORMULA 23343346 A 180 197 hydrogen peroxide SYSTEMATIC 23343346 A 199 207 H(2)O(2) FORMULA 23343346 A 2 16 cobalt chlorin SYSTEMATIC 23343346 A 228 243 perchloric acid SYSTEMATIC 23343346 A 245 252 HClO(4) FORMULA 23343346 A 257 269 benzonitrile SYSTEMATIC 23343346 A 26 36 Co(II)(Ch) FORMULA 23343346 A 271 275 PhCN FORMULA 23343346 A 315 325 Co(II)(Ch) FORMULA 23343346 A 357 373 cobalt porphyrin SYSTEMATIC 23343346 A 383 394 Co(II)(OEP) FORMULA 23343346 A 396 403 OEP(2-) ABBREVIATION 23343346 A 406 424 octaethylporphyrin SYSTEMATIC 23343346 A 506 510 O(2) FORMULA 23343346 A 514 535 1,1'-dibromoferrocene SYSTEMATIC 23343346 A 537 544 Br(2)Fc FORMULA 23343346 A 563 573 Co(II)(Ch) FORMULA 23343346 A 609 613 O(2) FORMULA 23343346 A 628 639 Co(II)(OEP) FORMULA 23343346 A 654 664 Co(II)(Ch) FORMULA 23343346 A 685 696 Co(II)(OEP) FORMULA 23343346 A 773 777 O(2) FORMULA 23343346 A 791 801 Co(II)(Ch) FORMULA 23343346 A 968 972 O(2) FORMULA 23343346 A 993 1003 Co(II)(Ch) FORMULA 23343346 T 137 151 cobalt chlorin SYSTEMATIC 23343346 T 36 44 dioxygen SYSTEMATIC 23343346 T 48 65 hydrogen peroxide SYSTEMATIC 23343565 A 1026 1033 acetone SYSTEMATIC 23343565 A 1078 1086 hydrogen SYSTEMATIC 23343565 A 1101 1108 ethanol SYSTEMATIC 23343565 A 126 138 [EMIM][NTf2] FORMULA 23343565 A 1273 1285 [EMIM][NTf2] FORMULA 23343565 A 1291 1298 ethanol SYSTEMATIC 23343565 A 1364 1371 ethanol SYSTEMATIC 23343565 A 140 201 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide SYSTEMATIC 23343565 A 208 220 [HMIM][NTf2] FORMULA 23343565 A 222 283 1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide SYSTEMATIC 23343565 A 290 297 acetone SYSTEMATIC 23343565 A 302 309 ethanol SYSTEMATIC 23343565 A 68 82 [EMIM][N(CN)2] FORMULA 23343565 A 84 123 1-ethyl-3-methylimidazolium dicyanimide SYSTEMATIC 23343565 A 998 1005 ethanol SYSTEMATIC 23343565 T 112 119 acetone SYSTEMATIC 23343565 T 124 131 ethanol SYSTEMATIC 23343565 T 60 74 [EMIM][N(CN)2] FORMULA 23343565 T 76 88 [EMIM][NTf2] FORMULA 23343565 T 94 106 [HMIM][NTf2] FORMULA 23344156 A 303 316 phlorotannins FAMILY 23344433 A 4 25 yohimbinoid alkaloids FAMILY 23344433 A 506 518 hydrindanone TRIVIAL 23344433 A 636 648 aminonitrile SYSTEMATIC 23344433 A 872 882 venenatine TRIVIAL 23344433 A 887 898 alstovenine TRIVIAL 23344433 T 45 66 yohimbinoid alkaloids FAMILY 23344433 T 67 77 venenatine TRIVIAL 23344433 T 82 93 alstovenine TRIVIAL 23344796 A 1154 1163 β-lactams FAMILY 23344796 A 1342 1350 hydrogen SYSTEMATIC 23344796 A 1554 1562 hydrogen SYSTEMATIC 23344796 A 1726 1735 β-lactams FAMILY 23344796 A 1812 1821 β-lactams FAMILY 23344796 A 267 275 β-lactam TRIVIAL 23344796 A 312 324 penicillin G TRIVIAL 23344796 A 402 411 β-lactams FAMILY 23344796 A 491 500 β-lactams FAMILY 23344796 A 591 599 β-lactam TRIVIAL 23344796 A 932 941 β-lactams FAMILY 23344796 T 66 74 β-lactam TRIVIAL 23344855 A 1092 1094 Ag FORMULA 23344855 A 1175 1177 Ag FORMULA 23344855 A 1178 1180 Au FORMULA 23344855 A 1397 1404 nitrate SYSTEMATIC 23344855 A 1426 1433 nitrate SYSTEMATIC 23344855 A 172 180 nitrates FAMILY 23344855 A 422 429 nitrate SYSTEMATIC 23344855 A 486 488 Au FORMULA 23344855 A 490 492 Ag FORMULA 23344855 A 53 61 nitrogen SYSTEMATIC 23344855 A 583 590 nitrate SYSTEMATIC 23344855 A 780 787 nitrate SYSTEMATIC 23344855 A 87 93 carbon SYSTEMATIC 23344855 A 872 874 Ag FORMULA 23344855 A 894 896 Au FORMULA 23344855 A 980 982 Ag FORMULA 23344855 T 108 115 nitrate SYSTEMATIC 23344855 T 54 56 Ag FORMULA 23344855 T 57 59 Au FORMULA 23344856 A 100 105 PBDEs ABBREVIATION 23344856 A 1037 1041 PBDE ABBREVIATION 23344856 A 1169 1173 PBDE ABBREVIATION 23344856 A 1205 1209 PBDE ABBREVIATION 23344856 A 1274 1279 PBDEs ABBREVIATION 23344856 A 1312 1330 hydroxylated PBDEs FAMILY 23344856 A 1332 1340 OH-PBDEs FAMILY 23344856 A 1420 1425 PBDEs ABBREVIATION 23344856 A 1462 1469 OH-PBDE FORMULA 23344856 A 1504 1512 OH-PBDEs FAMILY 23344856 A 1522 1527 PBDEs ABBREVIATION 23344856 A 1593 1598 PBDEs ABBREVIATION 23344856 A 237 267 pentabrominated diphenyl ether SYSTEMATIC 23344856 A 269 274 DE-71 TRIVIAL 23344856 A 366 371 PBDEs ABBREVIATION 23344856 A 444 449 PBDEs ABBREVIATION 23344856 A 572 577 PBDEs ABBREVIATION 23344856 A 68 98 polybrominated diphenyl ethers FAMILY 23344856 A 798 803 PBDEs ABBREVIATION 23344856 A 829 834 PBDEs ABBREVIATION 23344856 A 899 904 PBDEs ABBREVIATION 23344856 A 968 972 PBDE ABBREVIATION 23344856 T 65 95 pentabrominated diphenyl ether SYSTEMATIC 23344856 T 97 102 DE-71 TRIVIAL 23344974 A 1226 1239 phenylalanine TRIVIAL 23344983 A 1104 1106 Pb FORMULA 23344983 A 1231 1233 Pb FORMULA 23344983 A 1389 1391 Pb FORMULA 23344983 A 230 232 Pb FORMULA 23344983 A 330 332 Pb FORMULA 23344983 A 542 544 Pb FORMULA 23344983 A 6 8 Pb FORMULA 23344983 A 600 602 Pb FORMULA 23344983 A 657 668 glutathione TRIVIAL 23345067 A 1018 1020 Pt FORMULA 23345067 A 1021 1022 C FORMULA 23345067 A 1046 1053 glucose TRIVIAL 23345067 A 1057 1065 sorbitol TRIVIAL 23345067 A 1219 1234 2-deoxysorbitol SYSTEMATIC 23345067 A 1240 1247 glucose TRIVIAL 23345067 A 1255 1263 fructose TRIVIAL 23345067 A 426 434 hydrogen SYSTEMATIC 23345067 A 455 472 transition metals FAMILY 23345067 A 474 476 Ti FORMULA 23345067 A 478 479 V FORMULA 23345067 A 481 483 Cr FORMULA 23345067 A 485 487 Mn FORMULA 23345067 A 489 491 Zr FORMULA 23345067 A 493 495 Nb FORMULA 23345067 A 497 499 Mo FORMULA 23345067 A 501 503 Hf FORMULA 23345067 A 505 507 Ta FORMULA 23345067 A 509 511 We FORMULA 23345067 A 517 519 Re FORMULA 23345067 A 525 533 platinum SYSTEMATIC 23345067 A 548 550 Ru FORMULA 23345067 A 552 554 Rh FORMULA 23345067 A 556 558 Ir FORMULA 23345067 A 564 566 Pt FORMULA 23345067 A 574 582 sorbitol TRIVIAL 23345067 A 602 619 transition metals FAMILY 23345067 A 621 623 Fe FORMULA 23345067 A 625 627 Co FORMULA 23345067 A 629 631 Ni FORMULA 23345067 A 633 635 Cu FORMULA 23345067 A 637 639 Pd FORMULA 23345067 A 64 71 glucose TRIVIAL 23345067 A 641 643 Au FORMULA 23345067 A 649 651 Ag FORMULA 23345067 A 657 659 Al FORMULA 23345067 A 681 689 sorbitol TRIVIAL 23345067 A 694 709 2-deoxysorbitol SYSTEMATIC 23345067 A 729 746 transition metals FAMILY 23345067 A 748 750 In FORMULA 23345067 A 75 83 sorbitol TRIVIAL 23345067 A 752 754 Sn FORMULA 23345067 A 756 758 Sb FORMULA 23345067 A 760 762 Pb FORMULA 23345067 A 768 770 Bi FORMULA 23345067 A 784 786 Zn FORMULA 23345067 A 791 793 Cd FORMULA 23345067 A 807 809 Ni FORMULA 23345067 A 858 866 sorbitol TRIVIAL 23345067 A 87 102 2-deoxysorbitol SYSTEMATIC 23345067 A 895 897 Pb FORMULA 23345067 A 908 916 sorbitol TRIVIAL 23345067 A 983 985 Pt FORMULA 23345067 T 52 59 glucose TRIVIAL 23345167 A 0 5 NADPH ABBREVIATION 23345167 A 106 112 oxygen SYSTEMATIC 23345167 A 1066 1072 oxygen SYSTEMATIC 23345167 A 1115 1120 NADPH ABBREVIATION 23345167 A 122 127 NADPH ABBREVIATION 23345167 A 1252 1257 NADPH ABBREVIATION 23345167 A 1339 1355 diarylheptanoids FAMILY 23345167 A 1360 1367 lignans FAMILY 23345167 A 1422 1427 NADPH ABBREVIATION 23345167 A 1516 1521 NADPH ABBREVIATION 23345167 A 368 373 NADPH ABBREVIATION 23345167 A 50 55 NADPH ABBREVIATION 23345167 A 508 513 NADPH ABBREVIATION 23345167 A 747 752 NADPH ABBREVIATION 23345167 A 885 890 NADPH ABBREVIATION 23345167 A 955 960 NADPH ABBREVIATION 23345167 A 975 980 NADPH ABBREVIATION 23346856 A 0 7 Leucine TRIVIAL 23346856 A 1011 1032 methyl (meth)acrylate SYSTEMATIC 23346856 A 1059 1062 Boc ABBREVIATION 23346856 A 1182 1195 primary amine FAMILY 23346856 A 1580 1585 amine SYSTEMATIC 23346856 A 235 245 amino acid FAMILY 23346856 A 276 316 Boc-L-leucine methacryloyloxyethyl ester SYSTEMATIC 23346856 A 318 332 Boc-L-Leu-HEMA FORMULA 23346856 A 339 375 Boc-L-leucine acryloyloxyethyl ester SYSTEMATIC 23346856 A 377 390 Boc-L-Leu-HEA FORMULA 23346856 A 397 440 Boc-L-isoleucine methacryloyloxyethyl ester SYSTEMATIC 23346856 A 442 456 Boc-L-Ile-HEMA FORMULA 23346856 A 467 506 Boc-L-isoleucine acryloyloxyethyl ester SYSTEMATIC 23346856 A 508 521 Boc-L-Ile-HEA FORMULA 23346856 A 617 639 N, N-dimethylformamide SYSTEMATIC 23346856 A 641 644 DMF ABBREVIATION 23346856 A 8 18 isoleucine TRIVIAL 23346856 T 24 34 amino acid FAMILY 23346913 A 361 383 mercaptopropionic acid SYSTEMATIC 23346913 A 385 388 MPA ABBREVIATION 23346913 A 394 402 cysteine TRIVIAL 23346913 A 404 407 Cys FORMULA 23346913 A 458 464 TiO(2) FORMULA 23346913 A 548 551 Cys FORMULA 23346913 A 594 597 MPA ABBREVIATION 23346994 A 1500 1510 amino acid FAMILY 23346994 A 963 973 amino acid FAMILY 23347001 A 1037 1040 IHN ABBREVIATION 23347001 A 1092 1095 IHN ABBREVIATION 23347001 A 12 35 Inositol hexanicotinate TRIVIAL 23347001 A 1205 1208 IHN ABBREVIATION 23347001 A 1216 1222 niacin TRIVIAL 23347001 A 241 244 IHN ABBREVIATION 23347001 A 37 40 IHN ABBREVIATION 23347001 A 370 373 IHN ABBREVIATION 23347001 A 409 412 IHN ABBREVIATION 23347001 A 734 737 IHN ABBREVIATION 23347001 A 86 100 nicotinic acid TRIVIAL 23347001 A 903 906 IHN ABBREVIATION 23347001 A 982 985 IHN ABBREVIATION 23347001 T 42 65 inositol hexanicotinate TRIVIAL 23347043 A 1100 1103 ATP ABBREVIATION 23347043 A 614 617 ATP ABBREVIATION 23347089 A 1022 1038 aryl hydrocarbon FAMILY 23347089 A 467 478 bisphenol A TRIVIAL 23347089 A 480 483 BPA ABBREVIATION 23347089 A 653 678 perfluorooctane sulfonate SYSTEMATIC 23347089 A 680 684 PFOS ABBREVIATION 23347089 A 687 709 perfluorooctanoic acid SYSTEMATIC 23347089 A 711 715 PFOA ABBREVIATION 23347089 A 718 743 mono-ethylhexyl phthalate SYSTEMATIC 23347089 A 745 749 MEHP ABBREVIATION 23347089 A 755 782 di-(2-ethylhexyl) phthalate SYSTEMATIC 23347089 A 784 788 DEHP ABBREVIATION 23347089 A 852 860 estrogen FAMILY 23347089 A 898 906 androgen FAMILY 23347089 A 925 933 pregnane TRIVIAL 23347206 A 112 115 DON ABBREVIATION 23347206 A 121 132 zearalenone TRIVIAL 23347206 A 134 137 ZEN ABBREVIATION 23347206 A 440 443 DON ABBREVIATION 23347206 A 448 451 ZEN ABBREVIATION 23347206 A 96 110 deoxynivalenol TRIVIAL 23347584 A 122 134 ent-kauranes FAMILY 23347584 A 156 167 ent-kaurane TRIVIAL 23347584 A 173 185 diterpenoids FAMILY 23347584 A 348 379 ent-18-acetoxykaur-16-en-15-one SYSTEMATIC 23347584 A 430 440 superoxide TRIVIAL 23347584 A 95 103 kauranes FAMILY 23347584 T 18 30 diterpenoids FAMILY 23347954 A 1017 1022 H1152 IDENTIFIER 23347954 A 1171 1180 GSK429286 IDENTIFIER 23347954 A 1219 1224 H1152 IDENTIFIER 23347954 A 1459 1464 H1152 IDENTIFIER 23347954 A 1531 1536 H1152 IDENTIFIER 23347954 A 1665 1670 H1152 IDENTIFIER 23347954 A 1788 1793 H1152 IDENTIFIER 23347954 A 335 348 polyglutamine FAMILY 23347954 A 405 411 Y27632 IDENTIFIER 23347954 A 435 448 polyglutamine FAMILY 23347954 A 47 60 polyglutamine FAMILY 23347954 A 552 558 Y27632 IDENTIFIER 23347954 A 560 565 H1152 IDENTIFIER 23347954 A 570 579 GSK429286 IDENTIFIER 23347954 A 616 629 polyglutamine FAMILY 23347954 A 653 659 Y27632 IDENTIFIER 23347954 A 663 668 H1152 IDENTIFIER 23347954 A 771 777 Y27632 IDENTIFIER 23347954 A 779 784 H1152 IDENTIFIER 23347954 A 869 874 H1152 IDENTIFIER 23347954 A 915 928 polyglutamine FAMILY 23347954 T 0 5 H1152 IDENTIFIER 23347954 T 34 47 polyglutamine FAMILY 23348005 A 1014 1018 GSSG ABBREVIATION 23348005 A 1028 1037 Quercetin TRIVIAL 23348005 A 1139 1148 peroxides FAMILY 23348005 A 1197 1206 quercetin TRIVIAL 23348005 A 1261 1271 superoxide TRIVIAL 23348005 A 1296 1307 glutathione TRIVIAL 23348005 A 1400 1404 urea TRIVIAL 23348005 A 1437 1444 alanine TRIVIAL 23348005 A 1509 1518 quercetin TRIVIAL 23348005 A 1527 1536 quercetin TRIVIAL 23348005 A 1586 1602 triacyl glycerol FAMILY 23348005 A 178 187 quercetin TRIVIAL 23348005 A 247 257 oleic acid TRIVIAL 23348005 A 416 425 Oil-Red-O TRIVIAL 23348005 A 427 430 ORO ABBREVIATION 23348005 A 468 483 triacylglycerol FAMILY 23348005 A 485 488 TAG ABBREVIATION 23348005 A 705 712 glucose TRIVIAL 23348005 A 744 753 Quercetin TRIVIAL 23348005 A 820 823 TAG ABBREVIATION 23348005 A 887 894 glucose TRIVIAL 23348005 A 935 946 glutathione TRIVIAL 23348005 T 0 9 Quercetin TRIVIAL 23348005 T 86 96 oleic acid TRIVIAL 23348055 A 238 249 bisphenol A TRIVIAL 23348055 A 251 254 BPA ABBREVIATION 23348055 A 260 268 estrogen FAMILY 23348055 A 334 337 BPA ABBREVIATION 23348055 A 642 645 BPA ABBREVIATION 23348055 T 54 65 bisphenol A TRIVIAL 23348235 A 1139 1142 HCl FORMULA 23348235 A 1435 1445 mesalamine TRIVIAL 23348235 A 1536 1544 EUDRAGIT FAMILY 23348235 A 177 189 Prednisolone TRIVIAL 23348235 A 1843 1851 EUDRAGIT FAMILY 23348235 A 2006 2017 bicarbonate SYSTEMATIC 23348235 A 283 291 EUDRAGIT FAMILY 23348235 A 340 350 KH(2)PO(4) FORMULA 23348235 A 397 405 EUDRAGIT FAMILY 23348235 A 511 519 EUDRAGIT FAMILY 23348235 A 642 645 HCl FORMULA 23348235 A 801 811 mesalamine TRIVIAL 23348407 A 195 206 isoflavones FAMILY 23348407 A 419 430 isoflavones FAMILY 23348407 A 454 461 lignans FAMILY 23348407 A 485 495 coumestrol TRIVIAL 23348407 A 691 703 isoflavonoid FAMILY 23348407 A 765 771 lignan FAMILY 23348407 A 796 806 coumestrol TRIVIAL 23348407 A 896 908 isoflavonoid FAMILY 23348407 A 944 956 isoflavonoid FAMILY 23348500 A 1052 1056 NCFP ABBREVIATION 23348500 A 1070 1075 CPPHA ABBREVIATION 23348500 A 1180 1184 NCFP ABBREVIATION 23348500 A 1238 1243 CPPHA ABBREVIATION 23348500 A 13 22 glutamate TRIVIAL 23348500 A 1335 1339 NCFP ABBREVIATION 23348500 A 1478 1482 MPEP ABBREVIATION 23348500 A 583 587 MPEP ABBREVIATION 23348500 A 589 623 2-Methyl-6-(phenylethynyl)pyridine SYSTEMATIC 23348500 A 663 668 CPPHA ABBREVIATION 23348500 A 670 758 N-(4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl)-2-hydroxybenzamide SYSTEMATIC 23348500 A 947 952 CPPHA ABBREVIATION 23348500 A 967 971 NCFP ABBREVIATION 23348500 A 973 1049 N-(4-chloro-2-((4-fluoro-1,3-dioxoisoindolin-2-yl)methyl)phenyl)picolinamide SYSTEMATIC 23348500 T 21 30 glutamate TRIVIAL 23348755 A 1007 1043 guanosine-5'-0-(γ-thio)-triphosphate SYSTEMATIC 23348755 A 1189 1201 (+)-naloxone TRIVIAL 23348755 A 1217 1222 DAMGO ABBREVIATION 23348755 A 1257 1269 (-)-naloxone TRIVIAL 23348755 A 1314 1326 (+)-naloxone TRIVIAL 23348755 A 1402 1414 (+)-naloxone TRIVIAL 23348755 A 180 189 adenylate TRIVIAL 23348755 A 320 332 (-)-naloxone TRIVIAL 23348755 A 360 372 (+)-naloxone TRIVIAL 23348755 A 500 541 [D-Ala2, N-Me-Phe4, Glycinol5]-Enkephalin SYSTEMATIC 23348755 A 543 548 DAMGO ABBREVIATION 23348755 A 655 667 (-)-naloxone TRIVIAL 23348755 A 782 794 (-)-naloxone TRIVIAL 23348755 A 799 811 (+)-naloxone TRIVIAL 23348755 A 840 845 DAMGO ABBREVIATION 23348755 A 901 913 (-)-naloxone TRIVIAL 23348755 A 955 967 (+)-naloxone TRIVIAL 23348755 A 990 995 DAMGO ABBREVIATION 23348755 T 17 29 (+)-naloxone TRIVIAL 23349485 A 173 176 AMP ABBREVIATION 23349489 A 968 977 thymidine TRIVIAL 23349493 A 1192 1201 palmitate TRIVIAL 23349493 A 1420 1429 palmitate TRIVIAL 23349493 A 1443 1452 palmitate TRIVIAL 23349493 A 353 360 glucose TRIVIAL 23349524 A 1676 1683 glucose TRIVIAL 23349524 A 932 939 glucose TRIVIAL 23349535 A 1116 1127 aldosterone TRIVIAL 23349535 A 1203 1214 aldosterone TRIVIAL 23349535 A 1277 1288 aldosterone TRIVIAL 23349535 A 1382 1393 aldosterone TRIVIAL 23349535 A 1491 1502 aldosterone TRIVIAL 23349535 A 1686 1689 Ser FORMULA 23349535 A 1882 1893 aldosterone TRIVIAL 23349535 A 2017 2028 aldosterone TRIVIAL 23349535 A 2084 2098 spironolactone TRIVIAL 23349535 A 2100 2110 eplerenone TRIVIAL 23349535 A 2312 2323 aldosterone TRIVIAL 23349535 A 599 611 nitric oxide SYSTEMATIC 23349535 A 641 647 Ca(2+) FORMULA 23350627 A 101 111 graphdiyne TRIVIAL 23350627 A 117 121 TiO₂ FORMULA 23350627 A 117 130 TiO₂-graphene FORMULA 23350627 A 122 130 graphene TRIVIAL 23350627 A 237 241 TiO₂ FORMULA 23350627 A 247 257 graphdiyne TRIVIAL 23350627 A 426 430 TiO₂ FORMULA 23350627 A 497 501 TiO₂ FORMULA 23350627 A 507 517 graphdiyne TRIVIAL 23350627 A 599 613 methylene blue TRIVIAL 23350627 A 640 644 TiO₂ FORMULA 23350627 A 650 660 graphdiyne TRIVIAL 23350627 A 709 713 TiO₂ FORMULA 23350627 A 73 79 carbon SYSTEMATIC 23350627 A 753 757 TiO₂ FORMULA 23350627 A 763 771 graphene TRIVIAL 23350627 A 90 94 TiO₂ FORMULA 23350627 A 96 100 TiO₂ FORMULA 23350627 A 96 111 TiO₂-graphdiyne FORMULA 23350627 T 29 39 graphdiyne TRIVIAL 23350627 T 44 52 graphene TRIVIAL 23350627 T 62 66 TiO₂ FORMULA 23350690 A 1162 1175 cinnamic acid TRIVIAL 23350690 A 1390 1403 cinnamic acid TRIVIAL 23350690 A 24 37 cinnamic acid TRIVIAL 23350690 A 307 320 cinnamic acid TRIVIAL 23350690 A 599 612 cinnamic acid TRIVIAL 23350690 T 102 115 cinnamic acid TRIVIAL 23350692 A 1066 1069 CFX ABBREVIATION 23350692 A 1292 1295 AMX ABBREVIATION 23350692 A 1300 1303 CFX ABBREVIATION 23350692 A 18 29 Amoxicillin TRIVIAL 23350692 A 31 34 AMX ABBREVIATION 23350692 A 40 50 cefuroxime TRIVIAL 23350692 A 402 405 AMX ABBREVIATION 23350692 A 410 413 CFX ABBREVIATION 23350692 A 52 55 CFX ABBREVIATION 23350692 A 620 633 polypropylene SYSTEMATIC 23350692 A 687 690 AMX ABBREVIATION 23350692 A 709 712 CFX ABBREVIATION 23350692 A 833 836 AMX ABBREVIATION 23350692 T 17 28 amoxicillin TRIVIAL 23350692 T 33 43 cefuroxime TRIVIAL 23350733 A 1110 1120 sivelestat TRIVIAL 23350733 A 533 547 symplostatin 5 TRIVIAL 23350785 A 327 339 curcuminoids FAMILY 23350785 A 560 563 MTT ABBREVIATION 23350785 A 565 626 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide SYSTEMATIC 23350785 A 757 765 curcumin TRIVIAL 23350785 A 767 784 demethoxycurcumin SYSTEMATIC 23350785 A 790 810 bisdemethoxycurcumin SYSTEMATIC 23350785 A 968 980 curcuminoids FAMILY 23350926 A 1024 1033 H(2)O(2+) FORMULA 23350926 A 1096 1113 [Ru(phen)(3)](2+) FORMULA 23350926 A 117 126 phendione ABBREVIATION 23350926 A 1192 1209 [Ru(phen)(3)](2+) FORMULA 23350926 A 1272 1281 H(2)O(2+) FORMULA 23350926 A 129 158 1,10-phenanthroline-5,6-dione SYSTEMATIC 23350926 A 1371 1377 oxygen SYSTEMATIC 23350926 A 1519 1520 H FORMULA 23350926 A 1547 1552 sugar FAMILY 23350926 A 1634 1643 ruthenium SYSTEMATIC 23350926 A 188 194 oxygen SYSTEMATIC 23350926 A 31 44 ruthenium(II) SYSTEMATIC 23350926 A 324 336 acetonitrile SYSTEMATIC 23350926 A 387 394 quinone FAMILY 23350926 A 417 445 [(phen)(2)Ru(phenH(2)O)](2+) FORMULA 23350926 A 448 457 H(2)O(2+) FORMULA 23350926 A 45 52 quinone FAMILY 23350926 A 465 474 phenH(2)O FORMULA 23350926 A 477 509 1,10-phenanthroline-6-one-5-diol SYSTEMATIC 23350926 A 552 559 hydrate SYSTEMATIC 23350926 A 582 587 H(2)O FORMULA 23350926 A 663 671 carbonyl FAMILY 23350926 A 73 101 [(phen)(2)Ru(phendione)](2+) FORMULA 23350926 A 739 763 Ru(III) phen-semiquinone FORMULA 23350926 T 71 116 hydrated Ru(II) 1,10-phenanthroline-5,6-dione SYSTEMATIC 23351043 A 1046 1050 NaCl FORMULA 23351043 A 1068 1071 PAH ABBREVIATION 23351043 A 1072 1083 PHEMA-g-PAA ABBREVIATION 23351043 A 1091 1094 PAH ABBREVIATION 23351043 A 1095 1098 PAA ABBREVIATION 23351043 A 1223 1227 COOH FORMULA 23351043 A 1443 1447 NaCl FORMULA 23351043 A 1507 1511 NaCl FORMULA 23351043 A 323 339 poly(allylamine) FAMILY 23351043 A 341 344 PAH ABBREVIATION 23351043 A 360 418 poly(2-hydroxyethyl methacrylate)-graft-poly(acrylic acid) FAMILY 23351043 A 420 431 PHEMA-g-PAA ABBREVIATION 23351043 A 486 489 PAH ABBREVIATION 23351043 A 501 504 PAA ABBREVIATION 23351043 A 618 621 PAH ABBREVIATION 23351043 A 622 633 PHEMA-g-PAA ABBREVIATION 23351043 A 719 722 PAA ABBREVIATION 23351043 A 877 881 NaCl FORMULA 23351043 T 30 48 poly(acrylic acid) SYSTEMATIC 23351072 A 694 706 streptavidin TRIVIAL 23351072 A 707 713 biotin TRIVIAL 23351147 A 254 267 dianthramides FAMILY 23351147 A 285 295 flavonoids FAMILY 23351147 A 307 316 coumarins FAMILY 23351147 A 4 17 ethyl acetate SYSTEMATIC 23351147 T 26 39 ethyl acetate SYSTEMATIC 23351169 A 0 23 Poly(4-hydroxybutyrate) FAMILY 23351169 A 1090 1094 P3HP SYSTEMATIC 23351169 A 1099 1103 P4HB SYSTEMATIC 23351169 A 1384 1388 P3HP SYSTEMATIC 23351169 A 1393 1397 P4HB SYSTEMATIC 23351169 A 1419 1422 PHA ABBREVIATION 23351169 A 217 221 P4HB SYSTEMATIC 23351169 A 242 246 P3HP SYSTEMATIC 23351169 A 25 29 P4HB SYSTEMATIC 23351169 A 371 375 P3HP SYSTEMATIC 23351169 A 380 384 P4HB SYSTEMATIC 23351169 A 478 492 1,4-butanediol SYSTEMATIC 23351169 A 494 497 BDO ABBREVIATION 23351169 A 504 507 4HB SYSTEMATIC 23351169 A 519 523 P4HB SYSTEMATIC 23351169 A 572 587 1,3-propanediol SYSTEMATIC 23351169 A 589 592 PDO ABBREVIATION 23351169 A 599 602 3HP SYSTEMATIC 23351169 A 643 647 P3HP SYSTEMATIC 23351169 A 68 93 poly(3-hydroxypropionate) FAMILY 23351169 A 773 784 P3HP-b-P4HB SYSTEMATIC 23351169 A 850 854 P3HP SYSTEMATIC 23351169 A 861 865 P4HB SYSTEMATIC 23351169 A 870 874 P3HP SYSTEMATIC 23351169 A 881 885 P4HB SYSTEMATIC 23351169 A 942 955 P(3HP-co-4HB) SYSTEMATIC 23351169 A 95 99 P3HP SYSTEMATIC 23351169 T 58 107 p(3-Hydroxypropionate)-block-p(4-hydroxybutyrate) FAMILY 23351960 A 1048 1051 GSH ABBREVIATION 23351960 A 1084 1087 MDA ABBREVIATION 23351960 A 1449 1460 scopolamine TRIVIAL 23351960 A 481 491 superoxide TRIVIAL 23351960 A 509 520 glutathione TRIVIAL 23351960 A 595 614 reduced glutathione TRIVIAL 23351960 A 616 619 GSH ABBREVIATION 23351960 A 622 637 malondialdehyde TRIVIAL 23351960 A 639 642 MDA ABBREVIATION 23351960 A 733 744 scopolamine TRIVIAL 23351960 A 776 787 scopolamine TRIVIAL 23351960 T 51 62 scopolamine TRIVIAL 23351962 A 181 187 crocin TRIVIAL 23351962 A 220 223 STZ ABBREVIATION 23351962 A 276 282 Crocin TRIVIAL 23351962 A 30 44 streptozotocin TRIVIAL 23351962 A 381 384 STZ ABBREVIATION 23351962 A 46 49 STZ ABBREVIATION 23351962 A 506 521 malondialdehyde TRIVIAL 23351962 A 523 526 MDA ABBREVIATION 23351962 A 538 543 thiol FAMILY 23351962 A 559 570 glutathione TRIVIAL 23351962 A 598 601 STZ ABBREVIATION 23351962 A 675 678 MDA ABBREVIATION 23351962 A 733 739 Crocin TRIVIAL 23351962 A 824 827 MDA ABBREVIATION 23351962 A 858 863 thiol FAMILY 23351962 A 919 925 crocin TRIVIAL 23351962 T 27 33 crocin TRIVIAL 23351962 T 66 80 streptozotocin TRIVIAL 23352511 A 114 127 cyanopyridine SYSTEMATIC 23352511 A 136 153 2-aminopyrimidine SYSTEMATIC 23352511 A 165 184 pyrimidine-2-thione SYSTEMATIC 23352511 A 19 42 imidazo[1,2-a]pyridines FAMILY 23352511 A 397 416 pentylene tetrazole TRIVIAL 23352511 A 609 623 4-fluorophenyl SYSTEMATIC 23352511 A 655 677 imidazo[1,2-a]pyridine SYSTEMATIC 23352511 A 72 82 pyrazoline SYSTEMATIC 23352511 A 817 820 PTZ ABBREVIATION 23352511 A 91 104 cyanopyridone SYSTEMATIC 23352511 T 4 27 imidazo[1,2-a]pyridines FAMILY 23352834 A 1195 1201 sodium SYSTEMATIC 23352834 A 367 373 sodium SYSTEMATIC 23352834 T 103 109 sodium SYSTEMATIC 23352834 T 69 75 sodium SYSTEMATIC 23352909 A 1151 1163 Pluronic P85 TRIVIAL 23352909 A 1174 1178 DOXO ABBREVIATION 23352909 A 1256 1260 DOXO ABBREVIATION 23352909 A 1446 1453 PSO-PEO ABBREVIATION 23352909 A 4 44 poly(styrene oxide)-poly(ethylene oxide) FAMILY 23352909 A 459 470 doxorubicin TRIVIAL 23352909 A 46 53 PSO-PEO ABBREVIATION 23352909 A 472 476 DOXO ABBREVIATION 23352909 A 695 699 DOXO ABBREVIATION 23352909 A 763 767 DOXO ABBREVIATION 23352909 A 932 940 Pluronic FAMILY 23352909 T 0 40 Poly(styrene oxide)-poly(ethylene oxide) FAMILY 23352911 A 1133 1136 PLA ABBREVIATION 23352911 A 1312 1315 PLA ABBREVIATION 23352911 A 590 607 Poly(Lactic Acid) FAMILY 23352911 A 609 612 PLA ABBREVIATION 23352911 A 897 900 PLA ABBREVIATION 23352911 T 53 70 poly(lactic acid) SYSTEMATIC 23352980 A 1658 1666 SGI-1776 IDENTIFIER 23352980 A 1668 1677 ETP-45299 IDENTIFIER 23352980 A 1683 1695 tryptanthrin TRIVIAL 23352980 A 663 671 SGI-1776 IDENTIFIER 23352980 A 673 682 ETP-45299 IDENTIFIER 23352980 A 688 700 tryptanthrin TRIVIAL 23352986 A 0 23 All-trans retinoic acid TRIVIAL 23352986 A 1061 1065 atRA ABBREVIATION 23352986 A 1237 1241 atRA ABBREVIATION 23352986 A 1441 1445 atRA ABBREVIATION 23352986 A 155 168 retinoic acid TRIVIAL 23352986 A 25 29 atRA ABBREVIATION 23352986 A 368 372 atRA ABBREVIATION 23352986 A 480 484 atRA ABBREVIATION 23352986 A 53 62 vitamin A FAMILY 23352986 T 58 81 all-trans retinoic acid TRIVIAL 23353053 A 1048 1055 glucose TRIVIAL 23353053 A 1155 1158 PGG ABBREVIATION 23353053 A 1244 1251 glucose TRIVIAL 23353053 A 1305 1308 PGG ABBREVIATION 23353053 A 382 393 gallotannin FAMILY 23353053 A 403 440 1,2,3,4,6 penta-O-galloyl-β-d-glucose SYSTEMATIC 23353053 A 442 445 PGG ABBREVIATION 23353053 A 496 499 PGG ABBREVIATION 23353053 A 664 667 PGG ABBREVIATION 23353053 A 672 685 carbenoxolone TRIVIAL 23353053 A 687 690 CBX ABBREVIATION 23353053 A 901 915 corticosterone TRIVIAL 23353053 T 0 37 1,2,3,4,6 Penta-O-galloyl-β-d-glucose SYSTEMATIC 23353657 A 10 30 labdane diterpenoids FAMILY 23353657 A 139 159 labdane diterpenoids FAMILY 23353657 A 174 181 lignans FAMILY 23353657 A 32 47 calomacrins A-C MULTIPLE 23353657 A 65 85 diaryl butyrolactone FAMILY 23353657 A 91 97 lignan FAMILY 23353657 A 99 111 calomacrol A TRIVIAL 23353657 T 0 20 Labdane diterpenoids FAMILY 23353657 T 25 32 lignans FAMILY 23353700 A 122 130 Ceramide FAMILY 23353700 A 1269 1280 C6-ceramide TRIVIAL 23353700 A 1285 1294 tamoxifen TRIVIAL 23353700 A 1365 1374 tamoxifen TRIVIAL 23353700 A 1413 1424 C6-ceramide TRIVIAL 23353700 A 1590 1598 ceramide FAMILY 23353700 A 229 237 Ceramide FAMILY 23353700 A 368 379 C6-ceramide TRIVIAL 23353700 A 471 479 ceramide FAMILY 23353700 A 490 503 sphingolipids FAMILY 23353700 A 566 577 C6-ceramide TRIVIAL 23353700 A 697 706 tamoxifen TRIVIAL 23353700 A 708 714 VX-710 IDENTIFIER 23353700 A 716 725 verapamil TRIVIAL 23353700 A 730 743 cyclosporin A TRIVIAL 23353700 A 775 786 C6-ceramide TRIVIAL 23353700 A 841 852 C6-ceramide TRIVIAL 23353700 A 857 866 tamoxifen TRIVIAL 23353700 T 0 9 Tamoxifen TRIVIAL 23353700 T 42 50 ceramide FAMILY 23353701 A 1005 1009 AdOx ABBREVIATION 23353701 A 1274 1277 SAH ABBREVIATION 23353701 A 1348 1364 3-deazaadenosine SYSTEMATIC 23353701 A 1366 1370 DAZA ABBREVIATION 23353701 A 1598 1601 SAH ABBREVIATION 23353701 A 381 401 adenosylhomocysteine TRIVIAL 23353701 A 403 406 SAH ABBREVIATION 23353701 A 464 484 adenosine dialdehyde SYSTEMATIC 23353701 A 486 490 AdOx ABBREVIATION 23353701 A 538 558 adenosylhomocysteine TRIVIAL 23353701 A 560 563 SAH ABBREVIATION 23353701 A 59 65 methyl SYSTEMATIC 23353701 A 605 608 SAH ABBREVIATION 23353701 A 75 95 S-adenosylmethionine TRIVIAL 23353701 A 885 889 AdOx ABBREVIATION 23353701 A 97 100 SAM ABBREVIATION 23353701 T 79 99 adenosine dialdehyde SYSTEMATIC 23353736 A 63 81 methyl rosmarinate SYSTEMATIC 23353736 T 28 46 methyl rosmarinate SYSTEMATIC 23353744 A 140 157 N-tosylhydrazones FAMILY 23353744 A 163 175 aryl iodides FAMILY 23353744 A 18 29 benzoxepins FAMILY 23353744 A 182 191 palladium SYSTEMATIC 23353744 A 267 271 CA-4 ABBREVIATION 23353744 A 276 283 isoCA-4 ABBREVIATION 23353744 A 450 460 benzoxepin FAMILY 23353744 A 662 672 benzoxepin FAMILY 23353744 A 67 74 isoCA-4 ABBREVIATION 23353744 A 716 723 isoCA-4 ABBREVIATION 23353744 T 47 64 5-arylbenzoxepins FAMILY 23353744 T 96 117 isocombretastatin A-4 TRIVIAL 23353747 A 0 15 Naphthoquinones FAMILY 23353747 A 155 173 α- and β-lapachone MULTIPLE 23353747 A 211 230 1,4-naphthoquinones FAMILY 23353747 A 407 416 cisplatin TRIVIAL 23353747 A 881 895 naphthoquinone FAMILY 23353747 T 16 24 lapachol TRIVIAL 23353747 T 26 37 β-lapachone TRIVIAL 23353747 T 60 79 1,4-naphthoquinones FAMILY 23353749 A 1006 1016 l-arginine TRIVIAL 23353749 A 1018 1023 l-Arg FORMULA 23353749 A 149 164 trifluoromethyl SYSTEMATIC 23353749 A 182 192 tripeptide FAMILY 23353749 A 255 271 HCl. Leu-Gly-NH2 FORMULA 23353749 A 280 297 (S)-α-Tfm-proline TRIVIAL 23353749 A 327 338 CF3-(MIF-1) FORMULA 23353749 A 40 45 MIF-1 ABBREVIATION 23353749 A 462 467 MIF-1 ABBREVIATION 23353749 A 512 523 CF3-(MIF-1) FORMULA 23353749 A 662 668 nitric SYSTEMATIC 23353749 A 816 827 CF3-(MIF-1) FORMULA 23353749 A 887 895 naloxone TRIVIAL 23353749 A 901 913 nitric oxide SYSTEMATIC 23353749 A 939 965 l-N(G)-nitroarginine ester SYSTEMATIC 23353749 A 967 973 l-NAME ABBREVIATION 23353749 A 982 994 nitric oxide SYSTEMATIC 23353749 A 996 998 NO FORMULA 23353749 T 16 21 MIF-1 ABBREVIATION 23353749 T 54 83 (S)-α-trifluoromethyl-proline SYSTEMATIC 23353751 A 1 12 Zn(fpedtc)2 FORMULA 23353751 A 111 117 fpedtc ABBREVIATION 23353751 A 120 163 N-furfuryl-N-(2-phenylethyl)dithiocarbamate SYSTEMATIC 23353751 A 170 178 pyridine SYSTEMATIC 23353751 A 180 189 1,10-phen SYSTEMATIC 23353751 A 192 211 1,10-phenanthroline SYSTEMATIC 23353751 A 20 35 Zn(fpedtc)2(py) FORMULA 23353751 A 216 225 2,2'-bipy SYSTEMATIC 23353751 A 228 243 2,2'-bipyridine SYSTEMATIC 23353751 A 326 330 (1)H FORMULA 23353751 A 335 340 (13)C FORMULA 23353751 A 43 65 Zn(fpedtc)2(1,10-phen) FORMULA 23353751 A 600 602 Zn FORMULA 23353751 A 603 604 N FORMULA 23353751 A 76 98 Zn(fpedtc)2(2,2'-bipy) FORMULA 23353751 T 141 149 nitrogen SYSTEMATIC 23353751 T 71 132 bis(N-furfuryl-N-(2-phenylethyl)dithiocarbamato-S,S')zinc(II) SYSTEMATIC 23353753 A 102 121 agmatine dipeptides FAMILY 23353753 A 270 276 serine TRIVIAL 23353753 A 332 350 agmatine dipeptide FAMILY 23353753 A 768 777 aldehydes FAMILY 23353753 A 91 92 C FORMULA 23353753 T 6 24 agmatine dipeptide FAMILY 23353756 A 1017 1022 DOPAC ABBREVIATION 23353756 A 12 65 mono-substituted 4-phenylpiperidines and -piperazines MULTIPLE 23353756 A 29 65 4-phenylpiperidines and -piperazines MULTIPLE 23353756 A 316 346 3,4-dihydroxyphenylacetic acid SYSTEMATIC 23353756 A 348 353 DOPAC ABBREVIATION 23353756 A 676 684 dopamine TRIVIAL 23353756 A 709 718 monoamine FAMILY 23353756 A 915 920 DOPAC ABBREVIATION 23353756 T 100 119 4-phenylpiperazines FAMILY 23353756 T 76 95 4-phenylpiperidines FAMILY 23353805 A 372 383 doxorubicin TRIVIAL 23353805 A 385 388 DOX ABBREVIATION 23353805 A 435 445 iron oxide SYSTEMATIC 23353805 A 468 479 γ-Fe(2)O(3) FORMULA 23353805 A 690 693 DOX ABBREVIATION 23353805 A 787 798 doxorubicin TRIVIAL 23353807 A 1036 1043 fasudil TRIVIAL 23353807 A 1194 1201 fasudil TRIVIAL 23353807 A 1284 1291 fasudil TRIVIAL 23353807 A 1337 1344 fasudil TRIVIAL 23353807 A 1497 1504 fasudil TRIVIAL 23353807 A 1699 1702 MCT ABBREVIATION 23353807 A 1803 1810 fasudil TRIVIAL 23353807 A 485 492 fasudil TRIVIAL 23353807 A 494 501 HA-1077 IDENTIFIER 23353807 A 680 687 fasudil TRIVIAL 23353807 A 702 718 ammonium sulfate SYSTEMATIC 23353807 A 941 954 monocrotaline TRIVIAL 23353807 A 956 959 MCT ABBREVIATION 23353807 T 10 17 fasudil TRIVIAL 23353821 A 1051 1057 oxygen SYSTEMATIC 23353821 A 1531 1539 H(2)O(2) FORMULA 23353821 A 740 746 oxygen SYSTEMATIC 23353821 A 814 822 tyrosine TRIVIAL 23353901 A 1003 1006 DOI ABBREVIATION 23353901 A 1133 1140 M100907 IDENTIFIER 23353901 A 1163 1172 SB-242084 IDENTIFIER 23353901 A 1195 1204 SB-206553 IDENTIFIER 23353901 A 1398 1401 DOI ABBREVIATION 23353901 A 1444 1447 DOI ABBREVIATION 23353901 A 1817 1820 DOI ABBREVIATION 23353901 A 1972 1975 DOI ABBREVIATION 23353901 A 212 243 2,5-dimethoxy-4-iodoamphetamine SYSTEMATIC 23353901 A 245 248 DOI ABBREVIATION 23353901 A 529 532 DOI ABBREVIATION 23353901 A 711 720 CP 809101 IDENTIFIER 23353901 A 722 732 Ro 60-0175 IDENTIFIER 23353901 A 734 744 WAY 161503 IDENTIFIER 23353901 A 746 750 mCPP ABBREVIATION 23353901 A 756 772 1-methylpsilocin SYSTEMATIC 23353901 A 77 86 serotonin TRIVIAL 23353901 A 781 818 4-phenyl-2-N,N-dimethyl-aminotetralin SYSTEMATIC 23353901 A 820 823 PAT ABBREVIATION 23353901 A 88 92 5-HT SYSTEMATIC 23353901 A 922 929 M100907 IDENTIFIER 23353901 A 940 949 SB-242084 IDENTIFIER 23353901 A 967 976 SB-206553 IDENTIFIER 23353901 T 133 164 2,5-dimethoxy-4-iodoamphetamine SYSTEMATIC 23354151 A 158 172 hydrocortisone TRIVIAL 23354151 A 274 293 phosphatidylcholine FAMILY 23354151 A 327 376 d-α-tocopheryl polyethylene glycol 1000 succinate FAMILY 23354151 A 378 382 TPGS ABBREVIATION 23354151 A 408 428 polyvinylpyrrolidone SYSTEMATIC 23354151 A 430 433 PVP ABBREVIATION 23354151 A 558 572 hydrocortisone TRIVIAL 23354151 A 835 849 hydrocortisone TRIVIAL 23354457 A 144 158 organochlorine FAMILY 23354457 A 163 178 organophosphate FAMILY 23354532 A 1013 1021 caffeine TRIVIAL 23354532 A 11 19 Caffeine TRIVIAL 23354532 A 1149 1157 caffeine TRIVIAL 23354532 A 1226 1234 Caffeine TRIVIAL 23354532 A 125 133 caffeine TRIVIAL 23354532 A 1388 1396 caffeine TRIVIAL 23354532 A 480 488 caffeine TRIVIAL 23354532 A 631 639 caffeine TRIVIAL 23354532 A 641 644 CAF ABBREVIATION 23354532 A 851 854 CAF ABBREVIATION 23354532 T 0 8 Caffeine TRIVIAL 23354536 A 1016 1020 5-HT SYSTEMATIC 23354536 A 1033 1037 MDMA ABBREVIATION 23354536 A 1070 1080 tryptophan TRIVIAL 23354536 A 123 132 serotonin TRIVIAL 23354536 A 134 138 5-HT SYSTEMATIC 23354536 A 358 362 MDMA ABBREVIATION 23354536 A 44 77 3,4 methylenedioxymethamphetamine SYSTEMATIC 23354536 A 492 500 8-OHDPAT SYSTEMATIC 23354536 A 589 608 5-hydroxytryptophan SYSTEMATIC 23354536 A 610 615 5-HTP SYSTEMATIC 23354536 A 670 678 8-OHDPAT SYSTEMATIC 23354536 A 777 781 MDMA ABBREVIATION 23354536 A 79 83 MDMA ABBREVIATION 23354536 A 812 816 MDMA ABBREVIATION 23354536 A 844 848 5-HT SYSTEMATIC 23354536 A 873 878 5-HTP SYSTEMATIC 23354536 T 111 119 8-OHDPAT SYSTEMATIC 23354536 T 32 36 MDMA ABBREVIATION 23354542 A 1001 1003 Fe FORMULA 23354542 A 1009 1011 Na FORMULA 23354542 A 1188 1190 Ca FORMULA 23354542 A 1192 1193 P FORMULA 23354542 A 1199 1201 Mg FORMULA 23354542 A 1652 1654 Ca FORMULA 23354542 A 1656 1657 P FORMULA 23354542 A 1659 1661 Mg FORMULA 23354542 A 1667 1669 Fe FORMULA 23354542 A 725 736 nitric acid SYSTEMATIC 23354542 A 741 756 perchloric acid SYSTEMATIC 23354542 A 882 884 Ca FORMULA 23354542 A 889 891 Mg FORMULA 23354542 A 991 992 P FORMULA 23354542 A 994 995 S FORMULA 23354542 A 997 999 Zn FORMULA 23354728 A 1007 1017 fatty acid FAMILY 23354728 A 1037 1056 11-β-hydroxysteroid FAMILY 23354728 A 1341 1348 glucose TRIVIAL 23354728 A 734 741 glucose TRIVIAL 23354728 A 951 957 sodium SYSTEMATIC 23354728 A 966 973 glucose TRIVIAL 23354809 A 1097 1109 piperacillin TRIVIAL 23354809 A 1114 1124 tazobactam TRIVIAL 23354809 A 1390 1402 piperacillin TRIVIAL 23354809 A 1407 1417 tazobactam TRIVIAL 23354809 A 1471 1483 piperacillin TRIVIAL 23354809 A 1484 1494 tazobactam TRIVIAL 23354809 A 1577 1589 piperacillin TRIVIAL 23354809 A 1756 1768 piperacillin TRIVIAL 23354809 A 1769 1779 tazobactam TRIVIAL 23354809 A 470 482 piperacillin TRIVIAL 23354809 A 491 501 tazobactam TRIVIAL 23354809 A 654 666 piperacillin TRIVIAL 23354809 A 66 78 piperacillin TRIVIAL 23354809 A 671 681 tazobactam TRIVIAL 23354809 A 79 89 tazobactam TRIVIAL 23354809 A 957 969 piperacillin TRIVIAL 23354809 A 974 984 tazobactam TRIVIAL 23354809 T 31 43 piperacillin TRIVIAL 23354809 T 44 54 tazobactam TRIVIAL 23355192 A 163 176 methacrylates FAMILY 23355192 A 84 103 Iron bisterpyridine SYSTEMATIC 23355456 A 405 420 phenylbenzamide SYSTEMATIC 23355456 A 541 556 phenylbenzamide SYSTEMATIC 23355456 A 557 567 NSC 104999 IDENTIFIER 23355456 A 624 633 NSC 57148 IDENTIFIER 23355456 A 791 801 NSC 100874 IDENTIFIER 23355456 A 807 816 NSC 55158 IDENTIFIER 23355456 T 17 32 phenylbenzamide SYSTEMATIC 23357335 A 34 52 cyclic nucleotides FAMILY 23357335 A 656 673 cyclic nucleotide FAMILY 23357335 A 841 858 cyclic nucleotide FAMILY 23357361 A 1107 1116 β-asarone TRIVIAL 23357361 A 1200 1209 β-asarone TRIVIAL 23357361 A 1268 1277 β-asarone TRIVIAL 23357361 A 346 355 β-Asarone TRIVIAL 23357361 A 357 387 1-propenyl-2,4,5-methoxybenzol SYSTEMATIC 23357361 A 512 521 β-asarone TRIVIAL 23357361 A 627 630 MTT ABBREVIATION 23357361 A 915 924 β-Asarone TRIVIAL 23357361 A 999 1008 β-Asarone TRIVIAL 23357361 T 0 9 β-Asarone TRIVIAL 23357630 A 113 131 butyl lucidenate Q SYSTEMATIC 23357630 A 32 50 butyl lucidenate P SYSTEMATIC 23357630 A 402 404 NO FORMULA 23357630 A 56 77 butyl lucidenate D(2) SYSTEMATIC 23357630 A 83 104 butyl lucidenate E(2) SYSTEMATIC 23357630 A 9 30 lanostane triterpenes FAMILY 23357630 T 21 23 NO FORMULA 23357630 T 38 49 triterpenes FAMILY 23357951 A 1127 1136 Glutamate TRIVIAL 23357951 A 630 639 glutamate TRIVIAL 23357951 A 691 700 rapamycin TRIVIAL 23358195 A 1134 1147 acetaminophen TRIVIAL 23358195 A 662 675 acetaminophen TRIVIAL 23358195 A 982 995 acetaminophen TRIVIAL 23358236 A 1010 1021 doxorubicin TRIVIAL 23358236 A 1027 1037 paclitaxel TRIVIAL 23358236 A 1188 1199 stemofoline TRIVIAL 23358236 A 293 304 stemofoline TRIVIAL 23358236 A 433 453 Didehydrostemofoline TRIVIAL 23358236 A 542 553 doxorubicin TRIVIAL 23358236 A 555 566 vinblastine TRIVIAL 23358236 A 571 581 paclitaxel TRIVIAL 23358236 A 686 746 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide SYSTEMATIC 23358236 A 748 751 MTT ABBREVIATION 23358236 A 814 825 stemofoline TRIVIAL 23358236 A 848 853 OH-A1 FORMULA 23358236 A 855 860 NH-B6 FORMULA 23358236 A 865 870 NH-D6 FORMULA 23358236 A 927 938 doxorubicin TRIVIAL 23358236 A 940 951 vinblastine TRIVIAL 23358236 A 95 98 ATP ABBREVIATION 23358236 A 956 966 paclitaxel TRIVIAL 23358236 T 62 73 stemofoline TRIVIAL 23358249 A 1061 1068 quinone FAMILY 23358249 A 174 177 PQQ ABBREVIATION 23358249 A 233 236 PQQ ABBREVIATION 23358249 A 33 57 pyrroloquinoline quinone SYSTEMATIC 23358249 A 389 392 PQQ ABBREVIATION 23358249 A 470 473 PQQ ABBREVIATION 23358249 A 59 62 PQQ ABBREVIATION 23358249 A 735 744 Baicalein TRIVIAL 23358249 A 749 773 epigallocatechin gallate TRIVIAL 23358249 A 775 779 EGCG ABBREVIATION 23358249 A 841 848 quinone FAMILY 23358258 A 12 20 xanthine TRIVIAL 23358258 A 314 346 4-methyl-quinazoline-2-yl-methyl SYSTEMATIC 23358258 A 373 396 2-aminoethylaminomethyl SYSTEMATIC 23358258 A 44 53 methylene SYSTEMATIC 23358258 A 84 92 xanthine TRIVIAL 23358258 T 39 47 xanthine TRIVIAL 23358307 A 107 136 pyrido[4,3,2-mn]acridin-4-one SYSTEMATIC 23358307 A 312 323 styelsamine FAMILY 23358307 A 387 407 styelsamines B and D MULTIPLE 23358307 A 52 63 styelsamine FAMILY 23358307 A 521 554 cystodytin iminoquinone alkaloids FAMILY 23358307 A 623 634 styelsamine FAMILY 23358307 A 65 89 pyrido[4,3,2-mn]acridine SYSTEMATIC 23358307 A 95 105 cystodytin FAMILY 23358307 A 962 981 3-phenylpropanamide SYSTEMATIC 23358307 T 51 62 styelsamine FAMILY 23358307 T 67 77 cystodytin FAMILY 23358500 A 1005 1013 nicotine TRIVIAL 23358500 A 1176 1184 nicotine TRIVIAL 23358500 A 432 440 nicotine TRIVIAL 23358500 A 59 72 acetylcholine SYSTEMATIC 23358500 A 607 615 nicotine TRIVIAL 23358500 A 628 636 nicotine TRIVIAL 23358500 A 670 678 nicotine TRIVIAL 23358500 A 779 787 nicotine TRIVIAL 23358500 A 903 911 nicotine TRIVIAL 23358500 T 121 129 nicotine TRIVIAL 23358500 T 31 44 acetylcholine SYSTEMATIC 23358572 A 108 119 polyaniline SYSTEMATIC 23358572 A 147 158 polyaniline SYSTEMATIC 23358572 A 612 623 polyaniline SYSTEMATIC 23358572 T 85 96 polyaniline SYSTEMATIC 23359135 A 481 492 norflurazon TRIVIAL 23359135 A 494 503 triclosan TRIVIAL 23359135 A 509 533 N-phenyl-2-naphthylamine SYSTEMATIC 23359475 A 138 145 alcohol FAMILY 23359475 A 81 94 triglycerides FAMILY 23359599 A 149 154 amino FAMILY 23359599 A 162 170 carboxyl SYSTEMATIC 23359599 A 212 249 α,ω-bis-carboxy poly(ethylene glycol) FAMILY 23359599 A 254 259 amino FAMILY 23359599 A 271 312 poly(ethylene glycol-co-propylene glycol) FAMILY 23359599 A 316 355 α-methoxy-ω-amino poly(ethylene glycol) FAMILY 23359599 A 411 418 (125) I FORMULA 23359599 A 59 86 poly(glycidyl methacrylate) SYSTEMATIC 23359599 A 91 124 poly(2-hydroxyethyl methacrylate) FAMILY 23359599 T 0 3 PEG ABBREVIATION 23359599 T 25 52 Poly(Glycidyl Methacrylate) FAMILY 23359599 T 57 90 Poly(2-Hydroxyethyl Methacrylate) FAMILY 23360082 A 170 181 polystyrene SYSTEMATIC 23360082 A 206 234 poly-N-(isopropylacrylamide) FAMILY 23360082 A 267 283 titanium dioxide SYSTEMATIC 23360082 A 285 291 TiO(2) FORMULA 23360082 A 327 333 TiO(2) FORMULA 23360082 A 576 578 Ti FORMULA 23360082 A 772 778 TiO(2) FORMULA 23360082 A 902 908 TiO(2) FORMULA 23360118 A 155 163 flavones FAMILY 23360118 A 166 174 daidzein TRIVIAL 23360118 A 177 188 isoflavones FAMILY 23360118 A 190 202 flavopiridol TRIVIAL 23360118 A 205 214 stilbenes FAMILY 23360118 A 216 227 resveratrol TRIVIAL 23360118 A 230 246 indole alkaloids FAMILY 23360118 A 248 270 10-hydroxycamptothecin SYSTEMATIC 23360118 A 277 285 steroids FAMILY 23360118 A 287 305 2-methoxyestradiol SYSTEMATIC 23360118 A 369 381 flavopiridol TRIVIAL 23360118 A 386 415 2-methoxyestradiol glucosides FAMILY 23360118 A 452 463 glucosylate TRIVIAL 23360211 A 1040 1044 EGDE ABBREVIATION 23360211 A 189 221 ethylene glycol diglycidyl ether SYSTEMATIC 23360211 A 223 227 EGDE ABBREVIATION 23360211 A 259 263 EGDE ABBREVIATION 23360295 A 904 924 poly(β-amino) esters FAMILY 23360333 A 0 2 Si FORMULA 23360333 A 198 200 Si FORMULA 23360333 A 312 314 Si FORMULA 23360333 A 336 338 Si FORMULA 23360333 A 359 362 AlN FORMULA 23360333 A 368 377 (111)(Si) FORMULA 23360333 A 37 40 AlN FORMULA 23360333 A 386 389 AlN FORMULA 23360333 A 41 48 Si(111) FORMULA 23360333 A 447 450 AlN FORMULA 23360333 A 467 469 Si FORMULA 23360333 T 10 17 silicon SYSTEMATIC 23360333 T 41 57 aluminum nitride SYSTEMATIC 23360333 T 58 66 Si (111) FORMULA 23360443 A 1091 1103 posaconazole TRIVIAL 23360443 A 502 511 triazoles FAMILY 23360443 A 535 547 posaconazole TRIVIAL 23360443 A 640 652 posaconazole TRIVIAL 23360443 A 816 828 posaconazole TRIVIAL 23360443 A 893 905 Posaconazole TRIVIAL 23360443 T 10 22 posaconazole TRIVIAL 23360452 A 161 168 alkanes FAMILY 23360452 A 186 192 carbon SYSTEMATIC 23360452 A 367 375 n-hexane SYSTEMATIC 23360452 A 377 385 n-octane SYSTEMATIC 23360452 A 387 395 n-decane SYSTEMATIC 23360452 A 397 415 2,7-dimethyloctane SYSTEMATIC 23360452 A 421 432 cyclodecane SYSTEMATIC 23360452 A 455 461 carbon SYSTEMATIC 23360452 A 649 657 n-decane SYSTEMATIC 23360452 T 60 67 alkanes FAMILY 23360452 T 85 91 carbon SYSTEMATIC 23360475 A 1026 1038 tryptanthrin TRIVIAL 23360475 A 104 116 tryptanthrin TRIVIAL 23360475 A 1145 1157 tryptanthrin TRIVIAL 23360475 A 1483 1495 tryptanthrin TRIVIAL 23360475 A 20 32 tryptanthrin TRIVIAL 23360475 A 396 408 tryptanthrin TRIVIAL 23360475 T 66 79 tryptanthrins FAMILY 23360513 A 158 174 benzenehexathiol SYSTEMATIC 23360513 A 200 218 nickel(II) acetate SYSTEMATIC 23360513 A 43 65 nickel bis(dithiolene) SYSTEMATIC 23360513 T 13 35 nickel bis(dithiolene) SYSTEMATIC 23360549 A 1187 1190 SDS ABBREVIATION 23360549 A 1242 1246 CP-2 ABBREVIATION 23360549 A 1309 1313 CP-2 ABBREVIATION 23360549 A 1435 1439 CP-2 ABBREVIATION 23360549 A 1727 1731 CP-2 ABBREVIATION 23360549 A 1846 1867 cyclic D,L-α-peptides FAMILY 23360549 A 386 406 cyclic D,L-α-peptide TRIVIAL 23360549 A 585 606 cyclic D,L-α-peptides FAMILY 23360549 A 667 687 cyclic D,L-α-peptide TRIVIAL 23360549 A 689 693 CP-2 ABBREVIATION 23360549 A 804 816 thioflavin T TRIVIAL 23360549 A 843 847 CP-2 ABBREVIATION 23360549 T 72 92 cyclic D,L-α-peptide TRIVIAL 23360676 A 187 199 carbohydrate FAMILY 23360676 A 241 253 carbohydrate FAMILY 23360676 T 39 51 carbohydrate FAMILY 23360912 A 0 13 Metal nitride FAMILY 23360912 A 1007 1009 Li FORMULA 23360912 A 1150 1152 Li FORMULA 23360912 A 1317 1319 Li FORMULA 23360912 A 14 33 (Ni(0.33)Co(0.67))N FORMULA 23360912 A 1540 1546 Li(3)N FORMULA 23360912 A 158 163 NH(3) FORMULA 23360912 A 166 170 N(2) FORMULA 23360912 A 496 498 Co FORMULA 23360912 A 541 547 cobalt SYSTEMATIC 23360912 A 568 587 (Ni(0.33)Co(0.67))N FORMULA 23360912 A 646 648 Ni FORMULA 23360912 A 676 678 Li FORMULA 23360912 A 700 719 (Ni(0.33)Co(0.67))N FORMULA 23360912 A 814 816 Li FORMULA 23360912 A 82 93 NiCo(2)O(4) FORMULA 23360912 T 52 54 Ni FORMULA 23360912 T 61 75 cobalt nitride SYSTEMATIC 23360912 T 77 96 (Ni(0.33)Co(0.67))N FORMULA 23361121 A 360 363 CuO FORMULA 23361121 A 71 74 CuO FORMULA 23361121 T 28 31 CuO FORMULA 23361121 T 73 80 lithium SYSTEMATIC 23361257 A 1146 1149 EAN ABBREVIATION 23361257 A 423 444 ethylammonium nitrate SYSTEMATIC 23361257 A 446 449 EAN ABBREVIATION 23361257 A 455 517 1-ethyl-3-methylimidazolium bis(trifluoro-methylsulfonyl)imide SYSTEMATIC 23361257 A 519 528 EMIm TFSI ABBREVIATION 23361257 A 539 542 EAN ABBREVIATION 23361257 A 612 621 EMIm TFSI ABBREVIATION 23361257 A 908 911 EAN ABBREVIATION 23361257 A 983 987 EMIm ABBREVIATION 23361264 A 1407 1415 creatine TRIVIAL 23361264 A 1452 1461 idebenone TRIVIAL 23361264 A 236 251 dichloroacetate SYSTEMATIC 23361264 A 269 277 pyruvate TRIVIAL 23361264 A 302 310 arginine TRIVIAL 23361264 A 314 324 citrulline TRIVIAL 23361264 A 340 352 nitric oxide SYSTEMATIC 23361264 A 355 367 coenzyme Q10 TRIVIAL 23361264 A 369 374 CoQ10 ABBREVIATION 23361264 A 434 443 idebenone TRIVIAL 23361264 A 469 474 CoQ10 ABBREVIATION 23361264 A 477 484 EPI-743 IDENTIFIER 23361264 A 539 547 creatine TRIVIAL 23361264 A 564 579 phosphocreatine SYSTEMATIC 23361264 A 610 618 creatine TRIVIAL 23361264 A 620 629 α-lipoate TRIVIAL 23361264 A 635 640 CoQ10 ABBREVIATION 23361305 A 1409 1412 ATP ABBREVIATION 23361305 A 361 380 monolysocardiolipin TRIVIAL 23361305 A 381 392 cardiolipin TRIVIAL 23361313 A 0 2 Ag FORMULA 23361313 A 263 265 Pt FORMULA 23361313 A 3 5 Pt FORMULA 23361313 A 377 379 Ag FORMULA 23361313 A 380 382 Pt FORMULA 23361313 A 43 45 Pt FORMULA 23361313 A 431 433 Pt FORMULA 23361313 A 448 450 Ag FORMULA 23361313 A 615 617 Ag FORMULA 23361313 A 618 620 Pt FORMULA 23361313 A 656 664 methanol SYSTEMATIC 23361313 A 699 708 H(2)SO(4) FORMULA 23361313 A 735 743 methanol SYSTEMATIC 23361313 A 749 751 Ag FORMULA 23361313 A 752 754 Pt FORMULA 23361313 A 789 791 Pt FORMULA 23361313 A 813 815 CO FORMULA 23361313 A 880 882 Ag FORMULA 23361313 A 883 885 Pt FORMULA 23361313 A 911 913 CO FORMULA 23361313 T 29 31 Ag FORMULA 23361313 T 32 34 Pt FORMULA 23361313 T 75 77 Pt FORMULA 23361398 A 20 26 oxygen SYSTEMATIC 23361398 A 380 382 Ge FORMULA 23361398 A 389 400 superoxides FAMILY 23361398 A 405 414 peroxides FAMILY 23361398 A 433 435 Ge FORMULA 23361398 A 442 452 superoxide TRIVIAL 23361398 A 59 61 Ge FORMULA 23361398 A 595 603 peroxide SYSTEMATIC 23361398 A 624 627 OOH FORMULA 23361398 A 84 89 HClO4 FORMULA 23361398 A 869 877 hydrogen SYSTEMATIC 23361398 T 43 49 oxygen SYSTEMATIC 23361398 T 89 91 Ge FORMULA 23361404 A 1138 1142 PDMS ABBREVIATION 23361404 A 621 641 polydimethylsiloxane SYSTEMATIC 23361404 A 643 647 PDMS ABBREVIATION 23361404 A 796 800 PDMS ABBREVIATION 23361586 A 0 7 Glucose TRIVIAL 23361586 A 346 353 glucose TRIVIAL 23361586 A 611 618 glucose TRIVIAL 23361586 A 657 664 glucose TRIVIAL 23361586 A 81 88 glucose TRIVIAL 23361846 A 0 9 Methadone TRIVIAL 23361846 A 10 11 N FORMULA 23361846 A 1060 1069 methadone TRIVIAL 23361846 A 1070 1071 N FORMULA 23361846 A 1112 1121 methadone TRIVIAL 23361846 A 1193 1202 methadone TRIVIAL 23361846 A 260 269 methadone TRIVIAL 23361846 A 270 271 N FORMULA 23361846 A 352 363 ticlopidine TRIVIAL 23361846 A 461 471 alfentanil TRIVIAL 23361846 A 489 500 ticlopidine TRIVIAL 23361846 A 590 599 deuterium SYSTEMATIC 23361846 A 609 626 racemic methadone TRIVIAL 23361846 A 644 655 ticlopidine TRIVIAL 23361846 A 657 668 Ticlopidine TRIVIAL 23361846 A 723 732 methadone TRIVIAL 23361846 A 733 734 N FORMULA 23361846 A 779 788 methadone TRIVIAL 23361846 A 854 865 Ticlopidine TRIVIAL 23361846 A 945 963 R- and S-methadone MULTIPLE 23361846 T 30 39 methadone TRIVIAL 23361977 A 1074 1089 carboxylic acid SYSTEMATIC 23361977 A 1280 1295 carboxylic acid SYSTEMATIC 23361977 A 368 383 carboxylic acid SYSTEMATIC 23361977 A 4 19 carboxylic acid SYSTEMATIC 23361977 A 440 455 carboxylic acid SYSTEMATIC 23361977 A 673 688 carboxylic acid SYSTEMATIC 23361977 T 0 15 Carboxylic acid SYSTEMATIC 23362135 A 1426 1436 phosphorus SYSTEMATIC 23362135 A 1673 1674 C FORMULA 23362135 A 1800 1826 1,25-dihydroxyvitamin D(3) SYSTEMATIC 23362135 A 1828 1833 1,25D SYSTEMATIC 23362135 A 2151 2156 1,25D SYSTEMATIC 23362135 A 2224 2229 1,25D SYSTEMATIC 23362135 A 425 437 (111) Indium SYSTEMATIC 23362135 A 530 553 (18) fluorodeoxyglucose SYSTEMATIC 23362135 A 55 64 phosphate SYSTEMATIC 23362224 A 139 153 graphene oxide SYSTEMATIC 23362224 T 0 14 Graphene Oxide SYSTEMATIC 23362240 A 1383 1394 vemurafenib TRIVIAL 23362240 A 1446 1458 thapsigargin TRIVIAL 23362240 A 1507 1518 vemurafenib TRIVIAL 23362240 A 1609 1620 vemurafenib TRIVIAL 23362240 A 1649 1661 thapsigargin TRIVIAL 23362240 A 1700 1712 thapsigargin TRIVIAL 23362240 A 1795 1806 vemurafenib TRIVIAL 23362240 A 260 271 vemurafenib TRIVIAL 23362240 A 485 496 vemurafenib TRIVIAL 23362240 A 594 605 Vemurafenib TRIVIAL 23362240 A 673 680 calcium SYSTEMATIC 23362240 A 817 828 vemurafenib TRIVIAL 23362240 A 881 888 glucose TRIVIAL 23362240 T 0 11 Vemurafenib TRIVIAL 23362262 A 127 136 rapamycin TRIVIAL 23362262 A 782 788 PP242, IDENTIFIER 23362262 A 909 914 PP242 IDENTIFIER 23362262 T 72 81 rapamycin TRIVIAL 23362940 A 389 396 ferrite FAMILY 23362940 A 436 442 Fe(2+) FORMULA 23362940 A 446 452 Co(2+) FORMULA 23362940 A 918 924 Co(2+) FORMULA 23362940 A 977 980 FeO FORMULA 23362940 A 981 992 CoFe(2)O(4) FORMULA 23362940 T 34 45 metal oxide FAMILY 23363038 A 1409 1441 polycyclic aromatic hydrocarbons FAMILY 23363038 A 1443 1447 PAHs ABBREVIATION 23363038 A 1507 1511 PAHs ABBREVIATION 23363299 A 1062 1066 FeSe FORMULA 23363299 A 1256 1260 FeSe FORMULA 23363299 A 1346 1352 carbon SYSTEMATIC 23363299 A 1386 1390 FeSe FORMULA 23363299 A 1405 1409 FeSe FORMULA 23363299 A 1442 1444 O₂ FORMULA 23363299 A 237 241 FeSe FORMULA 23363299 A 383 385 Se FORMULA 23363299 A 390 410 iron acetylacetonate SYSTEMATIC 23363299 A 412 428 Fe(III)(C₅H₈O₂)₃ FORMULA 23363299 A 45 58 iron selenide SYSTEMATIC 23363299 A 572 576 FeSe FORMULA 23363299 A 751 755 FeSe FORMULA 23363299 A 775 781 carbon SYSTEMATIC 23363299 A 914 919 Au-Pd FORMULA 23363299 T 43 47 FeSe FORMULA 23363377 A 1008 1017 genistein TRIVIAL 23363377 A 108 121 polyglutamine FAMILY 23363377 A 123 128 polyQ ABBREVIATION 23363377 A 147 155 androgen FAMILY 23363377 A 574 583 genistein TRIVIAL 23363377 A 588 598 isoflavone FAMILY 23363377 A 789 798 genistein TRIVIAL 23363377 T 0 9 Genistein TRIVIAL 23363377 T 64 77 polyglutamine FAMILY 23363397 A 103 113 polyesters FAMILY 23363397 A 1066 1080 1,4-butanediol SYSTEMATIC 23363397 A 1102 1120 dimethyl succinate SYSTEMATIC 23363397 A 177 188 1,3-dioxane SYSTEMATIC 23363397 A 219 227 hydroxyl SYSTEMATIC 23363397 A 23 27 diol SYSTEMATIC 23363397 A 28 61 2,4:3,5-di-O-methylene-d-mannitol SYSTEMATIC 23363397 A 296 306 isosorbide TRIVIAL 23363397 A 4 16 carbohydrate FAMILY 23363397 A 580 598 dimethyl succinate SYSTEMATIC 23363397 A 805 814 polyester FAMILY 23363397 T 30 40 polyesters FAMILY 23363397 T 46 65 bicyclic D-mannitol TRIVIAL 23363575 A 0 36 2,3,7,8-Tetrachloro dibenzo-p-dioxin SYSTEMATIC 23363575 A 1007 1011 TCDD ABBREVIATION 23363575 A 1016 1030 corticosterone TRIVIAL 23363575 A 1211 1215 TCDD ABBREVIATION 23363575 A 1320 1324 TCDD ABBREVIATION 23363575 A 1328 1342 corticosterone TRIVIAL 23363575 A 1481 1485 TCDD ABBREVIATION 23363575 A 1516 1520 TCDD ABBREVIATION 23363575 A 216 220 TCDD ABBREVIATION 23363575 A 38 42 TCDD ABBREVIATION 23363575 A 421 425 TCDD ABBREVIATION 23363575 A 527 541 corticosterone TRIVIAL 23363575 A 596 600 TCDD ABBREVIATION 23363575 A 624 638 corticosterone TRIVIAL 23363575 A 699 703 TCDD ABBREVIATION 23363575 T 0 4 TCDD ABBREVIATION 23363575 T 9 23 corticosterone TRIVIAL 23364186 A 0 20 Tetrabenzoporphyrins FAMILY 23364186 A 337 357 tetrabenzoporphyrins FAMILY 23364186 A 389 398 porphyrin FAMILY 23364186 T 0 20 Tetrabenzoporphyrins FAMILY 23364509 A 1003 1015 atorvastatin TRIVIAL 23364509 A 604 616 atorvastatin TRIVIAL 23364619 A 30 52 petroleum hydrocarbons FAMILY 23364619 A 71 93 petroleum hydrocarbons FAMILY 23364619 A 975 1000 polyaromatic hydrocarbons FAMILY 23364619 T 39 60 petroleum hydrocarbon FAMILY 23364814 A 1015 1026 polyphenols FAMILY 23364814 A 1114 1125 polyphenols FAMILY 23364814 A 262 273 polyphenols FAMILY 23364814 A 71 82 polyphenols FAMILY 23364814 T 6 17 polyphenols FAMILY 23364815 A 0 6 Heroin TRIVIAL 23364815 A 1429 1435 sugars FAMILY 23364815 A 273 282 methadone TRIVIAL 23364815 A 293 306 buprenorphine TRIVIAL 23364815 A 353 363 naltrexone TRIVIAL 23364815 A 365 372 Sucrose TRIVIAL 23364815 A 507 516 methadone TRIVIAL 23364815 A 51 57 sugars FAMILY 23364815 A 520 533 buprenorphine TRIVIAL 23364815 A 540 550 naltrexone TRIVIAL 23364815 A 887 896 methadone TRIVIAL 23364886 A 101 114 norkhelloside TRIVIAL 23364886 A 48 71 heracleifolinosides A-F MULTIPLE 23364886 A 522 542 Heracleifolinoside B TRIVIAL 23364886 A 8 46 9,19-cycloartane triterpene glycosides FAMILY 23364886 T 0 23 Heracleifolinosides A-F MULTIPLE 23364886 T 29 50 triterpene glycosides FAMILY 23364935 A 865 892 p-phenylenevinylene trimers FAMILY 23364935 T 84 111 p-phenylenevinylene trimers FAMILY 23367873 A 1927 1938 ruxolitinib TRIVIAL 23367873 A 1965 1976 tofacitinib TRIVIAL 23367873 A 298 309 ruxolitinib TRIVIAL 23367873 A 311 317 Jakafi TRIVIAL 23367873 A 370 381 tofacitinib TRIVIAL 23367873 A 383 390 Xeljanz TRIVIAL 23367873 A 857 860 ATP ABBREVIATION 23367873 A 91 99 tyrosine TRIVIAL 23368280 A 1042 1051 β-glycine TRIVIAL 23368280 A 1133 1142 β-glycine TRIVIAL 23368280 A 1196 1206 amino acid FAMILY 23368280 A 124 133 β-glycine TRIVIAL 23368280 A 1472 1482 amino acid FAMILY 23368280 A 19 26 glycine TRIVIAL 23368280 A 263 272 β-glycine TRIVIAL 23368280 A 426 435 β-glycine TRIVIAL 23368280 A 623 632 α-glycine TRIVIAL 23368280 A 66 80 aluminum oxide SYSTEMATIC 23368280 A 764 771 glycine TRIVIAL 23368280 A 814 823 β-glycine TRIVIAL 23368280 A 82 85 AAO ABBREVIATION 23368280 A 856 859 AAO ABBREVIATION 23368280 A 926 936 amino acid FAMILY 23368710 A 0 22 Reduced graphene oxide SYSTEMATIC 23368710 A 1045 1051 oxygen SYSTEMATIC 23368710 A 1135 1140 epoxy SYSTEMATIC 23368710 A 1145 1153 carbonyl FAMILY 23368710 A 1224 1227 rGO ABBREVIATION 23368710 A 236 244 graphene TRIVIAL 23368710 A 24 27 rGO ABBREVIATION 23368710 A 256 262 oxygen SYSTEMATIC 23368710 A 418 421 rGO ABBREVIATION 23368710 A 536 539 rGO ABBREVIATION 23368710 A 714 722 carbonyl FAMILY 23368710 A 728 731 rGO ABBREVIATION 23368710 A 768 776 hydroxyl SYSTEMATIC 23368710 A 782 785 rGO ABBREVIATION 23368710 A 810 818 carbonyl FAMILY 23368710 A 822 830 hydroxyl SYSTEMATIC 23368710 A 857 863 carbon SYSTEMATIC 23368710 A 949 952 rGO ABBREVIATION 23368710 A 997 1003 oxygen SYSTEMATIC 23368710 T 90 112 reduced graphene oxide SYSTEMATIC 23368735 A 108 119 X ═ Cl or I FORMULA 23368735 A 112 114 Cl FORMULA 23368735 A 118 119 I FORMULA 23368735 A 212 218 iodido SYSTEMATIC 23368735 A 250 258 chlorido SYSTEMATIC 23368735 A 321 329 platinum SYSTEMATIC 23368735 A 336 345 cisplatin TRIVIAL 23368735 A 350 361 oxaliplatin TRIVIAL 23368735 A 39 76 [M(p-cymene)(azo/imino-pyridine)X](+) FAMILY 23368735 A 540 549 cisplatin TRIVIAL 23368735 A 611 617 iodido SYSTEMATIC 23368735 A 784 795 glutathione TRIVIAL 23368735 A 815 837 l-buthionine sulfoxime TRIVIAL 23368735 A 83 103 M = Ru(II) or Os(II) FORMULA 23368735 A 87 93 Ru(II) FORMULA 23368735 A 97 103 Os(II) FORMULA 23368735 T 28 34 iodido SYSTEMATIC 23368735 T 42 60 chlorido ruthenium SYSTEMATIC 23368735 T 65 101 osmium arene azo- and imino-pyridine MULTIPLE 23368753 A 131 138 Li₃NbO₄ FORMULA 23368753 A 1432 1437 Cu(I) FORMULA 23368753 A 1462 1467 Nb(V) FORMULA 23368753 A 1521 1530 Cu₂Nb₈O₂₁ FORMULA 23368753 A 1825 1830 Cu(I) FORMULA 23368753 A 1852 1858 oxides FAMILY 23368753 A 196 201 HNbO₃ FORMULA 23368753 A 206 214 LiOH·H₂O FORMULA 23368753 A 218 224 PEG200 ABBREVIATION 23368753 A 263 270 Li₃NbO₄ FORMULA 23368753 A 338 347 copper(I) SYSTEMATIC 23368753 A 378 382 CuCl FORMULA 23368753 A 433 437 CuCl FORMULA 23368753 A 494 503 Cu₂Nb₈O₂₁ FORMULA 23368753 A 714 718 NbO₇ FORMULA 23368753 A 74 79 Cu(I) FORMULA 23368753 A 753 757 CuO₄ FORMULA 23368753 A 80 87 niobate SYSTEMATIC 23368753 A 926 931 Cu(I) FORMULA 23368753 T 11 16 Cu(I) FORMULA 23368902 A 135 149 polynorbornene FAMILY 23368902 A 66 77 polylactide FAMILY 23368902 A 79 82 PLA ABBREVIATION 23368902 A 88 99 polystyrene SYSTEMATIC 23368996 A 20 45 (-)-petrosynoic acids A-D MULTIPLE 23368996 A 309 331 C31-C33 polyacetylenes FAMILY 23368996 A 79 122 pellynols A (5), C (6), D (7), F (8), and I MULTIPLE 23369012 A 131 135 NaOH FORMULA 23369072 A 184 197 succinic acid TRIVIAL 23369072 A 199 202 SuA ABBREVIATION 23369072 A 205 219 1,4-butanediol SYSTEMATIC 23369072 A 221 224 BDO ABBREVIATION 23369072 A 231 246 dimethylazelate SYSTEMATIC 23369072 A 248 252 DMAz ABBREVIATION 23369072 A 25 67 poly(butylenesuccinate-co-butyleneazelate) FAMILY 23369072 A 310 313 SuA ABBREVIATION 23369072 A 314 317 AzA ABBREVIATION 23369072 A 422 436 (co)polyesters FAMILY 23369072 A 69 82 P(BS-co-BAz)s FAMILY 23369072 A 701 704 SuA ABBREVIATION 23369072 A 705 708 AzA ABBREVIATION 23369072 A 729 741 copolyesters FAMILY 23369072 A 84 106 aliphatic copolyesters FAMILY 23369072 A 938 963 P(BS-co-BAz) copolyesters FAMILY 23369072 T 110 154 poly(butylene succinate-co-butylene azelate) FAMILY 23369072 T 9 19 polyesters FAMILY 23369093 A 1148 1151 PEO ABBREVIATION 23369093 A 1210 1228 sodium bicarbonate SYSTEMATIC 23369093 A 1280 1285 CO(2) FORMULA 23369093 A 1598 1616 sodium bicarbonate SYSTEMATIC 23369093 A 1681 1684 DTZ ABBREVIATION 23369093 A 234 237 PEO ABBREVIATION 23369093 A 383 406 Diltiazem hydrochloride SYSTEMATIC 23369093 A 408 411 DTZ ABBREVIATION 23369093 A 541 559 sodium bicarbonate SYSTEMATIC 23369093 A 683 686 PEO ABBREVIATION 23369093 A 691 709 sodium bicarbonate SYSTEMATIC 23369093 A 71 89 polyethylene oxide SYSTEMATIC 23369093 A 91 94 PEO ABBREVIATION 23369093 T 107 120 diltiazem HCl FORMULA 23369206 A 1000 1009 peramivir TRIVIAL 23369206 A 1014 1025 laninamivir TRIVIAL 23369206 A 1779 1790 phosphonate SYSTEMATIC 23369206 A 1804 1813 zanamivir TRIVIAL 23369206 A 1818 1830 oseltarmivir TRIVIAL 23369206 A 1924 1934 flavonoids FAMILY 23369206 A 2030 2048 phenyl-benzopyrane SYSTEMATIC 23369206 A 2246 2255 flavonoid FAMILY 23369206 A 908 919 oseltamivir TRIVIAL 23369206 A 924 933 zanamivir TRIVIAL 23369791 A 0 8 Thiamine TRIVIAL 23369791 A 13 25 benfotiamine TRIVIAL 23369791 A 225 235 alcoholics FAMILY 23369791 A 287 309 thiamine hydrochloride SYSTEMATIC 23369791 A 30 40 vitamin B1 TRIVIAL 23369791 A 313 325 benfotiamine TRIVIAL 23369791 A 361 368 alcohol FAMILY 23369791 A 406 414 thiamine TRIVIAL 23369791 A 423 439 phosphate esters FAMILY 23369791 A 45 59 pro-vitamin B1 TRIVIAL 23369791 A 519 527 thiamine TRIVIAL 23369791 A 580 592 benfotiamine TRIVIAL 23369791 A 628 636 thiamine TRIVIAL 23369791 A 673 681 thiamine TRIVIAL 23369791 A 743 751 thiamine TRIVIAL 23369791 A 756 768 benfotiamine TRIVIAL 23369791 A 826 834 thiamine TRIVIAL 23369791 A 86 96 Vitamin B1 TRIVIAL 23369791 A 971 983 benfotiamine TRIVIAL 23369791 A 997 1004 ethanol SYSTEMATIC 23369791 T 131 139 thiamine TRIVIAL 23369791 T 144 156 benfotiamine TRIVIAL 23369791 T 40 48 thiamine TRIVIAL 23369791 T 57 73 phosphate esters FAMILY 23369791 T 93 100 ethanol SYSTEMATIC 23369932 A 70 80 superoxide TRIVIAL 23369932 A 829 833 urea TRIVIAL 23369932 A 835 845 creatinine TRIVIAL 23369932 A 869 878 bilirubin TRIVIAL 23369932 A 898 912 gamma-glutamyl SYSTEMATIC 23369932 A 969 975 copper SYSTEMATIC 23369932 A 976 980 zinc SYSTEMATIC 23369932 A 985 1005 manganese superoxide SYSTEMATIC 23369932 T 101 111 superoxide TRIVIAL 23369934 A 1252 1260 urushiol TRIVIAL 23369934 A 478 486 urushiol TRIVIAL 23369934 A 493 501 urushiol TRIVIAL 23369934 A 523 543 ursodeoxycholic acid TRIVIAL 23369934 A 545 549 UDCA ABBREVIATION 23369934 A 557 561 UDCA ABBREVIATION 23369934 A 737 745 urushiol TRIVIAL 23369934 A 773 785 triglyceride FAMILY 23369934 A 89 97 urushiol TRIVIAL 23369934 A 910 921 cholesterol TRIVIAL 23369934 T 88 96 urushiol TRIVIAL 23369935 A 0 21 9-Methoxycamptothecin SYSTEMATIC 23369935 A 1060 1064 MCPT ABBREVIATION 23369935 A 211 215 MCPT ABBREVIATION 23369935 A 23 27 MCPT ABBREVIATION 23369935 A 412 416 MCPT ABBREVIATION 23369935 A 607 611 FITC ABBREVIATION 23369935 A 616 632 propidium iodide TRIVIAL 23369935 A 676 680 MCPT ABBREVIATION 23369935 A 832 836 MCPT ABBREVIATION 23369935 T 43 64 9-Methoxycamptothecin SYSTEMATIC 23369989 A 124 131 sulfate SYSTEMATIC 23369989 A 920 937 deoxypyridinoline SYSTEMATIC 23369989 A 986 987 C FORMULA 23370007 A 1000 1003 Cys FORMULA 23370007 A 1257 1259 Pb FORMULA 23370007 A 195 207 lead acetate SYSTEMATIC 23370007 A 209 211 Pb FORMULA 23370007 A 378 384 oxygen SYSTEMATIC 23370007 A 457 459 Pb FORMULA 23370007 A 484 486 Pb FORMULA 23370007 A 566 568 Pb FORMULA 23370007 A 787 789 Pb FORMULA 23370007 A 837 839 Pb FORMULA 23370007 A 980 982 Pb FORMULA 23370007 T 84 96 lead acetate SYSTEMATIC 23370194 A 13 47 2,5-disubstituted-1,3,4-oxadiazole FAMILY 23370194 A 137 186 2-substituted thio-5-substituted-1,3,4-oxadiazole FAMILY 23370194 A 331 347 Sulfo-Rodamine B TRIVIAL 23370194 A 349 352 SRB ABBREVIATION 23370194 A 56 125 3-substituted aminomethyl-5-substituted-1,3,4-oxadiazole-2(3H)-thione FAMILY 23370194 A 803 813 oxadiazole FAMILY 23370194 T 125 138 diphenylamine SYSTEMATIC 23370194 T 85 101 1,3,4-oxadiazole SYSTEMATIC 23370195 A 1627 1639 flurbiprofen TRIVIAL 23370195 A 330 342 Flurbiprofen TRIVIAL 23370198 A 276 308 tetrahydrotetramethylnaphthalene SYSTEMATIC 23370198 A 310 313 TMN ABBREVIATION 23370198 A 374 381 silicon SYSTEMATIC 23370198 A 393 396 TMN ABBREVIATION 23370198 A 679 680 C FORMULA 23370198 A 681 683 Si FORMULA 23370198 T 0 13 Organosilicon FAMILY 23370266 A 1522 1527 Ag(+) FORMULA 23370266 A 1537 1558 silver glutathionates FAMILY 23370266 A 1608 1613 Ag(+) FORMULA 23370266 A 1662 1673 glutathione TRIVIAL 23370266 A 1692 1697 Ag(+) FORMULA 23370266 A 600 606 Silver SYSTEMATIC 23370266 A 832 838 silver SYSTEMATIC 23370266 A 839 850 glutathione TRIVIAL 23370266 A 852 854 Ag FORMULA 23371492 A 1172 1180 cortisol TRIVIAL 23371492 A 621 629 cortisol TRIVIAL 23371492 A 712 720 cortisol TRIVIAL 23371492 T 12 20 cortisol TRIVIAL 23371548 A 105 111 Carbon SYSTEMATIC 23371548 A 112 116 SnO2 FORMULA 23371548 A 15 19 SnO2 FORMULA 23371548 A 241 247 carbon SYSTEMATIC 23371548 A 317 321 SnO2 FORMULA 23371548 A 366 370 SnO2 FORMULA 23371548 T 123 125 Li FORMULA 23371548 T 43 47 SnO2 FORMULA 23371801 A 266 272 pyrene SYSTEMATIC 23371801 A 288 295 thymine TRIVIAL 23372018 A 1033 1040 glucose TRIVIAL 23372018 A 1112 1121 manganese SYSTEMATIC 23372018 A 1170 1172 Mn FORMULA 23372018 A 1245 1254 manganese SYSTEMATIC 23372018 A 1295 1302 glucose TRIVIAL 23372018 A 1338 1345 glucose TRIVIAL 23372018 A 1381 1388 glucose TRIVIAL 23372018 A 1494 1503 manganese SYSTEMATIC 23372018 A 157 166 manganese SYSTEMATIC 23372018 A 1638 1640 Mn FORMULA 23372018 A 167 177 superoxide TRIVIAL 23372018 A 1691 1700 manganese SYSTEMATIC 23372018 A 1752 1761 manganese SYSTEMATIC 23372018 A 1814 1821 glucose TRIVIAL 23372018 A 338 342 iron SYSTEMATIC 23372018 A 373 382 manganese SYSTEMATIC 23372018 A 397 399 Mn FORMULA 23372018 A 495 497 Mn FORMULA 23372018 A 660 662 Mn FORMULA 23372018 A 704 706 Mn FORMULA 23372018 A 766 773 glucose TRIVIAL 23372018 A 939 948 Manganese SYSTEMATIC 23372018 T 0 9 Manganese SYSTEMATIC 23373428 A 1076 1088 vitamin D(3) TRIVIAL 23373428 A 1242 1254 vitamin K(1) TRIVIAL 23373428 A 1454 1476 vitamins D(3) and K(1) MULTIPLE 23373428 A 1509 1521 vitamin K(1) TRIVIAL 23373428 A 203 215 acetonitrile SYSTEMATIC 23373428 A 250 258 methanol SYSTEMATIC 23373428 A 407 415 methanol SYSTEMATIC 23373428 A 459 471 Vitamin D(3) TRIVIAL 23373428 A 476 484 probucol TRIVIAL 23373428 A 513 525 vitamin K(1) TRIVIAL 23373428 A 590 610 vitamin D(3) or K(1) MULTIPLE 23373428 A 885 893 vitamins FAMILY 23373428 A 946 958 vitamin D(3) TRIVIAL 23373428 A 96 118 vitamins D(3) and K(1) MULTIPLE 23373428 T 51 73 vitamins D(3) and K(1) MULTIPLE 23373513 A 1663 1673 iron oxide SYSTEMATIC 23373513 A 777 787 iron oxide SYSTEMATIC 23373677 A 120 126 AtO(+) FORMULA 23373677 A 51 74 astatine(III) hydroxide SYSTEMATIC 23373677 A 690 697 AtO(OH) FORMULA 23373677 T 17 30 astatine(III) SYSTEMATIC 23373696 A 47 80 N-(2-hydroxypropyl)methacrylamide SYSTEMATIC 23373696 A 737 741 HPMA ABBREVIATION 23373696 A 761 772 doxorubicin TRIVIAL 23373696 A 82 86 HPMA ABBREVIATION 23373701 A 439 447 dopamine TRIVIAL 23373701 A 475 485 quinpirole TRIVIAL 23373701 A 596 600 zinc SYSTEMATIC 23373701 A 729 739 raclopride TRIVIAL 23373701 A 806 815 potassium SYSTEMATIC 23373701 A 823 831 dopamine TRIVIAL 23373701 T 0 8 Dopamine TRIVIAL 23373704 A 174 175 H FORMULA 23373704 A 186 187 H FORMULA 23373704 A 466 467 H FORMULA 23373704 A 687 715 pentaerythritol tetranitrate SYSTEMATIC 23373704 A 844 849 (13)C FORMULA 23373704 A 851 856 (15)N FORMULA 23373704 A 862 866 (2)H FORMULA 23373704 T 43 44 H FORMULA 23373819 A 109 112 Arg FORMULA 23373819 A 116 119 Pro FORMULA 23373819 A 123 126 Pro FORMULA 23373819 A 130 133 Gly FORMULA 23373819 A 137 140 Phe FORMULA 23373819 A 144 147 Ser FORMULA 23373819 A 151 154 Pro FORMULA 23373819 A 158 161 Phe FORMULA 23373819 A 165 168 Arg FORMULA 23373819 A 332 339 proline TRIVIAL 23373819 A 350 353 Pro FORMULA 23373819 A 358 361 Pro FORMULA 23373819 A 370 373 Pro FORMULA 23373819 A 497 504 alanine TRIVIAL 23373819 A 534 542 prolines FAMILY 23373819 A 73 83 bradykinin TRIVIAL 23373819 A 744 751 proline TRIVIAL 23373819 A 89 99 amino acid FAMILY 23373819 T 28 35 proline TRIVIAL 23373819 T 56 66 bradykinin TRIVIAL 23373869 A 100 111 radioiodine SYSTEMATIC 23373869 A 328 334 iodine SYSTEMATIC 23374864 A 0 17 5-Nitropyrimidine SYSTEMATIC 23374864 A 198 234 endo-azabicyclic amines and alcohols MULTIPLE 23374864 A 313 348 exo-azabicyclic amines and alcohols MULTIPLE 23374864 A 436 453 5-Nitropyrimidine SYSTEMATIC 23374864 A 467 505 (2-fluoro-4-methylsulfonyl)phenylamino SYSTEMATIC 23374864 A 601 609 fluorine SYSTEMATIC 23374864 A 71 102 azabicyclic amines and alcohols MULTIPLE 23374864 T 39 56 5-nitropyrimidine SYSTEMATIC 23374864 T 70 81 azabicyclic FAMILY 23374873 A 32 91 2'-O,4'-C-methylene-bridged/linked bicyclic ribonucleotides FAMILY 23374873 A 386 395 methylene SYSTEMATIC 23374873 A 97 108 nucleotides FAMILY 23374873 T 74 133 2'-O,4'-C-methylene-bridged/linked bicyclic ribonucleotides FAMILY 23375228 A 332 344 quinoxalines FAMILY 23375813 A 372 376 (1)H FORMULA 23375813 A 381 386 (13)C FORMULA 23375813 A 60 78 bisindole alkaloid FAMILY 23375813 A 635 658 3'-R/S-hydroxyvoacamine MULTIPLE 23375813 A 79 102 3'-R/S-hydroxyvoacamine MULTIPLE 23375813 T 0 23 3'-R/S-Hydroxyvoacamine MULTIPLE 23376007 A 117 126 androgens FAMILY 23376007 A 155 167 testosterone TRIVIAL 23376007 A 189 208 dihydrotestosterone SYSTEMATIC 23376007 A 298 317 dihydrotestosterone SYSTEMATIC 23376007 A 342 354 testosterone TRIVIAL 23376007 A 766 785 dihydrotestosterone SYSTEMATIC 23376007 T 34 53 dihydrotestosterone SYSTEMATIC 23376097 A 1014 1017 Ala FORMULA 23376097 A 102 130 d-glyceraldehyde-3-phosphate SYSTEMATIC 23376097 A 1107 1110 Glu FORMULA 23376097 A 1192 1195 Asp FORMULA 23376097 A 135 141 indole SYSTEMATIC 23376097 A 17 27 tryptophan TRIVIAL 23376097 A 299 309 amino acid FAMILY 23376097 A 430 433 Ala FORMULA 23376097 A 627 637 amino acid FAMILY 23376097 A 71 98 indole-3-glycerol phosphate SYSTEMATIC 23376097 A 749 775 glyceraldehyde-3-phosphate SYSTEMATIC 23376097 A 816 826 amino acid FAMILY 23376097 T 48 58 tryptophan TRIVIAL 23376217 A 0 8 Acyl-CoA FAMILY 23376217 A 1014 1018 cAMP ABBREVIATION 23376217 A 365 369 cAMP ABBREVIATION 23376217 A 964 968 cAMP ABBREVIATION 23376217 T 53 61 acyl-CoA ABBREVIATION 23376247 A 16 64 thieno[2',3':4,5]pyrimido[1,2-b][1,2,4]triazines FAMILY 23376247 A 237 250 diclofenac Na FORMULA 23376247 A 410 455 thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidine SYSTEMATIC 23376247 A 516 564 thieno[2',3':4,5]pyrimido[1,2-b][1,2,4]triazines FAMILY 23376247 A 584 608 thienotriazolopyrimidine SYSTEMATIC 23376247 A 69 115 thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines FAMILY 23376247 T 39 88 thieno [2',3':4,5]pyrimido[1,2-b][1,2,4]triazines FAMILY 23376247 T 93 139 thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines FAMILY 23376250 A 162 174 cyrtominetin TRIVIAL 23376250 A 176 179 CTM ABBREVIATION 23376250 A 243 246 CTM ABBREVIATION 23376250 A 335 338 CTM ABBREVIATION 23376250 A 490 493 CTM ABBREVIATION 23376250 A 503 506 CTM ABBREVIATION 23376250 A 555 558 CTM ABBREVIATION 23376250 A 707 710 CTM ABBREVIATION 23376250 T 51 63 cyrtominetin TRIVIAL 23376258 A 113 116 ATP ABBREVIATION 23376258 A 15 26 vinclozolin TRIVIAL 23376258 A 260 271 vinclozolin TRIVIAL 23376258 A 28 31 VIN ABBREVIATION 23376258 A 703 713 superoxide TRIVIAL 23376258 A 748 751 ATP ABBREVIATION 23376258 A 819 822 VIN ABBREVIATION 23376258 A 854 857 VIN ABBREVIATION 23376258 A 878 884 oxygen SYSTEMATIC 23376258 A 974 977 ATP ABBREVIATION 23376258 T 56 67 vinclozolin TRIVIAL 23376345 A 1049 1052 GTP ABBREVIATION 23376345 A 1170 1179 8-oxo-GTP SYSTEMATIC 23376345 A 1191 1200 8-oxo-GDP SYSTEMATIC 23376345 A 1204 1213 8-oxo-GMP SYSTEMATIC 23376345 A 1220 1243 (14)C-labeled 8-oxo-GTP SYSTEMATIC 23376345 A 1259 1264 CaCl2 FORMULA 23376345 A 1369 1372 GTP ABBREVIATION 23376345 A 143 154 nucleotides FAMILY 23376345 A 1457 1481 8-oxo-7,8-dihydroguanine SYSTEMATIC 23376345 A 190 214 8-oxo-7,8-dihydroguanine SYSTEMATIC 23376345 A 318 326 cytosine TRIVIAL 23376345 A 331 338 adenine TRIVIAL 23376345 A 372 391 guanine nucleotides FAMILY 23376345 A 393 396 GMP ABBREVIATION 23376345 A 437 440 GDP ABBREVIATION 23376345 A 444 453 guanylate TRIVIAL 23376345 A 509 512 GMP ABBREVIATION 23376345 A 514 523 8-oxo-GMP SYSTEMATIC 23376345 A 552 555 GMP ABBREVIATION 23376345 A 57 63 oxygen SYSTEMATIC 23376345 A 578 587 8-oxo-GDP SYSTEMATIC 23376345 A 592 601 8-oxo-GTP SYSTEMATIC 23376345 A 645 654 8-oxo-GDP SYSTEMATIC 23376345 A 660 669 8-oxo-GMP SYSTEMATIC 23376345 A 689 698 8-oxo-GDP SYSTEMATIC 23376345 A 742 745 GDP ABBREVIATION 23376345 A 758 764 oxygen SYSTEMATIC 23376345 A 778 787 8-oxo-GDP SYSTEMATIC 23376345 A 820 829 8-oxo-GTP SYSTEMATIC 23376345 A 838 860 nucleoside-diphosphate FAMILY 23376345 A 872 881 adenylate TRIVIAL 23376345 A 9 15 oxygen SYSTEMATIC 23376345 A 931 934 GDP ABBREVIATION 23376345 A 938 941 GTP ABBREVIATION 23376345 A 963 972 8-oxo-GDP SYSTEMATIC 23376345 A 985 988 GDP ABBREVIATION 23376345 A 994 1003 8-oxo-GTP SYSTEMATIC 23376345 T 40 59 guanine nucleotides FAMILY 23376352 A 1031 1041 bradykinin TRIVIAL 23376352 A 1170 1180 Bradykinin TRIVIAL 23376352 A 1283 1286 ATP ABBREVIATION 23376352 A 1542 1552 Bradykinin TRIVIAL 23376352 A 1693 1703 bradykinin TRIVIAL 23376352 A 1832 1842 bradykinin TRIVIAL 23376352 A 1936 1939 ATP ABBREVIATION 23376352 A 194 197 ATP ABBREVIATION 23376352 A 2029 2039 Bradykinin TRIVIAL 23376352 A 467 477 bradykinin TRIVIAL 23376352 A 603 613 bradykinin TRIVIAL 23376352 A 759 769 bradykinin TRIVIAL 23376352 A 813 823 Bradykinin TRIVIAL 23376352 T 0 10 Bradykinin TRIVIAL 23376352 T 84 87 ATP ABBREVIATION 23376355 A 1006 1009 DIM ABBREVIATION 23376355 A 1201 1211 adriamycin TRIVIAL 23376355 A 124 134 adriamycin TRIVIAL 23376355 A 22 32 adriamycin TRIVIAL 23376355 A 293 303 adriamycin TRIVIAL 23376355 A 444 464 3,3'-diindolymethane SYSTEMATIC 23376355 A 466 469 DIM ABBREVIATION 23376355 A 555 565 adriamycin TRIVIAL 23376355 A 633 636 DIM ABBREVIATION 23376355 T 0 20 3,3'-Diindolymethane SYSTEMATIC 23376355 T 33 43 adriamycin TRIVIAL 23376356 A 461 469 LY294002 IDENTIFIER 23376356 A 645 653 SB203580 IDENTIFIER 23376356 A 674 682 SP600125 IDENTIFIER 23376356 A 745 753 LY294002 IDENTIFIER 23376546 A 1041 1044 BUP ABBREVIATION 23376546 A 1118 1122 NBUP ABBREVIATION 23376546 A 1188 1191 BUP ABBREVIATION 23376546 A 1215 1218 BUP ABBREVIATION 23376546 A 1280 1284 NBUP ABBREVIATION 23376546 A 133 136 BUP ABBREVIATION 23376546 A 1373 1376 BUP ABBREVIATION 23376546 A 1438 1442 NBUP ABBREVIATION 23376546 A 1547 1551 NBUP ABBREVIATION 23376546 A 1586 1590 NBUP ABBREVIATION 23376546 A 162 178 norbuprenorphine TRIVIAL 23376546 A 1686 1689 BUP ABBREVIATION 23376546 A 1694 1698 NBUP ABBREVIATION 23376546 A 180 184 NBUP ABBREVIATION 23376546 A 1943 1946 BUP ABBREVIATION 23376546 A 1951 1955 NBUP ABBREVIATION 23376546 A 2064 2067 BUP ABBREVIATION 23376546 A 2091 2094 BUP ABBREVIATION 23376546 A 2133 2137 NBUP ABBREVIATION 23376546 A 337 340 BUP ABBREVIATION 23376546 A 383 387 NBUP ABBREVIATION 23376546 A 43 56 buprenorphine TRIVIAL 23376546 A 543 546 BUP ABBREVIATION 23376546 A 551 555 NBUP ABBREVIATION 23376546 A 58 61 BUP ABBREVIATION 23376546 A 763 766 BUP ABBREVIATION 23376546 A 816 820 NBUP ABBREVIATION 23376546 A 916 920 NBUP ABBREVIATION 23376546 A 949 953 NBUP ABBREVIATION 23376546 A 993 997 NBUP ABBREVIATION 23376546 T 54 67 buprenorphine TRIVIAL 23376779 A 109 113 EGCG ABBREVIATION 23376779 A 1747 1750 NAC ABBREVIATION 23376779 A 1755 1759 EGCG ABBREVIATION 23376779 A 353 356 NAC ABBREVIATION 23376779 A 370 374 EGCG ABBREVIATION 23376779 A 386 397 polyphenols FAMILY 23376779 A 409 418 catechins FAMILY 23376779 A 428 432 EGCG ABBREVIATION 23376779 A 55 72 N-acetyl-cysteine SYSTEMATIC 23376779 A 74 77 NAC ABBREVIATION 23376779 A 83 107 epigallocatechin gallate TRIVIAL 23376779 T 102 105 NAC ABBREVIATION 23376779 T 93 97 EGCG ABBREVIATION 23376802 A 1127 1129 Pb FORMULA 23376802 A 1317 1319 Pb FORMULA 23376802 A 172 174 Pb FORMULA 23376802 A 435 437 Pb FORMULA 23376802 A 718 720 Pb FORMULA 23376823 A 103 122 diundecyl phthalate SYSTEMATIC 23376823 A 124 128 DUDP ABBREVIATION 23376823 A 134 154 ditridecyl phthalate SYSTEMATIC 23376823 A 156 160 DTDP ABBREVIATION 23376823 A 232 236 DUDP ABBREVIATION 23376823 A 240 244 DTDP ABBREVIATION 23376823 A 281 285 DUDP ABBREVIATION 23376823 A 290 294 DTDP ABBREVIATION 23376823 A 508 517 phthalate FAMILY 23376823 A 664 668 DUDP ABBREVIATION 23376823 A 77 101 dialkyl phthalate esters FAMILY 23376823 A 785 789 DUDP ABBREVIATION 23376823 A 804 808 DTDP ABBREVIATION 23376823 A 879 883 DUDP ABBREVIATION 23376823 T 43 78 diundecyl and ditridecyl phthalates MULTIPLE 23376975 A 0 8 Coumarin TRIVIAL 23376975 A 1130 1138 coumarin TRIVIAL 23376975 A 1317 1325 warfarin TRIVIAL 23376975 A 268 285 vitamin K epoxide FAMILY 23376975 A 39 47 warfarin TRIVIAL 23376975 A 424 432 coumarin TRIVIAL 23376975 A 49 62 acenocoumarol TRIVIAL 23376975 A 626 640 gamma-glutamyl SYSTEMATIC 23376975 A 67 80 phenprocoumon TRIVIAL 23376975 T 18 26 warfarin TRIVIAL 23376975 T 37 45 coumarin TRIVIAL 23377024 A 1117 1125 Caffeine TRIVIAL 23377024 A 1207 1215 caffeine TRIVIAL 23377024 A 1241 1248 alcohol FAMILY 23377024 A 1285 1292 alcohol FAMILY 23377024 A 1297 1305 caffeine TRIVIAL 23377024 A 1461 1469 caffeine TRIVIAL 23377024 A 1510 1517 alcohol FAMILY 23377024 A 1609 1616 alcohol FAMILY 23377024 A 162 170 caffeine TRIVIAL 23377024 A 195 202 alcohol FAMILY 23377024 A 46 54 caffeine TRIVIAL 23377024 A 657 665 caffeine TRIVIAL 23377024 A 712 719 alcohol FAMILY 23377024 A 729 736 alcohol FAMILY 23377024 A 95 102 alcohol FAMILY 23377024 A 994 1001 Alcohol SYSTEMATIC 23377024 T 11 19 caffeine TRIVIAL 23377024 T 24 31 alcohol FAMILY 23377618 A 1041 1054 acetaminophen TRIVIAL 23377618 A 1060 1073 rosiglitazone TRIVIAL 23377618 A 1113 1125 troglitazone TRIVIAL 23377618 A 1205 1218 acetaminophen TRIVIAL 23377618 A 471 484 acetaminophen TRIVIAL 23377618 A 486 498 troglitazone TRIVIAL 23377618 A 504 517 rosiglitazone TRIVIAL 23377618 A 870 877 glucose TRIVIAL 23378191 A 464 472 tyrosine TRIVIAL 23378600 A 139 152 sphingolipids FAMILY 23378600 A 1479 1489 fatty acid FAMILY 23378600 A 157 168 cholesterol TRIVIAL 23378600 A 443 453 fatty acid FAMILY 23379472 A 20 33 acetylcholine SYSTEMATIC 23379472 A 247 291 1,2,5,6-tetrahydropyridine-3-carboxylic acid SYSTEMATIC 23379472 A 531 556 [(3)H]N-methylscopolamine SYSTEMATIC 23379472 A 635 647 oxotremorine TRIVIAL 23379472 A 655 663 [(3)H]DA SYSTEMATIC 23379472 T 28 67 Tetrahydropyridine-3-carboxylate Esters FAMILY 23379514 A 113 117 heme FAMILY 23379514 A 167 171 iron SYSTEMATIC 23379514 A 17 21 iron SYSTEMATIC 23379514 A 201 205 heme FAMILY 23379514 A 353 355 HN FORMULA 23379514 A 357 358 N FORMULA 23379514 A 360 362 CO FORMULA 23379514 A 469 519 (E)-3-(4-(phenylamino)phenylcarbamoyl)acrylic acid SYSTEMATIC 23379514 A 528 592 (E)-N'-(4-(dimethylamino)benzylidene) diazenecarboximidhydrazide SYSTEMATIC 23379514 A 655 659 heme FAMILY 23379514 A 756 763 phenoxy SYSTEMATIC 23379514 T 43 47 iron SYSTEMATIC 23379514 T 58 62 heme FAMILY 23380374 A 203 213 nucleoside FAMILY 23380374 A 429 439 nucleoside FAMILY 23380374 A 441 444 d4T ABBREVIATION 23380374 A 465 469 TIBO ABBREVIATION 23380374 A 503 522 polyethylene glycol SYSTEMATIC 23380374 A 524 527 PEG ABBREVIATION 23380374 A 539 551 triphosphate SYSTEMATIC 23380374 A 555 568 d4T-6PEG-TIBO ABBREVIATION 23380374 T 97 109 triphosphate SYSTEMATIC 23380568 A 664 675 cholesterol TRIVIAL 23380568 A 697 709 triglyceride FAMILY 23380916 A 1181 1192 amphetamine TRIVIAL 23380916 A 1198 1202 NMDA ABBREVIATION 23380916 A 1206 1210 AMPA ABBREVIATION 23380916 A 1384 1393 glutamate TRIVIAL 23380916 A 293 302 glutamate TRIVIAL 23380916 A 307 315 dopamine TRIVIAL 23380916 A 562 573 amphetamine TRIVIAL 23380916 A 758 769 amphetamine TRIVIAL 23380916 A 804 824 N-methyl-D-aspartate SYSTEMATIC 23380916 A 826 830 NMDA ABBREVIATION 23380916 A 851 903 α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid SYSTEMATIC 23380916 A 905 909 AMPA ABBREVIATION 23380916 A 990 1001 amphetamine TRIVIAL 23380916 T 20 31 amphetamine TRIVIAL 23380916 T 59 68 glutamate TRIVIAL 23381641 A 1036 1050 Bafilomycin A1 TRIVIAL 23381641 A 1203 1204 N FORMULA 23381641 A 1230 1241 tunicamycin TRIVIAL 23381641 A 1533 1548 3-methyladenine SYSTEMATIC 23381641 A 544 550 oxygen SYSTEMATIC 23381641 A 55 61 serine TRIVIAL 23381641 A 62 71 threonine TRIVIAL 23381727 A 1508 1514 carbon SYSTEMATIC 23381727 A 181 187 Carbon SYSTEMATIC 23381727 A 674 680 carbon SYSTEMATIC 23381727 T 44 50 carbon SYSTEMATIC 23381904 A 127 132 PAMAM ABBREVIATION 23381904 A 141 146 PAMAM ABBREVIATION 23381904 A 158 165 PEI 423 TRIVIAL 23381904 A 20 34 polyamidoamine FAMILY 23381904 A 39 55 polyethylenimine SYSTEMATIC 23381904 A 454 461 PEI 423 TRIVIAL 23381904 A 523 528 PAMAM ABBREVIATION 23381904 A 558 565 PEI 423 TRIVIAL 23381904 A 62 69 PEI 423 TRIVIAL 23381904 A 622 627 PAMAM ABBREVIATION 23381904 A 635 638 PEI ABBREVIATION 23381904 A 708 715 PEI 423 TRIVIAL 23381904 A 78 85 PEI 423 TRIVIAL 23381904 T 33 47 Polyamidoamine SYSTEMATIC 23381904 T 53 60 PEI 423 TRIVIAL 23381936 A 1001 1013 atorvastatin TRIVIAL 23381936 A 41 53 atorvastatin TRIVIAL 23381936 A 617 629 Atorvastatin TRIVIAL 23381936 A 91 112 o-hydroxyatorvastatin SYSTEMATIC 23381936 T 31 43 atorvastatin TRIVIAL 23381968 A 1036 1047 sibutramine TRIVIAL 23381968 A 162 181 racemic sibutramine TRIVIAL 23381968 A 234 245 Sibutramine TRIVIAL 23381968 A 344 355 Clopidogrel TRIVIAL 23381968 A 360 374 clarithromycin TRIVIAL 23381968 A 403 414 sibutramine TRIVIAL 23381968 A 42 53 clopidogrel TRIVIAL 23381968 A 58 72 clarithromycin TRIVIAL 23381968 A 689 700 clopidogrel TRIVIAL 23381968 A 764 778 clarithromycin TRIVIAL 23381968 A 836 847 sibutramine TRIVIAL 23381968 T 21 32 clopidogrel TRIVIAL 23381968 T 37 51 clarithromycin TRIVIAL 23381968 T 96 107 sibutramine TRIVIAL 23382024 A 20 28 graphene TRIVIAL 23382024 A 32 39 Ir(111) FORMULA 23382024 A 402 410 graphene TRIVIAL 23382024 T 60 68 graphene TRIVIAL 23382024 T 72 79 ir(111) FORMULA 23382458 A 1136 1144 apixaban TRIVIAL 23382458 A 1255 1267 ketoconazole TRIVIAL 23382458 A 1271 1284 cyclosporin A TRIVIAL 23382458 A 1308 1313 Ko134 IDENTIFIER 23382458 A 1435 1443 Naproxen TRIVIAL 23382458 A 1454 1462 apixaban TRIVIAL 23382458 A 1522 1530 apixaban TRIVIAL 23382458 A 1572 1580 Naproxen TRIVIAL 23382458 A 1709 1717 apixaban TRIVIAL 23382458 A 574 582 apixaban TRIVIAL 23382458 A 636 644 apixaban TRIVIAL 23382458 A 783 791 apixaban TRIVIAL 23382458 A 89 97 apixaban TRIVIAL 23382458 A 939 947 Apixaban TRIVIAL 23382458 A 964 971 digoxin TRIVIAL 23382458 A 99 218 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide SYSTEMATIC 23382458 A 999 1011 Ketoconazole TRIVIAL 23382458 T 84 92 apixaban TRIVIAL 23383648 A 135 141 silica TRIVIAL 23383648 A 313 322 ruthenium SYSTEMATIC 23383648 A 366 372 silica TRIVIAL 23383648 A 546 553 Gd-DTPA FORMULA 23383648 A 589 595 silica TRIVIAL 23383648 A 814 833 Polyethylene glycol SYSTEMATIC 23383648 T 32 38 silica TRIVIAL 23383744 A 437 453 propylthiouracil SYSTEMATIC 23383744 A 455 458 PTU ABBREVIATION 23383744 A 578 581 PTU ABBREVIATION 23383744 A 922 937 thyroid hormone FAMILY 23384448 A 0 9 Acitretin TRIVIAL 23384448 A 1121 1124 ATP ABBREVIATION 23384448 A 1126 1129 ADP ABBREVIATION 23384448 A 1131 1140 tamoxifen TRIVIAL 23384448 A 1145 1163 4-hydroxytamoxifen SYSTEMATIC 23384448 A 1284 1287 ATP ABBREVIATION 23384448 A 1543 1546 ATP ABBREVIATION 23384448 A 1578 1584 Ca(2+) FORMULA 23384448 A 1613 1622 acitretin TRIVIAL 23384448 A 1782 1791 acitretin TRIVIAL 23384448 A 1919 1928 acitretin TRIVIAL 23384448 A 237 246 acitretin TRIVIAL 23384448 A 324 333 acitretin TRIVIAL 23384448 A 526 534 retinoid FAMILY 23384448 A 536 545 Acitretin TRIVIAL 23384448 A 668 671 ATP ABBREVIATION 23384448 A 720 723 ADP ABBREVIATION 23384448 A 789 798 Acitretin TRIVIAL 23384448 A 807 813 Ca(2+) FORMULA 23384448 A 885 903 adenine nucleotide TRIVIAL 23384448 A 931 940 Acitretin TRIVIAL 23384448 A 974 979 thiol FAMILY 23384448 T 0 9 Acitretin TRIVIAL 23384834 A 1144 1147 Dex ABBREVIATION 23384834 A 1227 1230 Dex ABBREVIATION 23384834 A 1293 1296 Dex ABBREVIATION 23384834 A 26 33 steroid FAMILY 23384834 A 279 292 dexamethasone TRIVIAL 23384834 A 294 297 Dex ABBREVIATION 23384834 A 432 435 Dex ABBREVIATION 23384834 A 494 497 Dex ABBREVIATION 23384834 A 706 709 Dex ABBREVIATION 23384834 A 871 874 Dex ABBREVIATION 23384834 A 902 917 [(3)H]thymidine SYSTEMATIC 23384997 A 0 8 Selenium SYSTEMATIC 23384997 A 10 12 Se FORMULA 23384997 A 114 128 selenocysteine TRIVIAL 23384997 A 1234 1249 sodium selenite SYSTEMATIC 23384997 A 1251 1258 Na2SeO3 FORMULA 23384997 A 1273 1287 selenocysteine TRIVIAL 23384997 A 1289 1302 Cys-Se-Se-Cys FORMULA 23384997 A 130 135 SeCys FORMULA 23384997 A 1337 1339 Se FORMULA 23384997 A 137 147 amino acid FAMILY 23384997 A 149 157 selenium SYSTEMATIC 23384997 A 1558 1560 Se FORMULA 23384997 A 1679 1681 Se FORMULA 23384997 A 1718 1720 Se FORMULA 23384997 A 1802 1804 Se FORMULA 23384997 A 183 185 Se FORMULA 23384997 A 1836 1838 Se FORMULA 23384997 A 2394 2402 selenium SYSTEMATIC 23384997 A 2501 2509 selenium SYSTEMATIC 23384997 A 2613 2621 selenium SYSTEMATIC 23384997 A 2981 2989 selenium SYSTEMATIC 23384997 A 3021 3029 selenium SYSTEMATIC 23384997 A 408 414 oxygen SYSTEMATIC 23384997 A 434 442 selenium SYSTEMATIC 23384997 A 627 638 Glutathione TRIVIAL 23384997 A 725 736 glutathione TRIVIAL 23384997 A 778 791 hydroperoxide FAMILY 23384997 A 792 803 glutathione TRIVIAL 23384997 T 185 193 selenium SYSTEMATIC 23384997 T 30 41 glutathione TRIVIAL 23384997 T 70 83 hydroperoxide FAMILY 23384997 T 84 95 glutathione TRIVIAL 23385032 A 1013 1056 Gemcitabine 5'-mono-, di- and triphosphates MULTIPLE 23385032 A 1121 1132 Gemcitabine TRIVIAL 23385032 A 1280 1290 nucleoside FAMILY 23385032 A 1721 1732 Gemcitabine TRIVIAL 23385032 A 1737 1748 Floxuridine TRIVIAL 23385032 A 1876 1887 Gemcitabine TRIVIAL 23385032 A 1927 1938 Gemcitabine TRIVIAL 23385032 A 321 331 nucleoside FAMILY 23385032 A 441 458 polyvinyl alcohol SYSTEMATIC 23385032 A 505 535 phosphorylated 5-FU nucleoside SYSTEMATIC 23385032 A 536 547 Floxuridine TRIVIAL 23385032 A 729 739 nucleoside FAMILY 23385032 A 887 898 Gemcitabine TRIVIAL 23385032 T 25 35 nucleoside FAMILY 23385210 A 115 124 imidazole SYSTEMATIC 23385210 A 130 138 triazole FAMILY 23385210 A 226 236 Darapladib TRIVIAL 23385210 A 269 294 quaternary ammonium salts FAMILY 23385210 A 449 459 Darapladib TRIVIAL 23385210 A 81 86 amide FAMILY 23385210 A 96 106 Darapladib TRIVIAL 23385210 T 127 152 quaternary ammonium salts FAMILY 23385210 T 24 33 imidazole SYSTEMATIC 23385210 T 38 46 triazole FAMILY 23385213 A 115 125 piperidine SYSTEMATIC 23385213 A 18 99 5(R)-[1,2,3]triazolylmethyl and (5R)-[(4-F-[1,2,3]triazolyl)methyl]oxazolidinones MULTIPLE 23385213 A 301 320 exo-cyanoethylidene SYSTEMATIC 23385213 A 348 358 piperidine SYSTEMATIC 23385213 A 418 427 linezolid TRIVIAL 23385213 A 436 446 penicillin FAMILY 23385213 T 46 56 piperidine SYSTEMATIC 23385213 T 69 151 (5R)-[1,2,3]triazolylmethyl and (5R)-[(4-F-[1,2,3]triazolyl)methyl] oxazolidinones MULTIPLE 23385219 A 1063 1067 AFB1 ABBREVIATION 23385219 A 1209 1213 AFB1 ABBREVIATION 23385219 A 123 135 aflatoxin B1 TRIVIAL 23385219 A 1320 1324 AFB1 ABBREVIATION 23385219 A 137 141 AFB1 ABBREVIATION 23385219 A 1381 1385 AFB1 ABBREVIATION 23385219 A 377 381 AFB1 ABBREVIATION 23385219 A 673 677 AFB1 ABBREVIATION 23385219 A 735 739 AFB1 ABBREVIATION 23385219 T 68 80 aflatoxin B1 TRIVIAL 23385325 A 245 253 hydrogen SYSTEMATIC 23385325 A 637 645 hydrogen SYSTEMATIC 23385325 A 661 662 C FORMULA 23385325 A 693 694 O FORMULA 23385325 A 716 732 carboxylic acids FAMILY 23385325 A 858 872 aspartic acids FAMILY 23385960 A 0 18 Doxazosin mesylate TRIVIAL 23385960 A 1054 1062 Eudragit TRIVIAL 23385960 A 1133 1141 Eudragit TRIVIAL 23385960 A 1219 1227 PEG 6000 TRIVIAL 23385960 A 1263 1266 DXM ABBREVIATION 23385960 A 1306 1314 PEG 6000 TRIVIAL 23385960 A 157 160 DXM ABBREVIATION 23385960 A 20 23 DXM ABBREVIATION 23385960 A 273 276 DXM ABBREVIATION 23385960 A 444 460 Polymethacrylate FAMILY 23385960 A 474 482 Eudragit TRIVIAL 23385960 A 535 559 polyethylene glycol 6000 SYSTEMATIC 23385960 A 561 569 PEG 6000 TRIVIAL 23385960 A 572 588 triethyl citrate SYSTEMATIC 23385960 A 590 593 TEC ABBREVIATION 23385960 T 48 66 doxazosin mesylate TRIVIAL 23386029 A 10 37 3,6-disubstituted α-pyrones FAMILY 23386029 A 168 219 3-alkylated 6-(1-methyl-1-propenyl)-2H-pyran-2-ones FAMILY 23386029 A 291 303 Nocapyrone H TRIVIAL 23386029 A 352 364 nitric oxide SYSTEMATIC 23386029 A 366 368 NO FORMULA 23386029 A 371 387 prostaglandin E2 TRIVIAL 23386029 A 389 393 PGE2 ABBREVIATION 23386029 A 39 54 nocapyrones H-J MULTIPLE 23386029 A 433 445 nocapyrone H TRIVIAL 23386029 A 489 491 NO FORMULA 23386029 T 0 15 Nocapyrones H-J MULTIPLE 23386029 T 17 44 3,6-Disubstituted α-Pyrones FAMILY 23386251 A 1406 1413 glucose TRIVIAL 23386251 A 242 255 tofogliflozin TRIVIAL 23386251 A 440 447 glucose TRIVIAL 23386251 A 479 486 glucose TRIVIAL 23386251 A 73 79 sodium SYSTEMATIC 23386251 A 756 763 glucose TRIVIAL 23386251 A 80 87 glucose TRIVIAL 23386251 T 58 64 sodium SYSTEMATIC 23386251 T 65 72 glucose TRIVIAL 23386368 A 1110 1116 SnO(2) FORMULA 23386368 A 1243 1249 SnO(2) FORMULA 23386368 A 1333 1345 metal oxides FAMILY 23386368 A 1355 1371 titanium dioxide SYSTEMATIC 23386368 A 1375 1386 iron oxides FAMILY 23386368 A 1459 1470 metal-oxide FAMILY 23386368 A 263 275 metal oxides FAMILY 23386368 A 277 288 tin dioxide SYSTEMATIC 23386368 A 290 296 SnO(2) FORMULA 23386368 A 47 54 lithium SYSTEMATIC 23386368 A 470 476 SnO(2) FORMULA 23386368 A 614 620 SnO(2) FORMULA 23386368 A 771 777 SnO(2) FORMULA 23386368 A 831 837 carbon SYSTEMATIC 23386368 A 839 845 carbon SYSTEMATIC 23386368 A 857 865 graphene TRIVIAL 23386368 A 901 903 Sn FORMULA 23386368 T 0 6 SnO(2) FORMULA 23386368 T 58 65 Lithium SYSTEMATIC 23386390 A 1109 1120 sitagliptin TRIVIAL 23386390 A 1170 1181 sitagliptin TRIVIAL 23386390 A 1407 1418 sitagliptin TRIVIAL 23386390 A 1532 1543 sitagliptin TRIVIAL 23386390 A 34 45 sitagliptin TRIVIAL 23386390 A 583 596 sulfonylureas FAMILY 23386390 A 627 636 metformin TRIVIAL 23386390 A 768 779 sitagliptin TRIVIAL 23386390 T 40 51 sitagliptin TRIVIAL 23386413 A 1209 1231 17-hydroxyprogesterone SYSTEMATIC 23386413 A 620 628 Androgen FAMILY 23386413 A 732 754 17-hydroxyprogesterone SYSTEMATIC 23386413 A 756 761 17OHP SYSTEMATIC 23386702 A 101 109 alcohols FAMILY 23386702 A 1025 1053 (R)-naproxen-β-d-glucuronide SYSTEMATIC 23386702 A 1055 1083 (S)-naproxen-β-d-glucuronide SYSTEMATIC 23386702 A 1085 1120 ibuprofen-β-d-glucuronide (racemic) SYSTEMATIC 23386702 A 111 117 amines FAMILY 23386702 A 1122 1149 clopidogrel-β-d-glucuronide SYSTEMATIC 23386702 A 1155 1180 valproate-β-d-glucuronide SYSTEMATIC 23386702 A 123 129 thiols FAMILY 23386702 A 1267 1293 Diclofenac-β-d-glucuronide SYSTEMATIC 23386702 A 1295 1322 clopidogrel-β-d-glucuronide SYSTEMATIC 23386702 A 1324 1349 ibuprofen-β-d-glucuronide SYSTEMATIC 23386702 A 1351 1379 (R)-naproxen-β-d-glucuronide SYSTEMATIC 23386702 A 1385 1413 (S)-naproxen-β-d-glucuronide SYSTEMATIC 23386702 A 145 167 Uridine 5'-diphosphate SYSTEMATIC 23386702 A 1574 1599 Valproate-β-d-glucuronide SYSTEMATIC 23386702 A 1604 1629 CGP 47292-β-d-glucuronide SYSTEMATIC 23386702 A 1699 1725 diclofenac-β-d-glucuronide SYSTEMATIC 23386702 A 1822 1839 acyl glucuronides FAMILY 23386702 A 1937 1954 acyl glucuronides FAMILY 23386702 A 278 294 carboxylic acids FAMILY 23386702 A 28 34 esters FAMILY 23386702 A 298 315 acyl glucuronides FAMILY 23386702 A 348 365 acyl glucuronides FAMILY 23386702 A 36 42 amides FAMILY 23386702 A 373 379 esters FAMILY 23386702 A 465 482 acyl glucuronides FAMILY 23386702 A 48 58 thioesters FAMILY 23386702 A 600 617 acyl glucuronides FAMILY 23386702 A 676 695 potassium phosphate SYSTEMATIC 23386702 A 70 86 carboxylic acids FAMILY 23386702 A 755 776 4-nitrophenyl acetate SYSTEMATIC 23386702 A 795 812 acyl glucuronides FAMILY 23386702 A 831 857 Diclofenac-β-d-glucuronide SYSTEMATIC 23386702 A 970 995 CGP 47292-β-d-glucuronide SYSTEMATIC 23386702 A 997 1023 diclofenac-β-d-glucuronide SYSTEMATIC 23386702 T 52 69 acyl glucuronides FAMILY 23386779 A 302 310 ketamine TRIVIAL 23386779 A 894 902 ketamine TRIVIAL 23386779 A 91 99 ketamine TRIVIAL 23386779 T 19 27 ketamine TRIVIAL 23387288 A 357 363 hexane SYSTEMATIC 23387288 A 394 407 ethyl acetate SYSTEMATIC 23387288 A 415 425 chloroform TRIVIAL 23387288 A 743 751 iridoids FAMILY 23387288 A 752 765 secoxyloganin TRIVIAL 23387288 A 767 776 sweroside TRIVIAL 23387288 A 781 788 loganin TRIVIAL 23387306 A 101 103 He FORMULA 23387306 A 75 90 tetrahydrofuran SYSTEMATIC 23387306 A 821 823 He FORMULA 23387306 T 52 67 tetrahydrofuran SYSTEMATIC 23387425 A 0 13 Azaspiracid-1 TRIVIAL 23387425 A 1169 1174 AZA-1 ABBREVIATION 23387425 A 1358 1363 AZA-1 ABBREVIATION 23387425 A 15 20 AZA-1 ABBREVIATION 23387425 A 1595 1600 AZA-1 ABBREVIATION 23387425 A 1876 1880 AZAs ABBREVIATION 23387425 A 209 214 AZA-1 ABBREVIATION 23387425 A 371 376 AZA-1 ABBREVIATION 23387425 A 497 502 AZA-1 ABBREVIATION 23387425 A 608 613 AZA-1 ABBREVIATION 23387425 A 648 662 chlorpromazine TRIVIAL 23387425 T 0 13 Azaspiracid-1 TRIVIAL 23387554 A 1072 1076 CTAB ABBREVIATION 23387554 A 111 123 stearic acid TRIVIAL 23387554 A 150 158 methanol SYSTEMATIC 23387554 A 225 235 chloroform TRIVIAL 23387554 A 239 247 methanol SYSTEMATIC 23387554 A 757 765 methanol SYSTEMATIC 23387554 A 858 864 silica TRIVIAL 23387554 T 69 75 silica TRIVIAL 23387824 A 121 141 12-hydroxycurcumenol SYSTEMATIC 23387824 A 160 173 spirolactones FAMILY 23387824 A 175 189 curcumanolides FAMILY 23387824 A 22 37 heyneanones A-D MULTIPLE 23387824 A 282 296 sesquiterpenes FAMILY 23387824 A 311 318 labdane TRIVIAL 23387824 A 324 334 diterpenes FAMILY 23387824 A 366 378 heyneanone A TRIVIAL 23387824 A 384 396 heyneanone C TRIVIAL 23387824 A 402 422 4,10-epizedoarondiol SYSTEMATIC 23387824 A 428 441 procurcumenol TRIVIAL 23387824 A 448 458 aerugidiol TRIVIAL 23387824 A 465 474 zerumin A TRIVIAL 23387824 A 485 527 (E)-15,16-bisnorlabda-8(17),11-dien-13-one SYSTEMATIC 23387824 A 551 559 tyrosine TRIVIAL 23387824 A 56 64 guaianes FAMILY 23387824 A 66 86 4,10-epizedoarondiol SYSTEMATIC 23387824 A 9 20 germacranes FAMILY 23387824 A 92 115 15-hydroxyprocurcumenol SYSTEMATIC 23387824 T 0 14 Sesquiterpenes FAMILY 23388072 A 1094 1105 doxorubicin TRIVIAL 23388072 A 1235 1244 PCL-b-PEO ABBREVIATION 23388072 A 189 232 poly(ε-caprolactone)-b-poly(ethylene oxide) FAMILY 23388072 A 234 243 PCL-b-PEO ABBREVIATION 23388072 A 275 337 cyclic (Arginine-Glycine-Aspartic acid-d-Phenylalanine-Lysine) TRIVIAL 23388072 A 353 380 fluorescein isothiocyannate SYSTEMATIC 23388072 A 382 386 FITC ABBREVIATION 23388072 A 680 684 (1)H FORMULA 23388072 A 845 856 doxorubicin TRIVIAL 23388072 A 858 861 DOX ABBREVIATION 23388095 A 1228 1233 NaOCl FORMULA 23388095 A 1310 1314 DMOG ABBREVIATION 23388095 A 1373 1386 acetylcholine SYSTEMATIC 23388095 A 1412 1417 NaOCl FORMULA 23388095 A 1434 1438 DMOG ABBREVIATION 23388095 A 1519 1524 NaOCl FORMULA 23388095 A 1536 1540 DMOG ABBREVIATION 23388095 A 1596 1600 heme FAMILY 23388095 A 1663 1667 DMOG ABBREVIATION 23388095 A 1705 1711 oxygen SYSTEMATIC 23388095 A 1730 1734 DMOG ABBREVIATION 23388095 A 225 231 oxygen SYSTEMATIC 23388095 A 242 248 prolyl TRIVIAL 23388095 A 455 476 dimethyloxalylglycine SYSTEMATIC 23388095 A 698 702 DMOG ABBREVIATION 23388095 A 704 725 dimethyloxalylglycine SYSTEMATIC 23388095 A 852 864 hypochlorite SYSTEMATIC 23388095 A 866 871 NaOCl FORMULA 23388095 A 932 936 NaCl FORMULA 23388095 A 940 944 DMOG ABBREVIATION 23388095 T 0 6 Prolyl TRIVIAL 23388705 A 1086 1097 tecadenoson TRIVIAL 23388705 A 1208 1219 tecadenoson TRIVIAL 23388705 A 1369 1380 tecadenoson TRIVIAL 23388705 A 164 175 Tecadenoson TRIVIAL 23388705 A 194 203 adenosine TRIVIAL 23388705 A 23 32 adenosine TRIVIAL 23388705 A 246 255 adenosine TRIVIAL 23388705 A 311 322 tecadenoson TRIVIAL 23388705 A 358 368 nucleoside FAMILY 23388705 A 431 441 nucleoside FAMILY 23388705 A 573 583 nucleoside FAMILY 23388705 A 601 612 tecadenoson TRIVIAL 23388705 A 667 678 tecadenoson TRIVIAL 23388705 A 767 792 nitrobenzylmercaptopurine SYSTEMATIC 23388705 A 868 879 tecadenoson TRIVIAL 23388705 A 981 992 tecadenoson TRIVIAL 23388705 T 16 25 adenosine TRIVIAL 23388705 T 166 176 nucleoside FAMILY 23388705 T 43 54 tecadenoson TRIVIAL 23388705 T 74 84 nucleoside FAMILY 23389090 A 194 198 (1)H FORMULA 23389090 A 200 205 (13)C FORMULA 23389090 A 603 608 sugar FAMILY 23389091 A 39 58 sinularcasbanes A-F MULTIPLE 23389091 A 452 464 nitric oxide SYSTEMATIC 23389091 A 466 468 NO FORMULA 23389091 A 8 28 casbane diterpenoids FAMILY 23389091 T 4 24 casbane diterpenoids FAMILY 23389324 A 726 736 iron oxide SYSTEMATIC 23389739 A 1184 1190 oxygen SYSTEMATIC 23389739 A 131 137 TiO(2) FORMULA 23389739 A 1363 1369 TiO(2) FORMULA 23389739 A 149 162 H(2)Ti(3)O(7) FORMULA 23389739 A 723 729 TiO(2) FORMULA 23389739 T 50 56 TiO(2) FORMULA 23389756 A 1047 1056 BMY-14802 IDENTIFIER 23389756 A 11 17 L-DOPA ABBREVIATION 23389756 A 1163 1172 BMY-14802 IDENTIFIER 23389756 A 1207 1213 L-DOPA ABBREVIATION 23389756 A 1223 1231 SKF81297 IDENTIFIER 23389756 A 1235 1245 quinpirole TRIVIAL 23389756 A 1264 1274 WAY-100635 IDENTIFIER 23389756 A 1346 1355 BMY-14802 IDENTIFIER 23389756 A 1396 1402 L-DOPA ABBREVIATION 23389756 A 379 388 BMY-14802 IDENTIFIER 23389756 A 432 438 L-DOPA ABBREVIATION 23389756 A 603 612 BMY-14802 IDENTIFIER 23389756 A 621 627 L-DOPA ABBREVIATION 23389756 A 655 663 SKF81297 IDENTIFIER 23389756 A 695 705 quinpirole TRIVIAL 23389756 A 784 793 BMY-14802 IDENTIFIER 23389756 A 824 834 WAY-100635 IDENTIFIER 23389756 A 961 970 BMY-14802 IDENTIFIER 23389756 A 979 985 L-DOPA ABBREVIATION 23389756 T 15 24 BMY-14802 IDENTIFIER 23389756 T 33 39 L-DOPA ABBREVIATION 23389756 T 45 53 dopamine TRIVIAL 23389830 A 1055 1059 K(+) FORMULA 23389830 A 1173 1179 Ca(2+) FORMULA 23389830 A 1192 1198 Ca(2+) FORMULA 23389830 A 1440 1446 Ca(2+) FORMULA 23389830 A 1461 1467 Ca(2+) FORMULA 23389830 A 1662 1668 Ca(2+) FORMULA 23389830 A 1679 1685 Ca(2+) FORMULA 23389830 A 1722 1728 Ca(2+) FORMULA 23389830 A 518 522 K(+) FORMULA 23389830 A 525 538 noradrenaline TRIVIAL 23389830 A 548 561 acetylcholine SYSTEMATIC 23389830 A 563 566 ACh ABBREVIATION 23389830 A 856 859 ACh ABBREVIATION 23389852 A 1171 1179 androgen FAMILY 23389862 A 105 116 roflumilast TRIVIAL 23389862 A 1109 1120 roflumilast TRIVIAL 23389862 A 1130 1152 fluticasone propionate SYSTEMATIC 23389862 A 1190 1201 Roflumilast TRIVIAL 23389862 A 1353 1363 formoterol TRIVIAL 23389862 A 1412 1423 roflumilast TRIVIAL 23389862 A 1440 1450 formoterol TRIVIAL 23389862 A 1622 1633 roflumilast TRIVIAL 23389862 A 1638 1648 formoterol TRIVIAL 23389862 A 1848 1859 Roflumilast TRIVIAL 23389862 A 418 429 roflumilast TRIVIAL 23389862 A 584 595 roflumilast TRIVIAL 23389862 A 799 810 roflumilast TRIVIAL 23389862 T 201 212 roflumilast TRIVIAL 23389862 T 54 64 formoterol TRIVIAL 23389878 A 209 217 androgen FAMILY 23389878 A 39 47 androgen FAMILY 23389878 A 743 746 NH2 FORMULA 23389878 A 930 933 NH2 FORMULA 23389878 T 65 73 androgen FAMILY 23390132 A 238 248 nucleotide FAMILY 23390932 A 113 126 Au102(pMBA)44 FORMULA 23390932 A 280 293 Au102(pMBA)44 FORMULA 23390932 A 4 17 Au102(pMBA)44 FORMULA 23391023 A 654 664 polyacenes FAMILY 23391037 A 130 137 benzene SYSTEMATIC 23391095 A 249 255 Ar-CH2 FORMULA 23391095 A 297 333 ortho-substituted benzyl phosphonium FAMILY 23391095 A 33 45 [Ga4L6](12-) FAMILY 23391095 A 465 473 methanol SYSTEMATIC 23391095 A 478 481 DMF ABBREVIATION 23391095 A 54 96 1,5-bis(2,3-dihydroxybenzamido)naphthalene SYSTEMATIC 23391095 A 566 584 benzyl phosphonium SYSTEMATIC 23391095 A 788 794 Ar-CH2 FORMULA 23391212 A 1171 1178 AZD7903 NO CLASS 23391212 A 216 221 (14)C FORMULA 23391212 A 32 39 AZD7903 NO CLASS 23391212 A 396 401 (14)C FORMULA 23391212 T 62 69 AZD7903 NO CLASS 23391273 A 321 332 Cholesterol TRIVIAL 23391274 A 101 102 H FORMULA 23391274 A 205 208 HCO FORMULA 23391274 A 67 68 C FORMULA 23391274 A 77 79 OH FORMULA 23391274 A 89 91 CO FORMULA 23391274 T 71 72 C FORMULA 23391274 T 75 77 OH FORMULA 23391274 T 80 82 CO FORMULA 23391274 T 85 86 H FORMULA 23391280 A 1079 1080 N FORMULA 23391280 A 1086 1087 O FORMULA 23391280 A 1122 1123 N FORMULA 23391280 A 1135 1146 Glutathione TRIVIAL 23391280 A 1221 1229 cysteine TRIVIAL 23391280 A 565 572 irgarol TRIVIAL 23391280 A 574 583 terbutryn TRIVIAL 23391280 A 585 593 tramadol TRIVIAL 23391280 A 599 610 venlafaxine TRIVIAL 23391280 A 793 807 clarithromycin TRIVIAL 23391280 A 812 821 valsartan TRIVIAL 23391336 A 238 243 CO(2) FORMULA 23391336 A 352 355 His FORMULA 23391336 A 392 426 aromatic/heterocyclic sulfonamides MULTIPLE 23391336 A 436 465 5-mercapto-1,3,4-thiadiazoles FAMILY 23391336 A 508 529 aromatic sulfonamides FAMILY 23391336 A 690 696 thiols FAMILY 23391336 T 31 42 Sulfonamide SYSTEMATIC 23391336 T 47 52 Thiol SYSTEMATIC 23391596 A 0 26 Benzaldehyde semicarbazone SYSTEMATIC 23391596 A 304 311 ethanol SYSTEMATIC 23391596 T 68 94 benzaldehyde semicarbazone SYSTEMATIC 23392120 A 16 18 Li FORMULA 23392120 A 19 21 Mn FORMULA 23392120 A 205 210 MnCO3 FORMULA 23392120 A 22 23 O FORMULA 23392120 A 285 290 Mn5O8 FORMULA 23392120 A 334 339 MnCO3 FORMULA 23392120 A 43 50 LiMn2O4 FORMULA 23392120 A 52 59 Li2MnO3 FORMULA 23392120 A 522 524 Li FORMULA 23392120 A 525 527 Mn FORMULA 23392120 A 528 529 O FORMULA 23392120 A 586 588 Li FORMULA 23392120 A 65 71 LiMnO2 FORMULA 23392120 A 72 79 Li2MnO3 FORMULA 23392120 T 102 107 MnCO₃ FORMULA 23392120 T 13 15 Li FORMULA 23392120 T 16 18 Mn FORMULA 23392120 T 19 20 O FORMULA 23392354 A 1054 1067 acetazolamide TRIVIAL 23392354 A 1089 1100 bicarbonate SYSTEMATIC 23392354 A 1199 1209 furosemide TRIVIAL 23392354 A 1241 1245 GABA ABBREVIATION 23392354 A 1275 1279 GABA ABBREVIATION 23392354 A 1300 1308 muscimol TRIVIAL 23392354 A 1378 1382 GABA ABBREVIATION 23392354 A 143 151 morphine TRIVIAL 23392354 A 1496 1500 GABA ABBREVIATION 23392354 A 1641 1645 GABA ABBREVIATION 23392354 A 1731 1739 dopamine TRIVIAL 23392354 A 251 259 dopamine TRIVIAL 23392354 A 361 365 GABA ABBREVIATION 23392354 A 433 437 GABA ABBREVIATION 23392354 A 562 566 GABA ABBREVIATION 23392354 A 780 790 furosemide TRIVIAL 23392354 A 794 799 Cl(-) FORMULA 23392354 A 883 891 morphine TRIVIAL 23392354 T 23 27 GABA ABBREVIATION 23392755 A 1012 1015 GHB ABBREVIATION 23392755 A 1020 1023 GBL ABBREVIATION 23392755 A 103 120 γ-hydroxybutyrate SYSTEMATIC 23392755 A 1030 1039 l-lactate TRIVIAL 23392755 A 1050 1053 GHB ABBREVIATION 23392755 A 122 125 GHB ABBREVIATION 23392755 A 1251 1254 GHB ABBREVIATION 23392755 A 1366 1375 l-lactate TRIVIAL 23392755 A 1413 1416 GHB ABBREVIATION 23392755 A 145 160 γ-butyrolactone SYSTEMATIC 23392755 A 1456 1465 l-lactate TRIVIAL 23392755 A 1581 1590 l-lactate TRIVIAL 23392755 A 162 165 GBL ABBREVIATION 23392755 A 1628 1631 GBL ABBREVIATION 23392755 A 1663 1672 l-lactate TRIVIAL 23392755 A 168 171 GHB ABBREVIATION 23392755 A 1735 1738 GHB ABBREVIATION 23392755 A 1743 1746 GBL ABBREVIATION 23392755 A 191 206 monocarboxylate SYSTEMATIC 23392755 A 243 246 GHB ABBREVIATION 23392755 A 277 280 GHB ABBREVIATION 23392755 A 357 360 GHB ABBREVIATION 23392755 A 361 364 GBL ABBREVIATION 23392755 A 393 396 GHB ABBREVIATION 23392755 A 401 404 GBL ABBREVIATION 23392755 A 600 603 GHB ABBREVIATION 23392755 A 608 611 GBL ABBREVIATION 23392755 A 643 652 l-lactate TRIVIAL 23392755 A 716 719 GHB ABBREVIATION 23392755 A 724 727 GBL ABBREVIATION 23392755 A 767 776 l-lactate TRIVIAL 23392755 A 899 908 l-lactate TRIVIAL 23392755 A 959 962 GHB ABBREVIATION 23392755 T 11 26 monocarboxylate SYSTEMATIC 23392755 T 117 132 γ-butyrolactone SYSTEMATIC 23392755 T 95 112 γ-hydroxybutyrate SYSTEMATIC 23392757 A 1199 1208 serotonin TRIVIAL 23392757 A 1279 1292 noradrenaline TRIVIAL 23392757 A 1475 1484 serotonin TRIVIAL 23392757 A 241 250 serotonin TRIVIAL 23392757 A 254 267 noradrenaline TRIVIAL 23392757 A 443 452 serotonin TRIVIAL 23392757 A 458 471 noradrenaline TRIVIAL 23392757 A 835 844 serotonin TRIVIAL 23392757 A 846 859 noradrenaline TRIVIAL 23392757 A 981 990 serotonin TRIVIAL 23392757 A 995 1008 noradrenaline TRIVIAL 23392757 T 82 91 serotonin TRIVIAL 23392757 T 96 109 noradrenaline TRIVIAL 23393127 A 101 105 cAMP ABBREVIATION 23393127 A 1079 1083 GnRH ABBREVIATION 23393127 A 1283 1287 GnRH ABBREVIATION 23393127 A 1504 1508 GnRH ABBREVIATION 23393127 A 1617 1621 GnRH ABBREVIATION 23393127 A 257 261 GnRH ABBREVIATION 23393127 A 410 414 GnRH ABBREVIATION 23393127 A 493 497 GnRH ABBREVIATION 23393127 A 638 641 H89 IDENTIFIER 23393127 A 67 71 GnRH ABBREVIATION 23393127 A 683 687 GnRH ABBREVIATION 23393127 A 728 732 GnRH ABBREVIATION 23393127 A 962 966 GnRH ABBREVIATION 23393127 T 0 4 GnRH ABBREVIATION 23393213 A 1331 1338 glucose TRIVIAL 23393218 A 663 670 glucose TRIVIAL 23393218 A 883 890 glucose TRIVIAL 23393220 A 0 32 5-Methoxy-N,N-dimethyltryptamine SYSTEMATIC 23393220 A 1020 1030 bufotenine TRIVIAL 23393220 A 1114 1123 harmaline TRIVIAL 23393220 A 1148 1158 bufotenine TRIVIAL 23393220 A 1200 1209 harmaline TRIVIAL 23393220 A 1230 1240 bufotenine TRIVIAL 23393220 A 137 154 indolealkylamines FAMILY 23393220 A 1403 1412 5-MeO-DMT SYSTEMATIC 23393220 A 1427 1436 harmaline TRIVIAL 23393220 A 1469 1478 harmaline TRIVIAL 23393220 A 1480 1489 5-MeO-DMT SYSTEMATIC 23393220 A 1495 1505 bufotenine TRIVIAL 23393220 A 1613 1622 harmaline TRIVIAL 23393220 A 1627 1636 5-MeO-DMT SYSTEMATIC 23393220 A 1717 1726 harmaline TRIVIAL 23393220 A 1727 1736 5-MeO-DMT SYSTEMATIC 23393220 A 215 224 monoamine FAMILY 23393220 A 253 262 harmaline TRIVIAL 23393220 A 304 313 5-MeO-DMT SYSTEMATIC 23393220 A 34 43 5-MeO-DMT SYSTEMATIC 23393220 A 393 402 harmaline TRIVIAL 23393220 A 407 416 5-MeO-DMT SYSTEMATIC 23393220 A 521 530 harmaline TRIVIAL 23393220 A 549 558 5-MeO-DMT SYSTEMATIC 23393220 A 559 560 O FORMULA 23393220 A 586 596 bufotenine TRIVIAL 23393220 A 60 65 5-MEO SYSTEMATIC 23393220 A 675 684 harmaline TRIVIAL 23393220 A 767 776 5-MeO-DMT SYSTEMATIC 23393220 A 848 857 5-MeO-DMT SYSTEMATIC 23393220 A 901 910 harmaline TRIVIAL 23393220 A 969 978 Harmaline TRIVIAL 23393220 T 37 46 Monoamine SYSTEMATIC 23393220 T 67 76 Harmaline TRIVIAL 23393220 T 81 113 5-Methoxy-N,N-Dimethyltryptamine SYSTEMATIC 23394067 A 14 24 polyesters FAMILY 23394067 A 695 703 acrylate SYSTEMATIC 23394067 T 14 23 Polyester FAMILY 23394134 A 123 144 zwitterionic siloxane FAMILY 23394134 A 282 301 zwitterion siloxane FAMILY 23394134 A 48 58 iron oxide SYSTEMATIC 23394134 T 100 122 zwitterated iron oxide SYSTEMATIC 23394284 A 103 117 kravanhins A-C MULTIPLE 23394284 A 11 23 diterpenoids FAMILY 23394284 A 129 140 kravanhin D TRIVIAL 23394284 A 160 178 labdane diterpenes FAMILY 23394284 A 266 287 isospongian diterpene FAMILY 23394284 A 41 63 tetracyclic diterpenes FAMILY 23394284 A 521 533 nitric oxide SYSTEMATIC 23394284 A 80 91 isospongian TRIVIAL 23394284 T 0 24 Tetracyclic diterpenoids FAMILY 23394284 T 41 52 isospongian TRIVIAL 23394284 T 66 86 labdane diterpenoids FAMILY 23394392 A 0 12 Methotrexate TRIVIAL 23394392 A 14 17 MTX ABBREVIATION 23394392 A 140 143 MTX ABBREVIATION 23394392 A 223 226 MTX ABBREVIATION 23394392 A 342 345 MTX ABBREVIATION 23394392 A 529 532 MTX ABBREVIATION 23394392 A 573 576 MTX ABBREVIATION 23394392 A 614 617 MTX ABBREVIATION 23394392 A 743 746 MTX ABBREVIATION 23394392 A 791 794 MTX ABBREVIATION 23394392 A 840 843 MTX ABBREVIATION 23394392 T 0 12 Methotrexate TRIVIAL 23394550 A 101 112 cyclohexane SYSTEMATIC 23394550 A 114 118 DMSO ABBREVIATION 23394550 A 120 127 ethanol SYSTEMATIC 23394550 A 133 146 ethyl acetate SYSTEMATIC 23394550 A 14 24 anthracene SYSTEMATIC 23394550 A 48 54 uracil TRIVIAL 23394550 A 501 505 (1)H FORMULA 23394550 A 570 578 hydrogen SYSTEMATIC 23394550 A 591 592 N FORMULA 23394550 A 605 611 uracil TRIVIAL 23394550 A 622 630 fluoride SYSTEMATIC 23394550 A 801 809 methanol SYSTEMATIC 23394550 T 107 115 fluoride SYSTEMATIC 23394550 T 40 46 uracil TRIVIAL 23394553 A 163 174 cholesterol TRIVIAL 23394553 A 331 342 cholesterol TRIVIAL 23394555 A 0 11 Thymidylate TRIVIAL 23394555 A 105 131 thymidine 5'-monophosphate SYSTEMATIC 23394555 A 133 137 dTMP TRIVIAL 23394555 A 158 161 ATP ABBREVIATION 23394555 A 166 172 Mg(2+) FORMULA 23394555 A 181 205 thymidine 5'-diphosphate SYSTEMATIC 23394555 A 207 211 dTDP TRIVIAL 23394555 A 241 266 thymidine 5'-triphosphate SYSTEMATIC 23394555 A 268 272 dTTP TRIVIAL 23394555 A 277 299 nucleoside-diphosphate FAMILY 23394555 A 46 56 pyrimidine SYSTEMATIC 23394555 A 576 586 nucleoside FAMILY 23394555 A 822 833 doxorubicin TRIVIAL 23394555 T 0 11 Thymidylate TRIVIAL 23394608 A 191 202 lipoic acid TRIVIAL 23394608 A 244 265 poly(ethylene glycol) SYSTEMATIC 23394608 A 719 730 glutathione TRIVIAL 23394608 A 851 866 carboxylic acid SYSTEMATIC 23394608 A 870 875 amine SYSTEMATIC 23394608 A 980 992 carbodiimide SYSTEMATIC 23394608 T 29 48 polyethylene glycol SYSTEMATIC 23394611 A 1128 1131 PbS FORMULA 23394611 A 21 24 PbS FORMULA 23394611 T 121 124 PbS FORMULA 23395169 A 0 10 Bile acids FAMILY 23395169 A 118 128 bile acids FAMILY 23395169 A 130 139 Bile acid FAMILY 23395169 A 300 309 bile acid FAMILY 23395169 A 32 43 cholesterol TRIVIAL 23395169 A 454 469 muricholic acid FAMILY 23395169 A 479 490 cholic acid TRIVIAL 23395169 A 662 673 cholesterol TRIVIAL 23395169 A 767 816 tauro-conjugated beta- and alpha-muricholic acids MULTIPLE 23395169 A 912 921 bile acid FAMILY 23395169 A 951 960 bile acid FAMILY 23395169 T 25 34 bile acid FAMILY 23395169 T 72 98 tauro-beta-muricholic acid TRIVIAL 23395171 A 1174 1180 Ca(2+) FORMULA 23395171 A 224 231 calcium SYSTEMATIC 23395171 A 234 240 Ca(2+) FORMULA 23395171 A 309 315 Ca(2+) FORMULA 23395171 A 447 453 Ca(2+) FORMULA 23395171 A 721 727 Ca(2+) FORMULA 23395171 A 846 852 Ca(2+) FORMULA 23395171 A 895 901 Ca(2+) FORMULA 23395171 T 17 24 calcium SYSTEMATIC 23395172 A 1058 1062 iron SYSTEMATIC 23395172 A 231 235 iron SYSTEMATIC 23395172 A 291 295 heme FAMILY 23395172 A 400 404 heme FAMILY 23395172 A 457 461 iron SYSTEMATIC 23395172 A 489 493 heme FAMILY 23395172 A 752 756 heme FAMILY 23395172 A 871 875 heme FAMILY 23395172 A 930 934 heme FAMILY 23395172 A 951 955 heme FAMILY 23395172 A 956 960 iron SYSTEMATIC 23395172 T 22 26 heme FAMILY 23395259 A 1291 1314 ethyl 2-methylbutanoate SYSTEMATIC 23395259 A 1316 1329 butyl acetate SYSTEMATIC 23395259 A 1331 1340 1-butanol SYSTEMATIC 23395259 A 1342 1357 ethyl hexanoate SYSTEMATIC 23395259 A 1359 1368 1-hexanol SYSTEMATIC 23395259 A 1370 1383 butanoic acid SYSTEMATIC 23395259 A 1385 1398 β-damascenone TRIVIAL 23395259 A 1400 1413 hexanoic acid SYSTEMATIC 23395259 A 1419 1432 octanoic acid SYSTEMATIC 23395668 A 1211 1226 bisphosphonates FAMILY 23395668 A 241 255 hydroxyapatite TRIVIAL 23395668 A 257 272 bisphosphonates FAMILY 23395668 A 42 57 bisphosphonates FAMILY 23395668 A 971 986 bisphosphonates FAMILY 23395668 T 27 42 bisphosphonates FAMILY 23395669 A 0 12 Sophocarpine TRIVIAL 23395669 A 1068 1080 sophocarpine TRIVIAL 23395669 A 1378 1390 sophocarpine TRIVIAL 23395669 A 435 445 oleic acid TRIVIAL 23395669 A 499 511 sophocarpine TRIVIAL 23395669 A 841 853 sophocarpine TRIVIAL 23395669 T 0 12 Sophocarpine TRIVIAL 23395695 A 282 307 2,4,-dinitrofluorobenzene SYSTEMATIC 23395695 A 309 313 DNFB ABBREVIATION 23395695 A 428 432 DNFB ABBREVIATION 23395695 A 817 846 cyclobutane pyrimidine dimers FAMILY 23395695 A 848 852 CPDs FAMILY 23395696 A 0 10 Oxysterols FAMILY 23395696 A 220 226 oxygen SYSTEMATIC 23395696 A 33 44 cholesterol TRIVIAL 23395696 A 331 341 oxysterols FAMILY 23395696 A 360 371 cholesterol TRIVIAL 23395696 A 445 455 Oxysterols FAMILY 23395696 A 612 622 oxysterols FAMILY 23395696 A 788 798 oxysterols FAMILY 23395696 A 815 826 cholesterol TRIVIAL 23395696 A 830 836 oxygen SYSTEMATIC 23395696 A 923 932 oxysterol FAMILY 23395696 T 12 21 oxysterol FAMILY 23395804 A 1076 1081 Cl(-) FORMULA 23395804 A 414 419 Na(+) FORMULA 23395804 A 420 425 Cl(-) FORMULA 23395804 A 459 464 Na(+) FORMULA 23395804 A 465 469 H(+) FORMULA 23395804 A 514 520 Ca(2+) FORMULA 23395804 T 52 55 Na+ FORMULA 23395804 T 56 59 Cl- FORMULA 23395821 A 1177 1188 decapeptide FAMILY 23395821 A 337 347 amino acid FAMILY 23395821 A 440 441 N FORMULA 23395967 A 1114 1117 aza SYSTEMATIC 23395967 A 242 263 meglumine antimoniate TRIVIAL 23395967 A 265 275 Glucantime TRIVIAL 23395967 A 554 556 Fe FORMULA 23395967 A 650 654 CuZn FORMULA 23395967 A 663 665 Mn FORMULA 23395967 A 909 913 (1)H FORMULA 23395981 A 179 186 alcohol FAMILY 23395981 A 310 317 alcohol FAMILY 23395981 A 424 434 methyl CpG SYSTEMATIC 23395981 A 6 13 alcohol FAMILY 23395981 A 619 626 ethanol SYSTEMATIC 23395981 A 641 648 ethanol SYSTEMATIC 23395981 A 742 752 methyl CpG SYSTEMATIC 23395981 A 944 950 MG-132 IDENTIFIER 23395981 T 0 7 Alcohol SYSTEMATIC 23395981 T 58 68 methyl CpG SYSTEMATIC 23395981 T 70 73 CpG ABBREVIATION 23396053 A 1403 1411 pregnane TRIVIAL 23396053 A 1424 1440 aryl hydrocarbon FAMILY 23396053 A 1466 1476 androstane TRIVIAL 23396138 A 1177 1180 BZA ABBREVIATION 23396138 A 1312 1316 PAHs ABBREVIATION 23396138 A 288 292 PAHs ABBREVIATION 23396138 A 29 61 polycyclic aromatic hydrocarbons FAMILY 23396138 A 427 430 PAH ABBREVIATION 23396138 A 431 445 benzanthracene SYSTEMATIC 23396138 A 447 450 BZA ABBREVIATION 23396138 A 592 595 BZA ABBREVIATION 23396138 A 63 67 PAHs ABBREVIATION 23396138 A 659 662 BZA ABBREVIATION 23396138 A 793 796 BZA ABBREVIATION 23396138 A 872 888 aryl hydrocarbon FAMILY 23396138 A 931 934 PAH ABBREVIATION 23396138 T 100 114 benzanthracene SYSTEMATIC 23396185 A 1011 1018 ONOO(-) FORMULA 23396185 A 1110 1118 pyruvate TRIVIAL 23396185 A 1219 1234 poly ADP ribose FAMILY 23396185 A 1383 1392 Quercetin TRIVIAL 23396185 A 1559 1572 peroxynitrite SYSTEMATIC 23396185 A 1795 1804 flavonoid FAMILY 23396185 A 402 411 Quercetin TRIVIAL 23396185 A 617 621 H2O2 FORMULA 23396185 A 681 690 Quercetin TRIVIAL 23396185 A 692 696 H2O2 FORMULA 23396185 A 821 832 glutathione TRIVIAL 23396185 A 941 948 nitrite SYSTEMATIC 23396185 A 950 956 NO2(-) FORMULA 23396185 A 962 972 superoxide TRIVIAL 23396185 A 980 985 O2(-) FORMULA 23396185 A 996 1009 peroxynitrite SYSTEMATIC 23396185 T 0 9 Quercetin TRIVIAL 23396185 T 78 95 hydrogen peroxide SYSTEMATIC 23396488 A 1220 1223 BFA ABBREVIATION 23396488 A 1714 1717 BFA ABBREVIATION 23396488 A 230 231 N FORMULA 23396488 A 397 408 brefeldin A TRIVIAL 23396488 A 410 413 BFA ABBREVIATION 23396488 A 714 717 BFA ABBREVIATION 23397054 A 108 117 elacridar TRIVIAL 23397054 A 1112 1121 elacridar TRIVIAL 23397054 A 1185 1194 elacridar TRIVIAL 23397054 A 119 128 Elacridar TRIVIAL 23397054 A 1224 1233 elacridar TRIVIAL 23397054 A 1743 1752 elacridar TRIVIAL 23397054 A 352 361 elacridar TRIVIAL 23397054 A 602 611 elacridar TRIVIAL 23397054 A 770 779 elacridar TRIVIAL 23397054 A 897 906 elacridar TRIVIAL 23397054 T 141 150 elacridar TRIVIAL 23398051 A 0 8 Hematite TRIVIAL 23398051 A 170 177 Co(OH)2 FORMULA 23398051 A 178 183 Co3O4 FORMULA 23398051 A 452 457 Fe2O3 FORMULA 23398051 A 458 461 H2O FORMULA 23398051 A 51 63 cobalt oxide SYSTEMATIC 23398051 A 528 535 Co(OH)2 FORMULA 23398051 A 536 541 Co3O4 FORMULA 23398051 A 727 735 hematite TRIVIAL 23398051 T 125 133 hematite TRIVIAL 23398173 A 1009 1012 C-O FORMULA 23398173 A 108 122 chloromethanol SYSTEMATIC 23398173 A 89 102 chlorocarbene SYSTEMATIC 23398173 T 58 66 carbenes FAMILY 23398189 A 1204 1207 SDS ABBREVIATION 23398189 A 1218 1222 CTAB ABBREVIATION 23398189 A 1353 1357 CTAB ABBREVIATION 23398189 A 1855 1859 DOPC ABBREVIATION 23398189 A 1861 1901 1,2-dioleoyl-sn-glycero-3-phosphocholine SYSTEMATIC 23398189 A 1904 1908 SOPC ABBREVIATION 23398189 A 1910 1944 stearoyl-oleoylphosphatidylcholine TRIVIAL 23398189 A 1947 1951 DMPC ABBREVIATION 23398189 A 1953 1996 1,2-dimyristoyl-sn-glycero-3-phosphocholine SYSTEMATIC 23398189 A 2003 2007 POPC ABBREVIATION 23398189 A 2009 2057 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine SYSTEMATIC 23398189 A 2238 2249 cholesterol TRIVIAL 23398189 A 2339 2350 cholesterol TRIVIAL 23398356 A 0 6 Quartz TRIVIAL 23398356 A 1010 1016 Al-PAM FORMULA 23398356 A 1097 1103 MF1011 IDENTIFIER 23398356 A 114 128 polyacrylamide SYSTEMATIC 23398356 A 1165 1174 kaolinite TRIVIAL 23398356 A 145 149 PAMs FAMILY 23398356 A 182 191 kaolinite TRIVIAL 23398356 A 193 202 Kaolinite TRIVIAL 23398356 A 250 259 kaolinite TRIVIAL 23398356 A 284 290 silica TRIVIAL 23398356 A 295 302 alumina TRIVIAL 23398356 A 405 416 Al(OH)3-PAM FORMULA 23398356 A 418 424 Al-PAM FORMULA 23398356 A 459 462 PAM ABBREVIATION 23398356 A 513 527 polyacrylamide SYSTEMATIC 23398356 A 529 535 MF1011 IDENTIFIER 23398356 A 554 565 anionic PAM ABBREVIATION 23398356 A 579 594 Cationic Al-PAM ABBREVIATION 23398356 A 662 668 silica TRIVIAL 23398356 A 685 694 kaolinite TRIVIAL 23398356 A 709 723 anionic MF1011 IDENTIFIER 23398356 A 745 761 aluminum-hydroxy SYSTEMATIC 23398356 A 812 818 silica TRIVIAL 23398356 A 922 930 hydrogen SYSTEMATIC 23398356 A 978 982 PAMs FAMILY 23398356 A 986 995 kaolinite TRIVIAL 23398356 T 22 36 polyacrylamide SYSTEMATIC 23398356 T 83 92 kaolinite TRIVIAL 23398356 T 99 105 quartz TRIVIAL 23398572 A 1078 1080 Pt FORMULA 23398572 A 12 25 glassy carbon TRIVIAL 23398572 A 205 211 oxygen SYSTEMATIC 23398572 A 38 43 Pt(n) FAMILY 23398572 A 488 490 Pt FORMULA 23398572 A 593 595 Pt FORMULA 23398572 A 6 11 Pt(n) FAMILY 23398572 A 642 647 Pt(n) FAMILY 23398572 A 741 747 carbon SYSTEMATIC 23398572 A 842 848 carbon SYSTEMATIC 23398572 A 94 102 Pt(n)(+) FAMILY 23398572 T 123 128 Pt(n) FAMILY 23398572 T 141 154 glassy carbon TRIVIAL 23398572 T 51 57 oxygen SYSTEMATIC 23398572 T 72 78 carbon SYSTEMATIC 23399444 A 1296 1303 lactate FAMILY 23399444 A 1539 1546 lactate FAMILY 23399444 A 155 171 selenomethionine SYSTEMATIC 23399444 A 1599 1604 SeMet FORMULA 23399444 A 1641 1643 Se FORMULA 23399444 A 1688 1690 Se FORMULA 23399444 A 173 178 SeMet FORMULA 23399444 A 1785 1791 Oxygen SYSTEMATIC 23399444 A 1892 1897 SeMet FORMULA 23399444 A 1910 1923 triglycerides FAMILY 23399444 A 1966 1971 SeMet FORMULA 23399444 A 2071 2076 SeMet FORMULA 23399444 A 2148 2153 SeMet FORMULA 23399444 A 2209 2217 tyrosine TRIVIAL 23399444 A 2257 2281 β-hydroxyacyl coenzyme A SYSTEMATIC 23399444 A 2304 2310 sterol FAMILY 23399444 A 2362 2372 methionine TRIVIAL 23399444 A 2520 2525 SeMet FORMULA 23399444 A 277 282 SeMet FORMULA 23399444 A 315 321 oxygen SYSTEMATIC 23399444 A 528 538 methionine TRIVIAL 23399444 A 592 597 SeMet FORMULA 23399444 A 653 655 Se FORMULA 23399444 A 908 921 triglycerides FAMILY 23399444 A 936 943 lactate FAMILY 23399444 A 990 1000 methionine TRIVIAL 23399444 T 108 118 methionine TRIVIAL 23399444 T 27 43 selenomethionine SYSTEMATIC 23400048 A 1043 1051 carboxyl SYSTEMATIC 23400048 A 1091 1092 H FORMULA 23400048 A 1130 1139 dialanine TRIVIAL 23400048 A 1279 1284 amide FAMILY 23400048 A 67 83 methyl-dialanine SYSTEMATIC 23400048 A 696 705 dialanine TRIVIAL 23400048 A 775 783 hydrogen SYSTEMATIC 23400048 A 798 806 carboxyl SYSTEMATIC 23400048 A 811 816 amide FAMILY 23400048 A 85 102 C(7)H(14)N(2)O(3) FORMULA 23400048 T 37 46 dialanine TRIVIAL 23400254 A 112 114 Au FORMULA 23400254 A 374 382 graphene TRIVIAL 23400254 T 35 43 graphene TRIVIAL 23400750 A 1004 1010 ketone SYSTEMATIC 23400750 A 1057 1072 2-butyl acetate SYSTEMATIC 23400750 A 1074 1090 2-pentyl acetate SYSTEMATIC 23400750 A 1141 1159 isopropyl butyrate SYSTEMATIC 23400750 A 1161 1178 2-pentyl butyrate SYSTEMATIC 23400750 A 160 165 ester FAMILY 23400750 A 220 227 alcohol FAMILY 23400750 A 232 238 ketone SYSTEMATIC 23400750 A 468 483 2-butyl acetate SYSTEMATIC 23400750 A 485 501 2-pentyl acetate SYSTEMATIC 23400750 A 503 521 isopropyl butyrate SYSTEMATIC 23400750 A 526 543 2-pentyl butyrate SYSTEMATIC 23400750 A 591 600 tenofovir TRIVIAL 23400750 A 991 998 alcohol FAMILY 23400848 A 1124 1136 Voriconazole TRIVIAL 23400848 A 1255 1267 voriconazole TRIVIAL 23400848 A 1489 1501 voriconazole TRIVIAL 23400848 A 193 205 voriconazole TRIVIAL 23400848 A 323 335 voriconazole TRIVIAL 23400848 A 448 460 voriconazole TRIVIAL 23400848 A 525 537 voriconazole TRIVIAL 23400848 A 610 622 voriconazole TRIVIAL 23400848 A 818 830 voriconazole TRIVIAL 23400848 A 92 104 voriconazole TRIVIAL 23400848 A 937 949 voriconazole TRIVIAL 23400848 T 32 44 voriconazole TRIVIAL 23401165 A 1020 1031 thioarsenic SYSTEMATIC 23401165 A 1081 1088 arsenic SYSTEMATIC 23401165 A 1101 1108 sulfide SYSTEMATIC 23401165 A 1191 1198 arsenic SYSTEMATIC 23401165 A 1273 1280 uranium SYSTEMATIC 23401165 A 1314 1325 bicarbonate SYSTEMATIC 23401165 A 1364 1371 arsenic SYSTEMATIC 23401165 A 166 178 uranium (VI) SYSTEMATIC 23401165 A 234 246 uranium (IV) SYSTEMATIC 23401165 A 416 420 iron SYSTEMATIC 23401165 A 422 428 sulfur SYSTEMATIC 23401165 A 434 441 arsenic SYSTEMATIC 23401165 A 453 460 acetate SYSTEMATIC 23401165 A 511 518 arsenic SYSTEMATIC 23401165 A 651 658 arsenic SYSTEMATIC 23401165 A 704 711 acetate SYSTEMATIC 23401165 A 734 741 arsenic SYSTEMATIC 23401165 A 776 784 arsenate SYSTEMATIC 23401165 A 786 791 As[V] FORMULA 23401165 A 815 823 arsenite SYSTEMATIC 23401165 A 825 832 As[III] FORMULA 23401165 A 848 855 acetate SYSTEMATIC 23401165 A 907 914 arsenic SYSTEMATIC 23401165 A 946 957 thioarsenic SYSTEMATIC 23401165 A 985 992 sulfate SYSTEMATIC 23401165 T 0 7 Arsenic SYSTEMATIC 23401173 A 0 7 Cubebin TRIVIAL 23401173 A 1052 1097 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one SYSTEMATIC 23401173 A 1099 1102 ODQ ABBREVIATION 23401173 A 1136 1147 (-)-Cubebin TRIVIAL 23401173 A 1275 1281 L-NAME ABBREVIATION 23401173 A 1286 1289 ODQ ABBREVIATION 23401173 A 1304 1316 indomethacin TRIVIAL 23401173 A 1331 1342 (-)-cubebin TRIVIAL 23401173 A 1362 1365 Phe FORMULA 23401173 A 1434 1445 (-)-cubebin TRIVIAL 23401173 A 1474 1476 NO FORMULA 23401173 A 1477 1481 cGMP ABBREVIATION 23401173 A 1512 1524 prostacyclin TRIVIAL 23401173 A 256 267 (-)-cubebin TRIVIAL 23401173 A 27 33 lignan FAMILY 23401173 A 317 330 phenylephrine TRIVIAL 23401173 A 332 335 Phe FORMULA 23401173 A 450 463 acetylcholine SYSTEMATIC 23401173 A 468 479 (-)-cubebin TRIVIAL 23401173 A 565 585 sodium nitroprusside SYSTEMATIC 23401173 A 590 601 (-)-cubebin TRIVIAL 23401173 A 665 668 Phe FORMULA 23401173 A 803 814 (-)-cubebin TRIVIAL 23401173 A 901 933 Nω-nitro-L-arginine methyl ester SYSTEMATIC 23401173 A 935 941 L-NAME ABBREVIATION 23401173 A 959 971 nitric oxide SYSTEMATIC 23401173 A 993 1005 indomethacin TRIVIAL 23401173 T 11 22 (-)-Cubebin TRIVIAL 23401173 T 4 10 Lignan FAMILY 23401173 T 80 92 Nitric Oxide SYSTEMATIC 23401228 A 102 113 [6]-shogaol TRIVIAL 23401228 A 1151 1162 [6]-shogaol TRIVIAL 23401228 A 1234 1243 H(2) O(2) FORMULA 23401228 A 1316 1327 [6]-shogaol TRIVIAL 23401228 A 1482 1493 [6]-shogaol TRIVIAL 23401228 A 306 317 [6]-shogaol TRIVIAL 23401228 A 470 481 [6]-shogaol TRIVIAL 23401228 A 518 535 hydrogen peroxide SYSTEMATIC 23401228 A 537 546 H(2) O(2) FORMULA 23401228 A 745 756 [6]-shogaol TRIVIAL 23401228 A 761 770 H(2) O(2) FORMULA 23401228 A 807 813 oxygen SYSTEMATIC 23401228 A 871 880 H(2) O(2) FORMULA 23401228 A 893 904 [6]-shogaol TRIVIAL 23401228 A 954 963 H(2) O(2) FORMULA 23401228 T 0 11 [6]-Shogaol SYSTEMATIC 23401228 T 45 62 Hydrogen Peroxide SYSTEMATIC 23401280 A 237 245 methanol SYSTEMATIC 23401280 A 503 522 labdane diterpenoid FAMILY 23401280 A 537 550 otostegindiol TRIVIAL 23401280 A 552 565 Otostegindiol TRIVIAL 23401280 A 965 978 otostegindiol TRIVIAL 23401280 T 35 54 Labdane Diterpenoid FAMILY 23401298 A 160 222 [(MnMo(6) O(18) )((OCH(2) )(3) C-NHCH(2) C(16) H(9) )(2) ](3-) FORMULA 23401298 A 237 340 [(MnMo(6) O(18) )((OCH(2) )(3) C-(CH(2) )(7) CHCH(2) )(1) ((OCH(2) )(3) C-NHCH(2) C(16) H(9) )(1) ](3-) FORMULA 23401298 A 27 29 Mn FORMULA 23401298 A 355 418 [(MnMo(6) O(18) )((OCH(2) )(3) C-NHC(O)CH(2) CHCH(2) )(2) ](3-) FORMULA 23401298 A 39 55 polyoxometalates FAMILY 23401298 A 438 501 [(MnMo(6) O(18) )((OCH(2) )(3) C-NHC(O)(CH(2) )(x) CH(3) )(2) ] FAMILY 23401298 A 438 502 [(MnMo(6) O(18) )((OCH(2) )(3) C-NHC(O)(CH(2) )(x) CH(3) )(2) ]) FORMULA 23401298 A 625 628 TBA ABBREVIATION 23401298 A 637 642 DMDOA ABBREVIATION 23401298 A 697 719 tetraphenylphosphonium SYSTEMATIC 23401298 A 721 727 PPh(4) FORMULA 23401298 A 81 145 [(MnMo(6) O(18) )((OCH(2) )(3) -C-(CH(2) )(7) CHCH(2) )(2) ](3-) FORMULA 23401298 T 112 114 Mn FORMULA 23401298 T 96 111 Polyoxometalate FAMILY 23401474 A 1012 1022 omeprazole TRIVIAL 23401474 A 1035 1045 omeprazole TRIVIAL 23401474 A 1046 1061 5-OH-omeprazole SYSTEMATIC 23401474 A 1096 1106 omeprazole TRIVIAL 23401474 A 1107 1122 5-OH-omeprazole SYSTEMATIC 23401474 A 1260 1270 omeprazole TRIVIAL 23401474 A 397 405 caffeine TRIVIAL 23401474 A 423 434 tolbutamide TRIVIAL 23401474 A 451 461 omeprazole TRIVIAL 23401474 A 479 499 dextromethorphan-HBr FORMULA 23401474 A 519 528 midazolam TRIVIAL 23401474 A 929 939 omeprazole TRIVIAL 23402292 A 0 45 Poly(lactic acid)-block-poly(ethylene glycol) FAMILY 23402292 A 1053 1056 PLA ABBREVIATION 23402292 A 1382 1411 tin(II) bis(2-ethylhexanoate) SYSTEMATIC 23402292 A 141 144 PLA ABBREVIATION 23402292 A 1416 1430 aluminum salan SYSTEMATIC 23402292 A 1441 1450 PLA-b-PEG ABBREVIATION 23402292 A 1508 1522 aluminum salen SYSTEMATIC 23402292 A 1533 1542 PLA-b-PEG ABBREVIATION 23402292 A 1622 1628 pyrene SYSTEMATIC 23402292 A 262 291 tin(II) bis(2-ethylhexanoate) SYSTEMATIC 23402292 A 293 307 aluminum salan SYSTEMATIC 23402292 A 313 327 aluminum salen SYSTEMATIC 23402292 A 442 460 l- and rac-lactide MULTIPLE 23402292 A 467 500 monomethoxy-poly(ethylene glycol) FAMILY 23402292 A 58 67 PLA-b-PEG ABBREVIATION 23402292 A 655 661 pyrene SYSTEMATIC 23402292 A 733 769 1,5,7-triaza-bicyclo[4.4.0]dec-5-ene SYSTEMATIC 23402292 A 806 810 (1)H FORMULA 23402292 T 77 122 poly(lactic acid)-block-poly(ethylene glycol) FAMILY 23402546 A 1153 1162 metformin TRIVIAL 23402546 A 1260 1271 vitamin B12 TRIVIAL 23402546 A 130 141 vitamin B12 TRIVIAL 23402546 A 1333 1342 metformin TRIVIAL 23402546 A 146 158 homocysteine TRIVIAL 23402546 A 1487 1496 metformin TRIVIAL 23402546 A 160 163 Hcy ABBREVIATION 23402546 A 1619 1628 metformin TRIVIAL 23402546 A 264 273 metformin TRIVIAL 23402546 A 333 342 metformin TRIVIAL 23402546 A 400 411 vitamin B12 TRIVIAL 23402546 A 495 498 Hcy ABBREVIATION 23402546 A 55 64 metformin TRIVIAL 23402546 A 655 658 Hcy ABBREVIATION 23402546 A 747 753 folate TRIVIAL 23402546 A 855 861 folate TRIVIAL 23402546 A 945 954 metformin TRIVIAL 23402546 A 988 997 metformin TRIVIAL 23402546 T 0 11 Vitamin B12 TRIVIAL 23402546 T 123 132 metformin TRIVIAL 23402546 T 16 28 homocysteine TRIVIAL 23402546 T 60 69 metformin TRIVIAL 23402652 A 110 117 thymine TRIVIAL 23402652 A 98 105 adenine TRIVIAL 23402729 A 1100 1108 boehmite TRIVIAL 23402729 A 510 518 boehmite TRIVIAL 23402729 A 534 558 aluminum oxide hydroxide SYSTEMATIC 23402729 A 560 567 AlO(OH) FORMULA 23402729 A 623 631 boehmite TRIVIAL 23402729 A 961 969 boehmite TRIVIAL 23402729 A 988 996 boehmite TRIVIAL 23402729 T 133 146 alumina oxide SYSTEMATIC 23402735 A 4 7 CoA ABBREVIATION 23402735 A 85 96 cholesterol TRIVIAL 23402788 A 0 4 H2O2 FORMULA 23402788 A 1059 1063 H2O2 FORMULA 23402788 A 1117 1121 H2O2 FORMULA 23402788 A 1325 1334 Carnitine TRIVIAL 23402788 A 1339 1354 acetylcarnitine SYSTEMATIC 23402788 A 1400 1404 H2O2 FORMULA 23402788 A 1460 1464 H2O2 FORMULA 23402788 A 1476 1485 carnitine TRIVIAL 23402788 A 1527 1531 H2O2 FORMULA 23402788 A 1635 1645 disulphide SYSTEMATIC 23402788 A 18 33 [(3)H]carnitine SYSTEMATIC 23402788 A 185 201 dithioerythritol SYSTEMATIC 23402788 A 203 219 N-acetylcysteine SYSTEMATIC 23402788 A 224 234 l-cysteine TRIVIAL 23402788 A 34 43 carnitine TRIVIAL 23402788 A 429 432 Cys FORMULA 23402788 A 468 471 Ser FORMULA 23402788 A 480 483 Val ABBREVIATION 23402788 A 811 814 Cys FORMULA 23402788 A 84 93 carnitine TRIVIAL 23402788 A 897 900 DTE ABBREVIATION 23402788 A 932 936 H2O2 FORMULA 23402788 A 94 107 acylcarnitine SYSTEMATIC 23402788 T 28 37 carnitine TRIVIAL 23402788 T 38 51 acylcarnitine SYSTEMATIC 23402788 T 67 71 H2O2 FORMULA 23402841 A 1049 1052 STX ABBREVIATION 23402841 A 1229 1235 oxygen SYSTEMATIC 23402841 A 1306 1309 GSH ABBREVIATION 23402841 A 1439 1442 STX ABBREVIATION 23402841 A 154 157 STX ABBREVIATION 23402841 A 23 33 saxitoxins FAMILY 23402841 A 35 38 STX ABBREVIATION 23402841 A 394 397 STX ABBREVIATION 23402841 A 408 420 neosaxitoxin TRIVIAL 23402841 A 425 436 gonyautoxin FAMILY 23402841 A 519 529 superoxide TRIVIAL 23402841 A 563 574 glutathione TRIVIAL 23402841 A 600 611 glutathione TRIVIAL 23402841 A 652 671 reduced glutathione TRIVIAL 23402841 A 673 676 GSH ABBREVIATION 23402841 T 83 92 saxitoxin TRIVIAL 23402861 A 105 116 nitric acid SYSTEMATIC 23402861 A 1094 1105 nitric acid SYSTEMATIC 23402861 A 325 336 nitric acid SYSTEMATIC 23402861 A 356 367 Nitric acid SYSTEMATIC 23402861 A 479 481 Mo FORMULA 23402861 A 483 485 Sn FORMULA 23402861 A 487 489 Sb FORMULA 23402861 A 491 493 Tl FORMULA 23402861 A 498 500 Th FORMULA 23402861 A 815 817 Al FORMULA 23402861 A 819 821 Ba FORMULA 23402861 A 826 828 Pb FORMULA 23402861 T 41 52 nitric acid SYSTEMATIC 23402862 A 1063 1072 hydroxyls FAMILY 23402862 A 1080 1087 benzene SYSTEMATIC 23402862 A 345 355 quinacrine TRIVIAL 23402862 A 381 390 etoposide TRIVIAL 23402862 A 398 408 flavonoids FAMILY 23402862 A 410 414 EGCG ABBREVIATION 23402862 A 422 430 curcumin TRIVIAL 23402862 A 438 446 apigenin TRIVIAL 23402862 A 457 466 quercetin TRIVIAL 23402862 A 623 632 etoposide TRIVIAL 23402862 A 764 774 Pyrogallol TRIVIAL 23402862 A 797 804 tannins FAMILY 23402862 A 879 889 pyrogallol TRIVIAL 23402862 A 897 914 3-methoxycatechol SYSTEMATIC 23402862 A 922 933 gallic acid TRIVIAL 23402862 A 945 963 1,2,4-benzenetriol SYSTEMATIC 23402880 A 175 191 7-methylindazole SYSTEMATIC 23402880 A 20 28 indazole SYSTEMATIC 23402880 A 282 290 indazole SYSTEMATIC 23402880 A 33 46 benzoxazolone SYSTEMATIC 23402880 A 47 58 amino acids FAMILY 23402880 A 80 90 d-tyrosine TRIVIAL 23402880 T 98 106 tyrosine TRIVIAL 23403012 A 238 257 dicalcium phosphate SYSTEMATIC 23403012 A 259 262 DCP ABBREVIATION 23403012 A 314 321 lactose TRIVIAL 23403012 A 495 503 coumarin TRIVIAL 23403012 A 505 508 COU ABBREVIATION 23403012 A 514 539 propranolol hydrochloride SYSTEMATIC 23403012 A 541 544 PRO ABBREVIATION 23403012 A 622 625 DCP ABBREVIATION 23403012 A 998 1001 DCP ABBREVIATION 23403014 A 105 118 carbamazepine TRIVIAL 23403014 A 1108 1121 EUDRAGIT E PO FAMILY 23403014 A 1198 1205 PVP K30 TRIVIAL 23403014 A 124 133 celecoxib TRIVIAL 23403014 A 80 90 felodipine TRIVIAL 23403014 A 92 103 fenofibrate TRIVIAL 23403016 A 1222 1225 GSH ABBREVIATION 23403016 A 1359 1363 EDTA ABBREVIATION 23403016 A 1403 1407 TETA ABBREVIATION 23403016 A 1527 1531 TETA ABBREVIATION 23403016 A 375 395 triethylenetetramine SYSTEMATIC 23403016 A 397 401 TETA ABBREVIATION 23403016 A 404 423 reduced glutathione TRIVIAL 23403016 A 424 427 GSH ABBREVIATION 23403016 A 433 465 ethylenediamine tetraacetic acid SYSTEMATIC 23403016 A 467 471 EDTA ABBREVIATION 23403016 A 51 57 Cu(2+) FORMULA 23403016 A 58 67 ascorbate TRIVIAL 23403016 A 594 600 Cu(2+) FORMULA 23403016 A 609 622 ascorbic acid TRIVIAL 23403016 A 698 702 TETA ABBREVIATION 23403016 A 704 708 EDTA ABBREVIATION 23403016 A 713 716 GSH ABBREVIATION 23403016 A 907 911 TETA ABBREVIATION 23403016 T 0 20 Triethylenetetramine SYSTEMATIC 23403016 T 75 81 copper SYSTEMATIC 23403058 A 1006 1015 iberverin TRIVIAL 23403058 A 1017 1023 iberin TRIVIAL 23403058 A 1028 1037 cheirolin TRIVIAL 23403058 A 152 164 sulforaphane TRIVIAL 23403058 A 261 273 sulforaphane TRIVIAL 23403058 A 294 303 iberverin TRIVIAL 23403058 A 305 311 iberin TRIVIAL 23403058 A 316 325 cheirolin TRIVIAL 23403058 A 420 435 isothiocyanates FAMILY 23403058 A 436 445 iberverin TRIVIAL 23403058 A 447 453 iberin TRIVIAL 23403058 A 458 467 cheirolin TRIVIAL 23403058 A 564 573 Iberverin TRIVIAL 23403058 A 575 581 iberin TRIVIAL 23403058 A 586 595 cheirolin TRIVIAL 23403058 A 755 773 γ-glutamylcysteine SYSTEMATIC 23403058 A 826 835 iberverin TRIVIAL 23403058 A 837 843 iberin TRIVIAL 23403058 A 848 857 cheirolin TRIVIAL 23403058 A 889 901 sulforaphane TRIVIAL 23403058 T 44 59 isothiocyanates FAMILY 23403058 T 60 69 iberverin TRIVIAL 23403058 T 71 77 iberin TRIVIAL 23403058 T 82 91 cheirolin TRIVIAL 23403092 A 0 14 Trichothecenes FAMILY 23403092 A 1147 1150 DON ABBREVIATION 23403092 A 393 396 DON ABBREVIATION 23403092 A 562 565 DON ABBREVIATION 23403092 A 592 595 DON ABBREVIATION 23403092 A 737 740 DON ABBREVIATION 23403092 A 812 815 DON ABBREVIATION 23403092 A 845 848 DON ABBREVIATION 23403092 T 21 35 deoxynivalenol TRIVIAL 23403203 A 0 8 Antofine TRIVIAL 23403203 A 1075 1081 Ca(2+) FORMULA 23403203 A 12 43 phenanthroindolizidine alkaloid FAMILY 23403203 A 1213 1221 antofine TRIVIAL 23403203 A 1244 1250 Ca(2+) FORMULA 23403203 A 1260 1268 BAPTA-AM ABBREVIATION 23403203 A 1354 1362 antofine TRIVIAL 23403203 A 1526 1534 antofine TRIVIAL 23403203 A 1626 1634 antofine TRIVIAL 23403203 A 255 263 antofine TRIVIAL 23403203 A 380 400 6-carboxyfluorescein SYSTEMATIC 23403203 A 505 513 antofine TRIVIAL 23403203 A 583 591 antofine TRIVIAL 23403203 A 792 800 antofine TRIVIAL 23403203 A 843 848 NH4Cl FORMULA 23403203 A 852 857 MG132 IDENTIFIER 23403203 T 0 8 Antofine TRIVIAL 23404092 A 1570 1579 ritonavir TRIVIAL 23404092 A 1588 1597 lopinavir TRIVIAL 23404092 A 1603 1613 atazanavir TRIVIAL 23404092 A 1663 1672 ritonavir TRIVIAL 23404092 A 1681 1690 darunavir TRIVIAL 23404092 A 1696 1706 saquinavir TRIVIAL 23404305 A 772 783 cholesterol TRIVIAL 23404305 A 796 806 creatinine TRIVIAL 23404505 A 1286 1287 C FORMULA 23404505 A 187 188 N FORMULA 23404505 A 194 195 C FORMULA 23404505 A 760 761 C FORMULA 23404505 A 952 953 N FORMULA 23404505 A 958 959 C FORMULA 23404733 A 0 21 11-Oxoetiocholanolone SYSTEMATIC 23404733 A 1064 1069 11-KT ABBREVIATION 23404733 A 1122 1127 11-KT ABBREVIATION 23404733 A 1156 1161 11-KT ABBREVIATION 23404733 A 1372 1381 11,17-DOA SYSTEMATIC 23404733 A 147 166 11-ketotestosterone SYSTEMATIC 23404733 A 1490 1495 11-KT ABBREVIATION 23404733 A 1526 1543 C19 O3 -androgens FAMILY 23404733 A 1551 1562 17ß-hydroxy SYSTEMATIC 23404733 A 1662 1670 cortisol TRIVIAL 23404733 A 168 173 11-KT ABBREVIATION 23404733 A 352 363 11-KT-3-CMO SYSTEMATIC 23404733 A 390 408 biotinylated 11-KT SYSTEMATIC 23404733 A 74 82 cortisol TRIVIAL 23404733 A 820 828 methanol SYSTEMATIC 23404733 A 879 884 11-KT ABBREVIATION 23404733 A 916 937 11,17-dioxoandrostane SYSTEMATIC 23404733 A 939 948 11,17-DOA SYSTEMATIC 23404733 T 25 44 11-ketotestosterone SYSTEMATIC 23404837 A 399 407 hydrogen SYSTEMATIC 23404837 A 525 533 phenolic FAMILY 23404837 A 637 649 desaspidinol TRIVIAL 23404837 A 651 665 syringaldehyde TRIVIAL 23404837 A 671 679 syringol TRIVIAL 23404837 A 946 957 formic acid SYSTEMATIC 23404837 A 963 971 hydrogen SYSTEMATIC 23404837 T 92 100 phenolic FAMILY 23404894 A 103 113 amino acid FAMILY 23404894 A 419 429 amino acid FAMILY 23406460 A 0 75 9-(5-O-α-D-galactopyranosyl)-D-arabinityl-1,3,7-trihydropurine-2,6,8-trione SYSTEMATIC 23406460 A 305 306 N FORMULA 23406460 A 427 437 arabinityl TRIVIAL 23406460 A 458 467 galactose TRIVIAL 23406460 A 587 596 galactose TRIVIAL 23406460 A 601 622 N-acetylgalactosamine SYSTEMATIC 23406460 T 51 58 UDP-Gal ABBREVIATION 23406497 A 973 979 FK-506 IDENTIFIER 23406515 A 509 512 H2O FORMULA 23406515 A 600 608 hydroxyl SYSTEMATIC 23406949 A 1116 1119 GSH ABBREVIATION 23406949 A 1241 1246 NO(3) FORMULA 23406949 A 1377 1382 NO(2) FORMULA 23406949 A 722 737 malondialdehyde TRIVIAL 23406949 A 739 742 MDA ABBREVIATION 23406949 A 748 767 reduced glutathione TRIVIAL 23406949 A 769 772 GSH ABBREVIATION 23406949 A 879 886 nitrite SYSTEMATIC 23406949 A 888 893 NO(2) FORMULA 23406949 A 899 906 nitrate SYSTEMATIC 23406949 A 908 913 NO(3) FORMULA 23406949 A 987 990 MDA ABBREVIATION 23406949 T 70 83 methyl esters FAMILY 23406955 A 100 135 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23406955 A 1016 1023 alanine TRIVIAL 23406955 A 1074 1084 tocopherol FAMILY 23406955 A 1151 1155 urea TRIVIAL 23406955 A 1157 1167 creatinine TRIVIAL 23406955 A 1244 1254 tocopherol FAMILY 23406955 A 137 141 TCDD ABBREVIATION 23406955 A 176 180 TCDD ABBREVIATION 23406955 A 271 281 tocopherol FAMILY 23406955 A 52 62 tocopherol FAMILY 23406955 A 669 673 TCDD ABBREVIATION 23406955 A 724 728 TCDD ABBREVIATION 23406955 A 946 957 cholesterol TRIVIAL 23406955 A 959 963 urea TRIVIAL 23406955 A 965 975 creatinine TRIVIAL 23406955 A 977 986 aspartate TRIVIAL 23406955 T 10 20 tocopherol FAMILY 23406955 T 92 127 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23406958 A 211 224 ethyl acetate SYSTEMATIC 23406958 A 248 258 chloroform TRIVIAL 23406958 A 381 389 n-hexane SYSTEMATIC 23406958 A 524 537 ethyl acetate SYSTEMATIC 23406958 A 574 584 chloroform TRIVIAL 23406958 A 619 627 n-hexane SYSTEMATIC 23406958 A 903 916 ethyl acetate SYSTEMATIC 23406958 A 921 931 chloroform TRIVIAL 23407741 A 102 106 phen ABBREVIATION 23407741 A 109 128 1,10-phenanthroline SYSTEMATIC 23407741 A 130 133 bpy ABBREVIATION 23407741 A 136 151 2,2'-bipyridine SYSTEMATIC 23407741 A 153 158 4idip SYSTEMATIC 23407741 A 161 203 4-indoleimidazo[4,5-f][1,10]phenanthroline SYSTEMATIC 23407741 A 4 29 ruthenium(ii) polypyridyl FAMILY 23407741 A 40 65 [Ru(phen)2(4idip)](ClO4)2 FORMULA 23407741 A 73 97 [Ru(bpy)2(4idip)](ClO4)2 FORMULA 23407741 A 944 953 ruthenium SYSTEMATIC 23407741 T 0 25 Ruthenium(II) polypyridyl FAMILY 23407781 A 1084 1115 2,5-dimethoxy-4-iodoamphetamine SYSTEMATIC 23407781 A 1117 1120 DOI ABBREVIATION 23407781 A 1158 1184 lysergic acid diethylamide SYSTEMATIC 23407781 A 1186 1189 LSD ABBREVIATION 23407781 A 1357 1372 (+)-amphetamine TRIVIAL 23407781 A 1403 1411 lisuride TRIVIAL 23407781 A 181 185 5-HT SYSTEMATIC 23407781 A 249 253 5-HT SYSTEMATIC 23407781 A 311 315 5-HT SYSTEMATIC 23408261 A 1013 1015 Pb FORMULA 23408261 A 1076 1078 Pb FORMULA 23408261 A 1196 1208 lead acetate SYSTEMATIC 23408261 A 1272 1274 Pb FORMULA 23408261 A 131 133 Pb FORMULA 23408261 A 1310 1312 Pb FORMULA 23408261 A 1431 1433 Pb FORMULA 23408261 A 1439 1451 lead acetate SYSTEMATIC 23408261 A 1492 1494 Pb FORMULA 23408261 A 210 222 lead acetate SYSTEMATIC 23408261 A 239 241 Pb FORMULA 23408261 A 307 309 Pb FORMULA 23408261 A 396 398 Pb FORMULA 23408261 A 474 476 Pb FORMULA 23408261 A 489 491 Pb FORMULA 23408261 A 70 72 Pb FORMULA 23408261 A 794 796 Pb FORMULA 23408261 T 68 70 Pb FORMULA 23408271 A 1007 1016 alkamides FAMILY 23408271 A 1048 1055 ethanol SYSTEMATIC 23408271 A 1116 1125 alkamides FAMILY 23408271 A 1393 1402 alkamides FAMILY 23408271 A 1407 1414 ketones FAMILY 23408271 A 1458 1467 Alkamides FAMILY 23408271 A 188 197 alkamides FAMILY 23408271 A 216 222 ketone SYSTEMATIC 23408271 A 325 332 ethanol SYSTEMATIC 23408271 A 517 526 alkamides FAMILY 23408271 A 611 619 alkamide FAMILY 23408271 A 690 697 ethanol SYSTEMATIC 23408271 A 785 794 alkamides FAMILY 23408271 A 812 820 alkamide FAMILY 23408271 A 831 837 ketone SYSTEMATIC 23408271 T 111 120 alkamides FAMILY 23408271 T 134 140 ketone SYSTEMATIC 23408421 A 1082 1089 BDE-209 IDENTIFIER 23408421 A 1096 1100 PBDE ABBREVIATION 23408421 A 1416 1420 TBPH ABBREVIATION 23408421 A 1475 1479 TBPH ABBREVIATION 23408421 A 170 200 polybrominated diphenyl ethers FAMILY 23408421 A 202 207 PBDEs ABBREVIATION 23408421 A 249 253 PBDE ABBREVIATION 23408421 A 341 356 Dechlorane Plus TRIVIAL 23408421 A 366 411 bis(2-ethylhexyl)-3,4,5,6-tetrabromophthalate SYSTEMATIC 23408421 A 413 417 TBPH ABBREVIATION 23408421 A 465 469 PBDE ABBREVIATION 23408421 A 499 503 TBPH ABBREVIATION 23408421 A 659 663 PBDE ABBREVIATION 23408421 A 668 672 PBDE ABBREVIATION 23408421 A 839 868 Brominated diphenyl ether-209 SYSTEMATIC 23408421 A 921 925 PBDE ABBREVIATION 23408421 A 962 966 PBDE ABBREVIATION 23408556 A 0 9 Chromones FAMILY 23408556 A 153 161 chromone TRIVIAL 23408556 A 363 383 chromone carboxamide SYSTEMATIC 23408556 T 35 57 chromone-2-carboxamide SYSTEMATIC 23408642 A 1260 1264 CLOD ABBREVIATION 23408642 A 687 702 bisphosphonates FAMILY 23408642 A 703 718 zoledronic acid TRIVIAL 23408642 A 728 738 clodronate TRIVIAL 23408642 A 740 744 CLOD ABBREVIATION 23408697 A 1123 1137 bisphosphonate SYSTEMATIC 23408697 A 1432 1446 bisphosphonate SYSTEMATIC 23408697 A 1602 1616 bisphosphonate SYSTEMATIC 23408697 A 1689 1704 bisphosphonates FAMILY 23408697 A 36 51 bisphosphonates FAMILY 23408697 A 446 461 bisphosphonates FAMILY 23408697 A 757 771 bisphosphonate SYSTEMATIC 23408697 A 870 884 Bisphosphonate SYSTEMATIC 23408697 T 0 15 Bisphosphonates FAMILY 23408858 A 124 130 uracil TRIVIAL 23408858 A 502 508 uracil TRIVIAL 23408858 A 632 638 uracil TRIVIAL 23408858 A 65 71 uracil TRIVIAL 23408858 A 740 746 uracil TRIVIAL 23408858 A 853 859 uracil TRIVIAL 23408858 T 56 62 uracil TRIVIAL 23409714 A 629 635 oxygen SYSTEMATIC 23409720 A 1299 1305 V4-015 IDENTIFIER 23409720 A 49 57 tyrosine TRIVIAL 23409720 A 929 935 V4-015 IDENTIFIER 23409722 A 1102 1112 olodaterol TRIVIAL 23409722 A 1114 1124 vilanterol TRIVIAL 23409722 A 1126 1136 milveterol TRIVIAL 23409722 A 1138 1148 carmoterol TRIVIAL 23409722 A 1154 1164 abediterol TRIVIAL 23409722 A 1208 1219 fluticasone TRIVIAL 23409722 A 1220 1230 salmeterol TRIVIAL 23409722 A 1232 1242 budesonide TRIVIAL 23409722 A 1243 1253 formoterol TRIVIAL 23409722 A 1255 1269 beclomethasone TRIVIAL 23409722 A 1270 1280 formoterol TRIVIAL 23409722 A 217 227 salbutamol TRIVIAL 23409722 A 233 242 fenoterol TRIVIAL 23409722 A 382 392 salmeterol TRIVIAL 23409722 A 397 407 formoterol TRIVIAL 23409722 A 525 535 salmeterol TRIVIAL 23409722 A 537 547 formoterol TRIVIAL 23409722 A 915 926 Indacaterol TRIVIAL 23409763 A 1196 1206 fatty acid FAMILY 23409763 T 57 67 fatty acid FAMILY 23409810 A 114 118 dNTP ABBREVIATION 23409810 A 1402 1406 dNTP ABBREVIATION 23409810 A 290 301 nucleotides FAMILY 23409810 A 84 112 deoxynucleoside triphosphate FAMILY 23409864 A 258 266 pyrazole SYSTEMATIC 23409864 A 315 323 pyrazole SYSTEMATIC 23409871 A 107 115 hydroxyl SYSTEMATIC 23409871 A 12 37 indazole arylsulfonamides FAMILY 23409871 A 155 163 indazole SYSTEMATIC 23409871 A 306 337 5-chlorothiophene-2-sulfonamide SYSTEMATIC 23409871 A 359 365 benzyl SYSTEMATIC 23409871 A 395 416 3-[(methylamino)acyl] SYSTEMATIC 23409871 A 476 481 amino FAMILY 23409871 A 552 563 morpholines FAMILY 23409871 A 707 718 GSK2239633A IDENTIFIER 23409871 A 765 781 Aryl sulfonamide FAMILY 23409871 A 893 913 indazole sulfonamide FAMILY 23409871 A 95 102 Methoxy SYSTEMATIC 23409871 T 50 75 indazole arylsulfonamides FAMILY 23409936 A 395 416 pyrazolobenzothiazine SYSTEMATIC 23409936 A 557 601 meta-fluoro-N-1-phenyl pyrazolobenzothiazine SYSTEMATIC 23409936 T 29 50 pyrazolobenzothiazine SYSTEMATIC 23409951 A 1014 1021 As(III) FORMULA 23409951 A 1032 1063 20-hydroxyeicosatetraenoic acid SYSTEMATIC 23409951 A 1146 1153 As(III) FORMULA 23409951 A 1172 1179 epoxide SYSTEMATIC 23409951 A 12 19 Arsenic SYSTEMATIC 23409951 A 1340 1347 As(III) FORMULA 23409951 A 1355 1371 arachidonic acid TRIVIAL 23409951 A 21 28 As(III) FORMULA 23409951 A 231 238 As(III) FORMULA 23409951 A 312 328 arachidonic acid TRIVIAL 23409951 A 380 387 As(III) FORMULA 23409951 A 533 540 As(III) FORMULA 23409951 A 568 593 epoxyeicosatrienoic acids FAMILY 23409951 A 595 599 EETs ABBREVIATION 23409951 A 687 694 As(III) FORMULA 23409951 A 715 743 dihydroxyeicosatrienoic acid SYSTEMATIC 23409951 A 745 750 DHETs FAMILY 23409951 A 805 810 DHETs FAMILY 23409951 A 842 847 DHETs FAMILY 23409951 A 862 869 As(III) FORMULA 23409951 A 94 101 arsenic SYSTEMATIC 23409951 T 6 13 arsenic SYSTEMATIC 23409951 T 62 78 arachidonic acid TRIVIAL 23409959 A 1066 1072 S23906 IDENTIFIER 23409959 A 1131 1139 S23906-1 IDENTIFIER 23409959 A 193 211 benzo-b-acronycine SYSTEMATIC 23409959 A 223 231 S23906-1 IDENTIFIER 23409959 A 242 261 guanine nucleobases FAMILY 23409959 A 655 661 S23906 IDENTIFIER 23409959 A 696 722 glyceraldehyde-3-phosphate SYSTEMATIC 23409959 A 765 771 S23906 IDENTIFIER 23409959 T 27 35 S23906-1 IDENTIFIER 23409959 T 90 116 glyceraldehyde-3-phosphate SYSTEMATIC 23410005 A 273 281 LY294002 IDENTIFIER 23410005 A 351 357 SF1126 IDENTIFIER 23410005 A 780 820 5-morpholino-7H-thieno[3,2-b]pyran-7-one SYSTEMATIC 23410005 T 61 102 5-morpholino-7H-thieno[3,2-b]pyran-7-ones FAMILY 23410094 A 193 202 hydrazide SYSTEMATIC 23410094 A 218 245 poly(N-isopropylacrylamide) SYSTEMATIC 23410094 A 247 253 pNIPAM ABBREVIATION 23410094 A 509 518 hydrazone FAMILY 23410094 A 87 95 aldehyde SYSTEMATIC 23410094 T 105 115 iron oxide SYSTEMATIC 23410094 T 59 86 poly(N-isopropylacrylamide) SYSTEMATIC 23410125 A 1259 1265 N acyl SYSTEMATIC 23410155 A 1178 1181 Gly FORMULA 23410155 A 1185 1188 Trp FORMULA 23410155 A 1195 1198 Ala FORMULA 23410155 A 1223 1224 H FORMULA 23410155 A 24 32 cysteine TRIVIAL 23410155 T 41 58 heteroarylnitrile FAMILY 23410167 A 462 473 galantamine TRIVIAL 23410167 A 482 495 physostigmine TRIVIAL 23410167 A 507 519 rivastigmine TRIVIAL 23410167 A 744 755 galantamine TRIVIAL 23410886 A 1076 1079 CpG ABBREVIATION 23410886 A 357 366 bisulfite SYSTEMATIC 23410886 A 462 465 CpG ABBREVIATION 23410886 A 839 842 CpG ABBREVIATION 23411074 A 17 33 isoaspulvinone E TRIVIAL 23411074 A 6 16 butenolide FAMILY 23411074 A 63 74 butenolides FAMILY 23411074 A 75 88 aspulvinone E TRIVIAL 23411074 A 97 108 pulvic acid TRIVIAL 23411074 T 0 12 Aspulvinones FAMILY 23411077 A 105 267 (6R,7R)-8-oxo-7-(2-oxo-2H-chromene-3-carboxamido)-3-((4-(2-oxo-2H-chromene-3-carboxamido)-phenylthio)methyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid SYSTEMATIC 23411077 T 44 50 Zn(II) FORMULA 23411081 A 0 21 Saturated fatty acids FAMILY 23411081 A 138 167 methoxy poly(ethylene glycol) FAMILY 23411081 A 169 173 MPEG ABBREVIATION 23411081 A 208 227 cyclotriphosphazene TRIVIAL 23411081 A 287 292 MPEGs FAMILY 23411081 A 371 382 fatty acids FAMILY 23411081 A 421 465 lauric, myristic, palmitic and stearic acids MULTIPLE 23411081 A 46 54 tyrosine TRIVIAL 23411081 A 500 511 fatty acids FAMILY 23411081 A 80 99 cyclotriphosphazene TRIVIAL 23411081 T 77 88 fatty acids FAMILY 23411169 A 152 160 graphene TRIVIAL 23411169 A 177 183 carbon SYSTEMATIC 23411169 A 255 280 sodium dodecyl sulphonate SYSTEMATIC 23411169 A 282 285 SDS ABBREVIATION 23411169 A 301 310 phosphate SYSTEMATIC 23411169 A 404 407 SDS ABBREVIATION 23411169 A 409 416 Sudan I TRIVIAL 23411169 A 511 518 Sudan I TRIVIAL 23411169 A 559 562 SDS ABBREVIATION 23411169 A 642 645 SDS ABBREVIATION 23411169 A 689 696 Sudan I TRIVIAL 23411169 A 77 84 Sudan I TRIVIAL 23411169 A 795 802 Sudan I TRIVIAL 23411169 A 972 979 Sudan I TRIVIAL 23411169 T 137 162 sodium dodecyl sulphonate SYSTEMATIC 23411169 T 33 40 Sudan I TRIVIAL 23411169 T 60 68 graphene TRIVIAL 23411169 T 85 91 carbon SYSTEMATIC 23411180 A 0 13 Pterostilbene TRIVIAL 23411180 A 1032 1045 pterostilbene TRIVIAL 23411180 A 205 218 pterostilbene TRIVIAL 23411180 A 342 364 dimethyl n-nitrosamine SYSTEMATIC 23411180 A 366 369 DMN ABBREVIATION 23411180 A 410 423 Pterostilbene TRIVIAL 23411180 A 562 575 Pterostilbene TRIVIAL 23411180 A 607 610 DMN ABBREVIATION 23411180 A 788 801 pterostilbene TRIVIAL 23411180 T 0 13 Pterostilbene TRIVIAL 23411180 T 23 42 dimethylnitrosamine SYSTEMATIC 23411188 A 219 229 flavonoids FAMILY 23411188 A 364 374 flavonoids FAMILY 23411188 A 845 855 flavonoids FAMILY 23411193 A 168 177 steroidal FAMILY 23411193 T 145 154 steroidal FAMILY 23411197 A 1034 1043 dioscorin TRIVIAL 23411197 A 213 218 thiol FAMILY 23411197 A 302 311 dioscorin TRIVIAL 23411197 A 36 45 dioscorin TRIVIAL 23411197 A 485 488 GSH ABBREVIATION 23411197 A 496 505 carnosine TRIVIAL 23411197 A 519 527 hydroxyl SYSTEMATIC 23411197 A 645 649 AAPH ABBREVIATION 23411197 A 673 679 oxygen SYSTEMATIC 23411197 A 901 914 methylglyoxal SYSTEMATIC 23411197 A 995 1000 thiol FAMILY 23411197 T 143 152 dioscorin TRIVIAL 23411197 T 42 47 thiol FAMILY 23411198 A 1077 1083 tricin TRIVIAL 23411198 A 13 19 tricin TRIVIAL 23411198 A 21 61 5,7,4'-trihydroxy-3',5'-dimethoxyflavone SYSTEMATIC 23411198 A 306 312 Tricin TRIVIAL 23411198 A 4 11 flavone TRIVIAL 23411198 A 507 513 tricin TRIVIAL 23411198 A 862 868 tricin TRIVIAL 23411198 A 895 901 tricin TRIVIAL 23411198 T 50 56 tricin TRIVIAL 23411201 A 694 696 C6 FORMULA 23411201 A 708 716 alcohols FAMILY 23411201 A 718 726 terpenes FAMILY 23411201 A 728 735 phenols FAMILY 23411201 A 740 758 C13-norisoprenoids FAMILY 23411204 A 316 320 (1)H FORMULA 23411204 A 643 653 polyphenol FAMILY 23411204 A 667 680 hippuric acid TRIVIAL 23411204 A 685 707 4-hydroxyhippuric acid SYSTEMATIC 23411204 A 723 733 creatinine TRIVIAL 23411204 A 738 751 dimethylamine SYSTEMATIC 23411204 A 878 888 polyphenol FAMILY 23411204 T 0 2 1H FORMULA 23411205 A 277 284 pyrazol SYSTEMATIC 23411205 A 300 371 4,4'[(4-cholorophenyl)methylene] bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) SYSTEMATIC 23411205 A 372 377 CMBPP ABBREVIATION 23411205 A 477 483 Fe(3+) FORMULA 23411205 A 488 494 Mn(2+) FORMULA 23411205 A 627 633 Mn(2+) FORMULA 23411205 A 638 644 Fe(3+) FORMULA 23411205 A 86 92 Mn(2+) FORMULA 23411205 A 97 103 Fe(3+) FORMULA 23411205 T 30 34 Mn2+ FORMULA 23411205 T 39 43 Fe3+ FORMULA 23411205 T 47 118 4,4'[(4-cholorophenyl)methylene] bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) SYSTEMATIC 23411216 A 329 340 anthocyanin FAMILY 23411216 A 345 351 tannin FAMILY 23411224 A 1010 1013 TAG ABBREVIATION 23411224 A 278 288 atty acids FAMILY 23411224 A 289 294 acyls FAMILY 23411224 A 61 74 triglycerides FAMILY 23411224 A 714 724 fatty acid FAMILY 23411224 A 788 799 fatty acyls FAMILY 23411224 A 803 816 triglycerides FAMILY 23411224 A 975 979 PUFA ABBREVIATION 23411224 T 64 77 triglycerides FAMILY 23411229 A 157 164 sucrose TRIVIAL 23411229 A 178 189 trehalulose TRIVIAL 23411229 A 208 218 isomaltose TRIVIAL 23411229 A 220 232 isomaltulose TRIVIAL 23411229 A 237 250 isomelezitose TRIVIAL 23411229 A 279 286 glucose TRIVIAL 23411229 A 291 299 fructose TRIVIAL 23411229 A 30 39 trehalose TRIVIAL 23411229 A 323 334 trehalulose TRIVIAL 23411229 A 520 531 trehalulose TRIVIAL 23411229 A 586 597 trehalulose TRIVIAL 23411229 A 620 627 sucrose TRIVIAL 23411229 A 653 659 sugars FAMILY 23411229 A 693 704 trehalulose TRIVIAL 23411229 A 908 919 trehalulose TRIVIAL 23411229 A 932 943 trehalulose TRIVIAL 23411229 T 64 75 trehalulose TRIVIAL 23411230 A 1013 1024 anthocyanin FAMILY 23411230 A 198 211 Ascorbic acid TRIVIAL 23411230 A 216 232 chlorogenic acid TRIVIAL 23411230 A 277 288 anthocyanin FAMILY 23411230 A 335 348 glycoalkaloid FAMILY 23411230 A 350 361 α-chaconine TRIVIAL 23411230 A 366 376 α-solanine TRIVIAL 23411230 A 436 448 ascorbic and TRIVIAL 23411230 A 449 465 chlorogenic acid TRIVIAL 23411230 A 482 496 glycoalkaloids FAMILY 23411230 A 498 509 α-chaconine TRIVIAL 23411230 A 514 524 α-solanine TRIVIAL 23411230 A 553 565 anthocyanins FAMILY 23411230 A 581 611 ascorbic and chlorogenic acids MULTIPLE 23411230 A 650 661 anthocyanin FAMILY 23411230 A 744 758 glycoalkaloids FAMILY 23411230 A 760 786 α-chaconine and α-solanine MULTIPLE 23411230 A 971 984 ascorbic acid TRIVIAL 23411230 A 986 1002 chlorogenic acid TRIVIAL 23411231 A 170 182 acetonitrile SYSTEMATIC 23411231 A 184 188 MeCN FORMULA 23411231 A 394 401 citrate FAMILY 23411231 A 492 515 primary secondary amine MULTIPLE 23411231 A 517 520 PSA ABBREVIATION 23411235 A 281 291 β-carotene TRIVIAL 23411235 A 292 301 linoleate TRIVIAL 23411235 A 343 354 cholesterol TRIVIAL 23411235 A 404 426 phytosteryl phenolates FAMILY 23411235 A 495 509 phenolic acids FAMILY 23411235 A 523 533 β-carotene TRIVIAL 23411235 A 534 543 linoleate TRIVIAL 23411235 A 577 599 phytosteryl phenolates FAMILY 23411235 A 644 665 phytosteryl ferulates FAMILY 23411235 A 716 738 phytosteryl phenolates FAMILY 23411235 A 84 106 phytosteryl phenolates FAMILY 23411235 A 972 994 phytosteryl phenolates FAMILY 23411235 T 24 46 phytosteryl phenolates FAMILY 23411238 A 135 141 silver SYSTEMATIC 23411238 A 192 202 tartrazine TRIVIAL 23411238 A 206 222 potassium iodate SYSTEMATIC 23411238 A 230 237 acetate SYSTEMATIC 23411238 A 56 66 tartrazine TRIVIAL 23411238 A 609 619 tartrazine TRIVIAL 23411238 A 698 708 tartrazine TRIVIAL 23411238 T 75 85 tartrazine TRIVIAL 23411240 A 128 155 furofuran lignan glucosides FAMILY 23411240 A 163 175 lactuberin A TRIVIAL 23411240 A 180 192 lactuberin B TRIVIAL 23411240 A 364 404 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane FAMILY 23411240 A 410 427 furofuran lignans FAMILY 23411240 A 545 553 phenolic FAMILY 23411240 A 568 580 caffeic acid TRIVIAL 23411240 A 582 598 chlorogenic acid TRIVIAL 23411240 A 603 628 3,5 dicaffeoylquinic acid SYSTEMATIC 23411240 A 730 734 DPPH ABBREVIATION 23411240 A 76 84 phenolic FAMILY 23411240 T 59 67 phenolic FAMILY 23411240 T 86 103 furofuran lignans FAMILY 23411241 A 186 190 DPPH ABBREVIATION 23411241 A 194 196 HO FORMULA 23411241 A 204 211 O(2)(-) FORMULA 23411241 A 225 231 ferric SYSTEMATIC 23411241 A 377 383 CCl(4) FORMULA 23411241 A 410 417 alanine TRIVIAL 23411241 A 436 445 aspartate TRIVIAL 23411241 A 512 527 malondialdehyde TRIVIAL 23411241 A 581 591 superoxide TRIVIAL 23411241 A 606 617 glutathione TRIVIAL 23411241 A 650 656 CCl(4) FORMULA 23411241 A 767 773 CCl(4) FORMULA 23411241 A 901 910 arabinose TRIVIAL 23411241 A 912 921 galactose TRIVIAL 23411241 A 926 943 galacturonic acid TRIVIAL 23411241 T 125 129 CCl4 FORMULA 23411245 A 1097 1100 EPI ABBREVIATION 23411245 A 1194 1197 EPI ABBREVIATION 23411245 A 1221 1231 o-quinones FAMILY 23411245 A 272 275 EPI ABBREVIATION 23411245 A 31 47 chlorogenic acid TRIVIAL 23411245 A 54 69 (-) epicatechin TRIVIAL 23411245 A 71 74 EPI ABBREVIATION 23411245 A 77 92 L-ascorbic acid TRIVIAL 23411245 A 791 794 EPI ABBREVIATION 23411245 A 857 867 o-quinones FAMILY 23411245 A 871 874 EPI ABBREVIATION 23411245 A 943 949 phenol SYSTEMATIC 23411245 T 40 47 phenols FAMILY 23411245 T 49 64 L-ascorbic acid TRIVIAL 23411245 T 94 100 oxygen SYSTEMATIC 23411251 A 530 541 polyphenols FAMILY 23411251 A 673 684 polyphenols FAMILY 23411251 A 822 836 phenolic acids FAMILY 23411251 A 838 848 flavonoids FAMILY 23411251 A 853 865 anthocyanins FAMILY 23411251 A 916 928 anthocyanins FAMILY 23411251 A 945 959 anthocyanidins FAMILY 23411253 A 1163 1167 acyl FAMILY 23411253 A 194 198 (1)H FORMULA 23411253 A 58 62 acyl FAMILY 23411253 A 729 733 acyl FAMILY 23411253 A 793 797 acyl FAMILY 23411253 A 907 911 (1)H FORMULA 23411253 T 119 123 acyl FAMILY 23411257 A 172 187 aluminium oxide SYSTEMATIC 23411257 A 192 202 silica gel TRIVIAL 23411257 A 230 241 Lewis acids FAMILY 23411257 A 533 541 nitrogen SYSTEMATIC 23411257 A 547 548 N FORMULA 23411257 A 562 565 ATP ABBREVIATION 23411259 A 302 309 alcohol FAMILY 23411259 A 348 356 naringin TRIVIAL 23411259 A 73 83 flavonoids FAMILY 23411259 A 777 788 cholesterol TRIVIAL 23411259 A 793 800 glucose TRIVIAL 23411259 T 136 147 cholesterol TRIVIAL 23411259 T 8 15 alcohol FAMILY 23411260 A 788 797 flavonoid FAMILY 23411263 A 1038 1049 piceatannol TRIVIAL 23411263 A 346 354 phenolic FAMILY 23411263 A 415 424 stilbenes FAMILY 23411263 A 476 488 anthocyanins FAMILY 23411263 A 490 499 flavonols FAMILY 23411263 A 505 516 gallic acid TRIVIAL 23411263 A 564 575 Piceatannol TRIVIAL 23411263 A 606 614 stilbene TRIVIAL 23411263 A 811 819 stilbene TRIVIAL 23411263 A 874 885 piceatannol TRIVIAL 23411263 A 896 905 stilbenes FAMILY 23411263 A 926 935 flavonols FAMILY 23411263 A 956 967 anthocyanin FAMILY 23411263 T 0 11 Piceatannol TRIVIAL 23411263 T 32 40 stilbene TRIVIAL 23411263 T 51 59 phenolic FAMILY 23411266 A 1013 1023 flavonoïds FAMILY 23411266 A 104 110 hexane SYSTEMATIC 23411266 A 112 128 dichloro-methane SYSTEMATIC 23411266 A 170 181 cholesterol TRIVIAL 23411266 A 201 214 ethyl acetate SYSTEMATIC 23411266 A 237 248 cholesterol TRIVIAL 23411266 A 250 263 triglycerides FAMILY 23411266 A 293 304 cholesterol TRIVIAL 23411266 A 352 363 cholesterol TRIVIAL 23411266 A 406 417 cholesterol TRIVIAL 23411266 A 463 482 thiobarbituric acid SYSTEMATIC 23411266 A 529 539 superoxide TRIVIAL 23411266 A 640 653 ethyl acetate SYSTEMATIC 23411266 A 704 712 phenolic FAMILY 23411266 A 717 726 flavonoïd FAMILY 23411266 A 756 764 methanol SYSTEMATIC 23411266 A 773 786 ethyl acetate SYSTEMATIC 23411266 A 79 87 methanol SYSTEMATIC 23411266 A 827 840 ethyl acetate SYSTEMATIC 23411266 A 89 102 ethyl acetate SYSTEMATIC 23411266 A 945 956 cholesterol TRIVIAL 23411269 A 624 630 β-Galf ABBREVIATION 23411269 A 671 677 β-Glcp ABBREVIATION 23411269 A 750 756 α-Manp ABBREVIATION 23411269 A 878 885 ferrous SYSTEMATIC 23411270 A 159 164 amine SYSTEMATIC 23411270 A 584 592 spermine TRIVIAL 23411270 A 597 607 spermidine TRIVIAL 23411270 T 57 62 amine SYSTEMATIC 23411275 A 165 175 β-carotene TRIVIAL 23411275 A 268 278 β-carotene TRIVIAL 23411275 A 484 494 β-carotene TRIVIAL 23411275 A 727 737 β-carotene TRIVIAL 23411275 A 835 845 β-carotene TRIVIAL 23411275 A 847 857 β-carotene TRIVIAL 23411275 T 24 34 β-carotene TRIVIAL 23411280 A 0 9 Histidine TRIVIAL 23411280 A 148 157 histamine TRIVIAL 23411280 A 262 275 ethyl acetate SYSTEMATIC 23411280 A 346 355 Rugosin D TRIVIAL 23411280 A 357 366 rugosin A TRIVIAL 23411280 A 368 390 rugosin A methyl ester SYSTEMATIC 23411280 A 415 432 tellimagrandin II TRIVIAL 23411280 A 57 66 histamine TRIVIAL 23411280 A 620 642 histidine methyl ester SYSTEMATIC 23411280 A 80 85 amine SYSTEMATIC 23411280 T 77 86 histidine TRIVIAL 23411281 A 108 114 Fe(2+) FORMULA 23411281 A 364 373 phenolics FAMILY 23411281 A 388 392 DPPH ABBREVIATION 23411281 A 427 440 ascorbic acid TRIVIAL 23411281 A 54 58 DPPH ABBREVIATION 23411281 A 553 562 phenolics FAMILY 23411281 A 571 575 DPPH ABBREVIATION 23411281 A 6 15 phenolics FAMILY 23411281 A 60 73 ascorbic acid TRIVIAL 23411281 A 658 671 ascorbic acid TRIVIAL 23411286 A 1126 1139 carbohydrates FAMILY 23411286 A 1156 1166 polyphenol FAMILY 23411286 A 164 175 polyphenols FAMILY 23411286 A 19 31 procyanidins FAMILY 23411286 A 253 264 procyanidin FAMILY 23411286 A 375 385 polyphenol FAMILY 23411286 A 399 413 Procyanidin B3 TRIVIAL 23411286 A 717 730 carbohydrates FAMILY 23411286 A 747 754 sucrose TRIVIAL 23411286 T 33 44 procyanidin FAMILY 23411286 T 89 102 carbohydrates FAMILY 23411287 A 35 52 β-mercaptoethanol SYSTEMATIC 23411287 A 471 481 disulphide SYSTEMATIC 23411287 A 601 606 thiol FAMILY 23411287 A 607 617 disulphide SYSTEMATIC 23411288 A 140 150 cyromazine TRIVIAL 23411288 A 160 168 melamine TRIVIAL 23411288 T 105 113 melamine TRIVIAL 23411288 T 90 100 cyromazine TRIVIAL 23411289 A 202 209 ethanol SYSTEMATIC 23411289 A 249 257 nitrogen SYSTEMATIC 23411289 A 308 311 Phe FORMULA 23411289 A 313 316 Val ABBREVIATION 23411289 A 318 321 Ala FORMULA 23411289 A 323 326 Gly FORMULA 23411289 A 328 331 Pro FORMULA 23411289 A 333 336 Asp FORMULA 23411289 A 338 341 Asn FORMULA 23411289 A 343 346 His FORMULA 23411289 A 351 354 Lys FORMULA 23411289 A 409 412 Met FORMULA 23411289 A 414 417 Cys FORMULA 23411289 A 419 422 Glu FORMULA 23411289 A 424 427 Gln FORMULA 23411289 A 429 432 Ser FORMULA 23411289 A 437 440 Arg FORMULA 23411289 A 442 450 Tyrosine TRIVIAL 23411289 A 452 455 Leu FORMULA 23411289 A 457 460 Ile FORMULA 23411289 A 465 468 Thr FORMULA 23411289 A 501 508 Glycine TRIVIAL 23411289 A 513 516 Pro FORMULA 23411289 A 6 16 amino acid FAMILY 23411289 A 750 753 AAs FAMILY 23411289 A 799 802 Leu FORMULA 23411289 A 876 884 nitrogen SYSTEMATIC 23411289 T 6 16 amino acid FAMILY 23411290 A 297 306 quercetin TRIVIAL 23411290 A 319 328 Quercetin TRIVIAL 23411290 A 419 428 quercetin TRIVIAL 23411293 A 100 104 iron SYSTEMATIC 23411293 A 122 132 Iron (III) SYSTEMATIC 23411293 A 148 157 iron (II) SYSTEMATIC 23411293 A 161 174 ascorbic acid TRIVIAL 23411293 A 224 236 polyurethane SYSTEMATIC 23411293 A 268 308 N,N-bis(salicylidene)-1,3-propanediamine SYSTEMATIC 23411293 A 310 314 SPDA ABBREVIATION 23411293 A 330 337 Fe (II) FORMULA 23411293 A 354 371 hydrochloric acid SYSTEMATIC 23411293 A 400 436 2,4,6-tri(2'-pyridyl)-1,3,5-triazine SYSTEMATIC 23411293 A 438 442 TPTZ ABBREVIATION 23411293 A 679 688 iron (II) SYSTEMATIC 23411293 A 775 779 iron SYSTEMATIC 23411293 T 123 163 N,N-bis(salicylidene)-1,3-propanediamine SYSTEMATIC 23411293 T 23 27 iron SYSTEMATIC 23411293 T 85 97 polyurethane SYSTEMATIC 23411294 A 214 222 phenolic FAMILY 23411294 A 366 375 phenolics FAMILY 23411294 A 403 423 apigenin-glucuronide TRIVIAL 23411294 A 425 434 lucenin-2 TRIVIAL 23411294 A 439 456 lithospermic acid TRIVIAL 23411294 A 556 561 apiin TRIVIAL 23411294 A 574 583 phenolics FAMILY 23411294 A 621 636 p-coumaric acid TRIVIAL 23411294 A 687 692 apiin TRIVIAL 23411294 A 791 799 phenolic FAMILY 23411294 A 870 880 polyphenol FAMILY 23411294 T 24 34 polyphenol FAMILY 23411297 A 1069 1080 polyphenols FAMILY 23411297 A 1329 1340 tocopherols FAMILY 23411297 A 170 199 2,2-diphenyl-1-picrylhydrazyl SYSTEMATIC 23411297 A 245 252 ferrous SYSTEMATIC 23411297 A 559 566 Ethanol SYSTEMATIC 23411297 A 590 600 polyphenol FAMILY 23411297 T 0 8 Phenolic FAMILY 23411300 A 272 279 ethanol SYSTEMATIC 23411300 A 324 335 anthocyanin FAMILY 23411300 A 345 351 tannin FAMILY 23411300 A 411 417 tannin FAMILY 23411300 A 466 477 anthocyanin FAMILY 23411300 A 487 493 tannin FAMILY 23411300 A 592 601 phenolics FAMILY 23411300 A 693 699 esters FAMILY 23411300 A 701 717 dimethyl sulfide SYSTEMATIC 23411300 A 719 727 glycerol TRIVIAL 23411300 A 75 84 phenolics FAMILY 23411300 A 837 861 isobutyl methoxypyrazine SYSTEMATIC 23411300 A 868 876 alcohols FAMILY 23411300 A 881 894 hexyl acetate SYSTEMATIC 23411303 A 225 226 D FORMULA 23411303 A 227 228 H FORMULA 23411303 A 371 379 hydrogen SYSTEMATIC 23411303 A 454 465 fatty acids FAMILY 23411303 A 48 56 hydrogen SYSTEMATIC 23411303 A 506 511 D(2)O FORMULA 23411303 A 629 634 D(2)O FORMULA 23411303 A 679 690 fatty acids FAMILY 23411303 A 857 866 deuterium SYSTEMATIC 23411303 T 0 1 D FORMULA 23411303 T 16 19 C-H FORMULA 23411303 T 2 3 H FORMULA 23411303 T 29 40 fatty acids FAMILY 23411305 A 0 12 Sulforaphane TRIVIAL 23411305 A 1020 1032 sulforaphane TRIVIAL 23411305 A 113 126 glucosinolate FAMILY 23411305 A 1180 1192 sulforaphane TRIVIAL 23411305 A 485 497 sulforaphane TRIVIAL 23411305 A 616 629 glucoraphanin TRIVIAL 23411305 A 716 728 sulforaphane TRIVIAL 23411305 A 733 753 sulforaphane nitrile SYSTEMATIC 23411305 A 786 799 glucoraphanin TRIVIAL 23411305 A 89 102 glucoraphanin TRIVIAL 23411305 T 27 39 sulforaphane TRIVIAL 23411317 A 1155 1162 lignans FAMILY 23411317 A 1238 1245 lignans FAMILY 23411317 A 15 21 lignan FAMILY 23411317 A 192 198 lignan FAMILY 23411317 A 372 379 ethanol SYSTEMATIC 23411317 A 402 418 sodium methoxide SYSTEMATIC 23411317 A 686 706 Secoisolariciresinol TRIVIAL 23411317 A 708 721 lariciresinol TRIVIAL 23411317 A 723 734 pinoresinol TRIVIAL 23411317 A 736 757 7-hydroxymatairesinol SYSTEMATIC 23411317 A 759 773 syringaresinol TRIVIAL 23411317 A 775 791 isolariciresinol TRIVIAL 23411317 A 793 825 secoisolariciresinol diglycoside FAMILY 23411317 A 827 854 lariciresinol monoglycoside FAMILY 23411317 A 856 895 pinoresinol mono-, di- and triglycoside MULTIPLE 23411317 A 897 906 sesaminol TRIVIAL 23411317 A 908 930 sesaminol triglycoside FAMILY 23411317 A 932 943 sesamolinol TRIVIAL 23411317 A 948 971 sesamolinol diglycoside FAMILY 23411317 T 34 41 lignans FAMILY 23411318 A 161 168 calcium SYSTEMATIC 23411318 A 442 445 Leu FORMULA 23411318 A 464 471 calcium SYSTEMATIC 23411318 A 595 598 Leu FORMULA 23411318 A 676 682 Ca(2+) FORMULA 23411318 A 734 737 Leu FORMULA 23411318 A 900 903 Ser FORMULA 23411318 A 979 982 Leu FORMULA 23411320 A 385 392 alcohol FAMILY 23411327 A 159 169 tartrazine TRIVIAL 23411327 A 189 225 brilliant blue and sunset yellow FCF MULTIPLE 23411327 A 589 599 tartrazine TRIVIAL 23411327 A 674 684 tartrazine TRIVIAL 23411327 T 17 27 tartrazine TRIVIAL 23411330 A 1007 1011 iron SYSTEMATIC 23411330 A 141 145 Iron SYSTEMATIC 23411330 A 203 218 ferrous sulfate SYSTEMATIC 23411330 A 233 237 iron SYSTEMATIC 23411330 A 376 380 iron SYSTEMATIC 23411330 A 411 430 γ-aminobutyric acid SYSTEMATIC 23411330 A 484 491 FeSO(4) FORMULA 23411330 A 557 561 Iron SYSTEMATIC 23411330 A 632 636 iron SYSTEMATIC 23411330 A 65 69 iron SYSTEMATIC 23411330 A 761 765 iron SYSTEMATIC 23411330 A 841 845 iron SYSTEMATIC 23411330 A 87 91 iron SYSTEMATIC 23411330 A 879 883 iron SYSTEMATIC 23411330 T 10 25 ferrous sulfate SYSTEMATIC 23411330 T 73 77 iron SYSTEMATIC 23411336 A 0 14 Betulinic acid TRIVIAL 23411336 A 153 167 β-cyclodextrin TRIVIAL 23411336 A 169 173 β-CD ABBREVIATION 23411336 A 31 55 pentacyclic triterpenoid FAMILY 23411336 A 335 342 BA-β-CD ABBREVIATION 23411336 T 68 82 betulinic acid TRIVIAL 23411344 A 0 10 Stevioside TRIVIAL 23411344 A 132 142 stevioside TRIVIAL 23411344 A 194 204 stevioside TRIVIAL 23411344 A 229 239 stevioside TRIVIAL 23411344 A 271 281 stevioside TRIVIAL 23411344 A 342 352 stevioside TRIVIAL 23411344 A 515 551 mono- and di-glucosylated stevioside MULTIPLE 23411344 A 570 580 stevioside TRIVIAL 23411344 A 694 705 steviosides FAMILY 23411344 A 797 808 steviosides FAMILY 23411344 T 22 32 stevioside TRIVIAL 23411507 A 1072 1082 25(OH)D(3) SYSTEMATIC 23411507 A 1148 1158 25(OH)D(3) SYSTEMATIC 23411507 A 1338 1348 25(OH)D(3) SYSTEMATIC 23411507 A 140 149 vitamin D FAMILY 23411507 A 1594 1604 25(OH)D(3) SYSTEMATIC 23411507 A 1673 1683 25(OH)D(3) SYSTEMATIC 23411507 A 168 190 25-hydroxyvitamin D(3) SYSTEMATIC 23411507 A 192 202 25(OH)D(3) SYSTEMATIC 23411507 A 41 50 vitamin D FAMILY 23411507 A 418 428 25(OH)D(3) SYSTEMATIC 23411507 A 578 585 calcium SYSTEMATIC 23411507 A 591 600 aspartate TRIVIAL 23411507 A 680 690 25(OH)D(3) SYSTEMATIC 23411507 A 704 715 cholesterol TRIVIAL 23411507 A 717 730 triglycerides FAMILY 23411507 A 756 767 cholesterol TRIVIAL 23411507 A 849 859 25(OH)D(3) SYSTEMATIC 23411507 A 876 886 25(OH)D(3) SYSTEMATIC 23411507 T 11 20 vitamin D FAMILY 23412112 A 1005 1012 cocaine TRIVIAL 23412112 A 1234 1241 Cocaine TRIVIAL 23412112 A 1451 1458 cocaine TRIVIAL 23412112 A 1557 1564 cocaine TRIVIAL 23412112 A 298 305 cocaine TRIVIAL 23412112 A 645 652 cocaine TRIVIAL 23412112 A 855 862 cocaine TRIVIAL 23412112 A 915 922 cocaine TRIVIAL 23412114 A 1066 1074 morphine TRIVIAL 23412114 A 1162 1170 morphine TRIVIAL 23412114 A 1195 1202 gallein TRIVIAL 23412114 A 1228 1235 gallein TRIVIAL 23412114 A 1268 1276 morphine TRIVIAL 23412114 A 1319 1327 morphine TRIVIAL 23412114 A 457 464 gallein TRIVIAL 23412114 A 536 544 morphine TRIVIAL 23412114 A 601 609 morphine TRIVIAL 23412114 A 614 621 gallein TRIVIAL 23412114 A 629 637 Morphine TRIVIAL 23412114 A 741 748 gallein TRIVIAL 23412114 A 791 799 morphine TRIVIAL 23412114 A 87 95 morphine TRIVIAL 23412114 A 874 882 morphine TRIVIAL 23412114 A 977 984 morphin TRIVIAL 23412114 A 987 994 Gallein TRIVIAL 23412114 T 48 56 morphine TRIVIAL 23412751 A 1058 1063 HPBCD ABBREVIATION 23412751 A 1147 1152 HPBCD ABBREVIATION 23412751 A 1302 1309 sucrose TRIVIAL 23412751 A 1387 1392 HPBCD ABBREVIATION 23412751 A 141 152 cholesterol TRIVIAL 23412751 A 1506 1517 cholesterol TRIVIAL 23412751 A 157 170 sphingolipids FAMILY 23412751 A 264 292 hydroxypropyl-β-cyclodextrin SYSTEMATIC 23412751 A 294 299 HPBCD ABBREVIATION 23412751 A 363 374 cholesterol TRIVIAL 23412751 A 379 391 gangliosides FAMILY 23412751 A 435 440 HPBCD ABBREVIATION 23412751 A 580 591 cholesterol TRIVIAL 23412751 A 844 849 HPBCD ABBREVIATION 23412751 T 44 55 cholesterol TRIVIAL 23412922 A 426 434 estrogen FAMILY 23413833 A 351 358 silicon SYSTEMATIC 23413833 A 452 459 silicon SYSTEMATIC 23413833 A 500 507 silicon SYSTEMATIC 23413833 T 0 10 Phosphorus SYSTEMATIC 23413833 T 17 24 silicon SYSTEMATIC 23414209 A 1298 1309 pilocarpine TRIVIAL 23414209 A 1328 1331 PVP ABBREVIATION 23414209 A 1332 1336 PAAc ABBREVIATION 23414209 A 1372 1383 pilocarpine TRIVIAL 23414209 A 140 151 pilocarpine TRIVIAL 23414209 A 223 243 polyvinylpyrrolidone SYSTEMATIC 23414209 A 244 262 poly(acrylic acid) SYSTEMATIC 23414209 A 264 267 PVP ABBREVIATION 23414209 A 268 272 PAAc ABBREVIATION 23414209 A 333 345 acrylic acid TRIVIAL 23414209 A 347 350 AAc ABBREVIATION 23414209 A 378 398 polyvinylpyrrolidone SYSTEMATIC 23414209 A 400 403 PVP ABBREVIATION 23414209 A 452 463 pilocarpine TRIVIAL 23414209 A 596 599 PVP ABBREVIATION 23414209 A 600 604 PAAc ABBREVIATION 23414209 A 74 85 pilocarpine TRIVIAL 23414209 A 893 904 Pilocarpine TRIVIAL 23414209 A 988 991 AAc ABBREVIATION 23414209 T 100 118 poly(acrylic acid) SYSTEMATIC 23414209 T 52 63 pilocarpine TRIVIAL 23414209 T 79 99 polyvinylpyrrolidone SYSTEMATIC 23414210 A 1015 1018 PEG ABBREVIATION 23414210 A 299 302 PEG ABBREVIATION 23414210 A 522 525 PEG ABBREVIATION 23414210 A 721 724 PEG ABBREVIATION 23414210 A 838 841 PEG ABBREVIATION 23414210 T 65 68 PEG ABBREVIATION 23414214 A 1120 1157 (99m)Tc(CO)3-Pz(3)-βAlaNleCycMSH(hex) FORMULA 23414214 A 1162 1199 (99m)Tc(CO)3-Pz(4)-βAlaNleCycMSH(hex) FORMULA 23414214 A 126 132 azolyl SYSTEMATIC 23414214 A 161 172 carboxylate SYSTEMATIC 23414214 A 198 204 methyl SYSTEMATIC 23414214 A 237 254 pyrazolyl-diamine SYSTEMATIC 23414214 A 330 342 (99m)Tc(CO)3 FORMULA 23414214 A 351 357 lactam SYSTEMATIC 23414214 A 365 406 cyclized α-melanocyte stimulating hormone TRIVIAL 23414214 A 419 437 βAlaNleCycMSH(hex) FORMULA 23414214 A 445 462 pyrazolyl-diamine SYSTEMATIC 23414214 A 503 519 βAlaNleCycMSHhex FORMULA 23414214 A 743 754 carboxylate SYSTEMATIC 23414214 A 768 774 azolyl SYSTEMATIC 23414214 A 867 904 (99m)Tc(CO)3-Pz(3)-βAlaNleCycMSH(hex) FORMULA 23414214 A 909 946 (99m)Tc(CO)3-Pz(4)-βAlaNleCycMSH(hex) FORMULA 23414214 A 981 1018 (99m)Tc(CO)3-Pz(1)-βAlaNleCycMSH(hex) FORMULA 23414214 T 76 86 99mTc(CO)3 FORMULA 23414214 T 95 134 cyclic α-melanocyte stimulating hormone TRIVIAL 23414235 A 33 41 tyrosine TRIVIAL 23414235 A 51 61 vegfrecine TRIVIAL 23414235 T 0 10 Vegfrecine TRIVIAL 23414235 T 42 50 Tyrosine TRIVIAL 23414340 A 0 20 Dimethylarsinic acid SYSTEMATIC 23414340 A 1015 1026 glutathione TRIVIAL 23414340 A 1028 1031 GSH ABBREVIATION 23414340 A 1044 1051 phorone TRIVIAL 23414340 A 1055 1058 BSO ABBREVIATION 23414340 A 1087 1094 DMAs(V) FORMULA 23414340 A 1129 1133 DMAs FORMULA 23414340 A 1184 1193 periodate SYSTEMATIC 23414340 A 1203 1212 adenosine TRIVIAL 23414340 A 1247 1254 DMAs(V) FORMULA 23414340 A 130 151 dimethylarsinous acid SYSTEMATIC 23414340 A 1321 1328 DMAs(V) FORMULA 23414340 A 1360 1363 GSH ABBREVIATION 23414340 A 1385 1390 thiol FAMILY 23414340 A 1401 1405 GSSG ABBREVIATION 23414340 A 1410 1426 dehydroascorbate SYSTEMATIC 23414340 A 1477 1492 aurothioglucose SYSTEMATIC 23414340 A 1497 1504 Sb(III) FORMULA 23414340 A 1526 1533 DMAs(V) FORMULA 23414340 A 153 162 DMAs(III) FORMULA 23414340 A 1570 1575 NADPH ABBREVIATION 23414340 A 1631 1638 DMAs(V) FORMULA 23414340 A 1784 1789 NADPH ABBREVIATION 23414340 A 191 202 glutathione TRIVIAL 23414340 A 1916 1923 DMAs(V) FORMULA 23414340 A 1944 1953 DMAs(III) FORMULA 23414340 A 1989 1992 GSH ABBREVIATION 23414340 A 203 204 S FORMULA 23414340 A 22 29 DMAs(V) FORMULA 23414340 A 237 244 arsenic SYSTEMATIC 23414340 A 302 309 DMAs(V) FORMULA 23414340 A 335 342 DMAs(V) FORMULA 23414340 A 424 431 DMAs(V) FORMULA 23414340 A 435 444 DMAs(III) FORMULA 23414340 A 536 543 DMAs(V) FORMULA 23414340 A 659 674 dimethylarsenic SYSTEMATIC 23414340 A 676 680 DMAs FORMULA 23414340 A 700 709 DMAs(III) FORMULA 23414340 A 727 734 DMAs(V) FORMULA 23414340 A 74 81 arsenic SYSTEMATIC 23414340 A 805 812 DMAs(V) FORMULA 23414340 A 816 825 DMAs(III) FORMULA 23414340 A 895 902 DMAs(V) FORMULA 23414340 A 925 934 DMAs(III) FORMULA 23414340 T 13 33 dimethylarsinic acid SYSTEMATIC 23414340 T 54 75 dimethylarsinous acid SYSTEMATIC 23414527 A 228 236 graphene TRIVIAL 23414527 A 24 33 graphenes FAMILY 23414527 A 363 377 graphene oxide SYSTEMATIC 23414527 A 466 474 graphene TRIVIAL 23414527 A 575 583 graphene TRIVIAL 23414527 T 59 67 graphene TRIVIAL 23414800 A 112 133 11beta-hydroxysteroid FAMILY 23414800 A 18 98 5-trans-hydroxyadamantan-2-yl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-ones FAMILY 23414800 A 190 213 7-membered cyclic amide SYSTEMATIC 23414800 T 19 42 7-membered cyclic amide SYSTEMATIC 23414800 T 69 89 1beta-hydroxysteroid FAMILY 23414805 A 198 218 5-sulfonyl tetrazole SYSTEMATIC 23414805 A 226 246 5-Sulfonyl tetrazole SYSTEMATIC 23414805 A 286 291 thiol FAMILY 23414805 A 306 326 5-sulfinyl tetrazole SYSTEMATIC 23414805 A 419 433 Cyclosporine A TRIVIAL 23414805 A 506 526 5-sulfonyl tetrazole SYSTEMATIC 23414805 A 618 632 cyclosporine A TRIVIAL 23414805 A 634 648 Cyclosporine A TRIVIAL 23414805 A 671 691 5-sulfinyl tetrazole SYSTEMATIC 23414805 T 40 60 5-sulfonyl tetrazole SYSTEMATIC 23414807 A 1067 1078 bicarbonate SYSTEMATIC 23414807 A 254 257 CO2 FORMULA 23414807 A 443 450 cyanate SYSTEMATIC 23414807 A 452 459 cyanide SYSTEMATIC 23414807 A 461 477 hydrogen sulfide SYSTEMATIC 23414807 A 479 495 hydrogen sulfite SYSTEMATIC 23414807 A 501 517 trithiocarbonate SYSTEMATIC 23414807 A 633 655 diethyldithiocarbamate SYSTEMATIC 23414807 A 657 666 sulfamide SYSTEMATIC 23414807 A 668 677 sulfamate SYSTEMATIC 23414807 A 679 697 phenylboronic acid SYSTEMATIC 23414807 A 702 720 phenylarsonic acid SYSTEMATIC 23414807 A 742 749 Halides FAMILY 23414807 A 751 758 bromide SYSTEMATIC 23414807 A 760 766 iodide SYSTEMATIC 23414807 A 769 780 bicarbonate SYSTEMATIC 23414807 A 785 794 carbonate FAMILY 23414807 A 903 914 bicarbonate SYSTEMATIC 23414808 A 183 191 isoprene TRIVIAL 23414808 A 233 244 phosphonate SYSTEMATIC 23414808 A 254 266 fosmidomycin TRIVIAL 23414808 A 284 293 tetrazoyl SYSTEMATIC 23414808 A 321 329 hydrogen SYSTEMATIC 23414808 A 343 344 N FORMULA 23414808 A 350 351 C FORMULA 23414808 A 364 373 tetrazole FAMILY 23414808 A 387 407 phosphonohydroxamate SYSTEMATIC 23414808 A 524 535 phosphonate SYSTEMATIC 23414808 A 536 545 phosphate SYSTEMATIC 23414808 T 36 61 phosphonohydroxamic acids FAMILY 23414839 A 0 22 Pentacycloundecylamine SYSTEMATIC 23414839 A 24 27 PCU ABBREVIATION 23414839 A 314 321 aza-PCU SYSTEMATIC 23414839 A 708 711 PCU ABBREVIATION 23414839 A 915 932 [(3)H]pentazocine SYSTEMATIC 23414839 A 950 957 oxa-PCU SYSTEMATIC 23414839 A 959 966 NGP1-01 IDENTIFIER 23414839 A 989 998 phenethyl SYSTEMATIC 23414839 T 31 54 pentacycloundecylamines FAMILY 23414844 A 0 14 Aminoglycoside FAMILY 23414844 A 1069 1083 aminoglycoside FAMILY 23414844 A 146 160 aminoglycoside FAMILY 23414844 A 229 243 aminoglycoside FAMILY 23414844 A 245 255 pyranmycin TRIVIAL 23414844 A 272 280 neomycin TRIVIAL 23414844 A 282 289 NEOF004 IDENTIFIER 23414844 A 329 343 aminoglycoside FAMILY 23414844 A 345 353 neomycin TRIVIAL 23414844 A 387 395 neomycin TRIVIAL 23414844 A 498 512 aminoglycoside FAMILY 23414844 A 762 777 aminoglycosides FAMILY 23414844 A 851 859 neomycin TRIVIAL 23414844 A 861 868 NEOF004 IDENTIFIER 23414844 A 968 976 neomycin TRIVIAL 23414844 T 78 93 aminoglycosides FAMILY 23414845 A 102 136 pyrazolo[4,3-c][2,1]benzothiazines FAMILY 23414845 A 271 354 8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide SYSTEMATIC 23414845 A 392 448 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin SYSTEMATIC 23414845 A 575 674 N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine 4,4-dioxide SYSTEMATIC 23415548 A 235 256 triterpene glycosides FAMILY 23415548 A 261 272 polyphenols FAMILY 23415548 T 26 47 triterpene glycosides FAMILY 23415548 T 52 63 polyphenols FAMILY 23415833 A 0 10 Profenofos TRIVIAL 23415833 A 1061 1064 BCP ABBREVIATION 23415833 A 1353 1363 profenofos TRIVIAL 23415833 A 1407 1410 BCP ABBREVIATION 23415833 A 1441 1451 profenofos TRIVIAL 23415833 A 188 198 Profenofos TRIVIAL 23415833 A 266 288 4-bromo-2-chlorophenol SYSTEMATIC 23415833 A 290 293 BCP ABBREVIATION 23415833 A 30 46 phosphorothioate SYSTEMATIC 23415833 A 361 364 BCP ABBREVIATION 23415833 A 47 63 organophosphorus FAMILY 23415833 A 484 487 BCP ABBREVIATION 23415833 A 530 540 creatinine TRIVIAL 23415833 A 573 583 creatinine TRIVIAL 23415833 A 622 632 profenofos TRIVIAL 23415833 A 701 704 BCP ABBREVIATION 23415833 A 816 826 profenofos TRIVIAL 23415833 A 913 923 profenofos TRIVIAL 23415833 A 927 930 BCP ABBREVIATION 23415833 T 14 24 profenofos TRIVIAL 23415833 T 28 50 4-bromo-2-chlorophenol SYSTEMATIC 23415902 A 1081 1093 Org 214444-0 IDENTIFIER 23415902 A 1105 1109 cAMP ABBREVIATION 23415902 A 1114 1123 estradiol TRIVIAL 23415902 A 1245 1257 Org 214444-0 IDENTIFIER 23415902 A 132 141 estradiol TRIVIAL 23415902 A 504 519 dihydropyridine SYSTEMATIC 23415902 A 541 553 Org 214444-0 IDENTIFIER 23415902 A 555 567 Org 214444-0 IDENTIFIER 23415902 A 690 702 Org 214444-0 IDENTIFIER 23415902 A 811 823 Org 214444-0 IDENTIFIER 23415902 A 890 894 cAMP ABBREVIATION 23415902 A 964 976 Org 214444-0 IDENTIFIER 23415903 A 237 243 BODIPY ABBREVIATION 23415903 A 244 247 TMR ABBREVIATION 23415903 A 470 476 BODIPY ABBREVIATION 23415903 A 477 480 TMR ABBREVIATION 23415903 A 50 53 ATP ABBREVIATION 23415903 T 70 73 ATP ABBREVIATION 23416003 A 0 43 Bicyclic pyrazinone and pyrimidinone amides MULTIPLE 23416003 A 330 338 hydrogen SYSTEMATIC 23416003 T 24 67 bicyclic pyrazinone and pyrimidinone amides MULTIPLE 23416004 A 0 14 Anacardic acid FAMILY 23416004 A 1044 1053 salicylic TRIVIAL 23416004 A 132 146 anacardic acid FAMILY 23416004 A 192 206 salicylic acid TRIVIAL 23416004 A 272 280 naphthyl SYSTEMATIC 23416004 A 292 300 naphthyl SYSTEMATIC 23416004 A 355 363 aldehyde SYSTEMATIC 23416004 A 434 448 o-anisic acids FAMILY 23416004 A 500 515 carboxylic acid SYSTEMATIC 23416004 A 579 593 tertiary amide SYSTEMATIC 23416004 A 660 674 tertiary amide SYSTEMATIC 23416004 A 736 750 tertiary amide SYSTEMATIC 23416004 A 825 835 carboxylic SYSTEMATIC 23416004 A 843 855 methyl ester SYSTEMATIC 23416004 A 897 903 sodium SYSTEMATIC 23416004 T 23 37 anacardic acid FAMILY 23416006 A 348 367 piperidinyl glycine SYSTEMATIC 23416006 A 73 122 piperidinyl glycine 2-cyano-4,5-methano pyrroline SYSTEMATIC 23416006 T 12 65 piperidinyl glycinyl 2-cyano-4,5-methano pyrrolidines FAMILY 23416007 A 305 312 proline TRIVIAL 23416040 A 1065 1073 nicotine TRIVIAL 23416040 A 1093 1101 nicotine TRIVIAL 23416040 A 1232 1240 nicotine TRIVIAL 23416040 A 1284 1292 nicotine TRIVIAL 23416040 A 1428 1436 nicotine TRIVIAL 23416040 A 1532 1540 nicotine TRIVIAL 23416040 A 1561 1569 nicotine TRIVIAL 23416040 A 1596 1604 nicotine TRIVIAL 23416040 A 1628 1636 nicotine TRIVIAL 23416040 A 1815 1823 nicotine TRIVIAL 23416040 A 1859 1867 nicotine TRIVIAL 23416040 A 217 225 nicotine TRIVIAL 23416040 A 336 344 nicotine TRIVIAL 23416040 A 459 467 nicotine TRIVIAL 23416040 A 551 559 nicotine TRIVIAL 23416040 A 660 668 nicotine TRIVIAL 23416040 A 808 816 nicotine TRIVIAL 23416040 A 81 94 acetylcholine SYSTEMATIC 23416040 A 818 826 nicotine TRIVIAL 23416040 A 862 870 nicotine TRIVIAL 23416040 A 922 930 nicotine TRIVIAL 23416040 T 20 33 acetylcholine SYSTEMATIC 23416040 T 60 68 nicotine TRIVIAL 23416040 T 89 97 nicotine TRIVIAL 23416065 A 1078 1088 diflunisal TRIVIAL 23416065 A 125 135 diflunisal TRIVIAL 23416065 A 196 206 diflunisal TRIVIAL 23416065 A 286 296 diflunisal TRIVIAL 23416065 A 32 42 diflunisal TRIVIAL 23416065 A 349 365 acetyldiflunisal SYSTEMATIC 23416065 A 411 421 fatty acid FAMILY 23416065 A 426 442 acetyldiflunisal SYSTEMATIC 23416065 A 457 473 acetyldiflunisal SYSTEMATIC 23416065 A 538 544 lysine TRIVIAL 23416065 A 583 599 acetyldiflunisal SYSTEMATIC 23416065 A 611 614 Lys FORMULA 23416065 A 682 692 diflunisal TRIVIAL 23416065 A 772 782 diflunisal TRIVIAL 23416065 A 879 895 acetyldiflunisal SYSTEMATIC 23416065 A 908 918 diflunisal TRIVIAL 23416065 T 38 48 diflunisal TRIVIAL 23416131 A 925 927 NO FORMULA 23416143 A 116 123 ethanol SYSTEMATIC 23416143 A 1293 1300 alcohol FAMILY 23416143 A 1315 1322 alcohol FAMILY 23416143 A 179 188 narirutin TRIVIAL 23416143 A 222 231 narirutin TRIVIAL 23416143 A 365 372 ethanol SYSTEMATIC 23416143 A 387 394 ethanol SYSTEMATIC 23416143 A 409 416 ethanol SYSTEMATIC 23416143 A 445 452 ethanol SYSTEMATIC 23416143 A 490 497 alcohol FAMILY 23416143 A 585 594 aspartate TRIVIAL 23416143 A 61 70 narirutin TRIVIAL 23416143 A 746 753 ethanol SYSTEMATIC 23416143 A 868 871 GSH ABBREVIATION 23416143 A 876 891 malondialdehyde TRIVIAL 23416143 A 963 970 alcohol FAMILY 23416143 T 0 9 Narirutin TRIVIAL 23416173 A 921 937 organophosphates FAMILY 23416178 A 1045 1050 DCVCS ABBREVIATION 23416178 A 1061 1066 DCVCS ABBREVIATION 23416178 A 1071 1076 TCVCS ABBREVIATION 23416178 A 1146 1150 DCVC ABBREVIATION 23416178 A 1155 1159 TCVC ABBREVIATION 23416178 A 1175 1179 DCVC ABBREVIATION 23416178 A 1184 1189 DCVCS ABBREVIATION 23416178 A 1339 1343 TCVC ABBREVIATION 23416178 A 1348 1353 TCVCS ABBREVIATION 23416178 A 1400 1404 DCVC ABBREVIATION 23416178 A 1441 1445 DCVC ABBREVIATION 23416178 A 152 160 cysteine TRIVIAL 23416178 A 1520 1524 AOAA ABBREVIATION 23416178 A 1528 1532 DCVC ABBREVIATION 23416178 A 1594 1599 DCVCS ABBREVIATION 23416178 A 1604 1609 TCVCS ABBREVIATION 23416178 A 161 162 S FORMULA 23416178 A 1720 1725 DCVCS ABBREVIATION 23416178 A 1730 1735 TCVCS ABBREVIATION 23416178 A 1775 1779 DCVC ABBREVIATION 23416178 A 1783 1787 TCVC ABBREVIATION 23416178 A 226 234 cysteine TRIVIAL 23416178 A 235 236 S FORMULA 23416178 A 259 291 S-(1,2-dichlorovinyl)-l-cysteine SYSTEMATIC 23416178 A 293 297 DCVC ABBREVIATION 23416178 A 303 338 S-(1,2,2-trichlorovinyl)-l-cysteine SYSTEMATIC 23416178 A 340 344 TCVC ABBREVIATION 23416178 A 361 365 DCVC ABBREVIATION 23416178 A 370 374 TCVC ABBREVIATION 23416178 A 48 65 trichloroethylene SYSTEMATIC 23416178 A 553 572 aminooxyacetic acid SYSTEMATIC 23416178 A 574 578 AOAA ABBREVIATION 23416178 A 589 593 DCVC ABBREVIATION 23416178 A 598 602 TCVC ABBREVIATION 23416178 A 67 70 TCE ABBREVIATION 23416178 A 686 728 S-(1,2-dichlorovinyl)-l-cysteine sulfoxide SYSTEMATIC 23416178 A 730 735 DCVCS ABBREVIATION 23416178 A 741 786 S-(1,2,2-trichlorovinyl)-l-cysteine sulfoxide SYSTEMATIC 23416178 A 76 95 tetrachloroethylene SYSTEMATIC 23416178 A 788 793 TCVCS ABBREVIATION 23416178 A 847 857 sulfoxides FAMILY 23416178 A 961 966 DCVCS ABBREVIATION 23416178 A 97 100 PCE ABBREVIATION 23416178 A 971 976 TCVCS ABBREVIATION 23416178 A 997 1002 TCVCS ABBREVIATION 23416178 T 20 28 cysteine TRIVIAL 23416178 T 29 30 S FORMULA 23416178 T 41 51 sulfoxides FAMILY 23416178 T 55 72 trichloroethylene SYSTEMATIC 23416178 T 77 96 tetrachloroethylene SYSTEMATIC 23416189 A 121 134 acid chloride FAMILY 23416189 A 135 211 3-methyl-1,6-diphenyl-1H-pyrazolo[3,4-b] pyrazine-5-carboxylic acid chloride SYSTEMATIC 23416189 A 17 58 indeno[2,1-e]pyrazolo[3,4-b]pyrazin-5-one SYSTEMATIC 23416189 A 222 227 AlCl3 FORMULA 23416189 A 239 242 CS2 FORMULA 23416189 A 318 342 Indenopyrazolopyrazinone FAMILY 23416189 T 45 86 indeno[2,1-e]pyrazolo[3,4-b]pyrazin-5-one SYSTEMATIC 23416410 A 1328 1332 TiO2 FORMULA 23416410 A 1334 1338 P-25 NO CLASS 23416410 A 1455 1459 P-25 NO CLASS 23416410 A 1575 1579 TiO2 FORMULA 23416410 A 280 284 TiO2 FORMULA 23416410 A 56 72 titanium dioxide SYSTEMATIC 23416410 A 79 83 TiO2 FORMULA 23416410 A 964 968 TiO2 FORMULA 23416410 T 28 32 TiO2 FORMULA 23416413 A 1258 1277 11-ketotestosterone SYSTEMATIC 23416413 A 126 142 naphthenic acids FAMILY 23416413 A 417 433 naphthenic acids FAMILY 23416413 A 862 870 steroids FAMILY 23416796 A 217 223 carbon SYSTEMATIC 23416796 A 427 433 carbon SYSTEMATIC 23416796 A 541 547 carbon SYSTEMATIC 23416796 A 731 737 carbon SYSTEMATIC 23416796 A 787 789 Ag FORMULA 23416796 T 144 150 carbon SYSTEMATIC 23416797 A 622 625 SDS ABBREVIATION 23417514 A 1025 1029 5-HT SYSTEMATIC 23417514 A 1044 1082 8-hydroxy-2-(di-n-propylamino)tetralin SYSTEMATIC 23417514 A 1084 1093 8-OH-DPAT SYSTEMATIC 23417514 A 1265 1269 5-HT SYSTEMATIC 23417514 A 1285 1330 (±)-2,5-dimethoxy-4-iodophenyl-2-aminopropane SYSTEMATIC 23417514 A 1332 1335 DOI ABBREVIATION 23417514 A 1386 1390 5-HT SYSTEMATIC 23417514 A 1469 1478 serotonin TRIVIAL 23417514 A 1891 1900 serotonin TRIVIAL 23417514 A 1912 1921 serotonin TRIVIAL 23417514 A 1969 1973 5-HT SYSTEMATIC 23417514 A 28 36 dopamine TRIVIAL 23417514 A 359 368 serotonin TRIVIAL 23417514 T 113 121 dopamine TRIVIAL 23417514 T 21 30 serotonin TRIVIAL 23417745 A 1137 1144 cadmium SYSTEMATIC 23417745 A 1148 1156 selenium SYSTEMATIC 23417745 A 233 240 cadmium SYSTEMATIC 23417745 A 245 253 selenium SYSTEMATIC 23417745 A 380 395 cadmium nitrate SYSTEMATIC 23417745 A 400 414 selenious acid SYSTEMATIC 23417745 A 567 574 cadmium SYSTEMATIC 23417745 A 579 587 selenium SYSTEMATIC 23417745 A 60 76 cadmium selenide SYSTEMATIC 23417745 A 763 770 cadmium SYSTEMATIC 23417745 A 775 783 selenium SYSTEMATIC 23417745 A 941 948 cadmium SYSTEMATIC 23417745 T 52 59 cadmium SYSTEMATIC 23417745 T 64 72 selenium SYSTEMATIC 23417974 A 199 206 silicon SYSTEMATIC 23418045 A 160 168 graphite TRIVIAL 23418045 A 24 43 zinc phthalocyanine SYSTEMATIC 23418045 A 242 250 graphene TRIVIAL 23418045 A 431 439 graphene TRIVIAL 23418045 A 49 68 zinc phthalocyanine SYSTEMATIC 23418045 A 594 614 zinc phthalocyanines FAMILY 23418045 A 75 79 oPPV ABBREVIATION 23418045 T 24 32 Graphene TRIVIAL 23418045 T 43 57 Phthalocyanine TRIVIAL 23418068 T 37 41 PVDF ABBREVIATION 23418081 A 104 111 diamine SYSTEMATIC 23418081 A 202 210 graphene TRIVIAL 23418081 A 21 29 graphene TRIVIAL 23418081 A 356 364 graphene TRIVIAL 23418081 T 35 43 graphene TRIVIAL 23418125 A 858 864 emodin TRIVIAL 23418125 A 868 889 hydroxylanthraquinone SYSTEMATIC 23418165 A 10 17 steviol TRIVIAL 23418165 A 108 129 diterpenoid glycoside FAMILY 23418165 A 131 141 stevioside TRIVIAL 23418165 A 310 317 steviol TRIVIAL 23418165 A 361 371 isosteviol TRIVIAL 23418165 A 50 60 isosteviol TRIVIAL 23418165 A 538 544 O-acyl FAMILY 23418165 A 569 628 ent-kaur-16-ene-13,19-diol 19-O-4',4',4'-trifluorocrotonate SYSTEMATIC 23418165 A 929 931 OH FORMULA 23418165 A 941 948 kaurane TRIVIAL 23418165 A 954 962 beyerane TRIVIAL 23418165 A 968 980 diterpenoids FAMILY 23418165 T 47 54 steviol TRIVIAL 23418165 T 59 69 isosteviol TRIVIAL 23418168 A 594 604 acetylenes FAMILY 23418168 A 606 622 matricaria ester TRIVIAL 23418168 A 705 719 sesquiterpenes FAMILY 23418168 A 799 815 matricaria ester TRIVIAL 23418168 A 816 835 caryophyllene oxide SYSTEMATIC 23418369 A 177 189 nicotinamide TRIVIAL 23418369 A 193 205 nicotinamide TRIVIAL 23418369 A 206 207 N FORMULA 23418369 A 265 273 aldehyde SYSTEMATIC 23418369 A 31 43 vitamin B(3) TRIVIAL 23418369 A 320 332 nicotinamide TRIVIAL 23418369 A 336 356 nicotinamide N-oxide SYSTEMATIC 23418369 A 631 651 nicotinamide N-oxide SYSTEMATIC 23418369 A 694 714 nicotinamide N-oxide SYSTEMATIC 23418369 A 7 19 nicotinamide TRIVIAL 23418369 T 0 12 Nicotinamide TRIVIAL 23418369 T 13 14 N FORMULA 23418719 A 326 328 Au FORMULA 23418719 A 333 335 Ag FORMULA 23418719 A 336 340 SiO2 FORMULA 23418719 A 46 51 Au-Ag FORMULA 23418719 A 499 501 Au FORMULA 23418719 A 52 56 SiO2 FORMULA 23418719 A 647 649 Au FORMULA 23418719 T 31 36 Au-Ag FORMULA 23418719 T 37 41 SiO₂ FORMULA 23418750 A 240 245 H2(+) FORMULA 23418750 A 250 256 Li2(+) FORMULA 23418750 A 522 526 Cu-B FORMULA 23418750 A 711 727 metalloboratrane FAMILY 23418750 T 15 20 boron SYSTEMATIC 23418750 T 8 14 copper SYSTEMATIC 23418783 A 0 16 Hydrogen sulfide SYSTEMATIC 23418783 A 18 23 H(2)S FORMULA 23418783 A 226 238 nitric oxide SYSTEMATIC 23418783 A 240 242 NO FORMULA 23418783 A 335 355 sodium nitroprusside SYSTEMATIC 23418783 A 357 360 SNP ABBREVIATION 23418783 A 366 371 H(2)S FORMULA 23418783 A 409 417 nitroxyl SYSTEMATIC 23418783 A 419 422 HNO FORMULA 23418783 A 475 478 SNP ABBREVIATION 23418783 A 483 488 H(2)S FORMULA 23418783 A 520 522 NO FORMULA 23418783 A 550 555 H(2)S FORMULA 23418783 A 571 574 HNO FORMULA 23418783 A 727 733 thiols FAMILY 23418783 A 735 738 SNP ABBREVIATION 23418783 A 751 756 H(2)S FORMULA 23418783 A 797 804 cyanide SYSTEMATIC 23418783 A 823 834 thiocyanate SYSTEMATIC 23418783 A 873 878 H(2)S FORMULA 23418783 A 910 923 nitroprusside SYSTEMATIC 23418783 A 997 1000 HNO FORMULA 23418783 T 137 140 HNO FORMULA 23418783 T 17 19 NO FORMULA 23418783 T 31 47 Hydrogen Sulfide SYSTEMATIC 23418783 T 52 65 Nitroprusside SYSTEMATIC 23418783 T 7 12 H(2)S FORMULA 23418783 T 89 97 Nitroxyl SYSTEMATIC 23418783 T 99 102 HNO FORMULA 23418815 A 19 48 5β-pregnane-2α,6α,20(S)-triol SYSTEMATIC 23418815 A 57 94 8-hydroxyl-3-methoxyl-2(1H)-quinolone SYSTEMATIC 23418956 A 270 285 polydiacetylene FAMILY 23418956 A 287 290 PDA ABBREVIATION 23418956 A 34 43 butadiyne SYSTEMATIC 23418956 A 75 81 phenyl SYSTEMATIC 23418956 T 90 100 butadiynes FAMILY 23419043 A 948 952 CFSE ABBREVIATION 23419390 A 516 524 carbonyl FAMILY 23419390 A 618 624 oxygen SYSTEMATIC 23419685 A 1410 1412 Mn FORMULA 23419685 A 920 929 manganese SYSTEMATIC 23419685 T 30 39 manganese SYSTEMATIC 23419776 A 1681 1684 BPs ABBREVIATION 23419776 A 537 552 bisphosphonates FAMILY 23419776 A 554 557 BPs ABBREVIATION 23419812 A 923 934 terbinafine TRIVIAL 23419816 A 0 16 Poly(amidoamine) FAMILY 23419816 A 1069 1077 carboxyl SYSTEMATIC 23419816 A 1080 1085 amine SYSTEMATIC 23419816 A 1091 1099 hydroxyl SYSTEMATIC 23419816 A 1128 1132 COOH FORMULA 23419816 A 1137 1140 NH2 FORMULA 23419816 A 1145 1147 OH FORMULA 23419816 A 1313 1318 PAMAM ABBREVIATION 23419816 A 1425 1430 PAMAM ABBREVIATION 23419816 A 18 23 PAMAM ABBREVIATION 23419816 A 303 308 PAMAM ABBREVIATION 23419816 A 438 443 PAMAM ABBREVIATION 23419816 A 552 557 PAMAM ABBREVIATION 23419816 A 888 893 amine SYSTEMATIC 23419816 A 898 906 hydroxyl SYSTEMATIC 23419816 T 36 52 poly(amidoamine) SYSTEMATIC 23419872 A 1001 1004 GSH ABBREVIATION 23419872 A 1095 1098 DIC ABBREVIATION 23419872 A 1104 1107 OGC ABBREVIATION 23419872 A 1260 1263 GSH ABBREVIATION 23419872 A 1332 1343 antimycin A TRIVIAL 23419872 A 1397 1400 GSH ABBREVIATION 23419872 A 1612 1615 GSH ABBREVIATION 23419872 A 852 865 dicarboxylate SYSTEMATIC 23419872 A 867 870 DIC ABBREVIATION 23419872 A 886 898 oxoglutarate SYSTEMATIC 23419872 A 900 903 OGC ABBREVIATION 23419872 A 988 999 glutathione TRIVIAL 23419872 T 28 39 glutathione TRIVIAL 23420023 A 206 208 Bi FORMULA 23420023 A 215 217 Cu FORMULA 23420023 A 283 291 Cu oxide SYSTEMATIC 23420023 A 323 326 CuO FORMULA 23420023 A 341 343 Bi FORMULA 23420023 A 346 348 Cu FORMULA 23420023 A 349 354 oxide SYSTEMATIC 23420023 A 386 393 CuBi2O4 FORMULA 23420023 A 395 397 Cd FORMULA 23420023 A 399 401 Zn FORMULA 23420023 A 403 405 Sn FORMULA 23420023 A 411 413 Co FORMULA 23420023 A 445 447 Cu FORMULA 23420023 A 448 454 oxides FAMILY 23420023 A 512 515 CuO FORMULA 23420023 A 517 519 Ag FORMULA 23420023 A 521 523 Cd FORMULA 23420023 A 529 531 Zn FORMULA 23420023 A 566 568 Bi FORMULA 23420023 A 571 573 Cu FORMULA 23420023 A 574 580 oxides FAMILY 23420023 A 614 621 CuBi2O4 FORMULA 23420023 A 64 66 Bi FORMULA 23420023 A 641 655 Bi-Ag-Cu oxide SYSTEMATIC 23420023 A 657 659 Bi FORMULA 23420023 A 662 664 Ag FORMULA 23420023 A 667 669 Cu FORMULA 23420023 A 69 71 Cu FORMULA 23420023 A 72 77 oxide SYSTEMATIC 23420023 A 744 751 CuBi2O4 FORMULA 23420023 A 790 798 hydrogen SYSTEMATIC 23420023 A 873 875 Pt FORMULA 23420023 T 134 142 hydrogen SYSTEMATIC 23420023 T 71 83 copper oxide SYSTEMATIC 23420023 T 88 108 copper bismuth oxide SYSTEMATIC 23420214 A 0 12 Succinyl-CoA TRIVIAL 23420214 A 100 106 ketone SYSTEMATIC 23420214 A 346 352 ketone SYSTEMATIC 23420214 A 411 414 CoA ABBREVIATION 23420214 A 427 439 succinyl-CoA TRIVIAL 23420214 A 448 463 acetoacetyl-CoA SYSTEMATIC 23420214 A 484 502 tricarboxylic acid SYSTEMATIC 23420214 T 42 54 succinyl-CoA TRIVIAL 23420700 A 8 22 methacrylamide SYSTEMATIC 23420700 T 8 22 Methacrylamide SYSTEMATIC 23421374 A 433 436 PEG ABBREVIATION 23421374 A 563 580 perylene-bisimide SYSTEMATIC 23421374 A 593 606 [60]fullerene TRIVIAL 23421374 A 638 650 camptothecin TRIVIAL 23421374 A 652 655 CPT ABBREVIATION 23421374 A 662 665 C60 TRIVIAL 23421374 A 825 828 CPT ABBREVIATION 23421374 A 916 919 CPT ABBREVIATION 23421432 A 10 33 lanostanoid triterpenes FAMILY 23421432 A 102 176 3β,7β,15β-trihydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid methyl ester SYSTEMATIC 23421432 A 186 259 3β,15β-dihydroxy-7,11,23-trioxo-lanost-8,16-dien-26-oic acid methyl ester SYSTEMATIC 23421432 A 287 292 EtOAc FORMULA 23421432 A 35 96 3β,7β,15β-trihydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid SYSTEMATIC 23421432 T 10 33 lanostanoid triterpenes FAMILY 23421434 A 234 237 GaP FORMULA 23421434 A 238 240 Si FORMULA 23421434 A 524 526 Si FORMULA 23421517 A 165 180 rosmarinic acid TRIVIAL 23421517 A 208 264 3-(4,5-Dimethylthiazol)-2,5-diphenyl tetrazolium bromide SYSTEMATIC 23421517 A 266 269 MTT ABBREVIATION 23421517 A 337 340 Adr ABBREVIATION 23421517 A 386 396 adriamycin TRIVIAL 23421517 A 398 410 rhodamine123 TRIVIAL 23421517 A 412 417 Rh123 ABBREVIATION 23421517 A 677 680 Adr ABBREVIATION 23421517 A 731 734 Adr ABBREVIATION 23421517 A 739 744 Rh123 ABBREVIATION 23421517 T 19 34 rosmarinic acid TRIVIAL 23421517 T 70 73 Adr ABBREVIATION 23421585 A 30 42 streptazones FAMILY 23421585 A 8 28 piperidine alkaloids FAMILY 23421585 T 8 28 piperidine alkaloids FAMILY 23421616 A 1166 1182 naphthothiazoles FAMILY 23421616 A 1238 1261 2-amino-naphthothiazole SYSTEMATIC 23421616 A 336 345 quinoidal FAMILY 23421616 A 363 371 thiazole SYSTEMATIC 23421616 T 65 81 naphthothiazoles FAMILY 23421620 A 16 32 sesquiterpenoids FAMILY 23421620 A 210 236 3β,11,12-trihydroxydrimene SYSTEMATIC 23421620 A 34 68 11,12-dihydroxy-15-drimeneoic acid SYSTEMATIC 23421620 A 77 103 3α,11,15-trihydroxydrimene SYSTEMATIC 23421620 A 8 15 drimane TRIVIAL 23421620 T 8 22 sesquiterpenes FAMILY 23421648 A 0 9 Berberine TRIVIAL 23421648 A 1116 1125 berberine TRIVIAL 23421648 A 1329 1338 berberine TRIVIAL 23421648 A 16 37 isoquinoline alkaloid FAMILY 23421648 A 201 210 berberine TRIVIAL 23421648 A 391 400 berberine TRIVIAL 23421648 A 613 622 berberine TRIVIAL 23421648 A 804 813 berberine TRIVIAL 23421648 A 847 856 berberine TRIVIAL 23421648 A 993 1002 berberine TRIVIAL 23421648 T 42 51 berberine TRIVIAL 23421649 A 102 118 sesquiterpenoids FAMILY 23421649 A 120 135 tremulenediol A TRIVIAL 23421649 A 141 162 2β-hydroxy-α-candinol SYSTEMATIC 23421649 A 168 178 epicubenol TRIVIAL 23421649 A 188 209 3β-hydroxy-δ-candinol SYSTEMATIC 23421649 A 26 41 tremulenolide D TRIVIAL 23421649 A 399 408 tremulane TRIVIAL 23421649 A 414 430 sesquiterpenoids FAMILY 23421649 A 447 462 perhydroazulene SYSTEMATIC 23421649 A 463 469 carbon SYSTEMATIC 23421649 A 50 71 muurolane-10β,15-diol SYSTEMATIC 23421649 A 8 24 sesquiterpenoids FAMILY 23421649 T 8 24 sesquiterpenoids FAMILY 23421650 A 177 190 myristic acid TRIVIAL 23421650 A 195 227 cetyl trimethylammonium chloride SYSTEMATIC 23421717 A 10 28 phenyl-ethanediols FAMILY 23421717 A 119 154 (1R)-(3-acetophenyl)-1,2-ethanediol SYSTEMATIC 23421717 A 277 307 (3-ethylphenyl)-1,2-ethanediol SYSTEMATIC 23421717 A 30 67 (1R)-(3-ethenylphenyl)-1,2-ethanediol SYSTEMATIC 23421717 A 316 346 (4-acetophenyl)-1,2-ethanediol SYSTEMATIC 23421717 A 73 109 (1R)-(3-formylphenyl)-1,2-ethanediol SYSTEMATIC 23421717 T 10 28 phenyl-ethanediols FAMILY 23421757 A 1143 1152 Silibinin TRIVIAL 23421757 A 752 761 Silibinin TRIVIAL 23421757 A 983 992 silibinin TRIVIAL 23421757 T 67 76 silibinin TRIVIAL 23421779 A 109 133 5,6,7-trimethoxycoumarin SYSTEMATIC 23421779 A 139 153 d-calycanthine TRIVIAL 23421779 A 159 173 calycanthoside TRIVIAL 23421779 A 179 189 xeroboside TRIVIAL 23421779 A 199 209 scopoletin TRIVIAL 23421779 A 36 52 nitensosides A-B MULTIPLE 23421779 A 8 27 coumarin glycosides FAMILY 23421779 A 95 103 scopolin TRIVIAL 23421779 T 8 27 coumarin glycosides FAMILY 23421798 A 1001 1005 CuCl FORMULA 23421798 A 1007 1011 CuBr FORMULA 23421798 A 1017 1020 CuI FORMULA 23421798 A 1070 1075 CuCCH FORMULA 23421798 A 1195 1200 Cu(+) FORMULA 23421798 A 1218 1224 CCH(-) FORMULA 23421798 A 1289 1294 Cu(+) FORMULA 23421798 A 1318 1324 CCH(-) FORMULA 23421798 A 152 155 ArF FAMILY 23421798 A 168 170 F2 FORMULA 23421798 A 35 40 CuCCH FORMULA 23421798 A 738 742 Cu-C FORMULA 23421798 A 895 901 Cu-C≡C FORMULA 23421798 A 996 999 CuF FORMULA 23421798 T 52 68 Copper Acetylide SYSTEMATIC 23421798 T 70 75 CuCCH FORMULA 23421850 A 1563 1567 NaCl FORMULA 23421850 A 241 245 NaCl FORMULA 23421850 A 979 983 mica TRIVIAL 23421879 A 1112 1134 LiNi0.70Co0.15Mn0.15O2 FORMULA 23421879 A 185 191 LiNiO2 FORMULA 23421879 A 226 228 Ni FORMULA 23421879 A 27 54 lithium nickel metal oxides FAMILY 23421879 A 388 391 NiO FORMULA 23421879 A 511 533 LiNi0.62Co0.14Mn0.24O2 FORMULA 23421879 A 56 73 Li[Ni(1-x)M(x)]O2 FAMILY 23421879 A 579 585 Ni(2+) FORMULA 23421879 A 607 609 Li FORMULA 23421879 A 683 703 polyvinylpyrrolidone SYSTEMATIC 23421879 A 705 708 PVP ABBREVIATION 23421879 A 725 727 Mn FORMULA 23421879 A 749 771 Ni0.7Co0.15Mn0.15(OH)2 FORMULA 23421879 A 84 86 Co FORMULA 23421879 A 88 90 Mn FORMULA 23421879 A 96 98 Al FORMULA 23421879 T 57 59 Ni FORMULA 23421930 A 147 162 stenocepflavone TRIVIAL 23421930 A 168 182 stenocepflavan TRIVIAL 23421930 A 192 203 stenocephol TRIVIAL 23421930 A 223 235 cirsimaritin TRIVIAL 23421930 A 241 284 5,7,5'-trihydroxy-3',4',6-trimethoxyflavone SYSTEMATIC 23421930 A 290 329 5,6,7,5'-tetrahydroxy-4'-methoxyflavone SYSTEMATIC 23421930 A 339 351 axillaroside TRIVIAL 23421930 A 34 47 ethyl acetate SYSTEMATIC 23421930 T 10 19 phenolics FAMILY 23422035 A 1093 1107 deoxynivalenol TRIVIAL 23422035 A 1112 1123 zearalenone TRIVIAL 23422073 A 451 458 glucose TRIVIAL 23422073 A 670 677 calcium SYSTEMATIC 23422225 A 110 118 catechin TRIVIAL 23422225 A 124 135 epicatechin TRIVIAL 23422225 A 141 164 epicatechin 3-O-gallate SYSTEMATIC 23422225 A 170 205 epicatechin 3-O-(3-O-methyl)gallate SYSTEMATIC 23422225 A 211 250 epicatechin 3-O-(3,5-O-dimethyl)gallate SYSTEMATIC 23422225 A 256 298 epicatechin 3-O-(3,4,5-O-trimethyl)gallate SYSTEMATIC 23422225 A 29 46 linamarin gallate TRIVIAL 23422225 A 304 337 quercetin 3-O-β-d-glucopyranoside SYSTEMATIC 23422225 A 343 348 rutin TRIVIAL 23422225 A 359 370 peltatoside TRIVIAL 23422225 A 539 559 cyanogenic glycoside FAMILY 23422225 A 55 68 walsuraside B TRIVIAL 23422225 A 663 683 cyanogenic glycoside FAMILY 23422225 A 774 778 (1)H FORMULA 23422225 A 780 785 (13)C FORMULA 23422225 A 8 27 phenolic glycosides FAMILY 23422225 A 929 959 2, 2-diphenyl-1-picrylhydrazyl SYSTEMATIC 23422225 A 961 965 DPPH ABBREVIATION 23422225 T 14 25 polyphenols FAMILY 23422298 A 0 14 Kynurenic acid TRIVIAL 23422298 A 1037 1041 KYNA ABBREVIATION 23422298 A 1153 1157 NMDA ABBREVIATION 23422298 A 1184 1188 KYNA ABBREVIATION 23422298 A 1343 1347 KYNA ABBREVIATION 23422298 A 1359 1363 KYNA ABBREVIATION 23422298 A 1418 1427 thiorphan TRIVIAL 23422298 A 156 160 KYNA ABBREVIATION 23422298 A 16 20 KYNA ABBREVIATION 23422298 A 1674 1678 KYNA ABBREVIATION 23422298 A 354 358 KYNA ABBREVIATION 23422298 A 413 417 NMDA ABBREVIATION 23422298 A 496 500 KYNA ABBREVIATION 23422298 A 54 64 kynurenine TRIVIAL 23422298 A 691 695 KYNA ABBREVIATION 23422298 A 859 863 KYNA ABBREVIATION 23422298 A 90 100 tryptophan TRIVIAL 23422298 T 19 33 kynurenic acid TRIVIAL 23422566 A 340 346 lysine TRIVIAL 23422566 A 763 769 lysine TRIVIAL 23422566 A 771 774 Lys FORMULA 23422569 A 1063 1073 superoxide TRIVIAL 23422569 A 1095 1100 NADPH ABBREVIATION 23422569 A 1199 1210 resveratrol TRIVIAL 23422569 A 1300 1311 resveratrol TRIVIAL 23422569 A 1419 1431 nicotinamide TRIVIAL 23422569 A 1515 1526 resveratrol TRIVIAL 23422569 A 1619 1624 NADPH ABBREVIATION 23422569 A 1909 1914 NADPH ABBREVIATION 23422569 A 192 198 NAD(+) ABBREVIATION 23422569 A 1949 1951 NO FORMULA 23422569 A 397 402 NADPH ABBREVIATION 23422569 A 444 450 oxygen SYSTEMATIC 23422569 A 52 57 NADPH ABBREVIATION 23422569 A 575 587 nicotinamide TRIVIAL 23422569 A 589 597 sirtinol TRIVIAL 23422569 A 599 604 EX527 IDENTIFIER 23422569 A 801 814 acetylcholine SYSTEMATIC 23422569 A 823 830 calcium SYSTEMATIC 23422569 A 841 847 A23187 IDENTIFIER 23422569 A 952 957 NADPH ABBREVIATION 23422569 A 976 984 apocynin TRIVIAL 23422569 A 988 998 superoxide TRIVIAL 23422569 T 15 20 NADPH ABBREVIATION 23422727 A 126 137 P[Asp(DET)] ABBREVIATION 23422727 A 159 178 polyethylene glycol SYSTEMATIC 23422727 A 179 198 (PEG)-b-P[Asp(DET)] ABBREVIATION 23422727 A 74 125 poly{N'-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} FAMILY 23422727 A 763 780 PEG-b-P[Asp(DET)] ABBREVIATION 23423570 A 1029 1036 dapsone TRIVIAL 23423570 A 1204 1211 glucose TRIVIAL 23423570 A 532 539 glucose TRIVIAL 23423570 A 687 693 oxygen SYSTEMATIC 23423570 T 5 12 glucose TRIVIAL 23423711 A 1269 1279 8-oxo-dGuo SYSTEMATIC 23423711 A 896 923 8-hydroxy-2'-deoxyguanosine SYSTEMATIC 23423711 A 925 935 8-oxo-dGuo SYSTEMATIC 23423904 A 0 6 Nickel SYSTEMATIC 23423904 A 1048 1054 Ca(2+) FORMULA 23423904 A 1058 1063 CaSO4 FORMULA 23423904 A 1075 1081 Mg(2+) FORMULA 23423904 A 1085 1090 MgSO4 FORMULA 23423904 A 1105 1110 Na(+) FORMULA 23423904 A 1114 1120 NaHCO3 FORMULA 23423904 A 1156 1158 Ni FORMULA 23423904 A 1193 1198 Na(+) FORMULA 23423904 A 1204 1208 NaCl FORMULA 23423904 A 1233 1235 Ni FORMULA 23423904 A 1338 1343 Cl(-) FORMULA 23423904 A 1386 1391 Cl(-) FORMULA 23423904 A 1440 1442 Ni FORMULA 23423904 A 257 259 Ni FORMULA 23423904 A 376 378 Ni FORMULA 23423904 A 469 475 Nickel SYSTEMATIC 23423904 A 611 617 Nickel SYSTEMATIC 23423904 A 700 702 Ni FORMULA 23423904 A 8 10 Ni FORMULA 23423904 A 946 952 Mg(2+) FORMULA 23423904 A 955 961 Ca(2+) FORMULA 23423904 A 964 969 Na(+) FORMULA 23423904 A 976 981 Cl(-) FORMULA 23423904 A 985 987 Ni FORMULA 23423904 T 35 41 nickel SYSTEMATIC 23423993 A 0 12 Nitrobenzene SYSTEMATIC 23423993 T 48 60 nitrobenzene SYSTEMATIC 23424203 A 670 679 histidine TRIVIAL 23424206 A 1014 1024 superoxide TRIVIAL 23424206 A 1099 1102 DOX ABBREVIATION 23424206 A 1108 1111 NAC ABBREVIATION 23424206 A 1126 1129 DOX ABBREVIATION 23424206 A 1144 1147 DOX ABBREVIATION 23424206 A 1153 1156 NAC ABBREVIATION 23424206 A 1215 1218 DOX ABBREVIATION 23424206 A 1274 1277 DOX ABBREVIATION 23424206 A 1285 1288 NAC ABBREVIATION 23424206 A 1379 1382 DOX ABBREVIATION 23424206 A 1435 1438 NAC ABBREVIATION 23424206 A 1451 1454 DOX ABBREVIATION 23424206 A 263 266 NAC ABBREVIATION 23424206 A 363 375 doxorubucine TRIVIAL 23424206 A 377 380 DOX ABBREVIATION 23424206 A 404 407 NAC ABBREVIATION 23424206 A 486 489 DOX ABBREVIATION 23424206 A 49 65 N-acetylcysteine SYSTEMATIC 23424206 A 499 502 DOX ABBREVIATION 23424206 A 67 70 NAC ABBREVIATION 23424206 A 729 748 thiobarbituric acid SYSTEMATIC 23424206 A 75 87 doxorubucine TRIVIAL 23424206 A 780 792 nitric oxide SYSTEMATIC 23424206 A 794 796 NO FORMULA 23424206 A 825 828 DOX ABBREVIATION 23424206 A 843 846 DOX ABBREVIATION 23424206 A 874 876 NO FORMULA 23424206 A 878 887 aspartate TRIVIAL 23424206 A 902 909 lactate FAMILY 23424206 A 928 936 creatine TRIVIAL 23424206 T 0 16 N-Acetylcysteine SYSTEMATIC 23424206 T 26 38 doxorubucine TRIVIAL 23424217 A 1144 1154 clonazepam TRIVIAL 23424217 A 1159 1168 tiagabine TRIVIAL 23424217 A 1376 1386 clonazepam TRIVIAL 23424217 A 1391 1400 tiagabine TRIVIAL 23424217 A 366 372 sodium SYSTEMATIC 23424217 A 524 528 GABA ABBREVIATION 23424217 A 617 621 GABA ABBREVIATION 23424217 A 639 649 clonazepam TRIVIAL 23424217 A 654 663 tiagabine TRIVIAL 23424217 A 765 775 Clonazepam TRIVIAL 23424217 A 812 816 GABA ABBREVIATION 23424217 A 897 906 Tiagabine TRIVIAL 23424217 A 922 926 GABA ABBREVIATION 23424217 T 12 16 GABA ABBREVIATION 23425034 A 224 233 acridines FAMILY 23425034 A 363 372 acridines FAMILY 23425034 A 819 827 acridine TRIVIAL 23425034 T 17 25 acridine TRIVIAL 23425125 A 457 466 carvacrol TRIVIAL 23425125 A 476 487 α-terpineol TRIVIAL 23425125 A 499 507 p-cymene TRIVIAL 23425125 A 522 531 carvacrol TRIVIAL 23425125 A 539 547 p-cymene TRIVIAL 23425125 A 560 568 α-pinene TRIVIAL 23425125 A 640 649 carvacrol TRIVIAL 23425199 A 0 9 Carbamate SYSTEMATIC 23425199 A 1045 1051 URB597 IDENTIFIER 23425199 A 106 118 carbamoylate SYSTEMATIC 23425199 A 14 18 urea TRIVIAL 23425199 A 147 150 Ser FORMULA 23425199 A 405 406 O FORMULA 23425199 A 422 428 URB597 IDENTIFIER 23425199 A 442 443 N FORMULA 23425199 A 460 470 JNJ1661610 IDENTIFIER 23425199 A 559 567 oleamide TRIVIAL 23425199 A 56 66 fatty acid FAMILY 23425199 A 56 72 fatty acid amide FAMILY 23425199 A 594 602 carbamic SYSTEMATIC 23425199 A 618 621 Ser FORMULA 23425199 A 67 72 amide FAMILY 23425199 A 786 808 piperazine carboxylate SYSTEMATIC 23425199 A 851 871 cyclohexyl carbamate SYSTEMATIC 23425199 A 885 891 URB597 IDENTIFIER 23425199 A 985 1002 N-piperazinylurea SYSTEMATIC 23425199 T 50 60 fatty acid FAMILY 23425199 T 50 66 fatty acid amide FAMILY 23425199 T 61 66 amide FAMILY 23425274 A 376 379 SDS ABBREVIATION 23425274 A 528 540 carbohydrate FAMILY 23425274 A 561 569 sarcosyl TRIVIAL 23425274 A 716 719 SDS ABBREVIATION 23425314 A 151 157 silver SYSTEMATIC 23425314 A 271 276 Ag(+) FORMULA 23425314 A 332 334 Ag FORMULA 23425314 A 386 417 poly(sulfobetaine methacrylate) FAMILY 23425314 A 419 424 pSBMA ABBREVIATION 23425314 A 430 463 poly(carboxybetaine methacrylate) FAMILY 23425314 A 465 470 pCBMA ABBREVIATION 23425314 A 523 529 silver SYSTEMATIC 23425314 A 546 552 silver SYSTEMATIC 23425314 A 585 590 pCBMA ABBREVIATION 23425314 A 614 619 pCBMA ABBREVIATION 23425314 A 620 626 silver SYSTEMATIC 23425314 A 638 640 Ag FORMULA 23425314 T 0 6 Silver SYSTEMATIC 23425969 A 138 201 10-ethyl-2-(diethylamino)pyrimido[1,2-a]benzimidazol-4(10H)-one SYSTEMATIC 23425969 A 209 272 10-ethyl-4-(diethylamino)pyrimido[1,2-a]benzimidazol-2(10H)-one SYSTEMATIC 23425969 A 37 108 10-substituted 2-(1-piperazinyl)pyrimido[1,2-a]benzimidazol-4(10H)-ones FAMILY 23425969 A 406 409 ADP ABBREVIATION 23425969 A 427 433 Ca(2+) FORMULA 23425969 A 444 450 A23187 IDENTIFIER 23425969 A 492 509 2-(1-piperazinyl) SYSTEMATIC 23425969 T 77 148 10-substituted 2-(1-piperazinyl)pyrimido[1,2-a]benzimidazol-4(10H)-ones FAMILY 23425970 A 18 32 pyranochalcone FAMILY 23425970 T 45 59 pyranochalcone FAMILY 23426858 A 17 21 (1)H FORMULA 23426955 A 1024 1035 hematoxylin TRIVIAL 23426955 A 1036 1041 eosin FAMILY 23426955 A 1052 1058 silver SYSTEMATIC 23426955 A 1069 1081 Voriconazole TRIVIAL 23426955 A 1085 1097 posaconazole TRIVIAL 23426955 A 1354 1366 voriconazole TRIVIAL 23426955 A 1388 1400 posaconazole TRIVIAL 23427017 A 125 133 atrazine TRIVIAL 23427017 A 1259 1267 atrazine TRIVIAL 23427017 A 1387 1395 atrazine TRIVIAL 23427017 A 373 381 atrazine TRIVIAL 23427017 A 636 644 atrazine TRIVIAL 23427017 A 969 977 atrazine TRIVIAL 23427017 A 982 990 atrazine TRIVIAL 23427017 T 25 33 atrazine TRIVIAL 23427190 A 1030 1040 vardenafil TRIVIAL 23427190 A 1162 1172 vardenafil TRIVIAL 23427190 A 1184 1194 Vardenafil TRIVIAL 23427190 A 284 294 vardenafil TRIVIAL 23427190 A 542 552 vardenafil TRIVIAL 23427190 A 785 795 vardenafil TRIVIAL 23427190 A 894 904 vardenafil TRIVIAL 23427190 A 969 979 vardenafil TRIVIAL 23427190 T 54 64 vardenafil TRIVIAL 23427194 A 119 128 serotonin TRIVIAL 23427194 A 1371 1374 CPZ ABBREVIATION 23427194 A 178 186 dopamine TRIVIAL 23427194 A 234 248 chlorpromazine TRIVIAL 23427194 A 250 253 CPZ ABBREVIATION 23427194 A 513 516 CPZ ABBREVIATION 23427194 A 612 615 CPZ ABBREVIATION 23427194 A 646 649 CPZ ABBREVIATION 23427194 A 728 739 risperidone TRIVIAL 23427194 A 741 749 zotepine TRIVIAL 23427194 A 751 762 perospirone TRIVIAL 23427194 A 814 824 olanzapine TRIVIAL 23427194 A 826 837 bromperidol TRIVIAL 23427194 A 843 854 haloperidol TRIVIAL 23427194 A 987 990 CPZ ABBREVIATION 23427194 T 104 115 haloperidol TRIVIAL 23427194 T 23 31 dopamine TRIVIAL 23427194 T 44 53 serotonin TRIVIAL 23427194 T 75 89 chlorpromazine TRIVIAL 23427194 T 91 102 bromperidol TRIVIAL 23427810 A 1117 1121 TMDC ABBREVIATION 23427810 A 14 46 transition metal dichalcogenides FAMILY 23427810 A 438 442 MoS2 FORMULA 23427810 A 48 53 TMDCs FAMILY 23427810 A 635 639 MoS2 FORMULA 23427810 A 724 728 SiO2 FORMULA 23427810 A 730 738 sapphire TRIVIAL 23427810 T 43 47 MoS₂ FORMULA 23427825 A 162 171 adenosine TRIVIAL 23427825 A 309 311 Me FORMULA 23427825 A 313 315 Ph FORMULA 23427825 A 317 322 CH2Ph FORMULA 23427825 A 339 343 acyl FAMILY 23427825 A 348 357 carbamoyl SYSTEMATIC 23427825 A 393 400 7-amino SYSTEMATIC 23427825 A 40 77 2-arylpyrazolo[4,3-d]pyrimidin-7-ones FAMILY 23427825 A 421 433 para-methoxy SYSTEMATIC 23427825 A 456 464 2-phenyl SYSTEMATIC 23427825 A 487 491 acyl FAMILY 23427825 A 615 626 7-acylamino SYSTEMATIC 23427825 A 744 777 pyrazolo[4,3-d]pyrimidin-7-amides FAMILY 23427825 A 810 821 oxaliplatin TRIVIAL 23427825 A 88 127 2-arylpyrazolo[4,3-d]pyrimidin-7-amines FAMILY 23427825 T 0 38 2-Arylpyrazolo[4,3-d]pyrimidin-7-amino FAMILY 23427825 T 88 97 Adenosine TRIVIAL 23427901 A 164 174 oxysporone TRIVIAL 23427901 A 182 201 dihydrofuropyranone SYSTEMATIC 23427901 A 61 71 phyllostin TRIVIAL 23427901 A 80 89 scytolide TRIVIAL 23427901 A 99 126 hexahydro-1,4-benzodioxines FAMILY 23427901 T 109 119 Phyllostin TRIVIAL 23427901 T 121 130 Scytolide TRIVIAL 23427901 T 136 146 Oxysporone TRIVIAL 23428094 A 599 604 H2SO4 FORMULA 23428109 A 1099 1107 baclofen TRIVIAL 23428109 A 179 187 baclofen TRIVIAL 23428109 A 191 220 3-aminopropyl phosphinic acid SYSTEMATIC 23428109 A 241 263 difluoromethyl ketones FAMILY 23428109 A 312 328 trifluoroacetate SYSTEMATIC 23428109 A 397 401 GABA ABBREVIATION 23428109 A 434 455 difluoromethyl ketone SYSTEMATIC 23428109 A 560 567 alcohol FAMILY 23428109 A 69 91 difluoromethyl ketones FAMILY 23428109 A 808 817 fluorines FAMILY 23428109 A 825 846 difluoromethyl ketone SYSTEMATIC 23428109 A 852 861 hydrogens FAMILY 23428109 A 944 965 difluoromethyl ketone SYSTEMATIC 23428109 T 14 36 difluoromethyl ketones FAMILY 23428109 T 56 75 γ-aminobutyric acid SYSTEMATIC 23428163 A 161 163 CO FORMULA 23428163 A 168 170 H2 FORMULA 23428163 A 446 451 Pt-Co FORMULA 23428163 A 719 721 Co FORMULA 23428163 A 746 748 Pt FORMULA 23428163 A 756 761 Pt-Co FORMULA 23428163 T 0 8 Platinum SYSTEMATIC 23428163 T 19 25 cobalt SYSTEMATIC 23428368 A 194 204 fatty acid FAMILY 23428368 A 251 267 triiodothyronine TRIVIAL 23428368 A 400 411 bezafibrate TRIVIAL 23428368 A 413 416 Bzf ABBREVIATION 23428368 A 473 476 Bzf ABBREVIATION 23428368 A 590 593 Bzf ABBREVIATION 23428368 A 714 717 ATP ABBREVIATION 23428368 A 767 770 Bzf ABBREVIATION 23428368 A 959 962 Bzf ABBREVIATION 23428403 A 1190 1193 ATP ABBREVIATION 23428403 A 157 168 polyphenols FAMILY 23428403 A 411 421 polyphenol FAMILY 23428403 A 622 631 flavonoid FAMILY 23428403 A 633 663 phloretin-3',5'-di-C-glucoside SYSTEMATIC 23428403 A 686 694 xanthone TRIVIAL 23428403 A 696 706 mangiferin TRIVIAL 23428403 A 742 751 flavanone TRIVIAL 23428403 A 840 852 triglyceride FAMILY 23428407 A 164 167 TBT ABBREVIATION 23428407 A 412 415 TBT ABBREVIATION 23428407 A 710 713 TBT ABBREVIATION 23428407 T 89 100 tributyltin SYSTEMATIC 23428645 A 0 29 (-)-Δ(9)-Tetrahydrocannabinol SYSTEMATIC 23428645 A 1037 1053 fatty acid amide FAMILY 23428645 A 1075 1105 phenylmethanesulfonyl fluoride SYSTEMATIC 23428645 A 1140 1155 (-)-cannabidiol TRIVIAL 23428645 A 1159 1169 anandamide TRIVIAL 23428645 A 1205 1220 (-)-cannabidiol TRIVIAL 23428645 A 1333 1348 (-)-cannabidiol TRIVIAL 23428645 A 1435 1446 cannabidiol TRIVIAL 23428645 A 249 264 (-)-cannabidiol TRIVIAL 23428645 A 639 654 (-)-cannabidiol TRIVIAL 23428645 A 683 698 (-)-cannabidiol TRIVIAL 23428645 A 806 821 (-)-Cannabidiol TRIVIAL 23428645 A 891 900 carbachol TRIVIAL 23428645 A 902 911 histamine TRIVIAL 23428645 A 942 957 (-)-cannabidiol TRIVIAL 23428645 A 968 978 anandamide TRIVIAL 23428645 A 984 995 virodhamine TRIVIAL 23428645 T 15 26 cannabidiol TRIVIAL 23428794 A 1102 1110 ketamine TRIVIAL 23428794 A 1246 1254 ketamine TRIVIAL 23428794 A 32 40 ketamine TRIVIAL 23428794 A 323 331 ketamine TRIVIAL 23428794 A 345 353 ketamine TRIVIAL 23428794 A 908 916 Ketamine TRIVIAL 23428794 T 29 37 ketamine TRIVIAL 23428833 A 1060 1062 Pb FORMULA 23428833 A 1134 1143 verapamil TRIVIAL 23428833 A 1148 1158 nimodipine TRIVIAL 23428833 A 1204 1208 urea TRIVIAL 23428833 A 1209 1217 nitrogen SYSTEMATIC 23428833 A 1222 1232 creatinine TRIVIAL 23428833 A 1260 1269 verapamil TRIVIAL 23428833 A 1274 1284 nimodipine TRIVIAL 23428833 A 131 138 calcium SYSTEMATIC 23428833 A 1310 1325 malondialdehyde TRIVIAL 23428833 A 1362 1373 super oxide TRIVIAL 23428833 A 1397 1408 glutathione TRIVIAL 23428833 A 152 154 Pb FORMULA 23428833 A 1528 1530 Pb FORMULA 23428833 A 1605 1607 Pb FORMULA 23428833 A 18 20 Pb FORMULA 23428833 A 217 224 calcium SYSTEMATIC 23428833 A 332 339 calcium SYSTEMATIC 23428833 A 364 373 verapamil TRIVIAL 23428833 A 378 388 nimodipine TRIVIAL 23428833 A 418 428 Pb acetate SYSTEMATIC 23428833 A 517 519 Pb FORMULA 23428833 A 530 539 verapamil TRIVIAL 23428833 A 551 560 verapamil TRIVIAL 23428833 A 571 581 nimodipine TRIVIAL 23428833 A 596 606 nimodipine TRIVIAL 23428833 A 625 635 Pb acetate SYSTEMATIC 23428833 A 731 733 Pb FORMULA 23428833 A 856 865 verapamil TRIVIAL 23428833 A 869 879 nimodipine TRIVIAL 23428833 A 904 913 verapamil TRIVIAL 23428833 A 918 928 nimodipine TRIVIAL 23428833 A 955 957 Pb FORMULA 23428833 T 27 34 calcium SYSTEMATIC 23428959 A 372 386 benzo[a]pyrene SYSTEMATIC 23428959 A 388 393 B[a]P ABBREVIATION 23428959 A 409 431 ethyl methanesulfonate SYSTEMATIC 23428959 A 433 436 EMS ABBREVIATION 23428959 A 867 872 B[a]P ABBREVIATION 23428960 A 622 628 citral TRIVIAL 23428960 A 630 647 cinnamic aldehyde TRIVIAL 23428960 A 652 662 isoeugenol TRIVIAL 23428981 A 148 151 CPF ABBREVIATION 23428981 A 40 52 chlorpyrifos TRIVIAL 23428981 A 54 57 CPF ABBREVIATION 23428981 A 681 694 acetylcholine SYSTEMATIC 23428981 A 957 960 CPF ABBREVIATION 23428981 T 47 59 chlorpyrifos TRIVIAL 23429263 A 1142 1153 brefeldin A TRIVIAL 23429263 A 130 140 amino acid FAMILY 23429263 A 798 799 C FORMULA 23429274 A 1121 1131 superoxide TRIVIAL 23429274 A 130 142 Nitric oxide SYSTEMATIC 23429274 A 176 185 guanylate TRIVIAL 23429274 A 214 218 cGMP ABBREVIATION 23429274 A 319 331 nitric oxide SYSTEMATIC 23429274 A 941 945 cGMP ABBREVIATION 23429274 T 33 45 nitric oxide SYSTEMATIC 23429274 T 67 76 guanylate TRIVIAL 23429907 A 1065 1077 nanographene TRIVIAL 23429907 A 263 275 nanographene TRIVIAL 23429907 A 476 484 graphene TRIVIAL 23429907 A 562 574 nanographene TRIVIAL 23429907 A 616 624 graphene TRIVIAL 23429907 A 803 811 hydrogen SYSTEMATIC 23429907 A 819 820 H FORMULA 23429907 A 89 97 graphene TRIVIAL 23429907 A 927 928 H FORMULA 23429907 T 87 99 nanographene TRIVIAL 23429912 A 1190 1194 TCDD ABBREVIATION 23429912 A 1206 1210 TCDD ABBREVIATION 23429912 A 1443 1447 TCDD ABBREVIATION 23429912 A 1548 1552 TCDD ABBREVIATION 23429912 A 1680 1684 TCDD ABBREVIATION 23429912 A 295 299 TCDD ABBREVIATION 23429912 A 30 66 2,3,7,8-tetrachlorodibenzo-p- dioxin SYSTEMATIC 23429912 A 569 573 TCDD ABBREVIATION 23429912 A 643 647 TCDD ABBREVIATION 23429912 A 68 72 TCDD ABBREVIATION 23429912 A 776 780 TCDD ABBREVIATION 23429912 T 0 4 TCDD ABBREVIATION 23430139 A 1165 1171 oxygen SYSTEMATIC 23430139 A 1306 1312 oxygen SYSTEMATIC 23430139 A 1543 1561 nickel subsulphide SYSTEMATIC 23430139 A 1566 1582 gallium arsenide SYSTEMATIC 23430139 A 1584 1588 GaAs FORMULA 23430139 A 1675 1681 oxygen SYSTEMATIC 23430139 A 1736 1740 GaAs FORMULA 23430139 A 1805 1823 nickel subsulphide SYSTEMATIC 23430139 A 1910 1916 oxygen SYSTEMATIC 23430139 A 1938 1942 GaAs FORMULA 23430139 A 2034 2040 oxygen SYSTEMATIC 23430139 A 2110 2114 GaAs FORMULA 23430139 A 2127 2145 nickel subsulphide SYSTEMATIC 23430139 A 2341 2345 GaAs FORMULA 23430139 A 2593 2599 oxygen SYSTEMATIC 23430139 A 417 423 oxygen SYSTEMATIC 23430139 A 596 602 oxygen SYSTEMATIC 23430139 A 829 835 oxygen SYSTEMATIC 23430139 A 950 956 oxygen SYSTEMATIC 23430410 A 1056 1076 monodehydroascorbate SYSTEMATIC 23430410 A 1159 1161 As FORMULA 23430410 A 1181 1197 dehydroascorbate SYSTEMATIC 23430410 A 1267 1269 As FORMULA 23430410 A 1277 1288 glutathione TRIVIAL 23430410 A 1371 1373 As FORMULA 23430410 A 1385 1387 NO FORMULA 23430410 A 152 159 arsenic SYSTEMATIC 23430410 A 1524 1526 As FORMULA 23430410 A 1575 1578 SNP ABBREVIATION 23430410 A 1608 1611 SNP ABBREVIATION 23430410 A 161 163 As FORMULA 23430410 A 1631 1634 chl ABBREVIATION 23430410 A 1639 1642 Pro FORMULA 23430410 A 1653 1656 AsA ABBREVIATION 23430410 A 1661 1664 GSH ABBREVIATION 23430410 A 1682 1685 GSH ABBREVIATION 23430410 A 1686 1690 GSSG ABBREVIATION 23430410 A 1800 1802 As FORMULA 23430410 A 1867 1869 NO FORMULA 23430410 A 1907 1909 As FORMULA 23430410 A 194 196 NO FORMULA 23430410 A 212 232 sodium nitroprusside SYSTEMATIC 23430410 A 234 237 SNP ABBREVIATION 23430410 A 243 245 As FORMULA 23430410 A 263 276 Na2HAsO4·7H2O FORMULA 23430410 A 364 375 chlorophyll FAMILY 23430410 A 377 380 chl ABBREVIATION 23430410 A 408 410 As FORMULA 23430410 A 425 432 proline TRIVIAL 23430410 A 434 437 Pro FORMULA 23430410 A 466 475 ascorbate TRIVIAL 23430410 A 477 480 AsA ABBREVIATION 23430410 A 533 535 As FORMULA 23430410 A 569 571 As FORMULA 23430410 A 602 605 MDA ABBREVIATION 23430410 A 610 614 H2O2 FORMULA 23430410 A 646 657 glutathione TRIVIAL 23430410 A 659 662 GSH ABBREVIATION 23430410 A 668 689 glutathione disulfide SYSTEMATIC 23430410 A 691 695 GSSG ABBREVIATION 23430410 A 73 85 nitric oxide SYSTEMATIC 23430410 A 754 756 As FORMULA 23430410 A 791 794 GSH ABBREVIATION 23430410 A 795 799 GSSG ABBREVIATION 23430410 A 854 863 ascorbate TRIVIAL 23430410 A 87 89 NO FORMULA 23430410 A 879 890 glutathione TRIVIAL 23430410 A 891 892 S FORMULA 23430410 A 963 965 As FORMULA 23430410 A 987 998 glutathione TRIVIAL 23430410 T 10 30 sodium nitroprusside SYSTEMATIC 23430410 T 42 49 arsenic SYSTEMATIC 23432060 A 1258 1262 Ca2+ FORMULA 23432060 A 1442 1446 Ca2+ FORMULA 23432060 A 1504 1508 Ca2+ FORMULA 23432060 A 1840 1844 Ca2+ FORMULA 23432062 A 377 381 Ca2+ FORMULA 23432062 A 406 410 Ca2+ FORMULA 23432062 A 449 453 Ca2+ FORMULA 23432065 A 203 212 Vanilloid FAMILY 23432090 A 0 17 Manganese-peroxos FAMILY 23432090 A 1103 1106 O-O FORMULA 23432090 A 1176 1187 Mn(III)-OOR FAMILY 23432090 A 1224 1227 O-O FORMULA 23432090 A 1247 1268 N-heterocyclic amines FAMILY 23432090 A 1364 1367 O-O FORMULA 23432090 A 1476 1486 peroxo O-O SYSTEMATIC 23432090 A 1543 1564 N-heterocyclic amines FAMILY 23432090 A 1647 1650 O-O FORMULA 23432090 A 428 439 Mn(III)-OOR FAMILY 23432090 A 528 539 Mn(III)-OOR FAMILY 23432090 A 584 606 Mn(III)-(η(1)-peroxos) FAMILY 23432090 A 910 913 O-O FORMULA 23432090 A 918 920 Mn FORMULA 23432090 A 923 933 N(py,quin) FORMULA 23432090 A 967 970 O-O FORMULA 23432090 A 974 976 Mn FORMULA 23432090 A 989 992 O-O FORMULA 23432090 T 126 162 manganese(III)-alkylperoxo complexes FAMILY 23432093 A 161 165 iron SYSTEMATIC 23432093 A 177 207 bis(2,4-methylpentadienyl)iron SYSTEMATIC 23432093 A 288 293 Fe3O4 FORMULA 23432093 A 297 304 α-Fe2O3 FORMULA 23432093 A 347 353 oxygen SYSTEMATIC 23432093 A 461 468 α-Fe2O3 FORMULA 23432093 A 490 494 H2O2 FORMULA 23432093 A 512 518 Fe(2+) FORMULA 23432093 A 519 525 Fe(3+) FORMULA 23432093 A 534 539 Fe3O4 FORMULA 23432093 A 68 79 iron oxides FAMILY 23432093 A 743 753 iron oxide SYSTEMATIC 23432093 A 798 805 α-Fe2O3 FORMULA 23432093 T 105 116 iron oxides FAMILY 23432124 A 0 7 IKM-159 IDENTIFIER 23432124 A 115 119 AMPA ABBREVIATION 23432124 A 198 205 IKM-159 IDENTIFIER 23432124 A 338 345 IKM-159 IDENTIFIER 23432124 A 414 452 (R)-2-amino-2-(4-methoxyphenyl)ethanol SYSTEMATIC 23432124 A 476 488 (2R)-IKM-159 IDENTIFIER 23432124 A 752 764 (2R)-IKM-159 IDENTIFIER 23432124 A 824 839 Racemic IKM-159 IDENTIFIER 23432124 A 83 92 glutamate TRIVIAL 23432124 A 946 958 (2R)-IKM-159 IDENTIFIER 23432124 A 990 1002 (2R)-IKM-159 IDENTIFIER 23432124 T 103 110 IKM-159 IDENTIFIER 23432124 T 14 75 (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid SYSTEMATIC 23432124 T 77 81 AMPA ABBREVIATION 23432134 A 110 153 (24R)- and (24S)-cycloart-25-en-3b,24-diols MULTIPLE 23432134 A 155 168 palmitic acid TRIVIAL 23432134 A 16 52 5αH,6βH,7αH,11αH-guaian-12,6α-olides FAMILY 23432134 A 173 186 1-octacosanol SYSTEMATIC 23432134 A 54 81 11-epi-8α-hydroxyarborescin SYSTEMATIC 23432134 T 6 17 guaianolide FAMILY 23432336 A 31 51 poly(ε-caprolactone) FAMILY 23432420 A 861 869 aldehyde SYSTEMATIC 23432420 T 91 99 Aldehyde SYSTEMATIC 23432465 A 103 107 PAHs ABBREVIATION 23432465 A 1141 1156 2-aminofluorene SYSTEMATIC 23432465 A 1161 1178 2-aminoanthracene SYSTEMATIC 23432465 A 1474 1478 PAHs ABBREVIATION 23432465 A 1483 1512 aryl- and heterocyclic amines MULTIPLE 23432465 A 154 166 acenaphthene TRIVIAL 23432465 A 1541 1553 nitrosamines FAMILY 23432465 A 168 182 acenaphthylene TRIVIAL 23432465 A 184 204 benzo[c]phenanthrene SYSTEMATIC 23432465 A 206 218 fluoranthene SYSTEMATIC 23432465 A 220 241 fluoranthene-2,3-diol SYSTEMATIC 23432465 A 247 260 1-nitropyrene SYSTEMATIC 23432465 A 292 304 acenaphthene TRIVIAL 23432465 A 309 323 acenaphthylene TRIVIAL 23432465 A 338 350 fluoranthene SYSTEMATIC 23432465 A 352 373 fluoranthene-2,3-diol SYSTEMATIC 23432465 A 378 391 1-nitropyrene SYSTEMATIC 23432465 A 445 449 PAHs ABBREVIATION 23432465 A 477 481 PAHs ABBREVIATION 23432465 A 489 519 7,12-dimethylbenz[a]anthracene SYSTEMATIC 23432465 A 521 560 7,12-dimethylbenz[a]anthracene-5,6-diol SYSTEMATIC 23432465 A 562 582 benzo[c]phenanthrene SYSTEMATIC 23432465 A 584 596 fluoranthene SYSTEMATIC 23432465 A 598 619 fluoranthene-2,3-diol SYSTEMATIC 23432465 A 621 637 5-methylchrysene SYSTEMATIC 23432465 A 639 661 benz[a]pyrene-4,5-diol SYSTEMATIC 23432465 A 663 686 benzo[a]pyrene-7,8-diol SYSTEMATIC 23432465 A 688 701 1-nitropyrene SYSTEMATIC 23432465 A 69 101 polycyclic aromatic hydrocarbons FAMILY 23432465 A 703 720 2-aminoanthracene SYSTEMATIC 23432465 A 722 737 2-aminofluorene SYSTEMATIC 23432465 A 743 764 2-acetylaminofluorene SYSTEMATIC 23432465 A 858 862 PAHs ABBREVIATION 23432465 A 867 896 aryl- and heterocyclic amines MULTIPLE 23432465 T 24 56 Polycyclic Aromatic Hydrocarbons FAMILY 23432465 T 61 89 Aryl and Heterocyclic Amines MULTIPLE 23432580 A 0 26 Farnesylthiosalisylic acid SYSTEMATIC 23432580 A 1381 1384 FTS ABBREVIATION 23432580 A 155 158 FTS ABBREVIATION 23432580 A 28 31 FTS ABBREVIATION 23432580 A 721 724 FTS ABBREVIATION 23432580 A 829 832 FTS ABBREVIATION 23432580 T 31 41 farnesoids FAMILY 23432580 T 51 59 steroids FAMILY 23432581 A 1160 1166 carbon SYSTEMATIC 23432581 A 311 317 carbon SYSTEMATIC 23432581 A 556 562 Carbon SYSTEMATIC 23432581 A 799 805 carbon SYSTEMATIC 23432581 T 19 25 carbon SYSTEMATIC 23432590 A 1090 1102 camptothecin TRIVIAL 23432590 A 131 144 camptothecins FAMILY 23432590 A 1386 1399 camptothecins FAMILY 23432590 A 1598 1611 camptothecins FAMILY 23432590 A 282 295 camptothecins FAMILY 23432590 A 497 509 camptothecin TRIVIAL 23432590 A 59 72 camptothecins FAMILY 23432590 A 677 689 camptothecin TRIVIAL 23432590 A 787 799 camptothecin TRIVIAL 23432590 T 0 12 Camptothecin TRIVIAL 23432662 A 1204 1216 carbonitrile SYSTEMATIC 23432662 A 309 316 glucose TRIVIAL 23432662 A 81 94 Rosiglitazone TRIVIAL 23432753 A 206 222 iron oxyfluoride SYSTEMATIC 23432753 A 878 879 F FORMULA 23432753 A 91 93 Li FORMULA 23432753 A 915 916 O FORMULA 23432753 A 927 928 F FORMULA 23432753 A 934 935 O FORMULA 23432753 A 968 970 Fe FORMULA 23432753 A 976 977 F FORMULA 23432753 T 79 83 FeOF FORMULA 23434031 A 105 122 6-methyl pyridone SYSTEMATIC 23434193 A 0 35 Omega-3 polyunsaturated fatty acids FAMILY 23434193 A 342 371 omega-3 eicosapentaenoic acid SYSTEMATIC 23434193 A 37 42 PUFAs ABBREVIATION 23434193 A 373 376 EPA ABBREVIATION 23434193 A 382 402 docosahexaenoic acid SYSTEMATIC 23434193 A 404 407 DHA ABBREVIATION 23434193 A 417 426 resolvins FAMILY 23434193 A 694 701 aspirin TRIVIAL 23434193 T 28 37 resolvins FAMILY 23434223 A 181 213 5-aryldihydro-3(2H)-thiophenones FAMILY 23434223 A 19 86 5-amino-2,7-diaryl-2,3-dihydrobenzo[b]thiophene-4,6-dicarbonitriles FAMILY 23434223 A 215 228 malononitrile TRIVIAL 23434223 A 233 251 aromatic aldehydes FAMILY 23434223 A 271 281 morpholine SYSTEMATIC 23434223 A 551 631 5-amino-2,7-bis(4-methoxyphenyl)-2,3-dihydrobenzo[b]thiophene-4,6-dicarbonitrile SYSTEMATIC 23434223 T 66 91 dihydrobenzo[b]thiophenes FAMILY 23434224 T 0 8 Pyridine SYSTEMATIC 23434224 T 12 19 aniline SYSTEMATIC 23434227 A 206 209 MTT ABBREVIATION 23434227 A 22 36 oleanolic acid TRIVIAL 23434227 A 453 454 H FORMULA 23434227 A 493 507 oleanolic acid TRIVIAL 23434227 T 41 55 oleanolic acid TRIVIAL 23434417 A 0 50 2-(Benzothiazol-2-yl)-phenyl-β-d-galactopyranoside SYSTEMATIC 23434417 T 0 50 2-(Benzothiazol-2-yl)-phenyl-β-d-galactopyranoside SYSTEMATIC 23434506 A 106 118 coenzyme Q10 TRIVIAL 23434506 A 123 128 CoQ10 ABBREVIATION 23434506 A 155 164 cisplatin TRIVIAL 23434506 A 307 312 CoQ10 ABBREVIATION 23434506 A 387 396 cisplatin TRIVIAL 23434506 A 504 509 CoQ10 ABBREVIATION 23434506 A 649 658 cisplatin TRIVIAL 23434506 A 797 802 CoQ10 ABBREVIATION 23434506 A 833 842 cisplatin TRIVIAL 23434506 A 925 930 CoQ10 ABBREVIATION 23434506 T 0 12 Coenzyme Q10 TRIVIAL 23434506 T 38 47 cisplatin TRIVIAL 23434663 A 132 148 timosaponin AIII TRIVIAL 23434663 A 150 156 TA-III ABBREVIATION 23434663 A 179 193 ginsenoside Re TRIVIAL 23434663 A 224 230 TA-III ABBREVIATION 23434663 A 731 737 TA-III ABBREVIATION 23434663 A 959 965 TA-III ABBREVIATION 23434663 T 37 53 Timosaponin AIII TRIVIAL 23434829 A 1014 1017 DUN ABBREVIATION 23434829 A 1102 1105 DUN ABBREVIATION 23434829 A 1222 1232 paclitaxel TRIVIAL 23434829 A 1234 1245 doxorubicin TRIVIAL 23434829 A 1247 1260 actinomycin-D TRIVIAL 23434829 A 1266 1275 rapamycin TRIVIAL 23434829 A 1392 1395 DUN ABBREVIATION 23434829 A 329 337 arginine TRIVIAL 23434829 A 338 345 glycine TRIVIAL 23434829 A 346 359 aspartic acid TRIVIAL 23434829 A 583 586 ATP ABBREVIATION 23434829 A 745 755 Daunomycin TRIVIAL 23434829 A 757 760 DUN ABBREVIATION 23434829 A 914 917 DUN ABBREVIATION 23434831 A 1053 1065 asperolide A TRIVIAL 23434831 A 1241 1253 asperolide A TRIVIAL 23434831 A 1334 1343 Cisplatin TRIVIAL 23434831 A 1460 1472 asperolide A TRIVIAL 23434831 A 296 308 asperolide A TRIVIAL 23434831 A 31 43 asperolide A TRIVIAL 23434831 A 531 543 asperolide A TRIVIAL 23434831 A 678 685 PD98059 IDENTIFIER 23434831 A 85 104 tetranorditerpenoid FAMILY 23434831 A 881 893 asperolide A TRIVIAL 23434831 T 0 12 Asperolide A TRIVIAL 23434831 T 31 50 tetranorditerpenoid FAMILY 23434832 A 1137 1144 lipid A TRIVIAL 23434832 A 285 292 lipid A TRIVIAL 23434832 A 4 11 lipid A TRIVIAL 23434832 A 437 444 lipid A TRIVIAL 23434832 A 63 88 hexaacylated disaccharide FAMILY 23434832 A 631 653 monophosphoryl lipid A TRIVIAL 23434832 A 728 764 pentaacylated monophosphoryl lipid A TRIVIAL 23434832 A 784 791 lipid A TRIVIAL 23434832 A 92 103 glucosamine TRIVIAL 23434832 T 16 38 monophosphoryl lipid A TRIVIAL 23435157 A 843 854 cholesterol TRIVIAL 23435157 A 878 885 aspirin TRIVIAL 23435160 A 215 222 glucose TRIVIAL 23435263 A 1070 1080 amino acid FAMILY 23435263 A 545 551 serine TRIVIAL 23435358 A 1011 1015 PFOA ABBREVIATION 23435358 A 1020 1024 PFOS ABBREVIATION 23435358 A 1079 1101 dehydroepiandrosterone TRIVIAL 23435358 A 1103 1107 DHEA ABBREVIATION 23435358 A 1122 1134 testosterone TRIVIAL 23435358 A 1179 1187 cortisol TRIVIAL 23435358 A 1192 1203 cholesterol TRIVIAL 23435358 A 1244 1248 PFOA ABBREVIATION 23435358 A 1253 1257 PFOS ABBREVIATION 23435358 A 1280 1284 DHEA ABBREVIATION 23435358 A 1289 1296 estrone TRIVIAL 23435358 A 1304 1308 PFOS ABBREVIATION 23435358 A 1319 1323 DHEA ABBREVIATION 23435358 A 1332 1336 PFOA ABBREVIATION 23435358 A 1379 1383 PFOS ABBREVIATION 23435358 A 1394 1401 estrone TRIVIAL 23435358 A 1403 1407 PFOA ABBREVIATION 23435358 A 1525 1541 FA methyl esters FAMILY 23435358 A 1543 1548 FAMEs FAMILY 23435358 A 1551 1580 mono- and poly-unsaturated FA MULTIPLE 23435358 A 1582 1586 MUFA ABBREVIATION 23435358 A 1591 1595 PUFA ABBREVIATION 23435358 A 1623 1627 PUFA ABBREVIATION 23435358 A 1642 1646 PFOA ABBREVIATION 23435358 A 1651 1655 PFOS ABBREVIATION 23435358 A 1688 1706 pentadecenoic MUFA SYSTEMATIC 23435358 A 1723 1728 PUFAs ABBREVIATION 23435358 A 1729 1745 α-linolenic acid TRIVIAL 23435358 A 1747 1750 ALA ABBREVIATION 23435358 A 1765 1786 eicosapentaenoic acid SYSTEMATIC 23435358 A 1788 1791 EPA ABBREVIATION 23435358 A 1811 1815 PUFA ABBREVIATION 23435358 A 1817 1833 arachidonic acid TRIVIAL 23435358 A 1835 1838 ARA ABBREVIATION 23435358 A 1850 1871 docosapentaenoic acid SYSTEMATIC 23435358 A 186 190 PFOS ABBREVIATION 23435358 A 1873 1876 DPA ABBREVIATION 23435358 A 1881 1885 PFOA ABBREVIATION 23435358 A 1890 1894 PFOS ABBREVIATION 23435358 A 195 199 PFOA ABBREVIATION 23435358 A 2168 2172 PFOS ABBREVIATION 23435358 A 2177 2181 PFOA ABBREVIATION 23435358 A 218 226 methanol SYSTEMATIC 23435358 A 553 560 steroid FAMILY 23435358 A 571 582 fatty acids FAMILY 23435358 A 584 587 FAs ABBREVIATION 23435358 A 731 735 PFOS ABBREVIATION 23435358 A 740 744 PFOA ABBREVIATION 23435358 A 90 94 PFOA ABBREVIATION 23435358 A 908 912 PFOA ABBREVIATION 23435358 A 98 102 PFOS ABBREVIATION 23435358 T 167 227 perfluorooctane sulfonic or perfluorooctane carboxylic acids MULTIPLE 23435358 T 58 69 fatty acids FAMILY 23435358 T 74 81 steroid FAMILY 23435367 A 118 125 steroid FAMILY 23435367 A 118 133 steroid hormone FAMILY 23435367 A 39 43 iron SYSTEMATIC 23435367 A 44 50 sulfur SYSTEMATIC 23435367 A 660 668 8Br-cAMP SYSTEMATIC 23435367 A 808 820 progesterone TRIVIAL 23435367 A 927 931 cAMP ABBREVIATION 23435367 A 963 970 steroid FAMILY 23435367 A 963 978 steroid hormone FAMILY 23435541 A 1015 1022 statins FAMILY 23435541 A 1171 1179 ceramide FAMILY 23435541 A 1342 1349 statins FAMILY 23435541 A 1364 1370 O2(.-) FORMULA 23435541 A 150 157 statins FAMILY 23435541 A 1531 1538 statins FAMILY 23435541 A 1695 1702 statins FAMILY 23435541 A 1815 1826 cholesterol TRIVIAL 23435541 A 571 578 statins FAMILY 23435541 A 590 601 pravastatin TRIVIAL 23435541 A 606 617 simvastatin TRIVIAL 23435541 A 61 66 NADPH ABBREVIATION 23435541 A 641 646 NADPH ABBREVIATION 23435541 A 739 746 statins FAMILY 23435541 A 811 819 ceramide FAMILY 23435541 A 863 870 statins FAMILY 23435541 A 935 945 superoxide TRIVIAL 23435541 A 947 953 O2(.-) FORMULA 23435541 T 15 22 statins FAMILY 23435614 A 245 252 Aspirin TRIVIAL 23435614 A 958 965 aspirin TRIVIAL 23435614 T 20 40 acetylsalicylic acid SYSTEMATIC 23435689 A 1084 1088 Cu2O FORMULA 23435689 A 124 128 Cu2O FORMULA 23435689 A 404 408 Cu2O FORMULA 23435689 A 467 472 4-MBA SYSTEMATIC 23435689 A 477 495 4-mercaptopyridine SYSTEMATIC 23435689 A 497 502 4-MPY SYSTEMATIC 23435689 A 52 74 4-mercaptobenzoic acid SYSTEMATIC 23435689 A 76 81 4-MBA SYSTEMATIC 23435689 A 842 846 Cu2O FORMULA 23435689 A 993 997 Cu2O FORMULA 23435689 T 59 63 Cu₂O FORMULA 23435915 A 0 8 Genistin TRIVIAL 23435915 A 1003 1011 genistin TRIVIAL 23435915 A 1043 1049 Ca(2+) FORMULA 23435915 A 1061 1069 Genistin TRIVIAL 23435915 A 1202 1208 Mg(2+) FORMULA 23435915 A 1344 1352 genistin TRIVIAL 23435915 A 1439 1447 genistin TRIVIAL 23435915 A 20 31 isoflavones FAMILY 23435915 A 201 209 genistin TRIVIAL 23435915 A 416 424 genistin TRIVIAL 23435915 A 559 572 acetylcholine SYSTEMATIC 23435915 A 57 65 genistin TRIVIAL 23435915 A 574 577 ACh ABBREVIATION 23435915 A 580 589 histamine TRIVIAL 23435915 A 596 602 Ca(2+) FORMULA 23435915 A 608 620 erythromycin TRIVIAL 23435915 A 662 670 genistin TRIVIAL 23435915 A 835 847 phentolamine TRIVIAL 23435915 A 852 863 propranolol TRIVIAL 23435915 A 911 919 genistin TRIVIAL 23435915 A 953 962 verapamil TRIVIAL 23435915 A 969 975 Ca(2+) FORMULA 23435915 T 23 31 genistin TRIVIAL 23436259 A 165 173 zaleplon TRIVIAL 23436259 A 654 662 zaleplon TRIVIAL 23436259 A 72 80 zaleplon TRIVIAL 23436259 A 989 997 Zaleplon TRIVIAL 23436259 T 45 53 zaleplon TRIVIAL 23436293 A 443 453 bile acids FAMILY 23436315 A 0 13 Acetaminophen TRIVIAL 23436315 A 1245 1258 acetaminophen TRIVIAL 23436315 A 129 142 acetaminophen TRIVIAL 23436315 A 1303 1316 acetaminophen TRIVIAL 23436315 A 173 186 acetaminophen TRIVIAL 23436315 A 208 224 propylene glycol SYSTEMATIC 23436315 A 355 368 acetaminophen TRIVIAL 23436315 A 598 611 acetaminophen TRIVIAL 23436315 A 972 988 Propylene glycol SYSTEMATIC 23436315 T 24 37 acetaminophen TRIVIAL 23436428 A 1261 1271 cilostazol TRIVIAL 23436428 A 140 150 cilostazol TRIVIAL 23436428 A 154 161 aspirin TRIVIAL 23436428 A 166 177 clopidogrel TRIVIAL 23436428 A 228 235 aspirin TRIVIAL 23436428 A 240 251 clopidogrel TRIVIAL 23436428 T 12 22 cilostazol TRIVIAL 23436437 A 563 572 aspartate TRIVIAL 23436437 A 587 594 alanine TRIVIAL 23436437 A 631 641 creatinine TRIVIAL 23436437 A 652 656 urea TRIVIAL 23436437 A 657 665 nitrogen SYSTEMATIC 23436442 A 0 17 Hydrogen peroxide SYSTEMATIC 23436442 A 197 205 H(2)O(2) FORMULA 23436442 A 363 371 H(2)O(2) FORMULA 23436442 A 409 422 boronic ester SYSTEMATIC 23436442 A 42 48 oxygen SYSTEMATIC 23436442 A 469 481 benzyl ether SYSTEMATIC 23436442 A 757 765 H(2)O(2) FORMULA 23436442 A 879 887 H(2)O(2) FORMULA 23436442 T 74 91 hydrogen peroxide SYSTEMATIC 23436494 A 1224 1236 mifepristone TRIVIAL 23436494 A 1420 1432 mifepristone TRIVIAL 23436494 A 1508 1520 mifepristone TRIVIAL 23436494 A 508 520 Mifepristone TRIVIAL 23436494 A 522 528 RU 486 IDENTIFIER 23436494 A 907 919 mifepristone TRIVIAL 23436494 T 0 12 Mifepristone TRIVIAL 23436709 A 104 112 aluminum SYSTEMATIC 23436709 A 117 124 gallium SYSTEMATIC 23436709 A 198 208 chloroform TRIVIAL 23436709 A 262 267 boron SYSTEMATIC 23436709 A 425 430 SubPz ABBREVIATION 23436709 A 43 59 subporphyrazines FAMILY 23436709 A 432 434 Al FORMULA 23436709 A 436 438 Ga FORMULA 23436709 A 486 491 SubPz ABBREVIATION 23436709 A 586 591 SubPc ABBREVIATION 23436709 A 593 595 Al FORMULA 23436709 A 597 599 Ga FORMULA 23436709 A 61 66 SubPz ABBREVIATION 23436709 A 672 677 SubPc ABBREVIATION 23436709 A 72 90 subphthalocyanines FAMILY 23436709 A 771 779 aluminum SYSTEMATIC 23436709 A 784 791 gallium SYSTEMATIC 23436709 A 825 830 boron SYSTEMATIC 23436709 A 92 97 SubPc ABBREVIATION 23436709 T 18 34 subporphyrazines FAMILY 23436709 T 39 57 subphthalocyanines FAMILY 23436709 T 63 71 aluminum SYSTEMATIC 23436709 T 76 83 gallium SYSTEMATIC 23437791 A 220 240 3-O-methyl-D-glucose SYSTEMATIC 23437791 A 242 245 3MG SYSTEMATIC 23437791 A 345 348 Ser FORMULA 23437791 A 432 439 glucose TRIVIAL 23437791 A 459 462 Tyr FORMULA 23437791 A 604 607 Thr FORMULA 23437791 A 66 73 glucose TRIVIAL 23437791 A 662 665 AMP ABBREVIATION 23437791 A 699 710 Gallic acid TRIVIAL 23437791 A 891 898 glucose TRIVIAL 23437791 T 75 82 glucose TRIVIAL 23437843 A 250 259 monoamine FAMILY 23437843 A 302 366 6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-alkylacetamide FAMILY 23437843 A 35 44 monoamine FAMILY 23437843 A 389 403 6'-Sulfonyloxy SYSTEMATIC 23437843 A 499 510 moclobemide TRIVIAL 23437843 A 568 580 6'-benzyloxy SYSTEMATIC 23437843 A 796 835 2-(1-benzofuran-3-yl)-N-methylacetamide SYSTEMATIC 23437843 A 848 883 4-N-methylcarboxamidomethylcoumarin SYSTEMATIC 23437843 T 197 206 monoamine FAMILY 23437843 T 91 157 6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-methylacetamides FAMILY 23438486 A 178 189 amino acids FAMILY 23438486 A 207 215 cysteine TRIVIAL 23438486 A 383 396 acetylcholine SYSTEMATIC 23439078 A 1034 1050 monosaccharaides FAMILY 23439078 A 172 179 sulfate SYSTEMATIC 23439078 A 38 50 carbohydrate FAMILY 23439078 A 625 633 Pyranose SYSTEMATIC 23439078 A 662 689 2-O-sulfo-α-l-iduronic acid SYSTEMATIC 23439078 A 996 1003 sulfate SYSTEMATIC 23439078 T 17 22 Sugar FAMILY 23439240 A 1005 1009 PLGA ABBREVIATION 23439240 A 1010 1021 PEO-PPO-PEO ABBREVIATION 23439240 A 126 130 PLGA ABBREVIATION 23439240 A 1302 1313 PEO-PPO-PEO ABBREVIATION 23439240 A 131 142 PEO-PPO-PEO ABBREVIATION 23439240 A 1379 1383 PLGA ABBREVIATION 23439240 A 1385 1396 PEO-PPO-PEO ABBREVIATION 23439240 A 1417 1421 PLGA ABBREVIATION 23439240 A 1422 1433 PEO-PPO-PEO ABBREVIATION 23439240 A 1513 1524 PEO-PPO-PEO ABBREVIATION 23439240 A 363 367 PLGA ABBREVIATION 23439240 A 368 379 PEO-PPO-PEO ABBREVIATION 23439240 A 834 838 PLGA ABBREVIATION 23439240 A 839 850 PEO-PPO-PEO ABBREVIATION 23439240 A 91 115 irinotecan hydrochloride SYSTEMATIC 23439240 T 117 121 PLGA ABBREVIATION 23439240 T 122 133 PEO-PPO-PEO ABBREVIATION 23439478 A 220 231 polyphenols FAMILY 23439478 A 326 336 flavonoids FAMILY 23439478 A 905 917 polyphenolic FAMILY 23439478 A 97 109 polyphenolic FAMILY 23439478 T 52 63 polyphenols FAMILY 23439479 A 1064 1066 SH FORMULA 23439479 A 1145 1152 silybin TRIVIAL 23439479 A 262 272 l-arginine TRIVIAL 23439479 A 371 381 l-arginine TRIVIAL 23439479 A 683 698 malondialdehyde TRIVIAL 23439479 A 755 766 glutathione TRIVIAL 23439479 A 768 779 glutathione TRIVIAL 23439479 A 792 803 glutathione TRIVIAL 23439479 A 815 825 superoxide TRIVIAL 23439479 A 92 102 l-arginine TRIVIAL 23439479 A 923 938 malondialdehyde TRIVIAL 23439479 A 961 972 glutathione TRIVIAL 23439479 A 973 974 S FORMULA 23439479 T 73 81 arginine TRIVIAL 23439480 A 1232 1239 Na2S2O5 FORMULA 23439480 A 1316 1323 Na2S2O5 FORMULA 23439480 A 207 227 sodium metabisulfite SYSTEMATIC 23439480 A 229 236 Na2S2O5 FORMULA 23439480 A 276 283 Na2S2O5 FORMULA 23439480 A 313 333 Sodium metabisulfite SYSTEMATIC 23439480 A 451 452 S FORMULA 23439480 A 453 462 sulfonate SYSTEMATIC 23439480 A 503 510 Na2S2O5 FORMULA 23439480 A 72 79 sulfite SYSTEMATIC 23439480 A 836 843 Na2S2O5 FORMULA 23439480 T 17 37 sodium metabisulfite SYSTEMATIC 23440512 A 0 9 Vitamin A FAMILY 23440512 A 13 20 retinol TRIVIAL 23440512 A 163 172 vitamin A FAMILY 23440512 A 218 241 all-trans retinoic acid TRIVIAL 23440512 A 243 247 atRA ABBREVIATION 23440512 A 394 407 retinoic acid TRIVIAL 23440512 A 58 65 vitamin FAMILY 23440512 A 668 677 vitamin A FAMILY 23440512 A 866 875 vitamin A FAMILY 23440512 T 0 9 Vitamin A FAMILY 23440512 T 14 22 retinoid FAMILY 23440577 A 1096 1105 imidazole SYSTEMATIC 23440577 A 1118 1151 indeno[1,2-b]quinoline-9,11-dione SYSTEMATIC 23440577 A 16 25 imidazole SYSTEMATIC 23440577 A 256 259 MTT ABBREVIATION 23440577 A 38 71 indeno[1,2-b]quinoline-9,11-dione SYSTEMATIC 23440577 A 673 687 imidazole-2-yl SYSTEMATIC 23440577 A 718 733 dihydropyridine SYSTEMATIC 23440577 A 802 812 cis-platin TRIVIAL 23440577 A 942 951 imidazole SYSTEMATIC 23440577 T 55 64 imidazole SYSTEMATIC 23440577 T 71 104 indeno[1,2-b]quinoline-9,11-dione SYSTEMATIC 23440580 A 196 203 glucose TRIVIAL 23441017 A 1010 1013 WB2 FORMULA 23441017 A 1020 1024 CrB2 FORMULA 23441017 A 1039 1043 CrB3 FORMULA 23441017 A 1153 1157 CrB4 FORMULA 23441017 A 1167 1171 CrB4 FORMULA 23441017 A 132 148 chromium borides FAMILY 23441017 A 203 207 CrB3 FORMULA 23441017 A 212 216 CrB4 FORMULA 23441017 A 362 365 MoB FORMULA 23441017 A 422 425 TiI FORMULA 23441017 A 445 448 CrB FORMULA 23441017 A 454 458 CrB2 FORMULA 23441017 A 465 468 WB2 FORMULA 23441017 A 543 547 CrB3 FORMULA 23441017 A 682 686 CrB4 FORMULA 23441017 A 848 852 CrB3 FORMULA 23441017 A 857 861 CrB4 FORMULA 23441017 T 42 58 chromium borides FAMILY 23441102 A 147 156 histidine TRIVIAL 23441102 A 171 192 poly(ethylene glycol) SYSTEMATIC 23441102 A 194 197 PEG ABBREVIATION 23441102 A 278 287 histidine TRIVIAL 23441102 A 49 58 histidine TRIVIAL 23441102 A 614 623 histidine TRIVIAL 23441102 A 633 644 methoxy-PEG FAMILY 23441102 A 914 923 histidine TRIVIAL 23441102 T 16 25 histidine TRIVIAL 23441686 A 1068 1070 Si FORMULA 23441686 A 1114 1120 HP20SS FAMILY 23441686 A 1126 1131 EtOAc FORMULA 23441686 A 1200 1202 Si FORMULA 23441686 A 1259 1265 HP20SS FAMILY 23441686 A 225 238 Diaion HP20SS FAMILY 23441686 A 253 264 polystyrene SYSTEMATIC 23441686 A 486 499 Diaion HP20SS FAMILY 23441686 A 65 71 silica TRIVIAL 23441686 A 73 75 Si FORMULA 23441976 A 155 167 Racemosolone TRIVIAL 23441976 A 195 215 pentacyclic phenolic FAMILY 23441976 A 263 275 cycloheptane SYSTEMATIC 23441976 A 292 301 furopyran FAMILY 23441976 A 522 535 n-tetracosane SYSTEMATIC 23441976 A 537 558 β-sitosteryl stearate TRIVIAL 23441976 A 560 575 eicosanoic acid SYSTEMATIC 23441976 A 577 589 stigmasterol TRIVIAL 23441976 A 591 603 β-sitosterol TRIVIAL 23441976 A 605 614 racemosol TRIVIAL 23441976 A 616 634 octacosyl ferulate TRIVIAL 23441976 A 636 657 de-O-methyl racemosol SYSTEMATIC 23441976 A 659 665 lupeol TRIVIAL 23441976 A 670 770 1,7,8,12b-tetrahydro-2,2,4-trimethyl-2H-benzo[6,7]cyclohepta [1,2,3-de] [1] benzopyran-5,10,11 triol SYSTEMATIC 23441976 T 6 24 pentacyclic phenol SYSTEMATIC 23441977 A 1027 1031 H2O2 FORMULA 23441977 A 1088 1094 Br3(-) FORMULA 23441977 A 1102 1107 Br(-) FORMULA 23441977 A 111 116 Br(-) FORMULA 23441977 A 1162 1167 Br(-) FORMULA 23441977 A 1281 1288 H2O(•+) FORMULA 23441977 A 303 308 Br(-) FORMULA 23441977 A 40 46 Br3(-) FORMULA 23441977 A 605 613 BrOH(-•) FORMULA 23441977 A 615 622 Br2(-•) FORMULA 23441977 A 628 634 Br3(-) FORMULA 23441977 A 722 729 Br2(•-) FORMULA 23441977 A 766 772 Br3(-) FORMULA 23441977 A 797 802 Br(-) FORMULA 23441977 A 818 823 OH(•) FORMULA 23441977 A 853 860 Br2(•-) FORMULA 23441977 A 887 892 OH(•) FORMULA 23441977 A 942 949 Br2(-•) FORMULA 23441977 A 993 998 OH(•) FORMULA 23441977 T 78 85 bromide SYSTEMATIC 23442147 A 98 111 carbohydrates FAMILY 23442161 A 151 154 ATP ABBREVIATION 23442788 A 0 9 Palytoxin TRIVIAL 23442788 A 1022 1026 PLTX ABBREVIATION 23442788 A 11 15 PLTX ABBREVIATION 23442788 A 1118 1122 PLTX ABBREVIATION 23442788 A 117 120 Na+ FORMULA 23442788 A 1186 1190 PLTX ABBREVIATION 23442788 A 121 123 K+ FORMULA 23442788 A 1218 1221 OUA ABBREVIATION 23442788 A 1252 1256 PLTX ABBREVIATION 23442788 A 1353 1356 OUA ABBREVIATION 23442788 A 1384 1388 PLTX ABBREVIATION 23442788 A 140 147 ouabain TRIVIAL 23442788 A 149 152 OUA ABBREVIATION 23442788 A 209 213 PLTX ABBREVIATION 23442788 A 290 294 PLTX ABBREVIATION 23442788 A 380 383 Na+ FORMULA 23442788 A 384 386 K+ FORMULA 23442788 A 443 447 PLTX ABBREVIATION 23442788 A 520 523 OUA ABBREVIATION 23442788 A 553 557 PLTX ABBREVIATION 23442788 A 660 664 PLTX ABBREVIATION 23442788 A 822 826 PLTX ABBREVIATION 23442788 A 890 893 OUA ABBREVIATION 23442788 A 907 911 PLTX ABBREVIATION 23442788 A 965 968 OUA ABBREVIATION 23442788 T 20 29 Palytoxin TRIVIAL 23442788 T 77 86 Palytoxin TRIVIAL 23443513 A 1015 1020 NaBH4 FORMULA 23443513 A 1115 1120 Ag(+) FORMULA 23443513 A 1122 1128 Au(3+) FORMULA 23443513 A 1130 1136 Cu(2+) FORMULA 23443513 A 1141 1147 Hg(2+) FORMULA 23443513 A 1240 1245 NaBH4 FORMULA 23443513 A 166 172 silver SYSTEMATIC 23443513 A 358 364 Hg(2+) FORMULA 23443513 A 450 456 Hg(2+) FORMULA 23443513 A 552 558 Zn(2+) FORMULA 23443513 A 563 569 Cd(2+) FORMULA 23443513 A 739 745 Hg(2+) FORMULA 23443513 A 769 777 cytosine TRIVIAL 23443513 A 866 872 Hg(2+) FORMULA 23443513 T 99 105 silver SYSTEMATIC 23443908 A 523 538 hydrogen halide FAMILY 23443908 A 552 555 HCl FORMULA 23443908 A 556 558 He FORMULA 23443908 T 150 153 HCl FORMULA 23443908 T 154 156 He FORMULA 23444040 A 0 7 Eugenol TRIVIAL 23444040 A 1182 1196 crystal violet TRIVIAL 23444040 A 1229 1232 SDS ABBREVIATION 23444040 A 1233 1247 polyacrylamide SYSTEMATIC 23444040 A 1362 1369 eugenol TRIVIAL 23444040 A 1435 1442 eugenol TRIVIAL 23444040 A 236 243 eugenol TRIVIAL 23444040 A 342 349 eugenol TRIVIAL 23444040 A 603 610 eugenol TRIVIAL 23444040 A 779 786 eugenol TRIVIAL 23444040 A 833 840 Eugenol TRIVIAL 23444040 T 0 7 Eugenol TRIVIAL 23444043 A 10 18 phenolic FAMILY 23444043 A 30 46 yunnanensins A-C MULTIPLE 23444043 T 0 8 Phenolic FAMILY 23444099 A 139 148 Aminoacyl SYSTEMATIC 23444099 A 593 608 lysyl-adenylate TRIVIAL 23444099 A 771 776 lysyl TRIVIAL 23444099 T 40 49 aminoacyl SYSTEMATIC 23444274 A 175 187 imidacloprid TRIVIAL 23444274 A 445 457 imidacloprid TRIVIAL 23444274 A 62 74 imidacloprid TRIVIAL 23444274 T 18 30 imidacloprid TRIVIAL 23444285 A 1315 1325 prednisone TRIVIAL 23444285 A 429 439 prednisone TRIVIAL 23444285 A 715 725 prednisone TRIVIAL 23444285 A 743 753 prednisone TRIVIAL 23444285 T 37 47 prednisone TRIVIAL 23444386 A 1017 1039 dehydroepiandrosterone TRIVIAL 23444386 A 1041 1045 DHEA ABBREVIATION 23444386 A 1069 1078 disulfide SYSTEMATIC 23444386 A 125 140 hydroxysteroids FAMILY 23444386 A 1286 1296 disulfides FAMILY 23444386 A 1419 1428 cysteines FAMILY 23444386 A 1438 1448 nucleotide FAMILY 23444386 A 145 155 bile acids FAMILY 23444386 A 1493 1503 nucleotide FAMILY 23444386 A 1508 1512 DHEA ABBREVIATION 23444386 A 1598 1607 disulfide SYSTEMATIC 23444386 A 1632 1641 disulfide SYSTEMATIC 23444386 A 496 505 disulfide SYSTEMATIC 23444386 A 592 597 thiol FAMILY 23444386 A 706 727 glutathione disulfide SYSTEMATIC 23444386 A 729 764 5,5'-dithiobis(2-nitrobenzoic acid) SYSTEMATIC 23444386 A 770 803 1,1'-azobis(N,N-dimethylformamide SYSTEMATIC 23444386 A 806 813 diamide SYSTEMATIC 23444386 A 846 855 disulfide SYSTEMATIC 23444386 T 105 114 Disulfide SYSTEMATIC 23444386 T 48 62 Hydroxysteroid FAMILY 23444428 A 832 842 Vancomycin TRIVIAL 23444779 A 0 8 Honokiol TRIVIAL 23444779 A 1675 1683 honokiol TRIVIAL 23444779 A 171 179 honokiol TRIVIAL 23444779 A 470 478 honokiol TRIVIAL 23444779 T 82 90 honokiol TRIVIAL 23445175 A 1049 1055 lysine TRIVIAL 23445175 A 145 156 fatty acids FAMILY 23445175 A 162 178 phytosphingosine TRIVIAL 23445175 A 182 200 dihydrosphingosine SYSTEMATIC 23445175 A 255 263 ceramide FAMILY 23445175 A 329 337 acyl-CoA ABBREVIATION 23445175 A 408 416 acyl-CoA ABBREVIATION 23445175 A 427 435 ceramide FAMILY 23445175 A 450 461 ceramidases FAMILY 23445175 A 530 538 cysteine TRIVIAL 23445175 A 580 589 cysteines FAMILY 23445175 A 643 644 N FORMULA 23445175 A 650 651 C FORMULA 23445175 A 754 763 cysteines FAMILY 23445175 A 831 840 disulfide SYSTEMATIC 23445175 A 883 894 amino acids FAMILY 23445189 A 1264 1269 alkyl FAMILY 23445189 A 1399 1412 alkylated-C60 FAMILY 23445189 A 1571 1576 alkyl FAMILY 23445189 A 426 431 alkyl FAMILY 23445189 A 911 916 alkyl FAMILY 23445219 A 139 143 BPAP ABBREVIATION 23445219 A 15 27 bisphenol AP TRIVIAL 23445219 A 216 220 BPAP ABBREVIATION 23445219 A 29 33 BPAP ABBREVIATION 23445219 A 457 465 hydrogen SYSTEMATIC 23445219 A 52 58 carbon SYSTEMATIC 23445219 A 566 570 BPAP ABBREVIATION 23445219 A 791 795 BPAP ABBREVIATION 23445219 A 821 828 ethanol SYSTEMATIC 23445219 A 829 843 sodium hydrate SYSTEMATIC 23445219 A 94 98 BPAP ABBREVIATION 23445219 A 959 963 BPAP ABBREVIATION 23445219 T 78 90 bisphenol AP TRIVIAL 23448197 A 789 796 glucose TRIVIAL 23448247 A 1093 1105 [CpRu(CO)2]2 FORMULA 23448247 A 1114 1120 CH2Cl2 FORMULA 23448247 A 1175 1192 [CpRu(CO)]2(μ-CO) FORMULA 23448247 A 199 211 CpRu(CO)2(•) FORMULA 23448247 A 22 34 [CpRu(CO)2]2 FORMULA 23448247 A 283 302 CpRu(CO)2P(OMe)3(•) FORMULA 23448247 A 369 371 CO FORMULA 23448247 A 38 45 P(OMe)3 FORMULA 23448247 A 415 417 CO FORMULA 23448247 A 455 463 carbonyl FAMILY 23448247 A 46 52 CH2Cl2 FORMULA 23448247 A 615 627 [CpFe(CO)2]2 FORMULA 23448247 A 752 754 CO FORMULA 23448247 A 765 784 CpRu(CO)2P(OMe)3(•) FORMULA 23448247 A 815 821 Fe-C-O FORMULA 23448247 A 852 871 CpFe(CO)2P(OMe)3(•) FORMULA 23448247 A 899 901 CO FORMULA 23448247 A 928 937 ruthenium SYSTEMATIC 23448247 T 29 37 carbonyl FAMILY 23448247 T 62 78 transition metal FAMILY 23448580 A 1019 1031 polyhexanide FAMILY 23448580 A 313 325 polyhexanide FAMILY 23448580 T 58 70 polyhexanide FAMILY 23449195 A 1525 1544 reduced glutathione TRIVIAL 23449195 A 1546 1561 malondialdehyde TRIVIAL 23449195 A 1580 1587 nitrite SYSTEMATIC 23449195 A 230 238 tween 80 FAMILY 23449195 A 4 29 minocycline hydrochloride SYSTEMATIC 23449195 A 801 814 acetylcholine SYSTEMATIC 23449195 A 825 844 reduced glutathione TRIVIAL 23449195 A 846 861 malondialdehyde TRIVIAL 23449195 A 872 879 nitrite SYSTEMATIC 23449195 T 94 105 minocycline TRIVIAL 23449197 A 0 78 7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole SYSTEMATIC 23449197 A 489 496 methoxy SYSTEMATIC 23449197 A 510 523 benzothiazole SYSTEMATIC 23449197 A 580 589 imidazole SYSTEMATIC 23449197 A 603 611 thiazole SYSTEMATIC 23449197 A 83 94 TASP0382088 IDENTIFIER 23449197 T 13 91 7-methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole SYSTEMATIC 23449197 T 93 104 TASP0382088 IDENTIFIER 23449198 A 1191 1203 theophylline TRIVIAL 23449198 A 1355 1373 magnesium stearate SYSTEMATIC 23449198 A 1633 1645 theophylline TRIVIAL 23449198 A 367 379 theophylline TRIVIAL 23449198 T 58 70 theophylline TRIVIAL 23449199 A 20 35 dihydro-β-ionol SYSTEMATIC 23449199 A 40 47 β-ionol TRIVIAL 23449199 A 401 416 dihydro-β-ionol SYSTEMATIC 23449199 A 529 548 (R)-dihydro-β-ionol SYSTEMATIC 23449199 A 646 654 β-ionone TRIVIAL 23449199 T 96 104 β-ionols FAMILY 23449204 A 10 17 orcinol TRIVIAL 23449204 A 19 43 3-hydroxy-5-methylphenol SYSTEMATIC 23449204 A 200 215 cleyeratannin A TRIVIAL 23449204 A 221 236 cleyeratannin B TRIVIAL 23449204 A 245 260 cleyeratannin C TRIVIAL 23449204 A 503 532 1,1-diphenyl-2-picrylhydrazyl SYSTEMATIC 23449204 A 534 538 DPPH ABBREVIATION 23449204 A 577 598 nitroblue tetrazolium TRIVIAL 23449204 A 600 603 NBT ABBREVIATION 23449204 A 605 615 superoxide TRIVIAL 23449204 A 69 76 tannins FAMILY 23449204 T 10 17 orcinol TRIVIAL 23449204 T 42 49 tannins FAMILY 23449888 A 0 8 Androgen FAMILY 23449888 A 1279 1280 N FORMULA 23449888 A 1474 1482 androgen FAMILY 23449888 A 1515 1516 N FORMULA 23449888 A 1530 1531 C FORMULA 23449888 A 548 556 androgen FAMILY 23449888 A 571 579 androgen FAMILY 23449888 A 829 837 androgen FAMILY 23449888 T 14 22 androgen FAMILY 23449981 A 0 13 Sphingomyelin FAMILY 23449981 A 1124 1127 CDP ABBREVIATION 23449981 A 1128 1135 alcohol FAMILY 23449981 A 1236 1239 CPE ABBREVIATION 23449981 A 196 210 phosphocholine SYSTEMATIC 23449981 A 216 235 phosphatidylcholine FAMILY 23449981 A 241 249 ceramide FAMILY 23449981 A 367 395 ceramide phosphoethanolamine FAMILY 23449981 A 397 400 CPE ABBREVIATION 23449981 A 428 440 sphingolipid FAMILY 23449981 A 460 463 CPE ABBREVIATION 23449981 A 633 636 CDP ABBREVIATION 23449981 A 637 649 ethanolamine SYSTEMATIC 23449981 A 650 658 ceramide FAMILY 23449981 A 659 671 ethanolamine SYSTEMATIC 23449981 A 721 724 CPE ABBREVIATION 23449981 A 751 754 CPE ABBREVIATION 23449981 A 800 803 CDP ABBREVIATION 23449981 A 804 811 alcohol FAMILY 23449981 T 0 28 Ceramide phosphoethanolamine FAMILY 23449981 T 80 92 ethanolamine SYSTEMATIC 23450164 A 1080 1101 methane sulfonic acid SYSTEMATIC 23450164 A 1109 1117 hydroxyl SYSTEMATIC 23450164 A 299 307 hydrogen SYSTEMATIC 23450164 A 31 52 methane sulfonic acid SYSTEMATIC 23450164 A 345 351 CH3SO3 FORMULA 23450164 A 356 359 H2O FORMULA 23450164 A 54 61 CH3SO3H FORMULA 23450164 A 592 599 CH3SO3H FORMULA 23450164 A 63 66 MSA ABBREVIATION 23450164 A 76 84 hydroxyl SYSTEMATIC 23450164 A 767 774 CH3SO3H FORMULA 23450164 A 779 781 HO FORMULA 23450164 A 864 867 H2O FORMULA 23450164 A 876 878 HO FORMULA 23450164 A 883 890 CH3SO3H FORMULA 23450164 A 94 96 HO FORMULA 23450164 T 26 47 methane sulfonic acid SYSTEMATIC 23450164 T 57 65 hydroxyl SYSTEMATIC 23450220 A 320 347 poly(N-isopropylacrylamide) SYSTEMATIC 23450220 A 349 355 PNIPAM ABBREVIATION 23452037 A 28 48 bacteriopheophytin a TRIVIAL 23452037 A 410 415 (13)C FORMULA 23452037 A 436 457 δ-aminolevulinic acid SYSTEMATIC 23452037 A 50 56 BPhe a ABBREVIATION 23452037 A 563 568 (13)C FORMULA 23452037 A 757 763 BPhe a ABBREVIATION 23452037 A 868 886 bacteriopheophytin TRIVIAL 23452037 T 0 20 Bacteriopheophytin a TRIVIAL 23452037 T 143 146 13C FORMULA 23452083 A 137 157 1,2-dihydropyridines FAMILY 23452083 A 42 48 diynes FAMILY 23452083 A 52 64 sulfonimines FAMILY 23452083 A 71 78 rhodium SYSTEMATIC 23452083 T 24 31 rhodium SYSTEMATIC 23452083 T 67 73 diynes FAMILY 23452083 T 77 89 sulfonimines FAMILY 23452185 A 189 200 Thiadiazole SYSTEMATIC 23452185 A 4 21 1,3,4-thiadiazole SYSTEMATIC 23452185 A 437 448 thiadiazole SYSTEMATIC 23452185 A 675 686 thiadiazole SYSTEMATIC 23452185 T 0 17 1,3,4-thiadiazole SYSTEMATIC 23452205 A 309 318 glutamate TRIVIAL 23452205 A 323 327 GABA ABBREVIATION 23452205 A 489 498 glutamate TRIVIAL 23452205 A 90 99 glutamate TRIVIAL 23452237 A 1265 1266 C FORMULA 23452237 A 14 22 arginine TRIVIAL 23452237 A 163 164 N FORMULA 23452237 A 353 375 Trimethylamine N-oxide SYSTEMATIC 23452237 A 437 447 molybdenum SYSTEMATIC 23452237 T 70 78 arginine TRIVIAL 23452243 A 1022 1032 phosphates FAMILY 23452243 A 1036 1049 phosphoserine SYSTEMATIC 23452243 A 1145 1153 arginine TRIVIAL 23452243 A 180 185 (13)C FORMULA 23452243 A 190 195 (31)P FORMULA 23452243 A 460 470 amino acid FAMILY 23452243 A 568 589 phosphorylated serine TRIVIAL 23452243 A 635 641 Ca(2+) FORMULA 23452243 A 646 652 Mg(2+) FORMULA 23452243 A 721 726 (13)C FORMULA 23452243 A 755 776 phosphorylated serine TRIVIAL 23452243 A 793 799 valine TRIVIAL 23452243 A 847 854 glycine TRIVIAL 23452243 A 859 866 leucine TRIVIAL 23452243 A 956 961 (31)P FORMULA 23452243 T 44 65 Phosphorylated Serine TRIVIAL 23453003 A 153 164 hydrocarbon FAMILY 23453003 A 981 993 hydrocarbons FAMILY 23453003 T 0 12 Hydrocarbons FAMILY 23453071 A 279 291 nicotinamide TRIVIAL 23453071 A 31 38 BRN-103 IDENTIFIER 23453071 A 363 472 2-{1-[1-(6-chloro-5-fluoropyrimidin-4-yl)ethyl]piperidin-4-ylamino}-N-(3-chlorophenyl) pyridine-3-carboxamide SYSTEMATIC 23453071 A 42 54 nicotinamide TRIVIAL 23453071 A 474 481 BRN-250 IDENTIFIER 23453071 A 676 683 BRN-250 IDENTIFIER 23453071 A 745 753 tyrosine TRIVIAL 23453071 A 892 899 BRN-250 IDENTIFIER 23453071 T 28 40 nicotinamide TRIVIAL 23453073 A 302 313 Niclosamide TRIVIAL 23453073 A 602 613 Niclosamide TRIVIAL 23453073 A 793 804 Niclosamide TRIVIAL 23453073 A 872 883 Niclosamide TRIVIAL 23453308 A 1267 1279 Jacaric acid TRIVIAL 23453308 A 1401 1425 jacaric and punicic acid MULTIPLE 23453308 A 1506 1517 fatty acids FAMILY 23453308 A 1550 1566 C-18 fatty acids FAMILY 23453308 A 1719 1735 C-18 fatty acids FAMILY 23453308 A 1830 1842 punicic acid TRIVIAL 23453308 A 1915 1927 jacaric acid TRIVIAL 23453308 A 2062 2073 fatty acids FAMILY 23453308 A 2253 2264 fatty acids FAMILY 23453308 A 246 262 C-18 fatty acids FAMILY 23453308 A 28 39 fatty acids FAMILY 23453308 A 361 372 fatty acids FAMILY 23453308 A 382 406 jacaric and punicic acid MULTIPLE 23453308 A 508 550 alpha- and beta-calendic and catalpic acid MULTIPLE 23453308 A 560 593 mono-unsaturated C-18 fatty acids FAMILY 23453308 A 595 623 trans- and cis-vaccenic acid MULTIPLE 23453308 A 626 638 Jacaric acid TRIVIAL 23453308 A 882 894 Jacaric acid TRIVIAL 23453308 T 0 12 Jacaric acid TRIVIAL 23453308 T 21 42 octadecatrienoic acid SYSTEMATIC 23453838 A 10 25 organophosphate FAMILY 23453838 A 357 419 β-substituted ethoxy and γ-substituted propoxy phosphonoesters MULTIPLE 23453838 A 432 465 p-NO(2)PhO-P(X)(R)[(O(CH(2))(n)Z] FAMILY 23453838 A 467 507 R=Me, Et; X=O, S; n=2, 3; Z=halogen, OTs FORMULA 23453838 A 469 471 Me FORMULA 23453838 A 473 475 Et FORMULA 23453838 A 479 480 O FORMULA 23453838 A 482 483 S FORMULA 23453838 A 495 502 halogen FAMILY 23453838 A 504 507 OTs FORMULA 23453838 A 591 623 β-fluoroethoxy methylphosphonate SYSTEMATIC 23453838 A 632 646 R=Me, Z=F, n=2 FORMULA 23453838 A 634 636 Me FORMULA 23453838 A 640 641 F FORMULA 23453838 A 729 737 paraoxon TRIVIAL 23453838 A 767 782 Z=Br, I, or OTs FORMULA 23453838 A 769 771 Br FORMULA 23453838 A 773 774 I FORMULA 23453838 A 779 782 OTs FORMULA 23453838 A 822 841 methyl phosphonates FAMILY 23453838 A 843 847 R=Me FORMULA 23453838 A 845 847 Me FORMULA 23453838 A 889 907 ethyl phosphonates FAMILY 23453838 A 909 913 R=Et FORMULA 23453838 A 911 913 Et FORMULA 23453838 A 944 952 thionate SYSTEMATIC 23453838 T 60 106 β- and γ-substituted alkoxy organophosphonates MULTIPLE 23453839 A 105 110 alkyl FAMILY 23453839 A 140 145 NADNJ ABBREVIATION 23453839 A 168 188 tertiary carboxamide SYSTEMATIC 23453839 A 32 38 NADNJs FAMILY 23453839 A 6 30 N-alkyldeoxynojirimycins FAMILY 23453839 T 0 23 N-Alkyldeoxynojirimycin FAMILY 23453839 T 56 70 tertiary amide SYSTEMATIC 23453840 A 102 105 ABH ABBREVIATION 23453840 A 225 239 tertiary amine SYSTEMATIC 23453840 A 257 263 carbon SYSTEMATIC 23453840 A 455 463 nitrogen SYSTEMATIC 23453840 A 472 487 carboxylic acid SYSTEMATIC 23453840 A 502 505 Asp FORMULA 23453840 A 583 586 Asp FORMULA 23453840 A 71 100 2-amino-6-boronohexanoic acid SYSTEMATIC 23453840 A 727 730 ABH ABBREVIATION 23453840 T 0 44 2-Substituted-2-amino-6-boronohexanoic acids FAMILY 23454012 A 140 160 N-methyl-d-aspartate SYSTEMATIC 23454012 A 162 166 NMDA ABBREVIATION 23454012 A 588 591 GSH ABBREVIATION 23454012 A 599 616 (R)-α-lipoic acid TRIVIAL 23454012 A 663 667 NMDA ABBREVIATION 23454012 A 689 698 memantine TRIVIAL 23454012 A 700 703 MEM ABBREVIATION 23454012 A 788 797 glutamate TRIVIAL 23454012 T 0 9 Memantine TRIVIAL 23454012 T 10 16 sulfur SYSTEMATIC 23454112 A 0 9 Photofrin TRIVIAL 23454112 A 12 27 porfimer sodium SYSTEMATIC 23454112 A 299 308 Photofrin TRIVIAL 23454112 A 337 346 Photofrin TRIVIAL 23454112 A 377 386 Photofrin TRIVIAL 23454112 A 429 473 poly(ethylene glycol)-grafted poly(l-lysine) FAMILY 23454112 A 475 484 PLL-g-PEG ABBREVIATION 23454112 A 506 515 Photofrin TRIVIAL 23454112 A 546 555 PLL-g-PEG ABBREVIATION 23454112 A 656 671 PEG-grafted PLL ABBREVIATION 23454112 A 718 727 Photofrin TRIVIAL 23454112 A 728 737 PLL-g-PEG ABBREVIATION 23454112 A 785 794 Photofrin TRIVIAL 23454112 A 800 809 PLL-g-PEG ABBREVIATION 23454112 A 841 850 Photofrin TRIVIAL 23454112 A 863 872 Photofrin TRIVIAL 23454112 T 18 27 Photofrin TRIVIAL 23454112 T 32 41 PLL-g-PEG ABBREVIATION 23454113 A 1098 1126 cyclic tetra-amine disulfide SYSTEMATIC 23454113 A 1372 1399 cyclic polyamine disulfides FAMILY 23454113 A 207 234 cyclic polyamine disulfides FAMILY 23454113 A 501 527 cyclic polyamine disulfide FAMILY 23454113 A 548 578 spermine tetra-amine disulfide SYSTEMATIC 23454113 A 580 592 TetraN-3,4,3 SYSTEMATIC 23454113 A 663 680 cyclic disulfides FAMILY 23454113 A 719 746 cyclic polyamine disulfides FAMILY 23454113 A 757 777 hexa- and octa-amine MULTIPLE 23454113 A 892 930 cyclic tri- and tetra-amine disulfides MULTIPLE 23454113 A 940 978 cyclic hexa- and octa-amine disulfides MULTIPLE 23454113 T 138 157 polyamine disulfide FAMILY 23454113 T 60 75 disulfide amino SYSTEMATIC 23454150 A 139 151 nitric oxide SYSTEMATIC 23454150 A 153 155 NO FORMULA 23454150 A 171 177 oxygen SYSTEMATIC 23454150 A 288 303 malondialdehyde TRIVIAL 23454150 A 304 307 MDA ABBREVIATION 23454150 A 393 395 NO FORMULA 23454150 A 402 405 MDA ABBREVIATION 23454150 A 717 728 polyphenols FAMILY 23454150 A 733 743 flavonoids FAMILY 23454150 A 775 782 ferrous SYSTEMATIC 23454150 A 889 891 NO FORMULA 23454207 A 1119 1128 aspartate TRIVIAL 23454207 A 1150 1157 alanine TRIVIAL 23454207 A 1221 1247 poly(lactide-co-glycolide) SYSTEMATIC 23454207 A 1274 1280 sodium SYSTEMATIC 23454207 A 140 150 Rotigotine TRIVIAL 23454207 A 160 168 ergoline TRIVIAL 23454207 A 178 186 dopamine TRIVIAL 23454207 A 247 257 rotigotine TRIVIAL 23454207 A 350 376 poly(lactide-co-glycolide) SYSTEMATIC 23454207 A 848 856 dopamine TRIVIAL 23454207 A 903 913 rotigotine TRIVIAL 23454207 T 55 65 rotigotine TRIVIAL 23454269 A 1061 1065 6His FORMULA 23454269 A 1126 1141 cobalt chloride SYSTEMATIC 23454269 A 1268 1283 cobalt chloride SYSTEMATIC 23454269 A 130 146 aryl hydrocarbon FAMILY 23454269 A 1441 1448 glucose TRIVIAL 23454269 A 1545 1549 6His FORMULA 23454269 A 466 470 6His FORMULA 23454269 A 586 590 6His FORMULA 23454269 A 692 696 6His FORMULA 23454269 A 799 803 6His FORMULA 23454269 A 811 815 6His FORMULA 23454269 T 127 143 aryl hydrocarbon FAMILY 23454296 A 276 284 squalene TRIVIAL 23454296 A 379 387 Squalene TRIVIAL 23454296 A 48 56 Squalene TRIVIAL 23454296 A 548 556 Squalene TRIVIAL 23454296 A 701 709 squalene TRIVIAL 23454296 A 834 842 squalene TRIVIAL 23454296 T 44 52 squalene TRIVIAL 23454300 A 50 61 polystyrene SYSTEMATIC 23454306 A 0 10 Glyphosate TRIVIAL 23454306 A 1292 1299 Roundup TRIVIAL 23454306 A 1383 1390 Roundup TRIVIAL 23454306 A 145 155 glyphosate TRIVIAL 23454306 A 314 321 Roundup TRIVIAL 23454306 A 351 361 glyphosate TRIVIAL 23454306 A 436 443 Roundup TRIVIAL 23454306 A 674 681 Roundup TRIVIAL 23454306 A 801 808 Roundup TRIVIAL 23454306 A 946 953 Roundup TRIVIAL 23454306 T 31 38 Roundup TRIVIAL 23454513 A 1053 1079 β-lactam amino acid amides FAMILY 23454513 A 1099 1109 colchicine TRIVIAL 23454513 A 164 189 β-lactam phosphate esters FAMILY 23454513 A 536 562 β-lactam amino acid amides FAMILY 23454513 A 64 72 β-lactam TRIVIAL 23454513 A 768 783 β-lactam amides FAMILY 23454513 A 86 104 combretastatin A-4 TRIVIAL 23454513 A 875 884 phosphate SYSTEMATIC 23454513 T 121 145 β-lactam combretastatins FAMILY 23454513 T 58 68 amino acid FAMILY 23454513 T 73 82 phosphate SYSTEMATIC 23454514 A 108 114 iodide SYSTEMATIC 23454514 A 19 42 dihydropyrimidin-2-ones FAMILY 23454514 A 267 280 sodium iodide SYSTEMATIC 23454514 A 44 49 DHPMs FAMILY 23454514 A 467 472 DHPMs FAMILY 23454514 A 863 869 iodide SYSTEMATIC 23454514 T 106 119 sodium iodide SYSTEMATIC 23454514 T 69 92 dihydropyrimidin-2-ones FAMILY 23454526 A 1061 1086 5-methyl-2'-deoxycytidine SYSTEMATIC 23454526 A 1114 1121 cocaine TRIVIAL 23454526 A 1130 1136 heroin TRIVIAL 23454526 A 1244 1251 cocaine TRIVIAL 23454526 A 1255 1261 heroin TRIVIAL 23454526 A 1506 1513 cocaine TRIVIAL 23454526 A 1517 1523 heroin TRIVIAL 23454526 A 171 178 cocaine TRIVIAL 23454526 A 183 189 heroin TRIVIAL 23454526 A 292 298 heroin TRIVIAL 23454526 A 356 363 cocaine TRIVIAL 23454526 A 454 461 cocaine TRIVIAL 23454526 A 604 620 2'-deoxycytidine SYSTEMATIC 23454526 A 625 650 5-methyl-2'-deoxycytidine SYSTEMATIC 23454526 A 685 710 5-methyl-2'-deoxycytidine SYSTEMATIC 23454526 A 849 856 cocaine TRIVIAL 23454526 A 860 866 heroin TRIVIAL 23454526 A 945 952 cocaine TRIVIAL 23454526 T 18 24 heroin TRIVIAL 23454526 T 29 36 cocaine TRIVIAL 23454530 A 13 77 2-alkoxy-4-aryl-6-(1H-benzimidazol-2-yl)-3-pyridinecarbonitriles FAMILY 23454530 A 135 182 3-aryl-1-(1H-benzimidazol-2-yl)-2-propen-1-ones FAMILY 23454530 A 190 203 malononitrile TRIVIAL 23454530 A 207 228 ylidenemalononitriles FAMILY 23454530 A 236 262 2-acetyl-1H-benzimidazoles FAMILY 23454530 A 284 299 sodium alkoxide FAMILY 23454530 A 321 328 alcohol FAMILY 23454530 A 468 496 norepinephrine hydrochloride SYSTEMATIC 23454530 A 590 612 prazosin hydrochloride SYSTEMATIC 23454530 T 103 123 1H-benzimidazol-2-yl SYSTEMATIC 23454530 T 65 88 3-pyridinecarbonitriles SYSTEMATIC 23454532 A 16 63 2-heteroarylthio-6-substituted-quinazolin-4-one FAMILY 23454532 A 394 404 gentamicin FAMILY 23454532 A 590 600 amino acid FAMILY 23454532 A 601 604 Arg FORMULA 23454532 A 611 614 Lys FORMULA 23454532 T 108 142 2-heteroarylthio-quinazolin-4-ones FAMILY 23454655 A 1041 1055 deoxynivalenol TRIVIAL 23454655 A 1069 1080 zearalenone TRIVIAL 23454655 A 1109 1127 HT-2-and T-2-toxin MULTIPLE 23454655 A 1339 1353 deoxynivalenol TRIVIAL 23454655 A 1355 1366 zearalenone TRIVIAL 23454655 A 1382 1400 T-2 and HT-2 toxin MULTIPLE 23454655 A 301 315 deoxynivalenol TRIVIAL 23454655 A 317 339 3-acetyldeoxynivalenol SYSTEMATIC 23454655 A 341 364 15-acetyldeoxynivalenol SYSTEMATIC 23454655 A 366 377 zearalenone TRIVIAL 23454655 A 379 391 α-zearalenol TRIVIAL 23454655 A 393 405 β-zearalenol TRIVIAL 23454655 A 407 416 T-2-toxin TRIVIAL 23454655 A 418 428 HT-2-toxin TRIVIAL 23454655 A 476 502 deoxynivalenol-3-glucoside SYSTEMATIC 23454655 A 504 527 zearalenone-4-glucoside SYSTEMATIC 23454655 A 529 553 α-zearalenol-4-glucoside SYSTEMATIC 23454655 A 555 579 β-zearalenol-4-glucoside SYSTEMATIC 23454655 A 584 605 zearalenone-4-sulfate SYSTEMATIC 23454672 A 23 77 (24R/S)-24-hydroxy-3α 10α-epoxy-9-eip-cucurbita-25-ene SYSTEMATIC 23454672 A 8 21 triterpenoids FAMILY 23454831 A 12 18 carbon SYSTEMATIC 23454831 A 42 56 polyamidoamine FAMILY 23454831 T 39 45 carbon SYSTEMATIC 23454832 A 0 12 Microcystins FAMILY 23454832 A 1058 1063 MC-LR ABBREVIATION 23454832 A 1124 1129 MC-LR ABBREVIATION 23454832 A 1192 1197 MC-LR ABBREVIATION 23454832 A 226 240 microcystin-LR TRIVIAL 23454832 A 242 247 MC-LR ABBREVIATION 23454832 A 351 356 MC-LR ABBREVIATION 23454832 A 659 664 MC-LR ABBREVIATION 23454832 T 90 104 microcystin-LR TRIVIAL 23454833 A 37 43 silver SYSTEMATIC 23454833 T 37 43 silver SYSTEMATIC 23455059 A 122 126 (1)H FORMULA 23455059 A 278 286 platinum SYSTEMATIC 23455059 A 36 63 mono-aminophosphonate ester SYSTEMATIC 23455059 A 586 595 cisplatin TRIVIAL 23455059 A 8 20 platinum(II) SYSTEMATIC 23455059 T 0 12 Platinum(II) SYSTEMATIC 23455059 T 28 55 mono-aminophosphonate ester SYSTEMATIC 23455313 A 1014 1018 cAMP ABBREVIATION 23455313 A 1111 1115 cAMP ABBREVIATION 23455313 A 1350 1354 ATRA ABBREVIATION 23455313 A 182 205 all-trans-retinoic acid TRIVIAL 23455313 A 207 211 ATRA ABBREVIATION 23455313 A 254 264 Cyclic AMP TRIVIAL 23455313 A 293 301 retinoid FAMILY 23455313 A 334 338 ATRA ABBREVIATION 23455313 A 361 365 ATRA ABBREVIATION 23455313 A 432 436 ATRA ABBREVIATION 23455313 A 587 591 cAMP ABBREVIATION 23455313 T 90 98 Retinoid FAMILY 23455594 A 1386 1394 nicotine TRIVIAL 23455594 A 888 899 varenicline TRIVIAL 23455594 A 907 915 nicotine TRIVIAL 23455599 A 1119 1129 naltrexone TRIVIAL 23455599 A 1242 1251 bupropion TRIVIAL 23455599 A 1256 1266 naltrexone TRIVIAL 23455599 A 1560 1570 naltrexone TRIVIAL 23455599 A 1575 1584 bupropion TRIVIAL 23455599 A 1745 1754 bupropion TRIVIAL 23455599 A 213 222 bupropion TRIVIAL 23455599 A 227 237 naltrexone TRIVIAL 23455599 A 492 501 bupropion TRIVIAL 23455599 A 503 513 naltrexone TRIVIAL 23455599 A 647 656 bupropion TRIVIAL 23455599 A 676 686 naltrexone TRIVIAL 23455599 A 716 725 bupropion TRIVIAL 23455599 A 742 752 naltrexone TRIVIAL 23455599 A 964 973 bupropion TRIVIAL 23455599 T 29 38 bupropion TRIVIAL 23455599 T 43 53 naltrexone TRIVIAL 23455898 A 122 124 Mg FORMULA 23455898 A 126 127 K FORMULA 23455898 A 1269 1271 Mg FORMULA 23455898 A 1273 1274 K FORMULA 23455898 A 1276 1278 Zn FORMULA 23455898 A 1280 1282 Fe FORMULA 23455898 A 1287 1289 Cu FORMULA 23455898 A 129 131 Ca FORMULA 23455898 A 133 135 Mn FORMULA 23455898 A 137 139 Zn FORMULA 23455898 A 141 143 Fe FORMULA 23455898 A 145 147 Cu FORMULA 23455898 A 149 151 Cr FORMULA 23455898 A 153 155 Ni FORMULA 23455898 A 157 159 Cd FORMULA 23455898 A 164 166 Pb FORMULA 23455898 A 328 330 Zn FORMULA 23455898 A 332 334 Fe FORMULA 23455898 A 336 338 Cu FORMULA 23455898 A 340 342 Cr FORMULA 23455898 A 344 346 Ni FORMULA 23455898 A 348 350 Cd FORMULA 23455898 A 355 357 Pb FORMULA 23455898 A 706 708 Mn FORMULA 23456363 A 101 112 isoflavones FAMILY 23456363 A 1491 1502 isoflavones FAMILY 23456363 A 168 177 estrogens FAMILY 23456363 A 20 31 isoflavones FAMILY 23456363 A 543 552 estrogens FAMILY 23456815 A 549 557 methanol SYSTEMATIC 23456815 A 687 702 malondialdehyde TRIVIAL 23456815 A 710 720 superoxide TRIVIAL 23456815 A 732 743 glutathione TRIVIAL 23456815 A 748 759 glutathione TRIVIAL 23456815 A 790 802 aflatoxin B1 TRIVIAL 23456815 T 55 63 methanol SYSTEMATIC 23456850 A 1323 1342 25-hydroxyvitamin D SYSTEMATIC 23457022 A 18 33 chlorflavonin A TRIVIAL 23457022 A 48 60 diterpenoids FAMILY 23457022 A 62 78 aspergiloids E-H MULTIPLE 23457022 A 8 16 flavonol TRIVIAL 23457022 T 17 29 diterpenoids FAMILY 23457022 T 4 12 flavonol TRIVIAL 23457058 A 376 382 Carbon SYSTEMATIC 23457058 A 423 429 carbon SYSTEMATIC 23457058 A 444 452 graphene TRIVIAL 23457058 A 605 611 carbon SYSTEMATIC 23457058 A 768 774 carbon SYSTEMATIC 23457058 T 44 50 carbon SYSTEMATIC 23457114 A 118 127 ruthenium SYSTEMATIC 23457114 A 131 137 carbon SYSTEMATIC 23457114 A 139 141 Ru FORMULA 23457114 A 142 143 C FORMULA 23457114 A 319 327 hydrogen SYSTEMATIC 23457114 A 466 476 isosorbide TRIVIAL 23457114 A 520 528 hydrogen SYSTEMATIC 23457114 A 542 544 Ru FORMULA 23457114 A 545 546 C FORMULA 23457114 A 55 63 isoidide TRIVIAL 23457114 A 561 563 Ru FORMULA 23457114 A 636 644 isoidide TRIVIAL 23457114 A 651 661 isosorbide TRIVIAL 23457114 A 671 681 isomannide TRIVIAL 23457114 A 722 728 nickel SYSTEMATIC 23457114 A 750 752 Ru FORMULA 23457114 A 753 754 C FORMULA 23457114 A 827 829 Ru FORMULA 23457114 A 859 867 isoidide TRIVIAL 23457114 A 99 109 isosorbide TRIVIAL 23457114 T 13 21 Isoidide TRIVIAL 23457114 T 47 57 Isosorbide TRIVIAL 23457114 T 64 73 Ruthenium SYSTEMATIC 23457114 T 77 83 Carbon SYSTEMATIC 23457123 A 200 204 MeHg FORMULA 23457123 A 322 326 MeHg FORMULA 23457123 A 36 49 methylmercury SYSTEMATIC 23457123 A 401 411 [(18)F]FDG SYSTEMATIC 23457123 A 51 55 MeHg FORMULA 23457123 A 536 540 MeHg FORMULA 23457123 A 760 770 [(18)F]FDG SYSTEMATIC 23457123 A 880 884 MeHg FORMULA 23457123 T 99 112 methylmercury SYSTEMATIC 23458420 A 320 323 ThT ABBREVIATION 23458420 A 436 439 ThT ABBREVIATION 23458420 A 475 478 ThT ABBREVIATION 23458420 A 530 533 ThT ABBREVIATION 23458420 A 618 621 ThT ABBREVIATION 23458420 A 640 643 ThT ABBREVIATION 23458420 A 674 677 ThT ABBREVIATION 23458420 A 69 72 ThT ABBREVIATION 23458420 T 0 12 Thioflavin T TRIVIAL 23458618 A 1677 1679 Cu FORMULA 23458618 A 1681 1683 Zn FORMULA 23458618 A 1709 1711 Pb FORMULA 23458620 A 1255 1259 PLGA ABBREVIATION 23458620 A 157 188 poly (D,L-lactide-co-glycolide) FAMILY 23458620 A 190 194 PLGA ABBREVIATION 23458620 A 369 373 PLGA ABBREVIATION 23458620 A 648 652 PLGA ABBREVIATION 23458620 A 888 892 PLGA ABBREVIATION 23458894 A 0 14 Crotonaldehyde TRIVIAL 23458894 A 1027 1041 crotonaldehyde TRIVIAL 23458894 A 1103 1117 crotonaldehyde TRIVIAL 23458894 A 1225 1239 Crotonaldehyde TRIVIAL 23458894 A 140 154 Crotonaldehyde TRIVIAL 23458894 A 1469 1483 crotonaldehyde TRIVIAL 23458894 A 31 56 α, β-unsaturated aldehyde SYSTEMATIC 23458894 A 359 373 crotonaldehyde TRIVIAL 23458894 A 506 520 crotonaldehyde TRIVIAL 23458894 A 593 607 crotonaldehyde TRIVIAL 23458894 T 0 14 Crotonaldehyde TRIVIAL 23458897 A 1175 1179 PFOA ABBREVIATION 23458897 A 20 38 perfluorooctanoate SYSTEMATIC 23458897 A 40 44 PFOA ABBREVIATION 23458897 A 512 516 PFOA ABBREVIATION 23458897 A 670 674 PFOA ABBREVIATION 23458897 T 87 105 perfluorooctanoate SYSTEMATIC 23458950 A 102 117 cystodiones A-F MULTIPLE 23458950 A 304 316 meroterpenes FAMILY 23458950 A 336 359 cystodiones A (1) and B MULTIPLE 23458950 A 365 398 6-cis-amentadione-1'-methyl ether SYSTEMATIC 23458950 A 408 435 amentadione-1'-methyl ether SYSTEMATIC 23458950 A 516 528 usneoidone Z TRIVIAL 23458950 A 86 100 meroterpenoids FAMILY 23458950 T 34 48 Meroterpenoids FAMILY 23458966 A 0 10 Zinc oxide SYSTEMATIC 23458966 A 1087 1090 ZnO FORMULA 23458966 A 1174 1177 ZnO FORMULA 23458966 A 204 207 ZnO FORMULA 23458966 A 26 29 ZnO FORMULA 23458966 A 291 294 ZnO FORMULA 23458966 A 373 376 ZnO FORMULA 23458966 A 451 454 ZnO FORMULA 23458966 A 477 483 oxygen SYSTEMATIC 23458966 A 566 569 ZnO FORMULA 23458966 A 647 650 ZnO FORMULA 23458966 A 778 781 ZnO FORMULA 23458966 A 844 869 adenosine-5'-triphosphate SYSTEMATIC 23458966 A 871 874 ATP ABBREVIATION 23458966 A 918 921 ZnO FORMULA 23458966 A 943 946 ZnO FORMULA 23458966 T 0 10 Zinc oxide SYSTEMATIC 23458966 T 92 98 oxygen SYSTEMATIC 23459107 A 1068 1081 mono-ammonium SYSTEMATIC 23459107 A 131 141 iron oxide SYSTEMATIC 23459107 A 284 292 ammonium SYSTEMATIC 23459107 A 336 345 methylene SYSTEMATIC 23459107 A 365 379 bisphosphonate SYSTEMATIC 23459107 A 520 530 iron oxide SYSTEMATIC 23459107 A 598 606 ammonium SYSTEMATIC 23459107 A 720 749 hydroxyethylenebisphosphonate SYSTEMATIC 23459107 A 751 755 HEBP ABBREVIATION 23459107 A 848 852 HEBP ABBREVIATION 23459107 A 992 1000 ammonium SYSTEMATIC 23459107 T 53 63 iron oxide SYSTEMATIC 23459107 T 88 103 bisphosphonates FAMILY 23459473 A 599 617 Polyethylene oxide FAMILY 23459473 A 619 622 PEO ABBREVIATION 23459473 A 683 704 poly(ethylene glycol) SYSTEMATIC 23459473 A 736 739 PEG ABBREVIATION 23459473 A 985 988 PEO ABBREVIATION 23460265 A 24 32 dopamine TRIVIAL 23460265 A 477 492 [(11)C]SCH23390 SYSTEMATIC 23460265 A 497 510 [(11)C]NNC112 SYSTEMATIC 23460265 A 682 697 [(11)C]SCH23390 SYSTEMATIC 23460265 A 702 715 [(11)C]NNC112 SYSTEMATIC 23460265 A 726 741 [(11)C]SCH23390 SYSTEMATIC 23460265 A 746 759 [(11)C]NNC112 SYSTEMATIC 23460265 A 968 983 [(11)C]SCH23390 SYSTEMATIC 23460265 A 988 1001 [(11)C]NNC112 SYSTEMATIC 23460265 T 23 31 dopamine TRIVIAL 23460265 T 55 68 [(11)C]NNC112 SYSTEMATIC 23460265 T 73 89 [ (11)C]SCH23390 SYSTEMATIC 23460644 A 1529 1536 sulfate SYSTEMATIC 23461628 A 0 15 (+)-Laburnamine TRIVIAL 23461628 A 321 336 [(3)H]-dopamine SYSTEMATIC 23461628 A 488 496 nicotine TRIVIAL 23461628 A 518 526 nicotine TRIVIAL 23461628 T 0 15 (+)-Laburnamine TRIVIAL 23461763 A 608 619 (157)Gd(3+) FORMULA 23461763 A 707 718 (157)Gd(3+) FORMULA 23461860 A 203 214 Rhodamine B TRIVIAL 23461860 A 216 220 Rh B ABBREVIATION 23461860 A 226 252 fluorescein isothiocyanate TRIVIAL 23461860 A 254 258 FITC ABBREVIATION 23461860 A 361 389 poly lactic-co-glycolic acid FAMILY 23461860 A 391 395 PLGA ABBREVIATION 23462105 A 0 12 Aflatoxin M1 TRIVIAL 23462105 A 1198 1203 AF M1 ABBREVIATION 23462105 A 14 19 AF M1 ABBREVIATION 23462105 A 204 209 AF M1 ABBREVIATION 23462105 A 254 259 AF B1 ABBREVIATION 23462105 A 51 56 AF B1 ABBREVIATION 23462105 A 612 617 AF B1 ABBREVIATION 23462105 A 763 768 AF B1 ABBREVIATION 23462105 A 928 933 AF M1 ABBREVIATION 23462105 T 20 32 aflatoxin M1 TRIVIAL 23462105 T 77 89 aflatoxin B1 TRIVIAL 23462308 A 12 20 Ketamine TRIVIAL 23462308 A 1240 1248 ketamine TRIVIAL 23462308 A 1317 1325 ketamine TRIVIAL 23462308 A 245 253 ketamine TRIVIAL 23462308 A 590 598 ketamine TRIVIAL 23462308 A 671 679 ketamine TRIVIAL 23462308 A 793 801 ketamine TRIVIAL 23462308 A 906 914 ketamine TRIVIAL 23462308 A 985 993 ketamine TRIVIAL 23462308 T 26 34 Ketamine TRIVIAL 23462526 A 0 5 Boron SYSTEMATIC 23462526 A 472 491 boronophenylalanine SYSTEMATIC 23462526 T 111 116 Boron SYSTEMATIC 23462671 A 238 247 rapamycin TRIVIAL 23462671 A 470 481 isopropanol SYSTEMATIC 23462671 A 491 500 phosphate SYSTEMATIC 23462671 A 514 523 phosphate SYSTEMATIC 23462671 T 13 22 rapamycin TRIVIAL 23462672 A 1028 1032 PACA ABBREVIATION 23462672 A 235 262 poly(alkyl-2-cyanoacrylate) FAMILY 23462672 A 264 268 PACA ABBREVIATION 23462672 A 405 409 PACA ABBREVIATION 23462672 A 450 454 PACA ABBREVIATION 23462672 A 554 571 diclofenac sodium SYSTEMATIC 23462672 A 627 631 PACA ABBREVIATION 23462672 A 678 682 PACA ABBREVIATION 23462672 A 731 760 poly(n-butyl-2-cyanoacrylate) FAMILY 23462672 A 817 827 diclofenac TRIVIAL 23462672 A 963 967 PACA ABBREVIATION 23462672 T 0 23 Polyalkylcyanoacrylates FAMILY 23462797 A 1040 1055 triacylglycerol FAMILY 23462797 A 1140 1147 glucose TRIVIAL 23462797 A 1368 1379 cholesterol TRIVIAL 23462797 A 1394 1409 triacylglycerol FAMILY 23462797 A 621 628 glucose TRIVIAL 23462797 A 964 979 triacylglycerol FAMILY 23462814 A 1070 1078 graphene TRIVIAL 23462814 A 1249 1257 graphene TRIVIAL 23462814 A 158 166 graphene TRIVIAL 23462814 A 16 24 graphene TRIVIAL 23462814 A 211 219 graphene TRIVIAL 23462814 A 223 227 SiO2 FORMULA 23462814 A 379 387 graphene TRIVIAL 23462814 A 447 455 graphene TRIVIAL 23462814 A 501 509 graphene TRIVIAL 23462814 A 540 548 graphene TRIVIAL 23462814 A 56 60 SiO2 FORMULA 23462814 A 571 579 graphene TRIVIAL 23462814 A 626 634 graphene TRIVIAL 23462814 A 638 642 SiO2 FORMULA 23462814 A 685 693 graphene TRIVIAL 23462814 A 723 731 graphene TRIVIAL 23462814 A 78 86 graphene TRIVIAL 23462814 A 800 808 graphene TRIVIAL 23462814 A 820 824 SiO2 FORMULA 23462814 A 92 96 mica TRIVIAL 23462814 A 923 931 graphene TRIVIAL 23462814 A 945 949 mica TRIVIAL 23462814 T 44 52 graphene TRIVIAL 23464522 A 434 441 taxanes FAMILY 23464522 A 61 68 taxanes FAMILY 23464522 A 73 88 vinca alkaloids FAMILY 23464522 A 804 812 eribulin TRIVIAL 23464522 A 814 825 ixabepilone TRIVIAL 23464522 A 827 838 cabazitaxel TRIVIAL 23464522 A 855 858 DM1 ABBREVIATION 23464578 A 526 533 ethanol SYSTEMATIC 23464629 A 1121 1132 stachydrine TRIVIAL 23464629 A 1157 1166 enalapril TRIVIAL 23464629 A 1300 1311 stachydrine TRIVIAL 23464629 A 174 183 enalapril TRIVIAL 23464629 A 196 207 stachydrine TRIVIAL 23464629 A 222 233 stachydrine TRIVIAL 23464629 A 249 260 stachydrine TRIVIAL 23464629 A 45 56 stachydrine TRIVIAL 23464629 A 457 467 creatinine TRIVIAL 23464629 A 489 497 nitrogen SYSTEMATIC 23464629 T 10 21 stachydrine TRIVIAL 23464739 A 0 15 Uncinataflavone TRIVIAL 23464739 A 266 350 methyl 3-(5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-6-yl)-4-methoxybenzoate SYSTEMATIC 23464739 A 27 36 flavonoid FAMILY 23464739 A 519 548 1,1-diphenyl-2-picrylhydrazyl SYSTEMATIC 23464739 T 0 15 Uncinataflavone TRIVIAL 23464739 T 23 32 flavonoid FAMILY 23464739 T 40 55 methyl benzoate SYSTEMATIC 23464760 A 1035 1054 7-hydroxyisoflavone SYSTEMATIC 23464760 A 335 354 7-hydroxyisoflavone SYSTEMATIC 23464760 A 380 399 7-Hydroxyisoflavone SYSTEMATIC 23464760 A 570 589 7-Hydroxyisoflavone SYSTEMATIC 23464760 A 727 746 7-hydroxyisoflavone SYSTEMATIC 23464760 A 861 880 7-hydroxyisoflavone SYSTEMATIC 23464760 A 925 944 7-Hydroxyisoflavone SYSTEMATIC 23464760 T 24 43 7-hydroxyisoflavone SYSTEMATIC 23464805 A 136 167 8-oxo-tri-nor-eudesm-6-en-5α-ol SYSTEMATIC 23464805 A 176 206 tri-nor-eudesm-5-en-7β,8β-diol SYSTEMATIC 23464805 A 31 47 sesquiterpenoids FAMILY 23464805 A 8 25 tri-nor-eudesmane TRIVIAL 23464805 T 8 30 tri-nor-eudesmanolides FAMILY 23464810 A 1076 1083 silicon SYSTEMATIC 23464810 A 283 290 silicon SYSTEMATIC 23464810 T 108 110 Si FORMULA 23464829 A 22 32 songarin A TRIVIAL 23464829 A 232 247 d-galactosamine TRIVIAL 23464829 A 6 14 flavanol FAMILY 23464829 T 6 14 flavanol FAMILY 23464873 A 0 8 Graphene TRIVIAL 23464873 A 280 288 graphene TRIVIAL 23464873 T 76 84 graphene TRIVIAL 23465048 A 0 13 Thioacetamide SYSTEMATIC 23465048 A 1001 1016 [(13)C2D3]-TASO SYSTEMATIC 23465048 A 103 124 thioacetamide S-oxide SYSTEMATIC 23465048 A 126 130 TASO ABBREVIATION 23465048 A 1329 1334 amide FAMILY 23465048 A 1340 1347 amidine SYSTEMATIC 23465048 A 1372 1378 lysine TRIVIAL 23465048 A 1436 1443 amidine SYSTEMATIC 23465048 A 1480 1493 Thiobenzamide SYSTEMATIC 23465048 A 1589 1594 amide FAMILY 23465048 A 1599 1606 amidine SYSTEMATIC 23465048 A 162 173 S,S-dioxide SYSTEMATIC 23465048 A 1626 1632 lysine TRIVIAL 23465048 A 1654 1661 amidine SYSTEMATIC 23465048 A 175 180 TASO2 FORMULA 23465048 A 1829 1833 TASO ABBREVIATION 23465048 A 1882 1886 TASO ABBREVIATION 23465048 A 300 324 phosphatidylethanolamine SYSTEMATIC 23465048 A 349 355 lysine TRIVIAL 23465048 A 416 420 TASO ABBREVIATION 23465048 A 534 538 TASO ABBREVIATION 23465048 A 542 547 TASO2 FORMULA 23465048 A 583 587 TASO ABBREVIATION 23465048 A 733 745 [(14)C]-TASO SYSTEMATIC 23465048 A 88 89 S FORMULA 23465048 A 996 1000 TASO ABBREVIATION 23465048 T 19 32 Thioacetamide SYSTEMATIC 23466229 A 207 225 dihydroquinolinone SYSTEMATIC 23466229 A 236 264 tetrahydropyrazolopyridinone SYSTEMATIC 23466229 A 447 455 pyrazole SYSTEMATIC 23466229 A 74 82 pyrazole SYSTEMATIC 23466229 T 0 11 PF-04859989 IDENTIFIER 23466229 T 81 89 pyrazole SYSTEMATIC 23466230 A 105 120 methyl ferulate SYSTEMATIC 23466230 A 38 48 dabigatran TRIVIAL 23466230 A 406 426 dabigatran etexilate TRIVIAL 23466230 A 53 103 methyl (E)-3-(4-hydroxy-2-methoxyphenyl)propenoate SYSTEMATIC 23466230 T 57 67 dabigatran TRIVIAL 23466230 T 88 103 methyl ferulate SYSTEMATIC 23466232 A 39 44 sugar FAMILY 23466232 A 759 796 5-(p-toluenesulfonylamino)phthalimide SYSTEMATIC 23466232 A 86 123 5-(p-toluenesulfonylamino)phthalimide SYSTEMATIC 23466232 T 16 68 N2-substituted-5-(p-toluenesulfonylamino)phthalimide FAMILY 23466234 A 12 70 3-S-β-d-glucosides-4-arylideneamino-5-aryl-1,2,4-triazoles FAMILY 23466234 A 205 219 1,2,4-triazole SYSTEMATIC 23466234 A 221 232 Schiff base FAMILY 23466234 A 237 247 glucosides FAMILY 23466234 A 315 319 (1)H FORMULA 23466234 A 325 330 (13)C FORMULA 23466234 T 61 77 S-β-d-glucosides FAMILY 23466234 T 81 112 5-aryl-1,2,4-triazole-3-thiones FAMILY 23466330 A 260 274 norepinephrine TRIVIAL 23466330 A 461 475 norepinephrine TRIVIAL 23466331 A 59 68 glutamate TRIVIAL 23466342 A 227 235 mollugin TRIVIAL 23466342 A 322 332 adriamycin TRIVIAL 23466342 A 405 413 Mollugin TRIVIAL 23466342 A 496 504 Mollugin TRIVIAL 23466342 A 615 628 rhodamine-123 TRIVIAL 23466342 A 716 724 mollugin TRIVIAL 23466342 A 747 750 AMP ABBREVIATION 23466342 A 797 805 mollugin TRIVIAL 23466342 A 901 909 mollugin TRIVIAL 23466342 A 970 978 mollugin TRIVIAL 23466342 T 71 79 mollugin TRIVIAL 23466460 A 0 11 Polyphenols FAMILY 23466460 A 1158 1169 polyphenols FAMILY 23466460 A 224 233 quercetin TRIVIAL 23466460 A 235 259 epigallocatechin gallate TRIVIAL 23466460 A 264 272 curcumin TRIVIAL 23466460 A 457 464 glucose TRIVIAL 23466460 A 576 587 polyphenols FAMILY 23466460 A 993 1004 polyphenols FAMILY 23466460 T 38 49 polyphenols FAMILY 23466460 T 52 61 quercetin TRIVIAL 23466460 T 63 87 epigallocatechin gallate TRIVIAL 23466460 T 92 100 curcumin TRIVIAL 23466500 A 1044 1053 cisplatin TRIVIAL 23466500 A 1240 1249 LY 294002 IDENTIFIER 23466500 A 1377 1386 cisplatin TRIVIAL 23466500 A 600 609 cisplatin TRIVIAL 23466500 A 611 614 DDP ABBREVIATION 23466500 A 682 691 cisplatin TRIVIAL 23466500 A 720 723 DDP ABBREVIATION 23466500 A 874 883 cisplatin TRIVIAL 23466500 A 987 996 cisplatin TRIVIAL 23466500 T 15 24 cisplatin TRIVIAL 23466501 A 1119 1127 p-cresol TRIVIAL 23466501 A 1208 1216 p-cresol TRIVIAL 23466501 A 156 164 p-cresol TRIVIAL 23466501 A 23 31 p-cresol TRIVIAL 23466501 A 272 280 p-cresol TRIVIAL 23466501 A 478 486 p-cresol TRIVIAL 23466501 A 511 519 p-cresol TRIVIAL 23466501 A 616 624 p-cresol TRIVIAL 23466501 A 649 656 calcium SYSTEMATIC 23466501 A 763 771 p-cresol TRIVIAL 23466501 A 868 876 p-cresol TRIVIAL 23466501 A 922 928 serine TRIVIAL 23466501 T 0 8 p-Cresol TRIVIAL 23466526 A 764 768 zinc SYSTEMATIC 23466526 T 5 9 zinc SYSTEMATIC 23466565 A 0 10 Isosteviol TRIVIAL 23466565 A 1092 1105 acetylcholine SYSTEMATIC 23466565 A 180 214 ent-16β-hydroxybeyeran-19-oic acid SYSTEMATIC 23466565 A 287 294 acetate SYSTEMATIC 23466565 A 307 341 ent-16β-acetoxybeyeran-19-oic acid SYSTEMATIC 23466565 A 610 651 ent-7α-hydroxy-16-ketobeyeran-19-oic acid SYSTEMATIC 23466565 T 80 90 isosteviol TRIVIAL 23466606 A 120 140 sodium orthovanadate SYSTEMATIC 23466606 A 162 176 streptozotocin TRIVIAL 23466606 A 323 331 vanadium SYSTEMATIC 23466606 A 351 359 vanadium SYSTEMATIC 23466606 A 487 495 vanadium SYSTEMATIC 23466606 A 554 562 vanadium SYSTEMATIC 23466606 A 622 639 vanadium-flavonol FAMILY 23466606 A 747 750 STZ ABBREVIATION 23466606 T 105 108 STZ ABBREVIATION 23466606 T 24 41 vanadium-flavonol FAMILY 23466742 A 102 110 estrogen FAMILY 23466742 A 1068 1076 estrogen FAMILY 23466742 A 1309 1317 estrogen FAMILY 23466742 A 188 196 estrogen FAMILY 23466742 A 275 283 estrogen FAMILY 23466742 A 476 484 estrogen FAMILY 23466742 A 489 497 estrogen FAMILY 23466742 A 563 571 estrogen FAMILY 23466742 A 58 67 estrogens FAMILY 23466742 A 796 804 estrogen FAMILY 23466742 A 990 998 estrogen FAMILY 23466742 T 37 45 estrogen FAMILY 23467017 A 1032 1040 abacavir TRIVIAL 23467017 A 141 149 abacavir TRIVIAL 23467017 A 18 26 abacavir TRIVIAL 23467017 A 279 287 abacavir TRIVIAL 23467017 A 355 363 abacavir TRIVIAL 23467017 A 576 584 Abacavir TRIVIAL 23467017 A 616 617 N FORMULA 23467017 A 627 633 valine TRIVIAL 23467017 A 759 767 Abacavir TRIVIAL 23467017 A 768 774 valine TRIVIAL 23467017 A 870 878 abacavir TRIVIAL 23467017 A 947 955 abacavir TRIVIAL 23467017 T 11 19 abacavir TRIVIAL 23467017 T 62 70 aldehyde SYSTEMATIC 23468100 A 1092 1099 alcohol FAMILY 23468100 A 1143 1150 alcohol FAMILY 23468100 A 1518 1525 Alcohol SYSTEMATIC 23468100 A 1562 1569 Alcohol SYSTEMATIC 23468100 A 1637 1644 alcohol FAMILY 23468100 A 445 452 alcohol FAMILY 23468100 A 54 61 alcohol FAMILY 23468100 A 697 704 alcohol FAMILY 23468100 A 739 746 alcohol FAMILY 23468100 T 44 51 alcohol FAMILY 23468173 A 133 168 3-hydroxyazetidine carboxylic acids FAMILY 23468173 A 19 28 D-glucose SYSTEMATIC 23468173 A 197 222 3-hydroxyazetidine amides FAMILY 23468173 A 308 318 amino acid FAMILY 23468173 A 428 479 N,3-O-dibenzyl-2,4-dideoxy-2,4-imino-D-ribonic acid SYSTEMATIC 23468173 A 52 85 2,4-dideoxy-2,4-iminoribonic acid SYSTEMATIC 23468173 A 535 558 N-methylazetidine amide SYSTEMATIC 23468173 A 717 722 amide FAMILY 23468173 A 728 744 sugar amino acid FAMILY 23468173 A 759 769 iminosugar FAMILY 23468173 T 0 35 3-Hydroxyazetidine carboxylic acids FAMILY 23468173 T 55 66 amino acids FAMILY 23468386 A 1139 1141 Ag FORMULA 23468386 A 193 195 Ag FORMULA 23468386 A 49 51 Ag FORMULA 23468386 A 637 639 Ag FORMULA 23468386 A 760 762 Ag FORMULA 23468386 T 49 51 Ag FORMULA 23469760 A 103 117 methylthiolate SYSTEMATIC 23469760 A 122 136 phenylthiolate SYSTEMATIC 23469760 A 145 152 Au(111) FORMULA 23469760 A 194 208 organometallic FAMILY 23469760 A 222 236 methylthiolate SYSTEMATIC 23469760 A 241 255 phenylthiolate SYSTEMATIC 23469760 A 278 286 RS-Au-SR FAMILY 23469760 A 301 312 hydrocarbon FAMILY 23469760 A 383 394 CH3S-Au-SPh FORMULA 23469760 A 527 532 RS-Au FAMILY 23469760 A 583 594 trithiolate SYSTEMATIC 23469760 A 595 611 RS-Au-(SR)-Au-SR FAMILY 23469760 A 740 752 alkanethiols FAMILY 23469760 A 814 822 thiolate SYSTEMATIC 23469760 A 85 93 thiolate SYSTEMATIC 23469760 T 17 31 Phenylthiolate SYSTEMATIC 23469760 T 37 51 Methylthiolate SYSTEMATIC 23469760 T 90 97 Au(111) FORMULA 23469923 A 95 103 dopamine TRIVIAL 23469923 T 12 20 dopamine TRIVIAL 23469927 A 0 5 Soman TRIVIAL 23469927 A 1087 1092 soman TRIVIAL 23469927 A 1191 1196 soman TRIVIAL 23469927 A 1208 1216 tyrosine TRIVIAL 23469927 A 130 138 tyrosine TRIVIAL 23469927 A 1331 1336 soman TRIVIAL 23469927 A 167 176 pinacolyl TRIVIAL 23469927 A 186 191 soman TRIVIAL 23469927 A 221 248 pinacolyl methylphosphonate SYSTEMATIC 23469927 A 258 266 tyrosine TRIVIAL 23469927 A 303 311 Tyrosine TRIVIAL 23469927 A 319 331 pentapeptide FAMILY 23469927 A 367 372 soman TRIVIAL 23469927 A 390 395 soman TRIVIAL 23469927 A 41 49 tyrosine TRIVIAL 23469927 A 561 566 soman TRIVIAL 23469927 A 590 595 soman TRIVIAL 23469927 A 615 620 soman TRIVIAL 23469927 A 687 692 soman TRIVIAL 23469927 A 701 710 tyrosines FAMILY 23469927 A 757 767 amino acid FAMILY 23469927 A 77 86 tyrosines FAMILY 23469927 A 821 826 soman TRIVIAL 23469927 A 827 835 tyrosine TRIVIAL 23469927 A 855 865 amino acid FAMILY 23469927 T 23 28 Soman TRIVIAL 23469927 T 29 37 Tyrosine TRIVIAL 23470166 A 164 175 polyphenols FAMILY 23470166 A 206 216 polyphenol FAMILY 23470166 A 229 232 GSH ABBREVIATION 23470166 A 91 97 Cu(2+) FORMULA 23470166 T 84 95 polyphenols FAMILY 23470181 A 1056 1063 rubrene TRIVIAL 23470181 A 1128 1131 CdA FORMULA 23470181 A 1200 1207 rubrene TRIVIAL 23470181 A 1212 1215 CdA FORMULA 23470181 A 1311 1318 rubrene TRIVIAL 23470181 A 1352 1355 CdA FORMULA 23470181 A 1410 1413 CdA FORMULA 23470181 A 1529 1532 CdA FORMULA 23470181 A 1537 1544 rubrene TRIVIAL 23470181 A 177 184 rubrene TRIVIAL 23470181 A 217 235 cadmium arachidate SYSTEMATIC 23470181 A 237 240 CdA FORMULA 23470181 A 269 273 SiO2 FORMULA 23470181 A 274 276 Si FORMULA 23470181 A 323 326 CdA FORMULA 23470181 A 33 40 rubrene TRIVIAL 23470181 A 436 442 methyl SYSTEMATIC 23470181 A 534 537 CdA FORMULA 23470181 A 542 549 rubrene TRIVIAL 23470181 A 740 747 rubrene TRIVIAL 23470181 A 857 860 CdA FORMULA 23470181 A 965 968 CdA FORMULA 23470181 T 22 29 rubrene TRIVIAL 23470181 T 68 86 cadmium arachidate SYSTEMATIC 23470217 A 109 112 Gly FORMULA 23470217 A 141 148 calcium SYSTEMATIC 23470217 A 236 254 3-methyl-benzyl-PP SYSTEMATIC 23470217 A 256 263 3-MB-PP SYSTEMATIC 23470217 A 40 67 pyrazolo [3,4-d] pyrimidine SYSTEMATIC 23470217 T 40 47 Calcium SYSTEMATIC 23470287 A 1467 1470 SA9 ABBREVIATION 23470287 A 157 169 Sinapic acid TRIVIAL 23470287 A 1570 1573 SA9 ABBREVIATION 23470287 A 178 193 phenylpropanoid SYSTEMATIC 23470287 A 582 590 hydroxyl SYSTEMATIC 23470287 A 604 633 2,2-diphenyl-1-picrylhydrazyl SYSTEMATIC 23470287 A 635 642 DPPH(⋅) ABBREVIATION 23470287 A 749 803 1-Acetyl-sinapic acyl-4-(3'-chlorine-)benzylpiperazine SYSTEMATIC 23470287 A 805 808 SA9 ABBREVIATION 23470287 A 920 923 SA9 ABBREVIATION 23470287 A 945 948 SA9 ABBREVIATION 23470287 T 20 32 sinapic Acid TRIVIAL 23470629 A 121 147 3β-hydroxy-Δ(5)-bile acids FAMILY 23470629 A 267 277 bile acids FAMILY 23470629 A 380 406 3β-hydroxy-Δ(5)-bile acids FAMILY 23470629 A 625 634 bile salt FAMILY 23470629 A 683 709 3β-hydroxy-Δ(5)-bile acids FAMILY 23470629 A 824 850 3β-hydroxy-Δ(5)-bile acids FAMILY 23470629 A 869 879 bile acids FAMILY 23470629 A 888 904 glycocholic acid TRIVIAL 23470629 A 909 940 taurolithocholic acid 3-sulfate SYSTEMATIC 23470629 T 39 65 3β-Hydroxy-Δ(5)-bile Acids FAMILY 23470629 T 69 78 Bile Salt FAMILY 23470692 A 1228 1234 oxygen SYSTEMATIC 23471562 A 241 250 n-butanol SYSTEMATIC 23471562 A 371 383 indomethacin TRIVIAL 23471562 A 421 430 n-butanol SYSTEMATIC 23471562 A 475 479 PGE2 ABBREVIATION 23471562 A 550 559 n-butanol SYSTEMATIC 23471562 A 578 606 α-amyrin 3-O-glucopyranoside SYSTEMATIC 23471562 A 612 641 patuletin 7-O-glucopyranoside SYSTEMATIC 23471562 A 647 657 myricitrin TRIVIAL 23471562 A 672 699 oleanane triterpene saponin FAMILY 23471562 A 716 833 sophradiol 3-O-α-L-(1)C4-rhamnopyranosyl-(1'''→4'')-O-β-D-(4)C1-galactopyranosyl (1''→6')-O-β-D-(4)C1-glucopyranoside SYSTEMATIC 23471562 T 24 42 triterpene saponin FAMILY 23471769 A 101 110 Adenosine TRIVIAL 23471769 A 1032 1045 nitroglycerin SYSTEMATIC 23471769 A 115 127 dipyridamole TRIVIAL 23471769 A 1352 1363 regadenoson TRIVIAL 23471769 A 145 154 adenosine TRIVIAL 23471769 A 1475 1486 regadenoson TRIVIAL 23471769 A 389 400 Regadenoson TRIVIAL 23471769 A 568 581 nitroglycerin SYSTEMATIC 23471769 A 840 851 regadenoson TRIVIAL 23471769 A 864 889 technetium 99 m sestamibi SYSTEMATIC 23471769 A 909 920 regadenoson TRIVIAL 23471769 T 35 46 Regadenoson TRIVIAL 23471850 A 1018 1028 rhenium(I) SYSTEMATIC 23471850 A 1032 1044 rhenium(VII) SYSTEMATIC 23471850 A 1046 1059 palladium(II) SYSTEMATIC 23471850 A 1065 1079 lanthanum(III) SYSTEMATIC 23471850 A 1163 1171 alcohols FAMILY 23471850 A 1181 1182 O FORMULA 23471850 A 1291 1292 S FORMULA 23471850 A 1295 1296 C FORMULA 23471850 A 1303 1304 N FORMULA 23471850 A 146 154 alcohols FAMILY 23471850 A 194 200 sulfur SYSTEMATIC 23471850 A 203 209 carbon SYSTEMATIC 23471850 A 212 218 oxygen SYSTEMATIC 23471850 A 225 233 nitrogen SYSTEMATIC 23471850 A 353 361 alcohols FAMILY 23471850 A 386 393 alcohol FAMILY 23471850 A 614 622 alcohols FAMILY 23471850 A 830 839 iron(III) SYSTEMATIC 23471850 A 841 853 bismuth(III) SYSTEMATIC 23471850 A 859 868 gold(III) SYSTEMATIC 23471850 A 897 898 S FORMULA 23471850 A 901 902 C FORMULA 23471850 A 909 910 N FORMULA 23471850 A 938 945 Bi(III) FORMULA 23471850 T 74 82 Alcohols FAMILY 23471871 A 106 112 Fe3 S4 FORMULA 23471871 A 125 131 Fe4 S4 FORMULA 23471871 A 67 70 FeS FORMULA 23471871 A 701 704 FeS FORMULA 23471871 A 716 722 FeS(-) FORMULA 23471871 A 736 740 FeS2 FORMULA 23471871 A 754 762 FeS2 (-) FORMULA 23471871 A 776 782 Fe2 S2 FORMULA 23471871 A 78 82 FeS2 FORMULA 23471871 A 796 806 Fe2 S2 (-) FORMULA 23471871 A 821 827 Fe3 S4 FORMULA 23471871 A 842 852 Fe3 S4 (-) FORMULA 23471871 A 866 872 Fe4 S4 FORMULA 23471871 A 890 900 Fe4 S4 (-) FORMULA 23471871 A 91 97 Fe2 S2 FORMULA 23471871 A 916 922 Fe2 S2 FORMULA 23471871 A 925 931 Fe3 S4 FORMULA 23471871 A 934 944 Fe3 S4 (-) FORMULA 23471871 A 947 953 Fe4 S4 FORMULA 23471871 A 960 970 Fe4 S4 (-) FORMULA 23471871 T 28 31 FeS FORMULA 23471871 T 39 43 FeS2 FORMULA 23471871 T 52 58 Fe2 S2 FORMULA 23471871 T 67 73 Fe3 S4 FORMULA 23471871 T 86 92 Fe4 S4 FORMULA 23471970 A 597 601 cAMP ABBREVIATION 23471970 A 661 664 Ser FORMULA 23471970 T 4 8 cAMP ABBREVIATION 23472833 A 1007 1011 NaBr FORMULA 23472833 A 1017 1066 3,3-, 6,9-, or 6,12-ionene fluorides and bromides MULTIPLE 23472833 A 1127 1140 alkali halide FAMILY 23472833 A 1179 1191 12,12-ionene SYSTEMATIC 23472833 A 1266 1272 Na2SO4 FORMULA 23472833 A 169 196 sodium fluoride and bromide MULTIPLE 23472833 A 292 301 methylene SYSTEMATIC 23472833 A 344 352 fluoride SYSTEMATIC 23472833 A 354 361 bromide SYSTEMATIC 23472833 A 367 373 iodide SYSTEMATIC 23472833 A 409 423 sodium sulfate SYSTEMATIC 23472833 A 47 102 aliphatic 6,12- and 12,12-ionene bromides and fluorides MULTIPLE 23472833 A 493 529 3,3-, 6,9-, 6,12-, and 12,12-ionenes MULTIPLE 23472833 A 892 901 methylene SYSTEMATIC 23472833 A 999 1002 NaF FORMULA 23472857 A 215 218 AOT ABBREVIATION 23472857 A 219 229 Igepal-520 TRIVIAL 23472857 A 230 241 cyclohexane SYSTEMATIC 23472857 A 614 620 Igepal TRIVIAL 23472857 A 781 784 AOT ABBREVIATION 23472857 A 808 814 Igepal TRIVIAL 23472857 A 970 982 Coumarin-500 TRIVIAL 23472952 A 147 175 α,α-disubstituted amino acid FAMILY 23472952 A 223 284 (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid SYSTEMATIC 23472952 T 13 74 (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid SYSTEMATIC 23473053 A 12 49 benzo[de][1,7]naphthyridin-7(8H)-ones FAMILY 23473053 A 244 264 phthalazin-1(2H)-one SYSTEMATIC 23473053 A 664 668 H2O2 FORMULA 23473053 A 875 887 Temozolomide TRIVIAL 23473053 T 60 97 Benzo[de][1,7]naphthyridin-7(8H)-ones FAMILY 23473343 A 126 132 SrTiO3 FORMULA 23473343 A 134 137 STO ABBREVIATION 23473343 A 151 154 CFO ABBREVIATION 23473343 A 238 241 BFO ABBREVIATION 23473343 A 287 290 STO ABBREVIATION 23473343 A 441 444 STO ABBREVIATION 23473343 A 649 652 CFO ABBREVIATION 23473343 A 66 72 BiFeO3 FORMULA 23473343 A 662 665 STO ABBREVIATION 23473343 A 73 80 CoFe2O4 FORMULA 23473343 A 82 85 BFO ABBREVIATION 23473343 A 86 89 CFO ABBREVIATION 23473343 A 970 975 oxide SYSTEMATIC 23473343 T 40 46 BiFeO3 FORMULA 23473343 T 47 54 CoFe2O4 FORMULA 23473535 A 1102 1113 metal oxide FAMILY 23473535 A 257 271 aluminum oxide SYSTEMATIC 23473535 A 277 282 Al2O3 FORMULA 23473535 A 296 301 (16)O FORMULA 23473535 A 306 311 (13)N FORMULA 23473535 A 587 592 (13)N FORMULA 23473535 A 606 611 Al2O3 FORMULA 23473535 A 664 675 metal oxide FAMILY 23473535 A 761 766 (13)N FORMULA 23473535 T 135 146 metal oxide FAMILY 23473568 A 59 79 [Pb(L)(μ2-Br)(H2O)]n FAMILY 23473568 A 689 697 Pb3O2Br2 FORMULA 23473568 A 91 122 1H-1,2,4-triazole-3-carboxylate SYSTEMATIC 23473568 T 123 142 lead(II) oxybromide SYSTEMATIC 23473568 T 58 66 lead(II) SYSTEMATIC 23473679 A 144 172 (177)Lu-DOTA-GGNle-CycMSHhex FORMULA 23473679 A 270 298 (177)Lu-DOTA-GGNle-CycMSHhex FORMULA 23473679 A 480 508 (177)Lu-DOTA-GGNle-CycMSHhex FORMULA 23473679 A 615 643 (177)Lu-DOTA-GGNle-CycMSHhex FORMULA 23473679 A 755 783 (177)Lu-DOTA-GGNle-CycMSHhex FORMULA 23473679 A 78 106 (177)Lu-DOTA-GGNle-CycMSHhex FORMULA 23473679 A 895 923 (177)Lu-DOTA-GGNle-CycMSHhex FORMULA 23473679 T 33 39 Lu-177 FORMULA 23473679 T 48 54 lactam SYSTEMATIC 23473682 A 134 155 phenylaminopyrimidine SYSTEMATIC 23473682 A 163 166 PAP ABBREVIATION 23473682 A 191 199 imatinib TRIVIAL 23473682 A 281 289 hydrogen SYSTEMATIC 23473682 A 56 64 tyrosine TRIVIAL 23473682 T 108 111 PAP ABBREVIATION 23473682 T 79 100 phenylaminopyrimidine SYSTEMATIC 23473682 T 8 16 tyrosine TRIVIAL 23474014 A 529 543 corticosterone TRIVIAL 23474014 A 604 618 corticosterone TRIVIAL 23474014 A 620 624 CORT ABBREVIATION 23474014 A 909 913 CORT ABBREVIATION 23474014 T 26 40 corticosterone TRIVIAL 23474169 A 107 117 fosfomycin TRIVIAL 23474169 A 119 126 Monurol TRIVIAL 23474169 A 20 32 phosphonates FAMILY 23474169 A 41 57 phosphinothricin TRIVIAL 23474169 A 59 70 Glufosinate TRIVIAL 23474169 A 764 775 phosphonate SYSTEMATIC 23474169 A 780 791 phosphinate SYSTEMATIC 23474169 A 854 865 phosphonate SYSTEMATIC 23474169 A 878 892 phosacetamycin TRIVIAL 23474169 T 28 42 Phosacetamycin TRIVIAL 23474169 T 88 103 Phosphonic Acid SYSTEMATIC 23474218 A 107 117 neolignans FAMILY 23474218 A 1114 1124 neolignans FAMILY 23474218 A 118 132 eupomatenoid-5 TRIVIAL 23474218 A 138 148 conocarpan TRIVIAL 23474218 A 157 171 eupomatenoid-3 TRIVIAL 23474218 A 291 294 CO2 FORMULA 23474218 A 418 422 (1)H FORMULA 23474218 A 673 689 sulforhodamine B TRIVIAL 23474218 A 728 731 CO2 FORMULA 23474218 A 93 96 CO2 FORMULA 23474381 A 1007 1019 behenic acid TRIVIAL 23474381 A 1095 1107 behenic acid TRIVIAL 23474381 A 1145 1148 MPT ABBREVIATION 23474381 A 116 127 fatty acids FAMILY 23474381 A 1217 1220 MPT ABBREVIATION 23474381 A 1227 1239 behenic acid TRIVIAL 23474381 A 129 141 stearic acid TRIVIAL 23474381 A 1366 1369 MPT ABBREVIATION 23474381 A 147 159 behenic acid TRIVIAL 23474381 A 214 233 metoprolol tartrate TRIVIAL 23474381 A 235 238 MPT ABBREVIATION 23474381 A 336 346 fatty acid FAMILY 23474381 A 432 444 behenic acid TRIVIAL 23474381 A 492 504 stearic acid TRIVIAL 23474381 A 634 644 fatty acid FAMILY 23474381 A 798 809 fatty acids FAMILY 23474381 A 890 893 MPT ABBREVIATION 23474381 A 939 942 MPT ABBREVIATION 23474381 T 12 23 fatty acids FAMILY 23474389 A 24 82 3-(benzylthio)-5-(1H-indol-3-yl)-4H-1,2,4-triazol-4-amines FAMILY 23474389 A 300 334 indole-3-carboxylic acid hydrazide SYSTEMATIC 23474389 A 339 355 carbon disulfide SYSTEMATIC 23474389 A 392 393 S FORMULA 23474389 A 437 448 nitrobenzyl SYSTEMATIC 23474389 T 28 83 3-(benzylthio)-5-(1H-indol-3-yl)-1,2,4-triazol-4-amines FAMILY 23474547 A 123 129 carbon SYSTEMATIC 23474547 A 1324 1330 carbon SYSTEMATIC 23474547 A 247 253 carbon SYSTEMATIC 23474547 A 450 481 sulfur-nitrogen co-doped carbon SYSTEMATIC 23474547 A 489 490 S FORMULA 23474547 A 491 492 N FORMULA 23474547 A 649 650 S FORMULA 23474547 A 651 652 N FORMULA 23474547 A 67 73 oxygen SYSTEMATIC 23474547 A 726 734 methanol SYSTEMATIC 23474547 A 763 765 Pt FORMULA 23474547 A 766 767 C FORMULA 23474547 A 912 913 S FORMULA 23474547 A 914 915 N FORMULA 23474547 T 0 6 Sulfur SYSTEMATIC 23474547 T 135 141 oxygen SYSTEMATIC 23474547 T 43 49 carbon SYSTEMATIC 23474547 T 7 15 nitrogen SYSTEMATIC 23474650 A 1120 1121 N FORMULA 23474650 A 1139 1147 pyridine SYSTEMATIC 23474650 A 1155 1165 pyrimidine SYSTEMATIC 23474650 A 1201 1211 pyrimidine SYSTEMATIC 23474650 A 1225 1234 imidazole SYSTEMATIC 23474650 A 1380 1387 AZD3839 IDENTIFIER 23474650 A 1534 1549 aryl-pyrimidine FAMILY 23474650 A 159 235 (S)-1-pyridin-4-yl-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine SYSTEMATIC 23474650 A 1627 1633 carbon SYSTEMATIC 23474650 A 1669 1678 imidazole SYSTEMATIC 23474650 A 249 358 (S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate SYSTEMATIC 23474650 A 31 46 aminoisoindoles FAMILY 23474650 A 360 367 AZD3839 IDENTIFIER 23474650 A 536 543 AZD3839 IDENTIFIER 23474650 A 727 735 pyridine SYSTEMATIC 23474650 A 740 750 pyrimidine SYSTEMATIC 23474650 A 828 829 N FORMULA 23474650 A 847 855 pyridine SYSTEMATIC 23474650 A 863 873 pyrimidine SYSTEMATIC 23474650 A 897 909 4-pyrimidone SYSTEMATIC 23474650 A 914 934 pyrimidine-2,4-dione SYSTEMATIC 23474650 T 92 102 Pyrimidine SYSTEMATIC 23474807 A 1342 1347 NaNO3 SYSTEMATIC 23474807 A 909 924 cesium chloride SYSTEMATIC 23474807 A 965 984 polyethylene glycol SYSTEMATIC 23474807 A 986 989 PEG ABBREVIATION 23474845 A 1013 1019 MK-801 IDENTIFIER 23474845 A 103 112 glutamate TRIVIAL 23474845 A 1137 1146 WAY100635 IDENTIFIER 23474845 A 1184 1193 LSP1-2111 IDENTIFIER 23474845 A 1338 1347 LSP1-2111 IDENTIFIER 23474845 A 1408 1430 (R)-(+)-8-Hydroxy-DPAT SYSTEMATIC 23474845 A 189 198 LSP1-2111 IDENTIFIER 23474845 A 482 491 LSP1-2111 IDENTIFIER 23474845 A 642 651 LSP1-2111 IDENTIFIER 23474845 A 757 763 MK-801 IDENTIFIER 23474845 A 768 779 amphetamine TRIVIAL 23474845 A 818 821 DOI ABBREVIATION 23474845 A 953 962 LSP1-2111 IDENTIFIER 23474845 T 74 83 LSP1-2111 IDENTIFIER 23474897 A 0 13 Retinoic acid TRIVIAL 23474897 A 250 343 2-fluoro-4-[[[8-bromo-2,2-dimethyl-4-(4-methylphenyl)chroman-6-yl]carbonyl]amino]benzoic acid SYSTEMATIC 23474897 A 394 478 4-[[[8-bromo-2,2-dimethyl-4-(4-methylphenyl)chroman-6-yl]carbonyl]amino]benzoic acid SYSTEMATIC 23474897 T 25 33 chromene TRIVIAL 23474897 T 54 67 retinoic acid TRIVIAL 23474903 A 1008 1027 C60[>M(C3N6(+)C3)2] FAMILY 23474903 A 1067 1087 trifluoroacetic acid SYSTEMATIC 23474903 A 126 134 (I(-))10 FORMULA 23474903 A 168 174 oxygen SYSTEMATIC 23474903 A 205 213 hydroxyl SYSTEMATIC 23474903 A 236 246 superoxide TRIVIAL 23474903 A 357 363 O2(-)· FORMULA 23474903 A 391 399 (I(-))10 FORMULA 23474903 A 426 432 O2(-)· FORMULA 23474903 A 442 495 bis(2,4-dinitrobenzenesulfonyl)tetrafluorofluorescein SYSTEMATIC 23474903 A 48 93 decacationic methano[60]fullerene decaiodides FAMILY 23474903 A 572 578 iodide SYSTEMATIC 23474903 A 589 612 (3)C60*[>M(C3N6(+)C3)2] FAMILY 23474903 A 624 647 C60(-)·[>M(C3N6(+)C3)2] FAMILY 23474903 A 692 711 quaternary ammonium SYSTEMATIC 23474903 A 733 736 C60 TRIVIAL 23474903 A 876 905 malonato[60]fullerene diester SYSTEMATIC 23474903 A 917 931 C60[>M(t-Bu)2] FAMILY 23474903 A 94 122 C60[>M(C3N6(+)C3)2]-(I(-))10 FAMILY 23474903 A 948 957 fullerene TRIVIAL 23474903 T 13 51 decacationic [60]fullerene decaiodides FAMILY 23474903 T 86 96 superoxide TRIVIAL 23474904 A 131 164 imidazo[2,1-b][1,3,4]thiadiazoles FAMILY 23474904 A 14 50 [1,3,4]thiadiazolo[3,2-a]pyrimidines FAMILY 23474904 A 256 260 (1)H FORMULA 23474904 A 265 270 (13)C FORMULA 23474904 A 52 97 benzo[h][1,3,4]thiadiazolo[2,3-b]quinazolines FAMILY 23474904 A 99 125 benzothiadiazolotriazocine SYSTEMATIC 23474904 T 104 123 [1,3,4]thiadiazoles FAMILY 23474905 A 354 380 2-amino-1,4-naphthoquinone SYSTEMATIC 23474905 A 381 392 N,O-acetals FAMILY 23474905 A 39 50 N,O-acetals FAMILY 23474905 A 397 408 N,S-acetals FAMILY 23474905 A 55 66 N,S-acetals FAMILY 23474905 A 582 586 (1)H FORMULA 23474905 A 588 593 (13)C FORMULA 23474905 A 87 114 2-amino-1,4-naphthoquinones FAMILY 23474905 T 115 142 2-amino-1,4-naphthoquinones FAMILY 23474905 T 74 85 N,O-acetals FAMILY 23474905 T 90 101 N,S-acetals FAMILY 23475289 A 105 115 isoflavone FAMILY 23475289 A 1098 1105 estrone TRIVIAL 23475289 A 1110 1119 estradiol TRIVIAL 23475289 A 1172 1182 isoflavone FAMILY 23475289 A 125 132 glucose TRIVIAL 23475289 A 612 622 isoflavone FAMILY 23475289 A 698 705 glucose TRIVIAL 23475289 A 844 856 triglyceride FAMILY 23475289 T 0 10 Isoflavone TRIVIAL 23475289 T 48 60 triglyceride FAMILY 23475307 A 0 7 Arsenic SYSTEMATIC 23475307 A 1086 1088 As FORMULA 23475307 A 1090 1092 Cd FORMULA 23475307 A 1094 1096 Cu FORMULA 23475307 A 1098 1100 Hg FORMULA 23475307 A 1106 1108 Pb FORMULA 23475307 A 184 186 Ag FORMULA 23475307 A 188 190 As FORMULA 23475307 A 192 194 Cd FORMULA 23475307 A 196 198 Cu FORMULA 23475307 A 200 202 Hg FORMULA 23475307 A 204 206 Ni FORMULA 23475307 A 208 210 Pb FORMULA 23475307 A 216 218 Zn FORMULA 23475307 A 272 279 Arsenic SYSTEMATIC 23475307 A 327 340 arsenobetaine TRIVIAL 23475307 A 342 345 AsB ABBREVIATION 23475307 A 396 416 dimethylarsinic acid SYSTEMATIC 23475307 A 418 421 DMA ABBREVIATION 23475307 A 448 470 Monomethylarsonic acid SYSTEMATIC 23475307 A 472 475 MMA ABBREVIATION 23475307 A 481 486 As(V) FORMULA 23475307 A 586 594 Arsenite SYSTEMATIC 23475307 A 596 603 As(III) FORMULA 23475307 A 694 696 As FORMULA 23475307 T 0 7 Arsenic SYSTEMATIC 23475368 A 1167 1174 glucose TRIVIAL 23475368 A 281 289 tyrosine TRIVIAL 23475368 A 62 69 glucose TRIVIAL 23475368 A 638 645 glucose TRIVIAL 23475368 A 990 997 glucose TRIVIAL 23475368 T 53 60 glucose TRIVIAL 23475370 A 0 9 Strontium SYSTEMATIC 23475370 A 1164 1173 strontium SYSTEMATIC 23475370 A 1246 1255 strontium SYSTEMATIC 23475370 A 1311 1320 Strontium SYSTEMATIC 23475370 A 277 286 strontium SYSTEMATIC 23475370 A 347 356 strontium SYSTEMATIC 23475370 A 585 599 hydroxyproline SYSTEMATIC 23475370 A 933 942 strontium SYSTEMATIC 23475370 A 979 988 strontium SYSTEMATIC 23475370 T 11 20 Strontium SYSTEMATIC 23475432 A 1026 1034 nicotine TRIVIAL 23475432 A 1041 1049 nicotine TRIVIAL 23475432 A 1198 1206 nicotine TRIVIAL 23475432 A 121 128 arsenic SYSTEMATIC 23475432 A 1253 1261 nicotine TRIVIAL 23475432 A 1381 1388 arsenic SYSTEMATIC 23475432 A 1390 1398 Nicotine TRIVIAL 23475432 A 1415 1422 arsenic SYSTEMATIC 23475432 A 31 39 nicotine TRIVIAL 23475432 A 383 391 nicotine TRIVIAL 23475432 A 422 429 arsenic SYSTEMATIC 23475432 A 499 507 nicotine TRIVIAL 23475432 A 580 587 arsenic SYSTEMATIC 23475432 A 605 620 sodium arsenite SYSTEMATIC 23475432 A 641 649 Nicotine TRIVIAL 23475432 A 694 701 arsenic SYSTEMATIC 23475432 A 737 744 arsenic SYSTEMATIC 23475432 A 760 767 Arsenic SYSTEMATIC 23475432 A 862 873 Glutathione TRIVIAL 23475432 A 874 875 S FORMULA 23475432 A 930 937 arsenic SYSTEMATIC 23475432 A 942 950 nicotine TRIVIAL 23475432 A 987 994 arsenic SYSTEMATIC 23475432 T 10 18 nicotine TRIVIAL 23475432 T 35 42 arsenic SYSTEMATIC 23475784 A 313 322 fadrozole TRIVIAL 23475784 A 324 327 FAD ABBREVIATION 23475784 A 533 546 17β-estradiol SYSTEMATIC 23475784 A 847 850 FAD ABBREVIATION 23475784 A 998 1001 FAD ABBREVIATION 23475902 A 0 56 1-Hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol SYSTEMATIC 23475902 A 1040 1044 MJ33 IDENTIFIER 23475902 A 1270 1274 MJ33 IDENTIFIER 23475902 A 1393 1397 MJ33 IDENTIFIER 23475902 A 1561 1565 MJ33 IDENTIFIER 23475902 A 230 235 NADPH ABBREVIATION 23475902 A 284 290 oxygen SYSTEMATIC 23475902 A 316 320 MJ33 IDENTIFIER 23475902 A 477 481 MJ33 IDENTIFIER 23475902 A 497 501 MJ33 IDENTIFIER 23475902 A 58 62 MJ33 IDENTIFIER 23475902 A 634 638 MJ33 IDENTIFIER 23475902 A 916 920 MJ33 IDENTIFIER 23475902 T 48 53 NADPH ABBREVIATION 23475902 T 79 85 oxygen SYSTEMATIC 23477372 A 155 161 sulfur SYSTEMATIC 23477372 A 433 439 sulfur SYSTEMATIC 23477372 A 510 516 Gelsil NO CLASS 23477372 A 86 92 sulfur SYSTEMATIC 23477372 T 48 54 sulfur SYSTEMATIC 23477482 A 247 260 ascorbic acid TRIVIAL 23477482 A 262 271 vitamin C TRIVIAL 23477482 A 302 313 tocopherols FAMILY 23477482 A 315 324 vitamin E FAMILY 23477482 A 327 337 flavonoids FAMILY 23477482 A 343 356 capsaicinoids FAMILY 23477619 A 202 210 Aldehyde SYSTEMATIC 23477619 A 406 452 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone SYSTEMATIC 23477619 A 480 493 O(6)-methyl-G SYSTEMATIC 23477619 A 495 502 7-POB-G SYSTEMATIC 23477619 A 508 519 O(2)-POB-dT FORMULA 23477619 T 125 171 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone SYSTEMATIC 23477619 T 15 23 Aldehyde SYSTEMATIC 23477619 T 173 176 NNK TRIVIAL 23477624 A 0 11 Polycalcium FAMILY 23477624 A 1112 1116 DPYR ABBREVIATION 23477624 A 1148 1150 Ca FORMULA 23477624 A 1164 1165 P FORMULA 23477624 A 1437 1448 Polycalcium FAMILY 23477624 A 1528 1539 Polycalcium FAMILY 23477624 A 243 254 Polycalcium FAMILY 23477624 A 361 372 Polycalcium FAMILY 23477624 A 40 65 calcium lactate-gluconate SYSTEMATIC 23477624 A 429 446 deoxypyridinoline SYSTEMATIC 23477624 A 448 452 DPYR ABBREVIATION 23477624 A 555 556 C FORMULA 23477624 A 616 617 N FORMULA 23477624 A 656 663 calcium SYSTEMATIC 23477624 A 665 667 Ca FORMULA 23477624 A 674 684 phosphorus SYSTEMATIC 23477624 A 686 687 P FORMULA 23477624 A 768 779 Polycalcium FAMILY 23477624 A 798 809 Polycalcium FAMILY 23477624 A 954 956 Ca FORMULA 23477624 A 968 969 P FORMULA 23477624 T 23 34 polycalcium FAMILY 23478148 A 2 30 6-amidinotetrahydroquinoline SYSTEMATIC 23478148 A 242 252 BMS-593214 IDENTIFIER 23478148 A 352 362 BMS-593214 IDENTIFIER 23478148 A 456 466 BMS-593214 IDENTIFIER 23478148 A 511 514 Asp FORMULA 23478148 A 520 523 Lys FORMULA 23478148 T 38 48 BMS-593214 IDENTIFIER 23478338 A 365 375 amino-acid FAMILY 23478338 A 512 521 rapamycin TRIVIAL 23478338 A 653 663 amino-acid FAMILY 23478338 T 85 95 amino-acid FAMILY 23478802 A 1020 1024 pBQN ABBREVIATION 23478802 A 1050 1058 cysteine TRIVIAL 23478802 A 1208 1212 pBQN ABBREVIATION 23478802 A 1321 1330 cysteines FAMILY 23478802 A 1403 1416 iodoacetamide SYSTEMATIC 23478802 A 1440 1483 2-(trimethylammonium)ethyl methanesulfonate SYSTEMATIC 23478802 A 1569 1573 pBQN ABBREVIATION 23478802 A 1672 1681 carvacrol TRIVIAL 23478802 A 1702 1710 cysteine TRIVIAL 23478802 A 1802 1810 cysteine TRIVIAL 23478802 A 256 264 cysteine TRIVIAL 23478802 A 281 286 amino FAMILY 23478802 A 388 402 cinnamaldehyde TRIVIAL 23478802 A 584 601 para-benzoquinone SYSTEMATIC 23478802 A 603 607 pBQN ABBREVIATION 23478802 A 768 774 serine TRIVIAL 23478802 A 787 796 cysteines FAMILY 23478802 A 870 874 pBQN ABBREVIATION 23478802 T 0 12 Benzoquinone FAMILY 23478802 T 23 31 Cysteine TRIVIAL 23478908 A 751 782 Resorufin β-d-galactopyranoside SYSTEMATIC 23478908 A 784 787 RBG ABBREVIATION 23478908 A 882 917 isopropyl-β-d-thiogalactopyranoside SYSTEMATIC 23478908 A 919 923 IPTG ABBREVIATION 23479059 A 1059 1062 BPA ABBREVIATION 23479059 A 15 28 xenoestrogens FAMILY 23479059 A 326 339 xenoestrogens FAMILY 23479059 A 341 348 Paraben FAMILY 23479059 A 393 407 methyl paraben SYSTEMATIC 23479059 A 440 453 ethyl paraben SYSTEMATIC 23479059 A 474 488 propyl paraben SYSTEMATIC 23479059 A 523 536 butyl paraben SYSTEMATIC 23479059 A 562 565 BPA ABBREVIATION 23479059 A 676 693 Bromodeoxyuridine SYSTEMATIC 23479059 A 764 777 xenoestrogens FAMILY 23479059 A 825 828 BPA ABBREVIATION 23479059 T 11 19 parabens FAMILY 23479059 T 24 35 bisphenol A TRIVIAL 23479079 A 0 16 Hydrogen sulfide SYSTEMATIC 23479079 A 103 106 H2S FORMULA 23479079 A 1058 1065 sulfide SYSTEMATIC 23479079 A 1136 1143 sulfide SYSTEMATIC 23479079 A 1149 1156 sulfide SYSTEMATIC 23479079 A 1260 1267 sulfide SYSTEMATIC 23479079 A 170 173 H2S FORMULA 23479079 A 18 21 H2S FORMULA 23479079 A 297 300 H2S FORMULA 23479079 A 402 409 sulfide SYSTEMATIC 23479079 A 472 475 H2S FORMULA 23479079 A 483 504 sodium hydroxysulfide SYSTEMATIC 23479079 A 506 510 NaHS FORMULA 23479079 A 609 612 H2S FORMULA 23479079 A 644 651 sulfide SYSTEMATIC 23479079 A 707 711 NaHS FORMULA 23479079 A 732 739 Sulfide SYSTEMATIC 23479079 A 779 796 poly (ADP-ribose) SYSTEMATIC 23479079 A 878 885 sulfide SYSTEMATIC 23479079 A 933 940 sulfide SYSTEMATIC 23479079 T 0 7 Sulfide SYSTEMATIC 23479335 A 109 120 cholesterol TRIVIAL 23479335 A 1467 1473 statin FAMILY 23479335 A 148 165 cholesterol ester FAMILY 23479335 A 1489 1502 triglycerides FAMILY 23479335 A 1518 1529 cholesterol TRIVIAL 23479335 A 1650 1661 cholesterol TRIVIAL 23479335 A 827 839 triglyceride FAMILY 23479335 T 74 86 Triglyceride FAMILY 23479387 A 1046 1065 glyceryl trinitrate SYSTEMATIC 23479387 A 15 34 glyceryl trinitrate SYSTEMATIC 23479387 A 179 188 quercetin TRIVIAL 23479387 A 237 256 glyceryl trinitrate SYSTEMATIC 23479387 A 301 330 4-O-triphenylphosphoniumbutyl SYSTEMATIC 23479387 A 346 355 quercetin TRIVIAL 23479387 A 357 366 QTA-3BTPI SYSTEMATIC 23479387 A 371 378 Q-3BTPI SYSTEMATIC 23479387 A 397 406 quercetin TRIVIAL 23479387 A 430 449 glyceryl trinitrate SYSTEMATIC 23479387 A 530 539 QTA-3BTPI SYSTEMATIC 23479387 A 544 551 Q-3BTPI SYSTEMATIC 23479387 A 623 642 glyceryl trinitrate SYSTEMATIC 23479387 A 647 660 acetylcholine SYSTEMATIC 23479387 A 707 726 glyceryl trinitrate SYSTEMATIC 23479387 A 781 790 quercetin TRIVIAL 23479387 A 792 801 QTA-3BTPI SYSTEMATIC 23479387 A 870 877 Q-3BTPI SYSTEMATIC 23479387 A 899 906 nitrate SYSTEMATIC 23479387 T 0 9 Quercetin TRIVIAL 23479387 T 52 59 nitrate SYSTEMATIC 23479388 A 126 151 pentacyclic triterpenoids FAMILY 23479388 A 171 184 triterpenoids FAMILY 23479388 A 186 247 2α-O-trans-p-coumaroyl-3β,19α-dihydroxy-urs-12-en-28-oic acid SYSTEMATIC 23479388 A 256 315 2α-O-cis-p-coumaroyl-3β,19α-dihydroxy-urs-12-en-28-oic acid SYSTEMATIC 23479388 A 344 369 pentacyclic triterpenoids FAMILY 23479388 T 10 35 pentacyclic triterpenoids FAMILY 23479392 A 314 324 flavonoids FAMILY 23479392 A 326 335 flavonols FAMILY 23479392 A 337 347 flavanones FAMILY 23479392 A 350 363 isoflavonoids FAMILY 23479392 A 365 376 isoflavones FAMILY 23479392 A 378 388 coumestans FAMILY 23479392 A 391 398 lignans FAMILY 23479392 A 400 411 stilbenoids FAMILY 23479726 A 1000 1001 C FORMULA 23479726 A 11 17 serine TRIVIAL 23479726 A 1377 1383 serine TRIVIAL 23479726 A 278 294 phosphoglycerate SYSTEMATIC 23479726 A 349 359 amino acid FAMILY 23479726 A 398 414 phosphoglycerate SYSTEMATIC 23479726 A 65 78 phosphoserine SYSTEMATIC 23479726 A 798 813 l-phosphoserine SYSTEMATIC 23479726 A 885 900 l-phosphoserine SYSTEMATIC 23479726 A 988 991 His FORMULA 23479726 T 56 69 Phosphoserine SYSTEMATIC 23480235 A 1006 1014 fluorine SYSTEMATIC 23480235 A 1027 1033 benzyl SYSTEMATIC 23480235 A 1135 1144 adenosine TRIVIAL 23480235 A 12 70 N-[9-(ortho-fluorobenzyl)-2-phenyl-8-azapurin-6-yl]-amides FAMILY 23480235 A 1259 1317 N-[9-(ortho-fluorobenzyl)-2-phenyl-8-azapurin-6-yl]-amides FAMILY 23480235 A 1324 1333 adenosine TRIVIAL 23480235 A 141 150 adenosine TRIVIAL 23480235 A 229 237 fluorine SYSTEMATIC 23480235 A 272 280 9-benzyl SYSTEMATIC 23480235 A 430 447 meta-fluorophenyl SYSTEMATIC 23480235 A 467 482 carbonyl carbon SYSTEMATIC 23480235 A 490 495 amide FAMILY 23480235 A 648 656 fluorine SYSTEMATIC 23480235 A 669 677 9-benzyl SYSTEMATIC 23480235 A 935 946 8-azapurine SYSTEMATIC 23480235 T 0 58 N-[9-(ortho-Fluorobenzyl)-2-Phenyl-8-Azapurin-6-yl]-Amides FAMILY 23480235 T 98 107 Adenosine TRIVIAL 23480470 A 1008 1017 hexadecyl SYSTEMATIC 23480470 A 1018 1023 alkyl FAMILY 23480470 A 1038 1043 3-C16 MULTIPLE 23480470 A 108 113 oxime SYSTEMATIC 23480470 A 1105 1111 PNPDPP ABBREVIATION 23480470 A 148 195 3- hydroxyiminomethyl-1-alkylpyridinium bromide FAMILY 23480470 A 197 202 alkyl FAMILY 23480470 A 205 212 CnH2n+1 FAMILY 23480470 A 257 273 phosphate esters FAMILY 23480470 A 275 307 p-nitrophenyl diphenyl phosphate SYSTEMATIC 23480470 A 309 315 PNPDPP ABBREVIATION 23480470 A 321 353 bis(2,4-dinitrophenyl) phosphate SYSTEMATIC 23480470 A 355 360 BNDPP ABBREVIATION 23480470 A 386 409 cetylpyridinium bromide SYSTEMATIC 23480470 A 411 414 CPB ABBREVIATION 23480470 A 500 503 CPB ABBREVIATION 23480470 A 654 659 alkyl FAMILY 23480470 A 721 736 phosphate ester SYSTEMATIC 23480470 A 839 845 oximes FAMILY 23480470 A 876 881 oxime SYSTEMATIC 23480470 A 953 956 P═O FORMULA 23480470 A 967 994 tri- and diphosphate esters MULTIPLE 23480470 A 996 1002 Oximes FAMILY 23480470 T 138 165 Di- and Triphosphate Esters MULTIPLE 23480470 T 55 60 Oxime SYSTEMATIC 23480643 A 214 239 exo-2-oxazolidinone diene SYSTEMATIC 23480643 A 247 255 acrolein TRIVIAL 23480643 A 338 349 diarylamine FAMILY 23480643 A 386 395 carbazole SYSTEMATIC 23480643 A 408 410 Pd FORMULA 23480643 A 441 444 C-H FORMULA 23480643 A 61 70 carbazole SYSTEMATIC 23480643 A 71 82 clauraila A TRIVIAL 23480643 T 41 50 carbazole SYSTEMATIC 23480783 A 1140 1151 cholesterol TRIVIAL 23480783 A 1188 1199 Simvastatin TRIVIAL 23480783 A 1215 1224 metformin TRIVIAL 23480783 A 14 24 fatty acid FAMILY 23480783 A 370 379 metformin TRIVIAL 23480783 A 390 401 simvastatin TRIVIAL 23480783 A 414 423 metformin TRIVIAL 23480783 A 429 440 simvastatin TRIVIAL 23480783 A 518 525 glucose TRIVIAL 23480783 A 55 62 retinol TRIVIAL 23480783 A 977 988 cholesterol TRIVIAL 23480783 T 106 117 simvastatin TRIVIAL 23480783 T 122 131 metformin TRIVIAL 23480783 T 38 45 retinol TRIVIAL 23480783 T 5 15 fatty acid FAMILY 23480874 A 115 141 zinc tetraphenyl porphyrin SYSTEMATIC 23480874 A 166 179 1,4-butyndiol SYSTEMATIC 23480874 A 242 284 1,2-distearoyl-sn-glycero-3-phosphocholine SYSTEMATIC 23480874 A 286 290 DSPC ABBREVIATION 23480874 A 446 460 zinc porphyrin SYSTEMATIC 23480874 A 46 60 zinc porphyrin SYSTEMATIC 23480874 A 85 99 carboxylphenyl SYSTEMATIC 23480874 T 60 74 Zinc Porphyrin SYSTEMATIC 23481176 A 1039 1043 iron SYSTEMATIC 23481176 A 244 261 thioglycolic acid SYSTEMATIC 23481176 A 272 275 TGA ABBREVIATION 23481176 A 290 294 iron SYSTEMATIC 23481176 A 301 307 Fe(2+) FORMULA 23481176 A 308 314 Fe(3+) FORMULA 23481176 A 473 477 iron SYSTEMATIC 23481176 A 528 532 iron SYSTEMATIC 23481176 A 632 642 iron oxide SYSTEMATIC 23481176 A 770 774 iron SYSTEMATIC 23481176 A 83 93 iron oxide SYSTEMATIC 23481176 T 113 123 iron oxide SYSTEMATIC 23481256 A 1066 1072 lysine TRIVIAL 23481256 A 12 20 dilysine TRIVIAL 23481256 A 601 609 Dilysine TRIVIAL 23481256 A 637 643 lysine TRIVIAL 23481256 A 767 773 lysine TRIVIAL 23481256 A 947 948 C FORMULA 23481256 A 958 969 carboxylate SYSTEMATIC 23481256 A 991 997 lysine TRIVIAL 23481256 T 29 37 dilysine TRIVIAL 23481321 A 710 718 hydrogen SYSTEMATIC 23481590 A 1179 1191 testosterone TRIVIAL 23481590 A 1294 1306 testosterone TRIVIAL 23481590 A 1380 1388 androgen FAMILY 23481590 A 1473 1485 testosterone TRIVIAL 23481590 A 1535 1547 testosterone TRIVIAL 23481590 A 42 54 testosterone TRIVIAL 23481590 A 530 542 testosterone TRIVIAL 23481590 A 644 656 testosterone TRIVIAL 23481590 A 995 1007 testosterone TRIVIAL 23481590 T 0 12 Testosterone TRIVIAL 23481595 A 171 185 Ribonucleoside FAMILY 23481595 A 443 450 uridine TRIVIAL 23481595 A 489 499 guanosines FAMILY 23481643 A 47 54 tacrine TRIVIAL 23481643 T 6 13 tacrine TRIVIAL 23481645 A 112 124 diazomethane SYSTEMATIC 23481645 A 130 156 trans-dibenzyl glutaconate SYSTEMATIC 23481645 A 166 178 1-pyrazoline SYSTEMATIC 23481645 A 217 229 pyrazolidine SYSTEMATIC 23481645 A 288 290 Hg FORMULA 23481645 A 291 293 Al FORMULA 23481645 A 311 323 1-pyrazoline SYSTEMATIC 23481645 A 324 326 NN FORMULA 23481645 A 353 369 TMS diazomethane SYSTEMATIC 23481645 A 407 419 2-pyrazoline SYSTEMATIC 23481645 A 468 475 NaCNBH3 FORMULA 23481645 A 491 507 trans azakainate TRIVIAL 23481645 A 53 63 azakainoid TRIVIAL 23481645 A 562 572 isokainoid TRIVIAL 23481645 A 613 622 Glutamate TRIVIAL 23481645 A 665 674 azakaniod TRIVIAL 23481645 A 715 724 glutamate TRIVIAL 23481645 A 803 813 azakainoid TRIVIAL 23481645 A 852 861 glutamate TRIVIAL 23481645 T 44 63 iso and azakainoids MULTIPLE 23481651 A 112 119 Gd-DOTA FORMULA 23481651 A 146 155 copper(I) SYSTEMATIC 23481651 A 166 178 azide-alkyne FAMILY 23481651 A 34 40 alkyne FAMILY 23481651 A 69 76 sucrose TRIVIAL 23481651 A 95 100 azide SYSTEMATIC 23481651 T 19 26 sucrose TRIVIAL 23481676 A 26 38 diterpenoids FAMILY 23481676 A 40 56 krempfielins E-I MULTIPLE 23481676 A 9 19 eunicellin TRIVIAL 23481676 T 32 42 Eunicellin TRIVIAL 23481676 T 49 61 Diterpenoids FAMILY 23481678 A 10 22 azalomycin F TRIVIAL 23481678 A 134 178 25-malonyl demalonylazalomycin F5a monoester SYSTEMATIC 23481678 A 184 223 23-valine demalonylazalomycin F5a ester SYSTEMATIC 23481678 A 229 287 23-(6-methyl)heptanoic acid demalonylazalomycins F3a ester SYSTEMATIC 23481678 A 293 302 F4a ester SYSTEMATIC 23481678 A 311 320 F5a ester SYSTEMATIC 23481678 A 326 382 23-(9-methyl)decanoic acid demalonylazalomycin F4a ester SYSTEMATIC 23481678 A 391 451 23-(10-methyl)undecanoic acid demalony lazalomycin F4a ester SYSTEMATIC 23481678 A 550 578 azalomycins F3a, F4a and F5a MULTIPLE 23481678 T 4 16 Azalomycin F TRIVIAL 23482500 A 0 9 Sorafenib TRIVIAL 23482500 A 1147 1153 MPP(+) ABBREVIATION 23482500 A 1332 1341 sorafenib TRIVIAL 23482500 A 1457 1466 sorafenib TRIVIAL 23482500 A 1543 1552 rifamycin FAMILY 23482500 A 1576 1585 Sorafenib TRIVIAL 23482500 A 219 228 sorafenib TRIVIAL 23482500 A 282 291 sorafenib TRIVIAL 23482500 A 30 38 tyrosine TRIVIAL 23482500 A 449 465 [(14)C]Sorafenib SYSTEMATIC 23482500 A 590 606 [(14)C]sorafenib SYSTEMATIC 23482500 A 615 620 Na(+) FORMULA 23482500 A 697 707 ketoprofen TRIVIAL 23482500 A 726 742 [(14)C]sorafenib SYSTEMATIC 23482500 A 893 905 rifamycin SV TRIVIAL 23482500 A 958 969 decynium 22 TRIVIAL 23482500 A 985 1001 [(14)C]Sorafenib SYSTEMATIC 23482500 T 0 9 Sorafenib TRIVIAL 23483083 A 258 264 G-TiO2 FORMULA 23483083 A 388 396 graphene TRIVIAL 23483083 A 50 58 graphene TRIVIAL 23483083 A 512 520 graphene TRIVIAL 23483083 A 532 536 TiO2 FORMULA 23483083 A 537 545 graphene TRIVIAL 23483083 A 568 576 graphene TRIVIAL 23483083 A 59 63 TiO2 FORMULA 23483083 T 71 79 graphene TRIVIAL 23483083 T 80 84 TiO2 FORMULA 23483201 A 104 110 CORM-2 ABBREVIATION 23483201 A 1060 1072 nitric oxide SYSTEMATIC 23483201 A 1154 1162 morphine TRIVIAL 23483201 A 1233 1241 morphine TRIVIAL 23483201 A 1279 1285 CORM-2 ABBREVIATION 23483201 A 1289 1293 CoPP FORMULA 23483201 A 1361 1369 morphine TRIVIAL 23483201 A 1483 1491 morphine TRIVIAL 23483201 A 153 177 cobalt protoporphyrin IX SYSTEMATIC 23483201 A 1579 1585 CORM-2 ABBREVIATION 23483201 A 1590 1594 CoPP FORMULA 23483201 A 1652 1660 morphine TRIVIAL 23483201 A 1730 1742 nitric oxide SYSTEMATIC 23483201 A 179 183 CoPP FORMULA 23483201 A 28 43 carbon monoxide SYSTEMATIC 23483201 A 297 305 morphine TRIVIAL 23483201 A 429 441 nitric oxide SYSTEMATIC 23483201 A 495 501 CORM-2 ABBREVIATION 23483201 A 506 510 CoPP FORMULA 23483201 A 556 564 morphine TRIVIAL 23483201 A 592 604 nitric oxide SYSTEMATIC 23483201 A 64 96 tricarbonyldichlororuthenium(II) SYSTEMATIC 23483201 A 729 737 formalin TRIVIAL 23483201 A 742 753 acid acetic SYSTEMATIC 23483201 T 128 136 morphine TRIVIAL 23483201 T 28 43 carbon monoxide SYSTEMATIC 23484537 T 0 10 Paclitaxel TRIVIAL 23484537 T 35 55 boron dipyrromethene SYSTEMATIC 23484593 A 21 41 embellicines A and B MULTIPLE 23484593 A 394 407 embellicine A TRIVIAL 23484593 A 493 506 embellicine B TRIVIAL 23484593 A 609 621 embellicines FAMILY 23484593 A 76 81 EtOAc FORMULA 23484593 A 797 810 Embellicine B TRIVIAL 23484593 T 0 20 Embellicines A and B MULTIPLE 23484633 A 1023 1025 Sn FORMULA 23484633 A 1045 1047 Na FORMULA 23484633 A 1154 1156 Sn FORMULA 23484633 A 1184 1186 Na FORMULA 23484633 A 43 45 Na FORMULA 23484633 A 451 457 carbon SYSTEMATIC 23484633 A 516 518 Sn FORMULA 23484633 A 666 667 C FORMULA 23484633 A 668 670 Sn FORMULA 23484633 A 671 673 Ni FORMULA 23484633 A 73 75 Sn FORMULA 23484633 A 759 764 steel TRIVIAL 23484633 A 852 854 Na FORMULA 23484633 A 915 917 Sn FORMULA 23484633 A 946 948 Sn FORMULA 23484633 T 0 3 Tin SYSTEMATIC 23484633 T 32 38 sodium SYSTEMATIC 23484901 A 1037 1054 1-aminoanthracene SYSTEMATIC 23484901 A 1176 1188 Epothilone D TRIVIAL 23484901 A 1268 1284 allopregnanolone TRIVIAL 23484901 A 1309 1319 colchicine TRIVIAL 23484901 A 1405 1415 anthracene SYSTEMATIC 23484901 A 143 160 1-azidoanthracene SYSTEMATIC 23484901 A 197 214 1-azidoanthracene SYSTEMATIC 23484901 A 24 41 1-aminoanthracene SYSTEMATIC 23484901 A 657 672 aminoanthracene SYSTEMATIC 23484901 A 757 767 colchicine TRIVIAL 23484901 A 804 814 anthracene SYSTEMATIC 23484901 A 832 842 colchicine TRIVIAL 23484901 A 931 943 epothilone D TRIVIAL 23484901 A 947 961 discodermolide TRIVIAL 23484901 A 987 1004 1-aminoanthracene SYSTEMATIC 23484901 T 58 68 anthracene SYSTEMATIC 23484958 A 116 122 [FeFe] FORMULA 23484958 A 195 199 H(+) FORMULA 23484958 A 393 399 [FeFe] FORMULA 23484958 A 457 460 FeS FORMULA 23484958 A 91 99 hydrogen SYSTEMATIC 23484958 T 51 57 [FeFe] FORMULA 23485402 A 1278 1279 N FORMULA 23485402 A 297 309 Tetrodotoxin TRIVIAL 23485474 A 0 17 Polymethacrylates FAMILY 23485474 A 1163 1175 methacrylate TRIVIAL 23485474 A 119 132 Eudragit E PO FAMILY 23485474 A 134 141 n-butyl SYSTEMATIC 23485474 A 144 162 dimethylaminoethyl SYSTEMATIC 23485474 A 165 184 methyl-methacrylate SYSTEMATIC 23485474 A 185 195 terpolymer FAMILY 23485474 A 26 34 Eudragit TRIVIAL 23485474 A 510 517 n-butyl SYSTEMATIC 23485474 A 521 528 t-butyl SYSTEMATIC 23485474 A 558 589 dimethylaminoethyl methacrylate SYSTEMATIC 23485474 A 591 597 DMAEMA ABBREVIATION 23485474 A 641 650 isobornyl TRIVIAL 23485474 A 918 924 DMAEMA ABBREVIATION 23485474 T 28 45 polymethacrylates FAMILY 23485481 A 31 38 mercury SYSTEMATIC 23485481 A 359 366 Mercury SYSTEMATIC 23485481 A 547 549 Hg FORMULA 23485481 T 0 7 Mercury SYSTEMATIC 23485559 A 13 23 [HMIM]HSO4 FORMULA 23485559 A 130 145 2,5-hexanedione SYSTEMATIC 23485559 A 151 157 amines FAMILY 23485559 A 83 105 N-substituted pyrroles FAMILY 23485559 T 0 36 1-Methylimidazolium hydrogen sulfate SYSTEMATIC 23485559 T 71 106 2,5-dimethyl-N-substituted pyrroles FAMILY 23485615 A 1209 1227 γ-glutamylcysteine SYSTEMATIC 23485615 A 1248 1252 heme FAMILY 23485615 A 1273 1280 NAD(P)H ABBREVIATION 23485615 A 1281 1288 quinone FAMILY 23485615 A 1318 1329 glutathione TRIVIAL 23485615 A 1330 1331 S FORMULA 23485615 A 140 159 dimethylnitrosamine SYSTEMATIC 23485615 A 1412 1415 DMN ABBREVIATION 23485615 A 161 164 DMN ABBREVIATION 23485615 A 198 201 DMN ABBREVIATION 23485615 A 398 401 DMN ABBREVIATION 23485615 A 429 436 alanine TRIVIAL 23485615 A 464 473 aspartate TRIVIAL 23485615 A 537 552 malondialdehyde TRIVIAL 23485615 A 593 596 DMN ABBREVIATION 23485615 A 757 760 DMN ABBREVIATION 23485615 A 967 970 DMN ABBREVIATION 23485615 T 27 46 dimethylnitrosamine SYSTEMATIC 23485618 A 0 22 Ethyl lauroyl arginate SYSTEMATIC 23485618 A 1167 1170 LAE ABBREVIATION 23485618 A 24 27 LAE ABBREVIATION 23485618 A 29 72 ethyl-N-dodecanoyl-L-arginate hydrochloride SYSTEMATIC 23485618 A 755 758 LAE ABBREVIATION 23485618 A 795 802 ethanol SYSTEMATIC 23485618 A 831 838 ethanol SYSTEMATIC 23485618 A 928 959 dipropylene glycol methyl ether SYSTEMATIC 23485618 A 963 987 tributyl-o-acetylcitrate SYSTEMATIC 23485618 T 53 75 ethyl lauroyl arginate SYSTEMATIC 23485618 T 77 80 LAE ABBREVIATION 23485618 T 89 92 LAE ABBREVIATION 23485651 A 125 129 CdTe FORMULA 23485651 A 1346 1347 N FORMULA 23485651 A 1474 1478 CdTe FORMULA 23485651 A 154 158 CdTe FORMULA 23485651 A 1658 1662 CdTe FORMULA 23485651 A 1735 1740 CdCl2 FORMULA 23485651 A 1773 1780 cadmium SYSTEMATIC 23485651 A 1822 1826 CdTe FORMULA 23485651 A 281 287 oxygen SYSTEMATIC 23485651 A 364 383 reduced glutathione TRIVIAL 23485651 A 385 388 GSH ABBREVIATION 23485651 A 420 431 glutathione TRIVIAL 23485651 A 435 455 oxidized glutathione TRIVIAL 23485651 A 457 460 GSH ABBREVIATION 23485651 A 461 465 GSSG ABBREVIATION 23485651 A 552 562 superoxide TRIVIAL 23485651 A 628 639 glutathione TRIVIAL 23485651 A 640 641 S FORMULA 23485651 A 718 722 CdTe FORMULA 23485651 A 812 827 poly ADP-ribose SYSTEMATIC 23485651 A 859 877 phosphatidylserine FAMILY 23485651 A 93 110 cadmium telluride SYSTEMATIC 23485651 A 998 1002 CdTe FORMULA 23485651 T 0 17 Cadmium telluride SYSTEMATIC 23485652 A 158 169 amino acids FAMILY 23485652 A 1719 1730 bezafibrate TRIVIAL 23485652 A 1857 1868 bezafibrate TRIVIAL 23485652 A 2013 2024 bezafibrate TRIVIAL 23485652 A 2194 2205 bezafibrate TRIVIAL 23485652 A 27 41 alpha-ketoacid SYSTEMATIC 23485652 A 396 407 bezafibrate TRIVIAL 23485652 A 742 753 bezafibrate TRIVIAL 23485652 A 786 797 Bezafibrate TRIVIAL 23485652 T 40 55 alpha-keto acid SYSTEMATIC 23485652 T 95 106 bezafibrate TRIVIAL 23486447 A 169 182 Amitriptyline TRIVIAL 23486447 A 184 196 clomipramine TRIVIAL 23486447 A 198 205 doxepin TRIVIAL 23486447 A 207 217 imipramine TRIVIAL 23486447 A 223 235 trimipramine TRIVIAL 23486447 A 351 362 desipramine TRIVIAL 23486447 A 367 380 nortriptyline TRIVIAL 23486479 A 1157 1164 glucose TRIVIAL 23486479 A 1220 1227 glucose TRIVIAL 23486479 A 1279 1286 glucose TRIVIAL 23486479 A 1367 1374 glucose TRIVIAL 23486479 A 147 154 lactose TRIVIAL 23486479 A 158 169 allolactose TRIVIAL 23486479 A 1627 1634 glucose TRIVIAL 23486479 A 278 285 glucose TRIVIAL 23486479 A 310 317 lactose TRIVIAL 23486479 A 410 417 glucose TRIVIAL 23486479 A 502 509 glucose TRIVIAL 23486479 A 580 591 allolactose TRIVIAL 23486479 A 637 644 glucose TRIVIAL 23486479 A 64 71 lactose TRIVIAL 23486479 A 660 671 allolactose TRIVIAL 23486479 A 739 798 Bis-Tris (2,2-bis(hydroxymethyl)-2,2',2″-nitrilotriethanol) SYSTEMATIC 23486479 A 75 84 galactose TRIVIAL 23486479 A 803 811 l-ribose TRIVIAL 23486479 A 89 96 glucose TRIVIAL 23486479 A 911 914 Asn FORMULA 23486479 A 920 923 His FORMULA 23486479 A 929 932 Lys FORMULA 23486479 A 938 941 Ser FORMULA 23486479 A 947 950 Glu FORMULA 23486479 A 960 963 Trp FORMULA 23486479 A 969 972 Ser FORMULA 23486479 A 981 984 Glu FORMULA 23486479 T 136 147 Allolactose TRIVIAL 23486479 T 27 38 Allolactose TRIVIAL 23487168 A 1090 1101 telmisartan TRIVIAL 23487168 A 220 230 azilsartan TRIVIAL 23487168 A 232 243 candesartan TRIVIAL 23487168 A 245 255 eprosartan TRIVIAL 23487168 A 257 267 irbesartan TRIVIAL 23487168 A 269 277 losartan TRIVIAL 23487168 A 279 289 olmesartan TRIVIAL 23487168 A 291 302 telmisartan TRIVIAL 23487168 A 304 313 valsartan TRIVIAL 23487168 A 316 326 Azilsartan TRIVIAL 23487168 A 348 359 candesartan TRIVIAL 23487168 A 365 375 olmesartan TRIVIAL 23487256 A 1310 1322 levoglucosan TRIVIAL 23487256 A 1324 1336 abietic acid TRIVIAL 23487256 A 1342 1355 nitroguaiacol SYSTEMATIC 23487256 A 1361 1369 methanol SYSTEMATIC 23487256 A 1371 1383 acetaldehyde SYSTEMATIC 23487256 A 1385 1396 formic acid SYSTEMATIC 23487256 A 1402 1413 acetic acid SYSTEMATIC 23487256 A 1473 1484 glucic acid TRIVIAL 23487256 A 1490 1502 levoglucosan TRIVIAL 23487256 A 1504 1517 glycolic acid TRIVIAL 23487256 A 1523 1535 abietic acid TRIVIAL 23487256 A 1541 1549 methanol SYSTEMATIC 23487256 A 1554 1565 nitric acid SYSTEMATIC 23487256 A 1571 1584 nitroguaiacol SYSTEMATIC 23487256 A 1634 1645 glucic acid TRIVIAL 23487256 A 1647 1660 glycolic acid TRIVIAL 23487256 A 1662 1670 methanol SYSTEMATIC 23487256 A 1676 1687 nitric acid SYSTEMATIC 23487256 A 1825 1827 OH FORMULA 23487256 A 2003 2005 OH FORMULA 23487256 A 289 291 OH FORMULA 23487256 A 40 42 OH FORMULA 23487256 A 410 412 OH FORMULA 23487256 A 46 58 levoglucosan TRIVIAL 23487256 A 569 571 OH FORMULA 23487256 A 60 72 abietic acid TRIVIAL 23487256 A 686 688 OH FORMULA 23487256 A 755 757 OH FORMULA 23487256 A 78 91 nitroguaiacol SYSTEMATIC 23487256 A 883 885 OH FORMULA 23487256 A 989 991 OH FORMULA 23487256 T 137 139 OH FORMULA 23487256 T 14 16 OH FORMULA 23489438 A 1776 1783 glucose TRIVIAL 23489438 A 423 430 glucose TRIVIAL 23489627 A 11 23 bismuth(III) SYSTEMATIC 23489627 A 125 137 bismuth(III) SYSTEMATIC 23489627 A 147 168 Bi(L)(NO3)2(CH3CH2OH) FAMILY 23489627 A 180 225 2-acetylpyridine N(4)-phenylthiosemicarbazone SYSTEMATIC 23489627 A 293 297 (1)H FORMULA 23489627 A 39 57 thiosemicarbazones FAMILY 23489627 A 677 683 oxygen SYSTEMATIC 23489627 T 115 158 2-acetylpyridine N4-phenylthiosemicarbazone SYSTEMATIC 23489627 T 89 101 bismuth(III) SYSTEMATIC 23489628 A 265 292 N-(thiophen-2-yl) benzamide SYSTEMATIC 23489628 T 32 59 N-(thiophen-2-yl) benzamide SYSTEMATIC 23493819 A 293 300 CF3OOOI FORMULA 23493819 A 302 309 CF3OOIO FORMULA 23493819 A 311 318 CF3OIO2 FORMULA 23493819 A 324 328 CF2O FORMULA 23493819 A 331 335 FIO2 FORMULA 23493819 A 366 370 CF2O FORMULA 23493819 A 373 377 FOIO FORMULA 23493819 A 379 383 CF2O FORMULA 23493819 A 386 390 FOOI FORMULA 23493819 A 392 398 CF3OOI FORMULA 23493819 A 401 402 O FORMULA 23493819 A 410 415 CF3OI FORMULA 23493819 A 418 420 O2 FORMULA 23493819 A 442 446 CF3O FORMULA 23493819 A 449 452 OIO FORMULA 23493819 A 45 50 CF3O2 FORMULA 23493819 A 53 55 IO FORMULA 23493819 A 533 537 CF3O FORMULA 23493819 A 540 543 OIO FORMULA 23493819 A 597 601 FIO2 FORMULA 23493819 A 641 645 FIO2 FORMULA 23493819 A 723 730 CF3OOOI FORMULA 23493819 A 732 739 CF3OOIO FORMULA 23493819 A 744 751 CF3OIO2 FORMULA 23493819 A 837 845 hydrogen SYSTEMATIC 23493819 A 862 867 CX3O2 FAMILY 23493819 A 870 872 IO FORMULA 23493819 A 878 879 H FORMULA 23493819 A 884 885 F FORMULA 23493819 T 25 30 CF3O2 FORMULA 23493819 T 86 91 CF3O2 FORMULA 23493819 T 94 96 IO FORMULA 23494230 A 1058 1066 nicotine TRIVIAL 23494230 A 1108 1120 mecamylamine TRIVIAL 23494230 A 1222 1226 DHβE ABBREVIATION 23494230 A 1239 1247 nicotine TRIVIAL 23494230 A 1295 1303 nicotine TRIVIAL 23494230 A 1305 1316 Varenicline TRIVIAL 23494230 A 1351 1359 nicotine TRIVIAL 23494230 A 1369 1377 cytisine TRIVIAL 23494230 A 1429 1437 nicotine TRIVIAL 23494230 A 1526 1534 nicotine TRIVIAL 23494230 A 1536 1547 varenicline TRIVIAL 23494230 A 1553 1561 cytisine TRIVIAL 23494230 A 1636 1649 acetylcholine SYSTEMATIC 23494230 A 367 375 nicotine TRIVIAL 23494230 A 382 390 Nicotine TRIVIAL 23494230 A 392 403 varenicline TRIVIAL 23494230 A 409 417 cytisine TRIVIAL 23494230 A 499 511 mecamylamine TRIVIAL 23494230 A 516 538 dihydro-β-erythroidine SYSTEMATIC 23494230 A 540 544 DHβE ABBREVIATION 23494230 A 547 556 Midazolam TRIVIAL 23494230 A 561 569 morphine TRIVIAL 23494230 A 651 659 nicotine TRIVIAL 23494230 A 756 767 Varenicline TRIVIAL 23494230 A 772 780 cytisine TRIVIAL 23494230 A 810 818 nicotine TRIVIAL 23494230 A 841 849 nicotine TRIVIAL 23494230 A 913 921 nicotine TRIVIAL 23494230 A 937 945 Morphine TRIVIAL 23494230 A 94 107 acetylcholine SYSTEMATIC 23494230 A 969 977 nicotine TRIVIAL 23494230 A 987 996 midazolam TRIVIAL 23494230 T 9 17 nicotine TRIVIAL 23494236 A 1125 1133 nicotine TRIVIAL 23494236 A 1235 1243 nicotine TRIVIAL 23494236 A 1372 1380 nicotine TRIVIAL 23494236 A 1488 1496 nicotine TRIVIAL 23494236 A 1680 1688 Nicotine TRIVIAL 23494236 A 176 184 nicotine TRIVIAL 23494236 A 227 235 nicotine TRIVIAL 23494236 A 23 31 nicotine TRIVIAL 23494236 A 423 431 nicotine TRIVIAL 23494236 A 681 689 nicotine TRIVIAL 23494236 A 81 89 nicotine TRIVIAL 23494236 A 848 856 nicotine TRIVIAL 23494236 T 35 43 nicotine TRIVIAL 23494855 A 205 217 hydrous RuO2 FORMULA 23494855 A 232 238 silica TRIVIAL 23494855 A 310 314 RuO2 FORMULA 23494855 T 31 54 Hydrous Ruthenium Oxide SYSTEMATIC 23494855 T 69 75 Silica TRIVIAL 23494861 A 1080 1093 methylglyoxal SYSTEMATIC 23494904 A 130 157 fulleropyrrolidinium iodide SYSTEMATIC 23494904 A 159 162 FPI ABBREVIATION 23494904 A 168 171 FPI ABBREVIATION 23494904 A 178 182 PCBM ABBREVIATION 23494904 A 293 299 iodide SYSTEMATIC 23494904 A 303 306 FPI ABBREVIATION 23494904 A 315 324 fullerene TRIVIAL 23494904 A 75 85 fullerenes FAMILY 23494904 T 39 49 fullerenes FAMILY 23494944 A 0 9 Aluminium SYSTEMATIC 23494944 A 1004 1014 superoxide TRIVIAL 23494944 A 1189 1194 AlCl3 FORMULA 23494944 A 1329 1357 (-)-epigallocatechin gallate TRIVIAL 23494944 A 1362 1377 (-)-epicatechin SYSTEMATIC 23494944 A 278 296 aluminium chloride SYSTEMATIC 23494944 A 298 303 AlCl3 FORMULA 23494944 A 505 516 glutathione TRIVIAL 23494944 A 635 640 AlCl3 FORMULA 23494944 A 864 874 superoxide TRIVIAL 23494944 A 988 993 AlCl3 FORMULA 23494944 T 60 78 Aluminium Chloride SYSTEMATIC 23495155 A 113 119 sterol FAMILY 23495155 A 120 129 polyamine FAMILY 23495155 A 13 19 sterol FAMILY 23495155 A 20 29 polyamine FAMILY 23495155 A 456 467 cholic acid TRIVIAL 23495155 A 557 573 deoxycholic acid TRIVIAL 23495155 A 643 659 deoxycholic acid TRIVIAL 23495155 A 660 668 spermine TRIVIAL 23495155 A 718 729 cholic acid TRIVIAL 23495155 T 90 96 sterol FAMILY 23495155 T 97 106 polyamine FAMILY 23495205 A 0 71 4-{[(4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate SYSTEMATIC 23495205 A 102 104 Cl FORMULA 23495205 A 106 108 Br FORMULA 23495205 A 351 358 halogen FAMILY 23495205 A 386 393 halogen FAMILY 23495205 A 420 427 halogen FAMILY 23495205 A 467 476 methylene SYSTEMATIC 23495205 A 491 508 difluoromethylene SYSTEMATIC 23495205 A 536 552 para-cyanophenyl SYSTEMATIC 23495205 A 609 618 triazolyl SYSTEMATIC 23495205 A 633 643 imidazolyl SYSTEMATIC 23495205 A 698 707 imidazole SYSTEMATIC 23495205 A 758 765 steroid FAMILY 23495205 A 848 854 phenol SYSTEMATIC 23495205 A 99 100 F FORMULA 23495205 T 111 182 4-{[(4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate SYSTEMATIC 23495690 A 11 22 nucleotides FAMILY 23495690 T 12 22 nucleotide FAMILY 23495771 A 247 252 amino FAMILY 23495771 A 261 266 PU-Am ABBREVIATION 23495771 A 326 331 amino FAMILY 23495771 A 359 377 succinyl anhydride SYSTEMATIC 23495771 A 37 52 poly(allylurea) FAMILY 23495771 A 379 384 PU-Su ABBREVIATION 23495771 A 389 405 acetyl anhydride SYSTEMATIC 23495771 A 407 412 PU-Ac ABBREVIATION 23495771 A 600 605 PU-Am ABBREVIATION 23495771 A 62 80 poly(L-citrulline) FAMILY 23495771 A 702 707 PU-Am ABBREVIATION 23495771 A 762 767 PU-Am ABBREVIATION 23495771 A 772 777 PU-Su ABBREVIATION 23495771 A 837 842 PU-Am ABBREVIATION 23495771 A 883 888 PU-Su ABBREVIATION 23495825 A 257 264 proline TRIVIAL 23495825 A 286 293 glycine TRIVIAL 23495832 A 380 387 carvone TRIVIAL 23495832 A 392 400 limonene TRIVIAL 23495832 A 461 464 HCl FORMULA 23495832 A 465 472 ethanol SYSTEMATIC 23495832 A 618 628 omeprazole TRIVIAL 23495832 A 671 675 NaCl FORMULA 23495832 A 720 723 HCl FORMULA 23495832 A 724 728 EtOH FORMULA 23495832 A 943 953 omeprazole TRIVIAL 23495832 T 90 104 carbon dioxide SYSTEMATIC 23495918 A 455 462 silicon SYSTEMATIC 23495918 A 613 634 poly(ethylene glycol) SYSTEMATIC 23495918 A 636 639 PEG ABBREVIATION 23495918 A 823 826 PEG ABBREVIATION 23495918 A 891 903 polyethylene SYSTEMATIC 23495918 A 914 925 polystyrene SYSTEMATIC 23495918 A 980 983 PEG ABBREVIATION 23496094 A 127 132 THIQM ABBREVIATION 23496094 A 309 314 THIQM ABBREVIATION 23496094 A 443 451 hydrogen SYSTEMATIC 23496094 A 56 70 methyl lactate SYSTEMATIC 23496094 A 648 654 THIQMI ABBREVIATION 23496094 A 663 665 OH FORMULA 23496094 A 668 669 N FORMULA 23496094 A 670 678 hydrogen SYSTEMATIC 23496094 A 776 783 THIQMII ABBREVIATION 23496094 A 789 791 NH FORMULA 23496094 A 794 795 O FORMULA 23496094 A 796 804 hydrogen SYSTEMATIC 23496094 A 80 125 (S)-1,2,3,4-tetrahydro-3-isoquinolinemethanol SYSTEMATIC 23496094 T 127 141 Methyl Lactate SYSTEMATIC 23496094 T 76 121 (S)-1,2,3,4-Tetrahydro-3-isoquinolinemethanol SYSTEMATIC 23496772 A 1024 1027 FEE ABBREVIATION 23496772 A 1358 1361 CF3 FORMULA 23496772 A 1379 1382 FEE ABBREVIATION 23496772 A 1484 1487 FEE ABBREVIATION 23496772 A 215 218 CF3 FORMULA 23496772 A 526 544 CH3(CH2)20COCH2CH3 FORMULA 23496772 A 546 557 ethyl ether SYSTEMATIC 23496772 A 567 585 CH3(CH2)20COCH2CF3 FORMULA 23496772 A 587 610 fluorinated ethyl ether SYSTEMATIC 23496772 A 612 615 FEE ABBREVIATION 23496772 A 723 726 FEE ABBREVIATION 23496772 A 778 780 OH FORMULA 23496772 A 782 785 COC FORMULA 23496772 A 787 790 CH3 FORMULA 23496772 A 796 799 CF3 FORMULA 23496772 A 977 980 FEE ABBREVIATION 23497861 A 0 10 γ-Oryzanol TRIVIAL 23497861 A 196 206 γ-oryzanol TRIVIAL 23497861 A 313 324 cyanopropyl SYSTEMATIC 23497861 A 349 355 hexane SYSTEMATIC 23497861 A 356 360 MTBE ABBREVIATION 23497861 A 443 458 steryl ferulate TRIVIAL 23497861 A 460 471 p-coumarate TRIVIAL 23497861 A 476 491 caffeate esters FAMILY 23497861 A 521 535 trans-ferulate TRIVIAL 23497861 A 562 569 steroid FAMILY 23497861 T 47 57 γ-oryzanol TRIVIAL 23497861 T 66 77 p-coumarate TRIVIAL 23497861 T 82 90 caffeate TRIVIAL 23497865 A 318 324 esters FAMILY 23497865 A 359 374 docosahexaenoic SYSTEMATIC 23497865 A 397 402 oleic TRIVIAL 23497865 A 421 432 fatty acids FAMILY 23497865 A 434 445 Cholesterol TRIVIAL 23497865 A 485 496 fatty acids FAMILY 23497865 A 559 570 fatty acids FAMILY 23497865 A 604 611 taurine TRIVIAL 23497865 A 613 625 nicotinamide TRIVIAL 23497865 A 630 639 β-alanine TRIVIAL 23497865 A 728 739 lactic acid TRIVIAL 23497868 A 1006 1009 TFs FAMILY 23497868 A 147 158 theaflavins FAMILY 23497868 A 160 163 TFs FAMILY 23497868 A 245 248 TFs FAMILY 23497868 A 382 398 glycyl-sarcosine TRIVIAL 23497868 A 400 407 Gly-Sar FORMULA 23497868 A 457 467 dipeptides FAMILY 23497868 A 469 476 Val-Tyr FORMULA 23497868 A 481 488 Ile-Phe FORMULA 23497868 A 529 532 TFs FAMILY 23497868 A 554 569 TF 3'-O-gallate SYSTEMATIC 23497868 A 666 673 Gly-Sar FORMULA 23497868 A 720 730 Compound C TRIVIAL 23497868 A 735 738 AMP ABBREVIATION 23497868 A 833 836 TFs FAMILY 23497868 A 87 106 di- and tripeptides MULTIPLE 23497868 T 0 11 Theaflavins FAMILY 23497868 T 111 114 AMP ABBREVIATION 23497868 T 13 30 dimeric catechins FAMILY 23497870 A 635 658 unsaturated fatty acids FAMILY 23497871 A 365 376 lactic acid TRIVIAL 23497871 A 549 561 acetaldehyde SYSTEMATIC 23497871 A 563 571 diacetyl SYSTEMATIC 23497871 A 573 580 acetoin TRIVIAL 23497871 A 586 596 2-butanone SYSTEMATIC 23497871 A 846 858 acetaldehyde SYSTEMATIC 23497871 A 863 871 diacetyl SYSTEMATIC 23497871 T 123 134 lactic acid TRIVIAL 23497873 A 15 25 γ-glutamyl TRIVIAL 23497873 A 265 277 formaldehyde SYSTEMATIC 23497873 A 450 453 SDS ABBREVIATION 23497873 A 51 72 l-cysteine sulphoxide SYSTEMATIC 23497873 A 766 778 formaldehyde SYSTEMATIC 23497873 T 71 83 formaldehyde SYSTEMATIC 23497880 A 19 53 fructosyl-galacto-oligosaccharides FAMILY 23497880 A 343 377 fructosyl-galacto-oligosaccharides FAMILY 23497880 A 476 481 sugar FAMILY 23497880 A 59 68 lactulose TRIVIAL 23497880 A 599 633 fructosyl-galacto-oligosaccharides FAMILY 23497880 A 667 676 lactulose TRIVIAL 23497880 A 782 791 lactulose TRIVIAL 23497880 T 59 68 lactulose TRIVIAL 23497880 T 70 104 fructosyl-galacto-oligosaccharides FAMILY 23497885 A 1010 1019 flavonoid FAMILY 23497885 A 403 417 phenolic acids FAMILY 23497885 A 419 429 flavonoids FAMILY 23497885 A 431 442 triterpenes FAMILY 23497885 A 526 539 hippuric acid TRIVIAL 23497885 A 544 558 propyl gallate SYSTEMATIC 23497885 A 631 640 flavonoid FAMILY 23497885 A 664 673 berberine TRIVIAL 23497885 A 675 684 celastrol TRIVIAL 23497885 A 686 698 ellagic acid TRIVIAL 23497885 A 700 707 limonin TRIVIAL 23497885 A 709 723 oleanolic acid TRIVIAL 23497885 A 725 739 propyl gallate SYSTEMATIC 23497885 A 741 753 sinapic acid TRIVIAL 23497885 A 758 770 ursolic acid TRIVIAL 23497885 A 836 847 Chrysoeriol TRIVIAL 23497885 A 849 859 laricitrin TRIVIAL 23497885 A 861 894 myricetin 3',4',5'-trimethylether SYSTEMATIC 23497885 A 896 907 pinocembrin TRIVIAL 23497885 A 909 919 quercitrin TRIVIAL 23497885 A 921 932 tamarixetin TRIVIAL 23497885 A 934 942 tricetin TRIVIAL 23497885 A 947 979 tricetin 3',4',5'-trimethylether SYSTEMATIC 23497888 A 145 154 arabinose TRIVIAL 23497888 A 275 298 α-(1→5)-l-arabinotriose SYSTEMATIC 23497888 A 598 604 carbon SYSTEMATIC 23497888 A 605 611 carbon SYSTEMATIC 23497888 A 734 746 formaldehyde SYSTEMATIC 23497888 A 748 759 formic acid SYSTEMATIC 23497888 A 761 775 glycolaldehyde TRIVIAL 23497888 A 777 784 glyoxal TRIVIAL 23497888 A 786 797 acetic acid SYSTEMATIC 23497888 A 799 812 glycolic acid TRIVIAL 23497888 A 814 828 glyceraldehyde TRIVIAL 23497888 A 830 856 2-hydroxypropanedialdehyde SYSTEMATIC 23497888 T 28 41 arabinotriose TRIVIAL 23497892 A 341 351 amino acid FAMILY 23497892 A 497 507 phosphorus SYSTEMATIC 23497892 A 53 76 sodium trimetaphosphate SYSTEMATIC 23497892 A 734 745 amino acids FAMILY 23497892 A 78 82 STMP ABBREVIATION 23497895 A 1047 1084 cis-2,6-dimethyl-1,4-cyclohexanedione SYSTEMATIC 23497895 A 333 343 silica gel TRIVIAL 23497895 A 592 629 cis-2,6-dimethyl-1,4-cyclohexanedione SYSTEMATIC 23497895 A 739 776 cis-2,6-dimethyl-1,4-cyclohexanedione SYSTEMATIC 23497895 A 815 821 sugars FAMILY 23497895 A 834 849 monosaccharides FAMILY 23497895 A 908 929 2-hydroxy-3-pentanone SYSTEMATIC 23497895 A 934 955 1-hydroxy-2-propanone SYSTEMATIC 23497895 A 989 1004 monosaccharides FAMILY 23497895 T 51 88 cis-2,6-dimethyl-1,4-cyclohexanedione SYSTEMATIC 23497901 A 137 150 phlorotannins FAMILY 23497901 A 377 390 phlorotannins FAMILY 23497901 A 474 487 phlorotannins FAMILY 23497901 A 650 657 ethanol SYSTEMATIC 23497901 A 768 781 phlorotannins FAMILY 23497901 T 23 36 phlorotannins FAMILY 23497902 A 119 128 vitamin E FAMILY 23497902 A 130 134 VITE ABBREVIATION 23497902 A 173 186 carnosic acid TRIVIAL 23497902 A 188 192 CARN ABBREVIATION 23497902 A 231 235 CARN ABBREVIATION 23497902 A 395 404 vitamin E FAMILY 23497902 A 499 502 FAs ABBREVIATION 23497902 A 519 527 phenolic FAMILY 23497902 A 694 707 carnosic acid TRIVIAL 23497902 A 727 730 FAs ABBREVIATION 23497902 A 901 914 carnosic acid TRIVIAL 23497902 T 18 31 carnosic acid TRIVIAL 23497902 T 39 49 fatty acid FAMILY 23497905 A 112 124 ellagic acid TRIVIAL 23497905 A 234 246 ellagic acid TRIVIAL 23497905 A 32 44 ellagic acid TRIVIAL 23497905 T 80 92 ellagic acid TRIVIAL 23497907 A 1013 1022 5,6-epoxy SYSTEMATIC 23497907 A 1035 1044 5,8-epoxy SYSTEMATIC 23497907 A 1083 1088 epoxy SYSTEMATIC 23497907 A 112 122 zeaxanthin TRIVIAL 23497907 A 1151 1158 hydroxy SYSTEMATIC 23497907 A 1172 1178 lutein TRIVIAL 23497907 A 1180 1190 zeaxanthin TRIVIAL 23497907 A 1195 1210 β-cryptoxanthin TRIVIAL 23497907 A 127 145 cis-antheraxanthin TRIVIAL 23497907 A 640 655 β-cryptoxanthin TRIVIAL 23497907 A 69 85 cis-violaxanthin TRIVIAL 23497907 A 707 713 lutein TRIVIAL 23497907 A 718 728 zeaxanthin TRIVIAL 23497907 A 749 754 epoxy SYSTEMATIC 23497907 A 767 783 cis-violaxanthin TRIVIAL 23497907 A 788 806 cis-antheraxanthin TRIVIAL 23497907 A 87 93 lutein TRIVIAL 23497907 A 883 901 cis-antheraxanthin TRIVIAL 23497907 A 932 948 cis-violaxanthin TRIVIAL 23497907 A 95 110 β-cryptoxanthin TRIVIAL 23498899 A 1499 1506 glucose TRIVIAL 23498899 A 526 534 caffeine TRIVIAL 23498899 A 596 603 glucose TRIVIAL 23498899 A 71 78 glucose TRIVIAL 23498899 A 847 854 glucose TRIVIAL 23498899 A 922 929 Glucose TRIVIAL 23498899 T 105 112 glucose TRIVIAL 23499235 A 262 276 thienopyridine SYSTEMATIC 23499235 A 319 331 nitric oxide SYSTEMATIC 23499235 A 333 335 NO FORMULA 23499235 A 35 71 6-aryl-3-amino-thieno[2,3-b]pyridine FAMILY 23499235 A 364 378 thienopyridine SYSTEMATIC 23499235 A 594 596 NO FORMULA 23499235 A 693 729 6-aryl-3-amino-thieno[2,3-b]pyridine FAMILY 23499235 T 95 131 6-aryl-3-amino-thieno[2,3-b]pyridine FAMILY 23499661 A 1120 1128 formalin TRIVIAL 23499661 A 1179 1187 formalin TRIVIAL 23499661 A 1281 1291 naltrexone TRIVIAL 23499661 A 1374 1384 naltrexone TRIVIAL 23499661 A 1415 1427 naloxonazine TRIVIAL 23499661 A 1501 1511 naltrexone TRIVIAL 23499661 A 449 457 formalin TRIVIAL 23499661 A 567 577 Naltrexone TRIVIAL 23499661 A 697 709 naloxonazine TRIVIAL 23499661 A 802 812 naltrexone TRIVIAL 23499661 A 994 1004 naltrexone TRIVIAL 23499716 A 1706 1734 [(131)I] labeled fenofibrate SYSTEMATIC 23499716 A 501 522 iodinated fenofibrate TRIVIAL 23499716 A 943 973 [(131)I] iodinated fenofibrate SYSTEMATIC 23499716 T 123 147 radiolabeled fenofibrate TRIVIAL 23499717 A 1036 1047 doxorubicin TRIVIAL 23499717 A 1175 1186 doxorubicin TRIVIAL 23499717 A 569 580 doxorubicin TRIVIAL 23499717 A 585 594 magnetite TRIVIAL 23499717 A 674 683 nitroxide SYSTEMATIC 23499717 A 783 794 doxorubicin TRIVIAL 23499717 A 863 881 triethylene glycol SYSTEMATIC 23499717 A 913 928 carboxylic acid SYSTEMATIC 23499717 A 944 955 doxorubicin TRIVIAL 23499717 A 960 965 Fe3O4 FORMULA 23499717 T 65 76 doxorubicin TRIVIAL 23499717 T 81 90 magnetite TRIVIAL 23499718 A 1099 1104 PEG12 TRIVIAL 23499718 A 1246 1251 PEG12 TRIVIAL 23499718 A 1465 1470 PEG12 TRIVIAL 23499718 A 499 504 PEG12 TRIVIAL 23499718 A 525 530 PEG40 TRIVIAL 23499718 A 744 749 PEG12 TRIVIAL 23499718 A 952 957 PEG40 TRIVIAL 23499751 A 0 8 Atrazine TRIVIAL 23499751 A 1002 1010 atrazine TRIVIAL 23499751 A 1228 1236 atrazine TRIVIAL 23499751 A 177 185 atrazine TRIVIAL 23499751 A 419 427 atrazine TRIVIAL 23499751 A 481 492 glutathione TRIVIAL 23499751 A 493 494 S FORMULA 23499751 A 694 704 superoxide TRIVIAL 23499751 A 763 771 atrazine TRIVIAL 23499751 A 818 829 glutathione TRIVIAL 23499751 A 904 912 atrazine TRIVIAL 23499751 T 81 89 atrazine TRIVIAL 23499856 A 190 193 PEG ABBREVIATION 23499856 A 745 748 PEG ABBREVIATION 23499856 A 770 774 COOH FORMULA 23499857 A 0 15 Thienopyridines FAMILY 23499857 A 1265 1270 rutin TRIVIAL 23499857 A 128 139 ticlopidine TRIVIAL 23499857 A 1283 1295 ketoconazole TRIVIAL 23499857 A 141 152 clopidogrel TRIVIAL 23499857 A 1457 1462 rutin TRIVIAL 23499857 A 1479 1490 ticlopidine TRIVIAL 23499857 A 1492 1503 clopidogrel TRIVIAL 23499857 A 1505 1528 clopidogrel carboxylate SYSTEMATIC 23499857 A 1533 1542 prasugrel TRIVIAL 23499857 A 154 177 clopidogrel carboxylate SYSTEMATIC 23499857 A 182 191 prasugrel TRIVIAL 23499857 A 320 331 clopidogrel TRIVIAL 23499857 A 333 344 ticlopidine TRIVIAL 23499857 A 346 369 clopidogrel carboxylate SYSTEMATIC 23499857 A 374 383 prasugrel TRIVIAL 23499857 A 504 509 rutin TRIVIAL 23499857 A 552 564 ketoconazole TRIVIAL 23499857 A 677 682 rutin TRIVIAL 23499857 A 686 698 ketoconazole TRIVIAL 23499857 A 725 736 ticlopidine TRIVIAL 23499857 A 738 749 clopidogrel TRIVIAL 23499857 A 751 774 clopidogrel carboxylate SYSTEMATIC 23499857 A 779 788 prasugrel TRIVIAL 23499857 A 826 831 rutin TRIVIAL 23499857 A 844 856 ketoconazole TRIVIAL 23499857 A 949 961 ketoconazole TRIVIAL 23499857 A 965 970 rutin TRIVIAL 23499857 T 12 27 thienopyridines FAMILY 23499954 A 119 127 steroids FAMILY 23499954 A 17 31 salpichrolides FAMILY 23499954 A 189 192 HBr FORMULA 23499954 A 198 227 vicinal dibromo D-homosteroid FAMILY 23499954 A 246 275 1,4-diazabicyclo[2.2.2]octane SYSTEMATIC 23499954 A 277 282 DABCO ABBREVIATION 23499954 T 42 50 steroids FAMILY 23500040 A 43 53 metoprolol TRIVIAL 23500040 T 66 76 metoprolol TRIVIAL 23500058 A 841 856 sodium sulphate SYSTEMATIC 23500491 A 127 130 ATP ABBREVIATION 23500491 A 172 175 ATP ABBREVIATION 23500491 A 443 446 ATP ABBREVIATION 23500491 A 455 461 AMPPNP ABBREVIATION 23500491 A 463 488 adenylyl imidodiphosphate SYSTEMATIC 23500491 A 597 600 ATP ABBREVIATION 23500491 A 637 640 ATP ABBREVIATION 23500491 A 680 690 nucleotide FAMILY 23500491 A 713 716 ATP ABBREVIATION 23500491 A 860 869 phosphate SYSTEMATIC 23500491 A 897 906 phosphate SYSTEMATIC 23500491 T 25 28 ATP ABBREVIATION 23500545 A 0 10 Oxysterols FAMILY 23500545 A 1092 1102 oxysterols FAMILY 23500545 A 1283 1292 oxysterol FAMILY 23500545 A 260 270 oxysterols FAMILY 23500545 A 382 393 cholesterol TRIVIAL 23500545 A 405 435 3-hydroxy-3-methylglutaryl CoA SYSTEMATIC 23500545 A 501 511 Oxysterols FAMILY 23500545 A 569 580 cholesterol TRIVIAL 23500545 A 658 668 oxysterols FAMILY 23500545 A 744 755 cholesterol TRIVIAL 23500545 A 826 837 Cholesterol TRIVIAL 23500545 A 936 946 oxysterols FAMILY 23500545 A 948 958 Oxysterols FAMILY 23500545 T 0 10 Oxysterols FAMILY 23500546 A 1084 1091 TRAM-34 TRIVIAL 23500546 A 139 146 calcium SYSTEMATIC 23500546 A 157 161 K(+) FORMULA 23500546 A 917 925 SB203580 IDENTIFIER 23500546 A 948 955 PD98059 IDENTIFIER 23500546 A 984 992 LY294002 IDENTIFIER 23500659 A 0 8 Androgen FAMILY 23500659 A 1029 1041 testosterone TRIVIAL 23500659 A 104 112 Estrogen FAMILY 23500659 A 1285 1297 testosterone TRIVIAL 23500659 A 13 21 estrogen FAMILY 23500659 A 152 160 estrogen FAMILY 23500659 A 344 356 testosterone TRIVIAL 23500659 A 577 589 testosterone TRIVIAL 23500659 A 591 603 Testosterone TRIVIAL 23500659 A 810 822 testosterone TRIVIAL 23500660 A 0 8 Vanadium SYSTEMATIC 23500660 A 151 159 vanadium SYSTEMATIC 23500660 A 1678 1686 vanadium SYSTEMATIC 23500660 A 268 276 vanadium SYSTEMATIC 23500660 A 302 310 vanadium SYSTEMATIC 23500660 A 419 423 Iron SYSTEMATIC 23500660 T 0 8 Vanadium SYSTEMATIC 23500769 A 221 229 peroxide SYSTEMATIC 23500769 A 242 261 thiobarbituric acid SYSTEMATIC 23500769 A 291 302 cholesterol TRIVIAL 23500769 A 354 381 polyunsaturated fatty acids FAMILY 23500769 A 383 388 PUFAs ABBREVIATION 23500769 A 410 414 PUFA ABBREVIATION 23500769 A 410 418 PUFA n-3 ABBREVIATION 23500769 A 492 496 PUFA ABBREVIATION 23500769 A 578 580 O2 FORMULA 23500769 A 771 782 cholesterol TRIVIAL 23500775 A 417 431 anthraquinones FAMILY 23500775 A 668 681 anthraquinone SYSTEMATIC 23500775 A 899 912 anthraquinone SYSTEMATIC 23500775 T 36 49 anthraquinone SYSTEMATIC 23500776 A 1059 1063 EROD ABBREVIATION 23500776 A 1132 1136 EROD ABBREVIATION 23500776 A 115 163 halogenated and polycyclic aromatic hydrocarbons MULTIPLE 23500776 A 1286 1289 PHH ABBREVIATION 23500776 A 170 173 PAH ABBREVIATION 23500776 A 286 298 phenanthrene SYSTEMATIC 23500776 A 300 306 pyrene SYSTEMATIC 23500776 A 311 325 benzo(a)pyrene SYSTEMATIC 23500776 A 348 352 EROD ABBREVIATION 23500776 A 642 646 EROD ABBREVIATION 23500776 A 942 946 EROD ABBREVIATION 23500776 T 107 139 polycyclic aromatic hydrocarbons FAMILY 23501111 A 18 109 2-ferrocenyl-7-hydroxy-5-phenethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one SYSTEMATIC 23501111 A 234 238 (1)H FORMULA 23501111 T 13 57 ferrocenylpyrazolo[1,5-a][1,4]diazepin-4-one SYSTEMATIC 23501115 A 12 35 7,8-dehydrorutaecarpine SYSTEMATIC 23501115 A 652 660 curcumin TRIVIAL 23501115 A 698 704 Trolox TRIVIAL 23501115 T 28 51 7,8-dehydrorutaecarpine SYSTEMATIC 23503684 A 1023 1039 β-funaltrexamine TRIVIAL 23503684 A 1095 1105 naltrexone TRIVIAL 23503684 A 11 21 Naltrexone TRIVIAL 23503684 A 1153 1161 dopamine TRIVIAL 23503684 A 118 125 alcohol FAMILY 23503684 A 1185 1192 ethanol SYSTEMATIC 23503684 A 1264 1272 morphine TRIVIAL 23503684 A 1295 1303 dopamine TRIVIAL 23503684 A 1440 1447 ethanol SYSTEMATIC 23503684 A 1470 1478 dopamine TRIVIAL 23503684 A 1605 1613 dopamine TRIVIAL 23503684 A 1683 1691 dopamine TRIVIAL 23503684 A 1871 1879 dopamine TRIVIAL 23503684 A 1892 1899 ethanol SYSTEMATIC 23503684 A 1904 1912 morphine TRIVIAL 23503684 A 209 216 ethanol SYSTEMATIC 23503684 A 253 260 ethanol SYSTEMATIC 23503684 A 283 291 dopamine TRIVIAL 23503684 A 343 353 naltrexone TRIVIAL 23503684 A 358 374 β-funaltrexamine TRIVIAL 23503684 A 433 440 ethanol SYSTEMATIC 23503684 A 456 464 morphine TRIVIAL 23503684 A 487 495 dopamine TRIVIAL 23503684 A 610 617 Ethanol SYSTEMATIC 23503684 A 821 828 ethanol SYSTEMATIC 23503684 A 832 840 morphine TRIVIAL 23503684 A 868 876 dopamine TRIVIAL 23503684 A 992 1002 naltrexone TRIVIAL 23503684 T 134 141 ethanol SYSTEMATIC 23503684 T 52 60 dopamine TRIVIAL 23503684 T 73 80 ethanol SYSTEMATIC 23503684 T 85 93 morphine TRIVIAL 23503701 A 1198 1205 lithium SYSTEMATIC 23503701 A 12 19 Lithium SYSTEMATIC 23503701 A 1223 1230 lithium SYSTEMATIC 23503701 A 1337 1344 Lithium SYSTEMATIC 23503701 A 1534 1541 lithium SYSTEMATIC 23503701 A 1683 1690 lithium SYSTEMATIC 23503701 A 183 190 lithium SYSTEMATIC 23503701 A 309 316 lithium SYSTEMATIC 23503701 A 647 654 lithium SYSTEMATIC 23503701 A 688 695 lithium SYSTEMATIC 23503701 A 760 767 lithium SYSTEMATIC 23503701 A 819 826 lithium SYSTEMATIC 23503701 A 894 901 lithium SYSTEMATIC 23503701 A 988 995 lithium SYSTEMATIC 23503701 T 45 52 lithium SYSTEMATIC 23503702 A 11 18 Alcohol SYSTEMATIC 23503702 A 1175 1182 alcohol FAMILY 23503702 A 1248 1255 alcohol FAMILY 23503702 A 1298 1305 alcohol FAMILY 23503702 A 1353 1360 alcohol FAMILY 23503702 A 1493 1500 alcohol FAMILY 23503702 A 384 391 alcohol FAMILY 23503702 A 412 419 Alcohol SYSTEMATIC 23503702 A 476 483 alcohol FAMILY 23503702 A 620 627 alcohol FAMILY 23503702 A 666 673 alcohol FAMILY 23503702 A 746 753 alcohol FAMILY 23503702 A 792 799 alcohol FAMILY 23503702 A 902 909 alcohol FAMILY 23503702 A 937 944 alcohol FAMILY 23503702 A 993 1000 alcohol FAMILY 23503702 T 0 7 Alcohol SYSTEMATIC 23503702 T 83 90 alcohol FAMILY 23504441 A 1015 1017 Cu FORMULA 23504441 A 1032 1038 Copper SYSTEMATIC 23504441 A 1081 1087 copper SYSTEMATIC 23504441 A 1103 1108 Forum TRIVIAL 23504441 A 1135 1141 copper SYSTEMATIC 23504441 A 1238 1243 Forum TRIVIAL 23504441 A 1308 1314 copper SYSTEMATIC 23504441 A 1347 1352 Forum TRIVIAL 23504441 A 1578 1584 copper SYSTEMATIC 23504441 A 199 205 copper SYSTEMATIC 23504441 A 210 222 dimethomorph TRIVIAL 23504441 A 27 33 copper SYSTEMATIC 23504441 A 324 330 Copper SYSTEMATIC 23504441 A 38 50 dimethomorph TRIVIAL 23504441 A 409 421 dimethomorph TRIVIAL 23504441 A 459 464 Forum TRIVIAL 23504441 A 52 122 (E,Z)4-[3-(4-chlorophenyl)-3-(3-4dimethoxyphenyl) acryloyl] morpholine SYSTEMATIC 23504441 A 621 627 copper SYSTEMATIC 23504441 A 632 637 Forum TRIVIAL 23504441 A 764 776 dimethomorph TRIVIAL 23504441 A 787 792 Forum TRIVIAL 23504441 A 811 817 copper SYSTEMATIC 23504441 A 822 834 dimethomorph TRIVIAL 23504441 A 905 911 copper SYSTEMATIC 23504441 T 40 46 copper SYSTEMATIC 23504441 T 51 63 dimethomorph TRIVIAL 23505123 A 191 197 quartz TRIVIAL 23505123 A 283 305 sodium dodecyl sulfate SYSTEMATIC 23505123 A 29 35 carbon SYSTEMATIC 23505123 A 307 310 SDS ABBREVIATION 23505123 A 330 333 SDS ABBREVIATION 23505123 A 382 385 SDS ABBREVIATION 23505123 T 100 103 SDS ABBREVIATION 23505123 T 41 47 Carbon SYSTEMATIC 23505224 A 0 6 Carbon SYSTEMATIC 23505224 A 1007 1013 oxygen SYSTEMATIC 23505224 A 1105 1113 platinum SYSTEMATIC 23505224 A 1166 1174 platinum SYSTEMATIC 23505224 A 1202 1208 oxygen SYSTEMATIC 23505224 A 1297 1303 oxygen SYSTEMATIC 23505224 A 1325 1333 platinum SYSTEMATIC 23505224 A 17 19 Pt FORMULA 23505224 A 20 22 Au FORMULA 23505224 A 235 243 platinum SYSTEMATIC 23505224 A 393 401 platinum SYSTEMATIC 23505224 A 551 559 platinum SYSTEMATIC 23505224 A 628 634 copper SYSTEMATIC 23505224 A 730 738 platinum SYSTEMATIC 23505224 A 848 856 platinum SYSTEMATIC 23505224 A 88 96 platinum SYSTEMATIC 23505224 T 16 22 Oxygen SYSTEMATIC 23505224 T 67 75 Platinum SYSTEMATIC 23505325 A 63 95 poly(p-phenylenebutadiynylene) s FAMILY 23505325 A 97 101 PPBs FAMILY 23505325 T 13 32 phenyleneethynylene SYSTEMATIC 23505325 T 39 70 poly(pphenylenebutadiynylene) s FAMILY 23505396 A 1100 1141 sodium dodecyl sulfate polyacrylamide gel FAMILY 23505396 A 1159 1162 SDS ABBREVIATION 23505396 A 1248 1258 amino acid FAMILY 23505396 A 1691 1720 Tris(hydroxymethyl phosphine) SYSTEMATIC 23506042 A 1102 1105 αKG ABBREVIATION 23506042 A 181 187 carbon SYSTEMATIC 23506042 A 234 240 carbon SYSTEMATIC 23506042 A 245 253 nitrogen SYSTEMATIC 23506042 A 311 326 α-ketoglutarate TRIVIAL 23506042 A 328 331 αKG ABBREVIATION 23506042 A 338 344 carbon SYSTEMATIC 23506042 A 359 366 ammonia SYSTEMATIC 23506042 A 40 46 carbon SYSTEMATIC 23506042 A 51 59 nitrogen SYSTEMATIC 23506042 A 572 578 carbon SYSTEMATIC 23506042 A 583 591 nitrogen SYSTEMATIC 23506042 A 631 634 αKG ABBREVIATION 23506042 A 689 692 αKG ABBREVIATION 23506042 A 989 992 αKG ABBREVIATION 23506042 T 44 59 α-Ketoglutarate TRIVIAL 23506253 A 514 523 n-butanol SYSTEMATIC 23506253 A 681 693 acetonitrile SYSTEMATIC 23506253 A 702 713 formic acid SYSTEMATIC 23506253 A 827 848 codonopyrrolidum A, B MULTIPLE 23506253 A 853 865 codonoside A TRIVIAL 23506253 A 970 988 codonopyrrolidum A TRIVIAL 23506316 A 1608 1615 diamond TRIVIAL 23506316 A 1621 1627 carbon SYSTEMATIC 23506316 A 1639 1654 silicon-nitride SYSTEMATIC 23506316 A 1662 1669 silicon SYSTEMATIC 23506316 A 1711 1718 diamond TRIVIAL 23506316 A 1823 1830 diamond TRIVIAL 23506316 A 1836 1842 carbon SYSTEMATIC 23506316 A 1920 1935 silicon nitride SYSTEMATIC 23506469 A 1080 1083 PBD ABBREVIATION 23506469 A 1172 1175 PBD ABBREVIATION 23506469 A 1228 1231 PBD ABBREVIATION 23506469 A 1337 1340 PBD ABBREVIATION 23506469 A 1485 1488 PBD ABBREVIATION 23506469 A 1510 1513 PBD ABBREVIATION 23506469 A 737 748 hydrocarbon FAMILY 23506469 A 871 886 poly(butadiene) FAMILY 23506469 A 888 891 PBD ABBREVIATION 23506469 A 961 970 thiol-ene FAMILY 23506469 T 112 127 Poly(butadiene) FAMILY 23506469 T 164 173 Thiol-ene FAMILY 23506559 A 1865 1872 glucose TRIVIAL 23506559 A 1988 1995 glucose TRIVIAL 23506559 A 371 386 phosphoric acid SYSTEMATIC 23506559 A 754 756 N2 FORMULA 23506857 A 1023 1028 ROOHs FAMILY 23506857 A 1030 1041 glutathione TRIVIAL 23506857 A 1043 1055 α-tocopherol TRIVIAL 23506857 A 1228 1233 MC-LR ABBREVIATION 23506857 A 507 512 MC-LR ABBREVIATION 23506857 A 717 731 hydroperoxides FAMILY 23506857 A 733 738 ROOHs FAMILY 23506857 A 741 753 α-tocopherol TRIVIAL 23506857 A 755 766 glutathione TRIVIAL 23506857 A 796 806 superoxide TRIVIAL 23506857 A 900 905 MC-LR ABBREVIATION 23506857 T 36 50 microcystin-LR TRIVIAL 23507752 A 0 12 Isoprostanes FAMILY 23507752 A 1127 1148 11β-prostaglandin F2α SYSTEMATIC 23507752 A 1216 1239 15(R)-prostaglandin F2α TRIVIAL 23507752 A 1309 1312 DOX ABBREVIATION 23507752 A 1317 1321 TBHP ABBREVIATION 23507752 A 239 262 8-iso prostaglandin F2α SYSTEMATIC 23507752 A 264 293 8-iso-15(R)-prostaglandin F2α SYSTEMATIC 23507752 A 295 316 11β-prostaglandin F2α SYSTEMATIC 23507752 A 318 341 15(R)-prostaglandin F2α TRIVIAL 23507752 A 36 52 arachidonic acid TRIVIAL 23507752 A 398 410 isoprostanes FAMILY 23507752 A 458 472 8-iso-PGF2α-d4 SYSTEMATIC 23507752 A 540 552 isoprostanes FAMILY 23507752 A 753 764 isoprostane FAMILY 23507752 A 819 843 tert-butyl hydroperoxide SYSTEMATIC 23507752 A 845 849 TBHP ABBREVIATION 23507752 A 910 921 doxorubicin TRIVIAL 23507752 A 923 926 DOX ABBREVIATION 23507752 T 103 127 Tert-Butyl Hydroperoxide SYSTEMATIC 23507752 T 26 38 Isoprostanes FAMILY 23507752 T 88 99 Doxorubicin TRIVIAL 23508306 A 1120 1127 glucose TRIVIAL 23508306 A 1157 1160 LPA ABBREVIATION 23508306 A 1208 1211 LPA ABBREVIATION 23508306 A 1284 1291 glucose TRIVIAL 23508306 A 1576 1583 glucose TRIVIAL 23508306 A 1661 1664 LPA ABBREVIATION 23508306 A 1696 1703 glucose TRIVIAL 23508306 A 17 38 Lysophosphatidic acid TRIVIAL 23508306 A 1780 1783 LPA ABBREVIATION 23508306 A 1803 1810 glucose TRIVIAL 23508306 A 226 229 LPA ABBREVIATION 23508306 A 307 314 glucose TRIVIAL 23508306 A 358 361 LPA ABBREVIATION 23508306 A 365 372 glucose TRIVIAL 23508306 A 40 43 LPA ABBREVIATION 23508306 A 445 452 glucose TRIVIAL 23508306 A 530 533 LPA ABBREVIATION 23508306 A 699 706 glucose TRIVIAL 23508306 A 729 736 Glucose TRIVIAL 23508306 A 799 806 glucose TRIVIAL 23508306 A 821 828 glucose TRIVIAL 23508306 A 946 949 LPA ABBREVIATION 23508306 A 967 974 glucose TRIVIAL 23508306 A 999 1006 glucose TRIVIAL 23508306 T 0 21 Lysophosphatidic acid TRIVIAL 23508306 T 30 37 glucose TRIVIAL 23508556 A 1025 1032 alcohol FAMILY 23508556 A 104 111 alcohol FAMILY 23508556 A 1083 1090 alcohol FAMILY 23508556 A 1107 1114 alcohol FAMILY 23508556 A 1242 1249 alcohol FAMILY 23508556 A 1387 1394 alcohol FAMILY 23508556 A 1599 1606 alcohol FAMILY 23508556 A 160 167 alcohol FAMILY 23508556 A 1708 1715 alcohol FAMILY 23508556 A 411 418 alcohol FAMILY 23508556 A 578 585 alcohol FAMILY 23508556 A 589 596 alcohol FAMILY 23508556 A 67 74 alcohol FAMILY 23508556 A 709 716 Alcohol SYSTEMATIC 23508556 A 837 844 alcohol FAMILY 23508556 T 130 137 alcohol FAMILY 23508556 T 141 148 alcohol FAMILY 23508963 A 1272 1283 sialic acid TRIVIAL 23508963 A 213 224 sialic acid TRIVIAL 23508963 A 341 352 sialic acid TRIVIAL 23508963 A 513 524 sialic acid TRIVIAL 23508963 A 876 887 sialic acid TRIVIAL 23508963 A 88 99 sialic acid TRIVIAL 23508963 T 20 31 Sialic Acid FAMILY 23509956 A 710 730 N-acetyl-glucosamine SYSTEMATIC 23510389 A 269 322 poly(acrylamidoethylamine)90-block-poly(dl-lactide)40 FAMILY 23510389 A 324 340 PAEA90-b-PDLLA40 ABBREVIATION 23510389 A 814 819 PDLLA ABBREVIATION 23510389 A 830 841 lactic acid TRIVIAL 23510441 A 1027 1036 phosphate SYSTEMATIC 23510441 A 1110 1118 selenium SYSTEMATIC 23510441 A 1195 1203 selenium SYSTEMATIC 23510441 A 309 315 oxygen SYSTEMATIC 23510441 A 464 472 selenide SYSTEMATIC 23510441 A 496 505 phosphate SYSTEMATIC 23510441 A 566 574 selenide SYSTEMATIC 23510441 A 615 623 selenone FAMILY 23510441 T 30 47 Hydrogen Peroxide SYSTEMATIC 23511020 A 218 230 sulfonamides FAMILY 23511020 A 271 283 sulfonamides FAMILY 23511020 A 348 361 acetazolamide TRIVIAL 23511020 A 379 420 4-substituted ureido-benzene-sulfonamides FAMILY 23511020 A 422 432 sulfamates FAMILY 23511020 A 437 447 sulfamides FAMILY 23511020 T 112 124 sulfonamides FAMILY 23511020 T 126 136 sulfamates FAMILY 23511020 T 141 151 sulfamides FAMILY 23511348 A 1114 1125 polystyrene SYSTEMATIC 23511715 A 11 21 artesunate TRIVIAL 23511715 A 126 129 ARS ABBREVIATION 23511715 A 23 26 ARS ABBREVIATION 23511715 A 310 313 ARS ABBREVIATION 23511715 A 318 336 dihydroartemisinin SYSTEMATIC 23511715 A 338 341 DHA ABBREVIATION 23511715 A 535 538 ARS ABBREVIATION 23511715 A 780 783 ARS ABBREVIATION 23511715 A 788 791 DHA ABBREVIATION 23511715 A 906 909 ARS ABBREVIATION 23511715 A 914 917 DHA ABBREVIATION 23511715 T 45 55 artesunate TRIVIAL 23511945 A 1128 1134 copper SYSTEMATIC 23511945 A 1397 1403 copper SYSTEMATIC 23511945 A 1495 1501 copper SYSTEMATIC 23511945 A 1569 1575 copper SYSTEMATIC 23511945 A 1624 1630 copper SYSTEMATIC 23511945 A 229 235 copper SYSTEMATIC 23511945 A 303 309 copper SYSTEMATIC 23511945 A 420 426 copper SYSTEMATIC 23511945 A 520 526 copper SYSTEMATIC 23511945 A 626 632 copper SYSTEMATIC 23511945 A 710 716 copper SYSTEMATIC 23511945 A 883 889 copper SYSTEMATIC 23511945 T 2 8 copper SYSTEMATIC 23512126 A 0 2 Pt FORMULA 23512126 A 11 13 Ti FORMULA 23512126 A 276 282 oxygen SYSTEMATIC 23512126 A 3 7 TiO2 FORMULA 23512126 A 8 10 Pt FORMULA 23512126 T 62 66 TiO2 FORMULA 23512495 A 161 172 artemisinin TRIVIAL 23512495 A 393 404 artemisinin TRIVIAL 23512495 A 440 451 artemisinin TRIVIAL 23512495 A 479 490 artemisinin TRIVIAL 23512495 A 576 587 artemisinin TRIVIAL 23512495 A 756 767 artemisinin TRIVIAL 23512495 A 837 848 artemisinin TRIVIAL 23512495 T 3 14 Artemisinin TRIVIAL 23512496 A 101 117 prenylflavanones FAMILY 23512496 A 170 188 8-prenylnaringenin SYSTEMATIC 23512496 A 190 194 8-PN SYSTEMATIC 23512496 A 359 363 8-PN SYSTEMATIC 23512496 A 687 695 estrogen FAMILY 23512496 A 708 712 8-PN SYSTEMATIC 23512496 A 859 863 8-PN SYSTEMATIC 23512499 A 1122 1132 Cardamonin TRIVIAL 23512499 A 1147 1161 2-deoxyglucose SYSTEMATIC 23512499 A 1246 1255 rapamycin TRIVIAL 23512499 A 1257 1267 cardamonin TRIVIAL 23512499 A 1318 1327 rapamycin TRIVIAL 23512499 A 1359 1362 Ser FORMULA 23512499 A 146 155 rapamycin TRIVIAL 23512499 A 1496 1499 Ser FORMULA 23512499 A 1628 1638 cardamonin TRIVIAL 23512499 A 1643 1652 rapamycin TRIVIAL 23512499 A 1681 1688 glucose TRIVIAL 23512499 A 1793 1803 cardamonin TRIVIAL 23512499 A 1854 1863 rapamycin TRIVIAL 23512499 A 1928 1937 rapamycin TRIVIAL 23512499 A 24 33 rapamycin TRIVIAL 23512499 A 368 378 cardamonin TRIVIAL 23512499 A 433 442 rapamycin TRIVIAL 23512499 A 586 593 glucose TRIVIAL 23512499 A 665 674 rapamycin TRIVIAL 23512499 A 733 740 glucose TRIVIAL 23512499 A 929 932 Ser FORMULA 23512499 T 0 10 Cardamonin TRIVIAL 23512499 T 75 82 Glucose TRIVIAL 23512501 A 1050 1061 artemisinin TRIVIAL 23512501 A 1246 1257 artemisinin TRIVIAL 23512501 A 1259 1275 deoxyartemisinin SYSTEMATIC 23512501 A 1365 1376 artemisinin TRIVIAL 23512501 A 1409 1416 NAD(P)H ABBREVIATION 23512501 A 1419 1426 quinone FAMILY 23512501 A 439 446 NAD(P)H ABBREVIATION 23512501 A 449 456 quinone FAMILY 23512501 A 625 632 NAD(P)H ABBREVIATION 23512501 A 635 642 quinone FAMILY 23512501 A 767 774 NAD(P)H ABBREVIATION 23512501 A 777 784 quinone FAMILY 23512501 T 0 7 NAD(P)H ABBREVIATION 23512501 T 10 17 Quinone FAMILY 23512535 A 1006 1009 DOX ABBREVIATION 23512535 A 1054 1057 GSH ABBREVIATION 23512535 A 1067 1070 GSH ABBREVIATION 23512535 A 1208 1211 MDA ABBREVIATION 23512535 A 1255 1262 ω-3 FAs FAMILY 23512535 A 1278 1281 DOX ABBREVIATION 23512535 A 1341 1344 GSH ABBREVIATION 23512535 A 1354 1357 GSH ABBREVIATION 23512535 A 1427 1430 DOX ABBREVIATION 23512535 A 1456 1462 ω-3 FA SYSTEMATIC 23512535 A 285 288 DOX ABBREVIATION 23512535 A 304 307 DOX ABBREVIATION 23512535 A 361 371 DOX-ω-3 FA SYSTEMATIC 23512535 A 391 398 ω-3 FAs FAMILY 23512535 A 478 481 DOX ABBREVIATION 23512535 A 54 69 ω-3 fatty acids FAMILY 23512535 A 686 697 Glutathione TRIVIAL 23512535 A 699 702 GSH ABBREVIATION 23512535 A 708 723 malondialdehyde TRIVIAL 23512535 A 71 74 FAs ABBREVIATION 23512535 A 725 728 MDA ABBREVIATION 23512535 A 750 753 GSH ABBREVIATION 23512535 A 758 761 MDA ABBREVIATION 23512535 A 773 783 superoxide TRIVIAL 23512535 A 79 90 doxorubicin TRIVIAL 23512535 A 804 815 glutathione TRIVIAL 23512535 A 828 831 GSH ABBREVIATION 23512535 A 92 95 DOX ABBREVIATION 23512535 A 953 956 MDA ABBREVIATION 23512535 T 26 41 ω-3 fatty acids FAMILY 23512535 T 45 56 doxorubicin TRIVIAL 23512537 A 1468 1471 BDP ABBREVIATION 23512537 A 1613 1616 BDP ABBREVIATION 23512537 A 33 60 beclomethasone dipropionate SYSTEMATIC 23512537 A 422 425 BDP ABBREVIATION 23512537 A 585 588 BDP ABBREVIATION 23512537 A 62 65 BDP ABBREVIATION 23512537 A 752 755 BDP ABBREVIATION 23512537 A 861 864 BDP ABBREVIATION 23512537 T 14 41 Beclomethasone Dipropionate SYSTEMATIC 23512538 A 1466 1470 zinc SYSTEMATIC 23512538 A 212 244 polycyclic aromatic hydrocarbons FAMILY 23512538 A 246 249 PAH ABBREVIATION 23512538 A 255 288 halogenated aromatic hydrocarbons FAMILY 23512538 A 303 338 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23512538 A 340 344 TCDD ABBREVIATION 23512538 A 4 20 Aryl Hydrocarbon FAMILY 23512538 A 851 855 TCDD ABBREVIATION 23512538 T 54 70 Aryl Hydrocarbon FAMILY 23512732 A 1020 1026 Sircol TRIVIAL 23512732 A 1076 1097 nitroblue tetrazolium TRIVIAL 23512732 A 1156 1160 EGCG ABBREVIATION 23512732 A 1311 1315 EGCG ABBREVIATION 23512732 A 1432 1436 EGCG ABBREVIATION 23512732 A 144 152 catechin TRIVIAL 23512732 A 171 201 (-)-epigallocatechin-3-gallate TRIVIAL 23512732 A 203 207 EGCG ABBREVIATION 23512732 A 373 377 EGCG ABBREVIATION 23512732 A 606 610 EGCG ABBREVIATION 23512732 A 623 629 oxygen SYSTEMATIC 23512732 A 774 778 EGCG ABBREVIATION 23512732 T 0 26 Epigallocatechin-3-Gallate SYSTEMATIC 23512787 A 0 8 Puerarin TRIVIAL 23512787 A 1072 1075 GSH ABBREVIATION 23512787 A 1118 1122 MPTP ABBREVIATION 23512787 A 205 213 puerarin TRIVIAL 23512787 A 338 346 puerarin TRIVIAL 23512787 A 358 402 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine SYSTEMATIC 23512787 A 404 408 MPTP ABBREVIATION 23512787 A 478 486 dopamine TRIVIAL 23512787 A 498 506 Puerarin TRIVIAL 23512787 A 531 542 glutathione TRIVIAL 23512787 A 544 547 GSH ABBREVIATION 23512787 A 677 681 MPTP ABBREVIATION 23512787 A 734 740 oxygen SYSTEMATIC 23512787 A 808 816 puerarin TRIVIAL 23512787 A 829 833 MPTP ABBREVIATION 23512787 A 951 959 puerarin TRIVIAL 23512787 A 971 975 MPTP ABBREVIATION 23512787 T 27 35 Puerarin TRIVIAL 23512787 T 39 83 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine SYSTEMATIC 23512804 A 104 115 amino acids FAMILY 23512804 A 1146 1152 valine TRIVIAL 23512804 A 637 638 C FORMULA 23512804 A 649 650 N FORMULA 23512804 A 665 666 C FORMULA 23512804 A 672 673 N FORMULA 23514279 A 1048 1057 kaolinite TRIVIAL 23514279 A 159 168 kaolinite TRIVIAL 23514279 A 298 302 H2O2 FORMULA 23514279 A 4 58 meso-tetra(2,6-dichloro-3-sulfonatophenyl)porphyrinate SYSTEMATIC 23514279 A 62 85 manganese(III) chloride SYSTEMATIC 23514279 A 86 101 [Mn-(TDCPPS)Cl] FORMULA 23514442 A 0 11 γ-Coniceine TRIVIAL 23514442 A 1013 1028 N-methylconiine SYSTEMATIC 23514442 A 13 20 coniine TRIVIAL 23514442 A 175 195 (+)- and (-)-coniine MULTIPLE 23514442 A 239 250 γ-coniceine TRIVIAL 23514442 A 26 41 N-methylconiine SYSTEMATIC 23514442 A 274 289 N-methylconiine SYSTEMATIC 23514442 A 332 343 γ-coniceine TRIVIAL 23514442 A 360 375 N-methylconiine SYSTEMATIC 23514442 A 442 462 piperidine alkaloids FAMILY 23514442 A 517 530 acetylcholine SYSTEMATIC 23514442 A 563 574 γ-coniceine TRIVIAL 23514442 A 577 596 (-)-N-methylconiine SYSTEMATIC 23514442 A 599 618 (±)-N-methylconiine SYSTEMATIC 23514442 A 621 640 (+)-N-methylconiine SYSTEMATIC 23514442 A 670 681 γ-coniceine TRIVIAL 23514442 A 686 721 (-)-, (±)-, and (+)-N-methylconiine MULTIPLE 23514442 A 841 852 γ-coniceine TRIVIAL 23514442 A 902 917 N-methylconiine SYSTEMATIC 23514442 T 53 64 γ-Coniceine TRIVIAL 23514442 T 69 84 N-Methylconiine SYSTEMATIC 23514447 A 103 113 CexZr1-xO2 FAMILY 23514447 A 1194 1197 CZO ABBREVIATION 23514447 A 1249 1252 CZO ABBREVIATION 23514447 A 133 136 CZO ABBREVIATION 23514447 A 294 298 CeO2 FORMULA 23514447 A 303 307 ZrO2 FORMULA 23514447 A 384 387 KLE FAMILY 23514447 A 802 808 oxygen SYSTEMATIC 23514447 A 87 101 ceria-zirconia SYSTEMATIC 23514447 A 903 907 CeO2 FORMULA 23514447 A 908 912 ZrO2 FORMULA 23514447 T 101 107 Oxygen SYSTEMATIC 23514447 T 20 25 Oxide SYSTEMATIC 23514537 A 1259 1270 cholesterol TRIVIAL 23514537 A 1275 1278 GM1 ABBREVIATION 23514537 A 1575 1578 PSM ABBREVIATION 23514537 A 1654 1665 cholesterol TRIVIAL 23514537 A 1671 1675 DOPC ABBREVIATION 23514537 A 1681 1684 GM1 ABBREVIATION 23514537 A 1720 1723 GM1 ABBREVIATION 23514537 A 1810 1821 cholesterol TRIVIAL 23514537 A 1827 1830 PSM ABBREVIATION 23514537 A 1836 1840 DOPC ABBREVIATION 23514537 A 395 406 cholesterol TRIVIAL 23514537 A 450 465 ganglioside GM1 TRIVIAL 23514537 A 633 656 palmitoyl sphingomyelin TRIVIAL 23514537 A 658 661 PSM ABBREVIATION 23514537 A 664 675 cholesterol TRIVIAL 23514537 A 703 730 dioleoylphosphatidylcholine TRIVIAL 23514537 A 732 736 DOPC ABBREVIATION 23514537 A 825 828 GM1 ABBREVIATION 23514537 T 22 37 Ganglioside GM1 TRIVIAL 23514537 T 42 53 Cholesterol TRIVIAL 23514637 A 147 166 malonate half-ester SYSTEMATIC 23514637 A 374 386 methyl ester SYSTEMATIC 23514637 A 59 71 cheilanthane TRIVIAL 23514637 A 72 85 sesterterpene FAMILY 23514637 T 100 113 Sesterterpene FAMILY 23514637 T 40 96 Methyl (3R)-Malonyl-(13S)-hydroxycheilanth-17-en-19-oate SYSTEMATIC 23514973 A 138 150 PdCl2(X2Py)2 FAMILY 23514973 A 162 164 Py FORMULA 23514973 A 165 173 pyridine SYSTEMATIC 23514973 A 181 184 CH3 FORMULA 23514973 A 188 190 Cl FORMULA 23514973 A 208 211 MTT ABBREVIATION 23514973 A 30 32 Pd FORMULA 23514973 A 309 321 PdCl2(XnPy)2 FAMILY 23514973 A 37 39 Pt FORMULA 23514973 A 469 481 PdCl2(XnPy)2 FAMILY 23514973 A 58 71 palladium(II) SYSTEMATIC 23514973 A 583 589 Pd(II) FORMULA 23514973 T 23 29 Pd(II) FORMULA 23514973 T 45 78 mono- and disubstituted pyridines MULTIPLE 23515287 A 0 12 Testosterone TRIVIAL 23515287 A 1056 1063 3β-Diol SYSTEMATIC 23515287 A 1177 1184 3β-diol SYSTEMATIC 23515287 A 1324 1331 3β-diol SYSTEMATIC 23515287 A 1427 1434 3β-diol SYSTEMATIC 23515287 A 1628 1635 3β-diol SYSTEMATIC 23515287 A 1665 1672 3β-diol SYSTEMATIC 23515287 A 390 398 androgen FAMILY 23515287 A 503 515 testosterone TRIVIAL 23515287 A 571 590 dihydrotestosterone SYSTEMATIC 23515287 A 603 628 5α-androstane-3β,17β-diol SYSTEMATIC 23515287 A 630 637 3β-diol SYSTEMATIC 23515287 A 660 668 estrogen FAMILY 23515287 A 756 764 oxytocin TRIVIAL 23515287 A 812 819 3β-diol SYSTEMATIC 23515287 A 907 925 estradiol benzoate SYSTEMATIC 23515287 A 929 936 3β-diol SYSTEMATIC 23515287 T 105 113 Estrogen FAMILY 23515287 T 25 50 5α-Androstane-3β,17β-Diol SYSTEMATIC 23515287 T 4 12 Androgen FAMILY 23515287 T 52 59 3β-Diol SYSTEMATIC 23515287 T 76 84 Oxytocin TRIVIAL 23515498 A 1325 1328 MDA ABBREVIATION 23515498 A 1566 1569 MDA ABBREVIATION 23515498 A 233 248 malondialdehyde TRIVIAL 23515498 A 250 253 MDA ABBREVIATION 23515498 A 415 418 MDA ABBREVIATION 23515498 A 607 613 Fe(2+) FORMULA 23515498 A 625 634 ascorbate TRIVIAL 23515498 A 672 675 MDA ABBREVIATION 23515498 A 737 746 vitamin E FAMILY 23515940 A 0 11 Zearalenone TRIVIAL 23515940 A 1033 1039 Ca(2+) FORMULA 23515940 A 1041 1052 Zearalenone TRIVIAL 23515940 A 1147 1153 Ca(2+) FORMULA 23515940 A 469 475 Ca(2+) FORMULA 23515940 A 487 493 Ca(2+) FORMULA 23515940 A 533 544 zearalenone TRIVIAL 23515940 A 739 745 Ca(2+) FORMULA 23515940 A 753 758 Fluo3 TRIVIAL 23515940 A 792 803 zearalenone TRIVIAL 23515940 A 856 862 Ca(2+) FORMULA 23515940 T 0 6 Ca(2+) FORMULA 23515940 T 54 65 zearalenone TRIVIAL 23515941 A 0 12 Ochratoxin A TRIVIAL 23515941 A 1097 1100 OTA ABBREVIATION 23515941 A 1145 1164 N-acetyl-L-cysteine SYSTEMATIC 23515941 A 1166 1169 NAC ABBREVIATION 23515941 A 1183 1186 OTA ABBREVIATION 23515941 A 1297 1300 OTA ABBREVIATION 23515941 A 14 17 OTA ABBREVIATION 23515941 A 157 160 OTA ABBREVIATION 23515941 A 356 359 OTA ABBREVIATION 23515941 A 444 450 oxygen SYSTEMATIC 23515941 A 533 536 OTA ABBREVIATION 23515941 A 601 604 OTA ABBREVIATION 23515941 A 715 721 8-OHdG SYSTEMATIC 23515941 A 790 793 OTA ABBREVIATION 23515941 T 36 48 ochratoxin A TRIVIAL 23516041 A 265 290 adenosine triphosphophate SYSTEMATIC 23517076 A 610 620 gentamicin FAMILY 23517076 A 653 659 oxygen SYSTEMATIC 23517076 A 883 893 gentamicin FAMILY 23517076 T 11 21 Gentamicin FAMILY 23517076 T 54 60 Oxygen SYSTEMATIC 23517243 A 1078 1081 PTU ABBREVIATION 23517243 A 1740 1755 thyroid hormone FAMILY 23517243 A 338 354 triiodothyronine TRIVIAL 23517243 A 468 474 iodine SYSTEMATIC 23517243 A 505 521 propylthiouracil SYSTEMATIC 23517243 A 523 526 PTU ABBREVIATION 23517243 A 558 561 PTU ABBREVIATION 23517243 A 912 915 PTU ABBREVIATION 23517243 A 980 983 PTU ABBREVIATION 23517381 A 361 365 urea TRIVIAL 23517381 A 368 373 GdmCl FORMULA 23517381 A 438 442 urea TRIVIAL 23517381 A 577 581 urea TRIVIAL 23517381 A 621 625 urea TRIVIAL 23517381 A 64 68 urea TRIVIAL 23517381 A 73 93 guanidinium chloride SYSTEMATIC 23517381 A 735 739 urea TRIVIAL 23517381 A 95 100 GdmCl FORMULA 23517437 A 1052 1055 PAA ABBREVIATION 23517437 A 1056 1069 methacrylates FAMILY 23517437 A 1246 1252 pyrene SYSTEMATIC 23517437 A 1337 1350 methacrylates FAMILY 23517437 A 1470 1473 PAA ABBREVIATION 23517437 A 1474 1487 methacrylates FAMILY 23517437 A 688 706 poly(acrylic acid) SYSTEMATIC 23517437 A 708 711 PAA ABBREVIATION 23517437 A 750 761 methacrylic TRIVIAL 23517437 A 850 864 polyacrylamide SYSTEMATIC 23517479 A 1005 1013 morphine TRIVIAL 23517479 A 378 389 mitragynine TRIVIAL 23517479 A 38 46 morphine TRIVIAL 23517479 A 391 521 (E)-2-[(2S,3S)-3-ethyl-8-methoxy-1,2,3,4,6,7,12,12b-octahydroindolo[3,2-h]quinolizin-2-yl]-3-methoxyprop-2-enoic acid methyl ester SYSTEMATIC 23517479 A 523 547 9-methoxy coryantheidine SYSTEMATIC 23517479 A 557 577 7-hydroxymitragynine SYSTEMATIC 23517479 A 579 586 7-OH-MG SYSTEMATIC 23517479 A 952 960 naloxone TRIVIAL 23517558 A 1244 1251 AMG 221 IDENTIFIER 23517558 A 145 152 AMG 221 IDENTIFIER 23517558 A 361 368 AMG 221 IDENTIFIER 23517558 A 741 756 [(14)C] AMG 221 SYSTEMATIC 23517558 A 776 783 AMG 221 IDENTIFIER 23517558 T 71 78 AMG 221 IDENTIFIER 23517726 A 119 155 2-thiophenecarboxylic acid hydrazide SYSTEMATIC 23517726 A 179 192 ethyl alcohol SYSTEMATIC 23517726 A 217 235 thiosemicarbazides FAMILY 23517726 A 276 292 sodium hydroxide SYSTEMATIC 23517726 A 312 319 ethanol SYSTEMATIC 23517726 A 330 338 triazole FAMILY 23517726 A 401 417 secondary amines FAMILY 23517726 A 422 434 formaldehyde SYSTEMATIC 23517726 A 456 469 Mannich bases FAMILY 23517726 A 559 564 (13)C FORMULA 23517726 A 569 573 (1)H FORMULA 23517726 A 92 106 isothiocyanate FAMILY 23517726 T 50 61 aminomethyl SYSTEMATIC 23517726 T 77 144 4-substituted-5-(2-thienyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones FAMILY 23517728 A 1024 1038 oxyiminomethyl SYSTEMATIC 23517728 A 1071 1083 camptothecin TRIVIAL 23517728 A 143 172 diaminedichloro-platinum (II) SYSTEMATIC 23517728 A 318 327 topotecan TRIVIAL 23517728 A 332 340 platinum SYSTEMATIC 23517728 A 469 478 cisplatin TRIVIAL 23517728 A 529 537 Platinum SYSTEMATIC 23517728 A 549 562 camptothecins FAMILY 23517728 A 572 580 platinum SYSTEMATIC 23517728 A 682 686 SN38 IDENTIFIER 23517728 A 712 722 irinotecan TRIVIAL 23517728 A 846 856 irinotecan TRIVIAL 23517728 A 909 918 cisplatin TRIVIAL 23517728 A 968 997 diaminedichloro-platinum (II) SYSTEMATIC 23517728 A 98 126 7-oxyiminomethylcamptothecin SYSTEMATIC 23517728 T 66 78 camptothecin TRIVIAL 23517728 T 86 94 platinum SYSTEMATIC 23517784 A 1185 1190 DOTAP ABBREVIATION 23517784 A 1191 1195 Chol ABBREVIATION 23517784 A 21 27 silica TRIVIAL 23517784 A 405 446 1, 2-Dioleoyl-3-Trimethylammonium-Propane SYSTEMATIC 23517784 A 448 453 DOTAP ABBREVIATION 23517784 A 455 466 cholesterol TRIVIAL 23517784 A 468 473 DOTAP ABBREVIATION 23517784 A 474 478 Chol ABBREVIATION 23517784 T 11 17 silica TRIVIAL 23517910 A 1094 1102 nicotine TRIVIAL 23517910 A 152 160 nicotine TRIVIAL 23517910 A 208 222 N-nitrosamines FAMILY 23517910 A 482 490 nicotine TRIVIAL 23517910 A 571 579 nicotine TRIVIAL 23517910 A 594 602 nicotine TRIVIAL 23517910 A 685 693 nicotine TRIVIAL 23517910 A 800 808 nicotine TRIVIAL 23517910 T 124 138 N-nitrosamines FAMILY 23517910 T 67 75 nicotine TRIVIAL 23517910 T 94 102 nicotine TRIVIAL 23518278 A 122 131 arylamine FAMILY 23518278 A 132 133 N FORMULA 23518278 A 210 234 1 3,5-diaryl-1H-pyrazole FAMILY 23518278 A 60 83 3,5-diaryl-1H-pyrazoles FAMILY 23518278 T 109 110 N FORMULA 23518278 T 58 81 3,5-diaryl-1H-pyrazoles FAMILY 23518278 T 99 108 arylamine FAMILY 23518413 A 1099 1106 glucose TRIVIAL 23518413 A 1222 1225 ser FORMULA 23518413 A 1409 1420 mitomycin C TRIVIAL 23518413 A 651 657 serine TRIVIAL 23518413 A 665 672 alanine TRIVIAL 23518413 A 680 683 ATP ABBREVIATION 23518662 A 299 307 n-octane SYSTEMATIC 23518662 A 312 320 n-nonane SYSTEMATIC 23518662 A 38 47 n-alkanes FAMILY 23518662 A 661 669 n-octane SYSTEMATIC 23518662 T 58 66 n-alkane FAMILY 23519365 A 174 179 Au-Au FORMULA 23519365 A 194 199 Au-Ag FORMULA 23519365 A 353 358 Au-Au FORMULA 23519365 A 375 380 Au-Ag FORMULA 23519365 A 500 502 Au FORMULA 23519365 A 588 593 Au-Ag FORMULA 23519365 A 676 681 Au-Au FORMULA 23519392 A 1028 1039 cholesterol TRIVIAL 23519392 A 1080 1091 cholesterol TRIVIAL 23519392 A 1149 1159 Amprenavir TRIVIAL 23519392 A 331 339 pregnane TRIVIAL 23519392 A 595 605 amprenavir TRIVIAL 23519392 A 847 857 amprenavir TRIVIAL 23519392 A 859 869 Amprenavir TRIVIAL 23519392 A 980 990 amprenavir TRIVIAL 23519392 T 0 8 Pregnane TRIVIAL 23519392 T 80 90 Amprenavir TRIVIAL 23520133 A 1021 1028 glucose TRIVIAL 23520133 A 407 418 sialic acid TRIVIAL 23520133 A 52 63 sialic acid TRIVIAL 23521080 A 263 278 tranexamic acid TRIVIAL 23521080 A 280 283 TXA ABBREVIATION 23521080 A 298 304 lysine TRIVIAL 23521080 A 384 387 TXA ABBREVIATION 23521080 A 576 579 TXA ABBREVIATION 23521080 A 672 700 5-(4-piperidyl)-3-isoxazolol SYSTEMATIC 23521080 A 702 708 4-PIOL SYSTEMATIC 23521080 A 832 838 4-PIOL SYSTEMATIC 23521080 A 898 901 TXA ABBREVIATION 23521080 T 96 111 tranexamic Acid TRIVIAL 23521110 A 289 300 scutellarin TRIVIAL 23521110 A 960 968 hydrogen SYSTEMATIC 23521110 T 0 11 Scutellarin TRIVIAL 23521132 A 21 31 tripeptide FAMILY 23521132 A 93 122 ruthenium(II)tris(bipyridine) SYSTEMATIC 23522834 A 134 152 dihydropteridinone SYSTEMATIC 23523257 A 0 7 Tacrine TRIVIAL 23523257 A 398 404 oxygen SYSTEMATIC 23523257 A 484 491 tacrine TRIVIAL 23523257 A 608 615 tacrine TRIVIAL 23523257 A 659 665 8-OHdG SYSTEMATIC 23523257 A 831 838 tacrine TRIVIAL 23523257 A 9 12 THA ABBREVIATION 23523257 A 983 990 tacrine TRIVIAL 23523257 T 44 51 tacrine TRIVIAL 23523545 A 0 25 Poly-lactide-co-glycolide FAMILY 23523545 A 1497 1501 PLGA ABBREVIATION 23523545 A 27 31 PLGA ABBREVIATION 23523545 A 346 350 PLGA ABBREVIATION 23523545 A 400 404 PLGA ABBREVIATION 23523545 A 685 689 PLGA ABBREVIATION 23523664 A 108 116 steroids FAMILY 23523664 A 1259 1267 GLPG0492 IDENTIFIER 23523664 A 1273 1277 NAND ABBREVIATION 23523664 A 159 167 GLPG0492 IDENTIFIER 23523664 A 1691 1699 GLPG0492 IDENTIFIER 23523664 A 199 207 androgen FAMILY 23523664 A 326 334 GLPG0492 IDENTIFIER 23523664 A 522 542 α-methylprednisolone SYSTEMATIC 23523664 A 544 547 PDN ABBREVIATION 23523664 A 567 577 nandrolone TRIVIAL 23523664 A 579 583 NAND ABBREVIATION 23523664 A 799 802 PDN ABBREVIATION 23523664 A 807 811 NAND ABBREVIATION 23523664 A 813 821 GLPG0492 IDENTIFIER 23523664 A 949 957 GLPG0492 IDENTIFIER 23523664 T 0 8 GLPG0492 IDENTIFIER 23523664 T 28 36 androgen FAMILY 23523665 A 1082 1085 DBM ABBREVIATION 23523665 A 113 130 hydrogen peroxide SYSTEMATIC 23523665 A 1234 1250 poly(ADP-ribose) SYSTEMATIC 23523665 A 234 238 ABTS ABBREVIATION 23523665 A 295 312 poly(ADP-ribosyl) FAMILY 23523665 A 409 425 dibenzoylmethane SYSTEMATIC 23523665 A 427 430 DBM ABBREVIATION 23523665 A 502 519 hydrogen peroxide SYSTEMATIC 23523665 A 690 707 Hydrogen peroxide SYSTEMATIC 23523665 A 799 800 N FORMULA 23523665 A 843 847 DBMs FAMILY 23523665 T 15 31 dibenzoylmethane SYSTEMATIC 23523950 A 0 10 Avermectin TRIVIAL 23523950 A 1025 1028 AVM ABBREVIATION 23523950 A 1038 1044 Ca(2+) FORMULA 23523950 A 1138 1152 cyclosporine A TRIVIAL 23523950 A 1184 1187 AVM ABBREVIATION 23523950 A 12 15 AVM ABBREVIATION 23523950 A 1210 1216 Ca(2+) FORMULA 23523950 A 1244 1250 Ca(2+) FORMULA 23523950 A 1297 1312 trifluoperazine TRIVIAL 23523950 A 1342 1373 pyrrolidine dithiocarbamic acid SYSTEMATIC 23523950 A 1410 1413 AVM ABBREVIATION 23523950 A 1458 1461 AVM ABBREVIATION 23523950 A 176 179 ATP ABBREVIATION 23523950 A 307 310 AVM ABBREVIATION 23523950 A 34 41 lactone FAMILY 23523950 A 380 383 AVM ABBREVIATION 23523950 A 447 450 AVM ABBREVIATION 23523950 A 582 595 rhodamine 123 TRIVIAL 23523950 A 638 641 AVM ABBREVIATION 23523950 A 707 714 calcium SYSTEMATIC 23523950 A 731 737 Ca(2+) FORMULA 23523950 A 785 792 calcium SYSTEMATIC 23523950 A 837 845 chloride SYSTEMATIC 23523950 A 913 922 verapamil TRIVIAL 23523950 A 926 932 Ca(2+) FORMULA 23523950 A 954 967 niflumic acid TRIVIAL 23523950 A 971 979 chloride SYSTEMATIC 23523950 T 0 10 Avermectin TRIVIAL 23523950 T 65 72 calcium SYSTEMATIC 23523951 A 0 9 Gefitinib TRIVIAL 23523951 A 1147 1156 gefitinib TRIVIAL 23523951 A 1239 1256 poly (ADP-ribose) SYSTEMATIC 23523951 A 13 21 tyrosine TRIVIAL 23523951 A 1453 1462 gefitinib TRIVIAL 23523951 A 1595 1604 gefitinib TRIVIAL 23523951 A 198 207 gefitinib TRIVIAL 23523951 A 325 334 Gefitinib TRIVIAL 23523951 A 489 498 gefitinib TRIVIAL 23523951 A 890 899 gefitinib TRIVIAL 23523951 T 43 52 gefitinib TRIVIAL 23523965 A 1070 1076 copper SYSTEMATIC 23523965 A 224 230 copper SYSTEMATIC 23523965 A 346 352 copper SYSTEMATIC 23523965 A 471 477 oxygen SYSTEMATIC 23523965 A 558 562 BrdU ABBREVIATION 23523965 A 727 733 copper SYSTEMATIC 23523965 A 776 782 copper SYSTEMATIC 23523965 A 941 945 BrdU ABBREVIATION 23523965 T 0 6 Copper SYSTEMATIC 23523965 T 53 59 oxygen SYSTEMATIC 23524112 A 100 121 (R)-2-amino-1-butanol SYSTEMATIC 23524112 A 291 303 acylthiourea SYSTEMATIC 23524112 A 41 45 urea TRIVIAL 23524112 A 47 55 thiourea SYSTEMATIC 23524112 A 60 72 acylthiourea SYSTEMATIC 23524112 T 27 48 (R)-2-amino-1-butanol SYSTEMATIC 23524112 T 57 62 ureas FAMILY 23524112 T 64 73 thioureas FAMILY 23524112 T 78 91 acylthioureas FAMILY 23524238 A 1153 1163 oxysterols FAMILY 23524238 A 1168 1179 glutathione TRIVIAL 23524253 A 1255 1259 P188 IDENTIFIER 23524253 A 1263 1267 P407 IDENTIFIER 23524253 A 522 548 poloxamers (P407 and P188) MULTIPLE 23524255 A 503 517 hydroxyapatite TRIVIAL 23524255 A 553 562 phosphate SYSTEMATIC 23524255 A 974 983 phosphate SYSTEMATIC 23524316 A 1118 1119 N FORMULA 23524316 A 570 581 cholesterol TRIVIAL 23524316 A 623 635 triglyceride FAMILY 23524316 A 640 647 glucose TRIVIAL 23524316 A 69 78 quercetin TRIVIAL 23524316 T 10 19 quercetin TRIVIAL 23524567 A 360 368 platinum SYSTEMATIC 23524878 A 1057 1064 ferrous SYSTEMATIC 23524878 A 1299 1303 iron SYSTEMATIC 23524878 A 1435 1439 iron SYSTEMATIC 23524878 A 245 249 iron SYSTEMATIC 23524878 A 28 32 iron SYSTEMATIC 23524878 A 305 309 iron SYSTEMATIC 23524878 A 355 359 iron SYSTEMATIC 23524878 A 42 46 iron SYSTEMATIC 23524878 A 438 447 bilirubin TRIVIAL 23524878 A 556 560 iron SYSTEMATIC 23524878 A 660 668 methanol SYSTEMATIC 23524878 A 761 765 iron SYSTEMATIC 23524878 A 951 955 iron SYSTEMATIC 23524878 T 16 20 iron SYSTEMATIC 23524878 T 81 85 iron SYSTEMATIC 23524881 A 1096 1103 mercury SYSTEMATIC 23524881 A 1246 1253 mercury SYSTEMATIC 23524881 A 64 71 mercury SYSTEMATIC 23524881 A 924 931 mercury SYSTEMATIC 23524881 A 940 954 Methyl mercury SYSTEMATIC 23524881 T 29 36 mercury SYSTEMATIC 23525110 A 1051 1056 dNTPs ABBREVIATION 23525110 A 384 394 nucleotide FAMILY 23525110 A 483 487 dNTP ABBREVIATION 23525110 A 547 551 dNTP ABBREVIATION 23525110 A 585 589 dNTP ABBREVIATION 23525110 A 606 611 MgCl2 FORMULA 23525110 A 658 668 nucleotide FAMILY 23525110 A 898 902 dNTP ABBREVIATION 23525110 A 932 942 nucleotide FAMILY 23525110 A 965 975 nucleotide FAMILY 23525110 A 993 998 dNTPs ABBREVIATION 23525110 T 0 4 dNTP ABBREVIATION 23525110 T 126 136 nucleotide FAMILY 23525158 A 1012 1020 chloride SYSTEMATIC 23525158 A 1022 1027 Cl(-) FORMULA 23525158 A 1086 1088 Pt FORMULA 23525158 A 1092 1095 PPy ABBREVIATION 23525158 A 1196 1209 ascorbic acid TRIVIAL 23525158 A 1216 1225 uric acid TRIVIAL 23525158 A 1236 1253 4-acetamidophenol SYSTEMATIC 23525158 A 1277 1279 Pt FORMULA 23525158 A 1283 1286 PPy ABBREVIATION 23525158 A 1334 1342 methanol SYSTEMATIC 23525158 A 134 136 Pt FORMULA 23525158 A 1372 1378 oxygen SYSTEMATIC 23525158 A 1432 1434 CO FORMULA 23525158 A 1493 1495 Pt FORMULA 23525158 A 1496 1497 C FORMULA 23525158 A 1543 1545 Pt FORMULA 23525158 A 1549 1552 PPy ABBREVIATION 23525158 A 1577 1579 Pt FORMULA 23525158 A 24 26 Pt FORMULA 23525158 A 242 262 Polyvinylpyrrolidone FAMILY 23525158 A 264 267 PVP ABBREVIATION 23525158 A 40 43 PPy ABBREVIATION 23525158 A 461 463 Pt FORMULA 23525158 A 508 511 PPy ABBREVIATION 23525158 A 653 655 Pt FORMULA 23525158 A 732 734 Pt FORMULA 23525158 A 78 80 Pt FORMULA 23525158 A 826 828 Pt FORMULA 23525158 A 832 835 PPy ABBREVIATION 23525158 A 84 87 PPy ABBREVIATION 23525158 A 898 905 glucose TRIVIAL 23525158 T 37 39 Pt FORMULA 23525221 A 138 149 fatty acids FAMILY 23525221 A 608 612 GnRH ABBREVIATION 23525221 A 689 693 GnRH ABBREVIATION 23525221 T 5 16 fatty acids FAMILY 23525298 A 464 467 ZnS FORMULA 23525298 A 486 490 CdSe FORMULA 23525298 A 491 494 ZnS FORMULA 23525298 A 499 503 CdTe FORMULA 23525298 A 641 651 lanthanide FAMILY 23525512 A 0 12 Polyurethane FAMILY 23525512 A 1160 1194 2,2,3,3-tetrafluoro-1,4-butanediol SYSTEMATIC 23525512 A 117 119 HO FORMULA 23525512 A 120 135 tertiary amines FAMILY 23525512 A 1350 1378 diphenylmethane diisocyanate SYSTEMATIC 23525512 A 1383 1405 polyoxyethylene glycol FAMILY 23525512 A 139 144 diols FAMILY 23525512 A 260 272 polyurethane SYSTEMATIC 23525512 A 299 303 (1)H FORMULA 23525512 A 488 498 isocyanate SYSTEMATIC 23525512 A 547 560 polyurethanes FAMILY 23525512 A 66 79 diisocyanates FAMILY 23525512 A 81 90 polyether SYSTEMATIC 23525512 A 913 925 polyurethane SYSTEMATIC 23525512 A 95 112 polyester polyols FAMILY 23525512 T 116 128 polyurethane SYSTEMATIC 23525512 T 48 60 polyurethane SYSTEMATIC 23525522 A 1126 1130 HPMA ABBREVIATION 23525522 A 1250 1254 HPMA ABBREVIATION 23525522 A 313 346 poly(2-hydroxyethyl methacrylate) FAMILY 23525522 A 348 353 pHEMA ABBREVIATION 23525522 A 385 399 hydroxyapatite TRIVIAL 23525522 A 400 422 β-tricalcium phosphate SYSTEMATIC 23525522 A 534 567 N, O-dimethacryloyl hydroxylamine SYSTEMATIC 23525522 A 656 665 phosphate SYSTEMATIC 23525522 A 768 780 acrylic acid TRIVIAL 23525522 A 789 819 2-hydroxypropyl methacrylamide SYSTEMATIC 23525522 A 821 825 HPMA ABBREVIATION 23525522 A 942 946 HPMA ABBREVIATION 23525522 T 17 22 pHEMA ABBREVIATION 23525522 T 31 37 β -TCP ABBREVIATION 23526664 A 0 9 Phosphate SYSTEMATIC 23526664 A 1247 1261 nicotinic acid TRIVIAL 23526664 A 1308 1320 nicotinamide TRIVIAL 23526664 A 1327 1341 nicotinic acid TRIVIAL 23526664 A 1346 1358 nicotinamide TRIVIAL 23526664 A 1406 1416 phosphorus SYSTEMATIC 23526664 A 173 187 nicotinic acid TRIVIAL 23526664 A 233 243 phosphorus SYSTEMATIC 23526664 A 309 319 phosphorus SYSTEMATIC 23526664 A 450 456 niacin TRIVIAL 23526664 A 499 509 phosphorus SYSTEMATIC 23526664 A 560 566 niacin TRIVIAL 23526664 A 568 582 nicotinic acid TRIVIAL 23526664 A 584 595 niacinamide TRIVIAL 23526664 A 597 609 nicotinamide TRIVIAL 23526664 T 0 14 Nicotinic Acid TRIVIAL 23526664 T 19 31 Nicotinamide TRIVIAL 23526725 A 1021 1030 genistein TRIVIAL 23526725 A 1032 1042 coumestrol TRIVIAL 23526725 A 1046 1054 daidzein TRIVIAL 23526725 A 1147 1157 coumestrol TRIVIAL 23526725 A 1194 1202 estrogen FAMILY 23526725 A 1214 1223 ICI182780 IDENTIFIER 23526725 A 1370 1378 estrogen FAMILY 23526725 A 1421 1432 resveratrol TRIVIAL 23526725 A 1436 1446 coumestrol TRIVIAL 23526725 A 1456 1465 genistein TRIVIAL 23526725 A 497 517 manganese superoxide SYSTEMATIC 23526725 A 569 580 resveratrol TRIVIAL 23526725 A 582 592 coumestrol TRIVIAL 23526725 A 594 604 kaempferol TRIVIAL 23526725 A 606 615 genistein TRIVIAL 23526725 A 617 625 daidzein TRIVIAL 23526725 A 627 635 apigenin TRIVIAL 23526725 A 637 653 isoliquirtigenin TRIVIAL 23526725 A 658 666 glycitin TRIVIAL 23526725 A 778 789 resveratrol TRIVIAL 23526725 A 791 801 coumestrol TRIVIAL 23526725 A 803 813 kaempferol TRIVIAL 23526725 A 815 824 genistein TRIVIAL 23526725 A 829 837 daidzein TRIVIAL 23526725 A 941 958 hydrogen peroxide SYSTEMATIC 23526725 T 82 102 Manganese Superoxide SYSTEMATIC 23527529 A 1014 1023 midazolam TRIVIAL 23527529 A 1076 1083 IPI-926 IDENTIFIER 23527529 A 1168 1175 IPI-926 IDENTIFIER 23527529 A 12 19 IPI-926 IDENTIFIER 23527529 A 202 209 IPI-926 IDENTIFIER 23527529 A 45 56 cyclopamine TRIVIAL 23527529 A 549 556 IPI-926 IDENTIFIER 23527529 A 869 876 IPI-926 IDENTIFIER 23527529 A 942 954 testosterone TRIVIAL 23527529 A 957 964 IPI-926 IDENTIFIER 23527529 T 82 89 IPI-926 IDENTIFIER 23527615 A 1146 1161 2-oxo-prasugrel SYSTEMATIC 23527615 A 1207 1219 ethanolamine SYSTEMATIC 23527615 A 1224 1228 CPDH ABBREVIATION 23527615 A 1274 1278 (1)H FORMULA 23527615 A 1283 1288 (13)C FORMULA 23527615 A 1390 1393 H2O FORMULA 23527615 A 1400 1405 amine SYSTEMATIC 23527615 A 1413 1415 CO FORMULA 23527615 A 1416 1422 carbon SYSTEMATIC 23527615 A 1443 1464 thiolactone sulfoxide SYSTEMATIC 23527615 A 1594 1600 thiols FAMILY 23527615 A 1812 1817 thiol FAMILY 23527615 A 1832 1843 clopidogrel TRIVIAL 23527615 A 1913 1919 thiols FAMILY 23527615 A 1971 1993 thiolactone sulfoxides FAMILY 23527615 A 2054 2065 clopidogrel TRIVIAL 23527615 A 2070 2079 prasugrel TRIVIAL 23527615 A 211 222 thiolactone SYSTEMATIC 23527615 A 27 51 tetrahydrothienopyridine SYSTEMATIC 23527615 A 307 318 thiolactone SYSTEMATIC 23527615 A 351 364 sulfenic acid SYSTEMATIC 23527615 A 422 427 thiol FAMILY 23527615 A 461 474 sulfenic acid SYSTEMATIC 23527615 A 552 573 thiolactone sulfoxide SYSTEMATIC 23527615 A 60 71 clopidogrel TRIVIAL 23527615 A 619 630 thiolactone SYSTEMATIC 23527615 A 76 85 prasugrel TRIVIAL 23527615 A 789 811 thiolactone sulfoxides FAMILY 23527615 A 848 854 amines FAMILY 23527615 A 856 862 thiols FAMILY 23527615 A 867 889 cyclopentane-1,3-dione SYSTEMATIC 23527615 A 891 895 CPDH ABBREVIATION 23527615 A 915 923 dimedone TRIVIAL 23527615 A 942 955 sulfenic acid SYSTEMATIC 23527615 T 0 22 Thiolactone Sulfoxides FAMILY 23527615 T 111 120 Prasugrel TRIVIAL 23527615 T 95 106 Clopidogrel TRIVIAL 23527691 A 1032 1038 oxygen SYSTEMATIC 23527691 A 1139 1145 oxygen SYSTEMATIC 23527691 A 124 138 La1-xSrxCoO3-δ FAMILY 23527691 A 1242 1248 oxides FAMILY 23527691 A 140 143 LSC ABBREVIATION 23527691 A 232 235 LSC ABBREVIATION 23527691 A 278 284 SrTiO3 FORMULA 23527691 A 289 295 LaAlO3 FORMULA 23527691 A 297 302 (18)O FORMULA 23527691 A 39 45 oxygen SYSTEMATIC 23527691 A 81 87 oxides FAMILY 23527691 A 836 839 LSC ABBREVIATION 23527691 T 35 41 Oxygen SYSTEMATIC 23528045 A 985 995 2-pyridone SYSTEMATIC 23528296 A 120 134 arylpiperazine FAMILY 23528296 A 315 327 triglyceride FAMILY 23528296 T 0 15 Arylpiperazines FAMILY 23528296 T 19 29 fatty acid FAMILY 23528298 A 11 24 cyclic imides FAMILY 23528298 A 1132 1138 SC-558 IDENTIFIER 23528298 A 447 456 celecoxib TRIVIAL 23528298 A 568 578 diclofenac TRIVIAL 23528298 A 807 822 homosulfonamide SYSTEMATIC 23528298 A 909 915 SO2NH2 FORMULA 23528298 A 932 933 H FORMULA 23528298 A 959 962 Gln FORMULA 23528298 A 976 979 Phe FORMULA 23528298 A 996 999 Arg FORMULA 23528298 T 57 70 cyclic imides FAMILY 23528298 T 79 97 benzenesulfonamide SYSTEMATIC 23528363 A 1048 1054 oxygen SYSTEMATIC 23528363 A 1098 1137 2,7-dichlorodihydrofluorescin diacetate SYSTEMATIC 23528363 A 1139 1146 DCFH-DA ABBREVIATION 23528363 A 1641 1644 MDA ABBREVIATION 23528363 A 176 193 Glycyrrhizic acid TRIVIAL 23528363 A 213 225 Glycyrrhizin TRIVIAL 23528363 A 230 260 triterpenoid saponin glycoside FAMILY 23528363 A 905 915 superoxide TRIVIAL 23528363 A 945 960 malondialdehyde TRIVIAL 23528363 A 962 965 MDA ABBREVIATION 23528363 T 14 31 glycyrrhizic acid TRIVIAL 23528740 A 1279 1291 CHOL-PEG2000 TRIVIAL 23528740 A 279 282 PEG ABBREVIATION 23528740 A 378 381 PEG ABBREVIATION 23528740 A 647 659 prednisolone TRIVIAL 23528740 A 707 710 PEG ABBREVIATION 23528740 A 725 728 PEG ABBREVIATION 23528740 A 752 755 PEG ABBREVIATION 23528740 A 934 941 PEG2000 TRIVIAL 23528740 A 958 969 cholesterol TRIVIAL 23528740 A 971 983 CHOL-PEG2000 TRIVIAL 23528740 T 56 68 prednisolone TRIVIAL 23528741 A 587 594 polyene SYSTEMATIC 23528741 A 606 614 nystatin TRIVIAL 23528741 A 920 928 nystatin TRIVIAL 23528741 T 52 60 nystatin TRIVIAL 23529824 A 1150 1160 exemestane TRIVIAL 23529824 A 1438 1448 everolimus TRIVIAL 23529824 A 1454 1464 exemestane TRIVIAL 23529824 A 17 25 Afinitor TRIVIAL 23529824 A 257 266 letrozole TRIVIAL 23529824 A 270 281 anastrozole TRIVIAL 23529824 A 439 449 Everolimus TRIVIAL 23529824 A 496 505 rapamycin TRIVIAL 23529824 A 5 15 everolimus TRIVIAL 23529824 A 50 60 exemestane TRIVIAL 23529824 A 620 630 everolimus TRIVIAL 23529824 A 711 721 exemestane TRIVIAL 23529824 A 751 760 oestrogen FAMILY 23529824 A 902 912 everolimus TRIVIAL 23529824 A 916 926 exemestane TRIVIAL 23529824 T 0 10 Everolimus TRIVIAL 23529824 T 31 41 Exemestane TRIVIAL 23529825 A 1054 1064 lorcaserin TRIVIAL 23529825 A 1113 1123 lorcaserin TRIVIAL 23529825 A 1242 1252 lorcaserin TRIVIAL 23529825 A 1502 1512 lorcaserin TRIVIAL 23529825 A 1644 1654 lorcaserin TRIVIAL 23529825 A 17 23 BELVIQ TRIVIAL 23529825 A 402 412 lorcaserin TRIVIAL 23529825 A 41 50 serotonin TRIVIAL 23529825 A 5 15 lorcaserin TRIVIAL 23529825 A 508 518 lorcaserin TRIVIAL 23529825 A 708 718 lorcaserin TRIVIAL 23529825 A 864 874 lorcaserin TRIVIAL 23529825 T 0 10 Lorcaserin TRIVIAL 23529900 A 124 128 PMMA ABBREVIATION 23529900 A 52 54 Si FORMULA 23529900 T 60 62 Si FORMULA 23530003 A 435 442 glucose TRIVIAL 23530006 A 0 8 Graphene TRIVIAL 23530006 A 1151 1159 graphene TRIVIAL 23530006 A 141 149 graphene TRIVIAL 23530006 A 180 188 graphene TRIVIAL 23530006 A 509 517 graphene TRIVIAL 23530006 A 658 664 carbon SYSTEMATIC 23530006 T 50 58 graphene TRIVIAL 23530012 A 125 134 vitamin D FAMILY 23530012 A 1261 1270 vitamin D FAMILY 23530012 A 1363 1382 25-hydroxyvitamin D SYSTEMATIC 23530012 A 1489 1498 vitamin D FAMILY 23530012 A 1618 1627 vitamin D FAMILY 23530012 A 238 247 vitamin D FAMILY 23530012 A 440 459 25-hydroxyvitamin D SYSTEMATIC 23530012 A 461 468 25(OH)D SYSTEMATIC 23530012 A 471 494 1,25-dihydroxyvitamin D SYSTEMATIC 23530012 A 500 524 24,25-dihydroxyvitamin D SYSTEMATIC 23530012 A 653 660 calcium SYSTEMATIC 23530012 A 955 964 vitamin D FAMILY 23530012 T 12 21 Vitamin D FAMILY 23530031 A 1006 1019 purmorphamine TRIVIAL 23530031 A 1284 1287 CpG ABBREVIATION 23530031 T 104 107 CpG ABBREVIATION 23530049 A 1096 1105 dileucine TRIVIAL 23530049 A 1190 1199 Dileucine TRIVIAL 23530049 A 1377 1386 dileucine TRIVIAL 23530049 A 631 640 dileucine TRIVIAL 23530049 A 918 927 dileucine TRIVIAL 23530596 A 560 581 poly(ethylene glycol) SYSTEMATIC 23530596 A 583 586 PEG ABBREVIATION 23530596 A 599 605 biotin TRIVIAL 23530596 A 609 617 arginine TRIVIAL 23530596 A 618 625 glycine TRIVIAL 23530596 A 626 639 aspartic acid TRIVIAL 23530596 A 829 835 biotin TRIVIAL 23530626 A 107 123 sulforhodamine B TRIVIAL 23530626 A 198 214 nitrogen dioxide SYSTEMATIC 23530626 A 216 219 NO2 FORMULA 23530626 A 28 34 Ni(II) FORMULA 23530626 A 333 336 NO2 FORMULA 23530626 A 387 402 dithiocarbamate SYSTEMATIC 23530626 A 40 55 dithiocarbamate SYSTEMATIC 23530626 A 415 421 Ni(II) FORMULA 23530626 A 475 478 NO2 FORMULA 23530626 A 524 527 NO2 FORMULA 23530626 A 563 579 nitrogen dioxide SYSTEMATIC 23530626 T 0 26 Nickel(II) Dithiocarbamate SYSTEMATIC 23530626 T 114 130 Nitrogen Dioxide SYSTEMATIC 23530626 T 48 64 Sulforhodamine B TRIVIAL 23530668 A 1057 1069 ferrihydrite TRIVIAL 23530668 A 1165 1175 phosphorus SYSTEMATIC 23530668 A 227 236 magnetite TRIVIAL 23530668 A 37 46 magnetite TRIVIAL 23530668 A 589 591 Fe FORMULA 23530668 A 593 605 ferrihydrite TRIVIAL 23530668 A 610 619 magnetite TRIVIAL 23530668 A 687 699 ferrihydrite TRIVIAL 23530668 A 717 719 Fe FORMULA 23530668 A 729 738 magnetite TRIVIAL 23530668 A 866 868 Fe FORMULA 23530668 A 899 911 ferrihydrite TRIVIAL 23530668 A 942 951 magnetite TRIVIAL 23530668 A 983 995 ferrihydrite TRIVIAL 23530668 T 0 9 Magnetite TRIVIAL 23530747 A 116 123 Calcium SYSTEMATIC 23530747 A 31 38 calcium SYSTEMATIC 23530747 A 506 513 calcium SYSTEMATIC 23530747 A 686 693 glycine TRIVIAL 23530747 A 756 759 ATP ABBREVIATION 23530747 A 876 879 ATP ABBREVIATION 23530747 T 22 25 ATP ABBREVIATION 23530747 T 55 62 Calcium SYSTEMATIC 23530926 A 423 427 (1)H FORMULA 23530926 A 502 517 ricinoleic acid TRIVIAL 23530926 A 629 644 ricinoleic acid TRIVIAL 23530926 A 676 691 ricinoleic acid TRIVIAL 23530926 A 703 713 fatty acid FAMILY 23530926 A 86 98 p(SA-RA) 3:7 ABBREVIATION 23530926 T 50 65 Ricinoleic Acid TRIVIAL 23530926 T 72 93 Poly(ester-anhydride) FAMILY 23530959 A 787 795 catechol TRIVIAL 23530959 A 846 852 L-DOPA ABBREVIATION 23530959 A 870 878 catechol TRIVIAL 23530959 A 995 1003 Catechol TRIVIAL 23530959 T 148 152 DOPA ABBREVIATION 23530959 T 97 105 Catechol TRIVIAL 23531154 A 105 114 metformin TRIVIAL 23531154 A 1064 1067 Met FORMULA 23531154 A 1068 1071 TZD ABBREVIATION 23531154 A 115 128 sulphonylurea SYSTEMATIC 23531154 A 1167 1170 TZD ABBREVIATION 23531154 A 1257 1260 Met FORMULA 23531154 A 1261 1264 TZD ABBREVIATION 23531154 A 130 133 Met FORMULA 23531154 A 1347 1350 Met FORMULA 23531154 A 1351 1354 TZD ABBREVIATION 23531154 A 139 148 metformin TRIVIAL 23531154 A 149 166 thiazolidinedione FAMILY 23531154 A 1521 1524 TZD ABBREVIATION 23531154 A 1528 1531 Met FORMULA 23531154 A 168 171 Met FORMULA 23531154 A 172 175 TZD ABBREVIATION 23531154 A 181 194 sulphonylurea SYSTEMATIC 23531154 A 195 212 thiazolidinedione FAMILY 23531154 A 217 220 TZD ABBREVIATION 23531154 A 848 851 Met FORMULA 23531154 A 852 855 TZD ABBREVIATION 23531154 A 877 880 Met FORMULA 23531154 A 911 914 TZD ABBREVIATION 23531154 A 971 974 Met FORMULA 23531536 A 1155 1168 α-lipoic acid TRIVIAL 23531536 A 1328 1341 α-lipoic acid TRIVIAL 23531536 A 183 194 lipoic acid TRIVIAL 23531536 A 223 236 α-lipoic acid TRIVIAL 23531536 A 328 341 Malonaldehyde TRIVIAL 23531536 A 343 346 MDA ABBREVIATION 23531536 A 349 362 ascorbic acid TRIVIAL 23531536 A 364 373 vitamin C TRIVIAL 23531536 A 376 385 vitamin E FAMILY 23531536 A 38 51 α-lipoic acid TRIVIAL 23531536 A 387 398 glutathione TRIVIAL 23531536 A 400 403 GSH ABBREVIATION 23531536 A 409 419 superoxide TRIVIAL 23531536 A 541 546 NADPH ABBREVIATION 23531536 A 777 780 MDA ABBREVIATION 23531536 A 875 878 GSH ABBREVIATION 23531536 A 885 894 vitamin C TRIVIAL 23531536 A 899 908 vitamin E FAMILY 23531536 T 26 39 α-Lipoic Acid TRIVIAL 23531554 A 1065 1071 oxygen SYSTEMATIC 23531554 A 1368 1374 oxygen SYSTEMATIC 23531554 A 326 333 glucose TRIVIAL 23531554 A 348 354 oxygen SYSTEMATIC 23531554 A 514 520 oxygen SYSTEMATIC 23531554 A 563 569 oxygen SYSTEMATIC 23531554 A 676 682 oxygen SYSTEMATIC 23531554 A 719 725 oxygen SYSTEMATIC 23531554 T 10 16 oxygen SYSTEMATIC 23531555 A 104 120 titanium dioxide SYSTEMATIC 23531555 A 122 126 TiO2 FORMULA 23531555 A 1257 1261 TiO2 FORMULA 23531555 A 128 135 titania TRIVIAL 23531555 A 1324 1328 TiO2 FORMULA 23531555 A 1329 1332 MTT ABBREVIATION 23531555 A 159 162 MTT ABBREVIATION 23531555 A 164 224 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide SYSTEMATIC 23531555 A 293 296 MTT ABBREVIATION 23531555 A 380 383 MTT ABBREVIATION 23531555 A 441 449 formazan FAMILY 23531555 A 556 564 P25 TiO2 FORMULA 23531555 A 662 665 MTT ABBREVIATION 23531555 A 669 677 formazan FAMILY 23531555 A 704 708 TiO2 FORMULA 23531555 A 811 819 formazan FAMILY 23531555 A 870 874 TiO2 FORMULA 23531555 T 29 49 MTT tetrazolium salt TRIVIAL 23531555 T 53 57 TiO2 FORMULA 23532002 A 17 23 Sn(ii) FORMULA 23532002 A 183 191 P25 TiO2 FORMULA 23532002 A 254 260 Sn(ii) FORMULA 23532002 A 282 286 TiO2 FORMULA 23532002 A 314 318 TiO2 FORMULA 23532002 A 35 39 TiO2 FORMULA 23532002 A 352 355 tin SYSTEMATIC 23532002 A 581 589 hydrogen SYSTEMATIC 23532002 T 33 39 Sn(ii) FORMULA 23532002 T 40 44 TiO2 FORMULA 23532057 A 1046 1052 carbon SYSTEMATIC 23532057 A 116 135 gamma butyrolactone SYSTEMATIC 23532057 A 137 141 γ-BL ABBREVIATION 23532057 A 165 171 carbon SYSTEMATIC 23532057 A 36 57 pyrrolidinium nitrate SYSTEMATIC 23532057 A 407 411 γ-BL ABBREVIATION 23532057 A 528 532 γ-BL ABBREVIATION 23532057 A 59 70 [Pyrr][NO3] FORMULA 23532057 A 848 869 pyrrolidinium nitrate SYSTEMATIC 23532057 A 973 981 aluminum SYSTEMATIC 23532057 T 2 23 pyrrolidinium nitrate SYSTEMATIC 23532258 A 1340 1343 MMF ABBREVIATION 23532258 A 1539 1542 MMF ABBREVIATION 23532258 A 346 360 streptozotocin TRIVIAL 23532258 A 595 605 tacrolimus TRIVIAL 23532258 A 607 616 sirolimus TRIVIAL 23532258 A 618 628 everolimus TRIVIAL 23532258 A 632 653 mycophenolate mofetil TRIVIAL 23532258 A 655 658 MMF ABBREVIATION 23532258 A 951 961 everolimus TRIVIAL 23532258 A 963 973 tacrolimus TRIVIAL 23532258 A 978 987 sirolimus TRIVIAL 23532258 A 989 992 MMF ABBREVIATION 23532634 A 1040 1048 cortisol TRIVIAL 23532634 A 1170 1178 cortisol TRIVIAL 23532634 A 1332 1336 DHEA ABBREVIATION 23532634 A 1357 1367 creatinine TRIVIAL 23532634 A 1404 1414 creatinine TRIVIAL 23532634 A 1477 1485 cortisol TRIVIAL 23532634 A 1487 1501 delta cortisol TRIVIAL 23532634 A 1507 1517 delta DHEA ABBREVIATION 23532634 A 175 183 cortisol TRIVIAL 23532634 A 188 192 DHEA ABBREVIATION 23532634 A 470 478 cortisol TRIVIAL 23532634 A 487 491 DHEA ABBREVIATION 23532634 A 495 499 DHEA ABBREVIATION 23532634 A 505 513 cortisol TRIVIAL 23532634 A 560 568 cortisol TRIVIAL 23532634 A 604 612 cortisol TRIVIAL 23532634 A 633 641 cortisol TRIVIAL 23532634 A 655 659 DHEA ABBREVIATION 23532634 A 663 667 DHEA ABBREVIATION 23532634 A 674 688 delta cortisol TRIVIAL 23532634 A 690 694 ΔCor ABBREVIATION 23532634 A 697 707 delta DHEA ABBREVIATION 23532634 A 711 716 ΔDHEA ABBREVIATION 23532634 A 865 869 DHEA ABBREVIATION 23532634 A 888 892 DHEA ABBREVIATION 23532634 A 942 946 ΔCor ABBREVIATION 23532634 A 952 957 ΔDHEA ABBREVIATION 23532843 A 1031 1038 glucose TRIVIAL 23532843 A 369 379 tryptophan TRIVIAL 23532843 A 389 392 Trp FORMULA 23532843 A 575 585 tryptophan TRIVIAL 23532843 A 589 596 alanine TRIVIAL 23532843 A 821 824 Trp FORMULA 23532843 T 0 10 Tryptophan TRIVIAL 23532849 A 1034 1044 Amino acid FAMILY 23532849 A 1158 1168 methionine TRIVIAL 23532849 A 1265 1275 methionine TRIVIAL 23532849 A 1326 1336 methionine TRIVIAL 23532849 A 1452 1462 methionine TRIVIAL 23532849 A 1543 1563 S-adenosylmethionine TRIVIAL 23532849 A 181 191 lovastatin TRIVIAL 23532849 A 193 203 penicillin FAMILY 23532849 A 209 218 aflatoxin FAMILY 23532849 A 481 491 amino acid FAMILY 23532849 A 587 593 methyl SYSTEMATIC 23532849 A 679 685 methyl SYSTEMATIC 23532849 A 759 793 S-adenosyl-[methyl-(3)H]methionine SYSTEMATIC 23532849 T 84 102 S-Methylmethionine SYSTEMATIC 23532918 A 1064 1079 secondary amide FAMILY 23532918 A 1197 1201 NMDA ABBREVIATION 23532918 A 1210 1216 Ca(2+) FORMULA 23532918 A 1227 1234 calcium SYSTEMATIC 23532918 A 1430 1440 ifenprodil TRIVIAL 23532918 A 1545 1555 ifenprodil TRIVIAL 23532918 A 1593 1610 [(3) H]ifenprodil SYSTEMATIC 23532918 A 18 22 NMDA ABBREVIATION 23532918 A 381 391 Ifenprodil TRIVIAL 23532918 A 526 537 fluorescein TRIVIAL 23532918 A 822 832 ifenprodil TRIVIAL 23532918 A 873 883 ifenprodil TRIVIAL 23532918 A 891 899 benzylic TRIVIAL 23532918 A 920 926 phenol SYSTEMATIC 23532918 A 947 971 secondary amine or amide MULTIPLE 23532918 T 43 53 Ifenprodil TRIVIAL 23532918 T 60 71 Fluorescein TRIVIAL 23532918 T 99 119 N-Methyl-D-aspartate SYSTEMATIC 23532940 A 131 137 BHQ-10 IDENTIFIER 23534403 A 199 205 carbon SYSTEMATIC 23534403 T 27 33 carbon SYSTEMATIC 23534411 A 19 33 batzelladine K TRIVIAL 23534411 A 302 313 chloroquine TRIVIAL 23534411 A 367 378 chloroquine TRIVIAL 23534411 A 472 477 nonyl SYSTEMATIC 23534411 A 779 785 pentyl SYSTEMATIC 23534411 A 790 796 methyl SYSTEMATIC 23534411 A 951 970 tricyclic guanidine FAMILY 23534411 T 39 58 tricyclic guanidine FAMILY 23534411 T 72 86 batzelladine K TRIVIAL 23534530 A 137 142 Fe2O3 FORMULA 23534530 A 271 276 Fe2O3 FORMULA 23534530 A 31 42 polystyrene SYSTEMATIC 23534530 A 331 336 Fe2O3 FORMULA 23534530 T 31 42 Polystyrene SYSTEMATIC 23534530 T 43 48 Fe2O3 FORMULA 23534553 A 314 334 polydimethylsiloxane SYSTEMATIC 23534553 A 336 340 PDMS ABBREVIATION 23534553 A 428 435 silicon SYSTEMATIC 23534553 A 453 457 PDMS ABBREVIATION 23535327 A 178 206 di-tert-butylsilylene acetal SYSTEMATIC 23535327 A 50 83 7-O-p-cyanobenzoyl pyripyropene A SYSTEMATIC 23535327 T 100 108 acyl-CoA ABBREVIATION 23535327 T 109 120 cholesterol TRIVIAL 23535327 T 49 63 pyripyropene A TRIVIAL 23535337 A 1086 1093 proline TRIVIAL 23535337 A 263 267 NaCl FORMULA 23535337 A 272 280 sorbitol TRIVIAL 23535337 A 464 468 NaCl FORMULA 23535337 A 473 481 sorbitol TRIVIAL 23535337 A 555 562 proline TRIVIAL 23535337 A 589 597 sorbitol TRIVIAL 23535337 A 615 619 NaCl FORMULA 23535337 A 624 632 sorbitol TRIVIAL 23535337 A 8 14 lysine TRIVIAL 23535337 T 99 106 Proline TRIVIAL 23535338 A 117 128 fatty acids FAMILY 23535338 A 553 566 sphingomyelin FAMILY 23535338 A 796 816 polyenic fatty acids FAMILY 23535348 A 113 132 5-hydroxytryptamine SYSTEMATIC 23535348 A 1202 1210 muscimol TRIVIAL 23535348 A 1292 1296 5-HT SYSTEMATIC 23535348 A 134 138 5-HT SYSTEMATIC 23535348 A 1411 1415 GABA ABBREVIATION 23535348 A 44 83 8-hydroxy-2-(di-n-propylamino) tetralin SYSTEMATIC 23535348 A 593 612 γ-aminobutyric acid SYSTEMATIC 23535348 A 614 618 GABA ABBREVIATION 23535348 A 85 94 8-OH-DPAT SYSTEMATIC 23535348 A 946 955 8-OH-DPAT SYSTEMATIC 23535348 A 99 108 serotonin TRIVIAL 23535348 T 76 95 γ-aminobutyric acid SYSTEMATIC 23535348 T 97 101 GABA ABBREVIATION 23535349 A 1091 1102 risperidone TRIVIAL 23535349 A 1133 1143 quetiapine TRIVIAL 23535349 A 115 126 risperidone TRIVIAL 23535349 A 1253 1263 olanzapine TRIVIAL 23535349 A 128 138 quetiapine TRIVIAL 23535349 A 1402 1412 olanzapine TRIVIAL 23535349 A 143 153 olanzapine TRIVIAL 23535349 A 1437 1447 olanzapine TRIVIAL 23535349 A 592 603 risperidone TRIVIAL 23535349 A 605 615 quetiapine TRIVIAL 23535349 A 620 630 olanzapine TRIVIAL 23535349 T 40 51 risperidone TRIVIAL 23535349 T 53 63 quetiapine TRIVIAL 23535349 T 68 78 olanzapine TRIVIAL 23535361 A 1017 1028 perchlorate SYSTEMATIC 23535361 A 1132 1138 iodide SYSTEMATIC 23535361 A 1198 1209 perchlorate SYSTEMATIC 23535361 A 1291 1302 perchlorate SYSTEMATIC 23535361 A 1417 1423 iodide SYSTEMATIC 23535361 A 209 215 iodide SYSTEMATIC 23535361 A 223 232 thyroxine TRIVIAL 23535361 A 244 253 thyroxine TRIVIAL 23535361 A 271 287 triiodothyronine TRIVIAL 23535361 A 340 346 iodide SYSTEMATIC 23535361 A 390 401 perchlorate SYSTEMATIC 23535361 A 465 478 sodium iodide SYSTEMATIC 23535361 A 521 527 iodide SYSTEMATIC 23535361 A 635 646 perchlorate SYSTEMATIC 23535361 A 733 739 iodide SYSTEMATIC 23535361 A 792 798 iodide SYSTEMATIC 23535361 A 870 881 perchlorate SYSTEMATIC 23535361 A 965 971 iodide SYSTEMATIC 23535361 T 103 114 Perchlorate SYSTEMATIC 23535361 T 92 98 Iodide SYSTEMATIC 23535363 A 1351 1363 methacholine TRIVIAL 23535363 A 155 167 diisocyanate SYSTEMATIC 23535363 A 87 99 diisocyanate SYSTEMATIC 23535363 T 82 94 Diisocyanate SYSTEMATIC 23535364 A 1005 1019 deoxyguanosine SYSTEMATIC 23535364 A 1068 1072 MeIQ ABBREVIATION 23535364 A 158 188 2-Amino-9H-pyrido[2,3-b]indole SYSTEMATIC 23535364 A 210 237 heterocyclic aromatic amine FAMILY 23535364 A 716 759 2-amino-3,4-dimethylimidazo[4,5-f]quinoline SYSTEMATIC 23535364 A 761 765 MeIQ ABBREVIATION 23535364 T 24 54 2-Amino-9H-pyrido[2,3-b]indole SYSTEMATIC 23535364 T 59 102 2-Amino-3,4-dimethylimidazo[4,5-f]quinoline SYSTEMATIC 23535393 A 1054 1061 taurine TRIVIAL 23535393 A 1066 1076 methionine TRIVIAL 23535393 A 1099 1108 threonine TRIVIAL 23535393 A 1110 1117 proline TRIVIAL 23535393 A 1122 1129 glycine TRIVIAL 23535393 A 1130 1141 amino acids FAMILY 23535828 T 47 65 bicyclic azasugars FAMILY 23535828 T 67 78 carbasugars FAMILY 23536264 A 1048 1058 creatinine TRIVIAL 23536264 A 1070 1074 urea TRIVIAL 23536264 A 1075 1083 nitrogen SYSTEMATIC 23536264 A 111 115 urea TRIVIAL 23536264 A 116 124 nitrogen SYSTEMATIC 23536264 A 1243 1253 creatinine TRIVIAL 23536264 A 1265 1269 urea TRIVIAL 23536264 A 1270 1278 nitrogen SYSTEMATIC 23536264 A 282 292 creatinine TRIVIAL 23536264 A 304 308 urea TRIVIAL 23536264 A 309 317 nitrogen SYSTEMATIC 23536264 A 555 565 creatinine TRIVIAL 23536264 A 591 595 urea TRIVIAL 23536264 A 596 604 nitrogen SYSTEMATIC 23536264 A 654 664 creatinine TRIVIAL 23536264 A 707 711 urea TRIVIAL 23536264 A 712 720 nitrogen SYSTEMATIC 23536264 A 75 85 creatinine TRIVIAL 23536264 A 826 836 creatinine TRIVIAL 23536264 A 848 852 urea TRIVIAL 23536264 A 853 861 nitrogen SYSTEMATIC 23536264 A 943 953 creatinine TRIVIAL 23536264 A 965 969 urea TRIVIAL 23536264 A 970 978 nitrogen SYSTEMATIC 23536314 A 1123 1127 dUTP ABBREVIATION 23536314 A 1249 1259 cilostazol TRIVIAL 23536314 A 1376 1386 cilostazol TRIVIAL 23536314 A 1458 1468 Cilostazol TRIVIAL 23536314 A 189 199 cilostazol TRIVIAL 23536314 A 479 489 cilostazol TRIVIAL 23536314 A 992 1002 cilostazol TRIVIAL 23536314 T 27 37 Cilostazol TRIVIAL 23536316 A 1128 1135 chrysin TRIVIAL 23536316 A 1262 1269 chrysin TRIVIAL 23536316 A 1351 1358 chrysin TRIVIAL 23536316 A 137 144 Chrysin TRIVIAL 23536316 A 1477 1484 chrysin TRIVIAL 23536316 A 1488 1495 chrysin TRIVIAL 23536316 A 1501 1511 flavonoids FAMILY 23536316 A 170 179 flavonoid FAMILY 23536316 A 256 263 chrysin TRIVIAL 23536316 A 354 361 chrysin TRIVIAL 23536316 A 566 573 Chrysin TRIVIAL 23536316 A 784 791 chrysin TRIVIAL 23536316 A 893 900 chrysin TRIVIAL 23536316 T 0 7 Chrysin TRIVIAL 23536517 A 1088 1098 superoxide TRIVIAL 23536517 A 1113 1124 glutathione TRIVIAL 23536517 A 1160 1179 sodium taurocholate SYSTEMATIC 23536517 A 247 250 Tau ABBREVIATION 23536517 A 285 304 sodium taurocholate SYSTEMATIC 23536517 A 434 437 Tau ABBREVIATION 23536517 A 540 555 malondialdehyde TRIVIAL 23536517 A 67 74 taurine TRIVIAL 23536517 A 671 674 Tau ABBREVIATION 23536517 A 684 687 Tau ABBREVIATION 23536517 A 76 79 Tau ABBREVIATION 23536517 A 828 831 Tau ABBREVIATION 23536517 A 836 839 Tau ABBREVIATION 23536517 A 942 945 Tau ABBREVIATION 23536517 T 26 33 taurine TRIVIAL 23536518 A 1045 1064 omega-3 fatty acids FAMILY 23536518 A 1100 1107 omega-3 FAMILY 23536518 A 1126 1129 DBP ABBREVIATION 23536518 A 1267 1270 DBP ABBREVIATION 23536518 A 183 193 phthalates FAMILY 23536518 A 261 279 di-butyl phthalate SYSTEMATIC 23536518 A 281 284 DBP ABBREVIATION 23536518 A 433 436 DBP ABBREVIATION 23536518 A 564 567 DBP ABBREVIATION 23536518 A 601 613 testosterone TRIVIAL 23536518 A 61 96 omega-3 polyunsaturated fatty acids FAMILY 23536518 A 786 789 DBP ABBREVIATION 23536518 A 875 878 DBP ABBREVIATION 23536518 A 938 941 DBP ABBREVIATION 23536518 T 80 98 di-butyl phthalate SYSTEMATIC 23536519 A 1062 1073 resveratrol TRIVIAL 23536519 A 223 234 Resveratrol TRIVIAL 23536519 A 528 539 Resveratrol TRIVIAL 23536519 A 64 75 resveratrol TRIVIAL 23536519 A 677 684 citrate FAMILY 23536519 A 721 728 glucose TRIVIAL 23536519 A 785 796 resveratrol TRIVIAL 23536519 T 0 11 Resveratrol TRIVIAL 23536521 A 0 8 Selenium SYSTEMATIC 23536521 A 10 12 Se FORMULA 23536521 A 207 255 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one SYSTEMATIC 23536521 A 257 266 C21H2HOSe FORMULA 23536521 A 268 282 organoselenium FAMILY 23536521 A 288 303 sodium selenate SYSTEMATIC 23536521 A 315 317 Se FORMULA 23536521 A 322 331 adenosine TRIVIAL 23536521 A 407 419 nitric oxide SYSTEMATIC 23536521 A 421 423 NO FORMULA 23536521 A 440 446 thiols FAMILY 23536521 A 451 453 SH FORMULA 23536521 A 584 598 organoselenium FAMILY 23536521 A 695 697 NO FORMULA 23536521 A 737 739 Se FORMULA 23536521 A 768 788 sodium nitroprusside SYSTEMATIC 23536521 A 835 837 SH FORMULA 23536521 T 46 54 selenium SYSTEMATIC 23536521 T 68 77 adenosine TRIVIAL 23536974 A 0 15 Isoamyl nitrite SYSTEMATIC 23536974 A 1012 1020 nitrites FAMILY 23536974 A 1051 1058 cyanide SYSTEMATIC 23536974 A 1081 1095 sodium nitrite SYSTEMATIC 23536974 A 1121 1123 NO FORMULA 23536974 A 139 146 nitrite SYSTEMATIC 23536974 A 1446 1460 sodium nitrite SYSTEMATIC 23536974 A 161 175 sodium nitrite SYSTEMATIC 23536974 A 1653 1657 NaCN FORMULA 23536974 A 1841 1848 nitrite SYSTEMATIC 23536974 A 2012 2019 cyanide SYSTEMATIC 23536974 A 249 263 sodium nitrite SYSTEMATIC 23536974 A 268 283 isoamyl nitrite SYSTEMATIC 23536974 A 349 356 cyanide SYSTEMATIC 23536974 A 448 463 isoamyl nitrite SYSTEMATIC 23536974 A 534 548 isoamyl alchol SYSTEMATIC 23536974 A 583 598 isoamyl nitrite SYSTEMATIC 23536974 A 610 617 nitrite SYSTEMATIC 23536974 A 655 669 sodium nitrite SYSTEMATIC 23536974 A 719 726 cyanide SYSTEMATIC 23536974 A 72 79 cyanide SYSTEMATIC 23536974 A 905 919 sodium nitrite SYSTEMATIC 23536974 T 43 58 Isoamyl Nitrite SYSTEMATIC 23536974 T 63 77 Sodium Nitrite SYSTEMATIC 23536974 T 98 105 Cyanide SYSTEMATIC 23537005 A 0 30 Polybrominated diphenyl ethers FAMILY 23537005 A 1009 1020 monohydroxy SYSTEMATIC 23537005 A 1186 1192 BDE-47 ABBREVIATION 23537005 A 1240 1246 BDE-47 ABBREVIATION 23537005 A 1502 1508 BDE-47 ABBREVIATION 23537005 A 1594 1605 monohydroxy SYSTEMATIC 23537005 A 1646 1652 BDE-47 ABBREVIATION 23537005 A 1671 1688 2,4-dibromophenol SYSTEMATIC 23537005 A 1706 1712 BDE-47 ABBREVIATION 23537005 A 1754 1763 dihydroxy SYSTEMATIC 23537005 A 1848 1859 monohydroxy SYSTEMATIC 23537005 A 1987 1993 BDE-47 ABBREVIATION 23537005 A 202 236 2,2',4,4'-tetrabromodiphenyl ether SYSTEMATIC 23537005 A 238 244 BDE-47 ABBREVIATION 23537005 A 255 259 PBDE ABBREVIATION 23537005 A 32 37 PBDEs ABBREVIATION 23537005 A 333 339 BDE-47 ABBREVIATION 23537005 A 566 572 BDE-47 ABBREVIATION 23537005 A 672 683 monohydroxy SYSTEMATIC 23537005 A 706 715 dihydroxy SYSTEMATIC 23537005 A 859 903 5-hydroxy-2,2',4,4'-tetrabromodiphenyl ether SYSTEMATIC 23537005 A 905 916 5-OH-BDE-47 SYSTEMATIC 23537005 A 919 963 6-hydroxy-2,2',4,4'-tetrabromodiphenyl ether SYSTEMATIC 23537005 A 965 976 6-OH-BDE-47 SYSTEMATIC 23537005 T 21 55 2,2',4,4'-Tetrabromodiphenyl Ether SYSTEMATIC 23537005 T 57 63 BDE-47 ABBREVIATION 23537094 A 109 127 desmethylnobiletin TRIVIAL 23537094 A 129 145 pectolinarigenin TRIVIAL 23537094 A 13 23 flavonoids FAMILY 23537094 A 150 162 xanthomicrol TRIVIAL 23537094 A 298 320 3',4'-dimethoxywogonin SYSTEMATIC 23537094 A 325 342 4'-hydroxywogonin SYSTEMATIC 23537094 A 445 455 gardenin C TRIVIAL 23537094 T 0 10 Flavonoids FAMILY 23537160 A 123 133 flavonoids FAMILY 23537160 A 134 145 mauritianin TRIVIAL 23537160 A 151 161 kaempferol TRIVIAL 23537160 A 174 192 triterpene saponin FAMILY 23537160 A 193 242 β-D-glucopyranosyl 3β-hydroxy-olean-12-en-28-oate SYSTEMATIC 23537160 A 346 350 (1)H FORMULA 23537160 A 352 357 (13)C FORMULA 23537160 A 387 391 (1)H FORMULA 23537160 A 392 396 (1)H FORMULA 23537160 A 49 57 methanol SYSTEMATIC 23537160 A 576 594 triterpene saponin FAMILY 23537160 A 6 24 triterpene saponin FAMILY 23537160 T 4 24 triterpene glycoside FAMILY 23537427 A 1008 1010 Br FORMULA 23537427 A 1022 1030 methanes FAMILY 23537427 A 105 120 epichlorohydrin TRIVIAL 23537427 A 1057 1059 OH FORMULA 23537427 A 1121 1126 CHBr3 FORMULA 23537427 A 1128 1135 CHClBr2 FORMULA 23537427 A 1141 1148 CHCl2Br FORMULA 23537427 A 122 129 C3H5ClO FORMULA 23537427 A 551 553 OH FORMULA 23537427 A 559 566 CHCl2Br FORMULA 23537427 A 571 578 CHClBr2 FORMULA 23537427 A 66 68 OH FORMULA 23537427 A 83 92 bromoform SYSTEMATIC 23537427 A 906 908 OH FORMULA 23537427 A 94 99 CHBr3 FORMULA 23537427 T 115 122 C3H5ClO FORMULA 23537427 T 39 41 OH FORMULA 23537427 T 57 66 Bromoform SYSTEMATIC 23537427 T 68 73 CHBr3 FORMULA 23537427 T 76 83 CHBr2Cl FORMULA 23537427 T 85 92 CHBrCl2 FORMULA 23537427 T 98 113 Epichlorohydrin TRIVIAL 23537582 A 1038 1047 1-pyrenol SYSTEMATIC 23537582 A 1049 1055 4-n-NP SYSTEMATIC 23537582 A 1060 1069 4-tert-OP SYSTEMATIC 23537582 A 339 346 OH-PAHs FORMULA 23537582 A 348 358 1-naphthol SYSTEMATIC 23537582 A 360 372 9-phenantrol SYSTEMATIC 23537582 A 374 385 9-fluorenol SYSTEMATIC 23537582 A 387 396 1-pyrenol SYSTEMATIC 23537582 A 398 405 1OH-BaP SYSTEMATIC 23537582 A 410 417 3OH-BaP SYSTEMATIC 23537582 A 423 435 alkylphenols FAMILY 23537582 A 437 452 4-n-nonylphenol SYSTEMATIC 23537582 A 454 460 4-n-NP SYSTEMATIC 23537582 A 466 483 4-tertoctylphenol SYSTEMATIC 23537582 A 485 494 4-tert-OP SYSTEMATIC 23537582 A 753 762 1-pyrenol SYSTEMATIC 23537582 A 764 775 9-fluorenol SYSTEMATIC 23537582 A 780 786 4-n-NP SYSTEMATIC 23537598 A 102 110 phenolic FAMILY 23537598 A 153 161 phenolic FAMILY 23537598 A 317 352 ferulic, sinapinic and gallic acids MULTIPLE 23537598 A 354 364 kaempferol TRIVIAL 23537598 A 366 378 isorhamnetin TRIVIAL 23537598 A 383 388 rutin TRIVIAL 23537598 A 823 831 phenolic FAMILY 23537701 A 0 20 Tetrahydrocannabinol SYSTEMATIC 23537701 A 1008 1011 THC ABBREVIATION 23537701 A 1344 1347 THC ABBREVIATION 23537701 A 1482 1485 THC ABBREVIATION 23537701 A 1535 1538 THC ABBREVIATION 23537701 A 22 25 THC ABBREVIATION 23537701 A 326 329 THC ABBREVIATION 23537701 A 474 477 THC ABBREVIATION 23537701 A 638 641 THC ABBREVIATION 23537701 A 787 790 THC ABBREVIATION 23537701 A 826 829 THC ABBREVIATION 23537701 A 945 948 THC ABBREVIATION 23537701 T 21 41 tetrahydrocannabinol SYSTEMATIC 23537702 A 1052 1061 rapamycin TRIVIAL 23537702 A 1066 1080 retinoic acid) TRIVIAL 23537746 A 202 208 Ze 450 NO CLASS 23537746 T 45 51 Ze 450 NO CLASS 23537749 A 114 125 beta-lactam TRIVIAL 23537749 A 1241 1253 piperacillin TRIVIAL 23537749 A 1273 1285 piperacillin TRIVIAL 23537749 A 1300 1312 piperacillin TRIVIAL 23537749 A 1339 1348 meropenem TRIVIAL 23537749 A 1724 1735 beta-lactam TRIVIAL 23537749 A 414 424 ampicillin TRIVIAL 23537749 A 426 438 piperacillin TRIVIAL 23537749 A 440 449 cefazolin TRIVIAL 23537749 A 451 461 cefuroxime TRIVIAL 23537749 A 463 476 carbenicillin TRIVIAL 23537749 A 478 489 ceftazidime TRIVIAL 23537749 A 491 500 meropenem TRIVIAL 23537889 A 1007 1016 serotonin TRIVIAL 23537889 A 1066 1075 glutamate TRIVIAL 23537889 A 1080 1088 dopamine TRIVIAL 23537889 A 119 134 tryptorheedei B TRIVIAL 23537889 A 164 213 5-O-β-D-glucopyranosyl-2-hydroxyphenylacetic acid SYSTEMATIC 23537889 A 219 244 1-O-methylglucopyranoside SYSTEMATIC 23537889 A 246 258 entadamide A TRIVIAL 23537889 A 260 277 homogentisic acid TRIVIAL 23537889 A 282 317 3-O-β-D-glucopyranosyl-β-sitosterol TRIVIAL 23537889 A 32 55 N-sulfonyl-L-tryptophan SYSTEMATIC 23537889 A 57 72 tryptorheedei A TRIVIAL 23537889 A 717 727 indolamine TRIVIAL 23537889 A 765 775 tryptophan TRIVIAL 23537889 A 8 18 tryptophan TRIVIAL 23537889 A 82 117 3-(N-sulfonylindolyl)-D-lactic acid SYSTEMATIC 23537889 A 962 972 kynurenine TRIVIAL 23537889 T 8 18 tryptophan TRIVIAL 23538035 A 1036 1039 GSH ABBREVIATION 23538035 A 1262 1267 MC-RR ABBREVIATION 23538035 A 128 148 cyclic heptapeptides FAMILY 23538035 A 150 155 MC-RR ABBREVIATION 23538035 A 169 174 MC-LR ABBREVIATION 23538035 A 224 232 arginine TRIVIAL 23538035 A 236 243 leucine TRIVIAL 23538035 A 533 536 GSH ABBREVIATION 23538035 A 559 564 MC-RR ABBREVIATION 23538035 A 582 585 GSH ABBREVIATION 23538035 A 65 77 mycrocistins FAMILY 23538035 A 716 721 MC-LR ABBREVIATION 23538035 A 935 938 GSH ABBREVIATION 23538035 A 964 969 MC-RR ABBREVIATION 23538035 T 19 33 microcystin-RR TRIVIAL 23538162 A 1137 1140 Rg1 ABBREVIATION 23538162 A 123 138 Ginsenoside Rg1 TRIVIAL 23538162 A 140 143 Rg1 ABBREVIATION 23538162 A 381 384 Rg1 ABBREVIATION 23538162 A 413 416 Rg1 ABBREVIATION 23538162 A 562 570 nitrogen SYSTEMATIC 23538162 A 705 710 RU486 IDENTIFIER 23538162 A 730 735 U0126 IDENTIFIER 23538162 A 748 756 estrogen FAMILY 23538162 A 779 789 ICI 82,780 IDENTIFIER 23538162 A 834 837 Rg1 ABBREVIATION 23538162 T 72 87 ginsenoside Rg1 TRIVIAL 23538319 A 235 240 2,4-D SYSTEMATIC 23538319 A 295 300 2,4-D SYSTEMATIC 23538319 A 331 338 glucose TRIVIAL 23538319 A 343 350 lactate FAMILY 23538319 A 380 385 2,4-D SYSTEMATIC 23538319 A 420 427 glucose TRIVIAL 23538319 A 540 545 2,4-D SYSTEMATIC 23538319 A 58 63 2,4-D SYSTEMATIC 23538319 A 601 608 lactate FAMILY 23538319 A 717 722 2,4-D SYSTEMATIC 23538319 A 736 741 2,4-D SYSTEMATIC 23538319 A 750 757 glucose TRIVIAL 23538319 A 803 810 lactate FAMILY 23538319 T 12 42 2,4-dichlorophenoxyacetic acid SYSTEMATIC 23538319 T 50 57 glucose TRIVIAL 23538397 A 19 43 thieno[3,2-d]pyrimidines FAMILY 23538397 A 287 295 hydrogen SYSTEMATIC 23538397 A 347 370 4-aminothienopyrimidine SYSTEMATIC 23538397 A 398 423 4-substituted phenylamino SYSTEMATIC 23538397 A 440 464 4-thienopyrimidin-4-ones FAMILY 23538397 A 471 501 N-alkyl thienopyrimidin-4-ones FAMILY 23538397 A 508 533 4-chlorothienopyrimidines FAMILY 23538397 A 544 572 thienopyrimidoquinazolinones FAMILY 23538397 A 841 852 Doxorubicin TRIVIAL 23538397 T 24 48 thieno[3,2-d]pyrimidines FAMILY 23538844 A 1007 1014 cadmium SYSTEMATIC 23538844 A 256 263 cadmium SYSTEMATIC 23538844 A 330 339 phosphate SYSTEMATIC 23538844 A 45 52 cadmium SYSTEMATIC 23538844 A 459 466 cadmium SYSTEMATIC 23538844 A 582 589 cadmium SYSTEMATIC 23538844 A 647 654 cadmium SYSTEMATIC 23538844 A 706 713 cadmium SYSTEMATIC 23538844 T 0 7 Cadmium SYSTEMATIC 23539089 A 130 140 β-carotene TRIVIAL 23539089 A 414 428 hydro peroxide SYSTEMATIC 23539089 A 500 506 Fe(2+) FORMULA 23539089 A 552 572 ammonium thiocyanate SYSTEMATIC 23539089 T 94 104 β-Carotene TRIVIAL 23539147 A 1109 1120 cholesterol TRIVIAL 23539147 A 1136 1148 triglyceride FAMILY 23539147 A 1171 1183 triglyceride FAMILY 23539147 A 1270 1277 calcium SYSTEMATIC 23539147 A 169 176 calcium SYSTEMATIC 23539147 A 312 319 calcium SYSTEMATIC 23539147 A 35 42 calcium SYSTEMATIC 23539147 A 420 427 calcium SYSTEMATIC 23539147 A 962 969 calcium SYSTEMATIC 23539147 T 31 38 Calcium SYSTEMATIC 23539337 A 748 758 zantrin Z1 TRIVIAL 23539337 A 760 774 cinnamaldehyde TRIVIAL 23539337 A 776 783 totarol TRIVIAL 23539337 A 785 797 sanguinarine TRIVIAL 23539337 A 803 814 viriditoxin TRIVIAL 23540443 A 1322 1333 cholesterol TRIVIAL 23540443 A 284 295 cholesterol TRIVIAL 23540443 A 396 407 cholesterol TRIVIAL 23540443 A 421 432 cholesterol TRIVIAL 23540443 A 498 509 cholesterol TRIVIAL 23540443 A 522 533 cholesterol TRIVIAL 23540443 A 689 705 3H-triglycerides FAMILY 23540443 A 715 718 14C FORMULA 23540443 A 732 743 cholesterol TRIVIAL 23540443 A 757 777 3H-cholesteryl ester SYSTEMATIC 23540443 A 787 790 14C FORMULA 23540646 A 36 60 α,β-unsaturated carbonyl FAMILY 23540646 A 657 665 coumarin TRIVIAL 23540646 A 77 86 chalcones FAMILY 23540646 A 91 100 coumarins FAMILY 23540646 T 61 85 α,β-unsaturated carbonyl FAMILY 23540737 A 233 244 3-isopropyl SYSTEMATIC 23540737 A 249 257 3-iodine SYSTEMATIC 23540737 A 6 54 6-substituted-4-cycloalkyloxy-pyridin-2(1H)-ones FAMILY 23540737 A 79 89 nucleoside FAMILY 23540737 A 913 923 pyridinone FAMILY 23540737 T 36 46 Nucleoside FAMILY 23540737 T 6 16 Pyridinone FAMILY 23540838 A 15 28 maslinic acid TRIVIAL 23540838 A 182 193 acetic acid SYSTEMATIC 23540838 A 238 246 formalin TRIVIAL 23540838 A 265 274 capsaicin TRIVIAL 23540838 A 36 60 pentacyclic triterpenoid FAMILY 23540838 A 449 457 formalin TRIVIAL 23540838 A 592 605 maslinic acid TRIVIAL 23540838 T 39 52 Maslinic Acid TRIVIAL 23540838 T 56 80 Pentacyclic Triterpenoid FAMILY 23541086 A 1063 1077 glutaraldehyde TRIVIAL 23541086 A 1189 1197 abacavir TRIVIAL 23541086 A 1339 1347 abacavir TRIVIAL 23541086 A 1455 1463 abacavir TRIVIAL 23541086 A 1591 1599 abacavir TRIVIAL 23541086 A 1770 1778 abacavir TRIVIAL 23541086 A 1797 1805 abacavir TRIVIAL 23541086 A 458 466 abacavir TRIVIAL 23541086 A 681 689 abacavir TRIVIAL 23541086 A 726 734 abacavir TRIVIAL 23541086 A 925 933 abacavir TRIVIAL 23541086 T 60 68 Abacavir TRIVIAL 23541125 A 1056 1078 3,5-ditert-butylphenol SYSTEMATIC 23541125 A 1080 1095 coniferaldehyde TRIVIAL 23541125 A 1097 1109 formaldehyde SYSTEMATIC 23541125 A 1111 1126 perinaphthenone TRIVIAL 23541125 A 1128 1140 agathic acid TRIVIAL 23541125 A 1146 1163 isocupressic acid TRIVIAL 23541125 A 1343 1352 HC-030031 IDENTIFIER 23541125 A 1567 1578 glutathione TRIVIAL 23541125 A 1595 1602 menthol TRIVIAL 23541125 A 1658 1680 3,5-ditert-butylphenol SYSTEMATIC 23541125 A 488 495 calcium SYSTEMATIC 23541125 A 746 753 ethanol SYSTEMATIC 23541125 A 85 92 calcium SYSTEMATIC 23541472 A 1086 1093 amitraz TRIVIAL 23541472 A 1157 1163 5-HIAA SYSTEMATIC 23541472 A 1165 1169 MHPG ABBREVIATION 23541472 A 1171 1176 DOPAC ABBREVIATION 23541472 A 1181 1184 HVA ABBREVIATION 23541472 A 1237 1243 5-HIAA SYSTEMATIC 23541472 A 1273 1278 DOPAC ABBREVIATION 23541472 A 1366 1373 amitraz TRIVIAL 23541472 A 1421 1425 5-HT SYSTEMATIC 23541472 A 15 22 amitraz TRIVIAL 23541472 A 1511 1518 amitraz TRIVIAL 23541472 A 159 166 amitraz TRIVIAL 23541472 A 341 348 amitraz TRIVIAL 23541472 A 535 542 amitraz TRIVIAL 23541472 A 555 559 5-HT SYSTEMATIC 23541472 A 742 746 5-HT SYSTEMATIC 23541472 A 85 94 monoamine FAMILY 23541472 A 913 917 5-HT SYSTEMATIC 23541472 T 23 30 amitraz TRIVIAL 23541472 T 34 47 noradrenaline TRIVIAL 23541472 T 49 58 serotonin TRIVIAL 23541472 T 63 71 dopamine TRIVIAL 23541514 A 160 168 Tibolone TRIVIAL 23541514 A 207 211 PEGs ABBREVIATION 23541514 A 29 32 PEG ABBREVIATION 23541514 A 353 361 Tibolone TRIVIAL 23541514 A 426 429 PVP ABBREVIATION 23541514 A 442 448 PEG400 TRIVIAL 23541514 A 453 459 PEG600 TRIVIAL 23541514 A 585 593 Tibolone TRIVIAL 23541514 A 59 62 PVP ABBREVIATION 23541514 A 686 689 PEG ABBREVIATION 23541514 A 816 824 Tibolone TRIVIAL 23541514 A 829 832 PVP ABBREVIATION 23541514 A 833 836 PEG ABBREVIATION 23541514 T 15 18 PVP ABBREVIATION 23541514 T 19 22 PEG ABBREVIATION 23541647 A 0 10 Porphyrins FAMILY 23541647 A 15 23 chlorins FAMILY 23541647 A 283 302 bile acid porphyrin FAMILY 23541647 A 32 38 Foscan TRIVIAL 23541647 A 381 391 Bile acids FAMILY 23541647 A 599 638 5,10,15,20-tetrahydroxyphenylporphyrins FAMILY 23541647 A 644 661 propargyl bromide SYSTEMATIC 23541647 A 674 679 Cu(I) FORMULA 23541647 A 708 724 bile acid azides FAMILY 23541647 T 39 45 Foscan TRIVIAL 23541647 T 49 58 bile acid FAMILY 23541649 A 0 59 1-(7-Azabenzobicyclo[2.2.1]heptane)diazen-1-ium-1,2-diolate SYSTEMATIC 23541649 A 127 139 nitric oxide SYSTEMATIC 23541649 A 141 143 NO FORMULA 23541649 A 149 157 nitroxyl SYSTEMATIC 23541649 A 159 162 HNO FORMULA 23541649 A 283 285 NO FORMULA 23541649 A 296 299 HNO FORMULA 23541649 T 2 26 diazen-1-ium-1,2-diolate SYSTEMATIC 23541649 T 37 68 7-azabenzobicyclo[2.2.1]heptane SYSTEMATIC 23541649 T 81 93 nitric oxide SYSTEMATIC 23541649 T 98 106 nitroxyl SYSTEMATIC 23541668 A 11 16 ureas FAMILY 23541668 A 20 38 m-phenylenediamine SYSTEMATIC 23541668 A 54 58 DMPG ABBREVIATION 23541668 A 60 91 dimyristoylphosphatidylglycerol TRIVIAL 23541668 T 24 44 metaphenylenediamine SYSTEMATIC 23541672 A 139 157 pyrazole chalcones FAMILY 23541672 A 16 45 fluoro substituted pyrazoline FAMILY 23541672 A 174 197 polyethylene glycol-400 TRIVIAL 23541672 A 199 206 PEG-400 TRIVIAL 23541672 A 434 444 Diclofenac TRIVIAL 23541672 T 0 3 PEG ABBREVIATION 23541672 T 62 91 fluoro substituted pyrazoline FAMILY 23541674 A 203 209 Ni(2+) FORMULA 23541674 A 210 231 nitrilotriacetic acid SYSTEMATIC 23541674 A 233 236 NTA ABBREVIATION 23541674 A 272 281 histidine TRIVIAL 23541674 A 28 38 amino acid FAMILY 23541674 A 286 292 BpyAla FORMULA 23541674 A 294 300 BpyAla FORMULA 23541674 A 39 55 bipyridylalanine SYSTEMATIC 23541674 A 402 411 histidine TRIVIAL 23541674 A 416 422 BpyAla FORMULA 23541674 A 448 454 BpyAla FORMULA 23541674 A 490 496 Ni(2+) FORMULA 23541674 A 558 564 BpyAla FORMULA 23541674 A 57 63 BpyAla FORMULA 23541674 A 589 600 amino acids FAMILY 23541674 A 89 98 disulfide SYSTEMATIC 23541674 T 66 77 amino acids FAMILY 23541929 A 693 711 poly-vinyl alcohol FAMILY 23542080 A 13 22 glutamate TRIVIAL 23542080 A 1305 1313 LY341495 IDENTIFIER 23542080 A 376 398 dihydroxyphenylglycine SYSTEMATIC 23542080 A 400 404 DHPG ABBREVIATION 23542080 A 677 681 DHPG ABBREVIATION 23542080 A 785 789 DHPG ABBREVIATION 23542080 T 100 109 glutamate TRIVIAL 23542114 A 184 200 arsenic trioxide SYSTEMATIC 23542114 A 202 205 ATO ABBREVIATION 23542114 A 408 411 ATO ABBREVIATION 23542114 A 465 468 ATO ABBREVIATION 23542114 A 564 567 ATO ABBREVIATION 23542114 A 689 692 ATO ABBREVIATION 23542114 T 0 16 Arsenic trioxide SYSTEMATIC 23542166 A 1051 1105 2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles FAMILY 23542166 A 1193 1197 5-HT SYSTEMATIC 23542166 A 1211 1220 serotonin TRIVIAL 23542166 A 124 186 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole SYSTEMATIC 23542166 A 188 197 EMD386088 IDENTIFIER 23542166 A 215 269 2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles FAMILY 23542166 A 408 414 indole SYSTEMATIC 23542166 A 693 699 indole SYSTEMATIC 23542166 A 72 91 5-hydroxytryptamine SYSTEMATIC 23542166 A 733 738 alkyl FAMILY 23542166 A 753 761 2-methyl SYSTEMATIC 23542166 A 784 791 halogen FAMILY 23542166 A 812 818 indole SYSTEMATIC 23542166 A 831 837 fluoro SYSTEMATIC 23542166 A 839 845 chloro SYSTEMATIC 23542166 A 850 855 bromo SYSTEMATIC 23542166 A 917 932 benzenesulfonyl SYSTEMATIC 23542166 T 35 97 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole SYSTEMATIC 23542210 A 0 22 Sesquiterpene lactones FAMILY 23542210 A 1240 1248 santonin TRIVIAL 23542210 A 154 164 α-santonin TRIVIAL 23542210 A 24 27 SLs FAMILY 23542210 T 62 72 α-santonin TRIVIAL 23542230 A 324 334 methyldopa TRIVIAL 23542230 A 339 348 labetalol TRIVIAL 23542343 A 1026 1034 cysteine TRIVIAL 23542343 A 1091 1102 iron-sulfur SYSTEMATIC 23542343 A 1145 1148 Cys FORMULA 23542343 A 1163 1166 Ser FORMULA 23542343 A 1170 1173 Ala FORMULA 23542343 A 1266 1277 iron-sulfur SYSTEMATIC 23542343 A 1343 1346 Cys FORMULA 23542343 A 1363 1364 C FORMULA 23542343 A 1444 1455 iron-sulfur SYSTEMATIC 23542343 A 1640 1651 iron-sulfur SYSTEMATIC 23542343 A 422 426 iron SYSTEMATIC 23542343 A 595 596 C FORMULA 23542343 A 647 658 iron-sulfur SYSTEMATIC 23542343 A 784 795 iron-sulfur SYSTEMATIC 23542343 A 965 971 oxygen SYSTEMATIC 23542343 A 982 994 [4Fe-4S](2+) FORMULA 23542343 T 63 74 Iron-Sulfur SYSTEMATIC 23542494 A 1031 1040 reserpine TRIVIAL 23542494 A 1111 1116 CurDD ABBREVIATION 23542494 A 1199 1207 curcumin TRIVIAL 23542494 A 300 305 CurDD ABBREVIATION 23542494 A 63 83 curcumin didecanoate SYSTEMATIC 23542494 A 657 665 curcumin TRIVIAL 23542494 A 825 833 curcumin TRIVIAL 23542494 A 85 90 CurDD ABBREVIATION 23542494 A 859 864 CurDD ABBREVIATION 23542494 T 62 82 curcumin didecanoate SYSTEMATIC 23542495 A 1175 1181 AlClPc FORMULA 23542495 A 1187 1193 AlClPc FORMULA 23542495 A 145 175 chloroaluminium phthalocyanine SYSTEMATIC 23542495 A 17 47 poly(d,l-lactide-co-glycolide) FAMILY 23542495 A 177 183 AlClPc FORMULA 23542495 A 49 66 poly(d,l-lactide) FAMILY 23542495 A 71 114 polyethylene glycol-block-poly(d,l-lactide) FAMILY 23542495 A 758 764 AlClPc FORMULA 23542495 A 814 820 AlClPc FORMULA 23542495 T 0 30 Chloroaluminium phthalocyanine SYSTEMATIC 23542815 A 0 16 Arsenic trioxide SYSTEMATIC 23542815 A 1149 1157 LY364947 IDENTIFIER 23542815 A 1341 1344 ATO ABBREVIATION 23542815 A 1404 1407 ATO ABBREVIATION 23542815 A 18 23 As2O3 FORMULA 23542815 A 200 203 ATO ABBREVIATION 23542815 A 25 28 ATO ABBREVIATION 23542815 A 408 411 ATO ABBREVIATION 23542815 A 467 470 ATO ABBREVIATION 23542815 A 516 519 ATO ABBREVIATION 23542815 A 740 743 MTT ABBREVIATION 23542815 A 762 765 ATO ABBREVIATION 23542815 A 941 944 ATO ABBREVIATION 23542815 T 0 16 Arsenic trioxide SYSTEMATIC 23542816 A 208 224 phthalate esters FAMILY 23542816 A 226 229 PEs FAMILY 23542816 A 529 532 PEs FAMILY 23542816 A 980 989 phthalate FAMILY 23542816 T 9 18 phthalate FAMILY 23542817 A 633 644 glutathione TRIVIAL 23542817 A 646 649 GSH ABBREVIATION 23542817 A 655 670 malondialdehyde TRIVIAL 23542817 A 672 675 MDA ABBREVIATION 23542817 A 693 704 glutathione TRIVIAL 23542817 A 720 731 glutathione TRIVIAL 23542819 A 0 8 Mancozeb FAMILY 23542819 A 10 53 manganese/zinc ethylene bis-dithiocarbamate MULTIPLE 23542819 A 1099 1108 potassium SYSTEMATIC 23542819 A 1153 1161 Mancozeb FAMILY 23542819 A 275 283 Mancozeb FAMILY 23542819 A 339 347 Mancozeb FAMILY 23542819 A 473 482 manganese SYSTEMATIC 23542819 A 491 524 zinc ethylene bis-dithiocarbamate SYSTEMATIC 23542819 A 666 670 iron SYSTEMATIC 23542819 A 741 747 sodium SYSTEMATIC 23542819 A 806 810 iron SYSTEMATIC 23542819 A 812 818 Fe(3+) FORMULA 23542819 A 867 871 iron SYSTEMATIC 23542819 T 4 32 ethylene bis-dithiocarbamate SYSTEMATIC 23542819 T 43 51 Mancozeb FAMILY 23542819 T 82 91 potassium SYSTEMATIC 23543013 A 1009 1012 CpG ABBREVIATION 23543013 A 1085 1088 CpG ABBREVIATION 23543013 A 1155 1170 1-hydroxypyrene SYSTEMATIC 23543013 A 1542 1546 BPDE ABBREVIATION 23543013 A 1733 1737 PAHs ABBREVIATION 23543013 A 271 303 polycyclic aromatic hydrocarbons FAMILY 23543013 A 305 309 PAHs ABBREVIATION 23543013 A 328 331 PAH ABBREVIATION 23543013 A 411 426 1-hydroxypyrene SYSTEMATIC 23543013 A 473 482 bleomycin FAMILY 23543013 A 524 528 PAHs ABBREVIATION 23543013 A 617 626 bisulfite SYSTEMATIC 23543013 A 728 746 O(6)-methylguanine SYSTEMATIC 23543013 A 928 932 PAHs ABBREVIATION 23543013 A 947 950 PAH ABBREVIATION 23543013 T 139 170 polycyclic aromatic hydrocarbon FAMILY 23543426 A 540 548 creatine TRIVIAL 23543426 A 576 584 creatine TRIVIAL 23543426 A 593 603 creatinine TRIVIAL 23543426 A 605 614 glutamate TRIVIAL 23543426 A 615 626 oxalacetate TRIVIAL 23543426 A 647 656 glutamate TRIVIAL 23543426 A 657 665 pyruvate TRIVIAL 23543630 A 1002 1006 DMPC ABBREVIATION 23543630 A 1033 1039 MK-801 IDENTIFIER 23543630 A 1122 1126 DMPC ABBREVIATION 23543630 A 1159 1164 Cl(-) FORMULA 23543630 A 1183 1191 muscimol TRIVIAL 23543630 A 1256 1260 DMPC ABBREVIATION 23543630 A 162 172 oroxylin A TRIVIAL 23543630 A 28 38 oroxylin A TRIVIAL 23543630 A 357 367 oroxylin A TRIVIAL 23543630 A 380 440 5,7-dihydroxy-6-methoxy-2(4-phenoxyphenyl)-4H-chromene-4-one SYSTEMATIC 23543630 A 42 61 γ-aminobutyric acid SYSTEMATIC 23543630 A 442 446 DMPC ABBREVIATION 23543630 A 591 602 scopolamine TRIVIAL 23543630 A 641 647 MK-801 IDENTIFIER 23543630 A 652 672 N-methyl-D-aspartate SYSTEMATIC 23543630 A 739 745 MK-801 IDENTIFIER 23543630 A 827 831 DMPC ABBREVIATION 23543630 A 878 889 scopolamine TRIVIAL 23543630 A 894 900 MK-801 IDENTIFIER 23543630 T 28 88 5,7-dihydroxy-6-methoxy-2(4-phenoxyphenyl)-4H-chromene-4-one SYSTEMATIC 23543630 T 93 103 oroxylin A TRIVIAL 23543631 A 0 12 Tryptanthrin TRIVIAL 23543631 A 17 43 indoloquinazoline alkaloid FAMILY 23543631 A 202 214 Tryptanthrin TRIVIAL 23543631 A 392 394 NO FORMULA 23543631 A 408 414 PGE(2) ABBREVIATION 23543631 A 652 664 tryptanthrin TRIVIAL 23543631 T 27 39 tryptanthrin TRIVIAL 23543632 A 101 136 (3,4-dihydro-2H-pyran-2-yl)methanol SYSTEMATIC 23543632 A 137 176 5-(hydroxymethyl)dihydrofuran-2(3H)-one SYSTEMATIC 23543632 A 28 47 (E/Z)-Goniothalamin TRIVIAL 23543632 A 361 378 (Z)-Goniothalamin TRIVIAL 23543632 A 547 553 phenyl SYSTEMATIC 23543632 A 562 570 pyridine SYSTEMATIC 23543632 A 571 582 naphthalene SYSTEMATIC 23543632 A 615 623 lactones FAMILY 23543632 T 91 104 Goniothalamin TRIVIAL 23543737 A 1021 1030 glutamate TRIVIAL 23543737 A 1060 1063 ATP ABBREVIATION 23543737 A 1142 1145 ATP ABBREVIATION 23543737 A 1213 1220 calcium SYSTEMATIC 23543737 A 1357 1366 glutamate TRIVIAL 23543737 A 1387 1390 ATP ABBREVIATION 23543737 A 14 21 calcium SYSTEMATIC 23543737 A 281 290 glutamate TRIVIAL 23543737 A 410 419 glutamate TRIVIAL 23543737 A 554 561 calcium SYSTEMATIC 23543737 A 601 608 calcium SYSTEMATIC 23543737 A 634 635 N FORMULA 23543737 A 641 648 calcium SYSTEMATIC 23543737 A 708 709 N FORMULA 23543737 A 715 722 calcium SYSTEMATIC 23543737 A 788 795 calcium SYSTEMATIC 23543737 A 825 832 calcium SYSTEMATIC 23543737 A 897 906 glutamate TRIVIAL 23543737 A 911 914 ATP ABBREVIATION 23543737 T 148 151 ATP ABBREVIATION 23543737 T 8 15 Calcium SYSTEMATIC 23543737 T 97 106 Glutamate TRIVIAL 23543864 A 210 254 tetrabutylammonium trifluoromethanesulfonate SYSTEMATIC 23543864 A 258 269 2-pentanone SYSTEMATIC 23543864 A 271 281 2-hexanone SYSTEMATIC 23543864 A 283 294 2-heptanone SYSTEMATIC 23543864 A 296 306 2-octanone SYSTEMATIC 23543864 A 308 318 2-nonanone SYSTEMATIC 23543864 A 324 334 2-decanone SYSTEMATIC 23543864 A 64 78 n-alkyl ketone FAMILY 23543864 A 746 753 ketones FAMILY 23543864 A 758 764 ketone SYSTEMATIC 23543864 A 826 842 n-alkyl acetates FAMILY 23543864 A 847 862 n-alkyl acetate FAMILY 23543864 T 26 33 Ketones FAMILY 23543864 T 38 44 Ketone SYSTEMATIC 23543864 T 75 82 Acetate SYSTEMATIC 23544432 A 300 304 GABA ABBREVIATION 23544432 A 37 43 COR627 IDENTIFIER 23544432 A 439 447 baclofen TRIVIAL 23544432 A 48 54 COR628 IDENTIFIER 23544432 A 623 630 GS39783 IDENTIFIER 23544432 A 766 774 baclofen TRIVIAL 23544432 A 957 964 GS39783 IDENTIFIER 23544432 A 968 974 BHF177 IDENTIFIER 23544432 A 99 121 2-(acylamino)thiophene SYSTEMATIC 23544432 T 50 72 2-(Acylamino)thiophene SYSTEMATIC 23544459 A 166 179 γ-butenolides FAMILY 23544459 A 284 316 γ-tertiary and quaternary carbon MULTIPLE 23544459 A 328 339 butenolides FAMILY 23544459 A 4 16 γ-butenolide SYSTEMATIC 23544459 A 460 490 γ,γ- disubstituted butenolides FAMILY 23544459 A 521 550 γ,γ-disubstituted butenolides FAMILY 23544459 T 34 47 γ-Butenolides FAMILY 23544461 A 0 16 Organophosphorus FAMILY 23544461 A 192 208 transition metal FAMILY 23544461 A 263 269 P(O)-H FORMULA 23544461 A 297 313 organophosphorus FAMILY 23544461 A 373 379 P(O)-H FORMULA 23544461 A 393 399 carbon SYSTEMATIC 23544461 A 400 406 carbon SYSTEMATIC 23544461 A 515 521 P(O)-H FORMULA 23544461 A 537 543 carbon SYSTEMATIC 23544461 A 544 545 H FORMULA 23544461 A 561 562 H FORMULA 23544461 A 700 716 organophosphorus FAMILY 23544461 T 0 16 Transition metal FAMILY 23544461 T 97 113 organophosphorus FAMILY 23544465 A 191 205 organoselenium FAMILY 23544465 A 341 351 isoxazoles FAMILY 23544465 A 353 364 oxadiazoles FAMILY 23544465 A 366 375 triazoles FAMILY 23544465 A 377 388 pyrimidines FAMILY 23544465 A 390 400 pyrrolines FAMILY 23544465 A 402 411 indolines FAMILY 23544465 A 413 424 benzopyrans FAMILY 23544465 A 426 432 furans FAMILY 23544465 A 444 458 organoselenium FAMILY 23544465 T 8 16 selenium SYSTEMATIC 23544613 A 206 228 dimethyl terephthalate SYSTEMATIC 23544613 A 233 250 1,8-diaminooctane SYSTEMATIC 23544613 A 260 296 oligo(octamethylene terephthalamide) FAMILY 23544613 A 427 449 dimethyl terephthalate SYSTEMATIC 23544613 A 44 61 p-xylylenediamine SYSTEMATIC 23544613 A 454 471 p-xylylenediamine SYSTEMATIC 23544613 A 66 82 diethyl sebacate SYSTEMATIC 23544613 A 730 758 oligo(p-xylylene sebacamide) FAMILY 23544613 A 95 123 oligo(p-xylylene sebacamide) FAMILY 23544615 A 1005 1016 polystyrene SYSTEMATIC 23544615 A 306 317 polystyrene SYSTEMATIC 23544615 A 322 333 polystyrene SYSTEMATIC 23544615 A 468 479 polystyrene SYSTEMATIC 23545109 A 175 187 carboxylates FAMILY 23545109 A 191 207 hydroxamic acids FAMILY 23545456 A 2483 2493 gentamycin FAMILY 23545456 A 2494 2505 methicillin TRIVIAL 23545456 A 2681 2690 plumbagin TRIVIAL 23545456 A 3424 3433 plumbagin TRIVIAL 23545568 A 13 20 lithium SYSTEMATIC 23545568 A 24 31 lithium SYSTEMATIC 23545568 A 507 512 LiNi1 FORMULA 23545568 A 513 517 3Co1 FORMULA 23545568 A 518 522 3Mn1 FORMULA 23545568 A 523 526 3O2 FORMULA 23545568 A 528 535 LiFePO4 FORMULA 23545568 A 548 562 Li1.05Mn1.95O4 FORMULA 23545568 T 60 67 lithium SYSTEMATIC 23545721 A 0 12 Mitoxantrone TRIVIAL 23545721 A 1018 1021 MTX ABBREVIATION 23545721 A 1026 1043 naphtoquinoxaline SYSTEMATIC 23545721 A 1099 1102 MTX ABBREVIATION 23545721 A 111 114 MTX ABBREVIATION 23545721 A 1144 1147 MTX ABBREVIATION 23545721 A 1241 1244 MTX ABBREVIATION 23545721 A 1273 1276 MTX ABBREVIATION 23545721 A 1364 1367 MTX ABBREVIATION 23545721 A 14 17 MTX ABBREVIATION 23545721 A 1438 1441 MTX ABBREVIATION 23545721 A 1487 1504 naphtoquinoxaline SYSTEMATIC 23545721 A 155 158 MTX ABBREVIATION 23545721 A 1646 1649 MTX ABBREVIATION 23545721 A 1690 1693 MTX ABBREVIATION 23545721 A 220 223 MTX ABBREVIATION 23545721 A 322 325 MTX ABBREVIATION 23545721 A 365 368 MTX ABBREVIATION 23545721 A 373 376 MTX ABBREVIATION 23545721 A 449 452 MTX ABBREVIATION 23545721 A 463 466 MTX ABBREVIATION 23545721 A 562 565 MTX ABBREVIATION 23545721 A 606 609 MTX ABBREVIATION 23545721 A 738 741 MTX ABBREVIATION 23545721 A 858 869 glutathione TRIVIAL 23545721 A 884 903 monocarboxylic acid SYSTEMATIC 23545721 A 924 941 naphtoquinoxaline SYSTEMATIC 23545721 A 973 976 MTX ABBREVIATION 23545721 T 25 37 mitoxantrone TRIVIAL 23545721 T 60 72 mitoxantrone TRIVIAL 23546010 A 25 38 gypsophin A-F MULTIPLE 23546397 A 1006 1017 glutathione TRIVIAL 23546397 A 1019 1022 GSH ABBREVIATION 23546397 A 103 118 petroleum ether TRIVIAL 23546397 A 1042 1049 ethanol SYSTEMATIC 23546397 A 1202 1205 GSH ABBREVIATION 23546397 A 1224 1231 ethanol SYSTEMATIC 23546397 A 134 144 chloroform TRIVIAL 23546397 A 1364 1371 ethanol SYSTEMATIC 23546397 A 160 173 ethyl acetate SYSTEMATIC 23546397 A 296 303 ethanol SYSTEMATIC 23546397 A 485 492 ethanol SYSTEMATIC 23546397 A 577 637 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide SYSTEMATIC 23546397 A 643 654 neutral red TRIVIAL 23546397 A 859 866 ethanol SYSTEMATIC 23546397 A 943 949 oxygen SYSTEMATIC 23546397 T 71 78 ethanol SYSTEMATIC 23546398 A 255 262 citrate FAMILY 23546398 A 270 272 Ag FORMULA 23546398 A 28 34 silver SYSTEMATIC 23546398 A 355 374 polyethylene glycol SYSTEMATIC 23546398 A 382 384 Ag FORMULA 23546398 A 50 52 Ag FORMULA 23546398 T 27 34 citrate FAMILY 23546398 T 40 59 polyethylene glycol SYSTEMATIC 23546398 T 67 73 silver SYSTEMATIC 23546603 A 1057 1060 DES ABBREVIATION 23546603 A 1126 1134 androgen FAMILY 23546603 A 1347 1355 androgen FAMILY 23546603 A 1634 1642 androgen FAMILY 23546603 A 284 292 androgen FAMILY 23546603 A 383 406 testosterone propionate SYSTEMATIC 23546603 A 829 838 estrogens FAMILY 23546603 A 890 898 estrogen FAMILY 23546603 A 908 926 diethylstilbestrol SYSTEMATIC 23546603 A 928 931 DES ABBREVIATION 23546603 T 7 16 androgens FAMILY 23547762 A 1050 1053 BDS ABBREVIATION 23547762 A 107 114 HP-β-CD ABBREVIATION 23547762 A 1197 1199 Na FORMULA 23547762 A 1439 1442 BDS ABBREVIATION 23547762 A 160 166 sodium SYSTEMATIC 23547762 A 195 197 Na FORMULA 23547762 A 59 69 budesonide TRIVIAL 23547762 A 71 74 BDS ABBREVIATION 23547762 A 77 105 hydroxypropyl-β-cyclodextrin SYSTEMATIC 23547762 A 852 860 carbonyl FAMILY 23547762 A 862 865 C=O FORMULA 23547762 A 887 895 carboxyl SYSTEMATIC 23547762 A 905 908 BDS ABBREVIATION 23547762 T 0 10 Budesonide TRIVIAL 23547810 A 1000 1004 5-HT SYSTEMATIC 23547810 A 152 161 serotonin TRIVIAL 23547810 A 163 167 5-HT SYSTEMATIC 23547810 A 470 474 5-HT SYSTEMATIC 23547810 A 689 699 tryptophan TRIVIAL 23547810 A 766 770 5-HT SYSTEMATIC 23547810 T 0 9 Serotonin TRIVIAL 23547810 T 105 115 Tryptophan TRIVIAL 23547810 T 11 15 5-HT SYSTEMATIC 23547810 T 84 88 5-HT SYSTEMATIC 23547844 A 0 16 Hydrogen sulfide SYSTEMATIC 23547844 A 1107 1110 H2S FORMULA 23547844 A 163 166 H2S FORMULA 23547844 A 18 21 H2S FORMULA 23547844 A 237 240 H2S FORMULA 23547844 A 291 294 H2S FORMULA 23547844 A 351 354 H2S FORMULA 23547844 A 475 478 H2S FORMULA 23547844 A 565 573 perthiol SYSTEMATIC 23547844 A 622 625 H2S FORMULA 23547844 A 640 643 H2S FORMULA 23547844 A 709 714 thiol FAMILY 23547844 A 790 793 H2S FORMULA 23547844 A 924 927 H2S FORMULA 23547844 T 13 29 Hydrogen Sulfide SYSTEMATIC 23547884 A 104 116 drimentine C TRIVIAL 23547884 A 15 26 isoprenoids FAMILY 23547884 A 338 351 Indotertine B TRIVIAL 23547884 A 34 47 indotertine B TRIVIAL 23547884 A 395 401 N-C(O) FORMULA 23547884 A 56 68 drimentine H TRIVIAL 23547884 T 18 29 Isoprenoids FAMILY 23548027 A 707 717 fatty acid FAMILY 23548055 A 16 47 O-pivaloyl benzhydroxamic acids FAMILY 23548055 A 161 181 benzhydroxamic acids FAMILY 23548055 A 186 191 diazo SYSTEMATIC 23548055 A 225 252 2,2,2-trifluorodiazoethanes FAMILY 23548055 A 293 296 C-H FORMULA 23548055 A 372 377 diazo SYSTEMATIC 23548055 A 68 73 diazo SYSTEMATIC 23548055 A 93 105 isoindolones FAMILY 23548055 T 100 103 C-H FORMULA 23548055 T 14 24 Benzamides FAMILY 23548055 T 44 49 Diazo SYSTEMATIC 23548055 T 68 77 γ-Lactams FAMILY 23548055 T 82 89 Rh(III) FORMULA 23548165 A 1038 1047 pazopanib TRIVIAL 23548165 A 1141 1150 pazopanib TRIVIAL 23548165 A 1263 1272 pazopanib TRIVIAL 23548165 A 14 22 Votrient TRIVIAL 23548165 A 229 245 [(14)C]pazopanib SYSTEMATIC 23548165 A 279 288 pazopanib TRIVIAL 23548165 A 3 12 Pazopanib TRIVIAL 23548165 A 35 43 tyrosine TRIVIAL 23548165 A 391 407 [(14)C]pazopanib SYSTEMATIC 23548165 A 440 449 Pazopanib TRIVIAL 23548165 A 565 566 N FORMULA 23548165 A 805 814 Pazopanib TRIVIAL 23548165 A 978 987 pazopanib TRIVIAL 23548165 T 52 61 pazopanib TRIVIAL 23548584 A 1211 1214 PRZ ABBREVIATION 23548584 A 1294 1297 PRZ ABBREVIATION 23548584 A 1367 1378 glutathione TRIVIAL 23548584 A 1436 1447 glutathione TRIVIAL 23548584 A 1503 1513 superoxide TRIVIAL 23548584 A 1745 1748 PRZ ABBREVIATION 23548584 A 2042 2050 aldehyde SYSTEMATIC 23548584 A 438 446 pyrazole SYSTEMATIC 23548584 A 448 451 PRZ ABBREVIATION 23548584 A 839 842 PRZ ABBREVIATION 23548584 A 895 904 aspartate TRIVIAL 23548584 A 925 932 alanine TRIVIAL 23548584 A 957 972 malondialdehyde TRIVIAL 23548584 A 974 977 MDA ABBREVIATION 23548584 T 82 90 pyrazole SYSTEMATIC 23548704 A 237 246 quinolone FAMILY 23548704 A 259 277 thiazolidin-4-ones FAMILY 23548704 T 28 46 thiazolidin-4-ones FAMILY 23548704 T 6 15 quinolone FAMILY 23549272 A 1009 1014 thiol FAMILY 23549272 A 1253 1259 thiols FAMILY 23549272 A 527 535 cysteine TRIVIAL 23549272 A 540 550 methionine TRIVIAL 23549272 A 631 641 tripeptide FAMILY 23549272 A 643 660 thiol glutathione SYSTEMATIC 23549272 A 746 757 glutathione TRIVIAL 23549272 A 835 840 thiol FAMILY 23549272 A 886 897 glutathione TRIVIAL 23549272 A 948 959 glutathione TRIVIAL 23549272 T 19 25 thiols FAMILY 23549985 A 1019 1022 SCN FORMULA 23549985 A 1079 1090 amino acids FAMILY 23549985 A 1104 1107 SCN FORMULA 23549985 A 1176 1187 amino acids FAMILY 23549985 A 1191 1197 SCN(-) FORMULA 23549985 A 1251 1262 amino acids FAMILY 23549985 A 1273 1279 serine TRIVIAL 23549985 A 1281 1284 Ser FORMULA 23549985 A 1287 1294 proline TRIVIAL 23549985 A 1296 1299 Pro FORMULA 23549985 A 1306 1316 methionine TRIVIAL 23549985 A 1318 1321 Met FORMULA 23549985 A 1340 1350 asparagine TRIVIAL 23549985 A 1352 1355 Asp FORMULA 23549985 A 1400 1406 SCN(-) FORMULA 23549985 A 1436 1442 SCN(-) FORMULA 23549985 A 1557 1563 SCN(-) FORMULA 23549985 A 25 36 thiocyanate SYSTEMATIC 23549985 A 254 275 potassium thiocyanate SYSTEMATIC 23549985 A 277 281 KSCN FORMULA 23549985 A 298 308 superoxide TRIVIAL 23549985 A 364 373 ascorbate TRIVIAL 23549985 A 38 44 SCN(-) FORMULA 23549985 A 460 471 amino acids FAMILY 23549985 A 49 60 amino acids FAMILY 23549985 A 545 551 SCN(-) FORMULA 23549985 A 691 702 chlorophyll FAMILY 23549985 A 748 751 SCN FORMULA 23549985 A 947 953 SCN(-) FORMULA 23549985 T 21 32 thiocyanate SYSTEMATIC 23549985 T 88 99 amino acids FAMILY 23550028 A 1093 1101 SB203580 IDENTIFIER 23550028 A 1219 1250 2-hydroxy-3-methylanthraquinone SYSTEMATIC 23550028 A 238 252 anthraquinones FAMILY 23550028 A 593 624 2-hydroxy-3-methylanthraquinone SYSTEMATIC 23550028 A 666 697 2-hydroxy-3-methylanthraquinone SYSTEMATIC 23550028 A 865 896 2-hydroxy-3-methylanthraquinone SYSTEMATIC 23550028 A 947 954 PD98059 IDENTIFIER 23550028 A 997 1028 2-hydroxy-3-methylanthraquinone SYSTEMATIC 23550028 T 0 31 2-Hydroxy-3-methylanthraquinone SYSTEMATIC 23550937 A 0 8 Curcumin TRIVIAL 23550937 A 463 471 curcumin TRIVIAL 23550937 A 608 611 ATP ABBREVIATION 23550937 A 640 648 curcumin TRIVIAL 23550937 A 686 689 Ser FORMULA 23550937 A 690 693 Thr FORMULA 23550937 T 0 21 Monocarbonyl Curcumin SYSTEMATIC 23550966 A 10 35 cycloartane triterpenoids FAMILY 23550966 A 111 127 dikamaliartane D TRIVIAL 23550966 A 49 63 carinatins A-H MULTIPLE 23550966 A 89 102 secaubryolide TRIVIAL 23550966 T 63 76 Triterpenoids FAMILY 23551063 A 1019 1022 HFC ABBREVIATION 23551063 A 1027 1030 UDP ABBREVIATION 23551063 A 1031 1046 glucuronic acid TRIVIAL 23551063 A 1135 1138 HFC ABBREVIATION 23551063 A 1279 1282 HFC ABBREVIATION 23551063 A 13 16 UDP ABBREVIATION 23551063 A 257 292 7-hydroxy-4-trifluoromethylcoumarin SYSTEMATIC 23551063 A 294 297 HFC ABBREVIATION 23551063 A 386 389 HFC ABBREVIATION 23551063 A 505 508 HFC ABBREVIATION 23551063 A 646 649 HFC ABBREVIATION 23551063 A 918 921 HFC ABBREVIATION 23551063 T 108 111 UDP ABBREVIATION 23551063 T 51 86 7-hydroxy-4-trifluoromethylcoumarin SYSTEMATIC 23551255 A 1074 1086 alkali-metal FAMILY 23551255 A 1093 1098 Rb(+) FORMULA 23551255 A 1103 1108 Cs(+) FORMULA 23551255 A 1241 1245 CsCl FORMULA 23551255 A 1250 1254 RbCl FORMULA 23551255 A 330 352 alkali-metal chlorides FAMILY 23551255 A 364 368 LiCl FORMULA 23551255 A 370 374 NaCl FORMULA 23551255 A 376 380 RbCl FORMULA 23551255 A 385 389 CsCl FORMULA 23551255 A 418 436 1,2-dichloroethane SYSTEMATIC 23551255 A 449 524 bis(triphenylphosphor anylidene) ammonium tetrakis(pentafluorophenyl)borate SYSTEMATIC 23551255 A 526 535 BTPPATPFB ABBREVIATION 23551255 A 658 663 Li(+) FORMULA 23551255 A 665 670 Rb(+) FORMULA 23551255 A 672 677 Cs(+) FORMULA 23551255 A 679 687 BTPPA(+) ABBREVIATION 23551255 A 693 700 TPFB(-) ABBREVIATION 23551255 A 933 945 alkali-metal FAMILY 23551255 A 952 957 Li(+) FORMULA 23551255 A 962 967 Na(+) FORMULA 23551255 A 995 1002 TPFB(-) ABBREVIATION 23551255 T 31 49 1,2-Dichloroethane SYSTEMATIC 23551295 A 1042 1046 h-BN ABBREVIATION 23551295 A 1231 1233 Ar FORMULA 23551295 A 1250 1254 h-BN ABBREVIATION 23551295 A 1323 1327 h-BN ABBREVIATION 23551295 A 1394 1402 graphene TRIVIAL 23551295 A 1406 1415 ruthenium SYSTEMATIC 23551295 A 1424 1428 neon SYSTEMATIC 23551295 A 319 332 boron nitride SYSTEMATIC 23551295 A 382 395 boron nitride SYSTEMATIC 23551295 A 397 401 h-BN ABBREVIATION 23551295 A 454 461 Rh(111) FORMULA 23551295 A 491 496 argon SYSTEMATIC 23551295 A 51 62 noble gases FAMILY 23551295 A 618 623 argon SYSTEMATIC 23551295 A 647 651 h-BN ABBREVIATION 23551295 A 676 678 Rh FORMULA 23551295 A 762 767 argon SYSTEMATIC 23551295 T 67 80 Boron Nitride SYSTEMATIC 23551329 A 1186 1189 DEX ABBREVIATION 23551329 A 1381 1384 DEX ABBREVIATION 23551329 A 1459 1462 DEX ABBREVIATION 23551329 A 1602 1605 DEX ABBREVIATION 23551329 A 25 38 dexamethasone TRIVIAL 23551329 A 275 278 DEX ABBREVIATION 23551329 A 40 43 DEX ABBREVIATION 23551329 A 466 483 poly (ADP-ribose) SYSTEMATIC 23551329 A 654 668 corticosterone TRIVIAL 23551329 A 730 733 DEX ABBREVIATION 23551329 A 753 756 DEX ABBREVIATION 23551329 T 9 22 Dexamethasone TRIVIAL 23552260 A 0 9 Cisplatin TRIVIAL 23552260 A 427 437 creatinine TRIVIAL 23552260 A 448 452 urea TRIVIAL 23552260 A 453 461 nitrogen SYSTEMATIC 23552260 A 730 740 creatinine TRIVIAL 23552260 T 113 122 cisplatin TRIVIAL 23552263 A 1001 1008 tannins FAMILY 23552263 A 1013 1023 terpenoids FAMILY 23552263 A 557 570 ethyl acetate SYSTEMATIC 23552263 A 733 742 n-butanol SYSTEMATIC 23552263 A 959 967 saponins FAMILY 23552263 A 980 990 flavonoids FAMILY 23552263 A 992 999 phenols FAMILY 23552267 A 663 670 calcium SYSTEMATIC 23552267 A 672 678 sodium SYSTEMATIC 23552267 A 684 688 zinc SYSTEMATIC 23552267 A 690 692 Zn FORMULA 23552267 A 791 798 cadmium SYSTEMATIC 23552267 A 800 807 lithium SYSTEMATIC 23552267 A 809 818 magnesium SYSTEMATIC 23552267 A 820 829 manganese SYSTEMATIC 23552267 A 835 837 Zn FORMULA 23552267 A 918 920 Zn FORMULA 23552269 A 1184 1194 sugammadex TRIVIAL 23552269 A 1321 1331 rocuronium TRIVIAL 23552269 A 1336 1346 sugammadex TRIVIAL 23552269 A 205 215 sugammadex TRIVIAL 23552269 A 245 255 rocuronium TRIVIAL 23552269 A 349 359 rocuronium TRIVIAL 23552269 A 399 409 rocuronium TRIVIAL 23552269 A 420 430 sugammadex TRIVIAL 23552269 A 459 469 rocuronium TRIVIAL 23552269 A 480 490 sugammadex TRIVIAL 23552269 A 519 529 sugammadex TRIVIAL 23552269 A 546 556 sugammadex TRIVIAL 23552269 A 592 607 sodium chloride SYSTEMATIC 23552269 A 60 70 Rocuronium TRIVIAL 23552269 A 625 635 Sugammadex TRIVIAL 23552269 A 672 682 rocuronium TRIVIAL 23552269 T 10 20 sugammadex TRIVIAL 23552269 T 24 34 rocuronium TRIVIAL 23552831 A 102 105 NDI ABBREVIATION 23552831 A 117 120 NDI ABBREVIATION 23552831 A 143 149 flavin FAMILY 23552831 A 225 231 flavin FAMILY 23552831 A 531 537 flavin FAMILY 23552831 A 62 68 flavin FAMILY 23552831 A 82 100 naphthalenediimide SYSTEMATIC 23552831 T 34 52 naphthalenediimide SYSTEMATIC 23552831 T 68 74 flavin FAMILY 23553331 A 57 59 Xe FORMULA 23553331 A 644 651 HXeOXeH FORMULA 23553331 A 885 887 Xe FORMULA 23553331 A 989 991 Xe FORMULA 23553331 T 108 115 HXeOXeF FORMULA 23553331 T 121 128 FXeOXeF FORMULA 23553331 T 99 106 HXeOXeH FORMULA 23553357 A 419 430 sitagliptin TRIVIAL 23553497 A 1186 1195 vitamin D FAMILY 23553497 A 429 438 tenofovir TRIVIAL 23553497 A 663 672 tenofovir TRIVIAL 23553497 A 753 762 vitamin D FAMILY 23553497 A 922 931 vitamin D FAMILY 23553497 A 998 1007 vitamin D FAMILY 23553739 A 297 305 graphene TRIVIAL 23553739 A 74 82 graphene TRIVIAL 23553739 T 47 55 Graphene TRIVIAL 23553772 A 0 14 Trialkylgermyl FAMILY 23553797 A 1556 1567 propranolol TRIVIAL 23554428 A 1033 1051 R- and S-lorazepam MULTIPLE 23554428 A 106 121 glucuronic acid TRIVIAL 23554428 A 1164 1173 lorazepam TRIVIAL 23554428 A 1293 1300 codeine TRIVIAL 23554428 A 1302 1313 fluconazole TRIVIAL 23554428 A 1315 1323 ketamine TRIVIAL 23554428 A 1325 1337 ketoconazole TRIVIAL 23554428 A 1339 1348 methadone TRIVIAL 23554428 A 1350 1358 morphine TRIVIAL 23554428 A 1360 1373 valproic acid TRIVIAL 23554428 A 1379 1389 zidovudine TRIVIAL 23554428 A 1421 1440 R- and S- lorazepam MULTIPLE 23554428 A 1534 1546 ketoconazole TRIVIAL 23554428 A 1576 1585 lorazepam TRIVIAL 23554428 A 177 186 lorazepam TRIVIAL 23554428 A 304 313 lorazepam TRIVIAL 23554428 A 382 385 UDP ABBREVIATION 23554428 A 464 483 R- and S- lorazepam MULTIPLE 23554428 A 47 60 R,S-lorazepam MULTIPLE 23554428 A 664 683 R- and S- lorazepam MULTIPLE 23554428 A 715 734 R- and S- lorazepam MULTIPLE 23554428 A 788 799 R-lorazepam TRIVIAL 23554428 T 23 42 R- and S- Lorazepam MULTIPLE 23554428 T 77 80 UDP ABBREVIATION 23556334 A 112 124 posaconazole TRIVIAL 23556334 A 1200 1212 posaconazole TRIVIAL 23556334 A 157 169 acetonitrile SYSTEMATIC 23556334 A 280 292 acetonitrile SYSTEMATIC 23556334 A 304 315 formic acid SYSTEMATIC 23556334 A 368 383 Posaconazole-d4 TRIVIAL 23556334 A 578 590 posaconazole TRIVIAL 23556334 A 859 871 posaconazole TRIVIAL 23556334 T 73 85 posaconazole TRIVIAL 23556338 A 112 120 apigenin TRIVIAL 23556338 A 1307 1315 luteolin TRIVIAL 23556338 A 1396 1404 apigenin TRIVIAL 23556338 A 1535 1543 luteolin TRIVIAL 23556338 A 1567 1575 apigenin TRIVIAL 23556338 A 1770 1780 flavonoids FAMILY 23556338 A 354 362 luteolin TRIVIAL 23556338 A 367 375 apigenin TRIVIAL 23556338 A 544 552 luteolin TRIVIAL 23556338 A 581 589 apigenin TRIVIAL 23556338 A 623 631 luteolin TRIVIAL 23556338 A 662 670 apigenin TRIVIAL 23556338 A 708 716 luteolin TRIVIAL 23556338 A 746 754 apigenin TRIVIAL 23556338 A 840 848 luteolin TRIVIAL 23556338 A 853 861 apigenin TRIVIAL 23556338 A 99 107 luteolin TRIVIAL 23556338 T 27 35 luteolin TRIVIAL 23556338 T 40 48 apigenin TRIVIAL 23556998 A 1030 1035 PAMAM ABBREVIATION 23556998 A 108 124 poly(amidoamine) SYSTEMATIC 23556998 A 125 130 PAMAM ABBREVIATION 23556998 A 1317 1320 SDS ABBREVIATION 23556998 A 1338 1343 PAMAM ABBREVIATION 23556998 A 1368 1373 PAMAM ABBREVIATION 23556998 A 1374 1377 SDS ABBREVIATION 23556998 A 1405 1411 silica TRIVIAL 23556998 A 192 214 sodium dodecyl sulfate SYSTEMATIC 23556998 A 216 219 SDS ABBREVIATION 23556998 A 240 246 silica TRIVIAL 23556998 A 512 517 PAMAM ABBREVIATION 23556998 A 571 577 silica TRIVIAL 23556998 A 670 673 SDS ABBREVIATION 23556998 A 828 831 SDS ABBREVIATION 23556998 T 16 21 PAMAM ABBREVIATION 23556998 T 38 41 SDS ABBREVIATION 23557027 A 306 338 dodecyltrimethylammonium bromide SYSTEMATIC 23557027 A 340 344 DTAB ABBREVIATION 23557027 A 355 377 sodium dodecyl sulfate SYSTEMATIC 23557027 A 379 382 SDS ABBREVIATION 23557027 A 434 455 sodium lauryl sulfate SYSTEMATIC 23557027 A 466 502 tetraethylene glycol monooctyl ether SYSTEMATIC 23557027 A 504 508 C8E4 FORMULA 23557027 A 524 540 Pluronic (P-123) TRIVIAL 23557230 A 1143 1149 sulfur SYSTEMATIC 23557230 A 195 204 l-cystine TRIVIAL 23557230 A 20 29 l-cystine TRIVIAL 23557230 A 220 229 l-cystine TRIVIAL 23557230 A 483 492 l-cystine TRIVIAL 23557230 A 706 710 COOH FORMULA 23557230 A 712 715 NH2 FORMULA 23557230 A 717 719 SH FORMULA 23557230 A 721 724 CH3 FORMULA 23557230 A 726 728 OH FORMULA 23557230 A 891 900 l-cystine TRIVIAL 23557230 T 50 59 l-Cystine TRIVIAL 23557687 A 1026 1029 BPA ABBREVIATION 23557687 A 164 167 BPA ABBREVIATION 23557687 A 410 413 BPA ABBREVIATION 23557687 A 42 53 bisphenol A TRIVIAL 23557687 A 529 542 17β-estradiol SYSTEMATIC 23557687 A 55 58 BPA ABBREVIATION 23557687 A 758 761 BPA ABBREVIATION 23557687 A 888 891 BPA ABBREVIATION 23557687 T 127 138 bisphenol A TRIVIAL 23557687 T 143 156 17β-estradiol SYSTEMATIC 23557688 A 297 312 organophosphate FAMILY 23557688 A 650 659 ornithine TRIVIAL 23557688 T 67 76 ornithine TRIVIAL 23557843 A 0 11 Deflazacort TRIVIAL 23557843 A 1007 1015 methanol SYSTEMATIC 23557843 A 13 16 DFZ ABBREVIATION 23557843 A 132 147 corticosteroids FAMILY 23557843 A 1594 1597 DFZ ABBREVIATION 23557843 A 33 45 prednisolone TRIVIAL 23557843 A 878 881 DFZ ABBREVIATION 23557843 T 27 38 Deflazacort TRIVIAL 23558232 A 1253 1262 cisplatin TRIVIAL 23558232 A 1281 1284 TSA ABBREVIATION 23558232 A 1491 1500 cisplatin TRIVIAL 23558232 A 1524 1527 TSA ABBREVIATION 23558232 A 1619 1628 cisplatin TRIVIAL 23558232 A 1657 1666 cisplatin TRIVIAL 23558232 A 1858 1861 TSA ABBREVIATION 23558232 A 1899 1902 TSA ABBREVIATION 23558232 A 1956 1963 calcium SYSTEMATIC 23558232 A 2071 2074 TSA ABBREVIATION 23558232 A 2139 2148 cisplatin TRIVIAL 23558232 A 2205 2208 TSA ABBREVIATION 23558232 A 2231 2240 cisplatin TRIVIAL 23558232 A 2347 2354 calcium SYSTEMATIC 23558232 A 251 265 trichostatin A TRIVIAL 23558232 A 267 270 TSA ABBREVIATION 23558232 A 307 316 cisplatin TRIVIAL 23558232 A 550 559 cisplatin TRIVIAL 23558232 A 569 572 TSA ABBREVIATION 23558232 A 631 634 TSA ABBREVIATION 23558232 A 655 658 TSA ABBREVIATION 23558232 A 664 673 cisplatin TRIVIAL 23558232 A 685 694 Rhodamine FAMILY 23558232 A 695 705 phalloidin TRIVIAL 23558232 A 97 106 cisplatin TRIVIAL 23558232 T 0 14 Trichostatin A TRIVIAL 23558232 T 32 41 cisplatin TRIVIAL 23558237 A 126 150 pyrido[3,2-d]pyrimidines FAMILY 23558237 A 154 163 histamine TRIVIAL 23558237 A 193 216 pyrido[3,2-d]pyrimidine SYSTEMATIC 23558237 A 301 311 PF-3893787 IDENTIFIER 23558237 A 366 375 histamine TRIVIAL 23558237 A 500 510 JNJ7777120 IDENTIFIER 23558237 A 515 525 PF-3893787 IDENTIFIER 23558237 A 531 555 pyrido[3,2-d]pyrimidines FAMILY 23558237 A 590 600 JNJ7777120 IDENTIFIER 23558237 A 641 651 PF-3893787 IDENTIFIER 23558237 A 666 690 pyrido[3,2-d]pyrimidines FAMILY 23558237 A 74 85 quinazoline SYSTEMATIC 23558237 T 157 167 PF-3893787 IDENTIFIER 23558237 T 18 27 histamine TRIVIAL 23558237 T 65 88 pyrido[3,2-d]pyrimidine SYSTEMATIC 23558295 A 1220 1223 TPA ABBREVIATION 23558295 A 523 533 Calcein AM TRIVIAL 23558295 A 535 548 acetoxymethyl SYSTEMATIC 23558295 A 719 750 Phorbol-12-myristate-13-acetate SYSTEMATIC 23558295 A 752 755 TPA ABBREVIATION 23558295 A 795 813 dimethyl sulfoxide SYSTEMATIC 23558295 A 815 819 DMSO ABBREVIATION 23558297 A 1042 1053 vinclozolin TRIVIAL 23558297 A 1106 1113 steroid FAMILY 23558297 A 1168 1176 androgen FAMILY 23558297 A 1225 1236 vinclozolin TRIVIAL 23558297 A 1288 1297 androgens FAMILY 23558297 A 1304 1313 flutamide TRIVIAL 23558297 A 18 29 vinclozolin TRIVIAL 23558297 A 511 522 vinclozolin TRIVIAL 23558297 A 966 974 androgen FAMILY 23558297 T 0 11 Vinclozolin TRIVIAL 23559222 A 1001 1004 HVA ABBREVIATION 23559222 A 1294 1303 Yohimbine TRIVIAL 23559222 A 1321 1325 MHPG ABBREVIATION 23559222 A 1330 1333 VMA ABBREVIATION 23559222 A 1342 1345 HVA ABBREVIATION 23559222 A 1347 1356 Yohimbine TRIVIAL 23559222 A 1433 1442 yohimbine TRIVIAL 23559222 A 1530 1539 Yohimbine TRIVIAL 23559222 A 1570 1574 MHPG ABBREVIATION 23559222 A 1949 1963 norepinephrine TRIVIAL 23559222 A 221 235 norepinephrine TRIVIAL 23559222 A 271 280 yohimbine TRIVIAL 23559222 A 298 312 norepinephrine TRIVIAL 23559222 A 376 389 catecholamine TRIVIAL 23559222 A 803 812 yohimbine TRIVIAL 23559222 A 880 894 norepinephrine TRIVIAL 23559222 A 896 927 3-methoxy-4-hydroxyphenylglycol SYSTEMATIC 23559222 A 929 933 MHPG ABBREVIATION 23559222 A 939 960 vanillylmandelic acid TRIVIAL 23559222 A 962 965 VMA ABBREVIATION 23559222 A 972 980 dopamine TRIVIAL 23559222 A 982 999 homovanillic acid TRIVIAL 23559222 T 0 14 Norepinephrine TRIVIAL 23559222 T 49 58 yohimbine TRIVIAL 23559258 A 147 149 Li FORMULA 23559258 A 159 161 Li FORMULA 23559258 A 17 19 Li FORMULA 23559258 A 185 190 LixC6 FAMILY 23559258 A 194 205 Li4+xTi5O12 FAMILY 23559258 A 232 234 Li FORMULA 23559258 A 279 284 LixC6 FAMILY 23559258 A 296 304 LixFePO4 FAMILY 23559258 A 324 329 LiPF6 FORMULA 23559258 A 477 486 Li4Ti5O12 FORMULA 23559258 A 61 63 Li FORMULA 23559258 T 12 14 Li FORMULA 23559258 T 57 59 Li FORMULA 23559517 A 120 126 I3 (-) FORMULA 23559517 A 128 132 I(-) FORMULA 23559517 A 137 156 [Fe(C10 H15 )2 ](+) FORMULA 23559517 A 158 171 Fe(C10 H15 )2 FORMULA 23560391 A 1097 1104 PDMAEMA ABBREVIATION 23560391 A 160 168 PDMAEMAs FAMILY 23560391 A 185 226 poly(2-(dimethylamino)ethyl methacrylate) FAMILY 23560391 A 228 235 PDMAEMA ABBREVIATION 23560391 A 610 618 PDMAEMAs FAMILY 23560391 A 737 744 PDMAEMA ABBREVIATION 23560391 A 767 774 PDMAEMA ABBREVIATION 23560391 A 820 828 PDMAEMAs FAMILY 23560391 A 933 941 PDMAEMAs FAMILY 23560391 T 76 117 Poly(2-(dimethylamino)ethyl methacrylate) FAMILY 23560438 A 1078 1081 PVA ABBREVIATION 23560438 A 1187 1199 nitric oxide SYSTEMATIC 23560438 A 1270 1273 PVA ABBREVIATION 23560438 A 1422 1425 PVA ABBREVIATION 23560438 A 1465 1467 NO FORMULA 23560438 A 1651 1654 PVA ABBREVIATION 23560438 A 1772 1774 NO FORMULA 23560438 A 1907 1910 PVA ABBREVIATION 23560438 A 676 695 poly(vinyl alcohol) SYSTEMATIC 23560438 A 697 700 PVA ABBREVIATION 23560438 A 746 749 PVA ABBREVIATION 23560438 T 0 19 Poly(vinyl alcohol) FAMILY 23560438 T 96 108 Nitric Oxide SYSTEMATIC 23560442 A 60 64 TiO2 FORMULA 23560442 T 83 87 TiO2 FORMULA 23560447 A 116 123 silicon SYSTEMATIC 23560447 A 269 277 graphene TRIVIAL 23560447 A 361 369 graphene TRIVIAL 23560447 A 543 551 graphene TRIVIAL 23560447 A 552 560 graphene TRIVIAL 23560447 A 60 68 graphene TRIVIAL 23560447 A 665 673 graphene TRIVIAL 23560447 T 0 8 Graphene TRIVIAL 23560504 A 517 521 CdSe FORMULA 23560571 A 127 129 Ti FORMULA 23560571 A 140 142 Au FORMULA 23560571 A 177 183 Au(3+) FORMULA 23560571 A 198 201 HCl FORMULA 23560571 A 212 214 Ti FORMULA 23560571 A 234 239 thiol FAMILY 23560571 A 464 466 Au FORMULA 23560571 A 474 476 Ti FORMULA 23560571 A 548 559 glutathione TRIVIAL 23560571 A 561 564 GSH ABBREVIATION 23560571 A 610 642 N-(2-mercapto-propionyl) glycine SYSTEMATIC 23560571 A 644 647 MPG ABBREVIATION 23560571 A 690 692 Au FORMULA 23560571 A 783 785 Au FORMULA 23560571 A 877 879 Au FORMULA 23560571 A 880 888 thiolate SYSTEMATIC 23560571 A 91 93 Au FORMULA 23560571 A 995 997 Au FORMULA 23560571 T 59 61 Au FORMULA 23560571 T 79 87 Titanium SYSTEMATIC 23561071 A 344 351 alcohol FAMILY 23561071 A 352 359 benzene SYSTEMATIC 23561071 A 417 434 hydrochloric acid SYSTEMATIC 23561071 A 527 538 isopropanol SYSTEMATIC 23561071 A 539 546 ethanol SYSTEMATIC 23561071 A 648 665 galacturonic acid TRIVIAL 23561071 A 83 95 carbohydrate FAMILY 23561071 A 858 875 galacturonic acid TRIVIAL 23561071 A 906 923 galacturonic acid TRIVIAL 23561080 A 51 60 aspartame TRIVIAL 23561080 A 666 675 aspartame TRIVIAL 23561080 A 730 739 aspartame TRIVIAL 23561080 A 959 968 aspartame TRIVIAL 23561080 T 22 31 aspartame TRIVIAL 23561081 A 289 310 isoflavone glycosides FAMILY 23561081 A 411 440 4-nitrophenyl β-d-glucuronide SYSTEMATIC 23561081 A 703 713 isoflavone FAMILY 23561081 A 793 803 isoflavone FAMILY 23561081 A 867 874 daidzin TRIVIAL 23561081 A 921 929 genistin TRIVIAL 23561081 T 18 38 isoflavone aglycones FAMILY 23561082 A 1020 1029 glabranin TRIVIAL 23561082 A 1059 1072 umbelliferone TRIVIAL 23561082 A 1081 1091 scopoletin TRIVIAL 23561082 A 115 144 1,1-diphenyl-2-picrylhydrazyl SYSTEMATIC 23561082 A 146 150 DPPH ABBREVIATION 23561082 A 189 199 β-carotene TRIVIAL 23561082 A 210 223 linoleic acid TRIVIAL 23561082 A 22 30 methanol SYSTEMATIC 23561082 A 286 290 DPPH ABBREVIATION 23561082 A 390 400 β-carotene TRIVIAL 23561082 A 4 17 ethyl acetate SYSTEMATIC 23561082 A 596 604 methanol SYSTEMATIC 23561082 A 643 657 pyranocoumarin TRIVIAL 23561082 A 659 668 glabranin TRIVIAL 23561082 A 674 687 umbelliferone TRIVIAL 23561082 A 693 703 scopoletin TRIVIAL 23561082 A 712 719 sesamin TRIVIAL 23561082 A 828 832 DPPH ABBREVIATION 23561082 A 924 934 β-carotene TRIVIAL 23561082 A 952 959 sesamin TRIVIAL 23561082 T 42 51 coumarins FAMILY 23561082 T 56 62 lignan FAMILY 23561085 A 0 10 Polyphenol FAMILY 23561085 A 244 252 phenolic FAMILY 23561085 A 366 374 phenolic FAMILY 23561085 A 425 433 phenolic FAMILY 23561085 A 48 57 phenolics FAMILY 23561085 A 629 637 Phenolic FAMILY 23561085 A 766 776 nucleotide FAMILY 23561085 A 904 914 amino acid FAMILY 23561085 T 19 29 polyphenol FAMILY 23561085 T 5 14 phenolics FAMILY 23561092 A 1081 1088 ethanol SYSTEMATIC 23561092 A 1116 1124 methanol SYSTEMATIC 23561092 A 1209 1216 ethanol SYSTEMATIC 23561092 A 1257 1265 methanol SYSTEMATIC 23561092 A 1330 1341 fatty acids FAMILY 23561092 A 302 309 ethanol SYSTEMATIC 23561092 A 313 321 methanol SYSTEMATIC 23561092 A 546 557 fatty acids FAMILY 23561092 A 654 659 oleic TRIVIAL 23561092 A 664 672 linoleic TRIVIAL 23561095 A 654 669 triacylglycerol FAMILY 23561095 A 71 79 stearins FAMILY 23561095 T 65 72 stearin TRIVIAL 23561096 A 110 122 flavan-3-ols FAMILY 23561096 A 198 215 proanthocyanidins FAMILY 23561096 A 217 220 PAs FAMILY 23561096 A 415 418 HCl FORMULA 23561096 A 475 485 bile salts FAMILY 23561096 A 846 849 PAs FAMILY 23561096 T 23 40 proanthocyanidins FAMILY 23561098 A 22 29 calcium SYSTEMATIC 23561098 T 50 57 calcium SYSTEMATIC 23561100 A 1037 1052 malondialdehyde TRIVIAL 23561100 A 1054 1057 GSH ABBREVIATION 23561100 A 1266 1273 alcohol FAMILY 23561100 A 275 285 flavonoids FAMILY 23561100 A 355 365 Hesperidin TRIVIAL 23561100 A 370 379 narirutin TRIVIAL 23561100 A 687 694 ethanol SYSTEMATIC 23561100 A 758 761 GSH ABBREVIATION 23561100 A 81 88 alcohol FAMILY 23561100 A 900 907 alcohol FAMILY 23561100 T 66 76 flavonoids FAMILY 23561100 T 85 92 alcohol FAMILY 23561102 A 1049 1058 carbamate FAMILY 23561102 A 108 114 carbon SYSTEMATIC 23561102 A 465 474 1-octanol SYSTEMATIC 23561102 A 54 63 carbamate FAMILY 23561102 T 0 6 Carbon SYSTEMATIC 23561102 T 146 155 carbamate FAMILY 23561106 A 1037 1040 QCA ABBREVIATION 23561106 A 1045 1049 MQCA ABBREVIATION 23561106 A 151 180 quinoxaline-2-carboxylic acid SYSTEMATIC 23561106 A 182 185 QCA ABBREVIATION 23561106 A 200 229 diethylaminoethylmethacrylate SYSTEMATIC 23561106 A 256 286 ethylene glycol dimethacrylate SYSTEMATIC 23561106 A 306 321 tetrahydrofuran SYSTEMATIC 23561106 A 466 469 QCA ABBREVIATION 23561106 A 495 498 QCA ABBREVIATION 23561106 A 503 541 methyl-3-quinoxaline-2-carboxylic acid SYSTEMATIC 23561106 A 543 547 MQCA ABBREVIATION 23561106 A 680 683 QCA ABBREVIATION 23561106 A 688 692 MQCA ABBREVIATION 23561106 A 78 102 quinoxaline-1,4-dioxides FAMILY 23561106 A 821 824 QCA ABBREVIATION 23561106 A 852 856 MQCA ABBREVIATION 23561106 T 111 140 quinoxaline-2-carboxylic acid SYSTEMATIC 23561106 T 145 183 methyl-3-quinoxaline-2-carboxylic acid SYSTEMATIC 23561114 A 0 18 Tetrahydrocurcumin SYSTEMATIC 23561114 A 137 145 curcumin TRIVIAL 23561114 A 20 23 THC ABBREVIATION 23561114 A 218 221 THC ABBREVIATION 23561114 A 227 234 alanine TRIVIAL 23561114 A 241 251 isoleucine TRIVIAL 23561114 A 258 265 proline TRIVIAL 23561114 A 272 278 valine TRIVIAL 23561114 A 285 298 phenylalanine TRIVIAL 23561114 A 305 312 glycine TRIVIAL 23561114 A 322 329 leucine TRIVIAL 23561114 A 383 386 THC ABBREVIATION 23561114 A 438 441 THC ABBREVIATION 23561114 A 595 598 THC ABBREVIATION 23561114 A 62 70 curcumin TRIVIAL 23561114 A 846 849 THC ABBREVIATION 23561114 A 939 942 THC ABBREVIATION 23561114 A 950 958 phenolic FAMILY 23561114 A 973 984 amino acids FAMILY 23561114 T 13 23 amino acid FAMILY 23561114 T 38 56 tetrahydrocurcumin SYSTEMATIC 23561115 A 1071 1084 triterpenoids FAMILY 23561115 A 1111 1122 β-damascone TRIVIAL 23561115 A 199 212 triterpenoids FAMILY 23561115 A 454 466 ursolic acid TRIVIAL 23561115 A 476 490 oleanolic acid TRIVIAL 23561115 A 8 62 ursanic, oleanic and lupanic pentacyclic triterpenoids MULTIPLE 23561115 T 13 26 triterpenoids FAMILY 23561117 A 177 183 xylose TRIVIAL 23561117 A 189 196 glucose TRIVIAL 23561117 A 202 210 fructose TRIVIAL 23561117 A 216 223 lactose TRIVIAL 23561117 A 229 236 maltose TRIVIAL 23561117 A 245 252 sucrose TRIVIAL 23561117 A 421 425 DPPH ABBREVIATION 23561117 A 455 458 SDS ABBREVIATION 23561117 A 616 621 amide FAMILY 23561118 A 152 159 ethanol SYSTEMATIC 23561118 A 268 276 phenolic FAMILY 23561118 A 281 290 flavonoid FAMILY 23561118 A 311 324 polyphenolics FAMILY 23561118 A 326 338 ferulic acid TRIVIAL 23561118 A 343 352 quercetin TRIVIAL 23561118 A 410 422 ferulic acid TRIVIAL 23561118 A 427 436 quercetin TRIVIAL 23561118 A 569 578 quercetin TRIVIAL 23561118 A 587 599 ferulic acid TRIVIAL 23561118 A 735 741 oxygen SYSTEMATIC 23561118 A 890 907 poly (ADP-ribose) SYSTEMATIC 23561119 A 0 14 Angiotensin II TRIVIAL 23561119 A 1005 1011 Ca(2+) FORMULA 23561119 A 16 22 Ang II ABBREVIATION 23561119 A 170 176 Ang II ABBREVIATION 23561119 A 199 205 Ca(2+) FORMULA 23561119 A 229 235 oxygen SYSTEMATIC 23561119 A 381 394 ethyl acetate SYSTEMATIC 23561119 A 413 419 Ang II ABBREVIATION 23561119 A 442 448 Ca(2+) FORMULA 23561119 A 482 488 Ang II ABBREVIATION 23561119 A 583 596 ethyl acetate SYSTEMATIC 23561119 A 616 629 ethyl acetate SYSTEMATIC 23561119 A 658 664 Ang II ABBREVIATION 23561119 A 867 880 ethyl acetate SYSTEMATIC 23561119 A 976 982 Ang II ABBREVIATION 23561119 T 40 54 angiotensin II TRIVIAL 23561123 A 1060 1071 fatty acids FAMILY 23561123 A 16 27 fatty acids FAMILY 23561123 A 245 266 saturated fatty acids FAMILY 23561123 A 268 273 C16:0 FORMULA 23561123 A 278 283 C18:0 FORMULA 23561123 A 311 334 unsaturated fatty acids FAMILY 23561123 A 336 343 C18:1n9 FAMILY 23561123 A 345 352 C18:2n6 FAMILY 23561123 A 357 364 C18:3n3 FAMILY 23561123 A 408 419 fatty acids FAMILY 23561123 A 457 468 fatty acids FAMILY 23561123 A 505 532 polyunsaturated fatty acids FAMILY 23561123 A 542 563 eicosapentaenoic acid SYSTEMATIC 23561123 A 568 588 docosahexaenoic acid SYSTEMATIC 23561123 A 627 638 fatty acids FAMILY 23561123 A 714 725 fatty acids FAMILY 23561123 A 801 812 fatty acids FAMILY 23561123 A 820 833 triglycerides FAMILY 23561123 A 880 886 carbon SYSTEMATIC 23561123 A 900 910 fatty acid FAMILY 23561123 A 991 1002 fatty acids FAMILY 23561123 T 5 15 fatty acid FAMILY 23561125 A 1006 1010 iron SYSTEMATIC 23561125 A 1012 1018 copper SYSTEMATIC 23561125 A 1023 1031 selenium SYSTEMATIC 23561125 A 939 954 sodium chloride SYSTEMATIC 23561127 A 223 229 tocols FAMILY 23561127 A 231 240 vitamin E FAMILY 23561127 A 246 261 avenanthramides FAMILY 23561127 A 518 524 oxygen SYSTEMATIC 23561127 A 806 820 Avenanthramide FAMILY 23561136 A 1007 1019 caffeic acid TRIVIAL 23561136 A 1021 1029 vanillin TRIVIAL 23561136 A 1031 1061 ortho- and para-coumaric acids MULTIPLE 23561136 A 1111 1125 phenolic acids FAMILY 23561136 A 1166 1181 p-coumaric acid TRIVIAL 23561136 A 1183 1191 vanillin TRIVIAL 23561136 A 1196 1209 ferulic acids FAMILY 23561136 A 1244 1258 phenolic acids FAMILY 23561136 A 135 145 flavonoids FAMILY 23561136 A 162 189 quercetin 3-O-robinobioside SYSTEMATIC 23561136 A 191 215 quercetin 3-O-rutinoside SYSTEMATIC 23561136 A 217 243 quercetin 3'-O-galactoside SYSTEMATIC 23561136 A 245 269 quercetin 3'-O-glucoside SYSTEMATIC 23561136 A 271 296 quercetin 3'-O-rhamnoside SYSTEMATIC 23561136 A 298 329 quercetin 3'-O-pentosylhexoside SYSTEMATIC 23561136 A 331 363 quercetin 3-O-6'malonylglucoside SYSTEMATIC 23561136 A 365 396 quercetin 3'-O-malonylglucoside SYSTEMATIC 23561136 A 398 429 luteolin 7-O-6'malonylglucoside SYSTEMATIC 23561136 A 431 460 luteolin 7-O-malonylglucoside SYSTEMATIC 23561136 A 462 487 myricetin 3-O-galactoside SYSTEMATIC 23561136 A 493 517 naringenin tri glycoside FAMILY 23561136 A 52 61 flavonoid FAMILY 23561136 A 577 587 flavonoids FAMILY 23561136 A 879 893 phenolic acids FAMILY 23561136 A 900 914 phenolic acids FAMILY 23561136 A 916 935 protocatechuic acid TRIVIAL 23561136 A 937 958 p-hydroxybenzoic acid SYSTEMATIC 23561136 A 960 972 ferulic acid TRIVIAL 23561136 A 974 990 chlorogenic acid TRIVIAL 23561136 A 992 1005 vanillic acid SYSTEMATIC 23561136 T 160 174 phenolic acids FAMILY 23561136 T 9 17 phenolic FAMILY 23561142 A 237 243 sodium SYSTEMATIC 23561142 A 516 528 carbohydrate FAMILY 23561142 A 753 762 phenolics FAMILY 23561143 A 466 478 α-tocopherol TRIVIAL 23561143 A 607 634 monounsaturated fatty acids FAMILY 23561143 A 739 758 omega-3 fatty acids FAMILY 23561143 A 763 775 α-tocopherol TRIVIAL 23561143 A 982 992 fatty acid FAMILY 23561146 A 266 279 Ethyl acetate SYSTEMATIC 23561146 A 280 289 n-butanol SYSTEMATIC 23561146 A 364 380 geniposidic acid TRIVIAL 23561146 A 382 395 Ethyl acetate SYSTEMATIC 23561146 A 396 403 ethanol SYSTEMATIC 23561146 A 445 457 caffeic acid TRIVIAL 23561146 A 459 475 chlorogenic acid TRIVIAL 23561146 A 480 492 ferulic acid TRIVIAL 23561146 A 506 516 flavonoids FAMILY 23561146 A 518 544 quercetin-3-O-sambubioside SYSTEMATIC 23561146 A 546 551 rutin TRIVIAL 23561146 A 556 569 isoquercitrin TRIVIAL 23561146 A 587 602 petroleum ether TRIVIAL 23561146 A 603 616 ethyl acetate SYSTEMATIC 23561146 A 617 625 methanol SYSTEMATIC 23561146 A 91 95 DPPH ABBREVIATION 23561146 A 941 945 DPPH ABBREVIATION 23561146 T 135 139 DPPH ABBREVIATION 23561148 A 1030 1039 phenolics FAMILY 23561148 A 1044 1053 vitamin C TRIVIAL 23561148 A 1211 1223 ellagic acid TRIVIAL 23561148 A 1294 1311 proanthocyanidins FAMILY 23561148 A 282 291 phenolics FAMILY 23561148 A 46 57 polyphenols FAMILY 23561148 A 493 501 flavonol TRIVIAL 23561148 A 502 511 myricetin TRIVIAL 23561148 A 528 540 ellagic acid TRIVIAL 23561148 A 589 609 Cyanidin 3-glucoside SYSTEMATIC 23561148 A 615 624 quercetin TRIVIAL 23561148 A 62 71 vitamin C TRIVIAL 23561148 A 686 703 proanthocyanidins FAMILY 23561148 A 785 794 vitamin C TRIVIAL 23561148 A 931 935 DPPH ABBREVIATION 23561148 A 937 941 ABTS ABBREVIATION 23561148 T 0 12 Ellagic acid TRIVIAL 23561148 T 41 58 proanthocyanidins FAMILY 23561148 T 69 78 phenolics FAMILY 23561148 T 80 89 vitamin C TRIVIAL 23561150 A 1031 1034 SDS ABBREVIATION 23561150 A 150 165 sodium chloride SYSTEMATIC 23561154 A 1005 1009 NaCl FORMULA 23561154 A 1075 1085 tryptophan TRIVIAL 23561154 A 1169 1179 tryptophan TRIVIAL 23561154 A 1197 1205 tyrosine TRIVIAL 23561154 A 1391 1395 NaCl FORMULA 23561154 A 326 329 SDS ABBREVIATION 23561154 A 336 346 Amino acid FAMILY 23561154 A 401 419 acidic amino acids FAMILY 23561154 A 430 436 lysine TRIVIAL 23561154 A 437 445 arginine TRIVIAL 23561154 A 527 535 tyrosine TRIVIAL 23561154 A 540 550 tryptophan TRIVIAL 23561154 A 765 775 tryptophan TRIVIAL 23561154 A 947 957 tryptophan TRIVIAL 23561154 T 11 15 NaCl FORMULA 23561155 A 146 154 lycopene TRIVIAL 23561155 A 292 306 (13)C-lycopene SYSTEMATIC 23561155 A 34 42 lycopene TRIVIAL 23561155 A 372 377 (13)C FORMULA 23561155 A 412 420 lycopene TRIVIAL 23561155 A 482 495 (13)C-glucose SYSTEMATIC 23561155 A 585 593 lycopene TRIVIAL 23561155 A 700 705 (13)C FORMULA 23561155 A 768 775 glucose TRIVIAL 23561155 A 792 800 lycopene TRIVIAL 23561155 A 817 831 (13)C-lycopene SYSTEMATIC 23561155 A 841 846 (13)C FORMULA 23561155 A 938 945 acetone SYSTEMATIC 23561155 A 950 956 hexane SYSTEMATIC 23561155 A 998 1006 lycopene TRIVIAL 23561155 T 123 136 (13)C-glucose SYSTEMATIC 23561155 T 32 46 (13)C-lycopene SYSTEMATIC 23561156 A 1186 1197 polyphenols FAMILY 23561156 A 402 409 sucrose TRIVIAL 23561160 A 1033 1065 bis(2-hydroxyethyl)terephthalate SYSTEMATIC 23561160 A 1089 1092 PET ABBREVIATION 23561160 A 1199 1202 PET ABBREVIATION 23561160 A 227 236 Aldehydes FAMILY 23561160 A 315 318 PET ABBREVIATION 23561160 A 432 435 CO2 FORMULA 23561160 A 461 473 formaldehyde SYSTEMATIC 23561160 A 475 487 acetaldehyde SYSTEMATIC 23561160 A 492 500 antimony SYSTEMATIC 23561160 A 502 504 Sb FORMULA 23561160 A 811 814 PET ABBREVIATION 23561160 A 832 842 phthalates FAMILY 23561160 A 89 92 PET ABBREVIATION 23561160 A 907 930 2,4-di-tert-butylphenol SYSTEMATIC 23561160 A 958 966 phenolic FAMILY 23561160 T 126 129 PET ABBREVIATION 23561160 T 98 124 polyethylene terephthalate SYSTEMATIC 23561163 A 144 151 ethanol SYSTEMATIC 23561163 A 179 188 aldehydes FAMILY 23561163 A 190 196 esters FAMILY 23561163 A 205 213 alcohols FAMILY 23561163 A 219 227 methanol SYSTEMATIC 23561163 A 258 292 gallic, vanilic and syringic acids MULTIPLE 23561163 A 294 308 siringaldehyde TRIVIAL 23561163 A 310 325 coniferaldehyde TRIVIAL 23561163 A 327 340 sinapaldehyde TRIVIAL 23561163 A 342 350 vanillin TRIVIAL 23561163 A 352 375 5-hydroxymethylfurfural SYSTEMATIC 23561163 A 380 388 furfural TRIVIAL 23561163 A 55 60 sugar FAMILY 23561163 A 745 753 vanillin TRIVIAL 23561163 A 755 767 vanilic acid TRIVIAL 23561163 A 769 783 syringaldehyde TRIVIAL 23561163 A 788 801 sinapaldehyde TRIVIAL 23561163 A 996 1001 sugar FAMILY 23561163 T 13 18 sugar FAMILY 23561166 A 1072 1079 glucose TRIVIAL 23561166 A 214 226 triglyceride FAMILY 23561166 A 267 274 glucose TRIVIAL 23561166 A 32 39 fisetin TRIVIAL 23561166 A 343 350 fisetin TRIVIAL 23561166 A 560 567 fisetin TRIVIAL 23561166 A 582 589 fisetin TRIVIAL 23561166 A 782 789 fisetin TRIVIAL 23561166 A 891 898 fisetin TRIVIAL 23561166 A 958 965 Fisetin TRIVIAL 23561166 T 11 18 fisetin TRIVIAL 23561166 T 62 69 glucose TRIVIAL 23561170 A 1089 1103 phloroglucinol TRIVIAL 23561170 A 636 642 ferric SYSTEMATIC 23561170 T 14 24 polyphenol FAMILY 23561172 A 164 171 dry-ice TRIVIAL 23561174 A 1105 1116 chlorophyll FAMILY 23561174 A 155 159 H2O2 FORMULA 23561174 A 164 182 2,4-dichlorophenol SYSTEMATIC 23561174 A 17 30 chlorophyll a TRIVIAL 23561174 A 184 191 2,4-DCP SYSTEMATIC 23561174 A 32 37 chl a ABBREVIATION 23561174 A 403 417 13(2) OH chl a SYSTEMATIC 23561174 A 422 444 15(1) OH lactone chl a SYSTEMATIC 23561174 A 485 490 chl a ABBREVIATION 23561174 A 561 572 chlorophyll FAMILY 23561174 A 693 700 2,4-DCP SYSTEMATIC 23561174 A 897 901 H2O2 FORMULA 23561174 A 904 911 2,4-DCP SYSTEMATIC 23561174 A 914 917 Chl ABBREVIATION 23561174 T 20 31 chlorophyll FAMILY 23561175 A 176 187 fatty acids FAMILY 23561175 A 202 210 phenolic FAMILY 23561175 A 608 621 linoleic acid TRIVIAL 23561175 A 853 869 feruloyl-sucrose TRIVIAL 23561175 A 935 955 sinapoyl-diglycoside FAMILY 23561175 T 40 48 phenolic FAMILY 23561179 A 240 253 linoleic acid TRIVIAL 23561179 A 695 719 butylated hydroxytoluene SYSTEMATIC 23561179 A 721 724 BHT ABBREVIATION 23561179 A 733 746 linoleic acid TRIVIAL 23561179 A 834 847 linoleic acid TRIVIAL 23561181 A 1014 1021 glucose TRIVIAL 23561181 A 106 113 glucose TRIVIAL 23561181 A 257 264 glucose TRIVIAL 23561181 A 405 412 glucose TRIVIAL 23561181 A 496 508 l-isoleucine TRIVIAL 23561181 A 514 523 l-leucine TRIVIAL 23561181 A 529 538 l-leucine TRIVIAL 23561181 A 544 556 l-isoleucine TRIVIAL 23561181 A 562 593 l-isoleucyl-l-leucine dipeptide TRIVIAL 23561181 A 599 630 l-leucyl-l-isoleucine dipeptide TRIVIAL 23561181 A 786 797 amino acids FAMILY 23561181 A 885 897 l-isoleucine TRIVIAL 23561181 A 914 935 l-leucyl-l-isoleucine TRIVIAL 23561181 T 19 29 amino acid FAMILY 23561181 T 2 11 dipeptide FAMILY 23561182 A 1170 1179 friedelin TRIVIAL 23561182 A 118 127 friedelin TRIVIAL 23561182 A 242 251 friedelin TRIVIAL 23561182 A 255 282 2,2-diphenyl-picrylhydrazyl SYSTEMATIC 23561182 A 284 288 DPPH ABBREVIATION 23561182 A 291 299 hydroxyl SYSTEMATIC 23561182 A 301 313 nitric oxide SYSTEMATIC 23561182 A 318 328 superoxide TRIVIAL 23561182 A 354 363 Friedelin TRIVIAL 23561182 A 402 406 DPPH ABBREVIATION 23561182 A 422 430 hydroxyl SYSTEMATIC 23561182 A 446 458 nitric oxide SYSTEMATIC 23561182 A 477 487 superoxide TRIVIAL 23561182 A 512 521 Friedelin TRIVIAL 23561182 A 613 617 CCl4 FORMULA 23561182 A 690 699 glutamate TRIVIAL 23561182 A 700 712 oxaloacetate SYSTEMATIC 23561182 A 740 749 glutamate TRIVIAL 23561182 A 750 758 pyruvate TRIVIAL 23561182 A 783 790 lactate FAMILY 23561182 A 848 858 superoxide TRIVIAL 23561182 A 892 911 reduced glutathione TRIVIAL 23561182 A 913 916 GSH ABBREVIATION 23561182 A 922 933 glutathione TRIVIAL 23561182 A 986 995 friedelin TRIVIAL 23561182 T 69 78 friedelin TRIVIAL 23561184 A 1071 1079 selenium SYSTEMATIC 23561184 A 1092 1100 selenium SYSTEMATIC 23561184 A 1110 1123 selenocystine SYSTEMATIC 23561184 A 1129 1157 oxidized selenium methionine SYSTEMATIC 23561184 A 1162 1181 selenium methionine SYSTEMATIC 23561184 A 1215 1220 SeMet FORMULA 23561184 A 259 267 selenium SYSTEMATIC 23561184 A 34 42 selenium SYSTEMATIC 23561184 A 347 355 selenium SYSTEMATIC 23561184 A 404 412 Selenium SYSTEMATIC 23561184 A 47 55 selenium SYSTEMATIC 23561184 A 541 543 Se FORMULA 23561184 A 553 572 selenium methionine SYSTEMATIC 23561184 A 577 605 oxidized selenium methionine SYSTEMATIC 23561184 A 704 717 Selenocystine SYSTEMATIC 23561184 A 759 761 Se FORMULA 23561184 A 762 784 (Methyl)selenocysteine SYSTEMATIC 23561184 A 799 807 selenium SYSTEMATIC 23561184 A 817 825 selenite TRIVIAL 23561184 A 830 838 selenate SYSTEMATIC 23561184 A 918 926 selenium SYSTEMATIC 23561184 T 34 42 selenium SYSTEMATIC 23561184 T 47 55 selenium SYSTEMATIC 23561187 A 1059 1071 anthocyanins FAMILY 23561187 A 237 248 anthocyanin FAMILY 23561187 A 586 598 anthocyanins FAMILY 23561187 A 700 711 anthocyanin FAMILY 23561187 A 969 980 anthocyanin FAMILY 23561187 T 26 37 anthocyanin FAMILY 23561189 A 127 136 Myricetin TRIVIAL 23561189 A 138 171 3,3',4',5,5',7-hexahydroxyflavone SYSTEMATIC 23561189 A 368 377 Myricetin TRIVIAL 23561189 A 543 552 Myricetin TRIVIAL 23561189 A 94 107 bioflavonoids FAMILY 23561189 T 22 31 myricetin TRIVIAL 23561195 A 330 336 phenol SYSTEMATIC 23561196 A 116 124 syringol TRIVIAL 23561196 A 126 133 eugenol TRIVIAL 23561196 A 139 155 trans-isoeugenol TRIVIAL 23561196 A 16 48 polycyclic aromatic hydrocarbons FAMILY 23561196 A 503 506 PAH ABBREVIATION 23561196 A 58 61 PAH ABBREVIATION 23561196 A 588 591 PAH ABBREVIATION 23561196 A 67 75 phenolic FAMILY 23561196 A 727 730 PAH ABBREVIATION 23561196 A 807 815 phenolic FAMILY 23561196 A 88 96 guaiacol TRIVIAL 23561196 A 98 114 4-methylguaiacol SYSTEMATIC 23561196 T 0 32 Polycyclic aromatic hydrocarbons FAMILY 23561196 T 34 37 PAH ABBREVIATION 23561196 T 43 51 phenolic FAMILY 23561204 A 192 209 2-aminoanthracene SYSTEMATIC 23561204 A 211 215 2-AA SYSTEMATIC 23561204 A 243 267 4-nitroquinoline-N-oxide SYSTEMATIC 23561204 A 269 274 4-NQO SYSTEMATIC 23561204 A 559 561 NO FORMULA 23561204 A 697 705 phenolic FAMILY 23561204 A 730 746 chlorogenic acid TRIVIAL 23561204 A 748 753 rutin TRIVIAL 23561204 A 755 764 quercetin TRIVIAL 23561204 A 766 774 luteolin TRIVIAL 23561204 A 779 789 kaempferol TRIVIAL 23561209 A 580 585 sugar FAMILY 23561209 A 661 677 isoamyl alcohols FAMILY 23561209 A 679 691 benzaldehyde SYSTEMATIC 23561209 A 696 704 guaiacol TRIVIAL 23561209 A 834 850 isoamyl alcohols FAMILY 23561209 A 852 867 ethyl vanillate SYSTEMATIC 23561209 A 872 884 benzoic acid SYSTEMATIC 23561209 A 964 972 phenolic FAMILY 23561211 A 252 260 saponins FAMILY 23561211 A 262 272 flavonoids FAMILY 23561211 A 277 284 sterols FAMILY 23561211 A 381 387 hexane SYSTEMATIC 23561211 A 389 404 dichloromethane SYSTEMATIC 23561211 A 601 603 NO FORMULA 23561211 A 646 661 dichloromethane SYSTEMATIC 23561211 A 951 962 triterpenes FAMILY 23561211 A 964 974 flavonoids FAMILY 23561211 A 979 986 sterols FAMILY 23561212 A 1154 1161 calcium SYSTEMATIC 23561212 A 285 292 calcium SYSTEMATIC 23561212 A 323 329 sodium SYSTEMATIC 23561212 A 343 359 calcium chloride SYSTEMATIC 23561212 A 438 444 sodium SYSTEMATIC 23561212 A 458 474 calcium chloride SYSTEMATIC 23561212 T 110 117 calcium SYSTEMATIC 23561212 T 23 35 carbohydrate FAMILY 23561214 A 119 129 β-carotene TRIVIAL 23561214 A 299 309 β-carotene TRIVIAL 23561214 A 402 412 β-carotene TRIVIAL 23561214 A 486 499 desferoxamine TRIVIAL 23561214 A 509 519 β-carotene TRIVIAL 23561214 A 692 704 α-tocopherol TRIVIAL 23561214 A 745 755 β-carotene TRIVIAL 23561214 A 941 951 β-carotene TRIVIAL 23561214 T 118 128 β-carotene TRIVIAL 23561219 A 407 426 Phosphatidylcholine FAMILY 23561219 A 433 457 phosphatidylethanolamine SYSTEMATIC 23561219 A 464 484 phosphatidylinositol TRIVIAL 23561220 A 558 573 sodium sulphate SYSTEMATIC 23561220 A 70 78 pyruvate TRIVIAL 23561223 A 1054 1076 delphinidin glycosides FAMILY 23561223 A 1127 1135 cyanidin TRIVIAL 23561223 A 1195 1206 anthocyanin FAMILY 23561223 A 1266 1287 anthocyanin phenolics FAMILY 23561223 A 1438 1449 anthocyanin FAMILY 23561223 A 1533 1541 phenolic FAMILY 23561223 A 298 309 anthocyanin FAMILY 23561223 A 319 322 ACN ABBREVIATION 23561223 A 355 367 anthocyanins FAMILY 23561223 A 376 397 anthocyanin phenolics FAMILY 23561223 A 457 468 Anthocyanin FAMILY 23561223 A 620 631 anthocyanin FAMILY 23561223 A 71 83 anthocyanins FAMILY 23561223 A 861 872 anthocyanin FAMILY 23561223 T 82 94 anthocyanins FAMILY 23562056 A 311 319 ethylene SYSTEMATIC 23562056 A 575 587 cyclopropane SYSTEMATIC 23562056 T 114 130 cis-cyclopropane SYSTEMATIC 23562056 T 77 88 isocytosine TRIVIAL 23562060 A 173 179 isatin TRIVIAL 23562060 A 267 272 ML129 IDENTIFIER 23562060 A 277 282 ML172 IDENTIFIER 23562060 A 376 382 isatin TRIVIAL 23562060 A 414 429 phenethyl ether SYSTEMATIC 23562060 A 529 544 phenethyl ether SYSTEMATIC 23562060 A 562 567 ML129 IDENTIFIER 23562060 A 568 573 ML172 IDENTIFIER 23562060 A 620 625 ML326 IDENTIFIER 23562060 A 627 636 VU0467903 IDENTIFIER 23562060 A 793 796 ACh ABBREVIATION 23562060 A 83 88 ML129 IDENTIFIER 23562060 A 93 98 ML172 IDENTIFIER 23562060 T 13 18 ML326 IDENTIFIER 23562063 A 131 234 (S)-3-[4-(1-{3,5-dimethyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}butyl)benzamido]propanoic acid SYSTEMATIC 23562063 A 663 670 glucose TRIVIAL 23562072 A 315 326 cholesterol TRIVIAL 23562072 T 8 19 cholesterol TRIVIAL 23562365 A 0 6 Evn-50 NO CLASS 23562365 A 1172 1178 EVn-50 NO CLASS 23562365 A 1182 1185 VB1 IDENTIFIER 23562365 A 12 18 lignan FAMILY 23562365 A 1347 1350 Ser FORMULA 23562365 A 1381 1384 Tyr FORMULA 23562365 A 1505 1511 EVn-50 NO CLASS 23562365 A 1515 1518 VB1 IDENTIFIER 23562365 A 1584 1590 EVn-50 NO CLASS 23562365 A 1592 1598 lignan FAMILY 23562365 A 187 193 EVn-50 NO CLASS 23562365 A 312 318 EVn-50 NO CLASS 23562365 A 328 334 lignan FAMILY 23562365 A 344 347 VB1 IDENTIFIER 23562365 A 362 368 EVn-50 NO CLASS 23562365 A 394 400 EVn-50 NO CLASS 23562365 A 405 408 VB1 IDENTIFIER 23562365 A 598 604 EVn-50 NO CLASS 23562365 A 608 611 VB1 IDENTIFIER 23562365 A 676 682 EVn-50 NO CLASS 23562365 A 686 689 VB1 IDENTIFIER 23562365 A 901 907 EVn-50 NO CLASS 23562365 T 0 7 Lignans FAMILY 23562376 A 1026 1035 metformin TRIVIAL 23562376 A 177 186 metformin TRIVIAL 23562376 A 339 348 metformin TRIVIAL 23562376 A 442 451 metformin TRIVIAL 23562376 A 524 533 metformin TRIVIAL 23562376 A 678 684 MPP(+) ABBREVIATION 23562376 A 775 779 H(+) FORMULA 23562376 A 816 825 metformin TRIVIAL 23562376 A 893 902 metformin TRIVIAL 23562376 T 12 21 metformin TRIVIAL 23562496 A 1019 1030 xanthohumol TRIVIAL 23562496 A 1092 1121 Neohesperidin dihydrochalcone SYSTEMATIC 23562496 A 1123 1140 4-methoxychalcone SYSTEMATIC 23562496 A 1146 1171 hesperidin methylchalcone TRIVIAL 23562496 A 1226 1237 Xanthohumol TRIVIAL 23562496 A 1242 1259 2-hydroxychalcone SYSTEMATIC 23562496 A 1316 1333 2-hydroxychalcone SYSTEMATIC 23562496 A 1338 1349 xanthohumol TRIVIAL 23562496 A 1470 1478 chalcone FAMILY 23562496 A 1535 1544 chalcones FAMILY 23562496 A 179 187 estrogen FAMILY 23562496 A 188 200 progesterone TRIVIAL 23562496 A 329 338 Chalcones FAMILY 23562496 A 371 381 flavonoids FAMILY 23562496 A 521 530 chalcones FAMILY 23562496 A 601 610 chalcones FAMILY 23562496 A 711 719 chalcone FAMILY 23562496 A 826 834 chalcone FAMILY 23562496 A 836 853 2-hydroxychalcone SYSTEMATIC 23562496 A 859 870 xanthohumol TRIVIAL 23562496 A 986 994 Chalcone TRIVIAL 23562496 A 996 1013 2-hydroxychalcone SYSTEMATIC 23562496 T 0 17 2-Hydroxychalcone SYSTEMATIC 23562496 T 22 33 xanthohumol TRIVIAL 23562534 A 1253 1261 Soluplus TRIVIAL 23562534 A 1284 1287 ITZ ABBREVIATION 23562534 A 1322 1325 ITZ ABBREVIATION 23562534 A 237 240 ITZ ABBREVIATION 23562534 A 479 482 ITZ ABBREVIATION 23562534 A 483 491 Soluplus TRIVIAL 23562534 A 525 528 ITZ ABBREVIATION 23562534 A 590 593 ITZ ABBREVIATION 23562534 A 785 788 ITZ ABBREVIATION 23562534 A 789 797 Soluplus TRIVIAL 23562534 A 80 92 itraconazole TRIVIAL 23562534 A 848 851 ITZ ABBREVIATION 23562534 A 931 934 ITZ ABBREVIATION 23562534 A 94 97 ITZ ABBREVIATION 23562534 A 944 946 OH FORMULA 23562534 A 944 950 OH-ITZ FORMULA 23562534 A 947 950 ITZ ABBREVIATION 23562534 A 989 997 Sporanox TRIVIAL 23562534 T 45 57 itraconazole TRIVIAL 23562534 T 58 66 Soluplus TRIVIAL 23562534 T 91 103 itraconazole TRIVIAL 23562630 A 1029 1036 phospho SYSTEMATIC 23562630 A 1037 1044 calcium SYSTEMATIC 23562630 A 1077 1084 phospho SYSTEMATIC 23562630 A 1149 1156 phospho SYSTEMATIC 23562630 A 1242 1255 acetylcholine SYSTEMATIC 23562630 A 1257 1260 Ach ABBREVIATION 23562630 A 14 26 asiaticoside TRIVIAL 23562630 A 1599 1602 Ach ABBREVIATION 23562630 A 996 1016 N-methyl-d-aspartate SYSTEMATIC 23562630 T 22 34 asiaticoside TRIVIAL 23562637 A 273 289 polyethylenimine SYSTEMATIC 23562637 A 291 294 PEI ABBREVIATION 23562637 A 437 443 sodium SYSTEMATIC 23562637 A 477 486 disulfide SYSTEMATIC 23562637 T 22 40 poly(ethylenimine) FAMILY 23562926 A 0 9 Aconitine TRIVIAL 23562926 A 1013 1020 glucose TRIVIAL 23562926 A 389 394 Na(+) FORMULA 23562926 A 406 413 Glucose TRIVIAL 23562926 A 520 525 Na(+) FORMULA 23562926 A 539 552 Cyclosporin A TRIVIAL 23562926 A 557 566 verapamil TRIVIAL 23562926 A 665 671 MK-571 IDENTIFIER 23562926 A 996 1002 sodium SYSTEMATIC 23562926 T 27 36 aconitine TRIVIAL 23563104 A 260 267 lactose TRIVIAL 23563104 A 269 282 hydroxypropyl SYSTEMATIC 23563248 A 1003 1007 cAMP ABBREVIATION 23563248 A 985 994 forskolin TRIVIAL 23563672 A 49 65 triiodothyronine TRIVIAL 23563672 A 78 87 thyroxine TRIVIAL 23563730 A 10 30 polydimethylsiloxane SYSTEMATIC 23563730 A 73 85 sulfobetaine SYSTEMATIC 23563730 T 28 32 PDMS ABBREVIATION 23564369 A 129 138 triclosan TRIVIAL 23564369 A 140 143 TCS ABBREVIATION 23564369 A 306 309 TCS ABBREVIATION 23564369 A 996 999 TCS ABBREVIATION 23564369 T 10 19 triclosan TRIVIAL 23564596 A 1019 1028 sorafenib TRIVIAL 23564596 A 1043 1046 FDG ABBREVIATION 23564596 A 499 521 18F-fluorodeoxiglucose SYSTEMATIC 23564596 A 555 558 FDG ABBREVIATION 23564596 A 620 623 FDG ABBREVIATION 23564596 A 699 702 FDG ABBREVIATION 23564596 A 823 832 sorafenib TRIVIAL 23564596 T 35 42 18F-FDG SYSTEMATIC 23564596 T 98 107 sorafenib TRIVIAL 23564645 A 605 615 rifampicin TRIVIAL 23564882 A 11 18 epoxide SYSTEMATIC 23564882 A 187 195 epoxides FAMILY 23564882 A 247 279 polycyclic aromatic hydrocarbons FAMILY 23564882 T 59 66 epoxide SYSTEMATIC 23564914 A 1118 1127 glutamine TRIVIAL 23564914 A 1149 1156 glucose TRIVIAL 23564914 A 279 288 glutamine TRIVIAL 23564914 A 338 345 glucose TRIVIAL 23564914 A 492 501 glutamine TRIVIAL 23564914 A 522 531 glutamine TRIVIAL 23564914 A 611 618 glucose TRIVIAL 23564914 A 72 79 glucose TRIVIAL 23564914 A 821 828 glucose TRIVIAL 23564914 A 861 870 Glutamine TRIVIAL 23564914 A 9 18 Glutamine TRIVIAL 23564914 A 904 911 glucose TRIVIAL 23564914 T 118 125 Glucose TRIVIAL 23564914 T 25 34 Glutamine TRIVIAL 23564917 A 105 108 CHO FORMULA 23564917 A 1057 1060 CHO FORMULA 23564917 A 1249 1252 CHO FORMULA 23564917 A 1358 1361 CHO FORMULA 23564917 A 333 336 CHO FORMULA 23564917 A 635 638 CHO FORMULA 23564917 A 688 691 CHO FORMULA 23564917 A 752 755 CHO FORMULA 23564917 A 758 761 CHO FORMULA 23564917 A 90 103 carbohydrates FAMILY 23564917 A 961 964 CHO FORMULA 23564917 T 4 16 Carbohydrate FAMILY 23564921 A 1101 1108 glucose TRIVIAL 23564921 A 1159 1166 glucose TRIVIAL 23564921 A 1407 1414 glucose TRIVIAL 23564921 A 1613 1620 glucose TRIVIAL 23564921 A 343 361 thiazolidinediones FAMILY 23564921 A 398 404 sodium SYSTEMATIC 23564921 A 405 412 glucose TRIVIAL 23564921 A 618 625 glucose TRIVIAL 23564921 A 859 866 glucose TRIVIAL 23564921 A 915 933 thiazolidinediones FAMILY 23565325 A 494 506 hydroxamates FAMILY 23565644 A 1026 1036 diclofenac TRIVIAL 23565644 A 1038 1051 carbamazepine TRIVIAL 23565644 A 1057 1069 troglitazone TRIVIAL 23565644 A 1157 1169 ketoconazole TRIVIAL 23565644 A 1174 1183 clozapine TRIVIAL 23565644 A 1217 1228 glutathione TRIVIAL 23565644 A 1355 1367 ketoconazole TRIVIAL 23565644 A 1372 1381 clozapine TRIVIAL 23565644 A 1450 1461 glutathione TRIVIAL 23565644 A 1466 1474 cysteine TRIVIAL 23565644 A 1489 1498 clozapine TRIVIAL 23565644 A 1601 1613 ketoconazole TRIVIAL 23565644 A 1618 1627 clozapine TRIVIAL 23565644 A 1689 1700 glutathione TRIVIAL 23565644 A 874 886 ketoconazole TRIVIAL 23565644 A 891 900 clozapine TRIVIAL 23565644 A 964 976 voriconazole TRIVIAL 23565644 A 981 991 olanzapine TRIVIAL 23565654 A 18 24 carbon SYSTEMATIC 23565654 A 217 223 carbon SYSTEMATIC 23565654 A 269 275 carbon SYSTEMATIC 23565654 A 873 879 carbon SYSTEMATIC 23565654 T 75 81 Carbon SYSTEMATIC 23565720 A 108 116 nitrogen SYSTEMATIC 23565720 A 201 208 diamond TRIVIAL 23565720 T 35 42 diamond TRIVIAL 23565755 A 222 230 androgen FAMILY 23565755 A 532 540 androgen FAMILY 23565755 T 133 141 androgen FAMILY 23565755 T 23 31 androgen FAMILY 23565755 T 44 52 androgen FAMILY 23565759 A 143 155 carbohydrate FAMILY 23566035 A 1420 1422 Pd FORMULA 23566035 A 1627 1643 transition metal FAMILY 23566035 A 336 347 benzylamine SYSTEMATIC 23566035 A 36 45 palladium SYSTEMATIC 23566035 A 372 389 aromatic alcohols FAMILY 23566035 A 407 416 aldehydes FAMILY 23566035 A 421 428 ketones FAMILY 23566035 A 434 440 phenol SYSTEMATIC 23566035 A 456 458 Au FORMULA 23566035 A 459 461 Pd FORMULA 23566035 A 47 49 Pd FORMULA 23566035 A 625 627 Pd FORMULA 23566035 A 86 88 Au FORMULA 23566035 A 90 92 Pd FORMULA 23566035 A 941 943 Au FORMULA 23566035 A 944 946 Pd FORMULA 23566035 T 35 44 Palladium SYSTEMATIC 23566035 T 57 66 Palladium SYSTEMATIC 23566056 A 1012 1020 Curcumin TRIVIAL 23566056 A 1148 1151 MDA ABBREVIATION 23566056 A 1162 1173 acetic acid SYSTEMATIC 23566056 A 1209 1217 curcumin TRIVIAL 23566056 A 133 134 N FORMULA 23566056 A 1387 1395 curcumin TRIVIAL 23566056 A 310 321 acetic acid SYSTEMATIC 23566056 A 378 389 acetic acid SYSTEMATIC 23566056 A 395 406 acetic acid SYSTEMATIC 23566056 A 407 415 curcumin TRIVIAL 23566056 A 417 425 Curcumin TRIVIAL 23566056 A 52 60 curcumin TRIVIAL 23566056 A 564 575 Acetic acid SYSTEMATIC 23566056 A 746 761 malondialdehyde TRIVIAL 23566056 A 763 766 MDA ABBREVIATION 23566056 T 11 19 Curcumin TRIVIAL 23566056 T 132 133 N FORMULA 23566056 T 84 95 Acetic Acid SYSTEMATIC 23566058 A 1147 1151 PGE2 ABBREVIATION 23566058 A 1455 1459 PGE2 ABBREVIATION 23566058 A 21 29 phenolic FAMILY 23566058 A 217 233 prostaglandin E2 TRIVIAL 23566058 A 235 239 PGE2 ABBREVIATION 23566058 A 793 797 PGE2 ABBREVIATION 23566058 T 83 99 prostaglandin e2 TRIVIAL 23566060 A 1186 1196 enterodiol TRIVIAL 23566060 A 1261 1274 enterolactone TRIVIAL 23566060 A 1400 1413 enterolignans FAMILY 23566060 A 1456 1469 enterolignans FAMILY 23566060 A 27 37 enterodiol TRIVIAL 23566060 A 329 342 enterolactone TRIVIAL 23566060 A 347 357 enterodiol TRIVIAL 23566060 A 49 56 lignans FAMILY 23566060 A 555 568 enterolignans FAMILY 23566060 A 774 780 lignan FAMILY 23566060 A 817 830 enterolignans FAMILY 23566060 A 851 864 enterolactone TRIVIAL 23566060 A 889 899 enterodiol TRIVIAL 23566060 A 9 22 Enterolactone TRIVIAL 23566060 A 964 977 enterolignans FAMILY 23566060 A 982 995 enterolactone TRIVIAL 23566060 T 17 30 enterolactone TRIVIAL 23566515 A 1160 1195 2-amino-3-carboxy-4-phenylthiophene SYSTEMATIC 23566515 A 134 141 retinal TRIVIAL 23566515 A 282 297 phenylthiophene SYSTEMATIC 23566515 T 50 86 2-amino-3-carboxy-4-phenylthiophenes FAMILY 23566520 A 18 23 amide FAMILY 23566520 A 39 51 lomefloxacin TRIVIAL 23566520 T 68 80 lomefloxacin TRIVIAL 23566884 A 0 10 Tomatidine TRIVIAL 23566884 A 1062 1072 tomatidine TRIVIAL 23566884 A 1170 1180 tomatidine TRIVIAL 23566884 A 1270 1278 LY294002 IDENTIFIER 23566884 A 1286 1291 U0126 IDENTIFIER 23566884 A 1304 1331 pyrrolidine dithiocarbamate SYSTEMATIC 23566884 A 1418 1428 tomatidine TRIVIAL 23566884 A 1628 1638 tomatidine TRIVIAL 23566884 A 217 227 tomatidine TRIVIAL 23566884 A 305 315 tomatidine TRIVIAL 23566884 A 422 432 tomatidine TRIVIAL 23566884 A 43 51 tomatine TRIVIAL 23566884 A 528 538 tomatidine TRIVIAL 23566884 A 63 73 Tomatidine TRIVIAL 23566884 A 649 659 Tomatidine TRIVIAL 23566884 A 779 787 cysteine TRIVIAL 23566884 A 928 938 tomatidine TRIVIAL 23566884 T 0 10 Tomatidine TRIVIAL 23567030 A 1106 1108 SH FORMULA 23567030 A 1162 1169 glucose TRIVIAL 23567030 A 1300 1308 phenolic FAMILY 23567030 A 1313 1323 flavonoids FAMILY 23567030 A 1434 1441 glucose TRIVIAL 23567030 A 411 418 glucose TRIVIAL 23567030 A 437 444 glucose TRIVIAL 23567030 A 525 527 SH FORMULA 23567030 A 578 589 polyphenols FAMILY 23567030 A 594 604 flavonoids FAMILY 23567030 A 606 610 iron SYSTEMATIC 23567030 A 645 649 DPPH ABBREVIATION 23567030 A 760 771 polyphenols FAMILY 23567030 A 776 786 flavonoids FAMILY 23567030 A 850 888 quercetin-3-O-(2-rhamnosyl) rutinoside SYSTEMATIC 23567030 A 890 929 kaempferol-3-O-(2-rhamnosyl) rutinoside SYSTEMATIC 23567030 A 931 955 quercetin-3-O-rutinoside SYSTEMATIC 23567030 A 960 985 kaempferol-3-O-rutinoside SYSTEMATIC 23567030 T 147 154 glucose TRIVIAL 23567030 T 99 101 SH FORMULA 23567032 A 1106 1118 carbohydrate FAMILY 23567032 A 233 240 ethanol SYSTEMATIC 23567032 A 600 614 streptozotocin TRIVIAL 23567032 A 741 748 glucose TRIVIAL 23567035 A 1987 1995 saponins FAMILY 23567035 A 1997 2007 flavonoids FAMILY 23567035 A 2009 2016 tannins FAMILY 23567035 A 2018 2032 anthraquinones FAMILY 23567035 A 2150 2157 ethanol SYSTEMATIC 23567035 A 414 421 ethanol SYSTEMATIC 23567039 A 0 12 Microcystins FAMILY 23567039 A 1193 1198 MC-RY ABBREVIATION 23567039 A 17 37 cyclic heptapeptides FAMILY 23567039 A 263 268 Thiol SYSTEMATIC 23567039 A 291 312 α,β-unsaturated amide SYSTEMATIC 23567039 A 329 341 microcystins FAMILY 23567039 A 483 495 microcystins FAMILY 23567039 A 700 711 microcystin FAMILY 23567039 A 876 888 microcystins FAMILY 23567039 A 927 954 microcystin-RY, -RL and -RA MULTIPLE 23567039 A 956 996 Microcystin-YR (2), -RR (3), and -RY (9) MULTIPLE 23567039 T 18 30 microcystins FAMILY 23567039 T 88 93 thiol FAMILY 23567043 A 1100 1111 acetic acid SYSTEMATIC 23567043 A 1175 1186 amine salts FAMILY 23567043 A 1190 1193 TEF ABBREVIATION 23567043 A 1198 1201 LOX ABBREVIATION 23567043 A 1214 1222 TEF-TEtA ABBREVIATION 23567043 A 1227 1235 LOX-TEtA ABBREVIATION 23567043 A 1269 1272 TEF ABBREVIATION 23567043 A 1277 1280 LOX ABBREVIATION 23567043 A 1396 1399 TEF ABBREVIATION 23567043 A 1404 1407 LOX ABBREVIATION 23567043 A 1455 1463 TEF-TEtA ABBREVIATION 23567043 A 1472 1480 LOX-TEtA ABBREVIATION 23567043 A 1529 1532 TEF ABBREVIATION 23567043 A 1537 1540 LOX ABBREVIATION 23567043 A 166 179 teriflunomide TRIVIAL 23567043 A 1765 1768 TEF ABBREVIATION 23567043 A 1773 1776 LOX ABBREVIATION 23567043 A 181 184 TEF ABBREVIATION 23567043 A 190 200 lornoxicam TRIVIAL 23567043 A 202 205 LOX ABBREVIATION 23567043 A 345 348 TEF ABBREVIATION 23567043 A 353 356 LOX ABBREVIATION 23567043 A 419 422 TEF ABBREVIATION 23567043 A 427 430 LOX ABBREVIATION 23567043 A 436 450 organic amines FAMILY 23567043 A 444 450 amines FAMILY 23567043 A 451 463 diethylamine SYSTEMATIC 23567043 A 465 469 DEtA ABBREVIATION 23567043 A 472 485 triethylamine SYSTEMATIC 23567043 A 487 491 TEtA ABBREVIATION 23567043 A 494 508 diethanolamine SYSTEMATIC 23567043 A 510 513 DEA ABBREVIATION 23567043 A 516 531 triethanolamine SYSTEMATIC 23567043 A 533 536 TEA ABBREVIATION 23567043 A 542 574 N-(2'-hydroxy-ethanol)-piperdine SYSTEMATIC 23567043 A 860 863 TEF ABBREVIATION 23567043 A 868 871 LOX ABBREVIATION 23567043 T 73 86 teriflunomide TRIVIAL 23567043 T 91 101 lornoxicam TRIVIAL 23567245 A 507 518 polyphenols FAMILY 23567245 A 586 598 nitric oxide SYSTEMATIC 23567245 A 643 655 nitric oxide SYSTEMATIC 23567245 A 657 659 NO FORMULA 23567245 A 665 678 nitrotyrosine SYSTEMATIC 23567245 A 846 848 NO FORMULA 23567245 A 916 929 nitrotyrosine SYSTEMATIC 23567316 A 1018 1026 rotenone TRIVIAL 23567316 A 1227 1235 Rotenone TRIVIAL 23567316 A 1276 1290 [(3)H]dopamine SYSTEMATIC 23567316 A 248 256 rotenone TRIVIAL 23567316 A 437 445 rotenone TRIVIAL 23567316 A 629 637 dopamine TRIVIAL 23567316 A 747 755 rotenone TRIVIAL 23567316 T 173 181 rotenone TRIVIAL 23567316 T 93 101 dopamine TRIVIAL 23567484 A 1003 1010 ferrous SYSTEMATIC 23567484 A 1114 1119 Sugar FAMILY 23567484 A 1212 1216 DLPC ABBREVIATION 23567484 A 1286 1290 DLPC ABBREVIATION 23567484 A 1468 1474 sugars FAMILY 23567484 A 366 410 1,2-dilinolenoyl-sn-glycero-3-phosphocholine SYSTEMATIC 23567484 A 412 416 DLPC ABBREVIATION 23567484 A 541 546 sugar FAMILY 23567484 A 571 575 DLPC ABBREVIATION 23567484 A 610 614 DLPC ABBREVIATION 23567484 A 688 695 ferrous SYSTEMATIC 23567484 A 704 711 sucrose TRIVIAL 23567484 A 806 810 DLPC ABBREVIATION 23567484 A 855 862 ferrous SYSTEMATIC 23567484 A 927 931 DLPC ABBREVIATION 23567484 A 948 955 sucrose TRIVIAL 23567490 A 398 412 5-fluorouracil SYSTEMATIC 23567490 T 119 123 5-FU SYSTEMATIC 23567948 A 10 23 ruthenium(II) SYSTEMATIC 23567948 A 34 59 [Ru(dmb)2(addppn)](ClO4)2 FORMULA 23567948 A 436 439 MTT ABBREVIATION 23567948 A 482 495 Hoechst 33258 TRIVIAL 23567948 A 68 93 [Ru(bpy)2(addppn)](ClO4)2 FORMULA 23567948 T 104 117 ruthenium(II) SYSTEMATIC 23567953 A 11 41 1,3,4-trisubstituted pyrazoles FAMILY 23567953 A 269 283 phenylbutazone TRIVIAL 23567953 T 19 49 1,3,4-trisubstituted pyrazoles FAMILY 23567956 A 101 105 JL34 IDENTIFIER 23567956 A 107 111 JL40 IDENTIFIER 23567956 A 1122 1145 indolyl carbohydrazides FAMILY 23567956 A 113 117 JL71 IDENTIFIER 23567956 A 119 123 JL87 IDENTIFIER 23567956 A 125 130 JL317 IDENTIFIER 23567956 A 132 137 JL432 IDENTIFIER 23567956 A 139 144 JL436 IDENTIFIER 23567956 A 163 187 3-indolyl carbohydrazide SYSTEMATIC 23567956 A 188 193 JL344 IDENTIFIER 23567956 A 195 227 3-(3-hydrazinylpropyl)-1H-indole SYSTEMATIC 23567956 A 229 233 JL72 IDENTIFIER 23567956 A 239 272 3-(1H-indol-3-yl)propanehydrazide SYSTEMATIC 23567956 A 274 279 JL418 IDENTIFIER 23567956 A 384 388 DPPH ABBREVIATION 23567956 A 429 433 DMSO ABBREVIATION 23567956 A 681 687 oxygen SYSTEMATIC 23567956 A 727 735 hydroxyl SYSTEMATIC 23567956 A 74 99 2-indolyl carbohydrazides FAMILY 23567956 A 806 810 JL40 IDENTIFIER 23567956 A 815 820 JL432 IDENTIFIER 23567956 T 66 98 2- and 3-indolyl carbohydrazides MULTIPLE 23567963 A 12 28 bisbenzaldehydes FAMILY 23567963 A 401 445 4,4'-[1,12-dodecanediyl(oxy)]bisbenzaldehyde SYSTEMATIC 23567963 A 686 697 neutral red TRIVIAL 23567963 T 25 41 bisbenzaldehydes FAMILY 23568452 A 287 293 methyl SYSTEMATIC 23568452 A 314 321 silicon SYSTEMATIC 23568452 A 89 96 silicon SYSTEMATIC 23568452 T 41 48 silicon SYSTEMATIC 23568554 A 1805 1812 glucose TRIVIAL 23568554 A 25 35 cyclic AMP TRIVIAL 23568554 T 0 10 Cyclic AMP TRIVIAL 23568566 A 13 15 Au FORMULA 23568566 T 53 55 Au FORMULA 23568627 A 1000 1011 glutathione TRIVIAL 23568627 A 1117 1133 chlorogenic acid TRIVIAL 23568627 A 137 153 chlorogenic acid TRIVIAL 23568627 A 157 176 silver sulfadiazine SYSTEMATIC 23568627 A 296 312 chlorogenic acid TRIVIAL 23568627 A 472 491 silver sulfadiazine SYSTEMATIC 23568627 A 73 89 chlorogenic acid TRIVIAL 23568627 A 831 847 chlorogenic acid TRIVIAL 23568627 A 895 911 chlorogenic acid TRIVIAL 23568627 A 964 974 superoxide TRIVIAL 23568627 T 33 49 Chlorogenic Acid TRIVIAL 23568773 A 1175 1178 Thr FORMULA 23568773 A 224 225 N FORMULA 23568773 A 4 5 N FORMULA 23568773 A 756 764 SB202190 IDENTIFIER 23568773 A 777 785 SB202190 IDENTIFIER 23569176 A 1705 1713 catechol TRIVIAL 23569176 A 1714 1715 O FORMULA 23569176 A 1845 1853 catechol TRIVIAL 23569176 A 779 787 catechol TRIVIAL 23569176 A 788 789 O FORMULA 23569204 A 125 126 N FORMULA 23569204 A 136 145 histidine TRIVIAL 23569204 A 373 387 phospho-serine SYSTEMATIC 23569204 A 392 408 phospho-tyrosine SYSTEMATIC 23569204 A 534 541 phospho SYSTEMATIC 23570232 A 1278 1286 DB[a,l]P ABBREVIATION 23570232 A 1347 1355 DB[a,l]P ABBREVIATION 23570232 A 1364 1371 adenine TRIVIAL 23570232 A 283 290 guanine TRIVIAL 23570232 A 305 312 adenine TRIVIAL 23570232 A 372 385 diol epoxides FAMILY 23570232 A 457 475 dibenzo[a,l]pyrene SYSTEMATIC 23570232 A 477 485 DB[a,l]P ABBREVIATION 23570232 A 537 544 guanine TRIVIAL 23570232 A 718 725 guanine TRIVIAL 23570232 A 730 737 adenine TRIVIAL 23570232 A 84 94 nucleotide FAMILY 23570232 T 0 7 Adenine TRIVIAL 23570232 T 125 132 Guanine TRIVIAL 23570232 T 56 74 Dibenzo[a,l]pyrene SYSTEMATIC 23570232 T 92 102 Nucleotide FAMILY 23570237 A 228 234 peroxy FAMILY 23570237 A 263 272 methylene SYSTEMATIC 23570237 T 13 48 Hydrocarbon Radicals and Biradicals MULTIPLE 23570261 A 110 117 Ir(111) FORMULA 23570261 A 156 158 Xe FORMULA 23570261 A 219 227 graphene TRIVIAL 23570261 A 375 383 graphene TRIVIAL 23570261 A 471 479 graphene TRIVIAL 23570261 A 98 106 graphene TRIVIAL 23570261 T 15 23 graphene TRIVIAL 23570261 T 24 31 ir(111) FORMULA 23570284 A 1058 1065 sorbate TRIVIAL 23570284 A 208 215 zeolite TRIVIAL 23570284 A 601 608 zeolite TRIVIAL 23570284 A 636 645 zeolite L TRIVIAL 23570284 A 949 956 zeolite TRIVIAL 23570284 T 28 37 zeolite L TRIVIAL 23570347 A 1256 1258 Ag FORMULA 23570347 A 1336 1338 Ag FORMULA 23570347 A 249 255 Silver SYSTEMATIC 23570347 A 257 259 Ag FORMULA 23570347 A 417 419 Ag FORMULA 23570347 A 639 641 Ag FORMULA 23570347 A 729 731 Ag FORMULA 23570347 T 0 6 Silver SYSTEMATIC 23570347 T 44 50 Silver SYSTEMATIC 23570467 A 1655 1665 thiopurine TRIVIAL 23570467 A 1746 1756 thiopurine TRIVIAL 23570467 A 36 46 thiopurine TRIVIAL 23570467 A 366 376 thiopurine TRIVIAL 23570467 A 432 442 thiopurine TRIVIAL 23570467 T 28 38 thiopurine TRIVIAL 23570469 A 772 779 lithium SYSTEMATIC 23570612 A 123 130 acetone SYSTEMATIC 23570612 A 1256 1264 graphene TRIVIAL 23570612 A 132 144 acetonitrile SYSTEMATIC 23570612 A 146 161 dichloromethane SYSTEMATIC 23570612 A 163 170 ethanol SYSTEMATIC 23570612 A 172 185 ethyl acetate SYSTEMATIC 23570612 A 187 193 hexane SYSTEMATIC 23570612 A 199 206 toluene TRIVIAL 23570612 A 211 219 graphene TRIVIAL 23570612 A 321 336 dichloromethane SYSTEMATIC 23570612 A 359 366 toluene TRIVIAL 23570612 A 404 412 graphene TRIVIAL 23570612 A 634 642 graphene TRIVIAL 23570612 A 651 659 coronene TRIVIAL 23570612 A 673 681 graphene TRIVIAL 23570612 T 41 49 graphene TRIVIAL 23570689 A 420 432 formaldehyde SYSTEMATIC 23570790 A 255 265 amino acid FAMILY 23570790 A 487 494 TSG-8-1 TRIVIAL 23570790 A 508 513 amide FAMILY 23570790 T 84 89 amide FAMILY 23570997 A 0 29 Pyranocycloartobiloxanthone A TRIVIAL 23570997 A 1065 1068 MDA ABBREVIATION 23570997 A 1082 1089 ethanol SYSTEMATIC 23570997 A 260 267 ethanol SYSTEMATIC 23570997 A 38 46 xanthone TRIVIAL 23570997 A 400 407 ethanol SYSTEMATIC 23570997 A 487 498 glutathione TRIVIAL 23570997 A 500 503 GSH ABBREVIATION 23570997 A 513 528 malondialdehyde TRIVIAL 23570997 A 536 539 MDA ABBREVIATION 23570997 A 542 554 nitric oxide SYSTEMATIC 23570997 A 556 558 NO FORMULA 23570997 A 576 586 sulfhydryl FAMILY 23570997 A 597 599 SH FORMULA 23570997 A 862 869 ethanol SYSTEMATIC 23570997 A 956 959 GSH ABBREVIATION 23570997 A 964 966 SH FORMULA 23570997 A 971 973 NO FORMULA 23570997 T 0 29 Pyranocycloartobiloxanthone A TRIVIAL 23570997 T 105 112 ethanol SYSTEMATIC 23571493 A 14 23 Potassium SYSTEMATIC 23571493 A 365 368 Na+ FORMULA 23571493 T 20 29 Potassium SYSTEMATIC 23571495 A 182 194 sphingolipid FAMILY 23571495 A 493 504 cholesterol TRIVIAL 23571495 A 606 617 cholesterol TRIVIAL 23571495 A 98 111 sphingomyelin FAMILY 23571495 T 0 13 Sphingomyelin FAMILY 23571664 A 1076 1079 PVA ABBREVIATION 23571664 A 1233 1236 PVA ABBREVIATION 23571664 A 1445 1460 hydroiodic acid SYSTEMATIC 23571664 A 309 328 poly(vinyl alcohol) SYSTEMATIC 23571664 A 330 333 PVA ABBREVIATION 23571664 A 342 350 graphene TRIVIAL 23571664 A 528 536 graphene TRIVIAL 23571664 A 562 565 PVA ABBREVIATION 23571664 A 682 690 graphene TRIVIAL 23571664 A 871 874 PVA ABBREVIATION 23571664 A 939 942 PVA ABBREVIATION 23571664 A 982 985 PVA ABBREVIATION 23571664 T 47 66 poly(vinyl alcohol) SYSTEMATIC 23571664 T 74 82 graphene TRIVIAL 23571753 A 838 849 nucleotides FAMILY 23572389 A 190 197 calcium SYSTEMATIC 23572390 A 337 348 super oxide TRIVIAL 23572390 A 449 464 malondialdehyde TRIVIAL 23572390 A 466 469 MDA ABBREVIATION 23572390 A 893 896 MDA ABBREVIATION 23572392 A 107 164 aromatic amines and aromatic or hetero-aromatic aldehydes MULTIPLE 23572392 A 196 212 bismuth triflate SYSTEMATIC 23572392 A 259 273 β-aminoketones FAMILY 23572392 A 442 456 β-aminoketones FAMILY 23572392 A 60 74 β-aminoketones FAMILY 23572392 A 80 93 cyclohexanone SYSTEMATIC 23572392 T 42 55 β-aminoketone FAMILY 23572392 T 60 81 bismuth(III) triflate SYSTEMATIC 23572394 A 1020 1025 thiol FAMILY 23572394 A 1030 1038 carbonyl FAMILY 23572394 A 1081 1085 H2O2 FORMULA 23572394 A 1153 1157 TCDD ABBREVIATION 23572394 A 1249 1253 H2O2 FORMULA 23572394 A 125 129 TCDD ABBREVIATION 23572394 A 1274 1282 carbonyl FAMILY 23572394 A 1373 1378 thiol FAMILY 23572394 A 1481 1489 lycopene TRIVIAL 23572394 A 232 240 lycopene TRIVIAL 23572394 A 353 360 toluene TRIVIAL 23572394 A 406 414 lycopene TRIVIAL 23572394 A 482 486 TCDD ABBREVIATION 23572394 A 504 521 Hydrogen peroxide SYSTEMATIC 23572394 A 523 527 H2O2 FORMULA 23572394 A 575 583 carbonyl FAMILY 23572394 A 610 630 uridine 5'-diphospho SYSTEMATIC 23572394 A 768 779 glutathione TRIVIAL 23572394 A 801 812 glutathione TRIVIAL 23572394 A 813 814 S FORMULA 23572394 A 831 842 glutathione TRIVIAL 23572394 A 88 123 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23572394 A 939 947 lycopene TRIVIAL 23572394 T 23 31 lycopene TRIVIAL 23572394 T 40 74 2,3,7,8-tetrachlorodibenzo-pdioxin SYSTEMATIC 23572405 A 221 228 glucose TRIVIAL 23572405 A 361 368 glucose TRIVIAL 23572405 A 868 875 glucose TRIVIAL 23572407 A 161 169 nicotine TRIVIAL 23572407 A 1612 1620 nicotine TRIVIAL 23572407 T 47 55 nicotine TRIVIAL 23572408 A 1069 1078 sorafenib TRIVIAL 23572408 A 1117 1129 temsirolimus TRIVIAL 23572408 A 1501 1511 everolimus TRIVIAL 23572408 A 1516 1524 axitinib TRIVIAL 23572408 A 1618 1627 sorafenib TRIVIAL 23572408 A 1632 1644 temsirolimus TRIVIAL 23572408 A 1657 1666 sunitinib TRIVIAL 23572408 A 1771 1780 sorafenib TRIVIAL 23572408 A 1782 1791 Sorafenib TRIVIAL 23572408 A 1793 1802 pazopanib TRIVIAL 23572408 A 1807 1815 axitinib TRIVIAL 23572408 A 2756 2765 sunitinib TRIVIAL 23572408 A 2767 2777 everolimus TRIVIAL 23572408 A 481 490 rapamycin TRIVIAL 23572408 A 736 745 pazopanib TRIVIAL 23572408 A 747 756 sunitinib TRIVIAL 23572408 A 881 890 pazopanib TRIVIAL 23572408 A 903 912 sunitinib TRIVIAL 23572408 A 986 995 tivozanib TRIVIAL 23573970 A 149 164 2-iminothiolane SYSTEMATIC 23573970 A 256 278 6,6´dithionicotinamide SYSTEMATIC 23573970 A 280 285 thiol FAMILY 23573970 A 310 319 disulfide SYSTEMATIC 23573970 A 523 539 thiobutylamidine SYSTEMATIC 23573970 A 697 706 disulfide SYSTEMATIC 23573970 A 723 739 thiobutylamidine SYSTEMATIC 23573970 A 740 760 mercaptonicotinamide SYSTEMATIC 23574049 A 297 304 ethanol SYSTEMATIC 23574049 A 306 313 acetone SYSTEMATIC 23574049 A 315 330 tetrahydrofuran SYSTEMATIC 23574049 A 332 351 N-dimethylformamide SYSTEMATIC 23574049 A 353 379 N-cyclohexyl-2-pyrrolidone SYSTEMATIC 23574049 A 665 671 carbon SYSTEMATIC 23574049 A 70 84 graphene oxide SYSTEMATIC 23574049 T 22 36 Graphene Oxide SYSTEMATIC 23574259 A 587 600 diphenylvinyl SYSTEMATIC 23574259 A 957 968 o-quinonoid FAMILY 23574259 T 86 97 o-Quinonoid FAMILY 23574272 A 0 10 Flavonoids FAMILY 23574272 A 1013 1020 flavone TRIVIAL 23574272 A 157 164 Flavone TRIVIAL 23574272 A 294 304 flavonoids FAMILY 23574272 A 417 427 flavonoids FAMILY 23574272 A 452 461 flavonoid FAMILY 23574272 A 512 520 flavones FAMILY 23574272 A 635 642 Flavone TRIVIAL 23574272 A 696 708 nicotinamide TRIVIAL 23574272 A 762 770 flavones FAMILY 23574272 A 824 832 flavones FAMILY 23574272 T 37 45 Flavones FAMILY 23574308 A 131 138 calcium SYSTEMATIC 23574308 A 246 254 hydrogen SYSTEMATIC 23574308 A 279 291 thapsigargin TRIVIAL 23574308 A 342 354 thapsigargin TRIVIAL 23574308 A 594 602 hydrogen SYSTEMATIC 23574308 A 87 99 thapsigargin TRIVIAL 23574308 T 53 65 Thapsigargin TRIVIAL 23574308 T 97 104 Calcium SYSTEMATIC 23574310 A 298 306 graphene TRIVIAL 23574310 A 506 527 polyvinyl pyrrolidone SYSTEMATIC 23574310 A 529 532 PVP ABBREVIATION 23574310 A 534 542 graphene TRIVIAL 23574310 A 556 564 methanol SYSTEMATIC 23574310 A 606 609 PVP ABBREVIATION 23574310 A 618 632 graphene oxide SYSTEMATIC 23574310 A 666 687 poly(4-vinylpyridine) FAMILY 23574310 A 688 696 graphene TRIVIAL 23574310 A 72 80 graphene TRIVIAL 23574310 A 84 102 dimethyl sulfoxide SYSTEMATIC 23574310 T 33 41 Graphene TRIVIAL 23574435 A 1119 1126 NNOH(+) FORMULA 23574435 A 27 35 nitrogen SYSTEMATIC 23574435 A 36 60 protonated nitrous oxide SYSTEMATIC 23574435 A 486 487 N FORMULA 23574435 A 498 506 nitrogen SYSTEMATIC 23574435 A 62 69 HNNO(+) FORMULA 23574435 A 656 657 N FORMULA 23574435 A 689 713 protonated nitrous oxide SYSTEMATIC 23574435 A 780 790 H-N═N(+)═O FORMULA 23574435 A 827 835 nitrogen SYSTEMATIC 23574435 A 856 866 N≡N(+)-O-H FORMULA 23574435 A 875 881 oxygen SYSTEMATIC 23574435 A 899 906 HNNO(+) FORMULA 23574435 A 951 958 NNOH(+) FORMULA 23574435 T 13 21 Nitrogen SYSTEMATIC 23574435 T 22 46 Protonated Nitrous Oxide SYSTEMATIC 23574435 T 48 55 HNNO(+) FORMULA 23574541 A 14 27 Desloratadine TRIVIAL 23574541 A 295 308 desloratadine TRIVIAL 23574541 A 440 453 desloratadine TRIVIAL 23574541 A 533 546 desloratadine TRIVIAL 23574541 A 601 614 Desloratadine TRIVIAL 23574541 A 639 648 histamine TRIVIAL 23574541 A 842 855 Desloratadine TRIVIAL 23574541 A 99 109 loratadine TRIVIAL 23574541 T 21 34 desloratadine TRIVIAL 23574729 A 1105 1113 cortisol TRIVIAL 23574729 A 114 122 cortisol TRIVIAL 23574729 A 1345 1353 cortisol TRIVIAL 23574729 A 1518 1548 dehydroepiandrosterone sulfate SYSTEMATIC 23574729 A 1568 1576 cortisol TRIVIAL 23574729 A 258 271 dexamethasone TRIVIAL 23574729 A 350 358 cortisol TRIVIAL 23574729 A 434 442 cortisol TRIVIAL 23574729 A 716 724 cortisol TRIVIAL 23574729 A 800 808 cortisol TRIVIAL 23574729 A 920 928 cortisol TRIVIAL 23574807 A 108 112 6-NQ SYSTEMATIC 23574807 A 51 60 serotonin TRIVIAL 23574807 A 648 652 6-NQ SYSTEMATIC 23574807 A 7 12 alkyl FAMILY 23574807 A 720 725 octyl SYSTEMATIC 23574807 A 731 736 decyl SYSTEMATIC 23574807 A 746 753 dodecyl SYSTEMATIC 23574807 A 759 763 6-NQ SYSTEMATIC 23574807 A 90 106 6-nitroquipazine SYSTEMATIC 23574807 T 71 91 Alkylnitroquipazines FAMILY 23574807 T 95 104 Serotonin TRIVIAL 23575745 A 124 130 BaTiO3 FORMULA 23575800 A 0 17 Trichloroethylene SYSTEMATIC 23575800 A 1084 1087 TCE ABBREVIATION 23575800 A 1156 1166 fatty acid FAMILY 23575800 A 1236 1239 TCE ABBREVIATION 23575800 A 1337 1374 lysophosphatidylcholine 18:0 and 18:1 MULTIPLE 23575800 A 1380 1399 phosphatidylcholine FAMILY 23575800 A 1413 1416 TCA ABBREVIATION 23575800 A 1493 1496 TCE ABBREVIATION 23575800 A 1601 1604 TCA ABBREVIATION 23575800 A 1610 1613 DCA ABBREVIATION 23575800 A 1667 1670 TCE ABBREVIATION 23575800 A 1701 1704 TCA ABBREVIATION 23575800 A 1733 1736 TCE ABBREVIATION 23575800 A 19 22 TCE ABBREVIATION 23575800 A 213 216 TCE ABBREVIATION 23575800 A 230 245 dichloroacetate SYSTEMATIC 23575800 A 247 250 DCA ABBREVIATION 23575800 A 256 272 trichloroacetate SYSTEMATIC 23575800 A 274 277 TCA ABBREVIATION 23575800 A 298 301 TCE ABBREVIATION 23575800 A 434 437 TCE ABBREVIATION 23575800 A 487 490 TCE ABBREVIATION 23575800 A 524 527 DCA ABBREVIATION 23575800 A 532 535 TCA ABBREVIATION 23575800 A 539 542 TCE ABBREVIATION 23575800 A 584 587 TCE ABBREVIATION 23575800 A 589 592 TCA ABBREVIATION 23575800 A 597 600 DCA ABBREVIATION 23575800 T 21 37 trichloroacetate SYSTEMATIC 23575800 T 64 81 trichloroethylene SYSTEMATIC 23575901 A 1267 1270 NaB FORMULA 23575901 A 1414 1417 NaB FORMULA 23575901 A 411 416 boron SYSTEMATIC 23575901 A 589 620 sodium pentaborate pentahydrate SYSTEMATIC 23575901 A 622 625 NaB FORMULA 23575901 A 975 982 calcium SYSTEMATIC 23575901 A 997 1000 NaB FORMULA 23575901 T 0 5 Boron SYSTEMATIC 23575940 A 539 550 fluconazole TRIVIAL 23576111 A 728 739 glutathione TRIVIAL 23576111 A 778 788 superoxide TRIVIAL 23576175 A 410 418 Emodinol TRIVIAL 23576175 A 431 441 triterpene FAMILY 23576175 A 591 599 emodinol TRIVIAL 23576175 A 785 801 monosodium urate SYSTEMATIC 23576175 A 855 863 emodinol TRIVIAL 23576175 A 93 109 monosodium urate SYSTEMATIC 23576175 A 950 966 monosodium urate SYSTEMATIC 23576175 T 34 42 Emodinol TRIVIAL 23576175 T 46 62 Monosodium Urate SYSTEMATIC 23576194 A 548 557 polyimide FAMILY 23576205 A 141 144 azo SYSTEMATIC 23576205 A 318 321 azo SYSTEMATIC 23576205 T 95 98 azo SYSTEMATIC 23576242 A 123 142 trimethylenemethane SYSTEMATIC 23576242 A 144 147 TMM ABBREVIATION 23576242 A 42 94 2-(4-benzoylphenyl)-2-phenyl-1-methylenecyclopropane SYSTEMATIC 23576242 T 88 91 TMM ABBREVIATION 23576269 A 102 111 threonine TRIVIAL 23576269 A 95 101 serine TRIVIAL 23576269 T 18 24 Serine TRIVIAL 23576269 T 25 34 Threonine TRIVIAL 23576424 A 101 109 α-methyl SYSTEMATIC 23576424 A 78 96 secondary alcohols FAMILY 23576424 T 40 48 Hydroxyl SYSTEMATIC 23576424 T 60 66 Methyl SYSTEMATIC 23577599 A 1201 1211 amino acid FAMILY 23577599 A 1222 1224 CH FORMULA 23577599 A 1252 1253 H FORMULA 23577599 A 1268 1275 glucose TRIVIAL 23577599 A 887 899 cellohexaose TRIVIAL 23577599 T 59 71 Heptapeptide FAMILY 23577636 A 50 77 tetrabutylammonium fluoride SYSTEMATIC 23577636 A 532 536 TBAF ABBREVIATION 23577636 A 562 566 acyl FAMILY 23577636 A 629 653 secondary alcohol esters FAMILY 23577636 A 678 682 TBAF ABBREVIATION 23577636 A 708 714 esters FAMILY 23577636 A 79 83 TBAF ABBREVIATION 23577636 T 25 29 TBAF ABBREVIATION 23577636 T 65 71 Esters FAMILY 23577649 A 41 44 H2O FORMULA 23577871 A 67 75 nitrogen SYSTEMATIC 23577871 A 76 84 nitrogen SYSTEMATIC 23577871 A 86 89 N-N FORMULA 23577871 T 30 38 Nitrogen SYSTEMATIC 23577871 T 39 47 Nitrogen SYSTEMATIC 23578300 A 1026 1033 glucose TRIVIAL 23578300 A 1059 1064 alkyl FAMILY 23578300 A 1292 1299 mannose TRIVIAL 23578300 A 187 199 carbohydrate FAMILY 23578300 A 245 257 carbohydrate FAMILY 23578300 A 294 299 alkyl FAMILY 23578300 A 333 345 carbohydrate FAMILY 23578300 A 700 705 sugar FAMILY 23578300 A 999 1010 α-d-mannose TRIVIAL 23578392 A 1508 1515 TCPOBOP TRIVIAL 23578392 A 17 27 androstane TRIVIAL 23578392 A 951 994 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene SYSTEMATIC 23578392 A 996 1003 TCPOBOP TRIVIAL 23578392 T 123 133 androstane TRIVIAL 23578607 A 0 16 6-Dehydroshogaol SYSTEMATIC 23578607 A 1033 1039 6-DHSG SYSTEMATIC 23578607 A 1050 1074 α,β-unsaturated carbonyl FAMILY 23578607 A 18 24 6-DHSG SYSTEMATIC 23578607 A 187 198 glutathione TRIVIAL 23578607 A 200 203 GSH ABBREVIATION 23578607 A 306 312 6-DHSG SYSTEMATIC 23578607 A 360 370 6-gingerol SYSTEMATIC 23578607 A 375 384 6-shogaol SYSTEMATIC 23578607 A 386 392 6-DHSG SYSTEMATIC 23578607 A 41 65 α,β-unsaturated carbonyl FAMILY 23578607 A 526 532 6-DHSG SYSTEMATIC 23578607 A 552 562 sulfhydryl FAMILY 23578607 A 584 595 glutathione TRIVIAL 23578607 A 597 600 GSH ABBREVIATION 23578607 A 605 622 N-acetyl cysteine SYSTEMATIC 23578607 A 624 627 NAC ABBREVIATION 23578607 A 638 651 ascorbic acid TRIVIAL 23578607 A 653 656 ASC ABBREVIATION 23578607 A 659 665 6-DHSG SYSTEMATIC 23578607 A 685 688 GSH ABBREVIATION 23578607 A 699 702 GSH ABBREVIATION 23578607 A 714 723 GS-6-DHSG SYSTEMATIC 23578607 A 807 818 glutathione TRIVIAL 23578607 A 819 820 S FORMULA 23578607 A 840 849 GS-6-DHSG SYSTEMATIC 23578607 A 901 907 6-DHSG SYSTEMATIC 23578607 A 977 980 GSH ABBREVIATION 23578607 T 0 11 Glutathione TRIVIAL 23578607 T 60 76 6-dehydroshogaol SYSTEMATIC 23578611 A 0 11 Polyphenols FAMILY 23578611 A 54 68 phenolic acids FAMILY 23578611 A 646 655 bile acid FAMILY 23578611 A 77 125 gentisic, p-hydroxybenoic, and chlorogenic acids MULTIPLE 23578612 A 526 541 sodium sulphite SYSTEMATIC 23578612 A 545 568 sodium dodecyl sulphate SYSTEMATIC 23578612 A 859 869 disulphide SYSTEMATIC 23578614 A 104 110 oxygen SYSTEMATIC 23578614 A 1041 1047 oxygen SYSTEMATIC 23578614 A 174 180 oxygen SYSTEMATIC 23578614 A 244 250 oxygen SYSTEMATIC 23578614 A 351 357 oxygen SYSTEMATIC 23578614 A 396 404 thionine TRIVIAL 23578614 A 406 414 glycerol TRIVIAL 23578614 A 416 424 P25 TiO2 FORMULA 23578614 A 943 949 oxygen SYSTEMATIC 23578614 T 35 41 oxygen SYSTEMATIC 23578617 A 10 22 (+)-catechin TRIVIAL 23578617 A 115 129 ethyl butyrate SYSTEMATIC 23578617 A 134 149 ethyl octanoate SYSTEMATIC 23578617 A 27 38 gallic acid TRIVIAL 23578617 A 272 280 Catechin TRIVIAL 23578617 A 334 340 esters FAMILY 23578617 A 342 359 ethyl isobutyrate SYSTEMATIC 23578617 A 361 375 ethyl butyrate SYSTEMATIC 23578617 A 380 395 ethyl octanoate SYSTEMATIC 23578617 A 403 414 gallic acid TRIVIAL 23578617 A 436 450 Ethyl butyrate SYSTEMATIC 23578617 A 455 470 ethyl octanoate SYSTEMATIC 23578617 A 526 534 catechin TRIVIAL 23578617 A 570 578 phenolic FAMILY 23578617 A 659 674 ethyl octanoate SYSTEMATIC 23578617 A 701 709 catechin TRIVIAL 23578617 A 754 760 esters FAMILY 23578617 A 79 94 isoamyl acetate SYSTEMATIC 23578617 A 816 824 phenolic FAMILY 23578617 A 935 943 phenolic FAMILY 23578617 A 96 113 ethyl isobutyrate SYSTEMATIC 23578617 T 13 21 phenolic FAMILY 23578617 T 87 93 esters FAMILY 23578618 A 100 112 sulfonamides FAMILY 23578618 A 114 117 SAs FAMILY 23578618 A 163 169 carbon SYSTEMATIC 23578618 A 254 259 Fe3O4 FORMULA 23578618 A 455 458 SAs FAMILY 23578618 A 736 739 SAs FAMILY 23578618 A 881 884 SAs FAMILY 23578618 T 22 34 sulfonamides FAMILY 23578618 T 79 85 carbon SYSTEMATIC 23578619 A 405 415 tocopherol FAMILY 23578619 A 437 446 vitamin E FAMILY 23578619 A 5 16 tocotrienol FAMILY 23578619 A 982 1010 geranylgeranyl pyrophosphate SYSTEMATIC 23578619 T 17 28 tocotrienol FAMILY 23578631 A 1082 1094 α-keto acids FAMILY 23578631 A 120 132 pyruvic acid TRIVIAL 23578631 A 134 161 4-hydroxyphenylpyruvic acid SYSTEMATIC 23578631 A 163 189 3-methyl-2-oxobutyric acid SYSTEMATIC 23578631 A 191 222 α-keto-γ-methylthiobutyric acid SYSTEMATIC 23578631 A 224 250 4-methyl-2-oxovaleric acid SYSTEMATIC 23578631 A 252 278 3-methyl-2-oxovaleric acid SYSTEMATIC 23578631 A 284 302 phenylpyruvic acid SYSTEMATIC 23578631 A 551 563 α-keto acids FAMILY 23578631 A 569 584 dansylhydrazine TRIVIAL 23578631 A 716 727 α-keto acid FAMILY 23578631 A 85 97 α-keto acids FAMILY 23578631 A 856 867 α-keto acid FAMILY 23578631 A 894 906 α-keto acids FAMILY 23578631 A 99 118 α-ketoglutaric acid TRIVIAL 23578631 T 17 29 α-keto acids FAMILY 23578635 A 221 231 amino acid FAMILY 23578635 A 613 623 amino acid FAMILY 23578635 A 782 792 amino acid FAMILY 23578635 T 0 10 Amino acid FAMILY 23578641 A 1046 1058 chlorophylls FAMILY 23578641 A 1084 1096 t-2-heptenal SYSTEMATIC 23578641 A 11 21 β-carotene TRIVIAL 23578641 A 1101 1113 1-octen-3-ol SYSTEMATIC 23578641 A 1121 1131 riboflavin TRIVIAL 23578641 A 1199 1209 β-carotene TRIVIAL 23578641 A 1246 1256 β-carotene TRIVIAL 23578641 A 1309 1315 oxygen SYSTEMATIC 23578641 A 175 181 oxygen SYSTEMATIC 23578641 A 197 211 hydroperoxides FAMILY 23578641 A 286 296 β-carotene TRIVIAL 23578641 A 384 396 chlorophylls FAMILY 23578641 A 472 482 β-carotene TRIVIAL 23578641 A 518 528 riboflavin TRIVIAL 23578641 A 52 63 chlorophyll FAMILY 23578641 A 575 585 β-carotene TRIVIAL 23578641 A 622 632 β-carotene TRIVIAL 23578641 A 67 77 riboflavin TRIVIAL 23578641 A 683 693 β-carotene TRIVIAL 23578641 A 821 833 t-2-heptenal SYSTEMATIC 23578641 A 838 850 1-octen-3-ol SYSTEMATIC 23578641 A 872 883 chlorophyll FAMILY 23578641 A 929 939 β-carotene TRIVIAL 23578641 A 982 988 oxygen SYSTEMATIC 23578641 T 45 55 β-carotene TRIVIAL 23578641 T 59 70 chlorophyll FAMILY 23578641 T 75 85 riboflavin TRIVIAL 23578644 A 1097 1104 calcium SYSTEMATIC 23578644 A 142 149 calcium SYSTEMATIC 23578644 A 220 227 calcium SYSTEMATIC 23578644 A 349 356 calcium SYSTEMATIC 23578644 A 393 406 linoleic acid TRIVIAL 23578644 A 73 86 linoleic acid TRIVIAL 23578644 A 838 862 1,25-dihydroxyvitamin D3 SYSTEMATIC 23578644 T 11 24 linoleic acid TRIVIAL 23578644 T 29 36 calcium SYSTEMATIC 23578647 A 215 243 dihydrobenzofuroisocoumarins FAMILY 23578647 A 245 275 (+)-platyphyllarin A (1) and B MULTIPLE 23578647 A 289 298 butanoate SYSTEMATIC 23578647 A 300 317 ethyltributanoate SYSTEMATIC 23578647 A 335 352 homoisoflavanones FAMILY 23578647 A 354 379 (-)-liriopein A (4) and B MULTIPLE 23578647 A 430 447 homoisoflavonoids FAMILY 23578647 A 453 461 chalcone FAMILY 23578647 A 467 473 amides FAMILY 23578647 A 479 485 lignan FAMILY 23578647 A 491 501 fatty acid FAMILY 23578647 A 534 544 benzenoids FAMILY 23578647 A 554 562 steroids FAMILY 23578647 T 48 76 dihydrobenzofuroisocoumarins FAMILY 23578647 T 81 98 homoisoflavonoids FAMILY 23578649 A 1093 1101 fluoride SYSTEMATIC 23578649 A 225 235 β carotene TRIVIAL 23578649 A 467 482 sodium fluoride SYSTEMATIC 23578649 A 504 519 sodium fluoride SYSTEMATIC 23578649 A 567 575 fluoride SYSTEMATIC 23578649 A 68 83 sodium fluoride SYSTEMATIC 23578649 A 801 809 Fluoride SYSTEMATIC 23578649 A 933 941 fluoride SYSTEMATIC 23578650 A 296 305 phenolics FAMILY 23578650 A 421 433 caffeic acid TRIVIAL 23578650 A 447 493 5-feruloylquinic and 5-p-coumaroylquinic acids MULTIPLE 23578650 A 556 565 phenolics FAMILY 23578650 A 589 594 rutin TRIVIAL 23578650 A 598 612 dicaffeic acid TRIVIAL 23578650 A 632 670 feruloylquinic and caffeoylquinic acid MULTIPLE 23578650 A 731 739 phenolic FAMILY 23578650 T 23 33 polyphenol FAMILY 23578688 A 12 30 carbamoylmethylene SYSTEMATIC 23578688 A 136 169 phosphoryloxymethylene carbamates FAMILY 23578688 A 188 222 α-aminoacyloxymethylene carbamates FAMILY 23578688 A 282 294 fumaric acid TRIVIAL 23578688 A 303 330 acyloxymethylene carbamates FAMILY 23578688 A 53 63 BMS-582949 IDENTIFIER 23578688 A 948 964 secondary amides FAMILY 23578688 T 28 46 carbamoylmethylene SYSTEMATIC 23578688 T 66 76 BMS-582949 IDENTIFIER 23578689 A 0 49 Racemic 5-(trans-2-aminomethylcyclopropyl)indoles FAMILY 23578689 A 183 192 serotonin TRIVIAL 23578689 A 289 321 3-cycloalkyl substituted indoles FAMILY 23578689 A 51 93 5-(trans-2-aminomethylcyclopentyl) indoles FAMILY 23578689 A 99 138 5-(cis-2-aminomethylcyclopentyl)indoles FAMILY 23578689 T 28 43 homotryptamines FAMILY 23578689 T 53 85 Indole-5-cycloalkyl methylamines FAMILY 23578689 T 99 108 serotonin TRIVIAL 23578846 A 202 237 poly (lactic acid-co-glycolic acid) FAMILY 23578846 A 239 243 PLGA ABBREVIATION 23578952 A 1021 1031 metyrapone TRIVIAL 23578952 A 1151 1167 monoacylglycerol SYSTEMATIC 23578952 A 1225 1239 corticosterone TRIVIAL 23578952 A 126 148 2-arachidonoylglycerol SYSTEMATIC 23578952 A 1338 1354 monoacylglycerol SYSTEMATIC 23578952 A 162 176 corticosterone TRIVIAL 23578952 A 284 300 monoacylglycerol SYSTEMATIC 23578952 A 318 324 JZL184 IDENTIFIER 23578952 A 353 367 corticosterone TRIVIAL 23578952 A 517 531 corticosterone TRIVIAL 23578952 A 560 566 JZL184 IDENTIFIER 23578952 A 606 620 corticosterone TRIVIAL 23578952 A 641 651 metyrapone TRIVIAL 23578952 A 719 725 JZL184 IDENTIFIER 23578952 A 743 757 corticosterone TRIVIAL 23578952 A 815 821 JZL184 IDENTIFIER 23578952 A 880 894 corticosterone TRIVIAL 23578952 T 0 16 Monoacylglycerol SYSTEMATIC 23578952 T 61 75 corticosterone TRIVIAL 23578993 A 1135 1144 Bilirubin TRIVIAL 23578993 A 115 135 carbon tetrachloride SYSTEMATIC 23578993 A 1164 1168 CCl4 FORMULA 23578993 A 1173 1176 TAA ABBREVIATION 23578993 A 1227 1230 NAC ABBREVIATION 23578993 A 1311 1315 CCl4 FORMULA 23578993 A 1320 1323 TAA ABBREVIATION 23578993 A 1343 1346 NAC ABBREVIATION 23578993 A 137 141 CCl4 FORMULA 23578993 A 1385 1388 GSH ABBREVIATION 23578993 A 147 160 thioacetamide SYSTEMATIC 23578993 A 1482 1485 NAC ABBREVIATION 23578993 A 162 165 TAA ABBREVIATION 23578993 A 1711 1715 CCl4 FORMULA 23578993 A 1720 1723 TAA ABBREVIATION 23578993 A 1850 1853 NAC ABBREVIATION 23578993 A 1900 1904 CCl4 FORMULA 23578993 A 1909 1912 TAA ABBREVIATION 23578993 A 1914 1917 NAC ABBREVIATION 23578993 A 217 221 CCl4 FORMULA 23578993 A 301 304 TAA ABBREVIATION 23578993 A 362 365 TAA ABBREVIATION 23578993 A 398 401 NAC ABBREVIATION 23578993 A 446 450 CCl4 FORMULA 23578993 A 455 458 TAA ABBREVIATION 23578993 A 54 57 NAC ABBREVIATION 23578993 A 611 618 Alanine TRIVIAL 23578993 A 643 652 Aspartate TRIVIAL 23578993 A 705 714 Bilirubin TRIVIAL 23578993 A 739 753 Hydroxyproline SYSTEMATIC 23578993 A 802 813 Glutathione TRIVIAL 23578993 A 835 846 Glutathione TRIVIAL 23578993 A 848 851 GSH ABBREVIATION 23578993 A 990 997 aniline SYSTEMATIC 23578993 T 10 27 N-acetyl cysteine SYSTEMATIC 23578993 T 29 32 NAC ABBREVIATION 23578993 T 38 50 organosulfur FAMILY 23578994 A 1082 1089 calcium SYSTEMATIC 23578994 A 1103 1110 glucose TRIVIAL 23578994 A 203 210 glucose TRIVIAL 23578994 A 331 338 glucose TRIVIAL 23578994 A 518 525 calcium SYSTEMATIC 23578994 A 606 613 glucose TRIVIAL 23578994 A 86 96 cyclic AMP TRIVIAL 23578994 A 860 870 Fatty Acid FAMILY 23579392 A 1022 1026 H2O2 FORMULA 23579392 A 1028 1031 MDA ABBREVIATION 23579392 A 1036 1043 proline TRIVIAL 23579392 A 1083 1086 AsA ABBREVIATION 23579392 A 113 119 oxygen SYSTEMATIC 23579392 A 1136 1139 GSH ABBREVIATION 23579392 A 1193 1195 Cu FORMULA 23579392 A 1282 1284 Cu FORMULA 23579392 A 1382 1392 superoxide TRIVIAL 23579392 A 1404 1413 ascorbate TRIVIAL 23579392 A 1426 1437 glutathione TRIVIAL 23579392 A 1452 1463 glutathione TRIVIAL 23579392 A 1532 1548 dehydroascorbate SYSTEMATIC 23579392 A 1563 1574 glutathione TRIVIAL 23579392 A 1575 1576 S FORMULA 23579392 A 1612 1618 Cu(2+) FORMULA 23579392 A 1743 1745 Cu FORMULA 23579392 A 1819 1821 Cu FORMULA 23579392 A 1942 1944 Cu FORMULA 23579392 A 238 244 copper SYSTEMATIC 23579392 A 246 248 Cu FORMULA 23579392 A 294 300 Cu(2+) FORMULA 23579392 A 390 405 malondialdehyde TRIVIAL 23579392 A 407 410 MDA ABBREVIATION 23579392 A 413 430 hydrogen peroxide SYSTEMATIC 23579392 A 432 436 H2O2 FORMULA 23579392 A 45 59 salicylic acid TRIVIAL 23579392 A 577 579 Cu FORMULA 23579392 A 590 603 ascorbic acid TRIVIAL 23579392 A 605 608 AsA ABBREVIATION 23579392 A 611 622 glutathione TRIVIAL 23579392 A 624 627 GSH ABBREVIATION 23579392 A 642 647 thiol FAMILY 23579392 A 658 665 proline TRIVIAL 23579392 A 727 730 AsA ABBREVIATION 23579392 A 804 814 superoxide TRIVIAL 23579392 A 816 824 O 2 (•-) FORMULA 23579392 A 831 835 H2O2 FORMULA 23579392 A 860 862 Cu FORMULA 23579392 A 984 986 Cu FORMULA 23579392 T 0 14 Salicylic acid TRIVIAL 23579392 T 26 32 copper SYSTEMATIC 23579421 A 11 17 carbon SYSTEMATIC 23579421 A 222 232 iron oxide SYSTEMATIC 23579421 T 9 15 carbon SYSTEMATIC 23579429 A 718 729 Cholesterol TRIVIAL 23580001 A 161 170 metformin TRIVIAL 23580001 A 24 33 metformin TRIVIAL 23580001 A 801 810 metformin TRIVIAL 23580001 A 992 1001 Metformin TRIVIAL 23580001 T 16 25 metformin TRIVIAL 23580312 A 101 111 dichlorvos TRIVIAL 23580312 A 113 123 dimethoate TRIVIAL 23580312 A 1160 1175 7-methylguanine SYSTEMATIC 23580312 A 1177 1190 ribothymidine TRIVIAL 23580312 A 1192 1203 cholic acid TRIVIAL 23580312 A 1205 1221 4-pyridoxic acid SYSTEMATIC 23580312 A 1223 1233 kynurenine TRIVIAL 23580312 A 1238 1253 indoxyl sulfate SYSTEMATIC 23580312 A 125 133 acephate TRIVIAL 23580312 A 1283 1296 hippuric acid TRIVIAL 23580312 A 1298 1308 creatinine TRIVIAL 23580312 A 1310 1319 uric acid TRIVIAL 23580312 A 1321 1334 gentisic acid TRIVIAL 23580312 A 1336 1358 C18-dihydrosphingosine SYSTEMATIC 23580312 A 1360 1376 phytosphingosine TRIVIAL 23580312 A 1378 1390 suberic acid TRIVIAL 23580312 A 138 145 phorate TRIVIAL 23580312 A 1395 1406 citric acid TRIVIAL 23580312 A 1566 1584 tricarboxylic acid SYSTEMATIC 23580312 A 68 83 organophosphate FAMILY 23580312 A 918 935 Dimethylphosphate SYSTEMATIC 23580312 A 940 963 dimethyldithiophosphate SYSTEMATIC 23580312 T 184 199 Organophosphate FAMILY 23580316 A 100 107 alcohol FAMILY 23580316 A 1041 1044 MDA ABBREVIATION 23580316 A 383 391 phenolic FAMILY 23580316 A 403 412 kampferol TRIVIAL 23580316 A 414 435 kampferol-3-glucoside SYSTEMATIC 23580316 A 440 463 kampferol-3-galactoside SYSTEMATIC 23580316 A 507 526 1-ethoxypentacosane SYSTEMATIC 23580316 A 528 543 heptacosan-1-ol SYSTEMATIC 23580316 A 548 560 β-sitosterol TRIVIAL 23580316 A 580 595 heptacosan-1-ol SYSTEMATIC 23580316 A 597 609 β-sitosterol TRIVIAL 23580316 A 614 637 kampferol-3-galactoside SYSTEMATIC 23580316 A 890 905 malondialdehyde TRIVIAL 23580316 A 907 910 MDA ABBREVIATION 23580332 A 1090 1098 decursin TRIVIAL 23580332 A 13 19 prolyl TRIVIAL 23580332 A 197 205 decursin TRIVIAL 23580332 A 383 391 decursin TRIVIAL 23580332 A 567 575 decursin TRIVIAL 23580332 A 692 700 decursin TRIVIAL 23580332 A 859 867 decursin TRIVIAL 23580332 A 914 922 Decursin TRIVIAL 23580332 A 977 985 decursin TRIVIAL 23580332 T 0 8 Decursin TRIVIAL 23580446 A 1118 1127 β-lactose TRIVIAL 23580446 A 1427 1436 rofecoxib TRIVIAL 23580446 A 30 41 prostanoids FAMILY 23580446 A 640 644 PGE2 ABBREVIATION 23580446 A 786 795 rofecoxib TRIVIAL 23580446 A 850 854 PGE2 ABBREVIATION 23580569 A 145 153 estrogen FAMILY 23580569 A 216 224 Estrogen FAMILY 23580611 A 1338 1342 cAMP ABBREVIATION 23580611 A 945 954 forskolin TRIVIAL 23580611 A 956 959 FSK ABBREVIATION 23581424 A 128 150 poly(dimethylsiloxane) SYSTEMATIC 23581424 A 152 156 PDMS ABBREVIATION 23581424 A 159 178 Polyethylene glycol SYSTEMATIC 23581424 A 180 183 PEG ABBREVIATION 23581424 A 252 256 PDMS ABBREVIATION 23581424 A 295 308 primary amine FAMILY 23581424 A 317 332 carboxylic acid SYSTEMATIC 23581424 A 375 379 PDMS ABBREVIATION 23581424 T 34 53 polyethylene glycol SYSTEMATIC 23581750 A 1000 1006 pyrene SYSTEMATIC 23581750 A 1011 1022 cholesterol TRIVIAL 23581750 A 134 138 ECPS ABBREVIATION 23581750 A 1406 1418 acetonitrile SYSTEMATIC 23581750 A 1592 1596 ECPS ABBREVIATION 23581750 A 238 246 n-hexane SYSTEMATIC 23581750 A 248 255 benzene SYSTEMATIC 23581750 A 261 272 1,4-dioxane SYSTEMATIC 23581750 A 351 357 pyrene SYSTEMATIC 23581750 A 40 51 cholesterol TRIVIAL 23581750 A 601 609 n-hexane SYSTEMATIC 23581750 A 61 132 N,N'-(ethane-1,2-diyl)-bis(N-(2-(chol-amino)ethyl)pyrene-1-sulfonamide) SYSTEMATIC 23581750 A 673 679 pyrene SYSTEMATIC 23581750 T 19 25 Pyrene SYSTEMATIC 23581750 T 40 51 Cholesterol TRIVIAL 23581964 A 101 109 graphene TRIVIAL 23581964 A 139 143 SiO2 FORMULA 23581964 A 144 146 Si FORMULA 23581964 A 238 246 graphene TRIVIAL 23581964 A 352 360 graphene TRIVIAL 23581964 A 361 365 SiO2 FORMULA 23581964 A 366 368 Si FORMULA 23581964 A 443 451 graphene TRIVIAL 23581964 A 575 583 graphene TRIVIAL 23581964 A 584 588 SiO2 FORMULA 23581964 A 654 658 SiO2 FORMULA 23581964 A 659 661 Si FORMULA 23581964 A 855 863 graphene TRIVIAL 23581964 A 864 868 SiO2 FORMULA 23581964 T 68 76 Graphene TRIVIAL 23581964 T 77 81 SiO2 FORMULA 23581964 T 82 84 Si FORMULA 23582019 A 1011 1025 bisphthalimide SYSTEMATIC 23582019 A 107 111 Ph2N FORMULA 23582019 A 130 145 2-benzothiazoyl SYSTEMATIC 23582019 A 167 186 9,9-diethylfluorene SYSTEMATIC 23582019 A 215 230 bisphthalimides FAMILY 23582019 A 365 379 bisphthalimide SYSTEMATIC 23582019 A 682 697 bisphthalimides FAMILY 23582019 T 49 57 Fluorene TRIVIAL 23582019 T 74 88 Bisphthalimide SYSTEMATIC 23582211 A 1132 1142 spermidine TRIVIAL 23582211 A 1362 1372 spermidine TRIVIAL 23582211 A 2031 2040 polyamine FAMILY 23582211 A 2049 2059 spermidine TRIVIAL 23582211 A 376 393 nucleotide dimers FAMILY 23582211 A 630 642 deoxyuridine TRIVIAL 23582211 A 718 730 deoxyuridine TRIVIAL 23582273 A 12 28 1,3,4-oxadiazole SYSTEMATIC 23582273 A 52 67 1,4-benzodioxan SYSTEMATIC 23582273 A 541 544 Met FORMULA 23582273 A 618 621 Met FORMULA 23582273 T 114 124 methionine TRIVIAL 23582273 T 36 52 1,3,4-oxadiazole SYSTEMATIC 23582273 T 64 79 1,4-benzodioxan SYSTEMATIC 23582408 A 1044 1053 berberine TRIVIAL 23582408 A 241 250 berberine TRIVIAL 23582408 A 437 451 streptozotocin TRIVIAL 23582408 A 658 665 glucose TRIVIAL 23582408 A 763 772 berberine TRIVIAL 23582408 T 58 67 berberine TRIVIAL 23583009 A 1005 1012 ethanol SYSTEMATIC 23583009 A 1088 1090 CO FORMULA 23583009 A 1124 1131 ethanol SYSTEMATIC 23583009 A 1165 1174 quercetin TRIVIAL 23583009 A 1222 1224 CO FORMULA 23583009 A 131 146 carbon monoxide SYSTEMATIC 23583009 A 148 150 CO FORMULA 23583009 A 19 28 quercetin TRIVIAL 23583009 A 247 256 quercetin TRIVIAL 23583009 A 285 292 ethanol SYSTEMATIC 23583009 A 399 406 ethanol SYSTEMATIC 23583009 A 489 496 ethanol SYSTEMATIC 23583009 A 55 62 ethanol SYSTEMATIC 23583009 A 615 624 quercetin TRIVIAL 23583009 A 641 650 Quercetin TRIVIAL 23583009 A 732 739 Ethanol SYSTEMATIC 23583009 A 797 806 quercetin TRIVIAL 23583009 A 862 866 heme FAMILY 23583009 A 881 883 CO FORMULA 23583009 A 922 931 quercetin TRIVIAL 23583009 A 93 97 heme FAMILY 23583009 A 957 959 CO FORMULA 23583009 T 0 9 Quercetin TRIVIAL 23583009 T 38 45 ethanol SYSTEMATIC 23583009 T 99 101 CO FORMULA 23583257 A 0 5 NADPH ABBREVIATION 23583257 A 120 126 oxygen SYSTEMATIC 23583257 A 1225 1233 quinones FAMILY 23583257 A 333 340 quinone FAMILY 23583257 A 456 463 quinone FAMILY 23583257 A 477 483 AA-861 TRIVIAL 23583257 A 485 491 tBuBHQ ABBREVIATION 23583257 A 493 498 tBuBQ ABBREVIATION 23583257 A 504 515 duroquinone TRIVIAL 23583257 A 705 712 NAD(P)H ABBREVIATION 23583257 A 713 720 quinone FAMILY 23583257 A 881 890 disulfide SYSTEMATIC 23583257 A 899 902 Cys FORMULA 23583257 A 907 910 Cys FORMULA 23583257 T 0 7 Quinone FAMILY 23583257 T 62 67 NADPH ABBREVIATION 23583258 A 0 11 Cholesterol TRIVIAL 23583258 A 1061 1075 phenolic acids FAMILY 23583258 A 1080 1090 flavonoids FAMILY 23583258 A 1296 1306 oxysterols FAMILY 23583258 A 1421 1431 oxysterols FAMILY 23583258 A 1492 1501 phenolics FAMILY 23583258 A 1550 1559 oxysterol FAMILY 23583258 A 1629 1637 phenolic FAMILY 23583258 A 1724 1733 oxysterol FAMILY 23583258 A 1847 1857 oxysterols FAMILY 23583258 A 408 418 oxysterols FAMILY 23583258 A 44 54 oxysterols FAMILY 23583258 A 444 455 cholesterol TRIVIAL 23583258 A 618 624 oxygen SYSTEMATIC 23583258 A 653 658 NADPH ABBREVIATION 23583258 A 78 89 cholesterol TRIVIAL 23583258 A 876 885 Oxysterol FAMILY 23583258 T 0 8 Phenolic FAMILY 23583258 T 122 132 oxysterols FAMILY 23583436 A 124 140 hemiketal carbon SYSTEMATIC 23583436 A 148 157 simonol B TRIVIAL 23583436 A 177 190 dihydronfuran SYSTEMATIC 23583436 A 243 250 ethanol SYSTEMATIC 23583436 A 54 63 simonol A TRIVIAL 23583436 A 679 693 5-Fluorouracil SYSTEMATIC 23583436 A 8 25 sesqui-neolignans FAMILY 23583436 A 99 116 5,5-dihydro-pyran SYSTEMATIC 23583436 T 0 16 Simonols A and B MULTIPLE 23583436 T 28 45 sesqui-neolignans FAMILY 23583456 A 0 11 Cholesterol TRIVIAL 23583456 A 175 186 cholesterol TRIVIAL 23583456 A 417 428 cholesterol TRIVIAL 23583456 A 455 465 mevalonate TRIVIAL 23583456 A 543 568 24(S),25-epoxycholesterol SYSTEMATIC 23583456 T 55 66 cholesterol TRIVIAL 23583486 A 217 232 diallyl sulfide SYSTEMATIC 23583486 A 234 237 DAS ABBREVIATION 23583486 A 240 257 diallyl disulfide SYSTEMATIC 23583486 A 259 263 DADS ABBREVIATION 23583486 A 266 284 diallyl trisulfide SYSTEMATIC 23583486 A 286 290 DATS ABBREVIATION 23583486 A 296 302 ajoene TRIVIAL 23583486 A 381 385 DADS ABBREVIATION 23583486 A 395 407 organosulfur FAMILY 23583486 T 52 69 diallyl disulfide SYSTEMATIC 23583495 A 1326 1330 PLGA ABBREVIATION 23583495 A 151 155 PLGA ABBREVIATION 23583495 A 290 294 PLGA ABBREVIATION 23583495 A 455 459 PLGA ABBREVIATION 23583495 A 54 80 poly(lactide-co-glycolide) SYSTEMATIC 23583495 A 561 565 PLGA ABBREVIATION 23583495 A 661 665 PLGA ABBREVIATION 23583495 A 797 801 PLGA ABBREVIATION 23583495 A 82 86 PLGA ABBREVIATION 23583495 T 75 79 PLGA ABBREVIATION 23583512 A 28 45 l-deoxynucleotide FAMILY 23583512 A 50 67 d-deoxynucleotide FAMILY 23583512 T 62 79 l-deoxynucleotide FAMILY 23583603 A 1094 1097 ICI ABBREVIATION 23583603 A 1274 1277 Ser FORMULA 23583603 A 1330 1333 ICI ABBREVIATION 23583603 A 1437 1440 ICI ABBREVIATION 23583603 A 269 272 ICI ABBREVIATION 23583603 A 27 38 ICI 182,780 IDENTIFIER 23583603 A 381 390 Estradiol TRIVIAL 23583603 A 40 43 ICI ABBREVIATION 23583603 A 400 412 progesterone TRIVIAL 23583603 A 472 475 ICI ABBREVIATION 23583603 A 539 547 estrogen FAMILY 23583603 A 603 615 progesterone TRIVIAL 23583603 A 822 825 ICI ABBREVIATION 23583603 T 22 33 ICI 182 780 IDENTIFIER 23583736 A 1060 1068 caffeine TRIVIAL 23583736 A 1130 1142 testosterone TRIVIAL 23583736 A 1198 1208 spilanthol TRIVIAL 23583736 A 1369 1381 N-alkylamide FAMILY 23583736 A 1425 1435 spilanthol TRIVIAL 23583736 A 1506 1516 spilanthol TRIVIAL 23583736 A 1768 1778 spilanthol TRIVIAL 23583736 A 360 370 spilanthol TRIVIAL 23583736 A 375 387 N-alkylamide FAMILY 23583736 A 486 494 caffeine TRIVIAL 23583736 A 496 508 testosterone TRIVIAL 23583736 A 513 522 ibuprofen TRIVIAL 23583736 A 667 677 spilanthol TRIVIAL 23583736 A 704 716 aflatoxin B1 TRIVIAL 23583736 A 718 730 ochratoxin A TRIVIAL 23583736 A 732 744 fumonisin B1 TRIVIAL 23583736 A 746 754 citrinin TRIVIAL 23583736 A 756 767 zearalenone TRIVIAL 23583736 A 769 778 T-2 toxin TRIVIAL 23583736 A 807 817 Spilanthol TRIVIAL 23583736 A 944 953 ibuprofen TRIVIAL 23583736 A 993 1003 spilanthol TRIVIAL 23583736 T 51 74 N-alkylamide spilanthol FAMILY 23583802 A 1034 1044 nimodipine TRIVIAL 23583802 A 1046 1050 MeHg FORMULA 23583802 A 1145 1155 nimodipine TRIVIAL 23583802 A 1280 1290 Nimodipine TRIVIAL 23583802 A 1339 1343 MeHg FORMULA 23583802 A 160 164 MeHg FORMULA 23583802 A 238 245 calcium SYSTEMATIC 23583802 A 303 309 Ca(2+) FORMULA 23583802 A 388 395 calcium SYSTEMATIC 23583802 A 452 456 MeHg FORMULA 23583802 A 493 500 calcium SYSTEMATIC 23583802 A 515 519 MeHg FORMULA 23583802 A 598 600 Hg FORMULA 23583802 A 605 609 MeHg FORMULA 23583802 A 637 647 nimodipine TRIVIAL 23583802 A 651 666 dihydropryidine SYSTEMATIC 23583802 A 675 681 Ca(2+) FORMULA 23583802 A 722 732 Nimodipine TRIVIAL 23583802 A 833 843 nimodipine TRIVIAL 23583802 A 936 940 MeHg FORMULA 23583802 T 39 52 methylmercury SYSTEMATIC 23583802 T 8 18 nimodipine TRIVIAL 23583804 A 1150 1153 MDA ABBREVIATION 23583804 A 32 42 triptolide TRIVIAL 23583804 T 39 49 triptolide TRIVIAL 23583804 T 54 64 triptolide TRIVIAL 23583902 A 1038 1049 polyphenols FAMILY 23583902 A 1157 1168 polyphenols FAMILY 23583902 A 1363 1379 Chlorogenic acid TRIVIAL 23583902 A 1431 1444 phenolic acid FAMILY 23583902 A 1930 1941 polyphenols FAMILY 23583902 A 1957 1973 chlorogenic acid TRIVIAL 23583902 A 530 540 polyphenol FAMILY 23583902 A 610 626 Chlorogenic acid TRIVIAL 23583902 T 139 155 chlorogenic acid TRIVIAL 23583903 A 714 717 MTS ABBREVIATION 23583911 A 262 279 thienopyrimidines FAMILY 23583911 A 571 584 tartaric acid TRIVIAL 23583911 T 62 87 thieno[3,2-d]pyrimidinone SYSTEMATIC 23583911 T 92 113 thieno[1,2,3]triazine SYSTEMATIC 23584353 A 1080 1083 MFA ABBREVIATION 23584353 A 275 292 meclofenamic acid TRIVIAL 23584353 A 294 297 MFA ABBREVIATION 23584353 A 470 473 MFA ABBREVIATION 23584353 A 545 559 Lucifer yellow TRIVIAL 23584353 A 826 829 MFA ABBREVIATION 23584353 A 936 943 aspirin TRIVIAL 23584353 A 948 963 flufenamic acid TRIVIAL 23584353 A 965 968 FFA ABBREVIATION 23584353 T 0 17 Meclofenamic acid TRIVIAL 23584434 A 521 529 arginine TRIVIAL 23584543 A 0 10 Copper(II) SYSTEMATIC 23584543 A 101 106 Fc-aa ABBREVIATION 23584543 A 115 142 ferrocenylmethyl-l-tyrosine SYSTEMATIC 23584543 A 144 151 Fc-TyrH ABBREVIATION 23584543 A 154 183 ferrocenylmethyl-l-tryptophan SYSTEMATIC 23584543 A 185 192 Fc-TrpH ABBREVIATION 23584543 A 198 227 ferrocenylmethyl-l-methionine SYSTEMATIC 23584543 A 21 37 [Cu(Fc-aa)(cur)] FORMULA 23584543 A 229 236 Fc-MetH ABBREVIATION 23584543 A 412 427 Acetylacetonate SYSTEMATIC 23584543 A 429 433 acac ABBREVIATION 23584543 A 445 462 [Cu(Fc-aa)(acac)] FORMULA 23584543 A 47 55 curcumin TRIVIAL 23584543 A 57 61 Hcur ABBREVIATION 23584543 A 67 99 N-ferrocenylmethyl-l-amino acids FAMILY 23584543 T 21 31 copper(II) SYSTEMATIC 23584543 T 45 53 curcumin TRIVIAL 23584543 T 58 90 N-ferrocenylmethyl-l-amino acids FAMILY 23584895 A 416 426 epirubicin TRIVIAL 23584895 T 0 7 Diamond TRIVIAL 23584984 A 12 18 nickel SYSTEMATIC 23584984 A 164 166 Si FORMULA 23584984 A 192 203 azidopropyl SYSTEMATIC 23584984 A 230 237 silicas TRIVIAL 23584984 A 276 285 L(t) (Bu) FORMULA 23584984 A 294 300 Ni(II) FORMULA 23584984 A 312 357 [Ni(L(t) (Bu) )(OAc)2 (H2 O)] (L(t) (Bu) /Ni) FORMULA 23584984 A 362 401 [Ni(L(t) (Bu) )2 ]BF4 (2 L(t) (Bu) /Ni) FORMULA 23584984 A 38 40 Ni FORMULA 23584984 A 432 434 Ni FORMULA 23584984 A 44 98 bis(2-pyridylmethyl)(1H-1,2,3-triazol-4-ylmethyl)amine SYSTEMATIC 23584984 A 465 467 Ni FORMULA 23584984 A 504 508 NiL2 FAMILY 23584984 A 567 569 Ni FORMULA 23584984 A 617 628 cyclohexane SYSTEMATIC 23584984 A 634 657 m-chloroperbenzoic acid SYSTEMATIC 23584984 A 659 664 mCPBA ABBREVIATION 23584984 A 762 771 L(t) (Bu) FORMULA 23584984 A 773 775 Ni FORMULA 23584984 A 862 864 Ni FORMULA 23584984 T 0 6 Alkane FAMILY 23584984 T 146 152 Silica TRIVIAL 23584984 T 35 41 Nickel SYSTEMATIC 23585309 A 1294 1301 glucose TRIVIAL 23585309 A 1584 1591 glucose TRIVIAL 23585309 A 266 273 glucose TRIVIAL 23585332 A 0 22 tert-Butylhydroquinone SYSTEMATIC 23585332 A 233 237 tBHQ ABBREVIATION 23585332 A 24 28 tBHQ ABBREVIATION 23585332 A 313 317 tBHQ ABBREVIATION 23585332 A 442 446 tBHQ ABBREVIATION 23585332 A 623 627 tBHQ ABBREVIATION 23585332 A 655 659 tBHQ ABBREVIATION 23585332 A 709 721 triglyceride FAMILY 23585332 A 732 743 cholesterol TRIVIAL 23585332 A 890 894 tBHQ ABBREVIATION 23585332 A 934 938 tBHQ ABBREVIATION 23585332 T 0 22 tert-Butylhydroquinone SYSTEMATIC 23585333 A 100 104 SiO2 FORMULA 23585333 A 287 294 glucose TRIVIAL 23585333 A 29 36 glucose TRIVIAL 23585333 A 57 64 mannose TRIVIAL 23585333 A 80 86 Fe3 O4 FORMULA 23585333 A 88 92 SiO2 FORMULA 23585333 A 97 99 Ag FORMULA 23585333 T 29 36 Glucose TRIVIAL 23586436 A 207 220 silicon oxide SYSTEMATIC 23586436 A 248 272 octadecyltrichlorosilane SYSTEMATIC 23586470 A 1024 1033 histidine TRIVIAL 23586470 A 1179 1180 S FORMULA 23586470 A 1212 1214 Ni FORMULA 23586470 A 1259 1260 S FORMULA 23586470 A 206 214 Ni(2)(+) FORMULA 23586470 A 266 267 S FORMULA 23586470 A 605 613 Ni(2)(+) FORMULA 23586470 A 748 750 Ni FORMULA 23586470 A 921 929 Ni(2)(+) FORMULA 23586470 T 73 82 Histidine TRIVIAL 23586669 A 134 179 4-imidazo[2,1-b]thiazole-1,4-dihydropyridines FAMILY 23586669 A 208 215 calcium SYSTEMATIC 23586669 A 238 269 imidazo[2,1-b]thiazole-1,4-DHPs FAMILY 23586669 A 836 869 4-imidazo[2,1-b]thiazole-1,4-DHPs FAMILY 23586669 T 32 39 Calcium SYSTEMATIC 23586669 T 51 94 Imidazo[2,1-b]thiazole-1,4-Dihydropyridines FAMILY 23586680 A 1133 1138 oxide SYSTEMATIC 23586680 A 1303 1311 hydrogen SYSTEMATIC 23586680 A 134 145 hydrocarbon FAMILY 23586680 A 1356 1371 hydroiodic acid SYSTEMATIC 23586680 A 1496 1504 hydrogen SYSTEMATIC 23586680 A 1538 1546 hydrogen SYSTEMATIC 23586680 A 736 743 alumina TRIVIAL 23586680 A 873 887 aluminum oxide SYSTEMATIC 23586702 A 1179 1187 graphene TRIVIAL 23586702 A 293 310 pristine graphene TRIVIAL 23586702 A 331 339 graphene TRIVIAL 23586702 A 485 502 pristine graphene TRIVIAL 23586702 A 544 552 graphene TRIVIAL 23586702 A 62 70 graphene TRIVIAL 23586702 A 680 688 graphene TRIVIAL 23586702 A 877 885 graphene TRIVIAL 23586702 T 52 60 graphene TRIVIAL 23586737 A 110 139 alkyl polyoxyethylene sulfate FAMILY 23586737 A 1261 1263 OH FORMULA 23586737 A 1360 1368 hydrogen SYSTEMATIC 23586737 A 141 145 AE3S ABBREVIATION 23586737 A 163 169 Mg(2+) FORMULA 23586737 A 216 220 AE3S ABBREVIATION 23586737 A 268 274 Ca(2+) FORMULA 23586737 A 278 284 Mg(2+) FORMULA 23586737 A 378 400 sodium dodecyl sulfate SYSTEMATIC 23586737 A 402 405 SDS ABBREVIATION 23586737 A 630 639 magnesium SYSTEMATIC 23586737 A 649 653 AE3S ABBREVIATION 23586737 A 911 915 AE3S ABBREVIATION 23586737 A 920 935 hydrated Mg(2+) FORMULA 23586737 A 998 1007 magnesium SYSTEMATIC 23586737 T 144 153 magnesium SYSTEMATIC 23586757 A 154 158 Heme FAMILY 23586757 A 260 264 heme FAMILY 23586757 A 345 354 quinoline SYSTEMATIC 23586757 A 381 392 chloroquine TRIVIAL 23586757 A 394 401 quinine TRIVIAL 23586757 A 403 414 amodiaquine TRIVIAL 23586757 A 560 569 quinoline SYSTEMATIC 23586757 A 570 574 heme FAMILY 23586757 A 646 655 quinoline SYSTEMATIC 23586757 A 810 819 quinoline SYSTEMATIC 23586757 T 0 9 Quinoline SYSTEMATIC 23586757 T 15 19 Heme FAMILY 23586849 A 0 17 Fumiquinazoline L TRIVIAL 23586849 A 369 375 valine TRIVIAL 23586849 A 439 456 Fumiquinazoline L TRIVIAL 23586849 T 40 57 Fumiquinazoline L TRIVIAL 23586868 A 0 10 Fostriecin TRIVIAL 23586868 A 1056 1069 malonyl ester TRIVIAL 23586868 A 1138 1145 lactone FAMILY 23586868 A 1166 1169 FST ABBREVIATION 23586868 A 12 15 FST ABBREVIATION 23586868 A 678 697 unsaturated lactone SYSTEMATIC 23586868 A 818 828 PD 113,271 IDENTIFIER 23586868 A 834 837 FST ABBREVIATION 23586868 A 917 930 malonyl ester TRIVIAL 23586868 T 72 82 Fostriecin TRIVIAL 23586925 A 302 313 polystyrene SYSTEMATIC 23586925 A 525 542 polyvinyl alcohol SYSTEMATIC 23586925 A 544 547 PVA ABBREVIATION 23586938 A 534 540 silica TRIVIAL 23586938 A 778 790 silicic acid TRIVIAL 23586938 A 938 944 silica TRIVIAL 23586970 A 214 227 nocardiamides FAMILY 23586970 A 29 42 nocardiamides FAMILY 23586970 A 461 480 d- and one l-valine MULTIPLE 23586970 A 8 27 cyclic hexapeptides FAMILY 23586970 T 0 21 Nocardiamides A and B MULTIPLE 23586970 T 27 44 Cyclohexapeptides FAMILY 23587425 A 44 67 imidazo[1,2-a]pyrazines FAMILY 23587425 A 72 97 imidazo[1,2-c]pyrimidines FAMILY 23587425 T 50 72 imidazo[1,2-a]pyrazine SYSTEMATIC 23587425 T 78 102 imidazo[1,2-c]pyrimidine SYSTEMATIC 23587503 A 1041 1049 carbonyl FAMILY 23587503 A 119 130 Duroquinone TRIVIAL 23587503 A 146 162 1,4-benzoquinone SYSTEMATIC 23587503 A 234 245 duroquinone TRIVIAL 23587503 A 402 413 duroquinone TRIVIAL 23587503 A 495 498 ATP ABBREVIATION 23587503 A 553 564 duroquinone TRIVIAL 23587503 A 711 719 carbonyl FAMILY 23587503 A 734 744 superoxide TRIVIAL 23587503 A 828 839 duroquinone TRIVIAL 23587503 A 892 903 duroquinone TRIVIAL 23587503 T 23 34 duroquinone TRIVIAL 23587526 A 1057 1064 ethanol SYSTEMATIC 23587526 A 1373 1380 ethanol SYSTEMATIC 23587526 A 1516 1520 GABA ABBREVIATION 23587526 A 1614 1621 ethanol SYSTEMATIC 23587526 A 1860 1867 ethanol SYSTEMATIC 23587526 A 1930 1937 ethanol SYSTEMATIC 23587526 A 356 363 ethanol SYSTEMATIC 23587526 A 614 621 ethanol SYSTEMATIC 23587526 A 648 654 U69593 IDENTIFIER 23587526 A 813 832 nor-binaltorphimine TRIVIAL 23587526 A 91 98 ethanol SYSTEMATIC 23587526 T 56 63 ethanol SYSTEMATIC 23587645 A 1016 1029 glibenclamide TRIVIAL 23587645 A 1030 1045 docusate sodium SYSTEMATIC 23587645 A 1730 1738 mannitol TRIVIAL 23587645 A 1810 1823 glibenclamide TRIVIAL 23587645 A 816 829 glibenclamide TRIVIAL 23587645 T 98 111 glibenclamide TRIVIAL 23587648 A 818 825 calcium SYSTEMATIC 23587648 T 88 95 calcium SYSTEMATIC 23587668 A 0 35 2,3,7,8-Tetrachlorodibenzo-p-dioxin SYSTEMATIC 23587668 A 1039 1043 TCDD ABBREVIATION 23587668 A 1264 1268 TCDD ABBREVIATION 23587668 A 1406 1410 TCDD ABBREVIATION 23587668 A 1489 1493 TCDD ABBREVIATION 23587668 A 257 261 TCDD ABBREVIATION 23587668 A 326 330 TCDD ABBREVIATION 23587668 A 37 41 TCDD ABBREVIATION 23587668 A 670 674 TCDD ABBREVIATION 23587668 A 809 813 TCDD ABBREVIATION 23587668 T 52 58 dioxin FAMILY 23587849 A 1159 1162 ENs FAMILY 23587849 A 1290 1293 ENs FAMILY 23587849 A 1358 1361 ENs FAMILY 23587849 A 43 46 ENs FAMILY 23587849 A 487 495 Dextrose TRIVIAL 23587849 A 591 594 ENs FAMILY 23587849 A 679 682 ENs FAMILY 23587849 A 765 768 ENs FAMILY 23587849 T 17 39 enniatins A, A1, B, B1 MULTIPLE 23588096 A 1249 1257 methanol SYSTEMATIC 23588096 A 1793 1803 chloroform TRIVIAL 23588096 A 1805 1813 methanol SYSTEMATIC 23588096 A 592 600 Methanol SYSTEMATIC 23588096 A 807 817 chloroform TRIVIAL 23588096 A 819 827 methanol SYSTEMATIC 23588252 A 0 7 Bromate SYSTEMATIC 23588252 A 1106 1117 hematoxylin TRIVIAL 23588252 A 1122 1127 eosin FAMILY 23588252 A 1227 1244 bromodeoxyuridine TRIVIAL 23588252 A 1306 1325 8-oxodeoxyguanosine SYSTEMATIC 23588252 A 1327 1334 8-OH-dG SYSTEMATIC 23588252 A 1567 1575 BrO3 (-) FORMULA 23588252 A 1859 1867 BrO3 (-) FORMULA 23588252 A 1952 1960 BrO3 (-) FORMULA 23588252 A 492 497 KBrO3 FORMULA 23588252 A 647 655 BrO3 (-) FORMULA 23588252 A 679 684 KBrO3 FORMULA 23588252 A 9 17 BrO3 (-) FORMULA 23588252 T 101 108 bromate SYSTEMATIC 23588308 A 442 453 simvastatin TRIVIAL 23588308 A 679 691 cyclosporine TRIVIAL 23588308 A 814 826 cyclosporine TRIVIAL 23588585 A 1186 1195 silibinin TRIVIAL 23588585 A 1399 1408 silibinin TRIVIAL 23588585 A 802 811 silibinin TRIVIAL 23588585 A 963 972 silibinin TRIVIAL 23588585 T 24 33 Silibinin TRIVIAL 23589302 A 21 29 tyrosine TRIVIAL 23589302 A 270 273 Tyr FORMULA 23589302 A 278 281 Tyr FORMULA 23589302 A 286 289 Tyr FORMULA 23589302 A 297 300 Tyr FORMULA 23589302 T 8 16 tyrosine TRIVIAL 23589404 A 1028 1035 amalgam TRIVIAL 23589404 A 1078 1080 Hg FORMULA 23589404 A 1153 1155 Hg FORMULA 23589404 A 323 330 amalgam TRIVIAL 23589404 A 451 458 amalgam TRIVIAL 23589404 A 58 65 mercury SYSTEMATIC 23589404 A 582 584 Hg FORMULA 23589404 A 67 69 Hg FORMULA 23589404 A 693 695 Hg FORMULA 23589404 A 846 853 amalgam TRIVIAL 23589404 A 942 944 Hg FORMULA 23589404 T 12 19 mercury SYSTEMATIC 23589404 T 76 83 amalgam TRIVIAL 23589408 A 174 183 aflatoxin FAMILY 23589408 T 42 51 aflatoxin FAMILY 23589499 A 0 9 Monoamine SYSTEMATIC 23589499 A 105 119 3-arylcoumarin FAMILY 23589499 A 1191 1208 2-arylbenzofurans FAMILY 23589499 A 1213 1228 3-arylcoumarins FAMILY 23589499 A 216 230 trans-stilbene TRIVIAL 23589499 A 254 270 2-arylbenzofuran FAMILY 23589499 A 289 303 3-arylcoumarin FAMILY 23589499 A 534 571 5-Nitro-2-(4-methoxyphenyl)benzofuran SYSTEMATIC 23589499 A 611 621 benzofuran SYSTEMATIC 23589499 A 701 737 3-(4'-Methoxyphenyl)-6-nitrocoumarin SYSTEMATIC 23589499 A 857 865 coumarin TRIVIAL 23589499 A 896 912 3-phenylcoumarin SYSTEMATIC 23589499 T 27 44 2-Arylbenzofurans FAMILY 23589499 T 52 67 3-Arylcoumarins FAMILY 23589515 A 227 231 MoS2 FORMULA 23589515 A 323 327 MoS2 FORMULA 23589515 A 342 344 Si FORMULA 23589515 A 345 349 SiO2 FORMULA 23589515 A 650 654 MoS2 FORMULA 23589515 A 917 925 graphene TRIVIAL 23589515 T 60 64 MoS2 FORMULA 23590193 A 509 538 tris(2-carboxyethyl)phosphine SYSTEMATIC 23590193 A 540 544 TCEP ABBREVIATION 23590193 A 55 64 disulfide SYSTEMATIC 23590193 A 604 608 TCEP ABBREVIATION 23590193 A 773 785 thioflavin T TRIVIAL 23590193 A 883 887 TCEP ABBREVIATION 23590470 A 124 146 6-thioguanine riboside SYSTEMATIC 23590470 A 196 206 thiopurine TRIVIAL 23590470 A 351 363 sodium azide SYSTEMATIC 23590470 A 368 392 sodium heptane sulfonate SYSTEMATIC 23590470 A 403 415 acetonitrile SYSTEMATIC 23590470 A 54 70 6-mercaptopurine TRIVIAL 23590470 A 607 611 6-MP SYSTEMATIC 23590470 A 613 626 6-thioguanine SYSTEMATIC 23590470 A 628 653 6-mercaptopurine riboside SYSTEMATIC 23590470 A 658 680 6-thioguanine riboside SYSTEMATIC 23590470 A 72 76 6-MP SYSTEMATIC 23590470 A 79 92 6-thioguanine SYSTEMATIC 23590470 A 806 817 thiopurines FAMILY 23590470 A 912 916 6-MP SYSTEMATIC 23590470 A 94 119 6-mercaptopurine riboside SYSTEMATIC 23590470 T 106 111 azide SYSTEMATIC 23590470 T 25 41 6-mercaptopurine TRIVIAL 23590470 T 99 105 iodine SYSTEMATIC 23590563 A 1142 1151 NPHOS-PEO ABBREVIATION 23590563 A 1152 1155 SDS ABBREVIATION 23590563 A 1211 1216 NPHOS ABBREVIATION 23590563 A 1217 1220 SDS ABBREVIATION 23590563 A 1234 1237 PEO ABBREVIATION 23590563 A 1386 1391 NPHOS ABBREVIATION 23590563 A 1419 1422 PEO ABBREVIATION 23590563 A 178 187 NPHOS-PEO ABBREVIATION 23590563 A 212 234 sodium dodecyl sulfate SYSTEMATIC 23590563 A 236 239 SDS ABBREVIATION 23590563 A 463 482 dimethylaminomethyl SYSTEMATIC 23590563 A 493 498 NPHOS ABBREVIATION 23590563 A 550 559 NPHOS-PEO ABBREVIATION 23590563 A 560 563 SDS ABBREVIATION 23590563 A 939 944 NPHOS ABBREVIATION 23590563 A 98 176 poly[3,5-bis(dimethylaminomethyl)-4-hydroxystyrene]-block-poly(ethylene oxide) FAMILY 23590563 T 123 145 Sodium Dodecyl Sulfate SYSTEMATIC 23590563 T 40 118 Poly[3,5-bis(dimethylaminomethyl)-4-hydroxystyrene]-block-poly(ethylene oxide) FAMILY 23590572 A 36 48 phenylperoxy SYSTEMATIC 23590572 A 779 791 phenylperoxy SYSTEMATIC 23590572 A 977 989 phenylperoxy SYSTEMATIC 23590572 T 56 68 Phenylperoxy FAMILY 23590591 A 1325 1328 CpG ABBREVIATION 23590591 A 1497 1500 CpG ABBREVIATION 23590591 A 1543 1546 CpG ABBREVIATION 23590591 A 2093 2096 CpG ABBREVIATION 23590591 A 546 551 thiol FAMILY 23590591 A 561 578 pyridyl disulfide SYSTEMATIC 23590591 A 644 647 CpG ABBREVIATION 23590591 A 670 673 CpG ABBREVIATION 23590591 A 761 764 CpG ABBREVIATION 23590723 A 121 125 MoS2 FORMULA 23590723 T 39 43 MoS2 FORMULA 23590729 A 0 6 Sodium SYSTEMATIC 23590729 A 1393 1397 DTBN ABBREVIATION 23590729 A 16 29 maleamic acid TRIVIAL 23590729 A 45 57 lauryl ester TRIVIAL 23590729 A 523 546 di-tert-butyl nitroxide SYSTEMATIC 23590729 A 548 552 DTBN ABBREVIATION 23590729 A 61 69 tyrosine TRIVIAL 23590729 A 81 95 phenyl alanine TRIVIAL 23590729 T 74 84 l-Tyrosine TRIVIAL 23590729 T 89 105 l-Phenyl Alanine TRIVIAL 23591110 A 101 110 histamine TRIVIAL 23591110 A 31 41 aryl ureas FAMILY 23591110 T 13 23 aryl ureas FAMILY 23591110 T 28 39 aryl amides FAMILY 23591110 T 64 73 histamine TRIVIAL 23591115 A 102 121 phenanthroimidazole FAMILY 23591115 A 186 192 Hg(2+) FORMULA 23591115 A 274 283 thioamide SYSTEMATIC 23591115 A 327 332 amide FAMILY 23591115 A 43 49 Hg(2+) FORMULA 23591115 T 0 19 Phenanthroimidazole SYSTEMATIC 23591115 T 26 39 thiobenzamide SYSTEMATIC 23591115 T 97 108 mercury(II) SYSTEMATIC 23591125 A 1254 1266 bryostatin-1 TRIVIAL 23591125 A 545 557 bryostatin-1 TRIVIAL 23591125 A 665 677 bryostatin-1 TRIVIAL 23591125 A 905 916 alaproclate TRIVIAL 23591125 A 930 939 serotonin TRIVIAL 23591149 A 422 435 porphyrinoids FAMILY 23591149 T 28 40 porphyrinoid FAMILY 23591590 A 104 110 NO3(-) FORMULA 23591590 A 112 120 H2PO4(-) FORMULA 23591590 A 1164 1172 H2PO4(-) FORMULA 23591590 A 122 129 HSO4(-) FORMULA 23591590 A 1244 1247 oxo SYSTEMATIC 23591590 A 1298 1305 halides FAMILY 23591590 A 135 143 tosylate TRIVIAL 23591590 A 145 151 TsO(-) FORMULA 23591590 A 1498 1505 halogen FAMILY 23591590 A 1553 1560 halogen FAMILY 23591590 A 1565 1573 hydrogen SYSTEMATIC 23591590 A 349 355 C8F17I FORMULA 23591590 A 361 366 Br(-) FORMULA 23591590 A 371 375 I(-) FORMULA 23591590 A 385 389 I(-) FORMULA 23591590 A 391 397 NO3(-) FORMULA 23591590 A 399 406 HSO4(-) FORMULA 23591590 A 408 416 H2PO4(-) FORMULA 23591590 A 422 428 TsO(-) FORMULA 23591590 A 442 446 I(-) FORMULA 23591590 A 448 455 HSO4(-) FORMULA 23591590 A 460 466 TsO(-) FORMULA 23591590 A 84 89 Cl(-) FORMULA 23591590 A 91 96 Br(-) FORMULA 23591590 A 952 959 halogen FAMILY 23591590 A 98 102 I(-) FORMULA 23591590 T 38 45 halogen FAMILY 23591661 A 1095 1104 Cremophor TRIVIAL 23591661 A 1109 1120 plitidepsin TRIVIAL 23591661 A 1255 1269 polyamino acid FAMILY 23591661 A 196 213 polyglutamic acid FAMILY 23591661 A 215 218 PGA ABBREVIATION 23591661 A 325 336 plitidepsin TRIVIAL 23591661 A 435 449 polyamino acid FAMILY 23591661 A 628 639 plitidepsin TRIVIAL 23591661 T 50 64 polyamino acid FAMILY 23591959 A 1065 1073 selenium SYSTEMATIC 23591959 A 1146 1154 selenium SYSTEMATIC 23591959 A 1236 1244 fluoride SYSTEMATIC 23591959 A 1287 1295 selenium SYSTEMATIC 23591959 A 134 142 selenium SYSTEMATIC 23591959 A 1373 1381 selenium SYSTEMATIC 23591959 A 1443 1451 fluoride SYSTEMATIC 23591959 A 1486 1494 selenium SYSTEMATIC 23591959 A 1594 1602 selenium SYSTEMATIC 23591959 A 1833 1841 selenium SYSTEMATIC 23591959 A 2070 2078 selenium SYSTEMATIC 23591959 A 2088 2096 selenium SYSTEMATIC 23591959 A 2191 2199 selenium SYSTEMATIC 23591959 A 2271 2279 Selenium SYSTEMATIC 23591959 A 2407 2414 Na2SeO3 FORMULA 23591959 A 241 256 sodium fluoride SYSTEMATIC 23591959 A 2434 2442 fluoride SYSTEMATIC 23591959 A 272 275 NaF FORMULA 23591959 A 293 308 sodium selenite SYSTEMATIC 23591959 A 325 332 Na2SeO3 FORMULA 23591959 A 372 380 selenium SYSTEMATIC 23591959 A 383 386 NaF FORMULA 23591959 A 403 410 Na2SeO3 FORMULA 23591959 A 41 49 selenium SYSTEMATIC 23591959 A 439 442 NaF FORMULA 23591959 A 53 61 fluoride SYSTEMATIC 23591959 A 638 642 dUTP ABBREVIATION 23591959 A 940 948 fluoride SYSTEMATIC 23591959 A 958 966 selenium SYSTEMATIC 23591959 T 11 19 Selenium SYSTEMATIC 23591996 A 0 9 Melatonin TRIVIAL 23591996 A 1045 1052 timolol TRIVIAL 23591996 A 1084 1095 brimonidine TRIVIAL 23591996 A 1230 1239 melatonin TRIVIAL 23591996 A 1243 1252 5-MCA-NAT SYSTEMATIC 23591996 A 1293 1304 brimonidine TRIVIAL 23591996 A 1391 1400 5-MCA-NAT SYSTEMATIC 23591996 A 1434 1445 brimonidine TRIVIAL 23591996 A 1532 1543 brimonidine TRIVIAL 23591996 A 171 180 melatonin TRIVIAL 23591996 A 198 239 5-methoxycarbonylamino-N-acetyltryptamine SYSTEMATIC 23591996 A 241 250 5-MCA-NAT SYSTEMATIC 23591996 A 722 729 timolol TRIVIAL 23591996 A 779 790 brimonidine TRIVIAL 23591996 A 867 874 timolol TRIVIAL 23591996 A 903 912 melatonin TRIVIAL 23591996 A 916 925 5-MCA-NAT SYSTEMATIC 23591996 T 0 9 Melatonin TRIVIAL 23591996 T 27 36 5-MCA-NAT SYSTEMATIC 23591997 A 1267 1277 PF-573,228 IDENTIFIER 23592428 A 1475 1491 prostaglandin E2 TRIVIAL 23592577 A 0 8 Graphene TRIVIAL 23592577 A 127 131 MoS2 FORMULA 23592577 A 196 199 TTF ABBREVIATION 23592577 A 21 25 MoS2 FORMULA 23592577 A 236 240 MoS2 FORMULA 23592577 A 264 282 tetracyanoethylene SYSTEMATIC 23592577 A 329 333 MoS2 FORMULA 23592577 A 61 69 graphene TRIVIAL 23592577 A 71 89 Tetrathiafulvalene SYSTEMATIC 23592577 A 91 94 TTF ABBREVIATION 23592577 T 46 50 MoS2 FORMULA 23592577 T 55 73 Tetrathiafulvalene SYSTEMATIC 23592745 A 0 7 Wogonin TRIVIAL 23592745 A 13 22 flavonoid FAMILY 23592745 A 160 167 wogonin TRIVIAL 23592745 A 268 275 wogonin TRIVIAL 23592745 A 413 420 Wogonin TRIVIAL 23592745 A 666 673 wogonin TRIVIAL 23592745 A 684 691 wogonin TRIVIAL 23592745 A 798 806 tyrosine TRIVIAL 23592745 A 965 972 wogonin TRIVIAL 23592745 T 21 28 wogonin TRIVIAL 23592780 A 0 7 Glucose TRIVIAL 23592780 A 155 160 sugar FAMILY 23592780 A 281 288 glucose TRIVIAL 23592780 A 440 447 glucose TRIVIAL 23592780 A 451 459 fructose TRIVIAL 23592780 A 530 535 sugar FAMILY 23592780 A 545 560 monosaccharides FAMILY 23592780 A 581 588 glucose TRIVIAL 23592780 A 614 617 Lys FORMULA 23592780 A 650 658 fructose TRIVIAL 23592780 A 714 721 glucose TRIVIAL 23592780 A 759 762 Lys FORMULA 23592780 A 770 773 Lys FORMULA 23592780 A 839 846 glucose TRIVIAL 23592780 A 902 917 monosaccharides FAMILY 23592780 T 49 56 glucose TRIVIAL 23592839 A 1066 1075 rapamycin TRIVIAL 23592839 A 177 186 rapamycin TRIVIAL 23592839 A 19 28 rapamycin TRIVIAL 23592839 A 713 722 rapamycin TRIVIAL 23594027 A 513 517 SiO2 FORMULA 23594027 A 524 528 Na2O FORMULA 23594027 A 535 538 CaO FORMULA 23594027 A 548 552 P2O5 FORMULA 23594027 A 574 578 SiO2 FORMULA 23594027 A 585 588 CaO FORMULA 23594027 A 598 602 P2O5 FORMULA 23594027 A 81 94 orthosilicate TRIVIAL 23594027 A 895 908 orthosilicate TRIVIAL 23594047 A 200 205 TiO 2 FORMULA 23594047 A 247 265 titanium hydroxide SYSTEMATIC 23594047 A 408 413 TiO 2 FORMULA 23594047 A 45 50 TiO 2 FORMULA 23594047 A 566 569 H 2 FORMULA 23594047 A 598 603 TiO 2 FORMULA 23594047 A 94 100 OH (-) FORMULA 23594047 T 23 28 TiO 2 FORMULA 23594105 A 393 406 alkylammonium FAMILY 23594105 A 450 465 montmorillonite TRIVIAL 23594210 A 102 105 pH2 FORMULA 23594210 A 1020 1023 NH3 FORMULA 23594210 A 1068 1071 pH2 FORMULA 23594210 A 1186 1189 pH2 FORMULA 23594210 A 1236 1239 NH3 FORMULA 23594210 A 1253 1256 NH3 FORMULA 23594210 A 1261 1264 ND3 FORMULA 23594210 A 1485 1488 NH3 FORMULA 23594210 A 1587 1590 pH2 FORMULA 23594210 A 198 201 NH3 FORMULA 23594210 A 206 209 ND3 FORMULA 23594210 A 231 234 pH2 FORMULA 23594210 A 320 323 NH3 FORMULA 23594210 A 380 383 ND3 FORMULA 23594210 A 511 514 NH3 FORMULA 23594210 A 553 556 NH3 FORMULA 23594210 A 561 564 ND3 FORMULA 23594210 A 59 62 NH3 FORMULA 23594210 A 67 70 ND3 FORMULA 23594210 A 88 100 parahydrogen SYSTEMATIC 23594210 T 61 64 NH3 FORMULA 23594210 T 69 72 ND3 FORMULA 23594210 T 82 94 Parahydrogen SYSTEMATIC 23594301 A 1166 1175 meloxicam TRIVIAL 23594301 A 1341 1350 meloxicam TRIVIAL 23594301 A 1754 1763 meloxicam TRIVIAL 23594301 A 457 466 meloxicam TRIVIAL 23594301 A 629 638 meloxicam TRIVIAL 23594301 T 106 115 meloxicam TRIVIAL 23594304 A 1218 1229 phyllanthin TRIVIAL 23594304 A 1424 1435 phyllanthin TRIVIAL 23594304 A 1499 1510 phyllanthin TRIVIAL 23594304 A 1567 1578 phyllanthin TRIVIAL 23594304 A 1739 1750 phyllanthin TRIVIAL 23594304 A 200 211 phyllanthin TRIVIAL 23594304 A 213 224 Phyllanthin TRIVIAL 23594304 A 329 340 phyllanthin TRIVIAL 23594304 A 394 398 (1)H FORMULA 23594304 A 407 412 (13)C FORMULA 23594304 A 42 48 lignan FAMILY 23594304 A 451 462 phyllanthin TRIVIAL 23594304 A 498 509 phyllanthin TRIVIAL 23594304 A 698 709 phyllanthin TRIVIAL 23594304 A 838 849 phyllanthin TRIVIAL 23594304 A 878 893 petroleum ether TRIVIAL 23594304 A 9 20 Phyllanthin TRIVIAL 23594304 A 904 911 ethanol SYSTEMATIC 23594304 A 920 927 ethanol SYSTEMATIC 23594304 A 993 1004 Phyllanthin TRIVIAL 23594304 T 36 47 phyllanthin TRIVIAL 23594342 A 0 9 Genistein TRIVIAL 23594342 A 1003 1012 genistein TRIVIAL 23594342 A 1022 1025 PEO ABBREVIATION 23594342 A 1026 1031 PDLLA ABBREVIATION 23594342 A 225 234 genistein TRIVIAL 23594342 A 321 342 poly(d,l-lactic acid) FAMILY 23594342 A 344 349 PDLLA ABBREVIATION 23594342 A 352 372 poly(ethylene oxide) SYSTEMATIC 23594342 A 374 377 PEO ABBREVIATION 23594342 A 384 393 genistein TRIVIAL 23594342 A 519 528 genistein TRIVIAL 23594342 A 538 541 PEO ABBREVIATION 23594342 A 542 547 PDLLA ABBREVIATION 23594342 A 643 647 (1)H FORMULA 23594342 A 678 687 genistein TRIVIAL 23594342 A 882 891 genistein TRIVIAL 23594342 A 935 938 PEO ABBREVIATION 23594342 T 19 39 Poly(ethylene oxide) FAMILY 23594342 T 40 61 Poly(d,l-lactic acid) FAMILY 23594396 A 110 146 2,2,6,6-tetramethylpiperidine-1-oxyl SYSTEMATIC 23594396 A 148 153 TEMPO ABBREVIATION 23594396 A 304 310 sodium SYSTEMATIC 23594396 A 312 319 lithium SYSTEMATIC 23594396 A 321 330 potassium SYSTEMATIC 23594396 A 336 342 cesium SYSTEMATIC 23594396 A 343 354 carboxylate SYSTEMATIC 23594396 A 378 386 carboxyl SYSTEMATIC 23594396 A 400 404 COOH FORMULA 23594396 A 434 436 H2 FORMULA 23594396 A 49 57 hydrogen SYSTEMATIC 23594396 A 491 493 H2 FORMULA 23594396 A 495 497 N2 FORMULA 23594396 A 499 501 O2 FORMULA 23594396 A 507 510 CO2 FORMULA 23594396 A 707 709 H2 FORMULA 23594396 A 736 740 COOH FORMULA 23594396 A 885 902 metal carboxylate FAMILY 23594396 A 951 955 COOH FORMULA 23594396 A 993 995 H2 FORMULA 23594396 T 24 32 Hydrogen SYSTEMATIC 23595058 A 1088 1107 galactosylceramides FAMILY 23595058 A 141 159 glycosphingolipids FAMILY 23595058 A 167 194 axidjiferoside-A, -B and -C MULTIPLE 23595058 A 395 406 chloroquine TRIVIAL 23595058 A 485 512 β-galactopyranosylceramides FAMILY 23595058 A 525 562 2-amino-(6E)-octadec-6-en-1,3,4-triol SYSTEMATIC 23595058 A 583 599 axidjiferoside-A TRIVIAL 23595058 A 624 651 2-hydroxytetracosanoic acid SYSTEMATIC 23595058 A 855 870 axidjiferosides FAMILY 23595058 T 25 40 Axidjiferosides FAMILY 23595058 T 46 67 β-Galactosylceramides FAMILY 23595911 A 18 26 methanol SYSTEMATIC 23595911 A 1853 1861 methanol SYSTEMATIC 23595911 A 254 260 ethene SYSTEMATIC 23595911 A 268 275 propene SYSTEMATIC 23595911 A 30 37 olefins FAMILY 23595911 A 716 723 H-ZSM-5 FAMILY 23595911 A 728 737 H-SAPO-34 TRIVIAL 23595911 T 45 53 Methanol SYSTEMATIC 23595911 T 57 64 Olefins FAMILY 23596058 A 1025 1029 NOBA ABBREVIATION 23596058 A 1105 1112 nitrate SYSTEMATIC 23596058 A 1127 1147 nitrooxybutyl-esters FAMILY 23596058 A 1211 1215 NOBA ABBREVIATION 23596058 A 1220 1223 GTN ABBREVIATION 23596058 A 1246 1254 nitrates FAMILY 23596058 A 1288 1290 NO FORMULA 23596058 A 1332 1339 nitrite SYSTEMATIC 23596058 A 1343 1350 nitrate SYSTEMATIC 23596058 A 1541 1549 nitrates FAMILY 23596058 A 1636 1644 nitrates FAMILY 23596058 A 1774 1781 nitrate SYSTEMATIC 23596058 A 1785 1792 nitrite SYSTEMATIC 23596058 A 190 210 nitrooxybutyl-esters FAMILY 23596058 A 214 226 flurbiprofen TRIVIAL 23596058 A 231 243 ferulic-acid TRIVIAL 23596058 A 264 272 nitrates FAMILY 23596058 A 384 403 glyceryl trinitrate SYSTEMATIC 23596058 A 405 408 GTN ABBREVIATION 23596058 A 492 494 NO FORMULA 23596058 A 502 507 NOC-5 TRIVIAL 23596058 A 530 550 Nitrooxybutyl-esters FAMILY 23596058 A 63 71 nitrates FAMILY 23596058 A 648 655 nitrate SYSTEMATIC 23596058 A 663 684 nitrooxybutyl-alcohol SYSTEMATIC 23596058 A 686 690 NOBA ABBREVIATION 23596058 A 710 713 GTN ABBREVIATION 23596058 A 762 769 nitrite SYSTEMATIC 23596058 A 771 775 NOBA ABBREVIATION 23596058 A 802 809 nitrate SYSTEMATIC 23596058 A 842 844 NO FORMULA 23596058 A 851 856 NOC-5 TRIVIAL 23596058 A 858 862 NOBA ABBREVIATION 23596058 A 867 870 GTN ABBREVIATION 23596058 A 899 901 NO FORMULA 23596058 A 992 994 NO FORMULA 23596058 T 51 59 nitrates FAMILY 23596124 A 224 256 (E)-styryl-1H-benzo[d]imidazoles FAMILY 23596124 A 36 53 isopropylstilbene SYSTEMATIC 23596124 A 96 103 epoxide SYSTEMATIC 23596124 T 19 27 Stilbene TRIVIAL 23596124 T 39 46 Epoxide SYSTEMATIC 23596261 A 0 16 Organophosphates FAMILY 23596261 A 1074 1081 choline FAMILY 23596261 A 1190 1203 Methamidophos TRIVIAL 23596261 A 130 133 OPs FAMILY 23596261 A 1405 1418 Methamidophos TRIVIAL 23596261 A 18 21 OPs FAMILY 23596261 A 309 322 methamidophos TRIVIAL 23596261 A 508 521 methamidophos TRIVIAL 23596261 A 70 73 OPs FAMILY 23596261 A 825 838 Methamidophos TRIVIAL 23596261 A 858 865 choline FAMILY 23596261 A 955 962 choline FAMILY 23596261 T 0 13 Methamidophos TRIVIAL 23597018 A 289 312 polytetrafluoroethylene TRIVIAL 23597018 A 314 318 PTFE ABBREVIATION 23597018 A 345 349 TiO2 FORMULA 23597018 A 497 505 catechin TRIVIAL 23597018 A 630 632 Ti FORMULA 23597018 A 642 646 TiO2 FORMULA 23597018 A 681 689 catechin TRIVIAL 23597018 A 806 814 catechin TRIVIAL 23597018 A 881 889 catechin TRIVIAL 23597018 A 893 897 TiO2 FORMULA 23597018 T 93 97 TiO2 FORMULA 23597098 A 1094 1104 nucleotide FAMILY 23597098 A 1568 1578 nucleotide FAMILY 23597098 A 194 205 polypyrrole FAMILY 23597098 A 20 30 nucleoside FAMILY 23597098 A 308 319 nucleotides FAMILY 23597098 T 32 43 Polypyrrole FAMILY 23597402 A 230 241 pyrrolidine SYSTEMATIC 23597402 A 41 71 bis-homoallylic hydroxylamines FAMILY 23597402 T 17 25 thiourea SYSTEMATIC 23597443 A 0 16 Titanium dioxide SYSTEMATIC 23597443 A 18 22 TiO2 FORMULA 23597443 A 556 560 TiO2 FORMULA 23597443 A 776 780 TiO2 FORMULA 23597443 T 55 71 titanium dioxide SYSTEMATIC 23597506 A 1036 1046 anandamide TRIVIAL 23597506 A 1238 1248 anandamide TRIVIAL 23597506 A 1374 1384 anandamide TRIVIAL 23597506 A 1421 1435 R-flurbiprofen TRIVIAL 23597506 A 1447 1457 anandamide TRIVIAL 23597506 A 342 356 R-flurbiprofen TRIVIAL 23597506 A 434 448 R-flurbiprofen TRIVIAL 23597506 A 540 550 anandamide TRIVIAL 23597506 A 683 693 anandamide TRIVIAL 23597506 A 821 835 R-flurbiprofen TRIVIAL 23597506 A 907 917 anandamide TRIVIAL 23597506 A 987 997 fatty acid FAMILY 23597506 A 998 1003 amide FAMILY 23597506 T 0 10 Anandamide TRIVIAL 23597511 A 1049 1053 MDPV ABBREVIATION 23597511 A 1117 1121 METH ABBREVIATION 23597511 A 1162 1166 MDPV ABBREVIATION 23597511 A 1171 1175 METH ABBREVIATION 23597511 A 1382 1386 METH ABBREVIATION 23597511 A 1391 1395 MDPV ABBREVIATION 23597511 A 1521 1525 MDPV ABBREVIATION 23597511 A 1572 1576 MDPV ABBREVIATION 23597511 A 1654 1658 MDPV ABBREVIATION 23597511 A 1681 1685 MDPV ABBREVIATION 23597511 A 1774 1778 METH ABBREVIATION 23597511 A 320 324 MDPV ABBREVIATION 23597511 A 384 388 MDPV ABBREVIATION 23597511 A 438 455 d-methamphetamine TRIVIAL 23597511 A 45 75 3,4-methylenedioxypyrovalerone SYSTEMATIC 23597511 A 457 461 METH ABBREVIATION 23597511 A 617 621 MDPV ABBREVIATION 23597511 A 625 629 METH ABBREVIATION 23597511 A 769 773 MDPV ABBREVIATION 23597511 A 77 81 MDPV ABBREVIATION 23597511 A 777 781 METH ABBREVIATION 23597511 A 802 806 METH ABBREVIATION 23597511 A 811 815 MDPV ABBREVIATION 23597511 A 890 894 METH ABBREVIATION 23597511 A 922 926 MDPV ABBREVIATION 23597511 T 28 58 3,4-methylenedioxypyrovalerone SYSTEMATIC 23597511 T 60 64 MDPV ABBREVIATION 23597790 A 367 371 cGMP ABBREVIATION 23597790 A 408 412 cAMP ABBREVIATION 23597790 A 532 551 pyrazolodiazepinone SYSTEMATIC 23598043 A 1127 1129 Pb FORMULA 23598043 A 1240 1242 Pb FORMULA 23598043 A 168 170 Pb FORMULA 23598043 A 370 372 Pb FORMULA 23598043 A 44 46 Pb FORMULA 23598043 A 576 578 Pb FORMULA 23598363 A 1049 1057 imatinib TRIVIAL 23598363 A 1072 1081 cisplatin TRIVIAL 23598363 A 1274 1277 Trp FORMULA 23598363 A 1385 1394 cisplatin TRIVIAL 23598363 A 1453 1462 cisplatin TRIVIAL 23598363 A 1548 1557 cisplatin TRIVIAL 23598363 A 1712 1720 imatinib TRIVIAL 23598363 A 1743 1752 cisplatin TRIVIAL 23598363 A 1867 1875 imatinib TRIVIAL 23598363 A 1948 1957 cisplatin TRIVIAL 23598363 A 329 346 imatinib mesylate TRIVIAL 23598363 A 348 356 imatinib TRIVIAL 23598363 A 425 434 cisplatin TRIVIAL 23598363 A 468 476 imatinib TRIVIAL 23598363 A 663 671 imatinib TRIVIAL 23598363 A 685 694 cisplatin TRIVIAL 23598363 A 786 795 cisplatin TRIVIAL 23598363 A 937 945 imatinib TRIVIAL 23598363 A 966 975 cisplatin TRIVIAL 23598363 T 10 18 platinum SYSTEMATIC 23598364 A 156 161 boron SYSTEMATIC 23598364 A 168 175 diamond TRIVIAL 23598364 A 26 32 oxygen SYSTEMATIC 23598364 A 268 274 oxygen SYSTEMATIC 23598364 A 444 450 oxygen SYSTEMATIC 23598364 A 454 464 superoxide TRIVIAL 23598364 A 57 72 methyl viologen SYSTEMATIC 23598364 T 118 123 boron SYSTEMATIC 23598364 T 130 137 diamond TRIVIAL 23598364 T 71 86 methyl viologen SYSTEMATIC 23598364 T 96 102 oxygen SYSTEMATIC 23598368 A 114 123 prolinate TRIVIAL 23598368 A 1143 1156 [P66614][Pro] IDENTIFIER 23598368 A 125 130 [Pro] FORMULA 23598368 A 1279 1298 [P66614][3-CF3pyra] SYSTEMATIC 23598368 A 1303 1320 [P66614][2-CNpyr] SYSTEMATIC 23598368 A 133 149 2-cyanopyrrolide SYSTEMATIC 23598368 A 151 160 [2-CNpyr] SYSTEMATIC 23598368 A 1538 1541 CO2 FORMULA 23598368 A 167 196 3-(trifluoromethyl)pyrazolide SYSTEMATIC 23598368 A 198 209 [3-CF3pyra] SYSTEMATIC 23598368 A 279 282 CO2 FORMULA 23598368 A 30 33 CO2 FORMULA 23598368 A 38 69 trihexyl(tetradecyl)phosphonium SYSTEMATIC 23598368 A 419 429 tetraglyme TRIVIAL 23598368 A 533 536 CO2 FORMULA 23598368 A 601 604 CO2 FORMULA 23598368 A 632 642 tetraglyme TRIVIAL 23598368 A 651 654 N2O FORMULA 23598368 A 71 79 [P66614] IDENTIFIER 23598368 A 715 718 CO2 FORMULA 23598368 A 940 953 [P66614][Pro] IDENTIFIER 23598368 A 980 999 [P66614][3-CF3pyra] SYSTEMATIC 23598368 T 21 24 CO2 FORMULA 23598368 T 42 53 phosphonium SYSTEMATIC 23598400 A 1059 1066 alcohol FAMILY 23598400 A 1242 1249 alcohol FAMILY 23598400 A 142 149 alcohol FAMILY 23598400 A 449 456 alcohol FAMILY 23598400 T 58 65 alcohol FAMILY 23598442 A 1073 1082 melatonin TRIVIAL 23598442 A 122 131 Melatonin TRIVIAL 23598442 A 1243 1252 melatonin TRIVIAL 23598442 A 1728 1737 melatonin TRIVIAL 23598442 A 285 294 melatonin TRIVIAL 23598442 A 408 417 melatonin TRIVIAL 23598442 A 535 544 Melatonin TRIVIAL 23598442 A 573 577 cAMP ABBREVIATION 23598442 A 64 73 melatonin TRIVIAL 23598442 A 665 674 melatonin TRIVIAL 23598442 A 907 916 melatonin TRIVIAL 23598442 T 22 31 melatonin TRIVIAL 23600593 A 129 149 flavone C-glycosides FAMILY 23600593 A 251 318 6‴-(3-hydroxy-3-methylglutaroyl)-2″-O-β-d-galactopyranosyl orientin SYSTEMATIC 23600593 A 31 38 ethanol SYSTEMATIC 23600593 A 327 393 6‴-(3-hydroxy-3-methylglutaroyl)-2″-O-β-d-galactopyranosyl vitexin SYSTEMATIC 23600593 A 606 616 flavonoids FAMILY 23600593 T 0 20 Flavone C-glycosides FAMILY 23600748 A 222 223 C FORMULA 23600748 A 277 287 amino acid FAMILY 23600748 A 784 795 doxorubicin TRIVIAL 23600748 A 797 800 DOX ABBREVIATION 23600958 A 319 326 flavone TRIVIAL 23600958 A 556 588 5-hydroxy-4'-propargyloxyflavone SYSTEMATIC 23600958 A 590 597 5H4'FPE SYSTEMATIC 23600958 A 688 704 α-Naphthoflavone TRIVIAL 23600958 A 714 730 5-hydroxyflavone SYSTEMATIC 23600958 A 784 800 β-naphthoflavone TRIVIAL 23600958 A 806 813 flavone TRIVIAL 23600958 T 0 14 Pyranoflavones FAMILY 23601386 A 183 199 trans fatty acid FAMILY 23601386 A 26 42 trans fatty acid FAMILY 23601386 A 346 357 fatty acids FAMILY 23601386 A 571 588 trans fatty acids FAMILY 23601386 A 717 735 trans elaidic acid TRIVIAL 23601386 A 737 745 t9-C18:1 FORMULA 23601386 T 0 17 Trans fatty acids FAMILY 23601388 A 459 463 iron SYSTEMATIC 23601388 A 489 493 zinc SYSTEMATIC 23601388 A 518 524 folate TRIVIAL 23601388 A 550 559 vitamin D FAMILY 23601388 A 579 586 retinol TRIVIAL 23601392 A 1388 1399 cholesterol TRIVIAL 23601392 A 601 611 B vitamins FAMILY 23601392 A 624 634 vitamin B3 TRIVIAL 23601392 A 676 686 vitamin B1 TRIVIAL 23601392 A 732 742 vitamin B3 TRIVIAL 23601392 A 869 878 magnesium SYSTEMATIC 23601392 A 886 893 calcium SYSTEMATIC 23601392 A 902 912 phosphorus SYSTEMATIC 23601392 A 921 925 zinc SYSTEMATIC 23601392 A 934 938 iron SYSTEMATIC 23601392 A 950 960 vitamin B1 TRIVIAL 23601392 A 968 978 vitamin B2 TRIVIAL 23601392 A 989 999 vitamin B3 TRIVIAL 23601395 A 1017 1029 coenzyme Q10 TRIVIAL 23601395 A 1031 1038 taurine TRIVIAL 23601395 A 1040 1049 glutamine TRIVIAL 23601395 A 1051 1059 creatine TRIVIAL 23601395 A 1061 1071 creatinine TRIVIAL 23601395 A 1073 1082 carnosine TRIVIAL 23601395 A 1087 1095 anserine TRIVIAL 23601395 A 177 181 heme FAMILY 23601395 A 182 186 iron SYSTEMATIC 23601395 A 287 308 saturated fatty acids FAMILY 23601395 A 310 321 cholesterol TRIVIAL 23601395 A 684 688 heme FAMILY 23601395 A 689 693 iron SYSTEMATIC 23601395 A 719 730 fatty acids FAMILY 23601395 A 734 750 triacylglycerols FAMILY 23601395 A 823 850 polyunsaturated fatty acids FAMILY 23601395 A 928 944 vitamins E and A MULTIPLE 23601410 A 122 135 carbohydrates FAMILY 23601410 A 498 511 carbohydrates FAMILY 23601410 A 764 777 carbohydrates FAMILY 23601410 T 64 77 carbohydrates FAMILY 23601412 A 114 120 amines FAMILY 23601412 A 174 180 amines FAMILY 23601412 A 348 354 amines FAMILY 23601412 A 646 652 amines FAMILY 23601412 A 698 708 putrescine TRIVIAL 23601412 A 710 719 histamine TRIVIAL 23601412 A 724 732 tyramine TRIVIAL 23601412 T 9 15 amines FAMILY 23601413 A 631 633 Na FORMULA 23601413 A 640 642 Ca FORMULA 23601413 A 649 651 Fe FORMULA 23601649 A 1326 1338 camptothecin TRIVIAL 23601649 A 674 694 oxygenated flavonoid FAMILY 23601649 A 917 926 flavonoid FAMILY 23601700 A 1236 1239 SDS ABBREVIATION 23601700 A 1271 1274 SDS ABBREVIATION 23601700 A 440 443 SDS ABBREVIATION 23601700 A 622 625 SDS ABBREVIATION 23601700 A 700 703 SDS ABBREVIATION 23601700 A 770 780 disulphide SYSTEMATIC 23601700 A 863 866 SDS ABBREVIATION 23601700 A 878 881 SDS ABBREVIATION 23601753 A 1038 1045 calcium SYSTEMATIC 23601753 A 1213 1220 calcium SYSTEMATIC 23601753 A 309 316 calcium SYSTEMATIC 23601753 A 909 918 aspartate TRIVIAL 23601753 A 969 976 calcium SYSTEMATIC 23601990 A 109 120 cholesterol TRIVIAL 23601990 A 12 37 phosphorylated flavonoids FAMILY 23601990 A 300 310 flavonoids FAMILY 23601990 A 331 356 phosphorylated flavonoids FAMILY 23601990 A 661 669 hydroxyl SYSTEMATIC 23601990 A 694 703 phosphate SYSTEMATIC 23601990 A 731 756 phosphorylated flavonoids FAMILY 23601990 T 103 114 cholesterol TRIVIAL 23601990 T 39 64 phosphorylated flavonoids FAMILY 23602474 A 277 286 serotonin TRIVIAL 23602515 A 1067 1081 thymine glycol TRIVIAL 23602515 A 1351 1356 3'-PG SYSTEMATIC 23602515 A 775 795 3'-phosphoglycolates FAMILY 23602515 A 797 800 PGs FAMILY 23602515 A 837 842 3'-PG SYSTEMATIC 23602515 A 911 925 thymine glycol TRIVIAL 23602864 A 1101 1104 DOC ABBREVIATION 23602864 A 1195 1200 AHGDM ABBREVIATION 23602864 A 1205 1208 DOC ABBREVIATION 23602864 A 1384 1387 DOC ABBREVIATION 23602864 A 1621 1625 HPMA ABBREVIATION 23602864 A 1636 1645 docetaxel TRIVIAL 23602864 A 295 328 N-(2-hydroxypropyl)methacrylamide SYSTEMATIC 23602864 A 330 334 HPMA ABBREVIATION 23602864 A 447 454 glucose TRIVIAL 23602864 A 568 590 aminohexylgeldanamycin SYSTEMATIC 23602864 A 592 597 AHGDM ABBREVIATION 23602864 A 600 609 docetaxel TRIVIAL 23602864 A 611 614 DOC ABBREVIATION 23602864 A 620 629 cisplatin TRIVIAL 23602864 A 850 855 AHGDM ABBREVIATION 23602864 A 860 863 DOC ABBREVIATION 23602864 T 93 97 HPMA ABBREVIATION 23602984 A 1234 1237 ATP ABBREVIATION 23602984 A 1368 1372 GABA ABBREVIATION 23602984 A 230 234 GABA ABBREVIATION 23602985 A 1072 1083 vasopressin FAMILY 23602985 A 320 329 serotonin TRIVIAL 23602985 A 578 588 paroxetine TRIVIAL 23602985 A 734 744 paroxetine TRIVIAL 23602985 T 55 65 paroxetine TRIVIAL 23602997 A 167 174 octanol SYSTEMATIC 23603023 A 18 28 iron oxide SYSTEMATIC 23603023 A 336 346 iron oxide SYSTEMATIC 23603023 A 677 692 ricinoleic acid TRIVIAL 23603023 A 700 709 maghemite TRIVIAL 23603044 A 1084 1094 iodine-131 SYSTEMATIC 23603044 A 272 282 iodine-125 SYSTEMATIC 23603044 A 594 600 (125)I FORMULA 23603044 A 764 770 (131)I FORMULA 23603044 A 864 870 (131)I FORMULA 23603044 A 987 998 fluorine-18 SYSTEMATIC 23603045 A 204 224 triazolothiadiazoles FAMILY 23603045 A 229 249 triazolothiadiazines FAMILY 23603045 A 466 467 N FORMULA 23603045 T 0 20 Triazolothiadiazoles FAMILY 23603045 T 25 45 triazolothiadiazines FAMILY 23603058 A 1095 1104 bilirubin TRIVIAL 23603058 A 1228 1231 DON ABBREVIATION 23603058 A 1319 1322 DON ABBREVIATION 23603058 A 190 193 DON ABBREVIATION 23603058 A 213 216 DON ABBREVIATION 23603058 A 258 261 DON ABBREVIATION 23603058 A 384 387 DON ABBREVIATION 23603058 A 43 57 deoxynivalenol TRIVIAL 23603058 A 568 571 DON ABBREVIATION 23603058 A 59 62 DON ABBREVIATION 23603058 A 605 608 DON ABBREVIATION 23603058 A 907 910 DON ABBREVIATION 23603058 T 19 33 deoxynivalenol TRIVIAL 23603058 T 35 38 DON ABBREVIATION 23603103 A 608 617 galactose TRIVIAL 23603103 T 71 84 carbohydrates FAMILY 23603145 A 1477 1485 chromium SYSTEMATIC 23603145 A 1584 1592 Chromium SYSTEMATIC 23603145 A 2044 2052 chromium SYSTEMATIC 23603145 A 839 858 hexavalent chromium SYSTEMATIC 23603145 T 23 42 hexavalent-chromium SYSTEMATIC 23603191 A 549 559 kojic acid TRIVIAL 23603200 A 1126 1142 gold-thioglucose SYSTEMATIC 23603477 A 390 394 DEAE ABBREVIATION 23603477 A 926 929 SDS ABBREVIATION 23603478 A 1009 1015 BDE-47 ABBREVIATION 23603478 A 1138 1141 TBT ABBREVIATION 23603478 A 1154 1157 BPA ABBREVIATION 23603478 A 1183 1187 TCDD ABBREVIATION 23603478 A 1312 1316 PFOA ABBREVIATION 23603478 A 1318 1322 PFOS ABBREVIATION 23603478 A 1327 1331 HBCD ABBREVIATION 23603478 A 1341 1348 PCB-153 ABBREVIATION 23603478 A 1360 1363 HCB ABBREVIATION 23603478 A 451 462 tributyltin SYSTEMATIC 23603478 A 464 467 TBT ABBREVIATION 23603478 A 470 488 diethylstilbestrol SYSTEMATIC 23603478 A 490 493 DES ABBREVIATION 23603478 A 496 507 bisphenol A TRIVIAL 23603478 A 509 512 BPA ABBREVIATION 23603478 A 515 552 2,3,7,8-tetrachlorodibenzo-[p]-dioxin SYSTEMATIC 23603478 A 554 558 TCDD ABBREVIATION 23603478 A 561 594 2,2',4,4',5,5'-hexachlorobiphenyl SYSTEMATIC 23603478 A 596 603 PCB-153 ABBREVIATION 23603478 A 606 623 hexachlorobenzene SYSTEMATIC 23603478 A 625 628 HCB ABBREVIATION 23603478 A 631 653 hexabromocyclododecane SYSTEMATIC 23603478 A 655 659 HBCD ABBREVIATION 23603478 A 662 702 2,2',4,4'-tetrabrominated diphenyl ether SYSTEMATIC 23603478 A 704 710 BDE-47 ABBREVIATION 23603478 A 714 739 perfluorinated octyl acid SYSTEMATIC 23603478 A 741 745 PFOA ABBREVIATION 23603478 A 751 781 perfluorinated octyl sulfonate SYSTEMATIC 23603478 A 783 787 PFOS ABBREVIATION 23603478 A 876 879 DES ABBREVIATION 23603478 A 881 884 BPA ABBREVIATION 23603478 A 886 890 TCDD ABBREVIATION 23603478 A 892 898 BDE-47 ABBREVIATION 23603478 A 900 907 PCB-153 ABBREVIATION 23603478 A 916 919 HCB ABBREVIATION 23603554 A 1018 1026 diazepam TRIVIAL 23603554 A 1301 1309 diazepam TRIVIAL 23603615 A 1089 1092 DOX ABBREVIATION 23603615 A 1426 1437 doxorubicin TRIVIAL 23603615 A 1590 1601 doxorubicin TRIVIAL 23603615 A 563 574 doxorubicin TRIVIAL 23603615 A 576 579 DOX ABBREVIATION 23603615 A 632 635 DOX ABBREVIATION 23603615 A 745 748 DOX ABBREVIATION 23603615 A 846 849 DOX ABBREVIATION 23603615 A 933 936 DOX ABBREVIATION 23603615 T 35 46 doxorubicin TRIVIAL 23603918 A 447 454 glucose TRIVIAL 23603918 A 497 504 glucose TRIVIAL 23603918 T 92 99 Glucose TRIVIAL 23604205 A 365 367 Au FORMULA 23604390 A 1052 1059 cocaine TRIVIAL 23604390 A 1274 1281 cocaine TRIVIAL 23604390 A 1344 1351 cocaine TRIVIAL 23604390 A 1446 1453 cocaine TRIVIAL 23604390 A 1623 1630 cocaine TRIVIAL 23604390 A 176 183 cocaine TRIVIAL 23604390 A 258 265 cocaine TRIVIAL 23604390 A 369 376 cocaine TRIVIAL 23604390 A 45 52 cocaine TRIVIAL 23604390 A 590 597 cocaine TRIVIAL 23604390 A 686 693 cocaine TRIVIAL 23604390 A 701 708 cocaine TRIVIAL 23604390 A 973 980 cocaine TRIVIAL 23604390 T 25 32 cocaine TRIVIAL 23604717 A 1092 1096 PGE2 ABBREVIATION 23604717 A 110 120 salicylate SYSTEMATIC 23604717 A 1223 1228 SAL-2 SYSTEMATIC 23604717 A 142 158 4-hydroxynonenal SYSTEMATIC 23604717 A 160 163 HNE ABBREVIATION 23604717 A 298 303 SAL-2 SYSTEMATIC 23604717 A 448 453 SAL-2 SYSTEMATIC 23604717 A 476 479 HNE ABBREVIATION 23604717 A 535 538 GSH ABBREVIATION 23604717 A 539 543 GSSG ABBREVIATION 23604717 A 54 84 salicylideneamino-2-thiophenol SYSTEMATIC 23604717 A 565 572 (PG) E2 ABBREVIATION 23604717 A 598 614 arachidonic acid TRIVIAL 23604717 A 633 638 SAL-2 SYSTEMATIC 23604717 A 640 645 SAL-2 SYSTEMATIC 23604717 A 702 705 HNE ABBREVIATION 23604717 A 711 721 salicylate SYSTEMATIC 23604717 A 745 750 SAL-2 SYSTEMATIC 23604717 A 761 764 HNE ABBREVIATION 23604717 A 86 91 SAL-2 SYSTEMATIC 23604717 A 896 901 SAL-2 SYSTEMATIC 23604717 A 912 915 HNE ABBREVIATION 23604717 A 987 992 SAL-2 SYSTEMATIC 23604717 T 103 106 HNE ABBREVIATION 23604717 T 21 51 salicylideneamino-2-thiophenol SYSTEMATIC 23604720 A 1077 1108 methyl-3,5-di-O-caffeoylquinate SYSTEMATIC 23604720 A 1119 1129 galactitol TRIVIAL 23604720 A 1215 1222 glucose TRIVIAL 23604720 A 220 226 aldose FAMILY 23604720 A 246 256 galactitol TRIVIAL 23604720 A 301 308 glucose TRIVIAL 23604720 A 367 387 caffeoylquinic acids FAMILY 23604720 A 394 402 phenolic FAMILY 23604720 A 774 805 methyl-3,5-di-O-caffeoylquinate SYSTEMATIC 23604720 A 993 1024 methyl-3,5-di-O-caffeoylquinate SYSTEMATIC 23604722 A 0 25 Fructose-1,6-bisphosphate SYSTEMATIC 23604722 A 1088 1091 FBP ABBREVIATION 23604722 A 1130 1136 oxygen SYSTEMATIC 23604722 A 1202 1218 prostaglandin E2 TRIVIAL 23604722 A 1312 1315 FBP ABBREVIATION 23604722 A 237 240 FBP ABBREVIATION 23604722 A 27 30 FBP ABBREVIATION 23604722 A 821 824 FBP ABBREVIATION 23604722 A 933 936 FBP ABBREVIATION 23604722 T 0 25 Fructose-1,6-bisphosphate SYSTEMATIC 23604723 A 475 479 cAMP ABBREVIATION 23604723 A 665 669 cAMP ABBREVIATION 23604723 T 46 50 cAMP ABBREVIATION 23605048 A 1117 1120 GSH ABBREVIATION 23605048 A 397 412 sodium fluoride SYSTEMATIC 23605048 A 414 417 NaF FORMULA 23605048 A 438 441 NaF FORMULA 23605048 A 500 503 NaF FORMULA 23605048 A 730 740 Superoxide TRIVIAL 23605048 A 784 795 glutathione TRIVIAL 23605048 A 808 811 GSH ABBREVIATION 23605048 A 820 835 malondialdehyde TRIVIAL 23605048 A 837 840 MDA ABBREVIATION 23605050 A 1043 1050 glucose TRIVIAL 23605050 A 1051 1053 Fe FORMULA 23605050 A 358 362 iron SYSTEMATIC 23605050 A 370 377 glucose TRIVIAL 23605050 A 517 521 iron SYSTEMATIC 23605050 A 529 536 glucose TRIVIAL 23605050 A 680 684 iron SYSTEMATIC 23605050 A 693 703 superoxide TRIVIAL 23605050 A 728 739 glutathione TRIVIAL 23605050 A 849 856 glucose TRIVIAL 23605050 A 901 908 glucose TRIVIAL 23605050 A 913 917 iron SYSTEMATIC 23605050 A 972 979 glucose TRIVIAL 23605050 A 980 984 iron SYSTEMATIC 23605050 T 16 20 Iron SYSTEMATIC 23605050 T 25 32 Glucose TRIVIAL 23605694 A 0 10 Ospemifene TRIVIAL 23605694 A 12 19 Osphena TRIVIAL 23605694 A 295 305 Ospemifene TRIVIAL 23605694 A 323 331 estrogen FAMILY 23605694 A 43 51 estrogen FAMILY 23605694 A 596 606 ospemifene TRIVIAL 23605694 T 0 10 Ospemifene TRIVIAL 23605695 A 0 11 Pasireotide TRIVIAL 23605695 A 1048 1059 pasireotide TRIVIAL 23605695 A 1121 1129 cortisol TRIVIAL 23605695 A 1268 1279 Pasireotide TRIVIAL 23605695 A 13 21 Signifor TRIVIAL 23605695 A 1342 1354 somatostatin TRIVIAL 23605695 A 1481 1488 glucose TRIVIAL 23605695 A 1556 1567 pasireotide TRIVIAL 23605695 A 212 223 Pasireotide TRIVIAL 23605695 A 291 303 somatostatin TRIVIAL 23605695 A 345 357 somatostatin TRIVIAL 23605695 A 442 453 Pasireotide TRIVIAL 23605695 A 48 60 somatostatin TRIVIAL 23605695 A 615 626 pasireotide TRIVIAL 23605695 A 691 699 cortisol TRIVIAL 23605695 A 84 96 somatostatin TRIVIAL 23605695 A 958 969 pasireotide TRIVIAL 23605695 T 0 11 Pasireotide TRIVIAL 23606264 A 58 88 1,6-anhydro-β-L-idonojirimycin SYSTEMATIC 23606264 T 24 40 L-Idonojirimycin TRIVIAL 23606334 A 0 36 15-deoxy-delta12,14-prostaglandin J2 SYSTEMATIC 23606334 A 102 106 PGD2 ABBREVIATION 23606334 A 216 240 α,β-unsaturated carbonyl FAMILY 23606334 A 254 268 cyclopentenone SYSTEMATIC 23606334 A 38 46 15d-PGJ2 SYSTEMATIC 23606334 A 388 396 15d-PGJ2 SYSTEMATIC 23606334 A 457 478 biotinylated-15d-PGJ2 SYSTEMATIC 23606334 A 876 884 15d-PGJ2 SYSTEMATIC 23606334 T 61 100 15-deoxy-delta(12,14) -prostaglandin J2 SYSTEMATIC 23606349 A 324 332 colistin FAMILY 23606349 A 477 487 creatinine TRIVIAL 23606349 A 618 626 colistin FAMILY 23606349 A 92 100 colistin FAMILY 23606349 A 982 990 colistin FAMILY 23606349 T 32 40 Colistin FAMILY 23606423 A 337 377 2-methacryloyloxyethyl phosphorylcholine SYSTEMATIC 23606423 A 379 382 MPC ABBREVIATION 23606423 A 402 452 styrene-block-(ethylene-co-butylene)-block-styrene FAMILY 23606423 A 454 458 SEBS ABBREVIATION 23606423 A 554 558 SEBS ABBREVIATION 23606438 A 84 90 carbon SYSTEMATIC 23606438 T 67 73 Carbon SYSTEMATIC 23606510 A 291 293 Se FORMULA 23606510 A 34 45 glutathione TRIVIAL 23606510 A 453 462 porphyrin FAMILY 23606510 A 584 586 Se FORMULA 23606510 A 67 77 superoxide TRIVIAL 23606510 T 104 114 Superoxide TRIVIAL 23606523 A 1304 1311 glucose TRIVIAL 23606523 A 321 328 glucose TRIVIAL 23606523 A 482 489 glucose TRIVIAL 23606523 A 557 564 glucose TRIVIAL 23606523 A 650 657 glucose TRIVIAL 23606523 T 72 79 Glucose TRIVIAL 23606533 A 20 23 ZnO FORMULA 23606533 A 25 27 Mg FORMULA 23606533 A 29 32 MgO FORMULA 23606533 T 68 71 ZnO FORMULA 23606568 A 1168 1172 DOXO ABBREVIATION 23606568 A 1268 1271 MTT ABBREVIATION 23606568 A 1411 1415 DOXO ABBREVIATION 23606568 A 1954 1962 apatites FAMILY 23606568 A 406 414 apatites FAMILY 23606568 A 530 541 doxorubicin TRIVIAL 23606568 A 543 547 DOXO ABBREVIATION 23606568 T 42 49 Apatite FAMILY 23606657 A 318 320 Li FORMULA 23606657 A 354 362 graphene TRIVIAL 23606657 A 363 369 Fe3 O4 FORMULA 23606657 A 66 74 graphene TRIVIAL 23606657 T 37 45 Graphene TRIVIAL 23606657 T 46 57 Metal Oxide FAMILY 23606657 T 93 95 Li FORMULA 23607484 A 113 153 poly[2-(diethylamino)ethyl methacrylate] SYSTEMATIC 23607484 A 181 188 silicon SYSTEMATIC 23607484 A 543 546 D2O FORMULA 23607484 A 554 562 carbonyl FAMILY 23607484 A 720 723 D2O FORMULA 23607484 A 88 95 silicon SYSTEMATIC 23607484 A 96 99 D2O FORMULA 23607568 A 142 154 N-Me-Val-Thr FORMULA 23607568 A 29 42 viequeamide A TRIVIAL 23607568 T 50 63 Viequeamide A TRIVIAL 23608189 A 0 37 3-Hydroxy-3-methylglutaryl coenzyme A SYSTEMATIC 23608189 A 1041 1053 atorvastatin TRIVIAL 23608189 A 164 170 oxygen SYSTEMATIC 23608189 A 926 938 atorvastatin TRIVIAL 23608239 A 1019 1026 acetone SYSTEMATIC 23608239 A 1107 1111 DPPH ABBREVIATION 23608239 A 1127 1131 ABTS ABBREVIATION 23608239 A 1184 1193 quercetin TRIVIAL 23608239 A 1237 1244 ethanol SYSTEMATIC 23608239 A 1353 1360 ethanol SYSTEMATIC 23608239 A 1505 1508 GSH ABBREVIATION 23608239 A 1559 1566 ethanol SYSTEMATIC 23608239 A 1619 1632 ethyl acetate SYSTEMATIC 23608239 A 1851 1858 ethanol SYSTEMATIC 23608239 A 334 341 Acetone SYSTEMATIC 23608239 A 495 502 DPPH(•) ABBREVIATION 23608239 A 504 512 ABTS(•+) ABBREVIATION 23608239 A 534 551 phosphomolybdenum SYSTEMATIC 23608239 A 683 690 ethanol SYSTEMATIC 23608239 A 754 764 superoxide TRIVIAL 23608239 A 776 787 glutathione TRIVIAL 23608239 A 875 888 Ethyl acetate SYSTEMATIC 23608239 T 21 34 ethyl acetate SYSTEMATIC 23608239 T 77 84 ethanol SYSTEMATIC 23608240 A 1500 1521 cyclopeptid alkaloids FAMILY 23608240 A 1523 1533 flavonoids FAMILY 23608240 A 1541 1556 (-)-epicatechin SYSTEMATIC 23608240 A 1558 1567 quercetin TRIVIAL 23608240 A 1569 1579 kaempferol TRIVIAL 23608240 A 1581 1634 kaempferol-3-O-β-d-(6″-E-p-coumaryl)-glucopyranoside) SYSTEMATIC 23608240 A 1636 1643 tannins FAMILY 23608240 A 1645 1652 sterols FAMILY 23608240 A 1654 1662 terpenes FAMILY 23608240 A 1664 1672 saponins FAMILY 23608240 A 1674 1688 anthraquinones FAMILY 23608700 A 0 23 β-estradiol 17-valerate SYSTEMATIC 23608700 A 1214 1222 estrogen FAMILY 23608700 A 44 52 estrogen FAMILY 23608700 A 91 107 steroid hormones FAMILY 23608700 T 0 23 β-estradiol 17-valerate SYSTEMATIC 23608737 A 1117 1124 Cocaine TRIVIAL 23608737 A 1268 1275 cocaine TRIVIAL 23608737 A 1302 1305 PPT ABBREVIATION 23608737 A 1337 1344 cocaine TRIVIAL 23608737 A 1378 1381 DPN ABBREVIATION 23608737 A 1478 1485 cocaine TRIVIAL 23608737 A 1623 1630 cocaine TRIVIAL 23608737 A 300 309 estradiol TRIVIAL 23608737 A 327 334 cocaine TRIVIAL 23608737 A 581 588 cocaine TRIVIAL 23608737 A 657 670 17β-estradiol SYSTEMATIC 23608737 A 708 715 cocaine TRIVIAL 23608737 A 807 816 estradiol TRIVIAL 23608737 A 86 95 Estradiol TRIVIAL 23608737 A 893 896 PPT ABBREVIATION 23608737 A 926 929 DPN ABBREVIATION 23608737 T 0 9 Estradiol TRIVIAL 23608737 T 31 38 cocaine TRIVIAL 23608737 T 92 100 estrogen FAMILY 23608764 A 36 44 estrogen FAMILY 23608764 A 404 429 cycloartane triterpenoids FAMILY 23608764 T 21 29 estrogen FAMILY 23609108 A 231 242 polyphenols FAMILY 23609108 A 319 330 polyphenols FAMILY 23609108 T 51 62 Polyphenols FAMILY 23609940 A 1214 1218 GnRH ABBREVIATION 23609940 A 1479 1483 GnRH ABBREVIATION 23609940 A 1638 1642 GnRH ABBREVIATION 23609940 A 342 372 gonadotropin-releasing hormone TRIVIAL 23609940 A 374 378 GnRH ABBREVIATION 23609940 A 493 511 estradiol valerate TRIVIAL 23609940 A 742 746 GnRH ABBREVIATION 23609940 T 134 142 estrogen FAMILY 23609940 T 53 83 gonadotropin-releasing hormone TRIVIAL 23610039 A 244 249 CaCO3 FORMULA 23610039 A 366 371 CaCO3 FORMULA 23610039 A 394 401 calcite TRIVIAL 23610039 A 40 83 poly(glutamic acid)22 -block-poly(alanine)8 FAMILY 23610039 A 450 465 PGlu22 -b-PAla8 ABBREVIATION 23610039 A 538 543 CaCO3 FORMULA 23610039 A 700 706 Ca(2+) FORMULA 23610039 A 777 782 CaCO3 FORMULA 23610039 A 85 100 PGlu22 -b-PAla8 ABBREVIATION 23610039 T 77 94 Calcium Carbonate SYSTEMATIC 23610060 A 1043 1050 glucose TRIVIAL 23610060 A 1055 1067 fructosamine SYSTEMATIC 23610060 A 669 676 glucose TRIVIAL 23610060 A 888 895 glucose TRIVIAL 23610081 A 358 365 glucose TRIVIAL 23610081 A 499 506 glucose TRIVIAL 23610081 T 100 107 Glucose TRIVIAL 23610123 A 0 11 Aldosterone TRIVIAL 23610123 A 113 124 aldosterone TRIVIAL 23610123 A 1162 1173 aldosterone TRIVIAL 23610123 A 1305 1316 aldosterone TRIVIAL 23610123 A 1532 1543 aldosterone TRIVIAL 23610123 A 216 227 aldosterone TRIVIAL 23610123 A 380 391 aldosterone TRIVIAL 23610123 A 45 51 sodium SYSTEMATIC 23610123 A 56 65 potassium SYSTEMATIC 23610123 A 825 834 potassium SYSTEMATIC 23610123 A 904 915 aldosterone TRIVIAL 23611027 A 122 158 poly(benzyl 1,2-glycerol carbonate)s FAMILY 23611027 A 214 244 rac-/(R)-benzyl glycidyl ether MULTIPLE 23611027 A 250 253 CO2 FORMULA 23611027 A 260 275 [SalcyCo(III)X] FAMILY 23611027 A 296 305 carbonate FAMILY 23611027 A 345 354 carbonate FAMILY 23611027 A 423 452 poly(1,2-glycerol carbonate)s FAMILY 23611027 A 485 501 primary hydroxyl FAMILY 23611027 A 509 537 Poly(1,2-glycerol carbonate) FAMILY 23611027 A 599 627 poly(1,3-glycerol carbonate) FAMILY 23611027 A 67 103 poly(benzyl 1,2-glycerol carbonate)s FAMILY 23611027 A 728 741 polycarbonate FAMILY 23611027 T 35 64 Poly(1,2-glycerol carbonate)s FAMILY 23611039 A 11 24 tetracyclines FAMILY 23611039 A 312 325 tetracyclines FAMILY 23611039 A 553 566 tetracyclines FAMILY 23611039 T 32 45 Tetracyclines FAMILY 23611475 A 1038 1041 NIM ABBREVIATION 23611475 A 112 115 PEG ABBREVIATION 23611475 A 1243 1246 PEG ABBREVIATION 23611475 A 1248 1251 NIM ABBREVIATION 23611475 A 1286 1289 PEG ABBREVIATION 23611475 A 1312 1315 NIM ABBREVIATION 23611475 A 1390 1393 NIM ABBREVIATION 23611475 A 1419 1422 NIM ABBREVIATION 23611475 A 1443 1446 PEG ABBREVIATION 23611475 A 154 177 PEG 2000, 4000 and 6000 MULTIPLE 23611475 A 696 699 PEG ABBREVIATION 23611475 A 70 80 nimodipine TRIVIAL 23611475 A 82 85 NIM ABBREVIATION 23611475 A 91 110 polyethylene glycol SYSTEMATIC 23611475 T 36 46 nimodipine TRIVIAL 23611475 T 47 66 polyethylene glycol SYSTEMATIC 23611626 A 165 178 quinazolinone SYSTEMATIC 23611626 A 22 35 quinazolinone SYSTEMATIC 23611626 A 392 403 miltefosine TRIVIAL 23611626 A 580 592 nitric oxide SYSTEMATIC 23611626 T 53 66 Quinazolinone SYSTEMATIC 23611733 A 12 21 quinolone FAMILY 23611733 A 56 75 heterocyclic amines FAMILY 23611733 T 4 29 trifluoromethyl quinolone SYSTEMATIC 23612318 A 518 529 fatty acids FAMILY 23612369 A 866 873 sulfate SYSTEMATIC 23612369 A 965 972 sulfate SYSTEMATIC 23612422 A 1066 1070 MeOH FORMULA 23612422 A 292 296 MeOH FORMULA 23612422 A 545 556 chloroquine TRIVIAL 23612422 A 561 574 pyrimethamine TRIVIAL 23612422 A 731 735 MeOH FORMULA 23612689 A 209 211 Co FORMULA 23612689 A 258 260 Co FORMULA 23612689 A 26 28 Co FORMULA 23612689 A 421 427 cobalt SYSTEMATIC 23612689 A 521 523 Co FORMULA 23612689 A 576 580 Co-O FORMULA 23612689 A 678 682 Co-O FORMULA 23612689 A 77 83 carbon SYSTEMATIC 23612689 A 822 824 Co FORMULA 23612689 T 22 28 cobalt SYSTEMATIC 23612689 T 77 83 carbon SYSTEMATIC 23612710 A 523 529 Astrin NO CLASS 23612710 A 753 759 astrin NO CLASS 23612710 A 893 899 Astrin NO CLASS 23612967 A 1036 1040 cGMP ABBREVIATION 23612967 A 1170 1174 cGMP ABBREVIATION 23612967 A 314 324 Cyclic GMP TRIVIAL 23612967 A 482 486 cGMP ABBREVIATION 23612967 A 615 619 cGMP ABBREVIATION 23612967 A 928 932 cGMP ABBREVIATION 23612967 T 49 53 cGMP ABBREVIATION 23612980 A 1018 1022 Ca2+ FORMULA 23612980 A 326 327 N FORMULA 23612980 A 38 42 Ca2+ FORMULA 23612980 A 408 418 methionine TRIVIAL 23612980 A 655 656 N FORMULA 23612980 A 975 979 Ca2+ FORMULA 23612980 T 65 75 methionine TRIVIAL 23613084 A 109 124 sulfanilic acid TRIVIAL 23613084 A 129 136 aniline SYSTEMATIC 23613084 A 39 57 aryldiazonium salt FAMILY 23613084 A 65 87 azo-aryldiazonium salt FAMILY 23613084 A 91 94 azo SYSTEMATIC 23613084 T 40 43 Azo SYSTEMATIC 23613084 T 57 71 Diazonium Salt SYSTEMATIC 23613150 A 1271 1273 Ni FORMULA 23613150 A 1364 1366 Cd FORMULA 23613150 A 1503 1505 Cd FORMULA 23613150 A 254 256 Zn FORMULA 23613150 A 258 260 Cu FORMULA 23613150 A 262 264 Fe FORMULA 23613150 A 266 268 Mg FORMULA 23613150 A 270 272 Ni FORMULA 23613150 A 278 280 Cd FORMULA 23613150 A 360 362 Fe FORMULA 23613150 A 473 475 Mg FORMULA 23613150 A 752 754 Zn FORMULA 23613150 A 987 989 Cu FORMULA 23613450 A 0 18 Polysilsesquioxane FAMILY 23613450 A 1014 1020 Gd-PSQ FORMULA 23613450 A 1081 1088 Gd(III) FORMULA 23613450 A 109 125 trialkoxysilanes FAMILY 23613450 A 1152 1160 cysteine TRIVIAL 23613450 A 1165 1176 glutathione TRIVIAL 23613450 A 1205 1211 Gd-PSQ FORMULA 23613450 A 1317 1319 Gd FORMULA 23613450 A 1364 1370 Gd-PSQ FORMULA 23613450 A 1531 1540 anisamide TRIVIAL 23613450 A 1682 1684 Gd FORMULA 23613450 A 20 23 PSQ ABBREVIATION 23613450 A 288 291 PSQ ABBREVIATION 23613450 A 347 354 Gd(III) FORMULA 23613450 A 459 478 bis(trialkoxysilyl) FAMILY 23613450 A 494 533 Gd(III) diethylenetriamine pentaacetate SYSTEMATIC 23613450 A 535 542 Gd-DTPA FORMULA 23613450 A 555 564 disulfide SYSTEMATIC 23613450 A 621 627 Gd-PSQ FORMULA 23613450 A 710 716 Gd-PSQ FORMULA 23613450 A 776 783 Gd-DTPA FORMULA 23613450 T 14 32 Polysilsesquioxane FAMILY 23613484 A 100 106 copper SYSTEMATIC 23613484 A 108 114 Cu(2+) FORMULA 23613484 A 117 123 nickel SYSTEMATIC 23613484 A 125 131 Ni(2+) FORMULA 23613484 A 134 138 zinc SYSTEMATIC 23613484 A 140 146 Zn(2+) FORMULA 23613484 A 158 164 Pb(2+) FORMULA 23613484 A 83 89 cobalt SYSTEMATIC 23613484 A 91 97 Co(2+) FORMULA 23613484 T 28 73 2-(2,6-dichlorobenzylideneamino) benzenethiol SYSTEMATIC 23614367 A 157 165 tyrosine TRIVIAL 23614395 A 18 39 diterpenoid glycoside FAMILY 23614395 A 223 237 arjunglucoside TRIVIAL 23614395 A 246 271 kaempferol-3-O-rutinoside SYSTEMATIC 23614395 A 354 358 (1)H FORMULA 23614395 A 363 368 (13)C FORMULA 23614395 A 51 66 glaucocalyxin G TRIVIAL 23614395 A 6 17 ent-kaurane TRIVIAL 23614395 A 95 104 n-butanol SYSTEMATIC 23614395 T 18 39 diterpenoid glycoside FAMILY 23614395 T 6 17 ent-kaurane TRIVIAL 23614566 A 1006 1010 dCDP ABBREVIATION 23614566 A 1013 1023 anandamide TRIVIAL 23614566 A 1025 1050 N-acetylglucosaminylamine SYSTEMATIC 23614566 A 1076 1096 stearoyl-L-carnitine TRIVIAL 23614566 A 183 192 serotonin TRIVIAL 23614566 A 691 700 serotonin TRIVIAL 23614566 A 705 731 5-hydroxyindoleacetic acid SYSTEMATIC 23614566 A 807 816 harmaline TRIVIAL 23614566 A 925 936 L-carnitine TRIVIAL 23614566 A 938 956 acetyl-L-carnitine SYSTEMATIC 23614566 A 958 974 pantothenic acid TRIVIAL 23614566 A 976 1004 2'-deoxycytidine diphosphate SYSTEMATIC 23614663 A 1420 1426 silica TRIVIAL 23614663 A 145 153 silicate FAMILY 23614663 A 323 329 Silica TRIVIAL 23614663 A 806 812 silica TRIVIAL 23614663 T 63 69 Silica TRIVIAL 23614730 A 1031 1042 prallethrin TRIVIAL 23614730 A 1495 1497 NO FORMULA 23614730 A 1499 1502 MDA ABBREVIATION 23614730 A 1616 1627 prallethrin TRIVIAL 23614730 A 1715 1725 pyrethroid FAMILY 23614730 A 189 199 pyrethroid FAMILY 23614730 A 325 335 pyrethroid FAMILY 23614730 A 359 370 prallethrin TRIVIAL 23614730 A 618 629 prallethrin TRIVIAL 23614730 A 715 723 creatine TRIVIAL 23614730 A 774 784 superoxide TRIVIAL 23614730 A 802 814 nitric oxide SYSTEMATIC 23614730 A 816 818 NO FORMULA 23614730 A 821 836 malondialdehyde TRIVIAL 23614730 A 838 841 MDA ABBREVIATION 23614730 A 920 932 carbohydrate FAMILY 23614896 A 418 428 Novobiocin TRIVIAL 23615073 A 1093 1102 vitamin C TRIVIAL 23615073 A 1123 1132 vitamin C TRIVIAL 23615073 A 1236 1245 vitamin C TRIVIAL 23615073 A 174 183 vitamin C TRIVIAL 23615073 A 427 436 vitamin C TRIVIAL 23615073 A 750 759 vitamin C TRIVIAL 23615073 A 942 951 vitamin C TRIVIAL 23615073 T 0 9 Vitamin C TRIVIAL 23615124 A 1008 1012 DPPH ABBREVIATION 23615124 A 1014 1043 2,2-diphenyl-1-picrylhydrazyl SYSTEMATIC 23615124 A 1049 1053 ABTS ABBREVIATION 23615124 A 1055 1103 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonate SYSTEMATIC 23615124 A 1869 1880 gallic acid TRIVIAL 23615124 A 1882 1889 egallic FAMILY 23615124 A 2068 2078 flavonoids FAMILY 23615124 A 2277 2281 DPPH ABBREVIATION 23615124 A 2312 2316 ABTS ABBREVIATION 23615124 A 2329 2333 MeOH FORMULA 23615124 A 2369 2373 DPPH ABBREVIATION 23615124 A 2403 2407 ABTS ABBREVIATION 23615124 A 860 871 gallic acid TRIVIAL 23615124 A 873 885 ellagic acid TRIVIAL 23615124 A 887 894 tannins FAMILY 23615124 A 899 908 flavonols FAMILY 23615124 T 14 25 polyphenols FAMILY 23615471 A 0 28 Caffeic acid phenethyl ester SYSTEMATIC 23615471 A 1001 1005 CAPE ABBREVIATION 23615471 A 132 136 CAPE ABBREVIATION 23615471 A 273 277 CAPE ABBREVIATION 23615471 A 30 34 CAPE ABBREVIATION 23615471 A 415 419 CAPE ABBREVIATION 23615471 A 474 481 phospho SYSTEMATIC 23615471 A 486 489 Ser FORMULA 23615471 A 494 501 phospho SYSTEMATIC 23615471 A 537 544 phospho SYSTEMATIC 23615471 A 558 565 phospho SYSTEMATIC 23615471 A 587 594 phospho SYSTEMATIC 23615471 A 613 620 phospho SYSTEMATIC 23615471 A 624 627 Ser FORMULA 23615471 A 782 786 CAPE ABBREVIATION 23615471 A 827 831 CAPE ABBREVIATION 23615471 A 836 850 5-fluorouracil SYSTEMATIC 23615471 T 0 28 Caffeic Acid Phenethyl Ester SYSTEMATIC 23615708 A 313 321 flumorph TRIVIAL 23615708 A 56 64 flumorph TRIVIAL 23615708 A 677 685 flumorph TRIVIAL 23615708 T 35 43 flumorph TRIVIAL 23615905 A 1080 1087 glucose TRIVIAL 23615905 A 1150 1153 TCA ABBREVIATION 23615905 A 1198 1206 ectoines FAMILY 23615905 A 237 241 NaCl FORMULA 23615905 A 294 302 ectoines FAMILY 23615905 A 405 408 TCA ABBREVIATION 23615905 A 628 635 glucose TRIVIAL 23615905 A 738 747 gluconate TRIVIAL 23615905 A 749 757 pyruvate TRIVIAL 23615905 A 762 769 acetate SYSTEMATIC 23615905 A 805 854 [1-13C]-, [2-13C]-, [6-13C]- and [U-13C6]-glucose MULTIPLE 23615905 A 858 864 carbon SYSTEMATIC 23615905 A 948 956 ectoines FAMILY 23615905 A 975 982 glucose TRIVIAL 23616352 A 234 242 arginine TRIVIAL 23616352 A 266 269 ATP ABBREVIATION 23616352 A 47 50 ATP ABBREVIATION 23617223 A 222 232 paclitaxel TRIVIAL 23617223 A 275 278 Pax ABBREVIATION 23617223 A 531 541 paclitaxel TRIVIAL 23617223 A 635 645 paclitaxel TRIVIAL 23617223 A 647 650 Pax ABBREVIATION 23617223 A 93 103 paclitaxel TRIVIAL 23617223 T 21 31 Paclitaxel TRIVIAL 23617391 A 1497 1502 O-CH2 FORMULA 23617391 A 214 250 2'-O,4'-C-methylene-β-d-ribofuranose SYSTEMATIC 23617391 A 265 301 2'-O,4'-C-methylene-α-l-ribofuranose SYSTEMATIC 23617391 A 73 78 O-CH2 FORMULA 23617391 A 933 944 deoxyribose SYSTEMATIC 23617391 A 945 950 sugar FAMILY 23617391 A 95 109 furanose sugar FAMILY 23617426 A 1010 1015 boron SYSTEMATIC 23617426 A 104 109 boron SYSTEMATIC 23617426 A 928 933 boron SYSTEMATIC 23617429 A 1030 1035 boron SYSTEMATIC 23617429 A 111 116 Boron SYSTEMATIC 23617429 A 25 30 boron SYSTEMATIC 23617429 A 414 424 bortezomib TRIVIAL 23617429 A 426 433 Velcade TRIVIAL 23617429 A 474 479 boron SYSTEMATIC 23617429 A 629 634 boron SYSTEMATIC 23617429 A 74 79 boron SYSTEMATIC 23617429 A 786 791 boron SYSTEMATIC 23617429 A 851 856 boron SYSTEMATIC 23617429 T 0 5 Boron SYSTEMATIC 23617431 A 266 271 boron SYSTEMATIC 23617431 A 301 306 boron SYSTEMATIC 23617431 A 339 361 boronated carbohydrate FAMILY 23617431 A 549 558 carborane SYSTEMATIC 23617431 A 570 583 carbohydrates FAMILY 23617431 A 83 88 Boron SYSTEMATIC 23617431 T 0 22 Boronated carbohydrate FAMILY 23617431 T 48 53 boron SYSTEMATIC 23617539 A 176 183 citrate FAMILY 23617539 A 211 213 Au FORMULA 23617539 A 238 257 polyethylene glycol SYSTEMATIC 23617539 A 259 262 PEG ABBREVIATION 23617539 A 369 372 PEG ABBREVIATION 23617539 A 421 428 citrate FAMILY 23617539 A 637 639 Au FORMULA 23617539 A 712 715 PEG ABBREVIATION 23617539 A 837 839 Au FORMULA 23617539 A 986 988 Au FORMULA 23617539 A 996 999 PEG ABBREVIATION 23617615 A 1039 1050 hydrocarbon FAMILY 23617615 A 1216 1223 lipid A TRIVIAL 23617615 A 236 243 lipid A TRIVIAL 23617615 A 400 407 lipid A TRIVIAL 23617615 A 429 435 sugars FAMILY 23617615 A 870 881 hydrocarbon FAMILY 23617725 A 1026 1036 vancomycin TRIVIAL 23617725 A 1046 1051 N-Boc FORMULA 23617725 A 1052 1062 vancomycin TRIVIAL 23617725 A 107 120 aryl chloride FAMILY 23617725 A 135 147 boronic acid SYSTEMATIC 23617725 A 204 214 vancomycin TRIVIAL 23617725 A 336 347 D-Ala-D-Ala FORMULA 23617725 A 37 47 vancomycin TRIVIAL 23617725 A 528 557 chloro substituted vancomycin FAMILY 23617725 A 631 633 Cl FORMULA 23617725 A 637 639 CN FORMULA 23617725 A 643 646 OMe FORMULA 23617725 A 752 762 vancomycin TRIVIAL 23617725 A 800 804 VanB ABBREVIATION 23617725 T 24 34 Vancomycin TRIVIAL 23617725 T 42 55 Aryl Chloride FAMILY 23618899 A 1201 1209 arsenite SYSTEMATIC 23618899 A 1277 1285 arsenite SYSTEMATIC 23618899 A 1349 1357 arsenite SYSTEMATIC 23618899 A 147 154 arsenic SYSTEMATIC 23618899 A 1592 1600 arsenite SYSTEMATIC 23618899 A 441 449 arsenite SYSTEMATIC 23618899 A 795 803 arsenite SYSTEMATIC 23618899 A 979 987 arsenite SYSTEMATIC 23618899 T 60 68 arsenite SYSTEMATIC 23618901 A 1571 1579 SB431542 IDENTIFIER 23618901 A 1866 1874 Nicotine TRIVIAL 23619006 A 0 4 TCDD ABBREVIATION 23619006 A 1069 1085 lithium chloride SYSTEMATIC 23619006 A 1142 1146 TCDD ABBREVIATION 23619006 A 1419 1423 TCDD ABBREVIATION 23619006 A 177 181 TCDD ABBREVIATION 23619006 A 301 305 TCDD ABBREVIATION 23619006 A 608 612 TCDD ABBREVIATION 23619006 A 689 693 TCDD ABBREVIATION 23619006 A 864 868 TCDD ABBREVIATION 23619006 A 888 892 TCDD ABBREVIATION 23619006 T 0 12 2,3,7,8-TCDD SYSTEMATIC 23619018 A 1297 1305 baicalin TRIVIAL 23619018 A 1307 1316 berberine TRIVIAL 23619018 A 1318 1328 wogonoside TRIVIAL 23619018 A 1330 1337 wogonin TRIVIAL 23619018 A 1343 1348 rhein TRIVIAL 23619018 A 1400 1409 coptisine TRIVIAL 23619018 A 1411 1424 jatrorrhizine TRIVIAL 23619018 A 1426 1435 palmatine TRIVIAL 23619018 A 1437 1446 berberine TRIVIAL 23619018 A 1448 1457 baicalein TRIVIAL 23619018 A 1462 1468 emodin TRIVIAL 23619018 A 362 391 trinitrobenzene sulfonic acid SYSTEMATIC 23619018 A 393 397 TNBS ABBREVIATION 23619020 A 1387 1393 oxygen SYSTEMATIC 23619020 A 1466 1482 N-acetylcysteine SYSTEMATIC 23619020 A 1484 1487 NAC ABBREVIATION 23619020 A 688 691 MTT ABBREVIATION 23619020 A 854 862 tyrosine TRIVIAL 23619028 A 30 38 warfarin TRIVIAL 23619028 A 40 50 dabigatran TRIVIAL 23619028 A 510 518 apixaban TRIVIAL 23619028 A 52 63 rivaroxaban TRIVIAL 23619028 A 520 530 dabigatran TRIVIAL 23619028 A 535 546 rivaroxaban TRIVIAL 23619028 A 68 76 apixaban TRIVIAL 23619028 A 707 715 warfarin TRIVIAL 23619028 A 736 744 apixaban TRIVIAL 23619028 A 947 955 apixaban TRIVIAL 23619028 T 29 39 dabigatran TRIVIAL 23619028 T 41 52 rivaroxaban TRIVIAL 23619028 T 54 62 apixaban TRIVIAL 23619028 T 67 75 warfarin TRIVIAL 23619284 A 0 10 Tandutinib TRIVIAL 23619284 A 116 126 tandutinib TRIVIAL 23619284 A 185 195 Tandutinib TRIVIAL 23619284 A 333 344 doxorubicin TRIVIAL 23619284 A 346 359 rhodamine 123 TRIVIAL 23619284 A 35 43 tyrosine TRIVIAL 23619284 A 364 383 [H(3)] mitoxantrone SYSTEMATIC 23619284 A 428 438 tandutinib TRIVIAL 23619284 A 487 499 mitoxantrone TRIVIAL 23619284 A 553 563 tandutinib TRIVIAL 23619284 T 0 10 Tandutinib TRIVIAL 23619284 T 12 18 MLN518 IDENTIFIER 23619284 T 19 26 CT53518 IDENTIFIER 23619284 T 86 89 ATP ABBREVIATION 23619386 A 0 9 Rapamycin TRIVIAL 23619386 A 1070 1084 seco-rapamycin TRIVIAL 23619386 A 1142 1151 rapamycin TRIVIAL 23619386 A 1203 1212 rapamycin TRIVIAL 23619386 A 1373 1382 rapamycin TRIVIAL 23619386 A 141 150 rapamycin TRIVIAL 23619386 A 255 264 Rapamycin TRIVIAL 23619386 A 683 692 rapamycin TRIVIAL 23619386 A 900 909 rapamycin TRIVIAL 23619386 T 0 9 Rapamycin TRIVIAL 23619527 A 147 154 lithium SYSTEMATIC 23619527 A 1529 1536 lithium SYSTEMATIC 23619527 A 332 339 lithium SYSTEMATIC 23619527 A 484 491 lithium SYSTEMATIC 23619527 A 652 659 lithium SYSTEMATIC 23619527 A 737 744 lithium SYSTEMATIC 23619527 A 922 929 lithium SYSTEMATIC 23619527 T 96 103 lithium SYSTEMATIC 23620134 A 29 82 meso-5,10,15,20-tetrakis(undecyl)porphyrin copper(ii) SYSTEMATIC 23620134 A 431 439 graphite TRIVIAL 23620134 A 670 675 alkyl FAMILY 23620134 A 88 96 graphite TRIVIAL 23620134 A 97 112 1-octanoic acid SYSTEMATIC 23620134 T 16 25 porphyrin FAMILY 23620303 A 1324 1330 hexane SYSTEMATIC 23620303 A 1369 1377 methanol SYSTEMATIC 23620303 A 1379 1386 toluene TRIVIAL 23620303 A 1388 1408 carbon tetrachloride SYSTEMATIC 23620303 A 1410 1417 ethanol SYSTEMATIC 23620303 A 1422 1429 acetone SYSTEMATIC 23620303 A 1438 1444 hexane SYSTEMATIC 23620303 A 1488 1491 C-H FORMULA 23620303 A 1632 1639 toluene TRIVIAL 23620303 A 1653 1673 carbon tetrachloride SYSTEMATIC 23620303 A 1683 1690 toluene TRIVIAL 23620303 A 1747 1750 C-H FORMULA 23620303 A 1798 1805 silicon SYSTEMATIC 23620303 A 237 244 silicon SYSTEMATIC 23620303 A 426 429 C-H FORMULA 23620303 A 431 434 N-H FORMULA 23620303 A 436 439 O-H FORMULA 23620303 A 441 444 C-C FORMULA 23620303 A 446 449 N-O FORMULA 23620303 A 451 452 C FORMULA 23620303 A 483 484 O FORMULA 23620303 A 490 491 C FORMULA 23620303 A 522 523 N FORMULA 23620303 A 715 730 silicon dioxide SYSTEMATIC 23620303 A 787 794 silicon SYSTEMATIC 23620303 T 65 72 silicon SYSTEMATIC 23620436 A 1031 1034 MNU ABBREVIATION 23620436 A 1037 1049 testosterone TRIVIAL 23620436 A 1308 1311 MNU ABBREVIATION 23620436 A 435 438 MNU ABBREVIATION 23620436 A 464 476 testosterone TRIVIAL 23620436 A 894 897 MNU ABBREVIATION 23620484 A 0 5 AR-67 IDENTIFIER 23620484 A 1048 1059 carboxylate SYSTEMATIC 23620484 A 1166 1173 lactone FAMILY 23620484 A 1209 1220 carboxylate SYSTEMATIC 23620484 A 1338 1343 AR-67 IDENTIFIER 23620484 A 1344 1351 lactone FAMILY 23620484 A 1374 1379 AR-67 IDENTIFIER 23620484 A 1416 1421 AR-67 IDENTIFIER 23620484 A 1422 1433 carboxylate SYSTEMATIC 23620484 A 153 166 camptothecins FAMILY 23620484 A 22 34 camptothecin TRIVIAL 23620484 A 346 351 AR-67 IDENTIFIER 23620484 A 396 401 AR-67 IDENTIFIER 23620484 A 511 516 AR-67 IDENTIFIER 23620484 A 517 524 lactone FAMILY 23620484 A 644 649 AR-67 IDENTIFIER 23620484 A 650 661 carboxylate SYSTEMATIC 23620484 A 801 806 AR-67 IDENTIFIER 23620484 A 807 814 lactone FAMILY 23620484 A 990 995 AR-67 IDENTIFIER 23620484 A 996 1007 carboxylate SYSTEMATIC 23620484 T 81 93 Camptothecin TRIVIAL 23620484 T 94 99 AR-67 IDENTIFIER 23620529 A 516 522 sodium SYSTEMATIC 23620529 A 592 596 urea TRIVIAL 23620529 A 597 605 nitrogen SYSTEMATIC 23621317 A 309 330 poly(ethylene glycol) SYSTEMATIC 23621317 A 332 335 PEG ABBREVIATION 23621317 A 392 397 sugar FAMILY 23621317 A 507 517 iron oxide SYSTEMATIC 23621317 A 594 597 PEG ABBREVIATION 23621317 T 16 21 Sugar FAMILY 23621317 T 37 40 PEG ABBREVIATION 23621381 A 1156 1167 sitagliptin TRIVIAL 23621381 A 1169 1181 vildagliptin TRIVIAL 23621381 A 1183 1194 saxagliptin TRIVIAL 23621381 A 1196 1206 alogliptin TRIVIAL 23621381 A 1212 1223 linagliptin TRIVIAL 23621381 A 1341 1348 glucose TRIVIAL 23621381 A 192 199 glucose TRIVIAL 23621381 A 556 567 sitagliptin TRIVIAL 23621381 A 569 581 vildagliptin TRIVIAL 23621381 A 583 594 saxagliptin TRIVIAL 23621381 A 596 606 alogliptin TRIVIAL 23621381 A 612 623 linagliptin TRIVIAL 23621381 A 807 818 sitagliptin TRIVIAL 23621381 A 823 835 vildagliptin TRIVIAL 23621381 A 892 903 sitagliptin TRIVIAL 23621464 A 12 24 microcystins FAMILY 23621464 A 309 320 microcystin FAMILY 23621464 A 450 461 microcystin FAMILY 23621464 A 808 820 microcystins FAMILY 23621464 A 846 857 microcystin FAMILY 23621464 A 882 893 microcystin FAMILY 23621464 T 25 37 microcystins FAMILY 23621524 A 1000 1002 I2 FORMULA 23621524 A 1009 1016 Ar'BiI2 FAMILY 23621524 A 1033 1040 quinone FAMILY 23621524 A 1042 1088 3,3',5,5'-tetra-tert-butyl-4,4'-diphenoquinone SYSTEMATIC 23621524 A 109 132 Ar'Bi(C6H2tBu2-3,5-O-4) FAMILY 23621524 A 144 162 2,6-(Me2NCH2)2C6H3 SYSTEMATIC 23621524 A 265 268 CO2 FORMULA 23621524 A 273 276 COS FORMULA 23621524 A 282 286 Bi-C FORMULA 23621524 A 30 37 oxyaryl FAMILY 23621524 A 316 323 oxyaryl FAMILY 23621524 A 433 440 oxyaryl FAMILY 23621524 A 468 482 oxyarylcarboxy FAMILY 23621524 A 487 505 oxyarylthiocarboxy FAMILY 23621524 A 56 75 (C6H2tBu2-3,5-O-4)2 SYSTEMATIC 23621524 A 568 603 Ar'Bi[O2C(C6H2tBu2-3-5-O-4)-κ2O,O'] FAMILY 23621524 A 611 645 Ar'Bi[OSC(C6H2tBu2-3-5-O-4)-κ2O,S] FAMILY 23621524 A 664 677 Silyl halides FAMILY 23621524 A 682 695 pseudohalides FAMILY 23621524 A 697 702 R3SiX FAMILY 23621524 A 708 710 Cl FORMULA 23621524 A 712 714 CN FORMULA 23621524 A 716 718 N3 FORMULA 23621524 A 724 726 Me FORMULA 23621524 A 728 730 Ph FORMULA 23621524 A 764 771 bismuth SYSTEMATIC 23621524 A 776 780 R3Si FAMILY 23621524 A 788 795 oxyaryl FAMILY 23621524 A 796 802 oxygen SYSTEMATIC 23621524 A 811 841 Ar'Bi(X)(C6H2tBu2-3,5-OSiR3-4) FAMILY 23621524 A 85 93 Bi3+ NCN FORMULA 23621524 A 918 923 R3SiX FAMILY 23621524 A 936 943 Ar'BiX2 FAMILY 23621524 A 958 975 R3SiOC6H3tBu2-2,6 FAMILY 23621524 T 117 150 [2,6-(Me2NCH2)2C6H3]Bi(C6H2tBu2O) FORMULA 23621524 T 13 16 CO2 FORMULA 23621524 T 21 24 COS FORMULA 23621524 T 30 34 Bi-C FORMULA 23621524 T 58 69 Bismuth NCN SYSTEMATIC 23621524 T 91 98 Oxyaryl FAMILY 23621573 A 161 170 acetylene SYSTEMATIC 23621573 A 268 278 vinylidene SYSTEMATIC 23621573 A 536 542 :C=CH2 FORMULA 23621573 A 562 567 vinyl FAMILY 23621573 A 60 70 vinylidene SYSTEMATIC 23621573 A 669 679 vinylidene SYSTEMATIC 23621573 A 72 78 H2C=C: FORMULA 23621573 A 915 918 CCH FORMULA 23621573 T 119 125 :C=CH2 FORMULA 23621573 T 32 42 Vinylidene SYSTEMATIC 23621573 T 43 52 Acetylene SYSTEMATIC 23621647 A 358 380 poly(3-hexylthiophene) SYSTEMATIC 23621647 A 382 386 P3HT ABBREVIATION 23621647 A 392 434 [6,6]-phenyl C61 butyric acid methyl ester SYSTEMATIC 23621647 A 436 440 PCBM ABBREVIATION 23621647 A 539 543 P3HT ABBREVIATION 23621647 A 555 559 PCBM ABBREVIATION 23621647 A 618 622 P3HT ABBREVIATION 23621647 A 623 627 PCBM ABBREVIATION 23621647 A 643 675 poly(3,4-ethylenedioxythiophene) SYSTEMATIC 23621647 A 676 698 poly(styrenesulfonate) FAMILY 23621647 A 700 705 PEDOT ABBREVIATION 23621647 A 706 709 PSS ABBREVIATION 23621647 A 836 845 fullerene TRIVIAL 23621647 T 81 90 Fullerene TRIVIAL 23621689 A 0 9 Hydrazide SYSTEMATIC 23621689 A 10 19 hydrazone FAMILY 23621689 A 167 176 hydrazide SYSTEMATIC 23621689 A 394 403 hydrazide SYSTEMATIC 23621689 A 404 413 hydrazone FAMILY 23621689 T 0 10 Hydrazides FAMILY 23621689 T 11 21 Hydrazones FAMILY 23621768 A 1700 1724 Chlorpheniramine Maleate TRIVIAL 23621768 A 344 368 Chlorpheniramine Maleate TRIVIAL 23621768 A 374 386 Eudragit EPO TRIVIAL 23621768 A 46 70 Chlorpheniramine Maleate TRIVIAL 23621768 A 99 111 Eudragit EPO TRIVIAL 23621768 T 14 38 Chlorpheniramine Maleate TRIVIAL 23621769 A 1010 1013 PVA ABBREVIATION 23621769 A 1018 1033 sodium alginate SYSTEMATIC 23621769 A 110 113 PVA ABBREVIATION 23621769 A 1413 1416 PVA ABBREVIATION 23621769 A 1423 1438 sodium alginate SYSTEMATIC 23621769 A 458 461 PVA ABBREVIATION 23621769 A 462 477 sodium alginate SYSTEMATIC 23621769 A 526 529 PVA ABBREVIATION 23621769 A 570 585 sodium alginate SYSTEMATIC 23621769 A 91 108 polyvinyl alcohol SYSTEMATIC 23621769 A 912 915 PVA ABBREVIATION 23621813 A 103 116 cimilactone C TRIVIAL 23621813 A 33 51 yunnanterpenes A-F MULTIPLE 23621813 A 59 90 15,16-seco-cimiterpenes A and B MULTIPLE 23621813 A 9 19 triterpene FAMILY 23621813 T 0 11 Triterpenes FAMILY 23621840 A 166 179 cepharanthine TRIVIAL 23621840 A 425 437 oxyacanthine TRIVIAL 23621840 A 446 477 bisbenzylisoquinoline alkaloids FAMILY 23621840 A 494 508 methylenedioxy SYSTEMATIC 23621840 A 554 572 benzylisoquinoline SYSTEMATIC 23621840 A 577 594 seco-aristolactam TRIVIAL 23621840 A 627 657 bisbenzylisoquinoline alkaloid FAMILY 23621840 A 683 713 bisbenzylisoquinoline N-oxides FAMILY 23621840 A 8 39 bisbenzylisoquinoline alkaloids FAMILY 23621840 A 869 882 Cepharanthine TRIVIAL 23621840 T 10 41 Bisbenzylisoquinoline Alkaloids FAMILY 23623417 A 111 122 yuanhuacine TRIVIAL 23623417 A 128 139 yuanhuadine TRIVIAL 23623417 A 145 156 yuanhuahine TRIVIAL 23623417 A 162 175 genkwadaphnin TRIVIAL 23623417 A 181 193 genkwanine A TRIVIAL 23623417 A 199 211 genkwanine F TRIVIAL 23623417 A 221 233 genkwanine H TRIVIAL 23623417 A 262 270 methanol SYSTEMATIC 23623417 A 40 70 daphneresiniferins A (1) and B MULTIPLE 23623417 A 99 109 diterpenes FAMILY 23623417 T 25 46 daphnane diterpenoids FAMILY 23623491 A 12 37 pyrazolo[1,5-a]pyrimidine SYSTEMATIC 23623491 A 45 64 2-aminobenzothizole SYSTEMATIC 23623491 T 13 38 pyrazolo[1,5-a]pyrimidine SYSTEMATIC 23623491 T 46 64 aminobenzothiazole SYSTEMATIC 23623750 A 0 6 Flavin FAMILY 23623750 A 1052 1063 methimazole TRIVIAL 23623750 A 1068 1082 trimethylamine SYSTEMATIC 23623750 A 1107 1118 benzydamine TRIVIAL 23623750 A 1119 1120 N FORMULA 23623750 A 1326 1337 benzydamine TRIVIAL 23623750 A 1338 1339 N FORMULA 23623750 A 1443 1454 benzydamine TRIVIAL 23623750 A 346 356 Amino acid FAMILY 23623750 A 999 1010 benzydamine TRIVIAL 23623750 T 45 51 flavin FAMILY 23623790 A 1212 1222 piperidine SYSTEMATIC 23623790 A 1233 1246 N-di-isobutyl SYSTEMATIC 23623790 A 1256 1262 SCT-66 IDENTIFIER 23623790 A 1383 1389 SCT-66 IDENTIFIER 23623790 A 14 22 piperine TRIVIAL 23623790 A 1441 1449 piperine TRIVIAL 23623790 A 1585 1591 SCT-66 IDENTIFIER 23623790 A 166 189 gamma-aminobutyric acid SYSTEMATIC 23623790 A 191 195 GABA ABBREVIATION 23623790 A 424 428 GABA ABBREVIATION 23623790 A 437 445 chloride SYSTEMATIC 23623790 A 466 474 piperine TRIVIAL 23623790 A 479 485 SCT-66 IDENTIFIER 23623790 A 696 704 Piperine TRIVIAL 23623790 A 76 82 SCT-66 IDENTIFIER 23623790 A 83 152 ((2E,4E)-5-(1,3-benzodioxol-5-yl))-N,N-diisobutyl-2,4-pentadienamide) SYSTEMATIC 23623790 A 835 843 piperine TRIVIAL 23623790 T 29 37 piperine TRIVIAL 23623823 A 1208 1222 polyacrylamide SYSTEMATIC 23623838 A 1251 1254 NIC ABBREVIATION 23623838 A 1324 1332 nicotine TRIVIAL 23623838 A 374 381 cocaine TRIVIAL 23623838 A 386 397 amphetamine TRIVIAL 23623838 A 738 746 nicotine TRIVIAL 23623838 A 748 751 NIC ABBREVIATION 23623838 A 921 924 NIC ABBREVIATION 23623838 T 9 17 nicotine TRIVIAL 23623904 A 106 110 EtOH FORMULA 23623904 A 1104 1106 NO FORMULA 23623904 A 1261 1265 EtOH FORMULA 23623904 A 1588 1592 EtOH FORMULA 23623904 A 209 213 EtOH FORMULA 23623904 A 277 281 EtOH FORMULA 23623904 A 593 597 EtOH FORMULA 23623904 A 661 663 NO FORMULA 23623904 A 910 914 EtOH FORMULA 23623904 A 97 104 ethanol SYSTEMATIC 23623904 T 69 76 ethanol SYSTEMATIC 23624237 A 0 10 Porphyrins FAMILY 23624237 A 1101 1105 PPIX ABBREVIATION 23624237 A 1135 1139 PPIX ABBREVIATION 23624237 A 1181 1204 tetrapyrrole macrocycle FAMILY 23624237 A 1212 1222 propionate SYSTEMATIC 23624237 A 1269 1292 tetrapyrrole macrocycle FAMILY 23624237 A 1310 1320 propionate SYSTEMATIC 23624237 A 1331 1335 PPIX ABBREVIATION 23624237 A 1367 1370 ATP ABBREVIATION 23624237 A 161 171 Porphyrins FAMILY 23624237 A 335 352 protoporphyrin IX TRIVIAL 23624237 A 354 358 PPIX ABBREVIATION 23624237 A 431 435 PPIX ABBREVIATION 23624237 A 502 506 PPIX ABBREVIATION 23624237 A 617 621 PPIX ABBREVIATION 23624237 A 856 879 tetrapyrrole macrocycle FAMILY 23624237 A 888 898 propionate SYSTEMATIC 23624237 A 913 917 PPIX ABBREVIATION 23624237 A 955 977 adenosine triphosphate SYSTEMATIC 23624237 A 979 982 ATP ABBREVIATION 23624237 T 31 48 protoporphyrin IX TRIVIAL 23624326 A 738 749 polystyrene SYSTEMATIC 23624352 A 1368 1371 MTT ABBREVIATION 23624360 A 233 239 carbon SYSTEMATIC 23624360 T 36 42 carbon SYSTEMATIC 23624379 A 0 12 Chlorpyrifos TRIVIAL 23624379 A 1053 1062 vitamin E FAMILY 23624379 A 1066 1069 CPF ABBREVIATION 23624379 A 1271 1274 CPF ABBREVIATION 23624379 A 1301 1310 vitamin E FAMILY 23624379 A 1360 1363 CPF ABBREVIATION 23624379 A 176 179 CPF ABBREVIATION 23624379 A 277 280 CPF ABBREVIATION 23624379 A 335 344 vitamin E FAMILY 23624379 A 34 61 chlorinated organophosphate FAMILY 23624379 A 424 427 CPF ABBREVIATION 23624379 A 538 541 CPF ABBREVIATION 23624379 A 554 557 CPF ABBREVIATION 23624379 A 571 574 CPF ABBREVIATION 23624379 A 580 589 vitamin E FAMILY 23624379 A 629 632 CPF ABBREVIATION 23624379 A 729 732 CPF ABBREVIATION 23624379 A 785 791 oxygen SYSTEMATIC 23624379 A 825 851 8-hydroxy-2-deoxyguanosine SYSTEMATIC 23624379 A 856 871 malondialdehyde TRIVIAL 23624379 A 920 931 glutathione TRIVIAL 23624379 T 117 126 vitamin E FAMILY 23624379 T 28 40 chlorpyrifos TRIVIAL 23624422 A 589 595 nickel SYSTEMATIC 23624607 A 0 10 Fullerenes FAMILY 23624607 A 1066 1075 fullerene TRIVIAL 23624607 A 1267 1276 fullerene TRIVIAL 23624607 A 167 176 fullerene TRIVIAL 23624607 A 306 316 fullerenes FAMILY 23624607 A 384 390 oxygen SYSTEMATIC 23624607 A 41 47 carbon SYSTEMATIC 23624607 A 418 428 fullerenes FAMILY 23624607 A 491 501 fullerenes FAMILY 23624607 A 593 602 fullerene TRIVIAL 23624607 T 74 83 fullerene TRIVIAL 23624607 T 84 87 c60 TRIVIAL 23624811 A 21 34 acetylcholine SYSTEMATIC 23624811 A 432 440 nicotine TRIVIAL 23624811 A 872 880 nicotine TRIVIAL 23624811 T 24 37 acetylcholine SYSTEMATIC 23625273 A 1060 1069 phosphate SYSTEMATIC 23625273 A 1112 1122 phosphorus SYSTEMATIC 23625273 A 120 129 phosphate SYSTEMATIC 23625273 A 1200 1209 phosphate SYSTEMATIC 23625273 A 1272 1281 phosphate SYSTEMATIC 23625273 A 1302 1311 Aluminium SYSTEMATIC 23625273 A 1397 1404 Calcium SYSTEMATIC 23625273 A 166 175 phosphate SYSTEMATIC 23625273 A 1661 1689 calcium acetate or carbonate MULTIPLE 23625273 A 1830 1837 calcium SYSTEMATIC 23625273 A 1891 1898 calcium SYSTEMATIC 23625273 A 1933 1940 calcium SYSTEMATIC 23625273 A 1976 1983 calcium SYSTEMATIC 23625273 A 2050 2057 calcium SYSTEMATIC 23625273 A 2145 2152 calcium SYSTEMATIC 23625273 A 2266 2273 calcium SYSTEMATIC 23625273 A 2309 2318 sevelamer FAMILY 23625273 A 2320 2339 lanthanum carbonate SYSTEMATIC 23625273 A 2344 2353 magnesium SYSTEMATIC 23625273 A 2404 2411 calcium SYSTEMATIC 23625273 A 2436 2446 phosphorus SYSTEMATIC 23625273 A 2538 2547 Sevelamer FAMILY 23625273 A 2564 2571 calcium SYSTEMATIC 23625273 A 2583 2592 phosphate SYSTEMATIC 23625273 A 2744 2763 lanthanum carbonate SYSTEMATIC 23625273 A 2768 2777 magnesium SYSTEMATIC 23625273 A 2852 2861 lanthanum SYSTEMATIC 23625273 A 2878 2887 magnesium SYSTEMATIC 23625273 A 2965 2972 calcium SYSTEMATIC 23625273 A 2993 3000 calcium SYSTEMATIC 23625273 A 3130 3139 sevelamer FAMILY 23625273 A 3144 3153 lanthanum SYSTEMATIC 23625273 A 3208 3215 calcium SYSTEMATIC 23625273 A 3306 3315 phosphate SYSTEMATIC 23625273 A 347 357 phosphorus SYSTEMATIC 23625273 A 3507 3514 calcium SYSTEMATIC 23625273 A 3563 3573 phosphorus SYSTEMATIC 23625273 A 389 399 phosphorus SYSTEMATIC 23625273 A 718 727 phosphate SYSTEMATIC 23625273 A 755 765 phosphorus SYSTEMATIC 23625273 A 76 85 phosphate SYSTEMATIC 23625273 A 931 940 phosphate SYSTEMATIC 23625273 A 961 970 phosphate SYSTEMATIC 23625273 A 980 989 phosphate SYSTEMATIC 23625455 A 593 601 hydrogen SYSTEMATIC 23625693 A 516 527 rivaroxaban TRIVIAL 23625693 A 529 537 apixaban TRIVIAL 23625693 A 543 551 edoxaban TRIVIAL 23625804 A 0 10 Superoxide TRIVIAL 23625804 A 264 270 copper SYSTEMATIC 23625804 A 358 367 copper(I) SYSTEMATIC 23625804 A 628 637 disulfide SYSTEMATIC 23625804 A 694 703 cysteines FAMILY 23625804 A 904 910 copper SYSTEMATIC 23625804 T 115 124 Disulfide SYSTEMATIC 23625804 T 71 76 Cu(I) FORMULA 23625911 A 0 11 Ziprasidone TRIVIAL 23625911 A 1016 1026 metoprolol TRIVIAL 23625911 A 1031 1040 diltiazem TRIVIAL 23625911 A 1062 1073 ziprasidone TRIVIAL 23625911 A 1119 1129 metoprolol TRIVIAL 23625911 A 1134 1143 diltiazem TRIVIAL 23625911 A 1226 1237 ziprasidone TRIVIAL 23625911 A 174 184 metoprolol TRIVIAL 23625911 A 189 198 diltiazem TRIVIAL 23625911 A 202 213 ziprasidone TRIVIAL 23625911 A 400 411 ziprasidone TRIVIAL 23625911 A 470 481 ziprasidone TRIVIAL 23625911 A 494 504 metoprolol TRIVIAL 23625911 A 554 565 ziprasidone TRIVIAL 23625911 A 578 587 diltiazem TRIVIAL 23625911 T 0 10 Metoprolol TRIVIAL 23625911 T 15 24 diltiazem TRIVIAL 23625911 T 36 47 ziprasidone TRIVIAL 23625915 A 1014 1018 Ca2+ FORMULA 23625915 A 274 277 AMP ABBREVIATION 23625915 A 4 8 Ca2+ FORMULA 23625915 A 495 500 AICAR ABBREVIATION 23625915 A 538 544 serine TRIVIAL 23625915 A 582 586 Ca2+ FORMULA 23625915 A 603 608 AICAR ABBREVIATION 23625915 A 66 70 Ca2+ FORMULA 23625915 A 891 899 SB203580 IDENTIFIER 23625915 T 15 19 Ca2+ FORMULA 23625915 T 150 153 AMP ABBREVIATION 23626400 A 1045 1068 triamcinolone acetonide TRIVIAL 23626400 A 105 124 polyethylene glycol SYSTEMATIC 23626400 A 126 142 polycaprolactone SYSTEMATIC 23626400 A 143 153 polylatide FAMILY 23626400 A 156 159 PLA ABBREVIATION 23626400 A 160 163 PCL ABBREVIATION 23626400 A 164 167 PEG ABBREVIATION 23626400 A 168 171 PCL ABBREVIATION 23626400 A 172 175 PLA ABBREVIATION 23626400 A 251 259 steroids FAMILY 23626400 A 356 372 poly (L-lactide) FAMILY 23626400 A 374 378 PLLA ABBREVIATION 23626400 A 383 402 poly (D, L-lactide) FAMILY 23626400 A 404 409 PDLLA ABBREVIATION 23626400 A 499 522 triamcinolone acetonide TRIVIAL 23626400 A 568 571 PLA ABBREVIATION 23626400 A 572 575 PCL ABBREVIATION 23626400 A 576 579 PEG ABBREVIATION 23626400 A 580 583 PCL ABBREVIATION 23626400 A 584 587 PLA ABBREVIATION 23626400 A 629 632 PCL ABBREVIATION 23626400 A 633 636 PLA ABBREVIATION 23626400 A 674 697 triamcinolone acetonide TRIVIAL 23626400 A 77 87 polylatide FAMILY 23626400 A 797 820 triamcinolone acetonide TRIVIAL 23626400 A 88 104 polycaprolactone SYSTEMATIC 23626400 A 906 911 PDLLA ABBREVIATION 23626400 A 938 941 PCL ABBREVIATION 23626400 A 942 945 PEG ABBREVIATION 23626400 A 946 949 PCL ABBREVIATION 23626400 T 28 31 PLA ABBREVIATION 23626400 T 32 35 PCL ABBREVIATION 23626400 T 36 39 PEG ABBREVIATION 23626400 T 40 43 PCL ABBREVIATION 23626400 T 44 47 PLA ABBREVIATION 23627311 A 129 133 NMDA ABBREVIATION 23627311 A 270 284 acyclic amides FAMILY 23627311 A 306 328 tetrahydroisoquinoline SYSTEMATIC 23627311 A 499 505 Ca(2+) FORMULA 23627311 A 61 84 tetrahydroisoquinolines FAMILY 23627311 A 667 676 glutamate TRIVIAL 23627311 A 681 688 glycine TRIVIAL 23627311 A 726 730 NMDA ABBREVIATION 23627311 A 783 787 AMPA ABBREVIATION 23627311 A 789 796 kainate TRIVIAL 23627311 A 798 802 GABA ABBREVIATION 23627311 A 807 814 glycine TRIVIAL 23627311 A 959 963 NMDA ABBREVIATION 23627311 T 123 143 N-Methyl-D-Aspartate SYSTEMATIC 23627311 T 49 71 Tetrahydroisoquinoline SYSTEMATIC 23627352 A 456 480 pyrido[2,3-d]pyrimidines FAMILY 23627352 A 639 647 pivaloyl SYSTEMATIC 23627352 A 658 701 2,4-diamino-6-bromo-pyrido[2,3-d]pyrimidine SYSTEMATIC 23627352 T 50 73 pyrido[2,3-d]pyrimidine SYSTEMATIC 23627414 A 1149 1150 P FORMULA 23627414 A 125 128 H2O FORMULA 23627414 A 130 133 OF2 FORMULA 23627414 A 1300 1301 P FORMULA 23627414 A 135 139 OMe2 FORMULA 23627414 A 141 144 NH3 FORMULA 23627414 A 146 149 NF3 FORMULA 23627414 A 151 155 NMe3 FORMULA 23627414 A 157 160 H2S FORMULA 23627414 A 162 165 SF2 FORMULA 23627414 A 167 171 SMe2 FORMULA 23627414 A 173 176 PH3 FORMULA 23627414 A 178 181 PF3 FORMULA 23627414 A 183 187 PCl3 FORMULA 23627414 A 189 193 PMe3 FORMULA 23627414 A 308 313 AuPH3 FORMULA 23627414 A 315 320 AuPF3 FORMULA 23627414 A 325 331 AuPCl3 FORMULA 23627414 A 455 457 Au FORMULA 23627414 A 458 459 P FORMULA 23627414 A 592 594 Au FORMULA 23627414 A 608 610 Cu FORMULA 23627414 A 615 617 Ag FORMULA 23627414 A 686 689 PX3 FAMILY 23627414 A 710 713 SX2 FAMILY 23627414 A 718 721 NX3 FAMILY 23627414 A 722 725 OX2 FAMILY 23627414 A 796 807 Metal-thiol FAMILY 23627414 A 82 84 Cu FORMULA 23627414 A 832 838 AuSCH3 FORMULA 23627414 A 86 88 Ag FORMULA 23627414 A 94 96 Au FORMULA 23627414 A 972 974 Au FORMULA 23627637 A 24 56 transition metal dichalcogenides FAMILY 23627637 A 392 394 O2 FORMULA 23627637 A 402 405 H2O FORMULA 23627637 A 465 467 O2 FORMULA 23627637 A 475 478 H2O FORMULA 23627637 A 705 707 O2 FORMULA 23627637 A 715 718 H2O FORMULA 23627637 A 777 781 MoS2 FORMULA 23627637 A 786 791 MoSe2 FORMULA 23627637 A 959 963 WSe2 FORMULA 23627649 A 596 604 CoxNi1-x FAMILY 23627649 A 618 622 CeO2 FORMULA 23627649 A 623 629 SrTiO3 FORMULA 23627649 A 785 787 Ni FORMULA 23627649 A 797 805 CoxNi1-x FAMILY 23627670 A 1186 1197 amino acids FAMILY 23627670 A 140 156 α-O-disaccharide FAMILY 23627670 A 171 172 N FORMULA 23627670 A 182 191 threonine TRIVIAL 23627670 A 351 361 amino acid FAMILY 23627670 A 836 848 carbohydrate FAMILY 23627670 A 87 98 nonapeptide FAMILY 23627670 A 912 920 hydrogen SYSTEMATIC 23627699 A 110 116 silica TRIVIAL 23627699 A 1143 1152 PBDTT-DPP ABBREVIATION 23627699 A 1153 1159 PC60BM TRIVIAL 23627699 A 118 120 Au FORMULA 23627699 A 1181 1185 P3HT ABBREVIATION 23627699 A 1186 1192 PC60BM TRIVIAL 23627699 A 121 125 SiO2 FORMULA 23627699 A 1383 1392 PBDTT-DPP ABBREVIATION 23627699 A 1393 1399 PC60BM TRIVIAL 23627699 A 1569 1571 Au FORMULA 23627699 A 1572 1576 SiO2 FORMULA 23627699 A 1607 1611 P3HT ABBREVIATION 23627699 A 1612 1618 PC60BM TRIVIAL 23627699 A 1692 1701 PBDTT-DPP ABBREVIATION 23627699 A 1702 1708 PC60BM TRIVIAL 23627699 A 1916 1918 Au FORMULA 23627699 A 1919 1923 SiO2 FORMULA 23627699 A 284 290 silica TRIVIAL 23627699 A 318 320 Au FORMULA 23627699 A 38 63 octadecyltrimethoxysilane SYSTEMATIC 23627699 A 518 520 Au FORMULA 23627699 A 521 525 SiO2 FORMULA 23627699 A 560 564 OTMS ABBREVIATION 23627699 A 624 626 Au FORMULA 23627699 A 627 631 SiO2 FORMULA 23627699 A 65 69 OTMS ABBREVIATION 23627699 A 665 672 ethanol SYSTEMATIC 23627699 A 730 745 dichlorobenzene SYSTEMATIC 23627699 A 747 750 DCB ABBREVIATION 23627699 A 757 761 OTMS ABBREVIATION 23627699 A 777 779 Au FORMULA 23627699 A 780 784 SiO2 FORMULA 23627699 A 897 919 poly(3-hexylthiophene) SYSTEMATIC 23627699 A 920 962 [6,6]-phenyl-C61-butyric acid methyl ester SYSTEMATIC 23627699 A 964 968 P3HT ABBREVIATION 23627699 A 969 975 PCB60M SYSTEMATIC 23627699 A 994 1141 poly[2,6-4,8-di(5-ethylhexylthienyl)benzo[1,2-b;3,4-b]dithiophene-alt-5-dibutyloctyl-3,6-bis(5-bromothiophen-2-yl) pyrrolo[3,4-c]pyrrole-1,4-dione] FAMILY 23627699 T 44 46 Au FORMULA 23627699 T 47 51 SiO2 FORMULA 23627743 A 0 18 Poly(ethylenimine) FAMILY 23627743 A 1049 1052 PEI ABBREVIATION 23627743 A 1087 1090 PEI ABBREVIATION 23627743 A 1146 1149 PEI ABBREVIATION 23627743 A 1294 1298 NaCl FORMULA 23627743 A 1446 1449 PEI ABBREVIATION 23627743 A 1543 1546 PEI ABBREVIATION 23627743 A 1613 1616 PEI ABBREVIATION 23627743 A 1754 1757 PEI ABBREVIATION 23627743 A 1829 1832 PEI ABBREVIATION 23627743 A 20 23 PEI ABBREVIATION 23627743 A 349 352 PEI ABBREVIATION 23627743 A 434 437 PEI ABBREVIATION 23627743 A 789 792 PEI ABBREVIATION 23627743 A 862 865 PEI ABBREVIATION 23627743 A 913 916 PEI ABBREVIATION 23627743 A 948 951 PEI ABBREVIATION 23627743 T 113 116 PEI ABBREVIATION 23627743 T 54 72 poly(ethylenimine) FAMILY 23627743 T 74 77 PEI ABBREVIATION 23627804 A 1041 1044 ZCF ABBREVIATION 23627804 A 1148 1151 ZCF ABBREVIATION 23627804 A 1392 1395 PPF ABBREVIATION 23627804 A 1489 1492 PPF ABBREVIATION 23627804 A 395 398 PPF ABBREVIATION 23627804 A 444 447 PPF ABBREVIATION 23627804 A 50 74 poly(propylene fumarate) FAMILY 23627804 A 527 530 PPF ABBREVIATION 23627804 A 636 639 XTT ABBREVIATION 23627804 A 692 695 PPF ABBREVIATION 23627804 A 76 79 PPF ABBREVIATION 23627804 A 82 85 PPF ABBREVIATION 23627804 A 822 834 polyethylene SYSTEMATIC 23627804 A 925 937 polyurethane SYSTEMATIC 23627804 A 959 986 zinc diethyldithiocarbamate SYSTEMATIC 23627804 A 988 991 ZCF ABBREVIATION 23628456 A 0 13 Acetaminophen TRIVIAL 23628456 A 1066 1079 nitrotyrosine SYSTEMATIC 23628456 A 1176 1180 APAP ABBREVIATION 23628456 A 1247 1250 GSH ABBREVIATION 23628456 A 1284 1297 peroxynitrite SYSTEMATIC 23628456 A 1398 1402 APAP ABBREVIATION 23628456 A 15 19 APAP ABBREVIATION 23628456 A 234 238 APAP ABBREVIATION 23628456 A 326 330 APAP ABBREVIATION 23628456 A 469 480 glutathione TRIVIAL 23628456 A 482 485 GSH ABBREVIATION 23628456 A 672 675 GSH ABBREVIATION 23628456 A 780 786 oxygen SYSTEMATIC 23628456 A 818 821 GSH ABBREVIATION 23628456 A 871 880 glutamate TRIVIAL 23628456 A 881 889 cysteine TRIVIAL 23628456 A 939 951 nitric oxide SYSTEMATIC 23628456 T 54 67 acetaminophen TRIVIAL 23628456 T 97 108 glutathione TRIVIAL 23628762 A 896 901 amino FAMILY 23628791 A 1326 1328 Mn FORMULA 23628791 A 1377 1386 manganism SYSTEMATIC 23628791 A 253 262 manganism SYSTEMATIC 23628791 A 45 54 manganism SYSTEMATIC 23628791 A 460 462 Mn FORMULA 23628791 A 624 633 manganism SYSTEMATIC 23628791 A 689 691 Mn FORMULA 23628791 A 818 820 Mn FORMULA 23628791 A 929 931 Mn FORMULA 23628791 T 76 85 manganese SYSTEMATIC 23628841 A 652 681 2,2-bismethylolpropionic acid SYSTEMATIC 23628841 A 683 690 bis-MPA SYSTEMATIC 23628841 A 854 861 bis-MPA SYSTEMATIC 23628841 T 33 40 bis-MPA SYSTEMATIC 23629664 A 1006 1009 Na+ FORMULA 23629664 A 1031 1033 K+ FORMULA 23629664 A 1087 1089 H+ FORMULA 23629664 A 408 411 Na+ FORMULA 23629664 A 937 940 Na+ FORMULA 23629861 A 1014 1032 N-formylkynurenine SYSTEMATIC 23629861 A 1037 1047 kynurenine TRIVIAL 23629861 A 1304 1308 H2O2 FORMULA 23629861 A 1367 1371 H2O2 FORMULA 23629861 A 1372 1377 ONOO- FORMULA 23629861 A 1589 1593 H2O2 FORMULA 23629861 A 1594 1601 ONOO(-) FORMULA 23629861 A 1735 1739 H2O2 FORMULA 23629861 A 213 217 H2O2 FORMULA 23629861 A 222 235 peroxynitrite SYSTEMATIC 23629861 A 237 244 ONOO(-) FORMULA 23629861 A 593 600 ONOO(-) FORMULA 23629861 A 876 883 ONOO(-) FORMULA 23629861 A 952 956 H2O2 FORMULA 23629861 A 958 978 methionine sulfoxide SYSTEMATIC 23629861 A 984 994 tryptophan TRIVIAL 23629861 T 173 177 H2O2 FORMULA 23629861 T 29 33 H2O2 FORMULA 23629861 T 34 38 ONOO FORMULA 23629923 A 413 422 genistein TRIVIAL 23630137 A 92 100 luteolin TRIVIAL 23630137 T 45 53 Luteolin TRIVIAL 23630301 A 567 574 glucose TRIVIAL 23631440 A 14 41 pyrrolidine mercaptosulfide SYSTEMATIC 23631440 A 268 280 hydroxamates FAMILY 23631440 A 43 81 2-mercaptocyclopentane arylsulfonamide FAMILY 23631440 A 676 691 mercaptosulfide SYSTEMATIC 23631440 A 723 735 cyclopentane SYSTEMATIC 23631440 A 740 751 pyrrolidine SYSTEMATIC 23631440 A 87 127 3-mercapto-4-arylsulfonamido pyrrolidine FAMILY 23631440 A 948 968 mercaptosulfonamides FAMILY 23631440 T 49 70 3-Mercaptopyrrolidine SYSTEMATIC 23631463 A 1065 1072 alcohol FAMILY 23631463 A 139 146 alcohol FAMILY 23631463 A 233 249 aminoalkylindole FAMILY 23631463 A 262 269 JHW-073 IDENTIFIER 23631463 A 388 395 alcohol FAMILY 23631463 A 478 494 aminoalkylindole FAMILY 23631463 A 675 682 alcohol FAMILY 23631463 A 770 777 alcohol FAMILY 23631463 A 896 913 aminoalkylindoles FAMILY 23631463 T 140 147 Alcohol SYSTEMATIC 23631463 T 47 63 Aminoalkylindole FAMILY 23631494 A 32 43 Val-Pro-Pro FORMULA 23631494 A 528 537 enalapril TRIVIAL 23631494 A 539 548 captopril TRIVIAL 23631494 A 54 65 Ile-Pro-Pro FORMULA 23631494 A 760 773 8-isoprostane SYSTEMATIC 23631494 A 942 951 enalapril TRIVIAL 23631494 A 957 966 captopril TRIVIAL 23631494 T 23 34 Val-Pro-Pro FORMULA 23631494 T 39 50 Ile-Pro-Pro FORMULA 23631498 A 70 80 polyphenol FAMILY 23631528 A 1025 1033 paraoxon TRIVIAL 23631528 A 1090 1093 Glu FORMULA 23631528 A 1098 1101 Ser FORMULA 23631528 A 1236 1244 paraoxon TRIVIAL 23631528 A 1291 1294 Glu FORMULA 23631528 A 1296 1299 Ser FORMULA 23631528 A 1304 1307 His FORMULA 23631528 A 1525 1540 organophosphate FAMILY 23631528 A 161 164 Glu FORMULA 23631528 A 166 169 His FORMULA 23631528 A 174 177 Ser FORMULA 23631528 A 209 224 organophosphate FAMILY 23631528 A 226 234 paraoxon TRIVIAL 23631528 A 410 418 paraoxon TRIVIAL 23631528 A 455 466 amino acids FAMILY 23631528 A 496 507 amino acids FAMILY 23631528 A 637 645 paraoxon TRIVIAL 23631528 A 814 825 amino acids FAMILY 23631528 A 874 882 paraoxon TRIVIAL 23631528 T 55 63 paraoxon TRIVIAL 23631539 A 1157 1186 poly(lactic-co-glycolic acid) FAMILY 23631539 A 1187 1208 poly(ethylene glycol) SYSTEMATIC 23631539 A 1209 1238 poly(lactic-co-glycolic acid) FAMILY 23631539 A 1373 1382 cidofovir TRIVIAL 23631539 A 671 680 cidofovir TRIVIAL 23631590 A 25 36 polystyrene SYSTEMATIC 23631590 A 511 522 polystyrene SYSTEMATIC 23631590 A 601 612 polystyrene SYSTEMATIC 23631590 T 21 32 Polystyrene SYSTEMATIC 23631674 A 0 6 Silver SYSTEMATIC 23631674 A 184 186 Ag FORMULA 23631674 A 273 280 citrate FAMILY 23631674 A 374 376 Ag FORMULA 23631674 A 529 531 Ag FORMULA 23631674 A 642 644 Ag FORMULA 23631674 A 681 683 Au FORMULA 23631674 T 13 19 Silver SYSTEMATIC 23631736 A 0 12 Aminoalkenes FAMILY 23631736 A 115 142 {PhB(C5H4)(Ox(R))2}M(NMe2)2 FAMILY 23631736 A 1276 1279 N-H FORMULA 23631736 A 1407 1429 N-deutero-aminoalkenes FAMILY 23631736 A 148 150 Ti FORMULA 23631736 A 1496 1517 N-proteo-aminoalkenes FAMILY 23631736 A 152 154 Zr FORMULA 23631736 A 156 158 Hf FORMULA 23631736 A 160 165 Ox(R) ABBREVIATION 23631736 A 168 192 4,4-dimethyl-2-oxazoline SYSTEMATIC 23631736 A 1853 1856 C-N FORMULA 23631736 A 1861 1864 C-H FORMULA 23631736 A 1884 1887 N-H FORMULA 23631736 A 1916 1927 amidoalkene FAMILY 23631736 A 194 231 4S-isopropyl-5,5-dimethyl-2-oxazoline SYSTEMATIC 23631736 A 233 258 4S-tert-butyl-2-oxazoline SYSTEMATIC 23631736 A 333 354 N-heterocyclic amines FAMILY 23631736 A 535 557 Secondary aminopentene SYSTEMATIC 23631736 A 581 594 primary amine FAMILY 23631736 A 59 96 cyclopentadienylbis(oxazolinyl)borato SYSTEMATIC 23631736 A 620 632 Aminoalkenes FAMILY 23631736 A 668 687 zirconium monoamido SYSTEMATIC 23631736 A 696 734 {PhB(C5H4)(Ox(4S-iPr,Me2))2}Zr(NMe2)Cl FORMULA 23631736 A 740 796 cyclopentadienylmono(oxazolinyl)borato zirconium diamide SYSTEMATIC 23631736 A 797 834 {Ph2B(C5H4)(Ox(4S-iPr,Me2))}Zr(NMe2)2 FORMULA 23631736 T 24 33 Zirconium SYSTEMATIC 23631736 T 59 71 Aminoalkenes FAMILY 23631744 A 1012 1024 atorvastatin TRIVIAL 23631744 A 1098 1108 CP-778 875 IDENTIFIER 23631744 A 1174 1209 ortho- and para-hydroxyatorvastatin MULTIPLE 23631744 A 1258 1268 CP-778 875 IDENTIFIER 23631744 A 1270 1280 CP-778 875 IDENTIFIER 23631744 A 13 81 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid SYSTEMATIC 23631744 A 1355 1367 atorvastatin TRIVIAL 23631744 A 1433 1443 CP-778 875 IDENTIFIER 23631744 A 1533 1543 CP-778 875 IDENTIFIER 23631744 A 1737 1749 atorvastatin TRIVIAL 23631744 A 286 296 CP-778 875 IDENTIFIER 23631744 A 324 341 atorvastatin acid TRIVIAL 23631744 A 515 525 CP-778 875 IDENTIFIER 23631744 A 565 577 atorvastatin TRIVIAL 23631744 A 617 629 atorvastatin TRIVIAL 23631744 A 658 668 CP-778 875 IDENTIFIER 23631744 A 760 772 atorvastatin TRIVIAL 23631744 A 812 822 CP-778 875 IDENTIFIER 23631744 A 83 93 CP-778 875 IDENTIFIER 23631744 A 862 872 CP-778 875 IDENTIFIER 23631744 A 902 914 atorvastatin TRIVIAL 23631744 T 169 179 CP-778 875 IDENTIFIER 23631744 T 82 94 atorvastatin TRIVIAL 23631744 T 99 167 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid SYSTEMATIC 23631760 A 1101 1136 25-methoxydammarane-3β,12β,20-triol SYSTEMATIC 23631760 A 325 341 ammonium acetate SYSTEMATIC 23631760 A 353 365 acetonitrile SYSTEMATIC 23631760 A 40 51 25-OCH3-PPD SYSTEMATIC 23631760 A 498 517 20(R,S)-25-OCH3-PPD SYSTEMATIC 23631760 A 541 558 20(R,S)-25-OH-PPD SYSTEMATIC 23631760 A 622 641 20(R,S)-25-OCH3-PPD SYSTEMATIC 23631760 A 661 678 20(R,S)-25-OH-PPD SYSTEMATIC 23631760 A 789 815 20(R)- and (S)-25-OCH3-PPD MULTIPLE 23631760 A 907 922 20(S)-25-OH-PPD SYSTEMATIC 23631760 A 996 1011 20(R)-25-OH-PPD SYSTEMATIC 23631760 T 42 77 25-methoxydammarane-3β,12β,20-triol SYSTEMATIC 23631927 A 1047 1051 iron SYSTEMATIC 23631927 A 1172 1176 iron SYSTEMATIC 23631927 A 1293 1297 iron SYSTEMATIC 23631927 A 1346 1360 corticosterone TRIVIAL 23631927 A 186 190 iron SYSTEMATIC 23631927 A 317 321 iron SYSTEMATIC 23631927 A 343 347 Iron SYSTEMATIC 23631927 A 406 420 corticosterone TRIVIAL 23631927 A 62 66 iron SYSTEMATIC 23631927 A 633 647 corticosterone TRIVIAL 23631927 A 708 712 iron SYSTEMATIC 23631927 T 36 40 iron SYSTEMATIC 23632005 A 1005 1008 Gua ABBREVIATION 23632005 A 1056 1065 cisplatin TRIVIAL 23632005 A 1098 1101 Gua ABBREVIATION 23632005 A 1106 1109 Gua ABBREVIATION 23632005 A 1117 1139 thiamine pyrophosphate SYSTEMATIC 23632005 A 1173 1181 8-OH Gua SYSTEMATIC 23632005 A 1186 1189 Gua ABBREVIATION 23632005 A 1197 1205 thiamine TRIVIAL 23632005 A 1248 1270 thiamine pyrophosphate SYSTEMATIC 23632005 A 1322 1331 cisplatin TRIVIAL 23632005 A 1380 1388 thiamine TRIVIAL 23632005 A 151 160 cisplatin TRIVIAL 23632005 A 184 192 thiamine TRIVIAL 23632005 A 194 203 Cisplatin TRIVIAL 23632005 A 349 358 cisplatin TRIVIAL 23632005 A 39 61 thiamine pyrophosphate SYSTEMATIC 23632005 A 393 402 cisplatin TRIVIAL 23632005 A 474 494 thio barbituric acid SYSTEMATIC 23632005 A 622 633 glutathione TRIVIAL 23632005 A 63 66 TPP ABBREVIATION 23632005 A 635 638 GSH ABBREVIATION 23632005 A 644 654 superoxide TRIVIAL 23632005 A 672 675 TPP ABBREVIATION 23632005 A 775 784 cisplatin TRIVIAL 23632005 A 818 826 thiamine TRIVIAL 23632005 A 840 843 TPP ABBREVIATION 23632005 A 868 871 GSH ABBREVIATION 23632005 A 914 919 8-Gua SYSTEMATIC 23632005 A 921 928 guanine TRIVIAL 23632005 A 971 989 8-hydroxyl guanine SYSTEMATIC 23632005 A 991 999 8-OH Gua SYSTEMATIC 23632005 T 144 152 thiamine TRIVIAL 23632005 T 154 162 Thiamine TRIVIAL 23632005 T 167 189 thiamine pyrophosphate SYSTEMATIC 23632005 T 201 210 cisplatin TRIVIAL 23632005 T 34 56 thiamine pyrophosphate SYSTEMATIC 23632005 T 60 69 cisplatin TRIVIAL 23632006 A 1080 1082 Ag FORMULA 23632006 A 11 17 silver SYSTEMATIC 23632006 A 1199 1205 silver SYSTEMATIC 23632006 A 246 248 Ag FORMULA 23632006 A 254 261 Nanocid TRIVIAL 23632006 A 33 35 Ag FORMULA 23632006 A 347 353 silver SYSTEMATIC 23632006 A 485 492 Nanocid TRIVIAL 23632006 A 497 503 silver SYSTEMATIC 23632006 A 923 931 cortisol TRIVIAL 23632006 A 936 943 glucose TRIVIAL 23632006 A 954 961 Nanocid TRIVIAL 23632006 T 107 113 silver SYSTEMATIC 23632006 T 31 37 silver SYSTEMATIC 23632099 A 270 278 androgen FAMILY 23632304 A 0 12 Clothianidin TRIVIAL 23632304 A 1021 1033 clothianidin TRIVIAL 23632304 A 1071 1083 mecamylamine TRIVIAL 23632304 A 1093 1107 d-tubocurarine TRIVIAL 23632304 A 1155 1167 clothianidin TRIVIAL 23632304 A 1211 1218 calcium SYSTEMATIC 23632304 A 1273 1280 calcium SYSTEMATIC 23632304 A 1300 1304 cAMP ABBREVIATION 23632304 A 1315 1327 clothianidin TRIVIAL 23632304 A 1355 1368 acetylcholine SYSTEMATIC 23632304 A 1411 1418 calcium SYSTEMATIC 23632304 A 1436 1440 cAMP ABBREVIATION 23632304 A 186 199 acetylcholine SYSTEMATIC 23632304 A 269 281 Clothianidin TRIVIAL 23632304 A 315 327 imidacloprid TRIVIAL 23632304 A 383 387 cAMP ABBREVIATION 23632304 A 434 446 clothianidin TRIVIAL 23632304 A 491 495 cAMP ABBREVIATION 23632304 A 528 540 clothianidin TRIVIAL 23632304 A 597 609 Clothianidin TRIVIAL 23632304 A 659 671 clothianidin TRIVIAL 23632304 A 696 708 clothianidin TRIVIAL 23632304 A 721 725 cAMP ABBREVIATION 23632304 A 780 792 Clothianidin TRIVIAL 23632304 A 854 858 cAMP ABBREVIATION 23632304 A 930 942 clothianidin TRIVIAL 23632304 A 944 948 cAMP ABBREVIATION 23632304 T 0 7 Calcium SYSTEMATIC 23632304 T 137 150 acetylcholine SYSTEMATIC 23632304 T 25 29 cAMP ABBREVIATION 23632304 T 39 51 clothianidin TRIVIAL 23632310 A 273 290 glycyrrhizic acid TRIVIAL 23632310 A 32 49 Glycyrrhizic acid TRIVIAL 23632310 A 504 517 dexamethasone TRIVIAL 23632310 A 681 692 hematoxylin TRIVIAL 23632310 A 697 702 eosin FAMILY 23632310 T 28 45 Glycyrrhizic acid TRIVIAL 23632340 A 1031 1040 Fe(IV)oxo SYSTEMATIC 23632340 A 1059 1063 oxyl SYSTEMATIC 23632340 A 1121 1123 CH FORMULA 23632340 A 1139 1145 alkane FAMILY 23632340 A 562 565 C-H FORMULA 23632340 A 584 593 Fe(IV)oxo SYSTEMATIC 23632340 A 745 754 Fe(IV)oxo SYSTEMATIC 23632340 A 945 954 Fe(IV)oxo SYSTEMATIC 23632340 T 108 111 C-H FORMULA 23632448 A 1022 1025 CH4 FORMULA 23632448 A 1028 1031 CD4 FORMULA 23632448 A 1169 1176 methane SYSTEMATIC 23632448 A 636 643 methane SYSTEMATIC 23632448 A 92 99 methane SYSTEMATIC 23632448 T 47 54 methane SYSTEMATIC 23633618 A 214 224 amlodipine TRIVIAL 23633618 A 262 289 4-(4-chlorophenyl)imidazole SYSTEMATIC 23633618 A 516 526 paroxetine TRIVIAL 23633618 A 743 753 paroxetine TRIVIAL 23633618 A 75 85 paroxetine TRIVIAL 23633618 T 61 71 Paroxetine TRIVIAL 23634668 A 0 10 Methionine TRIVIAL 23634668 A 449 455 Mn(II) FORMULA 23634668 A 459 465 Zn(II) FORMULA 23634668 A 621 627 Co(II) FORMULA 23634668 A 64 74 methionine TRIVIAL 23634668 A 650 656 Co(II) FORMULA 23634668 A 719 746 2-(pyridin-2-yl)quinazoline SYSTEMATIC 23634668 A 854 860 Co(II) FORMULA 23634668 T 0 21 Pyridinylquinazolines FAMILY 23634668 T 48 58 Methionine TRIVIAL 23634707 A 145 156 metal-oxide FAMILY 23634759 A 450 466 anthrapyrazolone TRIVIAL 23634759 A 471 479 SP600125 IDENTIFIER 23634759 A 570 578 indazole SYSTEMATIC 23634759 A 673 681 indazole SYSTEMATIC 23634759 T 0 8 Indazole SYSTEMATIC 23634759 T 104 120 Anthrapyrazolone TRIVIAL 23634759 T 122 130 SP600125 IDENTIFIER 23635097 A 773 779 silver SYSTEMATIC 23635829 A 198 206 bis-DTPA ABBREVIATION 23635829 A 400 406 (68)Ga FORMULA 23635829 A 46 69 (68)Ga labeled bis-DOTA SYSTEMATIC 23635829 A 84 106 benzylidene-bis-indole SYSTEMATIC 23635829 T 39 62 (68)Ga labeled bis-DOTA SYSTEMATIC 23635829 T 63 114 3,3'-(benzylidene)-bis-(1H-indole-2-carbohydrazide) SYSTEMATIC 23636302 A 1739 1747 Nicotine TRIVIAL 23636302 A 209 217 nicotine TRIVIAL 23636302 A 38 46 nicotine TRIVIAL 23636302 A 543 551 nicotine TRIVIAL 23636302 A 707 715 nicotine TRIVIAL 23636302 T 88 96 nicotine TRIVIAL 23636640 A 1152 1164 vildagliptin TRIVIAL 23636640 A 1184 1196 vildagliptin TRIVIAL 23636640 A 1511 1523 vildagliptin TRIVIAL 23636640 A 539 551 vildagliptin TRIVIAL 23636640 A 734 741 glucose TRIVIAL 23636640 A 783 795 vildagliptin TRIVIAL 23636640 A 920 932 vildagliptin TRIVIAL 23636640 T 123 135 vildagliptin TRIVIAL 23636685 A 1087 1097 PT-ACRAMTU ABBREVIATION 23636685 A 1248 1258 PT-ACRAMTU ABBREVIATION 23636685 A 137 147 PT-ACRAMTU ABBREVIATION 23636685 A 148 176 ([PtCl(en)(ACRAMTU-S)](NO3)2 FORMULA 23636685 A 184 202 ethane-1,2-diamine SYSTEMATIC 23636685 A 204 211 ACRAMTU ABBREVIATION 23636685 A 214 265 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea SYSTEMATIC 23636685 A 267 277 PT-ACRAMTU ABBREVIATION 23636685 A 326 334 platinum SYSTEMATIC 23636685 A 430 438 acridine TRIVIAL 23636685 A 488 496 platinum SYSTEMATIC 23636685 A 559 569 PT-ACRAMTU ABBREVIATION 23636685 A 740 750 PT-ACRAMTU ABBREVIATION 23636685 A 939 946 ACRAMTU ABBREVIATION 23636685 T 14 22 Platinum SYSTEMATIC 23636685 T 23 31 Acridine TRIVIAL 23637347 A 609 620 cholesterol TRIVIAL 23638683 A 0 6 Helium SYSTEMATIC 23638683 A 150 152 He FORMULA 23638683 A 329 342 alkali metals FAMILY 23638683 A 572 585 alkali metals FAMILY 23638683 T 59 65 helium SYSTEMATIC 23638960 A 0 18 Methyl tortuoate D SYSTEMATIC 23638960 A 156 174 methyl tortuoate D SYSTEMATIC 23638960 A 438 451 lobophytone K TRIVIAL 23638960 A 63 78 bis-cembranoids FAMILY 23638960 A 711 722 ximaolide A TRIVIAL 23638960 T 23 41 methyl tortuoate D SYSTEMATIC 23638960 T 45 59 bis-cembranoid FAMILY 23639191 A 1098 1110 calycopterin TRIVIAL 23639191 A 1151 1163 calycopterin TRIVIAL 23639191 A 1199 1203 H2O2 FORMULA 23639191 A 1261 1273 calycopterin TRIVIAL 23639191 A 1320 1324 H2O2 FORMULA 23639191 A 1329 1333 H2O2 FORMULA 23639191 A 1349 1361 calycopterin TRIVIAL 23639191 A 1499 1511 calycopterin TRIVIAL 23639191 A 1528 1532 H2O2 FORMULA 23639191 A 1760 1772 calycopterin TRIVIAL 23639191 A 1810 1814 H2O2 FORMULA 23639191 A 1816 1828 calycopterin TRIVIAL 23639191 A 1851 1854 GSH ABBREVIATION 23639191 A 1965 1977 calycopterin TRIVIAL 23639191 A 1987 1991 H2O2 FORMULA 23639191 A 351 363 calycopterin TRIVIAL 23639191 A 368 372 H2O2 FORMULA 23639191 A 434 438 cAMP ABBREVIATION 23639191 A 554 566 calycopterin TRIVIAL 23639191 A 594 598 H2O2 FORMULA 23639191 A 755 771 glutamylcysteine TRIVIAL 23639191 A 878 889 glutathione TRIVIAL 23639191 A 891 894 GSH ABBREVIATION 23639191 T 106 118 calycopterin TRIVIAL 23639233 A 432 435 Leu FORMULA 23639233 A 443 446 Phe FORMULA 23639233 A 525 535 amino acid FAMILY 23639233 A 536 561 para-benzoylphenylalanine SYSTEMATIC 23639233 A 563 566 Bpa ABBREVIATION 23639233 T 117 127 Amino Acid FAMILY 23639246 A 0 10 Cyfluthrin TRIVIAL 23639246 A 1000 1010 cyfluthrin TRIVIAL 23639246 A 101 111 antipyrine TRIVIAL 23639246 A 1039 1040 O FORMULA 23639246 A 1057 1072 ethoxyresorufin SYSTEMATIC 23639246 A 1077 1078 O FORMULA 23639246 A 1096 1112 methoxyresorufin SYSTEMATIC 23639246 A 113 123 Antipyrine TRIVIAL 23639246 A 1195 1205 cyfluthrin TRIVIAL 23639246 A 1257 1268 lauric acid TRIVIAL 23639246 A 1313 1323 cyfluthrin TRIVIAL 23639246 A 1353 1362 palmitoyl TRIVIAL 23639246 A 1378 1387 carnitine TRIVIAL 23639246 A 1427 1437 cyfluthrin TRIVIAL 23639246 A 1506 1516 cyfluthrin TRIVIAL 23639246 A 1614 1624 cyfluthrin TRIVIAL 23639246 A 215 225 cyfluthrin TRIVIAL 23639246 A 293 303 Cyfluthrin TRIVIAL 23639246 A 365 375 antipyrine TRIVIAL 23639246 A 398 408 Cyfluthrin TRIVIAL 23639246 A 445 455 antipyrine TRIVIAL 23639246 A 469 482 norantipyrine TRIVIAL 23639246 A 484 503 4-hydroxyantipyrine SYSTEMATIC 23639246 A 508 533 3-hydroxymethylantipyrine SYSTEMATIC 23639246 A 647 657 cyfluthrin TRIVIAL 23639246 A 811 821 cyfluthrin TRIVIAL 23639246 T 84 94 Cyfluthrin TRIVIAL 23639249 A 1023 1026 I3S SYSTEMATIC 23639249 A 1031 1035 TCDD ABBREVIATION 23639249 A 1183 1186 I3S SYSTEMATIC 23639249 A 206 223 indoxyl 3-sulfate SYSTEMATIC 23639249 A 225 228 I3S SYSTEMATIC 23639249 A 311 314 I3S SYSTEMATIC 23639249 A 468 503 2,3,7,8-tetrachlorodibenzo-p-dioxin SYSTEMATIC 23639249 A 505 509 TCDD ABBREVIATION 23639249 A 690 693 I3S SYSTEMATIC 23639249 A 698 702 TCDD ABBREVIATION 23639249 A 800 803 I3S SYSTEMATIC 23639249 A 808 812 TCDD ABBREVIATION 23639249 A 848 912 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d]pyrimidine SYSTEMATIC 23639249 T 0 17 Indoxyl 3-sulfate SYSTEMATIC 23639363 A 393 405 nitric oxide SYSTEMATIC 23639363 A 407 409 NO FORMULA 23639363 A 412 428 prostaglandin E2 TRIVIAL 23639363 A 430 434 PGE2 ABBREVIATION 23639363 A 562 569 glucose TRIVIAL 23639363 A 848 850 NO FORMULA 23639363 A 863 867 PGE2 ABBREVIATION 23639363 T 32 39 glucose TRIVIAL 23639431 A 0 4 NMDA ABBREVIATION 23639431 A 1166 1170 NMDA ABBREVIATION 23639431 A 1304 1308 NMDA ABBREVIATION 23639431 A 174 178 NMDA ABBREVIATION 23639431 A 31 40 glutamate TRIVIAL 23639431 A 475 479 NMDA ABBREVIATION 23639431 A 534 541 carboxy SYSTEMATIC 23639431 A 647 648 C FORMULA 23639431 A 712 723 amino acids FAMILY 23639431 A 921 922 C FORMULA 23639431 T 48 52 NMDA ABBREVIATION 23639452 A 298 301 C12 FORMULA 23639452 A 304 310 (C12)2 FORMULA 23639452 A 316 336 cholesteryl-spermine TRIVIAL 23639452 A 508 519 cholesteryl TRIVIAL 23639538 A 0 23 Adenosine monophosphate SYSTEMATIC 23639538 A 25 28 AMP ABBREVIATION 23639538 A 291 308 homoisoflavonoids FAMILY 23639538 A 323 338 dihydrochalcone SYSTEMATIC 23639538 A 380 397 polygonatones A-D MULTIPLE 23639538 A 566 576 acetyl-CoA SYSTEMATIC 23639538 A 715 790 (3R)-5,7-dihydroxyl-6-methyl-8-methoxyl-3-(4'-hydroxylbenzyl)-chroman-4-one SYSTEMATIC 23639538 A 796 864 (3R)-5,7-dihydroxyl-6,8-dimethyl-3-(4'-hydroxylbenzyl)-chroman-4-one SYSTEMATIC 23639538 A 870 934 (3R)-5,7-dihydroxyl-6-methyl-3-(4'-hydroxylbenzyl)-chroman-4-one SYSTEMATIC 23639538 A 944 958 polygonatone D TRIVIAL 23639538 T 2 17 dihydrochalcone SYSTEMATIC 23639538 T 30 47 homoisoflavonoids FAMILY 23639538 T 92 115 adenosine monophosphate SYSTEMATIC 23639540 A 130 142 dorsomorphin TRIVIAL 23639540 A 147 157 LDN-193189 IDENTIFIER 23639540 A 166 170 DMH1 TRIVIAL 23639540 A 436 447 5-quinoline SYSTEMATIC 23639540 A 512 517 ML347 IDENTIFIER 23639540 A 67 92 pyrazolo[1,5-a]pyrimidine SYSTEMATIC 23639540 T 141 166 pyrazolo[1.5-a]pyrimidine SYSTEMATIC 23639540 T 210 215 ML347 IDENTIFIER 23639541 A 159 165 copper SYSTEMATIC 23639541 A 176 181 azide SYSTEMATIC 23639541 A 182 188 alkyne FAMILY 23639541 A 234 240 BODIPY ABBREVIATION 23639541 A 376 382 BODIPY ABBREVIATION 23639541 A 38 44 BODIPY ABBREVIATION 23639541 A 657 663 BODIPY ABBREVIATION 23639798 A 1053 1063 superoxide TRIVIAL 23639798 A 1115 1123 tyrosine TRIVIAL 23639798 A 1326 1334 rotenone TRIVIAL 23639798 A 138 146 rotenone TRIVIAL 23639798 A 245 253 rotenone TRIVIAL 23639798 A 334 342 Rotenone TRIVIAL 23639798 A 632 640 rotenone TRIVIAL 23639798 A 722 730 rotenone TRIVIAL 23639798 A 767 775 Rotenone TRIVIAL 23639798 A 841 846 thiol FAMILY 23639798 A 959 967 rotenone TRIVIAL 23639798 T 37 45 rotenone TRIVIAL 23639867 A 0 1 S FORMULA 23639867 A 145 146 S FORMULA 23639867 A 27 35 cysteine TRIVIAL 23639867 A 325 326 S FORMULA 23639867 A 327 334 nitroso SYSTEMATIC 23639867 A 405 420 organophosphine FAMILY 23639867 A 427 433 biotin TRIVIAL 23639867 A 454 455 S FORMULA 23639867 A 456 463 nitroso SYSTEMATIC 23639867 A 87 99 nitric oxide SYSTEMATIC 23639867 T 40 41 S FORMULA 23640034 A 1344 1363 reduced glutathione TRIVIAL 23640034 A 1368 1378 superoxide TRIVIAL 23640034 A 1458 1464 BDE209 TRIVIAL 23640034 A 1589 1595 BDE209 TRIVIAL 23640034 A 165 213 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether SYSTEMATIC 23640034 A 215 221 BDE209 TRIVIAL 23640034 A 295 325 polybrominated diphenyl ethers FAMILY 23640034 A 327 332 PBDEs ABBREVIATION 23640034 A 396 401 PBDEs ABBREVIATION 23640034 A 479 485 BDE209 TRIVIAL 23640034 A 561 567 BDE209 TRIVIAL 23640034 A 571 578 glucose TRIVIAL 23640034 A 630 636 BDE209 TRIVIAL 23640034 A 809 815 BDE209 TRIVIAL 23640034 T 13 19 BDE209 TRIVIAL 23640034 T 37 44 glucose TRIVIAL 23640283 A 104 108 TiO2 FORMULA 23640283 A 1062 1068 carbon SYSTEMATIC 23640283 A 138 140 Ag FORMULA 23640283 A 186 195 graphitic TRIVIAL 23640283 A 313 319 carbon SYSTEMATIC 23640283 A 428 430 Ag FORMULA 23640283 A 538 542 TiO2 FORMULA 23640283 A 830 833 RhB ABBREVIATION 23640283 A 838 844 phenol SYSTEMATIC 23640884 A 0 7 Proline TRIVIAL 23640884 A 1114 1122 2-MeSADP SYSTEMATIC 23640884 A 1131 1135 TxA2 ABBREVIATION 23640884 A 13 21 tyrosine TRIVIAL 23640884 A 1399 1410 thromboxane FAMILY 23640884 A 297 305 2-MeSADP SYSTEMATIC 23640884 A 511 514 ADP ABBREVIATION 23640884 A 544 555 thromboxane FAMILY 23640884 A 557 561 TxA2 ABBREVIATION 23640884 A 612 615 ADP ABBREVIATION 23640884 A 715 719 TxA2 ABBREVIATION 23640884 A 832 840 2-MeSADP SYSTEMATIC 23640884 A 861 865 TxA2 ABBREVIATION 23640884 A 948 952 TxA2 ABBREVIATION 23640884 T 35 46 thromboxane FAMILY 23641693 A 377 380 DM1 ABBREVIATION 23641693 A 760 763 DM1 ABBREVIATION 23641693 A 91 94 DM1 ABBREVIATION 23641701 A 247 251 EDTA ABBREVIATION 23641792 A 1008 1022 amine nitrogen SYSTEMATIC 23641792 A 1027 1038 SDS sulfate SYSTEMATIC 23641792 A 1140 1143 SDS ABBREVIATION 23641792 A 151 173 sodium dodecyl sulfate SYSTEMATIC 23641792 A 175 178 SDS ABBREVIATION 23641792 A 232 250 diethylenetriamine SYSTEMATIC 23641792 A 252 260 triamine SYSTEMATIC 23641792 A 265 285 triethylenetetramine SYSTEMATIC 23641792 A 287 296 tetramine SYSTEMATIC 23641792 A 308 311 SDS ABBREVIATION 23641792 A 435 457 tetraethylenepentamine SYSTEMATIC 23641792 A 459 468 pentamine SYSTEMATIC 23641792 A 474 495 pentaethylenehexamine SYSTEMATIC 23641792 A 497 505 hexamine SYSTEMATIC 23641792 A 760 769 tetramine SYSTEMATIC 23641792 A 773 782 pentamine SYSTEMATIC 23641792 A 872 875 SDS ABBREVIATION 23641792 A 880 894 amine nitrogen SYSTEMATIC 23641792 T 145 167 Sodium Dodecyl Sulfate SYSTEMATIC 23641901 A 1015 1028 alkynyl-PHEAA FAMILY 23641901 A 1048 1054 alkyne FAMILY 23641901 A 1070 1127 poly(2-(methacryloyloxy)ethyl trimethylammonium chloride) FAMILY 23641901 A 1129 1142 alkynyl-PMETA FAMILY 23641901 A 1183 1188 azide SYSTEMATIC 23641901 A 211 227 Ethylene sulfide SYSTEMATIC 23641901 A 234 261 propargyl carbonylimidazole SYSTEMATIC 23641901 A 263 266 PPC ABBREVIATION 23641901 A 272 300 azidoethyl carbonylimidazole SYSTEMATIC 23641901 A 302 305 AEC ABBREVIATION 23641901 A 320 325 amine SYSTEMATIC 23641901 A 333 341 hydroxyl SYSTEMATIC 23641901 A 386 391 thiol FAMILY 23641901 A 393 399 alkyne FAMILY 23641901 A 404 409 azide SYSTEMATIC 23641901 A 436 441 thiol FAMILY 23641901 A 446 452 alkyne FAMILY 23641901 A 460 465 azide SYSTEMATIC 23641901 A 539 544 thiol FAMILY 23641901 A 572 612 2-methacryloyloxyethyl phosphorylcholine SYSTEMATIC 23641901 A 614 617 MPC ABBREVIATION 23641901 A 631 636 thiol FAMILY 23641901 A 667 673 PPEGMA ABBREVIATION 23641901 A 699 703 PPFS ABBREVIATION 23641901 A 757 762 azide SYSTEMATIC 23641901 A 778 830 poly(poly(ethylene glycol)methyl ether methacrylate) FAMILY 23641901 A 832 844 azido-PPEGMA SYSTEMATIC 23641901 A 850 884 poly(2,3,4,5,6-pentafluorostyrene) FAMILY 23641901 A 886 896 azido-PPFS SYSTEMATIC 23641901 A 917 922 azide SYSTEMATIC 23641901 A 923 929 alkyne FAMILY 23641901 A 960 966 alkyne FAMILY 23641901 A 982 1013 poly(N-hydroxyethyl acrylamide) FAMILY 23642004 A 1459 1473 methyl acetate SYSTEMATIC 23642004 A 1490 1513 methyl trifluoroacetate SYSTEMATIC 23642004 A 1515 1521 esters FAMILY 23642004 A 39 44 ester FAMILY 23642004 A 458 463 ester FAMILY 23642004 A 551 557 esters FAMILY 23642004 A 713 718 ester FAMILY 23642004 A 826 835 hydroxide SYSTEMATIC 23642004 T 50 56 Esters FAMILY 23642033 A 194 200 Cu(2+) FORMULA 23642033 A 210 216 Cu(2+) FORMULA 23642033 A 365 371 Cu(2+) FORMULA 23642033 A 719 725 Cu(2+) FORMULA 23642124 A 0 2 Ag FORMULA 23642124 A 252 257 Ag-Au FORMULA 23642124 A 577 582 Ag-Au FORMULA 23642124 A 711 713 Ag FORMULA 23642124 A 864 869 Ag-Au FORMULA 23642124 A 925 927 Ag FORMULA 23642124 A 988 993 Ag-Au FORMULA 23642124 T 20 25 Ag-Au FORMULA 23642226 A 1014 1016 N2 FORMULA 23642226 A 123 131 nitrogen SYSTEMATIC 23642226 A 269 275 W(CO)6 FORMULA 23642226 A 32 34 CO FORMULA 23642226 A 519 527 nitrogen SYSTEMATIC 23642226 A 54 75 tungsten hexacarbonyl SYSTEMATIC 23642226 A 779 786 krypton SYSTEMATIC 23642226 A 879 881 Kr FORMULA 23642226 T 29 35 W(CO)6 FORMULA 23642262 A 329 339 nucleotide FAMILY 23642262 A 450 455 sugar FAMILY 23642262 A 456 465 phosphate SYSTEMATIC 23642262 A 538 545 guanine TRIVIAL 23642262 A 620 625 sugar FAMILY 23642262 A 626 635 phosphate SYSTEMATIC 23642262 A 771 781 nucleotide FAMILY 23642262 T 41 52 Nucleotides FAMILY 23642287 A 1136 1145 Pyrimidyn FAMILY 23642287 A 1201 1204 GTP ABBREVIATION 23642287 A 207 217 pyrimidine SYSTEMATIC 23642287 A 379 388 Pyrimidyn FAMILY 23642287 A 573 582 Pyrimidyn FAMILY 23642287 A 632 641 Pyrimidyn FAMILY 23642287 A 708 711 GTP ABBREVIATION 23642287 A 940 949 Pyrimidyn FAMILY 23642287 T 4 13 Pyrimidyn FAMILY 23642287 T 52 62 pyrimidine SYSTEMATIC 23643483 A 0 11 Glutathione TRIVIAL 23643483 A 12 13 S FORMULA 23643483 T 35 46 glutathione TRIVIAL 23643483 T 47 48 S FORMULA 23643631 A 0 8 Melamine TRIVIAL 23643631 A 1021 1029 apocynin TRIVIAL 23643631 A 107 115 melamine TRIVIAL 23643631 A 1084 1092 melamine TRIVIAL 23643631 A 1235 1243 melamine TRIVIAL 23643631 A 1318 1326 melamine TRIVIAL 23643631 A 429 437 melamine TRIVIAL 23643631 A 582 590 melamine TRIVIAL 23643631 A 714 722 melamine TRIVIAL 23643631 A 768 784 prostaglandin E2 TRIVIAL 23643631 A 786 790 PGE2 ABBREVIATION 23643631 A 814 822 melamine TRIVIAL 23643631 A 833 838 NADPH ABBREVIATION 23643631 A 920 926 oxygen SYSTEMATIC 23643631 A 966 974 melamine TRIVIAL 23643631 T 0 8 Melamine TRIVIAL 23643631 T 57 62 NADPH ABBREVIATION 23643682 A 1043 1046 Val ABBREVIATION 23643682 A 1377 1386 estradiol TRIVIAL 23643682 A 207 215 estrogen FAMILY 23643682 A 778 779 N FORMULA 23643682 A 830 839 estradiol TRIVIAL 23643682 T 24 27 Val ABBREVIATION 23643733 A 0 13 Acetylcholine SYSTEMATIC 23643733 A 547 560 acetylcholine SYSTEMATIC 23643746 A 1020 1024 GABA ABBREVIATION 23643746 A 1320 1324 AMPA ABBREVIATION 23643746 A 325 336 bicuculline TRIVIAL 23643746 A 647 651 GABA ABBREVIATION 23643746 A 733 737 AMPA ABBREVIATION 23643746 A 835 839 NMDA ABBREVIATION 23643747 A 1023 1035 okadaic acid TRIVIAL 23643747 A 1040 1051 calyculin A TRIVIAL 23643747 A 1087 1090 Ser FORMULA 23643747 A 1139 1150 haloperidol TRIVIAL 23643747 A 1214 1217 Ser FORMULA 23643747 A 1362 1365 Ser FORMULA 23643747 A 171 182 haloperidol TRIVIAL 23643747 A 248 251 Ser FORMULA 23643747 A 371 382 haloperidol TRIVIAL 23643747 A 393 396 Ser FORMULA 23643747 A 442 446 GABA ABBREVIATION 23643747 A 496 504 dopamine TRIVIAL 23643747 A 555 564 rapamycin TRIVIAL 23643747 A 606 615 rapamycin TRIVIAL 23643747 A 642 650 PF470867 IDENTIFIER 23643747 A 748 759 haloperidol TRIVIAL 23643747 A 763 766 Ser FORMULA 23643747 A 834 842 dopamine TRIVIAL 23643747 A 848 852 cAMP ABBREVIATION 23643747 T 0 11 Haloperidol TRIVIAL 23643747 T 82 90 dopamine TRIVIAL 23643747 T 96 100 cAMP ABBREVIATION 23643751 A 1174 1180 6-OHDA SYSTEMATIC 23643751 A 1293 1299 6-OHDA SYSTEMATIC 23643751 A 145 162 6-hydroxydopamine SYSTEMATIC 23643751 A 1451 1457 6-OHDA SYSTEMATIC 23643751 A 1531 1558 1-methyl-4-phenylpyridinium SYSTEMATIC 23643751 A 164 170 6-OHDA SYSTEMATIC 23643751 A 1680 1686 6-OHDA SYSTEMATIC 23643751 A 1771 1786 arylpiperazines FAMILY 23643751 A 234 295 N-{3-[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-picolinamide SYSTEMATIC 23643751 A 316 322 6-OHDA SYSTEMATIC 23643751 A 424 434 superoxide TRIVIAL 23643751 A 489 495 6-OHDA SYSTEMATIC 23643751 A 55 69 arylpiperazine FAMILY 23643751 A 816 822 6-OHDA SYSTEMATIC 23643751 A 916 931 3-methyladenine SYSTEMATIC 23643751 A 935 949 bafilomycin A1 TRIVIAL 23643751 T 0 14 Arylpiperazine FAMILY 23643751 T 84 101 6-hydroxydopamine SYSTEMATIC 23643752 A 1002 1008 URB597 IDENTIFIER 23643752 A 1162 1167 AM630 IDENTIFIER 23643752 A 1222 1228 URB597 IDENTIFIER 23643752 A 1255 1262 retinal TRIVIAL 23643752 A 1289 1295 URB597 IDENTIFIER 23643752 A 1371 1374 AEA ABBREVIATION 23643752 A 1430 1433 AEA ABBREVIATION 23643752 A 1446 1467 N-arachidonoylglycine SYSTEMATIC 23643752 A 1508 1530 2-arachidonoylglycerol SYSTEMATIC 23643752 A 1611 1617 URB597 IDENTIFIER 23643752 A 1627 1634 retinal TRIVIAL 23643752 A 1713 1719 URB597 IDENTIFIER 23643752 A 182 189 retinal TRIVIAL 23643752 A 21 47 N-arachidonoylethanolamine SYSTEMATIC 23643752 A 276 282 URB597 IDENTIFIER 23643752 A 452 458 URB597 IDENTIFIER 23643752 A 49 52 AEA ABBREVIATION 23643752 A 645 650 AM281 IDENTIFIER 23643752 A 680 685 AM630 IDENTIFIER 23643752 A 695 701 URB597 IDENTIFIER 23643752 A 788 794 URB597 IDENTIFIER 23643752 A 81 97 fatty acid amide FAMILY 23643752 A 841 847 URB597 IDENTIFIER 23643752 A 946 953 Retinal TRIVIAL 23643752 T 4 20 fatty acid amide FAMILY 23643752 T 42 48 URB597 IDENTIFIER 23643752 T 59 66 retinal TRIVIAL 23643755 A 1004 1007 CCh ABBREVIATION 23643755 A 587 596 Carbachol TRIVIAL 23643755 A 598 601 CCh ABBREVIATION 23643755 A 607 621 Norepinephrine TRIVIAL 23643784 A 1060 1063 MHH ABBREVIATION 23643784 A 107 110 MHH ABBREVIATION 23643784 A 112 128 C6H14O6(.)0.5H2O FORMULA 23643784 A 1175 1183 mannitol TRIVIAL 23643784 A 1325 1328 MHH ABBREVIATION 23643784 A 181 184 MHH ABBREVIATION 23643784 A 327 330 MHH ABBREVIATION 23643784 A 37 45 mannitol TRIVIAL 23643784 A 382 385 MHH ABBREVIATION 23643784 A 527 535 mannitol TRIVIAL 23643784 A 540 543 MHH ABBREVIATION 23643784 A 603 606 MHH ABBREVIATION 23643784 A 644 652 mannitol TRIVIAL 23643784 A 762 770 mannitol TRIVIAL 23643784 A 85 105 mannitol hemihydrate TRIVIAL 23643784 A 867 870 MHH ABBREVIATION 23643784 A 972 980 mannitol TRIVIAL 23643784 T 33 41 Mannitol TRIVIAL 23643798 A 0 14 Gentian violet TRIVIAL 23643798 A 1067 1069 1H FORMULA 23643798 A 1106 1108 1H FORMULA 23643798 A 36 50 triarylmethane FAMILY 23643798 T 50 64 gentian violet TRIVIAL 23643808 A 0 6 Prolyl TRIVIAL 23643808 T 14 20 prolyl TRIVIAL 23643828 A 1447 1453 Gö6976 IDENTIFIER 23643828 A 1682 1688 Gö6976 IDENTIFIER 23643828 A 298 336 Dialkyl 5-(hydroxymethyl)isophthalates FAMILY 23643828 A 38 44 serine TRIVIAL 23643828 A 45 54 threonine TRIVIAL 23643828 A 479 492 isophthalates FAMILY 23643828 A 613 626 isophthalates FAMILY 23643828 T 23 35 isophthalate SYSTEMATIC 23643831 A 191 199 triazole FAMILY 23643831 A 42 50 triazole FAMILY 23643831 A 670 682 iodiconazole TRIVIAL 23643831 A 90 97 benzene SYSTEMATIC 23643831 T 27 35 triazole FAMILY 23643831 T 74 81 benzene SYSTEMATIC 23643837 A 1086 1093 glucose TRIVIAL 23643837 A 1134 1141 glucose TRIVIAL 23643837 A 1171 1178 glucose TRIVIAL 23643837 A 902 909 glucose TRIVIAL 23643883 A 682 688 oxygen SYSTEMATIC 23643883 A 911 943 Z-Val-Ala-Asp-fluoromethylketone SYSTEMATIC 23643883 A 945 954 Z-VAD-fmk ABBREVIATION 23643932 A 0 10 Lipoxin A4 TRIVIAL 23643932 A 12 16 LXA4 ABBREVIATION 23643932 A 269 273 LXA4 ABBREVIATION 23643932 A 386 390 LXA4 ABBREVIATION 23643932 A 524 528 LXA4 ABBREVIATION 23643932 A 571 577 Ca(2+) FORMULA 23643932 A 677 681 cAMP ABBREVIATION 23643932 A 737 741 LXA4 ABBREVIATION 23643932 A 850 854 LXA4 ABBREVIATION 23643932 A 897 901 LXA4 ABBREVIATION 23643932 T 25 31 formyl SYSTEMATIC 23643932 T 82 92 lipoxin A4 TRIVIAL 23644193 A 18 53 1,2,3-triazole-dithiocarbamate-urea SYSTEMATIC 23644193 T 66 101 1,2,3-triazole-dithiocarbamate-urea SYSTEMATIC 23644199 A 34 51 echinocystic acid TRIVIAL 23644199 A 356 364 hydroxyl SYSTEMATIC 23644199 A 369 376 lactone FAMILY 23644199 A 401 407 carbon SYSTEMATIC 23644199 A 61 69 oleanane TRIVIAL 23644199 A 75 85 triterpene FAMILY 23644199 A 936 944 hydroxyl SYSTEMATIC 23644199 A 972 982 triterpene FAMILY 23644199 T 36 53 echinocystic acid TRIVIAL 23644203 A 22 69 N'-(benzofuroxan-5-yl)methylene]benzohydrazides FAMILY 23644203 A 816 828 benzofuroxan TRIVIAL 23644203 T 69 81 benzofuroxan TRIVIAL 23644205 A 30 68 N-alkylated 2,3,3-trimethylindolenines FAMILY 23644205 A 73 95 2-methylbenzothiazoles FAMILY 23644205 A 734 735 N FORMULA 23644205 A 791 805 Amphotericin B TRIVIAL 23644205 A 810 823 Thiabendazole TRIVIAL 23644205 T 0 38 N-Alkylated 2,3,3-trimethylindolenines FAMILY 23644205 T 43 65 2-methylbenzothiazoles FAMILY 23644210 A 1019 1025 ketone SYSTEMATIC 23644210 A 248 263 hydroxamic acid SYSTEMATIC 23644210 A 276 280 zinc SYSTEMATIC 23644210 A 386 429 spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] SYSTEMATIC 23644210 A 907 919 benzoxazines FAMILY 23644210 A 969 978 potassium SYSTEMATIC 23644210 T 45 88 spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] SYSTEMATIC 23644211 A 235 275 22β-hydroxy-3-oxoolean-12-en-28-oic acid SYSTEMATIC 23644211 A 295 304 aldehydes FAMILY 23644211 A 314 367 2-arylidene-22β-hydroxy-3-oxoolean-12-en-28-oic acids FAMILY 23644211 A 41 62 Lantadene A (1) and B MULTIPLE 23644211 A 658 667 cisplatin TRIVIAL 23644211 T 78 88 lantadenes FAMILY 23644213 A 422 433 rivaroxaban TRIVIAL 23644213 A 454 465 Arg-Gly-Asp FORMULA 23644213 A 690 715 1,2,4-oxadiazol-5(4H)-one SYSTEMATIC 23644219 A 12 57 N-(4-hydroxy-3-mercaptonaphthalen-1-yl)amides FAMILY 23644219 A 182 193 ortho-nitro SYSTEMATIC 23644219 A 207 214 benzene SYSTEMATIC 23644219 T 39 84 N-(4-hydroxy-3-mercaptonaphthalen-1-yl)amides FAMILY 23644411 A 1069 1093 steroidal glycoalkaloids FAMILY 23644411 A 1114 1116 NO FORMULA 23644411 A 1218 1238 steroidal glycosides FAMILY 23644411 A 1326 1333 hydroxy SYSTEMATIC 23644411 A 1350 1357 glucose TRIVIAL 23644411 A 1514 1538 steroidal glycoalkaloids FAMILY 23644411 A 1560 1578 furostanol saponin FAMILY 23644411 A 1740 1760 steroidal glycosides FAMILY 23644411 A 1920 1940 steroidal glycosides FAMILY 23644411 A 320 340 steroidal glycosides FAMILY 23644411 A 774 801 methyl thiazole tetrazolium SYSTEMATIC 23644411 A 803 806 MTT ABBREVIATION 23644411 A 856 876 steroidal glycosides FAMILY 23644411 A 878 890 nitric oxide SYSTEMATIC 23644411 A 892 894 NO FORMULA 23644411 T 0 20 Steroidal glycosides FAMILY 23644914 A 1173 1181 nicotine TRIVIAL 23644914 A 1448 1456 nicotine TRIVIAL 23644914 A 1608 1616 nicotine TRIVIAL 23644914 A 162 170 nicotine TRIVIAL 23644914 A 1692 1700 nicotine TRIVIAL 23644914 A 1728 1736 nicotine TRIVIAL 23644914 A 324 332 nicotine TRIVIAL 23644914 A 34 47 acetylcholine SYSTEMATIC 23644914 A 446 454 nicotine TRIVIAL 23644914 A 769 777 nicotine TRIVIAL 23644914 T 78 86 nicotine TRIVIAL 23644925 A 1000 1007 glucose TRIVIAL 23644925 A 1218 1237 polyhydroxysteroids FAMILY 23644925 A 155 204 (25S)-5α-cholestane-3β,6α,7α,8,15α,16β,26-heptaol SYSTEMATIC 23644925 A 253 276 distolasterosides D1-D3 MULTIPLE 23644925 A 70 78 steroids FAMILY 23644925 A 80 96 asterosaponin Р1 TRIVIAL 23644925 A 949 957 steroids FAMILY 23644925 A 98 149 (25S)-5α-cholestane-3β,4β,6α,7α,8,15α,16β,26-octaol SYSTEMATIC 23644925 A 993 999 oxygen SYSTEMATIC 23644925 T 50 58 Steroids FAMILY 23645630 A 154 160 oxygen SYSTEMATIC 23645630 A 700 706 oxygen SYSTEMATIC 23645630 T 126 132 Oxygen SYSTEMATIC 23646041 A 288 299 doxorubicin TRIVIAL 23646041 A 382 393 doxorubicin TRIVIAL 23646041 A 595 606 doxorubicin TRIVIAL 23646041 A 689 700 doxorubicin TRIVIAL 23646041 A 772 783 doxorubicin TRIVIAL 23646041 T 16 27 doxorubicin TRIVIAL 23646355 A 636 645 acetylene SYSTEMATIC 23646356 A 105 136 dichlorodiphenyltrichloroethane SYSTEMATIC 23646356 A 144 176 dichlorodiphenyldichloroethylene SYSTEMATIC 23646356 A 70 100 2,4-dichlorophenoxyacetic acid SYSTEMATIC CHEMDNER_CORPUS_BIOCREATIVE_4/CHEMDNER_DEVELOPMENT/Readme.txt0000644002344200234200000001246012204145003023676 0ustar mkrallingerBioinfoUnixCHEMDNER task development data annotation (Version 1.0 18th August 2013) ------------------------------------------------------------------------ This directory contains the development abstracts and manual annotations. 1) chemdner_abs_development.txt : Development set abstracts This file contains plain-text, UTF8-encoded PubMed abstracts in a tab-separated format with the following three columns: 1- Article identifier (PMID, PubMed identifier) 2- Title of the article 3- Abstract of the article In total 3,500 abstracts are provided in this development set. Note that the test set will be provided in the same format. 2) Development data annotations: chemdner_ann_development_13-08-16.txt This file contains manually generated annotations of chemical entities of the development dataset. It consists of tab-separated fields containing: 1- Article identifier (PMID) 2- Type of text from which the annotation was derived (T: Title, A: Abstract) 3- Start offset 4- End offset 5- Text string of the entity mention 6- Type of chemical entity mention (ABBREVIATION,FAMILY,FORMULA,IDENTIFIERS,MULTIPLE,SYSTEMATIC,TRIVIAL) 4) Development data Gold Standard file for the Chemical document indexing (CDI) sub-task: cdi_ann_development_13-08-16.txt Given a set of documents, for this subtask, the participants are asked to return for each of them a ranked list of chemical entities described within each of these documents. You are not required to provide the specific type of chemical entity class. It consists of tab-separated fields containing: 1- Article identifier (PMID) 2- Text string of the entity mention An example is shown below: 22006095 Serotonin 22006095 serotonin 22006095 venlafaxine XR 22056334 PCBs 22056334 PCDD 5) Development data Gold Standard file for the Chemical entity mention recognition (CEM) sub-task: cem_ann_development_13-08-16.txt Given a set of documents, for this subtask, the participants have to return the start and end indices corresponding to all the chemical entities mentioned in this document. You are not requested to provide the specific type of chemical entity subclass. It consists of tab-separated columns containing: 1- Article identifier (PMID) 2- Offset string consisting in a triplet joined by the ':' character. You have to provide the text type (T: Title, A:Abstract), the start offset and the end offset. An example illustrating the format is shown below: 22006095 A:285:294 22006095 A:498:512 22006095 A:622:636 22006095 T:0:9 22006095 T:79:93 22056334 A:1002:1010 Additional comments ------------------- To evaluate the performance of your system we recommend you to use the BioCreative evaluation library scripts. You can also directly download it from the BioCreative Resources page at: http://www.biocreative.org/resources/biocreative-ii5/evaluation-library/ This webpage explains in detail how to install the library and how it works. For both of the tasks you should use the --INT evaluation option like shown below: bc-evaluate --INT prediction_file evaluation_file As the --INT option is chosen by default, you can also run this script without the argument: bc-evaluate prediction_file evaluation_file Example evaluation files for both subtasks were described above. A) Prediction format for the CDI subtask Please make sure that your predictions are compliant with the formatting information provided for the --INT option of the evaluation library (The webpage and the bc-evaluate -h and bc-evaluate -d option provide you with more details.) In short, you have to provide a tab-separated file with: 1- Article identifier 2- The chemical entity mention string 3- The rank of the chemical entity returned for this document 4- A confidence score Example cases are provided online in the CHEMDNER sample set (June 25, 2013) (http://www.biocreative.org/resources/corpora/bc-iv-chemdner-corpus/#bc-iv-chemdner-corpus:downloads) An example prediction for the sample set is shown below: 6780324 LHRH 1 0.9 6780324 FSH 2 0.857142857143 6780324 3H2O 3 0.75 6780324 (Bu)2cAMP 4 0.75 6780324 vitro 5 0.666666666667 6780324 plasminogen 6 0.5 6780324 ethylamide 7 0.5 6780324 beta-3H]testosterone 8 0.5 6780324 NIH-FSH-S13 9 0.5 6780324 D-Ser-(But),6 10 0.5 6780324 4-h 11 0.5 6780324 3-isobutyl-l-methylxanthine 12 0.5 2231607 thymidylate 1 0.666666666667 2231607 acid 2 0.666666666667 2231607 TS 3 0.666666666667 B) Prediction format for the CEM subtask Please make sure that your predictions are compliant with the formatting information provided for the --INT option of the evaluation library (The webpage and the bc-evaluate -h and bc-evaluate -d option provide you with more details.) In short, you have to provide a tab-separated file with: 1- Article identifier (PMID) 2- Offset string consisting in a triplet joined by the ':' character. You have to provide the text type (T: Title, A:Abstract), the start offset and the end offset. 3- The rank of the chemical entity returned for this document 4- A confidence score Example from the sample set (from June 25, 2013) is shown below: 6780324 A:104:107 1 0.5 6780324 A:1136:1147 2 0.5 6780324 A:1497:1500 3 0.5 6780324 A:162:167 4 0.5 6780324 A:17:21 5 0.5 6780324 A:319:330 6 0.5 6780324 A:448:452 7 0.5 CHEMDNER_CORPUS_BIOCREATIVE_4/CHEMDNER_DEVELOPMENT/chemdner_abs_development.txt0000644002344200234200002255022212203440353027531 0ustar mkrallingerBioinfoUnix23517910 Chemical characterization of domestic oral tobacco products: Total nicotine, pH, unprotonated nicotine and tobacco-specific N-nitrosamines. In the United States, moist snuff has been studied more widely than other distinct categories of oral tobacco. In this study, we measured pH, moisture, nicotine (total and unprotonated), and tobacco-specific N-nitrosamines (TSNAs) for other established (twist, loose leaf, plug, and dry snuff without pouch) and emerging oral tobacco products (dry snuff pouch, US-made snus, and dissolvable tobacco). Among the seven product categories, product pH ranged from 4.7 to 7.9, and total nicotine concentration spanned from 3.9 to 40.1mg/g. The most readily absorbable form of nicotine (unprotonated nicotine) varied more than 350-fold, ranging from 0.01 to 3.7mg/g. While the highest total nicotine concentrations were observed in twist products, snus and dissolvable tobacco had the highest unprotonated nicotine levels. Among all products, total TSNA concentrations ranged from 313 to 76,500ng/g with dry snuff having the highest total TSNA concentrations. This study demonstrates the diversity among oral tobacco products and highlights the potential of these products to deliver a wide range of nicotine and carcinogenic TSNAs. Characterizing the chemical content of these products may be helpful in further understanding the risk of marketing these products to oral tobacco users and smokers as an alternative and discrete form of tobacco. 23192347 The crystal structure of the protein-disulfide isomerase family member ERp27 provides insights into its substrate binding capabilities. About one-third of all cellular proteins pass through the secretory pathway and hence undergo oxidative folding in the endoplasmic reticulum (ER). Protein-disulfide isomerase (PDI) and related members of the PDI family assist in the folding of substrates by catalyzing the oxidation of two cysteines and isomerization of disulfide bonds as well as by acting as chaperones. In this study, we present the crystal structure of ERp27, a redox-inactive member of the PDI family. The structure reveals its substrate-binding cleft, which is homologous to PDI, but is able to adapt in size and hydrophobicity. Isothermal titration calorimetry experiments demonstrate that ERp27 is able to distinguish between folded and unfolded substrates, only interacting with the latter. ERp27 is up-regulated during ER stress, thus presumably allowing it to bind accumulating misfolded substrates and present them to ERp57 for catalysis. 23160480 Severe growth deficiency is associated with STAT5b mutations that disrupt protein folding and activity. The first genetic defect in human signal transducer and activator of transcription (STAT)5b was identified in an individual with profound short stature and GH insensitivity, immune dysfunction, and severe pulmonary disease, and was caused by an alanine to proline substitution (A630P) within the Src homology-2 (SH2) domain. STAT5b(A630P) was found to be an inactive transcription factor based on its aberrant folding, diminished solubility, and propensity for aggregation triggered by its misfolded SH2 domain. Here we have characterized the second human STAT5b amino acid substitution mutation in an individual with similar pathophysiological features. This single nucleotide transition, predicted to change phenyalanine 646 to serine (F646S), also maps to the SH2 domain. Like STAT5b(A630P), STAT5b(F646S) is prone to aggregation, as evidenced by its detection in the insoluble fraction of cell extracts, the presence of dimers and higher-order oligomers in the soluble fraction, and formation of insoluble cytoplasmic inclusion bodies in cells. Unlike STAT5b(A630P), which showed minimal GH-induced tyrosine phosphorylation and no transcriptional activity, STAT5b(F646S) became tyrosine phosphorylated after GH treatment and could function as a GH-activated transcription factor, although to a substantially lesser extent than STAT5b(WT). Biochemical characterization demonstrated that the isolated SH2 domain containing the F646S substitution closely resembled the wild-type SH2 domain in secondary structure, but exhibited reduced thermodynamic stability and altered tertiary structure that were intermediate between STAT5b(A630P) and STAT5b(WT). Homology-based structural modeling suggests that the F646S mutation disrupts key hydrophobic interactions and may also distort the phosphopeptide-binding face of the SH2 domain, explaining both the reduced thermodynamic stability and impaired biological activity. 22564442 Presynaptic mGlu7 receptors control GABA release in mouse hippocampus. The functional role of presynaptic release-regulating metabotropic glutamate type 7 (mGlu7) receptors in hippocampal GABAergic terminals was investigated. Mouse hippocampal synaptosomes were preloaded with [(3)H]D-γ-aminobutyric acid ([(3)H]GABA) and then exposed in superfusion to 12 mM KCl. The K(+)-evoked [(3)H]GABA release was inhibited by the mGlu7 allosteric agonist N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082, 0.001-10 μM), as well as by the group III mGlu receptor agonist l-(+)-2-amino-4-phosphonobutyric acid [(l)-AP4, 0.01-1 mM]. The mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine [(S)-3,4-DCPG, 10-100 nM] was ineffective. AMN082 and (l)-AP4-induced effects were recovered by the mGlu7 negative allosteric modulator (NAM) 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one hydrochloride (MMPIP). AMN082 also inhibited in a MMPIP-sensitive manner the K(+)-evoked release of endogenous GABA. AMN082 and the adenylyl cyclase (AC) inhibitor MDL-12,330A reduced [(3)H]GABA exocytosis in a 8-Br-cAMP-sensitive. AMN082-inhibitory effect was additive to that caused by (-)baclofen, but insensitive to the GABA(B) antagonist 3-[[(3,4-Dichlorophenyl)methyl]amino]propyl] diethoxymethyl) phosphinic acid (CGP52432). Conversely, (-)baclofen-induced inhibition of GABA exocytosis was insensitive to MMPIP. Finally, the forskolin-evoked [(3)H]GABA release was reduced by AMN082 or (-)baclofen but abolished when the two agonists were added concomitantly. Mouse hippocampal synaptosomal plasmamembranes posses mGlu7 receptor proteins; confocal microscopy analysis unveiled that mGlu7 proteins colocalize with syntaxin-1A (Stx-1A), with vesicular GABA transporter (VGAT)-proteins and with GABA(B) receptor subunit proteins. We propose that presynaptic inhibitory mGlu7 heteroreceptors, negatively coupled to AC-dependent intraterminal pathway, exist in mouse hippocampal GABA-containing terminals, where they colocalize, but do not functionally cross-talk, with GABA(B) autoreceptors. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23383744 Effectiveness of preoperative plasmapheresis in a pregnancy complicated by hyperthyroidism and anti-thyroid drug-associated angioedema. Abstract Hyperthyroidism is not a rare entity in pregnancy and 85% of these cases attributed to Graves' disease (GD). There is no therapeutic modality for GD considered as totally safe in pregnancy. Fetal and neonatal risks of maternal hyperthyroid disease are related to the hyperthyroidism itself and/or to the medical treatment of the disease. There are no data supporting an association between congenital anomalies in the fetus and propylthiouracil (PTU). Hepatotoxicity, cytopenias - especially agranulocytosis and quite rarely, angioedema, may be seen as side effects of PTU. In this case report, we examine an instance of Graves' hyperthyroidism diagnosed during pregnancy. In this case, a serious side effect during anti-thyroid drug usage was encountered, eventually resulting in surgery in the second trimester. This intervention was assisted by the use of plasmapheresis to obtain rapid normalization of serum thyroid hormone levels. 23262200 Sequential delivery of TAT-HSP27 and VEGF using microsphere/hydrogel hybrid systems for therapeutic angiogenesis. Ischemic disease is associated with high mortality and morbidity rates, and therapeutic angiogenesis via systemic or local delivery of protein drugs is one potential approach to treat the disease. In this study, we hypothesized that combined delivery of TAT-HSP27 (HSP27 fused with transcriptional activator) and VEGF could enhance the therapeutic efficacy in an ischemic mouse model, and that sequential release could be critical in therapeutic angiogenesis. Alginate hydrogels containing TAT-HSP27 as an anti-apoptotic agent were prepared, and porous PLGA microspheres loaded with VEGF as an angiogenic agent were incorporated into the hydrogels to prepare microsphere/hydrogel hybrid delivery systems. Sequential in vitro release of TAT-HSP27 and VEGF was achieved by the hybrid systems. TAT-HSP27 was depleted from alginate gels in 7 days, while VEGF was continually released for 28 days. The release rate of VEGF was attenuated by varying the porous structures of PLGA microspheres. Sequential delivery of TAT-HSP27 and VEGF was critical to protect against muscle degeneration and fibrosis, as well as to promote new blood vessel formation in the ischemic site of a mouse model. This approach to controlling the sequential release behaviors of multiple drugs could be useful in the design of novel drug delivery systems for therapeutic angiogenesis. 23548027 Metabolism evolution based on network degrees of orthologous enzymes. The evolution of orthologous proteins opens a new era of research where the concepts of orthology and paralogy have become more and more substantial, as the whole-genome comparison allows their identification in complete genomes. Functional specificity of proteins is understood to be conserved among orthologs but it shows much more variability among paralogs. We used this laying claim to identify inter-species interactions based on orthologous protein networks which are crucial for understanding the evolution of orthologous proteins. We analyzed six classes of enzymatic protein sequence data using the node degrees of orthologous proteins. The results demonstrated the evolutionary importance of the fatty acid syntheses and the photosynthetic system in algae. Methods which have successfully exploited network structure at many different levels of detail are a cornerstone of systems biology. 23597790 Discovery of potent selective bioavailable phosphodiesterase 2 (PDE2) inhibitors active in an osteoarthritis pain model. Part II: Optimization studies and demonstration of in vivo efficacy. Selective phosphodiesterase 2 (PDE2) inhibitors are shown to have efficacy in a rat model of osteoarthritis (OA) pain. We identified potent, selective PDE2 inhibitors by optimizing residual PDE2 activity in a series of phosphodiesterase 4 (PDE4) inhibitors, while minimizing PDE4 inhibitory activity. These newly designed PDE2 inhibitors bind to the PDE2 enzyme in a cGMP-like binding mode orthogonal to the cAMP-like binding mode found in PDE4. Extensive structure activity relationship studies ultimately led to identification of pyrazolodiazepinone, 22, which was >1000-fold selective for PDE2 over recombinant, full length PDEs 1B, 3A, 3B, 4A, 4B, 4C, 7A, 7B, 8A, 8B, 9, 10 and 11. Compound 22 also retained excellent PDE2 selectivity (241-fold to 419-fold) over the remaining recombinant, full length PDEs, 1A, 4D, 5, and 6. Compound 22 exhibited good pharmacokinetic properties and excellent oral bioavailability (F=78%, rat). In an in vivo rat model of OA pain, compound 22 had significant analgesic activity 1 and 3h after a single, 10mg/kg, subcutaneous dose. 23385325 QM/MM simulations of vibrational spectra of bacteriorhodopsin and channelrhodopsin-2. Channelrhodopsin-2 is a light-gated ion channel, which has been studied intensively over the last decade. Vibrational spectroscopic experiments started to shed light on the structural changes, that occur during the photocycle, especially in the hydrogen-bonded network surrounding the protonated D156 and C128 - the DC gate. However, the interpretation of these experiments was only based on homology models. Since then, an X-ray structure and better computational models became available. In this article, we show that in combination with a recent reparametrization, the approximate DFT method, DFTB, is able to describe the effects of hydrogen bonding on the C[double bond, length as m-dash]O stretch vibration in carboxylic acids reliably and agrees well with full DFT results. We apply DFTB in a QM/MM framework to perform vibrational analysis of buried aspartic acids in bacteriorhodopsin and channelrhodopsin-2. Using this approach, we can simulate the FTIR spectral difference between D115 in the dark-adapted and K states of bacteriorhodopsin. The FTIR experiments on the DC gate in channelrhodopsin-2 are well described using an indirect model, where D156 and C128 are bridged via a water molecule. 23010670 Toxicological and mutagenic analysis of Artemisia dracunculus (tarragon) extract. Mutagenicity and liver toxicity of the herb tarragon (Artemisia dracunculus) were evaluated using single cell gel (comet) electrophoresis. Ten microlitres aliquots of peripheral venous human blood were incubated with tarragon extract, saline, or the mutagen sodium dichromate. Cell suspensions dispersed in low-melting agarose were electrophoresed in ethidium bromide. The resulting DNA migration trails were obtained using fluorescent microscopy at 400× magnification, and graded according to the mutagenicity index (MI) for each cell incubation condition. The in vivo liver toxicity of Artemisia dracunculus was assessed in the blood of mice treated orally with the extract of the herb, using alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as liver function indicators. Liver morphology was assessed using hematoxylin and eosin (HE) staining of liver tissue. The present study demonstrated a direct correlation between tarragon extract dosage and three major outcome variables: MI; serum liver enzyme activity; and liver histopathology. These outcomes are possibly due to the presence in tarragon of methylchavicol and other genotoxic compounds. These findings provide a preliminary guide for risk assessment of tarragon in diet and in possible therapeutic applications. 23089211 Cholesterol ester droplets and steroidogenesis. Intracellular lipid droplets (LDs) are dynamic organelles that contain a number of associated proteins including perilipin (Plin) and vimentin. Cholesteryl ester (CE)-rich LDs normally accumulate in steroidogenic cells and their mobilization is the preferred initial source of cholesterol for steroidogenesis. Plin1a, 1b and 5 were found to preferentially associate with triacylglycerol-rich LDs and Plin1c and Plin4 to associate with CE-rich LDs, but the biological significance of this remains unanswered. Vimentin null mice were found to have decreased ACTH-stimulated corticosterone levels, and decreased progesterone levels in females, but normal hCG-stimulated testosterone levels in males. Smaller LDs were seen in null cells. Lipoprotein cholesterol delivery to adrenals and ovary was normal, as was the expression of steroidogenic genes; however, the movement of cholesterol to mitochondria was reduced in vimentin null mice. These results suggest that vimentin is important in the maintenance of CE-rich LDs and in the movement of cholesterol for steroidogenesis. 23472857 Do the physical properties of water in mixed reverse micelles follow a synergistic effect: a spectroscopic investigation. In this contribution we have tried to investigate whether the mechanical properties of the reverse micellar (RM) interface dictate the physical properties of entrapped water molecules in the RM waterpool. We choose AOT/Igepal-520/cyclohexane (Cy) mixed RM as a model system which exhibits synergistic water solubilization behavior as a function of interfacial stoichiometry. Such a phenomenon associates systematic modification of the interface curvature. Dynamic light scattering (DLS) studies reveal linear increase in the droplet size and aggregation number of the RMs with increasing XIgepal (mole fraction of Igepal in the surfactant mixture). FTIR study in the 3000-3800 cm(-1) region identifies that the relative population of the surface-bound water molecules is higher in AOT RM compared to that in Igepal RM, and in mixed systems it also follows a linear trend with XIgepal. Water relaxation dynamics as probed by time-resolved fluorescence spectroscopy using Coumarin-500 also reveals an overall linear trend with no characteristic feature around the solubilization inflation point. Our study clearly identifies that the physical properties of water in RM are mostly governed by the interfacial stoichiometry and water content, and merely bares any dependence on the mechanical properties of the interface. 23256625 Evaluation of drug interactions of GSK1292263 (a GPR119 agonist) with statins: from in vitro data to clinical study design. 1. This work investigated the drug interaction potential of GSK1292263, a novel GPR119 agonist, with the HMG-coA reductase inhibitors simvastatin and rosuvastatin. 2. In vitro experiments assessed the inhibition of transporters and CYP enzymes by GSK1292263, and a clinical drug interaction study investigated the effect of GSK1292263 (300 mg BID) on the pharmacokinetic profile of simvastatin (40 mg single dose) and rosuvastatin (10 mg single dose). 3. In vitro, GSK1292263 demonstrated little/weak inhibition (IC50 values >30 μM) towards CYPs (CYP1A2, 2C9, 2C19, 2D6, 3A4), Pgp, OATP1B3, or OCT2. However, GSK1292263 inhibited BCRP and OATP1B1, which are transporters involved in statin disposition. 4. In the clinical study, small increases in the AUC(0-inf) of simvastatin [mean ratio (90% CI) of 1.34 (1.22, 1.48)] and rosuvastatin [mean ratio (90% CI) of 1.39 (1.30, 1.49)] were observed when co-administered with GSK1292263, which is consistent with an inhibitory effect on intestinal BCRP and CYP3A4. In contrast, GSK1292263 did not inhibit OATP1B1 based on the lack of changes in simvastatin acid exposure [mean AUC(0-inf) ratio (90% CI) of 1.05 (0.91, 1.21)]. 5. GSK1292263 has a weak drug interaction with simvastatin and rosuvastain. This study provides a mechanistic understanding of the in vivo inhibition of transporters and enzymes by GSK1292263. 23327735 Embelin accelerates cutaneous wound healing in diabetic rats. This study reports the effect of embelin (1) on cutaneous wound in streptozotocin (STZ)-induced diabetic rats. The effect was studied using excision, incision, and dead space models. In diabetic rats, topical application of embelin 5% (w/w) ointment showed a significant increase in wound contraction and better epithelialization, thereby facilitating the healing. Embelin was also active by the oral route (25 and 50 mg/kg) in the incision and dead space wound models. In incision wound model, wound granulation tissues were removed on 8th post-wounding day, and the hydroxyproline, hexosamine, total protein, and DNA contents were determined. In STZ diabetic rats, topical and oral applications of embelin showed an increase in hydroxyproline, hexosamine, total protein, and DNA contents. It also showed a significant increase in wound breaking strength. Embelin significantly increased granuloma tissue weight and breaking strength in dead space model. These results indicated that embelin accelerated wound healing in diabetic rat. 23458620 Potential use of polymeric nanoparticles for drug delivery across the blood-brain barrier. Nanomedicine is certainly one of the scientific and technological challenges of the coming years. In particular, biodegradable nanoparticles formulated from poly (D,L-lactide-co-glycolide) (PLGA) have been extensively investigated for sustained and targeted delivery of different agents, including recombinant proteins, plasmid DNA, and low molecular weight compounds. PLGA NPs present some very attractive properties such as biodegradability and biocompatibility, protection of drug from degradation, possibility of sustained release, and the possibility to modify surface properties to target nanoparticles to specific organs or cells. Moreover, PLGA NPs have received the FDA and European Medicine Agency approval in drug delivery systems for parenteral administration, thus reducing the time for human clinical applications. This review in particular deals on surface modification of PLGA NPs and their possibility of clinical applications, including treatment for brain pathologies such as brain tumors and Lysosomal Storage Disorders with neurological involvement. Since a great number of pharmacologically active molecules are not able to cross the Blood-Brain Barrier (BBB) and reach the Central Nervous System (CNS), new brain targeted polymeric PLGA NPs modified with glycopeptides (g7- NPs) have been recently produced. In this review several in vivo biodistribution studies and pharmacological proof-of evidence of brain delivery of model drugs are reported, demonstrating the ability of g7-NPs to create BBB interaction and trigger an efficacious BBB crossing. Moreover, another relevant development of NPs surface engineering was achieved by conjugating to the surface of g7-NPs, some specific and selective antibodies to drive NPs directly to a specific cell type once inside the CNS parenchyma. 23625693 The Cost-Effectiveness of Oral Direct Factor Xa Inhibitors Compared with Low-Molecular-Weight Heparin for the Prevention of Venous Thromboembolism Prophylaxis in Total Hip or Knee Replacement Surgery. INTRODUCTION: Major orthopedic surgery is associated with a high risk of venous thromboembolism (VTE). Anticoagulants are recommended to prevent VTE, and recently an oral direct factor Xa inhibitor (FXaI) was approved for this indication. We compared the cost-effectiveness of FXaIs with low-molecular-weight heparin (LMWH) in patients undergoing total hip replacement (THR) or total knee replacement (TKR) surgery. DESIGN: A decision-tree model was developed to compare the cost-effectiveness of oral direct FXaIs (rivaroxaban, apixaban, and edoxaban) to subcutaneous LMWHs (enoxaparin and dalteparin), with separate models for THR and TKR. The analysis was conducted over a 180-day postoperative time horizon from the U.S. Medicare perspective. The model was developed using TreeAge Pro 2011 (TreeAge Software Inc., Williamstown, MA, USA). METHODS: Efficacy and safety data (probabilities of distal and proximal deep vein thrombosis, symptomatic pulmonary embolism, and major bleeding) were derived from a systematic review and meta-analysis of phase II and III clinical trials. Costs and quality-adjusted life-years (QALYs) are reported. One-way and probabilistic sensitivity analyses were performed to evaluate parameter uncertainty. RESULTS: In the THR model, the average costs per patient for FXaIs and LMWHs were $18,762 and $18,897, respectively, and the QALYs were 0.938 and 0.932. In the TKR model, the average cost per patient for FXaIs and LMWHs were $18,804 and $18,991, respectively, and the QALYs were 0.935 and 0.931. In both models, FXaIs dominated LMWH (less costly and more efficacious). Neither model was sensitive to changes in any of the variables in the one-way sensitivity analyses. Probabilistic sensitivity analysis indicated that FXaIs were cost-effective in more than 99% of iterations in the THR population and in 98% of iterations in the TKR population assuming a willingness-to-pay threshold of $50,000/QALY. CONCLUSION: Oral direct FXaIs may be an economically dominant strategy compared with LMWHs for VTE prophylaxis in patients undergoing either THR or TKR surgery. 23553357 Once-Weekly Exenatide: An Extended-Duration Glucagon-Like Peptide Agonist for the Treatment of Type 2 Diabetes Mellitus. Type 2 diabetes affects over 25 million people in the United States. There are many treatment options for patients with type 2 diabetes, but current treatments must be administered on a daily basis. Once-weekly exenatide, an extended-duration glucagon-like peptide-1 (GLP-1) agonist, provides an option for patients to take a drug weekly, with pharmacotherapeutic effects that are superior to twice-daily exenatide and sitagliptin and comparable to insulin glargine. The DURATION trials provide evidence that once-weekly exenatide reduces hemoglobin A1c , and may result in weight loss. Once-weekly exenatide is marketed as a 2-mg injection administered subcutaneously once every 7 days. Adverse effects of once-weekly exenatide include gastrointestinal effects, hypoglycemia, injection-site reactions, pancreatitis, and antibody development. Patients with a self history or family history of thyroid tumors should avoid using once-weekly exenatide. Delayed gastric absorption with orally administered drugs is possible, and monitoring should occur to avoid loss in therapeutic effect. Once-weekly exenatide is a new extended-duration agent with efficacy and tolerability profiles comparative to older therapies. Appropriate patients for once-weekly exenatide would be those who are concerned about weight gain, hypoglycemia, or those who do not wish to administer injections daily. 23407452 Follistatin-like 3 (FSTL3) mediated silencing of transforming growth factor β (TGFβ) signaling is essential for testicular aging and regulating testis size. Follistatin-like 3 (FSTL3) is a glycoprotein that binds and inhibits the action of TGFβ ligands such as activin. The roles played by FSTL3 and activin signaling in organ development and homeostasis are not fully understood. The authors show mice deficient in FSTL3 develop markedly enlarged testes that are also delayed in their age-related regression. These FSTL3 knockout mice exhibit increased Sertoli cell numbers, allowing for increased spermatogenesis but otherwise showing normal testicular function. The data show that FSTL3 deletion leads to increased AKT signaling and SIRT1 expression in the testis. This demonstrates a cross-talk between TGFβ ligand and AKT signaling and leads to a potential mechanism for increased cellular survival and antiaging. The findings identify crucial roles for FSTL3 in limiting testis organ size and promoting age-related testicular regression. 23420023 Screening of transition and post-transition metals to incorporate into copper oxide and copper bismuth oxide for photoelectrochemical hydrogen evolution. A new dispenser and scanner system is used to create and screen Bi-M-Cu oxide arrays for cathodic photoactivity, where M represents 1 of 22 different transition and post-transition metals. Over 3000 unique Bi : M : Cu atomic ratios are screened. Of the 22 metals tested, 10 show a M-Cu oxide with higher photoactivity than CuO and 10 show a Bi-M-Cu oxide with higher photoactivity than CuBi2O4. Cd, Zn, Sn, and Co produce the most photoactive M-Cu oxides, all showing a 200-300% improvement in photocurrent over CuO. Ag, Cd, and Zn produce the highest photoactivity Bi-M-Cu oxides with a 200-400% improvement over CuBi2O4. Most notable is a Bi-Ag-Cu oxide (Bi : Ag : Cu atomic ratio of 22 : 3 : 11) which shows 4 times higher photocurrent than CuBi2O4. This material is capable of evolving hydrogen under illumination in neutral electrolyte solutions at 0.6 V vs. RHE when Pt is added to the surface as an electrocatalyst. 23343598 Generic legislation of new psychoactive drugs. New psychoactive drugs (NPDs, new psychoactive substances) enter the market all the time. However, it takes several months to ban these NPDs and immediate action is generally not possible. Several European countries and drug enforcement officers insist on a faster procedure to ban NPDs. Introduction of generic legislation, in which clusters of psychotropic drugs are banned in advance, has been mentioned as a possible solution. Here we discuss the pros and cons of such an approach. First, generic legislation could unintentionally increase the expenditures of enforcement, black market practices, administrative burden and health risks for users. Second, it may have a negative impact on research and the development of new treatments. Third, due to the complexity of generic legislation, problems in the enforcement are anticipated due to lack of knowledge about the chemical nomenclature. Finally, various legal options are already available to ban the use, sale and trade of NPDs. We therefore conclude that the currently used scientific benefit-risk evaluation should be continued to limit the adverse health effects of NPDs. Only in emergency cases, where fatal incidents (may) occur, should this approach be overruled. 23390932 Superatom paramagnetism enables gold nanocluster heating in applied radiofrequency fields. The Au102(pMBA)44 nanocluster becomes a superatom paramagnet after chemical oxidation. Solutions of paramagnetic Au102(pMBA)44 heat in an oscillating magnetic field component of an RF field, but not in the electric component. Combined, these experiments suggest that paramagnetic Au102(pMBA)44 heats through interactions of spin magnetic moment with an external oscillating magnetic field. These results may clarify some current controversy regarding gold nanoparticle heating in radiofrequency fields. 23266367 Small and colorful stones make beautiful mosaics: fragment-based chemogenomics. Smaller stones with a wide variety of colors make a higher resolution mosaic. In much the same way, smaller chemical entities that are structurally diverse are better able to interrogate protein binding sites. This feature article describes the construction of a diverse fragment library and an analysis of the screening of six representative protein targets belonging to three diverse target classes (G protein-coupled receptors ADRB2, H1R, H3R, and H4R, the ligand-gated ion channel 5-HT3R, and the kinase PKA) using chemogenomics approaches. The integration of experimentally determined bioaffinity profiles across related and unrelated protein targets and chemogenomics analysis of fragment binding and protein structure allow the identification of: (i) unexpected similarities and differences in ligand binding properties, and (ii) subtle ligand affinity and selectivity cliffs. With a wealth of fragment screening data being generated in industry and academia, such approaches will contribute to a more detailed structural understanding of ligand-protein interactions. 23014761 Function of the blood-brain barrier and restriction of drug delivery to invasive glioma cells: findings in an orthotopic rat xenograft model of glioma. Despite aggressive treatment with radiation and chemotherapy, recurrence of glioblastoma multiforme (GBM) is inevitable. The objective of this study was to show that the blood-brain barrier (BBB), through a combination of tight junctions and active efflux transporters in the brain microvasculature, can significantly restrict delivery of molecularly targeted agents to invasive glioma cells. Transgenic mice lacking P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) were used to study efflux of erlotinib at the BBB. A U87 rat xenograft model of GBM was used to investigate the regional distribution of erlotinib to the tumor, and brain regions surrounding the tumor. The effect of concurrent administration of elacridar on regional tumor distribution of erlotinib was evaluated. We show that erlotinib transport across an intact BBB is significantly restricted due to P-gp- and Bcrp-mediated efflux transport. We then show that the BBB is sufficiently intact in areas of brain adjacent to the tumor core to significantly restrict erlotinib delivery. Inhibition of P-gp and Bcrp by the dual inhibitor elacridar dramatically increased erlotinib delivery to the tumor core, rim, and normal brain. These results provide conclusive evidence of the impact that active efflux at the BBB has on the delivery of molecularly targeted therapy to different tumor regions in glioma. These data also support the possibility that the repeated failure of clinical trials of new drugs for gliomas may be in part due to a failure to achieve effective concentrations in invasive tumor cells that reside behind an intact BBB. 23256485 Aspartic protease inhibitors: effective drugs against the human fungal pathogen Candida albicans. Candida albicans can invade humans and may lead to mucosal and skin infections or to deep-seated mycoses of almost all inner organs, especially in immunocompromised patients. In this context, both the host immune status and the ability of C. albicans to modulate the expression of its virulence factors are relevant aspects that drive the candidal susceptibility or resistance; in this last case, culminating in the establishment of successful infection known as candidiasis. C. albicans possesses a potent armamentarium consisting of several virulence molecules that help the fungal cells to escape from the host immune responses. There is no doubt that the secretion of aspartic proteases, designated as Saps, is one of the major virulence attributes produced by C. albicans cells, since these hydrolytic enzymes participate in a wide range of fungal physiological processes as well as in different facets of the fungal-host interactions. For these reasons, Saps clearly hold promise as new potential drug targets. Corroborating this hypothesis, the introduction of anti-human immunodeficiency virus drugs of the aspartic protease inhibitor-type (HIV PIs) have emerged as new agents for the inhibition of Saps. The introduction of HIV PIs has revolutionized the treatment of HIV disease, reducing the opportunistic infections, especially candidiasis. The attenuation of candidal infections in HIV-infected individuals might not solely has not only resulted from improved immunological status, but also as a result of direct inhibition of C. albicans Saps as well as the blockage of several biological processes controlled by these proteolytic enzymes. The present article will discuss the updates on the functional implications of HIV PIs on the development of candidiasis. 23535393 Evidence of Anti-Proliferative Activities in Blue Mussel (Mytilus edulis) By-Products. Shellfish waste components contain significant levels of high quality protein and are therefore a potential source for biofunctional high-value peptides. The feasibility of applying a pilot scale enzymatic hydrolysis process to whole Mytilus edulis and, by fractionation, recover hydrolysates presenting a biological activity of interest, was evaluated. Fractions were tested on four immortalized cancerous cell lines: A549, BT549, HCT15 and PC3. The 50 kDa fraction, enriched in peptides, presented anti-proliferative activity with all cell lines and results suggest a bioactive molecule synergy within the fraction. At a protein concentration of 44 µg/mL, the 50 kDa fraction induced a mortality of 90% for PC3, 89% for A549, 85% for HCT15 and of 81% for BT549 cell lines. At the low protein concentration of only 11 µg/mL the 50 kDa fraction still entails a cell mortality of 76% for A549 and 87% for PC3 cell lines. The 50 kDa fraction contains 56% of proteins, 3% of lipids and 6% of minerals on a dry weight basis and the lowest levels detected of taurine and methionine and highest levels of threonine, proline and glycine amino acids. The enzymatic hydrolysis process suggests that Mytilus edulis by-products should be viewed as high-valued products with strong potential as anti-proliferative agent and promising active ingredients in functional foods. 23047828 Circulating very-low-density lipoprotein from subjects with impaired glucose tolerance accelerates adrenocortical cortisol and aldosterone synthesis. Apart from their role in cardiovascular homeostasis and immunomodulation, aldosterone and cortisol are also implicated in the pathogenesis of insulin resistance and type 2 diabetes mellitus (T2DM). Furthermore, glycoxidative modifications of lipoproteins are increasingly recognized as an etiological factor for increased cardiovascular morbidity and mortality in prediabetic individuals. The causative relationship between in vivo lipoprotein modifications and steroidogenesis in subjects with impaired glucose tolerance (IGT), however, is not well defined. Therefore, we aimed to investigate the impact of in vivo modified lipoproteins on aldosterone and cortisol release from human adrenocortical H295R cells. Following an oral glucose tolerance test, 20 individuals with normal glucose tolerance (NGT) and 20 IGT subjects were randomly selected from the ongoing PRAEDIAS prevention study in our department. Cells were incubated for 24 h with lipoproteins isolated from NGT and IGT individuals and aldosterone and cortisol release was measured in the supernatants. VLDL induced a greater stimulating effect on adrenocortical aldosterone and cortisol release compared to HDL and LDL. Moreover, IGT-VLDL evoked a significantly higher effect (p<0.05) on hormone release than NGT-VLDL. Incubation of cells with in vitro modified lipoproteins and specific pharmacological inhibitors suggests that VLDL presumably recruits ERK1/2 as one of the downstream effectors of Jak-2. In summary, in vivo modified VLDL are able to promote prediabetic hormonal dysregulation by modulating adrenocortical steroidogenesis via Jak-2-ERK dependent pathway. 23249384 Phase behavior and molecular dynamics simulation studies of new aqueous two-phase separation systems induced by HEPES buffer. Here, for the first time, we show that with addition of a biological buffer, 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES), into aqueous solutions of tetrahydrofuran (THF), 1,3-dioxolane, 1,4-dioxane, 1-propanol, 2-propanol, tert-butanol, acetonitrile, or acetone, the organic solvent can be excluded from water to form a new liquid phase. The phase diagrams have been determined at ambient temperature. In order to understand why and how a zwitterion solute (HEPES) induced phase separation of the investigated systems, molecular dynamics (MD) simulation studies are performed for HEPES + water + THF system. The MD simulations were conducted for the aqueous mixtures with 12 different compositions. The reliability of the simulation results of HEPES in pure water and beyond the phase separation mixtures was justified by comparing the densities obtained from MD with the experimental values. The simulation results of HEPES in pure THF and in a composition inside the phase separation region were justified qualitatively. Interestingly, all HEPES molecules entirely aggregated in pure THF. This reveals that HEPES is insoluble in pure THF, which is consistent with the experimental results. Even more interestingly, the MD simulation for the mixture with composition inside the phase separation region showed the formation of two phases. The THF molecules are squeezed out from the water network into a new liquid phase. The hydrogen bonds (HBs), HB lifetime, HB Gibbs energy (ΔG), radial distribution functions (RDFs), coordination numbers (CNs), electrostatic interactions, and the van der Waals interactions between the different species have been analyzed. Further, MD simulations for the other phase separation systems by choosing a composition inside the two liquids region for each system were also simulated. Our findings will therefore pave the way for designing new benign separation auxiliary agents. 23253100 Mass accommodation of water: bridging the gap between molecular dynamics simulations and kinetic condensation models. The condensational growth of submicrometer aerosol particles to climate relevant sizes is sensitive to their ability to accommodate vapor molecules, which is described by the mass accommodation coefficient. However, the underlying processes are not yet fully understood. We have simulated the mass accommodation and evaporation processes of water using molecular dynamics, and the results are compared to the condensation equations derived from the kinetic gas theory to shed light on the compatibility of the two. Molecular dynamics simulations were performed for a planar TIP4P-Ew water surface at four temperatures in the range 268-300 K as well as two droplets, with radii of 1.92 and 4.14 nm at T = 273.15 K. The evaporation flux from molecular dynamics was found to be in good qualitative agreement with that predicted by the simple kinetic condensation equations. Water droplet growth was also modeled with the kinetic multilayer model KM-GAP of Shiraiwa et al. [Atmos. Chem. Phys. 2012, 12, 2777]. It was found that, due to the fast transport across the interface, the growth of a pure water droplet is controlled by gas phase diffusion. These facts indicate that the simple kinetic treatment is sufficient in describing pure water condensation and evaporation. The droplet size was found to have minimal effect on the value of the mass accommodation coefficient. The mass accommodation coefficient was found to be unity (within 0.004) for all studied surfaces, which is in agreement with previous simulation work. Additionally, the simulated evaporation fluxes imply that the evaporation coefficient is also unity. Comparing the evaporation rates of the mass accommodation and evaporation simulations indicated that the high collision flux, corresponding to high supersaturation, present in typical molecular dynamics mass accommodation simulations can under certain conditions lead to an increase in the evaporation rate. Consequently, in such situations the mass accommodation coefficient can be overestimated, but in the present cases the corrected values were still close to unity with the lowest value at ≈0.99. 23495155 Towards squalamine mimics: synthesis and antibacterial activities of head-to-tail dimeric sterol-polyamine conjugates. Four dimeric sterol-polyamine conjugates have been synthesized from the homo- and hetero-connection of monomeric sterol-polyamine analogs in a head-to-tail manner. These dimeric conjugates show strong antibacterial activity against a broad spectrum of Gram-positive bacteria, whereas their corresponding activities against Gram-negative bacteria are relatively moderate. Though no significant difference was observed in the activities of these conjugates, cholic acid-containing dimeric conjugates generally exhibit higher activities than the corresponding deoxycholic acid-derived analogs. This is in contrast to the finding that a monomeric deoxycholic acid-spermine conjugate was more active than the corresponding cholic acid-derived analog. 23560391 Temperature-Induced Emission Enhancement of Star Conjugated Copolymers with Poly(2-(dimethylamino)ethyl methacrylate) Coronas for Detection of Bacteria. A facile strategy for temperature-induced emission enhancement of star conjugated copolymers has been developed for biodetection. The star copolymers (HCP-star-PDMAEMAs) with different poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) chain lengths were synthesized from the hyperbranched conjugated polymer (HCP) macroinitiator by atom transfer radical polymerization (ATRP). The star conjugated copolymers exhibited interesting thermoresponsive phase transitions with adjustable lower critical solution temperature (LCST) depending on the pH of copolymer solution. Above the LCST, the emission of HCP-star-PDMAEMAs was enhanced greatly through restriction of intermolecular aggregation of conjugated polymer cores by the collapse of PDMAEMA arms. By changing the PDMAEMA length, the emission performance of HCP-star-PDMAEMAs could be readily adjusted. Correspondingly, this temperature-dependent emission enhancement of HCP-star-PDMAEMAs was successfully applied in the highly sensitive detection of bacteria. Due to the existence of a hyperbranched conjugated core and many thermo-responsive PDMAEMA arms, the detection limit of E. coli could reach 10(2) cfu mL(-1). 23583486 Molecular mechanisms for the anti-cancer effects of diallyl disulfide. Considerable evidence in recent years suggests that garlic has anti-proliferative effects against various types of cancer. Garlic contains water-soluble and oil-soluble sulfur compounds. Oil-soluble compounds such as diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS) and ajoene are more effective than water-soluble compounds in protection against cancer. DADS, a major organosulfur compound derived from garlic, can decrease carcinogen-induced cancers in experimental animals and inhibit the proliferation of various types of cancer cells. Its mechanisms of action include: the activation of metabolizing enzymes that detoxify carcinogens; suppression of the formation of DNA adducts; antioxidant effects; regulation of cell-cycle arrest; induction of apoptosis and differentiation; histone modification; and inhibition of angiogenesis and invasion. These topics are discussed in depth in this review. 23127567 Nerium oleander derived cardiac glycoside oleandrin is a novel inhibitor of HIV infectivity. We evaluated the effectiveness of Anvirzel™, an aqueous extract of Nerium oleander on HIV infection of human peripheral blood mononuclear cells. Oleandrin, the principle cardiac glycoside (CG) in Anvirzel™ has been shown to exhibit anti-cancer properties but its efficacy against HIV is unknown. Treatment with Anvirzel™ significantly reduced the infectivity of virus produced from infected cells without any change in the total amount of virus produced. This is in contrast to treatment with AZT, a potent inhibitor of HIV replication that has been shown to significantly reduce virus production. Relative to untreated cultures, virus in cultures treated with oleandrin had significantly reduced expression of the envelope protein gp120, the sole determinant of virus infectivity, suggesting a novel mechanism underlying the impaired infectivity. These results support the potential utility of the Nerium oleander aqueous extract, containing the CG oleandrin as a novel candidate anti-HIV therapeutic. 23572241 Generic Development of Topical Dermatologic Products, Part II: Quality by Design for Topical Semisolid Products. The emergence of quality by design as a relatively new systematic science and risk-based approach has added a new dimension to pharmaceutical development and manufacturing. This review attempts to discuss the quality by design elements and concepts applied for topical semisolid products. Quality by design begins with defining a quality target product profile as well as critical quality attributes. Subsequently, this is followed by risk identification/risk analysis/risk evaluation to recognize critical material attributes and critical process parameters, in conjunction with design of experiments or other appropriate methods to establish control strategies for the drug product. Several design-of-experiment examples are included as practical strategies for the development and optimization of formulation and process for topical drug products. 23567245 Inhibition of UVB-induced skin phototoxicity by a grape seed extract as modulator of nitrosative stress, ERK/NF-kB signaling pathway and apoptosis, in SKH-1 mice. Molecular mechanisms concerning the modulation of nitrosative stress, signal transduction and proliferation/apoptosis by a grape seed extract, Burgund Mare variety (BM), in SKH-1 mice exposed to UVB, were investigated. The animals were irradiated with single and multiple doses of UVB in 10 consecutive days. In each experiment were used five groups of animals: control, vehicle, UVB irradiated, vehicle+UVB, BM+UVB. The extract was applied topically, 30min before each UVB exposure, in a dose of 4mg total polyphenols/cm(2). BM remarkably inhibited UVB-induced activation of inducible nitric oxide synthase (iNOS) and therefore generation of nitric oxide (NO) and nitrotyrosine, in a UVB single dose regimen. BM also suppressed NF-kB activation by UVB but did not affect the activity of total ERK 1/2. In multiple UVB irradiations, BM increased NO formation and total ERK 1/2 activity and reduced iNOS activity and nitrotyrosine levels, inhibited cell proliferation, diminished p53 and caspase-3 immunoreactivities and increased the percentage of Bcl-2 positive cells. We concluded that BM modulates the apoptotic response of SKH-1 mice skin in UVB irradiation by the inhibition of p53, caspase-3, Bax/Bcl-2 and proliferating cell nuclear antigen expressions, as well as by reducing the activation of iNOS and NF-kB. 23182423 Genomic deletions and point mutations induced in Saccharomyces cerevisiae by the trinucleotide repeats (GAA·TTC) associated with Friedreich's ataxia. Expansion of certain trinucleotide repeats causes several types of human diseases, and such tracts are associated with the formation of deletions and other types of genetic rearrangements in Escherichia coli, yeast, and mammalian cells. Below, we show that long (230 repeats) tracts of the trinucleotide associated with Friedreich's ataxia (GAA·TTC) stimulate both large (>50 bp) deletions and point mutations in a reporter gene located more than 1 kb from the repetitive tract. Sequence analysis of deletion breakpoints indicates that the deletions reflect non-homologous end joining of double-stranded DNA breaks (DSBs) initiated in the tract. The tract-induced point mutations appear to reflect a different mechanism involving single-strand annealing of DNA molecules generated by DSBs within the tract, followed by filling-in of single-stranded gaps by the error-prone DNA polymerase zeta. 23359121 Agrochemicals in field margins-assessing the impacts of herbicides, insecticides, and fertilizer on the common buttercup (ranunculus acris). The effects of herbicide, insecticide, and fertilizer inputs on the common buttercup Ranunculus acris in field margins were studied in an experimental field study. The test design allowed us to investigate the single and combined effects of repeated herbicide, insecticide, and fertilizer applications in successive growing seasons. To assess the effects of the agrochemical applications on R. acris, plant community assessments were carried out and a photodocumentation of the flowering intensity was performed over two years. In addition, the authors conducted a monitoring survey of R. acris in field margins in the proximity of the study site. In the field experiment, R. acris plant density decreased significantly with treatments including fertilizer. The herbicide caused a sublethal effect by reducing flower intensity by 85%. In the long run, both effects will result in a decline of R. acris and lead to shifts in plant communities in field margins. This was confirmed by the monitoring survey, where R. acris could hardly be observed in field margins directly adjacent to cereal fields, whereas in margins next to meadows the species was recorded frequently. Besides the implications for the plants, the sublethal effects may also affect many flower-visiting insects. The results indicate that the current risk assessment for nontarget plants is insufficiently protective for wild plant species in field margins and that consideration of sublethal effects is crucial to preserve biodiversity in agricultural landscapes. Environ. Toxicol. Chem. 2013;32:1124-1131. © 2013 SETAC. 23537889 Two new tryptophan derivatives from the seed kernels of Entada rheedei: Effects on cell viability and HIV infectivity. Two new tryptophan derivatives, N-sulfonyl-L-tryptophan (tryptorheedei A) (1) and 3-(N-sulfonylindolyl)-D-lactic acid (tryptorheedei B) (2) together with the known 5-O-β-D-glucopyranosyl-2-hydroxyphenylacetic acid (3), 1-O-methylglucopyranoside, entadamide A, homogentisic acid and 3-O-β-D-glucopyranosyl-β-sitosterol, were isolated from the seed kernels of Entada rheedei (Mimosaceae). Their structures were established using 1D and 2D NMR spectroscopy, mass spectrometry and by comparison with spectroscopic data reported in the literature. Compounds 1 and 2 showed no toxicity to TZM and Human PBMC cells. Both compounds 1 and 2 were found to promote early infection events in HIV, likely by inhibiting the enzyme indolamine 2,3-dioxygenase (IDO) and preventing tryptophan depletion. Inhibition of IDO acutely in HIV infection inhibits viral replication, but chronic activation of IDO leads to immune impairment in AIDS. IDO is also the gatekeeper enzyme for kynurenine metabolism, a pathway involved in serotonin and melatonin biosynthesis and the regulation of glutamate and dopamine levels in the brain. Therefore inhibition of IDO might explain both the reported medicinal and neuropsychiatric effects of E. rheedei. 23417745 Quantum dots exhibit less bioaccumulation than free cadmium and selenium in the earthworm Eisenia andrei. The present study addresses the bioaccumulation behavior of cadmium selenide quantum dots by Eisenia andrei earthworms in a terrestrial environment. Earthworms were exposed to quantum dot-treated soil for up to 4 wk and analyzed for cadmium and selenium concentration using inductively coupled plasma mass spectrometry. Results were compared with those from earthworms exposed to cadmium nitrate and selenious acid, as positive controls, and those exposed in untreated soil (negative control). Earthworms exposed to quantum dots showed significant bioaccumulation of cadmium and selenium (5.3- and 1.5-fold higher concentration over negative controls, respectively) after 4 wk. Over the same 4 wk, positive control earthworms accumulated 9.2- and 2.2-fold higher cadmium and selenium, respectively, than negative controls for a much more substantial final body burden of the 2 elements. The concentrations also increased with exposure time; cadmium concentrations increased from 3600 ± 310 ng/g to 8080 ± 660 ng/g, from 1 to 4 wk, suggesting that further bioaccumulation may take place with even longer exposure time. The molar ratio of cadmium to selenium in the quantum dot-exposed worms (6.2) is closer to the ratios seen in positive control worms (7.2) than to the pure quantum dots (1.8), which implies that quantum dots are taken up predominantly in the degraded form. The results suggest that chemical modification of quantum dots to protect them from environmental degradation could potentially reduce bioaccumulation of the nanoparticles by earthworms. Environ Toxicol Chem 2013;32:1288-1294. © 2013 SETAC. 23315586 Phenotypic profiling of structural cardiotoxins in vitro reveals dependency on multiple mechanisms of toxicity. Morphological damage to cardiomyocytes or loss of viability (structural cardiotoxicity) is a common cause of attrition in preclinical and clinical drug development. Currently, no predictive in vitro approaches are available to detect this liability early in drug discovery, and knowledge of the mechanisms involved is limited. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and the rat myoblastic H9c2 cell lines were used to phenotypically profile a panel of structural cardiotoxins by live-cell fluorescent imaging of mitochondrial membrane potential, endoplasmic reticulum integrity, Ca(2+) mobilization, and membrane permeability combined with an assessment of cell viability (ATP depletion). Assay results were normalized to known therapeutically relevant concentrations. By comparing the outcome of each assay to the known in vivo effects, hESC-CMs offered an improved model over H9c2 cells for the detection of structural cardiotoxicity at therapeutically relevant concentrations. Inhibition of the spontaneously beating phenotype, a feature of stem cell-derived cardiomyocytes, revealed some degree of cardioprotection following 10 out of 13 structural cardiotoxins, illustrating the intricate relationship between the function and structure of cardiomyocytes. Classification of structural cardiotoxins into mechanistic themes revealed mitochondria and calcium mobilization to be major distal targets, with only 4 out of 15 compounds affecting contractile function in freshly isolated canine cardiomyocytes at therapeutically relevant concentrations. Our data demonstrate the utility of hESC-CMs during drug development to support structural cardiotoxicity hazard identification and to gain insight into the intricate mechanisms implicated in structural cardiotoxicity. 23262028 Chemokine expression is upregulated in chondrocytes in diabetic fracture healing. Chemokines are thought to play an important role in several aspects of bone metabolism including the recruitment of leukocytes and the formation of osteoclasts. We investigated the impact of diabetes on chemokine expression in normal and diabetic fracture healing. Fracture of the femur was performed in streptozotocin-induced diabetic and matched normoglycemic control mice. Microarray analysis was carried out and chemokine mRNA levels in vivo were assessed. CCL4 were examined in fracture calluses by immunohistochemistry and the role of TNF in diabetes-enhanced expression was investigated by treatment of animals with the TNF-specific inhibitor, pegsunercept. In vitro studies were conducted with ATDC5 chondrocytes. Diabetes significantly upregulated mRNA levels of several chemokines in vivo including CCL4, CCL8, CCL6, CCL11, CCL20, CCL24, CXCL2, CXCL5 and chemokine receptors CCR5 and CXCR4. Chondrocytes were identified as a significant source of CCL4 and its expression in diabetic fractures was dependent on TNF (P<0.05). TNF-α significantly increased mRNA levels of several chemokines in vitro which were knocked down with FOXO1 siRNA (P<0.05). CCL4 expression at the mRNA and proteins levels was induced by FOXO1 over-expression and reduced by FOXO1 knockdown. The current studies point to the importance of TNF-α as a mechanism for diabetes enhanced chemokine expression by chondrocytes, which may contribute to the accelerated loss of cartilage observed in diabetic fracture healing. Moreover, in vitro results point to FOXO1 as a potentially important transcription factor in mediating this effect. 23416173 Linking pesticide exposure and dementia: What is the evidence? There has been a steep increase in the prevalence of dementia in recent decades, which has roughly followed an increase in pesticide use some decades earlier, a time when it is probable that current dementia patients could have been exposed to pesticides. This raises the question whether pesticides contribute to dementia pathogenesis. Indeed, many studies have found increased prevalence of cognitive, behavioral and psychomotor dysfunction in individuals chronically exposed to pesticides. Furthermore, evidence from recent studies shows a possible association between chronic pesticide exposure and an increased prevalence of dementia, including Alzheimer's disease (AD) dementia. At the cellular and molecular level, the mechanism of action of many classes of pesticides suggests that these compounds could be, at least partly, accountable for the neurodegeneration accompanying AD and other dementias. For example, organophosphates, which inhibit acetylcholinesterase as do the drugs used in treating AD symptoms, have also been shown to lead to microtubule derangements and tau hyperphosphorylation, a hallmark of AD. This emerging association is of considerable public health importance, given the increasing dementia prevalence and pesticide use. Here we review the epidemiological links between dementia and pesticide exposure and discuss the possible pathophysiological mechanisms and clinical implications of this association. 23265457 Quality of bread supplemented with mushroom mycelia. Mushroom mycelia of Antrodia camphorata, Agaricus blazei, Hericium erinaceus and Phellinus linteus were used to substitute 5% of wheat flour to make bread. Bread quality, including specific volume, colour property, equivalent umami concentration (EUC), texture profile analysis, sensory evaluation and functional components, was analysed. Mycelium-supplemented bread was smaller in loaf volume and coloured, and had lower lightness and white index values. White bread contained the lowest amounts of free umami amino acids and umami 5'-nucleotides and showed the lowest EUC value. Incorporating 5% mushroom mycelia into the bread formula did not adversely affect the texture profile of the bread. However, incorporating 5% mushroom mycelia into the bread formula did lower bread's acceptability. After baking, mycelium-supplemented bread still contained substantial amounts of γ-aminobutyric acid and ergothioneine (0.23-0.86 and 0.79-2.10 mg/g dry matter, respectively). Overall, mushroom mycelium could be incorporated into bread to provide its beneficial health effects. 22511336 Anti-hyperglycemic effect of fermented ginseng in type 2 diabetes mellitus mouse model. Ginseng has shown an efficacy in preventing and managing various health conditions. This study aimed to evaluate the effect of the fermented ginseng extract (FGE) in type 2 diabetes mellitus murine model. FGE was provided to male C57BL/ksJ-db/db mice for 8 weeks at 0.1% (w/w) dose in contrast to water for the control group. Potential anti-diabetic mechanisms were investigated with blood glucose, serum insulin, serum adiponectin, hemoglobin A1c (HbA1c), glucose tolerance, insulin secretion assay, quantitative real-time polymerase chain reaction, and hematoxylin-eosin staining. Compared with the control group, the FGE group had lower levels of blood glucose after 6 and 9 h fasting, HbA1c, and the area under the curve in an oral glucose tolerance test and higher levels of adiponectin and serum insulin (p < 0.05). The FGE group had higher levels of peroxisome proliferator-activated receptor gamma 2 and glucose transporter protein 2 mRNAs, a lower level of tumor necrosis factor-α (TNF-α) (p < 0.05), and less lymphocytes in pancreas than the control group had. The FGE exerted anti-diabetic effects in type 2 diabetic mice. 23408271 Echinacea sanguinea and Echinacea pallida extracts stimulate glucuronidation and basolateral transfer of Bauer alkamides 8 and 10 and ketone 24 and inhibit P-glycoprotein transporter in Caco-2 cells. The use of Echinacea as a medicinal herb is prominent in the United States, and many studies have assessed the effectiveness of Echinacea as an immunomodulator. We hypothesized that Bauer alkamides 8, 10, and 11 and ketone 24 were absorbed similarly either as pure compounds or from Echinacea sanguinea and Echinacea pallida ethanol extracts, and that these Echinacea extracts could inhibit the P-glycoprotein transporter in Caco-2 human intestinal epithelial cells. Using HPLC analysis, the permeation rate of Bauer alkamides by passive diffusion across Caco-2 cells corresponded with compound hydrophilicity (alkamide 8 > 10 > 11), independent of the plant extract matrix. Both Echinacea ethanol extracts stimulated apparent glucuronidation and basolateral efflux of glucuronides of alkamides 8 and 10 but not alkamide 11. Bauer ketone 24 was totally metabolized to more hydrophilic metabolites when administered as a single compound, but was also glucuronidated when present in Echinacea extracts. Bauer alkamides 8, 10, and 11 (175-230 µM) and ethanol extracts of E. sanguinea (1 mg/mL, containing ~ 90 µM total alkamides) and E. pallida (5 mg/mL, containing 285 µM total alkamides) decreased the efflux of the P-glycoprotein transporter probe calcein-AM from Caco-2 cells. These results suggest that other constituents in these Echinacea extracts facilitated the metabolism and efflux of alkamides and ketones, which might improve therapeutic benefits. Alkamides and Echinacea extracts might be useful in potentiating some chemotherapeutics, which are substrates for the P-glycoprotein transporter. 23528888 The molecular fingerprint of high grade serous ovarian cancer reflects its fallopian tube origin. High grade serous ovarian cancer (HGSC), the most lethal and frequent type of epithelial ovarian cancer (EOC), has poor long term prognosis due to a combination of factors: late detection, great metastatic potential and the capacity to develop resistance to available therapeutic drugs. Furthermore, there has been considerable controversy concerning the etiology of this malignancy. New studies, both clinical and molecular, strongly suggest that HGSC originates not from the surface of the ovary, but from the epithelial layer of the neighboring fallopian tube fimbriae. In this paper we summarize data supporting the central role of fallopian tube epithelium in the development of HGSC. Specifically, we address cellular pathways and regulatory mechanisms which are modulated in the process of transformation, but also genetic changes which accumulate during disease progression. Similarities between fallopian tube mucosa and the malignant tissue of HGSC warrant a closer analysis of homeostatic mechanisms in healthy epithelium in order to elucidate key steps in disease development. Finally, we highlight the importance of the cancer stem cell (CSC) identification and understanding of its niche regulation for improvement of therapeutic strategies. 23172156 On the origin of the halo stabilization. Monte Carlo simulations show that charge-regulation alone can cause highly charged zirconium nanoparticles to adsorb to a similarly charged or neutral silica particle and thereby stabilizing the latter. This mechanism, referred to as halo stabilization, is quite general and applicable in a range of systems provided that pH, van der Waals forces, and dissociation constants of the charge-regulating particles are properly chosen. In our modeling we see an overall attraction at low volume fractions of nanoparticles, while at higher a repulsive barrier is created, stabilizing the microparticles and protecting them from aggregation. The charge-regulation mechanism also turns the silica surface from positively charged, without nanoparticles, to negatively charged in the presence of nanoparticles. 23524253 Thermoreversible in situ gelling poloxamer-based systems with chitosan nanocomplexes for prolonged subcutaneous delivery of heparin: Design and in vitro evaluation. In situ forming systems including thermoreversible hydrogels, which undergo sol-gel transition upon an increase in temperature have been used for various biomedical applications. Heparins are the standard of anticoagulation in the prophylaxis and treatment of deep vein thrombosis and pulmonary embolism. Both conditions require long-lasting treatment with frequent subcutaneous administrations of heparin. The objective of this study was to prepare and evaluate in situ forming gel systems designed by combination of two poloxamers (P407 and P188) and hydroxypropylmethylcellulose (HPMC) for prolonged release of heparin. Thermoreversible hydrogels were prepared with heparin solution and dispersion of heparin/chitosan nanocomplexes. Nanocomplexes formed by self-assembly of heparin with chitosan at various mass ratios were thoroughly characterized. A heparin/chitosan mass ratio of 1:1 with pH 5.20 was the most appropriate for preparation of small, homogenous and stable nanocomplexes (mean diameter 123nm; polydispersity index 0.22 and zeta potential+35.5mV). Thermoreversible hydrogels were evaluated by gelation temperature, viscosity over the temperature range 20-40°C, rate of hydrogel dissolution, and heparin release in vitro. The addition of P188 to P407 gel formulations resulted in an increase in gelation temperature, decrease in viscosity at room temperature and faster gel dissolution. The opposite effects were observed with formulations containing HPMC which demonstrated 18-day-long gel dissolution and complete heparin release in 9days from gels containing heparin solution. Considerable prolongation of heparin release was achieved with incorporation of heparin/chitosan nanocomplexes into the gelling systems. It may be concluded that with poloxamer mixtures at specific concentrations, addition of HPMC and use of heparin/chitosan nanocomplexes dispersions, thermoreversible formulations for prolonged subcutaneous release of heparin are feasible. 22830954 Effects of clopidogrel and clarithromycin on the disposition of sibutramine and its active metabolites M1 and M2 in relation to CYP2B6*6 polymorphism. Plasma concentrations of sibutramine and its two active metabolites after single oral dose of sibutramine were determined in Korean healthy male subjects with different CYP2B6 genotypes (CYP2B6*1/*1, *1/*6 and *6/*6), either alone or after four-day pretreatment with clopidogrel or clarithromycin. The pretreatment with clopidogrel and clarithromycin raised the mean area under the concentration-time curve (AUC) of sibutramine by 163% and 255%, respectively. Co-administration of clarithromycin, combined with CYP2B6*6/*6 genotype, led to highest concentration of sibutramine. The molar sum AUC (M1 + M2) was raised by 35% in the clopidogrel phase but not significantly affected by clarithromycin or CYP2B6 genotype. The CYP2B6*6/*6 subjects in the clopidogrel phase showed the highest molar AUC (M1 + M2) among three genotype groups throughout the three phases. The exposure of sibutramine and its metabolites seemed to be associated with the CYP2B6 genotype. The treatment of clopidogrel significantly altered the disposition of active metabolites as well as sibutramine, but clarithromycin only affects the disposition of sibutramine. These results suggest that the perturbation of CYP2B6 activity may contribute to the inter-individual variation of sibutramine drug responses although the clinical relevance is remained to be established. 23601753 Robust autoactivation, chymotrypsin C independence and diminished secretion define a subset of hereditary pancreatitis associated cationic trypsinogen mutants. Mutations in human cationic trypsinogen cause hereditary pancreatitis by altering its proteolytic regulation of activation and degradation by chymotrypsin C (CTRC). CTRC stimulates trypsinogen autoactivation by processing the activation peptide to a shorter form but also promotes degradation by cleaving the calcium binding loop in trypsinogen. Mutations render trypsinogen resistant to CTRC-mediated degradation and/or increase processing of the activation peptide by CTRC. Here we demonstrate that activation peptide mutations D19A, D22G, K23R and K23_I24insIDK robustly increased the rate of trypsinogen autoactivation, both in the presence and absence of CTRC. Degradation of the mutants by CTRC was unchanged and processing of the activation peptide was increased only in the D19A mutant by 4-fold. Surprisingly, however, this increased processing had only a minimal effect on autoactivation. The tetra-aspartate motif in the trypsinogen activation peptide binds calcium (KD ~1.6 mM), which stimulates autoactivation. Unexpectedly, calcium binding was not compromised by any of the activation peptide mutations. Despite normal binding, autoactivation of mutants D22G and K23_I24insIDK was not stimulated by calcium. Finally, the activation peptide mutants exhibited reduced secretion from transfected cells, and secreted trypsinogen levels were inversely proportional with autoactivation rates. We conclude that D19A, D22G, K23R and K23_I24insIDK form a mechanistically distinct subset of hereditary pancreatitis associated mutations, which exert their effect primarily through direct stimulation of autoactivation, independently of CTRC. The potentially severe clinical impact of the markedly increased autoactivation is offset by diminished secretion, resulting in a clinical phenotype indistinguishable from typical hereditary pancreatitis. This article is protected by copyright. All rights reserved. 23561166 Effects of fisetin supplementation on hepatic lipogenesis and glucose metabolism in Sprague-Dawley rats fed on a high fat diet. The modulatory effects of daily fisetin supplementation for 8weeks on genes involved in hepatic lipogenesis and gluconeogenesis and hyperglycemia in rats fed a high fat (HF) diet were evaluated. Elevated levels of triglyceride (TG), along with hepatic TG content and glucose concentrations in a high fat diet group were found to be reduced by fisetin supplementation. The high fat diet significantly increased hepatic mRNA expressions of PPARγ, SREBP1C and SCD-1 genes in comparison to the control diet, which was subsequently reversed by supplementation with fisetin. In addition, fisetin supplementation significantly reduced hepatic mRNA abundance of FAS, ATPCL and G6Pase compared to the control group. Finally, epididymal mRNA abundance of GLUT4 was significantly increased by fisetin supplementation, compared to levels in the control and HF groups. Enhancement of GLUT4 expression by fisetin was further confirmed in differentiated 3T3-L1 adipocytes. Fisetin supplementation decreases cardiovascular risks by ameliorating hepatic steatosis and lowering circulating glucose concentrations. 23321613 Empirical power of very rare variants for common traits and disease: results from sanger sequencing 1998 individuals. The optimal study design for identifying rare variants associated with common disease is not yet clear and researchers have to decide whether to prioritize lower sequencing coverage on larger sample sizes, or higher coverage on smaller sample sizes. High-coverage sequencing affords several advantages, such as genotype accuracy and improved identification of very rare variants, but this comes at increased cost. However, the magnitude of the contribution of very rare variants to the statistical power of gene-based association tests is unknown. By using Sanger sequence data on seven genes from 1998 subjects with simulated phenotypes, we provide evidence that excluding very rare variants, in general, reduces the statistical power of rare variant association tests only modestly. However, if the probability of being causal and the effect size of the causal variants are inversely related to the minor allele frequency, then very rare variants do contribute to some power, however the absolute power remains low. As very rare variants constitute the majority of variants identified in sequencing studies, these findings suggest that careful attention need to be placed on the plausible relationship that exist between very rare variants and common disease.European Journal of Human Genetics advance online publication, 16 January 2013; doi:10.1038/ejhg.2012.284. 22898566 The role of long chain omega-3 polyunsaturated fatty acids in reducing lipid peroxidation among elderly patients with mild cognitive impairment: a case-control study. The present work explores the effect of dietary omega-3 polyunsaturated fatty acids (PUFAs) intake on lipid peroxidation among mild cognitive impairment (MCI) patients. The plasma lipid hydroperoxide (LPO) levels in 67 MCI patients were compared to those of 134 healthy elderly controls. Omega-3 PUFA intake was assessed using an interviewer-administered food frequency questionnaire. Apolipoprotein E genotyping was performed using polymerase chain reaction and restriction enzyme digestion. The association between various confounders and lipid peroxidation was evaluated using regression analysis. The influence of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) intake on LPO level was investigated. The results revealed that LPO levels were significantly higher in the MCI group than in the control group. Inverse correlations were found between DHA and EPA intake and LPO level among the MCI group. LPO levels decreased significantly with increasing DHA and EPA intake. In summary, the findings revealed that DHA and EPA can play a role in alleviating oxidative stress and reducing the risk of neurodegenerative diseases. 23321564 Indenoindolone derivatives as topoisomerase II-inhibiting anticancer agents. Based on known heterocyclic topoisomerase II inhibitors and anticancer agents, various indenoindolone derivatives were predicted as potential topoisomerase II-inhibiting anticancer agents. They are hydrazones, (thio)semicarbazones, and oximes of indenoindolones, and indenoindolols. These derivatives with suitable substitutions exhibited potent specific inhibition of human DNA TopoIIα while not showing inhibition of topoisomerase I and DNA intercalation, despite the fact that parent indenoindolones are known poor/moderate inhibitors of topoisomerase II. The potent topoisomerase II inhibitor indenoindolone derivatives exhibited good anticancer activities compared to etoposide and 5-fluorouracil, and relatively low toxicity to normal cells. These derivatizations of indenoindolones were found to result in enhancement of anticancer activities. 23244292 Generation of B-doped graphene nanoplatelets using a solution process and their supercapacitor applications. Chemically modified graphene (CMG) nanoplatelets have shown great promise in various applications due to their electrical properties and high surface area. Chemical doping is one of the most effective methods to tune the electronic properties of graphene materials. In this work, novel B-doped nanoplatelets (borane-reduced graphene oxide, B-rG-O) were produced on a large scale via the reduction of graphene oxide by a borane-tetrahydrofuran adduct under reflux, and their use for supercapacitor electrodes was studied. This is the first report on the production of B-doped graphene nanoplatelets from a solution process and on the use of B-doped graphene materials in supercapacitors. The B-rG-O had a high specific surface area of 466 m(2)/g and showed excellent supercapacitor performance including a high specific capacitance of 200 F/g in aqueous electrolyte as well as superior surface area-normalized capacitance to typical carbon-based supercapacitor materials and good stability after 4500 cycles. Two- and three-electrode cell measurements showed that energy storage in the B-rG-O supercapacitors was contributed by ion adsorption on the surface of the nanoplatelets in addition to electrochemical redox reactions. 23313632 Asymmetric synthesis and anti-protozoal activity of the 8,4'-oxyneolignans virolin, surinamensin and analogues. The asymmetric synthesis of 8,4'-oxyneolignans (-)-virolin, (-)-surinamensin and a number of analogues has been achieved. A divergent synthesis was used, with all compounds being elaborated from a single chiral aldehyde derived from ethyl lactate. In the 15 compounds that were tested, the level of substitution on the A-ring was found to directly influence the activity against Leishmania donovani whilst the activity against Plasmodium falciparum was influenced by numerous substitution and stereochemical factors. 23466229 PF-04859989 as a template for structure-based drug design: identification of new pyrazole series of irreversible KAT II inhibitors with improved lipophilic efficiency. The structure-based design, synthesis, and biological evaluation of a new pyrazole series of irreversible KAT II inhibitors are described herein. The modification of the inhibitor scaffold of 1 and 2 from a dihydroquinolinone core to a tetrahydropyrazolopyridinone core led to discovery of a new series of potent KAT II inhibitors with excellent physicochemical properties. Compound 20 is the most potent and lipophilically efficient of these new pyrazole analogs, with a k(inact)/K(i) value of 112,000 M(-1)s(-1) and lipophilic efficiency (LipE) of 8.53. The X-ray crystal structure of 20 with KAT II demonstrates key features that contribute to this remarkable potency and binding efficiency. 23381968 Different effects of clopidogrel and clarithromycin on the enantioselective pharmacokinetics of sibutramine and its active metabolites in healthy subjects. In this study, we assessed the effects of clopidogrel and clarithromycin, known CYP2B6 and CYP3A inhibitors, respectively, on the enantioselective disposition of racemic sibutramine in conjunction with CYP2B6 polymorphisms in humans. Sibutramine showed enantioselective plasma profiles with consistently higher concentrations of R-enantiomers. Clopidogrel and clarithromycin significantly increased the sibutramine plasma concentration, but their effects differed between enantiomers; a 2.2-fold versus 4.1-fold increase in the AUC in S-enantiomer and 1.8-fold versus 2.0-fold for the R-enantiomer, respectively. The AUCs of S- and R-desmethyl metabolites changed significantly during the clopidogrel phase (P < .001 and P < .001, respectively) but not during the clarithromycin phase (P = .099 and P = .090, respectively). Exposure to sibutramine was higher in subjects with the CYP2B6*6/*6 genotype, but no statistical difference was observed among the CYP2B6 genotypes. These results suggest that the enantioselective disposition of sibutramine and its active metabolites are influenced by the altered genetic and environmental factors of CYP2B6 and CYP3A activity in vivo. 23261679 Monotropein isolated from the roots of Morinda officinalis ameliorates proinflammatory mediators in RAW 264.7 macrophages and dextran sulfate sodium (DSS)-induced colitis via NF-κB inactivation. We previously demonstrated that monotropein isolated from the roots of Morinda officinalis (Rubiaceae) has anti-inflammatory effects in vivo. In the present study, we investigated the molecular mechanisms underlying the anti-inflammatory effects of monotropein in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and dextran sulfate sodium (DSS)-induced colitis mouse model. Monotropein was found to inhibit the expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) mRNA in LPS-induced RAW 264.7 macrophages. Treatment with monotropein decreased the DNA binding activity of nuclear factor-κB (NF-κB). Consistent with these findings, monotropein also suppressed phosphorylation and degradation of inhibitory κB-α (IκB-α), and consequently the translocations of NF-κB. In the DSS-induced colitis model, monotropein reduced disease activity index (DAI), myeloperoxidase (MPO) activity, and inflammation-related protein expressions by suppressing NF-κB activation in colon mucosa. Taken together, these findings suggest that the anti-inflammatory effects of monotropein are mainly related to the inhibition of the expressions of inflammatory mediators via NF-κB inactivation, and support its possible therapeutic role in colitis. 23444285 Pharmacokinetics of modified-release prednisone tablets in healthy subjects and patients with rheumatoid arthritis. In rheumatoid arthritis (RA), nocturnal release of proinflammatory cytokines is not adequately counteracted by endogenous glucocorticoid and is associated with symptoms of morning stiffness and pain. Taking exogenous glucocorticoid during the night reduces morning stiffness significantly more than treatment at the conventional time in the morning, although waking to take tablets is unacceptable for patients. Modified-release prednisone tablets were developed to allow administration at bedtime for programmed delivery of glucocorticoid during the night. Single-center crossover studies were conducted, each in ≤24 healthy subjects, to compare the pharmacokinetics of a single 5-mg oral dose of modified-release prednisone and conventional prednisone, as well as the effect of food on bioavailability. There was no substantial difference in pharmacokinetic parameters of the formulations apart from the programmed delay in release of glucocorticoid from the modified-release tablets (C(max) 97%, AUC(0-∞) 101%, 90% confidence intervals within the requisite range for bioequivalence). Administration after a full or light meal did not affect pharmacokinetic characteristics, but bioavailability was reduced under fasted conditions. Pharmacokinetic evaluation in 9 patients with RA confirmed that modified-release prednisone tablets taken at bedtime (around 22:00 h) with or after an evening meal result in programmed release of glucocorticoid 4 to 6 hours after intake. 23527691 Tensile Lattice Strain Accelerates Oxygen Surface Exchange and Diffusion in La1-xSrxCoO3-δ Thin Films. The influence of lattice strain on the oxygen exchange kinetics and diffusion in oxides was investigated on (100) epitaxial La1-xSrxCoO3-δ (LSC) thin films grown by pulsed laser deposition. Planar tensile and compressively strained LSC films were obtained on single-crystalline SrTiO3 and LaAlO3. (18)O isotope exchange depth profiling with ToF-SIMS was employed to simultaneously measure the tracer surface exchange coefficient k* and the tracer diffusion coefficient D* in the temperature range 280-475 °C. In accordance with recent theoretical findings, much faster surface exchange (∼4 times) and diffusion (∼10 times) were observed for the tensile strained films compared to the compressively strained films in the entire temperature range. The same strain effect-tensile strain leading to higher k* and D*-was found for different LSC compositions (x = 0.2 and x = 0.4) and for surface-etched films. The temperature dependence of k* and D* is discussed with respect to the contributions of strain states, formation enthalpy of oxygen vacancies, and vacancy mobility at different temperatures. Our findings point toward the control of oxygen surface exchange and diffusion kinetics by means of lattice strain in existing mixed conducting oxides for energy conversion applications. 23202847 Synthesis and antibacterial and antifungal evaluation of some chalcone based sulfones and bisulfones. Two series of chalcone based sulfone and bisulfone derivatives were synthesized using chalcone, thiophenol and sodium metal at room temperature, followed by oxidation of chalcone sulfides with m-CPBA at 0 °C in a novel method. Both sulfones and bisulfones were evaluated for their antimicrobial activities against Aspergillus niger and Candida albicans (yeast), Bacillus subtilis and Staphylococcus aureus (Gram (+) bacteria) and Pseudomonas aeruginosa and Salmonella typhimurium (Gram (-) bacteria) strains. Among them, compounds 2c, 3c, 6c, 7c, 8c and 9c have shown high antifungal activity against C. albicans compare to reference drugs viz. Amphotericin-B and Nystatin. Compound 1c has shown slightly better antibacterial activity against B. subtilis and compounds 5c, 6c and 7c have shown excellent antibacterial activity against S. typhimurium in compare to reference drugs Ampicillin and Kanamycin. 23265516 Stabilization of anthocyanin and skullcap flavone complexes--investigations with computer simulation and experimental methods. We examined the stabilization of anthocyanins with flavones from the practical and theoretical perspective. The influence of addition of skullcap flavones, heating to 50 °C, and 12 day storage time (in the presence and absence of light) on the stability of anthocyanins in honeysuckle concentrates was investigated experimentally. Theoretical study was conducted with molecular dynamics methods in a model system, preceded by simulated annealing and thermalization. By the methods of the computer simulation of the copigmentation process we determined the sites responsible for the stabilization of a cyanidin quinoidal base-baicalin complex. We revealed both direct and water-mediated hydrogen bondings that keep the lamellar stacking structure of these molecules in the bounded form in water medium. The stacking occurs also due to hydrophobic interactions of the rings of both molecules. The experimental part of the study confirmed the effectiveness of anthocyanins stabilization in a concentrate of honeysuckle with the use of skullcap flavones. 23546397 Hepatoprotective potential of Lavandula coronopifolia extracts against ethanol induced oxidative stress-mediated cytotoxicity in HepG2 cells. The present investigations were carried out to study the protective potential of four extracts (namely petroleum ether extract (LCR), chloroform extract (LCM), ethyl acetate extract (LCE), and alcoholic extract (LCL)) of Lavandula coronopifolia on oxidative stress-mediated cell death induced by ethanol, a known hepatotoxin in human hapatocellular carcinoma (HepG2) cells. Cells were pretreated with LCR, LCM, LCE, and LCL extracts (10-50 μg/ml) of L. coronopifolia for 24 h and then ethanol was added and incubated further for 24 h. After the exposure, cell viability using (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and neutral red uptake assays and morphological changes in HepG2 cells were studied. Pretreatment with various extracts of L. coronpifolia was found to be significantly effective in countering the cytotoxic responses of ethanol. Antioxidant properties of these L. coronopifolia extracts against reactive oxygen species (ROS) generation, lipid peroxidation (LPO), and glutathione (GSH) levels induced by ethanol were investigated. Results show that pretreatment with these extracts for 24 h significantly inhibited ROS generation and LPO induced and increased the GSH levels reduced by ethanol. The data from the study suggests that LCR, LCM, LCE, and LCL extracts of L. coronopifolia showed hepatoprotective activity against ethanol-induced damage in HepG2 cells. However, a comparative study revealed that the LCE extract was found to be the most effective and LCL the least effective. The hepatoprotective effects observed in the study could be associated with the antioxidant properties of these extracts of L. coronopifolia. 22531751 Selective activation of either mGlu2 or mGlu3 receptors can induce LTD in the amygdala. Group II metabotropic glutamate (mGlu) receptors are known to induce a long-term depression (LTD) of synaptic transmission in many brain regions including the amygdala. However the roles of the individual receptor subtypes, mGlu2 and mGlu3, in LTD are not well understood. In particular, it is unclear whether activation of mGlu3 receptors is sufficient to induce LTD at synapses in the CNS. In the present study, advantage was taken of a Wistar rat strain not expressing mGlu2 receptors (Ceolin et al., 2011) to investigate the function of mGlu3 receptors in the amygdala. In this preparation, the group II agonist, DCG-IV induced an LTD of the cortical, but not the intra-nuclear, synaptic input to the lateral amygdala. This LTD was concentration dependent and was blocked by the group II mGlu receptor antagonist, LY341495. To investigate further the role of mGlu3 receptors, we used LY395756 (an mGlu2 agonist and mGlu3 antagonist), which acts as a pure mGlu3 receptor antagonist in this rat strain. This compound alone had no effect on basal synaptic transmission, but blocked the LTD induced by DCG-IV. Furthermore, we found that DCG-IV also induces LTD in mGlu2 receptor knock-out (KO) mice to a similar extent as in wild-type mice. This confirms that the activation of mGlu3 receptors alone is sufficient to induce LTD at this amygdala synapse. To address whether mGlu2 activation alone is also sufficient to induce LTD at this synapse we used LY541850 (the active enantiomer of LY395756) in wild-type mice. LY541850 induced a substantial LTD showing that either receptor alone is capable of inducing LTD in this pathway. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23334855 Cloning and functional analysis of three genes encoding polygalacturonase-inhibiting proteins from Capsicum annuum and transgenic CaPGIP1 in tobacco in relation to increased resistance to two fungal pathogens. Polygalacturonase-inhibiting proteins (PGIPs) are plant cell wall glycoproteins that can inhibit fungal endopolygalacturonases (PGs). The PGIPs directly reduce the aggressive potential of PGs. Here, we isolated and functionally characterized three members of the pepper (Capsicum annuum) PGIP gene family. Each was up-regulated at a different time following stimulation of the pepper leaves by Phytophthora capcisi and abiotic stresses including salicylic acid, methyl jasmonate, abscisic acid, wounding and cold treatment. Purified recombinant proteins individually inhibited activity of PGs produced by Alternaria alternata and Colletotrichum nicotianae, respectively, and virus-induced gene silencing in pepper conferred enhanced susceptibility to P. capsici. Because three PGIP genes acted similarily in conferring resistance to infection by P. capsici, and because individually purified proteins showed consistent inhibition against PG activity of both pathogens, CaPGIP1 was selected for manipulating transgenic tobacco. The crude proteins from transgenic tobacco exhibited distinct enhanced resistance to PG activity of both fungi. Moreover, the transgenic tobacco showed effective resistance to infection and a significant reduction in the number of infection sites, number of lesions and average size of lesions in the leaves. All results suggest that CaPGIPs may be involved in plant defense response and play an important role in a plant's resistance to disease. 23238784 Phase 1 and phase 2 drug metabolism and bile acid production of HepaRG cells in a bioartificial liver in absence of dimethyl sulfoxide. The human liver cell line HepaRG has been recognized as a promising source for in vitro testing of metabolism and toxicity of compounds. However, currently the hepatic differentiation of these cells relies on exposure to dimethylsulfoxide (DMSO), which, as a side effect, has a cytotoxic effect and represses an all-round hepatic functionality. The AMC-bioartificial liver (AMC-BAL) is a three-dimensional bioreactor that has previously been shown to upregulate various liver functions of cultured cells. We therefore cultured HepaRG cells in the AMC-BAL without DMSO and characterized the drug metabolism. Within 14 days of culture, the HepaRG-AMC-BALs contained highly polarized viable liver-like tissue with heterogeneous expression of CYP3A4. We found a substantial metabolism of the tested substrates, ranging from 26% (UDP-glucuronosyltransferase 1A1), 47% (CYP3A4), to 240% (CYP2C9) of primary human hepatocytes. The CYP3A4 activity could be induced 2-fold by rifampicin, whereas CYP2C9 activity remained equally high. The HepaRG-AMC-BAL secreted bile acids at 43% the rate of primary human hepatocytes and demonstrated hydroxylation, conjugation, and transport of bile salts. Concluding, culturing HepaRG cells in the AMC-BAL yields substantial phase 1 and phase 2 drug metabolism, while maintaining high viability, rendering DMSO addition superfluous for the promotion of drug metabolism. Therefore, AMC-BAL culturing makes the HepaRG cells more suitable for testing metabolism and toxicity of drugs. 23385210 Design and synthesis of imidazole and triazole derivatives as Lp-PLA₂ inhibitors and the unexpected discovery of highly potent quaternary ammonium salts. New Lp-PLA(2) inhibitors were synthesized by the bioisosteric replacement of the amide group of Darapladib with an imidazole or a triazole. Unfortunately, the inhibitory activities of these derivatives were lower than that of Darapladib. But interestingly, a series of quaternary ammonium salts that were isolated as by-products during this synthetic work were found with high potency. Of these by-products, compound 22c showed a similar profile to Darapladib both in vitro and in vivo. 23621573 High-Accuracy Estimates for the Vinylidene-Acetylene Isomerization Energy and the Ground State Rotational Constants of :C=CH2. Highly accurate calculations are reported for properties of vinylidene (H2C=C:), specically the position of its zero-point vibrational level relative to that of acetylene and its equilibrium structure and ground state rotational constants. The isomerization energy of vinylidene calculated at the HEAT-456QP level of theory is 45.530.15 kcal mol1, in agreement with the previous best estimate, but associated with a much smaller uncertainty. In addition, the thermochemical calculations presented here also allow a determination of the :C=CH2 bond energy of the vinyl radical at the HEAT-345(Q) level of theory, which is 77.70.3 kcal mol1. The equilibrium structure of vinylidene, estimated with an additivity scheme that includes treatment of correlation eects beyond CCSD(T) as well as relativistic and adiabatic (diagonal Born-Oppenheimer correction) contributions is rCC=1.29820.0003 A; rCH=1.08440.0003 A; and CCH=120.050.05o, with zero-point rotational constants (including vibrational contributions and electronic contributions to the moment of inertia) estimated to be A0 = 9.49250.0150 cm1; B0 = 1.32170.0017 cm1 and C0 = 1.16020.0016 cm1. INTRODUCTION. 23219324 Inhibitory effects of metachromins L-Q and its related analogs against receptor tyrosine kinases EGFR and HER2. Metachromins are a series of sesquiterpenoid quinones isolated from Okinawan marine sponges. Inhibitory effects of metachromins L-Q (1-6), sesquiterpenoid quinones with an amino acid residue, and their related analogs (7-18) prepared from metachromins A (19) and C (20) against receptor tyrosine kinases EGFR and HER2 were investigated. Two analogs 11 and 12 showed relatively stronger inhibitory activity against EGFR, while metachromins L-Q (1-6) and seven analogs (8, 10, 11, and 15-18) showed inhibitory activities against HER2. 23265522 Burdock fructooligosaccharide induces fungal resistance in postharvest Kyoho grapes by activating the salicylic acid-dependent pathway and inhibiting browning. Burdock fructooligosaccharide (BFO) is a natural elicitor from Arcitum lappa. The effects of BFO in controlling postharvest disease in grape, apple, banana, kiwi, citrus, strawberry, and pear were investigated. The disease index, decay percentage, and area under the disease progress curve indicated that BFO has general control effects on postharvest disease of fruits. Kyoho grapes were studied to elucidate the mechanism of BFO in boosting the resistance of grapes to Botrytis cinerea infection. BFO treatment induced upregulation of the npr1, pr1, pal, and sts genes, and inhibited the total phenol content decrease, which activated chitinase and β-1,3-glucanase. These results indicated that the salicylic acid-dependent signalling pathway was induced. The delayed colour change and peroxidase and polyphenoloxidase activity suggested that BFO delayed grape browning. The reduced respiration rate, weight loss, and titratable acidity prolonged the shelf life of postharvest grapes. BFO is a promising elicitor in postharvest disease control. 23594304 Physicochemical characterization of phyllanthin from Phyllanthus amarus Schum. et Thonn. Abstract Phyllanthin is a major bioactive lignan component of Phyllanthus amarus, with several known biological activities. This study dealt with the isolation and physicochemical characterization of phyllanthin. Phyllanthin was isolated from P. amarus leaves by column chromatography and purified by recrystallization to obtain phyllanthin crystals with a purity of more than 98%. UV, IR, MS, (1)H NMR and (13)C NMR spectra were employed to identify phyllanthin. The physicochemical properties of phyllanthin were characterized using differential scanning calorimetry, thermogravimetric analysis, X-ray diffraction, pH-solubility, ionization property and lipophilicity. The results indicated that phyllanthin crystals had the melting point and melting enthalpy range of 96.67-97.03 °C and 109.61-116.34 J/g, respectively. Three kinds of phyllanthin crystals, recrystallized by petroleum ether, absolute ethanol and 25% ethanol solution, showed only one polymorph and no polymorphic impurity. Phyllanthin in a solid state was found to undergo significant thermal decomposition above 200 °C. The compound demonstrated good stability in aqueous solution over a pH range of 1.07-10.02 for at least 4 h. The solubility of phyllanthin appeared to be pH-independent of pH range from 1.07 to 10.26. Ionization property studied by absorbance spectroscopy method was in agreement with the result of pH-solubility study, showing that phyllanthin has no pKa over a pH range of 1.12-10.02. The log Pow value of phyllanthin was found to be 3.30 ± 0.05 at pH 7.48, suggesting that phyllanthin may have good permeability through biological membranes. The findings could be useful tools for the development of stable and bioavailable oral dosage forms of phyllanthin. 23608240 Botany, traditional uses, phytochemistry and pharmacology of Waltheria indica L. (syn. Waltheria americana): A review. ETHNOPHARMACOLOGICAL RELEVANCE: Waltheria indica L. (syn. Waltheria americana) is commonly used in traditional medicine in Africa, South America and Hawaii, mainly against pain, inflammation, conditions of inflammation, diarrhea, dysentery, conjunctivitis, wounds, abscess, epilepsy, convulsions, anemia, erectile dysfunctions, bladder ailments and asthma. AIM OF THE REVIEW: To provide an up-to-date overview of the botany, phytochemistry, traditional uses, pharmacological activities and toxicity data of Waltheria indica. Additionally, studies providing an evidence for local and traditional uses of Waltheria indica are discussed. Further phytochemical and pharmacological potential of this species are suggested for future investigations. MATERIALS AND METHODS: The information was collected from scientific journals, books, theses and reports via academic libraries and electronic search. These sources include Pubmed, Web of Science, Portal de Portales-Latindex, Science Research.com and Google scholar. These studies about the medical botanical, traditional uses, chemical, pharmacological and toxicological data on Waltheria indica were published in English, Portuguese, Spanish, German and French. RESULTS: Crude extracts and isolated compounds from Waltheria indica were investigated and showed analgesic, anti-inflammatory, antibacterial, antifungal, antimalarial, anti-anemic, anti-oxidant, sedative and anticonvulsant activities. The phytochemical investigations showed the presence of cyclopeptid alkaloids, flavonoids (e.g., (-)-epicatechin, quercetin, kaempferol, kaempferol-3-O-β-d-(6″-E-p-coumaryl)-glucopyranoside), tannins, sterols, terpenes, saponins, anthraquinones. Studies of acute toxicity in animal indicated that Waltheria indica can be toxic. CONCLUSION: Waltheria indica possess therapeutic potential in the treatment of inflammation, malaria, infectious diseases (e.g., lungs infection due to Klebsiella pneumoniae, diarrhea due to Candida albicans or Escherichia coli) and prevention of oxidative stress. Further studies are necessary to explore pure compounds responsible for the pharmacological effects and the mechanisms of action. Further investigations are also needed to provide an evidence base for traditional uses of this species against pain, anemia, convulsions and epilepsy. In addition, there is a pressing need to investigate the other traditional uses such as dysentery, syphilis, erectile dysfunctions and asthma. 23143802 Thyroid disruption in the lizard Podarcis bocagei exposed to a mixture of herbicides: a field study. Pesticide exposure has been related with thyroid disrupting effects in different vertebrate species. However, very little is known about the effects of these compounds in reptiles. In the Mediterranean area, lacertid lizards are the most abundant vertebrate group in agroecosystems, and have been identified as potential model species for reptile ecotoxicology. The aim of this study was to understand if the herbicides applied in corn fields have thyroid disruptive effects in the lizard Podarcis bocagei. Adult male lizards were captured in north-western Portugal in corn fields treated with herbicides (exposed sites), and in organic agricultural fields (reference sites). Thyroid and male gonad morphology and functionality, and testosterone levels were investigated through histological, immunohistochemical and biochemical techniques. Lizards from exposed locations displayed thyroid follicular lumens with more reabsorption vacuoles and significantly larger follicular area than those from reference fields. Furthermore, testes of lizards from exposed locations had significantly larger seminiferous tubule diameters, significantly higher number of spermatogenic layers and displayed an up-regulation of thyroid hormone receptors when compared with lizards from reference areas. These findings strongly suggest that the complex mixture of herbicides that lizards are exposed to in agricultural areas have thyroid disrupting effects which ultimately affect the male reproductive system. Alachlor, which has demonstrated thyroid effects in mammals, may be largely responsible for the observed effects. 23603634 Global analytical strategy to measure drug-plasma protein interactions: from high-throughput to in-depth analysis. The selection of drug candidates with improved pharmacokinetics is essential to reduce the attrition rates during drug development and represents one of the big challenges faced by the pharmaceutical industry. Plasma protein binding (PPB) is an important parameter with significant implications for in vivo drug performance. Today, the most widely used techniques for PPB measurement in the pharmaceutical community are equilibrium dialysis (ED) and ultrafiltration (UF). However, these techniques have some limitations. Thus, we emphasize an alternative strategy, based on a global, new and easy-to-follow methodology, to screen and perform determination of PPB, using orthogonal techniques (i.e. liquid chromatography, capillary electrophoresis (CE), surface plasmon resonance (SPR) based biosensor). We anticipate that the increased knowledge gained through this strategy will lead to improved drug candidates. 23249538 Recent developments in the study of opioid receptors. It is now about 40 years since Avram Goldstein proposed the use of the stereoselectivity of opioid receptors to identify these receptors in neural membranes. In 2012, the crystal structures of the four members of the opioid receptor family were reported, providing a structural basis for understanding of critical features affecting the actions of opiate drugs. This minireview summarizes these recent developments in our understanding of opiate receptors. Receptor function is also influenced by amino acid substitutions in the protein sequence. Among opioid receptor genes, one polymorphism is much more frequent in human populations than the many others that have been found, but the functional significance of this single nucleotide polymorphism (SNP) has been unclear. Recent studies have shed new light on how this SNP might influence opioid receptor function. In this minireview, the functional significance of the most prevalent genetic polymorphism among the opioid receptor genes is also considered. 23421930 Bioactive phenolics from Seriphidium stenocephalum. Chromatographic separation of the ethyl acetate soluble part of the methanolic extract from Seriphidium stenocephalum yielded three new compounds: stenocepflavone (1), stenocepflavan (2), and stenocephol (3), together with cirsimaritin (4), 5,7,5'-trihydroxy-3',4',6-trimethoxyflavone (5), 5,6,7,5'-tetrahydroxy-4'-methoxyflavone (6), and axillaroside (7). All isolates were characterized with the help of spectroscopic data including 1D, 2D NMR, and high resolution mass spectrometry and/or in comparison with the related compounds in literature. All compounds were tested for in vitro enzyme inhibitory activities against acetylcholinesterase, butyrylcholinesterase, and lipoxygenase. Compounds 1 and 4-7 exhibited significant activity against all the tested enzymes, whereas compounds 2 and 3 were found inactive. 23117207 The S349T mutation of SQSTM1 links Keap1/Nrf2 signalling to Paget's disease of bone. Mutations affecting the Sequestosome 1 (SQSTM1) gene commonly occur in patients with the skeletal disorder Paget's disease of bone (PDB), a condition characterised by defective osteoclast differentiation and function. Whilst most mutations cluster within the ubiquitin-associated (UBA) domain of the SQSTM1 protein, and are associated with dysregulated NFκB signalling, several non-UBA domain mutations have also been identified. Keap1 is a SQSTM1-interacting protein that regulates the levels and activity of the Nrf2 transcription factor. This in turn controls the expression of numerous cytoprotective genes that contribute to the cell's capacity to defend itself against chemical and oxidative stress, through binding to the antioxidant response element (ARE). The PDB-associated S349T mutation maps to the Keap1-interacting region (KIR) of SQSTM1, however the effects of PDB mutant SQSTM1 on Keap1 function have not been investigated. Here we show that unlike other SQSTM1 mutations, the S349T mutation results in neither impaired ubiquitin-binding function in pull-down assays, nor dysregulated NFκB signalling in luciferase reporter assays. Keap1 is expressed in differentiating osteoclast-like cells and the S349T mutation selectively impairs the SQSTM1-Keap1 interaction in co-immunoprecipitations, which molecular modelling indicates results from effects on critical hydrogen bonds required to stabilise the KIR-Keap1 complex. Further, S349T mutant SQSTM1, but not other PDB-associated mutants, showed reduced ability to activate Nrf2 signalling as assessed by ARE-luciferase reporter assays. Thus, SQSTM1-mediated dysregulation of the Keap1-Nrf2 axis, which could potentially lead to aberrant production of oxidative response genes, may contribute to disease aetiology in a subset of PDB patients. 22391562 A potent Chk1 inhibitor is selectively cytotoxic in melanomas with high levels of replicative stress. There are few effective treatments for metastatic melanoma. Checkpoint kinase 1 (Chk1) inhibitors are being trialled for their efficacy in enhancing conventional chemotherapeutic agents, but their effectiveness as single agents is not known. We have examined the effectiveness of two novel Chk1 selective inhibitors, AR323 and AR678, in a panel of melanoma cell lines and normal cell types. We demonstrate that these drugs display single-agent activity, with IC50s in the low nanomolar range. The drugs produce cytotoxic effects in cell lines that are most sensitive to these drugs, whereas normal cells are only sensitive to these drugs at the higher concentrations where they have cytostatic activity. The cytotoxic effect is the consequence of inhibition of S-phase Chk1, which drives cells prematurely from late S phase into an aberrant mitosis and results in either failure of cytokinesis or cell death through an apoptotic mechanism. The sensitivity to the Chk1 inhibitors was correlated with the level of endogenous DNA damage indicating replicative stress. Chk1 inhibitors are viable single-agent therapies that target melanoma cells with high levels of endogenous DNA damage. This sensitivity suggests that Chk1 is a critical component of an adaptation to replicative stress in these cells. It also suggests that markers of DNA damage may be useful in identifying the melanomas and potentially other tumour types that are more likely to be sensitive to Chk1 inhibitors as single agents. 23428407 Unraveling the mode of action of an obesogen: Mechanistic analysis of the model obesogen tributyltin in the 3T3-L1 cell line. Obesogenic compounds are chemicals that have an influence on obesity development. This study was designed to unravel the molecular mechanisms of the model obesogen TBT, using microarray analysis in the 3T3-L1 in vitro system, and to evaluate the use of toxicogenomics for obesogen screening. The microarray results revealed enrichment of Gene Ontology terms involved in energy and fat metabolism after 10days of TBT exposure. Pathway analysis unveiled PPAR signalling pathway as the sole pathway significantly enriched after 1day and the most significantly enriched pathway after 10days of exposure. To our knowledge, this is the first study delivering an in depth mechanistic outline of the mode of action of TBT as an obesogen, combining effects on both cell physiological and gene expression level. Furthermore, our results show that combining transcriptomics with 3T3-L1 cells is a promising tool for screening of potential obesogenic compounds. 23392757 Antidepressant treatment and emotional processing: can we dissociate the roles of serotonin and noradrenaline? The ability to match individual patients to tailored treatments has the potential to greatly improve outcomes for individuals suffering from major depression. In particular, while the vast majority of antidepressant treatments affect either serotonin or noradrenaline or a combination of these two neurotransmitters, it is not known whether there are particular patients or symptom profiles which respond preferentially to the potentiation of serotonin over noradrenaline or vice versa. Experimental medicine models suggest that the primary mode of action of these treatments may be to remediate negative biases in emotional processing. Such models may provide a useful framework for interrogating the specific actions of antidepressants. Here, we therefore review evidence from studies examining the effects of drugs which potentiate serotonin, noradrenaline or a combination of both neurotransmitters on emotional processing. These results suggest that antidepressants targeting serotonin and noradrenaline may have some specific actions on emotion and reward processing which could be used to improve tailoring of treatment or to understand the effects of dual-reuptake inhibition. Specifically, serotonin may be particularly important in alleviating distress symptoms, while noradrenaline may be especially relevant to anhedonia. The data reviewed here also suggest that noradrenergic-based treatments may have earlier effects on emotional memory that those which affect serotonin. 23411287 The protein interactions and rheological properties of skim milk heated in the presence of low levels of reducing agent. Skim milk with low levels of added β-mercaptoethanol (SM-ME) and untreated skim milk (SM) were heated and then made into acid gels. Acid gels prepared from heated SM-ME had markedly higher firmness and contained more protein connections than acid gels prepared from heated SM. Electrophoretic analyses of the milks showed that the levels of β-lactoglobulin and α-lactalbumin associated with the casein micelles increased with increasing β-ME concentration. The levels of disulphide-linked whey proteins were higher in SM-ME than in SM. This suggested that there may be higher levels of initiators for thiol-disulphide exchange reactions, resulting in an increase in the rate of the reactions and the formation of greater numbers of small aggregates, in SM-ME than in SM. Consequently, acid gels made from SM-ME may have more bonds and more particles participating in the network, resulting in firmer gels, than acid gels made from SM. 23268441 GBSA: a comprehensive software for analysing whole genome bisulfite sequencing data. High-throughput sequencing is increasingly being used in combination with bisulfite (BS) assays to study DNA methylation at nucleotide resolution. Although several programmes provide genome-wide alignment of BS-treated reads, the resulting information is not readily interpretable and often requires further bioinformatic steps for meaningful analysis. Current post-alignment BS-sequencing programmes are generally focused on the gene-specific level, a restrictive feature when analysis in the non-coding regions, such as enhancers and intergenic microRNAs, is required. Here, we present Genome Bisulfite Sequencing Analyser (GBSA-http://ctrad-csi.nus.edu.sg/gbsa), a free open-source software capable of analysing whole-genome bisulfite sequencing data with either a gene-centric or gene-independent focus. Through analysis of the largest published data sets to date, we demonstrate GBSA's features in providing sequencing quality assessment, methylation scoring, functional data management and visualization of genomic methylation at nucleotide resolution. Additionally, we show that GBSA's output can be easily integrated with other high-throughput sequencing data, such as RNA-Seq or ChIP-seq, to elucidate the role of methylated intergenic regions in gene regulation. In essence, GBSA allows an investigator to explore not only known loci but also all the genomic regions, for which methylation studies could lead to the discovery of new regulatory mechanisms. 23578612 Proposal of mechanism of the freeze-thaw fractionation of 7S and 11S globulins in soymilk. The mechanism underlying the freeze-thaw fractionation of 7S and 11S globulins in soymilk was investigated. Freeze-thawed soymilk demonstrated an increased particle size compared with raw soymilk. Further, when defatted raw soymilk was freeze-thawed, it was fractionated into 7S (supernatant) and 11S (precipitate) globulins, similar to what is found with freeze-thaw of raw soymilk. When raw soymilk samples with different ratios of 11S/7S were freeze-thawed, the 11S-deficient variety showed no precipitate. The addition of sodium sulphite or sodium dodecyl sulphate also inhibited precipitate formation after freeze-thawing, resulting in no fractionation. These results suggest that the fractionation is due to selective precipitation of aggregates of 11S globulins and/or 11S globulins and lipid complexes, in which the protein molecules interact through disulphide bonds and/or hydrophobic interactions. 23474955 Exact time-dependent density functional theory for impurity models. We employ the density matrix renormalization group to construct the exact time-dependent exchange-correlation potential for an impurity model with an applied transport voltage. Even for short-ranged interaction we find an infinitely long-ranged exchange-correlation potential which is built up instantly after switching on the voltage. Our result demonstrates the fundamental difficulties of transport calculations based on time-dependent density functional theory. While formally the approach works, important information can be missing in the ground-state functionals and may be hidden in the usually unknown non-equilibrium functionals. 22864625 Density functional study on the adsorption of the drug isoniazid onto pristine and B-doped single wall carbon nanotubes. The current study explores a new strategy to incorporate single wall carbon nanotubes (SWNTs)/doped SWNTs as carrier modules in target-specific administration of antitubercular chemotherapeutics through covalent and noncovalent functionalization onto the nanotube sidewall. Density functional studies illustrate that noncovalent functionalization of isoniazid (INH) is preferred over covalent attachment, exhibiting low adsorption energy values, HOMO-LUMO gap and comparison of quantum molecular descriptors performed in (5,5) and (9,0) SWNT systems. Substitution doping of boron facilitates the adsorption of INH onto the otherwise inert nanotube. Frontier orbital analysis reveals reorientation of electronic charge in the nanotubes after functionalization, the effect being more pronounced in the case of doped nanotubes. The charge transfer is significant in covalent functionalization of INH via the B-dopant atom, whereas in noncovalent functionalization a small amount of charge transfer is noted. Solvation studies demonstrate the dissolution of INH in B-doped (5,5) and (9,0) SWNTs to be higher compared to pristine nanotube-INH complexes. Functionalization of nanotubes via covalent and noncovalent means can foster pioneering prospects especially for experimental studies in this area of research. 23337525 Economic and technological drivers of generic sterile injectable drug shortages. Over the past few years, an increasing number of critically needed medicines have been in short supply. Using economic theory to frame the drug-shortage problem, this paper explores why and how manufacturing-quality problems could combine with other economic and technological factors to result in shortages of generic sterile injectable drugs. The fundamental problem we identify is the inability of the market to observe and reward quality. This lack of reward for quality can reinforce price competition and encourage manufacturers to keep costs down by minimizing quality investments. The US Food and Drug Administration's (FDA's) need to use its regulatory flexibility, on behalf of patients, to avoid shortages of medically necessary drugs may further strengthen the incentive to "push the envelope" on quality. These dynamics may have produced a market situation in which quality problems have become sufficiently common and severe to result in drug shortages. 22694127 Ibuprofen ion-exchange fiber complex: improved dissolution and gastric tolerance based on ion exchange. The purpose of the present study is to develop a novel method to improve the dissolution of water-insoluble drug ibuprofen and the gastric tolerance of this non-steroidal anti-inflammatory drug which has potentially serious gastrointestinal side effects. This method is based on ion exchange of ion-exchange fibers. Water-insoluble drug ibuprofen was dispersed in deionized water, and then the ion-exchange fibers in OH(-) type was immersed in it. Ibuprofen and the active groups of the ion-exchange fibers combined into ion pairs based on the acid-base reaction. This drug carrier did not release drugs in deionized water, but in water solution containing other ions it would release the drugs into the solution by ion exchange. Confirmed by the X-ray diffraction and the scanning electron microscopy, the ibuprofen combined onto the ion-exchange fibers was in a highly molecular level dispersed state. The improved dissolution of ibuprofen ion-exchange fiber complexes is likely to originate from this ibuprofen's highly dispersed state. Due to this, ibuprofen's highly dispersed state, ibuprofen ion-exchange fiber complexes significantly decreases the gastrointestinal side effects of ibuprofen by avoiding the solid ibuprofen's educing. The present study showed that ibuprofen ion-exchange fiber complexes have the two-fold advantages. One is to improve the dissolution of ibuprofen. The other is to decrease the ibuprofen's gastrointestinal toxicity. 23111803 Experimental exposure of red-legged partridges (Alectoris rufa) to seeds coated with imidacloprid, thiram and difenoconazole. Pesticide coated seeds are commonly used in agriculture, and may be an important source of food for some birds in times of scarcity, as well as a route of pesticide ingestion. We tested the lethal and sub-lethal effects of treated seed ingestion by the red-legged partridge (Alectoris rufa), a game bird of high socio-economic value in Spain. One year-old partridges (n = 42 pairs) were fed for 10 days in spring (prior to breeding) with wheat treated with difenoconazole (fungicide), thiram (fungicide) or imidacloprid (insecticide), using two doses for each pesticide (the one recommended, and its double to represent potential cases of abuse of pesticides). We investigated the direct and indirect effects on the body condition, physiology, immunology, coloration and subsequent reproduction of exposed partridges. For the latter, eggs were collected, measured and incubated and the growth and survival of chicks were monitored. Thiram and imidacloprid at high exposure doses produced mortalities of 41.6 and 58.3 %, respectively. The first death was observed at day 3 for imidacloprid and at day 7 for thiram. Both doses of the three pesticides caused sublethal effects, such as altered biochemical parameters, oxidative stress and reduced carotenoid-based coloration. The high exposure doses of imidacloprid and thiram also produced a decrease in cellular immune response measured by the phytohemagglutinin test in males. Bearing in mind the limitation of the small number of surviving pairs in some treatments, we found that the three pesticides reduced the size of eggs and imidacloprid and difenoconazole also reduced the fertilization rate. In addition, both thiram and imidacloprid reduced chick survival. These experiments highlight that the toxicity of pesticide-treated seeds is a factor to consider in the decline of birds in agricultural environments. 23242472 Multiphoton imaging reveals a new leukocyte recruitment paradigm in the glomerulus. In contrast with many capillary beds, the glomerulus readily supports leukocyte recruitment. However, little is known regarding the actions of leukocytes following their recruitment to glomeruli. We used multiphoton confocal microscopy to examine leukocyte behavior in the glomerular microvasculature. In normal glomeruli, neutrophils and monocytes were retained in capillaries for several minutes, remaining static or migrating intravascularly. Induction of glomerular inflammation resulted in an increase in the duration of retention of static and migratory leukocytes. In response to immune complex deposition, both static and migratory neutrophils generated oxidants in inflamed glomeruli via a Mac-1-dependent mechanism. Our results describe a new paradigm for glomerular inflammation, suggesting that the major effect of acute inflammation is to increase the duration of leukocyte retention in the glomerulus. Moreover, these findings describe a previously unknown form of multicellular intravascular patrolling that involves both monocytes and neutrophils, which may underlie the susceptibility of the glomerulus to inflammation. 23153618 Development of solid lipid nanoparticles (SLNs) of lopinavir using hot self nano-emulsification (SNE) technique. Solid lipid nanoparticles (SLNs) of poor orally bioavailable drug lopinavir were prepared using hot self nano-emulsification (SNE) technique. Hot isotropic mixture of stearic acid, poloxamer and polyethylene glycol was spontaneously self nano-emulsify in hot water and SLNs were formed with subsequent rapid cooling. Self nano-emulsification ability of stearic acid, poloxamer and polyethylene glycol mixture was assessed by ternary phase diagram study. Optimized SLNs were having particle size of 180.6 ± 2.32 nm (PDI=0.133 ± 0.001), 91.5 ± 1.3% entrapment efficiency and zeta potential of -13.4 ± 0.56 mV. SLNs were evaluated by transmission electron microscopy (TEM) and atomic force microscopy (AFM) for morphological study. Further, Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) of SLNs were also performed for checking solid state characterization. Higher oral bioavailability was found for lopinavir loaded SLNs in comparison to bulk lopinavir due to higher lymphatic drug transport (p<0.05). Results indicate that SLNs of higher fatty acids can be successfully prepared by hot SNE technique. 23344983 Expression of immunoregulatory genes and its relationship to lead exposure and lead-mediated oxidative stress in wild ungulates from an abandoned mining area. Lead (Pb) is a highly toxic metal that can induce oxidative stress and affect the immune system by modifying the expression of immunomodulator-related genes. The aim of the present study was to investigate the association between Pb exposure and the transcriptional profiles of some cytokines, as well as the relationship between Pb exposure and changes in oxidative stress biomarkers observed in the spleen of wild ungulates exposed to mining pollution. Red deer and wild boar from the mining area studied had higher spleen, liver, and bone Pb levels than controls, indicating a chronic exposure to Pb pollution. Such exposure caused a depletion of spleen glutathione levels in both species and disrupted the activity of antioxidant enzymes, suggesting the generation of oxidative stress conditions. Deer from the mining area also showed an induced T-helper (Th )-dependent immune response toward the Th 2 pathway, whereas boar from the mining area showed a cytokine profile suggesting an inclination of the immune response toward the Th 1 pathway. These results indicate that environmental exposure to Pb may alter immune responses in wild ungulates exposed to mining pollution. However, evidence of direct relationships between Pb-mediated oxidative stress and the changes detected in immune responses were not found. Further research is needed to evaluate the immunotoxic potential of Pb pollution, also considering the prevalence of chronic infectious diseases in wildlife in environments affected by mining activities. 23389090 Core oligosaccharide of Plesiomonas shigelloides PCM 2231 (Serotype O17) lipopolysaccharide--structural and serological analysis. The herein presented complete structure of the core oligosaccharide of lipopolysaccharide (LPS) P. shigelloides Polish Collection of Microorganisms (PCM) 2231 (serotype O17) was investigated by (1)H, (13)C NMR spectroscopy, mass spectrometry, chemical analyses and serological methods. The core oligosaccharide is composed of an undecasaccharide, which represents the second core type identified for P. shigelloides serotype O17 LPS. This structure is similar to that of the core oligosaccharide of P. shigelloides strains 302-73 (serotype O1) and 7-63 (serotype O17) and differs from these only by one sugar residue. Serological screening of 55 strains of P. shigelloides with the use of serum against identified core oligosaccharide conjugated with bovine serum albumin (BSA) indicated the presence of similar structures in the LPS core region of 28 O-serotypes. This observation suggests that the core oligosaccharide structure present in strain PCM 2231 could be the most common type among P. shigelloides lipopolysaccharides. 23432580 Immunomodulatory properties of farnesoids: the new steroids? Farnesylthiosalisylic acid (FTS) is a potent non-toxic anticancer drug that targets oncogenic and pathologically activated Ras. The mechanism of action of FTS is well understood. It interferes with the binding of activated Ras proteins to their escort chaperons and with Ras tethering to the plasma membrane. This agent has been evaluated successfully in phase II clinical trials of pancreatic and lung cancer patients. It is generally agreed that Ras proteins play an important role in cancer, but they also drive activation of the immune system. Therefore we hypothesized that inhibiting Ras might be beneficial in autoimmune and inflammatory conditions. Over the past decade we have extensively studied the effects of FTS in multiple animal models of such diseases. We were able to show potent anti-inflammatory properties of FTS in autoimmune disease models such as systemic lupus erythematous, antiphospholipd syndrome, Guillain-Barré syndrome, multiple sclerosis, and inflammatory bowel diseases. Its potential was also shown in type I and type II diabetes. Animal models of contact dermatitis, allergic inflammation, and proliferative nephritis were studied as well. We have also investigated the molecular mechanisms, signaling pathways, and inflammatory mediators underlying these conditions. In this review we summarize our (and others) published data, and conclude that FTS has great potential as a safe anti-inflammatory drug. 23530596 Biomimetic cryptic site surfaces for reversible chemo- and cyto-mechanoresponsive substrates. Chemo-mechanotransduction, the way by which mechanical forces are transformed into chemical signals, plays a fundamental role in many biological processes. The first step of mechanotransduction often relies on exposure, under stretching, of cryptic sites buried in adhesion proteins. Likewise, here we report the first example of synthetic surfaces allowing for specific and fully reversible adhesion of proteins or cells promoted by mechanical action. Silicone sheets are first plasma treated and then functionalized by grafting sequentially under stretching poly(ethylene glycol) (PEG) chains and biotin or arginine-glycine-aspartic acid (RGD) peptides. At unstretched position, these ligands are not accessible for their receptors. Under a mechanical deformation, the surface becomes specifically interactive to streptavidin, biotin antibodies, or adherent for cells, the interactions both for proteins and cells being fully reversible by stretching/unstretching, revealing a reversible exposure process of the ligands. By varying the degree of stretching, the amount of interacting proteins can be varied continuously. 23391037 High-resolution zero-field NMR J-spectroscopy of aromatic compounds. We report the acquisition and interpretation of nuclear magnetic resonance (NMR) J-spectra at zero magnetic field for a series of benzene derivatives, demonstrating the analytical capabilities of zero-field NMR. The zeroth-order spectral patterns do not overlap, which allows for straightforward determination of the spin interactions of substituent functional groups. Higher-order effects cause additional line splittings, revealing additional molecular information. We demonstrate resonance linewidths as narrow as 11 mHz, permitting resolution of minute frequency differences and precise determination of long-range J-couplings. The measurement of J-couplings with the high precision offered by zero-field NMR may allow further refinements in the determination of molecular structure and conformation. 23212238 Theoretical study of the reaction of CH2XO (X = F, Cl, Br) radicals with the NO radical. In this paper, we focus on the multiple-channel reactions of CH(2)XO (X = F, Cl, Br) radicals with the NO radical by means of direct dynamic methods. All structures of the stationary points were obtained at the MP2/6-311+G(d,p) level and vibrational frequency analysis was also performed at this level of theory. The minimum energy path (MEP) was obtained via the intrinsic reaction coordinate (IRC) theory at the MP2/6-311+G(d,p) level, and higher-level energetic information was refined by the MC-QCISD method. The rate constants for the three hydrogen abstraction reaction channels over the temperature range 200-1,500 K were calculated by the improved canonical variational transition state theory (ICVT) with a correction for small-curvature tunneling (SCT). The rate constants calculated in this manner were in good agreement with the available experimental data, and the three-parameter rate-temperature formulae for the temperature range 200-1,500 K were k(1a)(T) = 0.32 × 10(-18) T(1.83) exp(1748.54/T), k(2a)(T) = 0.22 × 10(-19) T(2.19) exp(1770.19/T), k(3a)(T) = 0.88 × 10(-20) T(2.20) exp(1513.82/T) (in units of cm(3) molecule(-1) s(-1)). 23458618 Potential Advantages of Using Synchrotron X-ray Based Techniques in Pediatric Research. Synchrotron radiation (SR), which combines extremely high intensity, high collimation, tunability, and continuous energy spectrum, allows the development of advanced X-ray based techniques that are becoming a uniquely useful tool in life science research, along providing exciting opportunities in biomedical imaging and radiotherapy. This review summarize emerging techniques and their potential to greatly enhance the exploration of dynamical biological process occurring across various spatial and temporal regimes, from whole body physiology, down to the location of individual chemical species within single cells. In recent years pediatric research and clinic practice have started to profit from these new opportunities, particularly by extending the diagnostic and therapeutic capabilities of these X-ray based techniques. In diagnosis, technical advances in DEI and KES imaging modalities have been demonstrated as particularly valuable for children and women since SR allows dose minimization, with significant reductions compared to conventional approaches. However, the greatest expectations are in the field of SR based radiotherapy, increasingly studies are demonstrating SR radiotherapy provides improved chances of recovery; this is especially the case for pediatric patients. In addition, we report on the applicability of advanced X-ray microscopy techniques that offer exceptional spatial and quantitative resolution in elemental detection. These techniques, which are useful for in vitro studies, will be particularly advantageous where investigators seek deeper understanding of diseases where mismetabolism of metals, either physiological important (i.e. Cu, Zn) or outright toxic (i.e. Pb), underlies pathogenesis. 23590591 pH-Responsive Nanoparticle Vaccines for Dual-Delivery of Antigens and Immunostimulatory Oligonucleotides. Protein subunit vaccines offer important potential advantages over live vaccine vectors but generally elicit weaker and shorter-lived cellular immune responses. Here we investigate the use of pH-responsive, endosomolytic polymer nanoparticles that were originally developed for RNA delivery as vaccine delivery vehicles for enhancing cellular and humoral immune responses. Micellar nanoparticles were assembled from amphiphilic diblock copolymers composed of an ampholytic core-forming block and a redesigned polycationic corona block doped with thiol-reactive pyridyl disulfide groups to enable dual-delivery of antigens and immunostimulatory CpG oligodeoxynucleotide (CpG ODN) adjuvants. Polymers assembled into 23 nm particles with simultaneous packaging of CpG ODN and a thiolated protein antigen, ovalbumin (ova). Conjugation of ova to nanoparticles significantly enhanced antigen cross-presentation in vitro relative to free ova or an unconjugated, physical mixture of the parent compounds. Subcutaneous vaccination of mice with ova-nanoparticle conjugates elicited a significantly higher CD8(+) T cell response (0.5% IFN-γ(+) of CD8(+)) compared to mice vaccinated with free ova or a physical mixture of the two components. Significantly, immunization with ova-nanoparticle conjugates electrostatically complexed with CpG ODN (dual-delivery) enhanced CD8(+) T cell responses (3.4% IFN-γ(+) of CD8(+)) 7-, 18-, and 8-fold relative to immunization with conjugates, ova administered with free CpG, or a formulation containing free ova and CpG complexed to micelles, respectively. Similarly, dual-delivery carriers significantly increased CD4(+)IFN-γ(+) (Th1) responses and elicited a balanced IgG1/IgG2c antibody response. Intradermal administration further augmented cellular immune responses, with dual-delivery carriers inducing ∼7% antigen-specific CD8(+) T cells. This work demonstrates the ability of pH-responsive, endosomolytic nanoparticles to actively promote antigen cross-presentation and augment cellular and humoral immune responses via dual-delivery of protein antigens and CpG ODN. Hence, pH-responsive polymeric nanoparticles offer promise as a delivery platform for protein subunit vaccines. 23520133 Positive Regulation of Insulin Signaling by Neuraminidase 1. Neuraminidases (sialidases) catalyze the removal of sialic acid residues from sialylated glycoconjugates. We now report that mammalian neuraminidase 1 (Neu1), in addition to its catabolic function in lysosomes, is transported to the cell surface where it is involved in regulation of insulin signaling. Insulin binding to its receptor rapidly induces interaction of the receptor with Neu1, which hydrolyzes sialic acid residues in the glycan chains of the receptor and, consequently, induces its activation. Cells from sialidosis patients with a genetic deficiency of Neu1 show impairment of insulin-induced phosphorylation of downstream protein kinase AKT, while treatment of these cells with purified Neu1 restores signaling. Genetically-modified mice with ∼10% of the normal Neu1 activity exposed to a high-fat diet develop hyperglycemia and insulin resistance twice as fast as their wild type counterparts. Together, these studies identify Neu1 as a novel component of the signaling pathways of energy metabolism and glucose uptake. 23548704 Novel quinolone substituted thiazolidin-4-ones as anti-inflammatory, anticancer agents: Design, synthesis and biological screening. Nuclear factor-kappaB (NF-κB) has been reported to regulate various genes involved in cancer and inflammation. Accordingly, drugs suppressing or inhibiting NF-κB may possess both anti-inflammatory and anticancer properties. A library of quinolone substituted thiazolidin-4-ones was docked into the active site of NF-κB and the top-ranked 31 compounds were synthesized and evaluated for anti-inflammatory and anticancer activity. The best-ranked compound 6b showed highest anti-inflammatory activity in carrageenan-induced paw edema model. In vitro anticancer studies revealed 1a and 16a as most active compounds against BT-549, HeLa, COLO-205 and ACHN human cancer cell lines. Compounds 1a and 16a exhibited NF-κB dependent anticancer properties and apoptosis mediated cell death. In vivo Ehrlich ascites carcinoma study further confirmed the antitumor activity of 1a and 16a. 22991293 Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia. X-linked hypophosphatemia (XLH/HYP)-with renal phosphate wasting, hypophosphatemia, osteomalacia, and tooth abscesses-is caused by mutations in the zinc-metallopeptidase PHEX gene (phosphate-regulating gene with homologies to endopeptidase on the X chromosome). PHEX is highly expressed by mineralized tissue cells. Inactivating mutations in PHEX lead to distal renal effects (implying accumulation of a secreted, circulating phosphaturic factor) and accumulation in bone and teeth of mineralization-inhibiting, acidic serine- and aspartate-rich motif (ASARM)-containing peptides, which are proteolytically derived from the mineral-binding matrix proteins of the SIBLING family (small, integrin-binding ligand N-linked glycoproteins). Although the latter observation suggests a local, direct matrix effect for PHEX, its physiologically relevant substrate protein(s) have not been identified. Here, we investigated two SIBLING proteins containing the ASARM motif-osteopontin (OPN) and bone sialoprotein (BSP)-as potential substrates for PHEX. Using cleavage assays, gel electrophoresis, and mass spectrometry, we report that OPN is a full-length protein substrate for PHEX. Degradation of OPN was essentially complete, including hydrolysis of the ASARM motif, resulting in only very small residual fragments. Western blotting of Hyp (the murine homolog of human XLH) mouse bone extracts having no PHEX activity clearly showed accumulation of an ∼35 kDa OPN fragment that was not present in wild-type mouse bone. Immunohistochemistry and immunogold labeling (electron microscopy) for OPN in Hyp bone likewise showed an accumulation of OPN and/or its fragments compared with normal wild-type bone. Incubation of Hyp mouse bone extracts with PHEX resulted in the complete degradation of these fragments. In conclusion, these results identify full-length OPN and its fragments as novel, physiologically relevant substrates for PHEX, suggesting that accumulation of mineralization-inhibiting OPN fragments may contribute to the mineralization defect seen in the osteomalacic bone characteristic of XLH/HYP. 22628292 The effects of an antiosteoporosis herbal formula containing epimedii herba, ligustri lucidi fructus and psoraleae fructus on density and structure of rat long bones under tail-suspension, and its mechanisms of action. An innovative anti-osteoporosis herbal formula containing Epimedii Herba, Ligustri Lucidi Fructus and Psoraleae Fructus (ELP) has been previously shown its bone protecting effects in ovariectomized osteoporotic rats and also in post-menopausal osteopenic women. This study aimed to investigate the efficacy of ELP against bone loss during physical inactivity or weightlessness. A hindlimb unloading tail-suspended rat model was used for studying the effects of ELP on bone mineral density (BMD) and bone micro-architecture. For in vitro mechanistic studies, rat mesenchymal stem cells (MSCs) and mouse macrophage cells (RAW264.7) were used for studying the effects of ELP on osteogenic/adipogenic differentiations and osteoclastogenesis, respectively. Our data illustrated that ELP had a significant preventive effect against bone loss induced by tail-suspension (TS) at day 28 (p < 0.01) as indicated in the reduction in BMD loss and the preservation of bone micro-architecture. ELP could significantly promote the osteogenesis and suppress the adipogenesis (p < 0.05) in MSCs. Besides, significant inhibition of osteoclast formation (p < 0.01) was found in ELP-treated RAW264.7 cells upon receptor activator of nuclear factor kappa-B ligand induction. Our study presents the first scientific evidence that ELP had a significant preventive effect against bone loss induced by TS through the actions of enhancing osteogenesis, suppressing adipogenesis and osteoclastogenesis. Copyright © 2012 John Wiley & Sons, Ltd. 23562630 Beneficial effects of asiaticoside on cognitive deficits in senescence-accelerated mice. The effect of asiaticoside isolated from Hydrocotyle sibthorpioides (AHS) on the promotion of cognition in senescence-accelerated mice (SAMP) was evaluated. Six-month old male SAMP8 mice were orally administered 20, 40 or 80mg/kg AHS daily for three months. SAMR1 mice were used as a "normal aging" control. The results showed that treatment with AHS significantly improved learning and memory abilities in behavioral tests. AHS-treated mice showed higher antioxidant enzyme activity and lower lipid oxidation in serum compared with untreated SAMP8 mice. Mechanistically, studies showed that AHS markedly reduced the content and deposition of β-amyloid peptide (Aβ) by inhibiting the expression of mRNA for amyloid protein precursor, β-site amyloid cleaving enzyme-1 and cathepsin B and promoting the expression of mRNA for neprilysin and insulin degrading enzyme. In addition, AHS significantly increased the expression of plasticity-related proteins including postsynaptic density-95, phosphor-N-methyl-d-aspartate receptor 1, phospho-calcium-calmodulin dependent kinase II, phospho-protein kinase A Catalyticβ subunit, protein kinase Cγ subunit, phospho-CREB and brain derived neurotrophic factor. Furthermore, AHS increased the levels of acetylcholine (Ach), but decreased cholinesterase (AchE) activity. These results demonstrated that AHS administration may prevent spatial learning and memory decline by scavenging free radicals, up-regulating the activity of antioxidant enzymes, decreasing the level of Aβ, ameliorating dysfunction in synaptic plasticity, and reversing abnormal changes in Ach level and AchE activity. Thus, AHS should be developed as a new drug to prevent age-related cognitive deficits. 23480235 N-[9-(ortho-Fluorobenzyl)-2-Phenyl-8-Azapurin-6-yl]-Amides as Potent and Selective Ligands for A1 Adenosine Receptors. A series of N-[9-(ortho-fluorobenzyl)-2-phenyl-8-azapurin-6-yl]-amides were synthesised and tested for their affinity toward A1 , A2A and A3 adenosine receptor subtypes. Biological results demonstrated that the introduction of a fluorine atom at the ortho position of the 9-benzyl group generally enhanced affinity toward A1 subtype and did not significantly affect A2A and A3 affinity. Very interesting is the compound bearing a meta-fluorophenyl substituent on the carbonyl carbon of the amide group, which shows significantly high A1 /A2A -A3 selectivity. Compounds of this new series, together with the previously published analogs without the fluorine atom on the 9-benzyl group, constituted the starting dataset for the development of QSAR models. The models obtained were able to rationally describe the affinity trends resulting from biological testing, and to enable investigation of the role of different substituents on the 8-azapurine scaffold, as well as the influence of the newly introduced fluorine atom on the benzyl moiety. The said QSAR models can also assist in the design of new compounds selectively active on A1 adenosine receptors. Furthermore, a molecular docking study was carried out in order to assess hypothetical binding mode of N-[9-(ortho-fluorobenzyl)-2-phenyl-8-azapurin-6-yl]-amides to A1 adenosine receptors. © 2013 John Wiley & Sons A/S. 23521132 A Redox Responsive, Fluorescent Supramolecular Metallohydrogel Consists of Nanofibers with Single-Molecule Width. The integration of a tripeptide derivative, which is a versatile self-assembly motif, with a ruthenium(II)tris(bipyridine) complex affords the first supramolecular metallo-hydrogelator that not only self assembles in water to form a hydrogel but also exhibits gel-sol transition upon oxidation of the metal center. Surprisingly, the incorporation of the metal complex in the hydrogelator results in the nanofibers, formed by the self-assembly of the hydrogelator in water, to have the width of a single molecule of the hydrogelator. These results illustrate that metal complexes, besides being able to impart rich optical, electronic, redox, or magnetic properties to supramolecular hydrogels, also offer a unique geometrical control to prearrange the self-assembly motif prior to self-assembling. The use of metal complexes to modulate the dimensionality of intermolecular interactions may also help elucidate the interactions of the molecular nanofibers with other molecules, thus facilitating the development of supramolecular hydrogel materials for a wide range of applications. 23606264 Bicyclic Derivatives of L-Idonojirimycin as Pharmacological Chaperones for Neuronopathic Forms of Gaucher Disease. New human β-glucocerebrosidase (GCase) ligands with rigid 1,6-anhydro-β-L-idonojirimycin cores have been designed with the aid of molecular modeling. Efficient pharmacological chaperones for the L444P (trafficking-incompetent) mutant GCase enzyme associated with type 2 and 3 Gaucher disease (GD) were identified. 23494236 Reinforcement enhancing effects of nicotine via smoking. RATIONALE: In animals, nicotine enhances reinforcement from stimuli unrelated to nicotine intake. Human research is suggestive but has not clearly shown a similar influence of nicotine. OBJECTIVES: We assessed acute effects of nicotine via smoking on enhancement of positive (money, music) or negative (termination of noise) reinforcers, or no "reward" (control). These different rewards determined the generalizability of nicotine effects. MATERIALS AND METHODS: Dependent (n = 25) and nondependent (n = 27) smokers participated in three sessions, each after overnight abstinence. Using a within-subjects design, sessions involved no smoking or smoking denicotinized (0.05 mg) or nicotine (0.6 mg) Quest(R) brand cigarettes. For comparison, a fourth session involved no abstinence prior to smoking one's own brand to gauge responses under typical nicotine satiation. Reinforcement was assessed by responses on a simple operant computer task for the rewards, each available singly on a progressive ratio schedule during separate trials. RESULTS: The reinforcing effect of music, but not other rewards, was greater due to the nicotine cigarette, compared to the denicotinized cigarette or no smoking. Reinforcement enhancing effects of nicotine did not differ between dependent and nondependent groups, indicating no influence of withdrawal relief. Responding due to acute nicotine after abstinence was very similar to responding to one's own brand after no abstinence. CONCLUSIONS: Acute nicotine intake per se from smoking after abstinence enhances the reinforcing value of rewards unassociated with smoking, perhaps in a manner comparable to ad lib smoking after no abstinence. Nicotine's reinforcement enhancing effects may be specific to certain rewards, perhaps those sensory in nature. 23500494 A Two-State Cooperative Expansion Converts the Procapsid Shell of Bacteriophage T5 into a Highly Stable Capsid Isomorphous to the Final Virion Head. Capsids of double-stranded DNA (dsDNA) bacteriophages initially assemble into compact procapsids, which undergo expansion upon the genome packaging. This shell remodeling results from a structural rearrangement of head protein subunits. It is a critical step in the capsid maturation pathway that yields final particles capable to withstand the huge internal pressure generated by the packed DNA. Here, we report on the expansion process of the large capsid (T=13) of bacteriophage T5. We purified the intermediate prohead II form, which is competent for packaging the 121-kbp dsDNA genome, and we investigated its morphology and dimensions using cryo-electron microscopy and small-angle X-ray scattering. Decreasing the pH or the ionic strength triggers expansion of prohead II, converting them into thinner and more faceted capsids isomorphous to the mature virion particles. At low pH, prohead II expansion is a highly cooperative process lacking any detectable intermediate. This two-state reorganization of the capsid lattice per se leads to a remarkable stabilization of the particle. The melting temperature of expanded T5 capsid is virtually identical with that of more complex shells that are reinforced by inter-subunit cross-linking (HK97) or by additional cementing proteins (T4). The T5 capsid with its "simple" two-state conversion thus appears to be a very attractive model for investigating the mechanism of the large-scale allosteric transition that takes place upon the genome packaging of dsDNA bacteriophages. 23560442 Enhancing Raman Scattering without Plasmons: Unprecedented Sensitivity Achieved by TiO2 Shell-Based Resonators. A remarkable enhancement of Raman scattering is achieved by TiO2 shell-based spherical resonators in the absence of plasmonic enhancers. This effect is ascribed to the synergistic combination of high refractive index of the shell layer, multiple light scattering through the spheres, and related geometrical factors and can be exploited to fabricate a new generation of self-diagnostic, recyclable SERS-active substrates. 23157698 The next frontier in composite tissue allotransplantation. Solid organ transplantations became a clinical option in the 1950s. The hand allograft was the pioneer of composite tissue allotransplantation (CTA), successfully started near the end of the last century despite arguments over the practicality and methods. Since then, CTA such as hand and face has continued to progress from the theoretical to clinical reality. The treatment principles, drug combinations, and mechanisms of the immunosuppression medications on which contemporary transplant surgeries have been based continue to develop as researchers and physicians gain more experience in the CTA field. It could be argued that the ethical issues associated with CTA have prevented evolution of the field rather than surgical or technical skill. This is particularly true for allo-head and body reconstruction (AHBR). How can leaders in the field of CTA develop a model that would satisfy ethical concerns? Bolstered by recent successes in the field, is it time to traverse the next frontier? Can AHBR ever be a feasible option in the clinical setting? The reader will be provided with a brief history of CTA from theory to research to clinical practice. A concise description of AHBR as it pertains to the critical procedure (i.e., surgery design) will also be discussed. 23295826 Dissection of pilus tip assembly by the FimD usher monomer. Type 1 pili are representative of a class of bacterial surface structures assembled by the conserved chaperone/usher pathway and used by uropathogenic Escherichia coli to attach to bladder cells during infection. The outer membrane assembly platform-the usher-is critical for the formation of pili, catalysing the polymerisation of pilus subunits and enabling the secretion of the nascent pilus. Despite extensive structural characterisation of the usher, a number of questions about its mechanism remain, notably its oligomerisation state, and how it orchestrates the ordered assembly of pilus subunits. We demonstrate here that the FimD usher is able to catalyse in vitro pilus assembly effectively in its monomeric form. Furthermore, by establishing the kinetics of usher-catalysed reactions between various pilus subunits, we establish a complete kinetic model of tip fibrillum assembly, able to account for the order of subunits in native type 1 pili. 23629923 Caveolae-Mediated Endocytosis of Conjugated Polymer Nanoparticles. Understanding the cellular entry pathways of synthetic biomaterials is highly important to improve overall labeling and delivery efficiency. Herein, cellular entry mechanisms of conjugated polymer nanoparticles (CPNs) are presented. CPNs are intrinsic fluorescent materials used for various biological applications. While CPNs cause no toxicity, decreased CPN uptake is observed from cancer cells pretreated with genistein, which is an inhibitor of caveolae-mediated endocytosis (CvME). CvME is further confirmed by high co-localization with caveolin-1 proteins found in the caveolae and caveosomes. Excellent photophysical properties, non-toxicity, and non-destructive delivery pathways support that CPNs are promising multifunctional carriers minimizing degradation of contents during delivery. 23455313 Activation of Both Protein Kinase A (PKA) Type I and PKA Type II Isozymes Is Required for Retinoid-Induced Maturation of Acute Promyelocytic Leukemia Cells. Acute promyelocytic leukemia (APL) is characterized by granulopoietic differentiation arrest at the promyelocytic stage. In most cases, this defect can be overcome by treatment with all-trans-retinoic acid (ATRA), leading to complete clinical remission. Cyclic AMP signaling has a key role in retinoid treatment efficacy: it enhances ATRA-induced maturation in ATRA-sensitive APL cells (including NB4 cells) and restores it in some ATRA-resistant cells (including NB4-LR1 cells). We show that the two cell types express identical levels of the Cα catalytic subunit and comparable global cAMP-dependent protein kinase A (PKA) enzyme activity. However, the maturation-resistant NB4-LR1 cells have a PKA isozyme switch: compared with the NB4 cells, they have decreased content of the juxtanuclearly located PKA regulatory subunit IIα and PKA regulatory subunit IIβ, and a compensatory increase of the generally cytoplasmically distributed PKA-RIα. Furthermore, the PKA regulatory subunit II exists mainly in the less cAMP-responsive nonautophosphorylated state in the NB4-LR1 cells. By the use of isozyme-specific cAMP analog pairs, we show that both PKA-I and PKA-II must be activated to achieve maturation in NB4-LR1 as well as NB4 cells. Therefore, special attention should be paid to activating not only PKA-I but also PKA-II in attempts to enhance ATRA-induced APL maturation in a clinical setting. 23424206 N-Acetylcysteine prevents doxorubucine-induced cardiotoxicity in rats. This study is designed to observe the effects of N-acetylcysteine (NAC) on doxorubucine-induced cardiac toxicity in rats both histologically and biochemically. Totally 32 rats divided equally into four groups were studied. The first group received only 200 mg/kg NAC intraperitoneal (i.p.) once every 24 h for 5 days (group 1); the second group received 20 mg/kg doxorubucine (DOX) i.p. single dose plus NAC 200 mg/kg i.p. once every 24 h for 5 days (group 2); the third group received DOX 20 mg/kg DOX i.p. single dose (group 3) and the fourth group, which is also the control group, received saline (group 4). Following 24 h of the final dose, blood samples were drawn from a portal vein and heart tissue were obtained. Tissue thiobarbituric acid reactive substance (TBARS) and nitric oxide (NO) levels were highest in the DOX group. In the DOX-treated rats, serum TBARS, NO, aspartate transaminase, lactate dehydrogenase and creatine kinase levels were highest when compared with other groups. Except for serum superoxide dismutase levels, all other parameters differed significantly between the DOX plus NAC group and the DOX group. In the DOX plus NAC group, general architecture was preserved better than the DOX group and myofibril loss was minimal compared with the DOX group. NAC demonstrated, both biochemically and histologically, to be effective in the prevention of DOX-induced cardiotoxicity in rat models. Evaluation of NAC's effect on DOX toxicity warrants further clinical trials on cancer patients. 23150226 Reduction of helical content by insertion of a disulfide bond leads to an antimicrobial peptide with decreased hemolytic activity. CAPs off to the S-S bond: Application of a strategy involving the introduction of intramolecular disulfide bonds to amphipathic cationic antimicrobial peptides (CAPs) led to decreased α-helicity and hydrophobicity. The mutant peptides were observed to have significantly increased (250-fold) minimum hemolytic concentrations while maintaining MIC values against E. coli, affording more therapeutically selective CAPs. 23381727 A review of fabrication and applications of carbon nanotube film-based flexible electronics. Flexible electronics offer a wide-variety of applications such as flexible circuits, flexible displays, flexible solar cells, skin-like pressure sensors, and conformable RFID tags. Carbon nanotubes (CNTs) are a promising material for flexible electronics, both as the channel material in field-effect transistors (FETs) and as transparent electrodes, due to their high intrinsic carrier mobility, conductivity, and mechanical flexibility. In this feature article, we review the recent progress of CNTs in flexible electronics by describing both the processing and the applications of CNT-based flexible devices. To employ CNTs as the channel material in FETs, single-walled carbon nanotubes (SWNTs) are used. There are generally two methods of depositing SWNTs on flexible substrates-transferring CVD-grown SWNTs or solution-depositing SWNTs. Since CVD-grown SWNTs can be highly aligned, they often outperform solution-processed SWNT films that are typically in the form of random network. However, solution-based SWNTs can be printed at a large-scale and at low-cost, rendering them more appropriate for manufacturing. In either case, the removal of metallic SWNTs in an effective and a scalable manner is critical, which must still be developed and optimized. Nevertheless, promising results demonstrating SWNT-based flexible circuits, displays, RF-devices, and biochemical sensors have been reported by various research groups, proving insight into the exciting possibilities of SWNT-based FETs. In using carbon nanotubes as transparent electrodes (TEs), two main strategies have been implemented to fabricate highly conductive, transparent, and mechanically compliant films-superaligned films of CNTs drawn from vertically grown CNT forests using the "dry-drawing" technique and the deposition or embedding of CNTs onto flexible or stretchable substrates. The main challenge for CNT based TEs is to fabricate films that are both highly conductive and transparent. These CNT based TEs have been used in stretchable and flexible pressure, strain, and chemical and biological sensors. In addition, they have also been used as the anode and cathode in flexible light emitting diodes, solar cells, and supercapacitors. In summary, there are a number of challenges yet to overcome to optimize the processing and performance of CNT-based flexible electronics; nonetheless, CNTs remain a highly suitable candidate for various flexible electronic applications in the near future. 23123771 An Indian butyrylcholinesterase variant L307P is not structurally stable: A molecular dynamics simulation study. The human butyrylcholinesterase (BChE) activity is less than 1% in the serum of silent variant individuals of Vysya community in India. They are homozygous for a point mutation at codon 307 (CTT→CCT) resulting in the substitution of leucine 307 by proline. The reason for the disappearance of the protein in the serum has not been explicated till date. Based on this background, we performed molecular dynamics simulation to probe the structural stability of Indian variant (L307P) in comparison with wild and other BChE variants (D70G, E497V, V142M) having differential esterase activity. The simulation of all the mutants except D70G showed a much larger Cα root mean square deviation from the wild BChE crystal structure, showing the overall conformational disturbance. Further analysis revealed that secondary structure of the mutant proteins was not stable. The orientation of the catalytic triad is also distorted in all the mutants. The distance between δ nitrogen of His438 to ε oxygen of Glu325 and ε nitrogen of His438 to γ oxygen of Ser198 were highly altered in L307P mutant than the wild and other three variants throughout the simulation. Such disparity of distances between the catalytic residues may be due to the change in the protein conformation attributing to their differential catalytic activity. Our studies thus prove that the Indian BChE L307P mutant with negligible activity is possibly due to its structural instability when compared to other BChE variants. 23496772 Why fluorination of the polar heads reverses the positive sign of the dipole potential of langmuir monolayers: a vibrational sum frequency spectroscopic study. Natural nonionic amphiphiles forming monolayers, bilayers, micelles, or biomembranes create a positive dipole potential at the boundary with water. In a series of papers we have reported on Langmuir monolayers with CF3 terminals of the polar heads, which show a negative surface dipole potential ΔV ( Petrov , J. G. ; Andreeva , T. D. ; Kurt , D. K. ; Möhwald , H. J. Phys. Chem. B 2005 , 109 , 14102 ). Here we use vibrational sum frequency spectroscopy (SF) to study the origin of the opposite ΔV signs of Langmuir films of CH3(CH2)20COCH2CH3 (ethyl ether, EE) and CH3(CH2)20COCH2CF3 (fluorinated ethyl ether, FEE). The vibrational sum frequency spectra are recorded at the same film density of the S-phase of the EE and FEE monolayers and analyzed in the spectral regions of OH, COC, CH3, and CF3 stretching vibrations because these functional groups could be responsible for the different dipole potentials. We compare the rearrangement of the pure water surface by EE and FEE monolayers and the conformations of EE and FEE polar heads. The analysis is performed according to the three-capacitor model of the dipole potential of Langmuir monolayers ( Demchak , R. T. ; Fort , T. , Jr. J. Colloid Interface Sci. 1974 , 46 , 191 ). The results show that reversal of the ΔV sign caused by fluorination of the polar heads originates from the upward-oriented CF3 terminals of the FEE heads, whose negative normal dipole moment component determines the negative dipole potential of the FEE monolayer. 23265465 Effect of the genistein metabolite on leptin secretion in murine adipocytes in vitro. Soy isoflavonoids have many useful properties. However, they are metabolized in vivo, including in humans. The effect of the metabolism of soy isoflavonoids on their properties is not fully understood. We have isolated the bacterial strain SY8519, which has been shown to metabolize daidzein to O-desmethylangolensin and to produce 2-(4-hydroxyphenyl)propionic acid from genistein. According to chiral HPLC analysis, the 2-(4-hydroxyphenyl)propionic acid obtained from the bacterium was optically active. To determine the absolute stereochemistry of the microbial product, we prepared (S)-2-(4-hydroxyphenyl)propionic acid from (S)-2-phenylpropionic and concluded that the microbial product had an R-configuration by chiral HPLC analysis. We also applied the metabolite to mouse adipocytes and found that 2-HPPA was less effective at reducing leptin secretion than the parent compound genistein. Our results suggested that 'O-desmethylangolensin-production' attenuates the effect of soy isoflavonoids by reducing not only the activity of daidzein but also that of genistein. 23245513 A dimeric form of N-methoxycarbonyl-2-amino-1,8-naphthyridine bound to the A-A mismatch in the CAG/CAG base triad in dsRNA. A dimeric form of N-methoxycarbonyl-2-amino-1,8-naphthyridine (MCND) connected at the C2 position with a three-atom linker was examined for the binding to mismatches in double stranded RNA. Despite the fully complementary hydrogen bonding groups to guanine, MCND did not bind to guanine-guanine mismatch but did to adenine-adenine mismatch. The base pairs flanking the mismatch had weak effect on the binding, with showing the strongest binding to the A-A mismatch in the CAG/CAG sequence. The A-A mismatch in the GAC/GAC sequence was a poor substrate for the MCND binding. A monomeric derivative of MCND and another derivative lacking a methylcarbamate group showed negligilble binding to the A-A mismatch and the sequence selectivity. These results are important clues for the better molecular design of RNA binding small molecules. 23578635 Amino acid profiles and quantitative structure-property relationship models as markers for Merlot and Torrontés wines. Quantitative structure-property relationships (QSPRs) were applied to the aminograms obtained by HPLC in our laboratories for Torrontés and Merlot wines. Dragon theoretical descriptors were derived for a set of optimized amino acid structures with the purpose of establishing QSPR models. The statistical Replacement Method was used for designing the best multi-parametric linear regression models, which included structural features selected from a pool containing 1497 constitutional, topological, geometrical or electronic molecular descriptors. Predicted QSPR results were in good agreement with experimental amino acid profiles. The developed QSPR approach showed to be of practical value for distinguishing each wine varietal, and for calculating experimentally non-available amino acid concentrations of Torrontés and Merlot wines. It was also useful for assessing wine authenticity; the models were especially suitable for Merlot and Torrontés wines. 23595593 Cannabis intoxication inhibits avoidance action tendencies: a field study in the Amsterdam coffee shops. RATIONALE: Experimental laboratory studies suggest that the approach bias (relatively fast approach responses) toward substance-related materials plays an important role in problematic substance use. How this bias is moderated by intention to use versus recent use remains unknown. Moreover, the relationship between approach bias and other motivational processes (satiation and craving) and executive functioning remains unclear. OBJECTIVES: The aim of this study was to investigate the cannabis approach bias before and after cannabis use in real-life setting (Amsterdam coffee shops) and to assess the relationship between approach bias, craving, satiation, cannabis use, and response inhibition. METHODS: Cannabis, tobacco, and neutral approach and avoidance action tendencies were measured with the Approach Avoidance Task and compared between 42 heavy cannabis users with the intention to use and 45 heavy cannabis users shortly after cannabis use. The classical Stroop was used to measure response inhibition. Multiple regression analyses were conducted to investigate relationships between approach bias, satiation, craving, cannabis use, and response inhibition. RESULTS: In contrast to the hypotheses, heavy cannabis users with the intention to use did not show a cannabis approach bias, whereas intoxicated cannabis users did show an approach bias regardless of image category. This could be attributed to a general slowing of avoidance action tendencies. Moreover, craving was negatively associated with the approach bias, and no relationships were observed between the cannabis approach bias, satiation, prior cannabis use, and response inhibition. CONCLUSION: Cannabis intoxication in a real-life setting inhibited general avoidance. Expression of the cannabis approach bias appeared not to be modulated by satiation or response inhibition. 23545568 Stable and high-rate overcharge protection for rechargeable lithium batteries. Rechargeable lithium or lithium-ion cells can be overcharge-protected by an electroactive polymer composite separator. The use of non-woven fibrous membranes instead of conventional microporous membranes as the composite substrates allowed better distribution of the electroactive polymer, which led to improved utilization and a 40-fold increase in sustainable current density. For the first time, stable overcharge protection for hundreds of cycles was demonstrated in several cell chemistries, including LiNi1/3Co1/3Mn1/3O2, LiFePO4, and spinel Li1.05Mn1.95O4 half-cells. Protection at a charging rate as high as 5 C was achieved at a steady state cell potential below 4.85 V. 23348755 The stereoisomer (+)-naloxone potentiates G-protein coupling and feeding associated with stimulation of mu opioid receptors in the parabrachial nucleus. Classically, opioids produce their effects by activating Gi-proteins that inhibit adenylate cyclase activity. Previous studies proposed that mu-opioid receptors can also stimulate adenylate cyclase due to an initial transient coupling to Gs-proteins. Treatment with ultra-low doses of the nonselective opioid antagonist (-)-naloxone or its inactive enantiomer (+)-naloxone blocks this excitatory effect and enhances Gi-coupling. Previously we reported that infusion of the mu-opioid receptor agonist [D-Ala2, N-Me-Phe4, Glycinol5]-Enkephalin (DAMGO) into the mu-opioid receptor expressing lateral parabrachial nucleus increases feeding. Pretreatment with (-)-naloxone blocks this effect. We used this parabrachial circuit as a model to assess cellular actions of ultra-low doses of (-)-naloxone and (+)-naloxone in modifying the effects of DAMGO. Our results showed that an ultra-low concentration of (-)-naloxone (0.001 nM) and several concentrations of (+)-naloxone (0.01-10 nM) enhanced DAMGO-stimulated guanosine-5'-0-(γ-thio)-triphosphate incorporation in parabrachial sections in vitro. Further, we analyzed the relevance of these effects in vivo. In the present study, we show that (+)-naloxone can potentiate DAMGO-induced feeding at doses at which (-)-naloxone was an antagonist. These results implicated (+)-naloxone as a novel tool for studying mu-opioid receptor functions and suggest that (+)-naloxone may have therapeutic value to enhance clinical actions of opiate drugs. 23180341 Chemical constituents from the fungus Amauroderma amoiensis and their in vitro acetylcholinesterase inhibitory activities. One new compound named amauroamoienin (1), together with thirteen known compounds (2-14), was isolated from the EtOAc extract of Amauroderma amoiensis. The structures of these compounds were elucidated by the analysis of 1D and 2D spectroscopic data and the MS technique. The bioassays of inhibitory activities of these isolates against acetylcholinesterase were evaluated, and compounds 1, 3, and 5 exhibited acetylcholinesterase inhibitory activities. 23435263 Rational development of novel leads from animal secretion based on coagulation and cell targets: 1. In silico analysis to explore a peptide derivative as lipocalins' signature. Animal venoms and secretions have been screened, in our research group, to discover, identify and isolate peptide molecules active in the mammalian haemostatic system. As result, this kind of research has provided a portfolio of promising drug candidates. These novel recombinant proteins have turned out to be multifunctional molecules, and are currently under different development phases. Lopap from bristles of the Lonomia obliqua moth caterpillar, for instance, is a prothrombin activator which belongs to the lipocalin family. It displays serine protease-like activity with procoagulant effect, and also induces cytokine secretion and antiapoptotic pathways in human cultured endothelial cells. Furthermore, a Lopap-derived peptide has showed to induce collagen synthesis in fibroblast culture and in animal dermis. Here, the molecular properties (steric, electronic, hydrophobic, geometric), which are strongly dependent on chemical structure, were investigated by applying chemometric and computational chemistry methods. It was considered different patterns of amino acid substitution related to the lipocalins' motif 2, which was recently shown to modulate cell survival. The calculated molecular properties were generally maintained in all investigated peptides extracted from three-dimensional structures of Protein Data Bank (1t0v, 1bbp, 1kxo, 2hzr, 1iiu, 1jyj, 1gka, 1s44, 3ebw) when compared to Lopap-derived peptide, specially the molecular shape and electronic density distribution, validating the lipocalin sequence signature previously reported. Indeed, those two properties are quite important for the molecular recognition process. 23108979 Ethyl acetate: X-ray, solvent and computed structures. Ethyl acetate (ethyl ethanoate) was crystallized in situ and the crystal structure was determined. In the solid, the molecule is flat with trans conformation. The geometric details of ethyl acetate as a solvate are analyzed statistically using the Cambridge Structural Database, uncovering a high degree of hidden disorder. Despite the disorder, they exhibit a preference of the trans over the gauche isomer, with a negligible contribution of the cis isomer. These results are compared to ab initio calculations on both solid-state and molecular level. For the molecular structures, the computed energy differences of the isomers match the statistics found as a solvent. Several DFT-D2 methods used to calculate the solid state yield results that differ significantly from the experiment. 23290048 Design, synthesis, characterization and biological evaluation of novel pyrazole integrated benzophenones. A series of novel pyrazole integrated benzophenones (9a-j) have been designed, synthesized from 1-methyl-5-(2,4,6-trimethoxy-phenyl)-1H-pyrazole 6. The structures of the regioisomers 6 and 7 were determined by 2D (1)H-(1)H COSY, (1)H-(13)C HSQC and (1)H-(13)C HMBC experiments. The newly synthesized compounds (9a-j) were evaluated for in vivo anti-inflammatory activity by carrageenan paw edema in rats and in vitro COX-1/COX-2 inhibition and antioxidant potential. Among the synthesized compounds, compounds 9b, 9d and 9f, were found to be active anti-inflammatory agents in addition to having potent antioxidant activity. 23180693 A new class of room-temperature multiferroic thin films with bismuth-based supercell structure. Intergrowth of two partially miscible phases of BiFeO(3) and BiMnO(3) gives a new class of room-temperature multiferroic phase, Bi(3) Fe(2) Mn(2) O(10+δ) , which has a unique supercell (SC) structure. The SC heterostructures exhibit simultaneously room-temperature ferrimagnetism and remanent polarization. These results open up a new avenue for exploring room-temperature single-phase multiferroic thin films by controlling the phase mixing of two perovskite BiRO(3) (R = Cr, Mn, Fe, Co, Ni) materials. 23127916 Polymorphisms in OCTN1 and OCTN2 transporters genes are associated with prolonged time to progression in unresectable gastrointestinal stromal tumours treated with imatinib therapy. The two basic mainstays of gastrointestinal stromal tumours (GIST) treatment are surgery and imatinib, a selective tyrosine kinase inhibitor that allows achieving a stable or responding disease in about 80% of patients with unresectable/metastatic GIST. Response to imatinib mainly depends from KIT and PDGFRα mutational status. Nevertheless, some patients with a potentially responsive genotype do not respond, and others develop a pattern of resistance to imatinib which is not associated with secondary mutations. This emphasizes the presence of mechanisms of resistance other than the receptor-related genotype, and the need of biological predictors to select the optimal therapeutic strategy, particularly now that other potent inhibitors are available. We investigated a panel of 31 polymorphisms in 11 genes, potentially associated with the pharmacogenetics of imatinib, in a group of 54 unresectable/metastatic GISTs treated with imatinib 400mg daily as first line therapy. Included in this analysis were polymorphisms in the transporters' family SLC22, SLCO, ABC, and in the metabolizing genes CYP-3A4 and -3A5. Time to progression was significantly improved in presence of the C allele in SLC22A4 (OCTN1 rs1050152), and the two minor alleles (G) in SLC22A5 (OCTN2 rs2631367 and rs2631372). Importantly, multivariate analysis, adjusting for age, gender, KIT/PDGFRα mutational status, and tumour size, revealed that all the three genotypes maintained independent predictive significance. In conclusion, in this study we showed that SLC22A4 and SLC22A5 genotypes may be an important predictor of time to progression in GIST patients receiving imatinib therapy. Further investigations are required in an attempt to further personalize GIST therapy. 23244594 Unique aggregation behavior of a carboxylate gemini surfactant with a long rigid spacer in aqueous solution. A new gemini surfactant with a long and rigid spacer, O,O'-bis(sodium 2-dodecylcarboxylate)-p-dibenzenediol (referred to as C(12)φ(2)C(12)), has been synthesized. Its aggregation in aqueous solution has been studied using static and dynamic light scattering measurements. The homologue O,O'-bis(sodium 2-dodecylcarboxylate)-p-benzenediol (C(12)φC(12)) whose spacer only contains a single phenyl group was also examined for comparison. Dynamic light scattering (DLS) revealed the unexpected existence of large aggregates in the solution of C(12)φ(2)C(12). However, C(12)φC(12) showed rather normal aggregation behavior. Both the results of intrinsic viscosity and light scattering demonstrated a loose structure for the large aggregates of C(12)φ(2)C(12). This behavior was attributed to an extending configuration of C(12)φ(2)C(12) with the two alkyl tails stretching toward the solution due to the rigidity of the long spacer. The large network-like aggregate formation was an inevitable outcome of spontaneously reducing the energy of the system. Freeze-fracture transmission electron microscopy (FF-TEM) images and (1)H NMR measurements supported this speculation. Due to the columnar-like molecular geometry, the large network-like aggregates were directly transformed into rodlike micelles with increasing surfactant concentration. Depending on further micellar growth, the wormlike micelles were finally formed as confirmed by rheological measurements. 23603045 Triazolothiadiazoles and triazolothiadiazines - Biologically attractive scaffolds. Contemporary medicinal chemistry faces diverse challenges from several directions, including the need for both potency and specificity of any therapeutic agent. Therefore, in the present perspective, the triazolothiadiazoles and triazolothiadiazines with broad spectrum biological profile have matured into indispensable heterocyclic scaffolds. This review article is an effort to summarize medicinal chemistry investigations over the last decade, in search for new N-bridged heterocycles which can be a rich source of promising biological activities. 22987483 Protective roles of single-wall carbon nanotubes in ultrasonication-induced DNA base damage. The overall level of ultrasonication-induced DNA damage is reduced in the presence of single-wall carbon nanotubes (SWCNTs), particularly for DNA lesions formed by one-electron reduction of intermediate radicals. The protective role of SWCNTs observed in this work suggests a contrary view to the general idea that carbon nanotubes have damaging effects on biomolecules. 23436261 The combination of exposure-response and case-control analyses in regulatory decision making. To reduce the bias introduced by confounding risk factors, a case-control comparison was incorporated in the exposure-response (ER) analysis to evaluate the recommended dosing regimen for trastuzumab in a pivotal trial. Results of Kaplan-Meier survival analysis suggest that patients with metastatic gastric cancer (mGC) in the lowest quartile trough concentrations of trastuzumab in cycle 1 (C(min 1) ) had shorter overall survival (OS) than did those in other quartiles. The result of the case-matched control comparison suggests that adjusting for these risk factors, patients with the lowest quartile of trastuzumab exposure did not benefit from addition of trastuzumab treatment to chemotherapy. The identified subgroup without survival benefit and the ER relationship support the recommendation on conducting clinical trials to identify a treatment regimen with greater exposure and acceptable safety profiles and to prospectively evaluate whether this treatment regimen will result in survival benefit for the identified subgroup. 23019138 Diuretic effects of cannabinoids. In vivo effects of cannabinoid (CB) agonists are often assessed using four well-established measures: locomotor activity, hypothermia, cataleptic-like effects, and analgesia. The present studies demonstrate that doses of CB agonists that produce these effects also reliably increase diuresis. Diuretic effects of several CB agonists were measured in female rats over 2 hours immediately after drug injection, and results were compared with hypothermic effects. Direct-acting CB1 agonists, including Δ(9)-tetrahydrocannabinol, WIN 55,212 [R-(1)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate], AM2389 [9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol], and AM4054 [9β-(hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol], produced dose-dependent increases in diuresis and decreases in colonic temperature, with slightly lower ED(50) values for diuresis than for hypothermia. The highest doses of cannabinoid drugs yielded, on average, 26-32 g/kg urine; comparable effects were obtained with 10 mg/kg furosemide and 3.0 mg/kg trans-(-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide (U50-488). Methanandamide (10.0 mg/kg) had lesser effect than other CB agonists, and the CB2 agonist AM1241 [1-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole], the anandamide transport inhibitor AM404, and the CB antagonist rimonabant did not have diuretic effects. In further studies, the diuretic effects of the CB1 agonist AM4054 were similar in male and female rats, displayed a relatively rapid onset to action, and were dose-dependently antagonized by 30 minutes pretreatment with rimonabant, but not by the vanilloid receptor type I antagonist capsazepine, nor were the effects of WIN 55,212 antagonized by the CB2 antagonist AM630 [(6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl) methanone)]. These data indicate that cannabinoids have robust diuretic effects in rats that are mediated via CB1 receptor mechanisms. 23389615 Public health challenges and prospects for malaria control and elimination. The past decade witnessed unprecedented efforts to control malaria, including renewed political and financial commitment and increased availability of both old and new strategies and tools. However, malaria still represents a major health burden, particularly in Africa. Important challenges such as the fragility of many health systems, the rise of insecticide and drug resistance, and particularly the expected decline both in funding and in the coverage of key interventions if they are not replaced as needed, urgently need to be addressed. Further research and development is also becoming increasingly crucial. Among other needs, common methodologies for estimating and tracking the malaria burden, new strategies to measure transmission, better understanding of immunity, and increased knowledge of the mechanisms and effects of resistance to drugs and insecticides stand out. The ongoing efforts in research and development for new antimalarial drugs, more sensitive point-of-care rapid diagnostic tests and new insecticides need further innovation and substantial strengthening. Clearly, efforts should focus not only on Plasmodium falciparum but also and increasingly on Plasmodium vivax, the neglected human malaria parasite. Addressing these challenges in a comprehensive and timely way will allow us to sustain the gains made so far and make further progress in control and progressive elimination. 23386462 Effectiveness of an educational intervention on prescription writing skill of preclerkship medical students in a problem-based learning curriculum. Medical school training for students in pharmacotherapy is suboptimal and junior doctors are not confident to prescribe drugs. This study evaluated the effectiveness of an optional educational intervention on prescribing skill of pre-clerkship medical students in a problem-based learning (PBL) program. Performance was assessed in seven end-unit objective structured practical examinations (OSPE). Physician-related prescription components (PRCs) and drug-related prescription components (DRCs) were assessed. The performance of students who attended the intervention sessions (attendees) and non-attendees was compared. Approximately half of the students attended the sessions. PRCs were written appropriately by most of the students. DRCs were written less competently by both attendees and non-attendees, specifically the dosage form, quantity to be dispensed and directions. Performance on individual DRCs was significantly better for attendees compared to non-attendees. The mean total score for all prescription components of attendees was significantly greater than that of non-attendees. The percentage of high achievers was significantly greater for attendees. A positive correlation was found between student attendance and the total score. An optional educational intervention during the preclerkship phase is an important determinant of prescribing performance of medical students. 23589302 The Fer tyrosine kinase is important for platelet-derived growth factor-BB-induced Stat3 phosphorylation, colony formation in soft agar and tumor growth in vivo. Fer is a cytoplasmic tyrosine kinase that is activated in response to platelet-derived growth factor (PDGF) stimulation. In the present report, we show that Fer associates with the activated PDGFbeta receptor (PDGFRbeta) through multiple autophosphorylation sites, i.e. Tyr579, Tyr581, Tyr740 and Tyr1021. Using low molecular weight inhibitors, we found that PDGF-BB-induced Fer activation is dependent on PDGFRbeta kinase activity, but not on the enzymatic activity of Src or Jak kinases. In cells in which Fer was downregulated using siRNA, PDGF-BB was unable to induce phosphorylation of Stat3, whereas phosphorylations of Stat5, Erk1/2 and Akt were unaffected. PDGF-BB-induced activation of Stat3 occurred also in cells expressing kinase-dead Fer, suggesting a kinase-independent adaptor role of Fer. Expression of Fer was dispensable for PDGF-BB-induced proliferation and migration, but essential for colony formation in soft agar. Tumor growth in vivo was delayed in cells depleted of Fer expression. Our data suggests a critical role of Fer in PDGF-BB-induced Stat3 activation and cell transformation. 23230266 Sequences associated with centromere competency in the human genome. Centromeres, the sites of spindle attachment during mitosis and meiosis, are located in specific positions in the human genome, normally coincident with diverse subsets of alpha satellite DNA. While there is strong evidence supporting the association of some subfamilies of alpha satellite with centromere function, the basis for establishing whether a given alpha satellite sequence is or is not designated a functional centromere is unknown, and attempts to understand the role of particular sequence features in establishing centromere identity have been limited by the near identity and repetitive nature of satellite sequences. Utilizing a broadly applicable experimental approach to test sequence competency for centromere specification, we have carried out a genomic and epigenetic functional analysis of endogenous human centromere sequences available in the current human genome assembly. The data support a model in which functionally competent sequences confer an opportunity for centromere specification, integrating genomic and epigenetic signals and promoting the concept of context-dependent centromere inheritance. 23472952 Discovery of (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid and congeners as highly potent inhibitors of human arginases I and II for treatment of myocardial reperfusion injury. Recent efforts to identify treatments for myocardial ischemia reperfusion injury have resulted in the discovery of a novel series of highly potent α,α-disubstituted amino acid-based arginase inhibitors. The lead candidate, (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid, compound 9, inhibits human arginases I and II with IC50s of 223 and 509 nM, respectively, and is active in a recombinant cellular assay overexpressing human arginase I (CHO cells). It is 28% orally bioavailable and significantly reduces the infarct size in a rat model of myocardial ischemia/reperfusion injury. Herein, we report the design, synthesis, and structure-activity relationships (SAR) for this novel series of inhibitors along with pharmacokinetic and in vivo efficacy data for compound 9 and X-ray crystallography data for selected lead compounds cocrystallized with arginases I and II. 23567022 Phylogenetic relationship among genera of Polymorphidae (Acanthocephala), inferred from nuclear and mitochondrial gene sequences. Acanthocephalans of the family Polymorphidae Meyer, 1931 are obligate endoparasites with complex life cycles. These worms use vertebrates (marine mammals, fish-eating birds and waterfowl) as definitive hosts and invertebrates (amphipods, decapods and euphausiids) as intermediate hosts to complete their life cycle. Polymorphidae has a wordwide distribution, containing 12 genera, with approximately 127 species. The family is diagnosed by having a spinose trunk, bulbose proboscis, double-walled proboscis receptacle, and usually four to eight tubular cement glands. To conduct a phylogenetic analysis, in the current study sequences of the small (18S) and large-subunit (28S) ribosomal RNA, and cytochrome c oxidase subunit 1 (cox 1) were generated for 27 taxa representing 10 of 12 genera of Polymorphidae, plus three additional species of acanthocephalans that were used as outgroups. Maximum likelihood (ML), maximum parsimony (MP), and Bayesian analyses were conducted on a combined nuclear rRNA (18S+28S) data set and on a concatenated dataset of nuclear plus one mitochondrial gene (18S+28S+cox 1). Phylogenetic analyses inferred with the concatenated dataset of three genes support the monophyly of nine genera (Andracantha, Corynosoma, Bolbosoma, Profilicollis, Pseudocorynosoma, Southwellina, Arhythmorhynchus, Hexaglandula and Ibirhynchus). However, the four sampled species of Polymorphus were nested within several clades, indicating that these species do not share a common ancestor, requiring further taxonomic revision using phylogenetic systematics, and reexamination of morphological and ecological data. By mapping definitive and intermediate host association onto the resulting cladogram, we observe that aquatic birds were the ancestral definitive hosts for the family with a secondary colonization and diversification to marine mammals. Whereas amphipods were ancestral intermediate hosts and that the association with decapods represent episodes of secondary colonization that arose several times during the evolutionary history of the family. Our results are useful to start testing hypothesis about the evolutionary history of this highly diverse family of acanthocephalans. 23197401 Photochemical properties and activity of water-soluble polymer/c(60) nanohybrids for photodynamic therapy. Water-soluble star-like poly(vinyl alcohol)/C(60) and poly{[poly(ethylene glycol) acrylate]-co-(vinyl acetate)}/C(60) nanohybrids are prepared by grafting macroradicals onto C(60) and are assessed as photosensitizers for photodynamic therapy. The photophysical and biological properties of both nanohybrids highlight key characteristics influencing their overall efficiency. The macromolecular structure (linear/graft) and nature (presence/absence of hydroxyl groups) of the polymeric arms respectively impact the photodynamic activity and the stealthiness of the nanohybrids. The advantages of both nanohybrids are encountered in a third one, poly[(N-vinylpyrrolidone)-co-(vinyl acetate)]/C(60) , which has linear grafts without hydroxyl groups, and shows a better photodynamic activity. 22511286 Prevention of hydrogen peroxide-induced red blood cells lysis by Ilex paraguariensis aqueous extract: participation of phenolic and xanthine compounds. The fresh leaves and stems of Ilex paraguariensis (Aquifoliaceae) are employed to prepare the commercial product used in North-eastern Argentina, Southern Brazil and Eastern Paraguay named yerba maté. The presence of polyphenols and xanthines, which present antioxidant activity, has been described in I. paraguariensis. In living organism, reactive oxygen species can cause tissue damage affecting erythrocyte membranes leading to hemolysis. The aim of this work was to evaluate the protective effect of an aqueous extract of I. paraguariensis (green leaves) on the hemolysis of red blood cells induced by hydrogen peroxide and to correlate this activity with the enzymatic activity related to hydrogen peroxide metabolism. The antioxidant activity of chlorogenic acid and caffeine was also analysed to evaluate their contribution to the activity of the crude extract. The extract as well as the isolated compounds protected red blood cells from hemolysis. This effect was related to a catalase-like activity. This study could contribute to the knowledge of the antioxidant activity of I. paraguariensis in view of the great quantities of yerba maté consumed by the population. 23132629 Unambiguous structure elucidation of heterocyclic products from condensation-cyclisation reactions of enaminones by 2D INADEQUATE and 15N NMR. The reaction of enaminones with 3-amino-2-cyanopent-2-enedinitrile can lead to an array of 12 possible products, depending on the reaction pathway and tautomerization. The use of 2D INADEQUATE and (15)N NMR for the unambiguous structure elucidation of the reaction products is discussed in this manuscript. 23369206 Recent progress and challenges in the discovery of new neuraminidase inhibitors. INTRODUCTION: At present, the key public health concern is to define the way in which the next influenza pandemic should be controlled. While influenza vaccines are available, their effectiveness could be significantly reduced if new strains differ significantly from those of the vaccines. Therefore, antiviral drugs play an important role in the prevention and management of influenza. The influenza neuraminidase (NA), a surface-glycoprotein enzyme involved in releasing the virus from the host cell, has been considered as an essential therapeutic target for treatment and prophylaxis of influenza infection. It is a highly conserved feature of the active site across all influenza A and B viruses and is of particular interest because compounds NA inhibitors (NAIs) can be cross-reactive against multiple types and subtypes of influenza. Currently, there are two NAI drugs which are licensed worldwide: oseltamivir and zanamivir, and two more drugs which have received recent approval in Japan: peramivir and laninamivir. Sudden changes in NAI susceptibility have stressed the urgent need in searching for novel inhibitors. AREAS COVERED: In this review, a potential pitfall in NA-based assays and the progress in the chemical synthesis of all patented NAIs from February 2006 to July 2012 are discussed. EXPERT OPINION: Both NA enzyme inhibition and X-ray crystallography data have suggested that the strategy of designing NAIs binding to the highly conserved region of NA can lead to inhibitors that are effective against all influenza NA subtypes. A number of new synthetic entries having unique structural frameworks that were designed based on computational study of X-ray structures of NA. They strongly exhibited the activity of NA in the low nanomolar range such as phosphonate congeners of zanamivir and oseltarmivir. Screening strategies based on the chemical diversity of natural products have revealed that flavonoids are the most prominent scaffolds possessing NA inhibitory activity. However, these substituted phenyl-benzopyrane compounds have been reported to exert a considerable quenching effect, causing false-positive results in the commonly used method of enzyme-based NA inhibition assays, and thus, reliability of the flavonoid-based NAIs reported in the literature. 23194828 Long term compulsivity on the 5-choice serial reaction time task after acute Chlorpyrifos exposure. Pesticide exposure has been associated with neuropsychological and psychiatric impairments and neurodegenerative disorders. Pesticide exposure commonly causes a deficit in inhibitory control behaviours. In the present study, we investigated whether acute exposure to organophosphate (OP) chlorpyrifos (CPF) is related to long-term lack of inhibitory control; we also examined the possible neurochemical basis of this association. Lister Hooded rats were exposed to an acute dose of CPF (250 mg/kg). Seven months later, we tested inhibitory control with the 5-choice serial reaction time task (5-CSRTT). We manipulated the baseline conditions of this task and also systemically pre-administered d-amphetamine, quinpirole, dizocilpine (MK-801) or ketanserin. We also analysed the post-mortem baseline levels of monoamines and amino acids in different brain regions. On the 5-CSRT task, CPF-exposed rats showed elevated perseverative responses that persisted across manipulation of baseline conditions of the task and under most of the pharmacological challenges tested. Only D-amphetamine induced a dose-dependent amelioration of the increased perseverative responses in the CPF group. The CPF group also exhibited increased levels of dopamine metabolism in the hippocampus and decreased levels of gamma-aminobutyric acid (GABA) and glutamate in the striatum compared to the vehicle group. These findings suggest that CPF induced a long-term compulsivity that was apparent in the 5-CSRT task and associated with changes in monoaminergic and amino acid brain systems of inhibitory control function. Exposure to high doses of OP should be taken into account in studies of environmental causes for neurodegenerative, neuropsychological and neuropsychiatric disorders. 23065531 Metabolism and quantification of [(18)F]DPA-714, a new TSPO positron emission tomography radioligand. [(18)F]DPA-714 [N,N-diethyl-2-(2-(4-(2[(18)F]-fluoroethoxy)phenyl)5,7dimethylpyrazolo[1,5a]pyrimidin-3-yl)acetamide] is a new radioligand currently used for imaging the 18-kDa translocator protein in animal models of neuroinflammation and recently in humans. The biodistribution by positron emission tomography (PET) in baboons and the in vitro and in vivo metabolism of [(18)F]DPA-714 were investigated in rats, baboons, and humans. Whole-body PET experiments showed a high uptake of radioactivity in the kidneys, heart, liver, and gallbladder. The liver was a major route of elimination of [(18)F]DPA-714, and urine was a route of excretion for radiometabolites. In rat and baboon plasma, high-performance liquid chromatography (HPLC) metabolic profiles showed three major radiometabolites accounting for 85% and 89% of total radioactivity at 120 minutes after injection, respectively. Rat microsomal incubations and analyses by liquid chromatography-mass spectrometry (LC-MS) identified seven metabolites, characterized as O-deethyl, hydroxyl, and N-deethyl derivatives of nonradioactive DPA-714, two of them having the same retention times than those detected in rat and baboon plasma. The third plasma radiometabolite was suggested to be a carboxylic acid compound that accounted for 15% of the rat brain radioactivity. O-deethylation led to a nonradioactive compound and [(18)F]fluoroacetic acid. Human CYP3A4 and CYP2D6 were shown to be involved in the oxidation of the radioligand. Finally an easy, rapid, and accurate method--indispensable for PET quantitative clinical studies--for quantifying [(18)F]DPA-714 by solid-phase extraction was developed. In vivo, an extensive metabolism of [(18)F]DPA-714 was observed in rats and baboons, identified as [(18)F]deethyl, [(18)F]hydroxyl, and [(18)F]carboxylic acid derivatives of [(18)F]DPA-714. The main route of excretion of the unchanged radioligand in baboons was hepatobiliary while that of radiometabolites was the urinary system. 23473053 Design, Synthesis, and Biological Evaluation of a Series of Benzo[de][1,7]naphthyridin-7(8H)-ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors. A series of benzo[de][1,7]naphthyridin-7(8H)-ones possessing a functionalized long-chain appendage have been designed and evaluated as novel PARP1 inhibitors. The initial effort led to the first-generation PARP1 inhibitor 26 bearing a terminal phthalazin-1(2H)-one framework and showing remarkably high PARP1 inhibitory activity (0.31 nM) but only moderate potency in the cell. Further effort generated the second-generation lead 41, showing high potency against both the PARP1 enzyme and BRCA-deficient cells, especially for the BRCA1-deficient MDA-MB-436 cells (CC50 < 0.26 nM). Mechanistic studies revealed that the new PARP1 inhibitors significantly inhibited H2O2-triggered PARylation in SKOV3 cells, induced cellular accumulation of DNA double-strand breaks, and impaired cell-cycle progression in BRCA2-deficient cells. Significant potentiation on the cytotoxicity of Temozolomide was also observed. The unique structural character and exceptionally high potency of 41 made it stand out as a promising drug candidate worthy for further evaluation. 23594396 Selective Permeation of Hydrogen Gas Using Cellulose Nanofibril Film. Biobased membranes that can selectively permeate hydrogen gas have been developed from aqueous dispersions of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-oxidized cellulose nanofibrils (TOCN) prepared from wood cellulose: TOCN-coated plastic films and self-standing TOCN films. Compared with TOCNs with sodium, lithium, potassium, and cesium carboxylate groups, TOCN with free carboxyl groups (TOCN-COOH) had much high and selective H2 gas permeation performance. Because permeabilities of H2, N2, O2, and CO2 gases through the membranes primarily depended on their kinetic diameters, the gas permeation behavior of the various TOCNs can be explained in terms of a diffusion mechanism. Thus, the selective H2 gas permeability for TOCN-COOH was probably due to a larger average size in free volume holes present between nanofibrils in the layer and film than those of other TOCNs with metal carboxylate groups. The obtained results indicate that TOCN-COOH membranes are applicable as biobased H2 gas separation membranes in fuel cell electric power generation systems. 23220618 Antithrombotic and profibrinolytic activities of isorhamnetin-3-O-galactoside and hyperoside. The potential anticoagulant activities of two single compounds, isorhamnetin-3-O-galactoside (IMG) and hyperoside, from Oenanthe javanica, were tested. The anticoagulant activities were investigated by measuring activated partial thromboplastin time (aPTT) and prothrombin time (PT), and the ability to inhibit production of thrombin and activated factor X (FXa) was investigated in human umbilical vein endothelial cells (HUVECs). And, the effects of the compounds on expression of plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were tested in tumor necrosis factor-(TNF)-α activated HUVECs. Treatment with IMG and hyperoside resulted in significantly prolonged aPTT and PT and inhibition of the activities of thrombin and FXa, and IMG or hyperoside inhibited production of thrombin and FXa in HUVECs. In accordance with these anticoagulant activities, both agents elicited anticoagulant effects in mouse. In addition, treatment with IMG and hyperoside resulted in inhibition of TNF-α-induced production of PAI-1, and treatment with IMG resulted in significant reduction of the PAI-1 to t-PA ratio. The anticoagulant and profibrinolytic effects of IMG were greater than those of hyperoside, indicating positive regulation of its anticoagulant function by the methoxy group of IMG. IMG and hyperoside possess antithrombotic activities and offer bases for development of a novel anticoagulant. 23380374 Bifunctional inhibition of HIV-1 reverse transcriptase: a first step in designing a bifunctional triphosphate. The onset of resistance to approved anti-AIDS drugs by HIV necessitates the search for novel inhibitors of HIV-1 reverse transcriptase (RT). Developing single molecular agents concurrently occupying the nucleoside and nonnucleoside binding sites in RT is an intriguing idea but the proof of concept has so far been elusive. As a first step, we describe molecular modeling to guide focused chemical syntheses of conjugates having nucleoside (d4T) and nonnucleoside (TIBO) moieties tethered by a flexible polyethylene glycol (PEG) linker. A triphosphate of d4T-6PEG-TIBO conjugate was successfully synthesized that is recognized as a substrate by HIV-1 RT and incorporated into a double-stranded DNA. 23482391 Comparative annotation of functional regions in the human genome using epigenomic data. Epigenetic regulation is dynamic and cell-type dependent. The recently available epigenomic data in multiple cell types provide an unprecedented opportunity for a comparative study of epigenetic landscape. We developed a machine-learning method called ChroModule to annotate the epigenetic states in eight ENCyclopedia Of DNA Elements cell types. The trained model successfully captured the characteristic histone-modification patterns associated with regulatory elements, such as promoters and enhancers, and showed superior performance on identifying enhancers compared with the state-of-art methods. In addition, given the fixed number of epigenetic states in the model, ChroModule allows straightforward illustration of epigenetic variability in multiple cell types. Using this feature, we found that invariable and variable epigenetic states across cell types correspond to housekeeping functions and stimulus response, respectively. Especially, we observed that enhancers, but not the other regulatory elements, dictate cell specificity, as similar cell types share common enhancers, and cell-type-specific enhancers are often bound by transcription factors playing critical roles in that cell type. More interestingly, we found some genomic regions are dormant in cell type but primed to become active in other cell types. These observations highlight the usefulness of ChroModule in comparative analysis and interpretation of multiple epigenomes. 23210854 Histone methyltransferase inhibitors: novel epigenetic agents for cancer treatment. Epigenetics is defined as heritable changes in gene activity and expression that occur without alteration in DNA sequence. The gene transcription is strictly correlated to chromatin structure, which could undergo covalent modifications of histones involving acetylation, methylation, phosphorylation and ubiquitination. Alterations in histones are implicated in many diseases, including cancer, by leading to tumor suppressor silencing or pro-apoptotic proteins downregulation. Although post-translational addition of methyl groups to the histone lysine has been discovered three decades ago, the importance of this epigenetic modification has emerged only in the last few years. Thenceforward histone methyltransferase inhibitors have been developed as potential therapeutic cancer agents. It should not be long before some selective inhibitors make their way into clinical trials. This review is mainly focused on the evolution in the development of new epigenetic modifier molecules modulating histone marks. 23566884 Tomatidine inhibits invasion of human lung adenocarcinoma cell A549 by reducing matrix metalloproteinases expression. Tomatidine is an aglycone of glycoalkaloid tomatine in tomato. Tomatidine is found to possess anti-inflammatory properties and may serve as a chemosensitizer in multidrug-resistant tumor cells. However, the effect of tomatidine on cancer cell metastasis remains unclear. This study examines the effect of tomatidine on the migration and invasion of human lung adenocarcinoma A549 cell in vitro. The data demonstrates that tomatidine does not effectively inhibit the viability of A549 cells. When treated with non-toxic doses of tomatidine, cell invasion is markedly suppressed by Boyden chamber invasion assay, while cell migration is not affected. Tomatidine reduces the mRNA level of matrix metalloproteinase-2 (MMP-2), MMP-9 and increases the expression of reversion-inducing cysteine-rich protein with kazal motifs (RECK), as well as tissue inhibitor of metalloproteinase-1 (TIMP-1). The immunoblotting assays indicate that tomatidine is very effective in suppressing the phosphorylation of Akt and extracellular signal regulating kinase (ERK). In addition, tomatidine significantly decreases the nuclear level of nuclear factor kappa B (NF-κB), which suggests that tomatidine inhibits NF-κB activity. Furthermore, the treatment of inhibitors specific for PI3K/Akt (LY294002), ERK (U0126), or NF-κB (pyrrolidine dithiocarbamate) to A549 cells reduced cell invasion and MMP-2/9 expression. The results suggest that tomatidine inhibits the invasion of A549 cells by reducing the expression of MMPs. It also inhibits ERK and Akt signaling pathways and NF-κB activity. These findings demonstrate a new therapeutic potential for tomatidine in anti-metastatic therapy. 23411293 Determination of total iron in food samples after flow injection preconcentration on polyurethane foam functionalized with N,N-bis(salicylidene)-1,3-propanediamine. A highly selective flow injection sorption system was developed for the fast determination of total iron in food samples. Iron (III) was reduced to iron (II) by ascorbic acid and preconcentrated on a mini-column packed with polyurethane foam (PUF) functionalized with N,N-bis(salicylidene)-1,3-propanediamine (SPDA). The retained Fe (II) was eluted with hydrochloric acid and subsequently reacted to 2,4,6-tri(2'-pyridyl)-1,3,5-triazine (TPTZ) then measured at 593 nm. The procedure has resulted preconcentration factor 36, sample frequency 20 h(-1) and detection limit 18 μg L(-1). The precision (RSD) was found to be 5.7% and 3.1% at concentration levels 0.1 and 5.0 μg mL(-1) iron (II), respectively. Finally, the method was successfully applied to determination of total iron in reference material and food samples. 23323890 Fasciospyrinadine, a novel sesquiterpene pyridine alkaloid from a Guangxi sponge Fasciospongia sp. Fasciospyrinadine (1), a novel sesquiterpene pyridine alkaloid with a previously unreported skeleton featuring a monocyclicfarnesane moiety attached to a 3-methylenepyridine residue, was isolated from the sponge Fasciospongia sp. from Weizhou Island, Guangxi Autonomous Region. The structure and the relative stereochemistry of 1 were elucidated on the basis of extensive analysis of its 1D and 2D NMR spectroscopic techniques. 23415903 A high-throughput-compatible, fluorescence anisotropy-based assay for ATP-dependent supercoiled DNA relaxation by human topoisomerase IIα. A novel, high-throughput-compatible assay for the ATP-dependent supercoiled DNA relaxing activity of human topoisomerase IIα (hTopoIIα) is described. The principle of detection is the preferential binding of the oligodeoxyribonucleotide BODIPY-TMR-5'-TTCTTCTTCT-3' to relaxed double-stranded plasmid containing the triplex forming sequence (TTC)9 versus the supercoiled plasmid. Binding of the oligonucleotide to the plasmid increases the fluorescence anisotropy of the BODIPY-TMR label. Optimization of the assay conditions was conducted to maximize the signal and the activity of the topoisomerase. The multiwell assay plate-based fluorescence anisotropy assay gave the same values for the potencies of several previously reported inhibitors of hTopoIIα as a gel electrophoresis-based assay of DNA relaxation. 23430139 Hypoxaemia affects male reproduction: a case study of how to differentiate between primary and secondary hypoxic testicular toxicity due to chemical exposure. Classification for fertility is based on two conditions, namely on evidence of an adverse effect on sexual function and fertility and that the effect is not secondary to other toxic effects. To decide on an adverse effect is a relatively simple day-to-day decision in toxicology but whether this effect is secondary often leads to serious controversy. As the seminiferous epithelium operates on the verge of hypoxia, oxygen deficit can lead to secondary impairment of testicular function. This is well known from healthy mountaineers exposing themselves to high altitude. They have reduced blood oxygen content that goes in parallel with impairment of testicular function and this effect remains for some time in spite of a compensatory polycythaemia. Similar findings are described for experimental animals exposed to hypobaric oxygen/high altitude. In addition, testicular function is affected in severe diseases in humans associated with systemic oxygen deficit like chronic obstructive pulmonary disease, sickle cell disease or beta-thalassaemia as well as in transgenic animals simulating haemolytic anaemia or sickle cell disease. The problem of insufficient oxygen supply as the underlying cause for testicular impairment has received relatively little attention in toxicology, mainly because blood oxygen content is generally not measured in these animal experiments. The difficulties associated with the decision whether testicular toxicity is primary or secondary to hypoxia are exemplified by the results of inhalation studies with nickel subsulphide and gallium arsenide (GaAs). Both of these particulate substances lead to severe lung toxicity that might impair oxygen uptake, but testicular toxicity is only observed with GaAs. This may first be explained by different effects on the blood: nickel subsulphide inhalation leads to a compensatory erythropoiesis that may mitigate pulmonary lack of oxygen uptake. In contrast, GaAs exposure is associated with microcytic haemolytic anaemia thereby aggravating any possible oxygen undersupply. Furthermore, the predominant pulmonary effect caused by GaAs (but not by nickel subsulphide) is alveolar proteinosis. Pulmonary alveolar proteinosis is also known as a severe disease in humans associated with hypoxaemia. Therefore, we conclude that the testicular effects observed after GaAs are secondary to hypoxaemia caused by the combination of pulmonary proteinosis and haemolytic anaemia. This publication tries to raise awareness to the severe consequences of hypoxaemia on testicular function that may already be caused by reduced oxygen pressure at high altitude without any chemical exposure. 23266665 Tri- and diorganotin(IV) complexes of biologically important orotic acid: synthesis, spectroscopic studies, in vitro anti-cancer, DNA fragmentation, enzyme assays and in vivo anti-inflammatory activities. Tri-and diorganotin(IV) orotates of general formula, R(n)Sn(H(2)Or)(m) [n = 3/2, m = 1/2, R = Me, n-Bu, n-Oct and Ph; H(2)Or(-) = monoanion of orotic acid (H(3)Or)] (n-Bu(2)Sn(HOr) as an exception) have been synthesized. On the basis of various spectroscopic studies it is revealed that R(3)Sn(H(2)Or) and R(2)Sn(H(2)Or)(2) exhibit distorted trigonal-bipyramidal and distorted octahedral geometry, respectively, and n-Bu(2)Sn(HOr) shows both five and six coordination geometry around tin. In vitro anti-cancer screening against MCF-7 (mammary), HEK-293 (kidney), PC-3 (prostate), HCT-15 (colon) and HepG-2 (liver) cancer cell lines suggest that the n-Oct(2)Sn(H(2)Or)(2) is the most active complex among all of the studied complexes. DNA fragmentation and antioxidant enzyme assays suggest that cytotoxic effect of the complexes is selectively mediated through the induction of apoptosis. They also exhibit low toxicity and good anti-inflammatory activity (in vivo). 23577636 Probing the Mechanism of TBAF-Catalyzed Deacylation of Cellulose Esters. The mechanism of the recently discovered, unusual tetrabutylammonium fluoride (TBAF) deacylation of cellulose esters has been investigated by methods including kinetic isotope effect (KIE) studies. The secondary KIE (kH/kD = 1.26 ± 0.04) measured for deacylation at C-2/3 suggests a mechanism involving a ketene intermediate for those positions. An inverse KIE (kH/kD = 0.87 ± 0.03) for the deacylation at C-6 indicates the involvement of a tetrahedral intermediate in the mechanism. Additional studies suggest the possibility that TBAF chelation by neighboring acyl groups may account for the unexpected regioselectivity at the secondary alcohol esters that is observed in the TBAF deacylation of cellulose esters. 23349524 The role of GH in adipose tissue: lessons from adipose-specific GH receptor gene-disrupted mice. GH receptor (GHR) gene-disrupted mice (GHR-/-) have provided countless discoveries as to the numerous actions of GH. Many of these discoveries highlight the importance of GH in adipose tissue. For example GHR-/- mice are insulin sensitive yet obese with preferential enlargement of the sc adipose depot. GHR-/- mice also have elevated levels of leptin, resistin, and adiponectin, compared with controls leading some to suggest that GH may negatively regulate certain adipokines. To help clarify the role that GH exerts specifically on adipose tissue in vivo, we selectively disrupted GHR in adipose tissue to produce Fat GHR Knockout (FaGHRKO) mice. Surprisingly, FaGHRKOs shared only a few characteristics with global GHR-/- mice. Like the GHR-/- mice, FaGHRKO mice are obese with increased total body fat and increased adipocyte size. However, FaGHRKO mice have increases in all adipose depots with no improvements in measures of glucose homeostasis. Furthermore, resistin and adiponectin levels in FaGHRKO mice are similar to controls (or slightly decreased) unlike the increased levels found in GHR-/- mice, suggesting that GH does not regulate these adipokines directly in adipose tissue in vivo. Other features of FaGHRKO mice include decreased levels of adipsin, a near-normal GH/IGF-1 axis, and minimal changes to a large assortment of circulating factors that were measured such as IGF-binding proteins. In conclusion, specific removal of GHR in adipose tissue is sufficient to increase adipose tissue and decrease circulating adipsin. However, removal of GHR in adipose tissue alone is not sufficient to increase levels of resistin or adiponectin and does not alter glucose metabolism. 23322769 Genome-wide screen for modulation of hepatic apolipoprotein A-I (ApoA-I) secretion. Control of plasma cholesterol levels is a major therapeutic strategy for management of coronary artery disease (CAD). Although reducing LDL cholesterol (LDL-c) levels decreases morbidity and mortality, this therapeutic intervention only translates into a 25-40% reduction in cardiovascular events. Epidemiological studies have shown that a high LDL-c level is not the only risk factor for CAD; low HDL cholesterol (HDL-c) is an independent risk factor for CAD. Apolipoprotein A-I (ApoA-I) is the major protein component of HDL-c that mediates reverse cholesterol transport from tissues to the liver for excretion. Therefore, increasing ApoA-I levels is an attractive strategy for HDL-c elevation. Using genome-wide siRNA screening, targets that regulate hepatocyte ApoA-I secretion were identified through transfection of 21,789 siRNAs into hepatocytes whereby cell supernatants were assayed for ApoA-I. Approximately 800 genes were identified and triaged using a convergence of information, including genetic associations with HDL-c levels, tissue-specific gene expression, druggability assessments, and pathway analysis. Fifty-nine genes were selected for reconfirmation; 40 genes were confirmed. Here we describe the siRNA screening strategy, assay implementation and validation, data triaging, and example genes of interest. The genes of interest include known and novel genes encoding secreted enzymes, proteases, G-protein-coupled receptors, metabolic enzymes, ion transporters, and proteins of unknown function. Repression of farnesyltransferase (FNTA) by siRNA and the enzyme inhibitor manumycin A caused elevation of ApoA-I secretion from hepatocytes and from transgenic mice expressing hApoA-I and cholesterol ester transfer protein transgenes. In total, this work underscores the power of functional genetic assessment to identify new therapeutic targets. 22884611 Objective and subjective cognitive enhancing effects of mixed amphetamine salts in healthy people. Psychostimulants such as mixed amphetamine salts (MAS, brand name Adderall) are widely used for cognitive enhancement by healthy young people, yet laboratory research on effectiveness has yielded variable results. The present study assessed the effects of MAS in healthy young adults with an adequately powered double-blind cross-over placebo-controlled trial. We examined effects in 13 measures of cognitive ability including episodic memory, working memory, inhibitory control, convergent creativity, intelligence and scholastic achievement, with the goals of determining (1) whether the drug is at least moderately enhancing (Cohen's d >= .5) to some or all cognitive abilities tested, (2) whether its effects on cognition are moderated by baseline ability or COMT genotype, and (3) whether it induces an illusory perception of cognitive enhancement. The results did not reveal enhancement of any cognitive abilities by MAS for participants in general. There was a suggestion of moderation of enhancement by baseline ability and COMT genotype in a minority of tasks, with MAS enhancing lower ability participants on word recall, embedded figures and Raven's Progressive Matrices. Despite the lack of enhancement observed for most measures and most participants, participants nevertheless believed their performance was more enhanced by the active capsule than by placebo. We conclude that MAS has no more than small effects on cognition in healthy young adults, although users may perceive the drug as enhancing their cognition. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23318598 Effects of celiac superior mesenteric ganglionectomy on glucose homeostasis and hormonal changes during oral glucose tolerance testing in rats. The liver plays an important role in maintaining glucose homeostasis in the body. In the prandial state, some of the glucose which is absorbed by the gastrointestinal tract is converted into glycogen and stored in the liver. In contrast, the liver produces glucose by glycogenolysis and gluconeogenesis while fasting. Thus, the liver contributes to maintaining blood glucose level within normoglycemic range. Glycogenesis and glycogenolysis are regulated by various mechanisms including hormones, the sympathetic and parasympathetic nervous systems and the hepatic glucose content. In this study, we examined a rat model in which the celiac superior mesenteric ganglion (CSMG) was resected. We attempted to elucidate how the celiac sympathetic nervous system is involved in regulating glucose homeostasis by assessing the effects of CSMG resection on glucose excursion during an oral glucose tolerance test, and by examining hepatic glycogen content and hepatic glycogen phosphorylase (GP) activity. On the oral glucose tolerance test, CSMG-resected rats demonstrated improved glucose tolerance and significantly increased GP activity compared with sham-operated rats, whereas there were no significant differences in insulin, glucagon or catecholamine levels between the 2 groups. These results suggest that the celiac sympathetic nervous system is involved in regulating the rate of glycogen consumption through GP activity. In conclusion, the examined rat model showed that the celiac sympathetic nervous system regulates hepatic glucose metabolism in conjunction with vagal nerve innervations and is a critical component in the maintenance of blood glucose homeostasis. 23473535 Biodistribution of different sized nanoparticles assessed by positron emission tomography: a general strategy for direct activation of metal oxide particles. The extraordinary small size of NPs makes them difficult to detect and quantify once distributed in a material or biological system. We present a simple and straightforward method for the direct proton beam activation of synthetic or commercially available aluminum oxide NPs (Al2O3 NPs) via the (16)O(p,α)(13)N nuclear reaction in order to assess their biological fate using positron emission tomography (PET). The radiolabeling of the NPs does not alter their surface or structural properties as demonstrated by TEM, DLS, and ζ-potential measurements. The incorporation of radioactive (13)N atoms in the Al2O3 NPs allowed the study of the biodistribution of the metal oxide NPs in rats after intravenous administration via PET. Despite the short half-life of (13)N (9.97 min), the accumulation of NPs in different organs could be measured during the first 68 min after administration. The percentage amount of radioactivity per organ was calculated to evaluate the relative amount of NPs per organ. This simple and robust activation strategy can be applied to any synthetic or commercially available metal oxide particle. 23216219 Extruder scale-up assessment in the process of extrusion-spheronization: comparison of radial and axial systems by a design of experiments approach. Scaling-up the extrusion-spheronization process involves the separate scale-up of each of the five process steps: dry mixing, granulation, extrusion, spheronization, and drying. The aim of the study was to compare two screw extrusion systems regarding their suitability for scaling-up. Two drug substances of high- and low-solubility in water were retained at different concentrations as formulation variables. Different spheronization times were tested. The productivity of the process was followed up using the extrusion rate and yield. Pellets were characterized by their size and shape, and by their structural and mechanical properties. A response surface design of experiments was built to evaluate the influence of the different variables and their interactions on each response, and to select the type of extrusion which provides the best results in terms of product quality, the one which shows less influence on the product after scale-up ("scalability") and when the formula used changes ("robustness"), and the one which allows the possibility to adjust pellet properties with spheronization variables ("flexibility"). Axial system showed the best characteristics in terms of product quality at lab and industrial scales, the best robustness at industrial scale, and the best scalability, by comparison with radial system. Axial system thus appeared as the easiest scaled-up system. Compared to lab scale, the conclusions observed at industrial scale were the same in terms of product quality, but different for robustness and flexibility, which confirmed the importance to test the systems at industrial scale before acquiring the equipment. 23317013 Solphenazines A-F, glycosylated phenazines from Streptomyces sp. strain DL-93. During a survey of actinobacteria known to suppress the growth of Streptomyces scabies (the causative agent of potato scab disease) in vivo, six new rhamnosylated alkaloids, the solphenazines A-F (1-6), were isolated from a biological control strain of Streptomyces (DL-93). The known rhamnosyl analogue of paraben (9) was also isolated along with a new rhamnosylated derivative of N-methyl-p-aminobenzoic acid (10). None of the compounds exhibited any antibacterial or antifungal activity against a standard panel of microorganisms, but compounds 1, 2, and 6 displayed some cytotoxicity against HCT-116 cancer cells. Additional in vitro testing provided data suggesting that the cytotoxic activity is not due to DNA intercalation or topoisomerase inhibition. 23434193 The role of omega-3 derived resolvins in arthritis. Omega-3 polyunsaturated fatty acids (PUFAs) are known to alleviate joint stiffness and pain in rheumatoid arthritis patients. However, the mechanisms by which omega-3s exert their beneficial effects has not been fully explored. Herein we discuss a novel class of bioactive lipid mediators, which are enzymatically biosynthesized in vivo from omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), termed resolvins. These lipid mediators exert anti-inflammatory and pro-resolving properties and are log-orders more potent than their precursors. We also highlight that formation of pro-resolving mediators can be enhanced by widely used anti-inflammatory and cardioprotective drugs (aspirin and statins) via the modification of cyclooxygenase-2 enzymatic activity. These bioactive pro-resolving lipid mediators provide further rationale for the beneficial effects of dietary supplementation with fish oils, and offer new avenues for developing therapeutics for inflammatory conditions such as rheumatoid arthritis. 23526664 Nicotinic Acid and Nicotinamide: A Review of Their Use for Hyperphosphatemia in Dialysis Patients. Phosphate binders have traditionally been used to treat hyperphosphatemia, a common complication in patients with end stage renal disease (ESRD). New evidence suggests that nicotinic acid and its metabolites may effectively decrease phosphorus absorption in the gastrointestinal tract, thereby reducing serum phosphorus concentrations. We conducted a literature search to identify studies of patients with ESRD on dialysis that evaluated the role of niacin and related compounds in decreasing serum phosphorus levels. We searched PubMed using the search terms niacin, nicotinic acid, niacinamide, nicotinamide and hyperphosphatemia. Limits were set to include only those articles published since 2002, conducted in human subjects, and written in the English language. Review articles captured through this process were mined for references to other primary literature that may not have been returned through the initial search. All studies were included if they met the search criteria and were conducted in patients with ESRD who received either hemodialysis or peritoneal dialysis. To identify current, ongoing studies, another search was conducted through clinicaltrials.gov. Among the seven studies that met our exclusion criteria, three used nicotinic acid as the therapeutic intervention and four used nicotinamide. Both nicotinic acid and nicotinamide were effective in significantly reducing serum phosphorus concentrations in patients with ESRD on either hemodialysis or peritoneal dialysis. Additional, large-scale studies that assess the appropriate dose as well as long-term safety and efficacy are recommended before clinicians can confirm their place in therapy. 23060411 Emergency do not consume/do not use concentrations for blended phosphates in drinking water. The U.S. Congress [PL 107-188] amended the Safe Drinking Water Act and required each community water system serving more than 3,000 people to conduct vulnerability assessments. These assessments address potential circumstances that could compromise the safety and reliability of municipal water. The present evaluation concerns the concentrations of the blended phosphates (also known as polyphosphates, condensed complex phosphates, polyphosphate glassy balls, and pyrophosphates) intended to aid regulatory agencies in decisions to avoid contact with affected water. Polyphosphates are direct food additives and they are used to treat municipal drinking water, but depending upon the concentration and duration of exposure these substances can induce chemical burns. Ingested polyphosphates are degraded by phosphatase enzymes to monophosphates, substances that are over-the-counter bowel purgatives. High oral doses of the monophosphates can induce transient hyperphosphatemia in older and susceptible young people, which can lead to acute phosphate nephropathy. In some patients, the condition is fatal. Based on the acute diarrhea after the ingestion of a single oral dose of monobasic (NaH2PO(4)) and dibasic (Na2HPO(4)) monophosphates in adults, a do not consume concentration of 600 mg PO(4)/L can be derived. Based on mild local irritation after topical application of 1.0% sodium metaphosphate [(NaPO(3))6 • H2O] to intact skin of sensitive volunteers, a do not use concentration of 8,000 mg PO4/L can be assigned. Given the lack of eye irritation in rabbits after direct instillation of 0.2% (NaPO(3))6 • H2O, an acute ocular contact limit of 50 mg PO4/L serves as the overall do not use level. 23423880 Nuclear Flux Densities during a Model Pericyclic Reaction with Energies Well Above and Below the Potential Barrier. Pericyclic reactions with energies E well above the potential energy barrier B (case E>B) proceed with quantum nuclear flux densities 〈j〉 which are essentially proportional to the nuclear densities ρ in the femtosecond time domain. This corresponds to the definition of classical (cl) mechanics, jcl =υcl ρcl , with almost constant velocity vcl . For the other case EM(C3N6(+)C3)2]-(I(-))10 [1-(I(-))10] capable of co-producing singlet oxygen (Type-II) and highly reactive hydroxyl radicals, formed from superoxide radicals in Type-I photosensitizing reactions, upon illumination at both UVA and white light wavelengths. The O2(-)·-production efficiency of 1-(I(-))10 was confirmed by using an O2(-)·-reactive bis(2,4-dinitrobenzenesulfonyl)tetrafluorofluorescein probe and correlated to the photoinduced electron-transfer event going from iodide anions to (3)C60*[>M(C3N6(+)C3)2] leading to C60(-)·[>M(C3N6(+)C3)2]. Incorporation of a defined number (ten) of quaternary ammonium cationic charges per C60 in 1 was aimed to enhance its ability to target pathogenic Gram-positive and Gram-negative bacterial cells. We used the well-characterized malonato[60]fullerene diester monoadduct C60[>M(t-Bu)2] as the starting fullerene derivative to provide a better synthetic route to C60[>M(C3N6(+)C3)2] via transesterification reaction under trifluoroacetic acid catalyzed conditions. These compounds may be used as effective photosensitizers and nano-PDT drugs for photoinactivation of pathogens. 23392354 Ventral tegmental area GABA neurons and opiate motivation. RATIONALE: Past research has demonstrated that when an animal changes from a previously drug-naive to an opiate-dependent and withdrawn state, morphine's motivational effects are switched from a tegmental pedunculopontine nucleus (TPP)-dependent to a dopamine-dependent pathway. Interestingly, a corresponding change is observed in ventral tegmental area (VTA) GABA(A) receptors, which change from mediating hyperpolarization of VTA GABA neurons to mediating depolarization. OBJECTIVES: The present study investigated whether pharmacological manipulation of VTA GABA(A) receptor activity could directly influence the mechanisms underlying opiate motivation. RESULTS: Using an unbiased place conditioning procedure, we demonstrated that in Wistar rats, intra-VTA administration of furosemide, a Cl(-) cotransporter inhibitor, was able to promote a switch in the mechanisms underlying morphine's motivational properties, one which is normally observed only after chronic opiate exposure. This behavioral switch was prevented by intra-VTA administration of acetazolamide, an inhibitor of the bicarbonate ion-producing carbonic anhydrase enzyme. Electrophysiological recordings of mouse VTA showed that furosemide reduced the sensitivity of VTA GABA neurons to inhibition by the GABA(A) receptor agonist muscimol, instead increasing the firing rate of a significant subset of these GABA neurons. CONCLUSIONS: Our results suggest that the carbonic anhydrase enzyme may constitute part of a common VTA GABA neuron-based biological pathway responsible for controlling the mechanisms underlying opiate motivation, supporting the hypothesis that VTA GABA(A) receptor hyperpolarization or depolarization is responsible for selecting TPP- or dopamine-dependent motivational outputs, respectively. 23411297 Phenolic compounds and antioxidant activities of selected species of seaweeds from Danish coast. Water and ethanolic extracts of 16 species of seaweeds collected along the Danish coasts were screened for antioxidant activities using four in vitro antioxidant assays (2,2-diphenyl-1-picrylhydrazyl radical scavenging activity, reducing power, ferrous ion-chelating and liposome model system). Furthermore their effectiveness in retarding lipid peroxidation in fish oil was evaluated by an accelerated stability test. Significant differences were observed in total and individual phenolic content and the antioxidant activities of seaweed species evaluated. Ethanol was more efficient for polyphenol extraction than water. Polysiphonia fucoides and all the Fucus species tested showed highest radical scavenging activity, reducing power, inhibition of oxidation in liposome model system and in fish oil and were high in phenolic content. These seaweeds could be potential rich sources of natural antioxidants for protection of foods against oxidation. In general, the various antioxidative assays correlated well with the total phenolic content, indicating that algal polyphenols are active components in these extracts. However, in some of the antioxidative assays some species with low total phenolic content also showed good antioxidative effects indicating that some other co-extracted active compounds such as pigments and tocopherols in ethanolic extracts and sulphated polysaccharides, proteins or peptides in water extracts may also contribute to the overall antioxidant properties and this needs further investigation. 22984796 Information for clinicians: commercially available molecular diagnosis testing in the evaluation of thyroid nodule fine-needle aspiration specimens. TSH receptor mRNA reverse transcription-polymerase chain reaction, the Veracyte and Asuragen commercial methods, and the noncommercial use of BRAF, RAS, RET/PTC, and PAX8/PPARγ testing have promising roles in the diagnosis and treatment of patients with nodular thyroid disease and thyroid cancer. However, at this time, experience with these molecular methods remains limited, and no test has perfect sensitivity and specificity. Peer-reviewed data evaluating the diagnostic performance of these tests are increasingly available. The American Thyroid Association (ATA) feels that until an expert consensus review of existing data (now underway by the ATA Guidelines Task Force) can be completed, no evidence-based recommendation for or against the use of these methods can be made. Clinicians are therefore advised to consider the use of these genetic diagnosis methods with appropriate caution, and to remain cognizant of the limitations of the data supporting their use. Patients who are interested in the use of these tests in their own care should discuss them thoroughly with their care providers. Until evidence-based recommendations are available, determining whether or not the limited data available support the use of these methods should be considered on a case-by-case basis. 23620436 A New Proposed Rodent Model of Chemically Induced Prostate Carcinogenesis: Distinct Time-Course Prostate Cancer Progression in the Dorsolateral and Ventral Lobes. BACKGROUND: Characterization of novel rodent models for prostate cancer studies requires evaluation of either spontaneous and carcinogen-induced tumors as well as tumor incidence in different prostatic lobes. We propose a new short-term rodent model of chemically induced prostate carcinogenesis in which prostate cancer progression occurs differentially in the dorsolateral and ventral lobes. METHODS: Adult gerbils were treated with MNU alone or associated with testosterone for 3 or 6 months of treatment. Tumor incidence, latency, localization, and immunohistochemistry (AR, PCNA, smooth muscle α-actin, p63, MGMT, and E-cadherin) were studied in both lobes. RESULTS: Comparisons between both lobes revealed that lesions developed first in the DL while the VL presented longer tumor latency. However, after 6 months, there was a dramatic increase in tumor multiplicity in the VL, mainly in MNU-treated groups. Lesions clearly progressed from a premalignant to a malignant phenotype over time and tumor latency was decreased by MNU + testosterone administration. Three-dimensional reconstruction of the prostatic complex showed that the DL developed tumors exclusively in the periurethral area and showed intense AR, PCNA, and MGMT immunostaining. Moreover, VL lesions emerged throughout the entire lobe. MNU-induced lesions presented markers indicative of an aggressive phenotype: lack of basal cells, rupture of the smooth muscle cell layer, loss of E-cadherin, and high MGMT staining. CONCLUSIONS: There are distinct pathways involved in tumor progression in gerbil prostate lobes. This animal provides a good model for prostate cancer since it allows the investigation of advanced steps of carcinogenesis with shorter latency periods in both lobes. Prostate © 2013 Wiley Periodicals, Inc. 23497873 Purification and characterisation of two enzymes related to endogenous formaldehyde in Lentinula edodes. In this study, γ-glutamyl transpeptidase (GGT) and l-cysteine sulphoxide lyase (C-S lyase) were purified from the fruiting body of Lentinula edodes in three steps and then characterised. We found that GGT together with C-S lyase caused the generation of endogenous formaldehyde in L. edodes. GGT was composed of a large subunit of 41 kDa and a small subunit of 25 kDa, and C-S lyase was composed of two identical subunits of 46 kDa, as determined by SDS-PAGE. GGT was stable at pH 8.0-10.0 with an optimum pH of 8.8, and was stable at 20-50°C with an optimum activity at 37°C. C-S lyase was stable at pH 8.0-9.0 with an optimum pH of 8.5, and was stable at 20-60°C with an optimum activity at 40°C. The present work supports the study of the mechanism of endogenous formaldehyde in L. edodes. 23358236 Inhibition of p-glycoprotein mediated multidrug resistance by stemofoline derivatives. Resistance to chemotherapy in cancer patients has been correlated to the overexpression of the ATP-binding cassette (ABC) drug transporters including P-glycoprotein (P-gp) that actively efflux chemotherapeutic drugs from cancer cells. We examined the mutidrug resistance reversing property of stemofoline derivatives in drug-resistance human cervical carcinoma (KB-V1) and human leukemic (K562/Adr) cell lines that overexpress P-gp. Didehydrostemofoline and eleven of its derivatives were synthesized and the cytotoxicity and their effect on doxorubicin, vinblastine and paclitaxel sensitivity in drug resistant (KB-V1 and K562/Adr) and drug sensitive (KB-3-1 and K562) cell lines by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were determined. We found that three out of the twelve stemofoline derivatives including OH-A1, NH-B6 and NH-D6 showed commitment efficiency to increase sensitivity to doxorubicin, vinblastine and paclitaxel in KB-V1 cells and increase sensitivity to doxorubicin, and paclitaxel in K562/Adr cells whereas the effects have not been seen in their parental sensitive cancer cell lines (KB-3-1 and K562). These results indicate that stemofoline derivatives reversed P-gp-mediated multidrug resistance in vitro, and thus could be developed as effective chemosensitizers to treat multidrug-resistant cancers. The molecular mechanism of modulation of P-gp would be further determined. 23558432 Association of serum adiponectin and IGF-I levels with parameters of cardiac remodeling in severely obese patients. Background. Obesity is associated with various changes in cardiac geometry and this process involves both hemodynamic and non-hemodynamic factors, among which adipocitokines and growth factors may play an important role The aim of this study was to identify the extent and pattern of cardiac remodeling in a group of severely obese patients and analyze the relationship between adiponectin, IGF-I and cardiac parameters reflecting obesity associated structural changes. Subjects and methods. Our study included 344 patients (104 men) with severe obesity (mean body mass index (BMI)= 45.7±8.5 kg/m2), extensively evaluated clinically and biologically (complete metabolic tests, serum adiponectin and IGF-I measurements). Left ventricular mass index (LVMI), left atrium (LA) size and LV geometry were determined by means of cardiac ultrasound. Results. The most prevalent pattern of LV geometry was eccentric hypertrophy (28.7% of patients). In a gender, age, BMI, diabetes and hypertension adjusted general linear model, patients with concentric or eccentric hypertrophy had significantly lower values of adiponectin than those with normal geometry (6.75±0.41, 6.96±0.53, versus 9.04±0.42 mg/l, p<0.05). In multivariate analysis, independent determinants for LVMI were BMI (B=0.364, p<0.001), systolic blood pressure (BP) (β=0.187, p=0.004), age (β=0.246, p<0.001), adiponectin (β=-0.151, p=0.012) and IGF-I z-score (β=0.134, p=0.025) while factors independently related to LA size were systolic BP (β=0.218, p<0.001), BMI (β=0.194, p<0.001), age (β=0.273, p<0.001), gender (β=-0.195, p<0.001) and adiponectin (β=-0.180, p=0.005). Conclusions: In patients with severe obesity, IGF-I z score and adiponectin correlate with parameters of cardiac remodeling independently of anthropometric, hemodynamic or metabolic factors. 22455790 Sarmentosamide, a novel hexadienamide from Thai soil actinomycetes. A new hexadienamide derivative named sarmentosamide (1) was identified from the culture of Streptomyces sp. SBI108 isolated from Thai soil under an herb. The structure was elucidated on the basis of spectroscopic data, and the absolute configuration was determined by chemical degradation. 23586849 Structure and Absolute Configuration of Fumiquinazoline L, an Alkaloid from a Gorgonian-Derived Scopulariopsis sp. Fungus. Fumiquinazoline L (1), an alkaloid with a heptacyclic skeleton formed via a bridging hemiaminal linkage, was isolated from a gorgonian-derived Scopulariopsis sp. fungus. The structure and absolute configuration of the new compound were identified by comprehensive spectroscopic data and X-ray diffraction analysis. During acid hydrolysis of 1, the isomerization of the valine residue was observed and also studied in different conditions. Fumiquinazoline L (1) showed no cytotoxic or antibacterial activities. 23376610 FGF signalling through Fgfr2 isoform IIIb regulates adrenal cortex development. Developmental signalling pathways are implicated in the formation and maintenance of the adrenal gland, but their roles are currently not well defined. In recent years it has emerged that Sonic hedgehog (Shh) and Wnt/β catenin signalling are crucial for the growth and development of the adrenal cortex. Here we demonstrate that Fibroblast growth factor receptor (Fgfr) 2 isoforms IIIb and IIIc are expressed mainly in the adrenal subcapsule during embryogenesis and that specific deletion of the Fgfr2 IIIb isoform impairs adrenal development, causing reduced adrenal growth and impaired expression of SF1 and steroidogenic enzymes. The hypoplastic adrenals also have thicker, disorganised capsules which retain Gli1 expression but no longer express Dlk1. Fgfr2 ligands were detected in both the capsule and the cortex, suggesting the importance of signalling between the capsule and the cortex in adrenal development. 23411198 Winter wheat hull (husk) is a valuable source for tricin, a potential selective cytotoxic agent. The flavone, tricin (5,7,4'-trihydroxy-3',5'-dimethoxyflavone) has great potential as an anticancer agent, due to its specific chemopreventive activity. In spite of these characteristics, its use in preclinical studies is still limited, mainly because of its limited availability and high production cost. Tricin is found mainly in cereal grains, such as wheat, rice, barley, oat and maize. However, its concentration in these plants is not sufficient for commercial use. To find a reliable, rich source of tricin, we investigated its distribution in different parts of wheat (Triticum aestivum) and designed an efficient method for its isolation and purification. The highest amount (770 ± 157 mg/kg dry weight) was found in the husks of winter wheat. This concentration is one of the highest in any plant species and is considered as a cheap source of natural tricin. The purified wheat husks tricin was found to be a selective potent inhibitor of two cancer cell lines of liver and pancreas, while having no side effects on normal cells. This selective action suggests that tricin could be considered as a potential candidate for pre-clinical trials as a chemopreventive agent. In addition, fibre-rich crude wheat husk could be used as a natural chemopreventive agent in food supplement. 22997007 Pitch-tunable size reduction patterning with a temperature-memory polymer. A scalable and pitch-tunable size reduction patterning method is introduced by exploiting the temperature memory effect of shape memory polymer and replica molding of UV-curable materials. 23564914 Effects of Intraduodenal Glutamine on Incretin Hormone and Insulin Release, the Glycemic Response to an Intraduodenal Glucose Infusion, and Antropyloroduodenal Motility in Health and Type 2 Diabetes. OBJECTIVEGlutamine reduces postprandial glycemia when given before oral glucose. We evaluated whether this is mediated by stimulation of insulin and/or slowing of gastric emptying.RESEARCH DESIGN AND METHODSTen healthy subjects were studied during intraduodenal (ID) infusion of glutamine (7.5 or 15 g) or saline over 30 min, followed by glucose (75 g over 100 min), while recording antropyloroduodenal pressures. Ten patients with type 2 diabetes mellitus (T2DM) were also studied with 15 g glutamine or saline.RESULTSID glutamine stimulated glucagon-like peptide 1 (GLP-1; healthy: P < 0.05; T2DM: P < 0.05), glucose-dependent insulinotropic polypeptide (GIP; P = 0.098; P < 0.05), glucagon (P < 0.01; P < 0.001), insulin (P = 0.05; P < 0.01), and phasic pyloric pressures (P < 0.05; P < 0.05), but did not lower blood glucose (P = 0.077; P = 0.5).CONCLUSIONSGlutamine does not lower glycemia after ID glucose, despite stimulating GLP-1, GIP, and insulin, probably due to increased glucagon. Its capacity for pyloric stimulation suggests that delayed gastric emptying is a major mechanism for lowering glycemia when glutamine is given before oral glucose. 23603554 Cardiovascular effects of Boophone disticha aqueous ethanolic extract on early maternally separated BALB/C mice. ETHNOPHARMACOLOGICAL RELEVANCE: There are a number of reports from traditional medical practice in Zimbabwe and neighboring countries and few in vitro studies suggesting an effect with extracts of Boophone disticha in some forms of anxiety disorders. AIM OF THE STUDY: In order to validate the use of Boophone disticha in treatment of anxiety, this study was set to determine the effects of the plant extracts on blood pressure (BP) and heart rate (HR) in adult BALB/c mice subjected to repeated early maternal separation (MS) stress. MATERIALS AND METHODS: To test whether early life stress increases anxiety in mice, non-invasive tail cuff method was used to examine the autonomic nervous system activity by assessing cardiovascular reactivity and response to acute mixing stress (AMS) and restraint stress (RS) in adult mice subjected to early postnatal stress as compared to control. AMS-induced cardiovascular response was then evaluated in adult MS mice treated with Boophone disticha as compared to vehicle and diazepam. RESULTS: Comparisons of the BP and HR measurements indicated that MS significantly reduced AMS-induced HR responses in BALB/c mice when compared with control. Boophone disticha treatment significantly reduced AMS-induced BP response in BALB/c MS as compared to vehicle and diazepam treatments. CONCLUSIONS: Our findings demonstrate for the first time that postnatal stress can induce short-term changes in the sensitivity of the cardiovascular system to subsequent stress which can be reduced by treatment with a freeze dried aqueous ethanolic extract of Boophone disticha. 23603044 Synthesis, radioiodination and in vivo screening of novel potent iodinated and fluorinated radiotracers as melanoma imaging and therapeutic probes. In order to develop new iodinated and fluorinated matched-pair radiotracers for Single-Photon Emission Computed Tomography (SPECT)/Positron Emission Tomography (PET) imaging and targeted radionuclide therapy of melanoma, we successfully synthesized and radiolabelled with iodine-125 seven new derivatives, starting from our previously described lead structure 3. The relevance of these radiotracers for gamma scintigraphic imaging of melanoma in rodent was assessed. The tumoural radioactivity uptake was most often high and specific even at early time points (12.1-18.3% ID/g at 3 h p.i. for [(125)I]39-42) and a fast clearance from the non-target organs was observed. Also, calculated effective doses that could be delivered to tumours when using corresponding [(131)I]-labelled analogues were generally higher than 100 cGy/MBq injected (98.9-150.5 cGy/MBq for [(131)I]39-42). These results make compounds 39-42 suitable candidates for (i) PET imaging of melanoma after labelling with fluorine-18 and (ii) targeted radionuclide therapy of disseminated melanoma after labelling with iodine-131. 22725249 Possibility for the development of cosmetics with PLGA nanospheres. The optimized preparation of Poly-(lactide-co-glycolic acid) (PLGA) nanospheres containing ubiquinone (UQ) for cosmetic products was pursued. By investigating various conditions for the preparation of UQ/PLGA nanospheres such as the molecular weight of PLGA, PLGA concentration, and UQ concentration, UQ/PLGA nanospheres with increased stability and slower drug release at a higher drug loading efficiency were prepared. Permeation tests on the prepared nanospheres using iontophoresis via electric dermal administration on membrane filters (200 nm pore size) and hairless mouse skin samples were also carried out. After iontophoresis, the nanospheres choked the membrane filter and remained on the horny layer of the hairless mouse skin, even after washing. Therefore, the prepared UQ/PLGA nanospheres and the established iontophoresis technique with the PLGA nanospheres in the present study can be applied to the future development of cosmetics. 23373428 A simple and sensitive method for determination of vitamins D(3) and K(1) in rat plasma: application for an in vivo pharmacokinetic study. Abstract Purpose: To develop and to validate a simple but sensitive method for determination of vitamins D(3) and K(1) in rat plasma. Methods: The sample treatment included protein precipitation by cold acetonitrile, evaporation, reconstitution with methanol and filtration. The chromatography conditions included Xterra RP18 3.5 µm 4.6 × 100 mm column at ambient temperature and mobile phase consisting of methanol/water (93/7, v/v) at 0.5 mL/min flow rate. Vitamin D(3) and probucol were detected at 265 nm and vitamin K(1) at 239 nm. Rats were administered intravenously by 0.1 mg/kg of vitamin D(3) or K(1) and the blood samples were withdrawn pre-administration and at pre-determined time points post-administration. The pharmacokinetic analysis was performed using a non-compartmental approach. Results: The calibration curves in rat plasma were linear up to 5000 ng/mL for both vitamins. The limit of quantification (LOQ) was 20 ng/mL for vitamin D(3) and 40 ng/mL for K(1). Inter- and intra-day precision and accuracy were below 15%. The pharmacokinetic parameters of vitamin D(3) following intravenous administration were: AUC(0-∞) = 11323 ± 1081 h × ng/mL, V(d) = 218 ± 80 mL/kg, CL = 8.9 ± 0.8 mL/h/kg, t(1/2) = 16.8 ± 5 h; and of vitamin K(1): AUC(0-∞) = 2495 ± 297 h × ng/mL, V(d) = 60 ±24 mL/kg, CL = 40.5 ± 5.1 mL/h/kg, t(1/2) = 1.1 ±0.5 h. Conclusion: The developed HPLC-UV assay is a simple and sensitive method for the determination of vitamins D(3) and K(1) in rat plasma. A higher dose of vitamin K(1) should be used in future studies for accurate estimation of pharmacokinetic parameters. The data show the suitability of the assay for pharmacokinetic studies in rats. 23504441 Simultaneous effects of two fungicides (copper and dimethomorph) on their phytoremediation using Lemna minor. Effects of two fungicides, copper and dimethomorph ((E,Z)4-[3-(4-chlorophenyl)-3-(3-4dimethoxyphenyl) acryloyl] morpholine) on Lemna minor growth and phytoremediation were evaluated. The toxicity of copper and dimethomorph alone and in combination, was assessed by growth inhibition of L. minor cultures after 96 and 168 h. Copper had a severe impact on growth (max. inhibition: 90 % at 1,000 μg L(-1)) while dimethomorph (as pure ingredient or formulated as Forum) did not (inhibition <45 % at 1,000 μg L(-1)) after 168 h of treatment. When both chemicals were combined, synergism was observed after 96 h of exposure to copper and Forum. However, this interaction was a simple additivity after 168 h. Additivity was also observed when the pure active ingredient (dimethomorph) replaced Forum in the mixture of copper and dimethomorph at 96 and 168 h. L. minor showed an excellent performance in removing copper from the medium since after 96 h, 36, 60, and 76 % removal were reached for 10, 20, and 30 μg L(-1) of Cu respectively. Copper accumulated in the plants. The removal of copper increased with Forum concentration. After 96 h copper (10 μg L(-1) initial concentration) elimination increased from 36.39 ± 5.86-60.70 ± 6.06 % when Forum concentration increased from 0 to 500 μg L(-1). Accumulation of copper in plants was also increased by Forum but not by the active ingredient alone. Depuration of Forum by L. minor varied between 10 and 40 % after 96 h and it was generally more efficient than that of the pure ingredient. This depuration decreased in the presence of copper possibly due to the metal toxicity. 23624360 Liberation of drugs from multi-wall carbon nanotube carriers. MWCNTs in the 'nanotube-drug' hybrids can play a role of carriers or additives (enhancers) in the more complex formulations. This work reviews qualitative and quantitative analyses of Drug Delivery Systems (DDSs) based on multi-wall carbon nanotubes (MWCNTs) and their chemically modified analogues (mainly oxidised MWCNTs). A special emphasis was placed on the chemical interactions between drug molecules and the nanotube carrier critical both in the stage of preparation/synthesis of the hybrids and liberation of the drug. 23401173 The Lignan (-)-Cubebin Inhibits Vascular Contraction and Induces Relaxation Via Nitric Oxide Activation in Isolated Rat Aorta. Cubebin, the most abundant lignan in Piper cubeba, has been described as having several effects as trypanocidal, antimycobacterial, antispasmodic, antimicrobial, anti-inflammatory, and analgesic. This study investigated the vasorelaxant effect produced by (-)-cubebin in isolated rat aortic rings pre-contracted with phenylephrine (Phe), and the possible mechanism involved in this event was evaluated. Endothelium-dependent relaxation was evoked by acetylcholine and (-)-cubebin in intact aortic rings, while endothelium-independent vasorelaxation was elicited by sodium nitroprusside and (-)-cubebin in denuded rings. Cumulative concentration-response curves for Phe (10(-10) -10(-5)  M) were determined for endothelium-intact and endothelium-denuded aortic rings in either the presence or absence of (-)-cubebin. Dose-response curves were also constructed for pre-incubation of vascular rings with Nω-nitro-L-arginine methyl ester (L-NAME) (a non-specific nitric oxide synthase inhibitor), indomethacin (an unspecific cyclooxygenase inhibitor), and 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ) (a guanylyl cyclase inhibitor). (-)-Cubebin was found to exert a vasorelaxant effect irrespective of the presence of endothelium, which was abolished by pretreatment with L-NAME and ODQ, but not with indomethacin. In addition, (-)-cubebin was able to reduce Phe contraction in the case of intact rings. These results suggest that (-)-cubebin promotes vasorelaxation via NO/cGMP pathway in rat aorta, without prostacyclin involvement. Copyright © 2013 John Wiley & Sons, Ltd. 23410886 High-resolution DNA methylome analysis of primordial germ cells identifies gender-specific reprogramming in mice. Dynamic epigenetic reprogramming occurs during mammalian germ cell development, although the targets of this process, including DNA demethylation and de novo methylation, remain poorly understood. We performed genome-wide DNA methylation analysis in male and female mouse primordial germ cells at embryonic days 10.5, 13.5, and 16.5 by whole-genome shotgun bisulfite sequencing. Our high-resolution DNA methylome maps demonstrated gender-specific differences in CpG methylation at genome-wide and gene-specific levels during fetal germline progression. There was extensive intra- and intergenic hypomethylation with erasure of methylation marks at imprinted, X-linked, or germline-specific genes during gonadal sex determination and partial methylation at particular retrotransposons. Following global demethylation and sex determination, CpG sites switched to de novo methylation in males, but the X-linked genes appeared resistant to the wave of de novo methylation. Significant differential methylation at a subset of imprinted loci was identified in both genders, and non-CpG methylation occurred only in male gonocytes. Our data establish the basis for future studies on the role of epigenetic modifications in germline development and other biological processes. 23097213 Novel screening assay for the selective detection of G-protein-coupled receptor heteromer signaling. Drugs targeting G-protein-coupled receptors (GPCRs) make up more than 25% of all prescribed medicines. The ability of GPCRs to form heteromers with unique signaling properties suggests an entirely new and unexplored pool of drug targets. However, current in vitro assays are ill equipped to detect heteromer-selective compounds. We have successfully adapted an approach, using fusion proteins of GPCRs and chimeric G proteins, to create an in vitro screening assay (in human embryonic kidney cells) in which only activated heteromers are detectable. Here we show that this assay can demonstrate heteromer-selective G-protein bias as well as measure transinhibition. Using this assay, we reveal that the δ-opioid receptor agonist ADL5859, which is currently in clinical trials, has a 10-fold higher potency against δ-opioid receptor homomers than δ/μ-opioid receptor heteromers (pEC(50) = 6.7 ± 0.1 versus 5.8 ± 0.2). The assay enables the screening of large compound libraries to identify heteromer-selective compounds that could then be used in vivo to determine the functional role of heteromers and develop potential therapeutic agents. 23320542 Evidence for self-association of the alternative sigma factor σ54. Sigma factor σ(54) has a distinct modus operandi for mediating the activation of bacterial RNA polymerase (RNAP) at promoter recognition motifs 12 and 24 bp upstream from transcription start sites. σ(54) was thought to act as monomer in all transcription steps. However, we provide evidence that σ(54) of Pseudomonas putida interacts stably with itself. The interface between monomers involves contacts in σ(54) regions I and III, sequences that play key roles in the transcription activation of σ(54)-RNAP holoenzyme. These roles include interactions with activator proteins and the -12 and -24 motifs. In particular, we detected inter-monomer contacts between region I, and between region I and the C-terminal portion of region III. Our results suggest a new auto-antagonistic regulatory state of σ(54). 23122163 Reverse micellar extraction of bovine serum albumin - a comparison between the effects of gemini surfactant and its corresponding monomeric surfactant. Gemini surfactant displayed distinct advantages over monomeric surfactant in the liquid-liquid reverse micellar extraction process. First, less amount of gemini surfactant than monomeric surfactant was needed for transferring almost complete bovine serum albumin (BSA) into organic phase from aqueous phase. Second, the loading capacity of gemini surfactant reverse micelle phase was much higher than that of the corresponding monomeric surfactant reverse micelle. Third, efficient backward extraction (75-92%) of BSA could be effected in a wide pH range from 4 to 9 with gemini surfactant reverse micelle while a pH of ca. 4.3 is prerequisite to the recovery of BSA from monomeric surfactant reverse micelle. So far, the reports about the effect of surfactant structure on protein extraction have been limited. This study indicates the important role of the spacer of gemini surfactant in protein extraction process and may provide more knowledge on how to optimise surfactant structure. 23042729 Establishment of a molecular embryonic stem cell developmental toxicity assay. The mouse embryonic stem cell test (EST) is a 10-day screen for teratogenic potential developed to reduce animal use for embryotoxicity testing of chemicals (Spielmann, 2005; Spielmann et al., 1997). In this study, we used the cytotoxicity IC(50) values and transcriptional expression changes as primary endpoints in a shorter 4-day version of the EST, the molecular embryonic stem cell assay. Mouse D3 embryonic stem cells were used for cytotoxicity assessment (monolayers) or grown as embryoid bodies in low attachment plates for transcriptional profiling. Sixty-five compounds with known in vivo teratogenicity (33 teratogens and 32 nonteratogens) were evaluated to develop a model for classifying compounds with teratogenic potential. The expression of 12 developmentally regulated gene targets (nanog, fgf5, gsc, cd34, axin2, apln, chst7, lhx1, fgf8, sox17, foxa2, and cxcr4) was measured following exposure of embryoid bodies to a single compound concentration (0.1 × the cytotoxicity IC(20)) for 4 days. In the decision-tree model, compounds with IC(50) values < 22 µM were categorized as teratogens, whereas compounds in the two groups with IC(50) values between 22-200 µM and > 200 µM were categorized as teratogens if ≥ 8 and 12 genes, respectively, were deregulated by at least 10%. Forty-seven of 65 compounds of the training set were correctly identified (72% total concordance). In a test set of 12 additional compounds (5 teratogens, 7 nonteratogens), 10 were correctly classified by this approach (83% concordance). The false positive rate in the training and test sets was 24 and 0%, respectively, indicating that this assay has potential to identify teratogens. 23303365 Enhancing catalytic selectivity of supported metal nanoparticles with capping ligands. Enhancing catalytic selectivity of supported metal nanoparticles with capping ligands is demonstrated using an Au/SiO(2) catalyst in liquid phase aerobic oxidation of benzyl alcohol. Chemisorption of an appropriate amount of polyvinylpyrrolidone on the Au/SiO(2) catalyst greatly enhances the benzaldehyde selectivity from 43% to ~100% and its yield from 4.9% to 7.2%. 22864849 Protection by chrysin, apigenin, and luteolin against oxidative stress is mediated by the Nrf2-dependent up-regulation of heme oxygenase 1 and glutamate cysteine ligase in rat primary hepatocytes. Chrysin, apigenin, and luteolin are flavones that differ in their number of hydroxyl groups in the B ring. In this study, we investigated the protection by chrysin, apigenin, and luteolin against tert-butyl hydroperoxide (tBHP)-induced oxidative stress and the possible mechanisms involved in rat primary hepatocytes. Chrysin, apigenin, and luteolin dose-dependently up-regulated the protein expression of heme oxygenase 1 (HO-1) and glutamate cysteine ligase (GCL) catalytic (GCLC) and modifier subunit (GCLM) and increased the intracellular glutathione (GSH) content and the ratio of GSH to oxidized GSH. Among the flavones studied, chrysin showed the greatest induction of HO-1, GCLC, and GCLM protein expression and GSH content. Cellular reactive oxygen species production induced by tBHP was attenuated by pretreatment with chrysin, apigenin, and luteolin (P < .05), and this protection was reversed by the GCL inhibitor l-buthionine-S-sulfoximine and the HO-1 inhibitor zinc protoporphyrin. Chrysin, apigenin, and luteolin activated extracellular signal-regulated protein kinase 2 (ERK2), nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, nuclear Nrf2-antioxidant responsive element (ARE) binding activity, and ARE-dependent luciferase activity. Both ERK2 and Nrf2 siRNAs attenuated chrysin-induced HO-1, GCLC, and GCLM protein expression. Taken together, these results suggest that chrysin, apigenin, and luteolin inhibit tBHP-induced oxidative stress by up-regulating HO-1, GCLC, and GCLM gene transcription via the ERK2/Nrf2/ARE signaling pathways in rat primary hepatocytes. 23206272 Invasion genetics of the introduced black rat (Rattus rattus) in Senegal, West Africa. An understanding of the evolutionary history and dynamics of invasive species is required for the construction of predictive models of future spread and the design of biological management measures. The black rat (Rattus rattus) is a major vertebrate invader with a worldwide distribution. Despite the severe ecological, economic and health impacts of this species, its evolutionary history has been little studied. We carried out extensive specimen sampling in Senegal, West Africa, and used microsatellite markers to describe the pattern and processes of invasion in this large continental area. The genetic data obtained were combined with historical knowledge concerning the presence of this species in Senegal. Data were analysed by a combination of Bayesian clustering and approximate Bayesian computation methods. The invasion pathways closely paralleled the history of human trade routes in Senegal. In several places, we detected the occurrence of multiple introductions from genetically different sources. Long-distance migration between towns and villages was also observed. Our findings suggest that genetic bottlenecks and admixture have played a major role in shaping the genetics of invasive black rats. These two processes may generate genetic novelty and favour rapid evolution along the invasion pathways. 22954533 Silver nanoparticle-induced cytotoxicity in rat brain endothelial cell culture. Silver nanoparticles (AgNPs) are among the most widely commercialised engineered nanomaterials, because of their antimicrobial properties. They are already commonly used in medical devices, household products and industry. Concerns have been raised about potential adverse health effects due to increasing dispersion of AgNPs in the environment. The present study examined the cytotoxic effects of spherical, citrate-coated AgNPs (10, 50 and 100 nm) in rat brain endothelial (RBE4) cells and investigated whether the observed effects can be explained by the intrinsic toxicity of the particles or the silver ions released from the particles. The results indicated that exposure of RBE4 cells to AgNPs lead to significant reduction in dye uptake as measured with the Neutral red (NR) assay. The effect was found to be related to particle size, surface area, dose and exposure time. In contrast, silver ions increased NR uptake (ca. 10%) in RBE4 cells after 1h, while a reduction in NR uptake was observed after 24h exposure at high concentrations (20-30 μM). Colony formation, as an indicator of proliferation ability, was completely inhibited by AgNPs at concentrations higher than 1 μg/ml. Silver ions had less effect on the colony formation of RBE4 cells than AgNPs. 23312283 Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than FMO1. FMO3 overexpression in mice significantly increases plasma TMAO levels while silencing FMO3 decreases TMAO levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis. 23626400 Novel pentablock copolymer (PLA-PCL-PEG-PCL-PLA) based nanoparticles for controlled drug delivery: Effect of copolymer compositions on the crystallinity of copolymers and in vitro drug release profile from nanoparticles. The purpose of this investigation was to design novel pentablock copolymers (polylatide-polycaprolactone-polyethylene glycol- polycaprolactone-polylatide) (PLA-PCL-PEG-PCL-PLA) to prepare nanoparticle formulations which provide continuous delivery of steroids over a longer duration with minimal burst effect. Another purpose was to evaluate the effect of poly (L-lactide) (PLLA) or poly (D, L-lactide) (PDLLA) incorporation on crystallinity of pentablock copolymers and in vitro release profile of triamcinolone acetonide (selected as model drug) from nanoparticles. PLA-PCL-PEG-PCL-PLA copolymers with different block ratio of PCL/PLA segment were synthesized. Release of triamcinolone acetonide from nanoparticles was significantly affected by crystallinity of the copolymers. Burst release of triamcinolone acetonide from nanoparticles was significantly minimized with incorporation of proper ratio of PDLLA in the existing triblock (PCL-PEG-PCL) copolymer. Moreover, pentablock copolymer based nanoparticles exhibited continuous release of triamcinolone acetonide. Pentablock copolymer based nanoparticles can be utilized to achieve continuous near zero-order delivery of corticosteroids from nanoparticles without any burst effect. 23199223 Thermally-limited exciton delocalization in superradiant molecular aggregates. We present two-dimensional Fourier transform optical spectroscopy measurements of two types of molecular J-aggregate thin films and show that temperature-dependent dynamical effects govern exciton delocalization at all temperatures, even in the presence of significant inhomogeneity. Our results indicate that in the tested molecular aggregates, even when the static structure disorder dominates exciton dephasing dynamics, the extent of exciton delocalization may be limited by dynamical fluctuations, mainly exciton-phonon coupling. Thus inhomogeneous dephasing may mediate the exciton coherence time whereas dynamical fluctuations mediate the exciton coherence length. 23354457 Pesticides and oncogenic modulation. Pesticides constitute a diverse class of chemicals used for the protection of agricultural products. Several lines of evidence demonstrate that organochlorine and organophosphate pesticides can cause malignant transformation of cells in in vitro and in vivo models. In the current minireview a comprehensive summary of recent in vitro findings is presented along with data reported from human population studies, regarding the impact of pesticide exposure on activation or dysregulation of oncogenes and tumor suppressor genes. Substantial mechanistic work suggests that pesticides are capable of inducing mutations in oncogenes and increase their transcriptional expression in vitro, whereas human population studies indicate associations between pesticide exposure levels and mutation occurrence in cancer-related genes. Further work is required to fully explore the exact mechanisms by which pesticide exposure affects the integrity and normal function of oncogenes and tumor suppressor genes in human populations. 23404894 Searching the coding region for microRNA targets. Finding microRNA targets in the coding region is difficult due to the overwhelming signal encoding the amino acid sequence. Here, we introduce an algorithm (called PACCMIT-CDS) that finds potential microRNA targets within coding sequences by searching for conserved motifs that are complementary to the microRNA seed region and also overrepresented in comparison with a background model preserving both codon usage and amino acid sequence. Precision and sensitivity of PACCMIT-CDS are evaluated using PAR-CLIP and proteomics data sets. Thanks to the properly constructed background, the new algorithm achieves a lower rate of false positives and better ranking of predictions than do currently available algorithms, which were designed to find microRNA targets within 3' UTRs. 23541668 Synthetic oligoureas of metaphenylenediamine mimic host defence peptides in their antimicrobial behaviour. Oligomeric ureas of m-phenylenediamine target anionic DMPG (dimyristoylphosphatidylglycerol) and possess promise as antimicrobial agents. Their similar size, shape and hydrophobicity to helical antimicrobial peptides (AMPs) may be important for activity to exist and the ability of these compounds to insert into a well ordered lipid environment. 23529825 Lorcaserin: a review of its use in chronic weight management. Oral lorcaserin (BELVIQ(®)), a selective serotonin 5-HT2C receptor agonist, is indicated in the US as an adjunct to diet and exercise in the chronic weight management of obese adults, or overweight adults with at least one weight-related comorbidity (e.g. dyslipidaemia, hypertension, type 2 diabetes). This article reviews the pharmacological properties, therapeutic efficacy and tolerability of oral lorcaserin in this patient population. In three large randomized, double-blind, multicentre studies, oral lorcaserin was more effective than placebo in the management of obese and overweight adults with or without type 2 diabetes mellitus. Following 12 months' therapy, significantly higher proportions of lorcaserin than placebo recipients achieved a ≥5 and ≥10 % reduction from baseline in their bodyweight and a significant between-group difference favouring lorcaserin over placebo was observed for the change from baseline in bodyweight. Moreover, among patients who had achieved a ≥5 % reduction in their bodyweight after 12 months' therapy with lorcaserin, a significantly higher proportion who received lorcaserin for a further 12 months than those who switched to placebo maintained ≥5 % weight loss at 24 months. In general, oral lorcaserin was well tolerated in clinical studies, with hypoglycaemia and headache the most frequently reported adverse events in those with or without type 2 diabetes, respectively. According to a pooled analysis, the risk of US-FDA-defined valvulopathy with lorcaserin is generally low and not statistically significantly different from placebo. From these and other data, the FDA has concluded that lorcaserin is unlikely to elevate the risk of valvulopathy. 23430741 Design of an Escherichia coli Expressed HIV-1 gp120 Fragment Immunogen That Binds to b12 and Induces Broad and Potent Neutralizing Antibodies. b12, one of the few broadly neutralizing antibodies against HIV-1, binds to the CD4 binding site (CD4bs) on the gp120 subunit of HIV-1 Env. Two small fragments of HIV-1 gp120, b121a and b122a, which display about 70% of the b12 epitope and include solubility-enhancing mutations, were designed. Bacterially expressed b121a/b122a were partially folded and could bind b12 but not the CD4bs-directed non-neutralizing antibody b6. Sera from rabbits primed with b121a or b122a protein fragments and boosted with full-length gp120 showed broad neutralizing activity in a TZM-bl assay against a 16-virus panel that included nine Tier 2 and 3 viruses as well as in a five-virus panel previously designed to screen for broad neutralization. Using a mean IC50 cut-off of 50, sera from control rabbits immunized with gp120 alone neutralized only one virus of the 14 non-Tier 1 viruses tested (7%), whereas sera from b121a- and b122a-immunized rabbits neutralized seven (50%) and twelve (86%) viruses, respectively. Serum depletion studies confirmed that neutralization was gp120-directed and that sera from animals immunized with gp120 contained lower amounts of CD4bs-directed antibodies than corresponding sera from animals immunized with b121a/b122a. Competition binding assays with b12 also showed that b121a/2a sera contained significantly higher amounts of antibodies directed toward the CD4 binding site than the gp120 sera. The data demonstrate that it is possible to elicit broadly neutralizing sera against HIV-1 in small animals. 23486542 Intragenic deletions of the IGF1 receptor gene in five individuals with psychiatric phenotypes and developmental delay. Haploinsufficiency of the gene encoding the insulin-like growth factor 1 receptor (IGF1R), either caused by telomeric 15q26 deletions, or by heterozygous point mutations in IGF1R, segregate with short stature and various other phenotypes, including microcephaly and dysmorphic facial features. Psychomotor retardation and behavioral anomalies have been seen in some cases. Here we report small, intragenic deletions of IGF1R, identified by chromosome microarray analysis in two unrelated families affected primarily with neuropsychiatric phenotypes including developmental delay, intellectual disability and aggressive/autoaggressive behaviors. The deletions are in frame, and both wild-type and mutant mRNAs are expressed as measured by quantitative real-time PCR. While short stature is considered a phenotypic hallmark of IGF1R haploinsufficiency, the present report suggests that in frame exon deletions of IGF1R present predominantly with cognitive and neuropsychiatric phenotypes.European Journal of Human Genetics advance online publication, 13 March 2013; doi:10.1038/ejhg.2013.42. 23454012 Memantine-sulfur containing antioxidant conjugates as potential prodrugs to improve the treatment of Alzheimer's disease. The approved treatments for Alzheimer's disease (AD) exploit mainly a symptomatic approach based on the use of cholinesterase inhibitors or N-methyl-d-aspartate (NMDA) receptor antagonists. Natural antioxidant compounds, able to pass through the blood-brain barrier (BBB), have been extensively studied as useful neuroprotective agents. A novel approach towards excitotoxicity protection and oxidative stress associated with excess β amyloid (Aβ) preservation in AD is represented by selective glutamatergic antagonists that possess as well antioxidant capabilities. In the present work, GSH (1) or (R)-α-lipoic acid (LA) (2) have been covalently linked with the NMDA receptor antagonists memantine (MEM). The new conjugates, proposed as potential antialzheimer drugs, should act both as glutamate receptor antagonists and radical scavenging agents. The physico-chemical properties and "in vitro" membrane permeability, the enzymatic and chemical stability, the demonstrated "in vitro" antioxidant activity associated to the capacity to inhibit Aβ(1-42) aggregation makes at least compound 2 a promising candidate for treatment of AD patients. 23583911 Design, synthesis and biological evaluation of new classes of thieno[3,2-d]pyrimidinone and thieno[1,2,3]triazine as inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2). Driven by a multidisciplinary approach combination (Structure-Based (SB) Three-Dimensional Quantitative Structure-Activity Relationships (3-D QSAR), molecular modeling, organic chemistry and various biological evaluations) here is reported the disclosure of new thienopyrimidines 1-3 as inhibitors of KDR activity and human umbilical vein endothelial cell (HUVEC) proliferation. More specifically, compound 2f represents a new lead compound that inhibits VEGFR-2 and HUVEC at μM concentration. Moreover by the mean of an endothelial cell tube formation in vitro model 2f tartaric acid salt proved to block angiogenesis of HUVEC at μM level. 23418081 Ultralight and highly compressible graphene aerogels. Chemically converted graphene aerogels with ultralight density and high compressibility are prepared by diamine-mediated functionalization and assembly, followed by microwave irradiation. The resulting graphene aerogels with density as low as 3 mg cm(-3) show excellent resilience and can completely recover after more than 90% compression. The ultralight graphene aerogels possessing high elasticity are promising as compliant and energy-absorbing materials. 23454530 Rational design, synthesis and QSAR study of vasorelaxant active 3-pyridinecarbonitriles incorporating 1H-benzimidazol-2-yl function. A variety of 2-alkoxy-4-aryl-6-(1H-benzimidazol-2-yl)-3-pyridinecarbonitriles 4a-r were prepared via either regioselective reaction of 3-aryl-1-(1H-benzimidazol-2-yl)-2-propen-1-ones 3 with malononitrile or ylidenemalononitriles 6 with 2-acetyl-1H-benzimidazoles 1 in the presence of sodium alkoxide in the corresponding alcohol. All the synthesized compounds showed significant vasodilation properties using isolated thoracic aortic rings of rats pre-contracted with norepinephrine hydrochloride standard technique. Compounds 4d, 4p, 4l, and 4f exhibited remarkable activity compared with prazosin hydrochloride, which was used as a reference standard in the present study. QSAR studies revealed a good predictive and statistically significant 3 descriptor model (r(2) = 0.913, radjusted(2)=0.8808, rprediction(2)=0.7911). 23089250 The interactive effects of selenomethionine and methylmercury on their absorption, disposition, and elimination in juvenile white sturgeon. Selenium (Se) and mercury (Hg) are prevalent pollutants of industrialized watersheds. However, when co-administered, Se has protective effects on organisms from Hg. The mechanism is not fully understood, but it is thought that Se reduces Hg availability, either by forming biologically inert complexes and/or associating with selenoproteins. Despite concerns with aquatic contaminations, relatively little information is available on the interaction in aquatic organisms. In the present study, the interactive effects of Se and Hg on their absorption, disposition, and elimination were examined in juvenile white sturgeon, a benthic fish species at high risk to exposures of both contaminants. Selenium and Hg were provided as L-selenomethionine (SeMet) and methylmercury (MeHg), respectively. Groups of 10 sturgeon were orally intubated with a single dose of either 0 (control), SeMet (500 μg Se/kg body weight; BW), MeHg (850 μg Hg/kg BW), or their combination (Se/Hg; 500 μg Se/kg and 850 μg Hg/kg BW). The blood was repeatedly sampled and urine collected from the fish, over a 48 h post intubation period. At 48 h, the fish were sacrificed for Se and Hg tissue concentration and distribution. The co-administration of SeMet and MeHg significantly (p<0.05) lowered blood concentrations of both Se and Hg and tissue Se concentrations. Similarly, assimilation of Se and Hg was also reduced significantly. The interaction has a more quantitative effect on Se metabolism because the reduction in the overall tissue Se is a consequence of reduced Se absorption at the gut and not from the metabolic effects after absorption. In contrast, given the pulse increase in blood Hg concentration, tissue redistribution, and increased urinary elimination, the interactive effect on tissue Hg concentration is likely to be post-absorption. Even in the absence of exogenous SeMet, Se and Hg co-accumulated in tissue at a Se:Hg molar ratio greater than 1. Thus, similar to mammals, maintaining at least a 1:1 molar ratio of Se and Hg is of great physiological importance in the white sturgeon. Interestingly, SeMet did not divert Hg from the brain. Allocation of Se from the kidneys may have occurred in order to maintain the high Se:Hg molar ratios in the brain of white sturgeon. In the current study, the combined use of kinetic analysis and that of the conventional approach of measuring tissue concentration changes provided a comprehensive understanding of the interactive effect of SeMet and MeHg on their respective metabolic processes in juvenile white sturgeon. 22508483 Anti-oncogenic potential of the eIF4E-binding proteins. The eIF4E-binding proteins (4E-BPs) are inhibitors of protein synthesis that sequester the mRNA cap-binding protein eIF4E and consequently block cell growth and proliferation. In most tumors however, their inhibitory function is compromised by major oncogenic signaling pathways. Recently, thanks to the generation of mouse genetic models, considerable progress has been made in elucidating the involvement of 4E-BPs and their unique target, eIF4E, in the process of carcinogenesis. Increasing evidence indicates that an 'addiction' to protein synthesis emerges in cancer cells, highlighting the potential that 4E-BPs have as targets for therapeutics. In this review, we summarize the biochemical function, regulation and anti-oncogenic activity of the 4E-BPs. 23265472 Nutritive value of masau (Ziziphus mauritiana) fruits from Zambezi Valley in Zimbabwe. Ziziphus mauritiana (masau) fruits are consumed by many people in Zimbabwe. The fruits contribute significantly to people's diet when they are in season. The objective of this study was to determine the nutritional content of the fruits and, hence, quantify their contribution to the diet. Samples of masau were collected in two seasons (August 2006 and August 2007). Both macronutrients and micronutrients were determined using standard AOAC methods of analysis. Dry matter content ranged from 21.1±0.2 to 24.1±0.3 g 100 g(-1) of edible portion of the sweet and sour fruits, and 84.8±0.2 to 87.2±0.2 g 100 g(-1) for the dried fruit. Crude protein per 100g edible portion of dry weight ranged between 7.9±0.0 and 8.7±0.0 g, crude fat from 0.8±0.0 to 1.5±0.0 g, crude fibre from 4.9±0.0 to 7.3±0.0 g, ash between 3.0±0.0 and 4.3±0.0 g and carbohydrate between 79.5±0.0 and 83.2±0.0 g. The fruits were rich in vitamin C (15.0±0.0-43.8±0.02 mg 100 g(-1)) and the energy values ranged between 1516.0±1.73 and 1575.0±2.3 kJ 100 g(-1). Furthermore, the fruits contained (mg 100 g(-1) of dry weight) potassium from 1865.0±1.3 to 2441.0±1.1, calcium from 160.0±0.3 to 254.0±0.1, sodium between 185.0±0.1 and 223.0±0.2, magnesium between 83.0±0.0 and 150.0±0.13 and phosphorous from 87.0±0.1 to 148.0±0.5. Manganese and copper contents ranged between 0.7±0.03 and 1.6±0.03, while iron and zinc ranged between 2.1±0.43 and 4.3±0.1, and 0.6±0.0-0.9±0.0 mg 100 g(-1) of dry weight, respectively. The masau fruit is therefore a good potential source of carbohydrates, proteins and micronutrients, such as calcium, potassium, sodium, phosphorous, copper, iron, Vitamin C and zinc. 23551295 Immobilizing Individual Atoms beneath a Corrugated Single Layer of Boron Nitride. Single atoms, and in particular the least reactive noble gases, are difficult to immobilize at room temperature. Ion implantation into a crystal lattice has this capability, but the randomness of the involved processes does not permit much control over their distribution within the solid. Here we demonstrate that the boron nitride nanomesh, a corrugated single layer of hexagonal boron nitride (h-BN) with a 3.2 nm honeycomb superstructure formed on a Rh(111) surface, can trap individual argon atoms at distinct subsurface sites at room temperature. A kinetic energy window for implantation is identified where the argon ions can penetrate the h-BN layer but not enter the Rh lattice. Scanning tunneling microscopy and photoemission data show the presence of argon atoms at two distinct sites within the nanomesh unit cell, confirmed also by density functional theory calculations. The single atom implants are stable in air. Annealing of implanted structures to 900 K induces the formation of highly regular holes of 2 nm diameter in the h-BN layer with adjacent flakes of the same size found on top of the layer. We explain this "can-opener" effect by the presence of a vacancy defect, generated during the penetration of the Ar ion through the h-BN lattice, and propagating along the rim of a nanomesh pore where the h-BN lattice is highly bent. The reported effects are also observed in graphene on ruthenium and for neon atoms. 23612001 In vitro antiproliferative effect of a water-soluble Laminaria japonica polysaccharide on human melanoma cell line A375. A water-soluble polysaccharide WPS-2-1, purified from Laminaria japonica, has been found to have antitumor activity. In this study, WPS-2-1 exhibited high anti-proliferative activity on A375 cells in a dosedependent manner. Further investigation indicated that WPS-2-1 induced A375 cells apoptosis. Moreover, WPS-2-1-induced apoptosis was associated with the alteration in expressions of Bcl-2 family proteins. Mitochonadrial apoptotic pathway was involved in WPS-2-1-induced apoptosis, which included the loss of mitochondrial membrane and activation of caspase-3/9. The results in this study suggested that WPS-2-1 could effectively inhibit proliferation of A375 cells in vitro and induce apoptosis via mitochondrial apoptotic pathway. It might serve as a potential anti-tumor agent. 23182946 Disrupted cytoskeletal homeostasis, astrogliosis and apoptotic cell death in the cerebellum of preweaning rats injected with diphenyl ditelluride. In the present report 15 day-old rats were injected with 0.3μmol of diphenyl ditelluride (PhTe)(2)/kg body weight and parameters of neurodegeneration were analyzed in slices from cerebellum 3 and 6 days afterwards. The earlier responses, at day 3 after injection, included hyperphosphorylation of intermediate filament (IF) proteins from astrocyte (glial fibrillary acidic protein - GFAP - and vimentin) and neuron (low-, medium- and high molecular weight neurofilament subunits: NF-L, NF-M and NF-H); increased mitogen-activated protein kinase (MAPK) (Erk and p38MAPK) and cAMP-dependent protein kinase (PKA) activities. Also, reactive astrogliosis takes part of the early responses to the insult with (PhTe)(2), evidenced by upregulated GFAP in Western blot, PCR and immunofluorescence analysis. Six days after (PhTe)(2) injection we found persistent astrogliosis, increased propidium iodide (PI) positive cells in NeuN positive population evidenced by flow cytometry and reduced immunofluorescence for NeuN, suggesting that the in vivo exposure to (PhTe)(2) progressed to neuronal death. Moreover, activated caspase 3 suggested apoptotic neuronal death. Neurodegeneration was related with decreased [(3)H]glutamate uptake and decreased Akt immunoreactivity, however phospho-GSK-3-β (Ser9) was not altered in (PhTe)(2) injected rat. Therefore, the present results show that the earlier cerebellar responses to (PhTe)(2) include disruption of cytoskeletal homeostasis that could be related with MAPK and PKA activation and reactive astrogliosis. Akt inhibition observed at this time could also play a role in the neuronal death evidenced afterwards. The later events of the neurodegenerative process are characterized by persistent astrogliosis and activation of apoptotic neuronal death through caspase 3 mediated mechanisms, which could be related with glutamate excitotoxicity. The progression of these responses are therefore likely to be critical for the outcome of the neurodegeneration provoked by (PhTe)(2) in rat cerebellum. 23604582 Contaminant driven genetic erosion and associated hypotheses on alleles loss, reduced population growth rate and increased susceptibility to future stressors: an essay. Microevolution due to pollution can occur mainly through genetic drift bottlenecks, especially of small sized populations facing intense lethal pulses of contaminants, through mutations, increasing allelic diversity, and through natural selection, with the disappearance of the most sensitive genotypes. This loss of genotypes can lead to serious effects if coupled to specific hypothetical scenarios. These may be categorized as leading, first, to the loss of alleles-the recessive tolerance inheritance hypothesis. Second, leading to a reduction of the population growth rate-the mutational load and fitness costs hypotheses. Third, leading to an increased susceptibility of further genetic erosion both at future inputs of the same contaminant-differential physiological recovery, endpoints (dis)association, and differential phenotypic plasticity hypotheses-and at sequential or simultaneous inputs of other contaminants-the multiple stressors differential tolerance hypothesis. Species in narrowly fluctuating environments (tropics and deep sea) may have a particularly high susceptibility to genetic erosion-the Plus ça change (plus c'est la meme chose) hypothesis. A discussion on the consequences of these hypotheses is what this essay aimed at. 23368753 Metastable Cu(I)-niobate semiconductor with a low-temperature, nanoparticle-mediated synthesis. A nanoparticle synthetic strategy for the preparation of a new metastable Cu(I)-niobate is described, and that involves multipored Li₃NbO₄ nanoparticles as a precursor. A hydrothermal reaction of HNbO₃ and LiOH·H₂O in PEG200 and water at ∼180 °C yields ∼15-40 nm Li₃NbO₄ particles. These particles are subsequently used in a solvothermal copper(I)-exchange reaction with excess CuCl at 150 °C. Heating these products within the used CuCl flux (mp = 430 °C) to 450 °C for 30 min yields ∼4-12 nm Cu₂Nb₈O₂₁ crystalline nanoparticles, and for a heating time of 24 h yields μm-sized, rod-shaped crystals. The new structure was characterized by single-crystal X-ray diffraction to have a condensed network consisting of NbO₇ polyhedra and chains of elongated CuO₄ tetrahedra. The compound thermally decomposes starting at ∼250 °C and higher temperatures, depending on the particle sizes, owing to the loss of the weakly coordinated Cu(I) cations from the structure and a concurrent disproportionation reaction at its surfaces. Thus, conventional solid-state reactions involving higher temperatures and bulk reagents have proven unsatisfactory for its synthesis. The measured bandgap size is ∼1.43-1.65 eV (indirect) and shows a dependence on the particle sizes. Electronic structure calculations based on density functional theory show that the bandgap transition results from the excitation of electrons at the band edges between filled Cu(I) 3d¹⁰-orbitals and empty Nb(V) 4d⁰-orbitals, respectively. The p-type nature of the Cu₂Nb₈O₂₁ particles was confirmed in photoelectrochemical measurements on polycrystalline films that show a strong photocathodic current under visible-light irradiation in aqueous solutions. These results demonstrate the general utility of reactive nanoscale precursors in the synthetic discovery of new Cu(I)-based semiconducting oxides and which also show promise for use in solar energy conversion applications. 23480783 Free fatty acid binding protein-4 and retinol binding protein-4 in polycystic ovary syndrome: response to simvastatin and metformin therapies. Abstract Free fatty acid binding protein-4 (FABP4) and retinol binding protein-4 (RBP4) contribute to metabolic syndrome. We investigated serum FABP4 and RBP4 responses to insulin sensitizing and lipid lowering therapies in polycystic ovary syndrome (PCOS). Sixty-two healthy, untreated women with PCOS (age 25.1 ± 3.6 years, BMI: 24.0 ± 4.7 kg/m(2)) were randomized to metformin (n = 24), simvastatin (n = 20) or metformin plus simvastatin (n = 18) for 3 months. Anthropometric measures, fasting blood tests and oral glucose tolerance tests (OGTT) were obtained at the baseline and the end. At the baseline serum FABP4 correlated with obesity (BMI: r = 0.63, p < 0.001), insulin resistance (fasting insulin: r = 0.44, p = 0.0002; QUICKI: r = -0.30, p = 0.02; OGTT-insulin sensitivity index: r = -0.27, p = 0.04), dyslipidemia (HDL: r = -0.26, p = 0.03) and hyperandrogenemia (free-testosterone: r = 0.23, p = 0.03; SHBG: r = -0.28, p = 0.03); while RBP4 correlated with total-cholesterol (r = 0.33, p = 0.009). Multiple regression analysis indicated that t best predictors of serum FABP4 and RBP4 were BMI (β = 1.02, p = 0.0003) and total cholesterol (β = 2326, p = 0.01), respectively. Simvastatin, alone or with metformin did not affect serum FABP4 or RBP4. Serum FABP4 related to the obesity, insulin resistance and inflammation while RBP4 related to lipids. Insulin sensitizing and lipid lowering therapies did not affect FABP4 or RBP4 levels in PCOS. 23338539 Subcutaneous bortezomib: in multiple myeloma. A subcutaneous formulation of bortezomib is now indicated in the EU and the US for the treatment of patients with multiple myeloma. This article reviews pharmacological, therapeutic efficacy and tolerability data relevant to the utilization of subcutaneous bortezomib (Velcade(®)) in the treatment of patients with multiple myeloma. In a randomized, nonblind, phase III study, subcutaneous bortezomib was noninferior to intravenous bortezomib in the treatment of adults with relapsed multiple myeloma, as determined by the overall response rate after four cycles of therapy (primary endpoint). No significant differences between the subcutaneous and intravenous bortezomib formulations were observed in the median time to first response, median progression-free survival, median time to progression and 1-year overall survival. Compared with intravenous bortezomib, subcutaneous bortezomib confers a significant advantage with respect to the incidence of peripheral neuropathy (all grades, grade ≥2 and grade ≥3). As a consequence, it provides a new treatment option for patients with multiple myeloma, particularly those with pre-existing neuropathy or at a high risk of developing peripheral neuropathy. 23348407 Dietary relevant mixtures of phytoestrogens inhibit adipocyte differentiation in vitro. Phytoestrogens (PEs) are naturally occurring plant components, with the ability to induce biological responses in vertebrates by mimicking or modulating the action of endogenous hormones. Single isoflavones have been shown to affect adipocyte differentiation, but knowledge on the effect of dietary relevant mixtures of PEs, including for instance lignans, is lacking. In the current study dietary relevant mixtures of isoflavones and their metabolites, lignans and their metabolites, coumestrol, and a mixture containing all of them, were examined for effects on adipogenesis in 3T3-L1 adipocytes, as well as tested for their PPARγ activating abilities. The results showed that mixtures of isoflavonoid parent compounds and metabolites, respectively, a mixture of lignan metabolites, as well as coumestrol concentration-dependently inhibited adipocyte differentiation. Furthermore, a mixture of isoflavonoid parent compounds, and a mixture of isoflavonoid metabolites were found to have PPARγ activating abilities. These results suggest that PEs can affect pathways known to play a role in obesity development, and indicate that the inhibitory effect on adipocyte differentiation does not appear to be strictly associated with PPARγ activation/inhibition. The current study support the hypothesis that compounds with endocrine activity can affect pathways playing a role in the development obesity and obesity related diseases. 23440512 Vitamin A and retinoid signaling: genomic and non-genomic effects. Vitamin A or retinol is arguably the most multifunctional vitamin in the human body as it is essential from embryogenesis to adulthood. The pleiotropic effects of vitamin A are exerted mainly by one active metabolite, all-trans retinoic acid (atRA), which regulates the expression of a battery of target genes through several families of nuclear receptors (RARs, RXRs and PPARβ/δ), polymorphic retinoic acid (RA) response elements and multiple coregulators. It also involves extra nuclear and non-transcriptional effects such as the activation of kinase cascades, which are integrated in the nucleus via the phosphorylation of several actors of RA signaling. However, vitamin A itself proved recently to be active and RARs to be present in the cytosol to regulate translation and cell plasticity. All these new concepts expand the scope of the biologic functions of vitamin A and RA. 23520173 Specific Transport of Target Molecules by Motor Proteins in Microfluidic Channels. Direct transport powered by motor proteins can alleviate the challenges presented by miniaturization of microfluidic systems. There have been several recent attempts to build motor-protein-driven transport systems based on simple capturing or transport mechanisms. However, to achieve a multifunctional device for practical applications, a more complex sorting/transport system should be realized. Herein, the proof of concept of a sorting device employing selective capture of distinct target molecules and transport of the sorted molecules to different predefined directions is presented. By combining the bottom-up functionality of biological systems with the top-down handling capabilities of micro-electromechanical systems technology, highly selective molecular recognition and motor-protein-based transport is integrated in a microfluidic channel network. 23373677 Investigation of astatine(III) hydrolyzed species: experiments and relativistic calculations. This work aims to resolve some controversies about astatine(III) hydroxide species present in oxidant aqueous solution. AtO(+) is the dominant species existing under oxidizing and acidic pH conditions. This is consistent with high-performance ion-exchange chromatography data showing the existence of one species holding one positive charge. A change in speciation occurs as the pH changes from 1 to 4, while remaining under oxidizing conditions. Dynamic experiments with ion-exchange resins evidence the existence of a neutral species witnessed by its elution in the void volume. Batch-experiments using a competition method show the exchange of one proton indicating the formation of the AtO(OH) species. The hydrolysis thermodynamic constant, extrapolated to zero ionic strength, was determined to be 10(-1.9). This value is supported by two-component relativistic quantum calculations and therefore allows disclosing unambiguously the structure of the formed species. 23462671 Carrier free rapamycin loaded drug eluting stent: In vitro and in vivo evaluation. In the search for improving the performance of drug eluting stent (DES) various developments are in progress worldwide including use of carrier free DES, use of biodegradable polymers, biodegradable stents etc. In this work, carrier free-rapamycin (RM) coated DES has been prepared, and evaluated by in vitro and in vivo procedures necessary for clinical development. In vitro drug release from the developed stents was carried in different release media, normal saline-isopropanol (NS-IP), phosphate buffer (PB), phosphate buffer saline (PBS) and in human plasma. Simultaneously, drug released at site of implantation and biocompatibility of developed stents was determined after subcutaneous implantation in the SD rats. Developed stent coating method enables fabrication of controllable and homogeneous crystalline RM coatings on stent scaffolds. Continuous release of RM was observed in different release conditions with different release rate, maximum in NS-IP and least in PB. Similarly, after subcutaneous implantation of these stents, RM was found in surrounding tissues and in implanted stent up to 28days. Biocompatibility studies showed no evidence for presence of necrosis, foreign body giant cell reaction or any type of increased severity of inflammatory reaction, proving potential of developed stents for further clinical development. 23583804 Acute and subacute toxicity studies on triptolide and triptolide-loaded polymeric micelles following intravenous administration in rodents. Except its anti-tumour effects, triptolide (TP) also shows multiple pharmacological side activities, such as immune-suppressive and male anti-fertility. To increase the therapeutic index of TP, a novel polymeric micelle system containing TP (TP-PM) has been developed to treat tumour. Our previous studies have demonstrated the good anti-tumour efficacy of TP-PM. This paper investigated the acute toxicity in mice and subacute toxicity in rats of TP-PM and TP. Results demonstrated that the LD50 for TP-PM and TP administered intravenously were 1.06mg/kg and 0.83mg/kg in mice, respectively. In subacute toxicity study, TP-PM and TP were administered intravenously at the dose levels of 0.1mg/kg and 0.3mg/kg for 14d. Compared to the control, there was significant decrease in the serum AST activities, the testis ACP activities, thymus index, testis index, and significant increase in spleen index, and obvious histopathological changes in rats treated with TP, however, the toxicities of TP-PM on liver, kidney, testis and spleen are slighter than TP. Compared to TP, TP-PM significantly increased the ACP activity of the testis and decreased the MDA level in serum. So, the polymeric micelles may be a novel drug delivery carrier of TP for reducing the toxicities of TP. 23363040 Association of Inhalation Toxicologists' (AIT) review of regulatory aspects for inhalation toxicology studies. Regulatory guidelines are intended to provide recommendations on ways to achieve greater harmonization in the interpretation and application of technical procedures and requirements for product registration in order to reduce or obviate replication of the testing carried out during the research and development of new products. The objectives of such harmonization are more economical use of human, animal and material resources; the elimination of unnecessary delay in the global development and availability of new products while maintaining safeguards on quality, safety and efficacy; and the fulfillment of regulatory obligations to protect public health. 23458894 Crotonaldehyde-exposed macrophages induce IL-8 release from airway epithelial cells through NF-κB and AP-1 pathways. Crotonaldehyde, a highly toxic α, β-unsaturated aldehyde, is a major component of cigarette smoke and a ubiquitous environmental pollutant. Crotonaldehyde exposure is known to have adverse effects on respiratory health, but the underlying mechanisms remain obscure. To examine the interaction between macrophages and airway epithelial cells after exposure to crotonaldehyde, BEAS-2B and A549 cells were treated with conditioned media from a human monocytic leukemia cell line (THP-1) cells stimulated with crotonaldehyde. We demonstrate that conditioned media from THP-1 cells stimulated with crotonaldehyde increased interleukin (IL)-8 production, enhanced nuclear factor (NF)-κB and AP-1 DNA-binding activity in BEAS-2B and A549 cells. Analysis of these conditioned media revealed marked increases in tumor necrosis factor (TNF)-α, IL-1β and IL-8 levels. Preincubation of conditioned media with either TNF-α- or IL-1β-neutralizing antibodies reduced IL-8 production. Furthermore, BEAS-2B and A549 cells directly treated with crotonaldehyde induced increase in IL-8 production. These data suggest that crotonaldehyde is capable of directly stimulating the production of IL-8 in both macrophages and airway epithelial cells. Crotonaldehyde-stimulated macrophages also amplify the inflammatory response by enhancing IL-8 release from airway epithelial cells mediated by NF-κB and AP-1 pathways through a mechanism involving TNF-α and IL-1β. These findings indicate that crotonaldehyde can cause lung inflammatory response via multiple mechanisms, and may contribute to chronic airway inflammation in smokers. 23294700 Inhibitors of the Yersinia protein tyrosine phosphatase through high throughput and virtual screening approaches. The bacterial protein tyrosine phosphatase YopH is an essential virulence determinant in Yersinia pestis and a potential antibacterial drug target. Here we report our studies of screening for small molecule inhibitors of YopH using both high throughput and in silico approaches. The identified inhibitors represent a diversity of chemotypes and novel pTyr mimetics, providing a starting point for further development and fragment-based design of multi-site binding inhibitors. We demonstrate that the applications of high throughput and virtual screening, when guided by structural binding mode analysis, is an effective approach for identifying potent and selective inhibitors of YopH and other protein phosphatases for rational drug design. 23321159 Regulation of μ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Morphine and related µ-opioid receptor (MOR) agonists remain among the most effective drugs known for acute relief of severe pain. A major problem in treating painful conditions is that tolerance limits the long-term utility of opioid agonists. Considerable effort has been expended on developing an understanding of the molecular and cellular processes that underlie acute MOR signaling, short-term receptor regulation, and the progression of events that lead to tolerance for different MOR agonists. Although great progress has been made in the past decade, many points of contention and controversy cloud the realization of this progress. This review attempts to clarify some confusion by clearly defining terms, such as desensitization and tolerance, and addressing optimal pharmacological analyses for discerning relative importance of these cellular mechanisms. Cellular and molecular mechanisms regulating MOR function by phosphorylation relative to receptor desensitization and endocytosis are comprehensively reviewed, with an emphasis on agonist-biased regulation and areas where knowledge is lacking or controversial. The implications of these mechanisms for understanding the substantial contribution of MOR signaling to opioid tolerance are then considered in detail. While some functional MOR regulatory mechanisms contributing to tolerance are clearly understood, there are large gaps in understanding the molecular processes responsible for loss of MOR function after chronic exposure to opioids. Further elucidation of the cellular mechanisms that are regulated by opioids will be necessary for the successful development of MOR-based approaches to new pain therapeutics that limit the development of tolerance. 23474650 Biotransformation of Two β-Secretase Inhibitors Including Ring Opening and Contraction of a Pyrimidine Ring. Recently, the discovery of the aminoisoindoles as potent and selective inhibitors of β-secretase was reported, including the close structural analogs compound (S)-1-pyridin-4-yl-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine [(S)-25] and (S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate (AZD3839), the latter being recently progressed to the clinic. The biotransformation of (S)-25 was investigated in vitro and in vivo in rat, rabbit, and human and compared with AZD3839 to further understand the metabolic fate of these compounds. In vitro, CYP3A4 was the major responsible enzyme and metabolized both compounds to a large extent in the commonly shared pyridine and pyrimidine rings. The main proposed metabolic pathways in various in vitro systems were N-oxidation of the pyridine and/or pyrimidine ring and conversion to 4-pyrimidone and pyrimidine-2,4-dione. Both compounds were extensively metabolized, and more than 90% was excreted in feces after intravenous administration of radiolabeled compound to the rat. Here, the main pathways were N-oxidation of the pyridine and/or pyrimidine ring and a ring contraction of the pyrimidine ring into an imidazole ring. Ring-contracted metabolites accounted for 25% of the total metabolism in the rat for (S)-25, whereas the contribution was much smaller for AZD3839. This metabolic pathway was not foreseen on the basis of the obtained in vitro data. In conclusion, we discovered an unusual metabolic pathway of aryl-pyrimidine-containing compounds by a ring-opening reaction followed by elimination of a carbon atom and a ring closure to form an imidazole ring. 23474905 Synthesis using microwave irradiation and antibacterial evaluation of new N,O-acetals and N,S-acetals derived from 2-amino-1,4-naphthoquinones. This paper describes a novel series of N,O-acetals and N,S-acetals (7a-o) derived from 2-amino-1,4-naphthoquinones that were synthesized and evaluated as potential antimicrobial agents. These compounds were obtained in good yields using microwave irradiation, and several of them showed promising antibacterial profiles. Three of our biologically active 2-amino-1,4-naphthoquinone N,O-acetals and N,S-acetals tested against hospital bacterial strains were identified as potential lead compounds. Characterization of all compounds was performed using one-dimensional NMR techniques ((1)H, (13)C-APT), IR spectra, elemental analyses and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). 23273260 Interaction of cisplatin with adenine and guanine: a combined IRMPD, MS/MS, and theoretical study. Infrared multiple photon dissociation (IRMPD) spectroscopy of cis-[Pt(NH(3))(2)(G)Cl](+) and cis-[Pt(NH(3))(2)(A)Cl](+) ions (where A is adenine and G is guanine) has been performed in two spectral regions, 950-1900 and 2900-3700 cm(-1). Quantum chemical calculations at the B3LYP/LACV3P/6-311G** level yield the optimized geometries and IR spectra for the conceivable isomers of cis-[Pt(NH(3))(2)(G)Cl](+) and cis-[Pt(NH(3))(2)(A)Cl](+), whereby the cisplatin residue is attached to the N7, N3, or carbonyl oxygen atom, (O6), of guanine and to the N7, N3, or N1 position of adenine, respectively. In addition to the conventional binding sites of native adenine, complexes with N7-H tautomers have also been considered. In agreement with computational results, the IR characterization of cis-[Pt(NH(3))(2)(G)Cl](+) points to a covalent structure where Pt is bound to the N7 atom of guanine. The characterized conformer has a hydrogen-bonding interaction between a hydrogen atom of one NH(3) ligand and the carbonyl group of guanine. The experimental C═O stretching feature of cis-[Pt(NH(3))(2)(G)Cl](+) at 1718 cm(-1), remarkably red-shifted with respect to an unperturbed C═O stretching mode, is indicative of a lengthened CO bond in guanine, a signature that this group is involved in hydrogen bonding. The IRMPD spectra of cis-[Pt(NH(3))(2)(A)Cl](+) are consistent with the presence of two major isomers, PtAN3 and PtAN1, where Pt is bound to the N3 and N1 positions of native adenine, respectively. 23616438 Side effects associated with psychotropic medications in patients with bipolar disorder: evidence from two independent samples. Available evidence concerning the side effects experienced by bipolar disorder (BD) patients under naturalistic conditions has been poorly investigated. The aim of this study was therefore to investigate side effects related to major psychotropic drugs in two independent samples of BD patients naturalistically treated with mood stabilizers, antidepressants, antipsychotics and/or anxiolytics. Overall, 3654 patients from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) sample and 282 patients from the Clinical Outcome and Psycho-Education for Bipolar Disorder (COPE-BD) sample were included. The primary outcome measure was the influence of each class of psychotropic drugs under investigation on the emergence of any side effect, as measured with the monitoring form in the STEP-BD study and the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale in the COPE-BD study. Secondary outcome measures included the effects of such drugs on psychic, neurologic, autonomic and other side effects. Mood stabilizers and antipsychotics were associated with high rates of side effects in both samples. Furthermore, antipsychotics were specifically associated with psychic side effects, whereas mood stabilizers were specifically associated with neurologic side effects. Our results largely confirm in a naturalistic setting results previously observed in randomized controlled trials focusing on BD patients. 23323712 Controlled assembly and release of retinoic acid based on the layer-by-layer method. All-trans retinoic acid (RA) has been proved to play important roles in regulating cell growth in various types of cells. Yet most experiments were performed by adding RA in solution previously. In this Article, we focus on the incorporation of RA, as a negatively charged moiety, into layered polyelectrolyte films on surfaces by means of layer-by-layer (LbL) deposition, followed by adding of capping layers to regulate the release of RA from the films. The incorporated RA was designed to release over 5 days in buffer solution. The assembly and release of RA were verified by UV and QCM results. The controlled release of RA from multilayer films can serve as a model system to study the influence of small molecules on cell growth. 23542494 Oily nanosuspension for long-acting intramuscular delivery of curcumin didecanoate prodrug: Preparation, characterization and in vivo evaluation. The objective of this study was to prepare the nanocrystals of curcumin didecanoate (CurDD) by wet ball milling and to investigate the comparative pharmacokinetics of oily nano- and micro-suspensions after intramuscular (i.m.) administration to rats. Upon optimizing the wet ball milling parameters, CurDD nanocrystals were produced with median particle size of ∼500nm and the freeze-dried nanocrystals were readily dispersed in peanut oil to form stable nanosuspensions. Although the nanosuspension appeared to exhibit slower clearance from the injection site after i.m. injection, compared to microsuspension (∼5μm), a significantly higher maximum plasma curcumin concentration (69.0ng/ml) was observed for the former than that for the latter (18.5ng/ml). In addition, the nanosuspension provided significant higher plasma curcumin concentrations and brain CurDD contents for at least 15days than the microsuspension, except for the initial times. A single i.m. injection of nanosuspension appeared to achieve reversal effect on reserpine-induced hypothermia for at least 13days. This study demonstrates that CurDD nanosuspension may act as a long-acting i.m. injectable for sustained delivery of curcumin, potentially applicable to elicit a long-lasting antidepressant effect. 23411081 Synthesis and physicochemical properties of new tripodal amphiphiles bearing fatty acids as a hydrophobic group. Saturated fatty acids (FA) were grafted using tyrosine as a spacer group to the cyclotriphosphazene ring along with equimolar hydrophilic methoxy poly(ethylene glycol) (MPEG) in cis-nongeminal way. Seven new cyclotriphosphazene amphiphiles were prepared from combinations of hydrophilic MPEGs with different molecular weights of 350, 550, 750 and 1000 and four different fatty acids of different hydrophobicity including lauric, myristic, palmitic and stearic acids. These steric amphiphiles bearing fatty acids as a hydrophobic group were found to form more stable micelles with very low critical micelle concentrations (CMC) (2.95-7.80mg/L) compared with oligopeptide analogues, and their highly hydrophobic core environment is unique and potentially useful for various biomedical applications. 23268987 The selective metabotropic glutamate 2/3 receptor agonist MGS0028 reverses psychomotor abnormalities and recognition memory deficits in mice lacking the pituitary adenylate cyclase-activating polypeptide. Previous studies suggest that metabotropic glutamate 2/3 receptors are involved in psychiatric disorders. In this study, we examined the effects of the selective metabotropic glutamate 2/3 (mGlu2/3) receptor agonist MGS0028 on behavioral abnormalities in mice lacking the pituitary adenylate cyclase-activating polypeptide (PACAP), an experimental model of psychiatric disorders such as schizophrenia and attention-deficit/hyperactivity disorder. We found that PACAP-deficient mice showed impairments in the novel object recognition test and these impairments were improved by MGS0028 (0.1 mg/kg). Similarly, MGS0028 improved hyperactivity and jumping behaviors, but did not reverse increased immobility times in the forced swim test in PACAP-deficient mice. These results suggest that MGS0028 may be a potential, novel treatment for psychiatric disorders. 23265895 Discovery and optimization of potent broad-spectrum arenavirus inhibitors derived from benzimidazole. A chemically diverse library of about 400,000 small molecules was screened for antiviral activity against lentiviral pseudotypes with the Lassa virus envelope glycoprotein (LASV GP) gene incorporated. High-throughput screening resulted in discovery of a hit compound (ST-37) possessing a benzimidazole core which led to a potent compound series. Herein, we report SAR studies which involved structural modifications to the phenyl rings and methylamino linker portion attached to the benzimidazole core. Many analogs in this study possessed single digit nanomolar potency against LASV pseudotypes. Compounds in this benzimidazole series also exhibited nanomolar antiviral activity against pseudotypes generated from other arenavirus envelopes indicating the potential for development of a broad-spectrum inhibitor. Ultimately, lead compound ST-193 was identified and later found to be efficacious in a lethal LASV guinea pig model showing superior protection compared to ribavirin treatment. 23393220 Pharmacokinetic Interactions between Monoamine Oxidase A Inhibitor Harmaline and 5-Methoxy-N,N-Dimethyltryptamine, and the Impact of CYP2D6 Status. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT or street name "5-MEO") is a newer designer drug belonging to a group of naturally occurring indolealkylamines. Our recent study has demonstrated that coadministration of monoamine oxidase A (MAO-A) inhibitor harmaline (5 mg/kg) increases systemic exposure to 5-MeO-DMT (2 mg/kg) and active metabolite bufotenine. This study is aimed at delineating harmaline and 5-MeO-DMT pharmacokinetic (PK) interactions at multiple dose levels, as well as the impact of CYP2D6 that affects harmaline PK and determines 5-MeO-DMT O-demethylation to produce bufotenine. Our data revealed that inhibition of MAO-A-mediated metabolic elimination by harmaline (2, 5, and 15 mg/kg) led to a sharp increase in systemic and cerebral exposure to 5-MeO-DMT (2 and 10 mg/kg) at all dose combinations. A more pronounced effect on 5-MeO-DMT PK was associated with greater exposure to harmaline in wild-type mice than CYP2D6-humanized (Tg-CYP2D6) mice. Harmaline (5 mg/kg) also increased blood and brain bufotenine concentrations that were generally higher in Tg-CYP2D6 mice. Surprisingly, greater harmaline dose (15 mg/kg) reduced bufotenine levels. The in vivo inhibitory effect of harmaline on CYP2D6-catalyzed bufotenine formation was confirmed by in vitro study using purified CYP2D6. Given these findings, a unified PK model including the inhibition of MAO-A- and CYP2D6-catalyzed 5-MeO-DMT metabolism by harmaline was developed to describe blood harmaline, 5-MeO-DMT, and bufotenine PK profiles in both wild-type and Tg-CYP2D6 mouse models. This PK model may be further employed to predict harmaline and 5-MeO-DMT PK interactions at various doses, define the impact of CYP2D6 status, and drive harmaline-5-MeO-DMT pharmacodynamics. 23629861 Basic evidence for epidermal H2O2/ONOO--mediated oxidation/nitration in segmental vitiligo is supported by repigmentation of skin and eyelashes after reduction of epidermal H2O2 with topical NB-UVB-activated pseudocatalase PC-KUS. Nonsegmental vitiligo (NSV) is characterized by loss of inherited skin color. The cause of the disease is still unknown despite accumulating in vivo and in vitro evidence of massive epidermal oxidative stress via H2O2 and peroxynitrite (ONOO(-)) in affected individuals. The most favored hypothesis is based on autoimmune mechanisms. Strictly segmental vitiligo (SSV) with dermatomal distribution is a rare entity, often associated with stable outcome. Recently, it was documented that this form can be associated with NSV (mixed vitiligo). We here asked the question whether ROS and possibly ONOO(-) could be players in the pathogenesis of SSV. Our in situ results demonstrate for the first time epidermal biopterin accumulation together with significantly decreased epidermal catalase, thioredoxin/thioreoxin reductase, and MSRA/MSRB expression. Moreover, we show epidermal ONOO(-) accumulation. In vivo FT-Raman spectroscopy reveals the presence of H2O2, methionine sulfoxide, and tryptophan metabolites; i.e., N-formylkynurenine and kynurenine, implying Fenton chemistry in the cascade (n=10). Validation of the basic data stems from successful repigmentation of skin and eyelashes in affected individuals, regardless of SSV or segmental vitiligo in association with NSV after reduction of epidermal H2O2 (n=5). Taken together, our contribution strongly supports H2O2/ONOO-mediated stress in the pathogenesis of SSV. Our findings offer new treatment intervention for lost skin and hair color.-Schallreuter, K. U., Salem, M. A. E. L., Holtz, S., Panske, A. Basic evidence for epidermal H2O2/ONOO(-)-mediated oxidation/nitration in segmental vitiligo is supported by repigmentation of skin and eyelashes after reduction of epidermal H2O2 with topical NB-UVB-activated pseudocatalase PC-KUS. 22548320 A new xanthone from the bark of Calophyllum thorelii. A new xanthone, calothorexanthone, together with five known compounds, garbogiol, 1,4,8-trihydroxyxanthone, δ-tocotrienol, 1,7-dihydroxyxanthone and globuxanthone, was isolated from a petroleum ether extract of the bark of Calophyllum thorelii. Their structures were established on the basis of spectroscopic methods, mainly one- and two-dimensional NMR. Antioxidant activity of the isolated compounds was tested using DPPH free radical scavenging assay and some exhibited remarkable effects with IC50 of 13.63-17.46 µg mL(-1). 23547872 Interfacial Nanoarchitectonics: Lateral and Vertical, Static and Dynamic. The exploration of nanostructures and nanomaterials is essential to the development of advanced functions. For such innovations, nanoarchitectonics has been proposed as a novel paradigm of nanotechnology aimed at assembling nanoscale structural units into predesigned configurations or arrangements. In this Feature Article, we provide an overview of several recent research works from the viewpoint of interfacial nanoarchitectonics with features developed in lateral directions or grown in vertical directions with construction on solid, static, or flexible dynamic surfaces. Lateral nanoarchitectonics at a static interface provides molecular organization by bottom-up nanoarchitectonics and can also be used to realize device integration by top-down nanoarchitectonics. In particular, in the latter case, the fabrication of novel devices, so-called atomic switches, are introduced as a demonstration of atomic-level electronics. Lateral nanoarchitectonics at dynamic interfaces is exemplified by 2D molecular patterning and molecular machine operation induced by macroscopic motion. The dynamic nature of interfaces enables us to operate molecular-sized machines by macroscopic mechanical stimuli such as our hand motion, which we refer to as hand-operated nanotechnology. Vertical nanoarchitectonics is mainly discussed in relation to layer-by-layer (LbL) assembly. By using this technique, we can assemble a variety of functional materials in ultrathin film structures of defined thickness and layer sequence. The organization of biomolecules (or even living cells) within thin films and their integration with device structures is exemplified. Finally, the anticipated research directions of interfacial nanoarchitectonics are described. 23190035 Recent studies of antioxidant quinoline derivatives. Quinoline derivatives constitute an important class of compounds for new drug development. As a large number of experimental and theoretical studies have shown that the quinoline ring system is an important structural unit widely existing in alkaloids, therapeutics and synthetic analogues with exciting biological activities. The present review provides recent antioxidant activities covering in vivo and in vitro studies of natural and synthetic analogues, as well as the proposed mechanisms of action and structure-activity relationships. 23535361 Evaluation of Perturbations in Serum Thyroid Hormones During Human Pregnancy Due to Dietary Iodide and Perchlorate Exposure Using a Biologically Based Dose-Response Model. A biologically based dose-response model (BBDR) for the hypothalamic pituitary thyroid (HPT) axis was developed in the near-term pregnant mother and fetus. This model was calibrated to predict serum levels of iodide, total thyroxine (T4), free thyroxine (fT4), and total triiodothyronine (T3) in the mother and fetus for a range of dietary iodide intake. The model was extended to describe perchlorate, an environmental and food contaminant, that competes with the sodium iodide symporter protein for thyroidal uptake of iodide. Using this mode-of-action framework, simulations were performed to determine the daily ingestion rates of perchlorate that would be associated with hypothyroxinemia or onset of hypothyroidism for varying iodide intake. Model simulations suggested that a maternal iodide intake of 75 to 250 µg/day and an environmentally relevant exposure of perchlorate (~0.1 µg/kg/day) did not result in hypothyroxinemia or hypothyroidism. For a daily iodide-sufficient intake of 200 µg/day, the dose of perchlorate required to reduce maternal fT4 levels to a hypothyroxinemic state was estimated at 32.2 µg/kg/day. As iodide intake was lowered to 75 µg/day, the model simulated daily perchlorate dose required to cause hypothyroxinemia was reduced by eightfold. Similarly, the perchlorate intake rates associated with the onset of subclinical hypothyroidism ranged from 54.8 to 21.5 µg/kg/day for daily iodide intake of 250-75 µg/day. This BBDR-HPT axis model for pregnancy provides an example of a novel public health assessment tool that may be expanded to address other endocrine-active chemicals found in food and the environment. 23453073 Small molecule modulators of Wnt/β-catenin signaling. The Wnt signal transduction pathway is dysregulated in many highly prevalent diseases, including cancer. Unfortunately, drug discovery efforts have been hampered by the paucity of targets and drug-like lead molecules amenable to drug discovery. Recently, we reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling by a unique mechanism, though the target responsible remains unknown. We interrogated the mechanism and structure-activity relationships to understand drivers of potency and to assist target identification efforts. We found inhibition of Wnt signaling by Niclosamide appears unique among the structurally-related anthelmintic agents tested and found the potency and functional response was dependent on small changes in the chemical structure of Niclosamide. Overall, these findings support efforts to identify the target of Niclosamide inhibition of Wnt/β-catenin signaling and the discovery of potent and selective modulators to treat human disease. 23535337 Disruption of AtWNK8 Enhances Tolerance of Arabidopsis to Salt and Osmotic Stresses via Modulating Proline Content and Activities of Catalase and Peroxidase. With no lysine kinases (WNKs) play important roles in plant growth and development. However, its role in salt and osmotic stress tolerance is unclear. Here, we report that AtWNK8 is mainly expressed in primary root, hypocotyl, stamen and pistil and is induced by NaCl and sorbitol treatment. Compared to the wild-type, the T-DNA knock-out wnk8 mutant was more tolerant to severe salinity and osmotic stresses, as indicated by 27% and 198% more fresh weight in the NaCl and sorbitol treatment, respectively. The wnk8 mutant also accumulated 1.43-fold more proline than the wild-type in the sorbitol treatment. Under NaCl and sorbitol stresses, catalase (CAT) activity in wnk8 mutant was 1.92- and 3.7-times of that in Col-0, respectively. Similarly, under salt and osmotic stress conditions, peroxidase (POD) activities in wnk8 mutant were 1.81- and 1.58-times of that in Col-0, respectively. Taken together, we revealed that maintaining higher CAT and POD activities might be one of the reasons that the disruption of AtWNK8 enhances the tolerance to salt stress, and accumulating more proline and higher activities of CAT and POD might result in the higher tolerance of WNK8 to osmotic stress. 23473682 BCR-ABL tyrosine kinase inhibitor pharmacophore model derived from a series of phenylaminopyrimidine-based (PAP) derivatives. To reveal novel insights into the inhibition of BCR-ABL tyrosine kinase, pharmacophore mapping studies were performed for a series of phenylaminopyrimidine-based (PAP) derivatives, including imatinib (Gleevec). A seven-point pharmacophore model with one hydrophobic group (H), two hydrogen bond donors (D) and four aromatic rings (R) was developed using phase (pharmacophore alignment & scoring engine). The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of 0.886 and a survival score of 4.97 for training set molecules. The model showed excellent predictive power, with a correlation coefficient of Q(2)=0.768 for an external test set of ten molecules. The results obtained from our studies provide a valuable tool for designing new lead molecules with potent activity. 23623823 Recent advances in quantitative neuroproteomics. The field of proteomics is undergoing rapid development in a number of different areas including improvements in mass spectrometric platforms, peptide identification algorithms and bioinformatics. In particular, new and/or improved approaches have established robust methods that not only allow for in-depth and accurate peptide and protein identification and modification, but also allow for sensitive measurement of relative or absolute quantitation. These methods are beginning to be applied to the area of neuroproteomics, but the central nervous system poses many specific challenges in terms of quantitative proteomics, given the large number of different neuronal cell types that are intermixed and that exhibit distinct patterns of gene and protein expression. This review highlights the recent advances that have been made in quantitative neuroproteomics, with a focus on work published over the last five years that applies emerging methods to normal brain function as well as to various neuropsychiatric disorders including schizophrenia and drug addiction as well as of neurodegenerative diseases including Parkinson's disease and Alzheimer's disease. While older methods such as two-dimensional polyacrylamide electrophoresis continued to be used, a variety of more in-depth MS-based approaches including both label (ICAT, iTRAQ, TMT, SILAC, SILAM), label-free (label-free, MRM, SWATH) and absolute quantification methods, are rapidly being applied to neurobiological investigations of normal and diseased brain tissue as well as of cerebrospinal fluid (CSF). While the biological implications of many of these studies remain to be clearly established, that there is a clear need for standardization of experimental design and data analysis, and that the analysis of protein changes in specific neuronal cell types in the central nervous system remains a serious challenge, it appears that the quality and depth of the more recent quantitative proteomics studies is beginning to shed light on a number of aspects of neuroscience that relates to normal brain function as well as of the changes in protein expression and regulation that occurs in neuropsychiatric and neurodegenerative disorders. 23582211 Condensation of DNA-A putative obstruction for repair process in abasic clustered DNA damage. Clustered DNA damages are defined as two or more closely located DNA damage lesions that may be present within a few helical turns of the DNA double strand. These damages are potential signatures of ionizing radiation and are often found to be repair resistant. Types of damaged lesions frequently found inside clustered DNA damage sites include oxidized bases, abasic sites, nucleotide dimers, strand breaks or their complex combinations. In this study, we used a bistranded two-lesion abasic cluster DNA damage model to access the repair process of DNA in condensate form. Oligomer DNA duplexes (47bp) were designed to have two deoxyuridine in the middle of the sequences, three bases apart in opposite strands. The deoxyuridine residues were converted into abasic sites by treatment with UDG enzyme creating an abasic clustered damage site in a precise position in each of the single strand of the DNA duplex. This oligomer duplex having compatible cohesive ends was ligated to pUC19 plasmid, linearized with HindIII restriction endonuclease. The plasmid-oligomer conjugate was transformed into condensates by treating them with spermidine. The efficiency of strand cleavage action of ApeI enzyme on the abasic sites was determined by denaturing PAGE after timed incubation of the oligomer duplex and the oligomer-plasmid conjugate in presence and absence of spermidine. The efficiency of double strand breaks was determined similarly by native PAGE. Quantitative gel analysis revealed that rate of abasic site cleavage is reduced in the DNA condensates as compared to the oligomer DNA duplex or the linear ligated oligomer-plasmid conjugates. Generation of double strand break is significantly reduced also, suggesting that their creation is not proportionate to the number of abasic sites cleaved in the condensate model. All these suggest that the ApeI enzyme have difficulty to access the abasic sites located deep into the condensates leading to repair refractivity of the damages. In addition, we found that presence of a polyamine such as spermidine has no notable effect in the incision activity of ApeI enzyme in linear oligomer DNA duplexes in our experimental concentration. 23541631 Targeting miRNAs to treat Hepatitis C Virus infections and liver pathology: Inhibiting the virus and altering the host. Hepatitis C Virus (HCV) infection-induced liver disease is a growing problem worldwide, and is the primary cause of liver failure requiring liver transplantation in North America. Improved therapeutic strategies are required to control and possibly eradicate HCV infections, and to modulate HCV-induced liver disease. Cellular microRNAs anneal to and regulate mRNA translation and stability and form a regulatory network that modulates virtually every cellular process. Thus, miRNAs are promising cellular targets for therapeutic intervention for an array of diseases including cancer, metabolic diseases, and virus infections. In this review we outline the features of miRNA regulation and how miRNAs may be targeted in strategies to modulate HCV replication and pathogenesis. In particular, we highlight miR-122, a miRNA that directly modulates the HCV life cycle using an unusual mechanism. This miRNA is very important since miR-122 antagonists dramatically reduced HCV titres in HCV-infected chimpanzees and humans and currently represents the most likely candidate to be the first miRNA-based therapy licensed for use. However, we also discuss other miRNAs that directly or indirectly alter HCV replication efficiency, liver cirrhosis, fibrosis and the development of hepatocellular carcinoma (HCC). We also discuss a few miRNAs that might be targets to treat HCV in cases of HCV/HIV co-infection. Finally, we review methods to deliver miRNA antagonists and mimics to the liver. In the future, it may be possible to design and deliver specific combinations of miRNA antagonists and mimics to cure HCV infection or to limit liver pathogenesis. 23378600 Implications of lipid moiety in oligomerization and immunoreactivities of GPI-anchored proteins. Glycosylphosphatidylinositol (GPI) enriches GPI-anchored proteins (GPI-AP) in lipid rafts by intimate interaction of its lipid moiety with sphingolipids and cholesterol. In addition to such lipid-lipid interactions, it has been reported that GPI may interact with protein moiety linked to GPI and affect protein conformations because GPI delipidation reduced immunoreactivities of protein. Here, we report that GPI-APs that have not undergone fatty acid remodeling exhibit reduced immunoreactivities in Western blotting, similar to delipidated proteins, compared with normal remodeled GPI-APs. In contrast, immunostaining in flow cytometry and immunoprecipitation did not show significant differences between remodeled and unremodeled GPI-APs. Moreover, detection with premixed primary/secondary antibody complexes or Fab fragments eliminated this difference in Western blotting. These results indicate that normally remodeled GPI enhanced oligomerization of GPI-APs and that inefficient oligomerization of unremodeled GPI-APs was responsible for reduced immunoreactivities. Moreover, the reduction in immunoreactivities of delipidated GPI-APs was most likely caused by the same effect. Finally, by chemical cross-linking of surface proteins in living cells and cell killing assay using a pore-forming bacterial toxin, we showed that enhanced oligomerization by GPI-remodeling occurs under a physiological membrane environment. Thus, this study clarifies the significance of GPI fatty acid remodeling in oligomerization of GPI-APs and provides useful information for technical studies of these cell components. 23341191 The role of silver and vanadium release in the toxicity of silver vanadate nanowires toward Daphnia similis. Nanomaterials are used in a wide spectrum of applications, including nanowires that are objects with at least one of its dimensions in the range of 1 to 100 nm. Recently, a new type of silver vanadate nanowire decorated with silver nanoparticles (SVSN-LQES1) with promising antimicrobial activity against different pathogenic bacteria was described. The objective of the present study was to evaluate the role of silver and vanadium release in the acute toxicity of this material using Daphnia similis. To verify the effect of the presence of the nanowires in the test solution, tests were performed before and after filtration. Total silver release to the testing media was determined using the method of inductively coupled plasma atomic emission spectroscopy (ICP-AES). Silver vanadate nanowires decorated with silver nanoparticles (SVSN-LQES1) are acutely toxic to D. similis. The release of silver from the nanomaterial trapped in the gut along with the silver released to the test media seems to be responsible for the observed toxicity. Although toxic to Daphnia, vanadium does not contribute to the toxicity of SVSN-LQES1. The observed increase in lipid droplets appears to be related to the exposure of the organisms to the nanomaterials, but the significance of this response needs further investigation. 23340494 Membrane tethered bursicon constructs as heterodimeric modulators of the Drosophila G protein-coupled receptor rickets. The study of complex heterodimeric peptide ligands has been hampered by a paucity of pharmacological tools. To facilitate such investigations, we have explored the utility of membrane tethered ligands (MTLs). Feasibility of this recombinant approach was explored with a focus on Drosophila bursicon, a heterodimeric cystine-knot protein that activates the G protein-coupled receptor rickets (rk). Rk/bursicon signaling is an evolutionarily conserved pathway in insects required for wing expansion, cuticle hardening, and melanization during development. We initially engineered two distinct MTL constructs, each composed of a type II transmembrane domain, a peptide linker, and a C terminal extracellular ligand that corresponded to either the α or β bursicon subunit. Coexpression of the two complementary bursicon MTLs triggered rk-mediated signaling in vitro. We were then able to generate functionally active bursicon MTLs in which the two subunits were fused into a single heterodimeric peptide, oriented as either α-β or β-α. Carboxy-terminal deletion of 32 amino acids in the β-α MTL construct resulted in loss of agonist activity. Coexpression of this construct with rk inhibited receptor-mediated signaling by soluble bursicon. We have thus generated membrane-anchored bursicon constructs that can activate or inhibit rk signaling. These probes can be used in future studies to explore the tissue and/or developmental stage-dependent effects of bursicon in the genetically tractable Drosophila model organism. In addition, our success in generating functionally diverse bursicon MTLs offers promise that such technology can be broadly applied to other complex ligands, including the family of mammalian cystine-knot proteins. 23536314 Neuroprotective Effects of Cilostazol on Retinal Ganglion Cell damage in Diabetic Rats. Neurodegeneration is an important component of diabetic retinopathy with increasing evidence that retinal ganglion cell (RGC) death occurs early in diabetes. We investigated the effects of cilostazol, which has been widely used to manage diabetic complications, on retinal ganglion cell death in diabetic retina. Four-week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) rats as matched nondiabetic controls were treated with daily oral cilostazol at 30mg/kg or 0.9 % saline solution. In OLETF rats at the age of 40 weeks, glial fibrillary acidic protein (GFAP) immunofluorescence staining was upregulated in vertical sections and showed a more ramified pattern in whole-mount retinas compared with that in LETO rats. Vascular endothelial growth factor (VEGF) expression was limited to the ganglion cell layer in LETO rats, but extended into the outer plexiform layer in OLETF rats. Immunofluorescence staining and western blotting demonstrated that cilostazol treatment reduced GFAP and VEGF expression in the retinas of OLETF rats. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNLEL) staining revealed an increase in the RGC layer in OLETF compared with LETO rats (P<0.05), and cilostazol treatment reduced the number of TUNEL-positive cells in OLETF rats (P<0.05). Relieving retinal ischemia by systemic cilostazol treatment had a noticeable protective effect on RGCs in diabetic rats. Cilostazol treatment may be useful for the management of diabetic retinal vascular dysfunction and neuronal degeneration. 23561148 Ellagic acid derivatives, ellagitannins, proanthocyanidins and other phenolics, vitamin C and antioxidant capacity of two powder products from camu-camu fruit (Myrciaria dubia). The aims of this study were the evaluation of polyphenols and vitamin C content, and antioxidant capacity of dehydrated pulp powder and the dried flour obtained from the skin and seeds residue remaining after pulp preparation from camu-camu (Myrciaria dudia). Fifty-three different phenolics were characterised by HPLC-DAD-ESI-MS-MS and UPLC-HR-QTOF-MS-MS. The phenolic content of camu-camu flour was higher than that of the pulp powder (4007.95mg/100g vs. 48.54mg/100g). In both products the flavonol myricetin and conjugates, ellagic acid and conjugates and ellagitannins were detected. Cyanidin 3-glucoside, and quercetin and its glycosides were only found in the pulp powder, while proanthocyanidins were only present in the flour (3.5g/100g, mean degree of polymerisation 3). The vitamin C content was lower in pulp powder (3.5%) than in the flour (9.1%). The radical-scavenging capacity of both powders was determined by the DPPH, ABTS and ORAC assays, and was higher for camu-camu flour as could be expected for its higher phenolics and vitamin C content. Comparative analyses with fresh camu-camu berries indicate that some transformations occur during processing. Analysis of fresh berries showed that ellagic acid derivatives and ellagitannins were mainly present in the seeds, while proanthocyanidins were present both in the seeds and skin. 23092304 On the pH-Responsive, Charge-Selective, Polymer-Brush-Mediated Transport Probed by Traditional and Scanning Fluorescence Correlation Spectroscopy. The complete and reversible charge-selective sequestration of fluorophores by a weak polyelectrolyte brush, poly(2-(dimethylamino)ethylmethacrylate) (PDMAEMA) was demonstrated using fluorescence correlation spectroscopy (FCS). The chemistry and thickness of the weak polyelectrolyte PDMAEMA was tuned reversibly between neutral and cationic polymer forms. Thus, by switching the pH successively, the brush architecture was tuned to selectively trap and release anionic dye probes while continuously excluding cationic molecules. In addition, line-scan FCS was implemented and applied for the first time to a synthetic polymer system and used to identify a new, slower diffusion time on the order of seconds for the sequestered anionic probe under acidic conditions. These results, which quantify the selective sequestration properties of the PDMAEMA brush, are important because they enable a better understanding of transport in polymers and establish a spectroscopic means of evaluating materials with proposed applications in separations science, charge storage/release, and environmental remediation. 23395172 HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis. Adult humans have about 25 trillion red blood cells (RBCs), and each second we recycle about 5 million RBCs by erythrophagocytosis (EP) in macrophages of the reticuloendothelial system. Despite the central role for EP in mammalian iron metabolism, the molecules and pathways responsible for heme trafficking during EP remain unknown. Here, we show that the mammalian homolog of HRG1, a transmembrane heme permease in C. elegans, is essential for macrophage iron homeostasis and transports heme from the phagolysosome to the cytoplasm during EP. HRG1 is strongly expressed in macrophages of the reticuloendothelial system and specifically localizes to the phagolysosomal membranes during EP. Depletion of Hrg1 in mouse macrophages causes attenuation of heme transport from the phagolysosomal compartment. Importantly, missense polymorphisms in human HRG1 are defective in heme transport. Our results reveal HRG1 as the long-sought heme transporter for heme-iron recycling in macrophages and suggest that genetic variations in HRG1 could be modifiers of human iron metabolism. 23161873 The role of the carbohydrate response element-binding protein in male fructose-fed rats. By 2030, nearly half of Americans will have nonalcoholic fatty liver disease. In part, this epidemic is fueled by the increasing consumption of caloric sweeteners coupled with an innate capacity to convert sugar into fat via hepatic de novo lipogenesis. In addition to serving as substrates, monosaccharides also increase the expression of key enzymes involved in de novo lipogenesis via the carbohydrate response element-binding protein (ChREBP). To determine whether ChREBP is a potential therapeutic target, we decreased hepatic expression of ChREBP with a specific antisense oligonucleotide (ASO) in male Sprague-Dawley rats fed either a high-fructose or high-fat diet. ChREBP ASO treatment decreased plasma triglyceride concentrations compared with control ASO treatment in both diet groups. The reduction was more pronounced in the fructose-fed group and attributed to decreased hepatic expression of ACC2, FAS, SCD1, and MTTP and a decrease in the rate of hepatic triglyceride secretion. This was associated with an increase in insulin-stimulated peripheral glucose uptake, as assessed by the hyperinsulinemic-euglycemic clamp. In contrast, ChREBP ASO did not alter hepatic lipid content or hepatic insulin sensitivity. Interestingly, fructose-fed rats treated with ChREBP ASO had increased plasma uric acid, alanine transaminase, and aspartate aminotransferase concentrations. This was associated with decreased expression of fructose aldolase and fructokinase, reminiscent of inherited disorders of fructose metabolism. In summary, these studies suggest that targeting ChREBP may prevent fructose-induced hypertriglyceridemia but without the improvements in hepatic steatosis and hepatic insulin responsiveness. 23572392 Ultrasonic synthesis, characterization of β-aminoketones by bismuth(III) triflate and determination of antigenotoxic properties. Direct-type catalytic Mannich reaction for the synthesis of β-aminoketones from cyclohexanone, substituted aromatic amines and aromatic or hetero-aromatic aldehydes has been applied in water with bismuth triflate under ultrasound. Good yields of the expected β-aminoketones were obtained from available substrates, at room temperature in 1-2 hours. This study was designed to evaluate the mutagenic and antimutagenic potential of synthesized β-aminoketones compounds using Ames/Salmonella and Escherichia coli WP2 bacterial reverse mutation assay systems. 23570467 New genetic associations in thiopurine-related bone marrow toxicity among inflammatory bowel disease patients. Background: The toxicity related to thiopurine drug therapy for inflammatory bowel disease (IBD) varies widely among patients. Almost 15-30% of patients with IBD develop side effects during treatment, often bone marrow suppression. Several factors have been implicated in determining this toxicity, mainly individual genetic variation related to formation of active thiopurine metabolites. The aim was to identify genes involved in thiopurine-related myelosuppression. Materials & methods: A two-stage investigation of 19,217 coding SNPs (cSNPs) was performed in a Spanish (Inflammatory Bowel Disease Group of Galicia [EIGA]) cohort of 173 IBD patients, 15 with bone marrow suppression. The top 20 cSNPs identified in the first stage with p < 10(-3) for allelic test association and SNPs that define the common TPMT alleles were replicated in a different Spanish (ENEIDA) cohort (87 patients, 29 with bone marrow suppression). Results: Several cSNPs showed a significant p-value in the allelic joint analysis (p-Cochran-Mantel-Haenszel test ≤2.55 × 10(-3)) despite no cSNP passing correction for multiple testing in the first cohort. Of note is rs3729961 in the gene IL6ST, a transducer signal chain shared by many cytokines including IL6 (p-value combined = 2.36 × 10(-4), odds ratio [95% CI]: 3.41 [1.71-6.78]). In addition, we detected association with rs3749598 in the FSTL5 gene that appears to interact with metalloproteases at the extracellular matrix level (p-value combined = 4.89 × 10(-4)), odds ratio (95% CI): 3.67 (1.68-8.01). Conclusion: We have identified IL6ST and FSLT5 as new bone marrow suppression susceptibility candidate genes after thiopurine treatment in IBD patients. This is the first report of variants associated with thiopurine-related myelosuppression that was identified by a genome-wide association study. Its validation awaits functional analyses and replication in additional studies. Original submitted 14 September 2012; Revision submitted 13 February 2013. 23421850 Human fibrinogen monolayers on latex particles: role of ionic strength. The adsorption of human serum fibrinogen on polystyrene latex particles was studied using the microelectrophoretic and concentration depletion methods. Measurements were carried out for pH 3.5 and an ionic strength range of 10(-3) to 0.15 M NaCl. The electrophoretic mobility of latex was determined as a function of the amount of adsorbed fibrinogen (surface concentration). A monotonic increase in the electrophoretic mobility (zeta potential) of the latex was observed, indicating a significant adsorption of fibrinogen on latex for all ionic strengths. No changes in the latex mobility were observed for prolonged time periods, suggesting the irreversibility of fibrinogen adsorption. The maximum coverage of fibrinogen on latex particles was precisely determined using the depletion method. The residual protein concentration after making contact with latex particles was determined by electrokinetic measurements and AFM imaging where the surface coverage of fibrinogen on mica was quantitatively determined. The maximum fibrinogen coverage increased monotonically with ionic strength from 1.8 mg m(-2) for 10(-3) M NaCl to 3.6 mg m(-2) for 0.15 M NaCl. The increase in the maximum coverage was interpreted in terms of the reduced electrostatic repulsion among adsorbed fibrinogen molecules. The experimental data agree with theoretical simulations made by assuming a 3D unoriented adsorption of fibrinogen. The stability of fibrinogen monolayers on latex was also determined in ionic strength cycling experiments. It was revealed that cyclic variations in NaCl concentration between 10(-3) and 0.15 M induced no changes in the latex electrophoretic mobility, suggesting that there were no irreversible molecule orientation changes in the monolayers. On the basis of these experimental data, a robust procedure of preparing fibrinogen monolayers on latex particles of well-controlled coverage was proposed. 23266309 Calpains participate in nerve terminal degeneration induced by spider and snake presynaptic neurotoxins. α-latrotoxin and snake presynaptic phospholipases A2 neurotoxins target the presynaptic membrane of axon terminals of the neuromuscular junction causing paralysis. These neurotoxins display different biochemical activities, but similarly alter the presynaptic membrane permeability causing Ca(2+) overload within the nerve terminals, which in turn induces nerve degeneration. Using different methods, here we show that the calcium-activated proteases calpains are involved in the cytoskeletal rearrangements that we have previously documented in neurons exposed to α-latrotoxin or to snake presynaptic phospholipases A2 neurotoxins. These results indicate that calpains, activated by the massive calcium influx from the extracellular medium, target fundamental components of neuronal cytoskeleton such as spectrin and neurofilaments, whose cleavage is functional to the ensuing nerve terminal fragmentation. 23315522 Complex II of the mitochondrial respiratory chain is the key mediator of divalent manganese-induced hydrogen peroxide production in microglia. Exposure to excessive levels of manganese (Mn) is associated with the development of movement disorders, with symptoms overlapping with Parkinson's disease. Oxidative damage has been implicated as a key contributor to Mn-induced neurotoxicity. We have recently reported that divalent Mn (Mn(2+)) stimulates brain microglia to produce and release hydrogen peroxide (H2O2), and microglial-free radical generation facilitates Mn(2+)-induced dopaminergic neurotoxicity. The goal of this study was to elucidate the underlying mechanism of the Mn(2+)-induced H2O2 production in microglia. Exposure to low micromolar concentrations of Mn(2+), but not divalent copper, cadmium, nickel, cobalt, zinc, and iron, induced a significant production of H2O2 from rat microglial but not astroglial cells. Subcellular fractionation studies revealed that Mn(2+) was capable of inducing significant H2O2 production in the mitochondrial but not the cytosolic or nuclear fraction prepared from microglia. Analysis of the relative contribution of mitochondrial respiratory chain complexes indicated that Mn(2+)-induced mitochondrial H2O2 production required the presence of complex II substrate succinate. In contrast, complex I substrates malate and glutamate failed to support H2O2 production in the presence of Mn(2+). Furthermore, the succinate-supported Mn(2+)-induced mitochondrial H2O2 production was abolished by pharmacological inhibition of complex II but not that of complexes I and III, suggesting that mitochondrial complex II is a key mediator in Mn(2+)-induced H2O2 production. These findings advance our knowledge on the mechanisms by which Mn induces oxidative stress and the potential contribution to Mn neurotoxicity. 23443908 On the accuracy of explicitly correlated methods to generate potential energy surfaces for scattering calculations and clustering: application to the HCl-He complex. We closely compare the accuracy of multidimensional potential energy surfaces (PESs) generated by the recently developed explicitly correlated coupled cluster (CCSD(T)-F12) methods in connection with the cc-pVXZ-F12 (X = D, T) and aug-cc-pVTZ basis sets and those deduced using the well-established orbital-based coupled cluster techniques employing correlation consistent atomic basis sets (aug-cc-pVXZ, X = T, Q, 5) and extrapolated to the complete basis set (CBS) limit. This work is performed on the benchmark rare gas-hydrogen halide interaction (HCl-He) system. These PESs are then incorporated into quantum close-coupling scattering dynamical calculations in order to check the impact of the accuracy of the PES on the scattering calculations. For this system, we deduced inelastic collisional data including (de-)excitation collisional and pressure broadening cross sections. Our work shows that the CCSD(T)-F12/aug-cc-pVTZ PES describes correctly the repulsive wall, the van der Waals minimum and long range internuclear distances whereas cc-pVXZ-F12 (X = D,T) basis sets are not diffuse enough for that purposes. Interestingly, the collision cross sections deduced from the CCSD(T)-F12/aug-cc-pVTZ PES are in excellent agreement with those obtained with CCSD(T)/CBS methodology. The position of the resonances and the general shape of these cross sections almost coincide. Since the cost of the electronic structure computations is reduced by several orders of magnitude when using CCSD(T)-F12/aug-cc-pVTZ compared to CCSD(T)/CBS methodology, this approach can be recommended as an alternative for generation of PESs of molecular clusters and for the interpretation of accurate scattering experiments as well as for a wide production of collisional data to be included in astrophysical and atmospherical models. 23103600 The diversity of microbial aldo/keto reductases from Escherichia coli K12. The genome of Escherichia coli K12 contains 9 open reading frames encoding aldo/keto reductases (AKRs) that are differentially regulated and sequence diverse. A significant amount of data is available for the E. coli AKRs through the availability of gene knockouts and gene expression studies, which adds to the biochemical and kinetic data. This together with the availability of crystal structures for nearly half of the E. coli AKRs and homologues of several others provides an opportunity to look at the diversity of these representative bacterial AKRs. Based around the common AKR fold of (β/α)8 barrel with two additional α-helices, the E. coli AKRs have a loop structure that is more diverse than their mammalian counterparts, creating a variety of active site architectures. Nearly half of the AKRs are expected to be monomeric, but there are examples of dimeric, trimeric and octameric enzymes, as well as diversity in specificity for NAD as well as NADP as a cofactor. However in functional assignments and characterisation of enzyme activities there is a paucity of data when compared to the mammalian AKR enzymes. 23298677 Induction of HO-1 through p38 MAPK/Nrf2 signaling pathway by ethanol extract of Inula helenium L. reduces inflammation in LPS-activated RAW 264.7 cells and CLP-induced septic mice. High mobility group box 1 (HMGB1) plays a crucial mediator in the pathogenesis of many inflammatory diseases. We recently proposed that heme oxygenase-1 (HO-1) negatively regulates HMGB1 in inflammatory conditions. We investigated whether ethanol extract of Inula helenium L. (EIH) activates p38 MAPK/Nrf2/HO-1 pathways in RAW264.7 cells and reduces inflammation in CLP-induced septic mice. EIH induced expression of HO-1 protein in a time- and concentration-dependent manner. EIH significantly diminished HO-1 expression in siNrf2 RNA-transfected cells. As expected, the inhibited expression of iNOS/NO, COX-2/PGE2, HMGB1 release by EIH in LPS-activated RAW264.7 cells was significantly reversed by siHO-1RNA transfection. Furthermore, EIH not only inhibited NF-κB luciferase activity, phosphorylation of IκBα in LPS-activated cells but also significantly suppressed expression of adhesion molecules (ICAM-1 and VCAM-1) in TNF-α activated human umbilical vein endothelial cells. The induction of HO-1 by EIH was inhibited by SB203580 but not by SP600125, PD98059, nor LY294002. Most importantly, administration of EIH significantly reduced not only increase in blood HMGB1, ALT, AST, BUN, creatinine levels but also decrease macrophage infiltrate in the liver of septic mice, which were reversed by ZnPPIX, a HO-1 inhibitor. We concluded that EIH has anti-inflammatory effect via the induction of p38 MAPK-dependent HO-1 signaling pathway. 23631760 Simultaneous determination by LC-MS/MS of 25-methoxydammarane-3β,12β,20-triol epimers and active metabolites in rat plasma after intravenous administration. Abstract 1. The pharmacokinetics of the 25-OCH3-PPD epimers and active metabolites in rat plasma after a single intravenous (i.v.) administration were studied by a rapid, selective and sensitive UPLC-MS/MS method. 2. Chromatographic separation was performed on an Acquity UPLC with Agela C18 column, and the solvents of 5 mM ammonium acetate (pH 7.8) - acetonitrile (65: 35, v/v) were used as mobile phase for elution. The quantification was performed with the transitions of m/z 493.5 → 475.5 for 20(R,S)-25-OCH3-PPD, m/z 479.5 → 461.5 for 20(R,S)-25-OH-PPD. The Lower Limit Of Quantitation (LLOQ) was 20.0 ng mL(-1) for 20(R,S)-25-OCH3-PPD, 2.0 ng mL(-1) for 20(R,S)-25-OH-PPD in the plasma samples assay. 3. The pharmacokinetic parameters of AUC, t1/2 and MRT had no difference between 20(R)- and (S)-25-OCH3-PPD, but S-epimer has a lower plasma clearance compared to the R-isomer. The active metabolite 20(S)-25-OH-PPD showed significantly higher AUC, MRT and a longer half-life than that of 20(R)-25-OH-PPD. These assay results are necessary for the evaluation of the pharmacokinetic behavior of 25-methoxydammarane-3β,12β,20-triol in vivo. 23376007 Of marsupials and men: "Backdoor" dihydrotestosterone synthesis in male sexual differentiation. Following development of the fetal bipotential gonad into a testis, male genital differentiation requires testicular androgens. Fetal Leydig cells produce testosterone that is converted to dihydrotestosterone in genital skin, resulting in labio-scrotal fusion. An alternative 'backdoor' pathway of dihydrotestosterone synthesis that bypasses testosterone has been described in marsupials, but its relevance to human biology has been uncertain. The classic and backdoor pathways share many enzymes, but a 3α-reductase, AKR1C2, is unique to the backdoor pathway. Human AKR1C2 mutations cause disordered sexual differentiation, lending weight to the idea that both pathways are required for normal human male genital development. These observations indicate that fetal dihydrotestosterone acts both as a hormone and as a paracrine factor, substantially revising the classic paradigm for fetal male sexual development. 22537580 Two new C-15 enolic acyl phragmalin-type limonoids from Chukrasia tabularis var. velutina. Two new C-15 enolic acyl phragmalin-type limonoid orthoesters, chukvelutilide G (1) and chukrasine F (2), were isolated from the stem barks of Chukrasia tabularis var. velutina. Their structures were elucidated by their extensive high resolution-electrospray ionization mass spectrometry (HR-ESI-MS), one- and two-dimensional spectroscopic analysis, including heteronuclear single quantum coherence (HSQC), HMBC and NOESY experiments. 23281020 A carbon nanotube synapse with dynamic logic and learning. A carbon nanotube (CNT) synapse emulates a biological synapse with its dynamic logic, learning, and memory functions induced by the interactions between CNTs and hydrogen ions in an electrochemical cell. A circuit of CNT synapses operates with extremely low-energy consumption and could potentially emulate the functions of the neuronal network. 22963497 A novel reproductive peptide, phoenixin. Normal anterior pituitary function is essential for fertility. Release from the gland of the reproductive hormones luteinising hormone and follicle-stimulating hormone is regulated primarily by hypothalamically-derived gonadotrophin-releasing hormone (GnRH), although other releasing factors (RF) have been postulated to exist. Using a bioinformatic approach, we have identified a novel peptide, phoenixin, that regulates pituitary gonadotrophin secretion by modulating the expression of the GnRH receptor, an action with physiologically relevant consequences. Compromise of phoenixin in vivo using small interfering RNA resulted in the delayed appearance of oestrus and a reduction in GnRH receptor expression in the pituitary. Phoenixin may represent a new class of hypothalamically-derived pituitary priming factors that sensitise the pituitary to the action of other RFs, rather than directly stimulating the fusion of secretary vesicles to pituitary membranes. 23624811 High-affinity nicotinic acetylcholine receptor expression and trafficking abnormalities in psychiatric illness. RATIONALE: Nicotinic acetylcholine receptors (nAChRs) are a critical component of the cholinergic system of neurotransmission in the brain that modulates important physiological processes such as reward, cognition, and mood. Abnormalities in this system are accordingly implicated in multiple psychiatric illnesses, including addiction, schizophrenia, and mood disorders. There is significantly increased tobacco use, and therefore nicotine intake, in patient populations, and pharmacological agents that act on various nicotinic receptor subtypes ameliorate clinical features of these disorders. Better understanding of the molecular mechanisms underlying cholinergic dysfunction in psychiatric disease will permit more targeted design of novel therapeutic agents. RESULTS: The objective of this review is to describe the multiple cellular pathways through which chronic nicotine exposure regulates nAChR expression, and to juxtapose these mechanisms with evidence for altered expression of high-affinity nAChRs in human psychiatric illness. Here, we summarize multiple studies from pre-clinical animal models to human in vivo imaging and post-mortem experiments demonstrating changes in nAChR regulation and expression in psychiatric illness. CONCLUSIONS: We conclude that a mechanistic explanation of nAChR abnormalities in psychiatric illness will arise from a fuller understanding of normal nAChR trafficking, along with the detailed study of human tissue, perhaps using novel biotechnological advances, such as induced pluripotent stem cells. 23199985 Encapsulation of ligninolytic enzymes and its application in clarification of juice. The thermal stability, physico-chemical properties and effect on juice clarification of hydrogel formulations of ligninolytic enzymes from Phanerochaete chrysosporium were evaluated. The results showed that enzyme entrapment increase significantly (P<0.05) the thermal stability of enzymes at 4 and 75 °C. At 75 °C, maximum activity decreased to non detectable values of 7.9% for free laccase, manganese peroxidase (MnP), lignin peroxidase (LiP), respectively; to 94%, 97%, 93% for laccase, MnP and LiP entrapped into Polyacrylamide/pectin, 94%, 98%, 88% for laccase, MnP and LiP encapsulated respectively into polyacrylamide/ gelatine and to 87%, 91%, 87% for laccase, MnP and LiP entrapped, respectively into polyacrylamide/carboxymethylcellulose (CMC). When particle size and viscosity of the formulation increased, enzyme stability increased. The polyphenolic reduction and clarity amelioration in mixed juice of berry and pomegranate was more significant (p>0.05) using encapsulated enzymes treatment than free enzymes. This suggested that enzymatic treatment was efficient for the juice clarification. 23210852 Synthesis and HIV-1 inhibitory activities of dicaffeoyl and digalloyl esters of quinic acid derivatives. Twenty analogues of the anti-HIV-1 integrase (IN) inhibitors dicaffeoylquinic acids (DCQAs) were prepared. Their IC(50) values for 3'-end processing and strand transfer against recombinant HIV-1IN were determined in vitro, and their cell toxicities and EC(50) against HIV-1 were measured in cells (ex vivo). Acetylated or benzylated and/or with cyclohexylidene group compounds exhibited no inhibition of integration in biochemical assays or viral replication in HIV-infected cells, with the exception of 16 and 36. Removal of these groups, however, correlated with potent inhibition. Compounds 19, 31, and 38, all digalloyls, exhibited the most robust inhibitory performance in biochemical assays as well as in cell culture and less toxicity than other molecules in the current study. 22939899 Cell transplantation approaches to retinal ganglion cell neuroprotection in glaucoma. Glaucoma is a complex neurodegenerative disease that involves interactions among multiple signaling pathways, ultimately leading to progressive retinal ganglion cell (RGC) death. The development of neuroprotective approaches to glaucoma therapy could preserve vision by modulating these pathologic pathways or by acting directly on RGCs to attenuate cell death and maintain function. Intraocular cell transplantation is being evaluated as one approach to achieve sustained RGC neuroprotection. Unlike traditional pharmacological approaches, transplanted cells might be capable of simultaneously targeting multiple pro-survival pathways via local delivery of secreted factors and/or via modulation of the intraocular microenvironment. Elucidating the mechanisms by which different cell types attenuate RGC death in models of glaucoma may uncover additional novel mechanisms of neuroprotection. In this review, we will discuss the rationale for transplantation-based approaches to neuroprotection for glaucoma and explore the various mechanisms of action proposed to account for RGC neuroprotection achieved by two distinct cell classes that have been studied most extensively for this purpose: glial cells and mesenchymal stem cells. 23076766 Hyaluronic acid modified mesoporous silica nanoparticles for targeted drug delivery to CD44-overexpressing cancer cells. In this paper, a targeted drug delivery system has been developed based on hyaluronic acid (HA) modified mesoporous silica nanoparticles (MSNs). HA-MSNs possess a specific affinity to CD44 over-expressed on the surface of a specific cancer cell line, HCT-116 (human colon cancer cells). The cellular uptake performance of fluorescently labelled MSNs with and without HA modification has been evaluated by confocal microscopy and fluorescence-activated cell sorter (FACS) analysis. Compared to bare MSNs, HA-MSNs exhibit a higher cellular uptake via HA receptor mediated endocytosis. An anticancer drug, doxorubicin hydrochloride (Dox), has been loaded into MSNs and HA-MSNs as drug delivery vehicles. Dox loaded HA-MSNs show greater cytotoxicity to HCT-116 cells than free Dox and Dox-MSNs due to the enhanced cell internalization behavior of HA-MSNs. It is expected that HA-MSNs have a great potential in targeted delivery of anticancer drugs to CD44 over-expressing tumors. 23122070 Syzygium aqueum leaf extract and its bioactive compounds enhances pre-adipocyte differentiation and 2-NBDG uptake in 3T3-L1 cells. The insulin-like and/or insulin-sensitising effects of Syzygium aqueum leaf extract and its six bioactive compounds; 4-hydroxybenzaldehyde, myricetin-3-O-rhamnoside, europetin-3-O-rhamnoside, phloretin, myrigalone-G and myrigalone-B were investigated in 3T3-L1 adipocytes. We observed that, S. aqueum leaf extract (0.04-5 μg/ml) and its six bioactive compounds (0.08-10 μM) at non-cytotoxic concentrations were effectively enhance adipogenesis, stimulate glucose uptake and increase adiponectin secretion in 3T3-L1 adipocytes. Clearly, the compounds myricetin-3-O-rhamnoside and europetin-3-O-rhamnoside showed insulin-like and insulin-sensitising effects on adipocytes from a concentration of 0.08 μM. These compounds were far better than rosiglitazone and the other isolated compounds in enhancing adipogenesis, stimulating 2-NBDG uptake and increasing adiponectin secretion at all the concentrations tested. These suggest the antidiabetic potential of S. aqueum leaf extract and its six bioactive compounds. However, further molecular interaction studies to explain the mechanisms of action are highly warranted. 23092751 An exploration of species boundaries in turret-building tarantulas of the Mojave Desert (Araneae, Mygalomorphae, Theraphosidae, Aphonopelma). Tarantulas in the North American genus Aphonopelma are poorly known due to their challenging patterns of morphological variation and questionable taxonomy; few specimens can be confidently identified using existing keys or comparisons to original descriptions. In an effort to identify new strategies for resolving what has been characterized as a "taxonomic and nomenclatural nightmare", we employed five different approaches for delimiting species in a group of closely related tarantulas from the Mojave Desert in the southwestern United States. These methods included the application of single techniques (morphology, DNA barcoding, shared genealogical exclusivity among independent loci, and generalized mixed Yule coalescent) and an integrative approach that incorporates genealogical and ecological information. Results demonstrate that the taxonomy of these spiders as presently defined underestimates actual species-level diversity and the group is in need of revision. The number of species delimited by each approach, however, was variable and we argue that it is this discordance that emphasizes the importance of incorporating multiple lines of evidence into an integrative taxonomic framework that can be used for constructing robust taxonomic hypotheses for Aphonopelma species. 23313714 In vitro and ex vivo models of human asthma. Asthma is an inflammatory disorder of the conducting airways which undergo distinct structural and functional changes leading to non-specific bronchial hyperresponsiveness (BHR) and airflow obstruction that fluctuate over time. It is a complex disease involving multiple genetic and environmental influences whose multifactorial interactions can result in a range of asthma phenotypes. Since our understanding of these gene-gene and gene-environment interactions is very poor, this poses a major challenge to the logical development of 'models of asthma'. However, use of cells and tissues from asthmatic donors allows genetic and epigenetic influences to be evaluated and can go some way to reflect the complex interplay between genetic and environmental stimuli that occur in vivo. Current alternative approaches to in vivo animal models involve use of a plethora of systems ranging from very simple models using human cells (e.g. bronchial epithelial cells and fibroblasts) in mono- or co-culture, whole tissue explants (biopsies, muscle strips, bronchial rings) through to in vivo studies in human volunteers. Asthma research has been greatly facilitated by the introduction of fibreoptic bronchoscopy which is now a commonly used technique in the field of respiratory disease research, allowing collection of biopsy specimens, bronchial brushing samples, and bronchoalveolar lavage fluid enabling use of disease-derived cells and tissues in some of these models. Here, we will consider the merits and limitations of current models and discuss the potential of tissue engineering approaches through which we aim to advance our understanding of asthma and its treatment. 23595911 Unraveling the Reaction Mechanisms Governing Methanol-to-Olefins Catalysis by Theory and Experiment. The conversion of methanol to olefins (MTO) over a heterogeneous nanoporous catalyst material is a highly complex process involving a cascade of elementary reactions. The elucidation of the reaction mechanisms leading to either the desired production of ethene and/or propene or undesired deactivation has challenged researchers for many decades. Clearly, catalyst choice, in particular topology and acidity, as well as the specific process conditions determine the overall MTO activity and selectivity; however, the subtle balances between these factors remain not fully understood. In this review, an overview of proposed reaction mechanisms for the MTO process is given, focusing on the archetypal MTO catalysts, H-ZSM-5 and H-SAPO-34. The presence of organic species, that is, the so-called hydrocarbon pool, in the inorganic framework forms the starting point for the majority of the mechanistic routes. The combination of theory and experiment enables a detailed description of reaction mechanisms and corresponding reaction intermediates. The identification of such intermediates occurs by different spectroscopic techniques, for which theory and experiment also complement each other. Depending on the catalyst topology, reaction mechanisms proposed thus far involve aromatic or aliphatic intermediates. Ab initio simulations taking into account the zeolitic environment can nowadays be used to obtain reliable reaction barriers and chemical kinetics of individual reactions. As a result, computational chemistry and by extension computational spectroscopy have matured to the level at which reliable theoretical data can be obtained, supplying information that is very hard to acquire experimentally. Special emphasis is given to theoretical developments that open new perspectives and possibilities that aid to unravel a process as complex as methanol conversion over an acidic porous material. 23474169 Discovery of the Antibiotic Phosacetamycin via a New Mass Spectrometry-Based Method for Phosphonic Acid Detection. Naturally occurring phosphonates such as phosphinothricin (Glufosinate, a commercially used herbicide) and fosfomycin (Monurol, a clinically used antibiotic) have proved to be potent and useful biocides. Yet this class of natural products is still an under explored family of secondary metabolites. Discovery of the biosynthetic pathways responsible for the production of these compounds has been simplified by using gene based screening approaches, but detection and identification of the natural products the genes produce have been hampered by a lack of high-throughput methods for screening potential producers under various culture conditions. Here, we present an efficient mass-spectrometric method for the selective detection of natural products containing phosphonate and phosphinate functional groups. We have used this method to identify a new phosphonate metabolite, phosacetamycin, whose structure, biological activity, and biosynthetic gene cluster are reported. 23270387 Noncovalent tailoring of the binding pocket of self-assembled cages by remote bulky ancillary groups. The binding properties of a self-assembled coordination cage were subtly tuned by ancillary groups on the metal corners of the cage. Since the bulky mesityl groups of the ligand hang over the cage cavity, the effective cavity volume is reduced. Due to the tighter guest packing inside the shrunken cavity, smaller guests were efficiently bound and guest motion was restricted even at high temperatures. 23432590 Camptothecin Resistance in Cancer: Insights into the Molecular Mechanisms of a DNA-Damaging Drug. Poisoning of DNA topoisomerase I is the mechanism by which camptothecins interfere with tumor growth. Although the clinical use of camptothecins has had a significant impact on cancer therapy, de novo or acquired clinical resistance to these drugs is common. Clinical resistance to camptothecins is still a poorly understood phenomenon, likely involving pharmacological and tumor-related factors. Experimental models including yeast and mammalian cell cultures suggest three general mechanisms of camptothecin resistance: i) reduced cellular accumulation of drugs, ii) alteration in the structure/expression of topoisomerase I, and iii) alterations in the cellular response to camptothecin-DNA-ternary complex formation. Some lines of evidence have also suggested links between cellular camptothecin resistance, the existence of a subset of tumor-initiating cells and miRNA deregulation. In this regard, a better definition of the molecular events clarifying the regulation of tumorigenesis and gene expression might contribute to gain insight into the molecular mechanisms on the basis of camptothecin resistance of tumors and to identify new molecular tools for targeting cancer cells. The relevance of these mechanisms to clinical drug resistance has not yet been completely defined, but their evaluation in clinical specimens should help to define personalized treatments including camptothecins as single agents or in combination with other cytotoxic and target-specific anticancer agents. The present review focuses on the cellular/ molecular aspects involved in resistance of tumor cells to camptothecins, including the potential role of cancer stem cells and deregulated miRNAs, and on the approaches proposed for overcoming resistance. 23167812 8,8-dialkyldihydroberberines with potent antiprotozoal activity. Semisynthetic 8,8-dialkyldihydroberberines (8,8-DDBs) were found to possess mid- to low-nanomolar potency against Plasmodium falciparum blood-stage parasites, Leishmania donovani intracellular amastigotes, and Trypanosoma brucei brucei bloodstream forms. For example, 8,8-diethyldihydroberberine chloride (5b) exhibited in vitro IC50 values of 77, 100, and 5.3 nM against these three parasites, respectively. In turn, two 8,8-dialkylcanadines, obtained by reduction of the corresponding 8,8-DDBs, were much less potent against these parasites in vitro. While the natural product berberine is a weak DNA binder, the 8,8-DDBs displayed no affinity for DNA, as assessed by changes in the melting temperature of poly(dA·dT) DNA. Selected 8,8-DDBs showed efficacy in mouse models of visceral leishmaniasis and African trypanosomiasis, with 8,8-dimethyldihydroberberine chloride (5a) reducing liver parasitemia by 46% in L. donovani-infected BALB/c mice when given at an intraperitoneal dose of 10 mg/kg/day for five days. The 8,8-DDBs may thus serve as leads for discovering new antimalarial, antileishmanial, and antitrypanosomal drug candidates. 23449981 Ceramide phosphoethanolamine biosynthesis in Drosophila is mediated by a unique ethanolamine phosphotransferase in the Golgi lumen. Sphingomyelin (SM) is a vital component of mammalian membranes, providing mechanical stability and a structural framework for plasma membrane organization. Its production involves the transfer of phosphocholine from phosphatidylcholine onto ceramide, a reaction catalyzed by SM synthase in the Golgi lumen. Drosophila lacks SM and instead synthesizes the SM analogue ceramide phosphoethanolamine (CPE) as the principal membrane sphingolipid. The corresponding CPE synthase shares mechanistic features with enzymes mediating phospholipid biosynthesis via the Kennedy pathway. Using a functional cloning strategy, we here identified a CDP-ethanolamine:ceramide ethanolamine phosphotransferase as the enzyme responsible for CPE production in Drosophila. CPE synthase constitutes a new branch within the CDP-alcohol phosphotransferase superfamily with homologues in Arthropoda (insects, spiders, mites, scorpions), Cnidaria (Hydra, sea anemones), and Mollusca (oysters) but not in most other animal phyla. The enzyme resides in the Golgi complex with its active site facing the lumen, contrary to the membrane topology of other CDP-alcohol phosphotransferases. Our findings open up an important new avenue to address the biological role of CPE, an enigmatic membrane constituent of a wide variety of invertebrate and marine organisms. 23531154 Progression to insulin for patients with diabetes mellitus on dual oral antidiabetic therapy using the US Department of Defense Database. AIM: To compare 'progression to insulin' for three cohorts on oral antidiabetic medication combinations: metformin/sulphonylurea (Met/SU), metformin/thiazolidinedione (Met/TZD) and sulphonylurea/thiazolidinedione (SU/TZD). METHODS: Retrospective cohort analysis design was used. The subjects were US nationwide members of military and their families. A total of 5608 patients who were on antidiabetic monotherapy for at least 1 year before adding a second agent to their medication regimen between October 2001 and September 2008 participated in this study. Mean age ranged from 64 to 71 years among the cohorts. Cox regression compared the progression to insulin, adjusting for demographics, months of follow-up and co-morbidities [measured with Chronic Disease Score (CDS)]. RESULTS: By the end of the 2- to 6-year follow-up period, 14.3% of the Met/TZD cohort, 23.6% of the Met/SU cohort and 28.2% of the SU/TZD cohort had insulin added to their regimen. Those in the Met/SU cohort had a 1.8 times higher probability of progression to insulin than those in the Met/TZD cohort [odds ratio (OR) = 1.80, 95% confidence interval (CI) = 1.51-2.14), and those in the SU/TZD cohort had a 2.5 times higher probability of progression to insulin than those in the Met/TZD cohort (OR = 2.51, 95% CI = 2.04-3.08). CONCLUSION: When sensitizers were paired (Met/TZD), a lower percentage of patients progressed to insulin during the study period, as opposed to patients who used a combination of a secretagogue with a sensitizer (SU/TZD or Met/SU). 23403058 Synthesis and Nrf2-inducing activity of the isothiocyanates iberverin, iberin and cheirolin. Numerous studies have reported a potent induction of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent gene expression by the isothiocyanate sulforaphane. However, little is known regarding the Nrf2-inducing activities of the lower structure-related sulforaphane homologues, such as iberverin, iberin and cheirolin, which exhibit different sulfur oxidation states. Therefore, in this study we synthesized the isothiocyanates iberverin, iberin and cheirolin with a high yield and purity and determined their Nrf2-inducing activity in NIH3T3 fibroblasts. Iberverin, iberin and cheirolin significantly induced Nrf2 nuclear translocation. The increase in nuclear Nrf2 levels was accompanied by a significant increase in heme oxygenase 1 (HO-1) and γ-glutamylcysteine synthetase (γGCS) mRNA and protein levels. Overall, iberverin, iberin and cheirolin exhibited a similar potency to sulforaphane in inducing Nrf2-dependent gene-expression. Furthermore, our data suggest that the induction of Nrf2 by iberverin, iberin and cheirolin may have occurred via an extracellular signal-related kinase (ERK)-dependent signal-transduction pathway. 23327722 Levels of thrombin activatable fibrinolysis inhibitor in gestational diabetes mellitus. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a procarboxypeptidase, which is synthesised in liver and activated by thrombin and the thrombin-thrombomodulin complex. TAFI suppresses fibrinolysis by removing carboxy-terminal lysine residues from partially degraded fibrin. In this study we aimed to assess the circulating levels of TAFI antigen, 'a fibrinolytic parameter' in women with gestational diabetes (GDM). Thirty-four pregnant women with GDM and 50 pregnant women with normal glucose tolerance were included in the study. Plasma TAFI antigen levels were significantly higher in pregnant women with GDM when compared with controls. Increased TAFI levels may contribute to the decreased fibrinolytic potency, causing a thrombophilic state. GDM is regarded as a specific form of diabetes, and it could in addition be a predictor of type 2 diabetes mellitus in the future and the risk of complications due to hypercoagulability increases in this disease. Increased TAFI levels may also have a role in increased risk of hypercoagulability. 23265455 Assessment of DFG-S19 method for the determination of common endocrine disruptor pesticides in wine samples with an estimation of the uncertainty of the analytical results. A gas chromatographic method for the determination of endocrine disruptor pesticides (Chlorpyrifos, Penconazole, Procymidone, Iprodione, Bromopropylate and Lambda-Cyhalothrin) in wine samples is described. A general DFG-S19 method for residual pesticide determination in all kind of food stuff was investigated to simplify and adopt for wine samples in this work. Alternative sample preparation routes were elucidated and compared according to their recovery values. Four different separation techniques were tested and the method employing florosil column after a LLE procedure was applied for wine samples with satisfactory recovery ratios (72-97%). The pesticides were extracted from the sample by cyclohexane-ethyl acetate mixture (1:1 v/v) and cleaned up by florosil column. The regression coefficients were at least 0.99 and relative standard deviations were no higher than 16%. Detection limits were in the range of 0.6-2.9 ng/mL and the relative expanded measurement uncertainties were calculated in the 7-22% range. 23646041 Self-assembling doxorubicin silk hydrogels for the focal treatment of primary breast cancer. Standard care for early stage breast cancer includes tumor resection and local radiotherapy to achieve long-term remission. Systemic chemotherapy provides only low locoregional control of the disease; therefore, we describe self-assembling silk hydrogels that can retain and then deliver doxorubicin locally. Self-assembling silk hydrogels show no swelling, are readily loaded with doxorubicin under aqueous conditions and release drug over 4 weeks in amounts that can be fine-tuned by varying the silk content. Following successful in vitro studies, locally injected silk hydrogels loaded with doxorubicin show excellent antitumor response in mice, outperforming the equivalent amount of doxorubicin delivered intravenously. In addition to reducing primary tumor growth, doxorubicin-loaded silk hydrogels reduce metastatic spread and are well tolerated in vivo. Thus, silk hydrogels are well suited for the local delivery of chemotherapy and provide a promising approach to improve locoregional control of breast cancer. 23301897 Bioactive flavaglines and other constituents isolated from Aglaia perviridis. Eight new compounds, including two cyclopenta[b]benzopyran derivatives (1, 2), two cyclopenta[b]benzofuran derivatives (3, 4), three cycloartane triterpenoids (5-7), and an apocarotenoid (8), together with 16 known compounds, were isolated from the chloroform-soluble partitions of separate methanol extracts of a combination of the fruits, leaves, and twigs and of the roots of Aglaia perviridis collected in Vietnam. Isolation work was monitored using human colon cancer cells (HT-29) and facilitated with an LC/MS dereplication procedure. The structures of the new compounds (1-8) were determined on the basis of spectroscopic data interpretation. The Mosher ester method was employed to determine the absolute configurations of 5-7, and the absolute configuration of the 9,10-diol unit of compound 8 was established by a dimolybdenum tetraacetate [Mo2(AcO)4] induced circular dichroism procedure. Seven known rocaglate derivatives (9-15) exhibited significant cytotoxicity against the HT-29 cell line, with rocaglaol (9) being the most potent (ED50 0.0007 μM). The new compounds 2-4 were also active against this cell line, with ED50 values ranging from 0.46 to 4.7 μM. The cytotoxic compounds were evaluated against a normal colon cell line, CCD-112CoN. In addition, the new compound perviridicin B (2), three known rocaglate derivatives (9, 11, 12), and a known sesquiterpene, 2-oxaisodauc-5-en-12-al (17), showed significant NF-κB (p65) inhibitory activity in an ELISA assay. 23553887 Tunable 3D Extended Self-Assembled Gold Metamaterials with Enhanced Light Transmission. The optical properties of metamaterials made by block copolymer self-assembly are tuned by structural and environmental variations. The plasma frequency red-shifts with increasing lattice constant and blue-shifts as the network filling fraction increases. Infiltration with dielectric liquids leads also to a red-shift of the plasma edge. A 300 nm-thick slab of gyroid-structured gold has a remarkable transmission of 20%. 22901687 Oleuropein supplementation increases urinary noradrenaline and testicular testosterone levels and decreases plasma corticosterone level in rats fed high-protein diet. The effects of oleuropein, a phenolic compound in extra virgin olive oil, on protein metabolism were investigated by measuring testicular testosterone and plasma corticosterone levels in rats fed diets with different protein levels. In Experiment 1, rats were fed experimental diets with different protein levels (40, 25 and 10 g/100 g casein) with or without 0.1 g/100 g oleuropein. After 28 days of feeding, the testosterone level in the testis was significantly higher and the plasma corticosterone level was significantly lower in rats fed the 40% casein diet with oleuropein than in those fed the same diet without oleuropein. The urinary noradrenaline level, nitrogen balance and hepatic arginase activity were significantly higher in rats fed the 40% casein diet with oleuropein supplementation than in those fed the 40% casein diet without oleuropein supplementation. In Experiment 2, the effects of oleuropein aglycone (a major phenolic compound in extra virgin olive oil and the absorbed form of oleuropein ingested in the gastrointestinal tracts) on the secretion of luteinizing hormone (LH) from the pituitary gland, which regulates testosterone production in the testis, were investigated in anesthetized rats. Plasma LH level increased dose dependently after the administration of oleuropein aglycone (P<.001, r=0.691). These findings suggest that dietary supplementation with 0.1 g/100 g oleuropein alters the levels of hormones associated with protein anabolism by increasing urinary noradrenaline and testicular testosterone levels and decreasing plasma corticosterone level in rats fed a high-protein diet. 23548165 Bioavailability, metabolism and disposition of oral pazopanib in patients with advanced cancer. 1. Pazopanib (Votrient) is an oral tyrosine kinase inhibitor that was recently approved for the treatment of renal cell carcinoma and soft tissue sarcoma. 2. In this two-part study, we investigated the metabolism, disposition of [(14)C]pazopanib, and the oral bioavailability of pazopanib tablets in patients with advanced cancer. 3. In part A, three men each received a single oral dose of [(14)C]pazopanib in suspension (400 mg, 70 µCi). Pazopanib was the predominant drug-related component in circulation. Two metabolites derived from hydroxylation and one from N-demethylation were also circulating, but were minor, each accounting for <5% of plasma radioactivity. Faecal elimination predominated, accounting for 82.2% of the administered radio-dose, with negligible renal elimination (2.6% of dose). Pazopanib was primarily excreted as the unchanged drug in faeces (67% of dose). 4. In part B, seven additional patients received a single intravenous administration of 5 mg pazopanib (day 1) followed by oral administration of 800 mg pazopanib tablet once daily for 26 days (days 3 or 5-28). In the three evaluable patients from part B, pazopanib had a slow plasma clearance and a small volume of distribution. The absolute oral bioavailability of the 800 mg pazopanib tablet ranged from 14% to 39%. 22815312 Quantitative prediction of CYP2B6 induction by estradiol during pregnancy: potential explanation for increased methadone clearance during pregnancy. There is considerable evidence that pregnancy changes the disposition of drugs in an enzyme- and gestational stage-specific manner. On the basis of probe drug studies, the activity of CYP3A4 and CYP2D6 increases and CYP1A2 decreases during human pregnancy. However, no studies of CYP2B6 activity during human pregnancy have been conducted. In rodent models and in HepG2 cells, CYP2B enzymes have been shown to be regulated by estradiol. Because estradiol concentrations increase by ∼50-fold during human pregnancy, it was hypothesized that the increasing estradiol concentrations during human pregnancy would result in induction of CYP2B6 activity. Hepatocytes from three female donors were treated with estradiol, and the EC(50) and E(max) were measured for CYP2B6 mRNA and bupropion hydroxylation activity. The measured values were used to predict the magnitude of CYP2B6 induction during human pregnancy. At 100 nM total estradiol, a concentration achievable during the third trimester of pregnancy, CYP2B6 activity was predicted to increase by 1.5-3-fold, based on increased CYP2B6 activity and mRNA. When the E(max) and EC(50) values were compared with those for carbamazepine and rifampin, estradiol was found to be as potent an inducer of CYP2B6 as rifampin and carbamazepine. These data suggest that, during human pregnancy, the increasing estradiol concentrations will result in increased clearance of drugs that have CYP2B6-mediated clearance pathways. This could in part explain the observed increase in methadone clearance during pregnancy. 23538397 Synthesis of some novel thieno[3,2-d]pyrimidines as potential cytotoxic small molecules against breast cancer. A variety of novel thieno[3,2-d]pyrimidines with different decorating functional groups were synthesized as a part of a study aiming to enrich the arsenal of chemotherapeutic agents for the treatment of cancer. The design of synthetic molecules based on DNA-interchelating properties by hydrogen bond formation. The reported compounds herein are: 4-aminothienopyrimidine derivatives 4a,b and their 4-substituted phenylamino analogues 8a,b; 4-thienopyrimidin-4-ones 5a,b; N-alkyl thienopyrimidin-4-ones 6a-g; 4-chlorothienopyrimidines 7a,b; and thienopyrimidoquinazolinones 9a,b which are the structural mimics of 8a,b. The synthesized molecules were evaluated for their in vitro cytotoxic activity against human breast cancer cell line (MCF-7). Biological screening revealed varying cytotoxic potencies of the tested molecules compared with Doxorubicin as a reference drug. The cytotoxicity results from the study suggested that the synthesized molecules are potential antitumor agents and compound 4a was the most potent with an IC 50 2.04 nM. 22757667 Phytochemical analysis of the essential oils of 10 endemic Cephalaria species from Turkey. The volatile composition of 10 endemic Cephalaria (Dipsacaceae) species (Cephalaria gazipashensis, Cephalaria lycica, Cephalaria paphlagonica, Cephalaria elmaliensis, Cephalaria stellipilis, Cephalaria scoparia, Cephalaria isaurica, Cephalaria cilicica, Cephalaria elazigensis var. purpurea and Cephalaria davisiana) was investigated. The essential oil mixtures were obtained by steam distillation in a Clevenger-type apparatus. Twenty-eight components were identified by GC-FID and GC-MS techniques. While total volatile percentages ranged from 68.99% to 84.57%, the total essential oil yields ranged between 38.15% and 64.05%. Geraniol, α-cedrene and p-cymene were determined as the main components. Geraniol was detected as a major component in C. cilicica (14.64%), and α-cedrene was detected as a major component with 26.03% for C. lycica, 16.93% for C. scoparia, 13.01% for C. davisiana and 10.94% for C. paphlagonica. Cephalaria scoparia, C. davisiana and C. gazipashensis have considerable amount of p-cymene as 12.86%, 12.70% and 11.16%, respectively. This was the first essential oil report concerning the Cephalaria genus. 23220614 MAPK signaling pathways regulate mitochondrial-mediated apoptosis induced by isoorientin in human hepatoblastoma cancer cells. Isoorientin (ISO) (CAS RN: 4261-42-1) is a flavonoid compound that can be extracted from several plant species, such as Phyllostachys pubescens, Patrinia, and Drosophyllum lusitanicum. ISO is able to induce apoptosis through mitochondrial dysfunction and inhibition of PI3K/Akt signaling pathway in HepG2 cells, however, the effects of ISO on MAPK signaling pathways remain unknown. The present study investigated the effects of ISO on this pathway, and the roles of MAPK kinases on mitochondrial-mediated apoptosis in HepG2 cells. The results showed that ISO induced cell death in a dose- and time-dependent manner, and induction apoptosis is main cause for ISO-induced cytotoxicity in HepG2 cells. ISO significantly inhibited the levels of ERK1/2 kinase and increased the expression of JNK and p38 kinases. Furthermore, U0126 (an ERK1/2 inhibitor) significantly enhanced the ISO-induced the Bax/Bcl-2 ratio, the release of cytochrome c to the cytosol fraction, and the levels of cleaved caspase-3. While SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor) markedly prevented the expression of these proteins induced by ISO. Furthermore, the ROS inhibitor (NAC) notably promoted the inhibited effect of ISO on the ERK1/2 kinase. NAC also suppressed the p-JNK and p-p38, but failed to reverse the effects of ISO. These results demonstrated for the first time that ISO induces apoptosis in HepG2 cells through inactivating ERK1/2 kinase and activating JNK and p38 kinases, and ROS stimulated by ISO is able to activate the MAPK singaling pathway as the upstream signaling molecules. Initiating event of the mitochondrial-mediated apoptosis induced by ISO is MAPK signals. 22987605 Polymer grafting to single-walled carbon nanotubes: effect of chain length on solubility, graft density and mechanical properties of macroscopic structures. Single-walled carbon nanotubes are grafted with polystyrene chains employing a graft-to protocol. Thermogravimetric analysis allows calculation of the grafted chain density and average interchain separation on the nanotube surface as a function of molecular weight. The separation scales with molecular weight as a power law with an exponent of ca. 0.588, showing the grafted chains to be in a swollen random walk conformation. This implies that chain packing is controlled by coil size in solution. In addition, the dispersed concentration of functionalized nanotubes scales with the size of the steric potential barrier that prevents aggregation of polymer functionalized nanotubes. It is also shown that the molecular weight of the grafted chains significantly affects the mechanical properties of nanotube films. 23610010 The Beneficial Effect of Total Glucosides of Paeony on Psoriatic Arthritis Links to Circulating Tregs and Th1 Cell Function. Total glycosides of peony (TGP) is a natural immuno-modulatory drug extracted from traditional Chinese herb peony. It has been approved by State Food and Drug Administration for the treatment of rheumatoid arthritis. However, data of TGP effect on psoriatic arthritis (PsA) is still scarce. In this study, 19 patients with PsA received 12-week treatment of TGP, and clinical efficacy in joint manifestations was evaluated by DAS28 at weeks 0, 4, 8 and 12. Peripheral percentages of Tregs, Th1, Th2 and NK cells were analyzed, and serum Th1-type cytokines (IL-12, IFN-γ and TNF-α), Th2-type cytokines (IL-4, IL-5 and IL-10) as well as pro-inflammatory factors (IL-2, IL-6 and IL-8) were concomitantly examined. Six patients (32%) exhibited ≥25% decrease of DAS28 (responders). Interestingly, all responders displayed a continuous decrease in Treg and Th1 numbers during TGP treatment, concomitant with significant decreases in Th1-type cytokine levels. Serum IL-6 also showed a significant decline in responders. Non-responders lacked these sequential alterations. Thus, TGP merits further consideration as a promising therapeutic option for PsA. The result indicated that recovery of Tregs and Th1 may serve as prognostic markers to assess responsiveness to TGP treatment in PsA. Copyright © 2013 John Wiley & Sons, Ltd. 23241082 A comparative study of the rotational dynamics of PF6(-) anions in the crystals and liquid states of 1-butyl-3-methylimidazolium hexafluorophosphate: results from 31P NMR spectroscopy. The rotational dynamics of the hexafluorophosphate anion (PF(6)(-)) in the crystalline and liquid states of the archetypal room temperature ionic liquid (RTIL) 1-butyl-3-methylimidazolium hexafluorophosphate ([C(4)mim]PF(6)) are investigated using (31)P NMR spectroscopy line shape analyses and spin-lattice relaxation time measurements. The PF(6)(-) anion performs isotropic rotation in all three polymorphic crystals phases α, β, and γ as well as in the liquid state with a characteristic time scale that ranges from a few ps to a few hundred ps over a temperature range of 180-280 K. The rotational correlation time τ(c) for PF(6)(-) rotation follows the sequence γ-phase < α-phase ≈ liquid < β-phase. On the other hand, in the liquid state, all local motions in the cation as well as its global rotational reorientation are characterized by time scales that are slower compared to that for the PF(6)(-) anion rotation. The time scale τ(c) and the activation energy of PF(6)(-) rotation in this RTIL are found to be comparable with those observed in ordinary alkali and ammonium salts despite the large counterion size and low melting point of the former. The high sphericity of the PF(6)(-) ion is hypothesized to play an important role in the decoupling of its rotational dynamics that appear to be practically independent of the averaged cation-anion interaction. 23142559 TNF-α-induced CXCL8 production by A549 cells: involvement of the non-neuronal cholinergic system. It was recently suggested that the non-neuronal cholinergic system has a regulatory role in pulmonary inflammation. We investigated this system's involvement in the control of cytokine production by the A549 human alveolar epithelial cell line. CXCL8 and acetylcholine (ACh) concentrations were measured using ELISA and LC-MS/MS, respectively. The mRNA expression of muscarinic receptor (MR) subtypes was determined using RT-PCR. In A549 cells, TNF-α increased the release of CXCL8 and ACh and the expression of the subtype 3 MR (M3R). Furthermore, TNF-α-induced CXCL8 secretion was (i) inhibited by the MR antagonist tiotropium and the M3R antagonist 4-DAMP and (ii) enhanced by the M1/M3R agonist pilocarpine and the cholinesterase inhibitor physostigmine. Taken as a whole, these results suggest that ACh release by A549 cells enhances TNF-α-induced CXCL8 secretion through activation of the M3R. Western blot analysis revealed that pilocarpine and physostigmine enhanced the TNF-α-induced phosphorylation of ERK1/2 and p38 MAPK and the degradation of IκBα. Inhibition of these pathways with specific inhibitors abrogated the pilocarpine-induced CXCL8 release. Our results suggest that the TNF-α-induced secretion of CXCL8 in A549 cells is regulated by the release of ACh, the latter's binding to the M3R and the downstream activation of NF-κB and the ERK1/2 and p38 MAPK signaling pathways. Our findings suggest that MR antagonists may have anti-inflammatory effects by preventing pro-inflammatory events driven by endogenous, non-neuronal ACh. 23434506 Coenzyme Q10 protects Pc12 cells from cisplatin-induced DNA damage and neurotoxicity. The purpose of this study was to investigate the neuroprotective effect of a water-soluble formulation of coenzyme Q10 (WS-CoQ10) in PC12 cells exposed to cisplatin, a chemotherapeutic agent with a dose-limiting factor due to neurotoxicity. In the cytokinesis-block micronucleus cytome assay (CBMN Cyt), WS-CoQ10 (at concentrations of 0.1, 0.5 and 1.0μgmL(-1)) protected PC12 cells from cisplatin-induced DNA damage (0.1μgmL(-1)), reducing the frequency of micronuclei (MNi) and nuclear buds (NBUDs). WS-CoQ10 did not alter the mRNA expression levels of Tp53 (at a concentration of 1.0μgmL(-1)) and exhibited neuroprotective activity by stimulating cisplatin-inhibited neurite outgrowth in nerve growth factor (NGF)-differentiated PC12 cells (at a concentration of 0.1μgmL(-1)). In conclusion, WS-CoQ10 protected the PC12 cells from cisplatin-induced DNA damage and neurotoxicity. Moreover, the neuroprotective effects of WS-CoQ10 suggest a possible application in chemotherapeutic protocols. 23258430 Detailed mechanism for the orthogonal polarization switching of gold nanorod plasmons. In this work, we describe an electro-optic material capable of orthogonally switching the polarization of the localized surface plasmon resonance scattering of single gold nanorods, independent of their orientation. Liquid crystal samples are prepared in a sandwich configuration with electrodes arranged so that an applied voltage induces alignment-switching of the liquid crystal molecules covering individual gold nanorods. Due to the birefringence of the nematic liquid crystal, the reorientation in the nematic director alignment causes a change in the output polarization of the scattered light. We propose the underlying mechanism to be based on a homogeneous nematic to twisted nematic phase transition and provide support for it via Jones calculus by modelling the effect of ideally aligned homogeneous nematic and twisted nematic phases on polarized light transmitted through the sample. In the model, we include the effects of sample thickness and surface plasmon resonance wavelength, expressed in terms of the phase retardation, χ, on the observed output polarization. We find four distinctively different trends for the output polarization as a function of the incident polarization as χ is varied. Two of these cases provide reproducible orthogonal polarization switching of the surface plasmon resonance while maintaining a high degree of polarization. These results are verified experimentally with liquid crystal cells of different thicknesses. The deviation of the experimental samples from ideal behaviour can be explained by the inherent variations in the surface plasmon resonance maximum and local cell thickness. 23361404 Microfluidic platforms for RNA interference screening of virus-host interactions. RNA interference (RNAi) is a powerful tool for functional genomics with the capacity to comprehensively analyze host-pathogen interactions. High-throughput RNAi screening is used to systematically perturb cellular pathways and discover therapeutic targets, but the method can be tedious and requires extensive capital equipment and expensive reagents. To aid in the development of an inexpensive miniaturized RNAi screening platform, we have developed a two part microfluidic system for patterning and screening gene targets on-chip to examine cellular pathways involved in virus entry and infection. First, a multilayer polydimethylsiloxane (PDMS)-based spotting device was used to array siRNA molecules into 96 microwells targeting markers of endocytosis, along with siRNA controls. By using a PDMS-based spotting device, we remove the need for a microarray printer necessary to perform previously described small scale (e.g. cellular microarrays) and microchip-based RNAi screening, while still minimizing reagent usage tenfold compared to conventional screening. Second, the siRNA spotted array was transferred to a reversibly sealed PDMS-based screening platform containing microchannels designed to enable efficient cell loading and transfection of mammalian cells while preventing cross-contamination between experimental conditions. Validation of the screening platform was examined using Vesicular stomatitis virus and emerging pathogen Rift Valley fever virus, which demonstrated virus entry pathways of clathrin-mediated endocytosis and caveolae-mediated endocytosis, respectively. The techniques here are adaptable to other well-characterized infection pathways with a potential for large scale screening in high containment biosafety laboratories. 23391280 Biotransformation pathways of biocides and pharmaceuticals in freshwater crustaceans based on structure elucidation of metabolites using high resolution mass spectrometry. So far, there is limited information on biotransformation mechanisms and products of polar contaminants in freshwater crustaceans. In the present study, metabolites of biocides and pharmaceuticals formed in Gammarus pulex and Daphnia magna were identified using liquid chromatography-high resolution mass spectrometry. Different confidence levels were assigned to the identification of metabolites without reference standards using a framework based on the background evidence used for structure elucidation. Twenty-five metabolites were tentatively identified for irgarol, terbutryn, tramadol, and venlafaxine in G. pulex (21 via oxidation and 4 via conjugation reactions) and 11 metabolites in D. magna (7 via oxidation and 4 via conjugation reactions), while no evidence of metabolites for clarithromycin and valsartan was found. Of the 360 metabolites predicted for the four parent compounds using pathway prediction systems and expert knowledge, 23 products were true positives, while 2 identified metabolites were unexpected products. Observed oxidative reactions included N- and O-demethylation, hydroxylation, and N-oxidation. Glutathione conjugation of selected biocides followed by subsequent reactions forming cysteine conjugates was described for the first time in freshwater invertebrates. 23477523 Thermorheological complexity and fragility in plasticized lignocellulose. It is demonstrated that plasticized lignocellulose fails to satisfy classic criteria normally required to validate time/temperature superposition (TTS) in dynamic mechanical analysis (DMA). However, insightful relaxation behavior is available and dismissing it would be a mistake. TTS was applied to Liriodendron tulipifera wood using parallel plate compressive-torsion DMA with specimens immersed in different organic liquids, ranging from weak to strong swelling power. While all storage moduli shifted smoothly, thermorheological complexity was detected in loss modulus shift failures, which themselves must reflect unknown structural features. Storage modulus shift factors clearly distinguished solvent specific relaxation behavior and interpretations through the WLF model or through fragility (cooperativity) analysis are useful. However, it is demonstrated that fragility analysis is preferred and solvents of different swelling power are compared. Coupled with other methods, TTS and fragility analysis warrant further development as a means to improve the understanding of structure/property relationships in plasticized lignocellulose. 23578649 Investigation on the role of Spirulina platensis in ameliorating behavioural changes, thyroid dysfunction and oxidative stress in offspring of pregnant rats exposed to fluoride. The study investigated the role of Spirulina platensis in reversing sodium fluoride-induced thyroid, neurodevelopment and oxidative alterations in offspring of pregnant rats. The total antioxidant activity, phycocyanins, and β carotene content were quantified in Spirulina. Thirty female pregnant rats were allocated to six groups and treatment initiated orally from embryonic day (ED) 6 to postnatal day (PND) 15. Treatment groups included control, Spirulina alone, sodium fluoride (20mg/kg) alone, and sodium fluoride along with Spirulina (250 and 500mg/kg). Serum fluoride levels were determined on ED 20 and PND 11. Offspring were subjected to behavioural testing, estimation of thyroid levels, oxidative measurements in brain mitochondrial fraction and histological evaluation of the cerebellum. Fluoride-induced alterations in thyroid hormones, behaviour and increased oxidative stress. Spirulina augmented the displacement of fluoride, facilitated antioxidant formation, improved behaviour and protected Purkinje cells. Supplementing Spirulina during pregnancy could reduce the risk of fluoride toxicity in offspring. 23542166 Structure-activity relationship of 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole analogues as 5-HT6 receptor agonists. To further investigate the structure-activity relationship (SAR) of the 5-hydroxytryptamine type 6 (5-HT6) receptor agonist 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (EMD386088, 6), a series of 2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles were synthesized, and in vitro affinity to, and functional activity at 5-HT6 receptors was tested. We focused on substituents made at the indole N(1)-, 2- and 5-positions and these were found to not only influence the affinity at 5-HT6 receptors but also the intrinsic activity leading to antagonists, partial agonists and full agonists. In order for a compound to demonstrate potent 5-HT6 receptor agonist properties, the indole N(1) should be unsubstituted, an alkyl group such as 2-methyl is needed and finally halogen substituents in the indole 5-position (fluoro, chloro or, bromo) were essential requirements. However, the introduction of a benzenesulfonyl group at N(1)-position switched the full agonist 6 to be a 5-HT6 receptor antagonist (30). A few compounds within the 2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles were also screened for off-targets and generally they displayed low affinity for other 5-HT subtypes and serotonin transporter protein (SERT). 23361264 Review of clinical trials for mitochondrial disorders: 1997-2012. Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q10 (CoQ10; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ10), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ10), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). The trial designs have varied from open-label/uncontrolled, open-label/controlled, or double-blind/placebo-controlled/crossover. Primary outcomes have ranged from single, clinically-relevant scores to multiple measures. Eight of these trials have been well-controlled, completed trials. Of these only 1 (treatment with creatine) showed a significant change in primary outcomes, but this was not reproduced in 2 subsequent trials with creatine with different patients. One trial (idebenone treatment of Leber hereditary optic neuropathy) did not show significant improvement in the primary outcome, but there was significant improvement in a subgroup of patients. Despite the paucity of benefits found so far, well-controlled clinical trials are essential building blocks in the continuing search for more effective treatment of mitochondrial disease, and current trials based on information gained from these prior experiences are in progress. Because of difficulties in recruiting sufficient mitochondrial disease patients and the relatively large expense of conducting such trials, advantageous strategies include crossover designs (where possible), multicenter collaboration, and the selection of very few, clinically relevant, primary outcomes. 23321074 Lessons on conditional gene targeting in mouse adipose tissue. Conditional gene targeting has been extensively used for in vivo analysis of gene function in adipocyte cell biology but often with debate over the tissue specificity and the efficacy of inactivation. To directly compare the specificity and efficacy of different Cre lines in mediating adipocyte specific recombination, transgenic Cre lines driven by the adipocyte protein 2 (aP2) and adiponectin (Adipoq) gene promoters, as well as a tamoxifen-inducible Cre driven by the aP2 gene promoter (iaP2), were bred to the Rosa26R (R26R) reporter. All three Cre lines demonstrated recombination in the brown and white fat pads. Using different floxed loci, the individual Cre lines displayed a range of efficacy to Cre-mediated recombination that ranged from no observable recombination to complete recombination within the fat. The Adipoq-Cre exhibited no observable recombination in any other tissues examined, whereas both aP2-Cre lines resulted in recombination in endothelial cells of the heart and nonendothelial, nonmyocyte cells in the skeletal muscle. In addition, the aP2-Cre line can lead to germline recombination of floxed alleles in ~2% of spermatozoa. Thus, different "adipocyte-specific" Cre lines display different degrees of efficiency and specificity, illustrating important differences that must be taken into account in their use for studying adipose biology. 23381936 Population pharmacokinetics of atorvastatin and its active metabolites in children and adolescents with heterozygous familial hypercholesterolemia: selective use of informative prior distributions from adults. The population pharmacokinetics (PPK) of atorvastatin and its principal active metabolite, o-hydroxyatorvastatin, were described in 6-17 years old pediatric hypercholesterolemia patients with a 2-compartment model for both parent and metabolite. Informative prior distributions on selected parameters, based on adult data, were required to stabilize the model and were implemented using a Bayesian penalty term on the likelihood function in the nonlinear mixed effects model (NONMEM VI with PRIOR). Concentrations below the limit of quantitation were treated as censored data using a conditional likelihood function. Atorvastatin apparent oral clearance (CL/F) was described as a function of body weight using an allometric equation. Based on the final model, the typical CL/F estimates for a Tanner Stage 1 patient (35 kg weight) and Tanner Stage ≥2 (50 kg weight), would be 553 and 543 L/hour, respectively. When scaled allometrically, CL/F was similar to values reported for adults. Variability in atorvastatin PK was primarily affected by weight. 23296027 A new scheme for significant enhancement of the second order nonlinear optical response from molecules to ordered aggregates. How to achieve maximum nonlinear optical (NLO) properties from the molecular to the macro block is very crucial to the development of nonlinear optical materials, which is the impetus of the present work. Buckybowls present large first hyperpolarizability ascribed to noncentrosymmetric charge distribution due to the curved shape of the system. The role of their packing pattern in maximizing the NLO response of buckybowl aggregates is investigated. In (corannulene)(10) and (sumanene)(10) aggregates, the first order hyperpolarizabilities (β(0)) per molecule are enhanced 5.59 and 6.21 times with respect to a single entity respectively. For a larger buckybowl, C(36)H(12), the β(0) value per molecule of its pentamer reaches 191.4 × 10(-30) esu which is much higher than conventional dipolar or octupolar NLO chromophores ones. The cohesive coupling among electric dipoles in packing of buckybowls is responsible for significant enhancement of the nonlinear optical response of the aggregates, which could pave the way for designing large 2nd order NLO materials with a good balance of nonlinearity, transparency, and stability. 22551778 MRI roadmap-guided transendocardial delivery of exon-skipping recombinant adeno-associated virus restores dystrophin expression in a canine model of Duchenne muscular dystrophy. Duchenne muscular dystrophy (DMD) cardiomyopathy patients currently have no therapeutic options. We evaluated catheter-based transendocardial delivery of a recombinant adeno-associated virus (rAAV) expressing a small nuclear U7 RNA (U7smOPT) complementary to specific cis-acting splicing signals. Eliminating specific exons restores the open reading frame resulting in translation of truncated dystrophin protein. To test this approach in a clinically relevant DMD model, golden retriever muscular dystrophy (GRMD) dogs received serotype 6 rAAV-U7smOPT via the intracoronary or transendocardial route. Transendocardial injections were administered with an injection-tipped catheter and fluoroscopic guidance using X-ray fused with magnetic resonance imaging (XFM) roadmaps. Three months after treatment, tissues were analyzed for DNA, RNA, dystrophin protein, and histology. Whereas intracoronary delivery did not result in effective transduction, transendocardial injections, XFM guidance, enabled 30±10 non-overlapping injections per animal. Vector DNA was detectable in all samples tested and ranged from <1 to >3000 vector genome copies per cell. RNA analysis, western blot analysis, and immunohistology demonstrated extensive expression of skipped RNA and dystrophin protein in the treated myocardium. Left ventricular function remained unchanged over a 3-month follow-up. These results demonstrated that effective transendocardial delivery of rAAV-U7smOPT was achieved using XFM. This approach restores an open reading frame for dystrophin in affected dogs and has potential clinical utility. 23395821 Molecular design of a highly selective and strong protein inhibitor against matrix metalloproteinase-2 (MMP-2). Synthetic inhibitors of matrix metalloproteinases (MMPs), designed previously, as well as tissue inhibitors of metalloproteinases (TIMPs) lack enzyme selectivity, which has been a major obstacle for developing inhibitors into safe and effective MMP-targeted drugs. Here we designed a fusion protein named APP-IP-TIMP-2, in which the ten amino acid residue sequence of APP-derived MMP-2 selective inhibitory peptide (APP-IP) is added to the N terminus of TIMP-2. The APP-IP and TIMP-2 regions of the fusion protein are designed to interact with the active site and the hemopexin-like domain of MMP-2, respectively. The reactive site of the TIMP-2 region, which has broad specificity against MMPs, is blocked by the APP-IP adduct. The recombinant APP-IP-TIMP-2 showed strong inhibitory activity toward MMP-2 (Ki(app) = 0.68 pm), whereas its inhibitory activity toward MMP-1, MMP-3, MMP-7, MMP-8, MMP-9, or MT1-MMP was six orders of magnitude or more weaker (IC50 > 1 μm). The fusion protein inhibited the activation of pro-MMP-2 in the concanavalin A-stimulated HT1080 cells, degradation of type IV collagen by the cells, and the migration of stimulated cells. Compared with the decapeptide APP-IP (t½ = 30 min), APP-IP-TIMP-2 (t½ ≫ 96 h) showed a much longer half-life in cultured tumor cells. Therefore, the fusion protein may be a useful tool to evaluate contributions of proteolytic activity of MMP-2 in various pathophysiological processes. It may also be developed as an effective anti-tumor drug with restricted side effects. 23345167 Characterisation of Nox4 inhibitors from edible plants. NADPH oxidases transport electrons from cytosolic NADPH through biological membranes to generate reactive oxygen species. NADPH oxidase 4, broadly expressed in humans, is an interesting pharmacological target, since its activity is deregulated in several diseases, including pulmonary fibrosis, diabetic nephropathy, and cardiac hypertrophy. Whereas several candidate NADPH oxidase 4 inhibitors were recently described, most of these compounds are either unspecific or toxic. Here we set out to identify new NADPH oxidase 4 inhibitors from edible plants, in an attempt to decrease the number of hits with toxic side effects. We screened a compound library prepared from edible plants for new bioactives with the ability to inhibit the activity of NADPH oxidase 4. Using both cell-based and cell-free assays, we identified several compounds with significant inhibitory activity towards NADPH oxidase 4. For selected compounds, the activity profile towards NADPH oxidase 2 and NADPH oxidase 5 was established, and controls were carried out to exclude general reactive oxygen species scavengers. A number of promising NADPH oxidase 4 inhibitors from edible plants was identified and characterised. Several new chemical entities are disclosed which act as NADPH oxidase 4 inhibitors, and the efficacies of our best hits, in particular several diarylheptanoids and lignans, are comparable to the best available pharmacological NADPH oxidase 4 inhibitors. These findings will provide valuable tools to study mechanisms of NADPH oxidase inhibition. 23224861 Membrane protein native state discrimination by implicit membrane models. Four implicit membrane models [IMM1, generalized Born (GB)-surface area-implicit membrane (GBSAIM), GB with a simple switching (GBSW), and heterogeneous dielectric GB (HDGB)] were tested for their ability to discriminate the native conformation of five membrane proteins from 450 decoys generated by the Rosetta-Membrane program. The energy ranking of the native state and Z-scores were used to assess the performance of the models. The effect of membrane thickness was examined and was found to be substantial. Quite satisfactory discrimination was achieved with the all-atom IMM1 and GBSW models at 25.4 Å thickness and with the HDGB model at 28.5 Å thickness. The energy components by themselves were not discriminative. Both van der Waals and electrostatic interactions contributed to native state discrimination, to a different extent in each model. Computational efficiency of the models decreased in the order: extended-atom IMM1 > all-atom IMM1 > GBSAIM > GBSW > HDGB. These results encourage the further development and use of implicit membrane models for membrane protein structure prediction. 23509956 Surface Thermodynamic and Adhesion Force Evaluation of the Role of Chitin-Binding Protein in the Physical Interaction between Pseudomonas aeruginosa and Candida albicans. Candida albicans and Pseudomonas aeruginosa are able to form pathogenic polymicrobial communities. P. aeruginosa colonizes and kills hyphae but is unable to attach to yeast. It is unknown why the interaction of P. aeruginosa is different with yeast than with hyphae. Here we aim to evaluate the role of P. aeruginosa chitin-binding protein (CbpD) in its physical interaction with C. albicans hyphae or yeast, based on surface thermodynamic and atomic force microscopic analyses. A P. aeruginosa mutant lacking CbpD was unable to express strong adhesion forces with hyphae (-2.9 nN) as compared with the parent strain P. aeruginosa PAO1 (-4.8 nN) and showed less adhesion to hyphae. Also blocking of CbpD using N-acetyl-glucosamine yielded a lower adhesion force (-4.3 nN) with hyphae. Strong adhesion forces were restored after complementing the expression of CbpD in P. aeruginosa PAO1 ΔcbpD yielding an adhesion force of -5.1 nN. These observations were confirmed with microscopic evaluation of adhesion tests. Regardless of the absence or presence of CbpD on the bacterial cell surfaces, or their blocking, P. aeruginosa experienced favorable thermodynamic conditions for adhesion with hyphae, which were absent with yeast. In addition, adhesion forces with yeast were less than 0.5 nN in all cases. Concluding, CbpD in P. aeruginosa is responsible for strong physical interactions with C. albicans hyphae. The development of this interaction requires time due to the fact that CbpDs have to invade the outermost mannoprotein layer on the hyphal cell surfaces. In order to do this, thermodynamic conditions at the outermost cell surfaces have to be favorable. 23540906 Emergence of Glass-like Behavior in Markov State Models of Protein Folding Dynamics. The extent to which glass-like kinetics govern dynamics in protein folding has been heavily debated. Here, we address the subject with an application of space-time perturbation theory to the dynamics of protein folding Markov state models. Borrowing techniques from the s-ensemble method, we argue that distinct active and inactive phases exist for protein folding dynamics, and that kinetics for specific systems can fall into either dynamical regime. We do not, however, observe a true glass transition in any system studied. We go on to discuss how these inactive and active phases might relate to general protein folding properties. 23064722 Regulation of adenosine levels during cerebral ischemia. Adenosine is a neuromodulator with its level increasing up to 100-fold during ischemic events, and attenuates the excitotoxic neuronal injury. Adenosine is produced both intracellularly and extracellularly, and nucleoside transport proteins transfer adenosine across plasma membranes. Adenosine levels and receptor-mediated effects of adenosine are regulated by intracellular ATP consumption, cellular release of ATP, metabolism of extracellular ATP (and other adenine nucleotides), adenosine influx, adenosine efflux and adenosine metabolism. Recent studies have used genetically modified mice to investigate the relative contributions of intra- and extracellular pathways for adenosine formation. The importance of cortical or hippocampal neurons as a source or a sink of adenosine under basal and hypoxic/ischemic conditions was addressed through the use of transgenic mice expressing human equilibrative nucleoside transporter 1 (hENT1) under the control of a promoter for neuron-specific enolase. From these studies, we conclude that ATP consumption within neurons is the primary source of adenosine in neuronal cultures, but not in hippocampal slices or in vivo mice exposed to ischemic conditions. 23574272 Screening and Structural Analysis of Flavones Inhibiting Tankyrases. Flavonoids are known for their beneficial effects on human health, and therefore the therapeutic potential of these compounds have been extensively studied. Flavone has been previously identified as a tankyrase inhibitor, and to further elucidate whether tankyrases would be inhibited by other flavonoids, we performed a systematic screening of tankyrase 2 inhibitory activity using 500 natural and naturally derived flavonoids covering nine different flavonoid classes. All identified tankyrase inhibitors were flavones. We report crystal structures of all the hit compounds in complex with the catalytic domain of human tankyrase 2. Flavone derivatives in all 10 crystal structures bind to the nicotinamide binding site of tankyrase 2. Potencies of the active flavones toward tankyrases vary between 50 nM and 1.1 μM, and flavones show up to 200-fold selectivity for tankyrases over ARTD1. The molecular details of the interactions revealed by cocrystal structures efficiently describe the properties of potent flavone derivatives inhibiting tankyrases. 23512495 Is Artemisinin the Only Antiplasmodial Compound in the Artemisia annua Tea Infusion? An in Vitro Study. In our ongoing investigation into Artemisia annua for the treatment of malaria, we decided to study the possibility that synergism might enhance the efficacy of artemisinin. Our main objective was to test tea infusions and nonpolar extracts prepared from different A. annua varieties against Plasmodium falciparum in vitro in order to determine if synergism will increase the effectiveness of artemisinin in the samples as compared to pure artemisinin. We found that the IC50 of artemisinin in the tea and nonpolar extracts was not significantly different to the IC50 of pure artemisinin. We could show that the year and country of harvest or storage conditions did not have any influence on the activity and that it narrowly followed the concentration of artemisinin in all the extracts. In conclusion, based on these in vitro results, artemisinin seems to be the only active antiplasmodial compound in A. annua. 23402735 Anti-atherosclerotic mechanisms of statin therapy. HMG-CoA-Reductase inhibitors, also known as statins, are currently the most powerful cholesterol-lowering drugs available on the market. Clinical trials and experimental evidence suggest that statins have anti-atherosclerotic effects. These are in part consequence of lipid lowering but also result from pleiotropic actions of the drugs. In this article, the anti-atherosclerotic actions of statins will be reviewed. 22989504 Gut microbiota, immune development and function. The microbiota of Westerners is significantly reduced in comparison to rural individuals living a similar lifestyle to our Paleolithic forefathers but also to that of other free-living primates such as the chimpanzee. The great majority of ingredients in the industrially produced foods consumed in the West are absorbed in the upper part of small intestine and thus of limited benefit to the microbiota. Lack of proper nutrition for microbiota is a major factor under-pinning dysfunctional microbiota, dysbiosis, chronically elevated inflammation, and the production and leakage of endotoxins through the various tissue barriers. Furthermore, the over-comsumption of insulinogenic foods and proteotoxins, such as advanced glycation and lipoxidation molecules, gluten and zein, and a reduced intake of fruit and vegetables, are key factors behind the commonly observed elevated inflammation and the endemic of obesity and chronic diseases, factors which are also likely to be detrimental to microbiota. As a consequence of this lifestyle and the associated eating habits, most barriers, including the gut, the airways, the skin, the oral cavity, the vagina, the placenta, the blood-brain barrier, etc., are increasingly permeable. Attempts to recondition these barriers through the use of so called 'probiotics', normally applied to the gut, are rarely successful, and sometimes fail, as they are usually applied as adjunctive treatments, e.g. in parallel with heavy pharmaceutical treatment, not rarely consisting in antibiotics and chemotherapy. It is increasingly observed that the majority of pharmaceutical drugs, even those believed to have minimal adverse effects, such as proton pump inhibitors and anti-hypertensives, in fact adversely affect immune development and functions and are most likely also deleterious to microbiota. Equally, it appears that probiotic treatment is not compatible with pharmacological treatments. Eco-biological treatments, with plant-derived substances, or phytochemicals, e.g. curcumin and resveratrol, and pre-, pro- and syn-biotics offers similar effects as use of biologicals, although milder but also free from adverse effects. Such treatments should be tried as alternative therapies; mainly, to begin with, for disease prevention but also in early cases of chronic diseases. Pharmaceutical treatment has, thus far, failed to inhibit the tsunami of endemic diseases spreading around the world, and no new tools are in sight. Dramatic alterations, in direction of a paleolithic-like lifestyle and food habits, seem to be the only alternatives with the potential to control the present escalating crisis. The present review focuses on human studies, especially those of clinical relevance. 23219869 N-POMC1-28 increases cyclin D expression and inhibits P27(kip1) in the adrenal cortex. The Adrenocorticotropic hormone (ACTH) and Pro-opimelanocortin (POMC) 1-28N-terminal peptide (N-POMC1-28) have been shown to act as an adrenal mitogen in vivo. A possible role for cyclin E in the zona glomerulosa (ZG) proliferation, following ACTH and/or N-POMC1-28 administration, has been previously demonstrated. In this study, we investigated the effect of ACTH and N-POMC1-28 on the expression of adrenal cortex proteins related to cell cycle control such as cyclins D and P27(kip1). The administration of N-POMC upregulated cyclin D1 and D2 expression in the outer zone of the adrenal cortex; cyclin D3 expression was upregulated in the cortex inner zone even after administration of ACTH. Both ACTH and N-POMC peptides induced a decrease in the P27(kip1) expression in the ZG. These novel findings suggest that the POMC-derivate peptides, ACTH and N-POMC, promote proliferation in the adrenal cortex by upregulating the D2 and D3 cyclins and downregulating the P27(kip1) expression. 23528298 Molecular design, synthesis and biological evaluation of cyclic imides bearing benzenesulfonamide fragment as potential COX-2 inhibitors. Part 2. A group of cyclic imides (1-10) was designed for evaluation as a selective COX-2 inhibitors and investigated in vivo for their anti-inflammatory activity. Compounds 6a, 6b, 8a, 8b, 9a, 9b, 10a and 10b were proved to be potent COX-2 inhibitors with IC50 range of 0.1-4.0μM. In vitro COX-1/COX-2 inhibition structure-activity studies identified compound 8a as a highly potent (IC50=0.1μM), and an extremely selective [COX-2 (SI)>1000] comparable to celecoxib [COX-2 (SI)>384], COX-2 inhibitor that showed superior anti-inflammatory activity (ED50=72.4mg/kg) relative to diclofenac (ED50=114mg/kg). Molecular modeling was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. The study showed that the homosulfonamide fragment of 8a inserted deep inside the 2°-pocket of the COX-2 active site, where the SO2NH2 group underwent H-bonding interaction with Gln(192)(2.95Å), Phe(518)(2.82Å) and Arg(513)(2.63 and 2.73Å). Docking study of the synthesized compound 8a into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor. 23611733 New trifluoromethyl quinolone derivatives: Synthesis and investigation of antimicrobial properties. A series of quinolone derivatives, containing different heterocyclic amines were prepared. Synthesized compounds were evaluated for their in vitro antimicrobial activities against two Gram-positive bacteria, three Gram-negative bacteria as well as four fungi. All the derivatives showed good activity towards Gram-positive bacteria and less activity towards Gram-negative bacteria. They also showed moderate to comparable activity against Aspergillus niger and Candida albicans and low to moderate antifungal activity against Aspergillus fumigatus and Aspergillus flavus. 23235690 Effect of multilayer structure on cyclic performance of Si/Fe anode electrode in lithium-ion secondary batteries. A buffer-strengthened Si/Fe multilayer film, consisting of amorphous silicon layers and polycrystalline Fe layers, is investigated as the anode for Li-ion batteries. This film can achieve a stable cycle-life performance with a high capacity. Decreasing the thickness of the Fe layer can lead to a higher capacity, which is related to the fast transport of the Li ion, but the cyclic performance deteriorates with repeated cycling. In contrast, increasing the thickness of the Fe buffer layers and the number of deposit stacks improves the cycle life with high reversibility. Because of the strain in the Si layers suppressed by the primary multilayer structure, the long-term strength is preserved and the substantial fracture toughness is enhanced by the increasing numbers of effective grain boundaries and interfacial layers. In addition, we demonstrate that the Ti underlayer promotes the electrochemical properties in the Si/Fe multilayer for various Fe layer thicknesses because of the enhanced adhesion of the interfacial electrode and current collector. The mechanically optimized Si/Fe multilayer films can have superior cycle-life performances and higher capacities. Notably, the 16-bilayer deposited electrode exhibits an excellent capacity retention of ~95% with ~204 mAh g(-1) over 300 cycles at a 1 C rate. 23265454 Inhibition effects and induction of apoptosis of flavonoids on the prostate cancer cell line PC-3 in vitro. Myricetin and myricitrin are naturally occurring flavonoids have been suggested to play a role in inhibition of proliferation and transformation of carcinogenic cell. However, the underlying molecular mechanisms of their activity have not yet to be revealed. The aim of the present study was to clarify the molecular mechanisms of apoptosis cell on the prostate cancer induced by myricetin, myricitrin, quercetin and quercitrin. The MTT assay confirmed that myricetin had the strongest inhibitory effect on human prostate cancer cell line PC-3, myricitrin was second, and quercitrin was the weakest. A noticeable synergistic effect was observed with the inhibition of cell proliferation when myricetin was used in combination with myricitrin. In the concentration range of 37.5-300 μmol/L, the inhibitory effects of these flavonoids were enhanced with increasing dose and treatment time. The acridine orange analysis and annexin V-FITC/PI double-staining results confirmed that myricetin and myricitrin were effective in inducing PC-3 cell apoptosis. The results showed that myricetin was more effective than myricitrin in inducing cell apoptosis. The apoptosis rate increased with increasing flavonoid concentration in a dose dependent manner. A synergistic effect was observed on the apoptosis rate when myricetin was used in combination with myricitrin. 23434831 Asperolide A, a marine-derived tetranorditerpenoid, induces G2/M arrest in human NCI-H460 lung carcinoma cells, is mediated by p53-p21 stabilization and modulated by Ras/Raf/MEK/ERK signaling pathway. Here we first demonstrate that asperolide A, a very recently reported marine-derived tetranorditerpenoid, leads to the inhibition of NCI-H460 lung carcinoma cell proliferation by G2/M arrest with the activation of the Ras/Raf/MEK/ERK signaling and p53-dependent p21 pathway. Treatment with 35 μM asperolide A (2 × IC(50)) resulted in a significant increase in the proportion of G2/M phase cells, about a 2.9-fold increase during 48 h. Immunoblot assays demonstrated time-dependent inhibition of G2/M regulatory proteins. Moreover, asperolide A significantly activated MAP kinases (ERK1/2, JNK and p38 MAP kinase) by phosphorylation, and only the inhibition of ERK activation by PD98059 reversed downregulation of G2/M regulatory proteins CDC2, and suppressed upregulation of p21 and p-p53 levels. Transfection of cells with dominant-negative Ras (RasN17) mutant genes up-regulated asperolide A-induced the decrease of cyclin B1 and CDC2, suppressed Raf, ERK activity and p53-p21 expression, and at last, abolished G2/M arrest. This study indicates that asperolide A-induced G2/M arrest in human NCI-H460 lung carcinoma cells relys on the participation of the Ras/Raf/MEK/ERK signaling pathway in p53-p21 stabilization. An in vivo study with asperolide A illustrated a marked inhibition of tumor growth, and little toxcity compared to Cisplatin therapy. Overall, these findings provide potential effectiveness and a theoretical basis for the therapeutic use of asperolide A in the treatment of malignancies. 23353747 Cytotoxicity of lapachol, β-lapachone and related synthetic 1,4-naphthoquinones against oesophageal cancer cells. Naphthoquinones have been found to have a wide range of biological activities, including cytotoxicity to cancer cells. The secondary metabolites lapachol, α- and β-lapachone and a series of 25 related synthetic 1,4-naphthoquinones were screened against the oesophageal cancer cell line (WHCO1). Most of the compounds exhibited enhanced cytotoxicity (IC50 1.6-11.7 μM) compared to the current drug of choice cisplatin (IC50 = 16.5 μM). This study also established that the two new synthetic halogenated compounds 12a and 16a (IC50 = 3.0 and 7.3 μM) and the previously reported compound 11a (IC50 = 3.9 μM), were non-toxic to NIH3T3 normal fibroblast cells. Cell death of oesophageal cancer cells by processes involving PARP cleavage caused by 11a was shown to be associated with elevated c-Jun levels, suggesting a role for this pathway in the mechanism of action of this cohort of naphthoquinone compounds. 23625731 Psychologic Disorders and Statin Use: A Propensity Score-Matched Analysis. STUDY OBJECTIVE: To evaluate the association between statin therapy and the risk of psychologic disorders including schizophrenia, psychosis, major depression, and bipolar disorder in a military population. DESIGN: Retrospective, observational, population-based, propensity score-matched, cohort study. SETTING: Database of a patient population enrolled in the San Antonio Military Multi-Market Area as Tricare Prime or Plus. PATIENTS: Medical records were reviewed from 46,249 patients aged 30-85 years who were continuously enrolled in the San Antonio Military Multi-Market Area as Tricare Prime or Plus from October 1, 2003-March 1, 2010. Data were obtained from the Military Health System Management Analysis and Reporting Tool (M2). Based on drug fills during fiscal year 2005, patients were stratified as statin users (13,626 patients received at least 90-days supply of statin) or nonusers (32,623 patients never received a statin during the study period). A propensity score-matched cohort of 6972 statin users and 6972 nonusers from this population was created. MEASUREMENTS AND MAIN RESULTS: The occurrence of psychologic disorders between October 1, 2005, and March 1, 2010, was determined using prespecified groups of ICD-9-CM, Psych1: schizophrenia, schizoaffective disorders, and other psychosis; Psych2: major depression and bipolar disorder; Psych3: all psychologic disorders as identified by the Agency for Health Research and Quality-Clinical Classifications (except for categories of childhood or developmental psychiatric disorders). Between matched pairs of statin users and nonusers, the odds ratios and 95% confidence intervals were as follows: Psych1 (0.9, 0.75-1.05), Psych2 (1.02, 0.94-1.11), and Psych3 (1.02, 0.96-1.1), respectively. CONCLUSION: The risk of developing psychologic disorders was similar in this cohort of propensity score-matched statin users and nonusers. 23642287 The Pyrimidyn compounds: dual-action small molecule pyrimidine-based dynamin inhibitors. Dynamin is required for clathrin-mediated endocytosis (CME). Its GTPase activity stimulated by phospholipid binding to its PH domain which induces helical oligomerization. We have designed a series of novel pyrimidine-based 'PyrimidynTM' compounds which inhibit the lipid stimulated GTPase activity of full length dynamin I and II with similar potency. The most potent analogue, Pyrimidyn 7, has an IC50 of 1.1 μM for dynamin I and 1.8 μM for dynamin II, making it among the most potent dynamin inhibitors identified to date. We investigated the mechanism of action of the Pyrimidyn compounds in detail by examining the kinetics of Pyrimidyn 7 inhibition of dynamin. The compound competitively inhibits both GTP and phospholipid interactions with dynamin I. While both mechanisms of action have been previously observed separately, this is the first inhibitor series to incorporate both and thereby targets two distinct domains of dynamin. Pyrimidyn 6 and 7 reversibly inhibit CME of both transferrin and EGF in a number of non-neuronal cell lines as well as inhibiting synaptic vesicle endocytosis (SVE) in nerve terminals. Therefore, Pyrimidyn compounds block endocytosis by directly competing with GTP and lipid binding to dynamin, limiting both the recruitment of dynamin to membranes and its activation. This dual mode of action provides an important new tool for molecular dissection of dynamin's role in endocytosis. 23427194 Comparison of the anti-dopamine D2 and anti-serotonin 5-HT2A activities of chlorpromazine, bromperidol, haloperidol and second-generation antipsychotics parent compounds and metabolites thereof. Second-generation antipsychotics, which have become the standard drug therapies for schizophrenia, are known to have a serotonin 5-HT2A receptor blocking effect in addition to a dopamine D2 receptor blocking effect. However, although chlorpromazine (CPZ) has a 5-HT2A receptor blocking effect and has the profile of a second-generation antipsychotic in vitro, it loses this pharmacological profile in vivo. In order to elucidate the differences between the in vivo and in vitro pharmacological characteristics of CPZ, we used a radioreceptor assay to measure the anti-D2 activity and the anti-5-HT2A activity of CPZ and five major metabolites of CPZ, and compared the results to the anti-D2 activity and anti-5-HT2A activity of risperidone, zotepine, perospirone, the major metabolites of each of these drugs, and olanzapine, bromperidol, and haloperidol. The subjects were 182 patients who had received diagnoses of schizophrenia based on the DSM-IV criteria. The results revealed that CPZ exhibited little anti-5-HT2A activity, regardless of the anti-D2 activity level, and that none of the metabolites possessed anti-5-HT2A activity. However, both the parent compounds and the metabolites of each of the second-generation antipsychotics possessed both anti-D2 activity and anti-5-HT2A activity. This clarified that, unlike second-generation antipsychotics, the reason CPZ loses its second-generation antipsychotic profiles in vivo is because it does not have any metabolites that possess anti-5-HT2A activity. 22796110 Leveraging the cortical cholinergic system to enhance attention. Attentional impairments are found in a range of neurodegenerative and neuropsychiatric disorders. However, the development of procognitive enhancers to alleviate these impairments has been hindered by a lack of comprehensive hypotheses regarding the circuitry mediating the targeted attentional functions. Here we discuss the role of the cortical cholinergic system in mediating cue detection and attentional control and propose two target mechanisms for cognition enhancers: stimulation of prefrontal α4β2* nicotinic acetylcholine receptors (nAChR) for the enhancement of cue detection and augmentation of tonic acetylcholine levels for the enhancement of attentional control. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23357361 β-Asarone induces senescence in colorectal cancer cells by inducing lamin B1 expression. Colorectal cancer is a leading cause of cancer mortality with a complex carcinogenesis that includes reduced cellular senescence. Lamin proteins are decreased in senescing cells, and frequently decreased in malignancies. This study identified a new drug candidate for colorectal cancer that appears to target cell senescence via a lamin protein. β-Asarone (1-propenyl-2,4,5-methoxybenzol) is a compound from the traditional medical herb Acorus calamus Linn. This study tested the in vitro and in vivo effects of β-asarone on colorectal cancer cells by testing cell viability using human colorectal cell lines HT29 and SW480 in MTT assays; tumorigenesis using xenografts in nude mice and a mouse model of colorectal cancer; cell senescence using senescence-associated β-galactosidase activity; and expression of cancer and senescence-related proteins, specifically lamins, Oct-1, p53, p21, and p15, by Western blot. β-Asarone appeared to increase expression of lamin B1, p53, p21, but not lamin A/C. β-Asarone regulates p15 expression by regulation of Oct-1 binding. Collectively, the results suggested that β-asarone inhibits colon cancer formation in vivo and in vitro by inducing senescence. Since β-asarone induced lamin B1 expression, a model is proposed in which β-asarone inhibits colorectal cancer by inducing senescence through lamin B1. 23456363 Hypoxia-inducible factor and vascular endothelial growth factor are targets of dietary soy during acute stroke in female rats. Dietary soy and soy isoflavones are neuroprotective in experimental cerebral ischemia. Because these isoflavones have estrogenic properties, we hypothesized that, like estrogens, they would inhibit acute vascular injury and the detrimental acute increase in hypoxia-induced vascular endothelial growth factor (VEGF) that leads to cerebral edema after stroke. Mature ovariectomized female Sprague Dawley rats were fed soy-free or soy-containing diets for 4 weeks followed by 90 minutes of transient middle cerebral artery occlusion. Similar to estrogens, dietary soy significantly reduced cerebral edema and vascular apoptosis 24 hours after stroke. Soy also inhibited the ischemia-induced increase in cortical VEGF and VEGF receptor (VEGFR)-2 protein expression observed 4 and 24 hours after stroke, although mRNA levels increased. The reduction in VEGF/VEGFR-2 was associated both with decreases in receptor phosphorylation and signaling to AKT and endothelial nitric oxide synthase. Furthermore degradation of the VEGFR-2 was increased with dietary soy. The primary ischemic stimulus for VEGF, hypoxia-inducible factor 1α (HIF1α), was similarly reduced by dietary soy 4 hours after transient middle cerebral artery occlusion in both the cortex and striatum. The inhibition of HIF1α activity was further confirmed by a significant decrease in the HIF1α-activated apoptotic mediator BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (Nip3-like protein X). These data suggest that soy isoflavones target events early in the ischemic cascade as part of their neuroprotective actions and counterbalance some of the detrimental effects of the endogenous response to cerebral injury. 23606657 Facile Preparation of Ordered Porous Graphene-Metal Oxide@C Binder-Free Electrodes with High Li Storage Performance. A facile and general method is reported to prepare ordered porous graphene-based binder-free electrodes on a large scale. This preparation process allows the easy adjustment of the selected components, weight ratio of componets, and the thickness of the electrodes. Such ordered porous electrodes demonstrate superior Li storage properties; for example, graphene-Fe3 O4 @C depicts high capacities of 1123.8 and 505 mAh g(-1) at current densities of 0.5 and 10 A g(-1) , respectively. 23353901 Support for 5-HT2C receptor functional selectivity in vivo utilizing structurally diverse, selective 5-HT2C receptor ligands and the 2,5-dimethoxy-4-iodoamphetamine elicited head-twitch response model. There are seemingly conflicting data in the literature regarding the role of serotonin (5-HT) 5-HT2C receptors in the mouse head-twitch response (HTR) elicited by the hallucinogenic 5-HT2A/2B/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Namely, both 5-HT2C receptor agonists and antagonists, regarding 5-HT2C receptor-mediated Gq-phospholipase C (PLC) signaling, reportedly attenuate the HTR response. The present experiments tested the hypothesis that both classes of 5-HT2C receptor compounds could attenuate the DOI-elicited-HTR in a single strain of mice, C57Bl/6J. The expected results were considered in accordance with ligand functional selectivity. Commercially-available 5-HT2C agonists (CP 809101, Ro 60-0175, WAY 161503, mCPP, and 1-methylpsilocin), novel 4-phenyl-2-N,N-dimethyl-aminotetralin (PAT)-type 5-HT2C agonists (with 5-HT2A/2B antagonist activity), and antagonists selective for 5-HT2A (M100907), 5-HT2C (SB-242084), and 5-HT2B/2C (SB-206553) receptors attenuated the DOI-elicited-HTR. In contrast, there were differential effects on locomotion across classes of compounds. The 5-HT2C agonists and M100907 decreased locomotion, SB-242084 increased locomotion, SB-206553 resulted in dose-dependent biphasic effects on locomotion, and the PATs did not alter locomotion. In vitro molecular pharmacology studies showed that 5-HT2C agonists potent for attenuating the DOI-elicited-HTR also reduced the efficacy of DOI to activate mouse 5-HT2C receptor-mediated PLC signaling in HEK cells. Although there were differences in affinities of a few compounds at mouse compared to human 5-HT2A or 5-HT2C receptors, all compounds tested retained their selectivity for either receptor, regardless of receptor species. Results indicate that 5-HT2C receptor agonists and antagonists attenuate the DOI-elicited-HTR in C57Bl/6J mice, and suggest that structurally diverse 5-HT2C ligands result in different 5-HT2C receptor signaling outcomes compared to DOI. 23569204 Structural and functional characterization of a phosphatase domain within yeast general transcription factor TFIIIC. Saccharomyces cerevisiae τ55, a subunit of the RNA polymerase III-specific general transcription factor TFIIIC, comprises an N-terminal histidine phosphatase domain (τ55-HPD) whose catalytic activity and cellular function is poorly understood. We solved the crystal structures of τ55-HPD and its closely related paralogue Huf and used in silico docking methods to identify phospho-serine and phospho-tyrosine containing peptides as possible substrates that were subsequently validated using in vitro phosphatase assays. A comparative phospho-proteomic study identified additional phosphopeptides as possible targets, which show the involvement of these two phosphatases in the regulation of a variety of cellular functions. Our results identify τ55-HPD and Huf as bona fide protein phosphatases, characterize their substrate specificities and provide a small set of regulated phosphosite targets in vivo. 23305709 Pharmacokinetics, metabolism, and excretion of the glycogen synthase kinase-3 inhibitor LY2090314 in rats, dogs, and humans: a case study in rapid clearance by extensive metabolism with low circulating metabolite exposure. LY2090314 (3-[9-fluoro-2-(piperidin-1-ylcarbonyl)-1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl]-4-imidazo[1,2-a]pyridin-3-yl-1H-pyrrole-2,5-dione) is an intravenous glycogen synthase kinase-3 inhibitor in oncology trials. Drug disposition was characterized after intravenous infusion of [(14)C]LY2090314 to rats and dogs, and was related to available clinical data. LY2090314 exhibited high clearance (approximating hepatic blood flow) and a moderate volume of distribution (∼1-2 l/kg) resulting in rapid elimination (half-life ∼0.4, 0.7, and 1.8-3.4 hours in rats, dogs, and humans, respectively). Scaled clearance from liver microsomes accurately predicted perfusion-limited clearance across species. LY2090314 was cleared by extensive metabolism, and the numerous metabolites were rapidly excreted into feces via bile (69-97% of dose; 62-93% within 0-24 hours); urinary recovery of drug-related material was low (≤3% of dose). Despite extensive metabolism, in rats and humans the parent compound was the sole identifiable drug-related moiety in plasma. Even in Mdr1a-, Bcrp-, and Mrp2-knockout rats, LY2090314 metabolites did not appear in circulation, and their urinary excretion was not enhanced, because the hypothesized impaired biliary excretion of metabolites in the absence of these canalicular transporters was not observed. Canine metabolite disposition was generally similar, with the notable exception of dog-unique LY2090314 glucuronide. This conjugate was formed in the dog liver and was preferentially excreted into the blood, where it accounted for the majority of circulating radioactivity at later times, and was predominantly recovered in urine (16% of dose). In conclusion, LY2090314 was rapidly cleared by extensive metabolism with negligible circulating metabolite exposures due to biliary excretion of metabolites into feces with no apparent intestinal reabsorption. 23108727 Room-temperature electron spin amplifier based on Ga(In)NAs alloys. The first experimental demonstration of a spin amplifier at room temperature is presented. An efficient, defect-enabled spin amplifier based on a non-magnetic semiconductor, Ga(In)NAs, is proposed and demonstrated, with a large spin gain (up to 2700% at zero field) for conduction electrons and a high cut-off frequency of up to 1 GHz. 23453071 Synthesis and evaluation of nicotinamide derivative as anti-angiogenic agents. Previously, we have found that BRN-103, a nicotinamide derivative, inhibits vascular endothelial growth factor (VEGF)-mediated angiogenesis signaling in human endothelial cells. During our continuous efforts to identify more potent anti-angiogenic agents, we synthesized various nicotinamide derivatives and evaluated their anti-angiogenic effects. We found that 2-{1-[1-(6-chloro-5-fluoropyrimidin-4-yl)ethyl]piperidin-4-ylamino}-N-(3-chlorophenyl) pyridine-3-carboxamide (BRN-250) significantly inhibited human umbilical vascular endothelial cells (HUVECs) proliferation, migration, tube formation, and microvessel growth in a concentration range of 10-100 nM. Furthermore, BRN-250 inhibited the VEGF-induced phosphorylation and intracellular tyrosine kinase activity of VEGF receptor 2 (VEGFR2) and the activation of its downstream AKT pathway. Taken together, these findings suggest that BRN-250 be considered a potential lead compound for cancer therapy. 23435354 Pro-inflammatory and pathogenic properties of Annexin-A1: The whole is greater than the sum of its parts. According to Aristotle, "The whole is greater than the sum of its parts" and yet, although a long time has passed still, we seem to struggle to accept this universal concept. Searching in the literature for the biological function of Annexin-A1, one would find a wealth of information on its homeostatic and protective anti-inflammatory effects. However, very little has been said on its emerging role in a wide variety of pathological conditions ranging from cancer to autoimmunity. In this commentary, we will focus our attention on this novel pro-inflammatory and pathogenic "dark side" of Annexin-A1. We will summarize our current understanding of the signaling pathways regulated by this protein and link it to clinical and experimental evidences. Finally we will discuss assets and limitations of Annexin-A1 therapeutic strategies. Most importantly, we hope that this commentary will provide scientific support to "controversial" findings one might encounter while studying this fascinating protein. 23543631 Progress in the studies on tryptanthrin, an alkaloid of history. Tryptanthrin, an indoloquinazoline alkaloid, was first obtained by sublimation of natural indigo and later isolated from the culture of fungus Candida lipolytica and a variety of other natural sources. Tryptanthrin showed a variety of intriguing biological properties such as antibacterial, antifungal, antiprotozoal, and antiparasitic activities, inhibitory activities against COX-2, 5-LOX, NO synthase and PGE(2) expression, as well as cytotoxic and antitumor activities. Present review covers recent studies on the natural sources, biological activities and mechanisms of their actions, synthesis, structure-activity relationship, and metabolism of tryptanthrin. 23410125 Identification of Novel Drug Targets in HpB38, HpP12, HpG27, Hpshi470, HpSJM180 Strains of Helicobacter pylori : An In Silico Approach for Therapeutic Intervention. Helicobacter species colonizes the stomach and are associated with the development of gastritis disease. Drugs for treatment of Helicobacter infection relieve pain or gastritis symptoms but they are not targeted specifically to Helicobacter pylori. Therefore, there is dire need for discovery of new drug targets and drugs for the treatment of H. pylori. The main objective of this study is to screen the potential drug targets by in silico analysis for the potent strains of H. pylori which include HpB38, HpP12, HpG27, Hpshi470 and HpSJM180. Genome and metabolic pathways of pathogen H. pylori and the host Homosapien sapiens are compared and genes which were unique to H. pylori were filtered and catalogued. These unique genes were subjected to gene property analysis to identify the potentiality of the drug targets. Among the total number of genes analysed in different strains of H. pylori nearly 558, 569, 539, 569, 567 number of genes in HpB38, HpP12, HpG27, Hpshi470 and HpSJM180 found qualified as unique molecules and among them 17 qualified as potential drug targets. Membrane fusion protein of hefABC efflux system, 50 S ribosomal protein L33, Hydrogenase expression protein/formation of HypD, Cag pathogenecity island protein X, Apolipoprotein N acyl transferase, DNA methyalse, Histone like binding protein, Peptidoglycan-associated lipoprotein OprL were found to be critical drug targets to H. pylori. Three (hefABC efflux system, Hydrogenase expression protein/formation of HypD, Cag pathogenecity island protein X) of the 17 predicted drug targets are already experimentally validated either genetically or biochemically lending credence to our unique approach. 23422225 Antioxidative polyphenols from Nigerian mistletoe Loranthus micranthus (Linn.) parasitizing on Hevea brasiliensis. Two new phenolic glycosides, linamarin gallate (1) and walsuraside B (2), together with nine known compounds, catechin (3), epicatechin (4), epicatechin 3-O-gallate (5), epicatechin 3-O-(3-O-methyl)gallate (6), epicatechin 3-O-(3,5-O-dimethyl)gallate (7), epicatechin 3-O-(3,4,5-O-trimethyl)gallate (8), quercetin 3-O-β-d-glucopyranoside (9), rutin (10), and peltatoside (11), were isolated from the leafy twigs of Nigerian mistletoe Loranthus micranthus (Linn.) parasitic on Hevea brasiliensis. Compound 1 was characterized as an unusual cyanogenic glycoside, while compound 8 was isolated for the first time from a natural source. This is the first report of a cyanogenic glycoside from mistletoes. The structures of the new compounds were unambiguously elucidated by 1D ((1)H, (13)C), 2D NMR (COSY, HSQC, and HMBC) and by mass spectroscopy. The antioxidant activities of the isolated compounds (1-11) were evaluated using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH) assay. 23500042 The influence of rolling friction on the shear behaviour of non-cohesive pharmaceutical granules - An experimental and numerical investigation. Granule shear behaviour was investigated experimentally and numerically to evaluate the reliability of the numerical model. Additionally, parameters affecting the ensuing flow regimes - elastic quasi-static and inertial non-collisional - were highlighted. Furthermore, the influence of using the Lees-Edwards periodic boundary conditions or the standard boundary conditions was studied. Experiments were performed with microcrystalline cellulose granules of three size distributions using the FT4 powder rheometer. The numerical parameters, particle size, effective density, and particle stiffness were selected to match the experimental conditions. Experimentally, an unexpected particle size effect was evident where the resistance to shear increased with particle size. Numerically, combining rolling friction and increased shear rate enabled a transition from the inertial non-collisional to the elastic quasi-static regime at a reduced sliding friction coefficient. Presumably, this is an effect of increased particle overlap creating stronger contacts and facilitating force chain formation. Both boundary conditions provided comparable results provided a correction of system size was made, where larger systems were required for the standard boundary conditions. A satisfactory qualitative agreement between the experimentally and numerically determined yield loci emphasised the predictive capacity of the DEM. Rolling friction was in addition concluded to be an essential model parameter for obtaining an improved quantitative agreement. 23298578 Lamivudine permeability study: a comparison between PAMPA, ex vivo and in situ Single-Pass Intestinal Perfusion (SPIP) in rat jejunum. In order to reach the bloodstream and thus the target receptor, an orally-administered drug must first cross the intestinal barrier, which can occur via a paracellular, passive transcellular, or carrier-mediated uptake and/or efflux process (active or concentration gradient-driven). Our work aimed to explore the transport mechanism of the antiretroviral lamivudine (deoxycytidine nucleoside analogue), using a three-part strategy: in vitro, an ex vivo and an in situ method, represented by PAMPA, rat jejunum patches and rat Single Pass Intestinal Perfusion (SPIP), respectively. The determined permeability coefficients were compared with those from a published Caco-2 and MDCK study. Computational prediction of human jejunal permeability was explored, using various non-human permeability coefficients as descriptors. The ex vivo technique was performed in Franz-type diffusion cells, mounted with male Wistar rat jejunum segment patches. PAMPA was performed with an acceptor solution simulating the binding of serum proteins, an artificial membrane impregnated with egg lecithin/cholesterol and a gradient of pH between donor and acceptor solutions. The SPIP was conducted by proximal jejunum cannulation and drug perfusion in a constant flow rate of 0.2 mL/min. The outcomes of our studies showed the following predicted pattern for lamivudine effective jejunal permeability: P(eff)(exvivoA>B)>P(eff)(SPIP)>P(eff)(exvivo B>A)>P(eff)(Caco-2)≈P(eff)(MDCK)≈P(eff)(PAMPA), strongly suggesting that this compound has carrier-mediated uptake as its dominant transport mechanism. Notwithstanding, Caco-2 cells may indicate an under-expression of uptake transporters and possibly an over-expression efflux transporters, compared to that found in the rat jejunum. 23495832 Extraction of the volatile oil from Carum carvi of Tunisia and Lithuania by supercritical carbon dioxide: chemical composition and antiulcerogenic activity. This study investigates whether the essential oil prepared from Carum carvi seeds exhibits antiulcerogenic activity. Its volatile oil was obtained by supercritical fluid extraction (SFE) and by hydrodistillation. The essential oils were analysed by GC-MS to monitor their composition. The chemical analysis revealed that the essential oils extracted under SFE conditions had high carvone and limonene contents. The antiulcerogenic activity was evaluated by the HCl/ethanol method, which causes injury to the gastric mucosa. Three treated groups received the essential oil (100-300 mg/kg). The reference group received omeprazole (30 mg/kg) and the control group received NaCl. After 30 min, all groups were treated with HCl/EtOH for gastric ulcer induction. The results show C. carvi essential oil enhanced a significant inhibition of 47%, 81% and 88%, respectively, for three doses of essential oil used, which was similar to that induced by omeprazole (95%) (p < 0.005). 23052058 Adipocyte fatty acid binding protein: a novel adipokine involved in the pathogenesis of metabolic and vascular disease? Adipocyte fatty acid binding protein (AFABP, also known as aP2 and FABP4) has recently been introduced as a novel fat-derived circulating protein. AFABP serum concentrations are positively correlated with markers of the metabolic syndrome and vascular disease in various cross-sectional and interventional studies. Furthermore, a small set of prospective studies indicates that high AFABP serum levels at baseline predict the risk for metabolic and vascular morbidity and mortality. Studies in Afabp (also known as Fabp4) knockout mice and AFABP inhibitor-treated animals suggest that total AFABP promotes insulin resistance, hypertriacylglycerolaemia and atherosclerosis by ligand/ligand delivery, as well as ligand-independent mechanisms. In contrast, the pathophysiological significance of circulating AFABP and the mechanisms leading to its release remain to be established. The current review summarises recent findings on the regulation and potential role of AFABP in metabolic and vascular disease. 23318354 Atomic pair distribution functions analysis of disordered low-Z materials. Results of high-energy X-ray diffraction experiments coupled to atomic pair distribution function analysis of disordered low-Z materials are presented. Several scientifically and technologically important classes of disordered low-Z materials such as small and large organic molecules, graphitic powders, polymers and liquids are intentionally explored to certify the technique's performance. Results clearly show that disordered low-Z materials can be well characterized in terms of material's phase identity, relative abundance in mixtures and atomic-scale structure. The demonstrated efficiency of the technique provides the scientific community with much needed confidence to apply it more often than now. 23210774 Kinase CK2 inhibition: an update. Protein kinase CK2 (Casein Kinase 2) is an essential, ubiquitous and highly pleiotropic protein kinase, implicated in several human diseases. In the last decade, several inhibitors of CK2, have been discovered and characterized to be ATP-competitive compounds. However, only one of them, CX-4945, has recently completed Phase I clinical trial as potential anticancer drug. In this review, we report all chemical classes of CK2 inhibitors available in literature, focusing our attention on conventional ATP-competitive and on non ATP-competitive inhibitors, which could represent a new frontier in CK2 inhibition and, consequently, a promising field of study in discovering new drug candidates. 23354809 Population pharmacokinetics of piperacillin/tazobactam in neonates and young infants. OBJECTIVES: To develop population pharmacokinetic (PK) models for piperacillin/tazobactam in neonates and infants of less than 2 months of age in order to determine the appropriate dosing regimen and provide a rational basis for the development of preliminary dosing guidelines suitable for this population. METHODS: A two-stage, open-label study was conducted in neonates and infants less than 2 months of age in the neonatal intensive care unit (NICU). A total of 207 piperacillin and 204 tazobactam concentration-time data sets from 71 patients were analyzed using a nonlinear mixed-effect modeling approach (NONMEM VII). PK models were developed for piperacillin and tazobactam. The final models were evaluated using both bootstrap and visual predictive checks. External model evaluations were made in 20 additional patients. RESULTS: For neonates and young infants less than 2 months of age, the median central clearance was 0.133 and 0.149 L/h/kg for piperacillin and tazobactam, respectively. Postmenstrual age (PMA) was identified as the most significant covariate on central clearance of piperacillin and tazobactam. However, the combination of current bodyweight (BW) and postnatal age proved to be superior to PMA alone. BW was the most important covariate for apparent central volume of distribution. Both internal and external evaluations supported the prediction of the final piperacillin and tazobactam PK models. The dosing strategy 44.44/5.56 mg/kg/dose piperacillin/tazobactam every 8 or 12 h evaluated in this study achieved the pharmacodynamic target (free piperacillin concentrations >4 mg/L for more than 50 % of the dosing interval) in about 67 % of infants. CONCLUSIONS: Population PK models accurately described the PK profiles of piperacillin/tazobactam in infants less than 2 months of age. The results indicated that higher doses or more frequent dosing regimens may be required for controlling infection in this population in NICU. 23044094 Establishment of an in vitro photoallergy test using NCTC2544 cells and IL-18 production. Differentiation between photoallergenic and phototoxic reactions induced by low molecular weight compounds represents a current problem. The use of keratinocytes as a potential tool for the detection of photoallergens as opposed to photoirritants is considered an interesting strategy for developing in vitro methods. We have previously demonstrated the possibility to use the human keratinocyte cell line NCTC2455 and the production of interleukin-18 (IL-18) to screen low molecular weight sensitizers. The purpose of this work was to explore the possibility to use the NCTC2544 assay to identify photoallergens and discriminate from phototoxic chemicals. First, we identified suitable condition of UV-irradiation (3.5 J/cm(2)) by investigating the effect of UVA irradiation on intracellular IL-18 on untreated or chloropromazine (a representative phototoxic compound)-treated NCTC2544 cells. Then, the effect of UVA-irradiation over NCTC2544 cells treated with increasing concentrations of 15 compounds including photoallergens (benzophenone, 4-ter-butyl-4-methoxy-dibenzoylmethane, 2-ethylexyl-p-methoxycinnamate, ketoprofen, 6-methylcumarin); photoirritant and photoallergen (4-aminobenzoic acid, chlorpromazine, promethazine); photoirritants (acridine, ibuprofen, 8-methoxypsoralen, retinoic acid); and negative compounds (lactic acid, SDS and p-phenilendiamine) was investigated. Twenty-four hours after exposure, cytotoxicity was evaluated by the MTT assay or LDH leakage, while ELISA was used to measure the production of IL-18. At the maximal concentration assayed with non-cytotoxic effects (CV80 under irradiated condition), all tested photoallergens induced a significant and a dose-dependent increase of intracellular IL-18 following UVA irratiation, whereas photoirritants failed. We suggest that this system may be useful for the in vitro evaluation of the photoallergic potential of chemicals. 23343190 Effect of doping on the magnetostructural ordered phase of iron arsenides: a comparative study of the resistivity anisotropy in doped BaFe2As2 with doping into three different sites. To unravel the role of doping in iron-based superconductors, we investigated the in-plane resistivity of BaFe(2)As(2) doped at one of the three different lattice sites, Ba(Fe(1-x)Co(x))(2)As(2), BaFe(2)(As(1-x)P(x))(2), and Ba(1-x)K(x)Fe(2)As(2), focusing on the doping effect in the low-temperature antiferromagnetic/orthorhombic (AFO) phase. A major role of doping in the high-temperature paramagnetic/tetragonal (PT) phase is known to change the Fermi surface by supplying charge carriers or exerting chemical pressure. In the AFO phase, we found a clear correlation between the magnitude of the residual resistivity and the resistivity anisotropy. This indicates that the resistivity anisotropy originates from anisotropic impurity scattering due to dopant atoms. The magnitude of the residual resistivity was also found to be a parameter controlling the suppression rate of the AFO ordering temperature. Therefore, the dominant role of doping in the AFO phase is to introduce disorder to the system, distinct from that in the PT phase. 23434673 International journal of molecular science best paper award 2013. Since 2012, International Journal of Molecular Science has instituted an annual award to recognize outstanding papers in the area of chemistry, molecular physics and molecular biology that meet the aims, scope and high standards of this journal [1]. We are pleased to announce the second "International Journal of Molecular Science Best Paper Award" for 2013. Nominations were made by the Section Editor-in-Chiefs of International Journal of Molecular Science, with all papers published in 2009 eligible for consideration. The awards are issued for reviews and articles separately. 22940575 Rhythm and blues: animal models of epilepsy and depression comorbidity. Clinical evidence shows a strong, bidirectional comorbidity between depression and epilepsy that is associated with decreased quality of life and responsivity to pharmacotherapies. At present, the neurobiological underpinnings of this comorbidity remain hazy. To complicate matters, anticonvulsant drugs can cause mood disturbances, while antidepressant drugs can lower seizure threshold, making it difficult to treat patients suffering from both depression and epilepsy. Animal models have been created to untangle the mechanisms behind the relationship between these disorders and to serve as screening tools for new therapies targeted to treat both simultaneously. These animal models are based on chemical interventions (e.g. pentylenetetrazol, kainic acid, pilocarpine), electrical stimulations (e.g. kindling, electroshock), and genetic/selective breeding paradigms (e.g. genetically epilepsy-prone rats (GEPRs), genetic absence epilepsy rat from Strasbourg (GAERS), WAG/Rij rats, swim lo-active rats (SwLo)). Studies on these animal models point to some potential mechanisms that could explain epilepsy and depression comorbidity, such as various components of the dopaminergic, noradrenergic, serotonergic, and GABAergic systems, as well as key brain regions, like the amygdala and hippocampus. These models have also been used to screen possible therapies. The purpose of the present review is to highlight the importance of animal models in research on comorbid epilepsy and depression and to explore the contributions of these models to our understanding of the mechanisms and potential treatments for these disorders. 23276134 Survey of recent literature related to the biologically active 4(3H)-quinazolinones containing fused heterocycles. The present review focuses on the synthesis and biological evaluation of polycyclic 4(3H)-quinazolinones containing fused aromatic or heteroaromatic rings. The first part of the review is related to compounds with ring fused to the pyrimidine part of the quinazoline core. Most of the quinazolinone alkaloids belong to this class of molecules. The second part presents molecules bearing extra ring(s) fused to the benzo moiety of the quinazolinone skeleton. Their structural diversity opens new fields in the search of active molecules. 23441976 A new pentacyclic phenol and other constituents from the root bark of Bauhinia racemosa Lamk. This work reported the isolation of one unknown (1) and 10 known compounds (2-11) from the root bark of Bauhinia racemosa Lamk. (family: Caesalpiniaceae). Racemosolone (1) was characterised as a pentacyclic phenolic compound possessing an unusual skeleton with a cycloheptane ring and a rare furopyran moiety. The structure elucidation was carried out on the basis of UV, infrared (IR), HR-ESI-MS, 1D and 2D NMR spectra and finally confirmed by the single crystal X-ray analysis. The known compounds were characterised as n-tetracosane, β-sitosteryl stearate, eicosanoic acid, stigmasterol, β-sitosterol, racemosol, octacosyl ferulate, de-O-methyl racemosol, lupeol and 1,7,8,12b-tetrahydro-2,2,4-trimethyl-2H-benzo[6,7]cyclohepta [1,2,3-de] [1] benzopyran-5,10,11 triol on the basis of spectroscopic data comparison with the literature value. Compounds with skeleton similar to 1 have never been reported from any natural or other source. 23503654 Inflammatory findings on species extrapolations: humans are definitely no 70-kg mice. Modern toxicology has embraced in vitro methods, and major hopes are based on the Omics technologies and systems biology approaches they bring along (Hartung and McBride in ALTEX 28(2):83-93, 2011; Hartung et al. in ALTEX 29(2):119-28, 2012). A culture of stringent validation has been developed for such approaches (Leist et al. in ALTEX 27(4):309-317, 2010; ALTEX 29(4):373-88, 2012a; Toxicol Res 1:8-22, 2012b), while the quality and usefulness of animal experiments have been little scrutinized. A new study (Seok et al. 2013) now shows the low predictivity of animal responses in the field of inflammation. These findings corroborate earlier findings from comparisons in the fields of neurodegeneration, stroke and sepsis. The low predictivity of animal experiments in research areas allowing direct comparisons of mouse versus human data puts strong doubt on the usefulness of animal data as key technology to predict human safety. 23597445 Complex mixtures: Relevance of combined exposure to substances at low dose levels. Upon analysis of chemically complex food matrices a forest of peaks is likely to be found. Identification of these peaks and concurrent determination of the toxicological relevance upon exposure is very time consuming, expensive and often requires animal studies. Recently, a safety assessment framework based on the Threshold of Toxicological Concern (TTC) was published to assess the safety of chemically complex matrices more efficiently. In this safety assessment framework, the toxicological relevance of exposure to unidentified substances in chemically complex food matrices can be related to the Cramer class III TTC threshold, currently set at 90μg/day. However, possible additive or synergistic effects of combined exposure is not covered. The current evaluation describes the relevance of combined low dose exposure to unidentified substances in chemically complex food matrices. It is concluded that to some extent cumulative effects at exposure levels for each substance at or below the Cramer class III TTC threshold, being present in a complex mixture including food, might occur. However the health relevance of possible cumulative effects at this dose level is considered to be that low that a need for a correction factor to cover possible cumulative effects is very low to absent. 23439478 Potential for preventive effects of cocoa and cocoa polyphenols in cancer. Prevention of cancer through the diet is receiving increasing interest, and cocoa because of its polyphenolic compounds has become an important potential chemopreventive and therapeutic natural agent. Cocoa and its main polyphenols have been reported to interfere at the initiation, promotion and progression of cancer. Cocoa flavonoids have been demonstrated to influence several important biological functions in vitro and in vivo by their free radical scavenging ability or through the regulation of signal transduction pathways to stimulate apoptosis and to inhibit inflammation, cellular proliferation, apoptosis, angiogenesis and metastasis. Nevertheless, these molecular mechanisms of action are not completely characterized and many features remain to be elucidated. The aim of this review is to provide insights into the molecular basis of the potential chemopreventive activity of cocoa and its polyphenolic components by summarizing cell culture and animal models studies, as well as interventional and epidemiological studies on humans. 23573971 Present and future approaches to screening of G-protein-coupled receptors. As G-protein-coupled receptors (GPCRs) mediate a multitude of cellular signal transduction events, affecting more or less all human disease areas, it is, therefore, no surprise that they comprise the largest family of current drug targets. Screening of compounds interacting with GPCRs has developed during the past decade from receptor binding assays, to various functional determination of coupling to G-proteins, and, more recently, G-protein-independent signal transduction events. Additional opportunities have been presented in drug discovery through novel pharmacological properties obtained for receptor dimers and by identification of ligands for orphan GPCRs. Furthermore, high-throughput formats and automation has substantially facilitated and accelerated the screening process providing powerful tools in improving modern drug discovery. 23212047 ADP-ribosylation of guanosine by SCO5461 protein secreted from Streptomyces coelicolor. The Streptomyces coelicolor A3(2) genome encodes a possible secretion protein, SCO5461, that shares a 30% homology with the activity domains of two toxic ADP-ribosyltransferases, pierisins and mosquitocidal toxin. We found ADP-ribosylating activity for the SCO5461 protein product through its co-incubation with guanosine and NAD(+), which resulted in the formation of N(2)-(ADP-ribos-1-yl)-guanosine ((ar2)Guo), with a K(m) value of 110 μM. SCO5461 was further found to ADP-ribosylate deoxyguanosine, GMP, dGMP, GTP, dGTP, and cyclic GMP with k(cat) values of 150-370 s(-1). Oligo(dG), oligo(G), and yeast tRNA were also ADP-ribosylated by this protein, although with much lower k(cat) values of 0.2 s(-1) or less. SCO5461 showed maximum ADP-ribosylation activity towards guanosine at 30 °C, and maintained 20% of these maximum activity levels even at 0 °C. This is the first report of the ADP-ribosylation of guanosine and guanine mononucleotides among the family members of various ADP-ribosylating enzymes. We additionally observed secretion of the putative gene product, SCO5461, in liquid cultures of S. coelicolor. We thus designated the SCO5461 protein product as S. coelicolor ADP-ribosylating protein, ScARP. Our current results could offer new insights into not only the ADP-ribosylation of small molecules but also signal transduction events via enzymatic nucleoside modification by toxin-related enzymes. 23122099 Salicylic acid-induced elicitation of folates in coriander (Coriandrum sativum L.) improves bioaccessibility and reduces pro-oxidant status. Foliage of Coriandrum sativum is a rich source of natural folates amenable for enhancement through salicylic acid-mediated elicitation, thereby holding a great promise for natural-mode alleviation of this vitamin (B(9)) deficiency. In the present study we report salicylic acid-mediated differential elicitation of different forms of folates - 5-methyltetrahydrofolate, 5-formyltetrahydrofolate and 10-formyltetrahydrofolate - their stabilities during microwave-drying and bioaccessibilities from fresh and dried foliage. The first two compounds nearly doubled and the third increased sixfold post-elicitation, with all three showing concomitant increase in bioaccessibilities. Although a slight decrease in bioaccessibility was observed in dried foliage, over twofold increase of each form of folate upon elicitation would deliver much higher levels of natural folates from this traditional culinary foliage, which is widely used in many cuisines. Elicitor-mediated folate enhancement also imparted reduction of oxidative status and the enhancement of antioxidant enzyme activities in coriander foliage. 23363299 Synthesis of superconducting nanocables of FeSe encapsulated in carbonaceous shell. The recent discovery of superconductivity in iron selenide has attracted considerable attention due to the simplicity of composition, unconventional nature of superconductivity, and ease of synthesis. We have synthesized superconducting FeSe nanowires with a simple catalyst-aided vapor transport reaction at 800 °C in an inert atmosphere. The precursors were chosen to be elemental Se and iron acetylacetonate [Fe(III)(C₅H₈O₂)₃]. These vaporized very easily, thereby facilitating transport, and also contributed to the formation of a carbonaceous shell encapsulating the FeSe nanowires. The superconductivity of these nanocables was confirmed through magnetic measurements and a T(c) of ≈8 K was obtained for an ensemble of nanocables. The length of FeSe filling inside the carbon nanofibers could be varied by controlling the reaction conditions while the diameter of nanowires was dependent on the thickness of Au-Pd coating used as a catalyst. Extensive analysis through high-resolution microscopy revealed that there was considerable lattice contraction of FeSe in the nanocable up to about 3.6% along the c-direction leading to a reduced spacing between the (001) lattice planes. Interestingly, this compression was more pronounced near the catalyst-FeSe interface and was reduced further along the length of the nanocable. The presence of carbon nanofibers as a shell around the FeSe protected the FeSe nanowires from both atmospheric O₂ and moisture attack, as was evident from the very long ambient condition shelf life of these nanocables, and also makes them more stable under e-beam irradiation. 23434832 Construction of monophosphoryl lipid A producing Escherichia coli mutants and comparison of immuno-stimulatory activities of their lipopolysaccharides. The lipid A moiety of Escherichia coli lipopolysaccharide is a hexaacylated disaccharide of glucosamine phosphorylated at the 1- and 4'-positions. It can be recognized by the TLR4/MD-2 complex of mammalian immune cells, leading to release of proinflammatory cytokines. The toxicity of lipid A depends on its structure. In this study, two E. coli mutants, HW001 and HW002, were constructed by deleting or integrating key genes related to lipid A biosynthesis in the chromosome of E. coli W3110. HW001 was constructed by deleting lacI and replacing lacZ with the Francisella novicida lpxE gene in the chromosome and only synthesizes monophosphoryl lipid A. HW002 was constructed by deleting lpxM in HW001 and synthesizes only the pentaacylated monophosphoryl lipid A. The structures of lipid A made in HW001 and HW002 were confirmed by thin layer chromatography and electrospray ionization mass spectrometry. HW001 and HW002 grew as well as the wild-type W3110. LPS purified from HW001 or HW002 was used to stimulate murine macrophage RAW264.7 cells, and less TNF-α were released. This study provides a feasible way to produce interesting lipid A species in E. coli. 23485615 Platycodi Radix attenuates dimethylnitrosamine-induced liver fibrosis in rats by inducing Nrf2-mediated antioxidant enzymes. The purpose of this study was to investigate the anti-fibrotic effects of the aqueous extract of the Platycodi Radix root (Changkil: CK) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. DMN treatment for 4weeks led to marked liver fibrosis as assessed by serum biochemistry, histopathological examination, and hepatic lipid peroxidation and collagen content. CK significantly inhibited DMN-induced increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, fibrosis score, and hepatic malondialdehyde and collagen content. CK also inhibited DMN-induced reductions in rat body and liver weights. Reverse transcription polymerase chain reaction (RT-PCR) and western blot analyses revealed that CK inhibited DMN-induced increases in matrix metalloproteinase-13 (MMP-13), tissue inhibitor of metalloproteinase-1 (TIMP-1), and tumor necrosis factor-α (TNF-α) mRNA, and collagen type I and α-smooth muscle actin protein. DMN-induced cyclooxygenase-2 (COX-2) expression and nuclear factor-kappa B (NF-κB) activation was reduced by CK treatment. Furthermore, CK induced activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant enzymes such as γ-glutamylcysteine synthetase (γ-GCS), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and glutathione-S-transferase (GST) in HepG2 cells. These results demonstrated that CK attenuates DMN-induced liver fibrosis through the activation of Nrf2-mediated antioxidant enzymes. 23605048 The Analog of Ginkgo biloba Extract 761 is a Protective Factor of Cognitive Impairment Induced by Chronic Fluorosis. Ginkgo biloba extract EGb761 is widely used to treat patients with learning and memory impairment in Alzheimer's disease and Parkinson's disease in China. However, it is not yet clear whether the analog of EGb761 (EGb) has a protective effect on the learning and memory damage induced by chronic fluorosis. In this study, 30 Wistar rats were randomly divided into three groups: a control group, a sodium fluoride (NaF) + EGb group, and a NaF group. The rats were administered 0.5 ml water containing NaF (100 mg/l) and EGb (120 mg/kg) per day via gavage. After 3 months, the rats' capacity for learning and memory was tested using a Y-maze. Damage to hippocampal neurons was evaluated by histological examination of the CA3 area. Superoxide dismutase (SOD) activity and the levels of glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) were measured. Furthermore, the expression levels of Bcl-2 and Bax and the levels of cleaved Caspase3 in the hippocampus were evaluated by RT-PCR and Western blotting. The results showed that EGb could improve learning and memory abilities, enhance the activities of SOD and GSH-Px, attenuate the level of MDA, upregulate the ratio of Bcl-2/Bax, and downregulate the level of cleaved Caspase3. 23585309 Simulating Lifetime Outcomes Associated with Complications for People with Type 1 Diabetes. OBJECTIVES: The aim of this study was to develop a discrete-time simulation model for people with type 1 diabetes mellitus, to estimate and compare mean life expectancy and quality-adjusted life-years (QALYs) over a lifetime between intensive and conventional blood glucose treatment groups. METHODS: We synthesized evidence on type 1 diabetes patients using several published sources. The simulation model was based on 13 equations to estimate risks of events and mortality. Cardiovascular disease (CVD) risk was obtained from results of the DCCT (diabetes control and complications trial). Mortality post-CVD event was based on a study using linked administrative data on people with diabetes from Western Australia. Information on incidence of renal disease and the progression to CVD was obtained from studies in Finland and Italy. Lower-extremity amputation (LEA) risk was based on the type 1 diabetes Swedish inpatient registry, and the risk of blindness was obtained from results of a German-based study. Where diabetes-specific data were unavailable, information from other populations was used. We examine the degree and source of parameter uncertainty and illustrate an application of the model in estimating lifetime outcomes of using intensive and conventional treatments for blood glucose control. RESULTS: From 15 years of age, male and female patients had an estimated life expectancy of 47.2 (95 % CI 35.2-59.2) and 52.7 (95 % CI 41.7-63.6) years in the intensive treatment group. The model produced estimates of the lifetime benefits of intensive treatment for blood glucose from the DCCT of 4.0 (95 % CI 1.2-6.8) QALYs for women and 4.6 (95 % CI 2.7-6.9) QALYs for men. Absolute risk per 1,000 person-years for fatal CVD events was simulated to be 1.37 and 2.51 in intensive and conventional treatment groups, respectively. CONCLUSIONS: The model incorporates diabetic complications risk data from a type 1 diabetes population and synthesizes other type 1-specific data to estimate long-term outcomes of CVD, end-stage renal disease, LEA and risk of blindness, along with life expectancy and QALYs. External validation was carried out using life expectancy and absolute risk for fatal CVD events. Because of the flexible and transparent nature of the model, it has many potential future applications. 23644199 Elucidation of the pharmacophore of echinocystic acid, a new lead for blocking HCV entry. To elucidate the pharmacophore of echinocystic acid (EA), an oleanane-type triterpene displaying substantial inhibitory activity on HCV entry, two microbial strains, Rhizopus chinensis CICC 3043 and Alternaria alternata AS 3.4578, were utilized to modify the chemical structure of EA. Eight new metabolites with regio- and stereo-selective introduction of hydroxyl and lactone groups at various inert carbon positions were obtained. The anti-HCV entry activity of the metabolites 2-13, along with their parental compound EA and other analogs 14-15, were evaluated. Most of the metabolites showed no improvement but detrimental effect on potency except compound 5 and 6, which showed similar and even a litter higher anti-HCV entry activity than that of EA. The results demonstrated that ring A, B, C and the left side of ring E of EA are highly conserved, while ring D and the right side of ring E of EA are flexible. Introduction of a hydroxyl group at C-16 enhanced the triterpene potency. Further analysis indicated that the hemolytic effect of EA disappeared upon such modifications. 23553772 High Mobility Field-Effect Transistors with Versatile Processing from a Small-Molecule Organic Semiconductor. Trialkylgermyl functionalization allows development of high-performance soluble small-molecule organic semiconductors with mobilities greater than 5 cm(2) V(-1) s(-1) . Spray-deposited organic thin-film transistors show a record mobility of 2.2 cm(2) V(-1) s(-1) and demonstrate the potential for incorporation in large-area, low-cost electronic applications. 23368710 The impact of functionalization on the stability, work function, and photoluminescence of reduced graphene oxide. Reduced graphene oxide (rGO) is a promising material for a variety of thin-film optoelectronic applications. Two main barriers to its widespread use are the lack of (1) fabrication protocols leading to tailored functionalization of the graphene sheet with oxygen-containing chemical groups, and (2) understanding of the impact of such functional groups on the stability and on the optical and electronic properties of rGO. We carry out classical molecular dynamics and density functional theory calculations on a large set of realistic rGO structures to decompose the effects of different functional groups on the stability, work function, and photoluminescence. Our calculations indicate the metastable nature of carbonyl-rich rGO and its favorable transformation to hydroxyl-rich rGO at room temperature via carbonyl-to-hydroxyl conversion reactions near carbon vacancies and holes. We demonstrate a significant tunability in the work function of rGO up to 2.5 eV by altering the composition of oxygen-containing functional groups for a fixed oxygen concentration, and of the photoluminescence emission by modulating the fraction of epoxy and carbonyl groups. Taken together, our results guide the application of tailored rGO structures in devices for optoelectronics and renewable energy. 23436442 Readily accessible fluorescent probes for sensitive biological imaging of hydrogen peroxide. Hydrogen peroxide is a major component of oxygen metabolism in biological systems that, when present in high concentrations, can lead to oxidative stress in cells. Noninvasive molecular imaging of H(2)O(2) using fluorogenic systems represents an effective way to detect and measure the accumulation of this metabolite. Herein, we detail the development of robust H(2)O(2)-sensitive fluorescent probes using a boronic ester trigger appended to the fluorophore through a benzyl ether linkage. A major advantage of the probes presented here is their synthetic accessibility, with only one step needed to generate the probes on the gram scale. The sensitivity of the probes was evaluated in simulated physiological conditions, showing micromolar sensitivity to H(2)O(2). The probes were tested in biological model systems, demonstrating effective imaging of unstimulated, endogenous H(2)O(2) levels in RAW 264.7 cells and murine brain tissue. 23605050 Effects of High Iron and Glucose Concentrations over the Relative Expression of Bcl2, Bax, and Mfn2 in MIN6 Cells. Type 2 diabetes is characterized by hyperglycemia and oxidative stress. Hyperglycemia is linked to mitochondrial dysfunction and reduced β-cell mass due to the reduced expression of genes such as Mfn2 as well as the participation of the Bcl2 gene family, responsible for increased apoptosis. The purpose of this study was to describe the effect of different iron and/or glucose concentrations over Mfn2, Bax, and Bcl2 expressions in a β-pancreatic cell line (MIN6 cells). MIN6 cells were pre-incubated with different iron and/or glucose concentrations, and the relative mRNA abundance of the Bcl2/Bax ratio and of Mfn2 genes was measured by qRT-PCR. Heme oxygenase (HO) activity, iron uptake, superoxide dismutase activity, and glutathione content were also determined. The Bcl2/Bax ratio increased and Mfn2 expression decreased in MIN6 cells after glucose stimulation. These effects were higher when glucose and iron were incubated together. Additionally, treatment with glucose/iron showed a higher HO activity. Our study revealed that high glucose/Fe concentrations in MIN6 cells induced an increase of the Bcl2/Bax ratio, an indicator of increased cell apoptosis. 23327546 Unprecedented transformation of tetrathienoanthracene into pentacene on Ni(111). The imaging and characterization of single-molecule reaction events is essential to both extending our basic understanding of chemistry and applying this understanding to challenges at the frontiers of technology, for example, in nanoelectronics. Specifically, understanding the behavior of individual molecules can elucidate processes critical to the controlled synthesis of materials for applications in multiple nanoscale technologies. Here, we report the synthesis of an important semiconducting organic molecule through an unprecedented reaction observed with submolecular resolution by scanning tunneling microscopy (STM) under ultrahigh vacuum (UHV) conditions. Our images reveal a sulfur abstraction and cyclization reaction that converts tetrathienoanthracene precursors into pentacene on the Ni(111) surface. The identity of the final reaction product was confirmed by time-of-flight secondary ion mass spectrometry (TOF-SIMS). This reaction has no known literature analogue, and highlights the power of local-probe techniques for exploring new chemical pathways. 23576424 Configurational Assignment of Secondary Hydroxyl Groups and Methyl Branches in Polyketide Natural Products through Bioinformatic Analysis of the Ketoreductase Domain. Profile hidden Markov models (HMMs) were used to predict the configuration of secondary alcohols and α-methyl branches of modular polyketides. Based on the configurations of two chiral centers in these polyketides, 78 ketoreductases were classified into four different types of polyketide producers. The identification of positions that discriminate between these protein families was followed by fitting six profile HMMs to the data set and the corresponding subsets, to model the conserved regions of the protein types. Ultimately, the profile HMMs described herein predict protein subtypes based on the complete information-rich region; consequently, slight changes in a multiple sequence alignment do not significantly alter the outcome of this classification method. Additionally, Viterbi scores can be used to assess the reliability of the classification. 23085334 Binding of Gq protein stabilizes the activated state of the muscarinic receptor type 1. Activation of G protein coupled receptors (GPCRs) induces various cellular responses through interactions with G proteins. The key trigger of GPCR activation is agonist binding. It is reportedly known that the agonist-bound active conformation of the GPCRs, such as the muscarinic acetylcholine receptor type 1 (M(1)R), can be affected by the coupling of G proteins and by depolarization of the membrane potential. Here we aimed at investigating their effects on the structural rearrangements of the M(1)Rs between the active and quiescent states, using the fluorescence resonance energy transfer (FRET) technique. For this purpose, fluorescent M(1)R constructs that maintained intact activation of the Gq pathway and interaction with Gq were used. We captured the agonist-induced conformational changes of the M(1)R as the FRET decreases and found that the FRET decreases were enhanced by co-expression of the Gq subunits. In addition, co-expression of the Gq subunits decelerated the recovery of the declined FRET upon removal of the agonists, which was slower than the dissociation of the Gq subunits from the receptor. These results suggested that Gq binding stabilizes the agonist-induced activated conformation of the M(1)R. We also found that depolarization of the membrane potential slightly but significantly enhanced the agonist-induced FRET decrease, by accelerating the agonist-induced conformational changes. Thus, structural rearrangement analyses by FRET revealed that Gq coupling stabilizes the active conformation of the M(1)R and also suggested that depolarization accelerates the transition from quiescent to activation conformation. 23340514 Exploring resources for intrafamilial communication of cancer genetic risk: we still need to talk. While the importance of intrafamilial communication of hereditary cancer risk has been acknowledged, the factors that promote and act as barriers to patients disclosing their information to their families are complex and emerging. This raises the question: How are patients guided in practice to contemplate intrafamilial communication? Focusing on breast cancer, we conducted an exploratory study examining current resources supporting patients and health-care professionals, and isolated the messages surrounding intrafamilial communication of cancer risk. We find the duty for health-care professionals to counsel patients regarding intrafamilial communication is acknowledged to varying degrees by multiple actors in the cancer care delivery landscape, including health-care professional associations, health service organizations, and patient groups. A range of medical, psychosocial, and other factors underlying intrafamilial communication are acknowledged in messages to patients. Patients, however, are often referred to a single group of health-care professionals to discuss their diverse and complex needs. At the same time, messages aimed at patients appear to place the emphasis on barriers that could exist for patients contemplating intrafamilial communication, while highlighting the benefits families derive from such communication. Taken together, this points to a lack of coherence within materials directed to patients and suggests the need to do coordinated research among stakeholders to address two related issues: (1) determining who are the actors best positioned to send messages surrounding intrafamilial communication to patients and (2) addressing the content of messages conveyed in patient materials.European Journal of Human Genetics advance online publication, 23 January 2013; doi:10.1038/ejhg.2012.286. 23093023 Phosphoinositide-dependent kinase-1 and protein kinase Cδ contribute to endothelin-1 constriction and elevated blood pressure in intermittent hypoxia. Obstructive sleep apnea (OSA) is associated with cardiovascular complications including hypertension. Previous findings from our laboratory indicate that exposure to intermittent hypoxia (IH), to mimic sleep apnea, increases blood pressure in rats. IH also increases endothelin-1 (ET-1) constrictor sensitivity in a protein kinase C (PKC) δ-dependent manner in mesenteric arteries. Because phosphoinositide-dependent kinase-1 (PDK-1) regulates PKCδ activity, we hypothesized that PDK-1 contributes to the augmented ET-1 constrictor sensitivity and elevated blood pressure following IH. Male Sprague-Dawley rats were exposed to either sham or IH (cycles between 21% O(2)/0% CO(2) and 5% O(2)/5% CO(2)) conditions for 7 h/day for 14 or 21 days. The contribution of PKCδ and PDK-1 to ET-1-mediated vasoconstriction was assessed in mesenteric arteries using pharmacological inhibitors. Constrictor sensitivity to ET-1 was enhanced in arteries from IH-exposed rats. Inhibition of PKCδ or PDK-1 blunted ET-1 constriction in arteries from IH but not sham group rats. Western analysis revealed similar levels of total and phosphorylated PDK-1 in arteries from sham and IH group rats but decreased protein-protein interaction between PKCδ and PDK-1 in arteries from IH- compared with sham-exposed rats. Blood pressure was increased in rats exposed to IH, and treatment with the PDK-1 inhibitor OSU-03012 [2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}-acetamide] (33 mg/day) lowered blood pressure in IH but not sham group rats. Our results suggest that exposure to IH unmasks a role for PDK-1 in regulating ET-1 constrictor sensitivity and blood pressure that is not present under normal conditions. These novel findings suggest that PDK-1 may be a uniquely effective antihypertensive therapy for OSA patients. 23623491 Synthesis of pyrazolo[1,5-a]pyrimidine linked aminobenzothiazole conjugates as potential anticancer agents. A series of pyrazolo[1,5-a]pyrimidine linked 2-aminobenzothizole conjugates (6a-t) were synthesized and evaluated for their anticancer activity against five human cancer cell lines. Among them two compounds 6p and 6m showed significant anticancer activity with IC50 values ranging from 2.01 to 7.07 and 1.94-3.46μM, respectively. Moreover, cell cycle arrest in G2/M and reduction in Cdk1 expression level were observed upon treatment of these compounds and they also induced caspase-3 dependent apoptosis. This was further confirmed by staining as well as DNA fragmentation analysis. 23360333 Epitaxial silicon dots self-assembled on aluminum nitride/Si (111). Si nanoscale dots are synthesized on AlN/Si(111) by molecular beam epitaxy. A dot density of 2.2 × 10(11) cm(-2) with a mean radius of 5.6 ± 2.8 nm is obtained in Volmer-Weber growth mode. A double Si coverage leads to a decrease in dot density and increase in dot size. The dot orientations are [11[overline]0](Si) (or [1[overline]10](Si))//[112[overline]0](AlN) and (111)(Si)//(0001)(AlN), which are similar (or identical) to the orientation of AlN relative to the Si substrate. 23001363 Ion disturbance and clustering in the NaCl water solutions. Ion clustering and the solvation properties in the NaCl solutions are explored by molecular dynamics simulations with several popular force fields. The existence of ions has a negligible disturbance to the hydrogen bond structures and rotational mobility of water beyond the first ion solvation shells, which is suggested by the local hydrogen bond structures and the rotation times of water. The potential of mean force (PMF) of ion pair in the dilute solution presents a consistent view with the populations of ion clusters in the electrolyte solutions. The aggregation level of ions is sensitive to the force field used in the simulations. The ion-ion interaction potential plays an important role in the forming of the contact ion pair. The entropy of water increases as the ion pair approaches each other and the association of ion pair is driven by the increment of water entropy according to the results from the selected force fields. The kinetic transition from the single solvent separated state to the contact ion pair is controlled by the enthalpy loss of solution. 23103330 The high bone mass phenotype is characterised by a combined cortical and trabecular bone phenotype: findings from a pQCT case-control study. High bone mass (HBM), detected in 0.2% of DXA scans, is characterised by a mild skeletal dysplasia largely unexplained by known genetic mutations. We conducted the first systematic assessment of the skeletal phenotype in unexplained HBM using pQCT in our unique HBM population identified from screening routine UK NHS DXA scans. pQCT measurements from the mid and distal tibia and radius in 98 HBM cases were compared with (i) 65 family controls (constituting unaffected relatives and spouses), and (ii) 692 general population controls. HBM cases had substantially greater trabecular density at the distal tibia (340 [320, 359] mg/cm(3)), compared to both family (294 [276, 312]) and population controls (290 [281, 299]) (p<0.001 for both, adjusted for age, gender, weight, height, alcohol, smoking, malignancy, menopause, steroid and estrogen replacement use). Similar results were obtained at the distal radius. Greater cortical bone mineral density (cBMD) was observed in HBM cases, both at the midtibia and radius (adjusted p<0.001). Total bone area (TBA) was higher in HBM cases, at the distal and mid tibia and radius (adjusted p<0.05 versus family controls), suggesting greater periosteal apposition. Cortical thickness was increased at the mid tibia and radius (adjusted p<0.001), implying reduced endosteal expansion. Together, these changes resulted in greater predicted cortical strength (strength strain index [SSI]) in both tibia and radius (p<0.001). We then examined relationships with age; tibial cBMD remained constant with increasing age amongst HBM cases (adjusted β -0.01 [-0.02, 0.01], p=0.41), but declined in family controls (-0.05 [-0.03, -0.07], p<0.001) interaction p=0.002; age-related changes in tibial trabecular BMD, CBA and SSI were also divergent. In contrast, at the radius HBM cases and controls showed parallel age-related declines in cBMD and trabecular BMD. HBM is characterised by increased trabecular BMD and by alterations in cortical bone density and structure, leading to substantial increments in predicted cortical bone strength. In contrast to the radius, neither trabecular nor cortical BMD declined with age in the tibia of HBM cases, suggesting attenuation of age-related bone loss in weight-bearing limbs contributes to the observed bone phenotype. 23202986 The protein amide ¹H(N) chemical shift temperature coefficient reflects thermal expansion of the N-H···O=C hydrogen bond. The protein amide (1)H(N) chemical shift temperature coefficient can be determined with high accuracy by recording spectra at different temperatures, but the physical mechanism responsible for this temperature dependence is not well understood. In this work, we find that this coefficient strongly correlates with the temperature coefficient of the through-hydrogen-bond coupling, (3h)J(NC'), based on NMR measurements of protein GB3. Parallel tempering molecular dynamics simulation suggests that the hydrogen bond distance variation at different temperatures/replicas is largely responsible for the (1)H(N) chemical shift temperature dependence, from which an empirical equation is proposed to predict the hydrogen bond thermal expansion coefficient, revealing responses of individual hydrogen bonds to temperature changes. Different expansion patterns have been observed for various networks formed by β strands. 23411288 A novel colloidal gold-based lateral flow immunoassay for rapid simultaneous detection of cyromazine and melamine in foods of animal origin. A rapid and sensitive lateral flow immunoassay (LFIA) based on competitive format was developed and validated for simultaneous detection of cyromazine (CA) and melamine (MA) in foods of animal origin. With this method, the cut-off value for the two test lines were achieved at 25 ng/g, which was lower than the maximum residue levels (MRLs) established for CA and MA. At three fortified levels (50, 100, and 150 ng/g), the recoveries for CA and MA ranged from 73.9% to 104.2% with the relative standard deviation (RSD) less than 11.9%, based on within day and interday analysis. The lower detection limit for CA and MA in matrix sample were 0.22 ng/ml and 0.26 ng/ml, respectively, which were lower than those of published literatures. A parallel analysis of CA and MA in real samples conducted by HPLC showed comparable results to those obtained from LFIA. The results of LFIA were in good agreement with those of high performance liquid chromatography (HPLC) in the analysis of CA and MA in foods of animal origin, demonstrating the practical applicability of the developed assay in real samples. Overall, to our knowledge, this is the first report of quantitative or semi-quantitative simultaneous detection for CA and MA by immunochromatographic assay. 23258548 5-cholesten-3β,25-diol 3-sulfate decreases lipid accumulation in diet-induced nonalcoholic fatty liver disease mouse model. Sterol regulatory element-binding protein-1c (SREBP-1c) increases lipogenesis at the transcriptional level, and its expression is upregulated by liver X receptor α (LXRα). The LXRα/SREBP-1c signaling may play a crucial role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We previously reported that a cholesterol metabolite, 5-cholesten-3β,25-diol 3-sulfate (25HC3S), inhibits the LXRα signaling and reduces lipogenesis by decreasing SREBP-1c expression in primary hepatocytes. The present study aims to investigate the effects of 25HC3S on lipid homeostasis in diet-induced NAFLD mouse models. NAFLD was induced by feeding a high-fat diet (HFD) in C57BL/6J mice. The effects of 25HC3S on lipid homeostasis, inflammatory responses, and insulin sensitivity were evaluated after acute treatments or long-term treatments. Acute treatments with 25HC3S decreased serum lipid levels, and long-term treatments decreased hepatic lipid accumulation in the NAFLD mice. Gene expression analysis showed that 25HC3S significantly suppressed the SREBP-1c signaling pathway that was associated with the suppression of the key enzymes involved in lipogenesis: fatty acid synthase, acetyl-CoA carboxylase 1, and glycerol-3-phosphate acyltransferase. In addition, 25HC3S significantly reduced HFD-induced hepatic inflammation as evidenced by decreasing tumor necrosis factor and interleukin 1 α/β mRNA levels. A glucose tolerance test and insulin tolerance test showed that 25HC3S administration improved HFD-induced insulin resistance. The present results indicate that 25HC3S as a potent endogenous regulator decreases lipogenesis, and oxysterol sulfation can be a key protective regulatory pathway against lipid accumulation and lipid-induced inflammation in vivo. 22935511 Effects of anti-cocaine vaccine and viral gene transfer of cocaine hydrolase in mice on cocaine toxicity including motor strength and liver damage. In developing an vivo drug-interception therapy to treat cocaine abuse and hinder relapse into drug seeking provoked by re-encounter with cocaine, two promising agents are: (1) a cocaine hydrolase enzyme (CocH) derived from human butyrylcholinesterase and delivered by gene transfer; (2) an anti-cocaine antibody elicited by vaccination. Recent behavioral experiments showed that antibody and enzyme work in a complementary fashion to reduce cocaine-stimulated locomotor activity in rats and mice. Our present goal was to test protection against liver damage and muscle weakness in mice challenged with massive doses of cocaine at or near the LD50 level (100-120mg/kg, i.p.). We found that, when the interceptor proteins were combined at doses that were only modestly protective in isolation (enzyme, 1mg/kg; antibody, 8mg/kg), they provided complete protection of liver tissue and motor function. When the enzyme levels were ∼400-fold higher, after in vivo transduction by adeno-associated viral vector, similar protection was observed from CocH alone. 23568452 Thin films: organic vapor passivation of silicon at room temperature (adv. Mater. 14/2013). Initiated chemical vapor deposition is used to achieve air-stable organic passivation of silicon, as reported by Karen K. Gleason and co-workers on page 2078. This layer also functions as an anti-reflection coating. Resistively heated wires produce reactive gas phase species, including methyl radicals, while the silicon surface below remains near room temperature. Photoshop enhanced image by Felice C. Frankel. 23266733 Fucoidan prevents multiple myeloma cell escape from chemotherapy-induced drug cytotoxicity. Minimal residual disease (MRD) occurrence with some chemotherapy drugs that promote tumor cell escape is also a key factor in blood malignancy relapse. We observed that cytarabine promotes multiple myeloma (MM) cell escape and that the number of cells in the lower chamber increased with increasing clinical disease stage in in vitro model which was constructed by a Boyden chamber, matrigel glue and serum from MM patients in different disease stages. The mechanism of cytarabine that promotes MM cell escape is closely associated with the up-regulation of CXCR4. SDF-1α can up-regulate the expression of MMP9 and RHoC proteins in MM cells with up-regulated CXCR4, and further promote the cell escape. Fucoidan, a sulfated polysaccharide in the cell wall matrix of brown algae, has attracted much attention for its multiple biological activities, and we further explored the effects and possible underlying mechanisms of fucoidan on MM cell escape from cytarabine cytotoxicity. The results show that fucoidan may decrease MM cell escape from cytarabine cytotoxicity, and that fucoidan can down-regulate CXCR4, MMP9 and RHoC expression. This research provides new direction for investigating MRD occurrence and prevention. 23306788 The hepatoprotection of caffeic acid and rosmarinic acid, major compounds of Perilla frutescens, against t-BHP-induced oxidative liver damage. Perilla frutescens leaves are often used in East Asian gourmet food. In this study, we investigated the hepatoprotective effects of caffeic acid (CA), rosmarinic acid (RA), and their combination. P. frutescens contains 1.32μg CA/mg dry material (DM) and 26.84μg RA/mg DM analyzed by HPLC-DAD and HPLC-MS. CA remarkably reduced the oxidative damage than rosmarinic acid in an in vitro study. Oral intubation with CA or RA alone for five days was conducted prior to treatment with a single dose of tert-butyl hydroperoxide (0.5mmol/kg b.w., i.p.), which led to a significant reduction of indicators of hepatic toxicity, such as aspartate aminotransferase, alanine aminotransferase, oxidized glutathione, lipid peroxidation and enzyme activities related to antioxidant such as catalase, glutathione peroxidase and superoxide dismutase. Interestingly, compared to treatment with CA or RA alone, a combination of both compounds more increased the endogenous antioxidant enzymes and glutathione (GSH) and decreased lipid peroxidation in livers. These results suggest that CA from perilla leaves plays a role in the increased hepatic GSH concentration, and shows an additive hepatic protection with RA against oxidative hepatic damage. 23297831 Tunable morphology and mesophase formation by naphthalene-containing poly(aryl ether) dendron-based low-molecular-weight fluorescent gels. Novel poly(aryl ether) dendron-based low-molecular-weight organogelaters (LMWG) containing naphthalene units at the core have been synthesized, and the self-assembly of the system has been examined in a variety of solvents and solvent mixtures. The compounds readily form gels with attractive critical gel concentration values associated with gelation-induced enhanced emission (GIEE). In addition to the remarkable properties of the previously reported anthracene and pyrene analogues (Rajamalli, P.; Prasad, E. Org. Lett.2011, 13, 3714 and Rajamalli, P.; Prasad, E. Soft Matter2012, 8, 8896), the self-assembled systems exhibit distinctly different structure-property relationships. Unlike the reported ones, the present system forms sheetlike morphology in nonpolar solvent mixtures, giant vesicles in polar solvent mixtures, and lamellar or hexagonal columnar phases in single solvents. The unique properties of the self-assembled systems, which were analyzed through electron microscopic (SEM, TEM, AFM) and spectroscopic techniques (POM, fluorescence), are attributed to the replacement of anthracene/pyrene units by naphthalene units. The present work unravels the subtle role of minute structural change in altering the properties of LMWGs based on poly(aryl ether) dendrons. 23046379 Immune-induced expression of lipocalin-2 in brain endothelial cells: relationship with interleukin-6, cyclooxygenase-2 and the febrile response. Interleukin (IL)-6 is critical for the febrile response to peripheral immune challenge. However, the mechanism by which IL-6 enables fever is still unknown. To characterise the IL-6-dependent fever generating pathway, we used microarray analysis to identify differentially expressed genes in the brain of lipopolysaccharide (LPS)-treated IL-6 wild-type and knockout mice. Mice lacking IL-6 displayed a two-fold lower expression of the lipocalin-2 gene (lcn2), and this difference was confirmed by real-time reverse transcriptase-polymerase chain reaction. Conversely, the induction of lipocalin-2 protein was observed in brain vascular cells following i.p. administration of recombinant IL-6, suggesting a direct relationship between IL-6 and lipocalin-2. Immunohistochemical analysis also revealed that LPS-induced lipocalin-2 is expressed by brain endothelial cells and is partly co-localised with cyclooxygenase-2 (Cox-2), the rate-limiting enzyme for the production of inflammatory induced prostaglandin E(2) (PGE(2) ), which is the key mediator of fever. The direct role of lipocalin-2 in fever was examined in LPS-challenged lipocalin-2 knockout mice. In both male and female mice, normal fever responses were observed at near-thermoneutral conditions (29-30 °C) but when recorded at normal room temperature (19-20 °C), the body temperature of lipocalin-2 knockout female mice displayed an attenuated fever response compared to their wild-type littermates. This difference was reflected in significantly attenuated mRNA expression of Cox-2 in the brain of lipocalin-2 knockout female mice, but not of male mice, following challenge with peripheral LPS. Our findings suggest that IL-6 influences the expression of lipocalin-2, which in turn may be involved in the control of the formation of Cox-2, and hence central PGE(2) -production. We have thus identified lipocalin-2 as a new factor in the pathway of inflammatory IL-6 signalling. However, the effect of lipocalin-2 on fever is small, being sex-dependent and ambient temperature-specific, and thus lipocalin-2 cannot be considered as a major mediator of the IL-6-dependent fever generating pathway. 23566056 Effects of Curcumin on Apoptosis and Oxidoinflammatory Regulation in a Rat Model of Acetic Acid-Induced Colitis: The Roles of c-Jun N-Terminal Kinase and p38 Mitogen-Activated Protein Kinase. Abstract The present study evaluated the effects of curcumin on epithelial cell apoptosis, the immunoreactivity of the phospho-c-Jun N-terminal kinase (JNK) and phospho-p38 mitogen-activated protein kinases (MAPKs) in inflamed colon mucosa, and oxidative stress in a rat model of ulcerative colitis induced by acetic acid. Rats were randomly divided into three groups: control, acetic acid, and acetic acid+curcumin. Curcumin (100 mg/kg per day, intragastrically) was administered 10 days before the induction of colitis and was continued for two additional days. Acetic acid-induced colitis caused a significant increase in the macroscopic and microscopic tissue ranking scores as well as an elevation in colonic myeloperoxidase (MPO) activity, malondialdehyde (MDA) levels, and the number of apoptotic epithelial cells in colon tissue compared to controls. In the rat colon, immunoreactivity of phospho-p38 MAPK was increased, whereas the phospho-JNK activity was decreased following the induction of colitis. Curcumin treatment was associated with amelioration of macroscopic and microscopic colitis sores, decreased MPO activity, and decreased MDA levels in acetic acid-induced colitis. Furthermore, oral curcumin supplementation clearly prevented programmed cell death and restored immunreactivity of MAPKs in the colons of colitic rats. The results of this study suggest that oral curcumin treatment decreases colon injury and is associated with decreased inflammatory reactions, lipid peroxidation, apoptotic cell death, and modulating p38- and JNK-MAPK pathways. 23582019 Exciplex Formation in Blended Spin-Cast Films of Fluorene-Linked Dyes and Bisphthalimide Quenchers. Spin-cast films of dyes (donor-π-donor, donor-π-acceptor, and acceptor-π-acceptor type, where the donor is Ph2N-, the acceptor is 2-benzothiazoyl, and the π-linker is 9,9-diethylfluorene) blended with nonconjugated bisphthalimides were prepared. Upon visible-light excitation of the dyes, quenching of the excited state occurs by exciplex formation between dye and bisphthalimide molecules or, in some cases, by excimer formation or aggregation-induced emission between two dye molecules. The extent of exciplex formation is dependent on the driving force, which can be calculated using the energy difference between the lowest unoccupied molecular orbitals (LUMOs) of the dyes and bisphthalimides. The results show that complete exciplex formation occurs when this driving force is greater than 0.57 eV whereas partial exciplex formation occurs when the driving force is between 0.28 and 0.57 eV. The exciplex emission energies can also be predicted by calculating the difference between the LUMO level of the bisphthalimide and the highest occupied molecular orbital (HOMO) of the dye. These calculated values, which were obtained from the electrochemically determined energy levels, showed good agreement with the observed emission energies. The exciplex lifetimes were found to be significantly longer than the lifetimes of the lone dyes. These exciplexes formed from nonlinked donors and acceptors in the solid state might have potential uses in nonlinear photonics. 22940001 Rett syndrome treatment in mouse models: searching for effective targets and strategies. Rett syndrome (RTT) is a pervasive developmental disorder, primarily affecting girls with a prevalence of 1 in every 10,000 births; it represents the second most common cause of intellectual disability in females. Mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2) have been identified as clear etiological factors in more than 90% of classical RTT cases. Whereas the mechanisms leading to the severe, progressive and specific neurological dysfunctions when this gene is mutated still remain to be elucidated, a series of different mouse models have been generated, bearing different Mecp2 mutation. Neurobehavioural analysis in these mouse lines have been carried out and phenotyping analysis can be now utilised to preclinically evaluate the effects of potential RTT treatments. This review summarizes the different results achieved in this research field taking into account different key targets identified to ameliorate RTT phenotype in mouse models, including those not directly downstream of MeCP2 and those limited to the early phases of postnatal development. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. 22006095 Serotonin receptor 2A (HTR2A) gene polymorphism predicts treatment response to venlafaxine XR in generalized anxiety disorder. Generalized anxiety disorder (GAD) is a chronic psychiatric disorder with significant morbidity and mortality. Antidepressant drugs are the preferred choice for treatment; however, treatment response is often variable. Several studies in major depression have implicated a role of the serotonin receptor gene (HTR2A) in treatment response to antidepressants. We tested the hypothesis that the genetic polymorphism rs7997012 in the HTR2A gene predicts treatment outcome in GAD patients treated with venlafaxine XR. Treatment response was assessed in 156 patients that participated in a 6-month open-label clinical trial of venlafaxine XR for GAD. Primary analysis included Hamilton Anxiety Scale (HAM-A) reduction at 6 months. Secondary outcome measure was the Clinical Global Impression of Improvement (CGI-I) score at 6 months. Genotype and allele frequencies were compared between groups using χ(2) contingency analysis. The frequency of the G-allele differed significantly between responders (70%) and nonresponders (56%) at 6 months (P=0.05) using the HAM-A scale as outcome measure. Similarly, using the CGI-I as outcome, the G-allele was significantly associated with improvement (P=0.01). Assuming a dominant effect of the G-allele, improvement differed significantly between groups (P=0.001, odds ratio=4.72). Similar trends were observed for remission although not statistically significant. We show for the first time a pharmacogenetic effect of the HTR2A rs7997012 variant in anxiety disorders, suggesting that pharmacogenetic effects cross diagnostic categories. Our data document that individuals with the HTR2A rs7997012 single nucleotide polymorphism G-allele have better treatment outcome over time. Future studies with larger sample sizes are necessary to further characterize this effect in treatment response to antidepressants in GAD. 23611475 Physicochemical characterization of nimodipine-polyethylene glycol solid dispersion systems. Abstract This study investigates the solid-solid interactions between nimodipine (NIM) and polyethylene glycol (PEG) of different mean molecular weights (PEG 2000, 4000 and 6000), in solid dispersion systems, applying differential scanning calorimetry (DSC), Fourier-Transform infrared spectroscopy, powder X-ray diffraction (PXRD), hot stage microscopy (HSM) and theoretical modeling by the Flory-Huggins (FH) solution theory. Phase diagrams constructed with the aid of DSC and FH solution theory showed sensitivity on the estimated values of the FH interaction parameter (χ). When χ is considered a constant number (χ = α, α ≠ 0), formation of a eutectic mixture is predicted in the 70-80% w/w PEG concentration region, while when χ was considered as a function of concentration and temperature (χ = f(φ,Τ)), the model predicts the formation of monotectic systems. Construction of more precise phase diagrams by HSM to the aid of Kofler's "contact preparation" method confirmed the monotectic nature of the examined systems. Studies on NIM's re-crystallization process in the solid dispersions revealed a strong dependence of the crystallization rate, as well as the resulting crystal form, on the mean molecular weight and concentration of PEG: NIM crystallization rates decrease as PEG's MW increases, while NIM mod II crystals predominate in dispersions prepared at temperatures above NIM's liquidus and growth of NIM mod I prevailing in PEG-rich samples. 23298236 Novel P2 tris-tetrahydrofuran group in antiviral compound 1 (GRL-0519) fills the S2 binding pocket of selected mutants of HIV-1 protease. GRL-0519 (1) is a potent antiviral inhibitor of HIV-1 protease (PR) possessing tris-tetrahydrofuran (tris-THF) at P2. The high resolution X-ray crystal structures of inhibitor 1 in complexes with single substitution mutants PR(R8Q), PR(D30N), PR(I50V), PR(I54M), and PR(V82A) were analyzed in relation to kinetic data. The smaller valine side chain in PR(I50V) eliminated hydrophobic interactions with inhibitor and the other subunit consistent with 60-fold worse inhibition. Asn30 in PR(D30N) showed altered interactions with neighboring residues and 18-fold worse inhibition. Mutations V82A and I54M showed compensating structural changes consistent with 6-7-fold lower inhibition. Gln8 in PR(R8Q) replaced the ionic interactions of wild type Arg8 with hydrogen bond interactions without changing the inhibition significantly. The carbonyl oxygen of Gly48 showed two alternative conformations in all structures likely due to the snug fit of the large tris-THF group in the S2 subsite in agreement with high antiviral efficacy of 1 on resistant virus. 23474389 Synthesis and evaluation of 3-(benzylthio)-5-(1H-indol-3-yl)-1,2,4-triazol-4-amines as Bcl-2 inhibitory anticancer agents. A series of substituted 3-(benzylthio)-5-(1H-indol-3-yl)-4H-1,2,4-triazol-4-amines has been synthesised and tested in vitro as potential pro-apoptotic Bcl-2-inhibitory anticancer agents. Synthesis of the target compounds was readily accomplished in good yields through a cyclisation reaction between indole-3-carboxylic acid hydrazide and carbon disulfide under basic conditions, followed by S-benzylation. Active compounds, such as the nitrobenzyl analogue 6c, were found to exhibit sub-micromolar IC50 values in Bcl-2 expressing human cancer cell lines. Molecular modelling and ELISA studies further implicated anti-apoptotic Bcl-2 as a candidate molecular target underpinning anticancer activity. 23353805 Magnetic field triggered drug release from polymersomes for cancer therapeutics. Local and temporal control of drug release has for long been a main focus in the development of novel drug carriers. Polymersomes, which can load both hydrophilic and hydrophobic species and, at the same time, be tailored to respond to a desired stimulus, have drawn much attention over the last decade. Here we describe polymersomes able to encapsulate up to 6% (w/w) of doxorubicin (DOX) together with 30% (w/w) of superparamagnetic iron oxide nanoparticles (USPIO; γ-Fe(2)O(3)). Upon internalization in HeLa cells and when a high frequency AC magnetic field (14mT at 750kHz) was applied, the developed delivery system elicited an 18% increase in cell toxicity, associated with augmented DOX release kinetics. In order to ensure that the observed cytotoxicity arose from the increased doxorubicin release and not from a pure magnetic hyperthermia effect, polymersomes loaded with magnetic nanoparticles alone were also tested. In this case, no increased toxicity was observed. We hypothesize that the magnetic field is inducing a very local hyperthermia effect at the level of the polymersome membrane, increasing drug release. This approach opens new perspectives in the development of smart delivery systems able to release drug upon demand and therefore, improving treatment control. 23424203 Evaluation of the mutagenic potential and acute oral toxicity of standardized extract of Ocimum sanctum (OciBest™). Ocimum sanctum L. (Lamiaceae) is found throughout India and in many parts of world. O. sanctum is used for the treatment of various health indications. In this lieu, it is of prime importance to investigate the safety aspects of the plant. Hence, the present study was conducted to investigate the possible genotoxic potential and acute oral toxicity of the extract of O. sanctum (OciBest™). The standard battery of in vitro genotoxicity tests, namely bacterial reverse mutation, chromosome aberration and micronucleus (MN) tests were employed to assess the possible mutagenic activity. The results showed that OciBest™ (7.9-2500.0 µg/mL) did not increase the number of histidine revertant colonies in Salmonella typhimurium strains (TA98 and TAMix) with and without exogenous metabolic activation (S9). OciBest™ (10.0-100.0 µg/mL) did not show structural chromosomal aberrations or increase in MN induction, with and without S9, at the tested dose range in both 4-h and 18-h exposure cell cultures. Thus, OciBest™ is not genotoxic in bacterial reverse mutation, chromosomal aberration and MN tests. In an acute oral toxicity test, rats were treated with 5 g/kg of OciBest™ and observed for signs of toxicity for 14 days and the results did not show any treatment-related toxic effects to Wistar rats. 23208411 Simple colorimetric bacterial detection and high-throughput drug screening based on a graphene-enzyme complex. A simple, colorimetric, sensitive, cost-effective and high-throughput system based on a positively charged graphene oxide-enzyme complex was developed for bacterial detection and drug screening. 23530003 Carotid body denervation prevents the development of insulin resistance and hypertension induced by hypercaloric diets. Increased sympathetic activity is a well-known pathophysiological mechanism in insulin resistance (IR) and hypertension (HT). The carotid bodies (CB) are peripheral chemoreceptors that classically respond to hypoxia by increasing chemosensory activity in the carotid sinus nerve (CSN), causing hyperventilation and activation of the sympathoadrenal system. Besides its role in the control of ventilation, the CB has been proposed as a glucose sensor being implicated in the control of energy homeostasis. However, to date no studies have anticipated its role in the development of IR. Herein we propose that CB overstimulation is involved in the aetiology of IR and HT, core metabolic and hemodynamic disturbances of highly prevalent diseases like the metabolic syndrome, type 2 diabetes and obstructive sleep apnoea. We demonstrated CB activity is increased in IR animal models and that CSN resection prevents CB-overactivation and diet-induced IR and HT. Moreover we showed that insulin triggers CB, highlighting a new role for hyperinsulinemia as a stimulus for CB-overactivation. We propose that CB is implicated in the pathogenesis of metabolic and hemodynamic disturbances through sympathoadrenal overactivation and may represent a novel therapeutic target in these diseases. 23535349 Risk of ischemic stroke with the use of risperidone, quetiapine and olanzapine in elderly patients: a population-based, case-crossover study. We conducted a case-crossover study to evaluate the comparative risk of ischemic stroke associated with the use of risperidone, quetiapine and olanzapine in geriatric patients using the Korean Health Insurance Review and Assessment Service database. Cases included elderly patients >64 years old who had experienced their first ischemic stroke (International Classification of Disease, Tenth Revision (ICD-10), I63) hospitalization from July 2005 to June 2006 and who had been without prior cerebrovascular diseases (ICD-10, I60-I69), or transient ischemic attack (ICD-10, G45). Exposures to risperidone, quetiapine and olanzapine were assessed during the 30 days prior to the stroke episode. We set two control periods with lengths which were the same as the hazard periods. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were estimated by conditional logistic regression. A total of 1601 cases of ischemic stroke with a mean age of 75.6 (±6.7) years were identified, among which 933 (58.3%) were female. An increased risk of ischemic stroke was associated with the use of risperidone (aOR=3.5, 95% CI 3.3-4.6) and quetiapine (aOR=2.7, 95% CI 2.0-3.6) during the 30 days prior to stroke: however, no significant risk was observed with olanzapine (aOR=1.2, 95% CI 0.7-2.0). The increased stroke risk in demented patients, assessed within 30 days after exposure, was also observed with olanzapine. However, the sample of olanzapine users was small and underpowered. 23605694 Ospemifene: first global approval. Ospemifene (Osphena™) is an oral selective estrogen receptor modulator (SERM), with tissue-specific estrogenic agonist/antagonist effects. QuatRx Pharmaceuticals conducted the global development of the agent before licensing it to Shionogi for regulatory filing and commercialization worldwide. Ospemifene is the first non-estrogen treatment approved for moderate to severe dyspareunia in women with menopause-related vulvar and vaginal atrophy. The drug is approved in the USA, and application for EU regulatory approval is underway. This article summarizes the milestones in the development of ospemifene leading to this first approval for moderate to severe dyspareunia, a symptom of postmenopausal vulvar and vaginal atrophy. 22519721 A simple method of microneedle array fabrication for transdermal drug delivery. The outermost layer of skin, stratum corneum, being lipophilic limits the passive transport of hydrophilic and large molecular weight drugs. Microfabrication technology has been adapted to fabricate micron scale needles, which are minimally invasive, yet able to deliver the drugs across this barrier layer. In this study, we fabricated microneedles from a biocompatible polymer, namely, poly (ethylene glycol) diacrylate. A simple lithographical approach was developed for microneedle array fabrication. Several factors including polymerization time, ultraviolet light intensity and distance from light source were studied for their effects on microneedle formation. The microneedle length and tip diameter can be controlled by varying these factors. The microneedles were shown to be able to penetrate cadaver pig skin. Model drug rhodamine B was encapsulated in the range of 50 µg to 450 µg per microneedle array. The fabricated microneedles containing rhodamine B increased the permeability by four times than the control. Altogether, we demonstrated that the microneedle arrays can be fabricated through a simple single-step process and needles were mechanically strong to penetrate skin, increasing the permeability of encapsulated drug through skin. 23628841 Dendritic architectures based on bis-MPA: functional polymeric scaffolds for application-driven research. Dendritic polymers are highly branched, globular architectures with multiple representations of functional groups. These nanoscale organic frameworks continue to fascinate researchers worldwide and are today under intensive investigation in application-driven research. A large number of potential application areas have been suggested for dendritic polymers, including theranostics, biosensors, optics, adhesives and coatings. The transition from potential to real applications is strongly dictated by their commercial accessibility, scaffolding ability as well as biocompatibility. A dendritic family that fulfills these requirements is based on the 2,2-bismethylolpropionic acid (bis-MPA) monomer. This critical review is the first of its kind to cover most of the research activities generated on aliphatic polyester dendritic architectures based on bis-MPA. It is apparent that these scaffolds will continue to be in the forefront of cutting-edge research as their structural variations are endless including dendrons, dendrimers, hyperbranched polymers, dendritic-linear hybrids and their hybridization with inorganic surfaces. 23611626 Discovery of a New Class of Natural Product-Inspired Quinazolinone Hybrid as Potent Antileishmanial agents. The high potential of quinazolinone containing natural products and their derivatives in medicinal chemistry led us to discover four novel series of 53 compounds of quinazolinone based on the concept of molecular hybridization. Most of the synthesized analogues exhibited potent leishmanicidal activity against intracellular amastigotes (IC50 from 0.65 ± 0.2 to 7.76 ± 2.1 μM) as compared to miltefosine (IC50 = 8.4 ± 2.1 μM) and nontoxic toward the J-774A.1 cell line and Vero cells. Moreover, activation of Th1 type and suppression of Th2 type immune responses and induction in nitric oxide generation proved that 8a and 8g induce murine macrophages to prevent survival of parasites. Compounds 8a and 8g exhibited significant in vivo inhibition of parasite 73.15 ± 12.69% and 80.93 ± 10.50% against Leishmania donovani /hamster model. Our results indicate that compounds 8a, 8g, and 9f represent a new structural lead for this serious and neglected disease. 23200254 Inhibitors of HIV-1 attachment. Part 10. The discovery and structure-activity relationships of 4-azaindole cores. A series of 4-azaindole oxoacetic acid piperazine benzamides was synthesized and evaluated in an effort to identify an oral HIV-1 attachment inhibitor with the potential to improve upon the pre-clinical profile of BMS-378806 (7), an initial clinical compound. Modifications at the 7-position of the 4-azaindole core modulated potency significantly and SAR showed that certain compounds with a 5-membered ring heteroaryl group at that position were the most potent. Four of the compounds with the best profiles were evaluated in a rat pharmacokinetic model and all had superior oral bioavailability and lower clearance when compared with 7. 23239587 Loading metal nanostructures on cotton fabrics as recyclable catalysts. Noble metal nanostructures of varying compositions and shapes are loaded on cotton fabrics. The fabric-supported metal nanostructures can function as effective catalysts for different liquid-phase catalytic reactions. They exhibit superior recyclability, with the catalytic activities remaining nearly unchanged even after ten cycles of catalytic reactions for all of the three tested reactions. 23621768 Evaluation of Chlorpheniramine Maleate microparticles in orally disintegrating film and orally disintegrating tablet for pediatrics. Abstract Objective: To mask the bitterness of Chlorpheniramine Maleate via encapsulating drug into Eudragit EPO microparticles, and then incorporate these microparticles into orally disintegrating films (ODF) and orally disintegrating tablets (ODT) for pediatric uses. Methods: Spray drying of water-in-oil emulsion was utilized to encapsulate Chlorpheniramine Maleate into Eudragit EPO microparticles. Based on an orthogonal experimental design L9 (3(3)), polynomial regression models were developed to evaluate correlation between microparticle properties (encapsulation efficiency and drug release) and variables (X1: weight ratio of polymer to drug, X2: volume ratio of oil to water and X3: Q-flow of spray dryer). ODF and ODT formulations were evaluated including weight variation, content uniformity, tensile strength, disintegration time, friability and dissolution profiles. The bitterness taste test was evaluated in 10 adult volunteers. Results and discussion: From polynomial regression analysis, the best values of variables leading to the optimized microparticles were X1 = 10, X2 = 3 and X3 = 45. The optimized microparticles were incorporated into ODF and ODT with satisfactory weight and drug content uniformity, and acceptable physical strength. Both dosage forms disintegrated immediately (less than 40 s) in simulated saliva solutions. The outcome of taste-masking test indicated that microparticles alleviated drug bitterness significantly; bitterness was not discernible with microparticles incorporated in ODT, whereas only slight bitterness was detected from microparticles incorporated into ODF. Conclusion: Both ODF and ODT are shown to be suitable vehicles for taste masked Chlorpheniramine Maleate microparticles with potential for pediatric uses. 23376355 3,3'-Diindolymethane ameliorates adriamycin-induced cardiac fibrosis via activation of a BRCA1-dependent anti-oxidant pathway. The cardiotoxicity of adriamycin greatly limits its application in the treatment of cancer. Heart failure that is caused by adriamycin-treatment induced cardiac fibrosis is a major cause of death in patients who are treated with this medication. The severe oxidative stress that is induced by adriamycin is considered to be one of the primary mechanisms by which fibrogenesis of cardiac tissue occurs. In the present study, we demonstrate that 3,3'-diindolymethane (DIM) exhibits a significant anti-fibrosis effect on cardiac tissue in an animal model of adriamycin-induced cardiac fibrosis (AICF). Further studies demonstrated that DIM is able to dramatically up-regulate the expression of breast cancer type 1 susceptibility protein (BRCA1) in cardiac tissue and fibroblast, which subsequently activate the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The upregulation of this transcription factor resulted in the expression of several anti-oxidant genes in the cell. Because DIM is a safe food additive that has been used for decades, our findings suggest that there is a great potential for this chemical to be developed into a clinical medication for the treatment of adriamycin-induced heart failure during cancer therapy. 23619527 Insulin-like growth factor 1 (IGF-1) expression is up-regulated in lymphoblastoid cell lines of lithium responsive bipolar disorder patients. Bipolar disorder (BD) is a debilitating psychiatric disease characterized by alternating episodes of mania and depression. Among mood stabilizers, lithium is the mainstay for the treatment of BD, with approximately one-third of patients showing remission from episode recurrence. While there is evidence suggesting genetic load for lithium response in BD, its molecular underpinnings are still not completely understood. To identify genes potentially involved in (or correlated with) lithium response, we carried out a genome-wide expression analysis on lymphoblastoid cell lines (LCLs) from 10 BD patients responders (R) and 10 non-responders (NR) to lithium. We compared expression levels of the two groups and tested whether in vitro lithium treatment had different effects in LCLs of R compared to NR. At basal, 2060 genes were differentially expressed between R and NR while no genes were differentially regulated by lithium in the two groups. After pathway analysis based on the 2060 genes, 9 genes were selected for validation with qRT-PCR. Eight genes were validated in the same sample of LCLs while only insulin-like growth factor 1 (IGF-1) was significantly over-expressed in R compared to NR in the same sample as well as in an independent sample comprised of 6 R and 6 NR (sample 1, fold change=1.94; p=0.005; sample 2, fold change=2.21; p=0.005). IGF-1 was also significantly over-expressed in R but not in NR when compared to a sample of non-psychiatric controls. Our findings suggest that IGF-1 may be involved in lithium response, supporting further investigation on its potential as a biomarker. 23619006 2,3,7,8-TCDD induces neurotoxicity and neuronal apoptosis in the rat brain cortex and PC12 cell line through the down-regulation of the Wnt/β-catenin signaling pathway. TCDD exposure has various toxic effects on in the human nervous system resulting in various developmental and behavioral deficits. However the underlying molecular mechanism of TCDD-induced adverse effects on the CNS and associated signaling pathways remains largely unknown. Herein we analyzed acute TCDD exposure in the rat brain cortex to investigate whether misregulation of the Wnt/β-catenin signaling pathway plays a role in neurotoxicity. Western blot and immunohistochemical experiments revealed a significant down-regulation of β-catenin and phospho-glycogen synthase kinase-3β (pSer9-GSK-3β) after TCDD exposure. TUNEL assay results showed apoptosis occurs mainly at day 7 after TCDD treatment. Immunofluorescent labeling indicated that β-catenin was localized mainly in the neurons; co-localization of β-catenin and active caspase-3 was found following TCDD exposure. Further, TCDD exposure decreased the level of pSer9-GSK-3β and β-catenin, and increased apoptosis in the PC12 neuronal cell line in a dose-dependent manner. Interestingly the application of lithium chloride, a GSK-3β inhibitor, reversed the suppressive effect of TCDD on β-catenin in PC12 cells and primary cortical neurons restoring cell viability and protecting cells from apoptosis as compared to untreated controls. Taken together, these results indicate that the canonical Wnt/β-catenin signaling pathway may play an important role in TCDD-induced neurotoxicity and neuronal apoptosis. 23416413 Reproductive and health assessment of fathead minnows (Pimephales promelas) inhabiting a pond containing oil sands process-affected water. Previous laboratory based studies have shown that oil sands process-affected waters (OSPWs) containing high concentrations of naphthenic acids (>25 mg/l) have adverse effects on the reproductive physiology of fish. The purpose of this study was to assess the reproductive development and health of a wild population of fathead minnows (Pimephales promelas) inhabiting an OSPW pond that has moderate concentrations of naphthenic acids (~10 mg/l). Fathead minnows were collected at various times during the period of 2006 through 2008 from Demonstration Pond (OSPW) located at Syncrude Canada Ltd., and two reference sites, Beaver Creek reservoir and Poplar Creek reservoir, which are all north of Fort McMurray, AB, Canada. Condition factor, gill histopathology, gonadosomatic indices, liver somatic indices, male secondary sexual characteristics, and plasma sex steroids were examined. Depending on the time of year that fathead minnows were collected, there were differences in the condition factor, gonadosomatic indices, liver somatic indices, and secondary sexual characteristics of fathead minnows (in males) from Demonstration Pond when compared to the fathead minnows from the reference sites. In comparison to reference fish, lower concentrations of 11-ketotestosterone were measured in the plasma of male fathead minnows collected from Demonstration Pond in June 2006 and July 2007. Black spot disease and Ligula intestinalis were prevalent in fathead minnows from the reference sites but were not observed in fathead minnows from Demonstration Pond. The opercula of fathead minnows from Demonstration Pond also differed from those of reference fish. An examination of the gills of fathead minnows from Demonstration Pond revealed that were a number of proliferative and degenerative alterations relative to reference fish. Even though the fathead minnow population has been maintained in this OSPW pond since 1993, the results of this study demonstrate that the OSPW continues to affect the reproductive development and health of the fathead minnows compared to fish collected at reference sites. 23195330 Chronic autoimmune-mediated inflammation: a senescent immune response to injury. The increasing prevalence of chronic autoimmune-mediated inflammatory diseases (AIMIDs) in ageing western societies is a major challenge for the drug development industry. The current high medical need for more-effective treatments is at least in part caused by our limited understanding of the mechanisms that drive chronic inflammation. Here, we postulate a role for immunosenescence in the progression of acute to chronic inflammation via a dysregulated response to primary injury at the level of the damaged target organ. A corollary to this notion is that treatment of acute versus chronic phases of disease might require differential targeting strategies. 23561094 An integrated approach for flavour quality evaluation in muskmelon (Cucumis melo L. reticulatus group) during ripening. Numerous and diverse physiological changes occur during fruit ripening and maturity at harvest is one of the key factors influencing the flavour quality of fruits. The effect of ripening on chemical composition, physical parameters and sensory perception of three muskmelon (Cucumis melo L. reticulatus group) cultivars was evaluated. Significant correlations emerging from this extensive data set are discussed in the context of identifying potential targets for melon sensory quality improvement. A portable ultra-fast gas-chromatograph coupled with a surface acoustic wave sensor (UFGC-SAW) was also used to monitor aroma volatile concentrations during fruit ripening and evaluated for its ability to predict the sensory perception of melon flavour. UFGC-SAW analysis allowed the discrimination of melon maturity stage based on six measured peaks, whose abundance was positively correlated to maturity-specific sensory attributes. Our findings suggest that this technology shows promise for future applications in rapid flavour quality evaluation. 23435157 All-Cause and Cardiovascular Mortality in Middle-Aged People With Type 2 Diabetes Compared With People Without Diabetes in a Large U.K. Primary Care Database. OBJECTIVEMiddle-aged people with diabetes have been reported to have significantly higher risks of cardiovascular events than people without diabetes. However, recent falls in cardiovascular disease rates and more active management of risk factors may have abolished the increased risk. We aimed to provide an up-to-date assessment of the relative risks associated with type 2 diabetes of all-cause and cardiovascular mortality in middle-aged people in the U.K.RESEARCH DESIGN AND METHODSUsing data from the General Practice Research Database, from 2004 to 2010, we conducted a cohort study of 87,098 people, 40-65 years of age at baseline, comparing 21,798 with type 2 diabetes and 65,300 without diabetes, matched on age, sex, and general practice. We produced hazard ratios (HRs) for mortality and compared rates of blood pressure testing, cholesterol monitoring, and use of aspirin, statins, and antihypertensive drugs.RESULTSPeople with type 2 diabetes, compared with people without diabetes, had a twofold increased risk of all-cause mortality (HR 2.07 [95% CI 1.95-2.20], adjusted for smoking) and a threefold increased risk of cardiovascular mortality (3.25 [2.87-3.68], adjusted for smoking). Women had a higher relative risk than men, and people <55 years of age had a higher relative risk than those >55 years of age. Monitoring and medication rates were higher in those with diabetes (all P < 0.001).CONCLUSIONSDespite efforts to manage risk factors, administer effective treatments, and develop new therapies, middle-aged people with type 2 diabetes remain at significantly increased risk of death. 22910795 Impact of lead and mercuric ions on the interleukin-2-dependent proliferation and survival of T cells. Mercury and lead are widespread in the environment, causing chronic exposure of a large population to low concentrations of these metals. While several studies demonstrated that low levels of both metals affect the immune system, little is known about underlying molecular mechanisms. The objective of this study was to investigate the impact of mercuric (Hg(2+)) and lead (Pb(2+)) ions on T cells. Up to 100 μM Pb(NO(3))(2) had no effect on cellular viability and proliferation. In contrast, HgCl(2) caused a concentration-dependent decline of viable leukocytes and especially of activated T cells. Additionally, Hg(2+) induced reactive oxygen species (ROS) generation accompanied by the loss of mitochondrial transmembrane potential, measured by Dihydrorhodamine and Rhodamine-123, respectively. The antioxidant N-acetylcysteine partially reversed the toxic effects of Hg(2+), pointing to an involvement of ROS. The major cytokine controlling T-cell survival and proliferation is interleukin (IL)-2. Hg(2+) had no effect on the secretion of IL-2, but on IL-2 mediated signal transduction pathways, reducing phosphorylation of the downstream kinases ERK1/2 and AKT. Moreover, Hg(2+) led to an arrest of the cells in the S phase of the cell cycle. Taken together, these data fit a model in which Hg(2+) disrupts mitochondria, and the resulting release of ROS inhibits IL-2-dependent signal transduction, reducing proliferation and survival of T cells. 23363575 TCDD and corticosterone on testicular steroidogenesis and antioxidant system of epididymal sperm in rats. 2,3,7,8-Tetrachloro dibenzo-p-dioxin (TCDD), an endocrine-disrupting environmental pollutant, has been found to cause male reproductive toxicity. Glucocorticoids have been found to influence the metabolic pathway of TCDD. Stress, which affects the male reproductive function, is marked by an increase in the level and activity of glucocorticoids in the body. The present study was carried out to understand the effect of TCDD on testicular steroidogenesis and sperm antioxidant system under the influence of increased level of corticosterone in the body. Adult male rats were treated with either TCDD (100 ng/kg bw/ day) or corticosterone (3 mg/kg bw/day) or both for 15 days. Treatment with either TCDD or corticosterone was found to suppress the levels of steroidogenic acute regulatory protein and androgen-binding protein and reduce the activities of steroidogenic enzymes in testis while increasing oxidative stress in ventral prostate, seminal vesicles and epididymal sperm. In rats treated with both TCDD and corticosterone, the suppression of testicular steroidogenesis and increase in oxidative stress observed in ventral prostate, seminal vesicles and epididymal sperm were significant as compared to TCDD alone treated rats. The levels of Fas and FasL proteins were also increased in rats subjected to either TCDD or corticosterone treatment. In rats treated with both compounds, the increase observed in testicular levels of Fas and FasL was significant as compared to TCDD alone treated rats. Effect of TCDD on testicular steroidogenesis and antioxidant system of epididymal sperm may get enhanced under increased level of glucocorticoids in the body. 23376250 Molecular insight into the inhibition mechanism of cyrtominetin to α-hemolysin by molecular dynamics simulation. The protein α-hemolysin (α-HL) is a self-assembling exotoxin that binds to the membrane of a susceptible host cell. In this paper, experimental studies show that cyrtominetin (CTM) can inhibit the hemolytic activity of α-HL. To understand how CTM can affect hemolytic activity, molecular dynamics simulations were carried out for α-HL-CTM complex and these results were compared with the crystal structure of monomeric α-HL. With this approach, the analysis revealed that the inhibition of CTM involves CTM directly binding to α-HL. Due to the binding of CTM, the conformation of the critical "Loop" region was restrained. This mechanism was confirmed by the experimental data. These findings indicate that CTM hinders the lysis activity of α-HL through a novel mechanism. 23625273 Hyperphosphataemia: Treatment Options. Hyperphosphataemia can be induced by three main conditions: a massive acute phosphate load, a primary increase in renal phosphate reabsorption, and an impaired renal phosphate excretion due to acute or chronic renal insufficiency. Renal excretion is so efficient in normal subjects that balance can be maintained with only a minimal rise in serum phosphorus concentration even for a large phosphorus load. Therefore, acute hyperphosphataemia usually resolves within few hours if renal function is intact. The most frequent cause of chronic hyperphosphataemia is chronic renal failure. Hyperphosphataemia in chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality. Lowering the phosphate load and maintaining serum phosphorus levels within the normal range are considered important therapeutic goals to improve clinical outcomes in CKD patients. Treatment consists of diminishing intestinal phosphate absorption by a low phosphate diet and phosphate binders. In CKD patients on dialysis an efficient dialysis removal of phosphate should be ensured. Dietary restriction of phosphorus while maintaining adequate protein intake is not sufficient to control serum phosphate levels in most CKD patients; therefore, the prescription of a phosphate binder is required. Aluminium-containing agents are efficient but no longer widely used because of their toxicity. Calcium-based salts are inexpensive, effective and most widely used, but there is now concern about their association with hypercalcaemia, parathyroid gland suppression, adynamic bone disease, and vascular and extraosseous calcification. The average daily dose of calcium acetate or carbonate prescribed in the randomised controlled trials to control hyperphosphataemia in dialysis patients ranges between 1.2 and 2.3 g of elemental calcium. Such doses are greater than the recommended dietary calcium intake and can lead to a positive calcium balance. Although large amounts of calcium salts should probably be avoided, modest doses (<1 g of elemental calcium) may represent a reasonable initial approach to reduced serum phosphorus levels. A non-calcium-based binder can then be added when large doses of binder are required. At present, there are three types of non-calcium-based phosphate binders available: sevelamer, lanthanum carbonate and magnesium salts. Each of these compounds is as effective as calcium salts in lowering serum phosphorus levels depending on an adequate prescribed dose and adherence of the patient to treatment. Sevelamer is the only non-calcium-containing phosphate binder that does not have potential for systemic accumulation and presents pleiotropic effects that may impact on cardiovascular disease. In contrast, lanthanum carbonate and magnesium salts are absorbed in the gut and their route of excretion is biliary for lanthanum and urinary for magnesium. There are insufficient data to establish the comparative superiority of non-calcium binding agents over calcium salts for such important patient-level outcomes as all-cause mortality and cardiovascular end points. Moreover, full adoption of sevelamer and lanthanum by government drug reimbursement agencies in place of calcium salts would lead to a large increase in health-care expenditure. Therefore, the choice of phosphate binder should be individualised, considering the clinical context, the costs, and the individual tolerability the concomitant effects on other parameters of mineral metabolism, such as serum calcium and parathyroid hormone, besides those on serum phosphorus. 23552269 Effect of sugammadex on rocuronium induced changes in pancreatic mast cells. Mast cells play a vital role in hypersensitivity reactions. Rocuronium is known to cause mast cell mobilization, hypersensitivity, and pancreatitis. The aim of this study was to investigate the effects of sugammadex on pancreatic changes due to rocuronium. A total of 42 Sprague-Dawley male rats were divided into six equal groups to receive either rocuronium 1 mg/kg intravenously (i.v., R group), rocuronium 1 mg/kg + sugammadex 16 mg/kg i.v. (RS16 group), rocuronium 1 mg/kg + sugammadex 96 mg/kg i.v. (RS96 group), sugammadex 16 mg/kg (S16), sugammadex 96 mg/kg i.v. (S96 group), or 0.9% sodium chloride (control group). Sugammadex was administered 5s later following rocuronium. In R group, mast count was higher, and the distribution rate of granules and nuclear changes were different compared with other groups. Distribution rate of granules in groups S16 and S96 were similar to the control group and lower compared with other groups. The amount of mast cells and granule density in groups RS16 and RS96 was lower compared with R group. The amount of mast cells in groups RS16 and RS96 was significantly lower compared with other treatment groups. These results suggest that sugammadex may have an inhibitory effect on mobilization and morphological changes in pancreatic mast cells induced by administration of rocuronium and sugammadex in rats. 23454672 Lipophilic components from Fructus Viticis Negundo and their anti-tumor activities. Two new triterpenoids, (24R/S)-24-hydroxy-3α 10α-epoxy-9-eip-cucurbita-25-ene (1a, b), as well as six known compounds (3-8), were isolated from the extraction of Fructus Viticis Negundo. Their structures were established on the basis of spectral analysis. In addition, all the compounds were tested for inhibitory effect against K-562 and A-549 cell lines. 22648611 Metabonomic Study of Genkwa Flos-induced Hepatotoxicity and Effect of Herb-Processing Procedure on Toxicity. A urinary metabonomic approach based on ultraperformance liquid chromatography coupled with mass spectrometry (UPLC-MS) was developed to study the metabolic disturbances caused by the administration of Genkwa Flos (GF) to rats. Potential biomarkers of GF-induced toxic effects were screened out and identified, and the underlying toxicological mechanism as well as the detoxification of vinegar-processing procedure on this herb was discussed. Urine samples were analyzed by the established UPLC-MS method. With the help of serum biochemistry and histopathology results, metabolic disturbances induced by the exposure to GF and the detoxification of processing procedure were confirmed. The differences in the metabolic profiles of healthy and treated rats were clearly discriminated with the principal component analysis of the chromatographic data. Eight significantly changed metabolites were identified and interpreted as biomarkers for the hepatotoxicity and detoxification of processing procedure. This study indicated that a UPLC-MS-based metabonomic analysis of urine samples could be considered as a promising tool to predict the hepatotoxicity induced by the GF and the detoxification of traditional vinegar-processing procedure on this herb. Copyright © 2012 John Wiley & Sons, Ltd. 23122147 Non-targeted metabolomic approach reveals urinary metabolites linked to steroid biosynthesis pathway after ingestion of citrus juice. Citrus juice intake has been highlighted because of its health-promoting effects. LC-MS based metabolomics approaches are applied to obtain a better knowledge on changes in the concentration of metabolites due to its dietary intake and allow a better understanding of involved metabolic pathways. Eight volunteers daily consumed 400 mL of juice for four consecutive days and urine samples were collected before intake and 24h after each citrus juice intake. Urine samples were analysed by nanoHPLC-q-TOF, followed by principal component analysis (PCA) and Student's t-test (p<0.05). PCA showed a separation between two groups (before and after citrus juice consumption). This approach allowed the identification of four endocrine compounds (tetrahydroaldosterone-3-glucuronide, cortolone-3-glucuronide, testosterone-glucuronide and 17-hydroxyprogesterone), which belonged to the steroid biosynthesis pathway as significant metabolites upregulated by citrus juice intake. Additionally, these results confirmed the importance of using the non-targeted metabolomics technique to identify new endogenous metabolites, up- or down-regulated as a consequence of food intake. 23469760 Hybridization of Phenylthiolate- and Methylthiolate-Adatom Species at Low Coverage on the Au(111) Surface. Using scanning tunneling microscopy we observed reaction products of two chemisorbed thiolate species, methylthiolate and phenylthiolate, on the Au(111) surface. Despite the apparent stability, organometallic complexes of methylthiolate and phenylthiolate with the gold-adatom (RS-Au-SR, with R - the hydrocarbon group) undergo a stoichiometric exchange reaction, forming hybridized CH3S-Au-SPh complexes. Complementary density functional theory calculations suggest that the reaction is most likely mediated by a monothiolate RS-Au complex bonded to the gold surface, which forms a trithiolate RS-Au-(SR)-Au-SR complex as a key intermediate. This work therefore reveals the novel chemical reactivity of the low-coverage "striped" phase of alkanethiols on gold and strongly points to the involvement of monoadatom thiolate intermediates in this reaction. By extension, such intermediates may be involved in the self-assembly process itself, shedding new light on this long-standing problem. 23195733 Synthesis and antiplasmodial evaluation of novel (4-aminobutyloxy)quinolines. A variety of 5-, 6- and 8-(4-aminobutyloxy)quinolines as novel oxygen analogues of known 4- and 8-(4-aminobutylamino)quinoline antimalarial drugs was generated from hydroxyquinolines through a three-step approach with a rhodium-catalyzed hydroformylation as the key step. Antiplasmodial assays of these new quinolines revealed micromolar potency for all representatives against a chloroquine-sensitive strain of Plasmodium falciparum, and three compounds showed submicromolar activity against a chloroquine-resistant strain of P. falciparum with IC(50)-values ranging between 150 and 680 nM. 23604720 Aldose Reductase Inhibitory Compounds from Xanthium strumarium. As part of our ongoing search for natural sources of therapeutic and preventive agents for diabetic complications, we evaluated the inhibitory effects of components of the fruit of Xanthium strumarium (X. strumarium) on aldose reductase (AR) and galactitol formation in rat lenses with high levels of glucose. To identify the bioactive components of X. strumarium, 7 caffeoylquinic acids and 3 phenolic compounds were isolated and their chemical structures were elucidated on the basis of spectroscopic evidence and comparison with published data. The abilities of 10 X. strumarium-derived components to counteract diabetic complications were investigated by means of inhibitory assays with rat lens AR (rAR) and recombinant human AR (rhAR). From the 10 isolated compounds, methyl-3,5-di-O-caffeoylquinate showed the most potent inhibition, with IC50 values of 0.30 and 0.67 μM for rAR and rhAR, respectively. In the kinetic analyses using Lineweaver-Burk plots of 1/velocity and 1/substrate, methyl-3,5-di-O-caffeoylquinate showed competitive inhibition of rhAR. Furthermore, methyl-3,5-di-O-caffeoylquinate inhibited galactitol formation in the rat lens and in erythrocytes incubated with a high concentration of glucose, indicating that this compound may be effective in preventing diabetic complications. 23165858 Bacteriophages as templates for manufacturing supramolecular structures. SS phages are genetically enginnered by replacing 2 N-terminal amino acids of the p8 coat protein of the fd phage. AGE and zeta potential measurements show that SS phages carry at least 1/4 less net negative surface charge than fd phages. Morphology and thickness of phages are studied at different counterion concentrations (10(-3) , 10(-2) and 10(-1)  M) by AFM, SEM and immunofluorescence analyses. Bundles induced by CoCl2 and CaCl2 are either metallized by chemical reduction or biomineralized for apatite-like material formation. EDX spectroscopy confirms the presence of Co, P and Ca peaks in mineralized samples. Such bottom-up manufactured phage scaffolds might be applied in bioengineering studies. 23305495 Semisynthesis and myocardial activity of thaliporphine N-homologues. The N-homologues and optical isomers of thaliporphine (5a), a potent antiarrhythmic agent, were prepared starting from laurolitsine (1), an abundant aporphine present in Phoebe formosana. Treating N-propylnorglaucine with 90% H2SO4 yielded one additional product, an 11-sulfonyl-1,11-anhydroaporphine. Reaction of N-formylnorglaucine (3a) with 90% H2SO4, however, yielded the 9-sulfonyl-seco product as a major product. Treatment of 3a with 98% H2SO4 yielded pancordine (10), which, upon catalytic hydrogenation, yielded (±)-wilsonirine. (1)H NMR spectroscopic analysis was applied successfully to monitor the optical purity of the crystalline salt while undertaking optical resolution. Thaliporphine (5a) was demonstrated to possess better positive inotropic and less negative chronotropic effects than the left-hand optical isomer and showed the best activity on rat cardiac tissue among the N-homologues prepared. 23364815 Opiate agonists and antagonists modulate taste perception in opiate-maintained and recently detoxified subjects. Heroin addicts consume large quantities of refined sugars. This study investigated the effect of opiate use and antagonism on sweet taste in opiate-maintained drug users and detoxified former chronic opiate users, using a within-subject design. Seven opiate users received methadone and seven buprenorphine maintenance. Six detoxified subjects received naltrexone. Sucrose recognition thresholds and measurements of pleasantness and intensity were determined before and four hours after 1) a single dose of methadone or buprenorphine or 2) naltrexone. Control data were taken from a cohort of healthy volunteers including smokers. All measures of sweet and salt taste perception were significantly greater in opiate users and recently detoxified subjects compared to control subjects, with the exception of sweet pleasantness, which returned to control level after detoxification. Acute methadone administration reduced salt thresholds and unpleasantness to control levels. Increased sweet thresholds and salt unpleasantness in detoxified subjects were reversed by acute opioid antagonism, returning to control levels. These results suggest that opiate use and antagonism alters taste perception. Some of the alterations reverse on detoxification (sweet pleasantness), and others can be reversed by opioid antagonism (sweet threshold, salt unpleasantness). Changes in taste perception may underlie altered consumption of refined sugars in opiate users. 23449195 Formulation, optimization, in vivo pharmacokinetic, behavioral and biochemical estimations of minocycline loaded chitosan nanoparticles for enhanced brain uptake. The minocycline hydrochloride (MH), at higher doses, is useful in the treatment of neurodegenerative disorders and owing to its antioxidant potential, it may have nootropic effects. MH loaded nanoparticles (MHNP) were coated with tween 80 (cMHNP) to improve its brain uptake followed by their optimization employing two factor-three level (3(2)) central composite design (CCD) in order to minimize particle size and maximize drug entrapment efficiency (DEE) and validated. The optimized formulations were further subjected to in vitro drug release study; in vivo biodistribution studies in male wistar rats. The pharmacodynamic study was carried out using elevated plus maze (EPM) and Morris water maze (MWM) behavioral models for nootropic activity in swiss albino mice; and biochemical estimations (acetylcholine esterase, reduced glutathione, malondialdehyde and brain nitrite level). After intravenous (i.v.) administration, the concentration of MH in brain of cMHNP (6.21±0.64 µg/mL) treated rats was significantly higher with MH solution treated (0.70±0.06 µg/mL) as well as MHNP (1.03±0.12 µg/mL) treated animals. Pharmacodynamic studies revealed a significant improvement in memory of MH, MHNP and cMHNP treated swiss albino mice than saline treated control group. However, cMHNP revealed maximum decrease in transfer latency (TL) in EPM and maximum increase in time spent in target quadrant (TSTQ) in MWM. Although cMHNP did not produce significant change in brain acetylcholinesterase, but, significantly increased reduced glutathione, malondialdehyde and reduced brain nitrite level as compared to saline, MH solution and MHNP treated groups. The results suggest that cMHNP is a promising candidate for improved brain uptake of MH with better nootropic effect. 23582326 Nr4a1-Dependent Ly6C(low) Monocytes Monitor Endothelial Cells and Orchestrate Their Disposal. The functions of Nr4a1-dependent Ly6C(low) monocytes remain enigmatic. We show that they are enriched within capillaries and scavenge microparticles from their lumenal side in a steady state. In the kidney cortex, perturbation of homeostasis by a TLR7-dependent nucleic acid "danger" signal, which may signify viral infection or local cell death, triggers Gαi-dependent intravascular retention of Ly6C(low) monocytes by the endothelium. Then, monocytes recruit neutrophils in a TLR7-dependent manner to mediate focal necrosis of endothelial cells, whereas the monocytes remove cellular debris. Prevention of Ly6C(low) monocyte development, crawling, or retention in Nr4a1(-/-), Itgal(-/-), and Tlr7(host-/-BM+/+) and Cx3cr1(-/-) mice, respectively, abolished neutrophil recruitment and endothelial killing. Prevention of neutrophil recruitment in Tlr7(host+/+BM-/-) mice or by neutrophil depletion also abolished endothelial cell necrosis. Therefore, Ly6C(low) monocytes are intravascular housekeepers that orchestrate the necrosis by neutrophils of endothelial cells that signal a local threat sensed via TLR7 followed by the in situ phagocytosis of cellular debris. 23620134 Polymorphism in porphyrin monolayers: the relation between adsorption configuration and molecular conformation. Self-assembled monolayers of meso-5,10,15,20-tetrakis(undecyl)porphyrin copper(ii) on a graphite/1-octanoic acid interface have been studied by Scanning Tunnelling Microscopy. Four distinct polymorphs were observed, varying in their unit cell size. Arrays of unit cells of the various polymorphs seamlessly connect to each other via shared unit cell vectors. The monolayers are not commensurate, but coincident with the underlying graphite substrate. The seamless transition between the polymorphs is proposed to be the result of an adaptation of the molecular conformations in the polymorphs and at the boundaries, which is enabled by the conformational freedom of the alkyl tails of these molecules. 23506537 Paths to selection on life history loci in different natural environments across the native range of Arabidopsis thaliana. Selection on quantitative trait loci (QTL) may vary among natural environments due to differences in the genetic architecture of traits, environment-specific allelic effects or changes in the direction and magnitude of selection on specific traits. To dissect the environmental differences in selection on life history QTL across climatic regions, we grew a panel of interconnected recombinant inbred lines (RILs) of Arabidopsis thaliana in four field sites across its native European range. For each environment, we mapped QTL for growth, reproductive timing and development. Several QTL were pleiotropic across environments, three colocalizing with known functional polymorphisms in flowering time genes (CRY2, FRI and MAF2-5), but major QTL differed across field sites, showing conditional neutrality. We used structural equation models to trace selection paths from QTL to lifetime fitness in each environment. Only three QTL directly affected fruit number, measuring fitness. Most QTL had an indirect effect on fitness through their effect on bolting time or leaf length. Influence of life history traits on fitness differed dramatically across sites, resulting in different patterns of selection on reproductive timing and underlying QTL. In two oceanic field sites with high prereproductive mortality, QTL alleles contributing to early reproduction resulted in greater fruit production, conferring selective advantage, whereas alleles contributing to later reproduction resulted in larger size and higher fitness in a continental site. This demonstrates how environmental variation leads to change in both QTL effect sizes and direction of selection on traits, justifying the persistence of allelic polymorphism at life history QTL across the species range. 23153668 Retinal drug delivery using eyedrop preparations of poly-L-lysine-modified liposomes. The purpose of this study was to develop surface-modified liposomes that enhance the efficiency of eye drop drug delivery to the retina. Various molecular weights and concentrations of the water-soluble cationic polymer poly-L-lysine (PLL) were used to modify the surface of submicronized (100 nm) liposomes. Physicochemical properties of surface-modified liposomes were determined in vitro, and the efficiency of drug delivery to the retina was investigated in vivo. Using coumarin-6 as a model drug and fluorescent marker, we show that liposome surface modification by PLL dramatically increased delivery to mouse retina segments after eye drop administration. However, when PLL of high molecular weight (>30,000) was used at higher concentrations (>0.05%), aggregation of surface-modified liposomes increased particle size and hampered distribution to inner ocular tissues. As a result, the efficiency of drug delivery of these aggregated surface-modified liposomes was the same as unmodified liposomes. The optimal molecular weight and concentration of PLL in drug-delivering liposomes were 15,000-30,000 and 0.005%, respectively. Under these conditions, PLL-modified liposomes were not cytotoxic in corneal or conjunctival cells. In conclusion, surface-modified liposomes have great potential as effective retinal drug delivery carriers in eye drop formulations. 23097157 A single-device universal logic gate based on a magnetically enhanced memristor. Memristors are one of the most promising candidates for future information and communications technology (ICT) architectures. Two experimental proofs of concept are presented based on the intermixing of spintronic and memristive effects into a single device, a magnetically enhanced memristor (MEM). By exploiting the interaction between the memristance and the giant magnetoresistance (GMR), a universal implication (IMP) logic gate based on a single MEM device is realized. 23613450 Biodegradable Polysilsesquioxane Nanoparticles as Efficient Contrast Agents for Magnetic Resonance Imaging. Polysilsesquioxane (PSQ) nanoparticles are crosslinked homopolymers formed by condensation of functionalized trialkoxysilanes, and provide an interesting platform for developing biologically and biomedically relevant nanomaterials. In this work, the design and synthesis of biodegradable PSQ particles with extremely high payloads of paramagnetic Gd(III) centers is explored, for use as efficient contrast agents for magnetic resonance imaging (MRI). Two new bis(trialkoxysilyl) derivatives of Gd(III) diethylenetriamine pentaacetate (Gd-DTPA) containing disulfide linkages are synthesized and used to form biodegradable Gd-PSQ particles by base-catalyzed condensation reactions in reverse microemulsions. The Gd-PSQ particles, PSQ-1 and PSQ-2, carry 53.8 wt% and 49.3 wt% of Gd-DTPA derivatives, respectively. In addition, the surface carboxy groups on the PSQ-2 particles can be modified with polyethylene glycol (PEG) and the anisamide (AA) ligand to enhance biocompatibility and cell uptake, respectively. The Gd-PSQ particles are readily degradable to release the constituent Gd(III) chelates in the presence of endogenous reducing agents such as cysteine and glutathione. The MR relaxivities of the Gd-PSQ particles are determined using a 3T MR scanner, with r1 values ranging from 5.9 to 17.8 mMs(-1) on a per-Gd basis. Finally, the high sensitivity of the Gd-PSQ particles as T1 -weighted MR contrast agents is demonstrated with in vitro MR imaging of human lung and pancreatic cancer cells. The enhanced efficiency of the anisamide-functionalized PSQ-2 particles as a contrast agent is corroborated by both confocal laser scanning microscopy imaging and ICP-MS analysis of Gd content in vitro. 23418165 Cytotoxic and apoptosis-inducing activities of steviol and isosteviol derivatives against human cancer cell lines. Seventeen steviol derivatives, i.e., 2-18, and 19 isosteviol derivatives, i.e., 19-37, were prepared from a diterpenoid glycoside, stevioside (1). Upon evaluation of the cytotoxic activities of these compounds against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3) cancer cell lines, nine steviol derivatives, i.e., 5-9 and 11-14, and five isosteviol derivatives, i.e., 28-32, exhibited activities with single-digit micromolar IC(50) values against one or more cell lines. All of these active compounds possess C(19)-O-acyl group, and among which, ent-kaur-16-ene-13,19-diol 19-O-4',4',4'-trifluorocrotonate (14) exhibited potent cytotoxicities against four cell lines with IC(50) values in the range of 1.2-4.1 μM. Compound 14 induced typical apoptotic cell death in HL60 cells upon evaluation of the apoptosis-inducing activity by flow-cytometric analysis. These results suggested that acylation of the 19-OH group of kaurane- and beyerane-type diterpenoids might be useful for enhancement of their cytotoxicities with apoptosis-inducing activity. 23322418 Insights into TIM-barrel prenyl transferase mechanisms: crystal structures of PcrB from Bacillus subtilis and Staphylococcus aureus. Well structured: As a new triose phosphate isomerase (TIM) barrel-fold prenyl transferase, PcrB catalyzes the production of heptaprenylglyceryl phosphate from heptaprenyl diphosphate and glycerol-1-phosphate. Crystal structures of PcrB from Bacillus subtilis and Staphylococcus aureus in complex with ligands were solved, and together with site-directed mutagenesis and bioinformatics analyses, clearly reveal the catalytic mechanism of the enzyme. 23615073 Vitamin C forestalls cigarette smoke induced NF-κB activation in alveolar epithelial cells. Cigarette smoking causes cellular oxidative stress resulting in inflammatory diseases of lung wherein transcription factor NF-κB plays an important role. It is possible that vitamin C, an antioxidant, may prevent cigarette smoke (CS)-induced NF-κB activation that involves degradation of I-κBε and nuclear translocation of c-Rel/p50 in alveolar epithelial cells. Therefore, to examine the hypothesis, we verified the effect of vitamin C on CS-induced expression of NF-κB driven luciferase reporter and NF-κB binding at its target DNA by EMSA in alveolar epithelial A549 cells. We also examined the level of I-κBε and sub-cellular distribution of c-Rel by western blotting and immunofluorescence respectively in CSE-treated A549 cells with or without vitamin C pretreatment. We observed a significant reduction in CSE induced luciferase expression, NF-κB DNA binding, I-κBε degradation and c-Rel nuclear translocation in cells pretreated with vitamin C. To further validate the result, we examined sub-cellular distribution of c-Rel in lungs of CS-exposed guinea pigs treated or untreated with vitamin C. Result showed that vitamin C treatment resulted in markedly reduced c-Rel nuclear translocation. All these results demonstrate that vitamin C prevents CS(E)-induced NF-κB activation and thus it could be used for the prevention of CS-induced inflammatory diseases. 23572389 Hypermethylation of P15, P16, and E-cadherin genes in ovarian cancer. Both p16 and p15 proteins are inhibitors of cyclin-dependent kinases that prevent the cell going through the G1/S phase transaction. E-cadherin is a transmembrane glycoprotein that mediates calcium-dependent interactions between adjacent epithelial cells. Two groups of patients were selected: the first group suffered from epithelial serous ovarian tumors and the second group suffered from benign ovarian lesions; ovarian tissue samples from all the subjects (benign and malignant) were subjected to methylation-specific polymerase chain reaction for methylated and unmethylated alleles of the genes (E-cadherin, p15, and p16). Results obtained showed that aberrant methylation of p15 and p16 genes were detected in 64.29 and 50% of ovarian cancer patients, while E-cadherin hypermethylation was detected in 78.57% of ovarian cancer patients. Methylation of E-cadherin was significantly correlated with different stage of disease (p < 0.05). It was found that the risk of E-cadherin hypermethylation was 1.347-fold, while risk of p15 hypermethylation was 1.543-fold and p16 was 1.2-fold among patients with ovarian cancer than that among patients with benign ovarian lesions. In conclusion, Dysfunction of the cell cycle and/or the cell-cell adhesion molecule plays a role in the pathogenesis of ovarian cancer and that the analysis of the methylation of p15 and E-cadherin genes can provide clinically important evidence on which to base the treatment. 23127499 Down-regulation of 8-oxoguanine DNA glycosylase 1 expression in the airway epithelium ameliorates allergic lung inflammation. Allergic airway inflammation is characterized by increased expression of pro-inflammatory mediators, inflammatory cell infiltration, mucus hypersecretion, and airway hyperresponsiveness, in parallel with oxidative DNA base and strand damage, whose etiological role is not understood. Our goal was to establish the role of 8-oxoguanine (8-oxoG), a common oxidatively damaged base, and its repair by 8-oxoguanine DNA glycosylase 1 (Ogg1) in allergic airway inflammatory processes. Airway inflammation was induced by intranasally administered ragweed (Ambrosia artemisiifolia) pollen grain extract (RWPE) in sensitized BALB/c mice. We utilized siRNA technology to deplete Ogg1 from airway epithelium; 8-oxoG and DNA strand break levels were quantified by Comet assays. Inflammatory cell infiltration and epithelial methaplasia were determined histologically, mucus and cytokines levels biochemically and enhanced pause was used as the main index of airway hyperresponsiveness. Decreased Ogg1 expression and thereby 8-oxoG repair in the airway epithelium conveyed a lower inflammatory response after RWPE challenge of sensitized mice, as determined by expression of Th2 cytokines, eosinophilia, epithelial methaplasia, and airway hyperresponsiveness. In contrast, 8-oxoG repair in Ogg1-proficient airway epithelium was coupled to an increase in DNA single-strand break (SSB) levels and exacerbation of allergen challenge-dependent inflammation. Decreased expression of the Nei-like glycosylases Neil1 and Neil2 that preferentially excise ring-opened purines and 5-hydroxyuracil, respectively, did not alter the above parameters of allergic immune responses to RWPE. These results show that DNA SSBs formed during Ogg1-mediated repair of 8-oxoG augment antigen-driven allergic immune responses. A transient modulation of OGG1 expression/activity in airway epithelial cells could have clinical benefits. 23362940 Tuning the magnetic properties of metal oxide nanocrystal heterostructures by cation exchange. For three types of colloidal magnetic nanocrystals, we demonstrate that postsynthetic cation exchange enables tuning of the nanocrystal's magnetic properties and achieving characteristics not obtainable by conventional synthetic routes. While the cation exchange procedure, performed in solution phase approach, was restricted so far to chalcogenide based semiconductor nanocrystals, here ferrite-based nanocrystals were subjected to a Fe(2+) to Co(2+) cation exchange procedure. This allows tracing of the compositional modifications by systematic and detailed magnetic characterization. In homogeneous magnetite nanocrystals and in gold/magnetite core shell nanocrystals the cation exchange increases the coercivity field, the remanence magnetization, as well as the superparamagnetic blocking temperature. For core/shell nanoheterostructures a selective doping of either the shell or predominantly of the core with Co(2+) is demonstrated. By applying the cation exchange to FeO/CoFe(2)O(4) core/shell nanocrystals the Neél temperature of the core material is increased and exchange-bias effects are enhanced so that vertical shifts of the hysteresis loops are obtained which are superior to those in any other system. 23380568 Association of serum proprotein convertase subtilisin/kexin type 9 with carotid intima media thickness in hypertensive subjects. OBJECTIVE: The clinical significance of the measurement of serum PCSK9 (proprotein subtilisin kexin type 9) is not well defined. This study investigated the association between serum PCSK9 levels and atherosclerosis assessed by carotid intima media thickness (IMT) in hypertensive patients. METHODS: A total of 126 hypertensive patients over the age of 45 were enrolled. The maximum carotid IMT (max-IMT) and the mean carotid IMT (mean-IMT) were measured at the time of enrollment. Clinical and laboratory parameters including serum PCSK9 were analyzed. RESULTS: Patients were divided into tertiles based on serum PCSK9 levels. After adjusting for age, sex, total cholesterol, HDL-cholesterol and triglyceride, max-IMT was significantly increased in the highest tertile of serum PCSK9 (0.969±0.033 vs 0.959±0.033 vs 1.077±0.033mm, respectively; P=0.026). Mean-IMT showed a tendency to increase across the tertile groups (0.773±0.025 vs 0.790±0.026 vs 0.856±0.025mm, respectively; P=0.059). Multivariate regression analysis revealed that serum PCSK9 was independently associated with carotid IMT (max-IMT: β=0.212, P=0.016; mean-IMT: β=0.184, P=0.04). CONCLUSION: The present study is the first to report the association between serum PCSK9 levels and carotid IMT in hypertensive patients. These results suggest that serum PCSK9 may have a certain role in early pathogenesis of atherosclerosis. 23298613 Biodegradable core-shell nanoassemblies for the delivery of docetaxel and Zn(II)-phthalocyanine inspired by combination therapy for cancer. Combination therapies for cancer aim to exploit either additive or synergistic effects arising from the action of two species with the final goal to maximize the therapeutic efficacy. In this work, we develop multifunctional nanoparticles (NPs) for co-delivery of the conventional anticancer drug docetaxel (DTX) and the second generation photosensitizer zinc-phthalocyanine (ZnPc) as potential dual carrier system for the combination of chemotherapy and photodynamic therapy (PDT). Biodegradable and amphiphilic block copolymers based on poly(ε-caprolactone) (PCL=B) and poly(ethylene oxide) (PEO=A), with AB and ABA architectures, were assembled in "core-shell" NPs and loaded with both DTX and ZnPc employing the melting/sonication method. Hydrodynamic diameters within the range 60-100nm and low polydispersity indexes were obtained. Zeta potential was negative for all the formulations and unaffected by drug encapsulation. Concerning drug loading ability of NPs, the entrapment efficiency was related to initial ZnPc/DTX ratio. Steady-stationary and time-resolved emission fluorescence measurements pointed out the embedding of monomeric ZnPc in the NPs, excluding the presence of ZnPc self-supramolecular oligomers. The release of DTX was biphasic whereas ZnPc remained mainly associated with NPs. Singlet oxygen generation was observed when ZnPc-loaded NPs were irradiated at 610nm within a 45min time range, despite that ZnPc was not released in the medium. Stability of NPs in the presence of serum proteins and plasma was excellent and no toxicity toward red blood cells was found. NPs cytotoxicity was evaluated in HeLa cells irradiated for 30min with a halogen lamp. After 72h, viability of cells treated with ZnPc/DTX-loaded NPs strongly decreased as compared to NPs loaded only with DTX, thus showing a combined effect of both DTX and ZnPc. Superior antitumor activity of ZnPc/DTX-loaded NPs as compared to DTX-loaded NPs was confirmed in an animal model of orthotopic amelanotic melanoma, thus pointing to the application of PEO-PCL NPs in the combined chemo-photodynamic therapy of cancer. 23097088 Intercellular adhesion molecule-2 is involved in apical ectoplasmic specialization dynamics during spermatogenesis in the rat. In this study, we investigated the role of intercellular adhesion molecule-2 (ICAM2) in the testis. ICAM2 is a cell adhesion protein having important roles in cell migration, especially during inflammation when leukocytes cross the endothelium. Herein, we showed ICAM2 to be expressed by germ and Sertoli cells in the rat testis. When a monospecific antibody was used for immunolocalization experiments, ICAM2 was found to surround the heads of elongating/elongated spermatids in all stages of the seminiferous epithelial cycle. To determine whether ICAM2 is a constituent of apical ectoplasmic specialization (ES), co-immunoprecipitation and dual immunofluorescence staining were performed. Interestingly, ICAM2 was found to associate with β1-integrin, nectin-3, afadin, Src, proline-rich tyrosine kinase 2, annexin II, and actin. Following CdCl₂ treatment, ICAM2 was found to be upregulated during restructuring of the seminiferous epithelium, with round spermatids becoming increasingly immunoreactive for ICAM2 by 6-16 h. Interestingly, there was a loss in the binding of ICAM2 to actin during CdCl₂-induced germ cell loss, suggesting that a loss of ICAM2-actin interactions might have facilitated junction restructuring. Taken collectively, these results illustrate that ICAM2 plays an important role in apical ES dynamics during spermatogenesis. 23543864 Mass and Ion Transport in Ketones and Ketone Electrolytes: Comparison with Acetate Systems. Self-diffusion coefficient measurements were performed for pure n-alkyl ketone liquids using the pulsed field gradient NMR spin-echo technique. Ionic conductivities and dielectric constants of 0.0055 mol·L(-1) tetrabutylammonium trifluoromethanesulfonate in 2-pentanone, 2-hexanone, 2-heptanone, 2-octanone, 2-nonanone, and 2-decanone were also measured. The temperature-dependent conductivities and diffusion coefficients over the range 5-80 °C can be described using the compensated Arrhenius formalism. Compensated Arrhenius equation plots were used to calculate the average activation energy for both sets of data. The average activation energy from conductivity data is approximately equal to that from diffusion data. The data for the pure ketones and ketone-based electrolytes are compared with analogous data for pure n-alkyl acetates and n-alkyl acetate-based electrolytes. 23473568 Sonochemical synthesis and characterization of nano-sized lead(II) 3D coordination polymer: Precursor for the synthesis of lead(II) oxybromide nanoparticles. Nanoparticles of a three-dimensional coordination polymer, [Pb(L)(μ2-Br)(H2O)]n (1), (L(-)=1H-1,2,4-triazole-3-carboxylate), have been synthesized by an ultrasonic method and characterized by scanning electron microscopy, X-ray powder diffraction, IR spectroscopy and elemental analyses. The thermal stability of compound 1 both its bulk and nano-size has been studied by thermal gravimetric (TG) and differential thermal (DTA) analyses and compared each other. Concentration of initial reagents effects and the role of power ultrasound irradiation on size and morphology of nano-structured compound 1, have been studied. Calcination of the compound 1 at 500°C under air atmosphere yields Pb3O2Br2 nanoparticles. 23621647 Atomic-Scale Interfacial Band Mapping across Vertically Phased-Separated Polymer/Fullerene Hybrid Solar Cells. Using cross-sectional scanning tunneling microscope (XSTM) with samples cleaved in situ in an ultrahigh vacuum (UHV) chamber, this study demonstrates the direct visualization of high-resolution interfacial band mapping images across the film thickness in an optimized bulk heterojunction polymer solar cell consisting of nanoscale phase segregated blends of poly(3-hexylthiophene) (P3HT) and [6,6]-phenyl C61 butyric acid methyl ester (PCBM). We were able to achieve the direct observation of the interfacial band alignments at the donor (P3HT)-acceptor (PCBM) interfaces and at the interfaces between the photoactive P3HT:PCBM blends and the poly(3,4-ethylenedioxythiophene) poly(styrenesulfonate) (PEDOT:PSS) anode modification layer with an atomic-scale spatial resolution. The unique advantage of using XSTM to characterize polymer:fullerene bulk heterojunction solar cells allows us to explore simultaneously the quantitative link between the vertical morphologies and their corresponding local electronic properties. This provides an atomic insight of interfacial band alignments between the two opposite electrodes, which will be crucial for improving the efficiencies of the charge generation, transport, and collection and the corresponding device performance of polymer solar cells. 22549410 TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype. Intellectual disability (ID) with autosomal recessive (AR) inheritance is believed to be common; however, very little is known about causative genes and genotype-phenotype correlations. The broad genetic heterogeneity of AR-ID, and its usually nonsyndromic nature make it difficult to pool multiple pedigrees with the same underlying genetic defect to achieve consistent nosology. Nearly all autosomal genes responsible for recessive cognitive disorders have been identified in large consanguineous families from the Middle East, and nonsense mutations in TRAPPC9 have been reported in a total of 5. Although several recurrent phenotypic abnormalities are described in some of these patients, the associated phenotype is usually referred to as nonsyndromic. By means of single-nucleotide polymorphism-array first and then by exome sequencing, we identified a new pathogenic mutation in TRAPPC9 in two Italian sisters born to healthy and apparently nonconsanguineous parents. It consists of a homozygous splice site mutation causing exon skipping with frameshift and premature termination, as confirmed by mRNA sequencing. By detailed phenotypic analysis of our patients, and by critical literature review, we found that homozygous TRAPPC9 loss-of-function mutations cause a distinctive phenotype, characterized by peculiar facial appearance, obesity, hypotonia (all signs resembling a Prader-Willi-like phenotype), moderate-to-severe ID, and consistent brain abnormalities. 22948773 Erectile dysfunction as a cardiovascular risk factor in patients with diabetes. Erectile dysfunction (ED) is a highly prevalent disorder among patients with diabetes mellitus (DM). In most cases, ED is considered a vascular disease and its development is significantly related to the exposure to CVD risk factors. In this context, ED and coronary artery disease (CAD) have been proposed as different manifestations of the same systemic disease; in nondiabetic patients, ED has progressively emerged as an important sentinel marker of the subsequent onset of CVD events. The aim of this review was to evaluate the association between ED and CAD in diabetic patients and to evaluate the role of ED as an independent CVD risk factor in these patients. Three large prospective studies confirmed that ED is a powerful predictor of CAD and cardiac mortality in patients with DM. Overall, diabetic patients with ED had roughly 1.4-fold higher risk of CAD as compared with those without ED. Interestingly, in diabetic patients, CAD is often silent and CAD screening according to the current guidelines can miss up to 40 % patients with occult myocardial perfusion abnormalities. Indeed, patients with ED have higher risk of silent myocardial ischemia compared to those without ED, and when ED is added to the risk factors, it can even improve the sensitivity of screening for asymptomatic CAD. Therefore, ED should be considered an independent CVD risk factor, and it could improve the identification of diabetic patients suitable for screening, leading to an early detection of CAD, and thus potentially enhancing the therapeutic effectiveness. 23588303 Why Clinical Inhibition of Efflux Transport at the Blood-Brain Barrier is Unlikely:The ITC Evidence-Based Position. Drug interactions due to efflux transporter inhibition at the blood-brain barrier have been receiving increasing scrutiny due to the theoretical possibility of adverse CNS effects based on findings from preclinical studies. In this commentary, evidence from pharmacokinetic, pharmacodynamic, imaging, pharmacogenetic, and pharmacovigilance studies, along with drug safety reports, is presented supporting a low probability of inhibiting efflux transporters at the human blood-brain barrier by currently marketed drugs.Clinical Pharmacology & Therapeutics (2013); accepted article preview 14 February 2013 doi:10.1038/clpt.2013.34. 23161844 Combining quantum mechanical ligand conformation analysis and protein modeling to elucidate GPCR-ligand binding modes. SAR beyond protein-ligand interactions: By combining structure-affinity relationships, protein-ligand modeling studies, and quantum mechanical calculations, we show that ligand conformational energies and basicity play critical roles in ligand binding to the histamine H4 receptor, a GPCR that plays a key role in inflammation. 23249626 An engineered human follistatin variant: insights into the pharmacokinetic and pharmocodynamic relationships of a novel molecule with broad therapeutic potential. Human follistatin is a regulatory glycoprotein with widespread biologic functions, including antiinflammatory activities, wound-healing properties, and muscle-stimulating effects. The role of follistatin in a wide range of biologic activities shows promise for potential clinical application, which has prompted considerable interest in the investigation of the protein as a potential disease-modifying agent. In spite of this potential, the development of follistatin as a broad use biotherapeutic has been severely hindered by a poor understanding and characterization of its pharmacokinetic/pharmacodynamic (PK/PD) relationships. Therefore, to better define these relationships, we performed in-depth analyses of the PK/PD relationships of native follistatin-315 (FST315). Our data indicate that the intrinsic PK/PD properties of native FST315 are poorly suited for acting as a parentally administered biotherapeutic with broad systemic effects. Here, we leveraged protein engineering to modify the PK characteristics of the native molecule by fusing FST315 to a murine IgG(1) Fc and removing the intrinsic heparan sulfate-binding activity of follistatin. The engineered variant molecule had ~100- and ~1600-fold improvements in terminal half-life and exposure, respectively. In contrast to the native FST315, the variant showed a robust, dose-dependent pharmacological effect when administered subcutaneously on a weekly basis in mouse models of muscle atrophy and degeneration. These studies highlight the underappreciated and critical relationship between optimizing multiple physical and chemical properties of follistatin on its overall PK/PD profile. Moreover, our findings provide the first documented strategy toward the development of a follistatin therapeutic with potential use in patients affected with skeletal muscle diseases. 23386413 CYP21A2 Mutations in Women with Polycystic Ovary Syndrome (PCOS). The question of the contribution of CYP21A2 heterozygosity to the development of polycystic ovary syndrome (PCOS) has repeatedly been raised in the literature. The available data, however, do not offer a satisfactory answer. The discrepancy must be attributed, primarily, to the small number of subjects in the various studies, the type of selected phenotype, and the number of searched mutations. The aim of the study was to define the contribution of CYP21A2 heterozygous mutations to the pathogenesis of PCOS. We searched for 14 molecular defects of the CYP21A2 gene in 197 PCOS women, employing allele specific PCR. Androgen levels were determined at baseline by appropriate methodology in the follicular phase. PCOS women with 17-hydroxyprogesterone (17OHP) basal values >2 ng/ml and/or post-ACTH >10 ng/ml were excluded. Appropriate controls were included. The frequency of the CYP21A2 heterozygous mutations in PCOS women and in controls was 7.6% and 5.9%, respectively [p-value (PCOS vs. controls): 0.663]. Homozygosity for CYP21A2 gene defects was not detected. In conclusion, the contribution of CYP21A2 heterozygous mutations to the pathogenesis of PCOS is not substantiated by our data. Moreover, 17-hydroxyprogesterone values of < 10 ng/ml post-ACTH exclude homozygosity of CYP21A2 mutations. 23452233 Extensive paternal mtDNA leakage in natural populations of Drosophila melanogaster. Strict maternal inheritance is considered a hallmark of animal mtDNA. Although recent reports suggest that paternal leakage occurs in a broad range of species, it is still considered an exceptionally rare event. To evaluate the impact of paternal leakage on the evolution of mtDNA, it is essential to reliably estimate the frequency of paternal leakage in natural populations. Using allele-specific real-time quantitative PCR (RT-qPCR), we show that heteroplasmy is common in natural populations with at least 14% of the individuals carrying multiple mitochondrial haplotypes. However, the average frequency of the minor mtDNA haplotype is low (0.8%), which suggests that this pervasive heteroplasmy has not been noticed before due to a lack of power in sequencing surveys. Based on the distribution of mtDNA haplotypes in the offspring of heteroplasmic mothers, we found no evidence for strong selection against one of the haplotypes. We estimated that the rate of paternal leakage is 6% and that at least 100 generations are required for complete sorting of mtDNA haplotypes. Despite the high proportion of heteroplasmic individuals in natural populations, we found no evidence for recombination between mtDNA molecules, suggesting that either recombination is rare or recombinant haplotypes are counter-selected. Our results indicate that evolutionary studies using mtDNA as a marker might be biased by paternal leakage in this species. 23421374 Glyconanosomes: disk-shaped nanomaterials for the water solubilization and delivery of hydrophobic molecules. Herein, we describe the first report on a new class of disk-shaped and quite monodisperse water-soluble nanomaterials that we named glyconanosomes (GNS). GNSs were obtained by sliding out the cylindrical structures formed upon self-organization and photopolymerization of glycolipid 1 on single-walled carbon nanotube (SWCNT) sidewalls. GNSs present a sheltered hydrophobic inner cavity formed by the carbonated tails, surrounded by PEG and lactose moieties. The amphiphilic character of GNSs allows the water solubility of insoluble hydrophobic cargos such as a perylene-bisimide derivative, [60]fullerene, or the anti-carcinogenic drug camptothecin (CPT). GNS/C60 inclusion complexes are able to establish specific interactions between peanut agglutinin (PNA) lectin and the lactose moiety surrounding the complexes, while CPT solubilized by GNS shows higher cytotoxicity toward MCF7-type breast cancer cells than CPT alone. Thus, GNS represents an attractive extension of nanoparticle-based drug delivery systems. 23558232 Trichostatin A protects against cisplatin-induced ototoxicity by regulating expression of genes related to apoptosis and synaptic function. OBJECTIVE: Although inhibition of histone deacetylases (HDACs) has been shown to protect against cisplatin-induced hearing loss, the underlying mechanism is still poorly understood. In the present study, we aim to investigate the protective effect of trichostatin A (TSA), a specific inhibitor of HDACs, on cisplatin-induced ototoxicity and to determine the differentially expressed genes involved in this process. METHODS: The basilar membrane of the cochlea was isolated from 3-day newborn Wistar rats. Organotypic cultures were treated with 150μM cisplatin or 200nM TSA. For combination treatment, cells were pre-incubated with TSA for 1h, followed by TSA plus cisplatin treatment. Rhodamine-phalloidin staining was used to label hair cells, and immunocytochemistry with an anti-neurofilament-200 antibody was applied to label spiral ganglion neurons (SGNs). Global expression profile microarray analysis was used to identify differentially expressed genes. Molecular function and signal pathway analysis were performed using a protein analysis through evolutionary relationships (PANTHER) classification system. Real-time quantitative PCR (qPCR) was carried out for data validation. RESULTS: Severe loss of hair cells and SGNs occurred after 48h of cisplatin incubation, while TSA significantly increased the number of hair cells and SGNs in the combination treatment group (P<0.05). Compared with control, expression of 71 genes were up-regulated and 383 genes were down-regulated upon cisplatin treatment. Addition of TSA induced the up-regulation of 1387 genes and down-regulation of 1226 genes as compared with cisplatin administration alone. After cisplatin treatment, we observed significant down-regulation of mRNA for several genes related to synaptic function genes, including Camk2a, Camk2b, Vglut1, Snap25 and Rab3b, whereas pretreatment with TSA elevated mRNA levels of these genes. TSA greatly decreased expression of genes related to the calcium signaling pathway (Capn1 and Capn2) and apoptosis signaling pathway (Tnfrsf1a and Tp53), while addition of TSA significantly reduced levels of Tnfrsf1a and Tp53 compared with cisplatin alone (P<0.01). CONCLUSIONS: Our results suggested that TSA might protect against cisplatin-induced ototoxicity via mediating expression of genes responsible for regulating apoptosis, intracellular calcium homeostasis, neurotransmitter synthesis and release, and synaptic plasticity. 23523542 System-wide hybrid MPC-PID control of a continuous pharmaceutical tablet manufacturing process via direct compaction. The next generation of QbD based pharmaceutical products will be manufactured through continuous processing. This will allow the integration of online/inline monitoring tools, coupled with an efficient advanced model-based feedback control systems, to achieve precise control of process variables, so that the predefined product quality can be achieved consistently. The direct compaction process considered in this study is highly interactive and involves time delays for a number of process variables due to sensor placements, process equipment dimensions, and the flow characteristics of the solid material. A simple feedback regulatory control system (e.g., PI(D)) by itself may not be sufficient to achieve the tight process control that is mandated by regulatory authorities. The process presented herein comprises of coupled dynamics involving slow and fast responses, indicating the requirement of a hybrid control scheme such as a combined MPC-PID control scheme. In this manuscript, an efficient system-wide hybrid control strategy for an integrated continuous pharmaceutical tablet manufacturing process via direct compaction has been designed. The designed control system is a hybrid scheme of MPC-PID control. An effective controller parameter tuning strategy involving an ITAE method coupled with an optimization strategy has been used for tuning of both MPC and PID parameters. The designed hybrid control system has been implemented in a first-principles model-based flowsheet that was simulated in gPROMS (Process System Enterprise). Results demonstrate enhanced performance of critical quality attributes (CQAs) under the hybrid control scheme compared to only PID or MPC control schemes, illustrating the potential of a hybrid control scheme in improving pharmaceutical manufacturing operations. 23434663 Rapid and Sensitive Determination of Timosaponin AIII in Rat Plasma by LC-MS/MS and Its Pharmacokinetic Application. A rapid sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for determination of timosaponin AIII (TA-III) in rat plasma, using ginsenoside Re as an internal standard (IS). TA-III and the IS were detected in MRM mode with a negative ionization electrospray mass spectrometer. The calibration curves were linear over the concentration ranges from 11.14 to 1114 ng/mL and the lower limit of quantification (LLOQ) was 11.14 ng/mL. Intra-day and inter-day precisions (RSD) were within 10%, and accuracy ranged from 6.4% to 9.1%. The extraction recovery at three concentrations ranged from 92.3% to 95.5%. The validated method was successfully applied to monitor the concentrations of TA-III in rat plasma after intragastric administration. The best fit pharmacokinetic model to estimate the pharmacokinetic parameters was a single compartment model with weight of 1/x2 for oral administration groups of rats for TA-III. 23591115 Phenanthroimidazole-based thiobenzamide as an effective sensor for highly selective detection of mercury(II). Based on highly selective and irreversible Hg(2+)-promoted desulfurization reaction, a new and simple phenanthroimidazole-type sensor was prepared and exhibited high selectivity towards Hg(2+) ion over other metal ions, accompanied by transformation of a weakly fluorescent thioamide moiety (colorless) to a highly fluorescent amide one (blue), with a 136-fold increase in fluorescent intensity in aqueous solution with a pH span 2.57-9.12. 23325562 Activation of AMP-activated Protein Kinase and Phosphorylation of Glycogen Synthase Kinase3 β Mediate Ursolic Acid Induced Apoptosis in HepG2 Liver Cancer Cells. Despite the antitumour effect of ursolic acid observed in several cancers, the underlying mechanism remains unclear. Thus, in the present study, the roles of AMP-activated protein kinase (AMPK) and glycogen synthase kinase 3 beta (GSK3β) were examined in ursolic acid induced apoptosis in HepG2 hepatocellular carcinoma cells. Ursolic acid significantly exerted cytotoxicity, increased the sub-G1 population and the number of ethidium homodimer and terminal deoxynucleotidyl transferase(TdT) mediated dUTP nick end labeling positive cells in HepG2 cells. Also, ursolic acid enhanced the cleavages of poly-ADP-ribose polymerase (PARP) and caspase3, attenuated the expression of astrocyte elevated gene (AEG1) and survivin in HepG2 cells. Interestingly, ursolic acid increased the phosphorylation of AMPK and coenzyme A carboxylase and also enhanced phosphorylation of GSK3β at inactive form serine 9, whereas ursolic acid attenuated the phosphorylation of AKT and mTOR in HepG2 cells. Conversely, AMPK inhibitor compound C or GSK3β inhibitor SB216763 blocked the cleavages of PARP and caspase 3 induced by ursolic acid in HepG2 cells. Furthermore, proteosomal inhibitor MG132 suppressed AMPK activation, GSK3β phosphorylation, cleaved PARP and deceased AEG-1 induced by ursolic acid in HepG2 cells. Overall, our findings suggest that ursolic acid induced apoptosis in HepG2 cells via AMPK activation and GSK3β phosphorylation as a potent chemopreventive agent. Copyright © 2013 John Wiley & Sons, Ltd. 23643828 The C1 domain-targeted isophthalate derivative HMI-1b11 promotes neurite outgrowth and GAP-43 expression through PKCα activation in SH-SY5Y cells. Protein kinase C (PKC) is a family of serine/threonine phosphotransferases ubiquitously expressed and involved in multiple cellular functions, such as proliferation, apoptosis and differentiation. The C1 domain of PKC represents an attractive drug target, especially for developing PKC activators. Dialkyl 5-(hydroxymethyl)isophthalates are a novel group of synthetic C1 domain ligands that exhibit antiproliferative effect in HeLa cervical carcinoma cells. Here we selected two isophthalates, HMI-1a3 and HMI-1b11, and characterized their effects in the human neuroblastoma cell line SH-SY5Y. Both of the active isophthalates exhibited significant antiproliferative and differentiation-inducing effects. Since HMI-1b11 did not impair cell survival even at the highest concentration tested (20μM), and supported neurite growth and differentiation of SH-SY5Y cells, we focused on studying its downstream signaling cascades and effects on gene expression. Consistently, genome-wide gene expression microarray and gene set enrichment analysis indicated that HMI-1b11 (10μM) induced changes in genes mainly related to cell differentiation. In particular, further studies revealed that HMI-1b11 exposure induced up-regulation of GAP-43, a marker for neurite sprouting and neuronal differentiation. These effects were induced by a 7-minute HMI-1b11 treatment and specifically depended on PKCα activation, since pretreatment with the selective inhibitor Gö6976 abolished the up-regulation of GAP-43 protein observed at 12hours In parallel, we found that a 7-minute exposure to HMI-1b11 induced PKCα accumulation to the cytoskeleton, an effect that was again prevented by pretreatment with Gö6976. Despite similar binding affinities to PKC, the isophthalates had different effects on PKC-dependent ERK1/2 signaling: HMI-1a3-induced ERK1/2 phosphorylation was transient, while HMI-1b11 induced a rapid but prolonged ERK1/2 phosphorylation. Overall our data are in accordance with previous studies showing that activation of the PKCα and ERK1/2 pathways participate in regulating neuronal differentiation. Furthermore, since PKC has been classified as one of the cognitive kinases, and activation of PKC is considered a potential therapeutic strategy for the treatment of cognitive disorders, our findings suggest that HMI-1b11 represents a promising lead compound in research aimed to prevent or counteract memory impairment. 23044992 Deletion of CD74, a putative MIF receptor, in mice enhances osteoclastogenesis and decreases bone mass. CD74 is a type II transmembrane protein that can act as a receptor for macrophage migration inhibitory factor (MIF) and plays a role in MIF-regulated responses. We reported that MIF inhibited osteoclast formation and MIF knockout (KO) mice had decreased bone mass. We therefore examined if CD74 was involved in the ability of MIF to alter osteoclastogenesis in cultured bone marrow (BM) from wild-type (WT) and CD74-deficient (KO) male mice. We also measured the bone phenotype of CD74 KO male mice. Bone mass in the femur of 8-week-old mice was measured by micro-computed tomography and histomorphometry. Bone marrow cells from CD74 KO mice formed 15% more osteoclast-like cells (OCLs) with macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL) (both at 30 ng/mL) compared to WT. Addition of MIF to WT cultures inhibited OCL formation by 16% but had no effect on CD74KO cultures. The number of colony forming unit granulocyte-macrophage (CFU-GM) in the bone marrow of CD74 KO mice was 26% greater than in WT controls. Trabecular bone volume (TBV) in the femurs of CD74 KO male mice was decreased by 26% compared to WT. In addition, cortical area and thickness were decreased by 14% and 11%, respectively. Histomorphometric analysis demonstrated that tartrate-resistant acid phosphatase (TRAP)(+) osteoclast number and area were significantly increased in CD74 KO by 35% and 43%, respectively compared to WT. Finally, we examined the effect of MIF on RANKL-induced-signaling pathways in bone marrow macrophage (BMM) cultures. MIF treatment decreased RANKL-induced nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and c-Fos protein in BMM cultures by 70% and 41%, respectively. Our data demonstrate that CD74 is required for MIF to affect in vitro osteoclastogenesis. Further, the bone phenotype of CD74 KO mice is similar to that of MIF KO mice. MIF treatment of WT cultures suppressed RANKL-induced activator protein 1 (AP-1) expression, which resulted in decreased osteoclast differentiation in vitro. We propose that CD74 plays a critical role in the MIF inhibition of osteoclastogenesis. 23361977 Carboxylic acid (bio)isosteres in drug design. The carboxylic acid functional group can be an important constituent of a pharmacophore, however, the presence of this moiety can also be responsible for significant drawbacks, including metabolic instability, toxicity, as well as limited passive diffusion across biological membranes. To avoid some of these shortcomings while retaining the desired attributes of the carboxylic acid moiety, medicinal chemists often investigate the use of carboxylic acid (bio)isosteres. The same type of strategy can also be effective for a variety other purposes, for example, to increase the selectivity of a biologically active compound or to create new intellectual property. Several carboxylic acid isosteres have been reported, however, the outcome of any isosteric replacement cannot be readily predicted as this strategy is generally found to be dependent upon the particular context (i.e., the characteristic properties of the drug and the drug-target). As a result, screening of a panel of isosteres is typically required. In this context, the discovery and development of novel carboxylic acid surrogates that could complement the existing palette of isosteres remains an important area of research. The goal of this Minireview is to provide an overview of the most commonly employed carboxylic acid (bio)isosteres and to present representative examples demonstrating the use and utility of each isostere in drug design. 23262035 Synthesis, crystal structure and antidiabetic activity of substituted (E)-3-(Benzo [d]thiazol-2-ylamino) phenylprop-2-en-1-one. A novel series of substituted (E)-3-(Benzo [d]thiazol-2-ylamino)phenylprop-2-en-1-onewere synthesized starting from 2-aminobenzothiazole and 1-aryl-3,3-bis- (methylsulfanyl)-2-propen-1-onesin the presence of a catalytic amount of sodium hydride in THF. The synthesised compounds' structures were confirmed by IR, Mass spectrometry, (1)H NMR, (13)C NMR and HRMS spectral data. These compounds were evaluated for their antidiabetic activity, and most of the derivatives of (E)-3-(Benzo [d]thiazol-2-ylamino)phenylprop-2-en-1-one displayed significant antidiabetic activity. 23150210 Synthesis and quantitative structure-activity relationships of selective BCRP inhibitors. The breast cancer resistance protein (BCRP/ABCG2) is a member of the ABC transporter superfamily. This protein has a number of physiological functions, including protection of the human body from xenobiotics. The overexpression of BCRP in certain tumor cell lines causes cross-resistance against various drugs used in chemotherapeutic treatment. In a previous work we showed that a new class of compounds derived from XR9576 (tariquidar) selectively inhibits BCRP. In this work we synthesized more members of this class, with modification on the second and third aromatic rings. The inhibitory activities against BCRP and P-gp were assayed using a Hoechst 33342 assay for BCRP and a calcein AM assay for P-gp. Finally, quantitative structure-activity relationships for both aromatic rings were established. The results obtained show the importance of the electron density on the third aromatic ring, influenced by substituents, pointing to interactions with aromatic residues of the protein binding site. In the second aromatic ring the activity of compounds is influenced by the steric volume of the substituents. 23106534 Cryopreservation of precision-cut tissue slices. 1.Cryopreservation of precision-cut tissue slices (PCTS) would have many advantages for drug development and would encourage more extensive use of the PCTS preparation. 2.Three methods have been studied to date: slow freezing, fast freezing, and vitrification. 3.Slow freezing can be very effective for some PCTS but is devastating to rat liver PCTS. Fast freezing can be successful for rat liver PCTS but is devastating to renal PCTS and has given inconsistent results even for rat liver PCTS. Vitrification has been effective for some slice systems but less effective for rat liver PCTS. Rat liver PCTS appear to be particularly difficult to cryopreserve well. 4.The general cryobiological principles of slow freezing, rapid freezing, and vitrification are reviewed. The empirical literature on the cryopreservation of PCTS has not taken sufficient account of these principles, and may, for example, include the effects of easily preventable osmotic injury. 5.More attention is needed to the effects of cryopreservation on specific cell types within PCTS and to the general integrity and viability of cryopreserved PCTS. Drug metabolism as a sole endpoint of study can be highly misleading. 6.Better application of cryobiological principles may enable improved results in the future. 23412922 Differential gene expression in ERα-positive and ERα-negative breast cancer cells upon leptin stimulation. In postmenopausal women, adipositas represents a serious risk factor for cancer development and progression. White adipose tissue secretes the 16 kDa hormone leptin which plays a key role in the regulation of appetite and metabolism. An increasing number of reports indicate that leptin also interferes with signal transduction pathways implicated in the development of breast cancer. In our previous study, we identified the estrogen receptor alpha (ERα) as a relevant enhancer of leptin-induced signal transduction leading to transactivation of signal transducer and activator of transcription 3 (Stat3). The purpose of this study is the investigation of specific target gene expression in response to leptin-mediated Stat3 signaling. We performed a comprehensive microarray analysis of ERα-positive and ERα-negative MDA-MB-231 cells upon leptin treatment and identified 49 genes which showed a significant ERα-dependent regulation in leptin-treated MDA-MB-231 cells. There was no intersection with genes which were merely up- or downregulated by ERα expression and only 9 and 11 genes overlapping targets which were regulated by leptin stimulation either in ERα-expressing or ERα-negative MDA-MB-231 cells, respectively. To demonstrate the specificity, expression of three target genes was validated by quantitative real-time PCR. In conclusion, these data imply that leptin can induce a different set of target genes dependent on ERα expression, which might contribute to the development and progression of cancer diseases. 23270990 The interactions of apamin and tetraethylammonium are differentially affected by single mutations in the pore mouth of small conductance calcium-activated potassium (SK) channels. Valine residues in the pore region of SK2 (V366) and SK3 (V520) were replaced by either an alanine or a phenylalanine to evaluate the impact on the interactions with the allosteric blocker apamin. Unlike TEA which showed high sensitivity to phenylalanine mutated channels, the binding affinity of apamin to the phenylalanine mutants was strongly reduced. In addition, currents from phenylalanine mutants were largely resistant to block by apamin. On the other hand, when the valine residue was replaced by an alanine residue, an increase of the binding affinity and the amount of block by apamin was observed for alanine mutated SK2 channels, but not for mutated SK3 channels. Interestingly, the VA mutation reduced the sensitivity to TEA. In silico data confirmed these experimental results. Therefore, such mutations in the pore region of SK channels show that the three-dimensional structure of the SK tetramers can be disorganized in the outer pore region leading to reduced interaction of apamin with its target. 23554428 The Glucuronidation of R- and S- Lorazepam: Human Liver Microsomal Kinetics, UDP-Glucuronosyltransferase Enzyme Selectivity, and Inhibition by Drugs. The widely used hypnosedative-anxiolytic agent R,S-lorazepam is cleared predominantly by conjugation with glucuronic acid in humans, but the enantioselective glucuronidation of lorazepam has received little attention. The present study characterized the kinetics of the separate R- and S- enantiomers of lorazepam by human liver microsomes (HLM) and by a panel of recombinant human UDP-glucuronosyltransferase (UGT) enzymes. Respective mean Km and Vmax values for R- and S- lorazepam by HLM were 29 ± 8.9 and 36 ± 10 μM, and 7.4 ± 1.9 and 10 ± 3.8 pmol/min.mg. Microsomal intrinsic clearances were not significantly different, suggesting the in vivo clearances of R- and S- lorazepam are likely to be similar. Both R- and S- lorazepam were glucuronidated by UGT 2B4, 2B7, and 2B15, while R-lorazepam was additionally metabolized by the extra-hepatic enzymes UGT 1A7 and 1A10. Based on in vitro clearances and consideration of available in vivo and in vitro data, UGT2B15 is likely to play an important role in the glucuronidation of R- and S-lorazepam. However, the possible contribution of other enzymes and the low activities observed in vitro indicate that the lorazepam enantiomers are of limited use as substrate probes for UGT2B15. In order to identify potential drug-drug interactions, codeine, fluconazole, ketamine, ketoconazole, methadone, morphine, valproic acid, and zidovudine were screened as inhibitors of R- and S- lorazepam glucuronidation by HLM. Of these drugs, in vitro - in vivo extrapolation suggested that only ketoconazole had the potential to inhibit lorazepam clearance to a clinically significant extent. 23171424 The mycobacterial binuclear iron monooxygenases require a specific chaperonin-like protein for functional expression in a heterologous host. The mimABCD gene clusters in Mycobacterium smegmatis strain mc(2) 155 and Mycobacterium goodii strain 12523 encode binuclear iron monooxygenases that oxidize propane and phenol. In this study, we attempted to express each mimABCD gene cluster in a heterologous host. The actinomycetous strain Rhodococcus opacus B-4, which is phylogenetically close to Mycobacterium, was selected as the host. Each mimABCD gene cluster was cloned into the Rhodococcus-Escherichia coli shuttle vector, pTip-QC2, and then introduced into R. opacus cells. Although whole-cell assays were performed with phenol as a substrate, the transformed R. opacus cells did not oxidize this substrate. SDS/PAGE analysis revealed that the oxygenase large subunit MimA was expressed in the insoluble fraction of R. opacus cells. We found that a gene designated mimG, which lies downstream of mimABCD, exhibits similarity in the amino acid sequence of its product with the products of genes encoding the chaperonin GroEL. When the mimG gene was cloned and coexpressed with each mimABCD gene cluster in R. opacus strain B-4, this host successfully acquired oxidation activity towards phenol. SDS/PAGE and western blotting analyses demonstrated that MimA was clearly soluble when in the presence of MimG. These results indicated that MimG played essential roles in the productive folding of MimA, and that the resulting soluble MimA protein led to the active expression of MimABCD. 23459473 Electrospinning covalently cross-linking biocompatible hydrogelators. Many hydrogel materials of interest are homogeneous on the micrometer scale. Electrospinning, the formation of sub-micrometer to micrometer diameter fibers by a jet of fluid formed under an electric field, is one process being explored to create rich microstructures. However, electrospinning a hydrogel system as it reacts requires an understanding of the gelation kinetics and corresponding rheology near the liquid-solid transition. In this study, we correlate the structure of electrospun fibers of a covalently cross-linked hydrogelator with the corresponding gelation transition and kinetics. Polyethylene oxide (PEO) is used as a carrier polymer in a chemically cross-linking poly(ethylene glycol)-high molecular weight heparin (PEG-HMWH) hydrogel. Using measurements of gelation kinetics from multiple particle tracking microrheology (MPT), we correlate the material rheology with the the formation of stable fibers. An equilibrated, cross-linked hydrogel is then spun and the PEO is dissolved. In both cases, microstructural features of the electrospun fibers are retained, confirming the covalent nature of the network. The ability to spin fibers of a cross-linking hydrogel system ultimately enables the engineering of materials and microstructural length scales suitable for biological applications. 23110414 Aryl-heteroaryl derivatives as novel wake-promoting agents. In search of a next generation molecule to the novel wake-promoting agent modafinil, a series of aryl-heteroayl-derived wakefulness enhancing agents (in rats) was developed. From this work, compound 16 was separated into its enantiomers to profile them individually. 23606349 Emergent Renal Dysfunction with Colistin Pharmacotherapy. STUDY OBJECTIVE: To evaluate the association between the administration of intravenous (IV) colistin and the emergence of renal dysfunction. DESIGN: A retrospective medical record review. SETTING: A tertiary care academic medical center. PATIENTS: A total of 174 critically ill patients who received at least one dose of IV colistin between 2004 and 2007. MEASUREMENTS AND MAIN RESULTS: The primary outcome was development of renal dysfunction, defined as an increase in serum creatinine of 50% or more during therapy or the initiation of renal replacement therapy (RRT), in patients who received at least one dose of colistin and were not already on RRT. The severity of renal dysfunction was further categorized by the RIFLE criteria. Demographic and clinical characteristics were analyzed by logistic regression for association with new renal dysfunction. A total of 174 patients were evaluated for renal dysfunction. Of these patients, 84 (48%) experienced renal dysfunction on colistin. On multivariate analysis, age in years (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01-1.05) and receipt of concurrent nephrotoxin(s) (OR 3.35, 95% CI 1.34-8.36) significantly increased the risk of developing renal dysfunction. CONCLUSION: In this critically ill population, renal dysfunction occurred frequently and was associated with older age and receipt of nephrotoxins. 23561082 Antioxidant activity-guided separation of coumarins and lignan from Melicope glabra (Rutaceae). The ethyl acetate and methanol bark extracts of Melicope glabra were evaluated for their antioxidant capacities by 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity and β-carotene bleaching/linoleic acid system. Both extracts exhibited strong inhibition against the DPPH radical (IC50 values of 24.81 and 13.01 μgml(-1), respectively) and strong antioxidant activity in β-carotene bleaching assay. Both samples were found to have high phenolic content with values of 39 and 44mg GAE/g as indicated by Follin-Ciocalteau's reagent. Antioxidant TLC assay-guided isolation on the methanol extract led to the isolation of a new pyranocoumarin, glabranin (1), umbelliferone (2), scopoletin (3) and sesamin (4), and their structures were determined by spectroscopy. Compounds (1-3) showed significant activities on DPPH free radical with the IC50 of 240.20, 810.02 and 413.19μgml(-1), respectively. However, in β-carotene bleaching assay, sesamin (4) showed higher inhibitory activity (1mgml(-1), 95%) than glabranin (1) (1mgml(-1), 74%), whilst umbelliferone (2) and scopoletin (3) were slightly pro-oxidant. 23459107 In vitro and in vivo evaluation of superparamagnetic iron oxide nanoparticles coated by bisphosphonates: The effects of electrical charge and molecule length. Physicochemical coating properties are often considered to be determining factors for in vivo characteristics of superparamagnetic iron oxide nanoparticles, used as contrast agent in Magnetic Resonance Imaging (MRI). To investigate the electrical charge (modified by zero, one or two ammonium groups) and the molecule length (3, 5 or 7 methylene chains) effects of bisphosphonate-type coatings, we assessed the complement activation, in vivo plasma and tissue relaxation time alterations of intravenously injected small iron oxide nanoparticles (<25nm) on male healthy Wistar rats. The presence of ammonium groups induces a weak activation of the complement whatever the size and the concentration of particles, whereas hydroxyethylenebisphosphonate (HEBP)-coated particles are poor complement activators only at the lowest concentration. In vivo, HEBP-coated nanoparticles have the greatest prolonged relaxation time effects, despite their higher negative electrical charge, contrary to two ammonium bearing coatings. No significant differences were observed between mono-ammonium molecular coatings. 23337529 Reversal of diet-induced obesity increases insulin transport into cerebrospinal fluid and restores sensitivity to the anorexic action of central insulin in male rats. Diet-induced obesity (DIO) reduces the ability of centrally administered insulin to reduce feeding behavior and also reduces the transport of insulin from the periphery to the central nervous system (CNS). The current study was designed to determine whether reversal of high-fat DIO restores the anorexic efficacy of central insulin and whether this is accompanied by restoration of the compromised insulin transport. Adult male Long-Evans rats were initially maintained on either a low-fat chow diet (LFD) or a high-fat diet (HFD). After 22 weeks, half of the animals on the HFD were changed to the LFD, whereas the other half continued on the HFD for an additional 8 weeks, such that there were 3 groups: 1) a LFD control group (Con; n = 18), 2) a HFD-fed, DIO group (n = 17), and 3) a HFD to LFD, DIO-reversal group (DIO-rev; n = 18). The DIO reversal resulted in a significant reduction of body weight and epididymal fat weight relative to the DIO group. Acute central insulin administration (8 mU) reduced food intake and caused weight loss in Con and DIO-rev but not DIO rats. Fasting cerebrospinal fluid insulin was higher in DIO than Con animals. However, after a peripheral bolus injection of insulin, cerebrospinal fluid insulin increased in Con and DIO-rev rats but not in the DIO group. These data provide support for previous reports that DIO inhibits both the central effects of insulin and insulin's transport to the CNS. Importantly, DIO-rev restored sensitivity to the effects of central insulin on food intake and insulin transport into the CNS. 23143892 A perspective on the contribution of metabolites to drug-drug interaction potential: the need to consider both circulating levels and inhibition potency. The 2012 drug-drug interaction (DDI) guidance from the European Medicines Agency (EMA) and the draft DDI guidance from the Food and Drug Administration (FDA) have proposed that metabolites present at >25% of the parent area under the time-concentration curve (AUC) (EMA and FDA) and >10% of the total drug-related exposure (EMA) should be investigated in vitro for their DDI potential. This commentary attempts to rationalize the clinically relevant levels of metabolite(s) that contribute to DDI by considering not only the abundance but also inhibition potency, physicochemical properties, and structural alerts of the metabolite. A decision tree is proposed for levels of metabolites that could trigger in vitro DDI assessment. When the parent is an inhibitor of cytochrome P450s (P450s), clinical DDI studies will assess the in vivo DDI effect of the combination of parent and metabolite(s). When the parent is not a P450 inhibitor, it is important to assess the inhibition potential of abundant metabolites in vitro. The proposal is to apply a default cutoff value of metabolite level which is 100% of the parent AUC. It is important to note that exceptions can occur, and different metabolite levels may be considered depending on the physiochemical properties of metabolites (e.g., increased lipophilicity) and whether the metabolite contains structural alerts for DDI (e.g., mechanism-based inhibition). A key objective of this commentary is to stimulate discussions among the scientific community on this important topic, so that appropriate in vitro metabolism studies are conducted on metabolites, to ensure the safety of drugs in development balanced with the desire to avoid creating unnecessary studies that will add little to no value in ensuring patient safety. 23201179 Aggression- and sex-induced neural activity across vasotocin populations in the brown anole. Activity within the social behavior neural network is modulated by the neuropeptide arginine vasotocin (AVT) and its mammalian homologue arginine vasopressin (AVP). However, central AVT/AVP release causes different behavioral effects across species and social environments. These differences may be due to the activation of different neuronal AVT/AVP populations or to similar activity patterns causing different behavioral outputs. We examined neural activity (assessed as Fos induction) within AVT neurons in male brown anole lizards (Anolis sagrei) participating in aggressive or sexual encounters. Lizards possess simple amniote nervous systems, and their examination provides a comparative framework to complement avian and mammalian studies. In accordance with findings in other species, AVT neurons in the anole paraventricular nucleus (PVN) were activated during aggressive encounters; but unlike in other species, a positive correlation was found between aggression levels and activation. Activation of AVT neurons within the supraoptic nucleus (SON) occurred nonspecifically with participation in either aggressive or sexual encounters. Activation of AVT neurons in the preoptic area (POA) and bed nucleus of the stria terminalis (BNST) was associated with engagement in sexual behaviors. The above findings are congruent with neural activation patterns observed in other species, even when the behavioral outputs (i.e., aggression level) differed. However, aggressive encounters also increased activation of AVT neurons in the BNST, which is incongruous with findings in other species. Thus, some species differences involve the encoding of social stimuli as different neural activation patterns within the AVT/AVP network, whereas other behavioral differences arise downstream of this system. 23608700 β-estradiol 17-valerate affects embryonic development and sexual differentiation in Japanese medaka (Oryzias latipes). β-estradiol 17-valerate (EV) is a synthetic estrogen widely used in combination with other steroid hormones in hormone replacement therapy drugs and is detected in natural waters. Although EV is known as an estrogenic chemical, there is still a lack of data on its developmental and reproductive toxicities in fish following exposure to EV during embryo-larval-, juvenile- and adult-life stages in Japanese medaka (Oryzias latipes). At the early life stage, the fertilized eggs of medaka were exposed to 1, 10, 100 and 1000ng/L EV for 15 days, and hatched larval fish were continually exposed to the same concentration range for an additional 15 days. The results showed that exposure to 10ng/L or above resulted in adverse effects on hatchability and time to hatching, and the number of hatched females was twice that of males at 10ng/L or above. When the hatched fish were continually exposed to 1, 10 and 100ng/L of EV for another 40 days, the hepatosomatic index (HSI) was increased in both males and females, and the gonadosomatic index (GSI) was decreased in females, and increased in males. Sex reversal was found in fish exposed to 1ng/L and above. Quantitative real-time RT-PCR showed that mRNA levels of estrogen receptor α (ER-α) and vitellogenin-I (VTG-I) in the liver of females were significantly down-regulated, while those of vitellogenin-I (VTG-I) in the liver of males were significantly up-regulated at all concentrations. These findings suggest that EV is a reproductive toxicant and estrogenic chemical in both male and female fish. 23108036 Arsenic inhibits the adipogenic differentiation of mesenchymal stem cells by down-regulating peroxisome proliferator-activated receptor gamma and CCAAT enhancer-binding proteins. Arsenic remains a top environmental concern in the United States as well as worldwide because of its global existence and serious health impacts. Apoptotic effect of arsenic in human mesenchymal stem cells (hMSCs) has been identified in our previous study; the effects of arsenic on hMSCs remain largely unknown. Here, we report that arsenic inhibits the adipogenic differentiation of human mesenchymal stem cells (hMSCs). Arsenic reduced the formation of lipid droplets and the expression of adipogenesis-related proteins, such as CCAAT enhancer binding protein-(C/EBPs), peroxisome proliferator-activated receptor-gamma (PPAR-γ), and adipocyte fatty acid-binding protein aP2 (aP2). Arsenic mediates this process by sustaining PPAR-γ activity. In addition, inhibition of PPAR-γ activity with T0070907 and up-regulation with its agonist troglitazone, showed the direct association of PPAR-γ and arsenic-mediated inhibition of differentiating hMSCs. Taken together, these results indicate that arsenic inhibits adipogenic differentiation through PPAR-γ pathway and suggest a novel inhibitory effect of arsenic on adipogenic differentiation in hMSCs. 23164932 Korean red ginseng ameliorates acute 3-nitropropionic acid-induced cochlear damage in mice. 3-Nitropropionic acid (3-NP), a mitochondrial toxin, has been reported to induce an acute cochlear damage. Korean red ginseng (KRG) is known to have protective effects from some types of hearing loss. This study aimed to observe the protective effect of KRG in an ototoxic animal model using 3-NP intratympanic injection. BALB/c mice were classified into 5 groups (n=15) and dose-dependent toxic effects after intratympanic injection with 3-NP (300-5000 mM) on the left ear were investigated to determine the appropriate toxicity level of 3-NP. For observation of the protective effects of KRG, 23 mice were grouped into 3-NP (500 mM, n=12) and KRG+3-NP groups (300 mg/kg KRG for 7 days before 500 mM 3-NP administration, n=11). Auditory brain response (ABR) and cochlear morphological evaluations were performed before and after drug administration. The ABR thresholds in the 800-5000 mM groups exceeded the maximum recording limit at 16 and 32 kHz 1 day after 3-NP administration. The ABR threshold in the 500 mM 3-NP+KRG group was significantly lower than that in the 500 mM 3-NP group from post 1 week to 1 month. The mean type II fibrocyte counts significantly differed between the control and 3-NP groups and between the 3-NP and 3-NP+KRG groups. Spiral ganglion cell degeneration in the 3-NP group was more severe than that in the 3-NP+KRG group. This animal model exhibited a dose-dependent hearing loss with histological changes. KRG administration ameliorated the deterioration of hearing by 3-NP. 23395695 Silymarin inhibits ultraviolet radiation-induced immune suppression through DNA repair-dependent activation of dendritic cells and stimulation of effector T cells. Silymarin inhibits UVB-induced immunosuppression in mouse skin. To identify the molecular mechanisms underlying this effect, we used an adoptive transfer approach in which dendritic cells (DCs) from the draining lymph nodes of donor mice that had been UVB-exposed and sensitized to 2,4,-dinitrofluorobenzene (DNFB) were transferred into naïve recipient mice. The contact hypersensitivity (CHS) response of the recipient mice to DNFB was then measured. When DCs were obtained from UVB-exposed donor mice that were not treated with silymarin, the CHS response was suppressed confirming the role of DCs in the UVB-induced immunosuppression. Silymarin treatment of UVB-exposed donor mice relieved this suppression of the CHS response in the recipients. Silymarin treatment was associated with rapid repair of UVB-induced cyclobutane pyrimidine dimers (CPDs) in DCs and silymarin treatment did not prevent UV-induced immunosuppression in XPA-deficient mice which are unable to repair UV-induced DNA damage. The CHS response in mice receiving DCs from silymarin-treated UV-exposed donor mice also was associated with enhanced secretion of Th1-type cytokines and stimulation of T cells. Adoptive transfer of T cells revealed that transfer of either CD8(+) or CD4(+) cells from silymarin-treated, UVB-exposed donors resulted in enhancement of the CHS response. Cell culture study showed enhanced secretion of IL-2 and IFNγ by CD8(+) T cells, and reduced secretion of Th2 cytokines by CD4(+) T cells, obtained from silymarin-treated UVB-exposed mice. These data suggest that DNA repair-dependent functional activation of DCs, a reduction in CD4(+) regulatory T-cell activity, and stimulation of CD8(+) effector T cells contribute to silymarin-mediated inhibition of UVB-induced immunosuppression. 23497880 Optimisation of synthesis of oligosaccharides derived from lactulose (fructosyl-galacto-oligosaccharides) with β-galactosidases of different origin. Batch synthesis of fructosyl-galacto-oligosaccharides from lactulose was performed with commercial β-galactosidase preparations from Aspergillus oryzae, Kluyveromyces lactis and Bacillus circulans. The enzyme from A. oryzae produced the highest yield and specific productivity of synthesis, being selected for further studies. Optimization of fructosyl-galacto-oligosaccharides synthesis was carried out using response surface methodology, considering temperature and initial sugar concentration as variables and yield and specific productivity as response parameters. Maximum yield of 0.41 g g(-1) fructosyl-galacto-oligosaccharides was obtained at 70°C and 60% w/w lactulose concentration, while maximum specific productivity of 1.2 g h(-1)mg(-1) was obtained at 70°C and 40% w/w lactulose concentration. 23084046 Sub-lethal effects of titanium dioxide nanoparticles on the physiology and reproduction of zebrafish. There are limited data on the sub-lethal physiological effects of titanium dioxide nanoparticles (TiO(2) NPs) in adult fishes, and the consequences of TiO(2) NP exposure on reproductive success are also unclear. This study aimed to examine the sub-lethal effects of a 14-d aqueous TiO(2) (TiO(2) NP, 0.1 or 1.0 mg l(-1); TiO(2) bulk, 1.0 mg l(-1)) exposure on the physiology and reproductive health of zebrafish. After the 14-d exposure, fish were examined for haematology, whole body electrolyte and trace metal profiles, biochemistry, and histopathology. Then, during a 21-d post exposure recovery period, effects of the TiO(2) exposure on reproductive success were evaluated. Whole body Ti concentrations increased significantly in fish exposed to both the 1.0 mg l(-1) TiO(2) NP and bulk TiO(2) compared to controls, but concentrations returned to control levels by the end of the recovery period. No change in erythrocyte counts were observed, but there was a two-fold decline in leukocyte counts in all TiO(2) treatment groups relative to time-matched controls. Whole body electrolyte and trace metal profiles were not affected by exposure to TiO(2), and there were no changes in Na(+)K(+)-ATPase activity in brain, gill or liver tissues. Total glutathione (GSH) levels in brain, gill and liver tissues were higher in fish exposed to TiO(2) NP (both 0.1 and 1.0 mg l(-1)) compared to bulk TiO(2) and control fish. Histological examination of gill, liver, brain and gonad tissues showed little evidence of treatment-related morphological change. At the end of the 14-d exposure adult zebrafish were able to reproduce; however, the cumulative number of viable embryos produced was lower in fish exposed to 1.0 mg l(-1) TiO(2) (both NP and bulk) by the end of the 21-d recovery period. Overall, this study showed limited toxicity of bulk or nano scale TiO(2) during the exposure; however reproduction was affected in both bulk and NP 1.0 mg l(-1) groups. 22940000 Adenosine and autism: a spectrum of opportunities. In rodents, insufficient adenosine produces behavioral and physiological symptoms consistent with several comorbidities of autism. In rodents and humans, stimuli postulated to increase adenosine can ameliorate these comorbidities. Because adenosine is a broad homeostatic regulator of cell function and nervous system activity, increasing adenosine's influence might be a new therapeutic target for autism with multiple beneficial effects. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. 23210463 Simulations of the two-dimensional electronic spectroscopy of the photosystem II reaction center. We report simulations of the two-dimensional electronic spectroscopy of the Q(y) band of the D1-D2-Cyt b559 photosystem II reaction center at 77 K. We base the simulations on an existing Hamiltonian that was derived by simultaneous fitting to a wide range of linear spectroscopic measurements and described within modified Redfield theory. The model obtains reasonable agreement with most aspects of the two-dimensional spectra, including the overall peak shapes and excited state absorption features. It does not reproduce the rapid equilibration from high energy to low energy excitonic states evident by a strong cross-peak below the diagonal. We explore modifications to the model to incorporate new structural data and improve agreement with the two-dimensional spectra. We find that strengthening the system-bath coupling and lowering the degree of disorder significantly improves agreement with the cross-peak feature, while lessening agreement with the relative diagonal/antidiagonal width of the 2D spectra. We conclude that two-dimensional electronic spectroscopy provides a sensitive test of excitonic models of the photosystem II reaction center and discuss avenues for further refinement of such models. 22342985 Defining "epileptogenesis" and identifying "antiepileptogenic targets" in animal models of acquired temporal lobe epilepsy is not as simple as it might seem. The "latent period" between brain injury and clinical epilepsy is widely regarded to be a seizure-free, pre-epileptic state during which a time-consuming cascade of molecular events and structural changes gradually mediates the process of "epileptogenesis." The concept of the "latent period" as the duration of "epileptogenesis" implies that epilepsy is not an immediate result of brain injury, and that anti-epileptogenic strategies need to target delayed secondary mechanisms that develop sometime after an initial injury. However, depth recordings made directly from the dentate granule cell layers in awake rats after convulsive status epilepticus-induced injury have now shown that whenever perforant pathway stimulation-induced status epilepticus produces extensive hilar neuron loss and entorhinal cortical injury, hyperexcitable granule cells immediately generate spontaneous epileptiform discharges and focal or generalized behavioral seizures. This indicates that hippocampal injury caused by convulsive status epilepticus is immediately epileptogenic and that hippocampal epileptogenesis requires no delayed secondary mechanism. When latent periods do exist after injury, we hypothesize that less extensive cell loss causes an extended period during which initially subclinical focal seizures gradually increase in duration to produce the first clinical seizure. Thus, the "latent period" is suggested to be a state of "epileptic maturation," rather than a prolonged period of "epileptogenesis," and therefore the antiepileptogenic therapeutic window may only remain open during the first week after injury, when some delayed cell death may still be preventable. Following the perhaps unavoidable development of the first focal seizures ("epileptogenesis"), the most fruitful therapeutic strategy may be to interrupt the process of "epileptic maturation," thereby keeping focal seizures focal. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'. 23362224 Graphene Oxide-Based Fluorescent Biosensor for Protein Detection via Terminal Protection of Small-Molecule-Linked DNA. A fluorescence method for protein detection is developed based on terminal protection of small-molecule-linked DNA by target protein and a graphene oxide-assisted DNA assay strategy. This design results in fluorescence-enhanced detection that is sensitive and selective for the target protein. 23265510 Binding of vitamin A with milk α- and β-caseins. The binding sites of retinol and retinoic acid with milk α- and β-caseins were determined, using constant protein concentration and various retinoid contents. FTIR, UV-visible and fluorescence spectroscopic methods as well as molecular modelling were used to analyse retinol and retinoic acid binding sites, the binding constant and the effect of retinoid complexation on the stability and conformation of caseins. Structural analysis showed that retinoids bind caseins via both hydrophilic and hydrophobic contacts with overall binding constants of K(retinol-)(α)(-caseins)=1.21 (±0.4)×10(5) M(-1) and K(retinol-)(β)(-caseins)=1.11 (±0.5)×10(5) M(-1) and K(retinoic acid-)(α)(-caseins)=6.2 (±0.6)×10(4) M(-1) and K(retinoic acid-)(β)(-caseins)=6.3 (±0.6)×10(4) M(-1). The number of bound retinol molecules per protein (n) was 1.5 (±0.1) for α-casein and 1.0 (±0.1) for β-casein, while 1 molecule of retinoic acid was bound in the α- and β-casein complexes. Molecular modelling showed different binding sites for retinol and retinoic acid on α- and β-caseins with more stable complexes formed with α-casein. Retinoid-casein complexation induced minor alterations of protein conformation. Caseins might act as carriers for transportation of retinoids to target molecules. 23454300 Phenotypic analysis of ovine antigen presenting cells loaded with nanoparticles migrating from the site of vaccination. Virus-sized particulate adjuvants such as ISCOMs, polystyrene nanoparticles and virus-like particles have been shown to target dendritic cells, resulting in the activation of T and B cells in vivo. Using an ovine pseudo-afferent lymph cannulation model to capture APC that traffic from the site of injection to the local lymph node, we show that 40-50nm nanoparticles are taken up at the site of injection by dendritic cells (DCs) migrating to the draining lymph node. These DCs can express CD11c, CD1b, CD5, MHC class II and CD8. Nanoparticles transported by DCs migrating from the site of injection to the local lymph node therefore needs to be considered as a new mechanism underlying the immunogenicity of virus-sized vaccine delivery systems. 23212107 New avenues for anticoagulation in atrial fibrillation. Vitamin K antagonists (VKAs) were, until recently, the only option for chronic anticoagulation in patients with atrial fibrillation. Three new oral anticoagulants have been tested for this indication in recent randomized trials: dabigatran, rivaroxaban, and apixaban. They offer the promise of consistent effect without the need for monitoring drug levels. Overall, efficacy and safety appear to be noninferior, and in some instances superior, to warfarin. However, the new drugs have their downsides, and switching from warfarin is not recommended for all patients. This review focuses on the available evidence and attempts to provide guidance to clinicians in the field. 23523664 GLPG0492, a novel selective androgen receptor modulator, improves muscle performance in the exercised-mdx mouse model of muscular dystrophy. Anabolic drugs may counteract muscle wasting and dysfunction in Duchenne muscular dystrophy (DMD); however, steroids have unwanted side effects. We focused on GLPG0492, a new non-steroidal selective androgen receptor modulator that is currently under development for musculo-skeletal diseases such as sarcopenia and cachexia. GLPG0492 was tested in the exercised mdx mouse model of DMD in a 4-week trial at a single high dose (30mg/kg, 6 day/week s.c.), and the results were compared with those from the administration of α-methylprednisolone (PDN; 1mg/kg, i.p.) and nandrolone (NAND, 5mg/kg, s.c.). This assessment was followed by a 12-week dose-dependence study (0.3-30mg/kg s.c.). The outcomes were evaluated in vivo and ex vivo on functional, histological and biochemical parameters. Similar to PDN and NAND, GLPG0492 significantly increased mouse strength. In acute exhaustion tests, a surrogate of the 6-min walking test used in DMD patients, GLPG0492 preserved running performance, whereas vehicle- or comparator-treated animals showed a significant increase in fatigue (30-50%). Ex vivo, all drugs resulted in a modest but significant increase of diaphragm force. In parallel, a decrease in the non-muscle area and markers of fibrosis was observed in GLPG0492- and NAND-treated mice. The drugs exerted minor effects on limb muscles; however, electrophysiological biomarkers were ameliorated in extensor digitorum longus muscle. The longer dose-dependence study confirmed the effect on mdx mouse strength and resistance to fatigue and demonstrated the efficacy of lower drug doses on in vivo and ex vivo functional parameters. These results support the interest of further studies of GLPG0492 as a potential treatment for DMD. 23371492 The role of cortisol and psychopathy in the cycle of violence. RATIONALE: Child abuse and neglect are universal risk factors for delinquency, violence, and aggression; this phenomenon is known as the cycle of violence. Additional factors-psychopathy, impulsiveness, and disruptions in the hypothalamic-pituitary-adrenal (HPA) axis-play a role in aggressive behavior but have rarely been examined in the same conceptual and experimental framework. OBJECTIVES: We sought to examine the above-mentioned risk factors for aggression in a prospective study employing psychopharmacologic and psychometric techniques. METHODS: Sixty-seven adult participants were given an acute dose of 20 mg cortisol in a placebo-controlled, within-subject, counter-balanced dosing design. Salivary cortisol was measured at baseline and at regular intervals across a 5 h testing period. Following dosing, state-aggressive behavior was measured by a laboratory task, the Point-Subtraction Aggression Paradigm. History of child abuse/neglect, psychopathy, impulsivity, and a trait measure of aggression were assessed through self-report questionnaires. RESULTS: Using multiple regression, a model including abuse/neglect, psychopathy, impulsivity, and baseline cortisol explained 58 % of the variance in trait aggression and 26 % of the variance in state aggression. Abuse/neglect predicted diminished HPA-axis reactivity and HPA-axis reactivity showed a trend toward predicting state and trait aggression, although it was not a significant mediating variable between abuse/neglect and aggression. CONCLUSIONS: The results indicate that child maltreatment, psychopathy and HPA-axis reactivity interact to provide a confluence over aggressive behavior, and intervention efforts need to consider all these factors. 23010565 Liquid crystalline phase nanodispersions enable skin delivery of siRNA. The ability of small interfering RNAs (siRNAs) to potently but reversibly silence genes in vivo has made them particularly well suited as a new class of drugs that interfere with disease-causing or disease-promoting genes. However, the largest remaining hurdle for the widespread use of this technology in skin is the lack of an effective delivery system. The aim of the present study was to evaluate nanodispersed systems in liquid crystalline phases that deliver siRNA into the skin. The proposed systems present important properties for the delivery of macromolecules in a biological medium, as they are formed by substances that have absorption-enhancing and fusogenic effects; additionally, they facilitate entrapment by cellular membranes due to their nano-scale structure. The cationic polymer polyethylenimine (PEI) or the cationic lipid oleylamine (OAM) were added to monoolein (MO)-based systems in different concentrations, and after dispersion in aqueous medium, liquid crystalline phase nanodispersions were obtained and characterized by their physicochemical properties. Then, in vitro penetration studies using diffusion cell and pig ear skin were carried out to evaluate the effect of the nanodispersions on the skin penetration of siRNA; based on these results, the nanodispersions containing MO/OA/PEI/aqueous phase (8:2:5:85, w/w/w/w) and MO/OA/OAM/aqueous phase (8:2:2:88, w/w/w/w) were selected. These systems were investigated in vivo for skin penetration, skin irritation, and the ability to knockdown glyceraldehyde 3-phosphate dehydrogenase (GAPDH) protein levels in animal models. The results showed that the studied nanodispersions may represent a promising new non-viral vehicle and can be considered highly advantageous in the treatment of skin disorders; they were effective in optimizing the skin penetration of siRNA and reducing the levels of the model protein GAPDH without causing skin irritation. 23337911 Toxicity assessment on trophoblast cells for some environment polluting chemicals and 17β-estradiol. The identification of reproductive toxicants is a major scientific challenge for human health. We investigated the effects of a selected group of environmental polluting chemicals mostly provided with estrogenic activity on the human trophoblast cell lines BeWo and HTR-8/SVneo. Cells were exposed for 24h to various concentrations (from 0.1 pM to 1 mM) of atrazine (ATR), diethylstilbestrol (DES), para-nonylphenol (p-NP), resveratrol (RES) and 17 β-estradiol (E2) and assayed for cell viability and human beta-Chorionic Gonadotropin (β-hCG) secretion. Decrease of cell viability as respect to control, vehicle-treated, cultures was obtained for all chemicals in the concentration range of 1 μM-1 mM in both cell types. A parallel decrease of β-hCG secretion was observed in BeWo cells, at 1 μM-1 mM concentrations, with the only exception of ATR which caused an increase at concentrations up to 1mM. β-hCG release was also unexpectedly inhibited by ATR, DES, p-NP and RES at non-toxic (pM-nM) concentrations. These findings raise concern about the negative, potential effects of various environmental polluting chemicals on pregnancy success and fetal health. 23262562 The electroreduction of benzoic acid: voltammetric observation of adsorbed hydrogen at a platinum microelectrode in room temperature ionic liquids. The electrochemical reduction of benzoic acid in the presence and absence of hydrogen (H(2)) has been investigated using a 10 μm diameter platinum microelectrode in four different room temperature ionic liquids (RTILs), namely [C(4)mim][NTf(2)], [C(4)mpyrr][NTf(2)], [C(4)mim][OTf] and [C(4)mim][BF(4)], versus Ag/Ag(+). In all cases, reductive voltammetry is observed, and is suggested to occur via a CE mechanism in which dissociation of benzoic acid is followed by electron transfer to H(+) ultimately forming adsorbed hydrogen. Furthermore, the adsorbed H atoms, formed from the reduction of benzoic acid, could be used to achieve the rapid hydrogenolysis of the organic compound (bis(benzyloxycarbonyl)-l-lysine) on the timescale of the voltammetric technique under moderate conditions (25 °C). 23558295 Characterization of a gap-junctional intercellular communication (GJIC) assay using cigarette smoke. Inhibition of gap-junctional intercellular communication (GJIC) via exposure to various toxic substances has been implicated in tumor promotion. In the present study, cigarette smoke total particulate matter (TPM), a known inhibitor of GJIC, were used to characterize a new GJIC screening assay in three independent experiments. The main features of this assay were automated fluorescence microscopy combined with non-invasive parachute technique. Rat liver epithelial cells (WB-F344) were stained with the fluorescent dye Calcein AM (acetoxymethyl) and exposed to TPM from the Kentucky Reference Cigarette 2R4F (a blend of Bright and Burley tobaccos) and from two single-tobacco cigarettes (Bright and Burley) for 3h. Phorbol-12-myristate-13-acetate (TPA) was used as positive control and 0.5% dimethyl sulfoxide (DMSO) as solvent control. The transfer of dye to adjacent cells (percentage of stained cells) was used as a measure of cellular communication. A clear and reproducible dose-response of GJIC inhibition following TPM exposure was seen. Reproducibility and repeatability measurements for the 2R4F cigarette were 3.7% and 6.9%, respectively. The half-maximal effective concentration values were 0.34ng/ml for TPA, 0.050mg/ml for the 2R4F, 0.044mg/ml for the Bright cigarette, and 0.060mg/ml for the Burley cigarette. The assay was able to discriminate between the two single-tobacco cigarettes (P<0.0001), and between the single-tobacco cigarettes and the 2R4F (P=0.0008, 2R4F vs. Burley and P<0.0001, 2R4F vs. Bright). Thus, this assay can be used to determine the activity of complex mixtures such as cigarette smoke with high throughput and high precision. 23470072 NTproBNP: An Important Biomarker in Cardiac Diseases. Natriuretic neuropeptides (ANP, BNP, CNP) are produced primarily in the cardiac atria under normal conditions. The main stimulus for ANP and BNP peptide synthesis and secretion is cardiac wall stress. Cardiac ventricular myocytes constitute the major source of BNP-related peptides. Ventricular NT-proBNP production is upregulated in cardiac failure and locally in the area surrounding a myocardial infarct. NT-proBNP is cleared passively by organs with high rate of blood flow (muscle, liver, kidney). It has a longer half life than BNP and higher plasma concentration. BNP and NTproBNP tend to be higher in women and lower in obese individuals. They are also higher in elderly, in left ventricular tachycardia, right ventricular overload, myocardial ischemia, hypoxaemia, renal dysfunction, liver cirrhosis, sepsis and infection. NT-proBNP is useful both in the diagnosis and prognosis of heart failure and is considered to be a gold standard biomarker in heart failure similar to BNP. A cut-off point 300 pg/ml has 99% sensitivity, 60%specificity and NPV 98%for exclusion of acute heart failure. NT proBNP has also a strong prognostic value of death in acute and chronic heart failure and also predicts short and long term mortality in patient with suspected or confirmed unstable CVD. Natriuretic peptides are also prognostic markers for the RV (Right Ventricular) Dysfunction. Their release is due to myocardial stretch from right ventricular pressure overload.Finally, there are data supporting that NT-proBNP might be useful to put a time frame on atrial fibrillation of unknown onset. 23600593 Flavone C-glycosides from the flowers of Trollius chinensis and their anti-complementary activity. Phytochemical investigation of ethanol extract from the flowers of Trollius chinensis Bunge resulted in the isolation of two new flavone C-glycosides (1-2), along with 10 known compounds (3-12). The structures of the new compounds were established as 6‴-(3-hydroxy-3-methylglutaroyl)-2″-O-β-d-galactopyranosyl orientin (1) and 6‴-(3-hydroxy-3-methylglutaroyl)-2″-O-β-d-galactopyranosyl vitexin (2) on the basis of various spectroscopic analysis (including different 1D and 2D NMR spectroscopies, high-resolution electrospray ionization mass spectrometry) and chemical evidences. Bioassay showed that eight flavonoids inhibited complement activation on the classic pathway in vitro, with their IC50 values ranging from 0.88 to 4.02 mM, which may contribute to the applications of the herb in treatment of acute respiratory distress syndrome, etc. 23483083 Enhanced photovoltaic performance of a dye-sensitized solar cell using graphene-TiO2 photoanode prepared by a novel in situ simultaneous reduction-hydrolysis technique. Enhanced photovoltaic performance of a DSSC using graphene-TiO2 photoelectrodes prepared by our recent in situ simultaneous reduction-hydrolysis technique (Adv. Funct. Mater., 2012, DOI: 10.1002/adfm.201202349, in press) was achieved. The DSSCs based on the G-TiO2 nanocomposites improved their overall energy conversion efficiency to 7.1%. The results prove that the promoting effect of graphene is strongly dependent on its content; namely, the efficiency of DSSCs increases and then decreases with increasing graphene content in TiO2-graphene composites. Excessive graphene in the nanocomposite leads to a decrease of the light harvest of dye molecules and thus a negative effect on the power conversion efficiency of DSSCs. 23233324 Event based analysis of chlorothalonil concentrations following application to managed turf. Chlorothalonil concentrations exceeding acute toxicity levels for certain organisms have been measured in surface water discharge events from managed turf watersheds. The duration of exceedence and the timing of these events related to precipitation/runoff and time since application, however, have not been explored. Chlorothalonil concentrations were measured from discharge waters draining a managed turf watershed in Duluth, Minnesota, USA, between 2003 and 2009. The median chlorothalonil concentration was 0.58 µg/L. Approximately 2% of all measured concentrations exceeded the 7.6 µg/L median lethal concentration (LC50) acute toxicity level for rainbow trout. One-twentieth the LC50 concentration, equivalent to the level of concern (0.38 µg/L) for endangered species, was exceeded 31% of the time during the present study. The concentrations that exceeded the LC50 threshold were associated with eight rainfall/runoff events. Low dose exposures are a more important biological concern than acute occurrences. Exceedence concentrations associated with acute effects were significantly (p < 0.05) correlated to time since application and were measured only in the fall following extensive application. A conflict exists between the transportability of chlorothalonil as suggested by its chemical properties and the data collected in the present study. With respect to course-wide golf course application, avoiding application until after the major autumn rainfall period but before the first snow coverage is recommended to reduce occurrence of chlorothalonil concentrations that exceed toxic levels associated with acute and chronic levels of concern. 23194514 Use of an electrodialytic reactor for the simultaneous β-lactoglobulin enzymatic hydrolysis and fractionation of generated bioactive peptides. The enzymatic hydrolysis of β-lactoglobulin and the fractionation of peptides were performed in one step in an electrodialysis cell with ultrafiltration membranes stacked. After 240 min of treatment, 15 anionic and 4 cationic peptides were detected in the anionic and cationic peptide recovery compartments. Amongst these 15 anionic peptides, 2 hypocholesterolemic, 3 antihypertensive and 1 antibacterial peptides were recovered and concentrated with migration rates ranging from 5.5% and 81.7%. Amongst the 4 cationic peptides, the peptide sequence ALPMHIR, identified as lactokinin and known to exert an important antihypertensive effect, was recovered with an estimated 66% migration rate. To our knowledge, it was the first attempt to perform hydrolysis under an electric field and to simultaneously separate anionic and cationic peptides produced. 23598455 Clinical implementation of pharmacogenetics: more than one gene at a time. Tricyclic antidepressant (TCA) clinical pharmacogenetic implementation guidelines for CYP2D6 and CYP2C19 genotypes highlight the importance of both genes. However, studies of the combined impact of the two genes are sparse, limiting the ability to make strong recommendations based on both genes. The warfarin pharmacogenetics literature highlights the strength of a multigenic approach for discovery and clinical implementation. For optimal impact and interpretation, investigators are encouraged to conduct studies in the context of previously well-defined pharmacogenetics markers. 23244629 Peptide/protein separation with cationic polymer brush nanosponges for MALDI-MS analysis. A cationic polymer nanobrush was synthesized, attached to a MALDI target, and used for the fractionation of peptides and proteins based on their pI, prior to analysis by MALDI-MS. The cationic polymer nanobrush was synthesized on a gold substrate by AIBN photoinitiated polymerization, using a 70:30 ratio of 2-aminoethyl methacrylate hydrochloride (AEMA):N-isopropylacrylamide (NIPAAM). This brush showed selectivity for adsorption of acidic peptides and proteins and allowed fractionation of simple two-component mixtures to be completed in less than 10 min. The brush-adsorbed biomolecules were recovered by treating the nanobrush with ammonium hydroxide, which effectively collapsed the brush, thereby releasing the trapped compounds for MALDI MS analysis. These results demonstrate that nanobrush can serve as a convenient platform for rapid fractionation of biomolecules prior to analysis by MALDI-MS. 23511020 Carbonic anhydrase inhibitors: Inhibition of the β-class enzyme from the pathogenic yeast Candida glabrata with sulfonamides, sulfamates and sulfamides. The fungal pathogen Candida glabrata encodes for a β-carbonic anhydrase (CA, EC 4.2.1.1), CgNce103, recently discovered. Only anions have been investigated as CgNce103 inhibitors up until now. Here we report the first sulfonamides inhibition study of this enzyme. Simple sulfonamides showed weak or moderate CgNce103 inhibitory properties, whereas acetazolamide, and a series of 4-substituted ureido-benzene-sulfonamides, sulfamates and sulfamides showed effective CgNce103 inhibitory properties, with KIs in the range of 4.1-115nM, being also ineffective as human CA II inhibitors. As there is significant resistance of C. glabrata clinical isolates to many classical antifungal agents, inhibition of the β-CA from this organism may allow an interesting means of controlling the pathogen growth, eventually leading to antifungals with a novel mechanism of action. 23172734 Contaminant-mobilizing capability of fullerene nanoparticles (nC60): Effect of solvent-exchange process in nC60 formation. Fullerene nanoparticles (nC(60)) in aqueous environments can significantly enhance the transport of hydrophobic organic contaminants by serving as a contaminant carrier. In the present study, the authors examine the effect of the solvent-exchange process on nC(60) aggregate formation and, subsequently, on nC(60) 's contaminant-mobilizing capability. A series of nC(60) samples were prepared using a modified toluene-water solvent-exchange method through the inclusion of a secondary organic solvent in the phase transfer of molecular C(60) in toluene to nC(60) in water. Two groups of solvents--a water-miscible group and a non-water-miscible group-of varied polarity were selected as secondary solvents. The involvement of a secondary solvent in the phase transfer process had only small effects on the particle size and distribution, ζ potential, and mobility of the nC(60) products but significantly influenced the capability of nC(60) to enhance the transport of 2,2',5,5'-polychlorinated biphenyl (PCB) in a saturated sandy soil column, regardless of whether the secondary solvent was water-miscible or non-water-miscible. The two groups of secondary solvents appear to affect the aggregation properties of nC(60) in water via different mechanisms. In general, nC(60) products made with a secondary water-miscible solvent have stronger capabilities to enhance PCB transport. Taken together, the results indicate that according to formation conditions and solvent constituents, nC(60) will vary significantly in its interactions with organic contaminants, specifically as related to adsorption or desorption as well as transport in porous media. 23275112 Biocompatibility and levofloxacin delivery of mesoporous materials. A comparative study of mesoporous matrices designed for both drug-loading methods, impregnation (IP) and surfactant-assisted drug loading (also denoted as one-pot, OP), has been carried out evaluating their physicochemical characteristics, cell response, drug delivery profiles, and antibacterial activity. Surfactant-free (calcined) and surfactant-templated (non-calcined) mesoporous silica have been used as IP and OP starting matrices, respectively. Both non-calcined and calcined matrices do not exert any cytotoxic effect on osteoblasts. However, non-calcined matrices induce on fibroblasts a significant proliferation delay with morphological alterations and dose-dependent increases in fibroblast size, internal complexity, and intracellular calcium content but without cell lysis and apoptosis. Residual ethanol and the surface silanol groups in these non-calcined matrices are involved in the observed fibroblast changes. Finally, both IP and OP matrices have been loaded with levofloxacin to compare them as drug delivery systems. Both IP and OP matrices exhibit similar in vitro levofloxacin release profiles, showing an initial fast delivery followed by a sustained release during long time periods. These profiles and the antimicrobial activity results suggest the use of these IP and OP matrices as local drug delivery systems in the osteomyelitis and other bone infection treatments. 23587425 Potency switch between CHK1 and MK2: Discovery of imidazo[1,2-a]pyrazine- and imidazo[1,2-c]pyrimidine-based kinase inhibitors. Chemistry has been developed to access both imidazo[1,2-a]pyrazines and imidazo[1,2-c]pyrimidines. Small structural modifications in both series led to a switch of potency between two kinases involved in mediating cell cycle checkpoint control, CHK1 and MK2. 23561123 Free fatty acid profiles of emulsified lipids during in vitro digestion with pancreatic lipase. Individual free fatty acids released from milk protein-stabilized emulsions prepared with milk fat, soya bean oil or tuna fish oil during in vitro digestion with pancreatic lipase were monitored using gas chromatography. The results showed that saturated fatty acids (C16:0 and C18:0) were released faster than unsaturated fatty acids (C18:1n9, C18:2n6 and C18:3n3) from soya bean oil emulsions; short chain fatty acids were released faster than long chain fatty acids from milk fat emulsions; long chain polyunsaturated fatty acids, such as eicosapentaenoic acid and docosahexaenoic acid, were released more slowly than other fatty acids from fish oil emulsions. The results confirm that the release behaviour of fatty acids from emulsions during digestion is related not only to the position of the fatty acids in the triglycerides in the fat/oil, but also to the length of the carbon chain of the fatty acid. The rates and the extents of the digestion of lipids consisting of short chain fatty acids are higher than those of lipids consisting of long chain fatty acids. 23194076 Diet, physical exercise and Orlistat administration increase serum Anti-Müllerian Hormone (AMH) levels in women with polycystic ovary syndrome (PCOS). The present study investigates the combined effect of diet, physical exercise and Orlistat for 24 weeks, on serum Anti-Müllerian Hormone (AMH) levels in overweight and obese women with polycystic ovary syndrome (PCOS) and in overweight and obese controls. Sixty-one (61) selected women with PCOS and 20 overweight and obese controls followed an energy-restricted diet, physical exercise plus Orlistat administration (120 mg, 3 times per day) for 24 weeks. At baseline, week 12 and week 24, serum levels of AMH, FSH, LH, PRL, androgens, sex hormone-binding globulin (SHBG), glucose, and insulin were measured and Free Androgen Index (FAI) and Insulin Resistance (IR) indices were calculated. In PCOS women, serum AMH levels increased after 12 and 24 weeks of treatment. After 12 weeks LH and SHBG were increased, while Testosterone decreased. After 12 and 24 weeks, FAI was decreased and all indices of IR were significantly improved. We concluded that in overweight and obese women with PCOS Orlistat administration, combined with diet and physical exercise, for 24 weeks, resulted in significant weight loss, improvement of hyperandrogenism and insulin sensitivity, and increased serum AMH levels. 23414210 High-Performance Surface Acoustic Wave Immunosensing System on a PEG/Aptamer Hybridized Surface. Label-free immunoassay systems have the advantages of procedural simplicity and a low construction cost of surfaces for immunosensing. When label-free immunoassay systems are considered, the nonspecific adsorption of unwanted materials should be eliminated unless it aids in the detection of error. PEG is well-known as a blocking agent for the prevention of the adsorption of nonspecific binding materials when coimmobilized with ligands for targets such as antibodies and oligonucleotides. The construction strategy for PEG/ligand coimmobilized surfaces is an important point in the preparation of a high-performance assays because the physiological condition of the ligand depends strongly on its interaction with the PEG chain. In this report, we investigate the interaction between thrombin and a thrombin-binding aptamer (TBA) on a PEG/TBA coimmobilized surface by using a shear horizontal surface acoustic wave (SAW) sensor. The thrombin-TBA binding property shows remarkable differences with changes in the PEG density and the distance from the gold surface to the aptamer. 23536264 Biomarkers of Lead Exposure Among a Population Under Environmental Stress. This study aimed to evaluate the relationship between blood lead and serum creatinine and blood lead and serum urea nitrogen levels as biomarkers of lead exposure from subjects living in a historic polymetallic mining area in China. Elevated levels were found for blood lead, serum creatinine, and serum urea nitrogen in the mining area with mean values at 245.65 μg/l, 74.16 μmol/l, and 12.79 mmol/l, which were significantly higher than those in the control area, respectively. Moreover, the coefficients between paired results for blood lead and serum creatinine and blood lead and serum urea nitrogen were positively statistically significant (serum creatinine vs. blood lead, r = 0.35, p < 0.05; serum urea nitrogen vs. blood lead, r = 0.48, p < 0.05). With respect to the effects of sex and age on the blood lead, serum creatinine, and serum urea nitrogen levels, data analysis revealed there was a tendency for higher blood lead, serum creatinine, and serum urea nitrogen levels in females than in males, and the levels of blood lead, serum creatinine, and serum urea nitrogen increased among older residents. We conclude that females and the older population in the mining area are more susceptible to lead exposure. Blood lead, serum creatinine, and serum urea nitrogen can be useful biomarkers of lead exposure among populations under environmental stress. 23592745 Protective effect of wogonin on proinflammatory cytokine generation via Jak1/3-STAT1/3 pathway in lipopolysaccharide stimulated BV2 microglial cells. Wogonin is a flavonoid compound which exhibits antioxidation, anti-inflammation, neuroprotection, and antitumorgenesis functions. However, the mechanism of how wogonin reduces proinflammatory cytokine generation in activated microglia is unclear. At present, we found wogonin inhibited lipopolysaccharide (LPS)-/interferon-γ (INF-γ)-induced generation of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Wogonin exhibited parallel inhibition on LPS-/INF-γ-induced expression of IL-6 and TNF-α messenger RNA at the same concentration range. LPS-/INF-γ-induced phosphorylation of signal transduction and transcription 1 and 3 (STAT1/3) were also inhibited by wogonin. Although wogonin expressed only weak inhibitory effect on LPS-/INF-γ-induced phosphorylation of Janus kinase-2 (Jak-2) and tyrosine kinase (Tyk)-2, it significantly attenuated the phosphorylation of Jak-1 and Jak-3. These results indicated that the blockade of IL-6 and TNF-α production by wogonin in LPS-/INF-γ-stimulated BV2 microglial cells was attributed mainly to the interference in Jak-1/-3-STAT1/3 signaling pathway. 23434223 A one-pot domino synthesis and discovery of highly functionalized dihydrobenzo[b]thiophenes as AChE inhibitors. A library of novel 5-amino-2,7-diaryl-2,3-dihydrobenzo[b]thiophene-4,6-dicarbonitriles have been synthesized regioselectively in good yields through the one-pot domino reactions of 5-aryldihydro-3(2H)-thiophenones, malononitrile and aromatic aldehydes in the presence of morpholine. This transformation presumably involves Knoevenagel condensation-Michael addition-intramolecular Thorpe-Ziegler cyclization-Tautomerization-Elimination sequence of reactions. These compounds were evaluated for their acetylcholinesterase (AChE) inhibitory activity and 5-amino-2,7-bis(4-methoxyphenyl)-2,3-dihydrobenzo[b]thiophene-4,6-dicarbonitrile was found to be the most potent against AChE with IC50 4.16 μmol/L. 23445189 Optoelectronic Functional Materials Based on Alkylated-π Molecules: Self-Assembled Architectures and Nonassembled Liquids. The engineering of single molecules into higher-order hierarchical assemblies is a current research focus in molecular materials chemistry. Molecules containing π-conjugated units are an important class of building blocks because their self-assembly is not only of fundamental interest, but also the key to fabricating functional systems for organic electronic and photovoltaic applications. Functionalizing the π-cores with "alkyl chains" is a common strategy in the molecular design that can give the system desirable properties, such as good solubility in organic solvents for solution processing. Moreover, the alkylated-π system can regulate the self-assembly behavior by fine-tuning the intermolecular forces. The optimally assembled structures can then exhibit advanced functions. However, while some general rules have been revealed, a comprehensive understanding of the function played by the attached alkyl chains is still lacking, and current methodology is system-specific in many cases. Better clarification of this issue requires contributions from carefully designed libraries of alkylated-π molecular systems in both self-assembly and nonassembly materialization strategies. Here, based on recent efforts toward this goal, we show the power of the alkyl chains in controlling the self-assembly of soft molecular materials and their resulting optoelectronic properties. The design of alkylated-C60 is selected from our recent research achievements, as the most attractive example of such alkylated-π systems. Some other closely related systems composed of alkyl chains and π-units are also reviewed to indicate the universality of the methodology. Finally, as a contrast to the self-assembled molecular materials, nonassembled, solvent-free, novel functional liquid materials are discussed. In doing so, a new journey toward the ultimate organic "soft" materials is introduced, based on alkylated-π molecular design. 23639538 A dihydrochalcone and several homoisoflavonoids from Polygonatum odoratum are activators of adenosine monophosphate-activated protein kinase. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a major cellular energy sensor and master regulator of metabolic homeostasis; thus, AMPK plays a central role in studies on diabetes and related metabolic diseases. From the rhizomes of Polygonatum odoratum (Mill.) Druce, six homoisoflavonoids (1-6) and one dihydrochalcone (7) were isolated, and the structures of polygonatones A-D (4-7) were elucidated by various spectroscopic analyses. Compounds 1-7 were evaluated for their effect on AMPK activation. The amount of active phosphorylated AMPK and acetyl-CoA carboxylase in rat liver epithelial IAR-20 cells increased when the cells were incubated with the aforementioned compounds. Specifically, (3R)-5,7-dihydroxyl-6-methyl-8-methoxyl-3-(4'-hydroxylbenzyl)-chroman-4-one (1), (3R)-5,7-dihydroxyl-6,8-dimethyl-3-(4'-hydroxylbenzyl)-chroman-4-one (2), (3R)-5,7-dihydroxyl-6-methyl-3-(4'-hydroxylbenzyl)-chroman-4-one (3), and polygonatone D (7) exhibited significant activation effects. 23360452 Mass transfer and adsorption equilibrium for low volatility alkanes in BPL activated carbon. The structure of a molecule and its concentration can strongly influence diffusional properties for transport in nanoporous materials. We study mass transfer of alkanes in BPL activated carbon using the concentration-swing frequency response method, which can easily discriminate among mass transfer mechanisms. We measure concentration-dependent diffusion rates for n-hexane, n-octane, n-decane, 2,7-dimethyloctane, and cyclodecane, which have different carbon numbers and geometries: straight chain, branched chain, and cyclic. Micropore diffusion is determined to be the controlling mass transfer resistance except at low relative saturation for n-decane, where an external mass transfer resistance also becomes important, showing that the controlling mass transfer mechanism can change with system concentration. Micropore diffusion coefficients are found to be strongly concentration dependent. Adsorption isotherm slopes obtained from measured isotherms, the concentration-swing frequency response method, and a predictive method show reasonably good agreement. 23590193 Vortex-induced amyloid superstructures of insulin and its component a and B chains. Insulin is an amyloid-forming polypeptide built of two disulfide-linked chains (A and B), both themselves amyloidogenic. An interesting property of insulin is that agitation strongly influences the course of its aggregation, resulting in characteristic chiral superstructures of amyloid fibrils. Here, we investigate the self-assembly of these superstructures by comparing the quiescent and vortex-assisted aggregation of insulin and its individual A and B chains in the presence or absence of reducing agent tris(2-carboxyethyl)phosphine (TCEP). Our study shows that only the B chain in the presence of TCEP is converted into aggregates with morphology (according to atomic force microscopy) and optical activity (manifested as an extrinsic Cotton effect induced in bound thioflavin T) characteristic of amyloid superstructures that are normally formed by insulin in the absence of TCEP. In contrast to more rigid B-peptide fibrils, elongated aggregates of the A peptide become amorphous upon agitation. Moreover, the aggregation of equimolar mixture of both peptides does not produce highly ordered entities. Our results suggest that the dynamics of the B chain are the driving force for the assembly of superstructures, with the A chain being complicit as long as its own dynamics are controlled by the firm attachment to the B chain provided by the intact covalent structure of insulin. 23561155 Biosynthesis of highly enriched (13)C-lycopene for human metabolic studies using repeated batch tomato cell culturing with (13)C-glucose. While putative disease-preventing lycopene metabolites are found in both tomato (Solanum lycopersicum) products and in their consumers, mammalian lycopene metabolism is poorly understood. Advances in tomato cell culturing techniques offer an economical tool for generation of highly-enriched (13)C-lycopene for human bioavailability and metabolism studies. To enhance the (13)C-enrichment and yields of labelled lycopene from the hp-1 tomato cell line, cultures were first grown in (13)C-glucose media for three serial batches and produced increasing proportions of uniformly labelled lycopene (14.3±1.2%, 39.6±0.5%, and 48.9±1.5%) with consistent yields (from 5.8 to 9mg/L). An optimised 9-day-long (13)C-loading and 18-day-long labelling strategy developed based on glucose utilisation and lycopene yields, yielded (13)C-lycopene with 93% (13)C isotopic purity, and 55% of isotopomers were uniformly labelled. Furthermore, an optimised acetone and hexane extraction led to a fourfold increase in lycopene recovery from cultures compared to a standard extraction. 23603154 MicroRNAs as pharmacological targets in endothelial cell function and dysfunction. Endothelial cell dysfunction is a term which implies the dysregulation of normal endothelial cell functions, including impairment of the barrier functions, control of vascular tone, disturbance of proliferative, migratory and morphogenic capacities of endothelial cells, as well as control of leukocyte trafficking. MicroRNAs (miRNAs) are short non-coding RNAs that have emerged as critical regulators of gene expression acting predominantly at the post-transcriptional level. This review summarizes the latest insights in the identification of endothelial-specific miRNAs and their targets, as well as their roles in controlling endothelial cell functions in both autocrine and paracrine manner. In addition, we discuss the therapeutic potential for the treatment of endothelial cell dysfunction and associated vascular pathophysiological conditions. 23430410 Exogenous sodium nitroprusside alleviates arsenic-induced oxidative stress in wheat (Triticum aestivum L.) seedlings by enhancing antioxidant defense and glyoxalase system. The present study investigates the possible regulatory role of exogenous nitric oxide (NO) in mitigating oxidative stress in wheat seedlings exposed to arsenic (As). Seedlings were treated with NO donor (0.25 mM sodium nitroprusside, SNP) and As (0.25 and 0.5 mM Na2HAsO4·7H2O) separately and/or in combination and grown for 72 h. Relative water content (RWC) and chlorophyll (chl) content were decreased by As treatment but proline (Pro) content was increased. The ascorbate (AsA) content was decreased significantly with increased As concentration. The imposition of As caused marked increase in the MDA and H2O2 content. The amount of reduced glutathione (GSH) and glutathione disulfide (GSSG) significantly increased with an increase in the level of As (both 0.25 and 0.5 mM), while the GSH/GSSG ratio decreased at higher concentration (0.5 mM). The ascorbate peroxidase and glutathione S-transferase activities consistently increased with an increase in the As concentration, while glutathione reductase (GR) activities increased only at 0.25 mM. The monodehydroascorbate reductase (MDHAR) and catalase (CAT) activities were not changed upon exposure to As. The activities of dehydroascorbate reductase (DHAR) and glyoxalase I (Gly I) decreased at any levels of As, while glutathione peroxidase (GPX) and glyoxalase II (Gly II) activities decreased only upon 0.5 mM As. Exogenous NO alone had little influence on the non-enzymatic and enzymatic components compared to the control seedlings. These inhibitory effects of As were markedly recovered by supplementation with SNP; that is, the treatment with SNP increased the RWC, chl and Pro contents; AsA and GSH contents and the GSH/GSSG ratio as well as the activities of MDHAR, DHAR, GR, GPX, CAT, Gly I and Gly II in the seedlings subjected to As stress. These results suggest that the exogenous application of NO rendered the plants more tolerant to As-induced oxidative damage by enhancing their antioxidant defense and glyoxalase system. 23530654 Cryptic genetic and wing pattern diversity in a mimetic Heliconius butterfly. Despite rampant colour pattern diversity in South America, Heliconius erato exhibits a 'postman' wing pattern throughout most of Central America. We examined genetic variation across the range of H. erato, including dense sampling in Central America, and discovered a deep genetic break, centred on the mountain range that runs through Costa Rica. This break is characterized by a novel mitochondrial lineage, which is nearly fixed in northern Central America, that branches basal to all previously described mitochondrial diversity in the species. Strong genetic differentiation also appears in Z-linked and autosomal markers, and it is further associated with a distinct, but subtle, shift in wing pattern phenotype. Comparison of clines in wing phenotype, mtDNA and nuclear markers indicate they are all centred on the mountains dividing Costa Rica, but that cline width differs among data sets. Phylogeographical analyses, accounting for this new diversity, rewrite our understanding of mimicry evolution in this system. For instance, these results suggest that H. erato originated west of the Andes, perhaps in Central America, and as many as 1 million years before its co-mimic, H. melpomene. Overall our data indicate that neutral genetic markers and colour pattern loci are congruent and converge on the same hypothesis-H. erato originated in northwest South America or Central America with a 'postman' phenotype and then radiated into the wealth of colour patterns present today. 23143926 In vitro exposure of precision-cut lung slices to 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole lysylamide dihydrochloride (NSC 710305, Phortress) increases inflammatory cytokine content and tissue damage. The anticancer drug (2-[4-amino-3-methylphenyl]-5-fluorobenzothiazole lysylamide dihydrochloride) (NSC 710305, Phortress) is a metabolically activated prodrug that causes DNA adduct formation and subsequent toxicity. Preclinically, it was found that hepatic, bone marrow, and pulmonary toxicity presented challenges to developing this drug. An ex vivo precision-cut lung slice (PCLS) model was used to search for concentration dependent effects of NSC 710305 (10, 25, 50, and 100 µM) on cytokine content, protein content, and immuno/histological endpoints. Preparation and culture of PCLS caused an initial spike in proinflammatory cytokine expression and therefore treatment with NSC 710305 was delayed until 48 h after initiating the slice cultures to avoid confounding the response to slicing with any drug response. PCLSs were evaluated after 24, 48, and 72 h exposures to NSC 710305. Reversibility of toxicity due to the 72-h treatment was evaluated after a 24-h recovery period. NSC 710305 caused a concentration-dependent cytokine response, and only the toxicity caused by a 72-h exposure to 25 µM reversed during the 24-h recovery period. Immuno/histological examination and quantitation of tissue protein levels indicated that tissue destruction, ED-1 (activated macrophage) staining, and protein levels were associated with the levels of proinflammatory cytokines in the tissue. In conclusion, the concentration- and time-dependent inflammatory response of PCLS to NSC 710305 preceded relevant tissue damage by a few days. The no-observable adverse effect level (NOAEL) for 24, 48, and 72 h exposures was established as 10 µM NSC 710305. 23275067 Discriminative stimulus effects of the GABAB receptor-positive modulator rac-BHFF: comparison with GABAB receptor agonists and drugs of abuse. GABA(B) receptor-positive modulators are thought to have advantages as potential medications for anxiety, depression, and drug addiction. They may have fewer side effects than GABA(B) receptor agonists, because selective enhancement of activated receptors could have effects different from nonselective activation of all receptors. To examine this, pigeons were trained to discriminate the GABA(B) receptor-positive modulator (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) from its vehicle. The discriminative stimulus effects of rac-BHFF were not mimicked by the GABA(B) receptor agonists baclofen and γ-hydroxybutyrate (GHB), not by diazepam, and not by alcohol, cocaine, and nicotine, whose self-administration has been reported to be attenuated by GABA(B) receptor-positive modulators. The discriminative stimulus effects of rac-BHFF were not antagonized by the GABA(B) receptor antagonist 3-aminopropyl (diethoxymethyl)phosphinic acid (CGP35348) but were attenuated by the less efficacious GABA(B) receptor-positive modulator 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol (CGP7930), suggesting the possibility that rac-BHFF produces its discriminative stimulus effects by directly activating GABA(B2) subunits of GABA(B) receptors. At a dose 10-fold lower than the training dose, rac-BHFF enhanced the discriminative stimulus effects of baclofen, but not of GHB. This study provides evidence that the effects of GABA(B) receptor-positive modulators are not identical to those of GABA(B) receptor agonists. In addition, the results suggest that positive modulation of GABA(B) receptors does not produce discriminative stimulus effects similar to those of benzodiazepines, alcohol, cocaine, and nicotine. Finally, the finding that rac-BHFF enhanced effects of baclofen but not of GHB is consistent with converging evidence that the populations of GABA(B) receptors mediating the effects of baclofen and GHB are not identical. 22082827 Tissues distribution of heavy metals and erythrocytes antioxidant status in rats exposed to Nigerian bonny light crude oil. The harmful effects of folkloric uses of Nigerian bonny light crude oil (BLCO) in ailments management may outweigh the expected beneficial effects. We investigated the levels of heavy metal concentrations in the tissues as well as the effect of BLCO on the antioxidant status of erythrocytes of rats after oral exposure to 0, 200 and 800 mg/kg BLCO for 7 days. Analysis of heavy metal concentrations in BLCO showed that Zn > Fe > Pb > Cu > Ni. The trend of accumulation of the metals in the tissues is blood-Fe > Pb >Zn whereas Cu and Ni levels were not affected; Liver-Ni > Zn > Fe > Cu > Pb and Testes-Ni > Cu > Pb > Zn > Fe. The order of concentration of the metals in the tissues is as follows: iron-blood > liver > testes; zinc-liver > blood > testes; lead-blood > liver > testes; copper-testes > liver > blood; nickel-liver > testes > blood. Activities of the antioxidant enzymes of erythrocytes such as superoxide dismutase, catalase, glutathione S-transferase and glutathione peroxidase increased significantly in a dose-dependent manner with significant elevation in hydrogen peroxide and malondialdehyde levels, whereas glutathione level was not significantly decreased in BLCO-treated animals. Collectively, the results showed that BLCO induces oxidative damage to erythrocytes of rats. 23437843 Discovery, biological evaluation, and structure-activity and -selectivity relationships of 6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-methylacetamides, a novel class of potent and selective monoamine oxidase inhibitors. The use of selective inhibitors of monoamine oxidase A (MAO-A) and B (MAO-B) holds a therapeutic relevance in the treatment of depressive disorders and Parkinson's disease (PD), respectively. Here, the discovery of a new class of compounds acting as monoamine oxidase inhibitors (MAO-Is) and bearing a 6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-alkylacetamide skeleton is reported. 6'-Sulfonyloxy derivatives exhibited outstanding affinities to MAO-A (7.0 nM < IC50 < 49 nM, much higher than moclobemide) and a pronounced MAO-A/B selectivity. The corresponding 6'-benzyloxy derivatives showed potent MAO-B inhibition and inverted selectivity profile. The rigid E-geometry of the exocyclic double bond allowed a more efficient binding conformation compared to more flexible and less active 2-(1-benzofuran-3-yl)-N-methylacetamide isomers and 4-N-methylcarboxamidomethylcoumarin analogues. Focused structural modifications and docking simulations enabled the identification of key molecular determinants for high affinity toward both MAO isoforms. These novel MAO-Is may represent promising hits for the development of safer therapeutic agents with a potential against depression, PD, and other age-related neurodegenerative pathologies. 22717743 Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPL(S447X)) gene therapy for lipoprotein lipase deficiency: an open-label trial. We describe the 2-year follow-up of an open-label trial (CT-AMT-011-01) of AAV1-LPL(S447X) gene therapy for lipoprotein lipase (LPL) deficiency (LPLD), an orphan disease associated with chylomicronemia, severe hypertriglyceridemia, metabolic complications and potentially life-threatening pancreatitis. The LPL(S447X) gene variant, in an adeno-associated viral vector of serotype 1 (alipogene tiparvovec), was administered to 14 adult LPLD patients with a prior history of pancreatitis. Primary objectives were to assess the long-term safety of alipogene tiparvovec and achieve a 40% reduction in fasting median plasma triglyceride (TG) at 3-12 weeks compared with baseline. Cohorts 1 (n=2) and 2 (n=4) received 3 × 10(11) gc kg(-1), and cohort 3 (n=8) received 1 × 10(12) gc kg(-1). Cohorts 2 and 3 also received immunosuppressants from the time of alipogene tiparvovec administration and continued for 12 weeks. Alipogene tiparvovec was well tolerated, without emerging safety concerns for 2 years. Half of the patients demonstrated a 40% reduction in fasting TG between 3 and 12 weeks. TG subsequently returned to baseline, although sustained LPL(S447X) expression and long-term changes in TG-rich lipoprotein characteristics were noted independently of the effect on fasting plasma TG. 23411201 Glycosidic aroma precursors of Syrah and Chardonnay grapes after an oak extract application to the grapevines. Syrah and Chardonnay grapevines were treated with an oak extract in order to determine the effect on glycosidic aroma precursors. Grapevines were treated at three different timings of the veraison (treatment 1, 2 and 3). Aglycons were obtained by enzymatic hydrolysis, and these were identified and quantified by means of gas chromatography-mass spectrometry (GC-MS). Results suggest that after the applications the majority of compounds from the oak extract were assimilated and stored as glycosidic forms in both cultivars. Also, other compounds not present in the extract were affected, with a different behaviour observed depending on the timing of application and the variety. In general, C6 compounds, alcohols, terpenes, phenols and C13-norisoprenoids in Syrah showed a decrease and in Chardonnay an increase. Thus, this study proved a change in the glycosidic aroma profile in grapes after the oak application, so these treated grapes could produce wines with different aromatic quality. 22956628 Delayed temporal increase of hepatic Hsp70 in ApoE knockout mice after prenatal arsenic exposure. Prenatal arsenic exposure accelerates atherosclerosis in ApoE(-/-) mice by unknown mechanism. Arsenic is a hepatotoxicant, and liver disease increases atherosclerosis risk. Prenatal arsenic exposure may predispose to liver disease by priming for susceptibility to other environmental insults. Earlier microarray analyses showed prenatal arsenic exposure increased Hsc70 (HspA8) and Hsp70 (HspA1a) mRNAs in livers of 10-week-old mice. We determined effects of prenatal arsenic exposure on hepatic Hsp70 and Hsc70 expression by Western blot and on DNA methylation by methyl acceptance assay during prenatal and postnatal development. Pregnant ApoE(-/-) mice were given drinking water containing 85 mg/l NaAsO(2) (49 ppm arsenic) from gestation day (GD) 8 to 18. Hsp70 and Hsc70 expression and DNA methylation were determined in GD18 fetuses and 3-, 10-, and 24-week-old mice. Hsc70 expression was unchanged at all ages. Hsp70 induction was observed at 3 and 10 weeks, but was unchanged in GD18 fetuses and 24-week livers of mice. Global DNA methylation increased with age; arsenic had no effects. Bisulfite sequencing of DNA from livers of 10-week-old mice showed Hsp70 promoter region methylation was unchanged, but methylation was increased within the transcribed region. Hsf1 and Nrf2 nuclear translocation were investigated as potential mechanisms of Hsp70 induction and found unaltered. Putative binding sites were identified in HSP70 for in utero arsenic exposure-suppressed microRNAs suggesting a possible mechanism. Thus, prenatal arsenic exposure causes delayed temporal hepatic Hsp70 induction, suggesting a transient state of stress in livers which can predispose the mice to developing liver disease. 23470287 A newly synthesized sinapic Acid derivative inhibits endothelial activation in vitro and in vivo. Inhibition of oxidative stress and inflammation in vascular endothelial cells (ECs) may represent a new therapeutic strategy against endothelial activation. Sinapic acid (SA), a phenylpropanoid compound, is found in natural herbs and high-bran cereals and has moderate antioxidant activity. We aimed to develop new SA agents with the properties of antioxidation and blocking EC activation for possible therapy of cardiovascular disease. We designed and synthesized 10 SA derivatives according to their chemical structures. Preliminary screening of the compounds involved scavenging hydroxyl radicals and 2,2-diphenyl-1-picrylhydrazyl (DPPH(⋅)), croton oil-induced ear edema in mice, and analysis of the mRNA expression of adhesion molecules in ECs. 1-Acetyl-sinapic acyl-4-(3'-chlorine-)benzylpiperazine (SA9) had the strongest antioxidant and anti-inflammatory activities both in vitro and in vivo. Thus, the effect of SA9 was further studied. SA9 inhibited tumor necrosis factor α-induced upregulation of adhesion molecules in ECs at both mRNA and protein levels, as well as the consequent monocyte adhesion to ECs. In vivo, result of face-to-face immunostaining showed that SA9 reduced lipopolysaccharide-induced expression of intercellular adhesion molecule-1 in mouse aortic intima. To study the molecular mechanism, results from luciferase assay, nuclear translocation of NF-κB, and Western blot indicated that the mechanism of the anti-inflammatory effects of SA9 might be suppression of intracellular generation of ROS and inhibition of NF-κB activation in ECs. SA9 is a prototype of a novel class of antioxidant with anti-inflammatory effects in ECs. It may represent a new therapeutic approach for preventing endothelial activation in cardiovascular disorders. 23354542 Age-related differences and relationships between elements in human amygdala and other limbic system or Basal Ganglia. To elucidate the compositional changes of the amygdala with aging, the authors investigated age-related differences of elements in human amygdalae. In addition, the relationships between the amygdala and other brain regions were investigated from a viewpoint of elements. After ordinary dissections at Nara Medical University were finished, the amygdalae were removed from the cerebra of the subjects who consisted of 22 men and 23 women, ranging in age from 70 to 101 years. In addition, the hippocampus, dentate gyrus, mammillary body of the limbic system and the caudate nucleus, putamen, and globus pallidus of the basal ganglia were also removed from the identical cerebra. After the brain samples were incinerated with nitric acid and perchloric acid, the element contents were determined by inductively coupled plasma-atomic emission spectrometry. It was found that both the Ca and Mg contents increased significantly in the amygdalae with aging, but the other five element contents (P, S, Zn, Fe, and Na) did not change significantly in the amygdalae with aging. Regarding the relationships among elements, very significant or significant direct correlations were found among the Ca, P, and Mg contents in the amygdalae. To explore the relationships between the amygdala and either other limbic system or basal ganglia, the correlations between seven elements of the amygdala and hippocampus, dentate gyrus, or mammillary body, and between those of the amygdala and caudate nucleus, putamen, or globus pallidus which derived from the identical cerebra, were analyzed with Pearson's correlation. It was found that regarding the four elements of Ca, P, Mg, and Fe, a close relationship existed between the amygdala and hippocampus, globus pallidus, or mammillary body. 22923220 Analysis of cytotoxic T lymphocyte antigen-4 (CTLA-4) promoter -318C/T and +49A/G gene polymorphisms in Turkish patients with familial Mediterranean fever. Either the role of the adaptive immune system or the interaction between innate and adaptive immune systems in familial Mediterranean fever (FMF) is not clear so far. So, we planned to search for the interaction between the innate and adaptive immune systems in the pathogenesis of FMF by investigating polymorphism for CTLA-4 gene, which plays a role in controlling antigen presentation to T cells. We also aimed to investigate whether there is an association between -318C/T and +49A/G polymorphisms in the CTLA-4 gene and the main clinical features of the disease. 75 FMF patients and 179 controls were studied. Polymorphism was detected by the PCR-RFLP technique. The CT genotype and T allele frequencies of the -318C/T polymorphism and the haplotype frequency for the -318T/+49A in the CTLA-4 gene were higher in the FMF (21.3, 21.3, and 10.7 %) when compared with the controls (10.6, 10.6, and 5.3 %; P = 0.029, 0.044, and 0.029). However, these differences did not reach a statistically significant level after the Bonferroni correction. A significant linkage disequilibrium was found between the -318C/T and +49A/G polymorphisms in the CTLA-4 gene (D' = 0.997, r(2) = 0.027, P = 0.0002). Genotype and carrier frequencies of the CTLA-4 gene +49A/G polymorphism were not significantly different between FMF patients and healthy controls. No association was found between the studied polymorphisms and the main clinical features of the disease. Our findings suggest that although not statistically significant, higher frequencies of CTLA-4 gene -318CT genotype, T allele, and -318T/+49A haplotype in FMF patients may be related to the non-autoimmune pathogenesis of FMF. 23300254 Sociocultural behavior, sex-biased admixture, and effective population sizes in Central African Pygmies and non-Pygmies. Sociocultural phenomena, such as exogamy or phylopatry, can largely determine human sex-specific demography. In Central Africa, diverging patterns of sex-specific genetic variation have been observed between mobile hunter-gatherer Pygmies and sedentary agricultural non-Pygmies. However, their sex-specific demography remains largely unknown. Using population genetics and approximate Bayesian computation approaches, we inferred male and female effective population sizes, sex-specific migration, and admixture rates in 23 Central African Pygmy and non-Pygmy populations, genotyped for autosomal, X-linked, Y-linked, and mitochondrial markers. We found much larger effective population sizes and migration rates among non-Pygmy populations than among Pygmies, in agreement with the recent expansions and migrations of non-Pygmies and, conversely, the isolation and stationary demography of Pygmy groups. We found larger effective sizes and migration rates for males than for females for Pygmies, and vice versa for non-Pygmies. Thus, although most Pygmy populations have patrilocal customs, their sex-specific genetic patterns resemble those of matrilocal populations. In fact, our results are consistent with a lower prevalence of polygyny and patrilocality in Pygmies compared with non-Pygmies and a potential female transmission of reproductive success in Pygmies. Finally, Pygmy populations showed variable admixture levels with the non-Pygmies, with often much larger introgression from male than from female lineages. Social discrimination against Pygmies triggering complex movements of spouses in intermarriages can explain these male-biased admixture patterns in a patrilocal context. We show how gender-related sociocultural phenomena can determine highly variable sex-specific demography among populations, and how population genetic approaches contrasting chromosomal types allow inferring detailed human sex-specific demographic history. 23432010 Bacterial infection probes and imaging strategies in clinical nuclear medicine and preclinical molecular imaging. At present, a limited number of strategies exist for diagnostic imaging of patients with bacterial infection. While radiolabeled probes and white blood cells provide robust solutions to detect bacteria in humans, they also give false positives in cases of sterile inflammation. With the onset of bacterial drug resistance, and a clinical trend toward reducing the prescription of antibiotics, the need for highly specific infection detection protocols has been renewed. The preclinical research community has recently utilized new optical imaging strategies, alongside traditional radioimaging research, to develop novel infection probes with translational potential. Here we review the current clinical methods for imaging bacteria in humans, and discuss the efforts within the preclinical community to validate new strategies. The review of preclinical infection imaging probes is limited to those probes that could be feasibly adapted for use in humans with currently available clinical modalities. 23601386 Trans fatty acids in a range of UK processed foods. A survey to determine the trans fatty acid content of a range of processed foods was carried out in response to recent reformulation work by the food industry to lower the artificial trans fatty acid content of processed products. Sixty two composite samples, made up of between 5 and 12 sub-samples, were collected in 2010 and were analysed for fatty acids, and a range of nutrients. The foods analysed included pizza, garlic bread, breakfast cereals, quiche, fat spreads, a range of fish and meat products, chips, savoury snacks, confectionery and ice cream. Levels of trans fatty acids were reduced considerably compared with previous UK analyses of similar foods where comparisons are possible. Concentrations of trans elaidic acid (t9-C18:1) from hydrogenated oils in all samples were <0.2g/100g food. These results confirm information provided by the food industry in 2007 on the levels of trans fats in key processed food sectors. 23396185 Quercetin prevents protein nitration and glycolytic block of proliferation in hydrogen peroxide insulted cultured neuronal precursor cells (NPCs): Implications on CNS regeneration. Survival along with optimal proliferation of neuronal precursors determines the outcomes of the endogenous cellular repair in CNS. Cellular-oxidation based cell death has been described in several neurodegenerative disorders. Therefore, this study was aimed at the identification of the potent targets of oxidative damage to the neuronal precursors and its effective prevention by a natural flavonoid, Quercetin. Neuronal precursor cells (NPCs), Nestin+ and GFAP (Glial fibrillary acidic protein)+ were isolated and cultured from adult rat SVZ (subventricular zone). These cells were challenged with a single dose of H2O2 (50μM) and/or pre-treated with different concentrations of Quercetin. H2O2 severely limited the cellular viability and expansion of the neurospheres. Cellular-oxidation studies revealed reduction in glutathione dependent redox buffering along with depletion of enzymatic cellular antioxidants that might potentiate the nitrite (NO2(-)) and superoxide anion (O2(-)) mediated peroxynitrite (ONOO(-)) formation and irreversible protein nitration. We identified depleted PK-M2 (M2 isoform of pyruvate kinase) activity and apoptosis of NPCs revealed by the genomic DNA fragmentation and elevated PARP (poly ADP ribose polymerase) activity along with increased Caspase activity initiated by severely depolarised mitochondrial membranes. However, the pre-treatment of Quercetin in a dose-response manner prevented these changes and restored the expansion of neurospheres preferably by neutralizing the oxidative conditions and thereby reducing peroxynitrite formation, protein nitration and PK-M2 depletion. Our results unravel the potential interactions of oxidative environment and respiration in the survival and activation of precursors and offer a promise shown by a natural flavonoid in the protective strategy for neuronal precursors of adult brain. 23621813 Triterpenes from the Aerial Parts of Cimicifuga yunnanensis and Their Antiproliferative Effects on p53(N236S) Mouse Embryonic Fibroblasts. Nine new triterpene derivatives, yunnanterpenes A-F (1-6), 15,16-seco-cimiterpenes A and B (7, 8), and cimilactone C (9), and 15 known analogues (10-24) were isolated from the aerial parts of Cimicifuga yunnanensis. The new structures were established using a combination of MS, NMR, and single-crystal X-ray diffraction techniques. WT MEFs (wild-type mouse embryonic fibroblasts) and tumorigenic cell lines p53(-/-)+H-RasV12 and p53(-/-)+p53(N236S)+H-RasV12 were used for evaluating active structures, targeting p53(N236S) (corresponding to p53(N239S) in humans) mutation. Compound 5 showed nonselective activities against these cell lines, with IC50 values of 5.8, 8.6, and 6.0 μM, respectively. Compound 4 exhibited greater selectivity against the p53(-/-)+p53(N236S)+H-RasV12 cells (IC50 5.5 μM) than against the WT MEFs cells (IC50 14.3 μM). 22855364 Self-assembled monolayers with dynamicity stemming from (bio)chemical conversions: from construction to application. Surfaces with "dynamicity" whereby surface properties can be modulated by an external stimulus on user demand have been actively exploited for the past decade. These switchable surfaces with dynamic properties are widely used for a number of applications such as micro/nanoarrays, biomolecule immobilization, basic cell studies, and tissue engineering on a variety of materials. This minireview highlights the dynamic control of surface properties on self-assembled monolayers and focuses on dynamicity that stems from (bio)chemical conversions achieved by electrical potentials, photoillumination, chemical reagents, enzymes, and pH. 23523545 Biodegradation and heart retention of polymeric microparticles in a rat model of myocardial ischemia. Poly-lactide-co-glycolide (PLGA) microparticles emerged as one of the most promising strategies to achieve site-specific drug delivery. Although these microparticles have been demonstrated to be effective in several wound healing models, their potential in cardiac regeneration has not yet been fully assessed. The present work sought to explore PLGA microparticles as cardiac drug delivery systems. PLGA microparticles were prepared by Total Recirculation One-Machine System (TROMS) after the formation of a multiple emulsion. Microparticles of different size were prepared and characterized to select the most suitable size for intramyocardial administration. Next, the potential of PLGA microparticles for administration in the heart was assessed in a MI rat model. Particle biodegradation over time and myocardial tissue reaction were studied by routine staining and confocal microscopy. Results showed that microparticles with a diameter of 5μm were the most compatible with intramyocardial administration in terms of injectability through a 29-gauge needle and tissue response. Particles were present in the heart tissue for up to 3months post-implantation and no particle migration toward other solid organs was observed, demonstrating good myocardial retention. CD68 immunolabeling revealed 31%, 47% and below 4% microparticle uptake by macrophages 1week, 1month, and 3months after injection, respectively (P<0.001). Taken together, these findings support the feasibility of the developed PLGA microparticles as vehicles for delivering growth factors in the infarcted myocardium. 23637347 The Atrial Natriuretic Peptide Genetic Variant Rs5068 Is Associated With a Favorable Cardiometabolic Phenotype in a Mediterranean Population. OBJECTIVEWe hypothesized that the minor allele of the atrial natriuretic peptide (ANP) genetic variant rs5068 is associated with a favorable cardiometabolic phenotype in a general Mediterranean population.RESEARCH DESIGN AND METHODSWe genotyped a random sample of the residents of Ventimiglia di Sicilia, Sicily, for rs5068.RESULTSGenotype frequencies of rs5068 are AA, 93.5%; AG, 6.4%; and GG, 0.1%. All subsequent analyses are AA versus AG+GG. After adjusting for age and sex, the minor G allele is associated with lower BMI (estimate [SE]: -1.7 kg/m(2) [0.8], P = 0.04). In the AG+GG group, males with HDL cholesterol levels <40 mg/dL are less frequent (P = 0.05) and obesity tends to be less prevalent (P = 0.07). Importantly, the G allele is associated with a lower prevalence of metabolic syndrome (P = 0.02). After adjusting for BMI, the above associations were attenuated. Independently of age, sex, and BMI, the minor allele is also associated with lower systolic blood pressure (-6.0 mmHg [2.5], P = 0.02) and lower prevalence of hypertension (odds ratio 0.41 [95% CI 0.20-0.83], P = 0.01).CONCLUSIONSThe association between the minor allele of rs5068 and a favorable cardiometabolic phenotype that we previously reported in a U.S. population is now replicated in a Mediterranean population in which the G allele of rs5068 is associated with lower blood pressure, BMI, and prevalence of hypertension and metabolic syndrome. These findings may lead to a diagnostic strategy to assess cardiometabolic risk and lay the foundation for the future development of an ANP or ANP-like therapy for metabolic syndrome. 23557601 Screening and evaluation of traditional Chinese medicine by microarray expression analysis. ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza is a Chinese medicinal herb, which is widely used for the treatment of cardiovascular disorders. In this article, we investigated the effects of Salvia miltiorrhiza and its hydrophilic and lipophilic components (HCS and LCS) on human umbilical vein endothelial cells (HUVECs), and the molecular mechanism was explored by microarray gene expression profiling. MATERIALS AND METHODS: Cell proliferation and migration were used to evaluate the angiogenic effects of HCS, LCS and total extract of Salvia miltiorrhiza (TES). Microarray technology was applied to detect the gene expression of HUVECs treated with TES, HCS and LCS. Besides, quantitative real-time PCR was used to verify the microarray results. RESULTS: Our results showed that LCS inhibited the proliferation and migration of HUVECs, HCS promoted the proliferation and migration of HUVECs, and TES did not affect the viability of HUVECs at the concentration of 5µg/mL. From the result of principle component analysis (PCA) of microarray data, the effect of LCS on HUVECs was significantly different from the other components. Moreover, there were more differentially expression genes in LCS group than in the other groups, which meant LCS had a strong influence on HUVECs. Compared with untreated cells, 511 significantly changed genes had been detected in LCS treated cells and 236 (approximately 46%) of them were up-regulated. The mRNA expression of IL-6 was found to be increased significantly in LCS group. CONCLUSIONS: In Salvia miltiorrhiza, HCS and LCS had opposite effects on HUVECs. LCS showed significantly inhibitory action on HUVECs proliferation and migration. It was proposed that LCS could apply in the diseases caused by vascular anomaly hyperplasia. In the mechanism of action of LCS on HUVECs, the pathways of ErbB, MAPK, p53, oxidative phosphorylation and inflammatory response were involved. 23600748 The receptor binding fragment of alpha-fetoprotein is a promising new vector for the selective delivery of antineoplastic agents. Abstract The alpha-fetoprotein (AFP) binding protein, a putative AFP receptor, is a tumour marker that is present on the surfaces of malignant cells. AFP enters cells through receptor-mediated endocytosis. The recombinant C-terminal fragment of AFP (AFP-3BC, which consists of amino acid residues 473-596) was obtained by the expression in Escherichia coli. AFP-3BC was shown to be bound specifically to the AFP putative receptor on tumour cells and accumulated by endocytosis in these cells in a similar manner to that of full-length human AFP. In lymphocytes, the binding and endocytosis of AFP-3BC were absent. Thus, the AFP receptor binding site was shown experimentally to be located within the AFP-3BC sequence. A conjugate of synthesised AFP-3BC with the antitumour antibiotic doxorubicin (DOX-AFP-3BC) demonstrated high antitumour activity in vitro. Thus, AFP-3BC can be used successfully as a vector for the targeted selective delivery of drugs into tumour cells. 23521110 Scutellarin from Scutellaria baicalensis Suppresses Adipogenesis by Upregulating PPARα in 3T3-L1 Cells. Adipocyte dysfunction is a major cause of obesity, which is associated strongly with many disorders including psychological and medical morbidities, metabolic abnormalities, and cardiovascular diseases as well as a series of cancers. This study investigated the antiadipogenic activity of scutellarin (1) in 3T3-L1 preadipocytes as well as the underlying molecular mechanisms. It was observed that 1 reduced adipocyte differentiation of 3T3-L1 cells potently, as evidenced by a decrease in cellular lipid accumulation. At the molecular level, mRNA expression of the master adipogenic transcription factors, PPARγ and C/EBPα, was decreased markedly. However, mRNA levels of C/EBPβ, the upstream regulator of PPARγ and C/EBPα, were not decreased by 1. Moreover, a dose-dependent upregulation of PPARα was observed for 1. Computational modeling indicated that 1 can bind to PPARα, γ, and δ each in a distinct manner, while it can activate PPARα only by forming a hydrogen bond with Y464, thus stabilizing the AF-2 helix and activating PPARα. Therefore, these results suggest that 1, a major component of Scutellaria baicalensis, attenuates fat cell differentiation by upregulating PPARα as well as downregulating the expression of PPARγ and C/EBPα, thus showing therapeutic potential for obesity-related diseases. 23125284 A mutation in the FAM36A gene, the human ortholog of COX20, impairs cytochrome c oxidase assembly and is associated with ataxia and muscle hypotonia. The mitochondrial respiratory chain complex IV (cytochrome c oxidase) is a multi-subunit enzyme that transfers electrons from cytochrome c to molecular oxygen, yielding water. Its biogenesis requires concerted expression of mitochondria- and nuclear-encoded subunits and assembly factors. In this report, we describe a homozygous missense mutation in FAM36A from a patient who displays ataxia and muscle hypotonia. The FAM36A gene is a remote, putative ortholog of the fungal complex IV assembly factor COX20. Messenger RNA (mRNA) and protein co-expression analyses support the involvement of FAM36A in complex IV function in mammals. The c.154A>C mutation in the FAM36A gene, a mutation that is absent in sequenced exomes, leads to a reduced activity and lower levels of complex IV and its protein subunits. The FAM36A protein is nearly absent in patient's fibroblasts. Cells affected by the mutation accumulate subassemblies of complex IV that contain COX1 but are almost devoid of COX2 protein. We observe co-purification of FAM36A and COX2 proteins, supporting that the FAM36A defect hampers the early step of complex IV assembly at the incorporation of the COX2 subunit. Lentiviral complementation of patient's fibroblasts with wild-type FAM36A increases the complex IV activity as well as the amount of holocomplex IV and of individual subunits. These results establish the function of the human gene FAM36A/COX20 in complex IV assembly and support a causal role of the gene in complex IV deficiency. 23419776 Proposed pathogenesis for atypical femoral fractures: Lessons from material research. Atypical femoral fractures (AFFs) have been well defined clinically and epidemiologically. Less clear are the underlying mechanisms responsible. This commentary points out the likely sources of decreased resistance to fracture using lessons from bone material studies and biomechanics. We hypothesize that the key element in the cascade of events leading to failure of the largest and strongest bone in the human body is long-term suppression of normal bone turnover caused by exposure to potent anti-remodeling agents, most notably the bisphosphonates (BPs). Suppressed bone turnover produces changes in bone that alter its material quality and these changes could lead to adverse effects on its mechanical function. At the submicroscopic [<1μm] level of collagen fibrils, suppression of bone turnover allows continued addition of non-enzymatic cross links that can reduce collagen's plasticity and this in turn contributes to reduced bone toughness. Further, adverse changes in hydroxyapatite crystalline structure and composition can occur, perhaps increasing collagen's brittleness. At the microscopic level [~1-500μm] of the bone-matrix structure, suppressed bone turnover allows full mineralization of cortical bone osteons and results in a microstructure of bone that is more homogeneous. Both brittleness and loss of heterogeneity allow greater progression of microscopic cracks that can occur with usual physical activity; in crack mechanical terms, normal mechanisms that dissipate crack tip growth energy are greatly reduced and crack progression is less impeded. Further, the targeted repair of cracks by newly activated BMUs appears to be preferentially suppressed by BPs. We further hypothesize that it is not necessary to have accumulation of many cracks to produce an AFF, just one that progresses - one that is not stopped by bone's several protective mechanisms and is allowed to penetrate through a homogeneous environment. The remarkable straight transverse fracture line is an indicator of the slow progression of a "mother crack" and the failure of usual mechanisms to bridge or deflect the crack. Research in AFF mechanisms has been focused at the organ level, describing the clinical presentation and radiologic appearance. Although today we have not yet connected all the dots in the pathophysiology of BP-induced AFF, recent advances in measuring bone mechanical qualities at the submicroscopic and tissue levels allow us to explain how spontaneous catastrophic failure of the femur can occur. 23293300 In vitro assessment of drug-drug interaction potential of boceprevir associated with drug metabolizing enzymes and transporters. The inhibitory effect of boceprevir (BOC), an inhibitor of hepatitis C virus nonstructural protein 3 protease was evaluated in vitro against a panel of drug-metabolizing enzymes and transporters. BOC, a known substrate for cytochrome P450 (P450) CYP3A and aldo-ketoreductases, was a reversible time-dependent inhibitor (k(inact) = 0.12 minute(-1), K(I) = 6.1 µM) of CYP3A4/5 but not an inhibitor of other major P450s, nor of UDP-glucuronosyltransferases 1A1 and 2B7. BOC showed weak to no inhibition of breast cancer resistance protein (BCRP), P-glycoprotein (Pgp), or multidrug resistance protein 2. It was a moderate inhibitor of organic anion transporting polypeptide (OATP) 1B1 and 1B3, with an IC(50) of 18 and 4.9 µM, respectively. In human hepatocytes, BOC inhibited CYP3A-mediated metabolism of midazolam, OATP1B-mediated hepatic uptake of pitavastatin, and both the uptake and metabolism of atorvastatin. The inhibitory potency of BOC was lower than known inhibitors of CYP3A (ketoconazole), OATP1B (rifampin), or both (telaprevir). BOC was a substrate for Pgp and BCRP but not for OATP1B1, OATP1B3, OATP2B1, organic cation transporter, or sodium/taurocholate cotransporting peptide. Overall, our data suggest that BOC has the potential to cause pharmacokinetic interactions via inhibition of CYP3A and CYP3A/OATP1B interplay, with the interaction magnitude lower than those observed with known potent inhibitors. Conversely, pharmacokinetic interactions of BOC, either as a perpetrator or victim, via other major P450s and transporters tested are less likely to be of clinical significance. The results from clinical drug-drug interaction studies conducted thus far are generally supportive of these conclusions. 23612318 Body composition assessment for the definition of cardiometabolic risk. Obesity is associated with a major prevalence of cardiovascular risk factors and high risk of cardiovascular events and contributes to the increase in cardiovascular morbidity and mortality worldwide. Beyond the fat mass per se, the pattern of fat distribution has a profound influence on cardiometabolic risk. The increase in abdominal adipose tissue confers an independent risk, while the amount of gluteofemoral body fat is thought to be protective. Changes in the capacity of different depots to store and release fatty acids and to produce adipocytokines are important determinants of fat distribution and its metabolic consequences. Because of the complexity of the assessment of body fat with imaging techniques, great attention has been paid to other measures of adiposity, such as waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR), which provide information on body fat distribution, although BMI is the established clinical measure to estimate the cardiovascular risk disease associated with excessive body weight. Abdominal obesity is a main predictive factor of the Metabolic Syndrome, so it is certain that it represents a better marker of cardiovascular risk than BMI. Visceral adiposity index (VAI) has recently proven to be a marker of visceral adipose distribution and function, associated with insulin sensitivity in patients at metabolic risk; however, the evidence needs to be further confirmed. In summary, BMI, WC, WHR, WHtR and VAI are all useful tools for assessing adiposity/obesity in clinical practice, and should be evaluated along with other cardiometabolic risk factors to define cardiovascular risk stratification. 23167526 Garcinia xanthones as orally active antitumor agents. Using a newly developed strategy whose key step is the regioselective propargylation of hydroxyxanthone substrates, 99 structurally diverse Garcinia natural-product-like xanthones based on gambogic acid were designed and synthesized and their in vitro antitumor activity was evaluated. A set of 40 related compounds was chosen for determination of their physicochemical properties including polar surface area, log D₇.₄, aqueous solubility, and permeability at pH 7.4. In the light of the in vitro antitumor activity and the physicochemical properties, two compounds were advanced into in vivo efficacy experiments. The antitumor activity of compound 112, administered po, showed more potent in vivo oral antitumor activity than gambogic acid. 23178198 Etazolate, an α-secretase activator, reduces neuroinflammation and offers persistent neuroprotection following traumatic brain injury in mice. Traumatic brain injury (TBI) evokes an intense neuroinflammatory reaction that is essentially mediated by activated microglia and that has been reported to act as a secondary injury mechanism that further promotes neuronal death. It involves the excessive production of inflammatory cytokines and the diminution of neuroprotective and neurotrophic factors, such as the soluble form alpha of the amyloid precursor protein (sAPPα), generated by the activity of α-secretases. Hence, the aim of this study was to examine the effects of etazolate, an α-secretase activator, on acute and belated post-TBI consequences. The mouse model of TBI by mechanical percussion was used and injured mice received either the vehicle or etazolate at the dose of 1, 3 or 10 mg/kg at 2 h post-TBI. Neurological score, cerebral œdema, IL-1β and sAPPα levels, microglial activation and lesion size were evaluated from 6 to 24 h post-TBI. Spontaneous locomotor activity was evaluated from 48 h to 12 weeks post-TBI, memory function at 5 weeks and olfactory bulb lesions at 13 weeks post-TBI. A single administration of etazolate exerted a dose-dependent anti-inflammatory and anti-œdematous effect accompanied by lasting memory improvement, reduction of locomotor hyperactivity and olfactory bulb tissue protection, with a therapeutic window of at least 2 h. These effects were associated with the restoration of the levels of the sAPPα protein post-TBI. Taken together, these results highlight for the first time the therapeutic interest of an α-secretase activator in TBI. 23314275 Tributyltin exposure influences predatory behavior, neurotransmitter content and receptor expression in Sebastiscus marmoratus. Tributyltin (TBT) is a ubiquitous marine contaminant due to its extensive use as a biocide, fungicide and antifouling agent. However, the neurotoxic effect of TBT has not been extensively studied, especially in marine fish. This study was conducted to investigate the effects of TBT (10, 100 and 1000 ng/L) on the predatory behavior of Sebastiscus marmoratus and to look into the mechanism involved. The results showed that TBT exposure depressed predatory activity after 50 days exposure. Dopamine levels in the fish brains increased in a dose-dependent manner, while 5-hydroxytryptamine and norepinephrine levels decreased significantly in the TBT exposure group compared to the control. The mRNA levels of dopamine receptors, which have functions such as cognition, motor activity, motivation and reward, mood, attention and learning, were significantly down-regulated by TBT exposure. Although the levels of amino acid neurotransmitters, including glutamate, did not show marked alteration, the expression of the glutamatergic signaling pathway such as N-methyl-D-aspartate receptors, a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor, calmodulin, Ca(2+)/calmodulin-dependent protein kinases-II and cyclic adenosine monophosphate responsive element binding protein, was significantly reduced by TBT exposure, which indicated that central nerve activities were in a state of depression, thus affecting the predatory activities of the fish. 23414235 Vegfrecine, an Inhibitor of VEGF Receptor Tyrosine Kinases Isolated from the Culture Broth of Streptomyces sp. A new inhibitor of VEGF receptor tyrosine kinases, vegfrecine (1), was isolated from the culture broth of Streptomyces sp. MK931-CF8. The molecular structure of 1 was determined by NMR and MS analysis combined with synthesis. Compound 1 showed potent inhibitory activity against vascular endothelial growth factor receptor (VEGFR) tyrosine kinases in in vitro enzyme assays, but platelet-derived growth factor receptors (PDGFRs), fibroblast growth factor receptor (FGFR), and epidermal growth factor receptor (EGFR) responded only weakly. Compound 1 is a promising new selective VEGFR inhibitor for investigating new treatments of cancer and inflammatory diseases. 23344856 Tissue accumulation and species-specific metabolism of technical pentabrominated diphenyl ether (DE-71) in two predator fish. The tissue-specific accumulation and species-specific metabolism of polybrominated diphenyl ethers (PBDEs) in two predator fish species (redtail catfish and oscar fish) feeding on the same prey (tiger barb) that was exposed to technical pentabrominated diphenyl ether (DE-71) in the laboratory were investigated. The trends in the wet-weight tissue concentration of PBDEs in two predatory fish species suggested that the tissue distribution of PBDEs occurs through a series of events involving passive diffusion to the lipid compartment. A comparison of the fugacities of PBDEs in various tissues and in the serum revealed that the liver, gill, and perivisceral adipose tissue readily achieved equilibrium with the serum, but the muscle, kidney, and intestine exhibited the potential to accumulate PBDEs. The lower fugacities of PBDEs in the intestine may have significance in the transportation of PBDEs from prey to predatory fish. No tissue-specific differences in PBDE congener profiles were found, while interspecies differences in PBDE profiles were evident. The difference in profiles between two species could be attributed to species-specific debromination of PBDE. No metabolic debromination of PBDE was observed in redtail catfish, but extensive debromination of PBDEs occurred in oscar fish. Several hydroxylated PBDEs (OH-PBDEs) were detected in serum samples from the two fish species, but no methoxylated PBDEs were found. The similarities in the OH-PBDE congener profile and the ratio of OH-PBDEs to total PBDEs between the two fish species indicated that the hydroxylation of PBDEs might not be species-specific. 22990878 Single molecule sensing with solid-state nanopores: novel materials, methods, and applications. This tutorial review will introduce and explore the fundamental aspects of nanopore (bio)sensing, fabrication, modification, and the emerging technologies and applications that both intrigue and inspire those working in and around the field. Although nanopores can be classified into two categories, solid-state and biological, they are essentially two sides of the same coin. For instance, both garner popularity due to their ability to confine analytes of interest to a nanoscale volume. Due to the vast diversity of nanopore platforms and applications, no single review can cover the entire landscape of published work in the field. Therefore, in this article focus will be placed on recent advancements and developments taking place in the field of solid-state nanopores. It should be stated that the intention of this tutorial review is not to cite all articles relating to solid-state nanopores, but rather to highlight recent, select developments that will hopefully benefit the new and seasoned scientist alike. Initially we begin with the fundamentals of solid-state nanopore sensing. Then the spotlight is shone on the sophisticated fabrication methods that have their origins in the semiconductor industry. One inherent advantage of solid-state nanopores is in the ease of functionalizing the surface with a range of molecules carrying functional groups. Therefore, an entire section is devoted to highlighting various chemical and bio-molecular modifications and explores how these permit the development of novel sensors with specific targets and functions. The review is completed with a discussion on novel detection strategies using nanopores. Although the most popular mode of nanopore sensing is based upon what has come to be known as ionic-current blockade sensing, there is a vast, growing literature based around exploring alternative detection techniques to further expand on the versatility of the sensors. Such techniques include optical, electronic, and force based methods. It is perhaps fair to say that these new frontiers have caused further excitement within the sensing community. 23103351 Comprehensive study on regional human intestinal permeability and prediction of fraction absorbed of drugs using the Ussing chamber technique. The purpose of this study was to evaluate the use of human intestinal tissue in Ussing chamber to predict oral and colonic drug absorption and intestinal metabolism. Data on viability, correlation between apparent permeability coefficients (P(app)) and fraction absorbed (f(a)) after oral and colonic administration, regional permeability, active uptake and efflux of drugs as well as intestinal metabolism were compiled from experiments using 159 human donors. Permeability coefficients for up to 28 drugs were determined using one or several of four intestinal regions: duodenum, jejunum, ileum and colon and 10 drugs were studied bidirectionally. Viability was monitored simultaneously with transport experiments by recording potential difference (PD), short-circuit current (SCC) and the resistance (TER). Intestinal metabolism was studied using testosterone and midazolam as probe substrates. There was a steep sigmoidal correlation between P(app) in the Ussing chamber, using jejunal segments, and oral f(a) in humans, for a set of 25 drugs (R(2): 0.85, p<0.01). A clear sigmoidal relationship was also obtained between P(app) in colonic segments and f(a) after colonic administration in humans for a set of 10 drugs (R(2): 0.93, p<0.05). Regional permeability data showed a tendency for highly permeable compounds to have higher or similar P(app) in colon as in the small intestinal segments, while the colonic regions showed a lower P(app) for more polar compounds as well as for d-glucose and l-leucine. Bidirectional transport (mucosa to serosa and serosa to mucosa direction) in jejunum showed well functioning efflux- and uptake asymmetry. Intestinal metabolic extraction during transport across jejunum segments was found for both testosterone and midazolam. In conclusion, viable excised human intestine mounted in the Ussing chamber, is a powerful technique for predicting regional fraction absorbed (f(a)), transporter-mediated uptake or efflux as well as intestinal metabolism of drug candidates in man. Furthermore, a sigmoidal relationship of P(app) vs. f(a) was obtained when permeability data from the present study were merged with data from 2 other independent laboratories (R(2): 0.83, p<0.01). The correlation curve reported can be used by any laboratory for predictions of human permeability and f(a)(.) In addition, for the first time a correlation curve between colonic P(app) and human colonic f(a) is reported, which demonstrates the usefulness of this methodology in early assessment of the colonic absorption potential of extended release formulation candidates. 23553497 Bone Health and Human Immunodeficiency Virus Infection. Low bone mineral density is common among persons with human immunodeficiency virus (HIV) infection, and studies reporting increased fracture rates in this patient population are emerging. The causes of low bone mineral density, osteoporosis, and fractures in persons with HIV are likely multifactorial, involving traditional risk factors, HIV infection, and exposure to antiretroviral treatment. Specific antiretrovirals such as tenofovir may cause a greater loss of bone mineral density compared with other agents and have recently been linked to an increased risk for fracture. As a result, recent treatment guidelines suggest that clinicians consider avoiding tenofovir as initial therapy in postmenopausal women. Evaluating bone mineral density and vitamin D status in persons with HIV may be important steps in identifying those requiring pharmacotherapy; however, the appropriate timing for bone mineral density and vitamin D screening is uncertain, as is the appropriate method of replacing vitamin D in HIV-positive patients who are deficient. Further study is necessary to definitively determine the approach to evaluating bone health and managing low bone mineral density and vitamin D deficiency in patients with HIV infection. 23412751 Cyclodextrin alleviates neuronal storage of cholesterol in Niemann-Pick C disease without evidence of detectable blood-brain barrier permeability. Niemann-Pick type C disease is an inherited autosomal recessive neurodegenerative disorder characterised by the accumulation of unesterified cholesterol and sphingolipids within the endosomal/lysosomal compartments. It has been observed that the administration of hydroxypropyl-β-cyclodextrin (HPBCD) delays onset of clinical symptoms and reduces accumulation of cholesterol and gangliosides within neuronal cells. It was assumed that HPBCD exerts its action by readily entering the CNS and directly interacting with neurones and other brain cells to facilitate removal of stored cholesterol from the late endosomal/lysosomal compartment. Here, we present evidence that refutes this hypothesis. We use two well established techniques for accurately measuring brain uptake of solutes from blood and show that there is no significant crossing of HPBCD into the brain. The two techniques are brain in situ perfusion and intraperitoneal injection followed by multi-time-point regression analysis. Neither study demonstrates significant, time-dependent uptake of HPBCD in either adult or neonatal mice. However, the volume of distribution available to HPBCD (0.113 ± 0.010 ml/g) exceeds the accepted values for plasma and vascular volume of the brain. In fact, it is nearly three times larger than that for sucrose (0.039 ± 0.006 ml/g). We propose that this indicates cell surface binding of HPBCD to the endothelium of the cerebral vasculature and may provide a mechanism for the mobilisation and clearance of cholesterol from the CNS. 23525221 Free fatty acids induce Lhb mRNA but suppress Fshb mRNA in pituitary LβT2 gonadotropes and diet-induced obesity reduces FSH levels in male mice and disrupts the proestrus LH/FSH surge in female mice. Female obesity is associated with insulin resistance, hyperandrogenemia, and reproductive dysfunction. We hypothesized that elevated free fatty acids (FFAs) might directly modulate pituitary gonadotropin production. FFAs caused a time and dose-dependent increase in phosphorylation of the MAP kinases p38MAPK, JNK1/2 and ERK1/2 in LβT2 gonadotrope cells. Furthermore, FFAs upregulated Lhb mRNA expression acutely, an effect that was blocked by JNK inhibition, but suppressed Fshb mRNA expression, an effect that was independent of MAPK signaling. FFAs enhanced the activation of the MAPKs in the presence of GnRH although the cotreatment did not alter Lhb induction, but did eliminate the GnRH induction of Fshb. FFAs also suppressed activin-induced Fshb expression. Knockdown experiments showed that the FFA effect on the inflammatory kinases p38MAPK and JNK and on Lhb, but not Fshb, mRNA expression is mediated via TLR2 and TLR4 and was mimicked by LPS stimulation. In vivo, male C57BL/6 mice on a high-fat diet (HFD) showed reduced FSH levels consistent with the suppression of Fshb seen in vitro. Histological analysis of the testes showed an increased number of abnormal seminiferous tubules. Female mice on HFD lacked the expected proestrus LH and FSH surge, exhibited an increase in the number of days at estrus and a reduced number of days at proestrus, and ovaries had significantly fewer corpora lutea. Taken together, our findings suggest that lipid excess can lead to reproductive defects in both male and female mice. 23541721 Tuning into diversity of homeostatic synaptic plasticity. Neurons are endowed with the remarkable ability to integrate activity levels over time and tune their excitability such that action potential firing is maintained within a computationally optimal range. These feedback mechanisms, collectively referred to as "homeostatic plasticity", enable neurons to respond and adapt to prolonged alterations in neuronal activity by regulating several determinants of cellular excitability. Perhaps the best-characterized of these homeostatic responses involves the regulation of excitatory glutamatergic transmission. This homeostatic synaptic plasticity (HSP) operates bidirectionally, thus providing a means for neurons to tune cellular excitability in response to either elevations or reductions in net activity. The last decade has seen rapid growth in interest and efforts to understand the mechanistic underpinnings of HSP in part because of the theoretical stabilization that HSP confers to neural network function. Since the initial reports describing HSP in central neurons, innovations in experimental approaches have permitted the mechanistic dissection of this cellular adaptive response and, as a result, key advances have been made in our understanding of the cellular and molecular basis of HSP. Here, we review recent evidence that outline the presence of distinct forms of HSP at excitatory glutamatergic synapses which operate at different sub-cellular levels. We further present theoretical considerations on the potential computational roles afforded by local, synapse-specific homeostatic regulation. This article is part of a Special Issue entitled 'Homeostatic Plasticity'. 23574807 Synthesis, Antidepressant Evaluation and Docking Studies of Long-Chain Alkylnitroquipazines as Serotonin Transporter Inhibitors. Twelve alkyl analogues (1-12) of the high-affinity serotonin transporter (SERT) inhibitor 6-nitroquipazine (6-NQ) were synthesized and studied using in vitro radioligand competition binding assays to determine their binding affinity (Ki ). The putative antidepressant activity of five of the binders with the highest SERT binding affinities was studied by the forced swim and locomotor activity mouse tests. The three-dimensional (3D) structures of 8 and 9 were determined using NOE NMR technique. Flexible docking of the compounds was undertaken to illustrate the binding of the compounds in the SERT model. Our results showed that several of the 6-NQ analogues are high-affinity SERT inhibitors and indicated that the octyl (8), decyl (10) and dodecyl (12) 6-NQ analogues exhibit moderate antidepressant activity. 23568434 Small-molecule regulators of autophagy and their potential therapeutic applications. Autophagy is a highly conserved process in which damaged proteins and organelles are sequestered in double-membrane autophagosomes and delivered to lysosomes for degradation and recycling. As an efficient response to cellular stress, autophagy is essential for the maintenance of cellular homeostasis. Defective autophagy is associated with a variety of diseases, including cancer. This article summarizes current knowledge about the molecular mechanism of autophagy and its role in tumorigenesis. Particular focus is placed on the development of small-molecule regulators of autophagy and their potential application as anticancer therapeutic agents. 23562927 Retrospective exposure data for baby and children care products: An analysis of 48 clinical studies. To conduct a reliable safety assessment, accurate exposure information for cosmetic products and ingredients is needed. The aim of the present retrospective study was to determine the amount per application and the daily exposure for some of the most commonly used baby cosmetic products. Consumption data from 48 clinical studies performed on 1481 babies and children (from 0 to 10years old) were reviewed and used to conduct a probabilistic evaluation of dermal exposure. Six categories of products were reviewed: rinseoff products for hair and body; rinse-off products for the whole body; leave-on products for face and body; cleansers for face and body; diaper dermatitis treatment products; shampoos. Subjects were provided with products and recorded detailed daily usage information over a 1-4-week period, depending on the study. Products were weighed at the start and upon completion of each study in order to determine the total amount of product used. The mean, median, standard deviation and 95th percentile were calculated for daily consumption and exposure, for several age groups from 0 to 10years old. This study provides current baby cosmetic exposure information for commonly used products which will be useful for risk assessment purposes. 23385213 Synthesis and antibacterial activities of new piperidine substituted (5R)-[1,2,3]triazolylmethyl and (5R)-[(4-F-[1,2,3]triazolyl)methyl] oxazolidinones. A novel series of 5(R)-[1,2,3]triazolylmethyl and (5R)-[(4-F-[1,2,3]triazolyl)methyl]oxazolidinones having various piperidine group were synthesized and evaluated antibacterial activity against clinically isolated resistant strains of Gram-positive and Gram-negative bacteria. The compound 12a having exo-cyanoethylidene group in the 4-position of piperidine ring was found to be two to threefold more potent than the linezolid against penicillin-resistant Staphylococcus pneumonia and Staphylococcus agalactiae, and also exhibited reduced MAO-B inhibitory activity. 23355192 Self-healing polymer coatings based on crosslinked metallosupramolecular copolymers. Self-healing coating based on metallopolymers are prepared and fully characterized. Iron bisterpyridine complexes are incorporated into a polymer network based on methacrylates, resulting in self-healing properties of these materials. Moreover, the influence of the comonomers on the thermal properties is studied in detail. 23561136 Assay of phenolic compounds from four species of ber (Ziziphus mauritiana L.) fruits: Comparison of three base hydrolysis procedure for quantification of total phenolic acids. The present study was undertaken to investigate the flavonoid profile in four species of ber (Ziziphus mauritiana Lamk.) fruit. The 12 flavonoids identified were quercetin 3-O-robinobioside, quercetin 3-O-rutinoside, quercetin 3'-O-galactoside, quercetin 3'-O-glucoside, quercetin 3'-O-rhamnoside, quercetin 3'-O-pentosylhexoside, quercetin 3-O-6'malonylglucoside, quercetin 3'-O-malonylglucoside, luteolin 7-O-6'malonylglucoside, luteolin 7-O-malonylglucoside, myricetin 3-O-galactoside, and naringenin tri glycoside. This is the first report on extraction of nine additional flavonoids from the ber fruits. In addition, we also compared the impact of three different base hydrolysis techniques namely ultrasonic assisted base hydrolysis (UABH), microwave assisted base hydrolysis (MWABH), and pressurised liquid assisted base hydrolysis (PLABH) for the quantification of total phenolic acids. Nine phenolic acids, protocatechuic acid, p-hydroxybenzoic acid, ferulic acid, chlorogenic acid, vanillic acid, caffeic acid, vanillin, ortho- and para-coumaric acids, were identified and quantified. The three major phenolic acids identified in all four ber species were p-coumaric acid, vanillin and ferulic acids. Higher amounts (p<0.05) of total phenolic acids in all cultivars were obtained with the PLABH technique as compared to other two procedures (UABH and MWABH). 23547938 A mass-tagging approach for enhanced sensitivity of dynamic cytokine detection using a label-free biosensor. Monitoring cytokine release by cells allows the investigation of cellular response to specific external stimuli, such as pathogens or candidate drugs. Unlike conventional colorimetric techniques, label-free detection of cytokines enables studying cellular secretions in real time by eliminating additional wash and labeling steps after the binding step. However, label-free techniques that are based on measuring mass accumulation on a sensor surface are challenging for measuring small cytokines binding to much larger capture agents (usually antibodies) because the relative signal change is small. This problem is exacerbated when the capturing antibodies desorb from the surface, a phenomenon that almost inevitably occurs in immunoassays but is rarely accounted for. Here, we demonstrate a quantitative dynamic detection of interleukine-6 (IL-6), a pro-inflammatory cytokine, using an interferometric reflectance imaging sensor (IRIS). We improved the accuracy of the quantitative analysis of this relatively small protein (21 kDa) by characterizing the antibody desorption rate and compensating for the antibody loss during the binding experiment. By correcting for protein desorption, we achieved an analytical limit of detection at 19 ng/mL IL-6 concentration. We enhanced the sensitivity by 7-fold by using detection antibodies that recognize a different epitope of the cytokine. We demonstrate that these detection antibodies, which we call "mass tags", can be used concurrently with the target analyte to eliminate an additional wash and binding step. Finally, we report successful label-free detection of IL-6 in cell culture medium (with 10% serum) with comparable signal to that obtained in PBS. This work is the first to report quantitative dynamic label-free detection of small protein in a complex biological fluid using IRIS. 23297676 Polar constituents composition of endemic Sideritis italica (MILL.) GREUTER et BURTER from Central Italy. Endemic Sideritis italica (MILL.) GREUTER et BURTER (Lamiaceae) occurs mainly in Southern Italy and Sicily and has previously only been studied for the essential oil composition. In this paper, we complete the phytochemical study of a sample of S. italica, previously analysed for its volatile constituents, occurring in the Appennino Umbro-Marchigiano (Central Italy), which is the northern border of the areal distribution of the species. The analysis of medium polarity constituents led to the isolation of several glycosides, such as flavonoids, i.e. scutellarein derivatives; phenylethanoids, i.e. verbascoside; and iridoids, i.e. melittoside and 5-allosyloxy-aucubin, besides the diterpene siderol. The data reported have chemotaxonomic relevance, since they are in contrast with the hypothesis that in Lamiaceae the species producing iridoids do not usually have relevant essential oil production and vice versa. 23382537 A large-scale zebrafish gene knockout resource for the genome-wide study of gene function. With the completion of the zebrafish genome sequencing project, it becomes possible to analyze the function of zebrafish genes in a systematic way. The first step in such an analysis is to inactivate each protein-coding gene by targeted or random mutation. Here we describe a streamlined pipeline using proviral insertions coupled with high-throughput sequencing and mapping technologies to widely mutagenize genes in the zebrafish genome. We also report the first 6144 mutagenized and archived F1's predicted to carry up to 3776 mutations in annotated genes. Using in vitro fertilization, we have rescued and characterized ∼0.5% of the predicted mutations, showing mutation efficacy and a variety of phenotypes relevant to both developmental processes and human genetic diseases. Mutagenized fish lines are being made freely available to the public through the Zebrafish International Resource Center. These fish lines establish an important milestone for zebrafish genetics research and should greatly facilitate systematic functional studies of the vertebrate genome. 23351043 Increased protein sorption in poly(acrylic acid)-containing films through incorporation of comb-like polymers and film adsorption at low pH and high ionic strength. In principle, incorporation of comb-like block copolymers in multilayer polyelectrolyte films can both increase film thickness relative to coatings containing linear polymers and provide more swollen films for increased sorption of proteins. In the absence of added salt, alternating adsorption of 5 bilayers of protonated poly(allylamine) (PAH) and comb-like poly(2-hydroxyethyl methacrylate)-graft-poly(acrylic acid) (PHEMA-g-PAA) leads to ∼2-fold thicker coatings than adsorption of PAH and linear PAA, and the difference in the thicknesses of the two coatings increases with the number of bilayers. Moreover, the (PAH/PHEMA-g-PAA)n films sorb 2- to 4-fold more protein than corresponding films prepared with linear PAA, and coatings deposited at pH 3.0 sorb more protein than coatings adsorbed at pH 5.0, 7.0, or 9.0. In fact changes in deposition pH and addition of 0.5 M NaCl to polyelectrolyte adsorption solutions alter protein sorption more dramatically than variations in the constituent polymer architecture. When deposited from 0.5 M NaCl at pH 3.0, both (PAH/PHEMA-g-PAA)5 and (PAH/PAA)5 films increase in thickness more than 400% upon adsorption of lysozyme. These films contain a high concentration of free -COOH groups, and subsequent deprotonation of these groups at neutral pH likely contributes to increased protein binding. Lysozyme sorption stabilizes these films, as without lysozyme films deposited at pH 3.0 from 0.5 M NaCl desorb at neutral pH. Films deposited at pH 9.0 from 0.5 M NaCl are more stable and also bind large amounts of lysozyme. The high binding capacities of these films make them attractive for potential applications in protein isolation or immobilization of enzymes. 23418168 Chemical composition and antimicrobial and allelopathic activity of Tunisian Conyza sumatrensis (Retz.) E.WALKER essential oils. Conyza sumatrensis (Retz.) E.WALKER (Asteraceae) is a spontaneous annual herb, fairly widespread throughout Tunisia, which has rarely been studied or valued in any sector. Essential oils were obtained by hydrodistillation of different parts (flower heads, leaves, stems, and roots) of C. sumatrensis plants, which were collected in autumn (November 2007) at the flowering stage in the area of Monastir, Tunisia. In total, 98 compounds, representing 88.1-99.3% of the oil composition, were identified by GC-FID and GC/MS analyses. The root essential oil was distinguished by its high content in acetylenes (matricaria ester, 4; 74.3%), while those from flower heads and leaves were dominated by oxygenated sesquiterpenes (61.1 and 50.3%, resp.). The oils of C. sumatrensis from Tunisia belonged to a matricaria ester/caryophyllene oxide chemotype. All the oils were evaluated for antibacterial, antifungal, and allelopathic activities. The results indicate that the leaf oil exhibited significant in vitro antibacterial activity against Enterococcus faecalis, Staphylococcus aureus, and Proteus mirabilis and that the C. sumatrensis oils isolated from the aerial parts presented high mycelia-growth inhibition of Candida albicans and the filamentous fungi tested. Moreover, the essential oils of the different plant parts inhibited the shoot and root growth of Raphanus sativus (radish) seedlings. Indeed, the inhibition of the hypocotyl growth varied from 28.6 to 90.1% and that of the radicle from 42.3 to 96.2%. 23022600 Association analysis between K and -116A variants of butyrylcholinesterase and Alzheimer's disease in a Brazilian population. In Alzheimer's disease (AD) a reduction in acetylcholinesterase (AChE) and an increase in butyrylcholinesterase (BChE) activity are observed. K variant (539T) is the most common variant of the BCHE gene and, although controversial, several studies reported association between K variant and AD. Previous results showed that the K variant alone is not capable of diminishing BChE activity, depending on the presence of the -116A variant. Considering that, we conducted a case-control association study using a clinically well defined group of AD patients (n=82) and age and sex matched control subjects (EC; n=78) in order to test the association with these variations of BCHE gene in a Brazilian population. The allele, genotype and haplotype frequencies of the K and the -116A variants of BCHE gene were not significantly different between cases and controls. Although not reaching statistical significance, the results suggested that the presence of -116A variant may have a protective effect against AD. The association of the K variant with AD in a controversial manner in different surveys is probably caused by its linkage disequilibrium with -116A that, by reducing BChE activity, potentially increases cholinergic transmission in comparison with usual genotypes. 23601383 FAO/INFOODS food composition database for biodiversity. Nutrient content can vary as much between different varieties of the same foods, as they do among different foods. Knowledge of varietal differences can therefore mean the difference between nutrient adequacy and inadequacy. The FAO/INFOODS food composition database for biodiversity has been developed with analytical data for foods described at the level of variety, cultivar and breed, and for underutilized and wild foods. It contains 6411 food entries and values for 451 components together with the bibliographic references and other information. The database is in MS Excel format and can be downloaded free-of-charge from the INFOODS website http://www.fao.org/infoods/biodiversity/index_en.stm. It is intended to annually publish new editions, making these data available for national and regional food composition databases. This database could be used to raise the awareness, promote and investigate food biodiversity and help to better estimate nutrient intakes. 23313661 A systematic identification of multiple toxin-target interactions based on chemical, genomic and toxicological data. Although the assessment of toxicity of various agents, -omics (genomic, proteomic, metabolomic, etc.) data has been accumulated largely, the acquirement of toxicity information of variety of molecules through experimental methods still remains a difficult task. Presently, a systems toxicology approach that integrates massive diverse chemical, genomic and toxicological information was developed for prediction of the toxin targets and their related networks. The procedures are: (1) by use of two powerful statistical methods, i.e., support vector machine (SVM) and random forest (RF), a systemic model for prediction of multiple toxin-target interactions using the extracted chemical and genomic features has been developed with its reliability and robustness estimated. And the qualitative classification of targets according to the phenotypic diseases has been taken into account to further uncover the biological meaning of the targets, as well as to validate the robustness of the in silico models. (2) Based on the predicted toxin-target interactions, a genome-scale toxin-target-disease network exampled by cardiovascular disease is generated. (3) A topological analysis of the network is carried out to identify those targets that are most susceptible in human to topical agents including the most critical toxins, as well as to uncover both the toxin-specific mechanisms and pathways. The methodologies presented herein for systems toxicology will make drug development, toxin environmental risk assessment more efficient, acceptable and cost-effective. 23624326 Viscosity of high concentration protein formulations of monoclonal antibodies of the IgG1 and IgG4 subclass - Prediction of viscosity through protein-protein interaction measurements. The purpose of this work was to explore the relation between protein-protein interactions (PPIs) and solution viscosity at high protein concentration using three monoclonal antibodies (mAbs), two of the IgG4 subclass and one of the IgG1 subclass. A range of methods was used to quantify the PPI either at low concentration (interaction parameter (kD) obtained from dynamic light scattering, DLS) or at high concentration (solution storage modulus (G') from ultrasonic shear rheology). We also developed a novel method for the determination of PPI using the apparent radius of the protein at either low or high protein concentration determined using DLS. The PPI measurements were correlated with solution viscosity (measured by DLS using polystyrene nanospheres and ultrasonic shear rheology) as a function of pH (4-9) and ionic strength (10, 50 and 150mM). Our measurements showed that the highest solution viscosity was observed under conditions with the most negative kD, the highest apparent radius and the lowest net charge. An increase in ionic strength resulted in a change in the nature of the PPI at low pH from repulsive to attractive. In the neutral to alkaline pH region the mAbs behaved differently with respect to increase in ionic strength. Two mAbs (A and B) showed little or no effect of increasing ionic strength, whereas mAb-C showed a remarkable decrease in attractive PPI and viscosity. Previous studies have mainly investigated mAbs of the IgG1 and IgG2 subclass. We show here, for the first time, that mAbs of the IgG4 subclass behave similar as the other subclasses. By comparison of the three tested mAbs with mAbs investigated in other studies a clear linear trend emerges between the pH of strongest attractive PPI and highest solution viscosity. The determination of PPI using either kD or apparent radius is thus a useful prediction tool in the determination of solution conditions that favors low solution viscosity at high protein concentration of therapeutically used mAb molecules. The novel methodology using apparent radius is a simple and rapid alternative to determine relative PPI directly under formulation conditions. The method can potentially serve as a high-throughput screening tool in formulation development. 23589499 MAO Inhibitory Activity of 2-Arylbenzofurans versus 3-Arylcoumarins: Synthesis, in vitro Study, and Docking Calculations. Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. Several 3-arylcoumarin derivatives were previously described as interesting selective MAO-B inhibitors. Preserving the trans-stilbene structure, a series of 2-arylbenzofuran and corresponding 3-arylcoumarin derivatives were synthesized and evaluated as inhibitors of both MAO isoforms, MAO-A and MAO-B. In general, both types of derivatives were found to be selective MAO-B inhibitors, with IC50 values in the nano- to micromolar range. 5-Nitro-2-(4-methoxyphenyl)benzofuran (8) is the most active compound of the benzofuran series, presenting MAO-B selectivity and reversible inhibition (IC50 =140 nM). 3-(4'-Methoxyphenyl)-6-nitrocoumarin (15), with the same substitution pattern as that of compound 8, was found to be the most active MAO-B inhibitor of the coumarin series (IC50 =3 nM). However, 3-phenylcoumarin 14 showed activity in the same range (IC50 =6 nM), is reversible, and also severalfold more selective than compound 15. Docking experiments for the most active compounds into the MAO-B and MAO-A binding pockets highlighted different interactions between the derivative classes (2-arylbenzofurans and 3-arylcoumarins), and provided new information about the enzyme-inhibitor interaction and the potential therapeutic application of these scaffolds. 23349485 Disruption of the cereblon gene enhances hepatic AMPK activity and prevents high fat diet-induced obesity and insulin resistance in mice. A nonsense mutation in cereblon (CRBN) causes a mild type of mental retardation in humans. An earlier study showed that CRBN negatively regulates the functional activity of AMP-activated protein kinase (AMPK) in vitro by binding directly to the α1 subunit of the AMPK complex. However, the in vivo role of CRBN was not studied. To elucidate the physiological functions of Crbn, a mouse strain was generated in which the Crbn gene was deleted throughout the whole body. In Crbn-deficient mice fed a normal diet, AMPK in the liver showed hyper-phosphorylation, which indicated the constitutive activation of AMPK. Since Crbn-deficient mice showed significantly less weight gain when fed a high fat diet and their insulin sensitivity was considerably improved, the functions of Crbn in the liver were primarily investigated. These results provide the first in vivo evidence that Crbn is a negative modulator of AMPK, which suggests that Crbn may be a potential target for metabolic disorders of the liver. 23586702 The role of external defects in chemical sensing of graphene field-effect transistors. A fundamental understanding of chemical sensing mechanisms in graphene-based chemical field-effect transistors (chemFETs) is essential for the development of next generation chemical sensors. Here we explore the hidden sensing modalities responsible for tailoring the gas detection ability of pristine graphene sensors by exposing graphene chemFETs to electron donor and acceptor trace gas vapors. We uncover that the sensitivity (in terms of modulation in electrical conductivity) of pristine graphene chemFETs is not necessarily intrinsic to graphene, but rather it is facilitated by external defects in the insulating substrate, which can modulate the electronic properties of graphene. We disclose a mixing effect caused by partial overlap of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) of adsorbed gas molecules to explain graphene's ability to detect adsorbed molecules. Our results open a new design space, suggesting that control of external defects in supporting substrates can lead to tunable graphene chemical sensors, which could be developed without compromising the intrinsic electrical and structural properties of graphene. 23147033 The influence of diet on the gut microbiota. Diet is a major factor driving the composition and metabolism of the colonic microbiota. The amount, type and balance of the main dietary macronutrients (carbohydrates, proteins and fats) have a great impact on the large intestinal microbiota. The human colon contains a dense population of bacterial cells that outnumber host cells 10-fold. Bacteroidetes, Firmicutes and Actinobacteria are the three major phyla that inhabit the human large intestine and these bacteria possess a fascinating array of enzymes that can degrade complex dietary substrates. Certain colonic bacteria are able to metabolise a remarkable variety of substrates whilst other species carry out more specialised activities, including primary degradation of plant cell walls. Microbial metabolism of dietary carbohydrates results mainly in the formation of short chain fatty acids and gases. The major bacterial fermentation products are acetate, propionate and butyrate; and the production of these tends to lower the colonic pH. These weak acids influence the microbial composition and directly affect host health, with butyrate the preferred energy source for the colonocytes. Certain bacterial species in the colon survive by cross-feeding, using either the breakdown products of complex carbohydrate degradation or fermentation products such as lactic acid for growth. Microbial protein metabolism results in additional fermentation products, some of which are potentially harmful to host health. The current 'omic era promises rapid progress towards understanding how diet can be used to modulate the composition and metabolism of the gut microbiota, allowing researchers to provide informed advice, that should improve long-term health status. 23360443 Safety of posaconazole. INTRODUCTION: The increasing number of invasive fungal infections (IFI) among immunocompromised hosts is a significant clinical issue. Diagnosis of IFI, choosing among the available antifungal drugs, and the high morbidity/mortality associated with IFI pose clinical challenges for healthcare providers. Besides efficacy, a thorough knowledge of the pharmacokinetics, drug-drug interactions and safety profile of the antifungal drugs is critical for appropriate drug selection. Among the commonly used triazoles, the recently released posaconazole is relatively less well investigated in terms of its safety. With expanding clinical use of posaconazole, the present review examines the safety of the drug and its propensity for drug-drug interaction. AREAS COVERED: This paper mainly discusses the safety profile of posaconazole, its adverse effects and drug-drug interaction. EXPERT OPINION: Posaconazole is generally safe and well tolerated. Lack of an intravenous formulation and unpredictable bioavailability of the suspension form are significant factors limiting the widespread use of posaconazole. 23335106 Fast, reversible, and general photomechanical motion in single crystals of various azo compounds using visible light. Pseudostilbene-type single crystals exhibit ubiquitous, fast, and reversible photomechanical motion under visible-light irradiation. Push-pull substituents impart extremely rapid switching using just one wavelength of light by shortening the lifetime of the cis-form. This results in a bending motion in the microsecond regime. The influence of crystal density, thickness, and molecular orientation on optimization of the photomechanical effect is investigated. 23157634 Proton magnetic resonance spectroscopy changes after antipsychotic treatment. Proton magnetic resonance spectroscopy ((1)H MRS) enables the observation of brain function in vivo. Several brain metabolites can be measured by the means of (1)H MRS: N-acetylaspartate (NAA), choline containing compounds (Cho), myo-inositol (mI) and glutamate (Glu), glutamine (Gln) and GABA (together as Glx complex or separately). (1)H MRS measures have been found to be abnormal in psychotic disorders such as schizophrenia. Here we specifically review the influence exerted by antipsychotic drugs on brain metabolism, as detected by (1)H MRS. We systematically reviewed the available literature and uncovered 27 studies, 16 before-after treatment and 11 cross-sectional. Most of them addressed the effects of antipsychotics in schizophrenia and mainly focusing on NAA alterations. Follow up studies indicated antipsychotic drugs may act by increasing NAA levels in selected brain areas (the frontal lobe and thalamus), especially during the short-time observation. This phenomenon seems to vanish after longer observation. Other studies indicated that glutamate measures are decreasing along with the duration of the disease, suggesting both a neurodegenerative process present in schizophrenic brain as well as an influence of antipsychotics. The above results were reviewed according to the most recent theories in the field accounting for the impact of antipsychotics (1)HMRS measures. 23298694 Evaluation of insulin-like growth factor acid-labile subunit as a potential biomarker of effect for deoxynivalenol-induced proinflammatory cytokine expression. Consumption of the trichothecene deoxynivalenol (DON) suppresses growth in experimental animals - an adverse effect that was used to establish the tolerable daily intake for this toxin. DON ingestion has been recently found to suppress plasma insulin-like growth factor acid-labile subunit (IGFALS), a protein essential for growth. Studies were conducted to explore the feasibility of using plasma IGFALS as a biomarker of effect for DON. In the first study, weanling mice were fed 0, 1, 2.5, 5 and 10 ppm DON and weight and plasma IGFALS determined at intervals over 9 wk. Reduced body weight gains were detectable beginning at wk 5 in the 10 ppm dose and wk 7 at the 5 ppm dose. Plasma IGFALS was significantly depressed at wk 5 in the 5 and 10 ppm groups at wk 9 in the 10 ppm group. Depressed IGFALS significantly correlated with reduced body weight at wk 5 and 9. Benchmark dose modeling revealed the BMDL and BMD for plasma IGFALS reduction were 1.1 and 3.0 ppm DON and for weight reduction were 2.1 and 4.5 ppm DON. In the second study, it was demonstrated that mice fed 15 ppm DON diet had significantly less plasma IGFALS than mice fed identical amounts of control diet. Thus DON's influence on IGFALS likely reflects the combined effects of reduced food intake as well as its physiological action involving suppressors of cytokine signaling. Taken together, these findings suggest that plasma IGFALS might be a useful biomarker for DON's adverse effects on growth. 23542114 Arsenic trioxide depletes cancer stem-like cells and inhibits repopulation of neurosphere derived from glioblastoma by downregulation of Notch pathway. Notch signaling has been demonstrated to have a central role in cancer stem-like cells (CSLCs) in glioblastoma multiforme (GBM). We have recently demonstrated the inhibitory effect of arsenic trioxide (ATO) on CSLCs in glioblastoma cell lines. In this study we used neurosphere recovery assay that measured neurosphere formation at three time points to assess the capacity of the culture to repopulate after ATO treatment. Our results provided strong evidence that ATO depleted CSLCs in GBM, and inhibited neurosphere recovery and secondary neurosphere formation. ATO inhibited the phosphorylation and activation of AKT and STAT3 through Notch signaling blockade. These data show that the ATO is a promising new approach to decrease glioblastoma proliferation and recurrence by downregulation of Notch pathway. 23268557 A simplified confinement method for calculating absolute free energies and free energy and entropy differences. A simple and robust formulation of the path-independent confinement method for the calculation of free energies is presented. The simplified confinement method (SCM) does not require matrix diagonalization or switching off the molecular force field, and has a simple convergence criterion. The method can be readily implemented in molecular dynamics programs with minimal or no code modifications. Because the confinement method is a special case of thermodynamic integration, it is trivially parallel over the integration variable. The accuracy of the method is demonstrated using a model diatomic molecule, for which exact results can be computed analytically. The method is then applied to the alanine dipeptide in vacuum, and to the α-helix ↔ β-sheet transition in a 16-residue peptide modeled in implicit solvent. The SCM requires less effort for the calculation of free energy differences than previous formulations because it does not require computing normal modes. The SCM has a diminished advantage for determining absolute free energy values, because it requires decreasing the MD integration step to obtain accurate results. An approximate confinement procedure is introduced, which can be used to estimate directly the configurational entropy difference between two macrostates, without the need for additional computation of the difference in the free energy or enthalpy. The approximation has convergence properties similar to those of the standard confinement method for the calculation of free energies. The use of the approximation requires about 5 times less wall-clock simulation time than that needed to compute enthalpy differences to similar precision from an MD trajectory. For the biomolecular systems considered in this study, the errors in the entropy approximation are under 10%. Practical applications of the methods to proteins are currently limited to implicit solvent simulations. 23235923 Control of CYP11B2/CYP11B1 expression ratio and consequences for the zonation of the adrenal cortex. Access of corticotropin to glucocorticoid synthesis in adrenocortical cells is provided by the expression of the ACTH receptor (MC2R). Activation of the MC2R increases stimulatory G-protein, adenylyl cyclase, and protein kinase A (PKA) activities. Furthermore, PKA phosphorylates transcription factors that have a stimulating effect on glucocorticoid synthesis. Sensitivity of adrenocortical cells to renin/angiotensin-2 is conferred by the expression of the inhibitory G-protein-linked angiotensin-2 type 1 receptor (AT1R) that additionally associates to the phospholipase C-activating G-protein q. The AT1R is connected to the adrenal potassium sensory system and regulates calcium influx as well as phospholipase C-β (PLC-β) and thus calmodulin kinase-dependent transcription of steroidogenic enzymes. While AT1R signaling suppresses the influence of corticotropin on the generation of cyclic adenosine monophosphate, the expression of the AT1R and its associated enzyme activities are under the control of glucocorticoids. Thus, dominance of one of the two signaling pathways is dependent on two factors: the extracellular concentration of their ligands and the products of their signaling pathways. These findings are in favor of the hypothesis that the centripetal blood flow through the adrenal gland builds up a glucocorticoid gradient creating a morphogenetic field along which adrenal cortical cells adopt different functional states, leading to the typical zonation of the adrenal cortex. 23274916 In vitro cytotoxicity and genotoxicity studies of titanium dioxide (TiO2) nanoparticles in Chinese hamster lung fibroblast cells. There are increasing safety concerns about the development and abundant use of nanoparticles. The unique physical and chemical characteristics of titanium dioxide (TiO2) nanoparticles result in different chemical and biological activities compared to their larger micron-sized counterparts, and can subsequently play an important role in influencing toxicity. Therefore, our objective was to investigate the cytotoxicity and genotoxicity of commercially available TiO2 nanoparticles with respect to their selected physicochemical properties, as well as the role of surface coating of these nanoparticles. While all types of tested TiO2 samples decrease cell viability in a mass-based concentration- and size-dependent manner, the polyacrylate-coated nano-TiO2 product was only cytotoxic at higher concentrations. A similar pattern of response was observed for induction of apoptosis/necrosis, and no DNA damage was detected in the polyacrylate-coated nano-TiO2 model. Given the increasing production of TiO2 nanoparticles, toxicological studies should take into account the physiochemical properties of these nanoparticles that may help researchers to develop new nanoparticles with minimum toxicity. 23500776 EROD activity induction in peripheral blood lymphocytes, liver and brain tissues of rats orally exposed to polycyclic aromatic hydrocarbons. Little is known in terms of multi-matrix cytochrome P450 activity induction under repeated oral exposure to planar halogenated and polycyclic aromatic hydrocarbons (PHH, PAH). In the present study, 60 rats were daily exposed, during 28days, to oral ingestion of a mixture consisting of phenanthrene, pyrene and benzo(a)pyrene at 0, 6 or 600μg/day. EROD activity, reflecting almost exclusively CYP1A1 and CYP1B1 activities, was measured in brain and liver microsomes as well as in peripheral blood lymphocytes (PBLs). All induction kinetics could be appropriately fitted using logistic-like models. After 28days of exposure to a 6μg/day dose, EROD activity was found to be 91, 152 and 94-fold increased in lymphocytes, liver and brain, respectively, compared to day 0. Plateau activities could be appropriately fitted versus ingested doses using Hill or Michaelis-Menten models. Correlations between matrices made it possible to conclude that EROD activity in PBL should be considered as a sensitive, convenient and non-destructive approach for (i) evaluating EROD activity in liver, which was found to represent 98% of the observed EROD activities in the three tested matrices and (ii) evaluating oral exposure of homogeneous groups of farm animals (race, diet) to CYP inducing PAH and PHH. 23281275 Self-assembled BolA-like amphiphilic peptides as viral-mimetic gene vectors for cancer cell targeted gene delivery. In this study, two types of BolA-like amphiphilic peptides with dual ligands comprising a tumor-targeting moiety of RGD sequence and a cell-penetrating moiety of R8 sequence are designed and synthesized as gene vectors. The BolA-structural peptide carriers can self-assemble into spherical nanoparticles with a hydrophilic core and shell, which are similar to the viral capsid and can bind plasmid DNA in an aqueous medium to form viral-mimetic complexes. It is found that the BolA-like dual ligands system exhibits significantly enhanced gene expression in both HeLa and 293T cell lines, as compared with poly(ethylenimine) PEI. These BolA-like amphiphilic peptides are promising in clinical trials of gene therapy. 23047462 Hierarchical rutile TiO2 flower cluster-based high efficiency dye-sensitized solar cells via direct hydrothermal growth on conducting substrates. Dye-sensitized solar cells (DSSCs) based on hierarchical rutile TiO(2) flower clusters prepared by a facile, one-pot hydrothermal process exhibit a high efficiency. Complex yet appealing rutile TiO(2) flower films are, for the first time, directly hydrothermally grown on a transparent conducting fluorine-doped tin oxide (FTO) substrate. The thickness and density of as-grown flower clusters can be readily tuned by tailoring growth parameters, such as growth time, the addition of cations of different valence and size, initial concentrations of precursor and cation, growth temperature, and acidity. Notably, the small lattice mismatch between the FTO substrate and rutile TiO(2) renders the epitaxial growth of a compact rutile TiO(2) layer on the FTO glass. Intriguingly, these TiO(2) flower clusters can then be exploited as photoanodes to produce DSSCs, yielding a power conversion efficiency of 2.94% despite their rutile nature, which is further increased to 4.07% upon the TiCl(4) treatment. 23249624 Mechanisms limiting distribution of the threonine-protein kinase B-RaF(V600E) inhibitor dabrafenib to the brain: implications for the treatment of melanoma brain metastases. Brain metastases are a common cause of death in stage IV metastatic melanoma. Dabrafenib is a BRAF (gene encoding serine/threonine-protein kinase B-Raf) inhibitor that has been developed to selectively target the valine 600 to glutamic acid substitution (BRAF(V600E)), which is commonly found in metastatic melanoma. Clinical trials with dabrafenib have shown encouraging results; however, the central nervous system distribution of dabrafenib remains unknown. Thus, the objective of the current study was to evaluate the brain distribution of dabrafenib in mice, and to see whether active efflux by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) restricts its delivery across the blood-brain barrier (BBB). In vitro accumulation studies conducted in Madin-Darby canine kidney II cells indicate that dabrafenib is an avid substrate for both P-gp and BCRP. Directional flux studies revealed greater transport in the basolateral to apical direction with corrected efflux ratios greater than 2 for both P-gp and Bcrp1 transfected cell lines. In vivo, the ratio of area under the concentration-time curve (AUC)(brain) to AUC(plasma) (K(p)) of dabrafenib after an i.v. dose (2.5 mg/kg) was 0.023, which increased by 18-fold in Mdr1 a/b(-/-)Bcrp1(-/-) mice to 0.42. Dabrafenib plasma exposure was ∼2-fold greater in Mdr1 a/b(-/-)Bcrp1(-/-) mice as compared with wild-type with an oral dose (25 mg/kg); however, the brain distribution was increased by ~10-fold with a resulting K(p) of 0.25. Further, compared with vemurafenib, another BRAF(V600E) inhibitor, dabrafenib showed greater brain penetration with a similar dose. In conclusion, the dabrafenib brain distribution is limited in an intact BBB model, and the data presented herein may have clinical implications in the prevention and treatment of melanoma brain metastases. 23500659 Role of the phytoestrogenic, pro-apoptotic and anti-oxidative properties of silymarin in inhibiting experimental benign prostatic hyperplasia in rats. Androgen and estrogen play an important role in the pathogenesis of benign prostatic hyperplasia (BPH). Estrogen exerts its action through two distinct estrogen receptors (ERs) either ER-α or ER-β. The phytoestrogenic property of silymarin (SIL) has been previously characterized. Thus, this study examined the protective effect of SIL against testosterone-induced BPH in rats. In an initial dose-response study, SIL in a dose of 50mg/kg was the most effective in preventing the rise in prostate weight, prostate weight/body weight ratio and histopathologic changes induced by testosterone. Testosterone significantly decreased ER-β and increased ER-α and AR expressions as compared to the control group and these effects were significantly ameliorated by SIL. Furthermore, SIL significantly protected against testosterone-provoked decline in mRNA expression of P21(WAF1/Cip1) and Bax/Bcl-xl ratio as well as caspase-3 activity. SIL minimized the number of proliferating cell nuclear antigen (PCNA) positive cells as compared to testosterone-treated group. Moreover, SIL significantly blunted the inducible NF-κB expression and restored the oxidative status to within normal values in the prostatic tissues. Collectively these findings elucidate the effectiveness of SIL in preventing testosterone-induced BPH in rats. This could be attributed, at least partly, to its phytoestrogenic, pro-apoptotic and anti-oxidative properties. 23466501 p-Cresol induces disruption of cardiomyocyte adherens junctions. Higher serum levels of p-cresol in chronic kidney disease populations have been associated with increased cardiovascular mortality. However, studies on how p-cresol affects intercellular junctions between cardiomyocytes were limited. This study investigated the effect of p-cresol on adherens junction (AJ) of neonatal cultured cardiomyocytes and its underlying mechanism. A loss of N-cadherin and p120-catenin (p120ctn) immunostaining from cell-cell contact sites was noted by p-cresol treatment. In addition, p-cresol disrupted AJs by inducing formation of intercellular gaps. Our previous study has revealed that p-cresol increased intracellular calcium levels and activated protein kinase Cα (PKCα) by phosphorylation. The PKCα activation was involved in the p-cresol-mediated AJ disassembly, since pharmacological inhibition of PKCα abolished the above-mentioned p-cresol effect. This PKCα activation also led to the serine dephosphorylation of p120ctn and caused the dissociation of p120ctn from N-cadherin. This hypothesis was further confirmed in H9c2 cells by siRNA approach. SiRNA knockdown of PKCα prevented p-cresol-induced serine dephosphorylation of p120ctn and splitting of AJ. In conclusion, p-cresol caused PKCα-dependent AJ disassembly of cardiomyocytes, which might be related to asychronized contraction. 23220145 Evernia prunastri and Pseudoevernia furfuraceae lichens and their major metabolites as antioxidant, antimicrobial and anticancer agents. The aim of this study is to investigate chemical composition of acetone extracts of the lichens Evernia prunastri and Pseudoevernia furfuraceae and in vitro antioxidant, antimicrobial, and anticancer activities of these extracts and some their major metabolites. HPLC-UV method was used for identification of secondary metabolites. Antioxidant activity was evaluated by free radical scavenging, superoxide anion radical scavenging, reducing power and determination of total phenolic compounds. As a result of the study physodic acid had largest antioxidant activities. Total content of phenol in extracts was determined as pyrocatechol equivalent. The antimicrobial activity was estimated by determination of the minimal inhibitory concentration by the broth microdilution method. The most active was also physodic acid. Anticancer activity was tested against FemX (human melanoma) and LS174 (human colon carcinoma) cell lines using MTT method. 23409763 The therapeutic potential of allosteric ligands for free fatty acid sensitive GPCRs. G protein coupled receptors (GPCRs) are the most historically successful therapeutic targets. Despite this success there are many important aspects of GPCR pharmacology and function that have yet to be exploited to their full therapeutic potential. One in particular that has been gaining attention in recent times is that of GPCR ligands that bind to allosteric sites on the receptor distinct from the orthosteric site of the endogenous ligand. As therapeutics, allosteric ligands possess many theoretical advantages over their orthosteric counterparts, including more complex modes of action, improved safety, more physiologically appropriate responses, better target selectivity, and reduced likelihood of desensitisation and tachyphylaxis. Despite these advantages, the development of allosteric ligands is often difficult from a medicinal chemistry standpoint due to the more complex challenge of identifying allosteric leads and their often flat or confusing SAR. The present review will consider the advantages and challenges associated with allosteric GPCR ligands, and examine how the particular properties of these ligands may be exploited to uncover the therapeutic potential for free fatty acid sensitive GPCRs. 23576343 Congruence of Phytochemical and Morphological Profiles along an Altitudinal Gradient in Origanum vulgare ssp. vulgare from Venetian Region (NE Italy). Plants of Origanum vulgare L. ssp. vulgare from the Veneto region (NE Italy) were selected to study the variability of the essential-oil composition from leaves and inflorescences throughout an elevation gradient. We investigated also the morphology of non-glandular and glandular trichomes, their distribution on the vegetative and reproductive organs, as well as the histochemistry of the secreted products, with special focus on the terpenoidic fraction. Since glandular trichomes are prerequisite for the essential-oil synthesis, the second objective was to establish whether its production is related to glandular hair number, and density. Essential-oil contents decline with increasing altitude, and the micromorphological observations revealed a decrease in trichome density along the same direction. Moreover, GC/MS analysis together with principal component analysis (PCA) showed that the three investigated populations were significantly different in chemical composition. Therefore, an important interpopulation variability for low-, mid-, and high-altitude sites was established, suggesting the likely occurrence of different biotypes associated with altitudinal levels. Hence, the involvement of abiotic factors such as temperature and drought in the chemical polymorphism of O. vulgare associated with elevation is briefly discussed. 23339966 5-((1-Aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones as potential anticancer agents with anti-inflammatory properties. A series of novel 5-((1-aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones (3a-z) have been evaluated for in vitro cytotoxicity against a panel of 60 human tumor cell lines. Compound 3k exhibited the most potent growth inhibition against melanoma MDA-MB-435 cells (GI(50)=850 nM), against leukemia SR cancer cells (GI(50)=1.45 μM), and OVCAR-3 (GI(50)=1.26 μM) ovarian cancer cell lines. The structurally related compound 3s had a GI(50) value of 1.77 μM against MDA-MB-435 cells. The N-naphthoyl analogue 3t had GI(50) values of 1.30 and 1.91 μM against HOP-92 non-small cell lung cancer and MDA-MB-435 melanoma cell lines, respectively. The related analogue 3w had GI(50) values of 1.09 μM against HOP-92 non-small cell lung cancer cell lines. Interestingly, docking of the two active molecules 3k and 3w into the active site of COX-2 indicates that these compounds are COX-2 ligands with strong hydrophobic and hydrogen bonding interactions. Thus, compounds 3k, 3t, 3s, and 3w constitute a new class of anticancer/anti-inflammatory agents that may have unique potential for cancer therapy. 23402652 Between superexchange and hopping: an intermediate charge-transfer mechanism in poly(A)-poly(T) DNA hairpins. We developed a model for hole migration along relatively short DNA hairpins with fewer that seven adenine (A):thymine (T) base pairs. The model was used to simulate hole migration along poly(A)-poly(T) sequences with a particular emphasis on the impact of partial hole localization on the different rate processes. The simulations, performed within the framework of the stochastic surrogate Hamiltonian approach, give values for the arrival rate in good agreement with experimental data. Theoretical results obtained for hairpins with fewer than three A:T base pairs suggest that hole transfer along short hairpins occurs via superexchange. This mechanism is characterized by the exponential distance dependence of the arrival rate on the donor/acceptor distance, k(a) ≃ e(-βR), with β = 0.9 Å(-1). For longer systems, up to six A:T pairs, the distance dependence follows a power law k(a) ≃ R(-η) with η = 2. Despite this seemingly clear signature of unbiased hopping, our simulations show the complete delocalization of the hole density along the entire hairpin. According to our analysis, the hole transfer along relatively long sequences may proceed through a mechanism which is distinct from both coherent single-step superexchange and incoherent multistep hopping. The criterion for the validity of this mechanism intermediate between superexchange and hopping is proposed. The impact of partial localization on the rate of hole transfer between neighboring A bases was also investigated. 22360570 The PP1 binding code: a molecular-lego strategy that governs specificity. Ser/Thr protein phosphatase 1 (PP1) is a single-domain hub protein with nearly 200 validated interactors in vertebrates. PP1-interacting proteins (PIPs) are ubiquitously expressed but show an exceptional diversity in brain, testis and white blood cells. The binding of PIPs is mainly mediated by short motifs that dock to surface grooves of PP1. Although PIPs often contain variants of the same PP1 binding motifs, they differ in the number and combination of docking sites. This molecular-lego strategy for binding to PP1 creates holoenzymes with unique properties. The PP1 binding code can be described as specific, universal, degenerate, nonexclusive and dynamic. PIPs control associated PP1 by interference with substrate recruitment or access to the active site. In addition, some PIPs have a subcellular targeting domain that promotes dephosphorylation by increasing the local concentration of PP1. The diversity of the PP1 interactome and the properties of the PP1 binding code account for the exquisite specificity of PP1 in vivo. 23145944 Dendrimeric bowties featuring hemispheric-selective decoration of ligands for microRNA-based therapy. Dendrimers feature a defined number of terminal groups that may bind RNA or be functionalized with bioactive molecules. These competing uses of terminal groups may create an impasse if the requisite density of ligands depletes the number of terminal groups for binding sufficient RNA, or vice versa. A novel dendrimeric platform is needed that maintains high ligand density while retaining sufficient microRNA-binding terminal groups. Here we present a dendrimeric "bowtie" consisting of one-half devoted to microRNA binding and the other half to ligand presentation. We demonstrate its suitability as a transfection agent by delivering miR-126 to human vascular endothial cells (HUVECs) via polyarginine- and RGD-modified bowties and evaluating the downstream effects on proliferation and tube formation. Our findings indicate that the bowtie elicits desired responses and may possess superior delivery properties compared to nondecorated dendrimeric materials. The bowtie system thereby provides a new design model for developing dendrimeric delivery vehicles for RNAi therapeutics. 23301582 Nanoparticle adhesion to the cell membrane and its effect on nanoparticle uptake efficiency. The interactions between nanosized particles and living systems are commonly mediated by what adsorbs to the nanoparticle in the biological environment, its biomolecular corona, rather than the pristine surface. Here, we characterize the adhesion toward the cell membrane of nanoparticles of different material and size and study how this is modulated by the presence or absence of a corona on the nanoparticle surface. The results are corroborated with adsorption to simple model supported lipid bilayers using a quartz crystal microbalance. We conclude that the adsorption of proteins on the nanoparticle surface strongly reduces nanoparticle adhesion in comparison to what is observed for the bare material. Nanoparticle uptake is described as a two-step process, where the nanoparticles initially adhere to the cell membrane and subsequently are internalized by the cells via energy-dependent pathways. The lowered adhesion in the presence of proteins thereby causes a concomitant decrease in nanoparticle uptake efficiency. The presence of a biomolecular corona may confer specific interactions between the nanoparticle-corona complex and the cell surface including triggering of regulated cell uptake. An important effect of the corona is, however, a reduction in the purely unspecific interactions between the bare material and the cell membrane, which in itself disregarding specific interactions, causes a decrease in cellular uptake. We suggest that future nanoparticle-cell studies include, together with characterization of size, charge, and dispersion stability, an evaluation of the adhesion properties of the material to relevant membranes. 22447662 Effects of the total alkaloidal extract of Murraya koenigii leaf on oxidative stress and cholinergic transmission in aged mice. Alzheimer's disease (AD) is characterized by signs of major oxidative stress and the loss of cholinergic cells. The present study was designed to investigate the role of the total alkaloidal extract from Murraya koenigii (MKA) leaves on age related oxidative stress and the cholinergic pathway in aged mice. Ascorbic acid (100 mg/kg, p.o.) was used as a standard drug. The MKA improved the level of protective antioxidants such as glutathione peroxidase (GPx), reduced glutathione (GSH), glutathione reductase (GRD), superoxide dismutase (SOD) and catalase (CAT) in brain homogenate at higher doses (20 and 40 mg/kg, p.o.). Moreover, a dose dependent decline was noted in lipid peroxidation (LPO) and the nitric oxide assay (NO) at all doses of MKA (10, 20 and 40 mg/kg, p.o.). Interestingly, significant progress was noted with the supplementation of MKA by an improvement of the acetylcholine (ACh) levels and a reduction in the acetylcholinesterase (AChE) activity in aged mouse brain. In addition, a significant elevation of serum albumin (ALBU), alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST) and total protein as well as a decline in creatinine, total cholesterol, urea nitrogen and glucose levels with MKA also ameliorated the hepatic and renal functions in normal ageing process. The results showed the possible utility of Murraya koenigii leaves in neuroprotection against neurodegenerative disorders such as Alzheimer's disease. 23363397 High T(g) bio-based aliphatic polyesters from bicyclic D-mannitol. The carbohydrate-based diol 2,4:3,5-di-O-methylene-d-mannitol (Manx) has been used to obtain aliphatic polyesters. Manx is a symmetric bicyclic compound consisting of two fused 1,3-dioxane rings and bearing two primary hydroxyl groups. In terms of stiffness, it is comparable to the widely known isosorbide, but it affords the additional advantages of being much more reactive in polycondensation and capable of producing stereoregular polymers with fairly high molecular weights. A fully bio-based homopolyester (PManxS) has been synthesized by polycondensation in the melt from dimethyl succinate and Manx. The high thermal stability of PManxS, its relatively high glass transition temperature (Tg = 68 °C) and elastic modulus, and its enhanced sensitivity to the action of lipases point to PManxS as a polyester of exceptional interest for those applications where biodegradability and molecular stiffness are priority requirements. In addition, random copolyesters (PBxManxyS) covering a broad range of compositions have been obtained using mixtures of Manx and 1,4-butanediol in the reaction with dimethyl succinate. All PBxManxyS were semicrystalline and displayed Tg values from -29 to +51 °C steadily increasing with the content in Manx units. The stress-strain behavior of these copolyesters largely depended on their content in Manx and they were enzymatically degraded faster than PBS. 23246578 Inhibitory effect of Crotalus durissus terrificus venom on chronic edema induced by injection of bacillus Calmette-Guérin into the footpad of mice. In this study, we evaluated the effect of the Crotalus durissus terrificus (Cdt) venom on the chronic paw edema induced by the injection of bacillus Calmette-Guérin (BCG) into the footpad of mice. The BCG injection evoked chronic edema, which was significantly diminished in animals treated subcutaneously (s.c.) with Cdt venom 1 h before or after the BCG injection. This inhibition persisted throughout the evaluation period (15 days). In mice injected with Cdt venom 6 or 11 days after injection of BCG, we observed a significant reduction in edema only in the period after the venom injection. While studying possible mechanisms involved in this inhibition, we observed that pre-treatment with dexamethasone, zileuton or Boc2 (a selective antagonist of formyl peptide receptors), but not with indomethacin, canceled out the inhibitory effect of Cdt venom on the edema induced by BCG. These results strongly suggest that this rattlesnake venom can stimulate the generation of mediators from the lipoxygenase pathway, which can down-regulate this chronic inflammatory edema. Using fractionated venom, the results indicated that crotoxin was the only component of Cdt venom responsible for this inhibitory effect. These results indicated that crotoxin, the main toxin of the C. durissus terrificus venom, has a significant inhibitory effect on BCG-induced chronic edema, possibly by generating anti-inflammatory mediators from the lipoxygenase pathway. 23348500 A novel metabotropic glutamate receptor 5 positive allosteric modulator acts at a unique site and confers stimulus bias to mGlu5 signaling. Metabotropic glutamate receptor 5 (mGlu5) is a target for the treatment of central nervous system (CNS) disorders, such as schizophrenia and Alzheimer's disease. Furthermore, mGlu5 has been shown to play an important role in hippocampal synaptic plasticity, specifically in long-term depression (LTD) and long-term potentiation (LTP), which is thought to be involved in cognition. Multiple mGlu5-positive allosteric modulators (PAMs) have been developed from a variety of different scaffolds. Previous work has extensively characterized a common allosteric site on mGlu5, termed the MPEP (2-Methyl-6-(phenylethynyl)pyridine) binding site. However, one mGlu5 PAM, CPPHA (N-(4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl)-2-hydroxybenzamide), interacts with a separate allosteric site on mGlu5. Using cell-based assays and brain slice preparations, we characterized the interaction of a potent and efficacious mGlu5 PAM from the CPPHA series termed NCFP (N-(4-chloro-2-((4-fluoro-1,3-dioxoisoindolin-2-yl)methyl)phenyl)picolinamide). NCFP binds to the CPPHA site on mGlu5 and potentiates mGlu5-mediated responses in both recombinant and native systems. However, NCFP provides greater mGlu5 subtype selectivity than does CPPHA, making it more suitable for studies of effects on mGlu5 in CNS preparations. Of interest, NCFP does not potentiate responses involved in hippocampal synaptic plasticity (LTD/LTP), setting it apart from other previously characterized MPEP site PAMs. This suggests that although mGlu5 PAMs may have similar responses in some systems, they can induce differential effects on mGlu5-mediated physiologic responses in the CNS. Such stimulus bias by mGlu5 PAMs may complicate drug discovery efforts but would also allow for specifically tailored therapies, if pharmacological biases can be attributed to different therapeutic outcomes. 23042952 Differential cell-protective function of two resveratrol (trans-3,5,4'-trihydroxystilbene) glucosides against oxidative stress. Resveratrol (trans-3,5,4'-trihydroxystilbene; RSV), a natural polyphenol, exerts a beneficial effect on health and diseases. RSV targets and activates the NAD(+)-dependent protein deacetylase SIRT1; in turn, SIRT1 induces an intracellular antioxidative mechanism by inducing mitochondrial superoxide dismutase (SOD2). Most RSV found in plants is glycosylated, and the effect of these glycosylated forms on SIRT1 has not been studied. In this study, we compared the effects of RSV and two glycosyl RSVs, resveratrol-3-O-β-d-glucoside (3G-RSV; polydatin/piceid) and resveratrol-4'-O-β-d-glucoside (4'G-RSV), at the cellular level. In oxygen radical absorbance capacity and 2,2-diphenyl-1-picrylhydrazyl radical scavenging assays, the antioxidant activity of 3G-RSV was comparable to that of RSV, whereas the radical-scavenging efficiency of 4'G-RSV was less than 50% of that of RSV. However, 4'G-RSV, but not 3G-RSV, induced SIRT1-dependent histone H3 deacetylation and SOD2 expression in mouse C2C12 skeletal myoblasts; as with RSV, SIRT1 knockdown blunted these effects. RSV and 4'G-RSV, but not 3G-RSV, mitigated oxidative stress-induced cell death in C2C12 cells and primary neonatal rat cardiomyocytes. RSV and 4'G-RSV inhibited C2C12 cell proliferation, but 3G-RSV did not. RSV was found in both the intracellular and extracellular fractions of C2C12 cells that had been incubated with 4'G-RSV, indicating that 4'G-RSV was extracellularly deglycosylated to RSV, which was then taken up by the cells. C2C12 cells did not deglycosylate 3G-RSV. Our results point to 4'G-RSV as a useful RSV prodrug with high water solubility. These data also show that the in vitro antioxidative activity of these molecules did not correlate with their ability to protect cells from oxidative stress-induced apoptosis. 23621769 Amniotic membrane extract-loaded double-layered wound dressing: evaluation of gel properties and wound healing. Abstract The conservative single-layered wound dressing system is decomposed when mixed in polyvinyl alcohol (PVA) solution, which means it cannot be used with a temperature-sensitive drug. The goal of this investigation was to make an amniotic membrane extract (AME)-loaded double-layered wound dressing with an improved healing result compared to the conservative single-layered wound dressing systems. The double-layered wound dressing was developed with PVA/sodium alginate using a freeze-melting technique; one layer was PVA layer and the other was the drug-loaded sodium alginate layer. Its gel properties were assessed compared to single-layered wound dressings. Moreover, in vivo wound-healing effects and histopathology were calculated compared to commercial products. The double-layered wound dressing gave a similar gel fraction and Young's module as single-layered wound bandages developed with only PVA, and a similar inflammation ability and WVTR as single-layered wound dressings developed with PVA and sodium alginate. Our data indicate that these double-layered wound bandages were just as swellable, but more elastic and stronger than single-layered wound dressings comprised of the same polymers and quantities, possibly giving an acceptable level of moisture and accumulation of exudates in the wound zone. Compared to the commercial product, the double-layered wound dressing comprising 6.7% PVA, 0.5% sodium alginate and 0.01% AME significantly enhanced the wound-healing effect in the wound-healing test. Histological investigations showed that superior full-thickness wound-healing effects compared to the commercial product. Therefore, the double-layered wound dressing would be an outstanding wound-dressing system with improved wound healing and good gel property. 23052190 Magnesium sulfate treatment against sarin poisoning: dissociation between overt convulsions and recorded cortical seizure activity. Sarin, a potent organophosphate cholinesterase inhibitor, induces an array of toxic effects including convulsions. Many antidotal treatments contain anticonvulsants to block seizure activity and the ensuing brain damage. Magnesium sulfate (MGS) is used to suppress eclamptic seizures in pregnant women with hypertension and was shown to block kainate-induced convulsions. Magnesium sulfate was evaluated herein as an anticonvulsant against sarin poisoning and its efficacy was compared with the potent anticonvulsants midazolam (MDZ) and caramiphen (CRM). Rats were exposed to a convulsant dose of sarin (96 μg/kg, im) and 1 min later treated with the oxime TMB4 and atropine to increase survival. Five minutes after initiation of convulsions, MGS, CRM, or MDZ were administered. Attenuation of tonic-clonic convulsions was observed following all these treatments. However, radio-telemetric electro-corticography (ECoG) monitoring demonstrated sustained seizure activity in MGS-injected animals while this activity was completely blocked by MDZ and CRM. This disrupted brain activity was associated with marked increase in brain translocator protein levels, a marker for brain damage, measured 1 week following exposure. Additionally, histopathological analyses of MGS-treated group showed typical sarin-induced brain injury excluding the hippocampus that was partially protected. Our results clearly show that MGS demonstrated misleading features as an anticonvulsant against sarin-induced seizures. This stems from the dissociation observed between overt convulsions and seizure activity. Thus, the presence or absence of motor convulsions may be an unreliable indicator in the assessment of clinical status and in directing adequate antidotal treatments following exposure to nerve agents in battle field or terror attacks. 23555191 Selecting One of Several Mating Types through Gene Segment Joining and Deletion in Tetrahymena thermophila. The unicellular eukaryote Tetrahymena thermophila has seven mating types. Cells can mate only when they recognize cells of a different mating type as non-self. As a ciliate, Tetrahymena separates its germline and soma into two nuclei. During growth the somatic nucleus is responsible for all gene transcription while the germline nucleus remains silent. During mating, a new somatic nucleus is differentiated from a germline nucleus and mating type is decided by a stochastic process. We report here that the somatic mating type locus contains a pair of genes arranged head-to-head. Each gene encodes a mating type-specific segment and a transmembrane domain that is shared by all mating types. Somatic gene knockouts showed both genes are required for efficient non-self recognition and successful mating, as assessed by pair formation and progeny production. The germline mating type locus consists of a tandem array of incomplete gene pairs representing each potential mating type. During mating, a complete new gene pair is assembled at the somatic mating type locus; the incomplete genes of one gene pair are completed by joining to gene segments at each end of germline array. All other germline gene pairs are deleted in the process. These programmed DNA rearrangements make this a fascinating system of mating type determination. 23170792 Stroke prevention: from available antiplatelet drugs to novel molecular targets. Stroke is the third most common cause of death in the industrialized countries and adequate primary and secondary prevention strategies are mandatory. In addition to lifestyle-changes and correction of cardiovascular risk factors, the mainstay of the atherothrombotic stroke prevention is represented by antiplatelet treatment. Although aspirin and thienopyridines have proved their efficacy in the prevention of arterial thrombotic events, limited efficacy, increased risk of bleeding, significant inter-individual variability in the response and extended duration of action that cannot be reversed if the need for haemostasis or emergency surgery arises represent major limitations of these drugs. Moreover, despite recommendations and guidelines about stroke prevention, registries data clearly suggest an underuse of antiplatelet drugs, mainly because of bleeding episodes fear. At variance with newer anticoagulant drugs, which showed a series of advantages as compared with the traditional warfarin treatment, newer antiplatelet drugs have only partially overcome these limitations. Although ad hoc studies on their efficacy in the stroke prevention are currently lacking, newer antiplatelet agents (mainly ticagrelor and prasugrel) do not provide a significant better protection over and above aspirin and/or clopidogrel in the prevention of atherothrombotic stroke. In addition, a significantly increased bleeding risk has been reported in subjects receiving these new thienopyridines. According to these data, the identification of further molecular targets is needed, in order to design future antiplatelet drugs. In this review, after summarizing major literature data about traditional and newer antiplatelet drugs, we will specifically focus on novel potential target candidates for antiplatelet therapy. 23336435 Novel anti-inflammatory phytoconstituents from Desmodium gangeticum. A new aliphatic enone, (17Z,20Z)-hexacosa-17,20-dien-9-one (3), and one new bisindole alkaloid, gangenoid (6), together with seven known compounds were isolated from the roots and aerial parts of Desmodium gangeticum (family: Leguminosae). All the compounds except 2 and 7 were isolated from this plant for the first time, which may be of chemotaxonomic importance. Structures of compounds 3 and 6 were determined on the basis of their detailed spectroscopic analyses (NMR, IR and mass). In addition, compounds 3 and 6 were investigated for their effects on lipopolysaccharide-stimulated macrophages for the production of pro-inflammatory cytokines such as tumour necrosis factor-α and interleukin-6. 23607646 Molecular Binoculars: How to Spatially Resolve Environmental Fluctuations by Following Two or More Single-Molecule Spectral Trails at a Time. We propose a novel type of spectral diffusion experiment that enables one to decouple spatial characteristics of the environmental fluctuations, such as their concentration, from the interaction with the chromophore. Traditional hole broadening experiments do not allow for such decoupling in the common case when the chromophore-environment interaction is scale invariant. Here we propose to simultaneously follow the spectral trails of a small number of nearby chromophores---two or more---which thereby sense a highly overlapping set of the fluctuations. To this end, we estimate the combined probability distribution for the frequencies of a set of chromophores contained within the {\em same} sample. The present setup introduces a new length scale, i.e., the inter-chromophore distance, which breaks the aforementioned scale invariance and enables one to determine independently the concentration of the environmental fluctuations and their coupling to the chromophores, by monitoring the time after which spectral diffusion of distinct chromophores becomes uncorrelated. We illustrate these results with structural excitations in low temperature glasses. 22975405 Opportunities for functional selectivity in GPCR antibodies. Monoclonal antibodies (mAbs) have been used for decades as tools to probe the biology and pharmacology of receptors in cells and tissues. They are also increasingly being developed for clinical purposes against a broad range of targets, albeit to a lesser extent for G-protein-coupled receptors (GPCRs) relative to other therapeutic targets. Recent pharmacological, structural and biophysical data have provided a great deal of new insight into the molecular details, complexity and regulation of GPCR function. Whereas GPCRs used to be viewed as having either "on" or "off" conformational states, it is now recognized that their structures may be finely tuned by ligands and other interacting proteins, leading to the selective activation of specific signaling pathways. This information coupled with new technologies for the selection of mAbs targeting GPCRs will be increasingly deployed for the development of highly selective mAbs that recognize conformational determinants leading to novel therapeutics. 23506469 Transition to Reinforced State by Percolating Domains of Intercalated Brush-Modified Cellulose Nanocrystals and Poly(butadiene) in Cross-Linked Composites Based on Thiol-ene Click Chemistry. The classic nanocomposite approach aims at percolation of low fraction of exfoliated individual reinforcing nanoscale elements within a polymeric matrix. By contrast, many of the mechanically excellent biological nanocomposites involve self-assembled and space-filled structures of hard reinforcing and soft toughening domains, with high weight fraction of reinforcements. Here we inspect a new concept toward mimicking such structures by studying whether percolation of intercalated domains consisting of alternating rigid and reinforcing, and soft rubbery domains could allow a transition to a reinforced state. Toward that, we present the functionalization of rigid native cellulose nanocrystals (CNCs) by esterification with a dense hydrocarbon chain brush containing cross-linkable double bonds. Composite films with 0-80 wt % of such modified CNCs (mCNCs) within a poly(butadiene) (PBD) rubber matrix were prepared via cross-linking by UV-light initiated thiol-ene click reaction. Transmission electron microscopy showed structures at two length scales, where the mCNCs and PBD form domains having internal aligned self-assemblies of alternating hard mCNCs and soft PBD with periodicity of ca. 40 nm, and where additional PBD connects such domains. Increasing the weight fraction of mCNCs causes an uncommon abrupt transition from PBD-dominated soft materials to significantly reinforced mCNC-dominated mechanical properties, suggesting that the intercalated self-assembled mCNC/PBD domains percolate in PBD upon passing 30-35 wt % of mCNCs. Maximum stress of 16 MPa at mCNC fraction of 80 wt % was obtained. The mechanical properties of the composites show exceptional insensitivity to air humidity. The shown simple concept of percolative intercalated nanocomposites suggests searching for more general biomimetic compositions involving several deformation mechanisms for improved mechanical properties. 23357335 The role of phosphodiesterases in hippocampal synaptic plasticity. Phosphodiesterases (PDEs) degrade cyclic nucleotides, signalling molecules that play important roles in synaptic plasticity and memory. Inhibition of PDEs may therefore enhance synaptic plasticity and memory as a result of elevated levels of these signalling molecules, and this has led to interest in PDE inhibitors as cognitive enhancers. The development of new mouse models in which PDE subtypes have been selectively knocked out and increasing selectivity of PDE antagonists means that this field is currently expanding. Roles for PDE2, 4, 5 and 9 in synaptic plasticity have so far been demonstrated and we review these studies here in the context of cyclic nucleotide signalling more generally. The role of other PDE families in synaptic plasticity has not yet been investigated, and this area promises to advance our understanding of cyclic nucleotide signalling in synaptic plasticity in the future. This article is part of a Special Issue entitled 'GluR-dep synaptic plasticity'. 23364048 The genome-defence gene Tex19.1 suppresses LINE-1 retrotransposons in the placenta and prevents intra-uterine growth retardation in mice. DNA methylation plays an important role in suppressing retrotransposon activity in mammalian genomes, yet there are stages of mammalian development where global hypomethylation puts the genome at risk of retrotransposition-mediated genetic instability. Hypomethylated primordial germ cells appear to limit this risk by expressing a cohort of retrotransposon-suppressing genome-defence genes whose silencing depends on promoter DNA methylation. Here, we investigate whether similar mechanisms operate in hypomethylated trophectoderm-derived components of the mammalian placenta to couple expression of genome-defence genes to the potential for retrotransposon activity. We show that the hypomethylated state of the mouse placenta results in activation of only one of the hypomethylation-sensitive germline genome-defence genes: Tex19.1. Tex19.1 appears to play an important role in placenta function as Tex19.1(-/-) mouse embryos exhibit intra-uterine growth retardation and have small placentas due to a reduction in the number of spongiotrophoblast, glycogen trophoblast and sinusoidal trophoblast giant cells. Furthermore, we show that retrotransposon mRNAs are derepressed in Tex19.1(-/-) placentas and that protein encoded by the LINE-1 retrotransposon is upregulated in hypomethylated trophectoderm-derived cells that normally express Tex19.1. This study suggests that post-transcriptional genome-defence mechanisms are operating in the placenta to protect the hypomethylated cells in this tissue from retrotransposons and suggests that imbalances between retrotransposon activity and genome-defence mechanisms could contribute to placenta dysfunction and disease. 23426858 Improved excitation uniformity in multiple-quantum NMR experiments of mixtures. Multiple-quantum (1)H NMR spectroscopy has been finding a renewed interest for its possible applications in the analysis of mixtures of small molecules, due to its simplification properties. A crucial aspect of this application of multiple-quantum NMR is the sensitivity of the spectrum intensity to the molecular structure and to the parameterization of the experiment, which could result in the missing of some components. We demonstrate that a general scheme to overcome this drawback consists in varying the experiment parameterizations over a small number of values, selected according the values of the couplings and the relaxation rates. 23578617 Influence of phenolic compounds on the sensorial perception and volatility of red wine esters in model solution: An insight at the molecular level. Impact of (+)-catechin and gallic acid on sensory perception and volatility of isoamyl acetate, ethyl isobutyrate, ethyl butyrate and ethyl octanoate was investigated in model solutions, by means of triangle tests, detection threshold determination and HS-GC-MS analyses. Catechin significantly altered the sensory perception of most esters (ethyl isobutyrate, ethyl butyrate and ethyl octanoate) while gallic acid displayed no impact. Ethyl butyrate and ethyl octanoate odour thresholds doubled or tripled in the presence of catechin, underlining a retention impact of phenolic compounds in liquid matrix. The headspace analyses displayed a decrease only in ethyl octanoate volatility in presence of catechin, whereas no significant difference in other esters concentrations was observed. This study indicated that phenolic compounds have a variable impact on aroma compounds' volatility and their sensory perception. The polarity of phenolic and volatile compounds as well as their spatial conformation also appeared to influence the interaction strength. 23313336 What are the physiological estrogens? Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ(4) bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including Δ(5)-androstenediol, 5α-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a 3β-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to estrogen receptor-α (ERα) and ERβ. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of ERα and ERβ. Our understanding of the physiological responses mediated by these "alternative" estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by ERα and ERβ a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities. 23118486 Structural asymmetry in the Thermus thermophilus RuvC dimer suggests a basis for sequential strand cleavages during Holliday junction resolution. Holliday junction (HJ) resolvases are structure-specific endonucleases that cleave four-way DNA junctions (HJs) generated during DNA recombination and repair. Bacterial RuvC, a prototypical HJ resolvase, functions as homodimer and nicks DNA strands precisely across the junction point. To gain insights into the mechanisms underlying symmetrical strand cleavages by RuvC, we performed crystallographic and biochemical analyses of RuvC from Thermus thermophilus (T.th. RuvC). The crystal structure of T.th. RuvC shows an overall protein fold similar to that of Escherichia coli RuvC, but T.th. RuvC has a more tightly associated dimer interface possibly reflecting its thermostability. The binding mode of a HJ-DNA substrate can be inferred from the shape/charge complementarity between the T.th. RuvC dimer and HJ-DNA, as well as positions of sulfate ions bound on the protein surface. Unexpectedly, the structure of T.th. RuvC homodimer refined at 1.28 Å resolution shows distinct asymmetry near the dimer interface, in the region harboring catalytically important aromatic residues. The observation suggests that the T.th. RuvC homodimer interconverts between two asymmetric conformations, with alternating subunits switched on for DNA strand cleavage. This model provides a structural basis for the 'nick-counter-nick' mechanism in HJ resolution, a mode of HJ processing shared by prokaryotic and eukaryotic HJ resolvases. 23291341 Bombesin receptor subtype-3 (BRS-3), a novel candidate as therapeutic molecular target in obesity and diabetes. BRS-3 KO-mice developed obesity and unbalanced glucose metabolism, suggesting an important role of BRS-3 receptor in glucose homeostasis. We explored BRS-3 expression in skeletal muscle from normal, obese or type-2 diabetic (T2D) patients, and the effect of [D-Phe(6), β-Ala(11),Phe(13),Nle(14)]bombesin(6-14)-BRS-3-agonist-peptide (BRS-3-AP) - on glucose-related effects, before or after BRS-3 gene silencing. In muscle tissue and primary cultured myocytes from altered metabolic states, BRS-3 gene/protein expressions were down-regulated. In normal, obese and T2D cells: A) BRS-3-AP as insulin enhanced BRS-3 and GLUT-4 mRNA/protein levels; improving glucotransporter translocation to plasma membrane, and B) BRS-3-AP caused a concentration-related-stimulation of glucose transport, being obese and T2D myocytes more sensitive to the ligand than normal. Wortmannin and PD98059, but not rapamycin, abolished the stimulatory action of BRS-3-AP on glucose transport. BRS-3 plays an important role in glucose metabolism, and could be use as a molecular target, and/or its ligand, as a therapeutic agent for obesity and diabetes treatments. 23427148 KBP-cytoskeleton interactions underlie developmental anomalies in Goldberg-Shprintzen syndrome. Goldberg-Shprintzen syndrome (GOSHS, MIM #609460) is an autosomal recessive disorder of intellectual disability, specific facial gestalt and Hirschsprung's disease (HSCR). In 2005, homozygosity mapping in a large consanguineous family identified KIAA1279 as the disease-causing gene. KIAA1279 encodes KIF-binding protein (KBP), whose function is incompletely understood. Studies have identified either the mitochondria or the cytoskeleton as the site of KBP localization and interactions. To better delineate the KIAA1279-related clinical spectrum and the molecular mechanisms involved in GOSHS, we studied five new patients from three different families. The homozygous KIAA1279 mutations in these patients (p.Arg90X, p.Ser200X or p.Arg202IlefsX2) led to nonsense-mediated mRNA decay and loss of KBP function. Despite the absence of functional KBP, respiratory chain complex activity in patient fibroblasts was normal. KBP did not co-localize with mitochondria in control human fibroblasts, but interacted with the actin and tubulin cytoskeleton. KBP expression directly affected neurite growth in a neuron-like cell line (human neuroblastoma SH-SY5Y), in keeping with the central (polymicrogyria) and enteric (HSCR) neuronal developmental defects seen in GOSHS patients. The KBP interactions with actin filaments and microtubules (MTs) demonstrated in our study constitute the first evidence that an actin MT cross-link protein is involved in neuronal development in humans. 23481321 First report on predictive chemometric modeling, 3D-toxicophore mapping and in silico screening of in vitro basal cytotoxicity of diverse organic chemicals. Classification and regression based quantitative structure-toxicity relationship (QSTR) as well as toxicophore models were developed for the first time on basal cytotoxicity data (in vitro 3T3 neutral red uptake data) of a diverse series of chemicals (including drugs and environmental pollutants) collected from the ACuteTox database (http://www.acutetox.eu/). Statistically significant QSTR models were obtained using linear discriminant analysis (classification) and partial least squares (regression) methodologies. Generated toxicophore models showed four important features responsible for basal cytotoxicity: (i) two hydrophobic aliphatic groups (HYD Aliphatic), (ii) ring aromatic group (RA) and (iii) hydrogen bond donor (HBD). The most predictive hypothesis (Hypo 1) had a correlation coefficient of 0.932 for the training set, a low rms deviation of 1.105, and an acceptable cost difference of 62.8 bits, which represents a true correlation and a good predictivity. QSTR and toxicophore models were rigorously validated internally as well as externally along with the randomization test to nullify the possibilities of chance correlation. Our in silico models enable to identify the essential structural attributes and quantify the prime molecular pre-requisites which were chiefly responsible for in vitro basal cytotoxicity. The developed models were also implemented to screen basal cytotoxicity for huge number DrugBank database (http://www.drugbank.ca/) compounds. 23084047 Toxic effects of microcystin-LR on the reproductive system of male Rana nigromaculata in vitro. This study aims to demonstrate that microcystin-LR (MC-LR) has toxic effects on the reproductive system of male Rana nigromaculata in vitro. R. nigromaculata were treated with 0, 0.1, 1, 10, and 100 nmol/L of MC-LR for 6 h. Results show that exposure to 1 nmol/L to 100 nmol/L of MC-LR decreased sperm motility and number of sperm cells and increased the sperm abnormality rate, whose values were significantly different from those of the control (P<0.01). Moreover, the same dosage of MC-LR increased reactive oxygen species production and malondialdehyde content. At the same time, antioxidant enzyme (catalase and glutathione S-transferase) activity and glutathione reduced content rapidly increased, whereas antioxidant enzyme superoxide dismutase activity significantly decreased. These results imply that the defense system of the testes quickly responds to oxidative stress. Ultrastructural observation shows distention of the mitochondria, endoplasmic reticulum, and Golgi apparatus and changes in the mitochondrial matrix color, cristae number, and morphology. Moreover, using real-time PCR, increased relative expressions of P450 aromatase and SF-1 genes were observed. The results demonstrate for the first time that MC-LR could induce toxicity in the male reproductive system of R. nigromaculata. The findings in this research will provide more insights into the relationships between aquatic microcystins and amphibians. 22455986 A comparative study of phytochemical composition of genetically and non-genetically modified soybean (Glycine max L.) and evaluation of antitumor activity. Colon cancer is one of the major causes of cancer mortality worldwide. The analysed feeds, containing non-genetically modified (GM) soybean and Roundup Ready soybean, showed a different polyphenolic content and lipophilic composition. Non-GM soybean extract possessed twice the polyphenolic content of GM soybean and the highest number of sterols. Among them, γ-sitosterol was found to be the major constituent. Methanolic extract of non-GM soybean extract was more potent than GM soybean extract against colon carcinoma cell line LoVo using MTT assay, while the second one showed a slightly higher anti-inflammatory activity. The findings add to epidemiological evidence for the therapeutic effects of soy foods in colorectal carcinoma. 23428645 The effects of cannabidiol on the antigen-induced contraction of airways smooth muscle in the guinea-pig. (-)-Δ(9)-Tetrahydrocannabinol has been demonstrated to have beneficial effects in the airways, but its psychoactive effects preclude its therapeutic use for the treatment of airways diseases. In the present study we have investigated the effects of (-)-cannabidiol, a non-psychoactive component of cannabis for its actions on bronchial smooth muscle in vitro and in vivo. Guinea-pig bronchial smooth muscle contractions induced by exogenously applied spasmogens were measured isometrically. In addition, contractile responses of bronchial smooth muscle from ovalbumin-sensitized guinea-pigs were investigated in the absence or presence of (-)-cannabidiol. Furthermore, the effect of (-)-cannabidiol against ovalbumin-induced airway obstruction was investigated in vivo in ovalbumin-sensitized guinea-pigs. (-)-Cannabidiol did not influence the bronchial smooth muscle contraction induced by carbachol, histamine or neurokinin A. In contrast, (-)-cannabidiol inhibited anandamide- and virodhamine-induced responses of isolated bronchi. A fatty acid amide hydrolase inhibitor, phenylmethanesulfonyl fluoride reversed the inhibitory effect of (-)-cannabidiol on anandamide-induced contractions. In addition, (-)-cannabidiol inhibited the contractile response of bronchi obtained from allergic guinea-pigs induced by ovalbumin. In vivo, (-)-cannabidiol reduced ovalbumin-induced airway obstruction. In conclusion, our results suggest that cannabidiol can influence antigen-induced airway smooth muscle tone suggesting that this molecule may have beneficial effects in the treatment of obstructive airway disorders. 23159791 Gene expression analysis by ESTs sequencing of the Brazilian frog Phyllomedusa nordestina skin glands. The subfamily Phyllomedusinae has attracted a great interest of many researchers mainly due to the high diversity of these frog species and plethora of pharmacological activities frequently observed for their skin secretions. Despite of this fact, mainly for new species, limited information is available regarding the molecular composition of these skin secretions and the cellular components involved in their production. Phyllomedusa nordestina is a recently described Brazilian frog species also popularly known as 'tree-frogs'. Aiming at contributing to the biological knowledge of this species, we show here the gene expression profile of this frog skin secretion using a global ESTs analysis of a cDNA library. The marked aspect of this analysis revealed a significant higher transcriptional level of the opioid peptide dermorphins in P. nordestina skin secretion than in Phyllomedusa hypochondrialis, which is its closest related species, belonging both to the same phylogenetic group. Precursors of bioactive peptides as dermaseptins, phylloseptins, tryptophyllins, and bradykinin-like peptideswere also found in this library. Transcripts encoding proteins related to ordinary cellular functions and pathways were also described. Some of them are chiefly involved in the production of the skin secretion. Taken together, the data reported here constitute a contribution to the characterization of the molecular diversity of gene-encoded polypeptides with potential possibility of pharmacological exploitation. The transcriptional composition of the skin secretion may also help to give the necessary support for the definition of P. nordestina as a new species, which actually relies basically on frog morphological characteristics and geographical distribution. 23187874 Effect of structural defects and chemical functionalisation on the intrinsic mechanical properties of graphene. Due to its unique mechanical properties, graphene can be applied for reinforcement in nanocomposites. We analyse the Young's modulus of graphene at the semi-empirical PM6 level of theory. The internal forces are calculated and the Young's modulus is predicted for a finite graphene sheet when external strain is applied on the system. These results are in a good agreement with theoretical and experimental results from the literature giving values of about 1 TPa for the Young's modulus. Stress-strain curves are computed for elongation up to 20%. In addition, the influence of the presence of a single vacancy, as well as for oxygenation of a vacancy, on the mechanical properties of graphene has been analysed. Our results indicate that when applying the deformation locally onto the system, higher local stress can be induced, as confirmed by Finite Element Analysis. Also, the presence of structural defects in the system will stiffen the system upon low strain, but reduces the elastic limit from more than 20% strain for pristine graphene to less than 10% strain when defects are present. 23512501 NAD(P)H : Quinone Oxidoreductase 1 Inducer Activity of Some Saudi Arabian Medicinal Plants. Medicinal plants are a rich source of biologically-active phytochemicals and have been used in traditional medicine for centuries. Specific phytochemicals and extracts of their plant sources have the ability to reduce the risk for chronic degenerative diseases by induction of enzymes involved in xenobiotic metabolism, many of which also have antioxidant and anti-inflammatory functions. One such multifunctional cytoprotective enzyme is NAD(P)H : quinone oxidoreductase. In this study, we prepared extracts of 27 Saudi Arabian medicinal plants which belong to 18 different plant families and tested their ability to induce NAD(P)H : quinone oxidoreductase in murine hepatoma cells grown in microtiter plate wells. In addition to the Brassicaceae, a known source of NAD(P)H : quinone oxidoreductase inducer activity, we found substantial inducer activity in extracts from the Apiaceae, Apocynaceae, and the Asteraceae families. Five out of a total of eight active extracts are from plants which belong to the Asteraceae family. We further show that artemisinin, an agent which is used clinically for the treatment of malaria, contributes but does not fully account for the inducer activity of the extract of Artemisia monosperma. In contrast to artemisinin, deoxyartemisinin is inactive in this assay, demonstrating the critical role of the endoperoxide moiety of artemisinin for inducer activity. Thus, the NAD(P)H : quinone oxidoreductase inducer activity of extracts of some Saudi Arabian medicinal plants indicates the presence of specific phytochemicals which have the potential to protect against chronic degenerative diseases. 23417514 An evaluation of the serotonin system and perseverative, compulsive, stereotypical, and hyperactive behaviors in dopamine transporter (DAT) knockout mice. RATIONALE: Mice lacking the dopamine transporter (DAT) display major behavioral alterations that include hyperactivity, perseverative locomotor patterns, and reduced prepulse inhibition of the acoustic startle reflex. OBJECTIVES: The objectives of this study were to investigate perseverative, compulsive, stereotypical, and hyperactive behaviors, as well as serotonin and its involvement with these behaviors, in DAT gene-altered mice. RESULTS: In the open field, mean turn angle and meandering were decreased in DAT knockout (DAT-KO) mice. DAT-KO mice displayed increased hyperactivity, increased velocity, less time immobile, and a failure to habituate over time in the open field unlike their DAT wildtype (DAT-WT) and heterozygous (DAT-HET) littermates. DAT-KO mice buried fewer marbles than DAT-WT and -HET mice in an assessment of compulsive-like behaviors, likely due to extreme hyperactivity and related inattention. Stereotypical head weaving was increased in untreated DAT-KO mice. Following administration of the 5-HT(1A/7) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), stereotypical head weaving and forepaw treading were increased more in DAT-KO mice than in DAT-WT or -HET mice. By contrast, head twitches induced by treatment with the 5-HT(2A/2C) agonist (±)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI) were similar in mice of all three DAT genotypes. 5-HT(1A) autoreceptor function was intact in DAT-KO mice. Compared to DAT-WT mice, serotonin levels were increased in DAT-HET and -KO mice in frontal cortex and hippocampus, respectively, and serotonin turnover rates were increased ∼30 % in the striatum of DAT-KO mice. CONCLUSIONS: These findings extend and confirm prior behavioral and biochemical characterization of DAT-KO mice. Hyperactivity, stereotypy, and perseverative behaviors are increased in these mice, with brain-area specific increases in serotonin levels and serotonin turnover, and marked increases in postsynaptic 5-HT(1A) receptor-mediated stereotypic responses. 23169459 Solid-state NMR studies of micelle-templated mesoporous solids. In this tutorial review we intend to give an overview of the potential of NMR spectroscopy, and in particular solid-state NMR, in characterising micelle-templated mesoporous materials. Different topics are covered including the study of formation mechanisms, the characterisation of structures, textures, surfaces and interfaces, functionalisation, dynamic properties and structure-reactivity correlations. Some selected examples illustrate the variety of information provided by this spectroscopy. Particular attention is paid to recent technological and/or methodological developments. 23543426 Comparison of the Therapeutic Effectiveness of Sustained Low-Efficiency Dialysis (SLED) with Continuous Blood Purification (CBP) in Critically Ill Patients. The differences in therapeutic effectiveness between sustained low-efficiency dialysis (SLED) and continuous blood purification (CBP) were investigated. In order to assess the different treatment methods, 56 critically ill patients were divided into two groups, the CBP group and the SLED group. A comparison was made between all the biochemical indicators, in-hospital duration, hemodynamic parameters, acute physiology and chronic health evaluation (APACHE-II), the survival, and the mortality rates. After treatment, the levels of serum creatine kinase isozyme MB (CK-MB), creatine kinase, creatinine, glutamate-oxalacetate transaminase (AST), glutamate-pyruvate transaminase (ALT), APACHE II score on the 1st, 2nd, and 7th day in both the treatment groups were lower than that before the treatment (P < 0.05). There are no statistical differences in in-hospital duration, biochemical indicators, APACHE II score, hemodynamic parameters, the survival rate and the mortality rate between the two groups (P > 0.05). It was concluded that SLED has similar hemodynamic stability with CBP and the two methods have similar treatment effects in critically ill patients. However, we noticed that SLED can be relatively economical and convenient for critically ill patients in clinical practice. 23142777 Toxicity in mice of lectin ebulin f present in dwarf Elderberry (Sambucus ebulus L.). Dwarf elder fruits (Sambucus ebulus) contain the ribosome-inactivating lectin ebulin f structurally related to ricin. We investigated intraperitoneal toxicity of ebulin f in mice and found that it triggers specific derangement of the intestines. Ebulin f was much less toxic than ricin to mice when administered intraperitoneally. The targets were cells of the intestinal crypts, which underwent apoptosis. Small intestine crypts were more sensitive than large intestine crypts. 23175103 Structure sensitivity of CO oxidation on Co3O4: a DFT study. The reaction mechanism of CO oxidation on the Co(3)O(4) (110) and Co(3)O(4) (111) surfaces is investigated by means of spin-polarized density functional theory (DFT) within the GGA+U framework. Adsorption situation and complete reaction cycles for CO oxidation are clarified. The results indicate that 1) the U value can affect the calculated energetic result significantly, not only the absolute adsorption energy but also the trend in adsorption energy; 2) CO can directly react with surface lattice oxygen atoms (O(2f)/O(3f)) to form CO(2) via the Mars-van Krevelen reaction mechanism on both (110)-B and (111)-B; 3) pre-adsorbed molecular O(2) can enhance CO oxidation through the channel in which it directly reacts with molecular CO to form CO(2) [O(2)(a)+CO(g)→CO(2)(g)+O(a)] on (110)-A/(111)-A; 4) CO oxidation is a structure-sensitive reaction, and the activation energy of CO oxidation follows the order of Co(3)O(4) (111)-A(0.78 eV)>Co(3)O(4) (111)-B (0.68 eV)>Co(3)O(4) (110)-A (0.51 eV)>Co(3)O(4) (110)-B (0.41 eV), that is, the (110) surface shows higher reactivity for CO oxidation than the (111) surface; 5) in addition to the O(2f), it was also found that Co(3+) is more active than Co(2+), so both O(2f) and Co(3+) control the catalytic activity of CO oxidation on Co(3)O(4), as opposed to a previous DFT study which concluded that either Co(3+) or O(2f) is the active site. 23454113 Examination of the effect of increasing the number of intra-disulfide amino functional groups on the performance of small molecule cyclic polyamine disulfide vectors. Establishing structure-activity relationships is vital if the efficacy of non-viral vectors is to match that of their viral counter-parts. Recently, we reported on the ability of a series of small molecule, cyclic polyamine disulfides to condense and cage plasmid DNA (pDNA) by a process of thermodynamically controlled template polymerization, leading to a series of corresponding pDNA-polyplex nanoparticles able to mediate high levels of transfection with no associated cytotoxicities. The leading cyclic polyamine disulfide was shown to be the spermine tetra-amine disulfide (TetraN-3,4,3). Herein we report on the significantly more challenging syntheses of cyclic disulfides with longer polyamine motifs. Two new cyclic polyamine disulfides, based on hexa- and octa-amine inserts, were prepared and their transfection efficacies and cytotoxicities compared with our previously reported cyclic tri- and tetra-amine disulfides. The new cyclic hexa- and octa-amine disulfides prove more effective at transfection in vitro, especially of lung epithelial A549 cell line. By contrast, our original cyclic tetra-amine disulfide remains the most efficient agent for the transfection of lung epithelial cells in vivo following intra-nasal administration. Hypothetical mechanistic reasons are presented to explain this outcome. Our data in toto support the concept of shorter cyclic polyamine disulfides as preferred agents for polycation-mediated controlled condensation and functional delivery of pDNA to lung epithelial cells in vivo. 23337568 Anti-obesity effects of 3-hydroxychromone derivative, a novel small-molecule inhibitor of glycogen synthase kinase-3. Glycogen synthase kinase 3 (GSK-3) plays a central role in cellular energy metabolism, and dysregulation of GSK-3 activity is implicated in a variety of metabolic disorders, including obesity, type 2 diabetes, and cancer. Hence, GSK-3 has emerged as an attractive target molecule for the treatment of metabolic disorders. Therefore, this research focused on identification and characterization of a novel small-molecule GSK-3 inhibitor. Compound 1a, a structure based on 3-hydroxychromone bearing isothiazolidine-1,1-dione, was identified from chemical library as a highly potent GSK-3 inhibitor. An in vitro kinase assay utilizing a panel of kinases demonstrated that compound 1a strongly inhibits GSK-3β. The potential effects of compound 1a on the inactivation of GSK-3 were confirmed in human liver HepG2 and human embryonic kidney HEK293 cells. Stabilization of glycogen synthase and β-catenin, which are direct targets of GSK-3, by compound 1a was assessed in comparison with two other GSK-3 inhibitors: LiCl and SB-415286. In mouse 3T3-L1 preadipocytes, compound 1a markedly blocked adipocyte differentiation. Consistently, intraperitoneal administration of compound 1a to diet-induced obese mice significantly ameliorated their key symptoms such as body weight gain, increased adiposity, dyslipidemia, and hepatic steatosis due to the marked reduction of whole-body lipid level. In vitro and in vivo effects were accompanied by upregulation of β-catenin stability and downregulation of the expression of several critical genes related to lipid metabolism. From these results, it can be concluded that compound 1a, a novel small-molecule inhibitor of GSK-3, has potential as a new class of therapeutic agent for obesity treatment. 23127600 Protective effect of cinnamon polyphenols against STZ-diabetic mice fed high-sugar, high-fat diet and its underlying mechanism. This study was designed to investigate the potential effects of 14days' intragastrically given of cinnamon polyphenols (CPS) in treating diabetic mice induced by intraperitoneal injection of streptozotocin (150mgkg(-1)) and fed high-sugar, high-fat diet. The diabetic mice model was successfully established through determining on fasting blood-glucose (FBG) test. As revealed by glucose oxidase (GOD) and radioimmunoassay (RIA), both dimethyldiguanide (DC, 0.6gkg(-1)d(-1)) and CPS (0.3, 0.6, 1.2gkg(-1)d(-1)) treatments significantly resulted in down-regulation of blood glucose and insulin levels in serum, while the levels of oxidative stress markers were markedly lowered through ELISA assay. Meanwhile, the pathological damage in islet with pancreatic beta cells was ameliorated by treatment of CPS at different doses, as shown in HE stain. At the same time, the treatments also caused notable reduction of iNOS, NF-κB expressions showing in Western blot analysis. These findings demonstrate that cinnamon polyphenols can exert the hypoglycemic and hypolipidemic effects through the mechanisms that may be associated with repairing pancreatic beta cells in diabetic mice and improving its anti-oxidative capacity, as well as attenuating cytotoxicity via inhibition of iNOS, NF-κB activation. 23398173 A detailed look at the reaction mechanisms of substituted carbenes with water. Two competitive reaction mechanisms for the gas-phase chemical transformation of singlet chlorocarbene into chloromethanol in the presence of one and two water molecules are examined in detail. An analysis of bond orders and bond order derivatives as well as of properties of bond critical points in the electron densities along the intrinsic reaction coordinates (IRCs for intermediates → transition state (TS) → products) suggests that, from the perspective of bond breaking/formation, both reactions should be considered to be highly nonsynchronous, concerted processes. Both transition states are early, resembling the intermediates, yielding rate constants whose magnitudes are mostly influenced by structural changes and to a lesser degree by bond breaking/formation. For the case of one water molecule, most of the energy in the reactants region of the IRC is used for structural changes, while the transition state region encompasses the majority of electron activity, except for the formation of the C-O bond, which extends well into the products region. In the case of two water molecules, very little electron flux and comparatively less work required for structural changes is noticed in the reactants region, leading to an earlier transition state and therefore to a smaller activation energy and to a larger rate constant. This, together with evidence gathered from other sources, allows us to provide plausible explanations for the observed difference in rate constants. 23347206 Masked mycotoxins are efficiently hydrolyzed by human colonic microbiota releasing their aglycones. Fusarium mycotoxins are secondary metabolites produced by Fusarium spp. in cereals. Among them, deoxynivalenol (DON) and zearalenone (ZEN) are widespread worldwide contaminants of cereal commodities and are ranked as the most important chronic dietary risk factors. Their conjugates, known as masked mycotoxins, have been described but are still not accounted for in risk assessment studies. This study demonstrates for the first time that DON and ZEN are effectively deconjugated by the human colonic microbiota, releasing their toxic aglycones and generating yet unidentified catabolites. For this reason, masked mycotoxins should be considered when evaluating population exposure. 23485652 Stimulation of rat liver branched-chain alpha-keto acid dehydrogenase activity by low doses of bezafibrate. Multienzyme branched-chain alpha-ketoacid dehydrogenase complex (BCKDH) catalyzes the regulatory step of oxidative catabolism of indispensable branched-chain amino acids (BCAA). The activity of the BCKDH complex is regulated by a reversible phosphorylation, end-product inhibition and by changes in the gene expression of BCKDH component enzymes. It has been shown previously that a high dose of bezafibrate (an agent added to rat chow at final concentration of 0.5%) changes mRNA levels of BCKDH-related enzymes and increases dephosphorylation of the complex leading to stimulation of liver BCKDH activity and the enhanced BCAA catabolism. The aim of the present study was to determine an in vivo effect of low, clinically relevant doses of bezafibrate on BCKDH activity in rat liver. Bezafibrate was administrated for 14 days by gastric gavage to Wistar male rats (fed low-protein chow; 8% protein) at one of the following daily doses of 5, 10 and 20mg/kgb.wt. The control group was given the vehicle (0.3% methylcellulose) only. The actual BCKDH and total BCKDH activities were assayed spectrophotometrically before and after incubation with a broad-specificity phosphatase, respectively. The mRNA levels of the selected genes (BCKDH catalytic subunits and regulatory enzymes) were quantified by means of semi-quantitative RT-PCR. Current catalytic activity of BCKDH (described as BCKDH activity state - the proportion of the BCKDH complex in its active dephosphorylated form) increased by 2.1±0.2, 2.3±0.2 and 2.7±0.2 fold (p<0.01). Changes in BCKDH activity did not correspond with changes in mRNA levels of the complex catalytic subunits. Moreover, mRNA levels of regulatory enzymes remained unaltered. Initially bezafibrate caused a transient insignificant reduction in body weight, but it had no effect on the final body weight. The highest dose of bezafibrate induced hepatomegaly. In conclusion, these data indicate that under conditions of dietary protein restriction low, clinically relevant doses of bezafibrate have a similar adverse effect on rat liver BCKDH activity and BCAA degradation rate as the high experimental dose. Up-regulation of liver BCKDH activity by low doses of bezafibrate appears to result mainly from changes in phosphorylation status of the complex (increased dephosphorylation) and is not associated with elevations in mRNA levels of BCKDH enzymatic components. 23353751 Synthesis, characterization, cytotoxicity and antimicrobial studies on bis(N-furfuryl-N-(2-phenylethyl)dithiocarbamato-S,S')zinc(II) and its nitrogen donor adducts. [Zn(fpedtc)2] (1), [Zn(fpedtc)2(py)] (2), [Zn(fpedtc)2(1,10-phen)] (3) and [Zn(fpedtc)2(2,2'-bipy)] (4) (where fpedtc = N-furfuryl-N-(2-phenylethyl)dithiocarbamate, py = pyridine, 1,10-phen = 1,10-phenanthroline and 2,2'-bipy = 2,2'-bipyridine) were synthesized. Characterization of the complexes were achieved by IR and NMR ((1)H and (13)C) spectra and in addition, for 2 and 3, by X-ray crystallography. Single crystal X-ray structural analysis of 2 and 3 showed that complex 2 is almost half way between trigonal bipyramidal and square pyramidal and complex 3 has a distorted octahedral geometry. Zn-N distances in 2 is shorter than that found in a six coordinate complex 3 due to the change in coordination number. These complexes were also screened for in vitro antibacterial and antifungal activities and significant activities have been found. In vitro cytotoxic activity of all the synthesized complexes was evaluated on HeLa cell line. Complex 1 exhibits maximum inhibitory effect at a concentration of 40 μg mL(-1) on HeLa cell line. 23358195 The spectrum of circulating RNA: a window into systems toxicology. Adverse effects caused by therapeutic drugs are a serious and costly health concern. Despite the body's systemic responses to therapeutics, the liver is often the focus of damage and is usually the focus of studies of toxic effects due to its active roles in the metabolism of xenobiotics. It is extremely difficult, however, to assess systemic responses with currently available methods. Comprehensive cataloging of cell-free circulating RNAs using next-generation sequencing technology may open a window to assess drug-associated adverse effects at the systems level. To explore this potential, we conducted an RNA profiling study using the well-characterized acetaminophen overdose mouse model on liver and plasma with microarray and next-generation sequencing platforms, respectively. After drug treatment, the levels of a number of transcripts, both endogenous and exogenous RNAs, showed significant changes in plasma, reflecting not only the classical liver injury induced by acetaminophen overdose but also damage in tissues other than the liver. The changes in exogenous RNAs also reflect alteration on dieting behavior after acetaminophen overdose. Besides reporting an extensive list of circulating RNA-based biomarker candidates, this study illustrates the possibility of using circulating RNAs to assess global effects of therapeutics. This could also lead to a new approach for a more comprehensive assessment of the efficacy and safety of therapeutics. 23531724 Systems approaches in risk assessment. Adverse drug events (ADEs) remain a universal problem in drug development, regulatory review, and clinical practice with a substantial financial burden on the global health-care system. Recent advances in molecular and "omics" technologies, along with online databases and bioinformatics, have enabled a more integrative approach to understanding drug-target (protein) interactions, both desirable and undesirable, within a biological system. This has led to the development of systems approaches to risk assessment in an attempt to complement and improve on contemporary observational and predictive strategies for assessing risk. Although still in an evolutionary phase, systems approaches have the potential to markedly advance our understanding of ADEs and ability to predict them. Systems approaches will also move personalized medicine forward by enabling better identification of individual and subgroup risk factors. 23509929 De novo fragment design: a medicinal chemistry approach to fragment-based lead generation. The use of fragments with low binding affinity for their targets as starting points has received much attention recently. Screening of fragment libraries has been the most common method to find attractive starting points. Herein, we describe a unique, alternative approach to generating fragment leads. A binding model was developed and a set of guidelines were then selected to use this model to design fragments, enabling our discovery of a novel fragment with high LE. 23404504 A pathophysiologic role for epidermal growth factor receptor in pemphigus acantholysis. The pemphigus family of autoimmune bullous disorders is characterized by autoantibody binding to desmoglein 1 and/or 3 (dsg1/dsg3). In this study we show that EGF receptor (EGFR) is activated following pemphigus vulgaris (PV) IgG treatment of primary human keratinocytes and that EGFR activation is downstream of p38 mitogen-activated protein kinase (p38). Inhibition of EGFR blocked PV IgG-triggered dsg3 endocytosis, keratin intermediate filament retraction, and loss of cell-cell adhesion in vitro. Significantly, inhibiting EGFR prevented PV IgG-induced blister formation in the passive transfer mouse model of pemphigus. These data demonstrate cross-talk between dsg3 and EGFR, that this cross-talk is regulated by p38, and that EGFR is a potential therapeutic target for pemphigus. Small-molecule inhibitors and monoclonal antibodies directed against EGFR are currently used to treat several types of solid tumors. This study provides the experimental rationale for investigating the use of EGFR inhibitors in pemphigus. 23262392 Caffeine-induced inhibition of the activity of glutamate transporter type 3 expressed in Xenopus oocytes. Caffeine has been known to trigger seizures, however, the precise mechanism about the proconvulsive effect of caffeine remains unclear. Glutamate transporters play an important role to maintain the homeostasis of glutamate concentration in the brain tissue. Especially, dysfunction of excitatory amino acid transporter type 3 (EAAT3) can lead to seizures. We investigated the effects of caffeine on the activity of EAAT3 and the involvement of protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K). Rat EAAT3 was expressed in Xenopus oocytes by injecting EAAT3 mRNA. l-Glutamate (30μM)-induced inward currents were recorded via the two-electrode voltage clamp method. Caffeine decreased EAAT3 activity in a dose-dependent manner. Caffeine (30μM for 3min) significantly reduced V(max), but did not alter K(m) value of EAAT3 for glutamate. When preincubated oocytes with phorbol-12-myristate-13-acetate (PMA, a PKC activator) were exposed to caffeine, PMA-induced increase in EAAT3 activity was abolished. Two PKC inhibitors (chelerythrine and staurosporine) significantly reduced basal EAAT3 activity. Whereas, there were no significant differences among the PKC inhibitors, caffeine, and PKC inhibitors+caffeine groups. In similarly fashion, wortmannin (a PI3K inhibitor) significantly decreased EAAT3 activity, however no statistical differences were observed among the wortmannin, caffeine, and wortmannin+caffeine groups. Our results demonstrate that caffeine attenuates EAAT3 activity and this reducing effect of caffeine seems to be mediated by PKC and PI3K. 23506559 Binding Specificity and Thermodynamics of Cellulose-Binding Modules from Trichoderma reesei Cel7A and Cel6A. In this work, Family 1 cellulose binding modules CBMCel7A and CBMCel6A were heterologously expressed and purified from Escherichia coli , and the binding properties between these CBMs and cellulose substrates were studied. Cellulose nanowhiskers (CNWs, the crystalline portion of cellulose), microcrystalline cellulose Avicel PH101 (partially crystalline cellulose), and phosphoric acid swollen cellulose (PASC, amorphous cellulose) were used as representative models for cellulose to better understand the binding interactions between the CBMs and different regions of native cellulose. Isothermal titration calorimetry (ITC) was combined with adsorption-isotherm experiment to analyze the thermodynamics of CBM binding to various cellulose substrates. N2 adsorption and static light scattering (SLS) data were used to estimate the accessible surface area of cellulose which was then used for ITC data analysis. A new method of determining the cellulose molarity based on the available surface area for CBM binding was developed, which allows different cellulose substrates to be compared for binding experiments. The ITC results showed that the binding constant (Ka) to crystalline CNWs was ∼10(5) M(-1) for CBMCel7A, while ∼10(6) M(-1) for CBMCel6A, suggesting a higher binding affinity of CBMCel6A to CNWs. For Avicel, lower binding constants for both CBMs were observed, and weak bindings to PASC were characterized, suggesting that the binding between CBMCel7A,Cel6A and cellulose to some extent relates to the crystallinity of cellulose. Additionally, the binding reactions were driven by a favorable enthalpy change, offset partially by an unfavorable entropy change. It is suggested that CBMCel6A preferentially binds to the reducing end of cellulose chain, while CBMCel7A does not show such end binding specificities. Cello-oligosaccharides less than two glucose units did not bind with CBMs, and improved binding affinities were observed for cello-oligosaccharides with longer glucose units. 23612710 Comparative phosphoproteomic analysis of checkpoint recovery identifies new regulators of the DNA damage response. How cells recover from a DNA damage-induced arrest is currently poorly understood. We performed large-scale quantitative phosphoproteomics to identify changes in protein phosphorylation that occurred during recovery from arrest in the G2 phase of the cell cycle caused by DNA damage. We identified 154 proteins that were differentially phosphorylated, and systematic depletion of each of these differentially phosphorylated proteins by small interfering RNA (siRNA) identified at least 10 potential regulators of recovery. Astrin, a protein associated with the mitotic spindle, was among the potential regulators of recovery. We found that astrin controlled the abundance of the cell cycle regulator p53 during DNA damage-induced arrest. Cells in which astrin was depleted had decreased murine double minute 2 (MDM2) abundance and increased p53 at the later stages of the DNA damage response. Astrin was required for continued expression of genes encoding proteins that promote cell cycle progression in arrested cells. Thus, by controlling p53 abundance in cells recovering from DNA damage, astrin maintains the cells in a state competent to resume the cell cycle. 23416131 Antitumor and immunomodulatory activity of a water-soluble low molecular weight polysaccharide from Schisandra chinensis (Turcz.) Baill. A water-soluble low molecular weight polysaccharide (SCPP11) was extracted and purified using DEAE-cellulose and Sephadex G-100 column from Schisandra chinensis (Turcz.) Baill. Its in vivo and in vitro antitumor and immunomodulatory activity were investigated. The results showed that SCPP11 with a molecular weight of 3.4×10(3)Da exhibited indirect cyctotoxic activity against tumor cells in vitro, but could significantly inhibit the growth of Heps cells in vivo at dose of 50mg/kg, and its inhibition rate is higher than that in the positive group. Moreover, SCPP11 could ameliorate the hematological and biochemical parameters to almost normal and no significant changes in organ weight, and could increase the body weight. In addition, SCPP11 (at 50mg/kg) could also increased in thymus indexes as well as IL-2 and TNF-α levels in serum in vivo and significantly enhance the phagocytosis activity and the productions of NO of RAW264.7 in vitro. The results indicated that antitumor properties of SCPP11 might be achieved by improving immune response. It could be explored as a potential adjuvant against cancer used in the health food and pharmaceutical therapy. 23246611 Evaluation of genotoxicity in leukocytes and testis following intra-vasal contraception with RISUG and its reversal by DMSO and NaHCO3 in Wistar albino rats. Evaluation of genotoxicity of RISUG(®) - a vas based contraceptive, was carried out in the present study. Animals were allotted into groups of sham operated control, vas occlusion with RISUG (5-7μl) for 360 days and reversal by DMSO (250-500μl) and 5% NaHCO3 (500μl). Blood samples and testis were collected at 360 days of vas occlusion and 90 days of vas occlusion reversal for comet analysis. Hydrogen peroxide induced samples were used as positive control. Olive moment, tail length and percentage DNA in tail were recorded with minimum variation in all groups for both leukocytes and testis. When compared with positive control the variation was highly significant for both 20μM and 50μM H2O2 (p<0.001). It is concluded that vas occlusion with RISUG at the contraceptive dose regimen is not associated with genotoxicity in leukocytes or the testis of pre- and post-reversal rats. 23345067 Electrocatalytic hydrogenation and deoxygenation of glucose on solid metal electrodes. This Full Paper addresses the electrocatalytic hydrogenation of glucose to sorbitol or 2-deoxysorbitol on solid metal electrodes in neutral media. Combining voltammetry and online product analysis with high-performance liquid chromatography (HPLC), provides both qualitative and quantitative information regarding the reaction products as a function of potential. Three groups of catalysts clearly show affinities toward: (1) hydrogen formation [on early transition metals (Ti, V, Cr, Mn, Zr, Nb, Mo, Hf, Ta, We, and Re) and platinum group metals (Ru, Rh, Ir, and Pt)], (2) sorbitol formation [on late transition metals (Fe, Co, Ni, Cu, Pd, Au, and Ag) and Al (sp metal)], and (3) sorbitol and 2-deoxysorbitol formation [on post-transition metals (In, Sn, Sb, Pb, and Bi), as well as Zn and Cd (d metals)]. Ni shows the lowest overpotential for the onset of sorbitol formation (-0.25 V) whereas Pb generates sorbitol with the highest yield (<0.7 mM cm(-2) ). Different from a smooth Pt electrode, a large-surface-area Pt/C electrode hydrogenates glucose to sorbitol from -0.21 V with relatively low current. This emphasizes the importance of the active sites and the surface area of the catalyst. The mechanism to form 2-deoxysorbitol from glucose and/or fructose is discussed according to the observed reaction products. The yield and selectivity of hydrogenated products are highly sensitive to the chemical nature and state of the catalyst surface. 23157631 Neurobiological basis of dyskinetic effects induced by antipsychotics: the contribution of animal models. Tardive dyskinesia (TD) is a movement disorder characterized by abnormal involuntary facial movements induced by chronic therapy with classical antipsychotic medications. Currently, there is no satisfactory pharmacotherapy for TD, which represents a major limitation to therapy with classical antipsychotics. In order to develop or optimize therapies for TD, and to develop new APDs with lower indices of motor side effects, the pathology underlying TD must first be understood. The use of animal models has been used to further this objective. Here, we review different preparations that have been used to model TD and discuss the contribution of neuroimaging studies conducted in these models. Studies in animal models have lead to several hypotheses of TD pathology, although none has yet emerged as the ultimate underlying cause of this syndrome. We discuss alterations in functional indices, neuron and synapse morphology and changes in specific neurotransmitter systems that have been described in animal models of TD, and outline how these findings have contributed to our understanding of antipsychotic-induced dyskinesias. We conclude that several non-mutually exclusive theories of TD are supported by animal studies, including increases in oxidative stress leading to structural and functional changes in specific neurotransmitter systems. Elucidating the mechanisms underlying TD neuropathology partly through the use of animal models will lead to the development of APDs with superior side effect profiles or more effective therapies for TD. 23411317 Effect of thermal heating on some lignans in flax seeds, sesame seeds and rye. Consumption of lignan rich food is presumed to have positive effects on human health. As numerous foods are consumed mainly in processed form it is important to investigate the changes of the lignan content during processing. To this end, unheated and heated sesame seeds, sesame products, rye grains, rye flour, rye bread and flax seeds were extracted by sonication with ethanol/water (70:30, v:v) or sodium methoxide. The extracts were additionally hydrolysed enzymatically (β-glucuronidase/arylsulphatase, cellulase), the compounds separated on a reversed phase column by gradient elution and detected by UV/ESI-MS in the negative ionisation multiple reaction monitoring mode (MRM). Secoisolariciresinol, lariciresinol, pinoresinol, 7-hydroxymatairesinol, syringaresinol, isolariciresinol, secoisolariciresinol diglycoside, lariciresinol monoglycoside, pinoresinol mono-, di- and triglycoside, sesaminol, sesaminol triglycoside, sesamolinol and sesamolinol diglycoside were identified. Moderate heating at 100°C did not degrade the lignan aglycones and glycosides in dry foods. In contrast, heating was responsible for the better extractability of the lignans. If samples with high moisture content were heated, the degradation of the lignans in sesame seeds and rye was observed already at 100°C. Higher roasting temperatures caused degradation of aglycones and glycosides. Especially at 250°C, lignans were degraded rapidly in sesame seeds and rye but not in flax seeds. 23276150 Display of amino groups on substrate surfaces by simple dip-coating of methacrylate-based polymers and its application to DNA immobilization. The implementation of a reactive functional group onto a material surface is of great importance. Reactive functional groups (e.g., an amino group and a hydroxyl group) are usually hydrophilic, which makes it difficult to display them on a dry polymer surface. We here propose a novel method for displaying amino groups on the surfaces of polymeric substrates through dip-coating of a methacrylate-based copolymer. We synthesized copolymers composed of methyl methacrylate and 2-aminoethyl methacrylate with different protecting groups or ion-complexes on their amino groups, then dip-coated the copolymers onto a poly(methyl methacrylate) (PMMA) substrate. Evaluation using a cleavable fluorescent compound, which was synthesized in the present study to quantify a small amount (pmol/cm(2)) of amino groups on a solid surface, revealed that the protection of amino groups affected their surface segregation in the copolymer coating. p-Toluenesulfonate ion-complex and tert-butoxycarbonyl (Boc) protection of amino groups were found to effectively display amino groups on the surface (more than 70 pmol/cm(2)). The density of amino groups displayed on a surface can be easily controlled by mixing the copolymer and PMMA before dip-coating. Dip-coating of the copolymer with Boc protection on various polymeric substrates also successfully displayed amino groups on their surfaces. Finally, we demonstrated that the amino groups displayed can be utilized for the immobilization of a DNA oligonucleotide on a substrate surface. 23574310 Water-Soluble Polymer Exfoliated Graphene: As Catalyst Support and Sensor. In this paper, we obtained various water-soluble polymer functionalized graphene in dimethyl sulfoxide under ultrasonication. The atomic force microscope analysis and control experiment shows the water-soluble polymer is the crucial part to help solvent molecules separate interlayer. Such polymer/graphene exhibits high conductivity and tunable surface property, as confirmed by the selected area electron diffraction and Raman and electrochemical impedance spectroscopy. As a result, a catalyst based on polyvinyl pyrrolidone (PVP)/graphene shows better methanol oxidation performance than that based on PVP/reduced graphene oxide. By changing to another polymer, poly(4-vinylpyridine)/graphene shows a stable and reversible response to pH, and demonstrates its potential for sensor application. 23536518 Influence of oily vehicles on fetal testis and lipid profile of rats exposed to di-butyl phthalate. It has been hypothesized that oils containing high levels of omega-3 polyunsaturated fatty acids, such as canola and fish oil, could counteract some of the adverse effects induced by phthalates. In the present study, the influence of different oily vehicles on di-butyl phthalate (DBP)-induced testicular toxicity and lipid profile was investigated. Pregnant Wistar rats were treated by oral gavage from gestation days 13 to 20 with DBP (500 mg/kg/day) diluted in three different vehicles: corn, canola or fish oil. Male fetuses were analyzed on gestation day 20. DBP exposure lowered intratesticular testosterone levels and anogenital distance, regardless of the vehicle used. The percentage of seminiferous cords containing multinucleated gonocytes and cord diameter was increased in DBP-exposed groups, compared with vehicle controls, with no difference between the three DBP-exposed groups. Clustering of Leydig cells was seen in all DBP groups. Lipid profile indicated that administration of canola and fish oil can increase the content of omega-3 fatty acids in rat testis. However, content of omega-3 was diminished in DBP-treated groups. Overall, our results indicate that different oily vehicles did not alter fetal rat testicular toxicity induced by a high DBP dose. 23316015 Innovation and originality in the strategies developed by bacteria to get access to iron. Pumping iron: Raymond's group has identified and described the molecular details of an ABC transporter. Together with a binding protein at the cell surface, it is able to extract an unstable form of ferricitrate. 23265539 Shelf-life of infrared dry-roasted almonds. Infrared heating was recently used to develop a more efficient roasting technology than traditional hot air roasting. Therefore, in this study, we evaluated the shelf-life of almonds roasted with three different approaches, namely infrared (IR), sequential infrared and hot air (SIRHA) and regular hot air (HA). Nine medium roasted almond samples produced by the aforementioned heating methods were processed at three different temperatures (130, 140 and 150 °C), packed in paper bags and then stored at 37 °C for three, six or eight months. Shelf-life of the roasted almonds was determined by measuring the changes in colour, peroxide value, moisture content, water activity, volatile components and sensory quality. No significant difference was observed in moisture content and water activity among the almond samples processed with different roasting methods and stored under the same conditions. GC/MS analysis showed that aldehydes, alcohols, and pyrazines were the main volatile components of almonds. Aliphatic aldehydes such as hexanal, (E)-2-octenal, and nonanal were produced as off-odours during storage. Although the overall quality of roasted almonds produced with SIRHA and HA heating was similar during the first three months of storage, their peroxide value and concentration of aliphatic aldehydes differed significantly for different roasting methods and increased significantly in all roasted samples during storage. We postulate that hexanal and nonanal might be better indicators of the shelf life of roasted almonds than the current standard, peroxide value. 23525217 Testicular Growth and Regression Are Not Correlated With Dio2 Expression in a Wild Male Songbird, Sturnus vulgaris, Exposed to Natural Changes in Photoperiod. Timing of seasonal breeding in birds and mammals is regulated by changing the day length and is dependent on the presence of thyroid hormones. A mechanism for thyroid-dependent control of seasonality has been proposed, in which exposure to long day lengths induces rapid local conversion of T4 to its bioactive form, T3, via the up-regulation of the enzyme type 2 iodothyronine deiodinase (Dio2) in the brain, and the down-regulation of Dio3 (which inactivates T3). Such changes were correlated with gonadotropin release and gonadal growth in quail. This mechanism was elucidated in a domesticated species (quail) exposed to unnatural acute changes in day length. Here we investigated the Dio2/Dio3 mechanism in a wild species, the European starling, under naturally changing day length. Although Dio2 expression varied seasonally, Dio3 did not. We found no correlation of Dio2 with photoperiod, seasonal regulation of GnRH, or testicular volume. The observed differences in data from starlings and quail could be a result of phylogeny, genetic drift from founder populations, or differences in reproductive seasonality in addition to or instead of arising from domestication or use of artificially changing photoperiods. Overall, the data indicate that in a wild species exposed to natural changes in day length, the current proposed mechanism for photoperiodic timing is less straightforward than is generally accepted and might not be as universally applicable as previously thought. 23183543 One pot synthesis and biological activity evaluation of novel Schiff bases derived from 2-hydrazinyl-1,3,4-thiadiazole. Considering the structural features of a group of known potent inhibitors of human platelet aggregation containing hydrazone structural backbone, a series of novel hydrazone derivatives of 2-hydrazinyl-1,3,4-thiadiazole were synthesized using a one-pot process and tested for their inhibitory activity against platelet aggregation induced by arachidonic acid and ADP. Among the derivatives, compounds 3l, 3o and 3p exhibited the highest antiplatelet aggregation activity. The derivatives were also screened for their potential antimycobacterial activity and compounds 3g, 3k, 3p and 3q were among the most active compounds. 23539337 Inhibitors of bacterial tubulin target bacterial membranes in vivo. FtsZ is a homolog of eukaryotic tubulin that is widely conserved among bacteria and coordinates the assembly of the cell division machinery. FtsZ plays a central role in cell replication and is a target of interest for antibiotic development. Several FtsZ inhibitors have been reported. We characterized the mechanism of these compounds in bacteria and found that many of them disrupt the localization of membrane-associated proteins, including FtsZ, by reducing the transmembrane potential or perturbing membrane permeability. We tested whether the reported phenotypes of a broad collection of FtsZ inhibitors disrupt the transmembrane potential in Bacillus subtilis strain 168. Using a combination of flow cytometry and microscopy, we found that zantrin Z1, cinnamaldehyde, totarol, sanguinarine, and viriditoxin decreased the B. subtilis transmembrane potential or perturbed membrane permeability, and influenced the localization of the membrane-associated, division protein MinD. These studies demonstrate that small molecules that disrupt membrane function in bacterial cells produce phenotypes that are similar to the inhibition of proteins associated with membranes in vivo, including bacterial cytoskeleton homologs, such as FtsZ. The results provide a new dimension for consideration in the design and testing of inhibitors of bacterial targets that are membrane-associated and provide additional insight into the structural characteristics of antibiotics that disrupt the membrane. 23247545 Gene transcription reflects poor health status of resident European eel chronically exposed to environmental pollutants. Understanding the effects of chronic exposure to pollutants on the genome and transcriptome of diadromous fish populations is crucial for their resilience under combined anthropogenic and environmental selective pressures. The catadromous European eel (Anguilla anguilla L.) has suffered a dramatic decline in recruitment for three decades, necessitating a thorough assessment of the transcriptional effects of environmental pollutants on resident and migrating eels in natural systems. We investigated the relationship between muscular bioaccumulation levels of metals (Hg, Cd, Pb, Cu, Zn, Ni, Cr, As and Se), PCBs and organochlorine pesticides (DDTs), the health status (condition factor and lipid reserves) and the associated transcriptional response in liver and gill tissues for genes involved in metal detoxification (metallothionein, MT) and oxidative metabolism (cytochrome P4501A, CYP1A) of xenobiotic compounds. In total 84 resident eels originating from three Belgian river basins (Scheldt, Meuse and Yzer) were analyzed along with five unpolluted aquaculture samples as control group. There was a large spatial variation in individual contaminant intensity and profile, while tissue pollution levels were strongly and negatively associated with condition indices, suggesting an important impact of pollution on the health of sub-adult resident eels. Gene transcription patterns revealed a complex response mechanism to a cocktail of pollutants, with a high variation at low pollution levels, but strongly down-regulated hepatic and gill gene transcription in highly polluted eels. Resident eels clearly experience a high pollution burden and seem to show a dysfunctional gene transcription regulation of detoxification genes at higher pollutant levels, correlated with low energy reserves and condition. To fully understand the evolutionary implications of pollutants on eel reproductive fitness, analyses of mature migrating eels and the characterization of their transcriptome-wide gene transcription response would be appropriate to unveil the complex responses associated with multiple interacting stressors and the long-term consequences at the entire species level. In the meanwhile, jointly monitoring environmental and tissue pollution levels at a European scale should be initiated, while preserving high quality habitats to increase the recovery chance of European eel in the future. 23252553 Design and exploration of novel boronic acid inhibitors reveals important interactions with a clavulanic acid-resistant sulfhydryl-variable (SHV) β-lactamase. Inhibitor resistant (IR) class A β-lactamases pose a significant threat to many current antibiotic combinations. The K234R substitution in the SHV β-lactamase, from Klebsiella pneumoniae , results in resistance to ampicillin/clavulanate. After site-saturation mutagenesis of Lys-234 in SHV, microbiological and biochemical characterization of the resulting β-lactamases revealed that only -Arg conferred resistance to ampicillin/clavulanate. X-ray crystallography revealed two conformations of Arg-234 and Ser-130 in SHV K234R. The movement of Ser-130 is the principal cause of the observed clavulanate resistance. A panel of boronic acid inhibitors was designed and tested against SHV-1 and SHV K234R. A chiral ampicillin analogue was discovered to have a 2.4 ± 0.2 nM K(i) for SHV K234R; the chiral ampicillin analogue formed a more complex hydrogen-bonding network in SHV K234R vs SHV-1. Consideration of the spatial position of Ser-130 and Lys-234 and this hydrogen-bonding network will be important in the design of novel antibiotics targeting IR β-lactamases. 23416410 Effects of nanoparticles of TiO2 on food depletion and life-history responses of Daphnia magna. The extent to which different forms of nanoparticles of titanium dioxide (nano-TiO2) aggregated with microalgae, decreased food levels and hence impaired growth, reproduction and fitness of Daphnia magna individuals were studied. Treatments included three different types of nano-TiO2 differing in their coating or crystalline structure but of similar primary size (20 nm) plus a micron-sized bulk material, two exposure levels (1, 10mg/l) and two food ration levels of the microalgae Chlorella vulgaris that included a non limiting (1.5 μgC/ml) and a limiting one (0.3 μgC/ml). Effects were assessed using standardized chronic tests and assays that maximized food depletion in the water column under semi-static and re-suspension conditions. Results indicated that the high ion levels in culture medium lead to the aggregation of nanoparticles followed by particle destabilization. Nanoparticle aggregates interacted with the algae cells, forming clusters. Large TiO2-algae agglomerates settled readily dramatically depleting the concentration of available food for D. magna. At limiting food rations food depletion by nanoparticle aggregation had dramatic effects on reproduction and fitness of exposed D. magna at 1mg/l irrespectively of the particle form. At high food rations effects were only observed for one of the nano-TiO2, P-25, at high exposure levels (10 mg/l) under both semi-static and particle re-suspension conditions, which suggest that P-25 effects were mediated by clogging the gut and hence diminishing food acquisition. These results indicate that nano-TiO2 may affect the transfer of energy throughout the planktonic aquatic food webs increasing the settlement of edible particles from the water column. 23231420 Synthesis of polystyrene/polysilsesquioxane core/shell composite particles via emulsion polymerization in the existence of poly(γ-methacryloxypropyl trimethoxysilane) sol. Here, we synthesized the polystyrene/polysilsesquioxane (PS/PSQ) core/shell latex particles via emulsion polymerization, which behave as an amusing morphology. First, the nanosized PSQ particles were prepared by the hydrolysis-condensation reaction of γ-methacryloxypropyl trimethoxysilane (MPTS) in ethanol medium. Subsequently, the as-obtained methacryloxypropylene functionalized PSQ (PMPTS) sol was directly added into the emulsion system of styrene (St) monomer, and PS/PSQ composite particles with core/shell structure were obtained through emulsion polymerization. We found that the structure of the composite particles can be affected by the synthesis parameters such as reaction time, content of PMPTS added in the reaction, amount of coemulsifier, and the pH value of emulsion system, which were systemically explored by transmission electron microscopy (TEM), scanning electron microscope (SEM), Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), and thermogravimetric analysis (TGA) in this work. These results indicate that the PMPTS particles in the size of about 5 nm could first absorb onto the surface of PS latex particles so as to assemble in a strawberry-like morphology. The further coalescence among the PMPTS particles would result in a continuous PMPTS shell around the PS core. Moreover, the hollow PSQ capsules were prepared after extraction of the PS core by organic solvent, further confirming the core/shell structure of the as-synthesized PS/PMPTS particles. Meanwhile, we also explored the application of the PS/PSQ core/shell particles as a new kind of Pickering emulsifier in the emulsion polymerization of St, and composite particles with complex patchy morphologies have been obtained finally under different ratios of styrene monomer to PS/PMPTS colloidal emulsifier. 23174144 Histopathological effects of waterborne copper nanoparticles and copper sulphate on the organs of rainbow trout (Oncorhynchus mykiss). It is unclear whether copper nanoparticles are more toxic than traditional forms of dissolved copper. This study aimed to describe the pathologies in gill, gut, liver, kidney, brain and muscle of juvenile rainbow trout, Oncorhynchus mykiss, exposed in triplicate to either a control (no added Cu), 20 or 100 μg l(-1) of either dissolved Cu (as CuSO(4)) or Cu-NPs (mean primary particle size of 87 ± 27 nm) in a semi-static waterborne exposure regime. Fish were sampled at days 0, 4, and 10 for histology. All treatments caused organ injuries, and the kinds of pathologies observed with Cu-NPs were broadly of the same type as CuSO(4) including: hyperplasia, aneurisms, and necrosis in the secondary lamellae of the gills; swelling of goblet cells, necrosis in the mucosa layer and vacuole formation in the gut; hepatitis-like injury and cells with pyknotic nuclei in the liver; damage to the epithelium of some renal tubules and increased Bowman's space in the kidney. In the brain, some mild changes were observed in the nerve cell bodies in the telencephalon, alteration in the thickness of the mesencephalon layers, and enlargement of blood vessel on the ventral surface of the cerebellum. Changes in the proportional area of muscle fibres were observed in skeletal muscle. Overall the data showed that pathology from CuSO(4) and Cu-NPs were of similar types, but there were some material-type effects in the severity or incidence of injuries with Cu-NPs causing more injury in the intestine, liver and brain than the equivalent concentration of CuSO(4) by the end of the experiment, but in the gill and muscle CuSO(4) caused more pathology. 23428960 The sensitivity of the KeratinoSens(™) assay to evaluate plant extracts: A pilot study. Several tests to assess skin sensitization hazard are in peer-review for pre-validation. These tests, as well as the animal tests they aim to replace, were developed (and validated) for the testing of pure substances. However, in the cosmetic field, active ingredients are often mixtures from natural sources. It is therefore important to understand which tests could be used to evaluate their safety. Here we describe a proof-of-concept study to test whether the KeratinoSens(™) assay is able to detect sensitizing constituents within botanical mixtures. Four extracts were spiked with different doses of the sensitizers citral, cinnamic aldehyde and isoeugenol. The tested extracts were negative in the test whereas they became positive in most cases when spiked with the sensitizers. Analysis of the results from the samples spiked with different doses allowed the determination of the minimal level of sensitizers being detectable. The contribution to sensitization potential of doses of 2% and above of the spiked sensitizers were reliably detected. There were limitations for an extract with high cytotoxicity, in which case detection of the artificially spiked sensitizers proved difficult. This study gives a proof of principle for testing of mixtures in the KeratinoSens(™) assay and indicates how sensitive the assay is to detect minor components with sensitizing potential. 23265893 Heterobivalent dual-target probe for targeting GRP and Y1 receptors on tumor cells. Receptor targeting ligands for imaging and/or therapy of cancer are limited by heterogeneity of receptor expression by tumor cells, both inter-patient and intra-patient. It is often more important for imaging agents to identify local and distant spread of disease than it is to identify a specific receptor presence. Two natural hormone peptide receptors, GRPR and Y1, are specifically interesting because expression of GRPR, Y1 or both is up-regulated in most breast cancers. We describe here the design and development of a new heterobivalent peptide ligand, truncated bombesin (t-BBN)/BVD15-DO3A, for dual-targeting of GRPR and Y1, and validation of its dual binding capability. Such a probe should be useful in imaging cells, tissues and tumors that are GRPR and/or Y1 positive and should target radioisotopes, for example, (68)Ga and/or (177)Lu, to more tumors cells than single GRPR or Y1 targeted probes. A GRP targeting ligand, J-G-Abz4-QWAVGHLM-NH(2) (J-G-Abz4-t-BBN), and an Y1 targeting ligand, INP-K[ε-J-(α-DO3A-ε-DGa)-K]-YRLRY-NH(2)([ε-J-(α-DO3A-ε-DGa)-K]-BVD-15), were synthesized and coupled to produce the heterobivalent ligand, t-BBN/BVD15-DO3A. Competitive displacement binding assays using t-BBN/BVD15-DO3A against (125)I-Tyr(4)-BBN yielded an IC(50) value of 18 ± 0.7 nM for GRPR in T-47D cells, a human breast cancer cell line. A similar assay using t-BBN/BVD15-DO3A against porcine (125)I-NPY showed IC(50) values of 80 ± 11 nM for Y1 receptor in MCF7 cells, another human breast cancer cell line. In conclusion, it is possible to construct a single DO3A chelate containing probe that can target both GRPR and Y1 on human tumor cells. 22564440 Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice. Human studies suggest that a variety of prenatal stressors are related to high risk for cognitive and behavioral abnormalities associated with psychiatric illness (Markham and Koenig, 2011). Recently, a downregulation in the expression of GABAergic genes (i.e., glutamic acid decarboxylase 67 and reelin) associated with DNA methyltransferase (DNMT) overexpression in GABAergic neurons has been regarded as a characteristic phenotypic component of the neuropathology of psychotic disorders (Guidotti et al., 2011). Here, we characterized mice exposed to prenatal restraint stress (PRS) in order to study neurochemical and behavioral abnormalities related to development of schizophrenia in the adult. Offspring born from non-stressed mothers (control mice) showed high levels of DNMT1 and 3a mRNA expression in the frontal cortex at birth, but these levels progressively decreased at post-natal days (PND) 7, 14, and 60. Offspring born from stressed mothers (PRS mice) showed increased levels of DNMTs compared to controls at all time-points studied including at birth and at PND 60. Using GAD67-GFP transgenic mice, we established that, in both control and PRS mice, high levels of DNMT1 and 3a were preferentially expressed in GABAergic neurons of frontal cortex and hippocampus. Importantly, the overexpression of DNMT in GABAergic neurons was associated with a decrease in reelin and GAD67 expression in PRS mice in early and adult life. PRS mice also showed an increased binding of DNMT1 and MeCP2, and an increase in 5-methylcytosine and 5-hydroxymethylcytosine in specific CpG-rich regions of the reelin and GAD67 promoters. Thus, the epigenetic changes in PRS mice are similar to changes observed in the post-mortem brains of psychiatric patients. Behaviorally, adult PRS mice showed hyperactivity and deficits in social interaction, prepulse inhibition, and fear conditioning that were corrected by administration of valproic acid (a histone deacetylase inhibitor) or clozapine (an atypical antipsychotic with DNA-demethylation activity). Taken together, these data show that prenatal stress in mice induces abnormalities in the DNA methylation network and in behaviors indicative of a schizophrenia-like phenotype. Thus, PRS mice may be a valid model for the investigation of new drugs for schizophrenia treatment targeting DNA methylation. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. 23497895 Identification of the odour-active cyclic diketone cis-2,6-dimethyl-1,4-cyclohexanedione in roasted Arabica coffee brew. We investigated odour-active trace compounds in roasted Brazilian Arabica coffee. Aroma dilution extract analysis (AEDA) applied to the volatile oil extracted from roasted coffee brew revealed 34 odour-active compounds. Among these, a pungent-smelling unknown odour-active compound was determined. The volatile oil was fractioned by silica gel column chromatography. Gas chromatography-olfactometry (GC-O) and multidimensional gas chromatography-mass spectrometry (MDGC-MS) of the fraction which contained a significant amount of the target unknown compound revealed the cyclic 1,4-diketone, cis-2,6-dimethyl-1,4-cyclohexanedione, which had a pungent odour, and was thus first identified in roasted coffee. Model experiments revealed that cis-2,6-dimethyl-1,4-cyclohexanedione was formed via thermal degradation of sugars, especially monosaccharides, under alkaline conditions. Further, we demonstrated that 2-hydroxy-3-pentanone and 1-hydroxy-2-propanone, thermal degradation products of monosaccharides, were closely related to the formation of cis-2,6-dimethyl-1,4-cyclohexanedione. 23540838 Antiallodynic and Analgesic Effects of Maslinic Acid, a Pentacyclic Triterpenoid from Olea europaea. The effects of maslinic acid (1), a pentacyclic triterpenoid obtained from Olea europaea, were studied in several tests for nociception in mice. Systemic administration of 1 reduced acetic acid-induced writhing, the inflammatory phase of formalin-induced pain, and capsaicin-induced mechanical allodynia. However, it did not induce motor incoordination in the rotarod test. The topical administration of 1 also reduced the inflammatory phase of the formalin test, indicating that at least some of its effects are mediated peripherally. The present results demonstrate for the first time that maslinic acid induces antinociceptive and antiallodynic effects. 23416143 Narirutin fraction from citrus peels attenuates alcoholic liver disease in mice. This study aimed to demonstrate protective activities of the narirutin fraction from peels of Citrus unshiu against ethanol-induced hepatic damage through an animal study. Citrus narirutin fraction (CNF), contained 75% of narirutin, was obtained by an ultra-sonicated extraction and further purification. ICR mice were divided into four groups; normaldiet control, ethanol control (6.5g ethanol/kg), low-CNF (ethanol+150mg CNF/kg) and high-CNF (ethanol+300mg CNF/kg) groups. Consumption of alcohol for 8weeks induced severe liver damage with increases in prognostic indicators such as aspartate transaminase, alanine transaminase in serum whereas co-administration of CNF suppressed their increases. Excessive accumulations in liver TG and TC in ethanol control group were also suppressed by co-administration of CNF. Co-administration of CNF maintained SOD activity, GSH and malondialdehyde levels close to those of the normal diet group. Chronic consumption of alcohol also stimulated abrupt increases in pro-inflammatory cytokines such as nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α and interleukin (IL)-1β in liver otherwise co-administration of CNF effectively suppressed production of these cytokines dose-dependently. These results indicate that co-administration of CNF with alcohol can alleviate alcohol induced liver damage through preventing lipid formation, protecting antioxidant system and suppressing productions of pro-inflammatory cytokines. 23591997 Focal adhesion kinase regulates collagen I-induced airway smooth muscle phenotype switching. Increased extracellular matrix (ECM) deposition and airway smooth muscle (ASM) mass are major contributors to airway remodeling in asthma. Recently, we have demonstrated that the ECM protein collagen I, which is increased surrounding asthmatic ASM, induces a proliferative, hypocontractile ASM phenotype. Little is known, however, on the signaling pathways involved. Using bovine tracheal smooth muscle, we investigated the role of focal adhesion kinase (FAK) and downstream signaling pathways in collagen I-induced ASM phenotype modulation. Phosphorylation of FAK was increased during adhesion to both uncoated and collagen I-coated culture dishes, without differences between these matrices. No differences in cellular adhesion were found either. Inhibition of FAK activity by overexpression of the FAK deletion mutants FAT (focal adhesion targeting domain) and FRNK (FAK-related non-kinase) attenuated adhesion. After attachment, FAK phosphorylation was time-dependently increased in cells cultured on collagen I, whereas no activation was found on an uncoated plastic matrix. In addition, collagen I time- and concentration-dependently increased cell proliferation, which was fully inhibited by FAT and FRNK. Similarly, the specific pharmacological FAK inhibitor PF-573,228 as well as specific inhibitors of p38 MAPK and Src also fully inhibited collagen I-induced proliferation, whereas partial inhibition was observed by inhibition of PI3-kinase and MEK. The inhibition of cell proliferation by these inhibitors was associated with attenuation of the collagen I-induced hypocontractility. Collectively, the results indicate that induction of a proliferative, hypocontractile ASM phenotype by collagen I is mediated by FAK and downstream signaling pathways. 23337257 Differential contribution of mesoaccumbens and mesohabenular dopamine to intracranial self-stimulation. The contribution of mesoaccumbens dopamine transmission to intracranial self-stimulation is well-established. However, although the nucleus accumbens comprises two main subregions, the shell and the core, little is known of the contribution of each to this behaviour. Our first aim was to study the effects of d-amphetamine infusions into the shell and core in order to understand their relative importance to reward and operant responding. Our second aim was to examine the contribution of a lesser studied group of dopamine neurons, those within the mesohabenular pathway, to intracranial self-stimulation. Male Sprague-Dawley rats were implanted with bilateral cannulae in the nucleus accumbens shell, core or in the lateral habenula and a monopolar stimulation electrode in the posterior mesencephalon, a brain site that is sensitive to changes in dopamine transmission. Using curve-shift scaling, we measured the reward- and performance-enhancing effects of intra-accumbens (1-20 μg) and intra-habenular (10-40 μg) infusions of d-amphetamine or vehicle. Within the nucleus accumbens, the use of multiple doses and long test sessions allowed us to observe an interaction between drug effect and infusion site. We show, for the first time, differences in the minimal doses necessary to enhance rewarding effectiveness and operant responding, in the magnitude of these enhancements as well as in their duration. Conversely, regardless of dose, intra-habenular d-amphetamine did not alter rewarding effectiveness or operant rate, highlighting the differential contribution of mesoaccumbens and mesohabenular dopamine pathways to intracranial self-stimulation. 23545109 Virtual medicinal chemistry: In silico pre-docking functional group transformation for discovery of novel inhibitors of botulinum toxin serotype A light chain. A novel method for applying high-throughput docking to challenging metalloenzyme targets is described. The method utilizes information-based virtual transformation of library carboxylates to hydroxamic acids prior to docking, followed by compound acquisition, one-pot (two steps) chemical synthesis and in vitro screening. In two experiments targeting the botulinum neurotoxin serotype A metalloprotease light chain, hit rates of 32% and 18% were observed. 23276278 Spatial variation of available electronic excitations within individual quantum dots. Quantum dots (QDs) allow for manipulation of the position and energy levels of electrons at sub-10 nm length scales through control of material chemistry, size, and shape. It is known from optical studies that the bandgap of semiconductor QDs increases as their size decreases due to the narrowing of the quantum confinement potential. The mechanism of quantum confinement also indicates that the localized properties within individual QDs should depend on their shape in addition to their size, but direct observations of this effect have proven challenging due to the limited spatial resolution of measurement techniques at this scale and the ability to remove contributions from the surroundings. Here we present experimental evidence of spatial variations in the lowest available electron transition energy within a series of single electrically isolated QDs due to a dome-shaped geometry, measured using electron energy-loss spectroscopy in a (scanning) transmission electron microscope [(S)TEM-EELS]. We observe a consistent increase in the energy onset of electronic excitations from the lateral center of the dot toward the edges, which we attribute purely to shape. This trend is in qualitative agreement with a simple quantum simulation of the local density of states in a dome-shaped QD. 23262161 Water soluble polymer films for intravascular drug delivery of antithrombotic biomolecules. Over the past 10years, the number of percutaneous coronary intervention (PCI) procedures performed in the United States has increased by 33%; however, restenosis, which inhibits complete functional recovery of the vessel wall, remains a complication of this procedure. To traverse the complications associated with PCI, the investigation of therapeutic delivery has become an integral topic in modern research. One such therapeutic, a mimic of the proteoglycan decorin, termed DS-SILY, can mask exposed collagen and thereby effectively decrease platelet activation, has recently been developed by our lab. Drawing inspiration from coating technologies developed by the pharmaceutical industry, a fast-dissolving polymer film has been developed to deliver active therapeutic agents from a balloon catheter during PCI. This research investigates the release of DS-SILY from fast-dissolving polymer films composed of poly(vinyl alcohol) (PVA) and poly(ethylene glycol) (PEG). Thin, uniform polymer films were produced via spin coating technique. The dissolution speed of the polymer films was found to be dependent on the concentration of polymer solution, where at least 65% of the films were shown to dissolve into nanometer sized polymer fragments within 2min. DS-SILY, up to 6.26μg/cm(2), was loaded into the films and functional release of the mimic was demonstrated by its successful binding to collagen upon release. Furthermore, DS-SILY released from films resulted in increased platelet inhibition. These results indicate that use of fast-dissolving polymer films allow for the successful release of biomolecules and further investigation of their use for localized drug delivery during PCI procedures is warranted. 23394555 Thymidylate kinase: an old topic brings new perspectives. Thymidylate kinase (TMPK) is a key enzyme for pyrimidine synthesis that catalyzes the phosphorylation of thymidine 5'-monophosphate (dTMP) in the presence of ATP and Mg(2+) to form thymidine 5'-diphosphate (dTDP), which is then converted to thymidine 5'-triphosphate (dTTP) by nucleoside-diphosphate kinase (NDK). TMPK has an important function in cell proliferation and its enzyme kinetics and related structures have been determined in various organisms. TMPK is well recognized as a potential drug target, with the most notable function being in the activation of anti-HIV nucleoside prodrugs. Recent studies have shown that TMPK is a validated target for antibiotic development against gram-positive bacterium of Staphylococcus aureus. In addition, inhibition of human TMPK increases the potential of anticancer agent doxorubicin toward colon cancer cells regardless of p53 status. Following the rapid expanding knowledge on TMPKs and the rising interests in TMPKs as a drug target, in this review we try to describe current research on TMPKs in various organisms of eukaryotes, prokaryotes and viruses and to provide information for designing new potential inhibitors against TMPKs. 23239458 FRET-capture: a sensitive method for the detection of dynamic protein interactions. Caught in the act: The FRET-Capture approach exploits a bound solvatochromic fluorophore, 4-N,N-dimethylamino-1,8-naphthalimide, as a FRET donor in both inter- and intramolecular energy transfer. A unique feature of this method is the additional level of signal selectivity as the FRET signal is only turned on when the donor is specifically bound to the protein of interest, eliminating high background and false positive signals. 22722026 How inhibition influences seizure propagation. Inhibitory neuron behaviour is of fundamental importance to epileptic pathophysiology. When inhibition is compromised, such as by GABAergic blockade (Curtis et al., 1970; Connors, 1984; Traub and Miles, 1991) or by shifts in GABAergic reversal potential (Huberfeld et al., 2007), epileptiform discharges occur far more readily. Other studies have shown enhanced inhibition in vivo in the surrounding cortical territories associated with both focal pathological and physiological activity (Prince and Wilder, 1967; Dichter and Spencer, 1969a,b; Goldensohn and Salazar, 1986; Traub and Miles, 1991; Liang and Jones, 1997; Liang et al., 1998; Schwartz and Bonhoeffer, 2001). This gave rise to the concept of an "inhibitory restraint". This concept can explain the often confusing anatomical reorganizations seen in chronically epileptic brains (Sloviter, 1987; Cossart et al., 2001), indicating which changes might be pro-epileptic, and which oppose the epileptic state. It also may explain key electrophysiological features of epileptic seizures. Here we describe current knowledge about the restraint, gleaned mainly from acute pharmacological experiments in animals, both in vivo and in vitro, and speculate how this may alter our understanding of human seizure activity in clinical practice. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'. 23498899 Gender and body mass index modify the effect of increasing amounts of caffeinated coffee on postprandial glucose and insulin concentrations; a randomized, controlled, clinical trial. OBJECTIVE: To examine the effects of different coffee amounts on blood glucose and insulin concentrations of healthy volunteers, and to assess potential effect modification by sex and body mass index category. MATERIALS/METHODS: Thirty-three volunteers [16♀/17♂, 16 normal-weight and 17 overweight/obese, 27.3±7.2 (19-44) y] took part in this randomized, crossover study. Ιn the morning of each experimental day volunteers received a standardized meal along with 200mL of water or instant coffee containing either 3 or 6mg of caffeine/kg body weight. Blood samples were obtained and analyzed for glucose and insulin concentrations in the fasting state, immediately after meal/drink consumption and at standard time points for the next 3h thereafter. RESULTS: Coffee delayed the rise of insulin in response to the standardized meal and the fall of glucose concentrations from its maximum levels in the entire study sample. Glucose incremental area under the curve (IAUC) was significantly different between interventions (P=.009) with both coffee amounts inducing a greater area compared to water. Secondary, subgroup analysis at the nominal level showed that this might be more evident among females (PIAUC=.05) and overweight/obese participants (PIAUC=.03). Furthermore, coffee, mainly the 6mg dose, could be lowering insulin concentrations the first 30min after its consumption compared to water in men and overweight/obese participants. CONCLUSIONS: Coffee exerts an acute effect on postprandial glucose and insulin concentrations. This effect may be modified by sex and overweight/obese status. Future research is necessary to elucidate underlying mechanisms. 23512787 Neuroprotective Effects of Puerarin on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson's Disease Model in Mice. Puerarin, an active component of Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep is well-known for its anti-oxidative and neuroprotective activities. Although anti-Parkinson's disease activity of puerarin was reported in both of in vivo and in vitro model, detailed mechanisms are not clarified. In this study, we addressed that puerarin attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits, dopaminergic neuronal degeneration and dopamine depletion. Puerarin administration enhanced glutathione (GSH) activity, glial cell line-derived neurotrophic factor (GDNF) expression and PI3K/Akt pathway activation, which might ameliorate MPTP injection-induced progressive elevation of reactive oxygen species (ROS) formation in mice. In addition to the effect on ROS, puerarin ameliorated MPTP-reduced lysosome-associated membrane protein type 2A (Lamp 2A) expression. Taken together, our data demonstrate that puerarin attenuates MPTP-induced dopaminergic neuronal degeneration via modulating GDNF expression, PI3K/Akt pathway and GSH activation, which subsequently ameliorate MPTP-induced ROS formation and decrease of Lamp 2A expression. Copyright © 2013 John Wiley & Sons, Ltd. 23406949 Evaluation of oxidant-antioxidant status in oral toxicity of fish oil methyl esters and diesel fuel in male rats. This study was conducted to compare the effects of oral toxicity induced by fish oil biodiesel and diesel fuel. Diesel and fish oil biodiesel were administered by oral gavage to rats. For this purpose, 35 rats were divided into five groups. Sunflower oil of 250 mg kg(-1) was administered to the rats in the control group by oral gavage. The rats in the D250 and D500 groups were administered by oral gavage 250 mg kg(-1) and 500 mg kg(-1) of diesel fuel dissolved in equal amounts of sunflower oil, respectively. The rats in the F250 and F500 groups were administered by oral gavage 250 mg kg(-1) and 500 mg kg(-1) of fish oil biodiesel dissolved in equal amounts of sunflower oil, respectively. At the end of the study, malondialdehyde (MDA) and reduced glutathione (GSH) levels were measured in the whole blood; catalase (CAT) activity level was measured in erythrocytes; and nitrite (NO(2)) and nitrate (NO(3)) levels were measured in the serum. It was observed that the whole blood MDA levels of the diesel groups were considerably different from those in the control and fish oil biodiesel groups (p < 0.001). GSH levels in the control group were observed to be considerably different from those in all other groups (p < 0.001). Serum NO(3) concentrations in the diesel groups were found to be considerably different from those in the control and biodiesel groups. Serum NO(2) concentrations in one of the diesel groups were significantly different from those in the control and biodiesel groups (p < 0.01 and p < 0.05, respectively). The CAT activity of the control group was observed to be different from that in the other groups. According to these results, both fish oil biodiesel and diesel fuel are thought to cause lipid peroxidation. It was observed that fish oil biodiesel does not induce as much oxidative damage as does the diesel fuel. It is suggested that fish oil biodiesel should be preferred as an alternative to the diesel. 23578614 Novel water-resistant UV-activated oxygen indicator for intelligent food packaging. For the first time, alginate polymer has been applied to prevent dyes from leaching out of colorimetric oxygen indicator films, which enable people to notice the presence of oxygen in the package in an economic and simple manner. The dye-based oxygen indicator film suffers from dye leaching upon contact with water. In this work, UV-activated visual oxygen indicator films were fabricated using thionine, glycerol, P25 TiO2, and zein as a redox dye, a sacrificial electron donor, UV-absorbing semiconducting photocatalyst, and an encapsulation polymer, respectively. When this zein-coated film was immersed in water for 24h, the dye leakage was as high as 80.80±0.45%. However, introduction of alginate (1.25%) as the coating polymer considerably diminished the dye leaching to only 5.80±0.06%. This is because the ion-binding ability of alginate could prevent the cation dye from leaching into water. This novel water-resistant UV-activated oxygen indicator was also successfully photo-bleached and regained colour fast in the presence of oxygen. 23570997 Pyranocycloartobiloxanthone A, a novel gastroprotective compound from Artocarpus obtusus Jarret, against ethanol-induced acute gastric ulcer in vivo. Pyranocycloartobiloxanthone A (PA), a xanthone derived from the Artocarpus obtusus Jarret, belongs to the Moraceae family which is native to the tropical forest of Malaysia. In this study, the efficacy of PA as a gastroprotective compound was examined against ethanol-induced ulcer model in rats. The rats were pretreated with PA and subsequently exposed to acute gastric lesions induced by absolute ethanol. The ulcer index, gastric juice acidity, mucus content, histological analysis, glutathione (GSH) levels, malondialdehyde level (MDA), nitric oxide (NO) and non-protein sulfhydryl group (NP-SH) contents were evaluated in vivo. The activities of PA as anti-Helicobacter pylori, cyclooxygenase-2 (COX-2) inhibitor and free radical scavenger were also investigated in vitro. The results showed that the oral administration of PA protects gastric mucosa from ethanol-induced gastric lesions. PA pretreatment significantly (p<0.05) restored the depleted GSH, NP-SH and NO levels in the gastric homogenate. Moreover, PA significantly (p<0.05) reduced the elevated MDA level due to ethanol administration. The gastroprotective effect of PA was associated with an over expression of HSP70 and suppression of Bax proteins in the ulcerated tissue. In addition, PA exhibited a potent FRAP value and significant COX-2 inhibition. It also showed a significant minimum inhibitory concentration (MIC) against H. pylori bacterium. The efficacy of PA was accomplished safely without the presence of any toxicological parameters. The results of the present study indicate that the gastroprotective effect of PA might contribute to the antioxidant and anti-inflammatory properties as well as the anti-apoptotic mechanism and antibacterial action against Helicobacter pylori. 22999711 Prospects of personalized medicine in cardiovascular diseases. Cardiovascular diseases remain the dominant cause of death worldwide. In the last decades, the remarkable advances in human genetic and genomic research, plus the now common use of genome-wide association studies, have led to the identification of numerous genetic variants associated with specific cardiovascular traits and diseases. Although the clinical applications are limited because the genetic risk of common cardiovascular disease is still unexplained, and the mechanisms of action of the genetic factor(s) are not known, these research advances have, in turn, widely opened the concept of personalized medicine. In this paper, the status and prospects of personalized medicine for cardiovascular disease will be presented. This will be followed by a discussion of issues regarding the implementation of personalized medicine. 23470692 Investigation of the effects of chest physiotherapy in different positions on the heart and the respiratory system after coronary artery bypass surgery. This trial was conducted to investigate the effect of chest physiotherapy in different positions on the heart and the respiratory system after coronary artery bypass surgery. Patients are divided into two groups of 30 patients each in the study. To the patients in the first group (30 patients), percussion-vibration was performed in the 45° supine position, while slightly laterally lying and endotracheal aspiration was performed in the supine position. To the patients in the second group (30 patients), percussion-vibration was performed in the 0° supine position, while slightly laterally lying and endotracheal aspiration was performed in the supine position. The procedures are repeated two times for all patients and their means were taken. The pre- and postapplication values of patients were measured from central venous and arterial catheters and the values of patient monitors were recorded. Comparison of the two groups in terms of respiratory values did not reveal a significant difference, but chest physiotherapy with the head of the bed at 0° was determined to improve cardiac functions. Evaluation of the groups in terms of pre- and postphysiotherapy applications showed a significant increase in mixed venous oxygen saturation in both groups. Chest physiotherapy with the head of the bed elevated to 45° may be recommended in patients who carry a risk of pulmonary complications and who are candidates for chest physiotherapy at an early stage. 22854821 A rosette cooling cell: more effective container for solubilization of single-walled carbon nanotubes under probe-type ultrasonic irradiation. Probe-type ultrasonication has been employed for surfactant-aided solubilization, or individualization, of single-walled carbon nanotubes (SWNTs). The resulting solution can be used not only for spectroscopic analyses such as absorption, photoluminescence, and circular dichroism, but also for separation by density gradient ultracentrifugation, dielectrophoresis, chromatography, and polymer wrapping. In spite of its importance, the sonochemical processing of SWNTs has not been considered seriously. Herein, we report on a more efficient cooling cell for probe-type ultrasonication. As compared with a conventional cylindrical cell, the concentration of the SWNTs solubilized in water was found to be almost double in a rosette cooling cell after ultracentrifugation. The efficiency of a rosette cell can be attributed to the higher efficiency in circulation and cooling of the SWNT dispersion as well as enhancement of the cavitation process. 23417974 Plasmonic-enhanced organic photovoltaics: breaking the 10% efficiency barrier. Recent advances in molecular organic photovoltaics (OPVs) have shown 10% power conversion efficiency (PCE) for single-junction cells, which put them in direct competition with PVs based on amorphous silicon. Incorporation of plasmonic nanostructures for light trapping in these thin-film devices offers an attractive solution to realize higher-efficiency OPVs with PCE≫10%. This article reviews recent progress on plasmonic-enhanced OPV devices using metallic nanoparticles, and one-dimensional (1D) and two-dimensional (2D) patterned periodic nanostructures. We discuss the benefits of using various plasmonic nanostructures for broad-band, polarization-insensitive and angle-independent absorption enhancement, and their integration with one or two electrode(s) of an OPV device. 23069372 Anti-tumor necrosis factor treatment in cherubism--clinical, radiological and histological findings in two children. Cherubism is a rare and disfiguring genetic disorder with excessive bone resorption and multilocular lesions in the mandible and/or maxilla. The disease-causing gain-of-function mutations in the SH3-binding protein 2 (SH3BP2) gene result in increased myeloid cell responses to macrophage colony stimulating factor and RANK ligand, formation of hyperactive osteoclasts (giant cells), and hyper-reactive macrophages that produce excessive amounts of the inflammatory cytokine tumor necrosis factor α (TNF-α). Recent findings in the cherubism mouse model suggest that TNF-α plays a major role in disease pathogenesis and that removal of TNF-α prevents development of the bone phenotype. We treated two children with cherubism with the TNF-α antagonist adalimumab for approximately 2.5 years and collected extensive clinical, radiological and histological follow-up data during the treatment. Histologically the treatment resulted in a significant reduction in the number of multinucleated giant cells and TNF-α staining positivity in both patients. As evaluated by computed tomography and magnetic resonance imaging, the lesions in Patient 1 showed either moderate enlargement (mandibular symphysis) or remained stable (mandibular rami and body, the maxilla). In Patient 2, the lesions in mandibular symphysis showed enlargement during the first 8 months of treatment, and thereafter the lesions remained unchanged. Bone formation and resorption markers remained unaffected. The treatment was well tolerated. Based on our findings, TNF-α antagonist may decrease the formation of pathogenic giant cells, but does not result in lesion regression or prevent lesion expansion in active cherubism. TNF-α modulator treatment thus does not appear to provide sufficient amelioration for patients suffering from cherubism. 23393213 Detectable subclinical myocardial necrosis is associated with cardiovascular risk in stable patients with diabetes. OBJECTIVE To investigate the relationship between different degrees of subclinical myocardial necrosis, glycemic control, and long-term adverse clinical outcomes within a stable patient population with diabetes mellitus. RESEARCH DESIGN AND METHODS We examined 1,275 stable patients with diabetes mellitus undergoing elective diagnostic coronary angiography with cardiac troponin I (cTnI) levels below the diagnostic cut-off for defining myocardial infarction (MI) (<0.03 ng/mL). The relationship of subclinical myocardial necrosis (cTnI 0.009-0.029 ng/mL) with incident major adverse cardiovascular events (MACE; defined as any death, MI, or stroke) over 3 years of follow-up was examined. RESULTS Subclinical myocardial necrosis was observed in 22% of patients. A strong association was observed between the magnitude of subclinical myocardial necrosis and risk of 3-year incident MACE (hazard ratio, 1.98; 95% confidence interval, 1.48-2.65; P < 0.001) and remained statistically significant even after adjustment for traditional risk factors, high-sensitivity C-reactive protein, and creatinine clearance. Only a weak correlation was observed between the presence of subclinical myocardial necrosis and either glycemic control (r = 0.06; P = 0.044 for hemoglobin A1c versus cTnI) or insulin resistance (r = 0.04; P = 0.094 for glucose-to-insulin ratio versus cTnI). CONCLUSIONS The presence of detectable subclinical myocardial necrosis in stable patients with diabetes mellitus is associated with heightened long-term risk for MACE, independent of traditional risk factors and glycemic control. 23566060 Flaxseed-derived enterolactone is inversely associated with tumor cell proliferation in men with localized prostate cancer. Abstract Enterolactone and enterodiol, mammalian lignans derived from dietary sources such as flaxseed, sesame seeds, kale, broccoli, and apricots, may impede tumor proliferation by inhibiting activation of nuclear factor kappa B (NFκB) and vascular endothelial growth factor (VEGF). We examined the associations between urinary enterolactone and enterodiol with prostatic tumor expression of NFκB, VEGF, and Ki67 among 147 patients with prostate cancer who participated in a presurgical trial of flaxseed supplementation (30 g/day) for ∼30 days. Urinary enterolignans and tissue biomarkers were determined by high-performance liquid chromatography and immunohistochemistry, respectively. After supplementation, we observed significant correlations between intakes of plant lignan and urinary concentrations of total enterolignans (ρ=0.677, P<.0001), enterolactone (ρ=0.676, P<.0001), and enterodiol (ρ=0.628, P<.0001). Importantly, we observed that total urinary enterolignans and enterolactone were significantly and inversely correlated with Ki67 in the tumor tissue (ρ=-0.217, P=.011, and ρ=-0.230, P=.007, respectively), and a near-significant inverse association was observed for enterodiol (ρ=-0.159, P=.064). An inverse association was observed between enterolactone and VEGF (ρ=-0.143, P=.141), although this did not reach statistical significance. We did not observe an association between enterolignans and NFκB. In conclusion, flaxseed-derived enterolignans may hinder cancer cell proliferation via VEGF-associated pathways. 23218718 Synthesis, antimalarial activity and cytotoxic potential of new monocarbonyl analogues of curcumin. A series of novel monocarbonyl analogues of curcumin have been designed, synthesized and tested for their activity against Molt4, HeLa, PC3, DU145 and KB cancer cell lines. Six of the analogues showed potent cytotoxicity towards these cell lines with IC(50) values below 1 μM, which is better than doxorubicin, a US FDA approved drug. Several analogues were also found to be active against both CQ-resistant (W2 clone) and CQ-sensitive (D6) strains of Plasmodium falciparum in an in-vitro antimalarial screening. This level of activity warrants further investigation of the compounds for development as anticancer and antimalarial agents. 23271001 Curcumin reverses glomerular hemodynamic alterations and oxidant stress in 5/6 nephrectomized rats. The administration of curcumin before and throughout the study attenuates oxidant stress and glomerular hemodynamic alterations induced by 5/6 nephrectomy (5/6NX). The purpose of this work was to study if curcumin is able to reverse established glomerular hemodynamic alterations (e.g. hyperfiltration and glomerular hypertension) and oxidant stress in rats with 5/6NX. Curcumin (120 mg/kg) was given to rats with established renal injury (30 days after surgery) and continued for 30 days (days 31-60 of the study). All rats were studied on day 60 after surgery. Curcumin was able (a) to reverse 5/6NX-induced glomerular hypertension and hyperfiltration, (b) to induce cell proliferation and nuclear translocation of Nrf2 and (c) to reverse 5/6NX-induced oxidant stress and decrease in antioxidant enzymes. These beneficial effects of curcumin were associated with the ability of this antioxidant to reverse renal structural alterations, proteinuria, hypertension, interstitial fibrosis, fibrotic glomeruli, tubular atrophy and mesangial expansion. It has been shown for the first time that curcumin is able to reverse established oxidants stress glomerular hypertension and hyperfiltration in rats with 5/6NX. These novel findings may play a key role in the attenuation of proteinuria and progression of renal damage in rats with 5/6NX. These data suggest that curcumin may be useful to reverse established hemodynamic alterations and renal injury in patients with chronic renal failure. 22850767 Powering the future of molecular artificial photosynthesis with light-harvesting metallosupramolecular dye assemblies. Chemical ingenuity will play a significant role in solving the greatest challenge currently facing society: providing clean and carbon neutral energy for all of humanity. Molecular artificial photosynthesis is an emerging technology based on principles learned from Nature where individual components perform the essential light-harvesting, charge-separation, and water splitting functions to store solar energy in the form of chemical bonds. This tutorial review focuses specifically on the application of metallosupramolecular self-assembly strategies to interface solar fuel catalysts with photosensitizers and construct light-harvesting antennae capable of achieving panchromatic absorption and directional energy concentration. 23194408 Arcuate nucleus homeostatic systems are not altered immediately prior to the scheduled consumption of large, binge-type meals of palatable solid or liquid diet in rats and Mice. Meal feeding is a critical issue in the over-consumption of calories leading to human obesity. To investigate the mechanisms involved in the regulation of meal feeding in rodents, we studied a scheduled feeding regime that induces substantial food intake over short periods of time. Male Sprague-Dawley rats and C57BL6 mice were fed one of four palatable diets [45% fat pellet, 60% fat pellet or standard pellet supplemented with Ensure (EN; Abbott Laboratories, Maidenhead, UK) or 12.5% sucrose (SUC)] either ad lib. or with daily 2-h scheduled access and standard pellet available for 22 h. Energy balance gene expression in the hypothalamic arcuate nucleus (ARC) and nucleus accumbens (NAcc) reward gene expression were assessed by in situ hybridisation. Rats fed ad lib. on 45% or 60% fat diet were heavier and fatter than controls, and had reduced neuropeptide Y (NPY) gene expression in the ARC. Mice fed ad lib. on any of the palatable diets were heavier, fatter and had higher blood leptin than controls, and had reduced NPY and increased cocaine- and-amphetamine-regulated transcript mRNA in the ARC. Schedule-fed rats and mice quickly adapted their feeding behaviour to 2-h access on palatable food. Three schedule-fed groups binged: the percentage of daily calories consumed in 2 h on 45% fat diet, 60% fat diet or EN, respectively, was 55%, 63% and 49% in rats, and 86%, 86% and 45% in mice. However, changed feeding behaviour was not reflected in an induction of orexigenic neuropeptide or suppression of anorexigenic neuropeptide gene expression in the ARC, in the 2-h period prior to scheduled feeding. The mechanisms underlying large meal/binge-type eating may be regulated by nonhomeostatic processes involving other genes in the hypothalamus or other brain areas. However, assessment of opioid and dopamine receptor gene expression in the NAcc did not reveal evidence of the involvement of these genes in driving large meals, at least at the investigated time point. 23583436 Simonols A and B, two novel sesqui-neolignans from the fruits of Illicium simonsii. Two new sesqui-neolignans with novel conjugation way, simonol A (1), featuring a unique motif of a 5,5-dihydro-pyran with a hemiketal carbon, while simonol B (2) possessing two dihydronfuran rings in the same direction, were isolated from the ethanol extract of the fruits of Illicium simonii. Their structures were elucidated by spectroscopic methods including 1D and 2D NMR, HRESIMS, and calculation of electronic circular dichroism (ECD) using density functional theory (DFT). The two isolates were evaluated for their inhibitory activities against the growth of four lines of human cancer cells (NCI-H460, SMMC-7721, MCF-7, BGC-823): 1 showed strong activities comparable to 5-Fluorouracil, and 2 to a less content. In addition, plausible biosynthetic routes for the two compounds were also proposed. 23483707 Liquid-Crystalline Blue Phase Laser with Widely Tunable Wavelength. A lasing peak shift of more than 100 nm is realized due to the large shift of a photonic bandgap of a liquid-crystalline blue phase. 23494861 Anti-biofilm Effects of Honey Against Wound Pathogens Proteus mirabilis and Enterobacter cloacae. Biofilm growth and its persistence within wounds have recently been suggested as contributing factors to impaired healing. The goal of this study was to investigate the anti-biofilm effects of several honey samples of different botanical origin, including manuka honey against Proteus mirabilis and Enterobacter cloacae wound isolates. Quantification of biofilm formation was carried out using a microtiter plate assay. All honeys at a sub-inhibitory concentration of 10% (w/v) significantly reduced the biofilm development of both isolates. Similarly, at a concentration of 50% (w/v), each of the honeys caused significant partial detachment of Pr. mirabilis biofilm after 24 h. On the other hand, no honey was able to significantly detach Ent. cloacae biofilm. In addition, treatment of Ent. cloacae and Pr. mirabilis biofilms with all honeys resulted in a significant decrease in colony-forming units per well values in a range of 0.35-1.16 and 1.2-7.5 log units, respectively. Of the tested honeys, manuka honey possessed the most potent anti-biofilm properties. Furthermore, methylglyoxal, an antibacterial compound of manuka honey, was shown to be responsible for killing biofilm-embedded wound bacteria. These findings suggest that manuka honey could be used as a potential therapy for the treatment of wounds containing Pr. mirabilis or Ent. cloacae. Copyright © 2013 John Wiley & Sons, Ltd. 23499718 PEGylation of interferon α2 improves lymphatic exposure after subcutaneous and intravenous administration and improves antitumour efficacy against lymphatic breast cancer metastases. The efficacy of protein-based therapeutics with indications in the treatment of lymphatic diseases is expected to be improved by enhancing lymphatic disposition. This study was therefore aimed at examining whether PEGylation can usefully be applied to improve the lymphatic uptake of interferon α2 and whether this ultimately translates into improved therapeutic efficacy against lymph-resident cancer. The lymphatic pharmacokinetics of interferon α2b (IFN, 19kDa) and PEGylated interferon α2b (IFN-PEG12, 31kDa) or α2a (IFN-PEG40, 60kDa) was examined in thoracic lymph duct cannulated rats. IFN was poorly absorbed from the SC injection site (Fabs 36%) and showed little uptake into lymph after SC or IV administration (≤1%). In contrast, IFN-PEG12 was efficiently absorbed from the SC injection site (Fabs 82%) and approximately 20% and 8% of the injected dose was recovered in thoracic lymph over 30h after SC or IV administration respectively. IFN-PEG40, however, was incompletely absorbed from the SC injection site (Fabs 23%) and showed similar lymphatic access after SC administration to IFN-PEG12 (21%). The recovery of IFN-PEG40 in thoracic lymph after IV administration, however, was significantly greater (29%) when compared to IV IFN-PEG12. The anti-tumour efficacy of interferon against axillary metastases of a highly lymph-metastatic variant of human breast MDA-MB-231 carcinoma was significantly increased by SC administration of lymph-targeted IFN-PEG12 when compared to the administration of IFN on the ipsilateral side to the axillary metastasis. Optimal PEGylation may therefore represent a viable approach to improving the lymphatic disposition and efficacy of therapeutic proteins against lymphatic diseases. 23411231 A multi-residue method for the determination of 124 pesticides in rice by modified QuEChERS extraction and gas chromatography-tandem mass spectrometry. A modified QuEChERS method for simultaneous determination of 124 pesticide residues in rice was established and validated. The rice samples were initially extracted with acetonitrile (MeCN), and the targeted pesticides were purified following the dispersive solid phase extraction (d-SPE) cleanup method and detected by gas chromatography-tandem mass spectrometry (GC-MS/MS). The efficiency of citrate-buffered and unbuffered method in liquid extraction procedure was compared; the amount of primary secondary amine (PSA) was optimised. In the method validation, correlation coefficients (r(2)) were higher than 0.990 with the linear ranging from 10 to 200 μg kg(-1). At the fortification levels of 20-200 μg kg(-1), average recoveries ranged from 70% to 122.7% with the RSD <20%. 23454207 Three-month subchronic intramuscular toxicity study of rotigotine-loaded microspheres in SD rats. Continuous dopaminergic stimulation (CDS) has been an important strategy of drug development for the treatment of Parkinson's disease (PD). Rotigotine is a non-ergoline D3/D2/D1 dopamine agonist for treating PD. As a new treatment option for CDS, rotigotine-loaded microspheres (RoMS), a long-acting sustained-release microspheres for injection with poly(lactide-co-glycolide) as drug carrier, are now being evaluated in clinical trial. In this study, subchronic toxicity of RoMS in SD rats has been characterized via intramuscular administration with RoMS (0-240mg/kg/week) on a consecutive weekly dosing schedule for 3months followed by 1-month recovery period. The No Observed Adverse Effect Level (NOAEL) was 45mg/kg/week. One male at 240mg/kg died from an extensive pulmonary embolism. The major toxicological effects were associated with the dopamine agonist-related pharmacodynamic properties of rotigotine (e.g. hyperactivity and stereotype, enlarged ovary, sporadic gastric mucous membrane lesions, decreased body weight, food consumption and prolactin, and increased mononuclear cell, neutrophil granulocyte, aspartate aminotransferase and alanine aminotransferase) and foreign body removal reaction induced by poly(lactide-co-glycolide) and carboxymethycellulose sodium. At the end of recovery period, all findings had recovered to a normal level or to a certain degree except foreign body reaction at injection sites. RoMS has exhibited high safety on SD rats. 23537702 Systematic evaluation of 640 FDA drugs for their effect on CD4(+)Foxp3(+) regulatory T cells using a novel cell-based high throughput screening assay. Regulatory T cells (Treg), which play a pivotal role in maintaining immune homeostasis by suppressing the proliferation of effector T cells, have great therapeutic potential for autoimmune diseases and transplantation. However, progress on their clinical application has been hampered by the lack of high throughput screening (HTS) strategies for the systematic and rapid evaluation of existing drugs and the identification of novel drug candidates. In this report, we present an innovative in vitro HTS assay using CD4(+) T cells from Foxp3-GFP transgenic mice that specifically express the GFP signal in Foxp3(+) Treg cells detectable by FACS analysis in a high throughput manner. Systematic evaluation of 640 FDA-approved drugs revealed that 70 drugs increased the number of Treg cells with suppression function only in the presence of TGFβ, 75 drugs increased Treg numbers even in the absence of TGFβ, and 32 drugs increased Treg numbers synergistically with TGFβ. The identified Treg-promoting drugs include those previously known to induce Treg (rapamycin and retinoic acid), statins, glucocorticoids and drugs in many other categories. Furthermore, Treg cells cultured with the identified drugs possess surface and intracellular markers characteristic of natural Treg cells and possess suppressive function. These results suggest that this Treg HTS assay can be used to screen compound libraries to identify novel chemical entities for Treg-based immune therapies. 23297842 Mechanism of solid state amorphization of glucose upon milling. Crystalline α-glucose is known to amorphize upon milling at -15 °C while it remains structurally invariant upon milling at room temperature. We have taken advantage of this behavior to compare the microstructural evolutions of the material in both conditions in order to identify the essential microstructural features which drive the amorphization process upon milling. The investigations have been performed by differential scanning calorimetry and by powder X-ray diffraction. The results indicate that two different amorphization mechanisms occur upon milling: an amorphization at the surface of crystallites due to the mechanical shocks and a spontaneous amorphization of the crystallites as they reach a critical size, which is close to 200 Å in the particular case of α-glucose. 23409864 Compound and compositions as TGR5 agonists: WO2012082947. The patent application WO2012082947 claims novel compounds as agonists of a plasma membrane-bound bile acid receptor TGR5. By activating TGR5, the agonists improve glycemic control and enhance energy expenditure. The basic generic claim of the patent covers pyrazole derivatives, different permutations on the core pyrazole ring are covered in the subsidiary claims. The claimed compounds are human TGR5 agonists having potency in the nM range. 22352409 Simultaneous determination of glucoraphanin and sulforaphane in Brassica oleracea seeds by high-performance liquid chromatography with evaporative light-scattering detector. In this article, a novel and efficient analysis method is described to simultaneously and quantitatively determine glucoraphanin and its major degradation product sulforaphane by reversed-phase high-performance liquid chromatography (HPLC) coupled with an evaporative light-scattering detector (ELSD). This method was validated according to the regulatory guidelines with respect to precision, accuracy and linearity. The HPLC-ELSD method was successfully used to assess the contents of glucoraphanin and sulforaphane in varieties of Brassica oleracea seeds. The developed analytical method not only avoids the underestimation of total glucoraphanin content, but also provides a reduction in analysis time and good efficiency and sensitivity compared to with conventional HPLC methods. 23303575 Halogen bonding: an interim discussion. Halogen bonding is a noncovalent interaction that is receiving rapidly increasing attention because of its significance in biological systems and its importance in the design of new materials in a variety of areas, for example, electronics, nonlinear optical activity, and pharmaceuticals. The interactions can be understood in terms of electrostatics/polarization and dispersion; they involve a region of positive electrostatic potential on a covalently bonded halogen and a negative site, such as the lone pair of a Lewis base. The positive potential, labeled a σ hole, is on the extension of the covalent bond to the halogen, which accounts for the characteristic near-linearity of halogen bonding. In many instances, the lateral sides of the halogen have negative electrostatic potentials, allowing it to also interact favorably with positive sites. In this discussion, after looking at some of the experimental observations of halogen bonding, we address the origins of σ holes, the factors that govern the magnitudes of their electrostatic potentials, and the properties of the resulting complexes with negative sites. The relationship of halogen and hydrogen bonding is examined. We also point out that σ-hole interactions are not limited to halogens, but can also involve covalently bonded atoms of Groups IV-VI. Examples of applications in biological/medicinal chemistry and in crystal engineering are mentioned, taking note that halogen bonding can be "tuned" to fit various requirements, that is, strength of interaction, steric factors, and so forth. 23206276 Multifunctional Fe3O4@Ag/SiO2/Au core-shell microspheres as a novel SERS-activity label via long-range plasmon coupling. Noble metallic nanostructures exhibit a phenomenon known as surface-enhanced Raman scattering (SERS) in which the Raman scattering cross sections are dramatically enhanced for the molecules adsorbed thereon. Due to their wide accessible potential range in aqueous solutions and the high biocompatibility, Au supports are preferred for spectro-electrochemical investigations. However, the optical range in SERS spectroscopy is restricted to excitation lines above 600 nm, which is shorter than the Ag supports. In addition, these SERS-activity materials are not easy to separate and reused. Herein, the present article reports the novel multifunctional Fe(3)O(4)@Ag/SiO(2)/Au core-shell microspheres that display long-range plasmon transfer of Ag to Au leading to enhanced Raman scattering. The well-designed microspheres have high magnetization and uniform sphere size. As a result, Fe(3)O(4)@Ag/SiO(2)/Au microspheres have the best enhancement effect in the Raman active research by using Rhodamine-b (RdB) as a probe molecule. The enhancement factor is estimated to be 2.2 × 10(4) for RdB from the long-range plasmon transfer of Ag to Au, corresponding to an attenuation of the enhancement by a factor of only 0.672 × 10(4) compared to RdB adsorbed directly on the Fe(3)O(4)@Ag microspheres. RdB can be detected down to 10(-9) M even without the resonance SERS effect. The unique nanostructure makes the microspheres novel stable and a high-enhancement effect for Raman detection. 23265476 Rapid detecting total acid content and classifying different types of vinegar based on near infrared spectroscopy and least-squares support vector machine. More than 3.2 million litres of vinegar is consumed every day in China. There are many types of vinegar in China. How to control the quality of vinegar is problem. Near infrared spectroscopy (NIR) transmission technique was applied to achieve this purpose. Ninety-five vinegar samples from 14 origins covering 11 provinces in China were collected. They were classified into mature vinegar, aromatic vinegar, rice vinegar, fruit vinegar, and white vinegar. Fruit vinegar and white vinegar were separated from the other traditional categories in the two-dimension principal component space of NIR after principle component analysis (PCA). Least-squares support vector machine (LS-SVM) as the pattern recognition was firstly applied to identify mature vinegar, aromatic vinegar, rice vinegar in this study. The top two principal components (PCs) were extracted as the input of LS-SVM classifiers by principal component analysis (PCA). The best experimental results were obtained using the radial basis function (RBF) LS-SVM classifier with σ=0.8. The accuracies of identification were more than 85% for three traditional vinegar categories. Compared with the back propagation artificial neural network (BP-ANN) approach, LS-SVM algorithm showed its excellent generalisation for identification results. As total acid content (TAC) is highly connecting with the quality of vinegar, NIR was used to prediction the TAC of samples. LS-SVM was applied to building the TAC prediction model based on spectral transmission rate. Compared with partial least-square (PLS) model, LS-SVM model gave better precision and accuracy in predicting TAC. The determination coefficient for prediction (R(p)) of the LS-SVM model was 0.919 and root mean square error for prediction (RMSEP) was 0.3226. This work demonstrated that near infrared spectroscopy technique coupled with LS-SVM could be used as a quality control method for vinegar. 23122166 Reduction of lipid accumulation in white adipose tissues by Cassia tora (Leguminosae) seed extract is associated with AMPK activation. Natural herbal medications may be one answer to the worldwide epidemic of obesity. This study examines the effects of Cassia seed ethanol extract (CSEE) upon lipid accumulation in white adipose tissue (WAT). CSEE exhibited a significant concentration-dependent decrease in the intracellular accumulation of trigycerides in 3T3-L1 adipocytes. After being fed a high-fat diet (HFD) for 2 weeks, rats were fed CSEE (100, 200 or 300 mg/kg) once daily for 8 weeks. CSEE caused dose-related reductions in body weight gain (as well as plasma lipid levels and epididymal WAT sizes in HFD-fed rats). CSEE enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and its primary downstream targeting enzyme, acetyl-CoA carboxylase, up-regulated gene expression of carnitine palmitoyl transferase 1, and down-regulated sterol regulatory element-binding protein 1 and fatty acid synthase protein levels in epididymal WAT of HFD-fed rats. CSEE could attenuate lipid accumulation in WAT via AMPK signaling pathway activation. 23174031 The relationship between carotid intima-media thickness and endogenous androgens in young women with polycystic ovary syndrome in Taiwan. Polycystic ovary syndrome (PCOS) is a common and complex female endocrinopathy that is associated with multiple vascular risk factors. Our objective was to investigate the relationship between carotid intima-media thickness (CIMT) and endogenous androgens in young Taiwanese-Chinese women with PCOS. We measured CIMT with B-mode ultrasound in 42 young PCOS patients and 43 controls. Atherosclerosis-associated profiles and endocrinological parameters were also measured. The results showed that although Taiwanese-Chinese PCOS patients tend to possess more risk factors for atherosclerosis than controls, there was no evidence to support that they have a greater CIMT at this age. Furthermore, androstenedione appears to be inversely associated with CIMT. 23589408 Amelioration of hepatotoxicity induced by aflatoxin using citrus fruit oil in broilers (Gallus domesticus). This study was conducted to evaluate the efficacy of citrus fruit oil (CFO; 2.5 g kg(-)(1)) on the clinicopathological changes in broilers fed with diets containing 1 ppm of aflatoxin (AF). A total of 160 Ross 308 broiler chicks of 1-day-old were procured from a commercial hatchery, divided randomly on 7th day of age into four groups with two replicates of 20 birds each and fed with basal diet (group A), basal diet + CFO (group B), basal diet + AF (group C) and CFO + basal diet + AF (group D). The gross and histopathological changes in the liver, kidney, spleen, thymus and bursa of Fabricius were investigated and relative organ weights were calculated. Slight to moderate hydropic degeneration, fatty change with the formation of cyst in some cases, periportal necrosis, infiltration of heterophils and mononuclear cells and bile duct hyperplasia were observed in chicks fed with 1 ppm AF-containing diet. The addition of CFO to AF-containing diet moderately decreased the magnitude and severity of lesions (hydropic degeneration and bile duct hyperplasia) in the liver. The supplementation of CFO to the basal diet did not produce any adverse effects in birds. 23514442 Stereoselective Potencies and Relative Toxicities of γ-Coniceine and N-Methylconiine Enantiomers. γ-Coniceine, coniine, and N-methylconiine are toxic alkaloids present in poison hemlock (Conium maculatum). We previously reported the comparison of the relative potencies of (+)- and (-)-coniine enantiomers. In this study, we synthesized γ-coniceine and the enantiomers of N-methylconiine and determined the biological activity of γ-coniceine and each of the N-methylconiine enantiomers in vitro and in vivo. The relative potencies of these piperidine alkaloids on cells expressing human fetal muscle-type nicotinic acetylcholine receptors had the rank order of γ-coniceine > (-)-N-methylconiine > (±)-N-methylconiine > (+)-N-methylconiine. The relative lethalities of γ-coniceine and (-)-, (±)-, and (+)-N-methylconiine in vivo using a mouse bioassay were 4.4, 16.1, 17.8, and 19.2 mg/kg, respectively. The results from this study suggest γ-coniceine is a more potent agonist than the enantiomers of N-methylconiine and that there is a stereoselective difference in the in vitro potencies of the enantiomers of N-methylconiine that correlates with the relative toxicities of the enantiomers in vivo. 23432090 Correlation between structural, spectroscopic, and reactivity properties within a series of structurally analogous metastable manganese(III)-alkylperoxo complexes. Manganese-peroxos are proposed as key intermediates in a number of important biochemical and synthetic transformations. Our understanding of the structural, spectroscopic, and reactivity properties of these metastable species is limited, however, and correlations between these properties have yet to be established experimentally. Herein we report the crystallographic structures of a series of structurally related metastable Mn(III)-OOR compounds, and examine their spectroscopic and reactivity properties. The four reported Mn(III)-OOR compounds extend the number of known end-on Mn(III)-(η(1)-peroxos) to six. The ligand backbone is shown to alter the metal-ligand distances and modulate the electronic properties key to bonding and activation of the peroxo. The mechanism of thermal decay of these metastable species is examined via variable-temperature kinetics. Strong correlations between structural (O-O and Mn···N(py,quin) distances), spectroscopic (E(πv*(O-O) → Mn CT band), ν(O-O)), and kinetic (ΔH(‡) and ΔS(‡)) parameters for these complexes provide compelling evidence for rate-limiting O-O bond cleavage. Products identified in the final reaction mixtures of Mn(III)-OOR decay are consistent with homolytic O-O bond scission. The N-heterocyclic amines and ligand backbone (Et vs Pr) are found to modulate structural and reactivity properties, and O-O bond activation is shown, both experimentally and theoretically, to track with metal ion Lewis acidity. The peroxo O-O bond is shown to gradually become more activated as the N-heterocyclic amines move closer to the metal ion causing a decrease in π-donation from the peroxo πv*(O-O) orbital. The reported work represents one of very few examples of experimentally verified relationships between structure and function. 23419872 Modulation of mitochondrial glutathione status and cellular energetics in primary cultures of proximal tubular cells from remnant kidney of uninephrectomized rats. Compensatory renal hypertrophy following reduction in renal mass leads to a hypermetabolic state and increases in basal mitochondrial oxidative stress and susceptibility to several nephrotoxicants. Previous studies provide conflicting data on whether renal mitochondria after reduction in renal mass undergo proliferation or hypertrophy or both. In the present study, our goal was to determine whether mitochondria of hypertrophied kidney undergo hypertrophy or proliferation after uninephrectomy using the uninephrectomized (NPX) rat model. Renal proximal tubular (PT) cells from NPX rats exhibited increased mitochondrial density, membrane potential and protein but no significant difference in mitochondrial DNA, as compared to PT cells from control rats. Our previous studies showed that overexpression of two mitochondrial anion transporters, the dicarboxylate (DIC, Slc25a10) and oxoglutarate (OGC, Slc25a11) carriers, in NRK-52E cells resulted in increased mitochondrial uptake of glutathione (GSH) and protection from chemically induced apoptosis. In the present study, we overexpressed DIC- and OGC-cDNA plasmids to assess their function in renal PT cells after compensatory renal hypertrophy. PT cells from NPX rats that were first preincubated with GSH were protected from cytotoxicity due to the mitochondrial inhibitor antimycin A by overexpression of either of the two mitochondrial GSH transporters. Our present results provide further evidence that compensatory renal hypertrophy is associated primarily with mitochondrial hypertrophy and hyperpolarization and that manipulation of mitochondrial GSH transporters in PT cells of hypertrophied kidney can alter susceptibility to chemically induced injury under appropriate conditions and may be a suitable therapeutic approach. 23127508 Nano- and microscaled particles for drug targeting to inflamed intestinal mucosa: a first in vivo study in human patients. Most of the drugs used in the treatment of inflammatory bowel disease (IBD) become systemically bioavailable and potentially bear strong adverse effects. Targeting the inflamed areas of the intestine and keeping the drug localised at its site of action can reduce adverse effects. In animal studies, luminal uptake into inflamed mucosal areas has been shown to be size dependent. We investigated the potential of nano- and microparticle uptake into the rectal mucosa of human IBD patients. Fluorescently labelled placebo nanoparticles (NP) 250nm in size and microparticles (MP) 3.0μm in size were prepared. 2h after rectal application to patients with Crohn's disease (CD) or ulcerative colitis (UC), confocal laser endomicroscopy was performed to visualise the particles in inflamed mucosal areas. In biopsies, ex vivo mucosal transport processes were investigated in miniaturised Ussing chambers. We examined 33 patients with IBD (19 patients with CD, 14 patients with UC) and 6 healthy controls. A significantly enhanced accumulation of MP in ulcerous lesions was observed (covered area=1.28% (range 0.83%-3.45%) vs. 0% in controls; p=0.011), while NP were visible only in traces on mucosal surfaces of all patients. The Ussing chamber experiments suggest persorption of particles through cellular voids; statistical significance was only reached for NP. Drug-containing particles may have great potential to more specifically target intestinal lesions to maximise therapeutic efficacy and minimise potential side effects. Nanoparticles may not be required for local drug delivery to intestinal lesions in humans, thereby minimising the risk of unintended translocation into the blood system. 23090793 Adsorption of multimeric T cell antigens on carbon nanotubes: effect on protein structure and antigen-specific T cell stimulation. Antigen-specific activation of cytotoxic T cells can be enhanced up to three-fold more than soluble controls when using functionalized bundled carbon nanotube substrates ((b) CNTs). To overcome the denaturing effects of direct adsorption on (b) CNTs, a simple but robust method is demonstrated to stabilize the T cell stimulus on carbon nanotube substrates through non-covalent attachment of the linker neutravidin. 22732440 Selective GABA(A) α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment. A condition of excess activity in the hippocampal formation is observed in the aging brain and in conditions that confer additional risk during aging for Alzheimer's disease. Compounds that act as positive allosteric modulators at GABA(A) α5 receptors might be useful in targeting this condition because GABA(A) α5 receptors mediate tonic inhibition of principal neurons in the affected network. While agents to improve cognitive function in the past focused on inverse agonists, which are negative allosteric modulators at GABA(A) α5 receptors, research supporting that approach used only young animals and predated current evidence for excessive hippocampal activity in age-related conditions of cognitive impairment. Here, we used two compounds, Compound 44 [6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one] and Compound 6 [methyl 3,5-diphenylpyridazine-4-carboxylate], with functional activity as potentiators of γ-aminobutyric acid at GABA(A) α5 receptors, to test their ability to improve hippocampal-dependent memory in aged rats with identified cognitive impairment. Improvement was obtained in aged rats across protocols differing in motivational and performance demands and across varying retention intervals. Significant memory improvement occurred after either intracereboventricular infusion with Compound 44 (100 μg) in a water maze task or systemic administration with Compound 6 (3 mg/kg) in a radial arm maze task. Furthermore, systemic administration improved behavioral performance at dosing shown to provide drug exposure in the brain and in vivo receptor occupancy in the hippocampus. These data suggest a novel approach to improve neural network function in clinical conditions of excess hippocampal activity. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23463664 Nanoparticle Accumulation in Angiogenic Tissues: Towards Predictable Pharmacokinetics. Nanoparticles are increasingly used in medical applications such as drug delivery, imaging, and biodiagnostics, particularly for cancer. The design of nanoparticles for tumor delivery has been largely empirical, owing to a lack of quantitative data on angiogenic tissue sequestration. Using fluorescence correlation spectroscopy, the deposition rate constants of nanoparticles into angiogenic blood vessel tissue are determined. It is shown that deposition is dependent on surface charge. Moreover, the size dependency strongly suggests that nanoparticles are taken up by a passive mechanism that depends largely on geometry. These findings imply that it is possible to tune nanoparticle pharmacokinetics simply by adjusting nanoparticle size. 23639363 Canna indica L. attenuates high-glucose- and lipopolysaccharide-induced inflammatory mediators in monocyte/macrophage. ETHNOPHARMACOLOGICAL RELEVANCE: Canna indica L. (CI) has been widely used as a folklore medicine in tropical and subtropical areas with beneficial effects in numerous diseases, including infection, rheumatism, hepatitis, and it has also been identified as an antioxidant. MATERIALS AND METHODS: The present study aimed to investigate the effect of CI ethanolic extract (CIE) on productions of nitric oxide (NO), prostaglandin E2 (PGE2), and interleukin-1β (IL-1β) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. In addition, the effects of CIE in high glucose (HG)-induced U937 monocytes on mRNA expressions of IL-8 and monocyte chemoattractant protein-1 (MCP-1), and regulation of mitogen-activated protein kinase (MAPK) pathways were also identified. RESULTS: CIE was found to inhibit the production of inflammatory mediators including NO, IL-1β, and PGE2 from LPS-induced RAW 264.7 macrophages. The increases in HG-induced mRNA expressions of IL-8 and MCP-1 were also significantly inhibited by CIE. Stimulation of HG in U937 monocytes resulted in activation of p38 MAPK, ERK1/2, and JNK. However, CIE treatment significantly decreased phosphorylation of p38 MAPK, ERK1/2, and JNK. CONCLUSION: The present study demonstrated that CIE suppressed the LPS-induced inflammatory mediator production and also inhibited HG-induced inflammatory mediator expression by the regulation of MAPK pathway. 23454655 Human exposure to mycotoxins and their masked forms through cereal-based foods in Belgium. In the present study, a quantitative dietary exposure assessment of mycotoxins and their masked forms was conducted on a national representative sample of the Belgian population using the contamination data of cereal-based foods. Cereal-based food products (n=174) were analysed for the occurrence of deoxynivalenol, 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol, zearalenone, α-zearalenol, β-zearalenol, T-2-toxin, HT-2-toxin, and their respective masked forms, including, deoxynivalenol-3-glucoside, zearalenone-4-glucoside, α-zearalenol-4-glucoside, β-zearalenol-4-glucoside and zearalenone-4-sulfate. Fibre-enriched bread, bran-enriched bread, breakfast cereals, popcorn and oatmeal were collected in Belgian supermarkets according to a structured sampling plan and analysed during the period from April 2010 to October 2011. The habitual intake of these food groups was estimated from a national representative food intake survey. According to a probabilistic exposure analysis, the mean (and P95) mycotoxin intake for the sum of the deoxynivalenol-equivalents, zearalenone-equivalents, and the sum of HT-2-and T-2-toxin for all cereal-based foods was 0.1162 (0.4047, P95), 0.0447 (0.1568, P95) and 0.0258 (0.0924, P95) μg kg(-1)body weight day(-1), respectively. These values were below the tolerable daily intake (TDI) levels for deoxynivalenol, zearalenone and the sum of T-2 and HT-2 toxin (1.0, 0.25 and 0.1 μg kg(-1)body weight day(-1), respectively). The absolute level exceeding the TDI for all cereal-based foods was calculated, and recorded 0.85%, 2.75% and 4.11% of the Belgian population, respectively. 23246797 New formulation approaches to improve solubility and drug release from fixed dose combinations: Case examples pioglitazone/glimepiride and ezetimibe/simvastatin. Low aqueous solubility is often a limiting aspect to the bioavailability of poorly soluble, but highly permeable drugs (class II compounds according to the Biopharmaceutics Classification System - BCS) administered in single drug products or as fixed dose combinations. The aim of the present series of experiments was to improve the solubility and dissolution of two fixed dose combination formulations (FDC), each consisting of two BCS class II drugs. The first FDC contained a weak acid (glimepiride) and a weak base (pioglitazone), while the second FDC contained two compounds (simvastatin and ezetimibe) that are essentially non-ionised over the physiological pH range. The formulation approaches used were as follows: (a) an inclusion complex with hydroxypropyl-β-cyclodextrin (HP-β-CD), (b) a solid dispersion with Soluplus®, a new highly water soluble polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol graft copolymer and (c) a ternary inclusion complex with both HP-β-CD and Soluplus®. Solid state analysis was performed for the pure drugs, and all formulations using powder X-ray diffraction (PXRD). The in vitro performance of the different formulation approaches, as gauged by solubility and dissolution experiments, was compared with that of the marketed products containing the respective fixed dose combinations, Tandemact® 30mg/4mg tablets and Inegy® 10mg/40mg tablets. The FDCs of the pure drugs and the marketed products showed very poor (and especially for pioglitazone, strongly pH-dependent) dissolution. By contrast, all binary and ternary inclusion complexes showed enhanced release for both drugs in the FDC. The ternary inclusion complex generated synergistic improvement in solubility and dissolution results for both FDCs. For example, in pH conditions of the fasted small intestine after a test duration of 240min, we observed 100% dissolution of both drugs from the ternary pioglitazone/glimepiride (30mg/4mg) complex formulation, whereas from the marketed formulation less than 5% pioglitazone, and only 25% glimepiride dissolved. Using the same conditions, 60% ezetimibe and 85% simvastatin dissolved from the ternary ezetimibe/simvastatin (10mg/40mg) complex formulation, whereas with less than 5% ezetimibe and 10% simvastatin dissolved after 240min, the marketed FDC formulation showed poor dissolution. Based on the results of the present study, the bioavailability of both drugs in the fixed dose combination is likely to be increased after oral administration of the new formulations, especially when the fixed dose combination is formulated as a ternary complex consisting of HP-β-CD and Soluplus®. 23111886 The protective effect of recombinant human erythropoietin against cisplatin-induced renal and hepatic dysfunctions in Wistar rats. Cisplatin (Cisp) is one of the most effective chemotherapeutic drugs. However, the dose of Cisp is greatly limited by its toxicity. Recombinant human erythropoietin (rhEPO), a hormone that regulates hematopoiesis, has also been shown to exert tissue-protective effects. The purpose of this study was to explore the protective effect of rhEPO against Cisp-induced renal and liver dysfunctions. Adult male Wistar rats were divided into six groups of six each: control, rhEPO-alone group, Cisp-alone group and rhEPO + Cisp group (pretreatment, cotreatment and posttreatment conditions). Our results showed that Cisp-induced a marked renal and liver failure characterized by a significant decrease in body weight, organ weight and organ ratio and a significant increase in creatinine, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, G-glutamyl transferase, alkaline phosphatase, bilirubin conjugated and bilirubin total levels in serum. Histological examination showed that Cisp caused kidney alterations. rhEPO treatments restored body weight, organ weight and organ ratio as well as serum biochemical parameters changed due to Cisp exposure. 23278314 Evolving therapeutic targets in ischemic stroke: a concise review. Ischemic stroke is the leading cause of mortality and morbidity worldwide for which the assemblage of therapeutic interventions has remained outstandingly limited. Several new insights into the causes of neuronal death during ischemic event have led to the identification of some important novel targets for intervention. This article highlights some of the promising protein targets, which are in the validation process and have the potential to get translated into viable neurotherapeutics against ischemic stroke. 23147639 Anti-proliferative effect of (19Z)-halichondramide, a novel marine macrolide isolated from the sponge Chondrosia corticata, is associated with G2/M cell cycle arrest and suppression of mTOR signaling in human lung cancer cells. Five oxazole-containing macrolides isolated from the marine sponge Chondrosia corticata were evaluated for their anti-proliferative activity in a panel of human solid cancer cell lines. (19Z)-Halichondramide ((19Z)-HCA), a novel trisoxazole-containing macrolide, exhibited the highest potency among the macrolides, with IC50 values in the submicro-molar ranges. Prompted by the high potency of growth inhibition of cancer cells, we investigated the mechanism of action of the anti-proliferative activity of (19Z)-HCA in human A549 lung cancer cells. (19Z)-HCA induced cell cycle arrest in the G2/M phase, and this event was highly correlated with the expression of checkpoint proteins, including the up-regulation of p53 and GADD45α and the down-regulation of cyclin B1, cyclin A, CDC2, and CDC25C. In addition, the growth inhibition by (19Z)-HCA was associated with the suppression of mTOR and its downstream effector molecules 4EBP1 and p70S6K. The modulation of mTOR signaling by (19Z)-HCA was found to be mediated by the regulation of upstream proteins, including the down-regulation of Akt and p38 MAPK and the up-regulation of AMPK. These data suggest the potential of (19Z)-HCA to serve as a candidate for cancer chemotherapeutic agents derived from marine organisms by virtue of arresting the cell cycle in the G2/M phase and the modulation of mTOR/AMPK signaling pathways. 23126280 Regulation of adipogenesis by cytoskeleton remodelling is facilitated by acetyltransferase MEC-17-dependent acetylation of α-tubulin. Cytoskeleton remodelling is a prerequisite step for the morphological transition from preadipocytes to mature adipocytes. Although microtubules play a pivotal role in organizing cellular structure, regulation of microtubule dynamics during adipogenesis remains unclear. In the present paper we show that acetylation of α-tubulin is up-regulated during adipogenesis, and adipocyte development is dependent on α-tubulin acetylation, as expression of an acetylation-resistant α-tubulin mutant significantly inhibits adipogenesis. Moreover, acetylation of α-tubulin is under the control of the acetyltransferase MEC-17 and deacetylases SIRT2 (Sirtuin 2) and HDAC6 (histone deacetylase 6). Adipocyte development is inhibited in MEC-17-knockdown cells, but enhanced in MEC-17-overexpressing cells. Finally, we show that katanin, a microtubule-severing protein with enhanced activity on acetylated α-tubulin, is actively involved in adipogenesis. We propose that co-ordinated up-regulation of α-tubulin acetylation initiates cytoskeleton remodelling by promoting α-tubulin severing by katanin which, in turn, allows expansion of lipid droplets and accelerates the morphological transition toward mature adipocytes. 23454134 DNA delivery via cationic solid lipid nanoparticles (SLNs). In recent years the use of solid lipid nanoparticles (SLNs) as transport systems for the delivery of drugs and biomolecules has become particularly important. The use of cationic SLNs developed by the technique of microemulsion, which are complexed with DNA in order to study their application as non-viral vectors in gene therapy, is reported. The nanoparticles are characterized by scanning electron microscopy and transmission electron microscopy (SEM and TEM), atomic force microscopy (AFM) and differential scanning calorimetry (DSC). Furthermore, the process of lyophilization of the samples and their stability was studied. The nanoparticles obtained presented a particle size of 340nm with a positive surface charge of 44mV and the capability of forming lipoplexes with DNA plasmids was stated. 23265312 Dynamic behavior of water droplet impact on microtextured surfaces: the effect of geometrical parameters on anisotropic wetting and the maximum spreading diameter. Textured silicon surfaces decorated by square arrays of pillars with adjustable pitch were fabricated. The wetting behavior, especially for direction-dependent water contact angles on textured silicon surfaces after silanization, was investigated by incorporating the contact line fraction into a modified Wenzel model. Also, the effect of geometrical parameters on the anisotropic wetting behavior of water was examined with respect to water droplet impact on the textured surface. Moreover, the maximum spreading factor was studied theoretically in terms of energy conservation, allowing for surface topography and viscous friction of the liquid flowing among the arrays of the posts. Theoretical models were found to be in good agreement with experimental data. 23063927 Copy number variation in ACHE/EPHB4 (7q22) and in BCHE/MME (3q26) genes in sporadic breast cancer. Gene amplifications and deletions are common changes in human cancer cells. Previous studies indicate that the regions, where the ACHE (7q22) and BCHE (3q26.1-q26.2) genes are localized, are suffering such structural modifications in breast cancer. Therefore, the products of these genes, acetylcholinesterase and butyrylcholinesterase, respectively, are related to the process of cell differentiation and proliferation, as well as apoptosis. This study also included two other genes involved in tumorigenesis, the EPHB4 (7q22.1) and MME (3q21-27). The aim of this study was to verify amplification and/or deletion in the ACHE, BCHE, EPHB4 and MME genes in 32 samples of sporadic breast cancer. The gene alterations were detected using real-time PCR and determined by relative quantification with the standard curve method. All samples presented genetic alterations, showing a higher tendency for amplification of the ACHE (62.5% vs. 37.5%; p>0.1) and EPHB4 (53.13% vs. 46.88%; p>0.5) genes, and for deletions of the BCHE and MME genes (56.25% vs. 43.75% for both; p>0.5). A positive correlation was found between alterations in ACHE-EPHB4 and BCHE-MME pairs (rs=0.5948; p=0.0004; rs=0.3581; p=0.0478, respectively) indicating that these changes comprise a wide region. In conclusion, the results suggest that these genomic regions may contain important genes for this pathology, such as the oncogenes MET (7q31) and PIK3CA (3q26), and thus being interesting targets for future studies in breast cancer research. 23641692 Bioanalysis of antibody-drug conjugates: American Association of Pharmaceutical Scientists Antibody-Drug Conjugate Working Group position paper. Antibody-drug conjugates (ADCs) typically consist of a cytotoxic drug covalently bound to an antibody by a linker. These conjugates have the potential to substantially improve efficacy and reduce toxicity compared with cytotoxic small-molecule drugs. Since ADCs are generally complex heterogeneous mixtures of multiple species, these novel therapeutic products present unique bioanalytical challenges. The growing number of ADCs being developed across the industry suggests the need for alignment of the bioanalytical methods or approaches used to assess the multiple species and facilitate consistent interpretation of the bioanalytical data. With limited clinical data, the current strategies that can be used to provide insight into the relationship between the multiple species and the observed clinical safety and efficacy are still evolving. Considerations of the bioanalytical strategies for ADCs based on the current industry practices that take into account the complexity and heterogeneity of ADCs are discussed. 23261757 Increased urinary excretion of albumin, hemopexin, transferrin and VDBP correlates with chronic sensitization to gentamicin nephrotoxicity in rats. Drug nephrotoxicity is a serious health and economic problem worldwide. Rats can be acutely sensitized to acute kidney injury (AKI) by subnephrotoxic treatments with potentially nephrotoxic drugs. Acquired sensitization to AKI poses a silent risk impossible to diagnose pre-emptively with the technology available at the clinical level. Herein, we hypothesized whether a chronic, subnephrotoxic insult to the kidneys might result in chronically acquired sensitization to AKI, and whether chronic sensitization might be detected through specific urinary markers. To this end, rats were treated with a subtoxic dosage of the experimental nephrotoxin uranyl nitrate (UN) in the drinking water for 21 weeks, or plain water (as control), and then with low-dose gentamicin for 7 days. Renal function and renal tissue damage were evaluated through the experiment. The mild renal damage caused by gentamicin was markedly magnified in rats having received UN chronically, which was evident both at the functional and histological level. Four proteins, namely albumin, hemopexin, transferrin and vitamin D binding protein were increased in the urine in temporal association with the appearance of chronic predisposition. Although further studies are necessary, our results suggest that these proteins might be potentially used as markers of hidden, chronic predisposition to gentamicin nephrotoxicity, in order to appropriately and pre-emptively stratify and handle individuals according to their specific risk in the long term, and to conveniently optimize their life conditions or additional clinical procedures or treatments that might trigger the disease. This might reduce AKI incidence and severity and the associated costs. 23398356 Probing adsorption of polyacrylamide-based polymers on anisotropic Basal planes of kaolinite using quartz crystal microbalance. Quartz crystal microbalance with dissipation (QCM-D) was applied to investigate the adsorption characteristics of polyacrylamide-based polymers (PAMs) on anisotropic basal planes of kaolinite. Kaolinite basal planes were differentiated by depositing kaolinite nanoparticles (KNPs) on silica and alumina sensors in solutions of controlled pH values. Adsorption of an in-house synthesized organic-inorganic Al(OH)3-PAM (Al-PAM) as an example of cationic hybrid PAM and a commercially available partially hydrolyzed polyacrylamide (MF1011) as an example of anionic PAM was studied. Cationic Al-PAM was found to adsorb irreversibly and preferentially on tetrahedral silica basal planes of kaolinite. In contrast, anionic MF1011 adsorbed strongly on aluminum-hydroxy basal planes, while its adsorption on tetrahedral silica basal planes was weak and reversible. Adsorption study revealed that both electrostatic attraction and hydrogen-bonding mechanisms contribute to adsorption of PAMs on kaolinite. The adsorbed Al-PAM layer was able to release trapped water overtime and became more compact, while MF1011 film became more dissipative as backbones stretched out from kaolinite surface with minimal overlapping. Experimental results obtained from this study provide clear insights into the phenomenon that governs flocculation-based solid-liquid separation processes using multicomponent flocculants of anionic and cationic nature. 23411266 Comparative study on hypocholesterolemic and antioxidant activities of various extracts of fenugreek seeds. The hypocholesterolemic and antioxidant activities of various extracts (water, methanol, ethyl acetate, hexane, dichloro-methane) of fenugreek seeds were investigated in cholesterol-fed rats. Only the ethyl acetate extract reduced total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C) and increased high-density lipoprotein cholesterol (HDL-C) compared with those of rats fed a cholesterol-rich diet (HCD). Furthermore, the content of thiobarbituric acid-reactive substances (TBARS), and catalase and superoxide dismutase (SOD) in liver, heart and kidney decreased significantly after oral administration of the ethyl acetate extract, compared with those of HCD-fed rats. The phenolic and flavonoïd contents were highest in the methanol and the ethyl acetate extracts. These results showed that the ethyl acetate extract of the fenugreek seeds had a significant hypocholesterolemic effect and antioxidant activity in cholesterol-fed rats, whether this is partly due to the presence of flavonoïds in the extract needs further study. 23444099 Selective inhibition of an apicoplastic aminoacyl-tRNA synthetase from Plasmodium falciparum. The resistance of malaria parasites to available drugs continues to grow, and this makes the need for new antimalarial therapies pressing. Aminoacyl-tRNA synthetases (ARSs) are essential enzymes and well-established antibacterial targets and so constitute a promising set of targets for the development of new antimalarials. Despite their potential as drug targets, apicoplastic ARSs remain unexplored. We have characterized the lysylation system of Plasmodium falciparum, and designed, synthesized, and tested a set of inhibitors based on the structure of the natural substrate intermediate: lysyl-adenylate. Here we demonstrate that selective inhibition of apicoplastic ARSs is feasible and describe new compounds that that specifically inhibit Plasmodium apicoplastic lysyl-tRNA synthetase and show antimalarial activities in the micromolar range. 23474547 Sulfur-nitrogen co-doped three-dimensional carbon foams with hierarchical pore structures as efficient metal-free electrocatalysts for oxygen reduction reactions. Despite the good progress in developing doped carbon catalysts for oxygen-reduction reaction (ORR), the current metal-free carbon catalysts are still far from satisfactory for large-scale applications of fuel cell. Developing new metal free doped carbon materials with abundance active sites as well as excellent electron transfer and reactant transport rate towards ORR may be a potential solution. Herein, we develop a novel three-dimensional (3D) sulfur-nitrogen co-doped carbon foams (S-N-CF) with hierarchical pore structures, using a convenient, economical, and scalable method. The experimental results have demonstrated that the obtained 3D S-N-CF exhibited better catalytic activity, longer-term stability and higher methanol tolerance than a commercial Pt/C catalyst. Such excellent performances may be attributed to the synergistic effect, which includes high catalytic sites for ORR provided by high S-N heteroatom loading, excellent reactant transport caused by hierarchical pore structures and high electron transfer rate provided by 3D continuous networks. Our results not only develop a new type of catalysts with excellent electrocatalytic performance by a commercially valid route, but also provide useful information for further clarification of the relationship between the microstructures of metal-free carbon materials and catalyst properties for ORR. More importantly, the idea to design hierarchical pore structures could be applied to other catalytic materials and serve as a general strategy for improving the activity of various ORR catalysts. 23613150 Comparative Study of Metals Accumulation in Cultured In Vitro Mycelium and Naturally Grown Fruiting Bodies of Boletus badius and Cantharellus cibarius. Cantharellus cibarius Fr. (chanterelle) and Boletus badius Pers. (bay bolete) harvested from natural sites in Poland were used to derive in vitro cultures. The optimal medium composition for cultures was developed. Concentrations of the chosen elements (Zn, Cu, Fe, Mg, Ni, and Cd) in mycelium samples were measured by means of atomic absorption spectrometry. Fe concentration in the analyzed mushroom materials was in the range 215.4-680.3 μg/g dry weight. Mean values of Mg were respectively (in micrograms per gram dry weight) 541.8 for mycelium of C. cibarius cultured in vitro and 1,004.1 for C. cibarius fruiting bodies and 928.9 for the mycelium of B. badius cultured in vitro and 906.4 for B. badius fruiting bodies. The mean concentrations of Zn were 442.7 μg/g dry weight in mycelium from in vitro cultures of B. badius and 172.1 in B. badius fruiting bodies and 131.9 in the case of C. cibarius in mycelium from in vitro cultures and 95.5 for the C. cibarius fruiting bodies. Cu exhibited a reversal tendency, i.e., the element concentrations in naturally grown mushrooms were significantly higher (43.57 μg/g dry weight for C. cibarius and 43.54 μg/g for B. badius) than in cultured in vitro mycelium (12.47 μg/g for C. cibarius and 4.17 μg/g for B. badius). Ni was found in lowest concentrations ranging from 0.33 to 1.88 μg/g dry weight. Toxic metal Cd was found in relatively high concentrations in naturally grown species (0.79 μg/g dry weight-1.02). The lowest was the concentration of Cd in C. cibarius mycelium from in vitro culture-0.06 μg/g dry weight-a bit higher than it was in the B. badius mycelium (0.21 μg/g). 23109258 Effects of repeated pulsed herbicide exposures on the growth of aquatic macrophytes. Many contaminants are released into aquatic systems intermittently in a series of pulses. Pulse timing and magnitude can vary according to usage, compound-specific physicochemical properties, and use area characteristics. Standard laboratory ecotoxicity tests typically employ continuous exposure concentrations over defined durations and thus may not accurately and realistically reflect the effects of certain compounds on aquatic organisms, resulting in potential over- or underestimation. Consequently, the relative effects of pulsed (2 and 4 d) and continuous exposures of the duckweed Lemna minor to isoproturon, metsulfuron-methyl, and pentachlorophenol over a period of 42 d were explored in the present study. At the highest test concentrations, exposure of L. minor to pulses of metsulfuron-methyl resulted in effects on growth similar to those of an equivalent continuous exposure. For isoproturon, pulsed exposures had a lower impact than a corresponding continuous exposure, whereas the effect of pentachlorophenol delivered in pulses was greater. These differences may be explained by compound-specific uptake and degradation or dissipation rates in plants and the recovery potential that occurs following pulses for different pesticides. Given these results, use of a simple time-weighted average approach to estimate effects of intermittent exposures from short-term standard toxicity studies may not provide an accurate prediction that reflects realistic exposure scenarios. Development of mechanistic modeling approaches may facilitate better estimates of effects from intermittent exposures. 23000445 Wogonoside induces autophagy in MDA-MB-231 cells by regulating MAPK-mTOR pathway. Previous studies have demonstrated that wogonoside, a bioactive flavonoid extracted from the root of Scutellaria baicalensis Gerogi, has anti-inflammatory and anti-angiogenic activities. In this study, we evaluated wogonoside-induced autophagy on human breast MDA-MB-231 cells. We report that wogonoside triggered the formation of microtubule-associated protein-light chain 3 (MAP-LC3) positive autophagosomes and the accumulation of acidic vesicular and autolysosomes in MDA-MB-231 cells. In addition, cells treated by wogonoside developed autophagosome-like characteristics, including single and double membrane vacuoles containing intact and degraded cellular debris. The results showed that wogonoside promotes the expression of LC3-II and Beclin-1. Furthermore, wogonoside inhibited cell growth of MDA-MB-231 cells in a concentration- and time-dependent manner, which was associated with wogonoside-induced autophagy. Wogonoside also suppressed the activation of mammalian target of rapamycin (mTOR) and p70-S6 kinase (p70S6K) by regulating the expression of the extracellular signal-regulated kinase (ERK1/2) and p38 involved mitogen-activated protein kinase (MAPK) signaling pathway. Taken together, these results suggest that wogonoside partially inhibits MDA-MB-231 cell growth by inducing autophagy through the MAPK-mTOR pathway and may be a promising anti-tumor agent. 23293130 Effects of trona on the redox status of cellular system of male rats. The effects of trona (Kaun), a food additive, on the redox status of the liver and kidney of male Wistar rats were investigated. A total of 60 male rats (145 ± 2.52 g) were grouped into four: A, B, C and D, where group A (the control) received 1 mL of distilled water orally while those in groups B, C and D (test groups) received orally, same volume of trona preparation corresponding to 100, 200 and 400 mg/kg body weight, respectively, for 28 days. Administration of trona significantly reduced (p < 0.05) alkaline phosphatase activity in the liver and kidney with corresponding increases in the serum enzyme. Acid phosphatase activity increased significantly (p < 0.05) in the liver and kidney with no significant change (p > 0.05) in the activity of the serum enzyme. The activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and the levels of reduced glutathione, vitamins C and E in the liver and kidney of the animals decreased significantly (p < 0.05). In contrast, malondialdehyde and lipid hydroperoxide of trona-treated animals increased significantly (p < 0.05) in liver and kidney. Overall, data from this study revealed that trona exhibited its toxic effect by suppressing or depleting the antioxidant systems and increasing the risk of attack by oxidants generated either from its metabolites or from other in vivo means on the rat cellular system. 23361398 A mechanistic study of the electrochemical oxygen reduction on the model semiconductor n-Ge(100) by ATR-IR and DFT. The electrochemical oxygen reduction reaction (ORR) on a n-Ge(100) surface in 0.1 M HClO4 was investigated in situ and operando using a combination of attenuated total reflection infrared (ATR-IR) spectroscopy and density functional (DFT) calculations. The vibrational modes of the detected intermediates were assigned based on DFT calculations of solvated model clusters such as Ge-bound superoxides and peroxides. ATR-IR shows the Ge-bound superoxide with a transition dipole moment oriented at (28 ± 10)° with respect to the surface normal. At slightly negative potentials, the surface-bound peroxide is identified by an OOH bending mode as a further intermediate, oriented at a similar angle. At strongly negative potentials, a surface-bound perchlorate is found. The findings indicate a multistep mechanism of the ORR. The reaction is furthermore coupled with the hydrogen evolution reaction (HER). 23530747 Exploiting the Unique ATP-Binding Pocket of Toxoplasma Calcium-Dependent Protein Kinase 1 To Identify Its Substrates. Apicomplexan parasites rely on calcium as a second messenger to regulate a variety of essential cellular processes. Calcium-dependent protein kinases (CDPK), which transduce these signals, are conserved among apicomplexans but absent from mammalian hosts, making them attractive targets for therapeutic intervention. Despite their importance, the signaling pathways CDPK regulate remain poorly characterized, and their protein substrates are completely unknown. In Toxoplasma gondii, CDPK1 is required for calcium-regulated secretion from micronemes, thereby controlling motility, invasion, and egress from host cells. CDPK1 is unique among parasite and mammalian kinases in containing glycine at the key "gatekeeper" residue, which results in an expanded ATP-binding pocket. In the present study, we use a synthetic ATPγS analogue that displays steric complementarity to the ATP-binding pocket and hence allows identification of protein substrates based on selective thiophosphorylation. The specificity of this approach was validated by the concordance between the identified phosphorylation sites and the in vitro substrate preference of CDPK1. We further demonstrate that the phosphorylation of predicted substrates is dependent on CDPK1 both in vivo and in vitro. This combined strategy for identifying the targets of specific protein kinases provides a platform for defining the roles of CDPKs in apicomplexans. 23093494 Distinct sensitivity of slo1 channel proteins to ethanol. Ethanol levels reached in circulation during moderate-to-heavy alcohol intoxication (50-100 mM) modify Ca(2+)- and voltage-gated K(+) (BK) channel steady-state activity, eventually altering both physiology and behavior. Ethanol action on BK steady-state activity solely requires the channel-forming subunit slo1 within a bare lipid environment. To identify the protein regions that confer ethanol sensitivity to slo1, we tested the ethanol sensitivity of heterologously expressed slo1 and structurally related channels. Ethanol (50 mM) increased the steady-state activities of mslo1 and Ca(2+)-gated MthK, the latter after channel reconstitution into phospholipid bilayers. In contrast, 50-100 mM ethanol failed to alter the steady-state activities of Na(+)/Cl(-)-gated rslo2, H(+)-gated mslo3, and an mslo1/3 chimera engineered by joining the mslo1 region encompassing the N terminus to S6 with the mslo3 cytosolic tail domain (CTD). Collectively, data indicate that the slo family canonical design, which combines a transmembrane 6 (TM6) voltage-gated K(+) channel (K(V)) core with CTDs that empower the channel with ion-sensing, does not necessarily render ethanol sensitivity. In addition, the region encompassing the N terminus to the S0-S1 cytosolic loop (missing in MthK) is not necessary for ethanol action. Moreover, incorporation of both this region and an ion-sensing CTD to TM6 K(V) cores (a design common to mslo1, mslo3, and the mslo1/mslo3 chimera) is not sufficient for ethanol sensitivity. Rather, a CTD containing Ca(2+)-sensing regulator of conductance for K(+) domains seems to be critical to bestow K(V) structures, whether of TM2 (MthK) or TM6 (slo1), with sensitivity to intoxicating ethanol levels. 23547884 Polycyclic Hybrid Isoprenoids from a Reed Rhizosphere Soil Derived Streptomyces sp. CHQ-64. Two new hybrid isoprenoids, named indotertine B (2) and drimentine H (3), along with the known analogue drimentine C (4), were isolated from the reed rhizosphere soil derived actinomycete Streptomyces sp. CHQ-64. The structures of these compounds, including absolute configurations, were elucidated by extensive NMR, MS, and CD analyses. Indotertine B (2) exists as a pair of rotamers about the N-C(O) bond with a 2:1 ratio and displays activities against HCT-8 and A549 tumor cell lines with IC50 values of 6.96 and 4.88 μM, respectively. 23542080 Antagonists reversibly reverse chemical LTD induced by group I, group II and group III metabotropic glutamate receptors. Metabotropic glutamate (mGlu) receptors are implicated in many neurological and psychiatric diseases and are the targets of therapeutic agents currently in clinical development. Their activation has diverse effects in the central nervous system (CNS) that includes an involvement in synaptic plasticity. We previously reported that the brief exposure of hippocampal slices to dihydroxyphenylglycine (DHPG) can result in a long-term depression (LTD) of excitatory synaptic transmission. Surprisingly, this LTD could be fully reversed by mGlu receptor antagonists in a manner that was itself fully reversible upon washout of the antagonist. Here, 15 years after the discovery of DHPG-LTD and its reversible reversibility, we summarise these initial findings. We then present new data on DHPG-LTD, which demonstrates that evoked epileptiform activity triggered by activation of group I mGlu receptors can also be reversibly reversed by mGlu receptor antagonists. Furthermore, we show that the phenomenon of reversible reversibility is not specific to group I mGlu receptors. We report that activation of group II mGlu receptors in the temporo-ammonic pathway (TAP) and mossy fibre pathway within the hippocampus and in the cortical input to neurons of the lateral amygdala induces an LTD that is reversed by LY341495, a group II mGlu receptor antagonist. We also show that activation of group III mGlu8 receptors induces an LTD at lateral perforant path inputs to the dentate gyrus and that this LTD is reversed by MDCPG, an mGlu8 receptor antagonist. In conclusion, we have shown that activation of representative members of each of the three groups of mGlu receptors can induce forms of LTD than can be reversed by antagonists, and that in each case washout of the antagonist is associated with the re-establishment of the LTD. This article is part of a Special Issue entitled 'GluR-dep synaptic plasticity'. 23499661 Involvement of μ-opioid receptors in antinociceptive action of botulinum toxin type A. Botulinum toxin A (BTX-A) is approved for treatment of chronic migraine and has been investigated in various other painful conditions. Recent evidence demonstrated retrograde axonal transport and suggested the involvement of CNS in antinociceptive effect of BTX-A. However, the mechanism of BTX-A central antinociceptive action is unknown. In this study we investigated the potential role of opioid receptors in BTX-A's antinociceptive activity. In formalin-induced inflammatory pain we assessed the effect of opioid antagonists on antinociceptive activity of BTX-A. Naltrexone was injected subcutaneously (0.02-2 mg/kg) or intrathecally (0.07 μg/10 μl-350 μg/10 μl), while selective μ-antagonist naloxonazine was administered intraperitoneally (5 mg/kg) prior to nociceptive testing. The influence of naltrexone (2 mg/kg s.c.) on BTX-A antinociceptive activity was examined additionally in an experimental neuropathy induced by partial sciatic nerve transection. To investigate the effects of naltrexone and BTX-A on neuronal activation in spinal cord, c-Fos expression was immunohistochemically examined in a model of formalin-induced pain. Antinociceptive effects of BTX-A in formalin and sciatic nerve transection-induced pain were prevented by non-selective opioid antagonist naltrexone. Similarly, BTX-A-induced pain reduction was abolished by low dose of intrathecal naltrexone and by selective μ-antagonist naloxonazine. BTX-A-induced decrease in dorsal horn c-Fos expression was prevented by naltrexone. Prevention of BTX-A effects on pain and c-Fos expression by opioid antagonists suggest that the central antinociceptive action of BTX-A might be associated with the activity of endogenous opioid system (involving μ-opioid receptor). These results provide first insights into the mechanism of BTX-A's central antinociceptive activity. 23548020 The impact of computer science in molecular medicine: enabling high- throughput research. The Human Genome Project and the explosion of high-throughput data have transformed the areas of molecular and personalized medicine, which are producing a wide range of studies and experimental results and providing new insights for developing medical applications. Research in many interdisciplinary fields is resulting in data repositories and computational tools that support a wide diversity of tasks: genome sequencing, genome-wide association studies, analysis of genotype-phenotype interactions, drug toxicity and side effects assessment, prediction of protein interactions and diseases, development of computational models, biomarker discovery, and many others. The authors of the present paper have developed several inventories covering tools, initiatives and studies in different computational fields related to molecular medicine: medical informatics, bioinformatics, clinical informatics and nanoinformatics. With these inventories, created by mining the scientific literature, we have carried out several reviews of these fields, providing researchers with a useful framework to locate, discover, search and integrate resources. In this paper we present an analysis of the state-ofthe- art as it relates to computational resources for molecular medicine, based on results compiled in our inventories, as well as results extracted from a systematic review of the literature and other scientific media. The present review is based on the impact of their related publications and the available data and software resources for molecular medicine. It aims to provide information that can be useful to support ongoing research and work to improve diagnostics and therapeutics based on molecular-level insights. 23315091 Occupational exposure to pentachlorophenol causing lymphoma and hematopoietic malignancy for two generations. OBJECTIVE: Pentachlorophenol (PCP) is characterized as likely carcinogen of lymphoma and hematopoietic neoplasm. But the carcinogenicity to human was uncertain based on population studies. A systematic review was conducted to explore two kinds of associations, one was between the workers exposed to PCP with lymphoma and hematopoietic neoplasm, the other was between childhood lymphoma and leukemia with their parents exposed to PCP. METHODS: Systematic search for epidemiologic studies was carried out and the data were collected from MEDLINE database and from the reference lists of relevant studies. Data were extracted from 20 included studies published between 1986 and 2012. RESULTS: The meta-analysis suggested a significant association between lymphoma and workers' occupational exposing to PCP, for the pooled odds ratio = 2.57 (95% confidence interval (CI) = 1.52-4.35). The subgroup analysis indicated significant association for non-Hodgkin's lymphoma, but not for Hodgkin's disease. The cohort studies also showed comparatively higher relative risk (RR) and standardized mortality ratio (SMR). Two of the cohort studies found increased RR as the cumulative exposure time added. Another cohort study discovered that the white males had significantly elevated non-Hodgkin's lymphoma mortality (SMR = 1.98, 95% CI = 1.15-3.17), and males of other races had increased leukemia mortality (SMR = 4.57, 95% CI = 1.25-11.7). For the relationship of childhood leukemia and parental exposure to PCP, three published studies suggested an increased risk of childhood leukemia because of their parental exposure to PCP at the preconception period. CONCLUSION: Our review provided the evidence that occupational exposure of workers to PCP might increase the risk of lymphoma and hematopoietic neoplasm in themselves and in their children. 23041424 One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1β. Interleukin-1β (IL-1β) is a key orchestrator in inflammatory and several immune responses. IL-1β exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1β monoclonal antibodies. Canakinumab is known to neutralize IL-1β by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1β bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1β signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1β. Furthermore, we characterized the epitopes on IL-1β employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1β and provide insight into the mechanisms leading to their distinct modulation of IL-1β signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1β causes competitive inhibition of the association of IL-1β and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1β and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1β pathway attenuation. 23371801 Selective fluorogenic chemosensors for distinct classes of nucleases. NUCLEASE SENSOR TRIO: Fluorogenic DNA sensors were developed for distinct classes of nucleases: 3'-exonucleases, 5'-exonucleases, and endonucleases. The highly selective sensors, built from very small modified DNA oligomers containing the unnatural fluorescent base pyrene, and employing thymine as a quencher, were found to function in a variety of complex biological media. 23414366 Embryonic and induced pluripotent stem cells: understanding, creating, and exploiting the nano-niche for regenerative medicine. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the capacity to differentiate into any specialized cell type of the human body, and therefore, ESC/iPSC-derived cell types offer great potential for regenerative medicine. However, key to realizing this potential requires a strong understanding of stem cell biology, techniques to maintain stem cells, and strategies to manipulate cells to efficiently direct cell differentiation toward a desired cell type. As nanoscale science and engineering continues to produce novel nanotechnology platforms, which inform, infiltrate, and impinge on many aspects of everyday life, it is no surprise that stem cell research is turning toward developments in nanotechnology to answer research questions and to overcome obstacles in regenerative medicine. Here we discuss recent advances in ESC and iPSC manipulation using nanomaterials and highlight future challenges within this area of research. 23305919 Mitochondrial dysfunction contributes to the cytotoxicity of some 3,5-bis(benzylidene)-4-piperidone derivatives in colon HCT-116 cells. The objectives of this study are to investigate the possible ways by which the curcumin analogs 2a and 2b exert their antiproliferative properties. The analogs 2a and 2b have submicromolar IC(50) values towards human HCT-116 colon cancer cells but are far less toxic to human non-malignant CRL-1790 colon cells. Both compounds affected a number of mitochondrial functions in HCT-116 cells namely increasing the intracellular concentrations of reactive oxygen species, inhibiting oxygen consumption and decreasing the mitochondrial membrane potential. These molecules also produced swelling of isolated rat liver mitochondria, supporting a mitochondrial mechanism of cytotoxicity. Both compounds reacted with glutathione in the presence of glutathione S-transferase π and hence they may be classified as thiol alkylators. 23103566 Reversal of the deleterious effects of chronic dietary HFCS-55 intake by PPAR-δ agonism correlates with impaired NLRP3 inflammasome activation. Although high-fructose corn syrup (HFCS-55) is the major sweetener in foods and soft-drinks, its potential role in the pathophysiology of diabetes and obesity ("diabesity") remains unclear. Peroxisome-proliferator activated receptor (PPAR)-δ agonists have never been tested in models of sugar-induced metabolic abnormalities. This study was designed to evaluate (i) the metabolic and renal consequences of HFCS-55 administration (15% wt/vol in drinking water) for 30 weeks on male C57Bl6/J mice and (ii) the effects of the selective PPAR-δ agonist GW0742 (1 mg/kg/day for 16 weeks) in this condition. HFCS-55 caused (i) hyperlipidemia, (ii) insulin resistance, and (iii) renal injury/inflammation. In the liver, HFCS-55 enhanced the expression of fructokinase resulting in hyperuricemia and caused abnormalities in known insulin-driven signaling events. In the kidney, HFCS-55 enhanced the expression of the NLRP3 (nucleotide-binding domain and leucine-rich-repeat-protein 3) inflammasome complex, resulting in caspase-1 activation and interleukin-1β production. All of the above effects of HFCS-55 were attenuated by the specific PPAR-δ agonist GW0742. Thus, we demonstrate for the first time that the specific PPAR-δ agonist GW0742 attenuates the metabolic abnormalities and the renal dysfunction/inflammation caused by chronic HFCS-55 exposure by preventing upregulation of fructokinase (liver) and activation of the NLRP3 inflammasome (kidney). 22424051 A new chromone from the leaves of Melaleuca cajuputi Powell. A new chromone, 5,7-dihydroxy-2 -(hydroxymethyl)-6,8-dimethyl-chromen-4-one, named melachromone, together with 12 known compounds, including chromones, anthraquinone, flavonoids, flavonoid glycosides, benzene derivatives, ellagic acids and terpenes, were isolated from the leaves of Melaleuca cajuputi Powell. Their structures were characterised by spectroscopic methods. 23584353 Meclofenamic acid blocks the gap junction communication between the retinal pigment epithelial cells. Aim: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage the pain and inflammation. NSAIDs can cause serious side effects, including vision problems. However, the underlying mechanisms are still unclear. Therefore, we aimed to investigate the effect of meclofenamic acid (MFA) on retinal pigment epithelium (RPE). Materials and methods: In our study, we applied image analysis and whole-cell patch clamp recording to directly measure the effect of MFA on the gap junctional coupling between RPE cells. Results: Analysis of Lucifer yellow (LY) transfer revealed that the gap junction communication existed between RPE cells. Functional experiments using the whole-cell configuration of the patch clamp technique showed that a gap junction conductance also existed between this kind of cells. Importantly, MFA largely inhibited the gap junction conductance and induced the uncoupling of RPE cells.Other NSAIDs, like aspirin and flufenamic acid (FFA), had the same effect. Conclusion: The gap junction functionally existed in RPE cells, which can be blocked by MFA. These findings may explain, at least partially, the vision problems with certain clinically used NSAIDs. 23526725 Multiple Phytoestrogens Inhibit Cell Growth and Confer Cytoprotection By Inducing Manganese Superoxide Dismutase Expression. Phytoestrogens are of interest because of their reported beneficial effects on many human maladies including cancer, neurodegeneration, cardiovascular disease and diabetes. As data on phytoestrogens continues to accumulate, it is clear that there is significant overlap in the cellular effects elicited by these various compounds. Here, we show that one mechanism by which a number of phytoestrogens achieve their growth inhibitory and cytoprotective effects is via induction of the mitochondrial manganese superoxide dismutase (MnSOD). Eight phytoestrogens, including resveratrol, coumestrol, kaempferol, genistein, daidzein, apigenin, isoliquirtigenin and glycitin, were tested for their ability to induce MnSOD expression in mouse C2C12 and primary myoblasts. Five of these, resveratrol, coumestrol, kaempferol, genistein and daidzein, significantly increased MnSOD expression, slowed proliferative growth and enhanced stress resistance (hydrogen peroxide LD50) . When siRNA was used to prevent the MnSOD induction by genistein, coumestrol or daidzein, none of these compounds exerted any effect on proliferative growth, and only the effect of coumestrol on stress resistance persisted. The estrogen antagonist ICI182780 prevented the increased MnSOD expression and also the changes in cell growth and stress resistance, indicating that these effects are mediated by estrogen receptors (ER). The absence of effects of resveratrol or coumestrol, but not genistein, in ERβ-null cells further indicated that this ER in particular is important in mediating these effects. Thus, an ER-mediated induction of MnSOD expression appears to underlie the growth inhibitory and cytoprotective activities of multiple phytoestrogens. Copyright © 2013 John Wiley & Sons, Ltd. 23537598 Antioxidant and anticancer activities of Chenopodium quinoa leaves extracts - In vitro study. The nutraceutical potential of Chenopodium quinoa Leaves (ChL) was assessed through analyses of their phenolic content, elucidation of the effect of ChL phenolic compounds on cancer cell properties and estimation of their antioxidative activity, bioaccessibility and bioavailability in vitro. Considerable amounts of ferulic, sinapinic and gallic acids, kaempferol, isorhamnetin and rutin were observed in the chemical ChL extract and were linked with its inhibitory effect on prostate cancer cell proliferation, motility and cellular competence for gap junctional communication. Both extracts, chemical and obtained after simulated digestion, exerted an inhibitory effect on lipoxygenase activity, paralleled by their considerable chelating, antioxidative, antiradical and reducing power. These observations indicate that phenolic ChL compounds may exert a chemopreventive and anticarcinogenic effect on oxidative stress and ROS-dependent intracellular signaling via synergic effects. The relatively high potential bioaccessibility and bioavailability of the compounds probably responsible for these effects demonstrates the suitability of ChL for dietary supplementation. 23198782 SAXS conformational tracking of amylose synthesized by amylosucrases. Amylose, a linear polymer of α(1,4)-linked glucosyl units and a major constituent of starch granules, can also be enzymatically synthesized in vitro from sucrose by bacterial amylosucrases. Depending on the initial sucrose concentration and the enzyme used, amylose oligomers (or polymers) are formed and self-associate during synthesis into various semicrystalline morphologies. This work describes for the first time a synchrotron SAXS study of the structure in solution of two amylosucrases, namely, NpAS and the thermostable DgAS, under conditions of polymer synthesis and, simultaneously, the amylose conformation. The structure in solution of both amylosucrases during the reaction was shown to be similar to the known crystallographic structures. The conformation of amylose produced at an early stage consists of a mixture of wormlike chains and double helical cylindrical structures. In the case of NpAS, in a second stage, individual double helices pack into clusters before crystallizing and precipitating. Amylose produced by DgAS never self-associates in such clusters due to the higher temperature used for amylose synthesis. All the dimensions determined for wormlike chains and cylindrical conformations at different times of NpAS synthesis are in very good agreement with structural features usually observed on gels of amylose extracted from starch. This provides new insights in understanding the mechanisms of amylose gelation. 23541929 Impact of flow pulsatility on arterial drug distribution in stent-based therapy. Drug-eluting stents reside in a dynamic fluid environment where the extent to which drugs are distributed within the arterial wall is critically modulated by the blood flowing through the arterial lumen. Yet several factors associated with the pulsatile nature of blood flow and their impact on arterial drug deposition have not been fully investigated. We employed an integrated framework comprising bench-top and computational models to explore the factors governing the time-varying fluid dynamic environment within the vasculature and their effects on arterial drug distribution patterns. A custom-designed bench-top framework comprising a model of a single drug-eluting stent strut and a poly-vinyl alcohol-based hydrogel as a model tissue bed simulated fluid flow and drug transport under fully apposed strut settings. Bench-top experiments revealed a relative independence between drug distribution and the factors governing pulsatile flow and these findings were validated with the in silico model. Interestingly, computational models simulating suboptimal deployment settings revealed a complex interplay between arterial drug distribution, Womersley number and the extent of malapposition. In particular, for a stent strut offset from the wall, total drug deposition was sensitive to changes in the pulsatile flow environment, with this dependence increasing with greater wall displacement. Our results indicate that factors governing pulsatile luminal flow on arterial drug deposition should be carefully considered in conjunction with device deployment settings for better utilization of drug-eluting stent therapy. 23565755 The role of intracrine androgen metabolism, androgen receptor and apoptosis in the survival and recurrence of prostate cancer during androgen deprivation therapy. Prostate cancer (CaP) is the most frequently diagnosed cancer and leading cause of cancer death in American men. Almost all men present with advanced CaP and some men who fail potentially curative therapy are treated with androgen deprivation therapy (ADT). ADT is not curative and CaP recurs as the lethal phenotype. The goal of this review is to apply our current understanding of CaP and castration-recurrent CaP (CR-CaP) to earlier studies that characterized ADT and the molecular mechanisms that facilitate the transition from androgen-stimulated CaP to CR-CaP. Reexamination of earlier studies also may provide a better understanding of how more newly recognized mechanisms, such as intracrine metabolism, may be involved with the early events that allow CaP survival after initiation of ADT and subsequent development of CR-CaP. 23512535 The protective effects of ω-3 fatty acids on doxorubicin-induced hepatotoxicity and nephrotoxicity in rats. This study aims to evaluate the protective effects of ω-3 fatty acids (FAs) on doxorubicin (DOX)-induced hepatotoxicity and nephrotoxicity in rats. A total of 24 adult male Sprague Dawley rats were divided into three groups. Control group was given only saline by intragastric gavage. DOX group received DOX at the dose of 30 mg/kg intraperitoneally on day 28. DOX-ω-3 FA group was given as ω-3 FAs at the dose of 400 mg/kg daily by intragastric gavage for 30 days and received DOX at the dose of 30 mg/kg intraperitoneally on day 28. At the end of the 30-day experimental period, the serum, liver and kidney tissue specimens were taken from the animals by giving a general anesthesia. Glutathione (GSH) and malondialdehyde (MDA) levels in serum and GSH and MDA levels and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in liver and kidney tissues were measured spectrophotometrically. In our study, a significant increase in MDA levels was observed in rats when given a dose of DOX and a significant decrease in the levels of GSH, SOD and GSH-Px activities in serum, liver and kidney tissues was determined when compared with control group. In addition, a significant decrease in MDA levels was observed in rats when a dose of ω-3 FAs was given with DOX and a significant increase was determined in the levels of GSH, SOD and GSH-Px activities in serum, liver and kidney tissues, when compared with DOX group. We concluded that ω-3 FA had favorable effects in rat liver and kidney tissues by preventing oxidative damage. 23161646 New horizons for diagnostics and therapeutic applications of graphene and graphene oxide. Graphene, a one-atom-thick two-dimensional (2D) layer of sp(2) -bonded carbon, has received worldwide attention owing to its extraordinary physical and chemical properties. Recently, great efforts have been devoted to explore potential applications of graphene and its oxide in life science, especially in disease-related diagnostics, near-Infrared (NIR) phototherapy and imaging. Here we will introduce recent advances and new horizons in this area, and focus on the rising progress on NIR photothermal therapy for cancer and Alzheimer's disease (AD), human telomerase detection, stem cell proliferation and differentiation on graphene substrate, diagnosis of cancer cell and related biomarkers, drug/nucleotide/peptide delivery and cell imaging, which have not been comprehensively reviewed. We hope to provide an outlook to the applications of graphene and its oxide, especially on the new horizons in this field, and inspire broader interests across various disciplines. 23570790 Structure-activity relationship of potent antimicrobial peptide analogs of Ixosin-B amide. There is a great urgency in developing a new generation of antibiotics and antimicrobial agents since the bacterial resistance to antibiotics have increased dramatically. A series of overlapped peptide fragments of Ixosin-B, an antimicrobial peptide with amino acid sequence of QLKVDLWGTRSGIQPEQHSSGKSDVRRWRSRY, was designed, synthesized and examined for their antimicrobial activities against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. A potent 11-mer peptide TSG-8-1, WWSYVRRWRSR-amide, was developed, which exhibited antimicrobial activity against E. coli and S. aureus while very little hemolytic activity in human erythrocytes was observed at high dose level. This peptide could be further modified for the development of a potent antimicrobial agent in the future. 23182087 Synthesis and anti-angiogenic activity of benzothiazole, benzimidazole containing phthalimide derivatives. Benzothiazole and benzimidazole containing phthalimide derivatives (NK037, NK041, NK042, NK0139A and NK0148) have been synthesized and their anti-angiogenic activity was evaluated using ex vivo egg yolk angiogenesis model. A comparative study with pure thalidomide (NKTA) has also been performed to describe the efficacy of these derivatives in blocking angiogenesis. NK037, NK041 and NK042 were equally potent in blocking egg yolk angiogenesis and the anti-angiogenesis effect was higher than NKTA suggesting the efficacy of these three derivatives in blocking angiogenesis when compare to control. Other two derivatives NK0139A and NK0148 showed effect less than NKTA and stronger than control in ex vivo angiogenesis. 23364935 Model for conformational relaxation of flexible conjugated polymers: application to p-phenylenevinylene trimers in nonpolar solvents. Photoexcitation of flexible conjugated polymers is invariably followed by a fast conformational/torsional relaxation towards a configuration favouring coplanarity of the conjugated segments. In general, the experimental relaxation rate constant (k(CR)) depends on the solvent viscosity (η) and temperature (T), and is not proportional to T/η. A theory capable of explaining the observed dependence of k(CR) on T and η over a wide range of these variables is not available. This gap is filled here by presenting a stochastic model that includes the participation of the oligomer side chain in storing and dissipating the stresses induced by photoexcitation. The model is able to account for the softening of solute-solvent interactions and its predictions are found to be in excellent agreement with the observed relaxation rate constants of a series of substituted p-phenylenevinylene trimers [ChemPhysChem 2009, 10, 448-454] on T, η and the size of the side-chains. 23280809 Persistence of the tricyclic antidepressant drugs amitriptyline and nortriptyline in agriculture soils. Amitriptyline and nortriptyline are widely used tricyclic antidepressant drugs. They have been detected in wastewater, surface runoff, and effluents from sewage treatment plants. As such, they could potentially reach agriculture land through the application of municipal biosolids or reclaimed water. In the absence of data on their fate in the environment, the persistence and dissipation pathways of radiolabeled amitriptyline were determined in three agriculture soils varying widely in texture and chemical properties (loam soil, clay loam soil, and sandy loam soil). Tritiated amitriptyline was added to laboratory microcosms containing soils, and the metabolism of the extractable (3) H was monitored during incubation at 30°C. The total solvent extractable radioactivity decreased in all three soils with times to dissipate 50% of material (DT50) ranging from 34.1 ± 3.2 (loam soil) to 85.3 ± 3.2 d (sandy soil). Nortriptyline (N-desmethyl amitriptyline) and amitriptyline-N-oxide were identified as major transformation products in all three soils by high performance liquid chromatography with photodiode array detector and time-of-flight mass spectrometry (HPLC-TOF-MS/UV). The addition of liquid municipal biosolids to the loam soil had no effect on the dissipation of amitriptyline. The persistence of nortriptyline was evaluated in the loam soil. The DT50 of nortriptyline was 40.5 ± 3.2 d estimated with HPLC-TOF-MS/UV. Approximately 10% of added nortriptyline was converted to hydroxylated products after 50 d of incubation. In summary, amitriptyline persisted in agricultural soils with major dissipation mechanisms, including forming nonextractable residues and producing various transformation products including the psychoactive drug nortriptyline. 23495690 P2X and P2Y nucleotide receptors as targets in cardiovascular disease. Endogenous nucleotides have widespread actions in the cardiovascular system, but it is only recently that the P2X and P2Y receptor subtypes, at which they act, have been identified and subtype-selective agonists and antagonists developed. These advances have greatly increased our understanding of the physiological and pathophysiological functions of P2X and P2Y receptors, but investigation of the clinical usefulness of selective ligands is at an early stage. Nonetheless, the evidence considered in this review demonstrates clearly that various cardiovascular disorders, including vasospasm, hypertension, congestive heart failure and cardiac damage during ischemic episodes, may be viable targets. With further development of novel, selective agonists and antagonists, our understanding will continue to improve and further therapeutic applications are likely to be discovered. 23132909 ApoA-IV promotes the biogenesis of apoA-IV-containing HDL particles with the participation of ABCA1 and LCAT. The objective of this study was to establish the role of apoA-IV, ABCA1, and LCAT in the biogenesis of apoA-IV-containing HDL (HDL-A-IV) using different mouse models. Adenovirus-mediated gene transfer of apoA-IV in apoA-I(-/-) mice did not change plasma lipid levels. ApoA-IV floated in the HDL2/HDL3 region, promoted the formation of spherical HDL particles as determined by electron microscopy, and generated mostly α- and a few pre-β-like HDL subpopulations. Gene transfer of apoA-IV in apoA-I(-/-) × apoE(-/-) mice increased plasma cholesterol and triglyceride levels, and 80% of the protein was distributed in the VLDL/IDL/LDL region. This treatment likewise generated α- and pre-β-like HDL subpopulations. Spherical and α-migrating HDL particles were not detectable following gene transfer of apoA-IV in ABCA1(-/-) or LCAT(-/-) mice. Coexpression of apoA-IV and LCAT in apoA-I(-/-) mice restored the formation of HDL-A-IV. Lipid-free apoA-IV and reconstituted HDL-A-IV promoted ABCA1 and scavenger receptor BI (SR-BI)-mediated cholesterol efflux, respectively, as efficiently as apoA-I and apoE. Our findings are consistent with a novel function of apoA-IV in the biogenesis of discrete HDL-A-IV particles with the participation of ABCA1 and LCAT, and may explain previously reported anti-inflammatory and atheroprotective properties of apoA-IV. 23369072 Biobased polyesters with composition-dependent thermomechanical properties: synthesis and characterization of poly(butylene succinate-co-butylene azelate). Environmentally friendly poly(butylenesuccinate-co-butyleneazelate) (P(BS-co-BAz)s) aliphatic copolyesters with composition-dependent thermomechanical properties were synthesized from succinic acid (SuA), 1,4-butanediol (BDO), and dimethylazelate (DMAz) through a two-step polycondensation reaction. The molar SuA/AzA ratio was varied from 4:1 to 1:4, and the chemical structure and molecular characteristics of resulting (co)polyesters were characterized by NMR and SEC, whereas thermal properties and crystallinity were studied by differential scanning calorimetry (DSC), dynamic mechanical thermal analyses (DMTA), and X-ray diffraction (XRD). A good agreement between theoretical and experimental SuA/AzA molar ratios in the copolyesters was achieved, together with the recovery of semicrystalline random copolymers of uniform composition along the chains. NMR, DSC, DMTA, and XRD results show that depending on their composition the P(BS-co-BAz) copolyesters might find applications from elastomers to high-impact thermoplastics. 23296904 Effect of Wine Polyphenol Resveratrol on the Contractions Elicited Electrically or by Norepinephrine in the Rat Portal Vein. We investigated the effects of resveratrol on rat portal vein (RPV) contractility without endothelium. Contractions were produced by electrical field stimulation of perivascular nerves (EFS), norepinephrine (NE), adenosine 5'-triphosphate (ATP), high K(+) solution and by calcium chloride (CaCl(2) ) in Ca(2+) -free and high K(+) , Ca(2+) -free solution. The EFS-evoked contractions were more sensitive to resveratrol and to NS1619-selective openers of big calcium-sensitive (BK(Ca) ) channels, than NE-evoked contractions. Effects of resveratrol on the ATP-evoked contractions were weak. Blockers of BK(Ca) channels partly inhibited the effect of resveratrol only in EFS-contracted preparations. Western blotting showed that RPV expressed K(Ca) 1.1 protein. Inhibitors of ATP- and voltage-sensitive K(+) channels did not modify the effects of resveratrol. None of the antagonists of K(+) channels affected the resveratrol inhibition of NE-evoked contractions and effect of high concentrations of resveratrol on the EFS-evoked contractions. Resveratrol more potently inhibited CaCl(2) than potassium chloride contractions of RPV. Thus, BK(Ca) channels partly mediate the inhibitory effect of resveratrol on the neurogenic contractions of RPV. The smooth muscle Ca(2+) channels and/or Ca(2+) mobilizing through cells might be involved in the effects of resveratrol on the contractility of RPV. Our results are important for better understanding the impact of resveratrol on the portal circulation. Copyright © 2013 John Wiley & Sons, Ltd. 23115221 Novel insights on the effect of nicotine in a murine colitis model. Studies showed that nicotine has a positive influence on symptoms of ulcerative colitis. In the present study, we explored the effect of nicotine treatment using different routes of administration in the dextran sodium sulfate (DSS) colitis mouse model. We also investigated the effects of cotinine, a major metabolite of nicotine, in the model. C57BL6 adult male mice were given DSS solution freely in the drinking water for seven consecutive days, and tap water was given thereafter. Disease severity, length of the colon, colon tissue histology, and inflammatory markers, including colonic myeloperoxidase activity and colonic tumor necrosis factor-α levels, were evaluated. The effect of nicotine and cotinine treatments via various different routes of administration were examined the DSS model. In addition, we measured the plasma levels of nicotine and cotinine in our treatment protocols. Administration of low, but not high, doses of oral nicotine in DSS-treated mice resulted in a significant decrease in disease severity, histologic damage scores, as well as colonic level of tumor necrosis factor-α. However, the anti-inflammatory effect of nicotine was not seen after chronic s.c. or minipump infusion of the drug. Differences in plasma levels of nicotine and cotinine do not seem to account for this lack of effect. Finally, oral cotinine alone failed to show a significant effect in the DSS model of colitis. These results highlight that dose and route of administration play a critical role in the protective effect of nicotine in the DSS mouse colitis model. 23472833 Presence of hydrophobic groups may modify the specific ion effect in aqueous polyelectrolyte solutions. Enthalpies of dilution of aqueous solutions of aliphatic 6,12- and 12,12-ionene bromides and fluorides and enthalpies of mixing with low molecular-weight salts, such as sodium fluoride and bromide, are determined. In the second part of the study, the various x,y-ionenes (x, y are numbers of methylene groups between the adjacent charges) with fluoride, bromide, and iodide counterions are mixed with aqueous sodium sulfate solution. The polyelectrolytes examined in this part of the work are 3,3-, 6,9-, 6,12-, and 12,12-ionenes. A comparison with theoretical results, based on the Poisson-Boltzmann cell model, is presented. The theory predicts for the enthalpy of dilution to be exothermic and the enthalpy of mixing endothermic, while experiments show that signs of the heat effects depend on the nature of the counterion of the added salt, as also on the hydrophobicity (numbers x, y of methylene groups) of the ionene. We show that the salts when ordered by heat effects produced by mixing of NaF and NaBr with 3,3-, 6,9-, or 6,12-ionene fluorides and bromides follow the opposite ordering than in the case when the same alkali halide salts are mixed with more hydrophobic 12,12-ionene salts. The results for the enthalpy of mixing of ionenes under study with Na2SO4 follow the same order as obtained for monovalent salts. 23054066 Parallel changes in serotonin levels in brain and blood following acute administration of MDMA. Recent studies have demonstrated a similar acute effect of 3,4- methylenedioxymethamphetamine (MDMA) in blood platelets and brain tissue via action on the serotonin transporter. To investigate the validity of blood serotonin as a peripheral marker for central serotonin in this regard, we administered MDMA (20 mg/kg i.p.) to rats and observed a parallel decrease in serotonin levels in the frontal cortex and blood at 2 h (63% and 46% respectively) with some recovery evident at 8 h (42% and 38%) and more so at 18 h (19% and 24% below control levels). Administration of a tryptophan supplement (82.5 mg/kg p.o.) to naïve rats produced parallel increases in serotonin levels 2 h later in the frontal cortex (39%) and blood (26%). Following MDMA administration, the same dose of tryptophan caused a smaller (26%) rise in brain serotonin whereas in blood it had no effect. We conclude that blood serotonin is a useful marker for brain serotonin levels in the rat following acute administration of MDMA and this finding highlights the possible use of platelet serotonin as a marker for brain serotonin in human studies involving MDMA. 23466742 GPER: A novel target for non-genomic estrogen action in the cardiovascular system. A key to harnessing the enormous therapeutic potential of estrogens is understanding the diversity of estrogen receptors and their signaling mechanisms. In addition to the classic nuclear estrogen receptors (i.e., ERα and ERβ), over the past decade a novel G-protein-coupled estrogen receptor (GPER) has been discovered in cancer and other cell types. More recently, this non-genomic signaling mechanism has been found in blood vessels, and mediates vasodilatory responses to estrogen and estrogen-like agents; however, downstream signaling events involved acute estrogen action remain unclear. The purpose of this review is to discuss the latest knowledge concerning GPER modulation of cardiovascular function, with a particular emphasis upon how activation of this receptor could mediate acute estrogen effects in the heart and blood vessels (i.e., vascular tone, cell growth and differentiation, apoptosis, endothelial function, myocardial protection). Understanding the role of GPER in estrogen signaling may help resolve some of the controversies associated with estrogen and cardiovascular function. Moreover, a more thorough understanding of GPER function could also open significant opportunities for the development of new pharmacological strategies that would provide the cardiovascular benefits of estrogen while limiting the potentially dangerous side effects. 23419390 The effects of cocoa supplementation, caloric restriction, and regular exercise, on oxidative stress markers of brain and memory in the rat model. The effects of treadmill running (8weeks, 5 times/week, 1h/day at 27m/min), caloric restriction, and cocoa supplementation on brain function and oxidative stress markers were tested. The Morris maze test was used to appraise rat memory. Regular exercise significantly improved spatial learning performance. The level of oxidative stress was measured by the concentration of carbonylated proteins. The free radical concentration increased in brain of the training groups but not the controls. The content of reactive carbonyl derivates did not change with exercise, suggesting that the increased production of reactive oxygen species (ROS) were well tolerated in this experimental model. Caloric restriction (CR) decreased the accumulation of free radicals in the frontal lobe. The protein content of brain-derived neutrophic factors (BDNFs) was evaluated and changes did not occur either with exercise or cocoa supplementation treatments. These data did not show significant effects of the administration of cocoa (2% w/w) on the concentration of ROS, BDNF or on spatial memory. Conversely, exercise and CR can play a role in ROS generation and brain function. 23469923 Targeted d4 dopamine receptors: implications for drug discovery and therapeutic development. A wealth of preclinical and clinical literature has established functional associations of CNS dopamine (DA) and its multiple G protein-coupled receptor (GPCR) types in the integration of key neurological processes linked to complex behavioral activities. Conversely, an equivalent vast literature supports the role of aberrant CNS DA expression and DA receptor signaling in the etiology and persistence of major psychiatric illnesses and has established selective targeting of DA-ergic systems as a cornerstone of pharmacotherapeutic intervention and current neuroleptic drug development. The present short review focuses on potential functional/behavioral alterations linked to polymorphisms in the primary DNA sequence of the DA receptor type 4 (DRD4) gene in reference to major psychiatric illnesses. The potential clinical relevance of major polymorphisms of the DRD4 gene are discussed within the context of practical aspects of typical and atypical neuroleptic drug usage within afflicted populations of psychiatric patients. It is anticipated that additional complementary molecular, biochemical, and behavioral studies of DRD4 gene polymorphisms will provide essential information for selective targeting of heterogeneous populations of CNS D4 receptors and advance drug discovery and therapeutic development efforts for highly efficacious treatment of psychiatric illnesses. 23411260 Effect of incorporating hydrothermal, kilned and defatted oats on antioxidant and chapatti making properties of wheat flour. Oats were subjected to treatments like defatting, hydrothermal cooking and kilning, milled into flour and then the control and treated flours were incorporated into wheat flour at 25% and 50% levels and chapatti making behaviour and antioxidant properties were studied. The treatments significantly affected the antioxidant properties of oats. Incorporating oat flours to wheat increased total phenolic content but lowered the antioxidant activity however both were decreased significantly upon baking. The reducing power of the oat blended flour was higher than the wheat flours and ranged from 8.0 to 15.5 μmol AAE/g and was further increased upon baking. The metal chelating activity of flour blends varied from 62.0% to 73.8% and further increased upon baking. After baking the total flavonoid content was lowered and ranged from 308 to 389 μg CE/g. The non-enzymatic browning index significantly increased up to 27.6% upon baking. 23229556 Understanding how noncatalytic carbohydrate binding modules can display specificity for xyloglucan. Plant biomass is central to the carbon cycle and to environmentally sustainable industries exemplified by the biofuel sector. Plant cell wall degrading enzymes generally contain noncatalytic carbohydrate binding modules (CBMs) that fulfil a targeting function, which enhances catalysis. CBMs that bind β-glucan chains often display broad specificity recognizing β1,4-glucans (cellulose), β1,3-β1,4-mixed linked glucans and xyloglucan, a β1,4-glucan decorated with α1,6-xylose residues, by targeting structures common to the three polysaccharides. Thus, CBMs that recognize xyloglucan target the β1,4-glucan backbone and only accommodate the xylose decorations. Here we show that two closely related CBMs, CBM65A and CBM65B, derived from EcCel5A, a Eubacterium cellulosolvens endoglucanase, bind to a range of β-glucans but, uniquely, display significant preference for xyloglucan. The structures of the two CBMs reveal a β-sandwich fold. The ligand binding site comprises the β-sheet that forms the concave surface of the proteins. Binding to the backbone chains of β-glucans is mediated primarily by five aromatic residues that also make hydrophobic interactions with the xylose side chains of xyloglucan, conferring the distinctive specificity of the CBMs for the decorated polysaccharide. Significantly, and in contrast to other CBMs that recognize β-glucans, CBM65A utilizes different polar residues to bind cellulose and mixed linked glucans. Thus, Gln(106) is central to cellulose recognition, but is not required for binding to mixed linked glucans. This report reveals the mechanism by which β-glucan-specific CBMs can distinguish between linear and mixed linked glucans, and show how these CBMs can exploit an extensive hydrophobic platform to target the side chains of decorated β-glucans. 23274345 The use of Reamer Irrigator Aspirator (RIA) autograft harvest in the treatment of critical-sized iliac wing defects in sheep: investigation of dexamethasone and beta-tricalcium phosphate augmentation. Bone grafts are commonly used for the treatment of segmental bone defects and fracture non-unions. Recently, osseous particles obtained during intermedullary canal reaming (using a Reamer-Irrigator-Aspirator (RIA) device) have been evaluated as graft material during in vitro and clinical studies. The aim of this study was to evaluate and quantify new bone formation after implantation of bone graft material obtained after reaming of the tibia in a bilateral critical-sized iliac wing defect in sheep and to investigate the effect of the augmentation of this graft. A reamer bone graft alone, or after short term incubation in a dexamethasone enriched solution, and a reamer graft collected using beta-tricalcium phosphate (β-TCP) granules in the filter of the RIA collection device were compared to autologous iliac wing graft. In addition, reamer graft was combined with the cellular fraction collected from the irrigation fluid with and without short-term incubation in a dexamethasone enriched solution. It was hypothesized that the amount of physical bone in the reamer bone graft groups would be higher than the amount in the autologous iliac wing graft group and that augmentation of a reamer bone graft would increase bone formation. Three months after implantation, the amount of new bone formation (as percentage of the total defect volume) in the defects was evaluated ex-vivo by means of micro-CT and histomorphometry. The mean amount of bone in the autologous iliac wing graft group was 17.7% and 16.8% for micro-CT and histomorphometry, respectively. The mean amount of bone in all reamer graft groups ranged between 20.4-29.2% (micro-CT) and 17.0-25.4% (histomorphometry). Reamer graft collected using β-TCP granules (29.2±1.7%) in the filter produced a significantly higher amount of bone in comparison to an autologous iliac wing graft evaluated by micro-CT. RIA bone grafts added a small increase in bone volume to the 3month graft volume in this preclinical sheep model. The current model does not support the use of short-term high concentration dexamethasone for augmentation of a graft volume. If avoidance of an iliac wing graft is desirable, or a reaming procedure is required, then a RIA graft or RIA graft plus β-TCP granules are as good as the current gold standard for this model. 23294188 Identification and characterization of new DNA G-quadruplex binders selected by a combination of ligand and structure-based virtual screening approaches. Nowadays, it has been demonstrated that DNA G-quadruplex arrangements are involved in cellular aging and cancer, thus boosting the discovery of selective binders for these DNA secondary structures. By taking advantage of available structural and biological information on these structures, we performed a high throughput in silico screening of commercially available molecules databases by merging ligand- and structure-based approaches by means of docking experiments. Compounds selected by the virtual screening procedure were then tested for their ability to interact with the human telomeric G-quadruplex folding by circular dichroism, fluorescence spectroscopy, and photodynamic techniques. Interestingly, our screening succeeded in retrieving a new promising scaffold for G-quadruplex binders characterized by a psoralen moiety. 23530031 Regulation of the Bone-restricted ifitm-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. Bril encodes a small membrane protein present in osteoblasts. In humans, a single recurrent mutation in the 5'UTR of BRIL causes osteogenesis imperfecta type V. The exact function of BRIL and the mechanism by which it contributes to disease are still unknown. The goal of the current study was to characterize the mechanisms governing Bril transcription in the human, rat and mouse. In the three species, as detected by luciferase reporter assays in UMR106 cells, we found that most of the baseline regulatory activity was localized within ≈250bp upstream of the coding ATG. Co-transfection experiments indicated that Sp1 and Sp3 were potent inducers of the promoter activity, through the binding several GC-rich boxes. Osterix was a weak activator but acted cooperatively with Sp1 and GLI2 to synergistically induce the BRIL promoter. GLI2, a mediator of hedgehog signaling pathway, was also a potent activator of BRIL through a single GLI binding site. Correspondingly, agonists of the Hedgehog pathway (purmorphamine and Indian hedgehog) in MC3T3 osteoblasts led to increased BRIL levels. The BRIL promoter activity was also found to be negatively modulated through two different mechanisms. First, the ZFP354C zinc finger protein repressed basal and Sp1-induced activity. Second, CpG methylation of the promoter region correlated with an inactive state, and prevented Sp1 activation. The data provide the very first analyses of the cis- and trans-acting factors regulating Bril transcription. They revealed key roles for the Sp members and GLI2 that possibly cooperate to activate Bril when the promoter becomes demethylated. 23571664 Bioinspired design and macroscopic assembly of poly(vinyl alcohol)-coated graphene into kilometers-long fibers. Nacre is characterized by its excellent mechanical performance due to the well-recognized "brick and mortar" structure. Many efforts have been applied to make nacre-mimicking materials, but it is still a big challenge to realize their continuous production. Here, we prepared sandwich-like building blocks of poly(vinyl alcohol) (PVA)-coated graphene, and achieved high-nanofiller-content kilometers-long fibers by continuous wet-spinning assembly technology. The fibers have a strict "brick and mortar" layered structure, with graphene sheet as rigid brick and PVA as soft mortar. The mortar thickness can be precisely tuned from 2.01 to 3.31 nm by the weight feed ratio of PVA to graphene, as demonstrated by both atomic force microscopy and X-ray diffraction measurements. The mechanical strength of the nacre-mimicking fibers increases with increasing the content of PVA, and it rises gradually from 81 MPa for the fiber with 53.1 wt% PVA to 161 MPa for the fiber with 65.8 wt% PVA. The mechanical performance of our fibers was independent of the molecular weight (MW) of PVA in the wide range of 2-100 kDa, indicating that low MW polymers can also be used to make strong nanocomposites. The tensile stress of fibers immersed in PVA 5 wt% solution reached ca. 200 MPa, surpassing the values of nacre and most of other nacre-mimicking materials. The nacre-mimicking fibers are highly electrically conductive (∼350 S m(-1)) after immersing in hydroiodic acid, enabling them to connect a circuit to illuminate an LED lamp. 23485616 Subchronic and reproductive toxicity of whole dried Hoodia parviflora aerial parts in the rat. Hoodia parviflora is being developed commercially for use in weight loss food and dietary supplement products. As part of the safety assessment process for H. parviflora, a freeze dried powder preparation was tested in a 90-day oral toxicity study with reproductive/recovery component in rats. Groups of 10 male and female Sprague-Dawley rats were administered H. parviflora dried powder at doses of 0, 100, 250, and 350mg/kg body weight/day by gavage for an 11-week pre-mating period and a 14-day co-habitation period, and for females, through lactation day 4. An additional 5 rats/sex/group received 0 or 350mg/kg bw/day for 90days and were sacrificed 28days after cessation of treatment. Statistically significant, non-adverse reductions in body weight, body weight gain, food consumption and food efficiency were observed at 250 and 350mg/kg/day in females. Food consumption was reduced in high-dose males. There were no adverse effects on hematological, blood biochemical, coagulation or urinalysis parameters or on the results of the functional observational battery and histopathological examinations. No evidence of any effect was noted on reproductive or developmental parameters. The NOAEL for dried H. parviflora powder was 350mg/kg bw/day, the highest permissible dose tested, for both male and female rats. 23323521 Optimization of Non-ATP Competitive CDK/Cyclin Groove Inhibitors through REPLACE-Mediated Fragment Assembly. A major challenge in drug discovery is to develop and improve methods for targeting protein-protein interactions. Further exemplification of the REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) strategy for generating inhibitors of protein-protein interactions demonstrated that it can be used to optimize fragment alternatives of key determinants, to combine these in an effective way, and this was achieved for compounds targeting the cyclin-dependent kinase 2 (CDK2) substrate recruitment site on the cyclin regulatory subunit. Phenylheterocyclic isosteres replacing a critical charge-charge interaction provided new structural insights for binding to the cyclin groove. In particular, these results shed light onto the key contributions of a H-bond observed in crystal structures of N-terminally capped peptides. Furthermore, the structure-activity relationship of a bis(aryl) ether C-terminal capping group mimicking dipeptide interactions was probed through ring substitutions, allowing increased complementarity with the primary hydrophobic pocket. This study further validates REPLACE as an effective strategy for converting peptidic compounds to more pharmaceutically relevant compounds. 23461801 Power spectral density of free-standing viscoelastic films by adiabatic approximation. In a previous study, we calculated the surface dynamics of noisy viscoelastic supported films by using an adiabatic approximation. An expression was derived for the time-dependent power spectral density (PSD), which was found to produce good agreement with experiment. In this study, we extend the treatment to viscoelastic free-standing films. Two sets of surface capillary normal modes, namely, the squeezing and bending modes, were found. The frequency dispersion relation of the former resembles that of supported films. The latter is distinctively different and diverges at long wavelengths. By incorporating the experimental conditions, we obtained satisfactory agreement between theory and experiment. 23347954 H1152 promotes the degradation of polyglutamine-expanded ataxin-3 or ataxin-7 independently of its ROCK-inhibiting effect and ameliorates mutant ataxin-3-induced neurodegeneration in the SCA3 transgenic mouse. Spinocerebellar ataxia type 3 (SCA3) caused by polyglutamine-expanded ataxin-3 is the most prevalent subtype of spinocerebellar ataxias. A compound, which decreases protein level of mutant ataxin-3 in SCA3 affected CNS regions, should be a promising therapeutic agent for SCA3. SCA3 and Huntington's disease (HD) belong to a family of polyglutamine neurodegenerative diseases. Rho-kinase (ROCK) inhibitor Y27632 reduced brain level of polyglutamine-expanded huntingtin in HD transgenic mouse. Therefore, we tested the possibility that ROCK inhibitors, Y27632, H1152 and GSK429286, downregulate protein expression of polyglutamine-expanded ataxin-3-Q79. Y27632 or H1152 reduced protein level of HA-tagged ataxin-3-Q79 (ATX-3-Q79HA) expressed in HEK 293 cells. Compared to Y27632, H1152 decreased ATX-3-Q79HA protein level with a significantly more potency and efficacy. H1152 also reduced protein level of HA-tagged polyglutamine-expanded ataxin-7-Q52 (ATX-7-Q52HA), which causes spinocerebellar ataxia type 7 (SCA7). H1152 decreased ATX-3-Q79HA or ATX-7-Q52HA protein level in vitro by augmenting proteasome activity and promoting ATX-3-Q79HA or ATX-7-Q52HA degradation. GSK429286, which is structurally different from H1152 but equally inhibits ROCK, failed to affect protein level of ATX-3-Q79HA or ATX-7-Q52HA. Furthermore, shRNA-mediated suppression of ROCK1 or ROCK2 expression in 293 cells did not affect protein level of ATX-3-Q79HA or ATX-7-Q52HA and H1152 reduction of ATX-3-Q79HA. Daily intraperitoneal administration of H1152 significantly decreased protein level of ATX-3-Q79HA in the cerebellum, pontine nuclei and spinal cord of SCA3 transgenic mice. H1152 also ameliorated pontine neuronal death and neurological phenotype of SCA3 transgenic mice. Our results suggest that H1152 might be an effective therapeutic agent for SCA3 or SCA7. 23425274 Gel electrophoretic methods for the analysis of biosimilar pharmaceuticals using the example of recombinant erythropoietin. Due to their versatility and cost-effectiveness, gel electrophoretic methods provide an important set of tools for the analysis of therapeutic proteins. As an increasing number of biosimilar pharmaceuticals are entering the market, techniques are required that allow reliable demonstration of comparability of these products with the reference products. Isoelectric focusing, SDS-PAGE, native PAGE and 2D electrophoresis (2D-PAGE) have been frequently applied for this purpose. Supplementary techniques are fluorophore-assisted carbohydrate electrophoresis and sarcosyl-PAGE. Of additional importance is the comparison of recombinant with endogenously synthesized glycoproteins. Reagent array analysis combined with SDS-PAGE and western blotting proved especially useful for this purpose. As an example for the application of these methods, the analysis of recombinant originator erythropoietins and some of their biosimilar counterparts is described. 23466606 A novel insulin mimetic vanadium-flavonol complex: Synthesis, characterization and in vivo evaluation in STZ-induced rats. Since 1985, when Heyliger et al., first demonstrated a serendipitous discovery that oral administration of 0.8 mg/ml of sodium orthovanadate in drinking water to streptozotocin-induced diabetic rats resulted in normoglycemia, numerous extensive studies have been pursued on the anti-diabetic and insulinomimetic actions of vanadium. The acceptance of vanadium compounds as promising therapeutic antidiabetic agents has been slowed due to the concern for chronic toxicity associated with vanadium accumulation. In order to circumvent the toxic effects of vanadium, we have taken up a combinational approach wherein a novel vanadium-flavonol complex was synthesized, characterized and its toxic as well as insulin mimetic potential was evaluated in STZ-induced experimental diabetes in rats. The results indicate that the complex is non-toxic and possess anti-diabetic activity. 23407741 Ruthenium(II) polypyridyl complexes as G-quadruplex inducing and stabilizing ligands in telomeric DNA. Two ruthenium(ii) polypyridyl complexes [Ru(phen)2(4idip)](ClO4)2 () and [Ru(bpy)2(4idip)](ClO4)2 () (phen = 1,10-phenanthroline, bpy = 2,2'-bipyridine, 4idip = 4-indoleimidazo[4,5-f][1,10]phenanthroline) designed as telomeric G-quadruplex ligands have been synthesized and characterized. The interaction of human telomeric G-quadruplex DNA (HTG21) with the designed ligands was explored by fluorescence analysis, absorption spectroscopy, continuous variation, circular dichroism spectroscopy, fluorescence resonance energy transfer (FRET) melting assay, polymerase chain reaction (PCR) stop assay, telomerase repeat amplification protocol (TRAP), and visual studies. The results showed that both complexes could induce and stabilize different G-quadruplex structures by using a 1 : 1 [quadruplex]/[complex] binding mode ratio. Complex exhibited higher interaction ability and better G-quadruplex selectivity than duplex DNA. Furthermore, both ruthenium complexes led to the inhibition of the enzyme telomerase, and complex was the significantly better inhibitor. 23544615 Impurity partitioning during colloidal crystallization. We have found that an impurity partitioning takes place during growth of colloidal crystals, which was recognized by the fact that the impurity concentration in the solid (CS) was different from that in the initial solution (C0). The effective partition coefficient keff (=CS/C0) was investigated for pure polystyrene and polystyrene dyed with fluorescent particles by changing the ratio of particle diameters dimp/dcryst and growth rate V. At each size ratio for the polystyrene impurity, keff was less than unity and increased to unity with increasing V, whereas at a given growth rate, keff increased to unity as dimp/dcryst approached unity. These results were consistent with the solute behavior analyzed using the Burton, Prim, and Slichter (BPS) model. The obtained k0, equilibrium partition coefficient, from a BPS plot increased as dimp/dcryst approached unity. In contrast, while the fluorescent particles also followed the BPS model, they showed higher k0 values than those of the same size of polystyrene particles. A k0 value greater than unity was obtained for impurities that were similar in size to the host particle. This behavior is attributed to the positive free energy of fusion associated with the incorporation of the fluorescent particles into the host matrix. Such positive free energy of fusion implies the presence of the enthalpy associated with interaction between particles. 23564917 Low-Carbohydrate Diet for the Treatment of Gestational Diabetes: A randomized controlled trial. OBJECTIVEMedical nutrition therapy based on the control of the amount and distribution of carbohydrates (CHO) is the initial treatment for gestational diabetes mellitus (GDM), but there is a need for randomized controlled trials comparing different dietary strategies. The purpose of this study was to test the hypothesis that a low-CHO diet for the treatment of GDM would lead to a lower rate of insulin treatment with similar pregnancy outcomes compared with a control diet.RESEARCH DESIGN AND METHODSA total of 152 women with GDM were included in this open, randomized controlled trial and assigned to follow either a diet with low-CHO content (40% of the total diet energy content as CHO) or a control diet (55% of the total diet energy content as CHO). CHO intake was assessed by 3-day food records. The main pregnancy outcomes were also assessed.RESULTSThe rate of women requiring insulin was not significantly different between the treatment groups (low CHO 54.7% vs. control 54.7%; P = 1). Daily food records confirmed a difference in the amount of CHO consumed between the groups (P = 0.0001). No differences were found in the obstetric and perinatal outcomes between the treatment groups.CONCLUSIONSTreatment of women with GDM using a low-CHO diet did not reduce the number of women needing insulin and produced similar pregnancy outcomes. In GDM, CHO amount (40 vs. 55% of calories) did not influence insulin need or pregnancy outcomes. 23624607 Growth and potential damage of human bone-derived cells on fresh and aged fullerene c60 films. Fullerenes are nanoparticles composed of carbon atoms arranged in a spherical hollow cage-like structure. Numerous studies have evaluated the therapeutic potential of fullerene derivates against oxidative stress-associated conditions, including the prevention or treatment of arthritis. On the other hand, fullerenes are not only able to quench, but also to generate harmful reactive oxygen species. The reactivity of fullerenes may change in time due to the oxidation and polymerization of fullerenes in an air atmosphere. In this study, we therefore tested the dependence between the age of fullerene films (from one week to one year) and the proliferation, viability and metabolic activity of human osteosarcoma cells (lines MG-63 and U-2 OS). We also monitored potential membrane and DNA damage and morphological changes of the cells. After seven days of cultivation, we did not observe any cytotoxic morphological changes, such as enlarged cells or cytosolic vacuole formation. Furthermore, there was no increased level of DNA damage. The increasing age of the fullerene films did not cause enhancement of cytotoxicity. On the contrary, it resulted in an improvement in the properties of these materials, which are more suitable for cell cultivation. Therefore, fullerene films could be considered as a promising material with potential use as a bioactive coating of cell carriers for bone tissue engineering. 23259708 Controlling the pulsed-laser-induced size reduction of Au and Ag nanoparticles via changes in the external pressure, laser intensity, and excitation wavelength. The laser-induced size reduction of aqueous noble metal nanoparticles has been the subject of intensive research, because of the mechanistic interest in the light-nanoparticle interactions and its potential application to size control. The photothermal evaporation hypothesis has gained solid support. However, the polydispersity of the final products is considered as an inherent drawback of the method. It is likely that the polydispersity arises from the uncontrolled heat dissipation caused by vapor bubble formation in the ambient atmosphere. To overcome this problem, we applied high pressures of 30-100 MPa. The particle size was regulated by adjusting three parameters: the pressure, laser intensity, and excitation wavelength. For example, starting from a colloidal solution of 100 nm diameter gold nanoparticles, highly monodisperse (±3-5%) spheres with various diameters ranging from 90 to 30 nm were fabricated by tuning the laser intensity at 100 MPa, using an excitation wavelength of 532 nm. Further size reduction of the diameter to 20 nm was achieved by reducing the pressure and switching the excitation wavelength to 355 nm. It was found that the application of high pressures led to the heat loss-controlled size-reduction of the gold nanoparticles. More complicated results were obtained for 100 nm silver nanoparticles, possibly because of the different size-dependent light-absorbing nature of these particles. Based on our extensive experimental studies, a detailed picture was developed for the nanosecond laser-induced fabrication of gold and silver nanoparticles, leading to unprecedented size control. 23500660 Vanadium exposure-induced neurobehavioral alterations among Chinese workers. Vanadium-containing products are manufactured and widely used in the modern industry. Yet the neurobehavioral toxicity due to occupational exposure to vanadium remained elusive. This cross-sectional study was designed to examine the neurotoxic effects of occupational vanadium exposure. A total of 463 vanadium-exposed workers (exposed group) and 251 non-exposed workers (control group) were recruited from a Steel and Iron Group in Sichuan, China. A WHO-recommended neurobehavioral core test battery (NCTB) and event-related auditory evoked potentials test (P300) were used to assess the neurobehavioral functions of all study subjects. A general linear model was used to compare outcome scores between the two groups while controlling for possible confounders. The exposed group showed a statistically significant neurobehavioral alteration more than the control group in the NCTB tests. The exposed workers also exhibited an increased anger-hostility, depression-dejection and fatigue-inertia on the profile of mood states (p<0.05). Performances in the simple reaction time, digit span, benton visual retention and pursuit aiming were also poorer among exposed workers as compared to unexposed control workers (p<0.05). Some of these poor performances in tests were also significantly related to workers' exposure duration. P300 latencies were longer in the exposed group than in the control (p<0.05). Longer mean reaction times and more counting errors were also found in the exposed workers (p<0.05). Given the findings of our study and the limitations of neurobehavioral workplace testing, we found evidence of altered neurobehavioral outcomes by occupational exposure to vanadium. 23401228 [6]-Shogaol Attenuates Neuronal Apoptosis in Hydrogen Peroxide-Treated Astrocytes Through the Up-Regulation of Neurotrophic Factors. Neuronal apoptosis induced by oxidative stress is a prominent feature of neurodegenerative disorders. [6]-shogaol, a bio-active compound in ginger, possesses potent anti-inflammatory actions and has recently emerged as a potential therapeutic agent for neurodegenerative disorders. However, the effects of [6]-shogaol on astroglial apoptosis following exogenously induced oxidative stress has not yet been investigated. Here, we show that the anti-apoptotic activity of [6]-shogaol in astrocytes following exposure to hydrogen peroxide (H(2) O(2) ) involves a marked up-regulation of neurotrophic factors such as nerve growth factor, glial cell line-derived neurotrophic factor, and brain-derived neurotrophic factor. Astrocytes co-treated with [6]-shogaol and H(2) O(2) for 1 h showed decrease in reactive oxygen species production compared with those only treated with H(2) O(2) . Moreover, [6]-shogaol counteracted the reduced expression of ERK1/2 in H(2) O(2) -treated astrocytes and protected these cells from oxidative stress and apoptosis by attenuating the impairment of mitochondrial function proteins such as Bcl-2 and Bcl-xL. Additionally, [6]-shogaol inhibits the expression of the apoptotic proteins Bax and caspase-3 in H(2) O(2) -treated astrocytes. This data suggest that following oxidative stress, [6]-shogaol protects astrocytes from oxidative damage through the up-regulating levels of neurotrophic factors. These findings provide further support for the use of [6]-shogaol as a therapeutic agent in neurodegenerative disorders. Copyright © 2013 John Wiley & Sons, Ltd. 23631440 Matrix Metalloproteinase Inhibitors Based on the 3-Mercaptopyrrolidine Core. New series of pyrrolidine mercaptosulfide, 2-mercaptocyclopentane arylsulfonamide, and 3-mercapto-4-arylsulfonamido pyrrolidine matrix metalloproteinase inhibitors (MMPIs) were designed, synthesized, and evaluated. Exhibiting unique properties over other MMPIs (e.g., hydroxamates), these newly reported compounds are capable of modulating activities of several MMPs in the low nanomolar range, including MMP-2 (~2 to 50 nM), MMP-13 (~2 to 50 nM), and MMP-14 (~4 to 60 nM). Additionally these compounds are selective to intermediate- and deep-pocket MMPs but not shallow-pocketed MMPs (e.g., MMP-1, ~850 to >50,000 nM; MMP-7, ~4,000 to >25,000 nM). Our previous work with the mercaptosulfide functionality attached to both cyclopentane and pyrrolidine frameworks demonstrated that the cis-(3S,4R)- stereochemistry was optimal for all of the MMPs tested. However, in our newest compounds an interesting shift of preference to the trans- form of the mercaptosulfonamides was observed with increased oxidative stability and biological compatibility. We also report several kinetic and biological characteristics showing that these compounds may be used to probe the mechanistic activities of MMPs in disease. 22983790 Experiences of microsurgical reconstruction for variant hepatic artery in living donor liver transplantation. There is an emergent need for improving the microsurgical technique of variant arterial anastomosis to reduce the often seen surgery-related complications. We describe in this article our experience in improving this technique, in 73 living donor liver grafts (64 right lobes, 9 left lobes) in patients with end-stage liver disease during living donor liver transplantation. The hepatic arteries were evaluated preoperatively with computed tomography and magnetic resonance angiography. In this series, 13 grafts (17.80 %) with variant hepatic artery were conducted arterioplasty on a back-table under a loupe or a high-power microscope, which included one recipient in situ interposition vessel graft of recipient proper hepatic artery for artery reconstruction. The back-table reconstruction time was 16 ± 5.6 min. No arterial thrombosis was found in these cases during the 6-month postoperative follow-up. On the basis of our experience, we suggest that back-table microsurgical plasty for graft with arterial variation should be applied to minimize operative difficulties and to avoid arterial complications in living donor liver transplantation. 23321216 Evaluation of a Self-Administered Oral Glucose Tolerance Test. OBJECTIVETo assess the feasibility of using a disposable, self-administered, capillary blood sampling oral glucose tolerance test (OGTT) device in a community setting.RESEARCH DESIGN AND METHODSEighteen healthy and 12 type 2 diabetic volunteers underwent six 75-g OGTTs using a prototype device in the following three settings: unaided at home (twice); unaided but observed in clinic (twice); and performed by a nurse with simultaneous laboratory glucose assays of 0- and 120-min venous plasma samples (twice). The device displayed no results. A detachable data recorder returned to the clinic provided plasma-equivalent 0- and 120-min glucose values and key parameters, including test date, start and end times, and time taken to consume the glucose drink.RESULTSThe device was universally popular with participants, was perceived as easy to use, and the ability to test at home was well-liked. Device failures meant that 0- and 120-min glucose values were obtained for only 141 (78%) of the 180 OGTTs performed, independent of setting. Device glucose measurements showed a mean bias compared with laboratory-measured values of +0.9 at 5.0 mmol/L increasing to +4.4 at 15.0 mmol/L. Paired device glucose values were equally reproducible across settings, with repeat testing showing no training effect regardless of setting order.CONCLUSIONSSelf-administered OGTTs can be performed successfully by untrained individuals in a community setting. With improved device reliability and appropriate calibration, this novel technology could be used in routine practice to screen people who might need a formal OGTT to confirm the presence of impaired glucose tolerance or diabetes. 23484593 Embellicines A and B: Absolute Configuration and NF-κB Transcriptional Inhibitory Activity. Two new metabolites, embellicines A and B (1 and 2), were isolated from the EtOAc extract of the fungus Embellisia eureka , an endophyte of the Moroccan plant Cladanthus arabicus (Asteraceae). The structures of these new compounds were determined on the basis of extensive one- and two-dimensional NMR spectroscopy as well as by high-resolution mass spectrometry. The absolute configuration of embellicine A (1) was determined by TDDFT ECD calculations of solution conformers, whereas that of embellicine B (2) was deduced based on ROESY correlations and on biogenetic considerations in comparison to 1. Both embellicines (1 and 2) are cytostatic, cytotoxic, and inhibit NF-κB transcriptional activity, indicating that inhibition of NF-κB may be a possible mechanism of action of these compounds. Embellicine B (2) was the most active compound encountered in this study and acts at nanomolar concentrations without affecting tumor microenvironment. 23293129 Antigenotoxic potencies of a lichen species, Evernia prunastri. In this article, the genotoxic and antigenotoxic effects of methanol extract of Evernia prunastri (Huds.) Willd. (MEP) were studied using WP2, Ames (TA1535 and TA1537) and sister chromatid exchange (SCE) test systems. The results obtained from bacterial test systems demonstrated that MEP has strong antimutagenic potencies on TA1537 and WP2 strains. The highest inhibition rates for MEP on TA1537 and WP2 strains were 37.70% and 69.70%, respectively. According to the SCE test system, MEP reduced the genotoxic effects of aflatoxin. In order to clarify the mechanism underlying the antigenotoxic effects of MEP, the antioxidants were determined. Cotreatments of 5, 10 and 20 µg/mL concentrations of MEP with aflatoxin B(1) decreased the frequencies of SCE and the malondialdehyde level and increased amount of superoxide dismutase, glutathione and glutathione peroxidase which were decreased by aflatoxin. The data obtained from this work have clearly shown that MEP has significant antigenotoxic effects which are thought to be partly due to the antioxidant activities and antioxidant inducing capability of MEP. This is the first report indicating the antigenotoxic activities of MEP against several mutagen agents such as N-methyl-N'-nitro-N-nitrosoguanidine, acridin and aflatoxin. 23453003 Hydrocarbons (jet fuel JP-8) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. Environmental compounds have been shown to promote epigenetic transgenerational inheritance of disease. The current study was designed to determine if a hydrocarbon mixture involving jet fuel (JP-8) promotes epigenetic transgenerational inheritance of disease. Gestating F0 generation female rats were transiently exposed during the fetal gonadal development period. The direct exposure F1 generation had an increased incidence of kidney abnormalities in both females and males, prostate and pubertal abnormalities in males, and primordial follicle loss and polycystic ovarian disease in females. The first transgenerational generation is the F3 generation, and the jet fuel lineage had an increased incidence of primordial follicle loss and polycystic ovarian disease in females, and obesity in both females and males. Analysis of the jet fuel lineage F3 generation sperm epigenome identified 33 differential DNA methylation regions, termed epimutations. Observations demonstrate hydrocarbons can promote epigenetic transgenerational inheritance of disease and sperm epimutations, potential biomarkers for ancestral exposures. 23639798 Valeriana officinalis attenuates the rotenone-induced toxicity in Drosophila melanogaster. In this study, we investigated the potential protective effects of Valeriana officinalis (V. officinalis) against the toxicity induced by rotenone in Drosophila melanogaster (D. melanogaster). Adult wild-type flies were concomitantly exposed to rotenone (500μM) and V. officinalis aqueous extract (10mg/mL) in the food during 7 days. Rotenone-fed flies had a worse performance in the negative geotaxis assay (i.e. climbing capability) and open-field test (i.e. mobility time) as well as a higher incidence of mortality when compared to control group. V. officinalis treatment offered protection against these detrimental effects of rotenone. In contrast, the decreased number of crossings observed in the flies exposed to rotenone was not modified by V. officinalis. Rotenone toxicity was also associated with a marked decrease on the total-thiol content in the homogenates and cell viability of flies, which were reduced by V. officinalis treatment. Indeed, rotenone exposure caused a significant increase in the mRNA expression of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) and also in the tyrosine hydroxylase gene (TH). The expression of SOD and CAT mRNAs were normalized by V. officinalis treatment. Our results suggest that V. officinalis extract was effective in reducing the toxicity induced by rotenone in D. melonogaster as well as confirm the utility of this model to investigate potential therapeutic strategies on movement disorders, including Parkinson disease (PD). 23388095 Prolyl-hydroxylase inhibition preserves endothelial cell function in a rat model of vascular ischemia reperfusion injury. Storage protocols of vascular grafts need further improvement against ischemia-reperfusion (IR) injury. Hypoxia elicits a variety of complex cellular responses by altering the activity of many signaling pathways, such as the oxygen-dependent prolyl-hyroxylase domain-containing enzyme (PHD). Reduction of PHD activity during hypoxia leads to stabilization and accumulation of hypoxia inducible factor (HIF) 1α. We examined the effects of PHD inhibiton by dimethyloxalylglycine on the vasomotor responses of isolated rat aorta and aortic vascular smooth muscle cells (VSMCs) in a model of cold ischemia/warm reperfusion. Aortic segments underwent 24 hours of cold ischemic preservation in saline or DMOG (dimethyloxalylglycine)-supplemented saline solution. We investigated endothelium-dependent and -independent vasorelaxations. To simulate IR injury, hypochlorite (NaOCl) was added during warm reperfusion. VSMCs were incubated in NaCl or DMOG solution at 4°C for 24 hours after the medium was changed for a supplied standard medium at 37°C for 6 hours. Apoptosis was assessed using the TUNEL method. Gene expression analysis was performed using quantitative real-time polymerase chain reaction. Cold ischemic preservation and NaOCl induced severe endothelial dysfunction, which was significantly improved by DMOG supplementation (maximal relaxation of aortic segments to acetylcholine: control 95% ± 1% versus NaOCl 44% ± 4% versus DMOG 68% ± 5%). Number of TUNEL-positive cell nuclei was significantly higher in the NaOCl group, and DMOG treatment significantly decreased apoptosis. Inducible heme-oxygenase 1 mRNA expressions were significantly higher in the DMOG group. Pharmacological modulation of oxygen sensing system by DMOG in an in vitro model of vascular IR effectively preserved endothelial function. Inhibition of PHDs could therefore be a new therapeutic avenue for protecting endothelium and vascular muscle cells against IR injury. 23252799 Selective separation of similarly sized proteins with tunable nanoporous block copolymer membranes. An integral asymmetric membrane was fabricated in a fast and one-step process by combining the self-assembly of an amphiphilic block copolymer (PS-b-P4VP) with nonsolvent-induced phase separation. The structure was found to be composed of a thin layer of densely packed highly ordered cylindrical channels with uniform pore sizes perpendicular to the surface on top of a nonordered sponge-like layer. The as-assembled membrane obtained a water flux of more than 3200 L m(-2) h(-1) bar(-1), which was at least an order of magnitude higher than the water fluxes of commercially available membranes with comparable pore sizes, making this membrane particularly well suited to size-selective and charge-based separation of biomolecules. To test the performance of the membrane, we conducted diffusion experiments at the physiological pH of 7.4 using bovine serum albumin (BSA) and globulin-γ, two proteins with different diameters but too close in size (2-fold difference in molecular mass) to be efficiently separated via conventional dialysis membrane processes. The diffusion rate differed by a factor of 87, the highest value reported to date. We also analyzed charge-based diffusive transport and separation of two proteins of similar molecular weight (BSA and bovine hemoglobin (BHb)) through the membrane as a function of external pH. The membrane achieved a selectivity of about 10 at pH 4.7, the isoelectric point (pI) of BSA. We then positively charged the membrane to improve the separation selectivity. With the modified membrane BSA was completely blocked when the pH was 7.0, the pI of BHb, while BHb was completely blocked at pH 4.7. Our results demonstrate the potential of our asymmetric membrane to efficiently separate biological substances/pharmaceuticals in bioscience, biotechnology, and biomedicine applications. 23339742 Single molecule characterization of the interactions between amyloid-β peptides and the membranes of hippocampal cells. Oligomers of the 40 and 42 residue amyloid-β peptides (Aβ40 and Aβ42) have been implicated in the neuronal damage and impaired cognitive function associated with Alzheimer's disease. However, little is known about the specific mechanisms by which these misfolded species induce such detrimental effects on cells. In this work, we use single-molecule imaging techniques to examine the initial interactions between Aβ monomers and oligomers and the membranes of live cells. This highly sensitive method enables the visualization of individual Aβ species on the cell surface and characterization of their oligomerization state, all at biologically relevant, nanomolar concentrations. The results indicate that oligomers preferentially interact with cell membranes, relative to monomers and that the oligomers become immobilized on the cell surface. Additionally, we observe that the interaction of Aβ species with the cell membrane is inhibited by the presence of ATP-independent molecular chaperones. This study demonstrates the power of this methodology for characterizing the interactions between protein aggregates and the membranes of live neuronal cells at physiologically relevant concentrations and opens the door to quantitative studies of the cellular responses to potentially pathogenic oligomers. 23552831 Synthesis and characterization of naphthalenediimide-functionalized flavin derivatives. Two acceptor-acceptor dyads have been synthesized featuring a flavin moiety and a naphthalenediimide (NDI) unit. The NDI unit is linked to the flavin through a short spacer group via either the N(3) or N(10) positions of the flavin. We have investigated the UV-Vis and redox properties of these multi-electron accepting systems which indicate that these materials display the collective properties of their component systems. Fluorescence spectroscopy measurements have revealed that their emission properties are dominated by the flavin unit. 23182766 Control of hypercholesterolemia and atherosclerosis using the cholesterol recognition/interaction amino acid sequence of the translocator protein TSPO. The translocator protein (18-kDa) TSPO is an ubiquitous high affinity cholesterol-binding protein reported to be present in the endothelial and smooth muscle cells of the blood vessels; its expression dramatically increased in macrophages found in atherosclerotic plaques. A domain in the carboxy-terminus of TSPO was identified and characterized as the cholesterol recognition/interaction amino acid consensus (CRAC). The ability of the CRAC domain to bind to cholesterol led us to hypothesize that this peptide could be used as an hypocholesterolemic, with potential anti-atherogenic properties, agent. We report herein the therapeutic benefit that resulted for the administration of the VLNYYVWR human CRAC sequence to guinea pigs fed with a high cholesterol diet and ApoE knock-out B6.129P2-Apoetm1Unc/J mice. CRAC treatment (3 and 30mg/kg once daily for 6 weeks) resulted in reduced circulating cholesterol levels in guinea pigs fed with 2% high cholesterol diet and ApoE knock-out B6.129P2-Apoetm1Unc/J mice. In high cholesterol fed guinea pigs, CRAC treatment administered once daily induced an increase in circulating HDL, decreased total, free and LDL cholesterol, and removed atheroma deposits in the aorta in a dose-dependent manner. The treatment also prevented the high cholesterol diet-induced increase in serum creatine kinase, total and isoforms, markers of neurological, cardiac and muscular damage. No toxicity was observed. Taken together these results support a role of TSPO in lipid homeostasis and atherosclerosis and indicate that CRAC may constitute a novel and safe treatment of hypercholesterolemia and atherosclerosis. 23303199 EPR spin Hamiltonian parameters of encapsulated spin-labels: impact of the hydrogen bonding topology. Encapsulation of spin-labels into "host" compounds, like cucurbit[n]urils or cyclodextrins, in solutions has profound effects on the EPR spin Hamiltonian parameters of the spin-labels. In this work we study the microscopic origin of the EPR spin Hamiltonian parameters of spin-labels enclosed in hydrophobic cavities. We focus on the dependence of the EPR properties of encapsulated spin-labels on the hydrogen bonding topologies that occur upon encapsulation, and quantize various contributions to these parameters according to specific hydrogen bonding patterns. The obtained results provide refined insight into the role of the hydrogen bonding induced encapsulation shifts of EPR spin Hamiltonian parameters in solvated "spin-label@host compound" complexes. 23514537 Colocalization of the Ganglioside GM1 and Cholesterol Detected by Secondary Ion Mass Spectrometry. The characterization of the lateral organization of components in biological membranes and the evolution of this arrangement in response to external triggers remain a major challenge. The concept of lipid rafts is widely invoked; however, direct evidence of the existence of these ephemeral entities remains elusive. We report here the use of secondary ion mass spectrometry (SIMS) to image the cholesterol-dependent cohesive phase separation of the ganglioside GM1 into nano- and microscale assemblies in a canonical lipid raft composition of lipids. This assembly of domains was interrogated in a model membrane system composed of palmitoyl sphingomyelin (PSM), cholesterol, and an unsaturated lipid (dioleoylphosphatidylcholine, DOPC). Orthogonal isotopic labeling of every lipid bilayer component and monofluorination of GM1 allowed generation of molecule specific images using a NanoSIMS. Simultaneous detection of six different ion species in SIMS, including secondary electrons, was used to generate ion ratio images whose signal intensity values could be correlated to composition through the use of calibration curves from standard samples. Images of this system provide the first direct, molecule specific, visual evidence for the colocalization of cholesterol and GM1 in supported lipid bilayers and further indicate the presence of three compositionally distinct phases: (1) the interdomain region; (2) micrometer-scale domains (d > 3 μm); (3) nanometer-scale domains (d = 100 nm to 1 μm) localized within the micrometer-scale domains and the interdomain region. PSM-rich, nanometer-scale domains prefer to partition within the more ordered, cholesterol-rich/DOPC-poor/GM1-rich micrometer-scale phase, while GM1-rich, nanometer-scale domains prefer to partition within the surrounding, disordered, cholesterol-poor/PSM-rich/DOPC-rich interdomain phase. 23354151 Drug "supersaturation" states induced by polymeric micelles and liposomes: a mechanistic investigation into permeability enhancements. The objective of this study was to investigate if the increase in apparent solubility induced by liposomalization or micellization of the poorly soluble drug hydrocortisone (HC) would lead to an enhancement of its permeability through biological membranes. For this purpose phosphatidylcholine liposome formulations as well as d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) micelle dispersions and polyvinylpyrrolidone (PVP) supersaturated solutions were prepared in order to increase the apparent solubility of HC. Both the apparent solubility of hydrocortisone (i.e. amount of drug entrapped plus non-entrapped in the carriers) as well as the concentration of molecularly dissolved drug (i.e. fraction non-entrapped into carriers, truly molecularly dissolved fraction) were characterized. Subsequently, the permeability of hydrocortisone was assessed for each type of formulation using the in vitro sheep nasal mucosa permeability assay. In all formulations where solubilizing agents are present, an enhanced flux of HC (compared to the pure drug powder suspension) is observed. The expected linear correlation between apparent solubilities and fluxes was not found, whereas, the concentrations of molecularly dissolved HC were found to be directly proportional to the respective fluxes. This is an experimental proof for the hypothesis that, of all the strategies to increase the apparent solubility of poorly soluble drugs, enhancement of the molecularly dissolved drug concentration (induction of true supersaturation) would lead to better permeation though membranes. 23180449 Three-dimensional hierarchical GeSe2 nanostructures for high performance flexible all-solid-state supercapacitors. Highly flexible stacked and in-plane all-solid-state supercapacitors are fabricated on 3D hierarchical GeSe2 nanostructures with high performance, and, when configured as a self-powered photodetector nanosystem, can be used to power CdSe nanowire photodetectors. 23396400 Meta-immunological profiling of children with type 1 diabetes identifies new biomarkers to monitor disease progression. Type 1 diabetes is characterized by autoimmune destruction of pancreatic β-cells in genetically susceptible individuals. Triggers of islet autoimmunity, time course and the precise mechanisms responsible for the progressive β-cell failure are not completely understood. The recent escalation of obesity in affluent countries has been suggested to contribute to the increased incidence of type 1 diabetes. Understanding the link between metabolism and immune tolerance could lead to the identification of new markers for the monitoring of disease onset and progression. We studied several immune cell subsets and factors with high metabolic impact as markers associated with disease progression in high-risk subjects, type 1 diabetes patients at onset, 12 and 24 months after diagnosis. A multiple correlation matrix among different parameters was evaluated statistically and assessed visually on two-dimensional graphs. Markers to predict residual β-cell function up to one year after diagnosis were identified in multivariate logistic regression models. The metaimmunological profile changed significantly over time in patients and a specific signature that associated with worsening disease was identified. A multivariate logistic regression model measuring age, body mass index (BMI), fasting C-peptide, number of circulating CD3(+)CD16(+)CD56(+) cells and the percentage of CD1c(+)CD19(-)CD14(-)CD303(-) type 1 myeloid dendritic cells (mDC1s) at disease onset had a significant predictive value. The identification of a specific meta-immunological profile associated to disease status may contribute to understand the basis of diabetes progression. 23444428 Prokaryotic multicellularity: a nanopore array for bacterial cell communication. The transition from unicellular to multicellular life, which occurred several times during evolution, requires tight interaction and communication of neighboring cells. The multicellular cyanobacterium Nostoc punctiforme ATCC 29133 forms filaments of hundreds of interacting cells exchanging metabolites and signal molecules and is able to differentiate specialized cells in response to environmental stimuli. Mutation of cell wall amidase AmiC2 leads to a severe phenotype with formation of aberrant septa in the distorted filaments, which completely lack cell communication and potential for cell differentiation. Here we demonstrate the function of the amidase AmiC2 in formation of cell-joining structures. The AmiC2 protein localizes to the young septum between cells and shows bona fide amidase activity in vivo and in vitro. Vancomycin staining identified the overall septum morphology in living cells. By electron microscopy of isolated peptidoglycan sacculi, the submicroscopic structure of the cell junctions could be visualized, revealing a novel function for a cell wall amidase: AmiC2 drills holes into the cross-walls, forming an array of ∼155 nanopores with a diameter of ∼20 nm each. These nanopores seem to constitute a framework for cell-joining proteins, penetrating the cell wall. The entire array of junctional nanopores appears as a novel bacterial organelle, establishing multicellularity in a filamentous prokaryote.-Lehner, J., Berendt, S., Dörsam, B., Pérez, R., Forchhammer, K., Maldener, I. Prokaryotic multicellularity: a nanopore array for bacterial cell communication. 23258772 Oral exposure to industrial effluent with exceptionally high levels of drugs does not indicate acute toxic effects in rats. The Patancheru area near Hyderabad in India is recognized as a key link in the global supply chain for many bulk drugs. A central treatment plant receives wastewater from approximately 90 different manufacturers, and the resulting complex effluent has contaminated surface, ground, and drinking water in the region. Ecotoxicological testing of the effluent has shown adverse effects for several organisms, including aquatic vertebrates, at high dilutions. In addition, a recent study of microbial communities in river sediment indicated that the contamination of antibiotic substances might contribute to the emergence and spread of antibiotic resistance genes. In an attempt to start investigating how exposure to effluent-contaminated water may directly affect humans and other terrestrial vertebrates, rats were tube-fed effluent. Several pharmaceuticals present in the effluent could be detected in rat blood serum at low concentrations. However, results from exploratory microarray and quantitative polymerase chain reaction assays indicated no marked effects on hepatic gene transcription after 5 d of exposure. Clinical analysis of blood serum constituents, used as biomarkers for human disease did not reveal any significant changes, nor was there an effect on weight gain. The authors could not find evidence for any acute toxicity in the rat; however, the authors cannot rule out that was there an effect on weight gain higher doses of effluent or a longer exposure time may still be associated with risks for terrestrial vertebrates. 23561182 Antioxidant, free radical scavenging and liver protective effects of friedelin isolated from Azima tetracantha Lam. leaves. The aim of the present study was to evaluate the antioxidant, free radical scavenging and liver protective effects of friedelin isolated from Azima tetracantha Lam. leaves. In in vitro antioxidant study, the free radical scavenging effect of friedelin on 2,2-diphenyl-picrylhydrazyl (DPPH), hydroxyl, nitric oxide and superoxide radicals were evaluated. Friedelin showed very good scavenging effect on DPPH (IC50 21.1mM), hydroxyl (IC50 19.8mM), nitric oxide (IC50 22.1mM) and superoxide (IC50 21.9mM) radicals. Friedelin also showed strong suppressive effect on lipid peroxidation. In in vivo antioxidant study, CCl4 induced oxidative stress on rats produced significant increase in serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT) and lactate dehydrogenase (LDH) levels along with reduction in liver superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathione peroxidase (GPx) levels. Pre-treatment of rats with friedelin at 40mg/kg for 7days restored these levels to normality and showed liver protection, comparable to the standard, silymarin (25mg/kg). These results clearly demonstrated that friedelin possessed marked antioxidant and liver protective effects. 23367873 Inhibitors of JAK2 and JAK3: an update on the patent literature 2010 - 2012. INTRODUCTION: Janus kinases (JAKs) comprise a family of four enzymes, JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2), centrally implicated in cell signaling processes important in cancer and immune-inflammatory diseases. Progression in the field has taken a recent step forward with the approval of ruxolitinib (Jakafi), a selective inhibitor of JAK1/2 and very recently tofacitinib (Xeljanz), a pan-JAK inhibitor. There are many new JAK family enzyme inhibitors in the clinic now with a range of selectivity profiles. More selective JAK2 or JAK3 compounds are now coming through in considerable numbers and this review attempts to provide an update of the recent patent literature of those new compounds. An overview is given on the diversity of core structures employed for inhibitor design showing that the vast majority of compounds are based on classic ATP-competitive kinase inhibitor heterocycles. AREAS COVERED: This review updates new patents claiming JAK2 and/or JAK3 inhibitors published from 2010 to 2012. Pre-2010 patents have been extensively covered in previous reviews. Comments on the context of each chemical series are given where applicable to orientate the readers on the bewildering array of molecular designs now available. This review does not cover JAK1 or TYK2 inhibitors but mention is made of these where they occur within series of JAK2/3 inhibitors. Given the overlap between many pharmacophores, it was not possible to completely separate inhibitors of JAK2 from JAK3, hence the material is organized by JAK2, JAK3 and JAK2/3 and within each section by alphabetical order of the patent assignee, some companies having published five or more patents, such as Ambit (10), Incyte (9), Galapagos (7), Almirall (6) and Biocryst (5). A total of 98 patents are reviewed herein. EXPERT OPINION: JAK inhibitor therapy is entering a significant new era with the advent on the market of the JAK1/2 inhibitor ruxolitinib and the pan-JAK inhibitor tofacitinib, with unprecedented speed of development. Selectivity against the four individual JAK family enzymes, JAK1, 2, 3 and TYK2, is now a key goal since they each play subtly different roles in cytokine-induced cell signaling. The future looks bright for patients as many new drugs are being developed and now combinations of JAK inhibitors with other targeted agents are being studied in the clinic. These advances are expected to lead to further significant progress improving patient outcomes and quality of life. 23601700 In Vitro Reconstitution of Complexes between proMatrix Metalloproteinase-9 and the Proteoglycans Serglycin and Versican. Previously we have shown that a fraction of the matrix metalloproteinase-9 (MMP-9) synthesized by the macrophage cell line THP-1 was bound to a chondroitin sulphate proteoglycan (CSPG) core protein as a reduction sensitive heteromer. It was also shown that the hemopexin-like (PEX) domain and the fibronectin-like (FnII) module in the enzyme are involved in the heteromer formation. In the present work we show that reduction sensitive and SDS-stable heteromers can be reconstituted in vitro by mixing proMMP-9 with either serglycin, versican or CSPGs isolated from various monocytic cell lines. In addition, a strong but SDS-soluble proMMP-9·CSPG heteromer was formed. The two macromolecules in the SDS-stable reduction sensitive heteromers were not linked together by disulphide bonds. As for the heteromer isolated from THP-1 cells, the in vitro reconstituted SDS-stable and SDS-soluble heteromers had a weaker binding to gelatin than the proMMP-9 monomer. Furthermore, gelatin inhibited the in vitro reconstitution of the heteromers, showing that the FnII module is involved in the complex formation. TIMP-1 could not be detected in the formed proMMP-9·CSPG complexes. However, the presence of TIMP-1 inhibited the formation of the SDS-soluble heteromer, but not the SDS-stable reduction sensitive heteromer. This indicates that different regions in the PEX domain are involved the formation of these heteromers. This article is protected by copyright. All rights reserved. 23391274 Quasiclassical trajectory and statistical quantum calculations for the C + OH → CO + H reaction on the first excited 1(2)A″ potential energy surface. We report quasiclassical trajectory dynamical calculations for the C((3)P) + OH(X(2)Π) → CO(a(3)Π) + H((2)S) using a recently developed ab initio potential energy surface for the first electronic state of HCO of 1(2)A″ symmetry. The dependence of integral cross sections on the collision energy was determined. Product energy and angular distributions have also been calculated. Integral cross sections show no energy threshold and decrease as the collision energy increases. The comparison with results obtained from a statistical quantum method seems to confirm that the reaction is mainly dominated by an indirect mechanism in which a long-lived intermediate complex is involved. 23562376 Transfer of metformin across the rat placenta is mediated by organic cation transporter 3 (OCT3/SLC22A3) and multidrug and toxin extrusion 1 (MATE1/SLC47A1) protein. In our previous studies we described functional expression of organic cation transporter 3 (OCT3) and multidrug and toxin extrusion 1 (MATE1) protein in the rat placenta. Since metformin is a substrate of both OCT3 and MATE1, in this study we used the model of dually perfused rat placenta to investigate the role of these transporters in metformin passage across the placenta. We observed concentration-dependent transplacental clearance of metformin in both maternal-to-fetal and fetal-to-maternal directions; in addition metformin crossed the placenta from the fetal to maternal compartment even against its concentration gradient. This transport was completely inhibited by MPP(+), a common OCT3 and MATE1 inhibitor. Furthermore, we observed that the oppositely directed H(+)-gradient can drive the secretion of metformin from placenta to maternal circulation, confirming apical efflux of metformin from trophoblast by MATE1. In conclusion, we suggest an important role of OCT3 and MATE1 in the transplacental transfer of metformin. 23178257 Vitamin D receptor signaling mechanisms: integrated actions of a well-defined transcription factor. The main physiological actions of the biologically most active metabolite of vitamin D, 1α,25-dihydroxyvitamin D(3) (1α,25(OH)(2)D(3)), are calcium and phosphorus uptake and transport and thereby controlling bone formation. Other emergent areas of 1α,25(OH)(2)D(3) action are in the control of immune functions, cellular growth and differentiation. All genomic actions of 1α,25(OH)(2)D(3) are mediated by the transcription factor vitamin D receptor (VDR) that has been the subject of intense study since the 1980's. Thus, vitamin D signaling primarily implies the molecular actions of the VDR. In this review, we present different perspectives on the VDR that incorporate its role as transcription factor and member of the nuclear receptor superfamily, its dynamic changes in genome-wide locations and DNA binding modes, its interaction with chromatin components and its primary protein-coding and non-protein coding target genes and finally how these aspects are united in regulatory networks. By comparing the actions of the VDR, a relatively well-understood and characterized protein, with those of other transcription factors, we aim to build a realistic positioning of vitamin D signaling in the context of other intracellular signaling systems. 23199989 Changes in the bound aroma profiles of 'Hayward' and 'Hort16A' kiwifruit (Actinidia spp.) during ripening and GC-olfactometry analysis. Bound volatiles are recognised as a potential source of aroma compounds in fruits. In this study, the bound volatiles of Actinidia deliciosa 'Hayward' and A. chinensis 'Hort16A' were studied at three different ripening stages. The bound volatile content tended to increase as the fruit ripened from under-ripe to ripe, and then decreased in over-ripe fruit. Glycosides of (Z)-3-hexen-1-ol and hexanol (green-note volatiles) were present in considerable amounts. β-Glucosidase activity in 'Hayward' and 'Hort16A' remained fairly constant throughout ripening. GC-olfactometry analysis of the hydrolysates of ripe 'Hayward' and 'Hort16A' revealed the presence of 2-phenylethanol, β-damascenone, vanillin and 2,5-dimethyl-4-hydroxy-3(2H)-furanone (DMHF). This is the first report of DMHF in 'Hayward' kiwifruit. For both 'Hayward' and 'Hort16A', the odour-active compounds found in the bound volatile extracts were different from those reported as contributors to the aroma of the ripe fruit, suggesting that bound volatiles are probably not significant contributors to the aroma of ripe kiwifruit. 23259731 Multimode multidrop serial coalescence effects during condensation on hierarchical superhydrophobic surfaces. The prospect of enhancing the condensation rate by decreasing the maximum drop departure diameter significantly below the capillary length through spontaneous drop motion has generated significant interest in condensation on superhydrophobic surfaces (SHS). The mobile coalescence leading to spontaneous drop motion was initially reported to occur only on hierarchical SHS, consisting of both nanoscale and microscale topological features. However, subsequent studies have shown that mobile coalescence also occurs on solely nanostructured SHS. Thus, recent focus has been on understanding the condensation process on nanostructured surfaces rather than on hierarchical SHS. In this work, we investigate the impact of microscale topography of hierarchical SHS on the droplet coalescence dynamics and wetting states during the condensation process. We show that isolated mobile and immobile coalescence between two drops, almost exclusively focused on in previous studies, are rare. We identify several new droplet shedding modes, which are aided by tangential propulsion of mobile drops. These droplet shedding modes comprise of multiple droplets merging during serial coalescence events, which culminate in formation of a drop that either departs or remains anchored to the surface. We directly relate postmerging drop adhesion to formation of drops in nanoscale as well as microscale Wenzel and Cassie-Baxter wetting states. We identify the optimal microscale feature spacing of the hierarchical SHS, which promotes departure of the highest number of microdroplets. This optimal surface architecture consists of microscale features spaced close enough to enable transition of larger droplets into micro-Cassie state yet, at the same time, provides sufficient spacing in-between the features for occurrence of mobile coalescence. 23614896 Identification of novel Gyrase B inhibitors as potential anti-TB drugs: Homology modeling, hybrid virtual screening and molecular dynamics simulations. Using an integrated computational approach involving homology modeling, Pharmacophore/Structure-Based virtual screening, molecular dynamics simulations and per-residue energy contribution, ten compounds were proposed as potential TB inhibitors. Via validated docking calculations, binding free energy calculations showed that the proposed compounds presented better binding affinity with DNA Gyrase B when compared to Novobiocin. The compiled in-silico approach employed in this study may serve as a useful tool in the process of the design and development of drugs, not only against TB, but also for a wide range of biological systems. This article is protected by copyright. All rights reserved. 23561102 Carbon nanotubes-reinforced hollow fibre solid-phase microextraction coupled with high performance liquid chromatography for the determination of carbamate pesticides in apples. An effective and sensitive method to determinate five carbamate pesticides in apples was developed by using carbon nanotubes-reinforced hollow fibre solid-phase microextraction (CNTs-HF-SPME) combined with high performance liquid chromatography-photodiode array detection (HPLC-DAD). The CNTs were dispersed in water via adding surfactant, and then were held in the pores of HF supported by capillary forces and sonification. The SPME device, which was wetted with 1-octanol, was placed in a stirred apple samples to extract target analytes. After extraction, analytes were desorbed and analyzed using HPLC-DAD. Under the optimized extraction conditions, the enrichment factors were achieved in the range from 49 to 308 with good inter-fibre repeatability and batch-to-batch reproducibility, while good linearity ranges and recoveries were obtained. The limits of detection ranged from 0.09 to 6.00ng/g. Therefore, the results demonstrated that this novel method was an efficient pretreatment and enrichment procedure for the determination of trace carbamate pesticides in apples. 23517340 Disordered Nanowrinkle Substrates for Inducing Crystallization over a Wide Range of Concentration of Protein and Precipitant. There are large number of proteins, the existence of which are known but not their crystal structure, because of difficulty in finding the exact condition for their crystallization. Heterogeneous nucleation on disordered porous substrates with small yet large distribution of pores is considered a panacea for this problem, but a universal nucleant suitable for crystallizing large variety of proteins does not really exist. To this end, we report here a nanowrinkled substrate which displays remarkable ability and control over protein crystallization. Experiments with different proteins show that on these substrates crystals nucleate even at very low protein concentration in buffer. A small number of very large crystals appear for precipitant concentrations varied over orders of magnitude, ∼0.003-0.3 M; for some proteins, crystals appear even without addition of any precipitant, not seen with any other heterogeneous substrates. In essence, these substrates significantly diminish the influence of the above two parameters, thought to be key factors for crystallization, signifying that this advantage can be exploited for finding out crystallization condition for other yet-to-be-crystallized proteins. 23436494 Mifepristone for management of Cushing's syndrome. Cushing's syndrome is a debilitating endocrine disorder caused by elevated circulating glucocorticoid levels. Although uncommon, Cushing's syndrome is associated with significant morbidity necessitating rapid reversal of hypercortisolemia. Primary therapy for most patients with Cushing's syndrome is surgical, but many patients will require additional treatments with radiation or drugs. Although several options for drug therapy exist, few are readily available and all have dose-limiting adverse effects. Mifepristone (RU 486), a first-in-class glucocorticoid receptor antagonist, was approved by the United States Food and Drug Administration in 2012 for use in Cushing's syndrome to control hyperglycemia in patients who are not surgical candidates or have not achieved remission from surgery. The drug is approved for oral once-daily administration. In its pivotal trial, 60% of patients responded to mifepristone with significant improvements in glycemic control and 38% had a reduction in diastolic blood pressure. The most common adverse events were nausea, fatigue, headache, endometrial hyperplasia, and hypokalemia. Adrenal insufficiency occurred in fewer than 5% of patients. The recommended starting dosage of mifepristone is 300 mg/day. The dosage may be increased every 2-4 weeks up to a maximum of 1200 mg/day, although it should not exceed 20 mg/kg/day. Significant drug-drug interactions exist due to mifepristone's effects on a number of cytochrome P450 enzymes. Despite its limitations, mifepristone is a welcome addition and an appropriate alternative to the available drug therapy for Cushing's syndrome. 23017411 An investigation into the supramolecular structure, solubility, stability and antioxidant activity of rutin/cyclodextrin inclusion complex. The formation of supramolecular inclusion complexes between rutin and four cyclodextrins, namely β-cyclodextrin (β-CD), (2-hydroxypropyl)-α-cyclodextrin (HP-α-CD), (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) and (2-hydroxypropyl)-γ-cyclodextrin (HP-γ-CD), and the effects of the complexation on the stability and antioxidant activity of rutin were investigated. Results from phase-solubility studies showed that rutin formed 1:1 stoichiometric inclusion complexes with HP-α-CD, β-CD, HP-β-CD and HP-γ-CD; the complexes formed with HP-γ-CD and HP-β-CD had the greatest stability constants, followed by β-CD and HP-α-CD. Thermodynamic studies demonstrate that the inclusion of rutin into HP-β-CD was an exothermic process which occurred spontaneously. Two-dimensional rotating-frame nuclear Overhauser effect spectroscopy (2D ROESY) (1)H NMR analyses show that the A ring of rutin was the part of the molecule that most likely inserted into the cavity of HP-β-CD, thus forming a supramolecular inclusion complex. Formation of such an inclusion complex conferred moderate degrees of protection to rutin from degradation by heat and UV radiation during storage, and significantly enhanced its antioxidant capacity as determined by three different procedures. 23572407 Clinical strategies to enhance the efficacy of nicotine replacement therapy for smoking cessation: a review of the literature. A number of smoking cessation pharmacotherapies have led to increases in quitting and thus to significant benefits to public health. Among existing medications, nicotine replacement therapy (NRT) has been available the longest, has the largest literature base in support, and is the only option for over-the-counter access. While the short-term efficacy of NRT is well documented in clinical trials, long-term abstinence rates associated with using NRT are modest, as most smokers will relapse. This literature review examines emerging clinical strategies to improve NRT efficacy. After an initial overview of NRT and its FDA-approved indications for use, we review randomized trials in which clinical delivery of NRT was manipulated and tested, in an attempt to enhance efficacy, through (1) duration of use (pre-quit and extended use), (2) amount of use (high-dose and combination NRT), (3) tailoring to specific smoker groups (genotype and phenotype), or (4) use of NRT for novel purposes (relapse prevention, temporary abstinence, cessation induction). Outcomes vary within and across topic area, and we highlight areas that offer stronger promise. Combination NRT likely represents the most promising strategy moving forward; other clinical strategies offer conflicting evidence but deserve further testing (pre-quit NRT or tailored treatment) or offer potential utility but are in need of further, direct tests. Some areas, though based on a limited set of studies, do not offer great promise (high-dose and extended treatment NRT). We conclude with a brief discussion of emergent NRT products (e.g., oral nicotine spray, among others), which may ultimately offer greater efficacy than current formulations. In order to further lower the prevalence of smoking, novel strategies designed to optimize NRT efficacy are needed. 23416007 A multivalent peptide as an activator of hypoxia inducible factor-1α. Hypoxia inducible factor-1α (HIF-1α) is a transcription factor found in mammalian cells under hypoxia. While HIF-1α in hypoxia translocates to the nucleus where it transcribes the target genes including vascular endothelial growth factor (VEGF) mRNA, HIF-1α is degraded under normoxia, which involves its proline hydroxylation and subsequent binding to the von Hippel-Lindau protein-Elongin B-Elogin C (VBC) complex. Previously, peptide inhibitors against this interaction between hydroxylated HIF-1α and VBC have been developed to stabilize the transcriptional activity of HIF-1α by preventing the degradation of the protein even under normoxia. Despite the specific inhibition by these peptides, their poor inhibition potency needs to be improved for further clinical application. In this work, we have designed and prepared a streptavidin-based multivalent peptide inhibitor against the HIF-1α-VBC complexation. We have evaluated the potency of the multivalent peptide in terms of stabilization of HIF-1α and the downstream effect. As the result, we have found that the inhibitor showed about 13-fold lowered IC50 value compared with that of the corresponding monovalent peptide, thereby activating HIF-1α and leading to up-regulation of VEGF protein at the cellular level. 23220641 Sirtuins as emerging anti-parasitic targets. Silent information regulator 2 (Sir2) enzymes or sirtuins are a family of NAD(+)-dependent protein N(ε)-acetyl-lysine (AcK) deacetylases. Sirtuins are also evolutionarily conserved proteins that are present in all kingdoms of life ranging from bacteria to humans. Interestingly, it was recently found that the sirtuins found in various human parasites (especially the Plasmodium, Trypanosoma, and Leishmania species) were pro-survival for the parasites under various conditions. Therefore, these parasitic sirtuins have emerged as novel anti-parasitic therapeutic targets. This article reviews the currently available structural, biochemical, pharmacological, and medicinal chemistry studies on these enzymes, and discusses the perspectives of selectively targeting the parasitic sirtuins as a novel therapeutic strategy for the human parasitic diseases. 23252613 Architecturing hierarchical function layers on self-assembled viral templates as 3D nano-array electrodes for integrated Li-ion microbatteries. This work enables an elegant bottom-up solution to engineer 3D microbattery arrays as integral power sources for microelectronics. Thus, multilayers of functional materials were hierarchically architectured over tobacco mosaic virus (TMV) templates that were genetically modified to self-assemble in a vertical manner on current-collectors, so that optimum power and energy densities accompanied with excellent cycle-life could be achieved on a minimum footprint. The resultant microbattery based on self-aligned LiFePO(4) nanoforests of shell-core-shell structure, with precise arrangement of various auxiliary material layers including a central nanometric metal core as direct electronic pathway to current collector, delivers excellent energy density and stable cycling stability only rivaled by the best Li-ion batteries of conventional configurations, while providing rate performance per foot-print and on-site manufacturability unavailable from the latter. This approach could open a new avenue for microelectromechanical systems (MEMS) applications, which would significantly benefit from the concept that electrochemically active components be directly engineered and fabricated as an integral part of the integrated circuit (IC). 23561150 Tenderization effect of soy sauce on beef M. biceps femoris. This study was conducted to evaluate the tenderization effect of soy sauce on beef M. biceps femoris (BF). Five marinades were prepared with 4% (w/v) sodium chloride and 25% (w/v) soy sauce solutions (4% salt concentration) and mixed with the ratios of 100:0 (S0, pH 6.52), 75:25 (S25, 5.40) 50:50 (S50, 5.24), 25:75 (S75, 5.05), and 0:100 (S100, 4.85), respectively. The BF samples which were obtained from Hanwoo cows at 48h postmortem (n=24) were marinated with five marinades for 72h at 4°C (1:4 w/w), and the effects of soy sauce on tenderness were evaluated. Soy sauce marination resulted in a decrease in the pH value of the BF sample. However, there were no significant differences in the water holding capacity (P<0.05). The S100 treatment showed the significant (P<0.05) increase in collagen solubility and myofibrillar fragmentation index, contributing to decreased shear force compared to S0 (control). Reduction in intensity of few myofibrillar protein bands were observed for S100 treatment compared to control using SDS-PAGE. Scanning electron microscopy revealed breakdown of connective tissue surrounding muscle fibers of the S100 treatment. The tenderization effect of soy sauce may attribute various mechanisms such as increased collagen solubility or proteolysis which depend on soy sauce level in marinade. 23418783 Beyond H(2)S and NO Interplay: Hydrogen Sulfide and Nitroprusside React Directly to Give Nitroxyl (HNO). A New Pharmacological Source of HNO. Hydrogen sulfide (H(2)S) has been increasingly recognized as an important signaling molecule that regulates both blood pressure and neuronal activity. Attention has been drawn to its interactions with another gasotransmitter, nitric oxide (NO). Here, we provide evidence that the physiological effects observed upon the application of sodium nitroprusside (SNP) and H(2)S can be ascribed to the generation of nitroxyl (HNO), which is a direct product of the reaction between SNP and H(2)S, not a consequence of released NO subsequently reacting with H(2)S. Intracellular HNO formation has been confirmed, and the subsequent release of calcitonin gene-related peptide from a mouse heart has been demonstrated. Unlike with other thiols, SNP reacts with H(2)S in the same way as rhodanese, i.e., the cyanide transforms into a thiocyanate. These findings shed new light on how H(2)S is understood to interact with nitroprusside. Additionally, they offer a new and convenient pharmacological source of HNO for therapeutic purposes. 23514637 Structure and Absolute Configuration of Methyl (3R)-Malonyl-(13S)-hydroxycheilanth-17-en-19-oate, a Sesterterpene Derivative from the Roots of Aletris farinosa. We report the isolation and structure elucidation of a new cheilanthane sesterterpene from the roots of Aletris farinosa that possesses an unusual malonate half-ester functional group. The structure of 1 was determined via mass spectrometry and 1D and 2D NMR spectroscopy, while its absolute configuration was determined via X-ray crystallographic analysis performed on its methyl ester derivative 2. 23409936 Structure-based discovery of pyrazolobenzothiazine derivatives as inhibitors of hepatitis C virus replication. The NS5B RNA-dependent RNA polymerase is an attractive target for the development of novel and selective inhibitors of hepatitis C virus replication. To identify novel structural hits as anti-HCV agents, we performed structure-based virtual screening of our in-house library followed by rational drug design, organic synthesis, and biological testing. These studies led to the identification of pyrazolobenzothiazine scaffold as a suitable template for obtaining novel anti-HCV agents targeting the NS5B polymerase. The best compound of this series was the meta-fluoro-N-1-phenyl pyrazolobenzothiazine derivative 4a, which exhibited an EC50 = 3.6 μM, EC90 = 25.6 μM, and CC50 > 180 μM in the Huh 9-13 replicon system, thus providing a good starting point for further hit evolution. 23620529 High salt diets during pregnancy affected fetal and offspring renal renin-angiotensin system. Intrauterine environments are linked to fetal renal development and postnatal health. Influence of salt diets during pregnancy on renal functions and renin-angiotensin system (RAS) were determined in the ovine fetus and offspring. Pregnant ewes were fed high-salt diet (HSD) or normal-salt diet (NSD) for two months during middle-later gestation. Fetal renal functions, plasma hormones, mRNA and protein expressions of the key elements of renal RAS were measured in the fetus and offspring. Fetal renal excretion of sodium was increased while urine volume decreased in HSD group. Fetal blood urea nitrogen was increased, while kidney/body weight ratio decreased in HSD group. The altered ratio also was observed in the offspring at 15-day-old and 90-day-old. Maternal and fetal plasma antidiuretic hormone was elevated without change in plasma renin activity and Ang I levels, while plasma Ang II was decreased. The key elements of local renal RAS, including angiotensinogen, ACE, ACE2, AT1 and AT2 receptor expression in both mRNA and protein, except renin, were altered following maternal high salt intake. The results suggest that High intake of salt during pregnancy affected fetal renal development associated with an altered expression of the renal key elements of RAS, some alterations of fetal origins remained after birth as possible risks in developing renal or cardiovascular diseases. 23597098 Magnetic-Nanoparticle-Decorated Polypyrrole Microvessels: Toward Encapsulation of mRNA Cap Analogues. Many phosphorylated nucleoside derivatives have therapeutic potential, but their application is limited by problems with membrane permeability and with intracellular delivery. Here, we prepared polypyrrole microvessel structures modified with superparamagnetic nanoparticles for use as potential carriers of nucleotides. The microvessels were prepared via the photochemical polymerization of the monomer onto the surface of aqueous ferrofluidic droplets. A complementary physicochemical analysis revealed that a fraction of the nanoparticles was embedded in the microvessel walls, while the other nanoparticles were in the core of the vessel. SQUID (superconducting quantum interference device) measurements indicated that the incorporated nanoparticles retained their superparamagnetic properties; thus, the resulting nanoparticle-modified microvessels can be directed by an external magnetic field. As a result of these features, these microvessels may be useful as drug carriers in biomedical applications. To demonstrate the encapsulation of drug molecules, two labeled mRNA cap analogues, nucleotide-derived potential anticancer agents, were used. It was shown that the cap analogues are located in the aqueous core of the microvessels and can be released to the external solution by spontaneous permeation through the polymer walls. Mass spectrometry analysis confirmed that the cap analogues were preserved during encapsulation, storage, and release. This finding provides a foundation for the future development of anticancer therapies and for the delivery of nucleotide-based therapeutics. 23527529 The pre-clinical absorption, distribution, metabolism and excretion properties of IPI-926, an orally bioavailable antagonist of the hedgehog signal transduction pathway. Abstract 1. IPI-926 is a novel semisynthetic cyclopamine derivative that is a potent and selective Smoothened inhibitor that blocks the hedgehog signal transduction pathway. 2. The in vivo clearance of IPI-926 is low in mouse and dog and moderate in monkey. The volume of distribution is high across species. Oral bioavailability ranges from moderate in monkey to high in mouse and dog. Predicted human clearance using simple allometry is low (24 L h(-1)), predicted volume of distribution is high (469 L) and predicted half-life is long (20 h). 3. IPI-926 is highly bound to plasma proteins and has minimal interaction with human α-1-acid glycoprotein. 4. In vitro metabolic stability ranges from stable to moderately stable. Twelve oxidative metabolites were detected in mouse, rat, dog, monkey and human liver microsome incubations and none were unique to human. 5. IPI-926 is not a potent reversible inhibitor of CYP1A2, 2C8, 2C9 or 3A4 (testosterone). IPI-926 is a moderate inhibitor of CYP2C19, 2D6 and 3A4 (midazolam) with KI values of 19, 16 and 4.5 µM, respectively. IPI-926 is both a substrate and inhibitor (IC50 = 1.9 µM) of P-glycoprotein. 6. In summary, IPI-926 has desirable pre-clinical absorption, distribution, metabolism and excretion properties. 23480470 Physicochemical Properties and Supernucleophilicity of Oxime-Functionalized Surfactants: Hydrolytic Catalysts toward Dephosphorylation of Di- and Triphosphate Esters. Aggregation and kinetic studies have been performed to understand the hydrolytic potencies of the series of oxime-functionalized surfactants, viz., 3- hydroxyiminomethyl-1-alkylpyridinium bromide (alkyl = CnH2n+1, n = 10, 12, 14, 16, 18) in the cleavage of phosphate esters, p-nitrophenyl diphenyl phosphate (PNPDPP) and bis(2,4-dinitrophenyl) phosphate (BNDPP), in mixed micelles with cetylpyridinium bromide (CPB). Micellization and surface properties of mixed micelles functional surfactants with CPB were studied by conductivity and surface tension measurements. Acid dissociation constants (pKa) were determined, the effect of functional surfactant alkyl chain length and pH on the observed rate constant (kobs) for phosphate ester cleavage has been discussed, and the effect of substrate on the supernucleophilicities of the studied oximes was monitored. Functionalized oxime-based surfactants were proved to be supernucleophiles to attack on the P═O center of tri- and diphosphate esters. Oximes with hexadecyl alkyl chain length (3-C16) showed maximum micellar effect on the rate constants toward PNPDPP. Micellar effects were analyzed in terms of the pseudophase model. 23625911 Metoprolol and diltiazem ameliorate ziprasidone-induced prolonged corrected QT interval in rats. Ziprasidone, an atypical antipsychotic agent, has been shown to increase the corrected QT (QTc) interval in some patients. The aim of this study was to reveal the effects of metoprolol and diltiazem on ziprasidone drug-induced prolonged QTc interval. A total of 24 rats were equally divided into the following four groups: the first group was used as the control and received 1 mL/kg saline; 3 mg/kg ziprasidone and saline were administered to the second group; 3 mg/kg ziprasidone and 1 mg/kg metoprolol were administered to the third group and 3 mg/kg ziprasidone and 2 mg/kg diltiazem were administered to the fourth group. Two hours following application of the drugs, the QTc was calculated by performing electrocardiography in derivation (D)I. The duration of QTc interval was compared among the four groups. The mean QTc intervals were significantly increased in the third and fourth groups compared with the second group (p < 0.0005 and p < 0.0001, respectively). The study demonstrated the effectiveness of metoprolol and diltiazem in the prevention of ziprasidone-induced elongation in the QTc interval. Both metoprolol and diltiazem may be considered in the prophylactic therapy of high-risk patients who are using ziprasidone. 23044908 Differing effects of PTH 1-34, PTH 1-84, and zoledronic acid on bone microarchitecture and estimated strength in postmenopausal women with osteoporosis: an 18-month open-labeled observational study using HR-pQCT. Whereas the beneficial effects of intermittent treatment with parathyroid hormone (PTH) (intact PTH 1-84 or fragment PTH 1-34, teriparatide) on vertebral strength is well documented, treatment may not be equally effective in the peripheral skeleton. We used high-resolution peripheral quantitative computed tomography (HR-pQCT) to detail effects on compartmental geometry, density, and microarchitecture as well as finite element (FE) estimated integral strength at the distal radius and tibia in postmenopausal osteoporotic women treated with PTH 1-34 (20 µg sc daily, n = 18) or PTH 1-84 (100 µg sc daily, n = 20) for 18 months in an open-label, nonrandomized study. A group of postmenopausal osteoporotic women receiving zoledronic acid (5 mg infusion once yearly, n = 33) was also included. Anabolic therapy increased cortical porosity in radius (PTH 1-34 32 ± 37%, PTH 1-84 39 ± 32%, both p < 0.001) and tibia (PTH 1-34 13 ± 27%, PTH 1-84 15 ± 22%, both p < 0.001) with corresponding declines in cortical density. With PTH 1-34, increases in cortical thickness in radius (2.0 ± 3.8%, p < 0.05) and tibia (3.8 ± 10.4%, p < 0.01) were found. Trabecular number increased in tibia with both PTH 1-34 (4.2 ± 7.1%, p < 0.05) and PTH 1-84 (5.3 ± 8.3%, p < 0.01). Zoledronic acid did not impact cortical porosity at either site but increased cortical thickness (3.0 ± 3.5%, p < 0.01), total (2.7 ± 2.5%, p < 0.001) and cortical density (1.5 ± 2.0%, p < 0.01) in tibia as well as trabecular volume fraction in radius (2.5 ± 5.1%, p < 0.05) and tibia (2.2 ± 2.2%, p < 0.01). FE estimated bone strength was preserved, but not increased, with PTH 1-34 and zoledronic acid at both sites, whereas it decreased with PTH 1-84 in radius (-2.8 ± 5.8%, p < 0.05) and tibia (-3.9 ± 4.8%, p < 0.001). Conclusively, divergent treatment-specific effects in cortical and trabecular bone were observed with anabolic and zoledronic acid therapy. The finding of decreased estimated strength with PTH 1-84 treatment was surprising and warrants confirmation. 23530049 E-cadherin polarity is determined by a multi-function motif mediating lateral membrane retention through ankyrin-G and apical-lateral transcytosis through clathrin. We report a highly conserved motif in the E-cadherin juxtamembrane domain that determines apical-lateral polarity by conferring both restricted mobility at the lateral membrane and transcytosis of apically mis-sorted protein to the lateral membrane. Mutations causing either increased lateral membrane mobility or loss of apical-lateral transcytosis result in partial mis-sorting of E-cadherin in MDCK cells. However, loss of both activities results in complete loss of polarity. We present evidence that residues required for restricted mobility mediate retention at the lateral membrane through interaction with ankyrin-G, while dileucine residues conferring apical-lateral transcytosis act through a clathrin-dependent process and function in an editing pathway. Ankyrin-G interaction with E-cadherin is abolished by the same mutations resulting in increased E-cadherin mobility. Clathrin heavy chain knockdown and dileucine mutation of E-cadherin both cause the same partial loss of polarity of E-cadherin. Moreover, clathrin knockdown causes no further change in polarity of E-cadherin with dileucine mutation, but does completely randomize E-cadherin mutants lacking ankyrin-binding. Dileucine mutation, but not loss of ankyrin-binding, prevented transcytosis of apically mis-sorted E-cadherin to the lateral membrane. Finally, neurofascin, which binds ankyrin but lacks dileucine residues, exhibited partial apical-lateral polarity that was abolished by mutation of its ankyrin-binding site but was not affected by clathrin knockdown. The polarity motif thus integrates complementary activities of lateral membrane retention through ankyrin-G and apical-lateral transcytosis of mis-localized protein through clathrin. Together, the combination of retention and editing function to ensure a high fidelity steady state localization of E-cadherin at the lateral membrane. 23416006 Substituted piperidinyl glycinyl 2-cyano-4,5-methano pyrrolidines as potent and stable dipeptidyl peptidase IV inhibitors. Synthesis and structure-activity relationship of a series of substituted piperidinyl glycine 2-cyano-4,5-methano pyrroline DPP-IV inhibitors are described. Improvement of the inhibitory activity and chemical stability of this series of compounds was respectively achieved by the introduction of bulky groups at the 4-position and 1-position of the piperidinyl glycine, leading to a series of potent and stable DPP-IV inhibitors. 23340305 Perfluoroalkylated compounds induce cell death and formation of reactive oxygen species in cultured cerebellar granule cells. The present communication investigates the effects of different perfluoroalkylated compounds (PFCs) on formation of reactive oxygen species (ROS) and cell death in cultured cerebellar granule cells. This allows direct comparison with similar effects found for other environmental contaminants like polychlorinated biphenyls and brominated flame-retardants. The increase in ROS formation and cell death was assayed using the fluorescent probe 2,7-dichlorofluorescin diacetate (DCFH-DA) and the trypan blue exclusion assay. The effects of the PFCs were structure dependent. Cell death was induced at relatively low concentrations by perfluorooctyl sulfonate (PFOS), perfluorooctane sulfonylamide (PFOSA) and the fluorotelomer alcohol 1H, 1H, 2H, 2H-perfluorodecanol (FTOH 8:2) with EC(50)-values of 62 ± 7.6, 13 ± 1.8 and 15 ± 4.2 μM (mean ± SD) respectively. PFOS, perfluorooctanoic acid (PFOA) and PFOSA induced a concentration dependent increase in ROS formation with EC(50)-values of 27 ± 9.0, 25 ± 11 and 57 ± 19μM respectively. Reduced cell viability and ROS formation were observed at concentration level close to what is found in serum of occupationally exposed workers. The effect of PFCs on ROS formation and cell viability was compared with other halogenated compounds and future investigations should emphasize effects of mixtures and how physical chemical properties of the compounds influence their toxicity. 23335025 Chemopreventive effects of Ginkgo biloba extract in estrogen-negative human breast cancer cells. Excessive level of estrogen is considered as a main cause of breast cancer, therefore, many studies have focused on estrogen receptor (ER)-positive breast cancer, even though ER-negative cancer has a poor prognosis than ER-positive breast cancer. We evaluated the anti-cancer effects of Ginkgo biloba extract (GBE) in estrogen-independent breast cancer. GBE has been traditionally used as a platelet activating factor, a circulatory stimulant, a tonic, and anti-asthmatic drug, and anti-cancer agent. However, anti-cancer effects of GBE on ER-negative breast cancer have not been proved yet. In this study, we tested chemotherapeutic potential of GBE in the MDA-MB-231 (ER-negative) human breast cancer cell line. Our results showed that cytotoxicity effects of GBE in MDA-MB-231 lead to DNA fragmentation at high concentrations (500 and 1,000 μg/ml). Caspase-3 was significantly activated and mRNA levels of apoptosis-related genes (Bcl-2 and Bax) were altered. These results indicate that GBE induces apoptosis in MDA-MB-231 cells. It is presumed that GBE has chemopreventive effects in ER-independent breast cancer through anti-proliferation and apoptosis-inducing activities. 23232078 Korean red ginseng (Panax ginseng) prevents obesity by inhibiting angiogenesis in high fat diet-induced obese C57BL/6J mice. Adipose tissue growth and development are thought to be associated with angiogenesis and extracellular matrix remodeling. Because ginseng has been shown to inhibit angiogenesis and matrix metalloproteinase (MMP) activity, we hypothesized that adipose tissue growth and obesity can be regulated by Korean ginseng (Panax ginseng C.A. Meyer). Wild-type C57BL/6J mice were fed for 8 weeks with a low fat diet, a high fat diet (HFD), or HFD supplemented with 0.5% or 5% Korean red ginseng extract. We measured body weight, adipose tissue mass, food intake, MMP activity, and the expression of genes involved in angiogenesis and MMPs. Administering ginseng to HFD-induced obese mice produced reductions in body weight and adipose tissue mass compared with untreated counterparts. Ginseng treatment decreased blood vessel density and MMP activity in adipose tissues. Ginseng also reduced mRNA levels of angiogenic factors (e.g., VEGF-A and FGF-2) and MMPs (e.g., MMP-2 and MMP-9), whereas it increased mRNA levels of angiogenic inhibitors (e.g., TSP-1, TIMP-1, and TIMP-2) in adipose tissues. These results demonstrate that ginseng effectively reduces adipose tissue mass and prevents obesity in diet-induced obese mice and that this process may be mediated in part through the anti-angiogenic actions of ginseng. 23639452 Cell-penetrating cationic siRNA and lipophilic derivatives efficient at nanomolar concentrations in the presence of serum and albumin. Despite its considerable interest in human therapy, in vivo siRNA delivery is still suffering from hurdles of vectorization. We have shown recently efficient gene silencing by non-vectorized cationic siRNA. Here, we describe the synthesis and in vitro evaluation of new amphiphilic cationic siRNA. C12-, (C12)2- and cholesteryl-sperminex-siRNA were capable of luciferase knockdown at nanomolar concentrations without vectorization (i.e. one to two orders of magnitude more potent than commercially available cholesteryl siRNA). Moreover, incubation in the presence of serum did not impair their efficiency. Finally, amphiphilic cationic siRNA was pre-loaded on albumin. In A549Luc cells in the presence of serum, these siRNA conjugates were highly effective and had low toxicity. 23588322 Model-Based Drug Development: A Rational Approach to Efficiently Accelerate Drug Development. The pharmaceutical industry continues to face significant challenges. Very few compounds that enter development reach the marketplace, and the investment required for each success can surpass $1.8 billion. Despite attempts to improve efficiency and increase productivity, total investment continues to rise whereas the output of new medicines declines. With costs increasing exponentially through each development phase, it is failure in phase II and phase III that is most wasteful. In today's development paradigm, late-stage failure is principally a result of insufficient efficacy. This is manifested as either a failure to differentiate sufficiently from placebo (shown for both novel and precedented mechanisms) or a failure to demonstrate sufficient differentiation from existing compounds. Set in this context, this article will discuss the role model-based drug development (MBDD) approaches can and do play in accelerating and optimizing compound development strategies through a series of illustrative examples.Clinical Pharmacology & Therapeutics (2013); advance online publication 1 May 2013. doi:10.1038/clpt.2013.54. 23394553 Statin intolerance: why and what to do - with a focus on diabetic people. The standards of medical care in diabetes recommend that statin therapy is added to lifestyle therapy for diabetic patients with overt cardiovascular disease (LDL cholesterol goal <70 mg/dl), or without cardiovascular disease who are over the age of 40 years and who have one or more other cardiovascular disease risk factors (LDL cholesterol goal <100 mg/dl). In order to reach strict LDL targets, high doses of statins may be required. However, the frequency of statin associated adverse effects and statin intolerance in clinical practice is high (up to 10-15% of statin users) especially at muscle level. The review overviews: 1) the known or hypothesised mechanisms through which causal and contributing factors are associated with adverse effects in diabetic people, and 2) the rationale of strategies for managing statin intolerant patients. 23478485 Chondroitin sulfate, hyaluronic Acid and chitin/chitosan production using marine waste sources: characteristics, applications and eco-friendly processes: a review. In the last decade, an increasing number of glycosaminoglycans (GAGs), chitin and chitosan applications have been reported. Their commercial demands have been extended to different markets, such as cosmetics, medicine, biotechnology, food and textiles. Marine wastes from fisheries and aquaculture are susceptible sources for polymers but optimized processes for their recovery and production must be developed to satisfy such necessities. In the present work, we have reviewed different alternatives reported in the literature to produce and purify chondroitin sulfate (CS), hyaluronic acid (HA) and chitin/chitosan (CH/CHs) with the aim of proposing environmentally friendly processes by combination of various microbial, chemical, enzymatic and membranes strategies and technologies. 23506253 Chemical constituents comparison of Codonopsis tangshen, Codonopsis pilosula var. modesta and Codonopsis pilosula. Dang-shen, radix Codonopsis is one of the best-known traditional Chinese medicines and is used mainly as a tonic agent. Nine commercial products belong to three species of Codonopsis genus, Codonopsis tangshen, Codonopsis pilosula var. modesta and a cultivated species of Codonopsis pilosula, which were purchased from drug stores in Taipei and Taichung, Taiwan. To determine the chemical differences between samples of Dang-shen, a method combining solvent partition and HPLC-UV was used. An enriched fraction of n-butanol was obtained, after partition. Then, the chemical profile was determined using a C18 reversed column chromatography in a gradient solvent system with 10-40% acetonitrile in 0.1% formic acid, for 60 min. A comparison of the constituents in the nine commercial products of Dang-shen showed that compounds codonopyrrolidum A, B and codonoside A only exist in C. tangshen, but not in C. pilosula var. modesta and C. pilosula. A predominate compound, codonopyrrolidum A, can be used to distinguish the herbs, C. tangshen from C. pilosula var. modesta and C. pilosula. Low secondary metabolite content was found in the cultivated species of C. pilosula. 23361846 Role of cytochrome P4502B6 in methadone metabolism and clearance. Methadone N-demethylation in vitro is catalyzed by hepatic cytochrome P4502B6 (CYP2B6) and CYP3A4, but clinical disposition is often attributed to CYP3A4. This investigation tested the hypothesis that CYP2B6 is a prominent CYP isoform responsible for clinical methadone N-demethylation and clearance, using the in vivo mechanism-based CYP2B6 inhibitor ticlopidine, given orally for 4 days. A preliminary clinical investigation with the CYP3A4/5 substrate probe alfentanil established that ticlopidine did not inhibit intestinal or hepatic CYP3A4/5. Subjects received intravenous plus oral (deuterium-labeled) racemic methadone before and after ticlopidine. Ticlopidine significantly and stereoselectively (S > R) inhibited methadone N-demethylation, decreasing plasma metabolite/methadone area under the curve ratios and metabolite formation clearances. Ticlopidine also significantly increased the dose-adjusted plasma area under the curve for R- and S-methadone by 20% and 60%, respectively, after both intravenous and oral dosing. CYP2B6 inhibition reduces methadone N-demethylation and clearance, and alters methadone concentrations, demonstrating an important role for CYP2B6 in clinical methadone disposition. 23340093 Impact of cooking and handling conditions on furanic compounds in breaded fish products. This study evaluates the influence of cooking and handling conditions on the quantity of furanic compounds (furan, 2-furfural, furfuryl alcohol, 2-pentylfuran, 5-hydroxymethylfurfural) in breaded fish products. Oven-baking and reheating in the microwave lead to low furanic compounds formation in comparison with deep-frying. The use of olive oil for deep-frying promoted higher levels of furanic compounds than sunflower oil. The amounts of these compounds diminished as the temperature and time of deep-frying decreased as well as after a delay after deep-frying. Thus, the generation of furanic compounds can be minimized by adjusting the cooking method and conditions, such as using an electric oven, deep-frying in sunflower oil at 160°C during 4min, or waiting 10min after cooking. However, these conditions that reduce furanic compounds levels also reduce the content of volatile compounds related to the aroma and flavour of fried foods. In this sense, new efforts should be done to reduce the formation of furanic compounds without being detrimental to the volatile profile. 22761031 Auraptene and its Effects on the Re-emergence of Colon Cancer Stem Cells. Recent studies indicate that auraptene (7-geranyloxycoumarin, AUR), a geranyloxycoumarin extracted from fruits of edible plants belonging to the Rutaceae family, may represent a novel lead compound for dietary colon cancer chemoprevention in rodents. As a continuation of studies aimed to better depict the pharmacological effects and mechanism of action of the title natural compound, the current investigation was undertaken to determine whether AUR would be able to prevent the growth and sphere (surrogate tumors) formation of FOLFOX-resistant colon cancer cells that are highly enriched in cancer stem cells (CSCs). Our results demonstrate that AUR at a concentration of 10 μM was able to inhibit the growth and formation of colonospheres of FOLFOX-resistant colon cancer HT-29 cells in vitro. The corresponding parental cells were also similarly affected by AUR at the same concentration level. The reduction in the growth and colonospheres formation in FOLFOX-resistant HT-29 was also associated with a concomitant decrease in phospho-epidermal growth factor receptor. These findings suggest that AUR could prevent the re-emergence of CSCs. Copyright © 2012 John Wiley & Sons, Ltd. 23414845 Structure-based discovery of cellular-active allosteric inhibitors of FAK. In order to develop potent and selective focal adhesion kinase (FAK) inhibitors, synthetic studies on pyrazolo[4,3-c][2,1]benzothiazines targeted for the FAK allosteric site were carried out. Based on the X-ray structural analysis of the co-crystal of the lead compound, 8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide 1 with FAK, we designed and prepared 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin derivatives which selectively inhibited kinase activity of FAK without affecting seven other kinases. The optimized compound, N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine 4,4-dioxide 30 possessed significant FAK kinase inhibitory activities both in cell-free (IC50=0.64μM) and in cellular assays (IC50=7.1μM). These results clearly demonstrated a potential of FAK allosteric inhibitors as antitumor agents. 23556998 Interactions of PAMAM Dendrimers with SDS at the Solid-Liquid Interface. This work addresses structural and nonequilibrium effects of the interactions between well-defined cationic poly(amidoamine) PAMAM dendrimers of generations 4 and 8 and the anionic surfactant sodium dodecyl sulfate (SDS) at the hydrophilic silica-water interface. Neutron reflectometry and quartz crystal microbalance with dissipation monitoring were used to reveal the adsorption from premixed dendrimer/surfactant solutions as well as sequential addition of the surfactant to preadsorbed layers of dendrimers. PAMAM dendrimers of both generations adsorb to hydrophilic silica as a compact monolayer, and the adsorption is irreversible upon rinsing with salt solution. SDS adsorbs on the dendrimer layer and at low bulk concentrations causes the expansion of the dendrimer layers on the surface. When the bulk concentration of SDS is increased, the surfactant layer consists of aggregates or bilayer-like structures. The adsorption of surfactant is reversible upon rinsing, but slight changes of the structure of the preadsorbed PAMAM monolayer were observed. The adsorption from premixed solutions close to charge neutrality results in thick multilayers, but the surface excess is lower when the bulk complexes have a net negative charge. A critical examination of the pathway of adsorption for the interactions of SDS with preadsorbed PAMAM monolayers and premixed PAMAM/SDS solutions with hydrophilic silica revealed that nonequilibrium effects are important only in the latter case, and the application of a thermodynamic model to such experimental data would be inappropriate. 23463352 Developmental Changes in the Expression and Function of Cytochrome P450 3A Isoforms: Evidence from In Vitro and In Vivo Investigations. The aim of this review is to discuss our current understanding of the developmental changes of the drug-metabolizing enzyme cytochrome P450 (CYP) 3A and its impact on drug therapy. In the last 10 years, several methods have been used to study the ontogeny of specific CYP3A isoforms in vitro and in vivo. Although most studies confirm previous findings that CYP3A4/5 activity is low at birth and reaches adult values in the first years of life, there are still important gaps in our knowledge of the exact developmental patterns of individual CYP3A isoforms, especially in this age range. Moreover, most in vivo clinical studies have also failed to cover the whole pediatric age range. To date, this information gap still hampers the design of age-specific dosing guidelines of CYP3A substrate drugs, especially in neonates and infants. Innovative study methods, including opportunistic sampling and sensitive analytical assays used in combination with physiologically based pharmacokinetics, and population pharmacokinetic model concepts may help to improve our understanding of the ontogeny of CYP3A and aid the application of this knowledge in clinical practice. 23318731 Oxidative and nitrosative stress and apoptosis in oral mucosa cells after ex vivo exposure to lead and benzo[a]pyrene. Exposure of human oral mucosa to lead (Pb) and benzo[a]pyrene (BaP) by inhalation and ingestion can lead to pathological conditions via apoptosis and oxidative and nitrosative stress. However, few studies have investigated the effects of Pb and BaP on oral mucosa cells. Furthermore, previous studies focused on chronic Pb and BaP exposure. Therefore, we evaluated important markers of apoptosis and oxidative and nitrosative stress in oral mucosa cells by incubating the cells with Pb and BaP for 5-360 min. Ex vivo samples of human oral mucosa were exposed to Pb or BaP, and immunohistochemical staining was performed to evaluate active caspase-3, 8-epi-prostaglandin F2 alpha (8-epi-PGF2a), and 3-nitrotyrosine (3-NT). Pb and BaP treatments significantly increased active caspase-3 levels in a time-dependent manner. Furthermore, the treatments induced an early increase in 3-NT level, which ceased with longer incubation times. 8-Epi-PGF2a level increased only after prolonged incubation with Pb, and this elevation was irrespective of BaP incubation duration. Smokers' samples had significantly lower levels of markers of oxidative and nitrosative stress than did nonsmokers' samples. Thus, single, short-term exposure to Pb or BaP increases the levels of apoptosis markers and markers of oxidative and nitrosative stress. 23561170 Enrichment of polyphenol contents and antioxidant activities of Irish brown macroalgae using food-friendly techniques based on polarity and molecular size. An efficient, food-friendly process for the enrichment of macroalgal phlorotannins from solid-liquid extracts (SLE) of three brown macroalgae, namely Fucus spiralis Linnaeus, Pelvetia canaliculata (Linnaeus) Decaisne & Thuret and Ascophyllum nodosum (Linnaeus) Le Jolis, has been demonstrated. The initial utilisation of molecular weight cut-off (MWCO) dialysis generated fractions of low molecular weight (LMW) (<3.5kDa) and of high molecular weight (HMW) (3.5-100kDa and >100kDa) from cold water, hot water and aqueous ethanolic SLE extracts. An enhancement of the total phenolic content (TPC), radical scavenging abilities (RSA) and ferric reducing antioxidant power (FRAP) in the HMW fractions of 3.5-100kDa and/or >100kDa from the cold water and aqueous ethanolic extracts was observed. The initial weak TPC, RSA and FRAP observed in the LMW fractions relative to the HMW fractions were substantially enhanced following a reverse-phase flash chromatography fractionation method. Quadrupole time-of-flight mass spectrometry (Q-Tof-MS) suggests that phlorotannins of varying degrees of phloroglucinol polymerisation are present in LMW fractions of the three brown macroalgal species. The development of a food-friendly process for the extraction and enrichment of phlorotannins from Irish macroalgae is vital to facilitate the use of this valuable resource in future developments of macroalgal-based functional foods. 23297736 Systematic literature review of the effects of food and drink advertising on food and drink-related behaviour, attitudes and beliefs in adult populations. A large body of research confirms that food advertising affects the food preferences and behaviour of children. The impact of food advertising on adults is less clear. We conducted a systematic review exploring the effects of advertising of food and non-alcoholic drinks (referred to as 'food' throughout) on food-related behaviour, attitudes and beliefs in adult populations. We searched seven electronic databases, grey literature sources, and references and citations of included material for experimental studies written in English investigating the effects of commercial food advertising on the food-related behaviours, attitudes and beliefs of adults aged 16 years and over. Nine studies, rated moderate to poor quality, were included in the review; all were from developed countries and explored the impact of televised food advertising. Overall, the results did not show conclusively whether or not food advertising affects food-related behaviour, attitudes or beliefs in adults, but suggest that the impact varies inconsistently within subgroups, including gender, weight and existing food psychology. The identification of a small number of relevant studies, none of which were high quality, and with substantial heterogeneity, highlights the need for further research. Future studies investigating longer term outcomes, diverse advertising formats, and in countries with different levels of economic development will be of particular value. 23467017 Monitoring abacavir bioactivation in humans: Screening for an aldehyde metabolite. The anti-HIV drug abacavir is associated with idiosyncratic hypersensitivity reactions and cardiotoxicity. Although the mechanism underlying abacavir-toxicity is not fully understood, drug bioactivation to reactive metabolites may be involved. This work was aimed at identifying abacavir-protein adducts in the hemoglobin of HIV patients as biomarkers of abacavir bioactivation and protein modification. The protocol received prior approval from the Hospital Ethics Committee, patients gave their written informed consent and adherence was controlled through a questionnaire. Abacavir-derived Edman adducts with the N-terminal valine of hemoglobin were analyzed by an established liquid chromatography-electrospray ionization-tandem mass spectrometry method. Abacavir-valine adducts were detected in three out of ten patients. This work represents the first evidence of abacavir-protein adduct formation in humans. The data confirm the ability of abacavir to modify self-proteins and suggest that the molecular mechanism(s) of some abacavir-induced adverse reactions may require bioactivation. 23434370 The MRN-CtIP pathway is required for metaphase chromosome alignment. Faithful duplication of the genome in S phase followed by its accurate segregation in mitosis is essential to maintain genomic integrity. Recent studies have suggested that proteins involved in DNA transactions are also required for whole-chromosome stability. Here we demonstrate that the MRN (Mre11, Rad50, and Nbs1) complex and CtIP are required for accurate chromosome segregation. Depletion of Mre11 or CtIP, antibody-mediated inhibition of Mre11, or small-molecule inhibition of MRN using mirin results in metaphase chromosome alignment defects in Xenopus egg extracts. Similarly, loss of MRN function adversely affects spindle assembly around DNA-coated beads in egg extracts. Inhibition of MRN function in mammalian cells triggers a metaphase delay and disrupts the RCC1-dependent RanGTP gradient. Addition of the Mre11 inhibitor mirin to egg extracts and mammalian cells reduces RCC1 association with mitotic chromosomes. Thus, the MRN-CtIP pathway contributes to Ran-dependent mitotic spindle assembly by modulating RCC1 chromosome association. 23294363 Mathematical modeling of oral absorption and bioavailability of a fluoroquinolone after its precipitation in the gastrointestinal tract. Abstract 1. The objective was to characterize the in vivo absorption and bioavailability (BA) of a low solubility, high permeability fluoroquinolone (CNV97101) that precipitates in the gastrointestinal (GI) tract by mathematical modeling approach. 2. In situ rat intestinal perfusion studies were performed to characterize the absorption mechanism. The oral fraction absorbed in vivo was lower than the predicted based on the in situ intestinal permeability. Two additional routes of administration, intraduodenal (ID) and intraperitoneal (IP) were investigated to explore if precipitation in stomach and subsequent partial re-dissolution were the causes of the lower in vivo BA. Ex vivo precipitation studies with the stomach content of fasted rats were also carried out. Fitting procedures were performed with NONMEM VII 1.2. 3. The in situ experiments confirmed simultaneous passive and carrier-mediated absorption processes. The ex vivo experiments confirmed precipitation in stomach lowering in vivo the oral fraction absorbed compared with the IP and ID administrations. Due to the almost complete availability of CNV97101 following IP administration, a first hepatic pass could be excluded. The ex vivo assay results and the pharmacokinetic modeling of in vivo data supported the hypothesis of precipitation in the stomach and partial re-dissolution. Nevertheless, other factors such as residence time in the GI may reduce the fraction absorbed even for low oral doses for which re-dissolution was almost complete in vivo. 23142105 Evaluation of presumptive biomarkers of oxidative stress, immune response and apoptosis in primary open-angle glaucoma. There is growing interest on the correlation among oxidative stress, inflammation, apoptosis and primary open-angle glaucoma initiation and progression. Reactive oxygen species are formed in the eyes following a wide variety of stressors, and are largely implicated in glaucoma pathogenesis. Immune-inflammatory response mediators have recently become a target of ophthalmologic concern, including glaucoma. Much attention has been derived to the role of specific pro and anti-apoptotic molecules in glaucoma. This article reviews the early evidence suggesting that reactive oxygen species, immune inflammatory response mediators, and apoptogenic molecules are engaged in glaucoma disease. Moreover, further research concerning the functions, effectors and signaling pathways of the above molecules and their interactions, may lead to specifically develop targeted screening tools based on presumptive biomarkers and surrogate endpoints against primary open-angle glaucoma progression and blindness. 23267008 A novel non-radioactive primase-pyrophosphatase activity assay and its application to the discovery of inhibitors of Mycobacterium tuberculosis primase DnaG. Bacterial DNA primase DnaG synthesizes RNA primers required for chromosomal DNA replication. Biochemical assays measuring primase activity have been limited to monitoring formation of radioactively labelled primers because of the intrinsically low catalytic efficiency of DnaG. Furthermore, DnaG is prone to aggregation and proteolytic degradation. These factors have impeded discovery of DnaG inhibitors by high-throughput screening (HTS). In this study, we expressed and purified the previously uncharacterized primase DnaG from Mycobacterium tuberculosis (Mtb DnaG). By coupling the activity of Mtb DnaG to that of another essential enzyme, inorganic pyrophosphatase from M. tuberculosis (Mtb PPiase), we developed the first non-radioactive primase-pyrophosphatase assay. An extensive optimization of the assay enabled its efficient use in HTS (Z' = 0.7 in the 384-well format). HTS of 2560 small molecules to search for inhibitory compounds yielded several hits, including suramin, doxorubicin and ellagic acid. We demonstrate that these three compounds inhibit Mtb DnaG. Both suramin and doxorubicin are potent (low-µM) DNA- and nucleotide triphosphate-competitive priming inhibitors that interact with more than one site on Mtb DnaG. This novel assay should be applicable to other primases and inefficient DNA/RNA polymerases, facilitating their characterization and inhibitor discovery. 23534403 Extended hückel theory for carbon nanotubes: band structure and transport properties. Extended Hückel theory (EHT) is a well established method for the description of the electronic structure of molecules and solids. In this article, we present a set of extended Hückel parameters for carbon nanotubes (CNTs), obtained by fitting the ab initio band structure of the (6,0) CNT. The new parameters are highly transferable to different types of CNTs. To demonstrate the versatility of the approach, we perform self-consistent EHT-based electron transport calculations for finite length CNTs with metal electrodes. 23560944 Synergistic Interactions between Grafted Hyaluronic Acid and Lubricin Provide Enhanced Wear Protection and Lubrication. Normal (e.g., adhesion) and lateral (friction) forces were measured between physisorbed and chemically grafted layers of hyaluronic acid (HA), an anionic polyelectrolyte in the presence of lubricin (Lub), a mucinous glycoprotein, on mica surfaces using a surface forces apparatus (SFA). This work demonstrates that high friction coefficients between the surfaces do not necessarily correlate with surface damage and that chemically grafted HA acts synergistically with Lub to provide friction reduction and enhanced wear protection to the surfaces. Surface immobilization of HA by grafting is necessary for such wear protection. Increasing the concentration of Lub enhances the threshold load that a chemically grafted HA surface can be subjected to before the onset of wear. Addition of Lub does not have any beneficial effect if HA is physisorbed to the mica surfaces. Damage occurs at loads less than 1 mN regardless of the amount of Lub, indicating that the molecules in the bulk play little or no role in protecting the surfaces from damage. Lub penetrates into the chemically bound HA to form a visco-elastic gel that reduces the coefficient of friction as well as boosts the strength of the surface against abrasive wear (damage). 23603477 Isolation and in vitro partial characterization of hemolytic proteins from the nematocyst venom of the jellyfish Stomolophus meleagris. Jellyfish venom contains various toxins and can cause itching, edema, muscle aches, shortness of breath, blood pressure depression, shock or even death after being stung. Hemolytic protein is one of the most hazardous components in the venom. The present study investigated the hemolytic activity of the nematocyst venom from jellyfish Stomolophus meleagris. Anion exchange chromatography, DEAE Sepharose Fast Flow, and gel filtration chromatography, Superdex200 had been employed to isolate hemolytic proteins from the nematocyst venom of jellyfish S. meleagris. Hemolysis of chicken red blood cells was used to quantify hemolytic potency of crude nematocyst venom and chromatography fractions during the purification process. Native-PAGE profile displayed one protein band in the purified hemolytic protein (SmTX); however, two protein bands with apparent molecular weights of ∼45kDa and 52kDa were observed in the reducing SDS-PAGE analysis. Approximately 70μg/mL of SmTX caused 50% hemolysis (HU50) of the erythrocyte suspension. The hemolytic activity of SmTX was shown to be temperature and pH dependent, with the optimum temperature and pH being 37°C and pH 5.0. The present study is the first report of isolation and partial characterization of hemolytic proteins from the nematocyst venom of the jellyfish S. meleagris. The mechanism of the hemolytic activity of SmTX is not clear and deserves further investigation. 23340250 Impaired fertility and FSH synthesis in gonadotrope-specific Foxl2 knockout mice. Impairments in pituitary FSH synthesis or action cause infertility. However, causes of FSH dysregulation are poorly described, in part because of our incomplete understanding of mechanisms controlling FSH synthesis. Previously, we discovered a critical role for forkhead protein L2 (FOXL2) in activin-stimulated FSH β-subunit (Fshb) transcription in immortalized cells in vitro. Here, we tested the hypothesis that FOXL2 is required for FSH synthesis in vivo. Using a Cre/lox approach, we selectively ablated Foxl2 in murine anterior pituitary gonadotrope cells. Conditional knockout (cKO) mice developed overtly normally but were subfertile in adulthood. Testis size and spermatogenesis were significantly impaired in cKO males. cKO females exhibited reduced ovarian weight and ovulated fewer oocytes in natural estrous cycles compared with controls. In contrast, ovaries of juvenile cKO females showed normal responses to exogenous gonadotropin stimulation. Both male and female cKO mice were FSH deficient, secondary to diminished pituitary Fshb mRNA production. Basal and activin-stimulated Fshb expression was similarly impaired in Foxl2 depleted primary pituitary cultures. Collectively, these data definitively establish FOXL2 as the first identified gonadotrope-restricted transcription factor required for selective FSH synthesis in vivo. 23180684 Bottom-up nutrient and top-down fish impacts on insect-mediated mercury flux from aquatic ecosystems. Methyl mercury (MeHg) is one of the most hazardous contaminants in the environment, adversely affecting the health of wildlife and humans. Recent studies have demonstrated that aquatic insects biotransport MeHg and other contaminants to terrestrial consumers, but the factors that regulate the flux of MeHg out of aquatic ecosystems via emergent insects have not been studied. The authors used experimental mesocosms to test the hypothesis that insect emergence and the associated flux of MeHg from aquatic to terrestrial ecosystems is affected by both bottom-up nutrient effects and top-down fish consumer effects. In the present study, nutrient addition led to an increase in MeHg flux primarily by enhancing the biomass of emerging insects whose tissues were contaminated with MeHg, whereas fish decreased MeHg flux primarily by reducing the biomass of emerging insects. Furthermore, the authors found that these factors are interdependent such that the effects of nutrients are more pronounced when fish are absent, and the effects of fish are more pronounced when nutrient concentrations are high. The present study is the first to demonstrate that the flux of MeHg from aquatic to terrestrial ecosystems is strongly enhanced by bottom-up nutrient effects and diminished by top-down consumer effects. 23225346 2-Phenoxy-nicotinamides are potent agonists at the bile acid receptor GPBAR1 (TGR5). Potency with potential: 2-Phenoxy-nicotinamides were identified as potent agonists at the GPBAR1 receptor, a target in the treatment of obesity, type 2 diabetes and metabolic syndrome. Extensive structure-activity relationship studies supported by homology modeling and docking resulted in the identification of optimized GPBAR1 agonists, potent against both human and mouse receptors, endowed with favorable physicochemical properties and good metabolic stability. 22708620 Composition and antioxidant capacity of the essential oil of leaves of Vitex megapotamica (Sprengel) Moldenke. This study is designed to examine the chemical composition and antioxidant activity of the essential oil of Vitex megapotamica. Gas chromatography-mass spectrometry analysis resulted in the detection of 27 components, representing 92.36% of the total oil composition. The main components in the oil were butylated hydroxytoluene (BHT) (34.17%), phytol (12.66%), α-caryophyllene (11.84%), δ-elemene (10.65%), β-caryophyllene (7.82%), γ-elemene (4.24%) and germacrene D (2.82%). The antioxidant activity of the oil was evaluated in terms of their free-radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl. The oil showed percentage inhibition of 35.62% and 75.25% at concentrations of 76 and 101.6 mg mL(-1), respectively. BHT (36.30%) was also determined by HPLC-DAD in the hexane fraction from the leaves. To the best of our knowledge, this is the first study of the composition and antioxidant activity of the essential oil of the species V. megapotamica. 23485481 Mercury in fishes from Augusta Bay (southern Italy): Risk assessment and health implication. Our study reports on the total mercury (HgT) concentrations measured in the muscles and livers of several benthic, demersal and pelagic fish species caught inside and outside of Augusta Bay (southern Italy), a semi-enclosed marine area, highly contaminated by the uncontrolled (since the 1950s to 1978s) discharge of the largest European petrochemical plant. Mercury levels in fish tissues are discussed with regard to specific habitat, size and/or age of the specimens and HgT distribution in the bottom sediments. Results suggest a still active Hg release mechanism from the polluted sediments to the marine environment. Also, the high HgT concentrations measured in fishes caught in the external area of the bay imply a potential role of Augusta Bay as a pollutant source for the Mediterranean ecosystem. Finally, values of hazard target quotient (THQ) and estimated weekly intake (EWI) demonstrate that consumption of fishes caught inside the bay represents a serious risk for human health. Also, data indicate that intake of fishes caught from the external area of the bay, especially for that concern demersal and benthic species, could be represent a significant component of risk for the local population. 23211363 Effects of dopamine D2/D3 receptor ligands on food-cocaine choice in socially housed male cynomolgus monkeys. Dopamine D2/D3 receptor partial agonists have been suggested as medications for cocaine dependence. The present experiments examined the effect of acute and repeated administration of drugs with varying intrinsic efficacy at D2/D3 receptors on the relative reinforcing strength of cocaine. Use of socially housed cynomolgus monkeys permitted the assessment of whether social status, known to alter D2/D3 receptor availability, influenced the behavioral effects of D2/D3 receptor compounds. The high-efficacy agonist R(-)-norpropylapomorphine [(-)-NPA], low-efficacy agonist aripiprazole (ARI), and antagonist eticlopride (ETIC) were administered acutely to monkeys self-administering cocaine under a food-cocaine choice procedure in which a cocaine self-administration dose-effect curve was determined daily. The effects of 5-day treatment with ARI and (-)-NPA were characterized under conditions in which monkeys did (ARI) or did not [ARI and (-)-NPA] self-administer cocaine during treatment. When administered acutely, ARI and ETIC increased the choice of low cocaine doses, and only (-)-NPA decreased the choice of higher cocaine doses and cocaine intake; effects were similar across social ranks. When administered repeatedly while self administration occurred only on days 1 and 5 of treatment, ARI, but not (-)-NPA, decreased cocaine choice in dominant monkeys, whereas (-)-NPA, but not ARI, did so in subordinates. When dominant monkeys self-administered cocaine on all five days of ARI treatment, however, these effects were not observed. The results indicate that the behavioral effects of D2/D3 receptor agonists can differ according to intrinsic efficacy and subject characteristics. Moreover, these results suggest that exposure to cocaine during treatment can counteract treatment-induced reductions in the reinforcing effects of cocaine. 23578631 Determination of α-keto acids in pork meat and Iberian ham via tandem mass spectrometry. An analytical method which offers accurate determination and identification of eight α-keto acids (α-ketoglutaric acid, pyruvic acid, 4-hydroxyphenylpyruvic acid, 3-methyl-2-oxobutyric acid, α-keto-γ-methylthiobutyric acid, 4-methyl-2-oxovaleric acid, 3-methyl-2-oxovaleric acid, and phenylpyruvic acid) in pork meat and Iberian ham samples is reported. The method utilises a highly selective and sensitive method of multiple reaction monitoring (MRM) by mass spectrometry. The analytical method is simple (although the chemical derivatisation of the α-keto acids with dansylhydrazine is required), precise (<18% RSD), accurate (90-110%), sensitive (0.01-0.34mg/kg of defatted and freeze-dried meat depending on the α-keto acid) and linear (R>0.99) over several orders of magnitude (until 0.01-146.1mg/kg of defatted and freeze-dried meat depending on the α-keto acid). Using this methodology, α-keto acids were found to be present in pork meat to a low extent, and their concentration increased when they were determined in Iberian ham. This is the first report of the presence of α-keto acids in both pork meats and Iberian hams. 23606334 Proteomic identification of the candidate target proteins of 15-deoxy-delta(12,14) -prostaglandin J2. 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) is an endogenous anti-inflammatory lipid derived from PGD2 . One potential mechanism for its activity is the covalent modification of cellular proteins, via a reactive α,β-unsaturated carbonyl group in its cyclopentenone ring, which in turn alters protein function. In order to identify the candidate target proteins covalently modified by 15d-PGJ2 in human aortic endothelial cell (EC), EC were treated with biotinylated-15d-PGJ2, the modified proteins extracted by Neutravidin affinity-purification and the proteins identified by LTQ Orbitrap mass spectrometer. Classification of the 358 identified proteins was performed using PANTHER classification system (www.pantherdb.org), showing that the proteins mapped to metabolic process, cellular process and transport activity. This protein data set highlights the potential for 15d-PGJ2 to covalently modify cellular proteins and provides a source of data that will aid further studies on the mechanism of action of this endogenous regulator of inflammation. This article is protected by copyright. All rights reserved. 23100157 Assessment of immunotoxicity and genotoxicity in workers exposed to low concentrations of formaldehyde. Formaldehyde (FA), which is an important chemical with a wide commercial use, has been classified as carcinogenic to humans by International Research on Cancer (IARC). The genotoxic and carcinogenic potential of FA has been documented in mammalian cells and in rodents. A recent evaluation by the E.U. Scientific Committee for Occupational Exposure Limits (SCOEL) anticipated that an 8-h time-weighted average exposure to 0.2 ppm FA would not be irritating and not genotoxic in humans. In order to verify this prediction, a field study was performed that aimed at evaluating immune alterations and genetic damage in peripheral lymphocytes of workers in medium density fiberboard plants exposed to a level of FA equivalent to the OEL recommended by SCOEL (0.2 ppm). Subsets of peripheral lymphocytes, immunoglobulins (IgG, IgA, IgM), complement proteins, and tumor necrosis factor-alpha (TNF-α) levels were evaluated. DNA damage of the workers was assessed by the Comet assay. The absolute numbers and the percentages of T lymphocytes and of natural killer cells, and the levels of TNF-α were higher than the controls, whereas IgG and IgM levels were found to be lower in workers. Other examined immunological parameters were not different from those of the controls. There was no increased DNA damage in the workers compared to controls. 23064097 Delivering the promise of miRNA cancer therapeutics. MicroRNAs (miRNAs) are pivotal post-transcriptional gene expression regulators. These endogenous small non-coding RNAs aberrantly expressed in cancer have significant roles in tumorigenesis and progression. Currently, miRNAs are being pursued as diagnostic and prognostic biomarkers, and as therapeutic tools in cancer. miRNA modulation provides the unique ability to fine-tune multiple genes simultaneously, thereby regulating relevant signaling pathways involved in cell differentiation, proliferation and survival. This unique miRNA feature shifts the traditional one drug one target paradigm to a novel one drug multiple targets paradigm. We herein review in vivo strategies of miRNA modulator (mimic and/or inhibitor) delivery in cancer models, a subject that remains the key challenge to the establishment of this novel class of RNA therapeutics. 23477372 Modeling ring/chain equilibrium in nanoconfined sulfur. The effect of nanoconfinement on the thermodynamics of free radical polymerization of sulfur is examined. We extend Tobolsky and Eisenberg's model of bulk sulfur polymerization to nanopores accounting for the confinement entropy of the chains and ring using scaling reported in literature. The model quantitatively captures literature data from Yannopoulos and co-workers for the extent of polymerization versus temperature for bulk sulfur polymerization and for polymerization in 20, 7.5, and 2.5 nm diameter Gelsil nanopores, assuming that the change of entropy of nanoconfined chains scales with molecular size to the second power and with nanopore diameter to either the -3.0 or -3.8 power, the former of which fits slightly better. The scaling, which is valid for strong confinement in spherical pores, predicts that the propagation equilibrium constant will depend on both nanopore size and chain length, such that the average chain length decreases significantly upon confinement. 23639246 Differential Induction of Cytochrome P450 Isoforms and Peroxisomal Proliferation by Cyfluthrin in Male Wistar Rats. Cyfluthrin effects on in vivo drug metabolizing enzymes were evaluated using the oxidative substrate antipyrine. Antipyrine pharmacokinetics in plasma and urinary excretion of its major metabolites with and without cyfluthrin oral treatment (20mg/kg/day for 6 days) were investigated in rats. Cyfluthrin increased the apparent intrinsic clearance and decreased the antipyrine half-life at β phase. Cyfluthrin also increased the clearance of the antipyrine metabolites, norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine and the formation rate constants for each of the three metabolites measured in urine. These results suggest that cyfluthrin affects hepatic cytochrome P450 (CYP) system. In order to confirm, a second experiment was carried out. We evaluated the effects of repeated exposure to cyfluthrin on hepatic and renal CYP2E, CYP1A and CYP4A subfamilies and peroxisomal proliferation in rats following oral administration (10 and 20mg/kg/day for 6 days). At the highest dose, cyfluthrin increased renal and hepatic O-deethylation of ethoxyresorufin and O-demethylation of methoxyresorufin, metabolism mediated by the CYP1A subfamily. Liver and kidney were susceptible to cyfluthrin-dependent induction of 12- and 11-hydroxylation of lauric acid, suggesting CYP4A subfamily induction. Also cyfluthrin increased the β-oxidation of palmitoyl-coenzyme A and carnitine acetyltransferase activity, supporting cyfluthrin as a peroxisome proliferator. In conclusion, the demonstration that cyfluthrin induced hepatic CYP1A, CYP4A subfamilies and peroxisomal proliferation raises the possibility of cyfluthrin could produce changes in oxidative stress. 23419816 Charge affects the oral toxicity of poly(amidoamine) dendrimers. Poly(amidoamine) (PAMAM) dendrimers have been evaluated for the influence of surface functionality and size on the epithelial barrier of the gut with the goal of identifying safe carriers that can be used for oral drug delivery. Limited studies are conducted to date, however, to assess the toxicity of PAMAM dendrimers in vivo when administered by the oral route. The goal of this research was to conduct an oral acute toxicity study of PAMAM dendrimers as a function of size and charge in immune competent CD-1 mice. Maximum tolerated doses (MTD) of PAMAM dendrimers as a function of size and surface functionality were established and clinical signs of toxicity monitored. Results demonstrate that positively charged dendrimers caused more toxicity, whereas their anionic counterparts were tolerated at ten times higher doses. Severe signs of toxicity observed for large (G7) cationic amine- or hydroxyl-terminated dendrimers include hemobilia and spleenomegaly. The MTD for these dendrimers ranged from 30mg/kg to 200mg/kg. Anionic G6.5 or smaller molecular weight carboxyl-, amine-, or hydroxyl-terminated dendrimers (G3.5-COOH, G4-NH2, G4-OH) on the other hand were tolerated at doses of up to 500mg/kg (300mg/kg in some cases) with minimal or no signs of toxicity. Establishing the MTD of orally delivered PAMAM dendrimers and the influence of surface functionality and size on toxicity aids in the rational design of PAMAM-drug conjugates for oral drug delivery applications. 23337256 Sex differences in the antidepressant-like effects of ketamine. Current medications for major depression suffer from numerous limitations. Once the right drug for treatment has been determined, it still takes several weeks for it to take effect and improve mood. This time lag is a serious concern for the healthcare community when dealing with patients with suicidal thoughts. However, recent clinical studies have shown that a single low-dose injection of ketamine, an N-methyl d-aspartate receptor (NMDAR) antagonist, has rapid antidepressant effects that are observed within hours and are long lasting. Although major depression affects twice as many women as men, all studies examining the rapid antidepressant effects of ketamine have focused on male subjects. Thus, we have investigated the behavioral and molecular effects of ketamine in both male and female rats and demonstrated greater sensitivity in female rats at a low dose of ketamine, a dose does not have antidepressant-like effects in male rats. The antidepressant-like effects of this low dose of ketamine were completely abolished when female rats were ovariectomized (OVX), and restored when physiological levels of estrogen and progesterone were supplemented, suggesting a critical role for gonadal hormones in enhancing the antidepressant-like effects of ketamine in female rats. In preclinical studies, the mammalian target of rapamycin (mTOR) in the medial prefrontal cortex and the eukaryotic elongation factor (eEF2) in the hippocampus have been proposed as critical mediators of ketamine's rapid antidepressant actions. In our hands, the increased sensitivity of female rats to a low dose of ketamine was not mediated through phosphorylation of mTOR or eEF2. 23265878 Lead optimization of isocytosine-derived xanthine oxidase inhibitors. We report our attempts at improving the oral efficacy of low-nanomolar inhibitors of xanthine oxidase from isocytosine series through chemical modifications. Our lead compound had earlier shown good in vivo efficacy when administered intraperitoneally but not orally. Several modifications are reported here which achieved more than twofold improvement in exposure. A compound with significant improvement in oral efficacy was also obtained. 23454832 The suppression of hematopoiesis function in Balb/c mice induced by prolonged exposure of microcystin-LR. Microcystins (MCs) cause normocytic anemia in patients in a hemodialysis unit in Caruaru, Brazil in 1996, but the underlying mechanisms are still unclear. In the present study, Balb/c mice were intraperitoneally injected with microcystin-LR (MC-LR) at the doses of 0.5, 2 and 8μg/kg body weight (bw) every 48h for 30d. After the prolonged exposure of MC-LR, significant decreases of red blood cell count (RBC), hemoglobin (Hb) and hematocrit (Ht) were observed in 2 and 8μg/kg bw groups, but erythrocyte mean corpuscular volume (MCV) showed no significant changes. Significantly elevated micronucleus frequency was observed in bone marrow cells (BMCs) in all MC-LR treatments. The proliferation of BMCs significantly declined in both 2 and 8μg/kg bw groups. Serum levels of some hematopoietic growth factors significantly changed in 8μg/kg bw group, mainly including granulocyte-macrophage (GM-CSF), erythropoietin (EPO), interleukin-3 (IL-3) and TNF-α. The transcriptional levels of these 4 genes in BMCs were also significantly changed in 8μg/kg bw group. MC-LR exposure significantly increased the apoptosis rates in all MC-LR treatments. The present study indicates prolonged exposure of MC-LR induces normocytic anemia, and the disturbed hematopoietic growth factors and BMCs apoptosis are responsible for this normocytic anemia. 23596261 Methamidophos exposure during the early postnatal period of mice: Immediate and late-emergent effects on the cholinergic and serotonergic systems and on behavior. Organophosphates (OPs) are among the most used pesticides. While some OPs have had their use progressively more restricted, other OPs are being used without sufficient investigation of their effects. Here, we investigated the immediate neurochemical and delayed neurochemical and behavioral actions of the OP methamidophos to verify whether there are concerns regarding exposure during early postnatal development. From the 3(rd) to the 9(th) postnatal day (PN), Swiss mice were subcutaneously injected with methamidophos (1 mg/kg). At PN10, we assessed cholinergic and serotonergic biomarkers in the cerebral cortex and brainstem. From PN60 to PN63, mice were submitted to a battery of behavioral tests and subsequently to biochemical analyses. At PN10, the effects were restricted to females and to the cholinergic system: Methamidophos promoted increased choline transporter binding in the brainstem. At PN63, in the brainstem, there was a decrease in choline transporter, a female-only decrease in 5HT1A and a male-only increase in 5HT2 receptor binding. In the cortex, choline acetyltransferase activity was decreased and 5HT2 receptor binding was increased both in males and females. Methamidophos elicited behavioral alterations suggestive of increased depressive-like behavior and impaired decision-making. There were no significant alterations on anxiety-related measures and on memory/learning. Methamidophos elicited cholinergic and serotonergic alterations that depended on brain region, sex and age of the animals. These outcomes, together with the behavioral effects, indicate that this OP is deleterious to the developing brain and that alterations are indeed identified long after the end of exposure. 23416757 Molecular phylogeny of the Indian Ocean Terpsiphone paradise flycatchers: Undetected evolutionary diversity revealed amongst island populations. We construct a molecular phylogeny of Terpsiphone flycatchers of the Indian Ocean and use this to investigate their evolutionary relationships. A total of 4.4kb of mitochondrial (cyt-b, ND3, ND2, control region) and nuclear (G3PDH, MC1R) sequence data were obtained from all species, sub-species and island populations of the region. Colonisation of the western Indian Ocean has been within the last two million years and greatly postdates the formation of the older islands of the region. A minimum of two independent continent-island colonisation events must have taken place in order to explain the current distribution and phylogenetic placement of Terpsiphone in this region. While five well-diverged Indian Ocean clades are detected, the relationship between them is unclear. Short intermodal branches are indicative of rapid range expansion across the region, masking exact routes and chronology of colonisation. The Indian Ocean Terpsiphone taxa fall into five well supported clades, two of which (the Seychelles paradise flycatcher and the Mascarene paradise flycatcher) correspond with currently recognised species, whilst a further three (within the Madagascar paradise flycatcher) are not entirely predicted by taxonomy, and are neither consistent with distance-based nor island age-based models of colonisation. We identify the four non-Mascarene clades as Evolutionarily Significant Units (ESUs), while the Mascarene paradise flycatcher contains two ESUs corresponding to the Mauritius and Réunion subspecies. All six ESUs are sufficiently diverged to be worthy of management as if they were separate species. This phylogenetic reconstruction highlights the importance of sub-specific molecular phylogenetic reconstructions in complex island archipelago settings in clarifying phylogenetic history and ESUs that may otherwise be overlooked and inadvertently lost. Our phylogenetic reconstruction has identified hidden pockets of evolutionary distinctiveness, which provide a valuable platform upon which to re-evaluate investment of conservation resources within the Terpsiphone flycatchers of the Indian Ocean. 23561214 Influence of pH, metal chelator, free radical scavenger and interfacial characteristics on the oxidative stability of β-carotene in conjugated whey protein-pectin stabilised emulsion. The influence of whey protein isolate (WPI)-beet pectin conjugates formed by dry-heating on the oxidative stability of β-carotene in O/W emulsions was studied. It was mainly focused on the influence of pH, metal chelator, free radical scavenger and interfacial characteristics on the degradation of β-carotene in the emulsion stabilised by conjugate. The conjugate increased the oxidative stability of β-carotene in the emulsion as compared to their unconjugated mixture at pH 7.0. The desferoxamine retarded β-carotene degradation at pH 4.0 more effectively than pH 7.0 and more effectively in the emulsion with the conjugate than the unconjugated mixture (p<0.05). The addition of 200mg/kg α-tocopherol significantly improved the stability of β-carotene in the conjugate stabilised emulsion. The emulsions were washed to remove conjugate not absorbed to the emulsion droplet interface, indicating that unabsorbed emulsifiers could protect β-carotene. It suggested that WPI-pectin conjugate could be used to protect bioactive lipids in emulsions. 23319077 Bioavailability and intravenous toxicokinetic parameters for Pacific ciguatoxin P-CTX-1 in rats. Ciguatoxins are sodium channel activator toxins responsible for ciguatera fish poisoning. In this study, we determined the toxicokinetic parameters of the Pacific ciguatoxin P-CTX-1 in rats after an intravenous (iv) dose of 0.13 ng P-CTX-1 per g of body weight. The ciguatoxin activity was assessed over time in blood using the sensitive functional Neuro2a assay. The data were analyzed with a two-compartmental model. After exposure, the ciguatoxin activity exhibited a rapid (alpha half-life of 6 min) and extensive distribution into tissues (apparent steady state volume of distribution of 7.8 L). Ciguatoxin elimination from blood was slower with a beta half-life estimated at 35.5 h. The toxicokinetic parameters determined from this study were compared to data previously obtained after oral and intraperitoneal exposure of rats to 0.26 ng P-CTX-1 per g of body weight. Maximal bioavailability was determined by the area under the concentration curve, and was used to calculate the absolute P-CTX-1 bioavailabilities for oral and intraperitoneal routes of exposures of 39% and 75%, respectively. 23220512 A polyacetylene-rich extract from Gymnaster koraiensis strongly inhibits colitis-associated colon cancer in mice. Gymnaster koraiensis (GK) is a Korean herb used in folk medicine and recently found to positively impact liver health. Because GK contains polyacetylenes and because other polyacetylenes have been found to exhibit anti-inflammatory and anti-cancer activities, we hypothesized that the polyacetylene gymnasterkoreayne B (GKB), known to increase hepatic detoxification enzymes, may also exert anti-inflammatory and anti-cancer activities. We fed male C57BL/6 mice purified AIN93G diets containing no additions, GKB or the GKB-rich fraction of an ethanol extract (GE) from GK to determine if these diets would slow or prevent either inflammation or inflammation-enhanced colon cancer, using the dextran sulfate sodium/azoxymethane mouse model. The GKB (500 μmol/kg diet daily) showed some anti-inflammatory activity, but GE, containing an equal dose of GKB, protected strongly against both inflammation and colon cancer, decreasing adenocarcinomas by 90%. These data support further research into GK as a promising potential anti-cancer agent. 23575901 Boron Enhances Odontogenic and Osteogenic Differentiation of Human Tooth Germ Stem Cells (hTGSCs) In Vitro. Stem cell technology has been a great hope for the treatment of many common problems such as Parkinson's disease, Alzheimer's disease, diabetes, cancer, and tissue regeneration. Therefore, the main challenge in hard tissue engineering is to make a successful combination of stem cells and efficient inductors in the concept of stem cell differentiation into odontogenic and osteogenic cell types. Although some boron derivatives have been reported to promote bone and teeth growth in vivo, the molecular mechanism of bone formation has not been elucidated yet. Different concentrations of sodium pentaborate pentahydrate (NaB) were prepared for the analysis of cell toxicity and differentiation evaluations. The odontogenic, osteogenic differentiation and biomineralization of human tooth germ stem cells (hTGSCs) were evaluated by analyzing the mRNA expression levels, odontogenic and osteogenic protein expressions, alkaline phosphatase (ALP) activity, mineralization, and calcium deposits. The NaB-treated group displayed the highest ALP activity and expression of osteo- and odontogenic-related genes and proteins compared to the other groups and baseline. In the current study, increased in vitro odontogenic and osteogenic differentiation capacity of hTGSCs by NaB application has been shown for the first time. The study offers considerable promise for the development of new scaffold systems combined with NaB in both functional bone and tooth tissue engineering. 23479079 Sulfide induces apoptosis and Rho kinase-dependent cell blebbing in Jurkat cells. Hydrogen sulfide (H2S) is a toxic gaseous substance, and accidental exposure to high concentrations of H2S has been reported to be lethal to humans. Inhaled and absorbed H2S is partially dissolved within the circulation and causes toxic effects on lymphocytes. However, the mechanisms involved in H2S toxicity have not been well documented. In this study, we examined the cellular uptake and injury of sulfide-exposed human T lymphocytes (Jurkat). Cells were exposed to a H2S donor, sodium hydroxysulfide (NaHS), at pH 6.0, 7.0, or 8.0 for 1 h at 37 °C in a sealed conical tube to avoid the loss of dissolved H2S gas. Cytotoxicity and cellular sulfide concentrations increased dramatically as the pH of the NaHS solution decreased. Sulfide enhanced the cleavage of caspase-3 and poly (ADP-ribose) polymerase and induced early cellular apoptosis. A pan-caspase inhibitor reduced sulfide-induced apoptosis. These results indicate that sulfide induces pH-dependent and caspase-dependent apoptosis. We also found that blebbing of the plasma membrane occurred in sulfide-exposed cells. Both ROCK-1 and ROCK-2 (Rho kinases) were activated by sulfide, and sulfide-induced cell blebbing was suppressed by a ROCK inhibitor, suggesting that a Rho pathway is involved in sulfide-induced blebbing in lymphocytes. 23613084 One-Pot in Situ Mixed Film Formation by Azo Coupling and Diazonium Salt Electrografting. So simple: The in situ synthesis of an aryldiazonium salt and an azo-aryldiazonium salt by azo coupling from sulfanilic acid and aniline is reported. Formation of a mixed organic layer is monitored by cyclic voltammetry and atomic force microscopy. A compact mixed layer is obtained with a global roughness of 0.4 nm and 10-15 % vertical extension in the range 1.5-6 nm. 23644205 N-Alkylated 2,3,3-trimethylindolenines and 2-methylbenzothiazoles. Potential lead compounds in the fight against Saccharomyces cerevisiae infections. The synthesis of a variety of N-alkylated 2,3,3-trimethylindolenines and 2-methylbenzothiazoles is reported herein. Their potential as antifungal agents is evaluated by preliminary screening against Saccharomyces cerevisiae (S. cerevisiae), Schizosaccharomyces pombe (S. pombe), and Candida albicans (C. albicans). Statistical analyses illustrate a strong relationship between chain length and growth inhibition for S. cerevisiae and S. pombe (p < 0.0001 in every case). Of particular interest is the activity of both sets of compounds against S. cerevisiae, as this is emerging as an opportunistic pathogen, especially in immunosuppressed and immunocompromised patients. Bioassays were set up to compare the efficacy of our range of N-alkylated compounds against classic antifungal agents; Amphotericin B and Thiabendazole. 23402292 Tacticity-induced changes in the micellization and degradation properties of poly(lactic acid)-block-poly(ethylene glycol) copolymers. Poly(lactic acid)-block-poly(ethylene glycol) copolymers (PLA-b-PEG) featuring varying tacticities (atactic, heterotactic, isotactic) in the PLA block were synthesized and investigated for their micellar stability, degradation, and thermal properties. Utilizing tin(II) bis(2-ethylhexanoate), aluminum salan, and aluminum salen catalysts, the copolymers were synthesized through the ring-opening polymerization of d-, l-, rac-, or a blend of l- and rac-lactide using monomethoxy-poly(ethylene glycol) as a macroinitiator. The critical micelle concentration, which reflects the micellar stability, was probed using a fluorescence spectroscopic method with pyrene as the probe. The copolymers were degraded in a methanolic solution of 1,5,7-triaza-bicyclo[4.4.0]dec-5-ene and the degradation was measured by (1)H NMR spectroscopic and gel permeation chromatographic analyses. Differential scanning calorimetry and thermogravimetric analysis provided information on the thermal properties of the copolymers. Atactic and heterotactic microstructures in the PLA block resulted in lower micellar stability, as well as faster degradation and shorter erosion time compared to polymers with high isotactic enchainment (Pm). By modification of the Pm, micellar stability, degradation, and erosion rates of the copolymers can be tuned to specific biomedical applications. Interestingly, while tin(II) bis(2-ethylhexanoate) and aluminum salan-catalyzed PLA-b-PEG copolymers exhibited similar micellization behavior, the aluminum salen-catalyzed PLA-b-PEG exhibited unique behavior at high micelle concentration in the presence of the pyrene probe. This unique behavior can be attributed to the disintegration of the micelles through the interactions of long isotactic stereoblock segments. 23453808 The n-SET domain of Set1 regulates H2B ubiquitylation-dependent H3K4 methylation. Past studies have documented a crosstalk between H2B ubiquitylation (H2Bub) and H3K4 methylation, but little (if any) direct evidence exists explaining the mechanism underlying H2Bub-dependent H3K4 methylation on chromatin templates. Here, we took advantage of an in vitro histone methyltransferase assay employing a reconstituted yeast Set1 complex (ySet1C) and a recombinant chromatin template containing fully ubiquitylated H2B to gain valuable insights. Combined with genetic analyses, we demonstrate that the n-SET domain within Set1, but not Swd2, is essential for H2Bub-dependent H3K4 methylation. Spp1, a homolog of human CFP1, is conditionally involved in this crosstalk. Our findings extend to the human Set1 complex, underscoring the conserved nature of this disease-relevant crosstalk pathway. As not all members of the H3K4 methyltransferase family contain n-SET domains, our studies draw attention to the n-SET domain as a predictor of an H2B ubiquitylation-sensing mechanism that leads to downstream H3K4 methylation. 23494230 Multiple nicotine training doses in mice as a basis for differentiating the effects of smoking cessation aids. RATIONALE: Receptor mechanisms underlying the behavioral effects of clinically used nicotinic acetylcholine receptor agonists have not been fully established. OBJECTIVE: Drug discrimination was used to compare receptor mechanisms underlying the effects of smoking cessation aids. METHODS: Separate groups of male C57BL/6J mice discriminated 0.56, 1, or 1.78 mg/kg of nicotine base. Nicotine, varenicline, and cytisine were administered alone, in combination with each other, and in combination with mecamylamine and dihydro-β-erythroidine (DHβE). Midazolam and morphine were tested to examine sensitivity to non-nicotinics. RESULTS: The ED50 value of nicotine to produce discriminative stimulus effects systematically increased as training dose increased. Varenicline and cytisine did not fully substitute for nicotine and, as compared with nicotine, their ED50 values varied less systematically as a function of nicotine training dose. Morphine did not substitute for nicotine, whereas midazolam substituted for the low and not the higher training doses of nicotine. As training dose increased, the dose of mecamylamine needed to produce a significant rightward shift in the nicotine dose-effect function also increased. DHβE antagonized nicotine in animals discriminating the smallest dose of nicotine. Varenicline did not antagonize the effects of nicotine, whereas cytisine produced a modest though significant antagonism of nicotine. CONCLUSIONS: These results suggest that differences in pharmacologic mechanism between nicotine, varenicline, and cytisine include not only differences in efficacy at a common subtype of nicotinic acetylcholine receptor, but also differential affinity and/or efficacy at multiple receptor subtypes. 23602864 Synergistic enhancement of cancer therapy using a combination of heat shock protein targeted HPMA copolymer-drug conjugates and gold nanorod induced hyperthermia. In the field of nanomedicine, selective delivery to cancer cells is a common goal, where active targeting strategies are often employed to increase tumor accumulation. In this study, tumor hyperthermia was utilized as a means to increase the active delivery of heat shock protein (HSP) targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates. Following hyperthermia, induced expression of cell surface heat shock protein (HSP) glucose regulated protein 78kDa (GRP78) was utilized for targeted drug therapy. Conjugates bearing the anticancer agents aminohexylgeldanamycin (AHGDM), docetaxel (DOC), or cisplatin and the GRP78 targeting peptide WDLAWMFRLPVG were synthesized and characterized. Binding to cell surface expressed heat shock protein GRP78 on the surface of human prostate cancer DU145 cells was evaluated. HSP targeted AHGDM and DOC conjugates demonstrated active binding comparable to native targeting peptide. They were then assessed in vitro for the ability to synergistically induce cytotoxicity in combination with moderate hyperthermia (43°C, 30min). HSP targeted DOC conjugates exhibited high potency against DU145 cells with an IC50 of 2.4nM. HSP targeted AHGDM and DOC conjugates demonstrated synergistic effects in combination with hyperthermia with combination index values of 0.65 and 0.45 respectively. Based on these results, HSP targeted DOC conjugates were selected for in vivo evaluation. In DU145 tumor bearing mice, a single treatment of tumor hyperthermia, induced via gold nanorod mediated plasmonic photothermal therapy, and intravenous administration of HSP targeted HPMA copolymer-docetaxel at 10mg/kg resulted in maintained tumor regression for a period of 30days. These results demonstrate the potential for tumor hyperthermia to increase the delivery of HSP targeted macromolecular chemotherapeutics. 23205634 Effects of the lipid environment, cholesterol and bile acids on the function of the purified and reconstituted human ABCG2 protein. The human ABCG2 multidrug transporter actively extrudes a wide range of hydrophobic drugs and xenobiotics recognized by the transporter in the membrane phase. In order to examine the molecular nature of the transporter and its effects on the lipid environment, we have established an efficient protocol for the purification and reconstitution of the functional protein. We found that the drug-stimulated ATPase and the transport activity of ABCG2 are fully preserved by applying excess lipids and mild detergents during solubilization, whereas a detergent-induced dissociation of the ABCG2 dimer causes an irreversible inactivation. By using the purified and reconstituted protein we demonstrate that cholesterol is an essential activator, whereas bile acids are important modulators of ABCG2 activity. Both wild-type ABCG2 and its R482G mutant variant require cholesterol for full activity, although they exhibit different cholesterol sensitivities. Bile acids strongly decrease the basal ABCG2-ATPase activity both in the wild-type ABCG2 and in the mutant variant. These data reinforce the results for the modulatory effects of cholesterol and bile acids of ABCG2 investigated in a complex cell membrane environment. Moreover, these experiments open the possibility to perform functional and structural studies with a purified, reconstituted and highly active ABCG2 multidrug transporter. 23507752 LC-MS/MS Determination of Isoprostanes in Plasma Samples Collected from Mice Exposed to Doxorubicin or Tert-Butyl Hydroperoxide. Isoprostanes are stable products of arachidonic acid peroxidation and are regarded as the most reliable markers of oxidative stress in vivo. Here we describe the LC-MS/MS procedure enabling simultaneous determination of four regioisomers (8-iso prostaglandin F2α, 8-iso-15(R)-prostaglandin F2α, 11β-prostaglandin F2α, 15(R)-prostaglandin F2α) in plasma samples collected from mice. The four plasma isoprostanes are determined by LC-ESI-MS/MS with deuterated 8-iso-PGF2α-d4 as an internal standard (I.S.). For plasma samples spiked with the isoprostanes at a level of 200 pg/mL each, the method imprecision has been below 7.1% and mean inaccuracy equaled 8.7%. The applicability of the proposed approach has been verified by the assessment of changes in isoprostane levels in plasma samples derived from mice exposed to tert-butyl hydroperoxide (TBHP), a model inducer of oxidative stress, or to antitumor drug doxorubicin (DOX) known for potent stimulation of redox cycling. Compared to the control group of mice, both oxidative stress inducers tested increased the levels of three out of four isoprostanes in exposed animals; 11β-prostaglandin F2α being the exception. The greatest rise was observed in the case of 15(R)-prostaglandin F2α, by about 50% and 70% in plasma samples derived from mice exposed to DOX and TBHP, respectively. 23603058 The Fusarium toxin deoxynivalenol (DON) modulates the LPS induced acute phase reaction in pigs. The systemic effects of the Fusarium toxin deoxynivalenol (DON) and of bacterial lipopolysaccharides (LPS) were studied in male castrated pigs (40.4±3.7kg) infused intravenously with either DON or LPS alone (100μgDON/kg/h, 7.5μg/LPS/kg/h), or together (100μgDON plus 7.5μg/LPS/kg/h). The Control group received a saline infusion (n=6/treatment, 24h observation period). An additional DON infusion did not exacerbate the clinical signs observed in LPS-infused pigs. For example, rectal temperature climaxed after 4h (40.4±0.2°C) and 5h (40.1±0.3°C), in the LPS and LPS+DON groups, respectively. Saline and DON alone did not induce an acute phase reaction as indicated by unaltered plasma levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) while LPS caused a significant rise of both cytokines. TNF-alpha plasma peak concentrations were significantly higher in the LPS compared to the DON+LPS group (94.3±17.2ng/mL vs. 79.2±15.7ng/mL) while IL-6 climaxed earlier in the latter group (3h p.i. vs. 2h p.i.). From the tested clinical-chemical plasma characteristics the total bilirubin concentration and the ASAT activity were strongly elevated by the LPS infusion and additionally increased and decreased by DON, respectively. In conclusion, the LPS-induced effects were only marginally modified by DON. 23084158 Ultrasound-promoted coating of silk yarn with different morphology of magnesium hydroxide nanostructures. The growth of magnesium hydroxide nanostructures on silk yarn was achieved by sequential dipping steps in alternating bath of magnesium nitrate and potassium hydroxide under ultrasound irradiation. The effects of ultrasound irradiation, concentration, pH and sequential dipping steps on growth of the Mg(OH)(2) nanostructures have been studied. Morphology of the nanostructures, depending on pH and with decreasing pH from 13 to 8, changed from nanoparticle to nanoneedle. Results show a decrease in the particles size as the concentration and sequential dipping steps increased. The physicochemical properties of the nanostructures were determined by powder X-ray diffraction (XRD), scanning electron microscopy (SEM) and wavelength dispersive X-ray (WDX). 23404505 The propeptides of VEGF-D determine heparin binding, receptor heterodimerization, and effects on tumor biology. VEGF-D is an angiogenic and lymphangiogenic glycoprotein that can be proteolytically processed generating various forms differing in subunit composition due to the presence or absence of N- and C-terminal propeptides. These propeptides flank the central VEGF homology domain, that contains the binding sites for VEGF receptors (VEGFRs), but their biological functions were unclear. Characterization of propeptide function will be important to clarify which forms of VEGF-D are biologically active and therefore clinically relevant. Here we use VEGF-D mutants deficient in either propeptide, and in the capacity to process the remaining propeptide, to monitor the functions of these domains. We report for the first time that VEGF-D binds heparin, and that the C-terminal propeptide significantly enhances this interaction (removal of this propeptide from full-length VEGF-D completely prevents heparin binding). We also show that removal of either the N- or C-terminal propeptide is required for VEGF-D to drive formation of VEGFR-2/VEGFR-3 heterodimers which have recently been shown to positively regulate angiogenic sprouting. The mature form of VEGF-D, lacking both propeptides, can also promote formation of these receptor heterodimers. In a mouse tumor model, removal of only the C-terminal propeptide from full-length VEGF-D was sufficient to enhance angiogenesis and tumor growth. In contrast, removal of both propeptides is required for high rates of lymph node metastasis. The findings reported here show that the propeptides profoundly influence molecular interactions of VEGF-D with VEGF receptors, co-receptors, and heparin, and its effects on tumor biology. 23538035 The conjugation of microcystin-RR by human recombinant GSTs and hepatic cytosol. Many cyanobacterial species can produce cyanotoxins, among which mycrocistins (MC) are a group of ≈100 congeners of hepatotoxic cyclic heptapeptides. MC-RR differs from MC-LR, the most studied congener only for one residue (arginine vs leucine), resulting in a ten-fold difference in the acute toxicity in mice. Although humans may be exposed to MC through several routes and kinetics appeared to be the major factor affecting congener-specific toxicity, little is known on MC metabolism. The accepted pathway for MC detoxication is GSH conjugation: here the MC-RR conjugation with GSH catalyzed by 5 recombinant human GSTs and human liver cytosol (HLC) has been characterized and appeared to be more efficient than MC-LR conjugation. The catalytic efficiency score is T1-1>A1-1≈P1-1>M1-1>A3-3 (0.161-0.056pmol GSMC-RR (μgproteinminμM)(-1)). In HLC the spontaneous reaction is favored vs the enzymatic one (ratio 3:1) at physiological GSH content. However, at low MC-RR concentrations, representative of repeated oral exposure, and low GSH content (down to 0.05mM), possibly associated to exposure to drugs or in patients affected by several pathologies, the relevance of the enzymatic reaction progressively increases, providing the predominant contribution to MC-RR detoxication. 22687345 Risk factors for Parkinson's disease may differ in men and women: an exploratory study. Although several environmental and genetic risk or protective factors have been associated with Parkinson's disease (PD), their interactions overall and in men and women separately remain unknown. We used the medical records-linkage system of the Rochester Epidemiology Project to identify 196 subjects who developed PD in Olmsted County, MN, from 1976 through 1995. Each incident case was matched by age (±1 year) and sex to a general population control. We considered the following 12 risk or protective factors: personal history of head trauma, pesticide use, immunologic diseases, anemia, hysterectomy (in women only), cigarette smoking, coffee consumption, and education; and family history of parkinsonism, essential tremor, dementia, or psychiatric disorders. We used recursive partitioning analyses to explore interactions overall and in men and women separately and used logistic regression analyses to test for interactions. In the overall group, we observed the independent effects of anemia, lack of coffee consumption (never vs. ever), and head trauma; however, the findings were different in men and women. In men, we observed the independent effects of lack of coffee consumption (never vs. ever), head trauma, and pesticide use, and a suggestive synergistic interaction between immunologic diseases and family history of dementia. By contrast, in women, anemia was the most important factor and we observed a suggestive synergistic interaction between anemia and higher education. Risk factors for PD and their interactions may differ in men and women. 23547844 Controllable Hydrogen Sulfide Donors and Their Activity against Myocardial Ischemia-Reperfusion Injury. Hydrogen sulfide (H2S), known as an important cellular signaling molecule, plays critical roles in many physiological and/or pathological processes. Modulation of H2S levels could have tremendous therapeutic value. However, the study on H2S has been hindered due to the lack of controllable H2S releasing agents that could mimic the slow and moderate H2S release in vivo. In this work we report the design, synthesis, and biological evaluation of a new class of controllable H2S donors. Twenty-five donors were prepared and tested. Their structures were based on a perthiol template, which was suggested to be involved in H2S biosynthesis. H2S release mechanism from these donors was studied and proved to be thiol-dependent. We also developed a series of cell-based assays to access their H2S-related activities. H9c2 cardiac myocytes were used in these experiments. We tested lead donors' cytotoxicity and confirmed their H2S production in cells. Finally we demonstrated that selected donors showed potent protective effects in an in vivo murine model of myocardial ischemia-reperfusion injury, through a H2S-related mechanism. 23419815 Use of near-infrared spectroscopy to quantify drug content on a continuous blending process: Influence of mass flow and rotation speed variations. The aim of this study was to develop a quantitative Near-Infrared (NIR) method which monitors the homogeneity of a pharmaceutical formulation coming out of a continuous blender. For this purpose, a NIR diode array spectrometer with fast data acquisition was selected. Additionally, the dynamic aspects of a continuous blending process were studied; the results showed a well-defined cluster for the steady state, and the paths for the start-up and emptying stages were clearly identified. The end point of the start-up phase was detected by moving block of standard deviation, relative standard deviation, and principal component analysis. A partial least square (PLS) model was generated for the quantification of the drug, with a standard error of prediction of 0.2% m/m. The PLS model was successfully applied for monitoring the drug level at the outlet of the continuous blender. Furthermore, the PLS model was tested under different flow and stirring rates. Flow and stirring rate variations caused different powder flow dynamics, which were reflected on the NIR measurements. Therefore, the PLS model was sensitive to changes in mass flow and rotation speeds. 23627743 Interactions between solid surfaces with pre-adsorbed poly(ethylenimine) (PEI) layers: effect of unadsorbed free PEI chains. Poly(ethylenimine) (PEI) polyelectrolytes have been widely used to tune the stability, rheology, or adhesion properties of colloidal suspensions due to their strong tendency to adsorb to solid surfaces. They have also gained importance as gene carriers in biomedical applications, in which the anionic DNA chains are complexed and condensed to form PEI/DNA polyplexes. Some reported literatures have recently shown that the overdosed PEI chains, which are free in the solution mixture, also play a vital role in promoting the gene transfection, but the reason is unclear. In this work, we present the results of using total internal reflection microscopy (TIRM) to measure the interaction forces between a Brownian colloidal sphere and a flat glass plate in the presence of overdosed free PEI cationic chains, when both surfaces were saturated adsorbed with the PEI chains. The colloidal sphere pre-adsorbed with PEI chains was chosen to mimic the PEI/DNA polyplex. Results for the potential energy of interaction measured for model polyplex (e.g., PEI-coated sphere) interacting with a PEI-coated glass surface in the presence of overdosed free PEI chains at various pH values and salt concentrations were presented. As can be shown by direct force measurements, the interaction potentials in NaCl salt solution are dominated by repulsive forces originating from diffuse layer overlap and gravitational attraction. However, the presence of free PEI chains in the solution mixture produces a long-ranged (> 60 nm) attractive force between two PEI-coated surfaces with the range and magnitude tunable by pH value, PEI and salt concentrations. The possible mechanisms of this long-ranged attractive force are discussed. A better understanding of this free PEI-induced attractive force will be useful in the development of improved PEI/DNA polyplexes systems for biomedical applications. 23479059 A study of parabens and bisphenol A in surface water and fish brain tissue from the Greater Pittsburgh Area. Pollution from xenoestrogens has been discovered in the aquatic environment of the Greater Pittsburgh Area and is suspected to be caused by the failing sewer system. Personal care products and plasticizers have the potential to enter the water supply though treated and untreated sewage. Many of these compounds are suspected xenoestrogens. Paraben detection in surface waters was as follows: methyl paraben ranged between 2.2 to 17.3 ppt; ethyl paraben was not detectable; propyl paraben was detected at 9.2 and 12.0 ppt; butyl paraben was detected at 0.2 ppt. BPA was detected between 0.6 and 15.4 ppt. Estrogenic potential of extracts from fish brain tissue was tested via Bromodeoxyuridine MCF-7 analysis and paired with HPLC-MS to investigate the presence of xenoestrogens. All samples were non-detectable for parabens. BPA was detected in 44 of the 58 samples, with a range from non-detectable to 120 pg/g. BCFs were calculated. Results were statistically significant for location of capture (p < 0.05) and correlation existed between estrogenicity and BPA. 23072367 Controlling enzymatic action in living cells with a kinase-inducible bimolecular switch. Molecular probes designed to monitor or perturb signaling events in living cells rely on engineered molecular switches. Here, we show that a kinase-inducible bimolecular switch comprising a kinase-specific substrate and a phosphoamino acid binding domain can be used for acute regulation of cellular events. As a proof of concept, we employed a Protein Kinase A (PKA)-dependent switch and coupled it to a lipid phosphatase to manipulate the level of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) in living cells. PKA activation results in rapid degradation of PI(4,5)P(2). Conversely, when PKA is inhibited, dephosphorylation of the switch leads to the replenishment of PI(4,5)P(2). Thus, this strategy can be used for reversibly controlling enzymatic action in living cells. Furthermore, its genetic encodability and modular design should facilitate the adaptation of this approach to control different cellular activities as a function of phosphorylation-dependent input signals, thereby providing versatile tools for potentially perturbing or rewiring signaling pathways. 22443683 The biogenesis of active protein phosphatase 2A holoenzymes: a tightly regulated process creating phosphatase specificity. Protein phosphatase type 2A (PP2A) enzymes constitute a large family of Ser/Thr phosphatases with multiple functions in cellular signaling and physiology. The composition of heterotrimeric PP2A holoenzymes, resulting from the combinatorial assembly of a catalytic C subunit, a structural A subunit, and regulatory B-type subunit, provides the essential determinants for substrate specificity, subcellular targeting, and fine-tuning of phosphatase activity, largely explaining why PP2A is functionally involved in so many diverse physiological processes, sometimes in seemingly opposing ways. In this review, we highlight how PP2A holoenzyme biogenesis and enzymatic activity are controlled by a sophisticatedly coordinated network of five PP2A modulators, consisting of α4, phosphatase 2A phosphatase activator (PTPA), leucine carboxyl methyl transferase 1 (LCMT1), PP2A methyl esterase 1 (PME-1) and, potentially, target of rapamycin signaling pathway regulator-like 1 (TIPRL1), which serve to prevent promiscuous phosphatase activity until the holoenzyme is completely assembled. Likewise, these modulators may come into play when PP2A holoenzymes are disassembled following particular cellular stresses. Malfunctioning of these cellular control mechanisms contributes to human disease. The potential therapeutic benefits or pitfalls of interfering with these regulatory mechanisms will be briefly discussed. 23266310 Spontaneous and experimental poisoning by Marsdenia megalantha Goyder & Morillo in ruminants and a pig. Marsdenia megalantha is a rupicolous shrub with succulent roots from the semiarid region of Brazil that is known to cause fatal poisoning in livestock. We reported spontaneous cases of poisoning by M. megalantha roots in bovine, caprine, ovine, and equine species. The clinical and pathological findings of experimental administration of M. megalantha to sheep, goats, a calf and a pig are reported. Three goats, two sheep and a calf were dosed once orally with freshly chopped roots at dose of 25 g wet plant/kg bw; another sheep and a pig were dosed with 10 g wet plant/kg bw. Poisoning occurred in all of the animals except the three goats. Clinical signs of poisoning included tachycardia, opisthotonus, ruminal bloat, dyspnea, nystagmus, mydriasis, ataxia, and recumbence with paddling movements. Pathological evaluation showed segmental laminar neuronal necrosis and spongiosis in the telencephalic cortex and degeneration of Purkinje cells. The picrate paper procedure detected no cyanide in the plant roots, but the reaction used for nitrate detection gave a strongly positive response. In conclusion, M. megalantha is a poisonous plant that produces acute poisoning characterized mainly by nervous disturbances. Livestock producers should offer alternative food during the dry and early rainy seasons to avoid the poisoning by this plant. 23623789 Intestinal Organoids as Tissue Surrogates for Toxicological and Pharmacological Studies. Recently developed cell culture protocols have allowed for the derivation of multi-cellular structures dubbed intestinal "organoids" from embryonic stem cells (ESCs), induced pluripotent stem cells (IPSCs), and adult intestinal stem cells (ISCs). These structures resemble in vivo intestinal crypts, both in structure and developmental processes, and can be grown quickly and in relatively large quantities. Although much research has focused on developing intestinal organoids for tissue repair, more immediate applications include high-throughput screening for agents that target intestinal epithelium. Here we describe current methods for deriving mouse and human intestinal organoids and discuss some applications aimed at developing novel therapies or preventive agents for diseases of the lower GI tract such as inflammatory bowel diseases and colorectal cancer. 23428094 Generalized indirect Fourier transformation as a valuable tool for the structural characterization of aqueous nanocrystalline cellulose suspensions by small angle X-ray scattering. Small angle X-ray scattering (SAXS) is employed to characterize the inner structure and shape of aqueous nanocrystalline cellulose suspensions using the generalized indirect Fourier transformation (GIFT). The use of the GIFT approach provides a single fitting procedure for the determination of intra- and interparticle interactions due to a simultaneous treatment of the form factor P(q) and the structure factor S(q). Moreover, GIFT allows for the determination of particle charges and polydispersity indices. As test material, aqueous nanocrystalline cellulose suspensions (aNCS) prepared by the H2SO4 route have been investigated and characterized (SAXS, dynamic light scattering, zeta potential). 23455898 Effects of vegetative-periodic-induced rhizosphere variation on the uptake and translocation of metals in Phragmites australis (Cav.) Trin ex. Steudel growing in the Sun Island Wetland. To evaluate the vegetative periodic effect of rhizosphere on the patterns of metal bioaccumulation, the concentrations of Mg, K, Ca, Mn, Zn, Fe, Cu, Cr, Ni, Cd and Pb in the corresponding rhizosphere soil and tissues of Phragmites australis growing in the Sun Island wetland (Harbin, China) were compared. The concentrations of Zn, Fe, Cu, Cr, Ni, Cd and Pb in roots were higher than in shoots, suggesting that roots are the primary accumulation organs for these metals and there exists an exclusion strategy for metal tolerance. In contrast, the rest of the metals showed an opposite trend, suggesting that they were not restricted in roots. Harvesting would particularly be an effective method to remove Mn from the environment. The concentrations of metals in shoots were generally higher in autumn than in summer, suggesting that Ph. australis possesses an efficient root-to-shoot translocation system, which is activated at the end of the growing season and allows more metals into the senescent tissues. Furthermore, metal bioaccumulation of Ph. australis was affected by vegetative periodic variation through the changing of physicochemical and microbial conditions. The rhizospheric microbial characteristics were significantly related to the concentrations of Mg, K, Zn, Fe and Cu, suggesting that microbial influence on metal accumulation is specific and selective, not eurytopic. 22665065 Opposing functions of Fbxw7 in keratinocyte growth, differentiation and skin tumorigenesis mediated through negative regulation of c-Myc and Notch. The tumor suppressor Fbxw7 (also known as Sel-10, hCdc4, hAgo, or Fbw7) is an F-box protein that functions as the substrate-recognition subunit of an SCF ubiquitin ligase complex and targets a group of oncoproteins for degradation. We now show that Fbxw7 regulates the proliferation and differentiation of keratinocytes by mediating the degradation of c-Myc and Notch proteins. Fbxw7-deficient keratinocytes showed an increased proliferative capacity that was dependent on the accumulation of c-Myc but not on that of Notch. Fbxw7 deficiency also resulted in the premature differentiation of keratinocytes in a manner dependent on both c-Myc and Notch. Although Fbxw7-deficient keratinocytes proliferated excessively in vitro, loss of Fbxw7 did not predispose keratinocytes to the formation of squamous cell carcinoma in vivo induced by the expression of oncogenic Ras, possibly because the stem cell population of keratinocytes becomes exhausted as a result of enhanced Notch activity. Indeed, suppression of Notch signaling by additional ablation of RBP-J in Fbxw7-deficient keratinocytes conferred a more aggressive tumorigenic capacity. Collectively, these results indicate that Fbxw7 controls the proliferation and differentiation of keratinocytes, and that it exerts both inhibitory and stimulatory actions in skin carcinogenesis by counteracting the proliferation-promoting effect of c-Myc and the tumor-suppressive effect of Notch, respectively. 23453308 Jacaric acid and its octadecatrienoic acid geoisomers induce apoptosis selectively in cancerous human prostate cells: a mechanistic and 3-D structure-activity study. Plant-derived non-essential fatty acids are important dietary nutrients, and some are purported to have chemopreventive properties against various cancers, including that of the prostate. In this study, we determined the ability of seven dietary C-18 fatty acids to cause cytotoxicity and induce apoptosis in various types of human prostate cancer cells. These fatty acids included jacaric and punicic acid found in jacaranda and pomegranate seed oil, respectively, three octadecatrienoic geometric isomers (alpha- and beta-calendic and catalpic acid) and two mono-unsaturated C-18 fatty acids (trans- and cis-vaccenic acid). Jacaric acid and four of its octadecatrienoic geoisomers selectively induced apoptosis in hormone-dependent (LNCaP) and -independent (PC-3) human prostate cancer cells, whilst not affecting the viability of normal human prostate epithelial cells (RWPE-1). Jacaric acid induced concentration- and time-depedent LNCaP cell death through activation of intrinsic and extrinsic apoptotic pathways resulting in cleavage of PARP-1, modulation of pro- and antiapoptotic Bcl-2 family of proteins and increased cleavage of caspase-3, -8 and -9. Moreover, activation of a cell death-inducing signalling cascade involving death receptor 5 was observed. Jacaric acid induced apoptosis in PC-3 cells by activation of the intrinsic pathway only. The spatial conformation cis, trans, cis of jacaric and punicic acid was shown to play a key role in the increased potency and efficacy of these two fatty acids in comparison to the five other C-18 fatty acids tested. Three-dimensional conformational analysis using the PubChem Database (http://pubchem.ncbi.nlm.nih.gov) showed that the cytotoxic potency of the C-18 fatty acids was related to their degree of conformational similarity to our cytotoxic reference compound, punicic acid, based on optimized shape (ST) and feature (CT) similarity scores, with jacaric acid being most 'biosimilar' (ST(ST-opt)=0.81; CT(CT-opt)=0.45). This 3-D analysis of structural similarity enabled us to rank geoisomeric fatty acids according to cytotoxic potency, whereas a 2-D positional assessment of cis/trans structure did not. Our findings provide mechanistic evidence that nutrition-derived non-essential fatty acids have chemopreventive biological activities and Exhibit 3-D structure-activity relationships that could be exploited to develop new strategies for the prevention or treatment of prostate cancer regardless of hormone dependency. 23000446 Water extracts of tree Hypericum sps. protect DNA from oxidative and alkylating damage and enhance DNA repair in colon cells. Diet may induce colon carcinogenesis through oxidative or alkylating DNA damage. However, diet may also contain anticarcinogenic compounds that contribute to cancer prevention. DNA damage prevention and/or induction of repair are two important mechanisms involved in cancer chemoprevention by dietary compounds. Hypericum sps. are widely used in traditional medicine to prepare infusions due to their beneficial digestive and neurologic effects. In this study, we investigated the potential of water extracts from three Hypericum sps. and some of their main phenolic compounds to prevent and repair oxidative and alkylating DNA damage in colon cells. The results showed that water extracts of Hypericum perforatum, Hypericum androsaemum, Hypericum undulatum, quercetin and rutin have protective effect against oxidative DNA damage in HT29 cells. Protective effect was also observed against alkylating DNA damage induced by methyl-methanesulfonate, except for H. androsaemum. With regard to alkylating damage repair H. perforatum, H. androsaemum and chlorogenic acid increased repair of alkylating DNA damage by base excision repair pathway. No effect was observed on nucleotide excision repair pathway. Antigenotoxic effects of Hypericum sps. may contribute to colon cancer prevention and the high amount of phenolic compounds present in Hypericum sps. play an important role in DNA protective effects. 23528741 Technological and biopharmaceutical optimization of nystatin release from a multiparticulate based bioadhesive drug delivery system. Formulation considerations of a new drug delivery system include controlling the site of release of the active ingredient, maintaining drug level for a suitable time and decreasing dosage frequency. In research and development practice, these therapeutic benefits can be attained by selecting suitable active ingredients and optimizing procedure parameters, determining the composition of the medicine, and dissolution properties. The aim of our study was to design a pharmaceutical preparation with increased local therapeutic effect in the therapy of gastrointestinal candidiasis. The polyene antibiotic nystatin may be an optimal choice for active agent, incorporated in a bioadhesive multiparticulate system. Choosing the proper excipients in the proper dosage form and ensuring prolonged residence time may further improve the optimal treatment. Using an experimental design, the micropellets were prepared with 5% nystatin content, taking the factors average pellet size (∼200 to ∼800μm) and the amount of applied carbomer and hydroxyethylcellulose (0-5%) into consideration. Dissolution of the active ingredient was detected by UV spectrophotometric and microbiological assay. The bioadhesive character of the multiparticulate dosage form was examined by ex vivo wash-off test. The only factor which significantly influenced the examined parameters was average pellet size. The proportion of applied bioadhesive excipients had significance mostly in interactions with average pellet size. Eventually, optimized drug release (5-10min mean dissolution time, 50-55% bioadhesion retention) could be achieved with 550μm pellet size, containing carbomer and hydroxyethylcellulose in 85:15 ratio. 22370640 MTBP suppresses cell migration and filopodia formation by inhibiting ACTN4. Murine double minute (MDM2) binding protein (MTBP) has been implicated in cancer progression. Here, we demonstrate one mechanism by which MTBP inhibits cancer metastasis. Overexpression of MTBP in human osteosarcoma cell lines lacking wild-type p53 did not alter primary tumor growth in mice, but significantly inhibited metastases. MTBP downregulation increased the migratory potential of MDM2(-/-)p53(-/-) mouse embryonic fibroblasts, suggesting that MTBP inhibited cell migration independently of the Mdm2-p53 pathway. Co-immunoprecipitation and mass spectrometric analysis identified alpha-actinin-4 (ACTN4) as an MTBP-interacting protein. Endogenous MTBP interacted with and partially colocalized with ACTN4. MTBP overexpression inhibited cell migration and filopodia formation mediated by ACTN4. Increased cell migration by MTBP downregulation was inhibited by concomitant downregulation of ACTN4. MTBP also inhibited ACTN4-mediated F-actin bundling. We furthermore demonstrated that nuclear localization of MTBP was dispensable for inhibiting ACTN4-mediated cell migration and filopodia formation. Thus, MTBP suppresses cell migration, at least partially, by inhibiting ACTN4 function. Our study not only provides a mechanism of metastasis suppression by MTBP, but also suggests MTBP as a potential biomarker for cancer progression. 22981459 Human plasma-derived BuChE as a stoichiometric bioscavenger for treatment of nerve agent poisoning. Potent organophosphorous (OP) agents, such as VX, are hazardous by absorption through the skin and are resistant to conventional pharmacological antidotal treatments. The residence time of a stoichiometric bioscavenger, human butyrylcholinesterase (huBuChE), in the plasma more closely matches that of VX than do the residence times of conventional therapy drugs (oxime, anti-muscarinic, anticonvulsant). Intramuscular (i.m.) huBuChE afforded almost complete protection when administered prior to the onset of observable cholinergic signs of VX poisoning, but once signs of poisoning became evident the efficacy of i.m. huBuChE decreased. A combination of nerve agent therapy drugs (oxime, anti-muscarinic, anticonvulsant) with huBuChE (i.m.) protected 100% (8/8) of guinea-pigs from a lethal dose of VX (0.74mg/kg) to 48h, even when administered on signs of poisoning. Survival was presumed to be due to immediate alleviation of the cholinergic crisis by the conventional pharmacological treatment drugs, in conjunction with bioscavenger that prevented further absorbed agent reaching the AChE targets. Evidence to support this proposed mechanism of action was obtained from PKPD experiments in which multiple blood samples and microdialysate samples were collected from individual conscious ambulatory animals. Plasma concentrations of intramuscularly-administered atropine, diazepam and HI-6 reached a peak within 15min and were eliminated rapidly within 4h. Plasma concentrations of huBuChE administered by the i.m. route took approximately 24h to reach a peak, but were well-maintained over the subsequent 7days. Thus, the pharmacological therapy rapidly treated the initial signs of poisoning, whilst the bioscavenger provided prolonged protection by neutralising further nerve agent entering the bloodstream and preventing it from reaching the target organs. 23434227 Synthesis and cytotoxicity evaluation of oleanolic acid derivatives. Twelve derivatives of oleanolic acid (1) have been synthesized and evaluated for their inhibitory activities against the growth of prostate PC3, breast MCF-7, lung A549, and gastric BGC-823 cancer cells by MTT assays. Within these series of derivatives, compound 17 exhibited the most potent cytotoxicity against PC3 cell line (IC50=0.39 μM) and compound 28 displayed the best activity against A549 cell line (IC50=0.22 μM). SAR analysis indicates that H-donor substitution at C-3 position of oleanolic acid may be advantageous for improvement of cytotoxicity against PC3, A549 and MCF-7 cell lines. 22579759 A possible explanation for the population size discrepancy in tuna (genus Thunnus) estimated from mitochondrial DNA and microsatellite data. A recent study using both mitochondrial DNA (mtDNA) and microsatellite data reported on a population size discrepancy in the eastern tiger salamander where the effective population size (N(e)) estimate of the former exceeded that of the latter. That study suggested, among other hypotheses, that homoplasy of microsatellite alleles is responsible for the discrepancy. In this investigation, we report 10 new cases of a similar discrepancy in five species of tuna. These cases derive from our Bayesian inferences using data from Pacific Bluefin Tuna (Thunnus orientalis) and Yellowfin Tuna (Thunnus albacares), as well as from published estimates of genetic diversity for additional populations of Yellowfin Tuna and three other tuna species. Phylogenetic character analyses of inferred genealogies of Pacific Bluefin and Yellowfin Tuna reveal similar reduced levels of mtDNA and microsatellite homoplasy. Thus, the discrepancy between inferred population sizes from mtDNA and microsatellite data in tuna is most likely not an artifact of the chosen mutation models used in the microsatellite analyses, but may reflect behavioral differences between the sexes such as female-biased philopatry and male-biased dispersal. This explanation now warrants critical testing with more local populations of tuna and with other animal and plant groups that have different life histories. 23493912 Optically healable polymers. Polymers that can easily be repaired after being damaged are attractive as this characteristic can improve the reliability, functionality, and lifetime of many products. In the last decade, researchers have thus developed new approaches to create stimuli-responsive polymer systems, which have the ability to autonomously heal or can be repaired upon exposure to an external stimulus. This review summarizes the current knowledge of optically healable or photo-healable polymers. The use of light as a stimulus for healing offers several attractive features, including the ability to deliver the stimulus locally, which opens up the possibility of healing the material under load, as well as the ability to tailor the wavelength of light to selectively address a specific component of the material, e.g. only the damaged parts. So far, two main classes of optically healable polymers have been explored, which are structurally dynamic polymers and mechanically activated reactive systems. 23300287 Lower Adiponectin Levels at First Trimester of Pregnancy Are Associated With Increased Insulin Resistance and Higher Risk of Developing Gestational Diabetes Mellitus. OBJECTIVETo evaluate the associations between adiponectin levels and 1) the risk of developing gestational diabetes mellitus (GDM), and 2) insulin resistance/sensitivity, β-cell function, and compensation indices in a prospective cohort representative of the general population of pregnant women.RESEARCH DESIGN AND METHODSWe performed anthropometric measurements and collected blood samples at 1st (6-13 weeks) and 2nd (24-28 weeks) trimesters. Diagnosis of GDM was made at 2nd trimester, based on a 75-g oral glucose tolerance test (International Association of Diabetes and Pregnancy Study Group criteria). Insulin was measured (ELISA; Luminex) to estimate homeostasis model assessment of insulin resistance (HOMA-IR), β-cell function (HOMA-B), insulin sensitivity (Matsuda index), insulin secretion (AUC(insulin/glucose)), and β-cell compensation (insulin secretion sensitivity index-2). Adiponectin was measured by radioimmunoassay.RESULTSAmong the 445 participants included in this study, 38 women developed GDM. Women who developed GDM had lower 1st-trimester adiponectin levels (9.67 ± 3.84 vs. 11.92 ± 4.59 µg/mL in women with normal glucose tolerance). Lower adiponectin levels were associated with higher risk of developing GDM (OR, 1.12 per 1 µg/mL decrease of adiponectin levels; P = 0.02, adjusted for BMI and HbA(1c) at 1st trimester). Adiponectin levels at 1st and 2nd trimesters were associated with HOMA-IR (both: r = -0.22, P < 0.0001) and Matsuda index (r = 0.28, P < 0.0001, and r = 0.29, P < 0.0001). After adjustment for confounding factors, we found no significant association with HOMA-B and AUC(insulin/glucose).CONCLUSIONSPregnant women with lower adiponectin levels at 1st trimester have higher levels of insulin resistance and are more likely to develop GDM independently of adiposity or glycemic measurements. 23418369 Nicotinamide N-oxidation by CYP2E1 in human liver microsomes. Excess nicotinamide, a form of vitamin B(3), is metabolized through two enzymatic systems and eventually excreted from the body. The first system starts with the methylation of nicotinamide by nicotinamide N-methyltransferase, which can subsequently be oxidized by aldehyde oxidase. The second enzymatic system oxidizes nicotinamide to nicotinamide N-oxide. It is located in the endoplasmic reticulum of hepatocytes but the precise enzyme is unknown. We have used human liver microsomes in combination with selective cytochrome P450 inhibitors, specific substrates, and antibodies to identify CYP2E1 as the main activity producing nicotinamide N-oxide. Our results suggest the potential use of nicotinamide N-oxide as a biomarker of CYP2E1 activity from urine or blood samples. 23364619 Investigation of the toxicokinetics of petroleum hydrocarbon distillates with the earthworm Eisenia andrei. The Canada-wide standards for petroleum hydrocarbons in soils regulate petroleum hydrocarbons based on four distillate ranges: F1 (C6-C10), F2 (>C10-C16), F3 (>C16-C34), and F4 (>C34). Previous toxicity tests with earthworms and F2, as well as two subfractions of F3, F3a (>C16-C23) and F3a (>C23-C34), indicate that test durations might not be sufficiently long to reach threshold effect concentrations, likely because of the differing toxicokinetics for each distillate. A study was conducted to determine the toxicokinetics of both aliphatic and aromatic fractions of F2, F3a, and F3b with the earthworm Eisenia andrei. Peak accumulation curves were observed for F2 aliphatics and aromatics and F3a aromatics, likely as a result of changes in exposure concentration over the test duration via loss or a decrease in the bioavailable fraction. Biota-soil accumulation factors were >1 for total F2 aliphatics and aromatics and F3a aromatics as well as for several individual polyaromatic hydrocarbons for each distillate. Aromatics were disproportionately accumulated over aliphatics and were the main contributors to toxicity; therefore, aromatics and aliphatics should be regulated separately. The toxicokinetics were used to interpret previous toxicity data. Higher molecular weight distillates need longer-than-standard test durations to determine toxicity, so toxicity test results from fixed, standard-duration tests are not strictly comparable for these petroleum distillates. Environ. Toxicol. Chem. 2013;32:1006-1015. © 2013 SETAC. 23617725 Probing the Role of the Vancomycin E-Ring Aryl Chloride: Selective Divergent Synthesis and Evaluation of Alternatively Substituted E-Ring Analogues. The selective functionalization of a vancomycin aglycon derivative through direct conversion of the E-ring aryl chloride to a reactive boronic acid, and its use in the synthesis of a systematic series of vancomycin E-ring analogues are described. The series of analogues was used to examine the impact of the E-ring chloride in binding D-Ala-D-Ala and on antimicrobial activity. In contrast to the reduced activity of the unsubstituted E-ring derivatives, hydrophobic and relatively non-polar substituents approach or match the chloro substituted vancomycin and was insensitive to the electronic character of the substituent (e.g. Cl vs CN or OMe), whereas highly polar substituents fail to provide the enhancements. Moreover, the active permethylated vancomycin aglycon derivatives examined exhibit VanB VRE antimicrobial activity at levels that approach (typically within 2-fold) their activity against sensitive bacteria. The robust borylation reaction also enabled the selective functionalization of a minimally protected vancomycin aglycon (N-Boc vancomycin aglycon), and provides a direct method for the preparation of previously inaccessible analogues. 23287539 Differential anti-ischemic efficacy and therapeutic time window of trans- and cis-hinokiresinols: Stereo-specific antioxidant and anti-inflammatory activities. During cerebral ischemia, neurons are injured by various mechanisms including excitotoxicity, oxidative stress, and inflammatory responses. Thus, pharmacological manipulation of multiple cytotoxic pathways has been pursued for the treatment of ischemic injury. Cis-hinokiresinol, a naturally occurring phenylpropanoid, was previously reported to possess anti-oxidant, anti-inflammatory and estrogen-like activities. In the present study, we investigated anti-ischemic effects of trans- and cis-hinokiresinols using in vitro as well as in vivo experimental models. The ORAC and DPPH assays showed that two isomers had similar free radical scavenging activities. However, only trans-hinokiresinol significantly decreased neuronal injury in cultured cortical neurons exposed to oxygen-glucose deprivation (75 min) followed by re-oxygenation (9 h). The differential neuroprotective effect could be due to the stereo-specific augmentation of Cu/Zn-SOD activity by trans-hinokiresinol, when compared with cis-hinokiresinol. Similarly, in rats subjected to transient middle cerebral artery occlusion (1.5 h) followed by 24-h reperfusion, pre-ischemic treatment with trans-hinokiresinol, but not with cis-isomer, reduced cerebral infarct volume. Interestingly, however, post-ischemic treatment with both hinokiresinols (2 and 7 h after onset of ischemia) significantly reduced cerebral infarct. When administered after onset of ischemia, trans-hinokiresinol, but not its cis-isomer reduced nitrotyrosine immunoreactivity in ischemic regions. In contrast, both hinokiresinols suppressed neutrophil infiltration and IL-1β release to a similar extent. The observed differential anti-oxidant, but comparable anti-inflammatory, activities may explain the stereo-specific anti-ischemic activities and different therapeutic time windows of the hinokiresinols examined. More detailed delineation of the anti-ischemic mechanism(s) of hinokiresinols may provide a better strategy for development of efficacious regimens for cerebral ischemic stroke. 23643682 Genetic Polymorphism at Val(80) (rs700518) of the CYP19A1 Gene is Associated with Aromatase Inhibitor Associated Bone Loss in Women with ER (+) Breast Cancer. PURPOSE: Polymorphisms in the CYP19A1 (aromatase) gene have been reported to influence disease-free survival and the incidence of musculoskeletal complaints in patients taking aromatase inhibitors (AIs) for estrogen receptor positive (ER+) breast cancer. Bone loss and fractures are well-recognized complications from AI therapy. The objective of this study is to determine the influence of polymorphisms in the CYP19A1 gene on bone loss among patients taking aromatase inhibitors for ER+ breast cancer. PATIENTS AND METHODS: The subjects consisted of 97 postmenopausal women with ER+ breast cancer who were initiated on third-generation AIs. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry at baseline and at 6 and 12 months. Twenty-four hour urine N-telopeptide (NTX) was measured by Elisa and serum estradiol was measured by ultrasensitive radioimmunoassay at baseline, and at 6 months. Genotyping was done by Taqman SNP allelic discrimination assay. RESULTS: Women with the AA genotype for the rs700518 (G/A at Val(80)) developed significant bone loss at the lumbar spine and the total hip at 12 months relative to patients carrying the G allele (GA/GG); both p=0.03. There was a borderline greater increase in urinary NTX in those with the AA genotype compared to patients with the G allele, p=0.05; but no significant difference in changes in estradiol levels among the genotypes. CONCLUSION: Patients with the AA genotype for the rs700518 polymorphism in the CYP19A1 gene are at risk for AI-associated bone loss and deserve close follow-up during long-term AI therapy. 23220489 Improvement in pelvic pain with botulinum toxin type A - Single vs. repeat injections. The aim of this prospective study was to report the outcomes of pain and vaginal pressures of successive botulinum toxin type A injections for women with objective pelvic floor muscle overactivity and a two-year history of pelvic pain. Between 2005 and 2008, 37 women underwent injection of 100 IU of botulinum toxin type A into the puborectalis and pubococcygeous muscles with dysmenorrhoea, dyspareunia, dyschesia, and non-menstrual pelvic pain assessed using a visual analogue scale (VAS), and vaginal pressure measured by vaginal manometry, at 0, 4, 12 and 26 weeks from each injection. 26 women (70%) had one injection of botulinum toxin type A and 11 (30%) had 2 or more injections. The second injection was performed at the earliest at 26 weeks after the first, with subsequent injections having a median time to re-injection of 33.4 weeks (range 9.4-122.7 weeks). Single and repeated injections both demonstrated a statistically significant reduction in dyspareunia by VAS scores from 54 to 30 in the single injection group and from 51 to 23 in the multiple injection group (p = .001), non-menstrual pelvic pain VAS from 37 to 25 (p = .04), as well as vaginal pressures; 40 versus 34 cm H(2)O (p = .02). No statistically significant difference in dysmenorrhoea or dyschesia was observed for either group from their baseline scores. Multiple injections of botulinum toxin type A in women with pelvic floor muscle overactivity provide significant relief from dyspareunia and non-menstrual pelvic pain. The upper limit between re-injection is not yet determined, nor is the maximum number of treatments. Clinical outcomes for single and subsequent injection of botulinum toxin type A for recurrent pelvic pain are equivalent. Women who have had benefit from a single injection of botulinum toxin type A can be reassured that if symptoms reoccur, repeated injections can be expected to be equally efficacious. 23085522 Evaluating the neurotoxic effects of lactational exposure to persistent organic pollutants (POPs) in Spanish children. Although the brain continues developing in the postnatal period, epidemiological studies on the effects of postnatal exposure to neurotoxic POPs through breast-feeding remain mostly inconclusive. Failure to detect associations between postnatal exposure and health outcomes may stem from the limitations of commonly employed approaches to assess lactational exposure. The aim of the present study was to assess whether lactational exposure to polychlorinated biphenyl-153 (PCB-153), dichlorodiphenyldichloroethylene (DDE), or hexachlorobenzene (HCB) as estimated with a physiologically based pharmacokinetic (PBPK) model, is associated with decrements in mental and psychomotor development scores of the Bayley Scales of Infant Development (BSID) test in children aged around 14-months of a subsample (N=1175) of the Spanish INMA birth cohort, and to compare this with the effects of prenatal exposure. Although in the present study population PCB-153, DDE and HCB exposure increased within the first months of postnatal life, no associations were found between different periods of postnatal exposure to these compounds and mental or psychomotor scores. Increasing prenatal PCB-153 concentrations were associated with worse mental and psychomotor scores, although significance was only reached for psychomotor development (β [95%CI]=-1.36 [-2.61, -0.11]). Indeed, the association between exposure and effects observed during prenatal life weakened gradually across periods of postnatal life. Results of the present study suggest that, although breastfeeding increases children's blood persistent organic pollutants (POPs) levels during postnatal life, deleterious effects of PCB-153 on neuropsychological development are mainly attributable to prenatal exposure. 23576242 The lifetime and efficiency of triplet-triplet fluorescence from the excited state of a TMM biradical determined using transient emission spectroscopy by two-color two-laser flash photolysis. The single laser flash photolysis (FP) of 2-(4-benzoylphenyl)-2-phenyl-1-methylenecyclopropane gave rise to a ground state trimethylenemethane (TMM) biradical with absorption bands at 362 and 545 nm and an excited state of this biradical that displays triplet-triplet fluorescence at 580 nm. The excited biradical is likely formed via an expected two-photon process as well as an unexpected one-photon process. The fluorescence quantum yield of the excited biradical, 0.021, was successfully determined by employing a two-color two-laser FP technique. 23270593 Exploring key orientations at protein-protein interfaces with small molecule probes. Small molecule probes that selectively perturb protein-protein interactions (PPIs) are pivotal to biomedical science, but their discovery is challenging. We hypothesized that conformational resemblance of semirigid scaffolds expressing amino acid side-chains to PPI-interface regions could guide this process. Consequently, a data mining algorithm was developed to sample huge numbers of PPIs to find ones that match preferred conformers of a selected semirigid scaffold. Conformations of one such chemotype (1aaa; all methyl side-chains) matched several biomedically significant PPIs, including the dimerization interface of HIV-1 protease. On the basis of these observations, four molecules 1 with side-chains corresponding to the matching HIV-1 dimerization interface regions were prepared; all four inhibited HIV-1 protease via perturbation of dimerization. These data indicate this approach may inspire design of small molecule interface probes to perturb PPIs. 23609949 CHRONIC IDIOPATIC URTICARIA AND GRAVES' DISEASE. Chronic urticaria is a common condition characterized by recurrent episodes of mast cell-driven wheal and flare-type skin reactions lasting for more than 6 weeks. In about 75% of cases, the underlying causes remain unknown, and the term chronic idiopathic urticaria (CIU) is used to emphasize that wheals develop independently of identified external stimuli. Although CIU affects about 1.0% of the general population, its etiopathogenesis is not yet well understood. It is now widely accepted that in many cases CIU should be regarded as an autoimmune disorder caused by circulating and functionally active IgG autoantibodies specific for the IgE receptor (FceRI) present on mast cells and basophils or for IgE itself. The well-known association of CIU with other autoimmune processes/diseases represents further indirect evidence of its autoimmune origin. Autoimmune thyroid diseases, especially autoimmune thyroiditis, represent the most frequently investigated diseases in association with CIU. Here we review this topic with particular regard to the association between Graves' disease and CIU. The possible pathogenetic mechanisms and the clinical implications of such an association are discussed. 23194506 A potential practical approach to reduce Ara h 6 allergenicity by gamma irradiation. Peanut allergen Ara h 6 was isolated and irradiated at 1, 3, 5, or 10 kGy, and a whole peanut protein extract (WPPE) was also treated by irradiation. Alteration in structure of Ara h 6 was characterised by circular dichroism (CD) spectroscopy, ultraviolet (UV) absorption spectroscopy, fluorescence spectroscopy and SDS-PAGE, and antigenicity was evaluated by immunoblotting and indirect ELISA with anti-Ara h 6 polyclonal antibody. Irradiation induced significant changes in the secondary and tertiary structures of Ara h 6, and the antigenicity of both purified Ara h 6 and WPPE were reduced upon increasing the irradiation doses. Moreover, a good correlation between the loss in α-helix and IgG binding to Ara h 6 was observed. This indicated that irradiation might be an efficient approach to reduce or eliminate peanut allergenicity. 23194156 Growth and differentiation of prechondrogenic cells on bioactive self-assembled peptide nanofibers. Restoration of cartilage defect remains a challenge, as the current treatments are ineffective to return tissue to its health. Thus, developing therapies for treatment of cartilage tissue damage caused by common joint diseases including osteoarthritis, rheumatoid arthritis, and accidents is crucial. Sulfated glycosaminoglycan molecules are vital constituents of both developing and mature cartilage extracellular matrix. The interplay between regulator proteins and glycosaminoglycan molecules has an essential role in coordinating differentiation, expansion, and patterning during cartilage development. In this study, we exploited the functional role of an extracellular matrix on chondrogenic differentiation by imitating extracellular matrix both chemically by imparting functional groups of native glycosaminoglycans and structurally through peptide nanofiber network. For this purpose, sulfonate, carboxylate, and hydroxyl groups were incorporated on self-assembled peptide nanofibers. We observed that when ATDC5 cells were cultured on functional peptide nanofibers, they rapidly aggregated in insulin-free medium and formed cartilage-like nodules and deposited sulfated glycosaminoglycans shown by Safranin-O staining. Moreover, collagen II and aggrecan gene expressions revealed by qRT-PCR were significantly enhanced, which indicated the remarkable bioactive role of this nanofiber system on chondrogenic differentiation. Overall, these results show that glycosaminoglycan mimetic peptide nanofiber system provides a promising platform for cartilage regeneration. 23483201 Effects of treatment with a carbon monoxide-releasing molecule and a heme oxygenase 1 inducer in the antinociceptive effects of morphine in different models of acute and chronic pain in mice. RATIONALE: Treatment with a carbon monoxide-releasing molecule (tricarbonyldichlororuthenium(II) dimer, CORM-2) or a classical heme oxygenase 1 inducer (cobalt protoporphyrin IX, CoPP) has potent anti-inflammatory effects, but the role played by these treatments in the antinociceptive effects of morphine during acute and chronic pain was not evaluated. OBJECTIVES: In wild type (WT), neuronal (NOS1-KO), or inducible (NOS2-KO) nitric oxide synthases knockout mice, we evaluated the effects of CORM-2 and CoPP treatments in the antinociceptive actions of morphine and their interaction with nitric oxide during acute, visceral, and chronic inflammatory or neuropathic pain. METHODS: Acute and visceral pain was assessed through formalin and acid acetic writhing tests. Chronic inflammatory pain induced by the intra-articular administration of complete Freund's adjuvant and neuropathic pain by partial ligation of sciatic nerve were evaluated by measuring allodynia and hyperalgesia using the von Frey filaments, plantar, or cold plate tests. RESULTS: While nitric oxide, synthetized by NOS1 and/or NOS2, increased the local antinociceptive effects of morphine during acute and chronic pain, it decreased the inhibitory effects of morphine after visceral pain. Moreover, while CORM-2 or CoPP treatments did not alter or reduced the antinociceptive effects of morphine during acute and visceral pain, both treatments improved the local antiallodynic and antihyperalgesic effects of morphine after chronic inflammatory or neuropathic pain in WT, but not in KO mice. CONCLUSIONS: CORM-2 and CoPP treatments improved the local antinociceptive effects of morphine during chronic inflammatory and neuropathic pain by interaction with nitric oxide synthetized by NOS1 and NOS2 isoforms. 22998240 A current opinion on electrophoretic deposition in pulsed and alternating fields. Electrophoretic deposition (EPD) is a colloidal production process developed in the early 20th century. Industrial scale EPD for the production of electronic components and phosphorescent screens and in the form of cataphoretic painting has known some success. Despite its limited practical applications, the inherent versatility of EPD has never ceased to fuel research into this technique. One of the major drives of this research was to render the method more environmentally friendly by enabling deposition from aqueous suspensions. One particular route, suggested to circumvent the problems caused by the use of water in EPD, is the use of alternating or pulsed fields. Recently, the use of alternating fields in EPD has been investigated for the deposition of biological matter in the form of cells and molecules. With this new avenue of research opening up and coinciding with a rise in biotechnological processes, one can expect a renewed interest in traditional EPD and fundamental research on the use of pulsed and alternating fields in this technique. Hence, this review attempts to summarize a century's worth of both fundamental and applied research for scientists venturing into the field of EPD. 23603918 Secular Changes in U.S. Prediabetes Prevalence Defined by Hemoglobin A1c and Fasting Plasma Glucose: National Health and Nutrition Examination Surveys, 1999-2010. OBJECTIVEUsing a nationally representative sample of the civilian noninstitutionalized U.S. population, we estimated prediabetes prevalence and its changes during 1999-2010.RESEARCH DESIGN AND METHODSData were from 19,182 nonpregnant individuals aged ≥12 years who participated in the 1999-2010 National Health and Nutrition Examination Surveys. We defined prediabetes as hemoglobin A1c 5.7 to <6.5% (39 to <48 mmol/mol, A1C5.7) or fasting plasma glucose (FPG) 100 to <126 mg/dL (impaired fasting glucose [IFG]). We estimated the prevalence of prediabetes, A1C5.7, and IFG for 1999-2002, 2003-2006, and 2007-2010. We calculated estimates age-standardized to the 2000 U.S. census population and used logistic regression to compute estimates adjusted for age, sex, race/ethnicity, poverty-to-income ratio, and BMI. Participants with self-reported diabetes, A1C ≥6.5% (≥48 mmol/mol), or FPG ≥126 mg/dL were included.RESULTSAmong those aged ≥12 years, age-adjusted prediabetes prevalence increased from 27.4% (95% CI 25.1-29.7) in 1999-2002 to 34.1% (32.5-35.8) in 2007-2010. Among adults aged ≥18 years, the prevalence increased from 29.2% (26.8-31.8) to 36.2% (34.5-38.0). As single measures among individuals aged ≥12 years, A1C5.7 prevalence increased from 9.5% (8.4-10.8) to 17.8% (16.6-19.0), a relative increase of 87%, whereas IFG remained stable. These prevalence changes were similar among the total population, across subgroups, and after controlling for covariates.CONCLUSIONSDuring 1999-2010, U.S. prediabetes prevalence increased because of increases in A1C5.7. Continuous monitoring of prediabetes is needed to identify, quantify, and characterize the population of high-risk individuals targeted for ongoing diabetes primary prevention efforts. 23639233 Monitoring Conformational Changes in Peroxisome Proliferator-Activated Receptor alpha by a Genetically Encoded Photo-Amino Acid, Cross-Linking, and Mass Spectrometry. Chemical cross-linking combined with an enzymatic digestion and mass spectrometric analysis of the reaction products has evolved into an alternative strategy to structurally resolve protein complexes. We investigated conformational changes in peroxisome proliferator-activated receptor α (PPARα) upon ligand binding. Using E. coli cells with a special tRNA/aminoacyl-tRNA synthetase pair, two PPARα variants were prepared, in which Leu-258 or Phe-273 were site-specifically replaced by the genetically encoded photo-reactive amino acid para-benzoylphenylalanine (Bpa). PPARα variants were subjected to UV-induced cross-linking, both in the absence and presence of ligands. After the photo-cross-linking reaction, reaction mixtures were enzymatically digested and peptides were analyzed by mass spectrometry. The inter-residue distances disclosed by the photo-chemical cross-links served to monitor conformational changes in PPARα upon agonist and antagonist binding. The data obtained with our strategy underline the potential of genetically encoded internal photo-cross-linkers in combination with mass spectrometry as an alternative method to monitor in-solution 3D-protein structures. 23643746 Enhanced excitability in the infralimbic cortex produces anxiety-like behaviors. The medial prefrontal cortex (mPFC) has been implicated in modulating anxiety. However, it is unknown whether excitatory or inhibitory neurotransmission in the infralimbic (IL) subregion of the mPFC underlies the pathology of anxiety-related behavior. To address this issue, we infused the GABAA receptor (GABAAR) antagonist bicuculline to temporarily activate the IL cortex. IL cortex activation decreased the time spent in the center area in the open field test, decreased exploration of the open-arms in the elevated plus maze test, and increased the latency to bite food in the novelty-suppressed feeding test. These findings substantiate the GABAergic system's role in anxiety-related behaviors. IL cortex inactivation with the AMPA receptor (AMPAR) antagonist CNQX produced opposite, anxiolytic effects. However, infusion of the NMDA receptor (NMDAR) antagonist AP5 into the IL cortex had no significant effect. Additionally, we did not observe motor activity deficits or appetite deficits following inhibition of GABAergic or glutamatergic neurotransmission. Interestingly, we found parallel and corresponding electrophysiological changes in anxious mice; compared to mice with relatively low anxiety, the relatively high anxiety mice exhibited smaller evoked inhibitory postsynaptic currents (eIPSCs) and larger AMPA-mediated evoked excitatory postsynaptic currents (eEPSCs) in pyramidal neurons in the IL cortex. The changes of eIPSCs and eEPSCs were due to presynaptic mechanisms. Our results suggest that imbalances of neurotransmission in the IL cortex may cause a net increase in excitatory inputs onto pyramidal neurons, which may underlie the pathogenic mechanism of anxiety disorders. 23632340 Electronic structure analysis of multistate reactivity in transition metal catalyzed reactions: the case of C-H bond activation by non-heme iron(iv)-oxo cores. This perspective discusses the principles of the multistate scenario often encountered in transition metal catalyzed reactions, and is organized as follows. First, several important theoretical concepts (physical versus formal oxidation states, orbital interactions, use of (spin) natural and corresponding orbitals, exchange enhanced reactivity and the connection between valence bond and molecular orbital based electronic structure analysis) are presented. These concepts are then used to analyze the electronic structure changes occurring in the reaction of C-H bond oxidation by Fe(IV)oxo species. The analysis reveals that the energy separation and the overlap between the electron donating orbitals and electron accepting orbitals of the Fe(IV)oxo complexes dictate the reaction stereochemistry, and that the manner in which the exchange interaction changes depends on the identity of these orbitals. The electronic reorganization of the Fe(IV)oxo species during the reaction is thoroughly analyzed and it is shown that the Fe(IV)oxo reactant develops oxyl radical character, which interacts effectively with the σCH orbital of the alkane. The factors that determine the energy barrier for the reaction are discussed in terms of molecular orbital and valence bond concepts. 23606523 A Model-Based Approach to Predict Longitudinal HbA1c, Using Early Phase Glucose Data From Type 2 Diabetes Mellitus Patients After Anti-Diabetic Treatment. Predicting late phase outcomes from early-phase findings can help inform decisions in drug development. If the measurements in early-phase differ from those in late phase, forecasting is more challenging. In this paper, we present a model-based approach for predicting glycosylated hemoglobin (HbA1c) in late phase using glucose and insulin concentrations from an early-phase study, investigating an anti-diabetic treatment. Two previously published models were used; an integrated glucose and insulin (IGI) model for meal tolerance tests and an integrated glucose-red blood cell-HbA1c (IGRH) model predicting the formation of HbA1c from the average glucose concentration (Cg,av ). Output from the IGI model was used as input to the IGRH model. Parameters of the IGI model and drug effects were estimated using data from a phase1 study in 59 diabetic patients receiving various doses of a glucokinase activator. Cg,av values were simulated according to a Phase 2 study design and used in the IGRH model for predictions of HbA1c. The performance of the model-based approach was assessed by comparing the predicted to the actual outcome of the Phase 2 study. We have shown that this approach well predicts the longitudinal HbA1c response in a 12-week study using only information from a 1-week study where glucose and insulin concentrations were measured. 23409720 Developing FGFR4 inhibitors as potential anti-cancer agents via in silico design, supported by in vitro and cell-based testing. Fibroblast growth factor receptor-4 (FGFR4) is a tyrosine kinase with a range of important physiological functions. However, it is also frequently mutated in various cancers and is now generating significant interest as a potential therapeutic target. Unfortunately, biochemical characterization of its role in disease, and further evaluation as a drug target is hampered by lack of a specific inhibitor. We aimed to discover new inhibitors for FGFR4 ab initio using a strategy combining in silico, in vitro and cell-based assays. We used the homologous FGFR1 to calculate docking scores of a chemically-diverse library of approximately 2000 potential kinase inhibitors. Nineteen potential inhibitors and ten randomly- selected negative controls were taken forward for in vitro FGFR4 kinase assays. All compounds with good docking scores significantly inhibited FGFR4 kinase activity, some with sub-micromolar (most potent being V4-015 with an IC(50) of 0.04 μM). Four of these compounds also demonstrated substantial activity in cellular assays using the FGFR4- overexpressing breast carcinoma cell line, MDA-MB453. Through immunoblot assays, these compounds were shown to block the phosphorylation of the FGFR4 adaptor protein, FGFR substrate protein-2α (FRS2α). The most potent compound to date, V4-015, suppressed proliferation of MDA-MB453 cells at sub-micromolar concentrations, activated the pro-apoptotic caspases 3/7 and inhibited cellular migration. While achieving complete selectivity of this compound for FGFR4 will require further lead optimization, this study has successfully identified new chemical scaffolds with unprecedented FGFR4 inhibition capacities that will support mechanism of action studies and future anti-cancer drug design. 23288053 An animal model of marginal iodine deficiency during development: the thyroid axis and neurodevelopmental outcome. Thyroid hormones (THs) are essential for brain development, and iodine is required for TH synthesis. Environmental chemicals that perturb the thyroid axis result in modest reductions in TH, yet there is a paucity of data on the extent of neurological impairments associated with low-level TH disruption. This study examined the dose-response characteristics of marginal iodine deficiency (ID) on parameters of thyroid function and neurodevelopment. Diets deficient in iodine were prepared by adding 975, 200, 125, 25, or 0 µg/kg potassium iodate to the base casein diet to produce five nominal iodine levels ranging from ample (Diet 1: 1000 μg iodine/kg chow, D1) to deficient (Diet 5: 25 µg iodine/kg chow, D5). Female Long Evans rats were maintained on these diets beginning 7 weeks prior to breeding until the end of lactation. Dams were sacrificed on gestational days 16 and 20, or when pups were weaned on postnatal day (PN) 21. Fetal tissue was harvested from the dams, and pups were sacrificed on PN14 and PN21. Blood, thyroid gland, and brain were collected for analysis of iodine, TH, and TH precursors and metabolites. Serum and thyroid gland iodine and TH were reduced in animals receiving two diets that were most deficient in iodine. T4 was reduced in the fetal brain but was not altered in the neonatal brain. Neurobehavior, assessed by acoustic startle, water maze learning, and fear conditioning, was unchanged in adult offspring, but excitatory synaptic transmission was impaired in the dentate gyrus in animals receiving two diets that were most deficient in iodine. A 15% reduction in cortical T4 in the fetal brain was sufficient to induce permanent reductions in synaptic function in adults. These findings have implications for regulation of TH-disrupting chemicals and suggest that standard behavioral assays do not readily detect neurotoxicity induced by modest developmental TH disruption. 23347089 The influence of endocrine disruptors in a selected population of infertile women. Abstract Several studies report that endocrine disrupting chemicals (EDC) able to interfere with endocrine homeostasis may affect women's reproductive health. We analyzed EDC serum levels and nuclear receptors (NRs) expression in order to have an indication of the internal dose of biologically active compounds and a measurement of indicators of their effects, as a result of the repeated uptake from environmental source. The percentage of patients with detectable bisphenol A (BPA) concentrations was significantly higher in the infertile patients compared with fertile subjects. No significant difference was found between the groups with regard to perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), mono-ethylhexyl phthalate (MEHP) and di-(2-ethylhexyl) phthalate (DEHP) concentrations. Among infertile women, the mean expression of estrogen receptor alpha (ERα) and beta (Erβ), androgen receptor (AR) and pregnane X receptor (PXR) was significantly higher than fertile patients. The mean expression of aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor gamma (PPARγ) did not show significant differences between two groups. Patients with endometriosis had higher levels of PPARγ than all women with other causes of infertility. This study led further support to EDC exposure as a risk factor for women's fertility. 23587503 The in vitro effect of duroquinone on functional competence, genomic integrity, and oxidative stress indices of sterlet (Acipenser ruthenus) spermatozoa. The sturgeon is a highly endangered fish species mostly due to over-fishing, habitat destruction, and water pollution. Duroquinone (derivative of 1,4-benzoquinone) is a xenobiotic compound widespread in the environment. The effect of duroquinone on motility, DNA integrity, and oxidative stress indices in sterlet, Acispenser ruthenus, spermatozoa was investigated. Sterlet sperm was exposed for 2h to duroquinone at concentrations of 25, 50, 100, and 150μM. Spermatozoa motility, velocity, and ATP content were significantly decreased with exposure to duroquinone. The level of DNA damage significantly increased at concentrations of 50μM and above. Oxidative stress indices (lipid peroxidation and content of carbonyl proteins) and superoxide dismutase (SOD) activity increased significantly with increasing concentrations of duroquinone. Oxidative stress in sterlet spermatozoa induced by duroquinone was shown to impair spermatozoa DNA integrity, motility parameters, and the antioxidant defense system. Spermatozoa motility, content of carbonyl proteins, and SOD activity were shown to be sensitive biomarkers, exhibiting strong responses to low concentrations of the xenobiotic. Results also suggested that fish spermatozoa in vitro assays may provide a simple and efficient means of monitoring residual pollutants in the aquatic environment. 23124594 Absolute quantitation of stevioside and rebaudioside A in commercial standards by quantitative NMR. The extract prepared from the leaves of Stevia rebaudiana BERTONI (Asteraceae) contains sweet steviol glycosides, mainly stevioside and rebaudioside A. Highly purified stevia extracts have become popular worldwide as a natural, low-calorie sweetener. They contain various types of steviol glycosides, and their main components are stevioside and rebaudioside A. The content of each steviol glycoside is quantified by comparing the ratios of the molecular weights and the chromatographic peak areas of the samples to those of stevioside or rebaudioside A standards of the Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Joint Expert Committee on Food Additives (JECFA) and other specifications. However, various commercial standard reagents of stevioside and rebaudioside A are available. Their purities are different and their exact purities are not indicated. Therefore, the measured values of stevioside and rebaudioside A contained in a sample vary according to the standard used for the quantification. In this study, we utilized an accurate method, quantitative NMR (qNMR), for determining the contents of stevioside and rebaudioside A in standards, with traceability to the International System of Units (SI units). The purities of several commercial standards were determined to confirm their actual values. 23132866 p21-Activated kinase 6 (PAK6) inhibits prostate cancer growth via phosphorylation of androgen receptor and tumorigenic E3 ligase murine double minute-2 (Mdm2). The androgen receptor (AR) signaling pathway plays a crucial role in the development and growth of prostate malignancies. Regulation of AR homeostasis in prostate tumorigenesis has not yet been fully characterized. In this study, we demonstrate that p21-activated kinase 6 (PAK6) inhibits prostate tumorigenesis by regulating AR homeostasis. First, we demonstrated that in normal prostate epithelium, AR co-localizes with PAK6 in the cytoplasm and translocates into the nucleus in malignant prostate. Furthermore, AR phosphorylation at Ser-578 by PAK6 promotes AR-E3 ligase murine double minute-2 (Mdm2) association, causing AR degradation upon androgen stimuli. We also showed that PAK6 phosphorylates Mdm2 on Thr-158 and Ser-186, which is critical for AR ubiquitin-mediated degradation. Moreover, we found that Thr-158 collaborates with Ser-186 for AR-Mdm2 association and AR ubiquitin-mediated degradation as it facilitates PAK6-mediated AR homeostasis. PAK6 knockdown promotes prostate tumor growth in vivo. Interestingly, we found a strong inverse correlation between PAK6 and AR expression in the cytoplasm of prostate cancer cells. These observations indicate that PAK6 may be important for the maintenance of androgen-induced AR signaling homeostasis and in prostate malignancy, as well as being a possible new therapeutic target for AR-positive and hormone-sensitive prostate cancer. 23572390 Physiological and biochemical mechanisms of allelopathy mediated by the allelochemical extracts of Phytolacca latbenia (Moq.) H. Walter. In allelopathy, one plant suppresses the growth and development of other plant/plants by negatively affecting a variety of physiological and biochemical reactions. We checked the effects of methanolic extracts (allelochemical extracts) of Phytolacca latbenia (Moq.) H. Walter on antioxidant enzyme activities such as peroxidases (PODs), super oxide dismutases (SODs) and catalase (CAT) and on total protein contents (TPC), cellular injury (CI), and malondialdehyde (MDA) in the germinating seeds of Brassica napus L. (dicot) and Triticum aestivum L. (monocot). Both the crude methanolic extract root (CMER) and crude methanolic extract aerial (CMEA) of P. latbenia at 10000 ppm significantly reduced the POD activity in both the test seeds. The activity of SODs was significantly decreased by both CMER and CMEA in B. napus germinating seeds. A linear increase in the activity of CAT, CI, and MDA contents was found in both the test seeds with the increasing concentrations of CMEA and CMER, while TPC of the germinating seeds was found decreased. It is inferred that both the CMEA and CMER inhibited/delayed the seed germination, reduced the seedling growth by affecting a variety of biochemical and physiological attributes, and also caused cellular membrane injury in the germinating seeds of both the monocot and dicot seeds. 23541672 PEG mediated synthesis and pharmacological evaluation of some fluoro substituted pyrazoline derivatives as antiinflammatory and analgesic agents. A new series of fluoro substituted pyrazoline derivatives 5a-g and 6a-g were synthesized in good to excellent yield from the corresponding pyrazole chalcones, 4a-g, by using polyethylene glycol-400 (PEG-400) as an alternative reaction medium. The newly synthesized compounds were characterized and screened for their in vivo antiinflammatory and analgesic activity. Compounds 5g and 6g were found to be more potent than standard drug Diclofenac and six other compounds 5b, 5c, 5f, 6b, 6c and 6f showed significant antiinflammatory activity as compared to standard drug. Compounds 5c, 5d, 5e, 5f, 6c, 6d, 6e and 6f showed significant analgesic activity as compared to standard drug Aspirin. 23565759 Real-time evaluation of binding mechanisms in multivalent interactions: a surface plasmon resonance kinetic approach. Multivalency is a key, ubiquitous phenomenon in nature characterized by a complex combination of binding mechanisms, with special relevance in carbohydrate-lectin recognition. Herein we introduce an original surface plasmon resonance kinetic approach to analyze multivalent interactions that has been validated with dendrimers as monodisperse multivalent analytes binding to lectin clusters. The method, based on the analysis of early association and late dissociation phases of the sensorgrams provides robust information of the glycoconjugate binding efficiency and real-time structural data of the binding events under the complex scenario of the glyco-cluster effect. Notably, it reveals the dynamic nature of the interaction and offers experimental evidence on the contribution of binding mechanisms. 23517381 Collapse of a hydrophobic polymer in a mixture of denaturants. The solvent quality of an aqueous mixture of two good solvents, urea and guanidinium chloride (GdmCl), for a hydrophobic polymer was investigated using atomistic molecular dynamics simulations. A counterintuitive collapse of the polymer was found, suggesting that mixing the two denaturants reduces the solvent quality. This cononsolvency of the polymer in the urea + GdmCl mixture is found to be caused by the preferential adsorption of urea on the polymer. The polymer collapses as a result of indirect long-range interactions between monomers resulting from the presence of urea clouds surrounding them. Surprisingly, urea behaves as the better solvent in the mixture not because there exists a stronger affinity of the polymer for urea. Instead, attractive interactions between two unlike denaturant molecules combined with the direct dispersion interactions of the polymer with both denaturants determine the solvent quality of the mixture. 23391273 Metabolically obese status with normal weight is associated with both the prevalence and severity of angiographic coronary artery disease. OBJECTIVE: We evaluated prevalence and severity of angiographic coronary artery disease (CAD) according to groups by metabolically obese (MO) and/or weight status. MATERIAL/METHODS: Normal weight was defined as body mass index (BMI, kg/m(2))<25 and obesity was defined as BMI≥25. The MO was determined using the National Cholesterol Education Program-Adult Treatment Panel III classification with Korean-specific cutoffs for abdominal obesity. Therefore, a total of 856 subjects were categorized as follows: (1) metabolically healthy and normal weight (MHNW); (2) metabolically obese but normal weight (MONW); (3) metabolically healthy but obese (MHO); and (4) metabolically abnormally obese (MAO). The presence of obstructive lesion≥50% of coronary artery was considered as an angiographic CAD and the Gensini scoring system was used for the severity. RESULTS: MONW or MO showed a higher prevalence of CAD than MHNW or non-MO after adjustment for age and sex, respectively (MONW, odds ratio [OR]=1.69, 95% confidence interval [CI]: 1.13-2.51 and MO, OR=1.44, 95% CI: 1.09-1.91). In subjects without diabetes mellitus (DM), MONW or MO showed a marginally higher prevalence of CAD (MONW, OR=1.58, 95% CI: 0.96-2.61 and MO, OR=1.41, 95% CI: 0.96-2.08). MONW was independently associated with a higher severity of angiographic CAD than MHNW after age, sex, glomerular filtration rate, smoking status, high sensitive C-reactive protein, and use of anti-platelet and anti-angina drugs (β=0.118, P=0.005). And MO was associated with a higher severity of angiographic CAD than non-MO after adjustment for age and sex (β=0.077, P=0.024). The above associations were also consistent in subjects without DM (MONW, β=0.147, P=0.003 and MO, β=0.129, P=0.005). CONCLUSIONS: MONW or MO is associated with both the prevalence and severity of angiographic CAD after adjustment for age and sex and MONW is independently associated with the severity of angiographic CAD irrespective of DM. Therefore, subjects with MO but normal weight (MONW) should be carefully examined for angiographic CAD. 23474014 Time-dependent effects of corticosterone on reward-based decision-making in a rodent model of the Iowa Gambling Task. Corticosteroid hormones, released after stress, are known to change neuronal activity in two time-domains: within minutes via non-genomic pathways and with a delay of >1 h through pathways involving transcriptional regulation. Recent evidence in rodents and humans indicates that these two modes of corticosteroid action differently affect cognitive tasks. Here, we investigated whether reward-based decision-making, in a rat model of the Iowa Gambling Task (rIGT), is also differently altered by rapid versus delayed actions of corticosterone. We targeted the rapid and delayed time domain by injecting corticosterone (CORT, 1 mg/kg, s.c.) at 30 min (rapid) or 180 min (delayed) respectively prior to behavioural testing, during the final 3 days of the behavioural paradigm. In saline treated rats, the number of visits to the disadvantageous arm decreased over trial blocks, whilst this was attenuated when CORT was administered 30 min before testing. This attenuation was associated with a significantly increased c-Fos expression in the lateral orbitofrontal cortex and insular cortex, and a trend for an increase in the infralimbic cortex. The rapid corticosteroid effect contrasted with treatment 180 min before testing, where the number of visits to the disadvantageous arm as well as c-Fos labelling was not affected. These findings indicate that rapid corticosteroid actions impair reward-based decision-making. 23229510 Identification and characterization of a potent activator of p53-independent cellular senescence via a small-molecule screen for modifiers of the integrated stress response. The Integrated Stress Response (ISR) is a signaling program that enables cellular adaptation to stressful conditions like hypoxia and nutrient deprivation in the tumor microenvironment. An important effector of the ISR is activating transcription factor 4 (ATF4), a transcription factor that regulates genes involved in redox homeostasis and amino acid metabolism and transport. Because both inhibition and overactivation of the ISR can induce tumor cell death, modulators of ATF4 expression could prove to be clinically useful. In this study, chemical libraries were screened for modulators of ATF4 expression. We identified one compound, E235 (N-(1-benzyl-piperidin-4-yl)-2-(4-fluoro-phenyl)-benzo[d]imidazo[2,1-b]thiazole-7-carboxamide), that activated the ISR and dose-dependently increased levels of ATF4 in transformed cells. A dose-dependent decrease in viability was observed in several mouse and human tumor cell lines, and knockdown of ATF4 significantly increased the antiproliferative effects of E235. Interestingly, low μM doses of E235 induced senescence in many cell types, including HT1080 human fibrosarcoma and B16F10 mouse melanoma cells. E235-mediated induction of senescence was not dependent on p21 or p53; however, p21 conferred protection against the growth inhibitory effects of E235. Treatment with E235 resulted in an increase in cells arrested at the G2/M phase with a concurrent decrease in S-phase cells. E235 also activated DNA damage response signaling, resulting in increased levels of Ser15-phosphorylated p53, γ-H2AX, and phosphorylated checkpoint kinase 2 (Chk2), although E235 does not appear to cause physical DNA damage. Induction of γ-H2AX was abrogated in ATF4 knockdown cells. Together, these results suggest that modulation of the ISR pathway with the small molecule E235 could be a promising antitumor strategy. 23254573 The photophysics of 7-(N,N'-diethylamino)coumarin-3-carboxylic acid in water/AOT/isooctane reverse micelles: an excitation wavelength dependent study. In this manuscript we have studied the photophysics of 7-(N,N'-diethylamino)coumarin-3-carboxylic acid (7-DCCA) in water/AOT/isooctane reverse micelles. For this purpose we have used steady state absorption and fluorescence emission spectroscopy and time resolved fluorescence spectroscopy. We have studied the spectral behaviour of 7-DCCA inside the water/AOT/isooctane reverse micelles with variation of excitation wavelength. We have studied the dynamics of solvent and rotational relaxation by using two different excitation wavelengths (λ(exi) = 375 nm and λ(exi) = 405 nm). We have observed the excitation wavelength dependent dynamics of 7-DCCA in the reverse micelles. The fluorescence quantum yield, decay time, solvent relaxation time and rotational relaxation time of 7-DCCA in reverse micelles vary with the excitation wavelength. A two step and wobbling-in-cone model was used to interpret the rotational relaxation dynamics of 7-DCCA in reverse micelles. 23508963 Molecular Basis for Sialic Acid-dependent Receptor Recognition by the Plasmodium falciparum Invasion Protein Erythrocyte-binding Antigen-140/BAEBL. Plasmodium falciparum erythrocyte invasion is dependent on high affinity recognition of sialic acid on cell surface receptors. The erythrocyte binding-like (EBL) family of invasion ligands mediates recognition of sialic acid on erythrocyte glycoproteins. Erythrocyte-binding antigen-140 (PfEBA-140/BAEBL) is a critical EBL ligand that binds sialic acid on its receptor glycophorin C. We present here the crystal structure of the two-domain receptor-binding region of PfEBA-140 in complex with a glycan containing sialic acid. The structure identifies two glycan-binding pockets unique to PfEBA-140 and not shared by other EBL ligands. Specific molecular interactions that enable receptor engagement are identified and reveal that the glycan binding mode is distinct from that of apicomplexan and viral cell surface recognition ligands as well as host immune factors that bind sialic acid. Erythrocyte binding experiments elucidated essential glycan contact residues and identified divergent functional roles for each receptor-binding site. One of four polymorphisms proposed to affect receptor binding was localized to a glycan-binding site, providing a structural basis for altered erythrocyte engagement. The studies described here provide the first full description of sialic acid-dependent molecular interactions at the P. falciparum erythrocyte invasion interface and define a framework for development of PfEBA-140-based therapeutics, vaccines, and diagnostics assessing vaccine efficacy and natural immunity to infection. 23537094 Flavonoids of Dikamali: A phytochemical reinvestigation. Eleven known flavonoids (1-11) were isolated from Dikamali, the gum resin of Gardenia lucida. Three of them, desmethylnobiletin, pectolinarigenin and xanthomicrol, are a new report from this source. Nuclear magnetic resonance (NMR) data are being given for all the isolates. For two of them, viz., 3',4'-dimethoxywogonin and 4'-hydroxywogonin, such data have not been reported in literature. Furthermore, correct NMR data are being provided for gardenin C as the data reported in literature were found to be incorrect. 23541086 T-Cells from HLA-B*57:01+ Human Subjects Are Activated with Abacavir through Two Independent Pathways and Induce Cell Death by Multiple Mechanisms. Susceptibility to abacavir hypersensitivity has been attributed to possession of the specific human leukocyte antigen allele HLA-B*57:01. HLA-B*57:01-restricted activation of CD8+ T-cells provides a link between the genetic association and the iatrogenic disease. The objectives of this study were to characterize the functionality of drug-responsive CD8+ T-cell clones generated from HLA-B*57:01+ drug-naive subjects and to explore the relationship between abacavir accumulation in antigen presenting cells and the T-cell response. Seventy-four CD8+ clones expressing different Vβ receptors were shown to proliferate and kill target cells via different mechanisms when exposed to abacavir. Certain clones were activated with abacavir in the absence of antigen presenting cells. Analysis of the remaining clones revealed two pathways of drug-dependent T-cell activation. Overnight incubation of antigen presenting cells with abacavir, followed by repeated washing to remove soluble drug, activated approximately 50% of the clones, and the response was blocked by glutaraldehyde fixation. In contrast, a 1 h antigen presenting cell pulse did not activate any of the clones. Accumulation of abacavir in antigen presenting cells was rapid (less than 1 h), and the intracellular concentrations were maintained for 16 h. However, intracellular abacavir was not detectable by mass spectrometry after pulsing. These data suggest that T-cells can be activated by abacavir through a direct interaction with surface and intracellular major histocompatibility complex (MHC) molecules. With the former, abacavir seemingly participates in the MHC T-cell receptor binding interaction. In contrast, the latter pathway likely involves MHC binding peptides displayed as a consequence of abacavir exposure, but not abacavir itself. 23594047 Formation Mechanism of TiO 2 Nanotubes and Their Applications in Photoelectrochemical Water Splitting and Supercapacitors. Structural observations of the transition of TiO 2 nanopores into nanotubes by increasing the OH (-) concentration in the electrolyte challenge the validity of existing formation mechanisms of anodic TiO 2 nanotubes. In this study, dehydration of titanium hydroxide in the cell wall is proposed as the mechanism that leads to the separation of neighboring nanotubes. Based on this understanding, bamboo-type TiO 2 nanotubes with large surface area and excellent interconnectivity are achieved by cycling high and low applied potentials. After thermal treatment in a H 2 atmosphere, the bamboo-type TiO 2 nanotubes show large photoelectrochemical water splitting efficiency and supercapacitors performace. 23624237 Structural requirements within protoporphyrin IX in the inhibition of heat shock protein 90. Porphyrins are used for photodynamic therapy for their light-absorbing properties, and some of them were approved for the treatment of certain types of cancers. Porphyrins prevent activation of hypoxia inducible factor-1α (HIF-1α) by inhibiting heat shock protein 90 (HSP90). This study investigated the structural requirements within protoporphyrin IX (PPIX) for the inhibition of HSP90 activity. In HCT116, HT29 and DLD-1 cells, PPIX treatment directly hindered the binding between HSP90 and HIF-1α; PPIX treatment inhibited the chaperone activity of HSP90, accelerating protein degradation of HIF-1α. In addition, PPIX treatment suppressed cancer cell migration, endothelial cell tube formation, and aortic ring sprouting, being consistent with its anti-tumor and anti-angiogenic activities. In silico analysis, molecular docking model indicated that a tetrapyrrole macrocycle and two propionate chains within PPIX are necessary for the binding to the adenosine triphosphate (ATP)-binding pocket of HSP90. The predicted structural requirement was verified by the differential inhibitory effects of PPIX analogs, or the precursor of PPIX, on HIF-1α; compounds lacking either the tetrapyrrole macrocycle or the propionate chains were inactive. Our results show that a tetrapyrrole macrocycle and two attached propionate chains in PPIX coordinately interact with the ATP-binding pocket of HSP90, offering structural information on the inhibitory effect of porphyrins on angiogenesis. 23320732 Determinants of regioselectivity and chemoselectivity in fosfomycin resistance protein FosA from QM/MM calculations. FosA is a manganese-dependent enzyme that utilizes a Mn(2+) ion to catalyze the inactivation of the fosfomycin antibiotic by glutathione (GSH) addition. We report a theoretical study on the catalytic mechanism and the factors governing the regioselectivity and chemoselectivity of FosA. Density functional theory (DFT) calculations on the uncatalyzed reaction give high barriers and almost no regioselectivity even when adding two water molecules to assist the proton transfer. According to quantum mechanics/molecular mechanics (QM/MM) calculations on the full solvated protein, the enzyme-catalyzed glutathione addition reaction involves two major chemical steps that both proceed in the sextet state: proton transfer from the GSH thiol group to the Tyr39 anion and nucleophilic attack by the GSH thiolate leading to epoxide ring-opening. The second step is rate-limiting and is facilitated by the presence of the high-spin Mn(2+) ion that functions as a Lewis acid and stabilizes the leaving oxyanion through direct coordination. The barrier for C1 attack is computed to be 8.9 kcal/mol lower than that for C2 attack, in agreement with the experimentally observed regioselectivity of the enzyme. Further QM/MM calculations on the alternative water attack predict a concerted mechanism for this reaction, where the deprotonation of water, nucleophilic attack, and epoxide ring-opening take place via the same transition state. The calculated barrier is 8.3 kcal/mol higher than that for GSH attack, in line with the observed chemoselectivity of the enzyme, which manages to catalyze the addition of GSH in the presence of water molecules around its active site. The catalytic efficiency, regioselectivity, and chemoselectivity of FosA are rationalized in terms of the influence of the active-site protein environment and the different stabilization of the distorted substrates in the relevant transition states. 22610748 Improvement of liver function in humans using a mixture of schisandra fruit extract and sesamin. This was a randomized, parallel, and placebo-controlled study. Forty subjects were divided into a test group and a placebo group. The study was focused on the potential effects of a mixture of Schisandra fruit extract and sesamin (hereinafter called 'SCH') in the subjects with borderline high levels (40-60 U/L) of alanine aminotransferase (ALT) or aspartate aminotransferase (AST). Twenty subjects taking SCH (four tablets per day) and 20 subjects taking a placebo (four tablets per day) were studied. The effects of SCH on ALT, AST, total bilirubin, direct bilirubin, free radical levels, total antioxidant status, glutathione peroxidase, glutathione reductase, and the lag time for low-density lipoprotein oxidation were determined. The total test period was 5 months. Intervention of SCH clearly reduced the levels of ALT and AST, but it made no change in the total bilirubin and direct bilirubin. Intake of SCH also greatly increased the antioxidant capacity and decreased the values of thiobarbituric acid reactive substances, total free radicals, and superoxide anion radicals in the plasma. The activities of glutathione peroxidase and reductase in the erythrocytes were significantly increased. In addition, the lag time for low-density lipoprotein oxidation, an inflammatory marker, was evidently increased. Fatty liver was found to have been significantly improved in this study. SCH proved to have the effects of antioxidation and improving liver function. Copyright © 2012 John Wiley & Sons, Ltd. 23442788 Characterization of Palytoxin Binding to HaCaT Cells Using a Monoclonal Anti-Palytoxin Antibody. Palytoxin (PLTX) is the reference compound for a group of potent marine biotoxins, for which the molecular target is Na+/K+-ATPase. Indeed, ouabain (OUA), a potent blocker of the pump, is used to inhibit some PLTX effects in vitro. However, in an effort to explain incomplete inhibition of PLTX cytotoxicity, some studies suggest the possibility of two different binding sites on Na+/K+-ATPase. Hence, this study was performed to characterize PLTX binding to intact HaCaT keratinocytes and to investigate the ability of OUA to compete for this binding. PLTX binding to HaCaT cells was demonstrated by immunocytochemical analysis after 10 min exposure. An anti-PLTX monoclonal antibody-based ELISA showed that the binding was saturable and reversible, with a K(d) of 3 × 10-10 M. However, kinetic experiments revealed that PLTX binding dissociation was incomplete, suggesting an additional, OUA-insensitive, PLTX binding site. Competitive experiments suggested that OUA acts as a negative allosteric modulator against high PLTX concentrations (0.3-1.0 × 10-7 M) and possibly as a non-competitive antagonist against low PLTX concentrations (0.1-3.0 × 10-9 M). Antagonism was supported by PLTX cytotoxicity inhibition at OUA concentrations that displaced PLTX binding (1 × 10-5 M). However, this inhibition was incomplete, supporting the existence of both OUA-sensitive and -insensitive PLTX binding sites. 23603478 Effects of endocrine disrupting chemicals on in vitro global DNA methylation and adipocyte differentiation. Recent studies suggest that endocrine disrupting chemicals (EDCs) may form a risk factor for obesity by altering energy metabolism through epigenetic gene regulation. The goal of this study is to investigate the effects of a range of EDCs with putative obesogenic properties on global DNA methylation and adipocyte differentiation in vitro. Murine N2A and human SK-N-AS neuroblastoma cells and murine preadipocyte fibroblasts (3T3-L1) were exposed to tributyltin (TBT), diethylstilbestrol (DES), bisphenol A (BPA), 2,3,7,8-tetrachlorodibenzo-[p]-dioxin (TCDD), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153), hexachlorobenzene (HCB), hexabromocyclododecane (HBCD), 2,2',4,4'-tetrabrominated diphenyl ether (BDE-47) , perfluorinated octyl acid (PFOA) and perfluorinated octyl sulfonate (PFOS). A modest decrease in global DNA methylation was observed in N2A cells exposed to 10μM DES, BPA, TCDD, BDE-47, PCB-153 and 1μM HCB, but no changes were found in the human SK-N-AS cells. We reveal for the first time that BDE-47 increases adipocyte differentiation in a dose-dependent manner (2.5-25μM). Adipocyte differentiation was also enhanced by TBT (⩾10nM) and BPA (>10μM) and inhibited by TCDD (⩾0.1nM). The other chemicals showed either modest or no effects on adipocyte differentiation at the concentrations tested (PFOA, PFOS and HBCD at 10μM; PCB-153, 3.4μM and HCB, 1μM). This study demonstrates that, selected EDCs can induce functional changes in murine adipocyte differentiation in vitro which are accompanied by decreased global DNA methylation. 23643798 Investigation on the interaction of the toxicant, gentian violet, with bovine hemoglobin. Gentian violet (GV) is a well-known triarylmethane dye that is used in aquacultural, industrial and medicinal fields. But concerns in growing number have been paid to its potential health problems to human beings and its hazardous effects to environment. Herein, the toxic interaction of GV with bovine hemoglobin (BHb) was investigated by a series of spectroscopic methods and molecular modeling method. The fluorescence emission profile exhibited a remarkable quenching upon addition of GV to the buffered aqueous solution of BHb and the analysis of results revealed the dominant role of static quenching mechanism in GV-BHb interaction. The negative ΔH and positive ΔS values demonstrated that the electrostatic interactions mainly stabilized this toxicant-protein complex. Synchronous fluorescence, UV-vis absorption and CD spectroscopic studies proved that the conformational change of BHb was induced by GV's combination. Molecular modeling studies exhibited the binding mode of GV-BHb complex and the detailed information of related driving forces. During the 1H nuclear magnetic resonance spectra (1H NMR) study, the chemical shift perturbation and spin-lattice relaxation times of different protons were further used to investigate the interaction of GV with BHb and the results indicated that GV bound orientationally to BHb. 23511348 Optoacoustic tweezers: a programmable, localized cell concentrator based on opto-thermally generated, acoustically activated, surface bubbles. We present a programmable, biocompatible technique for dynamically concentrating and patterning particles and cells in a microfluidic device. Since our technique utilizes opto-thermally generated, acoustically activated, surface bubbles, we name it "optoacoustic tweezers". The optoacoustic tweezers are capable of concentrating particles/cells at any prescribed locations in a microfluidic chamber without the use of permanent structures, rendering it particularly useful for the formation of flexible, complex cell patterns. Additionally, this technique has demonstrated excellent biocompatibility and can be conveniently integrated with other microfluidic units. In our experiments, micro-bubbles were generated by focusing a 405 nm diode laser onto a gold-coated glass chamber. By properly tuning the laser, we demonstrate precise control over the position and size of the generated bubbles. Acoustic waves were then applied to activate the surface bubbles, causing them to oscillate at an optimized frequency. The resulting acoustic radiation force allowed us to locally trap particles/cells, including 15 μm polystyrene beads and HeLa cells, around each bubble. Cell-adhesion tests were also conducted after cell concentrating to confirm the biocompatibility of this technique. 23567956 Analysis of the antioxidant properties of differently substituted 2- and 3-indolyl carbohydrazides and related derivatives. Herein, we report the antioxidant properties of some selected substituted 2-indolyl carbohydrazides (JL34, JL40, JL71, JL87, JL317, JL432, JL436), the substituted 3-indolyl carbohydrazide JL344, 3-(3-hydrazinylpropyl)-1H-indole (JL72) and 3-(1H-indol-3-yl)propanehydrazide (JL418), throughout the assessment of their antioxidative potential using different antioxidant assays such as DPPH, lipid peroxidation in the APPH, or the DMSO method. We conclude that these compounds are convenient templates for the design of useful drugs in to treat Alzheimer's disease (AD), a pathology characterized by extensive oxidative stress and inflammation, thus essentially affected by reactive oxygen species (ROS). Most of them are potent hydroxyl radical scavengers and inhibit in vitro lipid peroxidation. Compounds JL40 and JL432 presenting higher lipoxygenase inhibitory activity among the tested derivatives, were found to present a promising anti-inflammatory in vivo result, as well as antioxidant and LOX inhibitory profile. These results in combination to their known AChE/BuChE inhibitory activities led us to propose these indolyl carbohydrazides as new multifunctional compounds against AD. 23576194 Scanning protein analysis of electrofocusing gels using X-ray fluorescence. Recently, "metallomics," in addition to genomics and proteomics, has become a focus as a novel approach to identify sensitive fluctuations in homeostasis that accompany metabolic processes, such as stress responses, differentiation, and proliferation. Cellular elements and associated protein behavior provide important clues for understanding cellular and disease mechanism(s). It is important to develop a system for measuring the native status of the protein. In this study, we developed an original freeze-dried electrofocusing native gel over polyimide film (native-gel film) for scanning protein analysis using synchrotron radiation excited X-ray fluorescence (SPAX). To our knowledge, this is the first report detailing the successful mapping of metal-associated proteins of electrofocusing gels using X-ray fluorescence. SPAX can provide detection sensitivity equivalent to that of LA-ICP-MS. In addition to this increased sensitivity, SPAX has the potential to be combined with other X-ray spectroscopies. Our system is useful for further applications in proteomics investigating cellular element-associated protein behaviors and disease mechanisms. 22703447 Nanostructural difference of water-soluble pectin and chelate-soluble pectin among ripening stages and cultivars of Chinese cherry. Nanostructure of water-soluble pectin (WSP) and chelate-soluble pectin (CSP) of two Chinese cherry (Prunus pseudocerasus L.) cultivars (soft cultivar 'Caode' and crisp cultivar 'Bende') with two different ripening stages were characterised using atomic force microscopy. Both cultivars shared some common values of chain widths for WSP or CSP, and both pectins shared several values of chain widths including 37, 55 and 61 nm. The results indicate that different cultivars shared similar components of pectin, and cultivar textural difference might be related to the interaction between pectin and other cherry components or the dissociation of pectin. During ripening, the wide WSP and CSP gradually dissociate in width. The results demonstrated that the changes of WSP and CSP of Chinese cherry in widths were a dissociation process. 22905673 Preliminary evaluation of the in vitro release and in vivo absorption in rabbits of the modified-release dosage forms. Objective: The suitability of the rabbit as an animal model for the primary screening and selection of the pilot scale batches during the early stages of the formulation development was studied. Materials and methods: Three modified-release formulations of aminophylline consisted of Carbopol® 971P/HPMC K4M (F-I), and HPMC K100M (F-II) or HPMC K4M (F-III) were used. Commercial products were Aminofilin retard 350 mg tablets, Srbolek, Serbia (R-I) and Phyllocontin(®) 350, tablets Purdue Frederic, Canada (R-II). Results: Calculated release rate constants and the ƒ2 values between R-I/F-I (84.1) and R-II/F-III (83.4) indicated similar in vitro release while the coefficient n showed presence of different mechanisms of release from Anomalous transport, Fickian diffusion to Case-II transport. Higher Tmax, was found in the rabbits, dosed with F-II (12.00 h), F-III (10.50 h), and R-II (15.00 h) formulation. The highest Cmax (9.22 mg/L) was obtained with F-II, similar lower values was seen for F-I and F-III, while commercial products showed the lowest values R-I (5.58 mg/L) and R-II (4.18 mg/L). Higher AUC values were detected for all three formulations (from 115.90 to 204.06 mgh/L) in relation to commercial products (105.33 and 113.25 mgh/L). Discussion and conclusion: The results demonstrated a good correlation of Level A (r(2) = 0.97) for the two formulations (F-I, F-III) and commercial product (R-I) indicates that there is a reasonable assumption that the rabbit might be use as a model for the preliminary comparison of scale up formulations in the early stages of the product development. 23552260 Histological, ultrastructural and immunohistochemical studies on the protective effect of ginger extract against cisplatin-induced nephrotoxicity in male rats. Cisplatin (CP) is a widely used anticancer drug; however, it has several side effects such as nephrotoxicity. Ginger, the rhizome of Zingiber officinale, consumed since ancient times has numerous health benefits. The objective of this work was to evaluate the protective effect of ginger extract (GE) against CP-induced nephrotoxicity. CP group displayed a marked renal failure characterized by a significant increase in serum creatinine and blood urea nitrogen (BUN) levels in addition to severe histopathological and ultrastructural renal alterations. Also, CP group showed an increase in the immunohistochemical expression of Bax proapoptotic protein. In contrast, GE+CP group showed significant decrease in the elevated serum creatinine and BUN levels and an improvement in the histopathological and ultrastructural renal injury induced by CP. The overexpression of Bax proapoptotic protein was significantly decreased in the GE+CP group. Hence, the present results indicated that GE has a protective effect against CP-induced renal damage in rats. Thereby, such findings recommended the usage of GE to prevent and/or decrease the renal damage induced by CP chemotherapeutic treatment. 23643932 Heterologously expressed formyl peptide receptor 2 (FPR2/ALX) does not respond to lipoxin A4. Lipoxin A4 (LXA4) has been described as an anti-inflammatory mediator, which exerts its effects through the formyl peptide receptor FPR2, also known as ALX. However, there has been a controversy whether or not cells expressing FPR2/ALX, such as neutrophils, respond to LXA4. We, therefore, systematically examined the ability of the human and murine forms of the receptor to respond to LXA4. We show that both receptor orthologues responded to the FPR2/ALX peptide agonist WKYMVM when expressed heterologously. In contrast, LXA4 from different sources neither increased [Ca(2+)]i and extracellular-signal-regulated kinase (ERK) phosphorylation, nor did it induce a decrease in cAMP levels or a translocation of β-arrestin. Also, several LXA4 analogues were found to be unable to signal through FPR2/ALX. We conclude that FPR2/ALX is not activated by LXA4 and that the molecular mechanism by which LXA4 functions still needs to be identified. 23570232 Adenine-DNA Adducts Derived from the Highly Tumorigenic Dibenzo[a,l]pyrene Are Resistant to Nucleotide Excision Repair while Guanine Adducts Are Not. The structural origins of differences in susceptibilities of various DNA lesions to nucleotide excision repair (NER) are poorly understood. Here we compared, in the same sequence context, the relative NER dual incision efficiencies elicited by two stereochemically distinct pairs of guanine (N(2)-dG) and adenine (N(6)-dA) DNA lesions, derived from enantiomeric genotoxic diol epoxides of the highly tumorigenic fjord region polycyclic aromatic hydrocarbon dibenzo[a,l]pyrene (DB[a,l]P). Remarkably, in cell-free HeLa cell extracts, the guanine adduct with R absolute chemistry at the N(2)-dG linkage site is ∼35 times more susceptible to NER dual incisions than the stereochemically identical N(6)-dA adduct. For the guanine and adenine adducts with S stereochemistry, a similar but somewhat smaller effect (factor of ∼15) is observed. The striking resistance of the bulky N(6)-dA in contrast to the modest to good susceptibilities of the N(2)-dG adducts to NER is interpreted in terms of the balance between lesion-induced DNA distorting and DNA stabilizing van der Waals interactions in their structures, that are partly reflected in the overall thermal stabilities of the modified duplexes. Our results are consistent with the hypothesis that the high genotoxic activity of DB[a,l]P is related to the formation of NER-resistant and persistent DB[a,l]P-derived adenine adducts in cellular DNA. 23411180 Pterostilbene inhibits dimethylnitrosamine-induced liver fibrosis in rats. Pterostilbene, found in grapes and berries, exhibits pleiotropic effects, including anti-inflammatory, antioxidant, and anti-proliferative activities. This study was conducted to investigate the effect of pterostilbene on liver fibrosis and the potential underlying mechanism for such effect. Sprague-Dawley rats were intraperitoneally given dimethyl n-nitrosamine (DMN) (10mg/kg) 3 days per week for 4 weeks. Pterostilbene (10 or 20mg/kg) was administered by oral gavage daily. Liver function, morphology, histochemistry, and fibrotic parameters were examined. Pterostilbene supplementation alleviated the DMN-induced changes in the serum levels of alanine transaminase and aspartate transaminase (p<0.05). Fibrotic status and the activation of hepatic stellate cells were improved upon pterostilbene supplementation as evidenced by histopathological examination as well as the expression of α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and matrix metalloproteinase 2 (MMP2). These data demonstrated that pterostilbene exhibited hepatoprotective effects on experimental fibrosis, potentially by inhibiting the TGF-β1/Smad signaling. 23544459 Catalytic Asymmetric Synthesis of γ-Butenolides by Direct Vinylogous Reactions. The γ-butenolide structural motif is a prominent feature in many bioactive natural products and drugs. This short review summarizes catalytic asymmetric synthesis of γ-butenolides through direct vinylogous reactions by metal complexes and organocatalysts. In light of building chiral γ-tertiary and quaternary carbon centers of butenolides, three synthetic strategies are included: 1) the reactions with furanone derivatives as nucleophiles, 2) olefination of γ,γ- disubstituted butenolides and 3) the reactions by using γ,γ-disubstituted butenolides as nucleophiles. 23190093 Supramolecular hydrogels with reverse thermal gelation properties from (oligo)tyrosine containing block copolymers. Novel block copolymers comprising poly(ethylene glycol) (PEG) and an oligo(tyrosine) block were synthesized in different compositions by N-carboxyanhydride (NCA) polymerization. It was shown that PEG2000-Tyr(6) undergoes thermoresponsive hydrogelation at a low concentration range of 0.25-3.0 wt % within a temperature range of 25-50 °C. Cryogenic transmission electron microscopy (Cryo-TEM) revealed a continuous network of fibers throughout the hydrogel sample, even at concentrations as low as 0.25 wt %. Circular dichroism (CD) results suggest that better packing of the β-sheet tyrosine block at increasing temperature induces the reverse thermogelation. A preliminary assessment of the potential of the hydrogel for in vitro application confirmed the hydrogel is not cytotoxic, is biodegradable, and produced a sustained release of a small-molecule drug. 23542817 Disruption of the integrity and function of brain microvascular endothelial cells in culture by exposure to diesel engine exhaust particles. Diesel exhaust particles (DEPs), a by-product of diesel engine exhaust (DEE), are known to produce pro-oxidative and pro-inflammatory effects, thereby leading to oxidative stress-induced damage. Given the key role of DEPs in inducing oxidative stress, we investigated the role of DEPs in disrupting the integrity and function of immortalized human brain microvascular endothelial cells (HBMVEC). To study this, HBMVEC cells were exposed to media containing three different concentrations of DEPs or plain media for 24h. Those exposed to DEPs showed significantly higher oxidative stress than the untreated group, as indicated by the glutathione (GSH) and malondialdehyde (MDA) levels, and the glutathione peroxidase and glutathione reductase activities. DEPs also induced oxidative stress-related disruption of the HBMVEC cells monolayer, as measured by trans-epithelial electrical resistance. Taken together, these data suggest that DEPs induce cell death and disrupt the function and integrity of HBMVEC cells, indicating a potential role of DEPs in neurotoxicities. 23506857 Biomarkers of prolonged exposure to microcystin-LR in mice. The effects of prolonged exposure to microcystins (MCs) on health are not yet sufficiently understood and this type of poisoning is often undiagnosed. Even though chronic exposure has been linked with liver cancer and alterations have been described in liver damage marker enzymes in exposed populations, there are not profile parameters that indicate prolonged exposure to microcystins. The aim of this work is to determine, based on an animal model of prolonged exposure to successive i.p. doses of 25 μg MC-LR/kg body weight, several plasma parameters which could be useful as exposure biomarkers. Hemoglobin (Hb) and methemoglobin (MetHb) levels were determined on blood samples. We also studied plasma levels of hydroperoxides (ROOHs), α-tocopherol, glutathione and lipid profile as well as superoxide dismutase (SOD) and catalase (CAT) erythrocyte activities. In addition, the determination of MC-LR levels in liver, kidney, plasma, urine and feces of treated mice was carried out. We found that alteration in MetHb, ROOHs, glutathione, α-tocopherol levels, SOD activity and plasma lipid profile, correlates with those expected if the alteration derived from hepatic damage. The alterated plasma paramenters together with MC-LR determination could be used as biomarkers, helpful tools in screening and epidemiological studies. 23386390 Add-on therapy with the DPP-4 inhibitor sitagliptin improves glycemic control in insulin-treated Japanese patients with type 2 diabetes mellitus. The effect of add-on therapy with sitagliptin on glycemic control was prospectively investigated in patients with type 2 diabetes mellitus (T2DM) receiving insulin alone or insulin combined with oral antidiabetic drugs. Seventy-one patients were evaluated (38 men and 33 women aged 63.9±10.2 years). They were divided into three groups, which were 45 patients receiving premixed insulin twice daily, 15 patients receiving multiple daily insulin injections, and 11 patients receiving basal insulin with oral antidiabetic drugs (basal insulin therapy). Concomitant oral drugs included sulfonylureas, α-glucosidase inhibitors and metformin. The hemoglobin A1c (HbA1c) of all patients improved significantly from 8.1±1.2% to 7.6±1.1% after 12 weeks of add-on therapy with sitagliptin (p<0.01), and the insulin dosage was reduced from 27.3±15.8 U/day to 24.5±16.5 U/day (p<0.001). Body weight did not change after the start of concomitant therapy and severe hypoglycemia was not observed. The baseline HbA1c and glycated albumin levels were identified as factors that predicted the response to add-on therapy with sitagliptin. These findings suggest that add-on therapy with sitagliptin can be expected to achieve improvement of poor glycemic control irrespective of a patient's demographic profile. Stratified analysis based on the insulin regimen revealed a stronger antidiabetic effect and a high efficacy of sitagliptin when it was added to basal insulin therapy. The results of this investigation confirmed that add-on therapy with sitagliptin to various insulin regimens could improve glycemic control without severe hypoglycemia and/or weight gain. 23378191 Mending leaky blood vessels: the angiopoietin-Tie2 pathway in sepsis. Sepsis is a systemic inflammatory response to infection. A common end-feature, these patients regularly suffer from is the so-called multiple organ dysfunction syndrome, an often fatal consequence of organ hypoperfusion, coagulopathy, immune dysregulation, and mitochondrial dysfunction. Microvascular dysfunction critically contributes to the morbidity and mortality of this disease. The angiopoietin (Angpt)/Tie2 system consists of the transmembrane endothelial tyrosine kinase Tie2 and its circulating ligands (Angpt-1, -2, and -3/4). The balance between the canonical agonist Angpt-1 and its competitive inhibitor, Angpt-2, regulates basal endothelial barrier function and the leakage and vascular inflammation that develop in response to pathogens and cytokines. Here we summarize recent work in mice and men to highlight the therapeutic potential in this pathway to prevent or even reverse microvascular dysfunction in this deadly disease. 23210900 Probing of field-induced structures and tunable rheological properties of surfactant capped magnetically polarizable nanofluids. Oil-based nanofluid containing surfactant-capped magnetite nanoparticles are synthesized by a simple coprecipitation approach, and their magnetorheological properties are studied for different magnetic field strengths and volume fractions. We observe a distinct "plateau-like region" in the shear thinning viscosity curve, under an external magnetic field, possibly due to a peculiar alignment of the chains with respect to the field direction where the structure is stable against fragmentation. The observed plateau regime is reminiscent to that of kinetically arrested gel networks. Interestingly, such a plateau regime has been observed only above certain critical magnetic field when the dipolar interaction strength is much greater than the thermal energy where the aggregation becomes a nonequilibrium transport-limited process. The good collapse of specific viscosity data against Mason number for different magnetic field strengths onto a single curve suggests the dominance of hydrodynamic and magnetic forces on thermal force above a certain magnetic field strength. The observed increase in both static and dynamic yield stresses under the magnetic field confirms the formation of columnar structures that hinder the flow behavior. The hysteresis observed in the magnetic sweep experiments shows the inability of the chains to relax within the measurement time. The dynamic measurements confirm that the field-induced structures impart elastic behavior to the dispersion, which is found to increase with magnetic field and saturates at higher field strengths. 23238642 Characterization of arsenic resistant bacteria from arsenic rich groundwater of West Bengal, India. Sixty-four arsenic (As) resistant bacteria isolated from an arsenic rich groundwater sample of West Bengal were characterized to investigate their potential role in subsurface arsenic mobilization. Among the isolated strains predominance of genera Agrobacterium/Rhizobium, Ochrobactrum and Achromobacter which could grow chemolitrophically and utilize arsenic as electron donor were detected. Higher tolerance to As(3+) [maximum tolerable concentration (MTC): ≥10 mM], As(5+) (MTC: ≥100 mM) and other heavy metals like Cu(2+), Cr(2+), Ni(2+) etc. (MTC: ≥10 mM), presence of arsenate reductase and siderophore was frequently observed among the isolates. Ability to produce arsenite oxidase and phosphatase enzyme was detected in 50 and 34 % of the isolates, respectively. Although no direct correlation among taxonomic identity of bacterial strains and their metabolic abilities as mentioned above was apparent, several isolates affiliated to genera Ochrobactrum, Achromobacter and unclassified Rhizobiaceae members were found to be highly resistant to As(3+) and As(5+) and positive for all the test properties. Arsenate reductase activity was found to be conferred by arsC gene, which in many strains was coupled with arsenite efflux gene arsB as well. Phylogenetic incongruence between the 16S rRNA and ars genes lineages indicated possible incidence of horizontal gene transfer for ars genes. Based on the results we propose that under the prevailing low nutrient condition inhabitant bacteria capable of using inorganic electron donors play a synergistic role wherein siderophores and phosphatase activities facilitate the release of sediment bound As(5+), which is subsequently reduced by arsenate reductase resulting into the mobilization of As(3+) in groundwater. 23369935 TNFα and Fas/FasL pathways are involved in 9-Methoxycamptothecin-induced apoptosis in cancer cells with oxidative stress and G2/M cell cycle arrest. 9-Methoxycamptothecin (MCPT) has been recently reported to have a strong anticancer activity. However, its detailed mechanism of action in human cancer cells has not been well clarified. The results showed that MCPT induced cytotoxicity in seven human cancer cell lines in a dose dependent manner after 72h, with A2780 and Hela cell lines more sensitive, so the two cell lines were chosen to do further studies. MCPT induced strong G2/M arrest in both A2780 cells and Hela cells after 24h, following by substantial sub-G1 arrest (indicating apoptosis). The apoptosis was verified by staining with Annexin V-FITC and propidium iodide. ROS generation increased significantly in MCPT-induced apoptosis. Meanwhile, the apoptosis appeared to be dependent on caspase-3, -8 and -9 in A2780 cells, and caspase-3 in Hela cells. In addition, MCPT induced up-regulation expression of most of seventeen genes in both cell lines. Western blot verified that changes of TNFα, Fas, P53 and P27 protein level were consistent with their gene expression changes. Taken together, MCPT plays an important role in tumor growth suppression by inducing apoptosis in both cell lines via extrinsic and intrinsic apoptotic pathways, and has the potential to be developed into an antitumor agent. 23632448 First principles intensity calculations of the methane rovibrational spectra in the infrared up to 9300 cm(-1.) We report global calculations of rovibrational spectra and dipole transition intensities of methane using our recent ab initio dipole moment and potential surfaces [Nikitin et al., Chem. Phys. Lett., 2011, 501, 179; 2013, 565, 5]. For the full symmetry account, a recently published variational tensor formalism in normal modes [Rey et al., J. Chem. Phys., 2012, 136, 244106] is applied, the convergence of high-J calculations being improved by the use of vibrational eigenfunctions to make a compressed basis set for solving the rovibrational problem. Comparisons of theoretical predictions up to J = 25 for various complex polyads of methane involving strongly coupled vibration-rotation bands support the validity of this new approach. For the first time, positions and line intensities at 80 K and 296 K are shown to be in excellent agreement with raw experimental data, even for high energy ranges. The theoretical predictions also correctly describe the isotopic effects in line positions and intensities due to the CH4 → CD4 substitution which is considered as the test for the method. This work is a first step toward the theoretical interpretation of numerous methane bands which remain still unassigned and detailed line-by-line absorption/emission spectra analyses for atmospheric and planetological applications. 23567316 Neonatal exposure to lipopolysaccharide enhances accumulation of α-synuclein aggregation and dopamine transporter protein expression in the substantia nigra in responses to rotenone challenge in later life. Brain inflammation in early life may enhance adult susceptibility to develop neurodegenerative disorders triggered by environmental toxins. Our previous studies show that perinatal lipopolysaccharide (LPS) exposure enhances adult susceptibility to rotenone-induced injury to the dopaminergic system in the substantia nigra (SN) of the adult rat brain. To further investigate the enhanced adult susceptibility by neonatal LPS exposure to rotenone neurotoxicity, we used our neonatal rat model of LPS exposure (1mg/kg, intracerebral injection in postnatal day 5, P5, neonatal rats) to examine the protein levels of α-synuclein and dopamine transporters (DAT) in the adult rat. By P70, rats from the saline- or LPS-exposed group were challenged with rotenone, a commonly used pesticide, through subcutaneous mini-pump infusion at a dose of 1.25mg/kg/day for 14 days. The accumulation of α-synuclein aggregation and increment of DAT protein content were found in the SN of LPS-exposed rats. Neonatal LPS exposure enhanced rotenone-stimulated accumulation of α-synuclein aggregation and increment in DAT protein expression in the cytoplasmic compartment of the SN, and in the synaptosomal compartment of the striatum of adult rats. Rotenone treatment also resulted in reduction of [(3)H]dopamine uptake and mitochondrial complex I activity in the striatum of rats with neonatal LPS exposure, but not in those without this exposure. The current study suggests possible roles of α-synuclein aggregate and DAT distribution in the cytoplasm and synaptosome triggered by environmental toxins in later life in the development of neurodegenerative disorders. Our model may be useful in studying mechanisms involved in the pathogenesis of nonfamilial Parkinson's disease and for developing potential therapeutic treatments for this disease. 23121886 Metal bioavailability from different natural prey to a marine predator Nassarius siquijorensis. Gastropods are often the top predators in marine benthic environments, and trophic transfer is the predominant route by which metals are accumulated in these predators. In the present study, the potential influences of prey composition on the trophic transfer, accumulation, subcellular distribution and metallothionein induction of six metals (Ag, As, Cd, Cu, Pb and Zn) in a predator Nassarius siquijorensis were investigated. The snails were fed venerid clams Ruditapes philippinarum, mussels Perna viridis, oysters Crassostrea angulata or barnacles Fistulobalanus albicostatus, each differing greatly in their metal accumulation and handling patterns. N. siquijorensis showed prey-specific bioaccumulation and trophic transfer of the six metals. In general, the body burdens of metals in the viscera and muscles of N. siquijorensis increased with increasing exposure period and metal concentration in the four prey. The calculated trophic transfer factors (TTFs) of the metals in different prey varied and were the highest for clams and mussels prey, indicating that metal bioavailability from these prey was higher than that from barnacles and oysters. All the studied metals except Pb were enriched during transfer to the snails. The subcellular metal distribution in the viscera was affected by prey composition. Exposure to the four natural prey induced MTs, which may be used as a better biomarker for muscle than for viscera for metal stress. Our results imply that metals from different natural prey have different bioavailability and may help better understand the trophic transfer of metals in marine benthic food chain. 23570237 Reactions of Hydrocarbon Radicals and Biradicals. Experimental measurements of the rate coefficients for several types of gas phase radical reactions are reviewed. They include radical isomerization and dissociation, radical + radical association, and unimolecular reactions of peroxy radicals. Some reactions of methylene in its lowest singlet state are also considered. The links to theories of chemical reaction rates and especially of capture rates for radical + radical reactions are examined. Many of the reactions involve formation of adducts, which can isomerize and dissociate. Such reactions frequently involve energy distributions of the adducts that are far from Boltzmann, and the interpretation of measurements requires the use of master equation techniques. The basis of these methods and the use of matrix diagonalization and eigenvector/eigenvalue analysis to extract phenomenological rate coefficients are discussed. The relevance of the measurements to applications in atmospheric chemistry and, especially, in combustion is briefly considered. 23474381 Prilling of fatty acids as a continuous process for the development of controlled release multiparticulate dosage forms. In this study, prilling was evaluated as a technique for the development of multiparticulate dosage forms using the fatty acids, stearic acid, and behenic acid as potential matrix formers to control the release of metoprolol tartrate (MPT), a highly water soluble drug. The in vitro drug release was dependent on the drug load, type of fatty acid, and pH of the dissolution medium. Higher drug loads resulted in faster release with behenic acid releasing drug over longer periods relative to stearic acid. The in vitro drug release was pH-dependent at low drug load with the release being slower at lower pH. Due to ionization of the fatty acid at pH 7.4, drug release was susceptible to the ionic strength at this pH value. Solid state characterization indicated that the crystalline state of the fatty acids was not affected by thermal processing via prilling, while the crystallinity of MPT was decreased. During storage, the amorphous MPT fraction recrystallized in the entire matrix. Drug release from behenic acid matrices was increased during storage at 40°C; however, no polymorphism of behenic acid was detected. The bioavailability of MPT, after oral administration to dogs as prills containing 30% and 40% MPT using behenic acid as matrix former, was not significantly different from a commercial sustained release reference formulation, although the 40% MPT prills showed a burst release. 23500491 Structural Basis for the ATP-Induced Isomerization of Kinesin. Kinesin superfamily proteins (KIFs) are microtubule-based molecular motors driven by the energy derived from the hydrolysis of ATP. Previous studies have revealed that the ATP binding step is crucial both for the power stroke to produce motility and for the inter-domain regulation of ATPase activity to guarantee the processive movement of dimeric KIFs. Here, we report the first crystal structure of KIF4 complexed with the non-hydrolyzable ATP analog, AMPPNP (adenylyl imidodiphosphate), at 1.7Å resolution. By combining our structure with previously solved KIF1A structures complexed with two ATP analogs, molecular snapshots during ATP binding reveal that the closure of the nucleotide-binding pocket during ATP binding is achieved by closure of the backdoor. Closure of the backdoor stabilizes two mobile regions, switch I and switch II, to generate the phosphate tube from which hydrolyzed phosphate is released. Through the stabilization of switch II, the local conformational change at the catalytic center is further relayed to the neck-linker element that fully docks to the catalytic core to produce the power stroke. Because the neck linker is a sole element that connects the partner heads in dimeric KIFs, this tight structural coordination between the catalytic center and neck linker enables inter-domain communication between the partner heads. This study also revealed the putative microtubule-binding site of KIF4, thus providing structural insights that describe the specific binding of KIF4 to the microtubule. 22871218 Determination of 10 ginsenosides in Panax ginseng of different harvest times based on HPLC fingerprints and principal component analysis. A combinative method of HPLC fingerprinting and quantitative determination was successfully applied to monitor dynamic accumulation of ginsenosides in five-year-old Panax ginseng roots from different harvest times. The optimal chromatographic conditions were achieved on a C18 column with gradient elution using acetonitrile and 1 mmol · L(-1) KH2PO4 buffer solution at 203 nm. The result indicated that the contents of total ginsenosides showed significant variations, and a decrease tendency appeared in the growth period of the fifth year. 23601413 Laboratory performance on analysis of mandatory nutrients and preparation of nutrition labelling. This study assessed the performance of 17 laboratories in Thailand in analysing mandatory nutrients in salted, fried broad bean and in using data to prepare nutrition labels. Nutrient levels in the test material, as robust mean (x(∗)) and robust standard deviation (s(∗)), were assigned in line with ISO 13528. Data obtained from the laboratories were statistically evaluated against these values. Laboratories with satisfactory, questionable and unsatisfactory results for each nutrient were identified based on robust z-score. Laboratories achieving satisfactory analytical results (z-score⩽2) were for lipid, 82%; protein, 85%; Na, 82%; Ca, 62%; Fe, 81%; ash, 70%; and moisture, 62%. Reference values for some nutrients in broad bean powder were developed using data from satisfactorily performing laboratories. Less than 20% of the laboratories demonstrated good performance in preparing nutrition labels. Common mistakes were the nutrition information format, estimation of serving size and serving(s) per package. 23457022 New flavonol and diterpenoids from the endophytic fungus Aspergillus sp. YXf3. One new flavonol, chlorflavonin A (1), four new diterpenoids, aspergiloids E-H (3, 5-7), together with eight known compounds (2, 4, 8-13) were isolated from solid fermentation of Aspergillus sp. (strain no. YXf3), an endophytic fungus from Ginkgo biloba. Their structures were determined through detailed spectroscopic analysis combined with comparison of NMR spectra data with reported ones. All of them were screened on cytotoxicity against KB, SGC-7901, SW1116, and A549 cell lines; compounds 4, 9-11 exhibited moderate activities with IC50 values ranging from 6.74 to 46.64 µM. 23427901 Absolute Configurations of Fungal and Plant Metabolites by Chiroptical Methods. ORD, ECD, and VCD Studies on Phyllostin, Scytolide, and Oxysporone. The absolute configuration (AC) of the bioactive metabolites phyllostin (1) and scytolide (2), two hexahydro-1,4-benzodioxines produced by Phyllosticta cirsii, and oxysporone (3), a dihydrofuropyranone recently isolated from a strain of Diplodia africana, has been assigned by computational analysis of their optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) spectra. Computational prediction of ORD, ECD, and VCD allowed us to assign (3S,4aR,8S,8aR) AC to naturally occurring (-)-1, while (4aR,8S,8aR) AC was assigned to (-)-2 employing only ECD and VCD, because in this case ORD analysis turned out to be unsuitable for AC assignment. Theoretical prediction of both ORD and ECD spectra of 3 led to assignment of (4S,5R,6R) AC to (+)-3. In this case a satisfactory agreement between experimental and calculated VCD spectra was obtained only after taking into account solvent effects. This study shows that in the case of flexible and complex natural products only a concerted application of more than a single chiroptical technique permits unambiguous assignment of absolute configuration. 23454513 Synthesis and biochemical activities of antiproliferative amino acid and phosphate derivatives of microtubule-disrupting β-lactam combretastatins. The synthesis and biochemical activities of novel water-soluble β-lactam analogues of combretastatin A-4 are described. The first series of compounds investigated, β-lactam phosphate esters 7a, 8a and 9a, exhibited potent antiproliferative activity and caused microtubule disruption in human breast carcinoma-derived MCF-7 cells. They did not inhibit tubulin polymerisation in vitro, indicating that biotransformation was necessary for their antiproliferative and tubulin binding effects in MCF-7 cells. The second series of compounds, β-lactam amino acid amides (including 10k and 11l) displayed potent antiproliferative activity in MCF-7 cells, disrupted microtubules in MCF-7 cells and also inhibited the polymerisation of tubulin in vitro. This indicates that the β-lactam amides did not require metabolic activation to have antiproliferative effects, in contrast to the phosphate series. Both series of compounds caused mitotic catastrophe and apoptosis in MCF-7 cells. Molecular modelling studies indicated potential binding conformations for the β-lactam amino acid amides 10k and 11l in the colchicine-binding site of tubulin. Due to their aqueous solubility and potent biochemical effects, these compounds are promising candidates for further development as microtubule-disrupting agents. 23201337 Reduced plasma oxytocin levels in female patients with borderline personality disorder. The neuropeptide oxytocin is involved in social cognition and interaction across species and plays a crucial role in the regulation of affiliative behaviors. Oxytocin levels in cerebrospinal fluid (CSF), but also in plasma or urine, have been shown to be negatively associated with childhood traumata, aggressive behavior, and suicide attempts. Recently, an altered activity of the oxytocin system has been discussed to play a prominent role in borderline personality disorder (BPD), which is thought to be closely related to traumatic experiences in childhood and is characterized by (para)suicidal behaviors as well as aggressive outbursts. In the present study, we compared plasma oxytocin levels of women with and without BPD in the follicular phase and assessed the relationship between oxytocin concentrations and childhood traumata. Women diagnosed with BPD had significantly reduced oxytocin concentrations, even after controlling for estrogen, progesterone, and contraceptive intake. In addition, plasma oxytocin correlated negatively with experiences of childhood traumata, in particular with emotional neglect and abuse. The results of mediation analyses do not support a model of oxytocin being a prominent mediator in the link between childhood trauma and BPD. Thus, the findings indicate dysregulations in the oxytocin system of patients diagnosed with BPD with more longitudinal research being necessary to disentangle the relationship between childhood adversities, oxytocin system, and psychopathology. 23418750 A polar copper-boron one-electron σ-bond. Virtually all chemical bonds consist of one or several pairs of electrons shared by two atoms. Examples of σ-bonds made of a single electron delocalized over two neighboring atoms were until recently found only in gas-phase cations such as H2(+) and Li2(+) and in highly unstable species generated in solid matrices. Only in the past decade was bona fide one-electron bonding observed for molecules in fluid solution. Here we report the isolation and structural characterization of a thermally stable compound featuring a Cu-B one-electron bond, as well as its oxidized (nonbonded) and reduced (two-electrons-bonded) congeners. This triad provides an excellent opportunity to study the degree of σ-bonding in a metalloboratrane as a function of electron count. 23406958 Cytotoxic and phytotoxic actions of Heliotropium strigosum. This study describes the cytotoxic and phytotoxic activities of the crude extract of Heliotropium strigosum and its resultant fractions. In brine shrimp toxicology assays, profound cytotoxicity was displayed by ethyl acetate (LD(50) 8.3 μg/ml) and chloroform (LD(50) 8.8 μg/ml) fractions, followed by relatively weak crude methanolic extract of H. strigosum (LD(50) 909 μg/ml) and n-hexane fraction (LD(50) 1000 μg/ml). In case of phytotoxicity activity against Lemna acquinoctialis, highest phytotoxic effect was showed by ethyl acetate fraction (LD(50) 91.0 μg/ml), while chloroform fraction, plant crude extract and n-hexane, respectively, caused 50%, 30.76 ± 1.1% and 30.7 ± 1.1% inhibitory action at maximum concentration used, that is, 1000 μg/ml. These data indicates that H. strigosum exhibits cytotoxic and phytotoxic potential, which explore its use as anticancer and herbicidal medicine. The ethyl acetate and chloroform fractions were more potent for the evaluated toxicity effects, thus recommended for isolation and identification of the active compounds. 23437977 From rings to crescents: a novel fabrication technique uncovers the transition details. A novel fabrication route is reported for the generation of substrate-supported symmetric and asymmetric metal nanostructures. We combine a colloidal template and angled evaporation to deposit in situ mask materials for subsequent lithographic pattern transfer. The technique is demonstrated for the fabrication of concentric and nonconcentric gold rings and crescents. Optical properties of localized plasmon resonances in such structures are studied by UV-vis-NIR spectroscopy and finite-difference time domain simulations during the transition from rings to crescents revealing the development of strong quadrupolar modes. 23639191 Involvement of p-CREB and phase II detoxifying enzyme system in neuroprotection mediated by the flavonoid calycopterin isolated from Dracocephalum kotschyi. PURPOSE: There is an increasing amount of experimental evidence that oxidative stress has a central role in the neuropathology of neurodegenerative diseases. It has been suggested that the loss of cell function results from the increased oxidative damage to proteins and DNA. Herein, we investigated the effect of a natural neuroprotective flavonoid, calycopterin, on H2O2-induced disruption of phase II detoxifying enzyme system and cAMP response element binding protein (CREB) phosphorylation. METHODS: PC12 cells were treated with 25, 50 and 100μM of calycopterin for 3h, followed by adding H2O2 (150μM) for 24h. The extent of apoptosis was assessed by comet assay. The level of phosphorylated CREB, nuclear factor erythroid 2-related factor 2 (Nrf2), glutamylcysteine synthetase (γ-GCS) and heme oxygenase 1 (HO-1) were measured by western blot method. The concentration of glutathione (GSH) was determined in whole cell lysate using dithionitrobenzoic acid method. Superoxide dismutase (SOD) activity was measured by colorimetric assay. RESULT: Morphological analysis of protection induced by calycopterin, determined by comet assay, showed that calycopterin reduced DNA in tail. We found that H2O2 decreased mitochondrial membrane potential (MMP), while, calycopterin prevented this decrease in MMP in presence of H2O2. In H2O2-treated cells, calycopterin also suppressed cytochrome C release to cytosol that is necessary for maintaining mitochondrial homeostasis in survived cells. Moreover, calycopterin, in presence of H2O2 inhibited the decrease caused by oxidative stress in stress-sensing transcription factors, CREB and Nrf2, which play an important role in antioxidant capacity of the cell. There was also an increase in γ-GCS and HO-1 levels in calycopterin pretreated cells. In the presence of H2O2, calycopterin inhibited decrease in GSH level and SOD activity. CONCLUSION: We provided documentation of neuroprotective effect of a natural flavone, calycopterin, against H2O2-induced oxidative stress in differentiated PC12 cells by modulating the level of CREB phosphorylation and Nrf2 pathway. 23404733 Increased immunoreactive 11-ketotestosterone concentrations in sheep feces after acth challenge. 11-Oxoetiocholanolone and related substances are important metabolites of cortisol and are excreted via feces in ruminants. To investigate whether 11-ketotestosterone (11-KT) or its immunoreactive metabolites are formed and excreted in ruminant feces, an enzyme immunoassay (EIA) was developed and validated. The antibody was raised in rabbits against 11-KT-3-CMO:bovine serum albumin with biotinylated 11-KT as a label. The assay showed a sensitivity of 0.3 pg/well. To validate the assay biologically, 6 rams were injected with a synthetic analogue of the adrenocorticotropic hormone (Synacthen, 2 µg/kg body wt). An aliquot was collected of each fecal portion spontaneously defecated 8 h before Synacthen injection to 24 h after injection and stored at -20 °C until analysis. Samples (0.5 g) were extracted using 80% methanol and immunoreactive metabolites measured using the 11-KT EIA and an already established 11,17-dioxoandrostane (11,17-DOA) EIA. High-performance liquid chromatography separation revealed no peak in the same elution position as authentic 11-KT; therefore, reacting substances were referred to as 11-KT equivalents. In the case of 11-KT immunoreactive substances, the values increased from baseline (median, 136 ng/g feces) to a peak concentration (median, 424 ng/g) 10 to 14 h after Synacthen injection and declined afterwards. Concentrations of 11,17-DOA showed the same pattern, but the values were 2 to 4 times higher. From this data, the authors conclude that 11-KT-like substances, specifically C19 O3 -androgens with a 17ß-hydroxy group, were present in the feces. These substances originate from the adrenals and are most likely cortisol metabolites. Environ Toxicol Chem 2013;32:1332-1336. © 2013 SETAC. 23400048 Electron attachment to the dipeptide dialanine: influence of methylation on site selective dissociation reactions. Gas phase dissociative electron attachment (DEA) measurements with methyl-dialanine, C(7)H(14)N(2)O(3), are performed in a crossed electron-molecular beam experiment at high energy resolution (∼120 meV). Anion efficiency yields as a function of the incident electron energy are obtained for the most abundant fragments up to electron energies of ∼15 eV. There is no evidence of molecular anion formation whereas the dehydrogenated closed shell anion (M-H)(-) is one of the most dominant reaction products. Quantum chemical calculations are performed to investigate the electron attachment process and to elucidate site selective bond cleavage in the (M-H)(-) DEA-channel. Previous DEA studies on dialanine have shown that (M-H)(-) formation proceeds through abstraction of a hydrogen atom from the carboxyl and amide groups, contributing to two distinct resonances at 0.81 and 1.17 eV, respectively [D. Gschliesser, V. Vizcaino, M. Probst, P. Scheier and S. Denifl, Chem.-Eur. J., 2012, 18, 4613-4619]. Here we show that by methylation of the carboxyl group, all (calculated) thresholds for H-loss from the different sites in the dialanine molecule are shifted up to a maximum of 1.4 eV. The lowest lying resonance observed experimentally for (M-H)(-) remains operative from the amide group at the electron energy of 2.4 eV due to the methylation. We further study methylation-induced effects on the unimolecular dissociation leading to a variety of negatively charged DEA products. 23602515 Trimming of damaged 3' overhangs of DNA double-strand breaks by the Metnase and Artemis endonucleases. Both Metnase and Artemis possess endonuclease activities that trim 3' overhangs of duplex DNA. To assess the potential of these enzymes for facilitating resolution of damaged ends during double-strand break rejoining, substrates bearing a variety of normal and structurally modified 3' overhangs were constructed, and treated either with Metnase or with Artemis plus DNA-dependent protein kinase (DNA-PK). Unlike Artemis, which trims long overhangs to 4-5 bases, cleavage by Metnase was more evenly distributed over the length of the overhang, but with significant sequence dependence. In many substrates, Metnase also induced marked cleavage in the double-stranded region within a few bases of the overhang. Like Artemis, Metnase efficiently trimmed overhangs terminated in 3'-phosphoglycolates (PGs), and in some cases the presence of 3'-PG stimulated cleavage and altered its specificity. The nonplanar base thymine glycol in a 3' overhang severely inhibited cleavage by Metnase in the vicinity of the modified base, while Artemis was less affected. Nevertheless, thymine glycol moieties could be removed by Metnase- or Artemis-mediated cleavage at sites farther from the terminus than the lesion itself. In in vitro end-joining systems based on human cell extracts, addition of Artemis, but not Metnase, effected robust trimming of an unligatable 3'-PG overhang, resulting in a dramatic stimulation of ligase IV- and XLF-dependent end joining. Thus, while both Metnase and Artemis are biochemically capable of resolving a variety of damaged DNA ends for the repair of complex double-strand breaks, Artemis appears to act more efficiently in the context of other nonhomologous end joining proteins. 23334349 Investigations of dipeptide structures containing pyrrolysine as N-terminal residues: a DFT study in gas and aqueous phase. A set of six dipeptides containing pyrrolysine invariably at their N-terminal positions is studied in gas and aqueous phase using a polarizable continuum model (PCM). The molecular geometries of the dipeptides are fully optimized at B3LYP/6-31++G(d,p) level of theory and a second derivative (frequency) analysis confirms that all the optimized geometries are true minima. The effects of solvation and identity of the varying C-terminal residue on the energetics, structural features of the peptide planes, values of the ψ and ϕ dihedrals, geometry around the α-carbon atoms and theoretically predicted vibrational spectra of the dipeptides are thoroughly analyzed. Solvation effects are found to modify the gas phase conformation of the dipeptides around ψ dihedrals while the identity of the varying C-terminal residue affect the values of ϕ, planarity of the peptide planes and geometry around the α-carbon atoms. The presence or absence of three types of intramolecular H-bonds, namely O...H-N, N...H-N and O...H-C that leave noticeable signatures in the IR spectra, play crucial roles in influencing the geometry of the peptide planes and in determining the energetics of the dipeptides. 23396053 Functional expression and regulation of drug transporters in monolayer- and sandwich-cultured mouse hepatocytes. Primary hepatocyte cultures are now considered as convenient models for in vitro analyzing liver drug transport. However, if primary human and rat hepatocytes have been well-characterized with respect to drug transporter expression and regulation, much less is known for primary mouse hepatocytes. The present study was therefore designed to gain insights about this point. The profile of sinusoidal and canalicular drug transporter mRNA expression in short time (4h)-cultured mouse hepatocytes was found to be highly correlated with that of freshly isolated hepatocytes; by contrast, those of counterparts cultured for a longer time (until 4days) either in monolayer configurations on plastic or collagen or in sandwich configuration with matrigel were profoundly altered: uptake drug transporters such as Oct1, Oatps and Oat2 were thus down-regulated, whereas most of efflux transporters such as Mdr1a/b, Mrp3, Mrp4 and Bcrp were induced. Moreover, short time-cultured hepatocytes exhibited the highest levels of sinusoidal influx transporter activities. Transporter-mediated drug secretion into canalicular networks was however only observed in sandwich-cultured hepatocytes. Mouse hepatocytes cultured either in monolayer or sandwich configurations were finally shown to exhibit up-regulation of referent transporters in response to exposure to prototypical activators of the drug sensing receptors pregnane X receptor, aryl hydrocarbon receptor or constitutive androstane receptor. Taken together, these data demonstrate the feasibility of using primary mouse hepatocytes for investigating potential interactions of xenobiotics with hepatic transporter activity or regulation, provided that adequate culture conditions are retained. 23454112 Tumor delivery of Photofrin® by PLL-g-PEG for photodynamic therapy. Photofrin® (porfimer sodium) is a photosensitive reagent used for photodynamic therapy (PDT) of tumors and dysplasias. Because only photo-irradiated sites are damaged, PDT is less invasive than systemic treatments. However, a photosensitive reaction is a major side effect of systemically delivered Photofrin. To enhance localization of Photofrin to tumors, we have formulated Photofrin with the tumor-localizing graft copolymer poly(ethylene glycol)-grafted poly(l-lysine), PLL-g-PEG. We demonstrate that Photofrin preferentially interacts with PLL-g-PEG through both ionic and hydrophobic interactions. The serum competitive study showed that the highly PEG-grafted PLL is better for preventing serum binding to the Photofrin/PLL-g-PEG complex. In tumor-bearing mice, formulation of Photofrin with PLL-g-PEG enhanced tumor localization of Photofrin as twice as Photofrin alone and concomitantly suppressed the photosensitivity reaction drastically. 23059813 Defective neural crest migration revealed by a Zebrafish model of Alx1-related frontonasal dysplasia. Frontonasal dysplasia (FND) refers to a class of midline facial malformations caused by abnormal development of the facial primordia. The term encompasses a spectrum of severities but characteristic features include combinations of ocular hypertelorism, malformations of the nose and forehead and clefting of the facial midline. Several recent studies have drawn attention to the importance of Alx homeobox transcription factors during craniofacial development. Most notably, loss of Alx1 has devastating consequences resulting in severe orofacial clefting and extreme microphthalmia. In contrast, mutations of Alx3 or Alx4 cause milder forms of FND. Whilst Alx1, Alx3 and Alx4 are all known to be expressed in the facial mesenchyme of vertebrate embryos, little is known about the function of these proteins during development. Here, we report the establishment of a zebrafish model of Alx-related FND. Morpholino knock-down of zebrafish alx1 expression causes a profound craniofacial phenotype including loss of the facial cartilages and defective ocular development. We demonstrate for the first time that Alx1 plays a crucial role in regulating the migration of cranial neural crest (CNC) cells into the frontonasal primordia. Abnormal neural crest migration is coincident with aberrant expression of foxd3 and sox10, two genes previously suggested to play key roles during neural crest development, including migration, differentiation and the maintenance of progenitor cells. This novel function is specific to Alx1, and likely explains the marked clinical severity of Alx1 mutation within the spectrum of Alx-related FND. 23487256 Heterogeneous OH oxidation of biomass burning organic aerosol surrogate compounds: assessment of volatilisation products and the role of OH concentration on the reactive uptake kinetics. The reactive uptake coefficients (γ) of OH by levoglucosan, abietic acid, and nitroguaiacol serving as surrogate compounds for biomass burning aerosol have been determined employing a chemical ionisation mass spectrometer coupled to a rotating-wall flow-tube reactor over a wide range of [OH] ∼10(7)-10(11) molecule cm(-3). Volatilisation products of these organic substrates due to heterogeneous oxidation by OH have been determined at 1 atm using a high resolution proton transfer reaction time-of-flight mass spectrometer (HR-PTR-ToF-MS). γ range within 0.05-1 for [OH] = 2.6 × 10(7)-3 × 10(9) molecule cm(-3) for all investigated organic compounds, but decrease to 0.008-0.034 for [OH] = 4.1 × 10(10)-6.7 × 10(10) molecule cm(-3). γ as a function of [OH] can be described by a Langmuir-Hinshelwood model, neglecting bulk processes, suggesting that despite its strong reactivity, OH is mobile on surfaces prior to reaction. The best fit Langmuir-Hinshelwood parameters on average are K(OH) = 3.81 × 10(-10) cm(3) molecule(-1) and k(s) = 9.71 × 10(-17) cm(2) molecule(-1) s(-1) for all of the investigated organic compounds. Volatilised products have been identified indicating enhancements over background of 50% up to a factor of 15. Amongst the common volatile organic compounds (VOCs) identified between levoglucosan, abietic acid, and nitroguaiacol were methanol, acetaldehyde, formic acid, and acetic acid. VOCs having the greatest enhancement over background were glucic acid from levoglucosan, glycolic acid from abietic acid, and methanol and nitric acid from nitroguaiacol. Reaction mechanisms leading to the formation of glucic acid, glycolic acid, methanol, and nitric acid are proposed. Estimated lower limits of atmospheric lifetimes of biomass burning aerosol particles, 200 nm in diameter, by heterogeneous OH oxidation under fresh biomass burning plume conditions are ∼2 days and up to ∼2 weeks for atmospheric background conditions. However, estimated lifetimes depend crucially on [OH] and corresponding γ, emphasising the need to determine γ under relevant conditions. 22364642 Serratin a new metabolite obtained from Serratia marcescens, a bacterium isolated from the microflora associated with banana plantations. When cultures of Serratia marcescens, an enterobacteria isolated from the microflora associated with banana plantations incubated at 27°C in a yeast-calcium carbonate-dextrose solid medium (10 g of yeast extract, 20 g dextrose, 15 g bacteriological agar, 20 g calcium carbonate and 1000 mL distilled water) were extracted with chloroform and purified by column chromatography, we obtained a new colourless bacterial metabolite which according to spectroscopic data proved to be serratin. 23320893 What is the contact angle of water on graphene? Although experimental and theoretical studies have addressed the question of the wetting properties of graphene, the actual value of the contact angle of water on an isolated graphene monolayer remains unknown. While recent experimental literature indicates that the contact angle of water on graphite is in the range 90-95°, it has been suggested that the contact angle on graphene may either be as high as 127° or moderately enhanced in comparison with graphite. With the support of classical molecular dynamics simulations using empirical force-fields, we develop an argumentation to show that the value of 127° is an unrealistic estimate and that a value of the order of 95-100° should be expected. Our study establishes a connection between the variation of the work of adhesion of water on graphene-based surfaces and the interaction potential between individual water molecules and these surfaces. We show that a variation of the contact angle from 90° on graphite to 127° on graphene would imply that both of the first two carbon layers of graphite contribute approximately the same interaction energy with water. Such a situation is incompatible with the short-range nature of the interaction between water and this substrate. We also show that the interaction potential energy between water and the graphene-based substrates is the main contribution to the work of adhesion of water with a relative magnitude that is independent of the number of graphene layers. We introduce the idea that the remaining contribution is entropic in nature and is connected to the fluctuations in the water-substrate interaction energy. 23481651 Demonstration of a sucrose-derived contrast agent for magnetic resonance imaging of the GI tract. A scaffold bearing eight terminal alkyne groups was synthesized from sucrose, and copies of an azide-terminated Gd-DOTA complex were attached via copper(I)-catalyzed azide-alkyne cycloaddition. The resulting contrast agent (CA) was administered by gavage to C3H mice. Passage of the CA through the gastrointestinal (GI) tract was followed by T1-weighted magnetic resonance imaging (MRI) over a period of 47h, by which time the CA had exited the GI tract. No evidence for leakage of the CA from the GI tract was observed. Thus, a new, orally administered CA for MRI of the GI tract has been developed and successfully demonstrated. 22899102 Multidrug resistance-associated proteins are involved in the transport of the glutathione conjugates of the ultimate carcinogen of benzo[a]pyrene in human Caco-2 cells. A wide variety of contaminants are ingested through food, among them the pro-carcinogenic polycyclic aromatic hydrocarbon benzo[a]pyrene (BP) that is resorbed and partially metabolized in the enterocytes of the small intestine. Previous in vitro studies have revealed that BP phenols are excreted as Phase II metabolites including glucuronides and sulfates. This export is mediated by the breast cancer resistance protein (ABCG2). The ultimate carcinogenic Phase I BP metabolite anti-BP-7,8-dihydrodiol-9,10-epoxide (BPDE) can be detoxified by glutathione conjugate formation catalyzed by glutathione S-transferases. In the present study, differentiated human intestinal Caco-2 cells were used as a model for the human small intestine to investigate the detoxification of BPDE and excretion of stereoisomeric glutathione conjugates in the presence of an inhibitor of the glutathione-cleaving enzyme γ-glutamyl transpeptidase at the cell surface. The results indicate that the glutathione conjugates of BPDE are formed and excreted mainly to the apical and to a minor extent to the basolateral side of polarized Caco-2 monolayers. Inhibition studies revealed that the multidrug resistance-associated proteins (ABCCs) are involved in the transport of BPDE glutathione conjugates. Stable ABCC1, ABCC2 and ABCC3 knockdown cell lines were generated, thus making it possible to demonstrate that ABCC1 mediates the basolateral and ABCC2 the apical excretion of BPDE glutathione conjugates. In conclusion, the ultimate carcinogen BPDE is detoxified via glutathione conjugation and subsequently excreted by Caco-2 cells in both apical and basolateral directions. This finding is equivalent to a transport into feces as well as blood system in the in vivo situation. 23402862 Biological clues to potent DNA-damaging activities in food and flavoring. Population differences in age-related diseases and cancer could stem from differences in diet. To characterize DNA strand-breaking activities in selected foods/beverages, flavorings, and some of their constituent chemicals, we used p53R cells, a cellular assay sensitive to such breaks. Substances testing positive included reference chemicals: quinacrine (peak response, 51×) and etoposide (33×); flavonoids: EGCG (19×), curcumin (12×), apigenin (9×), and quercetin (7×); beverages: chamomile (11×), green (21×), and black tea (26×) and coffee (3-29×); and liquid smoke (4-28×). Damage occurred at dietary concentrations: etoposide near 5μg/ml produced responses similar to a 1:1000 dilution of liquid smoke, a 1:20 dilution of coffee, and a 1:5 dilution of tea. Pyrogallol-related chemicals and tannins are present in dietary sources and individually produced strong activity: pyrogallol (30×), 3-methoxycatechol (25×), gallic acid (21×), and 1,2,4-benzenetriol (21×). From structure-activity relationships, high activities depended on specific orientations of hydroxyls on the benzene ring. Responses accompanied cellular signals characteristic of DNA breaks such as H2AX phosphorylation. Breaks were also directly detected by comet assay. Cellular toxicological effects of foods and flavorings could guide epidemiologic and experimental studies of potential disease risks from DNA strand-breaking chemicals in diets. 23247407 Observation of direct vibrational excitation in gas-surface collisions of CO with Au(111): a new model system for surface dynamics. We report vibrational excitation of CO from its ground (v = 0) to first excited (v = 1) vibrational state in collision with Au(111) at an incidence energy of translation of E(I) = 0.45 eV. Unlike past work, we can exclude an excitation mechanism involving temporary adsorption on the surface followed by thermalization and desorption. The angular distributions of the scattered CO molecules are narrow, consistent with direct scattering occurring on a sub-ps time scale. The absolute excitation probabilities are about 3% of those expected from thermal accommodation. The surface temperature dependence of excitation, which was measured between 373 and 973 K, is Arrhenius-like with an activation energy equal to the energy required for vibrational excitation. Our measurements are consistent with a vibrational excitation mechanism involving coupling of thermally excited electron-hole pairs of the solid to CO vibration. 23059509 Metal distribution in tissues of free-range chickens near a lead-zinc mine in Kabwe, Zambia. Concentrations of Pb, Cd, and other metals in tissues of 17 free-range and 32 commercial broiler chickens from the Kabwe mining town in Zambia were determined. Mean concentrations of Pb and Cd exceeded maximum levels for human consumption in some organs including muscle (Pb only) in free-range chickens, in contrast to low levels in broiler chickens. Human consumers in Kabwe could be exposed to Pb and Cd in free-range chickens. 23479392 New Concepts, Experimental Approaches, and Dereplication Strategies for the Discovery of Novel Phytoestrogens from Natural Sources. Phytoestrogens constitute an attractive research topic due to their estrogenic profile and their biological involvement in woman's health. Therefore, numerous studies are currently performed in natural products chemistry area aiming at the discovery of novel phytoestrogens. The main classes of phytoestrogens are flavonoids (flavonols, flavanones), isoflavonoids (isoflavones, coumestans), lignans, stilbenoids as well as miscellaneous chemical groups abundant in several edible and/or medicinal plants, belonging mostly to the Leguminosae family. As for other bioactives, the detection of new structures and more potent plant-derived phytoestrogens typically follows the general approaches currently available in the natural product discovery process. Plant-based approaches selected from traditional medicine knowledge and bioguided concepts are routinely employed. However, these approaches are associated with serious disadvantages such as time-consuming, repeated, and labor intensive processes as well as lack of specificity and reproducibility. In recent years, the natural products chemistry became more technology-driven, and several different strategies have been developed. Structure-oriented procedures and miniaturized approaches employing advanced hyphenated analytical platforms have recently emerged. They facilitate significantly not only the discovery of novel phytoestrogens but also the dereplication procedure leading to the anticipation of major drawbacks in natural products discovery. In this review, apart from the traditional concepts followed in phytochemistry for the discovery of novel biologically active compounds, recent applications in the field of extraction, analysis, fractionation, and identification of phytoestrogens will be discussed. Moreover, specific methodologies combining identification of actives and biological evaluation in parallel, such as liquid chromatography-biochemical detection, frontal affinity chromatography-mass spectrometry and pulsed ultrafiltration-MS will also be presented. Finally, miniaturized methods (microchip and biosensor) will be also discussed.With the current review, we attempt to give a wide and holistic overview of the different approaches which could be employed in the discovery of new phytoestrogens. On the other hand, we anticipate to attract more scientists to the area of phytoestrogens and to indicate the need of multidisciplinary concepts. 23274570 Synthesis of spirolactone-type diterpenoid derivatives from kaurene-type oridonin with improved antiproliferative effects and their apoptosis-inducing activity in human hepatoma Bel-7402 cells. A series of novel spirolactone-type diterpenoid derivatives of oridonin (12a-j) were designed and synthesized. All the target compounds showed improved anti-proliferative activity against a panel of human cancer cell lines and the most effective compound 12j was more potent than positive control Taxol in K562 and Bel-7402 cells with IC(50) values of 0.39 μM and 1.39 μM, respectively. The cellular mechanisms showed that compound 12j induced apoptosis at low micromolar concentrations in human hepatoma Bel-7402 cells. These results demonstrate that the spirolactone-type diterpenoid derivatives of oridonin have optimized growth inhibitory activity against cancer cells and interesting apoptosis-inducing ability. 23558237 A novel series of histamine H4 receptor antagonists based on the pyrido[3,2-d]pyrimidine scaffold: Comparison of hERG binding and target residence time with PF-3893787. In this work we describe the optimization of a lead compound based on the quinazoline template to give a new series of potent pyrido[3,2-d]pyrimidines as histamine H4 receptor antagonists. The pyrido[3,2-d]pyrimidine ligands have significantly reduced hERG binding compared to clinical stage compound PF-3893787 while showing good affinities at the human and rodent histamine receptors. The receptor residence time of several of these new compounds was determined for the human H4R and compared with JNJ7777120 and PF-3893787. The pyrido[3,2-d]pyrimidines showed residence times lower than JNJ7777120 but comparable to the residence time of PF-3893787. Overall, the pyrido[3,2-d]pyrimidines show an excellent in vitro profile that warrants their further investigation in relevant models of human disease. 23470217 Optimizing Small Molecule Inhibitors of Calcium-Dependent Protein Kinase 1 to Prevent Infection by Toxoplasma gondii. Toxoplasma gondii is sensitive to bulky pyrazolo [3,4-d] pyrimidine (PP) inhibitors due to the presence of a Gly gatekeeper in the essential calcium dependent protein kinase 1 (CDPK1). Here we synthesized a number of new derivatives of 3-methyl-benzyl-PP (3-MB-PP, or 1). The potency of PP analogues in inhibiting CDPK1 enzyme activity in vitro (low nM IC50 values) and blocking parasite growth in host cell monolayers in vivo (low μM EC50 values) were highly correlated and occurred in a CDPK1-specific manner. Chemical modification of the PP scaffold to increase half-life in the presence of microsomes in vitro led to identification of compounds with enhanced stability while retaining activity. Several of these more potent compounds were able to prevent lethal infection with T. gondii in the mouse model. Collectively, the strategies outlined here provide a route for development of more effective compounds for treatment of toxoplasmosis and perhaps related parasitic diseases. 22690834 Solid lipid nanoparticles and nanosuspension of adefovir dipivoxil for bioavailability improvement: formulation, characterization, pharmacokinetic and biodistribution studies. The present study was aimed at developing colloidal formulations like solid lipid nanoparticles (SLN) and nanosuspension (NS) for improving bioavailability of adefovir dipivoxil (AD), a nucleoside reverse transcriptase inhibitor which displays poor oral bioavailability. SLNs were prepared by solvent injection method while NS was prepared by pearl milling method. The prepared formulations were characterized for physicochemical parameters such as particle size, ζ potential, drug content, X-ray Diffraction (XRD), Differential Scanning Calorimetry (DSC). Pharmacokinetic and biodistribution studies were performed in mice to evaluate in vivo fate of the formulations. The SLNs showed particle size of 267 ± 18 nm and entrapment efficiency of 73.5 ± 2.12%. The particle size obtained for NS was 393 ± 13 nm against 710 ± 70 μm for bulk drug, which led to significant improvement in saturation solubility. DSC and XRD studies of NS and SLN showed reduction in crystallinity while in vitro studies showed improved dissolution rate in both cases. Pharmacokinetics studies of orally administered formulations in mice exhibited higher plasma concentration compared to plain drug. Biodistribution studies showed higher accumulation of drug in liver, kidneys, intestine and stomach. The higher concentration of AD in liver after 24 hr highlights its potential advantage for effective treatment of chronic hepatitis infection. The relative bioavailability for adefovir NS and SLN were 52.46% and 78.23% respectively compared to 34.34% bioavailability obtained after administration of adefovir micro suspension (AMS), indicating suitability of both nanoparticulate formulations for improving bioavailability. SLNs were found to performed better as compared to NS for improving the bioavailability of AD. 23260346 Selective inhibitors and tailored activity probes for lipoprotein-associated phospholipase A(2). Lipoprotein-associated phospholipase A(2) (Lp-PLA(2) or PLA(2)G7) binds to low-density lipoprotein (LDL) particles, where it is thought to hydrolyze oxidatively truncated phospholipids. Lp-PLA(2) has also been implicated as a pro-tumorigenic enzyme in human prostate cancer. Several inhibitors of Lp-PLA(2) have been described, including darapladib, which is currently in phase 3 clinical development for the treatment of atherosclerosis. The selectivity that darapladib and other Lp-PLA(2) inhibitors display across the larger serine hydrolase family has not, however, been reported. Here, we describe the use of both general and tailored activity-based probes for profiling Lp-PLA(2) and inhibitors of this enzyme in native biological systems. We show that both darapladib and a novel class of structurally distinct carbamate inhibitors inactivate Lp-PLA(2) in mouse tissues and human cell lines with high selectivity. Our findings thus identify both inhibitors and chemoproteomic probes that are suitable for investigating Lp-PLA(2) function in biological systems. 23583736 Skin penetration enhancing properties of the plant N-alkylamide spilanthol. ETHNOPHARMACOLOGICAL RELEVANCE: Plants are often used for skin diseases in different ethnopharmacological systems. Local and systemic effects of topically applied compounds can be significantly increased by plant constituents having skin penetration enhancers. MATERIALS AND METHODS: In this study, we examined the proposed penetration enhancing properties of spilanthol, an N-alkylamide abundantly present in several Asteraceae plants like Spilanthes acmella L., on three model drugs (caffeine, testosterone and ibuprofen). Moreover, as plants are frequently contaminated with toxic environmental substances, the mutual influence on the transdermal behavior between spilanthol and six model mycotoxins (aflatoxin B1, ochratoxin A, fumonisin B1, citrinin, zearalenone, T-2 toxin) was investigated. RESULTS: Spilanthol exhibits component and concentration dependent penetration enhancing effects. No significant penetration enhancing effect for ibuprofen has been observed, but with increasing spilanthol concentration (from 0 up to 1w/V%), the permeability of caffeine increased, resulting in an enhancing ratio (ER) of 4.60. For testosterone, a maximal penetration enhancing concentration of 0.5% spilanthol was found (ER=4.13). Next to its beneficial applicability to increase local as well as systemic pharmacological effects of dermally co-administrated drug, this N-alkylamide negatively influences human health risk if spilanthol containing formulations are polluted with mycotoxins: the presence of spilanthol (0.3w/V%) induced a significant increase of permeability coefficient Kp of five investigated mycotoxins, with ER values ranging between 1.57 and 6.37. On the other hand, mycotoxins themselves do not significantly influence the transdermal behavior of spilanthol. CONCLUSIONS: The existence of a significant mutual influence of compounds towards skin penetration should always be considered during the development or as part of the functional quality evaluation of topical products. 22708657 A new caryolane sesquiterpene from Heteropappus altaicus (Willd.) Novopokr. A new caryolane sesquiterpene, 1β-methoxycaryol-9-one (1), along with eight known compounds (2-9), was isolated from the whole plant of Heteropappus altaicus. The structures were elucidated on the basis of comprehensive 1D- and 2D-NMR analysis and high-resolution mass spectrometry. The 13C-NMR data of compound 2 are reported for the first time. 23330557 Managing scientific, technical and regulatory innovation in regulated bioanalysis: a discussion paper from the European Bioanalysis Forum. On 12-13 June 2012, the European Bioanalysis Forum hosted its third Focus Meeting in Brussels (Belgium). At the meeting, a panel discussion was held on the hurdles that the bioanalytical community encounters when adopting new technologies or managing regulated bioanalysis expectations around emerging technologies. Over the last few years, the industry has seen many new technologies maturing. As they became available, the bioanalytical scientist has observed that implementing these technologies in the regulated environment has become increasingly challenging. For one, scientific developments and regulatory expectations may not go hand in hand. At the same time, the pharmaceutical industry has become increasingly risk averse in their response to these real or perceived higher expectations in regulated bioanalysis. As a downstream consequence, the potential result of overinterpretation of guidance or occasional widespread and premature implementation of responses to health authority inspections, industry may be contributing significantly to raising the bar on some processes related to day-to-day practices in the bioanalytical laboratory. Last but not least, with the community being satisfied with the performance of the current tools, potential complacency can be observed in the regulated bioanalytical community because existing technologies, such as LC-MS/MS and ligand-binding assays, have served and still are serving them extremely well. Hence, the question 'what's next after LC-MS/MS or ELISA?' is not resonating with many scientists as pertinently compared with 'What's next after RIA, GC or LC-UV?', which was the key question in the 1990s, certainly in the context of an increasing effort needed to validate these new tools. With this article, the European Bioanalysis Forum aims to stimulate an open dialogue between all stakeholders in regulated bioanalysis to positively influence how we balance science, process and regulations in day-to-day work. This discussion should facilitate the evaluation and the subsequent implementation of innovative techniques for the benefit of the patient, while stimulating our community to raise the bar on added-value science, but at the same time removing the bar on processes with limited or no added value. 23041232 Targeting peroxisome proliferator-activated receptor-β/δ in colon cancer: how to aim? Peroxisome proliferator-activated receptor-β/δ (PPARδ) is a ubiquitously expressed, ligand-activated transcriptional factor that performs diverse critical functions in normal cells (e.g., fatty acid metabolism, obesity, apoptosis, and inflammation). Various studies in humans have found that PPARδ is upregulated in primary colorectal cancers; however, these findings have been challenged by those of other reports. Similarly, various in vitro and in vivo mechanistic pre-clinical models have yielded data demonstrating that PPARδ promotes colonic tumorigenesis, but other models have yielded data that contradicts this notion. Definitive studies are therefore needed to establish the exact role of PPARδ in human colorectal tumorigenesis and to provide a theoretical basis for PPARδ therapeutic targeting. 23644203 Ligand-based design, synthesis, and experimental evaluation of novel benzofuroxan derivatives as anti-Trypanosoma cruzi agents. A set of substituted-[N'-(benzofuroxan-5-yl)methylene]benzohydrazides (4a-t), previously designed and synthesized, was experimentally assayed against Trypanosoma cruzi, the etiological agent of Chagas' disease, one of the most neglected tropical diseases. Exploratory data analysis, Hansch approach and VolSurf formalism were applied to aid the ligand-based design of novel anti-T. cruzi agents. The best 2D-QSAR model showed suitable statistical measures [n = 18; s = 0.11; F = 42.19; R(2) = 0.90 and Q(2) = 0.77 (SDEP = 0.15)], and according to the optimum 3D-QSAR model [R(2) = 0.98, Q(2) = 0.93 (SDEP = 0.08)], three latent variables explained 62% of the total variance from original data. Steric and hydrophobic properties were pointed out as the key for biological activity. Based upon the findings, six novel benzofuroxan derivatives (4u-z) were designed, synthesized, and in vitro assayed to perform the QSAR external prediction. Then, the predictability for the both models, 2D-QSAR (Rpred(2) = 0.91) and 3D-QSAR (Rpred(2) = 0.77), was experimentally validated, and compound 4u was identified as the most active anti-T. cruzi hit (IC50 = 3.04 μM). 23152189 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated production of reactive oxygen species is an essential step in the mechanism of action to accelerate human keratinocyte differentiation. Chloracne is commonly observed in humans exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); yet, the mechanism of toxicity is not well understood. Using normal human epidermal keratinocytes, we investigated the mechanism of TCDD-mediated enhancement of epidermal differentiation by integrating functional genomic, metabolomic, and biochemical analyses. TCDD increased the expression of 40% of the genes of the epidermal differentiation complex found on chromosome 1q21 and 75% of the genes required for de novo ceramide biosynthesis. Lipid analysis demonstrated that eight of the nine classes of ceramides were increased by TCDD, altering the ratio of ceramides to free fatty acids. TCDD decreased the expression of the glucose transporter, SLC2A1, and most of the glycolytic transcripts, followed by decreases in glycolytic intermediates, including pyruvate. NADH and Krebs cycle intermediates were decreased, whereas NAD(+) was increased. Mitochondrial glutathione (GSH) reductase activity and the GSH/glutathione disulfide ratio were decreased by TCDD, ultimately leading to mitochondrial dysfunction, characterized by decreased inner mitochondrial membrane potential and ATP production, and increased production of the reactive oxygen species (ROS), hydrogen peroxide. Aryl hydrocarbon receptor (AHR) antagonists blocked the response of many transcripts to TCDD, and the endpoints of decreased ATP production and differentiation, suggesting regulation by the AHR. Cotreatment of cells with chemical antioxidants or the enzyme catalase blocked the TCDD-mediated acceleration of keratinocyte cornified envelope formation, an endpoint of terminal differentiation. Thus, TCDD-mediated ROS production is a critical step in the mechanism of this chemical to accelerate keratinocyte differentiation. 22564439 mGlu3 receptor and astrocytes: partners in neuroprotection. Astrocytes are currently studied intensively because of their now highlighted relevance as key players with neurons that modulate a wide range of central functions, from synaptic plasticity and synaptogenesis to regulation of metabolic and neuroinflammatory processes. Since the discovery of mGlu3 receptors on astrocytes, accumulating evidence supports a role of these receptors not only in maintaining synaptic homeostasis and treating psychiatric disorders but also in promoting astrocyte survival in several pathologic conditions. This review focuses on providing up-to-date knowledge regarding effects of activating astroglial mGlu3 receptors on psychiatric disorders, astrocyte and neuronal survival, and neurodegenerative diseases. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23586757 Quinoline Drug-Heme Interactions and Implications for Antimalarial Cytostatic versus Cytocidal Activities. Historically, the most successful molecular target for antimalarial drugs has been heme biomineralization within the malarial parasite digestive vacuole. Heme released from catabolized host red blood cell hemoglobin is toxic, so malarial parasites crystallize heme to nontoxic hemozoin. For years it has been accepted that a number of effective quinoline antimalarial drugs (e.g., chloroquine, quinine, amodiaquine) function by preventing hemozoin crystallization. However, recent studies over the past decade have revealed a surprising molecular diversity in quinoline-heme molecular interactions. This diversity shows that even closely related quinoline drugs may have quite different molecular pharmacology. This paper reviews the molecular diversity and highlights important implications for understanding quinoline antimalarial drug resistance and for future drug design. 23503702 Alcohol dependent patients have weak negative rather than strong positive implicit alcohol associations. RATIONALE: Alcohol dependence is characterised by motivational conflict (or ambivalence) in controlled cognitive processes, but it is unclear if ambivalence also exists within automatic cognitive processes, and if ambivalence operates between controlled and automatic processes. OBJECTIVE: To investigate ambivalence operating within and between controlled and automatic processes in alcohol dependence. METHOD: Alcohol-dependent patients who had recently completed inpatient alcohol detoxification (N = 47) and social drinking controls (N = 40) completed unipolar implicit association tests and self-report measures of alcohol approach and avoidance motivation and alcohol outcome expectancies. RESULTS: As predicted, both positive and negative alcohol outcome expectancies were stronger in alcohol-dependent patients compared to controls, indicative of ambivalence. Groups did not differ on implicit alcohol-positive associations, but alcohol-dependent participants had significantly weaker alcohol-negative associations than controls. Regression analyses revealed that implicit negative associations accounted for unique variance in group membership after controlling for alcohol outcome expectancies. CONCLUSIONS: Our findings demonstrate that alcohol dependent patients possess weak automatic alcohol-negative associations but not strong automatic alcohol-positive associations, and they suggest the presence of conflict between controlled and automatic processes with regard to negative alcohol cognitions. 23543632 Design, synthesis, in vitro cytotoxicity evaluation and structure-activity relationship of Goniothalamin analogs. A series of six/five member (E/Z)-Goniothalamin analogs were synthesized from commercially available (3,4-dihydro-2H-pyran-2-yl)methanol/5-(hydroxymethyl)dihydrofuran-2(3H)-one in three steps with good to moderate overall yields and their cytotoxicity against lymphoblastic leukemic T cell line (Jurkat E6.1) have been evaluated. Among the synthesized analogs, (Z)-Goniothalamin appeared to be the most active in cytotoxicity (IC50 = 12 μM). Structure-activity relationship study indicates that introducing substituent in phenyl ring or replacing phenyl ring by pyridine/naphthalene, or decreasing the ring size of lactones (from six to five member) do not increase the cytotoxicity. 23265464 Development of a rapid and simple voltammetric method to determine total antioxidative capacity of edible oils. In this work we report on a new, rapid and simple voltammetric method to determine the total antioxidant capacity (TAC) of the edible oils. The method explores the ABTS radical (2,2'-azinobis(3-ethylbenzothiazoline-6-sulphonic acid)) assay as a redox probe and it relays on measuring catalytic voltammetric currents. The electrocatalysis comprises redox regeneration of the electrochemically created ABTS(+) radical either by Trolox (6-hydroxy-2,5,7,8-tetramethychroman-2-carboxylic acid) or by antioxidants present in studied oils. The detection limit of the method is determined to be 0.5 mg/L of Trolox equivalent, being a slightly lower than the corresponding UV-VIS spectrophotometric method. Applying the proposed voltammetric method the total antioxidant capacity of three types of commercially available cold-pressed edible oils are determined, and the results are found to be in a very good agreement with those obtained by UV-VIS spectrophotometry. The reported voltammetric method is cheap, rapid and simple, and it can be used as a sustainable alternative to the UV-VIS methods for the determination of total antioxidant capacitance of oils and other liquid lipophilic nutrients. Potent antioxidant capacity of studied oils was also confirmed by electron paramagnetic resonance spectroscopy of superoxide anion produced by macrophages. 23435158 Reduced Heart Rate Variability Is Associated With Increased Arterial Stiffness in Youth With Type 1 Diabetes: The SEARCH Cardiovascular Disease Study. OBJECTIVEReduced heart rate variability (HRV) and increased arterial stiffness (AS) are both present in youth with type 1 diabetes. However, it is unclear whether they are associated and whether their association is independent of cardiovascular disease (CVD) risk factors.RESEARCH DESIGN AND METHODSThe SEARCH Cardiovascular Disease Study explored the cross-sectional relationships between HRV and several measures of AS in youth with (n = 344) and without (n = 171) type 1 diabetes. The SphygmoCor device (AtCor Medical, Sydney, Australia) was used to measure HRV using SD of normal R-R interval (SDNN), as well as AS, using pulse wave velocity in the carotid to femoral segment (PWV-trunk) and augmentation index adjusted to a heart rate of 75 bpm (AIx75). Brachial distensibility (BrachD), another index of AS, was measured with a DynaPulse instrument (Pulse Metric, San Diego, CA). Multiple linear regression analyses explored the associations between HRV and each of the three AS measures, after adjusting for demographic characteristics and traditional CVD risk factors (blood pressure, lipids, obesity, microalbuminuria, and smoking) separately, for youth with and without type 1 diabetes.RESULTSAmong youth with type 1 diabetes, lower SDNN was associated with peripheral AS (lower BrachD, P = 0.01; r(2) = 0.30) and central AS (higher PVW-trunk, P < 0.0001; r(2) = 0.37; and higher AIx75, P = 0.007; r(2) = 0.08). These associations were attenuated with adjustment for CVD risk factors, but remained statistically significant for BrachD and PWV-trunk. While a similar association between HRV and BrachD was present in control youth, lower HRV was not associated with increased central AS or with AIx75.CONCLUSIONSLongitudinal studies are needed to understand the pathways responsible for these associations. 23364814 Cocoa polyphenols enhance positive mood states but not cognitive performance: a randomized, placebo-controlled trial. This study aimed to examine the acute and sub-chronic effects of cocoa polyphenols on cognition and mood. In a randomized, double-blind study, healthy middle-aged participants received a dark chocolate drink mix standardized to contain 500 mg, 250 mg or 0 mg of polyphenols (placebo) in a parallel-groups design. Participants consumed their assigned treatment once daily for 30 days. Cognition was measured with the Cognitive Drug Research system and self-rated mood with the Bond-Lader Visual Analogue Scale. Participants were tested at baseline, at 1, 2.5 and 4 h after a single acute dose and again after receiving 30 days of treatment. In total, 72 participants completed the trial. After 30 days, the high dose of treatment significantly increased self-rated calmness and contentedness relative to placebo. Mood was unchanged by treatment acutely while cognition was unaffected by treatment at all time points. This randomized controlled trial is perhaps the first to demonstrate the positive effects of cocoa polyphenols on mood in healthy participants. This provides a rationale for exploring whether cocoa polyphenols can ameliorate the symptoms associated with clinical anxiety or depression. 23530006 Universal rule on chirality-dependent bandgaps in graphene antidot lattices. Graphene with periodically patterned antidots has attracted intense research attention as it represents a facile route to open a bandgap for graphene electronics. However, not all graphene antidot lattices (GALs) can open a bandgap and a guiding rule is missing. Here, through systematic first-principles calculations, it is found that bandgaps in triangular GALs are surprisingly well defined by a chirality vector R = n a1 + ma2 connecting two neighboring antidots, where a1 and a2 are the basis vectors of graphene. The bandgap opens in the GALs with (n-m)mod3 = 0 but remains closed in those with (n-m)mod3 = ±1, reminiscent of the gap-chirality rule in carbon nanotubes. Remarkably, the gap value in GALs allows ample modulation by adjusting the length of chirality vectors, shape and size of the antidots. The gap-chirality relation in GALs stems from the chirality-dependent atomic structures of GALs as revealed by a super-atom model as well as Clar sextet analyses. This chirality-dependent bandgap is further shown to be a generic behavior in any parallelogram GAL and thus serves as an essential stepping stone for experimenters to realize graphene devices by antidot engineering. 23438888 Rare-variant genome-wide association studies: a new frontier in genetic analysis of complex traits. Genome-wide association studies have, in the last few years, identified thousands of common genetic variants associated with common complex traits and diseases, implicating many genes not previously known to be involved in the biology of those traits. However, these variants have so far explained little of the population variance in trait values or disease susceptibility. As large-scale genome sequencing efforts have revealed the extent of genetic variation at the low end of the frequency range in human populations, the effects of rare variants have been proposed as an explanation of the 'missing genetic variance.' Improved technologies for genotyping rare variants, including inexpensive whole-genome and whole-exome sequencing and rare-variant genotyping chips, coupled with novel analytical methods, are making genome-wide scans for the effects of rare variants possible, and seem likely to usher in a new era in the genetic analysis of complex traits. 23539147 The Relationship Between Serum Calcium Level, Blood Lipids, and Blood Pressure in Hypertensive and Normotensive Subjects who Come from a Normal University in East of China. Previous studies revealed that low calcium intake is related to high prevalence of cardiovascular diseases such as hypertension. However, the relationship between serum calcium and blood pressure was unclear. The prevalence of hypertension is high in China. Thus, the aim of this study was to evaluate the serum calcium level between hypertensive and normotensive groups and to investigate the correlation between serum calcium, blood pressure, and blood lipid parameters. A total of 1,135 adult subjects participated in this study and were divide into two study groups: a hypertensive group (n = 316) who had 140 mmHg or higher in systolic blood pressure (SBP) or 90 mmHg or higher in diastolic blood pressure (DBP) and an age- and sex-matched normotensive group (n = 819, 120 mmHg or less SBP and 80 mmHg or less DBP). Our results indicate a significant trend for men (60 years old or older) in the direction of decreasing blood pressure with increasing serum calcium level, but no trend for women was indicated. In the normotensive group, a significant positive correlation was found between DBP and total cholesterol (P < 0.01) and triglyceride (P < 0.01), Likewise, triglyceride was positively correlated with SBP (P < 0.01). Overall, these data suggest that serum calcium may have an influence in the blood pressure of older male subjects with hypertension and in blood lipid profiles of normotensive subjects. 23228472 Multiple microRNAs may regulate the DNA repair enzyme uracil-DNA glycosylase. Human nuclear uracil-DNA glycosylase UNG2 is essential for post-replicative repair of uracil in DNA, and UNG2 protein and mRNA levels rapidly decline in G2/M phase. Previous work has demonstrated regulation of UNG2 at the transcriptional level, as well as by protein phosphorylation and ubiquitylation. UNG2 mRNA, encoded by the UNG gene, contains a long 3'untranslated region (3'UTR) of previously unknown function. Here, we demonstrate that several conserved regions in the 3'UTR are potential seed sites for microRNAs (miRNAs), such as miR-16, miR-34c, and miR-199a. Our results show that these miRNAs down-regulate UNG activity, UNG mRNA, and UNG protein levels. Down-regulation was dependent on the 3'UTR, indicating that the miRNAs directly target the conserved seed sites in the 3'UTR. These results add miRNAs as a new modality to UNG's increasing list of complex regulatory mechanisms. 23249300 Interplay between structure and relaxations in perfluorosulfonic acid proton conducting membranes. This study focuses on changes in the structure of ionomer membranes, provided by the 3M Fuel Cells Component Group, as a function of the equivalent weight (EW) and the relationship between the structure and the properties of the membrane. Wide-angle X-ray diffraction results showed evidence of both non-crystalline and crystalline ordered hydrophobic regions in all the EW membranes except the 700 EW membrane. The spectral changes evident in the vibrational spectra of the 3M membranes can be associated with two major phenomena: (1) dissociation of the proton from the sulfonic acid groups even in the presence of small amounts of water; and (2) changes in the conformation or the degree of crystallinity of the poly(tetrafluoroethylene) hydrophobic domains both as a function of EW and membrane water content. All the membranes, regardless of EW, are thermally stable up to 360 °C. The wet membranes have conductivities between 7 and 20 mS/cm at 125 °C. In this condition, the conductivity values follow VTF behavior, which suggests that the proton migration occurs via proton exchange processes between delocalization bodies (DBs) that are facilitated by the dynamics of the host polymer. The conductivity along the interface between the hydrophobic and hydrophilic domains makes a larger contribution in the smaller EW membranes likely due to the existence of a greater number of interfaces in the membrane. The larger crystalline domains present in the higher EW membranes provide percolation pathways for charge migration between DBs, which reduces the probability of charge transfer along the interface. Therefore, at higher EWs although there is charge migration along the interface within the hydrophobic-hydrophilic domains, the exchange of protons between different DBs is likely the rate-limiting step of the overall conduction process. 23474807 Impact of the virus purification protocol on aggregation and electrokinetics of MS2 phages and corresponding virus-like particles. Previous experimental and theoretical studies have established that electrokinetic and aggregation properties of soft MS2 phages are not only governed by the physico-chemical features of their proteinaceous outer surface but are also significantly impacted by those of their inner RNA component (Dika et al. Appl. Environ. Microbiol., 2011, 14, 4939-4948). These conclusions contradict the recent findings of Nguyen et al. (Soft Matter, 2011, 7, 10449-10456) who reported identical electrokinetic and aggregation characteristics for MS2 and corresponding virus like particles (VLPs) that lack the internal RNA component. We demonstrate here that this contradiction originates from the different purification methods adopted prior to measurements. More generally, we show that stability and electrohydrodynamics of viruses differ according to purification by (i) dialysis, (ii) isopycnic centrifugation in the cesium chloride gradient, and (iii) precipitation using polyethylene glycol (PEG). Methods (i) and (iii) lead to aggregation of MS2 phages at pH ≤ 4 and pH ≤ 6 in 1-100 mM NaNO3 solutions, respectively, while under such conditions aggregation is not observed for MS2 and VLP suspensions prepared according to (ii). In addition, VLPs prepared following methods (i) and (iii) aggregate only at the isoelectric point (pH ~ 3-4) in 1 mM NaNO3 solution. Electrophoretic mobility data of stable MS2 and VLP particles were further examined using a recent formalism for electrokinetics of soft multilayered colloids. The analysis qualitatively shows how the purification protocol may affect either the outer particle surface properties and/or the inner particle content. Finally, the non-DLVO aggregation behavior of MS2 and VLPs purified via the above protocols is discussed in terms of the possible change in corresponding interparticular interactions. 23244683 Direct measurement of Dirac point energy at the graphene/oxide interface. We report the direct measurement of the Dirac point, the Fermi level, and the work function of graphene by performing internal photoemission measurements on a graphene/SiO(2)/Si structure with a unique optical-cavity enhanced test structure. A complete electronic band alignment at the graphene/SiO(2)/Si interfaces is accurately established. The observation of enhanced photoemission from a one-atom thick graphene layer was possible by taking advantage of the constructive optical interference in the SiO(2) cavity. The photoemission yield was found to follow the well-known linear density-of-states dispersion in the vicinity of the Dirac point. At the flat band condition, the Fermi level was extracted and found to reside 3.3 eV ± 0.05 eV below the bottom of the SiO(2) conduction band. When combined with the shift of the Fermi level from the Dirac point, we are able to ascertain the position of the Dirac point at 3.6 eV ± 0.05 eV with respect to the bottom of the SiO(2) conduction band edge, yielding a work function of 4.5 eV ± 0.05 eV which is in an excellent agreement with theory. The accurate determination of the work function of graphene is of significant importance to the engineering of graphene-based devices, and the measurement technique we have advanced in this Letter will have significant impact on numerous applications for emerging graphene-like 2-dimensional material systems. 23408556 Synthesis and NMR studies of novel chromone-2-carboxamide derivatives. Chromones are heterocyclic compounds of natural or synthetic origin that possess relevant pharmacological activities. Versatile functionalization of the chromone nucleus allows attaining of a chemical diversity suitable to perform structure-activity relationships in drug discovery and development programs. Accordingly, the synthesis and identification of novel chromone carboxamide derivatives with electron-donating and electron-withdrawing substituents in different positions of the exocyclic ring are reported in this work. Their complete structural characterization was performed using one-dimensional and two-dimensional resonance techniques. The data acquired are useful for a prompt analysis of related compounds that encompass our integrated medicinal chemistry sketch. 23508306 Lysophosphatidic acid impairs glucose homeostasis and inhibits insulin secretion in high-fat diet obese mice. AIMS/HYPOTHESIS: Lysophosphatidic acid (LPA) is a lipid mediator produced by adipocytes that acts via specific G-protein-coupled receptors; its synthesis is modulated in obesity. We previously reported that reducing adipocyte LPA production in high-fat diet (HFD)-fed obese mice is associated with improved glucose tolerance, suggesting a negative impact of LPA on glucose homeostasis. Here, our aim was to test this hypothesis. METHODS: First, glucose tolerance and plasma insulin were assessed after acute (30 min) injection of LPA (50 mg/kg) or of the LPA1/LPA3 receptor antagonist Ki16425 (5 mg kg(-1) day(-1), i.p.) in non-obese mice fed a normal diet (ND) and in obese/prediabetic (defined as glucose-intolerant) HFD mice. Glucose and insulin tolerance, pancreas morphology, glycogen storage, glucose oxidation and glucose transport were then studied after chronic treatment (3 weeks) of HFD mice with Ki16425. RESULTS: In ND and HFD mice, LPA acutely impaired glucose tolerance by inhibiting glucose-induced insulin secretion. These effects were blocked by pre-injection of Ki16425 (5 mg/kg, i.p.). Inhibition of glucose-induced insulin secretion by LPA also occurred in isolated mouse islets. Plasma LPA was higher in HFD mice than in ND mice and Ki16425 transiently improved glucose tolerance. The beneficial effect of Ki16425 became permanent after chronic treatment and was associated with increased pancreatic islet mass and higher fasting insulinaemia. Chronic treatment with Ki16425 also improved insulin tolerance and increased liver glycogen storage and basal glucose use in skeletal muscle. CONCLUSIONS/INTERPRETATION: Exogenous and endogenous LPA exerts a deleterious effect on glucose disposal through a reduction of plasma insulin; pharmacological blockade of LPA receptors improves glucose homeostasis in obese/prediabetic mice. 23353657 Labdane diterpenoids and lignans from Calocedrus macrolepis. Three new labdane diterpenoids, calomacrins A-C (1-3), and a new diaryl butyrolactone-type lignan, calomacrol A (8), as well as four known labdane diterpenoids and six known lignans, were isolated from the twigs and leaves of Calocedrus macrolepis. Structures of the new compounds were elucidated on the basis of their spectroscopic methods, including 1D and 2D NMR techniques. Compounds 3-14 were evaluated for cytotoxicity against HL-60, SMMC-7721, A-549, MCF-7, and SW480 cell lines. 23207679 Triterpene saponins from Clethra barbinervis and their hyaluronidase inhibitory activities. An extract of Clethra barbinervis with an inhibitory effect on hyaluronidase activity was fractionated guided by the results of an assay. From the active fractions, seven new triterpene saponins (1-4, 6-8) and a new lignan glycoside (14) were isolated together with 14 known compounds (5, 9-13, 15-22). Some of the saponins (2, 3, 9) were revealed as hyaluronidase inhibitors similar to epicatechin (17). 23187618 Quantification of silanol sites for the most common mesoporous ordered silicas and organosilicas: total versus accessible silanols. IR and NMR spectroscopy were used to determine the silanol content in the most common mesoporous ordered silicas: MCM-41, MCM-48, SBA-15 and SBA-16. In addition, a spray dried MCM-41 and an ethene bridged PMO are investigated. The results are compared with a commercial chromatographic silica (Nucleosil). The complete distribution of surface and bulk silanols, and of isolated, geminal and vicinal silanols for all these materials is presented. A distinction is made between the total silanol number and the reachable or surface silanol content. The latter is determined by controlled reactions with simple silanes. All mesoporous ordered silicas, and especially the thick walled SBA-type materials and the PMO contain a surprisingly high amount of total silanol sites, albeit that up to 90% of these silanols are buried inside the walls and are not reachable for small silanes. 23352986 Differential regulation of drug transporter expression by all-trans retinoic acid in hepatoma HepaRG cells and human hepatocytes. All-trans retinoic acid (atRA) is the active form of vitamin A, known to activate retinoid receptors, especially the heterodimer retinoid X receptor (RXR):retinoic acid receptor (RAR) that otherwise may play a role in regulation of some drug transporters. The present study was designed to characterize the nature of human hepatic transporters that may be targeted by atRA and the heterodimer RXR:RAR. Exposure of human hepatoma HepaRG cells and primary human hepatocytes to 5 μM atRA down-regulated mRNA levels of various sinusoidal solute carrier (SLC) influx transporters, including organic anion transporting polypeptide (OATP) 2B1, OATP1B1, organic cation transporter (OCT) 1 and organic anion transporter (OAT) 2, and induced those of the canalicular breast cancer resistance protein (BCRP). The retinoid concomitantly reduced protein expression of OATP2B1 and OATP1B1 and activity of OATPs and OCT1 and induced BCRP protein expression in HepaRG cells. Some transporters such as OATP1B3 and the bile salt export pump (BSEP) were however down-regulated by atRA in primary human hepatocytes, but induced in HepaRG cells, thus pointing out discrepancies between these two liver cell models in terms of detoxifying protein regulation. atRA-mediated repressions of OATP2B1, OATP1B1, OAT2 and OCT1 mRNA expression were finally shown to be counteracted by knocking-down expression of RARα and RXRα through siRNA transfection in HepaRG cells. atRA thus differentially regulated human hepatic drug transporters, mainly in a RXR:RAR-dependent manner, therefore establishing retinoids and retinoid receptors as modulators of liver drug transporter expression. 23188391 Lipotoxicity impairs incretin signalling. The incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic peptide are secreted by enteroendocrine cells and augment glucose-induced insulin secretion in response to food ingestion in a glucose-dependent manner. This mechanism forms the basis for incretin-based therapies in type 2 diabetes. However, the insulinotropic effect of incretins is diminished in type 2 diabetic patients, due in part to reduced expression of incretin receptors as a consequence of glucotoxicity. In this issue of Diabetologia, Kang et al (DOI: 10.1007/s00125-012-2776-x ) provide evidence that in addition to glucotoxicity, lipotoxicity also affects incretin receptor expression and signalling in insulin-secreting cells and isolated islets. In animal models of diabetes, the authors show that co-administration of a lipid-lowering drug with a dipeptidyl peptidase-4 inhibitor or a glucagon-like peptide-1 agonist improved glucose tolerance and beta cell mass. These novel findings provide convincing support for the notion that restoring normal circulating lipid levels in type 2 diabetes might help improve the efficacy of incretin-based therapies. 23169608 Metabolism and pharmacokinetics of 3-n-butylphthalide (NBP) in humans: the role of cytochrome P450s and alcohol dehydrogenase in biotransformation. 3-n-Butylphthalide (NBP) is a cardiovascular drug currently used for the treatment of cerebral ischemia. The present study aims to investigate the metabolism, pharmacokinetics, and excretion of NBP in humans and identify the enzymes responsible for the formation of major metabolites. NBP underwent extensive metabolism after an oral administration of 200 mg NBP and 23 metabolites were identified in human plasma and urine. Principal metabolic pathways included hydroxylation on alkyl side chain, particularly at 3-, ω-1-, and ω-carbons, and further oxidation and conjugation. Approximately 81.6% of the dose was recovered in urine, mainly as NBP-11-oic acid (M5-2) and glucuronide conjugates of M5-2 and mono-hydroxylated products. 10-Keto-NBP (M2), 3-hydroxy-NBP (M3-1), 10-hydroxy-NBP (M3-2), and M5-2 were the major circulating metabolites, wherein the areas under the curve values were 1.6-, 2.9-, 10.3-, and 4.1-fold higher than that of NBP. Reference standards of these four metabolites were obtained through microbial biotransformation by Cunninghamella blakesleana. In vitro phenotyping studies demonstrated that multiple cytochrome P450 (P450) isoforms, especially CYP3A4, 2E1, and 1A2, were involved in the formation of M3-1, M3-2, and 11-hydroxy-NBP. Using M3-2 and 11-hydroxy-NBP as substrates, human subcellular fractions experiments revealed that P450, alcohol dehydrogenase, and aldehyde dehydrogenase catalyzed the generation of M2 and M5-2. Formation of M5-2 was much faster than that of M2, and M5-2 can undergo β-oxidation to yield phthalide-3-acetic acid in rat liver homogenate. Overall, our study demonstrated that NBP was well absorbed and extensively metabolized by multiple enzymes to various metabolites prior to urinary excretion. 23561092 Characteristics of antioxidant activity and composition of pumpkin seed oils in 12 cultivars. The objective of this study was to determine the antioxidant properties, and provide characteristics, of the oil obtained from the seeds of 12 pumpkin varieties belonging to the species Cucurbita maxima Duch. and Cucurbita pepo L. Another objective was to establish which of the two extracting agents, ethanol or methanol, is more effective. The seeds of the pumpkin varieties examined differ in chemical composition and antioxidant activity. The seeds of the cultivars belonging to the species C. maxima are characterised by a higher content of fatty acids than are the cultivars of the species C. pepo. In the seed oil, unsaturated acids are dominant (oleic and linoleic), and their proportion depends on the pumpkin variety. The highest content of unsaturated acids has been measured in the oil extracted from the seeds of the cultivar, Jet F1 (C. pepo). Antioxidant activity analysis has produced the following findings. The seeds of the pumpkin varieties that belong to the species C. pepo exhibit better antioxidant properties, regardless of the extraction solvent used. 50% ethanol is more efficient than 80% methanol when used as an extracting agent. The antioxidant activity values obtained with 50% ethanol are higher than those achieved with 80% methanol. Owing to the considerable differences in composition among the fatty acids examined, it is possible to choose the desired pumpkin variety for the intended use. 23421717 Three new phenyl-ethanediols from the fruiting bodies of the mushroom Fomes fomentarius. Three new phenyl-ethanediols, (1R)-(3-ethenylphenyl)-1,2-ethanediol (1), (1R)-(3-formylphenyl)-1,2-ethanediol (2), and (1R)-(3-acetophenyl)-1,2-ethanediol (3), were isolated from the fruiting bodies of the mushroom Fomes fomentarius, together with two related known compounds, (3-ethylphenyl)-1,2-ethanediol (4) and (4-acetophenyl)-1,2-ethanediol (5). Their structures were elucidated by spectroscopic methods including extensive 2D NMR techniques. Compounds 1-3 showed weak antimicrobial activity. 23436259 The pharmacokinetics and pharmacodynamics of zaleplon delivered as a thermally generated aerosol in a single breath to volunteers. Pharmacokinetics, pharmacodynamics, safety, and tolerability of inhaled zaleplon were assessed in healthy volunteers. Forty participants received 0.5, 1, 2, or 4 mg zaleplon or placebo as a thermally generated aerosol in a randomized, double-blind, parallel-group, dose escalation study. Blood was collected up to 24 hours after dosing, and sedation was assessed up to 8 hours. Following inhalation, the observed median time to maximum plasma concentrations (25%, 75%) was 1.89 (1.45, 3.08) minutes and the mean (SD) elimination half-life was 1.24 (0.24) hours. The equilibration half-life for sedation (t(1/2) k(e0) ) was 1.16 (0.62, 2.17) minutes. The zaleplon AUC was dose proportional across doses, with a slope (90% confidence interval) of log-AUC versus log-dose of 0.92 (0.82, 1.02). No clinically significant changes were noted in laboratory values, vital signs, or spirometry. The most common adverse events were dizziness, somnolence, euphoria, headache, and visual disturbance. Zaleplon inhalation represents a safe, well-tolerated means of rapidly achieving effective plasma concentrations. 23537701 An ultra-low dose of tetrahydrocannabinol provides cardioprotection. Tetrahydrocannabinol (THC), the major psychoactive component of marijuana, is a cannabinoid agonist that exerts its effects by activating at least two specific receptors (CB1 and CB2) that belong to the seven transmembrane G-protein coupled receptor (GPCR) family. Both CB1 and CB2 mRNA and proteins are present in the heart. THC treatment was beneficial against hypoxia in neonatal cardiomyocytes in vitro. We also observed a neuroprotective effect of an ultra low dose of THC when applied to mice before brain insults. The present study was aimed to test and characterize the cardioprotective effects of a very low dose (0.002mg/kg) of THC which is 3-4 orders of magnitude lower than the conventional doses, administered before myocardial infarction in mice in vivo. Three regimens of THC administration were tested: single THC application 2h or 48h before the induction of infarct, or 3 weeks continuous treatment before MI. All protocols of THC administration were found to be beneficial. In the case of THC treatment 2h before MI, fractional shortening was elevated (37±4% vs. 42±1%, p<0.04), troponin T leakage to the blood was reduced (14±3ng/ml vs. 10±4ng/ml, p<0.008), infarct size decreased (29±4% vs. 23±4%, p<0.02), and the accumulation of neutrophils to the infarct area declined (36±10cells/field vs. 19±4cells/field, p<0.007) in THC- compared to vehicle-pretreated mice, 24h after MI. ERK1/2 phosphorylation following infarct was also inhibited by pre-treatment with THC (p<0.01). CONCLUSION: A single ultra low dose of THC before ischemia is a safe and effective treatment that reduces myocardial ischemic damage. 23348235 A novel coating concept for ileo-colonic drug targeting: Proof of concept in humans using scintigraphy. The in vivo proof of concept of a novel double-coating system, based on enteric polymers, which accelerated drug release in the ileo-colonic region, was investigated in humans. Prednisolone tablets were coated with a double-coating formulation by applying an inner layer composed of EUDRAGIT® S neutralised to pH 8.0 and a buffer salt (10% KH(2)PO(4)), which was overcoated with layer of standard EUDRAGIT® S organic solution. For comparison, a single coating system was produced by applying the same amount of EUDRAGIT® S organic solution on the tablet cores. Dissolution tests on the tablets were carried out using USP II apparatus in 0.1N HCl for 2h and subsequently in pH 7.4 Krebs bicarbonate buffer. For comparison, tablets were also tested under the USP method established for modified release mesalamine formulations. Ten fasted volunteers received the double-coated and single-coated tablets in a two-way crossover study. The formulations were radiolabelled and followed by gamma scintigraphy; the disintegration times and positions were recorded. There was no drug release from the single-coated or double-coated tablets in 0.1N HCl for 2h. The single-coated tablets showed slow release in subsequent Krebs bicarbonate buffer with a lag time of 120min, while in contrast drug release from the double-coated tablets was initiated at 60min. In contrast, using the USP dissolution method, normally employed for modified release mesalamine products, no discrimination was attained. The in vivo disintegration of the single-coated EUDRAGIT® S tablets in the large intestine was erratic. Furthermore, in 2 volunteers, the single-coated tablet was voided intact. Double-coated tablets disintegrated in a more consistent way, mainly in the ileo-caecal junction or terminal ileum. The accelerated in vivo disintegration of the double-coating EUDRAGIT® S system can overcome the limitations of conventional enteric coatings targeting the colon and avoid the pass-through of intact tablets. Moreover, Krebs bicarbonate buffer has the ability to discriminate between formulations designed to target the ileo-colonic region. 23339664 From isolated metaatoms to photonic metamaterials: evolution of the plasmonic near-field. Metamaterials are artificial media which can provide optical properties not available from natural materials. These properties often result from the resonant excitation of plasmonic modes in the metallic building blocks ("metaatoms") of the metamaterial. Electromagnetic interactions between the metaatoms significantly modify the resonances of the individual metaatoms and influence the optical properties of the whole metamaterial. To better understand these interactions, we study in this Letter the evolution of the plasmonic near-field in the course of the transition from an isolated metaatom, in our case a split-ring resonator (SRR), to a photonic metamaterial via electron energy-loss spectroscopy. For small SRR ensembles, we observe the formation of discrete optical bright and dark modes due to coupling of the metaatoms. Large SRR arrays reveal a quasi-continuum of modes in the interior and distinct edge modes at the boundaries of the array. Our experimental results are in excellent agreement with numerical calculations. 23229136 Utilizing Eisenia andrei to assess the ecotoxicity of platinum mine tailings disposal facilities. South Africa is an important platinum mining country which results in environmental impacts due to the construction of tailing disposal facilities (TDFs). It is unclear what the effects of ageing are on the ecotoxicity of TDFs and whether it increases or decreases over time. The aim of this study was to determine the ecotoxicity of differently aged TDFs by investigating earthworm (Eisenia andrei) responses viz. growth, reproduction, neutral red retention times (NRRT) and tissue metal concentrations. Further, to evaluate the status of these in terms of a geoaccumulation index (I(geo)), pollution index and integrated pollution index. Results indicated that earthworms showed reduced reproductive success (hatchlings per cocoon) and decreased NRRT in all the sites. Juveniles per cocoon between all of the different treatment groups were; control (2.83 ± 0.54) > site 2 (20 years old; 1.83 ± 0.27) > sites 1 and 3 (40 years old; 1.06 ± 0.15 and 6 years old; 0.88 ± 0.39). This might be ascribed to the elevated levels of Cr (±200 to 1,166 μg g(-1)) and Ni (±100 to 316 μg g(-1)) in all of the sites. Earthworms did not bioaccumulate metals with bioconcentration factors for all the different treatments <0.01. Studies like these could be useful when establishing a ranking of TDFs in the future to provide legislative institutions with an indication of the environmental liabilities of platinum mines. 22931187 Disposition and metabolism of [¹⁴C]PTZ601 in healthy volunteers. 1. Six healthy male subjects were given a single dose of 500 mg of [14C]PTZ601 (mean radioactivity 79.2 μCi) by intravenous (IV) infusion over 1 h, and observed for 5 days post-dose during which pharmacokinetic (PK) samples were collected. Plasma PTZ601 concentrations and metabolite identification were determined using LC-MS/MS; PK parameters were estimated by non-compartmental analysis. Excretion and mass balance were determined with liquid scintillation analysis and metabolites profiling was characterized by HPLC online radiochemical detection. 2. The disposition of PTZ601 was best described by a fast absorption, followed by a biphasic elimination phase. Peak PTZ601 plasma concentrations were reached within 0.5-1 h. The mean elimination half-life was 1.6 h and clearance was 13 L/h. 3. Recovery of the radioactivity dose was complete (mean 92%). The main route of excretion (parent and metabolites) was the renal route, as urine accounted for 69-77%, while feces only 13-22%, of the total radioactivity. 4. The majority of the drug was excreted in urine as multiple open ring metabolites: M17.3 (oxidative ring-opened product) and M22.2 (di-cysteine conjugate of 17.3); unchanged PTZ601 in urine contributed to 15% of radioactivity. The major metabolites detected in plasma were M17.3, M12.8 (acetylated M17.3), M22.2, and M41.4 (methylated M17.3). 5. PTZ601 was well tolerated. 23384316 Maximal Raman optical activity in hybrid single molecule-plasmonic nanostructures with multiple dipolar resonances. We show that a hybrid system built of a plasmonic nanoparticle cluster and a single molecule can attain maximal Raman optical activity (ROA), converting linearly polarized light into purely circularly polarized light at the Raman-scattered frequency. In contrast to standard molecular ROA, the effect described here does not involve magnetic modes and is attributed to off-resonance excitation of electric-dipole plasmon modes of the nanoparticle cluster. A model based on a combination of harmonic oscillators excited at the frequency of the Raman-scattered light is shown to successfully capture the physics of the effect. 23594301 Development and validation of NIR-chemometric methods for chemical and pharmaceutical characterization of meloxicam tablets. Abstract Context: Near-Infrared (NIR) spectroscopy is an important component of a Process Analytical Technology (PAT) toolbox and is a key technology for enabling the rapid analysis of pharmaceutical tablets. Objective: The aim of this research work was to develop and validate NIR-chemometric methods not only for the determination of active pharmaceutical ingredients content but also pharmaceutical properties (crushing strength, disintegration time) of meloxicam tablets. Materials and methods: The development of the method for active content assay was performed on samples corresponding to 80%, 90%, 100%, 110% and 120% of meloxicam content and the development of the methods for pharmaceutical characterization was performed on samples prepared at seven different compression forces (ranging from 7 to 45 kN) using NIR transmission spectra of intact tablets and PLS as a regression method. Results: The results show that the developed methods have good trueness, precision and accuracy and are appropriate for direct active content assay in tablets (ranging from 12 to 18 mg/tablet) and also for predicting crushing strength and disintegration time of intact meloxicam tablets. Discussion: The comparative data show that the proposed methods are in good agreement with the reference methods currently used for the characterization of meloxicam tablets (HPLC-UV methods for the assay and European Pharmacopeia methods for determining the crushing strength and disintegration time). Conclusion: The results show the possibility to predict both chemical properties (active content) and physical/pharmaceutical properties (crushing strength and disintegration time) directly, without any sample preparation, from the same NIR transmission spectrum of meloxicam tablets. 23601410 Codex dietary fibre definition - Justification for inclusion of carbohydrates from 3 to 9 degrees of polymerisation. The main controversy about the DF definition, adopted by the commission of Codex Alimentarius, refers to the inclusion of carbohydrates of 3-9 degrees of polymerisation (DP), decision which may be made individually by the authorities of each country. Due to the possibility of having two definitions and the negative impact it would cause over the harmonisation of nutritional information, a bibliographic review was carried, from 2009 to 2011, aiming to gather justifications for the inclusion of carbohydrates of 3-9 DP in the definition. The current review presents scientific bases that are directed to three topics: physiological aspects; repercussion over the analytical method; and impact on consumers and other users. The decision of including unavailable carbohydrates of 3-9 DP in the definition of DF may cause effective global harmonisation in the nutritional labelling, considering that the main goal is to help consumers choose healthy foods. 23395668 Biomedical applications of bisphosphonates. Since their discovery over 100 years ago, bisphosphonates have been used industrially as corrosion inhibitors and complexing agents. With the discovery of their pharmacological activity in the late 1960s, implicating their high affinity for hydroxyapatite, bisphosphonates have been employed in the treatment of bone diseases and as targeting agents for colloids and drugs. They have notably been investigated for the treatment of Paget's disease, osteoporosis, bone metastases, malignancy-associated hypercalcemia, and pediatric bone diseases. Currently, they are first-line medications for several of these diseases and are taken by millions of patients worldwide, mostly postmenopausal women. A major problem associated with their use is their low oral bioavailability. Several delivery systems have been proposed to improve their absorption and to direct them to sites other than bone tissues. Beyond their important pharmacological role, the medical applications of bisphosphonates are numerous. In addition, their metal-chelating properties have been exploited to coat and stabilize implants, nanoparticulates, and contrast agents. In this contribution, we review the pharmacological and clinical uses of bisphosphonates and highlight their novel applications in the pharmaceutical and biomedical fields. 22708639 Inhibitory action on rat uterine muscle contraction in vitro and acute toxicity in rats of the Thai traditional preparation Prasaplai. The activity of an aqueous extract of Prasaplai, a Thai traditional medicine, was studied on the isolated rat uterus in the oestrus stage. The results showed that the extract inhibited the contraction induced by a submaximal dose of acetylcholine (2.04×10(-4) mg mL(-1)), oxytocin (1.54×10(-4) mg mL(-1)) and prostaglandin E2 (PGE2) (6.00×10(-4) mg mL(-1)). The inhibition was concentration-dependent and reversible by tissue washing. The IC50 of Prasaplai extracts expressed as milligram of powdered preparation per millilitre of perfusion solution for acetylcholine, oxytocin and PGE2 were 11.70, 10.00 and 5.75 mg mL(-1), respectively. These data reveal that Prasaplai has an antispasmodic effect against uterine contraction by different mechanisms and corroborate the traditional use in the treatment of dysmenorrhoea. Oral administration of single dose of the water extract, calculated as powdered Prasaplai up to 20 g kg(-1) in rats, showed no sign and symptom of acute toxicity, and no rat died even at the maximum dose. 22749926 Nicotine facilitates memory consolidation in perceptual learning. Perceptual learning is a special type of non-declarative learning that involves experience-dependent plasticity in sensory cortices. The cholinergic system is known to modulate declarative learning. In particular, reduced levels or efficacy of the neurotransmitter acetylcholine were found to facilitate declarative memory consolidation. However, little is known about the role of the cholinergic system in memory consolidation of non-declarative learning. Here we compared two groups of non-smoking men who learned a visual texture discrimination task (TDT). One group received chewing tobacco containing nicotine for 1 h directly following the TDT training. The other group received a similar tasting control substance without nicotine. Electroencephalographic recordings during substance consumption showed reduced alpha activity and P300 latencies in the nicotine group compared to the control group. When re-tested on the TDT the following day, both groups responded more accurately and more rapidly than during training. These improvements were specific to the retinal location and orientation of the texture elements of the TDT suggesting that learning involved early visual cortex. A group comparison showed that learning effects were more pronounced in the nicotine group than in the control group. These findings suggest that oral consumption of nicotine enhances the efficacy of nicotinic acetylcholine receptors. Our findings further suggest that enhanced efficacy of the cholinergic system facilitates memory consolidation in perceptual learning (and possibly other types of non-declarative learning). In that regard acetylcholine seems to affect consolidation processes in perceptual learning in a different manner than in declarative learning. Alternatively, our findings might reflect dose-dependent cholinergic modulation of memory consolidation. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23369093 Formulation, in vitro evaluation and study of variables on tri-layered gastro-retentive delivery system of diltiazem HCl. Abstract Context: Tri-layered floating tablets using only one grade of polyethylene oxide (PEO) would enable easy manufacturing, reproducibility and controlled release for highly soluble drugs. Objective: To evaluate the potential of PEO as a sole polymer for the controlled release and to study the effect of formulation variables on release and gastric retention of highly soluble Diltiazem hydrochloride (DTZ). Methods: Tablets were compressed with middle layer consisting of drug and polymer while outer layers consisted of polymer with sodium bicarbonate. Design of formulation to obtain 12 h, zero-order release and rapid floatation was done by varying the grades, quantity of PEO and sodium bicarbonate. Dissolution data were fitted in drug release models and swelling/erosion studies were undertaken to verify the drug release mechanism. Effect of formulation variables and tablet surface morphology using scanning electron microscopy were studied. Results and discussion: The optimized formula passed the criteria of USP dissolution test I and exhibited floating lag-time of 3-4 min. Drug release was faster from low molecular weight (MW) PEO as compared to high MW. With an increase in the amount of sodium bicarbonate, faster buoyancy was achieved due to the increased CO(2) gas formation. Drug release followed zero-order and gave a good fit to the Korsmeyer-Peppas model, which suggested that drug release was due to diffusion through polymer swelling. Conclusion: Zero-order, controlled release profile with the desired buoyancy can be achieved by using optimum formula quantities of sodium bicarbonate and polymer. The tri-layered system shows promising delivery of DTZ, and possibly other water-soluble drugs. 23344156 Beneficial effects of marine algal compounds in cosmeceuticals. The name "cosmeceuticals" is derived from "cosmetics and pharmaceuticals", indicating that a specific product contains active ingredients. Marine algae have gained much importance in cosmeceutical product development due to their rich bioactive compounds. In the present review, marine algal compounds (phlorotannins, sulfated polysaccharides and tyrosinase inhibitors) have been discussed toward cosmeceutical application. In addition, atopic dermatitis and the possible role of matrix metalloproteinase (MMP) in skin-related diseases have been explored extensively for cosmeceutical products. The proper development of marine algae compounds will be helpful in cosmeceutical product development and in the development of the cosmeceutical industry. 23302592 Schisphenlignans A-E: five new dibenzocyclooctadiene lignans from Schisandra sphenanthera. Five new dibenzocyclooctadiene lignans, schisphenlignans A-E (1-5), together with eight known ones, were isolated from the stems of Schisandra sphenanthera. The structures of 1-5 were elucidated based on the analysis of their NMR, MS and circular dichroism (CD) spectra. Some isolates were tested for their acute activities on insulin sensitivity in 3T3-L1 differentiated adipocytes, but none of them showed significant bioactivity with 10 µM administration of the tested compounds. 23178632 Herb-drug interaction of Fucus vesiculosus extract and amiodarone in rats: a potential risk for reduced bioavailability of amiodarone in clinical practice. Fucus vesiculosus is a seaweed claimed to be useful for obesity management. Therefore, considering the relationship between obesity and cardiovascular diseases, this work aimed to assess the potential for an herb-drug interaction among a standardized F. vesiculosus extract (GMP certificate) and amiodarone (a narrow therapeutic index drug) in rats. In a first pharmacokinetic study, rats were simultaneously co-administered with a single-dose of F. vesiculosus (575 mg/kg, p.o.) and amiodarone (50 mg/kg, p.o.); in a second study, rats were pre-treated during 14 days with F. vesiculosus (575 mg/kg/day, p.o.) and received amiodarone (50 mg/kg, p.o.) on the 15th day. Rats of the control groups received the corresponding volume of vehicle. After analysis of the pharmacokinetic data it deserves to be highlighted the significant decrease in the peak plasma concentration of amiodarone (55.4%) as well as the reduction of systemic exposure to the parent drug (~30%) following the simultaneous co-administration of F. vesiculosus extract and amiodarone. This paper reports, for the first time, the herb-drug interaction between F. vesiculosus and amiodarone, which determined a considerable decrease on amiodarone bioavailability in rats. Therefore, the therapeutic efficacy of amiodarone may be compromised by the concurrent administration of herbal slimming medicines/dietary supplements containing F. vesiculosus. 23201622 High levels of ephrinB2 over-expression increases the osteogenic differentiation of human mesenchymal stem cells and promotes enhanced cell mediated mineralisation in a polyethyleneimine-ephrinB2 gene-activated matrix. Gene therapy can be combined with tissue engineering constructs to produce gene-activated matrices (GAMs) with enhanced capacity for repair. Polyethyleneimine (PEI), a non-viral vector, has previously been optimised for high efficiency gene transfer in rat mesenchymal stem cells (rMSCs). The use of PEI to transfect human MSCs (hMSCs) with ephrinB2 is assessed here. Recently a role for the ephrinB2 ligand and EphB4 receptor duo has been proposed in bone remodelling. Herein, over-expression of the ephrinB2 ligand resulted in increased osteogenic differentiation in hMSCs. As ephrinB2 is a cell surface anchored ligand which only interacts with cells expressing the cognate EphB4 receptor through direct contact, we have shown that direct cell-cell contact between two neighbouring cells is responsible for enhanced osteogenesis. In an effort to begin to elucidate the molecular mechanisms at play downstream of ephrinB2 over-expression, RT-PCR was performed on the GAMs which revealed no significant changes in runx2 or BMP2 expression but an upregulation of osterix (Osx) and Dlx5 expression prompting the belief that the mode of osteogenesis is independent of the BMP2 pathway. This select interaction, coupled with the transient gene expression profile of PEI, makes the PEI-ephrinB2 GAM an ideal candidate matrix for a bone targeted GAM. 23135241 Investigating the roles of different monoamine transmitters and impulse control using the 5-choice serial reaction time task. Previous studies have shown that drugs which block the reuptake of catecholamine neurotransmitters improve impulse control in diseases such as attention deficit hyperactivity disorder (ADHD). Serotonin-specific reuptake inhibitors (SSRI) lack efficacy in ADHD and have been linked to increased suicide risk. The present study investigated drugs with affinity for one or more of the monoamine reuptake transporters using the 5-choice serial reaction time task, a model of attention and impulsivity in rodents. We also tested the effects of the alpha(2)-adreoceptor antagonist, idazoxan and novel antidepressant, agomelatine, which both increase cortical noradrenaline concentrations through non-reuptake mechanisms. Improvements in impulse control were observed with venlafaxine, a serotonin and noradrenaline re-uptake inhibitor (SNRI) but not bupropion (dopamine and noradrenaline re-uptake inhibitor). Sibutramine (SNRI) reduced premature responses by ~50% at the highest dose tested but this was not significant. All three of the SSRIs tested reduced premature responding in a dose-dependent manner, although also slowed response and collection latencies. Neither idazoxan nor agomelatine significantly reduced premature responding, suggesting a lack of efficacy at the doses tested. None of the drugs tested improved attention in this task but sibutramine (SNRI), fluoxetine (SSRI) and paroxetine (SSRI) all increased omissions at the highest dose tested. These data suggest that the SNRIs and SSRIs reduce premature responding but tend to be less specific than noradrenaline specific reuptake inhibitors in this model. SSRIs did not induce any specific impairment in impulse control in this model. 23500507 Achieving automated scorpion venom mass fingerprinting (VMF) in the nanogram range. During the past decade mass spectrometry (MS) has become one of the major suitable techniques for peptide and protein analysis from animal venoms, not only to identify new toxins within these complex mixtures, but also for toxin structural studies. The goal of the experiments presented here was to test the ultimate limit for producing scorpion venom mass fingerprinting (VMF; i.e. a comprehensive list of all masses in presence). Thanks to recent developments in nano ultra high performance liquid chromatography (UHPLC) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS), we sought the experimental conditions for setting up an automated data acquisition workflow. As the main result, we demonstrate the possibility to easily achieve VMF having in hand only tens of nanogram of venom. ELISA on-line was also beneficial to monitor in the picogram range for toxin families using specific antisera raised against major toxins. 23337598 Novel naphthoquinone derivatives: synthesis and activity against human African trypanosomiasis. A series of naphthoquinone derivatives has been synthesized and tested for its biological activity against human African trypanosomiasis. The use of reverse micellar medium not only enhanced the conversion rate, but also showed selectivity towards mono-coupled product in aryl chloride-aniline coupling reactions. Two derivatives of naphthoquinone (9b and 9c) exhibited potent activity against Trypanosoma brucei in vitro with low cytotoxicity. 23627311 Synthesis and Structure Activity Relationship of Tetrahydroisoquinoline-based Potentiators of GluN2C and GluN2D Containing N-Methyl-D-Aspartate Receptors. We describe here the synthesis and evaluation of a series of tetrahydroisoquinolines that show subunit-selective potentiation of NMDA receptors containing the GluN2C or GluN2D subunits. Bischler-Napieralski conditions were employed in the key step for the conversion of acyclic amides to the corresponding tetrahydroisoquinoline containing analogs. Compounds were evaluated using both two electrode voltage clamp recordings from Xenopus laevis oocytes and imaging of mammalian BHK cells loaded with Ca(2+)-sensitive dyes. The most potent analogues had EC50 values of 300 nM and showed over 2-fold potentiation of the response to maximally effective concentrations of glutamate and glycine, but had no effect on responses from NMDA receptors containing the GluN2A or GluN2B subunits, AMPA, kainate, GABA, or glycine receptors or a variety of other potential targets. These compounds represent a potent class of small molecule subunit-selective potentiators of NMDA receptors. 23489628 Identification and synthesis of N-(thiophen-2-yl) benzamide derivatives as BRAF(V600E) inhibitors. The V600E BRAF kinase mutation, which activates the downstream MAPK signaling pathway, commonly occurs in about 8% of all human malignancies and about 50% of all melanomas. In this study, we employed virtual screening and chemical synthesis to identify a series of N-(thiophen-2-yl) benzamide derivatives as potent BRAF(V600E) inhibitors. Structure-activity relationship studies of these derivatives revealed that compounds b40 and b47 are the two most potent BRAF(V600E) inhibitors in this series. 23220290 Lecithin in mixed micelles attenuates the cytotoxicity of bile salts in Caco-2 cells. This study was designed to investigate the cytotoxicity of bile salt-lecithin mixed micelles on the Caco-2 cell model. Cell viability and proliferation after mixed micelles treatments were evaluated with the MTT assay, and the integrity of Caco-2 cell monolayer was determined by quantitating the transepithelial electrical resistance and the flux of tracer, FITC-dextran 4400. The apoptosis induced by mixed micelles treatments was investigated with the annexin V/PI protocol. The particle size of mixed micelles was all smaller than 100 nm. The mixed micelles with lower than 0.2mM sodium deoxycholate (SDC) had no significant effects on cell viability and proliferation. When the level of SDC was higher than 0.4mM and the lecithin/SDC ratio was lower than 2:1, the mixed micelles caused significant changes in cell viability and proliferation. Furthermore, the mixed micelles affected tight junctions in a composition-dependent manner. Specifically, the tight junctions were transiently opened rather than damaged by the mixed micelles with SDC of between 0.2 and 0.6mM. The mixed micelles with more lecithin also induced less apoptosis. These results demonstrate that relatively higher concentrations of mixed micelles are toxic to Caco-2 cells, while phospholipids can attenuate the toxicity of the bile salts. 23562056 Conformational restriction approach to BACE1 inhibitors II: SAR study of the isocytosine derivatives fixed with a cis-cyclopropane ring. To improve the efficacy of the conformationally restricted BACE1 inhibitors, structural modifications were investigated using two strategies: (a) modification of the terminal aromatic ring and (b) insertion of a spacer between the aromatic rings. In the latter approach, another type of inhibitor 17 bearing an ethylene spacer between two aromatic rings was found to exhibit good BACE1 inhibitory activity, while the corresponding conformationally unrestricted compound 25 showed no activity. This result revealed an interesting effect of a conformational restriction with a cyclopropane ring. 23017425 Citrus phenylpropanoids and defence against pathogens. Part II: gene expression and metabolite accumulation in the response of fruits to Penicillium digitatum infection. The effect of infection of Citrus sinensis (var. Navelina) fruits with Penicillium digitatum was studied at gene expression and metabolite levels. In this study, expression of genes involved in the phenylpropanoid pathway was studied in the flavedo (outer coloured part of the peel) and albedo (inner white part) in response to pathogen infection. Results of the time-course experiment showed that maximal expression of 10 out of 17 phenylpropanoid genes analysed occurred at 48h post-inoculation, when decay symptoms started to appear, and mRNA levels either kept constant or decreased after 72h post-inoculation. To further investigate the putative involvement of the phenylpropanoid pathway in the defence of citrus fruit, changes in the metabolic profile of both tissues infected with P. digitatum was studied by means of HPLC-PDA-FD. Metabolite accumulation levels along the time course suggest that flavanones, flavones, polymethoxylated flavones and scoparone are induced in citrus fruit in response to P. digitatum infection, although with different trends depending on the tissue. 22861486 Inhibitory function of the dorsomedial hypothalamic nucleus on the hypothalamic-pituitary-adrenal axis response to an emotional stressor but not immune challenge. Accumulating evidence implicates the dorsomedial hypothalamic nucleus (DMH) in the regulation of autonomic and neuroendocrine stress responses. However, although projections from the DMH to the paraventricular hypothalamic nucleus (PVN), which is the critical site of the neuroendocrine stress axis, have been described, the impact of DMH neurones in the modulation of hypothalamic-pituitary-adrenal (HPA) axis activation during stress is not fully understood. The present study aimed to investigate the role of the DMH in HPA axis responses to different types of stimuli. Male Sprague-Dawley rats fitted with a chronic jugular venous catheter were exposed to either an emotional stressor (elevated platform-exposure) or immune challenge (systemic interleukin-1β administration). Bilateral electrolytic lesions of the DMH disinhibited HPA axis responses to the emotional stressor, as indicated by higher plasma adrenocorticotrophic hormone levels during and after elevated platform exposure in lesioned animals compared to sham-lesioned controls. Moreover, DMH-lesioned animals showed increased neuronal activation in the PVN, as indicated by a higher c-Fos expression after elevated-platform exposure compared to controls. By contrast, DMH-lesions had no effects on HPA axis responses to immune challenge. Taken together, our data suggest an inhibitory role of DMH neurones on stress-induced HPA axis activation that is dependent upon the nature of the stimulus being important in response to an emotional stressor but not to immune challenge. 23343565 Binary diffusion coefficients for mixtures of ionic liquids [EMIM][N(CN)2], [EMIM][NTf2], and [HMIM][NTf2] with acetone and ethanol by dynamic light scattering (DLS). Mutual diffusivities for binary mixtures of the ionic liquids (ILs) [EMIM][N(CN)2] (1-ethyl-3-methylimidazolium dicyanimide), [EMIM][NTf2] (1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide), and [HMIM][NTf2] (1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide) with acetone and ethanol were studied in dependence on composition in the temperature range from 283.15 to 323.15 K, applying dynamic light scattering (DLS). The influence of experimental parameters on the achievable uncertainties was analyzed to ensure the acquisition of accurate data in adequate measurement times. For all probed systems, increasing binary diffusion coefficients were found for increasing temperatures. The systematic variation of anion and cation of the investigated ILs as well as a comparison with the literature data demonstrates the considerable influence of different ions on the resulting binary diffusion coefficients. Mutual diffusivities were found to be lower for the mixtures with ethanol than for those with acetone, which could be related to the formation of hydrogen bonds between ethanol and the ions. Most of the investigated IL solvent mixtures show increasing binary diffusion coefficients with increasing solvent concentration. For the mixtures of [EMIM][NTf2] with ethanol, however, a minimum of the mutual diffusivities was found in the ethanol mole fraction range from 0.7 to 0.8, which may hint at the vicinity of a critical demixing point. The viscosity of the pure ILs turned out to be no reliable indicator for the mutual diffusivity in mixtures with the same solvent. 23548029 Multi-classifier based on hard instances- new method for prediction of human immunodeficiency virus drug resistance. There are several classification problems, which are difficult to solve using a single classifier because of the complexity of the decision boundary. Whereas a wide variety of multiple classifier systems have been built with the purpose of improving the recognition process, there is no universal method performing the best. This paper provides a review of different multi-classifiers and some application of them. Also it is shown a novel model of combining classifiers and its application to predicting human immunodeficiency virus drug resistance from genotype. The proposal is based on the use of different classifier models. It clusters the dataset considering the performance of the base classifiers. The system learns how to decide from the groups, by using a meta-classifier, which are the best classifiers for a given pattern. The proposed model is compared with well-known classifier ensembles and individual classifiers as well resulting the novel model in similar or even better performance. 23576177 Dioecy in Plants - Is It an Important Factor for Phytochemists to Consider? Plants with separate male and female flowers are termed dioecious. Dioecy is not rare, yet is a characteristic that could potentially impact the phytochemical and subsequent pharmacological properties of a species. This is a brief insight which highlights why the sex of the plant might be an important factor to consider for researchers within phytochemistry related fields. 23444040 Eugenol alters the integrity of cell membrane and acts against the nosocomial pathogen Proteus mirabilis. Eugenol, a member of the phenylpropanoids class of chemical compounds, is a clear to pale yellow oily liquid extracted from certain essential oils especially from clove oil, nutmeg, cinnamon, and bay leaf. The antibacterial activity of eugenol and its mechanism of bactericidal action against Proteus mirabilis were evaluated. Treatment with eugenol at their minimum inhibitory concentration [0.125 % (v/v)] and minimum bactericidal concentration [0.25 % (v/v)] reduced the viability and resulted in complete inhibition of P. mirabilis. A strong bactericidal effect on P. mirabilis was also evident, as eugenol inactivated the bacterial population within 30 min exposure. Chemo-attractant property and the observance of highest antibacterial activity at alkaline pH suggest that eugenol can work more effectively when given in vivo. Eugenol inhibits the virulence factors produced by P. mirabilis as observed by swimming motility, swarming behavior and urease activity. It interacts with cellular membrane of P. mirabilis and makes it highly permeable, forming nonspecific pores on plasma membrane, which in turn directs the release of 260 nm absorbing materials and uptake of more crystal violet from the medium into the cells. SDS-polyacrylamide gel, scanning electron microscopy and Fourier transform infrared analysis further proves the disruptive action of eugenol on the plasma membrane of P. mirabilis. The findings reveal that eugenol shows an excellent bactericidal activity against P. mirabilis by altering the integrity of cell membrane. 23193282 Allen Brain Atlas: an integrated spatio-temporal portal for exploring the central nervous system. The Allen Brain Atlas (http://www.brain-map.org) provides a unique online public resource integrating extensive gene expression data, connectivity data and neuroanatomical information with powerful search and viewing tools for the adult and developing brain in mouse, human and non-human primate. Here, we review the resources available at the Allen Brain Atlas, describing each product and data type [such as in situ hybridization (ISH) and supporting histology, microarray, RNA sequencing, reference atlases, projection mapping and magnetic resonance imaging]. In addition, standardized and unique features in the web applications are described that enable users to search and mine the various data sets. Features include both simple and sophisticated methods for gene searches, colorimetric and fluorescent ISH image viewers, graphical displays of ISH, microarray and RNA sequencing data, Brain Explorer software for 3D navigation of anatomy and gene expression, and an interactive reference atlas viewer. In addition, cross data set searches enable users to query multiple Allen Brain Atlas data sets simultaneously. All of the Allen Brain Atlas resources can be accessed through the Allen Brain Atlas data portal. 23212109 Computation as the mechanistic bridge between precision medicine and systems therapeutics. Over the past 50 years, like molecular cell biology, medicine and pharmacology have been driven by a reductionist approach. The focus on individual genes and cellular components as disease loci and drug targets has been a necessary step in understanding the basic mechanisms underlying tissue/organ physiology and drug action. Recent progress in genomics and proteomics, as well as advances in other technologies that enable large-scale data gathering and computational approaches, is providing new knowledge of both normal and disease states. Systems-biology approaches enable integration of knowledge from different types of data for precision medicine and systems therapeutics. In this review, we describe recent studies that contribute to these emerging fields and discuss how together these fields can lead to a mechanism-based therapy for individual patients. 23422569 SIRT1 inhibits NADPH oxidase activation and protects endothelial function in the rat aorta: Implications for vascular aging. Vascular aging is characterized by up-regulation of NADPH oxidase, oxidative stress and endothelial dysfunction. Previous studies demonstrate that the activity of the evolutionarily conserved NAD(+)-dependent deacetylase SIRT1 declines with age and that pharmacological activators of SIRT1 confer significant anti-aging cardiovascular effects. To determine whether dysregulation of SIRT1 promotes NADPH oxidase-dependent production of reactive oxygen species (ROS) and impairs endothelial function we assessed the effects of three structurally different inhibitors of SIRT1 (nicotinamide, sirtinol, EX527) in aorta segments isolated from young Wistar rats. Inhibition of SIRT1 induced endothelial dysfunction, as shown by the significantly reduced relaxation to the endothelium-dependent vasodilators acetylcholine and the calcium ionophore A23187. Endothelial dysfunction induced by SIRT1 inhibition was prevented by treatment of the vessels with the NADPH oxidase inhibitor apocynin or superoxide dismutase. Inhibition of SIRT1 significantly increased vascular superoxide production, enhanced NADPH oxidase activity, and mRNA expression of its subunits p22(phox) and NOX4, which were prevented by resveratrol. Peroxisome proliferator-activated receptor-α (PPARα) activation mimicked the effects of resveratrol while PPARα inhibition prevented the effects of this SIRT1 activator. SIRT1 co-precipitated with PPARα and nicotinamide increased the acetylation of the PPARα coactivator PGC-1α, which was suppressed by resveratrol. In conclusion, impaired activity of SIRT1 induces endothelial dysfunction and up-regulates NADPH oxidase-derived ROS production in the vascular wall, mimicking the vascular aging phenotype. Moreover, a new mechanism for controlling endothelial function after SIRT1 activation involves a decreased PGC-1α acetylation and the subsequent PPARα activation, resulting in both decreased NADPH oxidase-driven ROS production and NO inactivation. 23543013 Global and MGMT promoter hypomethylation independently associated with genomic instability of lymphocytes in subjects exposed to high-dose polycyclic aromatic hydrocarbon. Global hypomethylation, gene-specific methylation, and genome instability are common events in tumorigenesis. To date, few studies have examined the aberrant DNA methylation patterns in coke oven workers, who are highly at risk of lung cancer by occupational exposure to polycyclic aromatic hydrocarbons (PAHs). We recruited 82 PAH-exposed workers and 62 unexposed controls, assessed exposure levels by urinary 1-hydroxypyrene, and measured genetic damages by comet assay, bleomycin sensitivity, and micronucleus assay. The PAHs in coke oven emissions (COE) were estimated based on toxic equivalency factors. We used bisulfite-PCR pyrosequencing to quantitate DNA methylation in long interspersed nuclear element-1 (LINE-1) and O(6)-methylguanine-DNA methyltransferase (MGMT). Further, the methylation alteration was also investigated in COE-treated human bronchial epithelial (16HBE) cells. We found there are higher levels of PAHs in COE. Among PAH-exposed workers, LINE-1 and MGMT methylation levels (with CpG site specificity) were significantly lowered. LINE-1, MGMT, and its hot CpG site-specific methylation were negatively correlated with urinary 1-hydroxypyrene levels (r = -0.329, p < 0.001; r = -0.164, p = 0.049 and r = -0.176, p = 0.034, respectively). In addition, LINE-1 methylation was inversely associated with comet tail moment and micronucleus frequency, and a significant increase of micronucleus in low MGMT methylation group. In vitro study revealed that treatment of COE in 16HBE cells resulted in higher production of BPDE-DNA adducts, LINE-1 hypomethylation, hypomethylation, and suppression of MGMT expression. These findings suggest hypomethylation of LINE-1 and MGMT promoter could be used as markers for PAHs exposure and merit further investigation. 23530626 Nickel(II) Dithiocarbamate Complexes Containing Sulforhodamine B as Fluorescent Probes for Selective Detection of Nitrogen Dioxide. We synthesized complexes of Ni(II) with dithiocarbamate ligands derived from the ortho and para isomers of sulforhodamine B fluorophores and demonstrated they are highly selective in reactions with nitrogen dioxide (NO2). Compared with the para isomer, the ortho isomer showed a much greater fluorescence increase upon reaction with NO2, which led to oxidation and decomplexation of the dithiocarbamate ligand from Ni(II). We applied this probe for visual detection of 1 ppm NO2 in the gas phase and fluorescence imaging of NO2 in macrophage cells treated with a nitrogen dioxide donor. 23104246 Dietary exposure to inorganic arsenic of the Hong Kong population: results of the first Hong Kong total diet study. Inorganic arsenic, a human carcinogen, can be found in the environment and food. In the first Hong Kong Total Diet Study, the dietary exposure of the Hong Kong people, including various age-gender subgroups, to inorganic arsenic was estimated for assessing the associated health risk. Food samples, which represented the Hong Kong people's diet, were collected and prepared "as consumed" for analysis. Concentrations of inorganic arsenic, as sum of arsenite (As(III)) and arsenate (As(V)) were determined in 600 composite samples by using inductively coupled plasma mass spectrometry. The dietary exposures were estimated by combining the analytical results with the local food consumption data of the adult population. The mean and 95th percentile of inorganic arsenic exposures of the Hong Kong people were 0.22 and 0.38μg/kg body weight (bw)/day, respectively. Among the 12 age-gender subgroups, the respective exposures ranged from 0.19 to 0.26μg/kg bw/day and from 0.33 to 0.46μg/kg bw/day. The main food category that contributed inorganic arsenic was "cereals and their products" (53.5% of the total exposure), particularly rice. Having considered the carcinogenic risk of inorganic arsenic to humans, it is suggested that efforts should be made to reduce the inorganic arsenic exposure of the Hong Kong population. 23376975 Optimal dosing of warfarin and other coumarin anticoagulants: the role of genetic polymorphisms. Coumarin anticoagulants, which include warfarin, acenocoumarol and phenprocoumon, are among the most widely prescribed drugs worldwide. There is now a large body of published data showing that genotype for certain common polymorphisms in the genes encoding the target vitamin K epoxide reductase (G-1639A/C1173T) and the main metabolizing enzyme CYP2C9 (CYP2C9*2 and *3 alleles) are important determinants of the individual coumarin anticoagulant dose requirement. Additional less common polymorphisms in these genes together with polymorphisms in other genes relevant to blood coagulation such as the cytochrome P450 CYP4F2, gamma-glutamyl carboxylase, calumenin and cytochrome P450 oxidoreductase may also be significant predictors of dose, especially in ethnic groups such as Africans where there have been fewer genetic studies compared with European populations. Using relevant genotypes to calculate starting dose may improve safety during the initiation period. Various algorithms for dose calculation, which also take patient age and other characteristics into consideration, have been developed for all three widely used coumarin anticoagulants and are now being tested in ongoing large randomised clinical trials. One recently completed study has provided encouraging results suggesting that calculation of warfarin dose on the basis of individual patient genotype leads to few adverse events and a higher proportion of time within the therapeutic coagulation rate window, but these findings still need confirmation. 23478148 Discovery and gram-scale synthesis of BMS-593214, a potent, selective FVIIa inhibitor. A 6-amidinotetrahydroquinoline screening hit was driven to a structurally novel, potent, and selective FVIIa inhibitor through a combination of library synthesis and rational design. An efficient gram-scale synthesis of the active enantiomer BMS-593214 was developed, which required significant optimization of the key Povarov annulation. Importantly, BMS-593214 showed antithrombotic efficacy in a rabbit arterial thrombosis model. A crystal structure of BMS-593214 bound to FVIIa highlights key contacts with Asp 189, Lys 192, and the S2 pocket. 23340689 Photoelectron imaging of small aluminum clusters: quantifying s-p hybridization. Photoelectron imaging experiments and detailed calculations are conducted on Al(n)(-) clusters (n = 3-6) and a calibration method is developed for connecting experimental observations of photoelectron angular distributions to theoretical predictions. It is shown that this method can be used to quantify the degree to which the molecular orbitals are built from s- or p-like atomic orbitals. The highest occupied molecular orbitals of these small aluminum clusters are found to contain varying degrees of s-p mixing, with Al(3)(-) containing the "most hybridized" orbital and Al(4)(-) containing the "least hybridized" orbital. It is shown experimentally that s-p hybridization is already present for the trimer species and, similar to other properties of small metal clusters, oscillates with cluster size. 23566035 Enhancing Catalytic Performance of Palladium in Gold and Palladium Alloy Nanoparticles for Organic Synthesis Reactions through Visible Light Irradiation at Ambient Temperatures. The intrinsic catalytic activity of palladium (Pd) is significantly enhanced in gold (Au)-Pd alloy nanoparticles (NPs) under visible light irradiation at ambient temperatures. The alloy NPs strongly absorb light and efficiently enhance the conversion of several reactions, including Suzuki-Miyaura cross coupling, oxidative addition of benzylamine, selective oxidation of aromatic alcohols to corresponding aldehydes and ketones, and phenol oxidation. The Au/Pd molar ratio of the alloy NPs has an important impact on performance of the catalysts since it determines both the electronic heterogeneity and the distribution of Pd sites at the NP surface, with these two factors playing key roles in the catalytic activity. Irradiating with light produces an even more profound enhancement in the catalytic performance of the NPs. For example, the best conversion rate achieved thermally at 30 °C for Suzuki-Miyaura cross coupling was 37% at a Au/Pd ratio of 1:1.86, while under light illumination the yield increased to 96% under the same conditions. The catalytic activity of the alloy NPs depends on the intensity and wavelength of incident light. Light absorption due to the Localized Surface Plasmon Resonance of gold nanocrystals plays an important role in enhancing catalyst performance. We believe that the conduction electrons of the NPs gain the light absorbed energy producing energetic electrons at the surface Pd sites, which enhances the sites' intrinsic catalytic ability. These findings provide useful guidelines for designing efficient catalysts composed of alloys of a plasmonic metal and a catalytically active transition metal for various organic syntheses driven by sunlight. 23420214 A structural mapping of mutations causing succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency. Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is a rare inherited metabolic disorder of ketone metabolism, characterized by ketoacidotic episodes and often permanent ketosis. To date there are ∼20 disease-associated alleles on the OXCT1 gene that encodes the mitochondrial enzyme SCOT. SCOT catalyzes the first, rate-limiting step of ketone body utilization in peripheral tissues, by transferring a CoA moiety from succinyl-CoA to form acetoacetyl-CoA, for entry into the tricarboxylic acid cycle for energy production. We have determined the crystal structure of human SCOT, providing a molecular understanding of the reported mutations based on their potential structural effects. An interactive version of this manuscript (which may contain additional mutations appended after acceptance of this manuscript) may be found on the web address: http://www.thesgc.org/jimd/SCOT . 23499716 How do in-vitro release profiles of nanosuspensions from Alzet® pumps correspond to the in-vivo situation? A case study on radiolabeled fenofibrate. In research and development sufficiently high and constant plasma levels of drug candidates are often requested, but simple solutions of hydrophobic drugs delivered from the commonly used micro-osmotic pumps cannot meet these demands. Nanosuspensions released from implanted osmotic devices can be a strategy to overcome this challenge but little is known about their pharmacokinetic behavior after subcutaneous application. In the current study, four different nanosuspension formulations containing iodinated fenofibrate were prepared, physicochemically characterized and investigated concerning their in-vitro release kinetics from osmotic pumps. One nanosuspension of lower viscosity exhibited thereby an unexpectedly first order release kinetics, whereas the higher viscous counterpart was released in the expected zero-order manner. To assess the relation of the in-vitro release kinetics to the in-vivo fate of nanosuspensions, various [(131)I] iodinated fenofibrate formulations were subcutaneously applied to mice. The biodistribution was followed by means of γ-scintigraphy and γ-scintillation. Two different nanosuspensions released from osmotic pumps were compared to bolus injections of a nanosuspension and an organic drug solution. The distribution and elimination of the bolus injected drug solution were almost completed within 48h. In contrast, a long lasting (>1week) depot at the injection site was formed by the bolus injected nanosuspension. Ex vivo examination of the organs showed a sustained, but exponential decrease of the radiolabel concentration. More constant drug levels in the organs were achieved within the nanosuspensions released from osmotic pumps. The organ levels of [(131)I] labeled fenofibrate were found to be more constant in case of the pump with the higher viscous nanosuspension in contrast to the lower viscous counterpart. However, the very different release profiles of the lower and higher viscous nanosuspension observed in-vitro were not observed in-vivo, as both pumps showed zero order release. In conclusion, nanosuspensions of poorly soluble compounds released from subcutaneously implanted osmotic pumps can be a suitable approach in pharmacokinetic studies. Although the in-vivo release of nanosuspensions differed in the expected release profile from the in-vitro test results, these in-vitro release tests present a valuable tool for the pre-selection of suitable nanosuspension candidates. 22847135 Naringin induces death receptor and mitochondria-mediated apoptosis in human cervical cancer (SiHa) cells. Cervical cancer is the second most common female cancer worldwide, and it remains a challenge to manage preinvasive and invasive lesions. Fruit-based cancer prevention entities, such as flavonoid and their derivatives, have demonstrated a marked ability to inhibit preclinical models of epithelial cancer cell growth and tumor formation. Here, we extend the role of naringin-mediated chemoprevention to that of cervical carcinogenesis. The present study sought to investigate the therapeutic potential effect of naringin on apoptosis in human cervical SiHa cancer cells. Viability of SiHa cells was evaluated by the MTT assay, apoptosis and mitochondrial transmembrane potential by flow cytometry, and pro-apoptotic related genes by Real-time quantitative PCR. Naringin showed a 50% inhibition of SiHa human cervical cancer cells at a concentration of 750μM. SiHa cells exhibited apoptotic cell death, intranucleosomal DNA fragmentation, morphological changes and decline in the mitochondrial transmembrane potential. In addition, administration of naringin increased the expression of caspases, p53 and Bax, Fas death receptor and its adaptor protein FADD. These results suggest that the induction of apoptosis by naringin is through both death-receptor and mitochondrial pathways. Taken together, our results suggest that naringin might be an effective agent to treat human cervical cancer. 23571495 Sphingomyelin in high-density lipoproteins: structural role and biological function. High-density lipoprotein (HDL) levels are an inverse risk factor for cardiovascular diseases, and sphingomyelin (SM) is the second most abundant phospholipid component and the major sphingolipid in HDL. Considering the marked presence of SM, the present review has focused on the current knowledge about this phospholipid by addressing its variable distribution among HDL lipoparticles, how they acquire this phospholipid, and the important role that SM plays in regulating their fluidity and cholesterol efflux from different cells. In addition, plasma enzymes involved in HDL metabolism such as lecithin-cholesterol acyltransferase or phospholipid transfer protein are inhibited by HDL SM content. Likewise, HDL SM levels are influenced by dietary maneuvers (source of protein or fat), drugs (statins or diuretics) and modified in diseases such as diabetes, renal failure or Niemann-Pick disease. Furthermore, increased levels of HDL SM have been shown to be an inverse risk factor for coronary heart disease. The complexity of SM species, described using new lipidomic methodologies, and their distribution in different HDL particles under many experimental conditions are promising avenues for further research in the future. 23341183 A "clickable" MTX reagent as a practical tool for profiling small-molecule-intracellular target interactions via MASPIT. We present a scalable synthesis of a versatile MTX reagent with an azide ligation handle that allows rapid γ-selective conjugation to yield MTX fusion compounds (MFCs) appropriate for MASPIT, a three-hybrid system that enables the identification of mammalian cytosolic proteins that interact with a small molecule of interest. We selected three structurally diverse pharmacologically active compounds (tamoxifen, reversine, and FK506) as model baits. After acetylene functionalization of these baits, MFCs were synthesized via a CuAAC reaction, demonstrating the general applicability of the MTX reagent. In analytical mode, MASPIT was able to give concentration-dependent reporter signals for the established target proteins. Furthermore, we demonstrate that the sensitivity obtained with the new MTX reagent was significantly stronger than that of a previously used non-regiomeric conjugate mixture. Finally, the FK506 MFC was explored in a cellular array screen for targets of FK506. Out of a pilot collection of nearly 2000 full-length human ORF preys, FKBP12, the established target of FK506, emerged as the prey protein that gave the highest increase in luciferase activity. This indicates that our newly developed synthetic strategy for the straightforward generation of MFCs is a promising asset to uncover new intracellular targets using MASPIT cellular array screening. 23470181 Crystalline growth of rubrene film enhanced by vertical ordering in cadmium arachidate multilayer substrate. The growth of highly crystalline rubrene thin films for organic field effect transistor (OFET) application remains a challenge. Here, we report on the vapor-deposited growth of rubrene films on the substrates made of cadmium arachidate (CdA) multilayers deposited onto SiO2/Si(100) via the Langmuir-Blodgett technique. The CdA films, containing 2n+1 layers, with integer n ranging from 0 to 4, are surface-terminated identically by the methyl group but exhibit the thickness-dependent morphology. The morphology and structure of both CdA and rubrene films are characterized by X-ray reflectivity (XRR), X-ray diffraction (XRD), near-edge X-ray absorption fine structure (NEXAFS) spectroscopy, and atomic force microscopy (AFM). Crystalline rubrene films, evidenced by XRD and marked by platelet features in AFM images, become observable when grown onto the CdA layer thicker than 5L. XRD data show that vertical ordering, that is, ordering along surface normal, of CdA multilayer substrates exerts a strong influence in promoting the crystalline growth of rubrene films. This promoted growth is not due to the surface energy of CdA layer but derived from the additional interaction localized between rubrene and CdA island sidewall and presumably strengthened by a close dimensional match between the a-axis of rubrene lattice and the layer spacing of CdA multilayer. The best OFET mobility is recorded for 9L CdA substrate and reaches 6.7 × 10(-2) cm(2) V(-1) s(-1), presumably limited by the roughness of the interface between CdA and rubrene films. 23578630 Thermal analysis of some natural polysaccharide materials by isoconversional method. Isoconversional thermal analysis of some important polysaccharides from functional foods is reported. Various thermal parameters including apparent activation energy (Ea), pre-exponential factor (A) were worked out, and the fitness of data to different models describing the degradation kinetics of polysaccharides was studied. The polysaccharides from Mimosa pudica (MP), Plantago ovata (PO), Argyreia speciosa (AS), Acacia nilotica (AN), P. ovata husk (HK) and Acacia modesta (AM) exhibited multistep degradation while those from Astragalus gummifer (AG), Salvia aegyptiaca (SA) and Ocimum basicilicum (OB) degraded mainly in single step. Generally, the degradation was exothermal. The average Ea values as determined by Flynn-Wall-Ozawa method were found to be in the range 132-187kJmol(-1). The mean comprehensive index of thermal stability (ITS) fell in the range 0.33-0.43. All the materials under investigation except those from SA and AS appear to be as stable as some of the important commercial materials used as pharmaceutical ingredients. Model-fitting analysis revealed that the major degradation step follows first-order kinetics. 23570284 A facile strategy to design zeolite L crystals with tunable morphology and surface architecture. Tailoring the anisotropic growth rates of materials to achieve desired structural outcomes is a pervasive challenge in synthetic crystallization. Here we discuss a method to selectively control the growth of zeolite crystals, which are used extensively in a wide range of industrial applications. This facile method cooperatively tunes crystal properties, such as morphology and surface architecture, through the use of inexpensive, commercially available chemicals with specificity for binding to crystallographic surfaces and mediating anisotropic growth. We examined over 30 molecules as potential zeolite growth modifiers (ZGMs) of zeolite L (LTL type) crystallization. ZGM efficacy was quantified through a combination of macroscopic (bulk) and microscopic (surface) investigations that identified modifiers capable of dramatically altering the cylindrical morphology of LTL crystals. We demonstrate an ability to tailor properties critical to zeolite performance, such as external porous surface area, crystal shape, and pore length, which can enhance sorbate accessibility to LTL pores, tune the supramolecular organization of guest-host composites, and minimize the diffusion path length, respectively. We report that a synergistic combination of ZGMs and the judicious adjustment of synthesis parameters produce LTL crystals with unique surface features, and a range of length-to-diameter aspect ratios spanning 3 orders of magnitude. A systematic examination of different ZGM structures and molecular compositions (i.e., hydrophobicity and binding moieties) reveal interesting physicochemical properties governing their efficacy and specificity. Results of this study suggest this versatile strategy may prove applicable for a host of framework types to produce unrivaled materials that have eluded more conventional techniques. 23517558 Intestinal and hepatic first-pass extraction of the 11β-HSD1 inhibitor AMG 221 in rats with chronic vascular catheters. Abstract 1. A catheterized rat model was used to define the intestinal and hepatic components of oral bioavailability for an 11β-HSD1 inhibitor, AMG 221. These data were integrated with standard in vivo metabolism studies to elucidate the components contributing to the oral disposition of a novel drug candidate. 2. Intestinal and hepatic extraction ratios of AMG 221 obtained using a five-catheter rat model were 0.56 and 0.32, respectively. Therefore, both intestinal and hepatic extraction contributed to the first-pass component of oral bioavailability. There was no evidence for significant gut extraction of systemically administered drug. 3. Mass balance data and in vivo metabolite characterization obtained after administration of [(14)C] AMG 221 to rat showed that AMG 221 was completely absorbed from the gut lumen following an oral dose, primarily excreted in urine and was almost completely metabolized prior to excretion. 4. Hepatic bioavailability (FH), measured in two animals at various time points after oral dose administration was somewhat variable but generally characterized by an initial reduction during the absorption phase followed by an increase during the elimination phase, consistent with hepatic distribution of AMG 221. 5. The five-catheter rat model afforded estimates of hepatic and intestinal contribution to oral bioavailability that were used with other data to define the preclinical ADME characteristics of a drug candidate. 22981796 Validation of an in vitro exposure system for toxicity assessment of air-delivered nanomaterials. To overcome the limitations of in vitro exposure of submerged lung cells to nanoparticles (NPs), we validated an integrated low flow system capable of generating and depositing airborne NPs directly onto cells at an air-liquid interface (ALI). The in vitro exposure system was shown to provide uniform and controlled dosing of particles with 70.3% efficiency to epithelial cells grown on transwells. This system delivered a continuous airborne exposure of NPs to lung cells without loss of cell viability in repeated 4h exposure periods. We sequentially exposed cells to air-delivered copper (Cu) NPs in vitro to compare toxicity results to our prior in vivo inhalation studies. The evaluation of cellular dosimetry indicated that a large amount of Cu was taken up, dissolved and released into the basolateral medium (62% of total mass). Exposure to Cu NPs decreased cell viability to 73% (p<0.01) and significantly (p<0.05) elevated levels of lactate dehydrogenase, intracellular reactive oxygen species and interleukin-8 that mirrored our findings from subacute in vivo inhalation studies in mice. Our results show that this exposure system is useful for screening of NP toxicity in a manner that represents cellular responses of the pulmonary epithelium in vivo. 23238558 Design, functionalization strategies and biomedical applications of targeted biodegradable/biocompatible polymer-based nanocarriers for drug delivery. Design and functionalization strategies for multifunctional nanocarriers (e.g., nanoparticles, micelles, polymersomes) based on biodegradable/biocompatible polymers intended to be employed for active targeting and drug delivery are reviewed. This review will focus on the nature of the polymers involved in the preparation of targeted nanocarriers, the synthesis methods to achieve the desired macromolecular architecture, the selected coupling strategy, the choice of the homing molecules (vitamins, hormones, peptides, proteins, etc.), as well as the various strategies to display them at the surface of nanocarriers. The resulting morphologies and the main colloidal features will be given as well as an overview of the biological activities, with a special focus on the main in vivo achievements. 23499235 Synthesis, preliminary structure-activity relationships, and in vitro biological evaluation of 6-aryl-3-amino-thieno[2,3-b]pyridine derivatives as potential anti-inflammatory agents. In our previous study, a series of 6-aryl-3-amino-thieno[2,3-b]pyridine derivatives exhibited potent antiproliferative activities and an unique hepatocellular carcinoma (HCC)-specific anticancer activity was also observed. In further anti-inflammatory research, thienopyridine derivative 1a showed potent inhibition of nitric oxide (NO) production. So a series of thienopyridine analogues of 1a were synthesized and evaluated for anti-inflammatory activities. The structure-activity relationships (SARs) revealed that the most potent analogues 1f and 1o were identified as potent inhibitors of NO production with IC50 values of 3.30 and 3.24 μM, respectively. These results suggest that these 6-aryl-3-amino-thieno[2,3-b]pyridine derivatives might potentially constitute a novel class of anti-inflammatory agents, which require further studies. 22503097 Continuous production of drug nanoparticle suspensions via wet stirred media milling: a fresh look at the Rehbinder effect. Nanoparticles of BCS Class II drugs are produced in wet stirred media mills operating in batch or recirculation mode with the goal of resolving the poor water-solubility issue. Scant information is available regarding the continuous production of drug nanoparticles via wet media milling. Griseofulvin and Naproxen were milled in both recirculation mode and multi-pass continuous mode to study the breakage dynamics and to determine the effects of suspension flow rate. The evolution of the median particle size was measured and described by an empirical breakage model. We found that these two operation modes could produce drug nanosuspensions with similar particle size distributions (PSDs). A reduced suspension flow rate slowed the breakage rate and led to a wider PSD and more differentiation between the two operation modes. The latter part of this study focused on the roles of stabilizers (hydroxypropyl cellulose and sodium lauryl sulfate) and elucidation of the so-called Rehbinder effect (reduction in particle strength due to adsorbed stabilizers such as polymers and surfactants). Milling the drugs in the absence of the stabilizers produced primary nanoparticles and their aggregates, while milling with the stabilizers produced smaller primary nanoparticles with minimal aggregation. Using laser diffraction, BET nitrogen adsorption, scanning electron microscopy imaging, and a microhydrodynamic analysis of milling, this study, for the first time, provides sufficient evidence for the existence of the Rehbinder effect during the milling of drugs. Not only do the polymers and surfactants allow proper stabilization of the nanoparticles in the suspensions, but they also do facilitate drug particle breakage. 23602474 Flies Cope with Uncontrollable Stress by Learned Helplessness. In a wide range of animals, uncontrollable stressful events can induce a condition called "learned helplessness." In mammals it is associated with low general activity, poor learning, disorders of sleep and feeding, ulcers, and reduced immune status, as well as with increased serotonin in parts of the brain. It is considered an animal model of depression in humans [1-4]. Here we investigate learned helplessness in Drosophila, showing that this behavioral state consists of a cognitive and a modulatory, possibly mood-like, component. A fly, getting heated as soon as it stops walking, reliably resumes walking to escape the heat. If, in contrast, the fly is not in control of the heat, it learns that its behavior has no effect and quits responding. In this state, the fly walks slowly and takes longer and more frequent rests, as if it were "depressed." This downregulation of walking behavior is more pronounced in females than in males. Learned helplessness in Drosophila is an example of how, in a certain situation, behavior is organized according to its expected consequences. 23542815 Arsenic trioxide induces cardiac fibroblast apoptosis in vitro and in vivo by up-regulating TGF-β1 expression. Arsenic trioxide (As2O3; ATO) is clinically effective in treating acute promyelocytic leukemia (APL); however, it frequently causes cardiotoxic effects. This study was designed to investigate whether ATO could induce apoptosis of cardiac fibroblasts (CFs) that play very important roles in maintaining the structure integrity and function of the heart. Cardiac fibroblasts from guinea pigs administered with ATO (1mg/kgbw) were used to test the pro-apoptotic role of ATO in vivo. The current study demonstrated that ATO induced morphological characteristics of apoptosis and Caspase-3 activation in CFs of guinea pigs along with a significant up-regulation in TGF-β1 protein expression, Bax/Bcl-2 ratio and ERK1/2 phosphorylation. In vitro MTT assay showed that ATO remarkably reduced the viability of cultured cardiac fibroblasts (NRCFs) from neonatal rat in a concentration- and time-dependent manner. Consistent with the notions in vivo, ATO significantly induced the apoptosis in NRCFs, dramatically up-regulated TGF-β1 protein level and Bax/Bcl-2 ratio in a time-dependent fashion and activated Caspase-3 and ERK1/2. Finally, pretreatment with LY364947, an inhibitor of TGF-β signaling could apparently reverse these changes. We therefore conclude that TGF-β is functionally linked to ERK1/2 and that TGF-β signaling is responsible for ATO-induced CFs apoptosis, which provides a novel mechanism of ATO related cardiac toxicology. 23590478 Use of Monte Carlo simulations in the assessment of calibration strategies - Part III: an evaluation of linear calibration. Background: The acceptance criteria for chromatographic bioassays are generally based upon the specifications found in the US FDA Guidance for Industry document, whereas regression analysis is a statistical process and, thus, most suited to large data populations, rather than the small populations used in assay calibration. Data that form part of the statistical population are often excluded in order that calibrations meet these acceptance criteria. Results/discussion: Monte Carlo simulations of various linear regression calibration strategies, which take into account guidance acceptance criteria, have been used to quantify calibration errors. Conclusion: It is concluded that 1/x(2) weighting generally produces results that meet both theoretical and regulatory requirements, and that use of single, rather than duplicate, calibrators can result in misleading statistics at the LLOQ. 23311400 Morphological control via chemical and shear forces in block copolymer self-assembly in the lab-on-chip. We investigate the effects of variation in chemical conditions (solvent composition, water content, polymer concentration, and added salt) on the morphologies formed by PS-b-PAA in DMF/dioxane/water mixtures in a two-phase gas-liquid segmented microfluidic reactor. The differences in morphologies between off-chip and on-chip self-assembly and on-chip morphological trends for different chemical conditions are explained by the interplay of top-down shear effects (coalescence and breakup) and bottom-up chemical forces. Using off-chip morphology results, we construct a water content-solvent composition phase diagram showing disordered, sphere, cylinder, and vesicle regions. On-chip morphologies are found to deviate from off-chip morphologies by three identified shear-induced paths: 1) sphere-to-cylinder, and 2) sphere-to-vesicle transitions, both via shear-induced coalescence when initial micelle sizes are small, and 3) cylinder-to-sphere transitions via shear-induced breakup when initial micelle sizes are large (high capillary number conditions). These pathways contribute to the generation of large extended bilayer aggregates uniquely on-chip, at either increased polymer or salt concentrations. Collectively these results demonstrate the broad utility of top-down directed molecular self-assembly in conjunction with chemical forces to control morphology and size of polymer colloids at the nanoscale. 23408601 Correlates of bone microarchitectural parameters and serum sclerostin levels in men - the STRAMBO study. Sclerostin is predominantly expressed by osteocytes. Serum sclerostin levels are positively correlated with areal bone mineral density (aBMD) measured by DXA and bone microarchitecture assessed by high resolution peripheral quantitative computed tomography (HR-pQCT) in small studies. We assessed the relation of serum sclerostin levels with aBMD and microarchitectural parameters based on HR-pQCT in 1134 men aged 20-87 years using multivariable models adjusted for confounders (age, body size, lifestyle, co-morbidities, hormones regulating bone metabolism, muscle mass and strength). The apparent age-related increase in serum sclerostin levels was faster before the age of 63 than afterwards (0.43SD vs 0.20SD per decade). In 446 men aged ≤63, aBMD (spine, hip, whole body), trabecular volumetric BMD (Tb.vBMD) and trabecular number (Tb.N) at the distal radius and tibia were higher in the highest sclerostin quartile vs the three lower quartiles combined. After adjustment for aBMD, men in the highest sclerostin quartile had higher Tb.vBMD (mainly in the central compartment) and Tb.N at both skeletal sites (p<0.05-0.001). In 688 men aged >63, aBMD was positively associated with serum sclerostin levels at all skeletal sites. Cortical vBMD (Ct.vBMD) and cortical thickness (Ct.Th) were lower in the first sclerostin quartile vs the three higher quartiles combined. Tb.vBMD increased across the sclerostin quartiles which was associated with lower Tb.N and more heterogeneous trabecular distribution (higher Tb.Sp.SD) in men in the lowest sclerostin quartile. After adjustment for aBMD, men in the lowest sclerostin quartile had lower Tb.vBMD and Tb.N, but higher Tb.Sp.SD (p<0.05-0.001) at both the skeletal sites. In conclusion, serum sclerostin levels in men are strongly positively associated with better bone microarchitectural parameters, mainly trabecular architecture, regardless of the potential confounders. © 2013 American Society for Bone and Mineral Research. 23205567 Acute pulmonary effects of sidestream secondhand smoke at simulated car concentrations. 1. Exposure to secondhand smoke (SHS) can occur in many places; however, regulations banning smoking may reduce the sources of exposure to SHS to personal areas such as the family car, a source of brief but potently intense exposure. 2. Fifteen non-smoking volunteers were exposed to sidestream SHS concentrations of 5000 µg/m(3), within a simulated car setting. The Fraction of Exhaled Nitric Oxide (FeNO) was calculated, dynamic flow volumes were assessed through spirometry; while airway impedance (Z), resistance (R), and reactance (X) was assessed through impulse oscillometry before and after exposure. 3. Exposure to sidestream SHS within this experimental condition did not affect dynamic flow volumes, however FENO decreased from 15.34 ppb to 11.15 ppb, (p < 0.001). Increases in airway resistance at R5Hz by 0.114 kPa/(L/s) (p = 0.002), at R10Hz by 0.093[kPa/(L/s)] (p = 0.006) and at R20Hz by 0.093[kPa/(L/s)] (p = 0.008) were noted. Correspondingly overall peripheral and central airway resistance was also found to increase by 40% (by 0.083 kPa/(L/s), p = 0.038) and 25% (by 0.045 kPa/(L/s), p = 0.047) respectively. 4. Brief but elevated exposure to sidestream SHS can alter airway resistance, and impedance indicating a potential additional mechanistic pathway between exposure to SHS and the development of respiratory disease. Further research is needed to verify these pilot results. 22591127 Fatty acid composition of selected macrophytes. The content of total lipids and the fatty acid (FA) profile were determined for eight macroalgae (Cystoseira abies-marina, Fucus spiralis, Chaetomorpha pachynema, Codium elisabethae, Porphyra sp., Osmundea pinnatifida, Pterocladiella capillacea and Sphaeroccoccus coronopifolius). Total lipids were extracted using a solvent mixture of methanol/chloroform (2/1, v/v) and further derivatised to FA methyl esters (FAME). The analyses of FAME samples were performed by gas chromatography coupled to a flame ionisation detector. The total lipid content ranged from 0.06 to 3.54 g (per 100 g). The most abundant saturated FA were palmitic (C16:0) and myristic (C14:0), while oleic (C18:1 n-9) was the dominant monounsaturated acid. All seaweeds contained linoleic FA (C18:2 n-6). The α-linolenic (C18:3 n-3) and eicosapentaenoic (20:5 n-3) acids were present only in Porphyra sp. (3.34% ± 0.13) and C. pachynema (0.47% ± 0.12), respectively. The n-6/n-3 and h/H ratios were low, suggesting a high nutritional value of the algae studied. 23608764 Discovery of natural estrogen receptor modulators with structure-based virtual screening. Eleven compounds were identified as estrogen receptor modulators from an in-house natural product database (NPD) by structure-based virtual screening for ERα and ERβ. Among them, 3 compounds were confirmed as ER agonists and 8 compounds were confirmed as ER antagonists by yeast two-hybrid (Y2H) assay, with EC50 values ranging from several micromolar to 100 micromolar. In this study, a novel series of cycloartane triterpenoids isolated from Schisandra glaucescens Diels was found to have ER antagonistic effect, the most potent antagonist of which exhibited activity with EC50 value of 2.55 and 4.68μM for ERα and ERβ, respectively. Moreover, the types of modulation and subtype selectivity were also investigated through molecular docking simulation. 23194534 Whey protein hydrolysate enhances the exercise-induced heat shock protein (HSP70) response in rats. Whey protein has been suggested to be potential protective agent against various forms of stress. The heat shock protein HSP70 confers greater cellular tolerance against stressors. The present study evaluated the effects of whey protein intake on HSP70 expression. Forty-eight male Wistar rats were divided into sedentary and exercised groups, and each group was fed as a protein source casein (CAS), whey protein (WP) or whey protein hydrolysate (WPH) for 3weeks. Exercise on a treadmill was used as the source of stress in the animals from the exercised group. The results showed a larger increase in HSP70 expression in the soleus, gastrocnemius and lung of the WPH-fed rats than WP or casein-fed rats. HSP70 expression in the sedentary rats was very low, independent of the diet or tissue. Protein carbonyls were lower in the group that consumed WPH. These data suggest that the consumption of WPH enhances HSP70 expression. 22884111 Sonochemical synthesis of hierarchical ZnO nanostructures. This work is about fabrication of ZnO nanostructures (ZnO-NS) via a simple sonochemical method. The chemicals used for the synthesis of various shaped ZnO are Zn salt, sodium hydroxide and ammonia solution without other structure directing agent or surfactant needed. This method is feasible and green, as it does not require high temperature and/or highly toxic chemicals. The shape of the ZnO-NS can be tuned by adjusting the ultrasound energy dissipated via varying the ultrasonication time from 5 to 60 min. It was found that uniform ZnO nanorods with diameter around 50 nm were formed after 15 min of ultrasonication while flowerlike ZnO-NS was formed after 30 min. This method produces high quality ZnO-NS with controllable shapes, uniformity, and purity. 23297250 Effect of major cations (Ca(2+) , Mg(2+) , Na(+) , K(+) ) and anions (SO 42-, Cl(-) , NO 3-) on Ni accumulation and toxicity in aquatic plant (Lemna minor L.): implications For Ni risk assessment. The effect of major cation activity (Ca(2+) , Mg(2+) , Na(+) , K(+) ) on Ni toxicity, with dose expressed as exposure (total dissolved Ni concentration NiTot ) or free Ni ion activity (in solution Ni(2+) ), or as tissue residue (Ni concentration in plant tissue NiTiss ) to the aquatic plant Lemna minor L. was examined. In addition, Ni accumulation kinetics was explored to provide mechanistic insight into current approaches of toxicity modeling, such as the tissue residue approach and the biotic ligand model (BLM), and the implications for plant Ni risk assessment. Major cations did not inhibit Ni accumulation via competitive inhibition as expected by the BLM framework. For example, Ca(2+) and Mg(2+) (sulfate as counter-anion) had an anticompetitive effect on Ni accumulation, suggesting that Ca or Mg forms a ternary complex with Ni-biotic ligand. The counter-anion of the added Ca (sulfate, chloride, or nitrate) affected plant response (percentage of root growth inhibition) to Ni. Generally, sulfate and chloride influenced plant response while nitrate did not, even when compared within the same range of Ca(2+) , which suggests that the anion dominated the observed plant response. Overall, although an effect of major cations on Ni toxicity to L. minor L. was observed at a physiological level, Ni(2+) or NiTot alone modeled plant response, generally within a span of twofold, over a wide range of water chemistry. Thus, consideration of major cation competition for improving Ni toxicity predictions in risk assessment for aquatic plants may not be necessary. 23249265 Extremely flexible nanoscale ultrathin body silicon integrated circuits on plastic. In recent years, flexible devices based on nanoscale materials and structures have begun to emerge, exploiting semiconductor nanowires, graphene, and carbon nanotubes. This is primarily to circumvent the existing shortcomings of the conventional flexible electronics based on organic and amorphous semiconductors. The aim of this new class of flexible nanoelectronics is to attain high-performance devices with increased packing density. However, highly integrated flexible circuits with nanoscale transistors have not yet been demonstrated. Here, we show nanoscale flexible circuits on 60 Å thick silicon, including functional ring oscillators and memory cells. The 100-stage ring oscillators exhibit the stage delay of ~16 ps at a power supply voltage of 0.9 V, the best reported for any flexible circuits to date. The mechanical flexibility is achieved by employing the controlled spalling technology, enabling the large-area transfer of the ultrathin body silicon devices to a plastic substrate at room temperature. These results provide a simple and cost-effective pathway to enable ultralight flexible nanoelectronics with unprecedented level of system complexity based on mainstream silicon technology. 23615124 Screening for polyphenols, antioxidant and antimicrobial activitiesof extracts from eleven Helianthemum taxa (Cistaceae) used in folk medicine in south-eastern Spain. ETHNOPHARMACOLOGICAL RELEVANCE: The Helianthemum genus contains approximately one hundred taxa. Some of them are important medicinal plants used in several countries for many different purposes. However, studies addressing the phytochemistry of many of these species or their biological activities are currently nonexistent. AIM OF THE STUDY: To perform a comparative analysis of the qualitative composition of secondary metabolites and biological activities of the leaves of the most commonly distributed and used Spanish Helianthemum taxa in order to find a relationship between chemotype, biological activity and uses. MATERIALS AND METHODS: water and 80% methanolic extracts derived from 11 different Helianthemum taxa were analyzed for their phytochemical composition using standard methods. Furthermore, HPLC analysis was performed for the estimation of gallic acid, ellagic acid, tannins and flavonols as marker compounds. The antioxidant activity was measured by employing the scavenging activity on DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS (2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonate) radicals. The 80% methanolic extracts were evaluated for antibacterial (Gram-positive Staphylococcus aureus, Enterococcus faecalis and Listeria monocytogenes and Gram-negative Escherichia coli and Salmonella enterica) activity using the micro dilution technique. RESULTS: The total polyphenolic content and antioxidant capabilities differed significantly among the Helianthemum leaf extracts. A strong correlation between total phenolic content, antioxidant properties and antimicrobial activity was found. The polyphenolic profile was specific for each taxon. Whereas Helianthemum alypoides, Helianthemum cinereum subsp. rotundifolium, Helianthemum hirtum, Helianthemum asperum, and Helianthemum marifolium subsp. marifolium were characterized by the presence of gallic acid, egallic derivatives and ellagitannins; the polyphenolic profile of Helianthemum apenninum subsp. cavanillesianum, Helianthemum syriacum and Helianthemum polygonoides was mostly based on flavonoids. Helianthemum cinereum, Helianthemum alypoides and Helianthemum marifolium consistently presented the strongest radical scavenging activity (in water extracts EC50 ranges from 29.88 to 38.1 against DPPH and from 8.11 to 20.8 against ABTS, and in 80% MeOH extracts from 25.3 to 31.8 against DPPH and from 6.15 to 8.6 against ABTS), total phenol content (>117mg GAE/l) and antimicrobial activities. CONCLUSION: The Helianthemum taxa used in folk medicine did not cluster in a unique section, being equally distributed in two out of the four sections analysed. There was not a clear relationship between the chemotype, based on the polyphenolic composition of the taxa, and their taxonomical classification. However, the composition of the methanolic and water extracts from the leaves of plants belonging to the Helianthemum genus was strongly related to their medicinal uses. 22708546 Cytotoxic and leishmanicidal properties of garcinielliptone FC, a prenylated benzophenone from Platonia insignis. Garcinielliptone FC (GFC), a natural prenylated benzophenone, was extracted from Platonia insignis Mart. (Clusiaceae), a native plant commonly known as bacuri and used in traditional Brazilian medicine for the treatment of skin diseases. The aim of this study was to evaluate the cytotoxic and leishmanicidal effects of GFC using in vitro models. The experimental data demonstrated that the polyisoprenylated benzophenone GFC possesses cytotoxic and leishmanicidal activities. 23240979 Understanding the dark and light-enhanced bactericidal action of cationic conjugated polyelectrolytes and oligomers. A multiscale investigation was carried out to study the dark and light-enhanced bactericidal mechanisms of poly(phenylene ethynylene) (PPE)-based cationic conjugated polyelectrolytes (CPEs) and oligo-phenylene ethynylenes (OPEs). On the morphological scale, Gram-negative E. coli cells exposed to CPE and OPE compounds in the dark show damage to the cell envelope, plasma membrane, and in some cases the cytoplasm, while with UV-irradiation, E. coli sustained catastrophic damages to both the cell envelope and cytoplasm. In contrast, the Gram-positive S. epi bacteria appeared intact when exposed to CPE and OPE compounds in the dark but showed damages to the cell envelope with UV-irradiation. To better understand the molecular basis of CPE- and OPE-induced morphological changes and damages to bacteria, we investigated the effect of these compounds on model bacterial plasma membrane and bacterial proteins and plasmid DNA. Measurements of dark membrane perturbation activity of the CPEs and OPEs using model lipid membranes support a carpet or detergent-like mechanism by which the antimicrobial compounds induce membrane collapse and phase transitions. Under UV-irradiation, E. coli bacteria exposed to CPEs and OPEs showed covalent modifications and damages to both cellular protein and plasmid DNA, likely through oxidative pathways mediated by singlet oxygen and subsequent reactive oxygen species sensitized by the CPE and OPE compounds. Our finding thus show that the antimicrobial polymers and oligomers exert toxicity toward Gram-negative bacteria by disrupting the morphology and structures of cell envelope and cytoplasm, including cellular components such as proteins and DNA, while exert toxicity toward Gram-positive bacteria by binding to and disrupting just the cell wall. 23369932 Short-term assessment of toxicological aspects, oxidative and inflammatory response to dietary melon superoxide dismutase in rats. The protective effects of SODB, a gastro-resistant encapsulated melon superoxide dismutase, on haematological and biochemical parameters and inflammatory and oxidative status, were evaluated in the blood and liver tissue. The study consisted in a 28-day experiment on rats supplemented with three doses (10, 40 and 160USOD/day) of SODB-M, SODB-D or SODB-S, different depending on the nature of the coating (palm oil, shellac or gum Arabic respectively). No mortality, abnormal clinical signs, behavioural changes or macroscopic findings were observed whatever the groups. Haematological parameters (total red blood cell count, haemoglobin content, haematocrit, red cell indices, white blood cell count and platelets count) were not modified in SODB treated-groups. No marked change was recorded in biochemical parameters (plasma urea, creatinine, lipids, electrolytes, bilirubin, transaminases and gamma-glutamyl transferase). The liver endogenous antioxidant enzymes (copper/zinc and manganese superoxide dismutase) expressions were significantly increased in the rats receiving the highest dose of SODB (160USOD/day) whatever the coating. Moreover, interleukin-6, a marker of inflammation, was significantly decreased in these high dose-treated-groups. The present study indicates that dietary supplementation of SODB on rats has no harmful side effects and could be beneficial especially at high doses. 23497868 Theaflavins, dimeric catechins, inhibit peptide transport across Caco-2 cell monolayers via down-regulation of AMP-activated protein kinase-mediated peptide transporter PEPT1. In the small intestine, peptide transporter 1 (PEPT1) plays a role in the transport of di- and tripeptides. In this study, we investigated whether theaflavins (TFs) affect the absorption of small peptides in human intestinal Caco-2 cells, since TFs do not penetrate through the cells and might be involved in intestinal transport systems. In transport experiments, the transport of glycyl-sarcosine (Gly-Sar, a model molecule for PEPT1 transport) and other dipeptides (Val-Tyr and Ile-Phe) were significantly reduced (P<0.05) in TFs-pretreated cells. In TF 3'-O-gallate-pretreated cells, Western blot analysis revealed attenuated expression of PEPT1 transporter and Gly-Sar transport was completely ameliorated by 10 μM Compound C, an AMP-activated protein kinase (AMPK) inhibitor. In conclusion, the present study demonstrated that TFs inhibit peptide transport across Caco-2 cell monolayers, probably through suppression of AMPK-mediated PEPT1 expression, which should be considered a new bioactivity of TFs in black tea. 23360211 Macroporous silk fibroin cryogels. Silk fibroin cryogels with remarkable properties were obtained from frozen fibroin solutions (4.2-12.6%) at subzero temperatures between -5 and -22 °C. This was achieved by the addition of ethylene glycol diglycidyl ether (EGDE) into the cryogelation system. EGDE triggers the conformational transition of fibroin from random coil to β-sheet structure and hence fibroin gelation. One of the unique features of fibroin cryogels is their elasticity that allows them to resist complete compression without any crack development, during which water inside the cryogel is removed. The compressed cryogel immediately swells during unloading to recover its original shape. The scaffolds obtained by freeze-drying of the cryogels consist of regular, interconnected pores of diameters ranging from 50 to 10 μm that could be regulated by the synthesis parameters. The mechanical compressive strength and the modulus of the scaffolds increase with decreasing pore diameter, that is, with decreasing gelation temperature or, with increasing fibroin or EGDE concentrations in the feed. The scaffolds produced at 12.6% fibroin exhibit a very high compressive modulus (50 MPa) making them good candidates as bone scaffold materials. 23200888 Effects of pubertal exposure to thiazole-Zn on thyroid function and development in female rats. Thiazole-Zn is a newly Chinese-created systemic fungicide, and belongs to the sort of thiadiazole compounds, some of which have been found to be thyroid disrupters. To determine the probable adverse effects of thiazole-Zn on thyroid gland and development function, the rodent 20-day Pubertal Female Assay in this study was used. Postnatal days (PND) 22-old Sprague-Dawley rats were administered with thiazole-Zn daily by oral gavage at doses 0, 40, 100, 200 mg/kg/day for 20 days. The thyroid endpoints and development endpoints were assessed. The results indicated that serum TT4 and TSH levels were significantly increased at all concentrations, serum TT3 levels were significantly reduced only at 40 mg/kg thiazole-Zn, but had no difference from controls at the other doses. Thyroid histology was significantly altered at all doses with a clear dose-dependent hypertrophy and hyperplasia of thyroid cell. No histological changes were observed in any of the other observed organs. In addition, this study also found that ovarian weights were significantly decreased, but age and weight at vaginal opening (VO), serum E2 levels were unaffected in all treatment groups. These results demonstrate that thiazole-Zn is likely a thyroid disrupter, but did not demonstrate that it has estrogenic/anti-estrogenic activity. 23398189 Prediction of micelle/water and liposome/water partition coefficients based on molecular dynamics simulations, COSMO-RS, and COSMOmic. Liposomes and micelles find various applications as potential solubilizers in extraction processes or in drug delivery systems. Thermodynamic and transport processes governing the interactions of different kinds of solutes in liposomes or micelles can be analyzed regarding the free energy profiles of the solutes in the system. However, free energy profiles in heterogeneous systems such as micelles are experimentally almost not accessible. Therefore, the development of predictive methods is desirable. Molecular dynamics (MD) simulations reliably simulate the structure and dynamics of lipid membranes and micelles, whereas COSMO-RS accurately reproduces solvation free energies in different solvents. For the first time, free energy profiles in micellar systems, as well as mixed lipid bilayers, are investigated, taking advantage of both methods: MD simulations and COSMO-RS, referred to as COSMOmic (Klamt, A.; Huniar, U.; Spycher, S.; Keldenich, J. COSMOmic: A Mechanistic Approach to the Calculation of Membrane-Water Partition Coefficients and Internal Distributions within Membranes and Micelles. J. Phys. Chem. B 2008, 112, 12148-12157). All-atom molecular dynamics simulations of the system SDS/water and CTAB/water have been applied in order to retrieve representative micelle structures for further analysis with COSMOmic. For the system CTAB/water, different surfactant concentrations were considered, which results in different micelle sizes. Free energy profiles of more than 200 solutes were predicted and validated by means of experimental partition coefficients. To our knowledge, these are the first quantitative predictions of micelle/water partition coefficients, which are based on whole free energy profiles from molecular methods. Further, the partitioning in lipid bilayer systems containing different hydrophobic tail groups (DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), SOPC (stearoyl-oleoylphosphatidylcholine), DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine), and POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine)) as well as mixed bilayers was calculated. Experimental partition coefficients (log P) were reproduced with a root-mean-square error (RMSE) of 0.62. To determine the influence of cholesterol as an important component of cellular membranes, free energy profiles in the presence of cholesterol were calculated and shown to be in good agreement with experimental data. 23171962 High electrochemical performance based on ultrathin porous CuO nanobelts grown on Cu substrate as integrated electrode. A facile and low-cost approach has been developed to fabricate porous CuO nanobelts directly grown on a Cu substrate. The as-prepared CuO samples can be directly used as integrated electrodes for lithium-ion batteries and pseudo-supercapacitors without the addition of other ancillary materials such as carbon black or a binder to enhance electrode conductivity and cycling stability. The unique nanostructural features endow them with excellent electrochemical performance as demonstrated by high capacities of 640 mA h g(-1) after 100 cycles at 0.2 C rate and an excellent specific capacitance of 340 F g(-1), which corresponds to the energy density of 45 W h kg(-1). The cyclability of the electrode demonstrates only a 10-15% loss in capacitance over 5000 cycles. 22438103 The marine alga Gelidium amansii promotes the development and complexity of neuronal cytoarchitecture. Neurotrophic factors are vital not only to support neuronal development but also to protect mature neurons from atrophy in neurodegenerative diseases. As an effort to explore natural sources that possess neurotrophic activity, we screened common marine algae for their neuritogenic activity in the developing rat hippocampal neurons in culture. Of the 22 seaweed species examined, ethanol extracts of Gelidium amansii (GAE) exhibited potent neuritogenic activity, followed by Undaria pinnatifida and Sargassum fulvellum extracts. The effects of GAE were dose dependent with an optimum concentration of 15 µg/mL. The GAE significantly promoted the initial neuronal differentiation from the stage I into the stage II and increased the indices of axonal and dendritic development such as the length, the numbers of primary processes, and branching frequencies by a minimum of twofold compared with the vehicle control. These results show that marine algae are promising candidates for neurotrophic potentials. 23575940 Cryptococcal infections: changing epidemiology and implications for therapy. Although the incidence of HIV-associated cryptococcosis has decreased in developed countries since the introduction of antiretroviral therapy, this disease continues to cause significant morbidity and mortality in sub-Saharan Africa among patients with AIDS. Important strides have been made in an attempt to decrease the burden of disease, particularly the development of the lateral flow assay cryptococcal antigen (LFA CrAg) as a diagnostic tool in resource-limited settings, coupled with the introduction of pre-emptive treatment with fluconazole for HIV-positive patients at risk for cryptococcosis with a positive LFA CrAg. Among solid organ transplant recipients, recent prospective studies have identified cryptococcosis as the third most common invasive fungal infection, and progress is being made toward earlier diagnosis and more effective therapy. Finally, the Cryptococcus gattii outbreak in British Columbia, Canada and the US Pacific Northwest is providing important new insights into the emergence of this pathogen in geographic areas previously considered low risk for acquisition of infection. Understanding the similarities and differences among C. gattii and C. neoformans infections will provide critical insights into the behavior of these organisms in the human host. Both pathogens affect immunocompetent and immunosuppressed hosts, causing pulmonary, central nervous system and widely disseminated infections. Treatment recommendations in the future will necessarily take into account the site of infection, clinical severity of the infection, Cryptococcus species, host immune status and economic resources. 23631539 Evaluation of intratympanic formulations for inner ear delivery: methodology and sustained release formulation testing. Abstract A convenient and efficient in vitro diffusion cell method to evaluate formulations for inner ear delivery via the intratympanic route is currently not available. The existing in vitro diffusion cell systems commonly used to evaluate drug formulations do not resemble the physical dimensions of the middle ear and round window membrane. The objectives of this study were to examine a modified in vitro diffusion cell system of a small diffusion area for studying sustained release formulations in inner ear drug delivery and to identify a formulation for sustained drug delivery to the inner ear. Four formulations and a control were examined in this study using cidofovir as the model drug. Drug release from the formulations in the modified diffusion cell system was slower than that in the conventional diffusion cell system due to the decrease in the diffusion surface area of the modified diffusion cell system. The modified diffusion cell system was able to show different drug release behaviors among the formulations and allowed formulation evaluation better than the conventional diffusion cell system. Among the formulations investigated, poly(lactic-co-glycolic acid)-poly(ethylene glycol)-poly(lactic-co-glycolic acid) triblock copolymer systems provided the longest sustained drug delivery, probably due to their rigid gel structures and/or polymer-to-cidofovir interactions. 23544432 Synthesis and Pharmacological Characterization of 2-(Acylamino)thiophene Derivatives as Metabolically Stable, Orally Effective, Positive Allosteric Modulators of the GABAB Receptor. Two recently reported hit compounds, COR627 and COR628, underpinned the development of a series of 2-(acylamino)thiophene derivatives. Some of these compounds displayed significant activity in vitro as positive allosteric modulators of the GABAB receptor by potentiating GTPγS stimulation induced by GABA at 2.5 and 25 μM while failing to exhibit intrinsic agonist activity. Compounds were also found to be effective in vivo, potentiating baclofen-induced sedation/hypnosis in DBA mice when administered either intraperitoneally or intragastrically. Although displaying a lower potency in vitro than the reference compound GS39783, the new compounds 6, 10, and 11 exhibited a higher efficacy in vivo: combination of these compounds with a per se nonsedative dose of baclofen resulted in shorter onset and longer duration of the loss of righting reflex in mice. Test compounds showed cytotoxic effects at concentrations comparable to or higher than those of GS39783 or BHF177. 23337567 Osteoblasts survive the arsenic trioxide treatment by activation of ATM-mediated pathway. Arsenic trioxide (ATO) is widely used in tumor treatment, but excessive arsenic exposure can have adverse effects. We recently found that, in primary osteoblasts, ATO produces oxidative stress and causes DNA tailing, but does not induce apoptosis. We further examined the signaling pathway by which osteoblasts survive ATO treatment, and found that they were arrested at G2/M phase of the cell cycle at 30h and overrode the G2/M boundary at 48h. After treatment for 30h, there was increased Cdc2 phosphorylation and expression of Wee1, a Cdc2 kinase, and expression of the cell cycle inhibitor, p21(waf1/cip1), which interacts with Cdc2. Furthermore, levels of the phosphatase Cdc25C, which activates Cdc2, were decreased, while the ratio of its phosphorylated/inactivated form to the total amount was increased. Moreover, phosphorylation/activation of the checkpoint kinases Chk1, Chk2 and p53 levels were increased, as were levels of activated ATM and γ-H2AX. The cell viability was decreased as an ATM inhibitor was added. Additionally, these effects of ATO on γ-H2AX, Chk1, Chk2, p53, and p21(waf1/cip1) were reduced by an ATM inhibitor. These findings suggest that G2/M phase arrest of osteoblasts is mediated by Chk1/Chk2 activation via an ATM-dependent pathway by which osteoblasts survive. 22616839 Single non-ionic surfactant based self-nanoemulsifying drug delivery systems: formulation, characterization, cytotoxicity and permeability enhancement study. Single non-ionic surfactant based self-nanoemulsifying drug delivery system (SNEDDS) was formulated and characterised for poor water soluble drug, Atorvastatin calcium. Capmul MCM oil showing highest solubility for Atorvastatin calcium was selected as oil phase. Self-nanoemulsifying capacity of Cremophor RH 40, Cremophor EL, Tween 20, Tween 60, Tween 80 and Labrasol were tested for the selected oil. In vitro dissolution studies were performed and were characterized by t85% and dissolution efficiency (DE). Cytotoxicity of the formulations and permeation enhancement of the drug across caco-2 cell monolayer was assessed. Capmul MCM was found to be better nanoemulsified in decreasing order of Cremophor RH 40 > Cremophor EL > Tween 20 > Tween 60 > Tween 80. Values of droplet size (range 11-83 nm), polydispersity index (range 0.07-0.65); zeta potential (range -3.97 to -19.0) and cloud point (60-85°C) before and after drug loading proves the uniformity and stability of the formulations. SNEDDS formulated with Tween 20 surfactant showed enhanced dissolution with t85% and DE values at 10 min and 78.70, respectively. None of the formulation showed cytotoxicity at the concentration tested. Tween 20 based SNEDDS enhanced permeation of the drug as compared with pure drug across cell lines. It can be concluded that SNEDDS can be formulated by using single non-ionic surfactant system for enhance dissolution and absorption of poorly soluble drug, Atorvastatin calcium. 23314050 Diminutive effect on T and B-cell proliferation of non-cytotoxic α-santonin derived 1,2,3-triazoles: a report. α-Santonin derived new series of 1,2,3-triazoles synthesized through Azide-Alkyne Huisgen 1,3-dipolar cycloaddition reaction between substituted aryl azide and a propargylated α-desmotrosantonin were bio-evaluated for their diminutive effect on ConA induced T-cell and LPS induced B-cell proliferation. Interestingly, most of the synthesized compounds showed better immunosuppressant activity than α-santonin. Triazole derivatives 9, 10, 17, 18, 29, and 30 displayed significant diminutive effect on cell proliferation. Compounds 12 and 13 were found selective against ConA T-cell proliferation exhibiting >90% inhibition at 1 × 10(-6) M concentration. The present study resulted in identification of several triazole derivatives as effective immunosuppressive agents. 23207056 Comparison of hydroxyl radical formation in aqueous solutions at different ultrasound frequencies and powers using the salicylic acid dosimeter. Ultrasonic frequencies of 20kHz, 382kHz, 584kHz, 862kHz (and 998kHz) have been compared with regard to energy output and hydroxyl radical formation utilising the salicylic acid dosimeter. The 862kHz frequency inputs 6 times the number of Watts into water, as measured by calorimetry, with the other frequencies having roughly the same value under very similar conditions. A plausible explanation involving acoustic fountain formation is proposed although enhanced coupling between this frequency and water cannot be discounted. Using the salicylic acid dosimeter and inputting virtually the same Wattages it is established that 862kHz is around 10% more efficient at generating hydroxyl radicals than the 382kHz but both of these are far more effective than the other frequencies. Also, it is found that as temperature increases to 42°C then the total dihydroxybenzoic acid (Total DHBA) produced is virtually identical for 382kHz and 862kHz, though 582kHz is substantially lower, when the power levels are set at approximately 9W for all systems. An equivalent power level of 9W could not be obtained for the 998kHz transducer so a direct comparison could not be made in this instance. These results have implications for the optimum frequencies chosen for both Advanced Oxidation Processes (AOPs) and organic synthesis augmented by ultrasound. 23550937 Monocarbonyl Curcumin Analogues: Heterocyclic Pleiotropic Kinase Inhibitors That Mediate Anticancer Properties. Curcumin is a biologically active component of curry powder. A structurally related class of mimetics possesses similar anti-inflammatory and anticancer properties. Mechanism has been examined by exploring kinase inhibition trends. In a screen of 50 kinases relevant to many forms of cancer, one member of the series (4, EF31) showed ≥85% inhibition for 10 of the enzymes at 5 μM, while 22 of the proteins were blocked at ≥40%. IC50 values for an expanded set of curcumin analogues established a rank order of potencies, and analyses of IKKβ and AKT2 enzyme kinetics for 4 revealed a mixed inhibition model, ATP competition dominating. Our curcumin mimetics are generally selective for Ser/Thr kinases. Both selectivity and potency trends are compatible with protein sequence comparisons, while modeled kinase binding site geometries deliver a reasonable correlation with mixed inhibition. Overall, these analogues are shown to be pleiotropic inhibitors that operate at multiple points along cell signaling pathways. 23333503 Nitric oxide generated by the compound RuBPY promotes the vascular smooth cell membrane hyperpolarization. The cis-[Ru(bpy)(2)(py)NO(2)](PF(6)) specie (RuBPY) has been used as nitric oxide (NO) delivery agent. It is an NO reservoir and it is thermodynamically stable in aqueous solution. This study aimed to evaluate the NO specie generated by RuBPY as compared to NO released from sodium nitroprusside (SNP) and to study the cellular mechanisms specially focusing the activation of soluble guanylyl-cyclase (sGC), K(+) channels and the cell membrane hyperpolarization, which are the main targets for NO-inducing vascular relaxation. NO generated by RuBPY and the vascular smooth muscle cell (VSMC) membrane potential were measured by confocal microscopy. The cellular mechanisms of aorta relaxation were investigated using K(+) channel blockers and sGC inhibitor. NO released from RuBPY was higher than NO released from SNP. RuBPY released only radicalar NO(0) and SNP released both NO(-) and NO(0). The concentration-effect curves for RuBPY-induced relaxation was shifted to the right by inhibition of sGC with ODQ and by the non-selective blockade of K(+) channels with TEA. The simultaneous combination of ODQ and TEA abolished the vasorelaxation induced by RuBPY. The membrane potential measured by the sensitive dye 4-Di-ANNEPS demonstrated that RuBPY induces cell membrane hyperpolarization. Taken together, our results indicate that the large amount of NO(0) specie generated by RuBPY induces vasorelaxation due to activation of sGC, K(+) channels sensitive to TEA, and cell membrane hyperpolarization. These results indicate that NO(0) generated from RuBPY can also directly activate the K(+) channels in an independent way of sGC. 23623796 The accurate measurement of second virial coefficients using self-interaction chromatography: Experimental considerations. Measurement of B22, the second virial coefficient, is an important technique for describing the solution behaviour of proteins, especially as it relates to precipitation, aggregation and crystallisation phenomena. This paper describes the best practise for calculating B22 values from self-interaction chromatograms (SIC) for aqueous protein solutions. Detailed analysis of SIC peak shapes for lysozyme shows that non-Gaussian peaks are commonly encountered for SIC, with typical peak asymmetries of 10%. This asymmetry reflects a non-linear chromatographic retention process, in this case heterogeneity of the protein-protein interactions. Therefore, it is important to use the centre of mass calculations for determining accurate retention volumes and thus B22 values. Empirical peak maximum chromatogram analysis, often reported in the literature, can result in errors of up to 50% in B22 values. A methodology is reported here for determining both the mean and the variance in B22 from SIC experiments, includes a correction for normal longitudinal peak broadening. The variance in B22 due to chemical effects is quantified statistically and is a measure of the heterogeneity of protein-protein interactions in solution. In the case of lysozyme, a wide range of B22 values are measured which can vary significantly from the average B22 values. 23643756 Assessment of subjective cognitive and emotional effects of antipsychotic drugs. Effect by defect? Antipsychotic medication represents the first-line treatment of schizophrenia. While it is undisputed that antipsychotics ameliorate positive symptoms, the exact cognitive and emotional pathways through which its effect is exerted has remained unclear. The present study investigated the subjective effects of antipsychotics across various domains of cognition and emotion in both patients with psychotic symptoms and patients with other psychiatric diagnoses. A total of 69 patients with a probable history of psychosis or psychotic symptoms and 26 patients with psychiatric diagnoses other than psychosis participated in a survey conducted over the Internet. Multiple control measures aimed to secure response validity. All patients were currently or had previously been treated with antipsychotic agents. A questionnaire comprising 49 items and measuring possible effects of antipsychotics on cognition and emotion was administered. For 30 out of 49 items a clear response pattern emerged, which was similar for patients with psychotic disorders and patients with other diagnoses. Factor analysis of these items revealed three main effects of antipsychotic medication related to doubt and self-doubt, cognitive and emotional numbing, and social withdrawal. Antipsychotic treatment appears to be connected to a number of negative subjective effects on cognition and emotion. Further studies are warranted to assess how these effects impact on the patients' subjective well-being and quality of life, as well as their association with antipsychotic efficacy on the one hand, and adherence rates on the other. The induction of doubt and the dampening of emotion may be one reason why antipsychotics work and at the same time offer an explanation why they are experienced as rather unpleasant and are eventually discontinued by many patients. 23561195 Extra virgin olive oil bitterness evaluation by sensory and chemical analyses. An experimental investigation was performed on blend extra virgin olive oils (EVOOs) from different cultivars and EVOO from different olive monovarieties (Coratina, Leccino, Maiatica, Ogliarola) with the aim to evaluate the possibility of estimating the perceived bitterness intensity by using chemical indices, such as the total phenol content and the compounds responsible for oil bitterness measured spectrophotometrically at 225nm (K225 value), as bitterness predictors in different EVOO. Therefore, a bitterness predictive model, based on the relationship between the perceived bitterness intensity of the selected stimuli and the chosen chemicals parameters has been built and validated. The results indicated that the oil bitterness intensity could be satisfactorily predicted by using the K225 values of oil samples. 23122081 Physicochemical parameters that influence carotenoids bioaccessibility from a tomato juice. In vitro digestion models have been developed to estimate carotenoid bioavailability but most do not consider that their diffusion from fruit matrix to the lipid phase of the bolus could be a limiting step. Therefore we designed a model in which tomato juice is mixed with oil or oil/water emulsions, and the carotenoids diffusing to oil are measured by spectrometry. Temperature, pH and tomato juice/peanut oil ratio were evaluated for their influence on carotenoid diffusion. When oil/tomato ratio was between 0.11 and 1, extraction of lycopene was limited by the saturation of the oil phase. With a large excess of oil, diffusion was also limited, as only 31 ± 1% of lycopene could be extracted from the juice. Diffusion did not vary significantly with pH but doubled when temperature rose from 10°C to 37°C. When the juice was mixed in an emulsion stabilised with bovine serum albumin or phospholipids the maximum extraction decreased to 14.5 ± 0.2% and 18.5 ± 1.5% respectively, indicating that in addition to the saturation of the oil phase at low oil/tomato ratio and in addition to intrinsic properties of the tomato juice in non-saturating conditions, lycopene diffusion was limited by the structure of the interface in emulsions. 23229583 EBEC 2012--an energetic time in Freiburg. The seventeenth European Bioenergetics Conference (EBEC) took place in September 2012 at the Albert-Ludwigs-University in Freiburg, Germany, and was hosted by Thorsten Friedrich. The conference is a biannual event that brings together researchers from across the globe to discuss progress in this diverse and challenging field. 23213044 Reduced graphene oxide nanoribbon networks: a novel approach towards scalable fabrication of transparent conductive films. An innovative approach is developed for the high-throughput, large-area, and low-cost fabrication of reduced graphene oxide (RGO) nanoribbon networks by using electrospun polymer-based nanowires as the etching mask. Combined with their tunable, controllable structures and transmittance/conductivity properties, the as-fabricated RGO nanoribbon networks exhibit potential as transparent conductive film electrodes, for example, in electrochromic devices. 23561156 Effect of recovery methods on the oxidative and physical stability of oil body emulsions. Three natural oil body emulsions of a similar fat content (∼5%), but differing in their protein composition were obtained from an aqueous maize germ extract. The first was prepared by concentrating the aqueous oil body extract with ultrafiltration to a fat content of ∼5%. The other two were prepared by initially recovering the oil bodies from the extract by centrifugation, either in the presence of sucrose or by applying isoelectric precipitation at pH 5.0 and then diluting the resulting oil body creams with deionized water. The oxidative and physical stability of the three emulsions, either as they were or after submission to thermal treatment (100°C for 15min), were studied following storage at 45°C. The emulsions differed both in their oxidative and physical stability, depending on the recovery method that in turn influenced their continuous phase and/or interfacial membrane protein and/or polar antioxidant composition. Ultrafiltration resulted in the most stable emulsion. Mixtures of the natural oil body emulsions with green tea extracts, aiming to serve as a base for functional beverages, were then prepared and studied for their creaming behaviour. The green tea polyphenols seem to interact with the oil bodies leading to intensive dispersion destabilisation which, however, was halted following carrageenan addition at a relatively very low level. 22989775 Aryl methylcarbamates: Potency and selectivity towards wild-type and carbamate-insensitive (G119S) Anopheles gambiae acetylcholinesterase, and toxicity to G3 strain An. gambiae. New carbamates that are highly selective for inhibition of Anopheles gambiae acetylcholinesterase (AChE) over the human enzyme might be useful in continuing efforts to limit malaria transmission. In this report we assessed 34 synthesized and commercial carbamates for their selectivity to inhibit the AChEs found in carbamate-susceptible (G3) and carbamate-resistant (Akron) An. gambiae, relative to human AChE. Excellent correspondence is seen between inhibition potencies measured with carbamate-susceptible mosquito homogenate and purified recombinant wild-type (WT) An. gambiae AChE (AgAChE). Similarly, excellent correspondence is seen between inhibition potencies measured with carbamate-resistant mosquito homogenate and purified recombinant G119S AgAChE, consistent with our earlier finding that the Akron strain carries the G119S mutation. Although high (100- to 500-fold) WT An. gambiae vs human selectivity is observed for several compounds, none of the carbamates tested potently inhibits the G119S mutant enzyme. Finally, we describe a predictive model for WT An. gambiae tarsal contact toxicity of the carbamates that relies on inhibition potency, molecular volume, and polar surface area. 23187878 The role of natriuretic peptides as biomarkers for guiding the management of chronic heart failure. The current standard treatment of chronic heart failure (HF) is based on clinical judgment, with the goal of achieving the maximally tolerated therapeutic program. The complexity of this approach may contribute to the well-established treatment gaps that exist in HF management; consequently, the risks for morbidity and mortality in this population remain extremely high. Alternative means are needed to improve the outcomes of patients with HF. Natriuretic peptides are biological markers for HF disease--its presence, severity, and prognosis--and show unique interactions with therapeutics known to have benefit in HF. Accordingly, interest has recently developed in "biomarker-guided" care for HF. This approach involves applying these assays to identify patients in need of therapy intensification and to provide an objective "monitor" of disease status. This review examines the biology of natriuretic peptides, discusses the rationale for their use in HF, and details the aggregate experience gained thus far in biomarker-guided care. 23265496 Structural property of soybean lunasin and development of a method to quantify lunasin in plasma using an optimized immunoassay protocol. Lunasin is a 43-amino acid naturally occurring chemopreventive peptide with demonstrated anti-cancer and anti-inflammatory properties. The objectives of this study were to determine the effect of temperature on the secondary structure of lunasin, to develop a method of isolating lunasin from human plasma using an ion-exchange microspin column and to quantify the amount of lunasin using an optimized enzyme-linked immunosorbent assay. Lunasin was purified using a combination of ion-exchange chromatography, ultrafiltration and gel filtration chromatography. Circular dichroism showed that increased in temperature from 25 to 100 °C resulted in changes on the secondary structure of lunasin and its capability to interact with rabbit polyclonal antibody. Enzyme linked immunosorbent assay showed that lunasin rabbit polyclonal antibody has a titer of 250 and a specific activity of 0.05 mL/μg. A linear response was detected between 16 to 48 ng lunasin per mL (y=0.03x-0.38, R(2)=0.96). The use of diethylaminoethyl microspin column to isolate spiked lunasin in human plasma showed that most lunasin (37.8-46.5%) bound to the column eluted with Tris-HCl buffer, pH 7.5 with a yield up to 76.6%. In conclusion, lunasin can be isolated from human plasma by a simple DEAE microspin column technique and can be quantified using a validated and optimized immunoassay procedure. This method can be used directly to quantify lunasin from plasma in different human and animal studies aiming to determine its bioavailability. 23086037 Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Despite the recent attention focused on the roles of the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in the pathogenesis of type 2 diabetes, little is known about the ex vivo profile of inflammasome activation in type 2 diabetic patients. In this study, we investigated patterns of NLRP3 inflammasome activation in monocyte-derived macrophages (MDMs) from drug-naïve patients with newly diagnosed type 2 diabetes. Type 2 diabetic subjects had significantly increased mRNA and protein expression of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and proinflammatory cytokines in MDMs cultured with autologous sera compared with healthy controls. Upregulated interleukin (IL)-1β maturation, IL-18 secretion, and caspase-1 cleavage were observed in MDMs from type 2 diabetic patients after stimulation with various danger molecules (ATP, high-mobility group protein B1, free fatty acids, islet amyloid polypeptide, and monosodium uric acid crystals). Mitochondrial reactive oxygen species and NLRP3 were required for IL-1β synthesis in MDMs. Finally, 2 months of therapy with the antidiabetic drug metformin significantly inhibited the maturation of IL-1β in MDMs from patients with type 2 diabetes through AMP-activated protein kinase (AMPK) activation. Taken together, these data suggest that NLRP3 inflammasome activation is elevated in myeloid cells from type 2 diabetic patients and that antidiabetic treatment with metformin contributes to modulation of inflammasome activation in type 2 diabetes. 23091188 Combination lopinavir and ritonavir alter exogenous and endogenous bile acid disposition in sandwich-cultured rat hepatocytes. Inhibition of the bile salt export pump (BSEP) can cause intracellular accumulation of bile acids and is a risk factor for drug-induced liver injury in humans. Antiretroviral protease inhibitors lopinavir (LPV) and ritonavir (RTV) are reported BSEP inhibitors. However, the consequences of LPV and RTV, alone and combined (LPV/r), on hepatocyte viability, bile acid transport, and endogenous bile acid disposition in rat hepatocytes have not been examined. The effect of LPV, RTV, and LPV/r on cellular viability and the disposition of [(3)H]taurocholic acid (TCA) and [(14)C]chenodeoxycholic acid (CDCA) was determined in sandwich-cultured rat hepatocytes (SCRH) and suspended rat hepatocytes. Lactate dehydrogenase and ATP assays revealed a concentration-dependent effect of LPV and RTV on cellular viability. LPV (5 µM), alone and combined with 5 µM RTV, significantly decreased [(3)H]TCA accumulation in cells + bile of SCRHs compared with control. LPV/r significantly increased [(3)H]TCA cellular accumulation (7.7 ± 0.1 pmol/mg of protein) compared with vehicle and 5 µM LPV alone (5.1 ± 0.7 and 5.0 ± 0.5 pmol/mg of protein). The [(3)H]TCA biliary clearance was reduced significantly by LPV and RTV and further reduced by LPV/r. LPV and RTV did not affect the initial uptake rates of [(3)H]TCA or [(14)C]CDCA in suspended rat hepatocytes. LPV (50 µM), RTV (5 µM), and LPV/r (5 and 50 µM/5 µM) significantly decreased the accumulation of total measured endogenous bile acids (TCA, glycocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, and α/β-tauromuricholic acid) in SCRH. Quantification of endogenous bile acids in SCRH may reveal important adaptive responses associated with exposure to known BSEP inhibitors. 23515498 Pathogenesis of preeclampsia: Implications of apoptotic markers and oxidative stress. This study aimed to investigate the implication of some apoptotic and lipid peroxidation markers in preeclampsia (PE). A total of 25 women with PE and 25 age- and parity-matched normal pregnant women were enrolled in this study. The malondialdehyde (MDA) level, caspase-9 activity and the percentage of DNA fragmentation were significantly higher in placental tissue of PE than in control women. The serum level of MDA was significantly elevated in women with PE having delivery by cesarean section (CS) than in women with PE having vaginal delivery. In vitro study demonstrated that the addition of 0.5 mM Fe(2+) and 0.1 mM ascorbate caused increase in the production of MDA level in placental tissue with PE than normal placentas, and vitamin E (100 µM) caused lower inhibition of in vitro lipid peroxidation in placental tissue with PE when compared with normal tissue. The activity of caspase-9 and percentage of DNA fragmentation were associated with the severity of the PE and both could differentiate between PE and control women with 88% and 100% sensitivity and 96% and 100% specificity, respectively. The activities of caspase-8 and/or -9 were positively correlated with the maternal age but only caspase-8 was negatively correlated with neonatal birth weight and placental weight. In conclusion, the elevations of MDA, caspase-9 activity and the percentage of DNA fragmentation in the placentas of women with PE implicate the involvement of lipid peroxidation and apoptosis in PE. The placenta represents a considerable source of the elevated circulating MDA in PE. 23416796 Improving correlated SERS measurements with scanning electron microscopy: an assessment of the problem arising from the deposition of amorphous carbon. For surface-enhanced Raman scattering (SERS) substrates with nonspherical symmetry, it is critical to correlate spectroscopy measurements with imaging by scanning electron microscopy (SEM). However, the deposition of carbon resulting from e-beam exposure during SEM imaging contaminates the surface of nanoparticles, potentially preventing their further functionalization with Raman probe molecules. In addition, the deposited carbon leads to unwanted background SERS signals. In this study, we systematically investigated the deposition of carbon during SEM imaging and examined how it affects the functionalization of nanoparticles with probe molecules and impacts the detection of SERS signals. Significantly, we found that the carbon could be removed or replaced from the surface of Ag nanoparticles through chemical or physical means, rendering the nanoparticles the capability for correlated SEM/SERS studies. 23598046 Nrp2 deficiency leads to trabecular bone loss and is accompanied by enhanced osteoclast and reduced osteoblast numbers. Neuropilin 1 (Nrp1) and Nrp2 are transmembrane receptors that can bind class 3 semaphorins (Sema3A-G) in addition to VEGF family members to play important roles in axonal guidance, vascularization and angiogenesis, as well as immune responses. Moreover, recent evidence implicates Sema3A/Nrp-mediated signaling in bone regulation. However, to date the expression of Nrp2 in bone has not been investigated and a possible role for Nrp2 in the maintenance of bone homeostasis in vivo remains unexplored. Here we show that Nrp2, together with its possible coreceptors (Plexin A family members and Plexin D1) and class 3 semaphorin ligands, were expressed during in vitro osteogenic differentiation of bone marrow stromal cells. Moreover, Nrp2 transcript and protein levels were highly induced in hematopoietic bone marrow cell-derived osteoclast cultures. Osteoblastic as well as osteoclastic Nrp2 expression was confirmed by immunohistochemistry of the long bones of mice. Interestingly, Nrp2 knockout mice were characterized by a low bone mass phenotype which was accompanied by an increased number of osteoclasts and a decreased osteoblast count. Collectively, these data point to a physiological role for Nrp2 in bone homeostasis. 23497905 Innovative microwave-assisted hydrolysis of ellagitannins and quantification as ellagic acid equivalents. The health-promoting effects of ellagic acid and its intestinal degradation products are well-known. In plants, ellagic acid mainly appears in the form of its precursors, the so-called ellagitannins. Therefore, determination of total ellagic acid content has been accomplished by cleaving ellagitannins with high temperatures and strong acids. Microwave-assisted extraction (MAE) has been shown to be a very effective and quick extraction technique. The aim of the present study was to establish an MAE-based method for a rapid hydrolysis of ellagitannins and to compare this method with a conventional acid hydrolysis. For this purpose, strawberries (Fragaria x ananassa), which have been identified as a major source of ellagitannins in human diet, were used as a model. The newly developed MAE method was quicker, less chemical-consuming and more effective in hydrolysing ellagitannins. 23386251 In vitro-in vivo correlation of the inhibition potency of sodium-glucose cotransporter inhibitors in rat: a pharmacokinetic and pharmacodynamic modeling approach. To evaluate the relationship between the in vitro and in vivo potency of sodium-glucose cotransporter (SGLT) inhibitors, a pharmacokinetic and pharmacodynamic (PK-PD) study was performed using normal rats. A highly selective SGLT2 inhibitor, tofogliflozin, and four other inhibitors with different in vitro inhibition potency to SGLT2 and selectivity toward SGLT2, versus SGLT1 were used as test compounds, and the time courses for urinary glucose excretion (UGE) and the plasma glucose and compound concentrations were monitored after administration of the compounds. A PK-PD analysis of the UGE caused by SGLT inhibition was performed on the basis of a nonlinear parallel tube model that took into consideration the consecutive reabsorption by different glucose transport properties of SGLT2 and SGLT1. The model adequately captured the time course of cumulative UGE caused by SGLT inhibition; then, the in vivo inhibition constants (Ki) of inhibitors for both SGLT1 and SGLT2 were estimated. The in vivo selectivity toward SGLT2 showed a good correlation with the in vitro data (r = 0.985; P < 0.05), with in vivo Ki values for SGLT2 in the range of 0.3-3.4-fold the in vitro data. This suggests that in vitro inhibition potency to both SGLT2 and SGLT1 is reflected in vivo. Furthermore, the complementary role of SGLT1 to SGLT2 and how selectivity toward SGLT2 affects the inhibitory potency for renal glucose reabsorption were discussed using the PK-PD model. 23273999 Michaelis-Menten kinetic analysis of drugs of abuse to estimate their affinity to human P-glycoprotein. The pharmacokinetics of various important drugs are known to be significantly influenced by the human ABC transporter P-glycoprotein (P-gp), which may lead to clinically relevant drug-drug interactions. In contrast to therapeutic drugs, emerging drugs of abuse (DOA) are sold and consumed without any safety pharmacology testing. Only some studies on their metabolism were published, but none about their affinity to the transporter systems. Therefore, 47 DOAs from various classes were tested for their P-gp affinity using human P-gp (hP-gp) to predict possible drug-drug interactions. DOAs were initially screened for general hP-gp affinity and further characterized by modeling classic Michaelis-Menten kinetics and assessing their K(m) and V(max) values. Among the tested drugs, 12 showed a stimulation of ATPase activity. The most intensive stimulating DOAs were further investigated and compared with the known P-gp model substrates sertraline and verapamil. ATPase stimulation kinetics could be modeled for the entactogen 3,4-methylenedioxy-α-ethylphenethylamine (3,4-BDB), the hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI), the abused alkaloid glaucine, the opioid-like drugs N-iso-propyl-1,2-diphenylethylamine (NPDPA), and N-(1-phenylcyclohexyl)-3-ethoxypropanamine (PCEPA), with K(m) and V(max) values within the same range as for verapamil or sertraline. As a consequence interactions with other drugs being P-gp substrates might be considered to be very likely and further studies should be encouraged. 23523606 Inhibition of the renin-angiotensin system for lowering coronary artery disease risk. The renin-angiotensin system when activated exerts proliferative and pro-inflammatory actions and thereby contributes to progression of atherosclerosis, including that occurring in the coronary arteries. It thus contributes as well to coronary artery disease (CAD). Several clinical trials have examined effects of renin-angiotensin system inhibition for primary and secondary prevention of coronary heart disease. These include important trials such as HOPE, EUROPA and PEACE using angiotensin converting enzyme inhibitors, VALIANT, OPTIMAAL and TRANSCEND using angiotensin receptor blockers, and the ongoing TOPCAT study in patients with preserved ejection fraction heart failure, many of who also have coronary artery disease. Data are unavailable as yet of effects of either direct renin inhibitors or the new angiotensin receptor/neprilysin inhibitor agents. Today, inhibition of the renin-angiotensin system is standard-of-care therapy for lowering cardiovascular risk in secondary prevention in high cardiovascular risk subjects. 23635829 Synthesis and biological evaluation of (68)Ga labeled bis-DOTA-3,3'-(benzylidene)-bis-(1H-indole-2-carbohydrazide) as a PET tracer for in vivo visualization of necrosis. The aim of the present study was to develop a (68)Ga labeled bis-DOTA derivative of benzylidene-bis-indole and compare the in vivo stability and biodistribution with that of the previously reported bis-DTPA derivate for in vivo imaging of necrosis using PET. Uptake of the tracer was evaluated in a mouse model of Fas-mediated hepatic apoptosis in correlation with histochemical stainings. The novel (68)Ga labeled tracer showed an improved in vivo stability and could therefore be used for selective non-invasive imaging of necrotic cell death using PET. 23137956 High-dose sodium selenite toxicity cannot be prevented by the co-administration of pharmacological levels of epigallocatechin-3-gallate which in turn aggravates the toxicity. Selenium, an essential trace element, can also be toxic at higher levels of exposure. Several lines of evidence show epigallocatechin-3-gallate (EGCG), a predominant component of green tea catechins with numerous health benefits, can ameliorate the toxicity of many agents. A proof-in-principle experiment was conducted to determine if EGCG would ameliorate sodium selenite-induced growth suppression. Mice were intraperitioneally injected with selenite once daily for five days at a dose of 3 mg Se/kg, which fully suppressed animal growth but did not cause death. Surprisingly the co-administration of the selenite and nontoxic doses of EGCG (10, 20 and 40 mg/kg, intraperitioneally) resulted in the mortality of treated mice in a dose and time-dependent manner (33.3%, 100% and 100%, respectively). EGCG-selenite induced lethality did not result from enhanced selenium accumulation but appeared to involve the suppression of a selenite-induced adaptive response as evidenced by hepatic glutathione S-transferase activity. While EGCG has been reported to ameliorate the toxicity of some agents, the induction of mortality by combined treatment with pharmacological doses of selenium and EGCG is a previously unrecognized synergism that must be considered not only in the remediation of high environmental selenium exposures but also in the development of pharmaceuticals and nutriceuticals. 23204111 TCDD inhibits heart regeneration in adult zebrafish. Normal adult zebrafish can completely regenerate lost myocardium following partial amputation of the ventricle apex. We report that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) significantly impairs this regeneration. Adult male zebrafish were injected with vehicle (control) or TCDD (70ng/g, ip) 1 day prior to partial amputation of the ventricle apex. Gross observation and histological analysis of the amputated heart at 21 days postamputation revealed that TCDD-exposed fish had not progressed beyond the initial clot formation stage, whereas the vehicle control fish showed substantial recovery and almost complete resolution of the formed clot. In contrast, hearts that were not surgically wounded showed no signs of TCDD toxicity. Striking features in the TCDD-exposed hearts were the absence of the normal sheath of new tissue enveloping the wound and the absence of intense cell proliferation at the site of the wound. In addition, the patterns of collagen deposition at the wound site were different between the TCDD and vehicle groups. Because the receptor for TCDD is the aryl hydrocarbon receptor ligand-activated transcriptional regulator, we examined the effects of TCDD exposure on gene expression in the ventricle using DNA microarrays. Samples were collected just prior to amputation and at 6h and 7 days postamputation. TCDD-pretreated hearts had dysregulated expression of genes involved in heart function, tissue regeneration, cell growth, and extracellular matrix. Because embryonic, but not adult, hearts are major targets for TCDD-induced cardiotoxicity, we speculate that the need for embryonic-like cells in regeneration is connected with the effects of TCDD in inhibiting the response to wounding. 23020786 Role of carbonyl reducing enzymes in the phase I biotransformation of the non-steroidal anti-inflammatory drug nabumetone in vitro. 1. Nabumetone is a clinically used non-steroidal anti-inflammatory drug, its biotransformation includes major active metabolite 6-methoxy-2-naphtylacetic acid and another three phase I as well as corresponding phase II metabolites which are regarded as inactive. One important biotransformation pathway is carbonyl reduction, which leads to the phase I metabolite, reduced nabumetone. 2. The aim of this study is the determination of the role of a particular human liver subcellular fraction in the nabumetone reduction and the identification of participating carbonyl reducing enzymes along with their stereospecificities. 3. Both subcellular fractions take part in the carbonyl reduction of nabumetone and the reduction is at least in vitro the main biotransformation pathway. The activities of eight cytosolic carbonyl reducing enzymes--CBR1, CBR3, AKR1B1, AKR1B10, AKR1C1-4--toward nabumetone were tested. Except for CBR3, all tested reductases transform nabumetone to its reduced metabolite. AKR1C4 and AKR1C3 have the highest intrinsic clearances. 4. The stereospecificity of the majority of the tested enzymes is shifted to the production of an (+)-enantiomer of reduced nabumetone; only AKR1C1 and AKR1C4 produce predominantly an (-)-enantiomer. This project provides for the first time evidence that seven specific carbonyl reducing enzymes participate in nabumetone metabolism. 22585412 Antiangiogenic effects of p-coumaric acid in human endothelial cells. p-Coumaric acid, a hydroxy derivative of cinnamic acid, has been known to possess antioxidant and anticancer activities. Despite its potential contribution to chemopreventive effects, the mechanism by which p-coumaric acid exerts its antiangiogenic actions remains elusive. In this study, we revealed that p-coumaric acid inhibited the sprouting of endothelial cells in rat aortic rings and inhibited the tube formation and migration of endothelial cells. We observed that p-coumaric acid could downregulate mRNA expression levels of the key angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor. Also, we demonstrated that p-coumaric acid inhibited both the AKT and ERK signaling pathways, which are known to be crucial for angiogenesis. Using a mouse model, we also showed that p-coumaric acid effectively suppressed tumor growth in vivo by lowering hemoglobin contents. Collectively, these findings indicate that p-coumaric acid possesses potent anticancer properties due to the inhibition of angiogenesis in vivo. Copyright © 2012 John Wiley & Sons, Ltd. 23440577 Synthesis and antiproliferative activity evaluation of imidazole-based indeno[1,2-b]quinoline-9,11-dione derivatives. A series of new imidazole substituted indeno[1,2-b]quinoline-9,11-dione derivatives were synthesized and evaluated for their antiproliferative effects on HeLa, LS180, MCF-7 and Jurkat human cancer cell lines. Antiproliferative effects were evaluated using MTT assay. Prepared compounds exhibited weak to good antiproliferative activity in evaluated cell lines. Prepared compounds were more potent in Jurkat cell line when compared to LS180, HeLa and MCF-7 cell lines. Compounds 29 (IC16 = 0.7 μM) and 31 (IC16 = 1.7 μM) and 33 (IC16 = 1.7 μM) were found to be the most potent molecules on Jurkat cell lines. Moreover; it was found that some of the tested compounds bearing imidazole-2-yl moiety on the C11-position of dihydropyridine ring exhibited superior antiproliferative activity in comparison to cis-platin especially in Jurkat cell line (compounds 29, 31, and 33). It seemed that the introduction of electron-withdrawing groups on the imidazole ring enhanced the antiproliferative potential of these compounds (compounds 27, 29 and 31). The results of this study proposed that some of the imidazole substituted indeno[1,2-b]quinoline-9,11-dione compounds may act as efficient anticancer agents in vitro, emphasizing their potential role as a source for rational design of potent antiproliferative agents. 23562240 Learning from our mistakes: The 'unknown knowns' in fragment screening. In the past 15 years, fragment-based lead discovery (FBLD) has been adopted widely throughout academia and industry. The approach entails discovering very small molecular fragments and growing, merging, or linking them to produce drug leads. Because the affinities of the initial fragments are often low, detection methods are pushed to their limits, leading to a variety of artifacts, false positives, and false negatives that too often go unrecognized. This Digest discusses some of these problems and offers suggestions to avoid them. Although the primary focus is on FBLD, many of the lessons also apply to more established approaches such as high-throughput screening. 23275471 Osteoblast lineage-specific effects of notch activation in the skeleton. Transgenic overexpression of the Notch1 intracellular domain inhibits osteoblast differentiation and causes osteopenia, and inactivation of Notch1 and Notch2 increases bone volume transiently and induces osteoblastic differentiation. However, the biology of Notch is cell-context-dependent, and consequences of Notch activation in cells of the osteoblastic lineage at various stages of differentiation and in osteocytes have not been defined. For this purpose, Rosa(Notch) mice, where a loxP-flanked STOP cassette placed between the Rosa26 promoter and the NICD coding sequence, were crossed with transgenics expressing the Cre recombinase under the control of the Osterix (Osx), Osteocalcin (Oc), Collagen 1a1 (Col2.3), or Dentin matrix protein1 (Dmp1) promoters. At 1 month, Osx-Cre;Rosa(Notch) and Oc-Cre;Rosa(Notch) mice exhibited osteopenia due to impaired bone formation. In contrast, Col2.3-Cre;Rosa(Notch) and Dmp1-Cre;Rosa(Notch) exhibited increased femoral trabecular bone volume due to a decrease in osteoclast number and eroded surface. In the four lines studied, cortical bone was either not present, was porous, or had the appearance of trabecular bone. Oc-Cre;Rosa(Notch) and Col2.3-Cre;Rosa(Notch) mice exhibited early lethality so that their adult phenotype was not established. At 3 months, Osx-Cre;Rosa(Notch) and Dmp1-Cre;Rosa(Notch) mice displayed increased bone volume, and increased osteoblasts although calcein-demeclocycline labels were diffuse and fragmented, indicating abnormal bone formation. In conclusion, Notch effects in the skeleton are cell-context-dependent. When expressed in immature osteoblasts, Notch arrests their differentiation, causing osteopenia, and when expressed in osteocytes, it causes an initial suppression of bone resorption and increased bone volume, a phenotype that evolves as the mice mature. 23190339 Identifying biases at different spatial and temporal scales of diversification: a case study in the Neotropical parrotlet genus Forpus. The temporal origins of the extraordinary biodiversity of the Neotropical region are highly debated. Recent empirical work has found support for alternative models on the tempo of speciation in Neotropical species further fuelling the debate. However, relationships within many Neotropical lineages are poorly understood, and it is unclear how this uncertainty impacts inferences on the evolution of taxa in the region. We examined the robustness of diversification patterns in the avian genus Forpus by testing whether the use of different units of biodiversity (i.e. biological species and statistically inferred species) impacted diversification rates and inferences regarding important biogeographic breaks in the genus. We found that the best-fit model of diversification for the biological species data set was a declining rate of diversification; whereas a model of constant diversification was the best-fit model for statistically inferred species or subspecies. Moreover, the relative importance of different landscape features in delimiting genetic structure across the landscape varied across data sets with differing units of biodiversity. Patterns based on divergence times among biological species indicated old speciation events across major geographic and river barriers. In contrast, data sets more inclusive of the diversity in Forpus illustrate the role of both old divergence across major landscape features and more recent divergences that are possibly attributed to Pleistocene climatic changes. Overall, these results indicate that conflicting models on the temporal origins of Neotropical birds may be attributable to sampling biases. 23291558 Aryl hydrocarbon receptor activation attenuates Per1 gene induction and influences circadian clock resetting. Light-stimulated adjustment of the circadian clock is an important adaptive physiological response that allows maintenance of behavioral synchrony with solar time. Our previous studies indicate that the aryl hydrocarbon receptor (AhR) agonist 2,3,7,8- tetrachlorodibenzo-p-dioxin attenuates light-induced phase resetting in early night. However, the mechanism of inhibition remains unclear. In this study, we showed that another potent AhR agonist-β-naphthoflavone (BNF)-significantly decreased light-induced phase shifts in wild-type (WT) mice, whereas AhR knockout mice had an enhanced response to light that was unaffected by BNF. Mechanistically, BNF blocked light induction of the Per1 transcript in suprachiasmatic nucleus and liver in WT mice, and BNF blocked forskolin (FSK)-induced Per1 transcripts in Hepa-1c1c7 (c7) cells. An E-box decoy did not affect BNF inhibition of FSK-induced Per1 transcripts in c7 cells. cAMP-response element (CRE)-dependent induction of Per1 promoter activity in response to FSK in combination with phorbol 12-tetradecanoate 13-acetate was suppressed in cells that expressed high levels of AhR (c7) compared with cells lacking functional AhR activity (c12). In addition, the inhibitory effect of BNF on FSK-induced Per1 was dependent on phosphorylation of JNK. Together, these results suggest that AhR activation inhibits light-induced phase resetting through the activation of JNK, negative regulation of CREs in the Per1 promoter, and suppression of Per1. 23257312 ADX71743, a potent and selective negative allosteric modulator of metabotropic glutamate receptor 7: in vitro and in vivo characterization. Metabotropic glutamate receptor 7 (mGlu(7)) has been suggested to be a promising novel target for treatment of a range of disorders, including anxiety, post-traumatic stress disorder, depression, drug abuse, and schizophrenia. Here we characterized a potent and selective mGlu(7) negative allosteric modulator (NAM) (+)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d]oxazol-4(5H)-one (ADX71743). In vitro, Schild plot analysis and reversibility tests at the target confirmed the NAM properties of the compound and attenuation of L-(+)-2-amino-4-phosphonobutyric acid-induced synaptic depression confirmed activity at the native receptor. The pharmacokinetic analysis of ADX71743 in mice and rats revealed that it is bioavailable after s.c. administration and is brain penetrant (cerebrospinal fluid concentration/total plasma concentration ratio at C(max) = 5.3%). In vivo, ADX71743 (50, 100, 150 mg/kg, s.c.) caused no impairment of locomotor activity in rats and mice or activity on rotarod in mice. ADX71743 had an anxiolytic-like profile in the marble burying and elevated plus maze tests, dose-dependently reducing the number of buried marbles and increasing open arm exploration, respectively. Whereas ADX71743 caused a small reduction in amphetamine-induced hyperactivity in mice, it was inactive in the mouse 2,5-dimethoxy-4-iodoamphetamine-induced head twitch and the rat conditioned avoidance response tests. In addition, the compound was inactive in the mouse forced swim test. These data suggest that ADX71743 is a suitable compound to help unravel the physiologic role of mGlu(7) and to better understand its implication in central nervous system diseases. Our in vivo tests using ADX71743, reported here, suggest that pharmacological inhibition of mGlu(7) is a valid approach for developing novel pharmacotherapies to treat anxiety disorders, but may not be suitable for treatment of depression or psychosis. 23598043 Microglial disruption in young mice with early chronic lead exposure. The mechanisms by which early chronic lead (Pb) exposure alter brain development have not been identified. We examined neuroimmune system effects in C57BL/6J mice with Pb exposure, including levels that may be common among children in lower socioeconomic income environments. Pups were exposed via dams' drinking water from birth to post-natal day 28 to low, high or no Pb conditions. We compared gene expression of neuroinflammatory markers (study 1); and microglial mean cell body volume and mean cell body number in dentate gyrus, and dentate gyrus volume (study 2). Blood Pb levels in exposed animals at sacrifice (post-natal day 28) ranged from 2.66 to 20.31μg/dL. Only interleukin-6 (IL6) differed between groups and reductions were dose-dependent. Microglia cell body number also differed between groups and reductions were dose-dependent. As compared with controls, microglia cell body volume was greater but highly variable in only low-dose animals; dentate gyri volumes in low- and high-dose animals were reduced. The results did not support a model of increased neuroinflammation. Instead, early chronic exposure to Pb disrupted microglia via damage to, loss of, or lack of proliferation of microglia in the developing brains of Pb-exposed animals. 23220538 The diverse roles of nonsteroidal anti-inflammatory drug activated gene (NAG-1/GDF15) in cancer. Nonsteroidal anti-inflammatory drug (NSAID) activated gene-1, NAG-1, is a divergent member of the transforming growth factor-beta (TGF-β) superfamily that plays a complex but poorly understood role in several human diseases including cancer. NAG-1 expression is substantially increased during cancer development and progression especially in gastrointestinal, prostate, pancreatic, colorectal, breast, melanoma, and glioblastoma brain tumors. Aberrant increases in the serum levels of secreted NAG-1 correlate with poor prognosis and patient survival rates in some cancers. In contrast, the expression of NAG-1 is up-regulated by several tumor suppressor pathways including p53, GSK-3β, and EGR-1. NAG-1 expression is also induced by many drugs and dietary compounds which are documented to prevent the development and progression of cancer in mouse models. Studies with transgenic mice expressing human NAG-1 demonstrated that the expression of NAG-1 inhibits the development of intestinal tumors and prostate tumors in animal models. Laboratory and clinical evidence suggest that NAG-1, like other TGF-β family members, may have different or pleiotropic functions in the early and late stages of carcinogenesis. Upon understanding the molecular mechanism and function of NAG-1 during carcinogenesis, NAG-1 may serve as a potential biomarker for the diagnosis and prognosis of cancer and a therapeutic target for the inhibition and treatment of cancer development and progression. 23561172 Influence of cold pre-fermentation treatments on the major volatile compounds of three wine varieties. The volatile compounds of wines made from three grape varieties (Monastrell, Cabernet Sauvignon and Syrah) using three pre-fermentation techniques (grape freezing, dry-ice and cold maceration) and a control treatment were measured. The different winemaking practices, which are intended to increase the aromatic properties of wines, produced results that depended on the variety concerned. For example, freezing the Cabernet Sauvignon and Syrah grapes produced different results compared with the respective controls, whereas few changes were found on freezing the Monastrell wine. Differences were significant in the case of some volatile compounds. Linear discriminant analysis allowed some grouping of the varieties at sampling but not of the pre-fermentation techniques used. 23357951 Constitutively active group I mGlu receptors and PKMzeta regulate synaptic transmission in developing perirhinal cortex. Synaptic transmission is essential for early development of the central nervous system. However, the mechanisms that regulate early synaptic transmission in the cerebral cortex are unclear. PKMζ is a kinase essential for the maintenance of LTP. We show for the first time that inhibition of PKMζ produces a profound depression of basal synaptic transmission in neonatal, but not adult, rat perirhinal cortex. This suggests that synapses in early development are in a constitutive LTP-like state. Furthermore, basal synaptic transmission in immature, but not mature, perirhinal cortex relies on persistent activity of metabotropic glutamate (mGlu) receptor, PI3Kinase and mammalian target of rapamycin (mTOR). Thus early in development, cortical synapses exist in an LTP-like state maintained by tonically active mGlu receptor-, mTOR- and PKMζ- dependent cascades. These results provide new understanding of the molecular mechanisms that control synapses during development and may aid our understanding of developmental disorders such as autism and schizophrenia. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23165727 EphrinB2/EphB4 inhibition in the osteoblast lineage modifies the anabolic response to parathyroid hormone. Previous reports indicate that ephrinB2 expression by osteoblasts is stimulated by parathyroid hormone (PTH) and its related protein (PTHrP) and that ephrinB2/EphB4 signaling between osteoblasts and osteoclasts stimulates osteoblast differentiation while inhibiting osteoclast differentiation. To determine the role of the ephrinB2/EphB4 interaction in the skeleton, we used a specific inhibitor, soluble EphB4 (sEphB4), in vitro and in vivo. sEphB4 treatment of cultured osteoblasts specifically inhibited EphB4 and ephrinB2 phosphorylation and reduced mRNA levels of late markers of osteoblast/osteocyte differentiation (osteocalcin, dentin matrix protein-1 [DMP-1], sclerostin, matrix-extracellular phosphoglycoprotein [MEPE]), while substantially increasing RANKL. sEphB4 treatment in vivo in the presence and absence of PTH increased osteoblast formation and mRNA levels of early osteoblast markers (Runx2, alkaline phosphatase, Collagen 1α1, and PTH receptor [PTHR1]), but despite a substantial increase in osteoblast numbers, there was no significant change in bone formation rate or in late markers of osteoblast/osteocyte differentiation. Rather, in the presence of PTH, sEphB4 treatment significantly increased osteoclast formation, an effect that prevented the anabolic effect of PTH, causing instead a decrease in trabecular number. This enhancement of osteoclastogenesis by sEphB4 was reproduced in vitro but only in the presence of osteoblasts. These data indicate that ephrinB2/EphB4 signaling within the osteoblast lineage is required for late stages of osteoblast differentiation and, further, restricts the ability of osteoblasts to support osteoclast formation, at least in part by limiting RANKL production. This indicates a key role for the ephrinB2/EphB4 interaction within the osteoblast lineage in osteoblast differentiation and support of osteoclastogenesis. 22410775 The receptor tyrosine kinase Axl is an essential regulator of prostate cancer proliferation and tumor growth and represents a new therapeutic target. Deregulation of the receptor tyrosine kinase Axl has been implicated in the progression of several human cancers. However, the role of Axl in prostate cancer remains poorly understood, and the therapeutic efficacy of Axl targeting remains untested. In this report we identified Axl as a new therapeutic target for prostate cancer. Axl is consistently overexpressed in prostate cancer cell lines and human prostate tumors. Interestingly, the blockage of Axl gene expression strongly inhibits proliferation, migration, invasion and tumor growth. Furthermore, inhibition of Axl expression by small interfering RNA regulates a transcriptional program of genes involved in cell survival, strikingly all connected to the nuclear factor-κB pathway. Additionally, blockage of Axl expression leads to inhibition of Akt, IKKα and IκBα phosphorylation, increasing IκBα expression and stability. Furthermore, induction of Akt phosphorylation by insulin-like growth factor 1 in Axl knockdown cells restores Akt activity and proliferation. Taken together, our results establish an unambiguous role for Axl in prostate cancer tumorigenesis with implications for prostate cancer treatment. 23586938 Biomimetic Silicification of Demineralized Hierarchical Collagenous Tissues. Unlike man-made composite materials, natural biominerals containing composites usually demonstrate different levels of sophisticated hierarchical structures which are responsible for their mechanical properties and other metabolic functions. However, the complex spatial organizations of the organic-inorganic phases are far beyond what they achieved by contemporary engineering techniques. Here, we demonstrate that carbonated apatite present in collagen matrices derived from fish scale and bovine bone may be replaced by amorphous silica, using an approach that simulates what is utilized by phylogenetically ancient glass sponges. The structural hierarchy of these collagen-based biomaterials is replicated by the infiltration and condensation of fluidic polymer-stabilized silicic acid precursors within the intrafibrillar milieu of type I collagen fibrils. This facile biomimetic silicification strategy may be used for fabricating silica-based, three-dimensional functional materials with specific morphological and hierarchical requirements. 22803803 Radiolabeled mass-balance excretion and metabolism studies in laboratory animals: a commentary on why they are still necessary. The necessity of conducting traditional radiolabeled absorption, distribution, metabolism and excretion (ADME) studies in animals during development of new investigative agents has been questioned in a recent review. We present a compilation of the benefits of such studies in the understanding of the in vivo pharmacological activity and disposition of new drug candidates, including interpretation of preclinical toxicology findings, characterization of circulating metabolites, and determination of principal pathways of clearance. This understanding is valuable in anticipating the human disposition of the drugs and the planning of the clinical development program. Because of new technologies, evolving regulatory expectations, and increased scientific understanding of the disposition of drugs, the traditional design and timing of both animal and human ADME studies should be reviewed. Innovative "fit-for-purpose" studies may well be a better choice in a particular drug development program than a standard animal ADME "package". However, we submit that, at this time, radiolabeled animal ADME studies still provide a definitive and irreplaceable component of our understanding of the in vivo actions and behaviors of drugs and should continue to be performed prior to the exposure of large numbers of human subjects to investigative drugs. 23126495 Bioactive constituents of Salvia chrysophylla Stapf. The dichloromethane extract of the aerial parts of Salvia chrysophylla Stapf (Lamiaceae), which is an endemic species to south-western Anatolia, was studied for non-volatile secondary metabolites for the first time in this study. Structures of the isolated compounds were elucidated as sclareol, β-sitosterol, salvigenin, oleanolic acid and ursolic acid. The lipid peroxidation inhibitory activity and the DPPH free radical scavenging activity of the pure isolates were investigated to establish their antioxidant potential. Their anticholinesterase activity was carried out by the Ellman assay against both enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase, and diterpene sclareol exhibited fairly good activity against both the enzymes while the two triterpenoids oleanolic and ursolic acids exhibited selective activity against AChE. 23464810 Spectral Phonon Scattering from Sub-10 nm Surface Roughness Wavelengths in Metal-Assisted Chemically Etched Si Nanowires. Frequency dependence in phonon surface scattering is a debated topic in fundamental phonon physics. Recent experiments and theory suggest such a phenomenon, but an independent agreement between the two remains elusive. We report low-temperature dependence of thermal conductivity in silicon nanowires fabricated using a two-step, metal-assisted chemical etch. By reducing etch rates down to 0.5 nm/s from the typical >100 nm/s, we report controllable roughening of nanowire surfaces and selectively focus on moderate roughness scales rather than the extreme scales investigated previously. This critically enables direct comparison with perturbation-based spectral scattering theory. Using experimentally characterized surface roughness, we show that a multiple scattering theory provides excellent agreement and explanation of the observed low-temperature dependence of rough surface nanowires. The theory does not employ any fitting parameters. A 5-10 nm roughness correlation length is typical in metal-assisted chemical etching and resonantly scatters dominant phonons in silicon, leading to the observed ∼T(1.6-2.4) behavior. Our work provides fundamental and quantitative insight into spectral phonon scattering from rough surfaces. This advances applications of nanowires in thermoelectric energy conversion. 23350883 Complementary and Alternative Medicine Use Among Patients with Thyroid Cancer. Background: To report on the incidence and predictors of use of complementary and alternative medicine (CAM) among patients with thyroid cancer. Methods: Data were collected using a web-based online anonymous survey under IRB approval from Boston University. This report is based on 1327 responses from subjects with thyroid cancer. Patient factors were compared by univariate and multivariate analyses. Results: After excluding multivitamin and prayer use, 74% (n=941) used CAM. Respondents were primarily over age 40, White, female and hold a college degree. The top five modalities were massage therapy, chiropraxy, special diets, herbal tea and yoga. Few patients reported perceiving a particular modality had a negative effect on treatment. CAM was more often used for treatment of symptoms (73%) than as part of thyroid cancer treatment (27%). Multivariable logistic regression demonstrated that patients reporting a poor health status, higher education, cardiovascular disease, pulmonary symptoms, or persistent, recurrent or metastatic disease were more likely to use CAM for treatment of thyroid cancer symptoms. Nearly 1/3 of respondents reported their CAM use was neither known, prescribed nor asked about by their physicians. Conclusion: In comparison to national surveys of the general U.S. population, patients with thyroid cancer use CAM therapies twice as often and report their use far less often. Physicians who treat patients with thyroid cancer should be aware of these data to further assist in their assessment and care. 23376122 Fibroblast-mediated drug resistance in cancer. Tumor progression relies upon the dynamic interaction of cancer cells with host fibroblasts, endothelial cells, immune cells and components of the extracellular matrix, collectively known as the tumor microenvironment. Despite this, relatively little is known about how normal host cells dictate the response of tumors to anti-cancer therapies. Emerging data suggests that host factors play a critical role in determining risks for tumor progression and decreased therapeutic responses. In particular, recent findings have provided evidence that the tumor microenvironment provides a protective niche that allows minor populations of cancer cells to escape from the cytotoxic effects of radiation, chemotherapy and targeted therapies. In this review we will outline the mechanisms by which tumor cells and host fibroblasts co-operate to drive tumor initiation and progression. In particular, we will focus upon the mechanisms by which tumor cells exposed to targeted therapies co-opt the host leading to therapeutic escape and resistance. We will end by discussing the idea that long-term responses to targeted anticancer therapies will only be achieved through strategies that target both the tumor and host. 23458420 Thioflavin T and its photoirradiative derivatives: exploring their spectroscopic properties in the absence and presence of amyloid fibrils. In this work, we found that, during storage or after UV irradiation, ThT is demethylated or oxidized, forming three derivatives. These three derivatives were purified by high performance liquid chromatography and characterized by mass and nuclear magnetic resonance spectroscopy and the spectroscopic properties of pure ThT and the derivatives carefully compared. Our results show that the emission peak at 450 nm results from oxidized ThT and not from the monomeric form of ThT, as previously proposed. The partial conversion of ThT into oxidized and demethylated derivatives has an effect on amyloid detection using ThT assay. Irradiated ThT has the same lag time as pure ThT in the amyloidogenesis of insulin, but the intensity of the emitted fluorescence is significantly decreased. 23080299 Improved preparation of methyl bis(2,2,2-trifluoroethoxy)-bromophosphonoacetate for the stereoselective synthesis of (E)-α-bromoacrylates. We have established an efficient method for preparing methyl bis(2,2,2-trifluoroethoxy)bromophosphonoacetate, which we developed for the stereoselective synthesis of (E)-α-bromoacrylates. This improved method enables the reagent to be prepared reproducibly in one step from methyl bis(2,2,2-trifluoroethoxy)phosphonoacetate. 23321689 Activation of the α7 nicotinic ACh receptor induces anxiogenic effects in rats which is blocked by a 5-HT1a receptor antagonist. The α7 nicotinic acetylcholine receptor (nAChR) is highly expressed in different regions of the brain and is associated with cognitive function as well as anxiety. Agonists and positive allosteric modulators (PAMs) of the α7 subtype of nAChRs have been shown to improve cognition. Previously nicotine, which activates both α7 and non-α7 subtypes of nAChRs, has been shown to have an anxiogenic effect in behavioral tests. In this study, we compared the effects of the α7-selective agonist (PNU-282987) and PAM (PNU-120596) in a variety of behavioral tests in Sprague Dawley rats to look at their effects on learning and memory as well as anxiety. We found that neither PNU-282987 nor PNU-120596 improved spatial-learning or episodic memory by themselves. However when cognitive impairment was induced in the rats with scopolamine (1 mg/kg), both PNU-120596 and PNU-282987 were able to reverse this memory impairment and restore it back to normal levels. While PNU-120596 reversed the scopolamine-induced cognitive impairment, it did not have any adverse effect on anxiety. PNU-282987 on the other hand displayed an increase in anxiety-like behavior at a higher dose (10 mg/kg) that was significantly reduced by the serotonin 5-HT1a receptor antagonist WAY-100135. However the α7 receptor antagonist methyllycaconitine was unable to reverse these anxiety-like effects seen with PNU-282987. These results suggest that α7 nAChR PAMs are pharmacologically advantageous over agonists, and should be considered for further development as therapeutic drugs targeting the α7 receptors. 23623552 Germ Cell Specification Requires Zygotic Mechanisms Rather Than Germ Plasm in a Basally Branching Insect. BACKGROUND: Primordial germ cell (PGC) specification is a universal process across animals, but the molecular mechanisms specifying PGCs are remarkably diverse. In Drosophila, PGCs are specified by maternally provided, asymmetrically localized cytoplasmic factors (germ plasm). In contrast, historical literature on most other arthropods reports that PGCs arise from mesoderm during midembryogenesis, suggesting that an arthropod last common ancestor may have specified PGCs via zygotic mechanisms. However, there has been no direct experimental evidence to date for germ plasm-independent arthropod PGC specification. RESULTS: Here we show that in a basally branching insect, the cricket Gryllus bimaculatus, conserved germ plasm molecules are ubiquitously, rather than asymmetrically, localized during oogenesis and early embryogenesis. Molecular and cytological analyses suggest that Gryllus PGCs arise from abdominal mesoderm during segmentation, and twist RNAi embryos that lack mesoderm fail to form PGCs. Using RNA interference we show that vasa and piwi are not required maternally or zygotically for PGC formation but rather are required for primary spermatogonial divisions in adult males. CONCLUSIONS: These observations suggest that Gryllus lacks a maternally inherited germ plasm, in contrast with many holometabolous insects, including Drosophila. The mesodermal origin of Gryllus PGCs and absence of instructive roles for vasa and piwi in PGC formation are reminiscent of mouse PGC specification and suggest that zygotic cell signaling may direct PGC specification in Gryllus and other Hemimetabola. 23614367 Grb10-mediated Negative Regulation of IGF1R-Activated Signalling Pathway Results in Cognitive Disorder in Diabetic Rats. Growth factor receptor-bound protein 10(Grb10)is a Src homology 2 (SH2) domain-containing protein and one of the binding partners for several trans-membrane tyrosine-kinase receptors, including insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1-R). The hippocampus, which is critical for cognitive functions, is one of the main distribution areas of Grb10 in the central nervous system. In recent years, diabetic encephalopathy has been defined as a third type of diabetes and the IGF1-IR pathway has been shown to be critical for the neuropathogenic process of cognitive disorder in diabetes. However, the role of endogenous Grb10 in regulating the IGF1-IR pathway and neurobehavioral changes is not explicit. The objective of this study was to determine the in vivo function of endogenous Grb10 in diabetic encephalopathy and the underlying mechanisms. Using stereotaxic surgical techniques and lentiviral vectors expressing specific short hairpin RNA (shRNA), we could steadily knock down Grb10 expression in the hippocampus. More importantly, we demonstrated that hippocampus-specific modulation of Grb10 protein levels led to a prominent remission of cognitive disorder, including improvements in both ultrastructural pathology and abnormal neurobehavioural changes. Our findings indicate that endogenous overexpression of Grb10 functions as a suppressor of the IGF1-IR pathway, which may represent an important mechanism that regulates cognitive disorder in diabetes. This article is protected by copyright. All rights reserved. 23528045 Exciton Coupling Mechanisms Analyzed with Subsystem TDDFT: Direct vs Pseudo Exchange Effects. The dominant effect in exciton coupling is usually the so-called Coulomb coupling contribution, that is the Coulomb interaction between transition densities of localized excitations. At short distances, Dexter-type exchange effects are discussed to play a role, which are not well described by (semi)local functionals in time-dependent density functional theory (TDDFT) calculations. Overall, a large effect of the percentage of exact exchange on the resulting exciton splittings is known. Subsystem TDDFT allows one to analyze the exciton coupling mechanism by distinguishing direct from indirect effects, that is, changes in the actual coupling mechanism from modifications in the underlying local excitations. Our analysis shows that the strong influence of exact exchange is not due to a direct Dexter-type (exchange) coupling, but rather to an increased Coulomb (or pseudo-exchange) coupling triggered by a change in transition densities. This is demonstrated in calculations for 2-pyridone and chlorophyll dimers. We finally propose a route to efficient calculations of excited states of large pigment aggregates with hybrid functionals, which so far has been out of reach for quantum chemical methods. 23202371 Tightly bound trions in monolayer MoS2. Two-dimensional (2D) atomic crystals, such as graphene and transition-metal dichalcogenides, have emerged as a new class of materials with remarkable physical properties. In contrast to graphene, monolayer MoS(2) is a non-centrosymmetric material with a direct energy gap. Strong photoluminescence, a current on/off ratio exceeding 10(8) in field-effect transistors, and efficient valley and spin control by optical helicity have recently been demonstrated in this material. Here we report the spectroscopic identification in a monolayer MoS(2) field-effect transistor of tightly bound negative trions, a quasiparticle composed of two electrons and a hole. These quasiparticles, which can be optically created with valley and spin polarized holes, have no analogue in conventional semiconductors. They also possess a large binding energy (~ 20 meV), rendering them significant even at room temperature. Our results open up possibilities both for fundamental studies of many-body interactions and for optoelectronic and valleytronic applications in 2D atomic crystals. 22691039 A new bromobenzyl methyl sulphoxide from marine red alga Symphyocladia latiuscula. A new bromophenol, 2,3,6-tribromo-4,5-dihydroxybenzyl methyl sulphoxide, was isolated from the EtOH extract of the marine alga Symphyocladia latiuscula. Its structure was confirmed by spectroscopic methods (1D- and 2D-NMR, HR-ESI-MS). This new bromophenol showed moderate antifungal activity against Candida albicans with MIC value of 37.5 µg mL(-1). 23534411 Synthesis and biological evaluation of tricyclic guanidine analogues of batzelladine K for antimalarial, antileishmanial, antibacterial, antifungal, and anti-HIV activities. Fifty analogues of batzelladine K were synthesized and evaluated for in vitro antimalarial (Plasmodium falciparum), antileishmanial (Leishmania donovani), antimicrobial (panel of bacteria and fungi), antiviral (HIV-1) activities. Analogues 14h and 20l exhibited potential antimalarial activity against chloroquine-sensitive D6 strain with IC(50) 1.25 and 0.88 μM and chloroquine-resistant W2 strain with IC(50) 1.64 and 1.07 μM, respectively. Analogues 12c and 14c having nonyl substitution showed the most potent antileishmanial activity with IC(50) 2.39 and 2.78 μM and IC(90) 11.27 and 12.76 μM, respectively. Three analogues 12c, 14c, and 14i were the most active against various pathogenic bacteria and fungi with IC(50) < 3.02 μM and MIC/MBC/MFC <6 μM. Analogue 20l having pentyl and methyl substituents on tricycle showed promising activities against all pathogens. However, none was found active against HIV-1. Our study demonstrated that the tricyclic guanidine compounds provide new structural class for broad spectrum activity. 22977165 Nephrogenic systemic fibrosis-like effects of magnetic resonance imaging contrast agents in rats with adenine-induced renal failure. Nephrogenic systemic fibrosis (NSF) is a scleroderma-like disease associated with prior administration of certain gadolinium chelates (GCs). NSF occurs in patients with severe renal failure. The purpose of this study was to set up a rat model of GC-associated NSF to elucidate the mechanism of this devastating disease. Firstly, after characterization of the model, male Wistar rats received a 0.75% adenine-enriched diet for 8, 14, or 16 days to obtain various degrees of renal failure. Rats received five consecutive daily iv injections of saline or gadodiamide (2.5 mmol/kg/day). Secondly, the safety profile and in vivo propensity to dissociate of all categories of marketed GCs (gadoterate, gadobutrol, gadobenate, gadopentetate, and gadodiamide) were compared in rats receiving adenine-enriched diet for 16 days. Serial skin biopsies were performed for blinded histopathological study. Total Gd concentration in tissues was measured by Inductively Coupled Plasma Mass Spectrometry. Relaxometry was used to evaluate the presence of dissociated Gd in skin and bone. Gadodiamide-induced high mortality and skin lesions (dermal fibrosis, calcification, and inflammation) were related to adenine diet duration. No skin lesions were observed with other molecules. Unlike macrocyclic GCs, gadodiamide, gadopentetate, and gadobenate gradually increased the r(1) relaxivity value, consistent with in vivo dissociation and release of soluble Gd (or, in the case of gadobenate, the consequence of protein binding). Gadodiamide-induced cutaneous and systemic toxicity depended on baseline renal function. We demonstrate in vivo dissociation of linear GCs, gadodiamide, and gadopentetate, whereas macrocyclic agents remained stable over the study period. 23085433 Target promiscuity and physicochemical properties contribute to pharmacologically induced ER-stress. In vivo toxicity of drug candidates remains a major problem in the pharmaceutical industry, and is a significant cause of late stage attrition. As a consequence predictive in vitro assays are developed and put in place early in the discovery pipeline to aid compound selection. Endoplasmic reticulum stress (ER-stress) has been implicated in many disease states, as well as compound-induced organ toxicities. We explored the role of ER-stress as a general mechanism of toxicity by utilizing a high-throughput in vitro assay to screen 316 chemically diverse Pfizer proprietary compounds with known in vivo toxicity outcome for nuclear accumulation of spliced x-box binding protein 1 (XBP1s), a key transcription factor of the unfolded protein response (UPR). We examined the correlation between physicochemical properties, such as molecular weight, pKA, lipophilicity, topological polar surface area, and passive permeability, as well as target promiscuity, between XBP1s hits and non-hits and found that lipophilicity, target promiscuity and low passive permeability significantly contributed to ER-stress. In addition, we have shown that compounds which cause ER-stress in the form of XBP1s activation at concentrations below 40 μM have a more than four times greater chance of causing in vivo toxicity at 10 μM plasma exposure. 22851333 Coronary microvascular function in patients with Cushing's syndrome. The aim of the study was to evaluate patients with Cushing's syndrome the coronary flow reserve (CFR), an index of coronary microvascular function. Fifteen newly diagnosed patients with Cushing's syndrome (1 male/14 females; mean age 45 ± 11 years), were selected for having no clinical evidence of ischemic heart disease. Twelve patients had pituitary-dependent Cushing's disease and three had an adrenal adenoma. Fifteen subjects matched for age, sex, and major cardiovascular risk factors were used as controls. Coronary flow velocity in the left anterior descending coronary artery was investigated by transthoracic Doppler echocardiography at rest and during adenosine infusion. CFR was obtained as the ratio hyperemic/resting diastolic flow velocity. A reduced coronary reserve (hyperemic/resting ratio ≤ 2.5) was found in 5/15 Cushing patients and 4/15 controls. In all patients with abnormal CFR, epicardial coronary stenosis was excluded by multi-slice computed tomographic coronary angiography. CFR was inversely related to urinary cortisol in patients with endogenous hypercortisolism (Spearman's rho = -0.57, P = 0.03), while no correlation was found in controls. Coronary microvascular function, as assessed by CFR, is pathologically reduced in a considerable number of patients with Cushing's syndrome without clinical symptoms of ischemic heart disease and in the absence of epicardial coronary artery lesions, as well as in controls matched for cardiovascular risk factors. The presence of comorbidities can explain this early coronary abnormality in both patients and controls. Whether urinary cortisol may be a predictor of coronary microvascular function in the setting of patients with Cushing's syndrome, needs further investigation. 23375813 3'-R/S-Hydroxyvoacamine, a potent acetylcholinesterase inhibitor from Tabernaemontana divaricata. Guided by the acetylcholinesterase inhibiting activity, the bisindole alkaloid 3'-R/S-hydroxyvoacamine was isolated from a stem extract of Tabernaemontana divaricata, a plant used in Thailand in traditional rejuvenation remedies for improving the memory. The structure of the alkaloid was elucidated by extensive use of NMR spectroscopy and the complete assignment of the (1)H and (13)C NMR spectra is reported. The alkaloid acted as a non-competitive inhibitor against AChE with an IC50 value of 7.00±1.99μM. An HPLC method was developed for the quantitative analysis of the AChE inhibitor. It suggested that there was 12.4% (w/w) of 3'-R/S-hydroxyvoacamine in the alkaloid enriched fraction of T. divaricata stem. 23567030 The influence of Bauhinia forficata Link subsp. pruinosa tea on lipid peroxidation and non-protein SH groups in human erythrocytes exposed to high glucose concentrations. ETHNOPHARMACOLOGICAL RELEVANCE: Bauhinia forficata (BF) has been traditionally used as tea in folk medicine of Brazil for treatment of Diabetes mellitus (DM). AIM OF THE STUDY: To evaluate the effects of BF leaf tea on markers of oxidative damage and antioxidant levels in an experimental model of hyperglycemia in human erythrocytes in vitro. MATERIALS AND METHODS: Human erythrocytes were incubated with high glucose concentrations or glucose and BF tea for 24h and 48h. After incubation lipid peroxidation and non-protein SH levels were analyzed. Moreover, quantification of polyphenols and flavonoids, iron chelating property, scavenging of DPPH, and prevention of lipid peroxidation in isolated lipids were also assessed. RESULTS: A significant amount of polyphenols and flavonoids was observed. The main components found by LC-MS analysis were quercetin-3-O-(2-rhamnosyl) rutinoside, kaempferol-3-O-(2-rhamnosyl) rutinoside, quercetin-3-O-rutinoside and kaempferol-3-O-rutinoside. BF tea presents important antioxidant and chelating properties. Moreover, BF tea was effective to increase non-protein SH levels and reduce lipid peroxidation induced by high glucose concentrations in human erythrocytes. CONCLUSION: The antioxidant effects of BF tea could be related to the presence of different phenolic and flavonoids components. We believe that these components can be responsible to protect human erythrocytes exposed to high glucose concentrations against oxidative damage. 23477624 Safety and efficacy of polycalcium for improving biomarkers of bone metabolism: a 4-week open-label clinical study. Polycalcium is a mixture of Polycan and calcium lactate-gluconate 1:9 (w/w) with demonstrated antiosteoporosis activity in vitro and in vivo studies. These studies were a 4-week open-label, single-center trial to evaluate the efficacy of oral Polycalcium on bone metabolism and safety. In total, 30 healthy women (range 40-60 years) were administered 400 mg of Polycalcium for 4 weeks. The primary efficacy parameter was urinary deoxypyridinoline (DPYR) levels, and serum osteocalcin (OSC), bone-specific alkaline phosphatase (BALP), urinary cross-linked C-telopeptide of type-1 collagen (CTx), urinary cross-linked N-telopeptide of type-1 collagen (NTx), calcium (Ca), and phosphorus (P) levels, which were evaluated for comparison before and after administration of Polycalcium. After 4 weeks of Polycalcium administration, 27 subjects completed the test plan. Three subjects withdrew their consent to participate. The values of blood OSC, BALP, serum Ca, and serum P from baseline to 4 weeks of treatment were changed by -28.44%, 14.37%, 6.11%, and 1.42%, respectively. Biomarkers of bone resorption: urinary DPYR, serum CTx, serum NTx, urinary Ca, and urinary P, at baseline after 4 weeks of treatment were changed by -13.40%, 6.67%, -5.13%, -22.43%, and -3.04%, respectively. Additionally, when considering the subjects' adverse effects and the results of the blood and urine tests over the 4-week trial period, the dose of 400  mg Polycalcium showed efficacy for improving bone metabolism and was well tolerated and safe. Polycalcium was apparently safe and efficacious. 23361304 Antenatal manifestations of mitochondrial disorders. Mitochondrial respiratory chain diseases are a heterogeneous group of pathologies caused by genetic alterations affecting mitochondrial energy production. Theoretically, this deficiency may lead to any symptoms, in any organ or tissue, at any age even before birth. The aim of our study was to identify the frequency and characterize antenatal manifestations identifying possible associations between mitochondrial disease and more specific and earlier manifestation. We retrospectively review the files of 44 paediatric subjects with genetic and biochemical alterations of respiratory chain identified in the first decade of life and compare data with a control group (n = 88). Our results show that maternal age was similar in both groups. The female gender was predominant in patients group. Gestational age at delivery was similar in both groups. Concerning birth weight, it was significantly lower (p = 0.001) in patients (2899.9 ± 538.3 vs. 3246.6 ± 460.2 g). Fifteen pregnancies of the patients group were considered abnormal. Our findings show that intrauterine growth restriction was the most frequent antenatal feature observed. Neonatal morbidity was significantly higher (fivefold) in patients (p < 0.001). The clinical findings are independent of the molecular defect type. Our results are preliminary and more studies are needed, in order to learn more about mitochondrial physiology and activity in embryological development for the assessment of mitochondrial disease progress in fetal life. However, the present work is a significant contribution, given the scarcity of information in this field. 23233286 Polariton dynamics under strong light-molecule coupling. We present a comprehensive experimental study of the photophysical properties of a molecule-cavity system under strong coupling conditions, using steady-state and femtosecond time-resolved emission and absorption techniques to selectively excite the lower and upper polaritons as well as the reservoir of uncoupled molecules. Our results demonstrate the complex decay routes in such hybrid systems and that, contrary to expectations, the lower polariton is intrinsically long-lived. 23568566 Highly Stretchable Patterned Gold Electrodes Made of Au Nanosheets. Multilayered Au nanosheets are suggested as a novel class of material for fabricating stretchable electrodes suitable for organic-based electronic devices. The electrodes show no difference in resistivity during repeated stretching cycles up to ϵ = 40%. 23199998 Determination of paralytic shellfish poisoning toxins by HILIC-MS/MS coupled with dispersive solid phase extraction. This paper describes the use of QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) for the extraction, cleanup and detection of 10 paralytic shellfish toxins (PSP) in sea food by HILIC-MS/MS with positive ESI. Matrix matched calibration standards were used to compensate for matrix effects. The toxins were extracted with acetonitrile/water (90:10, v/v) containing 0.1% formic acid and cleaned by HLB and GCB sorbents. Qualitative and quantitative detection for the analytes were carried out under the multiple reaction monitoring (MRM) in positive ionization mode after chromatography separation on a TSK-gel Amide-80® column (150 mm×2.0 mm×3 μm). Studies at three fortification levels for the toxins in the range of 8.1-225.5 μg/kg gave mean recoveries from 71.3% to 104.6% with relative standard deviation (RSD) ≤ 15.8%. The limit of detection (LOD) was below the recommended regulatory limit of 170 μgSTX(equ.)/kg and the proposed method fully meets the needs of daily monitoring. 23499663 Gap junction channels and hemichannels in the CNS: Regulation by signaling molecules. Coordinated interaction among cells is critical to develop the extremely complex and dynamic tasks performed by the central nervous system (CNS). Cell synchronization is in part mediated by connexins and pannexins; two different protein families that form gap junction channels and hemichannels. Whereas gap junction channels connect the cytoplasm of contacting cells and coordinate electric and metabolic activities, hemichannels communicate intra- and extra-cellular compartments and serve as diffusional pathways for ions and small molecules. Cells in the CNS depend on paracrine/autocrine communication via several extracellular signaling molecules, such as, cytokines, growth factors, transmitters and free radical species to sense changes in microenvironment as well as to adapt to them. These signaling molecules modulate crucial processes of the CNS, including, cellular migration and differentiation, synaptic transmission and plasticity, glial activation, cell viability and microvascular blood flow. Gap junction channels and hemichannels are affected by different signaling transduction pathways triggered by these paracrine/autocrine signaling molecules. Most of the modulatory effects induced by these signaling molecules are specific to the cell type and the connexin and pannexin subtype expressed in different brain areas. In this review, we summarized and discussed most of the relevant and recently published information on the effects of signaling molecules on connexin or pannexin based channels and their possible relevance in CNS physiology and pathology. This article is part of a Special Issue entitled 'Connexin based channels'. 23142112 Pushing short DNA fragments to the limit: Phylogenetic relationships of 'hydrobioid' gastropods (Caenogastropoda: Rissooidea). Although phylogenetic studies are increasingly utilizing multi-locus datasets, a review of GenBank data for the Gastropoda indicates a strong bias towards a few short gene fragments (most commonly COI, LSU rRNA, and SSU rRNA). This is particularly the case for the Rissooidea, one of the largest and most taxonomically difficult gastropod superfamilies. Here we analyze fragments of these three genes from 90 species to determine whether they can well resolve higher relationships within this superfamily, whether structurally aligned sequence datasets increase phylogenetic signal, and whether the inclusion of highly variable regions introduces noise. We also used the resulting phylogenetic data in combination with morphological/anatomical evidence to re-evaluate the taxonomic status of 'hydrobioid' family-level groups. Our results indicate that all three of the alignment strategies that were used resulted in phylogenies having similar signal levels. However, there was a slight advantage to using structural alignment for inferring family-level relationships. Moreover, the set of 'standard' gastropod genes supported recognition of many previously recognized families and provides new insight into the systematics of several problematic groups. However, some family-group taxa were unresolved and the relationships among families were also poorly supported, suggesting a need for more extensive sampling and inclusion of additional genes. 23560504 3D Spectroscopy of Vibrational Coherences in Quantum Dots: Theory. In semiconductor nanocrystals, called quantum dots (QD), electronic transition energies, phonon frequencies, and electron-phonon coupling strengths are all reported to depend on the size of the crystals. The size dependencies of the transition energies and the mode frequencies are well characterized and understood. At the same time, the electron-phonon coupling dependence on size is controversial-even the sign of the change is not settled. In this article, third-order response functions of a model QD resembling CdSe are calculated. The longitudinal optical (LO) mode is included as a relatively narrow Lorentzian contribution to the spectral density. A novel version of electronic 2D spectroscopy is investigated where a third Fourier transform is taken over a so-called population time, leading to 3D spectral representation. The amplitude and phase of the 2D cuts of the 3D spectral body around the LO mode frequency are analyzed. The analytical power and sensitivity of the cuts in determining the possible Huang-Rhys factor (electron-phonon coupling strength) and the LO mode frequency dependence on the QD size are investigated. Peak structures in the cuts with a tilt relative to the diagonal are identified as sensitive signatures for the size dependencies. The study elucidates the 3D representation of the electronic 2D spectroscopy as a powerful tool for obtaining insight into otherwise hardly accessible characteristics of the system. 23303733 Successful application of an ionic liquid carrying the fluoride counter-ion in biomacromolecular chemistry: microwave-assisted acylation of cellulose in the presence of 1-allyl-3-methylimidazolium fluoride/DMSO mixtures. The use of ionic liquids with fluoride anion (IL-F) is challenging because of side reactions. Neat 1-allyl-3-methylimidazolium fluoride (AlMeImF) is used as a solvent in microwave-assisted acylation of cellulose. The results are disappointing due to side reactions in the IL proper, and F(-) -mediated hydrolysis of the produced ester. A dramatic improvement is observed, when AlMeImF/DMSO mixture is employed. The results are comparable to those obtained when pure 1-allyl-3-methylimidazolium chloride is employed. FTIR spectroscopy shows that dissolving a carboxylic acid anhydride in IL-F leads to the formation of acyl fluoride. Thus ILs are far from being "spectator" solvents. The new approach (use of IL-F/DMSO) is attractive because of its efficiency, low cost, and applicability to the derivatization of any polymer. 23288867 Regiospecificity and stereospecificity of human UDP-glucuronosyltransferases in the glucuronidation of estriol, 16-epiestriol, 17-epiestriol, and 13-epiestradiol. The glucuronidation of estriol, 16-epiestriol, and 17-epiestriol by the human UDP-glucuronosyltransferases (UGTs) of subfamilies 1A, 2A, and 2B was examined. UGT1A10 is highly active in the conjugation of the 3-OH in all these estriols, whereas UGT2B7 is the most active UGT toward one of the ring D hydroxyls, the 16-OH in estriol and 16-epiestriol, but the 17-OH in 17-epiestriol. Kinetic analyses indicated that the 17-OH configuration plays a major role in the affinity of UGT2B7 for estrogens. The glucuronidation of the different estriols by the human liver and intestine microsomes reflects the activity of UGT1A10 and UGT2B7 in combination with the tissues' difference in UGT1A10 expression. The UGT1A10 mutant 1A10-F93G exhibited much higher V(max) values than UGT1A10 in estriol and 17-epiestriol glucuronidation, but a significantly lower value in 16-epiestriol glucuronidation. To this study on estriol glucuronidation we have added experiments with 13-epiestradiol, a synthetic estradiol in which the spatial arrangement of the methyl on C18 and the hydroxyl on C17 is significantly different than in other estrogens. In comparison with estradiol glucuronidation, the C13 configuration change decreases the turnover of UGTs that conjugate the 3-OH, but increases it in UGTs that primarily conjugate the 17-OH. Unexpectedly, UGT2B17 exhibited similar conjugation rates of both the 17-OH and 3-OH of 13-espiestradiol. The combined results reveal the strong preference of UGT1A10 for the 3-OH of physiologic estrogens and the equivalently strong preference of UGT2B7 and UGT2B17 for the hydroxyls on ring D of such steroid hormones. 23107818 Autophagy upregulation promotes survival and attenuates doxorubicin-induced cardiotoxicity. This study evaluated whether the manipulation of autophagy could attenuate the cardiotoxic effects of doxorubicin (DXR) in vitro as well as in a tumour-bearing mouse model of acute doxorubicin-induced cardiotoxicity. We examined the effect of an increase or inhibition of autophagy in combination with DXR on apoptosis, reactive oxygen species (ROS) production and mitochondrial function. H9C2 rat cardiac myoblasts were pre-treated with bafilomycin A1 (autophagy inhibitor, 10 nM) or rapamycin (autophagy inducer, 50 μM) followed by DXR treatment (3 μM). The augmentation of autophagy with rapamycin in the presence of DXR substantially ameliorated the detrimental effects induced by DXR. This combination treatment demonstrated improved cell viability, decreased apoptosis and ROS production and enhanced mitochondrial function. To corroborate these findings, GFP-LC3 mice were inoculated with a mouse breast cancer cell line (EO771). Following the appearance of tumours, animals were either treated with one injection of rapamycin (4 mg/kg) followed by two injections of DXR (10 mg/kg). Mice were then sacrificed and their hearts rapidly excised and utilized for biochemical and histological analyses. The combination treatment, rather than the combinants alone, conferred a cardioprotective effect. These hearts expressed down-regulation of the pro-apoptotic protein caspase-3 and cardiomyocyte cross-sectional area was preserved. These results strongly indicate that the co-treatment strategy with rapamycin can attenuate the cardiotoxic effects of DXR in a tumour-bearing mouse model. 23295645 Polymeric triamcinolone acetonide nanoparticles as a new alternative in the treatment of uveitis: In vitro and in vivo studies. The purpose of this work was to improve the efficacy of triamcinolone acetonide (TA) in the treatment of endotoxin-induced uveitis (EIU) using a polymeric nanoparticulate drug delivery system. Poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles were prepared using a modified emulsification/solvent diffusion method. Processing factors affecting loading and size were also studied. After physicochemical studies including in vitro release, X-ray powder diffraction, differential scanning calorimetry, and scanning electron microscopy, in vivo studies were conducted using nanoparticles sized 195nm with 3.16% drug loading. Inflammatory factors such as flare, cell, and fibrin were studied in rabbit's eye over 96h period, using laser flare meter and slit lamp examination. Inflammatory mediators such as NO, PGE2, cell, and protein were measured quantitatively 36h after intravitreal injection of endotoxin in aqueous humor, and the therapeutic effects were compared in different groups. Results indicated statistically significant differences between the effect of nanoparticles in the treatment of EIU compared to microparticles of TA and prednisolone acetate (PA). There were no significant differences between the effects of TA injection and TA nanoparticles. In conclusion, sustain release biodegradable TA nanoparticles are potential new topical treatment options which can provide better patient compliance. 23454831 In vitro nanotoxicity of single-walled carbon nanotube-dendrimer nanocomplexes against murine myoblast cells. Single-wall carbon nanotubes (SWCNTs) and polyamidoamine dendrimers (PAMAM) have been proposed for a variety of biomedical applications. The combination of both molecules makes this new composite nanomaterial highly functionalizable and versatile to theranostic and drug-delivery systems. However, recent toxicological studies have shown that nanomaterials such as SWCNTs and PAMAM may have high toxicity in biological environments. Aiming to elucidate such behavior, in vitro studies with different cultured cells have been conducted in the past few years. This study focuses on the effects of SWCNT-PAMAM nanomaterials and their individual components on the C2C12 murine cell line, which is a mixed population of stem and progenitor cells. The interactions between the cells and the nanomaterials were studied with different techniques usually employed in toxicological analyses. The results showed that SWCNT-PAMAM and PAMAM inhibited the proliferation and caused DNA damage of C2C12 cells. Data from flow cytometry revealed a less toxicity in C2C12 cells exposed to SWCNT compared to the other nanomaterials. The results indicated that the toxicity of SWCNT, SWCNT-PAMAM and PAMAM in C2C12 cells can be strongly correlated with the charge of the nanomaterials. 22790339 Density functional theory study on the reaction mechanism of synthesizing 1,3-dimethyl-2-imidazolidinone by urea method. We report a first-principles density functional theory investigation on tailoring the fundamental reaction mechanism of synthesizing 1,3-dimethyl-2-imidazolidinone (DMI) through the urea method with water serving as both solvent and catalyst. The nucleophilic cyclization reaction is implemented by two ammonia removal steps. One -NH group of dimethylethylenediamine (DMEDA) first attacks the carbon atom of urea, eliminating one -NH3 group and forming an intermediate state CH3NHC2H4N(CH3)CONH2 (IMI). IMI subsequently undergoes the cyclization process through a secondary ammonia removal via similar manner. Without water, the two ammonia removal steps are both slightly exothermic with high activation barriers (~50 kcal mol(-1)). As water participated in the reaction, the kinetics of the two steps can be significantly improved, respectively. The role that water plays, beside as solvent, more importantly, is to serve as a proton exchange bridge. Due to the spatial configuration, the direct proton migration from the N atoms of ethylenediamine to urea is difficult to occur. The water bridge facilitates the proton migration by shortening the migration distance. As a consequence, the activation barriers are considerably lowered down to ~30 kcal mol(-1), indicating a strong catalytic effect from water. In contrast, the three possible side reactions of IM(I), even catalyzed by water, have higher activation barriers due to strong steric inhibitive effect and consequently become difficult to occur at the same condition. The current computational understanding on the prototypical reaction to DMI can be extended to guide developing more efficient routes to synthesize imidazolidinone derivatives through the urea method. 22813627 Disposition of diiosononyl phthalate and its effects on sexual development of the male fetus following repeated dosing in pregnant rats. Pregnant Sprague-Dawley rats received 50, 250, and 500 mg/kg/day diisononyl phthalate (DiNP) from GD 12 to 19 via corn oil gavage to study the dose response for effects on fetal male rat sexual development as well as metabolite disposition in the dam and fetus. Monoisononyl phthalate (MiNP), mono(carboxy-isooctyl) phthalate (MCiOP), mono(hydroxyl-isononyl) phthalate (MHiNP), mono(oxo-isononyl) phthalate (MOiNP), and monoisononyl phthalate glucuronide (MiNP-G) were found in all measured tissues. MCiOP was the major metabolite, followed in decreasing order by MiNP, MHiNP, MOiNP, and MiNP-G. Percentage of dose absorbed decreased at 750 mg/kg/day. Testosterone concentration in the fetal testes was reduced at 250 and 750 mg/kg/day. Multinucleated germ cells were increased in the testes of rats at 250 and 750 mg/kg/day. The no observed effect level (NOEL) for this study was 50 mg/kg/day based on increased MNGs and reduced testes testosterone concentration in the fetal rat. 23371805 Role of autophagy in the progression from obesity to diabetes and in the control of energy balance. Autophagy plays a crucial role in cellular homeostasis through the degradation and recycling of organelles such as mitochondria or endoplasmic reticulum (ER) that are closely related to the pathogenesis of diabetes. In pancreatic β-cells producing insulin, autophagy helps maintain β-cell mass, structure and function. In mice with β-cell-specific deletion of Atg7 (autophagy-related 7), a critical autophagy gene, reduction of β-cell mass and pancreatic insulin content were observed together with impaired insulin secretory function. Because of such structural and functional defects, β-cell-specific Atg7-null mice showed hypoinsulinemia and hyperglycemia. However, those mice never developed diabetes. Obesity and lipids are physiological ER stressors that can precipitate β-cell dysfunction and insulin resistance. Recent studies showed that β-cell-specific Atg7-null mice, when bred with ob/ob mice, developed severe diabetes, suggesting that autophagy-deficient β-cells can handle basal metabolic stress but have problems dealing with increased metabolic stress. Thus, autophagy deficiency in β-cells could be a factor in the progression from obesity to diabetes due to an inappropriate response to obesity-induced ER stress. Autophagy also appears to play a role in the hypothalamic control of energy expenditure, appetite and body weight. Thus, autophagy is important to body and nutrient metabolism in many ways, and its dysregulation could contribute to the pathogenesis of metabolic disorders and diabetes. 23253130 Accounting for receptor flexibility and enhanced sampling methods in computer-aided drug design. Protein flexibility plays a major role in biomolecular recognition. In many cases, it is not obvious how molecular structure will change upon association with other molecules. In proteins, these changes can be major, with large deviations in overall backbone structure, or they can be more subtle as in a side-chain rotation. Either way the algorithms that predict the favorability of biomolecular association require relatively accurate predictions of the bound structure to give an accurate assessment of the energy involved in association. Here, we review a number of techniques that have been proposed to accommodate receptor flexibility in the simulation of small molecules binding to protein receptors. We investigate modifications to standard rigid receptor docking algorithms and also explore enhanced sampling techniques, and the combination of free energy calculations and enhanced sampling techniques. The understanding and allowance for receptor flexibility are helping to make computer simulations of ligand protein binding more accurate. These developments may help improve the efficiency of drug discovery and development. Efficiency will be essential as we begin to see personalized medicine tailored to individual patients, which means specific drugs are needed for each patient's genetic makeup. 23164618 Supra-normal stimulation of dopamine D1 receptors in the prelimbic cortex blocks behavioral expression of both aversive and rewarding associative memories through a cyclic-AMP-dependent signaling pathway. Dopamine (DA) receptor transmission through either D(1) or D(2)-like subtypes is involved critically in the processing of emotional information within the medial prefrontal cortex (mPFC). However the functional role of specific DA D(1)-like receptor transmission in the expression of emotionally salient associative memories (either aversive or rewarding) is not currently understood. Here we demonstrate that specific activation of DA D(1) receptors in the prelimbic (PLC) division of the mPFC causes a transient block in the behavioral expression of both aversive and rewarding associative memories. We report that intra-PLC microinfusions of a selective D(1) receptor agonist block the spontaneous expression of an associative olfactory fear memory, without altering the stability of the original memory trace. Furthermore, using an unbiased place conditioning procedure (CPP), intra-PLC D(1) receptor activation blocks the spontaneous expression of an associative morphine (5 mg/kg; i.p.) reward memory, while leaving morphine-primed memory expression intact. Interestingly, both intra-PLC D(1)-receptor mediated block of either fear-related or reward-related associative memories were dependent upon downstream cyclic-AMP (cAMP) signaling as both effects were rescued by co-administration of a cAMP signaling inhibitor. The blockade of both rewarding and aversive associative memories is mediated through a D(1)-specific signaling pathway, as neither forms of spontaneous memory expression were blocked by intra-PLC microinfusions of a D(2)-like receptor agonist. Our results demonstrate that the spontaneous expression of either rewarding or aversive emotionally salient memories shares a common, D(1)-receptor mediated substrate within the mPFC. 23085121 Cholinesterase confabs and cousins: Approaching forty years. In the past four decades of cholinesterase (ChE) research, we have seen substantive evolution of the field from one centered around substrate and inhibitor kinetic profiles and compound characterizations to the analysis of ChE structure, first through the gene families and then by X-ray crystallographic determinations of the free enzymes and their complexes and conjugates. Indeed, these endeavors have been facilitated by recombinant DNA technologies, structure determinations and parallel studies in related proteins in the α/β-hydrolase fold family. This approach has not only contributed to a fundamental understanding of structure and function of a large family of hydrolase-like proteins possessing functions other than catalysis, but also has been used to develop new practical strategies for scavenging and antidotal activity in cases of organophosphate insecticide or nerve agent exposure. 23270805 Coming full circle: contributions of central and peripheral oxytocin actions to energy balance. The neuropeptide oxytocin has emerged as an important anorexigen in the regulation of energy balance. Its effects on food intake have largely been attributed to limiting meal size through interactions in key regulatory brain regions such as the hypothalamus and hindbrain. Pharmacologic and pair-feeding studies indicate that its ability to reduce body mass extends beyond that of food intake, affecting multiple factors that determine energy balance such as energy expenditure, lipolysis, and glucose regulation. Systemic administration of oxytocin recapitulates many of its effects when administered centrally, raising the questions of whether and to what extent circulating oxytocin contributes to energy regulation. Its therapeutic potential to treat metabolic conditions remains to be determined, but data from diet-induced and genetically obese rodent models as well as application of oxytocin in humans in other areas of research have revealed promising results thus far. 23261051 Cell-cycle and DNA damage regulation of the DNA mismatch repair protein Msh2 occurs at the transcriptional and post-transcriptional level. DNA mismatch repair during replication is a conserved process essential for maintaining genomic stability. Mismatch repair is also implicated in cell-cycle arrest and apoptosis after DNA damage. Because yeast and human mismatch repair systems are well conserved, we have employed the budding yeast Saccharomyces cerevisiae to understand the regulation and function of the mismatch repair gene MSH2. Using a luciferase-based transcriptional reporter, we defined a 218-bp region upstream of MSH2 that contains cell-cycle and DNA damage responsive elements. The 5' end of the MSH2 transcript was mapped by primer extension and was found to encode a small upstream open reading frame (uORF). Mutagenesis of the uORF start codon or of the uORF stop codon, which creates a continuous reading frame with MSH2, increased Msh2 steady-state protein levels ∼2-fold. Furthermore, we found that the cell-cycle transcription factors Swi6, Swi4, and Mbp1-along with SCB/MCB cell-cycle binding sites upstream of MSH2-are all required for full basal expression of MSH2. Mutagenesis of the cell-cycle boxes resulted in a minor reduction in basal Msh2 levels and a 3-fold defect in mismatch repair. Disruption of the cell-cycle boxes also affected growth in a DNA polymerase-defective strain background where mismatch repair is essential, particularly in the presence of the DNA damaging agent methyl methane sulfonate (MMS). Promoter replacements conferring constitutive expression of MSH2 revealed that the transcriptional induction in response to MMS is required to maintain induced levels of Msh2. Turnover experiments confirmed an elevated rate of degradation in the presence of MMS. Taken together, the data show that the DNA damage regulation of Msh2 occurs at the transcriptional and post-transcriptional levels. The transcriptional and translational control elements identified are conserved in mammalian cells, underscoring the use of yeast as a model system to examine the regulation of MSH2. 23041041 Rational design of apoptosis signal-regulating kinase 1 inhibitors: discovering novel structural scaffold. Increased activity of apoptosis signal-regulating kinase 1 (ASK1) is associated with a number of human disorders and the inhibitors of ASK1 may become important compounds for pharmaceutical application. Here we report novel ASK1 inhibitor scaffold, namely 5-(5-Phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one, that has been identified using virtual screening and biochemical tests. A series of derivatives has been synthesized and evaluated in vitro towards human protein kinase ASK1. It was revealed that the most active compounds 4-((5Z)-5-{[5-(4-bromophenyl)-2-furyl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)butanoic acid and 6-((5Z)-5-{[5-(4-bromophenyl)-2-furyl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)hexanoic acid inhibit ASK1 with IC50 of 0.2 μM. Structure-activity relationships of 33 derivatives of 5-(5-Phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one have been studied and binding mode of this chemical class has been predicted. 23232123 Aberrant transcription of the LHCGR gene caused by a mutation in exon 6A leads to Leydig cell hypoplasia type II. The luteinizing hormone/chorionic gonadotropin receptor (LHCGR) is essential for normal male sex differentiation. Recently, the additional primate-specific exon 6A of the LHCGR was discovered and it was shown to act as regulatory element at the transcriptional level. Compound heterozygous mutations in exon 6A (c.580 A>G) and exon 11 (c.1244T>C) were identified in the LHCGR of a male 46,XY patient with genital malformation. Analysis revealed that mutation c.580A>G in exon 6A affects the splicing pattern resulting in an increase of transcripts containing the internal variants of exon 6A prone to nonsense-mediated decay. In contrast, mutation c.1244T>C results in an amino acid substitution (Ile415Thr), which abolishes signal transduction due to structural changes. When inherited in a compound heterozygous fashion these mutations result in Leydig cell hypoplasia (LCH) type II. Thus this study provides proof that mutations causing aberrant transcription can impair receptor function and thereby be causative of LCH. 23538844 Cadmium Tolerance and Removal from Cunninghamella elegans Related to the Polyphosphate Metabolism. The aim of the present work was to study the cadmium effects on growth, ultrastructure and polyphosphate metabolism, as well as to evaluate the metal removal and accumulation by Cunninghamella elegans (IFM 46109) growing in culture medium. The presence of cadmium reduced growth, and a longer lag phase was observed. However, the phosphate uptake from the culture medium increased 15% when compared to the control. Moreover, C. elegans removed 70%-81% of the cadmium added to the culture medium during its growth. The C. elegans mycelia showed a removal efficiency of 280 mg/g at a cadmium concentration of 22.10 mg/L, and the removal velocity of cadmium was 0.107 mg/h. Additionally, it was observed that cadmium induced vacuolization, the presence of electron dense deposits in vacuoles, cytoplasm and cell membranes, as well as the distinct behavior of polyphosphate fractions. The results obtained with C. elegans suggest that precipitation, vacuolization and polyphosphate fractions were associated to cadmium tolerance, and this species demonstrated a higher potential for bioremediation of heavy metals. 23471850 The Efficiency of the Metal Catalysts in the Nucleophilic Substitution of Alcohols is Dependent on the Nucleophile and Not on the Electrophile. In this study, we investigate the effect of the electrophiles and the nucleophiles for eight catalysts in the catalytic SN 1 type substitution of alcohols with different degree of activation by sulfur-, carbon-, oxygen-, and nitrogen-centered nucleophiles. The catalysts do not show any general variance in efficiency or selectivity with respect to the alcohols and follow the trend of alcohol reactivity. However, when it comes to the nucleophile, the eight catalysts show general and specific variances in the efficiency and selectivity to perform the desired substitution. Interestingly, the selectivity of the alcohols to produce the desired substitution products was found to be independent of the electrophilicity of the generated carbocations but highly dependent on the ease of formation of the cation. Catalysts based on iron(III), bismuth(III), and gold(III) show higher conversions for S-, C-, and N-centered nucleophiles, and Bi(III) was the most efficient catalyst in all combinations. Catalysts based on rhenium(I) or rhenium(VII), palladium(II), and lanthanum(III) were the most efficient in performing the nucleophilic substitution on the various alcohols with the O-centered nucleophiles. These catalysts generate the symmetrical ether as a by-product from the reactions of S-, C-, and N-centered nucleophiles as well, resulting in lower chemoselectivity. 23574259 Helicity as a Steric Force: Stabilization and Helicity-Dependent Reversion of Colored o-Quinonoid Intermediates of Helical Chromenes. Photolysis of regioisomeric helical chromenes 1 and 2 leads to colored reactive intermediates. While the latter generally decay quite rapidly, they are found to be longer lived in 1 and highly persistent in 2. The remarkable stability of the otherwise fleeting transient in 2 allowed isolation and structural characterization by X-ray crystallography. The structural analyses revealed that steric force inherent to the helical scaffold is the origin of stability as well as differentiation in the persistence of the intermediates of 1 and 2 (1Q and 2Q). The structure further shows that diphenylvinyl moiety in the TT isomer of 2Q gets splayed over the helical scaffold such that it is fraught with a huge steric strain to undergo required bond rotations to regenerate the precursor chromene. Otherwise, reversion of 2Q was found to occur at higher temperatures. Aazahelical chromenes 3 and 4 with varying magnitudes of helicity were designed in pursuit of o-quinonoid intermediates with graded activation barriers. Their photogenerated intermediates 3Q and 4Q were also isolated and structurally characterized. The activation barriers for thermal reversion of 2Q-4Q, as determined from Arrhenius and Eyring plots, are found to correlate nicely with the helical turn, which decisively determines the steric force. The exploitation of helicity is thus demonstrated to develop a novel set of photoresponsive helicenes 2-4 that lead to colored intermediates exhibiting graded stability. It is further shown that the photochromism of 2-4 in conjunction with response of 2Q-4Q to external stimuli (acid, heat, and visible radiation) permits development of molecular logic gates with INHIBIT function. 23617539 Dissecting Colloidal Stabilization Factors in Crowded Polymer Solutions by Forming Self-Assembled Monolayers on Gold Nanoparticles. An ideal colloidal system should be highly stable in a diverse range of buffer conditions while still retaining its surface accessibility. We recently reported that dispersing citrate-capped gold nanoparticles (AuNPs) in polymers such as polyethylene glycol (PEG) can achieve such a goal due to contributions from depletion stabilization. Since AuNPs can weakly adsorb PEG to exert steric stabilization and the remaining citrate can impart charge stabilization, the extent of the contribution of depletion stabilization is unclear. In this work, we aim to dissect the contribution of each stabilizing factor. This is achieved by coating AuNPs with a layer of thiolated compound, which inhibits the adsorption of PEG and also allows the control of surface charge. We found that depletion stabilization alone was insufficient to stabilize AuNPs at room temperature. However, when working together with other stabilization mechanisms, ultrahigh stability can be achieved. The size of both AuNPs and PEG was systematically varied and the trend was compared with theoretical calculations. Finally, we report the importance of the surface chemistry of commercial AuNPs. 23266735 Cytotoxicity and structure activity relationships of phytosterol from Phyllanthus emblica. Fourteen sterols (1-14), including two new sterols, trihydroxysitosterol (2) and 5α,6β,7α-7α-acetoxysitosterol (3), were isolated from the branches and leaves of Phyllanthus emblica L. The isolated compounds and a structurally related sterol 15 from Aphanamixis grandifolia were screened for cytotoxicity in two tumor cell lines (HL-60 and SMMC-7721) and a non-tumor cell line (HL-7702) using RSB assay. Within the series of phytosterol derivatives tested, compound 15 was the most active, displaying potent cytotoxicity against HL-60 with IC(50) of 5.10μmol/L, and most of the active compounds showed selective cytotoxicity against tumor and non-tumor cell lines, especially compound 10 with a safety index of 4.42. 23122161 Suppression of LPS-induced inflammatory activities by Rosmarinus officinalis L. Rosemary (Rosmarinus officinalis L.) has been used in folk medicine to treat headaches, epilepsy, poor circulation, and many other ailments. It was found that rosemary could act as a stimulant and mild analgesic and could reduce inflammation. However, the mechanisms underlying the anti-inflammatory effects of rosemary need more study to be established. Therefore, in this study, the effects of rosemary on the activation of nuclear factor kappa beta (NF-kB) and mitogen-activated protein kinases (MAPKs), the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and the production of nitric oxide (NO), prostaglandin E(2) (PGE(2)), and cytokine in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells were investigated. A methanol extract of rosemary and its hexane fraction reduced NO generation with an IC(50) of 2.75 and 2.83 μg/ml, respectively. Also, the methanol extract and the hexane fraction inhibited LPS-induced MAPKs and NF-kB activation associated with the inhibition of iNOS or COX-2 expression. LPS-induced production of PGE(2) and tumour necrosis factor-alpha (TNF-α) were blocked by rosemary. Rosemary extract and its hexane fraction are important for the prevention of phosphorylation of MAPKs, thereby blocking NF-kB activation, which in turn leads to decreased expression of iNOS and COX-2, thus preventing inflammation. 23578688 Synthesis and evaluation of carbamoylmethylene linked prodrugs of BMS-582949, a clinical p38α inhibitor. A series of carbamoylmethylene linked prodrugs of 1 (BMS-582949), a clinical p38α inhibitor, were synthesized and evaluated. Though the phosphoryloxymethylene carbamates (3, 4, and 5) and α-aminoacyloxymethylene carbamates (22, 23, and 26) were found unstable at neutral pH values, fumaric acid derived acyloxymethylene carbamates (2, 28, and 31) were highly stable under both acidic and neutral conditions. Prodrugs 2 and 31 were also highly soluble at both acidic and neutral pH values. At a solution dose of 14.2mpk (equivalent to 10mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10mpk of 1 itself. At a suspension dose of 142mpk (equivalent to 100mpk of 1), 2 demonstrated that it could overcome the solubility issue associated with 1 and provide a much higher exposure of 1. To our knowledge, the unique type of prodrugs like 2, 28, and 31 was not reported in the past and could represent a novel prodrug approach for secondary amides, a class of molecules frequently identified as drug candidates. 23583512 Thermal stability of oligodeoxynucleotide duplexes containing l-deoxynucleotide at termini. The effects of substituting l-deoxynucleotide for d-deoxynucleotide at duplex termini were evaluated and the terminal substitutions were found to show much less effects on duplex destabilization and to show a similar tendency in base pairing selectivity, compared with internal chiral substitutions. 23517437 Tailoring the Dependency between Rigidity and Water Uptake of a Microfabricated Hydrogel with the Conformational Rigidity of a Polymer Cross-Linker. Many diverse applications utilize hydrogels as carriers, sensors, and actuators, and these applications rely on the refined control of physical properties of the hydrogel, such as elastic modulus and degree of swelling. Often, hydrogel properties are interdependent; for example, when elastic modulus is increased, degree of swelling is decreased. Controlling these inverse dependencies remains a major barrier for broader hydrogel applications. We hypothesized that polymer cross-linkers with varied chain flexibility would allow us to tune the inverse dependency between the elastic modulus and the degree of swelling of the hydrogels. We examined this hypothesis by using alginate and poly(acrylic acid) (PAA) modified with a controlled number of methacrylic groups as model inflexible and flexible cross-linkers, respectively. Interestingly, the polyacrylamide hydrogel cross-linked by the inflexible alginate methacrylates exhibited less dependency between the degree of swelling and the elastic modulus than the hydrogel cross-linked by flexible PAA methacrylates. This critical role of the cross-linker's inflexibility was related to the difference of the degree of hydrophobic association between polymer cross-linkers, as confirmed with pyrene probes added in pregel solutions. Furthermore, hydrogels cross-linked with alginate methacrylates could tune the projection area of adhered cells by solely altering elastic moduli. In contrast, gels cross-linked with PAA methacrylates failed to modulate the cellular adhesion morphology due to a lower, and smaller, elastic modulus range to be controlled. Overall, the results of this study will significantly advance the controllability of hydrogel properties and greatly enhance the performance of hydrogels in various biological applications. 23352980 PIM1 kinase inhibitors induce radiosensitization in non-small cell lung cancer cells. Radiotherapy plays a critical role in the treatment of non-small cell lung cancer (NSCLC). However, radioresistance is a major barrier against increasing the efficiency of radiotherapy for NSCLC. To understand the mechanisms underlying NSCLC radioresistance, we previously focused on the potential involvement of PIM1, PRAS40, FOXO3a, 14-3-3, and protein phosphatases. Among these proteins, PIM1 functioned as an oncogene and was found to act as a crucial mediator in radioresistant NSCLC cells. Therefore, we investigated the use of PIM1-specific inhibitors as novel therapeutic drugs to regulate radiosensitivity in NSCLC. After structure-based drug selection, SGI-1776, ETP-45299, and tryptanthrin were selected as candidates of PIM1 inhibitors that act as radiosensitizers. With irradiation, these drugs inhibited only PIM1 kinase activity without affecting PIM1 mRNA/protein levels or cellular localization. When PIM1 kinase activity was suppressed by these inhibitors, PRAS40 was not phosphorylated. Consequently, unphosphorylated PRAS40 did not form trimeric complexes with 14-3-3 and FOXO3a, leading to increased nuclear localization of FOXO3a. Nuclear FOXO3a promoted the expression of pro-apoptotic proteins such as Bim and FasL, resulting in a radiosensitizing effect on radioresistant NSCLC cells. Moreover, an in vivo xenograft mouse model confirmed this radiosensitizing effect induced by PIM1 inhibitors. In these model systems, tumor volume was significantly reduced by a combinational treatment with irradiation and PIM1 inhibitors compared to irradiation alone. Taken together, our findings provided evidence that PIM1-specific inhibitors, SGI-1776, ETP-45299, and tryptanthrin, can act as novel radiosensitizers to enhance the efficacy of radiotherapy by inhibiting irradiation-induced signaling pathway associated with radioresistance. 23215051 Optical pumping of a single electron spin bound to a fluorine donor in a ZnSe nanostructure. Here we demonstrate optical pumping of a single electron within a semiconductor nanostructure comprised of a single fluorine donor located within a ZnSe/ZnMgSe quantum well. Experiments were performed to detect optical pumping behavior by observing single photons emitted from the nanostructure when the electron changes spin state. These results demonstrate initialization and read-out of the electron spin qubit and open the door for coherent optical manipulation of a spin by taking advantage of an unconventional nanostructure. 23411197 Antioxidant activities of the synthesized thiol-contained peptides derived from computer-aided pepsin hydrolysis of yam tuber storage protein, dioscorin. Our previous report showed that yam dioscorin and its peptic hydrolysates exhibit radical scavenging activities; however, the functions of these peptic hydrolases are still under investigation. In this study, the thiol-containing peptides derived from computer-aided simulation of pepsin hydrolysis of dioscorin, namely, KTCGNGME (diotide1), PPCSE (diotide2), CDDRVIRTPLT (diotide3), KTCGY (diotide4), and PPCTE (diotide5) were synthesized to compare their antioxidant activities with GSH and/or carnosine by examining hydroxyl radical scavenging activity by electron spin resonance spectrometry, anti-low-density lipoprotein peroxidation, anti-AAPH-induced hemolysis, and oxygen radical absorbance capacity activity. We found that while all the synthesized diotides showed antioxidant activity, diotide4 exhibited the highest levels. Moreover, all diotides (100 μM) showed protective effects against methylglyoxal-induced human umbilical vein endothelial cell death. These results suggest that thiol-containing diotides derived from dioscorin hydrolysis exhibit antioxidant activities and reveal the benefits of yam tuber as an antioxidant-rich food. 23628762 Charcot-Marie-Tooth disease-associated mutants of GDAP1 dissociate its roles in peroxisomal and mitochondrial fission. Mitochondria and peroxisomes can be fragmented by the process of fission. The fission machineries of both organelles share a set of proteins. GDAP1 is a tail-anchored protein of mitochondria and induces mitochondrial fragmentation. Mutations in GDAP1 lead to Charcot-Marie-Tooth disease (CMT), an inherited peripheral neuropathy, and affect mitochondrial dynamics. Here, we show that GDAP1 is also targeted to peroxisomes mediated by the import receptor Pex19. Knockdown of GDAP1 leads to peroxisomal elongation that can be rescued by re-expressing GDAP1 and by missense mutated forms found in CMT patients. GDAP1-induced peroxisomal fission is dependent on the integrity of its hydrophobic domain 1, and on Drp1 and Mff, as is mitochondrial fission. Thus, GDAP1 regulates mitochondrial and peroxisomal fission by a similar mechanism. However, our results reveal also a more critical role of the amino-terminal GDAP1 domains, carrying most CMT-causing mutations, in the regulation of mitochondrial compared to peroxisomal fission. 23421616 Synthesis, cytotoxicity and in vitro antileishmanial activity of naphthothiazoles. The leishmaniasis is a spectral disease caused by the protozoan Leishmania spp, which threatens millions of people worldwide. Current treatments exhibit high toxicity and there is no vaccine available. The need for new lead compounds with leishmanicidal activity is urgent. Considering that many lead leishmanicidal compounds contain a quinoidal scaffold and the thiazole heterocyclic ring is found in a number of antimicrobial drugs, we proposed a hybridization approach to generate a diverse set of semi-synthetic heterocycles with antileishmanial activity. We found that almost all synthesized compounds demonstrated potent activity against promastigotes of Leishmania (Viannia) braziliensis and reduced the survival index of Leishmania amastigotes in mammalian macrophages. Furthermore, the compounds were not cytotoxic to macrophages at 5-fold higher concentrations than the EC(50) for promastigotes. All molecules fulfilled Lipinski's Rule of Five, which predicts efficient orally absorption and permeation through biological membranes, the in silico pharmacokinetic profile confirmed these characteristics. The potent and selective activity of semi-synthetic naphthothiazoles against promastigotes and amastigotes reveals that the 2-amino-naphthothiazole ring may represent a scaffold for the design of compounds with leishmanicidal properties and encourage the development of drug formulation and new compounds for further studies in vivo. © 2013 John Wiley & Sons A/S. 22564031 The effect of process parameters on audible acoustic emissions from high-shear granulation. Product quality in high-shear granulation is easily compromised by minor changes in raw material properties or process conditions. It is desired to develop a process analytical technology (PAT) that can monitor the process in real-time and provide feedback for quality control. In this work, the application of audible acoustic emissions (AAEs) as a PAT tool was investigated. A condenser microphone was placed at the top of the air exhaust on a PMA-10 high-shear granulator to collect AAEs for a design of experiment (DOE) varying impeller speed, total binder volume and spray rate. The results showed the 10 Hz total power spectral densities (TPSDs) between 20 and 250 Hz were significantly affected by the changes in process conditions. Impeller speed and spray rate were shown to have statistically significant effects on granulation wetting, and impeller speed and total binder volume were significant in terms of process end-point. The DOE results were confirmed by a multivariate PLS model of the TPSDs. The scores plot showed separation based on impeller speed in the first component and spray rate in the second component. The findings support the use of AAEs to monitor changes in process conditions in real-time and achieve consistent product quality. 23458619 Pharmacogenomic approaches for tailored anti-leukemic therapy in children. Several lympholytic and cytotoxic agents are used in acute lymphoblastic leukemia (ALL) polychemotherapy. Genetic variants for cellular components involved in the pharmacokinetics and pharmacodynamics of these drugs can influence the pharmacological response, and molecular characterization of these genetic variants could be helpful for the comprehension of the mechanisms of resistance or increased sensitivity. The purpose of this review is to carry out an update of recent publications on genes that might influence ALL treatment in terms of outcome and/or toxicity and to underlie the role of genetic variants, particularly single nucleotide polymorphisms (SNP), in predicting clinical response, with particular reference to the current protocol for ALL therapy used in Italy, AIEOP-BFM ALL 2009. 23449204 Three new orcinol-conjugated hydrolysable tannins from the leaves of Cleyera japonica. Three new orcinol (3-hydroxy-5-methylphenol)-conjugated hydrolysable tannins, together with two known compounds were isolated from the leaves of Cleyera japonica (CJ), and have been tentatively named cleyeratannin A (1), cleyeratannin B (2) and cleyeratannin C (3). The chemical structures of these compounds were elucidated using 1 dimensional (1D)/2D NMR and high resolution FAB-MS, and the absolute configuration was confirmed by circular dichroism (CD). To evaluate their anti-oxidative activities, 1,1-diphenyl-2-picrylhydrazyl (DPPH)/free radical scavenging activity and nitroblue tetrazolium (NBT)/superoxide anion scavenging activity were determined. 23388072 c(RGDfK) decorated micellar drug delivery system for intravesical instilled chemotherapy of superficial bladder cancer. The aim of this work was to develop a targeted drug delivery system with potentials for intravesical instilled chemotherapy of superficial bladder cancer. The amphiphilic diblock copolymer poly(ε-caprolactone)-b-poly(ethylene oxide) (PCL-b-PEO) was first conjugated with the cyclic (Arginine-Glycine-Aspartic acid-d-Phenylalanine-Lysine) (c(RGDfK)) and fluorescein isothiocyannate (FITC) via the functional terminal groups of hydrophilic block, and then assembled into micelles. The interaction between micelles and various model cells was well studied by means of confocal laser scanning microscopy and flow cytometry. The c(RGDfK) on the surface of the micelle was confirmed by (1)H NMR analysis and cell affinity with human glioblastoma-astrocytoma cells (U87MG). The cell viability of bladder cancer cells (T-24 cells) after incubation with doxorubicin (DOX) loaded polymeric micelles was evaluated by in vitro cytotoxicity assay. The results revealed that c(RGDfK) modified micelles showed strong affinity to T-24 cells and strong inhibitory effect on the proliferation of T-24 cells when doxorubicin drug was loaded, indicating the high affinity of c(RGDfK) to bladder cancer cells. The c(RGDfK) modified micelles assembled from PCL-b-PEO diblock copolymers developed in this study are of great potentials as nano-scaled drug delivery system for intravesical instilled chemotherapy of superficial bladder cancer. 23111877 Single-agent duloxetine ingestions. Duloxetine is a serotonin and norepinephrine reuptake inhibitor, which is mainly used to treat depression. This retrospective study describes the demographic and clinical effects of duloxetine ingestions reported to the National Poison Data System (NPDS). NPDS data were searched for duloxetine exposures between 2004 and 2010. A total of 11,373 patients were included and exposures were divided into three groups of ages ≤6 years old, 7-12 years and >12 years. Neurological clinical effects occurred in 6.1% of the patients aged ≤6 years, 13.0% of the patients aged 7-12 years and 24.6% of the patients aged >12 years. Cardiovascular effects occurred in 1.4% of the patients aged ≤6 years old, 2.5% of the patients aged 7-12 years and 11.6% of the patients aged >12 years. Gastrointestinal effects occurred in 4.1% of the patients aged ≤6 years old, 16.6% of the patients aged 7-12 years and 13.8% of the patients aged >12 years. Tachycardia, nausea, vomiting, agitation/irritability, dizziness/vertigo and drowsiness were among the most common clinical effects in all three groups. Overall, 61.4% of the patients aged ≤6 years and 77.5% of the patients aged 7-12 years were managed in a non-health care facility, while 55.8% of the patients aged >12 years were referred to or already in a health care facility. We conclude that the majority of ingestions are benign in both pediatrics and adults. Most symptomatic patients have neurologic, gastrointestinal and cardiovascular effects. Most pediatric patients will be able to be managed in a non-health care facility. 23423711 Oxidative stress in the lung of mice exposed to cigarette smoke either early in life or in adulthood. Birth and early life stages are critical periods characterized by severe alterations of the redox balance and by "physiological" genomic changes in lung cells, which may be responsible for cancer and other diseases in adulthood. Oxidative stress is a major mechanism accounting for the carcinogenicity of cigarette smoke (CS), which becomes more potently carcinogenic in mice when exposure starts at birth and continues early in life. We compared herewith a variety of end-points related to oxidative stress, mitochondrial alterations, and cell turnover in the lung of Swiss H mice, either sham-exposed or CS-exposed for 4 weeks, starting either at birth or at 4 months of age. The results showed that the physiological levels of certain end-points are affected by age. In fact, the baseline proportion of hypodiploid cells and the mitochondrial potential and mass were higher in adults, whereas 8-hydroxy-2'-deoxyguanosine (8-oxo-dGuo) levels, the proportion of necrotic cells, and the extent of autophagy were higher early in life. Adult mice were more responsive to CS by increasing the proportion of necrotic cells and of cells in S/G2 phase, whereas young mice maintained a high extent of autophagy, exhibited a greater increase of lipid peroxidation products and 8-oxo-dGuo levels, and had a higher frequency of micronucleated cells. In addition, exposure to CS affected the mitochondrial potential/mass, especially in young mice. In conclusion, these data provide evidence that oxidative stress and the resulting DNA damage provide a major contribution to the high susceptibility of mice to CS early in life. 23561204 Inhibitory effects of water extract of Flos Inulae on mutation and tyrosinase. In this study, the effects of a water extract of Flos Inulae (WFI) on antioxidant, antimutation and antityrosinase were investigated. The results showed that WFI inhibited the mutagenicity of 2-aminoanthracene (2-AA), an indirect mutagen; and 4-nitroquinoline-N-oxide (4-NQO), a direct mutagen toward Salmonella typhimurium TA 98 and TA 100. In addition, WFI, in the range of 0.2-0.6mg/ml, showed radical scavenging, reducing activities and chelating activity as well as decreased lipid oxidative damage. Meanwhile, WFI also inhibited tyrosinase activity and NO generation in lipopolysaccharide (LPS) stimulated macrophages. High performance liquid chromatography analysis suggests that the major phenolic constituents in WFI are chlorogenic acid, rutin, quercetin, luteolin and kaempferol. These bioactive components may contribute to the protective effects of WFI. The obtained data suggests that Flos Inulae can be applied to antimutation, antityrosinase and anti-inflammation. 23363038 Adverse effects of wood smoke PM(2.5) exposure on macrophage functions. Epidemiological studies have shown a correlation between chronic biomass smoke exposure and increased respiratory infection. Pulmonary macrophages are instrumental in both the innate and the adaptive immune responses to respiratory infection. In the present study, in vitro systems were utilized where alveolar macrophages (AM) and bone marrow-derived macrophages (BMdM) were exposed to concentrated wood smoke-derived particulate matter (WS-PM) and mice were exposed in vivo to either concentrated WS-PM or inhaled WS. In vivo studies demonstrated that WS-exposed mice inoculated with Streptococcus pneumoniae had a higher bacterial load 24 h post-exposure, and corresponding AM were found to have decreased lymphocyte activation activity. Additionally, while classic markers of inflammation (cellular infiltration, total protein, neutrophils) were not affected, there were changes in pulmonary macrophages populations, including significant decreases in macrophages expressing markers of activation in WS-exposed mice. The lymphocyte activation activity of WS-PM-exposed AM was significantly suppressed, but the phagocytic activity appeared unchanged. In an effort to determine a pathway for WS-induced suppression, RelB activation, assessed by nuclear translocation, was observed in AM exposed to either inhaled WS or instilled WS-PM. Finally, an analysis of WS-PM fractions determined the presence of 4-5 polycyclic aromatic hydrocarbons (PAHs), and preliminary work suggests a potential role for these PAHs to alter macrophage functions. These studies show a decreased ability of WS-exposed pulmonary macrophages to effectively mount a defense against infection, the effect lasts at least a week post-exposure, and appears to be mediated via RelB activation. 23291030 Risk factors for atherosclerosis in patients with chronic kidney disease:recognition and management. Heart disease is the most common cause of death in patients with chronic kidney disease (CKD), particularly in those receiving dialysis. Atherosclerosic cardiovascular (CV) disease (CVD) accounts for a large number of these deaths. Atherosclerosis is accelerated in patients with CKD due predominantly to the high prevalence of traditional CVD risk factors in the CKD population. CKD aggravates pre-existent traditional risk factors such as hypertension and dyslipidemia due to secondary renal parenchymal hypertension and secondary dyslipidemia. In addition, a variety of non-traditional risk factors that occur commonly in CKD patients contribute to CV risk. Recent studies suggest that CKD itself may be an independent risk factor for CVD, particularly coronary heart disease (CHD). Many therapies aimed at CV risk factor modification that have been successful in reducing CV risk in the general population are less effective or ineffective in favorably modifying CV risk in CKD. 23440071 Lab-on-DVD: standard DVD drives as a novel laser scanning microscope for image based point of care diagnostics. We present a novel "Lab-on-DVD" system and demonstrate its capability for rapid and low-cost HIV diagnostics by counting CD4+ cells isolated from whole blood. We show that a commercial DVD drive can, with certain modifications, be turned into an improved DVD-based laser scanning microscope (DVD-LSM). The system consists of a multi-layered disposable polymer disc and a modified commercial DVD reader with rotational control for sample handling, temperature control for optimized bioassay, a photodiode array for detection, and software for signal processing and user interface - all the necessary components required for a truly integrated lab-on-a-chip system, with the capability to deliver high-resolution images down to 1 μm in size. Using discs modified with antibodies, we specifically captured CD4+ cells from whole blood, demonstrating single cell resolution imaging. The novel integrated DVD platform with sub-micron image resolution brings, for the first time, affordable cellular diagnostic testing to the point-of-care and should be readily applicable at resource-limited settings. 23528740 Complement activation by PEGylated liposomes containing prednisolone. Infusion of PEGylated liposomes can give rise to hypersensitivity reactions (HSRs) in a relatively large number of patients. Previously it has been shown that these reactions can be caused by activation of the complement (C) system by a negative charge on the anchor molecule of PEG at the liposomal surface. In this study it is tested whether the activation of the C system by PEG-liposomes could be significantly reduced to values comparable to nonreactive liposomal formulations, by changing the PEGylation-profile on the liposomal surface. Therefore, the formation of C activation markers SC5b-9, C3a, C4d and Bb in normal human serum by both prednisolone loaded and empty liposomes with a variation of PEG chain length, PEG surface concentration, PEG anchor molecule and liposomal size was determined using in vitro assays. The tested liposomes caused no or only mild (30%) activation of C except for one formulation wherein the PEG2000 was anchored to cholesterol (CHOL-PEG2000). The latter liposomes caused paralleling rises in SC5b-9 and Bb levels, suggesting excess activation of the alternative pathway. While the relative safety of weak C activator liposomes remains to be confirmed in vivo, the unique, non-charge and non-antibody-mediated direct conversion of C3 by CHOL-PEG2000 liposomes (although argues against the clinical development of these vesicles) opens new opportunities to understand liposomal C activation at the molecular level. 23448580 Enzyme responsive hyaluronic Acid nanocapsules containing polyhexanide and their exposure to bacteria to prevent infection. Antibacterial nanodevices could bring coatings of plastic materials and wound dressings a big step forward if the release of the antibacterial agents could be triggered by the presence of the bacteria themselves. Here, we show that novel hyaluronic acid (HA)-based nanocapsules containing the antimicrobial agent polyhexanide are specifically cleaved in the presence of hyaluronidase, a factor of pathogenicity and invasion for bacteria like Staphylococcus aureus and Escherichia coli. This resulted in an efficient killing of the pathogenic bacteria by the antimicrobial agent. The formation of different polymeric nanocapsules was achieved through a polyaddition reaction in inverse miniemulsion. After the synthesis, the nanocapsules were transferred to an aqueous medium and investigated in terms of size, size distribution, functionality, and morphology using dynamic light scattering, zeta potential measurements and scanning electron microscopy. The enzyme triggered release of a model dye and the antimicrobial polyhexanide was monitored using fluorescence and UV spectroscopy. The stability of the nanocapsules in several biological media was tested and the interaction of nanocapsules with human serum protein was studied using isothermal titration calorimetry. The antibacterial effectiveness is demonstrated by determination of the antibacterial activity and determination of the minimal bactericidal concentration (MBC). 23537746 The effect of a Cimicifuga racemosa extracts Ze 450 in the treatment of climacteric complaints - an observational study. BACKGROUND: Root extracts of Cimicifuga racemosa (L.) Nutt. have been successfully used in the treatment of climacteric complaints. METHOD: In this observational study, Cimicifuga racemosa (CR) extract Ze 450 was studied in 442 unselected ambulatory female outpatients with menopausal complaints under daily practice conditions. Physicians were suggested to treat patients for the first 3 months with 13mg/d CR (high dose, HD) and to continue over additional 6 months either with this treatment or to switch to 6.5mg/d CR (low dose, LD). The choice of treatment and its dose, however, was fully at the discretion of the physician. RESULTS: After 3-months treatment with HD, symptom severity (Kupperman Menopause Index, KMI) decreased significantly (p<0.001) from baseline values. Continuation of treatment with HD or LD decreased total KMI and its sub-item scores further (HD, LD: p<0.001). However, more patients (84.9%) responded to HD than to LD (78.4%) and showed an improvement of symptoms (p=0.011). CONCLUSION: This observational study demonstrated that treatment with CR in unselected patients with climacteric complaints under the conditions of daily practice resulted in a significant improvement of menopausal symptoms assessed by the total KMI score and its sub-item scores with an effect size similar to that in a previous randomized, controlled clinical trial. 23429713 A simple, rapid, low-cost diagnostic test for sickle cell disease. This communication describes a very simple, rapid and inexpensive point-of-care diagnostic test for sickle cell disease (SCD) that can conclusively differentiate between blood samples from normal healthy individuals, sickle cell trait carriers and SCD patients using the characteristic blood stain patterns produced by each sample on paper. 23474904 Synthesis, antimicrobial, antiquorum-sensing, antitumor and cytotoxic activities of new series of fused [1,3,4]thiadiazoles. New series of [1,3,4]thiadiazolo[3,2-a]pyrimidines, benzo[h][1,3,4]thiadiazolo[2,3-b]quinazolines, benzothiadiazolotriazocine, and imidazo[2,1-b][1,3,4]thiadiazoles have been synthesized and characterized by analytical and spectrometrical methods (IR, MS, (1)H and (13)C NMR). Twenty of the synthesized compounds were screened for antibacterial activity against Escherichia coli, Staphylococcus aureus and Bacillus cereus. They were found to be either moderately active, slightly active or inactive against the tested microorganisms. The antifungal activity of these compounds were also tested against Candida albicans, Aspergillus fumigatus 293 and Aspergillus flavus 3375. Compounds 3g, h showed potent antifungal activity against C. albicans. In addition, the same compounds were tested for antiquorum-sensing activity against Chromobacterium violacium ATCC 12472, where compounds 3b,c, 3f-h, 6b-d, 9, 10 and 12 demonstrated acceptable activity. Compounds 3d, 9 and 10 were screened for antitumor activity at National Cancer Institute, USA. The in vitro cytotoxic activity of eighteen of the synthesized compounds was studied by brine shrimp lethality bioassay, and results indicated that compounds 6c, 13, 3h, 6d and 3d have the highest cytotoxic activity. 23060276 Mechanistic sediment quality guidelines based on contaminant bioavailability: equilibrium partitioning sediment benchmarks. Globally, estimated costs to manage (i.e., remediate and monitor) contaminated sediments are in the billions of U.S. dollars. Biologically based approaches for assessing the contaminated sediments which pose the greatest ecological risk range from toxicity testing to benthic community analysis. In addition, chemically based sediment quality guidelines (SQGs) provide a relatively inexpensive line of evidence for supporting these assessments. The present study summarizes a mechanistic SQG based on equilibrium partitioning (EqP), which uses the dissolved concentrations of contaminants in sediment interstitial waters as a surrogate for bioavailable contaminant concentrations. The EqP-based mechanistic SQGs are called equilibrium partitioning sediment benchmarks (ESBs). Sediment concentrations less than or equal to the ESB values are not expected to result in adverse effects and benthic organisms should be protected, while sediment concentrations above the ESB values may result in adverse effects to benthic organisms. In the present study, ESB values are reported for 34 polycyclic aromatic hydrocarbon, 32 other organic contaminants, and seven metals (cadmium, chromium, copper, nickel, lead, silver, zinc). Also included is an overview of EqP theory, ESB derivation, examples of applying ESB values, and considerations when using ESBs. The ESBs are intended as a complement to existing sediment-assessment tools, to assist in determining the extent of sediment contamination, to help identify chemicals causing toxicity, and to serve as targets for pollutant loading control measures. 23245695 Overexpression of Escherichia coli nucleotide excision repair genes after cisplatin-induced damage. Cisplatin is currently used in tumor chemotherapy to induce the death of malignant cells through blockage of DNA replication. It is a commonly used chemotherapeutic agent binding mono- or bifunctionally to guanines in DNA. Escherichia coli K12 mutant strains deficient in nucleotide excision repair (NER) were submitted to increasing concentrations of cisplatin, and the results revealed that uvrA and uvrB mutants are sensitive to this agent, while uvrC and cho mutants remain as the wild type strain. The time required for both gene expression turn-off and return to normal weight DNA in wild-type E. coli was not accomplished even after 4 h post-treatment with cisplatin, while the same process takes place within 1.5 h after ultraviolet radiation (UV). Besides, a heavily damaging action of cisplatin can be seen not only by persistent nicks on genomic DNA, but also by NER gene expression exceeding manifold that seen after equivalent lethal doses of UV. Moreover, cisplatin caused an increase in uvrB gene expression from its putative upstream promoter P3 in an SOS-independent manner. 23471970 Ras/cAMP-dependent Protein Kinase (PKA) Regulates Multiple Aspects of Cellular Events by Phosphorylating the Whi3 Cell Cycle Regulator in Budding Yeast. The Start/G1 phase in the cell cycle is an important period during which cells determine their developmental fate, onset of mitotic progression, or the switch to developmental stages in response to both external and internal signals. In the budding yeast Saccharomyces cerevisiae, Whi3, a negative regulator of the G1 cyclins, has been identified as a positive regulator of cell size control and is involved in the regulation of Start. However, the regulatory pathway of Whi3 governing the response to multiple signals remains largely unknown. Here, we show that Whi3 is phosphorylated by the Ras/cAMP-dependent protein kinase (PKA) and that phosphorylation of Ser-568 in Whi3 by PKA plays an inhibitory role in Whi3 function. Phosphorylation of Whi3 by PKA led to its decreased interaction with CLN3 G1 cyclin mRNA and was required for the promotion of G1/S progression. Furthermore, we demonstrate that the phosphomimetic S568D mutation of Whi3 prevented the developmental fate switch to sporulation or invasive growth. Thus, PKA modulated the function of Whi3 by phosphorylation, thus implicating PKA-mediated modulation of Whi3 in multiple cellular events. 22876784 Toxicokinetics of methyleugenol in F344 rats and B6C3F₁ mice. 1. Methyleugenol (MEG) has been used as a flavouring agent in food, as a fragrance in cosmetic products, and as an insect attractant. MEG was carcinogenic in both rats and mice following gavage administration. In this study we investigated plasma toxicokinetics of MEG in F344 rats and B6C3F₁ mice of both sexes following single gavage (37, 75, or 150 mg/kg) and intravenous (IV) (37 mg/kg) administration. 2. Following IV administration, MEG was rapidly distributed and cleared from the systemic circulation in both species and sexes. Absorption of MEG was rapid following gavage administration with secondary peaks in the plasma MEG concentration-versus-time profiles. C(max) and AUC(T) increased and the clearance decreased greater than proportional to the dose in rats and mice of both sexes. In general, rats had higher internal exposure to MEG than mice. 3. The results for AUC(T) and clearance suggest that perhaps the metabolism of MEG is saturated at higher doses tested in this study. Absolute bioavailability following gavage administration of 37 mg/kg was low in both rats (~4%) and mice (7-9%) of both sexes indicating extensive first-pass metabolism. There was no sex difference in plasma toxicokinetics of MEG following gavage administration both in rats and mice. 23612980 The in vivo TRPV6 protein starts at a non-AUG triplet decoded as methionine upstream the canonical initiation at AUG. TRPV6 channels function as epithelial Ca2+ entry pathways in the epididymis, prostate and placenta. However, like of most proteins the identity of the endogenous TRPV6 protein relies on predicted gene coding regions and is only known to a certain level of approximation. We show that in vivo the TRPV6 protein has an extended N-terminus. Translation initiates at a non-AUG codon, at ACG, which is decoded by methionine and which is upstream of the annotated AUG which is not used for initiation. The in vitro properties of channels formed by the extended full length TRPV6 proteins and the so far annotated and shorter TRPV6 are similar, but the extended N-terminus increases trafficking to the plasma membrane and represents an additional scaffold for channel assembly. The increased translation of the shorter TRPV6 cDNA version may overestimate the in vivo situation where translation efficiency may represent an additional mechanism to tightly control the TRPV6-mediated Ca2+ entry in order to prevent deleterious Ca2+ overload. 23435367 Transcriptional regulation of human ferredoxin 1 in ovarian granulosa cells. Ferredoxin 1 (FDX1; adrenodoxin) is an iron-sulfur protein that is involved in various metabolic processes, including steroid hormone synthesis in mammalian tissues. We investigated the transcriptional regulation of FDX1 in ovarian granulosa cells. Previously, we reported that the NR5A family, including steroidogenic factor-1 (SF-1) and liver receptor homolog-1 could induce differentiation of human mesenchymal stem cells (hMSCs) into steroidogenic cells. A ChIP assay showed that SF-1 could bind to the FDX1 promoter in differentiated hMSCs. Luciferase reporter assays showed that transcription of FDX1 was synergistically activated by the NR5A family and 8Br-cAMP treatment through two SF-1 binding sites and a CRE-like sequence in a human ovarian granulosa cell line, KGN. Knockdown of FDX1 attenuated progesterone production in KGN cells. These results indicate transcription of FDX1 is regulated by the NR5A family and cAMP signaling, and participates in steroid hormone production in ovarian granulosa cells. 23376097 Long-range interactions in the alpha subunit of tryptophan synthase help to coordinate ligand binding, catalysis, and substrate channeling. The α-subunit of tryptophan synthase (αTS) catalyzes the conversion of indole-3-glycerol phosphate to d-glyceraldehyde-3-phosphate and indole. We propose that allosteric networks intrinsic to αTS are modulated by the binding of the β-subunit to regulate αTS function. Understanding these long-range amino acid networks in αTS thus gives insight into the coordination of the two active sites within TS. In this study, we have used Ala residues as probes for structural and dynamic changes of αTS throughout its catalytic cycle, in the absence of the β-subunit. Projection analysis of the chemical shift changes by site-specific amino acid substitutions and ligand titrations indicates that αTS has three important conformational states: ligand-free, glyceraldehyde-3-phosphate-bound(like), and the active states. The amino acid networks within these conformations are different, as suggested by chemical shift correlation analysis. In particular, there are long-range connections, only in the active state, between Ala47, which reports on structural and dynamic changes associated with the general acid/base Glu49, and residues within the β2α2 loop, which contains the catalytically important Asp60 residue. These long-range interactions are likely important for coordinating chemical catalysis. In the free state, but not in the active state, there are connections between the β2α2 and β6α6 loops that likely help to coordinate substrate binding. Changes in the allosteric networks are also accompanied by protein dynamic changes. During catalytic turnover, the protein becomes more rigid on the millisecond timescale and the active-site dynamics are driven to a faster nanosecond timescale. 23495825 Self-assembly of elastin-mimetic double hydrophobic polypeptides. We have constructed a novel class of "double-hydrophobic" block polypeptides based on the hydrophobic domains found in native elastin, an extracellular matrix protein responsible for the elasticity and resilience of tissues. The block polypeptides comprise proline-rich poly(VPGXG) and glycine-rich poly(VGGVG), both of which dehydrate at higher temperature but form distinct secondary structures, β-turn and β-sheet respectively. In water at 45 °C, the block polypeptides initially assemble into nanoparticles rich in β-turn structures, which further connect into long (>10 μm), beaded nanofibers along with the increase in the β-sheet content. The nanofibers obtained are well-dispersed in water, and show thermoresponsive properties. Polypeptides comprising each block component assemble into different morphologies, showing that the conjugation of poly(VPGXG) and poly(VGGVG) plays a role for beaded fiber formation. These results may provide innovative ideas for designing peptide-based materials but also opportunities for developing novel materials useful for tissue engineering and drug delivery systems. 23394392 Methotrexate pharmacogenetics in rheumatoid arthritis: a status report. Methotrexate (MTX), an antifolate drug, is the first-line disease-modifying agent for the treatment of rheumatoid arthritis (RA) worldwide. MTX has excellent long-term efficacy, tolerability and safety. Early initiation of MTX in patients with RA controls joint destruction and slows progression of disease. However, the clinical response to MTX and frequency of adverse effects from the drug exhibit marked interpatient variability. Over the past decade, there has been a quest to identify genetic markers that reliably predict MTX efficacy and toxicity and help optimize MTX therapy in RA; that is, the field of MTX pharmacogenetics. This review will summarize key pharmacogenetic studies examining SNPs in the genes encoding enzymes in the MTX cellular pathway and their association with MTX response in RA. As evident from this review, MTX pharmacogenetics in RA remains a muddled field, mostly due to inconsistent results from several small underpowered studies. 22719017 Chronic treatment with selective I2-imidazoline receptor ligands decreases the content of pro-apoptotic markers in rat brain. Selective I(2)-imidazoline receptor ligands induce neuroprotection through various molecular mechanisms including blockade of N-methyl-D-aspartate (NMDA) receptors. To investigate new neuroprotective mechanisms associated with I(2)-imidazoline receptors, the effects of selective (2-styryl-2-imidazoline (LSL 61122), 2-(2-benzofuranyl)-2-imidazoline (2-BFI), 2-(4,5-dihydroimidazol-2-yl) quinoline hydrochloride (BU-224)) and non-selective (idazoxan) I(2)-drugs on canonical apoptotic pathways were assessed in rat brain cortex. The acute treatment with LSL 61122 (10 mg/kg) reduced the content of mitochondrial (pro-apoptotic) Bax (-33%) and cytochrome c (-31%), which was prevented by idazoxan, an I(2)-receptor antagonist. The sustained stimulation of I(2)-imidazoline receptors with selective drugs (10 mg/kg, every 12 h for seven days) was associated with down-regulation of key components of the extrinsic (Fas receptor: -20%; Fas associated protein with death domain (FADD) adaptor: -47-54%) and/or intrinsic (Bax: -20-23%; cytochrome c: -22-28%) apoptotic signalling and/or up-regulation of survival anti-apoptotic factors (p-Ser194 FADD/FADD ratio: +1.6-2.5-fold; and/or Bcl-2/Bax ratio: +1.5-fold), which in the long-term could dampen cell death in the brain. Similar chronic treatments with LSL 60101 (the imidazole analogue of 2-BFI) and idazoxan (a mixed I(2)/α(2)-ligand) did not induce significant alterations of pro- or anti-apoptotic proteins. The disclosed anti-apoptotic mechanisms of selective I(2)-imidazoline drugs may work in concert with other molecular mechanisms of neuroprotection (e.g. blockade of NMDA receptors) that are engaged by I(2)-ligands. 23591661 A new potential nano-oncological therapy based on polyamino acid nanocapsules. A critical objective in cancer therapy is to reduce the systemic toxicity through the modification of the biodistribution of anticancer drugs. Herein, we disclose a new biodegradable nanocarrier, polyglutamic acid (PGA) nanocapsules, and present the in vivo pharmacokinetics/toxicity proof-of-concept for the anticancer drug plitidepsin. These novel nanocapsules were prepared using a modified solvent displacement technique where the polyamino acid was electrostatically deposited onto the lipid core. The nanocapsules exhibited an average size of 200nm, a negative zeta potential and a great capacity for the encapsulation of plitidepsin (encapsulation efficiency above 90%). In addition, the nanocapsules could be freeze-dried and showed an adequate stability profile upon storage. Finally, the in vivo proof-of-concept studies performed in mice indicated that the encapsulation provided the drug with a prolonged blood circulation and a significantly reduced toxicity. In fact, the maximum tolerated dose of the nanoencapsulated drug was more than 3 times that of the reference formulation (Cremophor® EL plitidepsin solution). Overall, beyond the value of this specific formulation, the work reported here represents the evidence of the potential of polyamino acid nanocapsules in nano-oncological therapy. 22393914 Development and characterization of coated-microparticles based on whey protein/alginate using the Encapsulator device. The aim of this study is to prepare whey protein (WP)-based microparticles (MP) using the Encapsulator(®) device. The viscosity dependence of the extrusion device required to mix WP with a food-grade and less viscous polymer. Mixed WP/ALG MP were obtained with the optimized WP/alginate (ALG) ratio (62/38). These particles were further coated with WP or ALG using non-traumatic and solvent-free coating process developed in this study. Size and morphology of coated and uncoated MP were determined. Then, swelling and degradation (WP release) of formulations were investigated in pH 1.2 and 7.5 buffers and in simulated gastric and intestinal fluids (SGF, SIF) and compared to pure ALG and pure WP particle behaviours. At pH 1.2, pure ALG shrank and pure WP swelled, whereas the sizes of mixed WP/ALG matrix were stable. In SGF, WP/ALG MP resisted to pepsin degradation compare to pure WP particles due to ALG shrinkage which limited pepsin diffusion within particles. Coating addition with WP or ALG slowed down pepsin degradation. At pH 7.5, WP/ALG particles were rapidly degraded due to ALG sensitivity but the addition of a WP coating limited effectively the swelling and the degradation of MP. In SIF, pancreatin accelerated MP degradation but ALG-coated MP exhibited interesting robustness. These results confirmed the interest and the feasibility to produce coated WP-based MP which could be a potential orally controlled release drug delivery system. 22524504 Stabilization of fenofibrate in low molecular weight hydroxypropylcellulose matrices produced by hot-melt extrusion. The objective of this study was to improve the dissolution rate and to enhance the stability of a poorly water-soluble and low glass-trasition temperature (T(g)) model drug, fenofibrate, in low molecular weight grades of hydroxypropylcellulose matrices produced by hot-melt extrusion (HME). Percent drug loading had a significant effect on the extrudability of the formulations. Dissolution rate of fenofibrate from melt extruded pellets was faster than that of the pure drug (p < 0.05). Incorporation of sugars within the formulation further increased the fenofibrate release rates. Differential scanning calorimetry results revealed that the crystalline drug was converted into an amorphous form during the HME process. Fenofibrate is prone to recrystallization due to its low T(g). Various polymers were evaluated as stabilizing agents among which polyvinylpyrrolidone 17PF and amino methacrylate copolymer exhibited a significant inhibitory effect on fenofibrate recrystallization in the hot-melt extrudates. Subsequently immediate-release fenofibrate tablets were successfully developed and complete drug release was achieved within 5 min. The dissolution profile was comparable to that of a currently marketed formulation. The hot-melt extruded fenofibrate tablets were stable, and exhibited an unchanged drug release profile after 3-month storage at 40°C/75% RH. 23092225 Bimodal surface ligand engineering: the key to tunable nanocomposites. Tuning the dispersion of inorganic nanoparticles within organic matrices is critical to optimizing polymer nanocomposite properties and is intrinsically difficult due to their strong enthalpic incompatibility. Conventional attempts to use polymer brushes to control nanoparticle dispersion are challenged by the need for high graft density to reduce particle core-core attractions and the need for low graft density to reduce the entropic penalty for matrix penetration into the brush. We validated a parametric phase diagram previously reported by Pryamtisyn et al. (Pryamtisyn, V.; Ganesan, V.; Panagiotopoulos, A. Z.; Liu, H.; Kumar, S. K. Modeling the Anisotropic Self-Assembly of Spherical Polymer-Grafted Nanoparticles. J. Chem. Phys.2009, 131, 221102) for predicting dispersion of monomodal-polymer-brush-modified nanoparticles in polymer matrices. The theoretical calculation successfully predicted the experimental observation that the monomodal-poly(dimethyl siloxane) (PDMS)-brush-grafted TiO(2) nanoparticles can only be well dispersed within a small molecular weight silicone matrix. We further extended the parametric phase diagram to analyze the dispersion behavior of bimodal-PDMS-brush-grafted particles, which is also in good agreement with experimental results. Utilizing a bimodal grafted polymer brush design, with densely grafted short brushes to shield particle surfaces and sparsely grafted long brushes that favor the entanglement with matrix chains, we dispersed TiO(2) nanoparticles in high molecular weight commercial silicone matrices and successfully prepared thick (about 5 mm) transparent high-refractive-index TiO(2)/silicone nanocomposites. 23376217 Characterization of the mouse promoter region of the acyl-CoA synthetase 4 gene: role of Sp1 and CREB. Acyl-CoA synthetase 4 (Acsl4) is involved in several cellular functions including steroidogenesis, synaptic development and cancer metastasis. Although the expression of Acsl4 seems to be regulated by tissue- and cell-specific factors as well as pituitary hormones and growth factors, the transcriptional mechanisms involved remain unknown. We demonstrated hCG and cAMP regulation of Acsl4 mRNA in mouse steroidogenic MA-10 Leydig cells. We characterized the transcription initiation site and promoter of the Acsl4 mouse gene and identified three alternative splice variants present in MA-10 cells. Sequence analysis of a 1.5-kb fragment of the Acsl4 promoter revealed the absence of a TATA box and the presence of many putative binding sites for transcription factors including Sp1 and CREB. Functional characterization revealed that the specificity protein/Krüppel-like factor Sp1 binding site in the proximal promoter is involved in basal activity and that the cAMP response element-binding site is involved in cAMP stimulation of Acsl4 transcription. 23146691 Emodin-6-O-β-D-glucoside inhibits HMGB1-induced inflammatory responses in vitro and in vivo. High mobility group box 1 (HMGB1) protein acts as a potent proinflammatory cytokine and is involved in the pathogenesis of several vascular diseases, such as, systemic vasculitis and sepsis. Emodin-6-O-β-D-glucoside (EG) is a new active compound from Reynoutria japonica, and its biologic activities have not been previously investigated. In this study, we first investigated the antiinflammatory activities of EG on HMGB1-mediated proinflammatory responses in human umbilical vein endothelial cells (HUVECs) and in a murine cecal ligation and puncture (CLP)-model of sepsis in mice. EG was found to suppress the release of HMGB1, the production of tumor necrosis factor (TNF)-α, and the activation of nuclear factor-κB (NF-κB) by HMGB1 in HUVECs, and to inhibit HMGB1-mediated hyperpermeability and leukocyte migration in mice. In the CLP model, HMGB1 was highly released, but this release was prevented by EG. Furthermore, EG also increased the survival times of CLP administered mice. Collectively, this study shows EG can protect barrier integrity and inhibit HMGB1-mediated inflammatory responses, which suggests a potential use as a therapy for sepsis or septic shock. 23327533 Species-dependent metabolism of a novel selective α7 neuronal acetylcholine receptor agonist ABT-107. Abstract 1. Metabolism of ABT-107 was investigated in in vitro hepatic systems, in rat and monkey receiving [(14)C]ABT-107, and in vivo plasma in rat, dog, monkey and human. 2. In in vitro hepatic systems, ABT-107 was primarily cleared via oxidative metabolism, and proceeded via two parallel pathways. Pathway 1, ABT-107 was oxidized at the nitrogen of quinuclidine moiety to form M1. Pathway 2, oxidation occurred at indole-containing moiety to form M2. Metabolism via N-oxidation was predominant in dog and rat, while in monkey and human, metabolism proceeded primarily via oxidation of indole-containing moiety. 3. ABT-107 was extensively metabolized in vivo in rat and monkey. M1 was primarily found in rat urine and bile; whereas, M2 was the major metabolite in monkey urine and feces. M1 was the predominant circulating metabolite in dog and rat. M2 was the primary circulating metabolite in monkey and human. 4. Enzymatic studies suggested M1 formation was primarily mediated by renal FMO1. CYP3A4, 1A2, 2J2 and 2D6 were primary enzymes catalyzing M2 formation. 5. Biotransformation of ABT-107 in human and monkey is markedly different from that in dog and rat, suggesting that monkey is an appropriate model for predicting human biotransformation and toxicology of ABT-107. 23122076 Identification of active compounds in vegetal extracts based on correlation between activity and HPLC-MS data. We propose a method identifying candidates for active compounds in vegetal extracts. From a collection of samples, the method requires, for each sample, a HPLC-MS analysis and a measurement of the activity. By applying a correlation analysis between the activity and the chromatographic area for each interval of elution time and m/z ratio, the peaks corresponding to candidates for active compounds can be identified. Additionally, when peaks are identified, a model can be estimated to predict the activity in new samples. Both methods are evaluated in one experiment involving the phenolic extract (PE) from 22 samples of extra virgin olive oil (EVOO) where the activity is a cytotoxicity index against JIMT-1 breast cancer cells. In this experiment, the samples were separated into two disjunct partitions: one was used for training (identification of candidates and estimation of prediction model), while the other was used for validation (by comparing the predicted and the measured activities). Three compounds were identified as candidates to be responsible for the cytotoxicity of the EVOO-PE against JIMT-1 cells. The prediction model provided an accurate estimation of the activity. 22646532 Combining GLP-1 receptor agonists with insulin: therapeutic rationales and clinical findings. Due to the increasing prevalence of type 2 diabetes mellitus (T2DM), the emergent trend towards diagnosis in younger patients and the progressive nature of this disease, many more patients than before now require insulin to maintain glycaemic control. However, there is a degree of inertia among physicians and patients regarding the initiation and intensification of insulin therapy, in part due to concerns about the associated weight gain and increased risk of hypoglycaemia. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase insulin release and suppress glucagon secretion in a glucose-dependent manner, thus conferring glycaemic control with a low incidence of hypoglycaemia. GLP-1RAs also promote weight loss, and have beneficial effects on markers of β cell function, lipid levels, blood pressure and cardiovascular risk markers. However, the durability of their effectiveness is unknown and, compared with insulin, the antihyperglycaemic efficacy of GLP-1RAs is limited. The combination of a GLP-1RA and insulin might thus be highly effective for optimal glucose control, ameliorating the adverse effects typically associated with insulin. Data from clinical studies support the therapeutic potential of GLP-1RA-insulin combination therapy, typically showing beneficial effects on glycaemic control and body weight, with a low incidence of hypoglycaemia and, in established insulin therapy, facilitating reductions in insulin dose. In this review, the physiological and pharmacological rationale for using GLP-1RA and insulin therapies in combination is discussed, and data from clinical studies that have assessed the efficacy and safety of this treatment strategy are outlined. 23160530 Gliotransmission and brain glucose sensing: critical role of endozepines. Hypothalamic glucose sensing is involved in the control of feeding behavior and peripheral glucose homeostasis, and glial cells are suggested to play an important role in this process. Diazepam-binding inhibitor (DBI) and its processing product the octadecaneuropeptide (ODN), collectively named endozepines, are secreted by astroglia, and ODN is a potent anorexigenic factor. Therefore, we investigated the involvement of endozepines in brain glucose sensing. First, we showed that intracerebroventricular administration of glucose in rats increases DBI expression in hypothalamic glial-like tanycytes. We then demonstrated that glucose stimulates endozepine secretion from hypothalamic explants. Feeding experiments indicate that the anorexigenic effect of central administration of glucose was blunted by coinjection of an ODN antagonist. Conversely, the hyperphagic response elicited by central glucoprivation was suppressed by an ODN agonist. The anorexigenic effects of centrally injected glucose or ODN agonist were suppressed by blockade of the melanocortin-3/4 receptors, suggesting that glucose sensing involves endozepinergic control of the melanocortin pathway. Finally, we found that brain endozepines modulate blood glucose levels, suggesting their involvement in a feedback loop controlling whole-body glucose homeostasis. Collectively, these data indicate that endozepines are a critical relay in brain glucose sensing and potentially new targets in treatment of metabolic disorders. 23574519 Immunopathology of rheumatoid arthritis. Rheumatoid arthritis (RA) is one of the most common autoimmune diseases. Genetic and epidemiologic studies point to a relevant role of adaptive T-cell response interactions with environmental factors such as smoking in the immunopathogenesis of the disease. These interactions result in a specific systemic autoantibody response that seems to contribute to the synovial inflammatory process. The reasons for specific localization of the autoimmune proinflammatory process to synovial tissue remain poorly known, but relevant local effector mechanisms have been recently unveiled and successfully targeted by new specific therapies. A relevant role for cytokine networks, where TNF-α displays a pivotal role, has been confirmed. The local pathology is hallmarked by immune cell accumulation and expansion of resident stromal and vascular cells. Crosstalk between these elements generates an aggressive environment that leads to cartilage and bone destruction.RA provides represents a model for systemic T-cell mediated systemic autoimmunity leading to local cellular and autoantibody mediated chronic inflammation. Whereas targeting of these elements with specific antagonists may interfere with the disease process, reestablishing tolerance and preventing further synovial inflammation has not been achieved. 23475432 Effect of nicotine pretreatment on arsenic-induced oxidative stress in male Wistar rats. Humans are commonly exposed to nicotine, one of the most important lifestyle chemicals. The occurrence of high levels of arsenic in the groundwater of the southeast region of Asia has received much attention in the past decade and has become a global health concern. Predominant occurrence of both these chemicals and ease of their human exposure led us to investigate the effect of nicotine, a major tobacco alkaloid, on arsenic toxicity. Adult male rats were pre-exposed to two different doses of nicotine (0.75 and 3 mg/kg, intraperitoneally) for 7 days followed by 30 days of arsenic exposure (50 ppm sodium arsenite in drinking water). Nicotine pre-exposure resulted in an increased brain arsenic accumulation and a decreased liver arsenic concentration. Arsenic also caused a significant oxidative stress in the blood, brain and liver of the exposed rats. Glutathione-S-transferase, a phase II enzyme, was inhibited by both arsenic and nicotine but no such inhibition was noted in arsenic-treated animals pre-exposed to nicotine. Upon nicotine pre-exposure, brain acetylcholinesterase increased, while monoamine oxidase (MAO) decreased. The toxic effects of MAO significantly attenuated with nicotine pre-exposure. The present study suggests that nicotine may not be the major contributing factor for the previously reported synergistic toxic interaction between tobacco and arsenic. Nicotine pre-exposure in arsenic-exposed animals revealed interesting toxicokinetics and oxidative stress modulating interactions in the brain and liver of rats, which requires further exploration. 23628791 Down-regulation of LRRK2 in control and DAT transfected HEK cells increases manganese-induced oxidative stress and cell toxicity. The extra-pyramidal symptoms associated with manganism often overlap with that seen in Parkinsonism suggesting a common link between the two disorders. Since wide deviations are observed in susceptibility and characteristics of the symptoms observed in manganism, these differences may be due to underlying genetic variability. Genes linked to early onset of Parkinsonism which includes ATP13A2 and parkin have already been suggested to promote development of Mn toxicity. Of the other Parkinson-linked genes, mutations in LRRK2, an autosomal dominant gene, represent another likely candidate involved in the development of manganism. In this paper the effect of shRNA LRRK2 knock-down on Mn toxicity was examined in control and DAT transfected HEK293 cells. Results demonstrate that LRRK2 down-regulation potentiates Mn toxicity in both control and DAT-transfected cell as well as potentiates DA toxicity. Combined treatment of Mn and DA further augments cell toxicity, ROS production and JNK phosphorylation in LRRK2 deficient cells compared to controls. Consistent with studies demonstrating that LRRK2 plays a role in the phosphorylation of p38, our results similarly demonstrate a decrease in p38 activation in LRRK2 knock-down cells. Our findings suggest that null mutations in LRRK2 which cause Parkinsonism potentiate Mn toxicity and increase susceptibility to develop manganism. 23401474 Drug cocktail interaction study on the effect of the orally administered lavender oil preparation silexan on cytochrome p450 enzymes in healthy volunteers. This cocktail study evaluated the interaction potential of the oral lavender oil preparation silexan with major P450 (cytochrome P450) enzymes. Subjects and Methods: Sixteen healthy male or female Caucasians completed this double-blind, randomized, 2-fold crossover study. Silexan (160 mg) or placebo were administered once daily for 11 days. Additionally, on day 11 of both study periods, 150 mg caffeine (CYP1A2), 125 mg tolbutamide (CYP2C9), 20 mg omeprazole (CYP2C19), 30 mg dextromethorphan-HBr (CYP2D6), and 2 mg midazolam (CYP3A4) were administered orally. Formal interaction was excluded if the 90% confidence interval (CI) for the silexan over placebo ratios for phenotyping metrics (primary: AUC0-t) was within a 0.70-1.43 range. Results: According to the AUC0-t comparisons, silexan had no relevant effect on CYP1A2, 2C9, 2D6, and 3A4 activity. Secondary phenotyping metrics confirmed this result. Mean ratios for all omeprazole-derived metrics were close to unity. The 90% CI for the AUC0-t ratio of omeprazole but not for omeprazole/5-OH-omeprazole plasma ratio 3 hours post-dose or omeprazole/5-OH-omeprazole AUC0-t ratio (secondary CYP2C19 metrics) was above the predefined threshold of 1.43, probably caused by the inherent high variability of omeprazole pharmacokinetics. Silexan and the phenotyping drugs were well tolerated. Repeated silexan (160 mg/day) administration has no clinically relevant inhibitory or inducing effects on the CYP1A2, 2C9, 2C19, 2D6, and 3A4 enzymes in vivo. 23368280 Stereochemical control of polymorph transitions in nanoscale reactors. Crystallization of glycine in the cylindrical nanopores of anodic aluminum oxide (AAO) revealed the formation of metastable β-glycine in pores having diameters less than 200 nm. Two-dimensional X-ray microdiffraction indicated that the [010] axis of the embedded β-glycine nanocrystals coincided with the pore direction, identical to behavior observed previously in the cylindrical nanopores of polymer monoliths. Whereas the β-glycine nanocrystals were stable indefinitely in ambient air and persisted upon heating, they transformed to the α polymorph upon standing at room temperature and 90% relative humidity (RH). The α-glycine nanocrystals were oriented with the [010] axis nearly perpendicular to the pore direction, reflecting a nearly 90° rotation of the glycine molecules during the transition. When the β-glycine nanocrystals were formed in the AAO cylinders in the presence of small amounts of racemic hydrophobic amino acid auxiliaries, which are known to bind selectively to the (010) and (010) faces on the fast-growing end of β-glycine enantiomorphs, the β → α phase transition at 90% RH was suppressed. In contrast, β-glycine nanocrystals grown in the presence of an enantiopure amino acid auxiliary, which binds to the fast-growing end of only one of the enantiomorphs, thus suppressing its formation and leaving the other enantiomorph unperturbed, transformed into the α polymorph under the same conditions. This observation confirms that binding of an amino acid to the {010} faces is stereoselective and that access of water to these faces is essential for the transition to the α polymorph. 23411169 Electrochemical determination of Sudan I in food samples at graphene modified glassy carbon electrode based on the enhancement effect of sodium dodecyl sulphonate. This paper describes a novel electrochemical method for the determination of Sudan I in food samples based on the electrochemical catalytic activity of graphene modified glassy carbon electrode (GMGCE) and the enhancement effect of an anionic surfactant: sodium dodecyl sulphonate (SDS). Using pH 6.0 phosphate buffer solution (PBS) as supporting electrolyte and in the presence of 1.5 × 10(-4)mol L(-1) SDS, Sudan I yielded a well-defined and sensitive oxidation peak at a GMGCE. The oxidation peak current of Sudan I remarkably increased in the presence of SDS. The experimental parameters, such as supporting electrolyte, concentration of SDS, and accumulation time, were optimised for Sudan I determination. The oxidation peak current showed a linear relationship with the concentrations of Sudan I in the range of 7.50 × 10(-8)-7.50 × 10(-6)mol L(-1), with the detection limit of 4.0 × 10(-8)mol L(-1). This new voltammetric method was successfully used to determine Sudan I in food products such as ketchup and chili sauce with satisfactory results. 23406515 Cause and prevention of moisture-induced degradation of resistance random access memory nanodevices. Dielectric thin films in nanodevices may absorb moisture, leading to physical changes and property/performance degradation, such as altered data storage and readout in resistance random access memory. Here we demonstrate using a nanometallic memory that such degradation proceeds via nanoporosity, which facilitates water wetting in otherwise nonwetting dielectrics. Electric degradation only occurs when the device is in the charge-storage state, which provides a nanoscale dielectrophoretic force directing H2O to internal field centers (sites of trapped charge) to enable bond rupture and charged hydroxyl formation. While these processes are dramatically enhanced by an external DC or AC field and electron-donating electrodes, they can be completely prevented by eliminating nanoporosity, depositing a barrier layer, or using an oxidation-resistant electrode. These findings provide insight for understanding high-performance memory and field-assisted degradation of nanodevices. 23448247 Direct observation of a bent carbonyl ligand in a 19-electron transition metal complex. The photochemistry of [CpRu(CO)2]2 in P(OMe)3/CH2Cl2 solution has been studied using picosecond time-resolved infrared (TRIR) spectroscopy. Photolysis at 400 nm leads to the formation of 17-electron CpRu(CO)2(•) radicals, which react on the picosecond time scale to form 19-electron CpRu(CO)2P(OMe)3(•) adducts. The TRIR spectra of this adduct display an unusually low CO stretching frequency for the antisymmetric CO stretching mode, suggesting that one carbonyl ligand adopts a bent configuration to avoid a 19-electron count at the metal center. This spectral assignment is supported by analogous experiments on [CpFe(CO)2]2 in the same solvent, combined with DFT studies on the structures of the 19-electron adducts. The DFT results predict a bent CO ligand in CpRu(CO)2P(OMe)3(•), whereas approximately linear Fe-C-O bond angles are predicted for CpFe(CO)2P(OMe)3(•). The observation of a bent CO ligand in the 19-electron ruthenium adduct is a surprising result, and it provides new insight into the solution-phase behavior of 19-electron complexes. TRIR spectra were also collected for [CpRu(CO)2]2 in neat CH2Cl2, and it is interesting to note that no singly bridged [CpRu(CO)]2(μ-CO) photoproduct was observed to form following 400- or 267-nm excitation, despite previous observations of this species on longer time scales. 23167531 Absorption, metabolism and excretion of darexaban (YM150), a new direct factor Xa inhibitor in humans. 1. The absorption, metabolism and excretion of darexaban (YM150), a novel oral direct factor Xa inhibitor, were investigated after a single oral administration of [(14)C]darexaban maleate at a dose of 60 mg in healthy male human subjects. 2. [(14)C]Darexaban was rapidly absorbed, with both blood and plasma concentrations peaking at approximately 0.75 h post-dose. Plasma concentrations of darexaban glucuronide (M1), the pharmacological activity of which is equipotent to darexaban in vitro, also peaked at approximately 0.75 h. 3. Similar amounts of dosed radioactivity were excreted via faeces (51.9%) and urine (46.4%) by 168 h post-dose, suggesting that at least approximately half of the administered dose is absorbed from the gastrointestinal tract. 4. M1 was the major drug-related component in plasma and urine, accounting for up to 95.8% of radioactivity in plasma. The N-oxides of M1, a mixture of two diastereomers designated as M2 and M3, were also present in plasma and urine, accounting for up to 13.2% of radioactivity in plasma. In faeces, darexaban was the major drug-related component, and N-demethyl darexaban (M5) was detected as a minor metabolite. 5. These findings suggested that, following oral administration of darexaban in humans, M1 is quickly formed during first-pass metabolism via UDP-glucuronosyltransferases, exerting its pharmacological activity in blood before being excreted into urine and faeces. 23591959 Effects of Selenium Intervention on Chronic Fluorosis-Induced Renal Cell Apoptosis in Rats. This study aims to explore the effect of selenium in fluoride-induced renal cell apoptosis in rats and determine the optimal level of selenium in drinking water to prevent fluorosis. Experimental animals were divided into a control group, a sodium fluoride-treated group (NaF, 50 mg/L), three sodium selenite-treated groups (Na2SeO3, 0.375, 0.75, and 1.5 mg/L), and three selenium + NaF-treated groups (Na2SeO3, 0.375, 0.75, and 1.5 mg/L; NaF, 50 mg/L). Ultrastructural changes in the kidney tissues of each group were observed by transmission electron microscopy. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and the expressions of Bcl-2 and Bax proteins were detected by immunohistochemical methods. The expressions of Bcl-2 and Bax mRNA were detected by reverse transcription-polymerase chain reaction. The results showed that Bcl-2, Bax, and Bax/Bcl-2 protein expressions in the fluoride and high selenium groups were highly elevated compared with the control group (P < 0.01). Bax expression in the low selenium group and Bcl-2, Bax, and Bax/Bcl-2 protein expressions in the moderate selenium groups were observably elevated (P < 0.05). Bax and Bax/Bcl-2 expressions in the fluoride group and Bax mRNA expression in the high selenium group were highly elevated (P < 0.01). Bax/Bcl-2 mRNA expression in the high selenium group was also highly elevated (P < 0.05). Compared with the fluoride group, the group treated with low selenium has Bax protein expression that was observably reduced (P < 0.05); the group treated with moderate selenium has Bcl-2 protein expression that was observably elevated (P < 0.05), Bax protein expression that was highly reduced (P < 0.01), and Bax/Bcl-2 protein expression that was observably reduced (P < 0.05); the group treated with high selenium has Bcl-2 protein expression that was highly elevated (P < 0.01), Bax protein expression that was highly elevated (P < 0.01), and Bax/Bcl-2 protein expression that was highly reduced (P < 0.01); the groups treated with moderate selenium and high selenium have Bax mRNA expression that was highly reduced (P < 0.01), and the groups treated with high selenium have Bax/Bcl-2 mRNA expression that was observably reduced (P < 0.05). Selenium may inhibit the apoptosis of renal cells in fluorosis rats by regulating the expressions of Bcl-2 and Bax. The optimal dose of Na2SeO3 to protect against fluoride-induced renal cell apoptosis was determined to be 1.5 mg/L. 23495771 Design of UCST Polymers for Chilling Capture of Proteins. Ureido-derivatized polymers, such as poly(allylurea) (PU) and poly(L-citrulline) derivatives, exhibited upper critical solution temperature (UCST) behavior under physiological buffer conditions as we previously reported. The PU derivatives having amino groups (PU-Am) also showed UCST behavior. In this study, we modified the amino groups of the polymer with succinyl anhydride (PU-Su) or acetyl anhydride (PU-Ac) to determine the effects of these ionic groups on the UCST behavior and to control interactions between the PU derivatives and biocomponents such as proteins and cells. Succinylation of PU-Am resulted in a significant decrease in phase separation temperature (Tp), whereas acetylation of PU-Am resulted in an increase in Tp. As expected, the Tp of PU-Am and PU-Su changed when the pH of the solution was changed. The Tp of PU-Am increased at higher pH, whereas that of PU-Su increased at lower pH, indicating that ionic charge decreases Tp of PU derivatives by increasing osmotic pressure and by increasing hydrophilicity of the polymer chains. Interestingly, these groups did not significantly change UCST when these groups were nonionic. We then examined capture and separation of particular proteins from a protein mixture by cooling-induced phase separation. Selective and rapid capture of particular proteins from protein mixture by PU derivatives was shown, indicating that the ureido-derivatized polymers are potential media for bioseparation under biofriendly conditions. 23470166 Biocompatible, functional spheres based on oxidative coupling assembly of green tea polyphenols. Green luminescent, monodisperse, smooth, porous and hollow spheres were simply prepared by Cu(2+) and temperature mediated oxidative coupling assembly of green tea polyphenols in water. These polymeric tea polyphenol spheres are GSH responsive, acid resistant but alkali-responsive, ideally used as platform for controlled delivery of functional guests. 23205514 Effects of single or repeated silymarin administration on pharmacokinetics of risperidone and its major metabolite, 9-hydroxyrisperidone in rats. 1. The interactions between herbal dietary supplements and therapeutic drugs have emerged as an important issue and P-glycoprotein (P-gp) has been reported as one of the significant factors of these interactions. 2. The objective of this article is to examine the effects of single and repeated administrations of silymarin on pharmacokinetics of a P-gp substrate, risperidone, and its major metabolite, 9-hydroxyrisperidone, in rats. 3. To determine the plasma levels of risperidone and 9-hydroxyrisperidone in rats, a HPLC method was developed using a liquid-liquid acid back extraction. When risperidone (6 mg/kg) was co-administered with silymarin (40 mg/kg) to rats orally, the C(max) of 9-hydroxyrisperidone was significantly increased to1.3-fold (p < 0.05), while the other pharmacokinetic parameters did not show any significant differences. Expanding the experiment where rats were repeatedly administered with silymarin for 5 days prior to giving risperidone, the C(max) of risperidone and 9-hydroxyrisperidone were significantly increased to 2.4-fold (p < 0.001) and 1.7-fold (p < 0.001), respectively, and the AUC(0-t), as well to 1.7-fold (p < 0.05) and 2.1-fold (p < 0.01), respectively. 4. The repeated exposures of silymarin, compared to single administration of silymarin, increased oral bioavailability and affected the pharmacokinetics of risperidone and 9-hydroxyrisperidone, by inhibiting P-gp. 23462308 Preclinical Assessment of Ketamine. BACKGROUND: Ketamine is used as a general anesthetic, and recent data suggest that anesthetics can cause neurodegeneration and/or neuroprotection. The precise mechanisms are not completely understood. AIMS: This review is to examine the work on ketamine and to address how developmental biology may be utilized when combined with biochemical, pathological, and pharmacokinetic assessments to produce a bridging model that may decrease the uncertainty in extrapolating preclinical data to human conditions. RESULTS: Advantages of using preclinical models to study critical issues related to ketamine anesthesia have been described. These include the relationships between ketamine-induced neurotoxicity/protection and the preclinical models/approaches in elucidating mechanisms associated with ketamine exposure. CONCLUSIONS: The discussions focus on the following: (1) the doses and time-course over which ketamine is associated with damage to, or protection of, neural cells, (2) how ketamine directs or signals neural cells to undergo apoptosis or necrosis, (3) how such exposures can trigger mitochondrial dysfunction, (4) how antioxidants and knockdowns of specific transcription modulators or receptors affect neurotoxicity induced by ketamine, and (5) whether the potential neural damage can be monitored after ketamine exposure in living animals using positron emission tomography. 23122142 Application of a qualitative and quantitative real-time polymerase chain reaction method for detecting genetically modified papaya line 55-1 in papaya products. Genetically modified (GM) papaya (Carica papaya L.) line 55-1 (55-1), which is resistant to papaya ringspot virus infection, has been marketed internationally. Many countries have mandatory labeling regulations for GM foods, and there is a need for specific methods for detecting 55-1. Here, an event- and construct-specific real-time polymerase chain reaction (PCR) method was developed for detecting 55-1 in papaya products. Quantitative detection was possible for fresh papaya fruit up to dilutions of 0.001% and 0.01% (weight per weight [w/w]) for homozygous SunUp and heterozygous Rainbow cultivars, respectively, in non-GM papaya. The limit of detection and quantification was as low as 250 copies of the haploid genome according to a standard reference plasmid. The method was applicable to qualitative detection of 55-1 in eight types of processed products (canned papaya, pickled papaya, dried fruit, papaya-leaf tea, jam, puree, juice, and frozen dessert) containing papaya as a main ingredient. 23368902 Self-assembly of symmetric brush diblock copolymers. Self-assembled structures of brush block copolymers (BrBCPs) with polylactide (PLA) and polystyrene (PS) side chains were studied. The polynorbornene-backbone-based BrBCPs containing approximately equal volume fractions of each block self-assembled into highly ordered lamellae with domain spacing ranging from 20 to 240 nm by varying molecular weight of the backbone in the bulk state, as revealed by small-angle X-ray scattering (SAXS). The domain size increased approximately linearly with backbone length, which indicated an extended conformation of the backbone in the ordered state. In situ SAXS measurements suggested that the BrBCPs self-assemble with an extremely fast manner which could be attributed to a reduced number of entanglements between chains. The strong segregation theory and Monte Carlo simulation also confirmed this near-linear dependence of the domain spacing on backbone length, rationalizing experimental results. 22887780 Vitamin D binding protein is a key determinant of 25-hydroxyvitamin D levels in infants and toddlers. Circulating 25-hydroxyvitamin D (25-OHD) levels vary among human populations. Only limited information regarding determinants of these measures is available for infants and children, particularly in minority groups at greatest risk for vitamin D deficiency. We identified demographic determinants of circulating 25-OHD in a large cohort of minority children, and now extend our studies to examine potential roles of vitamin D binding protein (DBP) as a determinant of 25-OHD levels. Serum DBP level and common single nucleotide polymorphisms (SNPs) at positions 432 and 436 in the GC gene, encoding DBP, were examined. We confirmed self-reported ancestry using ancestry informative markers (AIMs), and included quantitative AIMs scores in the analysis. The multivariate model incorporated previously identified demographic and nutritional determinants of 25-OHD in this cohort, as well as GC SNPs and circulating DBP. Genetic variants in GC differed by self-reported ancestry. The 1f allele (D432/T436) was enriched in African Americans, occurring in 71%. Homozygosity for the 1f allele (DDTT) occurred in 53% of African Americans but only 6% of Caucasians and 13% of Hispanics. Circulating DBP was significantly correlated with 25-OHD. GC SNPs were associated with both circulating DBP and 25-OHD. It appears that progressive substitution of lysine for threonine at the 436 position results in lower circulating 25-OHD. Multivariate analysis revealed that genetic variance in GC significantly contributes to circulating DBP as well as 25-OHD. Moreover, the effect of GC SNPs on 25-OHD are evident after adjusting for their effects on circulating DBP. Thus in young children genetic variance of the common GC T436K SNP affects circulating levels of the DBP protein, which in turn affects circulating 25-OHD. However, the GC genotype also affects circulating 25-OHD independently of its effect on circulating DBP. These findings provide data that may be important in the interpretation of vitamin D status in children of varying ancestral backgrounds. 23474753 Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers. Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.Oncogene advance online publication, 11 March 2013; doi:10.1038/onc.2013.48. 23230905 Equilibrium gold nanoclusters quenched with biodegradable polymers. Although sub-100 nm nanoclusters of metal nanoparticles are of interest in many fields including biomedical imaging, sensors, and catalysis, it has been challenging to control their morphologies and chemical properties. Herein, a new concept is presented to assemble equilibrium Au nanoclusters of controlled size by tuning the colloidal interactions with a polymeric stabilizer, PLA(1k)-b-PEG(10k)-b-PLA(1k). The nanoclusters form upon mixing a dispersion of ~5 nm Au nanospheres with a polymer solution followed by partial solvent evaporation. A weakly adsorbed polymer quenches the equilibrium nanocluster size and provides steric stabilization. Nanocluster size is tuned from ~20 to ~40 nm by experimentally varying the final Au nanoparticle concentration and the polymer/Au ratio, along with the charge on the initial Au nanoparticle surface. Upon biodegradation of the quencher, the nanoclusters reversibly and fully dissociate to individual ~5 nm primary particles. Equilibrium cluster size is predicted semiquantitatively with a free energy model that balances short-ranged depletion and van der Waals attractions with longer-ranged electrostatic repulsion, as a function of the Au and polymer concentrations. The close spacings of the Au nanoparticles in the clusters produce strong NIR extinction over a broad range of wavelengths from 650 to 900 nm, which is of practical interest in biomedical imaging. 23584743 Chronic Administration of Small Non-Erythropoietic Peptide Sequence of Erythropoietin Effectively Ameliorates the Progression of Post Myocardial Infarction Dilated Cardiomyopathy. The cardioprotective properties of erythropoietin (EPO) in pre-clinical studies are well documented, but erythropoietic and prothrombotic properties of EPO preclude its use in chronic heart failure (CHF). We tested the effect of long-term treatment with a small peptide sequence within the EPO molecule, Helix B surface peptide (HBSP), that possess tissue-protective, but not erythropoietic properties of EPO, on mortality and cardiac remodeling in post-myocardial infarction dilated cardiomyopaty in rats. Starting two weeks after permanent left coronary artery ligation, rats received i.p. injections of HBSP (60µg/kg) or saline 2 times/week for 10 months. Treatment did not elicit an immune response, and did not affect the hematocrit. Compared to untreated rats, HBSP treatment reduced mortality by 50% (p<0.05). Repeated echocardiography demonstrated remarkable attenuation of left ventricular dilatation (EDV: 41% vs. 86%; ESV: 44% vs. 135%; p<0.05), LV functional deterioration (EF: -4% vs. -63%; p<0.05) and MI expansion (3% vs. 38%; p<0.05). A hemodynamic assessment at study termination demonstrated normal preload independent stroke work (63±5 vs. 40±4; p<0.05) and arterio-ventricular coupling (1.2±0.2 vs. 2.7±0.7; p<0.05). Histological analysis revealed reduced apoptosis (p<0.05) and fibrosis (p<0.05), increased cardiomyocyte density (p<0.05), and increased number of cardiomyocytes in myocardium among HBSP-treated rats. The results indicate that HBSP effectively reduces mortality, ameliorates the MI expansion and CHF progression, and preserves systolic reserve in the rat post MI model. There is also a suggestion that HBSP promoted the increase of the myocytes number in the myocardial wall remote from the infarct. Thus HBSP peptide merits consideration for clinical testing. 23207409 Combining QSAR classification models for predictive modeling of human monoamine oxidase inhibitors. Due to their role in the metabolism of monoamine neurotransmitters, MAO-A and MAO-B present a significant pharmacological interest. For instance the inhibitors of human MAO-B are considered useful tools for the treatment of Parkinson Disease. Therefore, the rational design and synthesis of new MAOs inhibitors is considered of great importance for the development of new and more effective treatments of Parkinson Disease. In this work, Quantitative Structure Activity Relationships (QSAR) has been developed to predict the human MAO inhibitory activity and selectivity. The first step was the selection of a suitable dataset of heterocyclic compounds that include chromones, coumarins, chalcones, thiazolylhydrazones, etc. These compounds were previously synthesized in one of our laboratories, or elsewhere, and their activities measured by the same assays and for the same laboratory staff. Applying linear discriminant analysis to data derived from a variety of molecular representations and feature selection algorithms, reliable QSAR models were built which could be used to predict for test compounds the inhibitory activity and selectivity toward human MAO. This work also showed how several QSAR models can be combined to make better predictions. The final models exhibit significant statistics, interpretability, as well as displaying predictive power on an external validation set made up of chromone derivatives with unknown activity (that are being reported here for first time) synthesized by our group, and coumarins recently reported in the literature. 23274714 Trichothecene toxicity in eukaryotes: cellular and molecular mechanisms in plants and animals. Trichothecenes are sesquiterpenoid mycotoxins commonly found as contaminants in cereal grains and are a major health and food safety concern due to their toxicity to humans and farm animals. Trichothecenes are predominantly produced by the phytopathogenic Fusarium fungus, and in plants they act as a virulence factor aiding the spread of the fungus during disease development. Known for their inhibitory effect on eukaryotic protein synthesis, trichothecenes also induce oxidative stress, DNA damage and cell cycle arrest and affect cell membrane integrity and function in eukaryotic cells. In animals, trichothecenes can be either immunostimulatory or immunosuppressive and induce apoptosis via mitochondria-mediated or -independent pathway. In plants, trichothecenes induce programmed cell death via production of reactive oxygen species. Recent advances in molecular techniques have led to the elucidation of signal transduction pathways that manifest trichothecene toxicity in eukaryotes. In animals, trichothecenes induce mitogen-activated protein kinase (MAPK) signalling cascades via ribotoxic stress response and/or endoplasmic reticulum stress response. The upstream signalling events that lead to the activation trichothecene-induced ribotoxic stress response are discussed. In plants, trichothecenes exhibit elicitor-like activity leading to the inductions MAPKs and genes involved in oxidative stress, cell death and plant defence response. Trichothecenes might also modulate hormone-mediated defence signalling and abiotic stress signalling in plants. 23129806 Fat body dSir2 regulates muscle mitochondrial physiology and energy homeostasis nonautonomously and mimics the autonomous functions of dSir2 in muscles. Sir2 is an evolutionarily conserved NAD(+)-dependent deacetylase which has been shown to play a critical role in glucose and fat metabolism. In this study, we have perturbed Drosophila Sir2 (dSir2) expression, bidirectionally, in muscles and the fat body. We report that dSir2 plays a critical role in insulin signaling, glucose homeostasis, and mitochondrial functions. Importantly, we establish the nonautonomous functions of fat body dSir2 in regulating mitochondrial physiology and insulin signaling in muscles. We have identified a novel interplay between dSir2 and dFOXO at an organismal level, which involves Drosophila insulin-like peptide (dILP)-dependent insulin signaling. By genetic perturbations and metabolic rescue, we provide evidence to illustrate that fat body dSir2 mediates its effects on the muscles via free fatty acids (FFA) and dILPs (from the insulin-producing cells [IPCs]). In summary, we show that fat body dSir2 is a master regulator of organismal energy homeostasis and is required for maintaining the metabolic regulatory network across tissues. 23421879 A new type of protective surface layer for high-capacity Ni-based cathode materials: nanoscaled surface pillaring layer. A solid solution series of lithium nickel metal oxides, Li[Ni(1-x)M(x)]O2 (with M = Co, Mn, and Al) have been investigated intensively to enhance the inherent structural instability of LiNiO2. However, when a voltage range of Ni-based cathode materials was increased up to >4.5 V, phase transitions occurring above 4.3 V resulted in accelerated formation of the trigonal phase (P3m1) and NiO phases, leading to and pulverization of the cathode during cycling at 60 °C. In an attempt to overcome these problems, LiNi0.62Co0.14Mn0.24O2 cathode material with pillar layers in which Ni(2+) ions were resided in Li slabs near the surface having a thickness of ∼10 nm was prepared using a polyvinylpyrrolidone (PVP) functionalized Mn precursor coating on Ni0.7Co0.15Mn0.15(OH)2. We confirmed the formation of a pillar layer via various analysis methods (XPS, HRTEM, and STEM). This material showed excellent structural stability due to a pillar layer, corresponding to 85% capacity retention between 3.0 and 4.5 V at 60 °C after 100 cycles. In addition, the amount of heat generation was decreased by 40%, compared to LiNi0.70Co0.15Mn0.15O2. 23279867 Synthesis and biological activity against Trypanosoma cruzi of substituted 1,4-naphthoquinones. The discovery and development of essential drugs for Chagas disease is a major concern worldwide. New substituted 1,4-naphthoquinones were synthesized and tested against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease. These products exhibited substantial activity against T. cruzi, especially 2-((8E,11Z)-heptadeca-8,11-dienyl)-3-hydroxynaphthalene-1,4-dione (9) with IC(50) of 7.8 μM. 23099502 Toxicokinetic study and absolute oral bioavailability of deoxynivalenol, T-2 toxin and zearalenone in broiler chickens. Mycotoxins lead to economic losses in animal production. A way to counteract mycotoxicosis is the use of detoxifiers. The European Food Safety Authority stated that the efficacy of detoxifiers should be investigated based on toxicokinetic studies. Little information is available on the absolute oral bioavailability and the toxicokinetic parameters of deoxynivalenol, T-2 and zearalenone in broilers. Toxins were administered intravenously and orally in a two-way cross-over design. For deoxynivalenol a bolus of 0.75mg/kg BW was administered, for T-2 toxin 0.02mg/kg BW and for zearalenone 0.3mg/kg BW. Blood was collected at several time points. Plasma levels of the mycotoxins and their metabolite(s) were quantified using LC-MS/MS methods and toxicokinetic parameters were analyzed. Deoxynivalenol has a low absolute oral bioavailability (19.3%). For zearalenone and T-2 no plasma levels above the limit of quantification were observed after an oral bolus. Volumes of distribution were recorded, i.e. 4.99, 0.14 and 22.26L/kg for deoxynivalenol, T-2 toxin and zearalenone, respectively. Total body clearance was 0.12, 0.03 and 0.48L/minkg for deoxynivalenol, T-2 toxin and zearalenone, respectively. After IV administration, T-2 toxin had the shortest elimination half-life (3.9min), followed by deoxynivalenol (27.9min) and zearalenone (31.8min). 23631927 Spatial memory deficits in maternal iron deficiency paradigms are associated with altered glucocorticoid levels. "The goal of this study was to examine the effect of maternal iron deficiency on the developing hippocampus in order to define a developmental window for this effect, and to see whether iron deficiency causes changes in glucocorticoid levels. The study was carried out using pre-natal, post-natal, and pre+post-natal iron deficiency paradigm. Iron deficient pregnant dams and their pups displayed elevated corticosterone which, in turn, differentially affected glucocorticoid receptor (GR) expression in the CA1 and the dentate gyrus. Brain Derived Neurotrophic Factor (BDNF) was reduced in the hippocampi of pups following elevated corticosterone levels. Reduced neurogenesis at P7 was seen in pups born to iron deficient mothers, and these pups had reduced numbers of hippocampal pyramidal and granule cells as adults. Hippocampal subdivision volumes also were altered. The structural and molecular defects in the pups were correlated with radial arm maze performance; reference memory function was especially affected. Pups from dams that were iron deficient throughout pregnancy and lactation displayed the complete spectrum of defects, while pups from dams that were iron deficient only during pregnancy or during lactation displayed subsets of defects. These findings show that maternal iron deficiency is associated with altered levels of corticosterone and GR expression, and with spatial memory deficits in their pups." 23265528 Structure and antioxidant activity of β-lactoglobulin-glycoconjugates obtained by high-intensity-ultrasound-induced Maillard reaction in aqueous model systems under neutral conditions. Sonication is a new processing technology in the dairy industry. The aim of this study was to test glycation of β-lactoglobulin (BLG) in Maillard reaction (MR) induced by high-intensity ultrasound in aqueous solution under neutral conditions at 10-15 °C, which is not favourable for the MR. BLG was sonicated in the presence of glucose, galactose, lactose, fructose, ribose and arabinose. Formation of Maillard reaction products (MRPs) was monitored by mass spectrometry, spectrophotometry and fluorimetry. Ultrasound treatment resulted in formation of MRPs with all tested carbohydrates. Ribose induced the highest degree of modification resulting in 76% of BLG modified and an average of three anhydroribose units attached. Circular dichroism spectra analyses indicated only minor alterations in secondary and tertiary structures. MRP obtained by ultrasound exhibited 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activity and possessed increased iron-chelating activity and reducing power. High-intensity ultrasound efficiently promotes BLG-glycoconjugates formation by MR in aqueous solutions under non-denaturing conditions. 23643837 Metabolic Regulation of Brain Response to Food Cues. Identification of energy sources depends upon the ability to form associations between food cues and nutritional value. As such, cues previously paired with calories elicit neuronal activation in the nucleus accumbens (NAcc), which reflects the reinforcing value of food [1-4]. The identity of the physiological signals regulating this response remains elusive. Using fMRI, we examined brain response to noncaloric versions of flavors that had been consumed in previous days with either 0 or 112.5 calories from undetected maltodextrin. We report a small but perceptually meaningful increase in liking for the flavor that had been paired with calories and find that change in liking was associated with changes in insular responses to this beverage. In contrast, NAcc and hypothalamic response to the calorie-paired flavor was unrelated to liking but was strongly associated with the changes in plasma glucose levels produced by ingestion of the beverage when consumed previously with calories. Importantly, because each participant ingested the same caloric dose, the change in plasma glucose depended upon individual differences in glucose metabolism. We conclude that glucose metabolism is a critical signal regulating NAcc and hypothalamic response to food cues, and that this process operates independently from the ability of calories to condition liking. 23337041 Polyphosphates inhibit extracellular matrix mineralization in MC3T3-E1 osteoblast cultures. Studies on various compounds of inorganic phosphate, as well as on organic phosphate added by post-translational phosphorylation of proteins, all demonstrate a central role for phosphate in biomineralization processes. Inorganic polyphosphates are chains of orthophosphates linked by phosphoanhydride bonds that can be up to hundreds of orthophosphates in length. The role of polyphosphates in mammalian systems, where they are ubiquitous in cells, tissues and bodily fluids, and are at particularly high levels in osteoblasts, is not well understood. In cell-free systems, polyphosphates inhibit hydroxyapatite nucleation, crystal formation and growth, and solubility. In animal studies, polyphosphate injections inhibit induced ectopic calcification. While recent work has proposed an integrated view of polyphosphate function in bone, little experimental data for bone are available. Here we demonstrate in osteoblast cultures producing an abundant collagenous matrix that normally show robust mineralization, that two polyphosphates (PolyP5 and PolyP65, polyphosphates of 5 and 65 phosphate residues in length) are potent mineralization inhibitors. Twelve-day MC3T3-E1 osteoblast cultures with added ascorbic acid (for collagen matrix assembly) and β-glycerophosphate (a source of phosphate for mineralization) were treated with either PolyP5 or PolyP65. Von Kossa staining and calcium quantification revealed that mineralization was inhibited in a dose-dependent manner by both polyphosphates, with complete mineralization inhibition at 10μM. Cell proliferation and collagen assembly were unaffected by polyphosphate treatment, indicating that polyphosphate inhibition of mineralization results not from cell and matrix effects but from direct inhibition of mineralization. This was confirmed by showing that PolyP5 and PolyP65 bound to synthetic hydroxyapatite in a concentration-dependent manner. Tissue-nonspecific alkaline phosphatase (TNAP, ALPL) efficiently hydrolyzed the two PolyPs as measured by Pi release. Importantly, at the concentrations of polyphosphates used in this study which inhibited bone cell culture mineralization, the polyphosphates competitively saturated TNAP, thus potentially interfering with its ability to hydrolyze mineralization-inhibiting pyrophosphate (PPi) and mineralizing-promoting β-glycerophosphate (in cell culture). In the biological setting, polyphosphates may regulate mineralization by shielding the essential inhibitory substrate pyrophosphate from TNAP degradation, and in the same process, delay the release of phosphate from this source. In conclusion, the inhibition of mineralization by polyphosphates is shown to occur via direct binding to apatitic mineral and by mixed inhibition of TNAP. 23357630 Inhibitory effect on NO production of triterpenes from the fruiting bodies of Ganoderma lucidum. Four new lanostane triterpenes, butyl lucidenate P (1), butyl lucidenate D(2) (2), butyl lucidenate E(2) (3) and butyl lucidenate Q (4) along with 11 known compounds (5-15) were isolated from the fruiting bodies of Ganoderma lucidum. Their chemical structures were established mainly by 1D and 2D NMR techniques and mass spectrometry. Their anti-inflammatory activity was evaluated against LPS-induced NO production in macrophage RAW 264.7 cells. Compounds 1, 3, 4, 9, 10 and 15 showed inhibitory potency with IC(50) values of 7.4, 6.4, 4.3, 9.4, 9.2 and 4.5 μM, respectively. Compounds 1, 3 and 15 dose-dependently reduced the LPS-induced iNOS expressions. Preincubation of cell with 1, 3 and 15 significantly suppressed LPS-induced expression of COX-2 protein. 23353821 Cystathionase mediates senescence evasion in melanocytes and melanoma cells. The development of malignant melanoma is a highly complex process, which is still poorly understood. A majority of human melanomas are found to express a few oncogenic proteins, such as mutant RAS and BRAF variants. However, these oncogenes are also found in nevi, and it is now a well-accepted fact that their expression alone leads to senescence. This renders the understanding of senescence escape mechanisms an important point to understand tumor development. Here, we approached the question of senescence evasion by expressing the transcription factor v-myc myelocytomatosis viral oncogene homolog (c-MYC), which is known to act synergistically with many oncogenes, in melanocytes. We observed that MYC drives the evasion of reactive-oxygen stress-induced melanocyte senescence, caused by activated receptor tyrosine kinase signaling. Conversely, MIZ1, the growth suppressing interaction partner of MYC, is involved in mediating melanocyte senescence. Both, MYC overexpression and Miz1 knockdown led to a strong reduction of endogenous reactive-oxygen species (ROS), DNA damage and senescence. We identified the cystathionase (CTH) gene product as mediator of the ROS-related MYC and MIZ1 effects. Blocking CTH enzymatic activity in MYC-overexpressing and Miz1 knockdown cells increased intracellular stress and senescence. Importantly, pharmacological inhibition of CTH in human melanoma cells also reconstituted senescence in the majority of cell lines, and CTH knockdown reduced tumorigenic effects such as proliferation, H(2)O(2) resistance and soft agar growth. Thus, we identified CTH as new MYC target gene with an important function in senescence evasion.Oncogene advance online publication, 28 January 2013; doi:10.1038/onc.2012.641. 23289802 A new strategy for intracellular delivery of enzyme using mesoporous silica nanoparticles: superoxide dismutase. We developed mesoporous silica nanoparticle (MSN) as a multifunctional vehicle for enzyme delivery. Enhanced transmembrane delivery of a superoxide dismutase (SOD) enzyme embedded in MSN was demonstrated. Conjugation of the cell-penetrating peptide derived from the human immunodeficiency virus 1 (HIV) transactivator protein (TAT) to mesoporous silica nanoparticle is shown to be an effective way to enhance transmembrane delivery of nanoparticles for intracellular and molecular therapy. Cu,Zn-superoxide dismutase (SOD) is a key antioxidant enzyme that detoxifies intracellular reactive oxygen species, ROS, thereby protecting cells from oxidative damage. In this study, we fused a human Cu,Zn-SOD gene with TAT in a bacterial expression vector to produce a genetic in-frame His-tagged TAT-SOD fusion protein. The His-tagged TAT-SOD fusion protein was expressed in E. coli using IPTG induction and purified using FMSN-Ni-NTA. The purified TAT-SOD was conjugated to FITC-MSN forming FMSN-TAT-SOD. The effectiveness of FMSN-TAT-SOD as an agent against ROS was investigated, which included the level of ROS and apoptosis after free radicals induction and functional recovery after ROS damage. Confocal microscopy on live unfixed cells and flow cytometry analysis showed characteristic nonendosomal distribution of FMSN-TAT-SOD. Results suggested that FMSN-TAT-SOD may provide a strategy for the therapeutic delivery of antioxidant enzymes that protect cells from ROS damage. 22765351 Perturbing peptide cation-radical electronic states by thioxoamide groups: formation, dissociations, and energetics of thioxopeptide cation-radicals. Thioxodipeptides Gly-thio-Lys (GtK), Ala-thio-Lys (AtK), and Ala-thio-Arg (AtR) in which the amide group has been modified to a thioxoamide were made into dications by electrospray ionization and converted to cation-radicals, (GtK + 2H)(+•), (AtK + 2H)(+•), and (AtR + 2H)(+•), by electron transfer dissociation (ETD) tandem mass spectrometry using fluoranthene anion-radical as an electron donor. The common and dominant dissociation of these cation-radicals was the loss of a hydrogen atom. The dissociation products were characterized by collision-induced dissociation (CID) multistage tandem mass spectrometry up to CID-MS(5). The ground electronic states of several (GtK + 2H)(+•), (AtK + 2H)(+•), and (AtR + 2H)(+•) conformers were explored by extensive ab initio and density functional theory calculations of the potential energy surface. In silico electron transfer to the precursor dications, (GtK + 2H)(2+), (AtK + 2H)(2+), and (AtR + 2H)(2+), formed zwitterionic intermediates containing thioenol anion-radical and ammonium cation groups that were local energy minima on the potential energy surface of the ground electronic state. The zwitterions underwent facile isomerization by N-terminal ammonium proton migration to the thioenol anion-radical group forming aminothioketyl intermediates. Combined potential energy mapping and RRKM calculations of dissociation rate constants identified N-C(α) bond cleavages as the most favorable dissociation pathways, in a stark contrast to the experimental results. This discrepancy is interpreted as being due to the population upon electron transfer of low-lying excited electronic states that promote loss of hydrogen atoms. For (GtK + 2H)(+•), these excited states were characterized by time-dependent density functional theory as A-C states that had large components of Rydberg-like 3s molecular orbitals at the N-terminal and lysine ammonium groups that are conducive to hydrogen atom loss. 23348005 Quercetin ameliorate insulin resistance and up-regulates cellular antioxidants during oleic acid induced hepatic steatosis in HepG2 cells. Hepatic lipid accumulation and oxidative stress contribute to non-alcoholic fatty liver disease (NAFLD). Thus, we hypothesized that the hypolipidemic and antioxidant activity of quercetin would attenuate events leading to NAFLD. Addition of 2.0mM oleic acid (OA) into the culture media induced fatty liver condition in HepG2 cells by 24h. It was marked by significant accumulation of lipid droplets as determined by Oil-Red-O (ORO) based colorimetric assay, increased triacylglycerol (TAG) and increased lipid peroxidation. The inflammatory cytokines TNF-α and IL-8 levels were significantly increased with decreased antioxidant molecules. OA induced insulin resistance which was evident by inhibition of glucose uptake and cell proliferation. Quercetin (10 μM) increased cell proliferation by 3.05 folds with decreased TAG content (45%) and was effective in increasing insulin mediated glucose uptake by 2.65 folds. The intracellular glutathione content was increased by 2.0 folds without substantial increase in GSSG content. Quercetin (10 μM) decreased TNF-α and IL-8 by 59.74% and 41.11% respectively and inhibited generation of lipid peroxides by 50.5%. In addition, RT-PCR results confirmed quercetin (10 μM) inhibited TNF-alpha gene expression. Further, superoxide dismutase, catalase and glutathione peroxidase activities were increased by 1.68, 2.19 and 1.71 folds respectively. Albumin and urea content was increased while the alanine aminotransferase (ALAT) activity was significantly decreased by quercetin. Hence, quercetin effectively reversed NAFLD symptoms by decreased triacyl glycerol accumulation, insulin resistance, inflammatory cytokine secretion and increased cellular antioxidants in OA induced hepatic steatosis in HepG2 cells. 23601392 The nutrient composition of three cuts obtained from P-class South African pork carcasses. The shoulder, loin and leg from P-class pork carcasses were used to determine the nutrient composition of both raw and cooked cuts. Significantly lower fat content were observed in the current study for the leg (5.21g/100g) and loin (6.99g/100g) compared to the shoulder cut (10.32g/100g). The overall percentage fat for all three cuts was less than 10% which is recommended by the South African Heart Mark. The cooked loin cut contained the most protein (27.50g/100g) of the three cooked cuts. When compared to other meat products (beef, mutton and chicken) it is clear that pork is a good source of B vitamins, especially vitamin B3. The cooked loin cut contained the least vitamin B1 (0.22mg/100g), B2 (0.02mg/100g) but the most vitamin B3 (7.09mg/100g), of the three cooked cuts. The 100g cooked shoulder, loin and leg cuts provide on average 40.11% protein, 5.19% magnesium, 3.37% calcium, 24.29% phosphorus, 18.22% zinc, 22.33% iron and 22.50% vitamin B1, 2.57% vitamin B2 and 42.6% vitamin B3 of Recommended Daily Allowances for males, age 25-50. Energy from a 100g portion provides 5.81% of the Recommended Daily Allowances. To conclude, the pork cuts are undoubtedly a good source of nutrients that is required for good health because it is high in protein, have a low fat content and are a nutrient-packed choice for the family and compares favourably with the fat, energy, and cholesterol content of many other meats and poultry. 23471871 Energies and Spin States of FeS(0/-) , FeS2 (0/-) , Fe2 S2 (0/-) , Fe3 S4 (0/-) , and Fe4 S4 (0/-) Clusters. The structures and energies of the electronic ground states of the FeS(0/-) , FeS2 (0/-) , Fe2 S2 (0/-) , Fe3 S4 (0/-) , and Fe4 S4 (0/-) neutral and anionic clusters have been computed systematically with nine computational methods in combination with seven basis sets. The computed adiabatic electronic affinities (AEA) have been compared with available experimental data. Most reasonable agreements between theory and experiment have been found for both hybrid B3LYP and B3PW91 functionals in conjugation with 6-311+G* and QZVP basis sets. Detailed comparisons between the available experimental and computed AEA data at the B3LYP/6-311+G* level identified the electronic ground state of (5) Δ for FeS, (4) Δ for FeS(-) , (5) B2 for FeS2 , (6) A1 for FeS2 (-) , (1) A1 for Fe2 S2 , (8) A' for Fe2 S2 (-) , (5) A'' for Fe3 S4 , (6) A'' for Fe3 S4 (-) , (1) A1 for Fe4 S4 , and (1) A2 for Fe4 S4 (-) . In addition, Fe2 S2 , Fe3 S4 , Fe3 S4 (-) , Fe4 S4 , and Fe4 S4 (-) are antiferromagnetic at the B3LYP/6-311+G* level. The magnetic properties are discussed on the basis of natural bond orbital analysis. 23576269 The PIM Family of Serine/Threonine Kinases in Cancer. The proviral insertion site in Moloney murine leukemia virus, or PIM proteins, are a family of serine/threonine kinases composed of three different isoforms (PIM1, PIM2, and PIM3) that are highly evolutionarily conserved. These proteins are regulated primarily by transcription and stability through pathways that are controlled by Janus kinase/Signal transducer and activator of transcription, JAK/STAT, transcription factors. The PIM family proteins have been found to be overexpressed in hematological malignancies and solid tumors, and their roles in these tumors were confirmed in mouse tumor models. Furthermore, the PIM family proteins have been implicated in the regulation of apoptosis, metabolism, cell cycle, and homing and migration, which has led to the postulation of these proteins as interesting targets for anticancer drug discovery. In the present work, we review the importance of PIM kinases in tumor growth and as drug targets. 23335346 Studies of enantiomeric degradation of the triazole fungicide hexaconazole in tomato, cucumber, and field soil by chiral liquid chromatography-tandem mass spectrometry. Chiral pesticide enantiomers often show different bioactivity and toxicity; however, this property is usually ignored when evaluating their environmental and public health risks. Hexaconazole is a chiral fungicide used on a variety of crops for the control of many fungal diseases. This use provides opportunities for the pollution of food and soil. In this study, a sensitive and convenient chiral liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed and validated for measuring hexaconazole enantiomers in tomato, cucumber, and soil. Separation was by a reversed-phase Chiralcel OD-RH column, under isocratic conditions using a mixture of acetonitrile-2 mM ammonium acetate in water (60/40, v/v) as the mobile phase at a flow rate of 0.4 mL/min. Parameters including the matrix effect, linearity, precision, accuracy and stability were undertaken. Then the proposed method was successfully applied to investigate the possible enantioselective degradation of rac-hexaconazole in plants (tomato and cucumber) and soil under field conditions. The degradation of the two enantiomers of hexaconazole proved to be enantioselective and dependent on the media: The (+)-enantiomer showed a faster degradation in plants, while the (-)-enantiomer dissipated faster than the (+)-form in field soil, resulting in relative enrichment of the opposite enantiomer. The results of this work demonstrate that both the environmental media and environmental conditions influenced the direction and rate of enantioselective degradation of hexaconazole. 23355456 The discovery of phenylbenzamide derivatives as Grb7-based antitumor agents. Grb7 is a non-catalytic protein, the overexpression of which has been associated with the proliferative and migratory potentials of cancer cells. Virtual screening strategies involving a shape-based similarity search, molecular docking, and 2D-similarity searches complemented by experimental binding studies (Thermofluor and isothermal titration calorimetry) resulted in the identification of nine novel phenylbenzamide-based antagonists of the Grb7 SH2 domain. Moderate binding affinities were observed, ranging from K(d)=32.3 μM for lead phenylbenzamide NSC 104999 (1) to K(d)=1.1 μM for a structurally related compound, NSC 57148 (2). Deconvolution of the affinity data into its components revealed differences in lead binding, from being entropy based (lead 1) to enthalpically driven (NSC 100874 (3), NSC 55158 (4), and compound 2). Finally, the lead compound 1 was found to decrease the growth of MDA-MB-468 breast cancer cells, with an IC(50) value of 39.9 μM. It is expected that these structures will serve as novel leads in the development of Grb7-based anticancer therapeutics. 23122094 Effect of heat treatments on the essential oils of kumquat (Fortunella margarita Swingle). Kumquats (Fortunella margarita Swingle) cultivated in Taiwan are eaten raw or made into candied fruit or fruit tea. For the experiments described in this paper, essential oils were obtained from kumquat peels or whole fruit by cold pressing, steam distillation or heating in water at 90°C for 15 min followed by steam distillation. The volatile components contained in the essential oils were identified by direct injection (DI) or headspace-solid phase microextraction (HS-SPME) coupled with gas chromatography (GC). A total of 43 compounds were identified, of which 37 were verified by DI/GC and 31 by HS-SPME/GC. Hot water heating increased the yields of essential oils from both peels and whole fruit. The principal constituents of the oils were similar except for the minor compounds, including linalool, terpinen-4-ol and α-terpineol, the levels of which increased after steam distillation. The whole fruit also contained higher levels of terpene alcohols. 23273895 Nanodomain coupling at an excitatory cortical synapse. The coupling distance between presynaptic Ca(2+) influx and the sensor for vesicular transmitter release determines speed and reliability of synaptic transmission. Nanodomain coupling (<100 nm) favors fidelity and is employed by synapses specialized for escape reflexes and by inhibitory synapses involved in synchronizing fast network oscillations. Cortical glutamatergic synapses seem to forgo the benefits of tight coupling, yet quantitative detail is lacking. The reduced transmission fidelity of loose coupling, however, raises the question whether it is indeed a general characteristic of cortical synapses. Here we analyzed excitatory parallel fiber to Purkinje cell synapses, major processing sites for sensory information and well suited for analysis because they typically harbor only a single active zone. We quantified the coupling distance by combining multiprobability fluctuation analyses, presynaptic Ca(2+) imaging, and reaction-diffusion simulations in wild-type and calretinin-deficient mice. We found a coupling distance of <30 nm at these synapses, much shorter than at any other glutamatergic cortical synapse investigated to date. Our results suggest that nanodomain coupling is a general characteristic of conventional cortical synapses involved in high-frequency transmission, allowing for dense gray matter packing and cost-effective neurotransmission. 23423904 The influence of salinity on acute nickel toxicity to the two euryhaline fish species, Fundulus heteroclitus and Kryptolebias marmoratus. Nickel (Ni) is a common pollutant found in aquatic environments and may be harmful at elevated concentrations. Increasing salinity has been shown to decrease the bioavailability and toxicity of other metals to aquatic organisms. In the present study, acute Ni toxicity experiments (96-h) were conducted at various salinities (0-36 ppt) to determine the effects of salinity on Ni toxicity to 2 euryhaline fish species, Kryptolebias marmoratus and Fundulus heteroclitus. Nickel concentrations causing lethality to 50% of the fish ranged from 2 mg/L in moderately hard freshwater to 66.6 mg/L in 36 ppt saltwater. Nickel toxicity to F. heteroclitus decreased linearly with increasing salinity; however, Ni toxicity to K. marmoratus was only lowered by salinities above 6 ppt, demonstrating potential physiological differences between the 2 species when they are functioning as freshwater fish. Furthermore, the authors investigated the influence of Mg(2+) , Ca(2+) , Na(+) , and Cl(-) on Ni toxicity to F. heteroclitus. Freshwater with up to 120 mg/L Ca(2+) as CaSO4 , 250 mg/L Mg(2+) as MgSO4 , or 250 mg/L Na(+) as NaHCO3 did not provide protection against Ni toxicity. Alternatively, 250 mg/L Na(+) , as NaCl, was protective against Ni toxicity; and the extent of protection was similar to that demonstrated from salt water with the same Cl(-) concentration. These results suggest that Cl(-) is the predominant ion responsible for reducing Ni toxicity to K. marmoratus and F. heteroclitus in higher salinity waters. Environ Toxicol Chem 2013;32:1354-1359. © 2013 SETAC. 23549679 Cytokines as biomarkers of nanoparticle immunotoxicity. Nanoscale objects, whether of biologic origin or synthetically created, are being developed into devices for a variety of bionanotechnology diagnostic and pharmaceutical applications. However, the potential immunotoxicity of these nanomaterials and mechanisms by which they may induce adverse reactions have not received sufficient attention. Nanomaterials, depending on their characteristics and compositions, can interact with the immune system in several ways and either enhance or suppress immune system function. Cytokines perform pleiotropic functions to mediate and regulate the immune response and are generally recognized as biomarkers of immunotoxicity. While the specificity and validity of certain cytokines as markers of adverse immune response has been established for chemicals, small and macromolecular drugs, research on their applicability for predicting and monitoring the immunotoxicity of engineered nanomaterials is still ongoing. The goal of this review is to provide guidelines as to important cytokines that can be utilized for evaluating the immunotoxicity of nanomaterials and to highlight the role of those cytokines in mediating adverse reactions, which is of particular importance for the clinical development of nanopharmaceuticals and other nanotechnology-based products. Importantly, the rational design of nanomaterials of low immunotoxicity will be discussed, focusing on synthetic nanodevices, with emphasis on both the nanoparticle-forming materials and the embedded cargoes. 23192339 Transcriptional regulatory factor X6 (Rfx6) increases gastric inhibitory polypeptide (GIP) expression in enteroendocrine K-cells and is involved in GIP hypersecretion in high fat diet-induced obesity. Gastric inhibitory polypeptide (GIP) is an incretin released from enteroendocrine K-cells in response to nutrient ingestion. GIP potentiates glucose-stimulated insulin secretion and induces energy accumulation into adipose tissue, resulting in obesity. Plasma GIP levels are reported to be increased in the obese state. However, the molecular mechanisms of GIP secretion and high fat diet (HFD)-induced GIP hypersecretion remain unclear, primarily due to difficulties in separating K-cells from other intestinal epithelial cells in vivo. In this study, GIP-GFP knock-in mice that enable us to visualize K-cells by enhanced GFP were established. Microarray analysis of isolated K-cells from these mice revealed that transcriptional regulatory factor X6 (Rfx6) is expressed exclusively in K-cells. In vitro experiments using the mouse intestinal cell line STC-1 showed that knockdown of Rfx6 decreased mRNA expression, cellular content, and secretion of GIP. Rfx6 bound to the region in the gip promoter that regulates gip promoter activity, and overexpression of Rfx6 increased GIP mRNA expression. HFD induced obesity and GIP hypersecretion in GIP-GFP heterozygous mice in vivo. Immunohistochemical and flow cytometry analysis showed no significant difference in K-cell number between control fat diet-fed (CFD) and HFD-fed mice. However, GIP content in the upper small intestine and GIP mRNA expression in K-cells were significantly increased in HFD-fed mice compared with those in CFD-fed mice. Furthermore, expression levels of Rfx6 mRNA were increased in K-cells of HFD-fed mice. These results suggest that Rfx6 increases GIP expression and content in K-cells and is involved in GIP hypersecretion in HFD-induced obesity. 23210850 Multi-aspect candidates for repositioning: data fusion methods using heterogeneous information sources. Drug repositioning, an innovative therapeutic application of an old drug, has received much attention as a particularly costeffective strategy in drug R&D Recent work has indicated that repositioning can be promoted by utilizing a wide range of information sources, including medicinal chemical, target, mechanism, main and side-effect-related information, and also bibliometric and taxonomical fingerprints, signatures and knowledge bases. This article describes the adaptation of a conceptually novel, more efficient approach for the identification of new possible therapeutic applications of approved drugs and drug candidates, based on a kernel-based data fusion method. This strategy includes (1) the potentially multiple representation of information sources, (2) the automated weighting and statistically optimal combination of information sources, and (3) the automated weighting of parts of the query compounds. The performance was systematically evaluated by using Anatomical Therapeutic Chemical Classification System classes in a cross-validation framework. The results confirmed that kernel-based data fusion can integrate heterogeneous information sources significantly better than standard rank-based fusion can, and this method provides a unique solution for repositioning; it can also be utilized for de novo drug discovery. The advantages of kernel-based data fusion are illustrated with examples and open problems that are particularly relevant for pharmaceutical applications. 23288144 Sunitinib, a tyrosine kinase inhibitor, induces cytochrome P450 1A1 gene in human breast cancer MCF7 cells through ligand-independent aryl hydrocarbon receptor activation. Sunitinib (SUN) is a new multi-targeted oral tyrosine kinase inhibitor that has both anti-angiogenic and anti-tumor activities. However, information reported in the literature on the effects of SUN on the constitutive expression of cytochrome P450 1A1 (CYP1A1) gene in cells from mammalian species remains unclear. Therefore, the main objectives of the current work were to investigate the potentiality of SUN to induce CYP1A1 gene expression in human breast cancer MCF7 cells and to explore the molecular mechanisms involved. Our results showed that SUN induced the CYP1A1 mRNA, protein, and activity levels in a concentration-dependent manner in MCF7 cells. The increase in CYP1A1 mRNA by SUN was completely blocked by the transcriptional inhibitor, actinomycin D; implying that SUN increased de novo RNA synthesis. Furthermore, the ability of SUN to increase luciferase reporter gene expression suggests an aryl hydrocarbon receptor (AhR)-dependent transcriptional control and excludes the possibility of any posttranscriptional mechanisms. In addition, blocking of AhR activation by resveratrol, a well-known AhR antagonist, prevented the SUN-induced CYP1A1 gene expression, further confirms the involvement of AhR. Interestingly, this was associated with the inability of SUN to directly bind to and induce transformation of cytosolic AhR to its DNA-binding form in vitro, suggesting that the effect of SUN does not involve direct binding to AhR. The current manuscript provides the first evidence for the ability of SUN to induce CYP1A1 gene expression in MCF7 cells through AhR ligand-independent mechanisms. 23624183 Relationship between protein digestibility and allergenicity: Comparisons of pepsin and cathepsin. An association between protein allergenicity and resistance to pepsin digestion in the gastrointestinal tract has been proposed. However, although widely accepted, such an association is inconsistent with known labile allergens and resistant non-allergens. Given the central role of antigen presenting cells, and in particular dendritic cells (DCs), in the development of allergic responses, the stability of allergens to intracellular processing may be more relevant than resistance to extracellular pepsin digestion. We have characterised the expression by DC of cathepsins (proteolytic enzymes), and compared the proteolytic activity of the most highly expressed cathepsin with pepsin for a range of 9 allergens and 4 putative nonallergens. Cathepsin expression in bone marrow-derived DC (BM-DC) derived from BALB/c strain mice was characterised by flow cytometry; cathepsins D, E and S were identified, with cathepsin D being the most highly expressed. Digestion studies revealed that the majority of allergens (5/9) were pepsin resistant, whereas non-allergens (3/4) were labile. If the generation of pepsin-resistant fragments was considered as a feature of allergenicity, this increased to 7/9 allergens and 4/4 nonallergens. In contrast, most of the proteins examined were resistant to cathepsin digestion, with significant digestion recorded for only 2/9 allergens and 2/4 non-allergens. Chemical reduction (to mimic intracellular reducing conditions) increased the susceptibility of proteins to digestion by cathepsins, but did not improve discrimination between allergens and nonallergens on this basis. These data confirm that there is a general relationship between resistance to digestion with pepsin and allergenicity. The relationship is not absolute, but the information gained from this characteristic does provide useful information in a weight of evidence approach for allergenicity assessment. The most abundant cathepsin detected in antigen processing BM-DC, cathepsin D, is not an appropriate substitute for pepsin. The hypothesis that pepsin stability may be a surrogate for stability to digestion within DC may still hold true, but consideration of a single enzyme in this context is possibly an oversimplification. 22915370 Quantitative ultrasound of cortical bone in the femoral neck predicts femur strength: results of a pilot study. A significant risk of femoral neck (FN) fracture exists for men and women with an areal bone mineral density (aBMD) higher than the osteoporotic range, as measured with dual-energy X-ray absorptiometry (DXA). Separately measuring the cortical and trabecular FN compartments and combining the results would likely be a critical aspect of enhancing the diagnostic capabilities of a new technique. Because the cortical shell determines a large part of FN strength a novel quantitative ultrasound (QUS) technique that probes the FN cortical compartment was implemented. The sensitivity of the method to variations of FN cortical properties and FN strength was tested. Nine femurs (women, mean age 83 years) were subjected to QUS to measure the through transmission time-of-flight (TOF) at the FN and mechanical tests to assess strength. Quantitative computed tomography (QCT) scans were performed to enable analysis of the dependence of TOF on bone parameters. DXA was also performed for reference. An ultrasound wave propagating circumferentially in the cortical shell was measured in all specimens. Its TOF was not influenced by the properties of the trabecular compartment. Averaged TOF for nine FN measurement positions/orientations was significantly correlated to strength (R2  = 0.79) and FN cortical QCT variables: total BMD (R(2)  = 0.54); regional BMD in the inferoanterior (R2  = 0.90) and superoanterior (R2  = 0.57) quadrants; and moment of inertia (R2  = 0.71). The results of this study demonstrate that QUS can perform a targeted measurement of the FN cortical compartment. Because the method involves mechanical guided waves, the QUS variable is related to the geometric and material properties of the cortical shell (cortical thickness, tissue elasticity, and porosity). This work opens the way to a multimodal QUS assessment of the proximal femur, combining our approach targeting the cortical shell with the existing modality sensitive to the trabecular compartment. In vivo feasibility of our approach has to be confirmed with experimental data in patients. 23606438 Thermal and Electrical Transport in Ultralow Density Single-Walled Carbon Nanotube Networks. The thermal, electrical, and thermoelectric properties of aerogels of single-walled carbon nanotubes are characterized. Their ultralow density enables the transport properties of the junctions to be distinguished from those of the nanotubes themselves. Junction thermal and electrical conductances are found to be orders of magnitude larger than those found in typical dense SWCNT networks. In particular, the average junction thermal conductance is close to the theoretical maximum for a van der Waals bonded SWCNT junction. 23428833 Nephroprotective effect of calcium channel blockers against toxicity of lead exposure in mice. Exposure to lead (Pb) can induce kidney damage, which is related to induction of oxidative damage and disturbance of intracellular calcium homeostasis. Pb can readily permeate through dihydropyridine-sensitive L-type calcium channels and accumulate within cells. The objective of this study was to investigate protective effects of calcium channel blockers (CCBs) verapamil and nimodipine on nephrotoxicity induced by Pb acetate in mice. One hundred and twenty male mice were randomly divided into 6 groups: control, Pb, low-dose verapamil, high-dose verapamil, low-dose nimodipine and high-dose nimodipine (n=20 per group). Pb acetate was injected intraperitoneally (i.p.) at 40 mg/kg body weight/day for 10 days to establish the Pb toxicity model. While control mice received saline, mice of the treated groups simultaneously received i.p. injections of verapamil or nimodipine daily for 10 days. Both verapamil and nimodipine showed protection against Pb-induced kidney injury, including alleviation of renal pathological damage and decreasing the level of Pb in kidney homogenate and extent of apoptosis in nephrocytes. Moreover, verapamil and nimodipine significantly down-regulated levels of blood urea nitrogen and creatinine in the serum. In addition, verapamil and nimodipine administration decreased malondialdehyde content and increased activities of super oxide dismutase activity and glutathione peroxidase in the kidney homogenate. The findings in the present study implicate the therapeutic potential of CCBs for Pb-induced nephrotoxicity, which were at least partly due to the decrease of Pb uptake and inhibition of lipid peroxidation. 23298292 A design of experiments to optimize a new manufacturing process for high activity protein-containing submicron particles. A novel method for the manufacture of protein/peptide-containing submicron particles was developed in an attempt to provide particles with increased activity while using high energy input technologies. The method consists of antisolvent co-precipitation from an aqueous solution containing both an amino acid core material (e.g. D,L-valine), and either bovine serum albumin (BSA) or lysozyme (Lys) as model proteins. The aqueous solution was added to the organic phase by means of a nebulizer to increase the total surface area of interaction for the precipitation process. Sonication proved to be an effective method to produce small particle sizes while maintaining high activity of Lys. The use of a polysorbate or sorbitan ester derivatives as stabilizers proved to be necessary to yield submicron particles. Particles with very high yields (approximately 100%) and very high activity after manufacture (approximately 100%) could be obtained. A particle size of 439.0 nm, with a yield of 48.8% and with final remaining activity of98.7% was obtained. By studying various factors using a design of experiments strategy (DoE) we were able to establish the critical controlling factors for this new method of manufacture. 23601388 Application of ethnic food composition data for understanding the diet and nutrition of South Asians in the UK. Lack of food composition data, recipe information and portion sizes for ethnic foods are commonly reported problems for dietary assessment of ethnic minority groups. One of the main aims of this study was to use food composition data to validate portion sizes, identify important sources of nutrients and describe the characteristics of the South Asian diet. The top five ethnic foods containing highest levels of selected nutrients were lamb balti (3mg/100g iron), lamb kebab (3.2mg/100g zinc), mixed dhal (62μg/100g folate), fish curry (1.4μg/100g vitamin D), ghee (968μg/100g retinol) and toor dhal (9.1g/100g dietary fibre). Typical adult South Asian diets included traditional cereals (chapatti, rice and paratha) and low consumption of meat dishes; with vegetable curries contributing most towards energy intake. A higher consumption of full fat milk and fruit juices by toddlers and school children were observed when compared with the National Diet and Nutrition Survey of the UK. 23317570 Lead optimization of a pyridine-carboxamide series as DGAT-1 inhibitors. The structure-activity relationship studies of a novel series of carboxylic acid derivatives of pyridine-carboxamides as DGAT-1 inhibitors is described. The optimization of the initial lead compound 6 based on in vitro and in vivo activity led to the discovery of key compounds 10j and 17h. 23261643 Assessment of an automated in vitro basal cytotoxicity test system based on metabolically-competent cells. When in vitro test systems are evaluated for assessment of the toxicity of chemical compounds, particular efforts are made to mimic the in vivo reality as close as possible. Cellular models with appropriate metabolic competence, i.e. with the potency to biotransform chemical compounds, are considered crucial since some metabolites have a different toxicity than their parent compounds. In this study a cell based in vitro test system is proposed to investigate the basal cytotoxicity of several reference chemicals. Both metabolic competent HepaRG cells and cells with no or low hepatic enzyme activity (undifferentiated HepaRG and proliferating HepG2) were used. The classic Neutral Red Uptake (NRU) assay proved to be robust and reliable to be applied as viability assay. The test was performed on a robotic platform, which enabled fully automated and simultaneous screening of the compounds. The outcome of these tests grouped the tested compounds in three categories following their detoxification effect (benzo(a)pyrene, valproic acid), their bio-activation effect (aflatoxin B1) and their specific effect on inhibition of cell proliferation (cycloheximide, sodium lauryl sulphate, atropine sulphate monohydrate, acetylsalicylic acid). 23352911 Encapsulation of Nod1 and Nod2 receptor ligands into poly(lactic acid) nanoparticles potentiates their immune properties. Most successful vaccines are able to induce persistent antibody responses that can last a lifetime. Emerging evidences indicate that activation of immune cells through pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) or Nod-like receptors (NLRs) may be critical mechanisms. Among PRRs, the use of TLR ligands as adjuvants is already largely described whereas the use of NLRs ligands remains largely unexplored. As activation of intracytoplasmic NLRs is able to induce proinflammatory molecules, the added value of encapsulation of Nod1 and Nod2 receptor ligands into Poly(Lactic Acid) (PLA) biodegradable nanocarriers to modulate their immune properties on human dendritic cells (DCs) maturation has been evaluated. Their ability to induce systemic immune responses in mice was also measured and compared to free ligands and the Alum adjuvant. Nod ligands encapsulated into PLA NPs were efficiently taken up by DCs and subsequently induced a strong up-regulation of maturation markers and the enhancement of proinflammatory cytokine secretion by DCs. Furthermore, co-injection of encapsulated Nod-ligands with PLA particles carrying Gag p24 HIV-1 antigen allowed a 100 fold increase in antibody responses in comparison to Alum. These results suggest that encapsulation of Nod ligands into PLA-NPs could be an effective way to improve vaccine efficiency. 23381905 The influence of bypass procedures and other anatomical changes in the gastrointestinal tract on the oral bioavailability of drugs. The gastrointestinal (GI) tract plays an important role in the absorption of orally administered drugs. However, in some cases the anatomy of the GI tract is changed due to GI surgery, which has the potential of influencing drug bioavailability. In this review, we aim to compile, review, and comment the existing but sometimes fragmented scientific data regarding the impact of GI surgery on the oral bioavailability of drugs. Relevant reports were gathered through the PubMed database from database inception through January 2012. Drugs for which at least one trial or case report suggested a change in oral bioavailability or absorption caused by GI surgery are discussed in detail. Major methodological differences, such as study design, number of subjects and choice of reference group, were observed in the reported studies. Predicting the impact of GI surgery on the oral bioavailability was therefore difficult to perform, even the most sophisticated classification systems could not be used for predicting purposes. 23194529 The presence of D-fagomine in the human diet from buckwheat-based foodstuffs. Buckwheat (Fagopyrum esculentum Moench) groats contain the iminosugar D-fagomine as a minor component that might contribute to the alleged health benefits of this pseudo-cereal. This study presents analysis of D-fagomine in buckwheat-based foodstuffs by liquid chromatography coupled to mass spectrometry and an estimation of its presence in the human diet based on a published population-based cross-sectional nutrition survey. D-fagomine is present in common buckwheat-based foodstuffs in amounts ranging from 1 to 25 mg/kg or mg/L, it is stable during boiling, baking, frying and fermentation, and it is biosynthesised upon sprouting. The estimated total intake of D-fagomine resulting from a diet that includes such foodstuffs would be between 3 and 17 mg per day (mean for both genders; range from P5 to P95). A diet rich in buckwheat products would provide a daily amount of D-fagomine that may in part explain the beneficial properties traditionally attributed to buckwheat consumption. 23178681 Hyaluronic acid-dependent protection in H9C2 cardiomyocytes: a cell model of heart ischemia-reperfusion injury and treatment. Hyaluronic acid (HA), a glycosaminoglycan with high molecular weight, has been reported to promote cell proliferation and serves as an important extracellular matrix component. The aim of this study was to in vitro investigate whether HA is able to reduce reactive oxygen species (ROS)-induced heart ischemia-reperfusion injury and activate the cardiomyocyte's damage surveillance systems. Accordingly, rattus cardiomyocyte line, H9C2, was treated with H(2)O(2) as a heart ischemia-reperfusion model followed by incubation with low molecular weight hyaluronan (LMW-HA, 100 kDa) or high molecular weight hyaluronan (HMW-HA, 1000 kDa) and proteomic analysis was performed to investigate the physiologic protection of HA in H(2)O(2)-induced ischemia-reperfusion in cardiomyocyte. Our data demonstrated that HA treatment does protect cardiomyocyte in the ROS-induced ischemia-reperfusion model and the molecular weight of HA is a crucial factor. HMW-HA has been shown to significantly facilitate cell migration and wound healing via cytoskeletal rearrangement. Additionally, 2D-DIGE combined MALDI-TOF/TOF analysis showed that HMW-HA might modulate biosynthetic pathways, cell migration, cell outgrowth and protein folding to stimulate wound healing as well as prevent these ischemia-reperfusion-damaged cardiomyocytes from cell death. To our knowledge, we report for the first time the cell repair mechanism of HMW-HA against ischemia-reperfusion-damage in cardiomyocytes based on cell biology and proteomic analysis. 23631590 Synthesis of Amylose-Polystyrene Inclusion Complexes by a Facile Preparation Route. The formation of amylose-polystyrene inclusion complexes via a novel two-step approach is described. In the first-step, styrene was inserted inside the amylose helical cavity, followed by free radical polymerization in the second step. The inclusion complexes were characterized by Attenuated Total Reflection Fourier Transform Infrared Spectroscopy (ATR-FTIR), Ultraviolet Spectroscopy (UV), X-ray Diffraction (XRD), Atomic Force Microscopy (AFM), and Differential Scanning Calorimetry (DSC). The formation of polystyrene was confirmed by gel Permeation Chromatography (GPC). The molecular weight of polystyrene can be varied by using amylose bearing different molar masses. The approach described here is general and could be used to synthesis other host-polymer inclusion complexes for which long chains of polymeric guests are difficult to insert into the host cavity. 23111981 Unifying protein inference and peptide identification with feedback to update consistency between peptides. We first propose a new method to process peptide identification reports from databases search engines. Then via it we develop a method for unifying protein inference and peptide identification by adding a feedback from protein inference to peptide identification. The feedback information is a list of high-confidence proteins, which is used to update an adjacency matrix between peptides. The adjacency matrix is used in the regularization of peptide scores. Logistic regression (LR) is used to compute the probability of peptide identification with the regularized scores. Protein scores are then calculated with the LR probability of peptides. Instead of selecting the best peptide match for each MS/MS, we select multiple peptides. By testing on two datasets, the results have shown that the proposed method can robustly assign accurate probabilities to peptides, and have a higher discrimination power than PeptideProphet to distinguish correct and incorrect identified peptides. Additionally, not only can our method infer more true positive proteins but also infer less false positive proteins than ProteinProphet at the same false positive rate. The coverage of inferred proteins is also significantly increased due to the selection of multiple peptides for each MS/MS and the improvement of their scores by the feedback from the inferred proteins. 23592839 Nutrient signaling in protein homeostasis: an increase in quantity at the expense of quality. The discovery that rapamycin extends the life span of diverse organisms has triggered many studies aimed at identifying the underlying molecular mechanisms. Mammalian target of rapamycin complex 1 (mTORC1) regulates cell growth and may regulate organismal aging by controlling mRNA translation. However, how inhibiting mTORC1 and decreasing protein synthesis can extend life span remains an unresolved issue. We showed that constitutively active mTORC1 signaling increased general protein synthesis but unexpectedly reduced the quality of newly synthesized polypeptides. We demonstrated that constitutively active mTORC1 decreased translation fidelity by increasing the speed of ribosomal elongation. Conversely, rapamycin treatment restored the quality of newly synthesized polypeptides mainly by slowing the rate of ribosomal elongation. We also found distinct roles for mTORC1 downstream targets in maintaining protein homeostasis. Loss of S6 kinases, but not 4E-BP family proteins, which are both involved in regulation of translation, attenuated the effects of rapamycin on the quality of newly translated proteins. Our results reveal a mechanistic connection between mTORC1 and protein quality, highlighting the central role of nutrient signaling in growth and aging. 23322537 Cross-tolerance in amphibians: wood frog mortality when exposed to three insecticides with a common mode of action. Insecticide tolerance and cross-tolerance in nontarget organisms is often overlooked despite its potential to buffer natural systems from anthropogenic influence. We exposed wood frog tadpoles from 15 populations to three acetylcholine esterase-inhibiting insecticides and found widespread variation in insecticide tolerance and evidence for cross-tolerance to these insecticides. Our results demonstrate that amphibian populations with tolerance to one pesticide may be tolerant to many other pesticides. 23339830 Disorder imposed limits of mono- and bilayer graphene electronic modification using covalent chemistry. A central question in graphene chemistry is to what extent chemical modification can control an electronically accessible band gap in monolayer and bilayer graphene (MLG and BLG). Density functional theory predicts gaps in covalently functionalized graphene as high as 2 eV, while this approach neglects the fact that lattice symmetry breaking occurs over only a prescribed radius of nanometer dimension, which we label the S-region. Therefore, high chemical conversion is central to observing this band gap in transport. We use an electrochemical approach involving phenyl-diazonium salts to systematically probe electronic modification in MLG and BLG with increasing functionalization for the first time, obtaining the highest conversion values to date. We find that both MLG and BLG retain their relatively high conductivity after functionalization even at high conversion, as mobility losses are offset by increases in carrier concentration. For MLG, we find that band gap opening as measured during transport is linearly increased with respect to the I(D)/I(G) ratio but remains below 0.1 meV in magnitude for SiO(2) supported graphene. The largest transport band gap obtained in a suspended, highly functionalized (I(D)/I(G) = 4.5) graphene is about 1 meV, lower than our theoretical predictions considering the quantum interference effect between two neighboring S-regions and attributed to its population with midgap states. On the other hand, heavily functionalized BLG (I(D)/I(G) = 1.8) still retains its signature dual-gated band gap opening due to electric-field symmetry breaking. We find a notable asymmetric deflection of the charge neutrality point (CNP) under positive bias which increases the apparent on/off current ratio by 50%, suggesting that synergy between symmetry breaking, disorder, and quantum interference may allow the observation of new transistor phenomena. These important observations set definitive limits on the extent to which chemical modification can control graphene electronically. 23000249 Snake venom metalloproteinases. Recent proteomic analyses of snake venoms show that metalloproteinases represent major components in most of the Crotalid and Viperid venoms. In this chapter we discuss the multiple activities of the SVMPs. In addition to hemorrhagic activity, members of the SVMP family also have fibrin(ogen)olytic activity, act as prothrombin activators, activate blood coagulation factor X, possess apoptotic activity, inhibit platelet aggregation, are pro-inflammatory and inactivate blood serine proteinase inhibitors. Clearly the SVMPs have multiple functions in addition to their well-known hemorrhagic activity. The realization that there are structural variations in the SVMPs and the early studies that led to their classification represents an important event in our understanding of the structural forms of the SVMPs. The SVMPs were subdivided into the P-I, P-II and P-III protein classes. The noticeable characteristic that distinguished the different classes was their size (molecular weight) differences and domain structure: Class I (P-I), the small SVMPs, have molecular masses of 20-30 kDa, contain only a pro domain and the proteinase domain; Class II (P-II), the medium size SVMPs, molecular masses of 30-60 kDa, contain the pro domain, proteinase domain and disintegrin domain; Class III (P-III), the large SVMPs, have molecular masses of 60-100 kDa, contain pro, proteinase, disintegrin-like and cysteine-rich domain structure. Another significant advance in the SVMP field was the characterization of the crystal structure of the first P-I class SVMP. The structures of other P-I SVMPs soon followed and the structures of P-III SVMPs have also been determined. The active site of the metalloproteinase domain has a consensus HEXXHXXGXXHD sequence and a Met-turn. The "Met-turn" structure contains a conserved Met residue that forms a hydrophobic basement for the three zinc-binding histidines in the consensus sequence. 23086182 Assessing bioavailability and toxicity of permethrin and DDT in sediment using matrix solid phase microextraction. Matrix solid phase microextraction (matrix-SPME) was evaluated as a surrogate for the absorbed dose in organisms to estimate bioavailability and toxicity of permethrin and dichlorodiphenyltrichloroethane (DDT) in laboratory-spiked sediment. Sediments were incubated for 7, 28, and 90 days at room temperature to characterize the effect of aging on bioavailability and toxicity. Sediment toxicity was assessed using two freshwater invertebrates, the midge Chironomus dilutus and amphipod Hyalella azteca. Disposable polydimethylsiloxane fibers were used to estimate the absorbed dose in organisms and to examine bioavailability and toxicity. The equilibrium fiber concentrations substantially decreased with an increase in sediment aging time, indicating a reduction in bioavailability. Based on median lethal fiber concentrations (fiber LC50), toxicity of permethrin was not significantly different among the different aging times. Due to the substantial degradation of DDT to dichlorodiphenyldichloroethane (DDD) in sediment, sediment toxicity to C. dilutus increased, while it decreased for H. azteca with extended aging times. A toxic unit-based fiber LC50 value represented the DDT mixture (DDT and DDD) toxicity for both species. Significant linear relationships were found between organism body residues and the equilibrium fiber concentrations for each compound, across aging times. The study suggested that the matrix-SPME fibers mimicked bioaccumulation in the organisms, and enabled estimation of body residues, and could potentially be used in environmental risk assessment across matrices (e.g. sediment and water) to measure bioavailability and toxicity of hydrophobic pesticides. 23327691 The macrocyclic peptide natural product CJ-15,208 is orally active and prevents reinstatement of extinguished cocaine-seeking behavior. The macrocyclic tetrapeptide natural product CJ-15,208 (cyclo[Phe-d-Pro-Phe-Trp]) exhibited both dose-dependent antinociception and kappa opioid receptor (KOR) antagonist activity after oral administration. CJ-15,208 antagonized a centrally administered KOR selective agonist, providing strong evidence it crosses the blood-brain barrier to reach KOR in the CNS. Orally administered CJ-15,208 also prevented both cocaine- and stress-induced reinstatement of extinguished cocaine-seeking behavior in the conditioned place preference assay in a time- and dose-dependent manner. Thus, CJ-15,208 is a promising lead compound with a unique activity profile for potential development, particularly as a therapeutic to prevent relapse to drug-seeking behavior in abstinent subjects. 23473028 Xenobiotics and the human gut microbiome: metatranscriptomics reveal the active players. The human gut microbiome plays an important role in the metabolism of xenobiotics. In a recent issue of Cell, Maurice et al. (2013) identify the active members of the gut microbiome and show how gene-expression profiles change within the gut microbial community in response to antibiotics and host-targeted xenobiotics. 23644219 Synthesis and biological evaluation of N-(4-hydroxy-3-mercaptonaphthalen-1-yl)amides as inhibitors of angiogenesis and tumor growth. A series of N-(4-hydroxy-3-mercaptonaphthalen-1-yl)amides were synthesized and investigated for their in vitro antiangiogenic activity. Among these compounds, 6d, which possesses an ortho-nitro group at the benzene ring, exhibited potent inhibitory effect on the proliferation of HUVECs, A549, K562, PC-3, HCT116, MDA-MB-231 and MCF-7 cells (IC50 = 5.34, 40.53, 10.81, 52.52, 10.19, 21.37 and 2.81 μM, respectively). Meanwhile, compound 6d inhibited in vitro angiogenesis markedly in both HUVECs tube formation assay and the rat thoracic aorta rings test. Further kinase assay study showed that compound 6d had good VEGFR2, ALK, AKT1 and ABL inhibitory activities and moderate EGFR and PDGFR-β inhibitory activities. The data supports the further investigation of this class of compounds as potential antiangiogenic and anticancer agents. 23436709 UV/Vis spectra of subporphyrazines and subphthalocyanines with aluminum and gallium: a time-dependent DFT study. The UV/Vis spectra of selected substituted subporphyrazines (SubPz) and subphthalocyanines (SubPc) with aluminum and gallium as central atoms are analyzed through time-dependent DFT calculations in chloroform. The results are compared with previous results with boron as the central atom to analyze the photochemical properties of these two families of compounds on varying the metal along the same group. The absorptions of SubPz (Al, Ga) are redshifted or blueshifted with respect to SubPz (B) depending on the nature of the R substituents of the molecule, whereas the absorptions of SubPc (Al, Ga) structures are redshifted and with smaller energy gaps with respect to SubPc (B) for all kinds of R substituents. Looking at their absorption spectra, these systems with aluminum and gallium may also have, as in the case of boron, promising photochemical properties. 23300130 A Serum-Tolerant Hydroxyl-Modified Polyethylenimine as Versatile Carriers of pDNA/siRNA. The polyethylenimine (PEI) derivatives (PTn) are prepared by treating PEI25k with Tris(hydroxymethyl) acrylamidomethane via the Michael addition. These PTns can effectively condense nucleic acids into nanosized particles with positive surface charges. The PTns show lower cytotoxicity and better serum-resistant capacity than PEI25k. Specially, the transfection efficiency of PT26/DNA is 29-fold higher than that of PEI25k in HeLa cells in serum-containing medium. The PTn/siRNA complexes show superior knockdown effect in CT26 cells in serum-containing medium. In addition, flow cytometry analysis shows that the PTns can efficiently mediate the entry of nucleic acids into the cell. Thus, PTns are potentially applicable as non-viral carriers of nucleic acids and warrant further development for use in gene therapy. 23615471 Caffeic Acid Phenethyl Ester Suppresses Proliferation and Survival of TW2.6 Human Oral Cancer Cells via Inhibition of Akt Signaling. Caffeic acid phenethyl ester (CAPE) is a bioactive component extracted from honeybee hive propolis. Our observations indicated that CAPE treatment suppressed cell proliferation and colony formation of TW2.6 human oral squamous cell carcinoma (OSCC) cells dose-dependently. CAPE treatment decreased G1 phase cell population, increased G2/M phase cell population, and induced apoptosis in TW2.6 cells. Treatment with CAPE decreased protein abundance of Akt, Akt1, Akt2, Akt3, phospho-Akt Ser473, phospho-Akt Thr 308, GSK3β, FOXO1, FOXO3a, phospho-FOXO1 Thr24, phospho-FoxO3a Thr32, NF-κB, phospho-NF-κB Ser536, Rb, phospho-Rb Ser807/811, Skp2, and cyclin D1, but increased cell cycle inhibitor p27Kip. Overexpression of Akt1 or Akt2 in TW2.6 cells rescued growth inhibition caused by CAPE treatment. Co-treating TW2.6 cells with CAPE and 5-fluorouracil, a commonly used chemotherapeutic drug for oral cancers, exhibited additive cell proliferation inhibition. Our study suggested that administration of CAPE is a potential adjuvant therapy for patients with OSCC oral cancer. 22718571 Anti-diabetic Activity of Swertiamarin is due to an Active Metabolite, Gentianine, that Upregulates PPAR-γ Gene Expression in 3T3-L1 cells. We have previously shown the anti-diabetic effects of swertiamarin; however, pharmacokinetic analysis showed that swertiamarin had a plasma half-life of 1.3 h. Gentianine is an active metabolite of swertiamarin that possesses a pharmacophoric moiety. The aim of this study was to explore the possibility whether the anti-diabetic effect of swertiamarin is due to gentianine. Swertiamarin treatment had no significant effect on adipogenesis, or the mRNA expression of PPAR-γ and GLUT-4; however, there was a significant increase in the mRNA expression of adiponectin. On the other hand, treatment with gentianine significantly increased adipogenesis, which was associated with a significant increase in the mRNA expression of PPAR-γ, GLUT-4 and adiponectin. These findings suggest, for the first time, that the anti-diabetic effect of swertiamarin is due to gentianine, an active metabolite of swertiamarin. Copyright © 2012 John Wiley & Sons, Ltd. 23588308 A Physiologically-Based Pharmacokinetic Modelling Approach to Predict Disease-Drug Interactions: Suppression of CYP3A by IL-6. Elevated cytokine levels can down-regulate expression of cytochrome P450 enzymes (CYPs) and suppress their activity. Treatment of inflammation or infection with cytokine-modulating therapeutic proteins (TP) could reverse suppression manifesting as therapeutic protein-drug drug interactions (TP-DDI). A physiologically-based pharmacokinetic model was used to quantitatively predict the impact of IL-6 on sensitive CYP3A4 substrates. Elevated simvastatin AUC in virtual rheumatoid arthritis patients, following 100 pg/mL of IL-6 was comparable to observed clinical data (59% versus 58%). In virtual bone marrow transplant (BMT) patients, 500 pg/ml of IL-6 resulted in increase in cyclosporine AUC that was in good agreement with the observed data (45% versus 39%). In a different group of BMT patients treated with cyclosporine, the magnitude of interaction with IL-6 was under predicted ~3-fold. The complexity of TP-DDI highlights underlying pathophysiological factors to be considered but these simulations provide valuable first steps towards predictions of TP-DDI risk.Clinical Pharmacology & Therapeutics (2013); accepted article preview online 10 April 2013 doi:10.1038/clpt.2013.79. 23316933 Targeting adenosine signaling to treatment of diabetic nephropathy. Diabetic nephropathy (DN) continues being the primary cause of chronic hemodialysis and terminal renal disease worldwide. At tissue levels the DN occurs with glomerulopathy affecting the integrity of the filtration barrier and with an extensive glomerular and tubule-interstitial fibrosis. Current available therapeutic approaches have only demonstrated a modest effect on progression of kidney injury. Therefore, more research concerning the pathomechanisms and possible interventions are needed. Interestingly, in the last years it has been documented that DN progresses with growing levels of the nucleoside adenosine. This finding increased the interest in the events controlling the extracellular levels of the nucleoside. While the metabolism of extracellular ATP and cyclic AMP are well recognized sources, evidences regarding the role of the equilibrative nucleoside transporters in controlling adenosine availability and promoting diabetic glomerulopathy have recently acquired a pivotal role. The physiological effects of nucleoside are mediated by the P1 family of adenosine receptors. It has been shown in vivo that the use of an antagonist of the A2B receptor subtype can block the most remarkable early alterations seen in diabetic glomerulopathy. Furthermore, using models of chronic kidney injury it was demonstrated that fibrosis can also be blocked using treatment with the antagonist of A2B receptor subtype. This review highlights these findings that correlate the activity of a low affinity adenosine receptor with an increase in the ligand availability in the pathological state. In addition, we discuss the possible therapeutic interventions of adenosine signaling with regards to DN treatment. 23592428 Selective Smad4 Knockout in Ovarian Preovulatory Follicles Results in Multiple Defects in Ovulation. The TGF-β signaling pathway is involved with multiple processes in the mammalian ovary, including primordial follicle formation, granulosa cell (GC) proliferation, follicle atresia, ovulation, and feedback regulation between the pituitary and ovary. The transcriptional factor SMAD4 is the central component of the canonical TGF-β signaling pathway. Smad4 knockout using Amhr2-Cre, which is expressed in GCs of immature developing follicles, causes premature luteinization. In this study, we specifically depleted Smad4 in GCs of preovulatory follicles using Cyp19-Cre mice. As different from results with Smad4(fl/fl);Amhr2-Cre mice, Smad4 depletion in preovulatory follicles did not cause premature luteinization or suppress GC proliferation; rather, it increased follicle atresia. In addition, Nppc and Npr2 expressions were reduced by Smad4 depletion; thus, their effect of maintaining oocyte meiotic arrest was weakened in Smad4 conditional knockout mice. Smad4(fl/fl);Cyp19-Cre female mice were subfertile and had irregular estrous cycles and ovulation defects. Smad4 knockout also blocked luteinizing hormone (LH)-induced cumulus expansion and follicle rupture, but not oocyte meiotic resumption. Our results also indicated that SMAD4 was required for LH-stimulated activation of ERK1/2 and the expressions of ovulation-related genes. The defects arising from SMAD4 depletion could not be rescued by intra-ovarian mediators of LH actions, such as EGF-like factors and prostaglandin E2. Furthermore, corpus lutea did not form in Smad4(fl/fl);Cyp19-Cre female mice, indicating that SMAD4 was crucial for GCs terminal differentiation. Thus, by characterizing the ovarian phenotypes of preovulatory follicle-specific Smad4 knockout mice, we identified the developmental stage-specific functions of the canonical TGF-β signaling pathway in ovulation and luteinization. 23411205 Simultaneous determination of Mn2+ and Fe3+ as 4,4'[(4-cholorophenyl)methylene] bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) complexes in some foods, vegetable and water samples by artificial neural networks. A simple and sensitive spectrophotometric method to the simultaneous determination of Mn(2+) and Fe(3+) in foods, vegetable and water sample with the aid of artificial neural networks (ANNs) is described. It relies on the complexation of analytes with recently synthesised bis pyrazol base ligand as 4,4'[(4-cholorophenyl)methylene] bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)(CMBPP). The analytical data show that the ratio of ligand to metal in metal complexes is 1:1 and 1:2 for Fe(3+) and Mn(2+), respectively. It was found that the complexation reactions are completed at pH 6.7 and 5 min after mixing. The results showed that Mn(2+) and Fe(3+) could be determined simultaneously in the range of 0.20-7.5 and 0.30-9.0 mgl(-1), respectively. The analytical characteristics of the method such as the detection limit and the relative standard error predictions were calculated. The data obtained from synthetic mixtures of the metal ions were processed by radial basis function networks (RBFNs) and feed forward neural networks (FFNNs). The optimal conditions of the neural networks were obtained by adjusting various parameters by trial-and-error. Under the working conditions, the proposed methods were successfully applied to the simultaneous determination of elements in different water, tablet, rice, tea leaves, tomato, cabbage and lettuce samples. 22626763 Acetylation and deacetylation--novel factors in muscle wasting. We review recent evidence that acetylation and deacetylation of cellular proteins, including transcription factors and nuclear cofactors, may be involved in the regulation of muscle mass. The level of protein acetylation is balanced by histone acetyltransferases (HATs) and histone deacetylases (HDACs) and studies suggest that this balance is perturbed in muscle wasting. Hyperacetylation of transcription factors and nuclear cofactors regulating gene transcription in muscle wasting may influence muscle mass. In addition, hyperacetylation may render proteins susceptible to degradation by different mechanisms, including intrinsic ubiquitin ligase activity exerted by HATs and by dissociation of proteins from cellular chaperones. In recent studies, inhibition of p300/HAT expression and activity and stimulation of SIRT1-dependent HDAC activity reduced glucocorticoid-induced catabolic response in skeletal muscle, providing further evidence that hyperacetylation plays a role in muscle wasting. It should be noted, however, that although several studies advocate a role of hyperacetylation in muscle wasting, apparently contradictory results have also been reported. For example, muscle atrophy caused by denervation or immobilization may be associated with reduced, rather than increased, protein acetylation. In addition, whereas hyperacetylation results in increased degradation of certain proteins, other proteins may be stabilized by increased acetylation. Thus, the role of acetylation and deacetylation in the regulation of muscle mass may be both condition- and protein-specific. The influence of HATs and HDACs on the regulation of muscle mass, as well as methods to modulate protein acetylation, is an important area for continued research aimed at preventing and treating muscle wasting. 23201180 Fenamiphos is recalcitrant to the hydrolysis by alloforms PON1 Q192R of human serum. Fenamiphos (ethyl 4-methylthio-m-tolyl isopropylphosphoramidate) is a racemic organophosphorus nematicide widely used in agriculture around the world. The paraoxonase 1 from human serum (PON1) is a phosphotriesterase (PTE) that hydrolyses several xenobiotics including drugs and organophosphorus compounds (OPs). In this work, the separation of the enantiomers of fenamiphos by HPLC using the column CHIRALCEL OJ and a mobile phase of hexane/ethanol (99/1) is presented. A liquid-liquid extraction method was implemented for the characterization of commercial nematicide hydrolysis by PON1 Q192R alloforms of human serum from children and adults. The results show a recovery of 94% for each isomer from the biological matrix. The method resulted linear response in a range concentration between 50 and 800μM with a detection and quantification limit between 0.6 and 2μM for the (+)-fenamiphos, and between 0.7 and 2.3μM for the (-)-fenamiphos. The levels of the Ca(2+)-dependent hydrolysis (residual concentration [μM]) quantified during 30min of reaction were only just 4-14% for both fenamiphos enantiomers with the three alloforms of PON1 Q192R of the two groups of serum studied. These results demonstrate that human serum PON1 is could be involved in the detoxification of a limited number of organophosphorus insecticides. 23575745 Vortex domain structures of an epitaxial ferroelectric nanodot and its temperature-misfit strain phase diagram. Phase field simulations were conducted to investigate the effect of misfit strain on the vortex domain structure (VDS) in a BaTiO3 nanodot. Taking into account the effect of inhomogeneous eletromechanical fields, ambient temperature and surface effects, our calculations demonstrate a strong effect of misfit strain on the orientation and magnitude of the polarization dipoles. As a consequence, fruitful equilibrium vortex domain patterns can be obtained by adjusting the epitaxial misfit strain between the substrate and the nanodot. While the nanodot exhibits a single transition from a paraelectric to a near-rhombohedral vortex state at zero misfit strain with the decrease of temperature, complicated transformations of vortex domain patterns are found under nonzero misfit strain. Typically, orthorhombic, tetragonal and several unreported vortex domain patterns (e.g., with zero toroidal moment) are found. Moreover, misfit strain-induced transformations into these domain patterns are also predicted for a ferroelectric nanodot with initial near-rhombohedral vortex state. Combining effects of the ambient temperature and misfit strain, a "temperature-misfit strain" phase-diagram depicting the fruitful vortex domain patterns of the nanodot was obtained. Our simulations indicate promising application of strain engineering in controlling the VDS in ferroelectric nanostructures. 23291608 Altered matrix mineralization in a case of a sclerosing osteosarcoma. Little is known about the tumor matrix mineralization of highly sclerotic osteosarcoma. We used quantitative backscattered electron imaging (qBEI) to determine the Bone mineralization density distribution (BMDD) of a highly sclerosing osteosarcoma of the proximal tibia as well as adjacent normal bone of a 10-year-old girl following chemotherapy according to the EURAMOS-1 protocol. Data were compared to recently published normative reference data for young individuals. Backscattered electron imaging of the tumor region revealed a dense accumulation of mineralized tumor bone matrix (up to 90% of the medullar space). The BMDD was shifted tremendously towards higher matrix mineralization (CaMean +18.5%, CaPeak +22.5%, CaHigh +100 fold) compared to normal bone. Additionally the BMDD became much wider, indicating a higher heterogeneity in mineralization (CaWidth +40%). In contrast to lamellar bone, which mineralizes via a mineralization front, the mineralization of the tumor matrix starts by randomly distributed spots of mineral clusters fusing together to a highly mineralized non-lamellar bone matrix. We also found an altered BMDD of the patient's normal bone when compared with the reference BMDD of young individuals. In conclusion this high radiodensity region of the sclerosing sarcoma is not only due to the high amount of tumor matrix but also to its high mineralization density. Chemotherapy may lead to altered matrix mineralization of normal bone due to suppression of bone turnover. The mechanism of matrix mineralization in a sclerosing osteosarcoma warrants further studies. 23535363 Interferon-γ Promoter Is Hypermethylated in Blood DNA from Workers with Confirmed Diisocyanate Asthma. Risk factors have not been identified that determine susceptibility for development of diisocyanate-induced occupational asthma (DA). We hypothesized that diisocyanate (DI) exposure could modify gene promoter regions regulating transcription of cytokine mediators and thereby influence expression of DA. A cross-sectional study was designed to investigate the promoter methylation status of candidate genes in DI-exposed workers. Subjects consisted of 131 workers in three groups: 40 cases with DA confirmed by a positive specific inhalation challenge (SIC) (DA+), 41 exposed workers with lower respiratory symptoms and negative SIC (DA-), and 50 asymptomatic exposed workers (AWs). We studied four candidate genes (GSTM1, DUSP22, IFN-γ, and IL-4) for which altered promoter methylation has been previously investigated for relationships with a variety of other environmental exposures. Methylation status was determined using methylation-specific quantitative PCR performed on genomic DNA extracted from whole blood. Results showed that relative methylation of IFN-γ promoter was significantly increased in DA+ in comparison with both comparator groups (DA- and AW), and it exhibited good sensitivity (77.5%) and specificity (80%) for identifying DA workers in a multivariate predictive model after adjusting for type of DI exposure, smoking status, methacholine PC20, and gender. IL-4 promoter was slightly less methylated only in DA+ compared with AW among nonsmoking workers. Both GSTM1 and DUSP22 promoter methylations were found not associated with DA. Our finding suggests that exposure to occupational chemicals could play a heretofore undefined mechanistic role via epigenetic modification of specific genes in the promoter region. 23263362 Probing the structural, electronic and magnetic properties of multicenter Fe₂S₂⁰/⁻, Fe₃S₄⁰/⁻ and Fe₄S₄⁰/⁻ clusters. The structural, electronic and magnetic properties of neutral and anion Fe2S2, Fe3S4 and Fe4S4 have been investigated with the aid of previous photoelectron spectroscopy and density functional theory calculations. Theoretical electron detachment energies (both vertical and adiabatic) of anion clusters for the lowest energy structure were computed and compared with the experimental results to verify the ground states. The optimized structures show that the ground state structures of Fe2S2(0/-), Fe3S4(0/-) and Fe4S4(0/-) favor high spin state and are similar to their structures in proteins. The electron delocalization pattern for all the clusters and the nature of bonding between Fe and S atoms were studied by analyzing molecular orbitals. Natural population analysis demonstrates that Fe atoms act as an electron donor in all clusters, and the electron density difference map clearly shows the direction of the electron flow over the whole complex. Furthermore, the investigated magnetism shows that the Fe atoms carried most of the magnetic moments, which is due mainly to the 3d state, while only very small magnetic moments are found on S atoms. 23475307 Arsenic speciation and spatial and interspecies differences of metal concentrations in mollusks and crustaceans from a South China estuary. Arsenic speciation and concentrations were determined in mollusks and crustaceans in the intertidal zone from twelve locations in Zhanjiang estuary, South China. Metal concentrations (Ag, As, Cd, Cu, Hg, Ni, Pb, and Zn) were also concurrently determined in these species. Arsenic speciation analysis showed that the less-toxic arsenobetaine (AsB) constituted 80.6-98.8 % of all As compounds, and dimethylarsinic acid (DMA) constituted 0.47-3.44 %. Monomethylarsonic acid (MMA) and As(V) were only detected in the whelk Drupa fiscella and the crab Heteropilumnus ciliatus, respectively. Arsenite [As(III)] was not detected in any of the sampled specimens, but there were also unidentified other As species. A strong spatial variation of metals in the oyster Saccostrea cucullata was found in the estuary, confirming that oysters can be used as a good biomonitor of metal contamination in the studied area. The concentrations of eight metals in the studied mollusks and crustaceans clearly revealed that these invertebrates accumulated different metals to different degrees. Furthermore, As, Cd, Cu, Hg, and Pb contents in mollusks and crustacean samples were below the Food and Agricultural Organization (FAO) safe concentrations, thus there was no obvious health risk from the intake of the metals through marine mollusks and crustaceans consumption. 23503701 Differential antidepressant-like response to lithium treatment between mouse strains: effects of sex, maternal care, and mixed genetic background. BACKGROUND: Lithium is a mood stabilizer with both antidepressant and antimanic properties, however its mechanism of action is unclear. Identifying the genetic factors that influence lithium's therapeutic actions will be an important step to assist in identifying such mechanisms. We previously reported that lithium treatment of male mice has antidepressant-like effects in the C57BL/6J strain but that such effects were absent in the BALB/cJ strain. OBJECTIVES: This study aimed to assess the roles of both genetic and non-genetic factors such as sex and non-shared environmental conditions that may mediate differential behavioral responses to lithium. METHODS: Mice were treated with lithium for 10 days and then tested in the forced swim test followed by lithium discontinuation and retesting to assess effects of lithium withdrawal. We also assessed effects of sex and cross-fostering on lithium response between the C57BL/6J and BALB/cJ strains, and antidepressant-like effects of lithium in the hybrid CB6F1/J strain that is derived from C57BL/6J and BALB/cJ parental strains. RESULTS: Neither sex nor maternal care significantly influenced the differential antidepressant-like response to lithium. Withdrawal from lithium treatment reversed antidepressant-like effects in the C57BL/6J strain but had no effects in BALB/cJ mice. Lithium treatment did not result in antidepressant-like effects in the CB6F1/J strain. CONCLUSIONS: Genetic factors are likely primarily responsible for differential antidepressant-like effects of lithium in the C57BL/6J and BALB/cJ strains. Future studies identifying such genetic factors may help to elucidate the neurobiological mechanisms of lithium's therapeutic actions. 23178593 APLF promotes the assembly and activity of non-homologous end joining protein complexes. Non-homologous end joining (NHEJ) is critical for the maintenance of genetic integrity and DNA double-strand break (DSB) repair. NHEJ is regulated by a series of interactions between core components of the pathway, including Ku heterodimer, XLF/Cernunnos, and XRCC4/DNA Ligase 4 (Lig4). However, the mechanisms by which these proteins assemble into functional protein-DNA complexes are not fully understood. Here, we show that the von Willebrand (vWA) domain of Ku80 fulfills a critical role in this process by recruiting Aprataxin-and-PNK-Like Factor (APLF) into Ku-DNA complexes. APLF, in turn, functions as a scaffold protein and promotes the recruitment and/or retention of XRCC4-Lig4 and XLF, thereby assembling multi-protein Ku complexes capable of efficient DNA ligation in vitro and in cells. Disruption of the interactions between APLF and either Ku80 or XRCC4-Lig4 disrupts the assembly and activity of Ku complexes, and confers cellular hypersensitivity and reduced rates of chromosomal DSB repair in avian and human cells, respectively. Collectively, these data identify a role for the vWA domain of Ku80 and a molecular mechanism by which DNA ligase proficient complexes are assembled during NHEJ in mammalian cells, and reveal APLF to be a structural component of this critical DSB repair pathway. 23142505 Effects of phospholipase A2 and metalloprotease fractions of Russell's viper venom on cytokines and renal hemodynamics in dogs. Several enzymes in Russell's viper (Daboia siamensis) venom are involved in the venom effects and renal injury. The effects of fractional components of Russell's viper venom, phospholipase A(2) and metalloprotease fractions, were examined in two groups of four experimental dogs each. Animals received an intravenous injection of 140 μg/kg of each venom fraction. The inflammatory effects and renal hemodynamic changes were assessed. Plasma concentrations of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and PGE2 were elevated by both phospholipase A(2) (PLA(2)) and metalloprotease (MP) fractions. The plasma level of nitric oxide was increased after PLA(2) fraction injection but not with MP fraction injection. Leukocytosis with increase in lymphocytes, monocytes and granulocytes was observed after both PLA(2) and MP injections. Results from this study suggested that both PLA(2) and MP were inflammatory. Increased red blood cell count, hematocrit and hemoglobin concentration were observed in animals injected with PLA(2) fraction, but not with MP fraction. Hemodynamically, PLA(2) fraction induced marked decrease in mean arterial pressure with decreased renal vascular resistance initially followed later by increased renal vascular resistance. MP fraction caused less decrease of mean arterial pressure but increased renal vascular resistance throughout the experiment. Both enzymes decreased renal blood flow, glomerular filtration rate and urine flow. The findings indicate vasodilating effect of PLA(2) fraction and vasoconstricting effect and decreased cardiac function of MP fraction. 23414139 Immunosensor based on immobilization of antigenic peptide NS5A-1 from HCV and silk fibroin in nanostructured films. The peptide NS5A-1 (PPLLESWKDPDYVPPWHG), derived from hepatitis C virus (HCV) NS5A protein, was immobilized into layer-by-layer (LbL) silk fibroin (SF) films. Deposition was monitored by UV-vis absorption measurements at each bilayer deposited. The interaction SF/peptide film induced secondary structure in NS5A-1 as indicated by fluorescence and circular dichroism (CD) measurements. Voltammetric sensor (SF/NS5A-1) properties were observed when the composite film was tested in the presence of anti-HCV. The peptide-silk fibroin interaction studied here showed new architectures for immunosensors based on antigenic peptides and SF as a suitable immobilization matrix. 23257735 Characterization of steroidogenic enzyme expression in aldosterone-producing adenoma: a comparison with various human adrenal tumors. We analyzed the expression profiles of several steroidogenic enzymes in normal adrenals, aldosterone-producing adenomas (APA), cortisol-producing adenomas combined with Cushing's syndrome (CPA) or with subclinical Cushing's syndrome (SCPA), and nonfunctioning adrenal adenomas (NFA) to clarify the nature and characteristics of steroidogenesis in APA. Clinical data were collected for all subjects. In resected adrenal glands (normal adrenals, APA, CPA, SCPA, and NFA), the mRNA expression levels of the CYP17, HSD3B2, CYP11B1, and CYP11B2 genes were studied using real-time quantitative PCR and immunohistochemistry. The CYP11B2 mRNA level in APA was significantly higher than that in other groups. The CYP17/HSD3B2 ratio for mRNA in APA was significantly lower than those in the other groups. Low ratio of CYP17/HSD3B2 with high expression of CYP11B2 seems to explain steroidogenic characteristics of APA. 23621317 Magnetic Porous Sugar-Functionalized PEG Microgels for Efficient Isolation and Removal of Bacteria from Solution. Here we present a new microparticle system for the selective detection and magnetic removal of bacteria from contaminated solutions. The novelty of this system lies in the combination of a biocompatible scaffold reducing unspecific interactions with high capacity for bacteria binding. We apply highly porous poly(ethylene glycol) (PEG) microparticles and functionalize them introducing both sugar ligands for specific bacteria targeting and cationic moieties for electrostatic loading of superparamagnetic iron oxide nanoparticles. The resulting magnetic, porous, sugar-functionalized (MaPoS) PEG microgels are able to selectively bind and discriminate between different strains of bacteria Escherichia coli. Furthermore, they allow for a highly efficient removal of bacteria from solution as their increased surface area can bind three times more bacteria than non-porous particles. All in all, MaPoS particles represent a novel generation of magnetic beads introducing for the first time a porous, biocompatible and easy to functionalize scaffold and show great potential for various biotechnological applications. 22935770 Applicability of a keratinocyte gene signature to predict skin sensitizing potential. There is a need to replace animal tests for the identification of skin sensitizers and currently many alternative assays are being developed that have very promising results. In this study a gene signature capable of very accurate identification of sensitizers was established in the HaCaT human keratinocyte cell line. This signature was evaluated in a separate study using six chemicals that are either local lymph node (LLNA) false-positive or false-negative chemicals in addition to nine sensitizers and four non-sensitizers. Similar studies do not apply these more difficult to classify chemicals, which show the true potential for human predictions of an assay. Although the gene signature has improved prediction accuracy compared to the LLNA, the misclassified compounds were comparable between the two assays. Gene profiling also showed a sensitizer specific response of the Nrf2-keap1 and Toll-like receptor signaling pathways. After exposure to non-sensitizing chemicals that induce either of the pathways the signature misclassified all Nrf2-inducers, while the Toll-like receptor ligands were correctly classified. In conclusion, we confirm that keratinocyte based prediction assays may provide essential information on the properties of compounds. Furthermore, chemical selection is critical for assessment of the performance of in vitro alternative assays. 23617615 Structural Characterization of a Model Gram-negative Bacterial Surface Using Lipopolysaccharides from Rough Strains of Escherichia coli. Lipopolysaccharides (LPS) make up approximately 75% of the Gram-negative bacterial outer membrane (OM) surface, however, due to the complexity of the molecule, there are very few model OMs that include LPS. The LPS molecule consists of lipid A, which anchors the LPS within the OM, a core polysaccharide region and a variable O-antigen polysaccharide chain. In this work we used RcLPS (consisting of lipid A plus the first seven sugars of the core polysaccharide) from a rough strain of E. coli to form stable monolayers of LPS at the air-liquid interface. The vertical structure RcLPS monolayers were characterized using neutron and X-ray reflectometry whilst the lateral structure was investigated using grazing incidence X-ray diffraction and Brewster Angle Microscopy. It was found that RcLPS monolayers at surface pressures of 20 mN m(-1) and above are resolved as hydrocarbon tails, an inner headgroup and an outer headgroup of polysaccharide with increasing solvation from tails to outer headgroups. The lateral organization of the hydrocarbon lipid chains displays an oblique hexagonal unit cell at all surface pressures, with only the chain tilt angle changing with surface pressure. This is in contrast to lipid A which displays hexagonal or, above 20 mN m(-1), distorted hexagonal packing. This work provides the first complete structural analysis of a realistic E. coli OM surface model. 23479388 Cytotoxic pentacyclic triterpenoids from Prinsepia utilis. Phytochemical investigation of the aerial parts of Prinsepia utilis Royle resulted in the isolation and identification of ten pentacyclic triterpenoids, including two new triterpenoids, 2α-O-trans-p-coumaroyl-3β,19α-dihydroxy-urs-12-en-28-oic acid (1) and 2α-O-cis-p-coumaroyl-3β,19α-dihydroxy-urs-12-en-28-oic acid (2), along with eight known pentacyclic triterpenoids (3-10). The structures were elucidated by extensive spectroscopic methods and by comparison to previously reported spectroscopic data. Most of these compounds showed significant cytotoxic activities against four human cancer cell lines (A549, HCT116, MDA-MB-231, and CCRF-CEM), and the structure-activity relationships are also discussed. 22766391 Allosteric alpha-7 nicotinic receptor modulation and P50 sensory gating in schizophrenia: a proof-of-mechanism study. In this multicenter, double-blind, placebo-controlled, randomized, four way cross-over proof-of-mechanism study, we tested the effect of the positive allosteric α7 nicotinic acetylcholine receptor (nAChR) modulator JNJ-39393406 in a key translational assay (sensory P50 gating) in 39 regularly smoking male patients with schizophrenia. All patients were clinically stable and JNJ-39393406 was administered as an adjunct treatment to antipsychotics. No indication was found that JNJ-39393406 has the potential to reverse basic deficits of information processing in schizophrenia (sensory P50 gating) or has a significant effect on other tested electrophysiological markers (MMN, P300 and quantitative resting EEG). Sensitivity analyses including severity of disease, baseline P50 gating, medication and gene variants of the CHRNA7 gene did not reveal any subgroups with consistent significant effects. It is discussed that potential positive effects in subgroups not present or not large enough in the current study or upon chronic dosing are possible, but unlikely to be developed. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23389830 Contractile signaling pathways in mouse prostate smooth muscle. BACKGROUND: Prostate smooth muscle plays an important role in the physiological ejection of prostatic fluid and also in the pathogenesis of benign prostate hyperplasia. Although mouse is the best genetically engineered animal model to identify potential molecular targets for human diseases, only fragmentary information is available for basic mechanism of mouse prostate contraction. METHODS: Small smooth muscle tubular rings were excised from four mouse prostate lobes to measure their isometric contractions. High K(+) , noradrenaline (NA), or acetylcholine (ACh) was applied with and without various antagonists and/or inhibitors to examine the contractile signaling pathways. RESULTS: Maximum amplitude of agonist-induced contractions varied greatly with different lobes but not with different locations or orientations within each lobe. Both NA and ACh produced large contractions in ventral and dorsal rings, whereas only small contractions were elicited in lateral and anterior rings. Combination of alpha-1 and muscarinic antagonists suppressed K(+) depolarization-induced contraction potently in ventral rings, but slightly in anterior rings. Blocking of either Ca(2+) -release or Ca(2+) -influx reduced agonist-induced contraction of ventral rings, however, a considerable amount of contractility remained even with both blockers. Inhibitors of ROCK and PKC partially inhibited NA-induced contractions, whereas a combination of Ca(2+) -blockers and Ca(2+) -sensitization inhibitors strongly suppressed the contraction. CONCLUSIONS: The ejection of prostatic fluid is differentially regulated in each prostate lobe. In ventral prostate smooth muscle, Ca(2+) -release, Ca(2+) -influx, and ROCK- and PKC-mediated Ca(2+) -sensitizations are all involved in NA-induced contractions. This finding is a useful step toward the understanding of the phenotypic changes in the smooth muscle of BPH prostate. Prostate © 2013 Wiley Periodicals, Inc. 23282083 Aaptamine derivatives from the Indonesian sponge Aaptos suberitoides. Four new aaptamine derivatives (1-4) along with aaptamine (5) and three related compounds (6-8) were isolated from the ethanol extract of the sponge Aaptos suberitoides collected in Indonesia. The structures of the new compounds were unambiguously determined by one- and two-dimensional NMR and by HRESIMS measurements. Compounds 3, 5, and 6 showed cytotoxic activity against the murine lymphoma L5178Y cell line, with IC(50) values ranging from 0.9 to 8.3 μM. 23572394 Ameliorative effect of lycopene against 2,3,7,8-tetrachlorodibenzo-pdioxin- induced rat liver microsomal toxicity: An in vitro study. The objective of the current study was to investigate the potential oxidative damage of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in hepatic microsomal fractions in vitro and to further elucidate the potential modulatory effect of lycopene. Rat liver microsomes were divided into four groups. Group I served as a control and is incubated with vehicle (toluene). Groups II and IV were incubated with 20 µM lycopene for 1 h before further incubating; groups III and IV with 15 nM of TCDD for further 1 h. Hydrogen peroxide (H2O2) production, lipid peroxidation (LPO), protein carbonyl content and activities of uridine 5'-diphospho-glucuronyltransferase (UDPGT) and P450 were significantly increased. Moreover, the activity of antioxidant enzymes superoxide dismutase, glutathione peroxidase, catalse, glutathione-S-transferase and glutathione reductase as well as the microsomal thiol content were significantly decreased. Incubation with lycopene (group IV) maintained near normal activities of the enzymes, normalized thiol and carbonyl content and significantly reduced LPO and H2O2 production. In conclusion, the findings of the study indicate that TCDD induces a significant oxidative stress in liver microsomes as manifested by increased LPO, H2O2 production, protein carbonyl content and activities of UDPGT and P450 and decreased antioxidant enzymes activities and thiol content. By the reversal of biochemical and oxidative markers toward normalcy, the protective role of lycopene is illuminated in rat liver microsomal toxicity. 23532843 Tryptophan residue at active-site tunnel entrance of Trichoderma reesei cellobiohydrolase Cel7A is important to initiate degradation of crystalline cellulose. Glycoside hydrolase family-7 cellobiohydrolase from Trichoderma reesei (TrCel7A) is one of the best-studied cellulases with the ability to degrade highly crystalline cellulose (HCC). The catalytic domain (cat) and cellulose-binding domain (CBD) are both necessary for full activity on crystalline substrates. Our previous high-speed AFM studies showed that mutation of tryptophan residue (Trp40; W40) at the entrance of the catalytic tunnel drastically decreases the ability to degrade crystalline cellulose. Here, we examined the activities of the wild-type (WT) enzyme and tryptophan to alanine mutant (W40A) enzyme, with and without the CBD, towards various substrates. Evaluation and comparison of the specific activities of the enzymes (WT, WTcat, W40A, and W40Acat) adsorbed on crystalline cellulose indicated that Trp40 is involved in recruiting individual substrate chains into the active site tunnel to initiate processive hydrolysis. This idea was supported by molecular dynamics simulation study, i.e., the reducing-end glucose unit was effectively loaded into the active site of WTcat, but not into that of W40Acat. when the simulation was started from subsite -7. However, when the similar simulations were carried out starting from subsite -5, both enzymes hold the substrate in 50 ns, indicating that the major difference between WTcat and W40Acat is the length of free chain-end of the substrate required to allow initiation of processive movements; this also reflects the difference between crystalline and amorphous celluloses. The CBD is important for enhancing the enzyme population on crystalline substrate, but it also decreases the specific activity of the adsorbed enzyme, possibly by attaching the enzyme to non-optimal places on cellulose surface and/or hindering processive hydrolysis. 23644598 CENP-A confers a reduction in height on octameric nucleosomes. Nucleosomes with histone H3 replaced by CENP-A direct kinetochore assembly. CENP-A nucleosomes from human and Drosophila have been reported to have reduced heights as compared to canonical octameric H3 nucleosomes, thus suggesting a unique tetrameric hemisomal composition. We demonstrate that octameric CENP-A nucleosomes assembled in vitro exhibit reduced heights, indicating that they are physically distinct from H3 nucleosomes and negating the need to invoke the presence of hemisomes. 23477482 Secondary Metabolites of Capsicum Species and Their Importance in the Human Diet. The genus Capsicum (pepper) comprises a large number of wild and cultivated species. The plants are grown all over the world, primarily in tropical and subtropical countries. The fruits are an excellent source of health-related compounds, such as ascorbic acid (vitamin C), carotenoids (provitamin A), tocopherols (vitamin E), flavonoids, and capsaicinoids. Pepper fruits have been used for fresh and cooked consumption, as well as for medicinal purposes, such as treatment of asthma, coughs, sore throats, and toothache. Depending on its uses, there are several main characters important for product quality; pungency, bright attractive colors, highly concentrated extracts, and a small number of seeds are the main characters on which quality is based and priced. Herein, a general overview of biochemical composition, medical properties of these compounds, and characteristics of quality attributes of pepper fruits is presented. 23322558 Associations between perfluoroalkyl compounds and immune and clinical chemistry parameters in highly exposed bottlenose dolphins (Tursiops truncatus). Perfluoroalkyl compounds (PFCs) are ubiquitous, persistent chemical contaminants found in the environment, wildlife, and humans. Despite the widespread occurrence of PFCs, little is known about the impact these contaminants have on the health of wildlife populations. The authors investigated the relationship between PFCs (including ∑perfluorocarboxylates, ∑perfluoroalkyl sulfonates, perfluorooctane sulfonate, perfluorooctanoic acid, and perfluorodecanoic acid) and the clinocopathologic and immune parameters in a highly exposed population (n = 79) of Atlantic bottlenose dolphins (mean ∑PFCs = 1970 ng/ml; range 574-8670 ng/ml) sampled from 2003 to 2005 near Charleston, South Carolina, USA. Age-adjusted linear regression models showed statistically significant positive associations between exposure to one or more of the PFC totals and/or individual analytes and the following immunological parameters: absolute numbers of CD2+ T cells, CD4+ helper T cells, CD19+ immature B cells, CD21+ mature B cells, CD2/CD21 ratio, MHCII+ cells, B cell proliferation, serum IgG1, granulocytic, and monocytic phagocytosis. Several PFC analyte groups were also positively associated with serum alanine aminotransferase, gamma-glutamyltransferase, creatinine, phosphorus, amylase, and anion gap and negatively associated with cholesterol levels, creatinine phosphokinase, eosinophils, and monocytes. Based on these relationships, the authors suggest that the PFC concentrations found in Charleston dolphins may have effects on immune, hematopoietic, kidney, and liver function. The results contribute to the emerging data on PFC health effects in this first study to describe associations between PFCs and health parameters in dolphins. 23289528 Aβ interacts with both the iron center and the porphyrin ring of heme: mechanism of heme's action on Aβ aggregation and disaggregation. Amyloid β peptide (Aβ) aggregation is a pathological hallmark of Alzheimer's disease (AD). Modulation of the self-assembly processes, therefore, is thought to be an attractive strategy for the prevention and treatment of AD. Interestingly, heme has been found to inhibit Aβ aggregation and even dismantle Aβ aggregates. However, the mechanism remains unresolved. Recent research has shown that heme binds preferentially to the His(13) residue of Aβ with the iron center, while the hydrophobic domain of Aβ is also able to bind to heme. Herein, absorption spectrometric, Thioflavin T fluorescence, and circular dichroism spectroscopic and transmission electron microscopic measurements revealed that the iron center is not required for the inhibition of Aβ aggregation but do influence the binding affinity of heme toward Aβ and the dismantlement rate and degree of the Aβ aggregates. By studying the interaction of different truncated or mutated Aβ peptides with heme or protoporphyrin, we further found that the porphyrin ring of heme is implicated to interact preferentially with the Phe(19) residue, facilitating the binding of heme to Aβ and disturbing the interstrand aromatic interaction between the Phe residues, which is crucial for Aβ fibrillation. These findings open new avenues in the understanding of the interaction between the heme and Aβ and the pathways for modulation of Aβ aggregation and disaggregation, which would be helpful in designing therapeutic strategies against AD. 23265471 Exploration of Vanilla pompona from the Peruvian Amazon as a potential source of vanilla essence: quantification of phenolics by HPLC-DAD. This study provides the first chemical investigation of wild-harvested fruits of Vanilla pompona ssp. grandiflora (Lindl.) Soto-Arenas developed in their natural habitat in the Peruvian Amazon. Flowers were hand-pollinated and the resulting fruits were analysed at different developmental stages using an HPLC-DAD method validated for the quantification of glucovanillin and seven other compounds. The method showed satisfactory linearity (r(2)>0.9969), precision (coefficient of variation <2%), recoveries (70-100%), limit of detection (0.008-0.212 μg/ml), and limit of quantification (0.027-0.707 μg/ml). The evaluation of crude and enzyme-hydrolyzed Soxhlet-extracted samples confirmed the leading role of glucosides in fruit development. LC-ESI-MS studies corroborated the identities of four glucosides and seven aglycones, among them vanillin (5.7/100 g), 4-hydroxybenzyl alcohol (3.6/100 g), and anisyl alcohol (7.1/100 g) were found in high concentrations. The attractive flavor/aroma profile exhibited by wild V. pompona fruits supports studies focused on the development of this species as a specialty crop. 23450164 The gas-phase reaction of methane sulfonic acid with the hydroxyl radical without and with water vapor. The gas phase reaction between methane sulfonic acid (CH3SO3H; MSA) and the hydroxyl radical (HO), without and with a water molecule, was investigated with DFT-B3LYP and CCSD(T)-F12 methods. For the bare reaction we have found two reaction mechanisms, involving proton coupled electron transfer and hydrogen atom transfer processes that produce CH3SO3 and H2O. We also found a third reaction mechanism involving the double proton transfer process, where the products and reactants are identical. The computed rate constant for the oxidation process is 8.3 × 10(-15) cm(3) s(-1) molecule(-1). CH3SO3H forms two very stable complexes with water with computed binding energies of about 10 kcal mol(-1). The presence of a single water molecule makes the reaction between CH3SO3H and HO much more complex, introducing a new reaction that consists in the interchange of H2O between HO and CH3SO3H. Our kinetic calculations show that 99.5% of the reaction involves this interchange of the water molecule and, consequently, water vapor does not play any role in the oxidation reaction of methane sulfonic acid by the hydroxyl radical. 23439479 Biosafety and antioxidant effects of a beverage containing silymarin and arginine. A pilot, human intervention cross-over trial. The study objective was to investigate the potential of a beverage containing silymarin and l-arginine to alter basic physiological and urodynamic parameters in 22 normal healthy men aged 38-59years. The volunteers drank 500ml/day beverage without silymarin and l-arginine for 10days followed, after a 7-day washout period, by the beverage with 400mg silymarin and 295mg l-arginine for 10days. Blood and urine samples were collected on days 0, 10 and 27. The beverages were well-tolerated with no adverse effects. Most of the biochemical, hematological and urodynamic parameters remained unchanged. Total antioxidant capacity, total level of antioxidants, lipoperoxidation products (malondialdehyde), advanced oxidation products of proteins in plasma and glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase levels in erythrocytes were not influenced. Serum γ-glutamyl transferase, malondialdehyde level and activity of glutathione S-transferase in erythrocytes were lowered at day 27 and the concentration of total plasma SH-groups was higher on day 10. Using an ex vivo system, we found that silymarin/silybin at 10-100μM is able to adsorb onto human erythrocytes and the complexes displayed antioxidant properties as studied using ex situ square-wave voltammetry. The trial showed that silymarin in vivo may protect erythrocytes against oxidative damage. 23524881 Ophthalmic findings in acute mercury poisoning in adults: A case series study. The aim of this study is to report ophthalmic findings of acute mercury poisoning in 48 adults referred to emergency department. Full ophthalmologic examination including the best corrected visual acuity, external eye examination, reaction to light, a slit-lamp examination, funduscopy, intraocular pressure measurements, and visual field (VF) and color vision (CV) tests were performed at the presentation and repeated after 6 months. The parametric values of VF test, the mean deviation (MD), and pattern standard deviation (PSD) were recorded in order to compare patients and the 30 healthy controls. The mean parameter of color confusion index in patients was found to be statistically different than controls (p < 0.01). The MD and PSD in patients were different from controls statistically significant (p < 0.01 and p < 0.01, respectively). There was no correlation between the ocular findings and the urine and blood mercury levels. Methyl mercury, held in the school laboratory for experimental purpose, may be a source of poisoning. In this case series, we showed that acute exposure to mercury had hazardous effect on the visual system, especially CV and VF. We propose that emphasizing the public education on the potential hazards of mercury is crucial for preventive community health. 22902968 An appeal for the presentation of detailed human derived data for dose-response calculations in nutritional science. If a diet, food or food constituent is recognised to have both health benefits and health risks, the benefits have to be compared with the risks to develop coherent scientific evidence-based dietary advice. This means that both risk and benefit assessment should follow a similar paradigm and that benefits and risks are expressed in a common currency. Dose-response functions are vital for that purpose. However, the construction of these functions is often of second interest in the currently available (epidemiological) literature. In order to bring forward the potential of epidemiological studies for the construction of the dose-response functions for benefit-risk purposes, the scientific (nutrition and health) community is asked to expand on their data presentation, either by presenting more detailed data focusing on dose-response necessities, and/or by sharing primary data. 23103569 Biology and therapeutic potential of hydrogen sulfide and hydrogen sulfide-releasing chimeras. Hydrogen sulfide, H2S, is a colorless gas with a strong odor that until recently was only considered to be a toxic environmental pollutant with little or no physiological significance. However, the past few years have demonstrated its role in many biological systems and it is becoming increasingly clear that H2S is likely to join nitric oxide (NO) and carbon monoxide (CO) as a major player in mammalian biology. In this review, we have provided an overview of the chemistry and biology of H2S and have summarized the chemistry and biological activity of some natural and synthetic H2S-donating compounds. The naturally occurring compounds discussed include, garlic, sulforaphane, erucin, and iberin. The synthetic H2S donors reviewed include, GYY4137; cysteine analogs; S-propyl cysteine, S-allyl cysteine, S-propargyl cysteine, and N-acetyl cysteine. Dithiolethione and its NSAID and other chimeras such as, L-DOPA, sildenafil, aspirin, diclofenac, naproxen, ibuprofen, indomethacin, and mesalamine have also been reviewed in detail. The newly reported NOSH-aspirin that releases both NO and H2S has also been discussed. 23642089 A Minimal Transcriptional Controlling Network of Regulatory T Cell Development. Regulatory T cells (Treg) are a subpopulation of T cells that are central to immune homeostasis and develop under the control of a complex regulatory network consisting of FoxP3 and its partner factors. A central question about this network is how does it enable T cells to robustly specify and stably maintain their states despite intrinsic and environmental fluctuations. Inspired by recent experimental advances, we propose here a minimal transcriptional controlling network and use it to illustrate the robustness and dynamic features of Treg development. Our study shows that the controlling network may exhibit distinct dynamics depending on its parameter regimes and that the maintenance of multistability requires the orchestration of both its positive and negative feedback loops. In addition, system volume contributes monotonically to the increase of the network's robustness. We further show that the dynamics of our model varies with the alteration of FoxP3-DNA binding affinity, consistent with recent experimental findings. This minimal model thereby offers new insights into the dynamics and robustness of Treg development and may serve as a platform for future exploration towards a more quantitative and systematic understanding of the immune system. 23531213 Murabutide revisited: a review of its pleiotropic biological effects. Despite the great efforts put into their development, the list of clinically approved immunological adjuvants is still very short. Evolution of the knowledge of the immune system has enabled for rational design of novel adjuvants and has led to the conclusion that more than one type of adjuvant will be required. Derivatives of muramyl dipeptide (MDP), the minimal immunomodulatory structure of bacterial cell wall peptidoglycan, have gained considerable attention in the past decades, because of their potent adjuvant effects. Murabutide is a safe derivative of MDP, which interacts with cells of the immune system, both innate and adaptive, and exerts its effect through activation of Nod2. The transcriptional response of murabutide-stimulated macrophages revealed enhanced expression of genes coding for various proteins such as immune mediators and their receptors, transcription factors and kinases, ion channels/transporters and proteins involved in cell metabolic activity, thus reflecting a broad spectrum of biological effects. In addition to its well recognized adjuvant effect, murabutide has also been shown to enhance the host's resistance against microbial infections, nonspecific resistance against tumors and the induction of cytokines and chemokines implicated in enhancing the immune response and hematopoesis. This article provides an insight into the mechanism of action of murabutide and its interactions with the cells of the immune system in vitro and in vivo. On account of its numerous biological effects, murabutide has been the subject of several clinical studies. Many of these have confirmed its potential to synergize with cytokines of therapeutic interest in potentiating the tumoricidal activity of macrophages or targeting chronic viral diseases, as well as reducing the cytokine dosage needed to achieve a therapeutic effect. This review covers the findings of all relevant studies and focuses on the role of murabutide and its potential in the treatment of several microbial diseases. 23265523 Effect of cooking and germination on phenolic composition and biological properties of dark beans (Phaseolus vulgaris L.). Legumes are the basés diet in several countries. They hold a high nutritional value, but other properties related to human health are nowadays being studied. The aim of this work was to study the influence of processes (boiling or germination) on the phenolic composition of dark beans (Phaseolus vulgaris L. c.v. Tolosana) and their effect on their antioxidant, neuroprotective and anticancer ability. Phenolic composition of raw and processed dark beans was analysed by HPLC-PAD and HPLC-ESI/MS. The antioxidant activity was evaluated by ORAC. Astrocytes cultures (U-373) have been used to test their neuroprotective effect. Anticancer activities were evaluated on three different cell lines (renal adenocarcinoma (TK-10), breast adenocarcinoma (MCF-7) and melanoma (UACC-62)) by sulphorhodamine B method. Qualitative and quantitative differences in phenolic composition have been observed between raw and processed dark beans that influence the antioxidant activity, mainly for germinated samples which show a decrease of antioxidant capacity. Although every assayed extracts decreased reactive oxygen species release and exhibited cytotoxicity activities on cancer cell lines, raw beans proved to be the most active in neuroprotective and antitumoral effects; this sample is especially rich in phenolic compounds, mainly anthocyanins. This study further demonstrated that phenolic composition of dark beans is related with cooking process and so with their neuroprotective and anticancer activity; cooking of dark beans improves their digestion and absorption at intestinal level, while maintaining its protective ability on oxidative process at cellular level. 23452060 Interplay between BDF1 and BDF2 and their roles in regulating the yeast salt stress response. The homologous genes BDF1 and BDF2 in Saccharomyces cerevisiae encode bromodomain-containing transcription factors. Although double deletion of BDF1 and BDF2 is lethal, single deletion does not affect cell viability. The bdf2∆ cells showed normal growth upon salt stress. However, the absence of Bdf1p resulted in a salt-sensitive phenotype, and the salt sensitivity was suppressed by overexpression of BDF2. In this study, we further demonstrated that BDF2 shows dosage compensation in suppressing the salt sensitivity of bdf1∆. None of the tested domains replaced the function of intact Bdf1p. The 494-626 region in Bdf1p was more important than the other domains for salt resistance. In addition, Bdf1p negatively regulated the expression of BDF2 by binding its promoter at loci -387 to -48. However, Bdf2p did not affect the expression of BDF1. In addition, Bdf1p and its defective functional domain mutants could combine with Bdf2p. This physical interaction increased the salt tolerance of bdf1∆. The mitochondrial dysfunctions caused by BDF1 deletion were restored by overexpression of BDF2 under salt stress conditions. STRUCTURED DIGITAL ABSTRACT: BDF2 physically interacts with BDF1 by anti tag coimmunoprecipitation (View interaction) BDF2 physically interacts with BDF1 by pull down (View interaction). 23441102 Mussel-inspired histidine-based transient network metal coordination hydrogels. Transient network hydrogels cross-linked through histidine-divalent cation coordination bonds were studied by conventional rheologic methods using histidine-modified star poly(ethylene glycol) (PEG) polymers. These materials were inspired by the mussel, which is thought to use histidine-metal coordination bonds to impart self-healing properties in the mussel byssal thread. Hydrogel viscoelastic mechanical properties were studied as a function of metal, pH, concentration, and ionic strength. The equilibrium metal-binding constants were determined by dilute solution potentiometric titration of monofunctional histidine-modified methoxy-PEG and were found to be consistent with binding constants of small molecule analogs previously studied. pH-dependent speciation curves were then calculated using the equilibrium constants determined by potentiometric titration, providing insight into the pH dependence of histidine-metal ion coordination and guiding the design of metal coordination hydrogels. Gel relaxation dynamics were found to be uncorrelated with the equilibrium constants measured, but were correlated to the expected coordination bond dissociation rate constants. 23561117 Characteristics and antioxidant activity of water-soluble Maillard reaction products from interactions in a whey protein isolate and sugars system. The objective of this study was to determine antioxidant activities of water-soluble MRPs (Maillard reaction products) from the reactions between whey protein isolate (WPI) and xylose (X), glucose (G), fructose (F), lactose (L), maltose (M) and sucrose (S) at different initial pH values (3, 4, 5, 6, 7, 8 and 9). MRPs derived from the WPI-X system with increasing of pH rendered the highest browning, reducing power and DPPH radical-scavenging activity. SDS-PAGE analyses indicated formation of cross-linked proteins of large molecular mass produced from WPI-X systems. Results of FT-IR analysis indicated that the amide I, II and III bands of WPI from the WPI-X and WPI-G systems were changed by the Maillard reaction. CD spectroscopy showed that β-sheet, β-turns and random coil were increased while the α-helix was decreased after the WPI-G and WPI-X system aqueous solutions were heated. In conclusion, MRPs obtained from the WPI-X system had high antioxidant activity. 23627649 Combinatorial Growth and Anisotropy Control of Self-Assembled Epitaxial Ultrathin Alloy Nanowires. Self-assembled vertical epitaxial nanostructures form a new class of heterostructured materials that has emerged in recent years. Interestingly, such kind of architectures can be grown using combinatorial processes, implying sequential deposition of distinct materials. Although opening many perspectives, this combinatorial nature has not been fully exploited yet. This work demonstrates that the combinatorial character of the growth can be further exploited in order to obtain alloy nanowires coherently embedded in a matrix. This issue is illustrated in the case of a fully epitaxial system: CoxNi1-x nanowires in CeO2/SrTiO3(001). The advantage brought by the ability to grow alloys is illustrated by the control of the magnetic anisotropy of the nanowires when passing from pure Ni wires to CoxNi1-x alloys. Further exploitation of this combinatorial approach may pave the way toward full three-dimensional heteroepitaxial architectures through axial structuring of the wires. 23362135 Tumor localization and biochemical response to cure in tumor-induced osteomalacia. Tumor-induced osteomalacia (TIO) is a rare disorder of phosphate wasting due to fibroblast growth factor-23 (FGF23)-secreting tumors that are often difficult to locate. We present a systematic approach to tumor localization and post-operative biochemical changes in 31 subjects with TIO. All had failed either initial, or re-localization (in case of recurrence or metastases at outside institutions). Functional imaging with (111) Indium- octreotide with single photon emission computed tomography (octreo-SPECT or SPECT/CT), and (18) fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) were performed, followed by anatomic imaging (CT,MRI). Selective venous sampling (VS) was performed when multiple suspicious lesions were identified or high surgical risk was a concern. Tumors were localized in 20/31 subjects (64.5%). Nineteen of 20 subjects underwent octreo-SPECT imaging, and 16/20 FDG-PET/CT imaging. Eighteen of 19 (95%) were positive on octreo-SPECT, and 14/16 (88%) on FDG-PET/CT. Twelve of 20 subjects underwent VS; 10/12 (83%) were positive. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were: sensitivity=0.95, specificity=0.64, PPV=0.82 and NPV=0.88 for octreo-SPECT; sensitivity=0.88, specificity=0.36, PPV=0.62 and NPV=0.50 for FDG-PET/CT. Fifteen subjects had their tumor resected at our institution, and were disease-free at last follow-up. Serum phosphorus returned to normal in all subjects within 1-5 days. In 10 subjects who were followed for at least 7 days postoperatively, intact FGF23 (iFGF23) decreased to near undetectable within hours and returned to the normal range within 5 days. C-terminal FGF23 (cFGF23) decreased immediately but remained elevated, yielding a markedly elevated cFGF23/iFGF23 ratio. Serum 1,25-dihydroxyvitamin D(3) (1,25D) rose and exceeded the normal range. In this systematic approach to TIO tumor localization Octreo-SPECT was more sensitive and specific, but in many cases FDG-PET/CT was complementary. VS can discriminate between multiple suspicious lesions and increase certainty prior to surgery. Sustained elevations in cFGF23 and 1,25D were observed, suggesting novel regulation of FGF23 processing and 1,25D generation. © 2013 American Society for Bone and Mineral Research. 23606457 A Tunable Spherical Cap Microfluidic Electrically Small Antenna. A highly efficient microfluidic 3D electrically small antenna is created using a simple fabrication technique. It is easy to construct simply by pneumatically inflating a planar microfluidic antenna into a spherical cap. It has premium performance around its hemispherical shape, combining a wide working band with high efficiency. 23122331 NMR structure and dynamics of the C-terminal domain of R-type lectin from the earthworm Lumbricus terrestris. The C-terminal domain (Ch; C-half) of the R-type earthworm 29-kDa lectin (EW29), isolated from the earthworm Lumbricus terrestris, has two sugar-binding sites, in subdomains α and γ, and the protein uses the two sugar-binding sites for its function as a single domain-type haemagglutinin. Our previous NMR titration experiments showed that the α sugar-binding site is a high-affinity site and the γ sugar-binding site is a low-affinity site. However, it remains unclear why the α sugar-binding site of EW29Ch binds to lactose much more strongly because the crystal structure of lactose-bound EW29Ch showed that the interaction between the α sugar-binding site and lactose was almost same as that between the γ sugar-binding site and lactose. In the present study, we have determined the NMR structure of EW29Ch in the sugar-free state and performed (15)N relaxation experiments for EW29Ch in both the sugar-free state and the lactose-bound states. The conformation of EW29Ch in the sugar-free state was similar to that of EW29Ch in complex with lactose. Conformational changes upon binding of lactose were observed only for the α sugar-binding site. By contrast, the (15)N relaxation experiments revealed a conformational exchange at the α sugar-binding site in the sugar-free state, which was suppressed in the lactose-bound state. The conformational exchange phenomenon observed for the α sugar-binding site was not observed for the γ sugar-binding site. Differences in the conformational change and the backbone dynamics between subdomains α and γ may be associated with the difference of the sugar-binding modes between the two sugar-binding sites. DATABASE: Structural data for the NMR structure of EW29Ch in the sugar-free state have been deposited in the Protein Data Bank database under accession number 2RST. 23411241 Compositional characterisation of soluble apple polysaccharides, and their antioxidant and hepatoprotective effects on acute CCl4-caused liver damage in mice. Water-soluble apple peel polysaccharides (APP) and apple flesh polysaccharides (AFP) were isolated from Pink Lady fruits, and their in vitro antioxidant capacities were characterised by DPPH(), HO(), and O(2)(-) systems, and ferric-reducing antioxidant power assay. Oral administration of APP at 250 and 500 mg/kg bw in mice was shown to be as effective as AFP in lowering the CCl(4)-caused increases of serum alanine aminotransferase, aspartate aminotransferase and lactic dehydrogenase activities, and hepatic malondialdehyde level, and antagonising the decreases in antioxidant superoxide dismutase and glutathione peroxidase activities caused by CCl(4) (p<0.05). Histopathological examinations further confirmed that both APP and AFP could protect the liver from CCl(4)-induced histological alteration. HPLC analysis also showed similar profiles of monosaccharide composition for APP and AFP with arabinose, galactose and galacturonic acid being main component monosaccharides. All of these findings demonstrate that the extracts of both APP and AFP possess antioxidant and hepatoprotective potential. 23619020 The anti-cancer activity of Antrodia camphorata against human ovarian carcinoma (SKOV-3) cells via modulation of HER-2/neu signaling pathway. ETHNOPHARMACOLOGICAL RELEVANCE: Antrodia camphorata (AC) is well known in Taiwan as a traditional Chinese medicinal fungus. However, the anticancer activity of AC against human HER-2/neu-overexpressing ovarian cancers is poorly understood. MATERIALS AND METHODS: The aim of this study is to investigate whether a submerged fermentation culture of AC can inhibit human ovarian carcinoma cell (SKOV-3) proliferation by suppressing the HER-2/neu signaling pathway. Cell viability, colony formation, DCFH-DA fluorescence microscopy, western blotting, HER-2/neu immunofluorescence imaging, flow cytometry, and TUNEL assays were carried out to determine the anti-cancer effects of AC. RESULTS: MTT and colony formation assays showed that AC induced a dose-dependent reduction in SKOV-3 cell growth. Immunoblot analysis demonstrated that HER-2/neu activity and tyrosine phosphorylation were significantly inhibited by AC. Furthermore, AC treatment significantly inhibited the activation of PI3K/Akt and their downstream effector β-catenin. We also observed that AC caused G2/M arrest mediated by down-regulation of cyclin D1, cyclin A, cyclin B1, and Cdk1 and increased p27 expression. Notably, AC induced apoptosis, which was associated with DNA fragmentation, cytochrome c release, caspase-9/-3 activation, PARP degradation, and Bcl-2/Bax dysregulation. An increase in intracellular reactive oxygen species (ROS) was observed in AC-treated cells, whereas the antioxidant N-acetylcysteine (NAC) prevented AC-induced cell death, HER-2/neu depletion, PI3K/Akt inactivation, and Bcl-2/Bax dysregulation, indicating that AC-induced cell death was mediated by ROS generation. CONCLUSIONS: These results suggest that AC may exert anti-tumor activity against human ovarian carcinoma by suppressing HER-2/neu signaling pathways. 23223020 Hepatic glucose metabolism in late pregnancy: normal versus high-fat and -fructose diet. Net hepatic glucose uptake (NHGU) is an important contributor to postprandial glycemic control. We hypothesized that NHGU is reduced during normal pregnancy and in a pregnant diet-induced model of impaired glucose intolerance/gestational diabetes mellitus (IGT/GDM). Dogs (n = 7 per group) that were nonpregnant (N), normal pregnant (P), or pregnant with IGT/GDM (pregnant dogs fed a high-fat and -fructose diet [P-HFF]) underwent a hyperinsulinemic-hyperglycemic clamp with intraportal glucose infusion. Clamp period insulin, glucagon, and glucose concentrations and hepatic glucose loads did not differ among groups. The N dogs reached near-maximal NHGU rates within 30 min; mean ± SEM NHGU was 105 ± 9 µmol·100 g liver⁻¹·min⁻¹. The P and P-HFF dogs reached maximal NHGU in 90-120 min; their NHGU was blunted (68 ± 9 and 16 ± 17 µmol·100 g liver⁻¹·min⁻¹, respectively). Hepatic glycogen synthesis was reduced 20% in P versus N and 40% in P-HFF versus P dogs. This was associated with a reduction (>70%) in glycogen synthase activity in P-HFF versus P and increased glycogen phosphorylase (GP) activity in both P (1.7-fold greater than N) and P-HFF (1.8-fold greater than P) dogs. Thus, NHGU under conditions mimicking the postprandial state is delayed and suppressed in normal pregnancy, with concomitant reduction in glycogen storage. NHGU is further blunted in IGT/GDM. This likely contributes to postprandial hyperglycemia during pregnancy, with potential adverse outcomes for the fetus and mother. 23574049 Organic Solvent-Based Graphene Oxide Liquid Crystals: A Facile Route toward the Next Generation of Self-Assembled Layer-by-Layer Multifunctional 3D Architectures. We introduce soft self-assembly of ultralarge liquid crystalline (LC) graphene oxide (GO) sheets in a wide range of organic solvents overcoming the practical limitations imposed on LC GO processing in water. This expands the number of known solvents which can support amphiphilic self-assembly to ethanol, acetone, tetrahydrofuran, N-dimethylformamide, N-cyclohexyl-2-pyrrolidone, and a number of other organic solvents, many of which were not known to afford solvophobic self-assembly prior to this report. The LC behavior of the as-prepared GO sheets in organic solvents has enabled us to disperse and organize substantial amounts of aggregate-free single-walled carbon nanotubes (SWNTs, up to 10 wt %) without compromise in LC properties. The as-prepared LC GO-SWNT dispersions were employed to achieve self-assembled layer-by-layer multifunctional 3D hybrid architectures comprising SWNTs and GO with unrivalled superior mechanical properties (Young's modulus in excess of 50 GPa and tensile strength of more than 500 MPa). 23411286 Interaction between lysozyme and procyanidin: multilevel structural nature and effect of carbohydrates. The interaction of procyanidins with proteins has aroused extensive attention due to its important relationship with the bioavailability and astringent property of polyphenols. In the present work, we have investigated the interactions of lysozyme with procyanidin dimer (B3) using various biophysical approaches, which aims to provide insights into the mechanism of protein/polyphenol aggregation. Procyanidin B3 spontaneously binds lysozyme, inducing the multilevel structural changes in lysozyme and the formation of insoluble complexes. The relationship between lysozyme aggregation and the loss of enzymatic activity was monitored using dynamic light scattering and fluorescence quenching. The influences of two carbohydrates (gum arabic and sucrose) on lysozyme/B3 aggregation were also studied. Gum arabic effectively inhibited the formation of insoluble aggregates, but was unable to restore the fluorescence and activity of lysozyme. However, sucrose concomitantly decreased the aggregate size with the recovery of fluorescence and lysozyme activity. These results proposed two probable mechanisms by which these two carbohydrates inhibit protein/polyphenol aggregation. 23256531 Surfactant-Assisted Assembly of Fullerene (C(60)) Nanorods and Nanotubes Formed at a Liquid-Liquid Interface. Herein we report the surfactant-triggered assembly of fullerene (C(60)) into 3D flowerlike microcrystals at the liquid-liquid interface. C(60) crystals were grown using a liquid-liquid interfacial precipitation (LLIP) method by layering surfactant solution in butanol with a saturated solution of C(60) in benzene. In the LLIP method, it is suggested that the crystal formation mechanism is driven by supersaturation related to the low C(60) solubility in alcohol. We found that the dimensions of the synthesized C(60) flowers depend on the concentration and surfactant type. In the absence of surfactant (i.e., in the butanol/benzene system), 1D C(60) nanowhiskers (nanorods) and C(60) nanotubes (diameter 400 nm-2 μm and length 5-20 μm) are obtained. However, when surfactants are incorporated into the system flowerlike microcrystals consisting of C(60) nanotubes are observed. For instance, crystals grown at the interface of a 0.01% diglycerol monolaurate (C(12)G(2)) nonionic surfactant in butanol with benzene lead to the formation of flower-shaped microcrystals of average sizes in the range of 10-35 μm. To the best of our knowledge, this is the first example of the surfactant-assisted assembly of C(60) crystals. X-ray diffraction (XRD) and transmission electron microscopy (TEM) measurements have shown that fullerene flowers have a hexagonal structure with cell dimensions of a = 2.539 nm and c = 1.021 nm, which differ from that of pristine C(60). Mixtures of flower-shaped C(60) crystals and free-standing C(60) nanotubes are found in the 0.1% C(12)G(2)/butanol system. However, clusters or giant aggregates of nanowhiskers lacking any specific shape are observed in the 1% C(12)G(2)/butanol system although these crystals exhibit hexagonal close-packed structures. Flower-shaped C(60) microcrystals are also observed with anionic surfactants cetyltrimethylammonium bromide (CTAB) and cetyltrimethylammonium chloride (CTAC). C(60) flowers obtained from 0.01% CTAB and 0.01% CTAC also exhibit hexagonal structures with cell dimensions of a = 2.329 nm and c = 1.273 nm, a = 2.459 nm and c = 0.938 nm, respectively. Our C(60) flowers exhibit intense photoluminescence (PL) and a blue-shifted PL intensity maximum compared to the same parameters for pristine C(60), demonstrating the potential to control the optoelectronic properties of fullerene-based nanostructures. 22722027 Stimulation of serotonin 2A receptors facilitates consolidation and extinction of fear memory in C57BL/6J mice. Excessive fear is a hallmark of several emotional and mental disorders such as phobias and panic disorders. Considerable attention is focused on defining the neurobiological mechanisms of the extinction of conditioned fear memory in an effort to identify mechanisms that may hold clinical significance for remediating aberrant fear memory. Serotonin modulates the acquisition and retention of conditioned emotional memory, and the serotonin 2A receptor (5HT2AR) may be one of the postsynaptic targets mediating such effects. Here we tested the hypothesis that the 5HT2AR regulates the consolidation and extinction of fear memory in male C57BL/6J mice. The influence of 5HT2ARs on memory consolidation was further confirmed with a novel object recognition task. With a trace fear conditioning paradigm, administration of the 5HT2AR agonist TCB-2 (1.0 mg/kg, i.p.) before the extinction test facilitated the acquisition of extinction of fear memory as compared to vehicle treatment. In contrast, administration of the 5HT2AR antagonist MDL 11,939 (0.5 mg/kg, i.p.) delayed the acquisition of extinction of fear memory. Further, the post-conditioning administration of TCB-2 enhanced contextual and cued fear memory, possibly by facilitating the consolidation of fear memory. Administration of TCB-2 also facilitated the acquisition of extinction of fear memory in delay fear conditioned mice. Stimulation or blockade of 5HT2ARs did not affect the encoding or retrieval of conditioned fear memory. Finally, administration of TCB-2 right after training in an object recognition task enhanced the consolidation of object memory. These results suggest that stimulation of 5HT2ARs facilitates the consolidation and extinction of trace and delay cued fear memory and the consolidation of object memory. Blocking the 5HT2AR impairs the acquisition of fear memory extinction. The results support the view that serotonergic activation of the 5HT2AR provides an important modulatory influence on circuits engaged during extinction learning. Taken together these results suggest that the 5HT2AR may be a potential therapeutic target for enhancing hippocampal and amygdala-dependent memory. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23582408 The anti-diabetic effects and pharmacokinetic profiles of berberine in mice treated with Jiao-Tai-Wan and its compatibility. Jiao-Tai-Wan (JTW), a classical Chinese prescription, has been clinically employed to treat diabetes mellitus in recent years. To investigate the comparative evaluations on anti-diabetic effects and pharmacokinetics of the active ingredient berberine in mice treated with JTW in various combinations of its constituent herbs. In our study, the anti-diabetic study was carried out in diabetic mice induced by intraperitoneal injection of streptozotocin. The diabetic mice were randomly assigned to three therapy groups and orally administered with different prescription proportions of Rhizoma Coptidis and Cinnamomum cassia respectively. The level of plasma glucose, lipid profile and parameters related to oxidative stress were determined. The concentrations of berberine in non-diabetic mice plasma were determined using HPLC, and main pharmacokinetic parameters were investigated. The results indicated that the compatibility effects of ingredients present in Cinnamomum cassia could affect the anti-diabetic ability and pharmacokinetics of berberine in JTW. 22846850 Towards the use of hydrogels in the treatment of limbal stem cell deficiency. Corneal blindness caused by limbal stem cell deficiency (LSCD) is a prevailing disorder worldwide. Clinical outcomes for LSCD therapy using amniotic membrane (AM) are unpredictable. Hydrogels can eliminate limitations of standard therapy for LSCD, because they present all the advantages of AM (i.e. biocompatibility, inertness and a biodegradable structure) but unlike AM, they are structurally uniform and can be easily manipulated to alter mechanical and physical properties. Hydrogels can be delivered with minimum trauma to the ocular surface and do not require extensive serological screening before clinical application. The hydrogel structure is also amenable to modifications which direct stem cell fate. In this focussed review we highlight hydrogels as biomaterial substrates which may replace and/or complement AM in the treatment of LSCD. 23461628 (+)-Laburnamine, a Natural Selective Ligand and Partial Agonist for the α4β2 Nicotinic Receptor Subtype. (+)-Laburnamine (1), a rare alkaloid extracted from Laburnum anagyroides seeds (∼4 mg from 1 kg), was shown to bind with high affinity (Ki, 293 nM) to the α4β2 nicotinic receptor subtype, which is, respectively, 126 and 136 times higher than to the α3β4 (Ki 37 μM) and α7 subtypes (Ki 40 μM). When its ability to release [(3)H]-dopamine from striatal slices was tested in a functional assay, compound 1 behaved as a partial agonist with an EC50 of 5.8 μM and an Emax that was 43% that of nicotine. When incubated with nicotine in the same assay, 1 prevented a maximal effect from being reached. 23194546 Screening of whey protein isolate hydrolysates for their dual functionality: influence of heat pre-treatment and enzyme specificity. Heat pre-treated and non heat pre-treated whey protein isolate (WPI) were hydrolysed using α-chymotrypsin (chymotrypsin), pepsin and trypsin. The in vitro antioxidant activity, ACE-inhibition activity and surface hydrophobicities of the hydrolysates were measured in order to determine if peptides with dual functionalities were present. Dual functional peptides have both biological (e.g. antioxidant, ACE-inhibition, opioid activities) and technological (e.g. nanoemulsification abilities) functions in food systems. Heat pre-treatment marginally enhanced the hydrolysis of WPI by pepsin and trypsin but had no effect on WPI hydrolysis with chymotrypsin. With the exception of the hydrolysis by trypsin, heat pre-treatment did not affect the peptide profile of the hydrolysates as analysed using size exclusion chromatography, or the antioxidant activity (P>0.05). Heat pre-treatment significantly affected the ACE-inhibition activities and the surface hydrophobicities of the hydrolysates (P<0.05), which was a function of the specificity of the hydrolysing enzyme. Extended hydrolysis (up to 24 h) had no significant effect on the DH and the molecular weight profiles (P>0.05) but in some instances caused a reduction in the antioxidant activity of WPI hydrolysates. The chymotrypsin hydrolysate showed a broad MW size range, and was followed by pepsin and then trypsin. The bioactivities of the hydrolysates generally decreased in the order; chymotrypsin>trypsin>pepsin. This study showed that by manipulating protein conformation with pre-hydrolysis heat treatment, combined with careful enzyme selection, peptides with dual functionalities can be produced from WPI for use as functional ingredients in the manufacture of functional foods. 23265473 Development of sample preparation method for isoliquiritigenin, liquiritin, and glycyrrhizic acid analysis in licorice by ionic liquids-ultrasound based extraction and high-performance liquid chromatography detection. An ionic liquid-based ultrasonic-assisted extraction (ILUAE) method had been used for the effective extraction of isoliquiritigenin (IQ), liquiritin (LQ) and glycyrrhizic acid (GA) from licorice. The ionic liquids with different cations and anions were investigated in this work and 0.5 M 1-butyl-3-methylimidazolium bromide solution was selected as solvent. In addition, the technical parameters including soaking time, solid-liquid ratio, ultrasonic power and time were optimized. Compared with the conventional solvent extraction, the proposed approach exhibited higher efficiency, which indicated the ILUAE was an efficient, rapid and simple sample preparation technique. There was no degradation of the target analytes had been observed at the optimum conditions which was evidenced by the stability studies performed with standard of IQ, LQ and GA. The proposed method also showed high reproducibility and was environmental friendly. 23245699 Cockayne syndrome b maintains neural precursor function. Neurodevelopmental defects are observed in the hereditary disorder Cockayne syndrome (CS). The gene most frequently mutated in CS, Cockayne Syndrome B (CSB), is required for the repair of bulky DNA adducts in transcribed genes during transcription-coupled nucleotide excision repair. CSB also plays a role in chromatin remodeling and mitochondrial function. The role of CSB in neural development is poorly understood. Here we report that the abundance of neural progenitors is normal in Csb(-/-) mice and the frequency of apoptotic cells in the neurogenic niche of the adult subependymal zone is similar in Csb(-/-) and wild type mice. Both embryonic and adult Csb(-/-) neural precursors exhibited defective self-renewal in the neurosphere assay. In Csb(-/-) neural precursors, self-renewal progressively decreased in serially passaged neurospheres. The data also indicate that Csb and the nucleotide excision repair protein Xpa preserve embryonic neural stem cell self-renewal after UV DNA damage. Although Csb(-/-) neural precursors do not exhibit altered neuronal lineage commitment after low-dose UV (1J/m(2)) in vitro, neurons differentiated in vitro from Csb(-/-) neural precursors that had been irradiated with 1J/m(2) UV exhibited defective neurite outgrowth. These findings identify a function for Csb in neural precursors. 23142327 Divergence in androgen sensitivity contributes to population differences in sexual dimorphism of electrocommunication behavior. Weakly-electric fish (Apteronotidae) produce highly diverse electrocommunication signals. Electric organ discharges (EODs) vary across species, sexes, and in the magnitude and direction of their sexual dimorphism. Gonadal steroid hormones can modulate EODs, and differences in androgen sensitivity are hypothesized to underlie variation in the degree of sexual dimorphism across species. In this study, we asked whether variation in androgen sensitivity explained variation in sexual dimorphism of EODs within species, at the population level. We examined two populations of black ghost knifefish (Apteronotus albifrons), one from the Orinoco and the other from the Amazon River Basin. EOD frequency (EODf) and chirp rates were measured to characterize diversity in sexual dimorphism across populations. The magnitude of sexual dimorphism in EODf differed significantly across populations, and was more pronounced in the Orinoco population than in the Amazon population. Chirp rates were sexually monomorphic in both populations. 11-Ketotestosterone (11-kT) was administered over a two-week period to assess population differences in sensitivity to androgens. 11-kT masculinized EODf significantly more in the population with the greater degree of sexual dimorphism. 11-kT had no effect on the sexually monomorphic chirping rates. We conclude that population divergence in androgen sensitivity contributes to variation in sexual dimorphism of EODf in A. albifrons. 23389756 The effects of BMY-14802 against L-DOPA- and dopamine agonist-induced dyskinesia in the hemiparkinsonian rat. RATIONALE: L-DOPA continues to be the primary treatment for patients with Parkinson's disease; however, the benefits of long-term treatment are often accompanied by debilitating side effects known as dyskinesias. In recent years, several 5-HT(1A) receptor agonists have been found to reduce dyskinesia in clinical and experimental models of PD. The purported sigma-1 antagonist, BMY-14802 has been previously demonstrated to reduce L-DOPA induced dyskinesia in a 5-HT(1A) receptor dependent manner. OBJECTIVE: In the present study, we extend these findings by examining the anti-dyskinetic potential of BMY-14802 against L-DOPA, the D(1) receptor agonist SKF81297 and the D(2) receptor agonist, quinpirole, in the hemi-parkinsonian rat model. In addition, the receptor specificity of BMY-14802's effects was evaluated using WAY-100635, a 5-HT(1A) receptor antagonist. RESULTS: Results confirmed the dose-dependent (20 > 10 > 5 mg/kg) anti-dyskinetic effects of BMY-14802 against L-DOPA with preservation of anti-parkinsonian efficacy at 10 mg/kg. BMY-14802 at 10 and 20 mg/kg also reduced dyskinesia induced by both D(1) and D(2) receptor agonists. Additionally, BMY-14802's anti-dyskinetic effects against L-DOPA, but not SKF81297 or quinpirole, were reversed by WAY-100635 (0.5 mg/kg). CONCLUSION: Collectively, these findings demonstrate that BMY-14802 provides anti-dyskinetic relief against L-DOPA and direct DA agonist in a preclinical model of PD, acting via multiple receptor systems and supports the utility of such compounds for the improved treatment of PD. 23219155 Combining structure and function to evaluate glaucomatous progression: implications for the design of clinical trials. The selection of a suitable method for assessment of glaucomatous progression and estimation of rates of change is an essential component of the design of clinical trials investigating neuroprotective therapies for the disease. Due to the limitations of currently available tests, approaches combining structural and functional tests are essential in order to provide reliable detection of endpoints. This could also potentially enable shorter clinical trials with relatively smaller sample size requirements. A recent approach for estimating rates of retinal ganglion cell loss using a combination of structural and functional tests has been shown to perform better than isolated parameters from conventional tests for diagnosing, staging and detecting glaucoma progression and may prove useful as an outcome measure in clinical trials of the disease. 23443757 Computational drug repositioning: from data to therapeutics. Traditionally, most drugs have been discovered using phenotypic or target-based screens. Subsequently, their indications are often expanded on the basis of clinical observations, providing additional benefit to patients. This review highlights computational techniques for systematic analysis of transcriptomics (Connectivity Map, CMap), side effects, and genetics (genome-wide association study, GWAS) data to generate new hypotheses for additional indications. We also discuss data domains such as electronic health records (EHRs) and phenotypic screening that we consider promising for novel computational repositioning methods. 23601990 Synthesis and biological evaluation of phosphorylated flavonoids as potent and selective inhibitors of cholesterol esterase. A series of phosphorylated flavonoids were synthesized and investigated in vitro as inhibitors of pancreatic cholesterol esterase (CEase) and acetylcholinesterase (AChE). The results showed that most of the synthesized compounds exhibited nanomolar potency against CEase, much better than the parent flavonoids. Furthermore, these phosphorylated flavonoids demonstrated good to high selectivity for CEase over AChE, which only showed micromolar potency inhibition of AChE. The most selective and potent inhibitor of CEase (3e) had IC50 value of 0.72 nM and 11800-fold selectivity for CEase over AChE. The structure-activity relationships revealed that the free hydroxyl group at position 5 and phosphate group at position 7 of the phosphorylated flavonoids are favorable to the inhibition of CEase. The inhibition mechanism and kinetic characterization studies indicated that they are irreversible competitive inhibitors of CEase. 23053666 Claudin-3 and claudin-4 regulate sensitivity to cisplatin by controlling expression of the copper and cisplatin influx transporter CTR1. Claudin-3 (CLDN3) and claudin-4 (CLDN4) are the major structural molecules that form tight junctions (TJs) between epithelial cells. We found that knockdown of the expression of either CLDN3 or CLDN4 produced marked changes in the phenotype of ovarian cancer cells, including an increase in resistance to cisplatin (cDDP). The effect of CLND3 and CLDN4 on cDDP cytotoxicity, cDDP cellular accumulation, and DNA adduct formation was compared in the CLDN3- and CLDN4-expressing parental human ovarian carcinoma 2008 cells and CLDN3 and CLDN4 knockdown sublines (CLDN3KD and CLDN4KD, respectively). Knockdown of CLDN3 or CLDN4 rendered human ovarian carcinoma 2008 cells resistant to cDDP in both in vitro culture and in vivo xenograft model. The net accumulation of platinum (Pt) and the Pt-DNA adduct levels were reduced in CLDN3KD and CLDN4KD cells. The endogenous mRNA levels of copper influx transporter CTR1 were found to be significantly reduced in the knockdown cells, and exogenous expression of CTR1 restored their sensitivity to cDDP. Reexpression of an shRNAi-resistant CLDN3 or CLDN4 up-regulated CTR1 levels, reversed the cDDP resistance, and enhanced TJ formation in the knockdown cells. Baseline copper (Cu) level, Cu uptake, and Cu cytotoxicity were also reduced in CLDN3KD and CLDN4KD cells. Cu-dependent tyrosinase activity was also markedly reduced in both types of CLDN knockdown cells when incubated with the substrate l-DOPA. These results indicate that CLDN3 and CLDN4 affect sensitivity of the ovarian cancer cells to the cytotoxic effect of cDDP by regulating expression of the Cu transporter CTR1. 23552267 Trace and major element levels in rats after oral administration of diesel and biodiesel derived from opium poppy (Papaver somniferum L.) seeds. The study investigated the toxic effects of diesel and biodiesel derived from opium poppy (Papaver somniferum L.) oil seeds on the trace and major elements in kidney, lung, liver, and serum of rats. By the end of 21 days, trace and major element concentrations in kidney, lung, and liver tissues and the serum were measured using inductively coupled plasma-optical emission spectroscopy. We observed that trace and major element levels in kidney, lung, and liver tissues and the serum changed. Especially, important differences were detected in trace and major element concentrations in kidney and lung tissues. In kidney tissue, the concentration differences of calcium, sodium, and zinc (Zn) were found between diesel and biodiesel groups. In lung tissue, the concentration differences of cadmium, lithium, magnesium, manganese, and Zn were found between diesel and biodiesel groups. Among the significant findings, Zn concentration in serum and liver tissue of diesel and biodiesel were different from control (p < 0.05). However, the metal levels of biodiesel group were similar to control group. Due to lesser toxicity of biodiesel, it could be considered as an alternate fuel. 23414722 Kisspeptin as a link between metabolism and reproduction: Evidences from rodent and primate studies. Changes in metabolic status gate reproductive activity by still incompletely deciphered mechanisms. Many neuropeptides have been shown to be involved in restraining hypothalamic gonadotropin releasing hormone (GnRH) release under conditions of negative energy balance. Broadly, on the basis of their effect on feeding, these can be grouped as orexigenic and anorexigenic neuropeptides. Reciprocally correlated, in response to changes in systemic concentrations of metabolic hormones, the secretion of orexigenic neuropeptides increases while that of anorexigenic neuropeptides decreases during conditions of food restriction. Recently, kisspeptin signaling in hypothalamus has appeared as a pivotal regulator of the GnRH pulse generator. Kisspeptin apparently does not affect feeding, but in light of accumulating data, it has emerged as one of the major conduits in relaying body metabolic status information to GnRH neurons. The present review examines such data obtained from rodent and primate models, which suggest kisspeptin-Kiss1r signaling as a possible pathway providing a link between metabolism and reproduction. 23185042 Electronic transition moments of 6-methyl isoxanthopterin--a fluorescent analogue of the nucleic acid base guanine. Fluorescent nucleic acid base analogues are important spectroscopic tools for understanding local structure and dynamics of DNA and RNA. We studied the orientations and magnitudes of the electric dipole transition moments (EDTMs) of 6-methyl isoxanthopterin (6-MI), a fluorescent analogue of guanine that has been particularly useful in biological studies. Using a combination of absorption spectroscopy, linear dichroism (LD) and quantum chemical calculations, we identified six electronic transitions that occur within the 25,000-50,000 cm(-1) spectral range. Our results indicate that the two experimentally observed lowest-energy transitions, which occur at 29,687 cm(-1) (337 nm) and 34,596 cm(-1) (289 nm), are each polarized within the plane of the 6-MI base. A third in-plane polarized transition is experimentally observed at 47,547 cm(-1) (210 nm). The theoretically predicted orientation of the lowest-energy transition moment agrees well with experiment. Based on these results, we constructed an exciton model to describe the absorption spectra of a 6-MI dinucleotide-substituted double-stranded DNA construct. This model is in good agreement with the experimental data. The orientations and intensities of the low-energy electronic transitions of 6-MI reported here should be useful for studying local conformations of DNA and RNA in biologically important complexes. 23558297 Vinclozolin: A case study on the identification of endocrine active substances in the past and a future perspective. In the late 1980s vinclozolin was tested for prenatal developmental toxicity in rats for registration purposes in USA. At 1000mg/kgbw, 95% of all fetuses were female upon visual inspection (ano-genital distance determination). Anti-androgenic effects (AA) were also noted in a subsequent 2-generation study. These findings triggered mechanistic investigations at BASF and at US-EPA. Results published by the latter were the starting point of the endocrine disruption (ED) discussion in the 1990s. AA effects of vinclozolin are mediated by two metabolites, which have an antagonistic effect on the androgen receptor. Currently, determination of ED has become a major end-point in toxicology testing and the US-EPA has set up an elaborated testing paradigm to fulfill this requirement. Future screening for ED can be improved making use of new technologies. ED modes of action can be determined by three alternative (3R) methods. Steroid synthesis in H295R cells (1), androgen-receptor binding in modified yeast (2) and metabolomics (3). Using vinclozolin as a case study, results indicate: (1) an effect on steroid synthesis in vitro, (2) an antagonistic effect on the androgen receptor and (3) that the metabolome profile of vinclozolin is similar to that of other receptor mediated anti-androgens (e.g. flutamide). 23017419 A nanosised oxygen scavenger: preparation and antioxidant application to roasted sunflower seeds and walnuts. A novel oxygen scavenger using iron nanoparticle was produced and evaluated as a potential oxygen scavenger. Iron nanoparticle was prepared by liquid phase reduction method in microemulsion systems. The absorption capacity of different kinds of oxygen scavengers was measured as a function of time, and the absorption rate constant was evaluated at 25°C. The absorption kinetic analysis showed that the absorption process followed a first-order reaction. The absorption rate constant of nanosised and conventional oxygen scavenger were 0.45±0.044h(-1) and 0.05±0.006h(-1), respectively. Successful application of the nanosised oxygen scavenger on roasted sunflower seed and walnut demonstrated its ability to inhibit lipid oxidation in lipid-containing food. Roasted nut treated with nanosised oxygen scavenger possessed the lowest PV and AnV in all treatments after 120 days of storage. Therefore, it has the potential for broad application as an active packaging in a variety of oxygen-sensitive foods. 23262268 C(22)-steroidal lactone glycosides from stems and leaves of Paris polyphylla var. yunnanensis. Further phytochemical investigation on the stems and leaves of Paris polyphylla var. yunnanensis has led to the isolation of three C(22)-steroidal lactone glycosides. Two of these are new compounds, designated as chonglouoside SL-7 (1) and chonglouoside SL-8 (2). Their structures were elucidated on the basis of extensive spectroscopic analysis, as well as comparison with the reported spectroscopic data. This is the first report of C(22)-steroidal lactone glycosides isolated from the Paris genus. Compounds 1 and 3 showed moderate antimicrobic activity against Propionibacterium acnes with MIC values of 31.3 and 3.9μg/mL, respectively. 23561196 Polycyclic aromatic hydrocarbons (PAH) and phenolic substances in meat products smoked with different types of wood and smoking spices. The contents of polycyclic aromatic hydrocarbons (15+1 EU PAH) and phenolic substances (guaiacol, 4-methylguaiacol, syringol, eugenol, and trans-isoeugenol) were investigated in smouldering-smoked Frankfurters and mini-salamis. For the 51 smoking experiments wood chips of oak, poplar, hickory, spruce, fir, alder, beech, and beech with an apple-smoking spice mix, cherry-smoking spice mix, and a mix of juniper berries and bay leaves were tested. The use of poplar and hickory led to a decrease in the PAH contents in the range of 35-55% compared to the commonly used beech wood. Higher PAH contents by using softwood were not observed. The use of the rapidly growing poplar seems to be a reasonable approach for reducing the PAH contents in smoked meat products. Furthermore, the sum contents of the five phenolic substances in sausages smoked with poplar were higher, or only slightly lower, when compared to the use of beech. 23200942 A 10-minute point-of-care assay for detection of blood protein adducts resulting from low level exposure to organophosphate nerve agents. The OrganoTox test is a rapid, point-of-care assay capable of detecting clinically relevant organophosphate (OP) poisoning after low-level exposure to sarin, soman, tabun, or VX chemical nerve agents. The test utilizes either a finger stick peripheral blood sample or plasma specimen. While high-level nerve agent exposure can quickly lead to death, low-level exposure produces vague, nondescript signs and symptoms that are not easily clinically differentiated from other conditions. In initial testing, the OrganoTox test was used to detect the presence of blood protein-nerve agent adducts in exposed blood samples. In order to mimic the in vivo exposure as closely as possible, nerve agents stored in organic solvents were spiked in minute quantities into whole blood samples. For performance testing, 40 plasma samples were spiked with sarin, soman, tabun, or VX and 10 normal plasma samples were used as the negative control. The 40 nerve agent-spiked plasma samples included 10 replicates of each agent. At the clinically relevant low-level exposure of 10ng/ml, the OrganoTox test demonstrated 100% sensitivity for soman, tabun, and VX and 80% sensitivity for sarin. The OrganoTox test demonstrated greater than 97% specificity with 150 blood samples obtained from healthy adults. No cross-reactivity or interference from pesticide precursor compounds was found. A rapid test for nerve agent exposure will help identify affected patients earlier in the clinical course and trigger more appropriate medical management in a more timely manner. 23387425 Azaspiracid-1 inhibits the maturation of cathepsin D in mammalian cells. Azaspiracid-1 (AZA-1) inhibits endocytosis, but the consequences of this alteration on cellular processes are unknown. We hypothesized that the inhibition of endocytosis is a key step of the mode of action of AZA-1, leading to perturbation of cellular processes dependent on proper functioning of endocytic machinery. We tested this working hypothesis by probing whether AZA-1 can alter the maturation of cathepsin D in MCF-7 epithelial cells, as a model system. We found that cell treatment with AZA-1 inhibited the conversion of 52 kDa procathepsin D into the mature 30 kDa protein. The effects induced by AZA-1 were similar to those elicited by chlorpromazine and other agents preventing proper maturation of lysosomal enzymes, indicating that the inhibition of endocytic transfer of proforms to late endosomes/lysosomess is responsible for the effect induced by the toxin. By immunofluorescence microscopy, we found no colocalization of cathepsin D and the early endosomal marker EEA-1 in control cells, where most of cathepsin D resides in late endosomes/lysosomes. Co-localization of cathepsin D and EEA-1 immunoreactivity, in turn, was found in cells exposed to AZA-1, indicating that the toxin blocks protein maturation at the early steps of endocytosis, causing accumulation of procathepsin D in early endosomes. The molecular alteration induced by AZA-1 involved both secreted and intracellular pools of procathepsin D, showing that the toxin effect does not result from a general impairment of vesicular trafficking but is the outcome of a perturbed centripetal process. Furthermore, AZA-1 was found to inhibit procathepsin D maturation also in normal fibroblasts, showing that this molecular response is induced by this toxin in different cell types. The data we obtained corroborated our hypothesis and provide a unified molecular frame for the mode of action of AZAs in animal models, involving a primary alteration of endocytic processes. 22475036 A new abietane diterpenoid from Salvia xanthocheila Boiss. From the chloroform extract of aerial part of Salvia xanthocheila Boiss. one new abietane diterpenoid, xantoquinone (5α,6α-dimethoxy-7,11,14-trioxoabieta-8,12-diene) and one known oleanene triterpenoid namely 1β,3β-dihydroxy-12-oleanene were isolated. The structure of the new terpenoid was elucidated by comprehensive spectroscopic analysis including electron ionisation-mass spectra, (1)H NMR, (13)C NMR, distortionless enchancement by polarisation transfer, H,H correlation spectroscopy, heteronuclear multiple-quantum coherence and heteronuclear multiple-bond correlation. 23567948 DNA-binding, photocleavage, cytotoxicity in vitro, apoptosis and cell cycle arrest studies of symmetric ruthenium(II) complexes. Two novel ruthenium(II) complexes [Ru(dmb)2(addppn)](ClO4)2 (1) and [Ru(bpy)2(addppn)](ClO4)2 (2) were synthesized. The DNA-binding constants of complexes 1 and 2 were determined to be 4.78 (±0.49) × 10(5) and 7.42 (±0.53) × 10(5) M(-1). The results indicate that complexes 1 and 2 interact with CT DNA through intercalative mode. The cytotoxicity in vitro of the complexes toward BEL-7402, HeLa, MG-63 and SKBR-3 cells was assessed by MTT assay. The apoptosis was carried out with Hoechst 33258 staining method and flow cytometry. The cellular uptake was observed under fluorescence microscope. The cell cycle arrest shows that the antiproliferative mechanism induced by complexes 1 and 2 on BEL-7402 cells is G0/G1 phase arrest. 22876953 Mechanism-based modulator discovery for sirtuin-catalyzed deacetylation reaction. Silent information regulator 2 (Sir2) enzymes or sirtuins are a family of evolutionarily conserved intracellular protein deacetylases that can catalyze the acetyl group removal from the specific Nε-acetyl-lysine (AcK) side chains on a variety of proteins from all kingdoms of life. Yeast Sir2 was the first sirtuin identified, and so far seven sirtuins (i.e. SIRT1-7) have been found in mammals including humans. The sirtuin-catalyzed deacetylation reaction has captured tremendous interest during the past a few years because of (i) its increasingly demonstrated importance in many crucial biological processes such as gene transcription, metabolism, and aging, and thus its therapeutic potential for metabolic and age-related diseases and cancer, and (ii) its unique deacetylation chemistry. Specifically, the sirtuin-catalyzed AcK side chain deacetylation is not merely an amide hydrolysis reaction, instead is coupled to the nicotinamide cleavage from β-nicotinamide adenine dinucleotide (β-NAD+ or NAD+) with the generation of three enzymatic products, i.e. the deacetylated protein species, nicotinamide, and 2'-O-acetyl-ADP-ribose (2'-O-AADPR). Here the author would like to review the past endeavors on developing mechanism-based sirtuin modulators (inhibitors and activators). The first part of this article will provide an updated mechanistic picture of the sirtuin-catalyzed deacetylation reaction. The second part will be focused on how the mechanistic knowledge has been exploited for the design of effective sirtuin modulators. 23432093 Phase discrimination through oxidant selection in low-temperature atomic layer deposition of crystalline iron oxides. Control over the oxidation state and crystalline phase of thin-film iron oxides was achieved by low-temperature atomic layer deposition (ALD), utilizing a novel iron precursor, bis(2,4-methylpentadienyl)iron. This low-temperature (T = 120 °C) route to conformal deposition of crystalline Fe3O4 or α-Fe2O3 thin films is determined by the choice of oxygen source selected for the second surface half-reaction. The approach employs ozone to produce fully oxidized α-Fe2O3 or a milder oxidant, H2O2, to generate the Fe(2+)/Fe(3+) spinel, Fe3O4. Both processes show self-limiting surface reactions and deposition rates of at least 0.6 Å/cycle, a significantly high growth rate at such mild conditions. We utilized this process to prepare conformal iron oxide thin films on a porous framework, for which α-Fe2O3 is active for photocatalytic water splitting. 23141427 Relieving visceral hyperalgesia effect of Kangtai capsule and its potential mechanisms via modulating the 5-HT and NO level in vivo. Kangtai capsule (KT) is one type of traditional Chinese medicine preparation derived from the proved recipe, which was frequently applied as an effective clinical treatment of IBS. However, there still lack the reasonable and all-round analytical approach and the scientific studies on its underlying mechanisms. Therefore, our study aimed to develop the novel method for evaluating its quality as well as to interpret the potential mechanisms. In our study, high performance liquid chromatography (HPLC) fingerprint was applied to provide a chemical profile of KT. The neonatal maternal separation (NMS) on Sprague-Dawley pups was employed to evaluate the therapeutic effect of KT by virtue of various parameters including visceral hyperalgesia, serum nitric oxide (NO) level, and tissue 5-hydroxytryptamine (5-HT) level. Consequently, a chromatographic condition, which was carried at 30°C with a flow rate of 0.5 ml/min on AQUA 3μ C18 column with mobile phase of acetonitrile and water-phosphoric acid (100:0.1, v/v), was established to give a common fingerprint chromatography under 254 nm with a similarity index of 0.963 within ten batches of KT samples. On the NMS model, KT markedly elevated the pain threshold of NMS rats. Furthermore, KT at three doses significantly decreased 5-HT content from distal colon of visceral hyperalgesia rats induced by NMS, while the significant decrease of 5-HT content in serum was only observed in the group with KT at high dose. However, compared with that in NMS rats without KT, there was no apparent difference of 5-HT level from brain issue in the rats with various doses. Besides, KT could substantially elevate the concentration of NO in the serum. The results showed our study developed the simple, rapid, accurate, reproducible qualitative and quantitative analysis by HPLC fingerprint for the quality control for KT. Data from the pharmacological investigation suggested that the curative effect of KT to the visceral hypersensitivity may be concerned with the level of 5-HT and NO in vivo, promising its potential in irritable bowel syndrome treatment. 23473643 Co-ordination of base excision repair and genome stability. Base excision repair (BER) is a major DNA repair pathway employed in mammalian cells that is required to maintain genome stability, thus preventing several human diseases, such as ageing, neurodegenerative diseases and cancer. This is achieved through the repair of damaged DNA bases, sites of base loss and single strand breaks of varying complexity that are continuously induced endogenously or via exogenous mutagens. Whilst the enzymes involved in BER are now well known and characterised, the role of the co-ordination of BER enzymatic activities in the cellular response to DNA damage and the mechanisms regulating this process are only now being revealed. Post-translational modifications of BER proteins, including ubiquitylation and phosphorylation, are increasingly being identified as key processes that regulate BER. In this review we will summarise recent evidence discovering novel mechanisms that are involved in maintaining genome stability by regulation of the key BER proteins in response to DNA damage. 23271057 Ovarian function is restored after grafting of cryopreserved immature ovary in ewes. As a result of advances in medical treatment, almost 80% of children who are diagnosed with cancer survive long-term. The adverse consequences of cancer treatments include impaired puberty and fertility. In prepubertal girls, the only therapeutic option is the cryopreservation of an ovary. To date, a dozen births have been reported after reimplantation of cryopreserved mature ovaries. To analyze ovarian function after immature grafts, we performed ovarian grafting in a ewe model. Fresh or cryopreserved ovaries from immature ewes were autografted in prepubertal or adult ewes. Cyclic hormonal activity was recovered 3 mo after grafting. Histological analysis demonstrated the presence of all follicle populations and corpora lutea not affected by cryopreservation. After 3 reproductive seasons, births had been observed in all groups, and the follicle-stimulating hormone status was under the limit, which indicated an exhausted ovary. As an indicator of potential imprinting default, the methylation status of the Igf2r gene was analyzed and did not show significant alteration compared with that of nonmanipulated animals. Taken together, these results demonstrate that immature ovarian grafting is able to restore spontaneous puberty and fertility and could guide the reimplantation of immature cortex in women.-Sauvat, F., Bouilly, J., Capito, C., Lefèvre, A., Blachère, T., Borenstein, N., Sarnacki, S., Dandolo, L., Binart, N. Ovarian function is restored after grafting of cryopreserved immature ovary in ewes. 23644892 Correction: Wiedmann, M., et al. Exploration of the Role of the Non-Coding RNA SbrE in L. monocytogenes Stress Response. Int. J. Mol. Sci. 2013, 14, 378-393. The original version of the paper in Section 3.8 reports that "The peptide mass tolerance and fragment mass tolerance values were 10 ppm and 30 mDa, respectively" [1] (p. 387). To help others who may want to use the same methods in the future, the authors would like to correct the wording to: "The peptide mass tolerance and fragment mass tolerance values were 30 ppm and 0.15 Da, respectively. In order to decrease the probability of false peptide identification, only peptides with significance scores above the identity threshold (at the 95% confidence interval), defined by Mascot probability analysis (www.matrixscience.com/help/scoring_help.html#PBM), were considered to be confidently identified and used for protein identification.  Furthermore, only proteins identified in all four iTRAQ samples through at least two peptides with a p-value of <0.05 (expectation value) were further analyzed". The authors would like to apologize for any inconvenience this may have caused to the readers of this journal. 23458966 Zinc oxide nanoparticle induced autophagic cell death and mitochondrial damage via reactive oxygen species generation. Zinc oxide nanoparticles (ZnO-np) are used in an increasing number of industrial products such as paint, coating and cosmetics, and in other biological applications. There have been many suggestions of a ZnO-np toxicity paradigm but the underlying molecular mechanisms about the toxicity of ZnO-np remain unclear. This study was done to determine the potential toxicity of ZnO-np and to assess the toxicity mechanism in normal skin cells. Synthesized ZnO-np generated reactive oxygen species (ROS), as determined by electron spin resonance. After uptake into cells, ZnO-np induced ROS in a concentration- and time-dependent manner. To demonstrate ZnO-np toxicity mechanism related to ROS, we detected abnormal autophagic vacuoles accumulation and mitochondria dysfunction after ZnO-np treatment. Furthermore mitochondria membrane potential and adenosine-5'-triphosphate (ATP) production are decreased for culture with ZnO-np. We conclude that ZnO-np leads to cell death through autophagic vacuole accumulation and mitochondria damage in normal skin cells via ROS induction. Accordingly, ZnO-np may cause toxicity and the results highlight and need for careful regulation of ZnO-np production and use. 22451331 Effects of Bixa orellana L. seeds on hyperlipidemia. Bixa orellana L., urucum, or urucu, a native tropical tree of Central and South American rain forests is used to treat various diseases in popular medicine. In Ceará, Northeast of Brazil, the seeds of urucum have been used for the treatment of high lipid blood levels. The present study investigated the effects of the aqueous extract from Bixa orellana seeds (AEBO) in mice with hyperlipidemia induced by tyloxapol, fructose and ethanol. In hyperlipidemia induced by Triton WR1339, 400 and 800 mg/kg AEBO reduced triglycerides (TG) serum levels at 24 h and 48 h. In the study of hypertriglyceridemia induced by fructose, AEBO in doses of 400 mg/kg and 800 mg/kg reduced TG levels by 48.2% and 48.7%, respectively. Finally, the ethanol experimental model with 400 mg/kg AEBO promoted a reduction of 33.6% of TG levels, while the 800 mg/kg concentration reduced hypertriglyceridemia in 62.2%. In conclusion, the aqueous extract of the seeds of Bixa orellana was capable of reversing the hypertriglyceridemia induced by Triton, fructose and ethanol, demonstrating a hypolipidemic effect. However, further studies are necessary to discover the precise mechanism of action. 23537427 Measurements of Rate Constants for the OH Reactions with Bromoform (CHBr3), CHBr2Cl, CHBrCl2, and Epichlorohydrin (C3H5ClO). Measurements of the rate constants for the gas phase reactions of OH radicals with bromoform (CHBr3) and epichlorohydrin (C3H5ClO) were performed using a flash photolysis resonance-fluorescence technique over the temperature range 230-370 K. The temperature dependences of the rate constants can be represented by the following expressions: kBF(230-370 K) = (9.94 ± 0.76) × 10(-13) exp[-(387 ± 22)/T] cm(3) molecule(-1) s(-1) and kECH(230-370 K) = 1.05 × 10(-14)(T/298)(5.16) exp(+1082/T) cm(3) molecule(-1) s(-1). Rate constants for the reactions of OH with CHCl2Br and CHClBr2 were measured between 230 and 330 K. They can be represented by the following expressions: kDCBM(230-330 K) = (9.4 ± 1.3) × 10(-13) exp[-(513 ± 37)/T] cm(3) molecule(-1) s(-1) and kCDBM(230-330 K) = (9.0 ± 1.9) × 10(-13) exp[-(423 ± 61)/T] cm(3) molecule(-1) s(-1). The atmospheric lifetimes due to reactions with tropospheric OH were estimated to be 57, 39, 72, and 96 days, respectively. The total atmospheric lifetimes of the Br-containing methanes due to both reaction with OH and photolysis were calculated to be 22, 50, and 67 days for CHBr3, CHClBr2, and CHCl2Br, respectively. 23281657 New cyclomyrsinol diterpenes from Euphorbia aellenii with their immunomodulatory effects. Chloroform-acetone extract of the aerial parts of Euphorbia aellenii Rech. f. (Euphorbiaceae) was investigated for its diterpenoidal constituents. This led to the isolation of two new and one known cyclomyrsinol-type diterpenes 1-3. The structures were elucidated on the basis of 1D and 2D (1)H and (13)C NMR techniques, and in vitro immunomodulatory activity was evaluated by standard proliferation of human peripheral blood lymphocytes. Results showed that all the three compounds were found to inhibit lymphocyte proliferation significantly (p < 0.05) at 50 μg/ml concentration. Among them, compound 2 showed more activity against phytohemagglutinin-activated T-cell proliferation with an IC(50) of 40.4 ± 9.35 μg/ml. 23419685 The neurobehavioral impact of manganese: Results and challenges obtained by a meta-analysis of individual participant data. Results from a meta-analysis of aggregated data provoked a new analysis using individual data on the neuropsychological performance of occupationally exposed workers. Data from eight studies examining 579 exposed and 433 reference participants were included, 28 performance variables analyzed. The performance scores were adjusted for well-known individual-level covariates; the influence of possible, but unknown study-level covariates was attenuated by means of a z-normalization. Associations between performance and exposure were estimated by ANOVAs and ANCOVAs, the latter representing multi-level models. Four cognitive and motor performance variables each indicated significantly lower performances of exposed individuals when confounding was considered; slowed motor performances and deficits in attention and short-term memory were found. Performance on a single test was significantly related to the biomarker manganese in blood. The outcomes on susceptibility were weak. The slowing of responses was the most distinct feature of performances of exposed workers. It remains unclear, whether this result is related to the employed tests or provides important information about early stages of the neurotoxic impairment. More specific cognitive tests need to be employed to answer this question. The lack of dose-response relationships was related to features of the biomarker: it does not reflect the Mn in brain responsible for changes in performances. 23266491 Retinol deprivation partially rescues the skeletal mineralization defects of Phex-deficient Hyp mice. X-linked hypophosphatemic rickets (XLH) is a genetic disorder caused by mutational inactivation of the PHEX gene, encoding a transmembrane endopeptidase expressed in osteoblasts. Since several experiments involving Phex-deficient Hyp mice have demonstrated that an increased expression of Fgf23 in osteoblasts is causative for the renal phosphate loss characteristic of XLH, we performed genome-wide expression analysis to compare differentiated osteoblasts from wildtype and Hyp mice. Here we did not only observe the expected increase of Fgf23 expression in the latter ones, but also a differential expression of genes that are either induced by or involved in retinoic acid signaling, which led us to analyze whether dietary retinol deprivation would influence the phenotype of Hyp mice. Unexpectedly, feeding a retinol-free diet resulted in a partial rescue of the growth plate and bone mineralization defects in 6 weeks old Hyp mice. When we fed the same diet for 24 weeks the amount of non-mineralized bone matrix (osteoid) was reduced by more than 70%, although phosphate homeostasis was unaffected. In contrast, a dietary normalization of serum phosphate levels in Hyp mice reduced the osteoid amount by less than 30%, thereby demonstrating a previously unknown impact of retinol on the cell-autonomous mineralization defect of Phex-deficient osteoblasts. 23257178 Steroid toxicity and detoxification in ascomycetous fungi. In the last couple of decades fungal infections have become a significant clinical problem. A major interest into fungal steroid action has been provoked since research has proven that steroid hormones are toxic to fungi and affect the host/fungus relationship. Steroid hormones were found to differ in their antifungal activity in ascomycetous fungi Hortaea werneckii, Saccharomyces cerevisiae and Aspergillus oryzae. Dehydroepiandrosterone was shown to be the strongest inhibitor of growth in all three varieties of fungi followed by androstenedione and testosterone. For their protection, fungi use several mechanisms to lower the toxic effects of steroids. The efficiency of biotransformation in detoxification depended on the microorganism and steroid substrate used. Biotransformation was a relatively slow process as it also depended on the growth phase of the fungus. In addition to biotransformation, steroid extrusion out of the cells contributed to the lowering of the active intracellular steroid concentration. Plasma membrane Pdr5 transporter was found to be the most effective, followed by Snq2 transporter and vacuolar transporters Ybt1 and Ycf1. Proteins Aus1 and Dan1 were not found to be involved in steroid import. The research of possible targets of steroid hormone action in fungi suggests that steroid hormones inhibit ergosterol biosynthesis in S. cerevisiae and H. werneckii. Results of this inhibition caused changes in the sterol content of the cellular membrane. The presence of steroid hormones most probably causes the degradation of the Tat2 permease and impairment of tryptophan import. 23333208 Design and synthesis of D₁ agonist/D₂ antagonist for treatment of schizophrenia. A series of tetrahydroisoquinolines were designed, synthesized and evaluated as the first non-natural product type of compounds with dual D(1) receptor (D(1)R) agonism and D(2) receptor (D(2)R) antagonism properties for treatment of schizophrenia. The initial SAR of the series was explored. The lead in the series, 3g, exhibited high affinity and good potency. Compound 3g displayed 95% of D(1)R occupancy (10 mg/kg, sc) and 75% of D(2)R occupancy (10 mg/kg, sc) in the striatum of male CD-1 mice. The series exhibited unique pharmacology and merit as tool compounds for target validation and future optimizations. 23416040 The α3β4* nicotinic acetylcholine receptor subtype mediates nicotine reward and physical nicotine withdrawal signs independently of the α5 subunit in the mouse. The 15q25 gene cluster contains genes that code for the α5, α3, and β4 nicotinic acetylcholine receptor (nAChRs) subunits, and in human genetic studies, has shown the most robust association with smoking behavior and nicotine dependence to date. The limited available animal studies implicate a role for the α5 and β4 nAChR subunits in nicotine dependence and withdrawal; however studies focusing on the behavioral role of the α3β4* nAChR receptor subtype in nicotine dependence are lacking. Because of the apparent role of the α3β4* nAChR subtype in nicotine dependence, the goal of the current study was to better evaluate the involvement of this subtype in nicotine mediated behavioral responses. Using the selective α3β4* nAChR antagonist, α-conotoxin AuIB, we assessed the role of α3β4* nAChRs in acute nicotine, nicotine reward, and physical and affective nicotine withdrawal. Because α5 has also been implicated in nicotine dependence behaviors in mice and can form functional receptors with α3β4*, we also evaluated the role of the α3β4α5* nAChR subtype in nicotine reward and somatic nicotine withdrawal signs by blocking the α3β4* nAChR subtype in α5 nAChR knockout mice with AuIB. AuIB had no significant effect on acute nicotine behaviors, but dose-dependently attenuated nicotine reward and physical withdrawal signs, with no significant effect in affective withdrawal measures. Interestingly, AuIB also attenuated nicotine reward and somatic signs in α5 nAChR knockout mice. This study shows that α3β4* nAChRs mediate nicotine reward and physical nicotine withdrawal, but not acute nicotine behaviors or affective nicotine withdrawal signs in mice. The α5 subunit is not required in the receptor assembly to mediate these effects. Our findings suggest an important role for the α3β4* nAChR subtype in nicotine reward and physical aspects of the nicotine withdrawal syndrome. 23340653 Induction of heat shock protein 70 ameliorates ultraviolet-induced photokeratitis in mice. Acute ultraviolet (UV) B exposure causes photokeratitis and induces apoptosis in corneal cells. Geranylgeranylacetone (GGA) is an acyclic polyisoprenoid that induces expression of heat shock protein (HSP)70, a soluble intracellular chaperone protein expressed in various tissues, protecting cells against stress conditions. We examined whether induction of HSP70 has therapeutic effects on UV-photokeratitis in mice. C57 BL/6 mice were divided into four groups, GGA-treated (500 mg/kg/mouse) and UVB-exposed (400 mJ/cm2), GGA-untreated UVB-exposed (400 mJ/cm2), GGA-treated (500 mg/kg/mouse) but not exposed and naive controls. Eyeballs were collected 24 h after irradiation, and corneas were stained with hematoxylin and eosin (H&E) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). HSP70, reactive oxygen species (ROS) production, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and protein kinase B (Akt) expression were also evaluated. Irradiated corneal epithelium was significantly thicker in the eyes of mice treated with GGA compared with those given the vehicle alone (p < 0.01). Significantly fewer TUNEL-positive cells were observed in the eyes of GGA-treated mice than controls after irradiation (p < 0.01). Corneal HSP70 levels were significantly elevated in corneas of mice treated with GGA (p < 0.05). ROS signal was not affected by GGA. NF-κB activation was reduced but phospho-(Ser/Ther) Akt substrate expression was increased in corneas after irradiation when treated with GGA. GGA-treatment induced HSP70 expression and ameliorated UV-induced corneal damage through the reduced NF-κB activation and possibly increased Akt phosphorilation. 23206310 Belatacept utilization recommendations: an expert position. INTRODUCTION: There is a continuing need for an immunosuppressive therapy that offers a high benefit-risk profile for renal transplant recipients, supporting long-term patient and graft survival while minimizing cumulative nephrotoxicity and other side effects. Belatacept , the first biological agent developed for primary maintenance immunosuppression, was recently approved for use in Europe. Belatacept combined with corticosteroids and a mycophenolic acid is indicated for prophylaxis of graft rejection in adults receiving renal transplant. Its use is contraindicated in Epstein-Barr virus seronegative or serostatus unknown patients due to increased risk of developing posttransplant lymphoproliferative disorder. AREAS COVERED: This review provides practical recommendations for the use of belatacept, based on safety and efficacy data from Phase II and Phase III clinical trials in de novo kidney transplant recipients. EXPERT OPINION: Treatment with belatacept is associated with improved long-term graft function, making belatacept an important option for prevention of kidney allograft rejection. Furthermore, efficacy and safety data over several years of therapy suggest that belatacept is particularly suitable for long-term immunosuppression, and the selective targeting offered by belatacept may help avoid some of the non-specific chronic safety risks associated with calcineurin inhibitors and steroids. Future studies will clarify the optimal regimen for belatacept usage. 23211441 Protective effect of 70% ethanolic extract of Lindera obtusiloba Blume on tert-butyl hydroperoxide-induced oxidative hepatotoxicity in rats. Lindera obtusiloba Blume, a native plant of East Asia, has traditionally been used as a folk medicine for liver disease. We studied the in vitro antioxidant and in vivo hepatoprotective activities of a 70% ethanolic extract of L. obtusiloba (LOE) containing 62.9% quercitrin and 22.0% afzelin. LOE prevented tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in HepG2 cells. Along with its high antioxidant potency in vitro, our animal study confirmed that pretreatment with LOE (500 or 2000 mg/kg) for 7 days prior to a single dose of t-BHP (i.p.: 0.5 mmol/kg) significantly lowered the serum levels of alanine and aspartate aminotransferases. In addition, glutathione levels were increased in the liver, and lipid peroxidation levels were decreased in a dose-dependent manner. The histopathological examinations of rat livers showed that LOE significantly reduced the incidence of liver lesions induced by t-BHP. Therefore, we concluded that LOE has merit as a potent candidate to protect the liver against oxidative damage. 23524238 Placental ABC transporters, cellular toxicity and stress in pregnancy. The human placenta, in addition to its roles as a nutrient transfer and endocrine organ, functions as a selective barrier to protect the fetus against the harmful effects of exogenous and endogenous toxins. Members of the ATP-binding cassette (ABC) family of transport proteins limit the entry of xenobiotics into the fetal circulation via vectorial efflux from the placenta to the maternal circulation. Several members of the ABC family, including proteins from the ABCA, ABCB, ABCC and ABCG subfamilies, have been shown to be functional in the placenta with clinically significant roles in xenobiotic efflux. However, recent findings suggest that these transporters also protect placental tissue by preventing the cellular accumulation of cytotoxic compounds such as lipids, sterols and their derivatives. Such protective functions are likely to be particularly important in pregnancies complicated by inflammatory or oxidative stress, where the generation of toxic metabolites is enhanced. For example, ABC transporters have been shown to protect against the harmful effects of hypoxia and oxidative stress through increased expression and efflux of oxysterols and glutathione conjugated xenobiotics. However, this protective capacity may be diminished in response to the same stressors. Several studies in primary human trophoblast cells and animal models have demonstrated decreased expression and activity of placental ABC transporters with inflammatory, oxidative or metabolic stress. Several clinical studies in pregnancies complicated by inflammatory conditions such as preeclampsia and gestational diabetes support these findings, although further studies are required to determine the clinical relevance of the relationships between placental ABC transporter expression and activity, and placental function in stressed pregnancies. Such studies are necessary to fully understand the consequences of pregnancy disorders on placental function and viability in order to optimise pregnancy care and maximise fetal growth and health. 23596260 Temporal Concordance between Apical and Transcriptional Points-of-Departure for Chemical Risk Assessment. The number of legacy chemicals without toxicity reference values combined with the rate of new chemical development are overwhelming the capacity of the traditional risk assessment paradigm. More efficient approaches are needed to quantitatively estimate chemical risks. In this study, rats were dosed orally with multiple doses of six chemicals for 5 days, 2, 4, and 13 weeks. Target organs were analyzed for traditional histological and organ weight changes and transcriptional changes using microarrays. Histological and organ weight changes in this study and the tumor incidences in the original cancer bioassays were analyzed using benchmark dose (BMD) methods to identify noncancer and cancer points-of-departure. The dose-response changes in gene expression were also analyzed using BMD methods and the responses grouped based on signaling pathways. A comparison of transcriptional BMD values for the most sensitive pathway with BMD values for the noncancer and cancer apical endpoints showed a high degree of correlation at all time points. When the analysis included data from an earlier study with 8 additional chemicals, transcriptional BMD values for the most sensitive pathway were significantly correlated with noncancer (r = 0.830, p = 0.0016) and cancer-related (r = 0.943, p = 0.0001) BMD values at 13 weeks. The average ratio of apical-to-transcriptional BMD values was less than two suggesting that for the current chemicals, transcriptional perturbation did not occur at significantly lower doses than apical responses. Based on our results, we propose a practical framework for application of transcriptomic data to chemical risk assessment. 23265447 Mineral and sensory profile of seasoned cracked olives packed in diverse salt mixtures. This work studies the effect of packing cracked seasoned olives with NaCl, KCl, and CaCl(2) mixture brines on their mineral nutrients and sensory attributes, using RSM methodology. The Na, K, Ca, and residual natural Mn contents in flesh as well as saltiness, bitterness and fibrousness were significantly related to the initial concentrations of salts in the packing solution. This new process led to table olives with a significantly lower sodium content (about 31%) than the traditional product but fortified in K and Ca. High levels of Na and Ca in the flesh led to high scores of acidity and saltiness (the first descriptor) and bitterness (the second) while the K content was unrelated to any sensory descriptor. The new presentations using moderate proportions of alternative salts will therefore have improved nutritional value and healthier characteristics but only a slightly modified sensory profile. 23122120 Gangliosides and sialic acid effects upon newborn pathogenic bacteria adhesion: an in vitro study. The effect of the main gangliosides (GM(1), GM(3), GD(3)) and free sialic acid (Neu5Ac) upon the adhesion of pathogenic bacteria implicated in infant diarrhoea is assessed in vitro using the Caco-2 cell line. Concentrations of the bioactive compounds found in the bioaccessible (soluble) fraction of infant formula and human milk are employed. Bacterial adhesion behaviour included enterotoxigenic Escherichia coli (ETEC), enteropathogenic E.coli (EPEC), Listeria monocytogenes, Salmonella entericaserovartyphi, Shigella sonnei, Campylobacter jejuni and Helicobacter pylori. Three different approaches were assayed: pre-incubation of bacteria and compounds before addition to cells (competition); pre-incubation of the cells with compounds (exclusion); and pre-incubation of cells with bacteria (displacement). Furthermore, the spatial localization of the most abundant gangliosides, GM(3) and GD(3), in Caco-2 cells has been determined using confocal microscopy. Results show that GM(3), GD(3), GM(1) and Neu5Ac at the assayed concentrations are able to interfere with the adhesion of several pathogenic bacteria involved in neonatal diseases-the greatest effect corresponding to Neu5Ac, followed by GD(3), GM(1) and GM(3). Gangliosides GM(3) and GD(3) are located in the apical and basolateral membranes of the Caco-2 cells. 23484537 Paclitaxel is an inhibitor and its boron dipyrromethene derivative is a fluorescent recognition agent for botulinum neurotoxin subtype a. We have successfully identified one new inhibitor and one new fluorescent recognition agent for the botulinum neurotoxin subtype A (BoNT/A) using the virtual screening protocol "protein scanning with virtual ligand screening" (PSVLS). Hit selection used an in-house developed holistic binding scoring method. Selected hits were tested experimentally for inhibitory activity using fluorescence resonance energy transfer (FRET) assays against the light chain (catalytic domain) of BoNT/A. Ligand binding was determined against the light and heavy chain BoNT/A complex through either radiolabeled ligand binding assays (nonfluorescent ligands) or fluorescence intensity assays (fluorescent ligands). These experimental assays have confirmed one compound (paclitaxel) to inhibit BoNT/A's proteolytic activity experimentally with an IC50 of 5.2 μM. A fluorescent derivative was also confirmed to bind to the toxin and therefore is a suitable candidate for the rational design of new detection agents and for the development of fluorescence-based multiprobe detection assays. 23391389 Cell division: kinetochores SKAdaddle. Accurate chromosome segregation during cell division requires that kinetochores couple microtubule dynamics to chromosome movement. New research reveals that the kinetochore-associated Ska1 complex hangs on to depolymerizing microtubules and brings some important friends along for the ride. 23327445 High-contrast electrooptic modulation of a photonic crystal nanocavity by electrical gating of graphene. We demonstrate high-contrast electro-optic modulation of a photonic crystal nanocavity integrated with an electrically gated monolayer graphene. A silicon air-slot nanocavity provides strong overlap between the resonant optical field and graphene. Tuning the Fermi energy of the graphene layer to 0.85 eV enables strong control of its optical conductivity at telecom wavelengths, which allows modulation of cavity reflection in excess of 10 dB for a swing voltage of only 1.5 V. The cavity resonance at 1570 nm is found to undergo a shift in wavelength of nearly 2 nm, together with a 3-fold increase in quality factor. These observations enable a cavity-enhanced determination of graphene's complex optical sheet conductivity at different doping levels. Our simple device demonstrates the feasibility of high-contrast, low-power, and frequency-selective electro-optic modulators in graphene-integrated silicon photonic integrated circuits. 23295225 S-nitrosoglutathione covalently modifies cysteine residues of human carbonyl reductase 1 and affects its activity. Carbonyl reductase 1 (CBR1 or SDR21C1) is a ubiquitously-expressed, cytosolic, monomeric, and NADPH-dependent enzyme. CBR1 participates in apoptosis, carcinogenesis and drug resistance, and has a protective role in oxidative stress, cancer and neurodegeneration. S-Nitrosoglutathione (GSNO) represents the newest addition to its diverse substrate spectrum, which includes a wide range of xenobiotics and endogenous substances. GSNO has also been shown to covalently modify and inhibit CBR1. The aim of the present study was to quantify and characterize the resulting modifications. Of five candidate cysteines for modification by 2 mM GSNO (positions 26, 122, 150, 226, 227), the last four were analyzed using MALDI-TOF/TOF mass spectrometry and then quantified using the Selected Reaction Monitoring Approach on hyphenated HPLC with a triple quadrupole mass spectrometer. The analysis confirmed GSNO concentration-dependent S-glutathionylation of cysteines at positions 122, 150, 226, 227 which was 2-700 times higher compared to wild-type CBR1 (WT-CBR1). Moreover, a disulfide bond between neighboring Cys-226 and Cys-227 was detected. We suggest a role of these two cysteines as a redox-sensitive cysteine pair. The catalytic properties of wild-type and enzyme modified with 2 mM GSNO were also investigated by steady state kinetic experiments with various substrates. GSNO treatment of CBR1 resulted in a 2-5-fold decrease in kcat with menadione, 4-benzoylpyridine, 2,3-hexanedione, daunorubicin and 1,4-naphthoquinone. In contrast, the same treatment increased kcat for substrates containing a 1,2-diketo group in a ring structure (1,2-naphthoquinone, 9,10-phenanthrenequinone, isatin). Except for 9,10-phenanthrenequinone, all changes in kcat were at least in part compensated for by a similar change in Km, overall yielding no drastic changes in catalytic efficiency. The findings indicate that GSNO-induced covalent modification of cysteine residues affects the kinetic mechanism of CBR1 both in terms of substrate binding and turnover rate, probably by covalent modification of Cys-226 and/or Cys-227. 23462672 Polyalkylcyanoacrylates as in situ formed diffusion barriers in multimaterial drug carriers. Polymeric hydrogels typically release their drug payload rapidly due to their high water content and the diffusivity for drug molecules. This study proposes a multimaterial system to sustain the release by covering the hydrogel with a poly(alkyl-2-cyanoacrylate) [PACA]-based film, which should be formed by an in situ polymerization on the hydrogel surface initiated upon contact with water. A series of PACA-hydrogel hybrid systems with increasing PACA side chain hydrophobicity was prepared using physically crosslinked alginate films and hydrophilic diclofenac sodium as model hydrogel/drug system. Successful synthesis of PACA at the hydrogel surface was confirmed and the PACA layer was identified to be most homogeneous for poly(n-butyl-2-cyanoacrylate) on both the micro- and nanolevel. At the same time, the diclofenac release from the hybrid systems was substantially sustained from ~1day for unmodified hydrogels up to >14days depending on the type of PACA employed as diffusion barrier. Overall, in situ polymerized PACA films on hydrogels may be widely applicable to various hydrogel matrices, different matrix sizes as well as more complex shaped hydrogel carriers. 23621464 Microbial degradation of microcystins. Hepatotoxic microcystins that are produced by freshwater cyanobacteria pose a risk to public health. These compounds may be eliminated by enzymatic degradation. Here, we review the enzymatic pathways for the degradation of these hepatotoxins, some of which are newly discovered processes. The efficiencies of microcystin biodegradation pathways are documented in several papers and are compared here. Additionally, a comprehensive description of the microcystin enzymatic degradation scheme has been supplemented with a proposal for a new biodegradation pathway. Critical comments on less documented hypotheses are also included in this review. The genetic aspects of biodegradation activity are discussed in detail. We also describe some methods that are useful for studying the biological decomposition of microcystins, including screening for microcystin degraders and detecting microcystin degradation products, with an emphasis on mass spectrometric methodology. 23298138 Usefulness of ancillary methods for diagnosis, prognosis and targeted therapy in thyroid pathology. The development of molecular analyses for thyroid pathologies is on going. These analyses provide new diagnostic tools with the aim of accurately distinguishing malignant and benign thyroid tumors. They are particularly useful as most of them can be done preoperatively on thyroid fine-needle aspiration biopsy samples. Furthermore, molecular biomarkers may play a promising role since they are able to predict the prognosis of patients with thyroid tumors. Moreover, identification of molecular markers as well as a better understanding of thyroid carcinogenesis will help develop innovative targeted therapies, particularly in patients with metastatic iodo-resistant thyroid carcinoma. To date, four types of somatic genetic alterations are known to hold potential interest for the diagnosis and/or prognosis of follicular cell-derived thyroid carcinomas: BRAF and RAS mutations, and RET/PTC and PAX8/PPARγ rearrangements. Other recent molecular biomarkers have been investigated in thyroid oncology, in particular different microRNA signatures. This review describes the different aspects of ancillary methods, including those bassed on molecular biology, that are of current interest for the diagnosis, prognosis and treatment of follicular cell-derived thyroid carcinomas. 23402841 Hematologic and hepatic responses of the freshwater fish Hoplias malabaricus after saxitoxin exposure. The bioaccumulation of saxitoxins (STX) in the trophic chain, mainly in freshwater, are not completely known. This work aimed to elucidate the effects of STX on Hoplias malabaricus through trophic bioassay. The fish were fed once every five days with Astyanax sp. before being subjected to an intraperitoneal inoculation with the lysate of Cylindrospermopsis raciborskii culture containing 97% STX and 3% by neosaxitoxin and gonyautoxin during 20 days. The animal's liver was assessed using biomarkers as activities of superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), and glutathione peroxidase (GPx), and concentrations of reduced glutathione (GSH) and lipoperoxidation (LPO) and protein carbonylation (PCO). In the blood was analyzed the genotoxic and hematological parameters. The hepatosomatic index and the relative condition factor did not show a significant difference between the exposed and control groups. The values of mean corpuscular hemoglobin concentration and mean corpuscular hemoglobin increased in the STX group. The hepatic tissue from both groups exhibited a typical pattern that have been already described for most teleost fish. The results suggested the generation of reactive oxygen species, with increased activity of GPx and concentrations of LPO and GSH; whereas the specific activity of SOD decreased. However, no changes were observed in the CAT, PCO, and DNA damage. Although the STX effects are known as neurotoxic, this cyanotoxin caused liver biochemical alterations that can be considered ecologically relevant. 23384997 Characterization of cytosolic glutathione peroxidase and phospholipid-hydroperoxide glutathione peroxidase genes in rainbow trout (Oncorhynchus mykiss) and their modulation by in vitro selenium exposure. Selenium (Se) is an oligonutrient with both essential biological functions and recognized harmful effects. As the selenocysteine (SeCys) amino acid, selenium is integrated in several Se-containing proteins (selenoproteins), many of which are fundamental for cell homeostasis. Nevertheless, selenium may exert toxic effects at levels marginally above those required, mainly through the generation of reactive oxygen species (ROS). The selenium chemical speciation can strongly affect the bioavailability of this metal and its impact on metabolism, dictating the levels that can be beneficial or detrimental towards an organism. Glutathione peroxidase (GPxs) is the largest and the most studied selenoprotein family. Cytosolic glutathione peroxidase (cGPx, GPx1) and phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) are widely distributed throughout tissues, and play a pivotal role in regulating the oxidative status in the cell. In this study we have cloned GPx1 and GPx4 genes in rainbow trout (Oncorhynchus mykiss). The constitutive mRNA expression of these GPx genes was examined in 18 trout tissues and their responsiveness to Se availability was analysed using a rainbow trout liver cell line (RTL). An inorganic (sodium selenite, Na2SeO3) and organic (selenocysteine, Cys-Se-Se-Cys) selenocompound have been used as Se sources. GPx1 activity was also tested to verify the impact of transcript changes on the enzymatic function of these molecules. To understand if the results obtained from the transcript expression analysis were due to Se bioavailability or generation of ROS, the cytoxicity of the two selenocompounds was tested by measuring the impact of Se on cell membrane integrity. Lastly, Se availability was quantified by mass spectrophotometry to determine the amount of Se in the cell culture media, the Se background due to the foetal calf serum supplement and the contribution from the two selenocompounds used in the treatments. Three isoforms of genes for both GPx1 (GPx1a, 1b1 and 1b2) and GPx4 (GPx4a1, a2 and b) have been identified. The discovery of a third gene encoding for GPx1 and GPx4 hints that salmonids may have the biggest selenoproteome amongst all vertebrates. Transcripts of GPx4 genes were more highly expressed in most tissues examined in vivo (except blood, head kidney and spleen), whereas those of the GPx1 genes were more responsive to selenium exposure in vitro, especially to the organic form. Interestingly, GPx1a was the most sensitive to selenium availability in non stressful conditions, whereas GPx1b1 and GPx1b2 were highly induced by exposure to selenium levels that had some toxic effects on the cells. Although the different concentrations tested of the two selenocompounds modulate GPx1 transcript expression to various degrees, no significant change of GPx1 enzymatic activity was detectable. Our results lead us to conclude that trout GPx1 transcripts expression level may represent a sensitive biomarker for selenium intake, helping to evaluate if selenium concentration and chemical speciation impact on cell homeostasis. 23434031 Design, synthesis and SAR of novel glucokinase activators. Guided by co-crystal structures of compounds 15, 22 and 30, an SBDD approach led to the discovery of the 6-methyl pyridone series as a novel class of GKAs that potently activate GK in enzyme and cell assays. Anti-diabetic OGTT efficacy was demonstrated with 54 in a mouse model of type 2 diabetes. 23178804 Characterization of epitopes recognized by monoclonal antibodies: experimental approaches supported by freely accessible bioinformatic tools. Monoclonal antibodies (mAbs) have been used successfully both in research and for clinical purposes. The possible use of protective mAbs directed against different microbial pathogens is currently being considered. The fine definition of the epitope recognized by a protective mAb is an important aspect to be considered for possible development in epitope-based vaccinology. The most accurate approach to this is the X-ray resolution of mAb/antigen crystal complex. Unfortunately, this approach is not always feasible. Under this perspective, several surrogate epitope mapping strategies based on the use of bioinformatics have been developed. In this article, we review the most common, freely accessible, bioinformatic tools used for epitope characterization and provide some basic examples of molecular visualization, editing and computational analysis. 23548584 Aqueous extract of Artemisia capillaris exerts hepatoprotective action in alcohol-pyrazole-fed rat model. ETHNOPHARMACOLOGIC RELEVANCE: Artemisia capillaris, also called "InJin" in Korean, has been widely used to treat various hepatic disorders in traditional Oriental medicine. AIMS: The purpose of this study is to evaluate the hepatoprotective effect of Artemisia capillaris (aqueous extract, WAC) on alcoholic liver injury. MATERIALS AND METHODS: Liver injury was induced by oral administration of 30% alcohol (10mL/kg, twice per day) plus pyrazole (PRZ, 30mg/kg) with/without WAC (50, 100mg/kg, orally once per day) or silymarin (50mg/kg) for 10 days. The hepatoprotective effects were assessed by observing histopathological changes, hepatic transaminase enzymes, hepatic oxidation and antioxidant parameters, inflammatory cytokines, and alcohol metabolic enzymes in serum and hepatic gene expression level, respectively. RESULTS: Alcohol-PRZ treatment drastically increased the serum levels of aspartate transaminase (AST), alanine transaminase (ALT), and malondialdehyde (MDA) levels in serum and liver tissues while these changes were significantly ameliorated by WAC administration (p<0.05 or 0.01). The prominent microvesicular steatosis and mild necrosis in hepatic histopathology were induced by alcohol-PRZ treatment, but notably attenuated by WAC administration. Moreover, the alcohol-PRZ treatment-induced depletions of the antioxidant components including glutathione content, total antioxidant capacity (TAC), activities of glutathione peroxidase (GSH-Px), reductase (GSH-Rd), catalase, and superoxide dismutase (SOD) were significantly ameliorated by WAC administration (p<0.05, except GSH-Rd). These results were in accordance with the modulation of NF-E2-related factor (Nrf2) and heme oxygenase-1 (HO-1) gene expression. Alcohol-PRZ treatment increased the levels of tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) in hepatic tissues. However they were significantly normalized by WAC administration (p<0.05 or 0.01). In addition, WAC administration significantly attenuated the alterations of aldehyde dehydrogenase (ALDH) level in serum and hepatic gene expressions of ALDH and alcohol dehydrogenase (ADH). CONCLUSIONS: These results support the relevance in clinical use of Artemisia capillaris for alcohol-associated hepatic disorders. The underlying mechanisms may involve both enhancement of antioxidant activities and modulation of proinflammatory cytokines. 23339663 Inhibition pathways of the potent organophosphate CBDP with cholinesterases revealed by X-ray crystallographic snapshots and mass spectrometry. Tri-o-cresyl-phosphate (TOCP) is a common additive in jet engine lubricants and hydraulic fluids suspected to have a role in aerotoxic syndrome in humans. TOCP is metabolized to cresyl saligenin phosphate (CBDP), a potent irreversible inhibitor of butyrylcholinesterase (BChE), a natural bioscavenger present in the bloodstream, and acetylcholinesterase (AChE), the off-switch at cholinergic synapses. Mechanistic details of cholinesterase (ChE) inhibition have, however, remained elusive. Also, the inhibition of AChE by CBDP is unexpected, from a structural standpoint, i.e., considering the narrowness of AChE active site and the bulkiness of CBDP. In the following, we report on kinetic X-ray crystallography experiments that provided 2.7-3.3 Å snapshots of the reaction of CBDP with mouse AChE and human BChE. The series of crystallographic snapshots reveals that AChE and BChE react with the opposite enantiomers and that an induced-fit rearrangement of Phe297 enlarges the active site of AChE upon CBDP binding. Mass spectrometry analysis of aging in either H(2)(16)O or H(2)(18)O furthermore allowed us to identify the inhibition steps, in which water molecules are involved, thus providing insights into the mechanistic details of inhibition. X-ray crystallography and mass spectrometry show the formation of an aged end product formed in both AChE and BChE that cannot be reactivated by current oxime-based therapeutics. Our study thus shows that only prophylactic and symptomatic treatments are viable to counter the inhibition of AChE and BChE by CBDP. 23608239 Protective effect of ethyl acetate fraction of Acacia ferruginea DC. against ethanol-induced gastric ulcer in rats. ETHNOPHARMACOLOGICAL RELEVANCE: In traditional systems of medicine, stem bark of Acacia ferruginea DC. is used for the treatment of itching, leucoderma, ulcers, stomatitis and diseases of the blood. In the present study, we determined antioxidant and anti-ulcerogenic activities of Acacia ferruginea stem bark. MATERIALS AND METHODS: Acetone extract and its sub-fractions of Acacia ferruginea stem bark were subjected to assess their antioxidant potential using various in vitro systems such as DPPH(•), ABTS(•+) scavenging, FRAP and phosphomolybdenum reduction activities. Based on the antioxidant potential, the ethyl acetate fraction was used to evaluate the protective effect of ethanol-induced gastric damage in rat model. Enzyme activities such as superoxide dismutase, glutathione, catalase and lipid peroxidation were also determined in the stomach tissues. RESULTS: Ethyl acetate fraction (AFE) of Acacia ferruginea stem bark registered higher antioxidant and free radical scavenging activities than the crude acetone extract and other fractions. In addition, AFE exhibited that the IC50 values of DPPH (2.5µg/ml) and ABTS (1.8µg/ml) were lower when compared to the standard quercetin (12.4µg/ml and 4.7µg/ml, respectively). In ethanol induced gastric ulcer, administration of AFE at doses of 10mg/kg, 50mg/kg and 100mg/kg body weight prior to ethanol ingestion significantly protected the stomach ulceration. Consequently significant changes were observed in enzyme activities such as SOD, CAT, GSH and LPO in the stomach tissues when compared with ethanol control group. CONCLUSION: It is concluded that the ethyl acetate fraction of Acacia ferruginea stem bark possessed higher antioxidant and anti-ulcerogenic activities. Based on the results we suggest that Acacia ferruginea stem bark has potential to provide a therapeutic approach to ethanol mediated ulcer as an effective anti-ulcer agent. 22918489 Isolation and characterization of two new non-hemorrhagic metalloproteinases with fibrinogenolytic activity from the mapanare (Bothrops colombiensis) venom. Colombienases are acidic, low molecular weight metalloproteinases (Mr of 23,074.31 Da colombienase-1 and 23,078.80 Da colombienase-2; pI of 6.0 and 6.2, respectively) isolated from Bothrops colombiensis snake venom. The chromatographic profile in RP-HPLC and its partial sequence confirmed its high homogeneity. Both colombienases present fibrino(geno)lytic activity, but did not show any hemorrhagic, amidolytic, plasminogen activator or coagulant activities, and no effect on platelet aggregation induced by collagen or ADP. Both enzymes were strongly active on fibrinogen Aα chains followed by the Bβ chains, and colombienases-2, at high doses, also degraded the γ chains. This activity was stable at temperatures ranging between 4 and 37 °C, with a maximum activity at 25 °C, and at pHs between 7 and 9. The homology demonstrated by the comparison of sequences, with zinc-dependent metalloproteinases, as well as the metal chelant effects on, confirmed that the colombienases were metalloproteinases, particularly to α-fibrinogenases belonging to the P-I class of SVPMs (20-30 kDa), which contain only the single-domain proteins. The biological characteristics of the colombienases confer a therapeutic potential, since they contain a high fibrino(geno)lytic activity, devoid of hemorrhagic activity. These metalloproteinases might be explored as thrombolytic agents given that they dissolve fibrin clots or prevent their formation. 23303469 Voltage tuning of ferromagnetic resonance with bistable magnetization switching in energy-efficient magnetoelectric composites. Dual E- and H-field control of microwave performance with enhanced ferromagnetic resonance (FMR) tunability has been demonstrated in microwave composites FeGaB/PZN-PT(011). A voltage-impulse-induced non-volatile magnetization switching was also realized in this work, resulting from the hysteretic type of phase transition in PZN-PT(011) at high electric fields. The results provide a framework for developing lightweight, energy efficient, voltage-tunable RF/microwave devices. 23517726 Synthesis and biological activities of some novel aminomethyl derivatives of 4-substituted-5-(2-thienyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones. A novel series of compounds were synthesized by cyclic condensation reaction of substituted isothiocyanate (2a-c) with 2-thiophenecarboxylic acid hydrazide (1) in the presence of ethyl alcohol, to obtain intermediate thiosemicarbazides (3a-c), which were further treated with sodium hydroxide in the presence of ethanol to obtain triazole derivatives (4a-c). The latter were refluxed with substituted secondary amines and formaldehyde for 6-10 h to afford Mannich bases (5a-k). The synthesized compounds were characterized on the basis of their spectral (IR, (13)C and (1)H NMR) data and evaluated for biological activities. Some of the compounds were found to exhibit significant antimicrobial and antioxidant activity. 23425314 Silver-zwitterion organic-inorganic nanocomposite with antimicrobial and antiadhesive capabilities. In this work, we demonstrate a convenient, efficient, and environmentally benign strategy to achieving antimicrobial and antiadhesive purposes using a silver-zwitterion nanocomposite. The synthesis of the nanocomposite relies on loading zwitterionic polymer brushes with Ag(+) precursor ions, followed by their in situ reduction to Ag nanoparticle by ultraviolet (UV) irradiation. Both poly(sulfobetaine methacrylate) (pSBMA) and poly(carboxybetaine methacrylate) (pCBMA) have been studied as matrices for the embedding of silver. Well-dispersed silver nanoparticles are embedded into pCBMA matrices. The obtained pCBMA-silver hybrid (CB-Ag) is capable of killing bacteria upon contact and releasing dead bacteria under wet conditions. Results suggest the feasibility of using this nanocomposite system as a robust and reliable antimicrobial and antiadhesive platform for the prevention of microbial colonization. 23266827 Talin1 has unique expression versus talin 2 in the heart and modifies the hypertrophic response to pressure overload. Integrins are adhesive, signaling, and mechanotransduction proteins. Talin (Tln) activates integrins and links it to the actin cytoskeleton. Vertebrates contain two talin genes, tln1 and tln2. How Tln1 and Tln2 function in cardiac myocytes (CMs) is unknown. Tln1 and Tln2 expression were evaluated in the normal embryonic and adult mouse heart as well as in control and failing human adult myocardium. Tln1 function was then tested in the basal and mechanically stressed myocardium after cardiomyocyte-specific excision of the Tln1 gene. During embryogenesis, both Tln forms are highly expressed in CMs, but in the mature heart Tln2 becomes the main Tln isoform, localizing to the costameres. Tln1 expression is minimal in the adult CM. With pharmacological and mechanical stress causing hypertrophy, Tln1 is up-regulated in CMs and is specifically detected at costameres, suggesting its importance in the compensatory response to CM stress. In human failing heart, CM Tln1 also increases compared with control samples from normal functioning myocardium. To directly test Tln1 function in CMs, we generated CM-specific Tln1 knock-out mice (Tln1cKO). Tln1cKO mice showed normal basal cardiac structure and function but when subjected to pressure overload showed blunted hypertrophy, less fibrosis, and improved cardiac function versus controls. Acute responses of ERK1/2, p38, Akt, and glycogen synthase kinase 3 after mechanical stress were strongly blunted in Tln1cKO mice. Given these results, we conclude that Tln1 and Tln2 have distinct functions in the myocardium. Our data show that reduction of CM Tln1 expression can lead to improved cardiac remodeling following pressure overload. 23534615 Directing Chondrogenesis of Stem Cells with Specific Blends of Cellulose and Silk. Biomaterials that can stimulate stem cell differentiation without growth factor supplementation provide potent and cost-effective scaffolds for regenerative medicine. We hypothesize that a scaffold prepared from cellulose and silk blends can direct stem cell chondrogenic fate. We systematically prepared cellulose blends with silk at different compositions using an environmentally benign processing method based on ionic liquids as a common solvent. We tested the effect of blend compositions on the physical properties of the materials as well as on their ability to support mesenchymal stem cell (MSC) growth and chondrogenic differentiation. The stiffness and tensile strength of cellulose was significantly reduced by blending with silk. The characterized materials were tested using MSCs derived from four different patients. Growing MSCs on a specific blend combination of cellulose and silk in a 75:25 ratio significantly upregulated the chondrogenic marker genes SOX9, aggrecan, and type II collagen in the absence of specific growth factors. This chondrogenic effect was neither found with neat cellulose nor the cellulose/silk 50:50 blend composition. No adipogenic or osteogenic differentiation was detected on the blends, suggesting that the cellulose/silk 75:25 blend induced specific stem cell differentiation into the chondrogenic lineage without addition of the soluble growth factor TGF-β. The cellulose/silk blend we identified can be used both for in vitro tissue engineering and as an implantable device for stimulating endogenous stem cells to initiate cartilage repair. 23497870 Aqueous enzymatic process assisted by microwave extraction of oil from yellow horn (Xanthoceras sorbifolia Bunge.) seed kernels and its quality evaluation. In this study, aqueous enzymatic process (AEP) assisted by microwave extraction (ME) of oil from yellow horn (Xanthoceras sorbifolia Bunge.) seed kernel was investigated. Central composite design (CCD) and response surface methodology (RSM) were used to optimise an enzyme cocktail (cellulase, hemicellulase, pectinase) for AEP. The main factors of ME were also studied. A maximal oil extraction yield of 55.8% was achieved under optimal conditions. Moreover, scanning electron microscope (SEM) was applied to characterise the extraction process. Analysing chemical composition of the extracted oil by GC-MS showed that the content of unsaturated fatty acids by this emerging method (91.18%) was similar to that by conventional organic solvent extraction (88.76%). In addition, the main physicochemical properties and antioxidant activities of yellow horn oil were measured to evaluate its quality. The present research supported necessary data for the green extraction method of edible oil in food industry. 23147987 Effects-based marine ecological risk assessment at a polychlorinated biphenyl-contaminated site in Saglek, Labrador, Canada. Although the presence and distribution of polychlorinated biphenyls (PCBs) in Arctic marine environments has been well documented, the implications for the health of biota are poorly understood. In the present study, multiple lines of evidence, including site-specific effects data, were used to assess PCB-related risks to marine biota at a contaminated military site in Saglek Bay, Labrador, Canada, from 1997 to 1999. Risks were evaluated for three components of the ecosystem: benthic invertebrates, a bottom-feeding fish (shorthorn sculpin, Myoxocephalus scorpius), and a diving seabird (black guillemot, Cepphus grylle). Average sediment PCB concentrations exceeded the Canadian interim sediment quality guideline level by 41-fold. However, sediment toxicity testing and a benthic community survey showed no evidence of adverse effects. In contrast, shorthorn sculpin and black guillemot PCB exposures (measured as sum of 55 congeners) were elevated enough to pose risks to survival or reproduction. Based on the collective evidence, the authors estimated that risks were posed by sediment PCB concentrations greater than 77 ng/g dry weight for black guillemots and 750 ng/g dry weight for shorthorn sculpins. The present study, along with two parallel studies, provided information to support the management decisions concerning potential remedial action on the contaminated sediments. This ecological risk assessment describes the steps and rationale taken to evaluate the risk posed by an area of PCB-contaminated marine sediments in an otherwise relatively pristine northern coastal environment. 23583787 Biopharmaceutical classification of poorly soluble drugs with respect to "enabling formulations" The large number of drug candidates with poor dissolution characteristics seen in the past decade, has fostered interest in so-called "enabling formulations", i.e., formulations which shall make such drugs bio-available. Development of enabling formulations is currently being guided by the following (simplified) hypothesis: If a poorly soluble drug (BCS class II drug) can be transferred into a solubilized state, one can achieve an absorption profile close to that of a soluble drug (BCS class I drug). Thus, formulation development typically endeavors to achieve the most robust solubility enhancement. Here we critically review both common in vitro approaches and experimental data available in literature pertaining to the solubility and permeability of poorly soluble drugs from enabling formulations, and discuss their interplay. Recent in vitro data indicate, that commonly employed surfactants as well as endogenous surfactants present in the intestine, although enhancing drug solubility, mostly hamper drug permeation. Mechanistic studies demonstrate a direct correlation between passive transcellular diffusion and the concentration of molecularly dissolved drug. The latter may be reduced due to partitioning into micelles or other solubilizing carriers, but enhanced in supersaturating formulations. We conclude thus that biopharmaceutical assessment approaches that rely on the amount of molecularly dissolved drug should guide us towards successful enabling formulations. 23464629 Effect of stachydrine on endoplasmic reticulum stress-induced apoptosis in rat kidney after unilateral ureteral obstruction. Our study aimed at determining the effect of stachydrine on the PERK, CHOP, and caspase-3 in rat kidney with RIF. Rats were randomly divided into control group, model group, enalapril group, high stachydrine group, medium stachydrine group, and low stachydrine group. RIF models of five groups were developed by unilateral ureteral obstruction except the control group. The rats were sacrificed 12 days after surgery and blood samples were collected. Serum creatinine (Scr) and blood urea nitrogen (BUN) levels were detected. Renal tubular damage index was determined by HE staining. The area percentage of RIF was determined by the Masson method. Expressions of PERK, CHOP, and caspase-3 in kidney were determined by immunohistochemistry. Tubulointerstitial injury index, RIF, serum Scr, BUN level, and expressions of PERK, CHOP, and caspase-3 were different between the model and treatment groups (P < 0.05; P < 0.01). The expressions of PERK, CHOP, and caspase-3 in nephridial tissue were reduced (P < 0.05), tubulointerstitial injury and RIF were reduced (P < 0.05), and Scr and BUN were lower (P < 0.05) in the high stachydrine group than those in the enalapril group. The expressions of PERK, CHOP, and caspase-3 were reduced in the endoplasmic reticulum stress-related apoptosis pathway after stachydrine treatment. Consequently, apoptosis was prevented, and RIF was inhibited. 23458616 TRAIL-Based Therapeutic Approaches for the Treatment of Pediatric Malignancies. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a pro-apoptotic ligand that has shown the exquisite ability to trigger extrinsic apoptosis in various types of cancer cells without significant toxicity toward normal cells, when compared to other pro-apoptotic ligands such as tumor necrosis factor (TNF) α or Fas ligand. Consequently, TRAIL-based therapies aim to trigger apoptosis in cancer cells by providing the soluble TRAIL or monoclonal antibodies targeting the death receptors TRAIL-R1 or TRAIL-R2. In this review, we start by highlighting the relevance of the tumor microenvironment in tumor development and elimination. We then address conventional and targeted therapeutic approaches for cancer treatment, highlighting the mechanisms involved or targeted. We describe the extrinsic and intrinsic pro-apoptotic pathways of TRAIL, together with the evidences for its pro-survival signaling, and with the relevance of these pathways in therapy. Possible mechanisms of resistance to TRAIL-induced apoptosis are highlighted (i.e. c-FLIP, Bcl-2, IAPs, p53, NF-κ B) and the rationale for the combined administration of TRAIL with drugs targeting these mechanisms is provided. Preclinical data are reported and show encouraging evidences for TRAIL consideration in pediatric malignancies (i.e., leukemia, lymphomas, neuroblastoma, osteosarcoma, medulloblastoma). Clinical trials of TRAIL-based therapies on the overall population are in phase I or II, and we put particular focus on the pediatric population, on which only few trials have been conducted or are ongoing. Finally, we consider emerging cellular therapies based on TRAIL, such as TRAIL-engineered mesenchymal stem cells or 'inflammatory' dendritic cells. 23055445 Multi-fuel driven Janus micromotors. Here the first example of a chemically powered micromotor that harvests its energy from the reactions of three different fuels is presented. The new Al/Pd Janus microspheres-prepared by depositing a Pd layer on one side of Al microparticles-are propelled efficiently by the thrust of hydrogen bubbles generated from different reactions of Al in strong acidic and alkaline environments, and by an oxygen bubble thrust produced at their partial Pd coating in hydrogen peroxide media. High speeds and long lifetimes of 200 μm s(-1) and 8 min are achieved in strong alkaline media and acidic media, respectively. The ability to autonomously adapt to the presence of a new fuel (surrounding environment), without compromising the propulsion behavior is illustrated. These data also represent the first example of a chemically powered micromotor that propels autonomously and efficiently in alkaline environments (pH > 11) without additional fuels. The ability to use multiple fuel sources to power the same micromotor offers a broader scope of operation and considerable promise for diverse applications of micromotors in different chemical environments. 23589515 Direct Laser-Patterned Micro-Supercapacitors from Paintable MoS2 Films. Micrometer-sized electrochemical capacitors have recently attracted attention due to their possible applications in micro-electronic devices. Here, a new approach to large-scale fabrication of high-capacitance, two-dimensional MoS2 film-based micro-supercapacitors is demonstrated via simple and low-cost spray painting of MoS2 nanosheets on Si/SiO2 chip and subsequent laser patterning. The obtained micro-supercapacitors are well defined by ten interdigitated electrodes (five electrodes per polarity) with 4.5 mm length, 820 μm wide for each electrode, 200 μm spacing between two electrodes and the thickness of electrode is ∼0.45 μm. The optimum MoS2 -based micro-supercapacitor exhibits excellent electrochemical performance for energy storage with aqueous electrolytes, with a high area capacitance of 8 mF cm(-2) (volumetric capacitance of 178 F cm(-3) ) and excellent cyclic performance, superior to reported graphene-based micro-supercapacitors. This strategy could provide a good opportunity to develop various micro-/nanosized energy storage devices to satisfy the requirements of portable, flexible, and transparent micro-electronic devices. 22961093 Don't judge a neuron only by its cover: neuronal function in in vitro developmental neurotoxicity testing. Classical cases of developmental neurotoxicity (DNT) in humans and advances in risk assessment methods did not prevent the emergence of new chemicals with (suspected) DNT potential. Exposure to these chemicals may be related to the increased worldwide incidence of learning and neurodevelopmental disorders in children. DNT is often investigated in a traditional manner (in vivo using large numbers of experimental animals), whereas development of in vitro methods for DNT reduces animal use and increases insight into cellular and molecular mechanisms of DNT. Several essential neurodevelopmental processes, including proliferation, migration, differentiation, formation of axons and dendrites, synaptogenesis, and apoptosis, are already being evaluated in vitro using biochemical and morphological endpoints. Yet, investigation of chemical-induced effects on the development of functional neuronal networks, including network formation, inter- and intracellular signaling and neuronal network function, is underrepresented in DNT testing. This view therefore focuses on in vitro models and innovative experimental approaches for functional DNT testing, ranging from optical and electrophysiological measurements of intra- and intercellular signaling in neural stem/progenitor cells to measurements of network activity in neuronal networks using multielectrode arrays. The development of functional DNT assays will strongly support the decision-making process for measures to prevent potential chemical-induced adverse effects on neurodevelopment and cognition in humans. We therefore argue that for risk assessment, biochemical and morphological approaches should be complemented with investigations of neuronal (network) functionality. 23510389 Degradable Cationic Shell Cross-Linked Knedel-like Nanoparticles: Synthesis, Degradation, Nucleic Acid Binding, and in Vitro Evaluation. In this work, degradable cationic shell cross-linked knedel-like (deg-cSCK) nanoparticles were developed as an alternative platform to replace similar nondegradable cSCK nanoparticles that have been utilized for nucleic acids delivery. An amphiphilic diblock copolymer poly(acrylamidoethylamine)90-block-poly(dl-lactide)40 (PAEA90-b-PDLLA40) was synthesized, self-assembled in aqueous solution, and shell cross-linked using a hydrolyzable cross-linker to afford deg-cSCKs with an average core diameter of 45 ± 7 nm. These nanoparticles were fluorescently labeled for in vitro tracking. The enzymatic- and hydrolytic-degradability, siRNA binding affinity, cell uptake and cytotoxicity of the deg-cSCKs were evaluated. Esterase-catalyzed hydrolysis of the nanoparticles resulted in the degradation of ca. 24% of the PDLLA core into lactic acid within 5 d, as opposed to only ca. 9% degradation from aqueous solutions of the deg-cSCK nanoparticles in the absence of enzyme. Cellular uptake of deg-cSCKs was efficient, while exhibiting low cytotoxicity with LD50 values of ca. 90 and 30 μg/mL in RAW 264.7 mouse macrophages and MLE 12 cell lines, respectively, ca. 5- to 6-fold lower than the cytotoxicity observed for nondegradable cSCK analogs. Additionally, deg-cSCKs were able to complex siRNA at an N/P ratio as low as 2, and were efficiently able to facilitate cellular uptake of the complexed nucleic acids. 23643695 Epigenetic Mechanisms of Drug Addiction. Drug addiction involves potentially life-long behavioral abnormalities that are caused in vulnerable individuals by repeated exposure to a drug of abuse. The persistence of these behavioral changes suggests that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. Work over the past decade has demonstrated a crucial role for epigenetic mechanisms in driving lasting changes in gene expression in diverse tissues, including brain. This has prompted recent research aimed at characterizing the influence of epigenetic regulatory events in mediating the lasting effects of drugs of abuse on the brain in animal models of drug addiction. This review provides a progress report of this still early work in the field. As will be seen, there is robust evidence that repeated exposure to drugs of abuse induces changes within the brain's reward regions in three major modes of epigenetic regulation-histone modifications such as acetylation and methylation, DNA methylation, and non-coding RNAs. In several instances, it has been possible to demonstrate directly the contribution of such epigenetic changes to addiction-related behavioral abnormalities. Studies of epigenetic mechanisms of addiction are also providing an unprecedented view of the range of genes and non-genic regions that are affected by repeated drug exposure and the precise molecular basis of that regulation. Work is now needed to validate key aspects of this work in human addiction and evaluate the possibility of mining this information to develop new diagnostic tests and more effective treatments for addiction syndromes. 23391095 Solvent and pressure effects on the motions of encapsulated guests: tuning the flexibility of a supramolecular host. The supramolecular host assembly [Ga4L6](12-) [1; L = 1,5-bis(2,3-dihydroxybenzamido)naphthalene] contains a flexible, hydrophobic interior cavity that can encapsulate cationic guest molecules and catalyze a variety of chemical transformations. The Ar-CH2 bond rotational barrier for encapsulated ortho-substituted benzyl phosphonium guest molecules is sensitive to the size and shape of the host interior space. Here we examine how changes in bulk solvent (water, methanol, or DMF) or applied pressure (up to 150 MPa) affect the rotational dynamics of encapsulated benzyl phosphonium guests, as a way to probe changes in host cavity size or flexibility. When host 1 is dissolved in organic solvents with large solvent internal pressures (∂U/∂V)T, we find that the free energy barrier to Ar-CH2 bond rotation increases by 1-2 kcal/mol, compared with that in aqueous solution. Likewise, when external pressure is applied to the host-guest complex in solution, the bond rotational rates for the encapsulated guests decrease. The magnitude of these rate changes and the volumes of activation obtained using either solvent internal pressure or applied external pressure are very similar. NOE distance measurements reveal shorter average host-guest distances (~0.3 Å) in organic versus aqueous solution. These experiments demonstrate that increasing solvent internal pressure or applied external pressure reduces the host cavity size or flexibility, resulting in more restricted motions for encapsulated guest molecules. Changing bulk solvent or external pressure might therefore be used to tune the physical properties or reactivity of guest molecules encapsulated in a flexible supramolecular host. 23206867 Design, synthesis and bioevalution of novel benzamides derivatives as HDAC inhibitors. A series of novel benzamides derivatives was designed and synthesized as HDAC inhibitors. Exploration of the structure-activity relationships resulted in compounds that are potent in vitro. In addition, the best compound 1a exhibited an acceptable pharmacokinetic profile with bioavailability in rat of 81% and could be considered as a candidate compound for further development. 23161581 Influence of silver doping on electron transport in thin films of PbSe nanocrystals. Field-effect transistors are fabricated from thin films of Ag-doped PbSe nanocrystals to analyze the influence of electronically active impurities on electrical transport in this important material for nanocrystal applications. Data is collected as a function of nanocrystal size, dopant concentration, and temperature. Changes in the Fermi level and transport parameters indicate that Ag is acting as a p-type dopant (acceptor). 23364186 Tetrabenzoporphyrins: synthetic developments and applications. Tetrabenzoporphyrins have attracted considerable worldwide attention over the last few decades. Since the discovery of these pigments, chemists, biologists, medical professionals and material scientists have devoted pronounced efforts in order to develop synthetic methods and discover useful applications for these compounds. Nowadays, tetrabenzoporphyrins occupy a prominent position in porphyrin chemistry, and this review is intended to cover the main synthetic methods and applications of these compounds. 23303341 Sample solution constraints on motor-driven diagnostic nanodevices. The last decade has seen appreciable advancements in efforts towards increased portability of lab-on-a-chip devices by substituting microfluidics with molecular motor-based transportation. As of now, first proof-of-principle devices have analyzed protein mixtures of low complexity, such as target protein molecules in buffer solutions optimized for molecular motor performance. However, in a diagnostic work-up, lab-on-a-chip devices need to be compatible with complex biological samples. While it has been shown that such samples do not interfere with crucial steps in molecular diagnostics (for example antibody-antigen recognition), their effect on molecular motors is unknown. This critical and long overlooked issue is addressed here. In particular, we studied the effects of blood, cell lysates and solutions containing genomic DNA extracts on actomyosin and kinesin-microtubule-based transport, the two biomolecular motor systems that are most promising for lab-on-a-chip applications. We found that motor function is well preserved at defined dilutions of most of the investigated biological samples and demonstrated a molecular motor-driven label-free blood type test. Our results support the feasibility of molecular-motor driven nanodevices for diagnostic point-of-care applications and also demonstrate important constraints imposed by sample composition and device design that apply both to kinesin-microtubule and actomyosin driven applications. 23452237 Characterization of a pre-export enzyme-chaperone complex on the twin-arginine transport pathway. The Tat (twin-arginine translocation) system is a protein targeting pathway utilized by prokaryotes and chloroplasts. Tat substrates are produced with distinctive N-terminal signal peptides and are translocated as fully folded proteins. In Escherichia coli, Tat-dependent proteins often contain redox cofactors that must be loaded before translocation. Trimethylamine N-oxide reductase (TorA) is a model bacterial Tat substrate and is a molybdenum cofactor-dependent enzyme. Co-ordination of cofactor loading and translocation of TorA is directed by the TorD protein, which is a cytoplasmic chaperone known to interact physically with the TorA signal peptide. In the present study, a pre-export TorAD complex has been characterized using biochemical and biophysical techniques, including SAXS (small-angle X-ray scattering). A stable, cofactor-free TorAD complex was isolated, which revealed a 1:1 binding stoichiometry. Surprisingly, a TorAD complex with similar architecture can be isolated in the complete absence of the 39-residue TorA signal peptide. The present study demonstrates that two high-affinity binding sites for TorD are present on TorA, and that a single TorD protein binds both of those simultaneously. Further characterization suggested that the C-terminal 'Domain IV' of TorA remained solvent-exposed in the cofactor-free pre-export TorAD complex. It is possible that correct folding of Domain IV upon cofactor loading is the trigger for TorD release and subsequent export of TorA. 23399444 Effects of chronic dietary selenomethionine exposure on repeat swimming performance, aerobic metabolism and methionine catabolism in adult zebrafish (Danio rerio). In a previous study we reported impaired swimming performance and greater stored energy in adult zebrafish (Danio rerio) after chronic dietary exposure to selenomethionine (SeMet). The goal of the present study was to further investigate effects of chronic exposure to dietary SeMet on repeat swimming performance, oxygen consumption (MO2), metabolic capacities (standard metabolic rate [SMR], active metabolic rate [AMR], factorial aerobic scope [F-AS] and cost of transport [COT]) and gene expression of energy metabolism and methionine catabolism enzymes in adult zebrafish. Fish were fed SeMet at measured concentrations of 1.3, 3.4, 9.8 or 27.5 μg Se/g dry mass (d.m.) for 90 d. At the end of the exposure period, fish from each treatment group were divided into three subgroups: (a) no swim, (b) swim, and (c) repeat swim. Fish from the no swim group were euthanized immediately at 90 d and whole body triglycerides, glycogen and lactate, and gene expression of energy metabolism and methionine catabolism enzymes were determined. Individual fish from the swim group were placed in a swim tunnel respirometer and swimming performance was assessed by determining the critical swimming speed (U(crit)). After both Ucrit and MO2 analyses, fish were euthanized and whole body energy stores and lactate were determined. Similarly, individual fish from the repeat swim group were subjected to two U(crit) tests (U(crit-1) and U(crit-2)) performed with a 60 min recovery period between tests, followed by determination of energy stores and lactate. Impaired swim performance was observed in fish fed SeMet at concentrations greater than 3 μg Se/g in the diet. However, within each dietary Se treatment group, no significant differences between single and repeat U(crits) were observed. Oxygen consumption, SMR and COT were significantly greater, and F-AS was significantly lesser, in fish fed SeMet. Whole body triglycerides were proportional to the concentration of SeMet in the diet. While swimming resulted in lesser concentrations of glycogen in the body, exposure to SeMet in the diet had no significant effect on glycogen content. Exposure to SeMet significantly down-regulated mRNA abundance of protein tyrosine phosphatase 1B (PTP 1B) in muscle, and β-hydroxyacyl coenzyme A dehydrogenase (HOAD), sterol regulatory element binding protein 1 (SREBP 1) and methionine adenosyltransferase 1 alpha (MAT 1A) in liver of adult zebrafish. Overall the results of this study suggest chronic exposure of adult zebrafish to SeMet in the diet can cause both cellular and organismal effects that could affect fitness and survivability of fish. 23517076 Effects of Gentamicin on the Proteomes of Aerobic and Oxygen-Limited Escherichia coli. The key role of the bacterial ribosome makes it an important target for antibacterial agents. Indeed, a large number of clinically useful antibiotics target this complex translational ribonucleoprotein machinery. Unfortunately, the development of resistant bacterial strains has compromised the effectiveness of most classes of antibacterial agent, including the classes that target the ribosome. Combinations of two or more drugs can be used to help overcome resistance, and in certain circumstances their action may be synergistic. In this study we have used proteomic techniques to establish the effects of gentamicin on the proteomes of aerobic and oxygen-limited Escherichia coli. Ribosomal proteins L1, L9, L10, and S2 were found to be up-regulated in both conditions, and we postulate that these are candidate drug targets for the development of synergistic combinations with gentamicin. 22508482 Egr-1 mediates epidermal growth factor-induced downregulation of E-cadherin expression via Slug in human ovarian cancer cells. Loss of the cell adhesion protein E-cadherin increases the invasive capability of ovarian cancer cells. We have previously shown that epidermal growth factor (EGF) downregulates E-cadherin and induces ovarian cancer cell invasion through the H(2)O(2)/p38 MAPK-mediated upregulation of the E-cadherin transcriptional repressor Snail. However, the molecular mechanisms underlying the EGF-induced downregulation of E-cadherin are not fully understood. In the current study, we demonstrated that treatment of two ovarian cancer cell lines, SKOV3 and OVCAR5, with EGF induced the expression of the transcription factor Egr-1, and this induction was abolished by small interfering RNA (siRNA)-mediated depletion of the EGF receptor. EGF-induced Egr-1 expression required the activation of the ERK1/2 and PI3K/Akt signaling pathways and was unrelated to EGF-induced H(2)O(2) production and activation of the p38 MAPK pathway. Moreover, depletion of Egr-1 with siRNA abolished the EGF-induced downregulation of E-cadherin and increased cell invasion. Interestingly, siRNA depletion of Egr-1 attenuated the EGF-induced expression of Slug, but not that of Snail. Moreover, chromatin immunoprecipitation (ChIP) analysis showed that Slug is a target gene of Egr-1. These results provide evidence that Egr-1 is a mediator that is involved in the EGF-induced downregulation of E-cadherin and increased cell invasion. Our results also demonstrate that EGF activates two independent signaling pathways, which are the H(2)O(2)/p38 MAPK-mediated upregulation of Snail expression and the Egr-1-mediated upregulation of Slug expression. These two signaling pathways contribute to the EGF-induced downregulation of E-cadherin, which subsequently increases the invasive capability of ovarian cancer cells. 23561211 LC-ESI-TOF-MS identification of bioactive secondary metabolites involved in the antioxidant, anti-inflammatory and anticancer activities of the edible halophyte Zygophyllum album Desf. In this work, liquid chromatography coupled to electrospray time-of-flight mass spectrometry (LC-ESI-TOF-MS) has been applied to screen bioactive metabolites in shoot extract of the medicinal halophyte Zygophyllum album. Among 10 compounds identified (saponins, flavonoids and sterols) five were reported for the first time in Z. album. Furthermore, novel biological activities of hexane, dichloromethane and methanolic extracts were assessed. Results showed that methanolic extract exhibit the highest antioxidant activity using in vitro ORAC test and anti-inflammatory activity, inhibiting by 84.8% NO release in RAW264.7 macrophages. However, dichloromethane extract proved the utmost antioxidant activity in cell (WS1) based-assay (IC50=57μg/ml) and interesting anticancer capacity against human lung carcinoma (A-549) and colon adenocarcinoma (DLD-1) cells (IC50=37 and 48μg/ml, respectively). These findings can be attributed to the presence of triterpenes, flavonoids and sterols in Z. album, which are widely known as powerful antioxidants and used in various industrial fields. 23259848 Simple strategy to functionalize polymeric substrates via surface-initiated ATRP for biomedical applications. The functionalization of polymer surfaces via surface-initiated atom transfer radical polymerization (ATRP) is of crucial importance to prepare various functional materials. It is generally complicated to conduct ATRP on different organic material surfaces. In this work, a facile photoinduced one-step method was first developed for the covalent immobilization of ATRP initiators on the C-H group-containing substrates such as biaxially oriented polypropylene (BOPP). The C-H bonds of precise location of inert polymer surfaces were readily transferred to bromoalkyl initiator, followed by ATRP of 2-(dimethylamino)ethyl methacrylate (DMAEMA) and glycidyl methacrylate (GMA), respectively, to produce the resultant patterned BOPP-g-P(DMAEMA) and BOPP-g-P(GMA) films. The epoxy groups of the P(GMA) microdomains can be aminated for covalently coupling IgG, while the P(DMAEMA) microdomains were used for immobilizing IgG via electronic interactions. The resultant IgG-coupled microdomains could interact with the corresponding target proteins, anti-IgG. 23452185 1,3,4-thiadiazole and its derivatives: a review on recent progress in biological activities. The 1,3,4-thiadiazole nucleus is one of the most important and well-known heterocyclic nuclei, which is a common and integral feature of a variety of natural products and medicinal agents. Thiadiazole nucleus is present as a core structural component in an array of drug categories such as antimicrobial, anti-inflammatory, analgesic, antiepileptic, antiviral, antineoplastic, and antitubercular agents. The broad and potent activity of thiadiazole and their derivatives has established them as pharmacologically significant scaffolds. In this study, an attempt has been made with recent research findings on this nucleus, to review the structural modifications on different thiadiazole derivatives for various pharmacological activities. 23561100 Enzymatic modification enhances the protective activity of citrus flavonoids against alcohol-induced liver disease. Alcoholic liver disease (ALD) can be developed by a prolonged or large intake of alcohol in a short period of time. ALD is considered as a leading cause for a liver injury in modern dietary life. This study was aimed to investigate the effects of orally administrated citrus flavonoids (CFs) and their enzymatically modified ones (EM-CFs) to prevent ALD. Hesperidin and narirutin were extracted from peels of Citrus unshiu by ultra-sonication and purified further. These CFs were modified enzymatically through glycosylation and de-rhamnosylation by the actions of cyclodextrin glucanotransferase (CGTase) and hesperidinase, respectively. CFs and EM-CFs were fed to ICR mouse along with ethanol for 8weeks, and changes in lipid contents, lipid peroxidation, GSH, antioxidant enzymes activity and proinflammatory cytokines in hepatic tissues were observed. Administration of CFs and EM-CFs along with alcohol significantly suppressed increases in prognostic parameters of a hepatocellular injury. Especially, EM-CFs fed groups maintained malondialdehyde, GSH levels and catalase activity in hepatic tissues close to those of the normal diet fed group. Abrupt increases in proinflammatory cytokines such as IκB-α, TNF-α, IL-1β and IL-6 in hepatocytes due to a chronic alcohol uptake were significantly suppressed by co-administration of EM-CFs. These results indicate that although the administration of CFs can alleviate ALD through preventing excessive lipid formation, protecting the antioxidant system and suppressing induction of inflammation in hepatocytes, their effectiveness can be further improved by glycosylation and de-rhamnosylation. 23434417 2-(Benzothiazol-2-yl)-phenyl-β-d-galactopyranoside derivatives as fluorescent pigment dyeing substrates and their application for the assay of β-d-galactosidase activities. 2-(Benzothiazol-2-yl)-phenyl-β-d-galactopyranoside derivatives were synthesized as novel artificial fluorescent pigment dyeing substrates for β-d-galactosidase. The substrates, which exhibited non-fluorescence or weak fluorescence in solution phase, were smoothly hydrolyzed by β-d-galactosidase from Aspergillus oryzae and yielded a water-insoluble strong fluorescent pigment. The difference of fluorescent intensity exhibited a linear relationship with the amount of enzyme. 23092895 Recent advances in topical ophthalmic drug delivery with lipid-based nanocarriers. Ocular barriers and the poor water solubility of drug candidates present a number of problems for the development of ocular drug delivery systems. Recently, the emergence of lipid-based nanocarriers has provided a viable means of enhancing the bioavailability of ophthalmic formulations. A number of these formulations have been found to be clinically active and several others are currently undergoing clinical trials. In this review, the advantages of lipid-based nanocarriers as non-invasive topical ocular drug delivery systems are presented. Many systems, including emulsions, liposomes, cubosomes, niosomes and other lipid-based nanocarriers, are reviewed. 23161692 SchistoDB: an updated genome resource for the three key schistosomes of humans. The new release of SchistoDB (http://SchistoDB.net) provides a rich resource of genomic data for key blood flukes (genus Schistosoma) which cause disease in hundreds of millions of people worldwide. SchistoDB integrates whole-genome sequence and annotation of three species of the genus and provides enhanced bioinformatics analyses and data-mining tools. A simple, yet comprehensive web interface provided through the Strategies Web Development Kit is available for the mining and visualization of the data. Genomic scale data can be queried based on BLAST searches, annotation keywords and gene ID searches, gene ontology terms, sequence motifs, protein characteristics and phylogenetic relationships. Search strategies can be saved within a user's profile for future retrieval and may also be shared with other researchers using a unique web address. 23434224 Pyridine to aniline: an exceptional biologically driven rearrangement. During the course of our study on the innovative ligand for nicotinic acetylcholinergic receptors, LNAChR, and in order to assess activity and toxicity profiles of the drug's metabolites, synthesis of the main metabolites was undertaken. This synthesis work was done in parallel by organic chemistry and by biotransformation of LNAChR. Filamentous fungus Aspergillus alliaceus (NRRL 315) neatly afforded three of the main metabolites, one of which arose from a very unexpected and very uncommon rearrangement. 23627670 Conformational determinants of the activity of Antiproliferative factor glycopeptide. The antiproliferative factor (APF) involved in interstitial cystitis is a glycosylated nonapeptide (TVPAAVVVA) containing a sialylated core α-O-disaccharide linked to the N-terminal threonine. The chemical structure of APF was deduced using spectroscopic techniques and confirmed using total syn-thesis. The synthetic APF provided a platform to study amino acid modifications and their effect on APF activity, based on which a structure-activity relationship (SAR) for APF activity was previously proposed. However, this SAR model could not explain the change in activity associated with minor al-terations in the peptide sequence. Presented is computational analysis of 14 APF derivatives to identify structural trends from which a more detailed SAR is obtained. The APF activity is found to be dictated by the close interplay between carbohydrate-peptide and peptide-peptide interactions. The former in-volves hydrogen bond and hydrophobic interactions and the latter is dominated by hydrophobic interac-tions. The highly flexible hydrophobic peptide adopts collapsed conformations separated by low energy barriers. APF activity correlates with hydrophobic clustering associated with amino acids 4A, 6V and 8V. Peptide conformations are highly sensitive to single point mutations, which explain the experi-mental trends. The presented SAR will act as a guide for lead optimization of more potent APF ana-logues of potential therapeutic utility. 23421432 Three new lanostanoid triterpenes from the fruiting bodies of Ganoderma tropicum. Three new lanostanoid triterpenes, 3β,7β,15β-trihydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid (1), 3β,7β,15β-trihydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid methyl ester (2), and 3β,15β-dihydroxy-7,11,23-trioxo-lanost-8,16-dien-26-oic acid methyl ester (3) were isolated from the EtOAc extract of the fruiting bodies of Ganoderma tropicum. Their structures were elucidated on the basis of 1D and 2D NMR spectroscopy as well as MS. The bioassay of inhibitory activity against acetylcholinesterase (AChE) of these isolates was evaluated and compound 2 exhibited definite inhibitory activity against AChE. 23632304 Calcium pathways such as cAMP modulate clothianidin action through activation of alpha-bungarotoxin-sensitive and -insensitive nicotinic acetylcholine receptors. Clothianidin is a neonicotinoid insecticide developed in the early 2000s. We have recently demonstrated that it was a full agonist of α-bungarotoxin-sensitive and -insensitive nicotinic acetylcholine receptors expressed in the cockroach dorsal unpaired median neurons. Clothianidin was able to act as an agonist of imidacloprid-insensitive nAChR2 receptor and internal regulation of cAMP concentration modulated nAChR2 sensitivity to clothianidin. In the present study, we demonstrated that cAMP modulated the agonist action of clothianidin via α-bungarotoxin-sensitive and insensitive receptors. Clothianidin-induced current-voltage curves were dependent to clothianidin concentrations. At 10μM clothianidin, increasing cAMP concentration induced a linear current-voltage curve. Clothianidin effects were blocked by 0.5μM α-bungarotoxin suggesting that cAMP modulation occurred through α-bungarotoxin-sensitive receptors. At 1mM clothianidin, cAMP effects were associated to α-bungarotoxin-insensitive receptors because clothianidin-induced currents were blocked by 5μM mecamylamine and 20μM d-tubocurarine. In addition, we found that application of 1mM clothianidin induced a strong increase of intracellular calcium concentration. These data reinforced the finding that calcium pathways including cAMP modulated clothianidin action on insect nicotinic acetylcholine receptors. We proposed that intracellular calcium pathways such as cAMP could be a target to modulate the mode of action of neonicotinoid insecticides. 23605695 Pasireotide: A Review of Its Use in Cushing's Disease. Pasireotide (Signifor(®)) is a new subcutaneous somatostatin analogue that acts via somatostatin receptors to inhibit the secretion of corticotropin from the pituitary adenoma in patients with Cushing's disease. Pasireotide has a receptor binding profile that is distinct from that of other somatostatin analogues, binding with high affinity to somatostatin receptor subtype 5, which is strongly over expressed in corticotroph adenoma cells. Pasireotide is the first pituitary-directed agent to be approved for use in Cushing's disease. In a phase III clinical trial in patients with Cushing's disease, twice-daily pasireotide 600 or 900 μg for 6 months led to normalization of urinary free cortisol (UFC) levels in up to a quarter of all patients (primary endpoint) and significantly reduced mean UFC levels. The reduction in UFC levels is rapid (within one to two months) and sustained (up to 24 months). Most patients who do not have an early response to pasireotide do not respond at a later time point. Decreases in UFC levels achieved during pasireotide treatment are accompanied by decreases in serum and salivary cortisol levels, as well as improvements in clinical signs and symptoms, including body weight, blood pressure and health-related quality-of-life. Pasireotide has a generally similar tolerability profile to that of other somatostatin analogues, but is associated with a relatively high incidence of hyperglycaemia, requiring the addition or intensification of glucose-lowering medication in a substantial proportion of patients. Thus, pasireotide, together with on-going patient monitoring, provides a promising new option for the medical management of Cushing's disease. 23126422 2-Amino-4-arylthiazole compounds as TRPA1 antagonists (WO 2012085662): a patent evaluation. The patent claims 2-amino-4-arylthiazole derivative compounds as inhibitors of the TRPA1 (transient receptor potential ankyrin, member 1) receptor. These compounds are potent antagonists on the basis of the results of in vitro assays, and are expected to be useful for treating conditions and disorders associated with TRPA1 function such as pain, chronic pain, neuropathic pain, rheumatoid arthritic pain, osteoarthritic pain, diabetic neuropathy and inflammatory disorders. 22876943 Anti-inflammatory trends of 1, 3-diphenyl-2-propen-1-one derivatives. Chalcones (1, 3-Diphenyl-2-propen-1-one) are constituted by a three carbon α, β-unsaturated carbonyl system. The biosynthesis of flavonoids and isoflavonoids is initiated by chalcones. Notable pharmacological activities of chalcones and its derivatives include anti-inflammatory, antifungal, antibacterial, antimalarial, antituberculosis, antitumor, antimicrobial and antiviral effects respectively. Owing to simplicity of the chemical structures and a huge variety of pharmacological actions exhibited, the entities derived from chalcones are subjected to extensive consideration. This review article is an effort to sum up the anti-inflammatory activities of chalcone derived chemical entities. Effect of chalcones on lipid peroxidation, heme oxygenase 1(HO-1), cyclooxygenase (COX), interleukin 5 (IL-5), nitric oxide (NO) and expression of cell adhesion molecules (CAM) is summarized stepwise. 23280488 Combined effects of the herbicide terbuthylazine and temperature on different flagellates from the Northern Adriatic Sea. The triazinic herbicide terbuthylazine (TBA) is becoming an emergent contaminant in Italian rivers and in coastal and groundwater. A preliminary analysis of the sensitivity of marine flagellates to TBA was performed by monitoring the photosynthetic efficiency of nine species (belonging to the Dinophyceae or Raphidophyceae class) isolated from the Adriatic Sea. Different sensitivity levels for each flagellate were observed and the most sensitive microalgae, based on PSII inhibition, were: Gonyaulax spinifera>Fibrocapsa japonica>Lingulodinium polyedrum while the most resistant were two species belonging to the Prorocentrum genus. Then the response of two microalgae to drivers, such as temperature and terbuthylazine, applied in combination was also investigated. Two potentially toxic flagellates, Prorocentrum minimum and G. spinifera, were exposed, under different temperature conditions (15, 20 and 25°C), to TBA concentrations that did not completely affect PSII. For both flagellates, effects of TBA on algal growth, measured through cell density and carbon analysis, as well as on the photosynthetic activity are reported. All parameters analyzed showed a negative effect of TBA from the exponential phase. TBA effect on algal growth was significantly enhanced at the optimal temperature conditions (20 and 25°C), while no difference between control and herbicide treatments were detected for G. spinifera grown at 15°C, which represented a stress condition for this species. The maximum inhibition of photosynthetic efficiency was found at 20°C for both organisms. Both flagellates increased cell carbon and nitrogen content in herbicide treatments compared to the control, except G. spinifera grown at 15°C. Chlorophyll-a production was increased only in G. spinifera exposed to 5 μg L(-1) of TBA and the effect was enhanced with the increase of temperature. Herbicide-induced variations in cellular components determined changes in cellular carbon:nitrogen (C:N) and chlorophyll:carbon (Chl:C) ratios. The C:N ratio decreased in both species, while only G. spinifera showed an increase in the Chl:C ratio at all temperature conditions. In response to TBA exposure G. spinifera increased extracellular polysaccharides release at 20 and 25°C, while no difference was reported for P. minimum. Changes in nutrient uptake rates were also observed for P. minimum. Nitrate and phosphate uptake significantly increased in the presence of TBA and this response was enhanced at 25°C, while nitrate uptake increased in G. spinifera only when grown at 25°C. As for growth rates, the observed changes in intracellular component contents increased at optimal temperature conditions. In this work it is shown that temperature conditions can have an important role on the effect of terbuthylazine on algal growth and on the physiological responses of different species. Furthermore, the algal resistance and recovery can be dependent on nutrient availability. 22429027 Two new triterpenoid saponins from the husks of Xanthoceras sorbifolia. Two new oleanane triterpenoid saponins, xanthohuskisides A (1) and B (2), were isolated from the husks of Xanthoceras sorbifolia. The structures of these two compounds were established as 3-O-β-D-glucopyranosyl (1→6)-[β-D-glucopyranosyl (1→2)]-β-D-glucopyranosyl, 28-O-β-D-glucopyranosyl (1→6)-[α-L-rhamnopyranosyl (1→2)]-β-D-glucopyranosyl 16-deoxybarringtogenol C (1) and 3-O-β-D-glucopyranosyl (1→6)-[β-D-glucopyranosyl (1→2)]-β-D-glucopyranosyl, 28-O-β-D-glucopyranosyl (1→6)-β-D-glucopyranosyl 16-deoxybarringtogenol C (2), respectively, based on the analysis on their spectral data including NMR and HR-ESI-MS. The growth inhibitory activities of compounds 1 and 2 were assayed, and 2 showed moderate activity against U937 cell line with the IG(50) value of 82.85 ± 1.58 µM. 22708583 A new acylated flavone glycoside with antioxidant and radical scavenging activities from Teucrium polium leaves. The antioxidant properties of six flavones from Teucrium polium L., one of them isolated for the first time, have been established through the determination of their abilities to inhibit free radicals using DPPH, ABTS radicals and ORAC test. The structure of the new metabolite has been elucidated by 1-D (1H, 13C and DEPT) and 2-D (COSY, TOCSY, HSQC, CIGAR) NMR experiments and by ESI Q-TOF HRMS analysis. Flavones 1-3 presented an efficacious activity towards the stable DPPH radical. Analogously, compounds 2 and 3 resulted significantly active also versus ABTS cation radical. On the basis of the comparable bioactivity of luteolin-based compounds, the presence of an ortho-dihydroxy substitution in the flavone B-ring is supposed to be the structural feature responsible for the antioxidant activity. 23564921 Expansion of the Homeostasis Model Assessment of β-Cell Function and Insulin Resistance to Enable Clinical Trial Outcome Modeling Through the Interactive Adjustment of Physiology and Treatment Effects--iHOMA2. OBJECTIVETo describe and make available an interactive, 24-variable homeostasis model assessment (iHOMA2) that extends the HOMA2 model, enabling the modeling of physiology and treatment effects, to present equations of the HOMA2 and iHOMA2 models, and to exemplify iHOMA2 in two widely differing scenarios: changes in insulin sensitivity with thiazolidinediones and changes in renal threshold with sodium glucose transporter (SGLT2) inhibition.RESEARCH DESIGN AND METHODSiHOMA2 enables a user of the available software to examine and modify the mathematical functions describing the organs and tissues involved in the glucose and hormonal compartments. We exemplify this with SGLT2 inhibition modeling (by changing the renal threshold parameters) using published data of renal effect, showing that the modeled effect is concordant with the effects on fasting glucose from independent data.RESULTSiHOMA2 modeling of thiazolidinediones effect suggested that changes in insulin sensitivity in the fasting state are predominantly hepatic. SGLT2 inhibition modeled by iHOMA2 resulted in a decrease in mean glucose of 1.1 mmol/L. Observed data showed a decrease in glucose of 0.9 mmol/L. There was no significant difference between the model and the independent data. Manipulation of iHOMA2s renal excretion threshold variable suggested that a decrease of 17% was required to obtain a 0.9 mmol/L decrease in mean glucose.CONCLUSIONSiHOMA2 is an extended mathematical model for the assessment of insulin resistance and β-cell function. The model can be used to evaluate therapeutic agents and predict effects on fasting glucose and insulin and on β-cell function and insulin sensitivity. 23411227 Non-destructive determination of chemical composition in intact and minced pork using near-infrared hyperspectral imaging. In this study a near-infrared (NIR) hyperspectral imaging technique was investigated for non-destructive determination of chemical composition of intact and minced pork. Hyperspectral images (900-1700 nm) were acquired for both intact and minced pork samples and the mean spectra were extracted by automatic segmentation. Protein, moisture and fat contents were determined by traditional methods and then related with the spectral information by partial least-squares (PLS) regression models. The coefficient of determination obtained by cross-validated PLS models indicated that the NIR spectral range had an excellent ability to predict the content of protein (R(2)(cv)=0.88), moisture (R(2)(cv)=0.87) and fat (R(2)(cv)=0.95) in pork. Regression models using a few selected feature-related wavelengths showed that chemical composition could be predicted with coefficients of determination of 0.92, 0.87 and 0.95 for protein, moisture and fat, respectively. Prediction of chemical contents in each pixel of the hyperspectral image using these prediction models yielded spatially distributed visualisations of the sample composition. 23523965 Copper induces apoptotic cell death through reactive oxygen species-triggered oxidative stress in the intertidal copepod Tigriopus japonicus. The copepod, Tigriopus japonicus is an important model for toxicity testing. However, no attempt has been made in analyzing the effect of toxicants at the level of the ROS-mediated signal transduction pathway. To understand copper-induced cytotoxicity at the molecular level, we employed several cellular and biochemical assays after exposure to copper, and found a significant induction of enzyme activities of antioxidant proteins with increased intracellular reactive oxygen species (ROS) as well as an increase of TUNEL-positive cells, but a decrease of BrdU-positive cells. In addition, several important genes such as p38 MAPK, antioxidant-related genes, Hsps, and apoptosis-related genes were significantly modulated by copper exposure. Taken together, we suggest that copper-induced cytotoxicity is mediated by the formation of intracellular ROS and oxidative stress in T. japonicus. Whole body biochemical assays such as TUNEL- and BrdU-assay will provide a better understanding of cellular responses such as apoptosis and cell death upon cytotoxic exposure of copper in T. japonicus. 23127820 Nine new steroidal glycosides from the roots of Cynanchum stauntonii. Nine new steroidal glycosides, named as stauntosides C-K (2, 5, 7-10, 13, 14, and 16), along with seven known compounds (1, 3, 4, 6, 11, 12, and 15) were isolated from the 95% ethanol extract of the roots of Cynanchum stauntonii. The structures of these new compounds were elucidated on the basis of extensive spectroscopic analyses, mainly 1D and 2D NMR, and HRESI-MS, and qualitative chemical methods. Their significance in terms of the chemotaxonomy of C. stauntonii is discussed. 23531554 Effect of oxygen concentration and selected protocol factors on viability and gene expression of mouse liver slices. Precision cut liver slices (PCLSs) are widely used as a model to study hepatotoxicity. For culturing of PCLS diverse protocols are used which could affect slices viability and results. We aimed to identify the most optimal culture protocol for mouse PCLS. Slices were cultured for 24h under different concentrations of serum, glucose, insulin, and oxygen. Thereafter, slices viability was assessed by biochemical methods. Transcriptome analysis was performed to identify changes introduced by culture at different oxygen concentrations (20%, 40%, 60%, and 80% of oxygen). Medium composition did not affect the slices viability. Although metabolic competence was unaffected by oxygen concentrations, culturing at 80% of oxygen yielded slices with the best biochemical characteristics. The comparison of uncultured vs. cultured slices revealed 2524 genes to be differentially expressed. Genes involved in drug metabolism, peroxisomal and mitochondrial functions were down-regulated while several adaptive/stress response processes were up-regulated. Moreover, 80% of oxygen was the most favorable condition with respect to maintenance of expression of genes involved in drug and energy metabolism. The outcome of this study indicates that mouse PCLS are a valuable tool in research on hepatic functions and toxicity, particularly if they are cultured under a controlled oxygen concentration of 80%. 23411077 A novel fluorogenic substrate for dinuclear Zn(II)-containing metallo-β-lactamases. In an effort to prepare a fluorogenic substrate to be used in activity assays with metallo-β-lactamases, (6R,7R)-8-oxo-7-(2-oxo-2H-chromene-3-carboxamido)-3-((4-(2-oxo-2H-chromene-3-carboxamido)-phenylthio)methyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (CA) was synthesized and characterized. CA exhibited a fluorescence quantum yield (φ) of 0.0059, two fluorescence lifetimes of 3.63×10(-10) and 5.38×10(-9)s, and fluorescence intensity that is concentration-dependent. Steady-state kinetic assays revealed that CA is a substrate for metallo-β-lactamases (MβLs) L1 and CcrA, exhibiting Km and kcat values of 18μM and 5s(-1) and 11μM and 17s(-1), respectively. 23250808 Evaluation of percutaneous absorption of esculetin: effect of chemical enhancers. Percutaneous transdermal absorption of esculetin (6,7-dihydroxycoumarin), an oxidative damage inhibitor, was evaluated by means of in vitro permeation studies in which vertical Franz-type diffusion cells and pig ear skin were employed. To determine the absorption of esculetin, we validated a simple, accurate, precise, and rapid HPLC-UV method. Additionally, the effects of several percutaneous enhancers were studied. Pretreatment of porcine skin was performed with ethanol (control vehicle), decenoic acid, oleic acid, R-(+)-limonene, and laurocapram (Azone®) (5% in ethanol, w/w, respectively). Pretreatment of skin with oleic acid or laurocapram led to statistically significant differences in the transdermal flux of esculetin with respect to controls. Of the two enhancers, laurocapram showed the greatest capacity to enhance the flux of esculetin across pig skin. 23403092 The food contaminant deoxynivalenol activates the mitogen activated protein kinases in the intestine: interest of ex vivo models as an alternative to in vivo experiments. Trichothecenes induce changes in the intestinal barrier function through decreased expression of cell junction proteins and apoptosis of enterocytes. The mitogen activated protein kinases (MAPK) play an important role in the signaling pathways of cell turnover and differentiation. Using ex vivo and in vivo approaches, the purpose of this study was to investigate the ability of low doses of DON to induce histological changes in the intestine and to activate the MAPK ERK 1/2, p38 and JNK. Twelve weaning piglets received during four weeks a control diet or a DON-contaminated diet (2.3 mg DON/kg feed). Six weaning piglets were used to prepare jejunal explants (ex vivo model). Explants were exposed during 4 h to vehicle, 5 or 10 μM DON. Intestinal changes were graded using a histological score. Pigs fed a DON-diet and explants exposed to DON showed a significant decrease in the jejunal score. In both models, the toxin significantly enhanced phosphorylation of ERK 1/2 and p38, whereas the increased phosphorylation of JNK was non significant. Taken together these results indicate that in vivo or ex vivo exposure of intestinal tissue to DON lead to similar intestinal lesions and activation of MAPK. These effects could impair the homeostasis of intestinal tissue in the aspects of barrier function and immune protection. The similarity of the in vivo and ex vivo results provides also strong evidence that the jejunal explant model is a good alternative for toxicological studies in intestinal tissue. 23543737 Loss of Calcium/Calmodulin-Dependent Protein Kinase II Activity in Cortical Astrocytes Decreases Glutamate Uptake and Induces Neurotoxic Release of ATP. The extent of calcium/calmodulin-dependent protein kinase II (CaMKII) inactivation in the brain following ischemia correlates with the extent of damage. We have previously shown that a loss of CaMKII activity in neurons is detrimental to neuronal viability by inducing excitotoxic glutamate release. In the current study, we extend these findings to show that the ability of astrocytes to buffer extracellular glutamate is reduced when CaMKII is inhibited. Furthermore, CaMKII inhibition in astrocytes is associated with the rapid onset of intracellular calcium oscillations. Surprisingly, this rapid calcium influx is blocked by the N-type calcium channel antagonist, omega-conotoxin. While the function of N-type calcium channels within astrocytes is controversial, these voltage-gated calcium channels have been linked to calcium-dependent vesicular gliotransmitter release. When extracellular glutamate and ATP levels are measured following CaMKII inhibition within our enriched astrocyte cultures, no alterations in glutamate levels are observed, whereas ATP levels in the extracellular environment significantly increase. Extracellular ATP accumulation associated with CaMKII inhibition contributes both to calcium oscillations within astrocytes and ultimately cortical neuron toxicity. Thus, a loss of CaMKII signaling within astrocytes dysregulates glutamate uptake and supports ATP release, two processes that would compromise neuronal survival following ischemic/excitotoxic insults. 23489627 Synthesis, crystal structure and biological evaluation of a main group seven-coordinated bismuth(III) complex with 2-acetylpyridine N4-phenylthiosemicarbazone. Up to now, bismuth(III) complexes with thiosemicarbazones have been comparatively rare. Here, a main group seven-coordinated bismuth(III) complex [Bi(L)(NO3)2(CH3CH2OH)] (1) (HL = 2-acetylpyridine N(4)-phenylthiosemicarbazone) has been synthesized and characterized by elemental analysis, IR, (1)H NMR and single-crystal X-ray diffraction studies. The cytotoxicity data suggest that 1 exhibits higher in vitro antiproliferative activity in four human cancer cells tested. Its possible apoptotic mechanism has been evaluated in HepG2 cells. Compound 1 promotes a dose-dependent apoptosis in HepG2 cells and the apoptosis is associated with an increase in intracellular reactive oxygen species (ROS) production and reduction of mitochondrial membrane potential (MMP). 22985736 Di 2-ethyl hexyl phthalate affects differentiation and matrix mineralization of rat calvarial osteoblasts--in vitro. Di-2-ethyl hexyl phthalate (DEHP), an industrial plasticizer and a ubiquitous environmental contaminant, is an established endocrine disruptor (ED). Increasing evidences indicate that some EDs interfere with osteoblast differentiation and function. In the present study, we investigated the effects of DEHP on the expression of cell cycle proteins, differentiation markers, Runx2 and its co-activator TAZ in osteoblasts derived from neonatal rat calvaria. A significant decrease in protein levels of cyclin D1 and CDK-2 was found at high dosage of DEHP (100 μM) after 24h treatment. DEHP treatment caused a significant decrease in ALP mRNA. While DEHP treatment significantly decreased the TAZ at mRNA and protein levels, it decreased only the Runx2protein levels. Histochemical localization of ALP, collagen and mineralized nodules studied from cells treated with DEHP (10 and 100 μM) for 21 days revealed a drastic decrease in collagen, ALP and mineralization. In conclusion, DEHP affected differentiation of neonatal rat calvarial osteoblasts and mineralization of matrix secreted by these cells. 23603615 Multiple treatments with liposomal doxorubicin and ultrasound-induced disruption of blood-tumor and blood-brain barriers improve outcomes in a rat glioma model. The blood-brain-barrier (BBB) prevents the transport of most anticancer agents to the central nervous system and restricts delivery to infiltrating brain tumors. The heterogeneous vascular permeability in tumor vessels, along with several other factors, creates additional barriers for drug treatment of brain tumors. Focused ultrasound (FUS), when combined with circulating microbubbles, is an emerging noninvasive method to temporarily permeabilize the BBB and the "blood-tumor barrier". Here, we tested the impact of three weekly sessions of FUS and liposomal doxorubicin (DOX) in 9L rat glioma tumors. Animals that received FUS+DOX (N=8) had a median survival time that was increased significantly (P<0.001) compared to animals who received DOX only (N=6), FUS only (N=8), or no treatment (N=7). Median survival for animals that received FUS+DOX was increased by 100% relative to untreated controls, whereas animals who received DOX alone had only a 16% improvement. Animals who received only FUS showed no improvement. No tumor cells were found in histology in 4/8 animals in the FUS+DOX group, and in two animals, only a few tumor cells were detected. Adverse events in the treatment group included skin toxicity, impaired activity, damage to surrounding brain tissue, and tissue loss at the tumor site. In one animal, intratumoral hemorrhage was observed. These events are largely consistent with known side effects of doxorubicin and with an extensive tumor burden. Overall this work demonstrates that multiple sessions using this FUS technique to enhance the delivery of liposomal doxorubicin have a pronounced therapeutic effect in this rat glioma model. 23280691 Estrogenic effects along the river Saale. Sediments along the river Saale, one of the main tributaries of the river Elbe, were characterized with the yeast estrogen screen to elucidate possible sources of endocrine-disrupting compounds that might contribute to the downstream contamination of the river Elbe. At two sampling sites, elevated levels of estrogenic activity up to 55,000 ng ethinylestradiol equivalents per kilogram sediment dry weight were detected in the respective sediment extracts. Aliquots of the sediment extracts were analyzed for 4-nonylphenols and natural steroidal estrogens as possible candidates with an estrogenic potential. The maximal concentrations of 4-iso-nonylphenol and estrone were 115 mg/kg dry weight and 20 µg/kg dry weight at the sampling site Luppe, which showed in accordance the highest biological activity. Under consideration of compound concentration and compound specific estrogenic activity the 4-iso-nonylphenols contributed most to the observed estrogenic effect. A strong correlation between the measured estrogenic activity and the concentration of the sediment-associated 4-iso-nonylphenol underlines the relevance of this compound class as a xenoestrogen in the catchment area of the river Saale. 23475784 Developing Predictive Approaches to Characterize Adaptive Responses of the Reproductive Endocrine Axis to Aromatase Inhibition: II. Computational Modeling. Endocrine-disrupting chemicals can affect reproduction and development in humans and wildlife. We developed a computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows to predict dose-response and time-course (DRTC) behaviors for endocrine effects of the aromatase inhibitor, fadrozole (FAD). The model describes adaptive responses to endocrine stress involving regulated secretion of a generic gonadotropin (LH/FSH) from the hypothalamic-pituitary complex. For model development, we used plasma 17β-estradiol (E2) concentrations and ovarian cytochrome P450 (CYP) 19A aromatase mRNA data from two time-course experiments, each of which included both an exposure and a depuration phase, and plasma E2 data from a third 4-day study. Model parameters were estimated using E2 concentrations for 0, 0.5, and 3 µg/l FAD exposure concentrations, and good fits to these data were obtained. The model accurately predicted CYP19A mRNA fold changes for controls and three FAD doses (0, 0.5, and 3 µg/l) and plasma E2 dose response from the 4-day study. Comparing the model-predicted DRTC with experimental data provided insight into how the feedback control mechanisms in the HPG axis mediate these changes: specifically, adaptive changes in plasma E2 levels occurring during exposure and "overshoot" occurring postexposure. This study demonstrates the value of mechanistic modeling to examine and predict dynamic behaviors in perturbed systems. As this work progresses, we will obtain a refined understanding of how adaptive responses within the vertebrate HPG axis affect DRTC behaviors for aromatase inhibitors and other types of endocrine-active chemicals and apply that knowledge in support of risk assessments. 23374098 Mdm2 and MdmX inhibitors for the treatment of cancer: a patent review (2011-present). INTRODUCTION: One of the hallmarks of cancer cells is the inactivation of the p53 pathway either due to mutations in the p53 gene or over-expression of negative regulators, Mdm2 and/or MdmX. Pharmacological disruption of the Mdm2/X-p53 interaction to restore p53 activity is an attractive concept, aiming at a targeted and non-toxic cancer treatment. AREAS COVERED: The introduction covers the biological role of p53 pathway and its regulation by Mdm2 and MdmX in normal and cancer cells and the current repertoire and development status of inhibitors of the Mdm2/X-p53 interaction for the treatment of cancer. The main part of the article covers patents and patent applications describing small molecule inhibitors of the Mdm2/X-p53 interaction published from 2011 until 2012. EXPERT OPINION: The area of small molecule Mdm2/X-p53 interaction inhibitor development is progressing fast. Several Phase I clinical studies and preclinical programs are now in progress, however, the clinical proof concept has yet to be demonstrated. Multiple available compounds inhibit Mdm2-p53 interaction with nanomolar affinities, but MdmX is still missing such potent binders. Since research points to a complementary mode of Mdm2 and MdmX action, the future compound classes will possibly want to include dual actions versus Mdm2 and MdmX. 23343346 Efficient two-electron reduction of dioxygen to hydrogen peroxide with one-electron reductants with a small overpotential catalyzed by a cobalt chlorin complex. A cobalt chlorin complex (Co(II)(Ch)) efficiently and selectively catalyzed two-electron reduction of dioxygen (O(2)) by one-electron reductants (ferrocene derivatives) to produce hydrogen peroxide (H(2)O(2)) in the presence of perchloric acid (HClO(4)) in benzonitrile (PhCN) at 298 K. The catalytic reactivity of Co(II)(Ch) was much higher than that of a cobalt porphyrin complex (Co(II)(OEP), OEP(2-) = octaethylporphyrin dianion), which is a typical porphyrinoid complex. The two-electron reduction of O(2) by 1,1'-dibromoferrocene (Br(2)Fc) was catalyzed by Co(II)(Ch), whereas virtually no reduction of O(2) occurred with Co(II)(OEP). In addition, Co(II)(Ch) is more stable than Co(II)(OEP), where the catalytic turnover number (TON) of the two-electron reduction of O(2) catalyzed by Co(II)(Ch) exceeded 30000. The detailed kinetic studies have revealed that the rate-determining step in the catalytic cycle is the proton-coupled electron transfer reduction of O(2) with the protonated Co(II)(Ch) ([Co(II)(ChH)](+)) that is produced by facile electron-transfer reduction of [Co(III)(ChH)](2+) by ferrocene derivative in the presence of HClO(4). The one-electron-reduction potential of [Co(III)(Ch)](+) was positively shifted from 0.37 V (vs SCE) to 0.48 V by the addition of HClO(4) due to the protonation of [Co(III)(Ch)](+). Such a positive shift of [Co(III)(Ch)](+) by protonation resulted in enhancement of the catalytic reactivity of [Co(III)(ChH)](2+) for the two-electron reduction of O(2) with a lower overpotential as compared with that of [Co(III)(OEP)](+). 23574729 Proposed diagnostic criteria for subclinical Cushing's syndrome associated with adrenal incidentaloma. Subclinical Cushing's syndrome (SCS) associated with adrenal incidentaloma is usually characterized by autonomous cortisol secretion without overt symptoms of Cushing's syndrome (CS). Although the diagnostic criteria for SCS differ among countries, the 1 mg dexamethasone suppression test (DST) is essential to confirm the presence and the extent of cortisol overproduction. Since 1995, SCS has been diagnosed in Japan based on serum cortisol levels ≥3 μg/dl (measured by radioimmunoassay [RIA]) after a 1 mg DST. However, the increasing use of enzyme immunoassays (EIA) instead of RIA has hindered the diagnosis of SCS because of the differing sensitivities of commercially available assays, particularly for serum cortisol levels of around 3 μg/dl. One way to overcome this problem is to lower the cortisol threshold level after a 1 mg DST. In the present study, we examined the clinical applicability of lowering the cortisol threshold to 1.8 μg/dl, similar to the American Endocrine Society's guidelines for CS, by reanalyzing 119 patients with adrenal incidentaloma. Our findings indicate that serum cortisol levels ≥1.8 μg/dl after 1 mg DST are useful to confirm the diagnosis of SCS if both of the following criteria are met: (1) basal ACTH level <10 pg/ml (or poor plasma ACTH response to corticotrophin-releasing hormone) and (2) serum cortisol ≥5 μg/dl at 21:00 to 23:00 h. If only one of (1) and (2) are met, we recommend that other clinical features are considered in the diagnosis of SCS, including serum dehydroepiandrosterone sulfate levels, urine free cortisol levels, adrenal scintigraphy, and clinical manifestation. 23362240 Vemurafenib potently induces endoplasmic reticulum stress-mediated apoptosis in BRAFV600E melanoma cells. The V600E mutation in the kinase BRAF is frequently detected in melanomas and results in constitutive activation of BRAF, which then promotes cell proliferation by the mitogen-activated protein kinase signaling pathway. Although the BRAFV600E kinase inhibitor vemurafenib has remarkable antitumor activity in patients with BRAFV600E-mutated melanoma, its effects are limited by the onset of drug resistance. We found that exposure of melanoma cell lines with the BRAFV600E mutation to vemurafenib decreased the abundance of antiapoptotic proteins and induced intrinsic mitochondrial apoptosis. Vemurafenib-treated melanoma cells showed increased cytosolic concentration of calcium, a potential trigger for endoplasmic reticulum (ER) stress, which can lead to apoptosis. Consistent with an ER stress-induced response, vemurafenib decreased the abundance of the ER chaperone protein glucose-regulated protein 78, increased the abundance of the spliced isoform of the transcription factor X-box binding protein 1 (XBP1) (which transcriptionally activates genes involved in ER stress responses), increased the phosphorylation of the translation initiation factor eIF2α (which would be expected to inhibit protein synthesis), and induced the expression of ER stress-related genes. Knockdown of the ER stress response protein activating transcription factor 4 (ATF4) significantly reduced vemurafenib-induced apoptosis. Moreover, the ER stress inducer thapsigargin prevented invasive growth of tumors formed from vemurafenib-sensitive melanoma cells in vivo. In melanoma cells with low sensitivity or resistance to vemurafenib, combination treatment with thapsigargin augmented or induced apoptosis. Thus, thapsigargin or other inducers of ER stress may be useful in combination therapies to overcome vemurafenib resistance. 23259487 Iron L-edge X-ray absorption spectroscopy of oxy-picket fence porphyrin: experimental insight into Fe-O2 bonding. The electronic structure of the Fe-O(2) center in oxy-hemoglobin and oxy-myoglobin is a long-standing issue in the field of bioinorganic chemistry. Spectroscopic studies have been complicated by the highly delocalized nature of the porphyrin, and calculations require interpretation of multideterminant wave functions for a highly covalent metal site. Here, iron L-edge X-ray absorption spectroscopy, interpreted using a valence bond configuration interaction multiplet model, is applied to directly probe the electronic structure of the iron in the biomimetic Fe-O(2) heme complex [Fe(pfp)(1-MeIm)O(2)] (pfp ("picket fence porphyrin") = meso-tetra(α,α,α,α-o-pivalamidophenyl)porphyrin or TpivPP). This method allows separate estimates of σ-donor, π-donor, and π-acceptor interactions through ligand-to-metal charge transfer and metal-to-ligand charge transfer mixing pathways. The L-edge spectrum of [Fe(pfp)(1-MeIm)O(2)] is further compared to those of [Fe(II)(pfp)(1-MeIm)(2)], [Fe(II)(pfp)], and [Fe(III)(tpp)(ImH)(2)]Cl (tpp = meso-tetraphenylporphyrin) which have Fe(II)S = 0, Fe(II)S = 1, and Fe(III)S = 1/2 ground states, respectively. These serve as references for the three possible contributions to the ground state of oxy-pfp. The Fe-O(2) pfp site is experimentally determined to have both significant σ-donation and a strong π-interaction of the O(2) with the iron, with the latter having implications with respect to the spin polarization of the ground state. 23292747 Plasmon-Mediated Synthesis of Silver Cubes with Unusual Twinning Structures Using Short Wavelength Excitation. The plasmon-mediated synthesis of silver nanoparticles is a versatile synthetic method which leverages the localized surface plasmon resonance (LSPR) of nanoscale silver to generate particles with non-spherical shapes and control over dimensions. Herein, a method is reported for controlling the twinning structure of silver nanoparticles, and consequently their shape, via the plasmon-mediated synthesis, solely by varying the excitation wavelength between 400, 450, and 500 nm, which modulates the rate of Ag(+) reduction. Shorter, higher energy excitation wavelengths lead to faster rates of reaction, which in turn yield structures containing a greater number of twin boundaries. With this method, silver cubes can be synthesized using 450 nm excitation, which represents the first time this shape has been realized by a plasmon-mediated synthetic approach. In addition, these cubes contain an unusual twinning structure composed of two intersecting twin boundaries or multiple parallel twin boundaries. With respect to their twinning structure, these cubes fall between planar-twinned and multiply twinned nanoparticles, which are synthesized using 500 and 400 nm excitation, respectively. 22712554 Isolation and structure determination of new siderophore tsukubachelin B from Streptomyces sp. TM-74. The new siderophore tsukubachelin B (1) was isolated from the iron-deficient culture medium of the newly isolated strain Streptomyces sp. TM-74. The chemical structure of tsukubachelin B (1) was established via interpretation of 2D nuclear magnetic resonance and electrospray ionization-mass spectroscopic data. The structure of tsukubachelin B (1) comprises 6 mol of amino acids, including 2 mol of serine and 1 mol each of ornithine, N-α-methyl-N-δ-hydroxy-N-δ-formylornithine, N-α-methyl-N-δ-hydroxyornithine, and cyclic N-hydroxyornithine. 23205727 Flexible fiber nanogenerator with 209 V output voltage directly powers a light-emitting diode. On the basis of a vertically aligned ultralong Pb(Zr(0.52)Ti(0.48))O(3) (PZT) nanowire array fabricated using electrospinning nanofibers, we developed a new type of integrated nanogenerator (NG) with ultrahigh output voltage of 209 V and current density of 23.5 μA/cm(2), which are 3.6 times and 2.9 times of the previous record values, respectively. The output electricity can be directly used to stimulate the frog's sciatic nerve and to induce a contraction of a frog's gastrocnemius. The NG can instantaneously power a commercial light-emitting diode (LED) without the energy storage process. 23508556 Higher levels of trait impulsiveness and a less effective response inhibition are linked to more intense cue-elicited craving for alcohol in alcohol-dependent patients. RATIONALE: Cue-elicited craving is a well-researched phenomenon in alcohol literature. However, not all alcohol-dependent people display the same reactivity to alcohol cues. Personality factors such as multiple impulsivity traits may be responsible for individual differences in cue reactivity by modulating its intensity. Nevertheless, there has been a scarcity of empirical studies testing this assumption in alcohol literature. OBJECTIVES: The aim of the present study was to investigate the effects of response inhibition and trait impulsiveness on cue-elicited craving for alcohol in alcohol-dependent drinkers. METHODS: Participants (n = 41) were inpatients of the private clinic U-Center, Netherlands. Alcohol exposure took place in a real bar-restaurant close to the premises of the clinic, and participants were exposed to real alcohol cues. Response inhibition was assessed with the stop-signal task and trait impulsiveness with the Barratt impulsivity scale version 11. RESULTS: The cue exposure was successful as alcohol-dependent patients experienced higher craving for alcohol when exposed to alcohol rather than to neutral cues. Additionally, both response inhibition and trait impulsiveness predicted cue-elicited craving for alcohol. Trait impulsiveness predicted both the absolute craving in the bar-restaurant and the increase in cue-elicited craving during the whole alcohol cue exposure, while response inhibition predicted only the former. CONCLUSIONS: The results clearly implicate both trait impulsiveness and response inhibition in the modulation of cue-elicited craving in alcohol dependence. Theoretical and methodological issues in the findings and their clinical implications in alcohol treatment and relapse are discussed. 23591996 Melatonin and its analogue 5-MCA-NAT potentiate adrenergic receptor-mediated ocular hypotensive effects in rabbits: Significance for combination therapy in glaucoma. Melatonin is currently considered as a promising drug for glaucoma treatment due to its ocular hypotensive and neuroprotective effects. We have investigated the effect of melatonin and its analogue 5-methoxycarbonylamino-N-acetyltryptamine, 5-MCA-NAT, on β2/α2A-adrenergic receptor mRNA as well as protein expression in cultured rabbit non-pigmented ciliary epithelial cells. Quantitative PCR and immunocytochemical assays revealed a significant β2-adrenergic receptor down-regulation as well as α2A-adrenergic receptor up-regulation of treated cells (p<0.001, maximal significant effect). In addition, we have studied the effect of these drugs upon the ocular hypotensive action of a non-selective β-adrenergic receptor (timolol) and a selective α2-adrenergic receptor agonist (brimonidine) in normotensive rabbits. IOP experiments showed that the administration of timolol in rabbits pre-treated with melatonin or 5-MCA-NAT evoked an additional IOP reduction of 14.02 ± 5.8 % or 16.75 ± 5.48 % (p<0.01) in comparison with rabbits treated with timolol alone for 24 hours. Concerning brimonidine hypotensive action, an additional IOP reduction of 29.26 ± 5.21 % or 39.07 ± 5.81 % (p<0.001) was observed in rabbits pretreated with melatonin or 5-MCA-NAT when compared with animals treated with brimonidine alone for 24 hours. Additionally, a sustained potentiating effect of a single dose of 5-MCA-NAT was seen in rabbits treated with brimonidine once daily for up four days (extra IOP decrease of 15.57 ± 5.15%, p<0.05, compared to brimonidine alone). These data confirm the indirect action of melatoninergic compounds on adrenergic receptors and their remarkable effect upon the ocular hypotensive action mainly of α2-adrenergic receptor agonists but also of β-adrenergic antagonists. 23396138 AhR- and NF-κB-dependent induction of interleukin-6 by co-exposure to the environmental contaminant benzanthracene and the cytokine tumor necrosis factor-α in human mammary MCF-7 cells. Co-exposure to environmental polycyclic aromatic hydrocarbons (PAHs) and interleukin (IL)-1β induces expression of the tumor-promoting cytokine IL-6 in cancer cells. The present study was designed to determine whether such an IL-6 up-regulation also occurs in response to co-treatment by PAHs and tumor necrosis factor (TNF)-α, an inflammatory cytokine commonly found in tumor microenvironment. Co-exposure to the prototypical PAH benzanthracene (BZA) and TNF-α was found to markedly induce mRNA expression and secretion of IL-6 in human breast cancer cells MCF-7, whereas exposure to either BZA or TNF-α alone was without significant effect. Co-treatment by BZA and TNF-α-containing conditioned media from human inflammatory macrophages similarly up-regulated IL-6 expression in MCF-7 cells. BZA/TNF-α-mediated IL-6 induction in MCF-7 cells was counteracted by silencing aryl hydrocarbon receptor (AhR), known to mediates most of PAH effects. IL-6 up-regulation was moreover associated with NF-κB activation and was abolished by using chemical NF-κB inhibitors or knocking-down expression of the p65/RelA NF-κB subunit. Taken together, these data indicate that co-exposure to BZA/TNF-α induces IL-6 expression by AhR- and NF-κB-dependent pathways in MCF-7 cancer cells. This regulation of IL-6 by environmental PAHs, that is dependent of inflammatory cytokine microenvironment, may contribute to the well-known carcinogenic properties of these organic pollutants. 23551329 Low-Dose Dexamethasone Treatment Promotes Pro-Survival Signalling Pathway In Adult Rat Prefrontal Cortex. Synthetic glucocorticoid dexamethasone (DEX), a highly potent anti-inflammatory and immunosuppressive agent, is widely used in treatments of brain cancer, inflammatory and autoimmune diseases. The objective of the current study was to determine whether a low-dose subchronic DEX treatment (100 μg/kg for 8 consecutive days) exerts long-term effects on apoptosis in the adult rat prefrontal cortex (PFC) by examining the expression of cell death-promoting molecules (poly (ADP-ribose) polymerase (PARP), p53, procaspase 3, cleaved caspase 3, Bax) and cell-survival molecules (AKT, Bcl-2). Our results revealed that body, thymus and adrenal weight as well corticosterone level in the serum and PFC were reduced a day following last DEX injection. In PFC, DEX caused activation of AKT, augmentation of pro-survival Bcl-2 protein and enhanced Bcl-2/Bax protein ratio, as well Bcl-2 translocation to mitochondria. The unaltered profile in the protein expression of apoptotic molecules PARP, procaspase 3 and Bax was detected, while the p53 protein was decreased. Results of RT-PCR analysis showed decrease of p53 mRNA level and no significant difference in Bcl-2 and Bax mRNA expressions in DEX-treated rats. Finally, the DNA fragmentation assay and Fluoro-Jade staining demonstrated no considerable changes in the apoptosis in rat PFC. Our findings support the concept that a low-dose DEX creates the hypocorticoid state in the brain and indicate that subchronic DEX treatment activates pro-survival signalling pathway but does not change apoptotic markers in rat PFC. This mechanism might be relevant for DEX-induced apoptosis resistance observed during and after chemotherapy of patients with brain tumours. © 2013 British Society for Neuroendocrinology. 23625915 Store-operated Ca2+ Entry (SOCE) Induced by Protease-activated Receptor-1 mediates STIM1 Phosphorylation to inhibit SOCE in Endothelial Cells through AMP-activated Protein Kinase and p38beta Mitogen-activated Protein Kinase. The Ca2+ sensor STIM1 is crucial for activation of store-operated Ca2+ entry (SOCE) through TRPC and Orai channels. STIM1 phosphorylation serves as an off-switch for SOCE. However, the signaling pathway for STIM1 phosphorylation is unknown. Here we show that SOCE activates AMP-activated protein kinase (AMPK); its effector p38β mitogen-activated protein kinase (p38β MAPK) phosphorylates STIM1, thus inhibiting SOCE in human lung microvascular endothelial cells (ECs). Activation of AMPK using AICAR resulted in STIM1 phosphorylation on serine residues and prevented PAR-1-induced Ca2+ entry. Further, AICAR pretreatment blocked PAR-1-induced increase in permeability of mouse-lung microvessels. Activation of SOCE with thrombin caused phosphorylation of isoform α1, but not α2 of the AMPK catalytic subunit. Moreover, knockdown of AMPKα1 augmented SOCE induced by thrombin. Interestingly, SB203580, a selective inhibitor of p38 MAPK, blocked STIM1 phosphorylation and led to sustained STIM1-puncta formation and Ca2+ entry. Of the three p38 MAPK isoforms expressed in ECs, p38β knockdown prevented PAR-1-mediated STIM1 phosphorylation and potentiated SOCE. In addition, inhibition of the SOCE downstream target CaMKKβ or knockdown of AMPKα1 suppressed PAR-1-mediated phosphorylation of p38β and hence STIM1. Thus, our findings demonstrate that SOCE activates CaMKKβ-AMPKα1-p38β MAPK signaling to phosphorylate STIM1, thereby suppressing endothelial SOCE and permeability responses. 23287737 Remarkable stabilization of antiparallel DNA triplexes by strong stacking effects of consecutively modified nucleobases containing thiocarbonyl groups. The consecutive arrangement of 2'-deoxy-6-thioguanosines (s(6)Gs) and 4-thiothymidines (s(4)Ts) in antiparallel triplex-forming oligonucleotides (TFOs) considerably stabilized the resulting antiparallel triplexes with high base recognition ability by the strong stacking effects of thiocarbonyl groups. This result was remarkable because chemical modifications of the sugar moieties and nucleobases of antiparallel TFOs generally destabilize triplex structures. Moreover, in comparison with unmodified TFOs, it was found that TFOs containing s(6)Gs and s(4)Ts could selectively bind to the complementary DNA duplex but not to mismatched DNA duplexes or single-stranded RNA. 23454090 Return flight to the Canary Islands - The key role of peripheral populations of Afrocanarian blue tits (Aves: Cyanistes teneriffae) in multi-gene reconstructions of colonization pathways. Afrocanarian blue tits (Cyanistes teneriffae) have a scattered distribution on the Canary Islands and on the North African continent. To date, the Canary Islands have been considered the species' main Pleistocene evolutionary center, but their colonization pathways remain uncertain. We set out to reconstruct a dated multi-gene phylogeny and ancestral ranges for Cyanistes tit species including the currently unstudied, peripheral Libyan population of C. t. cyrenaicae. In all reconstructions the most easterly and westerly peripheral populations (in Libya and on La Palma) represented basal offshoots of C. teneriffae. These two peripheral populations shared all four major indels and differed in this respect from all other members of the Afrocanarian core group. The basal split of Afrocanarian blue tits from their European relatives was dated to the early Pliocene. The two ancestral area reconstructions were contradictory and suggested either a Canarian or a North African origin of C. teneriffae - but unambiguously ruled out a continental European ancestral range. We conclude that the peripheral populations of C. teneriffae represent relic lineages of a first faunal interchange, presumably downstream colonization from North Africa to the Canary Islands. Subsequent eastward stepping-stone colonization within the Canarian Archipelago culminated in a very recent late (possibly even post-) Pleistocene back-colonization from the Canary Islands to North Africa. 23484633 Tin-coated viral nanoforests as sodium-ion battery anodes. Designed as a high-capacity alloy host for Na-ion chemistry, a forest of Sn nanorods with a unique core-shell structure was synthesized on viral scaffolds, which were genetically engineered to ensure a nearly vertical alignment upon self-assembly onto a metal substrate. The interdigital spaces thus formed between individual rods effectively accommodated the volume expansion and contraction of the alloy upon sodiation/desodiation, while additional carbon-coating engineered over these nanorods further suppressed Sn aggregation during extended electrochemical cycling. Due to the unique nanohierarchy of multiple functional layers, the resultant 3D nanoforest of C/Sn/Ni/TMV1cys, binder-free composite electrode already and evenly assembled on a stainless steel current collector, exhibited supreme capacity utilization and cycling stability toward Na-ion storage and release. An initial capacity of 722 mA·h (g Sn)(-1) along with 405 mA·h (g Sn)(-1) retained after 150 deep cycles demonstrates the longest-cycling nano-Sn anode material for Na-ion batteries reported in the literature to date and marks a significant performance improvement for neat Sn material as alloy host for Na-ion chemistry. 22640596 Two new alkaloid galactosides from the kernel of Prinsepia uniflora. Two new alkaloid galactosides have been isolated from the kernel of Prinsepia uniflora. Their structures were elucidated as 5-[(α-D-galactopyranosyloxy) methyl]-1H-pyrrole-2-carbaldehyde (1) and 6-[(α-D-galactopyranosyloxy) methyl]-3-pyridinol (2) by various spectroscopic means including HR-ESI-MS, IR, 1D and 2D NMR. The determined structures were characterized with a unit of galactose which is rarely seen in the previously isolated pyrrole and pyridinol compounds. 23360295 Effects of polymer end-group chemistry and order of deposition on controlled protein delivery from layer-by-layer assembly. Layer-by-layer (LBL) assembly is an attractive platform for controlled release of biologics given its mild fabrication process and versatility in coating substrates of any shape. Proteins can be incorporated into LBL coatings by sequentially depositing oppositely charged polyelectrolytes, which self-assemble into nanoscale films on medical devices or tissue engineering scaffolds. However, previously reported LBL platforms often require the use of a few hundred layers to avoid burst release, which hinders their broad translation due to the lengthy fabrication process, cost, and batch-to-batch variability. Here we report a biodegradable LBL platform composed of only 10 layers with tunable protein release kinetics, which is an order of magnitude less than previously reported LBL platforms. We performed a combinatorial study to examine the effects of polymer chemistry and order of deposition of poly(β-amino) esters on protein release kinetics under 81 LBL assembly conditions. Using the optimal "polyelectrolyte couples" for constructing the LBL film, basic fibroblast growth factor (bFGF) was released gradually over 14 days with retained biological activity to stimulate cell proliferation. The method reported herein is applicable for coating various substrates including metals, polymers, and ceramics and may be used for a broad range of biomedical and tissue engineering applications. 23277288 PXR-mediated P-glycoprotein induction by small molecule tyrosine kinase inhibitors. The rapid development of drug resistance as a result of exposure to small molecule tyrosine kinase inhibitors (TKIs) is an important drawback to the successful use of these agents in the clinic. Although one of the most established mechanisms by which cells acquire drug resistance to anticancer drugs is the up regulation of drug efflux transporters such as P-glycoprotein (PGP), it is currently still unknown whether TKIs have the propensity to induce PGP. The effect of TKIs on the protein expression and activity of PGP was assessed after treatment of LS180 cells with clinically relevant concentrations of the TKIs. In addition, the involvement of the nuclear pregnane X receptor (PXR), a known regulator of PGP expression, was determined. At least five out of the nine tested TKIs (erlotinib, gefitinib, nilotinib, sorafenib, vandetanib) were able to induce the expression of PGP within 48 h in LS180 cells. Accordingly, these TKIs were also shown to affect the accumulation of a P-glycoprotein specific probe substrate. Furthermore, we showed that the pregnane X receptor (PXR), which is an important regulator of PGP induction, is involved in the upregulation of PGP protein expression following exposure to these TKIs. Our data show that PXR-mediated upregulation of PGP expression by TKIs might be a possible mechanism underlying acquired drug resistance in cancer cells. 23500040 In vitro, ex vivo and in vivo examination of buccal absorption of metoprolol with varying pH in TR146 cell culture, porcine buccal mucosa and Göttingen minipigs. This work studied the buccal absorption of metoprolol in vitro, ex vivo and in vivo as a function of buffered pH at 7.4, 8.5, 9.0 and 9.5. Permeability studies showed a correlation (r(2)=0.92) between in vitro TR146 cell culture and ex vivo porcine buccal mucosa in a modified Ussing chamber. A higher apparent permeability was observed at higher pH values, i.e. the more compound that was unionised the higher the permeability. In vivo studies were conducted in anaesthetised Göttingen mini-pigs. A clear influence of pH on the absorption was seen and a significant higher absolute bioavailability was obtained after buccal dosing (58-107%) compared to oral (3%) administration, ranging 58-107% and 3%, respectively. Macroscopically, no local toxic effects were observed by visual inspection of mini-pig cheeks. A very clear level C in vitro in vivo correlation (r(2)=0.98) was obtained between the observed in vitro permeabilities and the bioavailability observed in vivo, suggesting that the two in vitro models have good predictive power for drug delivery, which could be a useful tool for future formulation developments intended for buccal delivery. 23201441 Effect of body-weight loading onto the articular cartilage on the occurrence of quinolone-induced chondrotoxicity in juvenile rats. The effect of body-weight loading onto the articular cartilage on the occurrence of chondrotoxicity was investigated in male juvenile Sprague-Dawley rats given ofloxacin (OFLX) orally once at 900 mg/kg. Just after dosing of OFLX, hindlimb unloading was performed for 0, 2, 4, or 8 h by a tail-suspension method. Animals were sacrificed at 8h post-dose, and then the distal femoral articular cartilage was subjected to a histological examination and an investigation for gene expression of tumor necrosis factor receptor superfamily, member 12a (Tnfrsf12a); prostaglandin-endoperoxide synthase 2 (Ptgs2); plasminogen activator, urokinase receptor (Plaur); and matrix metalloproteinase 3 (Mmp3) by qRT-PCR analysis. As a result, cartilage lesions and up-regulations of these 4 genes that were seen in rats without the tail suspension were not observed in rats with the 8-h tail suspension, and a tendency to decrease in the incidence of the cartilage lesions and the gene expression was noted in a tail-suspension time dependent manner. Our results clearly indicate that body-weight loading onto the cartilage is necessary to induce cartilage lesions and gene expression of Tnfrsf12a, Ptgs2, Plaur, and Mmp3 in juvenile rats treated with OFLX. 23322284 Altered trace mineral milieu might play an aetiological role in the pathogenesis of polycystic ovary syndrome. Insulin resistance is a very common associate of polycystic ovary syndrome (PCOS). Pathophysiology in relation with the essential elements including copper, magnesium, zinc, manganese, chromium, and calcium has been reported in women with insulin resistance. This prospective study was designed to explore whether the women with PCOS do exhibit altered serum element levels in association with/without insulin resistance. One hundred and thirty-two women with PCOS and forty-six control women were studied. Women with PCOS were further divided based on the presence of insulin resistance (insulin resistant: n = 50; non-insulin resistant: n = 82). In all women, basal levels of gonadotropins, prolactin, testosterone, insulin, glucose, and the six different elements were measured. Serum levels of testosterone (p < 0.001), luteinizing hormone (p < 0.05), and fasting insulin (p < 0.004) were significantly higher in the PCOS population compared to controls as well as PCOS women without insulin resistance. Women with PCOS exhibited a significantly high calcium (p < 0.04) and lower manganese levels (p < 0.002) when compared to controls. However, the PCOS women with insulin resistance exhibited significantly lower serum levels of magnesium and chromium (p < 0.04), in addition to higher levels of zinc and copper (p < 0.04). The differences in calcium (p < 0.03) and manganese levels (p < 0.0001) became aggravated with the presence of insulin resistance when compared to control as well as PCOS women without insulin resistance. In PCOS-associated insulin resistance, circulating serum magnesium (r = -0.31; p < 0.03) and chromium (r = -0.38; p < 0.006) status significantly correlated with fasting insulin levels. We conclude that imbalanced element status may be a key foundation for insulin resistance in PCOS. The findings in this study should be investigated with further trials in order to obtain new insights into PCOS. 23497902 Effect of dietary carnosic acid on the fatty acid profile and flavour stability of meat from fattening lambs. Thirty-two lambs were fed with barley straw supplemented by a concentrate alone, or a concentrate enriched with either vitamin E (VITE006: 0.6 g kg(-1) feed concentrate) or carnosic acid (CARN006: 0.6 g kg(-1) feed concentrate; or CARN012: 1.2 g kg(-1) feed concentrate). In order to elucidate the influence of the dietary supplementation of carnosic compared with a reference diet antioxidant (vitamin E), the animals were slaughtered and the longissimus thoracis were lyophilised to determine the FAs profile and the phenolic compounds. In addition, longissimus lumborum slices were stored in a modified atmosphere package for 3 days and then grilled to determine volatile compounds. Dietary carnosic acid did not modify the FAs profile, but had a clear effect on the production of volatile compounds, in a dose-dependent manner. These results have implications for the food industry, since dietary carnosic acid seems to extend the shelf life of lamb meat. 23566058 Oligonol supplementation attenuates body temperature and the circulating levels of prostaglandin e2 and cyclooxygenase-2 after heat stress in humans. Abstract Oligonol, a phenolic production from lychee, has been reported to exhibit anti-oxidative and anti-inflammatory effects. This study investigated the effect of Oligonol supplementation on circulating levels of prostaglandin E2 (PGE2) and cyclooxygenase (COX)-2, as well as body temperature, after heat stress in 17 healthy human male volunteers (age, 21.6±2.1 years). All experiments were performed in an automated climate chamber (26.0°C±0.5°C, relative humidity 60%±3.0%, air velocity less than 1 m/sec) between 2 and 5 p.m. Subjects ingested an Oligonol (100 mg)-containing beverage or placebo beverage before half-body immersion into hot water (42°C±0.5°C for 30 min). Tympanic and skin temperatures were measured and mean body temperatures were calculated. Serum concentrations of PGE2 and COX-2 were analyzed before, immediately after, and 60 min after immersion. Oligonol intake significantly prevented elevation of tympanic (temperature difference: 0.17°C at Post, P<.05; 0.17°C at Re-60, P<.05) and mean body temperatures (temperature difference: 0.18°C at Post, P<.05; 0.15°C at Re-60, P<.05), and lowered concentrations of serum PGE2 (increased by 13.3% vs. 29.6% at Post, P<.05) and COX-2 (increased by 15.6% vs. 21.8% at Post, P<.05), compared to placebo beverage. Our result suggests that Oligonol has the potential to suppress increases in body temperature under heat stress, and this is associated with decreases in serum levels of PGE2 and COX-2. 23466234 Efficient synthesis and antimicrobial activity of some novel S-β-d-glucosides of 5-aryl-1,2,4-triazole-3-thiones derivatives. A series of 3-S-β-d-glucosides-4-arylideneamino-5-aryl-1,2,4-triazoles were rationally designed and synthesized according to the principle of superposition of bioactive substructures by the combination of 1,2,4-triazole, Schiff base and glucosides. The structures of the target compounds have been characterized by (1)H NMR, (13)C NMR, IR, MS and HRMS. All the newly synthesized compounds have been evaluated for their antimicrobial activities in vitro against Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 8099) as well as Monilia albican (ATCC 10231). The bioactive assay showed that most of the tested compounds displayed variable inhibitory effects on the growth of the Gram-positive bacterial strain (Staphylococcus aureus), Gram-negative bacterial strains (Escherichia coli) and fungal strains (Monilia albican). All the target compounds exhibited better antifungal activity than antibacterial activity. Especially, compounds 6b, 6c, 6f, 6j, 6k and 6l showed excellent activity against fungus Monilia albican with MIC values of 16 μg/mL. 23443513 Correlation of photobleaching, oxidation and metal induced fluorescence quenching of DNA-templated silver nanoclusters. Few-atom noble metal nanoclusters have attracted a lot of interest due to their potential applications in biosensor development, imaging and catalysis. DNA-templated silver nanoclusters (AgNCs) are of particular interest as different emission colors can be obtained by changing the DNA sequence. A popular analytical application is fluorescence quenching by Hg(2+), where d(10)-d(10) metallophilic interaction has often been proposed for associating Hg(2+) with nanoclusters. However, it cannot explain the lack of response to other d(10) ions such as Zn(2+) and Cd(2+). In our effort to elucidate the quenching mechanism, we studied a total of eight AgNCs prepared by different hairpin DNA sequences; they showed different sensitivity to Hg(2+), and DNA with a larger cytosine loop size produced more sensitive AgNCs. In all the cases, samples strongly quenched by Hg(2+) were also more easily photobleached. Light of shorter wavelengths bleached AgNCs more potently, and photobleached samples can be recovered by NaBH4. Strong fluorescence quenching was also observed with high redox potential metal ions such as Ag(+), Au(3+), Cu(2+) and Hg(2+), but not with low redox potential ions. Such metal induced quenching cannot be recovered by NaBH4. Electronic absorption and mass spectrometry studies offered further insights into the oxidation reaction. Our results correlate many important experimental observations and will fuel the further growth of this field. 22800435 Metastability in Pressure-Induced Structural Transformations of CdSe/ZnS Core/Shell Nanocrystals. The kinetics and thermodynamics of structural transformations under pressure depend strongly on particle size due to the influence of surface free energy. By suitable design of surface structure, composition, and passivation it is possible, in principle, to prepare nanocrystals in structures inaccessible to bulk materials. However, few realizations of such extreme size-dependent behavior exist. Here, we show with molecular dynamics computer simulation that in a model of CdSe/ZnS core/shell nanocrystals the core high-pressure structure can be made metastable under ambient conditions by tuning the thickness of the shell. In nanocrystals with thick shells, we furthermore observe a wurtzite to NiAs transformation, which does not occur in the pure bulk materials. These phenomena are linked to a fundamental change in the atomistic transformation mechanism from heterogeneous nucleation at the surface to homogeneous nucleation in the crystal core. 23146758 The 2,2',4,4'-tetrabromodiphenyl ether hydroxylated metabolites 5-OH-BDE-47 and 6-OH-BDE-47 stimulate estradiol secretion in the ovary by activating aromatase expression. The aim of the present study was to assess the effect of two hydroxylated BDE-47 metabolites, 5-OH-BDE-47 and 6-OH-BDE-47, on steroidogenesis in the ovary. Both metabolites failed to affect the production of androstenedione and testosterone but increased the secretion of estradiol at all concentrations tested. The increased secretion of estradiol was due to the stimulation of aromatase gene and protein expression. Direct assessment of aromatase activity by dibenzylfluorescein assay and indirect assessment of aromatase activity by measurement of the conversion of testosterone to estradiol confirmed that 5-OH-BDE-47 and 6-OH-BDE-47 stimulate aromatase activity. The aromatase inhibitor CGS 16949A abolished this stimulatory activity and reduced estradiol levels in the control and treatment groups. 23578392 The time point of β-catenin knockout in hepatocytes determines their response to xenobiotic activation of the constitutive androstane receptor. The constitutive androstane receptor (CAR) controls the expression of drug-metabolizing enzymes and regulates hepatocyte proliferation. Studies with transgenic mice with an early postnatal conditional hepatocyte-specific knockout of the β-catenin gene Ctnnb1 revealed that β-catenin deficiency decreases the magnitude of induction of drug-metabolizing enzymes by CAR activators, abrogates zonal differences in the hepatocytes' susceptibility to these compounds, and impacts on hepatocyte proliferation. These data, however, do not allow distinguishing between effects caused by β-catenin deficiency during postnatal liver development and acute effects of β-catenin deficiency in the adult animal at the time point of CAR activation. Therefore, CAR activation was now studied in a different mouse model allowing for the hepatocyte-specific knockout of β-catenin in adult mice. Treatment of these mice with 3mg/kg body weight of the model CAR activator 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) confirmed previous findings related to the coordinate regulation of drug metabolism by β-catenin and CAR. More importantly, the present study clarified that the impact of β-catenin signaling on CAR-mediated enzyme induction in the liver is not merely due to developmental defects caused by a postnatal lack of β-catenin, but depends on the presence of β-catenin at the time point of xenobiotic treatment. The study also revealed interesting differences between the two mouse models: hepatic zonation of TCPOBOP-dependent induction of drug-metabolizing enzymes was restored in mice with late knockout of β-catenin, and the strong proliferative response of female mice was exclusively abolished when using animals with a late β-catenin knockout. This suggests a β-catenin-dependent postnatal priming of hepatocytes during postnatal liver development, later affecting the proliferative response of adult animals to CAR-activating xenobiotics. 23301592 Aminoalkyl derivatives of guanidine diaromatic minor groove binders with antiprotozoal activity. Considering the strong DNA minor groove binding observed for our previous series of diaromatic symmetric and asymmetric guanidinium and 2-aminoimidazolinium derivatives, we report now the synthesis of new aminoalkyl derivatives of diaromatic guanidines with potential as DNA minor groove binders and antiprotozoal activity. The preparation of these aminoalkyl derivatives (12a-e, 13a-e, 14a-c,e, 15a-e, 16a-e) is presented as well as their affinity for DNA which was evaluated by means of DNA thermal denaturation experiments. Finally, the antiprotozoal activity of most of these aminoalkyl minor groove binders was evaluated in vitro against Trypanosoma brucei rhodesiense (8 compounds) and Plasmodium falciparum (18 compounds). The O-linked derivatives 13c and 14c showed 100 nM activities against P. falciparum, whereas for T. b. rhodesiense all compounds tested showed micromolar activity. Some of the derivatives prepared seem to exert the antimalarial activity by binding to the DNA minor groove whereas other sets of compounds could exert this antimalarial activity by inhibiting the parasite dihydrofolate reductase, for example. 23311471 Versatile biofunctionalization of polypeptide-based thermosensitive hydrogels via click chemistry. In this study, we report thermosensitive hydrogels based on poly(ethylene glycol)-block-poly(γ-propargyl-l-glutamate) (PEG-PPLG). (13)C NMR spectra, DLS, and circular dichroism spectra were employed to study the mechanism of the sol-gel phase transition. Mouse fibroblast L929 cells were encapsulated and cultured within the hydrogel matrices, and the encapsulated cells were shown to be highly viable in the gel matrices, suggesting that the hydrogels have excellent cytocompatibilities. The mass loss of the hydrogels in vitro was accelerated by the presence of proteinase K compared to the control group. In vivo biocompatibility studies revealed that the in situ formed gels in the subcutaneous layer last for ∼21 days, and H&E staining study suggested acceptable biocompatibility of our materials in vivo. The presence of alkynyl side groups in the PEG-PPLG copolymers allowed convenient further functionalization with azide-modified bioactive molecules, such as biotin and galactose. The biofunctionalized PEG-polypeptide block copolymers showed sol-gel phase transitions similar to the parent copolymers. Interestingly, the incorporation of galactose groups into the hydrogels was found to improve cell adhesion, likely due to the adsorption of fibronectin (FN) in cell-extracellular matrix (ECM). Because bioactive materials have shown unique advantages in biomedical applications, especially tissue engineering and regenerative medicine applications, we believe our novel functionalizable thermosensitive hydrogels have potential to serve as a versatile platform for the development of new biofunctional materials, for example, bioadhesive and bioresponsive hydrogels. 23317164 The oxygen therapy. Oxygen (O(2)) is a vital element. Shortage of O(2) results in deranged metabolism and important changes in vascular tone with opposite effects on the systemic and pulmonary circulation. During hypoxemia, oxidative stress exposes the organism to a sort of accelerated senescence as well as to several acute untoward effects. Thus, hypoxemia should be promptly recognized and treated, hopefully by measures tailored to the pathophysiological mechanisms underlying hypoxemia. However, O(2) therapy remains the most common therapy of hypoxemia, but it must be carefully tailored to relieve hypoxemia without provoking hyperoxia or hypercarbia. Then, the individual response to O(2) as well as changing needs of O(2) during sleep or exercise must be evaluated to provide the best O(2) therapy. Hyperoxia, the effect of overcorrection of hypoxia, can dramatically impact the health status and threaten the survival of the newborn and, through different mechanisms and effects, the adult. A thorough knowledge of the pathophysiological bases of hypoxemia and O(2) storage and delivery devices is then mandatory to administer O(2) therapy guaranteeing for optimal correction of hypoxemia and minimizing the risk of hyperoxia. Consistent with this aim also is a careful scrutiny of instruments and procedures for monitoring the individual response to O(2) over time. Thus, at variance from classical pharmacological therapy, performing O(2) therapy requires a vast array of clinical and technical competences. The optimal integration of these competences is needed to optimize O(2) therapy on individual bases. 23411275 Isomerisation of carrot β-carotene in presence of oil during thermal and combined thermal/high pressure processing. The effect of thermal processing (85-130°C) and combined thermal/high pressure processing (100°C combined with 0.1 to 700 MPa and 700 MPa combined with 85-115°C) on β-carotene isomerisation in an olive oil/carrot emulsion and pure olive oil phase enriched with carrot β-carotene was investigated. Thermal processing always resulted in an increase in the contribution of the cis-isomers, with the increase being more pronounced at higher temperatures. In the oil/carrot emulsion, less β-carotene isomerisation was observed during combined thermal/high pressure processing compared to thermal processing. This effect was attributed to strengthening of the carrot cell walls under high pressure, thereby hindering the transfer of β-carotene to the oil phase and lowering its susceptibility to isomerisation. In an oil phase enriched with β-carotene, β-carotene isomerisation was not influenced by the applied pressure at 100°C and became almost temperature insensitive at 700 MPa. 23642262 Base-Specific Ionization of Deprotonated Nucleotides by Resonance Enhanced Two-Photon Detachment. The intrinsic ionization energy of a base in DNA plays a critical role in determining the energies at which damage mechanisms may emerge. Here, a two-photon resonance-enhanced ionization scheme is presented that utilizes the 1ππ* transition, localized on the DNA base, to elucidate the base-specific ionization in a deprotonated nucleotide. In contrast to previous reports, the scheme is insensitive to competing ionization channels arising from the sugar-phosphate backbone. Using this approach, we demonstrate that for all bases except guanine, the lowest electron detachment energy corresponds to detachment from the sugar-phosphate backbone and allows us to determine the lowest adiabatic ionization energy for the other three bases for the first time in an isolated nucleotide. 23486479 Structural Explanation for Allolactose (lac Operon Inducer) Synthesis by lacZ β-Galactosidase and the Evolutionary Relationship between Allolactose Synthesis and the lac Repressor. β-Galactosidase (lacZ) has bifunctional activity. It hydrolyzes lactose to galactose and glucose and catalyzes the intramolecular isomerization of lactose to allolactose, the lac operon inducer. β-Galactosidase promotes the isomerization by means of an acceptor site that binds glucose after its cleavage from lactose and thus delays its exit from the site. However, because of its relatively low affinity for glucose, details of this site have remained elusive. We present structural data mapping the glucose site based on a substituted enzyme (G794A-β-galactosidase) that traps allolactose. Various lines of evidence indicate that the glucose of the trapped allolactose is in the acceptor position. The evidence includes structures with Bis-Tris (2,2-bis(hydroxymethyl)-2,2',2″-nitrilotriethanol) and l-ribose in the site and kinetic binding studies with substituted β-galactosidases. The site is composed of Asn-102, His-418, Lys-517, Ser-796, Glu-797, and Trp-999. Ser-796 and Glu-797 are part of a loop (residues 795-803) that closes over the active site. This loop appears essential for the bifunctional nature of the enzyme because it helps form the glucose binding site. In addition, because the loop is mobile, glucose binding is transient, allowing the release of some glucose. Bioinformatics studies showed that the residues important for interacting with glucose are only conserved in a subset of related enzymes. Thus, intramolecular isomerization is not a universal feature of β-galactosidases. Genomic analyses indicated that lac repressors were co-selected only within the conserved subset. This shows that the glucose binding site of β-galactosidase played an important role in lac operon evolution. 23610039 Amphiphilic Polypeptides as a Bifunctional Template in the Mineralization of Calcium Carbonate at the Air/Water Interface. A well-defined amphiphilic polypeptide, poly(glutamic acid)22 -block-poly(alanine)8 (PGlu22 -b-PAla8 ), which plays the roles of both soluble (functional) additive and insoluble (structural) matrix, is employed to mediate the mineralization of CaCO3 at the air/water interface. X-ray diffraction (XRD) and Raman spectroscopy, for example, show that the polymorph of CaCO3 particles obtained is calcite. The observations from SEM and TEM suggest that PGlu22 -b-PAla8 initiates the amorphous precursor phase and heterogeneous nucleation of CaCO3 at the air/water interface, while temporarily stabilizes the gelatinous precursors as a process-directing agent; nevertheless, the initial concentration of Ca(2+) controls the procedure of crystallization and the final morphology of CaCO3 particles. Such "bifunctional" amphiphilic-polypeptide-regulated mineralization at the air/water interface may be applied to the synthesis of many kinds of symmetrical inorganic/organic hybrids. 23525158 One-pot formation of multifunctional Pt-conducting polymer intercalated nanostructures. A novel multifunctional Pt nanoparticle@PPy nanofiber intercalated structure (Pt NP@PPy NF) has been synthesized facilely in one-pot. Pt NPs, with size and facet control, were nicely assembled and embedded into the polymer nanofiber network. Polyvinylpyrrolidone (PVP) was used during the synthesis process which would assist the self-assembly of the metal nanoparticles and polymer backbones into the intercalated structure. Space-confined distribution of the Pt NPs was achieved within the large dimension PPy nanofiber network, which could enhance the interfacial electron transfer process as well as diminish the catalyst deformation. The as-formed Pt NPs have a cluster-like structure and are mainly composed of 3.5 nm primary Pt particles with (100) surface atoms. Enhanced electrocatalytic properties were shown by the Pt NP@PPy NF intercalated structure, with sufficiently high enzyme-less glucose biosensitivity and a long linear range from 1-30 mM (R = 0.9995). High electrochemical cycling stability, chloride (Cl(-)) tolerance and good selectivity are also obtained for the Pt NP@PPy NF structure, as the electrode showed no obvious response to the common interfering agents, such as ascorbic acid (AA), uric acid (UA), and 4-acetamidophenol (AP). Furthermore, the Pt NP@PPy NF showed excellent catalytic activity for the methanol oxidation reaction (MOR) and oxygen reduction reaction (ORR), which displayed sufficient CO tolerance, and higher activity compared to the commercial Pt/C catalyst. This intrinsically multifunctional Pt NP@PPy NF with well-controlled Pt facets thus could serve as an advanced electrocatalyst for biosensing and fuel cell applications, surpassing the performance of many existing materials. 23022324 Inhibition of neurite outgrowth and alteration of cytoskeletal gene expression by sodium arsenite. Arsenic compounds that are often found in drinking water increase the risk of developmental brain disorders. In this study, we performed live imaging analyses of Neuro-2a cells expressing SCAT3, a caspase-3 cleavage peptide sequence linking two fluorescent proteins; enhanced cyan fluorescence protein (ECFP) and Venus, to determine whether sodium arsenite (NaAsO(2); 0, 1, 5, or 10 μM) affects both neurite outgrowth and/or induces apoptosis with the same doses and in the same cell cultures. We observed that the area ratio of neurite to cell body in SCAT3-expressing cells was significantly reduced by 5 and 10 μM NaAsO(2), but not by 1 μM, although the emission ratio of ECFP to Venus, an endpoint of caspase-3 activity, was not changed. However, cytological assay using apoptotic and necrotic markers resulted in that apoptosis, but not necrosis, was significantly induced in Neuro-2a cells when NaAsO(2) exposure continued after the significant effects of NaAsO(2) on neurite outgrowth were found by live imaging. These results suggested that neurite outgrowth was suppressed by NaAsO(2) prior to NaAsO(2)-induced apoptosis. Next, we examined the effects of NaAsO(2) on cytoskeletal gene expression in Neuro-2a cells. NaAsO(2) increased the mRNA levels of the light and medium subunits of neurofilament and decreased the mRNA levels of tau and tubulin in a dose-dependent manner; no significant effect was found in the mRNA levels of the heavy subunit of neurofilament, microtubule-associated protein 2, or actin. The changes in cytoskeletal gene expression are likely responsible for the inhibitory effects of NaAsO(2) on neurite outgrowth. 22447684 Quercetin reduces high-fat diet-induced fat accumulation in the liver by regulating lipid metabolism genes. To understand the molecular mechanisms underlying the influence of quercetin on the physiological effects of hyperlipidemia, we investigated its role in the prevention of high-fat diet (HFD)-induced obesity and found that it regulated hepatic gene expression related to lipid metabolism. Quercetin supplementation in mice significantly reduced the HFD-induced gains in body weight, liver weight, and white adipose tissue weight compared with the mice fed only with HFD. It also significantly reduced HFD-induced increases in serum lipids, including cholesterol, triglyceride, and thiobarbituric acid-reactive substance (TBARS). Consistent with the reduced liver weight and white adipose tissue weight, hepatic lipid accumulation and the size of lipid droplets in the epididymal fat pads were also reduced by quercetin supplementation. To further investigate how quercetin may reduce obesity, we analyzed lipid metabolism-related genes in the liver. Quercetin supplementation altered expression profiles of several lipid metabolism-related genes, including Fnta, Pon1, Pparg, Aldh1b1, Apoa4, Abcg5, Gpam, Acaca, Cd36, Fdft1, and Fasn, relative to those in HFD control mice. The expression patterns of these genes observed by quantitative reverse transcriptase-polymerase chain reaction were confirmed by immunoblot assays. Collectively, our results indicate that quercetin prevents HFD-induced obesity in C57B1/6 mice, and its anti-obesity effects may be related to the regulation of lipogenesis at the level of transcription. 23469927 Polyclonal Antibody to Soman-Tyrosine. Soman forms a stable, covalent bond with tyrosine 411 of human albumin, with tyrosines 257 and 593 in human transferrin, and with tyrosine in many other proteins. The pinacolyl group of soman is retained, suggesting that pinacolyl methylphosphonate bound to tyrosine could generate specific antibodies. Tyrosine in the pentapeptide RYGRK was covalently modified with soman simply by adding soman to the peptide. The phosphonylated-peptide was linked to keyhole limpet hemocyanin, and the conjugate was injected into rabbits. The polyclonal antiserum recognized soman-labeled human albumin, soman-mouse albumin, and soman human transferrin but not nonphosphonylated control proteins. The soman-labeled tyrosines in these proteins are surrounded by different amino acid sequences, suggesting that the polyclonal recognizes soman-tyrosine independent of the amino acid sequence. Antiserum obtained after 4 antigen injections over a period of 18 weeks was tested in a competition ELISA where it had an IC50 of 10(-11) M. The limit of detection on Western blots was 0.01 μg (15 picomoles) of soman-labeled albumin. In conclusion, a high-affinity, polyclonal antibody that specifically recognizes soman adducts on tyrosine in a variety of proteins has been produced. Such an antibody could be useful for identifying secondary targets of soman toxicity. 23643631 Melamine activates NFκB/COX-2/PGE2 pathway and increases NADPH oxidase-dependent ROS production in macrophages and human embryonic kidney cells. Melamine is a wildly used compound in manufactures of plastics and resins. A variety of toxic effects from melamine, including nephrolithiasis, chronic kidney inflammation, and bladder carcinoma, have been mentioned. Oxidative stress is considered to be an important pathogenic mechanism of kidney disease which may develop from an increasing free radical production through inflammation. The aim of this study is to investigate melamine-induced oxidative stress and inflammation in macrophage-like cell line RAW 264.7 and human embryonic kidney cell line HEK293. Results indicated melamine activated nuclear factor (NF)-κB through increasing IκB-α degradation and NF-κB p65/p50 DNA-binding activity. In addition, melamine significantly increased COX-2 expression and prostaglandin E2 (PGE2) production. Moreover, melamine activated NADPH oxidase (NOX), including NOX1, 2 and 4, accompanied with an increase in reactive oxygen species (ROS) production. Furthermore, melamine-induced ROS production could be attenuated by apocynin, a NOX inhibitor. In conclusion, our findings suggest melamine increased inflammation and oxidative stress via activation of NF-κB/COX-2 and NOX/ROS pathway, and first revealed the critical role of NOX in melamine-induced ROS production, suggesting the potential of NOX inhibitor against melamine toxicity. 23354532 Caffeine increases liking and consumption of novel-flavored yogurt. RATIONALE: Caffeine has been shown to increase preference for beverages with which it is paired; however, it is not known if caffeine alters liking for foods with which it is paired indirectly. OBJECTIVES: The purpose of the current experiment was to test the hypothesis that a caffeinated beverage paired with a novel-flavored yogurt will increase preference for that yogurt compared to one paired with placebo. We also tested the hypothesis that liking would increase more when caffeine was paired with high energy density yogurt. METHODS: Men and women (n = 62) were randomized to receive a beverage containing placebo (PLA) or caffeine (CAF) and to consume a low (LED) or high energy density (HED), novel-flavored yogurt. Participants rated, ranked, and consumed seven novel-flavored yogurts and then had a target yogurt paired with either PLA or CAF over four consecutive days. RESULTS: In general, yogurt liking increased over time, the HED yogurt was liked more than the LED yogurt, and yogurt paired with caffeine was liked more than yogurt paired with placebo. Participants showed a significant increase in liking of LED yogurt paired with caffeine compared to those with LED yogurt paired with placebo. CONCLUSIONS: Caffeine administration may increase liking and consumption of novel-flavored foods, particularly if the food is not highly liked at baseline. This suggests that caffeine pairing may be a way to increase liking of LED foods, such as vegetables and fruit. 23055540 INO-8875, a highly selective A1 adenosine receptor agonist: evaluation of chronotropic, dromotropic, and hemodynamic effects in rats. Selective pharmacological activation of the adenosine 1 receptor (A(1)R) is a promising new approach to achieve a potent block of atrioventricular (A-V)-nodal conduction without significant cardiovascular side effects. The purpose of the present study was to evaluate the cardiovascular profile of INO-8875, a highly selective A(1)R agonist, and to compare its properties with N-[3(R)-tetrahydrofuranyl]-6-aminopurine riboside (CVT-510), which has already been shown to induce negative dromotropic effects with minimal cardiovascular side effects in animals and in clinical studies. Dose-response experiments in the isolated hearts of rats were used to evaluate the functional selectivity of INO-8875 for the slowing of A-V-nodal conduction. Ventilated adult rats were used to study the effects of INO-8875, in vivo, on arterial blood pressure as well as on supraventricular electrophysiology. Ex vivo, INO-8875 (100 nM to 3 μM) progressively prolonged A-V-nodal conduction without reducing left ventricular function or coronary resistance. In vivo, INO-8875 up to a dose of 50 μg/kg did not reduce the carotid arterial blood pressure (n = 4). INO-8875 (1-50 μg/kg) and CVT-510 (20 and 50 μg/kg) both induced a dose-dependent decrease in heart rate and atrial refractoriness, as well as slowing of A-V-nodal conduction. However, compared with CVT-510, the activity of INO-8875 was more pronounced in A-V-nodal function. INO-8875 exhibited a greater duration of action, lasting up to 2.5 hours post dosing, whereas the effects of CVT-510 dissipated over 1 hour. INO-8875 demonstrates functional properties of a highly selective A(1)R agonist. INO-8875 exhibits an increased dromotropic effect and greater duration of action compared with CVT-510. 23632006 Effect of subacute exposure to silver nanoparticle on some hematological and plasma biochemical indices in silver carp (Hypophthalmichthys molitrix). The use of silver nanoparticles (Ag-NPs) is rapidly increasing, but there are limited data on their effects on the aquatic environment. The present study aimed to determine the acute toxicity and evaluate the effect of subacute concentrations of Ag-NPs (Nanocid®: average particle size of 61 nm) on hematological and plasma biochemical indices of silver carp, Hypophthalmichthys molitrix, after 3, 7 and 14 days. The 24-, 48-, 72- and 96-h median lethal concentration (LC50) values of Nanocid for silver carp were estimated at 0.810, 0.648, 0.383 and 0.202 mg/L, respectively; 20% and 10% of the 96-h LC50 values (0.04 and 0.02 mg/L) were selected for subacute study. Red blood cell (RBC) count, hemoglobin (Hb) count and hematocrit (Hct) level were significantly reduced at both concentrations tested (p < 0.05). White blood cell (WBC), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), cortisol and glucose levels in Nanocid-treated groups were significantly higher than the controlled group at experimental periods (p < 0.05). In conclusion, Ag-NPs intoxication resulted in erythrocyte reduction, hematological disturbances, leucocytosis and stress response in silver carp and offered a simple tool to evaluate toxicity-derived alterations. 23584543 Photocytotoxicity of copper(II) complexes of curcumin and N-ferrocenylmethyl-l-amino acids. Copper(II) complexes [Cu(Fc-aa)(cur)] (1-3) of curcumin (Hcur) and N-ferrocenylmethyl-l-amino acids (Fc-aa), viz., ferrocenylmethyl-l-tyrosine (Fc-TyrH), ferrocenylmethyl-l-tryptophan (Fc-TrpH) and ferrocenylmethyl-l-methionine (Fc-MetH), were prepared and characterized. The DNA photocleavage activity, photocytotoxicity and cellular localization in HeLa and MCF-7 cancer cells of these complexes were studied. Acetylacetonate (acac) complexes [Cu(Fc-aa)(acac)] (4-6) were prepared and used as controls. The chemical nuclease inactive complexes showed efficient pUC19 DNA cleavage activity in visible light. Complexes 1-3 showed high photocytotoxicity with low dark toxicity thus giving remarkable photodynamic effect. FACScan analysis showed apoptosis of the cancer cells. Fluorescence microscopic studies revealed primarily cytosolic localization of the complexes. 23369988 Hierarchical organization of osteoblasts reveals the significant role of CD166 in hematopoietic stem cell maintenance and function. The role of osteoblasts (OB) in maintaining hematopoietic stem cells (HSC) in their niche is well elucidated, but the exact definition, both phenotypically and hierarchically of OB responsible for these functions is not clearly known. We previously demonstrated that OB maturational status influences HSC function whereby immature OB with high Runx2 expression promote hematopoietic expansion. Here, we show that Activated Leukocyte Cell Adhesion Molecule (ALCAM) or CD166 expression on OB is directly correlated with Runx2 expression and high hematopoiesis enhancing activity (HEA). Fractionation of OB with lineage markers: Sca1, osteopontin (OPN), CD166, CD44, and CD90 revealed that Lin-Sca1-OPN+CD166+ cells (CD166+) and their subpopulations fractionated with CD44 and CD90 expressed high levels of Runx2 and low levels of osteocalcin (OC) demonstrating the relatively immature status of these cells. Conversely, the majority of the Lin-Sca1-OPN+CD166- cells (CD166-) expressed high OC levels suggesting that CD166- OB are more mature. In vitro hematopoietic potential of LSK cells co-cultured for 7days with fresh OB or OB pre-cultured for 1, 2, or 3 weeks declined precipitously with increasing culture duration concomitant with loss of CD166 expression. Importantly, LSK cells co-cultured with CD166+CD44+CD90+ OB maintained their in vivo repopulating potential through primary and secondary transplantation, suggesting that robust HEA activity is best mediated by immature CD166+ OB with high Runx2 and low OC expression. These studies begin to define the hierarchical organization of osteoblastic cells and provide a more refined definition of OB that can mediate HEA. 23421648 Calmodulin as a potential target by which berberine induce cell cycle arrest in human hepatoma Bel7402 cells. Berberine is an isoquinoline alkaloid that has drawn extensive attention since it possesses various biological activities. Several mechanisms have been proposed to interpret the anticancer activity of berberine. However, these explanations are mostly based on its downstream-regulated genes or proteins, information on the direct target proteins that mediate the antiproliferative action of berberine remain unclear. In the present study, a computational pipeline based on a ligand-protein inverse docking program and mining of the "Connectivity MAP" data was adopted to explore the potential target proteins for berberine. The results showed that four proteins, i.e., calmodulin, cytochrome P450 3A4, sex hormone-binding globulin and carbonic anhydrase II, were suggested to be the potential targets of berberine. The anti-calmodulin property of berberine was demonstrated with an in vitro phosphodiesterase activity assay. Flow cytometric analysis found that G1 cell cycle arrest induced by berberine in Bel7402 cells was enhanced by cotreatment with calmodulin inhibitors. Western blotting results indicated that berberine treatment decreased phosphorylation of calmodulin kinase II and blocked subsequent MEK1 activation as well as p27 protein degradation. These results suggested that calmodulin might play crucial roles in berberine-induced cell cycle arrest in cancer cells. © 2013 John Wiley & Sons A/S. 23318431 ErbB2, FoxM1 and 14-3-3ζ prime breast cancer cells for invasion in response to ionizing radiation. ErbB2 is frequently highly expressed in premalignant breast cancers, including ductal carcinoma in situ (DCIS); however, little is known about the signals or pathways it contributes to progression into the invasive/malignant state. Radiotherapy is often used to treat early premalignant lesions regardless of ErbB2 status. Here, we show that clinically relevant doses of ionizing radiation (IR)-induce cellular invasion of ErbB2-expressing breast cancer cells, as well as MCF10A cells overexpressing ErbB2. ErbB2-negative breast cancer cells, such as MCF7 and T47D, do not invade following treatment with IR nor do MCF10A cells overexpressing epidermal growth factor receptor. ErbB2 becomes phosphorylated at tyrosine 877 in a dose- and time- dependent manner following exposure to X-rays, and activates downstream signaling cascades including PI3K/Akt. Inhibition of these pathways, as well as inhibition of reactive oxygen species (ROS) with antioxidants, prevents IR-induced invasion. Activation of ErbB2-dependent signaling results in upregulation of the forkhead family transcription factor, FoxM1, and its transcriptional targets, including matrix metalloproteinase 2 (MMP2). Inhibition of FoxM1 by RNA interference prevented induction of invasion by IR, and overexpression of FoxM1 in MCF10A cells was sufficient to promote IR-induced invasion. Moreover, we found that 14-3-3ζ is also upregulated by IR in cancer cells in a ROS-dependent manner, is required for IR-induced invasion in ErbB2-positive breast cancer cells and together with FoxM1 is sufficient for invasion in ErbB2-negative breast cancer cells. Thus, our data show that IR-mediated activation of ErbB2 and induction of 14-3-3ζ collaborate to regulate FoxM1 and promote invasion of breast cancer cells and furthermore, may serve as therapeutic targets to enhance radiosensitivity of breast cancers.Oncogene advance online publication, 14 January 2013; doi:10.1038/onc.2012.629. 23210482 Stabilization and inhibition of protein-protein interactions: the 14-3-3 case study. Small-molecule modulation of protein-protein interactions (PPIs) is one of the most exciting but also difficult fields in chemical biology and drug development. As one of the most important "hub" proteins with at least 200-300 interaction partners, the 14-3-3 proteins are an especially fruitful case for PPI intervention. Here, we summarize recent success stories in small-molecule modulation, both inhibition and stabilization, of 14-3-3 PPIs. The chemical breath of modulators includes natural products such as fusicoccin A and derivatives but also compounds identified via high-throughput and in silico screening, which has yielded a toolbox of useful inhibitors and stabilizers for this interesting class of adapter proteins. Protein-protein interactions (PPIs) are involved in almost all biological processes, with any given protein typically engaged in complexes with other proteins for the majority of its lifetime. Hence, proteins function not simply as single, isolated entities but display their roles by interacting with other cellular components. These different interaction patterns are presumably as important as the intrinsic biochemical activity status of the protein itself. The biological role of a protein is therefore decisively dependent on the underlying PPI network that furthermore can show great spatial and temporal variations. A thorough appreciation and understanding of this concept and its regulation mechanisms could help to develop new therapeutic agents and concepts. 23561154 Effects of NaCl and pH on the structural conformations of kidney bean vicilin. Structural changes as a result of variations in pH value and salt concentration were determined for purified vicilin, the major globular protein in kidney beans using intrinsic fluorescence and circular dichroism (CD). The vicilin consisted of two polypeptide chains of about 43 and 45kDa in size when analysed under reducing SDS-PAGE. Amino acid analysis showed that the vicilin had high contents of acidic amino acids and a low lysine/arginine ratio. Intrinsic fluorescence measurements were performed to measure exposure of tyrosine and tryptophan as a means of estimating protein conformational changes. Generally, the vicilin showed an unfolded structure at pH 3.0, 5.0, 7.0, and 9.0 as evident by the extensive red shift (>350nm) of the wavelength of maximum tryptophan fluorescence intensity. At pH 3.0 and 5.0, the fluorescence intensity (FI) was greater than values obtained at pH 7.0 and 9.0, which suggests that the microenvironment of tryptophan was less hydrophilic at acidic pH. Addition of NaCl also led to increased FI, an indication of structural changes of tryptophan in response to the hydrophilic environment. These changes in FI were due mostly to tryptophan emission because tyrosine emission (at 303nm) was suppressed. The far-UV CD spectra showed that vicilin had minimal measurable secondary structures at pH 3.0 and 5.0 when compared to pH 7.0 and 9.0. Addition of NaCl led to an increase in the tertiary structure conformation of vicilin as determined from the near-UV CD spectra. 23190033 Phenolic compounds as antioxidants: carbonic anhydrase isoenzymes inhibitors. Antioxidant compounds can scavenge free radicals and increase shelf life by retarding the process of lipid peroxidation, which is one of the major reasons for deterioration of food, medicine and pharmaceutical products during processing and storage. An antioxidant molecule has been defined as any substance when found in low concentrations compared to that of an oxidizable substrate significantly delays or inhibits the oxidation. The major antioxidant compounds are especially phenolics and flavonoids, which are responsible for their health benefits. Carbonic anhydrase (EC 4.2.1.1., CA) is a pH regulatory/metabolic enzyme in all life kingdoms, being found in organisms all over the phylogenetic tree. It catalyzes the hydration of carbon dioxide (CO(2)) to bicarbonate (HCO(3) -) and the corresponding dehydration of HCO(3) -in acidic medium with regeneration of CO(2). Also, CA isoforms are found in a variety of tissues where they participate in several important biological processes such as acid-base balance, respiration, carbon dioxide and ion transport, bone resorption, ureagenesis, gluconeogenesis, lipogenesis and electrolyte secretion. On the other hand, the phenyl moiety of phenol was found to lay in the hydrophobic part of the CA active site, where CO(2), the physiologic substrate of the CAs, binds in the precatalytic complex, explaining thus the behavior of phenol as a unique CO(2) competitive inhibitor. This review consists of two main sections. The first section is devoted to main phenolic antioxidant compounds in the foodstuffs and beverages. The second general section is about some definitions of CA inhibitory effects of the main phenolic compounds used for antioxidant activity. The phenolic compounds and acids had marked especially CA I and CA II inhibitory effects and might be used as leads for generating CA isoenzyme inhibitors. This class of compounds may lead to isoform-selective inhibitors targeting just one or few of the medicinally relevant CAs. In addition, there are given some chemical and kinetic basis and technical details related to phenolic antioxidant compounds and carbonic anhydrase isoenzymes. 23350926 Cleavage of DNA by proton-coupled electron transfer to a photoexcited, hydrated Ru(II) 1,10-phenanthroline-5,6-dione complex. Visible light irradiation of a ruthenium(II) quinone-containing complex, [(phen)(2)Ru(phendione)](2+) (1(2+)), where phendione = 1,10-phenanthroline-5,6-dione, leads to DNA cleavage in an oxygen independent manner. A combination of NMR analyses, transient absorption spectroscopy, and fluorescence measurements in water and acetonitrile reveal that complex 1(2+) must be hydrated at the quinone functionality, giving [(phen)(2)Ru(phenH(2)O)](2+) (1H(2)O(2+), where phenH(2)O = 1,10-phenanthroline-6-one-5-diol), in order to access a long-lived (3)MLCT(hydrate) state (τ ∼ 360 ns in H(2)O) which is responsible for DNA cleavage. In effect, hydration at one of the carbonyl functions effectively eliminates the low-energy (3)MLCT(SQ) state (Ru(III) phen-semiquinone radical anion) as the predominant nonradiative decay pathway. This (3)MLCT(SQ) state is very short-lived (<1 ns) as expected from the energy gap law for nonradiative decay, (1) and too short-lived to be the photoactive species. The resulting excited state in 1H(2)O(2+)* has photophysical properties similar to the (3)MLCT state in [Ru(phen)(3)](2+)* with the added functionality of basic sites at the ligand periphery. Whereas [Ru(phen)(3)](2+)* does not show direct DNA cleavage, the deprotonated form of 1H(2)O(2+)* does via a proton-coupled electron transfer (PCET) mechanism where the peripheral basic oxygen sites act as the proton acceptor. Analysis of the small molecule byproducts of DNA scission supports the conclusion that cleavage occurs via H-atom abstraction from the sugar moieties, consistent with a PCET mechanism. Complex 1(2+) is a rare example of a ruthenium complex which 'turns on' both reactivity and luminescence upon switching to a hydrated state. 23587668 Cyp1a reporter zebrafish reveals target tissues for dioxin. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the unintentional byproduct of various industrial processes, is classified as human carcinogen and could disrupt reproductive, developmental and endocrine systems. Induction of cyp1a1 is used as an indicator of TCDD exposure. We sought to determine tissues that are vulnerable to TCDD toxicity using a transgenic zebrafish (Danio rerio) model. We inserted a nuclear enhanced green fluorescent protein gene (EGFP) into the start codon of a zebrafish cyp1a gene in a fosmid clone using DNA recombineering. The resulting recombineered fosmid was then used to generate cyp1a reporter zebrafish, embryos of which were exposed to TCDD. Expression pattern of EGFP in the reporter zebrafish mirrored that of endogenous cyp1a mRNA. In addition, exposure of the embryos to TCDD at as low as 10pM for 72h, which does not elicit morphological abnormalities of embryos, markedly increased GFP expression. Furthermore, the reporter embryos responded to other AhR ligands as well. Exposure of the embryos to TCDD revealed previously reported (the cardiovascular system, liver, pancreas, kidney, swim bladder and skin) and unreported target tissues (retinal bipolar cells, otic vesicle, lateral line, cloaca and pectoral fin bud) for TCDD. Transgenic cyp1a reporter zebrafish we have developed can further understanding of ecotoxicological relevance and human health risks by TCDD. In addition, they could be used to identify agonists of AhR and antidotes to TCDD toxicity. 23529900 Broadband Light-Trapping Enhancement in an Ultrathin Film a-Si Absorber Using Whispering Gallery Modes and Guided Wave Modes with Dielectric Surface-Textured Structures. An embedded nanosphere dielectric structure on an a-Si ultrathin film improves weighted absorption from 23.8% to 39.9%. The PMMA embedding layer offers a guided wave mode as well as mechanical robustness, in addition to the resonant whispering gallery modes coupling. Broadband light-trapping enhancements are observed by dielectric surface textured structures of hemispheres, nanocones, nanospheres, or embedded nanospheres. 23360118 Assessing the regioselectivity of OleD-catalyzed glycosylation with a diverse set of acceptors. To explore the acceptor regioselectivity of OleD-catalyzed glucosylation, the products of OleD-catalyzed reactions with six structurally diverse acceptors flavones- (daidzein), isoflavones (flavopiridol), stilbenes (resveratrol), indole alkaloids (10-hydroxycamptothecin), and steroids (2-methoxyestradiol)-were determined. This study highlights the first synthesis of flavopiridol and 2-methoxyestradiol glucosides and confirms the ability of OleD to glucosylate both aromatic and aliphatic nucleophiles. In all cases, molecular dynamics simulations were consistent with the determined product distribution and suggest the potential to develop a virtual screening model to identify additional OleD substrates. 23631674 Synthesis of Silver Octahedra with Controlled Sizes and Optical Properties via Seed-Mediated Growth. Silver octahedra with edge lengths controlled in the range of 20-72 nm were synthesized via seed-mediated growth. The key to the success of this synthesis is the use of single-crystal Ag seeds with uniform and precisely controlled sizes to direct the growth and the use of citrate as a selective capping agent for the {111} facets. Our mechanistic studies demonstrated that Ag seeds with both cubic and quasi-spherical shapes could evolve into octahedra. For the first time, we were able to precisely control the edge lengths of Ag octahedra below 100 nm, and the lower limit of size could even be pushed down to 20 nm. Using the as-obtained Ag octahedra as sacrificial templates, Au nanocages with an octahedral shape and precisely tunable optical properties were synthesized through a galvanic replacement reaction. Such hollow nanostructures are promising candidates for a broad range of applications related to optics, catalysis, and biomedicine. 23145985 PomZ, a ParA-like protein, regulates Z-ring formation and cell division in Myxococcus xanthus. Accurate positioning of the division site is essential to generate appropriately sized daughter cells with the correct chromosome number. In bacteria, division generally depends on assembly of the tubulin homologue FtsZ into the Z-ring at the division site. Here, we show that lack of the ParA-like protein PomZ in Myxococcus xanthus resulted in division defects with the formation of chromosome-free minicells and filamentous cells. Lack of PomZ also caused reduced formation of Z-rings and incorrect positioning of the few Z-rings formed. PomZ localization is cell cycle regulated, and PomZ accumulates at the division site at midcell after chromosome segregation but prior to FtsZ as well as in the absence of FtsZ. FtsZ displayed cooperative GTP hydrolysis in vitro but did not form detectable filaments in vitro. PomZ interacted with FtsZ in M. xanthus cell extracts. These data show that PomZ is important for Z-ring formation and is a spatial regulator of Z-ring formation and cell division. The cell cycle-dependent localization of PomZ at midcell provides a mechanism for coupling cell cycle progression and Z-ring formation. Moreover, the data suggest that PomZ is part of a system that recruits FtsZ to midcell, thereby, restricting Z-ring formation to this position. 23268549 Mitochondrial Permeability Transition Pore Inhibitors Prevent Ethanol-Induced Neuronal Death in Mice. Ethanol induces brain injury by a mechanism that remains partly unknown. Mitochondria play a key role in cell death processes, notably through the opening of the permeability transition pore (PTP). Here, we tested the effect of ethanol and PTP inhibitors on mitochondrial physiology and cell viability both in vitro and in vivo. Direct addition of ethanol up to 100 mM on isolated mouse brain mitochondria slightly decreased oxygen consumption but did not affect PTP regulation. In comparison, when isolated from ethanol-treated (two doses of 2 g/kg, 2 h apart) 7-day-old mouse pups, brain mitochondria displayed a transient decrease in oxygen consumption but no change in PTP regulation or H(2)O(2) production. Conversely, exposure of primary cultured astrocytes and neurons to 20 mM ethanol for 3 days led to a transient PTP opening in astrocytes without affecting cell viability and to a permanent PTP opening in 10 to 20% neurons with the same percentage of cell death. Ethanol-treated mouse pups displayed a widespread caspase-3 activation in neurons but not in astrocytes and dramatic behavioral alterations. Interestingly, two different PTP inhibitors (namely, cyclosporin A and nortriptyline) prevented both ethanol-induced neuronal death in vivo and ethanol-induced behavioral modifications. We conclude that PTP opening is involved in ethanol-induced neurotoxicity in the mouse. 23392120 Synthesis of Li-Mn-O mesocrystals with controlled crystal phases through topotactic transformation of MnCO₃. Mesocrystals of Li-Mn-O compounds, such as LiMn2O4, Li2MnO3, and LiMnO2-Li2MnO3, consisting of oriented nanoscale units were selectively produced under hydrothermal conditions from biomimetically prepared MnCO3 mesocrystals. Topotactic transformation through the intermediate phase of Mn5O8 inheriting a hierarchical structure of the MnCO3 precursor was essential for the formation of the mesocrystal compounds. The crystal phases were successfully controlled by varying the conditions for the hydrothermal reactions. The Li-Mn-O mesocrystals have considerable potential as cathodes of Li-ion batteries. 23411281 Antioxidant properties of different edible mushroom species and increased bioconversion efficiency of Pleurotus eryngii using locally available casing materials. Total phenolics, radical scavenging activity (RSA) on DPPH, ascorbic acid content and chelating activity on Fe(2+) of Pleurotus citrinopileatus, Pleurotus djamor, Pleurotus eryngii, Pleurotus flabellatus, Pleurotus florida, Pleurotus ostreatus, Pleurotus sajor-caju and Hypsizygus ulmarius have been evaluated. The assayed mushrooms contained 3.94-21.67 mg TAE of phenolics, 13.63-69.67% DPPH scavenging activity, 3.76-6.76 mg ascorbic acid and 60.25-82.7% chelating activity. Principal Component Analysis (PCA) revealed that significantly higher total phenolics, RSA on DPPH and growth/day was present in P. eryngii whereas P. citrinopileatus showed higher ascorbic acid and chelating activity. Agglomerative hierarchical clustering analysis revealed that studied mushroom species fall into two clusters; Cluster I included P. djamor, P. eryngii and P. flabellatus, while Cluster II included H. ulmarius, P. sajor-caju, P. citrinopileatus, P. ostreatus and P. florida. Enhanced yield of P. eryngii was achieved on spent compost casing material. Use of casing materials enhanced yield by 21-107% over non-cased substrate. 23432420 SNAIL Induces Epithelial-to-Mesenchymal Transition and Cancer Stem Cell-like Properties in Aldehyde Dehydroghenase-Negative Thyroid Cancer Cells. Background: Epithelial-to-mesenchymal transition (EMT) has been thought to play a critical role in invasion and metastasis of cancer and to be associated with cancer stem cell (CSC) properties. It is not clear if there is a link between EMT and CSCs in thyroid cancers. We therefore investigated CSC properties of thyroid cancers that underwent EMT. Method: To induce EMT (spindle-like cell morphology, loss and acquisition of expression of an epithelial marker E-cadherin and a mesenchymal marker vimentin, respectively) in an epithelial type thyroid cancer cell line ACT-1, we used transforming growth factor-beta (TGF-beta), BRAFV600E and/or Snail homolog 1 (SNAI1, also known as SNAIL) . CSC properties were analyzed with assays for cell proliferation, chemosensitivity, in vitro and in vivo tumor formation ability, cell surface antigens and intracellular aldehyde dehydrogenase (ALDH; a known CSC marker) activities. Results: EMT was induced most efficiently by SNAIL (ACT-SNAIL cells), whereas TGF-beta and BRAFV600E were less efficient. ACT-SNAIL cells showed slightly but significantly enhanced tumor formation ability in in vitro sphere assay (~3 fold) but not in vivo subcutaneous tumor growth assay, and showed comparable chemosensitivity, as compared to the parental ACT-1 cells. However, of interest, although in vitro sphere formation ability of ALDH+ cells was almost unchanged after SNAIL induction, SNAIL overexpression induced much higher (~14 fold) spheres in ALDH- cells. Thus, ALDH was no longer a CSC marker in ACT-SNAIL cells. Conclusions: All these data indicate that EMT confers CSC properties in ALDH- cells and appears to influence the ability of ALDH to enrich CSCs. 23374864 Synthesis and biological evaluation of 5-nitropyrimidine analogs with azabicyclic substituents as GPR119 agonists. 5-Nitropyrimidine analogs substituted with conformationally restricted azabicyclic amines and alcohols were prepared and evaluated their agonistic activity against human GPR119. The analogs bearing endo-azabicyclic amines and alcohols (7, 8, 11, and 12) exhibited full agonistic activities while the analogs with exo-azabicyclic amines and alcohols were proved as partial agonists (9, 10, 13, and 14) regardless of their EC(50) values. 5-Nitropyrimidine analogs with (2-fluoro-4-methylsulfonyl)phenylamino group (8, 10, 12, 14) showed more potent GPR119 activation activities than the analogs without fluorine in all cases (7, 9, 11, 13). 23103446 Can P-glycoprotein mediate resistance to nilotinib in human leukaemia cells? The effect of P-glycoprotein (P-gp, ABCB1, MDR1) expression on cell resistance to nilotinib was studied in human leukaemia cells. We used K562/Dox cells overexpressing P-gp and their variants (subclones) with a gradually decreased P-gp expression. These subclones were established by stable transfection of K562/Dox cells with a plasmid vector expressing shRNA targeting the ABCB1 gene. Functional analysis of P-gp using a specific fluorescent probe indicated gradually decreased dye efflux which was proportional to the P-gp expression. We observed that K562/Dox cells overexpressing P-gp contained a significantly reduced intracellular level of nilotinib when compared to their counter partner K562 cells, which do not express P-gp. This effect was accompanied by a decreased sensitivity of the K562/Dox cells to nilotinib. Importantly, cells with downregulated expression of P-gp gradually lost their ability to decrease the intracellular level of nilotinib although they still significantly decreased the intracellular level of daunorubicin (DNR). Accordingly, cells with the reduced expression of P-gp concomitantly failed to provide resistance to nilotinib, however, they exhibited a significant resistance to DNR. Taken together, we demonstrated that the conclusion as to whether P-gp is involved in nilotinib resistance or not strongly depends on its expression at protein level. 23592577 Charge-Transfer Interaction between Few-Layer MoS2 and Tetrathiafulvalene. Graphene look-alike: MoS2 has a layered structure similar to graphene. Tetrathiafulvalene (TTF) interacts with thin, few-layer MoS2 material by donating an electron, resulting in the formation of TTF radical cation and n-type doping of MoS2 . Electron-withdrawing tetracyanoethylene, in contrast, does not cause p-type doping in MoS2 . 23404837 Fractionation of organosolv lignin from olive tree clippings and its valorization to simple phenolic compounds. Lignin valorization practices have attracted a great deal of interest in recent years due to the large excess of lignin produced by the pulp and paper industry, together with second-generation bioethanol plants. In this work, a new lignin valorization approach is proposed. It involves ultrafiltration as a fractionation process to separate different molecular weight lignin fractions followed by a hydrogen-free, mild, hydrogenolytic, heterogeneously catalyzed methodology assisted by microwave irradiation to obtain simple phenolic, monomeric products by depolymerization using a nickel-based catalyst. The main products obtained were desaspidinol, syringaldehyde, and syringol; this proves the efficiency of the depolymerization conditions applied. The concentration of these observed compounds increased when the molecular weights of the lignin fractions increased. The applied depolymerization conditions, which take advantage of the use of formic acid as a hydrogen-donating solvent, did not generate any biochar in the systems. 23627637 Broad-Range Modulation of Light Emission in Two-Dimensional Semiconductors by Molecular Physisorption Gating. In the monolayer limit, transition metal dichalcogenides become direct-bandgap, light-emitting semiconductors. The quantum yield of light emission is low and extremely sensitive to the substrate used, while the underlying physics remains elusive. In this work, we report over 100 times modulation of light emission efficiency of these two-dimensional semiconductors by physical adsorption of O2 and/or H2O molecules, while inert gases do not cause such effect. The O2 and/or H2O pressure acts quantitatively as an instantaneously reversible "molecular gating" force, providing orders of magnitude broader control of carrier density and light emission than conventional electric field gating. Physi-sorbed O2 and/or H2O molecules electronically deplete n-type materials such as MoS2 and MoSe2, which weakens electrostatic screening that would otherwise destabilize excitons, leading to the drastic enhancement in photoluminescence. In p-type materials such as WSe2, the molecular physisorption results in the opposite effect. Unique and universal in two-dimensional semiconductors, the effect offers a new mechanism for modulating electronic interactions and implementing optical devices. 23092880 mTORC1 and mTORC2 regulate insulin secretion through Akt in INS-1 cells. Regulated associated protein of mTOR (Raptor) and rapamycin-insensitive companion of mTOR (rictor) are two proteins that delineate two different mTOR complexes, mTORC1 and mTORC2 respectively. Recent studies demonstrated the role of rictor in the development and function of β-cells. mTORC1 has long been known to impact β-cell function and development. However, most of the studies evaluating its role used either drug treatment (i.e. rapamycin) or modification of expression of proteins known to modulate its activity, and the direct role of raptor in insulin secretion is unclear. In this study, using siRNA, we investigated the role of raptor and rictor in insulin secretion and production in INS-1 cells and the possible cross talk between their respective complexes, mTORC1 and mTORC2. Reduced expression of raptor is associated with increased glucose-stimulated insulin secretion and intracellular insulin content. Downregulation of rictor expression leads to impaired insulin secretion without affecting insulin content and is able to correct the increased insulin secretion mediated by raptor siRNA. Using dominant-negative or constitutively active forms of Akt, we demonstrate that the effect of both raptor and rictor is mediated through alteration of Akt signaling. Our finding shed new light on the mechanism of control of insulin secretion and production by the mTOR, and they provide evidence for antagonistic effect of raptor and rictor on insulin secretion in response to glucose by modulating the activity of Akt, whereas only raptor is able to control insulin biosynthesis. 23411251 Evaluation of antioxidant activities and chemical characterisation of staghorn sumac fruit (Rhus hirta L.). Staghorn sumac (Rhus hirta L.) is a native tree in Eastern Canada whose fruit has been used by aboriginal peoples to treat various illnesses, and has recently been found to be a good source of antioxidants. However, the phytochemical composition of R. hirta is not known. In this study, we used Four highly accepted assays and confirmed its FRAP, ORAC, β-CLAMS and PCL values to be 79.95 μmol AAE/g DW, 1544 μmol TE/g DW, RAA 129% and 4513 μmol TE/g DW, respectively. The antioxidant activities correlated positively to the total polyphenols content, which was higher in the ethanolic extract (81.6 mg GAE/ g DW) compared to the water extract (46.3mg GAE/g DW), suggesting polyphenols play an important role. Quantitative data from UHPLC and qualitative studies using HPLC-DAD-MS showed that in addition to commonly found phenolic acids, flavonoids and anthocyanins, R. hirta fruit contained a novel group of unique anthocyanins with aglycones (anthocyanidins) at 449, 419 and 433 Da. Further studies on the identification and their health beneficial effects are being conducted. 22809709 Serotonergic involvement in the amelioration of behavioral abnormalities in dopamine transporter knockout mice by nicotine. Dopamine transporter knockout (DAT KO) mice exhibit elevated extracellular dopamine levels in brain regions that include the striatum and the nucleus accumbens, but not the prefrontal cortex. DAT KO mice model some aspects of psychiatric disorders, including schizophrenia. Smoking is more common in patients with schizophrenia, suggesting that nicotine might ameliorate aspects of the behavioral abnormalities and/or treatment side effects seen in these individuals. We report nicotine-induced normalization of effects on locomotion and prepulse inhibition of acoustic startle (PPI) in DAT KO mice that require intact serotonin 5-HT1A systems. First, we observed that the marked hyperactivity displayed by DAT KO mice was reduced by administration of nicotine. This nicotine effect was blocked by pretreatment with the non-specific nicotinic acetylcholine (nACh) receptor antagonist mecamylamine, or the 5-HT1A antagonist WAY100635. Secondly, we examined the effects of nicotine on PPI in DAT KO mice. Treatment with nicotine significantly ameliorated the PPI deficits observed in DAT KO mice. The ameliorating action of nicotine on PPI deficits in DAT KO mice was blocked by mecamylamine, the α₇ nACh receptor antagonist methyllycaconitine or WAY100635, while the α₄β₂ nACh receptor antagonist dihydro-β-erythroidinehydrobromide (DHβE) produced only a non-significant trend toward attenuation of nicotine effects. Finally, we observed that administration of the 5-HT1A receptor agonist 8-OH-DPAT also ameliorated the deficit in PPI observed in DAT KO mice. This amelioration was antagonized by pretreatment with WAY100635. These data support the idea that nicotine might ameliorate some of the cognitive dysfunctions found in schizophrenia in a 5-HT1A-dependent fashion. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23607809 Insight into the Structure of Single Antheraea pernyi Silkworm Fibers Using Synchrotron FTIR Microspectroscopy. Synchrotron FTIR (S-FTIR) microspectroscopy was used to monitor both protein secondary structures (conformations) and their orientations in single cocoon silk fibers of the Chinese Tussah silk moth ( Antheraea pernyi ). In addition, to understand further the relationship between structure and properties of single silk fibers, we studied the changes of orientation and content of different secondary structures in single A. pernyi silk fibers when subjected to different strains. The results showed that the content and orientation of β-sheet was almost unchanged for strains from 0 to 0.3. However, the orientation of α-helix and random coil improved progressively with increasing strain, with a parallel decrease in α-helix content and an increase in random coil. This clearly indicates that most of the deformation upon stretching of the single fiber is due to the change of orientation in the amorphous regions coupled with a conversion of some of the α-helix to random coil. These observations provide an explanation for the supercontraction behavior of certain animal silks and are likely to facilitate understanding and optimization of postdrawing used in the conjunction with the wet-spinning of silk fibers from regenerated silk solutions. Thus, our work demonstrates the power of S-FTIR microspectroscopy for studying biopolymers. 22440717 Molecular crosstalk between a chemical and a biological stressor and consequences on disease manifestation in rainbow trout. The aim of the present study was to examine the molecular and organism reaction of rainbow trout, Oncorhynchus mykiss, to the combined impact of two environmental stressors. The two stressors were the myxozoan parasite, Tetracapsuloides bryosalmonae, which is the etiological agent of proliferative kidney disease (PKD) and a natural stressor to salmonid populations, and 17β-estradiol (E2) as prototype of estrogen-active chemical stressors in the aquatic environment. Both stressors, the parasite and estrogenic contaminants, co-exist in Swiss rivers and are discussed as factors contributing to the decline of Swiss brown trout populations over the last decades. Using a microarray approach contrasting parasite-infected and non-infected rainbow trout at low or high estrogen levels, it was observed that molecular response patterns under joint exposure differed from those to the single stressors. More specifically, three major response patterns were present: (i) expression responses of gene transcripts to one stressor are weakened by the presence of the second stressor; (ii) expression responses of gene transcripts to one stressor are enhanced by the presence of the second stressor; (iii) expression responses of gene transcripts at joint treatment are dominated by one of the two stressors. Organism-level responses to concurrent E2 and parasite treatment - assessed through measuring parasite loads in the fish host and cumulative mortalities of trout - were dominated by the pathogen, with no modulating influence of E2. The findings reveal function- and level-specific responses of rainbow trout to stressor combinations, which are only partly predictable from the response to the single stressors. 22236017 Volatile compound in cut and un-cut flowers of tetraploid Freesia hybrida. The flower volatile compounds (FVCs) of two tetraploid Freesia hybrida (pink-yellow and yellow) cultivars and their cut flowers were analysed by headspace solid-phase microextraction combined with gas chromatography-mass spectrometry. Twelve FVCs were identified in the pink-yellow cultivar, with linalool as the major compound; 30 FVCs were identified in the yellow cultivar, with linalool and terpineol as the two major compounds. The FVCs (>1%) of the two cut flower cultivars were very similar to that of the un-cut flowers, and no significant difference was observed. 23432465 Metabolic Activation of Polycyclic Aromatic Hydrocarbons and Aryl and Heterocyclic Amines by Human Cytochromes P450 2A13 and 2A6. Human cytochrome P450 (P450) 2A13 was found to interact with several polycyclic aromatic hydrocarbons (PAHs) to produce Type I binding spectra, including acenaphthene, acenaphthylene, benzo[c]phenanthrene, fluoranthene, fluoranthene-2,3-diol, and 1-nitropyrene. P450 2A6 also interacted with acenaphthene and acenaphthylene, but not with fluoranthene, fluoranthene-2,3-diol, or 1-nitropyrene. P450 1B1 is well-known to oxidize many carcinogenic PAHs, and we found that several PAHs (i.e., 7,12-dimethylbenz[a]anthracene, 7,12-dimethylbenz[a]anthracene-5,6-diol, benzo[c]phenanthrene, fluoranthene, fluoranthene-2,3-diol, 5-methylchrysene, benz[a]pyrene-4,5-diol, benzo[a]pyrene-7,8-diol, 1-nitropyrene, 2-aminoanthracene, 2-aminofluorene, and 2-acetylaminofluorene) interacted with P450 1B1, producing Reverse Type I binding spectra. Metabolic activation of PAHs and aryl- and heterocyclic amines to genotoxic products was examined in Salmonella typhimurium NM2009, and we found that P450 2A13 and 2A6 (as well as P450 1B1) were able to activate several of these procarcinogens. The former two enzymes were particularly active in catalyzing 2-aminofluorene and 2-aminoanthracene activation, and molecular docking simulations supported the results with these procarcinogens, in terms of binding in the active sites of P450 2A13 and 2A6. These results suggest that P450 2A enzymes, as well as P450 Family 1 enzymes including P450 1B1, are major enzymes involved in activating PAHs and aryl- and heterocyclic amines, as well as tobacco-related nitrosamines. 23559516 In Vitro Inhibition of the Transcription Factor NF-κB and Cyclooxygenase by Bamboo Extracts. Several bamboo species have been used in traditional medicine for the treatment of inflammatory conditions. The present study evaluates the in vitro anti-inflammatory properties of the traditionally used bamboo species Phyllostachys nigra (Lodd.) Munro and Sasa veitchii (Carr.) Rehder to explore their future research opportunities and therapeutic potential as anti-inflammatory agents. The extracts were evaluated for their potential inhibitory activity at the level of NF-κB-induced gene expression and suppression of cyclooxygenase (COX)-1 and COX-2 enzyme activities, representative pharmacological targets for the anti-inflammatory action of glucocorticoids and non-steroidal anti-inflammatory drugs, respectively. The activity of P. nigra (Lodd.) Munro and S. veitchii (Carr.) Rehder was compared with bamboo species without traditional anti-inflammatory indications. High-performance liquid chromatography with diode-array detection and liquid chromatography-tandem mass spectrometry analyses were performed to phytochemically characterize the extracts. P. nigra (Lodd.) Munro leaf extract potently inhibited NF-κB-induced gene expression, while S. veitchii (Carr.) Rehder leaf extract exerted a selective COX-2 inhibition. The crude extracts consistently showed a more potent bioactivity than the solid phase extraction fractions. P. nigra (Lodd.) Munro and S. veitchii (Carr.) Rehder both exert anti-inflammatory properties, but act via a different molecular mechanism. Copyright © 2013 John Wiley & Sons, Ltd. 23238121 Single cell gene expression profiling of cortical osteoblast lineage cells. In tissues with complex architectures such as bone, it is often difficult to purify and characterize specific cell types via molecular profiling. Single cell gene expression profiling is an emerging technology useful for characterizing transcriptional profiles of individual cells isolated from heterogeneous populations. In this study we describe a novel procedure for the isolation and characterization of gene expression profiles of single osteoblast lineage cells derived from cortical bone. Mixed populations of different cell types were isolated from adult long bones of C57BL/6J mice by enzymatic digestion, and subsequently subjected to FACS to purify and characterize osteoblast lineage cells via a selection strategy using antibodies against CD31, CD45, and alkaline phosphatase (AP), specific for mature osteoblasts. The purified individual osteoblast lineage cells were then profiled at the single cell level via nanofluidic PCR. This method permits robust gene expression profiling on single osteoblast lineage cells derived from mature bone, potentially from anatomically distinct sites. In conjunction with this technique, we have also shown that it is possible to carry out single cell profiling on cells purified from fixed and frozen bone samples without compromising the gene expression signal. The latter finding means the technique can be extended to biopsies of bone from diseased individuals. Our approach for single cell expression profiling provides a new dimension to the transcriptional profile of the primary osteoblast lineage population in vivo, and has the capacity to greatly expand our understanding of how these cells may function in vivo under normal and diseased states. 23624422 Method for fabrication and verification of conjugated nanoparticle-antibody tuning elements for multiplexed electrochemical biosensors. There is a critical need for more accurate, highly sensitive and specific assay for disease diagnosis and management. A novel, multiplexed, single sensor using rapid and label free electrochemical impedance spectroscopy tuning method has been developed. The key challenges while monitoring multiple targets is frequency overlap. Here we describe the methods to circumvent the overlap, tune by use of nanoparticle (NP) and discuss the various fabrication and characterization methods to develop this technique. First sensors were fabricated using printed circuit board (PCB) technology and nickel and gold layers were electrodeposited onto the PCB sensors. An off-chip conjugation of gold NP's to molecular recognition elements (with verification technique) is described as well. A standard covalent immobilization of the molecular recognition elements is also discussed with quality control techniques. Finally use and verification of sensitivity and specificity is also presented. By use of gold NP's of various sizes, we have demonstrated the possibility and shown little loss of sensitivity and specificity in the molecular recognition of inflammatory markers as "model" targets for our tuning system. By selection of other sized NP's or NP's of various materials, the tuning effect can be further exploited. The novel platform technology developed could be utilized in critical care, clinical management and at home health and disease management. 23563672 Determination of pediatric reference levels of FT3, FT4 and TSH measured with ECLusys kits. Reference ranges for serum thyroid hormones free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) in children were set using the assay kits currently used in clinical settings. A total of 342 children (111 males and 231 females) who were negative for antithyroid antibodies (TgAb, TPOAb) and were found to have no abnormalities on ultrasonographic examination of the thyroid gland were divided into 6 age groups: 4-6 years (45 children), 7-8 years (40), 9-10 years (53), 11-12 years (65), 13-14 years (83), and 15 years (56) for the study. FT3, FT4 and TSH levels were determined by electrochemiluminescence immunoassay (ECLIA) (ECLusys FT3, FT4 and TSH).The reference range for FT3 (pg/mL) was 2.91-4.70 for the age group of 4-6 years, 3.10-5.10 for the age group of 7-8 years, 3.10-4.87 for the age group of 9-10 years, 2.78-4.90 for the age group of 11-12 years, 2.77-4.59 for the age group of 13-14 years, and 2.50-4.64 for the age group of 15 years . The reference range for FT4 (ng/dL) was 1.12-1.67, 1.07-1.61, 0.96-1.60, 1.02-1.52, 0.96-1.52, 0.95-1.53. The reference range for TSH (μU/mL) was 0.62-4.90, 0.53-5.16, 0.67-4.52, 0.62-3.36, 0.54-2.78, 0.32-3.00. Serum FT3, FT4 and TSH levels in children differ from those in adults. It is, therefore, of importance to perform evaluation of thyroid function in children using reference values appropriate for the chronological ages, because misdiagnosis of hypothyroidism or inappropriate secretion of TSH (SITSH) and oversight of mild subclinical hypothyroidism could occur if the diagnosis is made using reference values for adults. 23328624 Nucleophosmin mutations alter its nucleolar localization by impairing G-quadruplex binding at ribosomal DNA. Nucleophosmin (NPM1) is an abundant nucleolar protein implicated in ribosome maturation and export, centrosome duplication and response to stress stimuli. NPM1 is the most frequently mutated gene in acute myeloid leukemia. Mutations at the C-terminal domain led to variant proteins that aberrantly and stably translocate to the cytoplasm. We have previously shown that NPM1 C-terminal domain binds with high affinity G-quadruplex DNA. Here, we investigate the structural determinants of NPM1 nucleolar localization. We show that NPM1 interacts with several G-quadruplex regions found in ribosomal DNA, both in vitro and in vivo. Furthermore, the most common leukemic NPM1 variant completely loses this activity. This is the consequence of G-quadruplex-binding domain destabilization, as mutations aimed at refolding the leukemic variant also result in rescuing the G-quadruplex-binding activity and nucleolar localization. Finally, we show that treatment of cells with a G-quadruplex selective ligand results in wild-type NPM1 dislocation from nucleoli into nucleoplasm. In conclusion, this work establishes a direct correlation between NPM1 G-quadruplex binding at rDNA and its nucleolar localization, which is impaired in the acute myeloid leukemia-associated protein variants. 23444042 miR-7641 modulates the expression of CXCL1 during endothelial differentiation derived from human embryonic stem cells. MicroRNAs (miRNAs) are a class of small noncoding RNAs that negatively regulate gene expression through binding to 3' untranslated region. We identified and characterized the novel miRNA, miR-7641, in human mesenchymal stem cells. The expression of miR-7641 was downregulated during differentiation from human embryonic stem cells to endothelial cells. The CXCL1, a member of the CXC chemokine family, is known as promoting neovascularization by binding G-protein coupled receptors and is related to endothelial cells biogenesis such as angiogenesis, and it was predicted as target gene of miR-7641 by computerized analysis and the luciferase reporter assay. The miR-7641 significantly suppressed CXCL1 of transcriptional and post-translational levels. These data suggest that miR-7641 might be related with differentiation of human endothelial cells. 23541649 A diazen-1-ium-1,2-diolate analog of 7-azabenzobicyclo[2.2.1]heptane: Synthesis, nitric oxide and nitroxyl release, in vitro hemodynamic, and anti-hypertensive studies. 1-(7-Azabenzobicyclo[2.2.1]heptane)diazen-1-ium-1,2-diolate (16) was designed with the expectation that it would act as a dual nitric oxide (NO) and nitroxyl (HNO) donor that is not carcinogenic or genotoxic. Compound 16, with a suitable half-life (17.8min) in PBS at pH 7, released NO (19%) and HNO (22%) during a 2h incubation in PBS at pH 7. In addition, compound 16 exhibited a significant in vitro positive inotropic effect, increased the rates of contraction and relaxation, and increased coronary flow rate, but did not induce a chronotropic effect. Furthermore, compound 16 (13.7mgkg(-1), po dose) provided a significant reduction in the blood pressure of mice up to 3h post-drug administration. All these data suggest that compound 16 constitutes an attractive 'lead-compound' that could have potential applications to treat cardiovascular disease(s) such as congestive heart failure. 23382024 Absence of edge States in covalently bonded zigzag edges of graphene on ir(111). The zigzag edges of graphene on Ir(111) are studied by ab initio simulations and low-temperature scanning tunneling spectroscopy, providing information about their structural, electronic, and magnetic properties. No edge state is found to exist, which is explained in terms of the interplay between a strong geometrical relaxation at the edge and a hybridization of the d orbitals of Ir atoms with the graphene orbitals at the edge. 23615905 Role of central metabolism in the osmoadaptation of the halophilic bacterium Chromohalobacter salexigens. Bacterial osmoadaptation involves the cytoplasmic accumulation of compatible solutes in order to counteract extracellular osmolarity. The halophilic and highly halotolerant bacterium Chromohalobacter salexigens is able to grow up to 3 M NaCl in a minimal medium due to the de novo synthesis of ectoines. This is an osmoregulated pathway that burdens central metabolic routes by quantitatively drawing off TCA cycle intermediaries. Consequently, metabolism in C. salexigens has adapted to support this biosynthetic route. Metabolism of C. salexigens is more efficient at high salinity than at low salinity, as reflected by lower glucose consumption, lower metabolite overflow and higher biomass yield. At low salinity, by-products (mainly gluconate, pyruvate and acetate) accumulate extracellularly. Using [1-13C]-, [2-13C]-, [6-13C]- and [U-13C6]-glucose as carbon sources, we were able to determine the main central metabolic pathways involved in ectoines biosynthesis from glucose. C. salexigens uses the Entner-Doudoroff pathway rather than the standard glycolytic pathway for glucose catabolism, and anaplerotic activity is high to replenish the TCA cycle with the intermediaries withdrawn for ectoines biosynthesis. Metabolic flux ratios at low and high salinity were similar, revealing a certain metabolic rigidity, probably due to its specialization to support high biosynthetic fluxes and partially explaining why metabolic yields are so highly affected by salinity. This work represents an im-portant contribution to the elucidation of specific metabolic adaptations in compatible solute accumulating halophilic bacteria. 23017390 Phenolics profiles of olive fruits (Olea europaea L.) and oils from Ayvalık, Domat and Gemlik varieties at different ripening stages. Phenolic compounds in olive fruit and oils obtained from Ayvalık, Domat and Gemlik olive varieties collected at different ripening periods were evaluated by High Performance Liquid Chromatography (HPLC). Gallic acid and p-cumaric acid were identified for Ayvalık and Domat at each period of ripening, respectively. In addition, gallic acid, p-cumaric acid, sinapinic and apigenin acids were detected in Gemlik olive fruit. Hydroxytyrosol, rutin, oleoropein, luteolin, tyrosol, vanilic acid and gallic acid in Ayvalık olive fruit in all ripening periods were determined. The tyrasol contents varied between 0.18 to 1.57mg/kg. Luteolin contents of olive oils ranged at the levels between 0.12 to 2.28mg/kg. In contrast, oils had the lowest syringic, p-cumaric, chlorogenic and ferulic acids. Vanillic acid contents of oils ranged between 0.08 to 2.38mg/kg. 22614014 Macrophage cathepsin K promotes prostate tumor progression in bone. Bone marrow macrophages (BMMs) share common progenitors with osteoclasts and are critical components of bone-tumor microenvironment; however, their function in prostate tumor growth in the skeleton has not been explored. BMMs are the major source of inflammatory factors and proteases, including cysteine protease cathepsin K (CTSK). In this study, utilizing mice deficient in CTSK, we demonstrate the critical involvement of this potent collagenase in tumor progression in bone. We present the evidence that tumor growth and progression in the bone are impaired in the absence of CTSK. Most importantly, we show for the first time that BMM-supplied CTSK may be involved in CCL2- and COX-2-driven pathways that contribute to tumor progression in bone. Together, our data unravel novel roles for CTSK in macrophage-regulated processes, and provide evidence for close interplay between inflammatory, osteolytic and tumor cell-driven events in the bone-tumor microenvironment. 23622866 An archaeal RadA paralog influences presynaptic filament formation. Recombinases of the RecA family play vital roles in homologous recombination, a high-fidelity mechanism to repair DNA double-stranded breaks. These proteins catalyze strand invasion and exchange after forming dynamic nucleoprotein filaments on ssDNA. Increasing evidence suggests that stabilization of these dynamic filaments is a highly conserved function across diverse species. Here, we analyze the presynaptic filament formation and DNA binding characteristics of the Sulfolobus solfataricus recombinase SsoRadA in conjunction with the SsoRadA paralog SsoRal1. In addition to constraining SsoRadA ssDNA-dependent ATPase activity, the paralog also enhances SsoRadA ssDNA binding, effectively influencing activities necessary for presynaptic filament formation. These activities result in enhanced SsoRadA-mediated strand invasion in the presence of SsoRal1 and suggest a filament stabilization function for the SsoRal1 protein. 23571772 Clinical Pharmacology and the Catalysis of Regulatory Science: Opportunities for the Advancement of Drug Development and Evaluation. The "regulatory paradox" is a tension between aversion to uncertainty and willingness to accept unknowns about a drug before its approval. Finding the right balance may mean the difference between fostering and stifling innovation. Clinical pharmacology applied in the drug development and regulatory contexts can bridge mechanistic reasoning and empiricism to help reconcile the regulatory paradox. Here, we propose that the discipline of clinical pharmacology, in the regulatory setting, is well positioned to build on its past successes in the advancement and acceleration of drug development.Clinical Pharmacology & Therapeutics (2013); advance online publication 10 April 2013. doi:10.1038/clpt.2013.32. 23061623 Antioxidant evaluation of heterocyclic compounds by cytokinesis-block micronucleus assay. This article summarizes the results of using cytokinesis-block micronucleus (CBMN) assay to evaluate the antioxidant potential of heterocyclic compounds. Most studies were carried out with naturally occurring heterocyclic compounds such as plant polyphenols: flavonoids, xanthones, coumarins, and ellagitannins, or plant derived products (juices, extracts, supplements) rich in bioactive heterocyclic compounds. There are also some studies dealing with synthetic heterocyclic antioxidants. CBMN assay is an in vitro study that has been used to evaluate antioxidant and protective effects of heterocyclic compounds on induced chromosome aberration in human lymphocytes. 23264448 Significance of peptide transporter 1 in the intestinal permeability of valacyclovir in wild-type and PepT1 knockout mice. The purpose of this study was to quantitatively determine the contribution of PepT1 [peptide transporter 1 (SLC15A1)] to the intestinal permeability of valacyclovir, an ester prodrug of the antiviral drug acyclovir. In situ single-pass intestinal perfusions were employed (pH 6.5 × 90 minutes) to assess the effective permeability (P(eff)) of 100 μM [(3)H]valacyclovir in wild-type and PepT1 knockout mice. Acyclovir pharmacokinetics was also evaluated after oral administration of 25 nmol/g valacyclovir. In wild-type mice, jejunal uptake of valacyclovir was best described by both saturable (K(m) = 10.2 mM) and nonsaturable components where the saturable pathway accounted for 82% of total transport. Valacyclovir P(eff) was 2.4 × 10(-4) cm/s in duodenum, 1.7 × 10(-4) cm/s in jejunum, 2.1 × 10(-4) cm/s in ileum, and 0.27 × 10(-4) cm/s in colon. In Pept1 knockout mice, P(eff) values were about 10% of that in wild-type animals for these small intestinal segments. Valacyclovir P(eff) was similar in the colon of both genotypes. There were no differences in valacyclovir P(eff) between any of the intestinal segments of PepT1 knockout mice. Valacyclovir P(eff) was significantly reduced by the dipeptide glycylsarcosine and the aminocephalosporin cefadroxil, but not by the amino acids l-valine or l-histidine, the organic acid p-aminohippurate, or the organic base tetraethylammonium (all at 25 mM). PepT1 ablation resulted in 3- to 5-fold reductions in the in vivo rate and extent of valacyclovir absorption. Our findings conclusively demonstrate, using in situ and in vivo validations in genetically modified mice, that PepT1 has a major influence in improving the oral absorption of valacyclovir. 23130977 Steady-state of an enzymatic reaction is dependent on the density of reactant. The post-translational modification of proteins is controlled by the relative activities of two opposing enzymes. For example, the extent of phosphorylation of tyrosine residues reflects the balance of a kinase and a phosphatase enzyme. The present article uses as a model system a self-assembled monolayer that presents a peptide that can be phosphorylated by Abl kinase and subsequently dephosphorylated by Lambda phosphatase. Treatment of monolayers with a reaction mixture containing both enzymes reveals that the steady-state level of peptide phosphorylation is dependent on the density of the peptide. Using identical reaction mixtures, surfaces that presented the substrate at high density led to a phosphorylated peptide at steady-state, whereas surfaces that presented the substrate at low density led to unphosphorylated peptide at steady-state. This dependence owes to an autocatalytic phosphorylation reaction that operates at high densities of substrate. This work provides an example of an interfacial reaction that has properties that have no analogue in the corresponding solution phase reaction. It also provides a model system that is relevant to understanding mechanisms that regulate signaling at the cellular membrane. 23197046 Diagnostic accuracy of fine needle aspiration biopsy cytology and ultrasonography in patients with thyroid nodules diagnosed as benign or indeterminate before thyroidectomy. Fine-needle aspiration biopsy cytology (FNABC) and ultrasonography (US) play an important role in differentiating benign thyroid nodules from malignant nodules. We retrospectively investigated the prevalence of follicular thyroid carcinoma (FTC) in patients with thyroid nodules whose FNABC and US readings were not malignant before thyroidectomy. Between 2007 and 2008, 3333 patients underwent thyroidectomy at our institution, and the 737 of them who had thyroid nodule that had been diagnosed as hyperplastic nodule or follicular tumor by FNABC and US preoperatively were the subjects in this study. Postoperative histopathology showed hyperplastic nodule in 416 patients, follicular adenoma in 200 patients, FTC in 99 patients, and other disease in 22 patients. By FNABC, 34 (6.7%) of the 505 patients with diagnosis as benign and 65 (28%) of the 232 patients with diagnosis as indeterminate, were diagnosed as having FTC. The diagnosis was FTC in 56 (9.6%) of the 582 patients with a preoperative diagnosis of hyperplastic nodule by US and 43 (27.7%) of the 155 patients with a diagnosis of follicular tumor by US. The diagnosis of FTC was made in 21 (4.8%) of 438 patients who were concurrently diagnosed as benign by FNABC and as hyperplastic nodule by US, and in 30 (34.1%) of 88 patients who were diagnosed as indeterminate by FNABC and follicular tumor by US. FNABC has been the mainstay for the preoperative evaluation of thyroid nodule. The results of this study showed that US can also be a useful tool for diagnosing FTC. 23612967 A molecular mechanism for therapeutic effects of cGMP-elevating agents in pulmonary arterial hypertension. Pulmonary arterial hypertension (PAH)5 is a progressive, usually fatal disease with abnormal vascular remodeling. Pulmonary artery smooth muscle cells (PASMCs) from PAH patients are hyper-proliferative and apoptosis-resistant, and demonstrate decreased signaling in response to bone morphogenetic proteins (BMPs). Cyclic GMP-elevating agents are beneficial in PAH, but their mechanism(s) of action are incompletely understood. Here we show that BMP signaling via Smad1/5/8 requires cGMP-dependent protein kinase isotype I (PKGI) to maintain PASMCs in a differentiated, low-proliferative state. BMP cooperation with cGMP/PKGI was crucial for transcription of contractile genes, and suppression of pro-proliferative and anti-apoptotic genes. Lungs from mice with low or absent PKGI (Prkg1+/- and Prkg1-/- mice) exhibited impaired BMP signaling, decreased contractile gene expression, and abnormal vascular remodeling. Conversely, cGMP stimulation of PKGI restored defective BMP signaling in rats with hypoxia-induced PAH, consistent with cGMP-elevating agents reversing vascular remodeling in this PAH model. Our results provide a mechanism for the therapeutic effects of cGMP-elevating agents in PAH, and suggest that combining them with BMP mimetics may provide a novel, disease-modifying approach to PAH therapy. 23386368 SnO(2) -Based Nanomaterials: Synthesis and Application in Lithium-Ion Batteries. The development of new electrode materials for lithium-ion batteries (LIBs) has always been a focal area of materials science, as the current technology may not be able to meet the high energy demands for electronic devices with better performance. Among all the metal oxides, tin dioxide (SnO(2) ) is regarded as a promising candidate to serve as the anode material for LIBs due to its high theoretical capacity. Here, a thorough survey is provided of the synthesis of SnO(2) -based nanomaterials with various structures and chemical compositions, and their application as negative electrodes for LIBs. It covers SnO(2) with different morphologies ranging from 1D nanorods/nanowires/nanotubes, to 2D nanosheets, to 3D hollow nanostructures. Nanocomposites consisting of SnO(2) and different carbonaceous supports, e.g., amorphous carbon, carbon nanotubes, graphene, are also investigated. The use of Sn-based nanomaterials as the anode material for LIBs will be briefly discussed as well. The aim of this review is to provide an in-depth and rational understanding such that the electrochemical properties of SnO(2) -based anodes can be effectively enhanced by making proper nanostructures with optimized chemical composition. By focusing on SnO(2) , the hope is that such concepts and strategies can be extended to other potential metal oxides, such as titanium dioxide or iron oxides, thus shedding some light on the future development of high-performance metal-oxide based negative electrodes for LIBs. 23567043 Intra-articular drug delivery from an optimized topical patch containing teriflunomide and lornoxicam for rheumatoid arthritis treatment: Does the topical patch really enhance a local treatment? Patients with rheumatoid arthritis (RA) often bear joint destruction and symptomatic pain. The aim of this work is to develop a compound transdermal patch containing teriflunomide (TEF) and lornoxicam (LOX) to transport these drugs across the skin with the isochronous permeation rates for RA therapy and investigate intra-articular delivery of TEF and LOX following transdermal patches applied topically. The salts of TEF and LOX with organic amines diethylamine (DEtA), triethylamine (TEtA), diethanolamine (DEA), triethanolamine (TEA) and N-(2'-hydroxy-ethanol)-piperdine (NP) were prepared to improve the skin permeation of the parent drug. The optimized patch formulation is obtained from a 3-factor, 2-level central composite design. After topical application of the optimized compound patch to only one knee joint in rabbit, intra-articular delivery of TEF and LOX on the application site was compared with that on the non-application site. Anti-inflammatory and analgesic effects of the optimized compound patch were evaluated using the adjuvant arthritis model and the pain model induced by acetic acid, respectively. The in vitro experiment results showed that the amine salts of TEF and LOX, especially TEF-TEtA and LOX-TEtA, enhanced the skin permeation of TEF and LOX from the transdermal patch system. The optimal formulation successfully displayed isochronous permeation rates for TEF and LOX across rabbit skin, and was defined with 5% of TEF-TEtA, 10% of LOX-TEtA and 15% of azone. The in vivo study showed that TEF and LOX from transdermal patches were transferred into skin, ligament and fat pad on the application site by direct diffusion and on the non-application site by the redistribution of systemic blood supply, while local absorption of TEF and LOX in synovial fluid originated from the systemic blood supply rather than direct diffusion. In the RA rat model, the results of swelling inhibition on primary arthritis of bilateral hind paws further confirmed the above-mentioned point. The optimal formulation displayed a double response on joint inflammation and symptomatic pain. In conclusion, although transdermal administration applied topically can provide a local enhanced drug delivery for the superficial joint tissues by direct diffusion, it seemed unlikely to do that for the deeper tissue synovial fluid. 23370195 Statistical modeling, optimization and characterization of spray-dried solid self-microemulsifying drug delivery system using design of experiments. The present study systematically and simultaneously investigates the influence of process variables of spray-drying on the properties of solid self-microemulsifying drug delivery system (SMEDDS) using design of experiment (DOE) and optimizes them in order to produce solid-SMEDDS satisfying pre-defined powder quality attributes. Flurbiprofen-loaded liquid-SMEDDS was dispersed in dextran and spray-dried. After preliminary screening, the independent factors selected according to three-factor, three-level Box-Behnken design were inlet temperature (X(1)), feed rate (X(2)) and carrier concentration (X(3)). The responses used to compute the effects of independent factors were moisture content (Y(1)), yield (Y(2)), drug content (Y(3)) and droplet size (Y(4)) of the micro-emulsion. SMEDDS powder characteristics such as morphology, thermal behavior, crystallinity and flowability were also considered. Models were developed and model fitting analysis showed an adequate fit for all responses, indicating good predictability. Significant effects of processing parameters on powder characteristics were observed. The spray-drying process parameters were optimized as inlet temperature (134°C), feed rate (5%) and carrier concentration (0.6%) to produce solid-SMEDDS with acceptable moisture content (0.72±0.02%), yield (58.5±2.9%), drug content (70.1±2.7 mg/g) and droplet size (166.8±13.8 nm). Validation of the optimization process in five batches showed experimental value very close to the predicted one, ensuring the reproducibility of the developed models. Furthermore, optimized parameters resulted a highly crystalline flurbiprofen changed to an amorphous form. In conclusion, this study demonstrated the applicability of the DOE approach for optimizing the process parameters to manufacture solid-SMEDDS with desired quality attributes. 23611039 A New Face for Old Antibiotics: Tetracyclines in Treatment of Amyloidoses. The use of tetracyclines has declined because of the appearance of resistant bacterial strains. However, the indications of nonantimicrobial activities of these drugs have considerably raised interest and triggered clinical trials for a number of different pathologies. About 10 years ago we first reported that tetracyclines inhibited the aggregation of prion protein fragments and Alzheimer's β peptides, destabilizing their aggregates and promoting their degradation by proteases. On the basis of these observations, the antiamyloidogenic effects of tetracyclines on a variety of amyloidogenic proteins were studied and confirmed by independent research groups. In this review we comment on the data available on their antiamyloidogenic activity in preclinical and clinical studies. We also put forward that the beneficial effects of these drugs are a result of a peculiar pleiotropic action, comprising their interaction with oligomers and disruption of fibrils, as well as their antioxidant, anti-inflammatory, antiapoptotic, and matrix metalloproteinase inhibitory activities. 23353701 Involvement of Src and the actin cytoskeleton in the antitumorigenic action of adenosine dialdehyde. Transmethylation is an important reaction that transfers a methyl group in S-adenosylmethionine (SAM) to substrates such as DNA, RNA, and proteins. It is known that transmethylation plays critical roles in various cellular responses. In this study, we examined the effects of transmethylation on tumorigenic responses and its regulatory mechanism using an upregulation strategy of adenosylhomocysteine (SAH) acting as a negative feedback inhibitor. Treatment with adenosine dialdehyde (AdOx), an inhibitor of transmethylation-suppressive adenosylhomocysteine (SAH) hydrolase (SAHH), enhanced the level of SAH and effectively blocked the proliferation, migration, and invasion of cancer cells; the treatment also induced the differentiation of C6 glioma cells and suppressed the neovascular genesis of eggs in a dose-dependent manner. Through immunoblotting analysis, it was found that AdOx was capable of indirectly diminishing the phosphorylation of oncogenic Src and its kinase activity. Interestingly, AdOx disrupted actin cytoskeleton structures, leading to morphological changes, and suppressed the formation of a signaling complex composed of Src and p85/PI3K, which is linked to various tumorigenic responses. In agreement with these data, the exogenous treatment of SAH or inhibition of SAHH by specific siRNA or another type of inhibitor, 3-deazaadenosine (DAZA), similarly resulted in antitumorigenic responses, suppressive activity on Src, the alteration of actin cytoskeleton, and a change of the colocalization pattern between actin and Src. Taken together, these results suggest that SAH/SAHH-mediated transmethylation could be linked to the tumorigenic processes through cross-regulation between the actin cytoskeleton and Src kinase activity. 23553331 On the Vibrational linear and nonlinear optical properties of compounds involving noble gas atoms: HXeOXeH, HXeOXeF, and FXeOXeF. The vibrational (hyper)polarizabilities of some selected Xe derivatives are studied in the context of Bishop-Kirtman perturbation theory (BKPT) and numerical finite field methodology. It was found that for this set of rare gas compounds, the static vibrational properties are quite large, in comparison to the corresponding electronic ones, especially those of the second hyperpolarizability. This also holds for the dc-Pockels β(-ω;ω,0), Kerr γ(-ω;ω,0,0) and electric field second harmonic generation γ (-2ω;ω,ω,0) effects, although the computed nuclear relaxation (nr) vibrational contributions are smaller in magnitude than the static ones. HXeOXeH was used to study the effects of electron correlation, basis set, and geometry. Geometry effects were found to lead to noticeable changes of the vibrational and electronic second hyperpolarizability. A limited study of the effect of Xe insertion to the nr vibrational properties is also reported. Assessment of the results revealed that Xe insertion has a remarkable effect on the nr (hyper)polarizabilities. In terms of the BKPT, this is associated with a remarkable increase of the electrical and mechanical anharmonicity terms. The latter is consistent with the anharmonic character of several vibrational modes reported for rare gas compounds. © 2013 Wiley Periodicals, Inc. 23435541 Attenuation by statins of membrane raft-redox signaling in coronary arterial endothelium. Membrane raft (MR)-redox signaling platforms associated with NADPH oxidase are involved in coronary endothelial dysfunction. Here, we studied whether statins interfere with the formation of MR-redox signaling platforms to protect the coronary arterial endothelium from oxidized low-density lipoprotein (OxLDL)-induced injury and from acute hypercholesterolemia. In cultured human coronary arterial endothelial cells, confocal microscopy detected the formation of an MRs clustering when they were exposed to OxLDL, and such MR platform formation was inhibited markedly by statins, including pravastatin and simvastatin. In these MR clusters, NADPH oxidase subunits gp91(phox) and p47(phox) were aggregated and were markedly blocked by both statins. In addition, colocalization of acid sphingomyelinase (ASM) and ceramide was induced by OxLDL, which was blocked by statins. Electron spin resonance spectrometry showed that OxLDL-induced superoxide (O2(.-)) production in the MR fractions was substantially reduced by statins. In coronary artery intima of mice with acute hypercholesterolemia, confocal microscopy revealed a colocalization of gp91(phox), p47(phox), ASM, or ceramide in MR clusters. Such colocalization was rarely observed in the arteries of normal mice or significantly reduced by pretreatment of hypercholesterolemic mice with statins. Furthermore, O2(.-) production in situ was 3-fold higher in the coronary arteries from hypercholesterolemic mice than in those from normal mice, and such increase was inhibited by statins. Our results indicate that blockade of MR-redox signaling platform formation in endothelial cell membrane may be another important therapeutic mechanism of statins in preventing endothelial injury and atherosclerosis and may be associated with their direct action on membrane cholesterol structure and function. 23408697 Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: A systematic review and meta-analysis. While there is strong evidence that bisphosphonates prevent certain types of osteoporotic fractures, there are concerns that these medications may be associated with rare atypical femoral fractures (AFF). Recent published studies examining this potential association are conflicting in regards to the existence and strength of this association. We conducted a systematic review and meta-analysis of published studies examining the association of bisphosphonates with subtrochanteric, femoral shaft, and AFF. The random-effects model was used to calculate the pooled estimates of adjusted risk ratios (RR). Subgroup analysis was performed by study design, for studies that used validated outcome definitions for AFF, and for studies reporting on duration of bisphosphonate use. Eleven studies were included in the meta-analysis: five case-control and six cohort studies. Bisphosphonate exposure was associated with an increased risk of subtrochanteric, femoral shaft, and AFF with adjusted RR of 1.70 (95% CI 1.22-2.37). Subgroup analysis of studies using the ASBMR-criteria to define AFF suggests a higher risk of AFF with bisphosphonate use with RR of 11.78 (95% CI 0.39-359.69) as compared to studies using mainly diagnosis codes (RR 1.62, 95% CI 1.18-2.22), although there is a wide confidence interval and severe heterogeneity (I(2) =96.15%) in this subgroup analysis. Subgroup analysis of studies examining at least 5 years of bisphosphonate use showed adjusted RR of 1.62 (95% CI 1.29-2.04). This meta-analysis suggests there is an increased risk of subtrochanteric, femoral shaft, and AFF among bisphosphonate users. Further research examining the risk of AFF with long-term use of bisphosphonates is indicated as there was limited data in this subgroup. The public health implication of this observed increase in AFF risk is not clear. © 2013 American Society for Bone and Mineral Research. 23409810 Dynamics of site switching in DNA polymerase. DNA polymerases replicate DNA by catalyzing the template-directed polymerization of deoxynucleoside triphosphate (dNTP) substrates onto the 3' end of a growing DNA primer strand. Many DNA polymerases also possess a separate 3'-5' exonuclease activity that is used to remove misincorporated nucleotides from the nascent DNA (proofreading). The polymerase (pol) and exonuclease (exo) activities are spatially separated in different enzyme domains, indicating that a mechanism must exist to transfer the growing primer terminus from one site to the other. Here we report a single-molecule Förster resonance energy transfer (smFRET) system that directly monitors the movement of a DNA substrate between the pol and exo sites of DNA polymerase I Klenow fragment (KF). FRET trajectories recorded during the encounter between single polymerase and DNA molecules reveal that DNA can channel between the pol and exo sites in both directions while remaining closely associated with the enzyme (intramolecular transfer). In addition, it is evident from the trajectories that DNA can also dissociate from one site and subsequently rebind at the other (intermolecular transfer). Rate constants for each pathway have been determined by dwell-time analysis, revealing that intramolecular transfer is the faster of the two pathways. Unexpectedly, a mispaired primer terminus accesses the exo site more frequently when dNTP substrates are also present in solution, which is expected to enhance proofreading. Together, these results explain how the separate pol and exo activities of KF are physically coordinated to achieve efficient proofreading. 23623790 GABAA receptor modulation by piperine and a non-TRPV1 activating derivative. The action of piperine (the pungent component of pepper) and its derivative SCT-66 ((2E,4E)-5-(1,3-benzodioxol-5-yl))-N,N-diisobutyl-2,4-pentadienamide) on different gamma-aminobutyric acid (GABA) type A (GABAA) receptors, transient-receptor-potential-vanilloid-1 (TRPV1) receptors and behavioral effects were investigated. GABAA receptor subtypes and TRPV1 receptors were expressed in Xenopus laevis oocytes. Modulation of GABA-induced chloride currents (IGABA) by piperine and SCT-66 and activation of TRPV1 was studied using the two-microelectrode-voltage-clamp technique and fast perfusion. Their effects on explorative behavior, thermoregulation and seizure threshold were analyzed in mice. Piperine acted with similar potency on all GABAA receptor subtypes (EC50 range: 42.8±7.6μM (α2β2)-59.6±12.3μM (α3β2)). IGABA modulation by piperine did not require the presence of a γ2S-subunit, suggesting a binding site involving only α and β subunits. IGABA activation was slightly more efficacious on receptors formed from β2/3 subunits (maximal IGABA stimulation through α1β3 receptors: 332±64% and α1β2: 271±36% vs. α1β1: 171±22%, p<0.05) and α3-subunits (α3β2: 375±51% vs. α5β2:136±22%, p<0.05). Replacing the piperidine ring by a N-di-isobutyl residue (SCT-66) prevents interactions with TRPV1 and simultaneously increases the potency and efficiency of GABAA receptor modulation. SCT-66 displayed greater efficacy on GABAA receptors than piperine, with different subunit-dependence. Both compounds induced anxiolytic, anticonvulsant effects and reduced locomotor activity; however, SCT-66 induced stronger anxiolysis without decreasing body temperature and without the proconvulsive effects of TRPV1 activation and thus may serve as a scaffold for the development of novel GABAA receptor modulators. 23620269 Genetic Variants in 2q31 and 5p15 Are Associated With Aggressive Benign Prostatic Hyperplasia in a Chinese Population. BACKGROUND: Benign prostatic hyperplasia (BPH) is a common disease prevalent in elderly men. However, the genetic determinants of BPH remain unclear. Because BPH and prostate cancer (PCa) share some common pathological characteristics, we investigated whether susceptibility loci for PCa contributed to BPH risk and BPH aggressiveness in Chinese men. METHODS: Fourteen SNPs associated with PCa risk in a Chinese population were genotyped in 426 BPH cases (184 aggressive and 242 non-aggressive BPH cases) and 1,008 controls. The association between the SNPs and BPH risk/aggressiveness was estimated using logistic regression analysis. In addition, effects of the 14 SNPs on BPH related clinical traits, including International Prostate Symptom Score (IPSS), prostate volume, total PSA, and free PSA were evaluated using linear regression analysis. RESULTS: Two SNPs, rs12621278 in ITGA6 at 2q31 (OR = 0.82, P = 0.05) and rs339331 in RFX6 at 6q22 (OR = 1.22, P = 0.04) were significantly associated with BPH. In addition, rs12621278 (OR = 0.73, P = 0.05) and rs12653946, 13 kb upstream of IRX4 at 5p15 (OR = 1.40, 0.03), were significantly associated with aggressive BPH. Moreover, the risk allele of rs12621278 (G) and rs12653946 (T) for aggressive BPH were significantly associated with elevated IPSS after treatment (P = 0.01). CONCLUSIONS: This is the first systematic investigation on the contributions of PCa susceptibility loci to risk and aggressiveness of BPH. Our findings advance our understanding of the genetic basis of BPH, especially aggressive BPH. In addition, our results provide new insights into the genetic determinants shared between BPH and PCa. Prostate 9999:XX-XX. © 2013 Wiley Periodicals, Inc. 22301814 Green tea extract alleviates arsenic-induced biochemical toxicity and lipid peroxidation in rats. The present work was undertaken to evaluate the protective effect of an aqueous extract of green tea (GT, Camellia sinensis) leaves against arsenic (NaAsO2)-induced biochemical toxicity and lipid peroxidation production in experimental rats. The treatment with arsenic exhibited a significant increase in some serum hepatic and renal biochemical parameters (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total protein, albumin, bilirubin, cholesterol, urea and creatinine). But the co-administration of GT has increased the level of plasmatic concentration of biochemical parameters. Exposure of rats to arsenic caused also a significant increase in liver, kidney and testicular thiobarbituric acid reactive substances compared to control. However, the co-administration of GT was effective in reducing its level. To conclude, our data suggest that arsenic exposure enhanced an oxidative stress by disturbing the tissue antioxidant defense system, but the GT co-administration alleviates the toxicity induced by arsenic exposure. 23540646 Design, synthesis and biological activity of multifunctional α,β-unsaturated carbonyl scaffolds for Alzheimer's disease. A series of compounds containing an α,β-unsaturated carbonyl moiety, such as chalcones and coumarins were designed, synthesized and tested in a variety of assays to assess their potential as anti-Alzheimer's disease (AD) agents. The investigations included the inhibition of cholinesterases (AChE, BuChE), the inhibition of amyloid beta (Aβ) self-assembly and the disassembly of preformed Aβ oligomers. Several compounds showed excellent potential as multifunctional compounds for AD. Docking studies for 16 that performed well in all the assays gave a clear interpretation of various interactions in the gorge of AChE. Based on the results, the long-chain coumarin scaffold appears to be a promising structural template for further AD drug development. 23123249 Testing of novel brain-penetrating oxime reactivators of acetylcholinesterase inhibited by nerve agent surrogates. A critical need for combating the effects of organophosphate (OP) anticholinesterases, such as nerve agents, is the current lack of an effective oxime reactivator which can penetrate the blood-brain barrier (BBB), and therefore reactivate inhibited acetylcholinesterase (AChE) in the brain. Our laboratories have synthesized and have initiated testing of novel phenoxyalkyl pyridinium oximes (patent pending) that are more lipophilic than currently approved oximes. This is a preliminary report on these novel oximes which have been tested in vitro in rat brain homogenates with highly relevant surrogates for sarin (phthalimidyl isopropyl methylphosphonate; PIMP) and VX (nitrophenyl ethyl methylphosphonate; NEMP). The oximes demonstrated a range of 14-76% reactivation of rat brain AChE in vitro. An in vivo testing paradigm was developed in which the novel oxime was administered at the time of maximal brain AChE inhibition (about 80%) (1h) elicited by nitrophenyl isopropyl methylphosphonate (NIMP; sarin surrogate). This paradigm, with delayed administration of oxime to a time when brain AChE was starting to recover, was designed to minimize reactivation/reinhibition of peripheral AChE during the reactivation period which would decrease the availability of the surrogate for entry into the brain; this paradigm will allow proof of concept of BBB penetrability. The initial studies of these oximes in vivo with the sarin surrogate NIMP have indicated reactivation of up to about 25% at 30min after oxime administration and substantial attenuation of seizure behavior from some of the oximes. Therefore these novel oximes have considerable potential as brain-protecting therapeutics for anticholinesterases. 23395269 Understanding metabolic regulation and its influence on cell physiology. Metabolism impacts all cellular functions and plays a fundamental role in biology. In the last century, our knowledge of metabolic pathway architecture and the genomic landscape of disease has increased exponentially. Combined with these insights, advances in analytical methods for quantifying metabolites and systems approaches to analyze these data now provide powerful tools to study metabolic regulation. Here we review the diverse mechanisms cells use to adapt metabolism to specific physiological states and discuss how metabolic flux analyses can be applied to identify important regulatory nodes to understand normal and pathological cell physiology. 23354728 Investigational anti-hyperglycemic agents: the future of type 2 diabetes therapy? As the pandemic of type 2 diabetes spreads globally, clinicians face many challenges in treating an increasingly diverse patient population varying in age, comorbidities, and socioeconomic status. Current therapies for type 2 diabetes are often unable to alter the natural course of the disease and provide durable glycemic control, and side effects in the context of individual patient characteristics often limit treatment choices. This often results in the progression to insulin use and complex regimens that are difficult to maintain. Therefore, a number of agents are being developed to better address the pathogenesis of type 2 diabetes and to overcome limitations of current therapies. The hope is to provide more options for glucose lowering and complication reduction with less risk for hypoglycemia and other adverse effects. These agents include newer incretin-based therapies and PPAR agonists, as well as new therapeutic classes such as sodium-coupled glucose cotransporter 2 inhibitors, free fatty acid receptor agonists, 11-β-hydroxysteroid dehydrogenase type 1 inhibitors, glucokinase activators, and several others that may enter clinical use over the next decade. Herein we review these agents that are advancing through clinical trials and describe the rationale behind their use, mechanisms of action, and potential for glucose lowering, as well as what is known of their limitations. 23411330 Effect of ferrous sulfate fortification in germinated brown rice on seed iron concentration and bioavailability. The present study evaluated the effectiveness of germination and iron fortification on iron concentration and bioavailability of brown rice. Iron fortification during germination process with 0.05-2 g/L ferrous sulfate increased the iron concentration in germinated brown rice from 1.1 to 15.6 times than those in raw brown rice. Based on the recommended dietary allowance of iron, maximum germination rate and γ-aminobutyric acid, we recommend the brown rice fortified with 0.25 g/L FeSO(4) as a suitable fortification level to use in germination process. Iron fortification during the germination process has a positive effect on iron concentration and bioavailability. A significant difference was observed among the cultivars in respect to the capacity for iron accumulation and bioavailability. Germination alone could improve in vitro iron solubility, but had no effect on iron bioavailability in Caco-2 cell, the additional fortification process should be combined to get high amount of bioavailable iron from the brown rice. 23099503 Citrus peel polymethoxylated flavones extract modulates liver and heart function parameters in diet induced hypercholesterolemic rats. The primary aim of this study was to investigate the effects of Ortanique peel polymethoxylated flavones extract (PMF(ort)) on organ function parameters in the serum of hypercholesterolemic and normal rats. Thirty Sprague-Dawley rats were fed high cholesterol diets supplemented with 1.5% PMF(ort) and niacin respectively for 49days. Hypercholesterolemic rats fed PMF(ort) had significant reductions in the activities of aspartate aminotransferase and alkaline phosphatase (69.12±3.34 and 87.22±8.42U/L respectively) compared to the untreated hypercholesterolemic group (118.61±4.85 and 132.62±10.62U/L respectively, p<0.05). Supplementation of the diet with niacin or PMF(ort) resulted in no significant differences in the serum levels of creatinine or urea in any of the groups. Total bilirubin was highest in the untreated hypercholesterolemic group. Supplementation of the diets of hypercholesterolemic rats with PMF(ort) resulted in significant reductions in the activities of serum creatine kinase and lactate dehydrogenase (119.3±25.3; 222.5±50.3U/L, p<0.05) respectively relative to the untreated hypercholesterolemic group (257.2±48.3; 648.8±103U/L, p<0.05). The results would suggest that PMF(ort) modulates hypercholesterolemia-associated organ injury in rats. PMF(ort) could therefore be a suitable candidate for prophylactic and therapeutic treatment of hypercholesterolemia-associated organ injury. 23030793 Precision cut lung slices as an efficient tool for in vitro lung physio-pharmacotoxicology studies. 1.We review the specific approaches for lung tissue slices preparation and incubation systems and the research application fields in which lung slices proved to be a very efficient alternative to animal experimentation for biomechanical, physiological, pharmacological and toxicological approaches. 2.Focus is made on air-liquid interface dynamic organ culture systems that allow direct tissue exposure to complex aerosol and that best mimic in vivo lung tissue physiology. 3.A compilation of research applications in the fields of vascular and airway reactivity, mucociliary transport, polyamine transport, xenobiotic biotransformation, chemicals toxicology and complex aerosols supports the concept that precision cut lung slices are a very efficient tool maintaining highly differentiated functions similar to in vivo lung organ when kept under dynamic organ culture. They also have been successfully used for lung gene transfer efficiency assessment, for lung viral infection efficiency assessment, for studies of tissue preservation media and tissue post-conditioning to optimize lung tissue viability before grafting. 4.Taken all together, the reviewed studies point to a great interest for precision cut lung slices as an efficient and valuable alternative to in vivo lung organ experimentation. 22761042 Zanthoxylum usambarense (Engl.) Kokwaro (Rutaceae) Extracts Inhibit the Growth of the Breast Cancer Cell Lines MDA-MB-231 and MCF-7, But Not the Brain Tumour Cell Line U251 In Vitro. Zanthoxylum usambarense (Engl.) Kokwaro has traditionally been used for the treatment of malaria, upper respiratory tract infections, cough, rheumatism, tooth decay and sore gums in Kenya and other African countries. Dried ground parts of Z. usambarense were extracted by maceration using methanol (MeOH) at room temperature, extract was dried and reconstituted in 70% aq. MeOH and partitioned against n-hexane and chloroform (CHCl3 ) to obtain MeOH, n-hexane and CHCl3 extracts. All extracts were assessed for cytotoxicity against two breast cancer cell lines, MDA-MB-231 and MCF-7, and the brain tumour cell line U251 by the MTT assay. The free-radical scavenging activity of the extracts was also determined by the 2,2-diphenyl-1-picryhydrazyl (DPPH) assay. In the DPPH assay, the MeOH extract was found to be the most active free-radical scavenger with a RC50 value of 41.1 × 10(-3)  mg/mL. It also displayed significant cytotoxicity against the MCF-7 cell line (IC50 42.9 µg/mL) and appeared to have induced cell death through apoptosis. None of the test extracts showed any activity against the U251 cell line at test concentrations. The present findings demonstrated that Z. usambarense could be a potential source for new cytotoxic compounds for possible anticancer drug development. Copyright © 2012 John Wiley & Sons, Ltd. 23482500 Sorafenib Hepatobiliary Disposition: Mechanisms of Hepatic Uptake and Disposition of Generated Metabolites. Sorafenib is an orally active tyrosine kinase inhibitor used in the treatment of renal and hepatocellular carcinoma. This study was designed to establish whether transport proteins are involved in the hepatic uptake of sorafenib, and to determine the extent of biliary excretion of sorafenib/metabolites in human hepatocytes. Initial uptake was assessed in freshly isolated, suspended human hepatocytes in the presence of inhibitors and modulators. [(14)C]Sorafenib (1 μM) uptake at 4°C was ~61-63% of the uptake at 37°C, suggesting a high degree of passive diffusion. Hepatocyte uptake of [(14)C]sorafenib was not Na(+)-dependent or influenced by the organic anion transporter 2 (OAT2) inhibitor ketoprofen. However, initial [(14)C]sorafenib hepatocyte uptake was reduced by 46 and 30% compared to control values in the presence of the organic anion transporting polypeptide (OATP) inhibitor rifamycin SV, and the organic cation transporter (OCT) inhibitor decynium 22, respectively. [(14)C]Sorafenib (0.5 to 5 μM) uptake was significantly higher in hOCT1-transfected CHO cells compared to mock cells, and inhibited by the general OCT inhibitor, MPP(+). OCT1-mediated uptake was saturable with a Km of 3.80 ± 2.53 μM and Vmax of 116 ± 42 pmol/mg/min. The biliary excretion index (BEI) and in vitro biliary clearance (Clbiliary) of sorafenib (1 μM) in sandwich-cultured human hepatocytes were low (~11% and 11 ml/min/kg, respectively). Results suggest that sorafenib uptake in human hepatocytes occurs via passive diffusion, and by OCT1 and a rifamycin-sensitive transporter. Sorafenib undergoes modest biliary excretion, predominantly as glucuronide conjugate(s). 22887990 The development of better photocatalysts through composition- and structure-engineering. Semiconductor photocatalysts that can effectively utilize solar irradiation hold great potential for harnessing renewable-energy sources, as well as for environmental protection and -remediation. Exploring advanced photocatalysts that have improved performance has been a central theme in photocatalysis research. Herein, we review the recent developments in the design- and fabrication of photocatalysts with an emphasis on composition- and structural control over multiple length scales. This Focus Review will be of value for researchers in the area of photocatalysis, in particular, in the aspects of material design that lead to the synthesis of better photocatalysts. 23591149 Current status of liposomal porphyrinoid photosensitizers. The complete eradication of various targets, such as infectious agents or cancer cells, while leaving healthy host cells untouched, is still a great challenge faced in the field of medicine. Photodynamic therapy (PDT) seems to be a promising approach for anticancer treatment, as well as to combat various dermatologic and ophthalmic diseases and microbial infections. The application of liposomes as delivery systems for porphyrinoids has helped overcome many drawbacks of conventional photosensitizers and facilitated the development of novel effective photosensitizers that can be encapsulated in liposomes. The development, preclinical studies and future directions for liposomal delivery of conventional and novel photosensitizers are reviewed. 23571493 Plant High-Affinity Potassium (HKT) Transporters Involved in Salinity Tolerance: Structural Insights to Probe Differences in Ion Selectivity. High-affinity Potassium Transporters (HKTs) belong to an important class of integral membrane proteins (IMPs) that facilitate cation transport across the plasma membranes of plant cells. Some members of the HKT protein family have been shown to be critical for salinity tolerance in commercially important crop species, particularly in grains, through exclusion of Na+ ions from sensitive shoot tissues in plants. However, given the number of different HKT proteins expressed in plants, it is likely that different members of this protein family perform in a range of functions. Plant breeders and biotechnologists have attempted to manipulate HKT gene expression through genetic engineering and more conventional plant breeding methods to improve the salinity tolerance of commercially important crop plants. Successful manipulation of a biological trait is more likely to be effective after a thorough understanding of how the trait, genes and proteins are interconnected at the whole plant level. This article examines the current structural and functional knowledge relating to plant HKTs and how their structural features may explain their transport selectivity. We also highlight specific areas where new knowledge of plant HKT transporters is needed. Our goal is to present how knowledge of the structure of HKT proteins is helpful in understanding their function and how this understanding can be an invaluable experimental tool. As such, we assert that accurate structural information of plant IMPs will greatly inform functional studies and will lead to a deeper understanding of plant nutrition, signalling and stress tolerance, all of which represent factors that can be manipulated to improve agricultural productivity. 23219683 The effect of lead exposure on brain iron homeostasis and the expression of DMT1/FP1 in the brain in developing and aged rats. The relation between lead (Pb) and iron (Fe) becomes increasingly concerned because they are both divalent metals that are absorbed by the same intestinal mechanism, and Pb exposure and Fe deficiency in the developmental brain, as well as Fe overload in the aged brain, can cause cognitive deficits. However, the interaction between Pb exposure and Fe status in the brain has not been established. Therefore, in the current study, we examined the effects of maternal ingestion of Pb in drinking water during gestation and lactation on the Fe status and the expression of divalent metal transporter 1 (DMT1) and ferroportin 1 (FP1) in the brain of offspring. The offspring were followed through old age, with measurements taken at postnatal week 3 (PNW3), 41 (PNW41) and 70 (PNW70). Pb exposure increases the Fe content in the old-aged rats' brain, which might be not subjected to DMT1 mediating, but may be associated with the decrease expression of FP1. Furthermore, the effect of Pb on FP1 expression is regulated at transcriptional and posttranscriptional levels. The perturbation in Fe homeostasis may contribute to the neurotoxicology consequences induced by Pb exposure, and FP1 may play a role in Pb-induced Fe cumulation in the brain. 23499856 Quantum dots induced monocyte chemotactic protein-1 expression via MyD88-dependent Toll-like receptor signaling pathways in macrophages. Quantum dots (QDs) are nano-sized semiconductors. Previously, intratracheal instillation of QD705s induces persistent inflammation in mouse lungs. In our present study, QD705-COOH and QD705-PEG activated NF-κB and increased monocyte chemotactic protein-1 (MCP-1) expression in macrophages RAW264.7 via MyD88 dependent Toll-like receptor (TLR) signaling pathways. MyD88 is an adapter protein for most TLRs to activate NF-κB. Silencing expression of MyD88 or p65 with siRNA or co-treatment with a NF-κB inhibitor tremendously abolished QD705s-induced NF-κB activity and MCP-1 expression. The involved TLRs might locate either on the cell surface or inside of cells. Co-treatment with a TLR4 inhibitor completely prevented MCP-1 induction by QD705-PEG. Nevertheless, QD705-COOH readily entered cells, and co-treatment with either inhibitors of endocytosis or intracellular TLRs prevented MCP-1 induction. These findings indicate that, depending on their surface modification, OD705s activate MyD88 dependent-TLRs at the surface or inside of the cells, which is an important mechanism for nanoparticles-induced inflammatory responses. But other MyD88-independent pathways may also involve in these responses. 23086747 Effects of DMSA-coated Fe3O4 nanoparticles on the transcription of genes related to iron and osmosis homeostasis. In this article, we checked the effect of 2,3-dimercaptosuccinic acid-coated Fe(3)O(4) nanoparticles on gene expression of mouse macrophage RAW264.7 cells and found that the transcription of several important genes related to intracellular iron homeostasis were significantly changed. We thus speculated that the cellular iron homeostasis might be disturbed by this nanoparticle through releasing iron ion in cells. To verify this speculation, we first confirmed the transcriptional changes of several key iron homeostasis- related genes, such as Tfrc, Trf, and Lcn2, using quantitative PCR, and found that an iron ion chelator, desferrioxamine, could alleviate the transcriptional alterations of two typical genes, Tfrc and Lcn2. Then, we designed and validated a method based on centrifugation for assaying intracellular irons in ion and nanoparticle state. After extensive measures of intracellular iron in two forms and total iron, we found that the intracellular iron ion significantly increased with intracellular total iron and nanoparticle iron, demonstrating degradation of this nanoparticle into iron ion in cells. We next mimicked the intralysosomal environment in vitro and verified that the internalized iron nanoparticle could release iron ion in lysosome. We found that as another important compensatory response to intracellular overload of iron ion, cells significantly downregulated the expressions of genes belonging to solute carrier family which are responsible for transferring many organic solutes into cells, such as Slc5a3 and Slc44a1, in order to prevent more organic solutes into cells and thus lower the intracellular osmosis. Based on these findings, we profiled a map of gene effects after cells were treated with this iron nanoparticle and concluded that the iron nanoparticles might be more detrimental to cell than iron ion due to its intracellular internalization fashion, nonspecific endocytosis. 23639867 Direct methods for detection of protein S-nitrosylation. S-nitrosylation of protein cysteine residues is known to be an important mechanism for nitric oxide signaling. However, the detection of protein S-nitrosylation is still challenging due to technical limitations of current methods. This chapter provides a brief review on recent developments of methods, which directly target S-nitroso moieties for detection. We also describe in detail the protocol of an organophosphine-based biotin labeling of protein S-nitroso moieties. 23343308 SeDeM expert system a new innovator tool to develop pharmaceutical forms. Abstract Context: The SeDeM expert system is based on the experimental study and quantitative determination of the characterization parameters of powdered substances, the aim being to determine whether a substance is suitable for producing tablets by means of direct compression (DC) technology, thereby reducing the lead time for pre-formulation studies. Additionally, this expert system also provides formulations with a minimum number of excipients. Objective: We used this system to analyze suitable formulas for the production of orodispersible ibuprofen tablets. Method: Twenty-one disintegrants and ibuprophen were characterized using SeDeM methodology. Results: The results indicated that production of ibuprofen tablets by DC would require improvements in the dimension and compressibility factors of the active pharmaceutical ingredient. The expert system analysis provided the specific percentage of disintegrant needed to blend with ibuprofen and a standardized formula of lubricants in order to obtain a powder mix that would successfully produce tablets by DC. The eight formulas proposed by SeDeM were produced and tested in the laboratory. Conclusion: All eight formulas successfully produced tablets by DC, but only four of them could be considered suitable for use as an orodispersible tablet and accomplishes all the pharmaceutical quality parameters. So, in fact, the use of the SeDeM system reduced the time of medicine's development and therefore the cost of the activity. 23106567 Evaluation of the intestinal toxicity and transport of xenobiotics utilizing precision-cut slices. 1.The precision-cut intestinal slice (PCIS) technology is a relatively new addition to the battery of in vitro assays for evaluation of xenobiotic toxicity, metabolism, and transport. 2.The intestine is an important target for drug-induced toxicity due to its high exposure after oral administration. Therefore, the prediction of drug-induced intestinal side effects remains a significant safety issue in pharmaceutical development. Although animal experiments have been proven useful, species differences and the requirement for reduction of animal use warrant the development of in vitro methods which can apply human tissue. 3.The enterocytes lining the villi express high activities of enzymes and transporters involved in drug disposition. They vary highly in activities: along the length of the intestine and along the villi, gradients of expression levels of the enzymes and proteins exist, which necessitates an in vitro model that can reflect the different regions of the intestine. 4.In this chapter, the application of PCIS in studies on transport and toxicity of xenobiotics is reviewed. PCIS can be prepared from each region of the intestine and from various species in a similar manner, and the results published so far indicate that they represent a promising model to evaluate intestinal toxicity and transport. 23341212 Chemical variability of Algerian Myrtus communis L. The composition of 55 samples of essential oil isolated from the aerial parts of wild growing Myrtus communis L. harvested in 16 locations from East to West Algeria were investigated by GC (determination of retention indices) and (13) C-NMR analyses. The essential oils consisted mainly of monoterpenes, α-pinene (27.4-59.2%) and 1,8-cineole (6.1-34.3%) being the major components. They were also characterized by the absence of myrtenyl acetate. The compositions of the 55 oils were submitted to k-means partitioning and principal component analysis, which allowed the distinction of two groups within the oil samples, which could be subdivided into two subgroups each. Groups I (78% of the samples) and II were differentiated on the basis of the contents of α-pinene, linalool, and linalyl acetate. Subgroups IA and IB could be distinguished by their contents of α-pinene and 1,8-cineole. Subgroups IIA and IIB differed substantially in their contents of 1,8-cineole and limonene. All the samples contained 3,3,5,5,8,8-hexamethyl-7-oxabicyclo[4.3.0]non-1(6)-ene-2,4-dione (up to 4.9%). 23617429 Boron chemicals in diagnosis and therapeutics. Advances in the field of boron chemistry have expanded the application of boron from material use to medicine. Boron-based drugs represent a new class of molecules that possess several biomedical applications including use as imaging agents for both optical and nuclear imaging as well as therapeutic agents with anticancer, antiviral, antibacterial, antifungal and other disease-specific activities. For example, bortezomib (Velcade(®)), the only drug in clinical use with boron as an active element, was approved in 2003 as a proteasome inhibitor for the treatment of multiple myeloma and non-Hodgkin's lymphoma. Several other boron-based compounds are in various phases of clinical trials, which illustrates the promise of this approach for medicinal chemists working in the area of boron chemistry. It is expected that in the near future, several boron-containing drugs should become available in the market with better efficacy and potency than existing drugs. This article discusses the current status of the development of boron-based compounds as diagnostic and therapeutic agents in humans. 23493576 Blocking IL-1β Induces a Healing-associated Wound Macrophage Phenotype and Improves Healing in Type-2 Diabetes. Diabetes is associated with persistent inflammation and defective tissue repair responses. The hypothesis of this study was that IL-1β is part of a pro-inflammatory positive feedback loop that sustains a persistent pro-inflammatory wound macrophage phenotype which contributes to impaired healing in diabetes. Macrophages isolated from wounds in diabetic humans and mice exhibited a pro-inflammatory phenotype, including expression and secretion of IL-1β. The diabetic wound environment appears to be sufficient to induce these inflammatory phenomena as in vitro studies demonstrated that conditioned medium of both mouse and human wounds upregulates expression of pro-inflammatory genes and downregulates expression of pro-healing factors in cultured macrophages. Furthermore, inhibiting the IL-1β pathway using a neutralizing antibody and macrophages from IL1 receptor knockout mice blocked the conditioned medium-induced upregulation of pro-inflammatory genes and downregulation of pro-healing factors. Importantly, inhibiting the IL-1β pathway in wounds of diabetic mice using a neutralizing antibody induced a switch from pro-inflammatory to healing-associated macrophage phenotypes, increased levels of wound growth factors and improved healing of these wounds. Our findings indicate that targeting the IL-1β pathway represents a new therapeutic approach for improving the healing of diabetic wounds. 23256440 Nanoscale thermomechanics of wear-resilient polymeric bilayer systems. We explore the effect of an ultrathin elastic coating to optimize the mechanical stability of an underlying polymer film for nanoscale applications. The coating consists of a several nanometer thin plasma-polymerized norbornene layer. Scanning probes are used to characterize the system in terms of shear-force-induced wear and thermally assisted indentation. The layer transforms a weakly performing polystyrene film into a highly wear-resistive system, ideal for high-density and low-power data storage applications. The result can be understood from the indentation characteristics with a hot and sharp indenter tip. The latter gives rise to a deformation mode in the fully plastic regime, enabling a simple interpretation of the results. The softening transition and the yield stress of the system on a microsecond time scale and a nanometer size scale were obtained. We show that the plastic deformation is governed by yielding in the polystyrene sublayer, which renders the overall system soft for plastic deformation. The ultrathin protection layer contributes as an elastic skin, which shields part of the temperature and pressure and enables the high wear resistance against lateral forces. Moreover, the method of probing polymers at microsecond and nanometer size scales opens up new opportunities for studying polymer physics in a largely unexplored regime. Thus, we find softening temperatures of more than 100 °C above the polystyrene glass transition, which implies that for the short interaction time scales the glassy state of the polymer is preserved up to this temperature. 23208955 Protein-DNA arrays as tools for detection of protein-protein interactions by mass spectrometry. Analysis of multiple protein-protein interactions using microarray technology remains challenging, and site-specific immobilization of functional proteins is a key step in these approaches. Here we establish the efficient synthesis of protein-DNA conjugates for several members of a small family of GTPases. The family of Rab/Ypt GTPases is intimately involved in vesicular trafficking in yeast and serves as a model for the much larger group of analogous human proteins, the Rab protein family, with more than 60 members. The Ypt-DNA hybrid molecules described here are used for DNA-directed immobilization on glass- and silica-based microarrays. Methods for the detection of protein-DNA conjugates, as well as approaches for nucleotide exchange and distinguishing between GDP- and GTP-bound Ypts on microarrays, are reported. The high specificity of different Rab/Ypt-effector interactions, which also depends on the bound nucleotide, is shown by fluorescence readout of microarrays. Furthermore, initial experiments demonstrate that direct readout by mass spectrometry can be achieved with commercially available instruments. These developments will significantly contribute to the elucidation of complex transport networks in eukaryotic cells. 23278394 Treatment of estrogen receptor-positive breast cancer. Estrogen receptor (ER) expression is the main indicator of potential responses to endocrine therapy (ET), and approximately 70% of human breast cancers (BCs) are hormone-dependent and ER-positive. The introduction of adjuvant systemic therapy led to a significant improvement in post-surgical survival and a reduction in disease relapse, especially in women with early BC and those with ER+ tumors, who may receive ET alone or in combination with cytotoxic therapy. Adjuvant ET currently consists of (i) ovarian suppression, (ii) selective estrogen receptor modulators (SERMs) and down-regulators, and (iii) aromatase inhibitors (AIs). In patients with ER+ tumors pharmacologic ovary suppression with gonadotropin-releasing hormone agonists in combination with standard adjuvant therapy is generally more effective than adjuvant chemotherapy alone. Tamoxifen is the best established SERM, has favorable effects on BC control and bone metabolism, but also has adverse effects due to its estrogenic activity in other tissues. For these reasons, other SERMs have been developed. Fulvestrant is an ER down-regulator with several potential advantages over SERMs, including a 100-fold increase in its affinity for ER compared with tamoxifen and no estrogen-like activity in the uterus. The inhibition of the aromatase system with third-generation AIs is associated with improved survival in patients with advanced BC compared with SERMs. In postmenopausal patients with ER+ BC adjuvant treatment with AIs should be performed, either as sequential treatment after tamoxifen or as upfront therapy. Studies evaluating the role of AIs as first-line therapy are ongoing and the results are encouraging. 23080535 H-TiO(2) @MnO(2) //H-TiO(2) @C core-shell nanowires for high performance and flexible asymmetric supercapacitors. A flexible solid-state asymmetric supercapacitor device with H-TiO(2) @MnO(2) core-shell NWs as the positive electrode and H-TiO(2) @C core-shell NWs as the negative electrode is developed. This device operates in a 1.8 V voltage window and is able to deliver a high specific capacitance of 139.6 F g(-1) and maximum volumetric energy density of 0.30 mWh cm(-3) with excellent cycling performance and good flexibility. 23474032 Bioinspired peptides as versatile nucleic acid delivery platforms. Non-viral gene therapy approaches have strongly established the utility of peptides as integral constituents of delivery platforms devised for efficient transfer of therapeutic molecules into cells. Among these, cell-penetrating peptides (CPPs), encompassing a family of short peptide sequences and their chimeric derivatives, have gained versatility through the addition of de novo peptide ligands primarily to facilitate cell-specific nucleic acid delivery in vitro and in vivo. The review illustrates the structural requirements of a noteworthy peptide TAT-PTD and other derivatives chiefly to exemplify their implication in gene therapy. An overview of the emerging concept and recent explorations will be presented through unique examples which form a facet in nanotechnology-based cancer therapy. Finally the basis for the utility of CPPs in plants will be discussed in view of its biotechnological potential. 23199993 Phase behaviour and in vitro hydrolysis of wheat starch in mixture with whey protein. Network formation of whey protein isolate (WPI) with increasing concentrations of native wheat starch (WS) has been examined. Small deformation dynamic oscillation in shear and modulated temperature differential scanning calorimetry enabled analysis of binary mixtures at the macro- and micromolecular level. Following heat induced gelation, textural hardness was measured by undertaking compression tests. Environmental scanning electron microscopy provided tangible information on network morphology of polymeric constituents. Experiments involving in vitro starch digestion also allowed for indirect assessment of phase topology in the binary mixture. The biochemical component of this work constitutes an attempt to utilise whey protein as a retardant to the enzymatic hydrolysis of starch in a model system with α-amylase enzyme. During heating, rheological profiles of binary mixtures exhibited dramatic increases in G' at temperatures more closely related to those observed for single whey protein rather than pure starch. Results from this multidisciplinary approach of analysis, utilising rheology, calorimetry and microscopy, argue for the occurrence of phase separation phenomena in the gelled systems. There is also evidence of whey protein forming the continuous phase with wheat starch being the discontinuous filler, an outcome that is explored in the in vitro study of the enzymatic hydrolysis of starch. 23027505 Nanostructured superhydrophobic substrates trigger the development of 3D neuronal networks. The generation of 3D networks of primary neurons is a big challenge in neuroscience. Here, a novel method is presented for a 3D neuronal culture on superhydrophobic (SH) substrates. How nano-patterned SH devices stimulate neurons to build 3D networks is investigated. Scanning electron microscopy and confocal imaging show that soon after plating neurites adhere to the nanopatterned pillar sidewalls and they are subsequently pulled between pillars in a suspended position. These neurons display an enhanced survival rate compared to standard cultures and develop mature networks with physiological excitability. These findings underline the importance of using nanostructured SH surfaces for directing 3D neuronal growth, as well as for the design of biomaterials for neuronal regeneration. 23287727 Marked toxicity of Albizia bernieri extracts on embryo-larval development in the medaka fish (Oryzias latipes). Previous phytochemical studies have shown that the plants of the Albizia genus (Fabaceae) contain bioactive saponins, lignans, spermine alkaloids, flavonoids, glycosides phenols and pyridoxine derivatives. Their extracts sometimes display medical properties, but can have also toxic effects. The purpose of our study was to determine the in vivo toxicity of Albizia bernieri seeds in the experimental model of the medaka fish embryo, which is recommended for use in toxicity studies. Our results show clearly that incubating the embryos or larvae of the medaka fish in a medium containing A. bernieri extracts caused a dose-dependent reduction in embryo or larvae survival. Embryos exposed to an extract of A. bernieri displayed cerebral lesions, such as cell lysis and the emergence of lysosomes in the glial tissue. We conclude that when comparing with data obtained with different plant extracts tested on medaka development in our laboratory, A. bernieri displays an unusually high toxicity. Focussing on the cerebral target as well as the fish behaviour could bring more specific informations. 23313609 Antioxidant, antimicrobial and anti-proliferative activities of Solanum tuberosum L. var. Vitelotte. Solanum tuberosum L. var. Vitelotte is a potato variety widely used for human consumption. The pigments responsible for its attractive color belong to the class of anthocyanins. The objectives of this study were to characterize and measure the concentration of anthocyanins in pigmented potatoes and to evaluate their antioxidant and antimicrobial activities and their anti-proliferative effects in solid and hematological cancer cell lines. Anthocyanins exert anti-bacterial activity against different bacterial strains and a slight activity against three fungal strains. The Gram-positive bacterium Staphylococcus aureus and the fungus Rhyzoctonia solani were the most affected microorganisms. Antioxidant activities were evaluated by DPPH and FRAP methods; the extract showed a higher reducing capability than anti-radical activity. Moreover, we found that in different cancer cell models the anthocyanins cause inhibition of proliferation and apoptosis in a dose dependent manner. These biological activities are likely due to the high content of malvidin 3-O-p-coumaroyl-rutinoside-5-O-glucoside and petunidin 3-O-p-coumaroyl-rutinoside-5-O-glucoside. 23164921 Catalpol inhibits LPS plus IFN-γ-induced inflammatory response in astrocytes primary cultures. A large body of evidence suggests that the inflammatory reaction plays an important role in the pathogenesis of neurodegenerative diseases. Our previous studies described the neuroprotective effects of catalpol in lipopolysaccharide (LPS)-induced inflammatory models, in which catalpol was shown to prevent mesencephalic neuron death and ameliorate cognitive ability animals. To further investigate the protective effect and underlying mechanism of catalpol, astrocytes were pretreated with low (0.1mM) and high dose (0.5mM) catalpol for 1h prior to LPS plus interferon-γ stimulation. Biochemical analyses showed that NO and ROS production and iNOS activity were significantly reduced by catalpol. Data at transcriptional level also demonstrated that catalpol potently attenuated gene expressions involved in inflammation, such as iNOS, COX-2 and TLR4. In addition, our exploration further revealed that the suppressive action of catalpol on inflammation was mediated via inhibiting nuclear factor-κB (NF-κB) activation. Collectively, these results suggest that catalpol can exert inhibitory effects on the inflammatory reaction in astrocytes and that inactivation of NF-κB could be the major determinant for its anti-inflammatory mechanism. Therefore, catalpol may potentially be a highly effective therapeutic agent in treating neurodegenerative diseases associated with inflammation. 23615708 Assessment of genotoxic effects of flumorph by the comet assay in mice organs. The present study investigated the genotoxic effects of flumorph in various organs (brain, liver, spleen, kidney and sperm) of mice. The DNA damage, measured as comet tail length (µm), was determined using the alkaline comet assay. The comet assay is a sensitive assay for the detection of genotoxicity caused by flumorph using mice as a model. Statistically significant increases in comet assay for both dose-dependent and duration-dependent DNA damage were observed in all the organs assessed. The organs exhibited the maximum DNA damage in 96 h at 54 mg/kg body weight. Brain showed maximum DNA damage followed by spleen > kidney > liver > sperm. Our data demonstrated that flumorph had induced systemic genotoxicity in mammals as it caused DNA damage in all tested vital organs, especially in brain and spleen. 23252950 Role of pharmacogenetics in busulfan/cyclophosphamide conditioning therapy prior to hematopoietic stem cell transplantation. Hematopoietic stem cell transplantation (HSCT) is a curative treatment for several malignant and nonmalignant disorders. Busulfan (Bu) and cyclophosphamide (Cy) are the most commonly used alkylators in high-dose pretransplant conditioning for HSCT; a treatment that is correlated with drug-related toxicity and relapse. Pharmacogenetic investigations have shown that CYP450, as well as aldehyde dehydrogenase, are clearly involved with Cy metabolism and are associated with altered treatment response, Cy metabolism and the unique stem-cell sparing capacity. Moreover, glutathione-S-transferase isoenzymes have been associated with cellular outward transport of various alkylating agents, including Cy metabolites, melphalan, Bu and chlorambucil. A shift from genetic-based studies to whole-genome-based investigations of Cy- and Bu-associated markers may contribute to personalizing the conditioning therapy and enhancing the clinical outcome of HSCT. 23411204 1H NMR-based metabolic fingerprinting of urine metabolites after consumption of lingonberries (Vaccinium vitis-idaea) with a high-fat meal. The use of NMR metabolomics in clinical trials is growing; however, reports of postprandial experiments in humans are scarce. The present study investigated whether consumption of lingonberries as a supplement to an oil-rich meal modifies the postprandial fingerprints of human urine. Urine samples were analysed by (1)H NMR, and untargeted multivariate analysis was applied to the data for comprehensive fingerprinting. A clear separation of postprandial lingonberry meal samples was revealed. To evaluate statistical differences, a targeted approach was applied for the informative spectral areas. Significantly (p<0.05) increased levels of polyphenol metabolites, hippuric acid and 4-hydroxyhippuric acid, and decreased creatinine and dimethylamine levels were the major explanations for the grouping of the postprandial samples after the different meals. Thus, inclusion of polyphenol-rich lingonberry powder in a rapeseed oil-rich meal modifies the metabolic profile of urine which may be used to reveal both consumption of berries and health-promoting changes in the common metabolism. 23219526 Interleukin-6 induces vascular endothelial growth factor expression and promotes angiogenesis through apoptosis signal-regulating kinase 1 in human osteosarcoma. Osteosarcoma is characterized by a high malignant and metastatic potential. Angiogenesis is essential for the caner metastasis. Interleukin-6 (IL-6) is a multifunctional cytokine that is associated with the disease status and outcomes of cancers. However, the relationship between IL-6 and vascular endothelial growth factor (VEGF) expression in human osteosarcoma is mostly unknown. Here we found that the IL-6 and VEGF expression was correlated with tumor stage and significantly higher than that in normal bone. Incubation of osteosarcoma cells with IL-6 increased VEGF mRNA and protein expression. Pretreatment of cells with IL-6R antibody reduced IL-6-mediated VEGF production. The apoptosis signal-regulating kinase 1 (ASK1)/p38/AP-1 pathway was activated after IL-6 treatment, and IL-6-induced VEGF expression was abolished by the specific inhibitor and siRNA of ASK1, p38, and AP-1 cascades. Importantly, knockdown IL-6 reduced VEGF expression and abolished osteosarcoma conditional medium-mediated angiogenesis. Taken together, these results indicate that IL-6 occurs through ASK1 and p38, which in turn activates AP-1, resulting in the activations of VEGF expression and contributing the angiogenesis of human osteosarcoma cells. 23201051 pH-responsive lipid core micelles for tumour targeting. A new acid-sensitive drug-delivery nanocarrier has been developed for tumour targeting. The self-assembling co-polymer stearoyl-PEG-poly-sulfadimethoxine methacrylate (stearoyl-PEG-polySDM) was prepared to obtain micelles with responsive behaviour in the physiopathologic pH range. Stearoyl-PEG-polySDM was synthesised using a multi-step procedure that includes pH-sensitive sulfadimethoxine methacrylate polymerisation by AGET-ATRP at the amino terminal side of stearoyl-PEG-NH2. Chemical analysis showed that the stearoyl-PEG-polySDM co-polymer contained a mean of seven methacryloyl sulfadimethoxines per molecule. Potentiometric and turbidimetric analyses showed that stearoyl-PEG-polySDM has an apparent pKa of 7.2 and a cloud point at pH 7.0. In water at pH 7.4, the co-polymer assembled spontaneously into 13.2±3.1 nm micelles with a critical micelle concentration (CMC) of 36 μM. Cell-culture studies showed that the material was more biocompatible with respect to the control Brij-700®. The paclitaxel loading capacity of the micelles was 3.25±0.25% (w/w, %). The colloidal formulations were stable at pH 7.4 for several hours, while at pH 6.5, they rapidly rearranged and aggregated. Fluorescence spectroscopic and cytofluorimetric studies showed that the incubation of MCF-7 tumour cells with fluorescein-labelled stearoyl-PEG-polySDM at pH 6.5 resulted in massive time-dependent cell association, while the incubation at pH 7.4 showed significantly lower cell interaction. Confocal microscopy confirmed that at pH 6.5, the micelles are taken up by cells and that the fluorescein-labelled stearoyl-PEG-polySDM is distributed into the cytosol. At pH 6.5, paclitaxel-loaded stearoyl-PEG-polySDM micelles had a higher cytotoxic effect than the micelles incubated at pH 7.4. The former displayed similar cytotoxic activity to free paclitaxel. 23644193 Design, synthesis and antiproliferative activity studies of novel 1,2,3-triazole-dithiocarbamate-urea hybrids. A series of novel 1,2,3-triazole-dithiocarbamate-urea hybrids were designed, synthesized and their antiproliferative activities against four selected human cancer cell lines were evaluated. The results showed that a number of the hybrids exhibited potent activity in selected human cancer cell lines. Among them, compounds 27 and 34 showed broad spectrum anticancer activity with IC50 values ranging from 1.62 to 20.84 μM and 0.76 to 13.55 μM, respectively. Interestingly, compounds 27 and 34, being very potent against MGC-803 cells, exhibited no significant cytotoxicity against normal human embryonic kidney cells at up to 55 μM and 70 μM, respectively. Evidences of cell cycle arrest and apoptosis induction were obtained for the most effective compounds 27 and 34 by means of flow cytometry and microscopic techniques. 23560571 Peptide-Directed Preparation and X-ray Structural Study of Au Nanoparticles on Titanium Surfaces. We report the peptide-directed preparation and X-ray structural study of biofunctionalized Au nanoparticles (NPs) deposited on Ti surfaces. Au NPs were prepared by reduction of Au(3+) compound onto HCl-refreshed Ti in the presence of thiol-functionalized small peptides. A modified extended X-ray absorption fine-structure (EXAFS) technique, equipped with a rotating-stage and glancing-angle setup, was able to more sensitively detect the structure and bonding of Au NPs on Ti with low surface coverage. It was found that the use of the tripeptide glutathione (GSH) results in smaller NP size when compared to N-(2-mercapto-propionyl) glycine (MPG), a pseudodipeptide, over a wide range of Au/peptide molar ratios (20:1, 10:1, 5:1, and 2:1). By varying the ligand concentration, the Au NP structure in both systems can be controlled, generating nanocrystals, nanoclusters, and Au-thiolate polymer, which is unique for substrate-supported NP synthesis. This work presents a facile preparation of Au-peptide nanoparticles on biocompatible surfaces, and illustrates the high sensitivity of this modified EXAFS technique for structural studies of substrate-supported nanoparticles with low coverage. 23568627 Effect of Topical Application of Chlorogenic Acid on Excision Wound Healing in Rats. This study was undertaken to evaluate the therapeutic effects of topical chlorogenic acid on excision wounds in Wistar rats. A 1 % (w/w) chlorogenic acid or silver sulfadiazine ointment was applied topically once a day for 15 days on full-thickness excision wounds created on rats. The 1 % (w/w) chlorogenic acid ointment had potent wound healing capacity as evident from the wound contraction on the 15th post-surgery day, which was similar to that produced by 1 % (w/w) silver sulfadiazine ointment. Increased rates of epithelialization were observed in the treated rats. It also improved cellular proliferation, increased tumor necrosis factor-α levels during the inflammatory phase (12 h, 24 h, 48 h, and 72 h post-wounding) of wound healing, upregulated transforming growth factor-β1 and elevated collagen IV synthesis in the chlorogenic acid-treated group. The results also indicated that chlorogenic acid possesses potent antioxidant activity by increasing superoxide dismutase, catalase, and glutathione, and decreasing lipid peroxidation. In conclusion, these results demonstrate that topical application of chlorogenic acid can accelerate the process of excision wound healing by its ability to increase collagen synthesis through upregulation of key players such as tumor necrosis factor-α and transforming growth factor-β1 in different phases of wound healing as well as by its antioxidant potential. 23276229 Kinetics of the reaction of crystal violet with hydroxide ion in the critical solution of 2-butoxyethanol + water. The kinetics of alkaline fading of crystal violet (CV) has been studied by UV spectrophotometry and microcalorimetry in the critical binary solution of 2-butoxyethanol + water at the initial reaction stage and various temperatures. It was found that the first-order rate constants obtained from these two methods are well accorded with each other, and the temperature dependence of the rate constant obeyed the Arrhenius equation in a temperature region far from the critical point. The critical slowing down was detected by both methods near the critical point. A simple empirical crossover model was proposed and used to analyze the experimental data to obtain the critical exponents, which were 0.158 ± 0.013 and 0.133 ± 0.012 from UV spectrophotometry and microcalorimetry, respectively, and the former was in good agreement with the theoretical prediction of 0.151. The slight lower value derived from microcalorimetry was attributed to the stirring in the microcalorimeter, which weakened the critical reduction of the diffusion coefficient. 23472643 Nanoparticles Adsorbed at the Water/Oil Interface: Coverage and Composition Effects on Structure and Diffusion. Dissipative particle dynamics simulations are performed to study the structural and dynamical properties of various systems of nanoparticles accumulated at the water/oil interface. Homogeneous and Janus nanoparticles with different surface compositions are studied. For all nanoparticles, as the surface density increases, a transition from a liquidlike to a solidlike state is observed, as expected. At a high density of nanoparticles, hexagonal structures emerge and the nanoparticles' self-diffusion coefficient decreases because of caging effects. Similar results are observed for nanoparticles with different surface chemistry. Because different nanoparticles have different contact angles at the water/oil interface, the results obtained for systems containing mixed nanoparticles are more interesting. For example, our results show that the self-diffusion coefficient is not a monotonic function of the system composition, caused by the complex relation between hydrodynamic interactions and effective nanoparticle-nanoparticle interactions. 23168114 Stiripentol is anticonvulsant by potentiating GABAergic transmission in a model of benzodiazepine-refractory status epilepticus. Benzodiazepines (BZDs) are first-line therapy for treatment of status epilepticus (SE). However, BZD treatment is negatively affected by seizure duration due to decreases in BZD-sensitive GABA(A) receptors during prolonged SE. Stiripentol (STP) is an anticonvulsant that is used as add-on treatment for Dravet Syndrome. Recent studies have shown that STP is a positive allosteric modulator of the GABA(A) receptor. The subunit selectivity of STP at this receptor suggests that it would be anticonvulsant in both brief as well as prolonged SE. We tested this possibility by comparing the ability of STP and diazepam (DZP), a commonly used BZD, to terminate behavioral convulsions in a rodent model of pharmacoresistant SE. We found that STP was anticonvulsant in this model and remained effective during prolonged SE, unlike DZP which exhibited a 14 fold increase in its ED(50). Whole cell recording from hippocampal slices from these animals revealed that STP potentiated GABAergic IPSCs, as well as tonic GABAergic current by acting at a site on the GABA(A) receptor separate from the BDZ binding site. Potentiation of GABAergic currents by STP remained intact during prolonged SE, while potentiation by DZP was lost. Both IPSC potentiation and anticonvulsant activity of STP were greater in younger animals than in adults. These findings suggest that at doses that yield therapeutically relevant concentrations, STP is anticonvulsant by potentiating GABAergic inhibition and that the subunit selectivity profile of STP enables it to remain effective despite GABA(A) receptor subunit changes during prolonged SE. 23274898 Electrical Stimuli Release ATP to Increase GLUT4 Translocation and Glucose Uptake via PI3Kγ-Akt-AS160 in Skeletal Muscle Cells. Skeletal muscle glucose uptake in response to exercise is preserved in insulin-resistant conditions, but the signals involved are debated. ATP is released from skeletal muscle by contractile activity and can autocrinely signal through purinergic receptors, and we hypothesized it may influence glucose uptake. Electrical stimulation, ATP, and insulin each increased fluorescent 2-NBD-Glucose (2-NBDG) uptake in primary myotubes, but only electrical stimulation and ATP-dependent 2-NBDG uptake were inhibited by adenosine-phosphate phosphatase and by purinergic receptor blockade (suramin). Electrical stimulation transiently elevated extracellular ATP and caused Akt phosphorylation that was additive to insulin and inhibited by suramin. Exogenous ATP transiently activated Akt and, inhibiting phosphatidylinositol 3-kinase (PI3K) or Akt as well as dominant-negative Akt mutant, reduced ATP-dependent 2-NBDG uptake and Akt phosphorylation. ATP-dependent 2-NBDG uptake was also inhibited by the G protein βγ subunit-interacting peptide βark-ct and by the phosphatidylinositol 3-kinase-γ (PI3Kγ) inhibitor AS605240. ATP caused translocation of GLUT4myc-eGFP to the cell surface, mechanistically mediated by increased exocytosis involving AS160/Rab8A reduced by dominant-negative Akt or PI3Kγ kinase-dead mutants, and potentiated by myristoylated PI3Kγ. ATP stimulated 2-NBDG uptake in normal and insulin-resistant adult muscle fibers, resembling the reported effect of exercise. Hence, the ATP-induced pathway may be tapped to bypass insulin resistance. 23495205 Synthesis and Structure-Activity Relationship Studies of Derivatives of the Dual Aromatase-Sulfatase Inhibitor 4-{[(4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate. 4-{[(4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate and its ortho-halogenated (F, Cl, Br) derivatives are first-generation dual aromatase and sulfatase inhibitors (DASIs). Structure-activity relationship studies were performed on these compounds, and various modifications were made to their structures involving relocation of the halogen atom, introduction of more halogen atoms, replacement of the halogen with another group, replacement of the methylene linker with a difluoromethylene linker, replacement of the para-cyanophenyl ring with other ring structures, and replacement of the triazolyl group with an imidazolyl group. The most potent in vitro DASI discovered is an imidazole derivative with IC50 values against aromatase and steroid sulfatase in a JEG-3 cell preparation of 0.2 and 2.5 nM, respectively. The parent phenol of this compound inhibits aromatase with an IC50 value of 0.028 nM in the same assay. 23529548 Systematic review of anticholinergic risk scales in older adults. BACKGROUND: Anticholinergic drugs are often involved in explicit criteria for inappropriate prescribing in older adults. Several scales were developed for screening of anticholinergic drugs and estimation of the anticholinergic burden. However, variation exists in scale development, in the selection of anticholinergic drugs, and the evaluation of their anticholinergic load. This study aims to systematically review existing anticholinergic risk scales, and to develop a uniform list of anticholinergic drugs differentiating for anticholinergic potency. METHODS: We performed a systematic search in MEDLINE. Studies were included if provided (1) a finite list of anticholinergic drugs; (2) a grading score of anticholinergic potency and, (3) a validation in a clinical or experimental setting. We listed anticholinergic drugs for which there was agreement in the different scales. In case of discrepancies between scores we used a reputed reference source (Martindale: The Complete Drug Reference®) to take a final decision about the anticholinergic activity of the drug. RESULTS: We included seven risk scales, and evaluated 225 different drugs. Hundred drugs were listed as having clinically relevant anticholinergic properties (47 high potency and 53 low potency), to be included in screening software for anticholinergic burden. CONCLUSION: Considerable variation exists among anticholinergic risk scales, in terms of selection of specific drugs, as well as of grading of anticholinergic potency. Our selection of 100 drugs with clinically relevant anticholinergic properties needs to be supplemented with validated information on dosing and route of administration for a full estimation of the anticholinergic burden in poly-medicated older adults. 23358500 Variation in the α 5 nicotinic acetylcholine receptor subunit gene predicts cigarette smoking intensity as a function of nicotine content. A single-nucleotide polymorphism (SNP) in the α5 nicotinic acetylcholine receptor subunit gene, rs16969968, has been repeatedly associated with both smoking and respiratory health phenotypes. However, there remains considerable debate as to whether associations with lung cancer are mediated through effects on smoking behavior. Preclinical studies suggest that α5 receptor subunit expression and function may have a direct role in nicotine titration during self administration. The present study investigated the association of CHRNA5 polymorphisms and smoking topography in 66 smokers asked to smoke four nicotine-containing (nicotine yield=0.60 mg) and four placebo (nicotine yield <0.05 mg) cigarettes, during separate experimental sessions. Genotype at rs16969968 predicted nicotine titration, with homozygotes for the major allele (G:G) displaying significantly reduced puff volume in response to nicotine, whereas minor allele carriers (A:G or A:A) produced equivalent puff volumes for placebo and nicotine cigarettes. The present results suggest that puff volume may be a more powerful objective phenotype of smoking behavior than self-reported cigarettes per day and nicotine dependence. Further, these results suggest that the association between rs16969968 and lung cancer may be mediated by the quantity of smoke inhaled.The Pharmacogenomics Journal advance online publication, 29 January 2013; doi:10.1038/tpj.2012.50. 23612689 Structure of hydrated cobalt ions confined in the nanospace of single-walled carbon nanotubes. The structure of hydrated Co ions confined in the nanospace of single-walled carbon nanotubes (SWNTs) has been studied using the X-ray absorption fine structure (XAFS) technique. Water adsorption isotherms on Co-impregnated SWNTs indicate a high affinity of Co ions to water molecules. The results of XAFS analysis provided the information on the proportion of dissolved species in nanospaces against the total amount of cobalt ions adsorbed on the open-pored SWNT. The structural information of the first shell around a Co ion was expressed in terms of the hydration number, Co-O distance and Debye-Waller factor. The actual coordination number and the interatomic distance of Co-O for the dissolved species were remarkably reduced compared to the bulk aqueous solution indicating the dehydration of water molecules from Co ions and a compact hydrated structure in the micropore of SWNTs. 23059794 Chronic PFOS exposures induce life stage-specific behavioral deficits in adult zebrafish and produce malformation and behavioral deficits in F1 offspring. Perfluorooctane sulfonic acid (PFOS) is an organic contaminant that is ubiquitous in the environment. Few studies have assessed the behavioral effects of chronic PFOS exposure in aquatic organisms. The present study defined the behavioral effects of varying life span chronic exposures to PFOS in zebrafish. Specifically, zebrafish were exposed to control or 0.5 µM PFOS during 1 to 20, 21 to 120, or 1 to 120 d postfertilization (dpf). Exposure to PFOS impaired the adult zebrafish behavior mode under the tapping stimulus. The movement speed of male and female fish exposed for 1 to 120 dpf was significantly increased compared with control before and after tapping, whereas in the groups exposed for 1 to 20 and 21 to 120 dpf, only the males exhibited elevated swim speed before tapping. Residues of PFOS in F1 embryos derived from parental exposure for 1 to 120 and 21 to 120 dpf were significantly higher than control, and F1 embryos in these two groups also showed high malformation and mortality. The F1 larvae of parental fish exposed to PFOS for 1 to 20 or 21 to 120 dpf exhibited a higher swimming speed than control larvae in a light-to-dark behavior assessment test. The F1 larvae derived from parental fish exposed to PFOS for 1 to 120 dpf showed a significantly lower speed in the light period and a higher speed in the dark period compared with controls. Although there was little PFOS residue in embryos derived from the 1- to 20-dpf parental PFOS-exposed group, the adverse behavioral effects on both adult and F1 larvae indicate that exposure during the first 21 dpf induces long-term neurobehaviorial toxicity. The authors' findings demonstrate that chronic PFOS exposure during different life stages adversely affects adult behavior and F1 offspring morphology, behavior, and survival. 23151004 GPR55 and its interaction with membrane lipids: comparison with other endocannabinoid-binding receptors. A number of integral membrane G protein-coupled receptors (GPCRs) share common structural features (including palmytoilated aminoacid residues and consensus sequences specific for interaction with cholesterol) that allow them to interact with lipid rafts, membrane cholesterol-rich microdomains able to regulate GPCR signalling and functions. Among GPCRs, type-1 and type-2 cannabinoid receptors, the molecular targets of endocannabinoids (eCBs), control many physiological and pathological processes through the activation of several signal transduction pathways. Recently, the orphan GPR55 receptor has been proved to be activated by many eCBs, thus leading to the hypothesis that it might be the "type-3" cannabinoid receptor. While the biological activity of eCBs and the influence of membrane lipids on their functions are rather well established, information regarding GPR55 is still scarce and often controversial. Based on this background, here we shall review current data about GPR55 pharmacology and signalling, highlighting its involvement in several pathophysiological conditions. We shall also outline the structural features that allow GPR55 to interact with cholesterol and to associate with lipid rafts; how the latter lipid microdomains impact the biological activity of GPR55 is also addressed, as well as their potential for the discovery of new therapeutics useful for the treatment of those human diseases that might be associated with alterations of GPR55 activity. 22902308 The influence of the choice of digestion enzyme used to prepare rat hepatocytes on xenobiotic uptake and efflux. Isolated rat hepatocytes are widely used to assess the metabolism and toxicity of xenobiotics. The choice of digestion enzyme used to prepare the cells has been shown previously to influence their metabolic capability. This study investigates the effect of the digestion enzyme (collagenase II, collagenase A/trypsin inhibitor, or collagenase plus dispase) on the uptake of xenobiotics into, and efflux from, hepatocytes. The choice of digestion enzymes used in this study does not affect uptake of either pravastatin (an organic anion probe substrate for Oatp transporter) or metformin (an organic cation probe substrate for Oct transporter). With regard to efflux transporters, hepatocyte differentiation was better maintained when cells were isolated using collagenase II alone. 23578619 Investigation of tocotrienol biosynthesis in rice (Oryza sativa L.). Rice tocotrienol (T3) has gained attention due to its physiological activities (e.g., antiangiogenesis). However, the biosynthetic pathway for T3 production in rice grain has not been well studied. We hypothesized that T3 biosynthesis enzymes and/or precursors play an important role in T3 production in whole grain. This proposal was evaluated in rice (Oryza sativa L.) by PCR and HPLC techniques. Grain tocopherol as well as flag leaf vitamin E levels were also investigated for comparison. For rice samples 14days after flowering, grain was abundant in T3, but not in flag leaf. Expression of a gene encoding homogentisate geranylgeranyltransferase (HGGT, which has long been believed to be important for T3 production) differed significantly between grain and flag leaf. We then investigated rice samples during the grain maturation period, and found that grain T3 and HGGT levels increased in the early stage and then reached a plateau. T3 precursors such as homogentisate and geranylgeranyl pyrophosphate decreased during maturation. No increase in grain T3 from the middle to late stages of maturation and a decrease in T3 precursors during maturation suggest that HGGT would be an essential, but not limiting factor for T3 biosynthesis, and T3 precursors could regulate the T3 level in grain. The results of this study would be useful for nutraceutical purposes (e.g., development of T3-overproducing rice for the prevention of angiogenic disorders). 22965581 Robust and aligned carbon nanotube/titania core/shell films for flexible TCO-free photoelectrodes. Carbon nanotube (CNT)/semiconducting oxide hybrids are an ideal architecture for light-harvesting devices, in which the CNTs are expected to not only act as a scaffold but also provide fast transport paths for photogenerated charges in the oxide. However, the current potential of CNTs for charge transport is largely suppressed due to the nanotubes not being interconnected but isolated by the low conductive oxide coatings. Herein, a flexible and conductive CNT/TiO(2) core/shell heterostructure film is reported, with aligned and interconnected CNTs wrapped in a continuous TiO(2) coating. Without using additional transparent conducting oxide (TCO) substrates, this unique feature of the film boosts the incident photon-to-electron conversion efficiency to 32%, outperforming TiO(2) nanoparticle electrodes fabricated on TCO substrates. Moreover, the film shows high structural stability and can generate a stable photocurrent even after being bent hundreds of times. 23578647 The oestrogenic and anti-platelet activities of dihydrobenzofuroisocoumarins and homoisoflavonoids from Liriope platyphylla roots. The ethanolic extract of Liriope platyphylla (Liliaceae) roots showed potential oestrogenic and anti-platelet activities. Twenty-six compounds were isolated and classified as 10 skeletons, including two unusual new dihydrobenzofuroisocoumarins, (+)-platyphyllarin A (1) and B (2), one new butanoate, ethyltributanoate (3), and two new homoisoflavanones, (-)-liriopein A (4) and B (5), along with 21 known compounds, including six homoisoflavonoids, one chalcone, six amides, one lignan, one fatty acid derivative, one alkaloid, three benzenoids, and two steroids. The biosynthetic pathway of compounds 1 and 2 was proposed in the current investigation. The oestrogenic activity of the isolates was evaluated utilising the pER8:GUS reporter assay system in transgenic Arabidopsis plant as well as the SEAP reporter assay system in MCF-7 breast cancer cell-line; the anti-platelet activity was evaluated using the anti-platelet aggregation assay. Several components exhibited significant oestrogenic and anti-platelet activities; demonstrating for the first time the potential use of L. platyphylla as a nutritional supplement for cardiovascular and endocrine diseases. 22494026 A new flavonol from Oxytropis ochrocephala Bunge. A new acylated flavonoid, 3-O-rhamnocitrin-6-O-benzoyl-β-D-glucopyranoside (1), together with five known flavonoids, rhamnocitrin (2), pratensein (3), (3R)-7,3'-dihydroxy-2',4'-dimethoxyisoflavan (4), (3R)-7,2'-dihydroxy-3',4'-dimethoxyisoflavan (5) and isoliquiritigenin (6), was isolated from Oxytropis ochrocephala Bunge. The structural elucidation of the isolated compounds was primarily based on HRESIMS, IR and 1-D- and 2-D-NMR analyses. 23583802 Dietary nimodipine delays the onset of methylmercury neurotoxicity in mice. Adult-onset exposure is thought to result primarily in sensory and motor deficits but effects on learning are poorly understood. One mechanism by which chronic MeHg may exert its neurotoxicity is via sustained disruption of intracellular calcium homeostasis, with a consequent increase of intracellular Ca(2+) ions in vulnerable neurons. A biochemically heterogeneous group of compounds, calcium channel blockers, have been shown in vitro to attenuate MeHg's toxicity. To evaluate the role of calcium antagonism in MeHg toxicity in vivo, adult BALB/c mice were exposed chronically to 0 or 15ppm of Hg (as MeHg) via drinking water and to nimodipine, a dihydropryidine, L-type Ca(2+) channel blocker with action in the CNS. Nimodipine was administered orally in diets (0, 20, or 200ppm, producing approximately 0, 2, or 20mg/kg/day of nimodipine). An incremental repeated acquisition (IRA) of response chains procedure was used to detect MeHg-induced deficits in learning or motoric function and to evaluate possible neuroprotection by nimodipine. MeHg impaired performance on the IRA task, and this was partially or completely blocked by dietary nimodipine, depending on dose. Measures of learning co-varied with measures of motoric function as indicated by overall response rate. Nimodipine delayed or prevented the behavioral toxicity of MeHg exposure as evidenced by IRA performance; effects on learning seemed secondary to response rate decreases. 23072941 Design, synthesis, and in vitro evaluation of new amphiphilic cyclodextrin-based nanoparticles for the incorporation and controlled release of acyclovir. Acyclovir possesses low solubility in water and in lipid bilayers, so that its dosage forms do not allow suitable drug levels at target sites following oral, local, or parenteral administration. In order to improve this lack of solubility, new cyclodextrin-based amphiphilic derivatives have been designed to form nanoparticles, allowing the efficient encapsulation of this hydrophobic antiviral agent. The present work first describes the synthesis and characterization of five new O-2,O-3 permethylated O-6 alkylthio- and perfluoroalkyl-propanethio-amphiphilic β-cyclodextrins. These derivatives have been obtained with good overall yields. The capacity of these molecules to form nanoparticles in water and to encapsulate acyclovir has then been studied. The nanoparticles prepared from the new β-cyclodextrin derivatives have been characterized by dynamic light scattering and have an average size of 120nm for the fluorinated derivatives and 220nm for the hydrogenated analogs. They all allowed high loading and sustained release of acyclovir. 23161512 A method for assessing the potential for confounding applied to ionic strength in central Appalachian streams. Causal relationships derived from field data are potentially confounded by variables that are correlated with both the cause and its effect. The present study presents a method for assessing the potential for confounding and applies it to the relationship between ionic strength and impairment of benthic invertebrate assemblages in central Appalachian streams. The method weighs all available evidence for and against confounding by each potential confounder. It identifies 10 types of evidence for confounding, presents a qualitative scoring system, and provides rules for applying the scores. Twelve potential confounders were evaluated: habitat, organic enrichment, nutrients, deposited sediments, pH, selenium, temperature, lack of headwaters, catchment area, settling ponds, dissolved oxygen, and metals. One potential confounder, low pH, was found to be biologically significant and eliminated by removing sites with pH < 6. Other potential confounders were eliminated based on the weight of evidence. This method was found to be useful and defensible. It could be applied to other environmental assessments that use field data to develop causal relationships, including contaminated site remediation or management of natural resources. 23352909 Poly(styrene oxide)-poly(ethylene oxide) block copolymers: From "classical" chemotherapeutic nanocarriers to active cell-response inducers. Two poly(styrene oxide)-poly(ethylene oxide) (PSO-PEO) triblock copolymers with different chain lengths were analyzed as potential chemotherapeutic nanocarriers, and their ability to inhibit the P-glycoprotein (P-gp) efflux pump in a multidrug resistant (MDR) cell line were measured in order to establish possible cell-responses induced by the presence of the copolymer molecules. Thus, EO33SO14EO33 and EO38SO10EO38 polymeric micelles were tested regarding doxorubicin (DOXO) entrapment efficiency (solubilization test), physical stability (DLS), cytocompatibility (fibroblasts), release profiles at various pHs (in vitro tests), as well as P-gp inhibition and evasion and cytotoxicity of the DOXO-loaded micelles in an ovarian MDR NCI-ADR/RES cell line and in DOXO-sensitive MCF-7 cells. EO33SO14EO33 and EO38SO10EO38 formed spherical micelles (~13nm) at lower concentration than other copolymers under clinical evaluation (e.g. Pluronic®), exhibited 0.2% to 1.8% loading capacity, enhancing more than 60 times drug apparent solubility, and retained the cargo for long time. The copolymer unimers inhibited P-gp ATPase activity in a similar way as Pluronic P85, favoring DOXO accumulation in the resistant cell line, but not in the sensitive cell line. DOXO loaded in the micelles accumulated more slowly inside the cells, but caused greater cytotoxicity than free drug solutions in the NCI-ADR-RES cell line, which overexpressed P-gp. Hence, PSO-PEO block copolymers offer interesting features as new biological response modifiers to be used in the design of efficient nanocarriers for cancer chemotherapy. 23384772 Therapeutic potential of neuregulin-1 in cardiovascular disease. Neuregulin-1 (NRG-1)/ErbB signaling has an indispensable role in cardiac development and in the maintenance of the structural and functional integrity of the human adult heart in health and disease. Several animal studies have now demonstrated the therapeutic effects of NRG-1 during acute cardiac injury and during chronic heart failure, with improvements in cardiac performance and animal survival. Phase I and II clinical trials for chronic heart failure in humans are now in progress. 23435358 Changes in morphometry and association between whole-body fatty acids and steroid hormone profiles in relation to bioaccumulation patterns in salmon larvae exposed to perfluorooctane sulfonic or perfluorooctane carboxylic acids. In the present study, we have used salmon embryos whose continuous exposure to waterborne PFOA or PFOS at 100 μg/L started as freshly fertilized eggs, and lasted for a total of 52 days. PFOS and PFOA were dissolved in methanol (carrier vehicle) whose concentration never exceeded 0.01% of total tank volume. Samples were collected at day 21, 28, 35, 52, 49 and 56 after the start of the exposure. Note that days 49 and 56 represent end of exposure and 1 week after a recovery period, respectively. Tissue bioaccumulations were determined by HPLC/MS/MS, steroid hormones, fatty acids (FAs) and lipids were determined by GC-MS, while mRNA expression levels of genes were determined by qPCR in whole body homogenate. We observed that PFOS and PFOA showed a steady increase in whole body burden during the exposure period, with a slight decrease after the recovery period. Calculated somatic indexes showed that PFOA produced increases in heart-, thymus-, liver- and kidney somatic indexes (HSI, TSI, LSI and KSI). PFOA and PFOS exposure produced significant decreases in whole body dehydroepiandrosterone (DHEA), estrone and testosterone at sampling day 21 and a strong increase of cortisol and cholesterol at the end of recovery period (day 56). PFOA and PFOS effects differed with DHEA and estrone. While PFOS decreased DHEA levels, PFOA produced an increase at day 49, and while PFOS decreased estrone, PFOA produced a slight increase at day 56. We observed changes in FA composition that predominantly involved increases in FA methyl esters (FAMEs), mono- and poly-unsaturated FA (MUFA and PUFA) and a decrease in n-3/n-6 PUFA ratio by both PFOA and PFOS. Particularly, an increase in - pentadecenoic MUFA (15:1), two n-3 PUFAs α-linolenic acid [ALA: 18:3 n3] and eicosapentaenoic acid [EPA: 20:5 n-3] and n-6 PUFA: arachidonic acid [ARA: 20:4 n6], docosapentaenoic acid (DPA) by PFOA and PFOS were observed. These effects were associated with changes in mRNA expression of FA elongase (FAE), Δ5-desaturase (FAD5) and Δ6-desaturase (FAD6) genes. In summary, the changes in hormonal and FA profiles may represent cellular and/or physiological adaptation to continuous PFOS and PFOA exposure by increasing membrane fluidity, and/or overt developmental effects. The present findings provide some potential insights and basis for a better understanding on the possible mechanisms of PFCs toxicity in fish. 23414805 Chemical tagging of a drug target using 5-sulfonyl tetrazole. Irreversible modification is one of the most promising strategies to identify cellular receptors of bioactive small molecules. Here we report that receptor proteins can be chemically tagged using a 5-sulfonyl tetrazole probe. 5-Sulfonyl tetrazole easily accepted nucleophilic attack of thiol groups, while 5-sulfinyl tetrazole did not. These functional groups were introduced into probe molecules of a natural product. Cyclosporine A, an immunosuppressant produced by a microbe, was derivatized to possess 5-sulfonyl tetrazole and a tag group, which enabled chemical tagging of cyclophilin A, the cellular receptor of cyclosporine A. Cyclosporine A derivative possessing 5-sulfinyl tetrazole could not tag cyclophilin A. This technique will allow efficient identification of cellular receptors of bioactive small molecules. 23333305 RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection. The appropriate execution of DNA double-strand break (DSB) repair is critical for genome stability and tumor avoidance. 53BP1 and BRCA1 directly influence DSB repair pathway choice by regulating 5' end resection, but how this is achieved remains uncertain. Here we report that Rif1(-/-) mice are severely compromised for 53BP1-dependent class switch recombination (CSR) and fusion of dysfunctional telomeres. The inappropriate accumulation of RIF1 at DSBs in S phase is antagonized by BRCA1, and deletion of Rif1 suppresses toxic nonhomologous end joining (NHEJ) induced by PARP inhibition in Brca1-deficient cells. Mechanistically, RIF1 is recruited to DSBs via the N-terminal phospho-SQ/TQ domain of 53BP1, and DSBs generated by ionizing radiation or during CSR are hyperresected in the absence of RIF1. Thus, RIF1 and 53BP1 cooperate to block DSB resection to promote NHEJ in G1, which is antagonized by BRCA1 in S phase to ensure a switch of DSB repair mode to homologous recombination. 23620214 Random Regret-Based Discrete-Choice Modelling: An Application to Healthcare. BACKGROUND: A new modelling approach for analysing data from discrete-choice experiments (DCEs) has been recently developed in transport economics based on the notion of regret minimization-driven choice behaviour. This so-called Random Regret Minimization (RRM) approach forms an alternative to the dominant Random Utility Maximization (RUM) approach. The RRM approach is able to model semi-compensatory choice behaviour and compromise effects, while being as parsimonious and formally tractable as the RUM approach. OBJECTIVES: Our objectives were to introduce the RRM modelling approach to healthcare-related decisions, and to investigate its usefulness in this domain. METHODS: Using data from DCEs aimed at determining valuations of attributes of osteoporosis drug treatments and human papillomavirus (HPV) vaccinations, we empirically compared RRM models, RUM models and Hybrid RUM-RRM models in terms of goodness of fit, parameter ratios and predicted choice probabilities. RESULTS: In terms of model fit, the RRM model did not outperform the RUM model significantly in the case of the osteoporosis DCE data (p = 0.21), whereas in the case of the HPV DCE data, the Hybrid RUM-RRM model outperformed the RUM model (p < 0.05). Differences in predicted choice probabilities between RUM models and (Hybrid RUM-) RRM models were small. Derived parameter ratios did not differ significantly between model types, but trade-offs between attributes implied by the two models can vary substantially. CONCLUSION: Differences in model fit between RUM, RRM and Hybrid RUM-RRM were found to be small. Although our study did not show significant differences in parameter ratios, the RRM and Hybrid RUM-RRM models did feature considerable differences in terms of the trade-offs implied by these ratios. In combination, our results suggest that RRM and Hybrid RUM-RRM modelling approach hold the potential of offering new and policy-relevant insights for health researchers and policy makers. 23122067 Anthraquinone profile, antioxidant and antimicrobial activity of bark extracts of Rhamnus alaternus, R. fallax, R. intermedia and R. pumila. The quantity of phenols, as well as antioxidant and antimicrobial activities, were investigated in bark of Rhamnus alaternus L., R. fallax Boiss., R. intermedia Steud. et Hochst., and R. pumila Turra from natural stands in Croatia. The most abundant anthraquinones in the investigated extracts were chrysophanol in R. alaternus (3.14 mg/g), emodin in R. pumila (0.339 mg/g), and physcion in R. fallax (2.70 mg/g) and R. intermedia (0.285 mg/g). The species exhibiting the highest antioxidant activity were R. fallax and R. pumila. A positive correlation was observed between total phenolic and flavonoid levels of the extracts and antioxidant activity in some of the assays. All species showed antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida albicans, Aspergillus niger and Microsporum gypseum with minimal inhibitory concentrations equal to or below 2.500 mg/mL. The results indicate that the investigated Rhamnus species are a source of anthraquinones and other phenols, which act as multifunctional antioxidants with antimicrobial activity. 23223499 Induction of hepatic CYP3A enzymes by pregnancy-related hormones: studies in human hepatocytes and hepatic cell lines. CYP3A activity is induced by approximately 2-fold during the third trimester of human pregnancy. Placental growth hormone (PGH), estrogens (primarily 17β-estradiol), cortisol, and progesterone have the potential to modulate CYP3A activity. Therefore, we determined whether the elevated plasma concentrations of these hormones during pregnancy induce hepatic CYP3A expression. We incubated sandwich-cultured human hepatocytes (SCHH) from premenopausal female donors (n = 2) with the physiologic (unbound, 1× total) and the 10× total third trimester hormone plasma concentrations (individually and in combination) and determined their effect on CYP3A activity and the transcripts of CYP3A4, CYP3A5, and the respective hormone receptors (growth hormone receptor, glucocorticoid receptor, and estrogen receptor alpha). Of all the hormones, cortisol was the most potent inducer of CYP3A activity and CYP3A4, CYP3A5 mRNA expression. The combination of PGH/growth hormone and cortisol induced CYP3A activity and expression significantly more than did cortisol alone. When incubated with the unbound or total plasma concentration of all the hormones, CYP3A activity in SCHH was induced to an extent comparable to that observed in vivo during the third trimester. These hormones had only a modest effect on the mRNA expression of the hormone receptors. The pattern of induction observed in SCHH was reproduced in HepaRG cells but not in HuH7/HepG2 cells. SCHH or HepaRG cells could be used to determine the mechanistic basis of CYP3A induction during pregnancy and to predict the magnitude of induction likely to be observed during the first and second trimesters, when phenotyping studies to measure in vivo CYP3A activity are logistically difficult to perform. 23351034 Nano-optomechanical actuator and pull-back instability. This paper studies the nonlinear behavior of a nano-optomechanical actuator, consisting of a free-standing arc in a ring resonator that is coupled to a bus waveguide through evanescent waves. The arc deflects when a control light of a fixed wavelength and optical power is pumped into the bus waveguide, while the amount of deflection is monitored by measuring the transmission spectrum of a broadband probe light. This nanoactuator achieves a maximal deflection of 43.1 nm, with a resolution of 0.28 nm. The optical force is a nonlinear function of the deflection of the arc, leading to pull-back instability when the control light is red-tuned. This instability is studied by a combination of experiment and modeling. Potential applications of the nanoactuator include bio-nanomotor, optical switches, and optomechanical memories. 23597402 Enantioselective thiourea-catalyzed intramolecular cope-type hydroamination. Catalysis of Cope-type rearrangements of bis-homoallylic hydroxylamines is demonstrated using chiral thiourea derivatives. This formal intramolecular hydroamination reaction provides access to highly enantioenriched α-substituted pyrrolidine products and represents a complementary approach to metal-catalyzed methods. 23604723 The regulation of epidermal melanogenesis via cAMP and/or PKC signaling pathways: insights for the development of hypopigmenting agents. Abnormal pigmentation, particularly hyperpigmentation, is major issue of concern for people with colored skin. Several hypopigmenting agents, which exert their action by inhibiting tyrosinase activity and/or transcription, have been used for treatment. However, results have been discouraging. To manage abnormal pigmentation properly, the mechanisms of melanogenesis should be understood. Endogenous and exogenous factors affect melanogenesis via intracellular machineries. cAMP and PKC are critical factors of important transduction pathways and cross-talk between them could amplify the melanogenic effect. Here, factors involved in melanogenesis regulation via cAMP and/or PKC pathways are reviewed with their action mechanisms. 23208787 From in situ to in vivo: an in situ click-chemistry-derived carbonic anhydrase II imaging agent for positron emission tomography. CA II makes a good PET: Discovering positron emission tomography (PET) probes with high target affinities is challenging. PET probe discovery using in situ click chemistry uses (19) F-bearing fragments as (18) F surrogates. This ensures that the lead hits and PET probes have equivalent chemical or biological characteristics, making PET probe discovery predictable and reliable. 22982218 The PARP inhibitor PJ34 modifies proliferation, NIS expression and epigenetic marks in thyroid cancer cell lines. Since PARP-1 is supposed to be part of a multimeric repressor of sodium iodide symporter (NIS) expression, in this study the effect of the PARP inhibitor PJ34 on several properties of thyroid cancer cell lines was investigated. In TPC1, BCPAP, FRO, WRO cell lines PJ34 induced a strong increase in NIS mRNA levels. In BCPAP and TPC1 cells also significant increase of radio-iodine uptake was induced. Accordingly, in transfection experiments performed in TPC1 cells, treatment with PJ34 increased NIS promoter activity without affecting PARP-1 binding to the promoter sequence. We also investigated the epigenetic status of NIS promoter after PJ34 treatment in TPC1 cell line: in addition to an increase of histone modification activation marks (H3K9K14ac, H3K4me3), surprisingly we observed also an increase of H3K27me3, a classical repressive mark. Our data demonstrate that in various thyroid cancer cell lines PARP inhibition increases NIS gene expression through a particular modulation of transcriptional regulatory mechanisms. Therefore, we suggest that PARP inhibitors may deserve future investigations as tools for medical treatment of thyroid cancer. 23634707 Single Ion Channel Recordings with CMOS-Anchored Lipid Membranes. We present single-ion-channel recordings performed with biomimetic lipid membranes which are directly attached to the surface of a complementary metal-oxide-semiconductor (CMOS) preamplifier chip. With this system we resolve single-channel currents from several types of bacterial ion channels, including fluctuations of a single alamethicin channel at a bandwidth of 1 MHz which represent the fastest single-ion-channel recordings reported to date. The platform is also used for high-resolution α-hemolysin nanopore recordings. These results illustrate the high signal fidelity, fine temporal resolution, small geometry, and multiplexed integration which can be achieved by leveraging integrated semiconductor platforms for advanced ion channel interfaces. 23359475 Pharmacologic therapy for nonalcoholic fatty liver disease in adults. Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides in hepatocytes in the absence of excessive alcohol intake, ranging in severity from simple steatosis to nonalcoholic steatohepatitis (NASH). Nonalcoholic steatohepatitis can ultimately progress to cirrhosis and hepatocellular carcinoma. NAFLD is associated with cardiometabolic risk factors and is the most common chronic liver disease among adults in the Western Hemisphere. Although simple steatosis is generally considered a self-limiting disease, evidence suggests an increased risk of cardiovascular disease, and, less conclusively, mortality, among individuals with NAFLD and/or NASH. The current standard of care for the treatment of patients with NAFLD focuses on lifestyle interventions, particularly diet and exercise. There is a lack of consensus regarding the most effective and appropriate pharmacologic therapy. A PubMed search was conducted using the medical subject heading terms "fatty liver" and "steatohepatitis." This review focuses on the current pharmacologic options available for treating adults with NAFLD and/or NASH. Continued investigation of drugs or combinations that improve NAFLD progression is crucial. Clinicians, particularly pharmacists, must take an active role in identification and appropriate selection of pharmacotherapy for NAFLD. 23485651 Cadmium telluride quantum dots cause oxidative stress leading to extrinsic and intrinsic apoptosis in hepatocellular carcinoma HepG2 cells. The mechanisms of toxicity related to human hepatocellular carcinoma HepG2 cell exposures to cadmium telluride quantum dots (CdTe-QDs) were investigated. CdTe-QDs caused cytotoxicity in HepG2 cells in a dose- and time-dependent manner. Treated cells showed an increase in reactive oxygen species (ROS). Altered antioxidant levels were demonstrated by depletion of reduced glutathione (GSH), a decreased ratio of reduced glutathione to oxidized glutathione (GSH/GSSG) and an increased NF-E2-related Factor 2 (Nrf2) activation. Enzyme assays showed that superoxide dismutase (SOD) activity was elevated whereas catalase (CAT) and glutathione-S-transferase (GST) activities were depressed. Further analyses revealed that CdTe-QD exposure resulted in apoptosis, indicated by changes in levels of caspase-3 activity, poly ADP-ribose polymerase (PARP) cleavage and phosphatidylserine externalization. Extrinsic apoptotic pathway markers such as Fas levels and caspase-8 activity increased as a result of CdTe-QD exposure. Involvement of the intrinsic/mitochondrial apoptotic pathway was indicated by decreased levels of B-cell lymphoma 2 (Bcl2) protein and mitochondrial cytochrome c, and by increased levels of mitochondrial Bcl-2-associated X protein (Bax) and cytosolic cytochrome c. Further, mitogen-activated protein kinases (MAPKs) such as c-Jun N-terminal kinases (JNK), extracellular signal-regulated kinases (Erk1/2), and p38 were all activated. Our findings reveal that CdTe-QDs cause oxidative stress, interfere with antioxidant defenses and activate protein kinases, leading to apoptosis via both extrinsic and intrinsic pathways. Since the effects of CdTe-QDs on selected biomarkers were similar or greater compared to those of CdCl2 at equivalent concentrations of cadmium, the study suggests that the toxicity of CdTe-QDs arises from a combination of the effects of cadmium and ROS generated from the NPs. 23058251 Molecular mechanisms associated with increased tolerance to the neonicotinoid insecticide imidacloprid in the dengue vector Aedes aegypti. Mosquitoes are vectors of several major human diseases and their control is mainly based on the use of chemical insecticides. Resistance of mosquitoes to organochlorines, organophosphates, carbamates and pyrethroids led to a regain of interest for the use of neonicotinoid insecticides in vector control. The present study investigated the molecular basis of neonicotinoid resistance in the mosquito Aedes aegypti. A strain susceptible to insecticides was selected at the larval stage with imidacloprid. After eight generations of selection, larvae of the selected strain (Imida-R) showed a 5.4-fold increased tolerance to imidacloprid while adult tolerance level remained low. Imida-R larvae showed significant cross-tolerance to other neonicotinoids but not to pyrethroids, organophosphates and carbamates. Transcriptome profiling identified 344 and 108 genes differentially transcribed in larvae and adults of the Imida-R strain compared to the parental strain. Most of these genes encode detoxification enzymes, cuticle proteins, hexamerins as well as other proteins involved in cell metabolism. Among detoxification enzymes, cytochrome P450 monooxygenases (CYPs) and glucosyl/glucuronosyl transferases (UDPGTs) were over-represented. Bioassays with enzyme inhibitors and biochemical assays confirmed the contribution of P450s with an increased capacity of the Imida-R microsomes to metabolize imidacloprid in presence of NADPH. Comparison of substrate recognition sites and imidacloprid docking models of six CYP6s over-transcribed in the Imida-R strain together with Bemisia tabaci CYP6CM1vQ and Drosophila melanogaster CYP6G1, both able to metabolize imidacloprid, suggested that CYP6BB2 and CYP6N12 are good candidates for imidacloprid metabolism in Ae. aegypti. The present study revealed that imidacloprid tolerance in mosquitoes can arise after few generations of selection at the larval stage but does not lead to a significant tolerance of adults. As in other insects, P450-mediated insecticide metabolism appears to play a major role in imidacloprid tolerance in mosquitoes. 23200732 Lessons from the dissection of the activation functions (AF-1 and AF-2) of the estrogen receptor alpha in vivo. Estrogens influence most of the physiological processes in mammals, including but not limited to reproduction, cognition, behavior, vascular system, metabolism and bone integrity. Given this widespread role for estrogen in human physiology, it is not surprising that estrogen influence the pathophysiology of numerous diseases, including cancer (of the reproductive tract as breast, endometrial but also colorectal, prostate,…), as well as neurodegenerative, inflammatory-immune, cardiovascular and metabolic diseases, and osteoporosis. These actions are mediated by the activation of estrogen receptors (ER) alpha (ERα) and beta (ERβ), which regulate target gene transcription (genomic action) through two independent activation functions (AF)-1 and AF-2, but can also elicit rapid membrane initiated steroid signals (MISS). Targeted ER gene inactivation has shown that although ERβ plays an important role in the central nervous system and in the heart, ERα appears to play a prominent role in most of the other tissues. Pharmacological activation or inhibition of ERα and/or ERβ provides already the basis for many therapeutic interventions, from hormone replacement at menopause to prevention of the recurrence of breast cancer. However, the use of these estrogens or selective estrogen receptors modulators (SERMs) have also induced undesired effects. Thus, an important challenge consists now to uncouple the beneficial actions from other deleterious ones. The in vivo molecular "dissection" of ERα represents both a molecular and integrated approach that already allowed to delineate in mouse the role of the main "subfunctions" of the receptor and that could pave the way to an optimization of the ER modulation. 23542816 In utero phthalate effects in the female rat: A model for MRKH syndrome. Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is characterized by uterine and vaginal canal aplasia in normal karyotype human females and is a syndrome with poorly defined etiology. Reproductive toxicity of phthalate esters (PEs) occurs in rat offspring exposed in utero, a phenomenon that is better studied in male offspring than females. The current study reports female reproductive tract malformations in the Sprague-Dawley rat similar to those characteristic of MRKH syndrome, following in utero exposure to a mixture of 5 PEs. We determined that females are ~2-fold less sensitive to the effects of the 5-PE mixture than males for reproductive tract malformations. We were not fully successful in defining the critical exposure period for females; however, incidence of malformations was 88% following dosing from GD8 to 19 versus 22% and 0% for GD8-13 and GD14-19, respectively. Overall, this study provides valuable information regarding female vulnerability to in utero phthalate exposure and further characterizes a potential model for the human MRKH syndrome. 23580001 The efficacy of metformin in pregnant women with polycystic ovary syndrome: a meta-analysis of clinical trials. Objectives: The role of metformin in the treatment of pregnant women with polycystic ovary syndrome is controversial. Therefore, we evaluated whether the use of metformin during pregnancy in women with polycystic ovary syndrome could reduce pregnancy-related complications. Research design and methods: MEDLINE was searched to retrieve relevant trials. In addition, reviews and reference lists of the retrieved articles were scanned for further appropriate studies. The primary outcome measure was the incidence of complications of pregnancy, which included early pregnancy loss, gestational diabetes, preeclampsia and preterm delivery. Results: In total, eight studies with 1106 patients were included. The pooled ORs (95% CIs) of outcome for pregnant women with polycystic ovary syndrome prescribed metformin were 0.32 (0.19-0.55) for early pregnancy loss, 0.37 (0.25-0.56) for gestational diabetes, 0.53 (0.30-0.95) for preeclampsia and 0.30 (0.13-0.68) for preterm delivery. Conclusions: Metformin therapy throughout pregnancy decreased the ORs of early pregnancy loss, gestational diabetes, preeclampsia and preterm delivery in pregnant PCOS women with no serious detrimental sideeffects. 23307549 Ruxolitinib: a new treatment option for myelofibrosis. Myelofibrosis is a myeloproliferative neoplasm characterized by bone marrow fibrosis and extramedullary hematopoiesis. Evolution of myelofibrosis can lead to life-threatening complications, including transformation to leukemia, thrombotic events, and hemorrhagic episodes. The only curative therapy for myelofibrosis is allogeneic hematopoietic stem cell transplantation. Because this disease manifests primarily in the older population, many patients diagnosed with myelofibrosis are not considered medically fit for such aggressive therapy. Other available medical therapies do not halt disease progression; instead, current treatment strategies have focused on targeting specific symptomology, although with limited efficacy. The lack of effective treatment options for patients with myelofibrosis has rendered this orphan disease state an unmet medical need, and novel approaches to improve outcomes are necessary. Emerging research has identified numerous molecular mutations in patients with myelofibrosis, making this disease a potential candidate for molecularly targeted therapy. The most prevalent mutation identified is a gain-of-function mutation in the Janus kinase (JAK) family, JAK2 V617F, which has been identified in more than half of patients with myelofibrosis. This mutation results in a constitutively active JAK-signal transducer and activator of transcription pathway resulting in dysregulated cellular proliferation and hematopoiesis. Ruxolitinib is a small-molecule inhibitor of JAK1 and JAK2 and recently became the first drug approved by the United States Food and Drug Administration for the treatment of symptomatic intermediate- or high-risk myelofibrosis. In clinical trials, ruxolitinib demonstrated promising efficacy in reducing splenomegaly and myelofibrosis-related symptoms. However, ruxolitinib did not demonstrate disease-modifying potential and is not considered a curative therapeutic option. Adverse events associated with ruxolitinib are primarily hematologic, with thrombocytopenia and anemia being the most common toxicologic events identified. Future research will shed light on whether ruxolitinib in combination with other treatments will further enhance outcomes in myelofibrosis. 23544461 Transition metal-catalyzed efficient and green transformations of p(o)-h compounds to functional organophosphorus compounds. Organophosphorus compounds are of high importance in organic synthesis, catalysis, biochemistry, pharmaceuticals, and material science. In this mini review, we summarize our recent studies on transition metal-catalyzed green and atom efficient transformations of P(O)-H bonds to various versatile organophosphorus compounds, including the highly regio- and stereoselective P(O)-H additions to carbon-carbon unsaturated compounds, asymmetric hydrophosphorylation reactions, and dehydrogenative coupling reactions of P(O)-H compounds with carbon-H and heteroatom-H compounds. These new reactions provide efficient, general and practical ways for the preparation of a variety of well-defined functional organophosphorus compounds. Mechanistic aspects related to the catalytic processes are also discussed. 23265534 Optimization of ABTS radical cation assay specifically for determination of antioxidant capacity of intracellular extracts of microalgae and cyanobacteria. A renewed interest in antioxidants has arisen in recent years; microalgae and cyanobacteria are potential sources thereof for use as food/feed ingredients. However, improved methods for comprehensive screening of antioxidant capacity specifically in intracellular extracts of marine microorganisms are required - encompassing lipophilic and hydrophilic compounds simultaneously. The original ABTS method was thus improved, and in particular the procedures of cell disruption and storage were optimized. The best solvent found was ethanol/water (1:1, v/v). The reaction to form ABTS(+) in said solvent was essentially complete by eight hours, and this radical cation was stable for at least 6 days; at room temperature, the ABTS(+) solution remained within an allowable analytical range for up to 13 h. Ultra Turrax was the best cell disruption method, and refrigeration was the best preservation method. This improved methodology was validated with four representative strains that respond poorly to cell disruption. 23532258 Effects of immunosuppression on alpha and beta cell renewal in transplanted mouse islets. AIMS/HYPOTHESIS: Immunosuppressive drugs used in human islet transplantation interfere with the balance between beta cell renewal and death, and thus may contribute to progressive graft dysfunction. We analysed the influence of immunosuppressants on the proliferation of transplanted alpha and beta cells after syngeneic islet transplantation in streptozotocin-induced diabetic mice. METHODS: C57BL/6 diabetic mice were transplanted with syngeneic islets in the liver and simultaneously abdominally implanted with a mini-osmotic pump delivering BrdU alone or together with an immunosuppressant (tacrolimus, sirolimus, everolimus or mycophenolate mofetil [MMF]). Glycaemic control was assessed for 4 weeks. The area and proliferation of transplanted alpha and beta cells were subsequently quantified. RESULTS: After 4 weeks, glycaemia was significantly higher in treated mice than in controls. Insulinaemia was significantly lower in mice treated with everolimus, tacrolimus and sirolimus. MMF was the only immunosuppressant that did not significantly reduce beta cell area or proliferation, albeit its levels were in a lower range than those used in clinical settings. CONCLUSIONS/INTERPRETATION: After transplantation in diabetic mice, syngeneic beta cells have a strong capacity for self-renewal. In contrast to other immunosuppressants, MMF neither impaired beta cell proliferation nor adversely affected the fractional beta cell area. Although human beta cells are less prone to proliferate compared with rodent beta cells, the use of MMF may improve the long-term outcome of islet transplantation. 23377618 3D Organotypic Cultures of Human HepaRG Cells: A Tool for In Vitro Toxicity Studies. Drug-induced human hepatotoxicity is difficult to predict using the current in vitro systems. In this study, long-term 3D organotypic cultures of the human hepatoma HepaRG cell line were prepared using a high-throughput hanging drop method. The organotypic cultures were maintained for 3 weeks and assessed for (1) liver specific functions, including phase I enzyme and transporter activities, (2) expression of liver-specific proteins, and (3) responses to three drugs (acetaminophen, troglitazone, and rosiglitazone). Our results show that the organotypic cultures maintain high liver-specific functionality during 3 weeks of culture. The immunohistochemistry analyses illustrate that the organotypic cultures express liver-specific markers such as albumin, CYP3A4, CYP2E1, and MRP-2 throughout the cultivation period. Accordingly, the production rates of albumin and glucose, as well as CYP2E1 activity, were significantly higher in the 3D versus the 2D cultures. Toxicity studies show that the organotypic cultures are more sensitive to acetaminophen- and rosiglitazone-induced toxicity but less sensitive to troglitazone-induced toxicity than the 2D cultures. Furthermore, the EC50 value (2.7mM) for acetaminophen on the 3D cultures was similar to in vivo toxicity. In summary, the results from our study suggest that the 3D organotypic HepaRG culture is a promising in vitro tool for more accurate assessment of acute and also possibly for chronic drug-induced hepatotoxicity. 23333640 The inhibition of HIF-2α on the ATM/Chk-2 pathway is involved in the promotion effect of arsenite on benzo(a)pyrene-induced cell transformation. Both arsenite and benzo(a)pyrene (BaP) are known human carcinogens. Studies on the mode-of-action of arsenite indicate that it can also act as co-carcinogen or as a cancer promoter, and that it can facilitate progression of cancers. Some studies on development of lung cancers have suggested a synergism between arsenite exposure and cigarette smoking. The mechanism of action for such an effect, however, remains obscure. In the present study, we investigated the effects of HIF-2α on arsenite- and BaP-induced cell malignant transformation as well as on signal transduction pathways in human bronchial epithelial (HBE) cells. The results show that arsenite accelerates the neoplastic transformation and migration of cells and enhances chromosomal aberrations induced by BaP. HIF-2α is involved in blocking the effects of arsenite in activating the ATM/Chk-2 pathway and in repair of DNA damage induced by BaP. Moreover, blocking of HIF-2α prevents the effects of arsenite on the neoplastic transformation, cell migration, and chromosomal aberrations caused by BaP. These results indicate that the repressive effect of HIF-2α on the ATM/Chk-2 pathway leads to genomic instability, which is involved in arsenite-accelerated, BaP-induced malignant transformation of HBE cells. 23388705 Transport of A1 adenosine receptor agonist tecadenoson by human and mouse nucleoside transporters: evidence for blood-brain barrier transport by murine equilibrative nucleoside transporter 1 mENT1. The high density of A1 adenosine receptors in the brain results in significant potential for central nervous system (CNS)-related adverse effects with A1 agonists. Tecadenoson is a selective A1 adenosine receptor agonist with close similarity to adenosine. We studied the binding and transmembrane transport of tecadenoson by recombinant human equilibrative nucleoside transporters (hENTs) hENT1 and hENT2, and human concentrative nucleoside transporters (hCNTs) hCNT1, hCNT2, and hCNT3 in vitro and by mouse mENT1 in vivo. Binding affinities of the five recombinant human nucleoside transporters for tecadenoson differed (hENT1 > hCNT1 > hCNT3 > hENT2 > hCNT2), and tecadenoson was transported largely by hENT1. Pretreatment of mice with a phosphorylated prodrug of nitrobenzylmercaptopurine riboside, an inhibitor of mENT1, significantly decreased brain exposure to tecadenoson compared with that of the untreated (control) group, suggesting involvement of mENT1 in transport of tecadenoson across the blood-brain barrier (BBB). In summary, ENT1 was shown to mediate the transport of tecadenoson in vitro with recombinant and native human protein and in vivo with mice. The micromolar apparent Km value of tecadenoson for transport by native hENT1 in cultured cells suggests that hENT1 will not be saturated at clinically relevant (i.e., nanomolar) concentrations of tecadenoson, and that hENT1-mediated passage across the BBB may contribute to the adverse CNS effects observed in clinical trials. In contrast, in cases in which a CNS effect is desired, the present results illustrate that synthetic A1 agonists that are transported by hENT1 could be used to target CNS disorders because of enhanced delivery to the brain. 23444274 The neonicotinoid imidacloprid shows high chronic toxicity to mayfly nymphs. The present study evaluated the acute and chronic toxicity of imidacloprid to a range of freshwater arthropods. Mayfly and caddisfly species were most sensitive to short-term imidacloprid exposures (10 tests), whereas the mayflies showed by far the most sensitive response to long-term exposure of all seven arthropod species tested (28-d EC10 values of approximately 0.03 µg/L). The results indicated a high aquatic risk of chronic exposure of imidacloprid to mayflies. Environ. Toxicol. Chem. 2013;32:1096-1100. © 2013 SETAC. 23511945 A copper hyperaccumulation phenotype correlates with pathogenesis in Cryptococcus neoformans. Cryptococcus neoformans is a major human pathogen and a cause of meningoencephalitis in immunocompromised patients. Many factors contribute to the extraordinary survivability and pathogenicity of this fungus in humans, including copper homeostasis pathways. Previous work has shown that deletion of the copper-dependent regulator Cuf1 results in decreased virulence and dissemination in brain infection, suggesting that copper acquisition is important to the persistence of this pathogen. Here, we show that the minimal copper quota of C. neoformans is maintained at a high level even when grown under conditions of stringent copper limitation. Intriguingly, when this fungal pathogen is grown in standard and copper-enriched media, it sequesters even higher levels of this essential metal, achieving levels that are far higher than non-pathogenic S. cerevisiae. The hypothesis that copper acquisition plays an essential role in virulence is further corroborated by the findings that a hypovirulent CUF1-deletant strain of C. neoformans retrieved from infected mice contains almost a 6-fold lower concentration of intracellular copper than the pathogenic wild-type strain. The concentration difference arises in part from larger-sized cuf1Δ cell. Under in vitro growth conditions, the size of the cuf1Δ cells is normal and the hypertrophy phenotype is readily induced in vitro under conditions of copper starvation. Taken together, these data suggest that acquisition of extraordinary levels of copper is an important factor in the survivability of the pathogen in the copper-deplete environment of infection, and effective copper concentration may play an important role in the pathogenesis of C. neoformans. 23389862 Phosphodiesterase 4 inhibitors augment the ability of formoterol to enhance glucocorticoid-dependent gene transcription in human airway epithelial cells: a novel mechanism for the clinical efficacy of roflumilast in severe chronic obstructive pulmonary disease. Post-hoc analysis of two phase III clinical studies found that the phosphodiesterase 4 (PDE4) inhibitor, roflumilast, reduced exacerbation frequency in patients with severe chronic obstructive pulmonary disease (COPD) who were taking inhaled corticosteroids (ICS) concomitantly, whereas patients not taking ICS derived no such benefit. In contrast, in two different trials also performed in patients with severe COPD, roflumilast reduced exacerbation rates in the absence of ICS, indicating that PDE4 inhibition alone is sufficient for therapeutic activity to be realized. Given that roflumilast is recommended as an "add-on" medication to patients with severe disease who will inevitably be taking a long-acting β2-adrenoceptor agonist (LABA)/ICS combination therapy, we tested the hypothesis that roflumilast augments the ability of glucocorticoids to induce genes with anti-inflammatory activity. Using a glucocorticoid response element (GRE) luciferase reporter transfected into human airway epithelial cells [both bronchial epithelium + adenovirus 12 - SV40 hybrid (BEAS-2B) cells and primary cultures], roflumilast enhanced fluticasone propionate-induced GRE-dependent transcription. Roflumilast also produced a sinistral displacement of the concentration-response curves that described the augmentation of GRE-dependent transcription by the LABA formoterol. In BEAS-2B cells and primary airway epithelia, roflumilast interacted with formoterol in a positive cooperative manner to enhance the expression of several glucocorticoid-inducible genes that have anti-inflammatory potential. We suggest that the ability of roflumilast and formoterol to interact in this way supports the concept that these drugs together may impart clinical benefit beyond that achievable by an ICS alone, a PDE4 inhibitor alone, or an ICS/LABA combination therapy. Roflumilast may, therefore, be especially effective in patients with severe COPD. 23421517 Reversal effect of rosmarinic acid on multidrug resistance in SGC7901/Adr cell. Multidrug resistance (MDR) has been a major problem in cancer chemotherapy. In this study, the aim was to explore the reversal effect and its potential mechanism of rosmarinic acid (RA) on SGC7901/Adr cells. 3-(4,5-Dimethylthiazol)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to investigate the reversal index of RA in SGC7901/Adr cell line. The intracellular accumulation of adriamycin, rhodamine123 (Rh123), and the expression of P-glycoprotein (P-gp) were assayed by flow cytometry. The influence of RA on the transcription of MDR1 gene was determined by reverse transcription-polymerase chain reaction. The results showed that RA could reverse the MDR of SGC7901/Adr cells, increase the intracellular accumulation of Adr and Rh123, and decrease the transcription of MDR1 gene and the expression of P-gp in SGC7901/Adr cells. These results indicated that RA was a potential multidrug resistance-reversing agent and warranted further investigations. 23146755 The mechanism of carvacrol-evoked [Ca2+]i rises and non-Ca2+-triggered cell death in OC2 human oral cancer cells. Carvacrol is one of the main substances of essential oil which triggers intracellular Ca(2+) mobilization and causes cytotoxicity in diverse cell models. However, the mechanism of carvacrol-induced Ca(2+) movement and cytotoxicity is not fully understood. This study examined the effect of carvacrol on cytosolic free Ca(2+) concentrations ([Ca(2+)](i)), cell viability and apoptosis in OC2 human oral cancer cells. Carvacrol induced a [Ca(2+)](i) rise and the signal was reduced by removal of extracellular Ca(2+). Carvacrol-induced Ca(2+) entry was not altered by store-operated Ca(2+) channel inhibitors and protein kinase C (PKC) activator, but was inhibited by a PKC inhibitor. In Ca(2+) -free medium, treatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin (TG) or 2,5-di-tert-butylhydroquinone (BHQ) inhibited carvacrol-induced [Ca(2+)](i) rise. Conversely, incubation with carvacrol inhibited TG or BHQ-induced [Ca(2+)](i) rise. Inhibition of phospholipase C (PLC) with U73122 abolished carvacrol-induced [Ca(2+)](i) rise. Carvacrol decreased cell viability, which was not reversed when cytosolic Ca(2+) was chelated with BAPTA-AM (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester). Carvacrol-induced apoptosis and activation of reactive oxygen species (ROS) and caspase-3. Together, carvacrol induced a [Ca(2+)](i) rise by inducing PLC-dependent Ca(2+) release from the endoplasmic reticulum and Ca(2+) entry via PKC-sensitive, non store-operated Ca(2+) channels. Carvacrol-induced ROS- and caspase-3-associated apoptosis. 23535327 Synthesis and structure-activity relationship of pyripyropene A derivatives as potent and selective acyl-CoA:cholesterol acyltransferase 2 (ACAT2) inhibitors: Part 2. Synthesis and structure-activity relationships of 7-O-p-cyanobenzoyl pyripyropene A derivatives with modification at C1 and 11 are described. Regioselective mono-deprotection of di-tert-butylsilylene acetal was critical in their synthesis. 23561106 A sensitive and selective imprinted solid phase extraction coupled to HPLC for simultaneous detection of trace quinoxaline-2-carboxylic acid and methyl-3-quinoxaline-2-carboxylic acid in animal muscles. A new molecularly imprinted polymer (MIP), selective for major metabolites of quinoxaline-1,4-dioxides, was prepared through bulk polymerisation using quinoxaline-2-carboxylic acid (QCA) as template, diethylaminoethylmethacrylate as functional monomer and ethylene glycol dimethacrylate as cross-linker in tetrahydrofuran. The synthesised MIP was characterised by Fourier transform infrared and adsorption experiments. MIP exhibited high affinity, fast kinetics for QCA and good selectivity for QCA and methyl-3-quinoxaline-2-carboxylic acid (MQCA). MIP obtained was used as a selective sorbent for molecularly imprinted solid phase extraction (MISPE) coupled with HPLC to detect QCA and MQCA. Under the optimal conditions, the limits of detection (S/N=3) of porcine, chicken and fish muscles were 0.1, 0.3, 0.1μg/kg for QCA and 0.2, 0.3, 0.1μg/kg for MQCA, respectively and good recoveries were obtained in the range from 60.0 to 119.4%. These results indicated the MISPE-HPLC procedure could be successfully used for the determination QCA and MQCA in animal muscles. 23531536 The Protective Effects of α-Lipoic Acid on Kidneys in Type 2 Diabetic Goto-Kakisaki Rats via Reducing Oxidative Stress. To evaluate the protective effects of α-lipoic acid on the kidneys of Goto-Kakisaki (GK) diabetic rats, ten GK diabetic rats were randomly divided into a diabetic control group and a lipoic acid-treated diabetic group with α-lipoic acid 35 mg·Kg-1 intraperitoneal injections. Four healthy Wistar rats served as normal controls. Malonaldehyde (MDA), ascorbic acid (vitamin C), vitamin E, glutathione (GSH) and superoxide dismutase (SOD) levels in renal homogenate, and urine protein excretion were measured. The expression of mRNA for NF-κB, NADPH oxidase subunits p22phox and p47phox in renal tissue was examined by realtime PCR. Pathological changes in renal tissue were evaluated by light and electron microscopy. There were significant increases in urine protein excretion, MDA levels and the expression of mRNA of NF-κB, p22phox and p47phox, and significant decreases in GSH, SOD, vitamin C and vitamin E levels in the diabetic control group compared with the normal control group. Pathological changes of renal tissue were more progressive in the diabetic control group than in the normal control group. All the parameters above were improved in the α-lipoic acid-treated diabetic group. Oxidative stress is increased in the kidney of type 2 diabetic GK rats. It is associated with the progression of diabetic nephropathy. α-lipoic acid can protect renal function in diabetic rats via its antioxidant activity. 23136071 Influence of global climate change on chemical fate and bioaccumulation: the role of multimedia models. Multimedia environmental fate models are valuable tools for investigating potential changes associated with global climate change, particularly because thermodynamic forcing on partitioning behavior as well as diffusive and nondiffusive exchange processes are implicitly considered. Similarly, food-web bioaccumulation models are capable of integrating the net effect of changes associated with factors such as temperature, growth rates, feeding preferences, and partitioning behavior on bioaccumulation potential. For the climate change scenarios considered in the present study, such tools indicate that alterations to exposure concentrations are typically within a factor of 2 of the baseline output. Based on an appreciation for the uncertainty in model parameters and baseline output, the authors recommend caution when interpreting or speculating on the relative importance of global climate change with respect to how changes caused by it will influence chemical fate and bioavailability. 23514229 Cognitive impairment and dietary habits among elders: the velestino study. Abstract To investigate the association of dietary habits with cognitive function among elders (>65 years). Complete sociodemographic, dietary information, serum measurements, and Mini-Mental State Examination (MMSE) assessments were available for 237 elderly men and 320 women residing in Velestino, Greece (a rural Greek town). All models were adjusted for age, education, social activity, smoking, depression symptomatology (using the Geriatric Depression Scale), MedDietScore (range 0-55), and metabolic syndrome. About 49.8% men and 66.6% women had MMSE scores <24, with a mean MMSE score of 22.7±4.43 and 21.1±4.73, respectively. Adherence to the Mediterranean diet was moderate (mean MedDietScore of 34.1±3.25 in men and 35.1±2.48 in women). Indicative cognitive impairment (MMSE score <24) was positively associated with age and low education in women and with depressive symptoms, low education status, and low social activity in men. Adherence to the Mediterranean diet was positively associated with MMSE score in men (P=.02), but inversely associated in women (P=.04). Concerning the food groups studied, intake of pulses, nuts, and seeds was associated with lower likelihood of having MMSE score<24 in men (P=.04). Only the Mediterranean dietary pattern showed a significant association with MMSE score positive for cognitive impairment (i.e., protective in men, but not in women), while individual food groups or nutrients did not achieve significance. The latter findings support the role of whole diet in the prevention of mental disorders, and state a research hypothesis for a sex-diet interaction on cognitive function among elders. 23022048 Inhibition of GABA synthesis in the prefrontal cortex increases locomotor activity but does not affect attention in the 5-choice serial reaction time task. Attention deficits are a core cognitive symptom of schizophrenia; the neuropathology underlying these deficits is not known. Attention is regulated, at least in part, by the prefrontal cortex (PFC), a brain area in which pathology of γ-aminobutyric acid (GABA) neurons has been consistently observed in post-mortem analysis of the brains of people with schizophrenia. Specifically, expression of the 67-kD isoform of the GABA synthesis enzyme glutamic acid decarboxylase (GAD67) is reduced in parvalbumin-containing fast-spiking GABA interneurons. Thus it is hypothesized that reduced cortical GABA synthesis and release may contribute to the attention deficits in schizophrenia. Here the effect of reducing cortical GABA synthesis with l-allylglycine (LAG) on attention was tested using three different versions of the 5-choice serial reaction time task (5CSRTT). Because 5CSRTT performance can be affected by locomotor activity, we also measured this behavior in an open field. Finally, the expression of Fos protein was used as an indirect measure of reduced GABA synthesis. Intra-cortical LAG (10 μg/0.5 μl/side) infusions increased Fos expression and resulted in hyperactivity in the open field. Intra-cortical LAG infusions did not affect attention in any version of the 5CSRTT. These results suggest that a general decrease in GABA synthesis is not sufficient to cause attention deficits. It remains to be tested whether a selective decrease in GABA synthesis in parvalbumin-containing GABA neurons could cause attention deficits. Decreased cortical GABA synthesis did increase locomotor activity; this may reflect the positive symptoms of schizophrenia. 23327103 Covalently functionalized double-walled carbon nanotubes combine high sensitivity and selectivity in the electrical detection of small molecules. Atom-thick materials such as single-walled carbon nanotubes (SWCNTs) and graphene exhibit ultrahigh sensitivity to chemical perturbation partly because all of the constituent atoms are surface atoms. However, low selectivity due to nonspecific binding on the graphitic surface is a challenging issue to many applications including chemical sensing. Here, we demonstrated simultaneous attainment of high sensitivity and selectivity in thin-film field effect transistors (TFTs) based on outer-wall selectively functionalized double-walled carbon nanotubes (DWCNTs). With carboxylic acid functionalized DWCNT TFTs, we obtained excellent gate modulation (on/off ratio as high as 4000) with relatively high ON currents at a CNT areal density as low as 35 ng/cm(2). The devices displayed an NH(3) sensitivity of 60 nM (or ~1 ppb), which is comparable to small molecule aqueous solution detection using state-of-the-art SWCNT TFT sensors while concomitantly achieving 6000 times higher chemical selectivity toward a variety of amine-containing analyte molecules over that of other small molecules. These results highlight the potential of using covalently functionalized double-walled carbon nanotubes for simultaneous ultrahigh selective and sensitive detection of chemicals and illustrate some of the structural advantages of this double-wall materials strategy to nanoelectronics. 22935610 The prolyl-isomerase Pin1 activates the mitochondrial death program of p53. In response to intense stress, the tumor protein p53 (p53) tumor suppressor rapidly mounts a direct mitochondrial death program that precedes transcription-mediated apoptosis. By eliminating severely damaged cells, this pathway contributes to tumor suppression as well as to cancer cell killing induced by both genotoxic drugs and non-genotoxic p53-reactivating molecules. Here we have explored the role had in this pathway by the prolyl-isomerase Pin1 (peptidylprolyl cis/trans isomerase, NIMA-interacting 1), a crucial transducer of p53's phosphorylation into conformational changes unleashing its pro-apoptotic activity. We show that Pin1 promotes stress-induced localization of p53 to mitochondria both in vitro and in vivo. In particular, we demonstrate that upon stress-induced phosphorylation of p53 on Ser46 by homeodomain interacting protein kinase 2, Pin1 stimulates its mitochondrial trafficking signal, that is, monoubiquitination. This pathway is induced also by the p53-activating molecule RITA, and we demonstrate the strong requirement of Pin1 for the induction of mitochondrial apoptosis by this compound. These findings have significant implications for treatment of p53-expressing tumors and for prospective use of p53-activating compounds in clinics. 23580569 The absence of ERβ results in altered gene expression in ovarian granulosa cells isolated from in vivo preovulatory follicles. Determining the spatial and temporal expression of genes involved in the ovulatory pathway is critical for the understanding of the role of each estrogen receptor in the modulation of folliculogenesis and ovulation. Estrogen receptor (ER) β is highly expressed in ovarian granulosa cells and mice lacking ERβ (βERKO) are subfertile due to inefficient ovulation. Previous work has focused on isolated granulosa cells or cultured follicles and while informative, provides confounding results due to the heterogeneous cell types present including granulosa, theca and oocytes and exposure to in vitro conditions. Herein, we isolated preovulatory granulosa cells from WT and ERβ-null mice using laser capture microdissection to examine the genomic transcriptional response downstream of PMSG (mimicking FSH) and PMSG/hCG (mimicking LH) stimulation. This allows for a direct comparison of in vivo granulosa cells at the same stage of development from both WT and ERβ-null ovaries. ERβ-null granulosa cells showed altered expression of genes known to be regulated by FSH (Akap12 and Runx2) as well as not previously reported (Arnt2 and Pou5f1) in WT granulosa cells. Our analysis also identified 304 genes not previously associated with ERβ in granulosa cells. LH responsive genes including Abcb1b and Fam110c show reduced expression in ERβ-null granulosa cells; however novel genes including Rassf2 and Megf10 were also identified as being downstream of LH signaling in granulosa cells. Collectively, our data suggests that granulosa cells from ERβ-null ovaries may not be appropriately differentiated and are unable to respond properly to gonadotropin stimulation. 23296104 Comparison of tolerance to morphine-induced respiratory and analgesic effects in mice. Morphine is responsible for severe poisonings in chronically treated patients. We hypothesize that toxicity could be related to the development of weaker tolerance for morphine-induced deleterious respiratory effects in comparison to analgesic effects. Our objectives were to compare tolerance to both effects in mice and investigate possible mechanisms for such possible differences. Tolerance to morphine-induced analgesia and respiratory effects was assessed using hot plate response latencies and plethysmography, respectively. Mechanisms of tolerance were investigated using binding studies to mu-opioid receptors (MOR) and adenylate cyclase (AC) activity measurement in homogenates of cell membranes from the periaqueductal gray region (PAG) and brainstem. Morphine (2.5 mg/kg) was responsible for analgesia with significant increase in inspiratory time. Acute tolerance to analgesia (p<0.01) and effects on respiratory frequency (p<0.05) was observed in mice pre-treated with 100 mg/kg morphine in comparison to saline. Following repetitive administration (2.5 mg/kg/day during 10 days), we observed a 13-fold increase in the effective dose-50% (ED₅₀) of morphine-induced analgesia in comparison to a 2- or 4-fold increase in the ED₅₀ of its related increase in inspiratory time determined in air and 4% CO₂, respectively. No significant alteration in MOR expression was observed in either PAG or brainstem following repeated morphine administration. However, in PAG, in contrast to brainstem, superactivation of AC was observed in morphine-treated mice in comparison to controls (p<0.05). In conclusion, tolerance to morphine-induced respiratory effects is much more limited than tolerance to its analgesic effects in repeatedly morphine-treated mice. The difference in morphine-induced AC activation between the brainstem and the PAG contributes to the observed difference in tolerance between both morphine effects. 23625792 Exciton Dynamics in Semiconductor Nanocrystals. This review article provides an overview of recent advances in the study and understanding of dynamics of excitons in semiconductor nanocrystals (NCs) or quantum dots (QDs). Emphasis is placed on the relationship between exciton dynamics and optical properties, both linear and nonlinear. We also focus on the unique aspects of exciton dynamics in semiconductor NCs as compared to those in bulk crystals. Various experimental techniques for probing exciton dynamics, particularly time-resolved laser methods, are reviewed. Relevant models and computational studies are also briefly presented. By comparing different materials systems, a unifying picture is proposed to account for the major dynamic features of excitons in semiconductor QDs. While the specific dynamic processes involved are material-dependent, key processes can be identified for all the materials that include electronic dephasing, intraband relaxation, trapping, and interband recombination of free and trapped charge carriers (electron and hole). Exciton dynamics play a critical role in the fundamental properties and functionalities of nanomaterials of interest for a variety of applications including optical detectors, solar energy conversion, lasers, and sensors. A better understanding of exciton dynamics in nanomaterials is thus important both fundamentally and technologically. 23608189 Statins Protect Human Endothelial Cells from TNF-induced Inflammation via ERK5 Activation. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) exert pleiotropic effects on the cardiovascular system, in part through a decrease in reactive oxygen species (ROS) formation and reduction of vascular inflammation. To elucidate the molecular mechanisms involved in these effects, we investigated the effect of statins on TNF-α-induced ROS production, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression in human aortic endothelial cells (HAECs). Exposure of HAECs to TNF-α caused production of ROS via Rac-1 membrane translocation and activation. The Rac-1 activation and ROS liberation mediated TNF-stimulated NF-κB activation and the subsequent VCAM-1 and ICAM-1 expression. Extracellular-signal-regulated kinase 5 (ERK5) plays a central role in inhibiting endothelial inflammation. Immune complex kinase assay of protein extracts from HAECs treated with atorvastatin revealed increased ERK5 activity in a time- and dose-dependent manner. In addition, pretreatment with atorvastatin inhibited TNF-α-induced ROS production and VCAM-1 and ICAM-1 expression. Chemical or genetic inhibition of ERK5 ablated the statins inhibition of Rac-1 activation, ROS formation, NF-κB, VCAM-1 and ICAM-1 expression induced by TNF-α. Taken together, statins, via ERK5 activation, suppress TNF-stimulated Rac-1 activation, ROS generation, NF-κB activation and VCAM-1 and ICAM-1 expression in human ECs, which provides a novel explanation for the pleiotropic effects of statins that benefit the cardiovascular system. 23354536 Effects of repeated exposure to MDMA on 5HT1a autoreceptor function: behavioral and neurochemical responses to 8-OHDPAT. A consistent effect of repeated exposure to 3,4 methylenedioxymethamphetamine (MDMA) is a decrease in the tissue levels of serotonin (5-HT). A variety of behavioural and neurochemical tests were conducted to determine whether the tissue deficits were accompanied by an increased sensitivity of the 5-HT1a autoreceptor. Tests were conducted 2 weeks following MDMA exposure (four injections of 10.0 mg/kg, IP, administered at 2-h intervals in a single day). The response to the 5-HT1a agonist, 8-OHDPAT (0.003-0.5 mg/kg, SC), was assessed using lower lip retraction (LLR), hypoactivity, and 5-hydroxytryptophan (5-HTP) accumulation following decarboxylase inhibition. The 8-OHDPAT produced a dose-dependent increase in LLR and hypoactivity, but these effects were comparable for MDMA and saline pretreated groups. MDMA decreased tissue levels of 5-HT and the accumulation of 5-HTP, but these effects were not reflected in the changes in autoreceptor sensitivity. The data suggest that the decrease in tissue levels of 5-HT produced by MDMA is accompanied by a decrease in tryptophan hydroxylase activity but cannot be explained by supersensitivity of the 5-HT1a autoreceptor. 23386779 Hepatic effects of ketamine administration for 2 weeks in rats. The aim of the present study was to investigate the long-term and high-dose application of ketamine on the liver by employing histologic and biochemical methods. A total of 30 male rats were randomly assigned to control and four treatment groups (n: 6). Saline for control group and different doses of ketamine for four treatment groups (40, 60, 80 and 100 mg kg(-1)) were administered intraperitoneal twice a day for 2 weeks. Immunohistological staining, light and electron microscopy were used to study tissue specimens. Histopathological changes were more severe and diverse in groups 80 and 100 mg kg(-1) day(-1), and the least significant change was observed in groups 40 and 60 mg kg(-1) day(-1). The most important ultrastructural changes were seen in mitochondria and in the rough endoplasmic reticulum. The immunoreactivity of calcineurin was determined as different. Prolonged use of ketamine caused hepatocellualar toxicity and histological changes in hepatocytes in a dose-dependent manner in all experimental groups. 23391212 ADME characterization in rats revealed immediate secretion of AZD7903 into the stomach after IV dosing. Abstract 1. The distribution of AZD7903 and/or its metabolites was studied in rats following a single p.o. or i.v. dose using quantitative whole-body autoradiography (QWBA). At 5 min after i.v. administration of the (14)C compound, high levels of radioactivity were observed in the fundus of the stomach compared to blood and plasma and the rest of the stomach, indicating an active secretion of (14)C material into the stomach. 2. Also, excretion and pharmacokinetics were studied following p.o. and i.v. dosage in rats. The radioactivity was mainly excreted via feces, and even in i.v. administered bile-duct cannulated (BDC) animals a significant part of radioactivity (26% in males and 57% in females) was recovered in the feces in the form of parent compound and two minor metabolic products. 3. The compound was well absorbed (F% 98 in males and 76 in females), and showed low clearance in plasma (0.14 L/h/kg in males and 0.03 L/h/kg in females) and low-intermediate Vd(ss) (0.7 L/kg). Clear differences in metabolic pathways (qualitative) and rates (quantitative) and consequently in PK parameters between sexes were observed. 4. In summary, the results indicate AZD7903 being substrate for a transporter protein and support the hypothesis that the differences in disposition between sexes are due to differences in metabolic pathways and rates. 23527574 Path-Branching Representation for Nonadiabatic Electron Dynamics in Conical Intersection. Path-branching representation (or phase-space averaging and natural branching method (PSANB) as its approximation) of nonadiabatic electron wavepacket dynamics is now known to work well for avoided crossings in many dimensional nonadiabatic transitions [ Yonehara , T. ; Hanasaki , K. ; Takatsuka , K. Chem. Rev. 2012 , 112 , 499 ]. In this paper we examine feasibility of the path-branching representation in the theoretical studies of conical intersection (CI). The most characteristic feature of CI is the Herzberg-Longuet-Higgins phase (or the Berry phase) arising from the electronic part of the total wave function, and accordingly quantum phases of both electronic and nuclear dynamics should be taken into account in a balanced manner. We first show the PSANB can well capture the essential feature of the phase dynamics of CI. However, the nuclear phases, the wavelength of which is far shorter than that of the electronic phases, make the computation of nonadiabatic transition extremely oscillatory, resulting in very slow convergence with respect to the number of sampling paths. A similar difficulty quite often takes place in theoretical chemical dynamics. To cope with this situation, we devise a simple and tractable approximation in the application of PSANB resting on the fact that a small number of PSANB paths already reproduce accurate nonadiabatic transition probability. 23561097 Transport across Caco-2 monolayers of peptides arising from in vitro digestion of bovine milk proteins. The entire panel of peptides produced from caseins (CN) and whey proteins (WP) that survive in vitro sequential gastro-pancreatic digestion and translocate across monolayers of Caco-2 cells, used as a model of the intestinal epithelium, has been characterised by HPLC and mass spectrometry. Among the milk-derived bioactive peptides, only minor amounts of mono-phosphorylated peptides arising from αs1- and β-CN were detected. The absorption behaviour of two resistant β-lactoglobulin (β-Lg) domains, β-Lg 125-135 and β-Lg 40-60, was studied in detail using synthetic peptides. The IgE-binding properties of the digests recovered from the apical and basolateral monolayer compartments were evaluated by dot-blot, using the sera of milk allergic children (N=5). Outcomes indicated β-Lg 127-135 as a possible "immune sensitising factor"in vivo. The almost complete loss of the IgE-affinity of CN and WP after digestion points out the need to design in vivo experiments to track the metabolic fate of dietary proteins. 23136062 How is (68)Ga labeling of macrocyclic chelators influenced by metal ion contaminants in (68)Ge/(68)Ga generator eluates? To assess the influence of Zn(2+) , Cu(2+) , Fe(3+) , Al(3+) , Ti(IV) , and Sn(IV) on incorporation of (68) Ga(3+) into pendant-arm macrocyclic chelators, the (68) Ga labeling of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid]) (TRAP), and 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] (NOPO), as well as their peptide conjugates, was investigated in the presence of varying concentrations of these metal ions. The (68) Ga labeling yield for carboxylate-type chelators NOTA and DOTA is decreased at lower metal ion contaminant concentrations compared with phosphinate-type chelators TRAP and NOPO. The latter are able to rapidly exchange coordinated Zn(II) with (68) Ga(3+) , as confirmed by mass spectrometry and (31) P NMR spectroscopy. (68) Ga labeling of Zn(II) complexes of TRAP and NOPO proceeds as efficient as labeling of neat NOTA; this applies also to the corresponding peptide conjugates of these chelators. This behavior results in substantially improved selectivity for Ga(3+) and, therefore, in more robust and reliable (68) Ga labeling procedures. In addition, none of the investigated chelators binds (68) Ge, rendering post-labeling purification protocols, for example, solid-phase extraction, a reliable means of removal of (68) Ge contamination from (68) Ga radiopharmaceuticals. 23475289 Isoflavone supplementation influenced levels of triglyceride and luteunizing hormone in Korean postmenopausal women. We conducted a double-blind, randomized, placebo-controlled trial to evaluate the effects of soy-derived isoflavone on blood glucose, lipid profiles, and sex hormones related to cardiovascular disease in Korean postmenopausal women. One hundred thirteen postmenopausal women were recruited from the Seoul metropolitan area. To confirm postmenopausal and gynecologic status, the subjects were clinically examined by a gynecologist using ultra sound and X-ray. Finally, 85 postmenopausal women whose follicle-stimulating hormone (FSH) levels were higher than 40 IU/ml were enrolled. Subjects received either 70 mg isoflavone or placebo capsules daily for 12 weeks. As a result, the values of fasting glucose, insulin and HOMA-IR, as well as those of TC, LDL-C, HDL-C and FFA, were not different between the groups after supplementation. However, triglyceride (TG) levels in the treatment group decreased significantly compared with those of the placebo group (p = 0.0215). The levels of luteinizing hormone (LH) significantly decreased in the treatment group (p = 0.027); however, the levels of FSH, estrone and estradiol were not changed after intervention. In conclusion, isoflavone supplement of 70 mg/day for 12 weeks decreased blood levels of TG and LH in Korean postmenopausal women. 23634668 Pyridinylquinazolines Selectively Inhibit Human Methionine Aminopeptidase-1 in Cells. Methionine aminopeptidases (MetAPs), which remove the initiator methionine from nascent peptides, are essential in all organisms. While MetAP2 has been demonstrated to be a therapeutic target for inhibiting angiogenesis in mammals, MetAP1 seems to be vital for cell proliferation. Our earlier efforts identified two structural classes of human MetAP1 (HsMetAP1)-selective inhibitors (1-4), but all of them failed to inhibit cellular HsMetAP1. Using Mn(II) or Zn(II) to activate HsMetAP1, we found that 1-4 could only effectively inhibit purified HsMetAP1 in the presence of physiologically unachievable concentrations of Co(II). In an effort to seek Co(II)-independent inhibitors, a novel structural class containing a 2-(pyridin-2-yl)quinazoline core has been discovered. Many compounds in this class potently and selectively inhibited HsMetAP1 without Co(II). Subsequently, we demonstrated that 11j, an auxiliary metal-dependent inhibitor, effectively inhibited HsMetAP1 in primary cells. This is the first report that an HsMetAP1-selective inhibitor is effective against its target in cells. 23512126 Effect of voltage polarity and amplitude on electroforming of TiO2 based memristive devices. Pt/TiO2/Pt/Ti memristive devices were electrically formed to either the ON or OFF state using voltages of the same polarity but with different amplitudes. The forming step dictated the subsequent switching behaviour. A qualitative model based on the creation and migration of oxygen vacancies was proposed to explain the experimental results. 23497888 Roasting-induced changes in arabinotriose, a model of coffee arabinogalactan side chains. Thermal processing can promote reactions that change the structure of food constituents, often by unknown mechanisms, such as those occurring in arabinose residues of coffee arabinogalactan side chains. Aiming to know more about these modifications, the structurally related α-(1→5)-l-arabinotriose was roasted at 200°C and the products obtained were identified by ESI-MS and MALDI-MS and characterised by ESI-MS(n). Depolymerised and polymerised oligosaccharides with up to 16 residues and new types of linkages were formed. Also, products resulting from dehydration, oxidation, and cleavage of a carbon-carbon bond at the reducing end of the corresponding non-modified oligosaccharide were formed, probably promoting the release of formaldehyde, formic acid, glycolaldehyde, glyoxal, acetic acid, glycolic acid, glyceraldehyde, 2-hydroxypropanedialdehyde and lactic acid. As many of these compounds have been reported to occur in roasted coffee beans and/or brews, it can be suggested that the degradation of coffee arabinogalactan side chains can contribute to their formation upon roasting. 23411253 Relationships between the evolution of the percentage in weight of polar compounds and that of the molar percentage of acyl groups of edible oils submitted to frying temperature. The evolution of the molar percentage of several kinds of acyl groups of extra virgin olive, sunflower and virgin linseed oils was monitored throughout heating at frying temperature by means of (1)H nuclear magnetic resonance. Likewise, the evolution of the percentage in weight of the polar compounds of the same oils under the same heating conditions was also determined. Relationships between both sets of parameters, in each oil and in the oils as a group, were studied. An equation which is able to accurately predict the percentage in weight of the polar compounds, throughout the heating at frying temperature, of any one of these three oils, from the molar percentage of triunsaturated, diunsaturated and monounsaturated acyl groups, was obtained. In this way both molar percentage of acyl groups and percentage in weight of polar compounds can be obtained in a few minutes that registration of the (1)H NMR spectrum of the oil takes, in addition to the rest of information provided by this technique. The study reveals the close relationships between percentage in weight of polar compounds and the composition expressed in terms of molar percentages of acyl groups in edible oils heated at frying temperature. 23475370 Effects of Strontium on Collagen Content and Expression of Related Genes in Rat Chondrocytes Cultured In Vitro. Strontium stimulates cartilage matrix formation in vitro. However, the mechanisms governing these effects have not yet been extensively reported. In this study, chondrocytes were isolated from rat articular cartilage by enzymatic digestion and cultured for 24-72 h with 1-5 mM strontium. We investigated the effects of different concentrations of strontium on collagen content, type II collagen, insulin-like growth factor (IGF-1) and matrix metalloproteinase (MMP)-13 expression in rat cultured articular chondrocytes in vitro. The collagen content of the chondrocytes, determined as hydroxyproline, was measured by a colorimetry method. Type II collagen, IGF-1, and MMP-13 mRNA abundance and protein expression levels were determined by real-time polymerase chain reaction (real-time PCR) and western blot, respectively. The results showed that collagen content from the chondrocytes extracellular matrix increased with increasing strontium concentration. Moreover, 3 and 5 mM strontium strongly stimulated protein expression and mRNA levels of type II collagen and IGF-1. Conversely, MMP-13 expression in chondrocytes decreased dose-dependently with increasing strontium concentration. These results should provide insight into the ability of strontium to promote chondrocyte extracellular matrix synthesis. Strontium could promote collagen synthesis and suppress collagen degradation via the repression of MMP-13 expression. 23594210 Matrix Isolation Spectroscopy and Nuclear Spin Conversion of NH3 and ND3 in Solid Parahydrogen. We present matrix isolation infrared absorption spectra of NH3 and ND3 trapped in solid parahydrogen (pH2) at temperatures around 1.8 K. We used the relatively slow nuclear spin conversion (NSC) of NH3 and ND3 in freshly deposited pH2 samples as a tool to assign the sparse vibration-inversion-rotation (VIR) spectra of NH3 in the regions of the ν2, ν4, 2ν4, ν1, and ν3 bands and ND3 in the regions of the ν2, ν4, ν1, and ν3 fundamentals. Partial assignments are also presented for various combination bands of NH3. Detailed analysis of the ν2 bands of NH3 and ND3 indicates that both isotopomers are nearly free rotors; that the vibrational energy is blue-shifted by 1-2%; and that the rotational constants and inversion tunneling splitting are 91-94% and 67-75%, respectively, of the gas-phase values. The line shapes of the VIR absorptions are narrow (0.2-0.4 cm(-1)) for upper states that cannot rotationally relax and broad (>1 cm(-1)) for upper states that can rotationally relax. We report and assign a number of NH3-induced infrared absorption features of the pH2 host near 4150 cm(-1), along with a cooperative transition that involves simultaneous vibrational excitation of a pH2 molecule and rotation-inversion excitation of NH3. The NSCs of NH3 and ND3 were found to follow first-order kinetics with rate constants at 1.8 K of k = 1.88(16) × 10(-3) s(-1) and k = 1.08(8) × 10(-3) s(-1), respectively. These measured rate constants are compared to previous measurements for NH3 in an Ar matrix and with the rate constants measured for other dopant molecules isolated in solid pH2. 23530926 In Vivo Degradation and Elimination of Injectable Ricinoleic Acid-Based Poly(ester-anhydride). The in vivo degradation and elimination after subcutaneous implantation of injectable p(SA-RA) 3:7 copolymer in rats, followed by characterization of the polymer matrix composition during hydrolysis and erosion, is reported. Major chemical changes were observed during the first few days post implantation, the anhydride bonds hydrolyzed along with about 45% weight loss and a significant decrease in the molecular weight. (1)H NMR spectral analysis was used to determine the structures and content of ricinoleic acid containing oligomeric chains present in the degraded polymer. The polymer degrades into ester oligomers of 2-4 ricinoleic acid units which further degrade to ricinoleic acid, a natural fatty acid. The polymer hydrolytic degradation process fit the in vitro degradation process. 23512499 Cardamonin Ameliorates Insulin Resistance Induced by High Insulin and High Glucose through the mTOR and Signal Pathway. The mammalian target of rapamycin is crucial in the regulation of cell growth and metabolism. Recent studies suggest that the mammalian target of rapamycin and its downstream 70-kDa ribosomal S6 kinase 1 negatively modulate the insulin-signaling pathway, which is considered the main cause of insulin resistance. The aim of this study is to investigate the effects of cardamonin, a potential inhibitor of the mammalian target of the rapamycin, on insulin-resistant vascular smooth muscle cells and the molecular mechanisms involved. Vascular smooth muscle cells were cultured with high glucose and high insulin to induce insulin resistance. The mammalian target of rapamycin was overstimulated in cells that were incubated with high glucose and high insulin, as reflected by the excessive activation of S6 kinase 1. Insulin-resistant vascular smooth muscle cells displayed hyperphosphorylation of insulin receptor substrate-1 at Ser residues 636/639, which decreased the activity of insulin receptor substrate-1. Also, the activation of protein kinase B and phosphorylation of glycogen synthesis kinase-3β were inhibited. Cardamonin increased the 2-deoxyglucose uptake and glycogen concentration, which was reduced by insulin resistance. As with rapamycin, cardamonin inhibited the activity of the mammalian target of rapamycin and S6 kinase 1, decreased the Ser 636/639 phosphorylation of insulin receptor substrate-1 and increased the activation of protein kinase B. Both of them increased the Ser9 phosphorylation of glycogen synthesis kinase-3β and decreased the expression of glycogen synthesis kinase-3β. However, neither cardamonin nor rapamycin increased the expression of glucose transport 4 which decreased in insulin-resistant vascular smooth muscle cells. This study suggests that cardamonin inhibited the activity of the mammalian target of rapamycin and eliminated the negative feedback of the mammalian target of rapamycin and S6 kinase 1 on the insulin-signaling pathway. 23200943 Altered expression of genes involved in progesterone biosynthesis, metabolism and action in endometrial cancer. Endometrial cancer (EC) is one of the most common gynecological malignancies worldwide. It is associated with prolonged exposure to estrogens that is unopposed by the protective effects of progesterone, which suggests that altered progesterone biosynthesis, metabolism and actions might be implicated in the development of EC. Our aim was to evaluate these processes through quantitative real-time PCR expression analysis in up to 47 pairs of EC tissue and adjacent control endometrium. First, we examined the expression of genes encoding proteins associated with progesterone biosynthesis: steroidogenic acute regulatory protein (STAR); a side chain cleavage enzyme (CYP11A1); and 3β-hydroxysteroid dehydrogenase/ketosteroid isomerase (HSD3B). There were 1.9- and 10.0-fold decreased expression of STAR and CYP11A1, respectively, in EC versus adjacent control endometrium, with no significant differences in the expression of HSD3B1 and HSD3B2. Next, we examined expression of genes encoding five progesterone metabolizing enzymes: the 3-keto and 20-ketosteroid reductases (AKR1C1-AKR1C3) and 5α-reductases (SRD5A1 and SRD5A2); and the opposing 20α-hydroxysteroid dehydrogenase (HSD17B2). These genes are expressed in EC and adjacent control endometrium. No statistically significant differences were seen in mRNA levels of AKR1C1, AKR1C2, AKR1C3 and SRD5A1. Expression of HSD17B2 was 3.0-fold increased, and expression of SRD5A2 was 3.7-fold decreased, in EC versus adjacent control endometrium. We also examined mRNA levels of progesterone receptors A and B (PGR), and separately the expression of progesterone receptor B (PR-B). Here we saw 1.8- and 2.0-fold lower mRNA levels of PGR and PR-B, respectively, in EC versus adjacent control endometrium. This down-regulation of STAR, CYP11A1 and PGR in endometrial cancer may lead to decreased progesterone biosynthesis and actions although the effects on progesterone levels should be further studied. 23064325 Inhalable highly concentrated itraconazole nanosuspension for the treatment of bronchopulmonary aspergillosis. Cystic fibrosis (CF) patients are suffering from multiple often chronic endobronchial infection. The stiff mucus in these patients represents a compartment, which cannot easily be reached by systemic treatment. While bacterial infections are now successfully treated with repeated inhalation of antibiotics such as tobramycine, 57% of CF patients are colonized by Aspergillus species. About 10-20% of colonized patients develop symptoms of allergic bronchopulmonary aspergillosis (ABPA). While current standard of treatment of ABPA in CF patients is to suppress the allergy related symptoms by administration of glucocorticoids, itraconazole (ITRA), administered orally at high doses, can alleviate the symptoms of ABPA. However, no inhalable formulation of ITRA is available to enable local treatment of aspergillosis. The aim of this study was to describe an aqueous nanosuspension of ITRA and to characterize the pharmacokinetics after single dose inhalation. Using wet-milling with organic milling beads, a stable nanosuspension with particle size in the range of 200nm and an ITRA concentration of 20% (v/w) could be obtained, using polysorbate 80 at a concentration of 14% relative to ITRA. The suspension was stable if stored at 8°C for 3 months without particle growth and could be nebulized using standard nebulizer technologies including mesh technology and pressured air nebulizers. A 10% suspension was well tolerated upon repeated dose inhalation once daily for 7 days at a predicted dose of 45mg/kg in rats. A single dose inhalation at a predicted dose of 22.5mg/kg resulted in maximum lung tissue concentration of 21.4μg/g tissue with a terminal half-life of 25.4h. Serum concentrations were lower, with a maximum concentration of 104ng/ml at 4h after dosing and a terminal half-life of 10.5h. The data indicate that ITRA nanosuspension represents an interesting formulation for inhaled administration in CF patients suffering from ABPA. High and long lasting lung tissue concentrations well above the minimal inhibitory concentration of Aspergillus species enable once daily administration with minimal systemic exposure. 23360912 X-ray absorption spectroscopy and energy storage of Ni-doped cobalt nitride, (Ni(0.33)Co(0.67))N, prepared by a simple synthesis route. Metal nitride (Ni(0.33)Co(0.67))N nanoparticles are prepared by nitridation using NiCo(2)O(4) as a precursor material by heating at 335 °C for 2 h in flowing NH(3) + N(2) gas and characterized by X-ray diffraction (XRD), field emission-scanning electron microscopy (FE-SEM), high resolution-transmission electron microscopy (HR-TEM), along with selective area electron diffraction (SAED) and X-ray absorption spectroscopy (XAS) techniques. The X-ray absorption near edge structure (XANES) at the Co K-edge showed that the oxidation state of cobalt is close to 3+. The (Ni(0.33)Co(0.67))N showed a shift in edge energy towards lower values due to Ni-doping to cobalt site. The Li-storage behaviour of (Ni(0.33)Co(0.67))N nanoparticles was evaluated by galvanostatic cycling and cyclic voltammetry in the cells with Li-metal as counter electrode in the voltage range of 0.005-3.0 V at ambient temperature. When cycled at 250 mA g(-1), the first-cycle reversible capacity of 700 (±5) mA h g(-1) (~1.9 moles of Li) is obtained. It showed an initial decrease in capacity until the 10(th) cycle and a stable capacity of 400 (±5) mA h g(-1) (~1.09 moles of Li) is observed at the end of the 50(th) cycle. Excellent rate capability is also shown when cycling at 500 mA g(-1) (up to 50 cycles). The materials showed excellent Li-ion insertion/extraction, with the coulombic efficiency reaching almost 99% in the range of 10-50 cycles. The average charge and discharge potentials are ~2.03 and ~1.0 V, respectively for the decomposition/formation of Li(3)N as determined by electroanalytical techniques. 22956413 The effects of sonographic and demographic features and needle size on obtaining adequate cytological material in sonography-guided fine-needle aspiration biopsy of thyroid nodules. The aim of this study is to investigate the effects of the sonographic characteristics of the nodule, demographic features of patient, and nodule size and needle size used for sampling, on obtaining adequate cytological material (CM) in thyroid fine-needle aspiration biopsy (FNAB). We performed 270 FNAB between September 2010 and June 2012. Size, echogenicity, and localization of all nodules were evaluated by ultrasonography (US) before the biopsy. Nodules were grouped as <1, 1-3, and >3 cm according to their size and as hypoechoic, isoechoic, hyperechoic, or heterogeneous according to their US characteristics. 20-, 22-, and 24-G needles were used for the biopsies. Different sonographic characteristics of the nodules did not affect the needle selection. All specimens were classified as adequate or inadequate CM by a cytopathologist. A total of 270 nodules were biopsied, 184 (68.1 %) specimens were considered as adequate CM and 86 (31.9 %) specimens were considered as inadequate CM. Patient age and the presence of heterogeneous echogenicity were found to have prognostic significance in univariate analysis (p < 0.05). In a multivariate logistic regression model with forward stepwise method, advanced age (p = 0.001, OR = 1.042, 95CI 1.018-1.068) and heterogeneous echogenicity (p = 0.017, OR = 1.955, 95CI 1.129-3.385) remained associated with an increased risk of inadequate CM obtainment after adjustment for other potential confounders (nodule size >3 cm and needle size 20-G usage) and variables found to be statistically significant in univariate analysis. Non-diagnostic FNAB remains a significant problem in the evaluation of thyroid nodules and can be as high as 30 %. Inadequate CM rates for elderly patients and heterogeneous nodules were significantly higher than that for other factors. The nodule size and needle size used for sampling did not affect the adequacy of FNAB. 23344433 A divergent approach to the synthesis of the yohimbinoid alkaloids venenatine and alstovenine. The yohimbinoid alkaloids continue to receive considerable attention from the synthetic community because of their interesting chemical structures and varied biological activity. Although there are several elegant syntheses of certain members of this group of alkaloids, a truly unified approach has yet to be developed. In short, general approaches to this compound class are hampered by a lack of complete control in setting the C(3) stereocentre at a late stage. Herein, we report that a functionalized hydrindanone enables a divergent strategy that builds on existing precedent to address this long-standing challenge. Utilizing an aminonitrile intermediate, the stereochemistry at C(3) of the yohimbinoid skeleton can be controlled effectively in a Pictet-Spengler reaction. We applied this approach to the first total syntheses of the C(3) epimeric natural products venenatine and alstovenine. 23411074 Aspulvinones from a mangrove rhizosphere soil-derived fungus Aspergillus terreus Gwq-48 with anti-influenza A viral (H1N1) activity. A new butenolide isoaspulvinone E (1), together with two known butenolides aspulvinone E (2) and pulvic acid (3) were isolated from the marine-derived fungus, Aspergillus terreus Gwq-48. They showed significant anti-influenza A H1N1 virus activities, with IC50 values of 32.3, 56.9, and 29.1μg/mL, respectively. Moreover, only compound 1 exhibited effective inhibitory activity against H1N1 viral neuraminidase (NA), and docking of two isomers (1-2) into the active sites of NA showed that the E double bond Δ(5(10)) was essential to achieve activity. 23256716 Managing comorbidity in COPD: a difficult task. Chronic obstructive pulmonary disease is a public health problem that results in high morbidity, disability and mortality. Comorbidities are highly prevalent in COPD patients because of aging, common risk factors and pathways, rising mortality, and disability. In this review article we present the most prevalent co-morbidities in COPD patients, we face the issue of multimorbidity and discuss the practical management approach relevant to chest physicians and general practitioners. Issues on comorbidities management according to general guidelines as well as their implications for COPD are raised. The aim is to give clinicians an easy update with specific recommendations for each comorbidity. The implications of several medications used for comorbidities in COPD in terms of benefits, concerns, medication preference, medication avoidance and contraindications are also discussed. 23603200 Electroconvulsive seizures activate anorexigenic signals in the ventromedial nuclei of the hypothalamus. The ventromedial nucleus of the hypothalamus (VMH) plays an important role in feeding and energy homeostasis. Electroconvulsive seizure (ECS) therapy is highly effective in the treatment of several psychiatric diseases, including depression, but may also have beneficial effects in other neurological diseases. Although it has been reported that the neurons of the VMH are strongly activated by ECS stimulation, the specific effects of ECS in this hypothalamic subnucleus remain unknown. To address this issue, we investigated the changes in gene expression in microdissected-VMH samples in response to ECS in mice, and examined the behavioral effects of ECS on feeding behavior. ECS significantly induced the expression of immediate-early genes such as Fos, Fosb, and Jun, as well as Bdnf, Adcyap1, Hrh1, and Crhr2 in the VMH. Given that signals of these gene products are suggested to have anorexigenic roles in the VMH, we also examined the effect of ECS on food intake and body weight. Repeated ECS had a suppressive effect on food intake and body weight gain under both regular and high-fat diet conditions. Furthermore, gold-thioglucose-induced hypothalamic lesions, including the VMH and the arcuate nucleus, abolished the anorexigenic effects of ECS, indicating the requirement for the activation of the hypothalamus. Our data show an effect of ECS on increased expression of anorexigenic factors in the VMH, and suggest a role in the regulation of energy homeostasis by ECS. 23519110 UPR Signal Activation by Luminal Sensor Domains. The unfolded protein response (UPR) is a cell-signaling system that detects the accumulation of unfolded protein within the endoplasmic reticulum (ER) and initiates a number of cellular responses to restore ER homeostasis. The presence of unfolded protein is detected by the ER-luminal sensor domains of the three UPR-transducer proteins IRE1, PERK, and ATF6, which then propagate the signal to the cytosol. In this review, we discuss the various mechanisms of action that have been proposed on how the sensor domains detect the presence of unfolded protein to activate downstream UPR signaling. 23195959 Ubiquitin-dependent regulation of phospho-AKT dynamics by the ubiquitin E3 ligase, NEDD4-1, in the insulin-like growth factor-1 response. AKT is a critical effector kinase downstream of the PI3K pathway that regulates a plethora of cellular processes including cell growth, death, differentiation, and migration. Mechanisms underlying activated phospho-AKT (pAKT) translocation to its action sites remain unclear. Here we show that NEDD4-1 is a novel E3 ligase that specifically regulates ubiquitin-dependent trafficking of pAKT in insulin-like growth factor (IGF)-1 signaling. NEDD4-1 physically interacts with AKT and promotes HECT domain-dependent ubiquitination of exogenous and endogenous AKT. NEDD4-1 catalyzes K63-type polyubiquitin chain formation on AKT in vitro. Plasma membrane binding is the key step for AKT ubiquitination by NEDD4-1 in vivo. Ubiquitinated pAKT translocates to perinuclear regions, where it is released into the cytoplasm, imported into the nucleus, or coupled with proteasomal degradation. IGF-1 signaling specifically stimulates NEDD4-1-mediated ubiquitination of pAKT, without altering total AKT ubiquitination. A cancer-derived plasma membrane-philic mutant AKT(E17K) is more effectively ubiquitinated by NEDD4-1 and more efficiently trafficked into the nucleus compared with wild type AKT. This study reveals a novel mechanism by which a specific E3 ligase is required for ubiquitin-dependent control of pAKT dynamics in a ligand-specific manner. 23561146 Preparative isolation and purification of seven main antioxidants from Eucommia ulmoides Oliv. (Du-zhong) leaves using HSCCC guided by DPPH-HPLC experiment. Seven antioxidants were purified from Eucommia ulmoides Oliv. leaves using HSCCC guided by DPPH-HPLC experiment. HSCCC was successfully used to separate target antioxidants by three runs with different solvent systems after D101 column chromatography fractionation. Ethyl acetate-n-butanol-water (1:2:3, v/v/v) was selected as the optimum solvent system to purify geniposidic acid. Ethyl acetate-ethanol-water (4:1:5, v/v/v) was used to isolate caffeic acid, chlorogenic acid and ferulic acid. While three flavonoids, quercetin-3-O-sambubioside, rutin and isoquercitrin were purified by petroleum ether-ethyl acetate-methanol-water (1:5:1:5, v/v/v/v). The structures were identified by MS and NMR. Antioxidant activities were assessed, and compounds 2-7 showed strong antioxidant activities. This is the first report about separation of antioxidants from E. ulmoides leaves by HSCCC. The results indicated that the combinative methods using DPPH-HPLC and HSCCC could be widely applied for screening and isolation of antioxidants from complex extracts. 23409714 Myeloid derived suppressor cells and their role in diseases. Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of myeloid progenitors that can play a major role in tumour development and chronic inflammation. The importance of the suppressive function ofMDSCs was first suggested by studies involving cancer patients and cancer-bearing mice. In addition, recent studies have demonstrated that MDSCs can also be involved in many other pathological conditions. MDSCs have unique ways of abrogatingan immune response in addition to those utilised by other immune-suppressive cell types, for example via the induction of arginase-1 and consequent upregulation in reactive oxygen species (ROS) production. Due to their heterogeneity,they further can express a variety of lineage markers, which overlap with other myeloid cell types such as Gr1,CD11b, MHCIIlo, Ly6C and Ly6G, making it difficult to identify them by surface phenotype alone. The disparity between mouse and human MDSCs further complicates the identification of these elusive cell populations. In this review, we will summarise the recent updates on the methods for eliciting and studying different MDSC subsets, including newly proposed surface phenotypes, as well as insights into how their function is being characterised in both mice and humans. In addition, exciting new discoveries suggesting their involvement across a number of different pathological settings, such as sepsis, autoimmunity and Leishmaniasis, will be discussed. 23276631 PGRMC2, a yet uncharacterized protein with potential as tumor suppressor, migration inhibitor, and regulator of cytochrome P450 enzyme activity. PGRMC2 (progesterone receptor membrane component 2) is highly homologous if compared with PGRMC1, a cytochrome-related protein, which is induced in several cancers and linked to cell growth in these cancers. Further it seems to be involved in progesterone signalling and cytochrome P450 binding. For PGRMC2 only sparse information is available. Recent data show that PGRMC1 and 2 share several similar characteristics, but there are also important differences in expression and function of the both proteins. Several findings point to the fact that PGRMC2 might play a role in cancer as well. The protein influences the migration rate of ovarian cancer cells and a loss of PGRMC2 might result in higher metastasis rates. In contrast to PGRMC1 it seems more likely to act as a tumor suppressor than a promoter. Altered PGRMC2 expression was further detected in the context of term and preterm labour, though the implications of this finding are currently unknown and need further examination. PGRMC2 further might play a role in gynaecologic diseases like preterm labour and endometriosis. PGRMC2 shares the cellular localisation and the ability to bind cytochrome enzymes with PGRMC1. Further the protein was shown to influence the activity of CYP3A4. In conclusion, though not much is known about PGRMC2 so far, it deserves further examination as data point to a role of PGRMC2 as tumor suppressor, migration inhibitor and regulator of cytochrome P450 proteins. 23570469 Pharmacogenomics of bipolar disorder. Bipolar disorder (BD) is a lifelong severe psychiatric condition with high morbidity, disability and excess mortality. The longitudinal clinical trajectory of BD is significantly modified by pharmacological treatment(s), both in acute and in long-term stages. However, a large proportion of BD patients have inadequate response to pharmacological treatments. Pharmacogenomic research may lead to the identification of molecular predictors of treatment response. When integrated with clinical information, pharmacogenomic findings may be used in the future to determine the probability of response/nonresponse to treatment on an individual basis. Here we present a selective review of pharmacogenomic findings in BD. In light of the evidence suggesting a genetic effect of lithium reponse in BD, we focused particularly on the pharmacogenomic literature relevant to this trait. The article contributes a detailed overview of the current status of pharmacogenomics in BD and offers a perspective on the challenges that can hinder its transition to personalized healthcare. 22664304 Group III and subtype 4 metabotropic glutamate receptor agonists: discovery and pathophysiological applications in Parkinson's disease. Restoring the balance between excitatory and inhibitory circuits in the basal ganglia, following the loss of dopaminergic (DA) neurons of the substantia nigra pars compacta, represents a major challenge to treat patients affected by Parkinson's disease (PD). The imbalanced situation in favor of excitation in the disease state may also accelerate excitotoxic processes, thereby representing a potential target for neuroprotective therapies. Reducing the excitatory action of glutamate, the major excitatory neurotransmitter in the basal ganglia, should lead to symptomatic improvement for PD patients and may promote the survival of DA neurons. Recent studies have focused on the modulatory action of metabotropic glutamate (mGlu) receptors on neurodegenerative diseases including PD. Group III mGlu receptors, including subtypes 4, 7 and 8, are largely expressed in the basal ganglia. Recent studies highlight the use of selective mGlu4 receptor positive allosteric modulators (PAMs) for the treatment of PD. Here we review the effects of newly-designed group-III orthosteric agonists on neuroprotection, neurorestoration and reduction of l-DOPA induced dyskinesia in animal models of PD. The combination of orthosteric mGlu4 receptor selective agonists with PAMs may open new avenues for the symptomatic treatment of PD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23292859 Assessing the quality of absolute hydration free energies among CHARMM-compatible ligand parameterization schemes. Multipurpose atom-typer for CHARMM (MATCH), an atom-typing toolset for molecular mechanics force fields, was recently developed in our laboratory. Here, we assess the ability of MATCH-generated parameters and partial atomic charges to reproduce experimental absolute hydration free energies for a series of 457 small neutral molecules in GBMV2, Generalized Born with a smooth SWitching (GBSW), and fast analytical continuum treatment of solvation (FACTS) implicit solvent models. The quality of hydration free energies associated with small molecule parameters obtained from ParamChem, SwissParam, and Antechamber are compared. Given optimized surface tension coefficients for scaling the surface area term in the nonpolar contribution, these automated parameterization schemes with GBMV2 and GBSW demonstrate reasonable agreement with experimental hydration free energies (average unsigned errors of 0.9-1.5 kcal/mol and R(2) of 0.63-0.87). GBMV2 and GBSW consistently provide slightly more accurate estimates than FACTS, whereas Antechamber parameters yield marginally more accurate estimates than the current generation of MATCH, ParamChem, and SwissParam parameterization strategies. Modeling with MATCH libraries that are derived from different CHARMM topology and parameter files highlights the importance of having sufficient coverage of chemical space within the underlying databases of these automated schemes and the benefit of targeting specific functional groups for parameterization efforts to maximize both the breadth and the depth of the parameterized space. 23552263 Lipoxygenase and urease inhibition of the aerial parts of the Polygonatum verticillatum. Over expression of lipoxygenase (LOX) and urease has already contributed to the pathology of different human disease. Targeting the inhibition of these enzymes has proved great clinical utility. The aim of the present study was to scrutinised the inhibitory profile of the aerial parts of the Polygonatum verticillatum enzyme against LOX, urease, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using standard experimental protocols. When checked against lipoxygenase, the extracts revealed significant attenuation. Of the tested extracts, the ethyl acetate fraction was the most potent (half-maximal inhibitory concentration (IC50): 97 µg/mL) followed by aqueous fraction IC50: 109 µg/mL). Regarding urease inhibition, n-butanol was the most potent fraction (IC50: 97 µg/mL). However, the extracts did not show significant inhibition on AChE and BChE. In the preliminary phytochemical tests, the aerial parts of the plant showed the presence of saponins, alkaloids, flavonoids, phenols, tannins and terpenoids. The current findings could be attributed to these groups of compounds. 23641901 Barnacle Cement as Surface Anchor for 'Clicking' of Antifouling and Antimicrobial Polymer Brushes on Stainless Steel. Barnacle cement (BC) was utilized 'beneficially' as a surface anchor on stainless steel (SS) for coupling of functional polymer brushes via 'click' reactions in both "grafting-to" and "grafting-from" processes. Ethylene sulfide (ES), propargyl carbonylimidazole (PPC) and azidoethyl carbonylimidazole (AEC) reacted with amine and/or hydroxyl groups in BC to introduce the corresponding thiol, alkyne and azide groups on SS surfaces (SS-thiol, SS-alkyne and SS-azide, respectively). Antifouling zwitterionic SS-PMPC surface was prepared by thiol-ene photopolymerization of 2-methacryloyloxyethyl phosphorylcholine (MPC) from the SS-thiol surface. Protein-resistant SS-PPEGMA and protein-adsorbing SS-PPFS surfaces were prepared by coupling of the respective azide-functionalized poly(poly(ethylene glycol)methyl ether methacrylate) (azido-PPEGMA) and poly(2,3,4,5,6-pentafluorostyrene) (azido-PPFS) polymer brushes in azide-alkyne 'click' reaction. Antifouling alkyne-functionalized poly(N-hydroxyethyl acrylamide) (alkynyl-PHEAA) and antibacterial alkyne-functionalized poly(2-(methacryloyloxy)ethyl trimethylammonium chloride) (alkynyl-PMETA) polymer brushes were clicked on the SS-azide surface. Adsorption of bovine serum albumin and bacteria fouling of Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus epidermidis (S. epidermidis) were investigated on the polymer-functionalized SS surfaces. The versatile bio-anchor and functional polymer brush coatings are stable in abiotic aqueous environment for over a month. 23154194 Amino acid derivatives as transdermal permeation enhancers. Transdermal permeation enhancers are compounds that temporarily decrease skin barrier properties to promote drug flux. In this study, we investigated enhancers with amino acids (proline, sarcosine, alanine, β-alanine, and glycine) attached to hydrophobic chain(s) via a biodegradable ester link. The double-chain lipid-like substances displayed no enhancing effect, whereas single-chain substances significantly increased skin permeability. The proline derivative l-Pro2 reached enhancement ratios of up to 40 at 1% concentration, which is higher than that of the well-established and standard enhancers Azone, DDAIP, DDAK, and Transkarbam 12. No stereoselectivity was observed. l-Pro2 acted synergistically with propylene glycol. Infrared studies revealed that l-Pro2 forms a separate liquid ordered phase in the stratum corneum lipids and has no significant effect on proteins. l-Pro2 action was at least partially reversible as measured by skin electrical impedance. Toxicity in keratinocyte (HaCaT) and fibroblast (3T3) cell lines showed IC(50) values ranging from tens to hundreds of μM, which is comparable with standard enhancers. Furthermore, l-Pro2 was rapidly decomposed in plasma. In vivo transdermal absorption studies in rats confirmed the enhancing activity of l-Pro2 and suggested its negligible skin toxicity and minimal effect on transepidermal water loss. These properties make l-Pro2 a promising candidate for potential clinical use. 23104248 Reelin supplementation recovers sensorimotor gating, synaptic plasticity and associative learning deficits in the heterozygous reeler mouse. The lipoprotein receptor ligand Reelin is important for the processes of normal synaptic plasticity, dendritic morphogenesis, and learning and memory. Heterozygous reeler mice (HRM) show many neuroanatomical, biochemical, and behavioral features that are associated with schizophrenia. HRM show subtle morphological defects including reductions in dendritic spine density, altered synaptic plasticity and behavioral deficits in associative learning and memory and pre-pulse inhibition. The present studies test the hypothesis that in vivo elevation of Reelin levels can rescue synaptic and behavioral phenotypes associated with HRM. We demonstrate that a single in vivo injection of Reelin increases GAD67 expression and alters dendritic spine morphology. In parallel we observed enhancement of hippocampal synaptic function and associative learning and memory. Reelin supplementation also increases pre-pulse inhibition. These results suggest that characteristics of HRM, similar to those observed in schizophrenia, are sensitive to Reelin levels and can be modified with Reelin supplementation in male and female adults. 23358249 Partial peptide of α-synuclein modified with small-molecule inhibitors specifically inhibits amyloid fibrillation of α-synuclein. We have previously reported that pyrroloquinoline quinone (PQQ) prevents the amyloid formation of α-synuclein, amyloid β(1-42) (Aβ(1-42)), and mouse prion protein. Moreover, PQQ-modified α-synuclein and a proteolytic fragment of the PQQ-modified α-synuclein are able to inhibit the amyloid formation of α-synuclein. Here, we identified the peptide sequences that play an important role as PQQ-modified specific peptide inhibitors of α-synuclein. We demonstrate that the PQQ-modified α-Syn(36-46) peptide, which is a partial sequence of α-synuclein, prevented α-synuclein amyloid fibril formation but did not inhibit Aβ(1-42) fibril formation. In addition, the α-synuclein partial peptide modified with other small-molecule inhibitors, Baicalein and epigallocatechin gallate (EGCG), prevented α-synuclein fibril formation. Currently reported quinone amyloid inhibitors do not have selectivity toward protein molecules. Therefore, our achievements provide a novel strategy for the development of targeted specific amyloid formation inhibitors: the combination of quinone compounds with specific peptide sequence from target proteins involved in amyloid formation. 23491523 Diabetes and Cardiovascular Disease Outcomes in the Metabolically Healthy Obese Phenotype: A cohort study. OBJECTIVESTo determine the correlates of the "metabolically healthy obese" (MHO) phenotype and the longitudinal risks of diabetes and cardiovascular disease (CVD)/stroke associated with this phenotype.RESEARCH DESIGN AND METHODSThe North West Adelaide Health Study is a prospective cohort study of 4,056 randomly selected adults aged ≥18 years. Participants free of CVD/stroke and not underweight (n = 3,743) were stratified by BMI categories and metabolic risk, defined as having two or more International Diabetes Federation metabolic syndrome criteria, excluding waist circumference.RESULTSCorrelates of the MHO (n = 454 [12.1%]) included smoking, socioeconomic disadvantage, and physical inactivity. Compared with metabolically healthy normal-weight subjects (n = 1,172 [31.3%]), the MHO were more likely to develop metabolic risk (15.5 vs. 33.1%, P < 0.001) and incident diabetes (odds ratio 2.09 [95% CI 0.87-5.03]) but not CVD/stroke (1.16 [0.58-2.29]) during 5.5-10.3 years of follow-up. These risks were not seen in MHO subjects maintaining metabolic health (n = 188 [67%]). Sustained metabolic health in obese participants was associated with age ≤40 years and lower waist circumference. Compared with the metabolically at-risk obese, MHO women demonstrated a significantly higher (mean [SE]) percentage of leg fat (49.9 [0.5] vs. 53.2 [0.7]) and lower waist circumference (104 [0.6] vs. 101 cm [0.8]), despite no significant differences in overall adiposity.CONCLUSIONS"Healthy" obesity was a transient state for one-third of subjects. Persistence of a MHO phenotype, which was associated with favorable outcomes, was related to younger age and a more peripheral fat distribution. The MHO phenotype may be sustained by promoting lower waist circumferences. 23455594 Insula's functional connectivity with ventromedial prefrontal cortex mediates the impact of trait alexithymia on state tobacco craving. RATIONALE: Alexithymia is a personality trait characterized by difficulty indentifying and describing subjective emotional experiences. Decreased aptitude in the perception, evaluation, and communication of affectively laden mental states has been associated with reduced emotion regulation, more severe drug craving in addicts, and structural/functional alterations in insula and anterior cingulate cortex (ACC). The insula and ACC represent sites of convergence between the putative neural substrates of alexithymia and those perpetuating cigarette smoking. OBJECTIVES: We examined the interrelations between alexithymia, tobacco craving, and insula/ACC neurocircuitry using resting-state functional connectivity (rsFC). METHODS: Overnight-deprived smokers (n = 24) and nonsmokers (n = 20) completed six neuroimaging assessments on different days both in the absence of, and following, varenicline and/or nicotine administration. In this secondary analysis of data from a larger study, we assessed trait alexithymia and state tobacco craving using self-reports and examined the rsFC of bilateral insular subregions (anterior, middle, posterior) and dorsal ACC. RESULTS: Higher alexithymia in smokers predicted reduced rsFC strength between the right anterior insula (aI) and ventromedial prefrontal cortex (vmPFC). Higher alexithymia also predicted more severe tobacco craving during nicotine withdrawal. Critically, the identified aI-vmPFC circuit fully mediated this alexithymia-craving relation. That is, elevated alexithymia predicted decreased aI-vmPFC rsFC and, in turn, decreased aI-vmPFC rsFC predicted increased craving during withdrawal. A moderated mediation analysis indicated that this aI-vmPFC mediational effect was not observed following drug administration. CONCLUSIONS: These results suggest that a weakened right aI-vmPFC functional circuit confers increased liability for tobacco craving during smoking abstinence. Individual differences in alexithymia and/or aI-vmPFC functional coupling may be relevant factors for smoking cessation success. 23542495 Chloroaluminium phthalocyanine polymeric nanoparticles as photosensitisers: Photophysical and physicochemical characterisation, release and phototoxicity in vitro. Nanoparticles of poly(d,l-lactide-co-glycolide), poly(d,l-lactide) and polyethylene glycol-block-poly(d,l-lactide) were developed to encapsulate chloroaluminium phthalocyanine (AlClPc), a new hydrophobic photosensitiser used in photodynamic therapy (PDT). The mean nanoparticle size varied from 115 to 274nm, and the encapsulation efficiency ranged from 57% to 96% due to drug precipitation induced by different types of polymer. All nanoparticle formulations presented negative zeta potential values (-37mV to -59mV), explaining their colloidal stability. The characteristic photophysical parameters were analysed: the absorption spectrum profile, fluorescence quantum yield and transient absorbance decay, with similar values for free and nanoparticles of AlClPc. The time-resolved spectroscopy measurements for AlClPc triplet excited state lifetimes indicate that encapsulation in nanocapsules increases triplet lifetime, which is advantageous for PDT efficiency. A sustained release profile over 168h was obtained using external sink method. An in vitro phototoxic effect higher than 80% was observed in human fibroblasts at low laser light doses (3J/cm(2)) with 10μM of AlClPc. The AlClPc loaded within polymeric nanocapsules presented suitable physical stability, improved photophysical properties, sustained released profile and suitable activity in vitro to be considered a promising formulation for PDT. 23425970 Synthesis and biological evaluation of novel pyranochalcone derivatives as a new class of microtubule stabilizing agents. Twenty-five novel pyranochalcone derivatives were synthesized and evaluated for their in vitro and in vivo antiproliferative activities. Among them, compound 10i exhibited superior potent activity against 21 tumor cell lines including multidrug resistant phenotype with the IC50 values ranged from 0.09 to 1.30 μM. In addition, 10i significantly induced cell cycle arrest in G2/M phase, promoted tubulin polymerization into microtubules and caused microtubule stabilization. Further studies confirmed that 10i significantly suppressed the growth of tumor volume in HepG2 xenograft tumor model. Our study demonstrated that 10i could have beneficial antitumor activity as a novel microtubule stabilizing agent. 23557843 Dissolution enhancement of Deflazacort using hollow crystals prepared by antisolvent crystallization process. Deflazacort (DFZ), a derivate of prednisolone, is a poorly soluble drug which has been proposed to have major advantages over other corticosteroids. Poorly soluble drugs present limited bioavailability due to their low solubility and dissolution rate and several strategies have been developed in order to find ways to improve them. In general, pharmaceutical laboratories use a micronized process to reduce the particle size in order to increase the dissolution of the drugs. However, this process causes changes such as polymorphic transitions, particle agglomeration and a reduction in fluidity and wettability. These solid-state properties affect the dissolution behavior and stability performance of drugs. Crystallization techniques are widely used in the pharmaceutical industry and antisolvent crystallization has been used to obtain ultrafine particles. In this study, DFZ was investigated in terms of its antisolvent crystallization in different solvents and under various preparation conditions (methanol/water ratio, stirring and evaporation rate, etc.), in order to compare the physicochemical properties between crystallized samples and raw materials available on the Brazilian market with and without micronization. Crystalline structure, morphology, and particle size, and their correlation with the Intrinsic Dissolution Rate (IDR) and dissolution profile as relevant biopharmaceutical properties were studied. Crystallization conditions were achieved which provided crystalline samples of hollow-shaped crystals with internal channels, which increased the dissolution rate of DFZ. The antisolvent crystallization process allowed the formation of hollow crystals, which demonstrated a better dissolution profile than the raw material (crystalline and micronized), making this a promising technique as a crystallization strategy for improving the dissolution and thus the bioavailability of poorly soluble drugs. 23172744 Evaluation of whole effluent toxicity data characteristics and use of Welch's T-test in the test of significant toxicity analysis. The U.S. Environmental Protection Agency (U.S. EPA) and state agencies evaluate the toxicity of effluent and surface water samples based on statistical endpoints derived from multiconcentration tests (e.g., no observed effect concentration, EC25). The test of significant toxicity (TST) analysis is a two-sample comparison test that uses Welch's t test to compare organism responses in a sample (effluent or surface water) with responses in a control or site sample. In general, any form of t test (Welch's t included) is appropriate only if the data meet assumptions of normality and homogeneous variances. Otherwise, nonparametric tests are recommended. TST was designed to use Welch's t as the statistical test for all whole effluent toxicity (WET) test data. The authors evaluated the suitability of using Welch's t test for analyzing two-sample toxicity (WET) data, and within the TST approach, by examining the distribution and variances of data from over 2,000 WET tests and by conducting multiple simulations of WET test data. Simulated data were generated having variances and nonnormal distributions similar to observed WET test data for control and the effluent treatment groups. The authors demonstrate that (1) moderately unequal variances (similar to WET data) have little effect on coverage of the t test or Welch t test (for normally distributed data), and (2) for nonnormally distributed data (similar in distribution to WET data) TST, using Welch's t test, has close to nominal coverage on the basis of simulations with up to a ninefold difference in variance between the effluent and control groups (∼95th percentile based on observed WET test data). 23432124 Studies on an (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist IKM-159: asymmetric synthesis, neuroactivity, and structural characterization. IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists. However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis. By employment of (R)-2-amino-2-(4-methoxyphenyl)ethanol as a chiral auxiliary, (2R)-IKM-159 and the (2S)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2R)-IKM-159, whereas the (2S)-counterpart was inactive in both assays. Racemic IKM-159 was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing (2R)-IKM-159 at the glutamate binding site. (2R)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors. 23590572 Structure in the Visible Absorption Bands of Jet-Cooled Phenylperoxy Radicals. The visible absorption bands of the phenylperoxy radical in the gas phase have been investigated using cavity ring-down spectroscopy. Jet-cooling was used to reduce the spectral congestion. Structured spectra spanning the range from 17 500 to 19 000 cm(-1) are reported for the first time. Analyses of these data have been guided by the results from time-dependent density functional calculations. The observed spectrum was found to be dominated by the bands of the B̃(2)A″-X̃(2)A″ transition. An analysis of the rotational contour for the origin band yielded a homogeneous line width of 2.2 cm(-1), corresponding to a decay rate of 4.1 × 10(11) s(-1). The results provide a rationale for the lack of structure in room temperature spectra that have been previously attributed to phenylperoxy. They also indicate that the lower energy region of the spectrum may show resolvable structure at room temperature. If so, this would provide a more definitive signature for monitoring phenylperoxy in kinetic measurements. 23617391 Structures, Dynamics, and Stabilities of Fully Modified Locked Nucleic Acid (β-d-LNA and α-l-LNA) Duplexes in Comparison to Pure DNA and RNA Duplexes. Locked nucleic acid (LNA) is a chemical modification which introduces a -O-CH2- linkage in the furanose sugar of nucleic acids and blocks its conformation in a particular state. Two types of modifications, namely, 2'-O,4'-C-methylene-β-d-ribofuranose (β-d-LNA) and 2'-O,4'-C-methylene-α-l-ribofuranose (α-l-LNA), have been shown to yield RNA and DNA duplex-like structures, respectively. LNA modifications lead to increased melting temperatures of DNA and RNA duplexes, and have been suggested as potential therapeutic agents in antisense therapy. In this study, molecular dynamics (MD) simulations were performed on fully modified LNA duplexes and pure DNA and RNA duplexes sharing a similar sequence to investigate their structure, stabilities, and solvation properties. Both LNA duplexes undergo unwinding of the helical structure compared to the pure DNA and RNA duplexes. Though the α-LNA substituent has been proposed to mimic deoxyribose sugar in its conformational properties, the fully modified duplex was found to exhibit unique structural and dynamic properties with respect to the other three nucleic acid structures. Free energy calculations accurately capture the enhanced stabilization of the LNA duplex structures compared to DNA and RNA molecules as observed in experiments. π-stacking interaction between bases from complementary strands is shown to be one of the contributors to enhanced stabilization upon LNA substitution. A combination of two factors, namely, nature of the -O-CH2- linkage in the LNAs vs their absence in the pure duplexes and similar conformations of the sugar rings in DNA and α-LNA vs the other two, is suggested to contribute to the stark differences among the four duplexes studied here in terms of their structural, dynamic, and energetic properties. 23621381 Gliptins (dipeptidyl peptidase-4 inhibitors) and risk of acute pancreatitis. Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) play an increasing role in the management of type 2 diabetes. Such incretin-based therapies offer some advantages over other glucose-lowering agents, but might be associated with an increased risk of acute pancreatitis. Areas covered: An extensive literature search was performed to analyze clinical cases of acute pancreatitis reported in the literature or to the Food and Drug Administration (FDA), in randomized clinical trials, and in observational studies with five DPP-4 inhibitors: sitagliptin, vildagliptin, saxagliptin, alogliptin, and linagliptin. Expert opinion: An increased risk of pancreatitis has been reported in diabetic versus nondiabetic patients. Several anecdotal clinical cases of pancreatitis have been reported with sitagliptin and vildagliptin and an increased relative risk reported to the FDA with sitagliptin versus other comparators, but reporting bias cannot be excluded. In rather short-term clinical trials with well-selected diabetic patients, no increased risk of acute pancreatitis has been observed with any of the five commercialized DPP-4 inhibitors: sitagliptin, vildagliptin, saxagliptin, alogliptin, and linagliptin. Similarly, real-life cohort studies showed no increased incidence of pancreatitis with gliptins compared with other glucose-lowering agents, a finding recently challenged by a case- control study. These results must be confirmed in postmarketing surveillance programs and in ongoing large prospective trials with cardiovascular outcomes. 23561142 Physico-chemical characteristics and sensory evaluation of wheat bread partially substituted with banana (Musa acuminata X balbisiana cv. Awak) pseudo-stem flour. The physico-chemical and sensorial properties of the control (BCtr), commercial wheat flour (CWF) bread substituted with 10% BPF (banana pseudo-stem flour) (B10BPF) and B10BPF with added 0.8% w/w (flour weight basis) xanthan gum (XG) or sodium carboxymethylcellulose (CMC) (B10BPFXG and B10BPFCMC, respectively) were examined. The proximate analyses revealed that the composite bread had significantly higher moisture, ash, crude fibre, soluble, insoluble and total dietary fibre contents but lower protein, fat and carbohydrate contents than the BCtr. Bread incorporated with BPF resulted in a lower volume, darker crumb and lighter crust colour than the BCtr. The addition of CMC improved the bread volume. All breads containing BPF had greater total phenolics, and antioxidant properties than the control bread. Sensory evaluation indicated that the B10BPFCMC bread had the highest acceptability. 23561125 Characterisation of muscles from Frigate mackerel (Auxis thazard) and catfish (Clarias macrocephalus). Frigate mackerel (Auxis thazard) and catfish (Clarias macrocephalus) can be used as alternative sources for surimi production. However, the functionality of surimi is species-dependent. This study aimed to characterise certain chemical and physical compositions of dark and ordinary muscles from these species. Catfish, particularly ordinary muscle, was composed of higher contents of lipid and carotenoid than Frigate mackerel muscle (p<0.05) but ordinary muscle from Frigate mackerel had the highest phospholipid content (p<0.05). Both dark and ordinary muscles of Frigate mackerel had greater contents of myofibrillar proteins than had catfish muscle (p<0.05). Myosin heavy chain and actin were predominant proteins found in both muscle types of both species. Dark muscle from Frigate mackerel had the highest sarcoplasmic protein content, especially extractable myoglobin (p<0.05). Muscles from Frigate mackerel had greater content of sodium chloride than had catfish (p<0.05). The highest contents of iron, copper and selenium were found in Frigate mackerel dark muscle (p<0.05). The pH of ordinary muscle from both species was higher than that of dark muscle (p<0.05). Frigate mackerel, especilly dark muscle, exhibited the most dark-red colour, as shown by the lowest L(*) and b(*) values with the highest a(*) value and redness index (a(*)/b(*)) (p<0.05). 23370198 Organosilicon compounds as adult T-cell leukemia cell proliferation inhibitors. Aggressive forms of adult T-cell leukemia (ATL) respond poorly to conventional anticancer chemotherapy, and new lead compounds are required for the development of drugs to treat this fatal disease. Recently, we developed ATL cell-selective proliferation inhibitors based on a tetrahydrotetramethylnaphthalene (TMN) skeleton 1, and here we report the design and synthesis of silicon analogs of TMN derivatives. Among them, compound 13 showed the most potent growth-inhibitory activity towards the ATL cell line S1T, though its selectivity for S1T over the non-ATL cell line MOLT-4 was only moderate. This result, as well as computational studies, suggests that sila-substitution (C/Si exchange) is useful for structure optimization of these inhibitors. 23553739 Package-Free Flexible Organic Solar Cells with Graphene top Electrodes. Package-free flexible organic solar cells were fabricated with multilayer graphene as top transparent electrodes, which show the highest power conversion efficiency of about 3.2% and excellent flexibility and bending stability. The devices also show good air stability, indicating that multilayer graphene is a promising environmental barrier that can protect the organic solar cells from air contamination. 23573970 Design and in vitro evaluation of a novel polymeric excipient for buccal applications. Background: The objective of this study was to develop and evaluate a more effective mucoadhesive thiomer for buccal drug-delivery systems. Methods: 2-iminothiolane was covalently attached to a chitosan backbone. A preactivation step followed, mediated by 6,6´dithionicotinamide, thiol groups were modified by disulfide bonds formation. Mucoadhesion studies were performed on buccal mucosa. In addition, water-uptake capacity, disintegration, release and cytotoxicity studies were completed. Results: The obtained chitosan-thiobutylamidine conjugate displayed 647.4 ± 85.23 µmol/g immobilized thiol groups. Due to the preactivation, approximately 60% of thiol groups were modified by formation of disulfide bonds. Chitosan-thiobutylamidine-mercaptonicotinamide displayed 1.8-fold higher stability and 1.6-fold higher mucoadhesive properties, respectively. The release study demonstrated a 1.4-fold more prolonged drug release compared with corresponding thiomers. Conclusion: According to these results, preactivated thiomers demonstrate an improved stability and increased mucoadhesive properties. Therefore, they seem to be advantageous for buccal administration over corresponding thiomers and chitosan. 23219338 Anti-diabetic activities of Gegen Qinlian Decoction in high-fat diet combined with streptozotocin-induced diabetic rats and in 3T3-L1 adipocytes. Gegen Qinlian Decoction (GGQLD) is one of the well-known traditional Chinese medicines. Recently, it was reported that GGQLD had good clinical effects on type 2 diabetes mellitus. However, few studies have confirmed in detail the anti-diabetic activities of GGQLD in vivo and in vitro. In the present study, we investigated the anti-diabetic effects of GGQLD in high-fat diet combined with streptozotocin-induced diabetic rats and in 3T3-L1 adipocytes. The present results suggested GGQLD (4.95, 11.55 and 18.15 g/kg) decreased significantly fasting blood glucose, glycosylated serum protein, and glycosylated hemoglobin of diabetic rats (p<0.05), and GGQLD (4.95 and 18.15 g/kg) decreased significantly fasting serum insulin levels of diabetic rats (p<0.05); in 3T3-L1 adipocytes, Gegen Qinlian Decoction-containing serum (GGQLD-CS) (4%, 8% and 16%) enhanced glucose consumption, triglyceride (TG) content, adiponectin protein concentration and the mRNA expression of adiponectin. Adiponectin contributes to the regulation of lipid and glucose metabolism, and can play a critical role in the development of diabetes mellitus; the mechanisms of action of GGQLD might be related to augmentation of adiponectin protein concentration and up-regulation of the mRNA expression of adiponectin. However, the multi-target mechanisms of action of GGQLD need to be clarified further. The present study further validated the beneficial effects of GGQLD as an anti-diabetic agent. These findings provide a new insight into the anti-diabetic application for GGQLD in clinic and display the potential of GGQLD as a new drug candidate for the treatment of diabetes mellitus. 23590470 Determination of urinary 6-mercaptopurine and three of its metabolites by HPLC-UV coupled with the iodine-azide reaction. Background: The presented method is able to determine 6-mercaptopurine (6-MP), 6-thioguanine, 6-mercaptopurine riboside and 6-thioguanine riboside in urine, and is thereby dedicated to control of thiopurine therapy of children with acute lymphoblastic leukemia. Good separation of the mentioned compounds was achieved on a C18 stationary phase with a sodium azide and sodium heptane sulfonate solution, acetonitrile and water at ratio of 50:1:49 (v/v/v). Results: Coefficient of regression is >0.99 for all linearity ranges. LOD and LOQ are 0.3, 0.4, 0.3, 0.8 and 0.4, 0.6, 0.5 and 0.9 nmol/ml of urine for 6-MP, 6-thioguanine, 6-mercaptopurine riboside and 6-thioguanine riboside, respectively. Intra- and inter-day recovery and RSD are close to 100% and less than 10%, respectively, for all investigated thiopurines. Conclusion: The elaborated method was successfully applied for detection and quantitation of 6-MP and its selected metabolites in patients' urine samples. 23085295 Molecular analyses of dinosaur osteocytes support the presence of endogenous molecules. The discovery of soft, transparent microstructures in dinosaur bone consistent in morphology with osteocytes was controversial. We hypothesize that, if original, these microstructures will have molecular features in common with extant osteocytes. We present immunological and mass spectrometry evidence for preservation of proteins comprising extant osteocytes (Actin, Tubulin, PHEX, Histone H4) in osteocytes recovered from two non-avian dinosaurs. Furthermore, antibodies to DNA show localized binding to these microstructures, which also react positively with DNA intercalating stains propidium iodide (PI) and 4',6'-diamidino-2-phenylindole dihydrochloride (DAPI). Each antibody binds dinosaur cells in patterns similar to extant cells. These data are the first to support preservation of multiple proteins and to present multiple lines of evidence for material consistent with DNA in dinosaurs, supporting the hypothesis that these structures were part of the once living animals. We propose mechanisms for preservation of cells and component molecules, and discuss implications for dinosaurian cellular biology. 23603103 Thermal inactivation reaction rates for ricin are influenced by pH and carbohydrates. Ricin is a lethal protein toxin produced by the castor bean plant. Ricin is known to possess significant heat resistance. Therefore, we placed it in a variety of foods to study the influence of the food matrix on behavior of a thermally stable protein toxin. First order rate constants for the thermal inactivation of ricin in foods and simple buffers were measured using cytotoxicity assays. We observed greater thermal stability at 75°C for the cytotoxic activity of ricin when it was placed in a yogurt-containing fruit drink compared to its stability when placed in the other foods tested. We found that galactose and high molecular weight exopolysaccharides present in various dairy products contributed to the thermal stability of ricin. Differential scanning calorimetry also showed enhanced thermal stability for ricin at pH 4.5. Our results demonstrate the importance of considering pH and the presence of stabilizing ligands in the thermal inactivation of protein toxins in foods. 23322166 LPA1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation. There has been much recent interest in lysophosphatidic acid (LPA) signaling through one of its receptors, LPA1, in fibrotic diseases, but the mechanisms by which LPA-LPA1 signaling promotes pathological fibrosis remain to be fully elucidated. Using a mouse peritoneal fibrosis model, we demonstrate central roles for LPA and LPA1 in fibroblast proliferation. Genetic deletion or pharmacological antagonism of LPA1 protected mice from peritoneal fibrosis, blunting the increases in peritoneal collagen by 65.4 and 52.9%, respectively, compared to control animals and demonstrated that peritoneal fibroblast proliferation was highly LPA1 dependent. Activation of LPA1 on mesothelial cells induced these cells to express connective tissue growth factor (CTGF), driving fibroblast proliferation in a paracrine fashion. Activation of mesothelial cell LPA1 induced CTGF expression by inducing cytoskeleton reorganization in these cells, causing nuclear translocation of myocardin-related transcription factor (MRTF)-A and MRTF-B. Pharmacological inhibition of MRTF-induced transcription also diminished CTGF expression and fibrosis in the peritoneal fibrosis model, mitigating the increase in peritoneal collagen content by 57.9% compared to controls. LPA1-induced cytoskeleton reorganization therefore makes a previously unrecognized but critically important contribution to the profibrotic activities of LPA by driving MRTF-dependent CTGF expression, which, in turn, drives fibroblast proliferation.-Sakai, N., Chun, J., Duffield, J. S., Wada, T., Luster, A. D., Tager, A. M. LPA1-induced cytoskeleton reorganization drives fibrosis through CTGF-dependent fibroblast proliferation. 23321396 A common LRP4 haplotype is associated with bone mineral density and hip geometry in men-data from the Odense Androgen Study (OAS). Osteoporosis is a common disease characterized by an increased susceptibility to fracture. It is a complex disorder resulting from the interaction of several polymorphisms in different genes and environmental factors. Since we recently reported a role for low density lipoprotein-related protein (LRP)-4 in monogenic disorders with bone overgrowth, we now wanted to evaluate whether genetic variation in the LRP4 gene has an effect on the susceptibility to osteoporosis in a population based cohort from the Odense Androgen Study. We chose to genotype four common (minor allele frequency (MAF)≥0.05) and non-synonymous coding polymorphisms located in the extracellular region of the LRP4 protein: rs3816614 (A/g), rs2306029 (G/a), rs2306033 (C/t) and rs6485702 (G/a) (large and small characters indicate major and minor alleles, respectively). Bone mineral density (BMD) measurements of the hip, the spine and whole body as well as different hip geometry parameters were available for a total of 1404 Danish men from two age groups ([20-29 years]: n=804; [60-74 years]: n=600). Using linear regression analysis adjusted for age, height and weight, we found significant associations between both rs2306029 and rs6485702 and BMD at all sites except the lumbar spine. The most significant association was found with whole body BMD (p=4.7×10(-5)). In addition, we found these two polymorphisms to be associated with different geometry parameters especially of the femoral shaft. Analysis of the two associated SNPs in the separate age groups demonstrated that most associations are only present in the youngest group of Danish men. In the group of elderly men, one Bonferroni corrected association between whole body BMD and rs6485702 was found to be significant. Subsequently, all polymorphisms were included in haplotype analyses using the PLINK software (v1.07). After adjusting for age, height and weight, two out of five common haplotypes (MAF≥0.01) were found to be of particular interest in the regulation of hip and whole body BMD (AGCG, AACA). Additional analysis suggested that these latter associations are driven by the association of rs6485702. We suggest, based on these results and the localisation of the variant in the third β-propeller domain of LRP4, that the variant has possibly a functional effect. Hereby, we conclude that common variation in the LRP4 gene determines hip and whole body BMD and thus confirm previous results from different GWAs. In addition, our data proves an additional role for LRP4 in regulating hip structure. Finally, interaction analysis for LRP4 with SOST and LRP5 showed interaction with LRP5 for femoral shaft geometry. 23046389 Interspecies variation in the metabolism of zoniporide by aldehyde oxidase. 1. Aldehyde oxidase (AO) is a cytosolic enzyme that contributes to the Phase I metabolism of xenobiotics in human and preclinical species. 2. Current studies explored in vitro metabolism of zoniporide in various animal species and humans using S9 fractions. The animal species included commonly used pharmacology and toxicology models and domestic animals such as the cat, cow or bull, pig and horse. 3. In addition, gender and strain differences in some species were also explored. 4. All animals except the dog and cat converted zoniporide to 2-oxozoniporide (M1). 5. Michael-Menten kinetic studies were conducted in species that turned over zoniporide to M1. 6. Marked differences in KM, Vmax and Clint were observed in the oxidation of zoniporide. 7. Although the KM and Vmax of zoniporide oxidation in male and female human S9 was similar, some gender difference was observed in animals especially, in Vmax. 8. The domestic animals also showed marked species differences in the AO activity and affinity toward zoniporide. 23578650 Impact of blanching on polyphenol stability and antioxidant capacity of innovative coriander (Coriandrum sativum L.) pastes. Fresh coriander leaves were steam- and water-blanched at 100°C and at 90 and 100°C, respectively, for 1-10min, and subsequently comminuted to form a paste. Pasty products obtained from coriander fruits were processed after water-blanching applying the same time-temperature regimes. Among the 11 phenolics characterised in leaves by high-performance liquid chromatography coupled to mass spectrometric detection, several caffeic acid derivatives, 5-feruloylquinic and 5-p-coumaroylquinic acids were tentatively identified for the first time. In fruits, 10 phenolics were detected, whereas rutin, a dicaffeic acid derivative and two feruloylquinic and caffeoylquinic acid isomers were newly detected. Upon steam-blanching for 1min, phenolic contents and antioxidant capacities remained virtually unchanged. In contrast, water-blanching and extended steam-blanching even yielded increased levels compared to the unheated control, whereas short-time water-blanching resulted in higher values than prolonged heat treatment. Thus, short-time water-blanching is recommended as the initial unit in the processing of coriander leaves and fruits into novel pasty products. 23265451 Cashew apple (Anacardium occidentale L.) extract from by-product of juice processing: a focus on carotenoids. Cashew apple fibrous residue is a by-product of the cashew juice industry. After pressing using a helical type continuous press followed by crossflow microfiltration, an aqueous extract was obtained from these cashew apple fibres. It was characterised by an intense yellow colour due to carotenoid pigments. Carotenoids were identified and quantified in the cashew apple before extraction, in its aqueous extract and in the concentrate obtained by microfiltration. Cashew apple aqueous extract and its concentrate presented a carotenoid profile with 11 carotenoids, most of them were tentatively identified by HPLC-DAD-MS and are xanthophylls present under an esterified form. Auroxanthin and β-cryptoxanthin represented around 50% of total carotenoids. Concentration of the extract by microfiltration led to epoxy-furanoxy rearrangement of violaxanthin and antheraxanthin. The process allowed an increase of 10 times total carotenoid content compared with initial cashew apple. Total carotenoid content of the final concentrated extract reached 54 mg/kg. 22554350 "Vitamin E" fortified parenteral lipid emulsions: Plackett-Burman screening of primary process and composition parameters. The objective of this study was to screen the effect of eight formulations and process parameters on the physical attributes and stability of "Vitamin E"-rich parenteral lipid emulsions. Screening was performed using a 12-run, 8-factor, 2-level Plackett-Burman design. This design was employed to construct polynomial equations that identified the magnitude and direction of the linear effect of homogenization pressure, number of homogenization cycles, primary and secondary emulsifiers, pre-homogenization temperature, oil loading, and ratio of vitamin E to medium-chain triglycerides (MCT) in the oil phase on particle size, polydispersity index, short-term stability, and outlet temperature of manufactured emulsions. The viscosity of vitamin E was reduced from 3700 (100%) to 64 mPa.s (30%) by MCT addition. As viscosity is critical for efficient emulsification, vitamin/MCT ratio was the most significant contributor for the stability of emulsions. Particle size increased from 236 to 388 nm, and percentage vitamin remaining emulsified after 48 h dropped from 100 to 73% with increase in vitamin/MCT ratio from 30/70 to 70/30. Significant decrease in particle size and PI, and an increase in outlet temperature were also observed with increase in homogenization pressure and number of homogenization cycles. Emulsifiers and oil loading, however, had insignificant effect on the responses. Overall, stable submicron emulsions at vitamin/MCT ratio of 30/70 could be prepared at 25,000 psi and 25 cycles in ambient conditions. The identification of these parameters by a well-constructed design demonstrated the utility of screening studies in the "Quality by Design" approach to pharmaceutical product development. 23265511 Effect of genotype, environment, and their interaction on phytochemical compositions and antioxidant properties of soft winter wheat flour. The effect of genotype (G), growing environment (E), and their interaction (G×E) on the antioxidant properties and chemical compositions were investigated using the flour samples of 10 wheat varieties grown in four different locations in Maryland. Lutein content of wheat flour ranged from 0.10 to 0.69 μg/g, and α-tocopherol ranged from 0.12 to 0.83 μg/g. Total carotenoids were primarily affected by E (45.7%), while G×E interaction had a larger effect on the level of total tocopherols (71.6%). E had the largest effect on antioxidant activity against oxygen, hydroxyl, and ABTS(·+) radicals. G had the least influence on the measured phytochemicals and antioxidant activity assays. Total carotenoids had a significant correlation with average low air temperature (r=0.359, p<0.01) as well as precipitation level (r=0.214, p<0.01). ABTS(·+) radical scavenging capacity had a positive correlation with average air temperature (r=0.705, p<0.01), while hydroxyl radical scavenging capacity had a negative correlation with temperature (r=-0.269. p<0.01). These results show that environment, genotype, and their interaction could influence the levels of lipophilic antioxidants and antioxidant activities of wheat flour. 23423570 High-glucose environment enhanced oxidative stress and increased interleukin-8 secretion from keratinocytes: New insights on impaired diabetic wound healing. Impaired wound healing frequently occurs in patients with diabetes. Interluekin-8 (IL-8) production by keratinocyte is responsible for recruiting neutrophils during healing. Intense inflammation is associated with diabetic wounds while reduction of neutrophil infiltration is associated with enhanced healing. We hypothesized that increased neutrophil recruitment by keratinocytes may contribute to the delayed healing of diabetic wound. Using cultured human keratinocytes and diabetic rat model, the current study showed that high-glucose environment enhanced IL-8 production via epidermal growth factor receptor (EGFR) -extracelluar signal-regulated kinase (ERK) pathway in a reactive oxygen species (ROS)-dependent manner in keratinocytes. In addition, diabetic rat skin showed enhanced EGFR, ERK and IL-8 expression as compared to control rats. The dermal neutrophil infiltration of the wound, as represented by expression of myeloperoxidase level, was also significantly higher in diabetic rats. Treating diabetic rats with dapsone, an agent known to inhibit neutrophil function, was associated with improved healing. In conclusion, IL-8 production and neutrophil infiltration are increased in high-glucose environment due to elevated ROS level and contributed to impaired wound healing in diabetic skin. Targeting these dysfunctions may present novel therapeutic approaches. 23065592 Polymorphisms in the vitamin D receptor gene and risk of autoimmune thyroid diseases: a meta-analysis. Environmental and genetic factors are thought to be involved in the pathogenesis of autoimmune thyroid diseases (AITD), which include Graves' disease, Hashimoto's thyroiditis. Polymorphisms of vitamin D receptor (VDR) were implicated in AITDs risk. To date, many studies have evaluated the association between a functional polymorphism in the VDR gene and AITDs risk; however, the result is still ambiguous and inconclusive. To address the association of VDR gene FokI (rs10735810), TaqI (rs731236), BsmI (rs1544410), and ApaI (rs7975232) polymorphisms with AITD risk by meta-analysis. By searching the relevant literature, a total of eight studies were identified and meta-analyzed. HWE for each study are checked. Crude odds ratios (OR) with 95 % confidence intervals (CIs) were used to assess the strength of association in the allele polymorphism, codominant model, dominant model, and recessive model. The result indicates that the BsmI or TaqI polymorphisms is significantly associated with AITD risk (OR = 0.801 95 % CI 0.705, 0.910, Pz = 0.001 for B vs. b; OR = 0.854, 95 % CI 0.757, 0.963, Pz = 0.010 for t vs. T), while the ApaI or FokI polymorphism do not. In the subgroup analysis in Europeans, the decreased risk of AITD remained for the B or t variant. This gene-based analysis indicates that, based on current evidence from published studies, the cumulative effect of BsmI or TaqI polymorphisms in VDR is significantly associated with AITD. 23561118 Alternanthera paronychioides protects pancreatic β-cells from glucotoxicity by its antioxidant, antiapoptotic and insulin secretagogue actions. The antioxidant and antiglucotoxic effects of Alternanthera paronychioides on pancreatic β-cell were investigated. Antioxidant assays demonstrated that ethanol extracts of A. paronychioides (EEAP) exhibited the highest antioxidant activity, which also had the highest phenolic and flavonoid contents. Two major polyphenolics, ferulic acid and quercetin, were identified from EEAP by HPLC-DAD. Effects of EEAP, ferulic acid and quercetin on high glucose (25mmol/L)-induced pancreatic β-cell apoptosis and dysfunction were further evaluated. Results showed that EEAP and quercetin but not ferulic acid protected β-cells from glucotoxicity through several mechanisms, including: (1) maintaining β-cell viability; (2) suppressing reactive oxygen species production; (3) reducing characteristic features of apoptosis; (4) inhibiting the activation of caspase-9 and caspase-3 and the cleavage of poly (ADP-ribose) polymerase; (5) upregulating pancreatic and duodenal homeobox 1 gene expression and the insulin secretagogue action of pancreatic β-cells. These findings may shed light on the preventive actions of A. paronychioides on diabetic glucotoxicity. 23315277 Silica nanoparticles-induced cytotoxicity, oxidative stress and apoptosis in cultured A431 and A549 cells. In medicine, the use of silica nanoparticles (SiO(2) NPs) offers new perspectives in biosensor, drug delivery and cancer therapy. However, questions about potential toxic and deleterious effects of SiO(2) NPs have also been raised. The aim of this study was to investigate the induction of cytotoxicity, oxidative stress and apoptosis by SiO(2) NPs (size 15 nm) in human skin epithelial (A431) and human lung epithelial (A549) cells. SiO(2) NPs (concentration range 25-200 µg/ml) induced dose-dependent cytotoxicity in both types of cells, which was demonstrated by cell viability (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) and lactate dehydrogenase leakage assays. SiO(2) NPs were also found to induce oxidative stress in a dose-dependent manner, indicated by depletion of glutathione and induction of reactive oxygen species (ROS) generation and lipid peroxidation. Quantitative real-time polymerase chain reaction analysis showed that following the exposure of cells to SiO(2) NPs, the messenger RNA level of apoptotic genes (caspase-3 and caspase-9) were upregulated in a dose-dependent manner. Moreover, activities of caspase-3 and caspase-9 enzymes were also significantly higher in both kinds of cells exposed to SiO(2) NPs. This study suggested that SiO(2) NPs induce cytotoxicity and apoptosis in A431 and A549 cells, which is likely to be mediated through ROS generation and oxidative stress. 23396488 A non-enzymatic function of Golgi glycosyltransferases: Mediation of Golgi fragmentation by interaction with non-muscle myosin IIA. The Golgi apparatus undergoes morphological changes under stress or malignant transformation, but the precise mechanisms are not known. We recently showed that non-muscle myosin IIA (NMIIA) binds to the cytoplasmic tail of Core 2 N-acetylglucosaminyltransferase mucus-type (C2GnT-M) and transports it to the endoplasmic reticulum for recycling. Here, we report that Golgi fragmentation induced by brefeldin A (BFA) or coatomer protein (β-COP) knockdown (KD) in Panc1-bC2GnT-M (c-Myc) cells is accompanied by the increased association of NMIIA with C2GnT-M and its degradation by proteasomes. Golgi fragmentation is prevented by inhibition or KD of NMIIA. Using multiple approaches, we have shown that the speed of BFA-induced Golgi fragmentation is positively correlated with the levels of this enzyme in the Golgi. The observation is reproduced in LNCaP cells which express high levels of two endogenous glycosyltransferases-C2GnT-L and β-galactoside α2,3 sialyltransferase 1. NMIIA is found to form complexes with these two enzymes but not Golgi matrix proteins. The KD of both enzymes or the prevention of Golgi glycosyltransferases from exiting endoplasmic reticulum reduced Golgi-associated NMIIA and decreased the BFA-induced fragmentation. Interestingly, the fragmented Golgi detected in colon cancer HT-29 cells can be restored to a compact morphology after inhibition or KD of NMIIA. The Golgi disorganization induced by the microtubule or actin destructive agent is NMIIA-independent and does not affect the levels of glycosyltransferases. We conclude that NMIIA interacts with Golgi residential but not matrix proteins, and this interaction is responsible for Golgi fragmentation induced by β-COP KD or BFA treatment. This is a novel non-enzymatic function of Golgi glycosyltransferases. 23220340 A simple molecular modeling method for the characterization of polymeric drug carriers. A simple molecular modeling method for the characterization of polymeric drug carriers is presented. Six biodegradable polymers have been investigated as drug carriers using molecular simulations: l-polylactide, d-polylactide, chitosan, polyglycolic acid, polyethylene glycol and cellulose. Cyclosporine A has been chosen as a model drug substance. Classical molecular dynamics and docking calculations were employed to model and predict polymer-drug interactions. These interactions have been analyzed by non-bond interaction energy and interaction parameter calculated using Flory-Huggins theory. Flexibility of polymer chains has been characterized by the change of gyration radius along the molecular dynamics trajectory. The relationship between mixing energy, chain length and chain flexibility has been revealed for each polymer/drug system. 23335398 Electron transfer dissociation (ETD): the mass spectrometric breakthrough essential for O-GlcNAc protein site assignments-a study of the O-GlcNAcylated protein host cell factor C1. The development of electron-based, unimolecular dissociation MS, i.e. electron capture and electron transfer dissociation (ECD and ETD, respectively), has greatly increased the speed and reliability of labile PTM site assignment. The field of intracellular O-GlcNAc (O-linked N-acetylglucosamine) signaling has especially advanced with the advent of ETD MS. Only within the last five years have proteomic-scale experiments utilizing ETD allowed the assignment of hundreds of O-GlcNAc sites within cells and subcellular structures. Our ability to identify and unambiguously assign the site of O-GlcNAc modifications using ETD is rapidly increasing our understanding of this regulatory glycosylation and its potential interaction with other PTMs. Here, we discuss the advantages of using ETD, complimented with collisional-activation MS, in a study of the extensively O-GlcNAcylated protein Host Cell Factor C1 (HCF-1). HCF-1 is a transcriptional coregulator that forms a stable complex with O-GlcNAc transferase and controls cell cycle progression. ETD, along with higher energy collisional dissociation (HCD) MS, was employed to assign the PTMs of the HCF-1 protein isolated from HEK293T cells. These include 19 sites of O-GlcNAcylation, two sites of phosphorylation, and two sites bearing dimethylarginine, and showcase the residue-specific, PTM complexity of this regulator of cell proliferation. 23643784 Controlling the Physical form of Mannitol in Freeze-Dried Systems. A potential drawback with the use of mannitol as a bulking agent is its existence as mannitol hemihydrate (MHH; C6H14O6(.)0.5H2O) in the lyophile. Once formed during freeze-drying, MHH dehydration may require secondary drying under aggressive conditions which can be detrimental to the stability of thermolabile components. If MHH is retained in the lyophile, the water released by MHH dehydration during storage has the potential to cause product instability. We systematically identified the conditions under which anhydrous mannitol and MHH crystallized in frozen systems with the goal of preventing MHH formation during freeze-drying. When mannitol solutions were cooled, the temperature of solute crystallization was the determinant of the physical form of mannitol. Based on low temperature X-ray diffractometry (using both laboratory and synchrotron sources), MHH formation was observed when solute crystallization occurred at temperatures ⩽ -20 °C while anhydrous mannitol crystallized at temperatures ⩾ -10 °C. The transition temperature (anhydrate - MHH) appears to be ∼ -15 °C. The use of a freeze-dryer with controlled ice nucleation technology enabled anhydrous mannitol crystallization at ∼ -5 °C. Thus, ice crystallization followed by annealing at temperatures ⩾ -10 °C can be an effective strategy to prevent MHH formation. 23570689 Maps of open chromatin highlight cell type-restricted patterns of regulatory sequence variation at hematological trait loci. Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types, and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs, and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits. 23610060 Very Low Calorie Diet Mimics the Early Beneficial Effect of Roux-en-Y Gastric Bypass on Insulin Sensitivity and Beta-Cell Function in Type 2 Diabetic Patients. Marked improvement in glycemic control occurs in patients with type 2 diabetes (T2DM) shortly after Roux-en-Y gastric bypass surgery (RYGB) and before there is major weight loss. The objective of this study was to determine if the magnitude of this change is primarily due to caloric restriction or is unique to the surgical procedure. We studied eleven subjects who underwent RYGB and fourteen subjects mean-matched for BMI, HbA1c and diabetes duration who were admitted to our inpatient research unit and given a very low calorie diet (VLCD) of 500 kcal/day with a macronutrient content similar to that consumed by patients after RYGB. Frequently sampled intravenous glucose tolerance tests were performed before and after interventions. Both groups lost an equivalent amount of weight over a mean study period of 21 days. Insulin sensitivity, acute insulin secretion after intravenous glucose administration and beta-cell function as determined by disposition index improved to a similar extent in both groups. Likewise, changes in fasting glucose and fructosamine levels were similar. Based on these data, VLCD improves insulin sensitivity and beta-cell function just as well as RYGB in the short term. This study was registered in ClinicalTrials.gov NCT00627484. 23210639 Self-assembly process of soft ferritin-PNIPAAm conjugate bionanoparticles at polar-apolar interfaces. We describe an in-depth investigation on the dynamics and assembly behavior at polar-apolar interfaces of ferritin-PNIPAAm conjugates (poly-N-isopropylacrylamide). The stabilization of oil-water interfaces by the modified ferritin was investigated by dynamic surface tension measurements and compared to the individual components of the bionanoparticle conjugate, namely, unmodified ferritin and pure PNIMAAm of similar molecular weight. It was found that the modified ferritin, even at a low particle concentration, rapidly reduces the interfacial tension. The difference in interfacial stabilization was also shown by cryo-scanning electron microscopy and scanning force microscopy, which displayed very different morphologies at the polar-apolar interface for the unmodified ferritin, pure PNIPAAm, and the ferritin-PNIPAAm conjugate, respectively. The self-assembly of the ferritin-PNIPAAm was further analyzed by cryo-transmission electron microscopy and fluorescence microscopy, for which a fluorescently labeled polymer was used. Both techniques revealed details on the assembly of the protein-polymer conjugate at the oil-water interface. 23640863 Toxic Shock Syndrome: Characterization of Human Immune Responses to TSST-1 and Evidence for Sensitivity Thresholds. Noninvasive vaginal infections by S. aureus strains producing the superantigen TSST-1 can cause menstrual toxic shock syndrome (mTSS). With the objective of exploring the basis for differential susceptibility to mTSS the relative responsiveness to TSST-1 of healthy women has been investigated. Peripheral blood mononuclear cells from healthy donors were incubated with purified TSST-1, or with the T cell mitogen phytohaemmaglutinin (PHA), and proliferation measured. The concentrations of TSST-1 and PHA required to elicit a response equivalent to 15% of the maximal achievable response (EC15) was determined. Although with PHA EC15 values were comparable between donors, subjects could be classified as being of high, medium or low sensitivity based on responsiveness to TSST-1. Sensitivity to TSST-1-induced proliferation was associated with increased production of the cytokines interleukin (IL)-2 and interferon γ (IFN-γ). When the entire T lymphocyte population was considered, there were no differences between sensitivity groups with respect to the frequency of cells known to be responsive to TSST-1 (those bearing CD3(+) Vβ2(+)). However, there was an association between sensitivity to TSST-1 and certain HLA-class II haplotypes. Thus, the frequency of DR7DQ2, DR14DQ5, DR4DQ8, and DR8DQ4 haplotypes were greater among those with high sensitivity; a finding confirmed by analysis of responses to immortalized homozygous B cell lines.Collectively, the results reveal that factors other than neutralising antibody and the frequency of Vβ2(+) T lymphocytes determine immunological responsiveness to TSST-1. Differential responsiveness of lymphocytes to TSST-1 may form the basis of inter-individual variations in susceptibility to mTSS. 23590563 Polyelectrolyte-Surfactant Complexes of Poly[3,5-bis(dimethylaminomethyl)-4-hydroxystyrene]-block-poly(ethylene oxide) and Sodium Dodecyl Sulfate: Anomalous Self-Assembly Behavior. Polyelectrolyte-surfactant complexes (PE-S) formed by double hydrophilic cationic polyelectrolyte poly[3,5-bis(dimethylaminomethyl)-4-hydroxystyrene]-block-poly(ethylene oxide) (NPHOS-PEO) and anionic surfactant sodium dodecyl sulfate (SDS) in acidic aqueous solutions were studied by light scattering, SAXS, and scanning transmission electron microcopy in the environmental mode (wet-STEM) for various stoichiometric ratios between the numbers of SDS anions and dimethylaminomethyl groups of NPHOS in the complex. The obtained results show that the NPHOS-PEO/SDS system behaves differently from other systems of double hydrophilic block polyelectrolyte and oppositely charged ionic surfactant because it forms water-insoluble PE-S for compositions close to the zero net charge of the complex. This phase separation occurs, instead of the PE-S rearrangement to core-shell particles, which is hindered due to conformational rigidity of the NPHOS blocks. For the surfactant amounts below and above the precipitation region, large spherical aggregates and their clusters are present in the solution. SAXS measurements indicate that although the NPHOS-PEO/SDS system does not form the core-shell particles with the NPHOS/SDS core and the PEO shell as other PE-S of double hydrophilic polyelectrolytes, the aggregates contain domains of closely packed surfactant micelles which bind to both NPHOS polyelectrolyte blocks and PEO blocks. 23601390 Food composition activities in South Africa. Researchers at the South African Medical Research Council used the Bangkok Declaration, Thailand, 2009, as a guideline for their food composition activities. The vision is to build a comprehensive food composition database for the country. Activities are directed at increasing the number of food items with country-specific nutrient information; encouraging research organisations, universities and the food industry to become involved in nutrient data generation and the generation of yield factors for South African dishes. The introduction of the South African Food Data System (SAFOODS) website and a symposium were major food composition activities. Educating users on the correct application of food composition data is an important endeavour. The national South African Food Data Advisory Group (SAFDAG) formed in 2008, advises and supports food composition activities at SAFOODS. In conclusion, with the support of SAFDAG, SAFOODS activities are aimed at compiling a country-specific food composition database and promoting its scientific use. 23296098 Endocrine disrupting effects of ochratoxin A at the level of nuclear receptor activation and steroidogenesis. Ochratoxin A (OTA) is a mycotoxin and extrolite of fungi which has been reported in a range of foods. This study uses mammalian reporter gene assays (RGAs) with natural steroid receptors and the H295R steroidogenesis assay to assess the endocrine disrupting activity of OTA. At the receptor level, OTA (within a concentration range of 0.25-2500 ng/ml) did not induce an agonistic response in an oestrogen, androgen, progestagen or glucocorticoid RGA. An antagonistic effect was observed in all of the RGAs at the highest concentration tested (2500 ng/ml). However, while there was no significant cytotoxic effect observed in the MTT (thiazolyl blue tetrazolium bromide) cell viability assay at this concentration, there was a corresponding change in cell morphology which may be related to the resulting antagonistic effect. At the hormone production level, H295R cells were used as a steroidogenesis model and exposed to OTA (within a concentration range of 0.1-1000 ng/ml). Treatment of the cells with 1000 ng/ml OTA increased the production of estradiol (117±14 ng/ml) over 3 times that of the solvent control (36±9 pg/ml). Western blotting confirmed an increase in aromatase protein. Overall the results indicate that OTA does not appear to interact with steroid receptors but has the potential to cause endocrine disruption by interfering with steroidogenesis. This is the first study identifying the effect OTA may have on production of the steroid hormone estradiol. 23590723 Improved Carrier Mobility in Few-Layer MoS2 Field-Effect Transistors with Ionic-Liquid Gating. We report the fabrication of ionic liquid (IL)-gated field-effect transistors (FETs) consisting of bilayer and few-layer MoS2. Our transport measurements indicate that the electron mobility μ ≈ 60 cm(2) V(-1) s(-1) at 250 K in IL-gated devices exceeds significantly that of comparable back-gated devices. IL-FETs display a mobility increase from ≈100 cm(2) V(-1) s(-1) at 180 K to ≈220 cm(2) V(-1) s(-1) at 77 K in good agreement with the true channel mobility determined from four-terminal measurements, ambipolar behavior with a high ON/OFF ratio >10(7) (10(4)) for electrons (holes), and a near ideal subthreshold swing of ≈50 mV/dec at 250 K. We attribute the observed performance enhancement, specifically the increased carrier mobility that is limited by phonons, to the reduction of the Schottky barrier at the source and drain electrode by band bending caused by the ultrathin IL dielectric layer. 23539089 Chemical Stability of the Lipid Phase in Concentrated Beverage Emulsions Colored with Natural β-Carotene. The aim of this study was to examine the oxidation of selected plant oils in concentrated beverage emulsions colored with natural β-carotene. Carotenoid preparations obtained from carrots were dissolved in cold-pressed linseed oil, refined canola oil, and refined palm olein. Oxidative stability of the lipids was examined with and without addition of the pigment to the oil/water (O/W) emulsion. Carotenoid/lipid hydro peroxide (LOOH) concentration was evaluated using two different methods: LOOH + Fe(2+) reaction connected with a colored complex of ammonium thiocyanate determined with the help of a spectrophotometer, and LOOH determined with the help of a chemiluminometer. It was shown that oxidation rate of lipids in the O/W emulsions strongly depended on chemical composition of the lipid fraction (type of oil used). Presence of the carotenoid pigment increased the rate. Therefore, if a carotenoid-containing emulsion is to be stable, it should be based on oils of a high oxidative stability. 23085331 Effect of amorphization method on telmisartan solubility and the tableting process. Telmisartan (TLM), a poorly water-soluble angiotensin II receptor antagonist in crystalline form, was transformed into the amorphous state by the melt quench technique, as well as a cryogenic grinding method, in order to improve its physiochemical properties. The chemical stability of TLM, that is, the tendency of the material to resist change or decomposition due to internal reaction, or due to the effects of air, heat, light, pressure, etc., during formation of the amorphous phase was assessed by monitoring high performance liquid chromatography. The existence of the amorphous state was confirmed by differential scanning calorimetry and X-ray powder diffraction. The glass transition occurred at T(g)=401K. In the next stage, the solubility of TLM in 0.1M HCl, phosphate buffer, pH=6.8, and water (25°C and 37°C) was determined. Both amorphous forms of TLM (vitrified and cryogrinded) had a higher solubility (μg/ml) than their crystalline counterpart. An important and interesting problem of the study was to evaluate how the tableting process was affected by the choice of either a crystalline or an amorphous form of TLM. Eight different tablet formulations were evaluated using both the crystalline and the amorphous form of TLM. Measurements of the physical properties and dissolution tests of G4 formulations tablets with telmisartan in crystalline and amorphous form after different storage periods were also performed. 23186033 Evaluation of romidepsin for clinical activity and radioactive iodine reuptake in radioactive iodine-refractory thyroid carcinoma. Background: Historically, systemic therapy for radioactive iodine (RAI)-refractory thyroid cancer has been understudied. Available drugs have modest efficacy. Romidepsin is a histone deacetylase inhibitor with potent antitumor effects both in vitro and in vivo. In thyroid cancer cell lines, romidepsin increases expression of both thyroglobulin and the sodium iodide symporter messenger RNAs, suggesting the possibility of improved iodine concentrating ability of RAI-resistant tumors. Methods: This was a single-institution Simon 2-stage phase II clinical study. Eligible patients had progressive, RAI-refractory, recurrent/metastatic, nonmedullary, nonanaplastic thyroid cancer. Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 measurable disease and adequate organ/marrow function were required. Romidepsin 13 mg/m(2) was administered intravenously on days 1, 8, and 15, in cycles of 28 days. The primary endpoint was the response rate by RECIST; change in RAI avidity was a secondary endpoint. The study closed after the first stage due to the lack of response. Results: Twenty patients were enrolled: female, 50%; median age, 64 years; histology, 8 papillary/1 follicular/11 Hürthle. Grade 4-5 adverse events (AEs) possibly related to the drug: grade 5, 1 sudden death; grade 4, 1 pulmonary embolus. Twelve of 20 subjects had a reported adverse event. No RECIST major responses have been seen. Response per protocol: stable disease, 13; disease progression, 7. Restoration of RAI avidity was documented in two patients. Median overall survival and time on study was 33.2 (1-71+) and 1.7 (0.46-12) months, respectively. Conclusions: We observed preliminary signs of in vivo reversal of RAI resistance after treatment with romidepsin. However, no major responses were observed and accrual was poor after the grade 5 AE. 23334429 NMR investigation on the DNA binding and B-Z transition pathway of the Zα domain of human ADAR1. Human ADAR1, which has two left-handed Z-DNA binding domains, preferentially binds Z-DNA rather than B-DNA with a high binding affinity. Z-DNA can be induced in long genomic DNA by Z-DNA binding proteins through the formation of two B-Z junctions with the extrusion of one base pair from each junction. We performed NMR experiments on complexes of Zα(ADAR1) with three DNA duplexes at a variety of protein-to-DNA molar ratios. This study confirmed that the Zα(ADAR1) first binds to an 8-bp CG-rich DNA segment via a unique conformation during B-Z transition and the neighboring AT-rich region becomes destabilized. We also found that, when DNA duplexes have only 6-bp CG-rich segment, the interaction with Zα(ADAR1) did not affect the thermal stabilities of the 6-bp CG-rich segment as well as the neighboring two A·T base pairs. These results indicate that four Zα(ADAR1) proteins interact with the 8-bp DNA sequence containing a 6-bp CG-repeat segment as well as a dinucleotide step, even though the dinucleotid step contains A∙T base pairs. Thus this study suggests that the length of the CG-rich region is more important than the specific DNA sequence for determining which base-pair is extruded from the B-Z junction structure. This study also found that the Zα(ADAR1) in complex with a 11-bp DNA duplex exhibits a Z-DNA-bound conformation distinct from that of free Zα(ADAR1) and the initial contact conformations of Zα(ADAR1) complexed with 13-bp DNA duplexes. 23180790 DDBJ new system and service refactoring. The DNA data bank of Japan (DDBJ, http://www.ddbj.nig.ac.jp) maintains a primary nucleotide sequence database and provides analytical resources for biological information to researchers. This database content is exchanged with the US National Center for Biotechnology Information (NCBI) and the European Bioinformatics Institute (EBI) within the framework of the International Nucleotide Sequence Database Collaboration (INSDC). Resources provided by the DDBJ include traditional nucleotide sequence data released in the form of 27 316 452 entries or 16 876 791 557 base pairs (as of June 2012), and raw reads of new generation sequencers in the sequence read archive (SRA). A Japanese researcher published his own genome sequence via DDBJ-SRA on 31 July 2012. To cope with the ongoing genomic data deluge, in March 2012, our computer previous system was totally replaced by a commodity cluster-based system that boasts 122.5 TFlops of CPU capacity and 5 PB of storage space. During this upgrade, it was considered crucial to replace and refactor substantial portions of the DDBJ software systems as well. As a result of the replacement process, which took more than 2 years to perform, we have achieved significant improvements in system performance. 23316963 Matrix metalloproteinases as potential targets in the venous dilation associated with varicose veins. Varicose veins (VVs) are a common venous disease of the lower extremity characterized by incompetent valves, venous reflux, and dilated and tortuous veins. If untreated, VVs could lead to venous thrombosis, thrombophlebitis and chronic venous leg ulcers. Various genetic, hormonal and environmental factors may lead to structural changes in the vein valves and make them incompetent, leading to venous reflux, increased venous pressure and vein wall dilation. Prolonged increases in venous pressure and vein wall tension are thought to increase the expression/activity of matrix metalloproteinases (MMPs). Members of the MMPs family include collagenases, gelatinases, stromelysins, matrilysins, membrane- type MMPs and others. MMPs are known to degrade various components of the extracellular matrix (ECM). MMPs may also affect the endothelium and vascular smooth muscle, causing changes in the vein relaxation and contraction mechanisms. Endothelial cell injury also triggers leukocyte infiltration, activation and inflammation, which lead to further vein wall damage. The vein wall dilation and valve dysfunction, and the MMP activation and superimposed inflammation and fibrosis would lead to progressive venous dilation and VVs formation. Surgical ablation is an effective treatment for VVs, but may be associated with high recurrence rate, and other less invasive approaches that target the cause of the disease are needed. MMP inhibitors including endogenous tissue inhibitors (TIMPs) and pharmacological inhibitors such as zinc chelators, doxycycline, batimastat and marimastat, have been used as diagnostic and therapeutic tools in cancer, autoimmune and cardiovascular disease. However, MMP inhibitors may have side effects especially on the musculoskeletal system. With the advent of new genetic and pharmacological tools, specific MMP inhibitors with fewer undesirable effects could be useful to retard the progression and prevent the recurrence of VVs. 23625804 Mechanistic Aspects of hSOD1 Maturation from the Solution Structure of Cu(I) -Loaded hCCS Domain 1 and Analysis of Disulfide-Free hSOD1 Mutants. Superoxide dismutase 1 (SOD1) maturation within the cell is mainly accomplished with the SOD1-specific chaperone, CCS, a dimeric protein with three distinct domains in each monomer. We recently showed that the first domain of human CCS (hCCSD1) is responsible for copper transfer to its protein partner, human SOD1 (hSOD1). The NMR solution structure of the copper(I)-loaded form of hCCSD1 reported here contributes further to characterization of the copper-transfer mechanism to hSOD1. NMR spectroscopy was also used to examine the hSOD1 mutants C57A, C146A, and C57A/C146A, which are unable to form the structurally conserved disulfide bond in SOD1, in order to investigate the role of these cysteines during hSOD1 copper acquisition. Together, the information on both hCCS and hSOD1, along with a sequence analysis of eukaryotic CCSD1, allows us to propose important mechanistic aspects regarding the copper-transfer process from hCCS to hSOD1. 23524878 Amelioration of iron overload-induced liver toxicity by a potent antioxidant and iron chelator, Emblica officinalis Gaertn. In liver, the major site of iron storage, iron overload is associated with oxidative damage of protein, lipid, and DNA and causes protein oxidation, lipid peroxidation, and rupture of hepatocytes, leading to cell death. Serum ferritin and liver iron content are the main forecasters of moderate to severe iron overload in the liver. The sequels of excess iron deposition in the liver are fibrosis and enhanced levels of serum enzymes and bilirubin markers. Emblica officinalis (EO) fruit extract was found efficient in lessening intraperitoneally injected iron dextran-induced liver toxicity in Swiss albino mice. Mice administered with different doses of 70% methanol extract of EO (50, 100, and 200 mg kg(-1) body weight) showed significant decrease in liver iron, serum ferritin, and serum enzyme levels, along with the decrease in lipid peroxidation, protein oxidation, and collagen content. The activity was further supported by its considerable iron chelation with half-maximal inhibitory concentration of 70.24 ± 2.74 μg ml(-1) and the protection on ferrous ion-mediated DNA breakdown with 50% protection ([P]50) of 1.04 ± 0.01 μg ml(-1). Simultaneously, the extract effectively induced the antioxidant enzyme levels and also exhibited the potential activity of reductive release of ferritin iron. These findings suggest that the EO extract may be used as a potent drug for the treatment of pathological sequences arisen in the iron overload-induced liver damage. 23261589 Salsolinol induced apoptotic changes in neural stem cells: amelioration by neurotrophin support. Salsolinol (SAL), a catechol isoquinoline has invited considerable attention due to its structural similarity with dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Its high endogenous presence in Parkinsonian brain implicated its possible association with the disease process. SAL is also present in alcohol beverages and certain food materials and can get access to brain especially in conditions of immature or impaired BBB. Besides this, the effect of SAL on neural stem cells (NSCs) which are potential candidates for adult neurogenesis and transplantation mediated rejuvenating attempts for Parkinson's disease (PD) brain has not been known so far. NSCs in both the cases have to overcome suppressive cues of diseased brain for their survival and function. In this study we explored the toxicity of SAL toward NSCs focusing on apoptosis and status of PI3K survival signaling. NSCs cultured from embryonic day 11 rat fetal brain including those differentiated to TH(+ve) colonies, when challenged with SAL (1-100μM), elicited a concentration and time dependent cell death/loss of mitochondrial viability. 10μM SAL on which significant mitochondrial impairment initiated was further used to study mechanism of toxicity. Morphological impairment, enhanced TUNEL positivity, cleaved caspase-3 and decreased Bcl-2:Bax suggested apoptosis. Sal toxicity coincided with reduced pAkt level and its downstream effectors: pCREB, pGSK-3β, Bcl-2 and neurotrophins GDNF, BDNF suggesting repressed PI3K/Akt signaling. Multiple neurotrophic factor support in the form of Olfactory Ensheathing Cell's Conditioned Media (OEC CM) potentially protected NSCs against SAL through activating PI3K/Akt pathway. This was confirmed on adding LY294002 the PI3K inhibitor which abolished the protection. We inferred that SAL exerts substantial toxicity toward NSCs. These findings will lead to better understanding of endogenous threats that might affect the fate of transplanted NSCs and their probable antidotes. 23150659 Assembly of subtype 1 influenza neuraminidase is driven by both the transmembrane and head domains. Neuraminidase (NA) is one of the two major influenza surface antigens and the main influenza drug target. Although NA has been well characterized and thought to function as a tetramer, the role of the transmembrane domain (TMD) in promoting proper NA assembly has not been systematically studied. Here, we demonstrate that in the absence of the TMD, NA is synthesized and transported in a predominantly inactive state. Substantial activity was rescued by progressive truncations of the stalk domain, suggesting the TMD contributes to NA maturation by tethering the stalk to the membrane. To analyze how the TMD supports NA assembly, the TMD was examined by itself. The NA TMD formed a homotetramer and efficiently trafficked to the plasma membrane, indicating the TMD and enzymatic head domain drive assembly together through matching oligomeric states. In support of this, an unrelated strong oligomeric TMD rescued almost full NA activity, whereas the weak oligomeric mutant of this TMD restored only half of wild type activity. These data illustrate that a large soluble domain can force assembly with a poorly compatible TMD; however, optimal assembly requires coordinated oligomerization between the TMD and the soluble domain. 23421620 Two new sesquiterpenes from cultures of the basidiomycete Agaricus arvensis. Two new drimane sesquiterpenoids, 11,12-dihydroxy-15-drimeneoic acid (1) and 3α,11,15-trihydroxydrimene (2), were isolated from cultures of the basidiomycete Agaricus arvensis, together with one known compound 3β,11,12-trihydroxydrimene (3). Their structures were established by means of spectroscopic analysis. 23406497 Switchable Elastin-Like Polypeptides that Respond to Chemical Inducers of Dimerization. Elastin-like polypeptides (ELPs) are protein polymers that reversibly phase separate in response to increased temperature, pressure, concentration, ionic strength, and molecular weight. If it were possible to engineer their phase separation to respond to specific molecular substrates, ELP fusion proteins might be engineered as biosensors, smart biomaterials, diagnostic imaging agents, and targeted therapies. What has been lacking is a strategy to design ELPs to respond to specific substrates. To address this deficiency, we report that ELP fusion proteins phase separate in response to chemical inducers of dimerization (CID). The rationale is that ELP phase separation depends on molecular weight, concentration, and local hydrophobicity; therefore, processes that affect these properties, including noncovalent dimerization, can be tuned to produce isothermal phase separation. To test this hypothesis, constructs were evaluated consisting of an immunophilin: human FK-506 binding protein 12 (FKBP) attached to an ELP. Under stoichiometric binding of a CID, the fusion protein homodimerizes and triggers phase separation. This dimerization is reversible upon saturation with excess CID or competitive binding of a small lipophilic macrolide to FKBP. By modulating the ELP molecular weight, phase separation was tuned for isothermal response to CID at physiological ionic strength and temperature (37 °C). To interpret the relationship between transition temperature and equilibrium binding constants, an empirical mathematical model was employed. To the best of our knowledge, this report is the first demonstration of reversible ELP switching in response to controlled dimerization. Due to its simplicity, this strategy may be useful to design ELP fusion proteins that respond to specific dimeric biological entities. 23531597 Streptococcal collagen-like protein A and general stress protein 24 are immunomodulating virulence factors of group A Streptococcus. In Western countries, invasive infections caused by M1T1 serotype group A Streptococcus (GAS) are epidemiologically linked to mutations in the control of virulence regulatory 2-component operon (covRS). In indigenous communities and developing countries, severe GAS disease is associated with genetically diverse non-M1T1 GAS serotypes. Hypervirulent M1T1 covRS mutant strains arise through selection by human polymorphonuclear cells for increased expression of GAS virulence factors such as the DNase Sda1, which promotes neutrophil resistance. The GAS bacteremia isolate NS88.2 (emm 98.1) is a covS mutant that exhibits a hypervirulent phenotype and neutrophil resistance yet lacks the phage-encoded Sda1. Here, we have employed a comprehensive systems biology (genomic, transcriptomic, and proteomic) approach to identify NS88.2 virulence determinants that enhance neutrophil resistance in the non-M1T1 GAS genetic background. Using this approach, we have identified streptococcal collagen-like protein A and general stress protein 24 proteins as NS88.2 determinants that contribute to survival in whole blood and neutrophil resistance in non-M1T1 GAS. This study has revealed new factors that contribute to GAS pathogenicity that may play important roles in resisting innate immune defenses and the development of human invasive infections-Tsatsaronis, J. A., Hollands, A., Cole, J. N., Maamary, P. G., Gillen, C. M., Ben Zakour, N. L., Kotb, M., Nizet, V., Beatson, S. A. Walker, M. J., Sanderson-Smith, M. L. Streptococcal collagen-like protein A and general stress protein 24 are immunomodulating virulence factors of group A Streptococcus. 23298698 Locally administered prostaglandin E2 prevents aeroallergen-induced airway sensitization in mice through immunomodulatory mechanisms. Prostaglandin E2 attenuates airway pathology in asthmatic patients and exerts a protective effect in antigen-sensitized mice when administered systemically. We aimed to establish the consequences of intranasal PGE2 administration on airway reactivity to aeroallergens in mice and reveal the underlying immunoinflammatory mechanisms. PGE2 was administered either daily during a 10-day exposure to house dust mite (HDM) extracts or for limited intervals. Airway hyperreactivity was measured by whole-body and invasive plethysmography. The phenotypes of lung immune cells and cytokine production were analysed by flow cytometry and ELISA, respectively. Airway hyperreactivity was sustainably reduced only when PGE2 administration was restricted to the initial 5 days of exposure to HDM. Lung inflammation, IL-4 production, and airway mast cell activity were also prevented under this early short-term treatment with PGE2. Interestingly, a Th2 response was already committed on day 5 of exposure to HDM. This was paralleled by GM-CSF and osteopontin upregulation and a decreased number of plasmacytoid dendritic and T regulatory cells, as well as a trend towards reduced IL-10 expression. Local PGE2 administration prevented the increase of airway IL-13 and osteopontin and kept lung plasmacytoid dendritic cell counts close to baseline. GM-CSF and Tregs were unaffected by the treatment. These findings suggest that the protection provided by PGE2 is a result of the modulation of early lung immunomodulatory mechanisms, and possibly a shift in the balance of dendritic cells towards a tolerogenic profile. 23437791 Pu-erh tea hot-water extract activates Akt and induces insulin-independent glucose transport in rat skeletal muscle. Skeletal muscle is a major organ that is important for whole-body glucose metabolism. We found that when isolated rat epitrochlearis muscle was incubated with a Pu-erh tea hot-water extract (PTE) for 30 min, the rate of 3-O-methyl-D-glucose (3MG) transport increased in the absence of insulin. This activation was associated with an increase in Ser(473) phosphorylation of Akt, a signaling intermediary leading to insulin-dependent glucose transport, but not Tyr(458) phosphorylation of phosphoinositide 3-kinase p85, an upstream molecule of Akt. PTE-stimulated 3MG transport was also not accompanied by Thr(172) phosphorylation of the catalytic α-subunit of 5'-AMP-activated protein kinase (AMPK). Gallic acid, a water-soluble ingredient in Pu-erh tea, stimulated Akt phosphorylation, but not AMPK phosphorylation. These results suggest that Pu-erh tea potentially promotes skeletal muscle glucose transport at least in part by activating Akt. 23025634 Picosecond kinetics of strongly coupled excitons and surface plasmon polaritons. Coupling between excitons of CdSe nanocrystal quantum dots (NQDs) and surface plasmon polaritons (SPPs) of an Ag film attached to a prism have been studied by steady-state and transient reflectivity measurements in the Kretschmann geometry. In these experiments, the angle of incidence of the probe beam selects hybrid exciton/SPP states with different wavevectors and exciton/SPP compositions. The dynamics measured in the transient reflectivity experiments are sensitive to the composition of the hybrid states. Specifically, fast dynamics are observed at probe wavevectors where the lower hybrid state has predominant SPP character. In contrast, at probe wavevectors where the lower hybrid state is predominantly excitonic, the dynamics are similar to that measured for CdSe NQDs on glass. 23361586 Transcriptional regulators of hepatic gluconeogenesis. Glucose is a primary fuel for generating energy in basic daily activities. Thus, glucose homeostasis is tightly regulated by counter-regulatory hormones such as glucagon, cortisol, and insulin, which affect key organs including liver, skeletal muscle, pancreas, and adipocytes. Among metabolic tissues, liver plays a critical role in controlling glucose production under various hormonal and metabolic cues. Under fasting, acute activation of both glycogenolysis and gluconeogenesis is achieved by post-translational modification or allosteric activation of key rate-limiting enzymes, thereby enabling enhanced glucose production from the liver to maintain glucose homeostasis. More prolonged fasting or starvation leads to the chronic activation of gluconeogenesis that requires increased expression of key enzymes in the pathway, which is turned off under feeding conditions by the molecular events that are initiated by insulin. This process is normally achieved by the regulation of gene expression at the level of transcription. Recently, the transcriptional regulators of hepatic gluconeogenesis are considered as potential therapeutic targets for the treatment of type 2 diabetes. In this review, we would like to discuss the current knowledge regarding the key transcriptional activators and inhibitors of hepatic gluconeogenic program to provide the better insight into the control of glycemia in the disease status. 23461763 Grazing-incidence neutron-induced fluorescence probes density profiles of labeled molecules at solid/liquid interfaces. We report on the use of characteristic prompt γ-fluorescence after neutron capture induced by an evanescent neutron wave to probe densities and depth profiles of labeled molecules at solid/liquid interfaces. In contrast to classical scattering techniques and X-ray fluorescence, this method of "grazing-incidence neutron-induced fluorescence" combines direct chemical specificity, provided by the label, with sensitivity to the interface, inherent to the evanescent wave. We demonstrate that the formation of a supported lipid membrane can be quantitatively monitored from the characteristic fluorescence of (157)Gd(3+) ions bound to the headgroup of chelator lipids. Moreover, we were able to localize the (157)Gd(3+) ions along the surface normal with nanometer precision. This first proof of principle with a well-defined model system suggests that the method has a great potential for biology and soft matter studies where spatial resolution and chemical sensitivity are required. 23505224 Electrochemical Oxygen Reduction Behavior of Selectively Deposited Platinum Atoms on Gold Nanoparticles. Carbon-supported Pt@Au "core-shell" nanoparticles with varying surface concentration of platinum atoms have been synthesized using a novel redox-mediated synthesis approach. The synthesis technique allows for a selective deposition of platinum atoms on the surface of prefabricated gold nanoparticles. Energy dispersive spectroscopic analyses in a scanning electron microscope reveal that the platinum to gold atomic ratios are close to the nominal values, validating the synthesis scheme. X-ray diffraction data indicate an un-alloyed structure. The platinum to gold surface atomic ratio determined from cyclic voltammetry and copper under-potential deposition experiments reveal good agreement with the calculated values at low platinum concentration. However, there is an increase in non-uniformity in the deposition process upon increasing the platinum concentration. Koutecky-Levich analysis of the samples indicates a transition of the total number of electrons transferred (n) in the electrochemical oxygen reduction reaction from two to four electrons upon increasing the surface concentration of platinum atoms. Furthermore, the data indicate that isolated platinum atoms can reduce molecular oxygen but via a two-electron route. Moreover, successful four-electron reduction of molecular oxygen requires clusters of platinum atoms. 23270326 Protein synthesis inhibition and oxidative stress induced by cylindrospermopsin elicit apoptosis in primary rat hepatocytes. The increasing presence of cyanotoxin producers in several regions of the world is hazardous for humans and animals. Cylindrospermopsin (CYN) is nowadays recognized as a widely distributed freshwater cyanobacterial toxin. This toxin has been shown to induce protein synthesis inhibition as well as inhibition of glutathione synthesis. Given that the liver seems to be the main target of cylindrospermopsin, in this work we used cultures of primary rat hepatocytes to study the type of cell death induced by CYN nanomolar concentrations. The involvement of reactive oxygen species in toxin induced cell death, the relationship between protein synthesis inhibition and toxicity, and the cell endogenous antioxidant response regulation were studied. We show that cylindrospermopsin induces apoptosis in primary rat hepatocytes. At the concentrations used in this work, protein synthesis inhibition and oxidative stress were involved in the cytotoxic effect elicited by the toxin. Finally, activation of the cell antioxidant response was observed at the transcriptional and translational levels. 23603023 Targeting intracellular compartments by magnetic polymeric nanoparticles. Superparamagnetic iron oxide nanoparticles (SPIONs) show a great promise for a wide specter of bioapplications, due to their characteristic magnetic properties exhibited only in the presence of magnetic field. Their advantages in the fields of magnetic drug targeting and imaging are well established and their safety is assumed, since iron oxide nanoparticles have already been approved for in vivo application, however, according to many literature reports the bare metal oxide nanoparticles may cause toxic effects on treated cells. Therefore, it is reasonable to prevent the direct interactions between metal oxide core and surrounding environment. In the current research ricinoleic acid coated maghemite nanoparticles were successfully synthesized, characterized and incorporated in the polymeric matrix, resulting in nanosized magnetic polymeric particles. The carrier system was shown to exhibit superparamagnetic properties and was therefore responsive towards external magnetic field. Bioevaluation using T47-D breast cancer cells confirmed internalization of magnetic polymeric nanoparticles (MNPs) and their intracellular localization in various subcellular compartments, depending on presence/absence of external magnetic field. However, the number of internalized MNPs observed by fluorescent and transmission electron microscopy was relatively low, making such way of targeting effective only for delivery of highly potent drugs. The scanning electron microscopy of treated cells revealed that MNPs influenced the cell adhesion, when external magnetic field was applied, and that treatment resulted in damaged apical plasma membrane right after exposure to the magnetic carrier. On the other hand, MNPs showed only reversibly reduced cellular metabolic activity in concentrations up to 200μg/ml and, in the tested concentration the cell cycle distribution was within the normal range, indicating safety of the established magnetic carrier system for the treated cells. 23347043 Structural and mechanical heterogeneity of the erythrocyte membrane reveals hallmarks of membrane stability. The erythrocyte membrane, a metabolically regulated active structure that comprises lipid molecules, junctional complexes, and the spectrin network, enables the cell to undergo large passive deformations when passing through the microvascular system. Here we use atomic force microscopy (AFM) imaging and quantitative mechanical mapping at nanometer resolution to correlate structure and mechanics of key components of the erythrocyte membrane, crucial for cell integrity and function. Our data reveal structural and mechanical heterogeneity modulated by the metabolic state at unprecedented nanometer resolution. ATP-depletion, reducing skeletal junction phosphorylation in RBC cells, leads to membrane stiffening. Analysis of ghosts and shear-force opened erythrocytes show that, in the absence of cytosolic kinases, spectrin phosphorylation results in membrane stiffening at the extracellular face and a reduced junction remodeling in response to loading forces. Topography and mechanical mapping of single components at the cytoplasmic face reveal that, surprisingly, spectrin phosphorylation by ATP softens individual filaments. Our findings suggest that, besides the mechanical signature of each component, the RBC membrane mechanics is regulated by the metabolic state and the assembly of its structural elements. 23462583 Placental transfer of (125)Iodinated humanized immunoglobulin G2Δa in the Sprague Dawley rat. Antibody-like biopharmaceuticals cross the placenta by utilizing transport pathways available for transfer of maternal antibodies to the conceptus. To characterize the timing and magnitude of this transfer in the rat, embryo/fetal biodistribution of maternally administered radiolabeled humanized IgG2 was quantified over the course of gestation using gamma counting and whole body autoradiography. The result was humanized IgG2 found in rat embryo/fetal tissues as early as gestation day 11 with a >1000-fold increase in the amount of total IgG2 by day 21. The concentration of IgG2 in rat embryo/fetal tissues generally remained unchanged from gestation day 11 to 17 with a slight increase from day 17 to 21. In addition, fetal-maternal tissue concentration ratios remained stable during organogenesis with a slight increase from gestation day 17 to 21. Based on the empirical amount of antibody present in the embryo/fetus during specific developmental windows, direct antibody binding to biological targets could potentially result in adverse developmental outcomes. 23635097 3D Printed Bionic Ears. The ability to three-dimensionally interweave biological tissue with functional electronics could enable the creation of bionic organs possessing enhanced functionalities over their human counterparts. Conventional electronic devices are inherently two-dimensional, preventing seamless multidimensional integration with synthetic biology, as the processes and materials are very different. Here, we present a novel strategy for overcoming these difficulties via additive manufacturing of biological cells with structural and nanoparticle derived electronic elements. As a proof of concept, we generated a bionic ear via 3D printing of a cell-seeded hydrogel matrix in the anatomic geometry of a human ear, along with an intertwined conducting polymer consisting of infused silver nanoparticles. This allowed for in vitro culturing of cartilage tissue around an inductive coil antenna in the ear, which subsequently enables readout of inductively-coupled signals from cochlea-shaped electrodes. The printed ear exhibits enhanced auditory sensing for radio frequency reception, and complementary left and right ears can listen to stereo audio music. Overall, our approach suggests a means to intricately merge biologic and nanoelectronic functionalities via 3D printing. 23349489 β-Cells Are Not Generated in Pancreatic Duct Ligation-Induced Injury in Adult Mice. The existence of adult β-cell progenitors remains the most controversial developmental biology topic in diabetes research. It has been reported that β-cell progenitors can be activated by ductal ligation-induced injury of adult mouse pancreas and apparently act in a cell-autonomous manner to double the functional β-cell mass within a week by differentiation and proliferation. Here, we demonstrate that pancreatic duct ligation (PDL) does not activate progenitors to contribute to β-cell mass expansion. Rather, PDL stimulates massive pancreatic injury, which alters pancreatic composition and thus complicates accurate measurement of β-cell content via traditional morphometry methodologies that superficially sample the pancreas. To overcome this potential bias, we quantified β-cells from the entire pancreas and observed that β-cell mass and insulin content are totally unchanged by PDL-induced injury. Lineage-tracing studies using sequential administration of thymidine analogs, rat insulin 2 promoter-driven cre-lox, and low-frequency ubiquitous cre-lox reveal that PDL does not convert progenitors to the β-cell lineage. Thus, we conclude that β-cells are not generated in injured adult mouse pancreas. 23475902 A novel nontoxic inhibitor of the activation of NADPH oxidase reduces reactive oxygen species production in mouse lung. 1-Hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol (MJ33) is a fluorinated phospholipid analog that inhibits the phospholipase A2 (PLA2) activity of peroxiredoxin 6 (Prdx6). Prdx6 PLA2 activity is required for activation of NADPH oxidase 2 and subsequent generation of reactive oxygen species (ROS). In vitro, MJ33 inhibited agonist-stimulated production of ROS by the isolated perfused mouse lung, lung microvascular endothelial cells, and polymorphonuclear leukocytes. MJ33 (0.02-0.5 µmol MJ33/kg body weight) in mixed unilamellar liposomes was administered to C57BL/6 mice by either intratracheal (i.t.) or i.v. routes. Lung MJ33 content, measured by liquid chromatography/mass spectroscopy, showed uptake of 67-87% of the injected dose for i.t. and 23-42% for i.v. administration at 4 hours postinjection. PLA2 activity of lung homogenates was markedly inhibited (>85%) at 4 hours postadministration. Both MJ33 content and PLA2 activity gradually returned to near control levels over the subsequent 24-72 hours. Mice treated with MJ33 at 12.5-25 µmol/kg did not show changes (compared with control) in clinical symptomatology, body weight, hematocrit, and histology of lung, liver, and kidney during a 30- to 50-day observation period. Thus, the toxic dose of MJ33 was >25 µmol/kg, whereas the PLA2 inhibitory dose was approximately 0.02 µmol/kg, indicating a high margin of safety. MJ33 administered to mice prior to lung isolation markedly reduced ROS production and tissue lipid and protein oxidation during ischemia followed by reperfusion. Thus, MJ33 could be useful as a therapeutic agent to prevent ROS-mediated tissue injury associated with lung inflammation or in harvested lungs prior to transplantation. 22999913 Mechanistic systems modeling to guide drug discovery and development. A crucial question that must be addressed in the drug development process is whether the proposed therapeutic target will yield the desired effect in the clinical population. Pharmaceutical and biotechnology companies place a large investment on research and development, long before confirmatory data are available from human trials. Basic science has greatly expanded the computable knowledge of disease processes, both through the generation of large omics data sets and a compendium of studies assessing cellular and systemic responses to physiologic and pathophysiologic stimuli. Given inherent uncertainties in drug development, mechanistic systems models can better inform target selection and the decision process for advancing compounds through preclinical and clinical research. 23561174 Characterisation of chlorophyll oxidation mediated by peroxidative activity in olives (Olea europaea L.) cv. Hojiblanca. The oxidation of chlorophyll a (chl a) catalysed by peroxidase (POD) from mesocarp of the olive fruit (Olea europaea L., cv Hojiblanca) in the presence of H2O2 and 2,4-dichlorophenol (2,4-DCP), is characterised via the individualised quantification of the products of the enzymatic reaction using a new methodology of HPLC-UV spectrometry. This innovation has allowed the discovery that, in addition to 13(2) OH chl a and 15(1) OH lactone chl a, which are the first products of POD on chl a, the reaction process sequentially creates another series of oxidised chlorophyll derivatives which have not been previously described. Their origins have been linked to POD activity in the presence of 2,4-DCP. Likewise, a study of the effect of the concentration of the various cosubstrates on the POD reaction rate demonstrated that the correct establishment of the relative concentrations of the same ([H2O2]/[2,4-DCP]/[Chl]=1:3:0.02) is crucial to explaining inhibition effects by substrates and carrying out optimum measurements. Therefore, new essential parameters for the determination of POD activity on a chlorophyll substrate are established. 23389324 The effect of magnetically induced linear aggregates on proton transverse relaxation rates of aqueous suspensions of polymer coated magnetic nanoparticles. It has been recently reported that for some suspensions of magnetic nanoparticles the transverse proton relaxation rate, R(2), is dependent on the time that the sample is exposed to an applied magnetic field. This time dependence has been linked to the formation of linear aggregates or chains in an applied magnetic field via numerical modeling. It is widely known that chain formation occurs in more concentrated ferrofluids systems and that this has an affect on the ferrofluid properties. In this work we examine the relationships between colloidal stability, the formation of these linear structures, and changes observed in the proton transverse relaxation rate of aqueous suspensions of magnetic particles. A series of iron oxide nanoparticles with varying stabilizing ligand brush lengths were synthesized. These systems were characterized with dynamic light scattering, transmission electron microscopy, dark-field optical microscopy, and proton transverse relaxation rate measurements. The dark field optical microscopy and R(2) measurements were made in similar magnetic fields over the same time scale so as to correlate the reduction of the transverse relaxivity with the formation of linear aggregates. Our results indicate that varying the ligand length has a direct effect on the colloidal arrangement of the system in a magnetic field, producing differences in the rate and size of chain formation, and hence systematic changes in transverse relaxation rates over time. With increasing ligand brush length, attractive inter-particle interactions are reduced, which results in slower aggregate formation and shorter linear aggregate length. These results have implications for the stabilization, characterization and potentially the toxicity of magnetic nanoparticle systems used in biomedical applications. 23353053 1,2,3,4,6 Penta-O-galloyl-β-d-glucose, a bioactivity guided isolated compound from Mangifera indica inhibits 11β-HSD-1 and ameliorates high fat diet-induced diabetes in C57BL/6 mice. Methanolic leaf extract of Mangifera indica (MEMI) was subjected to bioactivity guided fractionation in order to identify the active antidiabetic constituent. 32 fractions were evaluated for possible 11β-HSD-1 inhibition activity under in vitro conditions. The EA-7/8-9/10-4 fraction was evolved as a most potent fraction among all the fractions and it was identified as well known gallotannin compound 1,2,3,4,6 penta-O-galloyl-β-d-glucose (PGG) by spectral analysis. Based on these results the PGG was further evaluated in ex vivo 11β-HSD-1 inhibition assay and high fat diet (HFD)-induced diabetes in male C57BL/6 mice. Single dose (10, 25, 50 and 100mg/kg) of PGG and carbenoxolone (CBX) have dose dependently inhibited the 11β-HSD-1 activity in liver and adipose tissue. Furthermore, HFD appraisal to male C57BL/6 mice caused severe hyperglycemia, hypertriglyceridemia, elevated levels of plasma corticosterone and insulin, increased liver and white adipose mass with increase in body weight was observed compare to normal control. Also, oral glucose tolerance was significantly impaired compare to normal control. Interestingly, post-treatment with PGG for 21 days had alleviated the HFD-induced biochemical alterations and improved oral glucose tolerance compare to HFD-control. In conclusion, the PGG isolated from MEMI inhibits 11β-HSD-1 activity and ameliorates HFD-induced diabetes in male C57BL/6 mice. 23318451 TRIM3, a tumor suppressor linked to regulation of p21(Waf1/Cip1). The TRIM family of genes is largely studied because of their roles in development, differentiation and host cell antiviral defenses; however, roles in cancer biology are emerging. Loss of heterozygosity of the TRIM3 locus in ∼20% of human glioblastomas raised the possibility that this NHL-domain containing member of the TRIM gene family might be a mammalian tumor suppressor. Consistent with this, reducing TRIM3 expression increased the incidence of and accelerated the development of platelet-derived growth factor -induced glioma in mice. Furthermore, TRIM3 can bind to the cdk inhibitor p21(WAF1/CIP1). Thus, we conclude that TRIM3 is a tumor suppressor mapping to chromosome 11p15.5 and that it might block tumor growth by sequestering p21 and preventing it from facilitating the accumulation of cyclin D1-cdk4.Oncogene advance online publication, 14 January 2013; doi:10.1038/onc.2012.596. 23624389 Regulation of bone morphogenetic protein signalling and cranial osteogenesis by Gpc1 and Gpc3. From birth, the vault of the skull grows at a prodigious rate, driven by the activity of osteoblastic cells at the fibrous joints (sutures) that separate the bony calvarial plates. One in 2500 children is born with a medical condition known as craniosynostosis because of premature bony fusion of the calvarial plates and a cessation of bone growth at the sutures. Bone morphogenetic proteins (BMPs) are potent growth factors that promote bone formation. Previously, we found that Glypican-1 (GPC1) and Glypican-3 (GPC3) are expressed in cranial sutures and are decreased during premature suture fusion in children. Although glypicans are known to regulate BMP signalling, a mechanistic link between GPC1, GPC3 and BMPs and osteogenesis has not yet been investigated. We now report that human primary suture mesenchymal cells coexpress GPC1 and GPC3 on the cell surface and release them into the media. We show that they inhibit BMP2, BMP4 and BMP7 activities, which both physically interact with BMP2 and that immunoblockade of endogenous GPC1 and GPC3 potentiates BMP2 activity. In contrast, increased levels of GPC1 and GPC3 as a result of overexpression or the addition of recombinant protein, inhibit BMP2 signalling and BMP2-mediated osteogenesis. We demonstrate that BMP signalling in suture mesenchymal cells is mediated by both SMAD-dependent and SMAD-independent pathways and that GPC1 and GPC3 inhibit both pathways. GPC3 inhibition of BMP2 activity is independent of attachment of the glypican on the cell surface and post-translational glycanation, and thus appears to be mediated by the core glypican protein. The discovery that GPC1 and GPC3 regulate BMP2-mediated osteogenesis, and that inhibition of endogenous GPC1 and GPC3 potentiates BMP2 responsiveness of human suture mesenchymal cells, indicates how downregulation of glypican expression could lead to the bony suture fusion that characterizes craniosynostosis. 23040268 Lipoprotein(a) metabolism: potential sites for therapeutic targets. Lipoprotein(a) [Lp(a)] resembles low-density lipoprotein (LDL), with an LDL lipid core and apolipoprotein B (apoB), but contains a unique apolipoprotein, apo(a). Elevated Lp(a) is an independent risk factor for coronary and peripheral vascular diseases. The size and concentration of plasma Lp(a) are related to the synthetic rate, not the catabolic rate, and are highly variable with small isoforms associated with high concentrations and pathogenic risk. Apo(a) is synthesized in the liver, although assembly of apo(a) and LDL may occur in the hepatocytes or plasma. While the uptake and clearance site of Lp(a) is poorly delineated, the kidney is the site of apo(a) fragment excretion. The structure of apo(a) has high homology to plasminogen, the zymogen for plasmin and the primary clot lysis enzyme. Apo(a) interferes with plasminogen binding to C-terminal lysines of cell surface and extracellular matrix proteins. Lp(a) and apo(a) inhibit fibrinolysis and accumulate in the vascular wall in atherosclerotic lesions. The pathogenic role of Lp(a) is not known. Small isoforms and high concentrations of Lp(a) are found in healthy octogenarians that suggest Lp(a) may also have a physiological role. Studies of Lp(a) function have been limited since it is not found in commonly studied small mammals. An important aspect of Lp(a) metabolism is the modification of circulating Lp(a), which has the potential to alter the functions of Lp(a). There are no therapeutic drugs that selectively target elevated Lp(a), but a number of possible agents are being considered. Recently, new modifiers of apo(a) synthesis have been identified. This review reports the regulation of Lp(a) metabolism and potential sites for therapeutic targets. 23094694 Restricted distribution and limited gene flow in the model ciliate Tetrahymena thermophila. The biogeography of microbial eukaryotes has long been debated, but few phylogeographic data have been available to assess whether protists tend to have ubiquitous or endemic distributions. We addressed this issue in the ciliate Tetrahymena thermophila, a highly successful model system in cell and molecular biology. We found that this species has a distribution that is restricted to the Eastern United States, with high diversity in the northeast and low diversity across the rest of its distribution. We find high levels of population subdivision, low rates of migration and significant isolation by distance, supporting the moderate endemicity model of protist biogeography. This restricted gene flow may be a result of small population size, which would reduce the probability of migration events, or the inability to establish after migration. This work lays the foundation for T. thermophila to become a valuable model system for studying population biology. 23255426 A metabonomics investigation of multiple sclerosis by nuclear magnetic resonance. Multiple sclerosis (MS) is a nervous system disease that affects the fatty myelin sheaths around the axons of the brain and spinal cord, leading to demyelination and a broad range of signs and symptoms. MS can be difficult to diagnose because its signs and symptoms may be similar to other medical problems. To find out which metabolites in serum are effective for the diagnosis of MS, we utilized metabolic profiling using proton nuclear magnetic resonance spectroscopy ((1)H-NMR). Random forest (RF) was used to classify the MS patients and healthy subjects. Atomic absorption spectroscopy was used to measure the serum levels of selenium. The results showed that the levels of selenium were lower in the MS group, when compared with the control group. RF was used to identify the metabolites that caused selenium changes in people with MS by building a correlation model between these metabolites and serum levels of selenium. For the external test set, the obtained classification model showed a 93% correct classification of MS and healthy subjects. The regression model of levels of selenium and metabolites showed the correlation (R(2)) value of 0.88 for the external test set. The results indicate the suitability of NMR as a screen for identifying MS patients and healthy subjects. A novel model with good prediction outcomes was constructed between serum levels of selenium and NMR data. 23640034 Mechanism of BDE209-induced impaired glucose homeostasis based on gene microarray analysis of adult rat liver. Several persistent organic pollutants are reported to be potentially associated with the risk of human diabetes that has become rapidly epidemic in China currently. 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE209) is commercially most important both in the production and in the use of polybrominated diphenyl ethers (PBDEs). It might bioaccumulate in wildlife and human and is the only PBDEs mixture still used today. In the present study, male adult rats treated with BDE209 (0, 0.05, 1, and 20 mg/kg) for 8 weeks were used to explore the effects of BDE209 on glucose homeostasis and possible mechanisms; 0.05 mg/kg of BDE209 induced dose-related hyperglycemia. Then, we performed the full-genome gene expression microarrays, gene ontology analysis, and pathway analysis in this group and control. BDE209 induced 1,257 liver gene transcript changes, and 18 canonical pathways were significantly enriched. Four of them were involved in immune diseases, including autoimmune thyroid disease, graft-versus-host disease, allograft rejection, and type I diabetes mellitus (T1MD), which was confirmed by the decrease in serum insulin. Subsequently, gene act network and gene co-expression network found that some MHC molecules and TNF-α were involved in T1DM pathway, which was then confirmed by the increase in serum TNF-α. Additionally, reduced glutathione and superoxide dismutase in plasma indicated that oxidative damage might partly contribute to BDE209-induced hyperglycemia. The results of this study provide some new experimental evidence that the exposure to high levels of BDE209 may contribute to the onset of diabetes in human populations. Further work needs to be done to confirm this link. 23559274 Obesity Modulates the Immune Response to Oxidized LDL in Hypertensive Patients. Obesity and hypertension have been recognized as inflammatory diseases capable of activating the immune system, thus contributing to an increased cardiovascular risk. However, the link between adaptive immunity, obesity, and hypertension is poorly understood. We investigated the relationship of the body mass index (BMI) on the inflammatory, vascular, and immune responses in patients with hypertension naïve of anti-hypertensive treatment. Hypertensive patients (N = 88) were divided into three groups: normal weight (NW), overweight (OW), and obese (OB) subjects. Anti-oxidized LDL autoantibodies (anti-oxLDL Abs), anti-ApoB-D peptide (anti-ApoB-D) Abs, interleukin (IL)-8 and IL-10, flow-mediated dilation (FMD) of the brachial artery, and 24-h ambulatory blood pressure monitoring (ABPM) were assessed. OB patients presented lower levels of anti-oxLDL Abs and IL-10, higher levels of IL-8, and impaired FMD, when compared to NW and OW (P < 0.05), without differences between groups regarding anti-ApoB-D Abs. After adjusting for age, systolic and diastolic blood pressure, anti-oxLDL Abs were inversely correlated with BMI and waist circumference (r = -0.24, P = 0.02 and r = -0.25, P = 0.02, respectively), whereas ApoB-D correlated with 24-h ABPM (r = 0.22, P = 0.05 for systolic, and r = 0.29, P = 0.01 for diastolic blood pressure). Regression analyses showed inverse associations of anti-oxLDL Abs with BMI (β = -0.05, P = 0.01) and waist circumference (β = -0.01, P = 0.02); anti-ApoB-D Abs were associated with systolic and diastolic 24-h ABPM (β = 0.96, P = 0.04; β = 1.02, P = 0.005, for systolic and diastolic 24-h ABPM, respectively). Among hypertensive patients, obesity modulates the immune and inflammatory milieu, determining an unfavorable balance of cytokines and reduction in titers of anti-oxLDL Abs. Twenty-four hour ABPM is associated with titers of anti-ApoB-D Abs. 23192785 Green asymmetric synthesis: β-amino alcohol-catalyzed direct asymmetric aldol reactions in aqueous micelles. The ability of chiral β-amino alcohols to catalyze the direct asymmetric aldol reaction was evaluated for the first time in aqueous micellar media. A family of cheap and easily accessible β-amino alcohols, obtained in one step from naturally occurring amino acids, was shown to successfully catalyze the asymmetric aldol reaction between a series of ketones and aromatic aldehydes. These aldol reactions furnished the corresponding β-hydroxy ketones with up to 93% isolated yield and 89% ee. (S)-2-phenylglycinol and Triton X-100 proved to be the best organocatalyst and surfactant, respectively. 23210738 Simultaneous control of composition and register of an AAB-type collagen heterotrimer. Control over composition and register of the peptide chains in AAB-type collagen mimetic heterotrimers is critical in developing systems that show fidelity to native collagen. However, their design is challenging due to the eight competing states possible for a mixture of nonidentical peptides A and B. Interpeptide salt-bridges have been used previously as keystone interactions to bias the population of competing states to favor a target heterotrimer. The designed heterotrimers were electroneutral and relied on pairing of acidic and basic residues but could not differentiate between all of the competing states and reported systems populated either multiple heterotrimer compositions or registers. Here our design methodology includes both positive and negative elements. First, an excess of acidic or basic residues, which always remain unpaired, introduces a negative design component to destabilize the competing triple helical compositions and registers. Second, charge pairs introduce a positive design component and stabilize the target assembly. These antagonistic factors are optimized in the target heterotrimer that forms the maximum number of charge pairs and minimizes unpaired charged residues. Additionally, we find that not just the number of paired and unpaired residues are important, but also the type. By a systematic study of different types of charge pairs and unpaired residues, we are able to populate a single composition-single register AAB heterotrimer. The insights gained here may be useful in designing composition and register specific heterotrimeric ligands with domains that recognize collagen-binding proteins. 22456328 Electroporation-mediated gene transfer directly to the swine heart. In vivo gene transfer to the ischemic heart via electroporation holds promise as a potential therapeutic approach for the treatment of heart disease. In the current study, we investigated the use of in vivo electroporation for gene transfer using three different penetrating electrodes and one non-penetrating electrode. The hearts of adult male swine were exposed through a sternotomy. Eight electric pulses synchronized to the rising phase of the R wave of the electrocardiogram were administered at varying pulse widths and field strengths following an injection of either a plasmid encoding luciferase or one encoding green fluorescent protein. Four sites on the anterior wall of the left ventricle were treated. Animals were killed 48 h after injection and electroporation and gene expression was determined. Results were compared with sites in the heart that received plasmid injection but no electric pulses or were not treated. Gene expression was higher in all electroporated sites when compared with injection only sites demonstrating the robustness of this approach. Our results provide evidence that in vivo electroporation can be a safe and effective non-viral method for delivering genes to the heart, in vivo. 23178323 Biochemical and biological characterization of two serine proteinases from Colombian Crotalus durissus cumanensis snake venom. Two clotting serine proteinases, named Cdc SI and Cdc SII, were isolated and characterized for the first time from Colombian Crotalus durissus cumanensis snake venom. The enzymes were purified using two chromatographic steps: molecular exclusion on Sephacryl S-200 and RP-HPLC on C8 Column. The molecular masses of the proteins, determined by MALDI-TOF mass spectrometry, were 28,561.4 and 28,799.2 Da for Cdc SI and Cdc SII, respectively. The aim of the present study was to evaluate enzymatic, coagulant and toxic properties of the two enzymes. The serine proteinases hydrolyzed specific chromogenic substrate (BaPNA) and exhibited a Michaelis-Menten behavior. Cdc SI had V(max) of 0.038 ± 0.003 nmol/min and K(M) of 0.034 ± 0.017 mM, while Cdc SII displayed values of V(max) of 0.267 ± 0.011 nmol/min and K(M) of 0.145 ± 0.023 mM. N-terminal sequences were VIGGDEXNIN and VIGGDICNINEHNFLVALYE for Cdc SI and Cdc SII, respectively. Molecular masses, N-terminal sequences, inhibition assays, and enzymatic profile suggest that Cdc SI and Cdc SII belong to the family of snake venom thrombin-like enzymes. These serine proteinases differed in their clotting activity on human plasma, showing a minimum coagulant dose of 25 μg and 0.571 μg for Cdc SI and Cdc SII, respectively. Enzymes also showed coagulant activity on bovine fibrinogen and degraded chain α of this protein. Toxins lack hemorrhagic and myotoxic activities, but are capable to induce defibrin(ogen)ation, moderate edema, and an increase in vascular permeability. These serine proteinases may contribute indirectly to the local hemorrhage induced by metalloproteinases, by causing blood clotting disturbances, and might also contribute to cardiovascular alterations characteristic of patients envenomed by C. d. cumanensis in Colombia. 23201092 Evidences for the regulation of GnRH and GTH expression by GnIH in the goldfish, Carassius auratus. Gonadotrophin-inhibitory hormone (GnIH) plays an important role in regulating of reproduction in teleosts. To clarify the mode of action of GnIH on the synthesis of gonadotropin releasing hormone (GnRH) and gonadotrophin (GtH), three GnIHR cDNAs were cloned from the goldfish brain. In situ hybridization results showed that GnIHRs were localized to the hypothalamus and pituitary. In the hypothalamus, GnIHRs were found in the NPP, NPO and NLT, whereas sGnRH neurons were reported to be located, and potentially regulated by GnIH. In the pituitary, only two GnIHRs were observed and they were localized to the PI instead of the adenohypophysis where GtH-expressing cells are localized, suggesting indirect regulation of GtH by GnIH. In vivo, intraperitoneal (i.p.) injections of synthetic goldfish GnIH-II peptide and GnIH-III peptide significantly decreased sGnRH and FSHβ mRNA levels. Only GnIH-II decreased LHβ mRNA levels significantly. In vitro, both GnIH-II and GnIH-III showed no effect on GtH synthesis, but an inhibition of GnRH-stimulated LHβ and FSHβ synthesis was observed when GnIH-III was applied to primary pituitary cells in culture. Thus, GnIH could contribute to the regulation of gonadotropin in the brain and pituitary in teleosts. 23085436 Chemical cholecystokinin receptor activation protects against obesity-diabetes in high fat fed mice and has sustainable beneficial effects in genetic ob/ob mice. The current study has determined the ability of (pGlu-Gln)-CCK-8 to counter the development of diet-induced obesity-diabetes and examined persistence of beneficial metabolic effects in high fat and ob/ob mice, respectively. Twice daily injection of (pGlu-Gln)-CCK-8 in normal mice transferred to a high fat diet reduced energy intake (p < 0.001), body weight (p < 0.01), circulating insulin and LDL-cholesterol (p < 0.001) and improved insulin sensitivity (p < 0.001) as well as oral and intraperitoneal (p < 0.001) glucose tolerance. Energy intake, body weight, circulating insulin and glucose tolerance of (pGlu-Gln)-CCK-8 mice were similar to lean controls. In addition, (pGlu-Gln)-CCK-8 prevented the effect of high fat feeding on triacylglycerol accumulation in liver and muscle. Interestingly, (pGlu-Gln)-CCK-8 significantly (p < 0.001) elevated pancreatic glucagon content. Histological examination of the pancreata of (pGlu-Gln)-CCK-8 mice revealed no changes in islet number or size, but there was increased turnover of beta-cells with significantly (p < 0.001) increased numbers of peripherally located alpha-cells, co-expressing both glucagon and GLP-1. Beneficial metabolic effects were observed similarly in ob/ob mice treated twice daily with (pGlu-Gln)-CCK-8 for 18 days, including significantly reduced energy intake (p < 0.05), body weight (p < 0.05 to p < 0.01), circulating glucose (p < 0.05 to p < 0.01) and insulin (p < 0.05 to p < 0.001) and improved glucose tolerance (p < 0.05) and insulin sensitivity (p < 0.001). Notably, these beneficial effects were still evident 18 days following cessation of treatment. These studies emphasize the potential of (pGlu-Gln)-CCK-8 for the treatment of obesity-diabetes. 23545721 The metabolic profile of mitoxantrone and its relation with mitoxantrone-induced cardiotoxicity. Mitoxantrone (MTX) is an antitumor agent that causes cardiotoxicity in 18 % patients. The metabolic profile of MTX was assessed after incubation of 100 μM MTX with hepatic S9 fraction isolated from rats. The presence of MTX and its metabolites was also assessed in vivo through the analysis of liver and heart extracts of MTX-treated rats. The cytotoxic effects of MTX and MTX metabolites were evaluated in the H9c2 cells after 24-h incubation with MTX alone and MTX + metabolites. The influence of CYP450- and CYP2E1-mediated metabolism for the cytotoxicity of MTX was assessed after 96-h incubation with MTX (100 nM and 1 μM) in the presence/absence of CYP450 or CYP2E1 inhibitors. After 4-h incubation in supplemented S9 fraction, the MTX content was 35 % lower and 5 metabolites were identified: an acetoxy ester derivative (never described before), two glutathione conjugates, a monocarboxylic acid derivative, and the naphtoquinoxaline, the later commonly related to MTX pharmacological effects. The presence of MTX and naphtoquinoxaline metabolite was evidenced in vivo in liver and heart of MTX-treated rats. The cytotoxicity caused by MTX + metabolites was higher than that observed in the H9c2 cells incubated with non-metabolized MTX group. The co-incubation of MTX with CYP450 and CYP2E1 inhibitors partially prevented the cytotoxicity observed in the MTX groups incubated with H9c2 cells, highlighting that the metabolism of MTX is relevant for its undesirable effects. The naphtoquinoxaline metabolite is described in heart and liver in vivo, highlighting that this metabolite accumulates in these tissues. It was demonstrated that MTX P450-mediated metabolism contributed to MTX toxicity. 23521080 Potent fibrinolysis inhibitor discovered by shape and electrostatic complementarity to the drug tranexamic Acid. Protein-protein interfaces provide an important class of drug targets currently receiving increased attention. The typical design strategy to inhibit protein-protein interactions usually involves large molecules such as peptides and macrocycles. One exception is tranexamic acid (TXA), which, as a lysine mimetic, inhibits binding of plasminogen to fibrin. However, the daily dose of TXA is high due to its modest potency and pharmacokinetic properties. In this study, we report a computational approach, where the focus was on finding electrostatic potential similarities to TXA. Coupling this computational technique with a high-quality low-throughput screen identified 5-(4-piperidyl)-3-isoxazolol (4-PIOL) as a potent plasminogen binding inhibitor with the potential for the treatment of various bleeding disorders. Remarkably, 4-PIOL was found to be more than four times as potent as the drug TXA. 23351960 Neuroprotective effects of inhaled lavender oil on scopolamine-induced dementia via anti-oxidative activities in rats. Lavender is used in traditional medicines in Asia, Europe, ancient Greece and Rome, and was mentioned in the Bible and in ancient Jewish texts. Also, lavender is reported to be an effective medical plant in treating inflammation, depression, stress and headache. The present study was undertaken in order to investigate the antioxidant and antiapoptotic activities of the lavender essential oils from Lavandula angustifolia ssp. angustifolia Mill. and Lavandula hybrida Rev. using superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT) specific activities, total content of reduced glutathione (GSH), malondialdehyde (MDA) level (lipid peroxidation) and DNA fragmentation assays in male Wistar rats subjected to scopolamine-induced dementia rat model. In scopolamine-treated rats, lavender essential oils showed potent antioxidant and antiapoptotic activities. Subacute exposures (daily, for 7 continuous days) to lavender oils significantly increased antioxidant enzyme activities (SOD, GPX and CAT), total content of reduced GSH and reduced lipid peroxidation (MDA level) in rat temporal lobe homogenates, suggesting antioxidant potential. Also, DNA cleavage patterns were absent in the lavender groups, suggesting antiapoptotic activity. Taken together, our results suggest that antioxidant and antiapoptotic activities of the lavender essential oils are the major mechanisms for their potent neuroprotective effects against scopolamine-induced oxidative stress in the rat brain. 23478908 Multiplex analysis of enzyme kinetics and inhibition by droplet microfluidics using picoinjectors. Enzyme kinetics and inhibition is important for a wide range of disciplines including pharmacology, medicine and industrial bioprocess technology. We present a novel microdroplet-based device for extensive characterization of the reaction kinetics of enzyme substrate inhibitor systems in a single experiment utilizing an integrated droplet picoinjector for bioanalysis. This device enables the scanning of multiple fluorescently-barcoded inhibitor concentrations and substrate conditions in a single, highly time-resolved experiment yielding the Michaelis constant (Km), the turnover number (kcat) and the enzyme inhibitor dissociation constants (ki, ki'). Using this device we determine Km and kcat for β-galactosidase and the fluorogenic substrate Resorufin β-d-galactopyranoside (RBG) to be 442 μM and 1070 s(-1), respectively. Furthermore, we examine the inhibitory effects of isopropyl-β-d-thiogalactopyranoside (IPTG) on β-galactosidase. This system has a number of potential applications, for example it could be used to screen inhibitors to pharmaceutically relevant enzymes and to characterize engineered enzyme variants for biofuels production, in both cases acquiring detailed information about the enzyme catalysis and enzyme inhibitor interaction at high throughput and low cost. 23398051 Atomic layer deposition of a submonolayer catalyst for the enhanced photoelectrochemical performance of water oxidation with hematite. Hematite photoanodes were coated with an ultrathin cobalt oxide layer by atomic layer deposition (ALD). The optimal coating-1 ALD cycle, which amounts to <1 monolayer of Co(OH)2/Co3O4-resulted in significantly enhanced photoelectrochemical water oxidation performance. A stable, 100-200 mV cathodic shift in the photocurrent onset potential was observed that is correlated to an order of magnitude reduction in the resistance to charge transfer at the Fe2O3/H2O interface. Furthermore, the optical transparency of the ultrathin Co(OH)2/Co3O4 coating establishes it as a particularly advantageous treatment for nanostructured water oxidation photoanodes. The photocurrent of catalyst-coated nanostructured inverse opal scaffold hematite photoanodes reached 0.81 and 2.1 mA/cm(2) at 1.23 and 1.53 V, respectively. 23296142 Membrane-initiated estradiol signaling in immortalized hypothalamic N-38 neurons. Regulation of sexual reproduction by estradiol involves the activation of estrogen receptors (ERs) in the hypothalamus. Of the two classical ERs involved in reproduction, ERα appears to be the critical isoform. The role of ERα in reproduction has been found to involve a nuclear ERα that induces a genomic mechanism of action. More recently, a plasma membrane ERα has been shown to trigger signaling pathways involved in reproduction. Mechanisms underlying membrane-initiated estradiol signaling are emerging, including evidence that activation of plasma membrane ERα involves receptor trafficking. The present study examined the insertion of ERα into the plasma membrane of N-38 neurons, an immortalized murine hypothalamic cell line. We identified, using western blotting and PCR that N-38 neurons express full-length 66kDa ERα and a 52kDa ERα spliced variant missing the fourth exon - ERαΔ4. Using surface biotinylation, we observed that treatment of N-38 neurons with estradiol or with a membrane impermeant estradiol elevated plasma membrane ERα protein levels, indicating that membrane signaling increased receptor insertion into the cell membrane. Insertion of ERα was blocked by the ER antagonist ICI 182,780 or with the protein kinase C (PKC) pathway inhibitor bisindolylmaleimide (BIS). Downstream membrane-initiated signaling was confirmed by estradiol activation of PKC-theta (PKCθ) and the release of intracellular calcium. These results indicate that membrane ERα levels in N-38 neurons are dynamically autoregulated by estradiol. 23614395 A new ent-kaurane diterpenoid glycoside from Isodon japonica var. glaucocalyx. A new ent-kaurane diterpenoid glycoside (1), named glaucocalyxin G, has been isolated from the n-butanol-soluble fraction of the dried whole plants of Isodon japonica var. glaucocalyx along with two known compounds, namely arjunglucoside (2) and kaempferol-3-O-rutinoside (3). The structures of the isolated compounds were assigned on the basis of their (1)H and (13)C NMR spectra including two-dimensional NMR techniques such as HMQC, HMBC, and NOESY experiments and comparison with the literature data. 23411300 Relationships between harvest time and wine composition in Vitis vinifera L. cv. Cabernet Sauvignon 1. Grape and wine chemistry. The study aimed to quantify the effects of grape maturity on wine alcohol, phenolics, flavour compounds and polysaccharides in Vitis vinifera L. cv Cabernet Sauvignon. Grapes were harvested at juice soluble solids from 20 to 26 °Brix which corresponded to a range of wine ethanol concentrations between 12% and 15.5%. Grape anthocyanin and skin tannin concentration increased as ripening progressed, while seed tannin declined. In the corresponding wines, monomeric anthocyanin and wine tannin concentration increased with harvest date, consistent with an enhanced extraction of skin-derived phenolics. In wines, there was an observed increase in yeast-derived metabolites, including volatile esters, dimethyl sulfide, glycerol and mannoproteins with harvest date. Wine volatiles which were significantly influenced by harvest date were isobutyl methoxypyrazine, C(6) alcohols and hexyl acetate, all of which decreased as ripening progressed. The implications of harvest date for wine composition is discussed in terms of both grape composition and yeast metabolism. 23398572 Strong effects of cluster size and air exposure on oxygen reduction and carbon oxidation electrocatalysis by size-selected Pt(n) (n ≤ 11) on glassy carbon electrodes. Model Pt(n)/glassy carbon electrodes (Pt(n)/GCE) were prepared by deposition of mass-selected Pt(n)(+) (n ≤ 11) on GCE substrates in ultrahigh vacuum. Electrocatalysis under conditions appropriate for the oxygen reduction reaction (ORR) was studied, for samples both in situ with no exposure to laboratory air and with air exposure prior to electrochemical measurements. Of the small clusters, only a few cluster sizes show the expected ORR activity, and in those cases, the activity per Pt atom is similar to that seen under identical conditions with a conventionally prepared electrode with Pt nanoparticles grown on a GCE. For other small Pt(n) on GCE, any ORR signal is overwhelmed by large oxidative currents attributed to catalysis of carbon oxidation by water. If the samples are exposed to air prior to electrochemistry, both ORR and carbon oxidation signals are absent, and instead only small capacitive currents or currents attributed to redox chemistry of adventitious organic adsorbates are observed, indicating that air exposure results in passivation of the small Pt clusters. 23296277 Signalling Pathways that Inhibit the Capacity of Precursor Cells for Myelin Repair. In demyelinating disorders such as Multiple Sclerosis (MS), targets of injury are myelin and oligodendrocytes, leading to severe neurological dysfunction. Regenerative therapies aimed at promoting oligodendrocyte maturation and remyelination are promising strategies for treatment in demyelinating disorders. Endogenous precursor cells or exogenous transplanted cells are potential sources for remyelinating oligodendrocytes in the central nervous system (CNS). Several signalling pathways have been implicated in regulating the capacity of these cell populations for myelin repair. Here, we review neural precursor cells and oligodendrocyte progenitor cells as potential sources for remyelinating oligodendrocytes and evidence for the functional role of key signalling pathways in inhibiting regeneration from these precursor cell populations. 23565720 Approach to dark spin cooling in a diamond nanocrystal. Using a Hartman-Hahn protocol, we demonstrate spin polarization transfer from a single, optically polarized nitrogen-vacancy (NV) center to the ensemble of paramagnetic defects hosted by an individual diamond nanocrystal. Owing to the strong NV-bath coupling, the transfer takes place on a short, microsecond time scale. Upon fast repetition of the pulse sequence, we observe strong polarization transfer blockade, which we interpret as an indication of spin bath cooling. Numerical simulations indicate that the spin bath polarization is nonuniform throughout the nanoparticle, averaging approximately 5% over the crystal volume, but reaching up to 25% in the immediate vicinity of the NV. These observations may prove relevant to the planning of future bath-assisted magnetometry tests. 23606423 Patterning Surfaces for Controlled Platelet Adhesion and Detection of Dysfunctional Platelets. Platelets play a fundamental role in thrombus formation and in the pathogenesis of arterial thrombosis. Patterning surfaces for controlled platelet adhesion paves the way for adhesion and activation mechanisms in platelets and detection of platelet functional defects. Here, a new and simple method based on controlled polymerization of 2-methacryloyloxyethyl phosphorylcholine (MPC) on the surface of styrene-block-(ethylene-co-butylene)-block-styrene (SEBS) is shown. The competition between polymerization and degradation enables platelet adhesion on SEBS to be switched on and off. The adhesive sites of the platelets can be down to single cell level, and the dysfunctional platelets can be quantitatively detected. 23256525 Optical activity of achiral ligand SCH3 adsorbed on achiral Ag55 clusters: relationship between adsorption site and circular dichroism. The electronic circular dichroism (CD) spectra of a methyl-thiol adsorbed at different sites on an icosahedral silver nanoparticle is studied by using time-perturbed density functional theory. Despite that separately molecule and nanoparticle are achiral and consequently optically inactive, the Ag(55)-SCH(3) compound emerges with a new symmetry, which may be chiral or not depending on the adsorption site and orientation of the molecule. It is found that chirality is favored when the thiol is adsorbed between two atoms of different coordination number. Chiral compounds have characteristic CD spectra in the UV-visible region, where Ag(55) shows optical absorption but SCH(3) does not; revealing that highly degenerated molecular-like electronic states of Ag(55) are modified by the presence of the molecule inducing optical activity. It is concluded that CD line-shapes and magnitude strongly depend on the site where the adsorption takes place, while its intensity is modulated by the molecule orientation. 23540443 Transfer of lipids to high-density lipoprotein (HDL) is altered in patients with familial hypercholesterolemia. OBJECTIVE: In familial hypercholesterolemia (FH), the metabolism and anti-atherogenic functions of HDL can be affected by the continuous interactions with excess LDL amounts. Here, lipid transfers to HDL, an important step for HDL intravascular metabolism and for HDL role in reverse cholesterol transport (RCT) were investigated in FH patients. METHODS: Seventy-one FH patients (39±15years, LDL-cholesterol=274±101; HDL-cholesterol=50±14mg/dl) and 66 normolipidemic subjects (NL) (38±11years, LDL-cholesterol=105±27; HDL-cholesterol=52±12mg/dl) were studied. In vitro, lipid transfers were evaluated by incubation of plasma samples (37°C, 1h) with a donor lipid nanoemulsion labeled with 3H-triglycerides (TG) and 14C-unesterified cholesterol (UC) or with 3H-cholesteryl ester (EC) and 14C-phospholipids (PL). Radioactivity was counted at the HDL fraction after chemical precipitation of apolipoprotein (apo) B-containing lipoproteins and the nanoemulsion. Data are % of total radioactivity measured in the HDL fraction. RESULTS: Transfer of UC to HDL was lower in FH than in NL (5.6±2.1 vs 6.7±2.0%, p=0.0005) whereas TG (5.5±3.1 vs 3.7±0.9%, p=0.018) and PL (20.9±4.6 vs 18.2±3.7 %, p=0.023) transfers were higher in FH. EC transfer was equal. By multivariate analysis, transfers of all four lipids correlated with HDL-cholesterol and with apo A-I. CONCLUSION: FH elicited marked changes in three of the four tested lipid transfers to HDL. The entry of UC into HDL for subsequent esterification is an important driving force for RCT and reduction of UC transfer to HDL was previously associated to precocious coronary heart disease. Therefore, in FH, HDL functions can be lessened, which can also contribute to atherogenesis. 23424217 Synergistic GABA-Enhancing Therapy against Seizures in a Mouse Model of Dravet Syndrome. Seizures remain uncontrolled in 30% of patients with epilepsy, even with concurrent use of multiple drugs, and uncontrolled seizures result in increased morbidity and mortality. An extreme example is Dravet syndrome (DS), an infantile-onset severe epilepsy caused by heterozygous loss of function mutations in SCN1A, the gene encoding the brain type-I voltage-gated sodium channel NaV1.1. Studies in Scn1a heterozygous knockout mice demonstrate reduced excitability of GABAergic interneurons, suggesting that enhancement of GABA signaling may improve seizure control and comorbidities. We studied the efficacy of two GABA-enhancing drugs, clonazepam and tiagabine, alone and in combination, against thermally evoked myoclonic and generalized tonic-clonic seizures. Clonazepam, a positive allosteric modulator of GABA-A receptors, protected against myoclonic and generalized tonic-clonic seizures. Tiagabine, a presynaptic GABA reuptake inhibitor, was protective against generalized tonic-clonic seizures but only minimally protective against myoclonic seizures and enhanced myoclonic seizure susceptibility at high doses. Combined therapy with clonazepam and tiagabine was synergistic against generalized tonic-clonic seizures but was additive against myoclonic seizures. Toxicity determined by rotorod testing was additive for combination therapy. The synergistic actions of clonazepam and tiagabine gave enhanced seizure protection and reduced toxicity, suggesting that combination therapy may be well tolerated and effective for seizures in DS. 23580312 Application of Ultra-Performance Liquid Chromatography/Mass Spectrometry-Based Metabonomic Techniques to Analyze the Joint Toxic Action of Long-Term Low-Level Exposure to a Mixture of Organophosphate Pesticides on Rat Urine Profile. In previously published articles, we evaluated the toxicity of four organophosphate (OP) pesticides (dichlorvos, dimethoate, acephate and phorate) to rats using metabonomic technology at their corresponding no observed adverse effect level (NOAEL). Results show that a single pesticide elicits no toxic response. The present study aimed to determine whether chronic exposure to a mixture of the above four pesticides (at their corresponding NOAEL) can lead to joint toxic action in rats using the same technology. Pesticides were administered daily to rats through drinking water for 24 weeks. The above mixture of the four pesticides showed joint toxic action at the NOAEL of each pesticide. The metabonomic profiles of rats urine were analyzed by ultra-performance liquid chromatography/mass spectrometry. The 16 metabolites statistically significantly changed in all treated groups compared with the control group. Dimethylphosphate and dimethyldithiophosphate exclusively detected in all treated groups can be used as early, sensitive biomarkers for exposure to a mixture of the OP pesticides. Moreover, exposure to the OP pesticides resulted in increased 7-methylguanine, ribothymidine, cholic acid, 4-pyridoxic acid, kynurenine and indoxyl sulfate levels, as well as decreased hippuric acid, creatinine, uric acid, gentisic acid, C18-dihydrosphingosine, phytosphingosine, suberic acid and citric acid. The results indicated that a mixture of OP pesticides induced DNA damage, oxidative stress, disturbed the metabolism of lipids as well as interfered with the tricarboxylic acid cycle. Ensuring food safety requires not only the toxicology test data of each pesticide for the calculation of the acceptable daily intake, but also the joint toxic action. 23590471 A dried blood spot update: still an important bioanalytical technique? This article discusses the benefits of dried blood spot sampling and the recent issues that have emerged when this technique is used in the regulated quantitative bioanalytical environment. The author explores what the way forward might be for this important technique and what some of the unexpected benefits of this change in sampling methodologies have been. 23518662 Experimental evidence for surface freezing in supercooled n-alkane nanodroplets. Intermediate chain length (16 ≤i≤ 50) n-alkanes are known to surface freeze at temperatures that are up to three degrees higher than the equilibrium melting point [B. M. Ocko et al., Phys. Rev. E, 1997, 55, 3164-3182]. Our recent experimental results suggest that highly supercooled nanodroplets of n-octane and n-nonane also surface freeze, and subsequently bulk crystallization occurs. The data yield surface and bulk nucleation rates on the order of ∼10(15) cm(-2) s(-1) and ∼10(22) cm(-3) s(-1), respectively, at temperatures between 180 K and 200 K. Molecular dynamics simulations at the united atom level were used to follow the freezing of a supercooled n-octane drop and show that an ordered monolayer develops on the surface of the droplet almost immediately, and the rest of the droplet then freezes in a layer-by-layer manner. 23339076 Structure prediction of binary pernitride MN2 compounds (M=Ca, Sr, Ba, La, and Ti). Metal-pernitride compounds belong to a class of chemical systems in which both the complex ions and the non-bonding electrons may play roles in the formation of their modified crystalline structures. To investigate this issue, the energy landscapes of pernitrides of metals with different maximum valence (M=Ca, Sr, Ba, La, and Ti) were globally explored on the ab initio level at standard and high pressures, thereby yielding possible (meta)stable modifications in these systems together with information on how the landscape changed as function of the valence of the metal cation. For all of the systems in which no compounds had been synthesized so far, we predicted the existence of kinetically stable modifications that should, in principle, be experimentally accessible. In particular, TiN2 should crystallize in a new structure type, TiN2-I. 23556447 Genes involved in hemorrhagic transformations that follow recombinant t-PA treatment in stroke patients. Aim: Despite the benefits of recombinant t-PA (rt-PA) for stroke patients some of them suffer from adverse hemorrhagic transformations (HTs) following treatment. Our objective is to study the transcriptomics of HTs patients. Methods: We studied by microarrays 11 blood samples from patients with stroke that had received rt-PA of whom six of them had suffered a HT. For replication step RNA was collected from 14 new subjects (seven with HT, seven without) and then analyzed by real-time PCR. Four proteins were measured by ELISA in 72 new subjects to analyze their role as potential protein biomarkers. Results: The microarray analysis revealed that 14 genes were altered among the HT patients. The replication study confirmed these results for six genes. Two of them (BCL2 and OLFM4) are associated with apoptosis, whereas the other four (LTF, LCN2 [also known as NGAL], CEACAM8 and CRISP3) are involved in the regulation of neutrophil processes. Conclusion: Our data revealed that genes related to apoptosis and neutrophil regulation pathways could be associated with HTs after rt-PA. Original submitted 7 September 2012; Revision submitted 23 January 2013. 23237860 Catalytic properties of a bacterial acylating acetaldehyde dehydrogenase: evidence for several active oligomeric states and coenzyme A activation upon binding. Until the last decade, two unrelated aldehyde dehydrogenase (ALDH) superfamilies, i.e. the phosphorylating and non-phosphorylating superfamilies, were known to catalyze the oxidation of aldehydes to activated or non-activated acids. However, a third one was discovered by the crystal structure of a bifunctional enzyme 4-hydroxy-2-ketovalerate aldolase/acylating acetaldehyde dehydrogenase (DmpFG) from Pseudomonas sp. strain CF600 (Manjasetty et al., Proc. Natl. Acad. Sci. USA 100 (2003) 6992-6997). Indeed, DmpF exhibits a non-phosphorylating CoA-dependent ALDH activity, but is structurally related to the phosphorylating superfamily. In this study, we undertook the characterization of the catalytic and structural properties of MhpEF from Escherichia coli, an ortholog of DmpFG in which MhpF converts acetaldehyde, produced by the cleavage of 4-hydroxy-2-ketovalerate by MhpE, into acetyl-CoA. The kinetic data obtained under steady-state and pre-steady-state conditions show that the aldehyde dehydrogenase, MhpF, is active as a monomer, a unique feature relative to the phosphorylating and non-phosphorylating ALDH superfamilies. Our results also reveal that the catalytic properties of MhpF are not dependent on its oligomeric state, supporting the hypothesis of a structurally and catalytically independent entity. Moreover, the transthioesterification is shown to be rate-limiting and, when compared with a chemical model, its catalytic efficiency is increased 10(4)-fold. Therefore, CoA binding to MhpF increases its reactivity and optimizes its positioning relative to the thioacylenzyme intermediate, thus enabling the formation of an efficient deacylation complex. 23422073 Proteomic and metabolomic approaches to the study of polycystic ovary syndrome. Polycystic ovary syndrome (PCOS) is considered a complex multifactorial disorder resulting from the interaction of genetic, environmental, and lifestyle influences. Nontargeted proteomics and metabolomics have been used in the past years with the aim of identifying molecules potentially involved in the pathophysiology of this frequent disorder. The biomolecules identified so far participate in many metabolic pathways, including energy metabolism (glucose and lipid metabolism), protein metabolic processes and protein folding, cytoskeleton structure, immune response, inflammation and iron metabolism, fibrinolysis and thrombosis, oxidative stress and intracellular calcium metabolism. These molecules provide key information about molecular functions altered in PCOS and raise questions concerning their precise role in the pathogenesis of this syndrome. The biomolecules identified by nontargeted proteomic and metabolomic approaches should be considered as candidates in future studies aiming to define specific molecular phenotypes of PCOS. 23631528 Designed amphiphilic β-sheet peptides as templates for paraoxon adsorption and detection. Amphiphilic peptides were designed to fold into a β-sheet monolayer structure while presenting the catalytic triad residues of the enzyme, acetylcholinesterase (Glu, His and Ser), to a solution containing the organophosphate, paraoxon. Three peptides, in which the catalytic triad residues were arranged in different orders along the strand, were generated to reveal potential differences in interactions with paraoxon as a function of the order of these amino acids. One additional peptide with amino acids introduced in random order was studied to highlight the contribution of the β-sheet secondary structure to any interactions with paraoxon. Langmuir isotherms, Brewster angle microscope at interfaces and circular dichroism measurements in bulk showed that both the β-sheet conformation and the order of the amino acids along the strand influenced the interactions of paraoxon with the peptides. Compression isotherm curves, as well as Brewster-angle microscopy images, provided evidence for enhanced adsorption of the paraoxon to the monolayers of peptides which present neighboring Glu and Ser residues along the hydrophilic face of the β-strand. Circular dichroism revealed that the peptide most sensitive to interactions with paraoxon was that with the triad residues in the order Glu, Ser and His, which appears to be appropriate for supporting a catalytic mechanism similar to that in acetylcholinesterase enzyme. These rationally designed peptides may be further utilized for the development of technologies for organophosphate adsorption and detection. 23436437 Blood Pressure Lowering Effect of Nigella sativa L. Seed Oil in Healthy Volunteers: A Randomized, Double-Blind, Placebo-controlled Clinical Trial. Nigella sativa L. seeds (N. sativa) have been used as a traditional remedy for a wide range of diseases including hypertension. The present study was performed to explore the effects of N. sativa oil on blood pressure (BP) in healthy volunteers. In a double-blind, randomized study, 70 healthy volunteers aged 34 to 63 years with systolic BP from 110 to 140 mmHg and diastolic BP from 60 to 90 mmHg were randomly allocated to receive 2.5 mL N. sativa oil or placebo two times a day for 8 weeks. The systolic and diastolic BPs, body mass index and blood levels of aspartate transaminase, alanine transaminase, alkaline phosphatase, creatinine and blood urea nitrogen were determined at baseline and endpoint. Results showed that in N. sativa oil treated group the systolic and diastolic BPs decreased significantly compared with baseline and placebo group at the endpoint. Other parameters did not significantly change in both groups at the endpoint. No adverse effects were reported. In conclusion, oral daily administration of 5 mL N. sativa oil to healthy volunteers for 8 weeks lowers systolic and diastolic BPs without any adverse effects. Copyright © 2013 John Wiley & Sons, Ltd. 23265524 Glucose, fructose and sucrose increase the solubility of protein-tannin complexes and at high concentration, glucose and sucrose interfere with bisulphite bleaching of wine pigments. Wines were modified with increasing sugar concentrations and decreasing tannin concentrations and analysed by a combination of protein precipitation and bisulphite bleaching. Increasing sugar concentration decreased the precipitation of tannin and protein-precipitable polymeric pigments (PPP). The use of a hydrogen bond disruptor (urea) to reduce protein-tannin and protein-pigment complex formation showed that the effect of sugar concentration occurred by increasing the solubility of the tannin-protein complex, not by interfering with protein-tannin complex formation. By increasing the solubility of pigment-protein complexes, non-protein-precipitable polymeric pigments (nPPP) appeared to increase. There was also an increase in total polymeric pigments at each tannin concentration with increasing glucose and sucrose concentration, indicating that sugar concentration might also affect bisulphite bleaching of wine pigments. While a significant effect of sugar concentration on tannin-protein complex solubility was observed, these effects were greatest at sugar concentrations far in excess of normal wine making conditions. Under normal wine making conditions, sugar concentration will have a negligible effect on protein-precipitable tannin, PPP and nPPP concentrations. 23146761 Cholestatic effect of epigallocatechin gallate in rats is mediated via decreased expression of Mrp2. Epigallocatechin gallate (EGCG) has been shown to be protective in various experimental models of liver injury, although opposite effects have also been reported. Since its effect on biliary physiology has not been thoroughly investigated, the present study evaluated effect of EGCG on bile flow and bile acid homeostasis in rats. Compared to controls, EGCG treatment decreased bile flow by 23%. Hepatic paracellular permeability and biliary bile acid excretion were not altered by EGCG administration, but biliary glutathione excretion was reduced by 70%. Accordingly, the main glutathione transporter on the hepatocyte canalicular membrane, multidrug resistance-associated protein 2 (Mrp2), was significantly decreased at the protein level. EGCG administration also doubled plasma bile acid levels compared to controls. While protein levels of the main hepatic bile acid transporters were unchanged, the rate-limiting enzyme in the bile acid synthesis, Cyp7a1, was significantly increased by EGCG. Enhanced bile acid synthesis in these animals was also confirmed by a 2-fold increase in plasma marker 7α-hydroxy-4-cholesten-3-one. In contrast, EGCG markedly downregulated major bile acid transporters (Asbt and Ostα) and regulatory molecules (Shp and Fgf15) in the ileum. When EGCG was coadministered with ethinylestradiol, a potent cholestatic agent, it did not show any additional effect on the induced cholestasis. This study shows ability of EGCG to raise plasma bile acid concentrations, mainly through Cyp7a1 upregulation, and to decrease bile production through reduction in Mrp2-mediated bile acid-independent bile flow. In conclusion, our data demonstrate that under certain conditions EGCG may induce cholestasis. 23364315 Engineering a serum-resistant and thermostable vesicular stomatitis virus G glycoprotein for pseudotyping retroviral and lentiviral vectors. Vesicular stomatitis virus G glycoprotein (VSV-G) is the most widely used envelope protein for retroviral and lentiviral vector pseudotyping; however, serum inactivation of VSV-G pseudotyped vectors is a significant challenge for in vivo gene delivery. To address this problem, we conducted directed evolution of VSV-G to increase its resistance to human serum neutralization. After six selection cycles, numerous common mutations were present. On the basis of their location within VSV-G, we analyzed whether substitutions in several surface exposed residues could endow viral vectors with higher resistance to serum. S162T, T230N and T368A mutations enhanced serum resistance, and additionally K66T, T368A and E380K substitutions increased the thermostability of VSV-G pseudotyped retroviral vectors, an advantageous byproduct of the selection strategy. Analysis of a number of combined mutants revealed that VSV-G harboring T230N+T368A or K66T+S162T+T230N+T368A mutations exhibited both higher in vitro resistance to human serum and higher thermostability, as well as enhanced resistance to rabbit and mouse serum. Finally, lentiviral vectors pseudotyped with these variants were more resistant to human serum in a murine model. These serum-resistant and thermostable VSV-G variants may aid the application of retroviral and lentiviral vectors to gene therapy.Gene Therapy advance online publication, 31 January 2013; doi:10.1038/gt.2013.1. 23265463 Hepatoprotective effect of 2,3-dehydrosilybin on carbon tetrachloride-induced liver injury in rats. The aim of this study was to investigate the protective effect of 2,3-dehydrosilybin (DHS) against carbon tetrachloride (CCl(4))-induced liver injury in rats. Administration of DHS significantly attenuated the levels of serum aspartate aminotransferase, alanine aminotransferase, and liver lipid peroxidation in CCl(4)-treated rats. Moreover, we showed that DHS prevented DNA damage and decreased the protein levels of γ-H2AX, which is a specific DNA damage marker, in CCl(4)-treated rat livers. DHS also markedly increased the activity of antioxidant enzymes, such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase in CCl(4)-treated rat livers. Furthermore, we found that DHS significantly inhibited the production of serum nitric oxide as well as the levels of serum IL-6, IFN-γ, and TNF-α in CCl(4)-treated rats. Additionally, DHS significantly suppressed iNOS expression on the protein levels in CCl(4)-treated rat livers. Collectively, the present study suggests that DHS protects the liver from CCl(4)-induced hepatic damage via antioxidant and anti-inflammatory mechanisms. 23327832 Jatropholane-type diterpenes from Euphorbia sikkimensis. Four new jatropholane-type diterpenes (1-4), named sikkimenoids A-D, were isolated from the aerial parts of Euphorbia sikkimensis. The structural elucidations of 1-4 were accomplished by extensive NMR analyses, and their absolute configurations were established by ECD calculations. Compound 2 exhibited weak antiangiogenic activity with an IC(50) value of 43.0 μM when evaluated using a zebrafish model. 23351962 Protective effects of oral crocin against intracerebroventricular streptozotocin-induced spatial memory deficit and oxidative stress in rats. Intracerebroventricular (ICV) streptozotocin (STZ) has been shown to cause cognitive impairment, associated with free radical generation. In this study, we evaluated the effects of crocin on cognitive performance in ICV STZ-lesioned rats (3mg/kg bilaterally, on day 1 and 3). Crocin (100mg/kg, p.o.) was administered for 21 consecutive days, starting 1h prior to the first dose of STZ. Cognitive performance was assessed using Morris water maze task while the parameters of oxidative stress assessed, were malondialdehyde (MDA) and total thiol levels besides glutathione peroxidase (GPx) activity. STZ-lesioned rats showed a severe deficit in memory associated with elevated MDA levels, reduced GPx activity and total thiol content. Crocin treatment improved cognitive performance and resulted in a significant reduction in MDA levels and elevation in total thiol content and GPx activity. This study demonstrates that crocin may have beneficial effects in the treatment of neurodegenerative disorders such as Alzheimer's disease. 23142635 Developing and advancing dry powder inhalation towards enhanced therapeutics. Enhanced therapeutics are drug products derived from existing generic drugs that provide additional benefits to the patients and the healthcare system. Enhanced therapeutics are considered to be an important and relatively low risk source of innovation. Pulmonary drug delivery is the major delivery route to treat chronic respiratory diseases and has been proven as a potential delivery route for complex drugs that cannot be delivered orally. Development of dry powder inhalation systems targets the delivery of fine drug particles to the deep lung surface by a combination of drug formulation, primary packaging and a device, whereby each contributes to the overall performance. Various methodologies for the non-clinical and clinical performance testing of orally inhaled products have been proposed and applied with variable success. Regulatory pathways have been developed and applied since. Considerable efforts have been made during the past decade to understand and optimize pulmonary drug delivery including their efficient commercial manufacturing. Pulmonary drug delivery remains an area of future innovation in the effective treatment of pulmonary diseases as well as the systemic delivery of systemically active complex drugs. 23379514 Small molecule antivirulents targeting the iron-regulated heme oxygenase (HemO) of P. aeruginosa. Bacteria require iron for survival and virulence and employ several mechanisms including utilization of the host heme containing proteins. The final step in releasing iron is the oxidative cleavage of heme by HemO. A recent computer aided drug design (CADD) study identified several inhibitors of the bacterial HemOs. Herein we report the near complete HN, N, CO, Cα, and Cβ chemical shift assignment of the P. aeruginosa HemO in the absence and presence of inhibitors (E)-3-(4-(phenylamino)phenylcarbamoyl)acrylic acid (3) and (E)-N'-(4-(dimethylamino)benzylidene) diazenecarboximidhydrazide (5). The NMR data confirm that the inhibitors bind within the heme pocket of HemO consistent with in silico molecular dynamic simulations. Both inhibitors and the phenoxy derivative of 3 have activity against P. aeruginosa clinical isolates. Furthermore, 5 showed antimicrobial activity in the in vivo C. elegans curing assay. Thus, targeting virulence mechanisms required within the host is a viable antimicrobial strategy for the development of novel antivirulants. 23289503 Induced expression of cytochrome P450 1A and NAD(P)H:quinone oxidoreductase determined at mRNA, protein, and enzyme activity levels in rats exposed to the carcinogenic azo dye 1-phenylazo-2-naphthol (Sudan I). Sudan I (1-phenylazo-2-hydroxynaphthol) is a suspected human carcinogen causing tumors in the livers and urinary bladders of rats, mice, and rabbits. Here, we investigated for the first time the influence of Sudan I exposure on the expression of several biotransformation enzymes in the livers, kidneys, and lungs of rats concomitantly at the mRNA and protein levels and assayed their enzymatic activities. We also studied its effect on the formation of Sudan I-derived DNA adducts in vitro. Sudan I increased the total amounts of cytochrome P450 (P450) in all organs tested. Western blots using antibodies raised against various P450s, NADPH:P450 reductase, and NAD(P)H:quinone oxidoreductase 1 (NQO1) showed that the expression of P450 1A1 and NQO1 was induced in the liver, kidney, and lung of rats treated with Sudan I. The higher protein levels correlated with increased enzyme activities of P450 1A1/2 and NQO1. Furthermore, 9.9-, 5.9-, and 2.8-fold increases in the formation of Sudan I oxidative metabolites catalyzed by microsomes isolated from the liver, kidney, and lung, respectively, of rats treated with Sudan I were found. The relative amounts of P450 1A and NQO1 mRNA, measured by real-time polymerase chain reaction (RT-PCR) analysis, demonstrated that Sudan I induced the expression of P450 1A1 and NQO1 mRNA in the liver, kidney, and lung, and of P450 1A2 mRNA in kidney and lung. Finally, microsomes isolated from livers, kidneys, and lungs of Sudan I exposed rats more effectively catalyzed the formation of Sudan I-DNA adducts than microsomes from organs of control rats. This was attributable to the higher P450 1A1 expression. Because P450 1A1 is playing a major role in the bioactivation of Sudan I in rat and human systems, its induction by Sudan I may have a profound effect on cancer risk by this azo dye. In addition, the induction of P450 1A1/2 and NQO1 enzymes can influence individual human susceptibility to other environmental carcinogens and have an effect on cancer risk. 23449197 Discovery of 7-methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole (TASP0382088): a potent and selective transforming growth factor-β type I receptor inhibitor as a topical drug for alopecia. 7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole 11 (TASP0382088) was synthesized and evaluated as transforming growth factor-β (TGF-β) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitor. Compound 11, a potent and selective ALK5 inhibitor, exhibited good enzyme inhibitory activity (IC50=4.8 nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50=17 nM). The introduction of a methoxy group to the benzothiazole ring in 1 and the break up of the planarity between the imidazole ring and the thiazole ring improved the solubility in the lotion base of 11. Furthermore, the topical application of 3% 11 lotion significantly inhibited Smad2 phosphorylation in mouse skin at 8 h after application (71% inhibition, compared with vehicle-treated animals). 23323975 Fundamental and Torsional Combination Bands of Two Isomers of the OCS-CO(2) Complex in the CO(2) ν(3) Region. Spectra of two isomers of the weakly bound complex OCS-CO(2) are observed in the region of the CO(2) ν(3) fundamental vibration (∼2349 cm(-1)), using an infrared tunable diode laser to probe a pulsed supersonic slit-jet expansion. Two bands are measured and analyzed for each isomer, the fundamental asymmetric stretch of the CO(2) component and a combination band involving this fundamental plus the intermolecular out-of-plane torsional mode. For one isomer, the corresponding torsional combination band is also detected in the OCS ν(1) stretching region (∼2060 cm(-1)). The resulting torsional frequencies are found to be 18.8 and 15.9 cm(-1) for isomers a and b of OCS-CO(2), respectively. This may be the first time that such a combination band is observed for a higher-energy isomer of a weakly bound complex. 23262201 Synthesis and evaluation of a backbone biodegradable multiblock HPMA copolymer nanocarrier for the systemic delivery of paclitaxel. The performance and safety of current antineoplastic agents, particularly water-insoluble drugs, are still far from satisfactory. For example, the currently widely used Cremophor EL®-based paclitaxel (PTX) formulation exhibits pharmacokinetic concerns and severe side effects. Thus, the concept of a biodegradable polymeric drug-delivery system, which can significantly improve therapeutic efficacy and reduce side effects is advocated. The present work aims to develop a new-generation of long-circulating, biodegradable carriers for effective delivery of PTX. First, a multiblock backbone biodegradable N-(2-hydroxypropyl)methacrylamide(HPMA) copolymer-PTX conjugate (mP-PTX) with molecular weight (Mw) of 335 kDa was synthesized by RAFT (reversible addition-fragmentation chain transfer) copolymerization, followed by chain extension. In vitro studies on human ovarian carcinoma A2780 cells were carried out to investigate the cytotoxicity of free PTX, HPMA copolymer-PTX conjugate with Mw of 48 kDa (P-PTX), and mP-PTX. The experiments demonstrated that mP-PTX has a similar cytotoxic effect against A2780 cells as free PTX and P-PTX. To further compare the behavior of this new biodegradable conjugate (mP-PTX) with free PTX and P-PTX in vivo evaluation was performed using female nu/nu mice bearing orthotopic A2780 ovarian tumors. Pharmacokinetics study showed that high Mw mP-PTX was cleared more slowly from the blood than commercial PTX formulation and low Mw P-PTX. SPECT/CT imaging and biodistribution studies demonstrated biodegradability as well as elimination of mP-PTX from the body. The tumors in the mP-PTX treated group grew more slowly than those treated with saline, free PTX, and P-PTX (single dose at 20 mg PTX/kg equivalent). Moreover, mice treated with mP-PTX had no obvious ascites and body-weight loss. Histological analysis indicated that mP-PTX had no toxicity in liver and spleen, but induced massive cell death in the tumor. In summary, this biodegradable drug delivery system has a great potential to improve performance and safety of current antineoplastic agents. 23373696 Polymer therapeutics with a coiled coil motif targeted against murine bcl1 leukemia. The specificity of polymer conjugates based on N-(2-hydroxypropyl)methacrylamide (HPMA) bearing cytostatic drugs for cancer cells could be significantly increased by the incorporation of a suitable targeting ligand, such as a monoclonal antibody (mAb). However, direct binding of the protein to the polymer carrier could cause considerable problems, such as decreasing the binding capacity of mAb to its target. Here, we introduce a novel strategy of joining a targeting moiety to a polymeric conjugate with cytostatic drug. The scFv of B1 mAb (specific for BCL1 leukemia cells) was tagged with peptide K ((VAALKEK)4). Peptide E ((VAALEKE)4), which forms a stable coiled coil structure heterodimer with peptide K, was assembled with the HPMA copolymers bearing doxorubicin. Such targeted polymeric conjugates possess very selective and high binding activity toward BCL1 cells. Similarly, targeted polymeric conjugates exert approximately 100 times higher cytostatic activity toward BCL1 cells in comparison to nontargeted conjugates in vitro. At the same time, the conjugates have comparable and rather low cytostatic activity for 38C13 cells, which are used as a negative control, in vitro. 23322633 Heterocycles as nonclassical bioisosteres of α-amino acids. Bioisosterism of α-amino acids is often accomplished by replacing the α-carboxylate with one of the many known carboxylic acid bioisosteres. However, bioisosterism of the whole α-amino acid moiety is accomplished with heterocyclic bioisosteres that often display an acidic function. In this Minireview, we summarized the reported heterocycles as nonclassical bioisosteres of α-amino acids, which include quinoxaline-2,4(1H)-dione, quinoxaline-2,3(1H)-dione and quinolin-2(1H)-one, azagrevellin and azepine-derived structures. The binding mode of the crystalized bioisosteres were compared with those of the crystalized α-amino acids that bind in the same domain, and where no data on the crystal structure were available, the displacement studies of known orthosteric ligands were used. The reported bioisosteres share the following essential structural features for mimicking α-amino acids: an aromatic ring system joined to a lactam ring system with an acidic feature next to the lactam carbonyl, where this acidic feature together with the lactam carbonyl can mimic the α-carboxylate, and the lactam nitrogen together with the aromatic ring system can mimic the α-ammonium. The majority of these heterocycles can be prepared from three common corresponding starting materials: the corresponding anilines, isatins or anthranilic esters. The data collected here show the potential of this class of bioisosteres in the design of glutamate receptor ligands and beyond. 23254341 Noncanonical WNT-5A signaling regulates TGF-β-induced extracellular matrix production by airway smooth muscle cells. Transforming growth factor β (TGF-β), a key mediator of fibrotic responses, is increased in asthma and drives airway remodeling by inducing expression of extracellular matrix (ECM) proteins. We investigated the molecular mechanisms underlying TGF-β-induced ECM expression by airway smooth muscle cells and demonstrate a novel link between TGF-β and Wingless/integrase 1 (WNT) signaling in ECM deposition. Airway smooth muscle expresses abundant WNT ligands, with the noncanonical WNT-5A being the most profoundly expressed. Interestingly, WNT-5A shows ∼2-fold higher abundance in airway smooth muscle cells isolated from individuals with asthma than individuals without asthma. WNT-5A is markedly induced in response to TGF-β (4-16-fold; EC50 0.3 ng/ml) and is required for collagen and fibronectin expression by airway smooth muscle. WNT-5A engages noncanonical WNT signaling pathways, as inhibition of Ca(2+) and c-Jun N-terminal kinase (JNK) signaling attenuated this TGF-β response, whereas the canonical WNT antagonist Dickkopf 1 (DKK-1) did not. Accordingly, WNT-5A induced JNK phosphorylation and nuclear translocation of nuclear factor of activated T cells c1 (NFATc1). Furthermore, silencing of the WNT-5A receptors Frizzled 8 (FZD8) and RYK attenuated TGF-β-induced ECM expression. Collectively, these findings demonstrate that noncanonical WNT-5A signaling is activated by and necessary for TGF-β-induced ECM production by airway smooth muscle cells, which could have significance in asthma pathogenesis.-Kumawat, K., Menzen, M. H.., Bos, I. S. T., Baarsma, H. A., Borger, P., Roth, M., Tamm, M., Halayko, A. J., Simoons, M., Prins, A., Postma, D. S., Schmidt, M., and Gosens, R. Noncanonical WNT-5A signaling regulates TGF-β-induced extracellular matrix production by airway smooth muscle cells. 23557832 Replication Dynamics: Biases and Robustness of DNA Fiber Analysis. The factors that govern replication programs are still poorly identified in metazoans, especially in mammalian cells. Thanks to molecular combing, the dynamics of DNA replication can be assessed at the genome-scale level from the cumulative analysis of single DNA fibers. This technique notably enables measurement of replication fork speed and fork asymmetry and that of distances separating either initiation or termination events. The results presented here aim to evaluate requirements critical to accurate measurement of replication parameters by molecular combing. We show that sample size, fiber length and DNA counterstaining are crucial to gain robust information concerning replication dynamics. Our results thus provide a methodological frame to investigate the DNA replication program through molecular combing analyses. 22922115 A step toward the reactivation of aged cholinesterases - Crystal structure of ligands binding to aged human butyrylcholinesterase. Organophosphorus nerve agents irreversibly inhibit cholinesterases. Phosphylation of the catalytic serine can be reversed by the mean of powerful nucleophiles like oximes. But the phosphyl adduct can undergo a rapid spontaneous reaction leading to an aged enzyme, i.e., a conjugated enzyme that is no longer reactivable by oximes. One strategy to regain reactivability is to alkylate the phosphylic adduct. Specific alkylating molecules were synthesized and the crystal structures of the complexes they form with soman-aged human butyrylcholinesterase were solved. Although the compounds bind in the active site gorge of the aged enzyme, the orientation of the alkylating function appears to be unsuitable for efficient alkylation of the phosphylic adduct. However, these crystal structures provide key information to design efficient alkylators of aged-butyrylcholinesterase and specific reactivators of butyrylcholinesterase. 23427190 The effects of the phosphodiesterase type 5 inhibitor vardenafil on cognitive performance in healthy adults: a behavioral- electroencephalography study. Phosphodiesterase type 5 inhibitors (PDE5-Is) improve cognitive performance of rodents, but the few human studies investigating their effects did not systematically investigate cognitive effects and the results have been quite contradictory. Therefore, we examined whether the PDE5-I vardenafil improves memory and executive functioning and affect electroencephalography (EEG) in healthy young adults. Participants were selected out of a group of volunteers, based on their performance on a memory screening and they were orally treated with vardenafil (10-20 mg or placebo). Memory and executive functioning were tested while EEG activity was recorded. Additionally, a simple reaction time task and questionnaires addressing various complaints were presented. No prominent effects of vardenafil on cognition were found: participants only made more mistakes on a reaction time task after 20 mg vardenafil. During encoding of words, the P300 was generally smaller after vardenafil treatment. Furthermore, the N400 was larger after vardenafil 10 mg than placebo treatment in a spatial memory task at Fz. Finally, headache and feeling weak were reported more after vardenafil treatment. Vardenafil did not affect cognitive performance of healthy adults and showed only some incidental effects on ERPs. These findings in humans do not corroborate the cognition-enhancing effects of PDE5-Is in healthy animals. 23183374 A combined nuclear and nucleolar localization motif in activation-induced cytidine deaminase (AID) controls immunoglobulin class switching. Activation-induced cytidine deaminase (AID) is a DNA mutator enzyme essential for adaptive immunity. AID initiates somatic hypermutation and class switch recombination (CSR) by deaminating cytosine to uracil in specific immunoglobulin (Ig) gene regions. However, other loci, including cancer-related genes, are also targeted. Thus, tight regulation of AID is crucial to balance immunity versus disease such as cancer. AID is regulated by several mechanisms including nucleocytoplasmic shuttling. Here we have studied nuclear import kinetics and subnuclear trafficking of AID in live cells and characterized in detail its nuclear localization signal. Importantly, we find that the nuclear localization signal motif also directs AID to nucleoli where it colocalizes with its interaction partner, catenin-β-like 1 (CTNNBL1), and physically associates with nucleolin and nucleophosmin. Moreover, we demonstrate that release of AID from nucleoli is dependent on its C-terminal motif. Finally, we find that CSR efficiency correlates strongly with the arithmetic product of AID nuclear import rate and DNA deamination activity. Our findings suggest that directional nucleolar transit is important for the physiological function of AID and demonstrate that nuclear/nucleolar import and DNA cytosine deamination together define the biological activity of AID. This is the first study on subnuclear trafficking of AID and demonstrates a new level in its complex regulation. In addition, our results resolve the problem related to dissociation of deamination activity and CSR activity of AID mutants. 23074095 In situ control of cell substrate microtopographies using photolabile hydrogels. Substratum topography can play a significant role in regulating cellular function and fate. To study cellular responses to biophysical cues, researchers have developed dynamic methods for controlling cell morphology; however, many of these platforms are limited to one transition between two predefined substratum topographies. To afford the user additional control over the presentation of microtopographic cues to cell populations, a photolabile, PEG-based hydrogel system is presented in which precisely engineered topographic cues can be formed in situ by controlled erosion. Here, the ability to produce precisely engineered static microtopographies in the hydrogel surface is first established. Human mesenchymal stem cell (hMSC) response to topographies with features of subcellular dimensions (~5 to 40 μm) and with various aspect ratios increasing from 1:1 to infinity (e.g., channels) are quantified, and the dynamic nature of the culture system is demonstrated by sequentially presenting a series of topographies through in situ modifications and quantifying reversible changes in cell morphology in response to substratum topographies altered in real time. 23479726 Structural Units Important for Activity of a Novel-type Phosphoserine Phosphatase from Hydrogenobacter thermophilus TK-6 Revealed by Crystal Structure Analysis. Novel-type serine-synthesizing enzymes, termed metal-independent phosphoserine phosphatases (iPSPs), were recently identified and characterized from Hydrogenobacter thermophilus, a chemolithoautotrophic bacterium belonging to the order Aquificales. iPSPs are cofactor-dependent phosphoglycerate mutase (dPGM)-like phosphatases that have significant amino acid sequence similarity to dPGMs but lack phosphoglycerate mutase activity. Genes coding dPGM-like phosphatases have been identified in a broad range of organisms; however, predicting the function of the corresponding proteins based on sequence information alone is difficult due to their diverse substrate preferences. Here, we determined the crystal structure of iPSP1 from H. thermophilus in the apo-form and in complex with its substrate l-phosphoserine to find structural units important for its phosphatase activity toward l-phosphoserine. Structural and biochemical characterization of iPSP1 revealed that the side chains of His(85) and C-terminal region characteristic of iPSP1 are responsible for the PSP activity. The importance of these structural units for PSP activity was confirmed by high PSP activity observed in two novel dPGM-like proteins from Cyanobacteria and Chloroflexus in which the two structural units were conserved. We anticipate that our present findings will facilitate understanding of the serine biosynthesis pathways of organisms that lack gene(s) encoding conventional PSPs, as the structural information revealed here will help to identify iPSP from sequence databases. 23212963 Adsorption of phenanthrene, 2-naphthol, and 1-naphthylamine to colloidal oxidized multiwalled carbon nanotubes: effects of humic acid and surfactant modification. Carbon nanotubes (CNTs) can exist in the form of colloidal suspension in aquatic environments, particularly in the presence of natural organic matter or surfactants, and may significantly affect the fate and transport of organic contaminants. In the present study, the authors examined the adsorption of phenanthrene, 2-naphthol, and 1-naphthylamine to three colloidal CNTs, including a stable suspension of oxidized multiwalled carbon nanotubes (O-MWNT), a humic acid (HA)-modified colloidal O-MWNT, and a sodium dodecyl sulfate (SDS)-modified colloidal O-MWNT. All three colloidal O-MWNTs exhibit strong adsorption affinities to the three test compounds (with K(OC) values orders of magnitude greater than those of natural organic matter), likely resulting from strong nonhydrophobic interactions such as π-π electron donor-acceptor interactions and Lewis acid-base interactions. When thoroughly mixed, HA (at ∼310 mg HA/g CNT) and SDS (at ∼750 mg SDS/g CNT) significantly affected the aggregation properties of O-MWNT, causing individually dispersed tubes to form a loosely entangled network. The effects of HA or SDS modification on adsorption are twofold. Adsorption of HA/SDS significantly reduces surface areas of O-MWNT; however, the entangled network allows adsorbate molecules to interact simultaneously with multiple tubes. An important implication is that humic substances and surfactant-like materials not only facilitate the formation of colloidal carbon nanoparticles but also affect how these colloidal carbon nanoparticles adsorb organic contaminants. 23409951 Acute arsenic treatment alters cytochrome P450 expression and arachidonic acid metabolism in lung, liver and kidney of C57Bl/6 mice. Abstract 1. Arsenic (As(III)) toxicity has received increasing attention as human exposure to arsenic is associated with pulmonary, hepatic and renal toxicities. Therefore, in the present study, we investigated the effect of acute As(III) treatment on pulmonary, hepatic and renal cytochrome (CYP) P450-mediated arachidonic acid metabolism. 2. Our results demonstrated that acute As(III) treatment (12.5 mg/kg) altered CYP epoxygenases, CYP ω-hydroxylases and EPHX2 mRNA levels that were isozyme and tissue specific. 3. Furthermore, As(III) increased the formation of epoxyeicosatrienoic acids (EETs) in the kidney without affecting their levels in the lung or liver. In addition, acute As(III) treatment increased dihydroxyeicosatrienoic acid (DHETs) formation in the lung, while it did not affect liver DHETs formation and decreased kidney DHETs formation. 4. As(III) also increased total epoxygenases activity in the lung while it decreased its levels in the kidney and had no effect on the liver. Furthermore, As(III) increased 20-hydroxyeicosatetraenoic acid formation in the liver while it decreased its formation in the kidney. 5. Lastly, As(III) increased soluble epoxide hydrolase activity in the lung, while it decreased its levels in the kidney and had no effect on the liver. In conclusion, this is the first demonstration that As(III) alters arachidonic acid metabolism in a tissue specific manner. 23603195 Anti-diarrhoeal activity of aqueous extract of Ocimum kilimandscharicum. ETHNOPHARMACOLOGICAL RELEVANCE: Ocimum kilimandscharicum Baker ex Güerke, commonly referred to as Kapur Tulsi, is a medicinal herb that belongs to the family of Lamiaceae. It is traditionally popular for its gastroprotective effects, including its use as a digestive and anti-diarrhoeal. AIM OF THE STUDY: The present study aims to prove the anti-diarrhoeal activity of aqueous extract of leaves of Ocimum kilimandscharicum in animal models. MATERIALS AND METHODS: The aqueous extract was tested at three different dose levels (100, 200 and 400mg/kg, p.o. in rats and the corresponding doses in mice) against castor-oil induced diarrhoea model and castor oil induced enteropooling assay in rats; and charcoal meal test/intestinal motility test in mice. The parameters observed were the onset of defecation, cumulative faecal weight and consistency of faeces in the castor oil induced diarrhoea model; the weight of intestinal content in castor oil induced enteropooling assay; and the distance travelled by charcoal in the intestinal motility test. RESULTS: A significant delay in the onset of defecation (p<0.05), reduction in the cumulative faecal weight (p<0.001), along with a change in the faecal consistency from watery to solid form was observed at the dose of 200mg/kg in the castor oil-induced diarrhoea model. Similarly, the extract at the doses of 100mg/kg (p<0.01) and 200mg/kg (p<0.001) significantly decreased the weight of intestinal content in castor oil induced enteropooling assay. In the charcoal meal test the extract at the dose of 280mg/kg (corresponding to 200mg/kg in rats) significantly (p<0.01) reduced the distance travelled by charcoal. CONCLUSION: The aqueous extract of leaves of Ocimum kilimandscharicum showed anti-diarrhoeal activity, which may be due to its anti-motility and anti-secretory effects, which thus proved the traditional claims. 23360513 π-Conjugated nickel bis(dithiolene) complex nanosheet. A π-conjugated nanosheet comprising planar nickel bis(dithiolene) complexes was synthesized by a bottom-up method. A liquid-liquid interfacial reaction using benzenehexathiol in the organic phase and nickel(II) acetate in the aqueous phase produced a semiconducting bulk material with a thickness of several micrometers. Powder X-ray diffraction analysis revealed that the crystalline portion of the bulk material comprised a staggered stack of nanosheets. A single-layer nanosheet was successfully realized using a gas-liquid interfacial reaction. Atomic force microscopy and scanning tunneling microscopy confirmed that the π-conjugated nanosheet was single-layered. Modulation of the oxidation state of the nanosheet was possible using chemical redox reactions. 23394284 Tetracyclic diterpenoids with isomerized isospongian skeleton and labdane diterpenoids from the fruits of Amomum kravanh. Four novel diterpenoids, including three tetracyclic diterpenes with isomerized isospongian skeletons, kravanhins A-C (1-3), and kravanhin D (4), and three new labdane diterpenes (5-7) were isolated from the fruits of Amomum kravanh. Compounds 1-4 had unprecedented isospongian diterpene skeletons with a trans-anti-cis fused tricyclic ring system. The structures of compounds 1-7 were established on the basis of extensive analysis of NMR spectra, CD, and X-ray crystallography. Compound 2 showed inhibitory activity on nitric oxide production in lipopolysaccharide-induced RAW264.7 macrophages with an IC(50) value of 36.2 μM. 23462526 Cell cycle arrest, extracellular matrix changes and intrinsic apoptosis in human melanoma cells are induced by Boron Neutron Capture Therapy. Boron Neutron Capture Therapy (BNCT) involves the selective accumulation of boron carriers in tumor tissue followed by irradiation with a thermal or epithermal neutron beam. This therapy is therefore a cellular irradiation suited to treat tumors that have infiltrated into healthy tissues. BNCT has been used clinically to treat patients with cutaneous melanomas which have a high mortality. Human normal melanocytes and melanoma cells were treated with BNCT at different boronophenylalanine concentrations for signaling pathways analysis. BNCT induced few morphological alterations in normal melanocytes, with a negligible increase in free radical production. Melanoma cells treated with BNCT showed significant extracellular matrix (ECM) changes and a significant cyclin D1 decrease, suggesting cell death by necrosis and apoptosis and cell cycle arrest, respectively. BNCT also induced a significant increase in cleaved caspase-3 and a decrease in the mitochondrial electrical potential with selectivity for melanoma cells. Normal melanocytes had no significant differences due to BNCT treatment, confirming the data from the literature regarding the selectivity of BNCT. The results from this study suggest that some signaling pathways are involved in human melanoma treatment by BNCT, such as cell cycle arrest, ECM changes and intrinsic apoptosis. 23389852 A mouse model of chronic prostatic inflammation using a human prostate cancer-derived isolate of Propionibacterium acnes. BACKGROUND: Prostatic inflammation has been linked to a number of prostatic diseases such as benign prostatic hyperplasia (BPH), prostatitis syndromes, and prostate cancer. Major unanswered questions include what pathogenic mechanisms, such as bacterial infections, may drive the accumulation of inflammatory infiltrates in the human prostate, and how inflammation might contribute to disease. To study this potential link in an in vivo system, we developed a mouse model of long-term bacteria-induced chronic inflammation of the prostate using a human prostatectomy-derived strain of Propionibacterium acnes. METHODS: C57BL/6J mice were inoculated, via urethral catheterization, with vehicle control or a prostatectomy-derived strain of P. acnes (PA2). Animals were assessed at 2 days, 1, 2, or 8 weeks post-inoculation via histology and immunohistochemistry (IHC). RESULTS: PA2 inoculation resulted in severe acute and chronic inflammation confined to the dorsal lobe of the prostate. Chronic inflammation persisted for at least 8 weeks post-inoculation. Inflammatory lesions were associated with an increase in the Ki-67 proliferative index, and diminished Nkx3.1 and androgen receptor (AR) production. Interestingly, the observed response required live bacteria and both IHC and in situ hybridization assays for P. acnes indicated a potential intracellular presence of P. acnes in prostate epithelial cells. CONCLUSIONS: To our knowledge, this is the first mouse model of long-term prostatic inflammation induced by P. acnes, and more generally, any prostatectomy-derived bacterial isolate. This model may serve as a valuable preclinical model of chronic prostatic inflammation that can be used to mechanistically study the link between inflammation and prostatic disease. Prostate © 2013 Wiley Periodicals, Inc. 23095245 Differential effects of antipsychotic agents on obsessive-compulsive symptoms in schizophrenia: a longitudinal study. Indirect evidence supports the assumption that antiserotonergic second-generation antipsychotics (SGA) induce and aggravate obsessive-compulsive symptoms (OCS) in schizophrenia. However, multimodal studies assessing the long-term interaction of pharmacotherapy and psychopathology are missing. Over 12 months, we followed-up 75 schizophrenia patients who were classified into two groups according to antipsychotic treatment: clozapine or olanzapine (group I) versus aripiprazole or amisulpride (group II). We applied the Yale Brown Obsessive Compulsive Scale (YBOCS) and investigated between-group changes over time as the primary endpoint. Group I showed markedly higher YBOCS scores at both time points. Repeated measure analyses of variance (ANOVAs) revealed significant interaction effects of group and time (per protocol sample (PP): p=0.006). This was due to persistently high OCS severity within group I, and decreasing YBOCS scores within group II. OCS severity correlated significantly with the negative and general psychopathology subscales of the Positive and Negative Syndrome Scale (PANSS), as well as with depressive symptoms. The progressive differences in OCS severity between our groups support the assumption of differential pharmacodynamic effects on comorbid OCS in schizophrenia. Further studies should address the pathogenetic mechanism, define patients at risk and facilitate early detection as well as therapeutic interventions. 23475368 Pharmacological inhibition of Eph receptors enhances glucose-stimulated insulin secretion from mouse and human pancreatic islets. AIMS/HYPOTHESIS: Type 2 diabetes is characterised by impaired glucose-stimulated insulin secretion (GSIS) from pancreatic islets. Since erythropoietin-producing hepatoma (Eph)-ephrin bidirectional signalling fine-tunes GSIS from pancreatic beta cells, we investigated Eph receptor tyrosine kinases (RTK) as potential drug targets for selectively increasing GSIS. METHODS: Insulin secretion assays were carried out using mouse and human pancreatic islets as well as mouse insulinoma (MIN6) cells in the presence or absence of two Eph RTK inhibitors. Furthermore, the most potent inhibitor was injected into mice to evaluate its effects on glucose tolerance and plasma insulin levels. RESULTS: We showed that the Eph RTK inhibitors selectively increased GSIS from MIN6 cells as well as mouse and human islets. Our results also showed that the insulin secretory effects of these compounds required Eph-ephrin signalling. Finally, pharmacological inhibition of Eph receptor signalling improved glucose tolerance in mice. CONCLUSIONS/INTERPRETATION: We showed for the first time that Eph RTKs represent targets for small molecules to selectively increase GSIS and improve glucose tolerance. 23348679 Targeting the epithelial cells in fibrosis: a new concept for an old disease. Fibrosis, which affects millions of individuals worldwide, is a leading cause of organ failure. For 40 years myofibroblasts have been recognized to be the key cellular players in fibrosis. Currently, several pharmaceutical targets are under investigation that may contribute to the activation of myofibroblasts. Recent preclinical and clinical evidence suggests that other components in the fibrotic microenvironment can trigger myofibroblast activation, providing new targets for pharmaceutical intervention. Epithelial cells may represent the most promising cellular phenotype that could be exploited in the design of new anti-fibrotic medicines through their paracrine action on myofibroblasts. The present review briefly highlights this hypothesis and discusses some interesting related pharmacological targets. 23598400 P300 during response inhibition is associated with ad-lib alcohol consumption in social drinkers. Reduced amplitude of the cortical P300 event-related potential (ERP) component during response inhibition is associated with vulnerability to alcohol use disorders. In the current study, we investigated the effect of an experimental manipulation of response conflict on the amplitude of the P300 component during response inhibition, and examined whether individual differences in the amplitude of this P300 component would predict voluntary ad-lib alcohol consumption, in social drinkers. Using a repeated measures design, 16 participants performed a stop-signal task after receiving instructions that either emphasised or de-emphasised response conflict while their electroencephalogram (EEG) was concurrently recorded, before their ad-lib drinking was assessed. Results revealed that task instructions had the predicted effects on behavioural indices of response inhibition and the associated P300 components. Most importantly, individual differences in the amplitude of P300 subcomponents during response inhibition were negatively correlated with ad-lib alcohol consumption. Results provide the first experimental support for theoretical models that posit that reduced amplitude of the P300 during response inhibition is associated with alcohol-seeking behaviour in humans. 23211707 Steroid receptor coactivator-1 mediates estrogenic actions to prevent body weight gain in female mice. Estrogen receptor-α (ERα) expressed by hypothalamic proopiomelanocortin and steroidogenic factor-1 neurons largely mediates the antiobesity effects of estrogens in females. However, the critical molecular events that are coupled to ERα and mediate estrogenic effects on energy balance remain unknown. In the current study, we demonstrated that steroid receptor coactivator-1 (SRC1), a nuclear receptor coactivator, is abundantly expressed by both proopiomelanocortin and steroidogenic factor-1 neurons. We further showed that central administration of an ERα agonist, propyl pyrazole triol, acutely increases physical interaction between SRC1 and ERα in the hypothalamus. Finally, we demonstrated that the effects of estrogens on energy homeostasis are significantly blunted in female mice lacking SRC1 globally. Collectively our results indicate that SRC1 is functionally required to mediate the antiobesity effects of estrogen-ERα signals. 23644213 Low molecular weight dual inhibitors of factor Xa and fibrinogen binding to GPIIb/IIIa with highly overlapped pharmacophores. Dual antithrombotic agents acting as anticoagulants and aggregation inhibitors could have substantial advantages over currently prescribed combinations of antithrombotic drugs. Herein, we report compounds with moderate inhibitory activity for factor Xa and fibrinogen GPIIb/IIIa binding (both in the micromolar range). These compounds resulted from our efforts to merge the pharmacophores of selective factor Xa inhibitor rivaroxaban with a mimic of the Arg-Gly-Asp (RGD) sequence of fibrinogen to obtain designed multiple ligands with potential antithrombotic activity. Resulting from this study, a structurally novel class of submicromolar fibrinogen GPIIb/IIIa binding inhibitor bearing 1,2,4-oxadiazol-5(4H)-one moiety is also described. 22998221 Enhanced oral bioavailability of isradipine via proniosomal systems. The objective of the present research was to develop a proniosomal formulation of isradipine and to evaluate the influence of proniosomal systems on the oral bioavailability of the drug in albino Wistar rats. Proniosomes were prepared by film deposition on carrier's method using various molar ratios of nonionic surfactants such as span20, span40, span60, and span80 with cholesterol as membrane stabilizing agent and dicetylphosphate as a charge inducer. The formation of niosomes and surface morphology of proniosome formulations were studied by optical and scanning electron microscopy (SEM), respectively. The prepared proniosomes have shown higher dissolution of isradipine compared with pure drug powder. Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffractometry studies were performed to understand the solid state properties of the drug. Ex vivo permeation enhancement assessed from flux, permeability coefficient, and enhancement ratio were significantly higher for proniosomes compared with control. The pharmacokinetic parameters were evaluated in male albino Wistar rats and a significant enhancement in the bioavailability (2.3-fold) was observed from optimized proniosome formulation compared with control (oral suspension). The stability study reveals that the proniosome formulations are stable when stored at 4°C. 23500117 In vivo sustained dermal delivery and pharmacokinetics of interferon alpha in biphasic vesicles after topical application. Biphasic vesicles, a novel nanostructured lipid-based delivery system show potential for topical application of interferon alpha (IFN α) for the treatment of human papillomavirus (HPV) infections (anogenital warts). Dermal delivery of IFN α encapsulated in biphasic vesicles (BPV-IFN α), applied topically to the skin, was characterized in a guinea pig model. BPV-IFN α (1g, 2MIU/g) was topically applied either as a single or multiple treatments on the skin of guinea pigs. As a comparison with currently used regimens, IFN α solution was administered intravenously or intradermally. Skin and serum samples were collected over 96h, IFN α levels were determined by an antiviral assay, and half-life (t1/2) and elimination (k) rates were calculated. Topical BPV-IFN α treatment resulted in maximum skin levels (about 100,000U/100cm(2)) of IFN α within 6h and maintained for 72-96h. Clearance from the skin after intradermal injections was initially fast (t1/2 0.62h, k 1.1179h(-1)), followed by a slower steady decrease after 6h. After intravenous and intradermal administration, IFN α was rapidly cleared from the serum, t1/2 0.75h, k 0.9271h(-1) and t1/2 1.28h, k 0.5421h(-1), respectively, whereas after topical application, IFN α levels remained below 100U/mL. Topical application of BPV- IFN α resulted in sustained delivery of biologically active IFN α locally into skin with minimal systemic exposure. 23597506 Anandamide deficiency and heightened neuropathic pain in aged mice. Damaging of peripheral nerves may result in chronic neuropathic pain for which the likelihood is increased in the elderly. We assessed in mice if age-dependent alterations of endocannabinoids contributed to the heightened vulnerability to neuropathic pain at old age. We assessed nociception, endocannabinoids and the therapeutic efficacy of R-flurbiprofen in young and aged mice in the spared nerve injury model of neuropathic pain. R-flurbiprofen was used because it is able to reduce neuropathic pain in young mice in part by increasing anandamide. Aged mice developed stronger nociceptive hypersensitivity after sciatic nerve injury than young mice. This was associated with low anandamide levels in the dorsal root ganglia, spinal cord, thalamus and cortex, which further decreased after nerve injury. In aged mice, R-flurbiprofen had only weak antinociceptive efficacy and it failed to restore normal anandamide levels after nerve injury. In terms of the mechanisms, we found that fatty acid amide hydrolase (FAAH) which degrades anandamide, was upregulated after nerve injury at both ages, so that this upregulation likely did not account for the age-dependent differences. However, enzymes contributing to oxidative metabolism of anandamide, namely cyclooxygenase-1 and Cyp2D6, were increased in the brain of aged mice, possibly enhancing the oxidative breakdown of anandamide. This may overwhelm the capacity of R-flurbiprofen to restore anandamide homeostasis and may contribute to the heightened risk for neuropathic pain at old age. 23365017 A method to predict and understand fish survival under dynamic chemical stress using standard ecotoxicity data. The authors present a method to predict fish survival under exposure to fluctuating concentrations and repeated pulses of a chemical stressor. The method is based on toxicokinetic-toxicodynamic modeling using the general unified threshold model of survival (GUTS) and calibrated using raw data from standard fish acute toxicity tests. The model was validated by predicting fry survival in a fish early life stage test. Application of the model was demonstrated by using Forum for Co-ordination of Pesticide Fate Models and Their Use surface water (FOCUS-SW) exposure patterns as model input and predicting the survival of fish over 485 d. Exposure patterns were also multiplied by factors of five and 10 to achieve higher exposure concentrations for fish survival predictions. Furthermore, the authors quantified how far the exposure profiles were below the onset of mortality by finding the corresponding exposure multiplication factor for each scenario. The authors calculated organism recovery times as additional characteristic of toxicity as well as number of peaks, interval length between peaks, and mean duration as additional characteristics of the exposure pattern. The authors also calculated which of the exposure patterns had the smallest and largest inherent potential toxicity. Sensitivity of the model to parameter changes depends on the exposure pattern and differs between GUTS individual tolerance and GUTS stochastic death. Possible uses of the additional information gained from modeling to inform risk assessment are discussed. 23351072 Denaturation-resistant bifunctional colloidal superstructures assembled via the proteinaceous barnase-barstar interface. To date, a number of biomolecule-mediated nanoparticle self-assembly systems have been developed that are amenable to controllable disassembly under relatively gentle conditions. However, for some applications such as design of self-assembled multifunctional theragnostic agents, high stability of the assembled structures can be of primary importance. Here, we report extraordinarily high durability of protein-assisted nanoparticle self-assembly systems yielding bifunctional colloidal superstructures resistant to extreme denaturing conditions intolerable for most proteins (e.g., high concentrations of chaotropic agents, high temperature). Among the tested systems (barnase-barstar (BBS), streptavidin-biotin, antibody-antigen, and protein A-immunoglobulin), the BBS is notable due to the combination of its high resistance to severe chemical perturbation and unique advantages offered by genetic engineering of this entirely protein-based system. Comparison of the self-assembly systems shows that whereas in all cases the preassembled structures proved essentially resistant to extreme conditions, the ability of the complementary biomolecular pairs to mediate assembly of the initial biomolecule-particle conjugates differs substantially in these conditions. 23247722 A comparative VCD study of methyl mandelate in methanol, dimethyl sulfoxide, and chloroform: explicit and implicit solvation models. Vibrational absorption (VA) and vibrational circular dichroism (VCD) spectra of methyl mandelate, a prototype chiral molecule, in a series of organic solvents, namely methanol (MeOH-d(4)), dimethyl sulfoxide (DMSO-d(6)), and chloroform (CDCl(3)), have been measured in the finger print region from 1800 to 1150 cm(-1). Implicit solvation models in the form of polarizable continuum model and explicit solvation models have been employed independently and simultaneously. The goal is to evaluate their efficiencies in dealing with solvent effects in each solution and to establish a general strategy to adequately account for effects of solvents. Molecular dynamics (MD) simulation and radial distribution function analysis have been performed to aid the construction of the explicit solvation models. Initial geometry searches have been carried out at the B3LYP/6-31G(d) level for the methyl mandelate monomer and its explicit 1 : 1 and 1 : 2 solute-solvent hydrogen-bonded complexes. B3LYP/cc-pVTZ has been used for all the final geometry optimizations, the vibrational frequency, VA and VCD intensity, and optical rotation dispersion (ORD) calculations. The results show that inclusion of solvent explicitly and implicitly at the same time has significant impacts on the appearance of the VA and VCD spectra, and is crucial for reliable spectral assignments when solvents are capable of hydrogen-bonding interactions with solutes. When no strong solvent-solute hydrogen-bonding interactions in the case of chloroform are expected, the gas phase monomer model is adequate for spectral interpretation, while inclusion of implicit solvation improves the frequency agreement with experiment. ORD spectra of methyl mandelate in the aforementioned solvents at different concentrations under 5 excitation wavelengths have also been measured. The comparison between the calculated and the experimental ORD spectra supports the conclusions drawn from the VA and VCD investigations. 23540695 Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Glioblastomas (GBMs) are highly vascular and lethal brain tumors that display cellular hierarchies containing self-renewing tumorigenic glioma stem cells (GSCs). Because GSCs often reside in perivascular niches and may undergo mesenchymal differentiation, we interrogated GSC potential to generate vascular pericytes. Here, we show that GSCs give rise to pericytes to support vessel function and tumor growth. In vivo cell lineage tracing with constitutive and lineage-specific fluorescent reporters demonstrated that GSCs generate the majority of vascular pericytes. Selective elimination of GSC-derived pericytes disrupts the neovasculature and potently inhibits tumor growth. Analysis of human GBM specimens showed that most pericytes are derived from neoplastic cells. GSCs are recruited toward endothelial cells via the SDF-1/CXCR4 axis and are induced to become pericytes predominantly by transforming growth factor β. Thus, GSCs contribute to vascular pericytes that may actively remodel perivascular niches. Therapeutic targeting of GSC-derived pericytes may effectively block tumor progression and improve antiangiogenic therapy. 23137796 The binding of multiple nuclear receptors to a single regulatory region is important for the proper expression of EDG84A in Drosophila melanogaster. Nuclear receptor transcription factor family members share target sequence similarity; however, little is known about how these factors exert their specific regulatory control. Here, we examine the mechanism regulating the expression of the Drosophila EDG84A gene, a target gene of the orphan nuclear receptor βFTZ-F1, as a model to study the cooperative behavior among nuclear receptors. We show that the three nuclear receptors βFTZ-F1, DHR3, and DHR39 bind to a common element in the EDG84A promoter. The expression level of the EDG84A promoter-lacZ reporter genes in DHR39-induced and mutant animals, respectively, suggests that DHR39 works as a repressor. The activity of a reporter gene carrying a mutation preventing DHR3 binding was reduced in ftz-f1 mutants and rescued by the induced expression of βFTZ-F1, suggesting that DHR3 and βFTZ-F1 activate the EDG84A gene in a redundant manner. A reporter gene carrying a mutation that abolishes DHR39 and FTZ-F1 binding was prematurely expressed, and the expression level of the reporter gene carrying a mutation preventing DHR3 binding was reduced. These findings suggest that the temporal expression of this gene is mainly controlled by βFTZ-F1 but that the binding of DHR3 is also important. Comparison of the binding site sequence among Drosophila species suggests that DHR3 binding ability was gained after the melanogaster subgroup evolved, and this ability may contribute to the robust expression of this gene. These results show the complicated regulatory mechanisms utilized by multiple nuclear receptors to properly regulate the expression of their target gene through a single target site. 23617431 Boronated carbohydrate derivatives as potential boron neutron capture therapy reagents. The treatment of cancer remains one of the most challenging problems for humanity. Boron neutron capture therapy is a binary approach for cancer treatment that is particularly attractive in treating high-grade gliomas and metastatic brain tumors. Among the types of boron-containing molecules used as boron neutron capture therapy agents, boronated carbohydrate derivatives have received significant attention because of their preferential uptake by growing tumor cells. This review provides a summary of the recent developments in the chemistry of carborane-containing carbohydrates. 23282065 Structure-based investigation of rat aldehyde oxidase inhibition by flavonoids. Abstract 1. Flavonoids are a group of polyphenolic plant metabolites most commonly known for their antioxidant activities. They also show inhibitory activities on molybdo-flavoenzymes family of enzymes which are involved in biotransformation of some exogenous and endogenous chemicals. Most notably, aldehyde oxidase (AO), a member of this family, is responsible for metabolism of some therapeutic agents. On the other hand, there are some therapeutics which inhibit AO. As flavonoids are ubiquitous in human diet and have potential to interact with AO, it is important to investigate their effects at the molecular details. 2. The inhibitory effects of 15 flavonoids on the activity of rat liver AO were assessed. Quantitative structure-activity relationship studies were performed using genetic algorithm coupled partial least square and stepwise multiple linear regression methods to elucidate the important structural properties responsible for the observed inhibitory effects. To further understand the mode of interaction between these flavonoids and AO, a homology model of the enzyme was built and flavonoids were docked into its active site. The most important amino acids involved in the interactions were identified. 3. Quercetin, myricetin and genistein were the most potent inhibitors establishing favorable interactions with the enzyme. However, the glycosylated flavonoids showed relatively weaker inhibition which may be attributed to their hindered binding into the active site of AO by bulky sugar groups. 23584434 Insulin- and glucagon-like peptide-1-induced changes in heart rate and vagosympathetic activity: why they matter. Heart rate (HR) predicts cardiovascular morbidity and mortality in individuals either with or without diabetes. In type 2 diabetic patients, cardiac autonomic neuropathy is a risk marker for cardiac morbidity and mortality. A major pathogenic potential may be attributed to vagal depression and sympathetic predominance. In this issue of Diabetologia, Berkelaar et al (DOI: 10.1007/s00125-013-2848-6 ) examined the effects of euglycaemic, and hyperglycaemic clamp with the addition of glucagon-like-peptide-1 (GLP-1) and arginine, on cardiac vagal control in a large number of healthy subjects. After adjustments for age, BMI and insulin sensitivity, insulin associations with HR remained partially intact while those with vagal control disappeared. This suggested that BMI and insulin sensitivity, but not insulin levels, were the main drivers of cardiac vagal control. GLP-1 infusion during hyperglycaemia increased HR and BP and produced a statistically non-significant decrease in measures of cardiac vagal control compared with values before any manipulation of insulin levels. This commentary summarises how, and to what extent, insulin and GLP-1 affect autonomic nervous system activity, HR and BP. More information is needed on the mechanisms through which acute administration of, and long-term treatment with, GLP-1 may affect haemodynamics and autonomic activity in diabetic and obese patients, since this may influence cardiovascular outcomes. 22935062 Drug metabolizing enzymes in the perinatal and neonatal period: differences in the expression and activity. Physiological changes occurring perinatally and in the first month of life can affect the answer to a pharmacological treatment and the individual response to a drug in terms of efficacy and toxicity is highly variable in the neonatal population. Among potential causes for such variability, differences in drug metabolism may have a great impact. This article aims to review qualitative and quantitative differences in drug metabolizing enzymes in neonates, since both phase I and phase II metabolic pathways are immature at birth and subject to maturational changes in the first period of extrauterine life. Moreover, clinical implications will be discussed. 23204517 The calmodulin regulator protein, PEP-19, sensitizes ATP-induced Ca2+ release. PEP-19 is a small, intrinsically disordered protein that binds to the C-domain of calmodulin (CaM) via an IQ motif and tunes its Ca(2+) binding properties via an acidic sequence. We show here that the acidic sequence of PEP-19 has intrinsic Ca(2+) binding activity, which may modulate Ca(2+) binding to CaM by stabilizing an initial Ca(2+)-CaM complex or by electrostatically steering Ca(2+) to and from CaM. Because PEP-19 is expressed in cells that exhibit highly active Ca(2+) dynamics, we tested the hypothesis that it influences ligand-dependent Ca(2+) release. We show that PEP-19 increases the sensitivity of HeLa cells to ATP-induced Ca(2+) release to greatly increase the percentage of cells responding to sub-saturating doses of ATP and increases the frequency of Ca(2+) oscillations. Mutations in the acidic sequence of PEP-19 that inhibit or prevent it from modulating Ca(2+) binding to CaM greatly inhibit its effect on ATP-induced Ca(2+) release. Thus, this cellular effect of PEP-19 does not depend simply on binding to CaM via the IQ motif but requires its acidic metal binding domain. Tuning the activities of Ca(2+) mobilization pathways places PEP-19 at the top of CaM signaling cascades, with great potential to exert broad effects on downstream CaM targets, thus expanding the biological significance of this small regulator of CaM signaling. 22703292 Antimicrobial and antioxidant properties of Betula aetnensis Rafin. (Betulaceae) leaves extract. This study aimed to evaluate the antimicrobial effects, the radical scavenging activity (by DPPH and ABTS tests) and the antioxidant capacity (by β-carotene bleaching test) of Betula aetnensis leaves extract. The antimicrobial activity was tested against 14 Gram-positive clinical strains, 2 ATCC Gram-positive strains, 10 Gram-negative clinical strains and 4 Gram-negative ATCC strains. Streptococcus pyogenes Ery-S and Ery-R1 were the most sensitive. Betula aetnensis was considerably active against three bacterial strains, namely Haemophilus influenzae ATCC 49247, Amp-R1 and Moraxella catarrhalis ATCC 25238. Standard ATCC strains of Gram-positive bacteria were more sensitive than Gram-negative. Betula aetnensis showed also an interesting reducing power with TEAC values of 9.7 and a good inhibition of linoleic acid oxidation with an IC50 value of 22.0 µg mL(-1) after 30 min of incubation. The total phenol and flavonoid contents were determined with the purpose to evaluate the relationship with the observed bioactivities. 23596327 Pheromone evolution, reproductive genes, and comparative transcriptomics in Mediterranean earthworms (Annelida, Oligochaeta, Hormogastridae). Animals inhabiting cryptic environments are often subjected to morphological stasis due to the lack of obvious agents driving selection, and hence chemical cues may be important drivers of sexual selection and individual recognition. Here we provide a comparative analysis of de novo assembled transcriptomes in two Mediterranean earthworm species with the objective to detect pheromone proteins and other reproductive genes that could be involved in cryptic speciation processes, as recently characterized in other earthworm species. cDNA libraries of unspecific tissue of Hormogaster samnitica and three different tissues of Hormogaster elisae were sequenced in an Illumina Genome Analyzer II or Hi-Seq. Two pheromones, Attractin and Temptin were detected in all tissue samples and both species. Attractin resulted in a reliable marker for phylogenetic inference. Temptin contained multiple paralogues and was slightly overexpressed in the digestive tissue, suggesting that these pheromones could be released with the casts. Genes involved in sexual determination and fertilization were highly expressed in reproductive tissue. This is thus the first detailed analysis of the molecular machinery of sexual reproduction in earthworms. 23601412 Biogenic amines content as a measure of the quality of wines of Abruzzo (Italy). Aim of this research was to study the effect of some agronomic and oenological factors on the content of biogenic amines as quality index of sixty-five Abruzzo wines. Sum of amines was found to be decreasing in the order: red (19.3±12.8mgL(-1)), rosé (9.20±6.34mgL(-1)), white (7.67±3.84mgL(-1)) wine. Significant differences in relationship among amines levels and chemical and chemico-physical characteristics of red, white and rosé wine are due to their different biotechnological process and winemaking. Besides the aging treatment, influential seems to be the effect of the winery, regardless of the area in which it is situated. The single amines significantly correlated with their sum were putrescine, histamine and tyramine, even if reached levels were below toxicity threshold, demonstrating a good quality of the wines of Abruzzo whose consumption is no risk to the health of the consumer following the rules of proper nutrition. 23562637 Bioreducible alginate-poly(ethylenimine) nanogels as an antigen-delivery system robustly enhance vaccine-elicited humoral and cellular immune responses. Although polysaccharide nanogels have emerged as a novel antigen delivery system for vaccine development, whether modulating the redox sensitivity of nanogels could improve vaccine efficacy remains unclear. In the present study, we generated bioreducible cationic alginate-polyethylenimine (PEI) nanogels as a novel vaccine delivery system. Briefly, nanogels were prepared by the electrostatic interaction of negatively charged alginate sodium with branched PEI2k, followed by disulfide cross-linking to generate bioreducible nanogels (AP-SS). The AP-SS nanogels demonstrated great antigen-loading capacity and minimal cytotoxicity. The in vitro study showed that reducible AP-SS nanogels not only facilitated antigen uptake by mouse bone marrow dendritic cells (BMDCs), but also promoted intracellular antigen degradation and cytosolic release. Moreover, AP-SS nanogels significantly enhanced both MHC class I and II antigen presentation by BMDCs. Compared with the non-reducible nanogels, AP-SS nanogels more potently enhanced vaccine-induced antibody production and CD8(+) T cell-mediated tumor cell lysis. Hence, the bioreducible alginate-PEI nanogels could serve as a potent adjuvant to improve vaccine-elicited humoral and cellular immune responses. 22777357 Terminal differentiation and loss of tumorigenicity of human cancers via pluripotency-based reprogramming. Pluripotent cells can be derived from various types of somatic cells by nuclear reprogramming using defined transcription factors. It is, however, unclear whether human cancer cells can be similarly reprogrammed and subsequently terminally differentiated with abrogation of tumorigenicity. Here, using sarcomas we show that human-derived complex karyotype solid tumors: (1) can be reprogrammed into a pluripotent-like state as defined by all in vitro criteria used to define pluripotent stem cells generated from somatic cells; (2) can be terminally differentiated into mature connective tissue and red blood cells; and (3) terminal differentiation is accompanied with loss of both proliferation and tumorigenicity. We go on to perform the first global DNA promoter methylation and gene expression analyses comparing human cancers to their reprogrammed counterparts and report that reprogramming/differentiation results in significant epigenetic remodeling of oncogenes and tumor suppressors, while not significantly altering the differentiation status of the reprogrammed cancer cells, in essence dedifferentiating them to a state slightly before the mesenchymal stem cell differentiation stage. Our data demonstrate that direct nuclear reprogramming can restore terminal differentiation potential to human-derived cancer cells, with simultaneous loss of tumorigenicity, without the need to revert to an embryonic state. We anticipate that our models would serve as a starting point to more fully assess how nuclear reprogramming overcomes the multitude of genetic and epigenetic aberrancies inherent in human cancers to restore normal terminal differentiation pathways. Finally, these findings suggest that nuclear reprogramming may be a broadly applicable therapeutic strategy for the treatment of cancer. 23643808 Alteration of prolyl oligopeptidase and activated alpha-2-macroglobulin in multiple sclerosis subtypes and in the clinically isolated syndrome. Prolyl oligopeptidase (PREP) has been considered as a drug target for the treatment of neurodegenerative diseases. In plasma, PREP has been found altered in several disorders of the central nervous system including multiple sclerosis (MS). Oxidative stress and the levels of an endogenous plasma PREP inhibitor have been proposed to decrease PREP activity in MS. In this work, we measured the circulating levels of PREP in patients suffering of relapsing remitting (RR), secondary progressive (SP), primary progressive (PP) MS, and in subjects with clinically isolated syndrome (CIS). We found a significantly lower PREP activity in plasma of RRMS as well as in PPMS patients and a trend to reduced activity in subjects diagnosed with CIS, compared to controls. No signs of oxidative inactivation of PREP, and no correlation with the endogenous PREP inhibitor, identified as activated α-2-macroglobulin (α2M*), were observed in any of the patients studied. However, a significant decrease of α2M* was recorded in MS. In cell cultures, we found that PREP specifically stimulates immune active cells possibly by modifying the levels of fibrinogen β, thymosin β4, and collagen. Our results open new lines of research on the role of PREP and α2M* in MS, aiming to relate them to the diagnosis and prognosis of this devastating disease. 23246469 Non-ionic Gd-based MRI contrast agents are optimal for encapsulation into phosphatidyldiglycerol-based thermosensitive liposomes. Thermosensitive liposomes (TSL) with encapsulated magnetic resonance imaging (MRI) longitudinal relaxation time (T(1)) contrast agents (CAs) have been proposed for MRI assisted interventional thermotherapy in solid tumors. Here the feasibility of 6 clinically approved CAs (Gd-DTPA, Gd-BOPTA, Gd-DOTA, Gd-BT-DO3A, Gd-DTPA-BMA, and Gd-HP-DO3A) for formulation into TSL was investigated. CAs were passively encapsulated with 323 mOs kg(-1) into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/1,2-distearoyl-sn-glycero-3-phosphocholine/1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol 50/20/30 (mol/mol) TSL (DPPG(2)-TSL) to obtain stable formulations. T(1) relaxivity (r(1)) and diffusive permeability to water (P(d)) across the membrane were determined. Shelf life at 4°C was investigated by determining lysolipid content up to 10 weeks after preparation. All preparations were monodispersed with comparable small vesicle sizes (~135 nm). Neither zeta potential nor phase transition temperature (T(m)) was affected by the CA. The formulations showed an increase in r(1) in the temperature range between 38 and 44°C. This correlated with the phase transition. Change in r(1) (Δr(1)=r(1)(45.3°C)-r(1)(37.6°C)) and r(1) (T CrambC1 > CrambA2, while Cramb816 lacked an effect. Only CrambC1 and Cramb816 partially blocked Na(+) total current. However, Cramb816 partially blocked Ca(2+) , while NcrambA2 did not. Since the blocking effect of Cramb816 on calcium currents has not been previously reported in detail, we further pharmacologically isolated the two main fractions of HVA Ca(2+) channels in neurons and investigated the Cramb816 effect on them. Here, we revealed that Cav1 or L-type calcium channels are the main target for Cramb816. These two families of guanidine alkaloids clearly showed a structure-activity relationship with the crambescins acting on voltage-gated potassium channels, while Cramb816 blocks the voltage-gated calcium channel Cav1 with higher potency than nifedipine. The novel evidence that Cramb816 partially blocked Ca(V) and Na(V) channels in neurons suggests that this compound might be involved in decreasing the neurotransmitter release and synaptic transmission in the central nervous system. The findings presented here provide the first detailed approach on the different effects of crambescin and crambescidin compounds in voltage-gated sodium, potassium, and calcium channels in neurons and thus provide a basis for future studies. 22961095 Involvement of interleukin-6-regulated nitric oxide synthase in hemorrhagic cystitis and impaired bladder contractions in young rats induced by acrolein, a urinary metabolite of cyclophosphamide. Hemorrhagic cystitis is a common complication in children receiving cyclophosphamide, a chemotherapeutic alkylating agent. Acrolein is a urinary metabolite from cyclophosphamide and can induce hemorrhagic cystitis. Here, we investigated the effects and mechanisms of acrolein by intravesical instillation on urinary bladder muscle contractions and pathological alterations in rats. Acrolein instillation significantly increased the muscle contractions of rat bladder detrusor after 1 and 6 h but markedly decreased detrusor contractions after 24 h. Acrolein increased phosphorylated protein kinase C (pan-PKC) expressions in bladders after 1 and 6 h but inhibited it after 24 h. Inducible nitric oxide (NO) synthase (iNOS) protein expressions were markedly induced in bladders 24 h after acrolein treatment. Twenty-four-hour acrolein instillation increased the levels of nitrite/nitrate and interleukin-6 (IL-6) in the urinary bladder. The iNOS inhibitors significantly inhibited the acrolein-increased nitrite/nitrate levels, but not IL-6 levels. IL-6-neutralizing antibodies effectively inhibited the acrolein-increased NOx levels. The increased detrusor contractions by 1-h acrolein treatment were significantly reversed by the PKC inhibitor RO32-0432, and the decreased detrusor contractions by 24-h acrolein treatment were significantly reversed by the iNOS inhibitor and IL-6-neutralizing antibody. Both the iNOS inhibitor and IL-6-neutralizing antibody effectively reversed the increased iNOS expression, decreased PKC phosphorylation, increased bladder weight, and hemorrhagic cystitis in rats 24 h after acrolein treatment. Taken together, these results suggest that an IL-6-regulated iNOS/NO signaling pathway participates in the acrolein-triggered detrusor contraction inhibition and hemorrhagic cystitis. These findings may help us to find a new strategy to treat cyclophosphamide-induced hemorrhagic cystitis. 23007888 Lattice Microbes: high-performance stochastic simulation method for the reaction-diffusion master equation. Spatial stochastic simulation is a valuable technique for studying reactions in biological systems. With the availability of high-performance computing (HPC), the method is poised to allow integration of data from structural, single-molecule and biochemical studies into coherent computational models of cells. Here, we introduce the Lattice Microbes software package for simulating such cell models on HPC systems. The software performs either well-stirred or spatially resolved stochastic simulations with approximated cytoplasmic crowding in a fast and efficient manner. Our new algorithm efficiently samples the reaction-diffusion master equation using NVIDIA graphics processing units and is shown to be two orders of magnitude faster than exact sampling for large systems while maintaining an accuracy of !0.1%. Display of cell models and animation of reaction trajectories involving millions of molecules is facilitated using a plug-in to the popular VMD visualization platform. The Lattice Microbes software is open source and available for download at http://www.scs.illinois.edu/schulten/lm 23421434 Strategies to control morphology in hybrid group III-V/group IV heterostructure nanowires. By combining in situ and ex situ transmission electron microscopy measurements, we examine the factors that control the morphology of "hybrid" nanowires that include group III-V and group IV materials. We focus on one materials pair, GaP/Si, for which we use a wide range of growth parameters. We show through video imaging that nanowire morphology depends on growth conditions, but that a general pattern emerges where either single kinks or inclined defects form some distance after the heterointerface. We show that pure Si nanowires can be made to exhibit the same kinks and defects by changing their droplet volume. From this we derive a model where droplet geometry drives growth morphology and discuss optimization strategies. We finally discuss morphology control for material pairs where the second material kinks immediately at the heterointerface and show that an interlayer between segments can enable the growth of unkinked hybrid nanowires. 23503684 μ-Opioid receptors in the stimulation of mesolimbic dopamine activity by ethanol and morphine in Long-Evans rats: a delayed effect of ethanol. RATIONALE: Naltrexone, a non-selective opioid antagonist, decreases the euphoria and positive subjective responses to alcohol in heavy drinkers. It has been proposed that the μ-opioid receptor plays a role in ethanol reinforcement through modulation of ethanol-stimulated mesolimbic dopamine release. OBJECTIVES: To investigate the ability of naltrexone and β-funaltrexamine, an irreversible μ-opioid specific antagonist, to inhibit ethanol-stimulated and morphine-stimulated mesolimbic dopamine release, and to determine whether opioid receptors on mesolimbic neurons contribute to these mechanisms. METHODS: Ethanol-naïve male Long Evans rats were given opioid receptor antagonists either intravenously, subcutaneously, or intracranially into the ventral tegmental area (VTA), followed by intravenous administration of ethanol or morphine. We measured extracellular dopamine in vivo using microdialysis probes inserted into the nucleus accumbens shell (n = 114). RESULTS: Administration of naltrexone (intravenously) and β-funaltrexamine (subcutaneously), as well as intracranial injection of naltrexone into the VTA did not prevent the initiation of dopamine release by intravenous ethanol administration, but prevented it from being as prolonged. In contrast, morphine-stimulated mesolimbic dopamine release was effectively suppressed. CONCLUSIONS: Our results provide novel evidence that there are two distinct mechanisms that mediate ethanol-stimulated mesolimbic dopamine release (an initial phase and a delayed phase), and that opioid receptor activation is required to maintain the delayed-phase dopamine release. Moreover, μ-opioid receptors account for this delayed-phase dopamine response, and the VTA is potentially the site of action of this mechanism. We conclude that μ-opioid receptors play different roles in the mechanisms of stimulation of mesolimbic dopamine activity by ethanol and morphine. 23595058 Antimalarial Activity of Axidjiferosides, New β-Galactosylceramides from the African Sponge Axinyssa djiferi. The marine sponge, Axinyssa djiferi, collected on mangrove tree roots in Senegal, was investigated for glycolipids. A mixture containing new glycosphingolipids, named axidjiferoside-A, -B and -C, accounted for 0.07% of sponge biomass (dry weight) and for 2.16% of total lipids. It showed a significant antimalarial activity, with a 50% inhibitory concentration (IC50) of 0.53 ± 0.2 μM against a chloroquine-resistant strain of Plasmodium falciparum. They were identified as homologous β-galactopyranosylceramides composed of 2-amino-(6E)-octadec-6-en-1,3,4-triol, and the major one, axidjiferoside-A (around 60%), contained 2-hydroxytetracosanoic acid. Cytotoxicity was studied in vitro on human cancer cell lines (multiple myeloma, colorectal adenocarcinoma, glioblastoma and two lung cancer NSCLC-N6 and A549). Results of this investigation showed that axidjiferosides are of interest, because they proved a good antiplasmodial activity, with only a low cytotoxicity against various human cell lines and no significant antitrypanosomal and antileishmanial activity. Thus, it seems that galactosylceramides with a β anomeric configuration may be suitable in searching for new antimalarial drugs. 23485474 Structural modifications of polymethacrylates: Impact on thermal behavior and release characteristics of glassy solid solutions. Polymethacrylates such as Eudragit® polymers are well established as drug delivery matrix. Here, we synthesize several Eudragit E PO (n-butyl-, dimethylaminoethyl-, methyl-methacrylate-terpolymer) analogues via free radical polymerization. These polymers are processed via hot melt extrusion, followed by injection molding and evaluated as carriers to produce immediate release solid solution tablets. Three chemical modifications increased the glass transition temperature of the polymer: (a) substitution of n-butyl by t-butyl groups, (b) reduction of the dimethylaminoethyl methacrylate (DMAEMA) content, and (c) incorporation of a bulky isobornyl repeating unit. These structural modifications revealed the possibility to increase the mechanical stability of the tablets via altering the polymer Tg without influencing the drug release characteristics and glassy solid solution forming properties. The presence of DMAEMA units proved to be crucial with respect to API/polymer interaction (essential in creating glassy solid solutions) and drug release characteristics. Moreover, these chemical modifications accentuate the need for a more rational design of (methacrylate) polymer matrix excipients for drug formulation via hot melt extrusion and injection molding. 23543630 The ameliorating effects of 5,7-dihydroxy-6-methoxy-2(4-phenoxyphenyl)-4H-chromene-4-one, an oroxylin A derivative, against memory impairment and sensorimotor gating deficit in mice. We previously reported that oroxylin A, a γ-aminobutyric acid A (GABAA) receptor antagonist, ameliorates drugs-induced memory impairments. We synthesized several oroxylin A derivatives in efforts to find a substance that has pro-cognitive effects as well as improves sensorimotor gating. The aim of the present study is to investigate the effect of a novel oroxylin A derivative, 5,7-dihydroxy-6-methoxy-2(4-phenoxyphenyl)-4H-chromene-4-one (DMPC), on pharmacological models of schizophrenia, which exhibit memory impairment and sensorimotor gating deficit. Memory impairment was induced by scopolamine, a muscarinic receptor antagonist, or MK-801, an N-methyl-D-aspartate receptor antagonist. Sensorimotor gating deficits were induced by MK-801 and measured by prepulse inhibition (PPI) of the acoustic startle response task. DMPC treatment (20 mg/kg) significantly attenuated scopolamine- or MK-801-induced memory impairment and it even enhanced cognitive performance of normal animals. Furthermore, DMPC significantly ameliorated MK-801-induced PPI deficits in the acoustic startle response task. In an in vitro study, DMPC (20 μM) inhibited intracellular Cl(-) influx induced by muscimol, a selective GABAA receptor agonist. These results suggest that DMPC would be a potential candidate for alleviating cognitive dysfunction and sensorimotor gating deficits in schizophrenia, and that its effects may be mediated, in part, via blockade of the GABAergic neurotransmitter system. 23485402 Therapeutic effectiveness of botulinum neurotoxin A: Potent blockade of autonomic transmission by targeted cleavage of only the pertinent SNAP-25. In search of a basis for the impressive potency of an endoprotease that cleaves SNAP-25, botulinum neurotoxin type A (BoNT/A), in treating numerous diseases due to hyper-active autonomic nerves, truncation of its target and inhibition of neurotransmission were studied in rat sympathetic neurons. Tetrodotoxin-sensitive spontaneous cholinergic neurotransmission was blocked >80% by 1 pM BoNT/A despite cleaving <20% of the SNAP-25. A maximum cleavage of ∼60% SNAP-25 could be achieved with >1 nM BoNT/A, despite an absence of non-cleavable SNAP-25 in the detergent-solubilised neurons. In contrast, BoNT/E (100 nM) truncated nearly all the SNAP-25 in the intact cells, but was unable to block neurotransmission at low concentrations like BoNT/A. Chimeras created by inserting the acceptor-binding HC domain of BoNT/A into BoNT/E still cleaved all the SNAP-25, indicating ubiquitous expression of BoNT/A acceptors. Accordingly, SV2 and SNAP-25 were found to be co-expressed and broadly co-localised in neurons, but absent from non-neuronal cells. On the other hand, partial cleavage by the BoNT/A protease persisted upon replacing its HC with counterparts from BoNT/E or BoNT/B. Moreover, limited cleavage of SNAP-25 was conferred onto the protease from BoNT/E when fused to the N-terminus of BoNT/A. Thus, the BoNT/A protease is uniquely well-adapted for selectively inactivating the SNAP-25 directly involved in neurotransmission; this together with the toxin's acceptor and its target being localised on the peri-somatic boutons likely contribute to its exceptional therapeutic utility in the clinic. 23192351 Forkhead box M1 is regulated by heat shock factor 1 and promotes glioma cells survival under heat shock stress. The forkhead box M1 (FoxM1) is a key transcription factor regulating multiple aspects of cell biology. Prior studies have shown that FoxM1 is overexpressed in a variety of human tumors, including brain tumor, and plays a critical role in cancer development and progression. In this study we found that FoxM1 was up-regulated by heat shock factor 1 (HSF1) under heat shock stress condition in multiple cell lines. Knockdown of HSF1 with HSF1 siRNA or inhibition of HSF1 with a HSF1 inhibitor abrogated heat shock-induced expression of FoxM1. Genetic deletion of HSF1 in mouse embryo fibroblast cells also abolished heat shock stress-induced FoxM1 expression. Moreover, we showed that HSF1 directly bound to FoxM1 promoter and increased FoxM1 promoter activity. Furthermore, we demonstrated that FoxM1 was required for the G(2)-M phase progression through regulating Cdc2, Cdc20, and Cdc25B under a mild heat shock stress but enhanced cell survival under lethal heat shock stress condition. Finally, in human glioblastoma specimens, FoxM1 overexpression correlated with elevated HSF1 expression. Our results indicate that FoxM1 is regulated by HSF1 and is critical for HSF1-mediated heat shock response. We demonstrated a novel mechanism of stress resistance controlled by HSF1 and a new HSF-FoxM1 connection that mediates cellular thermotolerance. 23418045 Tuning the Stability of Graphene Layers by Phthalocyanine-Based oPPV Oligomers Towards Photo- and Redoxactive Materials. In contrast to pristine zinc phthalocyanine (1), zinc phthalocyanine based oPPV-oligomers (2-4) of different chain lengths interact tightly and reversibly with graphite, affording stable and finely dispersed suspensions of mono- to few-layer graphene-nanographene (NG)-that are photoactive. The p-type character of the oPPV backbones and the increasing length of the oPPV backbones facilitate the overall π-π interactions with the graphene layers. In NG/2, NG/3, and NG/4 hybrids, strong electronic coupling between the individual components gives rise to charge transfer from the photoexcited zinc phthalocyanines to NG to form hundreds of picoseconds lived charge transfer states. The resulting features, namely photo- and redoxactivity, serve as incentives to construct and to test novel solar cells. Solar cells made out of NG/4 feature stable and repeatable photocurrent generation during several 'on-off' cycles of illumination with monochromatic IPCE values of around 1%. 23274143 The transcription bubble of the RNA polymerase-promoter open complex exhibits conformational heterogeneity and millisecond-scale dynamics: implications for transcription start-site selection. Bacterial transcription is initiated after RNA polymerase (RNAP) binds to promoter DNA, melts ~14 bp around the transcription start site and forms a single-stranded "transcription bubble" within a catalytically active RNAP-DNA open complex (RP(o)). There is significant flexibility in the transcription start site, which causes variable spacing between the promoter elements and the start site; this in turn causes differences in the length and sequence at the 5' end of RNA transcripts and can be important for gene regulation. The start-site variability also implies the presence of some flexibility in the positioning of the DNA relative to the RNAP active site in RP(o). The flexibility may occur in the positioning of the transcription bubble prior to RNA synthesis and may reflect bubble expansion ("scrunching") or bubble contraction ("unscrunching"). Here, we assess the presence of dynamic flexibility in RP(o) with single-molecule FRET (Förster resonance energy transfer). We obtain experimental evidence for dynamic flexibility in RP(o) using different FRET rulers and labeling positions. An analysis of FRET distributions of RP(o) using burst variance analysis reveals conformational fluctuations in RP(o) in the millisecond timescale. Further experiments using subsets of nucleotides and DNA mutations allowed us to reprogram the transcription start sites, in a way that can be described by repositioning of the single-stranded transcription bubble relative to the RNAP active site within RP(o). Our study marks the first experimental observation of conformational dynamics in the transcription bubble of RP(o) and indicates that DNA dynamics within the bubble affect the search for transcription start sites. 23583902 Anti-inflammatory activity of Cymbopogon citratus leaves infusion via proteasome and nuclear factor-κB pathway inhibition: Contribution of chlorogenic acid. ETHNOPHARMACOLOGICAL RELEVANCE: Cymbopogon citratus (DC) Stapf leaves infusion is used in traditional medicine for the treatment of inflammatory conditions, however little is known about their bio-active compounds. AIM OF THE STUDY: Investigate the compounds responsible for anti-inflammatory potential of Cymbopogon citratus (Cy) on cytokines production induced by lipopolysaccharide in human and mouse macrophages, and the action mechanisms involved. MATERIALS AND METHODS: An essential oil-free infusion of Cy was prepared and polyphenol-rich fractions (PFs) were obtained from it by column chromatography. Chlorogenic acid was identified, by HPLC/PDA/ESI-MS(n). The expression of cytokines, namely TNF-α and CCL5, was analyzed by real-time RT-PCR, on lipopolysaccharide-stimulated human macrophages. Activation of nuclear factor-κB, a master regulator of inflammation, was investigated by western blot and gene reporter assay. Proteasome activity was assessed using a fluorogenic peptide. RESULTS: Cymbopogon citratus extract and its polyphenols inhibited the cytokine production on human macrophages. This supports the anti-inflammatory activity of Cy polyphenols in physiologically relevant cells. Concerning the effect on the activation of nuclear factor (NF)-κB pathway, the results pointed to an inhibition of LPS-induced NF-κB activation by Cy and PFs. Chlorogenic acid was identified, by HPLC/PDA/ESI-MS(n), as the main phenolic acid of the Cy infusion, and it demonstrated to be, at least in part, responsible by that effect. Additionally, it was verified for the first time that Cy and PFs inhibited the proteasome activity, a complex that controls NF-κB activation, having CGA a strong contribution. CONCLUSIONS: The results evidenced, for the first time, the anti-inflammatory properties of Cymbopogon citratus through proteasome inhibition and, consequently NF-κB pathway and cytokine expression. Additionally, Cy polyphenols, in particular chlorogenic acid, were highlighted as bio-active compounds. 22862822 The interaction of amylin with other hormones in the control of eating. Twenty years of research established amylin as an important control of energy homeostasis. Amylin controls nutrient and energy fluxes by reducing energy intake, by modulating nutrient utilization via an inhibition of postprandial glucagon secretion and by increasing energy disposal via a prevention of compensatory decreases of energy expenditure in weight reduced individuals. Like many other gastrointestinal hormones, amylin is secreted in response to meals and it reduces eating by promoting meal-ending satiation. Not surprisingly, amylin interacts with many of these hormones to control eating. These interactions seem to occur at different levels because amylin seems to mediate the eating inhibitory effect of some of these gastrointestinal hormones, and the combination of some of these hormones seems to lead to a stronger reduction in eating than single hormones alone. Amylin's effect on eating is thought to be mediated by a stimulation of specific amylin receptors in the area postrema. Secondary brain sites that were defined to mediate amylin action - and hence potential additional sites of interaction with other hormones - include the nucleus of the solitary tract, the lateral parabrachial nucleus, the lateral hypothalamic area and other hypothalamic nuclei. The focus of this review is to summarize the current knowledge of amylin interactions in the control of eating. In most cases, these interactions have only been studied at a descriptive rather than a mechanistic level and despite the clear knowledge on primary sites of amylin action, the interaction sites between amylin and other hormones are often unknown. 23323600 Four new koumine metabolites in rat liver microsomes. Four new metabolites M-1 [1,2,18,19-tetradehydro-4-demethyl-3,17-epoxy-7,20(2H,19H)-cyclovobasan], M-2 [1,2,4,21,18,19-hexadehydro-4-demethyl-3,17-epoxy-7,20(2H,19H)-cyclovobasan], M-3 [1,2,18,19-tetradehydro-4-demethyl-4-formaldehyde-3,17-epoxy-7,20(2H,19H)-cyclovobasan], and M-4 [1,2,4,21,18,19-hexadehydro-4-demethyl-4-oxy-3,17-epoxy-7,20(2H,19H)-cyclovobasan] were isolated from the chloroform extract of koumine incubated with phenobarbital-treated rat liver microsomes. The structures of M-1, M-2, M-3, and M-4 were elucidated by spectroscopic methods including ESI-TOF-MS, 1D, and 2D NMR experiments. The metabolic pathway of koumine was proposed. The cytotoxic activities between koumine and its metabolites were also compared in the A549 cell line. 23524136 The Crystal Structure of the Lumenal Domain of Erv41p, a Protein Involved in Transport between the Endoplasmic Reticulum and Golgi Apparatus. Erv41p is a conserved integral membrane protein that is known to play a role in transport between the endoplasmic reticulum and Golgi apparatus, part of the early secretory pathway of eukaryotes. However, the exact function of the protein is not known, and it shares very low sequence identity with proteins of known structure or function. Here we present the structure of the full lumenal domain of Erv41p from Saccharomyces cerevisiae, determined by X-ray crystallography to a resolution of 2.0Å. The structure reveals the protein to be composed predominantly of two large β-sheets that form a twisted β-sandwich. Comparison to structures in the Protein Data Bank shows that the Erv41p lumenal domain displays only limited similarity to β-sandwich domains of other proteins. Analysis of the surface properties of the protein identifies an extensive patch of negative electrostatic potential on the exposed surface of one of the β-sheets, which likely forms a binding site for a ligand or interaction partner. A predominantly hydrophobic region close to the membrane interface is identified as a likely site for protein-protein interaction. This structure, the first of Erv41p or any of its homologues, provides a new starting point for studies of the roles of Erv41p and its interaction partners in the eukaryotic secretory pathway. 23174340 Pharmacological and behavioral characterization of the novel CRF(1) antagonist BMS-763534. BMS-763534 is a potent (CRF(1) IC(50) = 0.4 nM) and selective (>1000-fold selectivity vs. all other sites tested) CRF(1) receptor antagonist (pA2 = 9.47 vs. CRF(1)-mediated cAMP production in Y79 cells). BMS-763534 accelerated the dissociation of (125)I-o-CRF from rat frontal cortex membrane CRF(1) receptors consistent with a negative allosteric modulation of CRF binding. BMS-763534 produced dose-dependent increases in CRF(1) receptor occupancy and anxiolytic efficacy; lowest effective anxiolytic dose = 0.56 mg/kg, PO, which was associated with 71 ± 5% CRF(1) receptor occupancy of frontoparietal CRF(1) receptors. Sedative/ataxic effects of BMS-763534 were only observed at high dose multiples (54-179×) relative to the lowest dose required for anxiolytic efficacy. At doses of 5- to 18-fold higher than the lowest efficacious dose in the anxiety assay, BMS-763534 shared subjective effects with the benzodiazepine chlordiazepoxide. Interestingly BMS-790318, the O-demethylated metabolite of BMS-763534, showed weak affinity for the TBOB site of the GABA(A) receptor (67% inhibition at 10 μM) and augmented GABA evoked currents (EC(50) = 1.6 μM). Thus, the unanticipated signal in the drug discrimination assay may have resulted from an interaction of the metabolite BMS-790318 with the TBOB site on the GABA(A) channel where it appears to behave as an allosteric potentiator of GABA evoked currents. 23369012 pH-dependent motion of self-propelled droplets due to Marangoni effect at neutral pH. Oil droplets loaded with surfactant propel themselves with a velocity up to 6 mm s(-1) when they are placed in an aqueous phase of NaOH solution or buffer solution. The required driving force for such motion is generated on the interface of the droplets by the change in interfacial tension, due to deprotonation of the surfactant. This force induces Marangoni convection, which gives rise to a circulating flow inside the droplets. The droplets begin to move when the axis of this circulation deviates from the vertical line. This motion depends on the pH condition of the aqueous phase. When the initial value of pH is adjusted such that the pH exceeds the threshold at the equilibrium state, the droplets move spontaneously. It was seen that the droplets were independent of the material of the solid substrates because the droplets were not directly in contact with the surface of the substrate. The condition for the onset of this spontaneous motion was verified by comparing the prediction from the linear stability analysis with experiments. The stability analysis overestimates the value of the driving force, causing instability. 23389878 FOXO1 binds to the TAU5 motif and inhibits constitutively active androgen receptor splice variants. BACKGROUND: Aberrant activation of the androgen receptor (AR) is a major factor highly relevant to castration-resistant progression of prostate cancer (PCa). FOXO1, a key downstream effector of PTEN, inhibits androgen-independent activation of the AR. However, the underlying mechanism remains elusive. METHODS: The inhibitory effect of FOXO1 on full-length and constitutively active splice variants of the AR was examined by luciferase reporter assays and real-time reverse transcription polymerase chain reaction (RT-qPCR). In vitro protein binding assays and western blot analyses were used to determine the regions in FOXO1 and AR responsible for their interaction. RESULTS: We found that a putative transcription repression domain in the NH2-terminus of FOXO1 is dispensable for FOXO1 inhibition of the AR. In vitro protein binding assays showed that FOXO1 binds to the transcription activation unit 5 (TAU5) motif in the AR NH2-terminal domain (NTD), a region required for recruitment of p160 activators including SRC-1. Ectopic expression of SRC-1 augmented transcriptional activity of some, but not all AR splice variants examined. Forced expression of FOXO1 blocked the effect of SRC-1 on AR variants' transcriptional activity by decreasing the binding of SRC-1 to the AR NTD. Ectopic expression of FOXO1 inhibited expression of endogenous genes activated primarily by alternatively spliced AR variants in human castration-resistant PCa 22Rv1 cells. CONCLUSIONS: FOXO1 binds to the TAU5 motif in the AR NTD and inhibits ligand-independent activation of AR splice variants, suggesting the PTEN/FOXO1 pathway as a potential therapeutic target for inhibition of aberrant AR activation and castration-resistant PCa growth. Prostate © 2013 Wiley Periodicals, Inc. 23178895 Rat fertility and embryo fetal development: influence of exposure to the Wi-Fi signal. In recent decades, concern has been growing about decreasing fecundity and fertility in the human population. Exposure to non-ionizing electromagnetic fields (EMF), especially radiofrequency (RF) fields used in wireless communications has been suggested as a potential risk factor. For the first time, we evaluated the effects of exposure to the 2450MHz Wi-Fi signal (1h/day, 6days/week) on the reproductive system of male and female Wistar rats, pre-exposed to Wi-Fi during sexual maturation. Exposure lasted 3 weeks (males) or 2 weeks (females), then animals were mated and couples exposed for 3 more weeks. On the day before delivery, the fetuses were observed for lethality, abnormalities, and clinical signs. In our experiment, no deleterious effects of Wi-Fi exposure on rat male and female reproductive organs and fertility were observed for 1h per days. No macroscopic abnormalities in fetuses were noted, even at the critical level of 4W/kg. 23183177 The microsomal enzyme 17β-hydroxysteroid dehydrogenase 3 faces the cytoplasm and uses NADPH generated by glucose-6-phosphate dehydrogenase. Recent studies proposed a functional coupling between 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3)-dependent testosterone formation and 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1)-mediated interconversion of glucocorticoids through competition for the luminal pyridine nucleotide pool. To test this hypothesis, we used human embryonic kidney-293 cells transfected with 17β-HSD3 and/or 11β-HSD1, in the absence or presence of hexose-6-phosphate dehydrogenase that generates reduced nicotinamide adenine dinucleotide phosphate (NADPH) in the endoplasmic reticulum and determined enzyme activities. As an endogenous cell model, mouse MA-10 Leydig cells were used. 17β-HSD3-dependent reduction of Δ4-androstene-3,17-dione was affected by neither coexpression with 11β-HSD1 nor overexpression or knockdown of hexose-6-phosphate dehydrogenase. In contrast, knockdown of glucose-6-phosphate dehydrogenase decreased 17β-HSD3 activity, indicating dependence on cytoplasmic NADPH. Upon selective permeabilization of the plasma membrane by digitonin, 17β-HSD3 but not 11β-HSD1 was detected by antibodies against C-terminal epitope tags, suggesting a cytoplasmic orientation of 17β-HSD3. The cytoplasmic orientation was confirmed using proteinase K digestion of microsomal preparations and by analysis of glycosylation of wild-type 17β-HSD3 and chimera in which the N-terminal anchor sequences between 17β-HSD3 and 11β-HSD1 were exchanged. In conclusion, the results demonstrate a cytoplasmic orientation of 17β-HSD3 and dependence on glucose-6-phosphate dehydrogenase-generated NADPH, explaining the lack of a direct functional coupling with the luminal 11β-HSD1-mediated glucocorticoid metabolism. 23138112 Investigation of peripubertal expression of Lin28a and Lin28b in C57BL/6 female mice. Genome-wide association studies recently identified 32 loci that associate with the age at menarche (AAM) in humans. Because the locus most robustly associated with AAM is in/near LIN28B, the goal of this study was to investigate how the Lin28 pathway might modulate pubertal timing by examining expression of Lin28b, and its homologue, Lin28a, across the pubertal transition in female mice. Quantitative reverse-transcriptase PCR data indicate that, prior to the onset of puberty, expression of both Lin28b and Lin28a decreases in the ovary, while expression of only Lin28a decreases in the hypothalamus; the expression of Lin28a increases after the onset of puberty in the pituitary. Immunohistochemistry in ovarian tissue verified that Lin28a protein levels decreased in parallel with gene expression. Although these data do not demonstrate cause and effect, they do suggest that decreased expression of Lin28a/Lin28b may facilitate the transition into puberty, consistent with previous data showing that overexpression of Lin28a in transgenic mice leads to delayed puberty. In addition, although Lin28b and/or Lin28a expression significantly decreased prior to puberty, neither Let-7a nor Let-7g miRNA levels changed significantly, raising the possibility that some effects of Lin28b and Lin28a within the hypothalamic-pituitary-gonadal (HPG) axis may be Let-7 miRNA independent. Subsequent studies, such as tissue and age specific modulation of Lin28b and Lin28a expression, could determine whether the expression patterns observed are responsible for modulating the onset of puberty and delineate further the role of this pathway in the HPG axis. 23613484 Diaion HP-2MG modified with 2-(2,6-dichlorobenzylideneamino) benzenethiol as new adsorbent for solid phase extraction and flame atomic absorption spectrometric determination of metal ions. A solid phase extraction method for enrichment-separation and the determination of cobalt (Co(2+)), copper (Cu(2+)), nickel (Ni(2+)), zinc (Zn(2+)) and lead (Pb(2+)) ions in real samples has been proposed. The influences of some analytical parameters like pH, flow rate, eluent type and interference of matrix ions on recoveries of analytes were optimized. The limits of detection were found in the range of 1.6-3.9 µg L(-1), while preconcentration factor for all understudy metal ions were found to be 166 with loading half time (t 1/2) less than 10 min. The procedure was applied for the enrichment-separation of analyte ions in environmental samples with recoveries higher than 94.8% and relative SD <4.9% (N = 5). 23267856 First-time-in-human study with GSK249320, a myelin-associated glycoprotein inhibitor, in healthy volunteers. GSK249320, a monoclonal antibody directed against myelin-associated glycoprotein (MAG), is being developed for the enhancement of recovery of function poststroke. Potential safety concerns of adverse effects on myelin led to the inclusion of pharmacodynamic measures of peripheral and central neuronal function in this first-time-in-human (FTIH) study. The study also evaluated general safety, pharmacokinetics, and immunogenicity of GSK249320. Single intravenous infusions of GSK249320 (0.04, 0.4, 1.2, 3.5, 10, and 25 mg/kg) or placebo were administered to 47 healthy subjects aged 18-60 years. GSK249320 was well tolerated at all doses. No clinically significant abnormalities were observed in neurological examinations, nerve conduction tests (NCTs), quantitative sensory tests (QSTs), clinical laboratory tests, or electrocardiograms. There were no severe or serious adverse events. GSK249320 had a half-life (HL) of 21 days and a volume of distribution at steady state of 45.8 ml/kg, with AUC showing dose linearity. GSK249320 did not induce antidrug antibodies. 23355141 Evaporation-induced self-alignment and transfer of semiconductor nanowires by wrinkled elastomeric templates. The evaporation-induced self-alignment of semiconductor nanowires is achieved using wrinkled elastomeric templates. The wrinkled templates, which have a surface topography that can be tuned via changes in the mechanical strain, are used as both a template to align the nanowires and as a stamp to transfer the aligned nanowires to target substrates. 23371788 Selective fluorescence detection of small-molecule-binding proteins by using a dual photoaffinity labeling system. PHOTO OPPORTUNITY: We have developed a dual photoaffinity labeling system in which an active and an inactive probe bearing orthogonal detection groups are co-reacted in a single photoreaction. The approach allowed selective fluorescent detection of a model binding protein in cell lysate by either 1D or 2D electrophoresis. 23291323 In vitro study of intestinal transport of fluoride using the Caco-2 cell line. Water and food are the main sources of fluoride exposure and therefore it is necessary to study intestinal absorption in order to make a correct evaluation of the risk/benefit associated with exposure to fluoride. The present study characterizes intestinal transport of fluoride, using the Caco-2 cell line as a model of the intestinal epithelium, and evaluates the coefficients of apparent permeability and intracellular accumulation in various conditions (pH, temperature, opening of cell junctions, presence of anions). The results indicate that fluoride is an element with moderate absorption (<70%) in both directions (absorptive and secretory). Both in absorption (apical-basolateral) and in secretion (basolateral-apical) there is transport by the paracellular pathway, which may be considered predominant. Absorption and secretion of fluoride increase at acid pH levels, possibly because of its non-ionized state at these pHs and/or because of participation of a F(-)/H(+) cotransporter or a F(-)/OH(-) antiporter. The results also suggest transcellular participation of mechanisms involved in transport of Cl(-) and of an active transport in the secretory direction. The present study extend the knowledge on the cellular transport of fluoride and provide the basis for future studies aimed at identifying potential transporters involved in human fluoride absorption. 23432134 A new guaianolide from Artemisia roxburghiana. A new member of 5αH,6βH,7αH,11αH-guaian-12,6α-olides, 11-epi-8α-hydroxyarborescin, together with a mixture of (24R)- and (24S)-cycloart-25-en-3b,24-diols, palmitic acid and 1-octacosanol were isolated from the leaves of Artemisia roxburghiana Bess. (Asteraceae) of Vietnam. Their structures were determined on the basis of spectroscopic methods. 23460644 Decorin Potentiates Interferon-γ Activity in a Model of Allergic Inflammation. The proteoglycan decorin modulates leukocyte recruitment during delayed-type hypersensitivity responses. Decorin-deficient (Dcn(-/-)) mice show reduced edema formation during the first 24 h with a concurrent attenuated recruitment of CD8(+) leukocytes in the inflamed Dcn(-/-) ears. The aim of this study was to elucidate the molecular pathways affected by the loss of decorin. In vivo, reduced numbers of CD8(+) cells in Dcn(-/-) ears correlated with a reduced interferon-γ (Ifn-γ) and CXCL-10 expression. In vitro, Dcn(-/-) lymphocytes displayed an increased adhesion to brain microvascular (bEnd.3) endothelial cells. Decorin treatment of bEnd.3 increased Icam1 and down-regulated Vcam1 expression after TNF-α stimulation. However, Dcn(-/-) and wild-type lymphocytes produced IFN-γ after activation with CD3ε. Upon incubation with decorin, endothelial cells and fibroblasts responded differently to IFN-γ and TNF-α; CCL2 in bEnd.3 cells was more prominently up-regulated by TNF-α compared with IFN-γ. Notably, both factors were more potent in the presence of decorin. Compared with TNF-α, IFN-γ treatment induced significantly more CXCL-10, and both factors increased synthesis of CXCL-10 in the presence of decorin. The response to IFN-γ was similar in Dcn(-/-) and wild-type fibroblasts, an additional source of CXCL-10. However, addition of decorin yielded significantly more CXCL-10. Notably, decorin increased the stability of IFN-γ in vitro and potentiated IFN-γ-induced activation of STAT-1. Furthermore, only dermatan sulfate influenced IFN-γ signaling by significantly increasing CXCL-10 expression in contrast to decorin protein core alone. Our data demonstrate that decorin modulates delayed-type hypersensitivity responses by augmenting the induction of downstream effector cytokines of IFN-γ and TNF-α, thereby influencing the recruitment of CD8(+) lymphocytes into the inflamed tissue. 23301838 Optical probing of the electronic interaction between graphene and hexagonal boron nitride. Even weak van der Waals (vdW) adhesion between two-dimensional solids may perturb their various materials properties owing to their low dimensionality. Although the electronic structure of graphene has been predicted to be modified by the vdW interaction with other materials, its optical characterization has not been successful. In this report, we demonstrate that Raman spectroscopy can be utilized to detect a few percent decrease in the Fermi velocity (v(F)) of graphene caused by the vdW interaction with underlying hexagonal boron nitride (hBN). Our study also establishes Raman spectroscopic analysis which enables separation of the effects by the vdW interaction from those by mechanical strain or extra charge carriers. The analysis reveals that spectral features of graphene on hBN are mainly affected by change in v(F) and mechanical strain but not by charge doping, unlike graphene supported on SiO₂ substrates. Graphene on hBN was also found to be less susceptible to thermally induced hole doping. 23387288 Cytotoxic activity of Guettarda pohliana Müll. Arg. (Rubiaceae). The cytotoxic activity of crude extracts and their fractions from leaves and roots of G. pohliana was assessed against nine human cancer cell lines: melanoma (UACC-62), breast (MCF-7), breast expressing the multidrug resistance phenotype (NCI-ADR), lung (NCI-460), prostate (PCO-3), kidney (786-0), ovarian (OVCAR), colon (HT-29) and leukaemia (K-562). The hexane fraction from leaves (HL) and ethyl acetate (EAR), chloroform (CR) and hydromethanolic (HMR) fractions from roots were the most active fractions against K-562 with GI(50) values being lower than 1 μg mL(- 1). Also, CR and HMR fractions were active against UACC-62 cell line in the same order of magnitude. The phytochemical study of the CR fraction allowed identifying the known iridoids secoxyloganin, sweroside and loganin. 23325363 Dietary composition of carbohydrates contributes to the development of experimental type 2 diabetes. Evidence has emerged supporting a link between high glycaemic index (GI) diets and type 2 diabetes (T2D). The aim of this study was to determine if dietary GI influences the development of hyperglycaemia in C57BL/6 mice to more closely reflect T2D. Male C57BL/6 mice (n=30) were randomly divided into 3 dietary groups consisting of either standard rodent chow (4.8 % fat, 20 % protein), or a high fat (HF) diet (21-23 % fat, 19 % protein) with low GI (15.4 % starch; HF-LG) or high GI (50.5 % dextrose; HF-HG) ad libitum for 10 weeks. Body weight, blood glucose, glucose tolerance, and circulating cholesterol and triglyceride levels were measured for the duration of the study. We found that increasing the GI of a moderately HF diet induces severe hyperglycaemia and insulin resistance in C57BL/6 mice, reflective of criteria for diagnosis of T2D, whilst littermates consuming an equivalent low GI diet maintain glucose homeostasis. This study demonstrates the significant contribution of both dietary carbohydrate and fat composition in the aetiopathogenesis of T2D. 23370266 Temporal stability of magic-number metal clusters: beyond the shell closing model. The anomalous stability of magic-number metal clusters has been associated with closed geometric and electronic shells and the opening of HOMO-LUMO gaps. Despite this enhanced stability, magic-number clusters are known to decay and react in the condensed phase to form other products. Improving our understanding of their decay mechanisms and developing strategies to control or eliminate cluster instability is a priority, to develop a more complete theory of their stability, to avoid studying mixtures of clusters produced by the decay of purified materials, and to enable technology development. Silver clusters are sufficiently reactive to facilitate the study of the ambient temporal stability of magic-number metal clusters and to begin to understand their decay mechanisms. Here, the solution phase stability of a series of silver:glutathione (Ag:SG) clusters was studied as a function of size, pH and chemical environment. Cluster stability was found to be a non-monotonic function of size. Electrophoretic separations showed that the dominant mechanism involved the redistribution of mass toward smaller sizes, where the products were almost exclusively previously known cluster sizes. Optical absorption spectra showed that the smaller clusters evolved toward the two most stable cluster sizes. The net surface charge was found to play an important role in cluster stabilization although charge screening had no effect on stability, contrary to DLVO theory. The decay mechanism was found to involve the loss of Ag(+) ions and silver glutathionates. Clusters could be stabilized by the addition of Ag(+) ions and destabilized by either the addition of glutathione or the removal of Ag(+) ions. Clusters were also found to be most stable in near neutral pH, where they had a net negative surface charge. These results provide new mechanistic insights into the control of post-synthesis stability and chemical decay of magic-number metal clusters, which could be used to develop design principles for synthesizing specific cluster species. 23640102 The Development and Validation of a Decision-Analytic Model Representing the Full Disease Course of Acute Myeloid Leukemia. BACKGROUND: The treatment of acute myeloid leukemia (AML) is moving towards personalized medicine. However, due to the low incidence of AML, it is not always feasible to evaluate the cost-effectiveness of personalized medicine using clinical trials. Decision analytic models provide an alternative data source. OBJECTIVE: The aim of this study was to develop and validate a decision analytic model that represents the full disease course of AML. METHODS: We used a micro simulation with discrete event components to incorporate both patient and disease heterogeneity. Input parameters were calculated from patient-level data. Two hematologists critically evaluated the model to ensure face validity. Internal and external validity was tested by comparing complete remission (CR) rates and survival outcomes of the model with original data, other clinical trials and a population-based study. RESULTS: No significant differences in patient and treatment characteristics, CR rate, 5-year overall and disease-free survival were found between the simulated and original data. External validation showed no significant differences in survival between simulated data and other clinical trials. However, differences existed between the simulated data and a population-based study. CONCLUSIONS: The model developed in this study is proved to be valid for analysis of an AML population participating in a clinical trial. The generalizability of the model to a broader patient population has not been proven yet. Further research is needed to identify differences between the clinical trial population and other AML patients and to incorporate these differences in the model. 23131595 Alkaline phosphatase as a treatment of sepsis-associated acute kidney injury. Currently there are no pharmacological therapies licensed to treat sepsis-associated acute kidney injury (AKI). Considering the high incidence and mortality of sepsis-associated AKI, there is an urgent medical need to develop effective pharmacological interventions. Two phase II clinical trials recently demonstrated beneficial effects of the enzyme alkaline phosphatase (AP). In critically ill patients with sepsis-associated AKI, treatment with AP reduced the urinary excretion of tubular injury biomarkers and plasma markers of inflammation, which was associated with improvement of renal function. The dephosphorylating enzyme, AP, is endogenously present in the renal proximal tubule apical membrane but becomes depleted during ischemia-induced AKI, thereby possibly contributing to further renal damage. The exact mechanism of action of AP in AKI is unknown, but might be related to detoxification of circulating lipopolysaccharide and other proinflammatory mediators that lose their proinflammatory effects after dephosphorylation. Alternatively, tissue damage associated with systemic inflammation might be attenuated by an AP-mediated effect on adenosine metabolism. Adenosine is a signaling molecule that has been shown to protect the body from inflammation-induced tissue injury, which is derived through dephosphorylation of ATP. In this Perspectives article, we discuss the clinical activity of AP and its putative molecular modes of action, and we speculate on its use to treat and possibly prevent sepsis-associated AKI. 23464739 Uncinataflavone, a new flavonoid with a methyl benzoate substituent from Selaginella uncinata. Uncinataflavone (1), a new flavonoid, together with four known compounds (2-5), was isolated from Selaginella uncinata (Desv.) Spring. Compounds 2 and 3 were isolated from the genus selaginella for the first time. The structure of the new compound was determined as methyl 3-(5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-6-yl)-4-methoxybenzoate by means of spectroscopic evidence, including UV, IR, 1D and 2D NMR analyses as well as HR-ESI-MS. These compounds (1-5) were evaluated for the antioxidant activity in 1,1-diphenyl-2-picrylhydrazyl assay system. 23497871 Monitoring the effect of high pressure and transglutaminase treatment of milk on the evolution of flavour compounds during lactic acid fermentation using PTR-ToF-MS. In this study, the effects of thermal or high hydrostatic pressure (HHP) treatment of a milk base in the absence or presence of a transglutaminase (TGase) protein cross-linking step on the flavour development of yoghurt were investigated. The presence of several tentatively identified volatile flavour compounds (VOCs), both during the enzymatic treatment and the lactic acid fermentation of the milk base, were monitored using a proton transfer reaction time-of-flight mass spectrometer (PTR-ToF-MS). The formation of the major flavour compounds (acetaldehyde, diacetyl, acetoin, and 2-butanone) followed a sigmoidal trend described by the modified Gompertz model. The HHP treatment of milk increased significantly the volatile compound formation rate whereas it did not affect the duration of the lag phase of formation, with the exception of acetaldehyde and diacetyl formation. On the contrary, the TGase cross-linking of milk did not significantly modify the formation rate of the volatile compounds but shortened the duration of the lag phase of their formation. 23122065 Inhibitory effect of aqueous spinach extract on degranulation of RBL-2H3 cells. The inhibitory effect of an aqueous extract from spinach on degranulation of RBL-2H3 cells is herein reported. The extract significantly suppressed antigen-induced degranulation in a dose-dependent manner without affecting cell viability. Active substances in the extract were heat-stable and trypsin-resistant with molecular weights ranging from 500 Da to 14 kDa. The extract inhibited elevation of the intracellular Ca(2+) concentration caused by stimulation by antigen, while not suppressing degranulation induced by a calcium ionophore A23187. Immunoblot analysis revealed that the inhibitory effect results from downregulation of phosphorylation of both Syk kinase and phosphatidylinositol 3-kinase in the signalling pathways involved in degranulation caused by the antigen-antibody interaction. Taken together, these findings suggest that aqueous spinach extract has an anti-allergic activity that controls degranulation. 23584895 Diamond-Lipid Hybrids Enhance Chemotherapeutic Tolerance and Mediate Tumor Regression. Self-assembled nanodiamond-lipid hybrid particles (NDLPs) harness the potent interaction between the nanodiamond (ND)-surface and small molecules, while providing a mechanism for cell-targeted imaging and therapy of triple negative breast cancers. Epidermal growth factor receptor-targeted NDLPs are highly biocompatible particles that provide cell-specific imaging, promote tumor retention of ND-complexes, prevent epirubicin toxicities and mediate regression of triple negative breast cancers. 23485618 Migrants determination and bioaccessibility study of ethyl lauroyl arginate (LAE) from a LAE based antimicrobial food packaging material. Ethyl lauroyl arginate (LAE, ethyl-N-dodecanoyl-L-arginate hydrochloride) is a strong antimicrobial agent that was included as an active compound in an antimicrobial food packaging material. The potential existence of non-intentionally added substances (NIASs) such as impurities must therefore be checked before launching any food contact material onto the market. For this reason, an untargeted analysis of the migration was performed in both food simulants and fresh chicken breast fillets wrapped with the active material. The analysis was performed by liquid chromatography coupled to mass spectrometry detection with a quadrupole-time-of-flight analyzer, LC-MS(QTOF), for the identification of nonvolatile substances. The migration values found for LAE were 0.94±0.14 and 1.62±0.70μg/g in ethanol 10% v/v (simulant A) and in ethanol 95% v/v (simulant D), respectively, and 0.93±0.17μg/g in chicken. Other migrants such as dipropylene glycol methyl ether or tributyl-o-acetylcitrate, both coming from the coating were also found, but none of them have potential adverse effects. Bioaccessibility studies showed that after a simulated gastrointestinal digestion, LAE was not available anymore for subsequent intestinal absorption and new toxic compounds were not formed. 22495969 Continuous infusion of 20-hydroxyecdysone increased mass of triceps brachii in C57BL/6 mice. Phytoecdysteroids have been attributed with numerous pharmacological properties in animals, including increasing muscle mass, and 20-hydroxyecdysone (20E) is one of the most abundant phytoecdysteroids produced by plants. In this study, the physiological and gene expression effects of 20E were analyzed in C57BL/6 mice given a continuous infusion of saline or 20E (5 mg/kg/day) for 5 or 15 days using subcutaneously implanted Alzet® osmotic pumps. The masses of the total body, muscle groups and organs were determined. There was a significant increase ( p = 0.01) in the mass of triceps brachii in mice treated with 20E for 5 days (115 ± 8 mg) compared with mice treated with saline for 5 days (88 ± 3 mg), however, there were no differences in the other measured parameters. To determine potential mechanisms of 20E in skeletal muscle, Illumina's Mouse Whole Genome-6 v2.0 Expression BeadChips were used to evaluate changes in gene expression of the triceps brachii after 20E infusion. Ingenuity Pathways Analysis was used to identify genes with the most evidence for differential expression, of which, 16 genes involved in the skeletal and muscular system were identified. Overall, the data suggest that 20E does not have potent anabolic properties, however, a muscle-specific increase was observed and genes were identified to provide an explanation for the muscle accretion. 23557687 Global gene expression analysis reveals pathway differences between teratogenic and non-teratogenic exposure concentrations of bisphenol A and 17β-estradiol in embryonic zebrafish. Transient developmental exposure to 0.1μM bisphenol A (BPA) results in larval zebrafish hyperactivity and learning impairments in the adult, while exposure to 80μM BPA results in teratogenic responses, including craniofacial abnormalities and edema. The mode of action underlying these effects is unclear. We used global gene expression analysis to identify candidate genes and signaling pathways that mediate BPA's developmental toxicity in zebrafish. Exposure concentrations were selected and anchored to the positive control, 17β-estradiol (E2), based on previously determined behavioral or teratogenic phenotypes. Functional analysis of differentially expressed genes revealed distinct expression profiles at 24h post fertilization for 0.1μM versus 80μM BPA and 0.1μM versus 15μM E2 exposure, identification of prothrombin activation as a top canonical pathway impacted by both 0.1μM BPA and 0.1μM E2 exposure, and suppressed expression of several genes involved in nervous system development and function following 0.1μM BPA exposure. 23135549 The metallohormone cadmium modulates AhR-associated gene expression in the small intestine of rats similar to ethinyl-estradiol. Cadmium (Cd) affects the expression of estrogen receptor (ER) and aryl hydrocarbon receptor (AhR)-associated genes in rat uterus and elicits estrogen-like activity in vitro. The small intestine is highly exposed to dietary Cd which may mimic or antagonize estrogen action in this tissue. We investigated the effects of Cd and 17-alpha-ethinylestradiol (EE₂) on AhR-associated gene expression after oral exposure of ovariectomized female Wistar rats, and metallothionein (Mt1a) expression as a typical metal-response marker. Mt1a in the small intestine was strongly induced by co-treatment with CdCl₂ at 2 mg/kg b.wt (Cd 2) and 0.1 mg/kg b.wt EE2 than by the single compound (3-day gavage). The Cd 2-induced down-regulation of Cyp1a1, Gsta2, and Nqo1 mRNA was not antagonized by pure anti-estrogen (2.5 mg/kg b.wt ZK191703 s.c., ZK). Interestingly, the EE₂-induced down-regulation of Cyp1a1, Gsta2, and Nqo1 mRNA was antagonized by Cd 2 in vivo and in colon cancer cell lines (HT-29 and CaCo-2, treated 5 days with Cd 1 µM and/or E₂ 0.01 µM) with low or no ER-beta expression. Dose dependency was studied after Cd exposure with drinking water (5 and 50 ppm CdCl₂ equivalent to 0.4 and 4 mg/kg b.wt; Cd 0.4, Cd 4) for 28 days and EE₂ as reference. Intestinal Mt1a expression was dose dependently induced, while AhR target genes were down-regulated by Cd 0.4 similar to EE₂ and more pronounced than by Cd 4. We propose that Cd modulates intestinal AhR-associated gene expression similar to estrogens, but (contrary to its effects in uterus) via ER-independent and/or ER-beta-mediated mechanisms. Our new data suggest interference of Cd with estrogen and AhR signaling in the small intestine. 23636685 PT-ACRAMTU, A Platinum-Acridine Anticancer Agent, Lengthens and Aggregates, but does not Stiffen or Soften DNA. We used atomic force microscopy (AFM) to study the dose-dependent change in conformational and mechanical properties of DNA treated with PT-ACRAMTU ([PtCl(en)(ACRAMTU-S)](NO3)2, (en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea. PT-ACRAMTU is the parent drug of a family of non-classical platinum-based agents that show potent activity in non-small cell lung cancer in vitro and in vivo. Its acridine moiety intercalates between DNA bases, while the platinum group forms mono-adducts with DNA bases. AFM images show that PT-ACRAMTU causes some DNA looping and aggregation at drug-to-base pair ratio (r b) of 0.1 and higher. Very significant lengthening of the DNA was observed with increasing doses of PT-ACRAMTU, and reached saturation at an r b of 0.15. At r b of 0.1, lengthening was 0.6 nm per drug molecule, which is more than one fully stretched base pair stack can accommodate, indicating that ACRAMTU also disturbs the stacking of neighboring base pair stacks. Analysis of the AFM images based on the worm-like chain (WLC) model showed that PT-ACRAMTU did not change the flexibility of (non-aggregated) DNA, despite the extreme lengthening. The persistence length of untreated DNA and DNA treated with PT-ACRAMTU was in the range of 49-65 nm. Potential consequences of the perturbations caused by this agent for the recognition and processing of the DNA adducts it forms are discussed. 23636302 Cigarette craving and withdrawal symptoms during temporary abstinence and the effect of nicotine gum. RATIONALE: It is widely believed that nicotine withdrawal symptoms appear within a few hours of stopping smoking, but few data exist documenting their emergence in naturalistic settings. In several countries, nicotine replacement products are licensed for relief of withdrawal symptoms during temporary abstinence, but again, there are no data supporting this from naturalistic settings. OBJECTIVES: To examine the emergence of cigarette craving and withdrawal symptoms during temporary abstinence in a naturalistic setting while using either nicotine or placebo gum. METHODS: Double-blind, randomised, placebo-controlled study in which 132 dependent smokers abstained for 6 h with the assistance of either nicotine (2 mg, n = 42 or 4 mg, n = 24) or placebo (n = 66) gum while travelling on a non-smoking train. Outcome measures were ratings of craving and mood withdrawal symptoms prior to treatment and at regular intervals during abstinence. RESULTS: In a multivariate analysis of all symptoms, there was no interaction between treatment and time [F(21,110) = 1.28, p = 0.20, [Formula: see text] = 0.20] nor an effect of treatment [F(7,124) = 0.45, p = 0.87, [Formula: see text] = 0.03]. There was an effect of time [F(21,110) = 11.59, p < 0.001, [Formula: see text] = 0.69) and univariate analyses revealed that the majority of symptoms increased linearly throughout the period of abstinence with detectable onsets typically between the first 60 and 180 min of abstinence. CONCLUSIONS: Smokers who temporarily abstain in naturalistic settings experience craving and withdrawal symptoms that emerge linearly over the first 6 h of abstinence. Changes in craving and several mood withdrawal symptoms can be detected within the first 3 h. Nicotine gum may not have an acute effect on the development of these symptoms. 23313378 (-)-Xanthatin up-regulation of the GADD45γ tumor suppressor gene in MDA-MB-231 breast cancer cells: role of topoisomerase IIα inhibition and reactive oxygen species. Previously, we reported that (-)-xanthatin, a naturally occurring xanthanolide present in the Cocklebur plant, exhibits potent anti-proliferative effects on human breast cancer cells, accompanied by an induction of the growth arrest and DNA damage-inducible gene 45γ (GADD45γ), recognized recently as a novel tumor suppressor gene. However, the mechanisms mediating this activation were unknown. Topoisomerase IIα (Topo IIα) inhibition has been reported to produce a cell death response accompanied by an atypical DNA laddering fragmentation profile, similar to that noted previously for (-)-xanthatin. Therefore we hypothesized that (-)-xanthatin's GADD45γ activation was mediated through the Topo IIα pathway. Here, we identify that (-)-xanthatin does function as a catalytic inhibitor of Topo IIα, promoting DNA damage. In addition, reactive oxygen species (ROS) were elevated in cells treated with this agent. Mechanistically, it was determined that the induced levels of GADD45γ mRNA resulting from (-)-xanthatin exposures were stabilized by coordinately produced ROS, and that the consequent induction of GADD45γ mRNA, GADD45γ protein and ROS generation were abrogated by co-treatment with N-acetyl-l-cysteine. Taken together, the data support the concept that Topo IIα inhibition by (-)-xanthatin is a trigger that stimulates expression of DNA damage-inducible GADD45γ mRNA and that concomitantly produced ROS act downstream to further enhance the GADD45γ mRNA/GADD45γ protein induction process, resulting in breast cancer cell death. 23631744 Elucidation of the biochemical basis for a clinical drug-drug interaction between atorvastatin and 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778 875), a subtype selective agonist of the peroxisome proliferator-activated receptor alpha. Abstract 1.  5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid (CP-778 875), an agonist of the peroxisome proliferator-activated receptor alpha, has been evaluated in the clinic to treat dyslipidemia and type 2 diabetes mellitus. Herein, we investigate the effect of CP-778 875 on the pharmacokinetics of atorvastatin acid and its metabolites in humans. 2.  The study incorporated a fixed-sequence design conducted in two groups. Group A was designed to estimate the effects of multiple doses of CP-778 875 on the single dose pharmacokinetics of atorvastatin. Subjects in group A (n = 26) received atorvastatin (40 mg) on days 1 and 9 and CP-778 875 (1.0 mg QD) on days 5-12. Group B was designed to examine the effects of multiple doses of atorvastatin on the single dose pharmacokinetics of CP-778 875. Subjects in group B (n = 29) received CP-778 875 (0.3 mg) on days 1 and 9 and atorvastatin (40 mg QD) on days 5-12. 3.  Mean maximum serum concentration (Cmax) and area under the curve of atorvastatin were increased by 45% and 20%, respectively, upon co-administration with CP-778 875. Statistically significant increases in the systemic exposure of ortho- and para-hydroxyatorvastatin were also observed upon concomitant dosing with CP-778 875. CP-778 875 pharmacokinetics, however, were not impacted upon concomitant dosing with atorvastatin. 4.  Inhibition of organic anion transporting polypeptide 1B1 by CP-778 875 (IC50 = 2.14 ±0.40 μM) could be the dominant cause of the pharmacokinetic interaction as CP-778 875 did not exhibit significant inhibition of cytochrome P450 3A4/3A5, multidrug resistant protein 1 or breast cancer resistant protein, which are also involved in the hepatobiliary disposition of atorvastatin. 23321560 Cardioprotective potential of N,α-L-rhamnopyranosyl vincosamide, an indole alkaloid, isolated from the leaves of Moringa oleifera in isoproterenol induced cardiotoxic rats: in vivo and in vitro studies. Hitherto unknown protective effect of N,α-L-rhamnopyranosyl vincosamide (VR), isolated from Moringa oleifera leaves in isoproterenol (ISO)-induced cardiac toxicity was evaluated in rats. Oral administration of VR at 40 mg/kg for 7 days markedly reduced the ISO-induced increase in the levels of serum cardiac markers such as troponin-T, creatine kinase-MB, lactate dehydrogenase and glutamate pyruvate transaminase as well as cardiac lipid peroxidation with a parallel increase in the cellular antioxidants suggesting its cardio-protective and free radical scavenging potential, which was latter confirmed by in vitro study. Rats treated with test compound also improved the ISO-induced abnormal changes in ECG as well as in cardiac histology. A reduction in myocardial necrosis was further evidenced by the tri-phenyl tetrazolium chloride (TTC) stain in isolated test drug pretreated rats. These findings suggest the cardio-protective potential of the isolated alkaloid and possibly the beneficial action is mediated through its free radical scavenging property. 23150493 Susceptibility to fatty acid-induced β-cell dysfunction is enhanced in prediabetic diabetes-prone biobreeding rats: a potential link between β-cell lipotoxicity and islet inflammation. β-Cell lipotoxicity is thought to play an important role in the development of type 2 diabetes. However, no study has examined its role in type 1 diabetes, which could be clinically relevant for slow-onset type 1 diabetes. Reports of enhanced cytokine toxicity in fat-laden islets are consistent with the hypothesis that lipid and cytokine toxicity may be synergistic. Thus, β-cell lipotoxicity could be enhanced in models of autoimmune diabetes. To determine this, we examined the effects of prolonged free fatty acids elevation on β-cell secretory function in the prediabetic diabetes-prone BioBreeding (dp-BB) rat, its diabetes-resistant BioBreeding (dr-BB) control, and normal Wistar-Furth (WF) rats. Rats received a 48-h iv infusion of saline or Intralipid plus heparin (IH) (to elevate free fatty acid levels ~2-fold) followed by hyperglycemic clamp or islet secretion studies ex vivo. IH significantly decreased β-cell function, assessed both by the disposition index (insulin secretion corrected for IH-induced insulin resistance) and in isolated islets, in dp-BB, but not in dr-BB or WF, rats, and the effect of IH was inhibited by the antioxidant N-acetylcysteine. Furthermore, IH significantly increased islet cytokine mRNA and plasma cytokine levels (monocyte chemoattractant protein-1 and IL-10) in dp-BB, but not in dr-BB or WF, rats. All dp-BB rats had mononuclear infiltration of islets, which was absent in dr-BB and WF rats. In conclusion, the presence of insulitis was permissive for IH-induced β-cell dysfunction in the BB rat, which suggests a link between β-cell lipotoxicity and islet inflammation. 23497861 Performances of CN-columns for the analysis of γ-oryzanol and its p-coumarate and caffeate derivatives by normal phase HPLC and a validated method of quantitation. γ-Oryzanol is an important phytochemical used in pharmaceutical, alimentary and cosmetic preparations. The present article, for the first time, discloses the performances of NP-HPLC in separating γ-oryzanol components and develops a validated method for its routine quantification. The analysis is performed on a cyanopropyl bonded column using the hexane/MTBE gradient elution and UV detection at 325 nm. The method allows: the separation of steryl ferulate, p-coumarate and caffeate esters, the separation of cis- from trans-ferulate isomers, the splitting of steroid moieties into saturated and unsaturated at the side chain. The optimised method provides excellent linear response (R(2)=0.99997), high precision (RSD<1.0%) and satisfactory accuracy (R(∗)=70-86%). In conclusion, the established method presents the details of the procedure and the experimental conditions in order to achieve the required precision and instrumental accuracy. The method is fast and sensitive and it could be a suitable tool for quality assurance and determination of origin. 23604079 BID-induced structural changes in BAK promote apoptosis. The BCL-2-family protein BAK is responsible for mitochondrial outer-membrane permeabilization (MOMP), which leads to apoptosis. The BCL-2 homology 3 (BH3)-only protein BID activates BAK to perform this function. We report the NMR solution structure of the human BID BH3-BAK complex, which identified the activation site at the canonical BH3-binding groove of BAK. Mutating the BAK BH1 in the groove prevented activation and MOMP but not the binding of BID. BAK BH3 mutations allowed BID binding and activation but blunted function by blocking BAK oligomerization. BAK activation follows a 'hit-and-run' mechanism whereby BID dissociates from the trigger site, which allows BAK oligomerization at an overlapping interface. In contrast, the BH3-only proteins NOXA and BAD are predicted to clash with the trigger site and are not activators of BAK. These findings provide insights into the early stages of BAK activation. 23438322 Counterion Density Profile around Charged Cylinders: The Strong-Coupling Needle Limit. Charged rod-like polymers are not able to bind all their neutralizing counterions: a fraction of them evaporates, while the others are said to be condensed. We study here counterion condensation and its ramifications, both numerically by means of Monte Carlo simulations employing a previously introduced powerful logarithmic sampling of radial coordinates and analytically, with special emphasis on the strong-coupling regime. We focus on the thin rod or needle limit that is naturally reached under strong Coulombic couplings, where the typical intercounterion spacing a' along the rod is much larger than its radius R. This regime is complementary and opposite to the simpler thick rod case where a' ≪ R. We show that due account of counterion evaporation, a universal phenomenon in the sense that it occurs in the same clothing for both weakly and strongly coupled systems, allows one to obtain excellent agreement between the numerical simulations and the strong-coupling calculations. 23577650 Monitoring Controlled Release of Payload from Gold Nanocages Using Surface Enhanced Raman Scattering. Novel organic and inorganic nanostructures for localized and externally triggered delivery of therapeutic agents at a target site have received immense attention over the past decade owing to their enormous potential in treating complex diseases such as cancer. Gold nanocages, a novel class of hollow plasmonic nanostructures, have been recently demonstrated to serve as carriers for the delivery of payload with external trigger such as light or ultrasound. In this article, we demonstrate that surface enhanced Raman spectroscopy (SERS) can be employed to noninvasively monitor the release of payload from these hollow plasmonic nanostructures. The large enhancement of electromagnetic (EM) field at the interior surface of these nanostructures enables us to monitor the controlled release of Raman-active cargo from nanocages. Considering that SERS can be excited and collected in near-infrared (NIR) therapeutic window, this technique can serve as a powerful tool to monitor the drug release in vivo, providing additional control over externally triggered drug administration. 23517479 Orally Active Opioid Compounds from a Non-Poppy Source. The basic science and clinical use of morphine and other "opioid" drugs are based almost exclusively on the extracts or analogues of compounds isolated from a single source, the opium poppy (Papaver somniferum). However, it now appears that biological diversity has evolved an alternative source. Specifically, at least two alkaloids isolated from the plant Mitragyna speciosa, mitragynine ((E)-2-[(2S,3S)-3-ethyl-8-methoxy-1,2,3,4,6,7,12,12b-octahydroindolo[3,2-h]quinolizin-2-yl]-3-methoxyprop-2-enoic acid methyl ester; 9-methoxy coryantheidine; MG) and 7-hydroxymitragynine (7-OH-MG), and several synthetic analogues of these natural products display centrally mediated (supraspinal and spinal) antinociceptive (analgesic) activity in various pain models. Several characteristics of these compounds suggest a classic "opioid" mechanism of action: nanomolar affinity for opioid receptors, competitive interaction with the opioid receptor antagonist naloxone, and two-way analgesic cross-tolerance with morphine. However, other characteristics of the compounds suggest novelty, particularly chemical structure and possible greater separation from side effects. We review the chemical and pharmacological properties of these compounds. 23579392 Salicylic acid alleviates copper toxicity in rice (Oryza sativa L.) seedlings by up-regulating antioxidative and glyoxalase systems. The present study investigated the effect of salicylic acid (SA) on toxic symptoms, lipid peroxidation, reactive oxygen species generation and responses of antioxidative and glyoxalase systems in rice seedlings grown hydroponically under copper (Cu) stress for 48 h. Exposures of 75 and 150 μM Cu(2+) caused toxicity symptoms (chlorosis, necrosis and rolling in leaves), sharp increases in malondialdehyde (MDA), hydrogen peroxide (H2O2) contents and lipoxygenase (LOX) activity with concomitant reductions of chlorophyll (Chl) and relative water content (RWC). Both levels of Cu decreased ascorbic acid (AsA), glutathione (GSH), non-protein thiol (NPT) and proline contents in roots but rather increased in leaves except that AsA decreased in leaves too. These results together with overaccumulation of superoxide (O 2 (•-) ) and H2O2 in leaves revealed that Cu exposures induced oxidative stress. Contrary, SA-pretreatment (100 μM for 24 h) reduced toxicity symptoms and diminished Cu-induced increases in LOX activity, H2O2, MDA and proline contents while the levels of RWC, Chl, AsA and redox ratios were elevated. Higher levels of GSH and NPT were also observed in roots of SA-pretreated Cu-exposed seedlings. SA-pretreatment also exerted its beneficial role by inhibiting the Cu upward process. Studies on antioxidant enzymes showed that SA further enhanced the activities of superoxide dismutase, ascorbate peroxidase, glutathione reductase and glutathione peroxidase, and also elevated the depressed activities of catalase, dehydroascorbate reductase and glutathione S-transferase particularly at 150 μM Cu(2+) stress. In addition, the activity of glyoxalase system (glyoxalase I and II) was further elevated by SA pretreatment in the Cu-exposed seedlings. These results concluded that SA-mediated retention of Cu in roots and enhanced capacity of both antioxidative and glyoxalase systems might be associated with the alleviation of Cu-toxicity in rice seedlings. 22876949 Chalcones in Cancer: Understanding their Role in Terms of QSAR. II Part. Chalcones are a group of plant-derived polyphenolic compounds belonging to the flavonoids family and possess a wide variety of cytoprotective and modulatory functions. In this research we tried to review the anticancer effect of chalcones derivatives and to evaluate new QSARs which will help in the understanding of the role of chalcones and of their analogs on cancer. Simultaneously a comparative study will be presented. Our QSAR results reveal that: 1) the clog P (hydrophobicity/hydrophilicity) parameter plays an important part in three QSAR relationships (linear model), 2) the steric factors such as molar volume MgVol, molar refractivity CMR or the substituents molar refractivity MR (linear) are important. Electronic effects are comparatively unimportant. These results compared to our previous findings on the QSAR of anti-proliferative chalcones support primarily the role of bulk. 23179775 Therapy of adrenal insufficiency: an update. Adrenal insufficiency may be caused by the destruction or altered function of the adrenal gland with a primary deficit in cortisol secretion (primary adrenal insufficiency) or by hypothalamic-pituitary pathologies determining a deficit of ACTH (secondary adrenal insufficiency). The clinical picture is determined by the glucocorticoid deficit, which may in some conditions be accompanied by a deficit of mineralcorticoids and adrenal androgens. The substitutive treatment is aimed at reducing the signs and symptoms of the disease as well as at preventing the development of an addisonian crisis, a clinical emergency characterized by hypovolemic shock. The oral substitutive treatment should attempt at mimicking the normal circadian profile of cortisol secretion, by using the lower possible doses able to guarantee an adequate quality of life to patients. The currently available hydrocortisone or cortisone acetate preparations do not allow an accurate reproduction of the physiological secretion pattern of cortisol. A novel dual-release formulation of hydrocortisone, recently approved by EMEA, represents an advancement in the optimization of the clinical management of patients with adrenal insufficiency. Future clinical trials of immunomodulation or immunoprevention will test the possibility to delay (or prevent) the autoimmune destruction of the adrenal gland in autoimmune Addison's disease. 23280672 Evaluation of zebra mussels (Dreissena polymorpha) as biomonitors of mercury contamination in aquatic ecosystems. Zebra mussels have invaded many lakes in the United States and could be a useful tool for monitoring responses of aquatic biota to changes in mercury loading. The goal of the present study was to evaluate zebra mussels for use as a biomonitor of mercury contamination by comparing zebra mussel mercury concentrations between a lake with only indirect atmospheric mercury contamination (Otisco Lake, NY, USA) and a lake that was directly contaminated by mercury discharges (Onondaga Lake, NY, USA). Zebra mussels were sampled in both the spring and fall of 2004 and 2005. Total mercury (THg) concentrations in zebra mussels were approximately seven times greater in Onondaga Lake than in Otisco Lake, and water column mercury concentrations differed by an order of magnitude between the two lakes. Seasonal differences resulted in significantly higher zebra mussel THg concentrations during the fall for both lakes. There was also significant variation among different sampling sites in Onondaga Lake. Mussel methylmercury concentrations averaged 53% of THg concentrations but were highly variable. Strong relationships between water column THg and zebra mussel THg suggest that zebra mussels are a good indicator of aquatic mercury concentrations and could be used as an effective biomonitor of mercury contamination in aquatic ecosystems. 23190031 Mangiferin - a bioactive xanthonoid, not only from mango and not just antioxidant. Mangiferin is a plant natural polyphenol of C-glycosylxanthone structure and various pharmacological activities. It can be found in many plant species, among which the mango tree (Mangifera indica) is one of the primary sources. Mangiferin is also present in some medicinal herbs, influencing their therapeutic and preventive properties, and in honeybush (Cyclopia sp.), a popular South African herbal tea. Mangiferin dissolves well in water, so it can be easily extracted into infusions and decoctions. In the mangiferin molecule, four aromatic hydroxyl groups determine its strong antiradical and antioxidant properties. Mangiferin is also an efficient iron chelator, therefore preventing the generation of hydroxyl radical in Fenton-type reactions. Numerous published in vitro and in vivo pharmacological studies, demonstrated many other activities of mangiferin: analgesic, antidiabetic, antisclerotic, atimicrobial and antiviral, cardio-, hepato-, and neuroprotective, antiinflammatory, antiallergic, MAO inhibiting and memory improving, as well as radioprotective against X-ray, gamma, and UV radiation. Several studies indicated also its ability to inhibit cancerogenesis and cancer cells growth by apoptosis induction in vitro and in vivo. It is also used in cosmetics, due to antioxidant and UV-protecting properties. 23578952 Monoacylglycerol lipase inhibition-induced changes in plasma corticosterone levels, anxiety and locomotor activity in male CD1 mice. The hypothalamus-pituitary-adrenal-axis is strongly controlled by the endocannabinoid system. The specific impact of enhanced 2-arachidonoylglycerol signaling on corticosterone plasma levels, however, was not investigated so far. Here we studied the effects of the recently developed monoacylglycerol lipase inhibitor JZL184 on basal and stress-induced corticosterone levels in male CD1 mice, and found that this compound dramatically increased basal levels without affecting stress responses. Since acute changes in corticosterone levels can affect behavior, JZL184 was administered concurrently with the corticosterone synthesis inhibitor metyrapone, to investigate whether the previously shown behavioral effects of JZL184 are dependent on corticosterone. We found that in the elevated plus-maze, the effects of JZL184 on "classical" anxiety-related measures were abolished by corticosterone synthesis blockade. By contrast, effects on the "ethological" measures of anxiety (i.e. risk assessment) were not affected by metyrapone. In the open-field, the locomotion-enhancing effects of the compound were not changed either. These findings show that monoacylglycerol lipase inhibition dramatically increases basal levels of corticosterone. This endocrine effect partly affects the anxiolytic, but not the locomotion-enhancing effects of monoacylglycerol lipase blockade. 23439078 Does Microsecond Sugar Ring Flexing Encode 3D-Shape and Bioactivity in the Heparanome? The biological information encoded in carbohydrate sequences dwarfs that of proteins and nucleic acids. Deciphering structure-function relationships in heparin and heparan sulfate (the heparanome) is further compounded by extreme sequence diversity, experimental difficulties, and the computational cost of rigorous modeling. Here we perform unbiased microsecond dynamics simulations of 11 heparanome oligosaccharides (55 microseconds total) to investigate the effect of sequence on 3D-structure and to underpin a coarse-grained model that is consistent with long-time scale experimentally validated atomic motions in water. Pyranose ring flexing (puckering) in 2-O-sulfo-α-l-iduronic acid, which underlies heparin-mediated anticoagulation, was modulated by polymerization (chain position and adjacent residues), which is supported by previous experiments. Furthermore, in coarse-grained simulations, inclusion of puckering was essential to predict macroscopic hydrodynamic properties of heparan sulfate chains containing hundreds of monosaccharaides. Our structural findings and model enable rational molecular design, and we propose that, in the heparanome, puckering, polymer 3D-shape, and bioactivity are inextricably linked. 23499926 Recombinant proteins that trigger production of antibodies recognizing botulinum neurotoxin while not possessing sequences of this toxin. Sequences mimicking epitopes of pathogens can be used as effective tools for fast development and characterization of pathogen-specific antibodies. To demonstrate this, we used phage displays and isolated a number of short peptides mimicking epitopes of botulinum neurotoxin serotype A (BoNT/A). Presented data suggest that some of these peptides mimic linear epitopes while others mimic structural epitopes of BoNT/A. All tested peptides retained their ability to be recognized by BoNT/A-specific antibodies even when transferred into new carrier proteins. We demonstrated how such new hybrids can be used for fast conversion of pathogen-specific serums into panels of mono-epitope specific antibodies. We also demonstrated that hybrid proteins carrying multiple isolated peptides can be used as a substitute for BoNT/A in immunization studies and triggers production of BoNT/A-specific antibodies. 23572408 Optimal management of metastatic renal cell carcinoma: current status. The armamentarium for the systemic therapy of advanced renal cell carcinoma (RCC) has undergone dramatic changes over the past 6 years. While high-dose interleukin (IL)-2 remains an option for highly selected good and intermediate risk patients with clear-cell histology because of durable complete responses in a small fraction of patients, cytokine-based therapy including interferon (IFN) has been supplanted by vascular-endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors. Treatment decision is initially based on prognostication of the disease. As metastatic RCC (mRCC) is commonly an indolent disease, a period of observation should always been considered. For good and intermediate risk disease, pazopanib, sunitinib or the combination of bevacizumab plus IFN are considered. Notably, recent data suggest non-inferiority for the efficacy of pazopanib compared to sunitinib coupled with a better toxicity profile. A novel VEGF receptor inhibitor, tivozanib, is expected to be approved based on improvement in PFS when compared to sorafenib in the first-line setting. The use of temsirolimus for poor risk disease is supported by a phase III trial dedicated to this group of patients. The role of cytoreductive nephrectomy in the context of VEGF and mTOR inhibitors is being studied in randomized trials. Selected patients with solitary or oligometastatic disease may be eligible for metastatectomy. Following first-line VEGF inhibitors, second-line therapy with everolimus and axitinib have demonstrated benefits in progression-free survival (PFS). One phase III trial comparing sorafenib and temsirolimus in the post-sunitinib setting showed no difference in PFS, the primary endpoint, but did show a superior overall survival for sorafenib. Sorafenib, pazopanib and axitinib have all demonstrated clinical benefit following cytokines. Therapy following first-line mTOR inhibitors remains undefined, although VEGF inhibitors have demonstrated activity in this setting. Optimal sequencing of agents and individualized therapy based on biomarkers is undergoing investigation. Today, the choice of therapy is based on patient and physician decision, which is a function of comorbidities, toxicity profiles and costs. Clinical trials evaluating novel agents and combinations should be preferred when available since agents in the current therapeutic arsenal have not yielded cures despite extending median survival to greater than 2 years. One noteworthy new class of agents that has yielded durable responses is programmed death (PD)-1 inhibitors, which target a T-lymphocyte checkpoint and are heralding a resurgence of immunotherapy. Finally, optimal therapy for non-clear cell RCC remains to be delineated, although sunitinib, everolimus and other VEGFR-TKI or mTOR inhibitors have all demonstrated modest benefit. 23411245 Modelling the interactions between free phenols, L-ascorbic acid, apple polyphenoloxidase and oxygen during a thermal treatment. The kinetics of degradation of chlorogenic acid (CG), (-) epicatechin (EPI), L-ascorbic acid (AA) and polyphenoloxidase (PPO) activity from Marie-Ménard apple in pH 3.8 solutions at 20 and 50°C were investigated to provide information on the impact of the presence of CG, EPI and/or AA on PPO thermostability. The effect of the heat treatment on their degradation by enzymatic and/or nonenzymatic ways was also studied. Stoechiokinetic reactions on the basis of experimental data and literature and determination of the kinetic constants (k) at 20 and 50°C were elaborated before modelling the interaction among reactants, by fitting the reaction curves to predictive model. Apple PPO was thermolabile, denaturing after 10min at 70°C. Losses of PPO activity were favoured by the presence of EPI in model solutions, compared with CG, due to the formation of o-quinones of EPI (QEPI) lowering PPO stability. Temperature quickened both enzymatic phenol oxidations before PPO deteriorated and the whole set of the chemical reactions, including the production of secondary oxidation products and CG or EPI regeneration. Results also confirmed that AA in excess induced a fast regeneration of CG and EPI from the corresponding o-quinones formed enzymatically via redox chemical reactions. 23597511 The novel recreational drug 3,4-methylenedioxypyrovalerone (MDPV) is a potent psychomotor stimulant: Self-administration and locomotor activity in rats. Recreational use of the cathinone derivative 3,4-methylenedioxypyrovalerone (MDPV; "bath salts") has increased worldwide in past years, accompanied by accounts of health and legal problems in the popular media and efforts to criminalize possession in numerous jurisdictions. Minimal information exists on the effects of MDPV in laboratory models. This study determined the effects of MDPV, alongside those of the better studied stimulant d-methamphetamine (METH), using rodent models of intravenous self-administration (IVSA), thermoregulation and locomotor activity. Male Wistar rats were trained to self-administer MDPV or METH (0.05 mg/kg/infusion, i.v.) or were prepared with radiotelemetry implants for the assessment of body temperature and activity responses to MDPV or METH (0-5.6 mg/kg s.c.). METH and MDPV were consistently self-administered within 10 training sessions (mg/kg/h; METH Mean = 0.4 and Max = 1.15; MDPV Mean = 0.9 and Max = 5.8). Dose-substitution studies demonstrated that behavior was sensitive to dose for both drugs, but MDPV (0.01-0.50 mg/kg/inf) showed greater potency and efficacy than METH (0.1-0.25 mg/kg/inf). In addition, both MDPV and METH increased locomotor activity at lower doses (0.5-1.0 mg/kg, s.c.) and transiently decreased activity at the highest dose (5.6 mg/kg, s.c.). Body temperature increased monotonically with increasing doses of METH but MDPV had a negligible effect on temperature. Stereotypy was associated with relatively high self-administered cumulative doses of MDPV (∼1.5 mg/kg/h) as well as with non-contingent MDPV administration wherein the intensity and duration of stereotypy increased as MDPV dose increased. Thus, MDPV poses a substantial threat for compulsive use that is potentially greater than that for METH. 23580446 Pharmacological Inhibition of Platelet-tumor Cell Cross-talk Prevents Platelet-induced Overexpression of Cyclooxygenase-2 in HT29 Human Colon Carcinoma Cells. Cyclooxygenase(COX)-2-derived prostanoids can influence several processes that are linked to carcinogenesis. We aimed to address the hypothesis that platelets contribute to aberrant COX-2 expression in HT29 colon carcinoma cells and to reveal the role of platelet-induced COX-2 on the expression of proteins involved in malignancy and marker genes of epithelial-mesenchymal transition(EMT). Human platelets co-cultured with HT29 cells rapidly adhered to cancer cells and induced COX-2 mRNA expression, but not protein synthesis which required the late release of platelet PDGF and COX-2 mRNA stabilization. Platelet-induced COX-2-dependent PGE2 synthesis in HT29 cells was involved in downregulation of p21(WAF1/CIP1) and upregulation of cyclinB1, since these effects were prevented by rofecoxib(a selective COX-2 inhibitor) and rescued by exogenous PGE2. Galectin-3, highly expressed in HT29 cells, is unique among galectins because it contains a collagen-like domain. Thus, we studied the role of galectin-3 and platelet collagen receptors in platelet-induced COX-2 overexpression. Inhibitors of galectin-3 function(β-lactose, a dominant-negative form of galectin-3,Gal-3C, and anti-galectin-3 antibody M3/38) or collagen receptor-mediated platelet adhesion(revacept, a dimeric collagen receptor GPVI-Fc) prevented aberrant COX-2 expression. Inhibition of platelet-cancer cell interaction by revacept was more effective than rofecoxib in preventing platelet-induced mRNA changes of EMT markers suggesting that direct cell-cell contact and aberrant COX-2 expression synergistically induced gene expression modifications associated with EMT. In conclusion, our findings provide the rationale for testing blockers of collagen binding sites, such as revacept, and galectin-3 inhibitors in the prevention of colon cancer metastasis in animal models followed by studies in patients. 22992376 Acute effects of caffeine on attention: a comparison of non-consumers and withdrawn consumers. Despite the large number of studies on caffeine and attention, interpretation is often difficult because of methodological weaknesses. In the present study, use of a small battery of tests with four key outcome measures, combined with an appropriate sample size, addresses many of these problems. This methodology was used to examine whether effects of caffeine (a dose of 2 mg/kg) could be explained in terms of reversal of the effects of caffeine withdrawal. This was achieved by examining effects in non-consumers (N = 35), who could not be withdrawn, and also in a group of consumers (N = 35) who had undergone withdrawal for a week and no longer reported symptoms of withdrawal. The results showed no effect of short-term withdrawal on the performance measures, even though subjective reports showed an increase in symptoms after withdrawal. In contrast, the caffeine challenge carried out on Day 8 showed that ingestion of caffeine was associated with faster simple reaction time, fewer long responses, greater detection of targets in the cognitive vigilance task, and faster encoding of new information. These results suggest that it is important to continue to investigate mechanisms underlying these effects of caffeine and to further evaluate the practical implications of such effects. 23278399 Entry inhibitors directed towards glycoprotein gp120: an overview on a promising target for HIV-1 therapy. In spite of the unquestionable positive impact of HAART in the treatment of HIV infection, the discovery and development of novel agents directed towards other targets of the replicative cycle of the virus that differ from those targeted by the clinically approved drugs, emerges nowadays as an imperative need. The blockade of HIV entry is a highly promising strategy against the pathogen and glycoprotein gp120 is a central actor in this process. This review discusses the current status in the research of anti-HIV agents targeting specifically the envelope protein gp120. The diverse approaches devoted to the achievement of therapeutic agents against gp120 currently under study are organized and analyzed critically according to their specific mechanism of inhibition and structural features. 23586680 Synthesis of chemicals using solar energy with stable photoelectrochemically active heterostructures. Efficient and cost-effective conversion of solar energy to useful chemicals and fuels could lead to a significant reduction in fossil hydrocarbon use. Artificial systems that use solar energy to produce chemicals have been reported for more than a century. However the most efficient devices demonstrated, based on traditionally fabricated compound semiconductors, have extremely short working lifetimes due to photocorrosion by the electrolyte. Here we report a stable, scalable design and molecular level fabrication strategy to create photoelectrochemically active heterostructure (PAH) units consisting of an efficient semiconductor light absorber in contact with oxidation and reduction electrocatalysts and otherwise protected by alumina. The functional heterostructures are fabricated by layer-by-layer, template-directed, electrochemical synthesis in porous anodic aluminum oxide membranes to produce high density arrays of electronically autonomous, nanostructured, corrosion resistant, photoactive units (∼10(9)-10(10) PAHs per cm(2)). Each PAH unit is isolated from its neighbor by the transparent electrically insulating oxide cellular enclosure that makes the overall assembly fault tolerant. When illuminated with visible light, the free floating devices have been demonstrated to produce hydrogen at a stable rate for over 24 h in corrosive hydroiodic acid electrolyte with light as the only input. The quantum efficiency (averaged over the solar spectrum) for absorbed photons-to-hydrogen conversion was 7.4% and solar-to-hydrogen energy efficiency of incident light was 0.9%. The fabrication approach is scalable for commercial manufacturing and readily adaptable to a variety of earth abundant semiconductors which might otherwise be unstable as photoelectrocatalysts. 23281661 Fusion of bolaamphiphile micelles: a method to prepare stable supported biomimetic membranes. Supported biomimetic membranes (SBMs) on solid substrates have been commonly prepared from vesicle-forming double-tail lipids, such as zwitterionic phospholipids, using the method of vesicle fusion. Here we report on the preparation of SBMs on silica surfaces via a similar process of "micelle fusion" from a cationic single-tail bolaamphiphile GLH-20 that forms spherical and elongated thread-like micelles in solution. We demonstrate that, in contrast to zwitterionic phospholipids, GLH-20 self-assembles into a stable contiguous SBM at both low and high ionic strengths. The cationic charge of GLH-20 promotes the formation of a stable SBM through enhanced double-layer interactions with the negatively charged silica surface. It is also shown that spinach aquaporin PM-28 was successfully incorporated within bolaamphiphile SBM in a manner similar to SBMs prepared by vesicle/proteoliposome fusion; thereby the inherent curvature of the micelle surface does not inhibit protein reconstitution. The results suggest that SBMs based on charged bolaamphiphiles might be an attractive platform for applications such as water purification and biosensors, where the stability and low defect rate of SBMs in diverse conditions are crucial for achieving desired performance. 23283546 Why is quercetin a better antioxidant than taxifolin? Theoretical study of mechanisms involving activated forms. The stronger antioxidant capacity of the flavonoid quercetin (Q) compared with taxifolin (dihydroquercetin, T) has been the subject of previous experimental and theoretical studies. Theoretical work has focused on the analysis of hydrogen bond dissociation energies (BDE) of the OH phenolic groups, but consider mechanisms that only involve the transfer of one hydrogen atom. In the present work we consider other mechanisms involving a second hydrogen transfer in reactions with free radicals. The relative stability of the radicals formed after the first hydrogen transfer reaction is considered in discussing the antioxidant activity of Q and T. In terms of global and local theoretical reactivity descriptors, we propose that the radical arising from Q should be more persistent in the environment and with the capability to react with a second radical by hydrogen transfer, proton transfer and electron transfer mechanisms. These mechanisms could be responsible of the stronger antioxidant capacity of Q. 23442161 Through the looking glass: adventures in kinase inhibitor design and optimization. Developing a viable new drug candidate is difficult. Developing one that is a small molecule kinase inhibitor that binds competitively with respect to ATP with superb selectivity is even more difficult, which makes the design and optimization work described by Jimenez et al. (J. Med. Chem., DOI: 10.1021/jm301465a) particularly remarkable. They took a lead from a high-throughput screen against protein kinase C θ (PKCθ) through a series of optimization steps, culminating in the demonstration of in vivo activity in mice. Having identified and improved the hinge-binding "warhead" at one end of their lead molecule, they proceeded to use structure-based design tools to guide modification of the other end to enhance selectivity over a closely related isoform of the kinase. With that accomplished, they used a series of protection and deprotection maneuvers to modify the central portion of the series scaffold to further enhance potency against the target while also improving pharmacokinetic properties. The project was a success at the preclinical level: oral administration of the ultimate analogue obtained was effective at suppressing interleukin-2 induction in mice. 23270965 Safrole-2',3'-oxide induces atherosclerotic plaque vulnerability in apolipoprotein E-knockout mice. Safrole-2',3'-oxide (SFO) is the major electrophilic metabolite of safrole (4-allyl-1, 2-methylenedioxybenzene), a natural plant constituent found in essential oils of numerous edible herbs and spices and in food containing these herbs, such as pesto sauce, cola beverages and bologna sausages. The effects of SFO in mammalian systems, especially the cardiovascular system, are little known. Disruption of vulnerable atherosclerotic plaques in atherosclerosis, a chronic inflammatory disease, is the main cause of cardiovascular events. In this study, we investigated SFO-induced atherosclerotic plaque vulnerability (possibility of rupture) in apolipoprotein E-knockout (apoE(-/-)) mice. Lipid area in vessel wall reached 59.8% in high dose SFO (SFO-HD) treated group, which is only 31.2% in control group. SFO treatment changed the lesion composition to an unstable phenotype, increased the number of apoptotic cells in plaque and the endothelium in plaques was damaged after SFO treatment. Furthermore, compared with control groups, the plaque endothelium level of p75(NTR) was 3-fold increased and the liver level of p75(NTR) was 17.4-fold increased by SFO-HD. Meanwhile, the serum level of KC (a functional homolog of IL-8 and the main proinflammatory alpha chemokine in mice) in apoE(-/-) mice was up to 357pg/ml in SFO-HD treated group. Thus, SFO contributes to the instability of atherosclerotic plaque in apoE(-/-) mice through activating p75(NTR) and IL-8 and cell apoptosis in plaque. 23197323 New pockets in dengue virus 2 surface identified by molecular dynamics simulation. One of the factors limiting the search of new compounds based on the structure of target proteins involved in diseases is the limited amount of target structural information. Great advances in the search for lead compounds could be achieved to find new cavities in protein structures that are generated using well established computational chemistry tools. In the case of dengue, the discovery of pockets in the crystallographic structure of the E protein has contributed to the search for lead compounds aimed at interfering in conformational transitions involved in the pH-dependent fusion process. This is a complex mechanism triggered by the acid pH of the endosomes that leads to the initial changes in the E protein assembly at the virus surface. In the present work, an arrangement of three ectodomain portions of the E protein present on the surface of the mature dengue virus was studied through long all-atom molecular dynamics simulations with explicit solvent. In order to identify new pockets and to evaluate the influence of the acid pH on these pockets, the physiological neutral pH conditions and the acid pH of the endosomes that trigger the fusion process were modeled. Several pockets presenting pH-dependent characteristics were found in the contact regions between the chains. Pockets at the protein-protein interfaces induced by a monomer in another monomer were also found. Some of the pockets are good candidates for the design of lead compounds that could interfere in the rearrangements in E proteins along the fusion process contributing to the development of specific inhibitors of the dengue disease. 23557688 Environmental pesticide exposure modulates cytokines, arginase and ornithine decarboxylase expression in human placenta. To evaluate the cytokine balance and enzymatic alterations induced by environmental pesticide exposure during pregnancy, this transversal study explored placentas derived from non-exposed women (control group-CG), and from women living in a rural area (rural group-RG), collected during intensive organophosphate (OP) pesticide spraying season (RG-SS) and during non-spraying season (RG-NSS). The exposure biomarkers blood cholinesterase and placental carboxylesterase (CaE) were significantly decreased in RG-SS. Among the cytokines studied IL-8, IL-6, TNFα, IL-10, TGFβ and IL-13, the expression frequency of IL-13 increased in RG-SS. Arginase and ornithine decarboxylase (ODC) enzymes were induced in syncytiotrophoblast and endothelial cells. Interestingly, the decrease in CaE activity was associated with arginase and ODC activity induction. These findings suggest that environmental pesticide exposure impacts the placenta by increasing the expression frequency of the anti-inflammatory cytokine IL-13, which may be related to the up-regulation of enzymes implicated in tissue repair. 23470629 Measurement of Transport Activities of 3β-Hydroxy-Δ(5)-bile Acids in Bile Salt Export Pump and Multidrug Resistance-Associated Proteins Using LC-MS/MS. A method has been developed for the measurement of transport activities in membrane vesicles obtained from Sf9 cells for 3β-hydroxy-Δ(5)-bile acids by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Calibration curves for the bile acids were linear over the range of 10 to 2000 pmol/mL, and the detection limit was less than 1 pmol/mL for 3β-hydroxy-Δ(5)-bile acids using selected reaction monitoring analysis. The analytical method was applied to measurements of transport activities in membrane vesicles obtained from human multidrug resistance-associated protein 2-, 3-, and human bile salt export pump-expressing Sf9 cells for conjugated 3β-hydroxy-Δ(5)-bile acids. The present study demonstrated that human multidrug resistance-associated protein 3 vesicles accepted conjugated 3β-hydroxy-Δ(5)-bile acids along with common bile acids such as glycocholic acid and taurolithocholic acid 3-sulfate. 23368735 The contrasting activity of iodido versus chlorido ruthenium and osmium arene azo- and imino-pyridine anticancer complexes: control of cell selectivity, cross-resistance, p53 dependence, and apoptosis pathway. Organometallic half-sandwich complexes [M(p-cymene)(azo/imino-pyridine)X](+) where M = Ru(II) or Os(II) and X ═ Cl or I, exhibit potent antiproliferative activity toward a range of cancer cells. Not only are the iodido complexes more potent than the chlorido analogues, but they are not cross-resistant with the clinical platinum drugs cisplatin and oxaliplatin. They are also more selective for cancer cells versus normal cells (fibroblasts) and show high accumulation in cell membranes. They arrest cell growth in G1 phase in contrast to cisplatin (S phase) with a high incidence of late-stage apoptosis. The iodido complexes retain potency in p53 mutant colon cells. All complexes activate caspase 3. In general, antiproliferative activity is greatly enhanced by low levels of the glutathione synthase inhibitor l-buthionine sulfoxime. The work illustrates how subtle changes to the design of low-spin d(6) metal complexes can lead to major changes in cellular metabolism and to potent complexes with novel mechanisms of anticancer activity. 23562365 Lignans extracted from Vitex negundo possess cytotoxic activity by G2/M phase cell cycle arrest and apoptosis induction. Evn-50 is a lignan compounds mixture extracted from Vitex negundo, a widely used herb in traditional Chinese medicine. This study is aimed to define the spectrum of cytotoxic activity of EVn-50, and also to investigate mechanisms underlying the anticancer actions via assessing the influence on cell cycle using EVn-50, and the lignan compound VB1 purified from EVn-50. The cytotoxic effect of EVn-50 and VB1 was determined with SRB assay using a panel of cancer cell lines. Breast cancer cell line MDA-MB-435 and liver cancer cell line SMMC-7721 were selected for further evaluating the effect of EVn-50 or VB1 on cell cycle by flow cytometric analysis. Apoptosis exerted by EVn-50 or VB1 was measured by TUNEL assay and DAPI staining, and Western blot analysis was utilized to assess the influence on expression and phosphorylation of proteins which are closely related to cell cycle and apoptosis. EVn-50 possessed a broad spectrum of in vitro anticancer activity for those tested cancer cells, especially sensitive to MDA-MB-435, SKOV-3, BXPC-3, SMMC-7721, MCF-7, HO-8910, SGC-7901, BEL-7402, HCT-116, and 786-O, with the respective IC50 below 10μg/ml. Treatment with EVn-50 or VB1 resulted in arresting the MDA-MB-435 and SMMC-7721 cells at G2/M phase, which was further supported by observations of increased phosphorylation of Histone 3 at Ser10, phosphorylation of Cdk1 at Tyr15, expression of cyclin B1, and decreased expression of Cdc25c. Moreover, we found that exposure of MDA-MB-435 cells to EVn-50 or VB1 caused obvious apoptosis of MDA-MB-435 cells. Our data show that EVn-50, lignan compounds extracted from Vitex negundo, possesses a broad spectrum cytotoxic effect via arresting cancer cells at G2/M phase cell cycle and subsequently inducing apoptosis. 22837389 Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone. Results from clinical studies suggest that pregnancy alters hepatic drug metabolism in a cytochrome P450 (P450) isoform-specific manner, and rising concentrations of female hormones are potentially responsible for the changes. The objective of this study was to comprehensively characterize the effects of estrogen and progesterone on the expression and activity of major drug-metabolizing P450s. To this end, primary human hepatocytes were treated with estradiol and progesterone, and mRNA expression and activity levels of 10 different P450 isoforms were determined. The results showed that estradiol enhances CYP2A6, CYP2B6, and CYP3A4 expression, whereas progesterone induces CYP2A6, CYP2B6, CYP2C8, CYP3A4, and CYP3A5 expression. The induction was mainly observed when the average hormone concentrations were at the levels reached during pregnancy, suggesting that these effects are likely pregnancy-specific. Estradiol also increased enzyme activities of CYP2C9 and CYP2E1 without affecting the mRNA expression levels by unknown mechanisms. Taken together, our results show differential effects of estrogen and progesterone on P450 expression, suggesting involvement of different regulatory mechanisms in female hormone-mediated P450 regulation. Our findings potentially provide a basis in mechanistic understanding for altered drug metabolism during pregnancy. 23286284 Modulation of esterified drug metabolism by tanshinones from Salvia miltiorrhiza ("Danshen"). The roots of Salvia miltiorrhiza ("Danshen") are used in traditional Chinese medicine for the treatment of numerous ailments including cardiovascular disease, hypertension, and ischemic stroke. Extracts of S. miltiorrhiza roots in the formulation "Compound Danshen Dripping Pill" are undergoing clinical trials in the United States. To date, the active components of this material have not been conclusively identified. We have determined that S. miltiorrhiza roots contain potent human carboxylesterase (CE) inhibitors, due to the presence of tanshinones. K(i) values in the nM range were determined for inhibition of both the liver and intestinal CEs. As CEs hydrolyze clinically used drugs, the ability of tanshinones and S. miltiorrhiza root extracts to modulate the metabolism of the anticancer prodrug irinotecan (CPT-11) was assessed. Our results indicate that marked inhibition of human CEs occurs following incubation with both pure compounds and crude material and that drug hydrolysis is significantly reduced. Consequently, a reduction in the cytotoxicity of irinotecan is observed following dosing with either purified tanshinones or S. miltiorrhiza root extracts. It is concluded that remedies containing tanshinones should be avoided when individuals are taking esterified agents and that patients should be warned of the potential drug-drug interaction that may occur with this material. 22849377 Localisation and role of activin receptor-interacting protein 1 in mouse brain. Activin A, a stimulator of follicle-stimulating hormone secretion from the pituitary, acts as a neurotrophic and neuroprotective factor in the central nervous system. Activin receptor-interacting protein 1 (ARIP1) has been identified as a cytoplasmic protein that interacts with the type II receptor of activin (ActRII). However, the distribution pattern and function of ARIP1 are not well characterised in the brain. In the present study, we confirmed the existence of mRNA and protein of ARIP1 in the mouse brain, and found that ARIP1 was mainly localised at the hippocampus and hypothalamus in the cerebrum, granular layers in the cerebellum (especially in Purkinje cells of the cerebellum) and choroid epithelial cells by immunohistochemical staining. Furthermore, in contrast to the significant increase of activin A mRNA, ARIP1 mRNA and protein expression decreased in the mechanically lesioned brain of the mouse. Using neuroblastoma-derived Neuro-2a cells to investigate the function of ARIP1, we found that overexpression of ARIP1 down-regulated the activin A-induced signal transduction and significantly decreased the voltage-gated Na(+) current (I(Na) ). These data indicate that ARIP1 is a key molecule for the regulation of the action of activin in neurones, and also that decreased ARIP1 expression in the lesioned brain may be beneficial to the neurotrophic and neuroprotective roles of activin A in recovery after brain injury. 23474268 The crucial role of the MyD88 adaptor protein in the inflammatory response induced by Bothrops atrox venom. Most snake accidents in North Brazil are attributed to Bothrops atrox, a snake species of the Viperidae family whose venom simultaneously induces local and systemic effects in the victims. The former are clinically more important than the latter, as they cause severe tissue lesions associated with strong inflammatory responses. Although several studies have shown that inflammatory mediators are produced in response to B. atrox venom (BaV), there is little information concerning the molecular pathways involved in innate immune system signaling. Myeloid differentiation factor 88 (MyD88) is an adaptor molecule responsible for transmitting intracellular signals from most toll-like receptors (TLRs) after they interact with pathogen-associated molecular patterns (PAMPs) or other stimuli such as endogenous damage-associated molecular patterns (DAMPs). The MyD88-dependent pathway leads to activation of transcription factors, which in turn induce synthesis of inflammatory mediators such as eicosanoids, cytokines and chemokines. The aim of this study was to investigate the involvement of MyD88 on the acute inflammatory response induced by BaV. Wild-type (WT) C57BL/6 mice and MyD88 knockout (MyD88(-/-)) mice were intraperitoneally injected with BaV. Compared to WT mice, MyD88(-/-) animals showed an impaired inflammatory response to BaV, with lower influx of polymorphonuclear and mononuclear cells to the peritoneal cavity. Furthermore, peritoneal leukocytes from BaV-injected MyD88(-/-) mice did not induce COX-2 or LTB4 protein expression and released low concentrations of PGE2. These mice also failed to produce Th1 and Th17 cytokines and CCL-2, but IL-10 levels were similar to those of BaV-injected WT mice. Our results indicate that MyD88 signaling is required for activation of the inflammatory response elicited by BaV, raising the possibility of developing new therapeutic targets to treat Bothrops sp. poisoning. 23046524 Adverse outcome pathways during zebrafish embryogenesis: a case study with paraoxon. Using paraoxon as a reference acetylcholinesterase (AChE) inhibitor, the objective of this study was to develop an adverse outcome pathway (AOP) that provided quantitative linkages across levels of biological organization during zebrafish embryogenesis. Within normal zebrafish embryos, we first demonstrated that ache transcripts and AChE activity increased in a stage-dependent manner following segmentation. We then showed that static exposure of embryos to paraoxon (31.2-500 nM) from 5 to 96 hpf resulted in significant stage- and concentration-dependent AChE inhibition, albeit these effects were fully reversible within 48 h following transfer to clean water. However, even in the presence of significant AChE inhibition, exposure to non-teratogenic paraoxon concentrations (≤250 nM) did not adversely impact secondary motoneuron development at 96 hpf. Therefore, we investigated the potential effects of paraoxon exposure on spontaneous tail contractions at 26 hpf - an early locomotor behavior that results from innervation of primary (not secondary) motoneuron axons to target axial muscles. Based on these studies, the frequency of spontaneous tail contractions at 26 hpf - a developmental stage with minimal AChE expression and activity - was significantly higher following exposure to paraoxon concentrations as low as 31.2 nM. Overall, our data suggest that (1) normal AChE activity is not required for secondary motoneuron development and (2) spontaneous tail contractions at 26 hpf are sensitive to paraoxon exposure, an effect that may be independent of AChE inhibition. Using a well-studied reference chemical, this study highlights the potential challenges in developing quantitative AOPs to support chemical screening and prioritization strategies. 23462797 Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice. AIMS/HYPOTHESIS: Cholecystokinin (CCK) and leptin are important hormones with effects on energy balance. The present study assessed the biological effects of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, smaller isoforms of CCK and leptin, respectively. METHODS: The actions and overall therapeutic use of (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3, alone and in combination, were evaluated in normal and high-fat-fed mice. RESULTS: (pGlu-Gln)-CCK-8 had prominent (p < 0.01 to p < 0.001), acute feeding-suppressive effects, which were significantly augmented (p < 0.05 to p < 0.01) by [D-Leu-4]-OB3. In agreement, the acute dose-dependent glucose-lowering and insulinotropic actions of (pGlu-Gln)-CCK-8 were significantly enhanced by concurrent administration of [D-Leu-4]-OB3. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in high-fat-fed mice for 18 days decreased body weight (p < 0.05 to p < 0.001), energy intake (p < 0.01), circulating triacylglycerol (p < 0.01), non-fasting glucose (p < 0.05 to p < 0.001) and triacylglycerol deposition in liver and adipose tissue (p < 0.001). All treatment regimens improved glucose tolerance (p < 0.05 to p < 0.001) and insulin sensitivity (p < 0.001). Combined treatment with (pGlu-Gln)-CCK-8 and [D-Leu-4]-OB3 resulted in significantly lowered plasma insulin levels, normalisation of circulating LDL-cholesterol and decreased triacylglycerol deposition in muscle. These effects were superior to either treatment regimen alone. There were no changes in overall locomotor activity or respiratory exchange ratio, but treatment with (pGlu-Gln)-CCK-8 significantly reduced (p < 0.001) energy expenditure. CONCLUSIONS/INTERPRETATION: These studies highlight the potential of (pGlu-Gln)-CCK-8 alone and in combination with [D-Leu-4]-OB3 in the treatment of obesity and diabetes. 23299192 A 5-year retrospective evaluation of snakebite cases in Hatay, Turkey. Snakebites are relatively rare medical emergency cases that might lead to serious consequences. This study aims to evaluate snakebite cases in terms of medical follow-up, antivenom therapy and antivenom reactions. Medical records of patients admitted to emergency department between January 1, 2006 and December 31, 2010 were retrospectively investigated. Snakebite-related cases of a total of 125 patients were included in the scope of the study. Of the total 125 cases, 54.4% were male and 45.6% were female. Most of cases (n: 65, 52%) were aged over 30 years, while the mean age was 34.87 ± 19.29 years. Snakebite-related applications to the emergency department were mostly seen in June with 27 cases. Upon admitting, all patients were recorded to be conscious and showing good general conditions; however, they suffered from pain and edema at the site of bite. Of all, 25 patients only suffered from bite injury and ecchymosis due to snakebite. The site of bite was upper extremities in 66 patients (52.8%), whereas it was lower extremities in 58 (46.4%). Of all, antivenom was unnecessary in 25 (20%) patients, while four antivenoms were administered to each of the 23 (18.4%) patients. Furthermore, six (4.8%) patients needed nine antivenom administrations for each. Anaphylaxis (n: 2, 1.6%), compartment syndrome (n: 2, 1.6%) and serum sickness (n: 1, 0.8%) encountered in remaining cases. Of all, 86 (68.8%) patients were hospitalized in the emergency department, while 25 (20.0%) patients were followed up by observation in emergency service. Only one patient was treated and followed up in intensive care unit. Implementation of antivenom therapy is considered unnecessary for the treatment of all snakebite cases. Antivenom reactions and number of related cases might be reduced by continuous close monitoring, appropriate prophylaxis and controlled slow infusion administration of medications. 23264019 The response of soil organism communities to the application of the insecticide lindane in terrestrial model ecosystems. The EU plant protection regulation 1107/2009/EC defines the requirements for active ingredients to be approved, specifically including the assessment of effects on biodiversity and ecosystems. According to that, semi-field methods are expected to be more important in the near future. Therefore, a higher-tier experiment suitable to assess the risk for soil organisms was conducted to further develop the TME (terrestrial model ecosystems) methodology in a dose-response design with the persistent insecticidal model compound lindane (gamma-HCH). The effects of lindane on soil communities such as collembolans, oribatid mites, nematodes, soil fungi and plant biomass were determined in 42 TME. Intact TME-soil cores (diameter 300 mm, height 400 mm) from undisturbed grassland were stored outdoor under natural climatic conditions. Lindane was applied in five concentrations between 0.032 mg active ingredients (ai)/kg dry soil and 3.2 mg ai/kg dry weight soil, six-fold replicated each. Twelve TME served as untreated controls. Abundance and community structures of oribatids, collembolans, enchytraeids, nematodes and fungi were recorded. Oribatid mites' community responded 3 months after treatment, although they were not significantly affected by the overall treatment regimen. Collembolans in total and species-specific abundance as well as the community endpoints (principal response curves, diversity measures) were adversely affected by moderate dosages of lindane. Effects were transient between 3 and 5 months after treatment with a recovery within 1 year. No significant effects could be detected for enchytraeids, nematodes and fungi. The study design and the obtained results allow for calculations of no observed effect concentrations below the highest treatment level for populations and for soil communities as defined entities, as well as effective concentrations. The paper discusses the limits of effect detection in the light of achievable coefficients of variation and by means of minimum detectable differences. Outdoor TME are useful to analyze and assess functional and structural endpoints in soil organisms' communities and their possible recovery after pesticide treatment within 1 year. 23445175 Membrane Topology of Yeast Alkaline Ceramidase YPC1. Ypc1p and Ydc1p are alkaline ceramide hydrolases, which reside in the ER. Ypc1p can catalyze the reverse reaction, i.e. the condensation of free fatty acids with phytosphingosine or dihydrosphingosine and overexpression of YPC1 or YDC1 can provide enough ceramide synthesis as to rescue the viability of cells lacking the normal acyl-CoA-dependent ceramide synthases. To better understand the coexistence of acyl-CoA dependent ceramide synthases and ceramidases in the ER we investigated the membrane topology of Ypc1p by probing cysteine accessibility of natural and substituted cysteines with membrane non-permeating mass-tagged probes. The N- and C-terminal ends of Ypc1p are oriented towards the lumen and cytosol, respectively. Two of the 5 natural cysteines, Cys27 and Cys219, are essential for enzymatic activity and form a disulfide bridge. The data allow inferring that all amino acids of Ypc1p that are conserved in the pfam PF05875 ceramidase motif and the CREST superfamily are located in or near the ER lumen. Microsomal assays using a lysine-specific reagent show that the reverse ceramidase activity can only be blocked when the reagent has access to Ypc1p from the lumenal side. Overall the data suggest that the active site of Ypc1p resides at the lumenal side of the ER membrane. 23572405 Circulating glucagon to ghrelin ratio as a determinant of insulin resistance in hyperthyroidism. Due to stimulated overall metabolism, a state of nutritional inadequacy often ensues, during thyrotoxicosis. We aimed to investigate circulating levels of some major components of the system that regulates energy stores, glucose, and fat metabolism, during thyrotoxicosis compared to euthyroidism. Fasting serum ghrelin, leptin, adiponectin, insulin, glucagon, glucose, as well as body fat composition were analyzed during thyrotoxicosis in 40 hyperthyroid patients (50.5 ± 15.2 years old, 22 females, 31 with Graves disease, and 9 with toxic nodular goiter). The same measurements were repeated an average 3 months later, when all patients achieved euthyroidism. Compared to euthyroidism, in thyrotoxicosis, patients had lower ghrelin and fat mass; had comparable insulin, HOMA-IR, glucagon, and leptin levels; higher levels of circulating adiponectin. Fasting serum glucose tended to be higher during thyrotoxicosis. The unique correlation of HOMA-IR was with the-glucagon to ghrelin ratio-(r = 0.801, p < 0.001) in hyperthyrodism, and with glucagon itself in euthyroidism (r = -0.844, p < 0.001). Circulating levels of ghrelin are decreased; leptin, insulin, glucagon are unchanged; adiponectin are increased during hyperthyroidism. The fasting HOMA-IR tends to be higher, despite the decreased adiposity in hyperthyroidism. The-glucagon to ghrelin ratio-strongly correlates with fasting HOMA-IR in hyperthyroidism. 23384448 Acitretin affects bioenergetics of liver mitochondria and promotes mitochondrial permeability transition: Potential mechanisms of hepatotoxicity. Acitretin is a synthetic retinoid used for severe extensive psoriasis and it has been shown to be an effective and a safe therapeutic drug for other diseases including cancer when used in combination with other agents. However, cases of acitretin-associated liver injury have been documented, but the possible mechanisms of acitretin-associated hepatotoxicity and apoptosis are not entirely clarified. This study reports that mitochondrial dysfunctions may play an important role in liver injury and apoptosis induced by this retinoid. Acitretin (5-20μM) impaired mitochondrial phosphorylation efficiency as demonstrated by the decrease in the state 3 respiration and ATP levels, and by the increase in the lag phase of ADP phosphorylation cycle, without affecting the membrane potential. Acitretin induced Ca(2+)-mediated mitochondrial permeability transition (MPT) and decreased the adenine nucleotide translocase (ANT) content. Acitretin-induced MPT was not prevented by thiol group protecting and antioxidant agents, excluding the involvement of oxidative stress mechanisms. However, MPT was prevented by ANT ligands ATP, ADP, tamoxifen and 4-hydroxytamoxifen, implying that the MPT induction by acitretin is mediated by the ANT. ANT plays a major role in promoting apoptosis and ATP synthesis, and it is still considered as a structural component of the pore with a regulatory role in MPT formation. Therefore, our results, including the decrease in the state 3 respiration and the increase in the lag phase of phosphorylation cycle, the ATP depletion and the induction of Ca(2+)-mediated MPT, indicate that acitretin-associated liver toxicity and apoptosis is possibly related with mitochondrial dysfunctions due to interactions with the ANT. Additionally, the combination of acitretin with other drugs, such as antiestrogens, which are able to inhibit the MPT, may contribute to decrease the toxicity induced by acitretin. 23261646 Data management in large-scale collaborative toxicity studies: How to file experimental data for automated statistical analysis. High-throughput screening approaches are carried out for the toxicity assessment of a large number of chemical compounds. In such large-scale in vitro toxicity studies several hundred or thousand concentration-response experiments are conducted. The automated evaluation of concentration-response data using statistical analysis scripts saves time and yields more consistent results in comparison to data analysis performed by the use of menu-driven statistical software. Automated statistical analysis requires that concentration-response data are available in a standardised data format across all compounds. To obtain consistent data formats, a standardised data management workflow must be established, including guidelines for data storage, data handling and data extraction. In this paper two procedures for data management within large-scale toxicological projects are proposed. Both procedures are based on Microsoft Excel files as the researcher's primary data format and use a computer programme to automate the handling of data files. The first procedure assumes that data collection has not yet started whereas the second procedure can be used when data files already exist. Successful implementation of the two approaches into the European project ACuteTox is illustrated. 23563271 Resolving the phylogenetic history of the short-necked turtles, genera Elseya and Myuchelys (Testudines: Chelidae) from Australia and New Guinea. Phylogenetic relationships and taxonomy of the short-necked turtles of the genera Elseya, Myuchelys, and Emydura in Australia and New Guinea have long been debated as a result of conflicting hypotheses supported by different data sets and phylogenetic analyses. To resolve this contentious issue, we analyzed sequences from two mitochondrial genes (cytochrome b and ND4) and one nuclear intron gene (R35) from all species of the genera Elseya, Myuchelys, Emydura, and their relatives. Phylogenetic analyses using three methods (maximum parsimony, maximum likelihood, and Bayesian inference) produce a single, well resolved, and strongly corroborated hypothesis, which provides support for the three genera, with the exception that the genus Myuchelys is paraphyletic - Myuchelys purvisi is the sister taxon to the remaining Elseya, Myuchelys and Emydura. A new genus is proposed for the species Myuchelys purvisi to address this paraphyletic relationship. Time-calibration analysis suggests that diversification of the group in Australia coincides with periods of aridification in the late Eocene and between the mid-Miocene and early Pliocene. Other speciation events occurred during the faunal exchange between Australia and the island of New Guinea during the late Miocene and early Pliocene. Lineages distributed in New Guinea are likely influenced by the complex geologic history of the island, and include cryptic species diversity. 23361305 Left ventricular noncompaction (LVNC) and low mitochondrial membrane potential are specific for Barth syndrome. Barth syndrome (BTHS) is an X-linked mitochondrial defect characterised by dilated cardiomyopathy, neutropaenia and 3-methylglutaconic aciduria (3-MGCA). We report on two affected brothers with c.646G > A (p.G216R) TAZ gene mutations. The pathogenicity of the mutation, as indicated by the structure-based functional analyses, was further confirmed by abnormal monolysocardiolipin/cardiolipin ratio in dry blood spots of the patients as well as the occurrence of this mutation in another reported BTHS proband. In both brothers, 2D-echocardiography revealed some features of left ventricular noncompaction (LVNC) despite marked differences in the course of the disease; the eldest child presented with isolated cardiomyopathy from late infancy, whereas the youngest showed severe lactic acidosis without 3-MGCA during the neonatal period. An examination of the patients' fibroblast cultures revealed that extremely low mitochondrial membrane potentials (mtΔΨ about 50 % of the control value) dominated other unspecific mitochondrial changes detected (respiratory chain dysfunction, abnormal ROS production and depressed antioxidant defense). 1) Our studies confirm generalised mitochondrial dysfunction in the skeletal muscle and the fibroblasts of BTHS patients, especially a severe impairment in the mtΔΨ and the inhibition of complex V activity. It can be hypothesised that impaired mtΔΨ and mitochondrial ATP synthase activity may contribute to episodes of cardiac arrhythmia that occurred unexpectedly in BTHS patients. 2) Severe lactic acidosis without 3-methylglutaconic aciduria in male neonates as well as an asymptomatic mild left ventricular noncompaction may characterise the ranges of natural history of Barth syndrome. 23601403 The new on-line Czech Food Composition Database. The new on-line Czech Food Composition Database (FCDB) was launched on http://www.czfcdb.cz in December 2010 as a main freely available channel for dissemination of Czech food composition data. The application is based on a complied FCDB documented according to the EuroFIR standardised procedure for full value documentation and indexing of foods by the LanguaL™ Thesaurus. A content management system was implemented for administration of the website and performing data export (comma-separated values or EuroFIR XML transport package formats) by a compiler. Reference/s are provided for each published value with linking to available freely accessible on-line sources of data (e.g. full texts, EuroFIR Document Repository, on-line national FCDBs). LanguaL™ codes are displayed within each food record as searchable keywords of the database. A photo (or a photo gallery) is used as a visual descriptor of a food item. The application is searchable on foods, components, food groups, alphabet and a multi-field advanced search. 23299193 Subacute oral toxicity of combinations of selected synthetic pyrethroids, piperonyl butoxide, and tetramethrin in rats. In this study, 70 Wistar rats were randomly divided into seven equal groups (six experimental and one control), which consisted of animals belonging to both sexes. Different combinations of insecticides were administered daily to the experimental groups (group 1: cypermethrin + piperonyl butoxide (PBO); group 2: alphacypermethrin + PBO; group 3: deltamethrin + PBO; group 4: cypermethrin + PBO + tetramethrin; group 5: alphacypermethrin + PBO + tetramethrin; and group 6: deltamethrin + PBO + tetramethrin) for 28 days. During the study period, mortality and serious clinical findings were not observed in any animal. However, feed consumptions decreased in groups 1 and 3 (p < 0.05). Red blood cells, white blood cells, and hemoglobin levels, especially in cypermethrin and alphacypermethrin groups (groups 1, 2, and 4), were found to be higher than the control group (p < 0.05). Furthermore, biochemical changes related to liver, kidney functions, and protein metabolism occurred in males of almost all the groups. Relative liver and kidney weights of the male animals increased in the cypermethrin and alphacypermethrin groups (p < 0.05). The most common finding observed during the histopathological examination of all the experimental groups was centrilobular degeneration in the liver. It was concluded that although clinical symptoms were not observed, synthetic pyrethroid, synergist, and knockdown agent combinations might cause serious abnormalities when administered in certain doses in mammalians. 23506042 Structural Basis for Enzyme I Inhibition by α-Ketoglutarate. Creating new bacterial strains in which carbon and nitrogen metabolism are uncoupled is potentially very useful for optimizing yields of microbial produced chemicals from renewable carbon sources. However, the mechanisms that balance carbon and nitrogen consumption in bacteria are poorly understood. Recently, α-ketoglutarate (αKG), the carbon substrate for ammonia assimilation, has been observed to inhibit Escherichia coli enzyme I (EI), the first component of the bacterial phosphotransferase system (PTS), thereby providing a direct biochemical link between central carbon and nitrogen metabolism. Here we investigate the EI-αKG interaction by NMR and enzymatic assays. We show that αKG binds with a KD of ∼2.2 mM at the active site of EI, acting as a competitive inhibitor. In addition, we use molecular docking simulations to derive a structural model of the enzyme-inhibitor complex that is fully consistent with NMR and analytical ultracentrifugation data. We expect that the EI-αKG structure presented here will provide a starting point for structure-based design of EI mutants resistant to αKG. 23550966 Cytotoxic, Antitopoisomerase IIα, and Anti-HIV-1 Activities of Triterpenoids Isolated from Leaves and Twigs of Gardenia carinata. Eight new cycloartane triterpenoids (1-8), named carinatins A-H, and the known compounds secaubryolide (9) and dikamaliartane D (10) were isolated from the leaves and twigs of Gardenia carinata. Their structures were determined on the basis of spectroscopic methods. Cytotoxic, antitopoisomerase IIα, and anti-HIV-1 activities of compounds 1-7, 9, and 10 were investigated. 23561096 Simulated digestion of proanthocyanidins in grape skin and seed extracts and the effects of digestion on the angiotensin I-converting enzyme (ACE) inhibitory activity. This study investigated the effect of in vitro gastrointestinal digestion on the stability and composition of flavan-3-ols from red grape skin and seed extracts (raw and purified, which are high in proanthocyanidins (PAs)). In addition, the effects of digestion on the angiotensin I-converting enzyme (ACE) inhibitory activities of these extracts were evaluated. The extracts were digested with a mixture of pepsin-HCl for 2h, followed by a 2h incubation with pancreatin and bile salts including a cellulose dialysis tubing (molecular weight cut-off 12kDa) at 37°C with shaking in the dark and under N2. Under gastric conditions, the mean degree of polymerisation (mDP) of seed extracts, raw (mDP≈6, p<0.05), and purified (mDP≈10, p<0.05) was stable. The mDP of the raw skin extracts increased from 19 to 25 towards the end of the digestion. The PAs were significantly degraded (up to 80%) during the pancreatic digestion, yielding low-molecular-weight compounds that diffused into the serum-available fraction (mDP≈2). The overall mass transfer coefficient (K) of the seed extracts was 10(-7)m(2)/s. After simulated gastrointestinal digestion, over 80% of ACE inhibition by raw seed and skin extracts was preserved. However, the purified seed and skin extracts lost their ability to inhibit ACE after intestinal digestion. 23111881 Spectral analysis of thioacetamide-induced electroencephalographic changes in rats. Thioacetamide (TAA) is widely used as a model of hepatic encephalopathy (HE). The aim of our study was to investigate the effects of TAA on electroencephalographic (EEG) changes in rats and to compare them with human HE. Male Wistar rats were divided into groups: (1) saline-treated group and (2) TAA-treated groups: TAA(300) (300 mg/kg), TAA(600) (600 mg/kg), and TAA(900) (900 mg/kg). Daily dose of TAA (300 mg/kg) was administered intraperitoneally once (TAA(300)), twice (TAA(600)), or thrice (TAA(900)) in subsequent days. EEG changes were recorded about 24 h after the last dose of TAA. Absolute and relative power density in alpha bands were significantly higher in TAA(300) versus control group. In TAA(300), absolute beta power density was higher and relative beta power density was lower versus control group. Absolute alpha, theta, delta, and relative theta power were significantly lower, while relative power in delta band was significantly higher in TAA(900) versus control group (p < 0.01). In conclusion, decrease in EEG voltage with an increase in delta relative power, which correspond to the EEG manifestations of severe HE in humans, was observed in TAA(900) group. Electrical activity in TAA(300) group correlates with mild HE in humans. 22967140 Role of oestrogen receptors on the modulation of NADPH-diaphorase-positive cell number in supraoptic and paraventricular nuclei of ovariectomised female rats. Modulation of the nitric oxide producing system (demonstrated via the NADPH-diaphorase histochemical reaction) by oestradiol has been established in several structures of the rat brain. The present study aimed to explore the possible regulation of NADPH-diaphorase activity by oestradiol in neurones of the supraoptic (SON) and paraventricular (PVN) nuclei and the role of oestrogen receptors (ERα and ERβ) in this regulation. Adult ovariectomised rats were divided into six groups and injected either with vehicle or a single dose of oestradiol, a selective ERα agonist-PPT [4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol], a selective ERβ agonist-DPN [2,3-bis(4-hydroxyphenyl)-propionitrile], a selective ERα antagonist-MPP [1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride] or a selective ERβ antagonist-PHTPP (4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol). The number of NADPH-diaphorase positive elements in the SON and the PVN was modulated by both ERs but, depending on the nucleus, ERα and ERβ ligands induced different effects. These results suggest that the regulation of nitrergic system by ERs may play a role in the control of oestrogen-dependent physiological mechanisms regulated by the SON and the PVN. 23432066 Multiple Roles of Transient Receptor Potential (TRP) Channels in Inflammatory Conditions and Current Status of Drug Development. During inflammation, several Transient Receptor Potential (TRP) channels are directly or indirectly activated by inflammatory signaling molecules and microenvironmental changes including heat, oxidative conditions or low pH. In either case, specific TRP isoforms participate in chains of pro- or anti-inflammatory signaling cascades often including activation of transcription factors, protein kinases and phospholipases, which result in signal integration or amplification. In a few cases, their potentials as therapeutic targets for inflammatory conditions like pruritis, cystitis, dermatitis, asthma among other conditions are investigated pre-clinically or clinically by pioneering academic groups and industries. Significant efforts are still devoted to the understanding of the detailed physiological roles played by TRP channels during inflammation. This review intends to summarize key biological findings and reports of drug discovery activities when available, in an overview of the current status and recent developments in the field. 23401298 Exploring the Interplay Between Ligand Derivatisation and Cation Type in the Assembly of Hybrid Polyoxometalate Mn-Andersons. Herein a library of hybrid Mn-Anderson polyoxometalates anions are presented: 1, [(MnMo(6) O(18) )((OCH(2) )(3) -C-(CH(2) )(7) CHCH(2) )(2) ](3-) ; compound 2, [(MnMo(6) O(18) )((OCH(2) )(3) C-NHCH(2) C(16) H(9) )(2) ](3-) ; compound 3, [(MnMo(6) O(18) )((OCH(2) )(3) C-(CH(2) )(7) CHCH(2) )(1) ((OCH(2) )(3) C-NHCH(2) C(16) H(9) )(1) ](3-) ; compound 4, [(MnMo(6) O(18) )((OCH(2) )(3) C-NHC(O)CH(2) CHCH(2) )(2) ](3-) and compounds 5-9, [(MnMo(6) O(18) )((OCH(2) )(3) C-NHC(O)(CH(2) )(x) CH(3) )(2) ]), where x = 4, 10, 12, 14, and 18 respectively. The compounds resulting from the cation exchange of the anions 1-9 to give TBA (a) and DMDOA (b) salts, and additionally for compounds 1, 2 and 3, tetraphenylphosphonium (PPh(4) ) (c) salts, are explored at the air/water interface using scanning force microscopy, showing a range of architectures including hexagonal structures, nanofibers and other supramolecular forms. Additionally the solid-state structures for compounds 1c, 2c, 4a, 6a, 9a, are presented for the first time and these investigations demonstrate the delicate interplay between the structure of the covalently derivatised hybrid organo-clusters as well as the ion-exchange cation types. 23172726 Comparison of splicing factor 3b inhibitors in human cells. Name your splice: FR901464 analogues and herboxidiene inhibit constitutive splicing, most likely by inhibiting spliceosomal subunit SF3b. A parallel comparison of these compounds in a cell-based assay system showed meayamycin B as the most potent splicing inhibitor among these small molecules. 23609940 Resumption of menstruation and pituitary response to gonadotropin-releasing hormone in functional hypothalamic amenorrhea undertaking estrogen replacement therapy. Background: Functional hypothalamic amenorrhea (FHA) refers to a functional menstrual disorder with various causes and presentations. Recovery of menstrual cyclicity is common in long-term follow-up but the affecting factors remain unknown. Aim: To explore factors affecting the menstrual resumption and to evaluate the pituitary response to gonadotropin-releasing hormone (GnRH) in FHA. Materials and Methods: Thirty cases with FHA were recruited. All subjects were put on continuous 1mg/day estradiol valerate orally and followed up monthly. Recovery was defined as the occurrence of at least three consecutive regular cycles. Responder referred to those who recovered within two years of therapy. Gonadotropin response to the 50 microgram GnRH challenge was tested every three months. Results: Nineteen (63.3%) subjects recovered with a mean time to recovery of 26.8 months. Time to recovery was negatively correlated with body mass index (BMI) before and by amenorrhea. Twenty-one cases had undertaken therapy for more than two years and ten of them recovered. BMI before and by amenorrhea were negatively correlated with the recovery. Significant increase of serum luteinizing hormone (LH) and LH response to GnRH were noted after recovery. Conclusions: Menstrual resumption was common in FHA undertaking ERT. The likelihood of recovery was affected by their BMI before and by amenorrhea but not by the weight gain during therapy. Low serum LH and attenuated LH response to GnRH were the main features of pituitary deficiency in FHA. The menstrual resumption in FHA was accompanied by the recovery of serum LH and the LH response to GnRH. 23060524 TLR4 antagonist reduces early-stage atherosclerosis in diabetic apolipoprotein E-deficient mice. Although it has been reported that deficiency of toll-like receptor 4 (TLR4) is associated with reduced atherosclerosis in atherosclerosis-prone mice and attenuated pro-inflammatory state in diabetic mice, it remains undetermined whether treatment with a TLR4 antagonist reduces atherosclerosis in nondiabetic or diabetic mice that have TLR4 expression. In this study, we determined the effect of Rhodobacter sphaeroides lipopolysaccharide (Rs-LPS), an established TLR4 antagonist, on early-stage atherosclerosis in nondiabetic and streptozotocin-induced diabetic apolipoprotein E-deficient (Apoe(-/-)) mice. Analysis of atherosclerotic lesions of both en face aortas and cross sections of aortic roots showed that administration of Rs-LPS in 14-week-old diabetic Apoe(-/-) mice for 10 weeks significantly reduced atherosclerotic lesions. Although atherosclerotic lesions in nondiabetic Apoe(-/-) mice appeared to be decreased by Rs-LPS treatment, the difference was not statistically significant. Metabolic study showed that Rs-LPS significantly lowered serum levels of cholesterol and triglycerides in nondiabetic mice but not in diabetic mice. Furthermore, immunohistochemistry studies showed that Rs-LPS inhibited the expression of interleukin 6 and matrix metalloproteinase-9 and reduced the content of monocytes and macrophages in atherosclerotic plaques. Taken together, this study demonstrated for the first time that TLR4 antagonist inhibited vascular inflammation and atherogenesis in diabetic Apoe(-/-) mice and lowered serum cholesterol and triglyceride levels in nondiabetic Apoe(-/-) mice. 23335817 ZnO is a CO(2)-selective steam reforming catalyst. ZnO was tested as possible methanol and - since formaldehyde is one of the key intermediates in methanol conversion reactions - also as formaldehyde steam reforming catalyst. Catalytic experiments in a batch as well as a flow reactor resulted in highly selective steam reforming, though at low specific activities, of formaldehyde and methanol over ZnO toward CO(2) (selectivity of 95-99.6%). Comparison of the behavior of ZnPd near-surface intermetallic phases, unsupported intermetallic ZnPd and supported ZnPd/ZnO catalysts reveals that formaldehyde is formed from methanol in parallel with CO(2) on the former, while on unsupported intermetallic ZnPd and ZnO-supported ZnPd, it is efficiently reacted toward CO(2), thus, a beneficial role of ZnO in oxidizing formaldehyde-derived intermediates toward CO(2) is evident. 23395981 Alcohol modulates expression of DNA methyltranferases and methyl CpG-/CpG domain-binding proteins in murine embryonic fibroblasts. Fetal alcohol syndrome (FAS), presenting with a constellation of neuro-/psychological, craniofacial and cardiac abnormalities, occurs frequently in offspring of women who consume alcohol during pregnancy, with a prevalence of 1-3 per 1000 livebirths. The present study was designed to test the hypothesis that alcohol alters global DNA methylation, and modulates expression of the DNA methyltransferases (DNMTs) and various methyl CpG-binding proteins. Murine embryonic fibroblasts (MEFs), utilized as an in vitro embryonic model system, demonstrated ∼5% reduction in global DNA methylation following exposure to 200mM ethanol. In addition, ethanol induced degradation of DNA methyltransferases (DNMT-1, DNMT-3a, and DNMT-3b), as well as the methyl CpG-binding proteins (MeCP-2, MBD-2 and MBD-3), in MEF cells by the proteasomal pathway. Such degradation could be completely rescued by pretreatment of MEF cells with the proteasomal inhibitor, MG-132. These data support a potential epigenetic molecular mechanism underlying the pathogenesis of FAS during mammalian development. 23059508 Suppressive effect of accumulated aluminum trichloride on the hepatic microsomal cytochrome P450 enzyme system in rats. Aluminum (Al) is a low toxicological metal and can accumulate in the liver. The hepatic microsomal cytochrome P450 enzyme system (CYPS) plays important role in the transformation of the toxic materials. It is not clear if the CYPS is affected by Al exposure. Thus, the aim of this study is to investigate the effects of aluminum trichloride (AlCl(3)) on CYPS in rats. Forty male Wistar rats (5weeks old) weighing 110-120g were randomly allocated and orally exposed to 0, 64.18, 128.36 and 256.72mg/kg body weight (BW) AlCl(3) in drinking water for 120days. The body weight (BW) of rats, hepatosomatic index (HSI), hepatic Al content, the concentrations of cytochrome P450 (CYP450), cytochrome B5 (B5), microsomal protein and the activities of NADPH-cytochrome c reductase (CR), aminopyrin N-demethylase (AND), erythromycin N-demethylase (ERND) and aniline-4-hydeoxylase (AH) were assessed at the end of the experiment. The results showed that the increase in Al concentration decreased BW, HIS, concentrations of CYP450, B5, microsomal protein and the activity of CR, AND, ERND and AH in hepatic microsomes. The results revealed that exposure to AlCl(3) inhibited the microsomal CYP450 dependent enzyme system of liver. Our findings suggest that long term daily exposure of AlCl(3) exerts the suppressive effects and thus may cause dysfunction of hepatic CYP450 dependent enzyme system of rat. 23487175 Understanding multi-quantum NMR through secular approximation. With the development of technology and improved understanding of nuclear spin-spin interactions and their behavior in static/oscillating magnetic fields, NMR spectroscopy has emerged as a powerful tool for characterizing molecular structure in a wide range of systems of chemical, physical and biological relevance. Here in this article, we revisit the important connection between "Secular-Approximation" (a well-known fundamental concept) and NMR spectroscopy. Employing recent experimental results as the background, an alternate interpretation of the secular approximation is presented for describing and understanding the nuances of Multi-Quantum (MQ) NMR spectroscopy of quadrupolar nuclei. Since MQ NMR spectroscopy of quadrupolar nuclei forms the basis of the structural characterization of inorganic solids and clusters, we believe that the analytic theory presented herein would be beneficial both in the understanding and design of MQ NMR experiments. Additionally, the analytic results are corroborated with rigorous numerical simulations and could be employed in the quantitative interpretation of experimental results. 22239172 Diclavatol and tetronic acids from Penicillium griseoroseum. In our continuous studies on the chemistry of the endophytic fungus Penicillium griseoroseum, an endophyte isolated from fruits of Coffea arabica, we isolated clavatol, a dimethylated tetraketide, and its dimer which appears to be a novel natural compound. The studies also resulted in the identification of two known tetronic acids, viridicatic acid and terrestric acid, found in ethyl acetate and n-butanol extracts. Spectroscopic studies using 1-D and 2-D NMR and MS/MS analysis were performed to determine the structures of these compounds, first reported by this Penicillium. Two other tetronic acids congeners were identified through HPLC/MS/MS studies, based on fragmentation pattern of ions produced from ionised tetronic acids, and UV light absorptions. 23160481 FOXO1 controls thyroid cell proliferation in response to TSH and IGF-I and is involved in thyroid tumorigenesis. TSH and insulin/IGF-I synergistically induce the proliferation of thyroid cells mainly through the cAMP and phosphatidylinositol 3-kinase (PI3K) pathways. However, the events involved in this cooperative induction remain unknown, and molecules that are potentially controlled by both TSH and IGF-I are interesting candidates as integrators of both stimuli. The finding that the PI3K pathway is frequently activated in thyroid malignancies has attracted attention to this pathway in the thyroid field. One of the targets of PI3K is Forkhead box O (FoxO)-1, a widely expressed transcription factor involved in a variety of cellular processes such as differentiation, proliferation, and apoptosis. Here we show that FoxO1 is highly expressed in differentiated rat thyroid cells and human thyroid tissue compared with human thyroid tumor-derived cells and surgically removed thyroid tumors, in which its expression is reduced. In differentiated cells, TSH/cAMP treatment decreases FoxO1 mRNA and protein levels through proteasome activation, whereas both TSH and IGF-I control FoxO1 localization by promoting a rapid exclusion from the nucleus in an Akt-dependent manner. FoxO1 can control p27(KIP1) expression in differentiated and tumor cells of the thyroid. Furthermore, FoxO1 reexpression in tumor cells promotes a decrease in their proliferation rate, whereas FoxO1 interference in differentiated cells increases their proliferation. These data point to an important role of FoxO1 in mediating the effects of TSH and IGF-I on thyroid cell proliferation and provide a link between loss of FoxO1 expression and the uncontrolled proliferation of thyroid tumor cells. 23391211 Allometric scaling and prediction of concentration-time profiles of coagulation factors in humans from animals. Abstract 1. Allometric scaling is a useful tool in early drug development and can be used for the prediction of human pharmacokinetic (PK) parameters from animal PK parameters. The main objective of this work was to predict concentration-time profiles of coagulation factors in humans in a multi-compartment system using animal PK parameters. 2. The prediction of concentration-time profiles in humans in a multi-compartment system was based on the predicted values of clearance and volumes of distribution (V(c), V(ss) and V(β)) from animals. Five coagulation factors from the literature were chosen that were described by two-compartment model in both humans and animals. Clearance and volumes of distribution from animals were allometrically scaled to humans and then were used to predict concentration-time profiles in humans. 3. The predicted concentration-time profile for a given coagulation factor was accurate for most of the time points. Percent prediction error range varied across coagulation factors. The prediction error >50% was observed either at 1 or a maximum of two time points for a given drug. 4. The study indicated that the allometric scaling can be useful in the prediction of concentration-time profiles of coagulation factors in humans from animals and may be helpful in designing a first-in-human study. 22750077 Gene therapy and neurodevelopmental disorders. With a number of recent clinical successes, gene therapy is quickly becoming a realistic treatment option for neurological disorders. Advancements in global central nervous system (CNS) gene delivery, in particular, have accelerated to the point that treatments for neurological disorders such as lysosomal storage diseases seem within reach. Other neurodevelopmental disorders, such as Rett Syndrome, Fragile X, and autism still face significant obstacles to overcome before a viable human gene therapy can be considered. This review focuses on the most common CNS gene delivery vehicle, adeno-associated virus (AAV), and the current state of AAV vector design and delivery for CNS gene therapy. Relevant examples of gene therapy studies for neurodevelopmental disorders, as well as outstanding challenges, are discussed. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. 23410155 Profiling the structural determinants of heteroarylnitrile scaffold-based derivatives as falcipain-2 inhibitors by in silico methods. Evidence indicates that cysteine protease falcipain-2 plays essential role in malaria parasites; therefore the potent and selective inhibitors of falcipain-2 may be therapeutically useful drugs for treatment of various forms of malaria parasite plasmodium. In order to understand the structure-activity correlation of falcipain-2 inhibitors, a set of ligand- and receptor-based 3D-QSAR models were, for the first time, developed in the present work employing Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) for 240 promising molecules. Based on the ligand-based alignment, an optimal 3D-QSAR model was obtained with good predictive power of Q(2) = 0.501, R(2) ncv = 0.890, SEE = 0.282, F = 153.522 and R(2) pred = 0.768. And the contour maps intuitively suggest where to modify the molecular structures in order to improve the binding affinity. In addition, docking analysis and molecular dynamics simulation (MD) study were also carried out on the dataset with purpose of exploring the detailed binding modes of ligand in the falcipain-2 binding pocket. The combination of docking analysis and MD simulation shows that Gly83, Trp43 and Ala175 which formed several H-bonds are crucial for falcipain-2 inhibitors. The analysis of the best QSAR model reveals the structural features related to the activity, and provides an insight into molecular mechanisms of inhibition and possible modification of the molecules for better activity. 23257777 A theoretical analysis of the effect of the hydrogenation of graphene to graphane on its mechanical properties. We investigated the effect of the hydrogenation of graphene to graphane on its mechanical properties using first-principles calculations based on density-functional theory. The hydrogenation reduces the ultimate strengths in all three tested deformation modes--armchair, zigzag, and biaxial--and the in-plane stiffness by 1/3. The Poisson ratio was reduced from 0.178 to 0.078, a 56% decrease. However, the ultimate strain in zigzag deformation was increased by 8.7%. The shear mode elastic constants are more sensitive than longitudinal ones to hydrogenation. The fourth and fifth order longitudinal mode elastic constants are inert to the hydrogenation, in contrast to a large decrease of those in second and third order. The hydrogenation does not change the monotonic decrement of the Poisson ratio with increasing pressure, but the rate is tripled. Our results indicate that graphene-graphane systems could be used for hydrogen storage with high speed of charge-discharge of hydrogen. 23546010 Six New Cyclic Peptides from the Roots of Gypsophila oldhamiana. Six new cyclic peptides, gypsophin A-F (1-6), were isolated from Gypsophila oldhamiana. Their structures were elucidated by extensive NMR and chemical degradation. Compound 3 exhibited moderate activity of antiplatelet aggregation in vitro. 23614730 Toxicological impact of inhaled electric mosquito-repellent liquid on the rat: a hematological, cytokine indications, oxidative stress and tumor markers. Abstract Context: High malaria burden has led to the increased use of insecticides in the tropics and subtropics. This study thus aimed at assessing the hematological effects alteration of pyrethroid insecticide exposure using the experimental animal model. Objective: A commonly available Electric Mosquito-Repellent Liquid pyrethroid insecticide containing prallethrin 1.6% w/w is widely used for mosquito control in Saudi Arabia. The immunotoxic effects after inhalation exposures to the preparation for a continuous period of 24, 48, and 72 h were investigated in rats. Methods and materials: Rats were exposed to prallethrin 1.6% w/w by inhalation for 72 consecutive hours. Total blood count, blood indices of creatine kinase (CK), gamma-glutamyltranspeptidase (γ-GT), superoxide dismutase (SOD), nitric oxide (NO), malondialdehyde (MDA), interleukin (IL)-2, tumor necrosis factors (TNF)α, alpha-fetoprotein (AFP), carbohydrate antigen (CA) 19.9 and carcinoembrionic antigen (CEA) were assayed. Results: The administration of prallethrin 1.6% w/w created significant increased changes in the levels of total WBC, lymphocytes, RBC, hemoglobin, packed cell volume, platelets, mean corpuscular volume, and mean corpuscular hemoglobin in rats after 24, 48, and 72 h of continuous inhalation; however, there was a significant reduction in neutrophils at transient reduction in the monocytes after 24 and 48 h to return to normal after 72 h. Significant increases in the levels of CK, γ-GT, SOD, NO, MDA, AFP, IL-2, and TNFα were recorded. CA and CEA did not exhibit any change. Conclusions: Continuous inhalation to prallethrin 1.6% insecticides poses toxicity on hematological variables. It is also concluded that pyrethroid group of insecticide may cause hematological, biochemical, cytokine disturbances and possible mutagenic damage to the tissues. 23316053 Structure and dynamic regulation of Abl kinases. The c-abl proto-oncogene encodes a unique protein-tyrosine kinase (Abl) distinct from c-Src, c-Fes, and other cytoplasmic tyrosine kinases. In normal cells, Abl plays prominent roles in cellular responses to genotoxic stress as well as in the regulation of the actin cytoskeleton. Abl is also well known in the context of Bcr-Abl, the oncogenic fusion protein characteristic of chronic myelogenous leukemia. Selective inhibitors of Bcr-Abl, of which imatinib is the prototype, have had a tremendous impact on clinical outcomes in chronic myelogenous leukemia and revolutionized the field of targeted cancer therapy. In this minireview, we focus on the structural organization and dynamics of Abl kinases and how these features influence inhibitor sensitivity. 23090760 Enhanced charge carrier mobility in two-dimensional high dielectric molybdenum oxide. We demonstrate that the energy bandgap of layered, high-dielectric α-MoO(3) can be reduced to values viable for the fabrication of 2D electronic devices. This is achieved through embedding Coulomb charges within the high dielectric media, advantageously limiting charge scattering. As a result, devices with α-MoO(3) of ∼11 nm thickness and carrier mobilities larger than 1100 cm(2) V(-1) s(-1) are obtained. 23259533 Probing the Bonding and Electronic Structure of Single Atom Dopants in Graphene with Electron Energy Loss Spectroscopy. A combination of scanning transmission electron microscopy, electron energy loss spectroscopy, and ab initio calculations reveal striking electronic structure differences between two distinct single substitutional Si defect geometries in graphene. Optimised acquisition conditions allow for exceptional signal-to-noise levels in the spectroscopic data. The near-edge fine structure can be compared with great accuracy to simulations and reveal either an sp(3)-like configuration for a trivalent Si or a more complicated hybridized structure for a tetravalent Si impurity. 23432336 Nanobiocomposite adhesion: role of graft length and temperature in a hybrid biomimetic approach. Cellulose microspheres bearing poly(ε-caprolactone) grafts of different molecular weights were investigated to evaluate the effect of graft length on the interfacial properties. Surface force and friction measurements were performed using an atomic force microscope in colloidal probe mode. The maximum interaction distance and adhesion is dependent on the temperature and the time in contact via a diffusion controlled mechanism. The effects are highest for the longer grafts, and molecular weight thresholds were found to lie between 21 and 34 kDa at 25 °C and between 9 and 21 kDa at 40 °C. The interpenetration of the graft into a matrix leads to "hidden length" contributions to adhesion, analogous to those in natural biocomposites. The nanotribology results display Amontonian behavior, and the friction force at zero applied load is higher at the graft-graft interface than for a bare cellulose sphere interacting with the graft. These results clearly demonstrate the benefits of the grafted polymer layer on the adhesion, toughness, and resistance to shear in the design of cellulosic nanobiocomposites. 23333175 Novel anticoagulants in the therapy of peripheral arterial and coronary artery disease. Anticoagulant and antiplatelet drugs are used and studied in numerous trials for primary and secondary prevention of atherothrombosis since decades. The annual rate for cardiovascular morbidity and mortality is high in patients following an acute coronary syndrome and in patients with peripheral arterial disease (PAD) due to concomitant cardiac and cerebrovascular diseases. Plaque rupture and subsequent thrombosis involves activation of both platelets and coagulation factors. Therefore the combination of aspirin and warfarin to improve prevention of atherothrombosis compared to antiplatelet therapy alone was studied but could not be established due to significantly increased risk of major bleeding compared to a nonsignificant reduction in ischemic events. During the past two decades, clinical trials focused on combined antiplatelet therapies for the prevention of secondary events following acute coronary syndromes and very recently on the new oral anticoagulants in combination with antiplatelet therapy. This review discusses the role of the new oral anticoagulants such as Factor IIa (thrombin) and Factor Xa inhibitors in atherothrombosis, their pharmacological properties and recently published clinical data in secondary prevention of atherothrombotic events and potential implications for patients with PAD. 23440743 Unraveling a municipal effluent's toxicity to Tripneustes gratilla sperm fertilization. A tiered investigative approach was employed to characterize and identify substances responsible for the persistent toxicity of a primary-treated municipal effluent to gametes of the Hawaiian sea urchin, Tripneustes gratilla. Toxicity identification evaluation (TIE) procedures from the US Environmental Protection Agency were modified to account for the tolerance of T. gratilla gametes to various sample manipulations. Microtox rapid toxicity screening was applied in some aspects of the study after verifying a correlation between the pattern of toxic responses of T. gratilla gametes and that of the bioluminescent bacteria Vibrio fischeri. Toxicity identification evaluation phase I manipulations revealed a toxicity profile implicating surfactants as possible toxicants, and TIE phase II toxicity assessment of isolated fractions coupled with colorimetric surfactant analyses confirmed the possible role of surfactants in effluent toxicity. The toxic effects of standard reference surfactants on T. gratilla fertilization indicated a concordance with the effects of the more nonpolar effluent fractions. Treatability studies showed that biodegradation by activated sludge eliminated effluent toxicity to urchin gametes. Environ Toxicol Chem 2013;32:1382-1387. © 2013 SETAC. 23453838 Synthesis and anti-acetylcholinesterase properties of novel β- and γ-substituted alkoxy organophosphonates. Activated organophosphate (OP) insecticides and chemical agents inhibit acetylcholinesterase (AChE) to form OP-AChE adducts. Whereas the structure of the OP correlates with the rate of inhibition, the structure of the OP-AChE adduct influences the rate at which post-inhibitory reactivation or aging phenomena occurs. In this report, we prepared a panel of β-substituted ethoxy and γ-substituted propoxy phosphonoesters of the type p-NO(2)PhO-P(X)(R)[(O(CH(2))(n)Z] (R=Me, Et; X=O, S; n=2, 3; Z=halogen, OTs) and examined the inhibition of three AChEs by select structures in the panel. The β-fluoroethoxy methylphosphonate analog (R=Me, Z=F, n=2) was the most potent anti-AChE compound comparable (ki ∼6 × 10(6)M(-1)min(-1)) to paraoxon against EEAChE. Analogs with Z=Br, I, or OTs were weak inhibitors of the AChEs, and methyl phosphonates (R=Me) were more potent than the corresponding ethyl phosphonates (R=Et). As expected, analogs with a thionate linkage (PS) were poor inhibitors of the AChEs. 23553797 Bone remodeling is regulated by inner ear vestibular signals. Bone remodeling allows the conservation of normal bone mass despite constant changes in internal and external environments. The adaptation of the skeleton to these various stimuli led credence to the notion that bone remodeling is a true homeostatic function, and as such is under the control of specific centers in the central nervous system (CNS). Hypothalamic and brainstem centers, as well as the sympathetic nervous system (SNS), have been identified as regulators of bone remodeling. However, the nature of the afferent CNS stimuli that may modulate CNS centers involved in the control of bone remodeling, with the exception of leptin, remains unclear. Based on the partial efficacy of exercise and mechanical stimulation regimens to prevent microgravity-induced bone loss and the known alterations in vestibular functions associated with space flights, we hypothesized that inner ear vestibular signals may contribute to the regulation of bone remodeling. Using an established model of bilateral vestibular lesions and microtomographic and histomorphometric bone analyses, we show here that induction of bilateral vestibular lesion in rats generates significant bone loss, which is restricted to weight-bearing bones and associated with a significant reduction in bone formation, as observed in rats under microgravity conditions. Importantly, this bone loss was not associated with reduced locomotor activity or metabolic abnormalities, was accompanied with molecular signs of increased sympathetic outflow, and could be prevented by the β-blocker propranolol. Collectively, these data suggest that the homeostatic process of bone remodeling has a vestibulo-sympathetic regulatory component and that vestibular system pathologies might be accompanied by bone fragility. © 2013 American Society for Bone and Mineral Research. 23481644 The mammalian clock and chronopharmacology. Increases in our understanding of the molecular control of circadian rhythms and subsequent signaling pathways has allowed for new therapeutic drug targets to be identified as well as for a better understanding of how to more efficaciously and safely utilize current drugs. Here, we review recent advances in targeting components of the molecular clock in mammals for the development of novel therapeutics as well as describe the impact of the circadian rhythm on drug efficacy and toxicity. 23630137 Identification of an Inhibitory Mechanism of Luteolin on the Insulin-Like Growth Factor-1 Ligand-Receptor Interaction. Using single-molecule force measurement and fluorescence imaging, we have demonstrated that luteolin has an inhibitory effect on IGF-1 ligand-receptor binding, the initial step in IGF-1 signaling. This inhibition mechanism, which was confirmed by flow cytometry and molecular docking, could play a role in cancer therapy. 23532634 Adrenocortical reserves in hyperthyroidism. Explicit data regarding the changes in adrenocortical reserves during hyperthyroidism do not exist. We aimed to document the capability (response) of adrenal gland to secrete cortisol and DHEA-S during hyperthyroidism compared to euthyroidism, and to describe factors associated with these responses. A standard-dose (0.25 mg/i.v.) ACTH stimulation test was performed to the same patients before hyperthyroidism treatment, and after attainment of euthyroidism. Baseline cortisol (Cor0), DHEA-S (DHEA-S0), cortisol binding globulin (CBG), ACTH, calculated free cortisol (by Coolen's equation = CFC), free cortisol index (FCI), 60-min cortisol (Cor60), and DHEA-S (DHEA-S60), delta cortisol (ΔCor), delta DHEA-S (ΔDHEA-S) responses were evaluated. Forty-one patients [22 females, 49.5 ± 15.2 years old, 32 Graves disease, nine toxic nodular goiter] had similar Cor0, DHEA-S0, CFC, FCI, and DHEA-S60 in hyperthyroid and euthyroid states. Cor60, ΔCor, and ΔDHEA-S were lower in hyperthyroidism. In four (10 %) patients the peak ACTH-stimulated cortisol values were lower than 18 μg/dL. When the test repeated after attainment of euthyroidism, all of the patients had normal cortisol response. Regression analysis demonstrated an independent association of Cor60 with free T3 in hyperthyroidism. However, the predictors of CFC, FCI, and DHEA-S levels were serum creatinine levels in hyperthyroidism, and both creatinine and transaminase levels in euthyroidism. ACTH-stimulated peak cortisol, delta cortisol, and delta DHEA-S levels are decreased during hyperthyroidism, probably due to increased turnover. Since about 10 % of the subjects with hyperthyroidism are at risk for adrenal insufficiency, clinicians dealing with Graves' disease should be alert to the possibility of adrenal insufficiency during hyperthyroid stage. 23214934 Tracking the mechanism of fibril assembly by simulated two-dimensional ultraviolet spectroscopy. Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of plaque deposits in the human brain. The main component of these plaques consists of highly ordered structures called amyloid fibrils, formed by the amyloid β-peptide (Aβ). The mechanism connecting Aβ and AD is yet undetermined. In a previous study, a coarse-grained united-residue model and molecular dynamics simulations were used to model the growth mechanism of Aβ amyloid fibrils. On the basis of these simulations, a dock/lock mechanism was proposed, in which Aβ fibrils grow by adding monomers at either end of an amyloid fibril template. To examine the structures in the early time-scale formation and growth of amyloid fibrils, simulated two-dimensional ultraviolet spectroscopy is used. These early structures are monitored in the far ultraviolet regime (λ = 190-250 nm) in which the computed signals originate from the backbone nπ* and ππ* transitions. These signals show distinct cross-peak patterns that can be used, in combination with molecular dynamics, to monitor local dynamics and conformational changes in the secondary structure of Aβ-peptides. The protein geometry-correlated chiral xxxy signal and the non-chiral combined signal xyxy-xyyx were found to be sensitive to, and in agreement with, a dock/lock pathway. 23334082 A new method of segmentation of compact-appearing, transitional and trabecular compartments and quantification of cortical porosity from high resolution peripheral quantitative computed tomographic images. A transitional or cortico-trabecular junctional zone exists at any location composed of both cortical and trabecular bones such as the metaphyses of tubular bones and short bones like the femoral neck. The transitional zone comprises the inner cortex adjacent to the medullary canal and trabeculae abutting against the cortex contiguous with the endocortical surface. This is a site of vigorous remodeling. Intracortical remodeling cavitates the inner cortex expanding this transitional zone at the price of compact-appearing cortex so that it contains porosity, cortical fragments that resemble trabeculae, and trabeculae abutting the eroding cortex. The porosity of the transitional zone is an important source of bone loss. It reduces bone strength exponentially and is a quantifiable `fingerprint' of structural deterioration. A new automated method of segmentation of bone from background and bone into its compact-appearing cortex, transitional zone, and trabecular compartment is described, with a new approach to quantification of cortical porosity. Segmentation is achieved by automatically selecting attenuation profile curves perpendicular to the periosteal surface. Local bone edges are identified as the beginning and the end of the rising and falling S-shaped portions of the curve enabling the delineation of the compartments. Analyzing ~3600 consecutive overlapping profiles around the perimeter of each cross-sectional slice segments the compartments. Porosity is quantified as the average void volume fraction of all voxels within each compartment. To assess accuracy at the distal radius and tibia, μCT images of cadaveric specimens imaged at 19 μm voxel size served as the gold standard. To assess accuracy at the proximal femur, scanning electron microscopy (SEM) images of specimens collected at 2.5 μm resolution served as the gold standard. Agreement between HRpQCT and the gold standards for segmentation and quantification of porosity at the distal radius and tibia ranged from R(2)=0.87 to 0.99, and for the proximal femur ranged from 0.93 to 0.99. The precision error in vivo for segmentation and quantification of porosity in HRpQCT images at the distal radius, given by the root mean square error of the coefficient of variation, ranged from 0.54% for porosity of the transitional zone to 3.98% for area of the compact-appearing cortex. Segmentation of the transitional zone minimizes errors in apportioning cortical fragments and cortical porosity to the medullary compartment and so is likely to allow accurate assessment of fracture risk and the morphological effects of growth, aging, diseases and therapies. 22401710 Preparation and in vitro/in vivo evaluation of a ketoprofen orally disintegrating/sustained release tablet. Context: Orally disintegrating tablets (ODTs) with sustained release profiles are a new generation of ODTs called orally disintegrating/sustained release tablets (ODSRTs), which are convenient in use and able to slowly release drugs to maintain effective blood concentrations over a prolonged period of time. Ketoprofen, one of non-steroidal anti-inflammatory drugs, is an ideal model drug for ODSRTs. Methods: We designed a simple two-step process to develop novel ketoprofen orally disintegrating/sustained release tablets (KODSRTs). Firstly, sustained release ketoprofen fine granules were developed by spray drying the aqueous dispersions composed of Eudragit RS-30D, Starch 1500 and PEG 6000. The optimal parameters of spray drying were 100°C for inlet air temperature and 1.5 mL/min for feed rate. Subsequently, the obtained granules were directly compressed into KODSRTs after mixing with lactose, mannitol and a superdisintegrant, crosslinked polyvinylpyrrolidone (PVPP). The characteristics of KODSRTs, especially their potential for extended drug release, were evaluated. Results: Results of an in vitro release test demonstrated that KODSRTs could slowly release ketoprofen for 24 h after disintegrating within 30 s. Extended release properties of KODSRTs were decided by the ketoprofen sustained release fine granules in tablets. Besides, the disintegration time of KODSRTs depended on the percentage of PVPP in tablets. In vivo pharmacokinetic studies in beagles also showed that KODSRTs possessed a significantly extended release profile compared with ketoprofen normal capsules. Conclusion: KODSRTs were successfully prepared using a simple two-step process: spray drying and direct compression. 23079545 The arginine and GHRP-2 tests as alternatives to the insulin tolerance test for the diagnosis of adult GH deficiency in Japanese patients: a comparison. The arginine + GHRH test has been established as an alternative to the insulin tolerance test (ITT) for the diagnosis of adult GH deficiency (AGHD). However, the glucagon, arginine, and GH releasing peptide-2 (GHRP-2) test are recommended as alternatives in Japan. The objective of this study was to evaluate the arginine and GHRP-2 tests as alternatives to the ITT for the diagnosis of AGHD in a Japanese population. Three stimulation tests (ITT, arginine test, and GHRP-2 test) were conducted in 71 pre-operative adult patients with pituitary tumors (age, 18-65 years). The peak GH responses to each test were examined. The peak GH responses were significantly lower with the ARG test (median 4.43 μg/L) (p < 0.0001) than with the ITT (median 9.38 μg/L), and the peak GH responses with the GHRP-2 test (median 28.88 μg/L) were higher (p < 0.0001). However, among the AGHD patients, there was no significant difference between the peak GH responses to the ARG test and the ITT. The sensitivities and specificities of the ARG / GHRP-2 tests compared to the ITT for the diagnosis of severe AGHD (peak GH responses to ITT ≤ 1.8 μg/L) were 93.8% / 81.3% and 85.5% / 94.5%, respectively. The arginine and GHRP-2 stimulation tests are acceptable alternatives to the ITT for the diagnosis of AGHD in Japanese patients. The method and criterion for the diagnosis of AGHD should be reconsidered and adjusted to each population. 23559222 Norepinephrine and impulsivity: effects of acute yohimbine. RATIONALE: Rapid-response impulsivity, characterized by inability to withhold response to a stimulus until it is adequately appraised, is associated with risky behavior and may be increased in a state-dependent manner by norepinephrine. OBJECTIVE: We assessed effects of yohimbine, which increases norepinephrine release by blocking alpha-2 noradrenergic receptors, on plasma catecholamine metabolites, blood pressure, subjective symptoms, and laboratory-measured rapid-response impulsivity. METHODS: Subjects were 23 healthy controls recruited from the community, with normal physical examination and ECG, and negative history for hypertension, cardiovascular illness, and axis I or II disorder. Blood pressure, pulse, and behavioral measures were obtained before and periodically after 0.4 mg/kg oral yohimbine or placebo in a randomized, counterbalanced design. Metabolites of norepinephrine [3-methoxy-4-hydroxyphenylglycol (MHPG) and vanillylmandelic acid (VMA)] and dopamine [homovanillic acid (HVA)] were measured by high-pressure liquid chromatography with electrochemical detection. Rapid-response impulsivity was measured by commission errors and reaction times on the immediate memory task (IMT), a continuous performance test designed to measure impulsivity and attention. RESULTS: Yohimbine increased plasma MHPG and VMA but not HVA. Yohimbine increased systolic and diastolic blood pressure and pulse rate. On the IMT, yohimbine increased impulsive errors and impulsive response bias and accelerated reaction times. Yohimbine-associated increase in plasma MHPG correlated with increased impulsive response rates. Time courses varied; effects on blood pressure generally preceded those on metabolites and test performance. CONCLUSIONS: These effects are consistent with increased rapid-response impulsivity after pharmacological noradrenergic stimulation in healthy controls. Labile noradrenergic responses, or increased sensitivity to norepinephrine, may increase risk for impulsive behavior. 23466230 Design, synthesis and antithrombotic evaluation of novel dabigatran prodrugs containing methyl ferulate. A novel series of prodrugs containing dabigatran and methyl (E)-3-(4-hydroxy-2-methoxyphenyl)propenoate (methyl ferulate) were synthesized. All of them reveal the effect of thrombin-induced anti-platelet aggregation in vitro. In addition, in vivo experiment shows that one of the target compounds, X-2 (ED50=3.7 ± 1.0 μmol/kg) possesses a more potent activity for inhibiting venous thrombosis than that of dabigatran etexilate (ED50=7.8 ± 1.5 μmol/kg). 23450304 Droplet-based lipid bilayer system integrated with microfluidic channels for solution exchange. This paper proposes a solution exchange of a droplet-based lipid bilayer system, in which the inner solution of a droplet is replaced for the purpose of efficient ion channel analyses. In our previous report, we successfully recorded the channel conductance of alpha-hemolysin in a bilayer lipid membrane using a droplet contact method that can create a spontaneous lipid bilayer at the interface of contacting droplets; this method is widely used as highly efficient method for preparing planar lipid membranes. When only pipetting droplets of the solution, this method is highly efficient for preparing lipid membranes. However, the drawback of droplet-based systems is their inability to exchange the solution within the droplets. To study the effect of inhibitors and promoters of ion channels in drug discovery, it would be beneficial to conduct a solution exchange of droplets to introduce membrane proteins and to apply or wash-out the chemicals. In this study, we propose a droplet contact method that allows for the solution exchange of droplets via microfluidic channels. We experimentally and numerically investigated the bilayer stability with respect to exchanging flow rates, and then demonstrated a binding assay of an alpha-hemolysin using one of its blockers. The solution exchange in this system was conducted in less than 20 s without rupturing the membrane. We believe that the proposed system will enhance the efficiency of ion channel analyses. 23412112 Peer influences on drug self-administration: an econometric analysis in socially housed rats. Social-learning theories of substance use propose that members of peer groups influence the drug use of other members by selectively modeling, reinforcing, and punishing either abstinence-related or drug-related behaviors. The objective of the present study was to examine the social influences on cocaine self-administration in isolated and socially housed rats, under conditions where the socially housed rats were tested simultaneously with their partner in the same chamber. To this end, male rats were obtained at weaning and housed in isolated or pair-housed conditions for 6 weeks. Rats were then implanted with intravenous catheters and cocaine self-administration was examined in custom-built operant conditioning chambers that allowed two rats to be tested simultaneously. For some socially housed subjects, both rats had simultaneous access to cocaine; for others, only one rat of the pair had access to cocaine. An econometric analysis was applied to the data, and the reinforcing strength of cocaine was measured by examining consumption (i.e. quantity demanded) and elasticity of demand as a function of price, which was manipulated by varying the dose and ratio requirements on a fixed ratio schedule of reinforcement. Cocaine consumption decreased as a function of price in all groups. Elasticity of demand did not vary across groups, but consumption was significantly lower in socially housed rats paired with a rat without access to cocaine. These data suggest that the presence of an abstaining peer decreases the reinforcing strength of cocaine, thus supporting the development of social interventions in drug abuse prevention and treatment programs. 23643747 Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1. The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by haloperidol, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders. Administration of haloperidol increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which express dopamine D2 receptors (D2Rs). This effect was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1). We also found that the effect of haloperidol on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1). In line with this observation, incubation of striatal slices with okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation. These results show that haloperidol promotes mTORC1- and S6K1-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of PP-1. 23403012 Production of dosage forms for oral drug delivery by laminar extrusion of wet masses. Laminar extrusion of wet masses was studied as a novel technology for the production of dosage forms for oral drug delivery. Extrusion was carried out with a ram extruder. Formulations contained either microcrystalline cellulose (MCC) or dicalcium phosphate (DCP) as diluent, hydroxypropyl methylcellulose (HPMC), lactose, and water. Extrudates were characterized for their tensile strength, Young's modulus of elasticity, water absorption, gel forming capacity, and release of two model drugs, coumarin (COU) and propranolol hydrochloride (PRO). Cohesive extrudates could be produced with both filling materials (MCC and DCP) when HPMC was included as a binder at low amounts (3.3-4.5% w/w dry weight). Employing more HPMC, the elasticity of the wet masses increased which resulted in distinct surface defects. For MCC, the maximum HPMC amount that could be included in the formulations (15% w/w dry weight) did not affect the mechanical properties or decrease the drug release significantly. For DCP extrudates, the maximally effective HPMC amount was 30% (w/w dry weight) with influence on both the mechanical properties and drug release. This study suggests that laminar extrusion of wet masses is a feasible technique for the production of dosage forms for oral drug delivery. 23364886 Heracleifolinosides A-F, new triterpene glycosides from Cimicifuga heracleifolia, and their inhibitory activities against hypoxia and reoxygenation. Six new 9,19-cycloartane triterpene glycosides, heracleifolinosides A-F (1-6), and one new chromone, norkhelloside (7), were isolated from the rhizome of Cimicifuga heracleifolia, together with 15 known compounds (8-22). The structures of the new compounds were elucidated by means of spectroscopic methods including 2D NMR and mass spectrometry. The extracts of C. heracleifolia and all the isolated compounds were tested for activities against hypoxia and reoxygenation injury in human umbilical vein endothelial cells. Heracleifolinoside B (2) is effectively resistant to hypoxia and reoxygenation-induced human umbilical vein endothelial cell injury, with cell viabilities of 61.95 ± 2.04 %, 77.04 ± 4.44 %, and 83.65 ± 3.29 % at concentrations of 1, 10, and 100 µM, respectively. 23497892 Effect of pH on phosphorylation of potato protein isolate. Potato protein isolate (PPI) was phosphorylated with sodium trimetaphosphate (STMP) at ambient temperature and various reaction pH (5.2, 6.2, 8.0 and 10.5) to improve the functional properties without impairing the nutritional availability. Changes in chemical composition (total and coagulable protein content, ash and minerals content and amino acid composition), functional properties (protein solubility index, emulsifying activity and foaming capacity, water and oil absorption capacity) and phosphorus were determined. The chemical composition and functional properties of phosphorylated potato protein isolate (PP-PPI) were significantly different (p<0.05). The PP-PPI at pH 5.2 was characterised by the highest content of all amino acids, whereas, PP-PPI under alkaline conditions (pH 10.5) caused decrease in these compounds. PP-PPI at pH 8.0 had the highest oil absorption capacity, emulsion activity and foam capacity, whereas, PP-PPI at pH 10.5 had the highest WAC. 23123664 Elevation of cysteine consumption in tamoxifen-resistant MCF-7 cells. Tamoxifen (TAM) resistance is a main cause of therapeutic failure in breast cancers. Although methionine dependency is a phenotypic characteristic of tumor cells, the role of sulfur amino acid metabolism in chemotherapy resistance remains to be elucidated. This study compared metabolite profiles of sulfur amino acid metabolism from methionine to taurine or glutathione (GSH) between normal MCF-7 and TAM-resistant MCF-7 (TAMR-MCF-7) cells. TAMR-MCF-7 cells showed elevated levels and activities of enzymes involved in both transsulfuration from methionine to cysteine and metabolism of cysteine to GSH and taurine. Cysteine concentrations in TAMR-MCF-7 cells and medium conditioned by cell culture for 42h were markedly decreased, while GSH, hypotaurine, and taurine concentrations in the medium were increased. These results show that TAMR-MCF-7 cells display enhanced cysteine utilization. The addition of propargylglycine, a specific cystathionine γ-lyase inhibitor, and buthionine sulfoximine, a specific γ-glutamylcysteine ligase inhibitor, to TAMR-MCF-7 cells, but not to MCF-7 cells, resulted in cytotoxicity after sulfur amino acid deprivation. These results suggest that cell viability of TAMR-MCF-7 cells is affected by inhibition of sulfur amino acid metabolism, particularly cysteine synthesis from homocysteine and GSH synthesis from cysteine. Additionally, the S-adenosylmethionine/S-adenosylhomocysteine ratio, an index of transmethylation potential, in TAMR-MCF-7 cells increased to ~3.6-fold relative to that in MCF-7 cells, a finding that may result from upregulation of methionine adenosyltransferase IIa and S-adenosylhomocysteine hydrolase. In conclusion, this study suggests that TAMR-MCF-7 cells display enhanced cysteine utilization for synthesis of GSH and taurine, and are sensitive to inhibition of cysteine metabolism. 23585551 De-repression of FOXO3a death axis by microRNA-132 and -212 causes neuronal apoptosis in Alzheimer's disease. Alzheimer's disease (AD) is a multifactorial and fatal neurodegenerative disorder for which the mechanisms leading to profound neuronal loss are incompletely recognized. MicroRNAs (miRNAs) are recently discovered small regulatory RNA molecules that repress gene expression and are increasingly acknowledged as prime regulators involved in human brain pathologies. Here we identified two homologous miRNAs, miR-132 and miR-212, downregulated in temporal cortical areas and CA1 hippocampal neurons of human AD brains. Sequence-specific inhibition of miR-132 and miR-212 induces apoptosis in cultured primary neurons, whereas their overexpression is neuroprotective against oxidative stress. Using primary neurons and PC12 cells, we demonstrate that miR-132/212 controls cell survival by direct regulation of PTEN, FOXO3a and P300, which are all key elements of AKT signaling pathway. Silencing of these three target genes by RNAi abrogates apoptosis caused by the miR-132/212 inhibition. We further demonstrate that mRNA and protein levels of PTEN, FOXO3a, P300 and most of the direct pro-apoptotic transcriptional targets of FOXO3a are significantly elevated in human AD brains. These results indicate that the miR-132/miR-212/PTEN/FOXO3a signaling pathway contributes to AD neurodegeneration. 23122072 An improved mass spectrometric method for identification and quantification of phenolic compounds in apple fruits. Thirty-nine phenolic compounds were analysed using ultra high performance liquid chromatography (UHPLC) coupled with diode array and accurate mass spectrometry detection using electrospray ionisation (DAD/ESI-am-MS). Instrumental parameters such as scan speed, resolution, and mass accuracy were optimised to establish accurate mass measurements. The method was fully validated in terms of model deviation (r(2)>0.9990), range (typically 10-3500 ngg(-1)), intra/inter-day precision (<6% and <8%, respectively) and accuracy (typically 100 ± 10%). The mass accuracy of each selected phenolic compound was below 1.5 ppm. The results confirmed that the UHPLC-DAD/ESI-am-MS method developed here was convenient and reliable for the determination of phenolic compounds in apple extracts. 23369048 Synthesis and characterization of a matrix-metalloproteinase responsive silk-elastinlike protein polymer. Silk-elastinlike protein polymers (SELPs) are recombinant polymers consisting of tandem repeats of silk (GAGAGS) and elastin (GVGVP) units. By modification of the length and composition of these repeats, the properties of SELP hydrogels can be controlled for specific applications including nucleic acid and virus delivery and tissue engineering. Here, the structure of SELPs is further modified to include a sequence that is sensitive to matrix-metalloproteinases (MMPs). MMPs are a ubiquitous family of extracellular matrix-modifying enzymes that are commonly associated with numerous vital processes. Increased levels of MMPs are found at high levels locally in many types of solid tumors. By modifying the SELP backbone with MMP-sensitive peptide sequences, a hydrogel that is degradable by MMPs was produced. The MMP-sensitivity of the polymer was examined by incubation with MMP-2 and MMP-9, which yielded complete cleavage of all full-length polymers by 36 hours and 48 hours, respectively, with no observable effect on unmodified SELP. Hydrogel sensitivity was tested by exposure to MMP-2 or MMP-9 for 2 weeks, during which samples were taken to analyze protein loss from the hydrogel and release of 100 nm fluorescent beads. Following the incubation period, hydrogels were tested in mechanical compression to examine the loss of hydrogel stiffness due to degradation. It was found that MMP-2 and MMP-9 caused 63% and 44% increased protein loss and 65% and 95% increased release from MMP-sensitive hydrogels, while the compressive modulus decreased by 41% and 29%. These results suggest the potential of MMP-responsive SELPs for localized delivery of bioactive agents where MMPs are overexpressed. 23411259 A water-alcohol extract of Citrus grandis whole fruits has beneficial metabolic effects in the obese Zucker rats fed with high fat/high cholesterol diet. Epidemiological studies suggest that citrus fruits and compounds such as flavonoids, limonoids and pectins have health promoting effects. Our aim was to study the effects of Citrus grandis (L.) Osbeck var. tomentosa hort. fruit extract on the energy metabolism. A whole fruit powder from dry water and alcohol extracts of C. grandis containing 19% naringin flavonoid was prepared. The effects of the citrus extract were followed in the obese Zucker rats fed with the HFD. The circulatory levels of GLP-1 decreased significantly by the extract in comparison to the HFD group, whereas the decreased ghrelin levels were reversed. The levels of PYY were decreased in all HFD groups. The leptin amounts decreased but not significantly whereas insulin and amylin were unchanged. The cholesterol and glucose levels were somewhat but not systematically improved in the HFD fed rats. Further studies are needed to identify the active compounds and their mechanisms. 23212912 The V499G/Y501H mutation impairs fast motor kinetics of prestin and has significance for defining functional independence of individual prestin subunits. Outer hair cells (OHCs) are a mammalian innovation for mechanically amplifying sound energy to overcome the viscous damping of the cochlear partition. Although the voltage-dependent OHC membrane motor, prestin, has been demonstrated to be essential for mammalian cochlear amplification, the molecular mechanism by which prestin converts electrical energy into mechanical displacement/force remains elusive. Identifying mutations that alter the motor function of prestin provides vital information for unraveling the energy transduction mechanism of prestin. We show that the V499G/Y501H mutation does not deprive prestin of its voltage-induced motor activity, but it does significantly impair the fast motor kinetics and voltage operating range. Furthermore, mutagenesis studies suggest that Val-499 is the primary site responsible for these changes. We also show that V499G/Y501H prestin forms heteromers with wild-type prestin and that the fast motor kinetics of wild-type prestin is not affected by heteromer formation with V499G/Y501H prestin. These results suggest that prestin subunits are individually functional within a given multimer. 23267767 Development of hypoxia-inducible factor (HIF)-1α inhibitors: effect of ortho-carborane substituents on HIF transcriptional activity under hypoxia. A series of substituted ortho-carboranylphenoxyacetanilides were synthesized and evaluated for their ability to inhibit hypoxia-induced HIF-1 transcriptional activity using a cell-based reporter assay in HeLa cells expressing the HRE-dependent firefly luciferase reporter construct (HRE-Luc) and constitutively expressing CMV-driven Renilla luciferase reporter, and their ability to inhibit cell growth (GI(50)) using the MTT assay. Among the compounds synthesized, 1g and 1l showed significant inhibition of hypoxia-induced HIF-1 transcriptional activity (IC(50): 1.9 ± 0.4 and 1.4 ± 0.2 μM, respectively). Both compounds suppressed HIF-1α accumulation in a concentration-dependent manner. The porcine heart malate dehydrogenase (MDH) refolding assay revealed that compound 1l inhibited human Hsp60 chaperone activity (IC(50): 6.80 ± 0.25 μM) and this inhibition activity was higher than that of ETB (IC(50): 10.9 ± 0.63 μM). 22707396 Celiac disease in subjects with type 1 diabetes mellitus: a prevalence study in western Sicily (Italy). The association between celiac disease and type 1 diabetes mellitus is well known. Up to now, celiac disease prevalence in children and adults with type 1 diabetes in Sicily has not been reported. The aim of this study was to assess the prevalence of celiac disease in patients with type 1 diabetes mellitus who come from a defined geographical area in western Sicily and to investigate the clinical features of these subjects. The records of 492 consecutive patients with type 1 diabetes mellitus referred in a period of 5 years were analyzed. During the period of the survey, out of 492 patients with type 1 diabetes, 22 (4.5 %) had a previous diagnosis of celiac disease. There were 14 females and 8 males; these patients showed a mean age of 13 years at diabetes onset. Diagnosis of celiac disease was often simultaneous or subsequent to that of diabetes. Autoimmune thyroiditis was coexisting in 8 patients (36 %). Our data confirm, in a Sicilian population, the not unusual association between celiac disease and type 1 diabetes, although prevalence rate is lower than in others Italian studies. Autoimmune thyroiditis is present with high prevalence in these patients. Celiac disease diagnosis often followed onset of type 1 diabetes, particularly in female subjects with a young age at diabetes onset; therefore, in these subjects, an active search for the presence of celiac disease is warranted for many years after appearance of diabetes. 23210786 Differential action of phytochemicals on platelet apoptosis: a biological overview. Platelets are anuclear blood cells originating from bone megakaryocytes. Despite being anuclear, their number is maintained by apoptosis, a process of programmed cell death. The rate of apoptotic death of platelets is accelerated by oxidative and shear stress, ex vivo storage (blood banking conditions) and certain pathophysiological disorders. These factors initiate apoptotic events through the mitochondria- mediated intrinsic pathway. Besides, apoptotic platelets also release phosphatidylserine-positive membrane fractions called microparticles, which cause fibrin deposition and thrombus formation, and are involved in the promulgation of a host of disease conditions including cardiovascular diseases. In this context, several phytochemicals have been reported to be cardioprotective and work by inhibiting platelet aggregation or by dissolving the fibrin clots. Besides, ample reports focus on the positive effects of phytochemicals on normal physiology of platelets, but do not focus on their adverse effects on platelets. Moreover, platelets are reported to be extremely sensitive to therapeutic components in the blood. For example, resveratrol and thymoquinone are hitherto known compounds to possess proapoptotic effects on platelets. In contrast, cinnamtannin B1 and crocin exhibit antiapoptotic effects. Thus, the current review aims to elucidate the underlying mechanisms through which the phytochemicals mediate their effects on platelet apoptosis. Moreover, the need for scrutiny of therapeutic compounds for their effects on platelet functions before including them in treatment regimen is also being emphasized. 23619284 Tandutinib (MLN518/CT53518) targeted to stem-like cells by inhibiting the function of ATP-binding cassette subfamily G member 2. Tandutinib is a novel inhibitor of tyrosine kinases FLT3, PDGFR and KIT. Our study was to explore the capability of tandutinib to reverse ABC transporter-mediated multidrug resistance. Tandutinib reversed ABCG2-mediated drug resistance in ABCG2-482-R2, ABCG2-482-G2, ABCG2-482-T7 and S1-M1-80 cells and increased the accumulation of doxorubicin, rhodamine 123 and [H(3)] mitoxantrone in ABCG2-overexpressing cells. Importantly, tandutinib selectively sensitized side population cells to mitoxantrone. Taken together, our results advocate the potency of tandutinib as an ABCG2 modulator and stem-like cells targeted agent to increase efficiency of anticancer drugs. 23269496 Challenges of bringing next generation sequencing technologies to clinical molecular diagnostic laboratories. Molecular diagnosis of complex dual genome mitochondrial disorders is a challenge. It requires the identification of deleterious mutations in one of the ~1,500 nuclear genes and the mitochondrial genome. If the molecular defect is in the mitochondrial genome, quantification of degree of mutation load (heteroplasmy) in affected tissues is important. Due to the extreme clinical and genetic heterogeneity, conventional sequence analysis of the candidate genes one-by-one is impractical, if not impossible. The newly developed massively parallel next generation sequencing (NGS) technique, that allows simultaneous sequence analysis of multiple target genes, when appropriately validated with deep coverage and proper quality controls, can be used as an effective comprehensive diagnostic approach in CLIA certified clinical laboratories. 23411318 Dung-shen (Codonopsis pilosula) attenuated the cardiac-impaired insulin-like growth factor II receptor pathway on myocardial cells. Previous studies from our lab showed that increase in AngII in H9c2 cells causes elevated IGFII and IGFIIR through MEK and JNK, leading to rise in intracellular calcium, calcineurin activation by PLC-β3 via Gαq, insertion into mitochondrial membranes of Bad, and apoptosis via caspases 9 and 3. Codonopsis pilosula is traditionally used to lower blood pressure. The purpose of our study is to investigate if C. pilosula attenuates AngII plus Leu(27)-IGFII-induced calcium influx and apoptosis in H9c2 cardiomyoblasts. C. pilosula significantly attenuated AngII induced IGFIIR promoter activity. Leu(27)-IGFII was applied to enhance the AngII effect. C. pilosula also reversed Ca(2+) influx, MOMP and apoptosis increased by AngII plus Leu(27)-IGFII. Molecular markers in IGFIIR apoptotic pathway (IGFIIR, calcineurin, etc.) and IGFIIR-Gαq association were downregulated by C. pilosula. However, p-Bad(Ser136) and Bcl-2 were increased. Therefore, C. pilosula suppresses AngII plus Leu(27)-IGFII-induced IGFII/IGFIIR pathway in myocardial cells. 23352511 New imidazo[1,2-a]pyridines carrying active pharmacophores: synthesis and anticonvulsant studies. Five new series of imidazo[1,2-a]pyridines carrying biologically active pyrazoline (4a-e), cyanopyridone (5a, b), cyanopyridine (6a-f), 2-aminopyrimidine (7a-f) and pyrimidine-2-thione (8a-d) systems were designed and synthesized as prominent anticonvulsant agents. The target compounds were screened for their in vivo anticonvulsant activity following maximal electroshock (MES) and subcutaneous pentylene tetrazole (scPTZ) methods at a small test dose of 10 mg/kg. Further, Rotarod toxicity method was used to study the toxicity profile of selected compounds. Compounds 4b, 5a, 5b, 6a, 7e and 8d possessing 4-fluorophenyl substituent at 2nd position of imidazo[1,2-a]pyridine ring displayed potent anticonvulsant activity without displaying any toxicity. Enhanced activity profile was observed for new compounds in PTZ method over MES method. 23323808 Phase separation induced by Au catalysts in ternary InGaAs nanowires. We report a novel phase separation phenomenon observed in the growth of ternary In(x)Ga(1-x)As nanowires by metalorganic chemical vapor deposition. A spontaneous formation of core-shell nanowires is investigated by cross-sectional transmission electron microscopy, revealing the compositional complexity within the ternary nanowires. It has been found that for In(x)Ga(1-x)As nanowires high precursor flow rates generate ternary In(x)Ga(1-x)As cores with In-rich shells, while low precursor flow rates produce binary GaAs cores with ternary In(x)Ga(1-x)As shells. First-principle calculations combined with thermodynamic considerations suggest that this phenomenon is due to competitive alloying of different group-III elements with Au catalysts, and variations in elemental concentrations of group-III materials in the catalyst under different precursor flow rates. This study shows that precursor flow rates are critical factors for manipulating Au catalysts to produce nanowires of desired composition. 23089045 Developmental consequences of the ColQ/MuSK interactions. CollagenQ (ColQ) is a specific collagen that anchors acetylcholinesterase (AChE) in the synaptic basal lamina of the neuromuscular junction (NMJ). Over 30 mutations in the COLQ gene have been identified that are responsible for a congenital myasthenic syndrome with AChE deficiency, highlighting the importance of this collagen in the physiology of the NMJ. The anchoring of AChE at the synapse requires the interaction of ColQ with MuSK (Muscle-Specific Kinase), a tyrosine kinase expressed on the muscle membrane that is necessary for the formation and the maintenance of the NMJ. MuSK forms with its co-receptor LRP4, a member of the Low-density Related Protein family, a receptor complex for agrin and Wnts, representing the core system from which the postsynaptic domain is built, the growth cone attracted and the presynaptic element instructed for some aspects of its differentiation. Therefore, the discovery that ColQ binds to MuSK prompted us to study a possible regulatory function of ColQ during NMJ development. In this review, after a brief survey on ColQ, we summarize our recent data demonstrating that ColQ, in addition to its anchoring role, exerts signaling functions and controls some aspects of postsynaptic differentiation such as the clustering of acetylcholine receptors. Our results also strengthen the hypothesis that the defects observed in synaptic congenital myasthenic syndromes might be linked, at least in part, to alterations of ColQ signaling functions and not only to AChE deficiency. Finally, we discuss future research directions to understand how ColQ may modulate the action of the other ligands of the MuSK/LRP4 complex and cooperate with them to coordinate the different steps of NMJ formation and maintenance. 23454741 Molecular determinants of drug-receptor binding kinetics. It is increasingly appreciated that the rates at which drugs associate with and dissociate from receptors - the binding kinetics - directly impact drug efficacy and safety. The molecular determinants of drug-receptor binding kinetics remain poorly understood, however, especially when compared with the well-known factors that affect binding affinity. The rational modulation of kinetics during lead optimization thus remains challenging. We review some of the key factors thought to control drug-receptor binding kinetics at the molecular level - molecular size, conformational fluctuations, electrostatic interactions and hydrophobic effects - and discuss several possible approaches for the rational design of drugs with desired binding kinetics. 23159502 Season linked responses to fine and quasi-ultrafine Milan PM in cultured cells. Exposure to urbane airborne particulate matter (PM) is related to the onset and exacerbation of cardiovascular and respiratory diseases. The fine (PM1), and quasi-ultrafine (PM0.4) Milan particles collected during different seasons have been characterised and the biological effects on human epithelial lung A549, monocytes THP-1 cells and their co-culture, evaluated and compared with the results obtained on the PM10 and PM2.5 fractions. Chemical composition and transmission electron microscopy (TEM) analysis of PM0.4 showed that this fraction was very similar to PM1 for biological responses and dimension. All the winter fractions increased within 1h the level of reactive oxygen species (ROS), while only summer PM2.5 had this effect on A549 cells. The phosphorylation of H2AX (γH2AX), a marker of double strand DNA breaks (DSBs), was increased by all the winter fractions on A549 and THP-1 cells while summer PM samples did not induced this effect. PM0.4 and PM1 biological effects are partly similar and related to the season of sampling, with effects on ROS and DNA damage induced only by winter PM fractions. The winter PM damaging effect on DNA correlates with the presence of organic compounds. 23419812 Infected nail plate model made of human hair keratin for evaluating the efficacy of different topical antifungal formulations against Trichophyton rubrum in vitro. A novel model of infected nail plate for testing the efficacy of topical antifungal formulations has been developed. This model utilized keratin film made of human hair keratin as a nail plate model. Subsequent to infection by Trichophyton rubrum, the common causative agent of onychomycosis, keratin films as infected nail plate models were treated with selected topical formulations, that is cream, gel, and nail lacquer. Bovine hoof was compared to keratin film. In contrast to the common antifungal susceptibility test, the antifungal drugs tested were applied as ready-to-use formulations because the vehicle may modify and control the drug action both in vitro and in vivo. Extrapolating the potency of an antifungal drug from an in vitro susceptibility test only would not be representative of the in vivo situation since these drugs are applied as ready-to-use formulations, for example as a nail lacquer. Although terbinafine has been acknowledged to be the most effective antifungal agent against T. rubrum, its antifungal efficacy was improved by its incorporation into an optimal formulation. Different gels proved superior to cream. Therefore, this study is able to discriminate between efficacies of different topical antifungal formulations based on their activities against T. rubrum. 23265515 Arsenic speciation analysis in mono-varietal wines by on-line ionic liquid-based dispersive liquid-liquid microextraction. A highly efficient separation and pre-concentration method for arsenic species determination, based on ionic liquid (IL) dispersive microextraction technique implemented in a flow analysis system, is proposed. Highly selective separation of arsenite species [As(III)] was achieved by chelation with sodium diethyldithiocarbamate (DDTC) followed by dispersion with 40 mg of 1-octyl-3-methylimidazolium hexafluorophosphate ([C(8)mim][PF(6)]) IL. Analyte extraction, retention and separation of IL phase were achieved with a packed microcolumn and As(III) was determined in eluent solution by electrothermal atomic absorption spectrometry (ETAAS). Concentration of As(V) was deduced by the difference between total inorganic arsenic and As(III). Thus, determination of total arsenic was performed by previous degradation of organo-arsenic species, followed by a reduction. Under optimal conditions, As(III) extraction efficiency was 100% and a sensitivity enhancement factor of 46 was obtained with only 4.0 ml of sample The method was successfully applied for arsenic speciation studies in mono-varietal wines. 23619018 Relationships between pharmacokinetics and efficacy of Xie-xin decoction in rats with experimental ulcerative colitis. ETHNOPHARMACOLOGICAL RELEVANCE: Xie-xin decoction (XXD) has been used as a classic formula in China for the treatment of gastrointestinal dysfunction such as ulcerative colitis (UC). However, no potential action mechanisms and active compounds had been systematically investigated. AIM OF THE STUDY: To explore the effectiveness and the material basis of XXD in trinitrobenzene sulfonic acid (TNBS)-induced UC rats. MATERIALS AND METHODS: XXD was administered orally for 8 days at a dosage of 2 or 4g/kg/day. Plasma pharmacokinetic properties and colon tissue concentrations of multiple compounds from XXD were detected. Tissue damage scores, production of interleukin (IL)-10 and myeloperoxidase (MPO), expression of tumor necrosis factor-alpha (TNF-α) and nuclear factor-kappa Bp65 (NF-κBp65) in colon tissues were examined. Canonical correlation analysis was performed to evaluate the relationships between pharmacokinetics and efficacy to elucidate significantly active compounds of XXD. RESULTS: XXD promoted the recovery of colitis and inhibited the colonic inflammation damage in UC rats by reducing the level of MPO and the expression of TNF-α and NF-κBp65, and increasing the production of IL-10 in colon tissues. Efficacy of XXD was positively related with AUC of five plasma compounds (baicalin, berberine, wogonoside, wogonin, and rhein) and concentrations of six colon tissue compounds (coptisine, jatrorrhizine, palmatine, berberine, baicalein and emodin), respectively. CONCLUSIONS: The multiple compounds in plasma and colon tissues from XXD might be the main material basis for therapeutic potentials in UC rats. 23578846 Biodegradable microparticles for strictly regulating the release of neurotrophic factors. A lot of research has been carried out in the last decade to find a cure for neurodegenerative diseases especially Parkinson's disease but to little avail. In this study we have demonstrated the use of poly (lactic acid-co-glycolic acid) (PLGA)/collagen biodegradable microparticles formed using water-in-oil-in-water (W/O/W) double emulsion method, as a neurotrophic factor delivery vehicle. The microparticles were encapsulated with glial cell-derived neurotrophic factor (GDNF) fused with collagen binding peptide (CBP) immobilized to the inner collagen phase. The novelty lies in the strict regulation of release of GDNF-CBP from the microparticles as compared to a burst release from standard microparticles. The microparticles were demonstrated to be non-cytotoxic till 300μg/2×10(5) cells and revealed a maximum release of 250ng GDNF-CBP/mg microparticles in 0.3% collagenase. Differentiation of neural progenitor cells (NPCs) into mature neurons was demonstrated by co-culturing microparticles with cells in a medium containing collagenase which enabled the release of encapsulated GDNF-CBP, signaling the differentiation of NPCs into microtubule-associated protein 2 (MAP2)-expressing neurons. The successful ability of these microparticles to deliver neurotrophic factors and allow differentiation of NPCs into mature neurons provides some scope in its use for the treatment of Parkinson's disease and other neurodegenerative diseases. 23567484 Lyophilization of a triply unsaturated phospholipid: Effects of trace metal contaminants. As liquid liposomal formulations are prone to chemical degradation and aggregation, these formulations often require freeze drying (e.g., lyophilization) to achieve sufficient shelf-life. However, liposomal formulations may undergo oxidation during lyophilization and/or during prolonged storage. The goal of the current study was to characterize the degradation of 1,2-dilinolenoyl-sn-glycero-3-phosphocholine (DLPC) during lyophilization and to also probe the influence of metal contaminants in promoting the observed degradation. Aqueous sugar formulations containing DLPC (0.01mg/ml) were lyophilized, and DLPC degradation was monitored using HPLC/UV and GC/MS methods. The effect of ferrous ion and sucrose concentration, as well as lyophilization stage promoting lipid degradation, was investigated. DLPC degradation increased with higher levels of ferrous ion. After lyophilization, 103.1±1.1%, 66.9±0.8%, and 28.7±0.7% DLPC remained in the sucrose samples spiked with 0.0ppm, 0.2ppm, and 1.0ppm ferrous ion, respectively. Lipid degradation predominantly occurs during the freezing stage of lyophilization. Sugar concentration and buffer ionic strength also influence the extent of lipid degradation, and DLPC loss correlated with degradation product formation. We conclude that DLPC oxidation during the freezing stage of lyophilization dramatically compromises the stability of lipid-based formulations. In addition, we demonstrate that metal contaminants in sugars can become highly active when lyophilized in the presence of a reducing agent. 23403014 Stabilisation of amorphous drugs under high humidity using pharmaceutical thin films. In this study, the stabilization effects of three polymers on four model drugs (felodipine, fenofibrate, carbamazepine, and celecoxib) under saturated humidity were investigated. Three different types of thin films (solid dispersions, drug films with a polymer film coating and drug films laid on top of polymer coated surfaces) were prepared and compared with films containing the drug alone. ATR-FTIR spectroscopy, polarised light microscopy (PLM), scanning electron microscopy (SEM) and nano-thermal analysis (nano-TA) were performed on the model systems after storage under saturated humidity. The recrystallisation tendency of the drug in the drug containing thin films was found to be strongly related to the intrinsic crystallization tendency of the drug film alone and the strength of drug-polymer interactions. Additionally, under high humidity, the glass transition temperature of the polymer is no longer an indicator of its drug stabilization capability. Instead, it is the hygroscobicity of the polymer that appears to be the most important parameter. Amongst the polymers tested in this study, EUDRAGIT E PO was found to have the greatest inhibitory effect on crystallization, whilst PVP K30 was found to have the least protective effect; presumably because of its hygroscopic nature. 23581964 Enhanced Optical Second-Harmonic Generation from the Current-Biased Graphene/SiO2/Si(001) Structure. We find that optical second-harmonic generation (SHG) in reflection from a chemical-vapor-deposition graphene monolayer transferred onto a SiO2/Si(001) substrate is enhanced about 3 times by the flow of direct current electric current in graphene. Measurements of rotational-anisotropy SHG revealed that the current-induced SHG from the current-biased graphene/SiO2/Si(001) structure undergoes a phase inversion as the measurement location on graphene is shifted laterally along the current flow direction. The enhancement is due to current-associated charge trapping at the graphene/SiO2 interface, which introduces a vertical electric field across the SiO2/Si interface that produces electric field-induced SHG. The phase inversion is due to the positive-to-negative polarity switch in the current direction of the trapped charges at the current-biased graphene/SiO2 interface. 23187065 An ultrasonic-accelerated oxidation method for determining the oxidative stability of biodiesel. Biodiesel is considered an alternative energy because it is produced from fats and vegetable oils by means of transesterification. Furthermore, it consists of fatty acid alkyl esters (FAAS) which have a great influence on biodiesel fuel properties and in the storage lifetime of biodiesel itself. The biodiesel storage stability is directly related to the oxidative stability parameter (Induction Time - IT) which is determined by means of the Rancimat® method. This method uses condutimetric monitoring and induces the degradation of FAAS by heating the sample at a constant temperature. The European Committee for Standardization established a standard (EN 14214) to determine the oxidative stability of biodiesel, which requires it to reach a minimum induction period of 6h as tested by Rancimat® method at 110°C. In this research, we aimed at developing a fast and simple alternative method to determine the induction time (IT) based on the FAAS ultrasonic-accelerated oxidation. The sonodegradation of biodiesel samples was induced by means of an ultrasonic homogenizer fitted with an immersible horn at 480Watts of power and 20 duty cycles. The UV-Vis spectrometry was used to monitor the FAAS sonodegradation by measuring the absorbance at 270nm every 2. Biodiesel samples from different feedstock were studied in this work. In all cases, IT was established as the inflection point of the absorbance versus time curve. The induction time values of all biodiesel samples determined using the proposed method was in accordance with those measured through the Rancimat® reference method by showing a R(2)=0.998. 23111950 Effects of increasing supplementation of magnesium in diets on productive performance and eggshell quality of aged laying hens. Magnesium (Mg) concentrations in diets have been associated with performance and eggshell quality of laying hens, but the results have been inconclusive. In this experiment, the effects of increasing concentrations of dietary Mg on productive performance and eggshell quality of aged laying hens were evaluated. A total of 640 Hy-Line Brown laying hens of 72 weeks of age were randomly allotted to one of four dietary treatments with four replicates per treatment. A commercial-type basal diet containing 1.6 g/kg Mg was prepared, and three additional diets were prepared to contain 2.3, 2.6, or 3.0 g/kg Mg in diets by adding 1.0, 1.5, or 2.0 g of MgO to the basal diet. The diets were fed to hens ad libitum for 5 weeks. Results indicated that Mg concentrations in eggshells were increased (linear, P < 0.01) with increasing concentrations of Mg in diets. Increasing concentrations of Mg in diets decreased (linear and quadratic, P < 0.01) broken and shell-less egg production, but improved (linear, P < 0.05) eggshell strength. Feed intake was decreased (linear, P < 0.05) with the concentrations of Mg in diets, but hen-day egg production, egg weight, feed conversion ratio, and Haugh unit were not affected by increasing concentrations of Mg in diets. Hunter L* and a* values of eggshell were decreased (linear, P < 0.05) as the concentrations of Mg in diets increased. In conclusion, feeding aged laying hens with diets containing increasing concentrations of Mg up to 3.0 g/kg improves eggshell strength, but has no detrimental effects on laying performance. 23603145 Short-term toxicity of hexavalent-chromium to epipsammic diatoms of a microtidal estuary (Río de la Plata): Responses from the individual cell to the community structure. Diatoms are an integral and often dominant component of the benthic microalgal assemblage in estuarine and shallow coastal environments. Different toxic substances discharged into these ecosystems persist in the water, sediments, and biota for long periods. Among these pernicious agents, the toxicity in diatoms by metal is linked to different steps in the transmembrane and internal movements of the toxicant, causing perturbations in the normal structural and functional cellular components. These changes constitute an early, nontaxonomic warning signal that could potentially serve as an indicator of this type of pollution. The aim of this work was to study the environment-reflecting short-term responses at different levels of organization of epipsammic diatoms from the Río de la Plata estuary, Argentina that had been exposed to hexavalent chromium within experimental microcosms. To this end we monitored: (i) changes in the proportion of the diatoms in relation to other algal groups at the biofilm community level; (ii) shifts in species composition at the diatom-assemblage level; (iii) projected changes in the densities of the most representative species at the population level through comparison of relative growth rates and generation times; and (iv) the cytological changes at the cellular and subcellular levels as indicated by the appearance of teratological effects on individuals and nuclear alterations. The epipsammic biofilms were exposed for 96h to chromium at a concentration similar to that measured in highly impacted sites along the coast (80μgL(-1)). Chromium pollution, at this concentration and short exposure time did not affect the algal biomass and density of these mature biofilms. The biofilm composition, however, did change, as reflected in a decline in cyanophytes and an increment in the proportions of diatoms and chlorophytes; with Hippodonta hungarica, Navicula novaesiberica, Nitzschia palea, and Sellaphora pupula being the most frequent and abundant species. The most notable shifts related to chromium exposure were a decrease in the relative abundance of H. hungarica and a significant increase in the proportion of N. palea. Moreover, the species analyzed in the treatment microcosms showed higher growth rates than in the controls - N. palea grew faster, while H. hungarica replicated more slowly. The total nuclear abnormalities - as recorded in Fallacia pygmaea and N. novaesiberica - were significantly higher in the treatment microcosms; whereas in N. palea, the dominant species in treatment microcosms, neither nuclear alterations nor abnormal frustules were observed. 23410167 Multitarget drugs of plants origin acting on Alzheimer's disease. The etiopathology of Alzheimer's disease (AD) is extremely complex and heterogeneous, often associated with comorbidities. As a result it may be unlikely that AD may be mitigated by drug acting on a single specific target. The current tendency in drug design and discovery in AD is the rational design or "serendipitous" discovery of new drug entities challenging multiple targets. Since two of the presently approved drugs for AD are based on natural products (galantamine and the physostigmine-derivative rivastigmine), many plants are now under investigation as a potential source of new drugs. Multifunctional drugs often have their origin in natural sources. This review is limited to plant chemicals having different targets with actual (galantamine) or promising (drugs from Crocus sativus, Ginkgo biloba, Salvia species, and Huperzia serrata) clinical evidence in people with dementia or AD. 23561115 Influence of triterpenoids present in apple peel on inflammatory gene expression associated with inflammatory bowel disease (IBD). Various ursanic, oleanic and lupanic pentacyclic triterpenoids found in apple peel were studied for anti-inflammatory effects in vitro using T84 colon carcinoma cells. After pretreatment with single triterpenoids, cells were stimulated with pro-inflammatory cytokines (TNF-α, INF-γ, IL-1β). Regulation of mRNA expression was analysed for three specific inflammation-associated marker genes (TNF-α, IL-8, IP-10) using qRT-PCR. Furthermore, the effects of ursolic acid (UA) and oleanolic acid (OA) on the synthesis of certain pro-inflammatory proteins were examined. IP-10 expression was inhibited in a dose-dependent manner by all the tested compounds at concentrations ⩾25μM. The mRNA expression of TNF-α was slightly affected and the IL-8 level was increased. At the protein level, UA and OA (25μM) reduced the synthesis of IP-10; sICAM-1, IL-23 and GROα were slightly repressed. The TNF-α level was not modulated, whereas induction of IL-8 was increased. UA also enhanced the synthesis of IL-1ra, while OA suppressed the level of I-TAC. The present study confirms that triterpenoids present in apple peel and β-damascone may be implicated in the anti-inflammatory properties of apple constituents, suggesting that these substances might be helpful in the treatment of IBD as nutrient supplements. 21933113 Models to predict intestinal absorption of therapeutic peptides and proteins. Prediction of human intestinal absorption is a major goal in the design, optimization, and selection of drugs intended for oral delivery, in particular proteins, which possess intrinsic poor transport across intestinal epithelium. There are various techniques currently employed to evaluate the extension of protein absorption in the different phases of drug discovery and development. Screening protocols to evaluate protein absorption include a range of preclinical methodologies like in silico, in vitro, in situ, ex vivo and in vivo. It is the careful and critical use of these techniques that can help to identify drug candidates, which most probably will be well absorbed from the human intestinal tract. It is well recognized that the human intestinal permeability cannot be accurately predicted based on a single preclinical method. However, the present social and scientific concerns about the animal well care as well as the pharmaceutical industries need for rapid, cheap and reliable models predicting bioavailability give reasons for using methods providing an appropriate correlation between results of in vivo and in vitro drug absorption. The aim of this review is to describe and compare in silico, in vitro, in situ, ex vivo and in vivo methods used to predict human intestinal absorption, giving a special attention to the intestinal absorption of therapeutic peptides and proteins. 23602997 Evaluation of the suitability of chromatographic systems to predict human skin permeation of neutral compounds. Several chromatographic systems (three systems of high-performance liquid chromatography and two micellar electrokinetic chromatography systems) besides the reference octanol-water partition system are evaluated by a systematic procedure previously proposed in order to know their ability to model human skin permeation. The precision achieved when skin-water permeability coefficients are correlated against chromatographic retention factors is predicted within the framework of the solvation parameter model. It consists in estimating the contribution of error due to the biological and chromatographic data, as well as the error coming from the dissimilarity between the human skin permeation and the chromatographic systems. Both predictions and experimental tests show that all correlations are greatly affected by the considerable uncertainty of the skin permeability data and the error associated to the dissimilarity between the systems. Correlations with much better predictive abilities are achieved when the volume of the solute is used as additional variable, which illustrates the main roles of both lipophilicity and size of the solute to penetrate through the skin. In this way, the considered systems are able to give precise estimations of human skin permeability coefficients. In particular, the HPLC systems with common C18 columns provide the best performances in emulating the permeation of neutral compounds from aqueous solution through the human skin. As a result, a methodology based on easy, fast, and economical HPLC measurements in a common C18 column has been developed. After a validation based on training and test sets, the method has been applied with good results to the estimation of skin permeation of several hormones and pesticides. 23458897 Sub-acute, moderate-dose, but not short-term, low-dose dietary pre-exposure of mice to perfluorooctanoate aggravates concanavalin A-induced hepatitis. Exposure of mice to perfluorooctanoate (PFOA) evokes pronounced hepatomegaly along with significant alterations in both the histological structure and immune status of the liver. The present study was designed to evaluate the effects of this perfluorochemical on immune-mediated liver damage. In this connection, the influence of both sub-acute (10 days), moderate-dose (0.002% w/w=3±0.7mg/kg body weight/day) and short-term (28 days), low-dose (0.00005% w/w=70±2μg/kg body weight/day) dietary pretreatment with PFOA on the development of concanavalin A (Con A)-induced liver damage in mice was examined. With sub-acute, moderate, but not short-term, low-dose exposure, PFOA aggravated the acute liver damage caused by Con A, i.e., elevated serum levels of transaminases and led to more pronounced damage of hepatic tissue. This aggravation was associated with significantly enhanced hepatic level of interleukin-6 (IL-6), but unaltered hepatic levels of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and interleukin-4 (IL-4). Moreover, hepatic DNA fragmentation was not changed by sub-acute exposure to the moderate-dose. Our findings imply that exposure to PFOA may sensitize hepatic parenchymal cells to other toxicants that activate the hepatic immune system and thereby aggravate liver injury during acute inflammation. 23111876 The role of adenosine receptors on amitriptyline-induced electrophysiological changes on rat atrium. We investigated the role of adenosine receptors in amitriptyline-induced cardiac action potential (AP) changes in isolated rat atria. In the first group, APs were recorded after cumulative addition of amitriptyline (1 μM, 10 μM and 50 μM). In other groups, each atrium was incubated with selective adenosine A(1) antagonist (8-cyclopentyl-1,3-dipropylxanthine (DPCPX), 10(-4) M) or selective adenosine A(2a) receptor antagonist (8-(3-chlorostyryl) caffeine, 10(-5) M) before amitriptyline administration. Resting membrane potential, AP amplitude (APA), AP duration at 50% and 80% of repolarization (APD(50) and APD(80), respectively), and the maximum rise and decay slopes of AP were recorded. Amitriptyline (50 μM) prolonged the APD(50) and APD(80) (p < 0.001) and the maximum rise slope of AP was reduced by amitriptyline (p < 0.0001). Amitriptyline reduced maximum decay slope of AP only at 50 μM (p < 0.01). DPCPX significantly decreased the 50-μM amitriptyline-induced APD(50) and APD(80) prolongation (p < 0.001). DPCPX significantly prevented the effects of amitriptyline (1 μM and 50 μM) on maximum rise slope of AP (p < 0.05). DPCPX significantly prevented the amitriptyline-induced (50 μM) reduction in maximum decay slope of AP (p < 0.001). The selective adenosine A(1) receptor antagonist prevented the electrophysiological effects of amitriptyline on atrial AP. A(1) receptor stimulation may be responsible for the cardiovascular toxic effects produced by amitriptyline. 22982479 Antidepressant-like properties of three new α2-adrenoceptor antagonists. Evidence suggests that depression is associated with an increase in the high-affinity conformation of the α2-adrenoceptors in human brain. Such enhanced α2-adrenoceptor activity could explain the deficit in central noradrenergic transmission described in the aetiology of depression. Thus, administration of α2-adrenoceptor antagonists augments noradrenaline levels and provides an effective therapeutic approach for the treatment of depressive disorders. In previous studies, we have characterized three new synthesized guanidine and 2-aminoimidazoline aromatic derivatives (8b, 17b and 20b) as α2-adrenoceptor antagonists that are able to increase extracellular concentration of noradrenaline in rat brain. The purpose of the present study was to evaluate the in vivo antidepressant-like properties of these three new α2-adrenoceptor antagonists. For that aim, compounds were tested on the tail suspension test (TST) and forced swim test (FST), two classically widely-used behavioural paradigms for the evaluation of antidepressant-like activity. Compound 8b significantly reduced the immobility time at 10, 20 and 40 mg/kg doses in both TST and FST. Compound 17b reduced the immobility time at 40 mg/kg in both TST and FST. Compound 20b showed a significant decrease in the immobility time at 20 mg/kg in the TST. As drugs of reference, fluoxetine induced a significant antidepressant-like effect in both TST and FST, while mirtazapine induced a significant antidepressant-like effect only in the FST. Additionally, none of the tested compounds increased locomotor activity or displayed anxiolytic-like properties. These results suggest that these new synthesized α2-adrenoceptor antagonists may be useful as potential antidepressant drugs. 23394134 One-pot, exchange-free, room-temperature synthesis of sub-10 nm aqueous, noninteracting, and stable zwitterated iron oxide nanoparticles. Stable aqueous dispersions of superparamagnetic iron oxide nanoparticles were synthesized in one step in the presence of a zwitterionic siloxane as the stabilizing/capping/solubilizing ligand. The hydrodynamic diameter of the particles was tuned by controlling the concentration of zwitterion siloxane, which ultimately yielded monodisperse nanoparticles small enough for renal filtration (<6 nm diameter). The zwitterated nanoparticles were readily dispersed and stable in aqueous media in the pH range 6-9 but exhibited lower magnetization values than nonzwitterated materials due to amorphous content and spin canting, typical for particles of such size. Turbidimetry and light scattering studies revealed no interaction between the particles and proteins, suggesting the materials will circulate well in vivo. 23427825 2-Arylpyrazolo[4,3-d]pyrimidin-7-amino derivatives as new potent and selective human A3 Adenosine receptor antagonists. Molecular modeling studies and pharmacological evaluation. On the basis of our previously reported 2-arylpyrazolo[4,3-d]pyrimidin-7-ones, a set of 2-arylpyrazolo[4,3-d]pyrimidin-7-amines were designed as new human (h) A3 adenosine receptor (AR) antagonists. Lipophilic groups with different steric bulk were introduced at the 5-position of the bicyclic scaffold (R5 = Me, Ph, CH2Ph), and different acyl and carbamoyl moieties (R7) were appended on the 7-amino group, as well as a para-methoxy group inserted on the 2-phenyl ring. The presence of acyl groups turned out to be of paramount importance for an efficient and selective binding at the hA3 AR. In fact, most of the 7-acylamino derivatives showed low nanomolar affinity (Ki = 2.5-45 nM) and high selectivity toward this receptor. A few selected pyrazolo[4,3-d]pyrimidin-7-amides were effective in counteracting oxaliplatin-induced apoptosis in rat astrocyte cell cultures, an in vitro model of neurotoxicity. Through an in silico receptor-driven approach the obtained binding data were rationalized and the molecular bases of the observed hA3 AR affinity and hA3 versus hA2A AR selectivity were explained. 23645630 Antagonistic Basic Helix-Loop-Helix/bZIP Transcription Factors Form Transcriptional Modules That Integrate Light and Reactive Oxygen Species Signaling in Arabidopsis. The critical developmental switch from heterotrophic to autotrophic growth of plants involves light signaling transduction and the production of reactive oxygen species (ROS). ROS function as signaling molecules that regulate multiple developmental processes, including cell death. However, the relationship between light and ROS signaling remains unclear. Here, we identify transcriptional modules composed of the basic helix-loop-helix and bZIP transcription factors PHYTOCHROME-INTERACTING FACTOR1 (PIF1), PIF3, ELONGATED HYPOCOTYL5 (HY5), and HY5 HOMOLOGY (HYH) that bridge light and ROS signaling to regulate cell death and photooxidative response. We show that pif mutants release more singlet oxygen and exhibit more extensive cell death than the wild type during Arabidopsis thaliana deetiolation. Genome-wide expression profiling indicates that PIF1 represses numerous ROS and stress-related genes. Molecular and biochemical analyses reveal that PIF1/PIF3 and HY5/HYH physically interact and coordinately regulate the expression of five ROS-responsive genes by directly binding to their promoters. Furthermore, PIF1/PIF3 and HY5/HYH function antagonistically during the seedling greening process. In addition, phytochromes, cryptochromes, and CONSTITUTIVE PHOTOMORPHOGENIC1 act upstream to regulate ROS signaling. Together, this study reveals that the PIF1/PIF3-HY5/HYH transcriptional modules mediate crosstalk between light and ROS signaling and sheds light on a new mechanism by which plants adapt to the light environments. 22312035 Determination of aflatoxin M1 in milk by high-performance liquid chromatography in Mashhad (north east of Iran). The aim of this study was to evaluate aflatoxin M1 (AFM1) contamination in milk samples in Mashhad in Iran. A total of 60 milk samples were collected from retail stores of five regions in June 2011. The occurrence and concentration range of AFM1 in the samples were investigated by high-performance liquid chromatography method. AFM1 was found in 100% of the examined milk samples by average concentration of 16.16 ng/L and the contamination level ranging between 2 and 64 ng/L. The concentration of AFM1 in all the samples was lower than the Iranian national standard and Food and Drug Administration limit (500 ng/L), and only in one (1.6%) of the samples, the concentration of AFM1 was greater than the maximum tolerance limit (50 ng/L) accepted by European Union and Codex Alimentarius Commission. Statistical evaluation showed no significant difference between the mean concentrations of AFM1 in milk samples taken from different regions (p > 0.05). 23263360 Rational design of the survivin/CDK4 complex by combining protein-protein docking and molecular dynamics simulations. Survivin, the smallest inhibitor of apoptosis protein (IAP), is a valid target for cancer research. It mediates both the apoptosis pathway and the cell cycle and has been proposed to form a complex with the cyclin-dependent kinase protein CDK4. The resulting complex transports CDK4 from the cytosol to the nucleus, where CDK4 participates in cell division. Survivin has been recognized as a node protein that interacts with several partners; disruption of the formed complexes can lead to new anticancer compounds. We propose a rational model of the survivin/CDK4 complex that fulfills the experimental evidence and that can be used for structure-based design of inhibitors modifying its interface recognition. In particular, the suggested complex involves the alpha helical domain of survivin and resembles the mode of binding of survivin in the survivin/borealin X-ray structure. The proposed model has been obtained by combining protein-protein docking, fractal-based shape complementarity, electrostatics studies and extensive molecular dynamics simulations. 23188819 Insulin-degrading enzyme (IDE): a novel heat shock-like protein. Insulin-degrading enzyme (IDE) is a highly conserved zinc metallopeptidase that is ubiquitously distributed in human tissues, and particularly abundant in the brain, liver, and muscles. IDE activity has been historically associated with insulin and β-amyloid catabolism. However, over the last decade, several experimental findings have established that IDE is also involved in a wide variety of physiopathological processes, including ubiquitin clearance and Varicella Zoster Virus infection. In this study, we demonstrate that normal and malignant cells exposed to different stresses markedly up-regulate IDE in a heat shock protein (HSP)-like fashion. Additionally, we focused our attention on tumor cells and report that (i) IDE is overexpressed in vivo in tumors of the central nervous system (CNS); (ii) IDE-silencing inhibits neuroblastoma (SHSY5Y) cell proliferation and triggers cell death; (iii) IDE inhibition is accompanied by a decrease of the poly-ubiquitinated protein content and co-immunoprecipitates with proteasome and ubiquitin in SHSY5Y cells. In this work, we propose a novel role for IDE as a heat shock protein with implications in cell growth regulation and cancer progression, thus opening up an intriguing hypothesis of IDE as an anticancer target. 23444779 Characterization, pharmacokinetics, tissue distribution and antitumor activity of honokiol submicron lipid emulsions in tumor-burdened mice. Honokiol, isolated from the Chinese traditional herb magnolia, is a poorly water-soluble component and has been found to have anti-tumor properties. In the current study, honokiol submicron lipid emulsions (HK-SLEs) were prepared by high pressure homogenization technology. After HK-SLEs were physically characterized, their pharmacokinetics, tissue distribution and antitumor activity after intravenous (i.v.) administration to tumor-burdened mice were examined, using honokiol solution (HK-SOL) as the control. The results showed that the mean particle size, zeta potential, pH value, osmolality, drug loading (DL)% and entrapment efficiency (EE)% of HK-SLEs were 186.6 +/- 1.7 nm, -35.65 +/- 0.67 mV, 7.22 +/- 0.26, 298 +/- 2.3 mOsm/L, 7.1 +/- 0.2% and 95.5 +/- 0.2%, respectively. HK-SLEs were stable for at least 12 months when stored at 4 +/- 2 degrees C. The pharmacokinetic results showed that the drug concentration-time curves of HK-SLEs and HK-SOL could both be described by an open two-compartment model. The half-life of HK-SLEs (t1/2(alpha) = 8.014 min, t1/2(beta) = 35.784 min) was remarkably prolonged compared to that of HK-SOL (t1/2(alpha) = 4.318 min, t1/2(beta) = 15.522 min). HK-SLEs exhibited a greater AUC and reduced plasma clearance. The tissue distribution results indicated that HK-SLEs have better targeting properties to lung and tumor tissues compared with those of HK-SOL. Both HK-SLEs and HK-SOL tended to accumulate in brain tissue. In vivo study showed that HK-SLEs treatment caused significant inhibition of mouse sarcoma S180 tumor growth compared to HK-SOL. These results suggest that HK-SLEs might be an effective parenteral carrier for honokiol delivery in cancer treatment. 23525110 dNTP-dependent conformational transitions in the fingers subdomain of Klentaq1 DNA polymerase: insights into the role of the "nucleotide binding" state. DNA polymerases are responsible for the accurate replication of DNA. Kinetic, single molecule and X-ray studies show that multiple conformational states are important for DNA polymerase fidelity. Using high-precision FRET we show that Klentaq1 (the Klenow fragment of Thermus aquaticus DNA polymerase 1) is in equilibrium between three structurally distinct states. In the absence of nucleotide, the enzyme is mostly open, whereas in the presence of DNA and a correctly base-pairing dNTP it re-equilibrates to a closed state. In the presence of a dNTP alone, with DNA and an incorrect dNTP, or in elevated MgCl2 concentrations, an intermediate state termed ″nucleotide binding″ state predominates. Photon distribution and hidden Markov analysis revealed fast dynamic and slow conformational processes occurring between all three states in a complex energy landscape suggesting a mechanism in which dNTP delivery is mediated by the ″nucleotide binding″ state: After nucleotide binding, correct dNTPs are transported to the closed state while incorrect dNTPs are delivered to the open state. 23234434 Functionalization of monodisperse iron oxide NPs and their properties as magnetically recoverable catalysts. Here we report the functionalization of monodisperse iron oxide nanoparticles (NPs) with commercially available functional acids containing multiple double bonds such as linolenic (LLA) and linoleic (LEA) acids or pyridine moieties such as 6-methylpyridine-2-carboxylic acid, isonicotinic acid, 3-hydroxypicolinic acid, and 6-(1-piperidinyl)pyridine-3-carboxlic acid (PPCA). Both double bonds and pyridine groups can be reacted with noble metal compounds to form catalytically active species in the exterior of magnetic NPs, thus making them promising magnetically recoverable catalysts. We determined that both LLA and LEA stabilize magnetic iron oxide NPs, allowing the formation of π-complexes with bis(acetonitrile)dichloropalladium(II) in the NP shells. In both cases, this leads to the formation of NP aggregates because of interparticle complexation. In the case of pyridine-containing ligands, only PPCA with two N-containing rings is able to provide NP stabilization and functionalization whereas other pyridine-containing acids did now allow sufficient steric stabilization. The interaction of PPCA-based particles with Pd acetate also leads to aggregation because of interparticle interactions, but the aggregates that are formed are much smaller. Nevertheless, the catalytic properties in the selective hydrogenation of dimethylethynylcarbinol (DMEC) to dimethylvinylcarbinol were the best for the catalyst based on LLA, demonstrating that the NP aggregates in all cases are penetrable for DMEC. Easy magnetic separation of this catalyst from the reaction solution makes it promising as a magnetically recoverable catalyst. 23439240 Definition of formulation design space, in vitro bioactivity and in vivo biodistribution for hydrophilic drug loaded PLGA/PEO-PPO-PEO nanoparticles using OFAT experiments. Modified nanoprecipitation method was used for improved incorporation of hydrophilic drug (irinotecan hydrochloride) into the PLGA/PEO-PPO-PEO blended and blended/adsorbed nanoparticles. One factor at a time (OFAT) variation experiments were conducted in order to determine key formulation factors (concentration and volume of drug solution, evaporation rate and PLGA/PEO-PPO-PEO ratio) influencing nanoparticle properties (particle size and size distribution, encapsulation efficiency, drug content, zeta potential, drug dissolution rate, as well as protein binding capacity). The insight into in vivo behavior of prepared nanoparticles and their potential for effective anticancer treatment was gained by performing biodistribution and cell culture studies as part of OFAT experiments. The mean particle size, mainly dependent upon PLGA/PEO-PPO-PEO ratio, was in the range of 112-125nm, with narrow unimodal distribution (PDI∼0.1). Encapsulation efficiency (32-63%) was impacted by evaporation rate and PLGA/PEO-PPO-PEO ratio. Drug content (0.2-1.51%) and controlled release properties were related to the influence of all tested formulation factors. Structural information for the studied nanoparticles was obtained using DSC and FT-IR spectroscopy. Zeta potential values indicated that presence of PEO-PPO-PEO in the formulations shielded the high surface negative charge of PLGA. PEO-PPO-PEO surface coverage of PLGA/PEO-PPO-PEO blended as well as blended/adsorbed nanoparticles depended upon amount of used PEO-PPO-PEO during preparation procedure and was related to the protein resistant characteristics of nanoparticles. Results from in vivo studies evidenced prolonged blood circulation time of the prepared nanoparticles, while cell culture studies indicated higher in vitro bioefficacy compared to free drug. Performed experiments defined possible design space and justified further optimization of formulation using experimental design studies. 23516041 Mitochondrial disease in childhood: nuclear encoded. Primary mitochondrial disorders are clinically and genetically heterogeneous, caused by an alteration(s) in either mitochondrial DNA or nuclear DNA, and affect the respiratory chain's ability to undergo oxidative phosphorylation, leading to decreased production of adenosine triphosphophate and subsequent energy failure. These disorders may present at any age, but children tend to have an acute onset of disease compared with subacute or slowly progressive presentation in adults. Varying organ involvement also contributes to the phenotypic spectrum seen in these disorders. The childhood presentation of primary mitochondrial disease is mainly due to nuclear DNA mutations, with mitochondrial DNA mutations being less frequent in childhood and more prominent in adulthood disease. The clinician should be aware of the pediatric presentation of mitochondrial disease and have an understanding of the myriad of nuclear genes responsible for these disorders. The nuclear genes can be best understood by utilizing a classification system of location and function within the mitochondria. 23229056 Synthesis and antibacterial evaluation of novel 11,4″-disubstituted azithromycin analogs with greatly improved activity against erythromycin-resistant bacteria. A series of novel 11,4″-disubstituted azithromycin analogs were synthesized and evaluated for their antibacterial activity. All the 11,4″-disubstituted analogs exhibited excellent activity (0.03-0.12 μg/ml) against erythromycin-susceptible Streptococcus pneumoniae, and significantly improved activity against three phenotypes of erythromycin-resistant S. pneumoniae compared with erythromycin A, clarithromycin or azithromycin. Among them, compounds 26-28 showed the most potent activity (0.25, 0.03 and 2 μg/ml) against S. pneumoniae expressing the erm gene, the mef gene and the erm and mef genes, respectively. In addition, compound 28 was the most effective (0.03 and 0.12 μg/ml) against erythromycin-susceptible S. pneumoniae and Staphylococcus aureus as well. It is noteworthy that the most active compounds described above possess the same terminal 3,5-dinitrophenyl groups on their C-4″ bisamide side chains. 23529824 Everolimus in Combination with Exemestane: A Review of its Use in the Treatment of Patients with Postmenopausal Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer. Oral everolimus (Afinitor(®)) in combination with exemestane is indicated for the treatment of hormone receptor-positive, human epidermal growth factor receptor (HER) 2-negative advanced breast cancer in postmenopausal women after failure of treatment with letrozole or anastrozole (in the USA) or after recurrence of progression following a nonsteroidal aromatase inhibitor (AI) in women without symptomatic visceral disease (in the EU). Everolimus, a selective inhibitor of mammalian target of rapamycin (mTOR), inhibits the downstream signalling events of the mTOR pathway. This review summarizes the pharmacology of everolimus and reviews its efficacy and tolerability when administered in combination with exemestane in postmenopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer refractory to nonsteroidal AIs. In the well-designed BOLERO-2 study, the addition of everolimus to exemestane was shown to significantly prolong progression-free survival in this patient population. However, treatment-emergent adverse events and treatment discontinuations occurred more frequently with combination therapy than with exemestane alone, suggesting a need for careful benefit/risk assessment prior to initiating therapy. Mature survival data from this study are awaited and additional studies would help to further demonstrate the benefit of combination therapy. Nevertheless, current evidence suggests that everolimus plus exemestane combination therapy may be a useful treatment option in patients with postmenopausal hormone receptor-positive, HER2-negative, advanced breast cancer refractory to nonsteroidal AIs. 23293106 Dietary exposure of mink (Mustela vison) to fish from the upper Hudson River, New York, USA: effects on organ mass and pathology. The authors evaluated effects of feeding ranch mink (Mustela vison) diets containing polychlorinated biphenyl (PCB)-contaminated fish from the upper Hudson River (New York, USA) on adult and offspring organ mass and pathology. Diets contained 2.5 to 20% Hudson River fish, providing 0.72 to 6.1 µg ΣPCBs/g feed (4.8-38 pg toxic equivalents [TEQWHO 2005 ]/g feed). Absolute thyroid and adrenal gland masses were increased in adult females and 31-week-old juveniles, respectively, and absolute liver and heart masses were decreased in six-week-old kits exposed to dietary PCBs. Dietary concentrations of 0.72 µg ΣPCBs/g feed (4.8 pg TEQWHO 2005 /g feed) and greater induced mandibular and maxillary squamous epithelial proliferation in adult animals. The dietary concentration of ΣPCBs predicted to result in 20% incidence of the jaw lesion (EC20) was 2.3 µg ΣPCBs/g feed (15 pg TEQWHO 2005 /g feed), and the hepatic concentration was 2.8 µg ΣPCBs/g liver (89 pg TEQWHO 2005 /g liver). The EC20 values were greater than the dietary and hepatic concentrations predicted to result in a 20% increase in kit mortality (LC20) at six weeks of age (0.34 µg ΣPCBs/g feed or 2.6 pg TEQWHO 2005 /g feed and 0.80 µg ΣPCBs/g liver or 13 pg TEQWHO 2005 /g liver). However, the EC20 values reflect exposure of adults to PCBs for approximately six months, and the LC20 values reflect exposure of offspring from conception onward. 23481645 Synthesis, receptor binding and activity of iso and azakainoids. Two syntheses for the production of an unsubstituted azakainoid are described. The 1,3-dipolar cycloaddition of diazomethane with trans-dibenzyl glutaconate yields a 1-pyrazoline, which may be reduced directly to the pyrazolidine. An unexpected trans-cis isomerization is observed during Hg/Al reduction of the 1-pyrazoline NN bond. Alternatively, when TMS diazomethane is used as the dipole, the resulting 2-pyrazoline obtained after desilylation may be reduced with NaCNBH3 to provide the trans azakainate analog exclusively. The synthesis of an unsubstituted isokainoid via Michael addition is also described. Glutamate receptor binding assays revealed that the azakaniod has a moderate affinity for unspecified glutamate receptors. Membrane depolarization of Aplysia neurons upon application of the azakainoid demonstrates that it is an ionotropic glutamate receptor agonist. 23220037 Doxorubicin decreases paraquat accumulation and toxicity in Caco-2 cells. P-glycoprotein (P-gp) is an efflux pump belonging to the ATP-binding cassette transporter superfamily expressed in several organs. Considering its potential protective effects, the induction of de novo synthesis of P-gp could be used therapeutically in the treatment of intoxications by its substrates. The herbicide paraquat (PQ) is a P-gp substrate responsible for thousands of fatal intoxications worldwide that still lacks an effective antidote. The aim of the present work was to evaluate the effectiveness of such an antidote by testing whether doxorubicin (DOX), a known P-gp inducer, could efficiently protect Caco-2 cells against PQ cytotoxicity, 6 h after the incubation with the herbicide, reflecting a real-life intoxication scenario. Cytotoxicity was evaluated by the MTT assay and PQ intracellular concentrations were measured by gas chromatography-ion trap-mass spectrometry (GC-IT-MS). Also, the DOX modulatory effect on choline uptake transport system was assessed by measuring the uptake of [³H]-choline. The results show that DOX exerts protective effects against PQ cytotoxicity, preventing the intracellular accumulation of the herbicide. These protective effects were not completely prevented by the incubation with the UIC2 antibody, a specific P-gp inhibitor, suggesting the involvement of alternative protection mechanisms. In fact, DOX also efficiently inhibited the choline transport system that influences PQ cellular uptake. In conclusion, in this cellular model, DOX effectively protects against PQ toxicity by inducing P-gp and through the interaction with the choline transporter, suggesting that compounds presenting this double feature of promoting the efflux and limiting the uptake of PQ could be used as effective antidotes to treat intoxications. 23406955 Effect of tocopherol on biochemical blood parameters in pleuritis-induced rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. The aim of this study was to evaluate the effect of tocopherol on pleuritis-induced rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Rats were treated with a single TCDD dose of 5 μg/kg body weight (b.w.) and then for 3 weeks they were daily supplemented with tocopherol at a dose of 30 mg/kg b.w. The inflammation was initiated by intrapleural injection of a single dose of 1% carrageenin solution in a volume of 0.15 ml. Changes in biochemical blood parameters were measured three times at the 24th, 72nd and 120th hour of pleuritis and the blood was collected from 20 animals of each group of rats (group with the control inflammation; group treated with TCDD and with control inflammation; group treated with TCDD, supplemented with tocopherol and with the inflammation). The following biochemical parameters were measured: tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-2, IL-4, IL-6, procollagen, telopeptide, fibrinogen, cholesterol, urea, creatinine, aspartate aminotransferase (AspAT) and alanine aminotransferase (AlAT). Daily supplementation of tocopherol caused significant changes in the level of TNF, IL-1, IL-4, IL-6, urea, creatinine, AspAT and AlAT. According to the results of these studies, we suggest that tocopherol supplementation in high doses could act as a protective treatment to improve liver metabolism. 23471769 Acute Myocardial Infarction During Regadenoson Myocardial Perfusion Imaging. Pharmacologic stress testing uses vasodilators to provide objective evidence of myocardial ischemia. Adenosine and dipyridamole are nonselective adenosine receptor agonists that have been associated with myocardial infarction (MI) during intravenous infusion. Mechanisms postulated for this effect include coronary steal, transmural steal, global hypotension, and direct vasoconstriction. Regadenoson, a direct A2A agonist, was approved for use in stress testing in 2008. We describe a 68-year-old man who presented to our institution with typical angina, relieved by nitroglycerin. He did not have electrocardiogram (ECG) changes suggestive of myocardial pathology, and laboratory testing did not reveal a significant rise in troponin-I levels. To further assess the etiology of his symptoms, he underwent a pharmacologic stress test with regadenoson followed by technetium 99 m sestamibi. Six minutes after regadenoson infusion, the patient developed severe retrosternal chest pain accompanied by ST elevations on ECG. Sublingual nitroglycerin was administered that resolved both the pain and ECG changes. The patient subsequently underwent urgent coronary angiography and was found to have a 95% critical stenosis involving the left anterior descending artery. We conclude this case represents a MI secondary to coronary steal phenomenon induced by regadenoson infusion. Clinicians should be aware this adverse effect can occur despite the improved side-effect profile of regadenoson. Continuous monitoring of vital signs and the ECG with regular assessment of symptoms is imperative to identify this rare but potentially devastating adverse event. 23313270 Tricycloalternarenes F-H: three new mixed terpenoids produced by an endolichenic fungus Ulocladium sp. using OSMAC method. Three new mixed terpenoids, tricycloalternarenes (TCAs) F-H (1-3), together with ten known tricycloalternarenes (4-13), were isolated from the Czapek's culture of an endophytic fungus Ulocladium sp. Their structures were identified by extensive spectroscopic experiments (NMR and MS) and comparison with literature data. TCA 1b (5) showed weak activity against the Bacille Calmette-Guerin strain with the MIC of 125μg/mL. TCA 9b (10) exhibited strong cytotoxic activity against Hela cell line with IC50 of 8.58μM. 23414214 Influence of the bifunctional chelator on the pharmacokinetic properties of 99mTc(CO)3-labeled cyclic α-melanocyte stimulating hormone analog. Aiming at the design of specific melanocortin-1 receptor (MC1R) targeted imaging probes, we report on the effect of different azolyl-ring substitution patterns (carboxylate at the 4-position and/or methyl groups at the 3,5 positions) of pyrazolyl-diamine bifunctional chelators (Pz(2)-Pz(4)) on the pharmacokinetic profile of the (99m)Tc(CO)3-labeled lactam bridge-cyclized α-melanocyte stimulating hormone derivative, βAlaNleCycMSH(hex). Three pyrazolyl-diamine-containing chelators were conjugated to βAlaNleCycMSHhex, with the resulting peptide conjugates displaying subnanomolar MC1R binding affinity. Biodistribution studies in B16F1 melanoma-bearing mice show that all radiopeptides present a good melanoma uptake. The introduction of a carboxylate group in the azolyl-ring leads to a remarkable reduction of the kidney (>89%) and liver (>91%) accumulation for (99m)Tc(CO)3-Pz(3)-βAlaNleCycMSH(hex) and (99m)Tc(CO)3-Pz(4)-βAlaNleCycMSH(hex) when compared to the radiopeptide (99m)Tc(CO)3-Pz(1)-βAlaNleCycMSH(hex), where that group is absent. The good tumor uptake and favorable tumor-to-nontarget-organs ratios of (99m)Tc(CO)3-Pz(3)-βAlaNleCycMSH(hex) and (99m)Tc(CO)3-Pz(4)-βAlaNleCycMSH(hex) highlights the potential of both compounds as melanoma imaging agents. 23353749 Synthesis of an MIF-1 analogue containing enantiopure (S)-α-trifluoromethyl-proline and biological evaluation on nociception. The synthesis and the effect of a novel MIF-1 analogue on nociception during acute pain in rat model are reported. The synthesis of this enantiopure trifluoromethyl group containing tripeptide was performed through a peptide coupling reaction between the HCl. Leu-Gly-NH2 and the (S)-α-Tfm-proline. The analgesic effect of the CF3-(MIF-1) 2 has been evaluated in vivo on rat model by paw pressure (PP) and hot plate (HP) tests and compared to the native peptide MIF-1. Highest analgesic effect was observed with CF3-(MIF-1) 2 only in PP test. In order to study the mechanisms of nociception induced by the studied peptides, the involvement of the opioid and the nitric oxideergic systems was investigated. The results are in favor of a participation of both system since pretreatment, 20 min before injection of the CF3-(MIF-1) 2, with the non-competitive antagonist of opiate receptors naloxone, the nitric oxide synthase (NOS) inhibitor l-N(G)-nitroarginine ester (l-NAME) or the nitric oxide (NO) donor l-arginine (l-Arg) significantly decreased the pain perception in PP and HP tests. 23244033 General methodology of using oil-in-water and water-in-oil emulsions for coiling nanofilaments. Hydrophobic carbon nanotubes (CNTs) and hydrophilic nanofilaments such as oxidized CNTs, Pd nanowires (NWs), and MnO(2) NWs are transformed from wires to rings by a general methodology. We show that both oil-in-water and water-in-oil emulsions, so long as their droplet size is sufficiently small, can exert significant force to the entrapped nanostructures, causing their deformation. This effect can be easily achieved by simply mixing a few solutions in correct ratios. Even preformed oil droplets can take in CNTs from the aqueous solution converting them into rings, indicating the important role of thermodynamics: The question here is not if the droplets can exert sufficient force to bend the nanofilaments, because their random vibration may be already doing it. As long as the difference in solvation energy is large enough for a nanofilament, it would "want" to move away from the bulk solution and fit inside tiny droplets, even at the cost of induced strain energy. That said, the specific interactions between a droplet and a filament are also of importance. For example, when an oil droplet rapidly shrinks in size, it can compress the entrapped CNTs in multiple stages into structures with higher curvatures (thus higher strain) than that of a circular ring, which has minimal induced strain inside a spherical droplet. 23210782 Marine natural products with anti-HIV activities in the last decade. Marine organisms have been proven to be excellent sources of biologically active compounds against HIV. This review gives an overview of 132 natural products from marine sources obtained during the last decade (2002-2011), which exhibit anti-HIV activity toward different biological targets. Sponges contribute more than half of all anti-HIV natural products from marine organisms, mainly as alkaloids and cyclic depsipeptides. In addition, some macromolecules are considered as potential anti-HIV agents, including lectins from algae and marine invertebrates, as well as sulfated polysaccharides from algae. In the reviewed marine natural products, many active ingredients act as HIV entry inhibitors, one class of new anti-HIV agents, and may be regarded as potential candidates for the development of novel anti-HIV agents. The other features of development in the marine original anti-HIV natural products in this ten years are also discussed. 23344056 Aqueous self-sorting in extended supramolecular aggregates. Self-organization and self-sorting processes are responsible for the regulation and control of the vast majority of biological processes that eventually sustain life on our planet. Attempts to unveil the complexity of these systems have been devoted to the investigation of the binding processes between artificial molecules, complexes or aggregates within multicomponent mixtures, which has facilitated the emergence of the field of self-sorting in the last decade. Since, artificial systems involving discrete supramolecular structures, extended supramolecular aggregates or gel-phase materials in organic solvents or-to a lesser extent-in water have been investigated. In this review, we have collected diverse strategies employed in recent years to construct extended supramolecular aggregates in water upon self-sorting of small synthetic molecules. We have made particular emphasis on co-assembly processes in binary mixtures leading to supramolecular structures of remarkable complexity and the influence of different external variables such as solvent and concentration to direct recognition or discrimination processes between these species. The comprehension of such recognition phenomena will be crucial for the organization and evolution of complex matter. 23200255 Phosphodiesterase inhibitors. Part 5: hybrid PDE3/4 inhibitors as dual bronchorelaxant/anti-inflammatory agents for inhaled administration. (-)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (KCA-1490) exhibits moderate dual PDE3/4-inhibitory activity and promises as a combined bronchodilatory/anti-inflammatory agent. N-alkylation of the pyridazinone ring markedly enhances potency against PDE4 but suppresses PDE3 inhibition. Addition of a 6-aryl-4,5-dihydropyridazin-3(2H)-one extension to the N-alkyl group facilitates both enhancement of PDE4-inhibitory activity and restoration of potent PDE3 inhibition. Both dihydropyridazinone rings, in the core and extension, can be replaced by achiral 4,4-dimethylpyrazolone subunits and the core pyrazolopyridine by isosteric bicyclic heteroaromatics. In combination, these modifications afford potent dual PDE3/4 inhibitors that suppress histamine-induced bronchoconstriction in vivo and exhibit promising anti-inflammatory activity via intratracheal administration. 23597051 Investigation of Protein Detection Parameters Using Nanofunctionalized Organic Field-Effect Transistors. Biodetection using organic field-effect transistors (OFETs) is gaining increasing interest for applications as diverse as food security, environmental monitoring, and medical diagnostics. However, there still lacks a comprehensive, empirical study on the fundamental limits of OFET sensors. In this paper, we present a thorough study of the various parameters affecting biosensing using an OFET decorated with gold nanoparticle (AuNP) binding sites. These parameters include the spacing between receptors, pH of the buffer, and ionic strength of the buffer. To this end, we employed the thrombin protein and its corresponding DNA binding aptamer to form our model detection system. We demonstrate a detection limit of 100 pM for this protein with high selectivity over other proteases in situ. We describe herein a feasible approach for protein detection with OFETs and a thorough investigation of parameters governing biodetection events using OFETs. Our obtained results should provide important guidelines to tailor the sensor's dynamic range to suit other desired OFET-based biodetection applications. 23535364 DNA Adduct Formation of 2-Amino-9H-pyrido[2,3-b]indole and 2-Amino-3,4-dimethylimidazo[4,5-f]quinoline in Mouse Liver and Extrahepatic Tissues During a Subchronic Feeding Study. Tobacco smoking is a risk factor for cancers of the liver and gastrointestinal (GI) tract, but the causal agents responsible for these cancers are uncertain. 2-Amino-9H-pyrido[2,3-b]indole (AαC) is an abundant heterocyclic aromatic amine present in tobacco smoke. AαC is a liver carcinogen and both a transgene mutagen and inducer of aberrant crypt foci in the colon of mice. We hypothesize that AαC may contribute to DNA damage and tumorigenesis in these organs of smokers. The potential of AαC to induce DNA adduct formation in liver, organs of the GI tract, lung, and urinary bladder, which are target organs of cancer in smokers, was examined using the C57BL/6 mouse as an animal model. AαC (400 or 800 ppm) and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) (300 ppm), a liver and colon carcinogen in C57BL/6 mice, were given in the diet for up to 12 weeks. Liquid chromatography/mass spectrometry was employed to measure DNA adducts. The major DNA adducts of both carcinogens were identified as deoxyguanosine-C8 adducts. The levels of formation of AαC- and MeIQ-DNA adducts were similar in liver and extrahepatic tissues when adjusted for dose. The highest levels of adducts occurred in liver, followed by urinary bladder, and then in cecum and colon; lower DNA adduct levels were formed in the lung and pancreas following 12 weeks of feeding. The high levels of AαC adduct formed in liver, GI tract, and bladder of C57BL/6 mice reinforce the notion that AαC may contribute to DNA damage and cancer of these organs in smokers. 23346994 Stepwise colonization of the Andes by ruddy ducks and the evolution of novel β-globin variants. Andean uplift played a key role in Neotropical bird diversification, yet past dispersal and genetic adaptation to high-altitude environments remain little understood. Here we use multilocus population genetics to study population history and historical demographic processes in the ruddy duck (Oxyura jamaicensis), a stiff-tailed diving duck comprising three subspecies distributed from Canada to Tierra del Fuego and inhabiting wetlands from sea level to 4500 m in the Andes. We sequenced the mitochondrial DNA, four autosomal introns and three haemoglobin genes (α(A), α(D), β(A)) and used isolation-with-migration (IM) models to study gene flow between North America and South America, and between the tropical and southern Andes. Our analyses indicated that ruddy ducks dispersed first from North America to the tropical Andes, then from the tropical Andes to the southern Andes. While no nonsynonymous substitutions were found in either α globin gene, three amino acid substitutions were observed in the β(A) globin. Based on phylogenetic reconstruction and power analysis, the first β(A) substitution, found in all Andean individuals, was acquired when ruddy ducks dispersed from low altitude in North America to high altitude in the tropical Andes, whereas the two additional substitutions occurred more recently, when ruddy ducks dispersed from high altitude in the tropical Andes to low altitude in the southern Andes. This stepwise colonization pattern accompanied by polarized β(A) globin amino acid replacements suggest that ruddy ducks first acclimatized or adapted to the Andean highlands and then again to the lowlands. In addition, ruddy ducks colonized the Andean highlands via a less common route as compared to other waterbird species that colonized the Andes northwards from the southern cone of South America. 22986488 Ultraviolet B activated 1,25(OH)(2)D affects the level of fibroblast growth factor-23 in human. Fibroblast growth factor 23 (FGF-23) is known as a phosphaturic factor regulating phosphate homeostasis. Several studies suggest that dietary phosphate, serum phosphate and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] are candidate regulators of FGF-23. While the human studies, which modulated the dietary or serum phosphate showed in rather controversial results, manipulation of the active vitamin D definitely affected FGF-23 in animals. This study was conducted to elucidate the relationship between active vitamin D directly stimulated by ultraviolet B (UVB) exposure and FGF-23 level in human. Ten healthy young adults were recruited to get the UVB exposure thrice a week at sub-minimal erythemal dose with gradual increment by 10% only for 4 weeks. Serum calcium, phosphate, mineral-related hormones and bone turnover markers were analyzed before and after the UVB exposure every 4 week for 12 whole weeks. Twenty five-hydroxyvitamin D [25(OH)D] increased by 115% (19.8 ng/mL to 40.5 ng/mL, p < 0.001) after 4 weeks of UVB exposure. While 1,25(OH)(2)D increased by 75% (49.9 pg/mL to 64.4 pg/mL, p < 0.001) then both level decreased after 4 weeks of withdrawal. C-telopeptide peaked at 2nd week then decreased, while osteocalcin increased gradually. FGF-23 started to increase from the 4th week of UVB exposure then significantly at the 4th week after withdrawal of UVB (27.8 pg/mL to 41.4 pg/mL, p < 0.05). UVB exposure effectively increased 1,25(OH)(2)D with delayed stimulatory effect on FGF-23. This result could support the regulatory loop of 1,25(OH)(2)D and FGF-23 in human, FGF-23 regulation by 1,25(OH)(2)D. 23457058 Unique role of self-assembled monolayers in carbon nanomaterial-based field-effect transistors. Molecular self-assembly is a promising technology for creating reliable functional films in optoelectronic devices with full control of thickness and even spatial resolution. In particular, rationally designed self-assembled monolayers (SAMs) play an important role in modifying the electrode/semiconductor and semiconductor/dielectric interfaces in field-effect transistors. Carbon nanomaterials, especially single-walled carbon nanotubes and graphene, have attracted intense interest in recent years due to their remarkable physicochemical properties. The combination of the advantages of both SAMs and carbon nanomaterials has been opening up a thriving research field. In this Review article, the unique role of SAMs acting as either active or auxiliary layers in carbon nanomaterials-based field-effect transistors is highlighted for tuning the substrate effect, controlling the carrier type and density in the conducting channel, and even installing new functionalities. The combination of molecular self-assembly and molecular engineering with materials fabrication could incorporate diverse molecular functionalities into electrical nanocircuits, thus speeding the development of nanometer/molecular electronics in the future. 23390132 Development and characterization of an SMN2-based intermediate mouse model of Spinal Muscular Atrophy. Spinal Muscular Atrophy (SMA) is due to the loss of the survival motor neuron gene 1 (SMN1), resulting in motor neuron (MN) degeneration, muscle atrophy and loss of motor function. While SMN2 encodes a protein identical to SMN1, a single nucleotide difference in exon 7 causes most of the SMN2-derived transcripts to be alternatively spliced resulting in a truncated and unstable protein (SMNΔ7). SMA patients retain at least one SMN2 copy, making it an important target for therapeutics. Many of the existing SMA models are very severe, with animals typically living less than 2 weeks. Here, we present a novel intermediate mouse model of SMA based upon the human genomic SMN2 gene. Genetically, this model is similar to the well-characterized SMNΔ7 model; however, we have manipulated the SMNΔ7 transgene to encode a modestly more functional protein referred to as SMN read-through (SMN(RT)). By introducing the SMN(RT) transgene onto the background of a severe mouse model of SMA (SMN2(+/+);Smn(-/-)), disease severity was significantly decreased based upon a battery of phenotypic parameters, including MN pathology and a significant extension in survival. Importantly, there is not a full phenotypic correction, allowing for the examination of a broad range of therapeutics, including SMN2-dependent and SMN-independent pathways. This novel animal model serves as an important biological and therapeutic model for less severe forms of SMA and provides an in vivo validation of the SMN(RT) protein. 23408642 MMP driven endochondral fracture union proceeds independently of osteoclast activity. As new insights into the complexities of endochondral fracture repair emerge, the temporal role of osteoclast activity remains ambiguous. With numerous anti-resorptive agents available to treat bone disease, understanding their impact on bone repair is vital. Further, in light of recent work suggesting osteoclast activity may not be necessary during early endochondral fracture union, we hypothesize instead a pivotal role of MMP secreting cells in driving this process. While the role of MMPs in fracture healing has been examined, no directly comparative experiments exist. We examined a number of anti-resorptive treatments to either block osteoclast activity, including the potent bisphosphonates zoledronic acid (ZA) and clodronate (CLOD), which work via differing mechanisms, or antagonize osteoclastogenesis with recombinant OPG (HuOPG-Fc), comparing these directly to an inhibitor of matrix metalloproteinase (MMP) activity (MMI270). Endochondral ossification to union occurred normally in all anti-resorptive groups. In contrast, MMP inhibition greatly impaired endochondral union, significantly delaying cartilage callus removal. MMP inhibition also produced smaller, denser hard calluses. Hard callus remodeling was, as expected, delayed with ZA, CLOD and OPG treatment at 4 and 6 weeks, resulting in larger more mineralized calluses at 6 weeks. As a result of reduced hard callus turnover, bone formation was reduced with anti-resorptive agents at these time points. These results confirm that the achievement of endochondral fracture union occurs independently of osteoclast activity. Alternatively, MMP secretion by invading cells is obligatory to endochondral union. This study provides new insight into cellular contributions to bone repair and may abate concerns regarding anti-resorptive therapies impeding initial fracture union. © 2013 American Society for Bone and Mineral Research. 23295386 Direct transcriptional regulation of human hepatic cytochrome P450 3A4 (CYP3A4) by peroxisome proliferator-activated receptor alpha (PPARα). The nuclear receptor peroxisome proliferator-activated receptor (PPAR)α is known primarily as a regulator of fatty acid metabolism, energy balance, and inflammation, but evidence suggests a wider role in regulating the biotransformation of drugs and other lipophilic chemicals. We investigated whether PPARα directly regulates the transcription of cytochrome P450 3A4, the major human drug-metabolizing enzyme. Using chromatin immunoprecipitation in human primary hepatocytes as well as electrophoretic mobility shift and luciferase reporter-gene assays, we identified three functional PPARα-binding regions (PBR-I, -II, and -III) within ∼12 kb of the CYP3A4 upstream sequence. Furthermore, a humanized CYP3A4/3A7 mouse model showed in vivo induction of CYP3A4 mRNA and protein by [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY14,643) in liver but not in intestine, whereas hepatic occupancy of PBRs by PPARα was ligand independent. Using lentiviral gene knock-down and treatment with WY14,643 in primary human hepatocytes, PPARα was further shown to affect the expression of a distinct set of CYPs, including 1A1, 1A2, 2B6, 2C8, 3A4, and 7A1, but not 2C9, 2C19, 2D6, or 2E1. Interestingly, the common phospholipid 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-PC), previously proposed to reflect nutritional status and shown to be a specific endogenous ligand of PPARα, induced CYP3A4 (up to 4-fold) and other biotransformation genes in hepatocytes with similar selectivity and potency as WY14,643. These data establish PPARα as a direct transcriptional regulator of hepatic CYP3A4. This finding warrants investigation of both known and newly developed PPARα-targeted drugs for their drug-drug interaction potential. Furthermore, our data suggest that nutritional status can influence drug biotransformation capacity via endogenous phospholipid signaling. 23428368 Hyperthyroidism causes cardiac dysfunction by mitochondrial impairment and energy depletion. This study elucidates the role of metabolic remodeling in cardiac dysfunction induced by hyperthyroidism. Cardiac hypertrophy, structural remodeling, and expression of the genes associated with fatty acid metabolism were examined in rats treated with triiodothyronine (T3) alone (8 μg/100 g body weight (BW), i.p.) for 15 days or along with a peroxisome proliferator-activated receptor alpha agonist bezafibrate (Bzf; 30 μg/100 g BW, oral) and were found to improve in the Bzf co-treated condition. Ultrastructure of mitochondria was damaged in T3-treated rat heart, which was prevented by Bzf co-administration. Hyperthyroidism-induced oxidative stress, reduction in cytochrome c oxidase activity, and myocardial ATP concentration were also significantly checked by Bzf. Heart function studied at different time points during the course of T3 treatment shows an initial improvement and then a gradual but progressive decline with time, which is prevented by Bzf co-treatment. In summary, the results demonstrate that hyperthyroidism inflicts structural and functional damage to mitochondria, leading to energy depletion and cardiac dysfunction. 23127540 Sulfur fumigation, a better or worse choice in preservation of Traditional Chinese Medicine? Sulfur fumigation (SF) in Traditional Chinese Medicine (TCM) is a highly efficient and important traditional preservation method in China. This method has generated a great deal of concern and has been disputed in the last few years because of its uncertain safety. SF can alter the quality of TCMs by damaging the bioactive compounds, changing chemical profiles, and generating detrimental exogenous materials. However, SF is still widely used in the herbal medicinal industry because of its various benefits, such as its pesticidal and anti-bacterial effects, easy operation, and low-cost. This review contains the current situation, chemical mechanism and reactions during SF, the pharmacological and pharmacokinetic research, and the influence of quality caused by SF. In addition, a quantification-operation sulfur fumigation device (QOSFD), which can maintain the quality of TCMs by controlling the SF processing parameters, has been designed and introduced. The key technologies of this device involve controlling the O(2) content and the temperature of SO(2) as well as the quantification of sulfur in SF. This device can reduce the possibility of reaction between bioactive compounds and sulfur/sulfurous acid, as well as control the limitation of SO(2) residues. The QOSFD is regarded as a promising preservation technique in the field of TCM, medicinal materials, agriculture, and fruit industry. 23561189 Inhibitory effects of myricetin on mammalian DNA polymerase, topoisomerase and human cancer cell proliferation. In this study, the inhibitory activities against mammalian DNA polymerases (pols) of 16 major bioflavonoids were investigated. Myricetin (3,3',4',5,5',7-hexahydroxyflavone) was the most potent inhibitor of pols amongst the compounds tested, with IC50 values of 21.3-40.9μM. This compound did not affect the activities of plant (cauliflower) pol α or prokaryotic pols. Myricetin also inhibited human DNA topoisomerase II (topo II) activity with an IC50 value of 27.5μM, but did not inhibit the activities of other DNA metabolic enzymes tested. Myricetin also did not influence the direct binding to double stranded DNA as determined by thermal transition analysis. It was found to prevent the proliferation of human colon HCT116 carcinoma cells with an LD50 of 28.2μM, halt the cell cycle in G2/M phase, and induce apoptosis. These results suggest that the decrease of proliferation may be a result of the inhibition of cellular topoisomerase (topo) II rather than pols. 23525298 Doped quantum dots for chemo/biosensing and bioimaging. Quantum dots (QDs) have received great interest for diverse applications due to their distinct advantages, such as narrow and symmetric emission with tunable colors, broad and strong absorption, reasonable stability, and solution processibility. Doped QDs not only potentially retain almost all of the above advantages, but also avoid the self-quenching problem due to their substantial ensemble Stokes shift. Two obvious advantages of doped QDs, especially doped ZnS QDs, over typical CdSe@ZnS and CdTe QDs are longer dopant emission lifetime and potentially lower cytotoxicity. The lifetime of dopant emission from transition-metal ion or lanthanide ion-doped QDs is generally longer than that of the bandgap or defect-related emission of host, and that of biological background fluorescence, providing great opportunities to eliminate background fluorescence for biosensing and bioimaging. For bioimaging applications, fluorescent dopants may mitigate toxicity problems by producing visible or infrared emission in nanocrystals made from less-harmful elements than those currently used. In this review, recent advances in utilizing doped QDs for chemo/biosensing and bioimaging are discussed, and the synthetic routes and optical properties of doped QDs that make them excellent probes for various strategies in chemo/biosensing and bioimaging are highlighted. Moreover, perspectives on future exploration of doped QDs for chemo/biosensing and bioimaging are also given. 23233197 Human mesenchymal stem-cell behaviour on direct laser micropatterned electrospun scaffolds with hierarchical structures. Direct laser machining and electrospinning are utilized to obtain a bi-layered hybrid scaffold with hierarchical topographical features to mimic extracellular matrix-like microenvironment of cells. Adult bone marrow derived human mesenchymal stem cells (hMSCs) are cultured in vitro in these hybrid scaffolds, and cell orientation, proliferation, viability, and differentiation are evaluated. The results show that this novel hybrid scaffold not only supports cell growth like traditional scaffolds, but also elicits positive responses from the cells, like lineage commitment and alignment, which are essential features of future scaffolds. 22878908 Thiazolidinediones (TZDs) affect osteoblast viability and biomarkers independently of the TZD effects on aromatase. Thiazolidinediones (TZDs) are insulin sensitizers used for treatment of diabetes. We have previously reported that TZDs reduce estrogen synthesis by inhibiting aromatase activity in human granulosa cells (HGC). Multiple clinical trials demonstrated that TZDs increase the risk of fractures in postmenopausal women with type 2 diabetes. We studied mouse osteoblasts alone or in a co-culture with HGC to determine whether TZD inhibition of aromatase plays a role in their effects on bone metabolism. Mouse osteoblasts were cultured with and without HGC, and incubated in a medium with or without testosterone, pioglitazone or rosiglitazone. Cell growth, oleic acid uptake, alkaline phosphatase activity, and osteocalcin production were measured. TZDs inhibited estradiol production by up to 84% in HGC/mouse osteoblast co-cultures. TZDs induced mouse osteoblast death and increased oleic acid uptake. TZDs also inhibited alkaline phosphatase activity (58-75%, p<0.046) and osteocalcin production (52-75%, p<0.031). For all the parameters, there were no significant differences between the osteoblast cultures alone and the HCG/osteoblast co-cultures. TZD effects on osteoblast viability, oleic acid uptake, alkaline phosphatase and osteocalcin production are independent of their effects on aromatase. 23575800 Metabolomics reveals trichloroacetate as a major contributor to trichloroethylene-induced metabolic alterations in mouse urine and serum. Trichloroethylene (TCE)-induced liver toxicity and carcinogenesis is believed to be mediated in part by activation of the peroxisome proliferator-activated receptor α (PPARα). However, the contribution of the two TCE metabolites, dichloroacetate (DCA) and trichloroacetate (TCA) to the toxicity of TCE, remains unclear. The aim of the present study was to determine the metabolite profiles in serum and urine upon exposure of mice to TCE, to aid in determining the metabolic response to TCE exposure and the contribution of DCA and TCA to TCE toxicity. C57BL/6 mice were administered TCE, TCA, or DCA, and urine and serum subjected to ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS)-based global metabolomics analysis. The ions were identified through searching metabolomics databases and by comparison with authentic standards, and quantitated using multiple reactions monitoring. Quantitative polymerase chain reaction of mRNA, biochemical analysis, and liver histology were also performed. TCE exposure resulted in a decrease in urine of metabolites involved in fatty acid metabolism, resulting from altered expression of PPARα target genes. TCE treatment also induced altered phospholipid homeostasis in serum, as revealed by increased serum lysophosphatidylcholine 18:0 and 18:1, and phosphatidylcholine metabolites. TCA administration revealed similar metabolite profiles in urine and serum upon TCE exposure, which correlated with a more robust induction of PPARα target gene expression associated with TCA than DCA treatment. These data show the metabolic response to TCE exposure and demonstrate that TCA is the major contributor to TCE-induced metabolite alterations observed in urine and serum. 23150067 Design, synthesis and anticancer activity of N(3),N(11)-bis(2-hydroxyethyl)-14-aryl-14H-dibenzo[a,j]xanthenes-3,11-dicarboxamide. A series of novel N(3),N(11)-bis(2-hydroxyethyl)-14-aryl-14H-dibenzo[a,j]xanthenes-3,11-dicarboxamide, three N(3),N(11)-bis(2-hydroxyethyl)-14-aryl-14H-dibenzo[a,j]xanthene-3,11-dimethanamine derivatives and their intermediates 14-aryl-14H-dibenzo[a,j]xanthenes-3,11-dicarboxylic acid, were synthesized, and the structures of which were characterized by (1)H-NMR, (13)C-NMR, high resolution (HR)-MS, and IR spectra. The antitumor activities of these molecules were evaluated on five cancer cell lines. The results of in vitro assay against human hepatocellular carcinoma cell lines (SK-HEP-1 and HepG2 and SMMC-7721 cells), acute promyelocytic leukemia NB4 cells and uterine cervix cancer HeLa cells, show several compounds to be endowed with cytotoxicity in micromolar to submicromolar range. The carboxamide derivatives 6c and 6e exhibitted good inhibition on NB4 cancer cells, and the IC(50) values of which were 0.82 µM and 0.96 µM, respectively, much lower than 5.01 µM of the positive control As(2)O(3). Flow cytometric analysis results revealed that compounds 6e and 6f may induce tumor cell apoptosis. 23480643 A concise total synthesis of the natural carbazole clauraila A. A short and efficient total synthesis of naturally occurring carbazole clauraila A (1) is described. The approach is designed on the basis of the key regioselective Diels-Alder reaction of the properly substituted exo-2-oxazolidinone diene 3 with acrolein (4) to give the corresponding adduct 2. The latter is converted to functionalised diarylamine 8, which is cyclised to the desired carbazole 1 through a Pd-promoted or -catalysed double C-H bond activation process in a fairly good overall yield. 23419237 The CSB repair factor is overexpressed in cancer cells, increases apoptotic resistance, and promotes tumor growth. In the present study we show that a number of cancer cell lines from different tissues display dramatically increased expression of the Cockayne Syndrome group B (CSB) protein, a DNA repair factor, that has recently been shown to be involved in cell robustness. Furthermore, we demonstrated that ablation of this protein by antisense technology causes devastating effects on tumor cells through a drastic reduction of cell proliferation and massive induction of apoptosis, while non-transformed cells remain unaffected. Finally, suppression of CSB in cancer cells makes these cells hypersensitive to a variety of commonly used cancer chemotherapeutic agents. Based on these results, we conclude that cancer cells overexpress CSB protein in order to enhance their anti-apoptotic capacity. The fact that CSB suppression specifically affects only cancerous cells, without harming healthy cells, suggests that CSB may be a very attractive target for the development of new anticancer therapies. 23522834 Design and synthesis of highly selective, orally active Polo-like kinase-2 (Plk-2) inhibitors. Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-α-synuclein levels in the cerebral cortex. 23400750 Feasibility of a breath test for monitoring adherence to vaginal administration of antiretroviral microbicide gels. Adherence to microbicide gel use is critical to optimizing effectiveness in preventing human immunodeficiency virus transmission. The authors hypothesized that ester taggants added to vaginal gels would generate exhaled alcohol and ketone metabolites and provide a "breath test" for vaginal gel use. This 2-arm (vaginal and dermal), randomized, participant-blinded, pilot study tested this hypothesis. On 8 visits, healthy women (n = 8) received intravaginal taggant (2-butyl acetate, 2-pentyl acetate, isopropyl butyrate, or 2-pentyl butyrate; 30 mg) formulated in hydroxyethylcellulose or tenofovir placebo gel. A second group (n = 4) of women received the same formulations administered dermally on the forearm to determine if skin administration might confound the system. Breath samples were collected using bags before and after taggant administration for 1 hour. Samples were measured using a miniature gas chromatograph and/or gas chromatography-mass spectroscopy for ester taggant, alcohol, and ketone concentrations. After vaginal administration, 2-butyl acetate, 2-pentyl acetate, and metabolites were observed in breath, whereas isopropyl butyrate, 2-pentyl butyrate, and metabolites were not. Some women reported self-resolving, mild burning (24/64 visits) with vaginal administration or a "bubblegum" taste (7/64 visits). No taggants or metabolites were detected following dermal application. A "breath test" for adherence to antiretroviral vaginal gel application appears physiologically and technically feasible. 23376352 Bradykinin modulates spontaneous nerve growth factor production and stretch-induced ATP release in human urothelium. The urothelium plays a crucial role in integrating urinary bladder sensory outputs, responding to mechanical stress and chemical stimulation by producing several diffusible mediators, including ATP and, possibly, neurotrophin nerve growth factor (NGF). Such urothelial mediators activate underlying afferents and thus may contribute to normal bladder sensation and possibly to the development of bladder overactivity. The muscle-contracting and pain-inducing peptide bradykinin is produced in various inflammatory and non-inflammatory pathologies associated with bladder overactivity, but the effect of bradykinin on human urothelial function has not yet been characterized. The human urothelial cell line UROtsa expresses mRNA for both B1 and B2 subtypes of bradykinin receptors, as determined by real-time PCR. Bradykinin concentration-dependently (pEC50=8.3, Emax 4434±277nM) increased urothelial intracellular calcium levels and induced phosphorylation of the mitogen-activated protein kinase (MAPK) ERK1/2. Activation of both bradykinin-induced signaling pathways was completely abolished by the B2 antagonist icatibant (1μM), but not the B1 antagonist R715 (1μM). Bradykinin-induced (100nM) B2 receptor activation markedly increased (192±13% of control levels) stretch-induced ATP release from UROtsa in hypotonic medium, the effect being dependent on intracellular calcium elevations. UROtsa cells also expressed mRNA and protein for NGF and spontaneously released NGF to the medium in the course of hours (11.5±1.4pgNGF/mgprotein/h). Bradykinin increased NGF mRNA expression and accelerated urothelial NGF release to 127±5% in a protein kinase C- and ERK1/2-dependent manner. Finally, bradykinin up-regulated mRNA for transient-receptor potential vanilloid (TRPV1) sensory ion channel in UROtsa. In conclusion, we show that bradykinin represents a versatile modulator of human urothelial phenotype, accelerating stretch-induced ATP release, spontaneous release of NGF, as well as expression of sensory ion channel TRPV1. Bradykinin-induced changes in urothelial sensory function might contribute to the development of bladder dysfunction. 23143912 Metal-supported aluminosilicate ultrathin films as a versatile tool for studying the surface chemistry of zeolites. The application of a variety of "surface-science" techniques to elucidate surface structures and mechanisms of chemical reactions at zeolite surfaces has long been considered as almost impossible because of the poor electrical and thermal conductivity of those materials. Here, we show that the growth of a thin aluminosilicate film on a metal single crystal under controlled conditions results in adequate and well-defined model systems for zeolite surfaces. In principle, silicate films that contain metals other than Al (e.g. Ti, Fe, etc) may be prepared in a similar way. We believe that this approach opens up a new playground for experimental and theoretical modeling of zeolites, aimed at a fundamental understanding of structure-reactivity relationships in such materials. 23368996 Structures and cytotoxic evaluation of new and known acyclic Ene-Ynes from an American Samoa Petrosia sp. Sponge. Four new compounds, (-)-petrosynoic acids A-D (1-4), and five known congeners, pellynols A (5), C (6), D (7), F (8), and I (9), were isolated from a Petrosia sp. marine sponge collected in American Samoa. Isolation work was guided by cytotoxicity against human lung cancer cells (H460). The structures of the C31-C33 polyacetylenes (1-9) were determined on the basis of 1D- and 2D-NMR analysis, mass spectrometry, and comparison of specific rotation values. Compounds 1-9 were found to be broadly cytotoxic with limited selectivity for cancer cells, as they were all moderately active against the A2058 (melanoma), H522-T1 (lung), and H460 (lung) human cancer cell lines as well as IMR-90 quiescent human fibroblast cells. 23159360 Novel antitussive strategies. Acute and chronic cough represent one of the most common symptoms of medical importance but effective pharmacotherapy is, to all intents and purposes, absent. Numerous initiatives targeting the recently discovered tussive pathways are in progress. Here, we review the current antitussive armamentarium and provide an update on the novel strategies and compounds in development. 23518413 SMC6 is an essential gene in mice, but a hypomorphic mutant in the ATPase domain has a mild phenotype with a range of subtle abnormalities. Smc5-6 is a highly conserved protein complex related to cohesin and condensin involved in the structural maintenance of chromosomes. In yeasts the Smc5-6 complex is essential for proliferation and is involved in DNA repair and homologous recombination. siRNA depletion of genes involved in the Smc5-6 complex in cultured mammalian cells results in sensitivity to some DNA damaging agents. In order to gain further insight into its role in mammals we have generated mice mutated in the Smc6 gene. A complete knockout resulted in early embryonic lethality, demonstrating that this gene is essential in mammals. However, mutation of the highly conserved serine-994 to alanine in the ATP hydrolysis motif in the SMC6 C-terminal domain, resulted in mice with a surprisingly mild phenotype. With the neo gene selection marker in the intron following the mutation, resulting in reduced expression of the SMC6 gene, the mice were reduced in size, but fertile and had normal lifespans. When the neo gene was removed, the mice had normal size, but detailed phenotypic analysis revealed minor abnormalities in glucose tolerance, haematopoiesis, nociception and global gene expression patterns. Embryonic fibroblasts derived from the ser994 mutant mice were not sensitive to killing by a range of DNA damaging agents, but they were sensitive to the induction of sister chromatid exchanges induced by ultraviolet light or mitomycin C. They also accumulated more oxidative damage than wild-type cells. 23441686 Comparative Study of Chromatographic Medium-Associated Mass and Potential Antitumor Activity Loss with Bioactive Extracts. Natural product drug discovery programs often rely on the use of silica (Si) gel, reversed-phase media, or size-exclusion resins (e.g., RP-C(18), Sephadex LH-20) for compound purification. The synthetic polymer-based sorbent Diaion HP20SS (cross-linked polystyrene matrix) is used as an alternative to prepare purified natural product libraries. To evaluate the impact of chromatographic media on the isolation of biologically active, yet chromatographically unstable natural products, Diaion HP20SS was evaluated side-by-side with normal-phase sorbents for irreversible binding of extract constituents and their effects on bioactivity. An array of chemically diverse natural product-rich extracts was selected as a test panel, and a cell-based reporter assay for hypoxia-inducible factor-1 (HIF-1) was employed to monitor potential change(s) in bioactivity. Silica gel caused significant irreversible binding of three out of 10 extracts. Curcuma longa, Saururus cernuus, and Citrus reticulata extracts showed decreased HIF-1 inhibitory activity after elution through Si gel. An additional nonpolar column wash of HP20SS with EtOAc retained considerable bioactivities of active extracts. In general, Si gel produced the greatest loss of bioactivity. However, HP20SS elution reduced significantly HIF-1 inhibitory activity of certain extracts (e.g., Asimina triloba). 23587526 Kappa opioid receptors in the central amygdala regulate ethanol actions at presynaptic GABAergic sites. Human and animal studies indicate that kappa opioid receptor (KOR) systems are involved in ethanol drinking and dependence (Xuei et al., 2006; Walker and Koob, 2008; Walker et al., 2011). The central amygdala (CeA) is a critical brain region mediating anxiety-related behavior and drug reward and is a likely site for the interaction of the KOR system and ethanol, although few studies have explored this interaction. Using in vitro single-cell recording techniques in mouse brain slices, we examined the physiological effects of KOR activation in CeA on GABAergic neurotransmission and its interaction with acute ethanol. A selective KOR agonist (U69593, 1 μM) diminished evoked GABAergic inhibitory postsynaptic currents (IPSCs) by 18% (n = 10) in the CeA, whereas blockade of KORs with a selective antagonist (nor-binaltorphimine, 1 μM) augmented the baseline evoked GABAergic IPSCs by 14% (p < 0.01; n = 34), suggesting that the KOR system contributes to tonic inhibition of GABAergic neurotransmission in the CeA. In addition, the enhancement by acute ethanol of GABAergic IPSC amplitudes in the CeA was further augmented by pharmacological blockade of KORs, from 14 % (n = 36) to 27% (n = 26; p < 0.01), or by genetic deletion of KORs, from 14 % in WT mice (n = 19) to 34 % in KOR knockout (KO) mice (n = 13, p < 0.01), suggesting that the KOR system regulates acute ethanol actions in the CeA. Subsequent experiments using tetrodotoxin to block activity-dependent neurotransmission suggest that KORs regulate GABA release at presynaptic sites. Thus, KOR activation modulates GABAergic neurotransmission and ethanol effects in CeA in a manner similar to other subtypes of opioid receptors, i.e., mu and delta opioid receptors (Kang-Park et al., 2007; Kang-Park et al., 2009). Our data support the idea that KORs modulate GABAergic synaptic responses and ethanol effects as one of multiple opioid system-dependent actions of ethanol in the CeA, possibly in a circuit-specific manner. 23610123 Genetics of mineralocorticoid excess: an update for clinicians. Aldosterone plays a major role in regulating sodium and potassium homeostasis, and blood pressure. More recently aldosterone has emerged as a key hormone in mediating end organ damage. In extreme cases, dysregulated aldosterone production leads to primary aldosteronism, the most common form of secondary hypertension. However, even within the physiological range, high levels of aldosterone are associated with an increased risk of developing hypertension over time. Primary aldosteronism represents the most common and curable form of hypertension, with a prevalence that increases with the severity of hypertension. Although genetic causes underlying glucocorticoid remediable aldosteronism, one of the three Mendelian forms of primary aldosteronism, were established some time ago, somatic and inherited mutations in the potassium channel GIRK4 have only recently been implicated in the formation of aldosterone producing adenoma and in familial hyperaldosteronism type 3. Moreover, recent findings have identified somatic mutations in two additional genes, involved in maintaining intracellular ionic homeostasis and cell membrane potential, in a subset of aldosterone producing adenoma.This review summarizes our current knowledge on the genetic determinants that contribute to variations in plasma aldosterone and renin levels in the general population, and the genetics of familial and sporadic primary aldosteronism. Various animal models that have significantly improved our understanding of the pathophysiology of excess aldosterone production will also be discussed. Finally, we will outline the cardiovascular, renal and metabolic consequences of mineralocorticoid excess beyond blood pressure regulation. 23358191 Relative impact of incorporating pharmacokinetics on predicting in vivo hazard and mode of action from high-throughput in vitro toxicity assays. The use of high-throughput in vitro assays has been proposed to play a significant role in the future of toxicity testing. In this study, rat hepatic metabolic clearance and plasma protein binding were measured for 59 ToxCast phase I chemicals. Computational in vitro-to-in vivo extrapolation was used to estimate the daily dose in a rat, called the oral equivalent dose, which would result in steady-state in vivo blood concentrations equivalent to the AC 50 or lowest effective concentration (LEC) across more than 600 ToxCast phase I in vitro assays. Statistical classification analysis was performed using either oral equivalent doses or unadjusted AC 50 /LEC values for the in vitro assays to predict the in vivo effects of the 59 chemicals. Adjusting the in vitro assays for pharmacokinetics did not improve the ability to predict in vivo effects as either a discrete (yes or no) response or a low effect level (LEL) on a continuous dose scale. Interestingly, a comparison of the in vitro assay with the lowest oral equivalent dose with the in vivo endpoint with the lowest LEL suggested that the lowest oral equivalent dose may provide a conservative estimate of the point of departure for a chemical in a dose-response assessment. Furthermore, comparing the oral equivalent doses for the in vitro assays with the in vivo dose range that resulted in adverse effects identified more coincident in vitro assays across chemicals than expected by chance, suggesting that the approach may also be used to identify potential molecular initiating events leading to adversity. 22480349 New triterpenoids from Morus alba L. stem bark. Two lupeol-type pentacyclic triterpenoids characterised as lup-20(29)-en-3β-ol-27-oic acid (moruslupenoic acid A) and lup-12, 20(29)-dien-3β-ol-26-oic acid (moruslupenoic acid B) and lanst-5, 24-dien-3β-yl acetate (moruslanosteryl acetate) along with the known triterpenoidal phytoconstituents α-amyrin acetate, β-amyrin-β-D-glucopyranoside and betulinic acid have been isolated from the stem bark of Morus alba L. (Moraceae). The structures of the isolated phytoconstituents were established on the basis of spectral data analysis and chemical means. 23411323 Near infrared reflectance spectroscopy for determination of the geographical origin of wheat. The feasibility of using near infrared reflectance (NIR) spectroscopy combined with chemometrics was investigated to discriminate wheat geographical origins. A total of 240 wheat samples from two growing years from four major wheat producing regions in China were analyzed. After spectral data pre-treatment to wheat kernel and whole wheat flour, linear discriminant analysis (LDA) based on principal component scores and discriminant partial least squares analysis (DPLS) were applied to classify origins of samples excluding water spectrum. The results showed that there were significant differences among wheat NIR spectra from different regions. Wheat could be classified based on geographical origins with chemometrics. DPLS were better than LDA for wheat origin determination. In conclusion, NIRS combined with chemometrics is a promising method for identifying wheat according to geographical origin, but the effectiveness should be verified further. 23610081 Central Pulse Pressure and Its Hemodynamic Determinants in Middle-Aged Adults With Impaired Fasting Glucose and Diabetes: The Asklepios study. OBJECTIVEPulse pressure (PP), a strong predictor of cardiovascular events in type 2 diabetes, is a composite measure affected by several hemodynamic factors. Little is known about the hemodynamic determinants of central PP in type 2 diabetes or whether abnormalities in central pulsatile hemodynamics are already present in individuals with impaired fasting glucose (IFG). In a population-based study, we aimed to compare central PP and its hemodynamic determinants among adults with normal fasting glucose (n = 1654), IFG (n = 240), and type 2 diabetes (n = 33).RESEARCH DESIGN AND METHODSWe measured carotid pressure, left ventricular outflow, aortic root diameter, carotid artery flow, and distension in order to measure various structural and hemodynamic arterial parameters.RESULTSIFG was associated with a greater mean arterial pressure (MAP) but was not associated with intrinsic aortic stiffening or abnormal aortic pulsatile indices after adjustment for MAP. After adjustment for age, sex, and MAP, type 2 diabetes was associated with a higher aortic root characteristic impedance (Zc), aortic root elastance-thickness product (Eh), and aortic root pulse wave velocity (but not aortic root diameter), a greater carotid-femoral pulse wave velocity, and lower total arterial compliance and wave reflection magnitude. Carotid size, Zc, distensibility, or Eh did not significantly differ between the groups.CONCLUSIONSType 2 diabetes, but not IFG, is associated with greater large artery stiffness, without abnormalities in aortic root diameter or carotid stiffness. Subjects with type 2 diabetes demonstrate a decreased reflection magnitude, which may indicate an increased penetration of pulsatile energy to distal vascular beds. 23143619 Multi-cell type human liver microtissues for hepatotoxicity testing. Current 2-dimensional hepatic model systems often fail to predict chemically induced hepatotoxicity due to the loss of a hepatocyte-specific phenotype in culture. For more predictive in vitro models, hepatocytes have to be maintained in a 3-dimensional environment that allows for polarization and cell-cell contacts. Preferably, the model will reflect an in vivo-like multi-cell type environment necessary for liver-like responses. Here, we report the characterization of a multi-cell type microtissue model, generated from primary human hepatocytes and liver-derived non-parenchymal cells. Liver microtissues were stable and functional for 5 weeks in culture enabling, for example, long-term toxicity testing of acetaminophen and diclofenac. In addition, Kupffer cells were responsive to inflammatory stimuli such as LPS demonstrating the possibility to detect inflammation-mediated toxicity as exemplified by the drug trovafloxacin. Herewith, we present a novel 3D liver model for routine testing in 96-well format capable of reducing the risk of unwanted toxic effects in the clinic. 23247471 Selective focused-ion-beam sculpting of TiO2 nanotubes and mechanism understanding. Anodic TiO(2) nanotubes with different structures, doping agents, and decorations have been studied in order to improve energy conversion and storage efficiencies such as in dye sensitized solar cells, solar fuels, and electrochemical supercapacitors. However, the top surface modification of TiO(2) nanotubes has never been addressed. In this study, anodic TiO(2) nanotubes have been selectively closed by high energy focused ion beams and re-opened by low energy focused ion beams. Under a 30 kV Ga(+) beam, TiO(2) nanotubes are closed with a 65 nm shield layer covering the top entrance when the ion dose is larger than 1.2 × 10(17) ions per cm(2); under a 5 kV Ga(+) beam, the shield layer is removed and the closed tubes are re-opened. An ion-induced viscous flow model has been proposed to explain the influence of Ga(+) ion beam flux, substrate temperature, initial tube diameter, ion beam dwell time, and the incidence angle of the ion beam. 23476936 When bugs reveal biodiversity. One of the fundamental challenges of conservation biology is gathering data on species distribution and abundance. And unless conservationists know where a species is found and in which numbers, it is very difficult to apply effective conservation efforts. In today's age of increasingly powerful monitoring tools, instant communication and online databases, one might be forgiven for thinking that such knowledge is easy to come by. However, of the approximately 5,400 terrestrial mammals on the IUCN Red List, no fewer than 789 (ca. 14%) are listed as 'Data Deficient' (IUCN 2012) – IUCN’s term for 'haven't got a clue'. Until recently, the only way to gather information of numbers and distribution of terrestrial mammals (and many other vertebrates) was through observational-based approaches such as visual records, the presence of tracks or spoor or even identification from bushmeat or hunters' trophies pinned to the walls in local villages. While recent technological developments have considerably improved the efficacy of such approaches, for example, using remote-sensing devices such as audio- or camera-traps or even remote drones (Koh & Wich 2012), there has been a growing realization of the power of molecular methods that identify mammals based on trace evidence. Suitable substrates include the obvious, such as faecal and hair samples (e.g. Vigilant et al. 2009), to the less obvious, including environmental DNA extracted from sediments, soil or water samples (e.g. Taberlet et al. 2012), and as recently demonstrated, the dietary content of blood-sucking invertebrates (Gariepy et al. 2012; Schnell et al. 2012). In this issue of Molecular Ecology, Calvignac-Spencer et al. (2013) present a potentially powerful development in this regard; diet analysis of carrion flies. With their near global distribution, and as most field biologists know, irritatingly high frequency in most terrestrial areas of conservation concern (which directly translates into ease of sampling them), the authors present extremely encouraging results that indicate how carnivorous flies may soon represent a strong weapon in the conservation arsenal. 23186588 Neuronal P2X3 receptor activation is essential to the hyperalgesia induced by prostaglandins and sympathomimetic amines released during inflammation. We have demonstrated that the activation of P2X3 receptor on peripheral afferent neurons is critical to development of inflammatory hyperalgesia in peripheral tissue, although pharmacological administration of prostaglandin E(2) or sympathomimetic amines is enough to sensitize primary afferent neurons by acting directly in neuronal receptors. Therefore, to clarify this ambiguity this study verifies whether P2X3 receptor activation on primary afferent neurons enables the sensitization induced by prostaglandin E(2) or sympathomimetic amine. Initially, this study confirmed that co-administration of A317491 (60 μg/paw), a selective P2X3 receptor antagonist, or pre-treatment with dexamethasone (1 mg/mL/kg) prevents the mechanical hyperalgesia induced by carrageenan (300 μg/paw) in the rat's hind paw. Sub-threshold doses of PGE(2) (4 ng/paw) or dopamine (0.4 μg/paw), that do not induce hyperalgesia by themselves, when injected just following αβmeATP or carrageenan in rats treated with dexamethasone induced hyperalgesia, which is prevented by A317491 or treatment with periganglionar (DRG-L5) injections of ODN-antisense, against P2X3 receptor. Furthermore, because PKCɛ translocation induces an increase of neuronal susceptibility to inflammatory mediators, this study demonstrates that αβmeATP in peripheral tissue increases the expression of PKCɛ in cell membranes of DRG-L5, and in contrast, the administration of PKCɛ translocation inhibitor (1 μg/paw) in peripheral tissue 45 min before αβmeATP, prevented the hyperalgesia induced by sub-threshold dose of PGE(2) (4 ng/paw). In conclusion, this study suggests that neuronal P2X3 receptor activation and the consequent PKCɛ translocation increase the susceptibility of nociceptor to inflammatory mediators allowing the development of inflammatory hyperalgesia. 23375228 Discovery and structure-activity relationships of small molecules that block the human immunoglobulin G-human neonatal Fc receptor (hIgG-hFcRn) protein-protein interaction. The neonatal Fc receptor, FcRn, prolongs the half-life of IgG in the serum and represents a potential therapeutic target for the treatment of autoimmune disease. Small molecules that block the protein-protein interactions of human IgG-human FcRn may lower pathogenic autoantibodies and provide effective treatment. A novel class of quinoxalines has been discovered as antagonists of the IgG:FcRn protein-protein interaction through optimization of a hit derived from a virtual ligand-based screen. 23484901 Direct modulation of microtubule stability contributes to anthracene general anesthesia. Recently, we identified 1-aminoanthracene as a fluorescent general anesthetic. To investigate the mechanism of action, a photoactive analogue, 1-azidoanthracene, was synthesized. Administration of 1-azidoanthracene to albino stage 40-47 tadpoles was found to immobilize animals upon near-UV irradiation of the forebrain region. The immobilization was often reversible, but it was characterized by a longer duration consistent with covalent attachment of the ligand to functionally important targets. IEF/SDS-PAGE examination of irradiated tadpole brain homogenate revealed labeled protein, identified by mass spectrometry as β-tubulin. In vitro assays with aminoanthracene-cross-linked tubulin indicated inhibition of microtubule polymerization, similar to colchicine. Tandem mass spectrometry confirmed anthracene binding near the colchicine site. Stage 40-47 tadpoles were also incubated 1 h with microtubule stabilizing agents, epothilone D or discodermolide, followed by dosing with 1-aminoanthracene. The effective concentration of 1-aminoanthracene required to immobilize the tadpoles was significantly increased in the presence of either microtubule stabilizing agent. Epothilone D similarly mitigated the effects of a clinical neurosteroid general anesthetic, allopregnanolone, believed to occupy the colchicine site in tubulin. We conclude that neuronal microtubules are "on-pathway" targets for anthracene general anesthetics and may also represent functional targets for some neurosteroid general anesthetics. 23237450 Calcium-dependent ligand binding and G-protein signaling of family B GPCR parathyroid hormone 1 receptor purified in nanodiscs. GPCRs mediate intracellular signaling upon external stimuli, making them ideal drug targets. However, little is known about their activation mechanisms due to the difficulty in purification. Here, we introduce a method to purify GPCRs in nanodiscs, which incorporates GPCRs into lipid bilayers immediately after membrane solubilization, followed by single-step purification. Using this approach, we purified a family B GPCR, parathyroid hormone 1 receptor (PTH1R), which regulates calcium and phosphate homeostasis and is a drug target for osteoporosis. We demonstrated that the purified PTH1R in nanodiscs can bind to PTH(1-34) and activate G protein. We also observed that Ca(2+) is a weak agonist of PTH1R, and Ca(2+) in millimolar concentration can switch PTH(1-34) from an inverse agonist to an agonist. Hence, our results show that nanodiscs are a viable vehicle for GPCR purification, enabling studies of GPCRs under precise experimental conditions without interference from other cellular or membrane components. 23066870 Optimization of CD4/gp120 inhibitors by thermodynamic-guided alanine-scanning mutagenesis. As protein/protein interactions usually trigger signalling processes, inhibitors of those interactions must preclude protein binding without eliciting the signalling process themselves. To accomplish those goals, small molecules need to target those protein residues that contribute the most to binding (binding hotspots) without disturbing those residues that initiate signalling processes (allosteric hotspots). The availability of a blueprint identifying binding and allosteric hotspots will significantly aid inhibitor design and optimization. In this study, we show that in some situations the blueprint can be constructed by combining the standard technique of alanine-scanning mutagenesis with isothermal titration calorimetry (ITC). We demonstrate the approach by developing the combined binding and allosteric hotspots blueprint for CD4/gp120, the initial interaction leading to HIV-1 cell infection. A major finding of these studies is that not all binding hotspots are allosteric hotspots opening the possibility for the rational design of inhibitors and antagonist or agonist modulators. 23515287 The Androgen Metabolite, 5α-Androstane-3β,17β-Diol (3β-Diol), Activates the Oxytocin Promoter Through an Estrogen Receptor-β Pathway. Testosterone has been shown to suppress the acute stress-induced activation of the hypothalamic-pituitary-adrenal axis; however, the mechanisms underlying this response remain unclear. The hypothalamic-pituitary-adrenal axis is regulated by a neuroendocrine subpopulation of medial parvocellular neurons in the paraventricular nucleus of the hypothalamus (PVN). These neurons are devoid of androgen receptors (ARs). Therefore, a possibility is that the PVN target neurons respond to a metabolite in the testosterone catabolic pathway via an AR-independent mechanism. The dihydrotestosterone metabolite, 5α-androstane-3β,17β-diol (3β-diol), binds and activates estrogen receptor-β (ER-β), the predominant ER in the PVN. In the PVN, ER-β is coexpressed with oxytocin (OT). Therefore, we tested the hypothesis that 3β-diol regulates OT expression through ER-β activation. Treatment of ovariectomized rats with estradiol benzoate or 3β-diol for 4 days increased OT mRNA selectively in the midcaudal, but not rostral PVN compared with vehicle-treated controls. 3β-Diol treatment also increased OT mRNA in the hypothalamic N38 cell line in vitro. The functional interactions between 3β-diol and ER-β with the human OT promoter were examined using an OT promoter-luciferase reporter construct (OT-luc). In a dose-dependent manner, 3β-diol treatment increased OT-luc activity when cells were cotransfected with ER-β, but not ER-α. The 3β-diol-induced OT-luc activity was reduced by deletion of the promoter region containing the composite hormone response element (cHRE). Point mutations of the cHRE also prevented OT-luc activation by 3β-diol. These results indicate that 3β-diol induces OT promoter activity via ER-β-cHRE interactions. 23591125 Cerebral ischemia-induced difference in sensitivity to depression and potential therapeutics in rats. The 'vascular depression' hypothesis has recently attracted significant research attention, although the causal relationship between vascular-related injuries and depression has not been established. Here, we show that one episode of cerebral ischemia was sufficient to greatly increase the sensitivity of rats to potentially depressogenic events, evaluated at below-threshold intensities in the open space swim test. The induced 'ischemic depression' was lasting and sensitive to an acute administration of brain-derived neurotrophic factor or bryostatin-1, a relatively selective activator of protein kinase Cε, during the induction phase. Chronic treatment with bryostatin-1 (5 weeks) after the induction of depressive behavior reversed the depressive immobility and produced a lasting therapeutic effect, which remained effective 3 weeks after discontinuation of the treatment. Similar treatment with alaproclate, a selective serotonin reuptake inhibitor, in contrast, produced temporary relief from the depressive symptoms, with the therapeutic effect disappearing soon after the end of the treatment. The results strongly suggest that cerebral ischemia has a direct role in shaping the sensitivity of an individual to depressogenic events and that bryostatin-1-like agents may be developed as therapeutics for treating ischemic depression in humans. 23586436 Using in Situ X-ray Reflectivity to Study Protein Adsorption on Hydrophilic and Hydrophobic Surfaces: Benefits and Limitations. We have employed in situ X-ray reflectivity (IXRR) to study the adsorption of a variety of proteins (lysozyme, cytochrome c, myoglobin, hemoglobin, serum albumin, and immunoglobulin G) on model hydrophilic (silicon oxide) and hydrophobic surfaces (octadecyltrichlorosilane self-assembled monolayers), evaluating this recently developed technique for its applicability in the area of biomolecular studies. We report herein the highest resolution depiction of adsorbed protein films, greatly improving on the precision of previous neutron reflectivity (NR) results and previous IXRR studies. We were able to perform complete scans in 5 min or less with the maximum momentum transfer of at least 0.52 Å(-1), allowing for some time-resolved information about the evolution of the protein film structure. The three smallest proteins (lysozyme, cytochrome c, and myoglobin) were seen to deposit as fully hydrated, nondenatured molecules onto hydrophilic surfaces, with indications of particular preferential orientations. Time evolution was observed for both lysozyme and myoglobin films. The larger proteins were not observed to deposit on the hydrophilic substrates, perhaps because of contrast limitations. On hydrophobic surfaces, all proteins were seen to denature extensively in a qualitatively similar way but with a rough trend that the larger proteins resulted in lower coverage. We have generated high-resolution electron density profiles of these denatured films, including capturing the growth of a lysozyme film. Because the solution interface of these denatured films is diffuse, IXRR cannot unambiguously determine the film extent and coverage, a drawback compared to NR. X-ray radiation damage was systematically evaluated, including the controlled exposure of protein films to high-intensity X-rays and exposure of the hydrophobic surface to X-rays before adsorption. Our analysis showed that standard measuring procedures used for XRR studies may lead to altered protein films; therefore, we used modified procedures to limit the influence of X-ray damage. 23291047 Biophysical characterization of the drug-membrane interactions: The case of propranolol and acebutolol. The interaction of propranolol and acebutolol with biological membranes was assessed in the present work by using a range of biophysical techniques and liposomes, as membrane mimetic models. Liposomes were made of zwitterionic phosphatidylcholines and experiments were performed at physiologic pH and at various membrane physical states (gel, ripple and fluid phases). Fluorescence techniques were used to study the partition coefficient of β-blockers, the influence of drugs on membrane fluidity and the drugs-membrane binding. Moreover, small and wide angle X-ray scattering techniques were used to evaluate the β-blockers effect on long range bilayer order and hydrocarbon chain packing. The gathered results highlighted the importance of electrostatic interactions between propranolol and acebutolol with membranes. Furthermore, both β-blockers exhibited a membrane-fluidizing effect and the capacity to disturb the membrane organization. In general, propranolol unveiled a more pronounced effect on membrane fluidity and structure than acebutolol. In the current study, the obtained results were also correlated with the cardioprotective properties of the β-blockers studied. 23228652 Targeting VEGF signalling via the neuropilin co-receptor. The blockade of tumour vascularisation and angiogenesis continues to be a focus for drug development in oncology and other pathologies. Historically, targeting vascular endothelial growth factor (VEGF) activity and its association with VEGF receptors (VEGFRs) has represented the most promising line of attack. More recently, the recognition that VEGFR co-receptors, neuropilin-1 and -2 (NRP1 and NRP2), are also engaged by specific VEGF isoforms in tandem with the VEGFRs has expanded the landscape for the development of modulators of VEGF-dependent signalling. Here, we review the recent structural characterisation of VEGF interactions with NRP subdomains and the impact this has had on drug development activity in this area. 23609001 Designing degradable hydrogels for orthogonal control of cell microenvironments. Degradable and cell-compatible hydrogels can be designed to mimic the physical and biochemical characteristics of native extracellular matrices and provide tunability of degradation rates and related properties under physiological conditions. Hence, such hydrogels are finding widespread application in many bioengineering fields, including controlled bioactive molecule delivery, cell encapsulation for controlled three-dimensional culture, and tissue engineering. Cellular processes, such as adhesion, proliferation, spreading, migration, and differentiation, can be controlled within degradable, cell-compatible hydrogels with temporal tuning of biochemical or biophysical cues, such as growth factor presentation or hydrogel stiffness. However, thoughtful selection of hydrogel base materials, formation chemistries, and degradable moieties is necessary to achieve the appropriate level of property control and desired cellular response. In this review, hydrogel design considerations and materials for hydrogel preparation, ranging from natural polymers to synthetic polymers, are overviewed. Recent advances in chemical and physical methods to crosslink hydrogels are highlighted, as well as recent developments in controlling hydrogel degradation rates and modes of degradation. Special attention is given to spatial or temporal presentation of various biochemical and biophysical cues to modulate cell response in static (i.e., non-degradable) or dynamic (i.e., degradable) microenvironments. This review provides insight into the design of new cell-compatible, degradable hydrogels to understand and modulate cellular processes for various biomedical applications. 23213199 Estradiol exerts antiapoptotic effects in skeletal myoblasts via mitochondrial PTP and MnSOD. 17β-Estradiol (E(2)) protects several non-reproductive tissues from apoptosis, including skeletal muscle. We have shown that E(2) at physiological concentrations prevented apoptosis induced by H(2)O(2) in C2C12 skeletal myoblasts. As we also demonstrated the presence of estrogen receptors in mitochondria, the present work was focused on the effects of E(2) on this organelle. Specifically, we evaluated the actions of E(2) on the mitochondrial permeability transition pore (MPTP) by the calcein-acetoxymethylester/cobalt method using fluorescence microscopy and flow cytometry. Pretreatment with E(2) prevented MPTP opening induced by H(2)O(2), which preceded loss of mitochondrial membrane potential. In addition, it was observed that H(2)O(2) induced translocation of Bax to mitochondria; however, in the presence of the steroid this effect was abrogated suggesting that members of the Bcl-2 family may be regulated by E(2) to exert an antiapoptotic effect. Moreover, E(2) increased mitochondrial manganese superoxide dismutase protein expression and activity, as part of a mechanism activated by E(2) that improved mitochondrial performance. Our results suggest a role of E(2) in the regulation of apoptosis with a clear action at the mitochondrial level in C2C12 skeletal myoblast cells. 23147645 Effect of the disintegrin eristostatin on melanoma-natural killer cell interactions. Malignant melanoma is difficult to treat due to its resistance to chemotherapeutic regimens. Discovery of new pharmaceuticals with inhibitory potential can be helpful in the development of novel treatments. The snake venom disintegrin eristostatin, from the viper Eristicophis macmahoni, caused immunodeficient mice to be significantly protected from development of lung colonization when melanoma cells and the disintegrin were co-injected in vivo into the lateral tail vein compared to vehicle controls. Cytotoxicity assays suggested that eristostatin makes the melanoma cells a better target for lysis by human natural killer cells. Direct binding assays using atomic force microscopy showed eristostatin does specifically bind the surface of the six melanoma cell lines tested. Eristostatin binding was partially inhibited by the addition of soluble RGDS peptide, suggesting an integrin as one likely, but not the sole, binding partner. Studies done with melanoma cells on a culture dish and natural killer cells attached to a cantilever tip in atomic force microscopy showed four major populations of interactions which exhibited altered frequency and unbinding strength in the presence of eristostatin. 23220609 The estrogenic effects of benzylparaben at low doses based on uterotrophic assay in immature SD rats. Benzylparaben (BzP), a type of parabens being used as a preservative agent in cosmetics, food, and pharmaceutical products, may be ingested by humans. In this study, we performed an immature uterotrophic assay using Sprague Dawley (SD) rats by intragastric administration to determine the estrogenic effects of BzP and found significant increases in uterine weight with doses of 0.16 mg/kg body weight and higher (P<0.05). The in vivo estrogenicity of BzP was supported by in vitro results from the human estrogen receptor α (hERα)-coactivator recruiting assay and in silico molecular docking analysis performed in this study. The in vitro estrogenic activity of BzP can be observed at concentrations of 1.0×10(-8) M and higher. Molecular docking analysis showed that BzP fits well into the agonist pocket of hERα. The lowest observed effect dose (LOED) (0.16 mg/kg/day) of BzP is much lower than the documented LOEDs of other parabens. Actual risk may exist for people who consume a diet high in BzP or use BzP-laden cosmetics. In addition, we tested the sensitivity of Wistar rats to 17β-estradiol by immature uterotrophic assay, and no obvious uterotrophic response was observed in the rats given doses up to 100 μg/kg body weight. 23274893 EphA5-EphrinA5 interactions within the ventromedial hypothalamus influence counterregulatory hormone release and local glutamine/glutamate balance during hypoglycemia. Activation of β-cell EphA5 receptors by its ligand ephrinA5 from adjacent β-cells has been reported to decrease insulin secretion during hypoglycemia. Given the similarities between islet and ventromedial hypothalamus (VMH) glucose sensing, we tested the hypothesis that the EphA5/ephrinA5 system might function within the VMH during hypoglycemia to stimulate counterregulatory hormone release as well. Counterregulatory responses and glutamine/glutamate concentrations in the VMH were assessed during a hyperinsulinemic-hypoglycemic glucose clamp study in chronically catheterized awake male Sprague-Dawley rats that received an acute VMH microinjection of ephrinA5-Fc, chronic VMH knockdown, or overexpression of ephrinA5 using an adenoassociated viral construct. Local stimulation of VMH EphA5 receptors by ephrinA5-Fc or ephrinA5 overexpression increased, whereas knockdown of VMH ephrinA5 reduced counterregulatory responses during hypoglycemia. Overexpression of VMH ephrinA5 transiently increased local glutamate concentrations, whereas ephrinA5 knockdown produced profound suppression of VMH interstitial fluid glutamine concentrations in the basal state and during hypoglycemia. Changes in ephrinA5/EphA5 interactions within the VMH, a key brain glucose-sensing region, act in concert with islets to restore glucose homeostasis during acute hypoglycemia, and its effect on counterregulation may be mediated by changes in glutamate/glutamine cycling. 23632099 Non-classic congenital adrenal hyperplasia. Non-classic or late-onset congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive disorders. Reported prevalence is approximately 1 in 1000. Affected individuals typically present due to signs and symptoms of androgen excess. The purpose of this review is to provide current information regarding the pathophysiology, molecular genetics, and management of this common disorder. The treatment of NCAH needs to be directed towards the symptoms. For affected children, goals of treatment include normal linear growth velocity, normal rate of skeletal maturation, "on-time" puberty. For affected adolescent and adult women, goals of treatment include regular menstrual cycles, prevention or progression of hirsutism and acne, and fertility. Treatment needs to be individualized and should not be initiated merely to decrease abnormally elevated hormone concentrations. 23048186 Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. The melanocortin-4 receptor (MC4R) is well recognized as an important mediator of body weight homeostasis. Activation of MC4R causes dramatic weight loss in rodent models, and mutations in human are associated with obesity. This makes MC4R a logical target for pharmacological therapy for the treatment of obesity. However, previous studies in rodents and humans have observed a broad array of side effects caused by acute treatment with MC4R agonists, including increased heart rate and blood pressure. We demonstrate that treatment with a highly-selective novel MC4R agonist (BIM-22493 or RM-493) resulted in transient decreases in food intake (35%), with persistent weight loss over 8 weeks of treatment (13.5%) in a diet-induced obese nonhuman primate model. Consistent with weight loss, these animals significantly decreased adiposity and improved glucose tolerance. Importantly, we observed no increases in blood pressure or heart rate with BIM-22493 treatment. In contrast, treatment with LY2112688, an MC4R agonist previously shown to increase blood pressure and heart rate in humans, caused increases in blood pressure and heart rate, while modestly decreasing food intake. These studies demonstrate that distinct melanocortin peptide drugs can have widely different efficacies and side effects. 23457123 Delay and impairment in brain development and function in rat offspring after maternal exposure to methylmercury. Maternal exposure to the neurotoxin methylmercury (MeHg) has been shown to have adverse effects on neural development of the offspring in man. Little is known about the underlying mechanisms by which MeHg affects the developing brain. To explore the neurodevelopmental defects and the underlying mechanism associated with MeHg exposure, the cerebellum and cerebrum of Wistar rat pups were analyzed by [(18)F]FDG PET functional imaging, field potential analysis, and microarray gene expression profiling. Female rat pups were exposed to MeHg via maternal diet during intrauterinal and lactational period (from gestational day 6 to postnatal day (PND)10), and their brain tissues were sampled for the analysis at weaning (PND18-21) and adulthood (PND61-70). The [(18)F]FDG PET imaging and field potential analysis suggested a delay in brain activity and impaired neural function by MeHg. Genome-wide transcriptome analysis substantiated these findings by showing (1) a delay in the onset of gene expression related to neural development, and (2) alterations in pathways related to both structural and functional aspects of nervous system development. The latter included changes in gene expression of developmental regulators, developmental phase-associated genes, small GTPase signaling molecules, and representatives of all processes required for synaptic transmission. These findings were observed at dose levels at which only marginal changes in conventional developmental toxicity endpoints were detected. Therefore, the approaches applied in this study are promising in terms of yielding increased sensitivity compared with classical developmental toxicity tests. 23339744 Thyroid hormone levels within reference range are associated with heart rate, cardiac structure and function in middle-aged men and women. Background Triiodothyronine (T3) has many effects on the heart and marked changes in cardiac function and structure occur in patients with (subclinical) thyroid disease. We investigated whether between-subject variation in thyroid hormone levels within the euthyroid range is also associated with heart rate and echocardiographic heart function and structure. Methods Subjects were selected from the Asklepios study (n=2524), a population-representative random sample between 35 and 55 yrs, free from overt cardiovascular disease at baseline. Analyses were restricted to 2078 subjects (1013 women and 1065 men), not using antihypertensive or thyroid medication nor having anti-TPO levels above clinical cut-off or TSH levels outside the reference range. All subjects were phenotyped in-depth and underwent comprehensive echocardiography, including diastolic evaluation. Thyroid function parameters were determined by automated electrochemiluminescence. Results Heart rate was robustly positively associated with (quartiles of) (F)T3, both in subjects with TSH levels within reference (0.27-4.2 µU/l) as in narrow TSH-range (0.5-2.5 µU/l) (p≤0.0001). (F)T3 was negatively associated with LV (left ventricular) end-diastolic volume but positively with relative wall thickness. TT3 was associated with enhanced ventricular contraction (as assessed by tissue Doppler imaging). FT4, FT3 and TT3 were positively associated with late ventricular filling, and TT3 was associated with early ventricular filling. Conclusion We have demonstrated a strong positive association between thyroid hormone levels within the euthyroid range and heart rate, and more subtle effects on cardiac function and structure. More specifically, we suggest smaller LV cavity size (with increased relative wall thickness), an enhanced atrial and ventricular contraction and LV relaxation with higher circulating thyroid hormones. These results illustrate that variation of thyroid hormone levels even within the reference range exerts effects on the heart. 23444043 Phenolic constituents from Parakmeria yunnanensis and their anti-HIV-1 activity. Three new phenolic compounds, yunnanensins A-C (1-3), together with fourteen known ones (4-17), were isolated from the leaves and stems of Parakmeria yunnanensis. The structures of new compounds were established on the basis of extensive spectroscopic analyses. Several compounds showed weak anti-HIV-1 activity. 22591175 Improvement in solubility and bioavailability of puerarin by mechanochemical preparation. An efficient and solvent-free procedure was developed to improve the solubility and bioavailability of the poorly water-soluble drug puerarin by mechanochemical technology. The stable inclusion complex of puerarin and 2-hydroxypropyl-β-cyclodextrin (HPCD) was prepared by a ball mill under the following conditions: equimolar ratio of puerarin to HPCD; rotational speed of 250 rpm; milling time of 90 min; steel balls of 22 mm diameter. The solid complex was characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffractometry (XRD), and fourier transformation-infrared spectroscopy (FT-IR). Mechanochemical action could result in enhanced molecular encapsulation, homogeneous distribution and amorphization of the drug. In comparison to puerarin, a 1.64-fold increase in absolute bioavailability was obtained. The solubility of the inclusion complex was 25.33-fold higher and the drug release amount reached 79.44% at 15 min, 2.76-fold higher. 23637353 Diabetes Prevention and Treatment Strategies: Are we doing enough? OBJECTIVEEffective interventions to prevent, delay, or remit diabetes are currently available. However, their impact on the prevalence of diabetes at the population level is unknown. This study aimed to estimate the impact of a range of diabetes interventions on the population prevalence of diabetes for Australian adults between 2010 and 2025.RESEARCH DESIGN AND METHODSWe used the Australian Diabetes Projection Model to estimate the impact of a population-wide strategy, high-risk prevention, surgical diabetes treatment, and a combination strategy on the future population prevalence of diabetes and to estimate the number of diabetes cases that could be potentially prevented in the year 2025.RESULTSWe estimate that a population-wide strategy would reduce the number of diabetes cases by 60,000-85,000 in 2025 from an estimated 2 million cases under the status quo scenario. A high-risk prevention strategy would result in 106,000 to 150,000 fewer cases of diabetes in 2025, and surgically induced weight loss would result in 3,000-6,000 fewer cases. No single intervention, or combination of interventions, reversed the increasing trend in diabetes prevalence over the next 15 years.CONCLUSIONSTo reverse upward trends in diabetes prevalence in future years, it is essential that current approaches to diabetes prevention and treatment are optimized and implemented and that alternative approaches to reduce the prevalence of diabetes at a population level are developed. 23340474 Drug shortages: the cycle of quantity and quality. Shortages of pharmaceutical drugs pose a serious and growing threat to public health. Although the number of drugs in shortage in the United States in any given year is very small, the number of prescription drug shortages in the country nearly tripled between 2005 and 2010. Drug shortages are becoming more severe as well as more frequent. The affected medicines include cancer treatments, anesthesia drugs, and other drugs that are critical to the treatment and prevention of serious diseases and life-threatening conditions. (The White House, Office of the Press Secretary, Executive Order 13588-Reducing Prescription Drug Shortages (http://www.whitehouse.gov/the-press-office/2011/10/31/executive-order-reducing-prescription-drug-shortages)). 23199987 Effect of high-pressure treatment on biogenic amines formation in vacuum-packed trout flesh (Oncorhynchus mykiss). The effects of vacuum packaging followed by high pressure processing on the shelf-life of fillets of rainbow trout (Oncorhynchus mykiss) were examined. Samples were pressure-treated at 300 and 500 MPa and were stored at 3.5 and 12 °C for up to 28 days (control--0 MPa) and 42 or 70 days (pressure-treated; 12 and 3.5 °C resp.). The content of eight biogenic amines (putrescine, cadaverine, spermidine, spermine, histamine, tyramine, tryptamine and phenylethylamine) were determined. Putrescine, cadaverine and tyramine showed very good correspondence with the level of applied pressure and organoleptic properties. Samples of very good quality contained less than 10 mg/kg of each of these amines. Polyamines spermidine and spermine did not show statistically significant changes with the level of applied pressure and the time of storage. Tryptamine, phenylethylamine and histamine (with the single exception of a sample stored for 70 days) were not detected in pressure-treated samples kept at 3.5 °C. 23598368 Reaction kinetics of CO2 absorption in to phosphonium based anion-functionalized ionic liquids. The reaction kinetics between CO2 and trihexyl(tetradecyl)phosphonium ([P66614]) - based ionic liquids (ILs) with prolinate ([Pro]), 2-cyanopyrrolide ([2-CNpyr]), and 3-(trifluoromethyl)pyrazolide ([3-CF3pyra]) anions are studied at temperatures from 22-60 °C. The absorption of CO2 is carried out in a stirred reactor under pseudo first order conditions. ILs are diluted to concentrations of 0.05, 0.1 and 0.15 M with tetraglyme - a nonreactive, low volatility solvent with much lower viscosity than the ILs. Physical solubility of CO2 in the mixtures is calculated using correlations developed from CO2 solubility measurements in tetraglyme and the N2O-analogy for ILs and dilute IL solutions. The diffusivity of CO2 is estimated from viscosity-dependent correlations chosen after a thorough literature review. The results indicate partial first order reaction kinetics with respect to IL with values ranging from 19 500 L mol(-1) s(-1) ([P66614][Pro]) to 3200 L mol(-1) s(-1) ([P66614][3-CF3pyra]) at 22 °C. The second order reaction rate constants follow Arrhenius behavior with the highest activation energy of 43 kJ mol(-1) measured for [P66614][Pro]. ILs with aprotic heterocylic anions (AHA), on the other hand, show small activation energies of 18 and 11 kJ mol(-1) for [P66614][3-CF3pyra] and [P66614][2-CNpyr], respectively. The ILs studied in this work exhibit reactivity comparable to or higher than common aqueous amines. High reaction rates and tunable capacity make ILs, and AHA ILs in particular, attractive solvents for CO2 separations. 23353700 Tamoxifen magnifies therapeutic impact of ceramide in human colorectal cancer cells independent of p53. Poor prognosis in patients with later stage colorectal cancer (CRC) necessitates the search for new treatment strategies. Ceramide, because of its role in orchestrating death cascades in cancer cells, is a versatile alternative. Ceramide can be generated by exposure to chemotherapy or ionizing radiation, or it can be administered in the form of short-chain analogs (C6-ceramide). Because intracellular P-glycoprotein (P-gp) plays a role in catalyzing the conversion of ceramide to higher sphingolipids, we hypothesized that administration of P-gp antagonists with C6-ceramide would magnify cell death cascades. Human CRC cell lines were employed, HCT-15, HT-29, and LoVo. The addition of either tamoxifen, VX-710, verapamil, or cyclosporin A, antagonists of P-gp, enhanced C6-ceramide cytotoxicity in all cell lines. In depth studies with C6-ceramide and tamoxifen in LoVo cells showed the regimen induced PARP cleavage, caspase-dependent apoptosis, mitochondrial membrane permeabilization (MMP), and cell cycle arrest at G1 and G2. At the molecular level, the regimen, but not single agents, induced time-dependent upregulation of tumor suppressor protein p53; however, introduction of a p53 inhibitor staved neither MMP nor apoptosis. Nanoliposomal formulations of C6-ceramide and tamoxifen were also effective, yielding synergistic cell kill. We conclude that tamoxifen is a favorable adjuvant for enhancing C6-ceramide cytotoxicity in CRC, and demonstrates uniquely integrated effects. The high frequency of expression of P-gp in CRC presents an adventitious target for complementing ceramide-based therapies, a strategy that could hold promise for treatment of resistant disease. 23480874 Temperature-Dependent Conformations of a Membrane Supported Zinc Porphyrin Tweezer by 2D Fluorescence Spectroscopy. We studied the equilibrium conformations of a zinc porphyrin tweezer composed of two carboxylphenyl-functionalized zinc tetraphenyl porphyrin subunits connected by a 1,4-butyndiol spacer, which was suspended inside the amphiphilic regions of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) liposomes. By combining phase-modulation two-dimensional fluorescence spectroscopy (2D FS) with linear absorbance and fluorimetry, we determined that the zinc porphyrin tweezer adopts a mixture of folded and extended conformations in the membrane. By fitting an exciton-coupling model to a series of data sets recorded over a range of temperatures (17-85 °C) and at different laser center wavelengths, we determined that the folded form of the tweezer is stabilized by a favorable change in the entropy of the local membrane environment. Our results provide insights toward understanding the balance of thermodynamic factors that govern molecular assembly in membranes. 23411303 D/H exchange in C-H bonds of fatty acids: implication for geographical discrimination of food materials. The stable isotope analysis of non-exchangeable hydrogen in food materials has been believed as a powerful tool for tracing geographical origins and delivery of the materials. However, little information is available for the D/H exchanges even in hydrophobic molecules, which leads to potential uncertainty on the observed results. To further evaluate the reliability of hydrogen isotopes of organic molecules, we examined the isotope exchangeability in fatty acids within phospholipid bilayers exposed to D(2)O for 12h. The results indicate that the isotope ratio is clearly increased during all examines (e.g., 93-328 ‰ in 50% D(2)O), in which its magnitude depends on type of fatty acids and state of bilayers. However, these results also indicate very clearly that the observed exchange rate is negligible if samples are exposed to natural abundance of deuterium (0.0156%) in natural and laboratory environments before/during analysis. 23623750 Molecular and functional characterization of flavin-containing monooxygenases in cynomolgus macaque. Flavin-containing monooxygenases (FMOs), drug-metabolizing enzymes essential for the metabolism of endogenous biochemicals and foreign compounds, have been characterized in human (including FMO1-5 and FMO6P), but remain to be investigated in cynomolgus macaque. In this study, cDNAs of cynomolgus FMO1-5 and FMO6 were isolated and characterized. Amino acid sequences of cynomolgus FMO1-5, respectively, shared high sequence identities (94-98%) and were closely clustered in a phylogenetic tree, with human FMO1-5. Eight different transcripts, due to alternative splicing, were isolated for cynomolgus FMO6, which is highly identical (∼96%) to human FMO6P. Among the 10 tissue types analyzed, cynomolgus FMO1, FMO2, FMO4, and FMO6 were most abundantly expressed in kidney, while cynomolgus FMO3 and FMO5 were most abundantly expressed in liver. In kidney and liver, the most abundantly expressed cynomolgus FMO genes were FMO1 and FMO3 respectively. Cynomolgus FMO1, FMO2, FMO3, and FMO5 metabolized benzydamine, and FMO1/FMO3 and FMO3 also metabolized methimazole and trimethylamine, respectively. Rates of benzydamine N-oxygenation (catalyzed by FMO3) varied (approximately 20-fold) among the 28 cynomolgus livers and were significantly correlated with FMO3 protein expression, indicating that the inter-animal variations in benzydamine N-oxygenation might be partly accounted for by the variable FMO3 expression. Cynomolgus FMO6 metabolized benzydamine only slightly, but minimal expression of FMO6 in all tissue precludes the importance of FMO6 in drug metabolism, unlike cynomolgus FMO1, FMO2, FMO3, and FMO5 which were all functional. Abundant expression of FMO1 and FMO3 in kidney and liver, respectively, suggest their importance in drug metabolism in cynomolgus macaque, similar to human. 23411305 The potential to intensify sulforaphane formation in cooked broccoli (Brassica oleracea var. italica) using mustard seeds (Sinapis alba). Sulforaphane, a naturally occurring cancer chemopreventive, is the hydrolysis product of glucoraphanin, the main glucosinolate in broccoli. The hydrolysis requires myrosinase isoenzyme to be present in sufficient activity; however, processing leads to its denaturation and hence reduced hydrolysis. In this study, the effect of adding mustard seeds, which contain a more resilient isoform of myrosinase, to processed broccoli was investigated with a view to intensify the formation of sulforaphane. Thermal inactivation of myrosinase from both broccoli and mustard seeds was studied. Thermal degradation of broccoli glucoraphanin was investigated in addition to the effects of thermal processing on the formation of sulforaphane and sulforaphane nitrile. Limited thermal degradation of glucoraphanin (less than 12%) was observed when broccoli was placed in vacuum sealed bag (sous vide) and cooked in a water bath at 100°C for 8 and 12 min. Boiling broccoli in water prevented the formation of any significant levels of sulforaphane due to inactivated myrosinase. However, addition of powdered mustard seeds to the heat processed broccoli significantly increased the formation of sulforaphane. 23297245 Sources of mercury in a contaminated stream-implications for the timescale of recovery. Mercury contamination in East Fork Poplar Creek in Tennessee arises from dissolved mercury exiting a headwater industrial complex and residual mercury in the streambed and soil throughout the watershed downstream. The headwater inputs generate chronic base flow concentrations of total mercury of about 1,000 ng/L, but most of the annual export of mercury from the system appears to originate farther downstream. Effective targeting of remedial efforts requires determining how long downstream sources might continue to contaminate the system following elimination of the headwater mercury inputs. The authors calculations suggest that (1) contaminated soils and sediments account for >80% of the annual mercury export from the entire watershed, with most export occurring during wet weather events; (2) bank erosion and resuspension of streambed particulates are the major mercury sources maintaining high annual mercury export rates; and (3) the inventory of particle-associated mercury in the streambed was not large enough to sustain the estimated export rates for more than a few years. The authors findings imply that to prevent waterborne mercury contamination in this system from continuing for decades, remedial actions will have to control the headwater mercury source that sustains day-to-day base flow mercury concentrations and the riparian stream-bank sources that generate most of the mercury export from the system. 23196670 AhR-mediated changes in global gene expression in rat liver progenitor cells. Although the tumor-promoting effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), coplanar polychlorinated biphenyls (PCBs), and related compounds in liver tissue are primarily attributed to the activation of the aryl hydrocarbon receptor (AhR), the underlying molecular mechanisms are still unclear. Liver progenitor (oval) cells have been suggested to constitute a potential target for hepatocarcinogenic chemicals. To better understand AhR-driven pathways, we analyzed the transcriptional program in response to coplanar PCB 126 in contact-inhibited rat liver progenitor WB-F344 cells using high-density microarrays. After 6-h treatment, we identified 145 significantly deregulated genes considered to be direct AhR-dependent target genes. The number of differentially regulated genes increased to 658 and 968 genes after 24 and 72 h, respectively. Gene ontology analysis revealed that these genes were primarily involved in drug and lipid metabolism, cell cycle and growth control, cancer developmental processes, cell-cell communication, and adhesion. Interestingly, the Wnt and TGF-β signaling pathways, both being involved in developmental and tumorigenic processes, belonged to the most affected pathways. AhR- and ARNT-dependent regulation of selected target genes of interest was then confirmed using TCDD as a model AhR agonist, together with pharmacological inhibition of the AhR and by RNA-interference techniques. We demonstrated AhR-dependent regulation of emerging and novel AhR target genes, such as Fst, Areg, Hbegf, Ctgf, Btg2, and Foxq1. Among them, the transcription factor Foxq1, recently suggested to contribute to tumor promotion and/or progression, was found to be regulated at both mRNA and protein levels by AhR/ARNT activation. 23036330 Droplet Digital™ PCR quantitation of HER2 expression in FFPE breast cancer samples. The human epidermal growth factor receptor 2 (HER2, also known as erbB2) gene is involved in signal transduction for cell growth and differentiation. It is a cell surface receptor tyrosine kinase and a proto-oncogene. Overexpression of HER2 is of clinical relevance in breast cancer due to its prognostic value correlating elevated expression with worsening clinical outcome. At the same time, HER2 assessment is also of importance because successful anti-tumor treatment with Herceptin® is strongly correlated with HER2 overexpression in the tumor (approximately 30% of all breast tumors overexpress HER2). In a comprehensive national study, Wolff et al. [1] state that "Approximately 20% of current HER2 testing may be inaccurate" which underscores the importance of developing more accurate methods to determine HER2 status. Droplet Digital™ PCR (ddPCR™) has the potential to improve upon HER2 measurements due to its ability to quantitate DNA and RNA targets with high precision and accuracy. Here we present a study which investigates whether ddPCR can be used to assess HER2 transcript levels in formalin-fixed paraffin embedded (FFPE) human breast tumors and whether these ddPCR measurements agree with prior assessments of these same samples by pathologists using immunohistochemistry (IHC) and in some cases fluorescence in situ hybridization (FISH). We also determined the copy number of HER2 in these samples as compared to the CEP17 reference gene. Results: Clinical FFPE samples were successfully studied using ddPCR and compared to results from standard FISH and IHC methodology. The results demonstrate that ddPCR can rank order the samples in complete agreement with the current standard methods and that ddPCR has the added benefit of providing quantitative results, rather than relying on the expert skill of a seasoned pathologist for determination. 22820274 Lipid rafts, synaptic transmission and plasticity: impact in age-related neurodegenerative diseases. The synapse is a crowded area. In the last years, the concept that proteins can be organized in different membrane domains according to their structure has emerged. Cholesterol-rich membrane domains, or lipid rafts, form an organized portion of the membrane that is thought to concentrate signaling molecules. Accumulating evidence has shown that both the pre-synaptic and post-synaptic sites are highly enriched in lipid rafts, which are likely to organize and maintain synaptic proteins in their precise localization. Here we review recent studies highlighting the importance of lipid rafts for synaptic function and plasticity, as well as their relevance for age or disease-related cognitive impairment. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23435614 Pharmacogenomics of acetylsalicylic acid and other nonsteroidal anti-inflammatory agents: clinical implications. PURPOSE: Pharmacogenomics investigates interindividual genetic variability in the DNA sequence of drug targets, drug-metabolizing enzymes or disease genes, RNA expression, or protein translation of genes affecting drug response and drug safety. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications with well-documented variation in patient response in terms of efficacy and safety. This variation may in part be explained by pharmacogenomics. METHODS: In this paper I review data on the pharmacogenomics of aspirin and other NSAIDs focusing on clinical implications. RESULTS: Existing scientific evidence supports the pharmacogenomic basis of interindividual variation in treatment response to aspirin and NSAIDs, with clinical implications for antiplatelet action, cancer chemoprevention, and drug safety. However, further research efforts are needed before knowledge on the pharmacogenomics of aspirin and NSAIDs can be implemented in clinical practice. CONCLUSION: The outcome of these research efforts would be anticipated to have added value for both science and society, contributing to the enhanced efficacy and safety of these agents through patient selection. 23313271 Aphagrandinoids A-D, cycloartane triterpenoids with antibacterial activities from Aphanamixis grandifolia. Three new cycloartane triterpenoids, aphagrandinoids A-C (1-3), and a new natural product, aphagrandinoid D (4), together with a known compound, were isolated from the leaves and twigs of Aphanamixis grandifolia. Their structures were elucidated by extensive NMR and MS techniques. Aphagrandinoid A (1), a 29-nor-cycloart triterpenoid, features with a sprio ring system at the side chain, while aphagrandinoid C (3) is a pentnortriterpenoid. Antibacterial activities of these five compounds were also evaluated. Compounds 1 and 5 showed weak antibacterial activities (MIC values: 1.57-3.13μg/mL) against Staphylococcus aureus, MRSA 92(#), and MRSA 98(#). 23246481 Wogonin inhibits H2O2-induced vascular permeability through suppressing the phosphorylation of caveolin-1. Wogonin, a naturally occurring monoflavonoid extracted from the root of Scutellaria baicalensis Georgi, has been reported for its anti-oxidant activity. However, it is still unclear whether wogonin can inhibit oxidant-induced vascular permeability. In this study, we evaluated the effects of wogonin on H2O2-induced vascular permeability in human umbilical vein endothelial cells (HUVECs). We found that wogonin can suppress the H2O2-stimulated actin remodeling and albumin uptake of HUVECs, as well as transendothelial cell migration of the human breast carcinoma cell MDA-MB-231. The mechanism revealed that wogonin inhibited H2O2-induced phosphorylation of caveolin-1 (cav-1) associating with the suppression of stabilization of VE-cadherin and β-catenin. Moreover, wogonin repressed anisomycin-induced phosphorylation of p38, cav-1 and vascular permeability. These results suggested that wogonin could inhibit H2O2-induced vascular permeability by downregulating the phosphorylation of cav-1, and that it might have a therapeutic potential for the diseases associated with the development of both oxidant and vascular permeability. 22577972 A new method for preparing pentacyclic triterpene rich Centella asiatica extracts. This study evaluated microwave-assisted extraction (MAE) for four pentacyclic triterpenes as well as developed a method for preparing a pentacyclic triterpenene rich extract from Centella asiatica. MAE was capable of increasing the yield of the pentacyclic triterpenes up to twice that produced by the heat reflux method, and it was also much less time consuming. The optimal conditions of MAE employed were extraction with absolute ethanol as solvent, an irradiation power of 600 W, at 75°C, four irradiation cycles and four extraction times. Here, we provide a simple method for the preparation of the pentacyclic triterpene rich C. asiatica extracts, which contained not less than 65% w/w total pentacyclic triterpenes. The method involved a macroporous resin (Diaion® HP-20) column eluted with ethanol and a decolourisation step with activated charcoal. 23611646 A road map for molecular ecology. The discipline of molecular ecology has undergone enormous changes since the journal bearing its name was launched approximately two decades ago. The field has seen great strides in analytical methods development, made groundbreaking discoveries and experienced a revolution in genotyping technology. Here, we provide brief perspectives on the main subdisciplines of molecular ecology, describe key questions and goals, discuss common challenges, predict future research directions and suggest research priorities for the next 20 years. 23246460 Spontaneous renal tumors in two rats from a thirteen week rodent feeding study with grain from molecular stacked trait lepidopteran and coleopteran resistant (DP-ØØ4114-3) maize. A thirteen week feeding study was conducted by feeding young adult male and female Sprague Dawley [Crl:CD®(SD)] rats diets containing grain from genetically modified (GM) DP-ØØ4114-3 maize that was either untreated (4114) or treated in the field with glufosinate ammonium (4114GLU). Control rats were fed diets containing the same concentration of near isogenic, non-GM maize grain (091) or one of three types of commercially available non-GM maize grain. At the end of the in-life phase, renal tubule tumors were reported in two male rats consuming diets containing 4114 maize grain. An expert panel of pathologists was convened as a Pathology Working Group (PWG) to review coded kidney histology sections from control (091) and treated (4114 and 4114GLU) male rats. The objectives were for the panel to characterize the histopathologic findings and to interpret their relationship to consumption of the indicated diet. The PWG concluded unanimously that the kidney tumors were characteristic of amphophilic-vacuolar (AV) tumors and AV atypical tubular hyperplasia which represent a distinctive phenotype that has been reported to occur sporadically in young Sprague Dawley Rats. The PWG determined that the neoplasms and atypical tubular hyperplasias were multicentric and bilateral which typifies tumors of familial origin. Degenerative/regenerative or cytotoxic changes consistent with nephrotoxicity leading to tumor induction were not observed in these rats and thus supports the conclusion that tumors were unrelated to consumption of the test diet. It was the unanimous opinion of the PWG that the proliferative renal tubule cell lesions were spontaneous and not related to consumption of diets containing 4114 maize grain. 23065141 The toxicity of the N-hydroxy and 6-hydroxy metabolites of 3,4-dichloropropionanilide does not depend on calcium release-activated calcium channel inhibition. Each year ~1 billion kg of herbicides are used worldwide to control the unwanted growth of plants. In the United States, over a quarter of a billion kg of herbicides are used, representing 28% of worldwide use. (Kiely, T., Donaldson, D., and Grube, A. [2004]. Pesticide Industry Sales and Usage. 2000 and 2001 Market Estimates. Available at: http://www.epa.gov/pesticides/pestsales/01pestsales/market_estimates2001.pdf. Accessed October 25, 2012.) Propanil (3,4-dichloropropionanilide [DCPA]) is a commonly used herbicide in the United States, with 2-4 million kg applied annually to 2 million acres of crop land. The immunomodulatory effects of DCPA have been well documented, but limited data are available on the effects of its metabolites. (Salazar, K. D., Ustyugova, I. V., Brundage, K. M., Barnett, J. B., and Schafer, R. [2008]. A review of the immunotoxicity of the pesticide 3,4-dichloropropionanalide. J. Toxicol. Environ. Health B Crit. Rev. 11, 630-645.) In mammals, hepatic enzymes metabolize DCPA, resulting in the production of 3,4-dichloroaniline (DCA). Further biotransformation of DCA leads to the production of 6-hydroxy-3,4-dichloroaniline (6OH-DCA) and N-hydroxy-3,4-dichloroaniline (NOH-DCA). We report, for the first time, the immunotoxic effects of DCPA metabolites on T-cell function. Human Jurkat T cells were exposed to varying concentrations of DCPA or its metabolites and assayed for effects on T-cell function. In addition, fluorine analogs of DCPA and DCA were investigated to determine the relative role of chlorine substituents on T-cell immunotoxicity. Here we report that exposure of Jurkat T cells to DCPA and DCA alters IL-2 secretion, nuclear factor of activated T cells (NFAT) activity, and calcium influx. However, exposure to 6OH-DCA and NOH-DCA reduces IL-2 secretion and NFAT activity but has no effect on calcium flux. When both chlorines in DCPA and DCA were substituted with fluorines all effects were abrogated. Our data indicate that metabolites of DCPA have differential effects on T-cell function and the presence of chlorines plays an important role in eliciting these effects. 23036111 Natural products as sources of new fungicides (I): synthesis and antifungal activity of acetophenone derivatives against phytopathogenic fungi. Several series of 45 acetophenone derivatives bearing various alkyl or benzyl substituents were conveniently synthesized and their structures characterized by (1)H and (13)C NMR spectroscopy, HRMS and single-crystal X-ray analysis. Their in vitro antifungal activities against a panel of phytopathogenic fungi were evaluated by mycelial growth rate assay. Of them, 12 derivatives (e.g., 3a-c, 4c and 4e) exhibited more potent antifungal effects on some phytopathogens than a commercial fungicide hymexazol as positive control. In particular, compound 3b with IC50 values of 10-19 μg/mL was found to be the most active in this series and might be a potential lead structure for further optimization. The preliminary structure-activity relationship (SAR) studies of a series of acetophenones are also discussed. 23402546 Vitamin B12 and homocysteine status during pregnancy in the metformin in gestational diabetes trial: responses to maternal metformin compared with insulin treatment(†) AIM: The aim of the study is to compare the effects of metformin and insulin treatment for gestational diabetes mellitus (GDM) on vitamin B12 and homocysteine (Hcy) status. METHODS: Women with GDM, who met criteria for insulin treatment, were randomly assigned to metformin (n = 89) or insulin (n = 91) in the Adelaide cohort of the metformin in gestational diabetes (MiG) trial. Fasting serum total vitamin B12 (TB12 ), holotranscobalamin (HoloTC), a marker of functional B12 status and plasma Hcy concentrations were measured at 20-34 weeks (at randomization) and 36 weeks gestation, then at 6-8 weeks postpartum. RESULTS: Circulating TB12 , HoloTC and Hcy were similar in both treatment groups at each time point. Women who were taking dietary folate supplements at randomization had higher serum TB12 and HoloTC at randomization than those not taking folate. Overall, serum TB12 fell more between randomization and 36 weeks gestation in the metformin group than in the insulin group (metformin: -19.7 ± 4.7 pmol/l, insulin: -6.4 ± 3.6 pmol/l, p = 0.004). The decrease in serum TB12 during treatment was greater with increasing treatment duration in metformin-treated (p < 0.001), but not in insulin-treated women. CONCLUSIONS: Total, but not bioavailable, vitamin B12 stores were depleted during pregnancy to a greater extent in metformin-treated than in insulin-treated women with GDM, but neither analyte differed between groups at any stage. This adds further evidence supporting metformin as a safe alternative treatment to insulin in GDM. Further investigation is needed to evaluate whether women treated with metformin for longer periods in pregnancy require additional B12 or other supplementation. 23574277 Alexander böhm (1971-2012). On November 28, 2012 Alexander (Alex) Böhm, a bacterial geneticist, died at age 41, only a few months after taking up a position as an assistant professor at the LOEWE Center for Synthetic Microbiology in Marburg, Germany. Earlier in 2012 Alex had been diagnosed with an aggressive form of thyroid cancer that left him little time to live his scientific and personal dreams. 23347584 Anti-inflammatory diterpenoids from Croton tonkinensis. Phytochemical investigation of the methanolic extract of Croton tonkinensis afforded two known kauranes (1, 2), eight new ent-kauranes (3-10), and 16 known ent-kaurane-type diterpenoids (12-27). In addition, 30 known compounds were identified by comparison of their physical and spectroscopic data with reported data. Among the isolated compounds, ent-18-acetoxykaur-16-en-15-one (20) displayed the most significant inhibition of superoxide anion generation and elastase release. 23640283 The design and realization of a large-area flexible nanofiber-based mat for pollutant degradation: an application in photocatalysis. This work demonstrates a novel multifunctional nanofibrous mat for photocatalytic applications based on TiO2 nanocables functionalized by Ag nanoparticles and coated with a thin (∼2 nm) graphitic shell. In this mat, which was realized by an electrospinning technique, each component serves a unique function: the carbon coating acts as both an adsorption material for capturing pollutants and as a charge-transfer material, the Ag nanoparticles act as a visible-light sensitizing agent and also as a charge-transfer material, finally the TiO2 nanocable mat acts as a UV sensitive photocatalytic matrix and as the flexible substrate for the other functional components. This multicomponent nanocable mat exhibits excellent photocatalytic activity under simulated solar irradiation for the degradation of model pollutants including RhB and phenol. The significant photocatalytic properties are attributed to the synergetic effect of the three functional components and the unique charge transport "freeway" property of the nanofibrous mat. In addition, the porous carbon coating infiltrated into the nanocable matrix endows the mat with excellent flexibility and enables robust, large-area (10 × 10 cm) fabrication, representing a significant advantage over previous brittle ceramic nanofibrous mat photocatalyst substrates. This study provides new insight into the design and preparation of an advanced, yet commercially practical and scaleable photocatalytic composite membrane material. The as-prepared photocatalytic mat might also be of interest in solar cell, catalysis, separation technology, biomedical engineering, and nanotechnology. 23265489 Compositional analysis of leaf cuticular membranes isolated from tea plants (Camellia sinensis L.). Chemical constituents of cuticular membranes (CMs) isolated from three tea cultivars (Camellia sinensis (L.) O. Kuntze cvs. Yabukita, Samidori and Gokou) were compared. All CMs from the adaxial side of the leaves showed higher accumulation of wax, cutin and polysaccharide, while those from the abaxial side were abundant in cutan, showing the adaptation of the adaxial side to abiotic stresses, such as wind and rain, in contrast to the abaxial side, which provides defence against pathogens. Yabukita, a major tea cultivar in Japan, developed thick CMs while Samidori and Gokou, shade-cultivated tea cultivars, had lighter CMs, reflecting their thin and soft leaves. CMs rapidly accumulated 9,10-epoxy-18-hydroxyoctadecanoic acid at a very early stage of leaf development. Additionally, shade treatment did not influence cutin biosynthesis in CMs, reflecting high adaptation of tea leaves under low light levels. 23303698 STEPS: a grid search methodology for optimized peptide identification filtering of MS/MS database search results. For bottom-up proteomics, there are wide variety of database-searching algorithms in use for matching peptide sequences to tandem MS spectra. Likewise, there are numerous strategies being employed to produce a confident list of peptide identifications from the different search algorithm outputs. Here we introduce a grid-search approach for determining optimal database filtering criteria in shotgun proteomics data analyses that is easily adaptable to any search. Systematic Trial and Error Parameter Selection--referred to as STEPS--utilizes user-defined parameter ranges to test a wide array of parameter combinations to arrive at an optimal "parameter set" for data filtering, thus maximizing confident identifications. The benefits of this approach in terms of numbers of true-positive identifications are demonstrated using datasets derived from immunoaffinity-depleted blood serum and a bacterial cell lysate, two common proteomics sample types. 23237733 Isoliquiritigenin showed strong inhibitory effects towards multiple UDP-glucuronosyltransferase (UGT) isoform-catalyzed 4-methylumbelliferone (4-MU) glucuronidation. Isoliquiritigenin, a herbal ingredient with chalcone structure, has been speculated to be able to inhibit one of the most drug-metabolizing enzymes (DMEs) UDP-glucuronosyltransferase (UGT). Therefore, the aim of the present study was to investigate the inhibition of isoliquiritigenin towards important UGT isoforms in the liver and intestine, including UGT1A1, 1A3, 1A6, 1A7, 1A8, 1A9 and 1A10. The recombinant UGT-catalyzed 4-methylumbelliferone (4-MU) glucuronidation was used as probe reactions. The results showed that 100μM of isoliquiritigenin inhibited the activity of UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, and UGT1A10 by 95.2%, 76.1%, 78.9%, 87.2%, 67.2%, 94.8%, and 91.7%, respectively. The data fitting using Dixon plot and Lineweaver-Burk plot showed that the inhibition of UGT1A1, UGT1A9 and UGT1A10 by isoliquiritigenin was all best fit to the competitive inhibition, and the second plot using the slopes from the Lineweaver-Burk plot versus isoliquiritigenin concentrations was used to calculate the inhibition kinetic parameter (K(i)) to be 0.7μM, 0.3μM, and 18.3μM for UGT1A1, UGT1A9, and UGT1A10, respectively. All these results indicated the risk of clinical application of isoliquiritigenin on the drug-drug interaction and other possible diseases induced by the inhibition of isoliquiritigenin towards these UGT isoforms. 23578994 Pancreatic beta-cell response to increased metabolic demand and to pharmacologic secretagogues requires EPAC2A. Incretin hormone action on ß-cells stimulates in parallel two different intracellular cyclic AMP-dependent signaling branches mediated by PKA and EPAC2A. Both pathways contribute towards potentiation of glucose-stimulated insulin secretion (GSIS). However, the overall functional role of EPAC2A in ß-cells as it relates to in vivo glucose homeostasis remains incompletely understood. Therefore, we have examined in vivo GSIS in global EPAC2A knockout mice. Additionally, we have conducted in vitro studies of GSIS and calcium dynamics in isolated EPAC2A-deficient islets. EPAC2A deficiency does not impact glucose-stimulated insulin secretion in mice under basal conditions. However, when mice are exposed to diet-induced insulin resistance, pharmacologic secretagogue stimulation of ß-cells with an incretin hormone glucagon-like peptide-1 analogue or with a Fatty Acid Receptor 1/GPR40 selective activator, EPAC2A is required for the increased ß-cell response to secretory demand. Under these circumstances, EPAC2A is required for potentiating the early dynamic increase in islet calcium levels after glucose stimulation, which is reflected in potentiated first phase insulin secretion. These studies broaden our understanding of EPAC2A function and highlight its significance during increased secretory demand or drive on ß-cells. Our findings advance the rationale for developing EPAC2A selective pharmacologic activators for ß-cell targeted pharmacotherapy in type 2 diabetes mellitus. 22273350 Chemical composition and antioxidant activity of the essential oil of Tabernaemontana catharinensis A. DC. leaves. The essential oils obtained by hydrodistillation from the leaves of Tabernaemontana catharinensis had their composition analysed by GC-MS. A total of 18 substances were identified, consisting of a complex mixture of sesquiterpenes (83.52%), monoterpenes (5.46%) and triterpenes (4.56%). The main components in the oil were β-caryophyllene (56.87%), α-cadinol (12.52%), 8S,13-cedran-diol (5.41%), α-terpineol (3.99%), β-eudesmol (2.54%), caryophyllene oxide (2.51%) and ethyl iso-allocholate (2.03%) along with β-cubebene, γ-cadinene, cubenol, 1,8-cineol, o-cymene, curcumenol, spathulenol, friedeline and β-sitosterol as minor constituents. An antioxidant property was tested with the oil obtained by means of 1,1-diphenyl-2-picrylhydrazyl assay; the oil presented interesting radical scavenging activity. To the best of our knowledge, this is the first study of the composition and antioxidant activity of essential oil from the T. catharinensis collected from Brazil. 22939001 Ultrasound promoted one-pot synthesis of 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile scaffolds in aqueous media: a complementary 'green chemistry' tool to organic synthesis. A green and simple approach to assembling of 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile scaffolds via three-component reaction of kojic acid, malononitrile, and aromatic aldehydes in aqueous media under ultrasound irradiation is described. The combinatorial synthesis was achieved for this methodology with applying ultrasound irradiation while making use of water as green solvent. In comparison to conventional methods, experimental simplicity, good functional group tolerance, excellent yields, short routine, and selectivity without the need for a transition metal or base catalyst are prominent features of this green procedure. 23266726 Determination of bioactive, free isothiocyanates from a glucosinolate-containing phytotherapeutic agent: a pilot study with in vitro models and human intervention. Isothiocyanates (ITCs) derived from plants of the order Brassicales are known for their antibacterial, anti-inflammatory or anticarcinogenic potential. Although only the free ITCs exert bioactivity, quantification in vivo is almost exclusively performed on total ITC/metabolite content. We therefore investigated in a pilot study the amount of free ITC at different steps critical for therapeutic efficacy. A sensitive and specific GC-MS/MS method for the simultaneous quantification of individual free ITC after solid-phase extraction (SPE) was developed. We show here that release of biologically active ITC from plants occurs at not only alkaline but also acidic pH. Furthermore, in human urine conversion of the ultimate, inactive mercapturic acid conjugate back into its corresponding bioactive form is increased at alkaline as compared to neutral pH. This was also observed in the urine of human volunteers, where - in correlation with the pH value - a mean of 0.16 to 1.03 μmol ITC was detected after oral application of a phytotherapeutic agent containing 30.4 μmol of the initial pro-drugs. The amounts of free ITC being necessary for bioactivity in vitro were found to be indeed achieved in vivo. These data might be helpful to better understand the beneficial effects of ITC observed in vivo. 23150999 Membrane domains and the "lipid raft" concept. The bulk structure of biological membranes consists of a bilayer of amphipathic lipids. According to the fluid mosaic model proposed by Singer and Nicholson, the glycerophospholipid bilayer is a two-dimensional fluid construct that allows the lateral movement of membrane components. Different types of lateral interactions among membrane components can take place, giving rise to multiple levels of lateral order that lead to highly organized structures. Early observations suggested that some of the lipid components of biological membranes may play active roles in the creation of these levels of order. In the late 1980s, a diverse series of experimental findings collectively gave rise to the lipid raft hypothesis. Lipid rafts were originally defined as membrane domains, i.e., ordered structures created as a consequence of the lateral segregation of sphingolipids and differing from the surrounding membrane in their molecular composition and properties. This definition was subsequently modified to introduce the notion that lipid rafts correspond to membrane areas stabilized by the presence of cholesterol within a liquid-ordered phase. During the past two decades, the concept of lipid rafts has become extremely popular among cell biologists, and these structures have been suggested to be involved in a great variety of cellular functions and biological events. During the same period, however, some groups presented experimental evidence that appeared to contradict the basic tenets that underlie the lipid raft concept. The concept is currently being re-defined, with greater consistency regarding the true nature and role of lipid rafts. In this article we will review the concepts, criticisms, and the novel confirmatory findings relating to the lipid raft hypothesis. 23461860 Microneedle/nanoencapsulation-mediated transdermal delivery: Mechanistic insights. A systematic study was undertaken to gain more insight into the mechanism of transdermal delivery of nanoencapsulated model dyes across microneedle (MN)-treated skin, a complex process not yet explored. Rhodamine B (Rh B) and fluorescein isothiocyanate (FITC) as model hydrophilic and hydrophobic small/medium-size molecules, respectively, were encapsulated in poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) and delivered through full thickness porcine skin pretreated with MN array. Permeation through MN-treated skin was affected by physicochemical characteristics of NPs and the encapsulated dyes. Dye flux was enhanced by smaller particle size, hydrophilicity, and negative zeta potential of NPs. Regarding encapsulated dyes, solubility at physiological pH and potential interaction with skin proteins proved to outweigh molecular weight as determinants of skin permeation. Data were verified using confocal laser scanning microscopy imaging. Findings coupled with the literature data are supportive of a mechanism involving influx of NPs, particularly of smaller size, deep into MN-created channels, generating depot dye-rich reservoirs. Molecular diffusion of the released dye across viable skin layers proceeds at a rate determined by its molecular characteristics. Data obtained provide mechanistic information of importance to the development of formulation strategies for more effective intradermal and transdermal MN-mediated delivery of nanoencapsulated therapeutic agents. 23297714 Effects of garlic fractions consumption on male reproductive functions. Many researchers have focused on the preventive and curative effects of garlic (Allium sativum), particularly on cardiovascular diseases and cancer. However, its impacts on the male reproductive system have not been clearly defined. In this study, the effect of chronic consumption of two garlic fractions was tested: one soluble in water (aqueous solution obtained by grinding and centrifugation) and the other one precipitated by ethanol (alcoholic precipitate obtained by precipitation of the aqueous solution), on different variables of male rats' reproductive functions. These two fractions were targeted to try to identify the nature of the active garlic compounds responsible for the different modifications observed on testicular parameters. The observation of seminiferous tubules of rats treated with garlic fractions showed an increased number of tubules deprived of spermatozoa. In addition, garlic fractions induced apoptosis of testicular germ cells (TdT-mediated dUTP-X nick-end labeling [TUNEL] approach) and a decrease of serum testosterone levels and seminiferous tubule DNA concentrations. In summary, our histological and molecular results suggest that one or several substances, soluble in water and precipitated by alcohol, impaired spermatogenesis. 23151002 Membrane lipids in the function of serotonin and adrenergic receptors. G-protein coupled receptors (GPCRs) are the largest class of molecules involved in signal transduction across membranes, and represent major targets in the development of novel drug candidates in all clinical areas. Since GPCRs are integral membrane proteins, interaction of membrane lipids such as cholesterol and sphingolipids with GPCRs constitutes an emerging area of research in contemporary biology. Cholesterol and sphingolipids represent important lipid components of eukaryotic membranes and play a crucial role in a variety of cellular functions. In this review, we highlight the role of these vital lipids in the function of two representative GPCRs, the serotonin(1A) receptor and the adrenergic receptor. We believe that development in deciphering molecular details of the nature of GPCR-lipid interaction would lead to better insight into our overall understanding of GPCR function in health and disease. 23142073 First report of the use of a saxitoxin-protein conjugate to develop a DNA aptamer to a small molecule toxin. Saxitoxin (STX) is a low molecular weight neurotoxin mainly produced by certain marine dinoflagellates that, along with its family of similarly related paralytic shellfish toxins, may cause the potentially fatal intoxication known as paralytic shellfish poisoning. Illness and fatality rates are low due to the effective monitoring programs that determine when toxins exceed the established regulatory action level and effectuate shellfish harvesting closures accordingly. Such monitoring programs rely on the ability to rapidly screen large volumes of samples. Many of the screening assays currently available employ antibodies or live animals. This research focused on developing an analytical recognition element that would eliminate the challenges associated with the limited availability of antibodies and the use of animals. Here we report the discovery of a DNA aptamer that targets STX. Concentration-dependent and selective binding of the aptamer to STX was determined using a surface plasmon resonance sensor. Not only does this work represent the first reported aptamer to STX, but also the first aptamer to any marine biotoxin. A novel strategy of using a toxin-protein conjugate for DNA aptamer selection was successfully implemented to overcome the challenges associated with aptamer selection to small molecules. Taking advantage of such an approach could lead to increased diversity and accessibility of aptamers to low molecular weight toxins, which could then be incorporated as analytical recognition elements in diagnostic assays for foodborne toxin detection. The selected STX aptamer sequence is provided here, making it available to any investigator for use in assay development for the detection of STX. 23168115 Regulation of serotonin (5-HT) function by a VGLUT1 dependent glutamate pathway. Unraveling the mechanisms of 5-HT neuron control might provide new insights into depression pathophysiology. In addition to the inhibitory 5-HT1A autoreceptors, cortico-raphe glutamatergic descending pathways are suggested to modulate 5-HT activity in the DRN. Here we studied how decreased VGLUT1 levels in the brain stem affect glutamate regulation of 5-HT function. VGLUT1+/- mice (C57BL/6) and wild type (WT) littermates were used. VGLUT1 expression in the DRN, 5-HT turnover and immuno histochemical analysis of neuronal activity in different areas was studied. Moreover, the functionality of the inhibitory 5-HT1A autoreceptor was assessed using electrophysiological, biochemical and pharmacological approaches. VGLUT1 immunoreactivity was markedly lower in the DRN of the VGLUT1+/- mice and specifically, in the surroundings of GABA and 5-HT cell bodies. These mice showed decreased induced neuronal activity in 5-HT cells bodies and in different forebrain areas, as well as decreased hippocampal cell proliferation and 5-HT turnover. Further, 5-HT1A autoreceptor desensitization was evidenced by electrophysiological studies, GTP-γ-S coupling to 5-HT1A autoreceptor and a lower hypothermic response to 5-HT1A activation. This study shows first time that VGLUT1 dependent glutamate innervation of the DRN could modulate 5-HT function. 22948803 Generation of monoclonal antibodies against the Galβ1-4Gal epitope: a key tool in studies of species-specific glycans expressed in fish, amphibians and birds. Whereas the Galβ1-4Gal epitope is rarely found in mammalian glycans, it has been found in glycans of various species of non-mammalian vertebrates, such as fish, amphibians and birds. Although glycans containing Galβ1-4Gal in these vertebrates were detected by precise structural analysis of the glycans using mass spectrometry and/or NMR spectrometry, there are no convenient methods to detect Galβ1-4Gal from various samples. To analyze systematically the distribution of Galβ1-4Gal in nature, we generated mouse monoclonal antibodies (mAbs) specific for Galβ1-4Gal using extracts of medaka eggs as an immunogen. Four mAbs (two immunoglobulin (Ig)Ms and two IgG1s) were obtained by enzyme-linked immunosorbent assay-based screening. The specificities of these mAbs were evaluated by frontal affinity chromatography using 142 kinds of 2-aminopyridine (PA)-derivatized oligosaccharides. While all mAbs interacted with (Galβ1-4Gal)-containing oligosaccharides at their non-reducing termini with dissociation constants (K(d)) ranging from 1.0 x 10⁻⁵ to 2.8 x 10⁻⁴ M, no apparent interaction was observed with any other glycans. The number of branches containing Galβ1-4Gal on N-glycans did not significantly affect K(d) of mAbs of IgG1 subclasses, but those of IgM mAbs were decreased by ∼1 order of magnitude, in increments of the number of branches present. Using the mAbs, we established that Galβ1-4Gal is also expressed on glycoproteins in various tissues from the African clawed frog. Immunohistochemical staining of medaka sections revealed that Galβ1-4Gal epitopes were expressed in the endothelium, epithelium and epidermis, which directly contact the external environment or invading organisms. Thus, these mAbs are useful for systematically investigating the species-specific expression of glycans, which may act as a barrier against infection. 22511240 Macrophage immunomodulatory activity of a purified polysaccharide isolated from Ganoderma atrum. The objective of this study was to evaluate the immunomodulatory effects of the purified Ganoderma atrum polysaccharide (PSG-1) on murine macrophage cell line RAW264.7. Phagocytotic assay by fluorescein isothiocyanate-dextran internalization showed that PSG-1 stimulated the phagocytosis of macrophages. G. atrum polysaccharide increased the production of NO, and the level of mRNA expression of inducible nitric oxide synthase in a dose-response manner. G. atrum polysaccharide also dose-dependently induced the release of TNF-α and interleukin-1β. Generation of reactive oxygen species was promoted by PSG-1, as determined by flow cytometry. Moreover, PSG-1 induced nuclear factor-κB activation by elevation of p65 nuclear translocation, suggesting that PSG-1 probably stimulated macrophage activities by activating the nuclear factor-κB pathway. 23517243 Decreased expression of hepatic low-density lipoprotein related protein 1 in hypothyroidism: a novel mechanism of atherogenic dyslipidemia in hypothyroidism. Background: The atherogenic effects of hypothyroidism on lipid metabolism could result, in part, from the reduced clearance of remnant lipoproteins. In this study, we investigated the expression of hepatic low-density lipoprotein receptor-related protein 1 (LRP1), a receptor for remnant lipoproteins, in hypothyroidism and the effect of triiodothyronine (T3) treatment on hepatic LRP1 expression. Methods: C57BL/6 mice were fed a normal diet (control group) or a low iodine diet supplemented with 0.15 % propylthiouracil (PTU/LI group) for 4 weeks. Mice in PTU/LI group were injected intraperitoneally with T3 (0, 30, and 150 μg/kg of body weight) for 7 days. HepG2 cells were incubated in fetal bovine serum (FBS) or charcoal-stripped FBS (CSS) with various concentrations of T3. The expression and function of LRP1 in liver samples and cells were analyzed. Results: Hypothyroidism was successfully induced in PTU/LI group mice. Hepatic LRP1 protein expression was lower in the PTU/LI group than the control group. T3 treatment up-regulated hepatic LRP1 protein expression in PTU/LI group mice. LRP1 expression in HepG2 cells was reduced after incubation in media containing CSS, which mimics hypothyroidism in vitro, and was recovered by T3 treatment. The protein expression of LRP1 in HepG2 cells was increased by T3 treatment in a dose-dependent manner up to 2.0 nM T3. However, LRP1 mRNA transcription was not affected by hypothyroidism conditions or T3 treatment, either in liver samples or HepG2 cells. T3 treatment on HepG2 cells increased cellular uptake of lipid-conjugated apolipoprotein E through LRP1. Conclusions: Our data demonstrate that hepatic LRP1 expression and function decrease in hypothyroidism and are regulated by thyroid hormone. These results suggest that in hypothyroidism, decreased expression of hepatic LRP1 may be associated with reduced clearance of circulating remnant lipoproteins. 23561163 Congeners in sugar cane spirits aged in casks of different woods. The profile of volatile compounds and aging markers in sugar cane spirits aged for 36months in casks made of 10 types of wood were studied. The ethanol content, volatile acidity, aldehydes, esters, higher alcohols, and methanol were determined. In addition, gallic, vanilic and syringic acids, siringaldehyde, coniferaldehyde, sinapaldehyde, vanillin, 5-hydroxymethylfurfural and furfural were identified and quantified. The profile of volatile compounds characterised aging in each type of wood. The beverage aged in oak cask achieved the highest contents of maturation-related congeners. The Brazilian woods, similar to oak, were jequitibá rosa and cerejeira, which presented the highest contents of some maturation-related compounds, such as vanillin, vanilic acid, syringaldehyde and sinapaldehyde. Although oak wood conferred more chemical complexity to the beverage, Brazilian woods, singly or complementarily, present potential for spirit characterisation and for improving the quality of sugar cane spirits. 22301815 Changes in carbohydrate metabolism, oxidative stress and loss of cortisol secretion in adrenocortica l cells of Oreochromis niloticus exposed in vitro to endosulfan. The effects of endosulfan, an organochlorine pesticide regularly used in Niger Delta ecological zone, were examined and also its effects on various biochemical parameters in the serum of Oreochromis niloticus, a dominant fish species in Nigeria. One hundred and fifty juveniles of O. niloticus were used for the toxicity study. Lethal concentration of 50% mortality of sample (LC50) was determined using semi-static method. From the result of the LC50 determination, lower concentrations of endosulfan were prepared for sublethal test. Five fish per test concentration in three replicates were exposed to varying concentrations of endosulfan. Glucose level and the enzyme activities were measured spectrophotometrically at the end of 28 days of exposure. Glucose levels and glutathione-S-transferase activities were significantly (p < 0.05) higher than the control and the concentrations increased with increasing concentration of the toxicant and exposure duration. Cortisol secretion was significantly (p = 0.05) lower in the treated fish than the control. These findings indicated that endosulfan altered all the investigated parameters, which is an indication of their suitability as markers for fish and other aquatic organism toxicity study. 23564596 Metabolic response demonstrated by 18F-FDG-PET/CT in metastatic medullary thyroid carcinoma under sorafenib therapy. A 51-year-old woman with a medullary thyroid carcinoma (MTC) presented with a palpable nodule in the right breast. Serum calcitonin was 1,453 pg/ml and carcinoembryonic antigen was 201 ng/ml. Cervical ultrasound and bone scintigraphy were normal. Computed tomography (CT) showed nodules in the right breast and anterior thoracic wall and a hypodense lesion in the right hepatic lobe. Histology of the breast nodule confirmed metastasis from MTC. To evaluate the metabolic activity of these lesions, 18F-fluorodeoxiglucose positron emission tomography-CT (FDG-PET/CT) scan was requested. Axial fused images revealed high FDG uptake by the breast and thoracic wall nodules and the right hepatic lobe. FDG-PET/CT also showed uptake in sacrum and right iliac bone, undetected by CT and bone scintigraphy. After seven cycles of sorafenib PET/CT became negative. Calcitonin decreased to 82.5. A PET/CT performed 6 months later remained negative. This is the first published image of the complete metabolic response of MTC to sorafenib therapy using FDG-PET/CT. 23122079 Phillyrin attenuates high glucose-induced lipid accumulation in human HepG2 hepatocytes through the activation of LKB1/AMP-activated protein kinase-dependent signalling. Phillyrin, an active constituent found in many medicinal plants and certain functional foods, has anti-obesity activity in vivo. The aim of our study was to provide new data on the molecular mechanism(s) underlying the role of phillyrin in the prevention of high glucose-induced lipid accumulation in human HepG2 hepatocytes. We found that phillyrin suppressed high glucose-induced lipid accumulation in HepG2 cells. Phillyrin strongly inhibited high glucose-induced fatty acid synthase (FAS) expression by modulating sterol regulatory element-binding protein-1c (SREBP-1c) activation. Moreover, use of the pharmacological AMP-activated protein kinase (AMPK) inhibitor compound C revealed that AMPK is essential for suppressing SREBP-1c expression in phillyrin-treated cells. Finally, we found that liver kinase B1 (LKB1) phosphorylation is required for the phillyrin-enhanced activation of AMPK in HepG2 hepatocytes. These results indicate that phillyrin prevents lipid accumulation in HepG2 cells by blocking the expression of SREBP-1c and FAS through LKB1/AMPK activation, suggesting that phillyrin is a novel AMPK activator with a role in the prevention and treatment of obesity. 23474845 The antipsychotic-like effects of the mGlu group III orthosteric agonist, LSP1-2111, involves 5-HT1A signalling. RATIONALE: Several studies have suggested that modulation of the glutamatergic system via metabotropic glutamate receptors (mGlu) could be a new way to achieve antipsychotic-like activity. LSP1-2111, the group III mGlu receptor orthosteric agonist, with a high affinity towards mGlu4 receptors, was previously shown to exhibit antipsychotic-like action in animal models displaying positive symptoms of schizophrenia. OBJECTIVES: Here, we decided to investigate the possible role of LSP1-2111 in models of negative (social interaction) and cognitive (NOR) symptoms of psychosis. We also investigated the involvement of 5-HT1A receptors in the LSP1-2111-induced antipsychotic effects. Apart from the above-mentioned models of negative and cognitive symptoms, MK-801 and amphetamine-induced hyperactivity tests, plus the DOI-induced head twitches in mice as models for positive symptoms of psychosis, were used in this part of the investigations. RESULTS: LSP1-2111 (0.5, 2, and 5 mg/ kg) dose-dependently inhibited MK-801-induced deficits in social interaction and NOR tests. The effects of the drug were antagonized by 5-HT1A antagonist, WAY100635 (0.1 mg/kg). A similar inhibition of LSP1-2111-induced effects was observed in models of positive symptoms of schizophrenia. Moreover, the concomitant administration of subeffective doses of LSP1-2111 (0.3-0.5 mg/kg) with a subeffective dose of 5-HT1A agonist, (R)-(+)-8-Hydroxy-DPAT (0.01 mg/kg), induced a clear antipsychotic-like effect in all of the procedures used. CONCLUSIONS: Altogether, we propose that the activation of group III mGlu receptors may be a promising target for the development of novel antipsychotic drugs, towards not only positive but also negative and cognitive symptoms. The action of the compound is 5-HT1A-dependent. 23395696 Methods for oxysterol analysis: Past, present and future. Oxysterols are oxidised forms of cholesterol or its precursors. In this article we will concentrate specifically on those formed in mammalian systems. Oxidation may be catalysed by endogenous enzymes or through reactive oxygen species forming a myriad of potential products. A number of these products are biologically active, and oxysterols may have roles in cholesterol homeostasis, neurogenesis, protein prenylation and in the immune system. Oxysterols are also implicated in aetiology of disease states including atherosclerosis, neurodegenerative and inflammatory diseases. Reports indicating the levels of oxysterols in plasma, cerebrospinal fluid and various tissues are in many cases unrealistic owing to a lack of attention to the possibility of autoxidation, a process by which oxysterols are formed from cholesterol by oxygen in air. This article comprises a critical assessment of the technical difficulties of oxysterol analysis, highlights methodologies utilising best practise and discusses newer procedures. 23459936 Exploring the genetic basis of chronic periodontitis: a genome-wide association study. Chronic periodontitis (CP) is a common oral disease that confers substantial systemic inflammatory and microbial burden and is a major cause of tooth loss. Here, we present the results of a genome-wide association study of CP that was carried out in a cohort of 4504 European Americans (EA) participating in the Atherosclerosis Risk in Communities (ARIC) Study (mean age-62 years, moderate CP-43% and severe CP-17%). We detected no genome-wide significant association signals for CP; however, we found suggestive evidence of association (P < 5 × 10(-6)) for six loci, including NIN, NPY, WNT5A for severe CP and NCR2, EMR1, 10p15 for moderate CP. Three of these loci had concordant effect size and direction in an independent sample of 656 adult EA participants of the Health, Aging, and Body Composition (Health ABC) Study. Meta-analysis pooled estimates were severe CP (n = 958 versus health: n = 1909)-NPY, rs2521634 [G]: odds ratio [OR = 1.49 (95% confidence interval (CI = 1.28-1.73, P = 3.5 × 10(-7)))]; moderate CP (n = 2293)-NCR2, rs7762544 [G]: OR = 1.40 (95% CI = 1.24-1.59, P = 7.5 × 10(-8)), EMR1, rs3826782 [A]: OR = 2.01 (95% CI = 1.52-2.65, P = 8.2 × 10(-7)). Canonical pathway analysis indicated significant enrichment of nervous system signaling, cellular immune response and cytokine signaling pathways. A significant interaction of NUAK1 (rs11112872, interaction P = 2.9 × 10(-9)) with smoking in ARIC was not replicated in Health ABC, although estimates of heritable variance in severe CP explained by all single nucleotide polymorphisms increased from 18 to 52% with the inclusion of a genome-wide interaction term with smoking. These genome-wide association results provide information on multiple candidate regions and pathways for interrogation in future genetic studies of CP. 22439867 New immunosuppressive cyclomyrsinol diterpenes from Euphorbia kopetdaghi Prokh. Aceton: chloroform (1:2) extracts of the aerial parts of Euphorbia kopetdaghi Prokh. (Euphorbiaceae) were investigated for its diterpenoids and afforded three new five-membered ring, pentacyclic myrisinane polyester comprised of 3,5,10-O-triacetyl-8-O-isobutanoyl-14-O-benzoylcyclomyrsinol (1), 3,5,10,14-O-tetraacetyl-8-O-(2'-methyl butanoyl)-cyclomyrsinol (2) and 3,5,10,14-O-tetracetyl-8-O-isobutanoylcyclomyrsinol (3). The structures were elucidated based on (13)C- and (1)H-NMR as well as 2D-NMR, IR and different MS spectra and the immunomodulation activity for compound 1 was evaluated through lymphocyte proliferation assay, IL-2 assay, oxidative burst of phagocytic leukocytes and through their cytotoxicity on two cell lines. Compound 1 showed significant suppressive activity against phytohemagglutinin-activated T-cell proliferation with an IC(50) of 1.83 µg mL(-1), IL-2 suppressive activity with an IC(50) of 19.0 µg mL(-1) and oxidative burst suppressive activity with an IC(50) of 1.6 µg mL(-1) and ignorable cytotoxic effect on the CC-1 rat hepatocyte and 3T3-L1 mouse fibroblast cell-lines. 23079138 Novel and de novo PHEX mutations in patients with hypophosphatemic rickets. X-linked hypophosphatemic rickets (XLH) is the most common inherited rickets. XLH is caused by inactivating mutations in the PHEX gene and is transmitted as an X-linked dominant disorder. We investigated PHEX mutation in 10 patients from 6 unrelated Turkish families by PCR-sequence analysis. Six different PHEX mutations were detected in the patients. Four of them were novel: c.1217G>A (p.C406Y) in exon 11, c.2078G>T (p.C693F) in exon 21, a splice donor site mutation in intron 13 (IVS13+1G>T), and a splice acceptor site mutation in intron 13 (IVS13-2A>G). De novo PHEX mutations were found exclusively in female patients from 4 families and inherited mutations were detected from remaining two families. The patients' phenotype was consistent with the loss of PHEX function. Literature review of 78 sporadic cases shows that de novo mutations are present in 83% female patients and female/male ratio is 5 to 1. One patient had biallilic PHEX mutations at c.1735G>A (p.G579R) whereas her mother and two siblings carried a monoallelic mutation. The clinical and laboratory findings of the patient with biallilic PHEX mutation were similar to those with monoallelic mutation. The study shows that PHEX mutation is a common cause of either familial or sporadic hypophosphatemic rickets in Turkish population. Gene dosage effect is not observed. The frequent de novo mutations found in the female patients are likely resulting from mutagenesis of X chromosome in paternal germ cells. 23146750 Cultured human peripheral blood mononuclear cells alter their gene expression when challenged with endocrine-disrupting chemicals. Endocrine disrupting chemicals (EDCs) have the potential to interfere with the hormonal system and may negatively influence human health. Microarray analysis was used in this study to investigate differential gene expression in human peripheral blood cells (PBMCs) after in vitro exposure to EDCs. PBMCs, isolated from blood samples of four male and four female healthy individuals, were exposed in vitro for 18h to either a dioxin-like polychlorinated biphenyl (PCB126, 1μM), a non-dioxin-like polychlorinated biphenyl (PCB153, 10μM), a brominated flame retardant (BDE47, 10μM), a perfluorinated alkyl acid (PFOA, 10μM) or bisphenol (BPA, 10μM). ANOVA analysis revealed a significant change in the expression of 862 genes as a result of EDC exposure. The gender of the donors did not affect gene expression. Hierarchical cluster analysis created three groups and clustered: (1) PCB126-exposed samples, (2) PCB153 and BDE47, (3) PFOA and BPA. The number of differentially expressed genes varied per compound and ranged from 60 to 192 when using fold change and multiplicity corrected p-value as filtering criteria. Exposure to PCB126 induced the AhR signaling pathway. BDE47 and PCB153 are known to disrupt thyroid metabolism and exposure influenced the expression of the nuclear receptors PPARγ and ESR2, respectively. BPA and PFOA did not induce significant changes in the expression of known nuclear receptors. Overall, each compound produced a unique gene expression signature affecting pathways and GO processes linked to metabolism and inflammation. Twenty-nine genes were significantly altered in expression under all experimental conditions. Six of these genes (HSD11B2, MMP11, ADIPOQ, CEL, DUSP9 and TUB) could be associated with obesity and metabolic syndrome. In conclusion, microarray analysis identified that PBMCs altered their gene expression response in vitro when challenged with EDCs. Our screening approach has identified a number of gene candidates that warrant further study. 23295323 Daily sperm production: application in studies of prenatal exposure to nanoparticles in mice. We investigated the influence of maternal airway exposure to nanoparticulate titanium dioxide (TiO2, UV-Titan) and carbon black (CB, Printex90), on male reproductive function in the two following generations. Time-mated C57BL/6J mice were exposed by inhalation to UV-Titan, or by intratracheal instillation with Printex90. Body and testicle weight, sperm content per g testicular parenchyma and daily sperm production (DSP) were assessed. The protocol for assessment of DSP was optimized for application in mice (C57BL/6J) and the influence of different parameters was studied. Maternal particulate exposure did not affect DSP statistically significantly in the F1 generation, although TiO2 tended to reduce sperm counts. Overall, time-to-first F2 litter increased with decreasing sperm production. There was no effect on sperm production in the F2 generation originating after TiO2 exposure. F2 offspring, whose fathers were prenatally exposed to Printex90, showed lowered sperm production. Furthermore, we report statistically significant differences in sperm production between mouse strains. 23161521 Substituent variation drives metal/monolayer/semiconductor junctions from strongly rectifying to ohmic behavior. An eight-orders of magnitude enhancement in current across Hg/X-styrene-Si junctions is caused by merely altering a substituent, X. Interface states are passivated and, depending on X, the Si Schottky junction encompasses the full range from Ohmic to strongly rectifying. This powerful electrostatic molecular effect has immediate implications for interface band alignment and sensing. 22354902 RETRACTED: Detection of acute toxicity test of crude diesel oil on Beluga, Huso huso. RETRACTED. 23052191 Repeat oral dose toxicity studies of melamine in rats and monkeys. Melamine is an important and widely used organic industrial chemical. Recently, clinical findings of renal failure and kidney stones in infants have been associated with ingestion of melamine-contaminated infant formula. To understand the toxicity and clinical outcome of melamine exposure, repeated oral dose studies in rats and monkeys were performed to characterize the subchronic toxicity of melamine. Assessment of toxicity was based on mortality, clinical signs, body weights, ophthalmic findings, clinical pathology, gross pathology, organ weights, and microscopic observations. The first rat study was intended to be a 14-day oral study followed by an 8-day recovery period. The dose levels were 140, 700, and 1,400 mg/kg/day (lowered to 1,000 mg/kg/day subsequently due to mortality). Oral administration of melamine at 700 mg/kg/day for 14 consecutive days in rats produced compound-related clinical signs (red urine), decreased body weights, and changes in clinical pathology (increased serum urea nitrogen and creatinine) and anatomical pathology (renal tubular cell debris, crystal deposition, and hyperactive regeneration of renal tubular epithelium). The kidney was identified as the target organ. Oral administration at 1,400 mg/kg/day (subsequently lowered to 1,000 mg/kg/day) resulted in animal death and moribundity. There were no treatment-related findings in the 140 mg/kg/day group. There were no compound-related findings in the high-dose recovery animals. The second rat study was a 5-day oral toxicity study with genomic biomarkers assayed in the kidney tissues. At the top dose of 1,050 mg/kg/day, similar clinical and anatomical pathology findings as described above were observed. The genes measured, Kim-1, Clu, Spp1, A2m, Lcn2, Tcfrsf12a, Gpnmb, and CD44, were significantly up-regulated (fivefold to 550-fold), while Tff3 was significantly down-regulated (fivefold). These results indicated that genomic markers could sensitively diagnose melamine-induced kidney injury. A 3-month oral study with 4-week recovery in monkeys was also conducted. In this monkey study, the animals were treated with melamine at doses of 60, 200, or 700 mg/kg/day. The administration of 700 mg/kg/day melamine by nasal-gastric gavage to monkeys resulted in test article-related clinical signs including turbid and whitish urine, urine crystals, red blood cell changes, increased serum alanine aminotransferase and kidney and/or liver weights, and microscopic findings including nephrotoxicity, pericarditis, and increased hematopoiesis. Nephrotoxicity was also noted at 200 mg/kg/day. It was concluded that the kidney is the primary target organ and the NOAEL was estimated to be 140 mg/kg/day in rats following a 14-day oral administration and 60 mg/kg/day in the monkey study. 23449199 Discovery of aromatic components with excellent fragrance properties and biological activities: β-ionols with antimelanogenetic effects and their asymmetric syntheses. Both enantiomers of dihydro-β-ionol and β-ionol, contained in the aromatic components of Osmanthus flower and of Hakuto peach, were obtained with high optical purity by lipase-catalyzed kinetic resolution of the racemates. It was found that all these enantiomers had different characteristic favorable scents and high antimelanogenetic effects. The absolute configuration and the enantiomer ratios of dihydro-β-ionol in the aromatic components of Osmanthus flower and of Hakuto peach were determined. The asymmetric synthesis of (R)-dihydro-β-ionol, one of the most valuable raw materials for fragrance and flavor, was performed from inexpensive β-ionone via lipase-catalyzed dynamic kinetic resolution followed by reduction. 23494944 Influence of the Green Tea Leaf Extract on Neurotoxicity of Aluminium Chloride in Rats. Aluminium may have an important role in the aetiology/pathogenesis/precipitation of Alzheimer's disease. Because green tea (Camellia sinensis L.) reportedly has health-promoting effects in the central nervous system, we evaluated the effects of green tea leaf extract (GTLE) on aluminium chloride (AlCl3 ) neurotoxicity in rats. All solutions were injected into the cornu ammonis region 1 hippocampal region. We measured the performance of active avoidance (AA) tasks, various enzyme activities and total glutathione content (TGC) in the forebrain cortex (FbC), striatum, basal forebrain (BFb), hippocampus, brain stem and cerebellum. AlCl3 markedly reduced AA performance and activities of cytochrome c oxidase (COX) and acetylcholinesterase (AChE) in all regions. It decreased TGC in the FbC, striatum, BFb, hippocampus, brain stem and cerebellum, and increased superoxide dismutase activity in the FbC, cerebellum and BFb. GTLE pretreatment completely reversed the damaging effects of AlCl3 on AA and superoxide dismutase activity, markedly corrected COX and AChE activities, and moderately improved TGC. GTLE alone increased COX and AChE activities in almost all regions. GTLE reduces AlCl3 neurotoxicity probably via antioxidative effects and improves mitochondrial and cholinergic synaptic functions through the actions of (-)-epigallocatechin gallate and (-)-epicatechin, compounds most abundantly found in GTLE. Our results suggest that green tea might be beneficial in Alzheimer's disease. Copyright © 2013 John Wiley & Sons, Ltd. 22995584 Induction of apoptosis in human ovarian cancer cells by new anticancer compounds, epothilone A and B. Epothilones are a new group of compounds with action mechanisms similar to taxanes. The aim of this study was to compare the effects of epothilone A (Epo A) and epothilone B (Epo B) on ovarian cancer cell line SKOV-3 with those of paclitaxel (PTX), a classic taxane. We evaluate glycoprotein P (P-gp) activity in the ovarian cancer cell line. Apoptotic and necrotic cell levels were measured by double staining with Hoechst 33258 and propidium iodide (PI) as well as Annexin V staining. The production of reactive oxygen species (ROS) and changes in mitochondrial membrane potential (ΔΨm) in cells exposed to Epo A, Epo B and PTX were studied using specific fluorescence probes, DCFH(2)-DA (2',7'-dichlorodihydrofluorescein diacetate) and JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine). The cytotoxic activity of the drugs was determined by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) test. All probes were analyzed in both the presence and absence of the antioxidant N-acetylcysteine (NAC). The results obtained demonstrated that the antiproliferative capacity of Epo A and Epo B in SKOV-3 cell line (measured as IC(50) after 72 h continuous treatment) was six and five times greater than that of PTX's respectively. Epothilones induced timecourse-dependent apoptosis and necrosis. Apoptotic and necrotic events were partially blocked by NAC, indicating ROS played a substantial role in epothilone-induced apoptosis. Cell death was also associated with a decrease in mitochondrial membrane potential, which was more pronounced after treatment with epothilones as compared to paclitaxel. 23549985 Effects of exogenous thiocyanate on mineral nutrients, antioxidative responses and free amino acids in rice seedlings. The effects of exogenous thiocyanate (SCN(-)) on amino acids composition, content of mineral nutrients and antioxidative systems in plants were investigated. Young rice seedlings (Oryza sativa L. cv. XZX 45) were grown in nutrient solutions amended with potassium thiocyanate (KSCN). Activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX) in plant materials were analyzed in vivo. Mineral nutrients and free amino acids in rice seedlings were also measured to determine metabolic responses to SCN(-) exposure. A significant reduction in transpiration and relative growth was recorded with all treatments (p < 0.05), while changes of total chlorophyll content in leaves was negligible (p > 0.05). SCN-induced toxicity appeared to be more sensitive to activities of POD in shoots and APX activities in roots than the others. The content of nutrient elements in rice seedlings exposed to exogenous SCN(-) was variable, while the effects were more evident at the highest SCN-treatment (p < 0.05). Although the change of total free amino acids in shoots of SCN-exposed seedlings was negligible (p > 0.05), responses of different amino acids to SCN(-) application were quite different. Among fifteen free amino acids detected, serine (Ser), proline (Pro), and methionine (Met) increased, while asparagine (Asp) decreased with an increase of the doses of SCN(-) supplied. Phyto-transport of SCN(-) was apparent and the removal rates were positively correlated to the doses, suggesting that phyto-assimilation of SCN(-) is an enzymatic process through a potentially un-identified degradation pathway. 23452037 Bacteriopheophytin a in the active branch of the reaction center of rhodobacter sphaeroides is not disturbed by the protein matrix as shown by 13C photo-CIDNP MAS NMR. The electronic structure of bacteriopheophytin a (BPhe a), the primary electron acceptor (ΦA) in photosynthetic reaction centers (RCs) of the purple bacterium Rhodobacter sphaeroides, is investigated by photochemically induced dynamic nuclear polarization (photo-CIDNP) magic-angle spinning (MAS) NMR spectroscopy at atomic resolution. By using various isotope labeling systems, introduced by adding different (13)C selectively labeled δ-aminolevulinic acid precursors in the growing medium of R. sphaeroides wild type (WT), we were able to extract light-induced (13)C NMR signals originating from the primary electron acceptor. The assignments are backed by theoretical calculations. By comparison of these chemical shifts to those obtained from monomeric BPhe a in solution, it is demonstrated that ΦA in the active branch appears to be electronically close to free bacteriopheophytin. Hence, there is little effect of the protein surrounding on the cofactor functionally which contributes with its standard redox potential to the electron transfer process that is asymmetric. 23194280 Experimentally engineering the edge termination of graphene nanoribbons. The edges of graphene nanoribbons (GNRs) have attracted much interest due to their potentially strong influence on GNR electronic and magnetic properties. Here we report the ability to engineer the microscopic edge termination of high-quality GNRs via hydrogen plasma etching. Using a combination of high-resolution scanning tunneling microscopy and first-principles calculations, we have determined the exact atomic structure of plasma-etched GNR edges and established the chemical nature of terminating functional groups for zigzag, armchair, and chiral edge orientations. We find that the edges of hydrogen-plasma-etched GNRs are generally flat, free of structural reconstructions, and terminated by hydrogen atoms with no rehybridization of the outermost carbon edge atoms. Both zigzag and chiral edges show the presence of edge states. 23318726 Butein protects human dental pulp cells from hydrogen peroxide-induced oxidative toxicity via Nrf2 pathway-dependent heme oxygenase-1 expressions. Rhus verniciflua Stokes is a plant that is native to East Asian countries, such as Korea, China, and Japan. Butein, a plant polyphenol, is one of the major active components of R. verniciflua. Reactive oxygen species (ROS), produced via dental adhesive bleaching agents and pulpal disease, can cause oxidative stress. Here, we found that butein possesses cytoprotective effects on hydrogen peroxide (H2O2)-induced dental cell death. H2O2 is a representative ROS and causes cell death through necrosis in human dental pulp (HDP) cells. H2O2-induced cytotoxicity and production of ROS were blocked in the presence of butein, and these effects were dose dependent. Butein also increased heme oxygenase-1 (HO-1) protein expression and HO activity. In addition, butein-dependent HO-1 expression was required for the inhibition of H2O2-induced cell death and ROS generation. Furthermore, butein treatment caused nuclear accumulation of nuclear factor-E2-related factor 2 (Nrf2) and increased the promoter activity of antioxidant response elements (AREs). Treatment of HDP cells with a c-Jun NH2-terminal kinase (JNK) inhibitor also reduced butein-induced HO-1 expression, and butein treatment led to increased JNK phosphorylation. These results indicate that butein may be used to prevent functional dental cell death and thus may be useful as a pulpal disease agent. 23163337 Genetic requirements for Moraxella catarrhalis growth under iron-limiting conditions. Iron sequestration by the human host is a first line defence against respiratory pathogens like Moraxella catarrhalis, which consequently experiences a period of iron starvation during colonization. We determined the genetic requirements for M. catarrhalis BBH18 growth during iron starvation using the high-throughput genome-wide screening technology genomic array footprinting (GAF). By subjecting a large random transposon mutant library to growth under iron-limiting conditions, mutants of the MCR_0996-rhlB-yggW operon, rnd, and MCR_0457 were negatively selected. Growth experiments using directed mutants confirmed the GAF phenotypes with ΔyggW (putative haem-shuttling protein) and ΔMCR_0457 (hypothetical protein) most severely attenuated during iron starvation, phenotypes which were restored upon genetic complementation of the deleted genes. Deletion of yggW resulted in similar attenuated phenotypes in three additional strains. Transcriptional profiles of ΔyggW and ΔMCR_0457 were highly altered with 393 and 192 differentially expressed genes respectively. In all five mutants, expression of nitrate reductase genes was increased and of nitrite reductase decreased, suggesting an impaired aerobic respiration. Alteration of iron metabolism may affect nasopharyngeal colonization as adherence of all mutants to respiratory tract epithelial cells was attenuated. In conclusion, we elucidated the genetic requirements for M. catarrhalis growth during iron starvation and characterized the roles of the identified genes in bacterial growth and host interaction. 23293024 Deletion of STK40 protein in mice causes respiratory failure and death at birth. STK40 is a putative serine/threonine kinase and was shown to induce extraembryonic endoderm differentiation from mouse embryonic stem cells. However, little is known about its physiological function in vivo. Here, we generate Stk40 knock-out mice and demonstrate that loss of the Stk40 gene causes neonatal lethality at birth. Further examination reveals that the respiratory distress and atelectasis occur in the homozygous mutants. The maturation of lung and alveolar epithelium is delayed in the mutant, as indicated by narrowed air spaces, thickened interstitial septa, and increased glycogen content in the lungs of Stk40(-/-) mice. The reduction in levels of T1-α, SP-B, and SP-C indicates delayed maturation of both type I and type II respiratory epithelial cells in Stk40(-/-) lungs. Moreover, Stk40 is found to be most highly expressed in lungs of both fetal and adult mice among all organs tested. Mechanistically, a genome-wide RNA microarray analysis reveals significantly altered expression of multiple genes known to participate in lung development. The expression of some genes involved in lipid metabolism, immune response, and glycogen metabolism is also disrupted in the lung of Stk40(-/-) mice. Protein affinity purification identifies RCN2, an activator of ERK/MAPK signaling, as an STK40-associated protein. Consistently, Stk40 deficiency attenuates the ERK/MAPK activation, and inhibition of ERK/MAPK activities reduces surfactant protein gene expression in lung epithelial cells. Collectively, this study uncovers an important role of STK40 for lung maturation and neonatal survival. STK40 may associate with RCN2 to activate ERK/MAPK signaling and control the expression of multiple key regulators of lung development. 23200944 Origin and evolution of medium chain alcohol dehydrogenases. Different lines of alcohol dehydrogenases (ADHs) have separate superfamily origins, already recognized but now extended and re-evaluated by re-screening of the latest databank update. The short-chain form (SDR) is still the superfamily with most abundant occurrence, most multiple divergence, most prokaryotic emphasis, and most non-complicated architecture. This pattern is compatible with an early appearance at the time of the emergence of prokaryotic cellular life. The medium-chain form (MDR) is also old but second in terms of all the parameters above, and therefore compatible with a second emergence. However, this step appears seemingly earlier than previously considered, and may indicate sub-stages of early emergences at the increased resolution available from the now greater number of data entries. The Zn-MDR origin constitutes a third stage, possibly compatible with the transition to oxidative conditions on earth. Within all these three lines, repeated enzymogeneses gave the present divergence. MDR-ADH origin(s), at a fourth stage, may also be further resolved in multiple or extended modes, but the classical liver MDR-ADH of the liver type can still be traced to a gene duplication ~550 MYA (million years ago), at the early vertebrate radiation, compatible with the post-eon-shift, "Cambrian explosion". Classes and isozymes correspond to subsequent and recent duplicatory events, respectively. They illustrate a peculiar pattern with functional and emerging evolutionary distinctions between parent and emerging lines, suggesting a parallelism between duplicatory and mutational events, now also visible at separate sub-stages. Combined, all forms show distinctive patterns at different levels and illustrate correlations with global events. They further show that simple molecular observations on patterns, multiplicities and occurrence give much information, suggesting common divergence rules not much disturbed by horizontal gene transfers after the initial origins. 23582273 Synthesis and antitumor activity of 1,3,4-oxadiazole possessing 1,4-benzodioxan moiety as a novel class of potent methionine aminopeptidase type II inhibitors. A series of 1,3,4-oxadiazole derivatives containing 1,4-benzodioxan moiety (7a-7q) have been designed, synthesized and evaluated for their antitumor activity. Most of the synthesized compounds were proved to have potent antitumor activity and low toxicity. Among them, compound 7a showed the most potent biological activity against Human Umbilical Vein Endothelial cells, which was comparable to the positive control. The results of apoptosis and flow cytometry (FCM) demonstrated that compound 7a induce cell apoptosis by the inhibition of MetAP2 pathway. Molecular docking was performed to position compound 7a into MetAP2 binding site in order to explore the potential target. 23263984 The yeast eukaryotic translation initiation factor 2B translation initiation complex interacts with the fatty acid synthesis enzyme YBR159W and endoplasmic reticulum membranes. Using affinity purifications coupled with mass spectrometry and yeast two-hybrid assays, we show the Saccharomyces cerevisiae translation initiation factor complex eukaryotic translation initiation factor 2B (eIF2B) and the very-long-chain fatty acid (VLCFA) synthesis keto-reductase enzyme YBR159W physically interact. The data show that the interaction is specifically between YBR159W and eIF2B and not between other members of the translation initiation or VLCFA pathways. A ybr159wΔ null strain has a slow-growth phenotype and a reduced translation rate but a normal GCN4 response to amino acid starvation. Although YBR159W localizes to the endoplasmic reticulum membrane, subcellular fractionation experiments show that a fraction of eIF2B cofractionates with lipid membranes in a YBR159W-independent manner. We show that a ybr159wΔ yeast strain and other strains with null mutations in the VLCFA pathway cause eIF2B to appear as numerous foci throughout the cytoplasm. 23617275 LiGen: a High Performance workflow for chemistry driven de novo design. Tools for molecular de novo design are actively sought incorporating sets of chemical rules for fast and efficient identification of structurally new chemotypes endowed with a desired set of biological properties. In this paper, we present LiGen, a suite of programs which can be used sequentially or as stand-alone tools for specific purposes. In its standard application, LiGen modules are used to define input constraints, either structure-based, through active site identification, or ligand-based, through pharmacophore definition, to docking and to de novo generation. Alternatively, individual modules can be combined in a user-defined manner to generate project-centric workflows. Specific features of LiGen are the use of a pharmacophore-based docking procedure which allows Flexible docking without conformer enumeration and accurate and flexible reactant mapping coupled with reactant tagging through substructure searching. The full description of LiGen functionalities is herein presented. 23606510 A Dual Enzyme Microgel with High Antioxidant Ability Based on Engineered Seleno-Ferritin and Artificial Superoxide Dismutase. An antioxidant microgel with both glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities is reported. Using computational design and genetic engineering methods, the main catalytic components of GPx are fabricated onto the surface of ferritin. The resulting seleno-ferritin (Se-Fn) monomers can self-assemble into nanocomposites that exhibit remarkable GPx activity due to the well organized multi-GPx catalytic centers. Subsequently, a porphyrin derivative is synthesized as an SOD mimic, and is employed to construct a synergistic dual enzyme system by crosslinking Se-Fn nanocomposites into a microgel. Significantly, this dual enzyme microgel is demonstrated to display better antioxidant ability than single GPx or SOD mimics in protecting cells from oxidative damage. 22872606 Anti-inflammatory and antioxidant activity of thymoquinone in a rat model of acute bacterial prostatitis. Prostatitis plays a major role in morbidity and mortality related to prostate diseases. The aim of this study was to detect whether thymoquinone (TQ) could ameliorate oxidative damage and the proliferative response induced by Escherichia coli (E. coli) in rats. A total of 42 adult male Wistar rats were used. The rats were randomly divided into seven groups (three treatment groups, three infected groups and one control group). Control group received saline and was killed 24 h after saline administration. Infected rats were killed after 24, 48 and 72 h following direct injection of E. coli into the prostate. Treatment groups were administered with 10 mg/kg dose of TQ intraperitoneally following E. coli injection and after 24 and 48 h following E. coli injection. The rats were killed at 24, 48 and 72 h after the first drug administration. Each group was compared with each other and with the control group. In addition, infected groups were compared with treatment groups. Our findings show that the treatment with TQ has a protective effect against bacterial prostatitis-induced tissue injury. Increase in malondialdehyde levels and histological damage caused by E. coli were improved markedly with TQ treatment. TQ treatment particularly increased the activity of glutathione peroxidase and decreased the activities of catalase and superoxide dismutase. These observations might be attributed, at least in part, to the antioxidant effect of TQ and suggest that it could be a clinically valuable agent in the prevention of acute prostatitis caused by E. coli. 23643755 Differential Effects of Cholinergic and Noradrenergic Neuromodulation on Spontaneous Cortical Network Dynamics. Cholinergic and noradrenergic neuromodulation play a key role in determining overall behavioral state by shaping the underlying cortical network dynamics. The effects of these systems on synaptic and intrinsic cellular targets are quite diverse and a comprehensive understanding of how these neuromodulators regulate (spontaneous) cortical network activity has remained elusive. Here, we used multielectrode electrophysiology in vitro to investigate the effect of these neuromodulators on spontaneous network dynamics in acute slices of mouse visual cortex. We found that application of Carbachol (CCh) and Norepinephrine (NE) both enhanced the spontaneous network dynamics by increasing (1) the activity levels, (2) the temporal complexity of the network activity, and (3) the spatial complexity by decorrelating the network activity over a wide range of neuromodulator concentrations (1μM, 10μM, 50μM, and 100μM). Interestingly, we found that cholinergic neuromodulation was limited to the presence of CCh in the bath whereas the effects of NE, in particular for higher concentrations, induced plasticity that caused outlasting effects most prominently in the deep cortical layers. Together, these results provide a comprehensive network-level understanding of the similarities and differences of cholinergic and noradrenergic modulation of spontaneous network dynamics. 22951949 Diethyldithiocarbamate induces apoptosis in neuroblastoma cells by raising the intracellular copper level, triggering cytochrome c release and caspase activation. Dithiocarbamates are nitrogen- and sulfur-containing compounds commonly used in pharmacology, medicine and agriculture. The molecular effects of dithiocarbamates on neuronal cell systems are not fully understood, especially in terms of their ability to accumulate copper ions inside the cell. In this work, the molecular effects of N,N-diethyldithiocarbamate (DEDTC) were studied in human SH-SY5Y neuroblastoma cells to determine the role of copper in the DEDTC toxicity and the pathway trigged in cell by the complex Cu-DEDTC. From concentration-dependent studies, we found that 5 μM of this compound induced a drastic decrease in viable cells with a concomitant accumulation in intracellular copper resulted from complexation with DEDTC, measured by atomic absorption spectroscopy. The mechanism of DEDTC-induced apoptosis in neuronal model cells is thought to occur through the death receptor signaling triggered by DEDTC-copper complex in low concentration that is associated with the activation of caspase 8. Our results indicated that the mechanism of cell death involves cytochrome c release forming the apoptosome together with Apaf-1 and caspase 9, converting the caspase 9 into its active form, allowing it to activate caspase 3 as observed by immunofluorescence. This pathway is induced by the cytotoxic effects that occur when DEDTC forms a complex with the copper ions present in the culture medium and transports them into the cell, suggesting that the DEDTC by itself was not able to cause cell death and the major effect is from its copper-complex in neuroblastoma cells. The present study suggests a role for the influence of copper by low concentrations of DEDTC in the extracellular media, the absorption and accumulation of copper in the cell and apoptotic events, induced by the cytotoxic effects that occur when DEDTC forms a complex with the copper ions. 23547762 Budesonide/cyclodextrin complex-loaded lyophilized microparticles for intranasal application. Abstract Objective: Lyophilized microparticles composed of budesonide (BDS), hydroxypropyl-β-cyclodextrin (HP-β-CD), and hydroxypropylmethylcellulose (HPMC) or sodium carboxymethylcellulose (CMC-Na) were developed for intranasal delivery and their characteristics were evaluated. Materials and methods: The particle size and morphology were assessed by mean diameter measurement and scanning electron microscopy (SEM) image, respectively. The solid-state of products was tested by X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). In vitro drug release and cytotoxicity to the primary human nasal epithelial (HNE) cells were also evaluated. Results and discussion: Lyophilized microparticles exhibited vanishment of crystallinity of drug in XRPD analysis, the enfeeblement of carbonyl (C=O) stretching bands of carboxyl group in BDS in FT-IR spectra and the disappearance of endothermic peak of drug in the results of DSC study. Based on the results of solid-state studies, BDS was existed as an amorphous form in the lyophilized microparticles. CD complexation enhanced drug solubility and release rate, and HPMC or CMC-Na also improved drug dissolution rates. Cytotoxicity of developed microparticles to the HNE cells was measured and their safety to HNE cell was identified. Conclusion: Developed microparticles can efficiently deliver insoluble drug, such as BDS, to the nasal epithelium and thus it may improve therapeutic efficacy in the respiratory tract. 23612422 Antiprotozoal screening and cytotoxicity of extracts and fractions from the leaves, stem bark and root bark of Alstonia congensis. ETHNOPHARMACOLOGICAL RELEVANCE: To evaluate the antiprotozoal activity and cytotoxicity of extracts and fractions from the leaves, root bark and stem bark of Alstonia congensis (Apocynaceae), used in traditional medicine against parasitic diseases. MATERIALS AND METHODS: The aqueous and 80% MeOH extracts, and a series of fractions and subfractions from the leaves, stem and root bark of Alstonia congensis were tested in vitro for their antiprotozoal activity against Trypanosoma brucei brucei, Trypanosoma cruzi, Lesihamania infantum and the chloroquine and pyrimethamine-resitant K1 strain of Plasmodium falciparum. Their cytotoxicity on MRC-5 cells (human lung fibroblasts) was evaluated as well. RESULTS: The aqueous and 80% MeOH extracts and a series of subfractions of each plant part exhibited pronounced antiprotozoal activity against the K1 strain of Plasmodium falciparum with IC50 values ranging from 2 to 5µg/ml, and good activity against Trypanosoma brucei brucei and Trypanosoma cruzi with IC50 values ranging between 5 and 10µg/ml. The residual 80% MeOH extract from the leaves, and the total alkaloid extract from stem and root bark were the only subfractions active against Leishmania infantum with IC50 values <10µg/ml. None of the samples from the root bark was cytotoxic against MRC-cell lines (CC50>64µg/ml). In general, the aqueous extracts (traditional decoctions) showed the highest selectivity, especially against Plasmodium falciparum. CONCLUSION: These results can partly support and justify the traditional use of these plant parts of Alstonina congensis as raw materials for the preparation of traditional remedies to treat parasitic diseases such as malaria and trypanosomiasis. 23240995 Unconventional growth mechanism for monolithic integration of III-V on silicon. The heterogeneous integration of III-V optoelectronic devices with Si electronic circuits is highly desirable because it will enable many otherwise unattainable capabilities. However, direct growth of III-V thin film on silicon substrates has been very challenging because of large mismatches in lattice constants and thermal coefficients. Furthermore, the high epitaxial growth temperature is detrimental to transistor performance. Here, we present a detailed studies on a novel growth mode which yields a catalyst-free (Al,In)GaAs nanopillar laser on a silicon substrate by metal-organic chemical vapor deposition at the low temperature of 400 °C. We study the growth and misfit stress relaxation mechanism by cutting through the center of the InGaAs/GaAs nanopillars using focused ion beam and inspecting with high-resolution transmission electron microscopy. The bulk material of the nanopillar is in pure wurtzite crystal phase, despite the 6% lattice mismatch with the substrate, with all stacking disorders well confined in the bottom-most transition region and terminated horizontally. Furthermore, InGaAs was found to be in direct contact with silicon, in agreement with the observed crystal orientation alignment and good electrical conduction across the interface. This is in sharp contrast to many III-V nanowires on silicon which are observed to stem from thin SiN(x), SiO(2), or SiO(2)/Si openings. In addition, GaAs was found to grow perfectly as a shell layer on In(0.2)Ga(0.8)As with an extraordinary thickness, which is 15 times greater than the theoretical thin-film critical thickness for a 1.5% lattice mismatch. This is attributed to the core-shell radial geometry allowing the outer layers to expand and release the strain due to lattice mismatch. The findings in this study redefine the rules for lattice-mismatched growth on heterogeneous substrates and device structure design. 23322676 Effects of antiresorptive therapies on glucose metabolism: Results from the FIT, HORIZON-PFT and FREEDOM trials. In rodent models undercarboxylated osteocalcin (ucOC) acts as a hormone promoting insulin sensitivity and secretion. If ucOC plays a similar role in humans, then antiresorptive therapies, which reduce ucOC levels, may increase the risk of insulin resistance and diabetes. We tested whether antiresorptive therapies result in higher fasting glucose, increased weight, or greater diabetes incidence in post-hoc analyses of three randomized, placebo-controlled trials in postmenopausal women: Fracture Intervention Trial (FIT) (N=6151) of alendronate (4 years), Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON-PFT) (N=7113) of zoledronic acid (3 years), and Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial (N=7076) of denosumab (3 years). Fasting glucose was measured annually in FIT and HORIZON in a subset of women, and every 6 months in FREEDOM on all participants. Weight was measured annually in all trials. Incident diabetes was identified from adverse event reports, initiation of diabetes medication, or elevated fasting glucose. Differences in fasting glucose changes from randomization to trial conclusion between treatment and placebo groups were not statistically significant: -0.47 mg/dL in FIT, 0.20 mg/dL in HORIZON-PFT and 0.09 mg/dL in FREEDOM, all p>0.6. Weight change differed between treatment and placebo groups in FIT (0.32 kg, p=0.003) and FREEDOM (0.31 kg, p=0.023), but not in HORIZON-PFT (0.15 kg, p=0.132). In the three trials combined, diabetes occurred in 203 and 225 women assigned to treatment or placebo, respectively. Diabetes incidence was not increased in any of the treatment groups or in the pooled estimate (Pooled RR = 0.90; 95% CI 0.74, 1.10). Antiresorptive therapy does not have a clinically important effect on fasting glucose, weight or diabetes risk in postmenopausal women. Contrary to predictions from mouse models, reduced bone turnover does not appear to play a significant role in glucose metabolism in humans. © 2013 American Society for Bone and Mineral Research. 23577695 Carcinogenicity Prediction of Noncongeneric Chemicals by a Support Vector Machine. The ability to identify carcinogenic compounds is of fundamental importance to the safe application of chemicals. In this study, we generated an array of in silico models allowing the classification of compounds into carcinogenic and noncarcinogenic agents based on a data set of 852 noncongeneric chemicals collected from the Carcinogenic Potency Database (CPDBAS). Twenty-four molecular descriptors were selected by Pearson correlation, F-score, and stepwise regression analysis. These descriptors cover a range of physicochemical properties, including electrophilicity, geometry, molecular weight, size, and solubility. The descriptor mutagenic showed the highest correlation coefficient with carcinogenicity. On the basis of these descriptors, a support vector machine-based (SVM) classification model was developed and fine-tuned by a 10-fold cross-validation approach. Both the SVM model (Model A1) and the best model from the 10-fold cross-validation (Model B3) runs gave good results on the test set with prediction accuracy over 80%, sensitivity over 76%, and specificity over 82%. In addition, extended connectivity fingerprints (ECFPs) and the Toxtree software were used to analyze the functional groups and substructures linked to carcinogenicity. It was found that the results of both methods are in good agreement. 23303314 Roughening of Pt nanoparticles induced by surface-oxide formation. Using density functional theory (DFT) and thermodynamic considerations we studied the equilibrium shape of Pt nanoparticles (NPs) under electrochemical conditions. We found that at very high oxygen coverage, obtained at high electrode potentials, the experimentally-observed tetrahexahedral (THH) NPs consist of high-index (520) faces. Since high-index surfaces often show higher (electro-)chemical activity in comparison to their close-packed counterparts, the THH NPs can be promising candidates for various (electro-)catalytic applications. 23369791 Liver, plasma and erythrocyte levels of thiamine and its phosphate esters in rats with acute ethanol intoxication: a comparison of thiamine and benfotiamine administration. Thiamine and benfotiamine are vitamin B1 and pro-vitamin B1 substances, respectively. Vitamin B1 plays an essential role in energy metabolism, and its deficiency leads to neurologic and cardiovascular pathologies, as seen in alcoholics. This study presents new data about the effects of thiamine hydrochloride or benfotiamine treatment given to rats with acute alcohol intoxication, on the distribution of thiamine and its phosphate esters in liver, plasma and erythrocytes. The treatments were effective in increasing thiamine levels in plasma, erythrocytes and liver cells. The benfotiamine-treated group had its total plasma thiamine increased by 100%. In erythrocytes, thiamine levels were 4- and 25-fold higher in the groups treated with thiamine and benfotiamine, respectively, compared with the untreated groups. Liver thiamine was increased by 60% in the treated groups compared with the untreated groups. Thus, we verified the high bioavailability especially of benfotiamine within 6h of ethanol administration. 22697341 A modern approach for controlled transdermal delivery of diflunisal: optimization and in vivo evaluation. The purpose of the present work was to elaborate an optimized transdermal therapeutic system for diflunisal. Selection of suitable ingredients was done via solubility and phase behavior studies. Composition of microemulsion (ME) systems consisting of butyl lactate, Brij(®) 97, Transcutol(®) and water was optimized using augmented simplex lattice mixture design. The independent variables selected were the percentages of butyl lactate, surfactant mixture and water. The dependent variables were refractive index, pH, conductivity, viscosity, drug solubility in the ME formulation and the ex vivo skin permeation flux. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The statistical validity of the polynomials was established. Optimized formulation factors were selected by desirability approach. The optimized ME formulation was converted into gel using Carbomer(®) 934. The microemulsion based gel (MBG) showed better spreadability and 5.07-fold increase in the transdermal flux than Carbomer(®) 934 gel. The in vivo antihyperalgesia assay performed on mice showed significant reduction of the licking time in the treated group compared to the control group. This demonstrated the reliability of the simplex lattice statistical design for predicting optimum ME formulation. The developed MBG proved its in vivo efficiency for transdermal delivery of diflunisal. 23346913 Quantum-dot-sensitized solar cells: understanding linker molecules through theory and experiment. We have investigated the role of linker molecules in quantum-dot-sensitized solar cells (QDSSCs) using density-functional theory (DFT) and experiments. Linkers not only govern the number of attached QDs but also influence charge separation, recombination, and transport. Understanding their behavior is therefore not straightforward. DFT calculations show that mercaptopropionic acid (MPA) and cysteine (Cys) exhibit characteristic binding configurations on TiO(2) surfaces. This information is used to optimize the cell assembly process, yielding Cys-based cells that significantly outperform MPA cells, and reach power conversion efficiencies (PCE) as high as 2.7% under AM 1.5 illumination. Importantly, the structural information from theory also helps understand the cause for this improved performance. 23408261 Faecal Excretion Dynamic during Subacute Oral Exposure to Different Pb Species in Rattus norvegicus. Faecal excretion is a basic means of detoxification upon ingestion of Pb-contaminated feed. In order to determine a time course of Pb elimination after oral exposure to two different forms of this heavy metal (lead acetate vs. phyto-bound Pb), a feeding study was carried out in experimental rats using the Pb phyto-hyperaccumulator Pistia stratiotes as a model diet. The effect of starvation on Pb excretion was further studied in rats that were fed plant material. Twelve Pb doses (7 μg Pb/1 g BW) were administered orally over a 5-week period. Faeces samples were collected 24 and 72 h post-exposure. Inductively coupled plasma optical emission spectrometry and electrothermal absorption spectrometry methods were used for determination of heavy metal concentrations. Up to 53 % of ingested Pb was rapidly eliminated from the exposed rats via faeces within 24 h after exposure. Faecal excretion in exposed rats differed significantly when compared to that of the control group. Fasting before exposure reduced Pb excretion by up to 50 %. Faecal excretions of both examined Pb forms exhibited almost identical patterns. Considerable differences were revealed concerning total excretion levels; lead acetate was excreted in amount greater extent than those of phytobound Pb. Results of our study suggest that Pb forms occurring in the P. stratiotes tissues are absorbed through the gastrointestinal tract to a greater extent than Pb from lead acetate. Therefore, higher portions of ingested Pb can be available for potential accumulation in tissues of exposed subjects. 23323519 Self-assembly of ordered epitaxial nanostructures on polygonal nanowires. We study the self-assembly of ordered nanostructures, that is, nanorings (NRs) and quantum dots (QDs), epitaxially grown on a polygonal cross-section nanowire (PCS-NW) using both theoretical and phase-field modeling. Our studies show that, by increasing the PCS-NW size, transitions from ordered NRs to ordered QDs on facets and further to ordered QDs on ridges occur. The predicted morphologies and their transitions are in excellent agreement with existing experiments. Our study suggests a novel approach to fabricate ordered nanostructures on nanowires. 23454296 Genotoxicity assessment of vaccine adjuvant squalene. The genotoxic potential of the vaccine adjuvant Squalene was assessed by the chromosomal aberrations (CAs), sister chromatid exchanges (SCEs) and micronucleus (MNs) tests in human lymphocytes and comet assay in both human and rat lymphocytes. Five different concentrations of squalene (1250-20,000μg/ml for human lymphocytes and 0.07-1.12mg/kg for rat lymphocytes) were studied. Squalene did not affect the CAs and MN frequency, in all treatments in vitro. A significant increase in SCEs was observed in almost all concentrations at 24h treatment. Squalene did not affect significantly the comet tail length (CTL) (except 2500μg/ml) and comet tail intensity (CTI) at all treatments in vitro. In rats, squalene significantly increased and decreased CTL and CTI in some doses. Although there are increasing and reduction in the effect, squalene cannot be regarded as genotoxic in human lymphocytes. However, further in vivo studies are required to be sure on the effect. 23357170 Structural Basis of Signaling Blockade by Anti-IL-13 Antibody Lebrikizumab. The cytokine interleukin 13 (IL-13) is a major effector molecule for T-helper type 2 inflammation and is pathogenic in allergic diseases such as asthma. The effects of IL-13 are mediated via a pathway that is initiated by binding to a heterodimeric receptor consisting of IL-13Rα1 and IL-4Rα. Antibodies raised against IL-13 can block its inflammatory effects by interfering with binding to either of the two receptor polypeptides. Lebrikizumab is a monoclonal anti-IL-13 antibody that has shown clinical benefit in a phase II study for the treatment of moderate-to-severe uncontrolled asthma. Here we report the molecular structure of IL-13 in complex with the Fab from lebrikizumab by X-ray crystallography at 1.9Å resolution. We show that lebrikizumab inhibits IL-13 signaling by binding to IL-13 with very high affinity and blocking IL-13 binding to IL-4Rα. In addition, we use site-directed mutations to identify the most important antibody contributors to binding. Our studies define key features of lebrikizumab binding and its mechanism of action that may contribute to its clinical effects. 23243006 Complementary detection of embryotoxic properties of substances in the neural and cardiac embryonic stem cell tests. In developmental toxicity testing, in vitro screening assays are highly needed to increase efficiency and to reduce animal use. A promising in vitro assay is the cardiac embryonic stem cell test (ESTc), in which the effect of developmental toxicants on cardiomyocyte differentiation is assessed. Recently, we developed a neural differentiation variant of the stem cell test (neural embryonic stem cell test [ESTn]). In both of these models, we have previously performed a series of transcriptomic studies to characterize gene expression changes (1) across time during normal differentiation and (2) in response to a series of developmental toxicants in the ESTn and ESTc. Here, using the cumulative of these studies, we compared gene expression profiles of ESTn and ESTc over time as well as model-specific changes induced by seven compounds, comprising six known in vivo developmental toxicants and one negative control. Time-related gene expression profiles showed similarities between the two EST systems. However, specific genes could be identified changing over time differently in each model related to the two different lineages of differentiation. Interestingly, compound-induced gene expression changes were generally model specific, especially for methylmercury and flusilazole, which were predicted better in ESTn and ESTc, respectively. Valproic acid-induced gene expression changes were most comparable out of the six developmental toxicants between the ESTn and ESTc. Direct transcriptomic comparisons between the ESTn and ESTc indicate that combined transcriptomic analyses support and complement each other. Therefore, a combined approach incorporating ESTc and ESTn may improve developmental toxicant detection over individual assays. 23376823 Prenatal developmental toxicity studies on diundecyl and ditridecyl phthalates in Sprague-Dawley rats. This study evaluates the developmental toxicity of two high molecular weight dialkyl phthalate esters, diundecyl phthalate (DUDP) and ditridecyl phthalate (DTDP). Sprague-Dawley rats were administered 0, 0.25, 0.50, or 1g/kg/day of DUDP or DTDP, by gavage, on gestation days 6-20. DUDP and DTDP had no adverse effects on maternal body weight and food consumption. The number of live fetuses, percent of post-implantation loss and of resorptions, fetal sex, and fetal body weights were not affected by either phthalate. There was no evidence of teratogenicity, whatever treatment. Small decreases in the anogenital distance of male fetuses were noted at 0.5 and 1g DUDP/kg/day. The incidence of fetuses with supernumerary lumbar ribs was significantly higher than control at 0.5 and 1g DUDP/kg/day. Thus, DTDP was not developmentally toxic up to 1g/kg/day and there were signs of DUDP-induced fetal effects at 0.5 and 1g/kg/day. 23500777 The Procrustean bed of EU food safety notifications via the Rapid Alert System for Food and Feed: Does one size fit all? Previous reports demonstrated wide variations in contributions by EU Member States (MS) to the Rapid Alert System for Food and Feed (RASFF) especially for border notifications, emphasising that MS with major entry points play a vital role in ensuring that EU food imports meet EU standards. To further explore the variation this paper aimed to examine notification practices among MS by comparing the levels of detection as a function of the total food imported and population. RASFF notifications issued between 2003 and 2007 were analysed using descriptive statistics and network analysis for differences in notification practice between MS. Major variations in contributions to the RASFF database were observed, which did not correlate with MS size or population. For the key contrast of ratio: 'border: non-border notifications', variations between 7%:89% were observed for the average monthly contributions and, import tonnage per border notification revealed up to 129-fold differences between MS. In conclusion, wide variations in food safety practice exist between MS, including both number and type of contributions to the RASFF database, with some MS being relatively highly active in the key class of border notifications. These findings should inform EU food safety enforcement policies and practices; and central resource allocations. 23376247 Synthesis and biological evaluation of thieno [2',3':4,5]pyrimido[1,2-b][1,2,4]triazines and thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines as anti-inflammatory and analgesic agents. A new series of thieno[2',3':4,5]pyrimido[1,2-b][1,2,4]triazines and thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines was synthesized. The newly synthesized compounds were evaluated for their anti-inflammatory and analgesic activity using diclofenac Na as a reference standard. Additionally, the ulcerogenic effects and acute toxicity (ALD50) values of the active compounds were also determined. In general, the thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidine derivatives exhibited better biological activities than the thieno[2',3':4,5]pyrimido[1,2-b][1,2,4]triazines. Collectively, the thienotriazolopyrimidine derivatives 9, 13 and 14a were proved to display distinctive anti-inflammatory activity at the acute and subacute models as well as good analgesic profile with a delayed onset of action. Moreover, they revealed good gastrointestinal safety profile and are well tolerated by experimental animals with high safety margin (ALD50 > 0.3 g/kg). 23455599 Acute behavioural effects of bupropion and naltrexone, alone and in combination, in non-deprived male rats presented with palatable mash. RATIONALE: In appetite research, drugs frequently progress to clinical trials on the basis of outcome (reduced food intake/body weight gain) with insufficient attention to process (behavioural analysis). Although bupropion and naltrexone (alone and in combination) reduce food consumption in rodents and humans, their effects on behaviour during feeding tests have not been thoroughly investigated. OBJECTIVES: This study aimed to assess the behavioural specificity of anorectic responses to bupropion, naltrexone and their combination. METHODS: Video analysis was employed to characterise the behavioural effects of acute systemic treatment with bupropion (10.0-40.0 mg/kg), naltrexone (0.1-3.0 mg/kg) and combined bupropion (20 mg/kg) plus naltrexone (0.1-1.0 mg/kg) in non-deprived male rats exposed for 1 h to palatable mash. Particular attention was paid to the behavioural satiety sequence (BSS). RESULTS: In experiment 1, the anorectic response to 40 mg/kg bupropion was associated with significant psychomotor stimulation and a complete disruption of the BSS. In experiment 2, the anorectic response to 3 mg/kg naltrexone was associated with an accelerated but otherwise normal BSS. In experiment 3, the co-administration of 20 mg/kg bupropion and naltrexone (0.1 and 1.0 mg/kg) not only produced an additive anorectic profile (including a reduced rate of eating), but the addition of the opioid receptor antagonist also concurrently attenuated the psychomotor stimulant response to the atypical antidepressant. CONCLUSIONS: Low-dose co-treatment with naltrexone and bupropion produces a stronger suppression of appetite than that seen with either agent alone and has the additional advantage of reducing some of the unwanted effects of bupropion. 23194515 The heat treatment and the gelation are strong determinants of the kinetics of milk proteins digestion and of the peripheral availability of amino acids. This study aimed to determine the kinetics of milk protein digestion and amino acid absorption after ingestion of four dairy matrices by six minipigs: unheated or heated skim milk and corresponding rennet gels. Digestive contents and plasma samples were collected over a 7 h-period after meal ingestion. Gelation of milk slowed down the outflow of the meal from the stomach and the subsequent absorption of amino acids, and decreased their bioavailability in peripheral blood. The gelled rennet matrices also led to low levels of milk proteins at the duodenum. Caseins and β-lactoglobulin, respectively, were sensitive and resistant to hydrolysis in the stomach with the unheated matrices, but showed similar digestion with the heated matrices, with a heat-induced susceptibility to hydrolysis for β-lactoglobulin. These results suggest a significant influence of the meal microstructure (resulting from heat treatment) and macrostructure (resulting from gelation process) on the different steps of milk proteins digestion. 22691108 Aromadendrine, a new component of the flavonoid pattern of Olea europaea L. and its anti-inflammatory activity. Leaves of Olea europaea, cultivar Nocellara del Belice, were examined with respect to the medium-polar fraction, obtained by an ethyl acetate extraction of the whole extract. In the medium polar fraction, we isolated the two hydroxy-phenyl-ethyl alcohols (hydroxyl-tyrosol and tyrosol) that are the main component of olives. In addition, we isolated a flavonoidic compound, aromadendrine, a dihydroflavonol yet known but quite rare in nature. It is the first time that aromadendrine is isolated in O. europaea and we studied the aromadendrine biological activity. In particular, the ability of aromadendrine to reduce the inflammation induced in normal keratinocytes using an in vitro cell model was evaluated. The results of the present research indicate aromadendrine as a novel component in O. europaea with effective activity against skin inflammation. 23287046 Development of an in vitro skin sensitization test based on ROS production in THP-1 cells. Recently, it has been reported that reactive oxygen species (ROS) produced by contact allergens can affect dendritic cell migration and contact hypersensitivity. The aim of the present study was to develop a new in vitro assay that could predict the skin sensitizing potential of chemicals by measuring ROS production in THP-1 (human monocytic leukemia cell line) cells. THP-1 cells were pre-loaded with a ROS sensitive fluorescent dye, 5-(and 6-)-chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate, acetyl ester (CM-H2DCFDA), for 15min, then incubated with test chemicals for 30min. The fluorescence intensity was measured by flow cytometry. For the skin sensitizers, 25 out of 30 induced over a 2-fold ROS production at more than 90% of cell viability. In contrast, increases were only seen in 4 out of 20 non-sensitizers. The overall accuracy for the local lymph node assay (LLNA) was 82% for 50 chemicals tested. A correlation was found between the estimated concentration showing 2-fold ROS production in the ROS assay and the EC3 values (estimated concentration required to induce positive response) of the LLNA. These results indicated that the THP-1 cell-based ROS assay was a rapid and highly sensitive detection system able to predict skin sensitizing potentials and potency of chemicals. 23261423 3,4-Methylenedioxy-methamphetamine induces in vivo regional up-regulation of central nicotinic receptors in rats and potentiates the regulatory effects of nicotine on these receptors. Nicotine (NIC), the main psychostimulant compound of smoked tobacco, exerts its effects through activation of central nicotinic acetylcholine receptors (nAChR), which become up-regulated after chronic administration. Recent work has demonstrated that the recreational drug 3,4-methylenedioxy-methamphetamine (MDMA) has affinity for nAChR and also induces up-regulation of nAChR in PC 12 cells. Tobacco and MDMA are often consumed together. In the present work we studied the in vivo effect of a classic chronic dosing schedule of MDMA in rats, alone or combined with a chronic schedule of NIC, on the density of nAChR and on serotonin reuptake transporters. MDMA induced significant decreases in [(3)H]paroxetine binding in the cortex and hippocampus measured 24h after the last dose and these decreases were not modified by the association with NIC. In the prefrontal cortex, NIC and MDMA each induced significant increases in [(3)H]epibatidine binding (29.5 and 34.6%, respectively) with respect to saline-treated rats, and these increases were significantly potentiated (up to 72.1%) when the two drugs were associated. Also in this area, [(3)H]methyllycaconitine binding was increased a 42.1% with NIC+MDMA but not when they were given alone. In the hippocampus, MDMA potentiated the α7 regulatory effects of NIC (raising a 25.5% increase to 52.5%) but alone was devoid of effect. MDMA had no effect on heteromeric nAChR in striatum and a coronal section of the midbrain containing superior colliculi, geniculate nuclei, substantia nigra and ventral tegmental area. Specific immunoprecipitation of solubilised receptors suggests that the up-regulated heteromeric nAChRs contain α4 and β2 subunits. Western blots with specific α4 and α7 antibodies showed no significant differences between the groups, indicating that, as reported for nicotine, up-regulation caused by MDMA is due to post-translational events rather than increased receptor synthesis. 23586925 Does Colloid Shape Affect Detachment of Colloids by a Moving Air-Water Interface? Air-water interfaces interact strongly with colloidal particles by capillary forces. The magnitude of the interaction force depends on, among other things, the particle shape. Here, we investigate the effects of particle shape on colloid detachment by a moving air-water interface. We used hydrophilic polystyrene colloids with four different shapes (spheres, barrels, rods, and oblong disks), but otherwise identical surface properties. The nonspherical shapes were created by stretching spherical microspheres on a film of polyvinyl alcohol (PVA). The colloids were then deposited onto the inner surface of a glass channel. An air bubble was introduced into the channel and passed through, thereby generating a receding followed by an advancing air-water interface. The detachment of colloids by the air-water interfaces was visualized with a confocal microscope, quantified by image analysis, and analyzed statistically to determine significant differences. For all colloid shapes, the advancing air-water interface caused pronounced colloid detachment (>63%), whereas the receding interface was ineffective in colloid detachment (<1.5%). Among the different colloid shapes, the barrels were most readily removed (94%) by the advancing interface, followed by the spheres and oblong disks (80%) and the rods (63%). Colloid detachment was significantly affected by colloid shape. The presence of an edge, as it occurs in a barrel-shaped colloid, promoted colloid detachment because the air-water interface is being pinned at the edge of the colloid. This suggests that the magnitude of colloid mobilization and transport in porous media is underestimated for edged particles and overestimated for rodlike particles when a sphere is used as a model colloid. 23247008 Comparative genomics, molecular evolution and computational modeling of ALDH1B1 and ALDH2. Vertebrate ALDH2 genes encode mitochondrial enzymes capable of metabolizing acetaldehyde and other biological aldehydes in the body. Mammalian ALDH1B1, another mitochondrial enzyme sharing 72% identity with ALDH2, is also capable of metabolizing acetaldehyde but has a tissue distribution and pattern of activity distinct from that of ALDH2. Bioinformatic analyses of several vertebrate genomes were undertaken using known ALDH2 and ALDH1B1 amino acid sequences. Phylogenetic analysis of many representative vertebrate species (including fish, amphibians, birds and mammals) indicated the presence of ALDH1B1 in many mammalian species and in frogs (Xenopus tropicalis); no evidence was found for ALDH1B1 in the genomes of birds, reptiles or fish. Predicted vertebrate ALDH2 and ALDH1B1 subunit sequences and structures were highly conserved, including residues previously shown to be involved in catalysis and coenzyme binding for human ALDH2. Studies of ALDH1B1 sequences supported the hypothesis that the ALDH1B1 gene originated in early vertebrates from a retrotransposition of the vertebrate ALDH2 gene. Given the high degree of similarity between ALDH2 and ALDH1B1, it is surprising that individuals with an inactivating mutation in ALDH2 (ALDH2*2) do not exhibit a compensatory increase in ALDH1B1 activity. We hypothesized that the similarity between the two ALDHs would allow for dominant negative heterotetramerization between the inactive ALDH2 mutants and ALDH1B1. Computational-based molecular modeling studies examining predicted protein-protein interactions indicated that heterotetramerization between ALDH2 and ALDH1B1 subunits was highly probable and may partially explain a lack of compensation by ALDH1B1 in ALDH2(∗)2 individuals. 23500769 Health-related lipids components of sardine muscle as affected by photooxidation. The aim of this study was to evaluate the oxidative stability of sardine muscle lipids as related to the storage conditions. Whole sardines were stored at 4°C for 4h under light exposure and at dark. The lowest levels of peroxide value (PV), thiobarbituric acid reactive substances (TBARs), cholesterol oxidation products (COPs) and the highest level of polyunsaturated fatty acids (PUFAs) content, especially PUFA n-3, were found in the untreated sardines (time zero). After light exposure, PUFA dramatically dropped (up to a 19% decrease) and a marked increase of PV (11.8meq O2/kg fat), TBARs (3.7mg MDA/kg meat) and COPs (3.7μg/g muscle) was observed; under darkness, the values of the oxidation parameters were similar to those found in untreated sardines. Although cholesterol oxidation rate did not exceed 0.9%, further research is required about toxicity levels of the single COPs, to better understand if the COPs levels found in untreated and photoxidized muscle (0.62-3.72μg/g of muscle) do not represent a risk for human health. 23619028 Comparative effectiveness of dabigatran, rivaroxaban, apixaban and warfarin in the management of patients with non-valvular atrial fibrillation. Alternative anticoagulants to warfarin (dabigatran, rivaroxaban and apixaban) are becoming available for the prevention of thromboembolic stroke in atrial fibrillation, but there is a lack of information on their comparative effectiveness. We evaluated this using a discrete event simulation with a lifetime horizon of analysis, based on an indirect comparison of the RE-LY, ROCKET-AF and ARISTOTLE trial results for patients with the characteristics of the US atrial fibrillation population. Over a lifetime, apixaban, dabigatran and rivaroxaban accrued 0.130 (95% central range [CR] -0.030 to 0.264), 0.106 (95% CR -0.048 to 0.248) and 0.095 (95% CR -0.052 to 0.242) more quality-adjusted life-years than warfarin, respectively, with apixaban having a 55% probability of accruing the highest total lifetime QALYs. In the absence of a definitive trial, and acknowledging the limitations of an indirect comparison, the available evidence suggests apixaban to be the more effective anticoagulant.Clinical Pharmacology & Therapeutics (2013); accepted article preview online 25 April 2013; doi:10.1038/clpt.2013.83. 23497901 Determination of major phlorotannins in Eisenia bicyclis using hydrophilic interaction chromatography: seasonal variation and extraction characteristics. In this study, a hydrophilic interaction chromatography (HILIC) condition was developed for the simultaneous determination of five major phlorotannins from an extract of Eisenia bicyclis (Kjellman) Setchell with good linearity (r(2)>0.999). Based on this method, the seasonal variations and extraction characteristics, in terms of total extraction yield and the content of the phlorotannins, were investigated under various extraction conditions. In results, the yields and phlorotannins were increased two-to-four times in summer (June-October) and then, were decreased to normal levels in winter (November-March). In the extraction of E. bicyclis, ethanol percentage in water, extraction time and washing time significantly affected the yield of the extract and the phlorotannins, whereas the temperature and the sample/solvent ratio impacted the extraction to a lesser degree. These results will be useful information in the application of this macroalga in the commercial areas related to nutraceuticals, pharmaceuticals, and cosmeceuticals. 23117151 Androgen receptor CAG repeat length modifies the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on receptor activity in human prostate cells. Increased incidence of prostate cancer has been reported in men exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD acts through the aryl hydrocarbon receptor (AhR), which interacts with the androgen receptor (AR). The AR gene contains a polymorphic CAG repeat that influences its transcriptional activity. We investigated the influence of TCDD on prostate cancer cells (PC-3) and non-tumor prostate cells (PNT1A) on 5α-dihydrotestosterone-activated ARs containing CAG repeats within normal length range (16, 22, and 28). The AhR target gene CYP1A1 mRNA expression was induced by TCDD, but was not affected by the AR CAG length. TCDD had no effect on AR activity in PC-3 cells, whereas the shortest AR variant was induced by TCDD in PNT1A cells. In conclusion, the CAG length dependent effect of TCDD on AR activity in PNT1A, but not in PC-3 cells, indicates as a cell-specific effect of TCDD on AR activity. 23500775 Safety of purified decolorized (low anthraquinone) whole leaf Aloe vera (L) Burm. f. juice in a 3-month drinking water toxicity study in F344 rats. Decolorized (purified, low anthraquinone) whole leaf Aloe vera (L.) Burm. f. juice was administered at concentrations of 0%, 0.5%, 1% and 2% in the drinking water of F344Du® rats for 3months without any adverse effect. The no-observed-adverse-effect level (NOAEL) in this study was considered to be >2%w/v (>1845mg/kg bodyweight/day for males and >2920mg/kg bodyweight for females). The test material contained total anthraquinones at <0.1parts per million. In the present study there was a complete absence of any histological alteration in samples from the cecum, colon (proximal, mid and distal regions). Similar concentrations of non-decolorized (unpurified, high anthraquinone) Aloe vera extracts tested in other studies have resulted in an increased incidence and severity of diarrhea and colon adenomas and carcinomas. The results of this study supports the assertion that the high levels of anthraquinone present in orally administered, non-purified whole leaf Aloe vera extract may be responsible for the adverse effects observed on the colon. 23220616 Hepatic metabolism of sulfur amino acids in db/db mice. To determine the effect of type-2 diabetes and obesity on the hepatic metabolism of sulfur amino acids, hepatic sulfur amino acid metabolism was determined in db/db mice. Hepatic methionine was markedly decreased in db/db mice, although the hepatic activity of betaine homocysteine methyltransferase was increased. The decrease in hepatic methionine was reflected by decreased sulfur-containing methionine metabolites, including S-adenosylmethionine, homocysteine, cysteine, and hypotaurine in liver and plasma. In contrast, S-adenosylhomocysteine, putrescine, and spermidine were increased in db/db mice. The hepatic level and activity of methionine adenosyltransferase I/III, an S-adenosylmethionine synthesizing enzyme, were significantly increased. These results suggest that increased polyamine synthesis, in conjunction with decreased hepatic methionine levels, is partly responsible for the reduction in hepatic S-adenosylmethionine. Decreased homocysteine in liver and plasma may be attributable to the decrease in hepatic methionine and upregulation of hepatic betaine homocysteine methyltransferase. Glutathione in liver and plasma did not change despite decreased γ-glutamylcysteine ligase activity. The decreased hepatic hypotaurine may be attributable to the downregulation of cysteine dioxygenase. The major finding of this study is that db/db mice exhibited decreases in hepatic methionine and its sulfurcontaining metabolites. 23525463 High-throughput identification of long-range regulatory elements and their target promoters in the human genome. Enhancer elements are essential for tissue-specific gene regulation during mammalian development. Although these regulatory elements are often distant from their target genes, they affect gene expression by recruiting transcription factors to specific promoter regions. Because of this long-range action, the annotation of enhancer element-target promoter pairs remains elusive. Here, we developed a novel analysis methodology that takes advantage of Hi-C data to comprehensively identify these interactions throughout the human genome. To do this, we used a geometric distribution-based model to identify DNA-DNA interaction hotspots that contact gene promoters with high confidence. We observed that these promoter-interacting hotspots significantly overlap with known enhancer-associated histone modifications and DNase I hypersensitive sites. Thus, we defined thousands of candidate enhancer elements by incorporating these features, and found that they have a significant propensity to be bound by p300, an enhancer binding transcription factor. Furthermore, we revealed that their target genes are significantly bound by RNA Polymerase II and demonstrate tissue-specific expression. Finally, we uncovered that these elements are generally found within 1 Mb of their targets, and often regulate multiple genes. In total, our study presents a novel high-throughput workflow for confident, genome-wide discovery of enhancer-target promoter pairs, which will significantly improve our understanding of these regulatory interactions. 23239602 Controlled Synthesis of Double-Wall a-FePO4 Nanotubes and their LIB Cathode Properties. Double-wall amorphous FePO4 nanotubes are prepared by an oil-phase chemical route. The inward diffusion of vacancies and outward diffusion of ions through passivation layers result in double-wall nanotubes with thin walls. Such a process can be extended to prepare hollow polydedral nanocrystals and hollow ellipsoids. The double-wall FePO4 nanotubes show interesting cathode performance in Li ion batteries. 23184149 X-linked dystonia parkinsonism syndrome (XDP, lubag): disease-specific sequence change DSC3 in TAF1/DYT3 affects genes in vesicular transport and dopamine metabolism. X-chromosomal dystonia parkinsonism syndrome (XDP, 'lubag') is associated with sequence changes within the TAF1/DYT3 multiple transcript system. Although most sequence changes are intronic, one, disease-specific single-nucleotide change 3 (DSC3), is located within an exon (d4). Transcribed exon d4 occurs as part of multiple splice variants. These variants include exons d3 and d4 spliced to exons of TAF1, and an independent transcript composed of exons d2-d4. Location of DSC3 in exon d4 and utilization of this exon in multiple splice variants suggest an important role of DSC3 in the XDP pathogenesis. To test this hypothesis, we transfected neuroblastoma cells with four expression constructs, including exons d2-d4 [d2-d4/wild-type (wt) and d2-d4/DSC3] and d3-d4 (d3-d4/wt and d3-d4/DSC3). Expression profiling revealed a dramatic effect of DSC3 on overall gene expression. Three hundred and sixty-two genes differed between cells containing d2-d4/wt and d2-d4/DSC3. Annotation clustering revealed enrichment of genes related to vesicular transport, dopamine metabolism, synapse function, Ca(2+) metabolism and oxidative stress. Two hundred and eleven genes were differentially expressed in d3-d4/wt versus d3-d4/DSC3. Annotation clustering highlighted genes in signal transduction and cell-cell interaction. The data show an important role of physiologically occurring transcript d2-d4 in normal brain function. Interference with this role by DSC3 is a likely pathological mechanism in XDP. Disturbance of dopamine function and of Ca(2+) metabolism can explain abnormal movement; loss of protection against reactive oxygen species may account for the neurodegenerative changes in XDP. Although d3-d4 also affect genes potentially related to neurodegenerative processes, their physiologic role as splice variants of TAF1 awaits further exploration. 22788802 Effects of collisional and vibrational velocity on proton and deuteron transfer in the reaction of HOD+ with CO. Reaction of HOD(+) with CO was studied over the collision energy (E(col)) range between 0.18 and 2.87 eV, for HOD(+) in its ground state and with one quantum in each of its vibrational modes: (001)--predominantly OH stretch; (010)--bend, and (100)--predominately OD stretch. In addition to integral cross sections, product recoil velocity distributions were also measured for each initial condition. The dominant reactions are near-thermoneutral proton and deuteron transfer, generating HCO(+) and DCO(+) product ions by a predominantly direct mechanism. The HCO(+) and DCO(+) channels occur with a combined efficiency of 76% for ground state HOD(+) at our lowest E(col), increasing to 94% for E(col) around 0.33 eV, then falling at high E(col) to ~40%. The HCO(+) and DCO(+) channels have a complicated dependence on the HOD(+) vibrational state. Excitation of the OH or OD stretch modes enhances H(+) or D(+) transfer, respectively, and inhibits D(+) or H(+) transfer. Bend excitation preferentially enhances H(+) transfer, with no effect on D(+) transfer. There is no coupling of energy initially in any HOD(+) vibrational mode to recoil velocity of either of the product ions, even at low E(col) where vibrational excitation doubles or triples the energy available to products. The results suggest that transfer of H or D atoms is enhanced if the atom in question has a high vibrational velocity, and that this effect offsets what is otherwise a general inhibition of reactivity by added energy. HOCO(+) + D and DOCO(+) + H products are also observed, but as minor channels despite being barrierless and exoergic. These channels appear to be complex mediated at low E(col), essentially vanish at intermediate E(col), then reappear with a direct reaction mechanism at high E(col). 23580611 Caspase-14 suppresses GCM1 acetylation and inhibits placental cell differentiation. Glial cell missing 1 (GCM1) transcription factor regulates placental cell fusion into the syncytiotrophoblast. Caspase-14 is proteolytically activated to mediate filaggrin processing during keratinocyte differentiation. Interestingly, altered expression of nonactivated caspase-14 proenzyme is associated with tumorigenesis and diabetic retinopathy, suggesting that caspase-14 may perform physiological functions independently of its protease activity. Here, we performed tandem affinity purification coupled with mass spectrometry analysis to identify caspase-14 proenzyme as a GCM1-interacting protein that suppresses GCM1 activity and syncytiotrophoblast differentiation. Immunohistochemistry revealed that caspase-14 and GCM1 colocalize to placental cytotrophoblast cells at 8 wk of gestation and syncytiotrophoblast layer at term. Further, we demonstrated that caspase-14 mRNA level is decreased by 40% in placental BeWo cells treated with forskolin (FSK). To the contrary, stimulation of GCM1-regulated placental cell fusion and human chorionic gonadotropin β (hCGβ) expression by FSK is enhanced by caspase-14 knockdown. Indeed, GCM1 protein level is increased by 40% in the caspase-14-knockdown BeWo cells. Because GCM1 is stabilized by acetylation, we subsequently showed that caspase-14 impedes the interaction between GCM1 and cAMP response element-binding protein (CREB)-binding protein (CBP) to suppress CBP-mediated acetylation and transcriptional coactivation of GCM1. Therefore, caspase-14 can suppress placental cell differentiation through down-regulation of GCM1 activity.-Wu, Y.-H., Lo, H.-F., Chen, S.-H., Chen, H. Caspase-14 suppresses GCM1 acetylation and inhibits placental cell differentiation. 23429765 Microfluidic oscillators with widely tunable periods. We present experiments and theory of a constant flow-driven microfluidic oscillator with widely tunable oscillation periods. This oscillator converts two constant input-flows from a syringe pump into an alternating, periodic output-flow with oscillation periods that can be adjusted to between 0.3 s to 4.1 h by tuning an external membrane capacitor. This capacitor allows multiple adjustable periods at a given input flow-rate, thus providing great flexibility in device operation. Also, we show that a sufficiently large external capacitance, relative to the internal capacitance of the microfluidic valve itself, is a critical requirement for oscillation. These widely tunable microfluidic oscillators are envisioned to be broadly useful for the study of biological rhythms, as on-chip timing sources for microfluidic logic circuits, and other applications that require variation in timed flow switching. 23274413 New targets for the antitumor activity of gambogic acid in hematologic malignancies. Gambogic acid (GA) is the main active ingredient of gamboge, a brownish to orange dry resin secreted from Garcinia hanburyi, a plant that is widely distributed in nature. Recent in vitro and in vivo studies have demonstrated that GA exerts potent antitumor effects against solid tumors of various derivations, and its antitumor mechanisms have been thoroughly investigated. On the other hand, normal cells remain relatively resistant to GA, indicating a therapeutic window. GA is currently in clinical trials in China. Over the last decade, our laboratory demonstrates that GA exhibits potent anticancer activities against hematological malignancies. This review focuses on the new mechanisms through which GA inhibits proliferation and induces apoptosis in malignant hematological cells. These include the regulation of expression and intracellular positioning of nucleoporin and nucleophosmin; downregulation of steroid receptor coactivator-3 (SRC-3) and its downstream proteins; upregulation of death inducer-obliterator (DIO-1); downregulation of HERG potassium channel; as well as induction of reactive oxygen species (ROS) accumulation. 23291595 Preparation, preliminary screening of new types of steroid conjugates and their activities on steroid receptors. There were synthesized new types of ribbon type steroidal dimers derived from three types of steroidal skeletons (cholic acid, etienic acid, estrone) using Cu(I) catalyzed 1, 3-dipolar cycloaddition reaction. Steroid parts of the molecular "ribbons" are linked by heterocyclic moiety, namely by 2,6-bis((1H-1,2,3-triazol-1-yl)-methyl)pyridine. Compounds synthesized possess different cytotoxic and hormone receptor modulating activities. 23422035 Applications of flow cytometry to toxicological mycotoxin effects in cultured mammalian cells: A review. This review gives an overview of flow cytometry applications to toxicological studies of several physiological target sites of mycotoxins on different mammalian cell lines. Mycotoxins are secondary metabolites of fungi that may be present in food, feed, air and water. The increasing presence of mycotoxins in crops, their wide distribution in the food chain, and their potential for toxicity demonstrate the need for further knowledge. Flow cytometry has become a valuable tool in mycotoxin studies in recent years for the rapid analysis of single cells in a mixture. In toxicology, the power of these methods lies in the possibility of determining a wide range of cell parameters, providing valuable information to elucidate cell growth and viability, metabolic activity, mitochondrial membrane potential and membrane integrity mechanisms. There are studies using flow cytometry technique on Alternaria, Aspergillus, Fusarium and Penicillium mycotoxins including information about cell type, assay conditions and functional parameters. Most of the studies collected in the literature are on deoxynivalenol and zearalenone mycotoxins. Cell cycle analysis and apoptosis are the processes more widely investigated. 23142789 Effects of octylphenol and bisphenol A on the expression of calcium transport genes in the mouse duodenum and kidney during pregnancy. Octylphenol (OP) is the degradative product of alkylphenol ethoxylates that are widely used to produce rubber, pesticides, and paints. Bisphenol A (BPA) is an organic compound with two functional phenol groups, and used for manufacturing polycarbonate plastic and epoxy resins, as well as other applications. OP and BPA are known as endocrine disruptors (EDs) with estrogenic activities, and may disturb natural calcium (Ca) metabolism. In the present study, the effects of OP and BPA on Ca levels in the serum and expression of Ca transport genes in the duodenum, and kidney were investigated in pregnant mice. Calbindin refers to several Ca-binding proteins originally described as vitamin D-dependent Ca-binding factors in the intestine, and kidney of birds and mammals. Transient receptor potential cation channel, subfamily V, member 6 (TRPV6) and transient receptor potential cation channel, subfamily V, member 5 (TRPV5) are Ca entry channels responsible for Ca absorption in the kidney and intestine, respectively. From 6.5 to 16.5 day post coitus (dpc), pregnant mice were given oral doses of 17α-ethynylestradiol (EE, 0.2mg/kg/day), BPA (5 or 50mg/kg/day), or OP (3, 12, or 48 mg/kg/day) dissolved in corn oil. Samples of the duodenum, kidney, and blood were obtained from the mice on day 17.5 of pregnancy. Serum Ca levels were decreased in the groups treated with OP and BPA. The expression levels of Ca transport genes, TRPV5 and calbindin-D9k (CaBP-9k), in the kidney were decreased after treatment with OP and BPA. Duodenal expression of TRPV6 was also reduced by BPA and OP administration. CaBP-9k expression was differentially regulated by BPA and OP. Transcriptional and translational levels of CaBP-9k were decreased by EE and BPA but increased by a high dose of OP. Taken together, our findings demonstrate that OP and BPA regulated the expression of genes associated with Ca transport in the pregnant mice, which may result in the decreased serum Ca levels. 23542210 Induction of G2/M arrest, caspase activation and apoptosis by α-santonin derivatives in HL-60 cells. Sesquiterpene lactones (SLs) are natural products with a variety of biological activities. Previously, we demonstrated the cytotoxic effects of three new α-santonin derivatives on different tumor cell lines with low toxic effects upon peripheral human leukocytes. Here, we evaluated the mechanism of action triggered by these derivatives. HL-60 cell cycle determined after 24h treatment revealed a significant inhibition on cell-cycle progression and leading to an increasing of cells in G2/M [7.6% and 9.0% for compound 3% and 9.0% and 8.6% for compound 4 (1 and 2μM, respectively)]. However, after 48h exposure, all compounds caused G2/M reduction and a significant DNA fragmentation. Compounds 2, 3 and 4 were able to induce apoptosis on leukemia cells, which was corroborated by phosphatidyserine externalization and activation of caspases-3 and -7 after 24h exposure. None of the derivatives analyzed caused depolarization of mitochondrial membrane within 24h of incubation, suggesting the involvement of the extrinsic apoptotic pathway in the death process. The antiproliferative action of these compounds is related to the DNA synthesis inhibition and cell cycle arrest, which probably lead to apoptosis activation. Therefore, these santonin derivatives are promising lead candidates for development of new cytotoxic agents. 23059538 The quest for probiotic effector molecules--unraveling strain specificity at the molecular level. Pharmaceutical agents are widely applied for the treatment of gastrointestinal (and systemic) disorders and their role as modulators of host cell responses is relatively well characterized. By contrast, we are only beginning to understand the molecular mechanisms by which health-promoting, probiotic bacteria act as host cell modulators. The last decade has seen a rapid development of the genomics field for the widely applied probiotic genus Lactobacillus, and nowadays dozens of full genome sequences are available, as well as sophisticated post genomic and genetic engineering tools. This development has enabled comparative (functional) genomics approaches to identify the bacterial effector molecules involved in molecular communication with the host system that may underlie the probiotic effects observed. These efforts can also be complemented with dedicated mutagenesis approaches to eliminate or alter these effector molecules, followed by assessment of the host interaction consequences thereof, allowing the elucidation of the molecular mechanisms involved in probiotic health effects. Many of these approaches have pinpointed that the Lactobacillus cell envelope contains several effector molecules that are pivotal in the direct signaling capacity of these bacteria that underlies their immunomodulatory effects, including lipoteichoic acid, peptidoglycan, and (glyco)proteins. Moreover, the cell envelope contains several compounds such as wall teichoic acid and capsular polysaccharides that may not be involved in direct signaling to the host cell, but still affect signaling through shielding of other bacterial effector molecules. Initial structural studies revealed subtle strain- and species-specific biochemical differences in the canonical cell envelope compounds that are involved in these host interactions. These biochemical variations include the degree and positioning of d-alanyl and glycosyl substitution in lipoteichoic acids, and acetylation of peptidoglycan. Furthermore, specific peptides derived from peptidoglycan and envelope associated (glyco)proteins were recently identified as potent immunomodulators. The latter findings are exciting in the light of the possibility of more pharmacological application of these bioactive probiotic molecules, and especially cost-effective production and targeted delivery of bioactive peptides seems to emerge as a feasible strategy to harness this knowledge. 23643862 Architecture of Cortical Bone Determines in Part its Remodelling and Structural Decay. Bone remodelling accelerates and becomes unbalanced after menopause; less bone is deposited than resorbed from the surface of canals traversing the cortex. The canals enlarge so the intracortical surface area enlarges. We hypothesized that cortical bone with a larger internal surface area, due to more or larger canals, is more liable to being remodelled, further enlarging the internal surface area and facilitating more remodelling and structural deterioration. For 95 monozygotic twin pairs aged 40-61 years, we measured internal cortical surface areas and structure of the distal tibia using high resolution peripheral computed tomography, and three circulating bone remodelling markers. Using principal components (PC) analyses, we identified one summary measure of intracortical and endocortical bone surface areas, cortical porosity and volumetric bone mineral density (structure PC), and one summary measure of bone remodelling markers (remodelling PC). We applied a twin regression analysis (Inference on Causation by Examination of Familial Confounding; ICE FALCON) to assess consistency with a causal component in the association between a predictor (X) and an outcome (Y) by testing if the regression coefficient for the X value of the co-twin decreases after adjusting for the X value of the twin herself. With Y = remodelling PC, the regression coefficient for structure PC in the co-twin was 0.29 (p < 0.001) before, and 0.18 (p = 0.03) after, adjusting for her own structure PC (40% lower; p = 0.06). With Y = structure PC, the regression coefficient for remodelling PC in the co-twin was 0.17 (p = 0.01) before, and 0.20 (p < 0.001) after, adjusting for her own remodelling PC (22% higher; p = 0.7). The structure of bone, its surface area to bone matrix volume configuration, contributes in part to its own remodelling and deterioration, but not vice versa. 22717740 Measles virus selectively blind to signaling lymphocyte activation molecule as a novel oncolytic virus for breast cancer treatment. Oncolytic viruses hold much promise as novel therapeutic agents that can be combined with conventional therapeutic modalities. Measles virus (MV) is known to enter cells using the signaling lymphocyte activation molecule (SLAM), which is expressed on cells of the immune system. Although human breast cancer cell lines do not express SLAM, we found that a wild-type MV (HL strain) efficiently infected various breast cancer cell lines, causing cell death. Based on this finding, we used reverse genetics to generate a recombinant MV selectively unable to use SLAM (rMV-SLAMblind). The rMV-SLAMblind lacked infectivity for SLAM-positive lymphoid cells, while retaining oncolytic activity against breast cancer cells. We showed that, unlike the MV vaccine strains, rMV-SLAMblind used PVRL4 (polio virus receptor-related 4) as a receptor to infect breast cancer cells and not the ubiquitously expressed CD46. Consistent with this, rMV-SLAMblind infected CD46-positive primary normal human cells at a much-reduced level, whereas a vaccine strain of the Edmonston lineage (rMV-Edmonston) efficiently infected and killed them. The rMV-SLAMblind showed antitumor activity against human breast cancer xenografts in immunodeficient mice. The oncolytic activity of rMV-SLAMblind was significantly greater than that of rMV-Edmonston. To assess the in vivo safety, three monkeys seronegative for MV were inoculated with rMV-SLAMblind, and no clinical symptoms were documented. On the basis of these results, rMV-SLAMblind could be a promising candidate as a novel oncolytic virus for breast cancer treatment. 23147004 Organization of the BcgI restriction-modification protein for the transfer of one methyl group to DNA. The Type IIB restriction-modification protein BcgI contains A and B subunits in a 2:1 ratio: A has the active sites for both endonuclease and methyltransferase functions while B recognizes the DNA. Like almost all Type IIB systems, BcgI needs two unmethylated sites for nuclease activity; it cuts both sites upstream and downstream of the recognition sequence, hydrolyzing eight phosphodiester bonds in a single synaptic complex. This complex may incorporate four A(2)B protomers to give the eight catalytic centres (one per A subunit) needed to cut all eight bonds. The BcgI recognition sequence contains one adenine in each strand that can be N(6)-methylated. Although most DNA methyltransferases operate at both unmethylated and hemi-methylated sites, BcgI methyltransferase is only effective at hemi-methylated sites, where the nuclease component is inactive. Unlike the nuclease, the methyltransferase acts at solitary sites, functioning catalytically rather than stoichiometrically. Though it transfers one methyl group at a time, presumably through a single A subunit, BcgI methyltransferase can be activated by adding extra A subunits, either individually or as part of A(2)B protomers, which indicates that it requires an assembly containing at least two A(2)B units. 23487168 A systematic comparison of the properties of clinically used angiotensin II type 1 receptor antagonists. Angiotensin II type 1 receptor antagonists (ARBs) have become an important drug class in the treatment of hypertension and heart failure and the protection from diabetic nephropathy. Eight ARBs are clinically available [azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan]. Azilsartan (in some countries), candesartan, and olmesartan are orally administered as prodrugs, whereas the blocking action of some is mediated through active metabolites. On the basis of their chemical structures, ARBs use different binding pockets in the receptor, which are associated with differences in dissociation times and, in most cases, apparently insurmountable antagonism. The physicochemical differences between ARBs also manifest in different tissue penetration, including passage through the blood-brain barrier. Differences in binding mode and tissue penetration are also associated with differences in pharmacokinetic profile, particularly duration of action. Although generally highly specific for angiotensin II type 1 receptors, some ARBs, particularly telmisartan, are partial agonists at peroxisome proliferator-activated receptor-γ. All of these properties are comprehensively reviewed in this article. Although there is general consensus that a continuous receptor blockade over a 24-hour period is desirable, the clinical relevance of other pharmacological differences between individual ARBs remains to be assessed. 23400370 Chromogenic and fluorogenic chemosensors and reagents for anions. A comprehensive review of the years 2010-2011. This review focuses on examples reported in the years 2010-2011 dealing with the design of chromogenic and fluorogenic chemosensors or reagents for anions. 23627804 Evaluation of the In Vitro Cytotoxicity of Cross-Linked Biomaterials. This study evaluated the in vitro cytotoxicity of poly(propylene fumarate) (PPF). PPF is an aliphatic biodegradable polymer that has been well characterized for use in bone tissue engineering scaffolds. Four different cell types, human mesenchymal stem cells (hMSC), fibroblasts (L929), preosteoblasts (MC3T3), and canine mesenchymal stem cells (cMSC), were used to evaluate the cytotoxicity of PPF. These cell types represent the tissues that PPF would interact with in vivo as a bone tissue scaffold. The sol fraction of the PPF films was measured and then utilized to estimate cross-linking density. Cytotoxicity was evaluated using XTT assay and fluorescence imaging. Results showed that PPF supported similar cell metabolic activities of hMSC, L929, MC3T3, and cMSC compared to the noncytotoxic control, high-density polyethylene (HDPE) and were statistically different than those cultured with the cytotoxic control, a polyurethane film containing 0.1% zinc diethyldithiocarbamate (ZCF). Results showed differing cellular responses to ZCF, the cytotoxic control. The L929 cells had the lowest cell metabolic activity levels after exposure to ZCF compared to the cell metabolic activity levels of the MC3T3, hMSC, or cMSC cells. Qualitative verification of the results using fluorescence imaging demonstrated no change in cell morphology, vacuolization, or detachment when cultured with PPF compared to HDPE or blank media cultures. Overall, the cytotoxicity response of the cells to PPF was demonstrated to be similar to the cytotoxic response of cells to known noncytotoxic materials (HDPE). 23499954 Synthesis and antifungal activity of C-21 steroids with an aromatic D ring. Six analogues of salpichrolides with a simplified side chain (6-11) were synthesized using a new methodology to obtain steroids with an aromatic D-ring. The key step was the elimination of HBr in a vicinal dibromo D-homosteroid by treatment with 1,4-diazabicyclo[2.2.2]octane (DABCO). All new compounds were completely characterized by 2D NMR techniques and tested on two fungal pathogenic species, Fusarium virguliforme and Fusarium solani. 23220041 Capreomycin supergenerics for pulmonary tuberculosis treatment: preparation, in vitro, and in vivo characterization. The pulmonary route is one of the main strategies investigated to improve tuberculosis therapy. The aim of this study was to develop a simple and scalable method to produce capreomycin inhalable powders to use as supergeneric. In vitro antimycobacterial activity and in vivo acute toxicity were assessed using agar proportion susceptibility test on Mycobacterium tuberculosis and chicken chorioallantoic membrane assay, respectively. Capreomycin and three different hydrophobic counterions, namely oleate, linoleate, and linolenate, were combined in solution to obtain hydrophobic ion-pairs that were successively spray-dried. Ion-pairing efficiency was influenced by the spray-dryer employed to produce the powder. In the case of capreomycin oleate, both instruments, mini and nano spray-dryer, were suitable to maintain a high ion-paired content, while for capreomycin linoleate and linolenate, mini spray-dryer was the most appropriate instrument. The three formulations showed morphology and particle sizes potentially suitable for inhalation. Capreomycin oleate and linoleate showed the same efficacy of capreomycin sulfate against M. tuberculosis, while capreomycin linolenate showed a reduced efficacy, even though strain growth was inhibited at 10(-4) mycobacterial inoculum. In vivo acute toxicity studies evidenced the lowest toxic potential for capreomycin oleate when compared to the single components or the other two salts. Overall, capreomycin oleate seems to possess the most promising characteristics to be used as supergenerics in pulmonary tuberculosis treatment. 23627352 Design, synthesis and molecular modeling of novel pyrido[2,3-d]pyrimidine analogs as antifolates: Application of Buchwald-Hartwig aminations of heterocycles. Opportunistic infections caused by Pneumocystis jirovecii (P. jirovecii, pj), Toxoplasma gondii (T. gondii, tg) and Mycobacterium avium (M. avium, ma) are the principal causes of morbidity and mortality in patients with acquired immunodeficiency syndrome (AIDS). The absence of any animal models for human Pneumocystis jirovecii pneumonia and the lack of crystal structures of pjDHFR and tgDHFR make the design of inhibitors challenging. A novel series of pyrido[2,3-d]pyrimidines as selective and potent DHFR inhibitors against these opportunistic infections are presented. Buchwald-Hartwig coupling reaction of substituted anilines with pivaloyl protected 2,4-diamino-6-bromo-pyrido[2,3-d]pyrimidine was successfully explored to synthesize these analogs. Compound 26 was the most selective inhibitor with excellent potency against pjDHFR. Molecular modeling studies with a pjDHFR homology model explained the potency and selectivity of 26. Structural data are also reported for 26 with pcDHFR and 16 and 22 with variants of pcDHFR. 23372018 Manganese supplementation protects against diet-induced diabetes in wild type mice by enhancing insulin secretion. Mitochondrial dysfunction is both a contributing mechanism and complication of diabetes, and oxidative stress contributes to that dysfunction. Mitochondrial manganese-superoxide dismutase (MnSOD) is a metalloenzyme that provides antioxidant protection. We have previously shown in a mouse model of hereditary iron overload that cytosolic iron levels affected mitochondrial manganese availability, MnSOD activity, and insulin secretion. We therefore sought to determine the metallation status of MnSOD in wild-type mice and whether altering that status affected β-cell function. 129/SvEVTac mice given supplemental manganese exhibited a 73% increase in hepatic MnSOD activity and increased metallation of MnSOD. To determine whether manganese supplementation offered glucose homeostasis under a situation of β-cell stress, we challenged C57BL/6J mice, which are more susceptible to diet-induced diabetes, with a high-fat diet for 12 weeks. Manganese was supplemented or not for the final 8 weeks on that diet, after which we examined glucose tolerance and the function of isolated islets. Liver mitochondria from manganese-injected C57BL/6J mice had similar increases in MnSOD activity (81%) and metallation as were seen in 129/SvEVTac mice. The manganese-treated group fed high fat had improved glucose tolerance (24% decrease in fasting glucose and 41% decrease in area under the glucose curve), comparable with mice on normal chow and increased serum insulin levels. Isolated islets from the manganese-treated group exhibited improved insulin secretion, decreased lipid peroxidation, and improved mitochondrial function. In conclusion, MnSOD metallation and activity can be augmented with manganese supplementation in normal mice on normal chow, and manganese treatment can increase insulin secretion to improve glucose tolerance under conditions of dietary stress. 23515940 Ca(2+)-dependent suicidal erythrocyte death following zearalenone exposure. Zearalenone, a cereal mycotoxin with mycoestrogen activity and effect on fertility, is known to trigger apoptosis of a variety of nucleated cell types including hematopoietic progenitor cells. In analogy to apoptosis of nucleated cells, eryptosis, the suicidal death of erythrocytes, leads to cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the erythrocyte surface. The most important stimulator of eryptosis is an increase in cytosolic Ca(2+) activity ([Ca(2+)]i). The present study explored whether zearalenone triggers eryptosis. Erythrocyte volume was estimated from forward scatter, phosphatidylserine exposure at the erythrocyte surface from annexin-V binding, hemolysis from hemoglobin release, and [Ca(2+)]i from Fluo3 fluorescence. A 48-h exposure to zearalenone (≥25 μM) was followed by a significant increase in [Ca(2+)]i and annexin-V binding, and a significant decrease in forward scatter. The effect on annexin-V binding was significantly blunted in the nominal absence of extracellular Ca(2+). Zearalenone stimulates the suicidal erythrocyte death, an effect at least partially due to stimulation of Ca(2+) entry. 23299080 3D structures and ligand specificities of nuclear xenobiotic receptors CAR, PXR and VDR. The nuclear receptors constitutive androstane receptor (CAR), pregnane X receptor (PXR) and vitamin D receptor (VDR) control a large array of genes that code for important proteins in humans including metabolic enzymes and transporters. 3D structures for the ligand-binding domain (LBD) of these receptors are abundantly available, providing valuable insights into the ligand-binding specificity as well as the activation mechanisms. The ligand-binding site of PXR is large and flexible, whereas those of CAR and VDR are compact and rigid, respectively. In general, the ligand profiles of the receptors are in agreement with the LBD structures. The crystal structures have greatly helped us to understand the promiscuity and/or specificity of CAR, PXR and VDR. 23212976 Immunological and reproductive health assessment in herring gulls and black-crowned night herons in the Hudson-Raritan Estuary. Previous studies have shown inexplicable declines in breeding waterbirds within western New York/New Jersey Harbor between 1996 and 2002 and elevated polychlorinated dibenzo-p-dioxins and polychlorinated biphenyls (PCBs) in double-crested cormorant (Phalacrocorax auritus) eggs. The present study assessed associations between immune function, prefledgling survival, and selected organochlorine compounds and metals in herring gulls (Larus argentatus) and black-crowned night herons (Nycticorax nycticorax) in lower New York Harbor during 2003. In pipping gull embryos, lymphoid cells were counted in the thymus and bursa of Fabricius (sites of T and B lymphocyte maturation, respectively). The phytohemagglutinin (PHA) skin response assessed T cell function in gull and heron chicks. Lymphocyte proliferation was measured in vitro in adult and prefledgling gulls. Reference data came from the Great Lakes and Bay of Fundy. Survival of prefledgling gulls was poor, with only 0.68 and 0.5 chicks per nest surviving to three and four weeks after hatch, respectively. Developing lymphoid cells were reduced 51% in the thymus and 42% in the bursa of gull embryos from New York Harbor. In vitro lymphocyte assays demonstrated reduced spontaneous proliferation, reduced T cell mitogen-induced proliferation, and increased B cell mitogen-induced proliferation in gull chicks from New York Harbor. The PHA skin response was suppressed 70 to 80% in gull and heron chicks. Strong negative correlations (r = -0.95 to -0.98) between the PHA response and dioxins and PCBs in gull livers was strong evidence suggesting that these chemicals contribute significantly to immunosuppression in New York Harbor waterbirds. 23416797 The first report on some toxic effects of green scat, Scatophagus argus an Iranian Persian Gulf venomous fish. Green scat namely as Scatophagus argus is a venomous aquarium fish belonging to Scatophagidae family. It can induce painful wounds in injured hand with partial paralysis to whom that touch the spines. Dorsal and ventral rough spines contain cells that produce venom with toxic activities. According to unpublished data collected from local hospitals in southern coastal region of Iran, S. argus is reported as a venomous fish. Envenomation induces clinical symptoms such as local pain, partial paralysis, erythema and itching. In the present study green scat (spotted scat) was collected from Persian Gulf coastal waters. SDS-PAGE indicated 12 distinct bands in the venom ranged between 7 and 250 kDa. The crude venom had hemolytic activity on human erythrocytes (1%) with an LC100 (Lytic Concentration) of about 1.7 μg. The crude venom can release 813 μg protein from 0.5% casein. Phospholipase C activity was recorded at 3.125 μg of total venom. Our findings showed that the edematic activity remained over 24 h after injection. The results demonstrated that crude venom extracted from Iranian coastal border has different toxic and enzymatic activities. This study is pending to further investigation on animal model regarding protein purification and in vivo studies. 23353736 Synthesis of derivatives of methyl rosmarinate and their inhibitory activities against matrix metalloproteinase-1 (MMP-1). A series of MMP-1 inhibitors have been identified based upon a methyl rosmarinate scaffold using structure-based drug design methods. The best compound in the series showed an IC50 value of 0.4 μM. A docking study was conducted for compound (S)-10n in order to investigate its binding interactions with MMP-1. The structure-activity relationships (SAR) were also briefly discussed. Useful SAR was established which provides important guidelines for the design of future generations of potent inhibitors against MMP-1. 23245206 Sheehan's syndrome. Sheehan's syndrome (SS) is characterized by various degrees of hypopituitarism, and develops as a result of ischemic pituitary necrosis due to severe postpartum hemorrhage. Increased pituitary volume, small sella size, disseminated intravascular coagulation and autoimmunity are the proposed factors in the pathogenesis of SS. Hormonal insufficiencies, ranging from single pituitary hormone insufficiency to total hypopituitarism, are observed in patients. The first most important issue in the diagnosis is being aware of the syndrome. Lack of lactation and failure of menstrual resumption after delivery that complicated with severe hemorrhage are the most important clues in diagnosing SS. The most frequent endocrine disorders are the deficiencies of growth hormone and prolactin. In patients with typical obstetric history, prolactin response to TRH seems to be the most sensitive screening test in diagnosing SS. Other than typical pituitary deficiency, symptoms such as anemia, pancytopenia, osteoporosis, impairment in cognitive functions and impairment in the quality of life are also present in these patients. Treatment of SS is based on the appropriate replacement of deficient hormones. Growth hormone replacement has been found to have positive effects; however, risk to benefit ratio, side effects and cost of the treatment should be taken into account. 23234271 Design and synthesis of diazatricyclodecane agonists of the G-protein-coupled receptor 119. A series of GPR119 agonists based on a 2,6-diazatricyclo[3.3.1.1∼3,7∼]decane ring system is described. Also provided is a detailed account of the development of a multigram scale synthesis of the diazatricyclic ring system, which was achieved using a Hofmann-Löffler-Freytag reaction as the key step. The basis for the use of this complex framework lies in an attempt to constrain one end of the molecule in the "agonist conformation" as was previously described for 3-oxa-7-aza-bicyclo[3.3.1]nonanes. Optimization of carbamate analogues of the diazatricylic compounds led to the identification of 32i as a potent agonist of the GPR119 receptor with low unbound human liver microsomal clearance. The use of an agonist response weighted ligand lipophilic efficiency (LLE) termed AgLLE is discussed along with the issues of applying efficiency measures to agonist programs. Ultimately, solubility limited absorption and poor exposure reduced further interest in these molecules. 23350989 Letter to the Editor: Prescience of a Surgeon in 1980. A photo copy of a page from an unpublished document written in 1980 by the surgeon Mr. Selwyn Taylor and entitled "The Thyroid and the Thymus", provides remarkable prescience concerning thyroid lymphocytic infiltrates in Graves' disease and the implications for treating or resolving exophthalmos. 23444144 Pseudo-complementary PNA actuators as reversible switches in dynamic DNA nanotechnology. The structural reorganization of nanoscale DNA architectures is a fundamental aspect in dynamic DNA nanotechnology. Commonly, DNA nanoarchitectures are reorganized by means of toehold-expanded DNA sequences in a strand exchange process. Here we describe an unprecedented, toehold-free switching process that relies on pseudo-complementary peptide nucleic acid (pcPNA) by using a mechanism that involves double-strand invasion. The usefulness of this approach is demonstrated by application of these peptide nucleic acids (PNAs) as switches in a DNA rotaxane architecture. The monomers required for generating the pcPNA were obtained by an improved synthesis strategy and were incorporated into a PNA actuator sequence as well as into a short DNA strand that subsequently was integrated into the rotaxane architecture. Alternate addition of a DNA and PNA actuator sequence allowed the multiple reversible switching between a mobile rotaxane macrocycle and a stationary pseudorotaxane state. The switching occurs in an isothermal process at room temperature and is nearly quantitative in each switching step. pcPNAs can potentially be combined with light- and toehold-based switches, thus broadening the toolbox of orthogonal switching approaches for DNA architectures that open up new avenues in dynamic DNA nanotechnology. 23517728 Design, modeling, synthesis and biological activity evaluation of camptothecin-linked platinum anticancer agents. The design, modeling, synthesis and biological activity evaluation of two hybrid agents formed by 7-oxyiminomethylcamptothecin derivatives and diaminedichloro-platinum (II) complex are reported. The compounds showed growth inhibitory activity against a panel of human tumor cell lines, including sublines resistant to topotecan and platinum compounds. The derivatives were active in all the tested cell lines, and compound 1b, the most active one, was able to overcome cisplatin resistance in the osteosarcoma U2OS/Pt cell line. Platinum-containing camptothecins produced platinum-DNA adducts and topoisomerase I-mediated DNA damage with cleavage pattern and persistence similar to SN38, the active principle of irinotecan. Compound 1b exhibited an appreciable antitumor activity in vivo against human H460 tumor xenograft, comparable to that of irinotecan at lower well-tolerated dose levels and superior to cisplatin. The results support the interpretation that the diaminedichloro-platinum (II) complex conjugated via an oxyiminomethyl linker at the 7-position of the camptothecin resulted in a new class of effective antitumor compounds. 23628456 Fas receptor-deficient lpr mice are protected against acetaminophen hepatotoxicity due to higher glutathione synthesis and enhanced detoxification of oxidant stress. Acetaminophen (APAP) overdose is a classical model of hepatocellular necrosis; however, the involvement of the Fas receptor in the pathophysiology remains controversial. Fas receptor-deficient (lpr) and C57BL/6 mice were treated with APAP to compare the mechanisms of hepatotoxicity. Lpr mice were partially protected against APAP hepatotoxicity as indicated by reduced plasma ALT and GDH levels and liver necrosis. Hepatic Cyp2e1 protein, adduct formation and hepatic glutathione (GSH) depletion were similar, demonstrating equivalent reactive metabolite generation. There was no difference in cytokine formation or hepatic neutrophil recruitment. Interestingly, hepatic GSH recovered faster in lpr mice than in wild type animals resulting in enhanced detoxification of reactive oxygen species. Driving the increased GSH levels, mRNA induction and protein expression of glutamate-cysteine ligase (gclc) were higher in lpr mice. Inducible nitric oxide synthase (iNOS) mRNA and protein levels at 6h were significantly lower in lpr mice, which correlated with reduced nitrotyrosine staining. Heat shock protein 70 (Hsp70) mRNA levels were substantially higher in lpr mice after APAP. Conclusion: Our data suggest that the faster recovery of hepatic GSH levels during oxidant stress and peroxynitrite formation, reduced iNOS expression and enhanced induction of Hsp70 attenuated the susceptibility to APAP-induced cell death in lpr mice. 23215039 Functional imaging of legumain in cancer using a new quenched activity-based probe. Legumain is a lysosomal cysteine protease whose biological function remains poorly defined. Legumain activity is up-regulated in most human cancers and inflammatory diseases most likely as the result of high expression in populations of activated macrophages. Within the tumor microenvironment, legumain activity is thought to promote tumorigenesis. To obtain a greater understanding of the role of legumain activity during cancer progression and inflammation, we developed an activity-based probe that becomes fluorescent only upon binding active legumain. This probe is highly selective for legumain, even in the context of whole cells and tissues, and is also a more effective label of legumain than previously reported probes. Here we present the synthesis and application of our probe to the analysis of legumain activity in primary macrophages and in two mouse models of cancer. We find that legumain activity is highly correlated with macrophage activation and furthermore that it is an ideal marker for primary tumor inflammation and early stage metastatic lesions. 23536519 Resveratrol inhibits proliferation, angiogenesis and induces apoptosis in colon cancer cells: Calorie restriction is the force to the cytotoxicity. The aim of this study was to examine the antitumour activity of resveratrol in human colorectal cancer cell lines (HCT116 and Caco2) and to explore its mechanism of action assuming that it is by calorie-restriction effect. Resveratrol inhibited the proliferation of colon cancer cells with half maximal inhibitory concentration (IC50) equal to 50 and 130 μM for HCT116 and Caco2, respectively. Caco2 cells appeared with significant time-dependent increase in the glycolytic pathway, a behaviour that was absent in HCT116 cells. Resveratrol (100 μM) significantly decreased the glycolytic enzymes (pyruvate kinase and lactate dehydrogenase) in Caco2 cells, while an increase in citrate synthase activity and a decrease in glucose consumption were observed in both cell lines. Moreover, resveratrol downregulated the expressions of leptin and c-Myc, and decreased the content of vascular endothelial growth factor. The apoptotic markers, caspases 3 and 8, were activated and the Bax/BCl2 ratio was increased. The study suggested a promising anticancer activity of resveratrol, calorie-restriction pathway may be one of the driving forces for this activity. 23530668 Magnetite Biomineralization in Magnetospirillum gryphiswaldense: Time-Resolved Magnetic and Structural Studies. Magnetotactic bacteria biosynthesize magnetite nanoparticles of high structural and chemical purity that allow them to orientate in the geomagnetic field. In this work we have followed the process of biomineralization of these magnetite nanoparticles. We have performed a time-resolved study on magnetotactic bacteria Magnetospirillum gryphiswaldense strain MSR-1. From the combination of magnetic and structural studies by means of Fe K-edge X-ray absorption near edge structure (XANES) and high-resolution transmission electron microscopy we have identified and quantified two phases of Fe (ferrihydrite and magnetite) involved in the biomineralization process, confirming the role of ferrihydrite as the source of Fe ions for magnetite biomineralization in M. gryphiswaldense. We have distinguished two steps in the biomineralization process: the first, in which Fe is accumulated in the form of ferrihydrite, and the second, in which the magnetite is rapidly biomineralized from ferrihydrite. Finally, the XANES analysis suggests that the origin of the ferrihydrite could be at bacterial ferritin cores, characterized by a poorly crystalline structure and high phosphorus content. 23603191 Effect of a Garcinia garderiana (Planchon and Triana) Zappi hydroalcoholic extract on melanogenesis in B16F10 melanoma cells. ETHNOPHARMACOLOGY RELEVANCE: Garcinia gardneriana (Planchon and Triana) Zappi (Clusiaceae) is popularly called "bacopari" in southern Brazil. The leaves of this plant are traditionally used to treat skin disorders. AIM OF STUDY: This study evaluated the effects of a hydroalcoholic extract of Garcinia gardneriana leaves (HEGG) on B16F10 murine melanoma cells in order to search for new depigmenting agents. MATERIALS AND METHODS: The effects of HEGG were assessed in melanin content assays in B16F10 melanoma cells compared with the reference drug kojic acid (500mM). Melanin content was measured after spontaneous melanogenesis, UVB-induced melanogenesis and melanogenesis induced by α-MSH. At the same time, cell viability assays were conducted. Intracellular and mushroom tyrosinase activity assays were employed to evaluate the effect of HEGG on tyrosinase activity. RESULTS: HEGG decreased the level of melanin under all three experimental conditions of melanin content evaluation without reducing cell viability. In intracellular tyrosinase assays, the enzyme's activity was reduced about 19% with extract concentrations ranging 0.1-10µg/mL. In the mushroom tyrosinase activity assay a maximal inhibition of 35% (1000µg/mL) was observed. CONCLUSION: These results suggest that HEGG inhibition relates to its tyrosinase activity. Therefore, the hydroalcoholic extract of Garcinia gardneriana shows great potential for use as a depigmenting agent in hyperpigmentation disorders. 23591590 Structure and energetics of gas phase halogen-bonding in mono-, bi-, and tri-dentate anion receptors as studied by BIRD. Complexes of mono-, bi- (RB), and tridentate (RT) receptors with a range of anions (Cl(-), Br(-), I(-), NO3(-), H2PO4(-), HSO4(-), and tosylate (TsO(-))) have been studied in the gas phase by both experimental and theoretical methods. Temperature dependent blackbody infrared radiative dissociation (BIRD) experiments were performed on complexes of C8F17I with Br(-) and I(-), RB with I(-), NO3(-), HSO4(-), H2PO4(-), and TsO(-), and RT with I(-), HSO4(-) and TsO(-) and the observed Arrhenius parameters are reported here. Master equation modeling of the BIRD kinetics data was carried out to determine threshold dissociation energies. Geometry optimizations and thermochemistry calculations were performed using the B3LYP/6-31+G(d,p) level of theory. Additional single point energies were calculated using MP2/6-311++G(2d,p). Results were examined in terms of the binding order of various anions as well as the added binding strength from additional halogen bonding (XB) interactions. The relative binding energies of ions were generally consistent with the ordering previously reported from solution phase experiments; however, the relatively strong binding of H2PO4(-) to the bidentate receptor contrasted the solution phase observation of oxoanions having weaker interactions when compared to halides. An increase in the energy required to remove the same anion from the tridentate receptor when compared to the bidentate and monodentate receptors is explained as being due to the increase in halogen bonding interactions. The possibility of mixed halogen and hydrogen bonded complexes were considered. 23294378 Arundinols A-C and arundinones A and B from the plant endophytic fungus Microsphaeropsis arundinis. Three new ent-eudesmane sesquiterpenoids, arundinols A-C (1-3), one isochroman-1-one, arundinone A (4), and a polyoxygenated benzofuran-3(2H)-one dimer, arundinone B (5), were isolated from the extract of a plant endophytic fungus, Microsphaeropsis arundinis. Their structures were elucidated primarily by NMR experiments, and 1 was confirmed by X-ray crystallography. The absolute configuration of 1 was assigned by X-ray crystallography using Cu Kα radiation, whereas those of the C-11 tertiary alcohols in 2 and 3 were deduced via the circular dichroism data of the in situ formed [Rh(2)(OCOCF(3))(4)] complexes. Arundinone B (5) represents the first dimeric benzofuran-3(2H)-one, showing cytotoxicity against T24 and A549 cells. The co-isolated known compound 6 showed a modest inhibitory effect against Staphylococcus aureus. 23614566 Potential role of CYP2D6 in the central nervous system. Abstract 1. Cytochrome P450 2D6 (CYP2D6) is a pivotal enzyme responsible for a major drug oxidation polymorphism in human populations. Distribution of CYP2D6 in brain and its role in serotonin metabolism suggest that CYP2D6 may have a function in the central nervous system. 2. To establish an efficient and accurate platform for the study of CYP2D6 in vivo, a human CYP2D6 (Tg-2D6) model was generated by transgenesis in wild-type (WT) C57BL/6 mice using a P1 phage artificial chromosome clone containing the complete human CYP2D locus, including the CYP2D6 gene and 5'- and 3'-flanking sequences. 3. Human CYP2D6 was expressed not only in the liver but also in the brain. The abundance of serotonin and 5-hydroxyindoleacetic acid in brain of Tg-2D6 is higher than in WT mice, either basal levels or after harmaline induction. Metabolomics of brain homogenate and cerebrospinal fluid revealed a significant up-regulation of L-carnitine, acetyl-L-carnitine, pantothenic acid, 2'-deoxycytidine diphosphate (dCDP), anandamide, N-acetylglucosaminylamine and a down-regulation of stearoyl-L-carnitine in Tg-2D6 mice compared with WT mice. Anxiety tests indicate Tg-2D6 mice have a higher capability to adapt to anxiety. 4. Overall, these findings indicate that the Tg-2D6 mouse model may serve as a valuable in vivo tool to determine CYP2D6-involved neurophysiological metabolism and function. 23395259 Sonication in combination with heat and low pressure as an alternative pasteurization treatment--effect on Escherichia coli K12 inactivation and quality of apple cider. Escherichia coli K12 cells suspended in apple cider were treated by manothermosonication (MTS, 400 kPa/59 °C), thermosonication (TS, 100 kPa/59 °C), and manosonication (MS, 400 kPa/55 °C) for up to 4 min. A 5-log reduction was achieved in 1.4 min by MTS, 3.8 min by TS, and 2.5 min by MS. The inactivation curves of the E. coli exhibited a fast initial reduction followed by a slow inactivation section. The Weibull, log-logistic, and biphasic linear models showed a good fit of the inactivation data. Quality analyses were conducted with raw apple cider (control), thermally-pasteurized (TP), and MTS-, TS-, and MS-treated cider samples over a 3-week period at refrigeration temperature. Titratable acidity and pH did not differ among any of the samples. During storage, the turbidity value of the control was the highest, followed by TP, TS, MTS and MS. All color parameters of the TP sample were significantly different from those receiving the other treatments. The control and sonicated samples showed similar color parameters during storage. In total, 97 aroma compounds were identified in the control, TS-, MS-, and MTS-treated cider samples, while 95 aroma compounds were found in the TP at Week 0. Among all the aroma compounds, 9 key ones were identified in all samples, including ethyl 2-methylbutanoate, butyl acetate, 1-butanol, ethyl hexanoate, 1-hexanol, butanoic acid, β-damascenone, hexanoic acid, and octanoic acid. The profiles of the key aroma compounds in all sonicated samples were more similar to the control than the TP sample at Weeks 0 and 3. 23402788 Inhibition of mitochondrial carnitine/acylcarnitine transporter by H2O2: Molecular mechanism and possible implication in pathophysiology. H2O2 inhibits the [(3)H]carnitine/carnitine antiport catalysed by the mitochondrial carnitine/acylcarnitine transporter reconstituted in proteoliposomes. The inhibition was reversed by dithioerythritol, N-acetylcysteine and l-cysteine. Inhibition time-dependence revealed a faster and a slower reaction stages with orders of reaction of 1.0 and 1.9, respectively. Inhibition was tested on mutants in which one or more of the six Cys residues had been substituted with Ser or with Val. The four replacement mutant C23S/C58S/C89S/C283S containing C136 and C155 was inhibited as the wild-type. Mutants C23V/C58V/C155V/C89S/C283S and C23V/C58V/C136V/C89S/C283S containing only C136 or C155, respectively, were inhibited at a much lower extent respect to the wild-type, while the mutant C136S/C155S in which the two Cys were substituted and the C-less protein were virtually insensitive to inhibition. DTE reversed the inhibition of the H2O2 sensitive proteins except that in the case of the mutants containing only C136 or C155 after long time of incubation with H2O2. The IC50 values obtained by dose-response curves of H2O2 inhibition were 0.17mM for the wild-type, 0.39mM for the four replacement mutant containing C136 and C155, 2.23 or 1.8mM in the five replacement mutants containing the single C136 or C155, respectively. Carnitine and acetylcarnitine protected the protein from the inhibition by H2O2. Inhibition kinetics showed a competitive behaviour of H2O2 respect to carnitine. All the data concur to demonstrate that H2O2 interacts with C136 and C155 and completely inactivates the transporter by inducing the formation of a disulphide. 23150428 Hepatic Cyp2d and Cyp26a1 mRNAs and activities are increased during mouse pregnancy. There is considerable evidence that drug disposition is altered during human pregnancy and based on probe drug studies, CYP2D6 activity increases during human pregnancy. The aim of this study was to determine whether the changes of CYP2D6 activity observed during human pregnancy could be replicated in the mouse, and explore possible mechanisms of increased CYP2D6 activity during pregnancy. Cyp2d11, Cyp2d22, Cyp2d26 and Cyp2d40 mRNA was increased (P < 0.05) on gestational days (GD) 15 and 19 compared with the non-pregnant controls. There was no change (P > 0.05) in Cyp2d9 and Cyp2d10 mRNA. In agreement with the increased Cyp2d mRNA, Cyp2d-mediated dextrorphan formation from dextromethorphan was increased 2.7-fold (P < 0.05) on GD19 (56.8±39.4 pmol/min/mg protein) when compared with the non-pregnant controls (20.8±11.2 pmol/min/mg protein). An increase in Cyp26a1 mRNA (10-fold) and retinoic acid receptor (Rar)β mRNA (2.8-fold) was also observed during pregnancy. The increase in Cyp26a1 and Rarβ mRNA during pregnancy indicates increased retinoic acid signaling in the liver during pregnancy. A putative retinoic acid response element was identified within the Cyp2d40 promoter and the mRNA of Cyp2d40 correlated (P < 0.05) with Cyp26a1 and Rarβ. These results show that Cyp2d mRNA is increased during mouse pregnancy the and mouse may provide a suitable model to investigate the mechanisms underlying the increased clearance of CYP2D6 probes observed during human pregnancy. Our findings also suggest that retinoic acid signaling in the liver is increased during pregnancy, which may have broader implications to energy homeostasis in the liver during pregnancy. 23254198 Inhibitory effects of a bazedoxifene/conjugated equine estrogen combination on human breast cancer cells in vitro. Breast cancer incidence is increased in women receiving menopausal hormone therapy with estrogen plus progestin but not with estrogen alone. The use of a tissue-selective estrogen complex (TSEC) has been proposed as a novel menopausal hormone therapy strategy to eliminate the requirement for a progestogen. Combination of bazedoxifene (BZA) with conjugated estrogens (CEs), the first TSEC, has shown beneficial effects. Whether it would exert antiestrogenic effects on breast cancer is not clear. To address this issue, we compared estradiol (E(2)) and CE alone on proliferation and apoptosis in MCF-7 breast cancer cells. CE stimulated growth of MCF-7 cells at a peak concentration 10-fold higher than required for E(2). Both CE and E(2) alone increased DNA synthesis and reduced apoptosis with activation of MAPK, Akt, and p70S6K and up-regulation of antiapoptotic factors survivin, Bcl-2, and X-linked inhibitor of apoptosis protein, These effects could be completely blocked by BZA. Gene expression studies demonstrated that CE and E(2) were equally potent on expression of cMyc, pS2, and WNT1 inducible signaling pathway protein 2, whereas the stimulatory effects of CE on progesterone receptor and amphiregulin expression were weaker than E(2). BZA effectively blocked each of these effects and showed no estrogen agonistic effects when used alone. Our results indicate that the stimulatory effects of E(2) or CE on breast cancer cells could be completely abrogated by BZA. These studies imply that the CE/BZA, TSEC, exerts antiestrogenic effects on breast cancer cells and might block the growth of occult breast neoplasms in postmenopausal women, resulting in an overall reduction in tumor incidence. 23481678 New Azalomycin F Analogs from Mangrove Streptomyces sp. 211726 with Activity against Microbes and Cancer Cells. Seven new azalomycin F analogs (1-7) were isolated from the broth of mangrove Streptomyces sp. 211726, and respectively identified as 25-malonyl demalonylazalomycin F5a monoester (1), 23-valine demalonylazalomycin F5a ester (2), 23-(6-methyl)heptanoic acid demalonylazalomycins F3a ester (3), F4a ester (4) and F5a ester (5), 23-(9-methyl)decanoic acid demalonylazalomycin F4a ester (6) and 23-(10-methyl)undecanoic acid demalony lazalomycin F4a ester (7). Their structures were established by their spectroscopic data and by comparing with those of azalomycins F3a, F4a and F5a. Biological assays exhibited that 1-7 showed broad-spectrum antimicrobial and anti HCT-116 activities. 23477455 Mechanisms of vesicle spreading on surfaces: coarse-grained simulations. Exposition of unilamellar vesicles to attractive surfaces is a frequently used way to create supported lipid bilayers. Although this approach is known to produce continuous supported bilayer coatings, the mechanism of their formation and its dependence on factors like surface interaction and roughness or membrane tension as well as the interplay between neighboring vesicles or the involvement of preadsorbed bilayer patches are not well understood. Using dissipative particle dynamics simulations, we assess different mechanisms of vesicle spreading on attractive surfaces, placing special emphasis on the orientation of the resulting bilayer. Making use of the universality of collective phenomena in lipid membranes, we employed a solvent-free coarse-grained model, enabling us to cover the relatively large system sizes and time scales required. Our results indicate that one can control the mechanism of vesicle spreading by tuning the strength and range of the interactions with the substrate as well as the surface's roughness, resulting in a switch from a predominant inside-up to an outside-up orientation of the created supported bilayer. 23122121 A simple GC-MS method for the screening of betulinic, corosolic, maslinic, oleanolic and ursolic acid contents in commercial botanicals used as food supplement ingredients. The occurrence of triterpene pentacyclic acids in plants is extensive, but little is known about their availability in commercial extracts. A simple GC-MS method for the simultaneous determination of betulinic, corosolic, maslinic, oleanolic and ursolic acids was developed and applied to 38 different commercial plant extracts sold as ingredients for dietary supplements. A suitable protocol was set up to perform routine control of a diverse array of samples with different botanical, chemical and physical characteristics. Remarkable quantities of corosolic acid were found in dried extracts from aerial parts of Lagerstroemia speciosa and Ortosiphon stamineus (14233 and 1132 mg/kg, respectively), while oleanolic acid was abundant in O. stamineus and Crataegus monogyna flowers (2774 and 2339 mg/kg); ursolic was identified in O. stamineus, C. monogyna, L. speciosa and Arctostaphylos uva-ursi leaves (7773, 4165, 2108 and 1034 mg/kg). Only L. speciosa was rich in maslinic acid (4958 mg/kg), while minor amounts of betulinic acid (257 and 80 mg/kg) were detected in L. speciosa and C. monogyna extracts. Lower quantities of triterpenic acids were identified in dried extracts of Harpagophyton procumbens root, propolis, Punica granatum root, Styrax benzoin, Vaccinium myrtillus fruits and Vitis vinifera seeds. Decoctions and fluid extracts lacked or contained very low amounts of triterpenic acids. Results are discussed in terms of quality and safety of these ingredients. 23237835 Synthesis and structure-activity relationship of piperidine-derived non-urea soluble epoxide hydrolase inhibitors. A series of potent amide non-urea inhibitors of soluble epoxide hydrolase (sEH) is disclosed. The inhibition of soluble epoxide hydrolase leads to elevated levels of epoxyeicosatrienoic acids (EETs), and thus inhibitors of sEH represent one of a novel approach to the development of vasodilatory and anti-inflammatory drugs. Structure-activities studies guided optimization of a lead compound, identified through high-throughput screening, gave rise to sub-nanomolar inhibitors of human sEH with stability in human liver microsomal assay suitable for preclinical development. 23596975 Determining osmotic pressure of drug solutions by air humidity in equilibrium method. Abstract Objective: To establish a new osmotic pressure measuring method with a wide measuring range. Method: The osmotic pressure of drug solutions is determined by measuring the relative air humidity in equilibrium with the solution. The freezing point osmometry is used as a control. Results: The data obtained by the proposed method are comparable to those by the control method, and the measuring range of the proposed method is significantly wider than that of the control method. Conclusion: The proposed method is performed in an isothermal and equilibrium state, so it overcomes the defects of the freezing point and dew point osmometries which result from the heterothermal process in the measurement, and therefore is not limited to diluted solutions. 23205668 Spontaneous periodic diameter oscillations in InP nanowires: the role of interface instabilities. We have observed that thin InP nanowires generated by vapor-liquid-solid growth display spontaneous periodic diameter oscillations when large group III supersaturations are used. Diameter variations are associated with a large number of stacking faults and crystallographic phase changes(wurtzite/zinc-blende); also the axial distance between oscillations depends on the indium precursor flow used during the run. We attribute the morphology changes to a substantial deformation of the triple phase line (vapor-liquid-solid) at the catalyst nanoparticle edge originated from multistep nucleation during growth. The deformation alters the mechanical force balance acting on the nanoparticle during growth in such a way that the particle displaces from the nanowire top and wets the nanowire sidewall. Subsequently, as catalytic growth occurs at the sidewall, the associated increase in diameter will eventually push the NP back to its original wire-top position until the onset of a new instability at the triple phase line. 23303717 A fluorescent "allosteric scorpionand" complex visualizes a biological recognition event. We describe a new class of fluorescent reporter and its employment to visualize the biotin/avidin binding interaction. Derivatives of the azamacrocycle cyclam that contain a pendant naphthalimide dye are inherently fluorescent when zinc(II) is coordinated. Introducing a second pendant group--biotin--affords an unsymmetrical bis-triazole-scorpionand ligand that interacts specifically with avidin. This ligand has been assembled by using a one-pot "double-click" strategy and complexed with copper(II) and zinc(II). The zinc(II) complex is fluorescent, and its fluorescence output changes in the presence of avidin. Upon avidin binding, the fluorescence output is diminished by interaction with the protein, at [complex]/[avidin] ratios of up to 4:1. The observed change might arise from a specific quenching effect in the biotin binding pocket or from a binding-induced change in the coordination geometry of the complex. 23629664 Differential Activity of Plasma and Vacuolar Membrane Transporters Contributes to Genotypic Differences in Salinity Tolerance in a Halophyte Species, Chenopodium quinoa. Halophytes species can be used as a highly convenient model system to reveal key ionic and molecular mechanisms that confer salinity tolerance in plants. Earlier, we reported that quinoa (Chenopodium quinoa Willd.), a facultative C3 halophyte species, can efficiently control the activity of slow (SV) and fast (FV) tonoplast channels to match specific growth conditions by ensuring that most of accumulated Na+ is safely locked in the vacuole (Bonales-Alatorre et al. (2013) Plant Physiology). This work extends these finding by comparing the properties of tonoplast FV and SV channels in two quinoa genotypes contrasting in their salinity tolerance. The work is complemented by studies of the kinetics of net ion fluxes across the plasma membrane of quinoa leaf mesophyll tissue. Our results suggest that multiple mechanisms contribute towards genotypic differences in salinity tolerance in quinoa. These include: (i) a higher rate of Na+ exclusion from leaf mesophyll; (ii) maintenance of low cytosolic Na+ levels; (iii) better K+ retention in the leaf mesophyll; (iv) a high rate of H+ pumping, which increases the ability of mesophyll cells to restore their membrane potential; and (v) the ability to reduce the activity of SV and FV channels under saline conditions. These mechanisms appear to be highly orchestrated, thus enabling the remarkable overall salinity tolerance of quinoa species. 23483712 Protein-protein nanoimprinting of silk fibroin films. Protein-protein imprinting of silk fibroin is introduced as a rapid, high-throughput method for the fabrication of nanoscale structures in silk films, through the application of heat and pressure. Imprinting on conformal surfaces is demonstrated with minor adjustments to the system, at resolutions comparable to other currently available nonplanar nanoimprint lithography techniques. 23601407 Dietary fibre: Challenges in production and use of food composition data. Dietary fibre is a heterogeneous group of components for which several definitions and analytical methods were developed over the past decades, causing confusion among users and producers of dietary fibre data in food composition databases. An overview is given of current definitions and analytical methods. Some of the issues related to maintaining dietary fibre values in food composition databases are discussed. Newly developed AOAC methods (2009.01 or modifications) yield higher dietary fibre values, due to the inclusion of low molecular weight dietary fibre and resistant starch. For food composition databases procedures need to be developed to combine 'classic' and 'new' dietary fibre values since re-analysing all foods on short notice is impossible due to financial restrictions. Standardised value documentation procedures are important to evaluate dietary fibre values from several sources before exchanging and using the data, e.g. for dietary intake research. 23319078 Identification of α2β1 integrin inhibitor VP-i with anti-platelet properties in the venom of Vipera palaestinae. Integrins are receptors of the extracellular matrix (ECM), playing a vital role in pathophysiological processes. They bind to ECM ligands like collagens and can mediate wound healing as well as tumor metastasis and thrombosis, thus being a part of cell adhesion and migration as well as platelet aggregation. For this reason, identifying α2β1 integrin-specific antagonists can assist in the development of drugs to treat tumor progression, angiogenesis, and cardiovascular diseases. Snake venoms have been shown to contain antagonists which target collagen-binding integrins. EMS16, rhodocetin, and VP12 are three toxins belonging to the C-type lectin-related protein family and have been proven to inhibit the α2β1 integrin, specifically the α2 integrin A domain. To specifically isolate antagonists targeting the α2β1 integrin A domain, we developed a protocol based on affinity chromatography. Using this novel approach, the toxin VP-i was isolated from Vipera palaestinae venom. We show that VP-i binds to the α2 integrin A domain and that it successfully inhibits adhesion of various cells to type I collagen as well as cell migration. Moreover, our results indicate that VP-i differs structurally from the previously purified VP12, although not functionally, and therefore is a further venom compound which can be utilized for drug development. 23122126 Immunoreactivity of hen egg allergens: influence on in vitro gastrointestinal digestion of the presence of other egg white proteins and of egg yolk. Hen egg white comprises of a complex mixture of proteins, which greatly differ in their physicochemical characteristics and relative abundance. We aimed to identify potential undiscovered egg allergens within the egg white proteome and investigated the existence of matrix effects on the proteolytic stability and resultant IgE-binding of the allergenic proteins. In addition to the main egg allergens: ovalbumin (OVA), ovomucoid (OM) and lysozyme (LYS), two minor egg white proteins, tentatively identified as ovoinhibitor and clusterin, were found to react with serum IgE from egg-allergic patients. Egg white exhibited residual immunoreactivity after gastrointestinal digestion due to the presence of intact OVA and LYS, as well as of several IgE-binding peptides derived from OVA. The presence of egg yolk slightly increased the susceptibility to hydrolysis of egg white proteins and abrogated bile salt-induced precipitation of LYS in the duodenal medium. However, the resultant immunoreactivity against IgE of egg white proteins after in vitro digestion was not significantly modified by the presence of yolk components. 23589404 Exposure to mercury among dental health workers in Turkey: Correlation with amalgam work and own fillings. PURPOSE: To investigate the current status of exposure to mercury (Hg) among dental health workers in Turkey. METHODS: A total of 115 persons working in the same hospital were included in the study and were divided into three groups. Group 1 consisted of 67 dentists; group 2 consisted of 21 dental personnel who work with amalgam, and group 3 consisted of 27 control subjects who work in the same hospital but are non-dental personnel. The number of amalgam fillings that have been made by the dentists and the number of own fillings of the subjects were recorded. RESULTS: Plasma Hg levels were found to be 3.76 ± 1.84, 3.54 ± 1.83, and 2.69 ± 0.97 µg/L in groups 1, 2, and 3, respectively. Hg concentrations in group 1 were significantly higher than the control group. There was no significant difference between groups 1 and 2. The number of amalgam fillings made by the dentists in the previous year correlated significantly with plasma Hg levels (r = 0.378, p < 0.01). There was no significant correlation between the own amalgam fillings in the teeth of the subjects and Hg levels. CONCLUSION: Preventive measures for protection from exposure to Hg are necessary for occupational health in dentistry and proper industrial hygiene rules should be emphasized to avoid contamination during work. 23341458 The factor VII-activating protease (FSAP) enhances the activity of bone morphogenetic protein-2 (BMP-2). Factor VII-activating protease (FSAP) is a circulating protease involved in the pathogenesis of atherosclerosis, calcification, and fibrotic processes. To understand how FSAP controls the balance of local growth factors, we have investigated its effect on the regulation of bone morphogenetic proteins (BMPs). BMP-2 is produced as a large pro-form and secreted as a mature heparin-binding growth factor after intracellular processing by pro-protein convertases (PCs). In this study, we discovered that FSAP enhances the biological activity of mature BMP-2 as well as its pro-form, as shown by osteogenic differentiation of C2C12 myoblasts. These findings were complemented by knockdown of FSAP in hepatocytes, which revealed BMP-2 processing by endogenous FSAP. N-terminal sequencing indicated that pro-BMP-2 was cleaved by FSAP at the canonical PC cleavage site, giving rise to mature BMP-2 (Arg(282)↓Gln(283)), as well as in the N-terminal heparin binding region of mature BMP-2, generating a truncated mature BMP-2 peptide (Arg(289)↓Lys(290)). Similarly, mature BMP-2 was also cleaved to a truncated peptide within its N-terminal region (Arg(289)↓Lys(290)). Plasmin exhibited a similar activity, but it was weaker compared with FSAP. Thrombin, Factor VIIa, Factor Xa, and activated protein C were not effective. These results were further supported by the observation that the mutation of the heparin binding region of BMP-2 inhibited the processing by FSAP but not by PC. Thus, the proteolysis and activation of pro-BMP-2 and mature BMP-2 by FSAP can regulate cell differentiation and calcification in vasculature and may explain why polymorphisms in the gene encoding for FSAP are related to vascular diseases. 23601382 Sustainable diets: Harnessing the nutrition agenda. There has been rapid growth in the global population over the last century and estimates for 2050 are a global population of over 9billion. These mouths need to be fed and the nutritional quality of the food received will be a key determinant of future health. Alongside this expansion in the world's population, rapid economic growth in China, India and South America is increasing demand for protein-rich foods, especially meat and dairy products, causing concern about the impact this may have on green house gas emissions. As economies strengthen and dietary and lifestyle patterns become more westernised, the so-called diseases of affluence are becoming ever more evident, often alongside malnutrition. This paper considers these challenges and the need to embed thinking about nutrition into discussions about sustainability of the food supply. 23379472 Structural Modifications to Tetrahydropyridine-3-carboxylate Esters en Route to the Discovery of M(5)-Preferring Muscarinic Receptor Orthosteric Antagonists. The M(5) muscarinic acetylcholine receptor is suggested to be a potential pharmacotherapeutic target for the treatment of drug abuse. We describe herein the discovery of a series of M(5)-preferring orthosteric antagonists based on the scaffold of 1,2,5,6-tetrahydropyridine-3-carboxylic acid. Compound 56, the most selective compound in this series, possesses an 11-fold selectivity for the M(5) over M(1) receptor and shows little activity at M(2)-M(4). This compound, although exhibiting modest affinity (K(i) = 2.24 μM) for the [(3)H]N-methylscopolamine binding site on the M(5) receptor, is potent (IC(50) = 0.45 nM) in inhibiting oxotremorine-evoked [(3)H]DA release from rat striatal slices. Further, a homology model of human M(5) receptor based on the crystal structure of the rat M(3) receptor was constructed, and docking studies of compounds 28 and 56 were performed in an attempt to understand the possible binding mode of these novel analogues to the receptor. 23159669 TGF-β as a therapeutic target in high grade gliomas - promises and challenges. Transforming growth factor-β (TGF-β) is a cytokine with a key role in tissue homeostasis and cancer. TGF-β elicits both tumor suppressive and tumor promoting functions during cancer progression, in a wide range of cancers. Here, we review the tumor promoting function of TGF-β and its possible promise as a therapeutic target in high grade gliomas, including glioblastoma multiforme (GBM), a disease with very poor prognosis. TGF-β signaling is highly active in high grade gliomas and elevated TGF-β activity has been associated with poor clinical outcome in this deadly disease. Common features of GBMs include fast cell proliferation, invasion into normal brain parenchyma, hypoxia, high angiogenic - and immunosuppressive activity, characteristics that all have been linked to activation of the TGF-β pathway. TGF-β signaling has also been connected with the cancer stem cell (CSC) phenotype in GBM. CSCs represent a subset of GBM cells thought to be responsible for tumor initiation, progression and relapse of disease. Following the description of these different properties of TGF-β signaling and the underlying mechanisms identified thus far, the promise of TGF-β targeted therapy in malignant gliomas is discussed. Several drugs targeting TGF-β signaling have been developed that showed potent antitumor activity in preclinical models. A number of agents are currently evaluated in early clinical studies in glioma patients. Available results of these studies are highlighted and a perspective on the promise of TGF-β-targeted therapy is given. 23085547 Identifying the correlation between drug/stabilizer properties and critical quality attributes (CQAs) of nanosuspension formulation prepared by wet media milling technology. Wet media milling by top down method has proved to be an effective method to prepare nanosuspension of poorly soluble drugs/APIs. Few or no attempts have been made so far to understand the feasibility of nanosuspension formulation in terms of the mechanism of stabilization as a function of drug properties. The objective of this study was to understand the effect of drug substance and stabilizer properties to form a successful nanosuspension product. From this study, logP and enthalpy were concluded to have a direct correlation on the feasibility of formation of a stable nanosuspension. The most likely candidate for media milling was a drug substance with a high enthalpy and hydrophobicity which can be stabilized either electrostatically or sterically. The least likely candidate will be one that is hydrophilic and having a very low enthalpy value. Also the choice of an ideal stabilizer/surfactant was found to be influenced by the degree of hydrophobicity of the drug itself. Finally the morphology of the starting drug was found to significantly affect the milling time required to produce submicron particles. 23122134 Investigation on the phase behaviour of gelatin/agarose mixture in an environment of reduced solvent quality. Investigation on the phase behaviour of a biopolymer mixture has been performed using 7.5% (w/w) gelatin and 1.5% (w/w) agarose in the presence of variable amounts of polydextrose as the co-solute from low to high levels of total solids. Mechanical observation of the system was performed using small deformation dynamic oscillation in shear along with thermal studies using modulated differential scanning calorimetry. Micrographs provided images of the changing morphology of the network with the addition of co-solute. Agarose and gelatin form non-interactive bicontinuous phases in the aqueous environment. Systematic increase in the concentration of polydextrose prevents the formation of a stable agarose network, with the polysaccharide chains dispersing in the high solids environment. Gelatin, on the other hand, retains its conformational stability even at a saturating co-solute environment through enhanced protein structuring. Vitrification studies on the high solids system at subzero temperatures provides information on the structural and molecular relaxation identified as a glass transition phenomenon. Fourier transform infrared spectroscopy was used to analyse potential direct interaction between polymers and co-solute. The extent of amorphicity in the system was confirmed using wide angle X-ray diffraction. 23282011 Two [4Fe-4S] clusters containing radical SAM enzyme SkfB catalyze thioether bond formation during the maturation of the sporulation killing factor. The sporulation killing factor (SKF) is a 26-residue ribosomally assembled and posttranslationally modified sactipeptide. It is produced by Bacillus subtilis 168 and plays a key role in its sporulation. Like all sactipeptides, SKF contains a thioether bond, which links the cysteine residue Cys4 with the α-carbon of the methionine residue Met12. In this study we demonstrate that this bond is generated by the two [4Fe-4S] clusters containing radical SAM enzyme SkfB, which is encoded in the skf operon. By mutational analysis of both cluster-binding sites, we were able to postulate a mechanism for thioether generation which is in agreement with that of AlbA. Furthermore, we were able to show that thioether bond formation is specific toward hydrophobic amino acids at the acceptor site. Additionally we demonstrate that generation of the thioether linkage is leader-peptide-dependent, suggesting that this reaction is the first step in SKF maturation. 23255236 Characterization of disease-associated N-linked glycoproteins. N-linked glycoproteins play important roles in biological processes, including cell-to-cell recognition, growth, differentiation, and programmed cell death. Specific N-linked glycoprotein changes are associated with disease progression and identification of these N-linked glycoproteins has potential for use in disease diagnosis, prognosis, and prediction of treatments. In this review, we summarize common strategies for N-linked glycoprotein characterization and applications of these strategies to identification of glycoprotein changes associated with disease states. We also review the N-linked glycoproteins altered in diseases such as breast cancer, lung cancer, and prostate cancer. Although assays for these glycoproteins have potential clinical utility, research is needed to translate these glycoproteins to clinical biomarkers. 23643751 Arylpiperazine-mediated activation of Akt protects SH-SY5Y neuroblastoma cells from 6-hydroxydopamine-induced apoptotic and autophagic death. We investigated the ability of 19 recently synthesized arylpiperazine compounds to protect human SH-SY5Y neuroblastoma cells from the neurotoxin 6-hydroxydopamine (6-OHDA). The compound with the most potent neuroprotective action was N-{3-[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-picolinamide (6b), which reduced 6-OHDA-induced apoptotic death through stabilization of mitochondrial membrane and subsequent prevention of superoxide production, caspase activation and DNA fragmentation. 6-OHDA-triggered autophagic response was also reduced by 6b, which prevented inactivation of the main autophagy repressor mTOR, upregulation of pro-autophagic beclin-1, conversion of microtubule-associated protein 1 light chain 3 (LC3)-I to autophagosome-associated LC3-II, as well as intracytoplasmic acidification induced by 6-OHDA. The inhibition of autophagy using LC3β gene silencing or pharmacological autophagy blockers 3-methyladenine or bafilomycin A1, mimicked the cytoprotective effect of 6b. While the treatment with 6b had no effect on the phosphorylation of proapoptotic MAP kinases ERK and JNK, it markedly increased the phosphorylation of the prosurvival kinase Akt in 6-OHDA-treated cells. Akt inhibitor DEBC or RNA interference-mediated Akt silencing reduced the ability of 6b to block 6-OHDA-triggered apoptotic and autophagic responses, thus confirming their dependency on Akt activation. The cytoprotective effect of 6b was also observed in 6-OHDA-treated neuronal PC12 cells, but not in SH-SY5Y or PC12 cells exposed to 1-methyl-4-phenylpyridinium, indicating that the observed neuroprotection was dependent on the cytotoxic stimulus. Because of the ability to prevent 6-OHDA induced apoptotic/autophagic cell death through activation of Akt, the investigated arylpiperazines could be potential candidates for treatment of neurodegenerative diseases. 23620303 Chip-scale Mid-Infrared chemical sensors using air-clad pedestal silicon waveguides. Towards a future lab-on-a-chip spectrometer, we demonstrate a compact chip-scale air-clad silicon pedestal waveguide as a Mid-Infrared (Mid-IR) sensor capable of in situ monitoring of organic solvents. The sensor is a planar crystalline silicon waveguide, which is highly transparent, between λ = 1.3 and 6.5 μm, so that its operational spectral range covers most characteristic chemical absorption bands due to bonds such as C-H, N-H, O-H, C-C, N-O, C[double bond, length as m-dash]O, and C[triple bond, length as m-dash]N, as opposed to conventional UV, Vis, Near-IR sensors, which use weaker overtones of these fundamental bands. To extend light transmission beyond λ = 3.7 μm, a spectral region where a typical silicon dioxide under-clad is absorbing, we fabricate a unique air-clad silicon pedestal waveguide. The sensing mechanism of our Mid-IR waveguide sensor is based on evanescent wave absorption by functional groups of the surrounding chemical molecules, which selectively absorb specific wavelengths in the mid-IR, depending on the nature of their chemical bonds. From a measurement of the waveguide mode intensities, we demonstrate in situ identification of chemical compositions and concentrations of organic solvents. For instance, we show that when testing at λ = 3.55 μm, the Mid-IR sensor can distinguish hexane from the rest of the tested analytes (methanol, toluene, carbon tetrachloride, ethanol and acetone), since hexane has a strong absorption from the aliphatic C-H stretch at λ = 3.55 μm. Analogously, applying the same technique at λ = 3.3 μm, the Mid-IR sensor is able to determine the concentration of toluene dissolved in carbon tetrachloride, because toluene has a strong absorption at λ = 3.3 μm from the aromatic C-H stretch. With our demonstration of an air-clad silicon pedestal waveguide sensor, we move closer towards the ultimate goal of an ultra-compact portable spectrometer-on-a-chip. 23645151 Amylin Acts in the Central Nervous System to Increase Sympathetic Nerve Activity. The pancreatic hormone amylin acts in the central nervous system (CNS) to decrease food intake and body weight. We hypothesized that amylin action in the CNS promotes energy expenditure by increasing the activity of the sympathetic nervous system. In mice, ip administration of amylin significantly increased c-Fos immunoreactivity in hypothalamic and brainstem nuclei. In addition, mice treated with intracerebroventricular (icv) amylin (0.1 and 0.2 nmol) exhibited a dose-related decrease in food intake and body weight, measured 4 and 24 hours after treatment. The icv injection of amylin also increased body temperature in mice. Using direct multifiber sympathetic nerve recording, we found that icv amylin elicited a significant and dose-dependent increase in sympathetic nerve activity (SNA) subserving thermogenic brown adipose tissue (BAT). Of note, icv injection of amylin also evoked a significant and dose-related increase in lumbar and renal SNA. Importantly, icv pretreatment with the amylin receptor antagonist AC187 (20 nmol) abolished the BAT SNA response induced by icv amylin, indicating that the sympathetic effects of amylin are receptor-mediated. Conversely, icv amylin-induced BAT SNA response was enhanced in mice overexpressing the amylin receptor subunit, RAMP1, in the CNS. Our data demonstrate that CNS action of amylin regulates sympathetic nerve outflow to peripheral tissues involved in energy balance and cardiovascular function. 23621840 Cytotoxic Bisbenzylisoquinoline Alkaloids from Stephania epigaea. Six new bisbenzylisoquinoline alkaloids (1-6) and seven known compounds (8-14) were isolated from the tubers of Stephania epigaea, in addition to the major alkaloid, cepharanthine (7). The structures of 1-6 were elucidated by combined spectroscopic data analysis and chemical methods, with their configurations determined from their optical rotation values and confirmed using circular dichroism. Compounds 1-6 belong to the oxyacanthine type of bisbenzylisoquinoline alkaloids and have a rare methylenedioxy substituent. Compound 1, a dimer composed of benzylisoquinoline and seco-aristolactam units, represents a new type of bisbenzylisoquinoline alkaloid, while compounds 3-6 are bisbenzylisoquinoline N-oxides. These compounds were evaluated for their in vitro cytotoxicities against six human cancer cell lines (A-549, ECA109, HL-60, MCF-7, SMMC-7721, and SW480). Cepharanthine (7), the major component of S. epigaea, exhibited cytotoxicity against all of these cancer cell lines except ECA109, while its known analogue, 10, displayed cytotoxicity against all six cancer cell lines. 23567032 In vitro and in vivo anti-diabetic activity of Swertia kouitchensis extract. ETHNOPHARMACOLOGICAL RELEVANCE: Swertia kouitchensis has long been used as a folk medicine to treat hepatitis and diabetes in central-western China. Therefore, this study was aimed to evaluate the anti-diabetic activity of the plant ethanol extract. MATERIALS AND METHODS: Firstly, the extract was tested for its inhibitory activity on α-amylase and α-glucosidase in vitro. Following that, insulin secretion test in NIT-1cell was performed. Then, oral sucrose or starch tolerance test of the extract were carried out in normal mice. After that, acute effect of the extract was executed in normal and streptozotocin-induced (60mg/kg) diabetic mice. Eventually, long term effect of the extract was performed in diabetic mice for 4 weeks. Oral glucose tolerance test and biochemical parameters were estimated at the end of the study. RESULTS: Swertia kouitchensis extract could remarkably inhibit the activity of α-amylase and α-glucosidase and stimulate insulin secretion in vitro. And also the extract displayed anti-hyperglycemic activity, improved antioxidant capacity, ameliorated the hyperlipidemia and carbohydrate metabolism in diabetic mice. CONCLUSIONS: Swertia kouitchensis exhibits considerable anti-diabetic activity and metabolic alterations in diabetic mice. These results provide a rationale for the use of Swertia kouitchensis to treat diabetes mellitus. 23369934 Anti-oxidant and natural killer cell activity of Korean red ginseng (Panax ginseng) and urushiol (Rhus vernicifera Stokes) on non-alcoholic fatty liver disease of rat. Anti-oxidative and immunologic effects of the Korea red ginseng (KRG; Panax ginseng) and urushiol (Rhus vernicifera Stokes) on non-alcoholic fatty liver disease (NAFLD) were evaluated. Forty-five rats (five Long-Evans Tokushima Otsuka and 40 Otsuka Long-Evans Tokushima Fatty [OLETF] rats) received chew diets for 10months; after this period. The OLETF rats were divided into the following four groups according to diet for 2months: NAFLD (chew), KRG (chew+KRG [200mg/kg/day]), urushiol (chew+urushiol [0.5mg/kg/day]), and ursodeoxycholic acid (UDCA) (chew+UDCA [15mg/kg/day]) groups. Liver function, lipid profiles and anti-oxidant activity of liver and serum, natural killer (NK) cell activity, and pathology were compared. In KRG and urushiol groups, the level of serum triglyceride ([302.0±70.4 and 275.2±63.8] vs. 527.7±153.3mg/dL) were lower compared with that of NAFLD group (p<0.05). The levels of HDL-cholesterol (liver tissue: [4.8±0.2 and 4.8±0.5] vs. 4.2±0.2mg/g) and NK cell activity ([3485±910 and 3559±910] vs. 2486±619 counts) were significantly higher than those of the NAFLD group (p<0.001). Inflammation with neutrophil infiltration was observed in only two rats in the NAFLD group. These results suggest that 2months of oral KRG or urushiol administration improves lipid profiles and stimulates NK cell activity, while inhibiting steatohepatitis in OLEFT rats. 23562496 2-Hydroxychalcone and xanthohumol inhibit invasion of triple negative breast cancer cells. Breast cancer is estimated as one of the most common causes of cancer death among women. In particular, triple negative breast cancers (TNBCs), which do not express the genes for estrogen/progesterone receptors (ER/PR) and human epidermal growth factor receptor 2 (HER2), have been associated with poor prognosis and metastasis. Chalcones, the biosynthetic precursors of flavonoids present in edible plants, exert cytotoxic and chemopreventive activities. Although mounting evidence suggests the anticancer properties of chalcones, limited information is available regarding the inhibitory effects of chalcones on the aggressiveness of breast cancer cells. The present study aimed to investigate the effects of chalcone and its derivatives on the growth and the invasiveness of TNBC cells. Here, we showed that treatment with chalcone, 2-hydroxychalcone, and xanthohumol for 24h inhibited the growth of MDA-MB-231cells with IC50 values of 18.1, 4.6, and 6.7μM, respectively. Similarly, Chalcone, 2-hydroxychalcone, and xanthohumol also exerted cytotoxicity in another TNBC cell line, Hs578T. Neohesperidin dihydrochalcone, 4-methoxychalcone, and hesperidin methylchalcone did not show the cytotoxicity on the MDA-MB-231cells. Xanthohumol and 2-hydroxychalcone induced apoptosis by Bcl-2 downregulation. Importantly, 2-hydroxychalcone and xanthohumol exerted more potent inhibitory effects on the proliferation, MMP-9 expression and invasive phenotype of MDA-MB-231 than chalcone. These results suggest a potential application of these chalcones as anticancer agents that can alleviate malignant progression of TNBC. 23197647 Identification of transporters associated with Etoposide sensitivity of stomach cancer cell lines and methotrexate sensitivity of breast cancer cell lines by quantitative targeted absolute proteomics. Membrane transporter proteins may influence the sensitivity of cancer cells to anticancer drugs that can be recognized as substrates. The purpose of this study was to identify proteins that play a key role in the drug sensitivity of stomach and breast cancer cell lines by measuring the absolute protein expression levels of multiple transporters and other membrane proteins and examining their correlation to drug sensitivity. Absolute protein expression levels of 90 membrane proteins were examined by quantitative targeted absolute proteomics using liquid chromatography-linked tandem mass spectrometry. Among them, 11 and 14 membrane proteins, including transporters, were present in quantifiable amounts in membrane fraction of stomach cancer and breast cancer cell lines, respectively. In stomach cancer cell lines, the protein expression level of multidrug resistance-associated protein 1 (MRP1) was inversely correlated with etoposide sensitivity. MK571, an MRP inhibitor, increased both the cell-to-medium ratio of etoposide and the etoposide sensitivity of MRP1-expressing stomach cancer cell lines. In breast cancer cell lines, the protein expression level of reduced folate carrier 1 (RFC1) was directly correlated with methotrexate (MTX) sensitivity. Initial uptake rate and steady-state cell-to-medium ratio of [(3)H]MTX were correlated with both RFC1 expression level and MTX sensitivity. These results suggest that MRP1 modulates the etoposide sensitivity of stomach cancer cell lines and RFC1 modulates the MTX sensitivity of breast cancer cell lines. Our results indicate that absolute quantification of multiple membrane proteins could be a useful strategy for identification of candidate proteins involved in drug sensitivity. 23277358 (R)-β-lysine-modified elongation factor P functions in translation elongation. Post-translational modification of bacterial elongation factor P (EF-P) with (R)-β-lysine at a conserved lysine residue activates the protein in vivo and increases puromycin reactivity of the ribosome in vitro. The additional hydroxylation of EF-P at the same lysine residue by the YfcM protein has also recently been described. The roles of modified and unmodified EF-P during different steps in translation, and how this correlates to its physiological role in the cell, have recently been linked to the synthesis of polyproline stretches in proteins. Polysome analysis indicated that EF-P functions in translation elongation, rather than initiation as proposed previously. This was further supported by the inability of EF-P to enhance the rate of formation of fMet-Lys or fMet-Phe, indicating that the role of EF-P is not to specifically stimulate formation of the first peptide bond. Investigation of hydroxyl-(β)-lysyl-EF-P showed 30% increased puromycin reactivity but no differences in dipeptide synthesis rates when compared with the β-lysylated form. Unlike disruption of the other genes required for EF-P modification, deletion of yfcM had no phenotypic consequences in Salmonella. Taken together, our findings indicate that EF-P functions in translation elongation, a role critically dependent on post-translational β-lysylation but not hydroxylation. 23620484 The Effect of BCRP, MDR1 and OATP1B3 on the Antitumor Efficacy of the Lipophilic Camptothecin AR-67 In Vitro. AR-67 is a lipophilic camptothecin analogue, currently under early stage clinical trials. Transporters are known to have an impact on the disposition of camptothecins and on the response to chemotherapeutics in general due to their expression in tumor tissues. Therefore, the interplay between the BCRP, MDR1 and OATP1B1/OATP1B3 transporters and AR-67 and their impact on the toxicity profile of AR-67 was investigated. Using cell lines expressing the aforementioned transporters, we showed that the lipophilic AR-67 lactone form is a substrate for efflux transporters BCRP and MDR1. Additionally, OATP1B1 and OATP1B3 facilitated the uptake of AR-67 carboxylate in SLCO1B1 and SLCO1B3-transfected cell systems compared to the mock-transfected ones. Notably, both BCRPand MDR1, conferred resistance to AR-67 lactone. Prompted by recent studies showing increased OATP1B3 expression in certain cancer types, we investigated the effect of OATP1B3 expression on cell viability after exposure to AR-67 carboxylate. OATP1B3 expressing cells had increased carboxylate uptake as compared to mock transfected cells, but were not sensitized because the intracellular amount of lactone was fifty-fold higher than that of carboxylate and comparable between OATP1B3 expressing and non-expressing cells. In conclusion, BCRP- and MDR1-mediated efflux of AR-67 lactone confers resistance to AR-67, but OATP1B3-mediated uptake of the AR-67 carboxylate does not sensitize OATP1B3 expressing tumor cells. 23473343 Engineered Magnetic Shape Anisotropy in BiFeO3-CoFe2O4 Self-Assembled Thin Films. We report growth of various phase architectures of self-assembled BiFeO3-CoFe2O4 (BFO-CFO) thin films on differently oriented SrTiO3 (STO) substrates. CFO forms segregated square, stripe, and triangular nanopillars embedded in a coherent BFO matrix on (001)-, (110)-, and (111)-oriented STO substrates, respectively. Nanostructures with an aspect ratio of up to 5:1 with a prominent magnetic anisotropy were obtained on both (001) and (110) STO along out-of-plane and in-plane directions. Magnetic easy axis rotation from in-plane to out-of-plane directions was realized through aspect ratio control. An intractable in-plane anisotropy was fixed in CFO on (111) STO due to the triangular shape of the ferromagnetic phase nanopillars. These studies established a detailed relationship of magnetic anisotropy with specific shape and dimensions of ordered magnetic arrays. The results suggest a way to effectively control the magnetic anisotropy in patterned ferromagnetic oxide arrays with tunable shape, aspect ratio, and elastic strain conditions of the nanostructures. 23397054 Saturable active efflux by p-glycoprotein and breast cancer resistance protein at the blood-brain barrier leads to nonlinear distribution of elacridar to the central nervous system. The study objective was to investigate factors that affect the central nervous system (CNS) distribution of elacridar. Elacridar inhibits transport mediated by P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) and has been used to study the influence of transporters on brain distribution of chemotherapeutics. Adequate distribution of elacridar across the blood-brain barrier (BBB) and into the brain parenchyma is necessary to target tumor cells in the brain that overexpress transporters and reside behind an intact BBB. We examined the role of P-gp and Bcrp on brain penetration of elacridar using Friend leukemia virus strain B wild-type, Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)Bcrp1(-/-) mice. Initially, the mice were administered 2.5 mg/kg of elacridar intravenously, and the plasma and brain concentrations were determined. The brain-to-plasma partition coefficient of elacridar in the wild-type mice was 0.82, as compared with 3.5 in Mdr1a/b(-/-) mice, 6.6 in Bcrp1(-/-) mice, and 15 in Mdr1a/b(-/-)Bcrp1(-/-) mice, indicating that both P-gp and Bcrp limit the brain distribution of elacridar. The four genotypes were then administered increasing doses of elacridar, and the CNS distribution of elacridar was determined. The observed and model predicted maximum brain-to-plasma ratios (Emax) at the highest dose were not significantly different in all genotypes. However, the ED50 was lower for Mdr1a/b(-/-) mice compared with Bcrp1(-/-) mice. These findings correlate with the relative expression of P-gp and Bcrp at the BBB in these mice and demonstrate the quantitative enhancement in elacridar CNS distribution as a function of its dose. Overall, this study provides useful concepts for future applications of elacridar as an adjuvant therapy to improve targeting of chemotherapeutic agents to tumor cells in the brain parenchyma. 23296369 Liver transplantation and cell therapies for inborn errors of metabolism. Liver transplantation is now very successful with >85 % long term survival into adult life. When considering the impact of liver transplantation for metabolic disease two independent factors need to be considered; whether or not the defect causes liver disease and whether or not it is confined to the liver. When considering transplantation many factors need to be considered including the local success of transplantation, the impact of the metabolic disease on the patient and family and the potential for future therapeutic developments. Where transplantation is undertaken for a liver based defect there is a lifelong complete correction of the defect. Where there is a residual extrahepatic defect this will have an impact on the outcome of liver transplantation and the severity of this defect must be considered as part of the transplant assessment process. Access to a multi-disciplinary team with expertise in metabolic disease, liver disease and other relevant organ based specialists is crucial. Most children will receive transplantation from cadaveric donor but living related transplantation from a heterozygote parent is usually safe and effective. Auxiliary liver transplantation has a small but useful role where partial correction of the defect is helpful and there is a future prospect of gene therapy. The first-generation of hepatocyte transplants have shown proof of principle but to date have had a rather modest and temporary metabolic effect. Stem cells may have the potential to produce a more sustained and significant metabolic correction, but must be shown to be effective in controlled trials. 23452205 mGluR2 positive allosteric modulators: a patent review (2009 - present). Introduction: The mGlu2 receptor, which belongs to the group II subfamily of metabotropic glutamate receptors (mGlu) along with the mGlu3 receptor, has proven to be of particular importance in neuropharmacology. Preferentially expressed on presynaptic nerve terminals, the mGlu2 receptor negatively modulates glutamate and GABA release and is widely distributed in the brain. High levels of mGlu2 receptors are seen in brain areas such as prefrontal cortex, hippocampus and amygdala where glutamate hyperfunction may be implicated in disorders and diseases such as anxiety and schizophrenia. Given the promise offered by mGlu2/3 receptor activation, there is increased interest in identifying small molecules which activate the receptor. A preferred approach is via positive allosteric modulators (PAMs) which bind at an alternative site to agonists. Areas covered: This review covers the patent applications which were published between April 2009 and December 2012 on PAMs of the mGlu2, and it is a continuation of an earlier review published in this journal. Expert opinion: Advances in medicinal chemistry and pharmacology have set the stage in the field of mGlu2 receptor PAMs. Compounds currently advancing in clinical trials will soon establish the therapeutic potential of this allosteric approach. 23546603 Excess androgens in utero alters fetal testis development. Prenatal androgenization induces a polycystic ovary syndrome-like phenotype in adult female offspring, which is associated with alterations that can be detected in the fetal ovary, suggesting gestational origins of this condition. We therefore investigated whether increased prenatal androgen exposure also altered testicular development using ovine animal models. Biweekly maternal testosterone propionate (TP; 100 mg) from day 62 to day 70/day 90 of gestation altered male developmental trajectory. In male fetuses serum LH was decreased (P < .01), and testicular STAR, CYP11, and CYP17 abundance were reduced. Coincident with this, basal testicular T synthesis was decreased in vitro (P < .001). Leydig cell distribution was severely perturbed in all testes prenatally exposed to TP (P < .001). To examine the contribution of estrogens, fetuses were injected with TP (20 mg), the potent estrogen agonist, diethylstilbestrol (DES; 20 mg), or vehicle control at day 62 and day 82 and assessed at day 90. The effects of fetal (direct) TP treatment, but not DES, paralleled maternal (indirect) TP exposure, supporting a direct androgen effect. Cessation of maternal androgenization at day 102 returned Leydig cell distribution to normal but increased basal T output, at day 112, demonstrating Leydig cell developmental plasticity. Earlier maternal androgen exposure from day 30 similarly influenced Leydig cell development at day 90 but additionally affected the expression of Sertoli and germ cell markers. We show in this study that increased prenatal androgen exposure alters development and function of Leydig cells at a time when androgen production is paramount for male development. This supports the concept that gestational antecedents associated with polycystic ovary syndrome may have effects on the male fetus. 23418815 Two new compounds from Scolopendra multidens Newport. Two new compounds, 5β-pregnane-2α,6α,20(S)-triol (1) and 8-hydroxyl-3-methoxyl-2(1H)-quinolone (2), were isolated from Scolopendra multidens Newport. Their structures were elucidated on the basis of spectroscopic methods including 1D and 2D NMR and HR-TOF-MS. 23307703 Tuning optical properties of Si quantum dots by π-conjugated capping molecules. The absorption and photoluminescence (PL) properties of silicon quantum dots (QDs) are greatly influenced by their size and surface chemistry. Herein, we examined the optical properties of three Si QDs with increasing σ-π conjugation length: octyl-, (trimethylsilyl)vinyl-, and 2-phenylvinyl-capped Si QDs. The PL photon energy obtained from as-prepared samples decreased by 0.1-0.3 eV, while the PL excitation (PLE) extended from 360 nm (octyl-capped Si QDs) to 400 nm (2-phenylvinyl-capped Si QDs). A vibrational PL feature was observed in all samples with an energy separation of about 0.192±0.013 eV, which was explained based on electron-phonon coupling. After soft oxidization through drying, all samples showed blue PL with maxima at approximately 410 nm. A similar high-energy peak was observed with the bare Si QD sample. The changes in the optical properties of Si QDs were mainly explained by the formation of additional states arising from the strong σ-π conjugation and QD oxidation. 23190297 2,5-Dihydroxy-4-methoxybenzophenone: a novel major in vitro metabolite of benzophenone-3 formed by rat and human liver microsomes. 1. When benzophenone-3 (2-hydroxy-4-methoxybenzophenone; BP-3) was incubated with liver microsomes of untreated rats in the presence of NADPH, the 5-hydroxylated metabolite, 2,5-dihydroxy-4-methoxybenzophenone (5-OH-BP-3), was formed as a major novel metabolite of BP-3. The 4-desmethylated metabolite, 2,4-dihydroxybenzophenone (2,4-diOH-BP), previously reported as the major in vivo metabolite of BP-3, was also detected. However, the amount of 5-OH-BP-3 formed in vitro was about the same as that of 2,4-diOH-BP. 2. The oxidase activity affording 5-OH-BP-3 was inhibited by SKF 525-A and ketoconazole, and partly by quinidine and sulfaphenazole. The oxidase activity affording 2,4-diOH-BP was inhibited by SKF 525-A, ketoconazole and α-naphthoflavone, and partly by sulfaphenazole. 3. The oxidase activity affording 5-OH-BP-3 was enhanced in liver microsomes of dexamethasone-, phenobarbital- and 3-methylcholanthrene-treated rats. The activity affording 2,4-diOH-BP was enhanced in liver microsomes of 3-methylcholanthrene- and phenobarbital-treated rats. 4. When examined recombinant rat cytochrome P450 isoforms catalyzing the metabolism of BP-3, 5-hydroxylation was catalyzed by P450 3A2, 1A1, 2B1, 2C6 and 2D1, while 4-desmethylation was catalyzed by P450 2C6 and 1A1. 23642033 Nanoscale Patterning of Membrane-Bound Proteins Formed through Curvature-Induced Partitioning of Phase-Specific Receptor Lipids. This work describes a technique for forming high-density arrays and patterns of membrane-bound proteins through binding to a curvature-organized compositional pattern of metal-chelating lipids (Cu(2+)-DOIDA or Cu(2+)-DSIDA). In this bottom-up approach, the underlying support is an e-beam formed, square lattice pattern of hemispheres. This curvature pattern sorts Cu(2+)-DOIDA to the 200 nm hemispherical lattice sites of a 600 nm X 600 nm unit cell in Ld - Lo phase separated lipid multibilayers. Binding of histidine-tagged green fluorescent protein (His-GFP) creates a high density array of His-GFP-bound pixels localized to the square lattice sites. In comparison, the negative pixel pattern is created by sorting Cu(2+)-DSIDA in Ld - Lβ' phase separated lipid multibilayers to the flat grid between the lattice sites followed by binding to His-GFP. Lattice defects in the His-GFP pattern lead to interesting features such as pattern circularity. We also observe defect-free arrays of His-GFP that demonstrate perfect arrays can be formed by this method suggesting the possibility of using this approach for the localization of various active molecules to form protein, DNA, or optically active molecular arrays. 23421779 Two new coumarin glycosides from Chimonanthus nitens. Two new coumarin glycosides, namely nitensosides A-B (1-2), together with six known compounds, scopolin (3), 5,6,7-trimethoxycoumarin (4), d-calycanthine (5), calycanthoside (6), xeroboside (7), and scopoletin (8), were isolated from Chimonanthus nitens. The structures of the new compounds were elucidated by comprehensive analysis of IR, MS, and NMR spectroscopic data. Compounds 3, 4, 7, and 8 showed moderate inhibitory activity against Micrococcus luteus. 23350692 Iontophoresis of amoxicillin and cefuroxime: rapid therapeutic concentrations in skin. Abstract Context: Amoxicillin (AMX) and cefuroxime (CFX) are antibiotics used often to treat skin bacterial infections. Typically, high oral doses are required to achieve minimum inhibitory concentration (MIC) at the site of infection that may affect only a very small area of skin. Objectives: To lower side effects and increase therapeutic effectiveness, the percutaneous absorption and retention of AMX and CFX administered by iontophoresis was investigated in a rabbit model by measuring dermis concentrations via microdialysis. Methods: Iontophoresis was performed using a stainless steel electrode and a non-woven polypropylene pad. The cartridge pad was soaked with a solution of AMX in glycerin or of CFX in glycerin/water (60:40). Constant current density of 0, 100, 200 or 300 µA/cm(2) was applied for 60 min. Results: For AMX, therapeutically effective skin concentrations were detected immediately after the application of electrical current for any of the current density tested and remained above it for at least 2 h from the end of iontophoresis. For CFX, skin concentrations rose above MIC only at the higher current densities and fell below the MIC by the end of the experiment. Conclusion: Iontophoresis is a promising method to obtain a fast and sustained concentration of AMX and CFX in skin. 23587849 Reduction of the enniatins A, A1, B, B1 by an in vitro degradation employing different strains of probiotic bacteria: Identification of degradation products by LC-MS-LIT. The degradation of the Fusarium mycotoxins ENs by 9 bacterial strains characteristic of the gastrointestinal tract like Bb. longum, Bb. bifidum, Bb. breve, Bb. adolescentes, Lb. rhamnosus, Lb. casei-casei, S. termofilus, Lb. ruminis, Lb. casei and twenty two strains of Saccharomyces cerevisiae was studied. The fermentations were carried out in the liquid medium of De Man Rogosa Sharpe (MRS) under anaerobic conditions for Bifidobacteria Streptococcus and Lactobacillus, and in Potato Dextrose Broth (PDB) for Saccharomyces strains, during 48 h. The degradation of the bioactive compounds ENs was also studied in a food system composed by wheat flour naturally contaminated by ENs through fermentation by a strain of Fusarium tricinctum. The determination of the ENs in the fermentation mediums was performed using the technique of the liquid chromatography coupled to the mass spectrometry detector in tandem (LC-MS/MS), whereas the identification of the degradation products produced by microbial fermentation was carried out using the technique of the LC coupled to the linear ion trap (LIT). All the bacteria analyzed in this study showed a significant ENs reduction in vitro during the fermentation processes, with degradation data ranging from 5 to the 99%. In the food system, the ENs degradation data evidenced ranged from 1.3 to 49.2%. Also three ENs degradation products were identified. 23561187 Oregon 'Pinot noir' grape anthocyanin enhancement by early leaf removal. Complete cluster zone leaf removal of 'Pinot noir' was initiated at three separate pre-véraison growth stages (bloom, grain-pea size, and bunch closure) and maintained leaf free until harvest, for four growing seasons (2008-2011). Fruit anthocyanin composition was examined at harvest for the last two vintages (2010 and 2011) and compared to a control-no cluster zone leaf removal. Experiments were conducted at two commercially operating Oregon vineyards (site A=420 rootstock/'Pinot noir' 115 scion and site B=3309C rootstock/'Pinot noir' 777 scion). All clusters contained the five anthocyanins typically found in 'Pinot noir'. Leaf removal at bloom and maintained until harvest produced maximum anthocyanin accumulation in 'Pinot noir' grapes (site A=85.24mg/100g and site B=125.06mg/100g), compared to no leaf removal (control; site A=57.91mg/100g and site B=97.56mg/100g). Even leaf removal at bunch closure (last leaf removal initiation period) increased grape anthocyanin (site A=73.22mg/100g and site B=118.93mg/100g) compared to control, but total anthocyanins were lower than grapes from bloom leaf removal (first time period). Results differed slightly by vineyard site and rootstock/scion combination. 23632005 An investigation of the effect of thiamine pyrophosphate on cisplatin-induced oxidative stress and DNA damage in rat brain tissue compared with thiamine: Thiamine and thiamine pyrophosphate effects on cisplatin neurotoxicity. This study investigated the effects of thiamine pyrophosphate (TPP) at dosages of 10 and 20 mg/kg on oxidative stress induced in rat brain tissue with cisplatin and compared this with thiamine. Cisplatin neurotoxicity represents one of the main restrictions on the drug being given in effective doses. Oxidative stress is considered responsible for cisplatin toxicity. Our results showed that cisplatin increased the levels of oxidant parameters such as lipid peroxidation (thio barbituric acid reactive substance (TBARS)) and myeloperoxidase (MPO) in brain tissue and suppressed the effects of antioxidants such as total glutathione (GSH) and superoxide dismutase (SOD). TPP, especially at a dosage of 20 mg/kg, significantly reduced TBARS and MPO levels that increase with cisplatin administration compared with the thiamine group, while TPP significantly increases GSH and SOD levels. In addition, the level of 8-Gua (guanine), a product of DNA damage, was 1.7 ± 0.12 8-hydroxyl guanine (8-OH Gua)/105 Gua in brain tissue in the control group receiving cisplatin, compared with 0.97 ± 0.03 8-OH Gua/105 Gua in the thiamine pyrophosphate (20 mg/kg) group and 1.55 ± 0.11 8-OH Gua/105 Gua in the thiamine (20 mg/kg) group. These results show that thiamine pyrophosphate significantly prevents oxidative damage induced by cisplatin in brain tissue, while the protective effect of thiamine is insignificant. 23152558 Dynorphin-still an extraordinarily potent opioid peptide. This issue of Molecular Pharmacology is dedicated to Dr. Avram Goldstein, the journal's founding editor and one of the leaders in the development of modern pharmacology. This article focuses on his contributions to the discovery of the dynorphins and evidence that members of this family of opioid peptides are endogenous agonists for the kappa opioid receptor. In his original publication describing the purification and sequencing of dynorphin A, Avram described this peptide as "extraordinarily potent" ("dyn" from the Greek, dynamis = power and "orphin" for endogenous morphine peptide). The name originally referred to its high affinity and great potency in the bioassay that was used to follow its activity during purification, but the name has come to have a second meaning: studies of its physiologic function in brain continue to provide powerful insights to the molecular mechanisms controlling mood disorders and drug addiction. During the 30 years since its discovery, we have learned that the dynorphin peptides are released in brain during stress exposure. After they are released, they activate kappa opioid receptors distributed throughout the brain and spinal cord, where they trigger cellular responses resulting in different stress responses: analgesia, dysphoria-like behaviors, anxiety-like responses, and increased addiction behaviors in experimental animals. Avram predicted that a detailed molecular analysis of opiate drug actions would someday lead to better treatments for drug addiction, and he would be gratified to know that subsequent studies enabled by his discovery of the dynorphins resulted in insights that hold great promise for new treatments for addiction and depressive disorders. 23602984 Cannabinoids increase type 1 cannabinoid receptor expression in a cell culture model of striatal neurons: Implications for Huntington's disease. The type 1 cannabinoid receptor (CB1) is a G protein-coupled receptor that is expressed at high levels in the striatum. Activation of CB1 increases expression of neuronal trophic factors and inhibits neurotransmitter release from GABA-ergic striatal neurons. CB1 mRNA levels can be elevated by treatment with cannabinoids in non-neuronal cells. We wanted to determine whether cannabinoid treatment could induce CB1 expression in a cell culture model of striatal neurons and, if possible, determine the molecular mechanism by which this occurred. We found that treatment of STHdh(7/7) cells with the cannabinoids ACEA, mAEA, and AEA produced a CB1 receptor-dependent increase in CB1 promoter activity, mRNA, and protein expression. This response was Akt- and NF-κB-dependent. Because decreased CB1 expression is thought to contribute to the pathogenesis of Huntington's disease (HD), we wanted to determine whether cannabinoids could increase CB1 expression in STHdh(7/111) and (111/111) cells expressing the mutant huntingtin protein. We observed that cannabinoid treatment increased CB1 mRNA levels approximately 10-fold in STHdh(7/111) and (111/111) cells, compared to vehicle treatment. Importantly, cannabinoid treatment improved ATP production, increased the expression of the trophic factor BDNF-2, and the mitochondrial regulator PGC1α, and reduced spontaneous GABA release, in HD cells. Therefore, cannabinoid-mediated increases in CB1 levels could reduce the severity of some molecular pathologies observed in HD. 23228886 Oxidative modification of neurofilament-L and neuronal cell death induced by the catechol neurotoxin, tetrahydropapaveroline. Tetrahydropapaveroline (THP), which is an endogenous neurotoxin, has been suspected to be associated with dopaminergic neurotoxicity of l-DOPA. In this study, we examined oxidative modification of neurofilament-L (NF-L) and neuronal cell death induced by THP. When disassembled NF-L was incubated with THP, protein aggregation was increased in a time- and THP dose-dependent manner. The formation of carbonyl compounds and dityrosine were observed in the THP-mediated NF-L aggregates. Radical scavengers reduced THP-mediated NF-L modification. These results suggest that the modification of NF-L by THP may be due to oxidative damage resulting from the generation of reactive oxygen species (ROS). When THP exposed NF-L was subjected to amino acid analysis, glutamate, proline and lysine residues were found to be particularly sensitive. We also investigated the effects of copper ions on THP-mediated NF-L modification. At a low concentration of THP, copper ions enhanced the modification of NF-L. Treatment of C6 astrocyte cells with THP led to a concentration-dependent reduction in cell viability. When these cells were treated with 100μM THP, the levels of ROS increased 3.5-fold compared with control cells. Furthermore, treatment of cells with THP increased NF-L aggregate formation, suggesting the involvement of NF-L modification in THP-induced cell damage. 23291051 Sub-lethal coral stress: detecting molecular responses of coral populations to environmental conditions over space and time. In order for sessile organisms to survive environmental fluctuations and exposures to pollutants, molecular mechanisms (i.e. stress responses) are elicited. Previously, detrimental effects of natural and anthropogenic stressors on coral health could not be ascertained until significant physiological responses resulted in visible signs of stress (e.g. tissue necrosis, bleaching). In this study, a focused anthozoan holobiont microarray was used to detect early and sub-lethal effects of spatial and temporal environmental changes on gene expression patterns in the scleractinian coral, Montastraea cavernosa, on south Florida reefs. Although all colonies appeared healthy (i.e. no visible tissue necrosis or bleaching), corals were differentially physiologically compensating for exposure to stressors that varied over time. Corals near the Port of Miami inlet experienced significant changes in expression of stress responsive and symbiont (zooxanthella)-specific genes after periods of heavy precipitation. In contrast, coral populations did not demonstrate stress responses during periods of increased water temperature (up to 29°C). Specific acute and long-term localized responses to other stressors were also evident. A correlation between stress response genes and symbiont-specific genes was also observed, possibly indicating early processes involved in the maintenance or disruption of the coral-zooxanthella symbiosis. This is the first study to reveal spatially- and temporally-related variation in gene expression in response to different stressors of in situ coral populations, and demonstrates that microarray technology can be used to detect specific sub-lethal physiological responses to specific environmental conditions that are not visually detectable. 23159886 Biochemical and molecular mechanisms of N-acetyl cysteine and silymarin-mediated protection against maneb- and paraquat-induced hepatotoxicity in rats. Oxidative stress is one of the major players in the pathogenesis of maneb (MB) and paraquat (PQ)-induced disorders. N-acetyl cysteine (NAC), a glutathione (GSH) precursor and silymarin (SIL), a naturally occurring antioxidant, encounter oxidative stress-mediated cellular damage. The present study was aimed to investigate the effects of NAC and SIL against MB and/or PQ-induced hepatotoxicity in rats. The levels of hepatotoxicity markers - alanine aminotransaminase (ALT), aspartate aminotransaminase (AST) and total bilirubin, histological changes, oxidative stress indices, phase I and phase II xenobiotic metabolizing enzymes - cytochrome P450 (CYP) and glutathione S-transferase (GST) and pro-inflammatory molecules - inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured in animals treated with MB and/or PQ in the presence or absence of NAC and SIL. MB and/or PQ augmented ALT, AST, total bilirubin, lipid peroxidation and nitrite contents and catalytic activities of superoxide dismutase and glutathione peroxidase however, the GSH content was attenuated. NAC and SIL restored the above-mentioned alterations towards basal levels but the restorations were more pronounced in SIL treated groups. Similarly, MB and/or PQ-mediated histopathological symptoms and changes in the catalytic activities/expressions of CYP1A2, CYP2E1, iNOS, TNF-α, and IL-1β were alleviated by NAC and SIL. Conversely, MB and/or PQ-induced GSTA4-4 expression/activity was further increased by NAC/SIL and glutathione reductase activity was also increased. The results obtained thus suggest that NAC and SIL protect MB and/or PQ-induced hepatotoxicity by reducing oxidative stress, inflammation and by modulating xenobitic metabolizing machinery and SIL seems to be more effective. 23194532 The in vivo antioxidant and antifibrotic properties of green tea (Camellia sinensis, Theaceae). The in vivo antioxidant and antifibrotic properties of green tea (Camellia sinensis, Theaceae) were investigated with a study of carbon tetrachloride (CCl(4))-induced oxidative stress and hepatic fibrosis in male ICR mice. Oral administration of green tea extract at doses of 125, 625 and 1250 mg/kg for 8 weeks significantly reduced (p<0.05) the levels of thiobarbituric acid-reactive substances (TBARS) and protein carbonyls in the liver by at least 28% compared with that was induced by CCl(4) (1 mL/kg) in mice. Moreover, green tea extract administration significantly increased (p<0.05) the activities of catalase, glutathione peroxidase (GSH-Px) and glutathione reductase (GSH-Rd) in the liver. Our study found that oral administration of green tea extract prevented CCl(4)-induced hepatic fibrosis, as evidenced by a decreased hydroxyproline level in the liver and a reduced incidence of hepatic fibrosis by histological observations. These results indicate that green tea exhibits potent protective effects against CCl(4)-induced oxidative stress and hepatic fibrosis in mice by inhibiting oxidative damage and increasing antioxidant enzyme activities. 22578098 Discovery and structural characterization of a phospholamban-binding cyclic peptide and design of novel inhibitors of phospholamban. The interplay between cardiac sarcoplasmic Ca(2+)ATPase and phospholamban is a key regulating factor of contraction and relaxation in the cardiac muscle. In heart failure, aberrations in the inhibition of sarcoplasmic Ca(2+)ATPase by phospholamban are associated with anomalies in cardiac functions. In experimental heart failure models, modulation of the interaction between these two proteins has been shown to be a potential therapeutic approach. The aim of our research was to find molecules able to interfere with the inhibitory activity of phospholamban on sarcoplasmic Ca(2+)ATPase. For this purpose, a portion of phospholamban was synthesized and used as target for a phage-display peptide library screening. The cyclic peptide C-Y-W-E-L-E-W-L-P-C-A was found to bind to phospholamban (1-36) with high specificity. Its functional activity was tested in Ca(2+)uptake assays utilizing preparations from cardiac sarcoplasmic reticulum. By synthesizing and testing a series of alanine point-mutated cyclic peptides, we identified which amino acid was important for the inhibition of the phospholamban function. The structures of active and inactive alanine-mutated cyclic peptides, and of phospholamban (1-36), were determined by NMR. This structure-activity analysis allowed building a model of phospholamban -cyclic peptide complex. Thereafter, a simple pharmacophore was defined and used for the design of small molecules. Finally, examples of such molecules were synthesized and characterized as phospholamban inhibitors. 23201371 Antimutagenic evaluation of vitamins B1, B6 and B12 in vitro and in vivo, with the Ames test. The aim of this work is to evaluate vitamins B antimutagenic effect against alkylatings methyl-N-nitro-N-nitrosoguanidine (MNNG), ethyl-N-nitro-N'- nitrosoguanidine (ENNG), frameshift mutagens 2-aminoanthracene (2AA) and 2-acetyl-amino-fluorene (2AF) and ROS-generating antibiotics norfloxacin (NOR) and nalidixic acid (NLX), using the in vitro Ames test. In vivo antimutagenesis studies were performed against urinary mutagens induced by NOR (70 mg/kg) or NLX (100 mg/kg) in CD1 mice. Vitamin B1 was antimutagenic against alkylatings MNNG (P<0.05) or ENNG (P<0.001). In fact as per the results observed during the current study, none of the vitamins reduced mutagenesis caused by frameshift mutagens. All of them reduced mutagenesis of NOR or NLX (P<0.001). In vivo studies showed that vitamins B1 and B6 (10 or 100 mg/kg) reduced urinary mutagens from NOR (P<0.001) or NLX (P<0.02) either free or β-glucoronidase-conjugates. None of the studied samples were toxic for the employed antimutagenic system. Vitamin B12 (4 mg/kg) reduced urinary mutagens of NOR or NLX (P<0.02). Vitamins B inhibited DNA mutations induced by ROS generated by NLX or NOR, both in vitro and in vivo. Vitamin B1is antimutagenic against mutations induced by the alkylating MNNG or ENNG. Based on the observations, employment of vitamins B in vivo can be a promising alternative to reduce genotoxic risk exposure to ROS. 23246437 Spp1, a member of the Set1 Complex, promotes meiotic DSB formation in promoters by tethering histone H3K4 methylation sites to chromosome axes. Meiotic chromosomes are organized into arrays of loops that are anchored to the chromosome axis structure. Programmed DNA double-strand breaks (DSBs) that initiate meiotic recombination, catalyzed by Spo11 and accessory DSB proteins, form in loop sequences in promoters, whereas the DSB proteins are located on chromosome axes. Mechanisms bridging these two chromosomal regions for DSB formation have remained elusive. Here we show that Spp1, a conserved member of the histone H3K4 methyltransferase Set1 complex, is required for normal levels of DSB formation and is associated with chromosome axes during meiosis, where it physically interacts with the Mer2 DSB protein. The PHD finger module of Spp1, which reads H3K4 methylation close to promoters, promotes DSB formation by tethering these regions to chromosome axes and activating cleavage by the DSB proteins. This paper provides the molecular mechanism linking DSB sequences to chromosome axes and explains why H3K4 methylation is important for meiotic recombination. 22499272 Antihyperglycemic and antihyperlipidemic activities of ethanolic extract of Zygophyllum album in streptozotocin-induced diabetic mice. Zygophyllum album has been mentioned in Tunisian system of folk medicine to be of value in the treatment of diabetes mellitus. The present study was designed to investigate the possible antihyperglycemic effects of ethanolic extracts of the whole plant of Z. album on blood glucose, plasma insulin, serum lipids and hepatic glycogen and metabolism enzymes of carbohydrate in streptozotocin (STZ)-induced diabetic mice. Administration of the ethanolic extract from plant (100 and 300 mg/kg body weight) for 14 days resulted in significant reduction in plasma glucose, cholesterol, triglycerides, low-density lipoprotein, very-low-density liprotein, hepatic glucokinase and glycogen in STZ diabetic mice. In addition to that, significant increase in plasma high-density lipoprotein, hepatic phosphofructokinase and glucose-6 phosphate dehydrogenase was observed in STZ diabetic mice. After administration of the ethanolic extract, the increased level of plasma insulin is not significant in diabetic mice. In conclusion, the present results showed that the ethanolic extract of Z. album possesses significant antihyperglycemic and antihyperlipidemic effects in experimental model of diabetes mellitus. 23194537 A new QSAR model, for angiotensin I-converting enzyme inhibitory oligopeptides. A new quantitative structure activity relationship (QSAR) model is established for oligopeptides that inhibit angiotensin I-converting enzyme (ACE). Information concerning the C-terminal pentapeptide is considered to describe the peptide structure in the model. A database is constructed, with 263 ACE inhibitory peptides and 38 physicochemical descriptors, abstracted from the published literature. The model is generated through a generalised linear model, with a gamma distribution that yields a coefficient of determination of 94.4%. The whole C-terminal pentapeptide information is a determinant for modelling the ACE inhibition activity of oligopeptides. Starting from the C-terminus, the C-1 position is the most relevant position in the model; this is followed by position C-4. In C-1, there is a preference for aliphatic and tiny residues. However, in the C-4 position, the model indicates a clear preference for bulky hydrophobic amino acids and for sulphur-containing amino acids. Due to its good predictive capability, this model could be used as a tool for identifying and prioritizing the potential ACE inhibitory peptides present in a complex matrix. 23208822 Enantiospecific total synthesis of (-)-bengamide E. Total synthesis of the polyhydroxy caprolactam amide natural product, bengamide E, is accomplished starting from tartaric acid. Key reactions in the synthesis include desymmetrization of the bis(dimethylamide) unit of tartaric acid, Zn(BH(4))(2)-mediated anti-selective reduction, and a Horner-Wadsworth-Emmons olefination. 23524316 Effect of quercetin-rich onion peel extracts on arterial thrombosis in rats. The aim of this study was to examine whether oral supplementation of quercetin-rich onion peel extract (OPE) influences blood coagulation and arterial thrombosis in Sprague-Dawley (SD) rats. 24 male rats, 5weeks old, were divided into three groups with different diets (C: control, 2mg OPE: chow diet with 2mg OPE supplementation, 10mg OPE: chow diet with 10mg OPE supplementation) for 6weeks. Blood coagulation parameters including prothrombin time (PT), activated partial thromboplastin time (aPTT) and platelet aggregation were examined. The OPE did not affect blood cholesterol levels but significantly decreased blood triglyceride and glucose levels. PT, aPTT and platelet aggregation were not significantly different among all tested groups. However, in vivo arterial thrombosis was significantly delayed in groups that were fed 2mg and 10mg OPE diets compared to the control group. In addition, the OPE greatly diminished thrombin-induced expression of tissue factor in human umbilical vein endothelial cells (HUVECs), a coagulation initiator. In addition, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways activated by thrombin treatment were prevented by the OPE pre-treatment. These results indicate that OPE may have anti-thrombotic effects through restricting the induced expression of tissue factor via down-regulating mitogen-activated protein kinase (MAPK) activation upon coagulation stimulus, leading to the prolongation of time for arterial thrombosis. 23249276 Enhancement of the water solubility of flavone glycosides by disruption of molecular planarity of the aglycone moiety. Enhancement of the water solubility by disruption of molecular planarity has recently been reviewed as a feasible approach in small-molecule drug discovery programs. We applied this strategy to some natural flavone glycosides, especially diosmin, a highly insoluble citroflavonoid prescribed as an oral phlebotropic drug. Disruption of planarity at the aglycone moiety by 3-bromination or chlorination afforded 3-bromo- and 3-chlorodiosmin, displaying a dramatic solubility increase compared with the parent compound. 23586970 Nocardiamides A and B, Two Cyclohexapeptides from the Marine-Derived Actinomycete Nocardiopsis sp. CNX037. Two new cyclic hexapeptides, nocardiamides A (1) and B (2), were isolated from the culture broth of marine-derived actinomycete CNX037 strain that was identified as a Nocardiopsis species. The planar structures of nocardiamides A (1) and B (2) were assigned on the basis of 1D and 2D NMR and HRESIMS spectroscopic analyses. Their absolute configurations were deduced by the advanced Marfey's method and chiral-phase HPLC analysis. The challenge of locating two d- and one l-valine residue in 1 and 2 was accomplished by total synthesis using solid-phase peptide synthetic methods. Both 1 and 2 showed negligible antimicrobial activities against seven indicator strains and exhibited no cytotoxicity against HCT-116. 23214973 Preparation of functionalized alkynyl magnetic microspheres for the selective enrichment of cell glycoproteins based on click chemistry. Functionalized alkynyl polyvinyl alcohol magnetic microspheres (PVA MMs) were developed for the specific enrichment of sialic acid-rich glycoproteins by click chemistry. The capture capability for proteins was evaluated through a novel dual-labeled bovine serum albumin (BSA) that utilizes fluorescence resonance energy transfer (FRET). The PVA MM parameters, including the size and coverage of functionalized groups, were optimized by response surface methodology. The optimal parameters obtained were 1.25-6.31 μm in size and 48.53-73.05% in coverage. Then, the optimal PVA MMs were synthesized, and the morphology and surface chemical properties were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FT-IR). To capture glycoproteins from the cell surface, a bioorthogonal chemical method was applied to metabolically label them with an azide group. The functionalized alkynyl PVA MMs showed a high specificity and strong binding capability for glycoproteins through a [3 + 2] cycloaddition reaction. The results indicated that the functionalized alkynyl PVA MMs could be applied to the enrichment of cell glycoproteins, and the merits of the MMs suggested an attractive and potential way to facilitate glycoprotein research. 23519980 Chd4 and associated proteins function as corepressors of Sox9 expression during BMP-2-induced chondrogenesis. Mouse embryonic fibroblasts (MEFs) differentiate into fully functional chondrocytes in response to bone morphogenetic protein-2 (BMP-2). However, the comprehensive proteomic aspect of BMP-2-induced chondrogenesis remains unknown. We took advantage of quantitative proteomic analysis based on isobaric tag for relative and absolute quantitation (iTRAQ) and on-line 2D nano-liquid chromatography/tandem mass spectrometry (LC/MS/MS) to identify proteins differentially expressed during BMP-2-induced chondrogenic differentiation of MEFs. We found 85 downregulated proteins, and Ingenuity Pathways Analysis (IPA) revealed a protein-protein network with chromodomain-helicase-DNA-binding protein 4 (Chd4) in the center. Chromatin immunoprecipitation (ChIP) and nuclease hypersensitivity assays showed that Chd4, interacting with Hdac1/2, cooperates with its related proteins Kap1 and Cbx1 to bind at -207/-148 of the Sox9 promoter. We also provided evidence that let-7a targets the 3'UTR of Chd4 to promote chondrogenesis of MEFs. Together, our findings indicate that BMP-2 induced the upregulation of let-7a, targeting Chd4 and positively controlling the chondrogenic differentiation of MEFs. These findings illustrate epigenetic regulation of the chondrogenic differentiation process and also expand the understanding of the involved intracellular mechanisms. © 2013 American Society for Bone and Mineral Research. 23271680 Source apportionment of trace element pollution in surface sediments using positive matrix factorization combined support vector machines: application to the Jinjiang River, China. In this study, a method of positive matrix factorization (PMF) combined support vector machines (SVMs) was adopted to identify possible sources and apportion contributions for trace element pollution in surface sediments from the Jinjiang River, Southeastern China. Utilizing diagnostics tools, four significant factors were extracted from sediment samplers, which were collected in December 2010 at 15 different sites. By treating source identification as a pattern recognition problem, the factor loadings derived from PMF were classified by SVM classifiers which have been trained and validated with fingerprints of eight potential source categories. Using SVM, industrial wastewater from lead ore mining and metal handcraft manufacture, atmospheric deposition, and natural background were identified as main sources of trace element pollution in surface sediments from the Jinjiang River, which were affirmed by visually comparing compound patterns and the differences between the predicted and actual fractional compositions. Apportionment results showed that source of lead ore mining made the largest contribution (33.62 %), followed by atmospheric deposition (30.99 %), metal handcraft manufacture (30.09 %), and natural background (5.29 %). 23485559 1-Methylimidazolium hydrogen sulfate catalyzed convenient synthesis of 2,5-dimethyl-N-substituted pyrroles under ultrasonic irradiation. Ionic liquid [HMIM]HSO4 was found to be an efficient catalyst for the synthesis of N-substituted pyrroles through the reaction of 2,5-hexanedione with amines under ultrasonic irradiation at room temperature. These reactions proceed with good yields under short reaction time. Furthermore, the green catalytic system can be recycled specific times with no decreases in yields and reaction rates. 23468173 3-Hydroxyazetidine carboxylic acids: non-proteinogenic amino acids for medicinal chemists. The formation from D-glucose of both enantiomers of 2,4-dideoxy-2,4-iminoribonic acid is the first chemical synthesis of unprotected 3-hydroxyazetidine carboxylic acids. The long-term stability of 3-hydroxyazetidine amides is established at acidic and neutral pH and implies their value as non-proteinogenic amino acid components of peptides, providing medicinal chemists with a new class of peptide isosteres. The structure of N,3-O-dibenzyl-2,4-dideoxy-2,4-imino-D-ribonic acid was established by X-ray crystallographic analysis. An N-methylazetidine amide derivative is a specific inhibitor of β-hexosaminidases at the micromolar level, and is only the second example of potent inhibition of any glycosidase by an amide of a sugar amino acid related to an iminosugar. 23621524 Insertion of CO2 and COS into Bi-C Bonds: Reactivity of a Bismuth NCN Pincer Complex of an Oxyaryl Dianionic Ligand, [2,6-(Me2NCH2)2C6H3]Bi(C6H2tBu2O). The reactivity of the unusual oxyaryl dianionic ligand, (C6H2tBu2-3,5-O-4)2-, in the Bi3+ NCN pincer complex Ar'Bi(C6H2tBu2-3,5-O-4), 1, [Ar' = 2,6-(Me2NCH2)2C6H3] has been explored with small molecule substrates and electrophiles. The first insertion reactions of CO2 and COS into Bi-C bonds are observed with this oxyaryl dianionic ligand complex. These reactions generate new dianions that have quinoidal character similar to the oxyaryl dianionic ligand in 1. The oxyarylcarboxy and oxyarylthiocarboxy dianionic ligands were identified by X-ray crystallography in Ar'Bi[O2C(C6H2tBu2-3-5-O-4)-κ2O,O'], 2 and Ar'Bi[OSC(C6H2tBu2-3-5-O-4)-κ2O,S], 3, respectively. Silyl halides and pseudohalides, R3SiX (X = Cl, CN, N3; R = Me, Ph), react with 1 by attaching X to bismuth and R3Si to the oxyaryl oxygen to form Ar'Bi(X)(C6H2tBu2-3,5-OSiR3-4) complexes, a formal addition across five bonds. These react with additional R3SiX to generate Ar'BiX2 complexes and R3SiOC6H3tBu2-2,6. The reaction of 1 with I2 forms Ar'BiI2 and the coupled quinone, 3,3',5,5'-tetra-tert-butyl-4,4'-diphenoquinone, by oxidative coupling. 23122111 Neferine induces reactive oxygen species mediated intrinsic pathway of apoptosis in HepG2 cells. Evidence has accumulated concerning the medicinal application of Nelumbo nucifera in the treatment of various diseases. Neferine, an alkaloid from N. nucifera was found to exert cytotoxicity on liver cancer cells HepG2 in a dose-dependent manner. We evaluated its anticancer potential by studying its effect on mitochondrial membrane potential, intracellular calcium levels [Ca(2+)](i), cell membrane integrity, apoptotic body formation and DNA fragmentation in cultured HepG2 cells. The reactive oxygen species level has been increased upon neferine treatment with concomitant decrease in reduced glutathione. Our data further indicate reduction of ΔψM and increased [Ca(2+)](i) during apoptosis induction by neferine with increased expression of apoptotic proteins such as Bax, Bad, cleaved forms of caspase 3, caspase 9 and PARP, with the downregulation of anti-apoptotic protein Bcl2 in HepG2 cells. Moreover, the expressions of tumour suppressor proteins p53 and PTEN were upregulated along with the downregulation of P-Akt. In addition, expression levels of TNF-α, p38 and ERK1/2 MAP kinases were increased upon neferine treatment. These results imply that mitochondrial-mediated ROS generation induced by neferine leads to caspase-dependent apoptosis in HepG2 cells. 22443216 Intraspecific chemical variability of essential oil from leaves of Cupressus atlantica Gaussen, an endemic and endangered coniferous species in Morocco. The composition of essential oils isolated from leaves of 11 natural populations of Cupressus atlantica, an endemic and endangered coniferous species from Morocco, was investigated by GC-MS. In total, 42 essential oil components were identified, accounting for 73.1-97.7% of the total oil. Monoterpene (25.2-84.9%) and sesquiterpene hydrocarbons (12.2-46.8%) were the principal subclasses of compounds, with α-pinene (15-65.4%), germacrene D (5.9-30.5%), δ-3-carene (2-16.6%) and γ-cadinene (1.3-9.8%) as the main constituents. The results of the oil composition were analysed by hierarchical cluster and principal component analysis that established three main groups of essential oils. These oils were differentiated by the content of the major constituents (α-pinene, germacrene D, δ-3-carene and γ-cadinene), geographical location and climatic characteristics. 23307551 Prevalence of and factors that influence board certification among pharmacy practice faculty at United States colleges and schools of pharmacy. Board certification is a means of demonstrating expertise above the minimum licensing standards. For many health care professionals, this credential is a necessity. As pharmacists become involved in more advanced patient care services, board certification becomes an essential component to ensuring quality care. The prevalence of United States pharmacy practice faculty members who are board certified, however, is unknown. In addition, to our knowledge, factors that serve to motivate or discourage faculty from obtaining board certification have not been previously described; thus, 900 pharmacy practice faculty members listed in the American Association of Colleges of Pharmacy (AACP) online directory were invited to complete an online survey regarding motivators and barriers for board certification. In addition, a list of board-certified pharmacists, obtained from the Board of Pharmacy Specialties, was used to check the board certification status of all pharmacy practice faculty members listed in the AACP directory. In 2011, the prevalence of board certification among the 2867 pharmacy practice faculty members was 37% (1063 pharmacists), with the highest prevalence found among assistant professors (39.4%). A total of 322 faculty members (36% response rate) completed the survey; of these, 308 self-identified as pharmacy practice faculty, and their responses were included in the analysis. Current board certification in pharmacy specialties was reported by 163 respondents (52.9%); 14 (4.5%) were previously certified. Among the 308 respondents, the most common perceived reason why pharmacy practice faculty become board certified was the desire to be recognized as an expert in the field (71.5%). Those who were currently board certified indicated personal growth as the most important reason (60.1%). Those previously certified indicated no perceived benefit as the most common reason for not recertifying (71.4%). Among those never certified, no perceived need (52.0%) or benefit (44.8%) were the most common reasons for not becoming certified; however, a majority of those never certified (68%) stated that they would become board certified if there was no associated cost and they were confident they would pass. To increase the prevalence of board certification in pharmacy practice faculty at U.S. schools and colleges of pharmacy, the benefits of this credential must be addressed at each institution. Steps should be taken to assist and encourage board certification. 23594105 Ultralow Thermal Conductivity in Organoclay Nanolaminates Synthesized via Simple Self-Assembly. Because interfaces impede phonon transport of thermal energy, nanostructuring can transform fully dense solids into ultralow thermal conductivity materials. Here we report a simple self-assembly approach to synthesizing organoclay nanolaminates with cross-planar thermal conductivities below 0.10 W m(-1) K(-1)-a 5-fold decrease compared to unmodified clay. These organoclays are produced via alkylammonium cation exchange with colloidally dispersed montmorillonite clay sheets followed by solvent casting. Time-domain thermoreflectance (TDTR) is used to evaluate the thermal conductivity of the organoclay nanolaminates. Variations in both organic layer thickness and cation chemistry are investigated. At these interface densities (1.0-1.5 interfaces/nm), we demonstrate that thermal conductivity is relatively independent of nanolaminate spacing. A simple series resistance model describes the behavior and gives an interfacial thermal conductance value of ≈150 MW m(-2) K(-1) for the organic/clay interface, consistent with similar organic-inorganic interfaces. The wide range of compositional substitutions and structural variations possible in these materials, make organoclays a versatile new platform for investigating the underlying physics of nanolaminate structures. 23298577 Synthesis, characterization and targeting potential of zidovudine loaded sialic acid conjugated-mannosylated poly(propyleneimine) dendrimers. The present investigation was aimed at exploring dual targeting of anti-HIV drug, zidovudine (ZDV) via sialic acid conjugated-mannosylated poly(propyleneimine) (PPI) dendritic nano-constructs. Fourth generation PPI dendrimers, sialic acid conjugated PPI dendrimers (SPPI), mannose conjugated PPI dendrimers (MPPI) and dual ligand system i.e. sialic acid conjugated-mannosylated PPI dendrimers (SMPPI) were synthesized and characterized by FT-IR and (1)H NMR spectroscopies and were further confirmed by size exclusion chromatography and differential scanning calorimetry. Various parameters like drug loading, pH dependent in vitro release, hemolytic toxicity, macrophage uptake and cytotoxicity concerning PPI, SPPI, MPPI and SMPPI dendrimers were evaluated. ZDV loaded SMPPI, SPPI and MPPI have shown reduced hemolytic toxicity, cytotoxicity and in vitro drug release at pH 7.4. Extremely significant (P<0.001) increase in cellular uptake of ZDV by macrophage cells was observed in case of SMPPI as compared to PPI and free drug. The in vivo blood level and tissue distribution studies in albino rats also demonstrated potential of dual targeted system towards sialoadhesin and carbohydrate receptors. The drug concentration in lymph nodes was increased to about 28 times in case of SMPPI (1335 ± 17.6 ng/g) as compared to free drug (48 ± 5.8 ng/g) at 6th hr. The results suggested that such dual ligand dendritic system (SMPPI) hold potential to enhance biocompatibility and site specific delivery of antiretroviral drug, ZDV. 23438375 pH-controlled nanoaggregation in amphiphilic polymer co-networks. Domain formation and control in pH-responsive amphiphilic polymer co-networks are studied theoretically. Two different molecular architectures of the polymer network are considered, depending on whether the pH-sensitive motif is borne by the hydrophobic or the hydrophilic monomer. When the hydrophobic polymer contains acidic groups, such chains form nanometric aggregates at acidic conditions, but they are found in a swollen state at alkaline pH. At intermediate pH, the nanoaggregation behavior of the hydrophobic polymer depends critically on the environment salt concentration. Moreover, our results indicate the presence of microphase separation into domains of swollen and aggregated hydrophobic chains. If the hydrophilic polymer is the ionizable component of the network, the nanoaggregation of hydrophobic monomers is weakly dependent on the pH and salt concentration, and except at very low volume fraction, the aggregate is the most probable conformation of the network in the entire range of pH and salt concentration studied. The two different hydrogels display quantitatively similar swelling transition and apparent pKa, but at the nanoscale, their behavior is qualitatively different. The spatial distribution of electric charge on the network as well as the local density of the different chemical species within the hydrogel can be controlled, as a function of pH and salt concentration, by the molecular architecture of the polymer network. These findings have relevance for applications in biomaterials and nanotechnology, in particular, in the design of oral delivery devices for the administration of hydrophobic drugs. 23287726 Trypsin and chymotrypsin inhibitor peptides from the venom of Chinese Daboia russellii siamensis. Two trypsin inhibitors and one chymotrypsin inhibitor from Chinese Daboia russellii siamensis venom, denoted as CBPTI-1, CBPTI-2 and CBPTI-3 were purified, characterized and cloned from lyophilized venom-derived cDNA libraries. The N-terminus of CBPTI-1 was modified and not amenable to Edman degradation sequencing, however an internal partial sequence was found to be SGRCRGHLRRIYYNPDSNKCE. The N-termini of CBPTI-2 and CBPTI-3 were unmodified and their partial sequences were established as HDRPTFCNLAPESGRCRAH and HDRPKFCYLPADPGECMAYIRSFYYDS respectively. From cloning studies CBPTI-1 was found to consist of 66 amino acid residues, while CBPTI-2 and CBPTI-3 precursors consist of 60 amino acid residues, including 6 cysteine residues. Another cDNA sequence (CBPTI-4) was also obtained. Alignment of cDNA sequences showed that CBPTI-3 exhibited similar sequence homology to CBPTI-4 cDNA except for an 8 nucleotide deletion in the open-reading frame. CBPTI-1 and CBPTI-2 were demonstrated to be potent trypsin inhibitors, but were also shown to be effectively potent in chymotrypsin inhibition. The K(i) values of CBPTI-1 and CBPTI-2 for trypsin inhibition were 4.07 × 10(-7) M and 6.66 × 10(-7) M, respectively, and they were non-competitive in their activity. CBPTI-3 showed chymotrypsin inhibition activity with a K(i) value of 2.55 × 10(-9) M, but did not show trypsin inhibitor activity. 23618901 Smad3 mediates cigarette smoke extract (CSE) induction of VEGF release by human fetal lung fibroblasts. Cigarette smoke is the major cause of chronic obstructive pulmonary disease (COPD), yet pathogenic mechanisms are not fully understood. Vascular endothelial growth factor (VEGF) is one of the major regulators of endothelial cell survival and is believed to play a role in the pathogenesis of COPD. Fibroblasts are a significant source of VEGF in the lungs; however the effect of cigarette smoke exposure on VEGF release by fibroblasts is not fully understood. We hypothesized that cigarette smoke-induced disturbed VEGF release by human lung fibroblasts is a potential pathogenic mechanism that could contribute to COPD. Cigarette smoke extract (CSE) was prepared by modification of the methods of Carp and Janoff (American Review of Respiratory Disease, 1978). Human fetal lung fibroblasts (HFL-1) were exposed to different concentrations of CSE and for different durations. VEGF release into the media was measured using ELISA. TGF-β1 receptor (TβR1)/Smad3 as a potential pathway for CSE modulated VEGF release was also investigated using biochemical analyses and siRNA inhibition of Smad3 and siRNA and pharmacologic inhibition of TβR1. CSE induced VEGF release by HFL-1 in concentration and time dependent manner. This was confirmed in two additional types of primary human fetal lung fibroblasts. CSE induced Smad3 phosphorylation and nuclear translocation in HFL-1 cells. Silencing of Smad3 by siRNA not only eliminated the stimulatory effect of CSE on VEGF release but also inhibited baseline VEGF production. Suppression of TβR1 by the pharmacological inhibitor (SB431542) markedly reduced VEGF release by HFL-1 in response to CSE and this effect was confirmed by TβR1 siRNA. In contrast, nicotine inhibited VEGF release by HFL-1 in a dose and time dependent manner. Our findings indicate that CSE stimulates Smad3-mediated VEGF release by lung fibroblasts. Nicotine does not account for the CSE stimulation of VEGF in HFL-1. The ability of lung fibroblasts to produce VEGF may play a role in pathogenesis of cigarette smoke induced lung disease. 23059655 Nano-graphene in biomedicine: theranostic applications. Owing to their unique physical and chemical properties, graphene and its derivatives such as graphene oxide (GO), reduced graphene oxide (RGO) and GO-nanocomposites have attracted tremendous interest in many different fields including biomedicine in recent years. With every atom exposed on its surface, single-layered graphene shows ultra-high surface area available for efficient molecular loading and bioconjugation, and has been widely explored as novel nano-carriers for drug and gene delivery. Utilizing the intrinsic near-infrared (NIR) optical absorbance, in vivo graphene-based photothermal therapy has been realized, achieving excellent anti-tumor therapeutic efficacy in animal experiments. A variety of inorganic nanoparticles can be grown on the surface of nano-graphene, obtaining functional graphene-based nanocomposites with interesting optical and magnetic properties useful for multi-modal imaging and imaging-guided cancer therapy. Moreover, significant efforts have also been devoted to study the behaviors and toxicology of functionalized nano-graphene in animals. It has been uncovered that both surface chemistry and sizes play key roles in controlling the biodistribution, excretion, and toxicity of nano-graphene. Biocompatibly coated nano-graphene with ultra-small sizes can be cleared out from body after systemic administration, without rendering noticeable toxicity to the treated mice. In this review article, we will summarize the latest progress in this rapidly growing field, and discuss future prospects and challenges of using graphene-based materials for theranostic applications. 23043183 Metabolism and disposition of vilanterol, a long-acting β(2)-adrenoceptor agonist for inhalation use in humans. The metabolism and disposition of vilanterol, a novel long-acting β(2)-adrenoceptor agonist (LABA) for inhalation use, was investigated after oral administration in humans. Single oral administrations of up to 500 μg of vilanterol were shown to be safe and well tolerated in two clinical studies in healthy men. In a human radiolabel study, six healthy men received a single oral dose of 200 μg of [(14)C]vilanterol (74 kBq). Plasma, urine, and feces were collected up to 168 hours after the dose and were analyzed for vilanterol, metabolites, and radioactivity. At least 50% of the radioactive dose was orally absorbed. The primary route of excretion of drug-related material was via O-dealkylation to metabolites, which were mainly excreted in urine. Vilanterol represented a very small percentage (<0.5%) of the total drug-related material in plasma, indicative of extensive first-pass metabolism. Circulating metabolites resulted mainly from O-dealkylation and exhibited negligible pharmacologic activity. The therapeutic dose level for vilanterol is 25 μg by the inhalation route. At this low-dose level, the likelihood of pharmacologically inactive metabolites causing unexpected toxicity is negligible. In addition to providing an assessment of the disposition of vilanterol in human, this work highlights a number of complexities associated with determining human absorption, distribution, metabolism, and excretion (ADME) for inhaled molecules--mainly related to the low chemical doses and complications associated with the inhalation route of administration. 23246732 Influence of developmental lead exposure on expression of DNA methyltransferases and methyl cytosine-binding proteins in hippocampus. Developmental exposure to lead (Pb) has adverse effects on cognitive functioning and behavior that can persist into adulthood. Exposures that occur during fetal or early life periods may produce changes in brain related to physiological re-programming from an epigenetic influence such as altered DNA methylation status. Since DNA methylation is regulated by DNA methyltransferases and methyl cytosine-binding proteins, this study assessed the extent to which developmental Pb exposure might affect expression of these proteins in the hippocampus. Long Evans dams were fed chow with or without added Pb acetate (0, 150, 375, 750 ppm) prior to breeding and remained on the same diet through weaning (perinatal exposure group). Other animals were exposed to the same doses of Pb but exposure started on postnatal day 1 and continued through weaning (early postnatal exposure group). All animals were euthanized on day 55 and hippocampi were removed. Western blot analyses showed significant effects of Pb exposure on DNMT1, DNMT3a, and MeCP2 expression, with effects often seen at the lowest level of exposure and modified by sex and developmental window of Pb exposure. These data suggest potential epigenetic effects of developmental Pb exposure on DNA methylation mediated at least in part through dysregulation of methyltransferases. 23315644 Characterization of four new mouse cytochrome P450 enzymes of the CYP2J subfamily. The cytochrome P450 superfamily encompasses a diverse group of enzymes that catalyze the oxidation of various substrates. The mouse CYP2J subfamily includes members that have wide tissue distribution and are active in the metabolism of arachidonic acid (AA), linoleic acid (LA), and other lipids and xenobiotics. The mouse Cyp2j locus contains seven genes and three pseudogenes located in a contiguous 0.62 megabase cluster on chromosome 4. We describe four new mouse CYP2J isoforms (designated CYP2J8, CYP2J11, CYP2J12, and CYP2J13). The four cDNAs contain open reading frames that encode polypeptides with 62-84% identity with the three previously identified mouse CYP2Js. All four new CYP2J proteins were expressed in Sf21 insect cells. Each recombinant protein metabolized AA and LA to epoxides and hydroxy derivatives. Specific antibodies, mRNA probes, and polymerase chain reaction primer sets were developed for each mouse CYP2J to examine their tissue distribution. CYP2J8 transcripts were found in the kidney, liver, and brain, and protein expression was confirmed in the kidney and brain (neuropil). CYP2J11 transcripts were most abundant in the kidney and heart, with protein detected primarily in the kidney (proximal convoluted tubules), liver, and heart (cardiomyocytes). CYP2J12 transcripts were prominently present in the brain, and CYP2J13 transcripts were detected in multiple tissues, with the highest expression in the kidney. CYP2J12 and CYP2J13 protein expression could not be determined because the antibodies developed were not immunospecific. We conclude that the four new CYP2J isoforms might be involved in the metabolism of AA and LA to bioactive lipids in mouse hepatic and extrahepatic tissues. 22743996 The pathways of mitophagy for quality control and clearance of mitochondria. Selective autophagy of mitochondria, known as mitophagy, is an important mitochondrial quality control mechanism that eliminates damaged mitochondria. Mitophagy also mediates removal of mitochondria from developing erythrocytes, and contributes to maternal inheritance of mitochondrial DNA through the elimination of sperm-derived mitochondria. Recent studies have identified specific regulators of mitophagy that ensure selective sequestration of mitochondria as cargo. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the autophagic machinery to mitochondria, while mammalian Nix is required for degradation of erythrocyte mitochondria. The elimination of damaged mitochondria in mammals is mediated by a pathway comprised of PTEN-induced putative protein kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. PINK1 and Parkin accumulate on damaged mitochondria, promote their segregation from the mitochondrial network, and target these organelles for autophagic degradation in a process that requires Parkin-dependent ubiquitination of mitochondrial proteins. Here we will review recent advances in our understanding of the different pathways of mitophagy. In addition, we will discuss the relevance of these pathways in neurons where defects in mitophagy have been implicated in neurodegeneration. 23194542 Simple multiresidue extraction method for the determination of fungicides and plant growth regulator in bean sprouts using low temperature partitioning and tandem mass spectrometry. A simple multiresidue analytical method is developed for the simultaneous determination of carbendazim (CB), thiabendazole (TB), and 6-benzyl aminopurine (6-BA) in bean sprouts. The samples were extracted with acetonitrile followed by partitioning at -80°C for 5-10 min. A YMC C(8) column was used to separate the analytes before being qualitatively and quantitatively determined by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) in positive ion mode using multiple reaction monitoring (MRM). The matrix-matched calibration curves showed good linearity in the range 0.01-1.0 mg/kg with correlation coefficients in excess of 0.998. The mean recoveries were in the range of 80.4-96.3% at 0.1 and 0.5 spiked levels, and the relative standard deviations (RSDs) were in the range of 0.5-7.6%. The limits of quantifications (LOQ) were in the range of 0.005-0.01 mg/kg. The method was successfully applied to 90 samples (among which 45 were organic) collected from a commercial bean sprout production house throughout the city. Except for 6-BA, the rest of the analytes had values lower than their LOQs. In sum, carbendazim, thiabendazole, and 6-BA were extracted in a single step, and no steps for clean-up or concentration of the extracts were needed. The current method can be used for sensitive and accurate determination and confirmation of residues in bean sprout samples. 23173549 Xenobiotic receptor humanized mice and their utility. The nuclear receptors pregnane X receptor, constitutive androstane receptor, and peroxisome proliferator-activated receptor alpha have important endogenous functions and are also involved in the induction of drug-metabolizing enzymes and transporters in response to exogenous xenobiotics. Though not belonging to the same protein family, the Per-Sim-ARNT domain receptor aryl hydrocarbon receptor functionally overlaps with the three nuclear receptors in many aspects and is therefore included in this review. Significant species differences in ligand affinity and biological responses as a result of activation of these receptors have been described. Several xenobiotic receptor humanized mice have been created to overcome these species differences and to provide in vivo models that are more predictive for human responses. This review provides an overview of the different xenobiotic receptor humanized mouse models described to date and will summarize how these models can be applied in basic research and improve drug discovery and development. Some of the key applications in the evaluation of drug induction, drug-drug interactions, nongenotoxic carcinogenicity, other toxicity, or efficacy studies are described. We also discuss relevant considerations in the interpretation of such data and potential future directions for the use of xenobiotic receptor humanized mice. 23277289 Development of a dry, stable and inhalable acyl-homoserine-lactone-acylase powder formulation for the treatment of pulmonary Pseudomonas aeruginosa infections. In the lungs of cystic fibrosis (CF) patients, Pseudomonas aeruginosa commonly causes chronic infections. It has been shown that the P. aeruginosa quorum sensing (QS) system controls the expression of virulence factors during invasion and infection to host cells. PvdQ is an acyl-homoserine lactone (AHL) acylase able to degrade the signal molecule of P. aeruginosa QS. The role of PvdQ in inhibiting the QS and its successive virulence determinants has been established in in vitro as well as in in vivo, the latter in a Caenorabdhitis elegans model. For the treatment of pulmonary P. aeruginosa infections, we propose that PvdQ can be best administered directly to the lungs of the patients as a dry powder because this is expected to give specific advantages in delivery as compared to nebulizing. Therefore in this study we investigated the production of a PvdQ powder by spray-freeze drying using mannitol, trehalose and inulin as excipient. The activity of PvdQ in the powder was determined immediately after production and after subsequent storage during 4 weeks at 20°C and 55°C. We found that the enzymatic activity of PvdQ is fully maintained during spray-freeze drying using mannitol, trehalose or inulin as excipient. However, mannitol was not able to stabilize the protein during storage, while PvdQ incorporated in trehalose or inulin was fully stabilized even during storage at 55°C for at least 4 weeks. The poor stabilizing capacities of mannitol during storage could be related to its crystalline nature while the excellent stabilizing capacities of trehalose and inulin during storage could be related to their amorphous nature. The trehalose and inulin-based particles consisted of porous spheres with a volume average aerodynamical diameter of ∼1.8 μm implying that they are suitable for pulmonary delivery. This is the first study in which an AHL-degrading enzyme is processed into spray-freeze-dried powder suitable for inhalation. 23429912 TCDD inhibition of canonical wnt signaling disrupts prostatic bud formation in mouse urogenital sinus. In mice, in utero exposure to 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) reduces the number of dorsolateral prostatic buds resulting in a smaller dorsolateral prostate and prevents formation of ventral buds culminating in ventral prostate agenesis. The genes and signaling pathways affected by TCDD that are responsible for disrupting prostate development are largely unknown. Here we show that treatment of urogenital sinus (UGS) organ cultures with known inhibitors of canonical Wnt signaling also inhibits prostatic bud formation. In support of the hypothesis that TCDD decreases canonical Wnt signaling, we identify inhibitory effects of TCDD on multiple components of the canonical Wnt signaling pathway in the UGS that temporally coincide with the inhibitory effect of TCDD on prostatic bud formation: (1) expression of R-spondins (Rspo2 and Rspo3) that promote canonical Wnt signaling is reduced; (2) expression of Lef1, Tcf1, and Wif1, established canonical Wnt target genes, is decreased; (3) expression of Lgr5, a RSPO receptor that activates canonical Wnt signaling, is reduced; and (4) expression of Dickkopfs (Dkks), inhibitors of canonical Wnt signaling, is not increased by TCDD. Thus, the TCDD-induced reduction in canonical Wnt signaling is associated with a decrease in activators (Rspo2 and Rspo3) rather than an increase in inhibitors (Dkk1 and Dkk2) of the pathway. This study focuses on determining whether treatment of TCDD-exposed UGS organ cultures with RSPO2 and/or RSPO3 is capable of rescuing the inhibitory effects of TCDD on canonical Wnt signaling and prostatic bud formation. We discovered that each RSPO alone or in combination partially rescues TCDD inhibition of both canonical Wnt signaling and prostatic bud formation. 23325374 A functional NPSR1 gene variant and environment shape personality and impulsive action: A longitudinal study. Neuropeptide S and its receptor NPSR1 are involved in the regulation of arousal, attention and anxiety. We examined whether the NPSR1 gene functional polymorphism Asn(107)Ile (rs324981, A>T) influences personality, impulsivity, and attention-deficit/hyperactivity disorder (ADHD)-related symptoms in a population-representative sample, and whether any eventual associations depend on age, sex, family relations and stressful life events (SLE). We used self-reports or teachers' ratings for both the younger (n=593) and older (n=583) cohort of the longitudinal Estonian Children Personality, Behaviour and Health Study. Males with the TT genotype displayed more ADHD-related symptoms. Adaptive impulsivity and Extraversion increased the most from age 18 to 25. While highest increases were observed in AA men, TT women exhibited the largest decreases. For participants with the AA genotype, Warmth in family was inversely associated with Neuroticism, and positively associated with Extraversion and Adaptive impulsivity. High exposure to SLE increased impulsivity and ADHD scores in TT genotype subjects. We conclude that the NPSR1 A/T polymorphism is associated with impulsivity, ADHD symptoms and personality, mirroring the activity- and anxiety-mediating role of NPSR1. Heterozygous individuals were the least sensitive to environmental factors, whereas subjects with the AA genotype and TT genotype reacted to different types of environmental adversities. 23177260 Ginkgo biloba extract attenuates hippocampal neuronal loss and cognitive dysfunction resulting from trimethyltin in mice. The present study was an attempt to investigate the neuromodulatory potential of Ginkgo biloba extract (GBE) against hippocamapal structural and functional damages induced by trimethyltin (TMT) a potent neurotoxicant. Male Balb/C mice were administered with Ginkgo biloba extract for 14 days at a dose of 70 mg/kg body weight interperitoneally and on 11-day of treatment animals were exposed to Trimethyltin (2.5 mg/kg b.w) single intraperitoneal injection. The co-administered of TMT with GBE showed marked improvement in memory and aggressive behavior. Which were in turn reflected in the levels of serotonin and acetylcholine esterase. The conjunctive treatment also showed significant decrease in oxidative stress as assessed by MDA levels and the antioxidant enzymes (GSH, GSSH, GPX, total glutathione, Catalase and Superoxide dismutase) which were depressed by TMT treatment was significantly improved by GBE. Correspondingly, induction of Bcl-2 mitochondrial apoptotic pathway by trimethyltin was down regulated by Ginkgo biloba treatment. The structural analysis of dentate gyrus revealed improvement in degenerating neurons by treatment with GBE. Therefore, it is suggested that prophylactic treatment of Ginkgo biloba extract protects against the trimethyltin induced neurodegenration by multiple mechanism involved in its antioxidant effects and may be useful in developing therapies against neurodegenration. 23325370 The high harm score of alcohol. Time for drug policy to be revisited? The aim of this paper is to create awareness of the negative health impact and economic burden and benefits associated to alcohol consumption. Worldwide about two billion people consume alcohol. Low intake of alcohol has a minor protective cardiovascular effect. On the other hand, even moderate alcohol consumption appears to be weakly, but significantly, associated to a limited number of chronic diseases. Alcohol causes a considerable economic burden to society due to the high absolute number of alcohol consumers. As such, alcohol abuse is more harmful for public health and society than illicit drug use. Some 3.7% of alcohol consumers (worldwide 76 million people) have an alcohol use disorder leading to 60-70% of the societal costs related to alcohol. Therefore, policy measures should, in addition to regulatory measures to reduce alcohol use, aim at closing the treatment gap and improving treatment effectiveness of people with an alcohol use disorder. The key message is that policy-makers unjustifiably focus on the harm of illicit drugs, whereas they underestimate the harm of alcohol use. Policy makers should therefore consider alcohol to be at least as harmful as illicit drugs and invest more in prevention and harm reduction strategies for alcohol abuse and dependence. 23288505 Pharmacokinetic profile of artemisinin derivatives and companion drugs used in artemisinin-based combination therapies for the treatment of Plasmodium falciparum malaria in children. Malaria is one of the most common parasitic infections worldwide. Plasmodium falciparum is the most prevalent strain in Africa and also the most fatal. The disease especially affects children, with those under age 5 years accounting for approximately 86 % of malaria deaths in 2010. The objectives of this review are to summarize and evaluate published literature reporting the pharmacokinetic parameters of artemisinin-based combinations used to treat P. falciparum in paediatric populations and to identify and discuss controversies regarding pharmacokinetics of these agents in children. A search of MEDLINE (1948-September 2012), EMBASE (1980-September 2012), International Pharmaceutical Abstracts (1970-September 2012), Google and Google Scholar was conducted for articles describing pharmacokinetics of antimalarials in children. Our search produced 30 articles, of which 23 were included in the review: artemisinin compounds, 12 articles; lumefantrine, four articles; amodiaquine, five articles; sulfadoxine, six articles; pyrimethamine, one article; mefloquine, three articles; and piperaquine, two articles. Studies were summarized based on comparison groups and major findings. Many controversies were identified, including pharmacokinetic equivalence of novel dosage forms, altered pharmacokinetic parameters in children versus adults, effect of drug interactions, and association of pharmacokinetic changes with clinical outcomes. A large variation in pharmacokinetic parameters of many antimalarial agents was shown, which may be a consequence of the wide range of ages and/or bodyweights of each paediatric cohort. These studies may mask important associations with age and bodyweight and produce mean data that do not adequately represent the paediatric population as a whole. In order to properly assess the clinical implications of such pharmacokinetic changes and recommend safe and effective dosage regimens, there is an urgent need for dose-optimization studies for all recommended first- and second-line agents, along with the different drug formulations, used in paediatric populations with P. falciparum. 23146664 Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1. Mesalamine (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon. Knowledge about the molecular and cellular targets of 5-ASA is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking. We sought to identify molecular pathways interfered by 5-ASA, using CRC cell lines with different genetic background. Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29). Filtering and analysis of data identified three oncogenic pathways interfered by 5-ASA: MAPK/ERK pathway, cell adhesion and β-catenin/Wnt signaling. PAK1 emerged as a consensus target of 5-ASA, orchestrating these pathways. We further investigated the effect of 5-ASA on cell adhesion. 5-ASA increased cell adhesion which was measured by cell adhesion assay and transcellular-resistance measurement. Moreover, 5-ASA treatment restored membranous expression of adhesion molecules E-cadherin and β-catenin. Role of PAK1 as a mediator of mesalamine activity was validated in vitro and in vivo. Inhibition of PAK1 by RNA interference also increased cell adhesion. PAK1 expression was elevated in APC(min) polyps and 5-ASA treatment reduced its expression. Our data demonstrates novel pharmacological mechanism of mesalamine in modulation of cell adhesion and role of PAK1 in APC(min) polyposis. We propose that inhibition of PAK1 expression by 5-ASA can impede with neoplastic progression in colorectal carcinogenesis. The mechanism of PAK1 inhibition and induction of membranous translocation of adhesion proteins by 5-ASA might be independent of its known anti-inflammatory action. 23142547 A non-catalytic function of Rev1 in translesion DNA synthesis and mutagenesis is mediated by its stable interaction with Rad5. DNA damage tolerance consisting of template switching and translesion synthesis is a major cellular mechanism in response to unrepaired DNA lesions during replication. The Rev1 pathway constitutes the major mechanism of translesion synthesis and base damage-induced mutagenesis in model cell systems. Rev1 is a dCMP transferase, but additionally plays non-catalytic functions in translesion synthesis. Using the yeast model system, we attempted to gain further insights into the non-catalytic functions of Rev1. Rev1 stably interacts with Rad5 (a central component of the template switching pathway) via the C-terminal region of Rev1 and the N-terminal region of Rad5. Supporting functional significance of this interaction, both the Rev1 pathway and Rad5 are required for translesion synthesis and mutagenesis of 1,N(6)-ethenoadenine. Furthermore, disrupting the Rev1-Rad5 interaction by mutating Rev1 did not affect its dCMP transferase, but led to inactivation of the Rev1 non-catalytic function in translesion synthesis of UV-induced DNA damage. Deletion analysis revealed that the C-terminal 21-amino acid sequence of Rev1 is uniquely required for its interaction with Rad5 and is essential for its non-catalytic function. Deletion analysis additionally implicated a C-terminal region of Rev1 in its negative regulation. These results show that a non-catalytic function of Rev1 in translesion synthesis and mutagenesis is mediated by its interaction with Rad5. 23453839 N-Alkyldeoxynojirimycin derivatives with novel terminal tertiary amide substitution for treatment of bovine viral diarrhea virus (BVDV), Dengue, and Tacaribe virus infections. Novel N-alkyldeoxynojirimycins (NADNJs) with two hydrophobic groups attached to a nitrogen linker on the alkyl chain were designed. A novel NADNJ containing a terminal tertiary carboxamide moiety was discovered that was a potent inhibitor against BVDV. Further optimization resulted in a structurally more stable lead compound 24 with a submicromolar EC50 against BVDV, Dengue, and Tacaribe; and low cytotoxicity. 23553379 Baseline Albumin Is Associated with Worsening Renal Function in Patients with Acute Decompensated Heart Failure Receiving Continuous Infusion Loop Diuretics. STUDY OBJECTIVES: To identify baseline predictors of worsening renal function (WRF) in an acute decompensated heart failure (ADHF) patient population receiving continuous infusion loop diuretics. DESIGN: Retrospective observational analysis. SETTING: Academic tertiary medical center. PATIENTS: A total of 177 patients with ADHF receiving continuous infusion loop diuretics from January 2006 through June 2009. MEASUREMENTS AND MAIN RESULTS: The mean patient age was 61 years, 63% were male, ~45% were classified as New York Heart Association functional class III, and the median length of loop diuretic infusion was 4 days. Forty-eight patients (27%) developed WRF, and 34 patients (19%) died during hospitalization. Cox regression time-to-event analysis was used to determine the time to WRF based on different demographic and clinical variables. Baseline serum albumin 3 g/dl or less was the only significant predictor of WRF (hazard ratio [HR] 2.87, 95% confidence interval [CI] 1.60-5.16, p=0.0004), which remained significant despite adjustments for other covariates. CONCLUSION: Serum albumin 3 g/dl or less is a practical baseline characteristic associated with the development of WRF in patients with ADHF receiving continuous infusion loop diuretics. 23278403 Identification of novel androgen receptor antagonists using structure- and ligand-based methods. Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer (PCa). The AR hormone-binding site (HBS) is intensively studied and represents the target area for current antiandrogens including Bicalutamide and structurally related Enzalutamide. As resistance to antiandrogens invariably emerges in advanced prostate cancer, there exists a high medical need for the identification and development of novel AR antagonists of different chemotypes. Given the wealth of structural information on the AR in complex with a variety of ligands, we have applied an integrated structure- and ligand-based virtual screening methodology to identify novel AR antagonists. Virtual hits generated by a consensus voting approach were experimentally evaluated and resulted in the discovery of a number of structurally diverse submicromolar antagonists of the AR. In particular, one identified compound demonstrated anti-AR potency in vitro that is comparable to the clinically used Bicalutamide. These results set a ground for the development of novel classes of PCa drugs that are structurally different from current AR antagonists. 23403055 Optimized glucocorticoid therapy: Teaching old drugs new tricks. Glucocorticoids (GCs) are commonly used in the treatment of a wide range of rheumatic and other inflammatory diseases. They exert their potent anti-inflammatory and immunosuppressive effects primarily via so called genomic mechanisms, mediated by the cytosolic glucocorticoid receptor (cGR). This mechanism of GC action can be divided into the transactivation and the transrepression processes. However, also rapid effects of GCs exist which are mediated by specific and unspecific non-genomic mechanisms. A clinical relevance of this mode of GC action is assumed for effects mediated by membrane-bound glucocorticoid receptors, but detailed knowledge on the underlying mechanisms is still missing. Great efforts have been made in the past to diminish GC-induced adverse effects, thus improving the benefit/risk ratio of the drugs. Besides approaches to improve the treatment with conventional glucocorticoids currently available to clinicians, new innovative GCs or GC receptor ligands are also being developed. 23207055 A systematic study of the degradation of dimethyl phthalate using a high-frequency ultrasonic process. A comprehensive study of the sonochemical degradation of dimethyl phthalate (DMP) was carried out using high-frequency ultrasonic processes. The effects of various operating parameters were investigated, including ultrasonic frequency, power density, initial DMP concentration, solution pH and the presence of hydrogen peroxide. In general, a frequency of 400kHz was the optimum for achieving the highest DMP degradation rate. The degradation rate was directly proportional to the power density and inversely related to the initial DMP concentration. It was interesting to find that faster removal rate was observed under weakly acidic condition, while hydrolysis effect dominated in extreme-basic condition. The addition of hydrogen peroxide can increase the radical generation to some extent. Furthermore, both hydroxylation of the aromatic ring and oxidation of the aliphatic chain appear to be the major mechanism of DMP degradation by sonolysis based on LC/ESI-MS analysis. Among the principle reaction intermediates identified, tri- and tetra-hydroxylated derivatives of DMP, as well as hydroxylated monomethyl phthalates and hydroxylated phthalic acid were reported for the first time in this study. Reaction pathways for DMP sonolysis are proposed based on the detected intermediates. 22926007 Anticholinesterase insecticide retrospective. The anticholinesterase (antiChE) organophosphorus (OP) and methylcarbamate (MC) insecticides have been used very effectively as contact and systemic plant protectants for seven decades. About 90 of these compounds are still in use - the largest number for any insecticide chemotype or mode of action. In both insects and mammals, AChE inhibition and acetylcholine accumulation leads to excitation and death. The cholinergic system of insects is located centrally (where it is protected from ionized OPs and MCs) but not at the neuromuscular junction. Structural differences between insect and mammalian AChE are also evident in their genomics, amino acid sequences and active site conformations. Species selectivity is determined in part by inhibitor and target site specificity. Pest population selection with OPs and MCs has resulted in a multitude of modified AChEs of altered inhibitor specificity some conferring insecticide resistance and others enhancing sensitivity. Much of the success of antiChE insecticides results from a suitable balance of bioactivation and detoxification by families of CYP450 oxidases, hydrolases, glutathione S-transferases and others. Known inhibitors for these enzymes block detoxification and enhance potency which is particularly important in resistant strains. The current market for OPs and MCs of 19% of worldwide insecticide sales is only half of that of 10years ago for several reasons: there have been no major new compounds for 30years; resistance has eroded their effectiveness; human toxicity problems are still encountered; the patents have expired reducing the incentive to update registration packages; alternative chemotypes or control methods have been developed. Despite this decline, they still play a major role in pest control and the increasing knowledge on their target sites and metabolism may make it possible to redesign the inhibitors for insensitive AChEs and to target new sites in the cholinergic system. The OPs and MCs are down but not out. 23122113 A sensitive enzyme-linked immunosorbent assay for the determination of fish protein in processed foods. Fish is one of the most common causes of food allergy and its major allergen is parvalbumin, a 12 kDa muscular protein. In this study, a sandwich enzyme-linked immunosorbent assay (ELISA) for the determination of fish protein in processed foods was developed using a polyclonal antibody raised against Pacific mackerel parvalbumin. The developed sandwich ELISA showed 22.6-99.0% reactivity (based on the reactivity to Pacific mackerel parvalbumin) to parvalbumins from various species of fish. The limits of detection and quantitation were estimated to be 0.23 and 0.70 μg protein per g of food, respectively. When the sandwich ELISA was subjected to inter-laboratory validation, spiked fish protein was recovered from five model processed foods in the range of 69.4-84.8% and the repeatability and reproducibility relative standard deviations were satisfactorily low (≤ 10.5%). Thus, the sandwich ELISA was judged to be a useful tool to determine fish protein in processed foods. 23303727 Promiscuous catalysis of asymmetric Michael-type additions of linear aldehydes to β-nitrostyrene by the proline-based enzyme 4-oxalocrotonate tautomerase. Exploiting catalytic promiscuity: The proline-based enzyme 4-oxalocrotonate tautomerase (4-OT) promiscuously catalyzes asymmetric Michael-type additions of linear aldehydes--ranging from acetaldehyde to octanal--to trans-β-nitrostyrene in aqueous solvent. The presence of 1.4 mol% of 4-OT effected formation of the anticipated γ-nitroaldehydes in fair to good yields with dr values of up to 93:7 and ee values of up to 81 %. 23203941 Synthesis, characterization and pharmacodynamics of vitamin-B(12)-conjugated glucagon-like peptide-1. Clearing the way: Glucagon-like peptide-1 (GLP-1) receptor agonists are proving a potent weapon in the treatment of type II diabetes. A new vitamin B(12)-GLP-1 conjugate is investigated and shown to have insulinotropic properties similar to the unmodified peptide. These results are critical to the exploitation of the vitamin B(12) oral uptake pathway for peptide delivery. 23165154 Three-month subchronic intramuscular toxicity study of rotigotine-loaded microspheres in Cynomolgus monkeys. Continuous dopaminergic stimulation (CDS) is an important drug development strategy in the treatment of Parkinson's disease (PD). Rotigotine is a non-ergoline D(3)/D(2)/D(1) dopamine receptor agonist for treating PD. As a new treatment option for CDS, rotigotine-loaded microspheres (RoMS), long-acting sustained-release microspheres with poly(lactide-co-glycolide) as drug carrier, are now being evaluated in clinical trial. In the present study, the subchronic toxicity in Cynomolgus monkeys has been characterized via intramuscular administration with RoMS at 0, 10, 40 and 160 mg/kg, weekly for 3 months with a 1-month recovery period. The NOAEL was 10 mg/kg/week. One male at 160 mg/kg died from an extensive pulmonary embolism. The major toxicological effects were associated with dopamine agonist-related pharmacodynamic properties of rotigotine (e.g., hyperactivity and stereotype, decreased serum prolactin level) and foreign body removal reaction induced by poly(lactide-co-glycolide) and carboxymethycellulose sodium (e.g., increased mononuclear cells and neutrophils, thymus atrophy and vacuolar degeneration of adrenal cortex, foreign body granuloma with foam cells accumulation at injection sites and foam cells accumulation in spleen and multiple lymph sinuses). At the end of recovery period, above findings recovered to a normal level or to a certain degree except vacuolar degeneration of adrenal gland. RoMS has exhibited high safety on monkeys. 23531555 The noncellular reduction of MTT tetrazolium salt by TiO2 nanoparticles and its implications for cytotoxicity assays. We report results of noncellular tests, revealing the occurrence of photocatalytic interactions between titanium dioxide (TiO2, titania) nanoparticles and the MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide] cytotoxicity indicator. These interactions induce the reduction of MTT and formation of purple formazan under biologically relevant conditions. Classical MTT assays have been performed to evaluate the production of formazan in DMEM-F12 and RPMI-1640 cell culture media (containing 10% fetal bovine serum-FBS) treated with Degussa-P25 TiO2 nanoparticles, in the absence of cells. The colorimetric determinations revealed the noncellular MTT to formazan transformation induced by TiO2 nanoparticles, under conditions commonly used for in vitro cytotoxicity testing of nanomaterials. The formazan precipitation was found to be proportional to the TiO2 concentration, being enhanced under laboratory daylight exposure. The photocatalytic nature of the studied effect was assessed under UV irradiation at 365nm. The biological significance of the reported reaction was established with respect to cellular reference experiments performed on V79-4, HeLa and B16 cell lines. The results show false viability increases with up to 14% (for TiO2 concentrations generally higher than 50μg/ml), induced by the TiO2-MTT reaction. This type of artifacts may lead to underestimated toxicity or false proliferation results. 23581750 A Butterfly-Shaped Pyrene Derivative of Cholesterol and Its Uses as a Fluorescent Probe. A butterfly-shaped pyrene derivative of cholesterol, namely, N,N'-(ethane-1,2-diyl)-bis(N-(2-(chol-amino)ethyl)pyrene-1-sulfonamide) (ECPS), has been designed and synthesized. Solvent effect studies revealed that in good solvents such as n-hexane, benzene, and 1,4-dioxane, the profile of the fluorescence emission of the compound is characterized by pyrene monomer emission, but in poor solvent such as water, the emission is dominated by pyrene excimer emission. Quantitatively speaking, the ratio of the excimer emission to monomer emission changes from 50 to 0 when ECPS is dissolved in water and n-hexane, respectively. In contrast, for a commonly used polarity probe pyrene, the ratio of I3/I1 varies only from ∼0.6 to ∼1.7, where I3 and I1 stand for the intensities of the fluorescence emission at peak 3 and peak 1, respectively. This value suggests that a more powerful discriminating ability of the new compound in polarity sensing. Furthermore, unlike the main components of the compound, pyrene and cholesterol, its main chain is composed of multiple hydrophilic structures, and it is this structure that makes the emission of the compound in organic solvents sensitive to the presence of water. Accordingly, the applicability of the compound in determination of the trace amount of water in some organic solvents was evaluated. As expected, the detection limit of the compound toward water in acetonitrile reaches 7 ppm, a result never reached before. Furthermore, the fluorescence emission of the compound is also sensitive to viscosity variation. Therefore, it is assumed that ECPS may be used both as a polarity probe and a viscosity probe. On the bases of a series of steady-state and time-resolved fluorescence, as well as dynamic light scattering studies, a structural model was proposed to rationalize the fluorescence behavior of the compound in different solvents and its polarity and viscosity probing performances. 23122151 Identification of flavonoids and flavonoid rhamnosides from Rhododendron mucronulatum for. albiflorum and their inhibitory activities against aldose reductase. To investigate the therapeutic potential of compounds from natural sources, Rhododendron mucronulatum for. albiflorum flowers (RMAF) and R. mucronulatum flowers (RMF) were tested for inhibition of aldose reductase (AR). The methanol extracts of RMAF and RMF exhibited AR inhibitory activities (IC(50) values 1.07 and 1.29 μg/mL, respectively). The stepwise polarity fractions of RMAF were tested for in vitro inhibition of AR from rat lenses. Of these, the ethyl acetate (EtOAc) fraction exhibited AR inhibitory activity (IC(50) 0.15 μg/mL). A chromatography of the active EtOAc fraction of RMAF led to the isolation of six flavonoids, which were identified by spectroscopic analysis as kaempferol (1), afzelin (2), quercetin (3), quercitrin (4), myricetin (5) and myricitrin (6). Compounds 1-6 exhibited high AR inhibitory activity, with IC(50) values of 0.79, 0.31, 0.48, 0.13, 11.92 and 2.67 μg/mL, respectively. HPLC/UV analysis revealed that the major flavonoids of RMAF and RMF are quercitrin (4) and myricitrin (6). Our results suggest that RMAF containing these six flavonoids could be a useful natural source in the development of a novel AR inhibitory agent against diabetic complications. 23536316 Chrysin Ameliorates Chemically Induced Colitis in the Mouse Through Modulation of a PXR/NF-κB Signaling Pathway. Targeted activation of pregnane X receptor (PXR) in recent years has become a therapeutic strategy for inflammatory bowel disease (IBD). Chrysin is a naturally occurring flavonoid with anti-inflammation activity. The current study investigated the role of chrysin as a putative mouse PXR agonist in preventing experimental colitis. Pre-administration of chrysin ameliorated inflammatory symptoms in mouse models of colitis (DSS- and TNBS-induced) and resulted in down-regulation of NF-κB target genes (iNOS, ICAM-1, MCP-1, Cox2, TNF-α and IL-6) in the colon mucosa. Chrysin inhibited the phosphorylation/degradation of IκBα, which correlated with the decline in the activity of myeloperoxidase (MPO) and the levels of TNF-α and IL-6 in the colon. Consistent with the in vivo results, chrysin blocked LPS-stimulated nuclear translocation of NF-κB p65 in mouse macrophage RAW264.7. Furthermore, chrysin dose-dependently activated human/mouse PXR in reporter gene assays and up-regulated xenobiotic detoxification genes in the colon mucosa, but not in the liver. Silencing of PXR by RNAi demonstrated necessity of PXR in mediating chrysin's ability to induce xenobiotic detoxification genes and NF-κB inactivation. The repression of NF-κB transcription activity by chrysin was confirmed by in vitro PXR transduction. These findings suggest the effect of chrysin in preventing chemically induced colitis is mediated in large part by a PXR/NF-κB pathway. The data also suggest that chrysin or chrysin-like flavonoids could be further developed as intestine-specific PXR activators. 23519392 Pregnane X Receptor Mediates Dyslipidemia Induced by the HIV Protease Inhibitor Amprenavir in Mice. HIV protease inhibitors (PIs) have been used successfully in extending the lifespan of people infected with HIV. The use of PIs has also been associated with dyslipidemia and an increased risk of cardiovascular disease but the underlying mechanisms remain elusive. Several PIs have been implicated to activate the nuclear receptor pregnane X receptor (PXR), which acts as a xenobiotic sensor to regulate xenobiotic metabolism in the liver and intestine. Recent studies indicate that PXR may also play an important role in the regulation of lipid homeostasis. In the present study, we identified amprenavir, a widely used HIV PI, as a potent PXR-selective agonist. Computational docking studies combined with site-direct mutagenesis identified several key residues within the ligand binding pocket of PXR that constitute points of interaction with amprenavir. Amprenavir efficiently activated PXR and induced PXR target gene expression in vitro and in vivo. Short-term exposure to amprenavir significantly increased plasma total cholesterol and atherogenic low-density lipoprotein cholesterol levels in wild-type mice, but not in PXR-deficient mice. Amprenavir-mediated PXR activation stimulated the expression of several key intestinal genes involved in lipid homeostasis. These findings provide critical mechanistic insight for understanding the impact of PIs on cardiovascular disease and demonstrate a potential role of PXR in mediating adverse effects of HIV PIs in humans. 23535338 Lipid Status of the Two High Latitude Fish Species, Leptoclinus maculatus and Lumpenus fabricii. A comparative study of the lipid status (i.e., the total lipid and phospholipid concentrations and the percentage of fatty acids of the total lipids) of adult specimens of daubed shanny (Leptoclinus maculatus) from Svalbard waters (Isfjord) and slender eel blenny (Lumpenus fabricii) from the White Sea (Onega Bay and Tersky shore) was performed to study the metabolism and functions of lipids of these fishes in ontogeny and under various ecological conditions. Slender eel blenny from both areas of the White Sea were distinguished by a high level of sphingomyelin compared with the daubed shanny from Svalbard, and the amount of total phospholipids was higher in slender eel blenny from Onega Bay than in slender eel blenny from the Tersky shore. The extent of saturation and the signature of polyenic fatty acids varied according to the specific species of the Stichaeidae family under study. These results demonstrate the differences in the trophoecological and hydrobiological conditions of habitations of these species and highlighted the importance of considering certain trends in the lipid profiles of these fishes as specific features of the organization of the ecological and biochemical mechanisms of adaptation. 23164619 Glucose attenuates impairments in memory and CREB activation produced by an α4β2 but not an α7 nicotinic receptor antagonist. Glucose improves memory for a variety of tasks when administered to rats and mice near the time of training. Prior work indicates glucose may enhance memory by increasing the synthesis and release of the neurotransmitter acetylcholine in the brain. To investigate if specific acetylcholine receptor subtypes may mediate some of the memory-enhancing actions of glucose, we examined the effects of subtype-specific nicotinic acetylcholine receptor antagonists on memory in Fischer-344 rats and also examined the ability of glucose to reverse drug-induced impairments. Pre-training peripheral injections of methyllycaconitine (MLA) or dihydro-beta-erythroidine (DHβE), which are specific α7 and α4β2 nicotinic receptor antagonists, respectively, dose-dependently impaired retention latencies in an inhibitory avoidance task when tested 7-days but not 1 h after training. Immediate post-training glucose injections attenuated the impairments, but were more effective in attenuating the DHβE-induced impairments. Likewise, peripheral or direct intrahippocampal injections of MLA or DHβE dose-dependently impaired spatial working memory scores on a spontaneous alternation task. Concurrent administration of glucose reversed DHβE- but not MLA-induced impairments. CREB phosphorylation downstream of cholinergic signaling was assessed 30 min after spontaneous alternation testing and intrahippocampal drug infusions. Both MLA and DHβE impaired hippocampal CREB phosphorylation; glucose reversed DHβE- but not MLA-induced deficits. The effectiveness of glucose in reversing DHβE- but not MLA-induced impairments in behavioral performance and CREB phosphorylation suggests that activation of α7 receptors may play an important role in memory enhancement by glucose. 23527553 A multiple perspectives on atypical polypoid adenomyoma of uterus. Abstract Atypical polypoid adenomyoma (APA) is a rare benign uterine tumor, with less than 200 cases have been reported in English literature. Although, it is considered as a benign lesion and treated conservatively previously, more and more cases show that APA has a high rate of recurrence or residual, and is found to precede the development of carcinoma. Given the data from present research on APA, the therapy of APA becomes more complex and must be cautious, especially for the nulliparous and premenopausal patients. In addition, because of the low incidence, studies on this disease are less, and the etiology and pathogenesis of APA is still unclear. In this review, we aim to summarize recent researches concerning APA from multiple perspectives, including clinical presentation, histogenesis, immunohistochemistry and molecular features, diagnosis and differential diagnosis, treatment opinion and prognosis, which may provide theory and clinical basis for the future clinical treatment and research of this rare disease. 22980732 Solving the lost in translation problem: improving the effectiveness of translational research. Translational research frequently fails to replicate in the clinic what has been demonstrated in the laboratory. This has been true for neuroprotection in the central nervous system, neuroprotection in glaucoma, as well as many other areas of medicine. Two fundamental reasons for this 'Lost in Translation' problem are the 'Butterfly Effect' (chaotic behavior of many animal models) and the 'Two Cultures' problem (differences between the methodologies for preclinical and clinical research). We propose several strategies to deal with these issues, including the use of ensembles of animal models, adding intraocular pressure lowering to preclinical neuroprotection studies, changing the way in which preclinical research is done, and increasing interactions between the preclinical and clinical teams. 22475047 A new amide and a new monoterpene from the seeds of Clausena lansium. A new amide (2) and a new monoterpene (6) were isolated from the seeds of Clausena lansium together with four known ones (1, 3-5). The structures of the new compounds were elucidated by extensive spectroscopic analyses. The absolute configurations of 1, 2 and 6 were determined by optical rotation and the modified Mosher's method. 22982007 Ultrasound-assisted coating of silk yarn with sphere-like Mn3O4 nanoparticles. The growth of sphere-like trimanganese tetraoxide (Mn(3)O(4)) nanoparticles on silk fiber was achieved by sequential dipping in an alternating bath of potassium hydroxide and manganese(II) nitrate under ultrasound irradiation. Some parameters such as the effect of pH, numerous sequential dipping and ultrasonic irradiation on growth of the nanoparticles have been studied. The samples were characterized with powder X-ray diffraction (XRD), scanning electron microscopy (SEM) and wavelength dispersive X-ray (WDX). 23361257 Adsorbed and near surface structure of ionic liquids at a solid interface. The structure of solid-ionic liquid (IL) interfaces has been characterised with unprecedented clarity by employing a range of atomic force microscopy (AFM) imaging techniques and tip pressures appropriate for the system under study. Soft contact and amplitude-modulation (AM) AFM imaging have been used to elucidate the lateral structure of ILs adsorbed onto mica, and in the near surface ion layers. Data is presented for ethylammonium nitrate (EAN) and 1-ethyl-3-methylimidazolium bis(trifluoro-methylsulfonyl)imide (EMIm TFSI). Whereas EAN is a protic IL that forms a nanostructured sponge phase in the bulk, EMIm TFSI is aprotic and has weak (or absent) bulk association structure. Comparison of results obtained for the two liquids elucidates how the strength of bulk liquid morphology effects lateral organisation at the surface, and any effect of IL class, i.e. protic versus aprotic. Imaging reveals EAN self assembles at the solid surface in a worm-like morphology, whereas EMIm cations adsorb in a more isolated fashion, but still in rows templated by the mica surface. To the authors' knowledge, the wormlike structures present at the EAN-mica interface are the smallest self-assembled aggregates ever imaged on a solid surface. 23350733 Potent elastase inhibitors from cyanobacteria: structural basis and mechanisms mediating cytoprotective and anti-inflammatory effects in bronchial epithelial cells. We discovered new structural diversity to a prevalent, yet medicinally underappreciated, cyanobacterial protease inhibitor scaffold and undertook comprehensive protease profiling to reveal potent and selective elastase inhibition. Structure-activity relationship (SAR) studies and X-ray cocrystal structure analysis allowed a detailed assessment of critical and tunable structural elements. To realize the therapeutic potential of these cyclodepsipeptides, we probed the cellular effects of a novel and representative family member, symplostatin 5 (1), which attenuated the downstream cellular effects of elastase in an epithelial lung airway model system, alleviating clinical hallmarks of chronic pulmonary diseases such as cell death, cell detachment, and inflammation. This compound attenuated the effects of elastase on receptor activation, proteolytic processing of the adhesion protein ICAM-1, NF-κB activation, and transcriptomic changes, including the expression of pro-inflammatory cytokines IL1A, IL1B, and IL8. Compound 1 exhibited activity comparable to the clinically approved elastase inhibitor sivelestat in short-term assays and demonstrated superior sustained activity in longer-term assays. 23598442 Npas4 is activated by melatonin, and drives the clock gene Cry1 in the ovine pars tuberalis. Seasonal mammals integrate changes in the duration of nocturnal melatonin secretion to drive annual physiological cycles. Melatonin receptors within the proximal pituitary region, the pars tuberalis (PT), are essential in regulating seasonal neuroendocrine responses. In the ovine PT, melatonin is known to influence acute changes in transcriptional dynamics coupled to the onset (dusk) and offset (dawn) of melatonin secretion, leading to a potential interval-timing mechanism capable of decoding changes in day-length (photoperiod). Melatonin offset at dawn is linked to cAMP accumulation, which directly induces transcription of the clock gene Per1. The rise of melatonin at dusk induces a separate and distinct cohort, including the clock-regulated genes Cry1 and Nampt, but little is known of the up-stream mechanisms involved. Here, we used next generation sequencing of the ovine PT transcriptome at melatonin onset, and identified Npas4 as a rapidly induced bHLH-PAS domain transcription factor. In vivo we show nuclear localisation of NPAS4 protein in presumptive melatonin target cells of the PT (αGSU-expressing cells), while in situ hybridisation studies identified acute and transient expression in the PT of Npas4 in response to melatonin. In vitro, NPAS4 forms functional dimers with bHLH-PAS domain co-factors ARNT, ARNT2 and ARNTL, transactivating both Cry1 and Nampt ovine promoter reporters. Using a combination of 5` deletions and site-directed mutagenesis we show NPAS4:ARNT transactivation to be co-dependent upon two conserved central midline elements (CMEs) within the Cry1 promoter. Our data thus reveal NPAS4 as a candidate immediate early-response gene in the ovine PT, driving molecular responses to melatonin. 23643483 Interactive effects of smoking and glutathione S-transferase polymorphisms on the development of non-alcoholic fatty liver disease. Glutathione S-transferases (GSTs) protect cells against exogenous and endogenous oxidative stress. GST polymorphisms are associated with the development of cardiovascular disease (CVD) and diabetes mellitus (DM), especially in current-smokers. Non-alcoholic fatty liver disease (NAFLD) is a predictor of future CVD or DM, because oxidative stress contributes to their pathogenesis. This study investigated whether the combination of smoking status and GST genotypes could affect the risk for NAFLD. A cross-sectional analysis was conducted among 713 Japanese participants (458 males and 255 females) during a health screening program. The GSTM1 null, GSTT1 null, GSTP1 *A/*B or *B/*B and GSTA1 *A/*B or *B/*B genotypes were determined and deemed to be high-risk genotypes. The prevalence of NAFLD was 18.7%. Among never-smokers, carriers of one, and those of two or more high-risk GSTM1, GSTP1 or GSTA1 genotypes were at a higher risk for NAFLD than those who were not carriers [odds ratio (95% confidence interval): 2.6 (1.1-5.9) and 3.3 (1.3-8.1), respectively], and the risk was further increased among current-smokers [4.6 (1.6-13.0) and 5.4 (1.2-23.7), respectively]. This is the first report to show that the combination of current-smoking and harboring high-risk GSTM1, GSTP1 and/or GSTA1 genotypes is interactively associated with the risk of NAFLD. 23261672 Thirteen week rodent feeding study with grain from molecular stacked trait lepidopteran and coleopteran protected (DP-ØØ4114-3) maize. The results from a subchronic feeding study conducted in Sprague–Dawley rats fed with diets containing grain from 4114 (OECD unique identifier: DP-ØØ4114-3) maize that was untreated (4114) or sprayed in field with glufosinate ammonium (4114GLU) in a design similar to previous studies are reported. The test material, 4114 maize, is a hybrid maize produced by transformation with a DNA construct encoding 4 different transgenic proteins for resistance to lepidopteran pests, coleopteran pests, and tolerance to the herbicidal active ingredient glufosinate ammonium. There were a total of 144 rats divided into 12 groups of 12 rats/sex/group. All experimental diets were formulated by Purina Mills, LLC (St. Louis, MO) in accordance with the standards of Purina Mills Labdiet® Certified Rodent LabDiet® 5002. The incorporation rate of maize grain in all diets was 32% (wt/wt). No biologically significant, treatment related differences in body weight, food consumption, clinical pathology parameters (hematology, blood chemistry, urinalysis, or organ weight) were observed in rats consuming the diets containing 4114 maize grain compared with rats fed conventional maize diets. A number of histologic observations were noted in this study but were background lesions and representative of what would be expected for rats of this age and strain. An independent panel of experts determined certain observations to be spontaneous and not related to the test diet. Accordingly, these results support the conclusion that 4114 maize grain is as safe and nutritious as conventional maize grain. 23321957 Microwave absorption in powders of small conducting particles for heating applications. In microwave chemistry there is a common misconception that small, highly conducting particles heat profusely when placed in a large microwave electric field. However, this is not the case; with the simple physical explanation that the electric field (which drives the heating) within a highly conducting particle is highly screened. Instead, it is the magnetic absorption associated with induction that accounts for the large experimental heating rates observed for small metal particles. We present simple principles for the effective heating of particles in microwave fields from calculations of electric and magnetic dipole absorptions for a range of practical values of particle size and conductivity. For highly conducting particles, magnetic absorption dominates electric absorption over a wide range of particle radii, with an optimum absorption set by the ratio of mean particle radius a to the skin depth δ (specifically, by the condition a = 2.41δ). This means that for particles of any conductivity, optimized magnetic absorption (and hence microwave heating by magnetic induction) can be achieved by simple selection of the mean particle size. For weakly conducting samples, electric dipole absorption dominates, and is maximized when the conductivity is approximately σ ≈ 3ωε(0) ≈ 0.4 S m(-1), independent of particle radius. Therefore, although electric dipole heating can be as effective as magnetic dipole heating for a powder sample of the same volume, it is harder to obtain optimized conditions at a fixed frequency of microwave field. The absorption of sub-micron particles is ineffective in both magnetic and electric fields. However, if the particles are magnetic, with a lossy part to their complex permeability, then magnetic dipole losses are dramatically enhanced compared to their values for non-magnetic particles. An interesting application of this is the use of very small magnetic particles for the selective microwave heating of biological samples. 23175530 Conformational dynamics of Kir3.1/Kir3.2 channel activation via δ-opioid receptors. This study assessed how conformational information encoded by ligand binding to δ-opioid receptors (DORs) is transmitted to Kir3.1/Kir3.2 channels. Human embryonic kidney 293 cells were transfected with bioluminescence resonance energy transfer (BRET) donor/acceptor pairs that allowed us to evaluate independently reciprocal interactions among signaling partners. These and coimmunoprecipitation studies indicated that DORs, Gβγ, and Kir3 subunits constitutively interacted with one another. GαoA associated with DORs and Gβγ, but despite being part of the complex, no evidence of its direct association with the channel was obtained. DOR activation by different ligands left DOR-Kir3 interactions unmodified but modulated BRET between DOR-GαoA, DOR-Gβγ, GαoA-Gβγ, and Gβγ-Kir3 interfaces. Ligand-induced BRET changes assessing Gβγ-Kir3.1 subunit interaction 1) followed similar kinetics to those monitoring the GαoA-Gβγ interface, 2) displayed the same order of efficacy as those observed at the DOR-Gβγ interface, 3) were sensitive to pertussis toxin, and 4) were predictive of whether a ligand could evoke channel currents. Conformational changes at the Gβγ/Kir3 interface were lost when Kir3.1 subunits were replaced by a mutant lacking essential sites for Gβγ-mediated activation. Thus, conformational information encoded by agonist binding to the receptor is relayed to the channel via structural rearrangements that involve repositioning of Gβγ with respect to DORs, GαoA, and channel subunits. Further, the fact that BRET changes at the Gβγ-Kir3 interface are predictive of a ligand's ability to induce channel currents points to these conformational biosensors as screening tools for identifying GPCR ligands that induce Kir3 channel activation. 23561130 Microcapsule production employing chickpea or lentil protein isolates and maltodextrin: Physicochemical properties and oxidative protection of encapsulated flaxseed oil. Flaxseed oil was microencapsulated, employing a wall material matrix of either chickpea (CPI) or lentil protein isolate (LPI) and maltodextrin, followed by freeze-drying. Effects of oil concentration (5.3-21.0%), protein source (CPI vs. LPI) and maltodextrin type (DE 9 and 18) and concentration (25.0-40.7%), on both the physicochemical characteristics and microstructure of the microcapsules, were investigated. It was found that an increase in emulsion oil concentration resulted in a concomitant increase in oil droplet diameter and microcapsule surface oil content, and a decrease in oil encapsulation efficiency. Optimum flaxseed oil encapsulation efficiency (∼83.5%), minimum surface oil content (∼2.8%) and acceptable mean droplet diameter (3.0μm) were afforded with 35.5% maltodextrin-DE 9 and 10.5% oil. Microcapsules, formed by employing these experimental conditions, showed a protective effect against oxidation versus free oil over a storage period of 25d at room temperature. 23489438 Baseline HbA1c predicts attainment of 7.0% HbA1c target with structured titration of insulin glargine in type 2 diabetes: a patient-level analysis of 12 studies. AIMS: To determine whether baseline characteristics, especially haemoglobin A1c (HbA1c), predict the likelihood of reaching HbA1c ≤ 7.0% or the risk of experiencing hypoglycaemia after the addition of insulin glargine to oral therapy in type 2 diabetes. METHODS: Pooled patient-level data from 12 prospective, randomized, controlled studies that used insulin glargine in a treat-to-target titration regimen seeking fasting glucose levels ≤5.5 mmol/l (100 mg/dl) were analysed. Baseline characteristics were evaluated by logistic regression models as predictors of reaching a target HbA1c ≤ 7.0% or experiencing confirmed hypoglycaemia. The effect of prior glycaemic control was further explored by analysis of categorical ranges of baseline HbA1c. RESULTS: Of 2312 participants, 95% completed 24 weeks of treatment. Lower HbA1c at baseline was independently associated with reaching HbA1c target [adjusted odds ratio (OR) for 1% difference: 0.538, p < 0.0001] and also with likelihood of experiencing confirmed hypoglycaemic events (adjusted OR: 0.835, p < 0.0001) at week 24. In an unadjusted analysis by baseline HbA1c range, the strong association between baseline control and attaining target HbA1c was confirmed (75% with baseline HbA1c < 8.0%, 60% with baseline HbA1c ≥ 8.0 and <9.0% and 38% with baseline HbA1c ≥ 9.0% attained HbA1c ≤ 7.0%). The incidence of hypoglycaemia confirmed <3.9 mmol/l (70 mg/dl) was higher in the lower baseline HbA1c ranges but severe hypoglycaemia was infrequent at all baseline HbA1c levels. CONCLUSIONS: Systematically titrated insulin glargine, added to oral agents, was effective over a wide range of baseline HbA1c. Lower baseline HbA1c was the best clinical predictor of achieving HbA1c ≤ 7.0% and also associated with higher risk of glucose-confirmed hypoglycaemia. Severe hypoglycaemia was infrequent using this treatment approach. 23526452 Use of magnetic forces to promote stem cell aggregation during differentiation, and cartilage tissue modeling. Magnetic forces induce cell condensation necessary for stem cell differentiation into cartilage and elicit the formation of a tissue-like structure: Magnetically driven fusion of aggregates assembled by micromagnets results in the formation of a continuous tissue layer containing abundant cartilage matrix. 23584984 Alkane Oxidation by an Immobilized Nickel Complex Catalyst: Structural and Reactivity Differences Induced by Surface-Ligand Density on Mesoporous Silica. Immobilized nickel catalysts SBA*-L-x/Ni (L=bis(2-pyridylmethyl)(1H-1,2,3-triazol-4-ylmethyl)amine) with various ligand densities (L content (x)=0.5, 1, 2, 4 mol % Si) have been prepared from azidopropyl-functionalized mesoporous silicas SBA-N3 -x. Related homogeneous ligand L(t) (Bu) and its Ni(II) complexes, [Ni(L(t) (Bu) )(OAc)2 (H2 O)] (L(t) (Bu) /Ni) and [Ni(L(t) (Bu) )2 ]BF4 (2 L(t) (Bu) /Ni), have been synthesized. The L/Ni ratio (0.9-1.7:1) in SBA*-L-x/Ni suggests the formation of an inert [NiL2 ] site on the surface at higher ligand loadings. SBA*-L-x/Ni has been applied to the catalytic oxidation of cyclohexane with m-chloroperbenzoic acid (mCPBA). The catalyst with the lowest loading shows high activity in its initial use as the homogeneous L(t) (Bu) /Ni catalyst, with some metal leaching. As the ligand loading increases, the activity and Ni leaching are suppressed. The importance of site-density control for the development of immobilized catalysts has been demonstrated. 23340670 NMR crystallography of α-poly(L-lactide). A complementary approach that combines NMR measurements, analysis of X-ray and neutron powder diffraction data and advanced quantum mechanical calculations was employed to study the α-polymorph of L-polylactide. Such a strategy, which is known as NMR crystallography, to the best of our knowledge, is used here for the first time for the fine refinement of the crystal structure of a synthetic polymer. The GIPAW method was used to compute the NMR shielding parameters for the different models, which included the α-PLLA structure obtained by 2-dimensional wide-angle X-ray diffraction (WAXD) at -150 °C (model M1) and at 25 °C (model M2), neutron diffraction (WAND) measurements (model M3) and the fully optimized geometry of the PLLA chains in the unit cell with defined size (model M4). The influence of changes in the chain conformation on the (13)C σ(ii) NMR shielding parameters is shown. The correlation between the σ(ii) and δ(ii) values for the M1-M4 models revealed that the M4 model provided the best fit. Moreover, a comparison of the experimental (13)C NMR spectra with the spectra calculated using the M1-M4 models strongly supports the data for the M4 model. The GIPAW method, via verification using NMR measurements, was shown to be capable of the fine refinement of the crystal structures of polymers when coarse X-ray diffraction data for powdered samples are available. 23322587 Korean guidelines for pharmacoeconomic evaluation (second and updated version) : consensus and compromise. The first version of the Korean guidelines for pharmacoeconomic evaluation was published by Health Insurance Review and Assessment Service (HIRA) in 2006. Since the introduction of the first version, domestic experience with the application of the recommendations has accumulated, and methodologies in certain areas have progressed considerably. Based on these experiences, HIRA initiated a guidelines revision project to address the need for revisions. The purpose of this study is to share the process used to complete these guideline revisions and to provide the contents of the revised guidelines. In developing the current revision, meetings with the advisory committee and working-level meetings with pharmaceutical companies were held several times to reach as much of a consensus as possible, and the results of a survey of pharmaceutical companies and decision makers regarding the existing guidelines were considered. The second version of the guidelines clarified the level of data requirement ('must', 'recommended', 'preferred') based on the data availability, the information needs of the decision makers and the strength of the evidence. The recommended perspective economic studies should take has been modified and additional guidance has been provided on QALY measurement. Manuals for systematic reviews and indirect comparisons have been published, and a standardized reporting format for expert opinions has been added. Sections on preferred methods for evaluations, sensitivity analysis, modelling and time horizon have been elucidated. The revised guidelines clarify the expression of the recommendations, making them more user-friendly, and provide more specific guidance to improve the quality and comparability across submissions. 23370007 APE1/Ref-1 prevents oxidative inactivation of ERK for G1-to-S progression following lead acetate exposure. Apurinic/apyrimidinic endonuclease 1 (APE1)/redox effector factor-1 is a multifunctional enzyme involved in DNA base excision repair and protein redox regulation. Previously, we have showed that lead acetate (Pb) elicits EGFR activation to initiate the SFK/PKCα/Ras/Raf-1/MKK1/2/ERK signaling cascade functioning against genotoxicity. Here, we explore whether APE1 and reactive oxygen species (ROS) affect ERK signaling and cell cycle progression following Pb exposure. We found that Pb induced APE1 expression and ROS generation in CL3 human lung cancer cells. The Pb-elicited ROS levels and cytotoxicity were further enhanced by introducing small interfering RNA specific for APE1 (siAPE1). E3330, an inhibitor of APE1 redox activity, also augmented the ROS levels and cytotoxicity in Pb-treated cells. Intriguingly, the capability of Pb to activate ERK was abolished under siAPE1 or E3330 co-treatments; conversely, forced expression of APE1 up-regulated the ERK activation by Pb or serum in both Cys65-redox activity dependent and independent manners. Moreover, APE1 formed complex with ERK2, and its redox activity could rescue ERK oxidative inactivation. APE1 redox activity also facilitated the Cyclin D1 expression and G1-to-S progression following Pb exposure. In summary, the results indicate that APE1 is a direct redox regulator of ERK for maintaining the kinase activity to promote cell proliferation. 22705273 Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments. In cortical and hippocampal neurons, cation-chloride cotransporters (CCCs) control the reversal potential (EGABA) of GABAA receptor-mediated current and voltage responses and, consequently, they modulate the efficacy of GABAergic inhibition. Two members of the CCC family, KCC2 (the major neuron-specific K-Cl cotransporter; KCC isoform 2) and NKCC1 (the Na-K-2Cl cotransporter isoform 1 which is expressed in both neurons and glial cells) have attracted much interest in studies on GABAergic signaling under both normal and pathophysiological conditions, such as epilepsy. There is tentative evidence that loop diuretic compounds such as furosemide and bumetanide may have clinically relevant antiepileptic actions, especially when administered in combination with conventional GABA-mimetic drugs such as phenobarbital. Furosemide is a non-selective inhibitor of CCCs while at low concentrations bumetanide is selective for NKCCs. Search for novel antiepileptic drugs (AEDs) is highly motivated especially for the treatment of neonatal seizures which are often resistant to, or even aggravated by conventional AEDs. This review shows that the antiepileptic effects of loop diuretics described in the pertinent literature are based on widely heterogeneous mechanisms ranging from actions on both neuronal NKCC1 and KCC2 to modulation of the brain extracellular volume fraction. A promising strategy for the development of novel CCC-blocking AEDs is based on prodrugs that are activated following their passage across the blood-brain barrier. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'. 23383648 High-relaxivity and luminescent silica nanoparticles as multimodal agents for molecular imaging. The design and synthesis of a new bimodal contrast agent for magnetic resonance imaging and optical imaging is reported. Tunable-sized silica nanoparticles were synthesized by a microemulsion-mediated pathway and used as carriers for paramagnetic and luminescent probes. The near-infrared luminescent agent was a ruthenium complex that was directly entrapped in the silica shell to provide photoluminescence enhancement and to make it highly photostable as it was protected from the surrounding environment. The paramagnetic activity came from a Gd-DTPA derivative that was grafted on the silica surface. NMRD profiles showed a strong relaxivity enhancement (increase of 432% in the r1 value at 20 MHz) when the paramagnetic complex was grafted at the nanoparticle surface, because of a reduction of its mobility. Polyethylene glycol was also grafted at the nanoparticle surface to enhance the nanoparticle residence time in the bloodstream. A thorough characterization of the material confirmed its potential as a very effective bimodal contrast agent. 23312474 Identification of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives and their orally active prodrug esters as dual-acting alpha4-beta1 and alpha4-beta7 receptor antagonists. N-Acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives of type 4 were designed to replace the 2,6-dichlorobenzoylamine portion of compound 1 in order to identify novel compounds with improved potency against α4-integrins. Several derivatives were identified as very potent dual-acting α4-integrin, α4β1 and α4β7 antagonists. Investigation of a limited number of prodrug esters led to the discovery of the ethyl ester prodrug 42, which demonstrated good intestinal fluid stability and good permeability. Despite low solubility, 42 gave acceptable blood levels of 30 when dosed orally in non-human primates. Additionally, 42 had an overall excellent profile and was selected for clinical trials. Investigation of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives led to the discovery of several very potent dual-acting α4-integrin antagonists. Ethyl ester prodrug 42 advanced to human clinical trials based on the excellent intestinal fluid stability, good permeability and superior efficacy in non-human primates. 23223802 Aqueous phase synthesis of copper nanoparticles: a link between heavy metal resistance and nanoparticle synthesis ability in bacterial systems. We demonstrate aqueous phase biosynthesis of phase-pure metallic copper nanoparticles (CuNPs) using a silver resistant bacterium Morganella morganii. This is particularly important considering that there has been no report that demonstrates biosynthesis and stabilization of pure copper nanoparticles in the aqueous phase. Electrochemical analysis of bacterial cells exposed to Cu(2+) ions provides new insights into the mechanistic aspect of Cu(2+) ion reduction within the bacterial cell and indicates a strong link between the silver and copper resistance machinery of bacteria in the context of metal ion reduction. The outcomes of this study take us a step closer towards designing rational strategies for biosynthesis of different metal nanoparticles using microorganisms. 23263864 Methylation-controlled J-protein MCJ acts in the import of proteins into human mitochondria. Loss of expression of the methylation-controlled J gene, MCJ (DNAJC15), is observed in cases of several tumors and plays a crucial role in the chemoresistance of ovarian cancer cells. Aside from the pathophysiological effects, almost nothing is known about the cellular function of MCJ. Here, we provide the first evidence that MCJ acts in the biogenesis of mitochondria. Our results demonstrate that MCJ is located in mitochondria. It is anchored in the mitochondrial inner membrane with the C-terminal J domain facing the matrix space. We show that MCJ forms a stable subcomplex with a component of the mitochondrial import motor, MAGMAS, a protein overexpressed in cells treated with granulocyte-macrophage colony-stimulating factor and in prostate carcinomas. In addition, MCJ and MAGMAS interact with the core components of the TIM23 pre-protein translocase. We demonstrate that the recombinant soluble MCJ domain stimulates the ATPase activity of the human mtHsp70 chaperone, mortalin, the central component of the import motor of the TIM23 translocase. This stimulation is counteracted by MAGMAS. Moreover, pre-protein import into mitochondria is impaired in the absence of MCJ. Interestingly, MCJ is able to take over the function of Tim14, the essential J co-chaperone of the mitochondrial protein import motor in yeast. In summary, our results show that MCJ functions as J co-chaperone of the human TIM23 pre-protein translocase, suggesting a link between mitochondrial pre-protein import and tumorigenesis. 23298809 Optimization of benzyloxazoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase to enhance Y181C potency. Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase with improved activity towards Tyr181Cys containing variants was pursued with the assistance of free energy perturbation (FEP) calculations. Optimization of the 4-R substituent in 1 led to ethyl and isopropyl analogs 1e and 1f with 1-7 nM potency towards both the wild-type virus and a Tyr181C variant. 23584356 A simple, sensitive and accurate method for rat paw volume measurement and its expediency in preclinical animal studies. Several methods are used to evaluate the inflammatory changes. Measurement of edema is the most commonly used method for evaluating artificially induced inflammation in rat model. In this context, we present a method for the measurement of volume of rat paw, in which two glass columns containing fluid are connected by a glass tube. Paw is immersed in one column and the other column is placed on weighing balance. Upon immersion of paw, equal volume of fluid displaced applies a force F, which shows specific and proportional increment in the level of fluid in both the columns, which could then be detected by weighing balance, as 'Force = Weight' of displaced fluid, using the specific gravity of the fluid and the volume of paw, and thus the change in the volume of paw can be calculated. The rat paw immersed in column without touching the wall of the column facilitates the accurate measurement of volume of paw when measured several times. Present method is validated for its accuracy and reproducibility when internal radii of both the columns were same or different. Presented method is also cost-effective and hence can be used for the academic and the commercial animal research purpose, without compromising the precision of the evaluation. 22876950 Snake venom induced local toxicities: plant secondary metabolites as an auxiliary therapy. Snakebite is a serious medical and socio-economic problem affecting the rural and agricultural laborers of tropical and sub-tropical region across the world leading to high morbidity and mortality. In most of the snakebite incidences, victims usually end up with permanent tissue damage and sequelae with high socioeconomic and psychological impacts. Although, mortality has been reduced markedly due to anti-venom regimen, it is associated with several limitations. Snake venom metalloprotease, hyaluronidase and myotoxic phospholipase A2 are the kingpins of tissue necrosis and extracellular matrix degradation. Thus, inhibition of these enzymes is considered to be the rate limiting step in the management of snakebite. Unfortunately, tissue necrosis and extracellular matrix degradation persists even after the administration of anti-venom. At present, inhibitors from snake serum and plasma, several synthetic compounds and their analogs have been demonstrated to possess anti-snake venom activities, but the use of plant metabolites for this purpose has an added advantage of traditional knowledge and will make the treatment cheaper and more accessible to the affected population. Therefore, the clinical and research forums are highly oriented towards plant metabolites and interestingly, certain phytochemicals are implicated as the antibody elicitors against venom toxicity that can be exploited in designing effective anti-venoms. Based on these facts, we have made an effort to enlist plant based secondary metabolites with antiophidian abilities and their mechanism of action against locally acting enzymes/toxins in particular. The review also describes their functional groups responsible for therapeutic beneficial and certainly oblige in designing potent inhibitors against venom toxins. 23249751 Rapid and specific purification of Argonaute-small RNA complexes from crude cell lysates. Small interfering RNAs (siRNAs) direct Argonaute proteins, the core components of the RNA-induced silencing complex (RISC), to cleave complementary target RNAs. Here, we describe a method to purify active RISC containing a single, unique small RNA guide sequence. We begin by capturing RISC using a complementary 2'-O-methyl oligonucleotide tethered to beads. Unlike other methods that capture RISC but do not allow its recovery, our strategy purifies active, soluble RISC in good yield. The method takes advantage of the finding that RISC partially paired to a target through its siRNA guide dissociates more than 300 times faster than a fully paired siRNA in RISC. We use this strategy to purify fly Ago1- and Ago2-RISC, as well as mouse AGO2-RISC. The method can discriminate among RISCs programmed with different guide strands, making it possible to deplete and recover specific RISC populations. Endogenous microRNA:Argonaute complexes can also be purified from cell lysates. Our method scales readily and takes less than a day to complete. 23360475 Design, synthesis, and structure-activity relationship studies of tryptanthrins as antitubercular agents. The natural product tryptanthrin (1a) represents a potential lead for new tuberculosis (TB) drugs since tryptanthrin and its synthetic analogues possess potent in vitro activity against Mycobacterium tuberculosis (Mtb). However, in spite of their in vitro activity, none of these agents have been shown to be efficacious in vivo against animal models of TB. Described herein are syntheses of new tryptanthrin analogues together with a systematic investigation of their in vitro antitubercular activity and ADME properties followed by pharmacokinetic characterization in rodents for the most promising compounds. Those with the best potency and oral bioavailability were progressed to evaluations of efficacy against acute murine TB. The work aimed to prove the concept that this compound class can limit growth of Mtb during infection as well as to establish the SAR for in vitro activity against Mtb and the range of in vitro ADME parameters for this class of natural products. Novel C-11-deoxy (5b) and A-ring-saturated (6) tryptanthrin analogues were discovered that maintained activity against Mtb and showed improved solubility compared to tryptanthrin as well as evidence of oral bioavailability in rodents. However, neither 5b nor 6 demonstrated efficacy against acute murine TB following administration at doses up to 400 mg/kg daily for 4 weeks. Although 5b and 6 failed to inhibit replication or kill Mtb in vivo, they illuminate a path to new structural variations of the tryptanthrin scaffold that may maximize the potential of this class of compounds against TB. 23325437 Losmapimod concentration-QT relationship in healthy volunteers: meta-analysis of data from six clinical trials. PURPOSE: The objective of this work was to describe the losmapimod concentration-QT relationship using meta-analysis of data from clinical trials with healthy volunteers and to evaluate the covariates that have significant impact on the QT prolongation. METHODS: Losmapimod plasma concentration and QT interval data were collected from six early clinical studies with healthy volunteers. The electrocardiograms (ECGs) were collected at baseline and at a number of post-dose time points (losmapimod or placebo). The population pharmacokinetic/pharmacodynamic (PK/PD) modelling approach was applied to investigate the relationship between losmapimod concentration and QT prolongation. RESULTS: The dataset for analysis comprised 190 healthy adults who took at least one dose of losmapimod or placebo. Of the 2,494 QT observations collected, 1,532 observations had matched QT and losmapimod plasma concentration data. Population PK/PD analyses indicated that the model with the individual heart rate correction factor (α) fitted the data better than those using fixed α (0.33 for Fridericia's correction or 0.5 for Bazett's correction) and that there was no relationship between losmapimod concentration and QT interval. Female volunteers had about a 3 % higher QT interval at baseline than the male volunteers. No other covariates had a significant effect on the QT interval. CONCLUSIONS: It is appropriate to apply population PK/PD analysis to investigate the effect of drug concentration on QT prolongation. Our meta-analysis of healthy volunteer data indicated no relationship between systemic losmapimod concentration and QT interval in healthy volunteers. 23570906 Identification of miRNA modulators to PARP inhibitor response. Based on the principle of synthetic lethality, PARP inhibitors have been shown to be very effective in killing cells deficient in homologous recombination (HR), such as those bearing mutations in BRCA1/2. However, questions regarding their wider use persist and other determinants of responsiveness to PARP inhibitor remain to be fully explored. MicroRNAs (miRNAs) are small non-coding RNAs, which serve as post-transcriptional regulators of gene expression and are involved in a wide variety of cellular processes, including the DNA damage response (DDR). However, little is known about whether miRNAs might influence sensitivity to PARP inhibitors. To investigate this, we performed a high throughput miRNA mimetic screen, which identified several miRNAs whose over-expression results in sensitization to the clinical PARP inhibitor olaparib. In particular, our findings indicate that hsa-miR-107 and hsa-miR-222 regulate the DDR and sensitise tumour cells to olaparib by repressing expression of RAD51, thus impairing DSB repair by HR. Moreover, elevated expression of hsa-miR-107 has been observed in a subset of ovarian clear cell carcinomas, which correlates with PARP inhibitor sensitivity and reduced RAD51 expression. Taken together, these observations raise the possibility that these miRNAs could be used as biomarkers to identify patients that may benefit from treatment with PARP inhibitors. 23395804 Prolactin regulates transcription of the ion uptake Na+/Cl- cotransporter (ncc) gene in zebrafish gill. Prolactin (PRL) is a well-known regulator of ion and water transport within osmoregulatory tissues across vertebrate species, yet how PRL acts on some of its target tissues remains poorly understood. Using zebrafish as a model, we show that ionocytes in the gill directly respond to systemic PRL to regulate mechanisms of ion uptake. Ion-poor conditions led to increases in the expression of PRL receptor (prlra), Na(+)/Cl(-) cotransporter (ncc; slc12a10.2), Na(+)/H(+) exchanger (nhe3b; slc9a3.2), and epithelial Ca(2+) channel (ecac; trpv6) transcripts within the gill. Intraperitoneal injection of ovine PRL (oPRL) increased ncc and prlra transcripts, but did not affect nhe3b or ecac. Consistent with direct PRL action in the gill, addition of oPRL to cultured gill filaments stimulated ncc in a concentration-dependent manner, an effect blocked by a pure human PRL receptor antagonist (Δ1-9-G129R-hPRL). These results suggest that PRL signaling through PRL receptors in the gill regulates the expression of ncc, thereby linking this pituitary hormone with an effector of Cl(-) uptake in zebrafish for the first time. 23265470 Differentiation of Sparidae species by DNA sequence analysis, PCR-SSCP and IEF of sarcoplasmic proteins. The increasing global trade of fishery and aquaculture products makes it necessary to develop methods for species identification in case of fish fillets or other highly processed seafood with external morphological characteristics (e.g. gills, fins) of the original fish being removed. Species identification methods based on DNA- or protein-analysis, like DNA sequencing of PCR products, PCR-SSCP (polymerase chain reaction - single strand conformation polymorphism), and isoelectric focusing (IEF) of water-soluble proteins of fish fillet were applied successfully to distinguish between various sparid species including Sparus aurata, Spondyliosoma cantharus, Boops boops, Acanthopagrus bifasciatus, Argyrops spinifer, Pagellus bogaraveo and Lithognathus mormyrus of the family Sparidae available on European markets. Indication of the presence of parvalbumins in light muscle of all of the studied species is presented by the location of heat-stable proteins in the anodic range of the IEF gels. 23598363 Rescue of platinum-damaged oocytes from programmed cell death through inactivation of the p53 family signaling network. Non-proliferating oocytes within avascular regions of the ovary are exquisitely susceptible to chemotherapy. Early menopause and sterility are unintended consequences of chemotherapy, and efforts to understand the oocyte apoptotic pathway may provide new targets for mitigating this outcome. Recently, the c-Abl kinase inhibitor imatinib mesylate (imatinib) has become the focus of research as a fertoprotective drug against cisplatin. However, the mechanism by which imatinib protects oocytes is not fully understood, and reports of the drug's efficacy have been contradictory. Using in vitro culture and subrenal grafting of mouse ovaries, we demonstrated that imatinib inhibits the cisplatin-induced apoptosis of oocytes within primordial follicles. We found that, before apoptosis, cisplatin induces c-Abl and TAp73 expression in the oocyte. Oocytes undergoing apoptosis showed downregulation of TAp63 and upregulation of Bax. While imatinib was unable to block cisplatin-induced DNA damage and damage response, such as the upregulation of p53, imatinib inhibited the cisplatin-induced nuclear accumulation of c-Abl/TAp73 and the subsequent downregulation of TAp63 and upregulation of Bax, thereby abrogating oocyte cell death. Surprisingly, the conditional deletion of Trp63, but not ΔNp63, in oocytes inhibited apoptosis, as well as the accumulation of c-Abl and TAp73 caused by cisplatin. These data suggest that TAp63 is the master regulator of cisplatin-induced oocyte death. The expression kinetics of TAp63, c-Abl and TAp73 suggest that cisplatin activates TAp63-dependent expression of c-Abl and TAp73 and, in turn, the activation of TAp73 by c-Abl-induced BAX expression. Our findings indicate that imatinib protects oocytes from cisplatin-induced cell death by inhibiting c-Abl kinase, which would otherwise activate TAp73-BAX-mediated apoptosis. Thus, imatinib and other c-Abl kinase inhibitors provide an intriguing new way to halt cisplatin-induced oocyte death in early follicles and perhaps conserve the endocrine function of the ovary against chemotherapy.Cell Death and Differentiation advance online publication, 19 April 2013; doi:10.1038/cdd.2013.31. 23159885 Aldehyde dehydrogenases: from eye crystallins to metabolic disease and cancer stem cells. The aldehyde dehydrogenase (ALDH) superfamily is composed of nicotinamide adenine dinucleotide (phosphate) (NAD(P)(+))-dependent enzymes that catalyze the oxidation of aldehydes to their corresponding carboxylic acids. To date, 24 ALDH gene families have been identified in the eukaryotic genome. In addition to aldehyde metabolizing capacity, ALDHs have additional catalytic (e.g. esterase and reductase) and non-catalytic activities. The latter include functioning as structural elements in the eye (crystallins) and as binding molecules to endobiotics and xenobiotics. Mutations in human ALDH genes and subsequent inborn errors in aldehyde metabolism are the molecular basis of several diseases. Most recently ALDH polymorphisms have been associated with gout and osteoporosis. Aldehyde dehydrogenase enzymes also play important roles in embryogenesis and development, neurotransmission, oxidative stress and cancer. This article serves as a comprehensive review of the current state of knowledge regarding the ALDH superfamily and the contribution of ALDHs to various physiological and pathophysiological processes. 23571753 A capture approach for supercoiled plasmid DNA using a triplex-forming oligonucleotide. Proteins that recognize and bind specific sites in DNA are essential for regulation of numerous biological functions. Such proteins often require a negative supercoiled DNA topology to function correctly. In current research, short linear DNA is often used to study DNA-protein interactions. Although linear DNA can easily be modified, for capture on a surface, its relaxed topology does not accurately resemble the natural situation in which DNA is generally negatively supercoiled. Moreover, specific binding sequences are flanked by large stretches of non-target sequence in vivo. Here, we present a straightforward method for capturing negatively supercoiled plasmid DNA on a streptavidin surface. It relies on the formation of a temporary parallel triplex, using a triple helix forming oligonucleotide containing locked nucleic acid nucleotides. All materials required for this method are commercially available. Lac repressor binding to its operator was used as model system. Although the dissociation constants for both the linear and plasmid-based operator are in the range of 4 nM, the association and dissociation rates of Lac repressor binding to the plasmid-based operator are ∼18 times slower than on a linear fragment. This difference underscores the importance of using a physiologically relevant DNA topology for studying DNA-protein interactions. 23411257 Evaluation of sea bream (Sparus aurata) shelf life using an optoelectronic nose. A new optoelectronic nose for the shelf-life assessment of fresh sea bream in cold storage has been developed. The chromogenic array used eight sensing materials (based on aluminium oxide and silica gel) containing pH indicators, Lewis acids and an oxidation-reduction indicator. The colour changes of the sensor array were characteristic of sea bream spoilage. Colour modulations were measured on day 0 and for the samples held in cold storage for 2, 4, 7, 9 and 11 days. Determination of moisture content, pH, total volatile basic nitrogen (TVB-N), drip loss, ATP-related compounds and K(1)-value and microbial (mesophilic bacteria and Enterobacteriaceae) analyses were carried out on the same days. The changes in the chromogenic arrays data were processed by statistical analysis (PCA). Moreover, PLS statistical studies allowed the creation of models to correlate the chromogenic data with concentrations of mesophilic and Enterobacteriaceae. The results suggest the feasibility of this system to help develop optoelectronic noses for fish freshness monitoring. 23229057 Neutral and charged phosphine/scorpionate copper(I) complexes: effects of ligand assembly on their antiproliferative activity. Ligand-exchange reactions of copper(I) precursors ([Cu(CH(3)CN)(4)]BF(4), CuCl) with a panel of bis(azolyl)borates or poly(pyrazolyl)methanes and a tertiary monodentate phosphine (PTA = 1,3,5-triaza-7-phosphaadamantane, PCN = tris(cyanoethyl)phosphine) produced two series of heteroleptic, either '2 + 1 + 1'- or '3 + 1'-type complexes, which have been characterized by elemental analysis, FT-IR, ESI-MS and multinuclear (31)P and (1)H NMR. '2 + 1 + 1'-type complexes include a N,N-bidentate chelate and two monodentate phosphines (1-8) and '3 + 1'-type complexes comprise a N,N,O- or N,N,N-tridentate chelate and one monodentate phosphine (9-12). All these complexes adopt a four-coordinate, tetrahedral geometry. '3 + 1' complexes show better red-ox stability and a greater tendency to retain the native '3 + 1' mixed-ligand structure. Conversely, '2 + 1 + 1' complexes exhibit increased propensity to dissociation as shown by ESI-MS measurements and X-ray structure determination at low temperature (150 K) of the polymeric complex {[H(2)B(tz(NO2))(2)]Cu[PCN]}(n)6b. In this complex, either the bis(triazolyl)borate and the PCN ligands act as bidentate, with PCN being also the μ(2)-bridiging linker between adjacent monomers. Compound 6b is the first reported example of a polymeric PCN compound with a tetra-coordinate metal centre. Cytotoxic activity of all compounds has been evaluated by MTT test against a panel of several human tumor cell lines including examples of breast (MCF-7), colon (HCT-15 and LoVo), lung (A549), cervix (A431) and ovarian (2008 and its cisplatin resistant variant, C13*) carcinoma, melanoma (A375) and promyelocytic leukemia (HL60). Copper complexes generally show in vitro antitumour activity comparable to that of cisplatin. In particular, neutral '3 + 1'-type complexes 9 and 10, show IC(50) values appreciably lower than those exhibited by the reference metallodrug. 23585920 Inhibition of Ras-Effector Interaction by Cyclic Peptides. A combinatorial library of 6 × 10(6) cyclic peptides was synthesized in the one bead-two compound format, with each bead displaying a unique cyclic peptide on its surface and a linear peptide encoding tag in its interior. Screening of the library against K-Ras identified compounds that bound K-Ras with submicromolar affinity and disrupted its interaction with effector proteins. 23289830 Neuron-type specific cannabinoid-mediated G protein signalling in mouse hippocampus. Type 1 cannabinoid receptor (CB1) is expressed in different neuronal populations in the mammalian brain. In particular, CB1 on GABAergic or glutamatergic neurons exerts different functions and display different pharmacological properties in vivo. This suggests the existence of neuron-type specific signalling pathways activated by different subpopulations of CB1. In this study, we analysed CB1 expression, binding and signalling in the hippocampus of conditional mutant mice, bearing CB1 deletion in GABAergic (GABA-CB1-KO mice) or cortical glutamatergic neurons (Glu-CB1-KO mice). Compared to their wild-type littermates, Glu-CB1-KO displayed a small decrease of CB1 mRNA amount, immunoreactivity and [³H]CP55,940 binding. Conversely, GABA-CB1-KO mice showed a drastic reduction of these parameters, confirming that CB1 is present at much higher density on hippocampal GABAergic interneurons than glutamatergic neurons. Surprisingly, however, saturation analysis of HU210-stimulated [(35) S]GTPγS binding demonstrated that 'glutamatergic' CB1 is more efficiently coupled to G protein signalling than 'GABAergic' CB1. Thus, the minority of CB1 on glutamatergic neurons is paradoxically several fold more strongly coupled to G protein signalling than 'GABAergic' CB1. This selective signalling mechanism raises the possibility of designing novel cannabinoid ligands that differentially activate only a subset of physiological effects of CB1 stimulation, thereby optimizing therapeutic action. 23210742 Photoreversible micellar solution as a smart drag-reducing fluid for use in district heating/cooling systems. A photoresponsive micellar solution is developed as a promising working fluid for district heating/cooling systems (DHCs). It can be reversibly switched between a drag reduction (DR) mode and an efficient heat transfer (EHT) mode by light irradiation. The DR mode is advantageous during fluid transport, and the EHT mode is favored when the fluid passes through heat exchangers. This smart fluid is an aqueous solution of cationic surfactant oleyl bis(2-hydroxyethyl)methyl ammonium chloride (OHAC, 3.4 mM) and the sodium salt of 4-phenylazo benzoic acid (ACA, 2 mM). Initially, ACA is in a trans configuration and the OHAC/ACA solution is viscoelastic and exhibits DR (of up to 80% relative to pure water). At the same time, this solution is not effective for heat transfer. Upon UV irradiation, trans-ACA is converted to cis-ACA, and in turn, the solution is converted to its EHT mode (i.e., it loses its viscoelasticity and DR) but it now has a heat-transfer capability comparable to that of water. Subsequent irradiation with visible light reverts the fluid to its viscoelastic DR mode. The above property changes are connected to photoinduced changes in the nanostructure of the fluid. In the DR mode, the OHAC/trans-ACA molecules assemble into long threadlike micelles that impart viscoelasticity and DR capability to the fluid. Conversely, in the EHT mode the mixture of OHAC and cis-ACA forms much shorter cylindrical micelles that contribute to negligible viscoelasticity and effective heat transfer. These nanostructural changes are confirmed by cryo-transmission electron microscopy (cryo-TEM), and the photoisomerization of trans-ACA and cis-ACA is verified by (1)H NMR. 23271679 Bioavailability of stabilised ferrous gluconate with glycine in fresh cheese matrix: a novel iron compound for food fortification. Iron fortification of foods continues to be one of the preferred ways of improving the iron status of the population. Dairy product is a common product in the diet; therefore, it is a plausible vehicle for iron fortification. This study aims to investigate the bioavailability of ferrous gluconate stabilised with glycine (FGSG) in a fresh cheese fortified with zinc. The iron bioavailability of fresh cheese fortified with either FGSG and with or without zinc and FGSG in aqueous solution and a water solution of ferrous ascorbate (reference dose) was studied using double radio iron ((55)Fe and (59)Fe) erythrocyte incorporation in 15 male subjects. All subjects presented with normal values for iron status parameters. The geometric mean of iron bioavailability for the water solution of FGSG was 38.2 %, adjusted to 40 % from reference doses (N.S.). Iron bioavailability in fresh cheese fortified with Ca and Zn was 15.4 % and was 23.1 % without Zn, adjusted to 40 % from reference doses (N.S.). The results of the present study show that the novel iron compound ferrous gluconate stabilised with glycine in a fresh cheese matrix is a good source of iron and can be used in iron fortification programmes. 23544613 Enzyme-Catalyzed Synthesis of Aliphatic-Aromatic Oligoamides. Enzymatically catalyzed polycondensation of p-xylylenediamine and diethyl sebacate resulted in oligo(p-xylylene sebacamide) with high melting temperatures (223-230 °C) and the enzymatic polycondensation of dimethyl terephthalate and 1,8-diaminooctane leads to oligo(octamethylene terephthalamide) with two melting temperatures at 186 and 218 °C. No oligoamides, but products 1 and 2, were formed from the enzymatic reaction of dimethyl terephthalate and p-xylylenediamine. All reactions were catalyzed by CAL-B, icutinase, or CLEA cutinase. All reactions catalyzed by CAL-B show higher conversion than reactions catalyzed by icutinase or CLEA cutinase. The highest DPmax of 15 was achieved in a one-step and two-step synthesis of oligo(p-xylylene sebacamide) catalyzed by CLEA cutinase. 23481643 Novel tacrine-related drugs as potential candidates for the treatment of Alzheimer's disease. A summary of the recently published efforts on tacrine derivatives as a renewed potential therapeutic approach for the treatment of Alzheimer's disease is presented. 23237384 Sulfonylureas have antifungal activity and are potent inhibitors of Candida albicans acetohydroxyacid synthase. The sulfonylurea herbicides exert their activity by inhibiting plant acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway. It has previously been shown that if the gene for AHAS is deleted in Candida albicans , attenuation of virulence is achieved, suggesting AHAS as an antifungal drug target. Herein, we have cloned, expressed, and purified C. albicans AHAS and shown that several sulfonylureas are inhibitors of this enzyme and possess antifungal activity. The most potent of these compounds is ethyl 2-(N-((4-iodo-6-methoxypyrimidin-2-yl)carbamoyl)sulfamoyl)benzoate (10c), which has a K(i) value of 3.8 nM for C. albicans AHAS and an MIC₉₀ of 0.7 μg/mL for this fungus in cell-based assays. For the sulfonylureas tested there was a strong correlation between inhibitory activity toward C. albicans AHAS and fungicidal activity, supporting the hypothesis that AHAS is the target for their inhibitory activity within the cell. 23644925 Neuritogenic and Neuroprotective Effects of Polar Steroids from the Far East Starfishes Patiria pectinifera and Distolasterias nipon. The neuritogenic and neuroprotective activities of six starfish polar steroids, asterosaponin Р1, (25S)-5α-cholestane-3β,4β,6α,7α,8,15α,16β,26-octaol, and (25S)-5α-cholestane-3β,6α,7α,8,15α,16β,26-heptaol (1-3) from the starfish Patiria pectinifera and distolasterosides D1-D3 (4-6) from the starfish Distolasterias nipon were analyzed using the mouse neuroblastoma (NB) C-1300 cell line and an organotypic rat hippocampal slice culture (OHSC). All of these compounds enhanced neurite outgrowth in NB cells. Dose-dependent responses to compounds 1-3 were observed within the concentration range of 10-100 nM, and dose-dependent responses to glycosides 4-6 were observed at concentrations of 1-50 nM. All the tested substances exhibited notable synergistic effects with trace amounts of nerve growth factor (NGF, 1 ng/mL) or brain-derived neurotrophic factor (BDNF, 0.1 ng/mL). Using NB cells and OHSCs, it was shown for the first time that starfish steroids 1-6 act as neuroprotectors against oxygen-glucose deprivation (OGD) by increasing the number of surviving cells. Altogether, these results suggest that neurotrophin-like neuritogenic and neuroprotective activities are most likely common properties of starfish polyhydroxysteroids and the related glycosides, although the magnitude of the effect depended on the particular compound structure. 23306106 Lipid composition of Chlorella vulgaris (Trebouxiophyceae) as a function of different cadmium and phosphate concentrations. Fatty acids are the fundamental structural components of membrane lipids, and the degree of saturation of the long hydrocarbon chains in microalgae contributes to regulation of growth, biomass production and reproduction of aquatic consumers. This research aimed at evaluating the effects of cadmium (2×10(-8); 10(-7) mol L(-1) Cd) on lipid class and fatty acid composition of the microalga Chlorella vulgaris under varying phosphate (PO(4)(3-)) concentrations (6.0×10(-7) to 2.3×10(-4) mol L(-1)). Under PO(4)(3-) limitation and Cd stress, the storage lipid class triacylglycerol (TAG) was the most accumulated among the lipid classes. Fatty acid composition revealed that the degree of saturation increased with increasing Cd stress and PO(4)(3-) limitation. Decreasing PO(4)(3-) and increasing Cd concentrations resulted in higher saturated fatty acid (SAFA) and monounsaturated FA (MUFA) concentrations. Total polyunsaturated FA (PUFA) and ω3 PUFA, and PUFA:SAFA ratios were higher in the control (2.3×10(-4) mol L(-1) PO(4)(3-)) cells than in either PO(4)(3-) limitation or Cd stress, or in the combination of both stresses. Contrasting with all the other PUFAs, 18:2n - 6 increased as PO(4)(3-) limitation increased. A significant positive relationship of PUFAs, acetone mobile polar lipids (AMPL) and phospholipids (PL) with phosphate concentration in the culture media was obtained, while TAG concentrations had a positive association with total MUFA and SAFA. Total SAFA, 14:0, 18:1n - 9 and 18:2n - 6 were positively correlated with Cd and negatively with PO(4)(3-) concentrations. The microalga responded to combined PO(4)(3-) limitation and Cd exposure by increasing its total lipid production and significantly altering its lipid composition. The FA 18:2n - 6 may be considered a stress biomarker for PO(4)(3-) limitation and Cd stress in C. vulgaris. 22713803 Hierarchical clustering analysis of blood plasma lipidomics profiles from mono- and dizygotic twin families. Twin and family studies are typically used to elucidate the relative contribution of genetic and environmental variation to phenotypic variation. Here, we apply a quantitative genetic method based on hierarchical clustering, to blood plasma lipidomics data obtained in a healthy cohort consisting of 37 monozygotic and 28 dizygotic twin pairs, and 52 of their biological nontwin siblings. Such data are informative of the concentrations of a wide range of lipids in the studied blood samples. An important advantage of hierarchical clustering is that it can be applied to a high-dimensional 'omics' type data, whereas the use of many other quantitative genetic methods for analysis of such data is hampered by the large number of correlated variables. For this study we combined two lipidomics data sets, originating from two different measurement blocks, which we corrected for block effects by 'quantile equating'. In the analysis of the combined data, average similarities of lipidomics profiles were highest between monozygotic (MZ) cotwins, and became progressively lower between dizygotic (DZ) cotwins, among sex-matched nontwin siblings and among sex-matched unrelated participants, respectively. Our results suggest that (1) shared genetic background, shared environment, and similar age contribute to similarities in blood plasma lipidomics profiles among individuals; and (2) that the power of quantitative genetic analyses is enhanced by quantile equating and combination of data sets obtained in different measurement blocks. 23231351 Porphyrin metabolisms in human skin commensal Propionibacterium acnes bacteria: potential application to monitor human radiation risk. Propionibacterium acnes (P. acnes), a Gram-positive anaerobic bacterium, is a commensal organism in human skin. Like human cells, the bacteria produce porphyrins, which exhibit fluorescence properties and make bacteria visible with a Wood's lamp. In this review, we compare the porphyrin biosynthesis in humans and P. acnes. Also, since P. acnes living on the surface of skin receive the same radiation exposure as humans, we envision that the changes in porphyrin profiles (the absorption spectra and/or metabolism) of P. acnes by radiation may mirror the response of human cells to radiation. The porphyrin profiles of P. acnes may be a more accurate reflection of radiation risk to the patient than other biodosimeters/biomarkers such as gene up-/down-regulation, which may be non-specific due to patient related factors such as autoimmune diseases. Lastly, we discuss the challenges and possible solutions for using the P. acnes response to predict the radiation risk. 23525522 Biocomposites of pHEMA with HA/β -TCP (60/40) for bone tissue engineering: Swelling, hydrolytic degradation, and in vitro behavior. The field of bone and cartilage tissue engineering has a pressing need for novel, biocompatible, biodegradable biocomposites comprising polymers with bioceramics or bioglasses to meet numerous requirements for these applications. We created hydrolytically degradable hydrogel/bioceramic biocomposites, comprising poly(2-hydroxyethyl methacrylate) (pHEMA) hydrogels and 50 wt% biphasic hydroxyapatite/β-tricalcium phosphate (60/40) through in situ polymerization. The hydrolytic degradation starts with hydrolysis of the cross-linker, N, O-dimethacryloyl hydroxylamine, which was synthesized in house. Swelling and degradation were examined in details at a phosphate buffered saline solution at 37 °C over a 12-week period of time. To vary degradability, a co-monomer, acrylic acid (AA) or 2-hydroxypropyl methacrylamide (HPMA), was introduced, coupled with altering the concentration of the cross-linker and of the bioceramic. The co-monomer HPMA was found to be more effective than AA in enhancing degradation, though AA led to greater swelling ratios. 33% of weight loss was achieved in some of the biocomposites containing HPMA. Porous structures were developed during swelling and degradation in biocomposites with AA but not in those containing HPMA, suggesting different degradation mechanisms: bulk erosion vs. bulk degradation. Good biocompatibility, as evidenced by attachment and proliferation of mouse-derived osteoblast precursor cells from the MC3T3-E1 lineage, was observed on these biomaterials, regardless of the type of the co-monomer. The rationale and approaches employed here open up new opportunities for creating novel, complex organic-inorganic biomaterials in orthopedic tissue engineering. 23339052 Synthesis of long-circulating, backbone degradable HPMA copolymer-doxorubicin conjugates and evaluation of molecular-weight-dependent antitumor efficacy. Backbone degradable, linear, multiblock N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (DOX) conjugates are synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization followed by chain extension via thiol-ene click reaction. The examination of molecular-weight-dependent antitumor activity toward human ovarian A2780/AD carcinoma in nude mice reveals enhanced activity of multiblock, second-generation, higher molecular weight conjugates when compared with traditional HPMA copolymer-DOX conjugates. The examination of body weight changes during treatment indicates the absence of non-specific adverse effects. 23322705 The regulation of Runx2 by FGF2 and connexin43 requires the inositol polyphosphate/protein kinase Cδ cascade. Connexin43 (Cx43) plays a critical role in osteoblast function and bone mass accrual, yet the identity of the second messengers communicated by Cx43 gap junctions, the targets of these second messengers and how they regulate osteoblast function remain largely unknown. We have shown that alterations of Cx43 expression in osteoblasts can impact the responsiveness to fibroblast growth factor-2 (FGF2), by modulating the transcriptional activity of Runx2. In this study, we examined the contribution of the phospholipase Cγ1/inositol polyphosphate/ PKCδ cascade to the Cx43-dependent transcriptional response of MC3T3 osteoblasts to FGF2. Knockdown of expression and/or inhibition of function of phospholipase Cγ1, inositol polyphosphate multikinase, which generates InsP(4) and InsP(5) , and inositol hexakisphosphate kinase 1/2, which generates inositol pyrophosphates, prevented the ability of Cx43 to potentiate FGF2-induced signaling through Runx2. Conversely, overexpression of phospholipase Cγ1 and inositol hexakisphosphate kinase 1/2 enhanced FGF2 activation of Runx2 and the effect of Cx43 overexpression on this response. Disruption of these pathways blocked the nuclear accumulation of PKCδ and the FGF2-dependent interaction of PKCδ and Runx2, reducing Runx2 transcriptional activity. These data reveal that FGF2-signaling involves the inositol polyphosphate cascade, including IP6K, and demonstrate that IP6K regulates Runx2 and osteoblast gene expression. Additionally, these data implicate the water-soluble inositol polyphosphates as mediators of the Cx43-dependent amplification of the osteoblast response to FGF2, and suggest that these low molecular weight second messengers may be biologically relevant mediators of osteoblast function that are communicated by Cx43-gap junctions. © 2013 American Society for Bone and Mineral Research. 23338044 Electronic and EPR spectra of the species involved in [W10O32]4- photocatalysis. A relativistic DFT investigation. The decatungstate anion [W(10)O(32)](4-) is widely used as a photocatalyst in different transformations, during which it undergoes one-electron reduction to [W(10)O(32)](5-), possibly protonated; the bi-reduced species [W(10)O(32)](6-) is obtained by ensuing disproportionation. Relativistic DFT calculations were used to predict the UV-VIS spectra and EPR parameters of all such species. 23359135 Effect propagation in a toxicokinetic/toxicodynamic model explains delayed effects on the growth of unicellular green algae scenedesmus vacuolatus. Ecotoxicological standard tests assess toxic effects by exposing an organism to high concentrations over defined periods of time. To evaluate toxicity under field conditions such as fluctuating and pulsed exposures, process-based toxicokinetic/toxicodynamic (TK/TD) models may be used for extrapolation from the existing evidence. A TK/TD model was developed that simulates the effect on growth of the green algae Scenedesmus vacuolatus continuously exposed to the model chemicals norflurazon, triclosan, and N-phenyl-2-naphthylamine. A pharmacological time-response model describing the effects of anticancer treatments on cancer cell growth was adapted and modified to model the affected growth of synchronized algae cells. The TK/TD model simulates the temporal effect course by linking the ambient concentration of a chemical to the observable adverse effect via an internal concentration and a sequence of biological events in the organism. The parameters of the toxicodynamic model are related to the growth characteristics of algae cells, a no effect concentration, the chemical efficacy as well as the ability of recovery and repair, and the delay during damage propagation. The TK/TD model fits well to the observed algae growth. The effect propagation through cumulative cell damage explained the observed delayed responses better than just the toxicokinetics. The TK/TD model could facilitate the link between several effect levels within damage propagation, which prospectively may be helpful to model adverse outcome pathways and time-dependent mixture effects. Environ. Toxicol. Chem. 2013;32:1161-1172. © 2013 SETAC. 23563104 A protocol for the classification of wet mass in extrusion-spheronization. In this study, a structured protocol for the classification of wet mass in extrusion-spheronization was developed to predict formation and pellet quality. The wet masses of 120 formulae were prepared taking microcrystalline celluloses as pelletization aid and lactose, hydroxypropyl methylcellulose grades, herbal medicines as model drugs. Physical properties of the wet masses such as hardness, adhesiveness, springiness, cohesiveness, chewiness, and resilience were tested, respectively, using a texture analyzer. Particles were produced by spheronization process, and the quality of spherical pellets was also evaluated. Data were analyzed by principal component analysis, factor analysis, and classification analysis. The wet masses could be classified into five groups taking the ratio of hardness to springiness (Ha/Sp) as the first classification index and chewiness, resilience as the second and the third classification index. The wet masses of different classification could correspondingly form the different shapes. So, a new protocol could be devised, for example, if the range of Ha/Sp of the wet masses was 30,992-47,689g, at the same time, the value of chewiness was less than 4842, and the value of resilience was no more than 0.139; it would form spherical pellets under the experimental condition. These results demonstrate that the proposed protocol could be a valuable asset in a formulation development project to assess the physical properties of wet masses and to predict formation and pellet quality. So, the tedious and expensive pre-production (pre-formulation and optimization) work could be considerably reduced. 23474588 Aortic Distensibility in Type 1 Diabetes. OBJECTIVESTo evaluate the relationship between long-term glycemia, traditional cardiovascular disease (CVD) risk factors, and ascending aortic stiffness in type 1 diabetes.RESEARCH DESIGN AND METHODSEight hundred seventy-nine subjects in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study were evaluated. The stiffness/distensibility of the ascending thoracic aorta (AA) was measured with magnetic resonance imaging. Associations of AA distensibility and CVD risk factors, mean HbA1c, and cardiovascular complications including macroalbuminuria were assessed using multivariate linear regression models.RESULTSThe mean age of the subjects was 50 ± 7 years (47% women, mean diabetes duration of 28 years). Over 22 years of follow-up, 27% of participants had cardiovascular complications. After adjusting for gender and cohort, AA distensibility was lower with increasing age, mean systolic blood pressure, LDL, and HbA1c measured over an average of 22 years (-26.3% per 10 years, -11.0% per 10 mmHg SBP, -1.8% per 10 mg/dL of LDL, and -9.3% per unit mean HbA1c [%], respectively). Patients with macroalbuminuria had 25% lower AA distensibility compared with those without (P < 0.0001). Lower AA distensibility also was associated with greater ratio of left ventricular mass to volume (-3.4% per 0.1 g/mL; P < 0.0001).CONCLUSIONSOur findings indicate strong adverse effects of hypertension, chronic hyperglycemia and macroalbuminuria on AA stiffness in type 1 diabetes in the DCCT/EDIC cohort. 22665062 Nucleophosmin is essential for c-Myc nucleolar localization and c-Myc-mediated rDNA transcription. The transcription factor c-Myc has a critical role in cell proliferation and growth. The control of ribosome biogenesis by c-Myc through the regulation of transcription mediated by all three RNA polymerases is essential for c-Myc-driven proliferation. Specifically, in the nucleolus, c-Myc has been shown to be recruited to ribosomal DNA and activate RNA polymerase (pol) I-mediated transcription of ribosomal RNA (rRNA) genes. In addition, c-Myc accumulates in nucleoli upon inhibition of the proteasome, suggesting nucleolar localization also has a role in c-Myc proteolysis. Nucleophosmin (NPM), a predominantly nucleolar protein, is also critical in ribosome biogenesis and, like c-Myc, is found overexpressed in many types of tumors. Previously, we demonstrated that NPM directly interacts with c-Myc and controls c-Myc-induced hyperproliferation and transformation. Here, we show that NPM is necessary for the localization of c-Myc protein to nucleoli, whereas c-Myc nucleolar localization is independent of p53, Mdm2 and ARF. Conversely, high transient NPM expression enhances c-Myc nucleolar localization, leading to increased c-Myc proteolysis. In addition, NPM is necessary for the ability of c-Myc to induce rRNA synthesis in the nucleolus, and constitutive NPM overexpression stimulates c-Myc-mediated rRNA synthesis. Taken together, these results demonstrate an essential role for NPM in c-Myc nucleolar localization and c-Myc-mediated rDNA transcription. 23239629 High-throughput screening of substrate chemistry for embryonic stem cell attachment, expansion, and maintaining pluripotency. Appropriate surface attachment is essential for growing embryonic stem (ES) cells in an undifferentiated state. It is challenging to identify the optimal surface chemistry of the substrata for ES cell attachment and maintenance. Using a rapid, high-throughput polymerization and screening platform with a comprehensive library of 66 monomer-grafted membrane surfaces, the optimal substrate, N-[3-(dimethylamino)propyl] methacrylamide (DMAPMA) has been identified to support strong attachment, high expansion capacity, and long-term self-renewal of ES cells (up to 7 passages). This monomer-based, chemically defined, scalable, sustainable, relatively inexpensive, covalently grafted, and controllable polymeric substrate provides a new opportunity to manipulate surface chemistry for pluripotent stem culture. 23091168 Multiple NSAID-induced hits injure the small intestine: underlying mechanisms and novel strategies. Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause serious gastrointestinal (GI) injury including jejunal/ileal mucosal ulceration, bleeding, and even perforation in susceptible patients. The underlying mechanisms are largely unknown, but they are distinct from those related to gastric injury. Based on recent insights from experimental models, including genetics and pharmacology in rodents typically exposed to diclofenac, indomethacin, or naproxen, we propose a multiple-hit pathogenesis of NSAID enteropathy. The multiple hits start with an initial pharmacokinetic determinant caused by vectorial hepatobiliary excretion and delivery of glucuronidated NSAID or oxidative metabolite conjugates to the distal small intestinal lumen, where bacterial β-glucuronidase produces critical aglycones. The released aglycones are then taken up by enterocytes and further metabolized by intestinal cytochrome P450s to potentially reactive intermediates. The "first hit" is caused by the NSAID and/or oxidative metabolites that induce severe endoplasmic reticulum stress or mitochondrial stress and lead to cell death. The "second hit" is created by the significant subsequent inflammatory response that would follow such a first-hit injury. Based on these putative mechanisms, strategies have been developed to protect the enterocytes from being exposed to the parent NSAID and/or oxidative metabolites. Among these, a novel strategy already demonstrated in a murine model is the selective disruption of bacteria-specific β-glucuronidases with a novel small molecule inhibitor that does not harm the bacteria and that alleviates NSAID-induced enteropathy. Such mechanism-based strategies require further investigation but provide potential avenues for the alleviation of the GI toxicity caused by multiple NSAID hits. 23331575 Semi-Synthetic Mithramycin SA Derivatives with Improved AntiCancer Activity. Mithramycin (MTM) is a potent anti-cancer agent that has recently garnered renewed attention. This manuscript describes the design and development of mithramycin derivatives through a combinational approach of biosynthetic analogue generation followed by synthetic manipulation for further derivatization. Mithramycin SA is a previously discovered analogue produced by the M7W1 mutant strain alongside the improved mithramycin analogues mithramycin SK and mithramycin SDK. Mithramycin SA shows decreased anti-cancer activity compared to mithramycin and has a shorter, two carbon aglycon side chain that is terminated in a carboxylic acid. The aglycon side chain is responsible for an interaction with the DNA-phosphate backbone as mithramycin interacts with its target DNA. It was therefore decided to further functionalize this side chain through reactions with the terminal carboxylic acid in an effort to enhance the interaction with the DNA phosphate backbone and improve the anti-cancer activity. This side chain was modified with a variety of molecules increasing the anti-cancer activity to a comparable level to mithramycin SK. This work shows the ability to transform the previously useless mithramycin SA into a valuable molecule and opens the door to further functionalization and semi-synthetic modification for the development of molecules with increased specificity and/or drug formulation. 23287390 Role for membrane remodeling in cell death: implication for health and disease. Recently it has become clear that exposure to xenobiotics may result in various forms of cell death; not only passive cell deaths like necrosis, or programmed cell deaths such as apoptosis, but also regulated necrosis, autophagy, senescence, or mitotic catastrophe. Complex cell signaling networks influence the processing of cell death. Furthermore, recent research has revealed early complex molecular interactions between organelles prior to the final triggering of cell death. The plasma membrane may play an important role in the early cell death signaling events. Regarding this latter aspect, drugs and environmental pollutants have been reported to affect plasma membrane characteristics which may further affect cell fate. Changes in membrane fluidity or in composition and function of specialized membrane microdomains (plasma membrane remodeling) have been proven to be involved in the regulation of many important physiological signaling pathways, including cell death. Furthermore, it has been suggested that a crosstalk between chemical-induced cellular membrane effects and other organelles may be of vital importance to explain the final outcome of chemical exposure. Here, we review the effects of plasma membrane remodeling on cell survival and cell death; we describe how the cell signaling pathways activated by changes in plasma membrane characteristics may influence cell fate. Since plasma membrane function plays an important role in the regulation of a number of cellular responses, it has been implicated in the development or progress of several diseases. A better knowledge of the effects of various chemicals on plasma membrane remodeling may be important for understanding the pathogenesis of major diseases, and may assist in developing new therapeutic strategies. 23017405 Transglutaminase cross-linking effect on sensory characteristics and antioxidant activities of Maillard reaction products from soybean protein hydrolysates. To improve the yield of Maillard peptides, a microbial transglutaminase (MTGase) was used to increase the content of 1000-5000Da peptides in soybean protein hydrolysates by using a cross-linking reaction. The sensory characteristics and antioxidant activities of corresponding Maillard Reaction Products (MSPC) was then evaluated. After cross-linking treatment the content of 1000-5000Da peptides in protein hydrolysates and the yield of Maillard peptides increased by 21.19% and 8.71%, respectively, which contributed to the improved mouthfulness of MSPC. The bitter amino acids were significantly decreased and the umami acids were markedly increased in MSPC. Volatile compounds identified by GC-MS analysis showed that the content of the important meaty flavour compounds (such as 2-methyl-3-furanthiol, bis(2-methyl-3-furyl)disulfide) of MSPC were dramatically higher than that of MRPs from uncross-linking peptides. Combined with sensory evaluation, it was confirmed that MTGase cross-linking improved the flavour Characteristics and did not affect the antioxidant activity of MSPC. 23481176 Efficient MRI labeling of endothelial progenitor cells: Design of thiolated surface stabilized superparamagnetic iron oxide nanoparticles. The aim of this study was to design thiolated surface stabilized superparamagnetic iron oxide nanoparticles (TSS-SPIONs) for efficient internalization with high MRI sensitivity. TSS-SPIONs were developed by chelation between thiolated chitosan-thioglycolic acid (chitosan-TGA) hydrogel and iron ions (Fe(2+)/Fe(3+)). Likely, unmodified chitosan hydrogel SPIONs (UC-SPIONs) and uncoated SPIONs were used as control. Moreover, TSS-SPIONs were investigated regarding to their iron core size, hydrodynamic diameter, zeta potential, iron contents, molar relaxivities (r1 and r2), and cellular internalization. TSS-SPIONs demonstrated an iron oxide core diameter (crystallite size by XRD) of 3.1±0.02nm, a hydrodynamic diameter of 94±20nm, a zeta potential of +21±5mV, and an iron content of 3.6±0.9mg/mL. In addition, internalization of TSS-SPIONs into human endothelial progenitor cells (EPC) from umbilical cord blood was more than threefold and 17-fold higher in contrast to UC-SPIONs and SPIONs, respectively. With twofold lower incubation iron concentration of TSS-SPIONs, more than threefold higher internalization was achieved as compared to Resovist®. Also, cell viability of more than 90% was observed in the presence of TSS-SPIONs after 24h. The molar MR relaxivities (r2) value at 1.5T was threefold higher than that of Resovist® and demonstrated that TSS-SPIONs have the potential as very effective T2 contrast-enhancement agent. According to these findings, TSS-SPIONs with efficient internalization, lower cytotoxicity, and high MRI sensitivity seem to be promising for cell tracking. 23329687 Lack of dosage compensation accompanies the arrested stage of sex chromosome evolution in ostriches. Sex chromosome evolution is usually seen as a process that, once initiated, will inevitably progress toward an advanced stage of degeneration of the nonrecombining chromosome. However, despite evidence that avian sex chromosome evolution was initiated >100 Ma, ratite birds have been trapped in an arrested stage of sex chromosome divergence. We performed RNA sequencing of several tissues from male and female ostriches and assembled the transcriptome de novo. A total of 315 Z-linked genes fell into two categories: those that have equal expression level in the two sexes (for which Z-W recombination still occurs) and those that have a 2-fold excess of male expression (for which Z-W recombination has ceased). We suggest that failure to evolve dosage compensation has constrained sex chromosome divergence in this basal avian lineage. Our results indicate that dosage compensation is a prerequisite for, not only a consequence of, sex chromosome evolution. 23519365 Compositional-asymmetry influenced non-linear optical processes of plasmonic nanoparticle dimers. The influences of compositional asymmetry on the two-photon photoluminescence and the second harmonic generation processes in weakly coupled plasmonic dimers were addressed. Au-Au homodimer and Au-Ag heterodimer arrays produced using electron-beam lithography were investigated using confocal nonlinear optical imaging and spectroscopy. Compared to the Au-Au homodimers, the Au-Ag dimers showed slightly broadened two-photon photoluminescence near the X symmetry point at the first Brillouin zone of Au, whilst that from the L symmetry point stayed the same. Additionally, weakly coupled Au-Ag heterodimers generated strong second harmonic signals which were invisible in the Au-Au homodimers. The observations highlighted the importance of compositional asymmetry in the non-linear optical studies of plasmonic dimers. 23348055 The male mammary gland: a target for the xenoestrogen bisphenol A. Males of some strains of mice retain their mammary epithelium even in the absence of nipples. Here, we have characterized the mammary gland in male CD-1 mice both in whole mounts and histological sections. We also examined the effects of bisphenol A (BPA), an estrogen mimic that alters development of the female mouse mammary gland. BPA was administered at a range of environmentally relevant doses (0.25-250μg/kg/day) to pregnant and lactating mice and then the mammary glands of male offspring were examined at several periods in adulthood. We observed age- and dose-specific effects on mammary gland morphology, indicating that perinatal BPA exposures alter the male mammary gland in adulthood. These results may provide insight into gynecomastia, the most common male breast disease in humans, where proliferation of the mammary epithelium leads to breast enlargement. 23587648 Regulation of connexin hemichannel activity by membrane potential and the extracellular calcium in health and disease. Connexins are thought to solely mediate cell-to-cell communication by forming gap junction channels composed of two membrane-spanning hemichannels positioned end-to-end. However, many if not all connexin isoforms also form functional hemichannels (i.e., the precursors of complete channels) that mediate the rapid exchange of ions, second messengers and metabolites between the cell interior and the interstitial space. Electrical and molecular signaling via connexin hemichannels is now widely recognized to be important in many physiological scenarios and pathological conditions. Indeed, mutations in connexins that alter hemichannel function have been implicated in several diseases. Here, we present a comprehensive overview of how hemichannel activity is tightly regulated by membrane potential and the external calcium concentration. In addition, we discuss the genetic mutations known to alter hemichannel function and their deleterious effects, of which a better understanding is necessary to develop novel therapeutic approaches for diseases caused by hemichannel dysfunction. This article is part of a Special Issue entitled 'Connexin based channels'. 23588563 Aspects of physicians' attitudes towards the rational use of drugs at a training and research hospital: a survey study. PURPOSE: The rational use of drugs (RUD) is primarily the responsibility of physicians. The aim of this study was to investigate whether physicians are aware of RUD principles and how they apply them in daily medical practice. METHODS: A total 136 physicians working at the Kartal Training and Research Hospital in Istanbul were enrolled in the study between February and March 2012. A face-to-face interview was conducted with physicians to assess their knowledge and attitude regarding RUD. RESULTS: A large majority of the physicians declared that consultation time was insufficient (84 %). The data obtained from the survey indicate that 54 % of the enrolled physicians monitored the therapeutic outcome and that 27 % found the information given to the patient to be sufficient. Participating physicians stated that the less known characteristics of the drugs they prescribed were drug interactions, traceability in market, and price. The most preferred reference source was Vademecum (a drug guideline prepared by the private sector). Two major factors contributing to prescribing patterns were "self study" and "observation of teachers" at clinical training. There was a significant difference between internists-surgeons and residents-specialists in the number of prescribed drugs per prescription (p < 0.001) and in the information provided to the patient on the prescribed drugs (name, effect, dose, instructions, possible side effect) (p < 0.05), respectively. CONCLUSIONS: Our findings overall show that the principles of RUD were not fully applied in daily medical practice by the participating physicians. One important reason for this is a heavy patient load, which requires a change in managerial practices within the healthcare system. The other, more essential explanation is education; consequently, serious consideration should be given to including effective clinical pharmacotherapy training and RUD courses in the medical education curriculum. 23411240 Root tubers of Lactuca tuberosa as a source of antioxidant phenolic compounds and new furofuran lignans. From the root tubers of Lactuca tuberosa, a wild edible plant species, nine phenolic compounds were isolated, including two new furofuran lignan glucosides, named lactuberin A and lactuberin B. Their structures were elucidated by spectroscopic methods, especially HRESIMS and 2D NMR techniques. This is the first time that compounds belonging to the epi series of 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane type furofuran lignans have been found in Lactuca species. The total phenolic content of the root tuber extract was evaluated and its major phenolic constituents, caffeic acid, chlorogenic acid and 3,5 dicaffeoylquinic acid, known to possess antioxidant activity, were quantified. Additionally, the root tuber extract showed DPPH radical scavenging activity implying its potential as functional food. 23202852 Hybrid furoxanyl N-acylhydrazone derivatives as hits for the development of neglected diseases drug candidates. Neglected diseases represent a major health problem. It is estimated that one third of the world population is infected with tuberculosis and additionally Leishmaniosis and Chagas disease affect approximately 30 million people. N-Acylhydrazone moiety is a repeated functional group present in several prototypes and drug candidates for these neglected diseases. On the other hand, furoxan system has been studied as pharmacophore for Leishmaniosis and Chagas diseases. Here we report on the design and preparation of forty hybrid furoxanyl N-acylhydrazones and on their activity on Mycobacterium tuberculosis, H37Rv and MDR strains, Trypanosoma cruzi, and Leishmania amazonensis. Among them, four derivatives displayed excellent to good selectivity indexes against the three different microorganisms. Hybrid compound N'-(4-phenyl-3-furoxanylmethylidene)isoniazide 9 showed the best antibacterial profile with MIC value 4.5 lesser than the value for the reference isoniazid against MDR strain. Furoxanyl N-acylhydrazone (E)-2-methyl-N'-(4-phenyl-3-furoxanylmethylidene)-4H-imidazo[1,2-a]pyridine-3-carbohydrazide 15 was ten-fold more potent against T. cruzi Amastigotes than the standard drug nifurtimox. On the other hand, derivatives (E)-N'-(5-benzofuroxanylmethylidene)benzo[d][1,3]dioxole-5-carbohydrazide 25 and (E)-N'-(4-hydroxy-3-methoxyphenylmethylidene)-3-methylfuroxan-4-carbohydrazide 37 emerged as leads for the development of new leishmanicidal agents. The adequate stability, in simulated biological system and plasma, and the lack of mutagenicity of these derivatives allow us to propose them as candidates for further pre-clinical studies. 23194548 Purification, physicochemical characterisation and anticancer activity of a polysaccharide from Cyclocarya paliurus leaves. A Cyclocarya paliurus (Batal.) Iljinskaja polysaccharide (CPP) was isolated and purified by hot water extraction, ethanol precipitation, deproteinisation and anion-exchange chromatography. Its physicochemical properties were characterised by gel permeation chromatography (GPC), gas chromatography-mass spectrometry (GC-MS), thermal gravimetric analysis (TGA), Fourier transform infrared spectrometry (FTIR), UV-visible spectrophotometry, dynamic light scattering (DLS) and viscometry analysis. The anticancer effect of CPP in human gastric cancer HeLa cells was also evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The results showed that the molecular weight of CPP was 900 kDa, and it contained 64.8% total sugar, 23.5% uronic acid, 9.26% protein, and six kinds of monosaccharides, including glucose, rhamnose, arabinose, xylose, mannose and galactose, with molar percentages of 32.7%, 9.33%, 30.6%, 3.48%, 10.4%, and 13.5%, respectively. Furthermore, the results showed that CPP exhibited a strong inhibition effect on the growth of human gastric cancer HeLa cells. 23169610 The role of cytochrome P450-dependent metabolism in the regulation of mouse hepatic growth hormone signaling components and target genes by 3-methylcholanthrene. 3-Methylcholanthrene (MC) is a readily metabolized aryl hydrocarbon receptor (AHR) agonist. MC disrupts expression of mouse hepatic growth hormone (GH) signaling components and suppresses cytochrome P450 2D9 (Cyp2d9), a male-specific gene controlled by pulsatile GH via signal transducer and activator of transcription 5b (STAT5b). To determine if these effects of MC depend on hepatic microsomal P450-mediated activity, we examined biologic responses to MC treatment in liver Cpr-null (LCN) mice with hepatocyte-specific conditional deletion of NADPH-cytochrome P450 oxidoreductase (POR). MC caused mild induction of Por and a hepatic inflammatory marker in wild-type mice, whereas MC caused strong induction of AHR target genes, Cyp1a1, Cyp1a2, and Cyp1b1 in wild-type and LCN mice. Two mouse hepatic STAT5b target genes, Cyp2d9 and major urinary protein 2 (Mup2), were suppressed by MC in wild-type mice, and the CYP2D9 mRNA response was maintained in LCN mice. In wild-type mice only, MC decreased hepatic GH receptor (GHR) mRNA but increased GHR protein levels. There was an apparent impairment of STAT5 phosphorylation by MC in wild-type and LCN mice, but large interanimal variation prevented achievement of statistical significance. In vehicle-treated mice, basal levels of MUP2 mRNA, GHR mRNA, GHR protein, and the activation status of extracellular signal-regulated kinase 2 and Akt were influenced by hepatic Por genetic status. These results indicate that the effects of MC on hepatic GH signaling components and target genes are complex, involving aspects that are both dependent and independent of hepatic microsomal P450-mediated activity. 23353081 History of scorpion antivenom: One Arizonan's view. This paper was originally presented as the Elsevier Lecture in July, 2012 at the International Society on Toxinology/Venom Week combined meeting in Honolulu, Hawaii. In it, the author addresses the ancient history of venom and immunity, from the Silurian Era to the 1890s; the development of the first antivenoms; the impact of shifting political and economic pressures; the special case of Arizona; the relative stability of the 1960s through 1990s; the transition to regulatory compliance that took place at the time of the author's own research; and concluding thoughts regarding the instability of apparent success. 23123662 Contributions of rat Ctr1 to the uptake and toxicity of copper and platinum anticancer drugs in dorsal root ganglion neurons. Dorsal root ganglion (DRG) neurons are affected by platinum-induced neurotoxicity and neurodegenerative processes associated with disturbed copper homeostasis and transport. This study aimed to understand the role of copper transporter 1 (Ctr1) in the uptake and toxicity of copper and platinum drugs in cultured rat DRG neurons, and the functional activities of rat Ctr1 (rCtr1) as a membrane transporter of copper and platinum drugs. Heterologous expression of rCtr1 in HEK293 cells (HEK/rCtr1 cells) increased the uptake and cytotoxicity of copper, oxaliplatin, cisplatin and carboplatin, in comparison to isogenic vector-transfected control cells. Cultured rat DRG neurons endogenously expressed rCtr1 protein on their neuronal cell body plasma membranes and cytoplasm, and displayed substantial capacity for taking up copper, but were resistant to copper toxicity. The uptake of copper by both cultured rat DRG neurons and HEK/rCtr1 cells was saturable and inhibited by cold temperature, silver and zinc, consistent with it being mediated by rCtr1. Cultured rat DRG neurons accumulated platinum during their exposure to oxaliplatin and were sensitive to oxaliplatin cytotoxicity. The accumulation of platinum by both cultured rat DRG neurons and HEK/rCtr1 cells, during oxaliplatin exposure, was saturable and temperature dependent, but was inhibited by copper only in HEK/rCtr1 cells. In conclusion, rCtr1 can transport copper and platinum drugs, and sensitizes cells to their cytotoxicities. DRG neurons display substantial capacity for accumulating copper via a transport process mediated by rCtr1, but appear able to resist copper toxicity and use alternative mechanisms to take up oxaliplatin. 23338843 Local deposition of anisotropic nanoparticles using scanning electrochemical microscopy (SECM). We demonstrate localized electrodeposition of anisotropic metal nanoobjects, namely Au nanorods (GNR), on indium tin oxide (ITO) using scanning electrochemical microscopy (SECM). A gold microelectrode was the source of the gold ions whereby double pulse chronoamperometry was employed to generate initially Au seeds which were further grown under controlled conditions. The distance between the microelectrode and the ITO surface as well as the different experimental parameters (electrodeposition regime, solution composition and temperature) were optimized to produce faceted gold seeds with the required characteristics (size and distribution). Colloidal chemical synthesis was successfully exploited for better understanding the role of the surfactant and different additives in breaking the crystallographic symmetry and anisotropic growth of GNR. Experiments performed in a conventional three-electrode cell revealed the most appropriate electrochemical conditions allowing high yield synthesis of nanorods with well-defined shape as well as nanocubes and bipyramids. 23288298 Drug repositioning by structure-based virtual screening. Approved drugs have favourable or validated pharmacokinetic properties and toxicological profiles, and the repositioning of existing drugs for new indications can potentially avoid expensive costs associated with early-stage testing of the hit compounds. In recent years, technological advances in virtual screening methodologies have allowed medicinal chemists to rapidly screen drug libraries for therapeutic activity against new biomolecular targets in a cost-effective manner. This review article outlines the basic principles and recent advances in structure-based virtual screening and highlights the powerful synergy of in silico techniques in drug repositioning as demonstrated in several recent reports. 22935038 Postpartum corticosterone administration reduces dendritic complexity and increases the density of mushroom spines of hippocampal CA3 arbours in dams. Postpartum depression (PPD) affects approximately 15% of mothers after giving birth. A complete understanding of depression during the postpartum period has yet to be established, although disruptions in the hypothalamic-pituitary-adrenal axis and stress during the postpartum may be involved. To model these components in rats, we administered high corticosterone (CORT) postpartum, which increases immobility in the forced swim test (FST), and reduces maternal care, body weight and hippocampal cell proliferation in dams. The hippocampus is altered in response to chronic stress, exposure to high glucocorticoids and in major depression in humans. In the present study, we examined whether high CORT reduced dendritic complexity and spines in the CA3 region of the hippocampus. Additionally, housing complexity was manipulated so that dams and litters were housed either with tubes (complex) or without tubes (impoverished) to investigate the consequences of new animal care regulations. Dams received 40 mg/kg/day of CORT or oil starting on day 2 postpartum for 23 days. Maternal behaviours were assessed on postpartum days 2-8 and dams were tested using the FST on days 21 and 22. Dams were killed on day 24 and brains were processed for Golgi impregnation. Pyramidal cells in the CA3 subfield were traced using a camera lucida and analysed for branch points and dendritic complexity, as well as spine density and type on both basal and apical arbours. As previously established, high CORT postpartum reduced maternal care and increased immobility in the FST, which is a measure of depressive-like behaviour. High CORT postpartum reduced the complexity of basal arbours and increased mushroom spines on both apical and basal dendrites. Housing complexity had no effect on spines of CA3 pyramidal cells but modest effects on cell morphology. These data show that chronic high CORT in postpartum females alters hippocampal morphology and may provide insight regarding the neurobiological consequences of high stress or CORT during the postpartum period, as well as be relevant for postpartum stress or depression. 23197773 Analysis of tolerance and behavioral/physical dependence during chronic CB1 agonist treatment: effects of CB1 agonists, antagonists, and noncannabinoid drugs. Behavioral studies of chronic CB(1) receptor activation may provide a pharmacological approach to understanding efficacy-related differences among CB(1) ligands as well as mechanistic commonalities between cannabinoid and noncannabinoid drugs. In the present studies, the effects of CB(1) agonists [(6aR,10aR)-3-(1-adamantyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydrobenzo[c]chromen-1-ol (AM411), 9β-(hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol (AM4054), R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN55,212.2), Δ(9)-tetrahydrocannabinol (Δ(9)-THC), (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide (methanandamide)], CB(1) antagonists [5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (SR141716A), 5-(4-alkylphenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (AM4113)], and dopamine (DA)-related [methamphetamine, (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF82958), (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390), (6aR)-5,6,6a,7-tetrahydro-6-propyl-4H-dibenzo[de,g]quinoline-10,11-diol (R-(-)-NPA), haloperidol] and opioid (morphine, naltrexone) drugs on scheduled-controlled responding under a 30-response fixed ratio schedule of stimulus-shock termination in squirrel monkeys were compared before and during chronic treatment with the long-acting CB(1) agonist AM411 (1.0 mg/kg per day, i.m.). Prechronic treatment with all drugs except naltrexone (1-10 mg/kg) produced dose-related decreases in responses rates. Dose-response re-determinations during chronic treatment revealed the following: 1) >250-fold (AM411, methanandamide) and >45-fold (AM4054, WIN55,212.2, Δ(9)-THC) rightward shifts in the ED(50) values for CB(1) agonists; 2) >100-fold and >20-fold leftward shifts in the ED(50) values for SR141716A and AM4113, respectively; and 3) approximately 4.8-fold and 10-fold rightward shifts in the ED(50) values for methamphetamine and the DA D(2) agonist R-(-)-NPA, respectively. Dose-response relationships for other DA-related and opioid drugs were unchanged by chronic CB(1) agonist treatment. Differences in the magnitude of tolerance among CB(1) agonists during chronic treatment may be indicative of differences in their pharmacological efficacy, whereas the enhanced sensitivity to behaviorally disruptive effects of CB(1) antagonists may provide evidence for CB(1)-related behavioral and/or physical dependence. Finally, the development of cross-tolerance to methamphetamine and R-(-)-NPA bolsters previous evidence of interplay between CB(1) and DA D(2) signaling mechanisms. 23541514 Development of PVP/PEG mixtures as appropriate carriers for the preparation of drug solid dispersions by melt mixing technique and optimization of dissolution using artificial neural networks. The effect of plasticizer's (PEG) molecular weight (MW) on PVP based solid dispersions (SDs), prepared by melt mixing, was evaluated in the present study using Tibolone as a poorly water soluble model drug. PEGs with MW of 400, 600, and 2000g/mol were tested, and the effect of drug content, time and temperature of melt mixing on the physical state of Tibolone, and the dissolution characteristics from SDs was investigated. PVP blends with PEG400 and PEG600 were completely miscible, while blends were heterogeneous. Furthermore, a single Tg recorded in all samples, indicating that Tibolone was dispersed in a molecular lever (or in the form of nanodispersions), varied with varying PEG's molecular weight, melt mixing temperature, and drug content, while FTIR analysis indicated significant interactions between Tibolone and PVP/PEG matrices. All prepared solid dispersion showed long-term physical stability (18months in room temperature). The extent of interaction between mixture components was verified using Fox and Gordon-Taylor equations. Artificial neural networks, used to correlate the studied factors with selected dissolution characteristics, showed good prediction ability. 23246798 Preparation of highly porous gastroretentive metformin tablets using a sublimation method. The present investigation is aimed to formulate floating gastroretentive tablets containing metformin using a sublimation material. In this study, the release of the drug from a matrix tablet was highly dependent on the polymer concentrations. In all formulations, initial rapid drug release was observed, possibly due to the properties of the drug and polymer. The effect of the amount of PEO on swelling and eroding of the tablets was determined. The water-uptake and erosion behavior of the gastroretentive (GR) tablets were highly dependent on the amount of PEO. The water-uptake increased with increasing PEO concentration in the tablet matrix. The weight loss from tablets decreased with increasing amounts of PEO. Camphor was used as the sublimation material to prepare GR tablets that are low-density and easily floatable. Camphor was changed to pores in the tablet during the sublimation process. SEM revealed that the GR tablets have a highly porous morphology. Floating properties of tablets and tablet density were affected by the sublimation of camphor. Prepared floating gastroretentive tablets floated for over 24 h and had no floating lag time. However, as the amount of camphor in the tablet matrix increased, the crushing strength of the tablet decreased after sublimation. Release profiles of the drug from the GR tablets were not affected by tablet density or porosity. In pharmacokinetic studies, the mean plasma concentration of the GR tablets after oral administration was greater than the concentration of glucophase XR. Also, the mean AUC(0-∞) values for the GR tablets were significantly greater than the plasma concentrations of glucophase XR. 23445219 Rapid method for the separation and recovery of endocrine-disrupting compound bisphenol AP from wastewater. The removal of bisphenol AP (BPAP) by a multiwalled carbon nanotube (MWCNT) was investigated. BPAP, representing typical scenarios for the BPAP-MWCNT interactions, was employed as a probe molecule. It was found that BPAP exhibited great adsorptive affinity to MWCNT, and the adsorption kinetics equilibrium was arrived within 4.0 min following the pseudo-second-order model. The overall rate process was mainly controlled by the external mass transfer. The hydrogen bond, hydrophobic, and π-π stacking interactions were dominant factors for the strong adsorption of BPAP, instead of the pH ionic strength and other ionic species in contaminated water. The MWCNT has higher stability within 8 removal-regeneration recycles, and up to 95% of recovery could be obtained by eluting the adsorbed BPAP on MWCNT adsorbent using ethanol/sodium hydrate solution. The results of the experiment on real samples verified the effectiveness for the recovery and removal of BPAP from wastewater samples. 23260350 Identification of benzofuran central cores for the inhibition of leukotriene A(4) hydrolase. Leukotrienes (LT's) are known to play a physiological role in inflammatory immune response. Leukotriene A(4) hydrolase (LTA(4)H) is a cystolic enzyme that stereospecifically catalyzes the transformation of LTA(4) to LTB(4). LTB(4) is a known pro-inflammatory mediator. This paper describes the identification and synthesis of substituted benzofurans as LTH(4)H inhibitors. The benzofuran series demonstrated reduced mouse and human whole blood LTB(4) levels in vitro and led to the identification one analog for advanced profiling. Benzofuran 28 showed dose responsive target engagement and provides a useful tool to explore a LTA(4)H inhibitor for the treatment of inflammatory diseases, such as asthma and inflammatory bowel disease (IBD). 23353753 Novel agmatine dipeptide inhibitors against the West Nile virus NS2B/NS3 protease: A P3 and N-cap optimization study. This communication describes the synthesis and inhibitory activities of thirty-seven novel C-terminal agmatine dipeptides used as screening compounds to study the structure-activity relationship between active-site peptidomimetics and the West Nile virus (WNV) NS2B/NS3 serine protease. Our efforts lead to the discovery of a novel agmatine dipeptide inhibitor (compound 33, IC50 2.6 ± 0.3 μM) with improved inhibitory activity in comparison to the most potent inhibitor described in our recent report [IC50 4.7 ± 1.2 μM; Lim et al., Eur. J. Med. Chem. 46 (2011) 3130-3134]. In addition, our study cleared the contention surrounding the previous X-ray co-crystallization study and an enzyme inhibition report on the binding conformation adopted by active-site peptide aldehydes. Our data should provide valuable insights into the design of future peptidomimetic antivirals against WNV infections. 23380916 Impairing effect of amphetamine and concomitant ionotropic glutamate receptors blockade in the ventral striatum on spatial learning in mice. RATIONALE: Accumulating evidence supports the involvement of the ventral striatum (VS) in spatial information processing. The multiple cortical glutamatergic and mesolimbic dopaminergic (DAergic) afferences on the same neurons in the ventral striatum provide the neuroanatomical substrate for glutamate and dopamine functional interaction. However, there is little evidence in the literature on how this interaction affects the ability to encode spatial information. OBJECTIVE: First, we evaluated the effect of intra-VS bilateral infusion of different doses of amphetamine (0.3, 0.75, and 1.5 μg/side) on the ability to detect spatial novelty in mice. Next, we examined the impact produced on the same abilities by intra-VS infusion of ineffective doses of amphetamine (0.3 μg/side) in association with N-methyl-D-aspartate (NMDA) (3.125 ng/side) or α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) (0.25 ng/side) receptor antagonist. RESULTS: The results show that infusion of amphetamine impairs detection of spatial novelty, affecting also exploratory activity and marginally the detection of nonspatial novelty. In contrast, an association of subthreshold doses of amphetamine with NMDA or AMPA receptor antagonists exerted a selective effect on reactivity to a spatial change. CONCLUSIONS: These findings demonstrate that enhanced DAergic activity in the VS enhances glutamate receptor antagonist-induced impairment in learning and memory. 23534553 Engineering the Microstructure of Electrospun Fibrous Scaffolds by Microtopography. Controlling the structure and organization of electrospun fibers is desirable for fabricating scaffolds and materials with defined microstructures. However, the effects of microtopography on the deposition and, in turn, the organization of the electrospun fibers are not well understood. In this study, conductive polydimethylsiloxane (PDMS) templates with different micropatterns were fabricated by combining photolithography, silicon wet etching, and PDMS molding techniques. The fiber organization was varied by fine-tuning the microtopography of the electrospinning collector. Fiber conformity and alignment were influenced by the depth and the slope of microtopography features, resulting in scaffolds comprising either an array of microdomains with different porosity and fiber alignment or an array of microwells. Microtopography affected the fiber organization for hundreds of micrometers below the scaffold surface, resulting in scaffolds with distinct surface properties on each side. In addition, the fiber diameter was also affected by the fiber conformity. The effects of the fiber arrangement in the scaffolds on the morphology, migration, and infiltration of cells were examined by in vitro and in vivo experiments. Cell morphology and organization were guided by the fibers in the microdomains, and cell migration was enhanced by the aligned fibers and the three-dimensional scaffold structure. Cell infiltration was correlated with the microdomain porosity. Microscale control of the fiber organization and the porosity at the surface and through the thickness of the fibrous scaffolds, as demonstrated by the results of this study, provides a powerful means of engineering the three-dimensional structure of electrospun fibrous scaffolds for cell and tissue engineering. 23617223 In Vitro Activity of Paclitaxel-Loaded Polymeric Expansile Nanoparticles in Breast Cancer Cells. Through a series of in vitro studies, the essential steps for intracellular drug delivery of paclitaxel using a pH-responsive nanoparticle system have been investigated in breast cancer cells. We successfully encapsulated paclitaxel within polymeric expansile nanoparticles (Pax-eNPs) at 5% loading via a miniemulsion polymerization procedure. Fluorescently tagged eNPs were readily taken up by MDA-MB-231 breast cancer cells grown in culture as confirmed by confocal microscopy and flow cytometry. The ability of the encapsulated paclitaxel to reach the cytoplasm was also observed using confocal microscopy and fluorescently labeled paclitaxel. Pax-eNPs were shown to be efficacious against three in vitro human breast adenocarcinoma cell lines (MDA-MB-231, MCF-7 and SK-BR-3) as well as cells isolated from the pleural effusions of two different breast cancer patients. Lastly, macropinocytosis was identified as the major cellular pathway responsible for eNP uptake, as confirmed using temperature-sensitive metabolic reduction, pharmacologic inhibitors, and fluid-phase marker co-localization. 23210789 Therapeutically important proteins from in vitro plant tissue culture systems. Plant cells cultured in liquid medium in bioreactors are now being used commercially to produce biopharmaceutical proteins. The emergence of in vitro plant cell culture as a production vehicle reflects the importance of key biosafety and biocontainment concerns affecting the competitiveness of alternative systems such as mammalian cell culture and agriculture. Food plant species are particularly attractive as hosts for in vitro protein production: the risk of transgene escape and food chain contamination is eliminated using containment facilities, while regulatory approval for oral delivery of drugs may be easier than if non-edible species were used. As in whole plants, proteolysis in cultured plant cells can lead to significant degradation of foreign proteins after synthesis; however, substantial progress has been made to counter the destructive effects of proteases in plant systems. Although protein secretion into the culture medium is advantageous for product recovery and purification, measures are often required to minimise extracellular protease activity and product losses due to irreversible surface adsorption. Disposable plastic bioreactors, which are being used increasingly in mammalian cell bioprocessing, are also being adopted for plant cell culture to allow rapid scale-up and generation of saleable product. This review examines a range of technical and regulatory issues affecting the choice of industrial production platform for foreign proteins, and assesses progress in the development of in vitro plant systems for biopharmaceutical production. 23494904 Solution-processible highly conducting fullerenes. n-Doping of solution-processible organic semiconductors: highly conductive fullerenes are demonstrated through solution-processed fulleropyrrolidinium iodide (FPI) and FPI-doped PCBM to reach a high conductivity (3.2 S/m). The n-doping proceeds via anion-induced electron transfer between the iodide on FPI and the fullerene in the solid state. 23588252 Changes in mRNA and protein expression in the renal cortex of male and female F344 rats treated with bromate. Bromate (BrO3 (-)), a by-product of ozonation of drinking water, induces nephrotoxicity in male rats at much lower doses than in female rats. This difference appears to be related to the development of α-2u-globulin nephropathy in males. To determine sex-dependent changes in mRNA and protein expression in the renal cortex attributable to α-2u-globulin nephropathy, we performed microarray and immunohistochemical analyses in proximal renal tubules of male and female F344 rats treated with KBrO3 for 28 days. Particular attention was paid to molecular biomarkers of renal tubular injury. Microarray analysis of male and female rats treated with BrO3 (-) at low doses (125 mg/L KBrO3) displayed marked sex-dependent changes in renal gene expression. The greatest differences were seen in genes encoding for cellular differentiation, apoptosis, ion transport, and cell proliferation. Differences by sex were especially prominent for the cell cycle checkpoint gene p21, the renal injury protein Kim-1, and the kidney injury and cancer biomarker protein osteopontin. Dose-related nephrotoxicity, assessed by hematoxylin and eosin staining, was greater in males compared to female rats, as was cellular proliferation, assessed by bromodeoxyuridine staining. The fraction of proximal renal cells with elevated 8-oxodeoxyguanosine (8-OH-dG) was only increased at the high dose and did not differ by sex. Dose-dependent increases in the expression of osteopontin were detected immunohistochemically only in male rats and were localized in proximal tubule cells. Similarly, BrO3 (-) treatment increased clusterin and Kim-1 staining in the proximal tubules; however, staining for these proteins did not differ appreciably between males and females. These data demonstrate both qualitative and quantitative differences in the response of male versus female kidneys to BrO3 (-)-treatment. These sex-dependent effects likely contribute to renal carcinogenesis of BrO3 (-) in the male rat. 23344796 Organic anion transporter 3 interacts selectively with lipophilic β-lactam antibiotics. Transporters are major determinants of the disposition of xenobiotics and endogenous chemicals in the body. Organic anion transporter 3 (Oat3) functions in the kidney and brain to remove metabolic waste, toxins, and drugs, and thus transports diverse chemicals. Some β-lactam antibiotics interact with Oat3, and penicillin G exhibits a strong dependence on Oat3 for renal elimination. However, over 80 β-lactams exist, and many have not been assessed for an interaction with Oat3. Moreover, β-lactams continue to receive U.S. Food and Drug Administration approval. This study identified new β-lactam-Oat3 interactions, provided a head-to-head comparison with Oat1, and characterized the physicochemical determinants of affinity for Oat3. Cells expressing mouse Oat3 (mOat3) and Oat1 (mOat1), and human OAT3 (hOAT3) were used to test inhibitors, and high-performance liquid chromatography (HPLC) was used to measure transport. Of 26 β-lactams tested, 12 were clear inhibitors of Oat3, and 14 exhibited poor interactions. Inhibitors exhibited a nearly identical rank-order of potency against mOat3 and hOAT3. Oat1 demonstrated a poor interaction with most β-lactams. The majority of Oat3 inhibitors were substrates, and there were clear physicochemical differences between inhibitors and noninhibitors. That is, inhibitors had nearly 40% fewer hydrogen bond donors (P < 0.001), a lower total polar surface area (P < 0.05), and greater lipophilicity (LogP of inhibitors, +1.41; noninhibitors, -1.54; P < 0.001). Pharmacophore mapping revealed a prohibitive hydrogen bond donor group in noninhibitors adjacent to a hydrophobic moiety that was important for binding to Oat3. These findings indicate that Oat3 recognizes lipophilic β-lactams more readily. Moreover, this study has potential implications for designing β-lactams to avoid renal accumulation or brain efflux via Oat3. 23360549 In vitro and mechanistic studies of an antiamyloidogenic self-assembled cyclic D,L-α-peptide architecture. Misfolding of the Aβ protein and its subsequent aggregation into toxic oligomers are related to Alzheimer's disease. Although peptides of various sequences can self-assemble into amyloid structures, these structures share common three-dimensional features that may promote their cross-reaction. Given the significant similarities between amyloids and the architecture of self-assembled cyclic D,L-α-peptide, we hypothesized that the latter may bind and stabilize a nontoxic form of Aβ, thereby preventing its aggregation into toxic forms. By screening a focused library of six-residue cyclic D,L-α-peptides and optimizing the activity of a lead peptide, we found one cyclic D,L-α-peptide (CP-2) that interacts strongly with Aβ and inhibits its aggregation. In transmission electron microscopy, optimized thioflavin T and cell survival assays, CP-2 inhibits the formation of Aβ aggregates, entirely disassembles preformed aggregated and fibrillar Aβ, and protects rat pheochromocytoma PC12 cells from Aβ toxicity, without inducing any toxicity by itself. Using various immunoassays, circular dichroism spectroscopy, photoinduced cross-linking of unmodified proteins (PICUP) combined with SDS/PAGE, and NMR, we probed the mechanisms underlying CP-2's antiamyloidogenic activity. NMR spectroscopy indicates that CP-2 interacts with Aβ through its self-assembled conformation and induces weak secondary structure in Aβ. Upon coincubation, CP-2 changes the aggregation pathway of Aβ and alters its oligomer distribution by stabilizing small oligomers (1-3 mers). Our results support studies suggesting that toxic early oligomeric states of Aβ may be composed of antiparallel β-peptide structures and that the interaction of Aβ with CP-2 promotes formation of more benign parallel β-structures. Further studies will show whether these kinds of abiotic cyclic D,L-α-peptides are also beneficial as an intervention in related in vivo models. 23020239 Anti-breast cancer agents from Chinese herbal medicines. Chinese Herbal Medicines (CHM) have been used in disease prevention and treatment for centuries in China. A number of anti-breast cancer agents isolated from CHM recently, showed very interesting structures, although some of the mechanism of action is not quite clear. These unique chemical structures could be an important information resource for new anti-breast cancer drugs' design and discovery. This review summarizes these findings on anti-breast cancer agents from CHM. 23376802 Lead at 2.5 and 5.0 μM induced aberrant MH-II surface expression through increased MII exocytosis and increased autophagosome formation in Raw 267.4 cells. Aberrant major histocompatibility complex class II (MHC-II) surface expression on antigen presenting cells (APCs) is associated with dysregulated immune homeostasis. Lead (Pb) is known to increase MHC-II surface expression on murine peritoneal macrophages ex vivo at concentrations exceeding 25 μM. Little data exist examining this effect at physiologically relevant concentrations. To address this deficit, we examined the effects of Pb on MHC-II surface expression, secondary T-cell activation markers (CD80, CD86, CD40), cell viability, cellular metabolic activity, and β-hexosaminidase activity in RAW 267.4 macrophage cell lines, with changes in cell ultrastructure evaluated by electron and confocal microscopy. Pb induced an increase in MHC-II, CD86, and lysosome-associated LAMP-1 and LAMP-2 surface mean expression during one doubling cycle (17 h), which was mirrored by increased β-hexosaminidase activity. Although cell viability was unaffected, cellular metabolism was inhibited. Electron microscopy revealed evidence of lipid vacuolization, macroautophagy and myelin figure formation in cells cultured with either Pb or LPS. Confocal microscopy with antibodies against LC3B showed a punctate pattern consistent with the presence of mature autophagosomes. Collectively, these data suggest that 2.5-5.0 μM Pb increased MHC-II surface expression by inhibiting metabolic activity, inducing autophagy, and increasing MHC-II trafficking in a macrophage cell line. 23414807 Anion inhibition studies of the α-carbonic anhydrase from the pathogenic bacterium Vibrio cholerae. An α-carbonic anhydrase (CA, EC 4.2.1.1) has been recently cloned and characterized in the human pathogenic bacterium Vibrio cholerae, denominated VchCA (Del Prete et al. J. Med. Chem.2012, 55, 10742). This enzyme shows a good catalytic activity for the CO2 hydration reaction, comparable to that of the human (h) isoform hCA I. Many inorganic anions and several small molecules were investigated as VchCA inhibitors. Inorganic anions such as cyanate, cyanide, hydrogen sulfide, hydrogen sulfite, and trithiocarbonate were effective VchCA inhibitors with inhibition constants in the range of 33-88μM. Other effective inhibitors were diethyldithiocarbamate, sulfamide, sulfamate, phenylboronic acid and phenylarsonic acid, with KIs of 7-43μM. Halides (bromide, iodide), bicarbonate and carbonate were much less effective VchCA inhibitors, with KIs in the range of 4.64-28.0mM. The resistance of VchCA to bicarbonate inhibition may represent an evolutionary adaptation of this enzyme to living in an environment rich in this ion, such as the gastrointestinal tract, as bicarbonate is a virulence enhancer of this bacterium. 23324406 Phthalazinone inhibitors of inosine-5'-monophosphate dehydrogenase from Cryptosporidium parvum. Cryptosporidium parvum (Cp) is a potential biowarfare agent and major cause of diarrhea and malnutrition. This protozoan parasite relies on inosine 5'-monophosphate dehydrogenase (IMPDH) for the production of guanine nucleotides. A CpIMPDH-selective N-aryl-3,4-dihydro-3-methyl-4-oxo-1-phthalazineacetamide inhibitor was previously identified in a high throughput screening campaign. Herein we report a structure-activity relationship study for the phthalazinone-based series that resulted in the discovery of benzofuranamide analogs that exhibit low nanomolar inhibition of CpIMPDH. In addition, the antiparasitic activity of select analogs in a Toxoplasma gondii model of C. parvum infection is also presented. 23319147 Mechanical characteristics of human red blood cell membrane change due to C60 nanoparticle infiltration. The mechanical characteristics of human red blood cell (RBC) membrane change due to C(60) nanoparticle (NP) infiltration have been investigated in the present work. Using experimental approaches, including optical tweezer (OT) stretching and atomic force microscopy (AFM) indentation, we found that RBCs in the presence of C(60) NPs are softer than normal RBCs. The strain-stress relations of both normal and C(60) infiltrated RBC membranes are extracted from the data of AFM indentation, from which we proved that C(60) NP infiltration can affect the mechanical properties of RBC membrane and tend to weaken the tensile resistance of lipids bilayers. In order to explain this experimental phenomenon, a mechanical model has been developed. Based on this model, the strain-stress relations of both normal and C(60) infiltrated lipid bilayers are calculated with consideration of intermolecular interactions. The theoretical results are in great agreement with the experimental results. The influence of C(60) NP concentration on the mechanical properties of RBC membrane is successfully predicted. Higher concentrations of C(60) NPs in the lipid bilayers will lead to increased damage to the cell membrane, implying that the dosage of C(60) NPs should be controlled in medical applications. 23360082 Electronic structure of individual hybrid colloid particles studied by near-edge X-ray absorption fine structure (NEXAFS) spectroscopy in the X-ray microscope. The electronic structure of individual hybrid particles was studied by nanoscale near-edge X-ray absorption spectromicroscopy. The colloidal particles consist of a solid polystyrene core and a cross-linked poly-N-(isopropylacrylamide) shell with embedded crystalline titanium dioxide (TiO(2)) nanoparticles (d = 6 ± 3 nm). The TiO(2) particles are generated in the carrier network by a sol-gel process at room temperature. The hybrid particles were imaged with photon energy steps of 0.1 eV in their hydrated environment with a cryo transmission X-ray microscope (TXM) at the Ti L(2,3)-edge. By analyzing the image stacks, the obtained near-edge X-ray absorption fine structure (NEXAFS) spectra of our individual hybrid particles show clearly that our synthesis generates TiO(2) in the anastase phase. Additionally, our spectromicroscopy method permits the determination of the density distribution of TiO(2) in single carrier particles. Therefore, NEXAFS spectroscopy combined with TXM presents a unique method to get in-depth insight into the electronic structure of hybrid materials. 23171703 Assessment of pre- and postoperative endocrine function in 94 patients with Rathke's cleft cyst. We reviewed 94 patients with Rathke's cleft cyst (RCC) who were surgically treated at Nippon Medical School Hospital between December 1995 and July 2009 to clarify the effect of surgery on their endocrine function. In our statistical analysis we considered their age and sex, the cyst volume, and preoperative MRI findings. Using simple linear- and multiple regression analysis we evaluated the association between these factors and their preoperative hormone baseline levels. To assess pre- and postoperative anterior pituitary function we subjected the results of various hormone loading tests to the Wilcoxon rank sum test. Surgery improved headache and visual impairment in most patients and elevated PRL levels were significantly normalized after surgery (p = 0.004). However, pre- and postoperative anterior pituitary hormone loading tests revealed that the levels of GH, TSH, LH, and FSH were not improved significantly by surgery. Although the ACTH loading test showed postoperative improvement, the change was not statistically significant. We suggest that RCC patients with headache or visual impairment are good candidates for surgery. We also recommend that patients with hyperprolactinemia and those with ACTH deficiency whose MRI findings reveal low-intensity on T1WI and high-intensity on T2WI are likely to benefit from surgery. In contrast, RCC patients with other hormone dysfunctions do not appear to benefit from surgical intervention. 23578871 Cell biology: notch recycling is numbed. During asymmetric cell division, the Notch regulator Numb segregates unequally to establish different cell fates in the two daughter cells. Numb is thought to act as an endocytic protein. Two new studies show that Numb antagonizes Notch signaling by also regulating recycling of Sanpodo-Notch complexes via AP-1. 23586868 Identification of the Post-Polyketide Synthase Modification Enzymes for Fostriecin Biosynthesis in Streptomyces pulveraceus. Fostriecin (FST, 1) is a natural product with promising antitumor activity produced by Streptomyces pulveraceus. Its antitumor activity is associated with the selective inhibition of protein phosphatase activities. The biosynthetic gene cluster for FST has recently been cloned and sequenced. To better understand the post-polyketide synthase (PKS) modification steps in the biosynthetic pathway of FST, we constructed and characterized three post-PKS modification gene mutants of fosG, fosK, and fosM by knockout inactivation in S. pulveraceus. As a result, we determined that a fosK-encoded cytochrome P450 monooxygenase is responsible for C-18 hydroxylation, formation of an unsaturated lactone is dependent upon FosM, and the fosG gene product is involved in hydroxylation at C-4 after the action of FosM to yield PD 113,271 from FST. The accumulated analogues from the ΔfosK and ΔfosM mutant strains possessed a malonyl ester moiety that suggested that all the post-PKS modification steps in FST biosynthesis occur with the polyketide chain bearing a malonyl ester at the C-3 position, with formation of the unsaturated six-membered lactone as the last step in FST biosynthesis. 23397584 HepG2 cells simultaneously expressing five P450 enzymes for the screening of hepatotoxicity: identification of bioactivable drugs and the potential mechanism of toxicity involved. Use of the HepG2 cell line to assess hepatotoxicity induced by bioactivable compounds is hampered by their low cytochrome P450 expression. To overcome this limitation, we have used adenoviral transfection to develop upgraded HepG2 cells (ADV-HepG2) expressing the major P450 enzymes involved in drug metabolism (CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4) at levels comparable to those of human hepatocytes. The potential utility of this new cell model for the in vitro screening of bioactivable drugs was assessed using a high-content screening assay that we recently developed to simultaneously measure multiple parameters indicative of cell injury. To this end, ADV-HepG2 and HepG2 cells, cultured in 96-well plates, were exposed for 24 h to a wide range of concentrations of 12 bioactivable and 3 non-bioactivable compounds. The cell viability and parameters associated with nuclear morphology, mitochondrial function, intracellular calcium concentration, and oxidative stress indicative of prelethal cytotoxicity and representative of different mechanisms of toxicity were evaluated. Bioactivable compounds showed lower IC(50) values in ADV-HepG2 cells than in HepG2 cells. Moreover, significant differences in the other parameters analyzed were observed between both cell models, while similar effects were observed for non-bioactivable compounds (negative controls). The changes in cell parameters detected in our assay for a given compound are in good agreement with the previously reported toxicity mechanism. Overall, our results indicate that this assay may be a suitable new in vitro approach for early screening of compounds to identify bioactivable hepatotoxins and the mechanism(s) involved in their toxicity. 23512804 The Minimum Activation Peptide from ilvH Can Activate the Catalytic Subunit of AHAS from Different Species. Acetohydroxyacid synthases (AHASs), which catalyze the first step in the biosynthesis of branched-chain amino acids, are composed of a catalytic subunit (CSU) and a regulatory subunit (RSU). The CSU harbors the catalytic site, and the RSU is responsible for the activation and feedback regulation of the CSU. Previous results from Chipman and co-workers and our lab have shown that heterologous activation can be achieved among isozymes of Escherichia coli AHAS. It would be interesting to find the minimum peptide of ilvH (the RSU of E. coli AHAS III) that could activate other E. coli CSUs, or even those of ## species. In this paper, C-terminal, N-terminal, and C- and N-terminal truncation mutants of ilvH were constructed. The minimum peptide to activate ilvI (the CSU of E. coli AHAS III) was found to be ΔN 14-ΔC 89. Moreover, this peptide could not only activate its homologous ilvI and heterologous ilvB (CSU of E. coli AHAS I), but also heterologously activate the CSUs of AHAS from Saccharomyces cerevisiae, Arabidopsis thaliana, and Nicotiana plumbaginifolia. However, this peptide totally lost its ability for feedback regulation by valine, thus suggesting different elements for enzymatic activation and feedback regulation. Additionally, the apparent dissociation constant (Kd ) of ΔN 14-ΔC 89 when binding CSUs of different species was found to be 9.3-66.5 μM by using microscale thermophoresis. The ability of this peptide to activate different CSUs does not correlate well with its binding ability (Kd ) to these CSUs, thus implying that key interactions by specific residues is more important than binding ability in promoting enzymatic reactions. The high sequence similarity of the peptide ΔN 14-ΔC 89 to RSUs across species hints that this peptide represents the minimum activation motif in RSU and that it regulates all AHASs. 23481256 Rules for the recognition of dilysine retrieval motifs by coatomer. Cytoplasmic dilysine motifs on transmembrane proteins are captured by coatomer α-COP and β'-COP subunits and packaged into COPI-coated vesicles for Golgi-to-ER retrieval. Numerous ER/Golgi proteins contain K(x)Kxx motifs, but the rules for their recognition are unclear. We present crystal structures of α-COP and β'-COP bound to a series of naturally occurring retrieval motifs-encompassing KKxx, KxKxx and non-canonical RKxx and viral KxHxx sequences. Binding experiments show that α-COP and β'-COP have generally the same specificity for KKxx and KxKxx, but only β'-COP recognizes the RKxx signal. Dilysine motif recognition involves lysine side-chain interactions with two acidic patches. Surprisingly, however, KKxx and KxKxx motifs bind differently, with their lysine residues transposed at the binding patches. We derive rules for retrieval motif recognition from key structural features: the reversed binding modes, the recognition of the C-terminal carboxylate group which enforces lysine positional context, and the tolerance of the acidic patches for non-lysine residues. 23583257 Quinone compounds regulate the level of ROS production by the NADPH oxidase Nox4. NADPH oxidase Nox4 is expressed in a wide range of tissues and plays a role in cellular signaling by providing reactive oxygen species (ROS) as intracellular messengers. Nox4 oxidase activity is thought to be constitutive and regulated at the transcriptional level; however, we challenge this point of view and suggest that specific quinone derivatives could modulate this activity. In fact, we demonstrated a significant stimulation of Nox4 activity by 4 quinone derivatives (AA-861, tBuBHQ, tBuBQ, and duroquinone) observed in 3 different cellular models, HEK293E, T-REx™, and chondrocyte cell lines. Our results indicate that the effect is specific toward Nox4 versus Nox2. Furthermore, we showed that NAD(P)H:quinone oxidoreductase (NQO1) may participate in this stimulation. Interestingly, Nox4 activity is also stimulated by reducing agents that possibly act by reducing the disulfide bridge (Cys226, Cys270) located in the extracellular E-loop of Nox4. Such model of Nox4 activity regulation could provide new insight into the understanding of the molecular mechanism of the electron transfer through the enzyme, i.e., its potential redox regulation, and could also define new therapeutic targets in diseases in which quinones and Nox4 are implicated. 23199366 Assessment of immunotoxicity using precision-cut tissue slices. 1.When the immune system encounters incoming infectious agents, this generally leads to immunity. The evoked immune response is usually robust, but can be severely perturbed by potentially harmful environmental agents such as chemicals, pharmaceuticals and allergens. 2.Immunosuppression, hypersensitivity and autoimmunity may occur due to changed immune activity. Evaluation of the immunotoxic potency of agents as part of risk assessment is currently established in vivo with animal models and in vitro with cell lines or primary cells. 3.Although in vivo testing is usually the most relevant situation for many agents, more and more in vitro models are being developed for assessment of immunotoxicity. In this context, hypersensitivity and immunosuppression are considered to be a primary focus for developing in vitro methods. Three-dimensional organotypic tissue models are also part of current research in immunotoxicology. 4.In recent years, there has been a revival of interest in organotypic tissue models. In the context of immunotoxicity testing, precision-cut lung slices in particular have been intensively studied. Therefore, this review is very much focused on pulmonary immunotoxicology. Respiratory hypersensitivity and inflammation are further highlighted aspects of this review. Immunotoxicity assessment currently is of limited use in other tissue models, which are therefore described only briefly within this review. 23205584 A new perfluoropolyether-based hydrophobic and chemically resistant photoresist structured by two-photon polymerization. Two-photon polymerization technology has been used to fabricate submicrometer three-dimensional (3D) structures using a new polyfunctional perfluoropolyether-based resist, which is a polymer intrinsically hydrophobic and chemically resistant. The fluorinated resist was designed and synthesized in this work and successfully employed to fabricate woodpile structures in various experimental conditions. This is the first demonstration of the capability to fabricate hydrophobic and chemically resistant 3D structures with submicrometer resolution and arbitrary geometry. 23373819 Cis-trans isomerizations of proline residues are key to bradykinin conformations. A recent ion mobility-mass spectrometry (IM-MS) study of the nonapeptide bradykinin (BK, amino acid sequence Arg(1)-Pro(2)-Pro(3)-Gly(4)-Phe(5)-Ser(6)-Pro(7)-Phe(8)-Arg(9)) found evidence for 10 populations of conformations that depend upon the solution composition [J. Am. Chem. Soc. 2011, 133, 13810]. Here, the role of the three proline residues (Pro(2), Pro(3), and Pro(7)) in establishing these conformations is investigated using a series of seven analogue peptides in which combinations of alanine residues are substituted for prolines. IM-MS distributions of the analogue peptides, when compared to the distribution for BK, indicate the multiple structures are associated with different combinations of cis and trans forms of the three proline residues. These data are used to assign the structures to different peptide populations that are observed under various solution conditions. The assignments also show the connectivity between structures when collisional activation is used to convert one state into another. 23532849 A Novel Automethylation Reaction in the Aspergillus nidulans LaeA Protein Generates S-Methylmethionine. The filamentous fungi in the genus Aspergillus are opportunistic plant and animal pathogens that can adapt to their environment by producing various secondary metabolites including lovastatin, penicillin, and aflatoxin. The synthesis of these small molecules is dependent on gene clusters that are globally regulated by the LaeA protein. Null mutants of LaeA in all pathogenic fungi examined to date show decreased virulence coupled with reduced secondary metabolism. Although the amino acid sequence of LaeA contains the motifs characteristic of seven-beta-strand methyltransferases, a methyl-accepting substrate of LaeA has not been identified. In this work, we did not find a methyl-accepting substrate in A. nidulans with various assays including in vivo S-adenosyl-[methyl-(3)H]methionine labeling, targeted in vitro methylation experiments using putative protein substrates, or in vitro methylation assays using whole cell extracts grown under different conditions. However, in each experiment LaeA was shown to self-methylate. Amino acid hydrolysis of radioactively-labeled LaeA followed by cation exchange and reverse phase chromatography identified methionine as the modified residue. Point mutations show that the major site of modification of LaeA is on methionine-207. However, in vivo complementation showed that methionine-207 is not required for the biological function of LaeA. LaeA is the first protein to exhibit automethylation at a methionine residue. These findings not only indicate LaeA may perform novel chemistry with S-adenosylmethionine, but also provide new insights into the physiological function of LaeA. 23322677 Single-walled carbon nanotube/polyaniline/n-silicon solar cells: fabrication, characterization, and performance measurements. Carbon nanotube-silicon solar cells are a recently investigated photovoltaic architecture with demonstrated high efficiencies. Silicon solar-cell devices fabricated with a thin film of conductive polymer (polyaniline) have been reported, but these devices can suffer from poor performance due to the limited lateral current-carrying capacity of thin polymer films. Herein, hybrid solar-cell devices of a thin film of polyaniline deposited on silicon and covered by a single-walled carbon nanotube film are fabricated and characterized. These hybrid devices combine the conformal coverage given by the polymer and the excellent electrical properties of single-walled carbon nanotube films and significantly outperform either of their component counterparts. Treatment of the silicon base and carbon nanotubes with hydrofluoric acid and a strong oxidizer (thionyl chloride) leads to a significant improvement in performance. 23600708 Spatially-Resolved EELS Analysis of Antibody Distribution on Biofunctionalized Magnetic Nanoparticles. Spatially resolved electron energy loss spectroscopy (SR-EELS) using scanning transmission electron microscope (STEM) allows the identification and determination of the spatial distribution of the components/elements of immuno-functionalized core-shell superparamagnetic magnetite nanoparticles. Here, we report that SR-EELS measurements allow the direct identification and study of the biological moieties (protein G and anti-HRP antibody) in complex bionanocarriers of relevance for biomedical applications. Our findings show that the biomacromolecules are located on specific areas on the nanoparticles' surface. In addition, efficiency of this functionalization was evaluated by means of biochemical techniques. 23563248 Frequency of the GPR7 Tyr135Phe allelic variant in lean and obese subjects. Background: GPR7, the endogenous coupled receptor for neuropeptide B and neuropeptide W, is expressed in several regions of the Central Nervous System (CNS), which are involved in the regulation of feeding behaviour. GPR7 affects the regulation of energy balance through a mechanism independent of leptin and melanocortin pathways. Aim: Aim of this study was to investigate whether GPR7 gene mutations can be detected in human subjects and, in that event, if they are differently distributed among lean and obese subjects. Subjects and Methods: The coding region of GPR7 were sequenced in 150 obese patients and 100 normal-weight unrelated controls. Functional studies of the allelic variants were performed. Results: One genetic GPR7 variant was found (Tyr135Phe - rs33977775) in obese subjects (13,3%) and lean control (25%). Functional studies did not reveal significant differences between the wild type and the Tyr135Phe allelic variants in their NPW mediated capacity to inhibit forskolin-induced cAMP production. Conclusions: Screening of GPR7 gene mutations among lean and obese subjects revealed a Tyr135Phe allelic variant that was fairly common in the study population. As indicated by in vitro and in silico studies, this variant is unlikely to cause a functional derangement of the receptor. 23017398 Occurrence of ochratoxin A in cocoa by-products and determination of its reduction during chocolate manufacture. This work reports an investigation carried out to assess the natural occurrence of ochratoxin A in 168 samples from different fractions obtained during the technological processing of cocoa (shell, nibs, liquor, butter, cake and cocoa powder) and the reduction of ochratoxin A during chocolate manufacture. Ochratoxin A analyses were performed with immunoaffinity columns and detection by high performance liquid chromatography. Concerning the natural ochratoxin A contamination in cocoa by-products, the highest levels of ochratoxin A were found in the shell, cocoa powder and cocoa cake. The cocoa butter was the least contaminated, showing that ochratoxin A seems to remain in the defatted cocoa solids. Under the technological conditions applied during the manufacture of chocolate in this study and the level of contamination present in the cocoa beans, this experiment demonstrated that 93.6% of ochratoxin A present in the beans was reduced during the chocolate producing. 23421585 Two new piperidine alkaloids from Streptomyces sp. NEAU-Z4. Two new piperidine alkaloids, streptazones E (1) and F (2), were isolated from Streptomyces sp. NEAU-Z4. Their structures were elucidated on the basis of MS and NMR analysis. 23641701 A novel approach to capillary plasma microsampling for quantitative bioanalysis. Background: A novel device and procedure for the collection and isolation of microvolumes of plasma have been developed and two pilot rodent PK studies have been completed. Results: This method involves collection of blood into a plastic-wrapped, EDTA-coated capillary tube, containing a small amount of a thixotropic gel and a porous plug. Following blood collection, the capillary is placed into a secondary labeled container suitable for centrifugation and plasma is generated. During centrifugation, the thixotropic gel isolates the plasma from the red blood cells and creates a physical barrier between the two matrices. The plasma is then dispensed from the capillary tube into a separate container for storage or processing. Conclusion: A simple and robust novel approach for the collection of small plasma volumes from rodent TK studies has been demonstrated. 23323647 A new flavonoid with 6-phenyl substituent from Selaginella uncinata. A new flavonoid, 6-(5-acetyl-2-methoxyphenyl)-apigenin (1), together with nine known compounds (2-10), was isolated from Selaginella uncinata (Desv.) Spring. This is the first report of the spectroscopic data of compound 3. Compound 2 was first reported from this species. The structure of the new compound was elucidated on the basis of spectroscopic evidence, including 1D and 2D NMR as well as HR-EI-MS analysis. 23340252 The endocrine disrupting chemical tolylfluanid alters adipocyte metabolism via glucocorticoid receptor activation. Glucocorticoid signaling plays a critical role in regulating energy metabolism. Emerging data implicate environmental endocrine-disrupting chemicals as contributors to the obesity and diabetes epidemics. Previous studies have shown that the phenylsulfamide fungicide tolylfluanid (TF) augments glucocorticoid receptor (GR)-dependent luciferase expression in 3T3-L1 preadipocytes while modulating insulin action in primary murine and human adipocytes. Studies were performed to interrogate glucocorticoid signaling in primary adipocytes exposed to TF. TF mimicked the gene transcription profile of the murine glucocorticoid corticosterone (Cort). Cellular fractionation assays demonstrated that TF treatment promoted the activating serine phosphorylation of GR, augmenting its cytoplasmic-to-nuclear translocation as well as its enrichment at glucocorticoid response elements on the glucocorticoid-induced leucine zipper gene promoter. After acute treatment, Cort or TF promoted insulin receptor substrate-1 (IRS-1) gene and protein expression. Either treatment also enriched GR binding at an identified glucocorticoid response element in the IRS-1 gene. TF or Cort each increased insulin-stimulated lipogenesis, an effect resulting from increased lipogenic gene expression and enhanced insulin-stimulated dephosphorylation of acetyl-coenzyme A carboxylase. The augmentation of insulin-stimulated lipogenesis was mediated through a specific enhancement of Akt phosphorylation at T308. These findings support modulation of IRS-1 levels as a mechanism for glucocorticoid-mediated changes in insulin action in primary adipocytes. Albeit with less affinity than Cort, in silico analysis suggests that TF can interact with the ligand binding pocket of GR. Collectively, these studies identify TF as a structurally unique environmental glucocorticoid. Glucocorticoid signaling may thus represent a novel pathway by which environmental toxicants promote the development of metabolic diseases. 23514279 Oxidative and Photoxidative Polymerization of Humic Suprastructures by Heterogeneous Biomimetic Catalysis. The meso-tetra(2,6-dichloro-3-sulfonatophenyl)porphyrinate of manganese(III) chloride [Mn-(TDCPPS)Cl] biomimetic catalyst immobilized on spacer-functionalized kaolinite clay mineral was employed in the oxidative coupling reaction of a dissolved humic acid (HA) suprastructure with either chemical (H2O2) or UV-light oxidation. The changes in molecular size of humic matter subjected to catalyzed oxidative reaction were followed by high-performance size exclusion chromatography (HPSEC) with UV-vis and refractive index (RI) detectors in series, and by thermogravimetric (TGA) analysis. Both the enhanced molecular size shown by differences between HPSEC chromatograms of humic reaction mixtures at either pH 6 or 3.5 and the increase of thermogravimetric stability suggest that the heterogeneous biomimetic catalysis promoted the stabilization of humic conformations by new intermolecular covalent bonds during oxidative coupling. The similarity between chemical and light-induced oxidation results suggests potential multiple applications of the kaolinite-supported heterogeneous catalyst in controlling the reactivity of natural organic matter within biogeochemical cycles and environmental reactions. 23430747 Human Antigen R-mediated mRNA Stabilization Is Required for Ultraviolet B-induced Autoinduction of Amphiregulin in Keratinocytes. All members of the EGF family are produced as transmembrane precursors that are proteolytically processed into soluble forms by disintegrin and metalloproteinases (ADAMs) for autocrine/paracrine pathways. In turn, the ligand-activated EGF receptor (EGFR) induces the expression of EGF family members, so-called "autoinduction." However, it is not well understood how this autoinduction occurs. In this study, we investigated the molecular mechanism of the autoinduction of amphiregulin (AREG), a member of the EGF family. We found that ultraviolet B (UVB) exposure increased the AREG mRNA level by stabilization of its mRNA in a human immortalized keratinocyte cell line, HaCaT. The 3' UTR of AREG mRNA was responsible for binding to an mRNA-binding protein, human antigen R (HuR), and the interaction between AREG mRNA and HuR was enhanced by UVB. Inducible knockdown of HuR expression significantly decreased AREG mRNA stability. Interestingly, treatment of HaCaT cells with an EGFR inhibitor, an EGFR neutralizing antibody, or an ADAM inhibitor destabilized AREG mRNA. In the case of ADAM inhibition, administration of soluble AREG restored the mRNA level, indicating that the stabilization occurs in a shedding-dependent manner of EGFR ligands. The HuR dependence of AREG mRNA and protein expression was also confirmed in human primary keratinocytes. Taken together, we propose a novel mechanism by which HuR regulates the stability of AREG mRNA in keratinocytes after UVB exposure and suggest that targeting of HuR functions might be crucial for understanding skin cancers caused by aberrant EGF family member-EGFR signaling. 23303207 Lactobacillus johnsonii inhibits indoleamine 2,3-dioxygenase and alters tryptophan metabolite levels in BioBreeding rats. In our previous work, we found that feeding Lactobacillus johnsonii to BioBreeding diabetes-prone (BBDP) rats decreased the incidence of diabetes development. The aim of this study was to investigate host pathways affected by L. johnsonii, with specific focus on the rate-limiting enzyme of tryptophan catabolism, indoleamine 2,3-dioxygenase (IDO). Suspensions of L. johnsonii or an equal volume of vehicle were orally administered to BBDP rats. Tissue IDO was investigated using quantitative RT-PCR and Western blot, whereas tryptophan, kynurenine, and 5-hydroxytryptamine (5-HT) concentrations were quantified by HPLC and ELISA. IDO activity was also investigated using L. johnsonii culture cell-free supernatant (CFS) with affinity-purified IDO and HT-29 intestinal epithelial cells. L. johnsonii feeding resulted in a 17% reduction in serum kynurenine compared with that in vehicle-fed controls, correlating with a 1.4-fold elevation in 5-HT levels. H2O2 produced by L. johnsonii abolished IDO activity in vitro, and L. johnsonii feeding resulted in a 3.9-fold increase in ileum lumen H2O2. L. johnsonii CFS significantly reduced IDO activity in HT-29 intestinal epithelial cells (47% reduction) compared with that in vehicle-treated controls, an effect abolished by catalase treatment. These data support the role of H2O2 in commensal bacteria-host interactions and highlight the influence of commensal bacteria-derived H2O2 on host physiology.-Valladares, R., Bojilova, L., Potts, A. H., Cameron, E., Gardner, C., Lorca, G., Gonzalez, C. F. Lactobacillus johnsonii inhibits indoleamine 2,3-dioxygenase and alters tryptophan metabolite levels in BioBreeding rats. 23428981 Reversible effect of developmental exposure to chlorpyrifos on late-stage neurogenesis in the hippocampal dentate gyrus in mouse offspring. The effect of developmental exposure to chlorpyrifos (CPF) on hippocampal neurogenesis was examined in male mice after maternal dietary exposure to CPF at 0, 4, 20, or 100ppm from gestation day 10 to postnatal day (PND) 21. Cholinesterase activity was dose-dependently decreased in red blood cells at ≥4ppm and in the brain at 100ppm both in dams and offspring on PND 21. Immunohistochemically, doublecortin(+) cells were decreased at ≥20ppm in the subgranular zone (SGZ) of the dentate gyrus, and NeuN(+)-expressing mature neurons were decreased at 100ppm in the hilus on PND 21. There were no differences in the numbers of progenitor populations expressing Tbr2 or M1 muscarinic acetylcholine receptors. Transcript levels of Dcx also decreased at ≥20ppm, and those of Pcna, Casp3, Bax, Bcl2, Pax6 and Tbr2 were unchanged in the dentate gyrus by real-time RT-PCR. At PND 77, hippocampal neurogenesis was unchanged. These results suggest that developmental CPF exposure directly but transiently suppresses maturation of late-stage granule cell lineages in the SGZ and affects interneuron populations in the hilus. 23328895 Drug metabolism and transport during pregnancy: how does drug disposition change during pregnancy and what are the mechanisms that cause such changes? There is increasing evidence that pregnancy alters the function of drug-metabolizing enzymes and drug transporters in a gestational-stage and tissue-specific manner. In vivo probe studies have shown that the activity of several hepatic cytochrome P450 enzymes, such as CYP2D6 and CYP3A4, is increased during pregnancy, whereas the activity of others, such as CYP1A2, is decreased. The activity of some renal transporters, including organic cation transporter and P-glycoprotein, also appears to be increased during pregnancy. Although much has been learned, significant gaps still exist in our understanding of the spectrum of drug metabolism and transport genes affected, gestational age-dependent changes in the activity of encoded drug metabolizing and transporting processes, and the mechanisms of pregnancy-induced alterations. In this issue of Drug Metabolism and Disposition, a series of articles is presented that address the predictability, mechanisms, and magnitude of changes in drug metabolism and transport processes during pregnancy. The articles highlight state-of-the-art approaches to studying mechanisms of changes in drug disposition during pregnancy, and illustrate the use and integration of data from in vitro models, animal studies, and human clinical studies. The findings presented show the complex inter-relationships between multiple regulators of drug metabolism and transport genes, such as estrogens, progesterone, and growth hormone, and their effects on enzyme and transporter expression in different tissues. The studies provide the impetus for a mechanism- and evidence-based approach to optimally managing drug therapies during pregnancy and improving treatment outcomes. 23274394 Pharmacokinetics explain in vivo/in vitro discrepancies of carcinogen-induced gene expression alterations in rat liver and cultivated hepatocytes. Cultivated hepatocytes represent a well-established in vitro system. However, the applicability of hepatocytes in toxicogenomics is still controversially discussed. Recently, an in vivo/in vitro discrepancy has been described, whereby the non-genotoxic rat liver carcinogen methapyrilene alters the expression of the metabolizing genes SULT1A1 and ABAT, as well as the DNA damage response gene GADD34 in vitro, but not in vivo. If the collagen sandwich cultures of hepatocytes really produce false-positive data, this would compromise its application in toxicogenomics. To revisit the putative in vivo/in vitro discrepancy, we first analyzed and modeled methapyrilene concentrations in the portal vein of rats. The relatively short half-life of 2.8 h implies a rapid decrease in orally administered methapyrilene in vivo below concentrations that can cause gene expression alterations. This corresponded to the time-dependent alteration levels of GADD34, ABAT and SULT1A1 RNA in the liver: RNA levels are altered 1, 6 and 12 h after methapyrilene administration, but return to control levels after 24 and 72 h. In contrast, methapyrilene concentrations in the culture medium supernatant of primary rat hepatocyte cultures decreased slowly. This explains why GADD34, ABAT and SULT1A1 were still deregulated after 24 h exposure in vitro, but not in vivo. It should also be considered that the earliest analyzed time point in the previous in vivo studies was 24 h after methapyrilene administration. In conclusion, previously observed in vitro/in vivo discrepancy can be explained by different pharmacokinetics present in vitro and in vivo. When the in vivo half-life is short, levels of some initially altered genes may have returned to control levels already 24 h after administration. 23404305 Predicting Macro- and Microvascular Complications in Type 2 Diabetes: The Japan Diabetes Complications Study/the Japanese Elderly Diabetes Intervention Trial risk engine. OBJECTIVE To develop and validate a risk engine that calculates the risks of macro- and microvascular complications in type 2 diabetes. RESEARCH DESIGN AND METHODS We analyzed pooled data from two clinical trials on 1,748 Japanese type 2 diabetic patients without diabetes complications other than mild diabetic retinopathy with a median follow-up of 7.2 years. End points were coronary heart disease (CHD), stroke, noncardiovascular mortality, overt nephropathy defined by persistent proteinuria, and progression of retinopathy. We fit a multistate Cox regression model to derive an algorithm for prediction. The predictive accuracy of the calculated 5-year risks was cross-validated. RESULTS Sex, age, HbA1c, years after diagnosis, BMI, systolic blood pressure, non-HDL cholesterol, albumin-to-creatinine ratio, atrial fibrillation, current smoker, and leisure-time physical activity were risk factors for macro- and microvascular complications and were incorporated into the risk engine. The observed-to-predicted (O/P) ratios for each event were between 0.93 and 1.08, and Hosmer-Lemeshow tests showed no significant deviations between observed and predicted events. In contrast, the UK Prospective Diabetes Study (UKPDS) risk engine overestimated CHD risk (O/P ratios: 0.30 for CHD and 0.72 for stroke). C statistics in our Japanese patients were high for CHD, noncardiovascular mortality, and overt nephropathy (0.725, 0.696, and 0.767) but moderate for stroke and progression of retinopathy (0.636 and 0.614). By combining macro- and microvascular risks, the classification of low- and high-risk patients was improved by a net reclassification improvement of 5.7% (P = 0.02). CONCLUSIONS The risk engine accurately predicts macro- and microvascular complications and would provide helpful information in risk classification and health economic simulations. 23244626 Contrasting toxicokinetic evaluations and interspecies pharmacokinetic scaling approaches for small molecules and biologics: applicability to biosimilar development. 1. A 2-fold threshold typically used for prediction accuracy of interspecies scaling of clearance (CL) may be too liberal when using pharmacokinetic similarity in animals to advance biosimilar candidate selection for clinical testing. The purpose of this review is to identify interspecies scaling methods for use in de-risking biosimilar development prior to clinical testing. 2. Scaling approaches for predicting macromolecule CL were identified through literature review. Reports that evaluated predicted and observed human CLs for ≥5 individual compounds were considered. Absolute average fold-error (AAFE) was calculated for each method along with the proportion of compounds with individual fold-error values within a tighter threshold of 0.7-1.3. 3. Traditional simple allometry with a minimum of three species and the rule of exponents performed inconsistently with some groups of compounds resulting in a greater than 2-fold error (i.e. AAFE > 2). For monoclonal antibodies (mAbs), simplified allometric approaches employing a single species (monkey) with a fixed exponent of 0.85 consistently resulted in lower AAFEs and a higher proportion of compounds within the tighter range of 0.7-1.3. 4. For macromolecules, and particularly mAbs, employing single-species monkey "simplified" allometric approaches with a fixed exponent of 0.85 may be more appropriate than traditional allometric approaches. 23360545 Comparative surface thermodynamic analysis of new fluid phase formation between a sphere and a flat plate. This paper investigates the behavior of confined fluid in the gap between a sphere and a flat plate by examining the curve of free energy of the system versus size of the new phase. Four possible situations corresponding to new phase formation out of confined liquid or vapor at pressures above or below the saturation pressure are studied. Using surface thermodynamics, the feasible shape of the meniscus (concave/convex), the possibility of phase transition, as well as the number and the nature (unstable/stable) of equilibrium states have been determined for each of these four situations. The effects of equilibrium contact angle, separation distance of confinement surfaces, and sphere size have been studied. We show that the number and nature of equilibrium states, along with the effect of different parameters in these four possible situations, can be well described under two categories of new phase formation with (a) concave or (b) convex meniscus. Our results reveal that in the sphere-plate gap, stable coexistence of the liquid and vapor phases is only possible when the meniscus is concave (which corresponds to either capillary condensation or capillary evaporation), and when the sphere and plate are separated by a distance less than a critical amount (where that critical amount is always less than the Kelvin radius). With convex menisci, no stable coexistence of liquid and vapor phase is possible. 22812637 Two new diterpenes from Caesalpinia minax Hance. Two new cassane-type diterpenes, Caesalpinolide F (1) and Caesalpinolide G (2) were isolated from Caesalpinia minax Hance. Their structures were elucidated on the basis of 1D and 2D NMR, MS and CD analysis. Compounds 1 and 2 were tested against colon carcinoma (HCT-8) and breast cancer (MCF-7) human cancer cell lines, and showed mild cytotoxicity activities. 23535828 Recent developments in design and synthesis of bicyclic azasugars, carbasugars and related molecules as glycosidase inhibitors. The importance of glycosidase inhibitors and especially the bicyclic molecules has led to design and assessment of many analogs of naturally occurring molecules. This review focuses on the synthesis and enzyme inhibitions of a few selected (synthetic or non-naturally occurring) molecules that have been reported in the last decade, which allow one to draw some connection between varying the structural features and their effect on glycosidase inhibitions. It is expected that further improvements based on these features could lead to improved inhibitors. 22796429 The NMDA receptor as a target for cognitive enhancement. NMDA receptors (NMDARs) play an important role in neural plasticity including long-term potentiation and long-term depression, which are likely to explain their importance for learning and memory. Cognitive decline is a major problem facing an ageing human population, so much so that its reversal has become an important goal for scientific research and pharmaceutical development. Enhancement of NMDAR function is a core strategy toward this goal. In this review we indicate some of the major ways of potentiating NMDAR function by both direct and indirect modulation. There is good evidence that both positive and negative modulation can enhance function suggesting that a subtle approach correcting imbalances in particular clinical situations will be required. Excessive activation and the resultant deleterious effects will need to be carefully avoided. Finally we describe some novel positive allosteric modulators of NMDARs, with some subunit selectivity, and show initial evidence of their ability to affect NMDAR mediated events. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23376345 Elimination and utilization of oxidized guanine nucleotides in the synthesis of RNA and its precursors. Reactive oxygen species are produced as side products of oxygen utilization and can lead to the oxidation of nucleic acids and their precursor nucleotides. Among the various oxidized bases, 8-oxo-7,8-dihydroguanine seems to be the most critical during the transfer of genetic information because it can pair with both cytosine and adenine. During the de novo synthesis of guanine nucleotides, GMP is formed first, and it is converted to GDP by guanylate kinase. This enzyme hardly acts on an oxidized form of GMP (8-oxo-GMP) formed by the oxidation of GMP or by the cleavage of 8-oxo-GDP and 8-oxo-GTP by MutT protein. Although the formation of 8-oxo-GDP from 8-oxo-GMP is thus prevented, 8-oxo-GDP itself may be produced by the oxidation of GDP by reactive oxygen species. The 8-oxo-GDP thus formed can be converted to 8-oxo-GTP because nucleoside-diphosphate kinase and adenylate kinase, both of which catalyze the conversion of GDP to GTP, do not discriminate 8-oxo-GDP from normal GDP. The 8-oxo-GTP produced in this way and by the oxidation of GTP can be used for RNA synthesis. This misincorporation is prevented by MutT protein, which has the potential to cleave 8-oxo-GTP as well as 8-oxo-GDP to 8-oxo-GMP. When (14)C-labeled 8-oxo-GTP was applied to CaCl2-permeabilized cells of a mutT(-) mutant strain, it could be incorporated into RNA at 4% of the rate for GTP. Escherichia coli cells appear to possess mechanisms to prevent misincorporation of 8-oxo-7,8-dihydroguanine into RNA. 23265872 Synthesis of new triazole acetamides with inotropic effects. A series of new triazole acetamides 5a-w were synthesized and evaluated for their positive inotropic activity of left atrium stroke volume on isolated rabbit-heart preparations. The majority of the derivatives presented favorable in vitro activity compared with the reference drug, milrinone. Among them triazole acetamide 5a was identified as the most potent with 20.29 ± 0.18% increased stroke volume (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10(-5) M. The chronotropic effects of the compounds having inotropic effects were also evaluated. 22553909 Preparation and cyclodextrin assisted dissolution rate enhancement of itraconazolium dinitrate salt. The poor solubility of itraconazole (ITR) results in its variable oral absorption and bioavailability and has also proven to be a major setback in developing an efficient oral delivery system. To improve its solubility and dissolution profile, itraconazolium dinitrate salt (ITRDNT) was prepared and characterized using various spectral and thermal techniques. The morphology of the salt was studied using optical and scanning electron microscopy (SEM). Broth microdilution assay demonstrated antifungal efficacy of ITRDNT similar to ITR against four different fungal strains namely, Asparagillus fumigatus, Microsporum canis, Microsporum gypsum and Trichophyton rubrum. The salt exhibited better solubility profile than ITR in water and a number of pharmaceutical solvents. Dissolution studies revealed the total amount of drug released from ITRDNT in 3 h was four times greater than that of ITR. To further improve dissolution characteristics, the physical mixtures of ITR and ITRDNT with two cyclodextrins, β-cyclodextrin (β-CD) and HP-β-cyclodextrin (HP-β-CD) were prepared and their molar ratios were optimized. It was observed that about 75% of drug was released in 30 min from 1:3 molar ratio of ITRDNT and HP-β-CD physical mixture, which was distinctly higher than ITR commercial capsules (70%). Owing to its facile and economical preparation and substantially better in vitro release profile, the ITRDNT and its CD physical mixtures could be better and cost effective alternatives to ITR and commercial ITR capsules. 23537749 Combination of essential oils and antibiotics reduce antibiotic resistance in plasmid-conferred multidrug resistant bacteria. In this study we investigated the relationship between several selected commercially available essential oils and beta-lactam antibiotics on their antibacterial effect against multidrug resistant bacteria. The antibacterial activity of essential oils and antibiotics was assessed using broth microdilution. The combined effects between essential oils of cinnamon bark, lavender, marjoram, tea tree, peppermint and ampicillin, piperacillin, cefazolin, cefuroxime, carbenicillin, ceftazidime, meropenem, were evaluated by means of the checkerboard method against beta-lactamase-producing Escherichia coli. In the latter assays, fractional inhibitory concentration (FIC) values were calculated to characterize interaction between the combinations. Substantial susceptibility of the bacteria toward natural antibiotics and a considerable reduction in the minimum inhibitory concentrations (MIC) of the antibiotics were noted in some paired combinations of antibiotics and essential oils. Out of 35 antibiotic-essential oil pairs tested, four of them showed synergistic effect (FIC≤0.5) and 31 pairs showed no interaction (FIC>0.5-4.0). The preliminary results obtained highlighted the occurrence of a pronounced synergistic relationship between piperacillin/cinnamon bark oil, piperacillin/lavender oil, piperacillin/peppermint oil as well as meropenem/peppermint oil against two of the three bacteria under study with a FIC index in the range 0.26-0.5. The finding highlighted the potential of peppermint, cinnamon bark and lavender essential oils being as antibiotic resistance modifying agent. Reduced usage of antibiotics could be employed as a treatment strategy to decrease the adverse effects and possibly to reverse the beta-lactam antibiotic resistance. 23192350 Silencing α1,3-fucosyltransferases in human leukocytes reveals a role for FUT9 enzyme during E-selectin-mediated cell adhesion. Leukocyte adhesion during inflammation is initiated by the binding of sialofucosylated carbohydrates expressed on leukocytes to endothelial E/P-selectin. Although the glycosyltransferases (glycoTs) constructing selectin-ligands have largely been identified using knock-out mice, important differences may exist between humans and mice. To address this, we developed a systematic lentivirus-based shRNA delivery workflow to create human leukocytic HL-60 cell lines that lack up to three glycoTs. Using this, the contributions of all three myeloid α1,3-fucosyltransferases (FUT4, FUT7, and FUT9) to selectin-ligand biosynthesis were evaluated. The cell adhesion properties of these modified cells to L-, E-, and P-selectin under hydrodynamic shear were compared with bone marrow-derived neutrophils from Fut4(-/-)Fut7(-/-) dual knock-out mice. Results demonstrate that predominantly FUT7, and to a lesser extent FUT4, forms the selectin-ligand at the N terminus of leukocyte P-selectin glycoprotein ligand-1 (PSGL-1) in humans and mice. Here, 85% reduction in leukocyte interaction was observed in human FUT4(-)7(-) dual knockdowns on P/L-selectin substrates. Unlike Fut4(-/-)Fut7(-/-) mouse neutrophils, however, human knockdowns lacking FUT4 and FUT7 only exhibited partial reduction in rolling interaction on E-selectin. In this case, the third α1,3-fucosyltransferase FUT9 played an important role because leukocyte adhesion was reduced by 50-60% in FUT9-HL-60, 70-80% in dual knockdown FUT7(-)9(-) cells, and ∼85% in FUT4(-)7(-)9(-) triple knockdowns. Gene silencing results are in agreement with gain-of-function experiments where all three fucosyltransferases conferred E-selectin-mediated rolling in HEK293T cells. This study advances new tools to study human glycoT function. It suggests a species-specific role for FUT9 during the biosynthesis of human E-selectin ligands. 23164985 Reproductive and developmental toxicity screening test of 3-cyanopyridine in rats. Crl:CD(SD)rats were given 3-cyanopyridine by gavage at 0, 5, 30 or 180 mg/kg/day. Males were dosed for 42 days beginning 14 days before mating, and females for 40-53 days beginning 14 days before mating to day 3 of lactation, including throughout the mating and gestation periods. General toxicity, mainly liver damage, was observed in males at ≥30 mg/kg/day and in females at ≥5 mg/kg/day. Sertoli cell vacuolation was observed at 180 mg/kg/day, and spermatocyte damages were observed at ≥30 mg/kg/day. Effects on estrous cycles, corpora lutea and implantations, and unsuccessfully mated females, despite additional mating, were observed at 180 mg/kg/day. Delayed initiation of delivery, dystocia, and deaths or moribundities of pregnant females were observed at 180 mg/kg/day, and only two pregnant rats delivered live pups at that dose. The NOAEL for reproductive/developmental toxicity was concluded to be 30 mg/kg/day. 23478338 Rab12 regulates mTORC1 activity and autophagy through controlling the degradation of amino-acid transporter PAT4. Autophagy is an evolutionarily conserved catabolic mechanism that targets intracellular molecules and damaged organelles to lysosomes. Autophagy is achieved by a series of membrane trafficking events, but their regulatory mechanisms are poorly understood. Here, we report small GTPase Rab12 as a new type of autophagic regulator that controls the degradation of an amino-acid transporter. Knockdown of Rab12 results in inhibition of autophagy and in increased activity of mTORC1 (mammalian/mechanistic target of rapamycin complex 1), an upstream regulator of autophagy. We also found that Rab12 promotes constitutive degradation of PAT4 (proton-coupled amino-acid transporter 4), whose accumulation in Rab12-knockdown cells modulates mTORC1 activity and autophagy. Our findings reveal a new mechanism of regulation of mTORC1 signalling and autophagy, that is, quality control of PAT4 by Rab12. 23596058 Metabolism and pathways for denitration of organic nitrates in the human liver. Liver first-pass metabolism differs considerably among organic nitrates but little information exists on the mechanism of denitration of these compounds in hepatic tissue. The metabolism of nitrooxybutyl-esters of flurbiprofen and ferulic-acid, a class of organic nitrates with potential therapeutic implication in variety of different conditions, was investigated in comparison with glyceryl trinitrate (GTN) in human liver by a multiple approach, using a spontaneous metabolism-independent NO donor (NOC-5) as a reference tool. Nitrooxybutyl-esters were rapidly and quantitatively metabolized to their respective parent compounds and the organic nitrate moiety nitrooxybutyl-alcohol (NOBA). Differently from GTN which was rapidly and completely metabolized to nitrite, NOBA was slowly metabolized to nitrate. In contrast to the spontaneous NO donor NOC-5, NOBA and GTN did not generate detectable NO and failed to suppress the activity of cytochromeP450; an enzyme known to be inhibited by NO. The direct identification of NOBA following liver metabolism targets this compound as the functional organic nitrate metabolite of nitrooxybutyl-esters. Moreover the investigation of the pathways for denitration of NOBA and GTN suggests that organic nitrates are not primarily metabolized to NO in the liver but to different extents of nitrite or nitrate depending from their different chemical structure. It follows that cytochromeP450-dependent metabolism of concomitant drugs is not likely to be affected by oral co-administration of organic nitrates. However the first-pass may differently affect the pharmacological profile of organic nitrates in connection with the different extent of denitration and the distinct bioactive species generated and exported from the liver (nitrate or nitrite). 22936205 Configuration space partitioning and matrix buildup scaling for the vibrational configuration interaction method. The accurate computation of anharmonic vibrational states for medium to large molecules is a requirement for the detailed understanding of nonlinear multidimensional infrared spectra and the dynamical information encoded in them. The vibrational configuration interaction (VCI) method constitutes a particularly promising tool in this respect. It is generally hampered though by its unfavorable scaling with respect to system size. We analyze the scaling behavior of several well-known as well as some new approximate VCI schemes in detail, which are complementary to the class of configuration selection schemes developed recently. We find that the combination of a configuration space partitioning, possibly based on configuration selection, with energetic thresholding and resonance screening provides an efficient scheme for the reduction of computational effort involved in VCI calculations while at the same time maintaining sufficient accuracy for the vibrational energies. 23325700 Design, synthesis, in vitro MAO-B inhibitory evaluation, and computational studies of some 6-nitrobenzothiazole-derived semicarbazones. Monoamine oxidase B (MAO-B) is an important drug target for the treatment of neurological disorders. A series of 6-nitrobenzothiazole-derived semicarbazones were designed, synthesized, and evaluated as inhibitors of the rat brain MAO-B isoenzyme. Most of the compounds were found to be potent inhibitors of MAO-B, with IC(50) values in the nanomolar to micromolar range. Molecular docking studies were performed with AutoDock 4.2 to deduce the affinity and binding mode of these inhibitors toward the MAO-B active site. The free energies of binding (ΔG) and inhibition constants (K(i)) of the docked compounds were calculated by the Lamarckian genetic algorithm (LGA) of AutoDock 4.2. Good correlations between the calculated and experimental results were obtained. 1-[(4-Chlorophenyl)(phenyl)methylene]-4-(6-nitrobenzothiazol-2-yl)semicarbazide emerged as the lead MAO-B inhibitor, with top ranking in both the experimental MAO-B assay (IC(50): 0.004±0.001 μM) and in computational docking studies (K(i): 1.08 μM). Binding mode analysis of potent inhibitors suggests that these compounds are well accommodated by the MAO-B active site through stable hydrophobic and hydrogen bonding interactions. Interestingly, the 6-nitrobenzothiazole moiety is stabilized in the substrate cavity with the aryl or diaryl residues extending up into the entrance cavity of the active site. According to our results, docking experiments could be an interesting approach for predicting the activity and binding interactions of this class of semicarbazones against MAO-B. Thus, a binding site model consisting of three essential pharmacophoric features is proposed, and this can be used for the design of future MAO-B inhibitors. 23122100 Short-term comparative study of the influence of fried edible oils intake on the metabolism of essential fatty acids in obese individuals. The effect of breakfast intake of fried oils containing natural antioxidants or a synthetic autooxidation inhibitor on the metabolism of essential fatty acids focused on obese individuals. Serum levels of eicosanoids were compared in individuals before and after intake of different breakfasts. Univariate descriptive analysis was used to characterise the cohort selected for this study and multivariate analysis to reveal statistical differences of normalised eicosanoids concentrations (determined by solid-phase extraction coupled to LC-MS/MS) depending on the edible oil used for breakfast preparation. The results showed that the intake of breakfast prepared with pure sunflower oil subjected to deep frying causes an effect over the eicosanoids profile that enables discrimination versus the rest of individuals. The effect was a significant increase in the concentration of hydroxyoctadecadienoic acid (HODE) metabolites, indicative markers of the intake of fried oils. The concentration of HODE metabolites was lower when the oil contained either natural antioxidants from olive-oil pomace or a synthetic autooxidation inhibitor as dimethylsiloxane. The comparison of the effect of fried sunflower oils with fried extra virgin olive oil shows the benefits associated to the consumption of the latter. 23536517 The protective effects of taurine on experimental acute pancreatitis in a rat model. The aim of this study was to investigate the protective effects of taurine (Tau) on experimental acute pancreatitis (AP) in a rat model by measuring cytokines and oxidant stress markers.Forty rats were randomly divided into four groups: sham, AP, Tau and AP + Tau. AP was induced with sodium taurocholate. No treatment was given to the AP. All rats were killed 5 days later. Pancreatic tissues of rats and blood samples were obtained.Tau treatment significantly decreased serum amylase activity (p < 0.001), total injury score (p < 0.001), malondialdehyde levels (p < 0.001) and myeloperoxidase (MPO) activity (p < 0.001). There was no significant difference between the Tau and AP + Tau groups in serum and pancreatic tumor necrosis factor-α, interleukin (IL)-1β and IL-6 levels (p = 1.000). Histopathologic scores in the AP + Tau and Tau groups were significantly lower compared with the AP group (both p < 0.001).These results showed that Tau reduces lipid peroxidation, amylase and MPO activities and the concentrations of proinflammatory cytokines secondary to AP and also increases superoxide dismutase and glutathione peroxidase activities in rats with sodium taurocholate-induced AP. It also has a marked ameliorative effect at histopathologic lesions. With these effects, Tau protects the cells from oxidative damage, reduces inflammation and promotes regression of pancreatic damage. 23561184 In vitro bioavailability of total selenium and selenium species from seafood. In vitro bioavailability of total selenium and selenium species from different raw seafood has been assessed by using a simulated gastric and intestinal digestion/dialysis method. Inductively coupled plasma-mass spectrometry (ICP-MS) was used to assess total selenium contents after a microwave assisted acid digestion, and also to quantify total selenium in the dialyzable and non-dialyzable fractions. Selenium speciation in the dialyzates was assessed by high performance liquid chromatography (HPLC) coupled with ICP-MS detection. Major Se species (selenium methionine and oxidized selenium methionine) from dialyzate were identified and characterized by HPLC coupled to mass spectrometry (HPLC-MS). Selenocystine was detected at low concentrations while Se-(Methyl)selenocysteine and inorganic selenium species (selenite and selenate) were not detected in the dialyzate. Low bioavailability percentages for total selenium (6.69±3.39 and 5.45±2.44% for fish and mollusk samples, respectively) were obtained. Similar bioavailability percentages was achieved for total selenium as a sum of selenium species (selenocystine plus oxidized selenium methionine and selenium methionine, mainly). HPLC-MS data confirmed SeMet oxidation during the in vitro procedure. 23474218 Anti-tuberculosis neolignans from Piper regnellii. The present study determined the anti-Mycobacterium tuberculosis activities of supercritical CO2 extracts, neolignans eupomatenoid-5 (1), conocarpan (4) and eupomatenoid-3 (7) and their derivatives (2, 3, 5, 6, and 8) from Piper regnellii, as well as their cytotoxicities. The supercritical CO2 extract from leaves was purified by chromatographic methods, yielding compounds (1), (4) and (7), which were identified by (1)H NMR and comparison with literature data. Anti-M. tuberculosis activity (H37Rv and clinical isolates) was evaluated using a resazurin microtiter assay plate (REMA) to determine the MIC. The cytotoxicity assay was carried out in macrophages J774G.8 by sulforhodamine B colorimetric assay. The supercritical CO2 extracts from leaves and stems, and compound (4) showed activity against M. tuberculosis (MIC 15.6μg/ml). Compound (1) showed the best activity (MIC 1.9μg/ml), with good SI. Compounds (7) and (8) showed low activity against M. tuberculosis H37Rv. The derivative compounds did not show increased anti-M. tuberculosis activity. This is the first report, to our knowledge, to describe neolignans from P. regnellii with activity against M. tuberculosis, and compound (1) is a potential candidate for future antituberculosis drugs. 23623838 Maternal nicotine exposure during lactation alters hypothalamic neuropeptides expression in the adult rat progeny. Maternal exposure to nicotine during lactation causes hyperleptinemia in the pups and, at adulthood, these animals are overweight and hyperleptinemic, while, in their hypothalamus, the leptin signaling pathway is reduced, evidencing a central leptin resistance. Then, we evaluated the expression of pro-opiomelanocortin (POMC), alpha-melanocyte stimulating hormone (α-MSH), cocaine and amphetamine-regulated transcript (CART), neuropeptide Y (NPY), agouti-related peptide (AgRP) and others in different hypothalamic nuclei in order to better understand the mechanisms underlying the obese phenotype observed in these animals at adulthood. On the 2nd postnatal day (P2), dams were subcutaneously implanted with osmotic minipumps releasing nicotine (NIC-6mg/kg/day) or saline for 14days. Offspring were killed in P180 and immunohistochemistry and Western blot analysis were carried out. Significance data had p<0.05. Adult NIC offspring showed more intense NPY staining in the paraventricular nucleus (PVN) (+21%) and increased number of POMC-positive cells in the: arcuate nucleus (+33%), as an increase in fiber density of α-MSH in PVN (+85%). However, the number of CART-positive cells was reduced in the PVN (-25%). CRH staining was more intense in NIC offspring (+136%). Orexins and AgRP were not altered. Thus, maternal nicotine exposure changes hypothalamic neuropeptides in the adult progeny that is partially compatible with leptin resistance. 23384834 Glucocorticoid-induced suppression of β-cell proliferation is mediated by Mig6. Glucocorticoids can cause steroid-induced diabetes or accelerate the progression to diabetes by creating systemic insulin resistance and decreasing functional β-cell mass, which is influenced by changes in β-cell function, growth, and death. The synthetic glucocorticoid agonist dexamethasone (Dex) is deleterious to functional β-cell mass by decreasing β-cell function, survival, and proliferation. However, the mechanism by which Dex decreases β-cell proliferation is unknown. Interestingly, Dex induces the transcription of an antiproliferative factor and negative regulator of epidermal growth factor receptor signaling, Mig6 (also known as gene 33, RALT, and Errfi1). We, therefore, hypothesized that Dex impairs β-cell proliferation by increasing the expression of Mig6 and thereby decreasing downstream signaling of epidermal growth factor receptor. We found that Dex induced Mig6 and decreased [(3)H]thymidine incorporation, an index of cellular replication, in mouse, rat, and human islets. Using adenovirally delivered small interfering RNA targeted to Mig6 in rat islets, we were able to limit the induction of Mig6 upon exposure to Dex, compared with islets treated with a control virus, and completely rescued the Dex-mediated impairment in replication. We demonstrated that both Dex and overexpression of Mig6 attenuated the phosphorylation of ERK1/2 and blocked the G(1)/S transition of the cell cycle. In conclusion, Mig6 functions as a molecular brake for β-cell proliferation during glucocorticoid treatment in β-cells, and thus, Mig6 may be a novel target for preventing glucocorticoid-induced impairments in functional β-cell mass. 23076740 Treadmill exercise promotes interleukin 15 expression in skeletal muscle and interleukin 15 receptor alpha expression in adipose tissue of high-fat diet rats. Interleukin 15 (IL-15) has recently been proposed as a myokine involved in regulating lipid metabolism. We investigated the effect of exercise training on IL-15 content in skeletal muscle and expression of IL-15 receptor (IL-15R) in adipose tissue of obese rats. After 12 weeks of a high-fat diet, obese rats underwent treadmill running at 26 m/min (60 min each, 5 days/week for 8 weeks). High-fat diet induced obesity, with increased body weight, body fat, and lipid profile. The level of IL-15 immunoreactivity (IL-15-ir) in plasma and gastrocnemius muscle was lower in obese than control rats, and the mRNA level of IL-15 in gastrocnemius muscle was markedly decreased. The mRNA and protein levels of IL-15R in adipose tissue were markedly lower in obese rats. Compared with sedentary obese rats, treadmill running showed decreased body weight and elevated mRNA expression of IL-15 in muscle and elevated IL-15-ir level in plasma and muscle. The mRNA and protein level of IL-15R were increased in adipose tissue in treadmill running obese rats. Our results showed that exercise training improve obesity and reversed the downregulation of the IL-15 in muscle and IL-15R in adipose tissue induced by high-fat diet. 23464873 Progress, challenges, and opportunities in two-dimensional materials beyond graphene. Graphene's success has shown that it is possible to create stable, single and few-atom-thick layers of van der Waals materials, and also that these materials can exhibit fascinating and technologically useful properties. Here we review the state-of-the-art of 2D materials beyond graphene. Initially, we will outline the different chemical classes of 2D materials and discuss the various strategies to prepare single-layer, few-layer, and multilayer assembly materials in solution, on substrates, and on the wafer scale. Additionally, we present an experimental guide for identifying and characterizing single-layer-thick materials, as well as outlining emerging techniques that yield both local and global information. We describe the differences that occur in the electronic structure between the bulk and the single layer and discuss various methods of tuning their electronic properties by manipulating the surface. Finally, we highlight the properties and advantages of single-, few-, and many-layer 2D materials in field-effect transistors, spin- and valley-tronics, thermoelectrics, and topological insulators, among many other applications. 22493952 New triterpenoids from the stem bark of Hypodaphnis zenkeri. A new pentacyclic triterpenoid and three new derivatives based on the taraxer-14-ene skeleton with a C-28 attached a carboxylic acid group have been isolated from the stem bark of Hypodaphnis zenkeri, together with six known compounds. The new product was identified as 2α,3α-dihydroxytaraxer-14-en-28-oic acid (1). Its derivatives, 2α,3α-diacetyltaraxer-14-en-28-oic acid (2), 2α,3α-di-O-carbonyl-2α,3α-dihydroxytaraxer-14-en-28-oic acid (3) and 2α,3α-dipropionyltaraxer-14-en-28-oic acid (4) were obtained by semisynthesis. The known compounds were identified as 3β-hydroxytaraxer-14-en-28-oic acid or aleuritolic acid (5) (McPhail, A.T., McPhail, D.R., Wani, M.C., Wall, M.E. & A.W., Nicholas, A.W. (1989). Identity of maprounic acid with aleuritolic acid. Revision of the structure of maprounic acid: X-ray crystal structure of p-bromobenzyl acetylmaprounate. Journal Natural Products, 52, 212), 3α-hydroxytaraxer-14-en-28-oic acid or isoaleuritolic acid (6), 3α-acetyltaraxer-14-en-28-oic acid acetate or aleuritolic acid acetate (7) (Chaudhuri, S.K., Fullas, F., Brown, D.M., Wani, M.C., Wall, M.E., Cai, L., … Kinghorn, A.D. (1995). Isolation and structural elucidation of pentacyclic triterpenoids from Maprounea africana. Journal of Natural Products, 58, 1-9), 3-oxo-taraxer-14-ene or taraxerone (8) β-sitosterol (9) and stigmasterol (10) (Kamboj & Saluja, 2011), together with fatty acids. Their structures were established on the basis of spectroscopic studies and chemical transformations. 23414209 Developing the potential ophthalmic applications of pilocarpine entrapped into polyvinylpyrrolidone-poly(acrylic acid) nanogel dispersions prepared by γ radiation. The aim of this study was to improve the stability and bioavailability of pilocarpine in order to maintain an adequate concentration of the pilocarpine at the site of action for prolonged period of time. Thus, pH-sensitive polyvinylpyrrolidone-poly(acrylic acid) (PVP/PAAc) nanogels prepared by γ radiation-induced polymerization of acrylic acid (AAc) in an aqueous solution of polyvinylpyrrolidone (PVP) as a template polymer were used to encapsulate pilocarpine. Factors affecting size and encapsulation efficiency were optimized to obtain nanogel suitable for entrapping drug efficiently. The PVP/PAAc nanogel particles were characterized by dynamic light scattering (DLS), zeta potential, Fourier transform infrared spectroscopy (FTIR), and transmission electron microscopy (TEM), and their size can be controlled by the feed composition and concentration as well as the irradiation dose. Pilocarpine was loaded into the nanogel particles through electrostatic interactions where the AAc-rich nanogels exhibited the highest loading efficiency. The transmittance, mucoadhesion, and rheological characteristics of the nanogel particles were studied to evaluate their ocular applicability. The in vitro release study conducted in simulated tear fluid showed a relatively long sustained release of pilocarpine from the prepared PVP/PAAc nanogel particles if compared with pilocarpine in solution. 23265889 Lead optimization of a dihydropyrrolopyrimidine inhibitor against phosphoinositide 3-kinase (PI3K) to improve the phenol glucuronic acid conjugation. Our lead compound for a phosphoinositide 3-kinase (PI3K) inhibitor (1) was metabolically unstable because of rapid glucuronidation of the phenol moiety. Based on structure-activity relationship (SAR) information and a FlexSIS docking simulation score, aminopyrimidine was identified as a bioisostere of phenol. An X-ray structure study revealed a hydrogen bonding pattern of aminopyrimidine derivatives. Finally, aminopyrimidine derivatives 33 showed strong tumor growth inhibition against a KPL-4 breast cancer xenograft model in vivo. 23564882 Expression of a novel mRNA transcript for human microsomal epoxide hydrolase (EPHX1) is regulated by short open reading frames within its 5'-untranslated region. Microsomal epoxide hydrolase (mEH, EPHX1) is a critical xenobiotic-metabolizing enzyme, catalyzing both detoxification and bioactivation reactions that direct the disposition of chemical epoxides, including the carcinogenic metabolites of several polycyclic aromatic hydrocarbons. Recently, we discovered that a previously unrecognized and primate-specific EPHX1 transcript, termed E1-b, was actually the predominant driver of EPHX1 expression in all human tissues. In this study, we identify another human EPHX1 transcript, designated as E1-b'. Unusually, both the E1-b and E1-b' mRNA transcripts are generated from the use of a far upstream gene promoter, localized ∼18.5 kb 5'-upstream of the EPHX1 protein-coding region. Although expressed at comparatively lower levels than E1-b, the novel E1-b' transcript is readily detected in all tissues examined, with highest levels maintained in human ovary. The E1-b' mRNA possesses unusual functional features in its 5'-untranslated region, including a GC-rich leader sequence and two upstream AUGs that encode for short peptides of 26 and 17 amino acids in length, respectively. Results from in vitro transcription/translation assays and direct transfection in mammalian cells of either the E1-b' transcript or the encoded peptides demonstrated that the E1-b' upstream open reading frames (uORFs) are functional, with their presence markedly inhibiting the translation of EPHX1 protein, both in cis and in trans configurations. These unique uORF peptides exhibit no homology to any other known uORF sequences but likely function to mediate post-transcription regulation of EPHX1 and perhaps more broadly as translational regulators in human cells. 23149118 Response to variable light intensity in photoacclimated algae and cyanobacteria exposed to atrazine. Atrazine is frequently detected in freshwater ecosystems exposed to agricultural waste waters and runoffs worldwide and it can affect non-target organisms (mainly photoautotrophic) and modify community structure. Meanwhile, light environment is known to vary between aquatic ecosystems, but also before and during the exposure to atrazine and these variations may modify the sensitivity to atrazine of photoautotroph organisms. In this study, 10 species of phytoplankton (chlorophytes, baccilariophytes and cyanophytes) acclimated to low or high light intensities were exposed to atrazine and light of different intensities to compare their combined effect. Our data showed that chlorophytes and baccilariophytes were more resistant to atrazine compared to cyanophytes for all light conditions. Atrazine was found to inhibit Φ'(M), Ψ(0), P(M) and non-photochemical quenching for all species indicating an effect on electron transport, primary production and photoregulation processes. These data also indicate a higher sensitivity of Ψ(0) (average Ψ(0)-EC(50) of 91 ± 11 nM or 19.6 ± 0.9 μgL(-1)) compared to Φ'(M) (average Φ'(M)-EC(50) of 217 ± 19 nM or 46.8 ± 4.1 μgL(-1)) and suggest that photoregulation processes activated in presence of light decrease the effect of atrazine. We also showed that increasing light intensity decreased Φ'(M)-EC(50) in both low (except baccilariophytes) and high light acclimated conditions. Despite this similarity, most species acclimated to high light were found to have higher or similar Φ'(M)-EC(50) compared to low light acclimated cells and thus, were less sensitive to atrazine in low light and high light environments. We concluded that an increase in the plastoquinone pool induced by acclimation to high light decreased the sensitivity to atrazine in phytoplankton and we hypothesized that the effect observed was the result of a dilution of atrazine toxicity through increased binding site availability (quinones) combined with increased photoregulation processes capacity. 23624608 Excitation and Adaptation in Bacteria-a Model Signal Transduction System that Controls Taxis and Spatial Pattern Formation. The machinery for transduction of chemotactic stimuli in the bacterium E. coli is one of the most completely characterized signal transduction systems, and because of its relative simplicity, quantitative analysis of this system is possible. Here we discuss models which reproduce many of the important behaviors of the system. The important characteristics of the signal transduction system are excitation and adaptation, and the latter implies that the transduction system can function as a "derivative sensor" with respect to the ligand concentration in that the DC component of a signal is ultimately ignored if it is not too large. This temporal sensing mechanism provides the bacterium with a memory of its passage through spatially- or temporally-varying signal fields, and adaptation is essential for successful chemotaxis. We also discuss some of the spatial patterns observed in populations and indicate how cell-level behavior can be embedded in population-level descriptions. 23506316 Mechanics of interaction and atomic-scale wear of amplitude modulation atomic force microscopy probes. Wear is one of the main factors that hinders the performance of probes for atomic force microscopy (AFM), including for the widely used amplitude modulation (AM-AFM) mode. Unfortunately, a comprehensive scientific understanding of nanoscale wear is lacking. We have developed a protocol for conducting consistent and quantitative AM-AFM wear experiments. The protocol involves controlling the tip-sample interaction regime during AM-AFM scanning, determining the tip-sample contact geometry, calculating the peak repulsive force and normal stress over the course of the wear test, and quantifying the wear volume using high-resolution transmission electron microscopy imaging. The peak repulsive tip-sample interaction force is estimated from a closed-form equation accompanied by an effective tip radius measurement procedure, which combines transmission electron microscopy and blind tip reconstruction. The contact stress is estimated by applying Derjaguin-Müller-Toporov contact mechanics model and also numerically solving a general contact mechanics model recently developed for the adhesive contact of arbitrary axisymmetric punch shapes. We discuss the important role that the assumed tip shape geometry plays in calculating both the interaction forces and the contact stresses. Contact stresses are significantly affected by the tip geometry while the peak repulsive force is mainly determined by experimentally controlled parameters, specifically, the free oscillation amplitude and amplitude ratio. The applicability of this protocol is demonstrated experimentally by assessing the performance of diamond-like carbon-coated and silicon-nitride-coated silicon probes scanned over ultrananocrystalline diamond substrates in repulsive mode AM-AFM. There is no sign of fracture or plastic deformation in the case of diamond-like carbon; wear could be characterized as a gradual atom-by-atom process. In contrast, silicon nitride wears through removal of the cluster of atoms and plastic deformation. 23466342 Reversal of P-glycoprotein-mediated multidrug resistance is induced by mollugin in MCF-7/adriamycin cells. P-glycoprotein (P-gp), an important efflux transporter, is encoded by the MDR1 class of genes and is a central element of the multidrug resistance (MDR) phenomenon in cancer cells. In the present study, we investigated whether mollugin, purified from roots of Rubica cordifolia L., down-regulated MDR1 expression in MCF-7/adriamycin (MCF-7/adr) cells, a human breast multidrug-resistant cancer cell line. Mollugin treatment significantly inhibited MDR1 expression by blocking MDR1 transcription. Mollugin treatment also significantly increased intracellular accumulation of the fluorescently-tagged P-gp substrate, rhodamine-123. The suppression of MDR1 promoter activity and protein expression was mediated through mollugin-induced activation of AMP-activated protein kinase (AMPK). Furthermore, mollugin inhibited MDR1 expression through the suppression of NF-κB and CREB activation. Interestingly, mollugin also inhibited COX-2 expression. These results suggest that mollugin treatment enhanced suppression of P-gp expression by inhibiting the NF-κB signaling pathway and COX-2 expression, as well as attenuating CRE transcriptional activity through AMPK activation. 23363003 Development of Inhibitors of the PAS-B Domain of the HIF-2α Transcription Factor. Hypoxia inducible factors (HIFs) are heterodimeric transcription factors induced in a variety of pathophysiological settings, including cancer. We describe the first detailed structure-activity relationship study of small molecules designed to inhibit HIF-2α-ARNT heterodimerization by binding an internal cavity of the HIF-2α PAS-B domain. Through a series of biophysical characterizations of inhibitor-protein interactions (NMR and X-ray crystallography), we have established the structural requirements for artificial inhibitors of the HIF-2α-ARNT PAS-B interaction. These results may serve as a foundation for discovering therapeutic agents that function by a novel mode of action. 23331859 Oxytocin in the central amygdaloid nucleus modulates the neuroendocrine responses induced by hypertonic volume expansion in the rat. The present study investigated the involvement of the oxytocinergic neurones that project into the central amygdala (CeA) in the control of electrolyte excretion and hormone secretion in unanaesthetised rats subjected to acute hypertonic blood volume expansion (BVE; 0.3 M NaCl, 2 ml/100 g of body weight over 1 min). Oxytocin and vasopressin mRNA expression in the paraventricular (Pa) and supraoptic nucleus (SON) of the hypothalamus were also determined using the real time-polymerase chain reaction and in situ hybridisation. Male Wistar rats with unilaterally implanted stainless steel cannulas in the CeA were used. Oxytocin (1 μg/0.2 μl), vasotocin, an oxytocin antagonist (1 μg/0.2 μl) or vehicle was injected into the CeA 20 min before the BVE. In rats treated with vehicle in the CeA, hypertonic BVE increased urinary volume, sodium excretion, plasma oxytocin (OT), vasopressin (AVP) and atrial natriuretic peptide (ANP) levels and also increased the expression of OT and AVP mRNA in the Pa and SON. In rats pre-treated with OT in the CeA, previously to the hypertonic BVE, there were further significant increases in plasma AVP, OT and ANP levels, urinary sodium and urine output, as well as in gene expression (AVP and OT mRNA) in the Pa and SON compared to BVE alone. Vasotocin reduced sodium, urine output and ANP levels, although no changes were observed in plasma AVP and OT levels or in the expression of the AVP and OT genes in both hypothalamic nuclei. The results of the present study suggest that oxytocin in the CeA exerts a facilitatory role in the maintenance of hydroelectrolyte balance in response to changes in extracellular volume and osmolality. 23537160 New triterpene glycoside and other chemical constituents from the leaves of Swartzia apetala Raddi var. glabra. A new triterpene saponin (1) was isolated from a methanol extract of Swartzia apetala Raddi var. glabra, together with the flavonoids mauritianin (2), kaempferol (3) and the triterpene saponin β-D-glucopyranosyl 3β-hydroxy-olean-12-en-28-oate (4). These compounds were characterised on the basis of their spectral data, mainly one-dimension (1D; (1)H, (13)C, APT) and two-dimension (2D; (1)H-(1)H-COSY, HMQC and HMBC) nuclear magnetic resonance (NMR) and HR-ESI-MS, and comparison with values in the literature. The analysis by HR-ESI-MS showed a mass compatible with that of triterpene saponin 1. This proposal was supported by molecular modelling. LC-HR-ESI-MS experiment was also used to evaluate the purity of 1 and allowed to speculate about the possibility of the presence of 5 in very small quantity. The extract and four compounds were assayed for antifungal activity against nine strains of Candida spp. 22981949 The involvement of Reelin in neurodevelopmental disorders. Reelin is a glycoprotein that serves important roles both during development (regulation of neuronal migration and brain lamination) and in adulthood (maintenance of synaptic function). A number of neuropsychiatric disorders including autism, schizophrenia, bipolar disorder, major depression, Alzheimer's disease and lissencephaly share a common feature of abnormal Reelin expression in the brain. Altered Reelin expression has been hypothesized to impair neuronal connectivity and synaptic plasticity, leading ultimately to the cognitive deficits present in these disorders. The mechanisms for abnormal Reelin expression in some of these disorders are currently unknown although possible explanations include early developmental insults, mutations, hypermethylation of the promoter for the Reelin gene (RELN), miRNA silencing of Reelin mRNA, FMRP underexpression and Reelin processing abnormalities. Increasing Reelin expression through pharmacological therapies may help ameliorate symptoms resulting from Reelin deficits. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. 22835502 Drug repurposing in pediatrics and pediatric hematology oncology. Drug 'repurposing', that is, using old drugs for new indications, has been proposed as a more efficient strategy for drug development than the current standard of beginning with novel agents. In this review, we explore the scope of drug repurposing in pediatric hematology oncology and in pediatrics in general. Drugs commonly used in children were identified using the Harriet Lane Handbook (HLH) and searched in PubMed for different uses. Additional drugs were identified by searching PubMed and Google.com for 'drug repurposing' or 'drug repositioning'. Almost 10% of drugs with primary uses in pediatrics have been repurposed in pediatric hematology oncology or pediatrics. The observant clinician, pharmacologist and translational bioinformatician, as well as structural targeting, will have a role in discovering new repurposing opportunities. 23394608 Growth of highly fluorescent polyethylene glycol- and zwitterion-functionalized gold nanoclusters. We have prepared and characterized a new set of highly fluorescent gold nanoclusters (AuNCs) using one-step aqueous reduction of a gold precursor in the presence of bidentate ligands made of lipoic acid anchoring groups, appended with either a poly(ethylene glycol) short chain or a zwitterion group. The AuNCs fluoresce in the red to near-infrared region of the optical spectrum with emission centered at ∼750 nm and a quantum yield of ∼10-14%, and they exhibit long fluorescence lifetimes (up to ∼300 ns). Dispersions of these AuNCs exhibit great long-term colloidal stability, over a wide range of pHs (2-13) and in the presence of high electrolyte concentrations, and a strong resistance to reducing agents such as glutathione. The growth strategy further permitted the controlled, in situ functionalization of the NCs with reactive groups (e.g., carboxylic acid or amine), making these nanoclusters compatible with common and simple-to-implement coupling strategies, such as carbodiimide chemistry. These properties combined make these fluorescent NCs greatly promising for use in various imaging and sensing applications where NIR and long-lived excitations are desired. 23291050 Cholinesterase and carboxylesterase inhibition in Planorbarius corneus exposed to binary mixtures of azinphos-methyl and chlorpyrifos. Though pesticide mixtures are commonly encountered in fresh water systems, the knowledge of their effects on non-target aquatic species is scarce. The present investigation was undertaken to explore the in vivo inhibition of the freshwater gastropod snail Planorbarius corneus cholinesterase (ChE) and carboxylesterases (CES) activities by the organophosphorus pesticides azinphos-methyl (AZM) and chlorpyrifos (CPF). To this end, snails were exposed for 48 h to different concentrations of AZM and CPF in single-chemical and binary-mixture studies, and ChE and CES activities were measured in the whole soft body tissues and hemolymph. ChE activity was measured with acetylthiocholine as substrate and CES activity was measured with four substrates: p-nitrophenyl acetate, p-nitrophenyl butyrate, 1- and 2-naphthyl acetate. Single-chemical experiments showed that CPF was a more potent inhibitor of ChE activity than AZM (350 and 27 times for the whole soft tissue and hemolymph, respectively). CES were 15 times more sensitive than ChE when the activities were measured in the whole soft tissue of the animals exposed to AZM. Based on a default assumption of concentration addition, P. corneus snails were exposed to mixtures of AZM+CPF designed to yield predicted soft tissue ChE inhibitions of 31% (mixture 1), 50% (mixture 2) and 61% (mixture 3). Results showed that ChE inhibition produced by mixture 1 followed a model of concentration addition. In contrast, the other mixtures showed synergism, both in whole soft tissue and hemolymph. In addition, results obtained when the snails were exposed sequentially to the pesticides showed that the sequence AZM/CPF produced at 48 h a higher ChE inhibition than the sequence CPF/CPF. A range of metabolic pathways and responses associated with bioactivation or detoxification may play important roles in organophosphorus interactions. In particular, the data presented in the present study indicate that CES enzymes would be important factors in determining the effects of the mixtures of OPs on P. corneus ChE activity. 23640884 Distinct role of PYK2 in mediating thromboxane generation downstream of both G12/13 and integrin αiibβ in platelets. Proline-rich tyrosine kinase 2 (Pyk2) is activated by various agonists in platelets. We evaluated the signaling mechanism and the functional role of Pyk2 in platelets by using pharmacological inhibitors and Pyk2-deficient platelets. We found that platelet aggregation and secretion in response to 2-MeSADP and AYPGKF were diminished in the presence of Pyk2 inhibitors or in Pyk2-deficient platelets, suggesting that Pyk2 plays a positive regulatory role in platelet functional responses. It has been shown that ADP-, but not thrombin-, induced thromboxane (TxA2) generation depends on integrin signaling. Unlike ADP, thrombin activates G12/13 pathways, and G12/13 pathways can substitute for integrin signaling for TxA2 generation. We found that Pyk2 was activated downstream of both G12/13 and integrin-mediated pathways, and both 2-MeSADP- and AYPGKF-induced TxA2 generation was significantly diminished in Pyk2-deficient platelets. In addition, TxA2 generation induced by co-stimulation of Gi and Gz pathways, which is dependent on integrin signaling, was inhibited by blocking Pyk2. Furthermore, inhibition of 2-MeSADP-induced TxA2 generation by fibrinogen receptor antagonist was not rescued by co-stimulation of G12/13 pathways in the presence of Pyk2 inhibitor. We conclude that Pyk2 is a common signaling effector downstream of both G12/13 and integrin αIIbβ3 signaling which contributes to thromboxane generation. 23425034 Binding of glyco-acridine derivatives to lysozyme leads to inhibition of amyloid fibrillization. While amyloid-related diseases are at the center of intense research efforts, no feasible cure is currently available for these diseases. The experimental and computational techniques were used to study the ability of glyco-acridines to prevent lysozyme amyloid fibrillization in vitro. Fluorescence spectroscopy and atomic force microscopy have shown that glyco-acridines inhibit amyloid aggregation of lysozyme; the inhibition efficiency characterized by the half-maximal inhibition concentration IC50 was affected by the structure and concentration of the derivative. We next investigated relationship between the binding affinity and the inhibitory activity of the compounds. The semiempirical quantum PM6-DH+ method provided a good correlation pointing to the importance of quantum effects on the binding of glyco-acridine derivatives to lysozyme. The contribution of linkers may be explained by the valence bond theory. Our data provide a basis for the development of new small molecule inhibitors effective in therapy of amyloid-related diseases. 22883213 New alloferon analogues: synthesis and antiviral properties. We have extended our study on structure/activity relationship studies of insect peptide alloferon (H-His-Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-His-Gly-OH) by evaluating the antiviral effects of new alloferon analogues. We synthesized 18 alloferon analogues: 12 peptides with sequences shortened from N- or C-terminus and 6 N-terminally modified analogues H-X(1)-Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-His-Gly-OH, where X(1) = Phe (13), Tyr (14), Trp (15), Phg (16), Phe(p-Cl) (17), and Phe(p-OMe) (18). We found that most of the evaluated peptides inhibit the replication of Human Herpesviruses or Coxsackievirus B2 in Vero, HEp-2 and LLC-MK(2) cells. Our results indicate that the compound [3-13]-alloferon (1) exhibits the strongest antiviral activity (IC(50) = 38 μM) among the analyzed compound. Moreover, no cytotoxic activity against the investigated cell lines was observed for all studied peptides at concentration 165 μM or higher. 23428109 Evaluation of difluoromethyl ketones as agonists of the γ-aminobutyric acid type B (GABAB) receptor. The design, synthesis, biological evaluation, and in vivo studies of difluoromethyl ketones as GABAB agonists that are not structurally analogous to known GABAB agonists, such as baclofen or 3-aminopropyl phosphinic acid, are presented. The difluoromethyl ketones were assembled in three synthetic steps using a trifluoroacetate-release aldol reaction. Following evaluation at clinically relevant GABA receptors, we have identified a difluoromethyl ketone that is a potent GABAB agonist, obtained its X-ray structure, and presented preliminary in vivo data in alcohol-preferring mice. The behavioral studies in mice demonstrated that this compound tended to reduce the acoustic startle response, which is consistent with an anxiolytic profile. Structure-activity investigations determined that replacing the fluorines of the difluoromethyl ketone with hydrogens resulted in an inactive analogue. Resolution of the individual enantiomers of the difluoromethyl ketone provided a compound with full biological activity at concentrations less than an order of magnitude greater than the pharmaceutical, baclofen. 23321677 The first self-sustainable microbial fuel cell stack. This study reports for the first time on the development of a self-sustainable microbial fuel cell stack capable of self-maintenance (feeding, hydration, sensing & reporting). Furthermore, the stack system is producing excess energy, which can be used for improved functionality. The self-maintenance is performed by the stack powering single and multi-channel peristaltic pumps. 23274907 Permanent Neonatal Diabetes in INSC94Y Transgenic Pigs. Mutations in the insulin (INS) gene may cause permanent neonatal diabetes mellitus (PNDM). Ins2 mutant mouse models provided important insights into the disease mechanisms of PNDM but have limitations for translational research. To establish a large animal model of PNDM, we generated INS(C94Y) transgenic pigs. A line expressing high levels of INS(C94Y) mRNA (70-86% of wild-type INS transcripts) exhibited elevated blood glucose soon after birth but unaltered β-cell mass at the age of 8 days. At 4.5 months, INS(C94Y) transgenic pigs exhibited 41% reduced body weight, 72% decreased β-cell mass (-53% relative to body weight), and 60% lower fasting insulin levels compared with littermate controls. β-cells of INS(C94Y) transgenic pigs showed a marked reduction of insulin secretory granules and severe dilation of the endoplasmic reticulum. Cataract development was already visible in 8-day-old INS(C94Y) transgenic pigs and became more severe with increasing age. Diabetes-associated pathological alterations of kidney and nervous tissue were not detected during the observation period of 1 year. The stable diabetic phenotype and its rescue by insulin treatment make the INS(C94Y) transgenic pig an attractive model for insulin supplementation and islet transplantation trials, and for studying developmental consequences of maternal diabetes mellitus. 23414808 Synthesis of tetrazole analogues of phosphonohydroxamic acids: an attempt to improve the inhibitory activity against the DXR. This work is focused on the design of new antimicrobial drugs and on the development of lipophilic inhibitors of the DXR, the second enzyme of the MEP pathway for the biosynthesis of isoprene units in most bacteria, by replacing the phosphonate group of fosmidomycin derivatives by a tetrazoyl moiety capable of multiple hydrogen bonding. The N- and C-substituted tetrazole analogues of phosphonohydroxamate inhibitors were synthesized and tested on the DXR of Escherichia coli. This work points out the hypothesis that the phosphonate/phosphate recognition site might be too rigid to accommodate other functional groups. 23358572 Dynamic pH mapping in microfluidic devices by integrating adaptive coatings based on polyaniline with colorimetric imaging techniques. In this paper we present a microfluidic device that has integrated pH optical sensing capabilities based on polyaniline. The optical properties of polyaniline coatings change in response to the pH of the solution that is flushed inside the microchannel offering the possibility of monitoring pH in continuous flow over a wide pH range throughout the entire channel length. This work also features an innovative detection system for spatial localisation of chemical pH gradients along microfluidic channels through the use of a low cost optical device. Specifically, the use of a microfluidic channel coated with polyaniline is shown to respond colorimetrically to pH and that effect is detected by the detection system, even when pH gradients are induced within the channel. This study explores the capability of detecting this gradient by means of imaging techniques and the mapping of the camera's response to its corresponding pH after a successful calibration process. The provision of an inherently responsive channel means that changes in the pH of a sample moving through the system can be detected dynamically using digital imaging along the entire channel length in real time, without the need to add reagents to the sample. This approach is generic and can be applied to other chemically responsive coatings immobilised on microchannels. 23373513 Synthesis of superparamagnetic particles with tunable morphologies: the role of nanoparticle-nanoparticle interactions. Superparamagnetic microparticles are extensively used in the purification of biomolecules due to the speed and ease of magnetic separation. It is desirable that the microparticles used in biological affinity separations have both high surface area and high magnetic mobility to facilitate a high binding capacity of target biomolecules and their rapid removal from solution, respectively. Scaling laws for conventional spherical superparamagnetic microparticles are such that increasing the microparticle specific surface area results in a significant decrease in the magnetic mobility. More favorable combinations of these key parameters can be found if alternative microparticle morphologies are developed for use in affinity separations. Emulsion-templated self-assembly of iron oxide nanoparticles into microparticles using oil-in-water emulsions was carried out using a modified Couette shear mixer with separate inlet ports for the oil and aqueous phases, enabling high throughput microparticle synthesis. By controlling the dissolved nanoparticle concentration and nanoparticle surface activity at the droplet interfaces, the resulting microparticles were tuned to spherical, dimpled, or crumpled morphologies. The specific binding capacity and magnetic mobility of each type of microparticle were measured by a peroxidase-based colorimetric assay and by their magnetic field-induced motion in a viscous fluid, respectively. Superparamagnetic microparticles with dimpled and crumpled morphologies were found to have higher specific binding capacities compared to spherical microparticles, while maintaining high magnetic field velocities due to their high iron oxide content. Superparamagnetic microparticles with these novel morphologies would make excellent tools for affinity-based bioseparations where binding capacity and magnetic mobility are key factors. 23638991 Non-Contact AFM Imaging in Water Using Electrically-Driven Cantilever Vibration. An atomic force microscopy (AFM) imaging mode is presented that can simultaneously record surface topography and local electrical properties in aqueous solutions without mechanical contact between the AFM tip and the sample. The interaction between the electrically biased tip and the grounded sample in aqueous medium causes the AFM cantilever to vibrate. This operation mode is based on the previously-developed SPFM technique, though using water as the medium instead of air introduces some important practical and theoretical differences, and also greatly extends the applicability of this technique. There are two vibration modes, one at the frequency of the applied voltage (ω) and one at twice this frequency (2ω). The surface topography can be imaged using feedback control of the 2 vibration amplitude, which is very sensitive to the tip-sample separation distance in the range of 1~10 nm. The amplitude and phase of the 1 vibration can be recorded simultaneously during imaging to obtain information on local surface charge or potential differences. Similar techniques exist for imaging in air or vacuum, but the addition of a polarizable medium such as water adds significant theoretical and practical complexities. This paper addresses those complexities, and demonstrates the effectiveness of the technique for surface imaging and analysis in aqueous environments. 23202848 Identification of novel chromenone derivatives as interleukin-5 inhibitors. A series of (E)-5-alkoxy-3-(3-phenyl-3-oxoprop-1-enyl)-4H-chromen-4-ones (4) and (E)-5-alkoxy-3-(3-hydroxy-3-phenylprop-1-enyl)-4H-chromen-4-ones (5) were synthesized and evaluated for their IL-5 inhibitory activity. Propenone analogs 4 possess some of the structurally important characteristics of isoflavone 2 and chalcone 3 previously known as potent IL-5 inhibitor. However, the inhibitory activity of 4 was weak and therefore this structural hybridization appears to be ineffective for the design of IL-5 inhibitor. Meanwhile the potent activity profile of compounds 5 was discovered. This enhanced activity of 5 compared to 4 could be due to the effective location of hydroxyl group of allylic alcohol moiety of 5 in the 3D structure. The electron withdrawing substituents at position 4 of phenyl ring of 5 enhances the activity possibly due to an increase in the strength of hydrogen bonding property of hydroxyl group of allylic alcohol moiety. 23567035 Safety assessment of the standardized extract of Carissa edulis root bark in rats. ETHNOPHARMACOLOGICAL RELEVANCE: Preparations of Carissa edulis (Vahl) have been used in the Nigerian traditional medicine for the management of fever, sickle cell disease, epilepsy, pain and inflammation for many years and their efficacy is widely acclaimed among the Hausa communities of northern Nigeria. AIM OF THE STUDY: The present studies aimed at evaluating the toxicological properties of the standardized ethanol extract of C. edulis root bark in rats, in order to determine its safety and to complement earlier efficacy studies on this widely used medicinal plant. MATERIALS AND METHODS: High performance liquid chromatography (HPLC) and preliminary phytochemical analysis of the extract were conducted and its oral median lethal dose (LD50) determined. Signs of toxicity, body weight changes, relative organs weight, feed and water consumption were monitored following 28 days of daily oral administration of graded doses of the extract in rats. Effects of the extract on sex hormones, low- and high-density lipids, hematological and biochemical parameters were examined and pathological changes of the vital organs after treatment with the extract were also investigated. RESULTS: The oral LD50 of the extract was estimated to be >5000mg/kg. The body weights of treated rats increased progressively, but the changes were not significantly different from the control groups. The extract neither produces significant changes in feed and water consumption nor affected the relative organs weight. Although some variations were observed in hormonal and lipid profiles hematological and biochemical indices, these important parameters were normal and within acceptable limits. No lesions or pathological changes of the organs attributable to treatment with the extract were observed from the pathological examinations. The HPLC fingerprint of the extract shows a spectrum profile characteristic of C. edulis, while the preliminary phytochemical screening revealed the presence of saponins, flavonoids, tannins, anthraquinones and cardiac glycosides. CONCLUSION: Our results provided evidence that short-term administration of the standardized ethanol extract of C. edulis root bark at doses lower than 1000mg/kg is safe in rats and may not exert severe toxic effects. 23486447 Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants. Polymorphisms in CYP2D6 and CYP2C19 affect the efficacy and safety of tricyclics, with some drugs being affected by CYP2D6 only, and others by both polymorphic enzymes. Amitriptyline, clomipramine, doxepin, imipramine, and trimipramine are demethylated by CYP2C19 to pharmacologically active metabolites. These drugs and their metabolites, along with desipramine and nortriptyline, undergo hydroxylation by CYP2D6 to less active metabolites. Evidence from published literature is presented for CYP2D6 and CYP2C19 genotype-directed dosing of tricyclic antidepressants. 23410005 Synthesis and cancer stem cell-based activity of substituted 5-morpholino-7H-thieno[3,2-b]pyran-7-ones designed as next generation PI3K inhibitors. Dysregulation of the phosphatidylinositol-3-kinase (PI3K) pathway in a wide range of tumors has made PI3K a consensus target to inhibit as illustrated by more than 15 inhibitors now in clinical trials. Our previous work, built on the early pioneering multikinase inhibitor LY294002, resulted in the only PI3K vascular-targeted PI3K inhibitor prodrug, SF1126, which has now completed Phase I clinical trials. This inhibitor has properties that impart more in vivo activity than should be warranted by its enzymatic potency, which in general is much lower than other clinical stage PI3K inhibitors. We embarked on the exploration of scaffolds that retained such properties while simultaneously exhibiting an increased potency toward PI3K. This work resulted in the discovery of the 5-morpholino-7H-thieno[3,2-b]pyran-7-one system as the foundation of a new compound class of potential PI3K inhibitors having improved potency toward PI3K. The synthesis and cancer stem cell-based activity of these compounds are reported herein. 23607657 Plasmonic resonances in self-assembled reduced symmetry gold nanorod structures. Self-assembled plasmonic Dolmen structures consisting of small gold nanorods (length = 50 nm and diameter = 20 nm) with a few nanometer gaps are observed to show coherent effects of super-radiance and characteristics of Fano resonance due to the significantly reduced symmetry of the structure. Relative to previous larger structures from top-down electron-beam lithography, the single crystallinity and atomically smooth surfaces of these self-assembled plasmonic structures result in 50% narrower resonances, and the small gaps with associated strong coupling enable observation of multiple dark and bright modes. By tilting the cap monomer with respect to the base dimer an order of magnitude increase in E-field enhancement at the Fano dip is obtained. In addition, a spectrally broad mode is observed indicating the strong impact of the geometry of the structure on the nature of coupled modes. The highly localized electric near-fields in the gaps will enable strong light matter interactions and the narrow resonances will be useful for improved figure of merits in inexpensive chemical and biosensing. 23359599 PEG-Modified Macroporous Poly(Glycidyl Methacrylate) and Poly(2-Hydroxyethyl Methacrylate) Microspheres to Reduce Non-Specific Protein Adsorption. To minimize non-specific protein adsorption on macroporous poly(glycidyl methacrylate) and poly(2-hydroxyethyl methacrylate) microspheres containing amino and/or carboxyl groups, the microspheres are coated with α,ω-bis-carboxy poly(ethylene glycol) and amino-terminated poly(ethylene glycol-co-propylene glycol) or α-methoxy-ω-amino poly(ethylene glycol). Adsorption of bovine serum albumin (BSA), γ-globulin, (125) I-BSA, pepsin, and chymotrypsin on neat and PEGylated microspheres is determined by UV-VIS spectroscopy of supernatants and eluates or by measurement of radioactivity in an ionization chamber. Neat and PEGylated microspheres adsorb 0.8-70% and 0.02-44% of protein, respectively. 23450212 Principles of electron capture and transfer dissociation mass spectrometry applied to peptide and protein structure analysis. This tutorial review describes the principles and practices of electron capture and transfer dissociation (ECD/ETD or ExD) mass spectrometry (MS) employed for peptide and protein structure analysis. ExD MS relies on interactions between gas phase peptide or protein ions carrying multiple positive charges with either free low-energy (∼1 eV) electrons (ECD), or with reagent radical anions possessing an electron available for transfer (ETD). As a result of recent implementation on sensitive, high resolution, high mass accuracy, and liquid chromatography timescale-compatible mass spectrometers, ExD, more specifically, ETD MS has received particular interest in life science research. In addition to describing the fundamental aspects of ExD radical ion chemistry, this tutorial provides practical guidelines for peptide de novo sequencing with ExD MS, as well as reviews some of the current capabilities and limitations of these techniques. The merits of ExD MS are discussed primarily within the context of life science research. 23385219 Integrated analysis of transcriptomics and metabonomics profiles in aflatoxin B1-induced hepatotoxicity in rat. The aim of this work was to identify mechanisms and potential biomarkers for predicting the development and progression of aflatoxin B1 (AFB1)-induced acute hepatotoxicity. In this study, microarray analysis and metabolites profiles were used to identify shifts in gene expression and metabolite levels associated with the affected physiological processes of rats treated with AFB1. Histopathological examinations and serum biochemical analysis were simultaneously performed; the results indicated that hepatotoxicity occurred in higher dosage groups. However, gene expression analysis and metabolite profiles are more sensitive than general toxicity studies for detecting AFB1-induced acute hepatotoxicity as the patterns of low-dose AFB1-treated rats in these two technique platforms were more similar to the rats in higher dosage groups than to the control rats. Integrated analysis of the results from general toxicity studies, transcriptomics and metabonomics profiles suggested that p53 signaling pathway induced by oxidative damage was the crucial step in AFB1-induced acute hepatotoxicity, whereas gluconeogenesis and lipid metabolism disorder were found to be the major metabolic effects after acute AFB1 exposure. The genes and metabolites significantly affected in common in rat liver or serum of three doses AFB1 treatments served as potential biomarkers for detecting AFB1-induced acute hepatotoxicity. 23219593 4-tert-Octylphenol stimulates the expression of cathepsins in human breast cancer cells and xenografted breast tumors of a mouse model via an estrogen receptor-mediated signaling pathway. Endocrine disrupting chemicals (EDCs) are defined as environmental compounds that modulate steroid hormone receptor-dependent responses an abnormal manner, resulting in adverse health problems for humans such as cancer growth and metastasis. Cathepsins are proteases that have been implicated in cancer progression. However, there have been few studies about the association between cathepsins and estrogenic chemicals during the cancer progression. In this study, we examined the effect(s) of 4-tert-octylphenol (OP), a potent EDC, on the expression of cathepsins B and D in human MCF-7 breast cancer cells and a xenograft mouse model. Treatment with OP significantly induced the proliferation MCF-7 cells in an MTT assay. In addition, the expression of cathepsins B and D was markedly enhanced in MCF-7 cells at both the transcriptional and the translational levels following treatment with E2 or OP up to 48h. These results demonstrated the ability of OP to disrupt normal transcriptional regulation of cathepsins B and D in human breast cancer cells. However, the effects of OP on cell growth or overexpression of cathepsins by inhibiting ER-mediated signaling were abolished by an ER antagonist and siRNA specific for ERα. In conclusion, our findings suggest that OP at 10(-6)M, like E2, may accelerate breast cancer cell proliferation and the expression of cathepsins through an ER-mediated signaling pathway. In addition, the breast cancer cells exposed with OP to a xenograft mouse model were more aggressive according to our histological analysis and showed markedly increased expression of cathepsin B. These effects of mouse model resulted in an increased potential for metastasis in breast cancer. Taken together, we determined that OP can adversely affect human health by promoting cancer proliferation and metastasis through the amplification of cathepsins B and D via the ER-mediated signaling pathway. 23572424 Multiple gene polymorphisms can improve prediction of non-vertebral fracture in postmenopausal women. Clinical risk factors (CRFs), with or without bone mineral density (BMD), are used to determine the risk of osteoporotic fracture (OF), which has a heritable component. This study investigated whether genetic profiling can additionally improve the ability to predict OF. Using 1,229 unrelated Korean postmenopausal women, 39 single-nucleotide polymorphisms (SNPs) in 30 human genomic loci were tested for association with osteoporosis-related traits, such as BMD, osteoporosis, vertebral fracture (VF), non-vertebral fracture (NVF), and any fracture. To estimate the effects of genetic profiling, the genetic risk score (GRS) was calculated using five prediction models: (model I) GRSs only; (model II) BMD only; (model III) CRFs only; (model IV) CRFs and BMD; and (model V) CRFs, BMD and GRS. A total of 21 SNPs within 19 genes associated with one or more osteoporosis-related traits and were included for GRS calculation. GRS associated with BMD before and after adjustment for CRFs (P = < 0.001 to 0.018). GRS associated with NVF before and after adjustment for CRFs and BMD (P = 0.017 to 0.045), and with any fracture after adjustment for CRFs and femur neck BMD (P = 0.049). In terms of predicting NVF, the area under the receptor-operator characteristics curve (AUC) for model I was 0.55, which was lower than the AUCs of models II (0.60), III (0.64), and IV (0.65). Adding GRS to model IV (in model V) increased the AUC to 0.67, and improved the accuracy of NVF classification by 11.5% (P = 0.014). In terms of predicting any fracture, the AUC of model V (0.68) was similar to that of model IV (0.68), and model V did not significantly improve the accuracy of any fracture classification (P = 0.39). Thus, genetic profiling may enhance the accuracy of NVF predictions and help to delineate the intervention threshold. 23265884 Discovery and preliminary structure-activity relationship analysis of 1,14-sperminediphenylacetamides as potent and selective antimalarial lead compounds. Screening of synthesized and isolated marine natural products for in vitro activity against four parasitic protozoa has identified the ascidian metabolite 1,14-sperminedihomovanillamide (orthidine F, 1) as being a non-toxic, moderate growth inhibitor of Plasmodium falciparum (IC(50) 0.89 μM). Preliminary structure-activity relationship investigation identified essentiality of the spermine polyamine core and the requirement for 1,14-disubstitution for potent activity. One analogue, 1,14-spermine-di-(2-hydroxyphenylacetamide) (3), exhibited two orders of magnitude increased anti-P. f activity (IC(50) 8.6 nM) with no detectable in vitro toxicity. The ease of synthesis of phenylacetamido-polyamines, coupled with potent nM levels of activity towards dual drug resistant strains of P. falciparum makes this compound class of interest in the development of new antimalarial therapeutics. 23258121 (4,4')-Bipyridine in vacuo and in solvents: a quantum chemical study of a prototypical floppy molecule from a molecular transport perspective. We report results of quantum chemical calculations for the neutral and anionic species of (4,4')-bipyridine (44BPY), a prototypical molecule with a floppy degree of freedom, placed in vacuo and in solvents. In addition to equilibrium geometries and vibrational frequencies and spectra, we present adiabatic energy curves for the vibrational modes with significant intramolecular reorganization upon charge transfer. Special attention is paid to the floppy strongly anharmonic degree of freedom of 44BPY, which is related to the most salient structural feature, namely the twist angle θ between the two pyridine rings. The relevance of the present results for molecular transport will be emphasized. We show that the solvent acts as a selective gate electrode and propose a scissor operator to account for solvent effects on molecular transport. Our result on the conductance G vs. cos(2)θ is consistent with a significant transmission in perpendicular conformation indicated by previous microscopic analysis. 23170957 Spo0A links de novo fatty acid synthesis to sporulation and biofilm development in Bacillus subtilis. During sporulation in Bacillus subtilis, the committed-cell undergoes substantial membrane rearrangements to generate two cells of different sizes and fates: the mother cell and the forespore. Here, we demonstrate that the master transcription factor Spo0A reactivates lipid synthesis during development. Maximal Spo0A-dependent lipid synthesis occurs during the key stages of asymmetric division and forespore engulfment. Spo0A reactivates the accDA operon that encodes the carboxylase component of the acetyl-CoA carboxylase enzyme, which catalyses the first and rate-limiting step in de novo lipid biosynthesis, malonyl-CoA formation. The disruption of the Spo0A-binding box in the promoter region of accDA impairs its transcriptional reactivation and blocks lipid synthesis. The Spo0A-insensitive accDA(0A) cells were proficient in planktonic growth but defective in sporulation (σ(E) activation) and biofilm development (cell cluster formation and water repellency). Exogenous fatty acid supplementation to accDA(0A) cells overcomes their inability to synthesize lipids during development and restores sporulation and biofilm proficiencies. The transient exclusion of the lipid synthesis regulon from the forespore and the known compartmentalization of Spo0A and ACP in the mother cell suggest that de novo lipid synthesis is confined to the mother cell. The significance of the Spo0A-controlled de novo lipid synthesis during B. subtilis development is discussed. 23210777 Bioprocessing of plant in vitro systems for the mass production of pharmaceutically important metabolites: paclitaxel and its derivatives. Taxol (paclitaxel) and its derivatives are microtubule-stabilizing drugs widely used in the treatment of several types of cancer, including mammary, prostate, ovarian and non-small-cell lung carcinoma, as well as AIDS-associated Kaposi's sarcoma and other types of tumor. Taxanes stabilize microtubules by enhancing their polymerization and inhibiting depolymerization. Microtubule dynamics are crucial to mitotic spindle formation and function; therefore, cells exposed to taxanes are unable to undergo chromosomal separation during mitosis, become arrested in the G2/M phases of the cell cycle, and are subsequently targeted for apoptosis. Plant cell cultures are used for industrial-scale biotechnological production of important bioactive plant secondary metabolites, including the anticancer agent paclitaxel. In the last two decades, there have been numerous empirical approaches to improve the biotechnological production of taxanes, leading to the conclusion that treatment of Taxus sp. cells with methyl jasmonate or other elicitors is the most effective strategy. However, little insight has been gained into how the elicitors increase taxane biosynthesis or how this process is regulated. In recent years, with the help of "omics" tools, a rational approach has provided new information about taxane metabolism and its control. Once pathway bottlenecks have been identified, it will be possible to engineer Taxus sp. cell lines with overexpression of genes that control the flux-limiting steps, thus boosting taxane productivity. This review describes the chemical and biological characterization of paclitaxel and its derivatives and discusses future prospects for their biotechnological production. 23414844 Investigation of antibacterial mode of action for traditional and amphiphilic aminoglycosides. Aminoglycoside represents a class of versatile and broad spectrum antibacterial agents. In an effort to revive the antibacterial activity against aminoglycoside resistant bacteria, our laboratory has developed two new classes of aminoglycoside, pyranmycin and amphiphilic neomycin (NEOF004). The former resembles the traditional aminoglycoside, neomycin. The latter, albeit derived from neomycin, appears to exert antibacterial action via a different mode of action. In order to discern that these aminoglycoside derivatives have distinct antibacterial mode of action, RNA-binding affinity and fluorogenic dye were employed. These studies, together with our previous investigation, confirm that pyranmycin exhibit the traditional antibacterial mode of action of aminoglycosides by binding toward the bacterial rRNA. On the other hand, the amphiphilic neomycin, NEOF004 disrupts the bacterial cell wall. In a broader perspective, it verifies that structurally modified neomycin can exert different antibacterial mode of action leading to the revival of activity against aminoglycoside resistant bacteria. 23401165 Arsenic geochemistry in a biostimulated aquifer: An aqueous speciation study. Stimulating microbial growth through the use of acetate injection wells at the former uranium mill site in Rifle, Colorado, USA, has been shown to decrease dissolved uranium (VI) concentrations through bacterial reduction to immobile uranium (IV). Bioreduction also changed the redox chemistry of site groundwater, altering the mobility of several other redox-sensitive elements present in the subsurface, including iron, sulfur, and arsenic. Following acetate amendment at the site, elevated concentrations of arsenic in the groundwater were observed. Ion chromatography-inductively coupled plasma-mass spectrometry was used to determine the aqueous arsenic speciation. Upgradient samples, unexposed to acetate, showed low levels of arsenic (≈1 μM), with greater than 90% as arsenate (As[V]) and a small amount of arsenite (As[III]). Downgradient acetate-stimulated water samples had much higher levels of arsenic (up to 8 μM), and 4 additional thioarsenic species were present under sulfate-reducing conditions. These thioarsenic species demonstrate a strong correlation between arsenic release and sulfide concentrations in groundwater, and their formation may explain the elevated total arsenic concentrations. An alternative remediation approach, enhanced flushing of uranium, was accomplished by addition of bicarbonate and did not result in highly elevated arsenic concentrations. Environ Toxicol Chem 2013;32:1216-1223. © 2013 SETAC. 22400496 Secondary metabolites from Marchantia paleacea calluses and their allelopathic effects on Arabidopsis seed growth. Rapid-growth Marchantia paleacea calluses were induced on MSK2 medium through surface sterilisation of the capsula. Ten known compounds including two steroids (1-2), six bibenzyls (3, 5-9), a flavonoid (10), and a terpenoid (4) were isolated from these calluses. The allelopathic effect of the six bibenzyls was assessed in Arabidopsis thaliana. Results revealed that bibenzyls could inhibit seedling growth in a dose-dependent manner. 22525271 PTPN14 interacts with and negatively regulates the oncogenic function of YAP. The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. The pivotal effector of this pathway is YAP, a transcriptional co-activator amplified in mouse and human cancers where it promotes epithelial-to-mesenchymal transition and malignant transformation. Here, we report a novel regulatory mechanism for the YAP oncogenic function via direct interaction with non-receptor tyrosine phosphatase 14 (PTPN14) through the WW domain of YAP and the PPxY domain of PTPN14. We also found that YAP is a direct substrate of PTPN14. In addition, luciferase reporter assay showed that the inhibition of the YAP transcriptional co-activator function by PTPN14 is mediated through their protein interactions and may result from an increase in the inactive cytoplasmic form of YAP. Last, knockdown of PTPN14 induces the nuclear retention of YAP and increases the YAP-dependent cell migration. In summary, our results indicate a potential regulatory role of PTPN14 on YAP and demonstrate a novel mechanism in YAP regulation. 23371548 One-Pot Facile Synthesis of Double-Shelled SnO2 Yolk-Shell-Structured Powders by Continuous Process as Anode Materials for Li-ion Batteries. Double-shelled SnO2 yolk-shell-structured powders are prepared by applying a new facile one-pot process. Carbon-SnO2 composite powder particles are first formed as an intermediate product inside a tubular reactor. Step-by-step combustion of carbon from outside the composite powder particles forms the double-shelled SnO2 yolk-shell-structured powder particles. The SnO2 yolk-shell-structured powders show excellent electrochemical properties. 23118028 Adaptive radiation-induced epigenetic alterations mitigated by antioxidants. Humans are exposed to low-dose ionizing radiation (LDIR) from a number of environmental and medical sources. In addition to inducing genetic mutations, there is concern that LDIR may also alter the epigenome. Such heritable effects early in life can either be positively adaptive or result in the enhanced formation of diseases, including cancer, diabetes, and obesity. Herein, we show that LDIR significantly increased DNA methylation at the viable yellow agouti (A(vy)) locus in a sex-specific manner (P=0.004). Average DNA methylation was significantly increased in male offspring exposed to doses between 0.7 and 7.6 cGy, with maximum effects at 1.4 and 3.0 cGy (P<0.01). Offspring coat color was concomitantly shifted toward pseudoagouti (P<0.01). Maternal dietary antioxidant supplementation mitigated both the DNA methylation changes and coat color shift in the irradiated offspring. Thus, LDIR exposure during gestation elicits epigenetic alterations that lead to positive adaptive phenotypic changes that are negated with antioxidants, indicating they are mediated in part by oxidative stress. These findings provide evidence that in the isogenic A(vy) mouse model, epigenetic alterations resulting from LDIR play a role in radiation hormesis, bringing into question the assumption that every dose of radiation is harmful. 23562072 Altered cholesterol homeostasis in aged macrophages linked to neovascular macular degeneration. Abnormal lipid metabolism has been linked to age-related macular degeneration (AMD); choroidal neovascularization in late AMD commonly causes blindness. Sene et al. (2013) now demonstrate that in aged macrophages decreased ABCA1 expression, regulated by liver X receptor and miR-33, impairs export of intracellular cholesterol, which promotes neovascular AMD. 23523665 Cytoprotective dibenzoylmethane derivatives protect cells from oxidative stress-induced necrotic cell death. Screening of a small in-house library of 1863 compounds identified 29 compounds that protected Jurkat cells from hydrogen peroxide-induced cytotoxicity. From the cytoprotective compounds eleven proved to possess antioxidant activity (ABTS radical scavenger effect) and two were found to inhibit poly(ADP-ribosyl)ation (PARylation), a cytotoxic pathway operating in severely injured cells. Four cytoprotective dibenzoylmethane (DBM) derivatives were investigated in more detail as they did not scavenge hydrogen peroxide nor did they inhibit PARylation. These compounds protected cells from necrotic cell death while caspase activation, a parameter of apoptotic cell death was not affected. Hydrogen peroxide activated extracellular signal regulated kinase (ERK1/2) and p38 MAP kinases but not c-Jun N-terminal kinase (JNK). The cytoprotective DBMs suppressed the activation of Erk1/2 but not that of p38. Cytoprotection was confirmed in another cell type (A549 lung epithelial cells), indicating that the cytoprotective effect is not cell type specific. In conclusion we identified DBM analogs as a novel class of cytoprotective compounds inhibiting ERK1/2 kinase and protecting from necrotic cell death by a mechanism independent of poly(ADP-ribose) polymerase inhibition. 23325847 Mutational analysis of the ribosome assembly GTPase RbgA provides insight into ribosome interaction and ribosome-stimulated GTPase activation. Ribosome biogenesis GTPase A protein (RbgA) is an essential GTPase required for the biogenesis of the 50S subunit in Bacillus subtilis. Homologs of RbgA are widely distributed in bacteria and eukaryotes and are implicated in ribosome assembly in the mitochondria, chloroplast and cytoplasm. Cells depleted of RbgA accumulate an immature large subunit that is missing key ribosomal proteins. RbgA, unlike many members of the Ras superfamily of GTPases, lacks a defined catalytic residue for carrying out guanosine triphosphate (GTP) hydrolysis. To probe RbgA function in ribosome assembly, we used a combined bioinformatics, genetic and biochemical approach. We identified a RNA-binding domain within the C-terminus of RbgA that is structurally similar to AmiR-NasR Transcription Anti-termination Regulator (ANTAR) domains, which are known to bind structured RNA. Mutation of key residues in the ANTAR domain altered RbgA association with the ribosome. We identified a putative catalytic residue within a highly conserved region of RbgA, His9, which is contained within a similar PGH motif found in elongation factor Tu (EF-Tu) that is required for GTP hydrolysis on interaction with the ribosome. Finally, our results support a model in which the GTPase activity of RbgA directly participates in the maturation of the large subunit rather than solely promoting dissociation of RbgA from the 50S subunit. 23202442 High-resolution solid-state 13C NMR spectroscopy of the paramagnetic metal-organic frameworks, STAM-1 and HKUST-1. Solid-state (13)C magic-angle spinning (MAS) NMR spectroscopy is used to investigate the structure of the Cu(II)-based metal-organic frameworks (MOFs), HKUST-1 and STAM-1, and the structural changes occurring within these MOFs upon activation (dehydration). NMR spectroscopy is an attractive technique for the investigation of these materials, owing to its high sensitivity to local structure, without any requirement for longer-range order. However, interactions between nuclei and unpaired electrons in paramagnetic systems (e.g., Cu(II)-based MOFs) pose a considerable challenge, not only for spectral acquisition, but also in the assignment and interpretation of the spectral resonances. Here, we exploit the rapid T(1) relaxation of these materials to obtain (13)C NMR spectra using a spin-echo pulse sequence at natural abundance levels, and employ frequency-stepped acquisition to ensure uniform excitation of resonances over a wide frequency range. We then utilise selective (13)C isotopic labelling of the organic linker molecules to enable an unambiguous assignment of NMR spectra of both MOFs for the first time. We show that the monomethylated linker can be recovered from STAM-1 intact, demonstrating not only the interesting use of this MOF as a protecting group, but also the ability (for both STAM-1 and HKUST-1) to recover isotopically-enriched linkers, thereby reducing significantly the overall cost of the approach. 23639541 Synthesis and in vitro evaluation of a PDT active BODIPY-NLS conjugate. Two new photosensitizers based on the BODIPY scaffold have been synthesized, of which one bears an NLS peptide, which is linked to the BODIPY's core using the copper catalysed azide-alkyne click reaction. The phototoxicities of these BODIPY based photosensitizers have been determined, as well as their dark toxicities. Although the conjugation of a single NLS peptide to the BODIPY did not lead to any observable nuclear localization, the photosensitizer did exhibit a superior photoxicity. Cellular co-localization experiments revealed a localization of both dyes in the lysosomes, as well as a partial localization within the ER (for the peptide-bearing BODIPY). 23438486 Isolation, characterization, cloning and expression of an alpha-neurotoxin from the venom of the Mexican coral snake Micrurus laticollaris (Squamata: Elapidae). A new member of short chain α-neurotoxic protein family from venom of the Mexican coral snake, Micrurus laticollaris, was characterized. This protein, named MlatA1, possesses 61 amino acids with 8 conserved cysteine residues, sharing 30-91% sequence identity with other fully sequenced Micrurus toxins. MlatA1 (LD50i.v. = 0.064 mg/kg) antagonizes with both fetal and adult nicotinic acetylcholine receptor (nAChR) as well as α-7 neuronal nAChR in a dose-dependent way. Specific rabbit anti-Mlat serum (titer higher than 18,000) does not show any protective ability against this toxin, nevertheless it was able to recognize protein bands in six out of twelve Micrurus venoms showing the existence of two distinct antigenic groups for α-neurotoxins in North American coral snakes species. The MlatA1 gene was cloned and used to produce recombinant toxin (rMlatA1) that was recognized by rabbit anti-native toxin but was depleted of toxic activity. 23561095 Studies of isothermal crystallisation kinetics of sunflower hard stearin-based confectionery fats. The crystallisation and polymorphic properties of three sunflower hard stearins (SHSs) and cocoa butter equivalents (CBEs) formulated by blending SHSs and palm mid fraction (PMF) were studied and compared with those from cocoa butter (CB), to explore their possibilities as confectionery fats. The isothermal crystallisation kinetics of these fats were examined by pNMR and DSC at three different temperatures. All samples studied displayed a two-step crystallisation profile that could be fitted to an exponential-Gompertz equation. Stop-and-return DSC studies showed that SHSs and CBEs exhibited different crystallisation mechanisms according to their triacylglycerol composition, with a quick formation of metastable crystals, followed by a polymorphic transition to the more stable β or β' forms. X-ray diffraction (XRD) was used to investigate the polymorphic forms of tempered SHSs and CBEs in the long term. In all cases the resulting fats displayed short spacing patterns associated with β polymorphism. These formulations based on SHSs and PMF met all the requirements to be considered as CBEs; therefore they could be used as an alternative to traditional confectionery fats. 23297362 The CMT4B disease-causing phosphatases Mtmr2 and Mtmr13 localize to the Schwann cell cytoplasm and endomembrane compartments, where they depend upon each other to achieve wild-type levels of protein expression. The demyelinating peripheral neuropathy Charcot-Marie-Tooth type 4B (CMT4B) is characterized by axonal degeneration and myelin outfoldings. CMT4B results from mutations in either myotubularin-related protein 2 (MTMR2; CMT4B1) or MTMR13 (CMT4B2), phosphoinositide (PI) 3-phosphatases that dephosphorylate phosphatidylinositol 3-phosphate (PtdIns3P) and PtdIns(3,5)P2, lipids which regulate endo-lysosomal membrane traffic. The catalytically active MTMR2 and catalytically inactive MTMR13 physically associate, although the significance of this association is not well understood. Here we show that Mtmr13 loss leads to axonal degeneration in sciatic nerves of older mice. In addition, CMT4B2-like myelin outfoldings are present in Mtmr13(-/-) nerves at postnatal day 3. Thus, Mtmr13(-/-) mice show both the initial dysmyelination and later degenerative pathology of CMT4B2. Given the key role of PI 3-kinase-Akt signaling in myelination, we investigated the state of the pathway in nerves of CMT4B models. We found that Akt activation is unaltered in Mtmr13(-/-) and Mtmr2(-/-) mice. Mtmr2 and Mtmr13 are found within the Schwann cell cytoplasm, where the proteins are partially localized to punctate compartments, suggesting that Mtmr2-Mtmr13 may dephosphorylate their substrates on specific intracellular compartments. Mtmr2-Mtmr13 substrates play essential roles in endo-lysosomal membrane traffic. However, endosomes and lysosomes of Mtmr13(-/-) and Mtmr2(-/-) Schwann cells are morphologically indistinguishable from those of controls, indicating that loss of these proteins does not cause wholesale dysregulation of the endo-lysosomal system. Notably, Mtmr2 and Mtmr13 depend upon each other to achieve wild-type levels of protein expression. Mtmr2 stabilizes Mtmr13 on membranes, indicating that the Mtmr13 pseudophosphatase is regulated by its catalytically active binding partner. 23182739 Cytotoxicity, antioxidant activity and an effect on CYP3A4 and CYP2D6 of Mutellina purpurea L. extracts. Mutellina purpurea is an aromatic Apiaceae plant known as Alpine lovage. Its polar extracts consist of phenolic acids, tannins and flavonoids. The cytotoxic effect of methanolic and aqueous extracts from M. purpurea was studied on the most frequently used cell lines: HeLa and BHK-21. Taking into account that the natural products are often used with other medicines there is a risk of reciprocal interaction on the metabolic level. Thus, the influence of M. purpurea extracts was investigated on the activity of CYP2D6 and CYP3A4, which are the most important P450 isoenzymes from the pharmacological and toxicological points of view. Additionally, because M. purpurea contains phenolic compounds, the antioxidative properties of this plant extracts were also studied and compared. 23458950 Antioxidant and Anti-inflammatory Meroterpenoids from the Brown Alga Cystoseira usneoides. A chemical study of the alga Cystoseira usneoides has led to the isolation of six new meroterpenoids, cystodiones A-F (1-6), together with six known related compounds (7-12). The structures of the new metabolites have been established by spectroscopic techniques. In antioxidant assays all of the tested meroterpenes, and in particular cystodiones A (1) and B (2), 6-cis-amentadione-1'-methyl ether (7), and amentadione-1'-methyl ether (8), exhibited strong radical-scavenging activity. In anti-inflammatory assays, usneoidone Z (11) and its corresponding 6E isomer (12) showed significant activity as inhibitors of the production of the proinflammatory cytokine TNF-α in LPS-stimulated THP-1 human macrophages. 23565654 Controlling the Effective Surface Area and Pore Size Distribution of sp(2) Carbon Materials and Their Impact on the Capacitance Performance of These Materials. A series of sp(2) carbon materials with different specific surface area (SSA) and controlled pore size distribution (PSD) were synthesized at large scale through a facile and low-cost method. The SSA and PSD of these carbon materials were controlled by using different carbon sources and preparation methods. With different total and effective SSA (E-SSA) and PSD, the impacts on their capacitance performance were investigated thoroughly, which demonstrated that both E-SSA and PSD played the most important roles in their capacitance performance. Furthermore, theoretical modeling was performed, and the results are in agreement with the experimental results for the influence of E-SSA and PSD on their capacitance performance. Based on these, a general model using the slit/cylindrical NL-DFT approach is proposed for the estimation of the specific capacitance of sp(2) carbon materials, which offers a simple but reliable method to predict the capacitance performance of these materials, thus speeding up the design and screening of the materials for high-performance supercapacitor and other surface area related devices. 23409710 The renin-angiotensin system: new insight into old therapies. Although the renin-angiotensin system (RAS) is already an old acquaintance, there are often exciting discoveries that improve our knowledge of it and open new therapeutic possibilities. Moreover, well-established drugs, such as angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), or beta-blockers, show that their mechanism of action may be the result of parallel pathways other than the ones initially established. A detailed analysis of the RAS can be carried out in part through the study of the enzymes, named angiotensinases, involved in its cascade, whose activity is a reflection of the functionality of their peptide substrates. The study of these enzymes offers the possibility of controlling the effects of angiotensins through various pharmacological manipulations. For example, angiotensinase inhibitors or activators are being used or have been proposed as antihypertensive agents. They have also been suggested as analgesic and antidepressant drugs or targets for drug development against different pathologies such as Alzheimer's disease, epilepsy or ischemia. On the other hand, the analysis of brain asymmetry has revealed surprising results about the laterality of central and peripheral components of the RAS. Such studies indicate that the neurovisceral integration, already proposed by Claude Bernard (1867) should also be analyzed from a bilateral perspective. In this review, the RAS and the role of various angiotensinases implicated in the cascade are revisited. Therapeutic strategies involving some components of the RAS with an unusual vision resulting from a bilateral perspective added to their study are discussed. 23247337 Colloids in Flatland: a perspective on 2D phase-separated systems, characterisation methods, and lineactant design. In 1861 Thomas Graham gave birth to a new field of science, today known as colloid science. Nowadays, the notion "colloid" is often used referring to systems consisting of two immiscible phases, one of which is finely dispersed into the other. Research on colloids deals mostly with sols (solids dispersed in a liquid), emulsions (liquids dispersed in liquid), and foams (gas dispersed in a liquid). Because the dispersed particles are small, there is a lot of interface per unit mass. Not surprisingly, therefore, the properties of the interface have often a decisive effect on the behaviour of colloids. Water-air interfaces have a special relevance in this field: many water-insoluble molecules can be spread on water and, given the right spreading conditions and enough available surface area, their spreading proceeds until a monolayer (a one-molecule thick layer) eventually remains. Several 2D phases have been identified for such monolayers, like "gas", "liquid expanded", "liquid condensed", and "solid". The central question of this review is whether these 2D phases can also exist as colloidal systems, and what stabilizes the dispersed state in such systems. We shall present several systems capable of yielding 2D phase separation, from those based on either natural or fluorinated amphiphiles, to polymer-based ones. We shall seek for analogies in 3D and we shall try to clarify if the lines between these 2D objects play a similar role as the interfaces between 3D colloidal systems. In particular, we shall consider the special role of molecules that tend to accumulate at the phase boundaries, that is, at the contact lines, which will therefore be denoted "line-actants" (molecules that adsorb at a 1D interface, separating two 2D colloidal entities), by analogy to the term "surfactant" (which indicates a molecule that adsorbs at a 2D interface separating two 3D colloidal entities). 23543009 Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis. Oxidative stress basically defines a condition in which prooxidant-antioxidant balance in the cell is disturbed; cellular biomolecules undergo severe oxidative damage, ultimately compromising cells viability. In recent years, a number of studies have shown that oxidative stress could cause cellular apoptosis via both the mitochondria-dependent and mitochondria-independent pathways. Since these pathways are directly related to the survival or death of various cell types in normal as well as pathophysiological situations, a clear picture of these pathways for various active molecules in their biological functions would help designing novel therapeutic strategy. This review highlights the basic mechanisms of ROS production and their sites of formation; detail mechanism of both mitochondria-dependent and mitochondria-independent pathways of apoptosis as well as their regulation by ROS. Emphasis has been given on the redox-sensitive ASK1 signalosome and its downstream JNK pathway. This review also describes the involvement of oxidative stress under various environmental toxin- and drug-induced organ pathophysiology and diabetes-mediated apoptosis. We believe that this review would provide useful information about the most recent progress in understanding the mechanism of oxidative stress-mediated regulation of apoptotic pathways. It will also help to figure out the complex cross-talks between these pathways and their modulations by oxidative stress. The literature will also shed a light on the blind alleys of this field to be explored. Finally, readers would know about the ROS-regulated and apoptosis-mediated organ pathophysiology which might help to find their probable remedies in future. 23265509 Purification, antioxidant activity and protein-precipitating capacity of punicalin from pomegranate husk. Punicalin is a kind of ellagitannin, existing in pomegranate husk, and has shown remarkable biological activities. A rapid and large-scale separation method of punicalin from pomegranate husk was established, using medium pressure liquid chromatography (MPLC). The optimal mobile phase consisted of 5% methanol and 0.1% (v/v) TFA in water, and the optimal loading amount and flow rate were 1.0 g and 80 ml/min, respectively. Under this condition, 339 mg of 95.9% punicalin could be obtained in 40 min. 59.7 mg of 78.0% gallic acid could be separated simultaneously. This method was practical for industrial utilisation of pomegranate husk. Afterwards, the antioxidant and protein-precipitating capacities of the purified punicalin, together with punicalagin, were evaluated. Results showed that punicalin had strong antioxidant activity, and it exhibited a low affinity for protein. This suggested that the antioxidant of punicalin would not be greatly masked by tannin-protein precipitation in application, and hence confirmed punicalin to be a promising antioxidant. 23462105 Correlation between aflatoxin M1 content of breast milk, dietary exposure to aflatoxin B1 and socioeconomic status of lactating mothers in Ogun State, Nigeria. Aflatoxin M1 (AF M1), a hydroxylated metabolite of AF B1, is an important toxin that can contaminate the milk of lactating mothers. A correlation study was conducted to determine the relationship between AF M1 content of breast milk, dietary exposure to AF B1 and socioeconomic status of lactating mothers in the three Senatorial districts of Ogun State, Nigeria. Equal amounts of breast milk (20ml) and food rations (40kg) obtained from 50 volunteer lactating mothers and eighty-two frequently consumed food commodities in the preceding month were used for the study. The level of contamination of the foods by AF B1 was low (0.16-0.33μg/kg) and differed significantly (p<0.05) across the state but did not exceed the EU limit of 2μg/kg. The occurrence level of AF B1 was however high (93.75-94.45%) and was more pronounced in Ogun East Senatorial district (94.45%). Eighty-two percent of the breast milk was contaminated with AF M1 (3.49-35ng/l) and 16% exceeded the EU limit of 25ng/l while a 100% occurrence risk was recorded in Ogun Central Senatorial district. The socioeconomic status of the mothers also significantly influenced their dietary exposure and exposure risk of the sucklings to AF M1. 23333184 Mineralocorticoid receptor antagonists for therapy of coronary artery disease and related complications. The perception of aldosterone action to be restricted to regulation of fluid balance via sodium reabsorption and potassium excretion is incomplete; plenty of experimental and clinical studies have shown that aldosterone plays a pivotal role in a variety of (patho-) physiologic conditions within the cardiovascular continuum. Deleterious effects include cardiovascular inflammation, endothelial dysfunction, structural and electrical remodelling. Mineralocorticoid receptor antagonists (MRAs), such as spironolactone and eplerenone, prevent some of these maladaptive effects on the cardiovascular system and have proven to be a highly efficacious pharmacological therapy. In this article we review the current clinical impact of MRAs in the treatment of coronary artery disease (CAD) and its related complications, for example, acute myocardial infarction (MI) and chronic heart failure. 23325372 Adjunctive aripiprazole therapy with escitalopram in patients with co-morbid major depressive disorder and alcohol dependence: clinical and neuroimaging evidence. The effective treatment of depression has been reported to reduce the severity of alcohol use, potentially reflecting improvements in common brain reward circuits. We hypothesized that augmentation therapy of escitalopram with aripiprazole would improve depressive symptoms as well as reduce craving for alcohol and cue-induced brain activity in patients with co-morbid alcohol dependence and major depressive disorder, compared with treatment with escitalopram alone. Thirty-five subjects with major depressive disorder and alcohol dependence were recruited and randomly assigned into 17 aripiprazole + escitalopram and 18 escitalopram only groups. At baseline and following six weeks of treatment, symptoms of depression, craving for alcohol and brain activity were evaluated. During the six week treatment period, Beck Depression Inventory and clinical global index-severity (CGI-S) scores decreased in both the aripiprazole + escitalopram and escitalopram only groups. In addition, following the treatment period, the Korean alcohol urge questionnaire scores in the aripiprazole + escitalopram group were reduced from 23.3±8.4 to 14.3±4.9, compared with those of the escitalopram group of from 21.6±8.4 to 19.3±7.1 (F=13.1, p<0.01). The activity within the anterior cingulate was increased in response to the presentation of alcohol drinking scenes following treatment in the aripiprazole + escitalopram group. The change of brain activity within the left anterior cingulate gyrus in all patients with co-morbid alcohol dependence and major depressive disorder was negatively correlated with the change in craving for alcohol. These findings suggest that the effects of aripiprazole on anterior cingulate cortex might mediate the successful treatment of alcohol dependence in patients with major depressive disorder. 23265450 Rapid detection and quantification of milk adulteration using infrared microspectroscopy and chemometrics analysis. The application of attenuated total reflectance mid-infrared microspectroscopy (MIR-microspectroscopy) was evaluated as a rapid method for detection and quantification of milk adulteration. Milk samples were purchased from local grocery stores (Columbus, OH, USA) and spiked at different concentrations of whey, hydrogen peroxide, synthetic urine, urea and synthetic milk. Samples were place on a 192-well microarray slide, air-dried and spectra were collected by using MIR-microspectroscopy. Pattern recognition analysis by Soft Independent Modeling of Class Analogy (SIMCA) showed tight and well-separated clusters allowing discrimination of control samples from adulterated milk. Partial Least Squares Regression (PLSR) showed standard error of prediction (SEP) ~2.33, 0.06, 0.41, 0.30 and 0.014 g/L for estimation of levels of adulteration with whey, synthetic milk, synthetic urine, urea and hydrogen peroxide, respectively. Results showed that MIR-microspectroscopy can provide an alternative methodology to the dairy industry for screening potential fraudulent practice for economic adulteration of cow's milk. 23535348 Further evidence for involvement of the dorsal hippocampus serotonergic and γ-aminobutyric acid (GABA)ergic pathways in the expression of contextual fear conditioning in rats. Intra-dorsal hippocampus (DH) injections of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a serotonin-1A (5-hydroxytryptamine (5-HT)-1A) receptor agonist, were previously shown to inhibit the expression of contextual fear when administered six hours after conditioning. However, further understanding of the consolidation and expression of aversive memories requires investigations of these and other mechanisms at distinct time points and the regions of the brain to which they are transferred. Thus, the purpose of the present study was to investigate the role of DH serotonergic and γ-aminobutyric acid (GABA)ergic mechanisms in the expression of contextual fear 24 h after conditioning, reflected by fear-potentiated startle (FPS) and freezing behavior. The recruitment of the amygdala and medial prefrontal cortex (mPFC) in these processes was also evaluated by measuring Fos protein immunoreactivity. Although intra-DH injections of 8-OH-DPAT did not produce behavioral changes, muscimol reduced both FPS and the freezing response. Fos protein immunoreactivity revealed that contextual fear promoted wide activation of the mPFC, which was significantly reduced after intra-DH infusions of muscimol. The present findings, together with previous data, indicate that in contrast to 5-HT, which appears to play a role during the early phases of contextual aversive memory consolidation, longer-lasting GABA-mediated mechanisms are recruited during the expression of contextual fear memories. 23410206 Hedgehog Signaling in Medullary Thyroid Carcinoma: A Novel Signaling Pathway. Background: Locally or widely metastatic medullary thyroid carcinoma (MTC) is difficult to treat and therapeutic options are limited. Recently, kinase inhibitors have shown partial efficacy in this cancer, but there is a continued need for the development of novel therapeutics. Within this context, the Hedgehog (Hh) pathway has been implicated in several types of human tumors, and early clinical trials with Hh antagonists have validated Hh as a novel therapeutic target. For the first time, we evaluated Hh pathway activity in MTC and examined the effect of Hh pathway perturbation in highly characterized MTC cell lines. Methods: We examined immunohistochemical expression of Hh signaling mediators Sonic Hedgehog (Shh) and Glioblastoma (Gli)2 in paraffin-embedded normal versus histologically characterized human MTC tissue. We examined pharmacologic disruption of Hh signaling in vitro using two established MTC cell lines (TT and MZ-CRC-1). Hh signaling was either pharmacologically activated (SAG) or inhibited (GDC-0449) in MTC cell lines; Hh activity was assessed by qRT-PCR, Western blot analysis, and quantification of cellular growth and apoptotic activity. Results: Our data showed increased expression of Hh signaling factors in human MTC compared to normal tissue. In vitro, activation of the Hh pathway resulted in increased expression of key Hh signaling components Smoothened (Smo) and Gli2. Conversely, inhibition of the Hh pathway decreased expression of these genes, leading to significantly reduced cellular growth and increased apoptosis. Conclusions: Hedgehog signaling components are markedly upregulated in MTC. Hh pathway inhibitors have potential as novel therapeutic options in patients with metastatic and/or surgically unresectable MTC. 23358307 Synthesis, DNA binding and antitumor evaluation of styelsamine and cystodytin analogues. A series of N-14 sidechain substituted analogues of styelsamine (pyrido[4,3,2-mn]acridine) and cystodytin (pyrido[4,3,2-mn]acridin-4-one) alkaloids have been prepared and evaluated for their DNA binding affinity and antiproliferative activity towards a panel of human tumor cell lines. Overall it was found that styelsamine analogues were stronger DNA binders, with the natural products styelsamines B and D having particularly high affinity (K(app) 5.33 × 10(6) and 3.64 × 10(6) M(-1), respectively). In comparison, the cystodytin iminoquinone alkaloids showed lower affinity for DNA, but were typically just as active as styelsamine analogues at inhibiting proliferation of tumor cells in vitro. Sub-panel selectivity towards non-small cell lung, melanoma and renal cancer cell lines were observed for a number of the analogues. Correlation was observed between whole cell activity and clogP, with the most potent antiproliferative activity being observed for 3-phenylpropanamide analogues 37 and 41 (NCI panel average GI(50) 0.4 μM and 0.32 μM, respectively) with clogP ~4.0-4.5. 23583258 Phenolic compounds present in Sardinian wine extracts protect against the production of inflammatory cytokines induced by oxysterols in CaCo-2 human enterocyte-like cells. Cholesterol auto-oxidation products, namely oxysterols, are widely present in cholesterol-rich foods. They are thought to potentially interfere with homeostasis of the human digestive tract, playing a role in intestinal mucosal damage. This report concerns the marked up-regulation in differentiated CaCo-2 colonic epithelial cells of two key inflammatory interleukins, IL-6 and IL-8, caused by a mixture of oxysterols representative of a high cholesterol diet. This strong pro-inflammatory effect appeared to be dependent on the net imbalance of red-ox equilibrium with the production of excessive levels of reactive oxygen species through the colonic NADPH-oxidase NOX1 activation. Induction of NOX1 was markedly while not fully inhibited by CaCo-2 cell pre-incubation with phenolic extracts obtained from well-selected wines from typical grape varieties grown in Sardinia. Oxysterol-dependent NOX1 activation, as well as interleukin synthesis, were completely prevented by Cannonau red wine extract that contains an abundant phenolic fraction, in particular phenolic acids and flavonoids. Conversely, cell pre-treatment with Vermentino white wine extract with smaller phenolic fraction showed only a partial NOX1 down-regulation and was ineffective in interleukin synthesis induced by dietary oxysterols. It is thus likely that the effects of Sardinian wine extracts against intestinal inflammation induced by dietary oxysterols are mainly due to their high phenolic content: low doses of phenolics would be responsible only for direct scavenging oxysterol-dependent ROS production. Besides this direct activity, an excess of phenolic compounds detectable in red wine, may exert an additional indirect action by blocking oxysterol-related NOX1 induction, thus totally preventing the pro-oxidant and pro-inflammatory events triggered by dietary oxysterols. 23598364 Use of 'split waves' for the measurement of electrocatalytic kinetics: methyl viologen mediated oxygen reduction on a boron-doped diamond electrode. The mediated reduction of oxygen via the reduced form of methyl viologen is studied voltammetrically. The investigation is facilitated through the use of a boron-doped diamond electrode, allowing the catalytic response to be clearly delineated from that of the direct oxygen reduction process at the electrode surface. From simulation a high homogeneous electron transfer rate (6 × 10(9) M(-1) s(-1)) is found for the one-electron reduction of oxygen to superoxide. This value is in close agreement with that found using non-electrochemical methods and is significantly higher than the values previously reported in electrochemical studies. In the latter case it is demonstrated that the underestimation of the electron transfer rate arises due to oversimplification of the reaction mechanism. 22079313 Fish consumption during child bearing age: a quantitative risk-benefit analysis on neurodevelopment. The fish ingredient N3-docosahexaenoic acid 22:6 n-3 (DHA) stimulates brain development. On the other hand methylmercury (MeHg) in fish disturbs the developing central nervous system. In this Context the IQ score in children is considered as an aggregate measure of in utero brain development. To determine the effect of DHA exposure on prenatal neurodevelopment the maternal DHA intake during pregnancy was compared with its epidemiologically observed effect on the IQ score of children. For MeHg the maternal intake was converted into its accumulation in the maternal body. The maternal body burden then was compared with its epidemiologically observed relationship with the IQ score. Taking the MeHg and DHA content of 33 fish species the net effect of these compounds on the IQ score was quantified. For most fish species the adverse effect of MeHg on the IQ score exceeded the beneficial effect of DHA. In the case of long-living predators a negative effect up to 10 points on the IQ score was found. The results of this study indicate that food interventions aiming at the beneficial effects of fish consumption should focus on fish species with a high DHA content, while avoiding fish species with a high MeHg content. 23413833 Phosphorus-doped silicon nanocrystals exhibiting mid-infrared localized surface plasmon resonance. Localized surface plasmon resonances (LSPRs) enable tailoring of the optical response of nanomaterials through their free carrier concentration, morphology, and dielectric environment. Recent efforts to expand the spectral range of usable LSPR frequencies into the infrared successfully demonstrated LSPRs in doped semiconductor nanocrystals. Despite silicon's importance for electronic and photonic applications, no LSPRs have been reported for doped silicon nanocrystals. Here we demonstrate doped silicon nanocrystals synthesized via a nonthermal plasma technique that exhibits tunable LSPRs in the energy range of 0.07-0.3 eV or mid-infrared wavenumbers of 600-2500 cm(-1). 23109114 Sclerostin antibody treatment improves bone mass, bone strength, and bone defect regeneration in rats with type 2 diabetes mellitus. Type 2 diabetes mellitus results in increased risk of fracture and delayed fracture healing. ZDF fa/fa rats are an established model of type 2 diabetes mellitus with low bone mass and delayed bone healing. We tested whether a sclerostin-neutralizing antibody (Scl-AbVI) would reverse the skeletal deficits of diabetic ZDF rats. Femoral defects of 3 mm were created in 11-week-old diabetic ZDF fa/fa and nondiabetic ZDF +/+ rats and stabilized by an internal plate. Saline or 25 mg/kg Scl-AbVI was administered subcutaneously (s.c.) twice weekly for 12 weeks (n = 9-10/group). Bone mass and strength were assessed using pQCT, micro-computed tomography (µCT), and biomechanical testing. Bone histomorphometry was used to assess bone formation, and the filling of the bone defect was analyzed by µCT. Diabetic rats displayed lower spinal and femoral bone mass compared to nondiabetic rats, and Scl-AbVI treatment significantly enhanced bone mass of the femur and the spine of diabetic rats (p < 0.0001). Scl-AbVI also reversed the deficit in bone strength in the diabetic rats, with 65% and 89% increases in maximum load at the femoral shaft and neck, respectively (p < 0.0001). The lower bone mass in diabetic rats was associated with a 65% decrease in vertebral bone formation rate, which Scl-AbVI increased by sixfold, consistent with a pronounced anabolic effect. Nondiabetic rats filled 57% of the femoral defect, whereas diabetic rats filled only 21% (p < 0.05). Scl-AbVI treatment increased defect regeneration by 47% and 74%, respectively (p < 0.05). Sclerostin antibody treatment reverses the adverse effects of type 2 diabetes mellitus on bone mass and strength, and improves bone defect regeneration in rats. 23416189 First synthesis and biological evaluation of indeno[2,1-e]pyrazolo[3,4-b]pyrazin-5-one and related derivatives. The synthesis of indeno[2,1-e]pyrazolo[3,4-b]pyrazin-5-one was achieved by intramolecular Friedel-Crafts reaction of the acid chloride 3-methyl-1,6-diphenyl-1H-pyrazolo[3,4-b] pyrazine-5-carboxylic acid chloride (4) using AlCl3 in boiling CS2. Compound 4 proved to be a versatile compound for the synthesis of several Indenopyrazolopyrazinone derivatives. The antibacterial and antifungal activities of selected derivatives were evaluated. 23425125 Essential oil composition and antibacterial activity of the different parts of Thymus maroccanus Ball: an endemic species in Morocco(†). Three essential oils from three samples: stems, leaves and inflorescences of Thymus maroccanus Ball, obtained by hydrodistillation, were analysed by gas chromatography and gas chromatography coupled to mass spectrometry. The oils of stems, leaves and inflorescences afforded 68, 49 and 51 constituents, respectively. Quantitative and qualitative differences have been found between the analysed parts. The most abundant components in the stems oil included carvacrol (60.8%), α-terpineol (4.7%) and p-cymene (2.4%), while carvacrol (33%), p-cymene (25.3%) and α-pinene (11.6%) were the main components in the leaves. In the inflorescences, carvacrol (84.9%) is the major component. Antibacterial activity of the T. maroccanus Ball leaves oil was tested against eight Gram-positive and Gram-negative bacteria by the disc diffusion method. The values of inhibition zones for bacterial strains, which were sensitive to the essential oil of T. maroccanus leaves, were in the range of 11-43 mm. 23280831 Mercury in the seafood and human exposure in coastal area of Guangdong province, South China. Consumption of fish and aquatic products is considered to be the main pathway of human exposure to methylmercury (MeHg). To assess human health risk through seafood consumption in a coastal area of Guangdong Province, South China, a total of 518 seafood samples (including fish, shrimp, crabs, and mollusks) were collected from 11 coastal cities for total mercury (THg) analysis. The THg concentrations varied significantly among different seafood groups and ranged from 0.11 to 317 ng/g (with a mean of 37.2 ng/g). The THg concentrations were relatively low compared with fish from Europe and North America, and no samples exceeded the national limit recommended by the Standardization Administration of China (0.5 ng/g wet wt). The ecological functional groups and cultured styles have significant effects on THg concentrations in the fish tissue. The median of probable daily intakes (PDIs) of MeHg via seafood consumption ranged from 42.6 to 71.4 ng/g for different age groups, with fish contributing the major portion (84%). The results indicated potential health risks associated with seafood consumption for the general population in the coastal area of Guangdong Province, South China. 23558614 Straight talk with...Miyoung Chun. It was a single tweet. In February, after US President Barack Obama made a subtle nod to a new neuroscience project in his annual State of the Union address, Francis Collins, director of the country's National Institutes of Health (NIH), posted on the @NIHDirector Twitter feed: "Obama mentions the #NIH Brain Activity Map in #SOTU." Instantly, scientists were buzzing with rumors that the Brain Activity Map could be the next moon shot, with a budget and timeline similar to the Human Genome Project. The brain map began as a brief white paper and has grown into a large-and still largely undefined-collaboration of several government agencies, nonprofit foundations and private companies. As the stakeholders describe in a commentary published last month ( 339, 1284-1285, 2013 10.1126/science.1236939), the goal of the initiative is to understand how thousands of neurons work in concert to control behavior and trigger disease. Miyoung Chun, vice president for science programs at The Kavli Foundation in Oxnard, California, has been developing the project since the beginning and is the self-described "glue" between its many diverse stakeholders. Chun spoke with Virginia Hughes about the evolution of the project and what it might mean for biomedicine. 23463168 Protein fibrillation and nanoparticle interactions: opportunities and challenges. Due to their ultra-small size, nanoparticles (NPs) have distinct properties compared with the bulk form of the same materials. These properties are rapidly revolutionizing many areas of medicine and technology. NPs are recognized as promising and powerful tools to fight against the human brain diseases such as multiple sclerosis or Alzheimer's disease. In this review, after an introductory part on the nature of protein fibrillation and the existing approaches for its investigations, the effects of NPs on the fibrillation process have been considered. More specifically, the role of biophysicochemical properties of NPs, which define their affinity for protein monomers, unfolded monomers, oligomers, critical nuclei, and other prefibrillar states, together with their influence on protein fibrillation kinetics has been described in detail. In addition, current and possible-future strategies for controlling the desired effect of NPs and their corresponding effects on the conformational changes of the proteins, which have significant roles in the fibrillation process, have been presented. 23394611 Correlating superlattice polymorphs to internanoparticle distance, packing density, and surface lattice in assemblies of PbS nanoparticles. Assemblies of 3.5 nm PbS nanoparticles (NPs) nucleate in three dominant superlattice polymorphs: amorphous, body-centered-cubic (bcc) and face-centered-cubic (fcc) phase. This superlattice relationship can be controlled by the inter-NP distance without changing the NP size. Upon increase of inter-NP distance, the packing density decreases, and the capping molecules at NP surfaces change in structure and accordingly modify the surface energy. The driving force for NP assembly develops from an entropic maximization to a reduction of total free energy through multiple interactions between surface molecules and NPs and resulting variation of surface molecules. Upon long-term aging and additional thermal treatment, fcc undergoes a tetragonal distortion and subsequently transforms to bcc phase, and simultaneously, the NPs embedded in supercrystals reduce surface energy primarily in {200} facets. Linking molecule-NP interactions with a series of changes of packing density and surface lattice spacings of NPs allows for an interpretation of principles governing the nucleation, structure stability, and transformation of PbS NP-assembled supercrystals. 23601649 An electrophoretic mobility shift assay identifies a mechanistically unique inhibitor of protein sumoylation. The dynamic, posttranslational modification of proteins with a small ubiquitin-like modifier (SUMO) tag has been recognized as an important cellular regulatory mechanism relevant to a number of cancers as well as normal embryonic development. As part of a program aimed toward the identification of inhibitors of SUMO-conjugating enzymes, we developed a microfluidic electrophoretic mobility shift assay to monitor sumoylation events in real time. We disclose herein the use of this assay to identify a cell-permeable compound capable of blocking the transfer of SUMO-1 from the E2 enzyme Ubc9 to the substrate. We screened a small collection of compounds and identified an oxygenated flavonoid derivative that inhibits sumoylation in vitro. Next, we carried out an in-depth mechanistic analysis that ruled out many common false-positive mechanisms such as aggregation or alkylation. Furthermore, we report that this flavonoid inhibits a single step in the sumoylation cascade: the transfer of SUMO from the E2 enzyme (Ubc9) thioester conjugate to the substrate. In addition to having a unique mechanism of action, this inhibitor has a discrete structure-activity relationship uncharacteristic of a promiscuous inhibitor. Cell-based studies showed that the flavonoid inhibits the sumoylation of topoisomerase-I in response to camptothecin treatment in two different breast cancer cell lines, while isomeric analogs are inactive. Importantly, this compound blocks sumoylation while not affecting ubiquitylation in cells. This work identifies a point of entry for pharmacologic inhibition of the sumoylation cascade and may serve as the basis for continued study of additional pharmacophores that modulate SUMO-conjugating enzymes such as Ubc9. 23440580 Epigenetic regulation of hypoxia inducible factor in diseases and therapeutics. Hypoxia-inducible factors (HIFs) are master regulators of angiogenesis and cellular adaptation in hypoxic microenvironments. Accumulating evidence indicates that HIFs also regulate cell survival, glucose metabolism, microenvironmental remodeling, cancer metastasis, and tumor progression, and thus, HIFs are viewed as therapeutic targets in many diseases. Epigenetic changes are involved in the switching 'on' and 'off' of many genes, and it has been suggested that the DNA hypermethylation of specific gene promoters, histone modifications (acetylation, phosphorylation, and methylation) and small interfering or micro RNAs be regarded epigenetic gene targets for the regulation of disease-associated cellular changes. Furthermore, the hypoxic microenvironment is one of the most important cellular stress stimuli in terms of the regulation of cellular epigenetic status via histone modification. Therefore, drug development and therapeutic approaches to ischemic diseases or cancer for targeting HIFs by modulation of epigenetic status become an attractive area. Here, the authors provide a review of the literature regarding the targeting of HIF, a key modulator of hypoxic-cell response under various disease conditions, by modulating histone or DNA using endogenous small RNAs or exogenous chemicals. 23316864 Extraction of essential oil from Cupressus sempervirens: comparison of global yields, chemical composition and antioxidant activity obtained by hydrodistillation and supercritical extraction(†). In this study, supercritical fluid extraction (SFE) with CO(2) and hydrodistillation (HD) were compared as methods to isolate the essential oil from Cupressus sempervirens. The odour of the oil obtained by SFE at 90 bar and 40°C was very close to the odour of the leaves of C. sempervirens before the extraction. Compounds extracted by both SFE and HD were identified by GC-FID and GC-MS. Moreover, the difference in the chemical composition obtained by SFE and HD was quite noticeable qualitatively and quantitatively. Phenolic composition and antioxidant activity were also determined. Compared to HD, the SFE method presents some advantages: the extraction was completed after 1 h in SFE, although 4 h is necessary for HD, and the yield was improved by 34%. Finally, it has also been shown that SFE is very selective towards some specific components such as manoyl oxide, trans-totarol and α-acoradiene. 23389739 Comparison of toxicity between the different-type TiO(2) nanowires in vivo and in vitro. In this study, we compared their toxicity in vivo and in vitro based on the physicochemical properties of three different types of TiO(2) nanowires, H(2)Ti(3)O(7) nanowires (1HTO), hydrothermal treatment (2HTO), and calcination (3HTO) of 1HTO. The surface of 1HTO was smooth, and the surface of 2HTO was much rougher. The negative charge on the surface increased in the order of 2HTO, 3HTO, and 1HTO, whereas the surface area increased in the order of 3HTO, 1HTO, and 2HTO. The lung is a main exposure route of nanoparticles. On day 28 after a single instillation (1 mg/kg), three nanowires induced a Th2-type inflammatory response together with the relative increase in CD4(+) T cells, especially by 2HTO. In vitro, three TiO(2) nanowires (10 μg/ml) commonly induced the generation of cell debris in eight cell lines which may be the potential target organ of nanoparticles, especially by 2HTO. It seemed that the generation of cell debris coincides with the increase in autophagosome-like vacuoles in the cytosol. In further study using BEAS-2B cells originated from the lung, the protein amount from cells exposed to 2HTO decreased more clearly although the generation of reactive oxygen species (ROS) was less compared to 1HTO and 3HTO. Based on these results, we suggest that surface area may act as an important factor depends on the biological response by TiO(2) nanowires. Furthermore, the increase in autophagosome-like vacuoles may be an important cause of cell death by nanoparticles with ROS. 23600958 Pyranoflavones: A Group of Small-Molecule Probes for Exploring the Active Site Cavities of Cytochrome P450 Enzymes 1A1, 1A2, and 1B1. Selective inhibition of P450 enzymes is the key to block the conversion of environmental procarcinogens to their carcinogenic metabolites in both animals and humans. To discover highly potent and selective inhibitors of P450s 1A1, 1A2, and 1B1, as well as to investigate active site cavities of these enzymes, 14 novel flavone derivatives were prepared as chemical probes. Fluorimetric enzyme inhibition assays were used to determine the inhibitory activities of these probes toward P450s 1A1, 1A2, 1B1, 2A6, and 2B1. A highly selective P450 1B1 inhibitor 5-hydroxy-4'-propargyloxyflavone (5H4'FPE) was discovered. Some tested compounds also showed selectivity between P450s 1A1 and 1A2. α-Naphthoflavone-like and 5-hydroxyflavone derivatives preferentially inhibited P450 1A2, while β-naphthoflavone-like flavone derivatives showed selective inhibition of P450 1A1. On the basis of structural analysis, the active site cavity models of P450 enzymes 1A1 and 1A2 were generated, demonstrating a planar long strip cavity and a planar triangular cavity, respectively. 23554451 Notch Signaling in Skeletal Health and Disease. Notch receptors are single-pass transmembrane proteins that determine cell fate. Upon Notch-ligand interactions, proteolytic cleavages release the Notch intracellular domain (NICD) which translocates to the nucleus to regulate the transcription of target genes, including Hairy enhancer of split (Hes) and Hes-related with YRPW-motif (Hey). Notch is critical for skeletal development and activity of skeletal cells, and dysregulation of Notch signaling is associated with human diseases affecting the skeleton. Inherited or sporadic mutations in components of the Notch signaling pathway are associated with spondylocostal and spondylothoracic dysostoses, and recessive brachydactyly, diseases characterized by skeletal patterning defects. Inactivating mutations of the Notch ligand JAG1 or of NOTCH2 are associated with Alagille syndrome, and activating mutations in NOTCH2 are associated with Hajdu-Cheney syndrome. Individuals affected by Hajdu-Cheney syndrome exhibit osteolysis in distal phalanges, and osteoporosis. NOTCH is activated in selected tumors, such as osteosarcoma, and in breast cancer cells that form osteolytic bone metastases. In conclusion, Notch regulates skeletal development and bone remodeling, and gain- or loss-of-function mutations of Notch signaling result in important skeletal diseases. 23143037 Gene transcription and biomarker responses in the clam Ruditapes philippinarum after exposure to ibuprofen. Pharmaceuticals are a class of emerging environmental contaminants that continuously enter aquatic environments. Presently, little information is available about the effects of these substances on non-target organisms, such as bivalves. We investigated the effects of ibuprofen (IBU) on the clam Ruditapes philippinarum. Clams were exposed for 1, 3, 5 and 7 days to 0, 100 and 1000 μgIBU/L, and established biomarker responses (haemolymph lysozyme, gill acetylcholinesterase and digestive gland superoxide dismutase activities) as well as digestive gland transcriptome were evaluated. A two-way ANOVA revealed significant effects of both "IBU concentration" and "exposure duration" on biomarker responses. Overall, the enzyme activities were generally lower in IBU-exposed clams than in controls. Although limited knowledge of the mollusc transcriptome makes it difficult to interpret the effects of IBU on clams, the gene transcription analysis using DNA microarrays enabled the identification of the putative molecular mode of action of the IBU. The functional analysis of differentially transcribed genes suggests that IBU can interfere with various signalling pathways in clams, such as arachidonic acid metabolism, apoptosis, peroxisomal proliferator-activated receptors, and nuclear factor-kappa B. In addition, several genes involved in the metabolism of xenobiotics (e.g., glutathione S-transferase, sulfotransferase, cytochrome P450) were also found to be significantly affected by IBU exposure. In summary, the integrated approach of gene transcription analysis and biomarker responses facilitated the elucidation of the putative mechanisms of action of IBU in non-target species. 23376779 Changes in skeletal muscle proteolytic gene expression after prophylactic supplementation of EGCG and NAC and eccentric damage. PURPOSE: The impact of prophylactic supplementation of N-acetyl-cysteine (NAC) and epigallocatechin gallate (EGCG) on intramuscular expression of proteolytic genes after unaccustomed eccentric muscle contractions was investigated. METHODS: Thirty apparently healthy males (mean±SD: 20.0±1.8years, 175±7.1cm, 76.1±16.9kg) ingested daily either 1800mg of NAC or 1800mg of EGCG (98% total polyphenols, 80% total catechins, and 50% EGCG), or 1000mg of a glucomannan placebo (PLA) in a double blind, prophylactic fashion for 14days. Subjects then completed an unaccustomed eccentric exercise bout (100 repetitions at 30°s(-1)) using the dominant knee extensors. Skeletal muscle biopsies were collected from the vastus lateralis at baseline and both 6 and 24h after exercise. The expression of proteolytic genes [i.e., muscle ring-finger 1 (MuRF1), atrogin-1, α-type 20S subunit C2 (HC2), α-type 20S subunit C3 (HC3), ubiquitin protein ligase 3B (UBE3B), μ-calpain, and m-calpain] was quantified using real-time RT-PCR. Separate 3×3 (group×time) repeated measures ANOVAs were used to analyze changes in gene expression over time between groups. RESULTS: No significant group×time interactions were detected between groups for the expression of any of the atrogenes or calpains (p>0.05). Significant main effects for time identified increases in MuRF1 (6h: 5.3±10.8 fold; p=0.046), UBE3B (6h: 5.3±7.7 fold; p=0.006; 24h: 3.3±4.5 fold; p=0.005), and m-calpain expression (6h: 2.7±4.4 fold; p=0.045) in all participants following exercise. Increases approached significance in HC2 (6h: 1.9±2.4 fold; p=0.079; 24h: 1.6±1.9 fold; p=0.084) and m-calpain expression (24h: 1.8±2.3 fold; p=0.084) following exercise. CONCLUSIONS: Prophylactic supplementation of NAC and EGCG did not impact acute changes in skeletal muscle proteolytic gene expression following eccentric exercise. Eccentric muscle contractions elevated MuRF1 and UBE3B, while m-calpain and HC2 mRNA tended to increase. 23435160 Changes in A1C Levels Are Significantly Associated With Changes in Levels of the Cardiovascular Risk Biomarker hs-CRP: Results from SteP Study. OBJECTIVEThe effect of therapeutic strategies on cardiovascular (CV) disease can be evaluated by monitoring changes in CV risk biomarkers. This study investigated the effect of a structured self-monitoring of blood glucose (SMBG) protocol and the resulting improvements in glycemic control on changes in high-sensitivity C-reactive protein (hs-CRP) in insulin-naïve patients with type 2 diabetes.RESEARCH DESIGN AND METHODSThe Structured Testing Program (STeP) study was a prospective, cluster-randomized, multicenter trial in which 483 poorly controlled, insulin-naïve patients with type 2 diabetes were randomized to active control (ACG) or structured testing (STG) that included quarterly structured SMBG. Changes in A1C, hs-CRP, and glycemic variability (STG subjects only) were measured at baseline and quarterly.RESULTSReductions in geometric mean hs-CRP values were significantly greater in the STG group at months 3 (P = 0.005), 6 (P = 0.0003), and 12 (P = 0.04) than in the ACG group. STG patients at high CV risk (>3 mg/L) showed significantly greater reductions in hs-CRP levels than ACG patients at high CV risk: -3.64 mg/dL (95% CI -4.21 to -3.06) versus -2.18 mg/dL (-2.93 to -1.43), respectively (P = 0.002). There was a strong correlation between reductions in hs-CRP and A1C in both groups: standardized coefficient (β) was 0.25 for the entire cohort (P < 0.0001), 0.31 for STG (P < 0.0001), and 0.16 for ACG (P = 0.02).CONCLUSIONSReductions in hs-CRP level are associated with reductions in A1C but not reductions in lipids or glycemic variability. Comprehensive structured SMBG-based interventions that lower A1C may translate into improvements in CV risk, as evidenced by levels of the biomarker hs-CRP. 23561080 Microencapsulation of aspartame by double emulsion followed by complex coacervation to provide protection and prolong sweetness. The objective of this work was to microencapsulate aspartame by double emulsion followed by complex coacervation, aiming to protect it and control its release. Six treatments were prepared using sunflower oil to prepare the primary emulsion and gelatin and gum Arabic as the wall materials. The microcapsules were evaluated structurally with respect to their sorption isotherms and release into water (36°C and 80°C). The microcapsules were multinucleated, not very water-soluble or hygroscopic and showed reduced rates of equilibrium moisture content and release at both temperatures. FTIR confirmed complexation between the wall materials and the intact nature of aspartame. The results indicated it was possible to encapsulate aspartame with the techniques employed and that these protected the sweetener even at 80°C. The reduced solubility and low release rates indicated the enormous potential of the vehicle developed in controlling the release of the aspartame into the food, thus prolonging its sweetness. 23579421 Endowing carbon nanotubes with superparamagnetic properties: applications for cell labeling, MRI cell tracking and magnetic manipulations. Coating of carbon nanotubes (CNTs) with magnetic nanoparticles (NPs) imparts novel magnetic, optical, and thermal properties with potential applications in the biomedical domain. Multi-walled CNTs have been decorated with iron oxide superparamagnetic NPs. Two different approaches have been investigated based on ligand exchange or "click chemistry". The presence of the NPs on the nanotube surface allows conferring magnetic properties to CNTs. We have evaluated the potential of the NP/CNT hybrids as a contrast agent for magnetic resonance imaging (MRI) and their interactions with cells. The capacity of the hybrids to magnetically monitor and manipulate cells has also been investigated. The NP/CNTs can be manipulated by a remote magnetic field with enhanced contrast in MRI. They are internalized into tumor cells without showing cytotoxicity. The labeled cells can be magnetically manipulated as they display magnetic mobility and are detected at a single cell level through high resolution MRI. 22532499 Effect of water extracts from edible myrtaceae plants on uptake of 2-(n-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose in TNF-α-treated FL83B mouse hepatocytes. This study investigated the glucose uptake activity of the water extracts from the leaves and fruit of edible Myrtaceae plants, including guava (Psidium guajava Linn.), wax apples [Syzygium samarangense (Blume) Merr. and L.M. Perry], Pu-Tau [Syzygium jambo (L.) Alston], and Kan-Shi Pu-Tau (Syzygium cumini Linn.) in FL83B mouse hepatocytes. The fluorescent dye 2-(n-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose was used to estimate the uptake ability of the cells. Glucose uptake test showed that pink wax apple fruit extract (PWFE) exhibits the highest glucose uptake activity, at an increment of 21% in the insulin-resistant FL83B mouse hepatocytes as compared with the TNF-α-treated control group. Vescalagin was isolated using column chromatography of PWFE. This compound, at the concentration of 6.25 µg/mL, exhibits the same glucose uptake improvement in insulin-resistant cells as PWFE at a 100-µg/mL dose. We postulate that vescalagin is an active component in PWFE that may alleviate the insulin resistance in mouse hepatocytes. 23432753 Comprehensive insights into the structural and chemical changes in mixed-anion FeOF electrodes by using operando PDF and NMR spectroscopy. In-depth analysis of operando X-ray pair distribution function (PDF) data is combined with Li NMR spectroscopy to gain comprehensive insights into the electrochemical reaction mechanism of high-performance iron oxyfluoride electrodes. While the full discharge capacity could be recovered upon charge, implying reversibility of the electrochemical reaction, the atomic structure of the electrode formed after cycling (discharge-charge) differs from the pristine uncycled electrode material. Instead, the "active" electrode that forms upon cycling is a nanocomposite of an amorphous rutile phase and a nanoscale rock salt phase. Bond valence sum analysis, based on the precise structural parameters (bond lengths and coordination number) extracted from the in situ PDF data, suggests that anion partitioning occurs during the electrochemical reaction, with the rutile phase being F-rich and the rock salt phase being O-rich. The F- and O-rich phases react sequentially; Fe in a F-rich environment reacts preferentially during both discharge and charge. 23164713 Enantioselective synthesis of derivatives and structure-activity relationship study in the development of NA255 as a novel host-targeting anti-HCV agent. Hepatitis C virus (HCV) infection represents a serious health-care problem. Previously we reported the identification of NA255 from our natural products library using a HCV sub-genomic replicon cell culture system. Herein, we report how the absolute stereochemistry of NA255 was determined and an enantioselective synthetic method for NA255 derivatives was developed. The structure-activity relationship of the NA255 derivatives and rat pharmacokinetic profiles of the representative compounds are disclosed. 23441017 Phase stability and elastic properties of chromium borides with various stoichiometries. Phase stability is important to the application of materials. By first-principles calculations, we establish the phase stability of chromium borides with various stoichiometries. Moreover, the phases of CrB3 and CrB4 have been predicted by using a newly developed particle swarm optimization (PSO) algorithm. Formation enthalpy-pressure diagrams reveal that the MoB-type structure is more energetically favorable than the TiI-type structure for CrB. For CrB2 , the WB2 -type structure is preferred at zero pressure. The predicted new phase of CrB3 belongs to the hexagonal P-6m2 space group and it transforms into an orthorhombic phase as the pressure exceeds 93 GPa. The predicted CrB4 (space group: Pnnm) phase is more energetically favorable than the previously proposed Immm structure. The mechanical and thermodynamic stabilities of predicted CrB3 and CrB4 are verified by the calculated elastic constants and formation enthalpies. The full phonon dispersion calculations confirm the dynamic stability of WB2 -type CrB2 and predicted CrB3 . The large shear moduli, large Young's moduli, low Poisson ratios, and low bulk and shear modulus ratios of CrB4 PSC and CrB4 PSD indicate that they are potential hard materials. Analyses of Debye temperature, electronic localization function, and electronic structure provide further understanding of the chemical and physical properties of these borides. 22736625 A Safety Assessment of the Antimalarial Herb Artemisia annua During Pregnancy in Wistar Rats. Artemisia annua is a Chinese antimalarial herb that has been used for more than 2000 years. The maternal and foetal safety of the ethanolic leaf extract of therapeutically active Artemisia annua (EAA), with previously determined artemisinin yield of 1.098% was evaluated in Wistar rats. Twenty pregnant rats, divided into four study groups of saline treated (control), and test groups administered orally with 100, 200 and 300 mg/kg body weights of EAA, respectively, from gestation days (GD) 8 to 19. Following overnight fast, animals were sacrificed on GD 20, and maternal blood was collected to evaluate biochemical and haematological markers. Foetuses were carefully removed, weighed, and observed for any possible malformation. Biochemical and haematological studies revealed that EAA did not result in maternal hepatotoxicity, haematotoxicity, and hyperlipidemia. While litter size significantly decreased (p < 0.05) at 100 mg/kg EAA, maternal estrogen levels decreased in all the EAA-treated groups. Non-viable (21%) and malformed (31%) foetuses were observed at the 300 mg/kg dose of EAA, which implies that although consumption of the leaf extract may not predispose users to hepatotoxicity, haematotoxicity, and hyperlipidemia, it should be taken with caution during pregnancy due to possible risk of embryotoxicity at concentrations higher than the therapeutic dose. Copyright © 2012 John Wiley & Sons, Ltd. 23248329 Association of Shiga toxin glycosphingolipid receptors with membrane microdomains of toxin-sensitive lymphoid and myeloid cells. Glycosphingolipids (GSLs) of the globo-series constitute specific receptors for Shiga toxins (Stxs) released by certain types of pathogenic Escherichia coli strains. Stx-loaded leukocytes may act as transporter cells in the blood and transfer the toxin to endothelial target cells. Therefore, we performed a thorough investigation on the expression of globo-series GSLs in serum-free cultivated Raji and Jurkat cells, representing B- and T-lymphocyte descendants, respectively, as well as THP-1 and HL-60 cells of the monocyte and granulocyte lineage, respectively. The presence of Stx-receptors in GSL preparations of Raji and THP-1 cells and the absence in Jurkat and HL-60 cells revealed high compliance of solid-phase immunodetection assays with the expression profiles of receptor-related glycosyltransferases, performed by qRT-PCR analysis, and Stx2-caused cellular damage. Canonical microdomain association of Stx GSL receptors, sphingomyelin, and cholesterol in membranes of Raji and THP-1 cells was assessed by comparative analysis of detergent-resistant membrane (DRM) and nonDRM fractions obtained by density gradient centrifugation and showed high correlation based on nonparametric statistical analysis. Our comprehensive study on the expression of Stx-receptors and their subcellular distribution provides the basis for exploring the functional role of lipid raft-associated Stx-receptors in cells of leukocyte origin. 23633618 A Structural Snapshot of Cytochrome P450 2B4 in Complex with Paroxetine Provides Insights into Ligand Binding and Clusters of Conformational States. An X-ray crystal structure of cytochrome P450 2B4 in complex with the drug paroxetine was solved at 2.14 Å resolution. The structure revealed a conformation intermediate to that of the recently solved complex with amlodipine and of the more compact complex with 4-(4-chlorophenyl)imidazole in terms of the placement of the F-G cassette. Moreover, the comparison of the new structure with 15 previously solved structures of P450 2B4 revealed some new insights into determinants of active site size and shape. The 2B4-paroxetine structure is nearly superimposable on a previously solved closed structure in a ligand free state. Despite the overall conformational similarity among multiple closed structures, the active site cavity volume of the paroxetine complex is enlarged. Further analysis of the accessible space and binding pocket near the heme reveals a new sub-chamber that resulted from the movement of secondary structural elements and rearrangements of active site side chains. Overall, the results from the comparison of all the 16 structures of P450 2B4 demonstrate a cluster of protein conformations that were observed in the presence or absence of various ligands. 23202134 Differences in lead tolerance between Kandelia obovata and Acanthus ilicifolius seedlings under varying treatment times. The effects of short-term (1 day) and long-term (49 days) of lead (Pb) stress on growth and physiological responses in the leaves and roots of two mangrove plants, Kandelia obovata and Acanthus ilicifolius, were compared. The growth of both species was affected by Pb at Day 49, whereas the root to shoot ratio of K. obovata remained unchanged. Compared with A. ilicifolius, less Pb accumulated in leaves of K. obovata, which indicates that this species is a typical Pb-excluder. Significant linear relationships were observed between the Pb concentrations in the roots and leaves and the Pb treatment concentrations in the sediments in A. ilicifolius but not in K. obovata. The proline concentration increased in both mangrove species at Day 49, especially in A. ilicifolius, but no changes were observed at Day 1. The tolerant species K. obovata tended to acclimate to metal stress by restricting the translocation of toxic metals and by increasing and/or maintaining high superoxide dismutase (SOD) activity, minimizing lipid peroxidation, and exhibiting prolonged unaltered growth (49 days) under Pb treatment. The non-tolerant species, A. ilicifolius, did not acclimate to metal stress, its leaves were seriously damaged with significant increased MDA content, and its SOD activity was decreased. An increase of endogenous jasmonic acid concentration was observed only in K. obovata, both at Day 1 and at Day 49, which suggests that this hormone plays an important role in metal tolerance under short-term and long-term metal treatment. 23270565 Synthesis and insight into the structure-activity relationships of chalcones as antimalarial agents. Licochalcone A (I), isolated from the roots of Chinese licorice, is the most promising antimalarial compound reported so far. In continuation of our drug discovery program, we isolated two similar chalcones, medicagenin (II) and munchiwarin (III), from Crotalaria medicagenia , which exhibited antimalarial activity against Plasmodium falciparum . A library of 88 chalcones were synthesized and evaluated for their in vitro antimalarial activity. Among these, 67, 68, 74, 77, and 78 exhibited good in vitro antimalarial activity against P. falciparum strains 3D7 and K1 with low cytotoxicity. These chalcones also showed reduction in parasitemia and increased survival time of Swiss mice infected with Plasmodium yoelii (strain N-67). Pharmacokinetic studies indicated that low oral bioavailability due to poor ADME properties. Molecular docking studies revealed the binding orientation of these inhibitors in active sites of falcipain-2 (FP-2) enzyme. Compounds 67, 68, and 78 showed modest inhibitory activity against the major hemoglobin degrading cysteine protease FP-2. 23261678 Olive oil oleuropein has anti-breast cancer properties with higher efficiency on ER-negative cells. Breast cancer constitutes a major health problem for women worldwide. However, its incidence varies between populations and geographical locations. These variations could be diet-related, since there are several carcinogenic compounds in the modern diet, while natural products contain various anti-cancer elements. Several lines of evidence indicate that, in addition to their clear preventive effect, these compounds could also be used as therapeutic agents. In the present report we have shown that oleuropein, a pharmacologically safe natural product of olive leaf, has potent anti-breast cancer properties. Indeed, oleuropein exhibits specific cytotoxicity against breast cancer cells, with higher effect on the basal-like MDA-MB-231 cells than on the luminal MCF-7 cells. This effect is mediated through the induction of apoptosis via the mitochondrial pathway. Moreover, oleuropein inhibits cell proliferation by delaying the cell cycle at S phase and up-regulated the cyclin-dependent inhibitor p21. Furthermore, oleuropein inhibited the anti-apoptosis and pro-proliferation protein NF-κB and its main oncogenic target cyclin D1. This inhibition could explain the great effect of oleuropein on cell proliferation and cell death of breast cancer cells. Therefore, oleuropein warrants further investigations to prove its utility in preventing/treating breast cancer, especially the less-responsive basal-like type. 23427810 Vapor-solid growth of high optical quality MoS₂ monolayers with near-unity valley polarization. Monolayers of transition metal dichalcogenides (TMDCs) are atomically thin direct-gap semiconductors with potential applications in nanoelectronics, optoelectronics, and electrochemical sensing. Recent theoretical and experimental efforts suggest that they are ideal systems for exploiting the valley degrees of freedom of Bloch electrons. For example, Dirac valley polarization has been demonstrated in mechanically exfoliated monolayer MoS2 samples by polarization-resolved photoluminescence, although polarization has rarely been seen at room temperature. Here we report a new method for synthesizing high optical quality monolayer MoS2 single crystals up to 25 μm in size on a variety of standard insulating substrates (SiO2, sapphire, and glass) using a catalyst-free vapor-solid growth mechanism. The technique is simple and reliable, and the optical quality of the crystals is extremely high, as demonstrated by the fact that the valley polarization approaches unity at 30 K and persists at 35% even at room temperature, suggesting a virtual absence of defects. This will allow greatly improved optoelectronic TMDC monolayer devices to be fabricated and studied routinely. 23391023 Signature of singlet open-shell character on the optically allowed singlet excitation energy and singlet-triplet energy gap. A signature of singlet open-shell character on the optically allowed singlet excitation energy and singlet-triplet energy gap is theoretically illuminated for open-shell singlet molecules. On the basis of a two-site diradical model with two electrons in two orbitals, the linear dependence of these excitation energies on the transfer integral, which is equivalent to the energy gap between the highest occupied (HOMO) and the lowest unoccupied (LUMO) molecular orbitals in the Hückel theory, is found to be broken down in the high diradical character region due to an increase in electron correlation in the open-shell singlet ground state. A series of polyacenes shows the similar behavior of the optically allowed singlet excitation energies obtained by time-dependent spin-flip density functional theory calculations and experiments, which bears testimony to the singlet open-shell character in long polyacenes. 23206865 Highly solvatochromic fluorescent naphthalimides: design, synthesis, photophysical properties and fluorescence switch-on sensing of ct-DNA. We report the design, synthesis and photophysical properties of highly solvatochromic donor/acceptor substituted naphthalimide based fluorophores. The synthesized naphthalimides containing propargyl ends showed highly solvatochromic intramolecular charge transfer (ICT) feature as was revealed from the UV-visible, fluorescence photophysical properties of these fluorophores and DFT/TDDFT calculation. Fluorescence life times for the imide fluorophores were also measured in different solvents. The solid state photophysical property of donor substituted naphthalimide 1 showed promising for future application in material sciences. Furthermore, both the donor/acceptor substituted naphthalimide fluorophores 1-2 were exploited in sensing calf-thymus DNA via switch-on fluorescence response. The propargyl linker containing naphthalimides can further be exploited for the synthesis of labeled biomolecular building blocks. 22348951 Exposure to contaminants exacerbates oxidative stress in amphipod Monoporeia affinis subjected to fluctuating hypoxia. Fitness and survival of an organism depend on its ability to mount a successful stress response when challenged by exposure to damaging agents. We hypothesized that co-exposure to contaminants may exacerbate oxidative stress in hypoxia-challenged benthic animals compromising their ability to recover upon reoxygenation. This was tested using the amphipod Monoporeia affinis exposed to hypoxia followed by reoxygenation in sediments collected in polluted and pristine areas. In both sediment types, oxygen radical absorbance capacity (ORAC) and antioxidant enzyme activities [superoxide dismutase (SOD) and catalase (CAT)] increased during hypoxia, suggesting that M. affinis has a strategy of preparation for oxidative stress that facilitates recovery after a hypoxic episode. Exposure to contaminants altered this anticipatory response as indicated by higher baselines of ORAC and SOD during hypoxia and no response upon reoxygenation. This coincided with significantly elevated oxidative damage evidenced by a marked reduction in glutathione redox status (ratio of reduced GSH/oxidized GSSG) and an increase in lipid peroxidation (TBARS levels). Moreover, RNA:DNA ratio, a proxy for protein synthetic activity, decreased in concert with increased TBARS, indicating a linkage between oxidative damage and fitness. Finally, inhibited acetylcholinesterase (AChE) activity in animals exposed to contaminated sediments suggested a neurotoxic impact, whereas significant correlations between AChE and oxidative biomarkers may indicate connections with redox state regulation. The oxidative responses in pristine sediments suggested a typical scenario of ROS production and removal, with no apparent oxidative damage. By contrast, co-exposure to contaminants caused greater increase in antioxidants, lipid peroxidation, and slowed recovery from hypoxia as indicated by CAT, GSH/GSSG, TBARS and AChE responses. These results support the hypothesized potential of xenobiotics to hamper ability of animals to cope with fluctuating hypoxia. They also emphasize the importance of understanding interactions between antioxidant responses to different stressors and physiological mechanisms of oxidative damage. 23278281 Biomarkers of toluene exposure in rats: mercapturic acids versus traditional indicators (urinary hippuric acid and o-cresol and blood toluene). Abstract 1. Toluene (TOL) is a neurotoxic, ototoxic and reprotoxic solvent which is metabolized via the glutathione pathway, producing benzylmercapturic, o-, m- and p-toluylmercapturic acids (MAs). These metabolites could be useful as biomarkers of TOL exposure. 2. The aims of this study were (1) to provide data on MAs excretion in rat urine following TOL exposure by inhalation, (2) to compare them to data from traditional TOL biomarkers, i.e. TOL in blood (Tol-B), and urinary hippuric acid (HA) and o-cresol (oCre) and (3) to establish a relationship between these different indicators and the airborne TOL concentration (Tol-A). 3. Sprague-Dawley rats were exposed to a range of TOL concentrations. Blood and urine were collected and analyzed to determine biomarker levels. 4. Levels of the four MAs correlate strongly with Tol-A (comparable to the correlation with Tol-B). 5. MAs are thus clearly superior to oCre and HA as potential markers of exposure to TOL. 23151001 Regulation of G protein-coupled receptor kinases by phospholipids. G protein coupled-receptor (GPCR) kinases (GRKs) initiate the deactivation of GPCRs by phosphorylating their cytoplasmic loops and C-terminal tails. They are regulated not only by allosteric interactions with activated GPCRs, but also by the membrane environment itself. Herein we describe how the various GRKs are recruited to lipid bilayers and, where evident, how specific anionic phospholipids help regulate their activity. Using crystal structures representing each of the three vertebrate GRK subfamilies, we map the lipid binding sites in order to better understand how these enzymes are oriented at the cell surface. This analysis suggests that GRKs bind lipid and active GPCRs in a coordinated manner. 23376546 Gender and strain contributions to the variability of buprenorphine-related respiratory toxicity in mice. While most deaths from asphyxia related to buprenorphine (BUP) overdose have been reported in males, higher plasma concentrations of BUP and its toxic metabolite norbuprenorphine (NBUP) have been observed in females. We previously demonstrated that P-glycoprotein (P-gp) modulation at the blood-brain barrier (BBB) contributes highly to BUP-related respiratory toxicity, by limiting NBUP entrance into the brain. In this work, we sought to investigate the role of P-gp-mediated transport at the BBB in gender and strain-related variability of BUP and NBUP-induced respiratory effects in mice. Ventilation was studied using plethysmography, P-gp expression using western blot, and transport at the BBB using in situ cerebral perfusion. In male Fvb and Swiss mice, BUP was responsible for ceiling respiratory effects. NBUP-related reduction in minute volume was dose-dependent but more marked in Fvb (p<0.01 at 1mg/kg NBUP and p<0.001 at 3 and 9mg/kg NBUP) than in Swiss mice (p<0.001 at 9mg/kg NBUP). Female Fvb mice were more susceptible to BUP than males with significantly increased inspiratory time (p<0.05) and to NBUP with significantly increased expiratory time (p<0.01). Following BUP administration, plasma BUP concentrations were significantly higher (p<0.01) and plasma NBUP concentrations significantly lower (p<0.001) in Fvb mice compared to Swiss mice. Plasma BUP concentrations were significantly higher (p<0.05) and plasma NBUP concentrations significantly lower (p<0.01) in male compared to female Fvb mice. In contrast, following NBUP administration, comparable plasma NBUP concentrations were observed in both genders and strains. No differences in P-gp expression or BUP and NBUP transport across the BBB were observed between male and female Fvb mice as well as between Swiss and Fvb mice. Our results suggest that P-gp-mediated transport across the BBB does not play a key-role in gender and strain-related variability in BUP and NBUP-induced respiratory toxicity in mice. Both gender- and strain-related differences in respiratory effects of BUP could be attributed to BUP itself rather than to its metabolite, NBUP. 23265532 Influence of processing on the volatile profile of strawberry spreads made with isomaltulose. A new strawberry spread formulated with fructose and isomaltulose (replacing sucrose partially or totally) and a high percentage of fruit was developed in line with the new trend of healthier products. This work studies the influence of some process variables (percentage of sugar, pectin and citric acid, and time of thermal treatment) on the volatile profile of these spreads with different formulations. The ripeness of the raw strawberries influences the concentrations of some of the compounds in the spreads, such as isobutyl acetate, butyl butyrate, 3-hexen-1-yl acetate or propan-2-ol. The process conditions have an important effect on the volatile profiles. Most of the esters and alcohols decreased whereas 13 new compounds appear, mostly furans (furfural, 2-acetylfurane, 5-methyl furfural, mesifurane) and aldehydes (octanal, nonanal, decanal and benzaldeyhde). In general, the spreads formulated with sucrose-isomaltulose that contained higher levels of pectin and citric acid gave better results in the preservation of the original aromatic compounds in raw strawberries. 23257627 Synthesis of substituted 6-amino-4-(2,4-dimethoxyphenyl)-[1,2]dithiolo[4,3-b]pyrrol-5-ones and their raising leukocyte count activities. The design and synthesis of a series of substituted 6-amino-4-(2,4-dimethoxyphenyl)-[1,2]dithiolo[4,3-b]pyrrol-5-ones are described. All the synthesized compounds were evaluated for raising leukocyte count activities in normal mice. Four compounds (8a, b, d, h) exhibited raising leukocyte count activities close or higher than positive control recombinant human granulocyte colony stimulating factor (rhG-CSF), and some (8e-g, k, p, r) had a moderate effect. Among them, the most potent compound 8a was evaluated for its antileukopenia activity in cyclophosphamide (CTX) treated mice. Interestingly, 8a exhibited significant antileukopenia activity as compared to rhG-CSF. The results suggest that this kind of compounds might be utilized for the development of new candidate for treatment of leukocytopenia. 23411336 Apoptosis of human breast cancer cells induced by microencapsulated betulinic acid from sour jujube fruits through the mitochondria transduction pathway. Betulinic acid (BA), a natural pentacyclic triterpenoid, was isolated from sour jujube fruits for the first time. An inclusion complex comprising BA and β-cyclodextrin (β-CD) was formed to improve the dissolution of BA, but little is known about its anticancer effect. In this study, the anti-proliferative and apoptosis mechanisms of BA-β-CD on human breast cancer MCF-7 cells were further investigated. Experimental results confirmed that the complexation model inhibited the growth of MCF-7 cells in a dose-dependent manner, arrested cell cycle in the G2/M phase and induced apoptosis via the mitochondria transduction pathway. Gene and protein analyses showed that the complexation model significantly inhibited Bcl-2 expression and promoted Bax expression, causing caspase-3 and caspase-9 cascade activation. These findings corroborated evidence on microencapsulated BA as an apoptosis inducer in MCF-7 cells. Thus, sour jujube fruits may have potential use as a breast cancer chemotherapeutic agent. 23608737 Estradiol replacement enhances cocaine-stimulated locomotion in female C57BL/6 mice through estrogen receptor alpha. Psychostimulant effects are enhanced by ovarian hormones in women and female rodents. Estradiol increases behavioral responses to psychostimulants in women and female rats, although the underlying mechanism is unknown. This study utilized mice to investigate the time frame and receptor mediation of estradiol's enhancement of cocaine-induced behavior as mice enable parallel use of genetic, surgical and pharmacological methods. The spontaneous behavior of Sham and Ovariectomized (Ovx) female wildtype (WT) mice was determined during habituation to a novel environment and after cocaine administration. Ovx mice were replaced with vehicle (sesame oil) or 17β-estradiol (E2) for 2 days or 30 min prior to a cocaine challenge to investigate the time course of E2's effects. To examine receptor mediation of estradiol effects, Ovx mice replaced for 2 days with either the ERα-selective agonist PPT or the ERβ-selective agonist DPN were compared to Sham mice, and mice lacking either ERα (αERKO) or ERβ (βERKO) were compared to WT littermates. Ovx mice exhibited fewer ambulations during habituation than Sham females. Cocaine-induced increases in behavioral ratings were greater in Sham than in Ovx mice. Two days but not 30 min of E2 replacement in Ovx mice increased cocaine responses to Sham levels. PPT replacement also increased the cocaine response relative to vehicle- or DPN- treated Ovx mice. αERKO mice displayed modestly attenuated behavioral responses to novelty and cocaine compared to αWT littermates, but no behavioral differences were found between βERKO and βWT mice. These results suggest that E2 enhances cocaine-stimulated locomotion in mice predominantly through ERα. 23223125 Hot charge-transfer excitons set the time limit for charge separation at donor/acceptor interfaces in organic photovoltaics. Photocurrent generation in organic photovoltaics (OPVs) relies on the dissociation of excitons into free electrons and holes at donor/acceptor heterointerfaces. The low dielectric constant of organic semiconductors leads to strong Coulomb interactions between electron-hole pairs that should in principle oppose the generation of free charges. The exact mechanism by which electrons and holes overcome this Coulomb trapping is still unsolved, but increasing evidence points to the critical role of hot charge-transfer (CT) excitons in assisting this process. Here we provide a real-time view of hot CT exciton formation and relaxation using femtosecond nonlinear optical spectroscopies and non-adiabatic mixed quantum mechanics/molecular mechanics simulations in the phthalocyanine-fullerene model OPV system. For initial excitation on phthalocyanine, hot CT excitons are formed in 10(-13) s, followed by relaxation to lower energies and shorter electron-hole distances on a 10(-12) s timescale. This hot CT exciton cooling process and collapse of charge separation sets the fundamental time limit for competitive charge separation channels that lead to efficient photocurrent generation. 23265460 Natural occurrence of deoxynivalenol in wheat from Paraná State, Brazil and estimated daily intake by wheat products. The occurrence of deoxynivalenol (DON) was evaluated in 113 wheat samples from the northern and central/southwestern regions of Paraná State, Brazil during the 2008 and 2009 growing seasons, and this rate of occurrence was used to estimate the DON dietary exposure. The DON determination was carried out by an indirect competitive enzyme-linked immunosorbent assay. DON was detected in 66.4% samples at levels ranging from 206.3 to 4732.3 μg/kg (mean 1894.9 μg/kg). The estimated daily intake (EDI) of DON through bread and pasta was evaluated in the inhabitants of Londrina City in northern Paraná State, Brazil. The average intake of these inhabitants was 0.79 μg/kg body weight (b.w.) for bread and 0.35 μg/kg b.w. for pasta. The total EDI was 1.13 μg/kg, which is above the Provisional Tolerable Daily Maximum Intake (PTDMI) of 1 μg/kg b.w. To our knowledge, this is the first report on natural DON occurrence in wheat and DON dietary exposure estimation from Paraná, Brazil. 23220035 Biological impact of phthalates. Esters of phthalic acid are chemical agents used to improve the plasticity of industrial polymers. Their ubiquitous use in multiple commercial products results in extensive exposure to humans and the environment. This study investigated cytotoxicity, endocrine disruption, effects mediated via AhR, lipid peroxidation and effects on expression of enzymes of xenobiotic metabolism caused by di-(2-ethy hexyl) phthalate (DEHP), diethyl phthalate (DEP), dibutyl phthalate (DBP) and benzyl butyl phthalate (BBP) in developing fish embryos. Oxidative stress was identified as the critical mechanism of toxicity (CMTA) in the case of DEHP and DEP, while the efficient removal of DBP and BBP by phase 1 enzymes resulted in lesser toxicity. DEHP and DEP did not mimic estradiol (E(2)) in transactivation studies, but at concentrations of 10mg/L synthesis of sex steroid hormones was affected. Exposure to 10mg BBP/L resulted in weak transactivation of the estrogen receptor (ER). All phthalates exhibited weak potency as agonists of the aryl hydrocarbon receptor (AhR). The order of potency of the 4 phthalates studied was; DEHP>DEP>BBP>DBP. The study highlights the need for simultaneous assessment of: (1) multiple cellular targets affected by phthalates and (2) phthalate mixtures to account for additive effects when multiple phthalates modulate the same pathway. Such cumulative assessment of multiple biological parameters is more realistic, and offers the possibility of more accurately identifying the CMTA. 23376609 Absence of CC chemokine receptors 2a and 2b from human adipose lineage cells. Previous results have suggested the existence of receptors for monocyte chemoattractant protein-1 (MCP-1), CC chemokine receptors 2 (CCR2), in human adipocytes and their involvement in mediating effects of MCP-1 on adipocyte functions. However, the presence of CCR2 present on non-adipose-lineage cells of adipose tissue has not been excluded. We have used human Simpson-Golabi-Behmel-Syndrome (SGBS) preadipocytes and in-vitro-differentiated mature adipocytes to investigate the expression of CCR2 in human (pre)adipocytes. We found that the cells are devoid of CCR2 receptor protein and mRNA expression and fail to respond to treatment with all known CCR2 chemokine agonists. CCR2 is also absent from (pre)adipocytes prepared in vitro from human multipotent adipose-derived stem cells, bone-marrow-derived mesenchymal stem cells, or from primary (pre)adipocytes. Conditions mimicking proinflammatory changes in adipose tissue did not induce CCR2 receptor expression. We conclude that CCR2 is absent from human adipose lineage cells. Functional effects previously described for MCP-1 in human adipose tissue may be mediated indirectly through paracrine effects on non-adipose-lineage cells or by a (pre)adipocyte receptor for MCP-1 distinct from CCR2. 23319588 An N-terminal nuclear export signal regulates trafficking and aggregation of Huntingtin (Htt) protein exon 1. Huntington disease is a dominantly inherited neurodegenerative condition caused by polyglutamine expansion in the N terminus of the huntingtin protein (Htt). The first 17 amino acids (N17) of Htt play a key role in regulating its toxicity and aggregation. Both nuclear export and cytoplasm retention functions have been ascribed to N17. We have determined that N17 acts as a nuclear export sequence (NES) within Htt exon and when fused to yellow fluorescent protein. We have defined amino acids within N17 that constitute the nuclear export sequence (NES). Mutation of any of the conserved residues increases nuclear accumulation of Htt exon 1. Nuclear export of Htt is sensitive to leptomycin B and is reduced by knockdown of exportin 1. In HEK293 cells, NES mutations decrease overall Htt aggregation but increase the fraction of cells with nuclear inclusions. In primary cultured neurons, NES mutations increase nuclear accumulation and increase overall aggregation. This work defines a bona fide nuclear export sequence within N17 and links it to effects on protein aggregation. This may help explain the important role of N17 in controlling Htt toxicity. 23586848 Interactions between oral antineoplastic agents and concomitant medication: a systematic review. Introduction: In recent years, the number of oral antitumoral agents has considerably increased. Oral administration increases the risk of interactions, because most oral anticancer drugs are taken on a daily basis. Interactions can increase exposure to antitumoral agents or cause treatment failure. Many antitumoral drugs undergo enzymatic metabolism by cytochrome P450. As some act as inducers or inhibitors of one or more isoenzymes, they can lead to decreases or increases in plasma concentrations of concomitant drugs. Hence, cytostatic drugs can act not only as victims but also as perpetrators. P-glycoprotein, an efflux transporter, can also be involved in pharmacokinetic interactions. Areas covered: A Medline search was performed to summarize the available evidence of the most clinically relevant interactions between oral chemotherapy agents and other drugs. The search covered the period from 1966 until August 2012 for each antitumoral drug using the medical subject headings 'Drug Interactions' OR 'Pharmacokinetics'. While the present review is not exhaustive, it aims to increase clinicians' awareness of potential drug-drug interactions. Expert opinion: As cancer patients are often polymedicated and treated by different physicians, the risk of drug interactions between antitumoral agents and other medications is high. More clinical interaction studies are encouraged to ensure appropriate antineoplastic pharmacokinetics in clinical practice. 23374506 Enter the matrix: shape, signal and superhighway. Mammalian skeletal muscle is notable for both its highly ordered biophysical structure and its regenerative capacity following trauma. Critical to both of these features is the specialized muscle extracellular matrix, comprising both the multiple concentric sheaths of connective tissue surrounding structural units from single myofibers to whole muscles and the dense interstitial matrix that occupies the space between them. Extracellular matrix-dependent interactions affect all activities of the resident muscle stem cell population (the satellite cells), from maintenance of quiescence and stem cell potential to the regulation of proliferation and differentiation. This review focuses on the role of the extracellular matrix in muscle regeneration, with a particular emphasis on regulation of satellite-cell activity. 23364509 Predicting metabolic clearance for drugs that are actively transported into hepatocytes: incubational binding as a consequence of in vitro hepatocyte concentration is a key factor. Incubational binding or the fraction of drug unbound in an in vitro incubation, fuinc, is an important parameter to predict or measure in the pursuit of accurate clearance predictions from in vitro data. Here we describe a method for fuinc determination directly in the hepatocyte intrinsic clearance (CLint) assay with emphasis on compounds that are actively transported into hepatocytes, hypothesizing that for such compounds the typical protocol of 1 million hepatocytes/ml systematically underestimates the maximum attainable unbound intracellular drug concentration. Using the transporter substrate atorvastatin as a test compound, incubations were performed and a mathematical model applied to describe metabolism, distribution, and binding at different hepatocyte concentrations. From these investigations it was evident that, since binding is more extensive intracellularly than in the medium, increased partitioning into the cellular volume, due to active uptake, increases the total amount of atorvastatin bound in the incubation. Consequently, a significant lowering of the hepatocyte concentration impacts the free drug concentration in the incubation and increases the observed rate of metabolism and therefore observed CLint (that is, when viewed from the media drug concentration). The applicability of the findings was tested for a series of 11 actively transported zwitterions for which standard rat hepatocyte metabolic CLint data (1 million cells/ml incubation) poorly predicted in vivo clearance (average fold error of 5.4). Using metabolic CLint determined at a lower hepatocyte concentration (0.125 million cells/ml) considerably improved clearance predictions (average fold error of 2.3). 23159464 Clinical risk factors, bone density and fall history in the prediction of incident fracture among men and women. The FRAX(tr) algorithm uses clinical risk factors (CRF) and bone mineral density (BMD) to predict fracture risk but does not include falls history in the calculation. Using results from the Hertfordshire Cohort Study, we examined the relative contributions of CRFs, BMD and falls history to fracture prediction. We studied 2299 participants at a baseline clinic that included completion of a health questionnaire and anthropometric data. A mean of 5.5years later (range 2.9-8.8years) subjects completed a postal questionnaire detailing fall and fracture history. In a subset of 368 men and 407 women, bone densitometry was performed using a Hologic QDR 4500 instrument. There was a significantly increased risk of fracture in men and women with a previous fracture. A one standard deviation drop in femoral neck BMD was associated with a hazards ratio (HR) of incident fracture (adjusted for CRFs) of 1.92 (1.04-3.54) and 1.77 (1.16-2.71) in men and women respectively. A history of any fall since the age of 45years resulted in an unadjusted HR of fracture of 7.31 (3.78-14.14) and 8.56 (4.85-15.13) in men and women respectively. In a ROC curve analysis, the predictive capacity progressively increased as BMD and previous falls were added into an initial model using CRFs alone. Falls history is a further independent risk factor for fracture. Falls risk should be taken into consideration when assessing whether or not to commence medication for osteoporosis and should also alert the physician to the opportunity to target falls risk directly. 22966073 The core cysteines, (C909) of islet antigen-2 and (C945) of islet antigen-2β, are crucial to autoantibody binding in type 1 diabetes. Cysteines are thought integral to conformational epitopes of islet antigen-2 (IA-2) autoantibodies (IA-2A), possibly through disulfide bond formation. We therefore investigated which cysteines are critical to IA-2A binding in patients with newly diagnosed type 1 diabetes. All 10 cysteines in the intracellular domain of IA-2 were modified to serine by site-directed mutagenesis, and the effects of these changes on autoantibody binding in comparison with wild-type control were investigated by radiobinding assay. Mutation of the protein tyrosine phosphatase (PTP) core cysteine (C909) in IA-2 caused large reductions in autoantibody binding. In contrast, little or no reduction in binding was seen following substitution of the other cysteines. Modification of the core cysteine (C945) in IA-2β also greatly reduced autoantibody binding. Lysine substitution of glutamate-836 in IA-2 or glutamate-872 in IA-2β resulted in modest reductions in binding and identified a second epitope region. Binding to IA-2 PTP and IA-2β PTP was almost abolished by mutation of both the core cysteine and these glutamates. The core cysteine is key to the major PTP conformational epitope, but disulfide bonding contributes little to IA-2A epitope integrity. In most patients, at disease onset, >90% of antibodies binding to the PTP domain of IA-2 recognize just two epitope regions. 23464522 Tubulin: an example of targeted chemotherapy. Anticancer drugs directed against the microtubule, including taxanes and vinca alkaloids, have been the backbone of many chemotherapy regimes for decades. These drugs have, however, significant limitations, which have prompted the development of novel microtubule targeting agents (MTAs). This article will discuss MTAs for anticancer therapies and recent debates regarding their mechanisms of action. Furthermore, the limitations of taxanes, including hypersensitivity reactions, neurotoxicity, drug resistance and lack of validated biomarkers to guide therapy will be discussed, all of which have driven the development of novel agents. The mechanisms of action and drug development of new generations of MTAs will also be outlined. Agents demonstrating utility in Phase III clinical trials, including eribulin, ixabepilone, cabazitaxel and trastuzumab-DM1 will be highlighted, as well as novel agents currently in development and future directions for MTAs. 23454306 Toxic and genotoxic effects of Roundup on tadpoles of the Indian skittering frog (Euflictis cyanophlyctis) in the presence and absence of predator stress. Glyphosate, a post emergent herbicide, has become the backbone of no-till agriculture and is considered safe for animals. However, the impact of glyphosate on non-target organisms, especially on amphibians, is the subject of major concern and debate in recent times. We examined the toxic and genotoxic effects of Roundup, a commercial formulation of glyphosate, in the tadpoles of the Indian skittering frog (Euflictis cyanophlyctis). Roundup at different concentrations (0, 1, 2, 3, 4 and 8mg acid equivalent (ae)/L), tested in a 2×6 factorial design in the presence and absence of predator stress, induced concentration-dependent lethality in tadpoles. The 96-h LC50 for Roundup in the absence and presence of predator stress were 3.76mgae/L and 3.39mgae/L, respectively. The 10-day LC50 value for Roundup was significantly lower, 2.12mgae/L and 1.91mgae/L in the absence and presence of predator stress, respectively. Lower concentrations of Roundup (1, 2 and 3mgae/L) induced the formation of micronuclei (MN) in the erythrocytes of tadpoles at 24-h (F3,56=10.286, p<0.001), 48-h (F3,56=48.255, p<0.001), 72-h (F3,56=118.933, p<0.001) and 96-h (F3,56=85.414, p<0.001) in a concentration-dependent manner. Presence of predator stress apparently increased the toxicity and genotoxicity of Roundup; but these effects were not statistically significant. These findings suggest that Roundup at environmentally relevant concentrations has lethal and genotoxic impact on E. cyanophlyctis; which may have long-term fitness consequence to the species. 23415704 Evidence-based review and assessment of botulinum neurotoxin for the treatment of urologic conditions. Botulinum neurotoxin (BoNT) can be injected to achieve therapeutic benefit across a large range of clinical conditions. To assess the efficacy and safety of BoNT injections for the treatment of certain urologic conditions, including detrusor sphincter dyssynergia (DSD), lower urinary tract symptoms due to benign prostatic hyperplasia (BPH), and detrusor overactivity (both neurogenic [NDO] and idiopathic [IDO]), an expert panel reviewed evidence from the published literature. Data sources included English-language studies identified via MEDLINE, EMBASE, CINAHL, Current Contents, and the Cochrane Central Register of Controlled Trials. Evidence tables generated in the 2008 Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN) review of the use of BoNT for autonomic disorders were also reviewed and updated. The panel evaluated evidence at several levels, supporting BoNT as a class, for the serotypes BoNT-A and BoNT-B, as well as for the four individual commercially available formulations: abobotulinumtoxinA (A/Abo), onabotulinumtoxinA (A/Ona), incobotulinumtoxinA (A/Inco), and rimabotulinumtoxinB (B/Rima). The panel ultimately made recommendations on the use of BoNT for the management of these urologic conditions based upon the strength of clinical evidence and following the AAN classification scale. For the treatment of DSD, the evidence supported a Level B recommendation for the use of A/Ona; A/Abo, A/Inco, and B/Rima received a Level U recommendation. For the treatment of NDO, there was sufficient clinical evidence to support a Level A recommendation for BoNT-A as well as for both A/Ona and A/Abo; no published data were identified for either A/Inco or B/Rima (Level U). For the treatment of IDO, the evidence supported a Level A recommendation for A/Ona; A/Inco, A/Abo, and B/Rima received a Level U recommendation. For the management of BPH, the evidence supported a Level B recommendation for BoNT and A/Ona; no published studies were identified for A/Abo, A/Inco, or B/Rima, warranting a Level U recommendation for these three formulations. Further studies are needed to evaluate the efficacy and safety of BoNT for the management of urologic conditions. 23205740 Interactions of sarin with polyelectrolyte membranes: a molecular dynamics simulation study. Nanostructured polyelectrolyte membranes (PEMs), which are widely used as permselective diffusion barriers in fuel cell technologies and electrochemical processing, are considered as protective membranes suitable for blocking warfare toxins, including water-soluble nerve agents such as sarin. In this article, we examine the mechanisms of sorption and diffusion of sarin in hydrated PEMs by means of atomistic molecular dynamics simulations. Three PEMs are considered: Nafion, sulfonated polystyrene (sPS) that forms the hydrophilic subphase of segregated sPS-polyolefin block copolymers, and random sPS-polyethylene copolymer. We found that sarin concentrates at the interface between the hydrophilic and hydrophobic subphases of hydrated Nafion acting as a surfactant. In hydrated sPS, where the scale of water-polymer segregation is much smaller (1-2 nm), sarin also interacts favorably with hydrophobic and hydrophilic components. Water diffusion slows as the sarin content increases despite the overall increase in solvent content, which suggests that sarin and water have somewhat different pathways through the segregated membrane. Upon replacement of counterions of monovalent potassium with those of divalent calcium, sarin diffusion slows but remains substantial in all ionomers considered, especially at high sarin concentrations. The behavior of sarin is similar to that of its common simulant, dimethyl methylphosphonate. 23159668 Effects of molecular weight on permeability and microstructure of mixed ethyl-hydroxypropyl-cellulose films. Films of ethyl cellulose (EC) and water-soluble hydroxypropyl cellulose (HPC) can be used for extended release coatings in oral formulations. The permeability and microstructure of free EC/HPC films with 30% w/w HPC were studied to investigate effects of EC molecular weight. Phase separation during film spraying and subsequent HPC leaching after immersion in aqueous media cause pore formation in such films. It was found that sprayed films were porous throughout the bulk of the films after water immersion. The molecular weight affected HPC leaching, pore morphology and film permeability; increasing the molecular weight resulted in decreasing permeability. A model to distinguish the major factors contributing to diffusion retardation in porous films showed that the trend in permeability was determined predominantly by factors associated with the geometry and arrangement of pores, independent of the diffusing species. The film with the highest molecular weight did, however, show an additional contribution from pore wall/permeant interactions. In addition, rapid drying and increasing molecular weight resulted in smaller pores, which suggest that phase separation kinetics affects the final microstructure of EC/HPC films. Thus, the molecular weight influences the microstructural features of pores, which are crucial for mass transport in EC/HPC films. 23588096 Antimicrobial interactions of Khoi-San poly-herbal remedies with emphasis on the combination; Agathosma crenulata, Dodonaea viscosa and Eucalyptus globulus. ETHNOPHARMACOLOGICAL RELEVANCE: Plants are often combined in traditional herbal remedies to increase medicinal efficacy, thus this investigation provides some insight into the antimicrobial efficacies of selected combinations. AIMS OF THE STUDY: The first aim was to scientifically validate antibacterial efficacy of plant mixtures that are traded within peri-urban centres of Cape Town (Western Cape, South Africa). This was followed by an in-depth evaluation of the most antimicrobially active mixture; Agathosma crenulata, Dodonaea viscosa with Eucalyptus globulus. MATERIALS AND METHODS: Methanol and aqueous extracts of six plant mixtures were screened for antibacterial properties against two Gram-negative and two Gram-positive bacteria using the minimum inhibitory microdilution method. Thereafter, chloroform: methanol (1:1; v/v) extracts, essential oils and aqueous extracts of Agathosma crenulata, Dodonaea viscosa and Eucalyptus globulus were assayed for antimicrobial activity independently and in various combinations. The fractional inhibitory concentration indices (ƩFIC) were determined for double and triple plant combinations to establish antimicrobial interactions. RESULTS: From the six plant mixtures prepared by herbalists, a methanol extract derived from combining Agathosma crenulata, Dodonaea viscosa and Eucalyptus globulus showed the best antibacterial activity. The MIC values of 49μg/ml for Staphylococcus aureus and Bacillus subtilis, and 98μg/ml for Klebsiella pneumoniae and Escherichia coli were recorded. When Agathosma crenulata, Dodonaea viscosa and Eucalyptus globulus were mixed in various 1:1 combinations, mostly additive and synergistic interactions were noted. The most noteworthy synergistic (ΣFIC value 0.07) 1:1 combinations were observed for the chloroform: methanol extracts of Agathosma crenulata mixed with Eucalyptus globulus against Klebsiella pneumoniae, Staphylococcus aureus and Bacillus subtilis. When combined in a mixture of three plants (1:1:1), enhanced efficacy was evident against most of the pathogens, for both organic and aqueous extracts. The triple combination against Bacillus subtilis demonstrated the greatest synergy (ΣFIC values of 0.03). CONCLUSIONS: The enhanced antimicrobial efficacy and synergistic interactions noted for some of the mixtures, particularly the combination of Agathosma crenulata, Dodonaea viscosa and Eucalyptus globulus support the Western Cape Khoi-San traditional medicinal practices of combining plants for enhanced efficacy. 23318833 Effect of enzymatically modified isoquercitrin on preneoplastic liver cell lesions induced by thioacetamide promotion in a two-stage hepatocarcinogenesis model using rats. To investigate the protective effect of enzymatically modified isoquercitrin (EMIQ) on the hepatocarcinogenic process, we used a two-stage hepatocarcinogenesis model in N-diethylnitrosamine-initiated and thioacetamide (TAA)-promoted rats. We examined the modifying effect of co-administration with EMIQ on the liver tissue environment including hepatic macrophages and lymphocytes and on the induction mechanism of preneoplastic cell apoptosis during early stages of hepatocellular tumor promotion. TAA increased the number and area of glutathione S-transferase placental form (GST-P)(+) liver cell foci and the numbers of proliferating and apoptotic cells in randomly selected areas in liver sections. Co-administration with EMIQ suppressed these effects. TAA also increased the numbers of ED2(+), cyclooxygenase-2(+), and heme oxygenase-1(+) liver cells, as well as the number of CD3(+) lymphocytes. These effects were also suppressed by EMIQ. EMIQ increased liver levels of thiobarbituric acid-reactive substance and 8-hydroxydeoxyguanosine, and TUNEL(+) apoptotic cells, death receptor 5 (DR5)(+) cells and 4-hydroxy-2-nonenal(+) cells within GST-P(+) foci. Outside the GST-P(+) foci, EMIQ decreased the numbers of apoptotic cells and DR5(+) cells. These results suggest that TAA-induced tumor promotion involves activation of hepatic macrophages producing proinflammatory factors. EMIQ may suppress the TAA-induced tumor-promoting activity by an anti-inflammatory mechanism mediated by suppressing the activation of these macrophages. Furthermore, EMIQ may suppress tumor-promoting activity differentially between the inside and outside of GST-P(+) foci. Within GST-P(+) foci, EMIQ facilitates the apoptosis of preneoplastic cells through the upregulation of DR5. Outside the GST-P(+) foci, EMIQ suppresses apoptosis and the subsequent regeneration of non-transformed liver cells. 23268106 Antioxidant properties of Neu2000 on mitochondrial free radicals and oxidative damage. Neu2000 [2-hydroxy-5-(2,3,5,6-tetrafluoro-4 trifluoromethylbenzylamino) benzoic acid] is a dual-acting neuroprotective agent that functions both as a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist and a free radical scavenger. In the present study, we investigated the scavenging activity of Neu2000 on various classes of reactive oxygen species and reactive nitrogen species (ROS/RNS) as well as its efficacy for reducing free radicals and oxidative stress/damage induced in spinal cord mitochondrial preparations. Neu2000 exerted scavenging activity against superoxide, nitric oxide, and hydroxyl radicals, and efficiently scavenged peroxynitrite. In the mitochondrial studies, Neu2000 markedly inhibited ROS/RNS and hydrogen peroxide levels following antimycin treatment. In addition, Neu2000 effectively scavenged hydroxyl radicals generated by iron(III)-ascorbate, reduced protein carbonyl formation mediated by hydroxyl radicals and peroxynitrite, and prevented glutathione oxidation caused by tert-butyl hydroperoxide in isolated mitochondria. Interestingly, incubation of isolated mitochondria with Neu2000 followed by centrifugation and removal of the supernatant also resulted in a concentration-dependent decrease in lipid peroxidation. This observation suggests that Neu2000 enters mitochondria to target free radicals or indirectly affects mitochondrial function in a manner that promotes antioxidant activity. The results of the present study demonstrate that Neu2000 possesses potent in vitro antioxidant activity due, most likely, to its active phenoxy group. 23561098 Purification and characterisation of sarcoplasmic calcium-binding protein, a novel allergen of red swamp crayfish (Procambarus clarkii). Crayfish sarcoplasmic calcium-binding protein (SCP) was purified. The physicochemical and polymorphic characterisations were also analysed. SCP was purified by column chromatography to reveal a single band with molecular mass of 22kDa and further confirmed by mass spectrometry. The results of physicochemical characterisation showed that SCP was stable in the processes of thermal or acid/alkali treatment, and could be digested by simulate gastrointestinal fluid. Importantly, the comparison of SCP polymorphism using sera from crustacean-allergic patients demonstrated SCP-II had a weaker IgE-binding activity. The isoelectric points of SCP subunits a, b and c were 4.6, 4.7, and 4.8, respectively, as determined by two-dimensional electrophoresis and IgE immunoblotting analysis showed that patients' sera reacted to three subunits of SCP. Finally, it can be concluded that SCP is a stable polymorphic allergen in crayfish, and all of its isotypes and subunits have allergenicity. 22956632 Toxicity profile of small-molecule IAP antagonist GDC-0152 is linked to TNF-α pharmacology. Inhibitor-of-apoptosis (IAP) proteins suppress apoptosis and are overexpressed in a variety of cancers. Small-molecule IAP antagonists are currently being tested in clinical trials as novel cancer therapeutics. GDC-0152 is a small-molecule drug that triggers tumor cell apoptosis by selectively antagonizing IAPs. GDC-0152 induces NF-κB transcriptional activity leading to expression of several chemokines and cytokines, of which tumor necrosis factor alpha (TNF-α) is the most important for single-agent tumor activity. TNF-α is a pleiotropic cytokine that drives a variety of cellular responses, comprising inflammation, proliferation, and cell survival or death depending on the cellular context. As malignant and normal cells produce TNF-α upon IAP antagonism, increased TNF-α could drive both efficacy and toxicity. The toxicity profile of GDC-0152 in dogs and rats was characterized after iv dose administration once every 2 weeks for four doses. Findings in both species consisted of a dose-related, acute, systemic inflammatory response, and hepatic injury. Laboratory findings included elevated plasma cytokines, an inflammatory leukogram, and increased liver transaminases with histopathological findings of inflammatory infiltrates and apoptosis/necrosis in multiple tissues; a toxicology profile consistent with TNF-α-mediated toxicity. Dogs exhibited more severe findings than rats, and humans did not exhibit these findings, at comparable exposures across species. Furthermore, elevations in blood neutrophil count, serum monocyte chemoattractant protein-1, and other markers of inflammation corresponded to GDC-0152 exposure and toxicity and thus may have utility as safety biomarkers. 23449888 ARF represses androgen receptor transactivation in prostate cancer. Androgen receptor (AR) signaling is essential for prostate cancer (PCa) development in humans. The initiation of prostate malignancy and progression to a castration-resistant stage are largely contributed by the modulation of AR activity through its coregulatory proteins. We and others previously reported that p14 alternative reading frame (ARF) expression is positively correlated with the disease progression and severity of PCa. Here, we provide evidence that p14ARF physically interacts with AR and functions as an AR corespressor in both an androgen-dependent and androgen-independent manner. Endogenous ARF (p14ARF in human and p19ARF in mouse) and AR colocalize in both human PCa cells in vitro and PCa tissues of mouse and human in vivo. Overexpression of p14ARF in PCa cells significantly attenuates the activities of androgen response region (ARR2)-probasin and prostate-specific antigen (PSA) promoters. The forced expression of p14ARF in cells resulted in a suppression of PSA and NK transcription factor locus 1 (NKX3.1) expression. Conversely, knockdown of endogenous p14ARF in human PCa cells with short hairpin RNA enhanced AR transactivation activities in a dose-dependent and p53-independent manner. Furthermore, we demonstrated that p14ARF binds to both the N-terminal domain and the ligand-binding domain of AR, and the human double minute 2 (HDM2)-binding motif of p14ARF is required for the interaction of p14ARF and AR proteins. p14ARF perturbs the androgen-induced interaction between the N terminus and C terminus of AR. Most importantly, we observed that the expression of PSA is reversely correlated with p14ARF in human prostate tissues. Taken together, our results reveal a novel function of ARF in modulation of AR transactivation in PCa. 23141426 Chinese medicine formula "Weikang Keli" induces autophagic cell death on human gastric cancer cell line SGC-7901. Weikang Keli (constitutes of Root of Codonopsis pilosula, Rhizoma Atractylodis Macrocephalae, Rhizoma Curcumae Aeruginosae, Rhizoma Pinelliae, Actinidia chinensis Planch, and Rhodiola rosea) is a well known Chinese herbal formula for gastric cancer therapy in clinical treatment. However, the detailed molecular mechanisms involved are still not fully understood. In this study, we found that Weikang Keli could induce patterns of autophagy in SGC-7901 cells, including intracellular vacuole formation, microtubule-associated protein 1 light chain 3 (LC3) conversion. Hoechst 33258 staining and Western blot analysis of apoptosis-related proteins showed that WK induced SGC-7901 cell death was not through apoptosis. In vivo study also revealed that i.g. administration of Weikang Keli once a day for 25 days could significantly reduce tumor volumes by about 50%. Collectively, the current data indicated that Weikang Keli induced gastric cancer cell death by autophagy effects. 23466565 Potent vasorelaxant analogs from chemical modification and biotransformation of isosteviol. Isosteviol (1) has been reported to exhibit moderate vasorelaxant activity. In order to enhance the bioactivity of this compound, chemical modification of 1 to the dihydro analog, ent-16β-hydroxybeyeran-19-oic acid (2), was undertaken. Compound 2 was then converted to the corresponding acetate derivative, ent-16β-acetoxybeyeran-19-oic acid (3). Biotransformation of compounds 1-3 by the fungus Cunninghamella echinulata NRRL 1386 was investigated and the metabolites 4-9 were obtained. The substrates and their metabolites were subjected to in vitro rat aorta relaxant activity evaluation. The metabolite 4, ent-7α-hydroxy-16-ketobeyeran-19-oic acid, exhibited the most highly potent activity, with EC50 of 3.46 nM, whereas the parent compound 1 showed relatively low activity (EC50 57.41 nM). A 17-fold increase in vasorelaxant activity of the analog 4 relative to compound 1 is of particular significant. Compound 4 exerted vasorelaxant activity at particularly low concentration and the vasorelaxant profile reached maximum at relatively low concentration, especially when compared with acetylcholine, the positive control. 23363377 Genistein, a natural product derived from soybeans, ameliorates polyglutamine-mediated motor neuron disease. Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ) tract within the androgen receptor (AR) gene. The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem, and diffuse nuclear accumulation and nuclear inclusions of mutant AR in residual motor neurons and certain visceral organs. AR-associated coregulator 70 (ARA70) was the first coregulator of AR to be identified, and it has been shown to interact with AR and increase its protein stability. Here, we report that genistein, an isoflavone found in soy, disrupts the interaction between AR and ARA70 and promotes the degradation of mutant AR in neuronal cells and transgenic mouse models of SBMA. We also demonstrate that dietary genistein ameliorates behavioral abnormalities, improves spinal cord and muscle pathology, and decreases the amounts of monomeric AR and high-molecular-weight mutant AR protein aggregates in SBMA transgenic mice. Thus, genistein treatment may be a potential therapeutic approach for alleviating the symptoms of SBMA by disrupting the interactions between AR and ARA70. 23517313 Outcome of patients with differentiated thyroid cancer risk stratified according to the American Thyroid Association and Latin American Thyroid Society risk of recurrence classification systems. Objective: To validate the proposed Latin-American Thyroid Society (LATS) risk of recurrence stratification system and to compare the findings with those of the American Thyroid Association (ATA) risk of recurrence stratification system. Subjects and Methods: Retrospective review of papillary thyroid cancer patients treated with total thyroidectomy and RAI at a single experienced thyroid cancer center and followed according to the LATS management guidelines. Each patient was risk stratified using both the LATS and ATA staging systems. The primary endpoints were (1) the best response to initial therapy defined as either remission (stimulated Tg < 1 ng/mL, negative US), or persistent disease (biochemical and/or structural) and (2) clinical status at final follow-up defined as either no evidence of disease (suppressed Tg <1 ng/mL, negative US), biochemical persistent disease (suppressed Tg > 1 ng/mL in the absence of structural disease), structural persistent disease (loco-regional or distant metastases) or recurrence (biochemical or structural disease identified after a period of no evidence of disease, NED). Results: One hundred and seventy one papillary thyroid cancer patients were included (mean age 45±16 yrs, followed for a median of 4 yrs after initial treatment). Both the ATA and LATS risk stratification systems provided clinically meaningful graded estimates with regard to the (1) likelihood of achieving remission in response to initial therapy, (2) the likelihood of having persistent structural disease in response to initial therapy and at final follow-up, (3) the likely locations of the persistent structural disease (loco-regional vs. distant metastases), (4) the likelihood of recurrence and (5) the likelihood of being NED at final follow-up. The likelihood of having persistent biochemical evidence of disease was not significantly different across the staging categories. Conclusions: Both the ATA and LATS risk of recurrence systems effectively risk stratify patients with regard to multiple important clinical outcomes. When used in conjunction with a staging system that predicts disease specific mortality, either of these systems can be used to guide risk adapted individualized initial management recommendations. 23086141 Stress-dependent and gender-specific neuroregulatory roles of the apelin receptor in the hypothalamic-pituitary-adrenal axis response to acute stress. The neuropeptide apelin is expressed in hypothalamic paraventricular and supraoptic nuclei and mediates its effects via activation of the apelin receptor (APJ). Evidence suggests a role for apelin and APJ in mediating the neuroendocrine response to stress. To understand the physiological role of APJ in regulation of the hypothalamic-pituitary-adrenal (HPA) axis, we measured ACTH and corticosterone (CORT) plasma levels in male and female mice lacking APJ (APJ knockout, APJ KO) and in wild-type controls, in response to a variety of acute stressors. Exposure to mild restraint, systemic injection of lipopolysaccharide (LPS), insulin-induced hypoglycaemia and forced swim (FS) stressors, elevated plasma ACTH and CORT levels in wild-type mice. Acute mild restraint significantly increased plasma ACTH and CORT to a similar level in APJ KO mice as in wild-type mice. However, an intact APJ was required for a conventional ACTH, but not CORT, response to LPS administration in male mice and to insulin-induced hypoglycaemia in male and female mice. In contrast, APJ KO mice displayed an impaired CORT response to acute FS stress, regardless of gender. These data indicate that APJ has a role in regulation of the HPA axis response to some acute stressors and has a gender-specific function in peripheral immune activation of the HPA axis. 23401280 In vivo Antimalarial Activity of a Labdane Diterpenoid from the Leaves of Otostegia integrifolia Benth. In Ethiopian traditional medicine, the leaves of Otostegia integrifolia Benth. are used for the treatment of several diseases including malaria. In an ongoing search for effective, safe and cheap antimalarial agents from plants, the 80% methanol leaf extract O. integrifolia was tested for its in vivo antimalarial activity, in a 4-day suppressive assay against Plasmodium berghei. Activity-guided fractionation of this extract which showed potent antiplasmodial activity resulted in the isolation of a labdane diterpenoid identified as otostegindiol. Otostegindiol displayed a significant (P < 0.001) antimalarial activity at doses of 25, 50 and 100 mg/kg with chemosuppression values of 50.13, 65.58 and 73.16%, respectively. Acute toxicity studies revealed that the crude extract possesses no toxicity in mice up to a maximum dose of 5000 mg/kg suggesting the relative safety of the plant when administered orally. The results of the present study indicate that otostegindiol is among the antimalarial principles in this medicinal plant, and further support claims for the traditional medicinal use of the plant for the treatment of malaria. Copyright © 2013 John Wiley & Sons, Ltd. 23418125 A Biochemical and Cellular Approach to Explore the Antiproliferative and Prodifferentiative Activity of Aloe Arborescens Leaf Extract. Aloe arborescens Miller, belonging to the Aloe genus (Liliaceae family), is one of the main varieties of Aloe used worldwide. Although less characterized than the commonest Aloe vera, Aloe arborescens is known to be richer in beneficial phytotherapeutic, anticancer, and radio-protective properties. It is commonly used as a pharmaceutical ingredient for its effect in burn treatment and ability to increase skin wound healing properties. However, very few studies have addressed the biological effects of Aloe at molecular level. The aim of the research is to provide evidences for the antiproliferative properties of Aloe arborescens crude leaf extract using an integrated proteomic and cellular biological approach. We analysed the composition of an Aloe arborescens leaf extract by gas chromatography-mass spectrometry analysis. We found it rich in Aloe-emodin, a hydroxylanthraquinone with known antitumoral activity and in several compounds with anti-oxidant properties. Accordingly, we show that the Aloe extract has antiproliferative effects on several human transformed cell lines and exhibits prodifferentiative effects on both primary and immortalized human keratinocyte. Proteomic analysis of whole cell extracts revealed the presence of proteins with a strong antiproliferative and antimicrobial activity specifically induced in human keratinocytes by Aloe treatment supporting its application as a therapeutical agent. Copyright © 2013 John Wiley & Sons, Ltd. 23265191 Mammalian frataxin controls sulfur production and iron entry during de novo Fe4S4 cluster assembly. Iron-sulfur (Fe-S) cluster-containing proteins are essential components of cells. In eukaryotes, Fe-S clusters are synthesized by the mitochondrial iron-sulfur cluster (ISC) machinery and the cytosolic iron-sulfur assembly (CIA) system. In the mammalian ISC machinery, preassembly of the Fe-S cluster on the scaffold protein (ISCU) involves a cysteine desulfurase complex (NFS1/ISD11) and frataxin (FXN), the protein deficient in Friedreich's ataxia. Here, by comparing the biochemical and spectroscopic properties of quaternary (ISCU/NFS1/ISD11/FXN) and ternary (ISCU/NFS1/ISD11) complexes, we show that FXN stabilizes the quaternary complex and controls iron entry to the complex through activation of cysteine desulfurization. Furthermore, we show for the first time that in the presence of iron and L-cysteine, an [Fe(4)S(4)] cluster is formed within the quaternary complex that can be transferred to mammalian aconitase (mACO2) to generate an active enzyme. In the absence of FXN, although the ternary complex can assemble an Fe-S cluster, the cluster is inefficiently transferred to ACO2. Taken together, these data help to unravel further the Fe-S cluster assembly process and the molecular basis of Friedreich's ataxia. 22410778 Oncogenic K-ras expression is associated with derangement of the cAMP/PKA pathway and forskolin-reversible alterations of mitochondrial dynamics and respiration. The Warburg effect in cancer cells has been proposed to involve several mechanisms, including adaptation to hypoxia, oncogenes activation or loss of oncosuppressors and impaired mitochondrial function. In previous papers, it has been shown that K-ras transformed mouse cells are much more sensitive as compared with normal cells to glucose withdrawal (undergoing apoptosis) and present a high glycolytic rate and a strong reduction of mitochondrial complex I. Recent observations suggest that transformed cells have a derangement in the cyclic adenosine monophosphate/cAMP-dependent protein kinase (cAMP/PKA) pathway, which is known to regulate several mitochondrial functions. Herein, the derangement of the cAMP/PKA pathway and its impact on transformation-linked changes of mitochondrial functions is investigated. Exogenous stimulation of PKA activity, achieved by forskolin treatment, protected K-ras-transformed cells from apoptosis induced by glucose deprivation, enhanced complex I activity, intracellular adenosine triphosphate (ATP) levels, mitochondrial fusion and decreased intracellular reactive oxygen species (ROS) levels. Several of these effects were almost completely prevented by inhibiting the PKA activity. Short-time treatment with compounds favoring mitochondrial fusion strongly decreased the cellular ROS levels especially in transformed cells. These findings support the notion that glucose shortage-induced apoptosis, specific of K-ras-transformed cells, is associated to a derangement of PKA signaling that leads to mitochondrial complex I decrease, reduction of ATP formation, prevalence of mitochondrial fission over fusion, and thereby opening new approaches for development of anticancer drugs. 23432217 Challenges in exploring the cytochrome P450 system as a source of variation in canine drug pharmacokinetics. Abstract The cytochrome P450 (CYP) superfamily constitutes a collection of enzymes responsible for the metabolism of a wide array of endo- and xenobiotic compounds. Much of the knowledge on substrate specificity and genetic identification of the various CYP isoforms is derived from research in rodents and humans and only limited information has been captured in the dog. Currently, there exist many gaps in our knowledge of canine CYP diversity as a result of the paucity of studies focusing on canine CYPs, canine CYP polymorphisms, and the therapeutic consequences of these genetic variants. Challenges engendered by this lack of information is further amplified by inter- and intraspecies differences in the specificity and affinity of substrates and inhibitors, prohibiting a simple extrapolation of probe substances used in human CYP research. This creates a need to develop and validate canine-specific CYP probes. Failure to understand this potential metabolic and pharmacogenomic diversity can also influence the interpretation of data generated in dogs to support human drug development. It is with these objectives in mind that we provide an overview of what is currently known about canine CYPs with the hope that it will encourage further exploration into this important area of research. 23638683 Charge transfer and Penning ionization of dopants in or on helium nanodroplets exposed to EUV radiation. Helium nanodroplets are widely used as a cold, weakly interacting matrix for spectroscopy of embedded species. In this work we excite or ionize doped He droplets using synchrotron radiation and study the effect onto the dopant atoms depending on their location inside the droplets (rare gases) or outside at the droplet surface (alkali metals). Using photoelectron-photoion coincidence imaging spectroscopy at variable photon energies (20-25eV), we compare the rates of charge-transfer to Penning ionization of the dopants in the two cases. The surprising finding is that alkali metals, in contrast to the rare gases, are efficiently Penning ionized upon excitation of the (n=2)-bands of the host droplets. This indicates rapid migration of the excitation to the droplet surface, followed by relaxation, and eventually energy transfer to the alkali dopants. 23215347 Improved analysis for determining diffusion coefficients from short, single-molecule trajectories with photoblinking. Two maximum likelihood estimation (MLE) methods were developed for optimizing the analysis of single-molecule trajectories that include phenomena such as experimental noise, photoblinking, photobleaching, and translation or rotation out of the collection plane. In particular, short, single-molecule trajectories with photoblinking were studied, and our method was compared to existing analytical techniques applied to simulated data. The optimal method for various experimental cases was established, and the optimized MLE method was applied to a real experimental system: single-molecule diffusion of fluorescent molecular machines known as nanocars. 23468100 Family history of alcoholism interacts with alcohol to affect brain regions involved in behavioral inhibition. RATIONALE: Impulsive behavior is associated with both alcohol use disorders and a family history of alcoholism (FHA). One operational definition of impulsive behavior is the stop-signal task (SST) which measures the time needed to stop a ballistic hand movement. OBJECTIVE: Employ functional magnetic resonance imaging (fMRI) to study right frontal responses to stop signals in heavy drinking subjects with and without FHA, and as a function of alcohol exposure. METHODS: Twenty-two family history-positive (FHP; age = 22.7 years, SD = 1.9) and 18 family history-negative (FHN; age = 23.7, SD = 1.8) subjects performed the SST in fMRI in two randomized visits: once during intravenous infusion of alcohol, clamped at a steady-state breath alcohol (BrAC) concentration of 60 mg/dL, and once during infusion of placebo saline. An independent reference group (n = 13, age = 23.7, SD = 1.8) was used to identify a priori right prefrontal regions activated by successful inhibition (Inh) trials, relative to "Go" trials that carried no need for inhibition [Inh > Go]. RESULTS: FHA interacted with alcohol exposure in right prefrontal cortex, where alcohol reduced [Inh > Go] activation in FHN subjects but not in FHP subjects. Within this right frontal cortical region, stop-signal reaction time also correlated negatively with [Inh > Go] activation, suggesting that the [Inh > Go] activity was related to inhibitory behavior. CONCLUSIONS: The results are consistent with the low level of response theory (Schuckit, J Stud Alcohol 55:149-158, 1980; Quinn and Fromme, Alcohol Clin Exp Res 35:1759-1770, 2011), with FHP being less sensitive to alcohol's effects. 23619286 How do polymeric micelles cross epithelial barriers? Non-parenteral delivery of drugs using nanotechnology-based delivery systems is a promising non-invasive way to achieve effective local or systemic drug delivery. The efficacy of drugs administered non-parenterally is limited by their ability to cross biological barriers, and epithelial tissues particularly present challenges. Polymeric micelles can achieve transepithelial drug delivery because of their ability to be internalized into cells and/or cross epithelial barriers, thereby delivering drugs either locally or systematically following non-parenteral administration. This review discusses the particular characteristics of various epithelial barriers and assesses their potential as non-parenteral routes of delivery. The material characteristics of polymeric micelles (e.g., size, surface charge, and surface decoration) and of unimers dissociated from polymeric micelles determine their interactions (non-specific and/or specific) with mucus and epithelial cells as well as their intracellular fate. This paper outlines the mechanisms governing the major modes of internalization of polymeric micelles into epithelial cells, with an emphasis on specific recent examples of the transport of drug-loaded polymeric micelles across epithelial barriers. 23194541 Total polyphenols, catechin profiles and antioxidant activity of tea products from purple leaf coloured tea cultivars. Black (aerated) and green (unaerated) tea products, processed from 10 green and 18 purple leaf coloured cultivars of Kenyan origin, and two tea products, from the Japanese cultivars, Yabukita and Yutakamidori, were assayed for total polyphenols (TP) content, individual catechin profiles and in vitro antioxidant capacity (AA). In addition, the phenolic content of the tea products was determined using the Folin-Ciocalteu phenol reagent. Catechin fractions were identified using reverse phase high performance liquid chromatography (HPLC) with a binary gradient elution system. The AA% of the tea products was determined using a 2,2'-diphenyl picrylhydrazyl (DPPH) radical assay method. The results showed that TPs, catechin profiles and antioxidant activities were significantly (p≤0.05) higher in unaerated than in aerated teas. Tea products from the purple leaf coloured tea cultivars had levels of TPs, total catechin (TC) and antioxidant activities similar to those from the green leaf coloured cultivars, except for teas from the Japanese cultivars that were very low in the assayed parameters. Caffeine content was significantly (p≤0.05) lower in products from the purple leaf coloured cultivars than in those from the green leaf coloured tea cultivars. Antioxidant activity (%) was higher in tea products from the Kenyan germplasm than in those from the Japanese cultivars. Antioxidant potency of tea products was significantly (r=0.789(∗∗), p≤0.01) influenced by the total anthocyanin content of the purple leaf coloured cultivars. Cyanidin-3-O-glucoside was the anthocyanin most highly correlated with AA% (r=0.843(∗∗), p≤0.01 in unaerated tea). Total catechins in the unaerated products from the green leaf coloured tea cultivars were also significantly correlated with antioxidant capacity (r=0.818(∗∗), p≤0.01). Results from this study suggest that the antioxidant potency of teas is dependent on the predominant flavonoid compound, the type of tea cultivar and the processing method. 23391444 Improved intratumoral nanoparticle extravasation and penetration by mild hyperthermia. Accumulation of nanoparticles in solid tumors depends on their extravasation. However, vascular permeability is very heterogeneous within a tumor and among different tumor types, hampering efficient delivery. Local hyperthermia at a tumor can improve nanoparticle delivery by increasing tumor vasculature permeability, perfusion and interstitial fluid flow. The aim of this study is to investigate hyperthermia conditions required to improve tumor vasculature permeability, subsequent liposome extravasation and interstitial penetration in 4 tumor models. Tumors are implanted in dorsal skin flap window chambers and observed for liposome (~85 nm) accumulation by intravital confocal microscopy. Local hyperthermia at 41°C for 30 min initiates liposome extravasation through permeable tumor vasculature in all 4 tumor models. A further increase in nanoparticle extravasation occurs while continuing heating to 1h, which is a clinically relevant duration. After hyperthermia, the tumor vasculature remains permeable for 8h. We visualize gaps in the endothelial lining of up to 10 μm induced by HT. Liposomes extravasate through these gaps and penetrate into the interstitial space to at least 27.5 μm in radius from the vessel walls. Whole body optical imaging confirms HT induced extravasation while liposome extravasation was absent at normothermia. In conclusion, a thermal dose of 41°C for 1h is effective to induce long-lasting permeable tumor vasculature for liposome extravasation and interstitial penetration. These findings hold promise for improved intratumoral drug delivery upon application of local mild hyperthermia prior to administration of nanoparticle-based drug delivery systems. 23017407 Green and gold kiwifruit peel ethanol extracts potentiate pentobarbital-induced sleep in mice via a GABAergic mechanism. Kiwifruit is one of the most popular fruits worldwide, and it has various biological properties, including antioxidant, anti-allergic, and cardiovascular protective effects. The peel of kiwifruit, which is a by-product of processing, is a good source of flavonoids; however, its bioactivity has not been widely investigated. In this study, we evaluated the hypnotic effects of green (GRPE, Actinidia deliciosa) and gold (GOPE, Actinidia chinensis) kiwifruit peel ethanol extracts and their solvent fractions, and the possible underlying mechanisms. Oral GRPE and GOPE administration (125-1000mg/kg) produced a dose-dependent decrease in sleep latency and an increase in sleep duration in pentobarbital-treated mice. Among three different solvent fractions of GRPE and GOPE, ethyl acetate (EA) fractions had the greatest effect on sleep duration at 250mg/kg. The total flavonoid contents of solvent fractions were proportional to sleep duration. Like diazepam (a GABA(A)-benzodiazepine (BZD) receptor agonist), the hypnotic effects of GRPE, GOPE, and their EA fractions were fully inhibited by flumazenil (a GABA(A)-BZD receptor antagonist). These results suggest that potentiation effects of GRPE and GOPE on pentobarbital-induced sleep in mice may be modulated by a GABAergic mechanism. 23447531 Signaling between Transforming Growth Factor β (TGF-β) and Transcription Factor SNAI2 Represses Expression of MicroRNA miR-203 to Promote Epithelial-Mesenchymal Transition and Tumor Metastasis. TGF-β promotes tumor invasion and metastasis by inducing an epithelial-mesenchymal transition (EMT). Understanding the molecular and epigenetic mechanisms by which TGF-β induces EMT may facilitate the development of new therapeutic strategies for metastasis. Here, we report that TGF-β induced SNAI2 to promote EMT by repressing miR-203. Although miR-203 targeted SNAI2, SNAI2 induced by TGF-β could directly bind to the miR-203 promoter to inhibit its transcription. SNAI2 and miR-203 formed a double negative feedback loop to inhibit each other's expression, thereby controlling EMT. Moreover, we found that miR-203 was significantly down-regulated in highly metastatic breast cancer cells. The restoration of miR-203 in highly metastatic breast cancer cells inhibited tumor cell invasion in vitro and lung metastatic colonization in vivo by repressing SNAI2. Taken together, our results suggest that the SNAI2 and miR-203 regulatory loop plays important roles in EMT and tumor metastasis. 23250802 Associations between diabetes, leanness, and the risk of death in the Japanese general population: the jichi medical school cohort study. OBJECTIVE To examine the BMI-stratified associations between diabetes and the risks of all-cause death, cardiovascular disease (CVD) death, and cancer death. RESEARCH DESIGN AND METHODS Using a prospective study with 12 rural Japanese general populations (n = 3,641, mean age, 53.7 years; 33.5% men), we examined the associations between diabetes and the risk of all-cause death, CVD death, and cancer death. We also examined the effects of BMI and age on such associations. RESULTS During an average duration of 10.2 years (37,278 person-years), 240 deaths occurred (54 deaths from CVD, 101 from cancer, and 85 from other causes). Cox regression analysis showed leanness (defined as the lowest quartile of entire BMI; mean, 19.5 kg/m(2)), but not obesity (BMI ≥25 kg/m(2)), and diabetes were independently associated with an increased risk of all-cause death (hazard ratio [HR] 1.70 and 1.65, respectively; both P < 0.01.). Stratification with cause-specific deaths showed that leanness and obesity were associated with CVD death (HR 3.77 and 2.94, respectively), whereas diabetes was associated with cancer death (HR 1.87; all P < 0.05). The increased risk of all-cause death in diabetes was substantially higher in lean subjects aged <65 years (HR 3.4) or those aged ≥65 years (HR 4.2), whereas the risk in obese diabetes patients was significant only in subjects aged <65 years (HR 2.32; all P < 0.05). CONCLUSIONS Among the Japanese general population, diabetes confers an increased risk of all-cause death. Particular attention must be paid to the pronounced high mortality in diabetes accompanied with leanness, regardless of age. 23204306 iReckon: simultaneous isoform discovery and abundance estimation from RNA-seq data. High-throughput RNA sequencing (RNA-seq) promises to revolutionize our understanding of genes and their role in human disease by characterizing the RNA content of tissues and cells. The realization of this promise, however, is conditional on the development of effective computational methods for the identification and quantification of transcripts from incomplete and noisy data. In this article, we introduce iReckon, a method for simultaneous determination of the isoforms and estimation of their abundances. Our probabilistic approach incorporates multiple biological and technical phenomena, including novel isoforms, intron retention, unspliced pre-mRNA, PCR amplification biases, and multimapped reads. iReckon utilizes regularized expectation-maximization to accurately estimate the abundances of known and novel isoforms. Our results on simulated and real data demonstrate a superior ability to discover novel isoforms with a significantly reduced number of false-positive predictions, and our abundance accuracy prediction outmatches that of other state-of-the-art tools. Furthermore, we have applied iReckon to two cancer transcriptome data sets, a triple-negative breast cancer patient sample and the MCF7 breast cancer cell line, and show that iReckon is able to reconstruct the complex splicing changes that were not previously identified. QT-PCR validations of the isoforms detected in the MCF7 cell line confirmed all of iReckon's predictions and also showed strong agreement (r(2) = 0.94) with the predicted abundances. 23505396 Resilin-Like Polypeptide Hydrogels Engineered for Versatile Biological Functions. Natural resilin, the rubber-like protein that exists in specialized compartments of most arthropods, possesses excellent mechanical properties such as low stiffness, high resilience and effective energy storage. Recombinantly-engineered resilin-like polypeptides (RLPs) that possess the favorable attributes of native resilin would be attractive candidates for the modular design of biomaterials for engineering mechanically active tissues. Based on our previous success in creating a novel RLP-based hydrogel and demonstrating useful mechanical and cell-adhesive properties, we have produced a suite of new RLP-based constructs, each equipped with 12 repeats of the putative resilin consensus sequence and a single, distinct biologically active domain. This approach allows independent control over the concentrations of cell-binding, MMP-sensitive, and polysaccharide-sequestration domains in hydrogels comprising mixtures of the various RLPs. The high purity, molecular weight and correct compositions of each new polypeptide have been confirmed via high performance liquid chromatography (HPLC), sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), and amino acid analysis. These RLP-based polypeptides exhibit largely random-coil conformation, both in solution and in the cross-linked hydrogels, as indicated by circular dichroic and infrared spectroscopic analyses. Hydrogels of various compositions, with a range of elastic moduli (1kPa to 25kPa) can be produced from these polypeptides, and the activity of the cell-binding and matrix metalloproteinase (MMP) sensitive domains was confirmed. Tris(hydroxymethyl phosphine) cross-linked RLP hydrogels were able to maintain their mechanical integrity as well as the viability of encapsulated primary human mesenchymal stem cells (MSCs). These results validate the promising properties of these RLP-based elastomeric biomaterials. 23501115 Synthesis and evaluation of 7,8-dehydrorutaecarpine derivatives as potential multifunctional agents for the treatment of Alzheimer's disease. A series of 7,8-dehydrorutaecarpine derivatives were synthesized and characterized as potential multifunctional agents for treatment of Alzheimer's disease (AD). All of these synthetic compounds showed high acetylcholinesterase (AChE) inhibitory activity with IC50 values ranged from 0.60 to 196.7 nM, and good selectivity for AChE over butyrylcholinesterase (BuChE) (125- to 3225-fold). A Lineweaver-Burk plot and molecular modeling study indicated these compounds could bind to both catalytic active site and the peripheral anionic site of AChE. Besides, compounds showed higher activity of inhibiting AChE-induced amyloid-beta (Aβ) aggregation than curcumin, higher anti-oxidative activity than Trolox, and could also be good metal chelators. Considering their low cytotoxicity, our results indicated that these derivatives provide good templates for developing new multifunctional agents for AD treatment. 23361121 Self-assembly of mesoporous CuO nanosheets-CNT 3D-network composites for lithium-ion batteries. A facile, flexible and large-scale technique was proposed to prepare a CuO-CNT 3D-network composite with the aid of electrostatic interactions in aqueous solution. The composite greatly improves the electrochemical performance. At a rate of 0.1 C, the cycling discharge capacity of the optimal composite is more than 2.3 times of that of unmodified mesoporous CuO nanosheets as the active material in an anode after 40 cycles. 23238226 Directional scrolling of SiGe/Si/Cr nanoribbon on Si(111) surfaces controlled by two-fold rotational symmetry underetching. The controllable fabrication of self-scrolling SiGe/Si/Cr helical nanoribbons on Si(111) substrates is investigated. The initial lateral etching profile of the Si(111) substrates shows a 2-fold rotational symmetry using 4% ammonia solution, which provides guidance for initial scrolling of one-end-fixed nanoribbons to form helical structures. The chirality of the SiGe/Si/Cr helices with isotropic Young's moduli is governed by the anisotropic underetching in the initial stage, which can be precisely judged, as the orientation of the ribbon is predesigned. Furthermore, the helicity angle and radius of the formed helices are investigated by the lateral etching behavior and Cosserat curve theory of the Si(111) substrates, respectively, which are consistent with the experimental data. The present work provides the scrolling rule of nanoribbons with an isotropic Young's modulus and anisotropic underetching in the formation of micro-/nanohelices. 23099319 Sex differences in effects of low level domoic acid exposure. Consumption of seafood containing the phytoplankton-derived toxin domoic acid (DOM) causes neurotoxicity in humans and in animals. It has been reported that DOM-induced symptoms may be more severe in men than women, but to date the effect of sex on DOM-induced effects in adults is not known. We investigated sex differences in DOM-induced effects in adult rats. Since low level exposure is of greatest relevance to human health (due to DOM regulatory limit), we examined the effects of low level exposure. Adult male and female Sprague Dawley rats were administered a single intraperitoneal injection of DOM (0, 1.0, 1.8 mg/kg). Behaviour was monitored for 3h and immunohistochemistry in the dorsal hippocampus and olfactory bulb was also examined. DOM increased locomotor and grooming activity, compared to vehicle group. DOM exposure also significantly increased stereotypic behaviours and decreased phosphorylated cAMP response element-binding protein immunoreactivity (pCREB-IR). There was no effect of sex on the magnitude of the behavioural responses, but the onset of DOM-induced locomotor activity and ear scratches was quicker in females than in males. Mixed effect modelling revealed the predicted peak in locomotor activity in response to DOM was also quicker in females than in males. Severe toxicity was evident in 2/7 male rats and 0/8 female rats dosed with 1.8 mg/kg DOM. These data suggest that males exposed to low level DOM may be more susceptible to severe neurotoxicity, whereas females are affected more quickly. Understanding sex differences in DOM-induced neurotoxicity may contribute to future protective strategies and treatments. 23297162 The antinociceptive effect of milnacipran in the monosodium iodoacetate model of osteoarthritis pain and its relation to changes in descending inhibition. Osteoarthritis (OA) is a chronic joint disorder whose principal symptom is chronic pain. Current analgesics are inadequate and the mechanisms contributing to this pain are poorly understood but likely to include both local joint changes and central consequences. These studies used monoamine receptor agents combined with behavioral studies and single-unit dorsal horn recordings to examine whether descending noradrenergic and serotonergic inhibitions are altered in the monosodium iodoacetate model of OA pain, and whether increasing these inhibitions with the serotonin/noradrenaline reuptake inhibitor milnacipran can attenuate the attendant hypersensitivity. Early and late in the course of this model, milnacipran (s.c.) reduced behavioral hypersensitivity, and inhibited evoked responses from sensitized dorsal horn neurons. In naïve animals and the early, but not late, phase of the model, spinal administration of the α(2)-adrenoceptor antagonist atipamezole fully reversed this neuronal inhibition, whereas atipamezole administered alone revealed that endogenous noradrenergic inhibition was reduced in the late phase. Blocking spinal 5-hydroxytryptamine-7 receptors with (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride suggested that the effects of milnacipran in the late phase were partly mediated by these receptors, and that descending serotonergic inhibition was increased in this phase. An opioidergic mechanism behind the effects of milnacipran was indicated by a partial reversal of these effects with naloxone. These studies demonstrate antinociceptive effects for milnacipran in a model of OA pain, whose effects come via descending serotonergic and noradrenergic, as well as opioidergic, pathways. Variations in the activity of these pathways over the course of this model may contribute to the presence of behavioral hypersensitivity and determine through which endogenous systems milnacipran exerts its effects. 23322586 Potential for metal contamination by direct sonication of nanoparticle suspensions. While conducting toxicity tests with nano titanium dioxide, the authors found that test suspensions were being contaminated with aluminum and titanium from tip erosion during direct sonication. The contaminating alloy particles had a measurable size distribution and zeta potential using dynamic light scattering, which changed the measured characteristics of the suspensions. Caution should be used when employing direct sonication for preparing test suspensions due to potential interferences of these particles in toxicological assessments. 23290051 Inhibition of HIV-1 replication by a tricyclic coumarin GUT-70 in acutely and chronically infected cells. The anti-HIV-1 activity of GUT-70, a natural product derived from the stem bark of Chlophyllum brasiliense, was evaluated. GUT-70 inhibited HIV-1 replication in both acutely and chronically infected cells through suppression of NF-κB. Our results strengthen the idea that NF-κB pathway is one of the potential targets to control HIV-1 replication and that GUT-70 could serve as a lead compound to develop novel therapeutic agents against HIV-1 infection. 23275442 The COP9 signalosome interacts with and regulates interferon regulatory factor 5 protein stability. The transcription factor interferon regulatory factor 5 (IRF5) exerts crucial functions in the regulation of host immunity against extracellular pathogens, DNA damage-induced apoptosis, death receptor signaling, and macrophage polarization. Tight regulation of IRF5 is thus warranted for an efficient response toward extracellular stressors and for limiting autoimmune and inflammatory responses. Here we report that the COP9 signalosome (CSN), a general modulator of diverse cellular and developmental processes, associates constitutively with IRF5 and promotes its protein stability. The constitutive CSN/IRF5 interaction was identified using proteomics and confirmed by endogenous immunoprecipitations. The CSN/IRF5 interaction occurred on the carboxyl and amino termini of IRF5; a single internal deletion from amino acids 455 to 466 (Δ455-466) was found to significantly reduce IRF5 protein stability. CSN subunit 3 (CSN3) was identified as a direct interacting partner of IRF5, and knockdown of this subunit with small interfering RNAs resulted in enhanced degradation. Degradation was further augmented by knockdown of CSN1 and CSN3 together. The ubiquitin E1 inhibitor UBEI-41 or the proteasome inhibitor MG132 prevented IRF5 degradation, supporting the idea that its stability is regulated by the ubiquitin-proteasome system. Importantly, activation of IRF5 by the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resulted in enhanced degradation via loss of the CSN/IRF5 interaction. This study defines CSN to be a new interacting partner of IRF5 that controls its stability. 23561085 Free phenolics and polyphenol oxidase (PPO): The factors affecting post-cut browning in eggplant (Solanum melongena). Polyphenol oxidase (PPO) catalyses oxidation of phenolics, which results in instant but differential browning in many cut fruits and vegetables, including eggplant. Eight cultivars of eggplant were characterised by their PPO specific activity, phenolic content, browning index, and PPO polymorphism. In fresh eggplant, browning was found to be dependent on both the phenolic content and PPO specific activity, whereas, total phenolic content played a major role in browning of stored fruits. Interestingly, although browning index increased in stored eggplant fruits, PPO activity reduced in four out of eight cultivars studied. Phenolic level was found to increase in all these cultivars during storage. Although a significant level of homology was observed in PPO nucleotide and conceptually translated protein sequence, two cultivars, which displayed highest PPO specific activity, differed in the 38 amino acid stretch in the peptide region 301-338. 23559258 Using waste Li ion batteries as cathodes in rechargeable Li-liquid batteries. The rechargeable Li-liquid battery was developed using waste Li ion battery materials immersed in water and used as the liquid cathode. Either the Li metal or Li ions (by the formation LixC6 or Li4+xTi5O12) was harvested from waste Li ion source materials such as a waste anode (LixC6), cathode (LixFePO4), and electrolyte (LiPF6 in EC:DEC) by charging the cell, which then discharged with the waste products in the liquid cathode solution to produce electric energy. When the Li4Ti5O12 was used as the anode with the waste products as the cathode in the proposed battery system, a good cycle-life with high coulombic efficiency was observed. 23592780 Structural mechanism of ring opening reaction of glucose by human serum albumin. Glucose reacts with proteins non-enzymatically under physiological conditions. Such glycation is exacerbated in diabetic patients with high level of blood sugar, and induces various complications. Human albumin serum (HSA) is the most abundant protein in plasma and is glycated by glucose. The glycation sites on HSA remain controversial among different studies. Here, we report two protein crystal structures of HSA in complex with either glucose or fructose. These crystal structures reveal that the presence of linear forms of sugar for both monosaccharides. The linear form of glucose forms a covalent bond to Lys195 of HSA, but not the case for fructose. Based on these structures, we propose a mechanism for glucose ring opening involving both residues Lys195 and Lys199. These results provide mechanistic insights to understand the glucose ring opening reaction and the glycation of proteins by monosaccharides. 23393218 Removal of Duodenum Elicits GLP-1 Secretion. OBJECTIVETo evaluate the effect of removal of the duodenum on the complex interplay between incretins, insulin, and glucagon in nondiabetic subjects.RESEARCH DESIGN AND METHODSFor evaluation of hormonal secretion and insulin sensitivity, 10 overweight patients without type 2 diabetes (age 61 ± 19.3 years and BMI 27.9 ± 5.3 kg/m(2)) underwent a mixed-meal test and a hyperinsulinemic-euglycemic clamp before and after pylorus-preserving pancreatoduodenectomy for ampulloma.RESULTSAll patients experienced a reduction in insulin (P = 0.002), C-peptide (P = 0.0002), and gastric inhibitory peptide (GIP) secretion (P = 0.0004), while both fasting and postprandial glucose levels increased (P = 0.0001); GLP-1 and glucagon responses to the mixed meal increased significantly after surgery (P = 0.02 and 0.031). While changes in GIP levels did not correlate with insulin, glucagon, and glucose levels, the increase in GLP-1 secretion was inversely related to the postsurgery decrease in insulin secretion (R(2) = 0.56; P = 0.012) but not to the increased glucagon secretion, which correlated inversely with the reduction of insulin (R(2) = 0.46; P = 0.03) and C-peptide (R(2) = 0.37; P = 0.04). Given that the remaining pancreas presumably has preserved intraislet anatomy, insulin secretory capacity, and α- and β-cell interplay, our data suggest that the increased glucagon secretion is related to decreased systemic insulin.CONCLUSIONSPylorus-preserving pancreatoduodenectomy was associated with a decrease in GIP and a remarkable increase in GLP-1 levels, which was not translated into increased insulin secretion. Rather, the hypoinsulinemia may have caused an increase in glucagon secretion. 23316011 An Anti-angiogenic Reverse Thermal Gel as a Drug-Delivery System for Age-Related Wet Macular Degeneration. Reverse thermal gels have numerous biomedical implications, as they undergo physical gelation upon temperature increases and can incorporate biomolecules to promote tissue repair. Such a material is developed for the sustained release of bevacizumab (Avastin), a drug used to treat age-related macular degeneration. The polymer, poly(ethylene glycol)-poly(serinol hexamethylene urethane) (ESHU), forms a physical gel when heated to 37 °C and shows good cytocompatibility with ocular cells. ESHU is capable of sustaining bevacizumab release over 17 weeks in vitro, and the release kinetics can be altered by changing the drug dose and the ESHU concentration. These results suggest that ESHU is biologically safe, and suitable for ocular drug delivery. 23471562 A new anti-inflammatory triterpene saponin isolated from Anabasis setifera. A bio-guided fractionation of Anabasis setifera Moq. (Chenopodiaceae) for anti-inflammatory activity was carried out using carrageenin rat paw edema model in rats. On the basis of percent edema inhibition after 3 h of carrageenin injection, n-butanol fraction showed promising activity through a significant (p < 0.05) decrease in paw volume by 85.6 % from control using indomethacin as reference standard. Moreover, the n-butanol fraction significantly (p < 0.05) decreased PGE2 and TNF-α in the exudates of rat paw edema. Chemical investigation of n-butanol fraction afforded α-amyrin 3-O-glucopyranoside (1), patuletin 7-O-glucopyranoside (2), myricitrin (3) and a new oleanane triterpene saponin derivative (4), sophradiol 3-O-α-L-(1)C4-rhamnopyranosyl-(1'''→4'')-O-β-D-(4)C1-galactopyranosyl (1''→6')-O-β-D-(4)C1-glucopyranoside. The structure of the new compound was determined by comprehensive analyses of their 1D and 2D NMR, mass spectral data and comparison with previously known analogs. Only compound 4 revealed a significant (p < 0.05) inhibition of cyclooxygenase 1 and 2 (COX) activities. 23179753 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Developmental neurotoxicity (DNT) and many forms of reproductive toxicity (RT) often manifest themselves in functional deficits that are not necessarily based on cell death, but rather on minor changes relating to cell differentiation or communication. The fields of DNT/RT would greatly benefit from in vitro tests that allow the identification of toxicant-induced changes of the cellular proteostasis, or of its underlying transcriptome network. Therefore, the 'human embryonic stem cell (hESC)-derived novel alternative test systems (ESNATS)' European commission research project established RT tests based on defined differentiation protocols of hESC and their progeny. Valproic acid (VPA) and methylmercury (MeHg) were used as positive control compounds to address the following fundamental questions: (1) Does transcriptome analysis allow discrimination of the two compounds? (2) How does analysis of enriched transcription factor binding sites (TFBS) and of individual probe sets (PS) distinguish between test systems? (3) Can batch effects be controlled? (4) How many DNA microarrays are needed? (5) Is the highest non-cytotoxic concentration optimal and relevant for the study of transcriptome changes? VPA triggered vast transcriptional changes, whereas MeHg altered fewer transcripts. To attenuate batch effects, analysis has been focused on the 500 PS with highest variability. The test systems differed significantly in their responses (<20 % overlap). Moreover, within one test system, little overlap between the PS changed by the two compounds has been observed. However, using TFBS enrichment, a relatively large 'common response' to VPA and MeHg could be distinguished from 'compound-specific' responses. In conclusion, the ESNATS assay battery allows classification of human DNT/RT toxicants on the basis of their transcriptome profiles. 23427017 Modeling toxic stress by atrazine in a marine consumer-resource system. The present study combines short-term experiments with food chain modeling to explore the long-term effects of the herbicide atrazine on consumer-resource dynamics in a marine intertidal ecosystem. Short-term (28 d) lab experiments indicated that the intrinsic rate of increase (r) and carrying capacity (K) of the marine diatom Seminavis robusta decreased with increasing atrazine exposure. This decrease did not show the concave shape expected from the lifetime productivity for nonexposed diatoms and from single-species toxicity data in the literature but instead was described best by a linear model. These experimentally observed atrazine-induced decreases of r and K were used to parameterize a Rosenzweig-MacArthur model representing a simple food chain including the tested diatom and its grazer, the harpacticoid copepod Delavalia palustris var. palustris. Stable oscillation zoo-phytobenthos systems were produced at diatom exposures of 0, 100, and 150 µg/L atrazine. An atrazine concentration of 150 µg/L contributed to a 15% increase of the oscillation periods of both diatoms and copepods as well as a 52% reduction of oscillation amplitudes compared with the control situation. Although the amplitudes of copepods increased only 7% at 150 µg/L atrazine, the maximum and minimum copepod densities at that concentration were reduced 61 and 63%, respectively. The effects of atrazine on periodicity and amplitudes were robust to 20% changes in the food-chain model parameters that represented allometric relationships. The simulations in the present study suggest food chain-mediated indirect effects on zoobenthos populations, indicating a reduced diatom and copepod availability throughout the year. Environ. Toxicol. Chem. 2013;32:1088-1095. © 2013 SETAC. 23561181 A dipeptide and an amino acid present in whey protein hydrolysate increase translocation of GLUT-4 to the plasma membrane in Wistar rats. Whey protein hydrolysate (WPH) is capable of increasing muscle glycogen reserves and of concentrating the glucose transporter in the plasma membrane (PM). The objective of this study was to determine which WPH components could modulate translocation of the glucose transporter GLUT-4 to the PM of animal skeletal muscle. Forty-nine animals were divided into 7 groups (n=7) and received by oral gavage 30% glucose plus 0.55g/kg body mass of the following WPH components: (a) control; (b) WPH; (c) l-isoleucine; (d) l-leucine; (e) l-leucine plus l-isoleucine; (f) l-isoleucyl-l-leucine dipeptide; (g) l-leucyl-l-isoleucine dipeptide. After receiving these solutions, the animals were sacrificed and the GLUT-4 analysed by western blot. Additionally, glycogen, glycaemia, insulin and free amino acids were also determined by standard methods. Of the WPH components tested, the amino acid l-isoleucine and the peptide l-leucyl-l-isoleucine showed greater efficiency in translocating GLUT-4 to the PM and of increasing glucose capture by skeletal muscle. 23108606 Synthesis and chiral recognition of nickel(II) macrocyclic complex with (R)-naphthylethyleneamine pendant groups and its self-assembled framework. A novel nickel(II) hexaaza macrocyclic complex, [Ni(L(R,R))](ClO(4))(2) (1), containing chiral pendant groups was synthesized by an efficient one-pot template condensation and characterized (L(R,R) ═1,8-di((R)-α-methylnaphthyl)-1,3,6,8,10,13-hexaazacyclotetradecane). The crystal structure of compound 1 was determined by single-crystal X-ray analysis. The complex was found to have a square-planar coordination environment for the nickel(II) ion. Open framework [Ni(L(R,R))](3) [C(6)H(3)(COO)(3)](2) (2) was constructed from the self-assembly of compound 1 with deprotonated 1,3,5-benzenetricarboxylic acid, BTC(3-). Chiral discrimination of rac-1,1'-bi-2-naphthol and rac-2,2,2-trifluoro-1-(9-anthryl)ethanol was performed to determine the chiral recognition ability of the chiral complex (1) and its self-assembled framework (2). Binaphthol showed a good chiral discrimination on the framework (2). The optimum experimental conditions for the chiral discrimination were examined by changing the weight ratio between the macrocyclic complex 1 or self-assembled framework 2 and racemates. The detailed synthetic procedures, spectroscopic data including single-crystal X-ray analysis, and the results of the chiral recognition for the compounds are described. 23323873 Successful factorial design for the optimization of methylprednisolone encapsulation in biodegradable nanoparticles. Due to their crystalline nature, the encapsulation of hydrophobic corticosteroids within polymeric nanoparticles by o/w solvent evaporation method is often difficult to achieve. The aim of this study was to evaluate the effect of both process and formulation parameters on the encapsulation of a model corticosteroid: methylprednisolone (MP). For this purpose, a 3(2)factorial design was performed evaluating the effects of the concentration of emulsifiers and sonication time on the manufactured nanoparticles, followed by a multiresponse optimization. The study also included the evaluation of other parameters such as the type of organic solvent used, polymer characteristics and the initial mass of drug. The optimal nanoparticle formulation using 0.25% (w/v) of emulsifying agent (Polyvinyl-alcohol, PVA) and 5 min of sonication was then characterized. The highest encapsulation was obtained with an organic phase consisting of acetone: dichloromethane (1:1), polyD,L-lactide-co-glycolide (PLGA) 50:50 as polymer and an initial mass of 6.6 mg of methylprednisolone. Nanoparticles size and ζ potential of optimized formulation were respectively around 230 nm and -14 mV. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) demonstrated that the drug was molecularly dispersed within the nanoparticles. Release study showed that MP-loaded nanoparticles sustained drug release for up to 120 h. This study reflects the importance of factorial design to optimize the manufacture of nanoparticles encapsulating hydrophobic drugs. 22982776 Persistent and high-level expression of human liver prolidase in vivo in mice using adenovirus. Human liver prolidase, a metal-dependent dipeptidase, is being tested as a potential catalytic bioscavenger against organophosphorus (OP) chemical warfare nerve agents. The purpose of this study was to determine whether persistent and high-levels of biologically active and intact recombinant human (rHu) prolidase could be introduced in vivo in mice using adenovirus (Ad). Here, we report that a single intravenous injection of Ad containing the prolidase gene with a 6× histidine-tag (Ad-prolidase) introduced high-levels of rHu prolidase in the circulation of mice which peaked on days 5-7 at 159±129U/mL. This level of prolidase is ∼120 times greater than that of the enzyme level in mice injected with Ad-null virus. To determine if all of Ad-prolidase-produced rHu prolidase was exported into the circulation, enzyme activity was measured in a variety of tissues. Liver contained the highest levels of rHu prolidase on day 7 (5647±454U/g) compared to blood or any other tissue. Recombinant Hu prolidase hydrolyzed DFP, a simulant of OP nerve agents, in vitro. In vivo, prolidase overexpression extended the survival of 4 out of 6 mice by 4-8h against exposure to two 1× LD50 doses of DFP. In contrast, overexpression of mouse butyrylcholinesterase (BChE), a proven stoichiometric bioscavenger of OP compounds, protected 5 out of 6 mice from DFP lethality and surviving mice showed no symptoms of DFP toxicity. In conclusion, the results suggest that gene delivery using Ad is capable of introducing persistent and high levels of human liver prolidase in vivo. The gene-delivered prolidase hydrolyzed DFP in vitro but provided only modest protection in vivo in mice, delaying the death of the animals by only 4-8h. 23024204 Metabolism of triethylenetetramine and 1,12-diamino-3,6,9-triazadodecane by the spermidine/spermine-N(1)-acetyltransferase and thialysine acetyltransferase. Triethylenetetramine (TETA; Syprine; Merck Rahway, NJ), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that TETA is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N(1)-acetyltransferase (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice compared with wild-type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase respons 2ible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane(SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2 and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and SpmTrien, SSAT2 is the main acetylator of TETA, whereas SpmTrien is primarily acetylated by SSAT1. 22335586 Formulation, in vitro and in vivo evaluation of transdermal patches containing risperidone. The efficacy of oral risperidone treatment in prevention of schizophrenia is well known. However, oral side effects and patient compliance is always a problem for schizophrenics. In this study, risperidone was formulated into matrix transdermal patches to overcome these problems. The formulation factors for such patches, including eudragit RL 100 and eudragit RS 100 as matrix forming polymers, olive oil, groundnut oil and jojoba oil in different concentrations as enhancers and amount of drug loaded were investigated. The transdermal patches containing risperidone were prepared by solvent casting method and characterized for physicochemical and in vitro permeation studies through excised rat skin. Among the tested preparations, formulations with 20% risperidone, 3:2 ERL 100 and ERS 100 as polymers, mixture of olive oil and jojoba oil as enhancer, exhibited greatest cumulative amount of drug permeated (1.87 ± 0.09 mg/cm(2)) in 72 h, so batch ROJ was concluded as optimized formulation and assessed for pharmacokinetic, pharmacodynamic and skin irritation potential. The pharmacokinetic characteristics of the optimized risperidone patch were determined using rabbits, while orally administered risperidone in solution was used for comparison. The calculated relative bioavailability of risperidone transdermal patch was 115.20% with prolonged release of drug. Neuroleptic efficacy of transdermal formulation was assessed by rota-rod and grip test in comparison with control and marketed oral formulations with no skin irritation. This suggests the transdermal application of risperidone holds promise for improved bioavailability and better management of schizophrenia in long-term basis. 23621689 Hydrazides/Hydrazones as antimicrobial and anticancer agents in the new millennium. Hydrazide/hydrazone derivatives are of quite interest for medicinal chemists because of their vast spectrum of biological activity. Literature reports reveal that the hydrazide derivatives have been extensively studied for their biological profile during the past decade. The aim of the present work is to collect literature reports focusing the antimicrobial and anticancer study of different hydrazide/hydrazone derivatives carried out during the past decade which will serve as a valuable source of information for the researchers working in the field of antimicrobial and anticancer research. 23136129 The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Haploinsufficiency of Progranulin (PGRN), a gene encoding a secreted glycoprotein, is a major cause of frontotemporal lobar degeneration with ubiquitin (FTLD-U) positive inclusions. Single nucleotide polymorphisms in the TMEM106B gene were recently discovered as a risk factor for FTLD-U, especially in patients with PGRN mutations. TMEM106B is also associated with cognitive impairment in amyotrophic lateral sclerosis patients. Despite these studies, little is known about TMEM106B at molecular and cellular levels and how TMEM106B contributes to FTLD. Here, we show that TMEM106B is localized in the late endosome/lysosome compartments and TMEM106B levels are regulated by lysosomal activities. Ectopic expression of TMEM106B induces morphologic changes of lysosome compartments and delays the degradation of endocytic cargoes by the endolysosomal pathway. Furthermore, overexpression of TMEM106B correlates with elevated levels of PGRN, possibly by attenuating lysosomal degradation of PGRN. These results shed light on the cellular functions of TMEM106B and the roles of TMEM106B in the pathogenesis of FTLD-U with PGRN mutations. 22856387 Pharmacokinetic characterization of the novel TAZ modulator TM-25659 using a multicompartment kinetic model in rats and a possibility of its drug-drug interactions in humans. This study evaluated the pharmacokinetics of the novel TAZ modulator TM-25659 in rats following intravenous and oral administration at dose ranges of 0.5-5 mg/kg and 2-10 mg/kg, respectively. Plasma protein binding, plasma stability, liver microsomal stability, CYP inhibition, and transport in Caco-2 cells were also evaluated. After intravenous injection, systemic clearance, steady-state volumes of distribution, and half-life were dose-independent, with values ranging from 0.434-0.890 mL · h(-1) · kg(-1), 2.02-4.22 mL/kg, and 4.60-7.40 h, respectively. Mean absolute oral bioavailability was 50.9% and was not dose dependent. Recovery of TM-25659 was 43.6% in bile and <1% in urine. In pharmacokinetic modeling studies, the three-compartment (3C) model was appropriate for understanding these parameters in rats. TM-25659 was stable in plasma. Plasma protein binding was approximately 99.2%, and was concentration-independent. TM-25659 showed high permeation of Caco-2 cells and did not appear to inhibit CYP450. TM-25659 was metabolized in phase I and II steps in rat liver microsomes. In conclusion, the pharmacokinetics of TM-25659 was characterized for intravenous and oral administration at doses of 0.5-5 and 2-10 mg/kg, respectively. TM-25659 was eliminated primarily by hepatic metabolism and urinary excretion. 23414527 Large-scale spinning assembly of neat, morphology-defined, graphene-based hollow fibers. Large-scale assembly of graphenes in a well-controlled macroscopic fashion is important for practical applications. We have developed a facile and straightforward approach for continuous fabrication of neat, morphology-defined, graphene-based hollow fibers (HFs) via a coaxial two-capillary spinning strategy. With a high throughput, HFs and necklace-like HFs of graphene oxide have been well-controlled produced with the ease of functionalization and conversion to graphene HFs via simply thermal or chemical reduction. This work paves the way toward the mass production of graphene-based HFs with desirable functionalities and morphologies for many of important applications in fluidics, catalysis, purification, separation, and sensing. 23329685 Environmental Survey Meta-analysis Reveals Hidden Diversity among Unicellular Opisthokonts. The Opisthokonta clade includes Metazoa, Fungi, and several unicellular lineages, such as choanoflagellates, filastereans, ichthyosporeans, and nucleariids. To date, studies of the evolutionary diversity of opisthokonts have focused exclusively on metazoans, fungi, and, very recently, choanoflagellates. Thus, very little is known about diversity among the filastereans, ichthyosporeans, and nucleariids. To better understand the evolutionary diversity and ecology of the opisthokonts, here we analyze published environmental data from nonfungal unicellular opisthokonts and report 18S ribosomal DNA phylogenetic analyses. Our data reveal extensive diversity among all unicellular opisthokonts, except for the filastereans. We identify several clades that consist exclusively of environmental sequences, especially among ichthyosporeans and choanoflagellates. Moreover, we show that the ichthyosporeans represent a significant percentage of overall unicellular opisthokont diversity, with a greater ecological role in marine environments than previously believed. Our results provide a useful phylogenetic framework for future ecological and evolutionary studies of these poorly known lineages. 22313530 CNS distribution of metabotropic glutamate 2 and 3 receptors: transgenic mice and [³H]LY459477 autoradiography. Group II metabotropic glutamate (mGlu) receptor agonists were efficacious in randomized clinical research trials for schizophrenia and generalized anxiety disorder. The regional quantification of mGlu(2) and mGlu(3) receptors remains unknown. A selective and structurally novel mGlu(2/3) receptor agonist, 2-amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY459477) was tritiated and the distribution of mGlu(2) and mGlu(3) receptors was studied in transgenic mice lacking either mGlu(2), mGlu(3) or both receptors. LY459477 is an agonist with 1-2 nM potency for rodent and human mGlu(2) and mGlu(3) receptors. The functional selectivity of LY459477 was demonstrated by over 640-fold selectivity and the displacement binding selectivity was greater than 320-fold for all glutamate receptors except mGlu(6) (∼230-fold). More than 1000-fold selectivity was demonstrated for all non-glutamate receptors known to be targeted by antipsychotic drugs. Like atypical antipsychotic drugs, LY459477 reversed in vitro electrophysiological effects of a serotonergic hallucinogen and behavioral effects of phencyclidine or amphetamine. There was virtually no binding of [(3)H]LY459477 to any brain region in mice with a deletion of both mGlu(2) and mGlu(3) receptors. Regions enriched in mGlu(2) receptors included the medial prefrontal cortex, select hippocampal regions, the medial mammillary nucleus, the medial habenula, and the cerebellar granular cell layer. Regions enriched in mGlu(3) receptors were the dorsolateral entorhinal cortex, the hippocampal CA1 field, the piriform cortex, the substantia nigra, the thalamic reticular nucleus, and primary sensory thalamic nuclei. These findings suggest [(3)H]LY459477 should be a useful tool to further define the role of mGlu(2) and mGlu(3) receptors throughout the brain with respect to major neuropsychiatric syndromes. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23625455 Solvated protein-DNA docking using HADDOCK. Interfacial water molecules play an important role in many aspects of protein-DNA specificity and recognition. Yet they have been mostly neglected in the computational modeling of these complexes. We present here a solvated docking protocol that allows explicit inclusion of water molecules in the docking of protein-DNA complexes and demonstrate its feasibility on a benchmark of 30 high-resolution protein-DNA complexes containing crystallographically-determined water molecules at their interfaces. Our protocol is capable of reproducing the solvation pattern at the interface and recovers hydrogen-bonded water-mediated contacts in many of the benchmark cases. Solvated docking leads to an overall improvement in the quality of the generated protein-DNA models for cases with limited conformational change of the partners upon complex formation. The applicability of this approach is demonstrated on real cases by docking a representative set of 6 complexes using unbound protein coordinates, model-built DNA and knowledge-based restraints. As HADDOCK supports the inclusion of a variety of NMR restraints, solvated docking is also applicable for NMR-based structure calculations of protein-DNA complexes. 23374873 2',4'-BNA/LNA aptamers: CE-SELEX using a DNA-based library of full-length 2'-O,4'-C-methylene-bridged/linked bicyclic ribonucleotides. DNA-based aptamers that contain 2'-O,4'-C-methylene-bridged/linked bicyclic ribonucleotides (B/L nucleotides) over the entire length were successfully obtained using a capillary electrophoresis systematic evolution of ligands by exponential enrichment (CE-SELEX) method. A modified DNA library was prepared with an enzyme mix of KOD Dash and KOD mutant DNA polymerases. Forty 2'-O,4'-C-methylene bridged/locked nucleic acid (2',4'-BNA/LNA) aptamers were isolated from an enriched pool and classified into six groups according to their sequence. 2',4'-BNA/LNA aptamers of groups V and VI bound human thrombin with K(d) values in the range of several 10 nanomolar levels. 23338536 Differentiating factors between erythropoiesis-stimulating agents: an update to selection for anaemia of chronic kidney disease. Erythropoiesis-stimulating agents (ESAs) have become a hallmark of anaemia therapy in patients with chronic kidney disease (CKD). Although different ESAs are available for the treatment of renal anaemia, each nephrologist should select a single ESA for an individual patient. Epoetin alfa and epoetin beta have been used 1-3 times weekly but extended-interval dosing up to every 4 weeks is also effective in a substantial majority of CKD patients. However, the epoetin dose necessary to achieve or maintain target haemoglobin (Hb) levels increases substantially as the dosing interval increases. Subcutaneous administration of short-acting ESAs is more effective than the intravenous route of administration. Darbepoetin alfa and the continuous erythropoietin receptor activator (CERA) have been developed as a treatment for anaemia with extended administration intervals (every 2 weeks and every 4 weeks, respectively). Dose requirements for these long-acting ESAs are independent of the route of administration. Patents of short-acting ESAs have expired, which has opened the field for biosimilars. Epoetin biosimilars approved by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) have been shown to have a comparable efficacy and safety profile to their originators. An alarming increase in pure red cell aplasia (PRCA) in Thailand with follow-on epoetins manufactured in Asia (but also those manufactured in Latin America) indicates that stringent country-specific approval and pharmacovigilance protocols for ESAs manufactured in non-North American and non-EU European countries are urgently needed. Two PRCA cases occurring with subcutaneous HX575 (one certain, one likely) indicate that chances of inducing a more immunogenic product are unpredictable, even with a biosimilar epoetin approved under the EMA biosimilar approval pathway. Phase III clinical trials with peginesatide, a pegylated synthetic peptide-based ESA without any homology to erythropoietin raised safety concerns in non-dialysis CKD patients but not in dialysis patients. 23287412 Inhibition of T-type calcium channels disrupts Akt signaling and promotes apoptosis in glioblastoma cells. Glioblastoma multiforme (GBM) are brain tumors that are exceptionally resistant to both radio- and chemotherapy regimens and novel approaches to treatment are needed. T-type calcium channels are one type of low voltage-gated channel (LVCC) involved in embryonic cell proliferation and differentiation; however they are often over-expressed in tumors, including GBM. In this study, we found that inhibition of T-type Ca(2+) channels in GBM cells significantly reduced their survival and resistance to therapy. Moreover, either T-type selective antagonists, such as mibefradil, or siRNA-mediated knockdown of the T-type channel alpha subunits not only reduced cell viability and clonogenic potential, but also induced apoptosis. In response to channel blockade or ablation, we observed reduced phosphorylation of Akt and Rictor, suggesting inhibition of the mTORC2/Akt pathway. This was followed by reduction in phosphorylation of anti-apoptotic Bad and caspases activation. The apoptotic response was specific for T-type Ca(2+) channels, as inhibition of L-type Ca(2+) channels did not induce similar effects. Our results implicate T-type Ca(2+) channels as distinct entities for survival signaling in GBM cells and suggest that they are a novel molecular target for tumor therapy. 23391336 Cloning, Characterization, and Sulfonamide and Thiol Inhibition Studies of an α-Carbonic Anhydrase from Trypanosoma cruzi, the Causative Agent of Chagas Disease. An α-carbonic anhydrase (CA, EC 4.2.1.1) has been identified, cloned, and characterized from the unicellular protozoan Trypanosoma cruzi, the causative agent of Chagas disease. The enzyme (TcCA) has a very high catalytic activity for the CO(2) hydration reaction, being similar kinetically to the human (h) isoform hCA II, although it is devoid of the His64 proton shuttle. A large number of aromatic/heterocyclic sulfonamides and some 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors. The aromatic sulfonamides were weak inhibitors (K(I) values of 192 nM to 84 μM), whereas some heterocyclic compounds inhibited the enzyme with K(I) values in the range 61.6-93.6 nM. The thiols were the most potent in vitro inhibitors (K(I) values of 21.1-79.0 nM), and some of them also inhibited the epimastigotes growth of two T. cruzi strains in vivo. 23161062 A kinesin-mediated mechanism that couples centrosomes to nuclei. The M-type kinesin isoform, Kif9, has recently been implicated in maintaining a physical connection between the centrosome and nucleus in Dictyostelium discoideum. However, the mechanism by which Kif9 functions to link these two organelles remains obscure. Here we demonstrate that the Kif9 protein is localized to the nuclear envelope and is concentrated in the region underlying the centrosome point of attachment. Nuclear anchorage appears mediated through a specialized transmembrane domain located in the carboxyl terminus. Kif9 interacts with microtubules in in vitro binding assays and effects an endwise depolymerization of the polymer. These results suggest a model whereby Kif9 is anchored to the nucleus and generates a pulling force that reels the centrosome up against the nucleus. This is a novel activity for a kinesin motor, one important for progression of cells into mitosis and to ensure centrosome-nuclear parity in a multinuclear environment. 23306378 Probing circulating tumor cells in microfluidics. Circulating tumor cells (CTCs) are important targets for study as we strive to better understand, diagnose, and treat cancers. However, CTCs are found in blood at extremely low concentrations; this makes isolation, enrichment, and characterization of CTCs technically challenging. Recently, the development of CTC separation devices has grown rapidly in both academia and industry. Part of this development effort centered on microfluidic platforms, exploiting the advantages of microfluidics to improve CTC separation performance and device integration. In this Focus article, we highlight some of the recent work in microfluidic CTC separation and detection systems and discuss our appraisal of what the field should do next. 23350627 Photocatalytic properties of graphdiyne and graphene modified TiO₂: from theory to experiment. The chemical structure and electronic properties of two-dimensional (2D) carbon-supported TiO₂, TiO₂-graphdiyne, and TiO₂-graphene composites have been studied by first-principles density functional theory. Calculation results show that TiO₂(001)-graphdiyne composites possess superior charge separation and oxidation properties, having the longest lifetimes of photoexcited carriers among all of the 2D composites containing TiO₂ of different facets. Our experimental results further proved that TiO₂(001)-graphdiyne composites could be a promising photocatalyst. For photocatalytic degradation of methylene blue, the rate constant of the TiO₂(001)-graphdiyne composite is 1.63 ± 0.15 times that of the pure TiO₂(001) and 1.27 ± 0.12 times that of the TiO₂(001)-graphene composite. 23146695 Puerarin mediates hepatoprotection against CCl4-induced hepatic fibrosis rats through attenuation of inflammation response and amelioration of metabolic function. This study was designed to evaluate the potential effects of puerarin (PR), an effective isoflavonoid compound purified from Pueraria lobata, in treating hepatic fibrosis (HF) rats induced by carbon tetrachloride (CCl(4), 2 mL kg(-1) d(-1)). Compared to model control, PR treatment effectively lowered the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (Alb), total protein (TP) in HF rats. Masson stained analysis showed that the condition of HF rats was mitigated. Meanwhile, the tumor necrosis factor alpha (TNF-α), nuclear factor-kappa B (NF-κB) expressions were significantly down-regulated at protein level by PR intervention. Additionally, the activity of superoxide dismutase (SOD) was elevated, while the content of malondialdehyde (MDA) was lessened in liver tissue. As revealed by immunohistochemistry assay, PR therapy resulted in reduced production of transforming growth factor-βl (TGF-βl). Moreover, it also was attributed to decreased mRNA level of inducible nitric oxide synthase (iNOS) using RT-PCR analysis. These findings demonstrate that puerarin successfully reverses hepatotoxicity in CCl(4)-induced HF rats via the underlying mechanisms of regulating serum enzymes and attenuating TNF-α/NF-κB pathway for anti-inflammation response, as well as improving metabolic function in liver tissue. 23256722 Novel modalities and agents in bronchoscopic lung volume reduction. The NETT study has shown the effectiveness of lung volume reduction surgery (LVRS) in improving functional parameters and exercise tolerance in selected patients with severe pulmonary emphysema of upper lobe predominance. A number of bronchoscopic techniques have since been developed under the term "bronchoscopic lung volume reduction" (BLVR), aiming to lower the complications and the cost while facilitating the procedure of lung volume approach in patients with emphysema. These include airway bypass by creation of airway/parenchyma communications, one-way endobronchial valves occluding the airways of the targeted lobes, endobronchial coils which mechanically contract the parenchyma, hot vapour ablation thermally destroying the targeted sites and sealant which fill the alveoli with polymer material. These methods are generally simple and safe, with a favourable complications profile, requiring less infrastructure and interventional experience than the open surgical approach. Bronchial valves have produced promising results in a very narrow phenotype of emphysema patients and have the major advantage of being reversible in their action. Parenchymal interventions at the cost of producing permanent effects and a transient inflammatory syndrome, may be effective in larger group of patients regardless of the fissure integrity and the presence of collateral ventilation. New, more extensive multicentre studies are underway which aim at better selection and stratification of patients in order to further evaluate the safety and effectiveness of these techniques, before wider use of this revolutionary approach for severe lung emphysema can be advocated. 23588585 Molecular Mechanisms of Silibinin-Mediated Cancer Chemoprevention with Major Emphasis on Prostate Cancer. Despite advances in early detection, prostate cancer remains the second highest cancer mortality in American men, and even successful interventions are associated with enormous health care costs as well as prolonged deleterious effects on quality of patient life. Prostate cancer chemoprevention is one potential avenue to alleviate these burdens. It is a regime whereby long-term treatments are intended to prevent or arrest cancer development, in contrast to more direct intervention upon disease diagnosis. Based on this intention, cancer chemoprevention generally focuses on the use of nontoxic chemical agents which are well-tolerated for prolonged usage that is necessary to address prostate cancer's multistage and lengthy period of progression. One such nontoxic natural agent is the flavonoid silibinin, derived from the milk thistle plant (Silybum marianum), which has ancient medicinal usage and potent antioxidant activity. Based on these properties, silibinin has been investigated in a host of cancer models where it exhibits broad-spectrum efficacy against cancer progression both in vitro and in vivo without noticeable toxicity. Specifically in prostate cancer models, silibinin has shown the ability to modulate cell signaling, proliferation, apoptosis, epithelial to mesenchymal transition, invasion, metastasis, and angiogenesis, which taken together provides strong support for silibinin as a candidate prostate cancer chemopreventive agent. 23422298 The neuroprotector kynurenic acid increases neuronal cell survival through neprilysin induction. Kynurenic acid (KYNA), one of the main product of the kynurenine pathway originating from tryptophan, is considered to be neuroprotective. Dysregulation of KYNA activity is thought to be involved in neurodegenerative diseases, the physiopathology of which evokes excitotoxicity, oxidative stress and/or protein aggregation. The neuroprotective effect of KYNA is generally attributed to its antagonistic action on NMDA receptors. However, this single target action appears insufficient to support KYNA beneficial effects against complex neurodegenerative processes including neuroinflammation, β-amyloid peptide (Aβ) toxicity and apoptosis. Novel insights are therefore required to elucidate KYNA neuroprotective mechanisms. Here, we combined cellular, biochemical, molecular and pharmacological approaches to demonstrate that low micromolar concentrations of KYNA strongly induce neprilysin (NEP) gene expression, protein level and enzymatic activity increase in human neuroblastoma SH-SY5Y cells. Furthermore, our studies revealed that KYNA exerts a protective effect on SH-SY5Y cells by increasing their viability through a mechanism independent from NMDA receptors. Interestingly, KYNA also induced NEP activity and neuroprotection in mouse cortical neuron cultures the viability of which was more promoted than SH-SY5Y cell survival under KYNA treatment. KYNA-evoked neuroprotection disappeared in the presence of thiorphan, an inhibitor of NEP activity. NEP is a well characterized metallopeptidase whose deregulation leads to cerebral Aβ accumulation and neuronal death in Alzheimer's disease. Therefore, our results suggest that a part of the neuroprotective role of KYNA may depend on its ability to induce the expression and/or activity of the amyloid-degrading enzyme NEP in nerve cells. 23267840 NMDA and AMPA receptor mediated excitotoxicity in cerebral cortex of streptozotocin induced diabetic rat: ameliorating effects of curcumin. Functional activity of neurotransmitter receptor and their sensitivity to regulation are altered in DM. We evaluated the neuroprotective effect of curcumin in glutamate mediated excitotoxicity in cerebral cortex of streptozotocin induced diabetic rats. Gene expression studies in diabetic rats showed a down regulation of glutamate decarboxylase mRNA leading to accumulation of glutamate. Radioreceptor binding assays showed a significant increase in α-amino-3-hydroxy-5-methyl-4-isoxazole propionate and N-methyl-D-aspartate receptors density which was confirmed by immunohistochemical studies. Decreased glutathione peroxidases gene expression indicates enhanced oxidative stress in diabetic rats. This leads to decreased expression of glutamate aspartate transporter, which in turn reduces glutamate transport. All these events lead to excitotoxic neuronal death in the cerebral cortex, which was confirmed by the increased expression of caspase 3, caspase 8 and BCL2-associated X protein. Curcumin and insulin treatment reversed these altered parameters to near control. We establish, a novel therapeutic role of curcumin by reducing the glutamate mediated excitotoxicity in cerebral cortex of diabetes through modulating the altered neurochemical parameters. 23583603 Agonistic activity of ICI 182 780 on activation of GSK 3β/AKT pathway in the rat uterus during the estrous cycle. We examined the ability of ICI 182,780 (ICI) to block uterine cell proliferation via protein kinase b/AKT pathway in the uterus of the rat during the estrous cycle. Intact rats, with regular estrous cycles, received a subcutaneous (s.c.) injection of either vehicle or ICI at 08:00h on the day of proestrus or at 00:00h on the day of estrus and sacrificed at 13:00h of metaestrus. Estradiol (E2) and progesterone (P4) plasma levels were measured by radioimmunoassay. Both ICI treatments, induced a significant decrease (p<0.01) in uterine estrogen receptor alpha (ERα) content, had no effect on uterine progesterone receptor (PR) protein expression and caused marked nuclear localization of cyclin D1, in both luminal and glandular uterine epithelium, as compared to vehicle-treated animals. Furthermore, we detected that ICI treatment induced glycogen synthase kinase (Gsk3-β) Ser 9 phosphorylation, which correlates with cyclin D1 nuclear localization. However, some differences were observed between the two different time schedules of administration. We observed that the administration of ICI at 08:00h on proestrus day produced a 15% inhibition of luminal epithelial cell proliferation, reduced uterine wet weight by 21% and caused reduction of Akt phosphorylation at Ser 473 as compared to vehicle-treated animals, whereas ICI treatment at 00:00h on estrus day had no effect on these parameters. The overall results indicate that ICI may exert agonistic and antagonistic effects on uterine cell proliferation through differential activation of the Akt pathway depending on the administration period during the estrous cycle, and indicates that the mechanism of cell proliferation during the physiological conditions of the estrous cycle, is under a different and more complex regulation than in the ovariectomized +E2 animal model. 23247048 MolShaCS: a free and open source tool for ligand similarity identification based on Gaussian descriptors. Molecular similarity evaluation is an important step in most drug development strategies, since molecular similarity is usually related to functional similarity. Here, we developed a method based on the Gaussian description of molecular shape and charge distribution for molecular similarity identification. The method was evaluated using the Directory of Useful Decoys (DUD) and a retrospective test. Enrichment factors computed for DUD targets showed that the proposed method performs very well in recognizing molecules with similar physicochemical properties and dissimilar topologies, reaching an average AUC of 0.63 and enrichment factor of 10 at 0.5% of decoys. A retrospective test also showed that nine mineralocorticoid ligands were ranked among the top ten molecules in a search of a database of approved drugs for molecules similar to aldosterone. Altogether, these data show that the Gaussian-based description of molecular shape and charge distribution implemented in the program MolShaCS is an efficient method for molecular similarity identification. The program is publicly available at the address http://www.ifsc.usp.br/biotechmol. 23073075 Fingolimod protects cultured cortical neurons against excitotoxic death. Fingolimod (FTY720), a novel drug approved for the treatment of relapsing-remitting multiple sclerosis, activates different sphingosine-1-phosphate receptor (S1PR) subtypes. Its primary mechanism of action is to reduce the egress of T lymphocytes from secondary lymphoid organs, thus restraining neuroinflammation and autoimmunity. However, recent evidence suggests that the action of FTY720 involves S1PRs expressed by cells resident in the CNS, including neurons. Here, we examined the effect of FTY720, its active metabolite, FTY720-P, and sphingosine-1-phosphate (S1P) on neuronal viability using a classical in vitro model of excitotoxic neuronal death. Mixed cultures of mouse cortical cells were challenged with toxic concentrations of N-methyl-d-aspartate (NMDA) for 10 min, and neuronal death was assessed 20 h later. FTY720, FTY720-P, and S1P were all neuroprotective when applied 18-20 h prior to the NMDA pulse. Neuroprotection was attenuated by pertussis toxin, and inhibited by the selective type-1 S1PR (S1P1R) antagonist, W146, and by inhibitors of the mitogen associated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PtdIns-3-K) pathways. Both FTY720 and FTY720-P retained their protective activity in pure cultures of mouse or rat cortical neurons. These data offer the first direct demonstration that FTY720 and its active metabolite protect neurons against excitotoxic death. 23146839 Male mating behaviour in relation to female sexual swellings, socio-sexual behaviour and hormonal changes in wild Barbary macaques. In many cercopithecine primates females display probabilistic cues of fertility to indicate the periovulatory period to males. These cues may include female behaviour, acoustic signals, and morphological signs such as the anogenital swelling. However, the extent to which males can utilise this information varies between species. We describe male sexual behaviour in relation to changes in anogenital swelling size, timing of ovulation and female socio-sexual behaviour in wild Barbary macaques (Macaca sylvanus). We further compare male sexual behaviour during conception and post-conception cycles to evaluate if males differentiate between these qualitatively different cycle types. Our results show that during conception cycles male mating behaviour was concentrated around the fertile phase implying that males inferred information from more than swelling size alone. Male mating frequency increased in line with female socio-sexual behaviour, namely female presenting and the frequency of copulations with copulation calls. Most strikingly our results show that males invested equally in mating during fertile and non-fertile, i.e. post-conception, maximum swelling phases. Whether post-conception swellings were merely a result of changes in hormone concentrations during pregnancy or part of a female reproductive strategy remains elusive. In sum, this study adds to the body of research on the evolution of female sexual signals and how males may infer information from these cues. 23597443 Comparative study on effects of two different types of titanium dioxide nanoparticles on human neuronal cells. Titanium dioxide (TiO2) are among most frequently used nanoparticles (NPs). They are present in a variety of consumer products, including food industry in which they are employed as an additive. The potential toxic effects of these NPs on mammal cells have been extensively studied. However, studies regarding neurotoxicity and specific effects on neuronal systems are very scarce and, to our knowledge, no studies on human neuronal cells have been reported so far. Therefore, the main objective of this work was to investigate the effects of two types of TiO2 NPs, with different crystalline structure, on human SHSY5Y neuronal cells. After NPs characterization, a battery of assays was performed to evaluate the viability, cytotoxicity, genotoxicity and oxidative damage in TiO2 NP-exposed SHSY5Y cells. Results obtained showed that the behaviour of both types of NPs resulted quite comparable. They did not reduce the viability of neuronal cells but were effectively internalized by the cells and induced dose-dependent cell cycle alterations, apoptosis by intrinsic pathway, and genotoxicity not related with double strand break production. Furthermore, all these effects were not associated with oxidative damage production and, consequently, further investigations on the specific mechanisms underlying the effects observed in this study are required. 23281710 Distinct and opposing roles for Rab27a/Mlph/MyoVa and Rab27b/Munc13-4 in mast cell secretion. Mediator release from mast cells is a critical step in allergic and inflammatory disease. However, the processes regulating the latter stages of granule release are yet to be fully understood. Rab27 small GTPases regulate release of secretory lysosomes in a variety of cells, including mast cell granules. In the present study, using murine bone marrow-derived mast cells (BMMC) from Rab27-deficient mutant mice, we found that, in contrast to Rab27b, Rab27a primarily plays an inhibitory role in regulating degranulation. Immunofluorescence analysis revealed that resting Rab27a-deficient (ashen) BMMCs display abnormal cortical F-actin distribution. Actin disassembly prior to IgE cross-linking increased wild-type BMMC secretion to ashen levels, suggesting that changes in the integrity of cortical F-actin underlie the ashen phenotype. Comparison of the secretory impairment of Rab27b knockout and Rab27a/b double knockout BMMCs highlighted a secondary positive role for Rab27a in enhancing degranulation. Rab27 is known to interact with actin via its effectors melanophilin (Mlph) and myosin Va (MyoVa) in other cell types. To better understand the differing roles of Rab27 proteins, we analysed the secretory phenotype of BMMCs derived from mice lacking Rab27 effector proteins. These experiments revealed that the phenotype of BMMCs deficient in Mlph (leaden) and BMMCs deficient in MyoVa (dilute) resembles the hyper-secretion of ashen BMMCs, while Munc13-4-deficient (jinx) BMMCs phenocopy the Rab27b knockout and double Rab27a/b knockout secretory impairment. We conclude that Rab27a and Rab27b regulate distinct steps in the BMMC degranulation pathway, with Rab27a/Mlph/MyoVa regulating cortical actin stability upstream of Rab27a/b/Munc13-4-dependent granule exocytosis. 23207323 Ion-exchange and iontophoresis-controlled delivery of apomorphine. The objective of this study was to test a drug delivery system that combines iontophoresis and cation-exchange fibers as drug matrices for the controlled transdermal delivery of antiparkinsonian drug apomorphine. Positively charged apomorphine was bound to the ion-exchange groups of the cation-exchange fibers until it was released by mobile counter-ions in the external solution. The release of the drug was controlled by modifying either the fiber type or the ionic composition of the external solution. Due to high affinity of apomorphine toward the ion-exchanger, a clear reduction in the in vitro transdermal fluxes from the fibers was observed compared to the respective fluxes from apomorphine solutions. Changes in the ionic composition of the donor formulations affected both the release and iontophoretic flux of the drug. Upon the application of higher co-ion concentrations or co-ions of higher valence in the donor formulation, the release from the fibers was enhanced, but the iontophoretic steady-state flux was decreased. Overall, the present study has demonstrated a promising approach using ion-exchange fibers for controlling the release and iontophoretic transdermal delivery of apomorphine. 23174518 Chemical characterization, antioxidant and cytotoxic activities of Brazilian red propolis. Propolis is known for a long time for its health benefits and biological activities. Here, the red variety from the northeast of Brazil was chemically analyzed and extracts were investigated regarding their antioxidant and antitumor activity. Hydroalcoholic extracts, obtained from the red propolis, revealed polyphenol content, 2,2-diphenyl-1-picrylhydrazyl scavenging potential and enzymatic activities for catalase-like and superoxide dismutase-like. Cytotoxic activity was evaluated for human laryngeal epidermoid carcinoma cell (Hep-2), human cervical adenocarcinoma (HeLa) and human normal epithelial embryonic kidney (Hek-293). Survival analysis for non-tumor cell line showed greater IC50 compared to tumor cell lines, suggesting an increased sensitivity that may correlate with the higher proliferative index of the tumor vs. normal cells. Our results indicate that the Brazilian red propolis is capable of inhibiting cancer cell growth and constitutes an excellent source of antioxidant and antitumor natural agent. 23349493 Galectin-3 Deficiency Accelerates High-Fat Diet Induced Obesity and Amplifies Inflammation in Adipose Tissue and Pancreatic Islets. Obesity-induced diabetes is associated with low-grade inflammation in adipose tissue and macrophage infiltration of islets. We show that ablation of Galectin-3, a galactoside-binding lectin, accelerates high-fat diet-induced obesity and diabetes. Obese LGALS3(-/-) mice have increased body weight, amount of total visceral adipose tissue, fasting blood glucose and insulin levels, HOMA-IR and markers of systemic inflammation compared to diet-matched WT animals. Obese LGALS3(-/-) visceral adipose tissue exhibited increased incidence of Type-1 T and NKT lymphocytes and pro-inflammatory CD11c+CD11b macrophages and decreased CD4+CD25+FoxP3+ Tregs and M2 macrophages. Pronounced mononuclear cell infiltrate, increased expression of NLRP3 inflammasome and IL-1β in macrophages and increased accumulation of advanced glycation endproducts (AGE) and receptor for AGE (RAGE) expression were present in pancreatic islets of obese LGALS3(-/-) animals accompanied with elevated phosphorilated NFκB p65 and mature Caspase-1 protein expression in pancreatic and visceral adipose tissue. In vitro stimulation of LGALS3(-/-) peritoneal macrophages with lypopolysaccharide (LPS) and saturated fatty acid palmitate caused increased Caspase-1 dependent IL-1β production and increased phosphorilation of NFκB p65 compared to WT cells. Transfection of LGALS3(-/-) macrophages with NLRP3 siRNA attenuated IL-1β production in response to palmitate and LPS plus palmitate. Obtained results suggest important protective roles for Gal-3 in obesity-induced inflammation and diabetes. 23602652 Pathogenesis, current treatments and future directions for idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD) of unknown origin characterized by epithelial cell dysfunctions, accumulation of fibroblasts and myofibroblasts and relentless deposition of extracellular matrix (ECM). Improved diagnostic accuracy and better trial design have provided important insights from recent clinical trials. Perhaps the most important insight was the realization that 'standard therapy' was actually harmful! This review summarizes the current understanding of the cell types that are altered in IPF and the pathogenic mechanisms that have been identified. It also reviews recent clinical trial results and interpretations. Finally, we highlight attractive biologic targets and therapies in development with recommendations for future therapeutic avenues. 23532057 A pyrrolidinium nitrate protic ionic liquid-based electrolyte for very low-temperature electrical double-layer capacitors. This study describes the use of the pyrrolidinium nitrate ([Pyrr][NO3]) protic ionic liquid (PIL) in a mixture with gamma butyrolactone (γ-BL) as an electrolyte for carbon-based supercapacitors with an operating voltage of 2.0 V and at very low temperature. Thermal and transport properties of this electrolyte were firstly evaluated from -40 °C to 80 °C. The evolution of conductivity with the addition of γ-BL rendered it possible to determine the optimal composition for electrochemical application, with a molar fraction of γ-BL of 0.6. This mixture shows a Newtonian behavior with a low viscosity value of 5 mPa s at 25 °C, and exhibits high conductivity values of up to 65 mS cm(-1) at 80 °C. At the same time, exceptional residual conductivity was measured for this composition at -40 °C (9 mS cm(-1)), thanks to the superionic character of pyrrolidinium nitrate PIL. Electrochemical characterization of this electrolyte demonstrated, at first, a passivation on the aluminum collector, secondly good cycling performances with an activated carbon electrode from 50 °C to -40 °C with capacitance up to 132 F g(-1) at room temperature and a wide voltage window (2.0 V). Finally at very low temperature (-40 °C), this system demonstrates an unprecedented combination of high specific capacitance (up to 117 F g(-1)), and rapid charging-discharging even at high current density, which is very promising for the progress of energy storage systems with environmentally friendly electrolytes at such very low temperatures. 23361460 Mini-chromosome maintenance complexes form a filament to remodel DNA structure and topology. Deregulation of mini-chromosome maintenance (MCM) proteins is associated with genomic instability and cancer. MCM complexes are recruited to replication origins for genome duplication. Paradoxically, MCM proteins are in excess than the number of origins and are associated with chromatin regions away from the origins during G1 and S phases. Here, we report an unusually wide left-handed filament structure for an archaeal MCM, as determined by X-ray and electron microscopy. The crystal structure reveals that an α-helix bundle formed between two neighboring subunits plays a critical role in filament formation. The filament has a remarkably strong electro-positive surface spiraling along the inner filament channel for DNA binding. We show that this MCM filament binding to DNA causes dramatic DNA topology change. This newly identified function of MCM to change DNA topology may imply a wider functional role for MCM in DNA metabolisms beyond helicase function. Finally, using yeast genetics, we show that the inter-subunit interactions, important for MCM filament formation, play a role for cell growth and survival. 22872142 Genotoxic damage in the oral mucosa cells of subjects carrying restorative dental fillings. A large proportion of the population carries restorative dental fillings containing either classic Hg-based amalgams and/or the more frequently used methacrylates. Both Hg- and resin-based materials have been shown to be released into the buccal cavity and to be spread systemically. In addition, they induce toxic and genotoxic alterations in experimental test systems. Using the comet assay, we previously demonstrated that circulating lymphocytes of subjects with dental fillings have an increased DNA damage. Here, we analyzed the oral mucosa cells of 63 young subjects of both genders, by using both the comet assay and the micronucleus (MN) test and by monitoring cell death markers. The results obtained show that both amalgams and resin-based composite fillings can induce genotoxic damage in human oral mucosa cells, as convincingly and dose-dependently inferred from the results of the MN test and, more marginally, from comet assay data. Lifestyle variables, also including alcohol intake and smoking habits, did not affect the genotoxic response and did not act as confounding factors. Thus, we provide unequivocal evidence for the genotoxicity of both amalgams and resin-based dental fillings in humans not only by testing circulating lymphocytes but also by analyzing oral mucosa cells. These findings are of particular relevance due to the circumstance that subjects with restorative materials are exposed continuously and for long periods of time. 23568773 Signaling mechanism of tumor cell-induced up-regulation of E3 ubiquitin ligase UBR2. The N-end rule pathway contributes significantly to accelerated muscle proteolysis mediated by the ubiquitin-proteasome pathway in various catabolic conditions. UBR2 (aka E3α-II) is the only known E3 ubiquitin ligase of the N-end rule pathway that is up-regulated by cachectic stimuli including proinflammatory cytokines and tumors. However, the signaling mechanism through which UBR2 is up-regulated remains undetermined. Here we identify a signaling pathway that mediates tumor cell-induced up-regulation of UBR2. UBR2 expression in C2C12 myotubes was up-regulated by conditioned medium from Lewis lung carcinoma cells or C26 colon adenocarcinoma cells, which was blocked by a pharmacological inhibitor of p38α/β mitogen-activated protein kinase (MAPK), SB202190. Similarly, SB202190 administration (i.p.) abolished UBR2 up-regulation in the tibialis anterior of LLC tumor-bearing mice. Genetic gain and loss of function assays in C2C12 myotubes indicated that tumor-induced activation of the p38β isoform is sufficient and necessary for UBR2 up-regulation. In addition, UBR2 up-regulation required p38β-mediated phosphorylation of CCAAT/enhancer binding protein (C/EBP)-β Thr-188, which was critical to C/EBPβ binding to the UBR2 promoter. Furthermore, luciferase reporter assay revealed that the C/EBPβ binding motif in the UBR2 promoter is a functional C/EBPβ-responsive cis-element that enhances the promoter activity on activation by p38β. Finally, genetic ablation of C/EBPβ blocked UBR2 up-regulation in LLC tumor-bearing mice. These results suggest that UBR2 up-regulation in cachectic muscle is mediated by the p38β-C/EBPβ signaling pathway responsible for the bulk of tumor-induced muscle proteolysis.-Zhang, G., Lin, R.-K., Kwon, Y. T., Li, Y.-P. Signaling mechanism of tumor cell-induced up-regulation of E3 ubiquitin ligase UBR2. 23514447 Defect Chemistry of Oxide Nanomaterials with High Surface Area: Ordered Mesoporous Thin Films of the Oxygen Storage Catalyst CeO2-ZrO2. Herein we report the electrical transport properties of a series of ordered mesoporous ceria-zirconia (CexZr1-xO2, referred to as mp-CZO) thin films with both a cubic structure of (17 ± 2) nm diameter pores and nanocrystalline walls. Samples over the whole range of composition, including bare CeO2 and ZrO2, were fabricated by templating strategies using the large diblock copolymer KLE as the structure-directing agent. Both the nanoscale structure and the chemical composition of the mesoporous materials were analyzed by a combination of scanning and transmission electron microscopy, grazing incidence small-angle X-ray scattering, X-ray photoelectron spectroscopy, and time-of-flight secondary ion mass spectrometry. The total conductivity as a function of the film composition, temperature, and oxygen partial pressure was measured using impedance spectroscopy. The mesoporous solid solutions of CeO2-ZrO2 prepared in this work showed a higher stability against thermal ripening than both binary oxides, making them ideal model systems to study both the charge transport properties and the oxygen storage at elevated temperatures. We find that the redox properties of nanocrystalline mp-CZO thin films differ significantly from those of bulk CZO materials reported in the literature and, therefore, propose a defect chemical model of surface regions. 23111348 Reversal of efflux mediated antifungal resistance underlies synergistic activity of two monoterpenes with fluconazole. Thymol (THY) and carvacrol (CARV), the principal chemical components of thyme oil have long been known for their wide use in medicine due to antimicrobial and disinfectant properties. This study, however, draws attention to a possible synergistic antifungal effect of these monoterpenes with azole antimycotic-fluconazole. Resistance to azoles in Candida albicans involves over-expression of efflux-pump genes MDR1, CDR1, CDR2 or mutations and over-expression of target gene ERG11. The inhibition of drug efflux pumps is considered a feasible strategy to overcome clinical antifungal resistance. To put forward this approach, we investigated the combination effects of these monoterpenes and FLC against 38 clinically obtained FLC-sensitive, and eleven FLC-resistant Candida isolates. Synergism was observed with combinations of THY-FLC and CARV-FLC evaluated by checkerboard microdilution method and nature of the interactions was calculated by FICI. In addition, antifungal activity was assessed using agar-diffusion and time-kill curves. The drug efflux activity was determined using two dyes, Rhodamine6G (R6G) and fluorescent Hoechst 33342. No significant differences were observed in dye uptakes between FLC-susceptible and resistant isolates, incubated in glucose free buffer. However, a significantly higher efflux was recorded in FLC-resistant isolates when glucose was added. Both monoterpenes inhibited efflux by 70-90%, showing their high potency to block drug transporter pumps. Significant differences, in the expression levels of CDR1 and MDR1, induced by monoterpenes revealed reversal of FLC-resistance. The selectively fungicidal characteristics and ability to restore FLC susceptibility in resistant isolates signify a promising candidature of THY and CARV as antifungal agents in combinational treatments for candidiasis. 23254253 Synthesis and characterization of self-bridged silver vanadium oxide/CNTs composite and its enhanced lithium storage performance. The improvement of the electrochemical properties of electrode materials with large capacity and good capacity retention is becoming an important task in the field of lithium ion batteries (LIBs). We designed a function-oriented hybrid material consisting of silver vanadium oxide (β-AgVO(3)) nanowires modified with uniform Ag nanoparticles and multi-walled carbon nanotubes (CNTs) as a high-performance cathode material for LIBs. The Ag nanoparticles which precipitated automatically in the synthetic process act as a bridge between the β-AgVO(3) nanowires and CNTs, creating a self-bridged network structure. The Ag particles at the junction of the nanowires and CNTs facilitate electron transport from the CNTs to the nanowires, and thereby improve the electrical conductivity of the β-AgVO(3) nanowires and the composite. Moreover, the self-bridged network is hierarchically porous with a high surface area. When used as a cathode material, this composite electrode reveals high discharge capacities, excellent rate capability, and good cycling stability. The improved performance of the composite arises from its unique nanosized β-AgVO(3) nanowires with short diffusion pathway for lithium ions, efficient electron collection and transfer in the presence of Ag nanoparticles, together with excellent electrical conductivity of CNTs. 23017392 Optimization of frozen sour cherries vacuum drying process. The objective of this research was to optimize the vacuum-drying of frozen sour cherries in order to preserve health-beneficial phytochemicals, as well as textural characteristics. Investigated range of temperature was 46-74°C and, of pressure, 17-583mbar, in a new design of vacuum-dryer equipment. The total solids, a(w) value, total phenolics, vitamin C, antioxidant activity, anthocyanin content, total colour change and firmness were used as quality indicators of dried sour cherry. Within the experimental range of studied variables, the optimum conditions of 54.03°C and 148.16mbar were established for vacuum drying of sour cherry. Separate validation experiments were conducted, under optimum conditions, to verify predictions and adequacy of the second-order polynomial models. Under these optimal conditions, the predicted amount of total phenolics was 744mg CAE/100 dw, vitamin C 1.44mg/100g per dry weight (g dw), anthocyanin content 125mg/100g dw, IC(50) 3.23mg/ml, total solids 70.72%, a(w) value 0.646, total colour change 52.61 and firmness 3395.4g. The investigated parameters had a significant effect on the quality of the dried sour cherries. 23385960 Preparation and evaluation of sustained-release doxazosin mesylate pellets. Doxazosin mesylate (DXM) sustained release pellets were prepared by an extrusion-spheronization and fluid-bed coating technique. The core pellets containing DXM were prepared by extrusion-spheronization technique, and coated by a fluid-bed coater to control the release of DXM. The factors affecting to properties of pellets, such as diluent content, type and coating level of coating agents and plasticizers were studied in the present study. Polymethacrylate derivatives (Eudragit® RS PO and RL PO) were used for coating agents, and polyethylene glycol 6000 (PEG 6000), triethyl citrate (TEC) and castor oil were as plasticizers. To evaluate the properties of prepared pellets, the size of prepared pellets was investigated by sieve analysis technique and the morphology of pellets was evaluated by scanning electron microscopy. Through the dissolution test, factors that have an effect on the dissolution of the drug were evaluated. As the content ratio of microcrystalline cellulose (MCC) had increased, the dissolution was proportionally sustained. Eudragit® RS PO had more marked sustaining effect on the dissolution rate than Eudragit® RL PO, and the effect was more pronounced with the increased coating level. PEG 6000 was an appropriate plasticizer for DXM pellets, and increasing the content of PEG 6000, was also slightly decreasing the dissolution rate. 23578618 Fast determination of sulfonamides from egg samples using magnetic multiwalled carbon nanotubes as adsorbents followed by liquid chromatography-tandem mass spectrometry. A simple and effective method based on magnetic separation has been developed for the extraction of sulfonamides (SAs) from egg samples using magnetic multiwalled carbon nanotubes (MMWCNTs) as an adsorbent. The MMWCNTs were simply prepared by depositing Fe3O4 onto MWCNTs that had been previously oxidised. The extraction procedure was carried out in a single step by blending and subsequently stirring the mixture of MMWCNTs and aqueous egg samples. The SAs were first extracted as described above, adsorbed onto the MMWCNTs directly and finally analysed by liquid chromatography-tandem mass spectrometry. The limits of detection obtained are in the range of 1.4-2.8ngg(-1). The proposed method was successfully applied in determining SAs in the eggs obtained from laying hens fed with SA standards, and compared to eggs purchased from local markets. The results demonstrate that SAs were detectable in the incurred egg samples. 23642004 Revisiting the Mechanism of Neutral Hydrolysis of Esters: Water Autoionization Mechanisms with Acid or Base Initiation Pathways. The mechanism of neutral hydrolysis of ester has long been explored by theoretical studies. However, reliable theoretical calculations show that the usual bifunctional catalysis mechanism reported by different authors cannot explain the experimental kinetics. An important advance was recently reported by Gunaydin and Houk , suggesting that ions are involved in the mechanism and the process initiates by water autoionization followed by protonation of the ester (WAIA mechanism). However, this mechanism does not explain the hydrolysis of activated esters. In this work, we have used ab initio calculations, continuum solvation models and ab initio classical trajectory to support the WAIA mechanism for normal ester. In the case of activated esters, the process can also be viewed as water autoionization with formation of hydroxide ion aided by a second water moleculeacting as a general base (WAIB mechanism). This is the mechanism proposed by Jencks and Carriuolo fifty years ago. Our analysis point out that the usual method for exploring mechanisms, searching for saddle points, may not work for problems like the present one, since there are no saddle points on the reaction pathway. Rather, the formation of a pair of ions from a neutral species may have an asymptotic barrier. The approach used in this paper allows the calculation of the free energy profile and enable us to explain the mechanism and kinetics of the neutral hydrolysis of normal (methyl acetate) and activated (methyl trifluoroacetate) esters. In addition, the present study suggests that formation of a pair of ions should be always considered in reactions in aqueous solution. 23373704 Fast protein motions are coupled to enzyme H-transfer reactions. Coupling of fast protein dynamics to enzyme chemistry is controversial and has ignited considerable debate, especially over the past 15 years in relation to enzyme-catalyzed H-transfer. H-transfer can occur by quantum tunneling, and the temperature dependence of kinetic isotope effects (KIEs) has emerged as the "gold standard" descriptor of these reactions. The anomalous temperature dependence of KIEs is often rationalized by invoking fast motions to facilitate H-transfer, yet crucially, direct evidence for coupled motions is lacking. The fast motions hypothesis underpinning the temperature dependence of KIEs is based on inference. Here, we have perturbed vibrational motions in pentaerythritol tetranitrate reductase (PETNR) by isotopic substitution where all non-exchangeable atoms were replaced with the corresponding heavy isotope ((13)C, (15)N, and (2)H). The KIE temperature dependence is perturbed by heavy isotope labeling, demonstrating a direct link between (promoting) vibrations in the protein and the observed KIE. Further we show that temperature-independent KIEs do not necessarily rule out a role for fast dynamics coupled to reaction chemistry. We show causality between fast motions and enzyme chemistry and demonstrate how this impacts on experimental KIEs for enzyme reactions. 23229552 PHF6 regulates cell cycle progression by suppressing ribosomal RNA synthesis. Mutation of PHF6, which results in the X-linked mental retardation disorder Börjeson-Forssman-Lehmann syndrome, is also present in about 38% of adult T-cell acute lymphoblastic leukemias and 3% of adult acute myeloid leukemias. However, it remains to be determined exactly how PHF6 acts in vivo and what functions of PHF6 may be associated with its putative tumor suppressor function. Here, we demonstrate that PHF6 is a nucleolus, ribosomal RNA promoter-associated protein. PHF6 directly interacts with upstream binding factor (UBF) through its PHD1 domain and suppresses ribosomal RNA (rRNA) transcription by affecting the protein level of UBF. Knockdown of PHF6 impairs cell proliferation and arrests cells at G(2)/M phase, which is accompanied by an increased level of phosphorylated H2AX, indicating that PHF6 deficiency leads to the accumulation of DNA damage in the cell. We found that increased DNA damage occurs at the ribosomal DNA (rDNA) locus in PHF6-deficient cells. This effect could be reversed by knocking down UBF or overexpressing RNASE1, which removes RNA-DNA hybrids, suggesting that there is a functional link between rRNA synthesis and genomic stability at the rDNA locus. Together, these results reveal that the key function of PHF6 is involved in regulating rRNA synthesis, which may contribute to its roles in cell cycle control, genomic maintenance, and tumor suppression. 23305550 Plasmonic coupling and long-range transfer of an excitation along a DNA nanowire. We demonstrate an excitation transfer along a fluorescently labeled dsDNA nanowire over a length of several micrometers. Launching of the excitation is done by exciting a localized surface plasmon mode of a 40 nm silver nanoparticle by 800 nm femtosecond laser pulses via two-photon absorption. The plasmonic mode is subsequently coupled or transformed to excitation in the nanowire in contact with the particle and propagated along it, inducing bleaching of the dyes on its way. In situ as well as ex situ fluorescence microscopy is utilized to observe the phenomenon. In addition, transfer of the excitation along the nanowire to another nanoparticle over a separation of 5.7 μm was clearly observed. The nature of the excitation coupling and transfer could not be fully resolved here, but injection of an electron into the DNA from the excited nanoparticle and subsequent coupled transfer of charge (Dexter) and delocalized exciton (Frenkel) is the most probable mechanism. However, a direct plasmonic or optical coupling and energy transfer along the nanowire cannot be totally ruled out either. By further studies the observed phenomenon could be utilized in novel molecular systems, providing a long-needed communication method between molecular devices. 23562534 Increased dissolution and oral absorption of itraconazole/Soluplus extrudate compared with itraconazole nanosuspension. The purpose of this article was to compare the in vitro and in vivo profiles of itraconazole (ITZ) extrudates and nanosuspension separately prepared by two different methods. And it was proved truly to form nanocrystalline and amorphous ITZ characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) analysis, Fourier transform infrared spectrum (FTIR), transmission electron microscope (TEM), and scanning electron microscope (SEM). The release of ITZ/Soluplus solid dispersions with amorphous ITZ was almost complete while only 40% release was obtained with ITZ nanocrystals. The amorphous state need not to cross over the crystal lattice energy upon dissolution while the crystalline need to overcome it. In the in vivo assay, the AUC(0-t) and Cmax of ITZ/Soluplus were 6.9- and 11.6-time higher than those of pure ITZ. The formulation of the extrudate had an AUC(0-t) and Cmax similar to those of ITZ and also OH-ITZ compared with the commercial capsule (Sporanox®). The relative bioavailability values with their 95% confidence limit were calculated to be 98.3% (92.5-104.1%) and 101.3% (97.9-104.1%), respectively. The results of this study showed increased dissolution and bioavailability of the solid dispersion of Soluplus-based carrier loading ITZ prepared by HME compared with the ITZ nanosuspension prepared by wet milling. 23542441 Cell adhesion and homeostatic synaptic plasticity. At synapses, pre- and post-synaptic cells get in direct contact with each other via cell adhesion molecules (CAMs). Several CAMs have been identified at the neuromuscular junction and at central synapses, where they regulate synaptic strength, by recruiting scaffolding proteins, neurotransmitter receptors and synaptic vesicles in response to the binding of counter-receptors across the synaptic cleft. Many synapses are also surrounded by astrocytic processes and embedded in conspicuous extracellular matrix (ECM). It is now widely recognized that astrocytes play a central role in regulating the synaptic machinery by exchanging information with the neuronal elements via diffusible molecules and direct physical interactions; this has lead to the concept of the 'tri-partite synapse'. More recently, the term 'tetra-partite synapse' has been introduced to underlie the importance of ECM in shaping synaptic function by mediating interaction and signaling between neurons and astrocytes. Here, we will review how this integrated view of the synapse can help us understand homeostatic synaptic plasticity at the neuromuscular junction and in the central nervous system. We will explore how synaptic CAMs regulate two forms of homeostatic plasticity: (i) postsynaptic scaling of synaptic currents to counteract changes in neuronal network activity and (ii) the compensatory modulation of presynaptic neurotransmitter release in response to changes in postsynaptic efficacy. We will discuss recent findings on activity-dependent trans-synaptic signaling events and the role of cell adhesion in the feedback control of network activity. This article is part of a Special Issue entitled 'Homeostatic Plasticity'. 23132773 An ion-induced low-oil-adhesion organic/inorganic hybrid film for stable superoleophobicity in seawater. Superoleophobicity under seawater: An ion-induced low-oil-adhesion film with underwater superoleophobicity is prepared by a typical layer-by-layer (LBL) method. Under an artificial marine environment with high ion-strength, the prepared polyelectrolytes/AuNPs hybrid film becomes rougher and possesses a higher water ratio, which in turn endows the film with superoleophobicity and low underwater oil adhesion. The as-prepared film shows excellent environmental stability in artificial seawater. This study provides a new strategy for controlling the self-cleaning property and accelerating the development of stable underwater superoleophobic films. 23561220 On the origin of sharp peaks in the X-ray diffraction patterns of xanthan powders. A series of xanthans containing different levels of the charged group pyruvate has been examined. The X-ray diffraction patterns of the powders of these materials had different levels of a sharp pattern superimposed on an amorphous background. As the moisture content increased so the intensity of the sharp pattern increased up to a level between 20% and 40% moisture content where the sharp pattern disappeared. X-ray diffraction pattern identification software and an inorganic X-ray diffraction database showed the origin of the sharp peaks to be due to sodium sulphate polymorphs. The behaviour of the xanthans was thought to be due to the differences in charge on the molecule; however, the increase in the crystalline component observed with increased amounts of water was unexpected. The possibility of the drying of samples was considered but the interplay between ions, the charged polymer and the water present was considered necessary to more closely describe the results. 23318758 GC-MS analysis of Eucalyptus citriodora leaf extract and its role on the dietary supplementation in transgenic Drosophila model of Parkinson's disease. The role of Eucalyptus citriodora L. leaf extract was studied on the transgenic Drosophila model of flies expressing normal human alpha synuclein (h-αS) in the neurons. These flies exhibit locomotor dysfunction as the age progresses. The leaf extract was prepared in acetone and was subjected to GC-MS analysis. The GC-MS analysis revealed the presence of nine major compounds. E. citriodora extract at final concentration of 0.25, 0.50 and 1.0μl/ml was supplemented with the diet and the flies were allowed to feed for 21days. The effect of extract was studied on the climbing ability and the oxidative stress on the PD model Drosophila expressing normal human alpha synuclein (h-αS) in the neurons. The supplementation of 0.25, 0.50 and 1.0μl/ml of E. citriodora extract showed a dose dependent significant delay in the loss of climbing ability and reduction in the oxidative stress in the brain of PD model flies. The results also support the utility of this model in studying PD symptoms. 22989414 Withaferin A-stimulated Ca2+ entry, ceramide formation and suicidal death of erythrocytes. Withaferin A, a triterpenoid component from Withania somnifera, counteracts malignancy, an effect attributed to stimulation of apoptosis. Withaferin A is partially effective through induction of oxidative stress, altered gene expression and mitochondrial depolarization. Erythrocytes lack mitochondria and nuclei but may enter apoptosis-like eryptosis, a suicidal cell death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the cell surface. Triggers of eryptosis include increase of cytosolic Ca(2+)-activity [Ca(2+)](i) following activation of oxidant-sensitive Ca(2+)-permeable cation channels, ceramide formation and/or ATP-depletion. The present study explored, whether withaferin A triggers eryptosis. To this end, [Ca(2+)](i) was estimated from Fluo3-fluorescence, cell volume from forward scatter, phosphatidylserine exposure from annexin-V-binding, hemolysis from hemoglobin release, oxidative stress from DCFDA-fluorescence and ceramide abundance utilizing antibodies. A 48 h exposure to withaferin A significantly decreased forward scatter (at ≥ 10 μM withaferin concentration) and increased [Ca(2+)](i) (≥ 5 μM), ROS-formation (≥ 10 μM) ceramide-formation ( ≥ 10 μM) as well as annexin-V-binding ( ≥ 5 μM). Withaferin A treatment was followed by slight but significant increase of hemolysis. Extracellular Ca(2+) removal, amiloride, and the antioxidant N-acetyl-l-cysteine significantly blunted withaferin A-triggered annexin-V-binding. The present observations reveal that withaferin A triggers suicidal erythrocyte death despite the absence of gene expression and key elements of apoptosis such as mitochondria. 23142599 Inhibition of vitellogenin gene induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin is mediated by aryl hydrocarbon receptor 2 (AHR2) in zebrafish (Danio rerio). Vitellogenins are hepatically derived yolk-protein precursors required for oogenesis in all oviparous teleosts. Altered gene-regulation of vitellogenesis by environmental contaminants can have profound effects on reproductive success, and ultimately population sustainability. To better understand chemical effects on vitellogenin gene regulation, we tested the hypothesis that activation of the aryl hydrocarbon receptor 2 (AHR2) by dioxin inhibits the estrogen receptor pathway regulation of 3 vitellogenin genes (vtg1-3) in vivo, using zebrafish (Danio rerio) as a model teleost. Using an embryo-larval bioassay, embryos were either treated with 1000 pptr (parts-per-trillion, pg/mL) 17α-ethynylestradiol (EE2) alone from 6h post fertilization (hpf) to 4 days post fertilization (dpf), or pre-treated with dioxin (4-5 hpf) prior to EE2. Pre-treatment with 400 pptr 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) or 1,2,3,7,8-pentachlorodibenzo-p-dioxin inhibited the EE2 induction of vtg1, vtg2 and vtg3 by >95% (p≤0.05). In comparison, a splice-blocking AHR2 morpholino used to down-regulate ahr2 expression significantly reduced the inhibition of vtg1, vtg2 and vtg3 by 400 pptr 2,3,7,8-TCDD (20.7-27.4% rescue). These studies demonstrate that 2,3,7,8-TCDD directly inhibits the vitellogenin pathway in vivo through activation of the AHR2. This work provides evidence for AHR2 dependent cross-talk inhibition of vitellogenin genes and offers insight into anti-estrogenic reproductive effects observed in oviparous species exposed to AHR agonist contaminants. 23386702 Reversible inhibition of human carboxylesterases by acyl glucuronides. Carboxylesterases hydrolyze esters, amides, and thioesters to produce carboxylic acids and resulting alcohols, amines, and thiols, respectively. Uridine 5'-diphosphate- glucuronosyltransferases are colocalized with carboxylesterases and have the potential to further metabolize carboxylic acids to acyl glucuronides, but it is currently unknown if acyl glucuronides, being esters, also interact with carboxylesterases. Objective: This study explores the ability of acyl glucuronides to act as substrates or inhibitors of human carboxylesterases 1 (hCES1) and 2 (hCES2). Methods: The stability of six acyl glucuronides in the presence of hCES1, hCES2, and buffer alone (100 mM potassium phosphate, pH 7.4, 37°C) were investigated. Reversible inhibition of 4-nitrophenyl acetate hydrolysis by the acyl glucuronides was also studied. Diclofenac-β-d-glucuronide was used to explore potential time-dependent inactivation. Results: The chemical stability half-life values for CGP 47292-β-d-glucuronide, diclofenac-β-d-glucuronide, (R)-naproxen-β-d-glucuronide, (S)-naproxen-β-d-glucuronide, ibuprofen-β-d-glucuronide (racemic), clopidogrel-β-d-glucuronide, and valproate-β-d-glucuronide were found to be 0.252, 0.537, 0.996, 1.77, 3.67, 5.02, and 15.2 hours, respectively. Diclofenac-β-d-glucuronide, clopidogrel-β-d-glucuronide, ibuprofen-β-d-glucuronide, (R)-naproxen-β-d-glucuronide, and (S)-naproxen-β-d-glucuronide selectively inhibited hCES1, with Ki values of 4.32 ± 0.47, 24.8 ± 4.2, 355 ± 38, 468 ± 21, 707 ± 64 µM, respectively, but did not significantly inhibit hCES2. Valproate-β-d-glucuronide and CGP 47292-β-d-glucuronide did not inhibit either hCES. Time-dependent inactivation of hCES1 by diclofenac-β-d-glucuronide was not observed. Lastly, both hCES1 and hCES2 were shown not to catalyze the hydrolysis of the acyl glucuronides studied. Conclusion: Drug-drug interaction studies may be warranted for drugs that metabolize to acyl glucuronides due to the potential inhibition of hCESs. 23417870 Polymers for the cell-specific immobilisation of megakaryocytic cell lines. Primary human megakaryocytes, the precursor cells of platelets, are difficult to collect and cultivate. Polymers that enrich these cells without affecting their regulation or function are of interest for basic research as well as for cord blood transplantation purposes since co-transplantation of enriched megakaryocyte concentrates increase the success of stem cell therapy. Herein, polymer microarrays were used for the discovery of substrates for MEG-01 cells, with five polymers identified which selectively bound cells of the megakaryocytic lineage. Flow cytometry and miRNA profiling revealed that immobilisation had only a minor effect on the cellular maturation status, making the identified substrates potential candidates for concentrating megakaryocytes from patients prior to transplantation. 23311532 Surface and tribological behaviors of the bioinspired polydopamine thin films under dry and wet conditions. Dopamine is a "sticky" biomolecule containing the typical functional groups of mussel adhesive proteins. It can self-polymerize into a nanoscale thin film on various surfaces. We investigated the surface, adhesion, friction, and cracking properties of polydopamine (PDA) thin films for their effective transfer to functional devices and biocompatible coatings. A series of surface characterizations and mechanical tests were performed to reveal the static and dynamic properties of PDA films coated on glass, polydimethylsiloxane (PDMS), and epoxy. We found that PDA films are highly hydrated under wet conditions because of their porous membrane-like nanostructures and hydrophilic functional groups. Upon dehydration, the films form cracks when they are coated on soft substrates due to internal stresses and the large mismatch in elastic modulus. The adhesive pull-off force or the effective work of adhesion increased with the contact time, suggesting dynamic interactions at the interface. A significant decrease in friction forces in water was observed on all three material surfaces coated with PDA; thus, the film might serve as a water-based lubrication coating. We attributed the different behavior of PDA films in air and in water to its hydration effects. These research findings provide insight into the stability, mechanical, and adhesive properties of the PDA films, which are critical for their applications. 22348222 Chemical composition and antibacterial activity of the volatile oil from seeds of Artemisia annua L. from Iran. The composition of essential oil of the seeds of Artemisia annua L. was analysed by GC-MS. Overall, 16 volatile components were identified on the basis of their mass spectra characteristics and retention indices representing 95.5% of the total oil. Trans-3(10)-caren-4-ol (22.3%), artemisia ketone (18.6%), 1,8-cineole (14.9%), δ-selinene (13.0%) and α-pinene (8.2%) were the major compounds. Oxygenated monoterpenes were the main compounds with 51.6% followed by sesquiterpene hydrocarbons (13.3%), monoterpene hydrocarbons (9.9%) and other compounds (8.3%). The essential oil was highly active against Escherichia coli and Enterococcus faecalis. 23565644 Human Precision-Cut Liver Slices as an ex Vivo Model to Study Idiosyncratic Drug-Induced Liver Injury. Idiosyncratic drug-induced liver injury (IDILI) is a major problem during drug development and has caused drug withdrawal and black-box warnings. Because of the low concordance of the hepatotoxicity of drugs in animals and humans, robust screening methods using human tissue are needed to predict IDILI in humans. According to the inflammatory stress hypothesis, the effects of inflammation interact with the effects of a drug or its reactive metabolite, precipitating toxic reactions in the liver. As a follow-up to our recently published mouse precision-cut liver slices model, an ex vivo model involving human precision-cut liver slices (hPCLS), co-incubated for 24 h with IDILI-related drugs and lipopolysaccharide (LPS), was developed to study IDILI mechanisms related to inflammatory stress in humans and to detect potential biomarkers. LPS exacerbated the effects of ketoconazole and clozapine toxicity but not those of their non-IDILI-related comparators, voriconazole and olanzapine. However, the IDILI-related drugs diclofenac, carbamazepine, and troglitazone did not show synergistic toxicity with LPS after incubation for 24 h. Co-incubation of ketoconazole and clozapine with LPS decreased the levels of glutathione in hPCLS, but this was not seen for the other drugs. All drugs affected LPS-induced cytokine release, but interestingly, only ketoconazole and clozapine increased the level of LPS-induced TNF release. Decreased levels of glutathione and cysteine conjugates of clozapine were detected in IDILI-responding livers following cotreatment with LPS. In conclusion, we identified ketoconazole and clozapine as drugs that exhibited synergistic toxicity with LPS, while glutathione and TNF were found to be potential biomarkers for IDILI-inducing drugs mediated by inflammatory stress. hPCLS appear to be suitable for further unraveling the mechanisms of inflammatory stress-associated IDILI. 23409840 Novel HldE-K Inhibitors Leading to Attenuated Gram Negative Bacterial Virulence. We report here the optimization of an HldE kinase inhibitor to low nanomolar potency, which resulted in the identification of the first reported compounds active on selected E. coli strains. One of the most interesting candidates, compound 86, was shown to inhibit specifically bacterial LPS heptosylation on efflux pump deleted E. coli strains. This compound did not interfere with E. coli bacterial growth (MIC > 32 μg/mL) but sensitized this pathogen to hydrophobic antibiotics like macrolides normally inactive on Gram-negative bacteria. In addition, 86 could sensitize E. coli to serum complement killing. These results demonstrate that HldE kinase is a suitable target for drug discovery. They also pave the way toward novel possibilities of treating or preventing bloodstream infections caused by pathogenic Gram negative bacteria by inhibiting specific virulence factors. 23079287 Ageing and gut microbes: perspectives for health maintenance and longevity. The ageing process affects the human gut microbiota phylogenetic composition and its interaction with the immune system. Age-related gut microbiota modifications are associated with immunosenescence and inflamm-ageing in a sort of self-sustaining loop, which allows the placement of gut microbiota unbalances among both the causes and the effects of the inflamm-ageing process. Even if, up to now, the link between gut microbiota and the ageing process is only partially understood, the gut ecosystem shows the potential to become a promising target for strategies able to contribute to the health status of older people. In this context, the consumption of pro/prebiotics may be useful in both prevention and treatment of age-related pathophysiological conditions, such as recovery and promotion of immune functions, i.e. adjuvant effect for influenza vaccine, and prevention and/or alleviation of common "winter diseases", as well as constipation and Clostridium difficile-associated diarrhoea. Moreover, being involved in different mechanisms which concur in counteracting inflammation, such as down-regulation of inflammation-associated genes and improvement of colonic mucosa conditions, probiotics have the potentiality to be involved in the promotion of longevity. 23335030 Room-temperature ferromagnetism in ZnO-encapsulated 1.9 nm FePt3 nanoparticle-composite thin films with giant interfacial anisotropy. As synthesized 1.9-nm FePt3 nanoparticles are superparamagnetic at room temperature. Coating those nanoparticles with ZnO renders them permanently ferromagnetic with coercivity field of 650 Oe at room temperature. First-principles calculations indicate that giant interfacial anisotropy, induced by the strong spin-orbit interaction of enhanced orbit momentum of Fe, overcomes the superparamagnetic limit, leading to exceptional room-temperature permanent ferromagnetism. The findings are important for the understanding of the origin of permanent ferromagnetism at ultrasmall size and critical for ultrahigh density recording and information processing. 23551255 Ion Distributions at the Water/1,2-Dichloroethane Interface: Potential of Mean Force Approach to Analyzing X-ray Reflectivity and Interfacial Tension Measurements. We present X-ray reflectivity and interfacial tension measurements of the electrified liquid/liquid interface between two immiscible electrolyte solutions for the purpose of understanding the dependence of interfacial ion distributions on the applied electric potential difference across the interface. The aqueous phase contains alkali-metal chlorides, including LiCl, NaCl, RbCl, or CsCl, and the organic phase is a 1,2-dichloroethane solution of bis(triphenylphosphor anylidene) ammonium tetrakis(pentafluorophenyl)borate (BTPPATPFB). Selected data for a subset of electric potential differences are analyzed to determine the potentials of mean force for Li(+), Rb(+), Cs(+), BTPPA(+), and TPFB(-). These potentials of mean force are then used to analyze both X-ray reflectivity and interfacial tension data measured over a wide range of electric potential differences. Comparison of X-ray reflectivity data for strongly hydrated alkali-metal ions (Li(+) and Na(+)), for which ion pairing to TPFB(-) ions across the interface is not expected, to data for weakly hydrated alkali-metal ions (Rb(+) and Cs(+)) indicates that the Gibbs energy of adsorption due to ion pairing at the interface must be small (<1 kBT per ion pair) for both the CsCl and RbCl samples. This paper demonstrates the applicability of the Poisson-Boltzmann potential of mean force approach to the analysis of X-ray reflectivity measurements that probe the nanoscale ion distribution and the consequences of these underlying distributions for thermodynamic studies, such as interfacial tension measurements, that yield quantities related to the integrated ion distribution. 23500546 Angiotensin II upregulates KCa3.1 channels and stimulates cell proliferation in rat cardiac fibroblasts. The proliferation of cardiac fibroblasts is implicated in the pathogenesis of myocardial remodeling and fibrosis. Intermediate-conductance calcium-activated K(+) channels (KCa3.1 channels) have important roles in cell proliferation. However, it is unknown whether angiotensin II (Ang II), a potent profibrotic molecule, would regulate KCa3.1 channels in cardiac fibroblasts and participate in cell proliferation. In the present study, we investigated whether KCa3.1 channels were regulated by Ang II, and how the channel activity mediated cell proliferation in cultured adult rat cardiac fibroblasts using electrophysiology and biochemical approaches. It was found that mRNA, protein, and current density of KCa3.1 channels were greatly enhanced in cultured cardiac fibroblasts treated with 1μM Ang II, and the effects were countered by the angiotensin type 1 receptor (AT1R) blocker losartan, the p38-MAPK inhibitor SB203580, the ERK1/2 inhibitor PD98059, and the PI3K/Akt inhibitor LY294002. Ang II stimulated cell proliferation and the effect was antagonized by the KCa3.1 blocker TRAM-34 and siRNA targeting KCa3.1. In addition, Ang II-induced increase of KCa3.1 expression was attenuated by transfection of activator protein-1 (AP-1) decoy oligodeoxynucleotides. These results demonstrate for the first time that Ang II stimulates cell proliferation mediated by upregulating KCa3.1 channels via interacting with the AT1R and activating AP-1 complex through ERK1/2, p38-MAPK and PI3K/Akt signaling pathways in cultured adult rat cardiac fibroblasts. 23259819 Novel strategy for preparation of graphene-Pd, Pt composite, and its enhanced electrocatalytic activity for alcohol oxidation. As advanced electrodes for direct alcohol fuel cells, graphene-Pd and graphene-Pt composites with a trace of SnO(2) have been successfully synthesized by a modified electroless plating technique. The surface of graphene oxide is first sensitized by Sn(2+) ions, and subsequently, Pd or Pt nanoparticles are deposited on the surface of graphene oxide. Finally, graphene oxide was reduced to graphene by further adding NaBH(4). Compared to other carbon-(e.g., Vulcan XC-72R) supported Pd and Pt, the resultant graphene-Pd and Pt composites exhibit better electrocatalytic activity and long-term stability toward alcohol electrooxidation. Additionally, a trace amount of SnO(2) formed around active catalysts may also be beneficial to the enhancement of electrochemical activity. 23497907 Thermal degradation kinetics of xanthophylls from blood orange in model and real food systems. Thermal degradation kinetics of the major blood orange xanthophylls (cis-violaxanthin, lutein, β-cryptoxanthin, zeaxanthin and cis-antheraxanthin) were investigated at 45, 60, 75, and 90°C in real juice and three model systems formulated to evaluate the impact of xanthophyll form (esterified or free) and pH (acid or neutral). Xanthophylls were monitored by HPLC-DAD and kinetic parameters were identified by non-linear regression. A second order model best fitted the degradation curves of xanthophylls. All degradation rates were the lowest in real juice. Esterified forms were more stable than were the free forms. In all acidic media, β-cryptoxanthin exhibited the lowest degradation rates followed by lutein and zeaxanthin. In comparison, the epoxy carotenoids cis-violaxanthin and cis-antheraxanthin degraded around 3-fold faster in their esterified form. In their free form, cis-antheraxanthin degraded 30-fold faster while cis-violaxanthin instantaneously disappeared because of the isomerisation of its 5,6-epoxy groups into 5,8-epoxy. By contrast, in neutral medium, free epoxy-xanthophylls were about 2-fold more stable than were the free hydroxy xanthophylls lutein, zeaxanthin and β-cryptoxanthin. Kinetic behaviours of xanthophylls were closely dependent on their chemical structures. 23297716 Essential oils of Thymus leucospermus Hartvig, a Greek endemic rich in phenolic monoterpenes. Thymus leucospermus Hartvig is a Greek endemic species of Section Teucrioides Jalas. The essential oils obtained from five populations growing wild in the National Park of Northern Pindhos (NW Greece) were studied. The oil content ranged between 1.1 and 2.0 mL per 100 g of dry plant weight. The oils were particularly rich in phenolic monoterpenes: they had a high thymol (64.7-92.0%) or carvacrol (93.4%) content, whereas in one of the oils considerable amount of both compounds was found (thymol 61.6% and carvacrol 26.4%). Our results show that T. leucospermus is a high-quality thyme species, with respect to both oil content and composition. 23454532 Nonclassical antifolates, part 3: Synthesis, biological evaluation and molecular modeling study of some new 2-heteroarylthio-quinazolin-4-ones. A new series of 2-heteroarylthio-6-substituted-quinazolin-4-one analogs was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 21, 25, and 39 proved to be active DHFR inhibitors with IC50 range of 0.3-0.8 μM. Compounds 25, 28, 33, 35 and 36 showed broad spectrum antimicrobial activity comparable to the known antibiotic gentamicin. Compound 29 showed broad spectrum antitumor activity toward several tumor cell lines with GI values range of 25.8-41.2%. Molecular modeling studies concluded that recognition with key amino acid Arg38 and Lys31 are essential for binding and biological activities. Flexible alignment; electrostatic and hydrophobic mappings revealed that the obtained model could be useful for the development of new DHFR inhibitors. 23458495 pH-Dependent Aggregation and Disaggregation of Native β-Lactoglobulin in Low Salt. The aggregation of β-lactoglobulin (BLG) near its isoelectric point was studied as a function of ionic strength and pH. We compared the behavior of native BLG with those of its two isoforms, BLG-A and BLG-B, and with that of a protein with a very similar pI, bovine serum albumin (BSA). Rates of aggregation were obtained through a highly precise and convenient pH/turbidimetric titration that measures transmittance to ±0.05 %T. A comparison of BLG and BSA suggests that the difference between pHmax (the pH of the maximum aggregation rate) and pI is systematically related to the nature of protein charge asymmetry, as further supported by the effect of localized charge density on the dramatically different aggregation rates of the two BLG isoforms. Kinetic measurements including very short time periods show well-differentiated first and second steps. BLG was analyzed by light scattering under conditions corresponding to maxima in the first and second steps. Dynamic light scattering (DLS) was used to monitor the kinetics, and static light scattering (SLS) was used to evaluate the aggregate structure fractal dimensions at different quench points. The rate of the first step is relatively symmetrical around pHmax and is attributed to the local charges within the negative domain of the free protein. In contrast, the remarkably linear pH dependence of the second step is related to the uniform reduction in global protein charge with increasing pH below pI, accompanied by an attractive force due to surface charge fluctuations. 23258565 From the bottom up: dimensional control and characterization in molecular monolayers. Self-assembled monolayers are a unique class of nanostructured materials, with properties determined by their molecular lattice structures, as well as the interfaces with their substrates and environments. As with other nanostructured materials, defects and dimensionality play important roles in the physical, chemical, and biological properties of the monolayers. In this review, we discuss monolayer structures ranging from surfaces (two-dimensional) down to single molecules (zero-dimensional), with a focus on applications of each type of structure, and on techniques that enable characterization of monolayer physical properties down to the single-molecule scale. 23481676 Cytotoxic and Anti-Inflammatory Eunicellin-Based Diterpenoids from the Soft Coral Cladiella krempfi. Five new eunicellin-based diterpenoids, krempfielins E-I (1-5) and seven known compounds (6-12) were isolated from the organic extract of a Taiwanese soft coral Cladiella krempfi. The structures of the new metabolites were elucidated on the basis of extensive spectroscopic analysis. Metabolites 5, 6, 10 and 12 were shown to exhibit cytotoxicity against a limited panel of cancer cell lines. Furthermore, compounds 6 and 10 could potently inhibit the accumulation of the pro-inflammatory iNOS protein, and 6 and 12 could significantly reduce the expression of COX-2 protein in LPS-stimulated RAW264.7 macrophage cells. 23561209 Evolution of the aromatic profile in Garnacha Tintorera grapes during raisining and comparison with that of the naturally sweet wine obtained. The postharvest dehydration is one of the most important steps in obtaining a high quality naturally sweet wine and it can play an important role in modulating the production and the release of volatile compounds. However, only a few studies have analysed the changes in the free and bound volatile compounds of grapes throughout the process. In this work, GC-MS was applied to determine the aromatic composition of Garnacha Tintorera grapes subjected to off-vine dehydration or raisining at several points during the process. The total water loss in 83days was about 62% and the sugar concentration rose from 225 to 464g/L. Within the free volatile compounds, isoamyl alcohols, benzaldehyde and guaiacol registered the largest increase above the concentration effect due to water loss; while within the bound volatile compounds were isoamyl alcohols, ethyl vanillate and benzoic acid. The aromatic profile of the raisins obtained were mainly caramelised, floral, phenolic and burned. 23256721 Stem cell therapy in chronic obstructive pulmonary disease. Seeking the prometheus effect. Chronic obstructive pulmonary disease is characterized by dramatic alterations in lung architecture associated to an exaggerated inflammatory process, alveolar epithelial cell apoptosis, endothelial dysfunction and extracellular matrix destruction due to a protease and anti-protease imbalance. In addition a significant inflammatory spillover into systemic circulation has been suggested to be responsible for a wide range of fatal comorbidities. In view of the current disappointing status of available pharmaceutical agents, there is an urgent need for alternative more effective therapeutic approaches that will fulfill the unmet need of modulating both local and systemic inflammation and at the same time accelerate alveolar epithelial and endothelial turnover intervening into disease natural course and not only relieving patient's symptoms. Regenerative medicine based on stem cells properties represents one promising option with several fruitful therapeutic applications in patients with COPD. Nevertheless, despite relative enthusiasm arising from experimental data, application of stem cell therapy in the clinical setting has been severely hampered by several safety concerns arising from the major lack of knowledge on the fate of exogenously administrated stem cells within the COPD lung as well as the mechanisms regulating activation of resident progenitor cells. The above evidence coupled with the rather disappointing results emerging from the first stem cell clinical trials in COPD patients underline the need for careful study design by setting realistic goals to assess efficacy such as biomarkers that reflect clinically inconspicuous alterations of the disease molecular phenotype before rigid conclusions can be safely drawn. 23278396 Targeted approaches to triple-negative breast cancer: current practice and future directions. Triple-negative breast cancer (TNBC), that is breast cancer which stains negatively at immunohistochemistry for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2), comprises a particularly aggressive subtype of breast cancer, with high rate of early local and distant relapse. TNBC have demonstrated sensitivity to cytotoxic treatment regimens, but in the absence of HER2, ER and PR there is no benefit from hormonal therapy or trastuzumab. The lack of known specific molecular targets has promoted abundant research in order to find possible "vulnerabilities" in TNBC and the evaluation of novel biomarkers overcoming the traditional approach based on hormonal receptors and HER2-targeted therapy is one of the priorities in breast cancer research. Drugs under investigation can be broadly subdivided into four groups: (1) Agents that create DNA damage (i.e. cisplatin, cyclophosphamide); (2) Agents that inhibit poly (ADP-ribose) polymerase (PARP); (3) Tyrosin-kinase inhibitors and monoclonal antibodies; (4) Agents that inhibit downstream signals. Several preclinical and early phase clinical trials for the treatment or management of patients with triple-negative breast tumors are underway. Nonetheless, so far the major issue to deal with when trying to provide evidence for TNBC is the small numbers of the sample in the clinical studies and the retrospective nature of most of them. Future large studies could help in defining optimal treatment strategies for TNBC, both in the advanced setting as well as in the (neo) adjuvant setting. 23123225 β-Asarone, an active principle of Acorus calamus rhizome, inhibits morphogenesis, biofilm formation and ergosterol biosynthesis in Candida albicans. Anti-Candida potential of Acorus calamus rhizome and its active principle, β-asarone, was evaluated against the human fungal pathogen, Candida albicans. β-Asarone exhibited promising growth inhibitory activity at 0.5mg/ml and it was fungicidal at 8 mg/ml. Time dependant kill curve assay showed that MFC of β-asarone was highly toxic to C. albicans, killing 99.9% inoculum within 120 min of exposure. β-Asarone caused significant inhibition of C. albicans morphogenesis and biofilm development at sub-inhibitory concentrations. Our data indicate that the growth inhibitory activity of β-asarone might be through inhibition of ergosterol biosynthesis. Hemolytic assay showed that β-asarone is non-toxic, even at concentrations approaching MIC value. Our results suggest that β-asarone may be safe as a topical antifungal agent. 23550028 2-Hydroxy-3-methylanthraquinone from Hedyotis diffusa Willd induces apoptosis in human leukemic U937 cells through modulation of MAPK pathways. The herb of Hedyotis diffusa Willd (H. diffusa Willd), an annual herb distributed in northeastern Asia, has been known as a traditional oriental medicine for the treatment of cancer. Recently, Chinese researchers have discovered that two anthraquinones isolated from a water extract of H. diffusa Willd showed apoptosis-inducing effects against cancer cells. However, the cellular and molecular mechanisms responsible for this phenomenon are poorly understood. The current study determines the role of mitogen-activated protein kinases (MAPK) in human leukemic U937 cells apoptosis induced by 2-hydroxy-3-methylanthraquinone from H. diffusa. Our results showed that 2-hydroxy-3-methylanthraquinone decreased phosphorylation-ERK1/2 (p-ERK1/2), and increased p-p38MAPK, but did not affect expressions of p-JNK1/2 in U937 cells. Moreover, treatment of U937 cells with 2-hydroxy-3-methylanthraquinone resulted in activation of caspase-3. Furthermore, PD98059 (ERK1/2 inhibitor) significantly enhanced 2-hydroxy-3-methylanthraquinone-induced apoptosis in U937 cells, whereas caspase-3 inhibitor or SB203580 (p-p38MAPK inhibitor), decreased apoptosis in U937 cells. Taken together, our study for the first time suggests that 2-hydroxy-3-methylanthraquinone is able to enhance apoptosis of U937 cells, at least in part, through activation of p-p38MAPK and downregulation of p-ERK1/2. Moreover, the triggering of caspase-3 activation mediated apoptotic induction. 23590729 pH-Responsive Aggregation States of Chiral Polymerizable Amphiphiles from l-Tyrosine and l-Phenyl Alanine in Water. Sodium salts of maleamic acid derivatives of lauryl ester of tyrosine (MTNa) and phenyl alanine (MPNa) in water exhibited strong pH-responsive behaviors of viscosity and specific conductivity that originate from the concentration and pH dependence of their aggregation states. The aggregates were characterized by a novel spin-probe-partitioning electron paramagnetic resonance (SPPEPR) method and dynamic light scattering (DLS). Results of high-precision fitting of the second-harmonic EPR spectra of the small spin probe di-tert-butyl nitroxide (DTBN) in these aggregates together with viscosity, conductivity, and DLS showed that, at pH ∼ 7.54, MTNa formed micelles and MPNa vesicles and MTNa exhibited a pH-induced micelle to vesicle transition as pH was lowered toward 6. MTNa, at pH ∼ 7.54, formed small micelles at low concentrations that transformed to long worm-like micelles for concentrations ≥ 0.05 M, accompanied by a 30-fold increase in solution viscosity. The hydrodynamic radii from DLS confirmed the presence of small micellar aggregates of radius ∼ 2 nm in MTNa at pH ∼ 7.54 at the lower concentrations, with coexisting micelles (∼2 nm) and vesicles (∼50 nm) at pH near 6.5, vesicles (radii ∼ 70 nm) at pH near 6, and large vesicles (85 nm) in MPNa at pH ∼ 7.60. Both MTNa and MPNa precipitated upon reduction of pH below 6 and below 7, respectively. The rate of transfer of DTBN between the aqueous phase and the aggregate was calculated from the high-field Lorentzian linewidths of the electron paramagnetic resonance (EPR) spectra. The activation energy for the transfer determined from the temperature dependence of the rate of transfer is 12.7 kJ/mol for MTNa vesicles (pH ∼ 6) and 20.6 ± 1.3 kJ/mol for MPNa (pH ∼ 7.60). The pH-induced transformations were reversible. 23562063 The design and synthesis of a potent glucagon receptor antagonist with favorable physicochemical and pharmacokinetic properties as a candidate for the treatment of type 2 diabetes mellitus. A novel and potent small molecule glucagon receptor antagonist for the treatment of diabetes mellitus is reported. This candidate, (S)-3-[4-(1-{3,5-dimethyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}butyl)benzamido]propanoic acid, has lower molecular weight and lipophilicity than historical glucagon receptor antagonists, resulting in excellent selectivity in broad-panel screening, lower cytotoxicity, and excellent overall in vivo safety in early pre-clinical testing. Additionally, it displays low in vivo clearance and excellent oral bioavailability in both rats and dogs. In a rat glucagon challenge model, it was shown to reduce the glucagon-elicited glucose excursion in a dose-dependent manner and at a concentration consistent with its rat in vitro potency. Its properties make it an excellent candidate for further investigation. 23644411 Steroidal glycosides from the bulbs of Easter lily (Lilium longiflorum Thunb.) promote dermal fibroblast migration in vitro. ETHNOPHARMACOLOGICAL RELEVANCE: Preparations derived from bulbs of various Lilium species have been used to promote the healing of skin abrasions, sores and burns and to aid in healing wounds in Traditional Chinese and Greco-Roman Medicine. AIM OF THE STUDY: To evaluate fractionated Easter lily bulb extracts and their steroidal glycosides (1-5) for the promotion of dermal fibroblast migration in vitro, as a model for the early events in wound healing. MATERIALS AND METHODS: An activity-guided screening approach was used by coupling sequential solvent extraction, gel permeation chromatography (GPC), and semi-preparative reverse-phase high performance liquid chromatography (RP-HPLC) with an in vitro dermal fibroblast migration assay. Cytotoxicity was evaluated with methyl thiazole tetrazolium (MTT). To gain insight into the mode of action of the steroidal glycosides, nitric oxide (NO) production, and expression of genes for transforming growth factor beta-1 (TGF-β) and its receptors were evaluated. RESULTS: Fractionated bulb extracts and the two isolated steroidal glycoalkaloids (1) and (2) induced NO production and TGF-β receptor I mRNA expression in fibroblast cell culture. In a cytotoxicity assay, steroidal glycosides (1) and (3) had IC50 values of 8.2 and 8.7µM, but the natural acetylation of the C-6″' hydroxy of the terminal glucose unit in (2) resulted in a 3-fold decrease in cell cytotoxicity when compared with (1). Results from the dermal fibroblast migration assay revealed that the steroidal glycoalkaloids (1) and (2), and the furostanol saponin (3) promoted fibroblast migration from the range of 23.7±5.7 to 37.7±5.1%, as compared with the control. CONCLUSION: Collectively, our data demonstrate that the steroidal glycosides present in Easter lily bulbs induce, at least in part, the observed dermal fibroblast migration activity of the bulb extracts. This is the first evidence that steroidal glycosides from L. longiflorum may potentially play a role in the wound healing process and may provide a scientific basis for the historical use of lily bulbs for this purpose. 23415902 Signaling of an allosteric, nanomolar potent, low molecular weight agonist for the follicle-stimulating hormone receptor. Follicle-stimulating hormone (FSH) activates FSH receptors (FSHR) in granulosa cells to induce follicle differentiation, growth and estradiol production. FSH is used clinically to treat female infertility and is administered by injection. To increase patient convenience and compliance, compound homogeneity and composition, low molecular weight (LMW), orally bioavailable, FSHR agonists are now being developed to replace FSH. In this study, we present the signaling mechanisms of a newly developed LMW dihydropyridine agonist of the FSHR, Org 214444-0. Org 214444-0 is shown to be a stereoselective, nanomolar potent FSHR agonist and selective over the structurally related LHR and TSHR. Org 214444-0 is an allosteric agonist interacting with the transmembrane region of the FSHR. When co-incubated with FSH, Org 214444-0 augments FSH's potency in binding (6.5-fold) and adenylyl cyclase/cAMP activation (3.5-fold) in a concentration-dependent manner. Like FSH, Org 214444-0 induces FSHR internalization and is only marginally effective in stimulating phospholipase C. Moreover, Org 214444-0 stimulates cAMP and estradiol production in human granulosa cells in culture and supports the follicular phase in mature female rats. We conclude that Org 214444-0 is a bonafide FSHR agonist. 23360676 Anti-inflammatory effects of a special carbohydrate-whey protein cake after exhaustive cycling in humans. Intense exercise induces increased levels of pro-inflammatory and anti-inflammatory cytokines. Thus, the purpose of this study was to examine the effects of a special cake (consisting of carbohydrate to whey protein 3.5:1) vs. an isocaloric carbohydrate cake on inflammatory markers after exhaustive cycling in humans. Nine subjects received either the experimental or placebo cake in a counterbalanced fashion using a crossover, double-blind, repeated-measures design. They performed one trial involving a 2h exercise on a cycle ergometer at 60-65% VO2max followed by a 4h recovery and then a second trial involving an 1h exercise at 60-65% VO2max which was increased at 95% VO2max. Blood samples were collected pre-exercise, 30min and 4h post-exercise, post-time Trial and 48h post-time Trial. Cakes were consumed immediately post-exercise and every 1h for the next 3h. The results showed that consumption of the experimental cake reduced significantly (p<0.05), 4h post-exercise, the pro-inflammatory protein levels IL-6 and CRP compared to the control group by 50% and 46% respectively. Moreover, in the experimental cake group, the level of the anti-inflammatory cytokine IL-10 was higher by 118%, 4h post-exercise, compared to the control group but not statistically significant. 23643831 Discovery of highly potent triazole antifungal derivatives by heterocycle-benzene bioisosteric replacement. On the basis of our previously discovered triazole antifungal lead compounds, heterocycle-benzene bioisosteric replacement was used to improve their pharmacokinetic profile. The designed new triazole derivatives have good antifungal activity toward a wide range of pathogenic fungi. Their binding mode with the target enzyme was clarified by molecular docking. The MIC value of the highly potent compound 8f against Candida albicans, Candida tropicalis, and Cryptococcus neoformans is 0.016 μg/mL, 0.004 μg/mL, and 0.016 μg/mL, respectively. Moreover, preliminary pharmacokinetic studies revealed that it showed improved oral absorption as compared to the lead compound iodiconazole and deserved for further evaluations. 23576205 Simultaneous two and three photon resonant enhancement of third-order NLO susceptibility in an azo-dye functionalized polymer film. We report the observation of simultaneous two and three photon resonances, enhancing the third-order NLO susceptibility in a thin film of an azo-dye polymer. The possibility of 2-3 orders of magnitude increase in χ((3)) susceptibility is sustained by quantum mechanical calculations. This improves the applications of azo-polymers in all optical signal processing as well as in nonlinear optical imaging. 23110812 SPIDIA-RNA: first external quality assessment for the pre-analytical phase of blood samples used for RNA based analyses. The diagnostic use of in vitro molecular assays can be limited by the lack of guidelines for collection, handling, stabilization and storage of patient specimens. One of the major goals of the EC funded project SPIDIA (www.spidia.eu) is to develop evidence-based quality guidelines for the pre-analytical phase of blood samples used for molecular testing which requires intracellular RNA analytes. To this end, a survey and a pan-European external quality assessment (EQA) were implemented. This report is the summary of the results of that trial. With the European Federation of Laboratory Medicine (EFLM) support, 124 applications for participation in the trial were received from 27 different European countries, and 102 laboratories actually participated in the trial. Each participating laboratory described their respective laboratory policies and practices as well as blood collection tubes typically used in performing this type of testing. The participating laboratories received two identical blood specimens: in an EDTA tubes (unstabilized blood; n=67) or in tubes designed specifically for the stabilization of intracellular RNA in blood (PAXgene® Blood RNA tubes; n=35). Laboratories were requested to perform RNA extraction according to the laboratory's own procedure as soon as possible upon receipt of the tubes for one tube and 24h after the first extraction for the second tube. Participants (n=93) returned the two extracted RNAs to SPIDIA facility for analysis, and provided details about the reagents and protocols they used for the extraction. At the SPIDIA facility responsible for coordinating the study, the survey data were classified, and the extracted RNA samples were evaluated for purity, yield, integrity, stability, and the presence of interfering substances affecting RT-qPCR assays. All participants received a report comparing the performance of the RNA they submitted to that of the other participants. All the results obtained by participants for each RNA quality parameter were classified as "in control", "warning", "out of control" and "missing" by consensus mean analysis. From the survey data, the most variable parameters were the volume of blood collected and the time and storage temperature between blood collection and RNA extraction. Analyzing the results of quality testing of submitted RNA samples we observed a data distribution of purity, yield, and presence of assay interference in agreement with expected values. The RNA Integrity Number (RIN) values distribution was, on the other hand, much wider than the optimal expected value, which led to an "in control" classification, even for partly degraded RNA samples. On the other hand, RIN values below 5 significantly correlated with a reduction of GAPDH expression levels. Furthermore, the distribution of the values of the four transcripts investigated (c-fos, IL-1β, IL-8, and GAPDH) was wide and the RNA instability between samples separated by 24h were similar. Assuming the presence of at least two quality parameters "out of control" as an indication of a critical performance of the laboratory, 33% of the laboratories were included in this group. The results of this study will be the basis for implementing a second pan-European EQA and the results of both EQAs will be pooled and will provide the basis for the implementation of evidence-based guidelines for the pre-analytical phase of RNA analysis of blood samples. 23334800 Electrochemical synthesis of CdTe/SWNT hybrid nanostructures and their tunable electrical and optoelectrical properties. A facile electrodeposition technique was utilized to deposit single-walled carbon nanotubes (SWNTs) with cadmium telluride (CdTe) with well-controlled size, density, surface morphology, and composition. By controlling the applied charge, the morphology of these hybrid nanostructures was altered from CdTe nanoparticles on SWNTs to SWNT/CdTe core/shell nanostructures and the composition of the CdTe nanoparticles was altered from Te-rich (29 at% Cd) to Cd-rich (79 at% Cd) CdTe by adjusting the deposition potential. The electrical and optoelectrical properties of these hybrid nanostructures showed that photo-induced current can be tuned by tailoring the conductivity type (n-type or p-type), morphology, and size of the CdTe nanostructures, with a maximum photosensitivity (ΔI/I(0)) of about 30% for SWNT/Cd-rich CdTe (n-type) core/shell nanostructures. This work demonstrates a novel approach for synthesizing metal chalcogenide/SWNT hybrid nanostructures for various electrical and optoelectrical applications. 23426955 Experimental models of disseminated scedosporiosis with cerebral involvement. Scedosporium apiospermum is a soil fungus which can cause severe and often fatal cerebral infections in both immunocompetent patients in the event of near drowning and immunosuppressed patients such as lung transplant recipients. Because of the low susceptibility of this fungus to antifungal drugs, and the low permeability of the blood-brain barrier (BBB), therapeutic drug monitoring is necessary to reach an effective tissue concentration with limited side effects. Indeed, diffusion of the drug in the brain is dependent on several parameters, such as the integrity of the BBB and the activity of efflux pumps. To evaluate drug diffusion, two experimental models were developed in immunocompetent and immunosuppressed rats. Inocula were administered via the penile vein and a clinical scale (0-9) was established, based on weight and clinical and neurologic signs evaluated by the tail suspension test. Cerebral involvement was confirmed by magnetic resonance imaging and histologic examination of brain sections after hematoxylin-eosin-safran or silver staining. Voriconazole or posaconazole was given to the rats at doses ranging from 10 to 75 mg/kg/day via i.v. or oral routes, respectively. Whatever the immune status, the effective doses (defined by a doubling of the survival time and the absence of neurologic sequelae) were 30 mg/kg/day for voriconazole and 50 mg/kg/day for posaconazole. Overall, the results demonstrated that these models may constitute valuable tools for the performance of pharmacokinetic and pharmacodynamic studies for pharmacokinetic-pharmacodynamic modeling. 22933435 Cost-effectiveness of hepatitis B vaccination in adults with diagnosed diabetes. OBJECTIVE To examine the cost-effectiveness of a hepatitis B vaccination program for unvaccinated adults with diagnosed diabetes in the U.S. RESEARCH DESIGN AND METHODS We used a cost-effectiveness simulation model to estimate the cost-effectiveness of vaccinating adults 20-59 years of age with diagnosed diabetes not previously vaccinated for or infected by hepatitis B virus (HBV). The model estimated acute and chronic HBV infections, complications, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. Data sources included surveillance data, epidemiological studies, and vaccine prices. RESULTS With a 10% uptake rate, the intervention will vaccinate 528,047 people and prevent 4,271 acute and 256 chronic hepatitis B infections. Net health care costs will increase by $91.4 million, and 1,218 QALYs will be gained, producing a cost-effectiveness ratio of $75,094 per QALY gained. Results are most sensitive to age, the discount rate, the hepatitis B incidence ratio for people with diabetes, and hepatitis B infection rates. Cost-effectiveness ratios rise with age at vaccination; an alternative intervention that vaccinates adults with diabetes 60 years of age or older had a cost-effectiveness ratio of $2.7 million per QALY. CONCLUSIONS Hepatitis B vaccination for adults with diabetes 20-59 years of age is modestly cost-effective. Vaccinating older adults with diabetes is not cost-effective. The study did not consider hepatitis outbreak investigation costs, and limited information exists on hepatitis progression among older adults with diabetes. Partly based on these results, the Advisory Committee on Immunization Practices recently recommended hepatitis B vaccination for people 20-59 years of age with diagnosed diabetes. 23353744 Design, synthesis and anticancer properties of 5-arylbenzoxepins as conformationally restricted isocombretastatin A-4 analogs. A series of novel benzoxepins 6 was designed and prepared as rigid-isoCA-4 analogs according to a convergent strategy using the coupling of N-tosylhydrazones with aryl iodides under palladium catalysis. The most potent compound 6b, having the greatest resemblance to CA-4 and isoCA-4 displayed antiproliferative activity at nanomolar concentrations against various cancer cell lines and inhibited tubulin assembly at a micromolar range. In addition, benzoxepin 6b led to the arrest of HCT116, K562, H1299 and MDA-MB231 cancer cell lines in the G2/M phase of the cell cycle, and strongly induced apoptosis at low concentrations. Docking studies demonstrated that benzoxepin 6b adopt an orientation similar to that of isoCA-4 at the colchicine binding site on β-tubulin. 22948775 Resistance training decreases serum inflammatory markers in diabetic rats. Inflammation plays an important role in the genesis and progression of diabetes. The purpose of this study was to investigate the effect of resistance training on serum levels of some inflammatory markers associated with diabetes mellitus. Twenty-four male Wistar rats (290 ± 19 g) were randomly divided into three groups: non-diabetic control (non-DC), diabetic control (DC), and diabetic trained (DT). Animals in DT group were subjected to a resistance training program with the use of a ladder (3 days/week, for 4 weeks). Body weight, serum high sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α, fasting glucose, and insulin were measured. Four weeks of resistance training decreased serum levels of TNF-α, hs-CRP, and IL-6 in diabetic rats when compared with DC animals. We conclude that resistance training with appropriate intensity, duration, and recovery between exercise bouts has marked anti-inflammatory effects on diabetic rats. This may be an efficient strategy to protect against some diabetic complications. 23568554 Cyclic AMP responsive element binding protein- a vital link in embryonic hormonal adaptation. The transcription factor cyclic AMP responsive element binding protein (CREB) and activating transcription factors (ATFs) are downstream components of the insulin/IGF cascade, playing crucial roles in maintaining cell viability and embryo survival. One of the CREB target genes is adiponectin which acts synergistically with insulin. We have studied the CREB-ATF-adiponectin network in rabbit preimplantation development in vivo and in vitro.From the blastocyst stage onwards CREB and ATF1, 3 and 4 are present with increasing expression for CREB, ATF1 and 3 during gastrulation and with a dominant expression in the embryoblast (EB). In vitro stimulation with insulin and IGF1 reduced CREB and ATF1 transcripts by approx. 50%, while CREB phosphorylation was increased. Activation of CREB was accompanied by subsequent reduction in adiponectin and adiponectin receptor 1 (adipoR1) expression.Under in vivo conditions of diabetes type 1, maternal adiponectin levels were up-regulated in serum and endometrium. Embryonic CREB expression was altered in a cell lineage-specific pattern. While in EB cells CREB localization did not change, it was translocated from the nucleus into the cytosol in trophoblast (TB) cells. In TB adiponectin expression was increased [diabetic 427.8±59.3 pg/ml versus normoinsulinaemic 143.9±26.5 pg/ml], while it was no longer measureable in the EB. Analysis of embryonic adiponectin receptors showed an increased expression of adipoR1 and no changes in adipoR2 transcription.We conclude that the transcription factors CREB and ATFs vitally participate in embryo-maternal crosstalk prior to implantation in a cell lineage-specific manner. Embryonic CREB/ATFs act as insulin/IGF sensors. Lack of insulin is compensated by a CREB-mediated adiponectin expression which may maintain glucose uptake in blastocysts grown in diabetic mothers. 23301655 Phenyl linker-induced dense PEG conformation improves the efficacy of C-terminally monoPEGylated staphylokinase. PEGylation can improve the protein efficacy by prolonging serum half-life and reducing proteolytic sensitivity and immunogenicity. However, PEGylation may decrease the bioactivity of a protein by interfering with binding of its substrate or receptors. Here, staphylokinase (SAK), a thrombolysis agent for therapy of myocardial infarction, was mono-PEGylated at the C-terminus of SAK far from its bioactive domain. Phenyl, propyl, and amyl moieties were used as linkers between SAK and polyethylene glycol (PEG), respectively. Flexible propyl and amyl linkers lead to loose conformation. In contrast, rigid and hydrophobic phenyl linker induces dense PEG conformation that can extensively shield most domains adjacent to C-terminus (e.g., the antigen epitopes and proteolytic sites) of SAK and inefficiently shield its bioactive domain. As compared with loose PEG conformation, dense PEG conformation is more efficient to maintain the bioactivity, increase the plasma half-life, and decrease the proteolytic sensitivity and immunogenicity of the PEGylated SAK. 23123224 Comparison the neuropreotective effect of Cortex Phellodendri chinensis and Cortex Phellodendri amurensis against beta-amyloid-induced neurotoxicity in PC12 cells. Cortex Phellodendron chinensis (CPC) and Cortex Phellodendron amurensis (CPA) derived from the dried bark of Phellodendron chinense Schneid. or Phellodendron amurense Rupr., respectively, are used interchangeably in clinical practice under the name "Huang Bai" for centuries in Chinese medicine for the treatment of various inflammatory conditions. Previous study in our laboratory demonstrated that CPC and CPA had different anti-diarrheal, anti-bacterial and anti-inflammatory effects. In this present study, we aimed to compare the protective effect of ethanol extract of Cortex Phellodendri chinensis (ECPC) and Cortex Phellodendri Amurensis (ECPA) against beta-amyloid (Aβ)-induced neurotoxicity in PC12 cells, a typical model of Alzheimer's disease. The results showed that ECPC and ECPA contain four common chemical markers such as berberine, but palmatine and jatrorrhizin were not found in CPC in contrast to the presence in CPA. In addition, both ECPC and ECPA can significantly increase the cell viability in Aβ-treated PC12 cells. Moreover, ECPC and ECPA can markedly elevate the ratio of the protein and mRNA levels of Bcl-2/Bax, while remarkably decrease the release of cytochrome c, and the protein and mRNA expression of caspase-3. Interestingly, ECPA has better protective effect than ECPC against Aβ-induced neurotoxicity in PC12 cells. These results indicate that both ECPC and ECPA have potential protective effect against Aβ-induced neurotoxicity in PC12 cells, and ECPA is more potential of the two species to be used in traditional medicine as a neuroprotective agent for the treatment of AD. The neuroprotective effect of the two species may be mediated, at least in part, via suppressing of the cellular apoptosis. 23562926 Transcellular transport of aconitine across human intestinal Caco-2 cells. Aconitine (AC) is a highly toxic compound present in plants of the genus Aconitum. The transcellular transport mechanism of AC was investigated using Caco-2 cells. The flux of AC was time- and concentration-dependent in both apical-to-basolateral and the reverse direction. The efflux of AC was more than two-fold that in the opposite direction. The influx of AC was temperature-, pH- and Na(+)-dependent. Glucose markedly decreased the absorption of AC. However, the efflux of AC was temperature- and pH-dependent, but Na(+)-independent. Cyclosporin A and verapamil, both inhibitors of P-glycoprotein (P-gp), significantly decreased the efflux of AC. In addition, MK-571, an inhibitor of multidrug resistance-associated protein 2 (MRP2), exhibited the same trend but to a lesser extent. These results indicate that both the influx and efflux of AC across Caco-2 monolayers were through an active process. A pH-dependent carrier-mediated transport system was the major absorption mechanism and a sodium-dependent glucose transporter may be involved. The active efflux of AC across Caco-2 cells was mediated mainly by ABC-transporter P-gp. It is involved in reducing the toxicity of AC to organisms and is the major reasons for the poor absorption of AC in vivo. 23143415 O2-independent formation of the inactive states of NiFe hydrogenase. We studied the mechanism of aerobic inactivation of Desulfovibrio fructosovorans nickel-iron (NiFe) hydrogenase by quantitatively examining the results of electrochemistry, EPR and FTIR experiments. They suggest that, contrary to the commonly accepted mechanism, the attacking O(2) is not incorporated as an active site ligand but, rather, acts as an electron acceptor. Our findings offer new ways toward the understanding of O(2) inactivation and O(2) tolerance in NiFe hydrogenases. 23561071 Effects of combination processes on the extraction of pectins from rapeseed cake (Brassica napus L.). In this study, rapeseed cake (RSC) was used as a source of pectins due to its high carbohydrate content. Different combinations of treatments were applied to investigate the effect of combination processes on the extraction of pectin from RSC. The treatments chosen for combination were a fat removal process (FRP) (solvent extraction using an alcohol-benzene mixture), a chemical treatment (CT) (hydrolysis using 1% hydrochloric acid), and an enzymatic hydrolysis (EH). After the combined processes, pectins were extracted by isopropanol/ethanol precipitation and the residues were analysed by HPLC or an elemental analyser. The pectin yields and galacturonic acid contents were increased by FRP because 72.13% of the total fat was removed; additionally, EH had a similar effect. However, CT decreased the yields because the treatment was too harsh and the galacturonic acid broke down. Pectin yields and galacturonic acid contents were highest in the combination process FRP/EH (6.23% and 64.23%, respectively). 23337602 3H-1,2,4-Dithiazol-3-one compounds as novel potential affordable antitubercular agents. Small molecules with oxathiazol-2-one moiety were recently reported as potent inhibitors of Mycobacterium bovis var. bacilli Calmette-Guérin (BCG), among which HT1171 was the most potent and selective proteasome inhibitor. Herein we synthesized a series of novel compounds by bioisosteric replacement of the oxathiazol-2-one ring with 3H-1,2,4-dithiazol-3-one, and also fifteen 1,3,4-oxathiazol-2-one molecules in order for potency comparison and structure-activity relationship elucidation since their antibacterial effects on the virulent strains were not evaluated before. All the compounds were assessed for antitubercular activities on the virulent H37Rv strain by a serial dilution method. Among the tested compounds, 3H-1,2,4-dithiazol-3-one compound 4n was found to be the most active with a lowest MIC(90) value of 1 μg/mL. Furthermore, the cytotoxicities of all the compounds against normal human liver cell line L02 were determined by an MTT method. Compound 4n displayed a lower inhibitory ratio than HT1171 at the concentration of 100 μM, indicating its better safety profile. 23341241 Accumulation of dietary methylmercury and effects on growth and survival in two estuarine forage fish: Cyprinodon variegatus and Menidia beryllina. Dietary methylmercury (MeHg) uptake by fish in relation to life stage, species, and level of exposure is poorly understood in lower trophic levels, particularly in estuarine species. The authors compared accumulation of dietary MeHg as well as sensitivity (survival and growth) to dietary MeHg exposure in two species of estuarine forage fish, Cyprinodon variegatus and Menidia beryllina. Fish were fed one of five dietary MeHg concentrations (ranging from 0.04 to 14 µg/g dry wt) over a period of 70 d. Growth rate and the level of dietary exposure influenced MeHg tissue concentrations in both species. Mercury in the diet exhibited a strong linear relationship with fish Hg tissue concentrations. Additionally, the authors found that M. beryllina was more sensitive to dietary MeHg exposure than C. variegatus. Both species showed some decreases in growth related to MeHg exposure, although these patterns were not consistent among treatments. Overall, C. variegatus and M. beryllina were found to have a high tolerance for dietary MeHg exposure. If fish occupying low trophic levels are capable of surviving with high Hg body burdens, this tolerance has important implications for Hg exposure of organisms occupying higher trophic levels. 23355085 Decoupling cell and matrix mechanics in engineered microtissues using magnetically actuated microcantilevers. A novel bio-magnetomechanical microtissue system is described for magnetic actuation of arrays of 3D microtissues using microcantilevers. This system enables both in situ measurements of fundamental mechanical properties of engineered tissue, such as contractility and stiffness, as well as dynamic stimulation of the microtissues. Using this system, cell and extracellular matrix contributions to the tissue mechanical properties are decoupled for the first time under both static and dynamic loading conditions. 22614004 Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer. Most solid tumors are characterized by a metabolic shift from glucose oxidation to glycolysis, in part due to actively suppressed mitochondrial function, a state that favors resistance to apoptosis. Suppressed mitochondrial function may also contribute to the activation of hypoxia-inducible factor 1α (HIF1α) and angiogenesis. We have previously shown that the inhibitor of pyruvate dehydrogenase kinase (PDK) dichloroacetate (DCA) activates glucose oxidation and induces apoptosis in cancer cells in vitro and in vivo. We hypothesized that DCA will also reverse the 'pseudohypoxic' mitochondrial signals that lead to HIF1α activation in cancer, even in the absence of hypoxia and inhibit cancer angiogenesis. We show that inhibition of PDKII inhibits HIF1α in cancer cells using several techniques, including HIF1α luciferase reporter assays. Using pharmacologic and molecular approaches that suppress the prolyl-hydroxylase (PHD)-mediated inhibition of HIF1α, we show that DCA inhibits HIF1α by both a PHD-dependent mechanism (that involves a DCA-induced increase in the production of mitochondria-derived α-ketoglutarate) and a PHD-independent mechanism, involving activation of p53 via mitochondrial-derived H(2)O(2), as well as activation of GSK3β. Effective inhibition of HIF1α is shown by a decrease in the expression of several HIF1α regulated gene products as well as inhibition of angiogenesis in vitro in matrigel assays. More importantly, in rat xenotransplant models of non-small cell lung cancer and breast cancer, we show effective inhibition of angiogenesis and tumor perfusion in vivo, assessed by contrast-enhanced ultrasonography, nuclear imaging techniques and histology. This work suggests that mitochondria-targeting metabolic modulators that increase pyruvate dehydrogenase activity, in addition to the recently described pro-apoptotic and anti-proliferative effects, suppress angiogenesis as well, normalizing the pseudo-hypoxic signals that lead to normoxic HIF1α activation in solid tumors. 23547810 Serotonin (5-HT) in the Regulation of Depression-Related Emotionality: Insight from 5-HT Transporter and Tryptophan Hydroxylase-2 Knockout Mouse Models. Disorders of emotion regulation such as anxiety disorders and depression are common and yet debilitating. Accumulating evidence suggests involvement of serotonin (5-HT) in the regulation of emotion. Mice with targeted deletion of genes encoding mediators of the serotonergic transmission have proven to be a powerful tool for understanding contributions of such mediators of emotion regulation. Over the last decade, research on mice with a targeted inactivation of the 5-HT transporter (5-Htt, Sert, Slc6a4) has considerably advanced our knowledge about functions that the 5-HTT plays in the context of emotion related to depression. Moreover, the recent advent of knockout (KO) mice for tryptophan hydroxylase 2 (Tph2 KO), which lacks the rate-limiting enzyme for 5-HT synthesis in the brain, has further provided insight to the brain serotonergic system and its role in emotion dysregulation. Here, we first highlight basic characteristics of the serotonergic system including the biosynthesis of 5-HT as well as the anatomy and firing activity of serotonergic neurons. Furthermore, characteristics of 5-Htt and Tph2 KO mice are covered together with association studies on human variants of 5-HTT and TPH2 in emotional regulation. Among various targets of serotonergic projections, which originate from the raphe nuclei in the brain stem, particular focus is placed on the hippocampus due to its unique dual role in memory and emotion. Finally, effects of therapeutic drugs and psychoactive drugs on KO mouse models as well as on synaptic plasticity will be discussed. 23540737 Novel Pyridinone Derivatives As Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) with High Potency against NNRTI-Resistant HIV-1 Strains. Novel 6-substituted-4-cycloalkyloxy-pyridin-2(1H)-ones were synthesized as non-nucleoside reverse transcriptase inhibitors (NNRTIs), and their biological activity was evaluated. Most of the compounds, especially 26 and 22, bearing a 3-isopropyl and 3-iodine group, respectively, exhibited highly potent activity against wild-type HIV-1 strains and those resistant to reverse transcriptase inhibitors (RTIs). The diastereoisomers of 26-trans and 26-cis were synthesized separately and confirmed with HPLC and NOESY spectra. The 26-trans isomers had an activity about 400-fold more potent than that of 26-cis. The pair of 26-trans enantiomers, one of the most potent inhibitors with EC50 of 4 nM and selectivity index (SI) of 75000, was highly effective against a panel of RTIs-resistant strains with single (Y181C and K103N) or double (A17) mutations in reverse transcriptase. The results suggest that these novel pyridinone derivatives have the potential to be further developed as new antiretroviral drugs with improved antiviral efficacy and drug resistance profile. 23428163 Platinum-modulated cobalt nanocatalysts for low-temperature aqueous-phase Fischer-Tropsch synthesis. Fischer-Tropsch synthesis (FTS) is an important catalytic process for liquid fuel generation, which converts coal/shale gas/biomass-derived syngas (a mixture of CO and H2) to oil. While FTS is thermodynamically favored at low temperature, it is desirable to develop a new catalytic system that could allow working at a relatively low reaction temperature. In this article, we present a one-step hydrogenation-reduction route for the synthesis of Pt-Co nanoparticles (NPs) which were found to be excellent catalysts for aqueous-phase FTS at 433 K. Coupling with atomic-resolution scanning transmission electron microscopy (STEM) and theoretical calculations, the outstanding activity is rationalized by the formation of Co overlayer structures on Pt NPs or Pt-Co alloy NPs. The improved energetics and kinetics from the change of the transition states imposed by the lattice mismatch between the two metals are concluded to be the key factors responsible for the dramatically improved FTS performance. 23020787 Transport of gemifloxacin, a 4th generation quinolone antibiotic, in the Caco-2 and engineered MDCKII cells, and potential involvement of efflux transporters in the intestinal absorption of the drug. The oral (po) bioavailability of gemifloxacin mesylate in rats and its possible association with efflux transporters was investigated. The apparent permeabilities (Papp) of gemifloxacin across the Caco-2 cell monolayer were 1.20 ± 0.09 × 10(-5) cm/s for apical to basal (absorptive) transport, and 2.13 ± 0.6 × 10(-5) cm/s for basal to apical (secretory) transport for a 5-500 μM concentration range, suggesting the involvement of a carrier-mediated efflux in the secretory transport. The secretory transport in Caco-2 cells was significantly decreased by MRP2 (MK571) and BCRP (Ko143) inhibitors. The secretory transport was distinct in MDCKII/P-gp, MDCKII/MRP2 and MDCKII/BCRP cells, and the affinity was highest for MRP2, followed by BCRP and P-gp. The efflux was significantly decreased by verapamil and Ko143, but not significantly by MK571. The comparative po bioavailability in rats was increased by the preadministration of Ko143 (four-fold), MK571 (two-fold) and verapamil (two-fold). Efflux transporters appeared to significantly limit the bioavailability of gemifloxacin in rats, suggesting their possible contribution to the low bioavailability of the drug in the human (70%). 22722028 Deep brain stimulation, histone deacetylase inhibitors and glutamatergic drugs rescue resistance to fear extinction in a genetic mouse model. Anxiety disorders are characterized by persistent, excessive fear. Therapeutic interventions that reverse deficits in fear extinction represent a tractable approach to treating these disorders. We previously reported that 129S1/SvImJ (S1) mice show no extinction learning following normal fear conditioning. We now demonstrate that weak fear conditioning does permit fear reduction during massed extinction training in S1 mice, but reveals specific deficiency in extinction memory consolidation/retrieval. Rescue of this impaired extinction consolidation/retrieval was achieved with d-cycloserine (N-methly-d-aspartate partial agonist) or MS-275 (histone deacetylase (HDAC) inhibitor), applied after extinction training. We next examined the ability of different drugs and non-pharmacological manipulations to rescue the extreme fear extinction deficit in S1 following normal fear conditioning with the ultimate aim to produce low fear levels in extinction retrieval tests. Results showed that deep brain stimulation (DBS) by applying high frequency stimulation to the nucleus accumbens (ventral striatum) during extinction training, indeed significantly reduced fear during extinction retrieval compared to sham stimulation controls. Rescue of both impaired extinction acquisition and deficient extinction consolidation/retrieval was achieved with prior extinction training administration of valproic acid (a GABAergic enhancer and HDAC inhibitor) or AMN082 [metabotropic glutamate receptor 7 (mGlu7) agonist], while MS-275 or PEPA (AMPA receptor potentiator) failed to affect extinction acquisition in S1 mice. Collectively, these data identify potential beneficial effects of DBS and various drug treatments, including those with HDAC inhibiting or mGlu7 agonism properties, as adjuncts to overcome treatment resistance in exposure-based therapies. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23548055 A Coupling of Benzamides and Donor/Acceptor Diazo Compounds To Form γ-Lactams via Rh(III)-Catalyzed C-H Activation. The coupling of O-pivaloyl benzhydroxamic acids with donor/acceptor diazo compounds provides isoindolones in high yield. The reaction tolerates a broad range of benzhydroxamic acids and diazo compounds, including substituted 2,2,2-trifluorodiazoethanes. Mechanistic experiments suggested that C-H activation is turnover-limiting and irreversible and that insertion of the diazo compound favors electron-deficient substrates. 22581512 Organ accumulation in mice after inhalation of single or mixed essential oil compounds. Essential oils are composed of multiple components. It is thought that the effect of essential oils is due to specific component ratios, which may differ from the original ratio when the essential oil is absorbed. However, very little detailed research exists in this area. We studied the distribution of essential oil components after inhalation of single and mixed components in mice. This research was done using four main components of Alpinia zerumbet (Pers.) B. L. Burtt. and R. M. Sm.: α-pinene, p-cymene, 1,8-cineole, and limonene. After inhalation of single or mixed components for 90 min, component levels in the brain and liver of mice were measured. The results indicated that the amount of α-pinene in the brain and liver was twofold greater after mixed-component inhalation than that after single-component inhalation. In a comparison of the components of the mixed inhalation, the ratio of α-pinene increased to about three times that of 1,8-cineole. It is thought that the absorption via the nasal mucus greatly influences this phenomenon. The results of this investigation of the bodily distribution of essential oil volatile components may provide clues for elucidating their action. 23436293 Drug-induced liver injury: the role of drug metabolism and transport. Many studies have pinpointed the significant contribution of liver-mediated drug metabolism and transport to the complexity of drug-induced liver injury (DILI). Phase I cytochrome P450 (CYP450) enzymes can lead to altered drug metabolism and formation of toxic metabolites, whilst Phase II enzymes are also associated with DILI. The emerging role of hepatic transporters in regulating the movement of endogenous and exogenous chemicals (e.g., bile acids and drugs) across cellular and tissue membranes is critical in determining the pathophysiology of liver disease as well as drug toxicity and efficacy. Genetic and environmental factors can have a significant impact on drug metabolism and transporter proteins, consequently increasing the risk of DILI in susceptible individuals. The assessment of these factors therefore represents an important approach for predicting and preventing DILI, by better understanding the pharmacological profile of a specific drug. This review focuses on the mechanisms of DILI associated with drug metabolism and hepatic transport, and how they can be influenced by underlying factors. 23607568 Total Synthesis of the Marine Cyclic Depsipeptide Viequeamide A. The first total synthesis of viequeamide A, a natural cyclic depsipeptide isolated from a marine button cyanobacterium, was achieved with the N-Me-Val-Thr peptide bond as the final macrocyclization site. The synthetic product gave nearly identical spectroscopic data to that reported for the natural product. 23219702 Antiviral activity of (+)-sattabacin against varicella zoster. The first report of the antiviral activity of (+)-sattabacin against varicella-zoster virus (VZV) is described. Our results show that (+)-sattabacin potently inhibits the growth of VZV at concentrations in the range of other drugs commonly prescribed for VZV infection. Experiments detailing the synthesis of (+)-sattabacin, quantification of cytotoxicity and gene expression data in human fibroblast cells are also presented. Gene expression data was obtained through microarray analysis from human fibroblast cells exposed to sattabacin in order to identify a possible mechanism by which (+)-sattabacin inhibits VZV replication. 22982248 NMDA receptor signaling mediates the expression of protein inhibitor of activated STAT1 (PIAS1) in rat hippocampus. Protein inhibitor of activated STAT1 (PIAS1) was shown to play an important role in inflammation and innate immune response, but how PIAS1 is regulated is not known. We have recently demonstrated that PIAS1 enhances spatial learning and memory performance in rats. In this study, we examined the signaling pathway and neural mechanism that regulate PIAS1 expression in the brain by using pharmacological and molecular approaches. Our results revealed that pias1 gene expression is rapidly induced upon NMDA receptor activation in rat hippocampus, but this effect is blocked by transfection of sub-threshold concentrations of ERK1 siRNA/ERK2 siRNA or CREB siRNA. Pias1 gene expression is similarly induced by overexpression of the ERK1/ERK2 plasmids in rat hippocampus, and this effect is also blocked by sub-threshold concentration of CREB siRNA transfection. On the other hand, transfection of ERK1 siRNA/ERK2 siRNA or CREB siRNA at a higher concentration is sufficient to down-regulate PIAS1 expression. Inhibition of PI-3 kinase signaling and CaMKII signaling, which both result in CREB inactivation, similarly decreases PIAS1 expression. But NMDA and MK-801 do not affect the expression of IL-6 and TNFα. NMDA also did not affect the expression of PIAS2, PIAS3 and PIAS4. Further, pias1 mRNA has a similar degradation rate to that of the zif268 gene. These results together suggest that pias1 may function as an immediate early gene in an activity-dependent manner and PIAS1 expression is regulated by the NMDA-MAPK/ERK-CREB signaling pathway implicated in neuronal plasticity. 23223177 Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes. Diabetic cardiomyopathy is associated with suppression of cardiac autophagy, and activation of AMP-activated protein kinase (AMPK) restores cardiac autophagy and prevents cardiomyopathy in diabetic mice, albeit by an unknown mechanism. We hypothesized that AMPK-induced autophagy ameliorates diabetic cardiomyopathy by inhibiting cardiomyocyte apoptosis and examined the effects of AMPK on the interaction between Beclin1 and Bcl-2, a switch between autophagy and apoptosis, in diabetic mice and high glucose-treated H9c2 cardiac myoblast cells. Exposure of H9c2 cells to high glucose reduced AMPK activity, inhibited Jun NH2-terminal kinase 1 (JNK1)-B-cell lymphoma 2 (Bcl-2) signaling, and promoted Beclin1 binding to Bcl-2. Conversely, activation of AMPK by metformin stimulated JNK1-Bcl-2 signaling and disrupted the Beclin1-Bcl-2 complex. Activation of AMPK, which normalized cardiac autophagy, attenuated high glucose-induced apoptosis in cultured H9c2 cells. This effect was attenuated by inhibition of autophagy. Finally, chronic administration of metformin in diabetic mice restored cardiac autophagy by activating JNK1-Bcl-2 pathways and dissociating Beclin1 and Bcl-2. The induction of autophagy protected against cardiac apoptosis and improved cardiac structure and function in diabetic mice. We concluded that dissociation of Bcl-2 from Beclin1 may be an important mechanism for preventing diabetic cardiomyopathy via AMPK activation that restores autophagy and protects against cardiac apoptosis. 23265873 Novel limonene and citral based 2,5-disubstituted-1,3,4-oxadiazoles: a natural product coupled approach to semicarbazones for antiepileptic activity. Two novel series of N(4)-(5-(2/3/4-substituted-phenyl)-1,3,4-oxadiazol-2-yl)-N(1)-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enylidene)semicarbazide and N(4)-(5-(2/3/4-substituted-phenyl)-1,3,4-oxadiazol-2-yl)-N(1)-(3,7-dimethylocta-3,6-dienylidene)-semicarbazide were synthesized to meet structural prerequisite indispensable for anticonvulsant activity. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure (MES), subcutaneous pentylenetrtrazole (scPTZ) and subcutaneous strychnine (scSTY) models. The rotorod test was conducted to evaluate neurotoxicity. Some of the selected active compounds were subjected to GABA assay to confirm their mode of action. The outcome of the present investigations proved that the four binding sites pharmacophore model is vital for anticonvulsant activity. The efforts were also made to establish structure-activity relationships among test compounds. 23583493 Particle sizing measurements in pharmaceutical applications: Comparison of in-process methods versus off-line methods. It has been previously described that when a sample's particle size is determined using different sizing techniques, the results can differ considerably. The purpose of this study was to review several in-process techniques for particle size determination (Spatial Filtering Velocimetry, Focused Beam Reflectance Measurements, Photometric Stereo Imaging, and the Eyecon® technology) and compare them to well-known and widespread off-line reference methods (laser diffraction and sieve analysis). To start with, a theoretical explanation of the working mechanism behind each sizing technique is presented, and a comparison between them is established. Secondly, six batches of granules and pellets (i.e., spherical particles) having different sizes were measured using these techniques. The obtained size distributions and related D10, D50, and D90 values were compared using the laser diffraction wet dispersion method as reference technique. As expected, each technique provided different size distributions with different D values. These dissimilarities were examined and explained considering the measurement principles behind each sizing technique. The particle property measured by each particle size analyzer (particle size or chord length) and how it is measured as well as the way in which size information is derived and calculated from this measured property and how results are presented (e.g., volume or mass distributions) are essential for the interpretation of the particle size data. 23454833 Evaluation of the adjuvant effect of silver nanoparticles both in vitro and in vivo. The immunological adjuvant effect of silver nanoparticles (AgNPs) was investigated both in vitro and in vivo. The in vivo adjuvant effect of AgNPs was evaluated with model antigen ovalbumin (OVA) and bovine serum albumin (BSA) in mice by intraperitoneal and subcutaneous immunization. Serum antigen-specific IgG level significantly increased in AgNPs-treated mice comparing to the control group. AgNPs induced the increase of IgG1/IgG2a ratio and antigen-specific IgE, indicating that AgNPs elicited Th2-biased immune responses. By in vitro assay, the mechanism of adjuvant effect was explored. After 48h treatment with AgNPs, both the number of leukocytes and levels of cytokines TNF-α and IFN-γ in abdominal lavage fluid of mice increased. The expression of the major histocompatibility complex class II molecule on the surface of peritoneal macrophages significantly increased. AgNPs can be easily phagocytosed by peritoneal macrophages, while do not affect antigen uptake by the cell. We therefore conclude that AgNPs have significant adjuvant effect and the mechanism of this effect is mainly ascribed to the recruitment and activation of local leukocytes and especially macrophages. For the first time we found the remarkable adjuvant effect of AgNPs, and the result is beneficial for the future applications, especially in biomedicine. 23620539 Metallothionein gene transfection reverses the phenotype of activated human hepatic stellate cells. Metallothionein (MT) gene therapy leads to resolution of liver fibrosis in mouse model. The present study was undertaken to test the hypothesis that reversal of the phenotype of activated hepatic stellate cells (HSC) contributes to the fibrinolysis effect of MT. Human HSC LX-2 cells were activated after cultured for 24 hrs, as indicated by expression of α-smooth muscle actin (α-SMA) and collagen-I, and depressed expression of collagenases. Transfection with a plasmid containing human MT-II gene in the activated HSCs effectively increased the protein level of MT. The expression of MT was accompanied by the reduction of protein levels of α-SMA and collagen-I, and the decrease in their mRNA levels. Importantly, MT gene transfection resulted in upregulation of MMP-1, -8 and -13, which are importantly involved in the resolution of liver fibrosis. This study demonstrates that reversal of the phenotype of activated HSCs, particularly the upregulation of collagenases, is likely involved in the resolution of liver fibrosis observed in MT gene therapy. 23530959 Multipart Copolyelectrolyte Adhesive of the Sandcastle Worm, Phragmatopoma californica (Fewkes): Catechol Oxidase Catalyzed Curing through Peptidyl-DOPA. Tube-building sabellariid polychaetes have major impacts on the geology and ecology of shorelines worldwide. Sandcastle worms, Phragmatopoma californica (Fewkes), live along the western coast of North America. Individual sabellariid worms build tubular shells by gluing together mineral particles with a multipart polyelectrolytic adhesive. Distinct sets of oppositely charged components are packaged and stored in concentrated granules in separate cell types. Homogeneous granules contain sulfated macromolecules as counter-polyanion to polycationic Pc2 and Pc5 proteins, which become major components of the fully cured glue. Heterogeneous granules contain polyphosphoproteins, Pc3A/B, paired with divalent cations and polycationic Pc1 and Pc4 proteins. Both types of granules contain catechol oxidase that catalyzes oxidative cross-linking of L-DOPA. Co-secretion of catechol oxidase guarantees rapid and spatially homogeneous curing with limited mixing of the preassembled adhesive packets. Catechol oxidase remains active long after the glue is fully cured, perhaps providing an active cue for conspecific larval settlement. 23219925 3-Hydroxykynurenine: an intriguing molecule exerting dual actions in the Central Nervous System. Kynurenine pathway is gaining attention due to the many metabolic processes in which it has been involved. The tryptophan conversion into several other metabolites through this pathway provides neuronal and redox modulators useful for maintenance of major functions in the brain. However, when physiopathological conditions prevail - i.e. oxidative stress, excitotoxicity, and inflammation - preferential formation and accumulation of toxic metabolites could trigger factors for degeneration in neurological disorders. 3-Hydroxykynurenine has been largely described as one of these toxic metabolites capable of inducing oxidative damage and cell death; consequently, this metabolite has been hypothesized to play a pivotal role in different neurological and psychiatric disorders. Supporting evidence has shown altered 3-hydroxykynurenine levels in samples of patients from several disorders. In contrast, some experimental studies have provided evidence of antioxidant and scavenging properties inherent to this molecule. In this review, we explored most of literature favoring one or the other concept, in order to provide an accurate vision on the real participation of this tryptophan metabolite in both experimental paradigms and human brain pathologies. Through this collected evidence, we provide an integrative hypothesis on how 3-hydroxykynurenine is exerting its dual actions in the Central Nervous System and what will be the course of investigations in this field for the next years. 23442147 Nanomechanical properties of proteins and membranes depend on loading rate and electrostatic interactions. Knowing the dynamic mechanical response of tissue, cells, membranes, proteins, nucleic acids, and carbohydrates to external perturbations is important to understand various biological and biotechnological problems. Atomic force microscopy (AFM)-based approaches are the most frequently used nanotechnologies to determine the mechanical properties of biological samples that range in size from microscopic to (sub)nanoscopic. However, the dynamic nature of biomechanical properties has barely been addressed by AFM imaging. In this work, we characterizethe viscoelastic properties of the native light-driven proton pump bacteriorhodopsin of the purple membrane of Halobacterium salinarum. Using force-distance curve (F-D)-based AFM we imaged purple membranes while force probing their mechanical response over a wide range of loading rates (from ∼0.5 to 100 μN/s). Our results show that the mechanical stiffness of protein and membrane increases with the loading rate up to a factor of 10 (from ∼0.3 to 3.2 N/m). In addition, the electrostatic repulsion between AFM tip and sample can alter the mechanical stiffness measured by AFM up to ∼60% (from ∼0.8 to 1.3 N/m).These findings indicate that the mechanical response of membranes and proteins and probably of other biomolecular systems should be determined at different loading rates to fully understand their properties. 22742738 Up-regulation of cytochrome P450 and phase II enzymes by xenobiotics in precision-cut tissue slices. 1.Induction of the drug-metabolising enzyme systems is a major cause of clinically relevant drug interactions. The potential of a drug to engage in such interactions may be assessed in in vitro systems such as precision-cut tissue slices. 2.Precision-cut tissue slices have a number of important advantages compared with the use of cells in culture, especially when tissues with a heterogeneous cellular population are concerned. 3.Extensive studies concerned with the induction of cytochrome P450 and Phase II enzymes in precision-cut tissue slices from various animal and human tissues, such as liver, lung and intestine, using established inducing agents have revealed that slices mimic the in vivo situation. 4.Precision-cut tissue slices is a reliable, informative and cost-effective technique for assessing the potential of chemicals to up-regulate drug-metabolising enzyme systems. 22998295 Combination of β-cyclodextrin inclusion complex and self-microemulsifying drug delivery system for photostability and enhanced oral bioavailability of methotrexate: novel technique. In the present study, we prepared an inclusion complex of methotrexate (MTX) with β-cyclodextrin (β-CD) in order to decrease its photosensitivity and enhance its aqueous solubility. Then we incorporated this inclusion complex in a self-microemulsifying drug delivery system (SMEDDS) overall to increase its oral bioavailability. The inclusion complex has been prepared by freeze drying method and characterized by differential scanning calorimetry (DSC), ultraviolet (UV), and infrared (IR) spectroscopy assays. The proper molecular ratio of MTX/β-CD was found to be of 1:7, and the water-solubility of MTX was increased in an average of 10-fold. The photostability studies showed that the MTX became stable on exposure to light. Construction of pseudoternary diagrams were investigated to prepare a MTX/β-CD inclusion complex loaded SMEDDS which was characterized by measuring the particle size and the zeta-potential. The optimum formulation of SMEDDS was a system consisting of ethyl oleate, tween 80, and propylene glycol with a mean droplet size of 39.42 nm. In vitro drug release in different pH media showed that the release profile of MTX from the MTX/β-CD loaded SMEDDS was influenced by the pH of the release medium and presented the characteristics of a sustained release profile. Finally, in-vivo studies showed an enhancement of the bioavailability of MTX from the MTX/β-CD loaded SMEDDS form of 1.57-fold. We concluded that the β-CD inclusion complex loaded SMEDDS improved the chemical and physiological properties of MTX and could be a promising means for the delivery of MTX and other unstable and lipophilic drugs by oral route. 22236093 Volatile organic compounds of Schenella pityophilus. Volatile organic compounds of Schenella pityophilus have been identified via solid-phase microextraction-gas chromatography-mass spectrometry analysis. Ten compounds have been identified, in which 3-methylthio-1-propene was the most significant component. Some other components were previously identified in Tuber aestivum and Tuber melanosporum. 23462814 Effect of surface morphology on friction of graphene on various substrates. The friction of graphene on various substrates, such as SiO2, h-BN, bulk-like graphene, and mica, was investigated to characterize the adhesion level between graphene and the underlying surface. The friction of graphene on SiO2 decreased with increasing thickness and converged around the penta-layers due to incomplete contact between the two surfaces. However, the friction of graphene on an atomically flat substrate, such as h-BN or bulk-like graphene, was low and comparable to that of bulk-like graphene. In contrast, the friction of graphene folded onto bulk-like graphene was indistinguishable from that of mono-layer graphene on SiO2 despite the ultra-smoothness of bulk-like graphene. The characterization of the graphene's roughness before and after folding showed that the corrugation of graphene induced by SiO2 morphology was preserved even after it was folded onto an atomically flat substrate. In addition, graphene deposited on mica, when folded, preserved the same corrugation level as before the folding event. Our friction measurements revealed that graphene, once exfoliated from the bulk crystal, tends to maintain its corrugation level even after it is folded onto an atomically flat substrate and that ultra-flatness in both graphene and the substrate is required to achieve the intimate contact necessary for strong adhesion. 23333424 Mitochondrial electron transport is inhibited by disappearance of metallothionein in human bronchial epithelial cells following exposure to silver nitrate. Silver (Ag) possesses antibacterial activity and has been used in wound dressings and deodorant powders worldwide. However, the metabolic behavior and biological roles of Ag in mammals have not been well characterized. In the present study, we exposed human bronchial epithelial cells (BEAS-2B) to AgNO3 and investigated uptake and intracellular distribution of Ag, expression of metallothionein (MT), generation of reactive oxygen species (ROS), and changes in mitochondrial respiration. The culture medium concentration of Ag decreased with time and stabilized at 12h. The concentration of both Ag and MT in the soluble cellular fraction increased up to 3h and then decreased, indicating that cytosolic Ag relocated to the insoluble fraction of the cells. The levels of mRNAs for the major human MT isoforms MT-I and MT-II paralleled with the protein levels of Ag-MT. The intensity of fluorescence derived from ROS was elevated in the mitochondrial region at 24h. Ag decreased mitochondrial oxygen consumption in a dose-dependent manner and the activity of mitochondrial complex I-IV enzymes was significantly inhibited following exposure to Ag. In a separate experiment, we found that hydrogen peroxide (H2O2) at concentrations as low as 0.001% (equivalent to the concentration of H2O2 in Ag-exposed cells) removed Ag from MT. These results suggest MT was decomposed by cytosolic H2O2, and then Ag released from MT relocated to insoluble cellular fractions and inhibited electron chain transfer of mitochondrial complexes, which eventually led to cell damage. 23642124 Synthesis of Hollow Ag-Au Bimetallic Nanoparticles in Polyelectrolyte Multilayers. Ag nanoparticles of ~20 nm size and rather uniform size distribution were synthesized in polyelectrolyte multilayers (PEMs) via an ion-exchange/reduction process in two stages (seeding and growth), which were used as sacrificial templates to fabricate Ag-Au bimetallic hollow nanoparticles via galvanic replacement reaction. The reaction process was monitored by UV-vis spectroscopy. The morphology and structure of the nanoparticles were characterized by transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopy, which confirmed the formation of hollow Ag-Au bimetallic nanoparticles. UV-vis absorbance spectroscopy and TEM results indicated that both size and optical properties of the Ag nanoparticles in the PEM can be controlled by manipulating ion content in the PEM and the number of the ion-exchange/reduction cycle, whereas that of Ag-Au bimetallic nanoparticles were dependent on size of the Ag templates and the replacement reaction kinetics. The hollow Ag-Au bimetallic nanoparticles exhibited a significant red shift in the surface plasmon resonance to the near-infrared region. The strategy enables facile preparation of hollow bimetallic nanoparticles in situ in polymer matrices. 23098878 Two new anthraquinone dimers from the fruit bodies of Bulgaria inquinans. Two new dimeric anthraquinone derivatives, bulgareone A(1) and bulgareone B(2), were isolated from the fruit bodies of Bulgaria inquinans. Their structures were elucidated on the basis of extensive spectroscopic analysis. The in vitro cytotoxic activity of compounds 1 and 2 was assayed. They displayed inhibitive activities against human cancer cell lines HL60 and K562. 23510462 Modeling Adsorption of Cationic Surfactants at Air/Water Interface without Using the Gibbs Equation. The Gibbs adsorption equation has been indispensable in predicting the surfactant adsorption at the interfaces, with many applications in industrial and natural processes. This study uses a new theoretical framework to model surfactant adsorption at the air/water interface without the Gibbs equation. The model was applied to two surfactants, C14TAB and C16TAB, to determine the maximum surface excesses. The obtained values demonstrated a fundamental change, which was verified by simulations, in the molecular arrangement at the interface. The new insights, in combination with recent discoveries in the field, expose the limitations of applying the Gibbs adsorption equation to cationic surfactants at the air/water interface. 23630301 Strong Parent-of-Origin Effects in the Association of KCNQ1 Variants with Type 2 Diabetes Mellitus in American Indians. Parent-of-origin effects were observed in an Icelandic population for several genetic variants associated with type 2 diabetes, including those in KLF14 (rs4731702), MOB2 (rs2334499) and KCNQ1 (rs2237892, rs231362). We analyzed parent-of-origin effects for these variants, along with two others in KCNQ1 identified in previous genome-wide association studies (rs2237895, rs2299620), in 7351 Pima Indians from 4549 nuclear families; 34% of participants had diabetes. In a subset of 287 normoglycemic individuals, acute insulin secretion was measured by an intravenous glucose tolerance test. Statistically significant (P<0.05) parent-of-origin effects were seen for association with type 2 diabetes for all variants. The strongest effect was seen at rs2299620 in KCNQ1: the C allele was associated with increased diabetes when maternally-derived (odds ratio=1.92, P=4.1x10(-12)), but not when paternally-derived (odds ratio=0.93, P=0.47; P=9.9x10(-6) for difference in maternal and paternal effects). A maternally-derived C allele was also associated with a 28% decrease in insulin secretion (P=0.002). This study confirms parent-of-origin effects in the association with type 2 diabetes for variants in KLF14, MOB2 and KCNQ1. In Pima Indians the effect of maternally-derived KCNQ1 variants appears to be mediated through decreased insulin secretion, and is particularly strong, accounting for 4% of the variance in liability to diabetes. 23411352 Effects of oil exposure and dispersant use upon environmental adaptation performance and fitness in the European sea bass, Dicentrarchus labrax. The worldwide increasing recourse to chemical dispersants to deal with oil spills in marine coastal ecosystems is a controversial issue. Yet, there exists no adequate methodology that can provide reliable predictions of how oil and dispersant-treated oil can affect relevant organism or population-level performance. The primary objective of the present study was to examine and compare the effects of exposure to untreated oil (weathered Arabian light crude oil), chemically dispersed oil (Finasol, TOTAL-Fluides) or dispersant alone, upon the ability of fish for environmental adaptation. To reach that goal, we implemented high-throughput, non-lethal challenge tests to estimate individual hypoxia and heat tolerance as surrogate measures of their capacity to face natural contingencies. Experimental populations were then transferred into semi-natural tidal ponds and correlates of individuals' fitness (growth and survival) were monitored over a period of 6 months. In accordance with our stated objectives, the contamination conditions tested corresponded to those observed under an oil slick drifting in shallow waters. Our results revealed that the response of control fish to both challenges was variable among individuals and temporally stable (repeatable) over a 2-month period. Exposure to chemical dispersant did not affect the repeatability of fish performance. However, exposure to oil or to a mixture of oil plus dispersant affected the repeatability of individuals' responses to the experimental challenge tests. At population level, no difference between contamination treatments was observed in the distribution of individual responses to the hypoxia and temperature challenge tests. Moreover, no correlation between hypoxia tolerance and heat tolerance was noticed. During the field experiment, hypoxia tolerance and heat tolerance were found to be determinants of survivorship. Moreover, experimental groups exposed to oil or to dispersant-treated oil displayed significantly lower survival than control or dispersant-exposed groups. Finally, from the four experimental populations tested, the one exposed to chemically dispersed oil presented the lowest growth rate. 23407781 Characterization of the head-twitch response induced by hallucinogens in mice : Detection of the behavior based on the dynamics of head movement. RATIONALE: The head-twitch response (HTR) is a rapid side-to-side rotational head movement that occurs in rats and mice after administration of serotonergic hallucinogens and other 5-HT(2A) agonists. The HTR is widely used as a behavioral assay for 5-HT(2A) activation and to probe for interactions between the 5-HT(2A) receptor and other transmitter systems. OBJECTIVE: High-speed video recordings were used to analyze the head movement that occurs during head twitches in C57BL/6J mice. Experiments were also conducted in C57BL/6J mice to determine whether a head-mounted magnet and a magnetometer coil could be used to detect the HTR induced by serotonergic hallucinations based on the dynamics of the response. RESULTS: Head movement during the HTR was highly rhythmic and occurred within a specific frequency range (mean head movement frequency of 90.3 Hz). Head twitches produced wave-like oscillations of magnetometer coil voltage that matched the frequency of head movement during the response. The magnetometer coil detected the HTR induced by the serotonergic hallucinogens 2,5-dimethoxy-4-iodoamphetamine (DOI; 0.25, 0.5, and 1.0 mg/kg, i.p.) and lysergic acid diethylamide (LSD; 0.05, 0.1, 0.2, and 0.4 mg/kg, i.p.) with extremely high sensitivity and specificity. Magnetometer coil recordings demonstrated that the non-hallucinogenic compounds (+)-amphetamine (2.5 and 5.0 mg/kg, i.p.) and lisuride (0.8, 1.6, and 3.2 mg/kg, i.p.) did not induce the HTR. CONCLUSIONS: These studies confirm that a magnetometer coil can be used to detect the HTR induced by hallucinogens. The use of magnetometer-based HTR detection provides a high-throughput, semi-automated assay for this behavior, and offers several advantages over traditional assessment methods. 23542230 Systematic review of the effects of maternal hypertension in pregnancy and antihypertensive therapies on child neurocognitive development. As many as 15% of women experience hypertension during pregnancy. Large proportions of them are receiving antihypertensive medications. This review investigated whether hypertension itself, or the antihypertensive medications, adversely affect long term child neurocognitive development. The existing evidence suggests that methyldopa and labetalol probably do not adversely affect neurobehavioral development. Although an increasing body of evidence suggests adverse neurocognitive effects of the hypertension itself, none of the existing studies examined simultaneously the effects of both hypertension and the drugs used therapeutically. The confounding effects by indication must be addressed in future studies. 23387554 Controlled fabrication of hexagonally close-packed Langmuir-Blodgett silica particulate monolayers from binary surfactant and solvent systems. We describe a controllable method to fabricate hexagonally close-packed Langmuir-Blodgett (LB) monolayers with stearic acid (SA) as co-surfactant and methanol as co-solvent. The optimal SA concentrations and volume ratios of chloroform to methanol are 0.8 mg/mL and 3:1 for particles of 140 nm, 0.50 mg/mL and 4:1 for particles of 300 nm, and 0.05 mg/mL and 5:1 for particles of 550 nm, respectively. Additionally, SEM detections of the monolayers transferred at different surface pressures indicate that the monolayers deposited from the binary systems are more compressible. The experimental results indicate that the interparticle repulsions and particle-water interactions can be enhanced without decreasing the particle hydrophobicity by adding SA and methanol; thus, particulate monolayers with large hexagonally close-packed domains composed of small silica particles can be successfully fabricated using LB technique. We propose that the enhanced interparticle repulsion is attributed to the Columbic repulsion resulting from the attachment of SA molecules to the CTAB modified particles around the three phase contact line. 23432581 Recent advances in carbon nanotubes as delivery systems for anticancer drugs. Problems associated with the administration of anticancer drugs, such as limited solubility, poor biodistribution,lack of selectivity, and healthy tissue damage, can be overcome by the implementation of drug delivery systems. A wide range of materials, including liposomes, microspheres, polymers and recently, carbon nanotubes (CNTs), have been investigated for delivering anticancer drugs on the purpose of reducing the number of necessary administrations, providing more localized and better use of the active agents, and increasing patient compliance. Carbon nanotubes (CNTs) have attracted particular attention as carriers of biologically relevant molecules due to their unique physical, chemical and physiological properties. The exact relationship between the physical-chemical properties of carbon nanotubes, their cell to-cell interactions, reactivity, and biological/systemic consequences are relevant issues and it is important to know suchinter-relationships beforehand to employ the benefits of these nanomaterials without the hazardous consequences. The purpose of this review is to present highlight of recent developments in the application of carbon nanotubes as cargoes for anti cancer drugs and in the diagnosis of cancer diseases. 23122157 Encapsulation of food grade antioxidant in natural biopolymer by electrospinning technique: a physicochemical study based on zein-gallic acid system. Gallic acid was successfully incorporated into zein ultra-fine fibres at different loading amount (5%, 10% and 20%) in order to develop an encapsulating technology for functional ingredient delivery using electrospinning. The produced fibres exhibit diameters ranging from 327 to 387 nm. The physical and thermal properties of encapsulated gallic acid were determined by X-ray diffraction (XRD) and differential scanning calorimetry (DSC); and the interaction between gallic acid and zein was attested by attenuated total reflection-Fourier transform infrared (ATR-FTIR). Thermogravimetric analysis (TGA) demonstrated a different thermal stability of the fabricated complex before and after the gallic acid incorporation. Lastly, the 1,1'-diphenyl-2-picrylhydrazyl (DPPH) assay showed that the gallic acid had retained its antioxidant activity after incorporation in zein electrospun fibres. Overall, electrospinning technique had shown promising results as an efficient and effective method for the preparation of sub-micron structured encapsulated functional ingredient that may find uses in food industry. 23556334 Liquid chromatography-mass spectrometry method for the quantification of posaconazole in human plasma: application to pharmacokinetics following single-dose administration in the fasted state and with a high-fat meal. A liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed to determine concentrations of posaconazole in human plasma precipitated by acetonitrile including internal standard. Rapid chromatographic separation was achieved in the mobile phase composition of acetonitrile, water and formic acid (v/v/v, 55:45:0.1) with a flow rate of 0.25 ml/min. Posaconazole-d4 was used as internal standard. Detection was undertaken with cation electrospray tandem mass spectrometry on a Sciex/API3000. The method was accurate, specific and sensitive for the analysis of posaconazole in human plasma in the concentration range of 2-1000 ng/ml. The inter- and intra-batch accuracy was within +/- 10% and the lower limit of quantification was 2 ng/ml. The method facilitated a clinical pharmacokinetic study after oral administration of a single-dose of posaconazole suspension in the fasted state and with a high-fat meal in a two-period crossover design. Cmax (maximum concentration) and AUC (area under serum drug concentration) were significantly increased, and Tmax (time to maximum plasma concentration) was delayed under fed condition, which suggested that simultaneous administration of posaconazole with food may help to achieve higher plasma concentrations and result in better antifungal efficacy. 23581424 Patchy surfaces stabilize dextran-polyethylene glycol aqueous two-phase system liquid patterns. This paper analyzes surface chemistry effects to stably pattern aqueous two-phase system (ATPS) droplets on chemically modified poly(dimethylsiloxane) (PDMS). Polyethylene glycol (PEG) and dextran (DEX) are used as phase-forming polymers for the ATPS. PDMS surface modifications studied include primary amine groups, carboxylic acid groups, and neutral polymer surfaces. The PDMS surfaces were characterized by fluorescent measurement, water and DEX contact angle measurements, and X-ray photoelectron spectroscopy (XPS) analysis to confirm surface properties. While homogeneous surfaces of different functional groups affect DEX droplet pinning somewhat, the most stable patterns were realized using surfaces with chemical heterogeneity. Arbitrary DEX solution patterning was achieved on a chemically patchy surface. 23275571 RNA dimerization plays a role in ribosomal frameshifting of the SARS coronavirus. Messenger RNA encoded signals that are involved in programmed -1 ribosomal frameshifting (-1 PRF) are typically two-stemmed hairpin (H)-type pseudoknots (pks). We previously described an unusual three-stemmed pseudoknot from the severe acute respiratory syndrome (SARS) coronavirus (CoV) that stimulated -1 PRF. The conserved existence of a third stem-loop suggested an important hitherto unknown function. Here we present new information describing structure and function of the third stem of the SARS pseudoknot. We uncovered RNA dimerization through a palindromic sequence embedded in the SARS-CoV Stem 3. Further in vitro analysis revealed that SARS-CoV RNA dimers assemble through 'kissing' loop-loop interactions. We also show that loop-loop kissing complex formation becomes more efficient at physiological temperature and in the presence of magnesium. When the palindromic sequence was mutated, in vitro RNA dimerization was abolished, and frameshifting was reduced from 15 to 5.7%. Furthermore, the inability to dimerize caused by the silent codon change in Stem 3 of SARS-CoV changed the viral growth kinetics and affected the levels of genomic and subgenomic RNA in infected cells. These results suggest that the homodimeric RNA complex formed by the SARS pseudoknot occurs in the cellular environment and that loop-loop kissing interactions involving Stem 3 modulate -1 PRF and play a role in subgenomic and full-length RNA synthesis. 23471665 Bladder Polypoid Cystitis-Derived A20 Associates with Tumorigenesis. Bladder chronic inflammation is associated with the pathogenesis of bladder cancer; the underlying mechanism is unclear. The PT53 gene is an important anticancer gene in the body, which is suppressed in cancer. The ubiquitin E3 ligase A20 (A20) plays a role in regulating the activities of epithelial cells. This study was designed to investigate the correlation between A20 and the pathogenesis of bladder cancer. The biopsy tissues of human bladder cancer, bladder polypoid cystitis, and chronic inflammation were collected; the levels of A20 and p53 were analyzed by quantitative real-time RT-PCR, Western blotting, and immune precipitation. HEK293 cells were employed to test the role of overexpression of A20 in the suppression of the p53 gene in the cells. Fifty-six patients with bladder cancer, 48 patients with bladder polypoid cystitis, and 16 patients with bladder chronic inflammation were recruited into this study. Human bladder cancer tissue and the polypoid tissue showed high levels of A20, which had a positive correlation with the tumorigenesis in the bladder; 12 out of 46 (26.1 %) patients with bladder polypoid cystitis were diagnosed as bladder cancer. A20 bound to p53 to form complexes in bladder cancer tissue and bladder polypoid tissue. The overexpression of A20 suppresses p53 protein levels in HEK293 cells. A20 has a positive correlation in the tumorigenesis of bladder polypoid disorders. 23478802 Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of TRPA1. The transient receptor potential ankyrin 1 (TRPA1) nonselective cation channel has a conserved function as a noxious chemical sensor throughout much of Metazoa. Electrophilic chemicals activate both insect and vertebrate TRPA1 via covalent modification of cysteine residues in the amino-terminal region. Although naturally occurring electrophilic plant compounds, such as mustard oil and cinnamaldehyde, are TRPA1 agonists, it is unknown whether arthropod-produced electrophiles activate mammalian TRPA1. We characterized the effects of the electrophilic arthropod defensive compound para-benzoquinone (pBQN) on the human TRPA1 channel. We used whole-cell recordings of human embryonic kidney cells heterologously expressing either wild-type TRPA1 or TRPA1 with three serine-substituted cysteines crucial for electrophile activation (C621S, C641S, C665S). We found that pBQN activates TRPA1 starting at 10 nM and peaking at 300 nM; higher concentrations caused rapid activation followed by a fast decline. Activation by pBQN required reactivity with cysteine residues, but ones that are distinct from those previously reported to be the key targets of electrophiles. The current reduction we found at higher pBQN concentrations was a cysteine-dependent desensitization of TRPA1, and did not require prior activation. The cysteines required for desensitization are not accessible to all electrophiles as iodoacetamide and internally applied 2-(trimethylammonium)ethyl methanesulfonate failed to cause desensitization (despite large activation). Interestingly, following pBQN desensitization, wild-type TRPA1 had dramatically reduced response to the nonelectrophile agonist carvacrol, whereas the triple cysteine mutant TRPA1 retained its full response. Our results suggest that modification of multiple cysteine residues by electrophilic compounds can generate both activation and desensitization of the TRPA1 channel. 23337597 Polyoxometalate-biomolecule conjugates: a new approach to create hybrid drugs for cancer therapeutics. Some polyoxometalate (POM) clusters have demonstrated attractive anticancer properties. Unfortunately, their cytotoxicity upon normal cell is one of fateful side effects obstructing their further clinic application as inorganic drugs. In this communication, we report a new approach to create hybrid drugs potentially for cancer therapeutics. At first, the POM cluster bioconjugates were created by attaching the bioactive ligands on an amine grafted POM via simple amidation reaction. The cytotoxicity study with breast cancer cells (MCF-7 and MDA-MB-231) and non-cancerous breast epithelial cell (MCF-10A) showed that rationally selected ligands with cancer-cell targeting ability on POM-biomolecule conjugates can impart enhanced anti-tumor activity and selectivity, thus representing a new concept to develop novel POM-biomolecule hybrid drugs with the potential synergistic effect: increased bioactivity and lower side effect. 23178441 Solubility-pH profiles of some acidic, basic and amphoteric drugs. The solubility vs. pH profiles of five ionizable drugs of different nature (a monoprotic acid, a monoprotic base, a diprotic base and two amphoteric compounds showing a zwitterionic species each one) have been determined through two different methodologies: the classical shake-flask (S-F) and the potentiometric Cheqsol methods using in both instances the appropriate Henderson-Hasselbalch (H-H) or derived relationships. The results obtained independently from both approaches are consistent. A critical revision about the influence of the electrolyte used as buffering agent in the S-F method on the obtained solubility values is also performed. Thus, some deviations of the experimental points with respect the H-H profiles can be attributed to specific interactions between the buffering electrolyte and the drug due to the hydrotrophic character of citric and lactic acids. In other cases, the observed deviations are independent of the buffers used since they are caused by the formation of new species such as drug aggregates (cefadroxil) or the precipitation of a salt from a cationic species of the analyzed compound (quetiapine). 23129783 Postexposure application of Fas receptor small-interfering RNA to suppress sulfur mustard-induced apoptosis in human airway epithelial cells: implication for a therapeutic approach. Sulfur mustard (SM) is a vesicant chemical warfare and terrorism agent. Besides skin and eye injury, respiratory damage has been mainly responsible for morbidity and mortality after SM exposure. Previously, it was shown that suppressing the death receptor (DR) response by the dominant-negative Fas-associated death domain protein prior to SM exposure blocked apoptosis and microvesication in skin. Here, we studied whether antagonizing the Fas receptor (FasR) pathway by small-interfering RNA (siRNA) applied after SM exposure would prevent apoptosis and, thus, airway injury. Normal human bronchial/tracheal epithelial (NHBE) cells were used as an in vitro model with FasR siRNA, FasR agonistic antibody CH11, and FasR antagonistic antibody ZB4 as investigative tools. In NHBE cells, both SM (300 µM) and CH11 (100 ng/ml) induced caspase-3 activation, which was inhibited by FasR siRNA and ZB4, indicating that SM-induced apoptosis was via the Fas response. FasR siRNA inhibited SM-induced caspase-3 activation when added to NHBE cultures up to 8 hours after SM. Results using annexin V/propidium iodide-stained cells showed that both apoptosis and necrosis were involved in cell death due to SM; FasR siRNA decreased both apoptotic and necrotic cell populations. Bronchoalveolar lavage fluid (BALF) of rats exposed to SM (1 mg/kg, 50 minutes) revealed a significant (P < 0.05) increase in soluble Fas ligand and active caspase-3 in BALF cells. These findings suggest an intervention of Fas-mediated apoptosis as a postexposure therapeutic strategy with a therapeutic window for SM inhalation injury and possibly other respiratory diseases involving the Fas response. 23561143 Variation in nutritionally relevant components in retail Jersey and Guernsey whole milk. This study investigates the quality of retail milk labelled as Jersey & Guernsey (JG) when compared with milk without breed specifications (NS) and repeatability of differences over seasons and years. 16 different brands of milk (4 Jersey & Guernsey, 12 non specified breed) were sampled over 2years on 4 occasions. JG milk was associated with both favourable traits for human health, such as the higher total protein, total casein, α-casein, β-casein, κ-casein and α-tocopherol contents, and unfavourable traits, such as the higher concentrations of saturated fat, C12:0, C14:0 and lower concentrations of monounsaturated fatty acids. In summer, JG milk had a higher omega-3:omega-6 ratio than had NS milk. Also, the relative increase in omega-3 fatty acids and α-tocopherol, from winter to summer, was greater in JG milk. The latter characteristic could be of use in breeding schemes and farming systems producing niche dairy products. Seasonality had a more marked impact on the fatty acid composition of JG milk than had NS milk, while the opposite was found for protein composition. Potential implication for the findings in human health, producers, industry and consumers are considered. 23644211 Synthesis and in vitro anticancer studies of novel C-2 arylidene congeners of lantadenes. The antitumor pentacyclic triterpenoids, Lantadene A (1) and B (2) were isolated from the leaves of weed Lantana camara L. (Verbenaceae) and were structurally transformed to bioactive intermediates 3-6. The Claisen-Schmidt reaction of 22β-hydroxy-3-oxoolean-12-en-28-oic acid (5) with requisite aldehydes afforded 2-arylidene-22β-hydroxy-3-oxoolean-12-en-28-oic acids (7-16). The compounds were evaluated for their in-vitro anticancer activity by National Cancer Institute (NCI), USA and some of these compounds showed marked cytotoxicity in micromolar range. The mean graph midpoint (MG_MID) value of compound 3 (MG_MID -5.69) was higher than standard drug cisplatin (MG_MID -5.66) while comparable in case of compound 12 (MG_MID -5.52). The NCI's COMPARE molecular mechanistic analysis showed that these compounds were in significant correlations with activity patterns of mechanistic set of compounds (PCC ≥ 0.60). 23618899 Expression of WWOX and FHIT is downregulated by exposure to arsenite in human uroepithelial cells. Ecological studies in Taiwan, Chile, Argentina, Bangladesh, and Mexico have confirmed significant dose-dependent associations between ingestion of arsenic-contaminated drinking water and the risk of various human malignancies. The FHIT and WWOX genes are active in common fragile sites FRA3B and FRA16D, respectively. Reduced expression of FHIT or WWOX is known to be an early indicator of carcinogen-induced cancers. However, the effect of arsenite on the expressions and molecular mechanisms of these markers is still unclear. The aims of this study were (i) to observe the expression of ATR, WWOX and FHIT proteins in urothelial carcinoma (UC) between endemic and non-endemic areas of blackfoot disease (BFD) by immunohistochemical analyses; (ii) to compare expression of these genes between arsenite-treated SV-HUC-1 human epithelial cells and rat uroepithelial cells; and (iii) to determine the role of DNMT and MEK inhibitors on expressions of WWOX and FHIT in response to arsenite in SV-HUC-1. The experiments revealed that expressions of ATR, WWOX and FHIT in UC significantly differed between BFD areas and non-BFD areas (p=0.003, 0.009 and 0.021, respectively). In fact, the results for the arsenite-treated groups showed that ATR, WWOX and FHIT are downregulated by arsenite in SV-HUC-1. However, the inhibitors suppressed the effects of arsenite on WWOX and FHIT proteins and mRNA expression. In conclusion, arsenite decreased expressions of ATR, WWOX and FHIT via ERK1/2 activation in SV-HUC-1 cells. These findings confirm that dysregulations of these markers may contribute to arsenite-induced carcinogenesis. 23634759 Indazole-based Potent and Cell-Active Mps1 Kinase Inhibitors: Rational Design from Pan-Kinase Inhibitor Anthrapyrazolone (SP600125). Monopolar spindle 1 (Mps1) is essential for centrosome duplication, the spindle assembly check point, and the maintenance of chromosomal instability. Mps1 is highly expressed in cancer cells, and its expression levels correlate with the histological grades of cancers. Thus, selective Mps1 inhibitors offer an attractive opportunity for the development of novel cancer therapies. To design novel Mps1 inhibitors, we utilized the pan-kinase inhibitor anthrapyrazolone (4, SP600125) and its crystal structure bound to JNK1. Our design efforts led to the identification of indazole-based lead 6 with an Mps1 IC50 value of 498 nM. Optimization of the 3- and 6-positions on the indazole core of 6 resulted in 23c with improved Mps1 activity (IC50 = 3.06 nM). Finally, application of structure-based design using the X-ray structure of 23d bound to Mps1 culminated in the discovery of 32a and 32b with improved potency for cellular Mps1 and A549 lung cancer cells. Moreover, 32a and 32b exhibited reasonable selectivities over 120 and 166 kinases, respectively. 23258566 Oxygen tracer diffusion along interfaces of strained Y2O3/YSZ multilayers. Heterophase boundaries can offer fast transport paths in solid electrolyte materials. In recent studies an enhancement of the ionic conductivity was indeed observed in micro-/nanoscaled Y(2)O(3)-stabilised ZrO(2) (YSZ) composites and hetero multilayers of thin films. As space charge regions can be neglected due to high charger carrier concentrations, we assume that strain and microstructural changes at the heterophase boundaries are responsible for the observed conductivity effects. In order to obtain independent information on the role of heterophase boundaries for fast transport in strained solid electrolytes, systematic measurements of the (18)O-tracer diffusion coefficient in nanoscaled YSZ/Y(2)O(3) multilayers were performed. Multilayer samples were prepared by Pulsed Laser Deposition (PLD) on (0001) Al(2)O(3) substrates and characterised by X-Ray Diffraction (XRD), Scanning Electron Microscopy (HRSEM) and Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS). To separate interface and bulk transport from the total oxygen diffusivity of the multilayer system, the (average) thickness of the YSZ-layers in the multilayers was varied from 45 nm to 12 nm. Upon decreasing the thickness of the YSZ layers, respectively increasing the density of parallel interfaces, the total diffusion coefficient of the multilayer system is increased by a factor of 2 compared to bulk YSZ. The experimental results agree well with formerly published data for ionic conductivity measurements. They also support a negligible contribution of partial electronic conductivity in the multilayer. 23523951 Evidence of securin-mediated resistance to gefitinib-induced apoptosis in human cancer cells. Gefitinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), has been used to treat numerous cancers; however, evidence has shown that cancer cells can become resistant to gefitinib during therapy. Here, we report a human proto-oncogene, securin, which displays resistance to death in cancer cells. Gefitinib treatment decreases securin levels at the protein level by inducing protein instability but did not affect on the securin gene expression. Treatment with gefitinib induced cytotoxicity in various human cancer cell types, including RKO (colon cancer), A549 (lung cancer), BFTC905 (bladder cancer), MCF7 (breast cancer) and A375 (skin cancer). BFTC905 and A549 cells expressed relatively high levels of the phosphorylated and total EGFR proteins; however, A375, MCF7 and RKO cells did not markedly express these proteins. Moreover, following treatment with gefitinib, the securin-wild type cancer cells were more resistant to apoptotic induction than the securin-null cancer cells. Surprisingly, both the securin-wild type and securin-null cancer cells expressed the EGFR protein at similar levels. Treatment with gefitinib induced mitochondrial dysfunction, cytochrome c release, caspase-3 activation and poly (ADP-ribose) polymerase protein cleavage, indicating that apoptosis occurred in these cancer cells. The transfection of a GPF-securin expression vector increased both the proliferation rates and resistance to gefitinib-induced death in these cancer cells. Taken together, these findings demonstrate that the presence of securin promotes resistance to gefitinib-induced apoptosis via an EGFR-independent pathway in human cancer cells. 23420700 Gelatin-Methacrylamide Hydrogels as Potential Biomaterials for Fabrication of Tissue-Engineered Cartilage Constructs. Gelatin-methacrylamide (gelMA) hydrogels are shown to support chondrocyte viability and differentiation and give wide ranging mechanical properties depending on several cross-linking parameters. Polymer concentration, UV exposure time, and thermal gelation prior to UV exposure allow for control over hydrogel stiffness and swelling properties. GelMA solutions have a low viscosity at 37 °C, which is incompatible with most biofabrication approaches. However, incorporation of hyaluronic acid (HA) and/or co-deposition with thermoplastics allows gelMA to be used in biofabrication processes. These attributes may allow engineered constructs to match the natural functional variations in cartilage mechanical and geometrical properties. 23560447 Graphene MEMS: AFM Probe Performance Improvement. We explore the feasibility of growing a continuous layer of graphene in prepatterned substrates, like an engineered silicon wafer, and we apply this as a mold for the fabrication of AFM probes. This fabrication method proves the fabrication of SU-8 devices coated with graphene in a full-wafer parallel technology and with high yield. It also demonstrates that graphene coating enhances the functionality of SU-8 probes, turning them conductive and more resistant to wear. Furthermore, it opens new experimental possibilities such as studying graphene-graphene interaction at the nanoscale with the precision of an AFM or the exploration of properties in nonplanar graphene layers. 23542730 Statins decrease all-cause mortality only in CKD patients not requiring dialysis therapy-A meta-analysis of 11 randomized controlled trials involving 21,295 participants. The available studies have reported the benefits of statins on all-cause and cardiovascular mortality in chronic kidney disease (CKD) patients. However studies in end-stage renal disease patients on dialysis yielded conflicting results. Therefore, we performed a meta-analysis and provide the most reliable trial data to date on the impact of statin therapy on cardiovascular events and death from all causes in CKD patients. Data from PubMed, Web of Science, Cochrane Library, and Scopus for the years 1966 to October 2012 were searched. The final meta-analysis included 11 randomized controlled trials involving 21,295 participants with CKD. Among them 6857 were on dialysis. The use of statins in subjects with non-dialysis-dependent CKD resulted in a marked reduction in death from all causes (relative risk [RR]: 0.66; 95% confidence interval [CI]: 0.55-0.79; p<0.0001), cardiac causes (RR: 0.69; 95%CI: 0.55-0.68; p=0.0012), cardiovascular events (RR: 0.55; 95%CI: 0.4-0.75; p=0.0001) and stroke (RR: 0.66; 95%CI: 0.5-0.88; p=0.0022). The use of statins in dialysis-dependent CKD patients resulted in a non-significant effect on death from all causes (RR: 0.99; 95%CI: 0.88-1.11; p=0.85) and stroke (RR: 1.31; 95%CI: 0.9-1.89; p>0.05), but had the effect of reducing death from cardiac causes (RR: 0.79; 95%CI: 0.64-0.98; p<0.05) and cardiovascular events (RR: 0.81; 95%CI: 0.7-0.94; p<0.05). In conclusion, the use of statins should be indicated in cardiovascular disease prevention especially in patients with non-dialysis-dependent CKD. According to the very limited data the obtained results suggest caution in expecting a reduction in cardiovascular events in patients on dialysis. 23617426 Interview with m frederick hawthorne. M Frederick Hawthorne is a world-renowned scientist in the field of molecular medicine and a pioneer in boron chemistry. He currently serves as the founding Director of the University of Missouri International Institute of Nano and Molecular Medicine (MO, USA). Prof. Hawthorne is a University of Missouri Curators' Distinguished Professor and University Professor of Chemistry Emeritus of the University of California, Los Angeles (CA, USA). He is a member of the US National Academy of Sciences and the recipient of many national and international honors, including the 2003 King Faisal Prize in Science, the American Chemical Society's 2009 Priestley Medal and the 2011 National Medal of Science. Prof. Hawthorne has authored or co-authored more than 540 research articles, 30 patents, ten book chapters and two books. Prof. Hawthorne spoke to Future Medicinal Chemistry on how he became involved in the field, the future of boron neutron capture therapy, and provides his advice for the next generation of boron scientists. Interview conducted by Isaac Bruce, Managing Commissioning Editor. 23302007 A powerful aluminum catalyst for the synthesis of highly functional organic carbonates. An aluminum complex based on an amino triphenolate ligand scaffold shows unprecedented high activity (initial TOFs up to 36,000 h(-1)), broad substrate scope, and functional group tolerance in the formation of highly functional organic carbonates prepared from epoxides and CO(2). The developed catalytic protocol is further characterized by low catalyst loadings and relative mild reaction conditions using a cheap, abundant, and nontoxic metal. 23313345 Exogenous T3 administration provides neuroprotection in a murine model of traumatic brain injury. Traumatic brain injury (TBI) induces primary and secondary damage in both the endothelium and the brain parenchyma. While neurons die quickly by necrosis, a vicious cycle of secondary injury in endothelial cells exacerbates the initial injury. Thyroid hormones are reported to be decreased in patients with brain injury. Controlled cortical impact injury (CCI) is a widely used, clinically relevant model of TBI. Here, using CCI in adult male mice, we set to determine whether 3,5,3'-triiodothyronine (T3) attenuates posttraumatic neurodegeneration and neuroinflammation in an experimental model of TBI. Treatment with T3 (1.2μg/100g body weight, i.p.) 1h after TBI resulted in a significant improvement in motor and cognitive recovery after CCI, as well as in marked reduction of lesion volumes. Mouse model for brain injury showed reactive astrocytes with increased glial fibrillary acidic protein, and formation of inducible nitric oxide synthase (iNOS). Western blot analysis revealed the ability of T3 to reduce brain trauma through modulation of cytoplasmic-nuclear shuttling of nuclear factor-κB (NF-κB). Twenty-four hours after brain trauma, T3-treated mice also showed significantly lower number of TUNEL(+) apoptotic neurons and curtailed induction of Bax, compared to vehicle control. In addition, T3 significantly enhanced the post-TBI expression of the neuroprotective neurotrophins (BDNF and GDNF) compared to vehicle. Our data provide an additional mechanism for the anti-inflammatory effects of thyroid hormone with critical implications in immunopathology at the cross-roads of the immune-endocrine circuits. 22426233 Functional selectivity induced by mGlu₄ receptor positive allosteric modulation and concomitant activation of Gq coupled receptors. Metabotropic glutamate receptors (mGlus) are a group of Family C Seven Transmembrane Spanning Receptors (7TMRs) that play important roles in modulating signaling transduction, particularly within the central nervous system. mGlu(4) belongs to a subfamily of mGlus that is predominantly coupled to G(i/o) G proteins. We now report that the ubiquitous autacoid and neuromodulator, histamine, induces substantial glutamate-activated calcium mobilization in mGlu(4)-expressing cells, an effect which is observed in the absence of co-expressed chimeric G proteins. This strong induction of calcium signaling downstream of glutamate activation of mGlu(4) depends upon the presence of H(1) histamine receptors. Interestingly, the potentiating effect of histamine activation does not extend to other mGlu(4)-mediated signaling events downstream of G(i/o) G proteins, such as cAMP inhibition, suggesting that the presence of G(q) coupled receptors such as H(1) may bias normal mGlu(4)-mediated G(i/o) signaling events. When the activity induced by small molecule positive allosteric modulators of mGlu(4) is assessed, the potentiated signaling of mGlu(4) is further biased by histamine toward calcium-dependent pathways. These results suggest that G(i/o)-coupled mGlus may induce substantial, and potentially unexpected, calcium-mediated signaling events if stimulation occurs concomitantly with activation of G(q) receptors. Additionally, our results suggest that signaling induced by small molecule positive allosteric modulators may be substantially biased when G(q) receptors are co-activated. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23623417 Melanogenesis inhibitory daphnane diterpenoids from the flower buds of Daphne genkwa. Two new daphnane-type diterpene esters, daphneresiniferins A (1) and B (2), along with seven known diterpenes, yuanhuacine (3), yuanhuadine (4), yuanhuahine (5), genkwadaphnin (6), genkwanine A (7), genkwanine F (8), and genkwanine H (9), were isolated from the methanol extract of the flower buds of Daphne genkwa. Their structures were elucidated on the basis of spectroscopic methods, especially 2D NMR spectra such as HMQC, HMBC, and NOESY. All the isolates were evaluated for their inhibitory effects of the melanogenesis against α-melanocyte stimulating hormone (α-MSH)-activated B16 melanoma cells. 23169609 Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjects. The disposition of ertugliflozin (PF-04971729), an orally active selective inhibitor of the sodium-dependent glucose cotransporter 2, was studied after a single 25-mg oral dose of [(14)C]-ertugliflozin to healthy human subjects. Mass balance was achieved with approximately 91% of the administered dose recovered in urine and feces. The total administered radioactivity excreted in feces and urine was 40.9% and 50.2%, respectively. The absorption of ertugliflozin in humans was rapid with a T(max) at ∼1.0 hour. Of the total radioactivity excreted in feces and urine, unchanged ertugliflozin collectively accounted for ∼35.3% of the dose, suggestive of moderate metabolic elimination in humans. The principal biotransformation pathway involved glucuronidation of the glycoside hydroxyl groups to yield three regioisomeric metabolites, M4a, M4b, and M4c (∼39.3% of the dose in urine), of which M4c was the major regioisomer (∼31.7% of the dose). The structure of M4a and M4c were confirmed to be ertugliflozin -4-O-β- and -3-O-β-glucuronide, respectively, via comparison of the HPLC retention time and mass spectra with authentic standards. A minor metabolic fate involved oxidation by cytochrome P450 to yield monohydroxylated metabolites M1 and M3 and des-ethyl ertugliflozin (M2), which accounted for ∼5.2% of the dose in excreta. In plasma, unchanged ertugliflozin and the corresponding 4-O-β- (M4a) and 3-O-β- (M4c) glucuronides were the principal components, which accounted for 49.9, 12.2, and 24.1% of the circulating radioactivity. Overall, these data suggest that ertugliflozin is well absorbed in humans, and eliminated largely via glucuronidation. 22732147 Melamine in prenatal and postnatal organs in rats. Melamine can be transferred to fetus in utero through placenta and to infant ex utero by breast feeding. In this study, we characterized the pharmacokinetics of melamine in prenatal and postnatal organs in rats. Single bolus of melamine was administered to pregnant rats at different gestational stages and to infants at different postnatal stages. Distribution of melamine in maternal serum was about 30% higher in late pregnancy than that in early pregnancy; and it was 2 folds higher in postnatal serum in early infants in young adulthood. Distribution of melamine in all postnatal organs was higher than that in prenatal organs. Postnatal kidneys in early infants had the highest maximum concentration and the lowest clearance of melamine than the other postnatal organs. It may relate to the high vulnerability to the toxicity of melamine in this population. 23279865 Structure-based design, synthesis and evaluation of novel anthra[1,2-d]imidazole-6,11-dione derivatives as telomerase inhibitors and potential for cancer polypharmacology. A series of anthra[1,2-d]imidazole-6,11-dione derivatives were synthesized and evaluated for telomerase inhibition, hTERT expression and suppression of cancer cell growth in vitro. All of the compounds tested, except for compounds 4, 7, 16, 24, 27 and 28 were selected by the NCI screening system. Among them, compounds 16, 39, and 40 repressed hTERT expression without greatly affecting cell growth, suggesting for the selectivity toward hTERT expression. Taken together, our findings indicated that the analysis of cytotoxicity and telomerase inhibition might provide information applicable for further developing potential telomerase and polypharmacological targeting strategy. 23344974 Using a fragment-based approach to target protein-protein interactions. The ability to identify inhibitors of protein-protein interactions represents a major challenge in modern drug discovery and in the development of tools for chemical biology. In recent years, fragment-based approaches have emerged as a new methodology in drug discovery; however, few examples of small molecules that are active against chemotherapeutic targets have been published. Herein, we describe the fragment-based approach of targeting the interaction between the tumour suppressor BRCA2 and the recombination enzyme RAD51; it makes use of a screening pipeline of biophysical techniques that we expect to be more generally applicable to similar targets. Disruption of this interaction in vivo is hypothesised to give rise to cellular hypersensitivity to radiation and genotoxic drugs. We have used protein engineering to create a monomeric form of RAD51 by humanising a thermostable archaeal orthologue, RadA, and used this protein for fragment screening. The initial fragment hits were thoroughly validated biophysically by isothermal titration calorimetry (ITC) and NMR techniques and observed by X-ray crystallography to bind in a shallow surface pocket that is occupied in the native complex by the side chain of a phenylalanine from the conserved FxxA interaction motif found in BRCA2. This represents the first report of fragments or any small molecule binding at this protein-protein interaction site. 23454189 PK/PD assessment in CNS drug discovery: Prediction of CSF concentration in rodents for P-glycoprotein substrates and application to in vivo potency estimation. The unbound drug concentration in brain parenchyma is considered to be the relevant driver for interaction with central nervous system (CNS) biological targets. Drug levels in cerebrospinal fluid (C_CSF) are frequently used surrogates for the unbound concentrations in brain. For drugs actively transported across the blood-brain barrier (BBB), C_CSF differs from unbound plasma concentration (Cu_p) to an extent that is commonly unknown. In this study, the relationship between CSF-to-unbound plasma drug partitioning in rats and the mouse Pgp (Mdr1a) efflux ratio (ER) obtained from in vitro transcellular studies has been investigated for a set of 61 CNS compounds exhibiting substantial diversity in chemical structure and physico-chemical properties. In order to understand the in vitro-in vivo extrapolation of Pgp efflux, a mechanistic model was derived relating in vivo CNS distribution kinetics to in vitro active transport. The model was applied to predict C_CSF from Cu_p and ER data for 19 proprietary Roche CNS drug candidates. The calculated CSF concentrations were correlated with CNS pharmacodynamic responses observed in rodent models. The correlation between in vitro and in vivo potency for different pharmacological endpoints indicated that the predicted C_CSF is a valuable surrogate of the concentration at the target site. Overall, C_CSF proved superior description of PK/PD data than unbound plasma or total brain concentration for Mdr1a substrates. Predicted C_CSF can be used as a default approach to understand the PK/PD relationships in CNS efficacy models and can support the extrapolation of efficacious brain exposure for new drug candidates from rodent to man. 23529829 Skeletal clinical characteristics of osteogenesis imperfecta caused by haploinsufficiency mutations in COL1A1. COL1A1 haploinsufficiency mutations lead to the mildest form of osteogenesis imperfecta (OI), OI type I. The skeletal clinical characteristics resulting from such mutations have not been characterized in detail. In this study we assessed 86 patients (36 male, 50 female; mean age 13.3 years; range 0.6 to 54 years) with COL1A1 haploinsufficiency mutations, of whom 70 were aged 21 years or less ('pediatric' patients). Birth history was positive for fracture or long-bone deformity in 12% of patients. The average rate of long-bone fracture (femur, tibia/fibula, humerus, radius /ulna) in pediatric patients was 0.62 fractures per year, half of which affected the tibia/fibula. Long-bone fracture rate was negatively associated with age and lumbar spine areal bone mineral density. Vertebral compression fractures were observed in 71% of the 58 pediatric patients who had lateral spine radiographs. The median number of vertebral fractures was higher for females (median 4; range 0 to 14) than for males (median 1, range 0 to 8) (P = 0.03). Lumbar spine areal bone mineral density was negatively associated with the severity of vertebral compression fractures, as reflected in the spine deformity index. Scoliosis was present in about 30% of pediatric patients but the Cobb angle was <30 degrees in all cases. The average final height z-score was -1.1, representing a deficit of 8 to 10 cm compared to the general population. In summary, OI patients with COL1A1 haploinsufficiency mutations have high rates of significant skeletal involvement. Systematic follow up of growing patients with COL1A1 haploinsufficiency mutations including radiographic screening for vertebral compression fractures and scoliosis is warranted. © 2013 American Society for Bone and Mineral Research. 22991246 Meta-analysis of vertebral augmentation compared with conservative treatment for osteoporotic spinal fractures. Cement augmentation is a controversial treatment for painful vertebral compression fractures (VCF). Our research questions for the meta-analysis were: Is there a clinical and statistical difference in pain relief, functional improvement, and quality of life between conservative care and cement augmentation for VCF and, if so, are they maintained at longer time points? We conducted a search of MEDLINE from January 1980 to July 2011 using PubMed, Cochrane Database of Systematic Reviews and Controlled Trials, CINAHL, and EMBASE. Searches were performed from medical subject headings. Terms "vertebroplasty" and "compression fracture" were used. The outcome variables of pain, functional measures, health-related quality of life (HRQOL), and new fracture risk were analyzed. A random effects model was chosen. Continuous variables were calculated using the standardized mean difference comparing improvement from baseline of the experimental group with the control group. New vertebral fracture risk was calculated using log odds ratio. Six studies met the criteria. The pain visual analog scale (VAS) mean difference was 0.73 (confidence interval [CI] 0.35, 1.10) for early (<12 weeks) and 0.58 (CI 0.19, 0.97) for late time points (6 to 12 months), favoring vertebroplasty (p < 0.001). The functional outcomes at early and late time points were statistically significant with 1.08 (CI 0.33, 1.82) and 1.16 (CI 0.14, 2.18), respectively. The HRQOL showed superior results of vertebroplasty compared with conservative care at early and late time points of 0.39 (CI 0.16, 0.62) and 0.33 (CI 0.16, 0.51), respectively. Secondary fractures were not statistically different between the groups, 0.065 (CI -0.57, 0.70). This meta-analysis showed greater pain relief, functional recovery, and health-related quality of life with cement augmentation compared with controls. Cement augmentation results were significant in the early (<12 weeks) and the late time points (6 to 12 months). This meta-analysis provides strong evidence in favor of cement augmentation in the treatment of symptomatic VCF fractures. 23142104 Nanomedicine for the treatment of retinal and optic nerve diseases. The earliest impact of nanomedicine in ophthalmology is likely to involve the areas of biopharmaceuticals, implantable materials (e.g. tissue regeneration scaffolds, bioresorbable materials), implantable devices (e.g. glaucoma drainage valves), and diagnostic tools (e.g. intraocular pressure (IOP) monitors). Nanotechnology will bring about the development of regenerative medicine (i.e. replacement and improvement of cells, tissues, and organs) and artificial vision. In this chapter, we review ophthalmic applications of nanotechnology in the following areas: drug and trophic factor therapy for glaucoma, retinal degenerative, and retinal vascular disease; gene therapy for retinal degenerative disease; regenerative medicine, including optogenetics and optic nerve regeneration; and diagnostics (minimally invasive IOP monitoring). Nanotechnology will play an important role in both early-stage and late-stage intervention in the management of blinding diseases. 23594027 DFT Modeling of 45S5 and 77S Soda-Lime Phospho-Silicate Glass Surfaces: Clues on Different Bioactivity Mechanism. The reactivity of bioglasses, which is related to the dissolution of cations and orthosilicate groups in the physiological fluid, strongly depends on the key structural features present at the glass surfaces. On the basis of the composition and the synthetic routes employed to make the glass, surfaces with very different characteristics and thus presenting different mechanisms of dissolution can be observed. In this paper, the surface structures of two very different bioglass compositions, namely 45S5 (46.1 SiO2, 24.4 Na2O, 26.9 CaO, and 2.6 P2O5 mol %) and 77S (80.0 SiO2, 16.0 CaO, and 4.0 P2O5 mol %), have been investigated by means of periodic DFT calculations based on a PBE functional and localized Gaussian basis set as encoded in the CRYSTAL code. Our calculations show that the two glass surfaces differ by the relative amount of key structural sites such as NBOs, exposed ions, orthosilicate units, and small rings. We have demonstrated how the number of these sites affects the surface stability and reactivity (bioactivity). 23350785 A novel approach to active compounds identification based on support vector regression model and mean impact value. Traditionally, active compounds were discovered from natural product extracts by bioassay-guided fractionation, which was with high cost and low efficiency. A well-trained support vector regression model based on mean impact value was used to identify lead active compounds on inhibiting the proliferation of the HeLa cells in curcuminoids from Curcuma longa L. Eight constituents possessing the high absolute mean impact value were identified to have significant cytotoxicity, and the cytotoxic effect of these constituents was partly confirmed by subsequent MTT (3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays and previous reports. In the dosage range of 0.2-211.2, 0.1-140.2, 0.2-149.9 μm, 50% inhibiting concentrations (IC50 ) of curcumin, demethoxycurcumin, and bisdemethoxycurcumin were 26.99 ± 1.11, 19.90 ± 1.22, and 35.51 ± 7.29 μm, respectively. It was demonstrated that our method could successfully identify lead active compounds in curcuminoids from Curcuma longa L. prior to bioassay-guided separation. The use of a support vector regression model combined with mean impact value analysis could provide an efficient and economical approach for drug discovery from natural products. 23583456 A comprehensive machine-readable view of the mammalian cholesterol biosynthesis pathway. Cholesterol biosynthesis serves as a central metabolic hub for numerous biological processes in health and disease. A detailed, integrative single-view description of how the cholesterol pathway is structured and how it interacts with other pathway systems is lacking in the existing literature. Here we provide a systematic review of the existing literature and present a detailed pathway diagram that describes the cholesterol biosynthesis pathway (the mevalonate, the Kandutch-Russell and the Bloch pathway) and shunt pathway that leads to 24(S),25-epoxycholesterol synthesis. The diagram has been produced using the Systems Biology Graphical Notation (SBGN) and is available in the SBGN-ML format, a human readable and machine semantically parsable open community file format. 23580316 Anti-Ulcerative Colitis Activity of Compounds from Euphorbia granuleta Forssk. The aim of the present study was to evaluate the anti-ulcerative colitis (UC) activity of the total alcohol extracts of Euphorbia granuleta Forssk. (Euphorpiaceae), isolate and identify the active compounds that could be responsible for the activity, in addition to determination of the possible mechanism of action. Six compounds were isolated and identified from this plant: three phenolic compounds (kampferol, kampferol-3-glucoside and kampferol-3-galactoside) in addition to three steroidal compounds (1-ethoxypentacosane, heptacosan-1-ol and β-sitosterol). Three compounds (heptacosan-1-ol, β-sitosterol and kampferol-3-galactoside) were found to be responsible for the anti-UC activity of E. granuleta extract. The anti-UC activity of these compounds may be explained by reducing the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α), in addition to reduction of colonic malondialdehyde (MDA) contents. No side effects were reported on liver and kidney functions. The active compounds reduced both serum TNF-α and mucosal MDA levels. Copyright © 2013 John Wiley & Sons, Ltd. 22241176 A simple detection system for adenovirus receptor expression using a telomerase-specific replication-competent adenovirus. Adenovirus serotype 5 (Ad5) is frequently used as an effective vector for induction of therapeutic transgenes in cancer gene therapy or of tumor cell lysis in oncolytic virotherapy. Ad5 can infect target cells through binding with the coxsackie and adenovirus receptor (CAR). Thus, the infectious ability of Ad5-based vectors depends on the CAR expression level in target cells. There are conventional methods to evaluate the CAR expression level in human target cells, including flow cytometry, western blotting and immunohistochemistry. Here, we show a simple system for detection and assessment of functional CAR expression in human tumor cells, using the green fluorescent protein (GFP)-expressing telomerase-specific replication-competent adenovirus OBP-401. OBP-401 infection induced detectable GFP expression in CAR-expressing tumor cells, but not in CAR-negative tumor cells, nor in CAR-positive normal fibroblasts, 24 h after infection. OBP-401-mediated GFP expression was significantly associated with CAR expression in tumor cells. OBP-401 infection detected tumor cells with low CAR expression more efficiently than conventional methods. OBP-401 also distinguished CAR-positive tumor tissues from CAR-negative tumor and normal tissues in biopsy samples. These results suggest that GFP-expressing telomerase-specific replication-competent adenovirus is a very potent diagnostic tool for assessment of functional CAR expression in tumor cells for Ad5-based antitumor therapy. 23638960 Structural revision of methyl tortuoate D, a bis-cembranoid from Hainan Sarcophyton tortuosum and its absolute stereochemistry. Methyl tortuoate D (1), together with five other known related bis-cembranoids, was isolated from Hainan soft coral Sarcophyton tortuosum. The structure of methyl tortuoate D (1a), firstly isolated and reported by Li et al. from the title organism, was corrected as 1 by an extensive analysis of its one-dimensional and two-dimensional nuclear magnetic resonance data and by comparison with those reported in the literature. In addition, lobophytone K (1b), recently isolated from Hainan soft coral Lobophytum pauciflorum by Lin et al., was proved to be the same compound as 1 and 1a. The absolute configuration of 1 was determined by comparing its electronic circular dichroism curve with that of co-occurring ximaolide A (2). 23577871 Natural Products Containing a Nitrogen-Nitrogen Bond. As of early 2013, over 200 natural products are known to contain a nitrogen-nitrogen (N-N) bond. This report categorizes these compounds by structural class and details their isolation and biological activity. 23301955 Increasing the order parameter of quasi-hexagonal micellar nanostructures by ultrasound annealing. Nanopatterning with block copolymers finds many applications ranging from optics to bioscience. Many of these uses demand highly ordered patterns that are difficult to obtain because of environmental influences during fabrication. Here we demonstrate that ultrasonication improves the hexagonal order of artificially disturbed micellar nanopatterns. 23578689 Conformationally restricted homotryptamines. Part 6: Indole-5-cycloalkyl methylamines as selective serotonin reuptake inhibitors. Racemic 5-(trans-2-aminomethylcyclopropyl)indoles, 5-(trans-2-aminomethylcyclopentyl) indoles, and 5-(cis-2-aminomethylcyclopentyl)indoles were synthesized and evaluated as selective serotonin reuptake inhibitors. These analogs followed SAR trends similar to those previously reported for 3-cycloalkyl substituted indoles. The most potent analogs exhibited single digit nanomolar inhibition at the human serotonin transporter but were 10-fold less active than the previously reported compounds. 23524567 FGFR4 genetic polymorphisms determine the chemotherapy response of Chinese patients with non-small cell lung cancer. Aim:To investigate the relationship of fibroblast growth factor receptor 4 (FGFR4) gene polymorphisms with the response of Chinese patients with non-small cell lung cancer (NSCLC) to chemotherapy.Methods:A total of 629 patients with Stage III (A+B) or IV NSCLC, as well as 729 age- and gender-matched healthy controls were recruited. All the patients received platinum-based chemotherapy, and the therapeutic effects were evaluated. Three polymorphisms in the FGFR4 gene (rs351855G/A, rs145302848C/G, and rs147603016G/A) were genotyped, and the association between the 3 polymorphisms and the chemotherapy effect was analyzed using SPSS software, version 16.0.Results:The genotype frequencies of rs145302848C/G and rs147603016G/A were not significantly different between NSCLC patients and healthy controls on one hand, and between the responders and non-responders to the chemotherapy on the other hand. The distribution of AA genotype and A-allele of rs351855G/A was significantly lower in NSCLC patients than in healthy controls. Using patients with the GG genotype as a reference, the AA carrier had a significantly reduced risk for the development of NSCLC after normalizing to age, sex and smoking habits. In NSCLC patients, this genotype occurred more frequently in the responders to the chemotherapy than in non-responders. The chance of being a responder was significantly increased with the AA genotype as compared to G genotype. The AA genotype of rs351855G/A had a better prognosis compared with GA and GG genotype carriers: the overall survival of patients with the AA genotype of rs351855G/A was significantly longer than those with the GG+GA genotype (21.1 vs 16.5 months).Conclusion:The rs351855G/A polymorphisms of FGFR4 gene can be used to predict the occurrence, chemotherapy response and prognosis of NSCLC. 22796428 A selective dopamine reuptake inhibitor improves prefrontal cortex-dependent cognitive function: potential relevance to attention deficit hyperactivity disorder. Drugs used to treat attention deficit hyperactivity disorder (ADHD) improve prefrontal cortex (PFC)-dependent cognitive function. The majority of ADHD-related treatments act either as dual norepinephrine (NE) and dopamine (DA) reuptake inhibitors (psychostimulants) or selective NE reuptake inhibitors (SNRIs). Certain benztropine analogs act as highly selective DA reuptake inhibitors while lacking the reinforcing actions, and thus abuse potential, of psychostimulants. To assess the potential use of these compounds in the treatment of ADHD, we examined the effects of a well-characterized benztropine analog, AHN 2-005, on performance of rats in a PFC-dependent delayed-alternation task of spatial working memory. Similar to that seen with all drugs currently approved for ADHD, AHN 2-005 dose-dependently improved performance in this task. Clinically-relevant doses of psychostimulants and SNRIs elevate NE and DA preferentially in the PFC. Despite the selectivity of this compound for the DA transporter, additional microdialysis studies demonstrated that a cognition-enhancing dose of AHN 2-005 that lacked locomotor activating effects increased extracellular levels of both DA and NE in the PFC. AHN 2-005 produced a larger increase in extracellular DA in the nucleus accumbens, although the magnitude of this was well below that seen with motor activating doses of psychostimulants. Collectively, these observations suggest that benztropine analogs may be efficacious in the treatment of ADHD or other disorders associated with PFC dysfunction. These studies provide a strong rationale for future research focused on the neural mechanisms contributing to the cognition-enhancing actions and the potential clinical utility of AHN 2-005 and related compounds. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23317370 What happens to the thiolates created by reductively desorbing SAMs? An in situ study using fluorescence microscopy and electrochemistry. In situ examination of the reductive desorption process for Au microelectrodes modified with a thiol self-assembled monolayer (SAM) using fluorescence microscopy enabled the study of the fate of the desorbed thiolate species. The Bodipy labeled alkyl-thiol SAM, when adsorbed, is not fluorescent due to quenching by the Au surface. Once reductively desorbed, the thiolate molecules fluoresce and their direction and speed are monitored. At moderately negative reduction potentials, the thiolate species hemispherically diffuse away from the microelectrode. Also observed is the influence of a closely positioned counter electrode on the direction of the desorbed thiolate movement. As the potential becomes more negative, the molecules move in an upward direction, with a speed that depends on the amount of dissolved H(2) produced by water reduction. Shown is that this motion is controlled, in large part, by the change in the electrolyte density near the electrode due to dissolved H(2). These results should help in explaining the extent of readsorption at oxidative potentials observed in cyclic voltammetry (CV) reductive desorption measurements, as well as improving the general understanding of the SAM removal process by reductive desorption. The electrogenerated H(2) was also shown to be able to reductively remove the thiol SAM from the Pt/Ir particles that decorate the microelectrode glass sheath. 23093496 Identification of determinants required for agonistic and inverse agonistic ligand properties at the ADP receptor P2Y12. The ADP receptor P2Y(12) belongs to the superfamily of G protein-coupled receptors (GPCRs), and its activation triggers platelet aggregation. Therefore, potent antagonists, such as clopidogrel, are of high clinical relevance in prophylaxis and treatment of thromboembolic events. P2Y(12) displays an elevated basal activity in vitro, and as such, inverse agonists may be therapeutically beneficial compared with antagonists. Only a few inverse agonists of P2Y(12) have been described. To expand this limited chemical space and improve understanding of structural determinants of inverse agonist-receptor interaction, this study screened a purine compound library for lead structures using wild-type (WT) human P2Y(12) and 28 constitutively active mutants. Results showed that ATP and ATP derivatives are agonists at P2Y(12). The potency at P2Y(12) was 2-(methylthio)-ADP > 2-(methylthio)-ATP > ADP > ATP. Determinants required for agonistic ligand activity were identified. Molecular docking studies revealed a binding pocket for the ATP derivatives that is bordered by transmembrane helices 3, 5, 6, and 7 in human P2Y(12,) with Y(105), E(188), R(256), Y(259), and K(280) playing a particularly important role in ligand interaction. N-Methyl-anthraniloyl modification at the 3'-OH of the 2'-deoxyribose leads to ligands (mant-deoxy-ATP [dATP], mant-deoxy-ADP) with inverse agonist activity. Inverse agonist activity of mant-dATP was found at the WT human P2Y(12) and half of the constitutive active P2Y(12) mutants. This study showed that, in addition to ADP and ATP, other ATP derivatives are not only ligands of P2Y(12) but also agonists. Modification of the ribose within ATP can result in inverse activity of ATP-derived ligands. 23631498 Inhibition of Foodborne Pathogens by Pomegranate Juice. Abstract Pomegranates have health-promoting benefits because of their polyphenol constituents. Previous studies have demonstrated the antimicrobial activity of aqueous and organic extracts of pomegranate components and by-products. We sought to determine the antimicrobial activity against 40 foodborne pathogens representing eight bacterial species using juice itself. In addition, we sought to determine the synergistic antimicrobial activity between pomegranate juice and other plant products displaying antimicrobial activity. The antimicrobial activity of pomegranate juice was dependent on the test organism, which varied to highly susceptible (four Gram-positive species) to unaffected (Salmonella and Escherichia coli O157:H7). Two Gram-negative species, which were inhibited were Helicobacter pylori and Vibrio parahemolyticus. No synergistic antimicrobial activity was seen between pomegranate and either barberry, oregano, or cranberry. The antimicrobial activity of pomegranate juice is dependent on the test organism and extraction method. The sensitivity of H. pylori suggests that pomegranate juice may be an alternative or supplemental treatment for gastric ulcers caused by this organism. 23576111 Protective effects of green tea on antioxidative biomarkers in chemical laboratory workers. Chemical materials are environmental contaminants, are extensively used in laboratories, and may cause various forms of health hazards in laboratory workers. Therefore, this toxicity most likely is a result of the oxidative metabolism of chemical to reactive products. As green tea (GT) possesses antioxidant effects, the objective of this study was to examine any amelioration oxidative stress in chemical laboratory workers drinking one cup (3 g/300 ml water) of freshly prepared tea once daily. Baseline characteristics including age, sex, smoking, fruit consumption, and duration of exposure were recorded via questionnaire to the subjects. Saliva level oxidative stress parameters such as total antioxidant capacity (TAC), glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) were estimated before and after consumption of GT in these workers. Treatment of subjects with GT induced a significant reduction in saliva GPx activity (406.61 ± 22.07 vs. 238.96 ± 16.26 U/l p = 0.001) and induction in TAC (0.46 ± 0.029 μmol/ml vs. 0.56 ± 0.031, p = 0.016). No statistically significant alteration was found for saliva SOD (0.080 ± 0.0019 vs. 0.079 ± 0.0014, p > 0.05) and CAT (20.36 ± 0.69 vs. 19.78 ± 0.71, p > 0.05) after 28 days treatment by GT. These results demonstrate that drinking GT during chemical exposure can reduce several parameters indicative of oxidative stress. In conclusion, using GT as a dietary supplement can be a rational protocol to control source of hazards in chemical laboratory workers. 23161868 Ras-dva is a novel Pit-1- and glucocorticoid-regulated gene in the embryonic anterior pituitary gland. Glucocorticoids play a role in functional differentiation of pituitary somatotrophs and lactotrophs during embryogenesis. Ras-dva was identified as a gene regulated by anterior neural fold protein-1/homeobox expressed in embryonic stem cells-1, a transcription factor known to be critical in pituitary development, and has an expression profile in the chicken embryonic pituitary gland that is consistent with in vivo regulation by glucocorticoids. The objective of this study was to characterize expression and regulation of ras-dva mRNA in the developing chicken anterior pituitary. Pituitary ras-dva mRNA levels increased during embryogenesis to a maximum on embryonic day (e) 18 and then decreased and remained low or undetectable after hatch. Ras-dva expression was highly enriched in the pituitary gland on e18 relative to other tissues examined. Glucocorticoid treatment of pituitary cells from mid- and late-stage embryos rapidly increased ras-dva mRNA, suggesting it may be a direct transcriptional target of glucocorticoids. A reporter construct driven by 4 kb of the chicken ras-dva 5'-flanking region, containing six putative pituitary-specific transcription factor-1 (Pit-1) binding sites and two potential glucocorticoid receptor (GR) binding sites, was highly activated in embryonic pituitary cells and up-regulated by corticosterone. Mutagenesis of the most proximal Pit-1 site decreased promoter activity in chicken e11 pituitary cells, indicating regulation of ras-dva by Pit-1. However, mutating putative GR binding sites did not substantially reduce induction of ras-dva promoter activity by corticosterone, suggesting additional DNA elements within the 5'-flanking region are responsible for glucocorticoid regulation. We have identified ras-dva as a glucocorticoid-regulated gene that is likely expressed in cells of the Pit-1 lineage within the developing anterior pituitary gland. 23565325 The C-terminus of Botulinum A Protease Has Profound and Unanticipated Kinetic Consequences Upon the Catalytic Cleft. Botulinum neurotoxins (BoNTs) are among the most deadly poisons known though ironically, they also are of great therapeutic utility. A number of research programs have been initiated to discover small molecule inhibitors of BoNTs metalloprotease activity. Many, though not all of these programs have screened against a truncated and more stable form of the enzyme, that possess comparable catalytic properties to the full length enzyme. Interestingly, several classes of inhibitors notably the hydroxamates, display a large shift in potency between the two enzyme forms. In this report we compare the kinetics of active-site, alpha-exosite and beta-exosite inhibitors versus truncated and full length enzyme. Molecular dynamics simulations conducted with the truncated and homology models of the fully length BoNT LC/A indicate the flexibility of the C-terminus of the full length enzyme is responsible for the potency shifts of active-site proximally binding inhibitors while distal binding (alpha-exosite) inhibitors remain equipotent. 22986947 Purinergic receptor antagonist a438079 protects against acetaminophen-induced liver injury by inhibiting p450 isoenzymes, not by inflammasome activation. Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in the western world. Controversy exists regarding the hypothesis that the hepatocyte injury is amplified by a sterile inflammatory response, rather than being the result of intracellular mechanisms alone. A recent study suggested that the purinergic receptor antagonist A438079 protects against APAP-induced liver injury by preventing the activation of the Nalp3 inflammasome in Kupffer cells and thereby preventing inflammatory injury. To test the hypothesis that A438079 actually affects the intracellular signaling events in hepatocytes, C57Bl/6 mice were treated with APAP (300 mg/kg) and A438079 (80 mg/kg) or saline and GSH depletion, protein adduct formation, c-jun-N-terminal kinase (JNK) activation, oxidant stress, and liver cell necrosis were determined between 0 and 6 h after APAP administration. APAP caused rapid GSH depletion, extensive protein adduct formation in liver homogenates and in mitochondria, JNK phosphorylation and mitochondrial translocation of phospho-JNK within 2 h, oxidant stress, and extensive centrilobular necrosis at 6 h. A438079 significantly attenuated GSH depletion, which resulted in a 50% reduction of total liver and mitochondrial protein adducts and substantial reduction of JNK activation, mitochondrial P-JNK translocation, oxidant stress, and liver injury. The same results were obtained using primary mouse hepatocytes. A438079 did not directly affect JNK activation induced by tert-butyl hydroperoxide and GSH depletion. However, A438079 dose-dependently inhibited hepatic P450 enzyme activity. Thus, the protective effect of A438079 against APAP hepatotoxicity in vivo can be explained by its effect on metabolic activation and cell death pathways in hepatocytes without involvement of the Nalp3 inflammasome. 23395967 In vitro activity of scorpiand-like azamacrocycle derivatives in promastigotes and intracellular amastigotes of Leishmania infantum and Leishmania braziliensis. The activity of a family scorpiand-like azamacrocycles against Leishmania infantum and Leishmania braziliensis was studied using promastigotes, axenic and intracellular amastigotes forms. All the compounds are more active and less toxic than meglumine antimoniate (Glucantime). Moreover, the data on infection rates and amastigotes showed that compounds P2Py, PN and P3Py are the most active against both species of Leishmania. On the other hand, studies on the inhibitory effect of these compounds on SOD enzymes showed that while the inhibition of the Fe-SOD enzyme of the promastigote forms of the parasites is remarkable, the inhibition of human CuZn-SOD and Mn-SOD from Escherichia coli is negligible. The ultrastructural alterations observed in treated promastigote forms confirmed that the compounds having the highest activity were those causing the largest cell damage. The modifications observed by (1)H NMR, and the amounts of catabolites excreted by the parasites after treatment with the compounds, suggested that the catabolic mechanism could depend on the structure of the side chains linked to the aza-scorpiand macrocycles. 23444386 Modification of the Catalytic Function of Human Hydroxysteroid Sulfotransferase hSULT2A1 by Formation of Disulfide Bonds. The human cytosolic sulfotransferase hSULT2A1 catalyzes the sulfation of a broad range of xenobiotics, as well as endogenous hydroxysteroids and bile acids. Reversible modulation of the catalytic activity of this enzyme could play important roles in its physiologic functions. Whereas other mammalian sulfotransferases are known to be reversibly altered by changes in their redox environment, this has not been previously shown for hSULT2A1. We have examined the hypothesis that the formation of disulfide bonds in hSULT2A1 can reversibly regulate the catalytic function of the enzyme. Three thiol oxidants were used as model compounds to investigate their effects on homogeneous preparations of hSULT2A1: glutathione disulfide, 5,5'-dithiobis(2-nitrobenzoic acid), and 1,1'-azobis(N,N-dimethylformamide) (diamide). Examination of the effects of disulfide bond formation with these agents indicated that the activity of the enzyme is reversibly altered. Studies on the kinetics of the hSULT2A1-catalyzed sulfation of dehydroepiandrosterone (DHEA) showed the effects of disulfide bond formation on the substrate inhibition characteristics of the enzyme. The effects of these agents on the binding of substrates and products, liquid chromatography-mass spectrometry identification of the disulfides formed, and structural modeling of the modified enzyme were examined. Our results indicate that conformational changes at cysteines near the nucleotide binding site affect the binding of both the nucleotide and DHEA to the enzyme, with the specific effects dependent on the structure of the resulting disulfide. Thus, the formation of disulfide bonds in hSULT2A1 is a potentially important reversible mechanism for alterations in the rates of sulfation of both endogenous and xenobiotic substrates. 23578607 Glutathione conjugation attenuates biological activities of 6-dehydroshogaol from ginger. 6-Dehydroshogaol (6-DHSG) is a bioactive α,β-unsaturated carbonyl compound isolated from fresh ginger with anti-inflammatory and phase II enzyme inducing activities. Here we describe the glutathione (GSH)-dependent metabolism and the effect of this metabolic transformation on the biological activities of 6-DHSG. Compared with other ginger compounds, such as 6-gingerol and 6-shogaol, 6-DHSG showed the most potent anti-inflammatory effect in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. The biological activities of 6-DHSG were attenuated by sulfhydryl antioxidants such as glutathione (GSH) or N-acetyl cysteine (NAC), but not ascorbic acid (ASC). 6-DHSG was metabolised by GSH to form a GSH conjugate (GS-6-DHSG) in RAW 264.7 cells, via a potential mechanism involving the catalytic activity of glutathione-S-transferase (GST). GS-6-DHSG showed reduced biological activities compared with 6-DHSG in multiple biological assays. Together, these results indicate that GSH conjugation attenuates the biological activities of 6-DHSG and other α,β-unsaturated carbonyl compounds. 23324033 The resolution of aglinin A epimers and their NMR assignments. Aglinin A (1) is a mixture of C(24)-epimeric 20S,24-epoxy-24,25-dihydroxy-3,4-secodammar-4(28)-en-3-oic acid and present in plants of the family Meliaceae. The two epimers of 1 were resolved through an acetonide reaction, and the absolute configurations of two derivatives were deduced by the analysis of their (13)C NMR differences induced by γ-gauche or steric effect. Based on it, the (13)C NMR assignment of 24R-1 and 24S-1 was also established. 23349496 TSG-6 produced by hMSCs delays the onset of autoimmune diabetes by suppressing Th1 development and enhancing tolerogenicity. Genetic and immunological screening for type 1 diabetes has led to the possibility of preventing disease in susceptible individuals. Here, we show that human Mesenchymal Stem/Stromal Cells (hMSCs) and TNF-α-stimulated gene 6 (TSG-6), a protein produced by hMSCs in response to signals from injured tissues, delayed the onset of spontaneous autoimmune diabetes in NOD mice by inhibiting insulitis and augmenting regulatory T cells (Tregs) within the pancreas. Importantly, hMSCs with a knockdown of tsg-6 were ineffective at delaying insulitis and the onset of diabetes in mice. TSG-6 inhibited the activation of both T cell and antigen presenting cells (APCs) in a CD44-dependent manner. Moreover, multiple treatments of TSG-6 rendered APCs more tolerogenic, capable of enhancing Treg generation and delaying diabetes in an adoptive transfer model. Therefore, these results could provide the basis for a novel therapy for the prevention of type 1 diabetes. 23614663 Two Substrate-Confined Sol-Gel Coassembled Ordered Macroporous Silica Structures with an Open Surface. A sol-gel cooperative assembly method was demonstrated for the fabrication of inverse opal films with an open surface. In this method, a sol-gel silicate precursor was cooperatively assembled into the interstitial spaces of microspheres at the same time when polystyrene templates formed in between two desired substrates. Silica inverse opals with a three-dimensional ordered macroporous (3DOM) structure were obtained after selective removing the colloidal templates by calcination. The open surfaces with a high degree of interconnected porosity and extremely uniform pore size were characterized by scanning electron microscope (SEM). Optical transmission spectra reveals the existence of considerable deep band gaps of up to 70% and steep band edges of up to 6%/nm in the [111] directions of the 3DOM silica samples. A little shrinkage confirmed by transmission spectra is not larger than 3%, in consistent with the results measured by SEM, which revealing the sufficient and compact infiltration into the interstitial spaces by our confined sol-gel coassembly method. With different incidence angles, the positions of pseudogaps can be easily tuned in the wide range from 720 nm to 887 nm, agreed well with the calculated values by the Bragg law. All the results prove that the sol-gel coassembly method with two substrates confinement is a simple, low cost, convenient and versatile method for the fabrication of silica inverse opals without overlayers in large domains. 22992332 Valproic acid but not D-cycloserine facilitates sleep-dependent offline learning of extinction and habituation of conditioned fear in humans. The effectiveness of D-cycloserine (DCS), an N-methyl-D-aspartate glutamate receptor partial agonist, and valproic acid (VPA), a histone deacetylase inhibitor, in facilitating the extinction of fear-conditioned memory has been explored in humans and animals. Here, we confirmed whether DCS (100 mg) and VPA (400 mg) act in off-line learning processes during sleep or waking, for further clinical application to anxiety disorders and posttraumatic stress disorder (PTSD). We performed a randomized, blind, placebo-controlled clinical trial in 90 healthy adults. Visual cues and electric shocks were used as the conditioned stimulus (CS) and unconditioned stimulus (US), respectively. The extinction effect was observed not in simple recall after the extinction of coupled CS-US, but was observed in the post-re-exposure phase after unexpected re-exposure to reinstatement CS-US coupling. Newly acquired conditioned fear was also eliminated or habituated by DCS and VPA administration, in line with previous findings. Furthermore, VPA facilitated the off-line learning process of conditioned fear extinction and habituation during sleep, while DCS facilitated this process during waking. These novel findings suggest that DCS and VPA might enhance exposure-based cognitive therapy for anxiety disorders and PTSD by reducing the vulnerability to reinstatement and preventing relapses of fear-conditioned responses, and provide evidence for a peculiarity of the sleep-dependent off-line learning process for conditioned fear extinction. This article is part of a Special Issue entitled 'Cognitive Enhancers'. 23305994 Preparation of apigenin nanocrystals using supercritical antisolvent process for dissolution and bioavailability enhancement. The aim of the study was to investigate the potential of nanocrystals to enhance the oral bioavailability of apigenin (AP), a bioactive flavonoid with various pharmacological activities but poor aqueous solubility. In the present investigation, the AP nanocrystals were prepared by the supercritical antisolvent process. In vitro characterization was performed by scanning electron microscopy, FT-IR, differential scanning calorimetry, X-ray powder diffractometry. In vitro dissolution of prepared nanocrystals was studied and compared with untreated coarse powder. In addition, the pharmacokinetic study of AP nanocrystals, in comparison to coarse powder, was also performed in rats after a single oral dose. The prepared AP nanocrystals, without change in crystalline structure, appeared in spherical shape with particle size of about 400-800 nm. The reduction of particle size resulted in a more rapid dissolution of AP from nanocrystals than from coarse powder. In comparison to coarse powder, AP nanocrystals exhibited a significantly decreased t(max), a 3.6-fold higher peak plasma concentration (C(max)) and 3.4-fold higher area under the curve (AUC). 23411224 Multidisciplinary analytical investigation of phospholipids and triglycerides in offshore farmed gilthead sea bream (Sparus aurata) fed commercial diets. In this work, a quantitative characterisation of lipid (both triglycerides and phospholipids) rearrangements in the muscle of offshore-raised gilthead sea bream was carried out as a function of fish growth between April and September. Relative percentages of lipid classes and fatty acids/acyls composition of the commercial feeds and fish dorsal muscles were assessed by means of an interdisciplinary analytical approach. A combination of preparative chemistry and experimental results from NMR spectroscopy, GC, 3D-TLC as well as proximate analysis permitted the observed growth parameters in key metabolic events to be linked with fish fattening and lipid turnover. While defined effects of feed composition on fatty acid profiles of fillets were ascertained, the relative increase of fatty acyls in triglycerides and phospholipids were also estimated enabling detailed evaluation of TAG:PL ratio in adult offshore-farmed gilthead sea bream. NMR was also used to quantify PUFA regiospecific distribution in TAG and PL. 23370194 Synthesis, quantitative structure-activity relationship and biological evaluation of 1,3,4-oxadiazole derivatives possessing diphenylamine moiety as potential anticancer agents. Synthesis of 2,5-disubstituted-1,3,4-oxadiazole (2a-c), 3-substituted aminomethyl-5-substituted-1,3,4-oxadiazole-2(3H)-thione (4a-m) and 2-substituted thio-5-substituted-1,3,4-oxadiazole (5a, b) had been described. All the synthesized derivatives were screened for anticancer activity against HT29 and MCF7 cancer cell lines using Sulfo-Rodamine B (SRB) standard method. Most of the tested compounds exploited potent antiproliferative activity against HT29 cancer cell line rather than MCF7 cancer cell line. Compounds 2a-c, 4f and 5a exhibited potent cytotoxicity (IC(50) 1.3-2.0 µM) and selectivity against HT29 cancer cell line. Quantitative structure-activity relationship (QSAR) study was applied to find a correlation between the experimental antiproliferative activities of the newly synthesized oxadiazole derivatives with their physicochemical parameter and topological index. 22893614 Negative regulation of osteoclast precursor differentiation by CD11b and β2 integrin-B-cell lymphoma 6 signaling. Negative regulation of osteoclastogenesis is important for bone homeostasis and prevention of excessive bone resorption in inflammatory and other diseases. Mechanisms that directly suppress osteoclastogenesis are not well understood. In this study we investigated regulation of osteoclast differentiation by the β2 integrin CD11b/CD18 that is expressed on myeloid lineage osteoclast precursors. CD11b-deficient mice exhibited decreased bone mass that was associated with increased osteoclast numbers and decreased bone formation. Accordingly, CD11b and β2 integrin signaling suppressed osteoclast differentiation by preventing receptor activator of NF-κB ligand (RANKL)-induced induction of the master regulator of osteoclastogenesis nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and of downstream osteoclast-related NFATc1 target genes. CD11b suppressed induction of NFATc1 by the complementary mechanisms of downregulation of RANK expression and induction of recruitment of the transcriptional repressor B-cell lymphoma 6 (BCL6) to the NFATC1 gene. These findings identify CD11b as a negative regulator of the earliest stages of osteoclast differentiation, and provide an inducible mechanism by which environmental cues suppress osteoclastogenesis by activating a transcriptional repressor that makes genes refractory to osteoclastogenic signaling. 23352465 C16 peptide shown to prevent leukocyte infiltration and alleviate detrimental inflammation in acute allergic encephalomyelitis model. Integrins are important adhesion receptors for leukocytes binding to endothelial cellular adhesion molecules. Previous studies have suggested that blocking relevant integrins might prevent leukocyte infiltration and suppress clinical and pathological features of neuroinflammatory disease. Experimental autoimmune encephalomyelitis (EAE), a rodent model of Multiple sclerosis (MS), is characterized by chronic inflammatory disorder of the central nervous system in which circulating leukocytes enter the brain and spinal cord leading to inflammation, myelin damage and subsequent paralysis. To prove this hypothesis and explore a promising application for MS treatment, the effects of C16, an ανβ3 integrin-binding peptide, were tested in vitro and in vivo by transendothelial assay, electron microscopy observation, multiple histological and immunohistochemical staining. The results showed C16 inhibited transendothelial migration of the C8166-CD4 lymphoblast cells, and alleviated extensive spinal cord and brain infiltration of leukocytes and macrophages in the EAE model. Furthermore, a significant amelioration of astrogliosis and a dramatic decrease in demyelination and axonal loss were observed in C16 treated animals. The attenuating inflammatory progression may improve the regional environment and trigger further neuroprotective effects on myelin and axons, all this suggests that C16 peptide may be a promising therapeutic agent for multiple sclerosis. 23411230 Effect of peeling and three cooking methods on the content of selected phytochemicals in potato tubers with various colour of flesh. The impact of peeling and three cooking treatments (boiling, baking and microwaving) on the content of selected phytochemicals in white-, yellow-, red- and purple-fleshed potatoes was investigated. Ascorbic acid and chlorogenic acid contents were determined by HPLC-DAD, total anthocyanin content by pH-differential spectrophotometry, glycoalkaloid, α-chaconine and α-solanine contents by HPLC-ESI/MS/MS. All cooking treatments reduced ascorbic and chlorogenic acid contents, total glycoalkaloids, α-chaconine and α-solanine with the exception of total anthocyanins. The losses of ascorbic and chlorogenic acids were minimised with boiling and total anthocyanin levels retained the highest. Boiling of peeled tubers decreased contents of total glycoalkaloids (α-chaconine and α-solanine) and appeared as the most favourable among the three tested methods. Moreover, due to higher initial levels, red- and purple-fleshed cultivars retained higher amounts of antioxidants (ascorbic acid, chlorogenic acid and total anthocyanin) after boiling and may be healthier as compared with white or yellow cultivars. 23566520 Synthesis, cytotoxicity and topoisomerase II inhibitory activity of lomefloxacin derivatives. A novel series of amide derivatives of lomefloxacin were synthesized and evaluated for their topoisomerase I and II inhibitory activity as well as cytotoxicity against a panel of five human cancer cell lines. Of the compounds prepared compounds 9d and 9g exhibited strong inhibition against topoisomerase II at 100μM. In addition, docking studies were performed to predict the inhibition mode. 23245515 Naphthyridinone (NTD) integrase inhibitors: N1 protio and methyl combination substituent effects with C3 amide groups. Substituent effects of a series of N1 protio and methyl naphthyridinone HIV-1 integrase strand-transfer inhibitors has been explored. The effects of combinations of the N1 substituent and C3 amide groups was extensively studied to compare enzyme inhibition, antiviral activity and protein binding effects on potency. The impact of substitution on ligand efficiency was considered and several compounds were advanced into in vivo pharmacokinetic studies ultimately leading to the clinical candidate GSK364735. 23408421 Concentrations and trends of halogenated flame retardants in the pooled serum of residents of Laizhou Bay, China. The south coast of Laizhou Bay, in northeastern China, is a production area for halogenated flame retardants (HFR). In 2007, the authors measured serum concentrations of polybrominated diphenyl ethers (PBDEs) in Laizhou Bay residents. To assess the PBDE concentration trend, and determine the concentrations of the emerging flame retardants Dechlorane Plus (DP) and bis(2-ethylhexyl)-3,4,5,6-tetrabromophthalate (TBPH), the authors measured the concentrations of 8 PBDE congeners, 2 DP isomers, and TBPH in 10 composite samples, which were pooled from the serum collected from 305 Laizhou Bay residents in October 2011. The average concentration of the total PBDE (∑8 PBDE) concentration in all serum pools was 240 ng/g lipid weight, and the highest serum pool concentration (in the 30- to 39-yr-old male group) was 780 ng/g lipid weight. Brominated diphenyl ether-209 was the dominant congener, accounting for 87% of ∑8 PBDE. Compared with a previous study, ∑8 PBDE serum concentrations in the present study showed no change in order of magnitude, but the relative contribution of BDE-209 to ∑8 PBDE was higher. The average concentration of ∑DP in all serum pools was 3.6 ng/g lipid weight, ranging from 1.4 ng/g lipid weight (in the 50- to 59-yr-old male group) to 11 ng/g lipid weight (in the 20- to 29-yr-old male group). The concentration of DP was lower than in other reported studies. The study also detected TBPH in the 30- to 39-yr-old female group, suggesting that TBPH, as an emerging HFR, requires further monitoring. Environ Toxicol Chem 2013;32:1242-1247. © 2013 SETAC. 23523257 Phellinus linteus mushroom protects against tacrine-induced mitochondrial impairment and oxidative stress in HepG2 cells. Tacrine (THA) was the first drug licensed for the treatment of Alzheimer's disease. Unfortunately, reversible hepatotoxicity is evident in about 30% of patients and limits its clinical use. The intracellular mechanisms have not yet been elucidated. Phellinus linteus (PL) is a mushroom that has long been used as a folk medicine. In our previous study, we found that PL could decrease the reactive oxygen species (ROS) formation in HepG2 cells. Presently, protective effects of PL on tacrine-induced ROS formation and mitochondria dysfunction were evaluated. The results showed that PL significantly reduced tacrine-induced ROS production, disruption of ΔΨm, 8-OHdG formation in mitochondrial DNA, and cytotoxicity in HepG2 cells. These data suggest that PL could attenuate the cytotoxicity and mitochondria dysfunction induced by tacrine in HepG2 cells. The protection is probably mediated by an antioxidant protective mechanism. Consumption of PL may be a plausible way to prevent tacrine-induced hepatotoxicity. 23434829 Upregulation of drug transporter expression by osteopontin in prostate cancer cells. Multidrug resistance is a major cause of chemotherapy failure. Recent studies indicate that drug resistance can be rapidly induced by some soluble factors, such as cytokines, chemokines, growth factors, and cell adhesion factors in the tumor microenvironment. Osteopontin (OPN), an extracellular matrix protein, has a functional arginine-glycine-aspartic acid (RGD) domain for binding to integrin. Here we found OPN expression to be upregulated by hypoxic condition in PC-3 prostate tumor cells. OPN increased the mRNA and protein expression of p-glycoprotein (P-gp), a subfamily of ATP-binding cassette transporter in a concentration- and time-dependent manner. The increase in P-gp transporter by OPN was mediated by binding to αvβ3 integrin. Daunomycin (DUN), a chemotherapeutic agent with autofluorescence, was used to evaluate the pump activity, and OPN increased the drug pumping-out activity. OPN inhibited DUN-induced cell death, which was antagonized by αvβ3 monoclonal antibody. Long-term treatment with DUN further enhanced the expression of OPN. Knockdown of endogenous OPN potentiated the DUN-induced apoptosis of PC-3 cells. Furthermore, knockdown of OPN enhanced cell death caused by other drugs, including paclitaxel, doxorubicin, actinomycin-D, and rapamycin, which are also P-gp substrates. The animal studies also showed that OPN knockdown enhanced the cytotoxic action of DUN. These results indicate that OPN is a potential therapeutic target for cancer therapy to reduce drug resistance in sensitive tumors. 23292158 Pregabalin abuse and dependence in Germany: results from a database query. PURPOSE: Pregabalin (PRG) is approved for the treatment of neuropathic pain, partial seizures and generalised anxiety disorder in many countries and currently under study for other indications. Supported by case reports and the results of a limited number of studies there is an ongoing debate on the potential of PRG to cause addictive behaviours. However, currently available evidence on this issue is sparse, and any definitive assessment of PRG's potential for abuse and dependence is not yet in sight. The aim of our study was to identify the number of cases of PRG abuse or dependence reported to the database of a German medical regulatory body and to obtain insights into further usage-specific parameters. METHODS: We conducted a query of the entire database of the German Federal Institute for Drugs and Medical Devices (BfArM) regarding reports of PRG abuse or dependence and analysed these cases on the basis of several parameters. RESULTS: A total of 55 reports of PRG abuse or dependence were identified (mean age 36 years, 64 % of reports involved males). The first reports were submitted to BfArM in 2008, and the reporting frequency has increased up to the present. Mean daily PRG dosage was 1424 mg. Current or previous polytoxicomania was present in 40 and 42 % of cases, respectively. Psychiatric diagnoses other than substance-related disorders were reported in 13 (24 %) cases. In about one-third of the patients withdrawal syndromes subsequent to discontinuation of PRG were reported. CONCLUSIONS: Cases of PRG abuse or dependence have been reported to the BfArM since 2008, with a marked increase of such reports in subsequent years. Male sex and a history of polytoxicomania may be possible risk factors for the development of addictive behaviours related to PRG. 23631561 Membrane fusion-competent virus-like proteoliposomes and proteinaceous supported bilayers made directly from cell plasma membranes. Virus-like particles are useful materials for studying virus-host interactions in a safe manner. However, the standard production of pseudovirus based on the Vesicular Stomatitis Virus (VSV) backbone is an intricate procedure that requires trained laboratory personnel. In this work, a new strategy for creating virus-like proteoliposomes (VLPLs) and virus-like supported bilayers (VLSBs) is presented. This strategy uses a cell blebbing technique to induce the formation of nanoscale vesicles from the plasma membrane of BHK cells expressing the hemagglutinin (HA) fusion protein of influenza X-31. These vesicles and supported bilayers contain HA and are used to carry out single particle membrane fusion events, monitored using total internal reflection fluorescence microscopy. The results of these studies show that the VLPLs and VLSBs contain HA proteins that are fully competent to carry out membrane fusion, including the formation of a fusion pore and the release of fluorophores loaded into vesicles. This new strategy for creating spherical and planar geometry virus-like membranes has many potential applications. VLPLs could be used to study fusion proteins of virulent viruses in a safe manner, or they could be used as therapeutic delivery particles to transport beneficial proteins co-expressed in the cells to a target cell. VLSBs could facilitate high throughput screening of antiviral drugs or pathogen-host cell interactions. 23479335 Association Between Lipids, Lipoproteins Composition of HDL Particles and Triglyceride-Rich Lipoproteins, and LCAT and CETP Activity in Post-renal Transplant Patients. High-density lipoprotein (HDL) remodeling within the plasma compartment and the association between lecithin-cholesterol acyltransferase (LCAT) and cholesterol ester transfer protein (CETP) activity, and lipid, lipoprotein concentrations and composition were investigated. The aim was to examine the high sensitivity of C-reactive protein (hsCRP), lipid, apolipoprotein B (apoB), apoAI, total apoAII, apoAIInonB, apoB-containing apoAII (apoB:AII), total apoCIII, apoCIIInonB, apoB-containing apoCIII (apoB:CIII) concentration and LCAT and CETP activity to gain an insight into the association between them and LCAT and CETP, 57 post-renal transplant (Tx) patients with and without statin therapy and in 15 healthy subjects. Tx patients had moderate hypertriglyceridemia, hypercholesterolemia, and dyslipoproteinemia, disturbed triglyceride-rich lipoproteins (TRLs) and HDL composition, decreased LCAT, and slightly increased hsCRP but no CETP activity. Spearman's correlation test showed the association between lipids and lipoproteins and LCAT or CETP, and multiple ridge stepwise forward regression showed that immunosuppressive therapy in Tx patients can disturb HDL and TRLs composition. The results suggest that inhibition or activation of LCAT is due, in part, to HDL-associated lipoprotein. Lipoprotein composition of apoAI, apoAIInonB, and apoCIIInonB in HDL particle and apoB:AII TRLs can contribute to decrease LCAT mass in Tx patients. Tx patients without statin and with lower triglycerides but higher HDL cholesterol concentration and disturbed lipoprotein composition of ApoAI and apoAII in HDL particle can decrease LCAT, increase LDL cholesterol, aggravate renal graft, and accelerate atherosclerosis and chronic heart diseases. 23411289 Total amino acid profiles of heat-processed fresh Elaeis guineensis and Raphia hookeri wines. Total amino acid (AA) profiles of heat-processed fresh Elaeis guineensis and Raphia hookeri wines were studied. Heating their fresh wines to 85°C, cooling and diluting to original volumes distilled off ethanol, but did not change their moisture and nitrogen contents. R. hookeri wine contained more (p<0.05) Phe, Val, Ala, Gly, Pro, Asp, Asn, His and Lys than E. guineensis wine which contained more (p<0.05) Met, Cys, Glu, Gln, Ser and Arg. Tyrosine, Leu, Ile and Thr contents did not vary (p>0.05). Glycine and Pro contents were low suggesting high globular protein concentrations. ∑basic AA/∑acidic AA ratios were >1 suggesting high basic protein contents. The E. guineensis and R. hookeri wines contained 58.25 ± 0.56% and 56.79 ± 0.4% essential AAs, respectively. Essential AA scores suggested Leu as their limiting AA. In conclusion, the wines can adequately meet daily nitrogen and essential AA needs when a 70 kg adult drinks 1425.45 ml. 23515941 Oxidative DNA damage is involved in ochratoxin A-induced G2 arrest through ataxia telangiectasia-mutated (ATM) pathways in human gastric epithelium GES-1 cells in vitro. Ochratoxin A (OTA), one of the most abundant mycotoxin food contaminants, is classified as "possibly carcinogenic to humans." Our previous study showed that OTA could induce a G2 arrest in immortalized human gastric epithelium cells (GES-1). To explore the putative roles of oxidative DNA damage and the ataxia telangiectasia-mutated (ATM) pathways on the OTA-induced G2 arrest, the current study systematically evaluated the roles of reactive oxygen species (ROS) production, DNA damage, and ATM-dependent pathway activation on the OTA-induced G2 phase arrest in GES-1 cells. The results showed that OTA exposure elevated intracellular ROS production, which directly induced DNA damage and increased the levels of 8-OHdG and DNA double-strand breaks (DSBs). In addition, it was found that OTA treatment induced the phosphorylation of the ATM protein, as well as its downstream molecules Chk2 and p53, in response to DNA DSBs. Inhibition of ATM by the pharmacological inhibitor caffeine or siRNA effectively prevented the activation of ATM-dependent pathways and rescued the G2 arrest elicited by OTA. Finally, pretreatment with the antioxidant N-acetyl-L-cysteine (NAC) reduced the OTA-induced DNA DSBs, ATM phosphorylation, and G2 arrest. In conclusion, the results of this study suggested that OTA-induced oxidative DNA damage triggered the ATM-dependent pathways, which ultimately elicited a G2 arrest in GES-1 cells. 23391596 Toxicological, toxicokinetic and gastroprotective evaluation of the benzaldehyde semicarbazone. Benzaldehyde semicarbazone (BS) has presented positive results in several pharmacological models, including anticonvulsivant and anti-inflammatory models. The present study evaluated the preclinical toxicity (acute and subchronic), as well as the toxicokinetic and gastroprotective effects of BS against ethanol lesions. Oral doses of 300 and 2000mg/kg were used in the preclinical acute toxicity study; 100, 200, and 300mg/kg were used in both the subchronic toxicity evaluation and the gastric study; and 300mg/kg was used in the toxicokinetic study. No impact from the dose of 300mg/kg could be identified; while, one animal died at 2000mg/kg in the acute toxicity test. In the subchronic toxicity test, changes in the biochemical parameters of the liver, as well as in the histopatological evaluation, demonstrated that BS is a hepatotoxic drug. BS proved to be effective for moderate and severe gastric lesions. In the toxicokinetics study, BS presented a low concentration and rapid plasma disappearance. Several results also indicate that BS is likely to be mostly eliminated from the liver and may well undergo a first-pass effect after oral absorption. It was impossible to estimate the noobserved-adverse-effect-levels (NOAEL) and lowest-observed-adverse-effect-levels (LOAEL) due to the presence of hepatotoxicity in all tested doses. 23536521 Differential effects of organic and inorganic selenium compounds on adenosine deaminase activity and scavenger capacity in cerebral cortex slices of young rats. Selenium (Se) has anti-inflammatory and antioxidant properties and is necessary for the development and normal function of the central nervous system. This study was aimed to compare the in vitro effects of 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one (C21H2HOSe; organoselenium) and sodium selenate (inorganic Se) on adenosine deaminase (ADA) activity, cell viability, lipid peroxidation, scavenger of nitric oxide (NO) and nonprotein thiols (NP-SH) content in the cerebral cortex slices of the young rats. A decrease in ADA activity was observed when the slices were exposed to organoselenium at the concentrations of 1, 10 and 30 µM. The same compound showed higher scavenger capacity of NO than the inorganic compound. Inorganic Se was able to protect against sodium nitroprusside-induced oxidative damage and increased the NP-SH content. Both the compounds displayed distinctive antioxidant capacities and were not cytotoxic for the cerebral cortex slices in the conditions tested. These findings are likely to be related to immunomodulatory and antioxidant properties of this compound. 23292798 Effects on gene expression in rat liver after administration of RXR agonists: UAB30, 4-methyl-UAB30, and Targretin (Bexarotene). Examination of three retinoid X receptor (RXR) agonists [Targretin (TRG), UAB30, and 4-methyl-UAB30 (4-Me-UAB30)] showed that all inhibited mammary cancer in rodents and two (TRG and 4-Me-UAB30) strikingly increased serum triglyceride levels. Agents were administered in diets to female Sprague-Dawley rats. Liver RNA was isolated and microarrayed on the Affymetrix GeneChip Rat Exon 1.0 ST array. Statistical tests identified genes that exhibited differential expression and fell into groups, or modules, with differential expression among agonists. Genes in specific modules were changed by one, two, or all three agonists. An interactome analysis assessed the effects on genes that heterodimerize with known nuclear receptors. For proliferator-activated receptor α/RXR-activated genes, the strongest response was TRG > 4-Me-UAB30 > UAB30. Many liver X receptor/RXR-related genes (e.g., Scd-1 and Srebf1, which are associated with increased triglycerides) were highly expressed in TRG and 4-Me-UAB30- but not UAB30-treated livers. Minimal expression changes were associated with retinoic acid receptor or vitamin D receptor heterodimers by any of the agonists. UAB30 unexpectedly and uniquely activated genes associated with the aryl hydrocarbon hydroxylase (Ah) receptor (Cyp1a1, Cyp1a2, Cyp1b1, and Nqo1). Based on the Ah receptor activation, UAB30 was tested for its ability to prevent dimethylbenzanthracene (DMBA)-induced mammary cancers, presumably by inhibiting DMBA activation, and was highly effective. Gene expression changes were determined by reverse transcriptase-polymerase chain reaction in rat livers treated with Targretin for 2.3, 7, and 21 days. These showed similar gene expression changes at all three time points, arguing some steady-state effect. Different patterns of gene expression among the agonists provided insight into molecular differences and allowed one to predict certain physiologic consequences of agonist treatment. 23588584 Factors Influencing Magnitude and Duration of Target Inhibition Following Antibody Therapy: Implications in Drug Discovery and Development. Antibodies or antibody-related fusion proteins binding to soluble antigens in plasma form an important subclass of approved therapeutics. Pharmaceutical companies are constantly trying to accelerate the pace of drug discovery and development of these antibodies and identify superior candidates in face of significant attrition rates. Understanding the interplay between drug- and target-related factors on magnitude and duration of target inhibition is imperative for successful advancement of these therapeutics. Simulations using a target-mediated drug disposition model were performed to evaluate the influence of antibody-target binding affinity, baseline target concentration, and target turnover on magnitude and duration of soluble target inhibition. These simulations assumed intravenous dosing of the antibody and evaluated multiple parameters over a wide range. These simulations reveal that improvement in affinity reaches a point of diminishing returns following which further improvement in affinity does not alter the magnitude and more importantly the duration of target inhibition. Evaluation of unbound antibody and target kinetics indicated that point of diminishing returns in duration of inhibition was due to target-mediated binding and subsequent elimination of antibody at later time points. Similarly, influence of baseline target concentration and target turnover on magnitude and duration of target inhibition in plasma is shown. Additionally, the fraction of dose eliminated via target mediated elimination (Fel(™)) can be a useful tool to enable selection of strategies to increase duration of target inhibition. The implications of these simulations in drug discovery and development with regard to target identification, antibody optimization, and backup candidate selection are discussed. 23643752 The fatty acid amide hydrolase inhibitor, URB597, promotes retinal ganglion cell neuroprotection in a rat model of optic nerve axotomy. The endocannabinoid, N-arachidonoylethanolamine (AEA), is degraded by the enzyme fatty acid amide hydrolase (FAAH). This study examined whether the FAAH inhibitor, URB597, increases retinal ganglion cell (RGC) survival following optic nerve axotomy in young and aged animals. URB597 alone, or together with either a CB1 or CB2 receptor antagonist, was administered daily for 1 or 2 weeks post-axotomy. Histological assessment of retinas indicated that URB597 increased RGC survival in young retina at 1 and 2 weeks post-axotomy. The increase in RGC survival at 2 weeks was accompanied by a reduction in phagocytic microglia. The CB1 antagonist, AM281, but not the CB2 antagonist, AM630, ablated URB597-mediated RGC neuroprotection. CB1 or CB2 antagonism increased phagocytic microglia in URB597 and vehicle-treated animals. In aged animals, URB597 increased RGC survival at 1 week, but not at 2 weeks post-axotomy and had no effect on microglia. Retinal Iba-1 positive microglia were also decreased in URB597-treated axotomized young animals and this decrease was mitigated by CB1 but not CB2 antagonism. As seen with phagocytotic microglia, the CB2 antagonist, AM630, increased Iba-1 positive microglia in the absence of URB597 treatment. Measurement of retinal endocannabinoid levels in URB597-treated animals at 2 weeks post-axotomy revealed a significant increase in AEA levels, accompanied by a decrease by a decrease in the AEA metabolite, N-arachidonoylglycine, in young animals but not aged animals. 2-arachidonoylglycerol levels were similar across all experimental groups. These data demonstrate that URB597-mediated retinal neuroprotective effects are mediated primarily through CB1 receptors and that URB597 neuroprotective efficacy declines with age. 23560438 Poly(vinyl alcohol) Physical Hydrogel Nanoparticles, Not Polymer Solutions, Exert Inhibition of Nitric Oxide Synthesis in Cultured Macrophages. Hydrogel nanoparticles (HNP) are an emerging tool of biomedicine with unique materials characteristics, scope, and utility. These hydrated, soft colloidal carriers can penetrate through voids with dimensions narrower than the size of the particle, provide stabilization for fragile biological cargo and allow diffusion and exchange of solutes with external phase. However, techniques to assemble HNP are few; solitary examples exist of biocompatible polymers being formulated into HNP; and knowledge on the biomedical properties of HNP remains rather cursory. In this work, we investigate assembly of HNP based on a polymer with decades of prominence in the biomedical field, poly(vinyl alcohol), PVA. We develop a novel method for production of PVA HNP through nanoprecipitation-based assembly of polymer nanoparticles and subsequent physical hydrogelation of the polymer. Polymer nanoparticles and HNP were visualized using scanning electron microscopy and fluorescence imaging, and characterized using dynamic light scattering and zeta potential measurements. Interaction of PVA HNP with mammalian cells was investigated using flow cytometry, viability screening, and measurements of nitric oxide production by cultured macrophages. The latter analyses revealed that PVA administered as a polymer solution or in the form of HNP resulted in no measurable increase in production of the inflammation marker. Unexpectedly, PVA HNP exerted a pronounced inhibition of NO synthesis by stimulated macrophages, that is, had an anti-inflammatory activity. This effect was accomplished with a negligible change in the cell viability and was not observed when PVA was administered as a polymer solution. To the best of our knowledge, this is the first observation of inhibition of NO synthesis in macrophages by administered nanoparticles and specifically hydrogel nanoparticles. Taken together, our results present PVA HNP as promising colloidal hydrogel nanocarriers for biomedical applications, specifically drug delivery and assembly of intracellular biosensors. 23473679 Melanoma targeting property of a Lu-177-labeled lactam bridge-cyclized alpha-MSH peptide. The purpose of this study was to determine the melanoma targeting property of (177)Lu-DOTA-GGNle-CycMSHhex in B16/F1 melanoma-bearing C57 mice. (177)Lu-DOTA-GGNle-CycMSHhex exhibited high receptor-mediated melanoma uptake and fast urinary clearance. The tumor uptake of (177)Lu-DOTA-GGNle-CycMSHhex was 20.25 ± 4.59 and 21.63 ± 6.27% ID/g at 0.5 and 2h post-injection, respectively. Approximately 83% of injected dose cleared out the body via urinary system at 2h post-injection. (177)Lu-DOTA-GGNle-CycMSHhex showed high tumor to normal organ uptake ratios except for the kidneys. The tumor/kidney uptake ratios of (177)Lu-DOTA-GGNle-CycMSHhex were 2.76 and 1.74 at 2 and 24h post-injection. The melanoma lesions were clearly visualized by SPECT/CT using (177)Lu-DOTA-GGNle-CycMSHhex as an imaging probe at 2h post-injection. Overall, high melanoma uptake coupled with fast urinary clearance of (177)Lu-DOTA-GGNle-CycMSHhex underscored its potential for melanoma treatment in the future. 23106203 Identification of two-component system AfsQ1/Q2 regulon and its cross-regulation with GlnR in Streptomyces coelicolor. The two-component system AfsQ1/Q2 of Streptomyces coelicolor was identified in our previous work as a pleiotropic regulator for antibiotic biosynthesis and morphological differentiation under the condition of a minimal medium supplemented with 75 mM glutamate. In this work, we report the dissection of the mechanism underlying the function of AfsQ1/Q2 on antibiotic production and also the identification of the AfsQ1/Q2 regulon. The results showed that AfsQ1/Q2 stimulated antibiotic ACT, RED and CDA production directly through the pathway-specific activator genes actII-ORF4, redZ and cdaR respectively. In addition, expression of sigQ that encodes a sigma factor and is divergently transcribed from afsQ1 was also subject to direct regulation by AfsQ1/Q2. The precise AfsQ1 binding sites in the upstream regions of these target genes were determined by DNase I footprinting assays coupled with site-directed DNA mutagenesis. By computational prediction and functional analysis, at least 17 new AfsQ1 targets were identified, including pstS gene encoding a high-affinity phosphate-binding protein and two developmental genes whiD, bldM. For the AfsQ1/Q2 regulon, an AfsQ1 binding motif comprising the sequence GTnAC-n(6) -GTnAC has been defined. Interestingly, we found from electrophoretic mobility shift assays and transcriptional analysis that AfsQ1/Q2 can also function as a repressor for nitrogen assimilation, and AfsQ1 can compete with GlnR for the promoter regions of glnA and nirB, suggesting the cross-regulation between AfsQ1/Q2 and GlnR in nitrogen metabolism. These findings suggested that AfsQ1/Q2 is important not only for antibiotic biosynthesis but also in maintaining the metabolic homeostasis of nutrient utilization under the stress of high concentration of glutamate in S. coelicolor. 23501111 Novel chiral ferrocenylpyrazolo[1,5-a][1,4]diazepin-4-one derivatives - Synthesis, characterization and inhibition against lung cancer cells. A series of novel 2-ferrocenyl-7-hydroxy-5-phenethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one derivatives with optical activity (2) was synthesized in the microwave-assisted condition and characterized by means of IR, (1)H NMR and mass spectroscopy, and furthermore confirmed by X-ray analysis of a representative compound (R)-2a. Preliminary biological evaluation showed that some compounds could suppress the growth of A549, H322 and H1299 lung cancer cells. Among the tested compounds, 2b-d were more effective and might perform their action through cell cycle arrest for A549 cell. Whereas these compounds inhibited growth of H1299 and H322 cells by inducing apoptosis. The anti-tumor activities of these compounds were related to the nature of substituents in benzene moiety. In addition, the results indicated also that compounds 2b-d possessed notable cytotoxicity and selectivity for A549 vs H1299 and H322 lung cancer cells. 23274909 Nogo-a downregulation improves insulin secretion in mice. Type 2 diabetes (T2D) is characterized by β-cell dysfunction and the subsequent depletion of insulin production, usually in a context of increased peripheral insulin resistance. T2D patients are routinely treated with oral antidiabetic agents such as sulfonylureas or dipeptidyl peptidase-4 antagonists, which promote glucose- and incretin-dependent insulin secretion, respectively. Interestingly, insulin secretion may also be induced by neural stimulation. Here we report the expression of Nogo-A in β-cells. Nogo-A is a membrane protein that inhibits neurite outgrowth and cell migration in the central nervous system. We observed that Nogo-A-deficient mice display improved insulin secretion and glucose clearance. This was associated with a stronger parasympathetic input and higher sensitivity of β-cells to the cholinergic analog carbachol. Insulin secretion was also improved in diabetic db/db mice treated with neutralizing antibody against Nogo-A. Together, these findings suggest that promoting the vagal stimulation of insulin secretion through the selective inhibition of Nogo-A could be a novel therapeutic approach in T2D. 23559517 A solar rechargeable flow battery based on photoregeneration of two soluble redox couples. Storable sunshine, reusable rays: A solar rechargeable redox flow battery is proposed based on the photoregeneration of I3 (-) /I(-) and [Fe(C10 H15 )2 ](+) /Fe(C10 H15 )2 soluble redox couples, which can be regenerated by flowing from a discharged redox flow battery (RFB) into a dye-sensitized solar cell (DSSC) and then stored in tanks for subsequent RFB applications This technology enables effective solar-to-chemical energy conversion. 23586669 Ligand Based Approach to L-Type Calcium Channel by Imidazo[2,1-b]thiazole-1,4-Dihydropyridines: from Heart Activity to Brain Affinity. The synthesis, characterization, and functional in vitro assay in cardiac and smooth muscle (vascular and nonvascular) of a series of 4-imidazo[2,1-b]thiazole-1,4-dihydropyridines are reported. To define the calcium blocker nature of the imidazo[2,1-b]thiazole-1,4-DHPs and their selectivity on Cav1.2 and Cav1.3 isoforms we performed binding studies on guinea pig atrial and ventricular membranes, on intact cells expressing the cloned Cav1.2a subunit and on rat brain cortex. To get major insights into the reasons for the affinity for Cav1.2 and/or Cav1.3 molecular modelling studies were also undertaken. Some physicochemical and pharmacokinetic properties of selected compounds were calculated and compared. All the biological data collected and reported herein allowed us to rationalize the structure-activity relationship of the 4-imidazo[2,1-b]thiazole-1,4-DHPs and to identify which of these enhanced the activity at the central level. 23337596 Understanding drugs and diseases by systems biology? Systems biology aims to provide a holistic and in many cases dynamic picture of biological function and malfunction, in case of disease. Technology developments in the generation of genome-wide datasets and massive improvements in computer power now allow to obtain new insights into complex biological networks and to copy nature by computing these interactions and their kinetics and by generating in silico models of cells, tissues and organs. The expectations are high that systems biology will pave the way to the identification of novel disease genes, to the selection of successful drug candidates--that do not fail in clinical studies due to toxicity or lack of human efficacy--and finally to a more successful discovery of novel therapeutics. However, further research is necessary to fully unleash the potential of systems biology. Within this review we aim to highlight the most important and promising top-down and bottom-up systems biology applications in drug discovery. 23506842 PCNA trimer instability inhibits translesion synthesis by DNA polymerase η and by DNA polymerase δ. Translesion synthesis (TLS), the process by which DNA polymerases replicate through DNA lesions, is the source of most DNA damage-induced mutations. Sometimes TLS is carried out by replicative polymerases that have evolved to synthesize DNA on non-damaged templates. Most of the time, however, TLS is carried out by specialized translesion polymerases that have evolved to synthesize DNA on damaged templates. TLS requires the mono-ubiquitylation of the replication accessory factor proliferating cell nuclear antigen (PCNA). PCNA and ubiquitin-modified PCNA (UbPCNA) stimulate TLS by replicative and translesion polymerases. Two mutant forms of PCNA, one with an E113G substitution and one with a G178S substitution, support normal cell growth but inhibit TLS thereby reducing mutagenesis in yeast. A re-examination of the structures of both mutant PCNA proteins revealed substantial disruptions of the subunit interface that forms the PCNA trimer. Both mutant proteins have reduced trimer stability with the G178S substitution causing a more severe defect. The mutant forms of PCNA and UbPCNA do not stimulate TLS of an abasic site by either replicative Pol δ or translesion Pol η. Normal replication by Pol η was also impacted, but normal replication by Pol δ was much less affected. These findings support a model in which reduced trimer stability causes these mutant PCNA proteins to occasionally undergo conformational changes that compromise their ability to stimulate TLS by both replicative and translesion polymerases. 22577127 RETRACTED: Effects of crude diesel oil on the enzymatic defenses of the Great sturgeon, Huso huso. RETRACTED. 23594342 Genistein-Modified Poly(ethylene oxide)/Poly(d,l-lactic acid) Electrospun Mats with Improved Antioxidant and Anti-inflammatory Properties. Genistein is a phytochemical with a broad range of desirable biological activity for wound healing. However, its poor bioavailability requires developing a new method for fabricating an appropriate carrier vehicle to deliver genistein in a sustained manner. Based on the guidance afforded by the ternary phase diagram of poly(d,l-lactic acid) (PDLLA), poly(ethylene oxide) (PEO), and genistein blends, certain selective compositions were electrospun. We obtained a uniformly smooth surface morphology in unmodified and genistein-modified PEO/PDLLA fibers, documented by scanning electron microscopy. Moreover, wide-angle X-ray diffraction and (1)H NMR studies revealed that the genistein molecules, successfully incorporated in the blends, remained chemically stable after electrospinning. Besides surface wettability and dimensional stability of the electrospun mats, the released genistein amount has been evaluated as a function of PEO concentration. Our biocompatibility investigations suggest that genistein-modified PEO/PDLLA electrospun mats exhibit strong antioxidant and anti-inflammatory activities which indicate they have potential applications for wound dressings. 23265494 UPLC and HPLC of caffeoyl esters in wild and cultivated Arctium lappa L. Analytical methods including ultra-performance liquid chromatography (UPLC) and high-performance liquid chromatography (HPLC) with photodiode array (PDA) detector were developed for the analysis of caffeoylquinic acid derivatives in seeds, leaves and roots of Arctium lappa L. Separation was performed on C(18) column utilising 5% (v/v) acetic acid in water and acetonitrile at 330 nm. Both methodologies were validated in terms of linearity, precision, and recovery. The results showed that the major advantages of UPLC, over HPLC were the fast analysis, narrow peaks, high sensitivity, and reduction of solvent consumption. Subsequently the methods were applied for the identification and quantification of chlorogenic acid (5-CQA) and 1,5-dicaffeoylquinic acid (1,5-DCQA) as main compounds in samples. The total phenolic content of samples ranged from 3.93 to 14.13 g of 5-CQA equivalent/100g dry weight (DW). There was a significant variability from 89 to 571 mg/100g for 5-CQA and 48 to 486 mg/100g for 1,5-DCQA in dry material. 23587645 Application of the combinative particle size reduction technology H 42 to produce fast dissolving glibenclamide tablets. Standard particle size reduction techniques such as high pressure homogenization or wet bead milling are frequently used in the production of nanosuspensions. The need for micronized starting material and long process times are their evident disadvantages. Combinative particle size reduction technologies have been developed to overcome the drawbacks of the standard techniques. The H 42 combinative technology consists of a drug pre-treatment by means of spray-drying followed by standard high pressure homogenization. In the present paper, spray-drying process parameters influencing the diminution effectiveness, such as drug and surfactant concentration, were systematically analyzed. Subsequently, the untreated and pre-treated drug powders were homogenized for 20 cycles at 1500bar. For untreated, micronized glibenclamide, the particle size analysis revealed a mean particle size of 772nm and volume-based size distribution values of 2.686μm (d50%) and 14.423μm (d90%). The use of pre-treated material (10:1 glibenclamide/docusate sodium salt ratio spray-dried as ethanolic solution) resulted in a mean particle size of 236nm and volume-based size distribution values of 0.131μm (d50%) and 0.285μm (d90%). These results were markedly improved compared to the standard process. The nanosuspensions were further transferred into tablet formulations. Wet granulation, freeze-drying and spray-drying were investigated as downstream methods to produce dry intermediates. Regarding the dissolution rate, the rank order of the downstream processes was as follows: Spray-drying>freeze-drying>wet granulation. The best drug release (90% within 10min) was obtained for tablets produced with spray-dried nanosuspension containing 2% mannitol as matrix former. In comparison, the tablets processed with micronized glibenclamide showed a drug release of only 26% after 10min. The H 42 combinative technology could be successfully applied in the production of small drug nanocrystals. A nanosuspension transfer to tablets that maintained the fast dissolution properties of the drug nanocrystals was successfully achieved. 23466500 miR-21 confers cisplatin resistance in gastric cancer cells by regulating PTEN. Resistance to chemotherapy is a major obstacle for the effective treatment of cancers. The mechanism of chemo-resistance is still poorly understood, however, mounting evidence supports a role for microRNAs (miRNAs) in modulating key cellular pathways mediating response to chemotherapy. microRNA-21 (miR-21) has been implicated in many cancers and contributed to chemo-resistance, but its role in gastric cancer drug resistance still remains unexplored. The aim of this study was to investigate whether miR-21 mediated resistance of the gastric cancer cell line SGC7901 to the chemotherapeutic agent cisplatin (DDP). Our study found that the expression of miR-21 upregulated in the cisplatin resistant cell line SGC7901/DDP compared to its parental line SGC7901. Moreover, over-expression of miR-21 significantly decreased antiproliferative effects and apoptosis induced by cisplatin, while knockdown of miR-21 dramatically increased antiproliferative effects and apoptosis induction by cisplatin. In addition, miR-21 induced cell survival and cisplatin resistance through downregulating the expression of phosphatase and tension homolog deleted on chromosome 10 (PTEN) and activation of Akt pathway. Inhibition of Akt using PI3K inhibitor LY 294002 could abrogate miR-21 induced cell survival. These results suggest that miR-21 may provide a novel mechanism for understanding cisplatin resistance in gastric cancer by modulating PTEN/PI3K/Akt pathway. 23604717 Inhibitory action of salicylideneamino-2-thiophenol on NF-κB signaling cascade and cyclooxygenase-2 in HNE-treated endothelial cells. In the present study, the anti-inflammatory effect of salicylideneamino-2-thiophenol (SAL-2), a derivative of salicylate, on a potent oxidant 4-hydroxynonenal (HNE)-induced oxidative stress was investigated using rat prostate endothelial (YPEN-1) cells. We focused on anti-inflammatory activity of SAL-2 which was determined by its ability to suppress COX-2 and iNOS gene expression through suppression of NF-κB and redox regulation. We found that SAL-2 effectively inhibited HNE-induced reactive species generation, while upregulated GSH/GSSG ratio. Prostagrandin (PG) E2 production stimulated by arachidonic acid was suppressed by SAL-2. SAL-2 also downregulated COX-2 and iNOS expression induced by HNE, but salicylate did not. We found that SAL-2 inhibited HNE-mediated IKK phosphorylation, IκBα degradation and nuclear translocation of p65 which are linked to NF-κB activation. Furthermore, SAL-2 inhibited HNE-induced activation of mitogen-activated protein kinases. Collectively, SAL-2 inhibited COX-2 and iNOS gene expression through suppression of NF-κB leading to the inhibition of PGE2 synthesis. Based on these data, we propose that with its combined effect on strong anti-oxidant and anti-inflammatory action, SAL-2 can be a potent anti-inflammatory agent for treatment of inflammatory-related diseases. 23641792 Solution pH and Oligoamine Molecular Weight Dependence of the Transition from Monolayer to Multilayer Adsorption at the Air-Water Interface from Sodium Dodecyl Sulfate/Oligoamine Mixtures. Neutron reflectivity and surface tension have been used to investigate the solution pH and oligoamine molecular weight dependence of the adsorption of sodium dodecyl sulfate (SDS)/oligoamine mixtures at the air-water interface. For diethylenetriamine, triamine, or triethylenetetramine, tetramine mixed with SDS, there is monolayer adsorption at pH 7 and 10, and multilayer adsorption at pH 3. For the slightly higher molecular weight tetraethylenepentamine, pentamine, and pentaethylenehexamine, hexamine, the adsorption is in the form of a monolayer at pH 3 and multilayers at pH 7 and 10. Hence, there is a pH driven transition from monolayer to multilayer adsorption, which shifts from low pH to higher pH as the oligoamine molecular weight increases from tetramine to pentamine. This results from the relative balance between the electrostatic attraction between the SDS and amine nitrogen group which decreases as the charge density decreases with increasing pH, the ion-dipole interaction between the amine nitrogen and SDS sulfate group which is dominant at higher pH, and the hydrophobic interalkyl chain interaction between bound SDS molecules which changes with oligoamine molecular weight. 22381584 Pharmacological evidence of functional inhibitory metabotrophic glutamate receptors on mouse arousal-related cholinergic laterodorsal tegmental neurons. Cholinergic neurons of the pontine laterodorsal tegmentum (LDT) are importantly involved in neurobiological mechanisms governing states of arousal such as sleep and wakefulness as well as other appetitive behaviors, such as drug-seeking. Accordingly, mechanisms controlling their excitability are important to elucidate if we are to understand how these LDT neurons generate arousal states. Glutamate mediates the vast majority of excitatory synaptic transmission in the vertebrate CNS and while presence of glutamate input in the LDT has been shown and ionotropic responses to glutamate have been reported in the LDT, characterization of metabotropic responses is lacking. Therefore, electrophysiological responses and changes in levels of intracellular Ca(2+) in mouse cholinergic LDT neurons following application of specific mGluR agonists and antagonists were examined. Unexpectedly, both the mGluR(5)specific agonist, CHPG, and the group II mGluR (mGlu(2/3)) agonist, LY379268 (LY), induced a TTX-insensitive outward current/hyperpolarization. Both outward currents were significantly reduced by the mGluR antagonist MCPG and the CHPG-induced current was blocked by the specific mGluR(5) antagonist MTEP. Concurrent Ca(2+)imaging revealed that while CHPG actions did include release of Ca(2+) from CPA/thapsigargin-sensitive intracellular stores, actions of LY did not. Both CHPG- and LY-induced outward currents were mediated by a TEA-sensitive potassium conductance. The large-conductance, Ca(2+)-dependent potassium (BK) channel blocker, iberiotoxin, attenuated CHPG actions. Consistent with actions on the BK conductance, CHPG enhanced the amplitude of the fast component of the after hyperpolarizing potential, concurrent with a reduction in the firing rate. We conclude that stimulation of mGluR(5) and group II (mGluR(2/3)) elicits postsynaptically-mediated outward currents/hyperpolarizations in cholinergic LDT neurons. Effects of glutamatergic input would be, thus, expected not only to be excitation via stimulation of ionotropic glutamate receptors and mGluR(1), but also inhibition via actions at mGluR(5) and mGluR(2/3) on these neurons. As these two processes counteract each other, these surprising findings necessitate revision of predictions regarding the net level of excitation generated by glutamate input to cholinergic LDT cells and, by extension, the functional outcome of glutamate transmission on processes which these neurons regulate. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23410094 Injectable superparamagnets: highly elastic and degradable poly(N-isopropylacrylamide)-superparamagnetic iron oxide nanoparticle (SPION) composite hydrogels. Injectable, in situ-gelling magnetic composite materials have been fabricated by using aldehyde-functionalized dextran to cross-link superparamagnetic nanoparticles surface-functionalized with hydrazide-functionalized poly(N-isopropylacrylamide) (pNIPAM). The resulting composites exhibit high water contents (82-88 wt.%) while also displaying significantly higher elasticities (G' >60 kPa) than other injectable hydrogels previously reported. The composites hydrolytically degrade via slow hydrolysis of the hydrazone cross-link at physiological temperature and pH into degradation products that show no significant cytotoxicity. Subcutaneous injections indicate only minor chronic inflammation associated with material degradation, with no fibrous capsule formation evident. Drug release experiments indicate the potential of these materials to facilitate pulsatile, "on-demand" changes in drug release upon the application of an external oscillating magnetic field. The injectable but high-strength and externally triggerable nature of these materials, coupled with their biological degradability and inertness, suggest potential biological applications in tissue engineering and drug delivery. 23530012 Circulating Vitamin D Metabolites and Subclinical Atherosclerosis in Type 1 Diabetes. OBJECTIVEPeople with type 1 diabetes are at high risk of premature atherosclerosis. Existing evidence suggests that impaired vitamin D metabolism may contribute to the development of atherosclerosis. We tested associations of circulating vitamin D metabolite concentrations with subclinical atherosclerosis among 1,193 participants with type 1 diabetes in the DCCT/EDIC study.RESEARCH DESIGN AND METHODSWe measured plasma concentrations of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D, and 24,25-dihydroxyvitamin D by mass spectrometry at the end of the DCCT. In a staggered cross-sectional design, we tested associations with coronary artery calcium (CAC), measured by computed tomography a median of 10 years later, and with common and internal carotid intima-media thickness (IMT), measured by B-mode ultrasonography on two occasions a median of 4 years later and a median of 10 years later. We hypothesized that lower concentrations of each vitamin D metabolite would be associated with increased risk of CAC and greater carotid IMT.RESULTSAt the time metabolites were measured, mean age was 32.4 years and mean duration of diabetes was 7.5 years. The prevalence and severity of CAC tended to be lower-not higher-with lower concentrations of each vitamin D metabolite. For instance, in a fully adjusted multinomial logistic model, a 25 nmol/L lower 25-hydroxyvitamin D was associated with a 0.8-fold decrease in the odds of having higher CAC (95% CI 0.68-0.96, P = 0.01). No vitamin D metabolite was associated with either common or internal mean IMT.CONCLUSIONSWe did not find evidence linking impaired vitamin D metabolism with increased subclinical atherosclerosis in type 1 diabetes. 23564369 Assessing triclosan-induced ecological and trans-generational effects in natural phytoplankton communities: a trait-based field method. We exposed replicated phytoplankton communities confined in semi-permeable membrane-based mesocosms to 0, 0.1, 1 and 10 μg L(-1) triclosan (TCS) and placed them back in their original environment to investigate the occurrence of trans-generational responses at individual, population and community levels. TCS diffused out of mesocosms with a half-life of less than 8 h, so that only the parental generation was directly stressed. At the beginning of the experiment and after 7 days (approximately 2 generations) we analysed responses in the phytoplankton using scanning flow-cytometry. We acquired information on several individually expressed phenotypic traits, such as size, biovolume, pigment fluorescence and packaging, for thousands of individuals per replicated population and derived population and community aggregated traits. We found significant changes in community functioning (increased productivity in terms of biovolume and total fluorescence), with maximal effects at 1 μg L(-1) TCS. We detected significant and dose-dependent responses on population traits, such as changes in abundance for several populations, increased average size and fluorescence of cells, and strong changes in within-population trait mean and variance (suggesting micro-evolutionary effects). We applied the Price equation approach to partition community effects (changes in biovolume or fluorescence) in their physiological and ecological components, and quantified the residual component (including also evolutionary responses). Our results suggested that evolutionary or inheritable phenotypic plasticity responses may represent a significant component of the total observed change following exposure and over relatively small temporal scales. 23401140 Key Articles and Guidelines in the Primary Prevention of Ischemic Stroke. Ischemic stroke is a prevalent disease with a large burden on the health system. Preventive strategies, therefore, are paramount. Primary prevention is aimed at reducing the risk of stroke in asymptomatic people. The most effective prevention is through control of modifiable risk factors. Due to the large amount of literature available on this topic, this bibliography (the first of a 2-part series) aims to provide a comprehensive resource for medical practitioners charged with caring for this population. 23066996 Alanine scan of an immunosuppressive peptide (CP): analysis of structure-function relationships. Core peptide is a hydrophobic peptide, the sequence of which is derived from the T-cell antigen receptor alpha-chain transmembrane region. Previous studies have shown that core peptide can inhibit T-cell-mediated immune responses both in vitro and in vivo. Here, we report the role each constituent amino acid plays within core peptide using an alanine scan and the amino acid effect on function using a biological antigen presentation assay. The biophysical behaviour of these analogues in model membranes was analysed using surface plasmon resonance studies and then binding correlated with T-cell function. Removal of any single hydrophobic amino acid between the two charged amino acids in core peptide (R, K) resulted in lower binding. Changing the overall net charge of core peptide, by removing either of the positively charged residues (R or K), had varying effects on peptide binding and IL-2 production. There was a direct correlation (ρ = 0.718) between peptide binding to model membranes and peptide ability to inhibit IL-2. Except for IL-2 inhibition, production of other T-cell cytokines such as GM-CSF, IFN-γ, IL-1α, IL-4, IL-5, IL-6, IL-10, IL-17 and T-cell antigen receptor alpha-chain was not detected using a fluorescent bead immunoassay. This study provides important structure-function relationships essential for further drug design. 22835278 Leydig cell hyperplasia and Leydig cell tumour in postmenopausal women: report of two cases. Leydig cell hyperplasia and Leydig cell tumours of the ovary are rare. We present two cases in which patients had increased blood levels of testosterone and frank hirsutism. Imaging showed minimal abnormalities. After adrenal disease had been ruled out, they underwent a bilateral oophorectomy. One case showed a Leydig cell hyperplasia, the other a Leydig cell tumour. An androgen producing tumour should be excluded in every woman with evidence of hirsutism or frank virilization and markedly elevated testosterone levels. Adrenal disease with androgen hypersecretion can be suspected by detailed clinical, laboratory and radiologic imaging. Although DHEAS has a good sensitivity in the detection of adrenal origin of hyperandrogenism (and hence a good negative predictive value) it is not specific (specificity ranging from 85 to 98%). Imaging of the ovaries can be helpful but does not rule out ovarian disease if normal. Indeed, diffuse stromal Leydig cell hyperplasia and Leydig cell tumours (usually small) may escape imaging and in some cases diagnosis can only be made on pathology. As these clinical entities represent a diagnostic and therapeutic challenge, oophorectomy should be considered in postmenopausal women with hirsutism and elevated testosterone levels, after the exclusion of adrenal causes. The procedure is relatively safe and effective. Follow-up remains indicated. 23340113 Shifting from the single to the multitarget paradigm in drug discovery. Increasing evidence that several drug compounds exert their effects through interactions with multiple targets is boosting the development of research fields that challenge the data reductionism approach. In this article, we review and discuss the concepts of drug repurposing, polypharmacology, chemogenomics, phenotypic screening and high-throughput in vivo testing of mixture-based libraries in an integrated manner. These research fields offer alternatives to the current paradigm of drug discovery, from a one target-one drug model to a multiple-target approach. Furthermore, the goals of lead identification are being expanded accordingly to identify not only 'key' compounds that fit with a single-target 'lock', but also 'master key' compounds that favorably interact with multiple targets (i.e. operate a set of desired locks to gain access to the expected clinical effects). 23422727 Block/homo polyplex micelle-based GM-CSF gene therapy via intraperitoneal administration elicits antitumor immunity against peritoneal dissemination and exhibits safety potentials in mice and cynomolgus monkeys. A block/homo-mixed polyplex micelle, comprising of cationic homo polymer: poly{N'-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} P[Asp(DET)] and block copolymer: polyethylene glycol (PEG)-b-P[Asp(DET)], has been reported to exhibit the efficient transgene expression in vivo by intratracheal and systemic administration. In the present study, we investigated the potential of immunogene therapy by intraperitoneal (i.p.) administration of block/homo polyplex micelles for peritoneal dissemination. For evaluation of transgene expression in vivo, block/homo polyplex micelles showed 12-fold higher level in luciferase expression evaluated by bioluminescence imaging system at 24h after the i.p. administration compared with block polyplex micelles composed with only PEG-b-P[Asp(DET)] in nude mice bearing peritoneal dissemination. The distribution of block/homo polyplex micelles and intracellular uptake of pDNA was observed in tumor nodules. The tumor growth and the prolonged survival rate for the mice harboring disseminated pancreatic cancer more significantly compared with the mock. The antitumor effect of GM-CSF gene therapy was mediated via the activation of natural killer cells. For safety evaluation, block/homo polyplex micelles indicated almost no adverse events for patho-physical findings and blood examinations in mice and cynomolgus monkeys, although slight increases in serum fibrinogen were observed in the monkey model. In conclusion, block/homo polyplex micelle-based immunogene therapy via i.p. administration may be a safe and effective approach for suppressing intractable peritoneal dissemination. 23252846 Low-noise nano superconducting quantum interference device operating in Tesla magnetic fields. Superconductivity in the cuprate YBa(2)Cu(3)O(7) (YBCO) persists up to huge magnetic fields (B) up to several tens of Teslas, and sensitive direct current (dc) superconducting quantum interference devices (SQUIDs) can be realized in epitaxially grown YBCO films by using grain boundary Josephson junctions (GBJs). Here we present the realization of high-quality YBCO nanoSQUIDs, patterned by focused ion beam milling. We demonstrate low-noise performance of such a SQUID up to B = 1 T applied parallel to the plane of the SQUID loop at the temperature T = 4.2 K. The GBJs are shunted by a thin Au layer to provide nonhysteretic current voltage characteristics, and the SQUID incorporates a 90 nm wide constriction which is used for on-chip modulation of the magnetic flux through the SQUID loop. The white flux noise of the device increases only slightly from 1.3 μΦ(0)/(Hz)(1/2) at B = 0 to 2.3 μΦ(0)/(Hz))(1/2) at 1 T. Assuming that a point-like magnetic particle with magnetization in the plane of the SQUID loop is placed directly on top of the constriction and taking into account the geometry of the SQUID, we calculate a spin sensitivity S(μ)(1/2) = 62 μ(B)/(Hz))(1/2) at B = 0 and 110 μ(B)/(Hz))(1/2) at 1 T. The demonstration of low noise of such a SQUID in Tesla fields is a decisive step toward utilizing the full potential of ultrasensitive nanoSQUIDs for direct measurements of magnetic hysteresis curves of magnetic nanoparticles and molecular magnets. 23385032 Application of activated nucleoside analogs for the treatment of drug-resistant tumors by oral delivery of nanogel-drug conjugates. A majority of nanoencapsulated drugs that have shown promise in cancer chemotherapy are administered intravenously. Development of effective oral nanoformulations presents a very challenging medical goal. Here, we describe successful applications of innovative polymeric nanogels in the form of conjugates with activated nucleoside analogs for oral administration in cancer chemotherapy. Previously, we reported the synthesis of amphiphilic polyvinyl alcohol and dextrin-based nanogel conjugates with the phosphorylated 5-FU nucleoside Floxuridine and demonstrated their enhanced activity against regular and drug-resistant cancers (T.H. Senanayake, G. Warren, S.V. Vinogradov, Novel anticancer polymeric conjugates of activated nucleoside analogs, Bioconjug. Chem. 22 (2011) 1983-1993). In this study, we synthesized and evaluated oral applications of nanogel conjugates of a protected Gemcitabine, the drug never used in oral therapies. These conjugates were able to quickly release an active form of the drug (Gemcitabine 5'-mono-, di- and triphosphates) by specific enzymatic activities, or slowly during hydrolysis. Gemcitabine conjugates demonstrated up to 127 times higher in vitro efficacy than the free drug against various cancer cells, including the lines resistant to nucleoside analogs. Surprisingly, these nanogel-drug conjugates were relatively stable in gastric conditions and able to actively penetrate through the gastrointestinal barrier based on permeability studies in Caco-2 cell model. In tumor xenograft models of several drug-resistant human cancers, we observed an efficient inhibition of tumor growth and extended the life-span of the animals by 3 times that of the control with orally treated Gemcitabine- or Floxuridine-nanogel conjugates. Thus, we have demonstrated a potential of therapeutic nanogel conjugates with the activated and stabilized Gemcitabine as a successful oral drug form against Gemcitabine-resistant and other drug-resistant tumors. 22703341 Feroniellides C-E, new apotirucallane triterpenoids from the stem bark of Feroniella lucida. Bioassay-directed isolation of Feroniella lucida stem bark yielded three new apotirucallane triterpenoids named feroniellides C-E. The structures of the new compounds were established by extensive analysis of spectroscopic data. Of triterpenoids examined, feroniellides D and E revealed anticancer activity against KB and HeLa cells with IC50 values in range of 3.4-14.2 µg mL(-1), which are significantly more potent than feroniellides A-C (IC50 25.5-60.0 µg mL(-1)). The present investigation suggests that an isovalerate moiety in feroniellides D and E is possibly associated with exerting cytotoxicity against cancer cells. 23281965 Thyroid hormone replacement therapy attenuates the decline of renal function in chronic kidney disease patients with subclinical hypothyroidism. Background: Subclinical hypothyroidism (SH) is not a rare condition in females, the elderly, or patients with chronic kidney disease (CKD). Even though previous studies have demonstrated that thyroid hormone replacement therapy (THRT) improved cardiac function and dyslipidemia in patients with subclinical hypothyroidism, it remains unclear as to whether THRT can improve renal function in CKD patients with SH. This study investigated the impact of THRT on changes in estimated glomerular filtration rates (eGFR) in this patient population. Methods: A total of 113 CKD patients with SH who were treated with L-thyroxine and had eGFR available for at least 24 months before and after THRT were enrolled between January 2005 and December 2011. A linear mixed model was used to compare patients' clinical and biochemical parameters at various time points. The slope of the decline in eGFR over time, both before and after THRT, was also calculated and compared using a linear mixed model. Results: The mean age of the study participants was 63.2 ± 12.7 years, and 36 patients (31.9%) were male. The mean follow-up duration before and after THRT was 28.6 ± 4.5 and 30.6 ± 6.4 months, respectively. At 24-months of THRT, TSH levels were significantly reduced [8.86 (0.49) vs. 1.41 (0.73) IU/mL, P < 0.001], but there were no significant changes in T3 and fT4 concentrations. Serum albumin, calcium, phosphate, cholesterol, and triglyceride levels were also comparable after THRT. The rates of decline in eGFR were significantly attenuated by THRT [-4.31 (0.51) vs. -1.08 (0.36) mL/min/year/1.73 m2, P < 0.001] even after adjustment for age, gender, diabetes, mean arterial pressure, serum albumin, cholesterol, and triglyceride concentrations (P < 0.001). Conclusion: THRT attenuated the rate of decline in renal function in CKD patients with SH, suggesting that THRT may delay reaching end-stage renal disease in these patients. 23499717 Construction of block copolymers for the coordinated delivery of doxorubicin and magnetite nanocubes. Multifunctional nanoparticles combine drug and imaging agent together to assign both therapeutic and diagnostic functions. However, particle aggregation/dissociation and/or major differences in the bio-distribution and targeting capability of drugs and imaging probes are main obstacles for the efficient, coordinated delivery of multiple agents, unless the different agents can be tightly bound and well-protected during their circulation in vivo. In this paper, we report the coordinated in vivo delivery of anti-cancer drugs and imaging agents by chemically loading doxorubicin and magnetite nanocubes (MNs) in the core of polymeric nanoparticles. Living polymerization, nitroxide-mediated radical polymerization (NMP), was applied to construct the optimal polymers to co-deliver doxorubicin and MNs. The resulting diblock polymers consisted of one block with triethylene glycol brushes and another block with carboxylic acid groups to bind doxorubicin and Fe3O4 MNs. The optimal polymer has narrow polydispersity (PDI=1.2) and high doxorubicin/MN loading (30wt.%/28wt.%). Core-shell particles were obtained with good stability and a suitable particle size of ~100nm. The doxorubicin and MNs loaded in this polymeric system showed highly coordinated bio-distribution in the balb/C mice model. This system may have important impact on the design of effective and stable dual-agent co-delivery systems. 23379795 Landscape heterogeneity shapes host-parasite interactions and results in apparent plant-virus codivergence. Knowledge on how landscape heterogeneity shapes host-parasite interactions is central to understand the emergence, dynamics and evolution of infectious diseases. However, this is an underexplored subject, particularly for plant-virus systems. Here, we analyse how landscape heterogeneity influences the prevalence, spatial genetic structure, and temporal dynamics of Pepper golden mosaic and Pepper huasteco yellow vein begomoviruses infecting populations of the wild pepper Capsicum annuum glabriusculum (chiltepin) in Mexico. Environmental heterogeneity occurred at different nested spatial scales (host populations within biogeographical provinces), with levels of human management varying among host population within a province. Results indicate that landscape heterogeneity affects the epidemiology and genetic structure of chiltepin-infecting begomoviruses in a scale-specific manner, probably related to conditions favouring the viruses' whitefly vector and its dispersion. Increased levels of human management of the host populations were associated with higher virus prevalence and erased the spatial genetic structure of the virus populations. Also, environmental heterogeneity similarly shaped the spatial genetic structures of host and viruses. This resulted in the congruence between host and virus phylogenies, which does not seem to be due to host-virus co-evolution. Thus, results provide evidence of the key role of landscape heterogeneity in determining plant-virus interactions. 23334864 Iron overload inhibits osteoblast biological activity through oxidative stress. Iron overload has recently been connected with bone mineral density in osteoporosis. However, to date, the effect of iron overload on osteoblasts remains poorly understood. The purpose of this study is to examine osteoblast biological activity under iron overload. The osteoblast cells (hFOB1.19) were cultured in a medium supplemented with different concentrations (50, 100, and 200 μM) of ferric ammonium citrate as a donor of ferric ion. Intracellular iron was measured with a confocal laser scanning microscope. Reactive oxygen species (ROS) were detected by 2,7-dichlorofluorescin diacetate fluorophotometry. Osteoblast biological activities were evaluated by measuring the activity of alkaline phosphatase (ALP) and mineralization function. Results indicated that iron overload could consequently increase intracellular iron concentration and intracellular ROS levels in a concentration-dependent manner. Additionally, ALP activity was suppressed, and a decline in the number of mineralized nodules was observed in in vitro cultured osteoblast cells. According to these results, it seems that iron overload probably inhibits osteoblast function through higher oxidative stress following increased intracellular iron concentrations. 23481590 Testosterone modulates spatial recognition memory in male rats. A growing body of research indicates that testosterone influences spatial cognition in male rats; however, the overwhelming majority of studies have been conducted on tasks motivated by either food deprivation or water escape. The hippocampus-dependent version of the Y-maze task, which characterizes spatial recognition memory, capitalizes on the propensity of rats to gravitate toward novel spatial environments and is not contingent upon either appetite or the stress associated with water escape, two factors also affected by testosterone. Accordingly, the aim of the current study was to examine the effects of orchidectomy and subsequent testosterone treatment on spatial recognition memory. Orchidectomy did not impact spatial recognition memory when the delay between the information and retention trials of the Y-maze task was 24h. Alternatively, on the second Y-maze task, which featured a 48-h delay between trials, orchidectomy reduced, and treatments that produced higher levels of testosterone restored, preference for the arm associated with the novel spatial environment. Importantly, there were no differences in activity levels as a function of orchidectomy or testosterone treatment on either of the two tasks. Consistent with previous findings, orchidectomy attenuated, and testosterone treatment restored, both body weight gain and the relative weight of the androgen-sensitive ischiocavernosus muscle, which confirmed the efficacy of orchidectomy and testosterone treatments on physiological outcomes. Therefore, testosterone influenced spatial cognition on a task that minimized the influence of non-mnemonic factors and took advantage of the innate preference of rodents to seek out novel spatial environments. 23387824 Sesquiterpenes from the rhizomes of Curcuma heyneana. Four new germacranes [heyneanones A-D (1-4)], three new guaianes [4,10-epizedoarondiol (5), 15-hydroxyprocurcumenol (6), 12-hydroxycurcumenol (7)], and two new spirolactones [curcumanolides C (8) and D (9)] were isolated from the rhizomes of Curcuma heyneana together with 13 known sesquiterpenes and two known labdane-type diterpenes. Among the isolated compounds, heyneanone A (1), heyneanone C (3), 4,10-epizedoarondiol (5), procurcumenol (16), aerugidiol (17), zerumin A (23), and (E)-15,16-bisnorlabda-8(17),11-dien-13-one (24) inhibited protein tyrosine phosphatase 1B (PTP1B) with IC(50) values of 42.5, 35.2, 35.1, 45.6, 35.7, 10.4, and 14.7 μM, respectively. 23273506 Non-productive DNA damage binding by DNA glycosylase-like protein Mag2 from Schizosaccharomyces pombe. Schizosaccharomyces pombe contains two paralogous proteins, Mag1 and Mag2, related to the helix-hairpin-helix (HhH) superfamily of alkylpurine DNA glycosylases from yeast and bacteria. Phylogenetic analysis of related proteins from four Schizosaccharomyces and other fungal species shows that the Mag1/Mag2 duplication is unique to the genus Schizosaccharomyces and most likely occurred in its ancestor. Mag1 excises N3- and N7-alkylguanines and 1,N(6)-ethenoadenine from DNA, whereas Mag2 has been reported to have no detectible alkylpurine base excision activity despite high sequence and active site similarity to Mag1. To understand this discrepancy we determined the crystal structure of Mag2 bound to abasic DNA and compared it to our previously determined Mag1-DNA structure. In contrast to Mag1, Mag2 does not flip the abasic moiety into the active site or stabilize the DNA strand 5' to the lesion, suggesting that it is incapable of forming a catalytically competent protein-DNA complex. Subtle differences in Mag1 and Mag2 interactions with the DNA duplex illustrate how Mag2 can stall at damage sites without fully engaging the lesion. We tested our structural predictions by mutational analysis of base excision and found a single amino acid responsible at least in part for Mag2's lack of activity. Substitution of Mag2 Asp56, which caps the helix at the base of the DNA intercalation loop, with the corresponding serine residue in Mag1 endows Mag2 with ɛA excision activity comparable to Mag1. This work provides novel insight into the chemical and physical determinants by which the HhH glycosylases engage DNA in a catalytically productive manner. 23464760 The antiviral effect of 7-hydroxyisoflavone against Enterovirus 71 in vitro. Enterovirus 71 (EV71) is the major causative agent of hand foot and mouth disease. And EV71 causes epidemics worldwide, particularly in the Asia-Pacific region. Unfortunately, currently there is no approved vaccine or antiviral drug for EV71-induced disease prevention and therapy. In screening for anti-EV71 candidates, we found that 7-hydroxyisoflavone was active against EV71. 7-Hydroxyisoflavone exhibited strong antiviral activity against three different EV71 strains. The 50% inhibitory concentration range was between 3.25 and 4.92 μM by cytopathic effect assay. 7-Hydroxyisoflavone could reduce EV71 viral RNA and protein synthesis in a dose-dependent manner. Time course study showed that treatment of Vero cells with 7-hydroxyisoflavone at indicated times after EV71 inoculation (0-6 h) resulted in significant antiviral activity. Results showed that 7-hydroxyisoflavone acted at an early step of EV71 replication. 7-Hydroxyisoflavone also exhibited strong antiviral activity against coxsackievirus B2, B3, and B6. In short, 7-hydroxyisoflavone may be used as a lead compound for anti-EV71 drug development. 22372659 Phytochemical composition of polar fraction of Stachys germanica L. subsp. salviifolia (Ten.) Gams, a typical plant of Majella National Park. In this study, we report the isolation and identification of several compounds present in the polar fraction of Stachys germanica L. subsp. salviifolia (Ten.) Gams, collected in the protected area of Majella National Park. In particular, we have isolated and identified harpagide, 7-β-hydroxy-harpagide, ajugol, 5-allosyloxy-aucubin, verbascoside and, for the first time in this genus, arbutin. 23352834 Sensitizing capacity and allergenicity of enzymatically cross-linked sodium caseinate in comparison to sodium caseinate in a mouse model for cow's milk allergy. A transglutaminase cross-linked caseinate was designed for use in dairy products to increase the viscosity of food matrices. The difference in structure of cross-linked caseinate might have implications for the risk of developing cow's milk allergy. The sensitizing capacity and the allergenicity (the potency to induce an allergic effector response) of cross-linked sodium caseinate was investigated using a mouse model for cow's milk allergy. Mice were orally sensitized with cross-linked caseinate or caseinate using cholera toxin as adjuvant. Anaphylactic shock reactions, change in body temperature, acute allergic skin response, caseinate-, cross-linked caseinate-IgE and mMCP-1 concentrations were determined after challenge with cross-linked caseinate or caseinate. Sensitization with cross-linked caseinate did not result in anaphylactic shock symptoms, drop in body temperature or release of serum mMCP-1. A tendency toward decreased casein-specific IgE levels was observed. The allergenicity did not differ between both products. These results indicate that in already caseinate-sensitized mice, cross-linked caseinate did not provoke more pronounced allergenic reactions compared to sodium caseinate. On top of that, reduced sensitization to cross-linked caseinate was observed. Cross-linked caseinate might therefore be an interesting new dietary concept for humans at risk for food allergy although more mechanistic studies and clinical trials are needed for validation. 23425062 Small-molecule inhibitors/modulators of amyloid-β peptide aggregation and toxicity for the treatment of Alzheimer's disease: a patent review (2010 - 2012). Introduction: Genetic, physiological, and biochemical data indicate that agglomerates of the 42-amino acid form of the amyloid-β (Aβ42) peptide are strongly linked to Alzheimer's disease (AD) etiology and thus represent a particularly attractive target for the development of an effective disease-modifying approach for AD treatment. A plethora of chemical entities able to modulate Aβ42 self-assembly have been developed in recent years, among them, several are in clinical or preclinical development. Areas covered: This review accounts for small-molecule inhibitors of Aβ peptide polymerization and toxicity, reported in the patent literature during the 2010 - 2012 period, and their potential use as disease-modifying therapeutics for AD cure. Expert opinion: The earliest pathogenic event is the formation of soluble Aβ oligomers that disrupt synaptic communication. Drug design strategies targeting these primary toxic agents could hold considerable promises for obtaining effective anti-AD drugs candidate. The heterogeneous aggregation of Aβ and the resulting difficulty to structurally characterize the peptide represent important drawbacks. 23408858 Novel inhibition of archaeal family-D DNA polymerase by uracil. Archaeal family-D DNA polymerase is inhibited by the presence of uracil in DNA template strands. When the enzyme encounters uracil, following three parameters change: DNA binding increases roughly 2-fold, the rate of polymerization slows by a factor of ∼5 and 3'-5' proof-reading exonuclease activity is stimulated by a factor of ∼2. Together these changes result in a significant decrease in polymerization activity and a reduction in net DNA synthesis. Pol D appears to interact with template strand uracil irrespective of its distance ahead of the replication fork. Polymerization does not stop at a defined location relative to uracil, rather a general decrease in DNA synthesis is observed. 'Trans' inhibition, the slowing of Pol D by uracil on a DNA strand not being replicated is also observed. It is proposed that Pol D is able to interact with uracil by looping out the single-stranded template, allowing simultaneous contact of both the base and the primer-template junction to give a polymerase-DNA complex with diminished extension ability. 23464829 A new flavanol from Cynomorium songaricum. A new flavanol, named songarin A (1), was isolated from Cynomorium songaricum Rupr. The structure was established on the basis of spectroscopic methods including 2D NMR techniques. Compound 1 displayed the protective effect against d-galactosamine-induced HepG2 damage and reduced the damage from 58.64% to 22.26%. 23377024 Effects of caffeine and alcohol on mood and performance changes following consumption of lager. RATIONALE: The present study examined whether caffeine would modify the behavioural effects of alcohol. OBJECTIVES: The aim of the study was to determine whether caffeine modifies the effects of alcohol on mood and psychomotor performance and to identify possible dose-response and temporal relationships. METHODS: A double-blind study examined the effects of three successive lager drinks (330 ml each) in the early afternoon on mood and psychomotor performance assessed at 30-min intervals over a 2-h period. Participants carried out a baseline session and were then randomly assigned to one of six conditions formed by combining three different doses of caffeine (0, 62.5 and 125 mg per drink) with either no alcohol or 4.3 % alcohol. One hundred and forty-six young adults (65 male, 81 female; age range 18-30 years) participated in the study. Mood (alertness, hedonic tone and anxiety) was assessed before and after performing simple reaction time and choice reaction time tasks. RESULTS: Alcohol was associated with higher hedonic tone (p < 0.005), reduced anxiety (p < 0.05) and reduced alertness (p < 0.005). Caffeine had no modifying effect on hedonic tone or anxiety. However, the highest dose of caffeine did remove the effect of alcohol on alertness (p < 0.05). Effects of alcohol and caffeine were found on the performance tasks (all p values < 0.05) but these were independent effects. CONCLUSIONS: The results from the present study confirm that caffeine does not remove the negative effects of alcohol on performance although high doses counteract the drop in subjective alertness produced by alcohol. 23418719 Optical response of individual Au-Ag@SiO₂ heterodimers. The optical extinction response of individual Au-Ag@SiO2 heterodimers whose individual morphologies are determined by transmission electron microscopy (TEM) is investigated using spatial modulation spectroscopy. The extinction spectra show two resonances spectrally close to the surface plasmon resonances of the constituting Au and Ag@SiO2 core-shell particles. The interparticle electromagnetic coupling is demonstrated to induce a large increase of the optical extinction of the dimer around its Au-like surface plasmon resonance for light polarized along its axis, as compared to that for perpendicular polarization and to that of an isolated Au nanoparticle. For spherical particles, this interaction also leads to comparable shifts with light polarization of the two dimer resonances, an effect masked or even reversed for particles significantly deviating from sphericity. Both amplitude and spectral effects are found to be in excellent quantitative agreement with numerical simulations when using the TEM-measured dimer morphology (i.e., size, shape, and orientation of the individual dimers), stressing the importance of individual morphology characterization for interpreting heterodimer optical response. 23583009 Quercetin suppressed CYP2E1-dependent ethanol hepatotoxicity via depleting heme pool and releasing CO. Naturally occuring quercetin protects hepatocytes from ethanol-induced oxidative stress, and heme oxygenase-1 (HO-1) induction and carbon monoxide (CO) metabolite may be implicated in the beneficial effect. However, the precise mechanism by which quercetin counteracts CYP2E1-mediated ethanol hepatotoxicity through HO-1 system is still remained unclear. To explore the potential mechanism, herein, ethanol (4.0g/kg.bw.) was administrated to rats for 90 days. Our data showed that chronic ethanol over-activated CYP2E1 but suppressed HO-1 with concurrent hepatic oxidative damage, which was partially normalized by quercetin (100mg/kg.bw.). Quercetin (100μM) induced HO-1 and depleted heme pool when incubated to human hepatocytes. Ethanol-stimulated (100mM) CYP2E1 upregulation was suppressed by quercetin but further enhanced by HO-1 inhibition with resultant heme accumulation. CO scavenging blocked the suppression of quercetin only on CYP2E1 activity. CO donor dose-dependently inactivated CYP2E1 of ethanol-incubated microsome, which was mimicked by HO-1 substrate but abolished by CO scavenger. Thus, CYP2E1-mediated ethanol hepatotoxicity was alleviated by quercetin through HO-1 induction. Depleted heme pool and CO releasing limited protein synthesis and inhibited enzymatic activity of CYP2E1, respectively. 23180691 Characterizing the lateral friction of nanoparticles on on-chip integrated black lipid membranes. The use of nanoparticles (NPs) in biomedical applications creates a need for appropriate model systems to systematically investigate NP-membrane interactions under well-defined conditions. Black lipid membranes (BLMs) are free-floating membranes with defined composition that are ideally suited for characterizing NP-membrane interactions free of any potential perturbation through a supporting substrate. Herein, arrays of microfabricated BLMs are integrated into a chip-based platform that is compatible with high-speed optical NP tracking. This system is used to investigate the lateral diffusion of 40 nm gold spheres tethered to biotinylated lipids through antibody-functionalized ligands (single-stranded DNA or polyethylene glycol). Although the NPs show an almost free and ergodic diffusion, their lateral motion is subject to substantial drag at the membrane surface, which leads to systematically smaller diffusion coefficients than those obtained for lipids in the membrane through fluorescence recovery after photobleaching. The lateral mobility of the NPs is influenced by the chemical composition and salt concentration at the NP-membrane interface, but is independent of the ligand density in the membrane. Together with the observation that nanoprisms, which have a larger relative contact area with the membrane than spherical NPs, show an even slower diffusion, these findings indicate that the lateral mobility of NPs tethered in close vicinity to a membrane is significantly reduced by the friction at the NP-membrane interface. 23532002 Analysis of visible-light-active Sn(ii)-TiO2 photocatalysts. The influence of Sn(ii) species on TiO2 is investigated. The absorption spectra of these materials are red-shifted by 115 nm to the visible region of the solar spectrum compared with P25 TiO2. This prominent red-shift is attributed to the interaction of Sn(ii) 5s orbitals with the TiO2 decreasing the band gap of TiO2 by raising its valence band. The tin oxidation state and the materials electronic structure are evaluated using Mössbauer spectroscopy and valence band X-ray photoelectron spectroscopy respectively. These materials are active for sacrificial photo-generation of hydrogen in visible light. 23233546 Genotype imputation via matrix completion. Most current genotype imputation methods are model-based and computationally intensive, taking days to impute one chromosome pair on 1000 people. We describe an efficient genotype imputation method based on matrix completion. Our matrix completion method is implemented in MATLAB and tested on real data from HapMap 3, simulated pedigree data, and simulated low-coverage sequencing data derived from the 1000 Genomes Project. Compared with leading imputation programs, the matrix completion algorithm embodied in our program MENDEL-IMPUTE achieves comparable imputation accuracy while reducing run times significantly. Implementation in a lower-level language such as Fortran or C is apt to further improve computational efficiency. 23289788 Antimutagenic effect of aqueous extract from Agaricus brasiliensis on culture of human lymphocytes. The mushroom Agaricus brasiliensis (sun mushroom), native from the southeast of Brazil, is well known by its medicinal properties that include effects on diabetes, cholesterol levels, and osteoporosis. The antimutagenic effects of A. brasiliensis has been investigated recently and revealed some controversial results depending on the temperature by which the A. brasiliensis tea is obtained. In the present study, we evaluated the effect of the A. brasiliensis extract prepared in two different temperatures, 4°C and 25°C, on the doxorubicin-induced DNA strand breaks and chromosomal aberrations (CAs) in human lymphocytes. The results demonstrated that A. brasiliensis was able to reduce the DXR-induced DNA damage in both temperatures; however, the CA test was more sensitive to demonstrate a better reduction when the cells were treated with an extract obtained at 25°C. A. brasiliensis extract obtained in different temperatures exhibited antigenotoxic and anticlastogenic effects in human lymphocytes. 23306105 Effects of tris(1,3-dichloro-2-propyl) phosphate and triphenyl phosphate on receptor-associated mRNA expression in zebrafish embryos/larvae. Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) and triphenyl phosphate (TPP) are frequently detected in biota, including fish. However, knowledge of the toxicological and molecular effects of these currently used flame retardants is limited. In the present study, an in vivo screening approach was developed to evaluate effects of TDCPP and TPP on developmental endpoints and receptor-associated expression of mRNA in zebrafish embryos/larvae. Exposure to TDCPP or TPP resulted in significantly smaller rates of hatching and survival, in dose- and time-dependent manners. The median lethal concentration (LC(50)) was 7.0 mg/L for TDCPP and 29.6 mg/L for TPP at 120 hour post-fertilization (hpf). Real-time PCR revealed alterations in expression of mRNAs involved in aryl hydrocarbon receptors (AhRs)-, peroxisome proliferator-activated receptor alpha (PPARα)-, estrogenic receptors (ERs)-, thyroid hormone receptor alpha (TRα)-, glucocorticoid receptor (GR)-, and mineralocorticoid receptor (MR)-centered gene networks. Exposure to positive control chemicals significantly altered abundances of mRNA in corresponding receptor-centered gene networks, a result that suggests that it is feasible to use zebrafish embryos/larvae to evaluate effects of chemicals on mRNA expression in these gene networks. Exposure to TDCPP altered transcriptional profiles in all six receptor-centered gene networks, thus exerting multiple toxic effects. TPP was easily metabolized and its potency to change expression of mRNA involved in receptor-centered gene networks was weaker than that of TDCPP. The PPARα- and TRα-centered gene networks might be the primary pathways affected by TPP. Taken together, these results demonstrated that TDCPP and TPP could alter mRNA expression of genes involved in the six receptor-centered gene networks in zebrafish embryos/larvae, and TDCPP seemed to have higher potency in changing the mRNA expression of these genes. 23143803 Effects of pyrene exposure and temperature on early development of two co-existing Arctic copepods. Oil exploration is expected to increase in the near future in Western Greenland. At present, effects of exposure to oil compounds on early life-stages of the ecologically important Calanus spp. are unknown. We investigated the effects of the oil compound pyrene, on egg hatching and naupliar development of the calanoid copepods Calanus glacialis and C. finmarchicus, two key species in the Disko Bay, Western Greenland. At low temperature the nauplii of C. glacialis experienced reduced growth when exposed to pyrene, and survival in both species decreased. Naupliar mortality increased with temperature at high pyrene concentration in C. finmarchicus. Both Calanus species were affected by pyrene exposure but C. finmarchicus was more sensitive compared to C. glacialis. Lowered growth rate and increased mortality of the naupliar stages entail reduced recruitment to copepod populations. Exposure to pyrene from an oil spill may reduce the standing stock of Calanus, which can lead to less energy available to higher trophic levels in the Arctic marine food web. 23335024 A novel canine model for prostate cancer. BACKGROUND: No existing animal model fully recapitulates all features of human prostate cancer. The dog is the only large mammal, besides humans, that commonly develops spontaneous prostate cancer. Canine prostate cancer features many similarities with its human counterpart. We sought to develop a canine model of prostate cancer that would more fully represent the features of human prostate cancer than existing models. METHODS: The Ace-1 canine prostate cancer cell line was injected transabdominally under transrectal ultrasound (TRUS) guidance into the prostates of immunosuppressed, intact, adult male dogs. Tumor progression was monitored by TRUS imaging. Some dogs were subjected to positron emission tomography (PET) for tumor detection. Time of euthanasia was determined based on tumor size, impingement on urethra, and general well-being. Euthanasia was followed by necropsy and histopathology. RESULTS: Ace-1 tumor cells grew robustly in every dog injected. Tumors grew in subcapsular and parenchymal regions of the prostate. Tumor tissue could be identified using PET. Histological findings were similar to those observed in human prostate cancer. Metastases to lungs and lymph nodes were detected, predominantly in dogs with intraprostatic tumors. CONCLUSIONS: We have established a minimally invasive dog model of prostate cancer. This model may be valuable for studying prostate cancer progression and distant metastasis. Prostate © 2013 Wiley Periodicals, Inc. 23289851 Class III phosphatidylinositol 3-kinase and its catalytic product PtdIns3P in regulation of endocytic membrane traffic. Endocytosis and subsequent membrane traffic through endosomes are cellular processes that are integral to eukaryotic evolution, and numerous human diseases are associated with their dysfunction. Consequently, it is important to untangle the molecular machineries that regulate membrane dynamics and protein flow in the endocytic pathway. Central in this context is class III phosphatidylinositol 3-kinase, an evolutionarily conserved enzyme complex that phosphorylates phosphatidylinositol into phosphatidylinositol 3-phosphate. Phosphatidylinositol 3-phosphate recruits specific effector proteins, most of which contain FYVE or PX domains, to promote endocytosis, endosome fusion, endosome motility and endosome maturation, as well as cargo sorting to lysosomes, the biosynthetic pathway or the plasma membrane. Here we review the functions of key phosphatidylinositol 3-phosphate effectors in regulation of endocytic membrane dynamics and protein sorting. 23274950 A novel stimuli-synchronized alloy-treated matrix for space-defined gastrointestinal delivery of mesalamine in the Large White pig model. The study focussed on designing a Stimuli-Synchronized Matrix (SSM) for space-defined colonic delivery of the anti-inflammatory drug mesalamine. The configured matrix provided time-independent delivery and stimuli targeting. Formulations were optimized according to a Box-Behnken experimental design that constituted mesalamine-loaded BaSO4-crosslinked chitosan dispersed within a pectin, carboxymethylcellulose and xanthan gum complex. The complex was compressed into matrices and subsequently alloy-treated with pectin and ethylcellulose. In vitro drug release was determined in the presence and absence of colonic enzymes and the mean dissolution time was used for formulation optimization. To mechanistically elucidate the synchronous catalytic action of the enzymes pectinase and glucosidase on the matrix, computer-aided 3D modelling of active fractions of the enzyme-substrate complexes was generated to predict the orientation of residues affecting the substrate domain. Drug release profiles revealed distinct colonic enzyme responsiveness with fractions of 0.402 and 0.152 of mesalamine released in the presence and absence of enzymes, respectively after 24h. The commercial comparator product showed irreproducible release profiles over the same period (SD=0.550) compared to the SSM formulation (SD=0.037). FTIR spectra of alloy-treated matrices showed no peaks from 1589 to 1512cm(-1) after colonic enzyme exposure. With increasing enzyme exposure there were also no peaks between 1646 and 1132cm(-1). This indicated polymeric enzyme cleavage for controlled and space-defined release of mesalamine. Plasma concentration profiles in the Large White pig model produced a Cmax of 3.77±1.375μg/mL compared to 10.604±2.846μg/mL for the comparator formulation. The SSM formulation proved superior over the comparator product by providing superiorly controlled enzyme-responsive colonic drug delivery. 23576175 Attenuation of Gouty Arthritis by Emodinol in Monosodium Urate Crystal-Treated Mice. A series of studies have recently demonstrated that the release of interleukin 1β induced by monosodium urate crystals is central to the experimental gouty arthritis. Elaeagnus pungens has been traditionally used for the treatment of gouty arthritis in China for more than thousands years. However, there is still little known about the active ingredients and mechanisms of E. pungens against gouty arthritis. Emodinol, as a major triterpene compound in E. pungens, has been seldom reported to have an effect on gouty arthritis. Therefore, the potential beneficial effects and mechanisms of emodinol on gouty arthritis were investigated in this study. Results showed that it significantly ameliorated the hyperalgesia, inflammation, and levels of multiple proinflammatory cytokines in monosodium urate crystals-treated mice. These findings elucidate that emodinol exhibits a prominent effect on improving symptoms of acute gouty arthritis induced by monosodium urate crystals through inhibiting the generation of proinflammatory cytokines. 22607130 Design and evaluation of a self-microemulsifying drug delivery system for apigenin. Objective of this study was to prepare, characterize and evaluate a self-microemulsifying drug delivery system (SMEDDS) with the aim to improve the solubility and dissolution of apigenin. Ternary phase diagrams were constructed in order to obtain the most efficient self-emulsification region, and the formulation of apigenin loaded SMEDDS was optimized by a simplex lattice experiment design. The optimal formulation of SMEDDS obtained was comprised of 60% Cremophor(®)EL, 30% Transcutol(®)HP and 10% Capryol™ 90. The equilibrium solubility of apigenin in SMEDDS was about 15 mg/g, and it could increase the solubility of apigenin in water for about 7500 folds. Apigenin loaded SMEDDS could turn into microemulsion when diluted with distilled water and the droplets were spherical under transmission electron microscope (TEM), the average particle size was 17.1 nm and zeta potential -5.18 mV. In vitro dissolution studies showed about 95% of apigenin was released within 10 min. All of the results showed that SMEDDS could enhance the solubility and dissolution of apigenin, and would be a potential carrier to improve the oral absorption of apigenin, a poorly water soluble drug. 23428959 What is Comet assay not telling us: AFLP reveals wider aspects of genotoxicity. DNA damage detected by genotoxicity biomarkers such as the Comet assay is not always a reliable indicator of the consequences that genotoxic agents can have on the genome integrity of the exposed organisms. Therefore, to reveal the existence of more permanent alterations of DNA structure after genotoxic stress, the RTG-2 rainbow trout cell line was exposed for 3days to benzo[a]pyrene (B[a]P, 0.1-10μM) and ethyl methanesulfonate (EMS, 0.1-1mM) followed by 3days of recovery period. Primary DNA damage was evaluated by the Comet assay and DNA alterations were assessed using AFLP (amplified fragment length polymorphism). Qualitative and quantitative modifications in AFLP profiles were analyzed in order to detect genetic alterations arising from mutation events and/or DNA damage. Significant induction in DNA damage measured by the Comet assay was noticed after B[a]P treatment at all concentrations but values returned to the control level after recovery. Exposure to EMS induced significant DNA damage only at the highest concentration and damage persisted after the recovery period. AFLP profiles detected DNA alterations even when Comet assay indicated complete DNA repair, revealing more persistent damage. Since such DNA damage can impair its structure and function, Comet assay results should preferably be supplemented with other methods in order to predict the consequences of genotoxic insult more accurately. 23409722 Long-Acting Beta-Agonists and their Association with Inhaled Corticosteroids in COPD. Inhaled bronchodilators, including beta2-agonists and antimuscaric receptor antagonists, are the mainstay of pharmacotherapy in chronic obstructive pulmonary disease (COPD). The short-acting beta2-agonists, including salbutamol, and fenoterol, have a rapid onset of action, a bronchodilating effect for 3-6 h and are used on demand. The longacting beta2-agonists (LABAs), including salmeterol and formoterol, have 12-hour duration of action and are used with a twice-daily dosing regimen for long-term COPD treatment. Unlike salmeterol, formoterol has a rapid onset of action. Pharmacological characteristics required by novel inhaled LABAs include 24 h bronchodilator effect in vivo which would make them suitable for once daily administration (ultra-LABA), high potency and selectivity for beta2-adrenoceptors, rapid onset of action, low oral bioavailability (< 5%) after inhalation, and high systemic clearance. Indacaterol, which has been approved for long-term treatment of COPD in Europe and in the USA, has a 24-h duration of action and a once-daily dosing regimen. Newer ultra-LABAs, including olodaterol, vilanterol, milveterol, carmoterol, and abediterol, are in development. Combination with ICS (fluticasone/salmeterol, budesonide/formoterol, beclomethasone/formoterol) appears to provide an additional benefit over the monocomponent therapy, although the extent of this benefit is variable and often not clinically significant in all the endpoints assessed. In patients with COPD, treatment with ICS is associated with increased risk of pneumonia which should be carefully considered when assessing the risk/benefit ratio of ICS/LABA combinations. Subphenotyping of patients with COPD (e.g., frequent exacerbations, sputum eosinophilia, mixed asthma/COPD phenotype) might help identify those patients who are most likely to benefit from addition of ICS to bronchodilating treatment. Ultra-LABA/ long-acting muscarinic receptor antagonist (LAMA) combination treatment is under development and is likely to become a standard pharmacological strategy for COPD. Dual-pharmacology inhaled muscarinic antagonist-beta2 agonist (MABA) molecules provide a new approach to the treatment of COPD. 22995439 Neurotoxic potential of iron oxide nanoparticles in the rat brain striatum and hippocampus. It has recently been reported that iron oxide nanoparticles (Fe(3)O(4)-NPs, 30 nm) have the ability to translocate directly from the olfactory nerve to the brain. The striatum and hippocampus are important structures in the brain and are associated with the development of Parkinson's and Alzheimer's diseases. Therefore, it is critical to evaluate Fe(3)O(4)-NPs and their potential to confer striatum and hippocampus neurotoxicity. This study focuses on the effects of Fe(3)O(4)-NPs on the striatum and hippocampus, including oxidative injury and the accumulation and retention of Fe(3)O(4)-NPs. This study also explores the molecular mechanism of oxidative damage in dopaminergic neurons; we were able to assess the neurotoxic effects of Fe(3)O(4)-NPs by incubating dopaminergic neurons with radioactive Fe(3)O(4)-NPs. A regional distribution of Fe(3)O(4)-NPs was observed in rat brains after the particles were intranasally instilled for seven days. The particles were found to be deposited at particularly high concentrations in the rat striata and hippocampi. Over half of the Fe(3)O(4)-NPs were retained in the striata for a minimum of 14 days, and may have induced oxidative damage to the region. However, no injuries were observed in the hippocampi. These in vitro studies demonstrate that Fe(3)O(4)-NPs may decrease neuron viability, trigger oxidative stress, and activate JNK- and p53-mediated pathways to regulate the cell cycle and apoptosis. These results also suggest that environmental exposure to Fe(3)O(4)-NPs may play a role in the development of neurodegenerative diseases. 23542819 The ethylene bis-dithiocarbamate fungicide Mancozeb activates voltage-gated KCNQ2 potassium channel. Mancozeb (manganese/zinc ethylene bis-dithiocarbamate) is an organometallic fungicide that has been associated with human neurotoxicity and neurodegeneration. In a high-throughput screen for modulators of KCNQ2 channel, a fundamental player modulating neuronal excitability, Mancozeb, was found to significantly potentiate KCNQ2 activity. Mancozeb was validated electrophysiologically as a KCNQ2 activator with an EC50 value of 0.92±0.23μM. Further examination showed that manganese but not zinc ethylene bis-dithiocarbamate is the active component for the positive modulation effects. In addition, the compounds are effective when the metal ions are substituted by iron but lack potentiation activity when the metal ions are substituted by sodium, signifying the importance of the metal ion. However, the iron (Fe(3+)) alone, organic ligands alone or the mixture of iron with the organic ligand did not show any potentiation effect, suggesting as the active ingredient is a specific complex rather than two separate additive or synergistic components. Our study suggests that potentiation on KCNQ2 potassium channels might be the possible mechanism of Mancozeb toxicity in the nervous system. 23563730 Polybetaine modification of PDMS microfluidic devices to resist thrombus formation in whole blood. Assembled polydimethylsiloxane microfluidic devices were modified with a sulfobetaine polymer through continuous "tip-to-tip" modification, significantly reducing blood clotting and extending device patency under blood flow. This technology can be designed to enable the development of devices that can continuously work in whole blood, especially in an extracorporeal or in vivo environment. 23393210 Regional Primary Care Team to Deliver Best-Practice Diabetes Care: A needs-driven health workforce model reflecting a biopsychosocial construct of health. OBJECTIVEBest-practice diabetes care can reduce the burden of diabetes and associated health care costs. But this requires access to a multidisciplinary team with the right skill mix. We applied a needs-driven evidence-based health workforce model to describe the primary care team required to support best practice diabetes care, paying particular attention to diverse clinic populations.RESEARCH DESIGN AND METHODSCare protocols, by number and duration of consultations, were derived for twenty distinct competencies based on clinical practice guidelines and structured input from a multidisciplinary clinical panel. This was combined with a previously estimated population profile of persons across 26 patient attributes (i.e., type of diabetes, complications, and threats to self-care) to estimate clinician contact hours by competency required to deliver best practice care in the study region.RESULTSA primary care team of 22.1 full-time-equivalent (FTE) positions was needed to deliver best practice primary care to a catchment of 1,000 persons with diabetes with the attributes of the Australian population. Competencies requiring greatest contact time were psychosocial issues and dietary advice at 3.5 and 3.3 FTE, respectively (1 FTE/∼300 persons); home (district) nursing at 3.2 FTE; and diabetes education at 2.8 FTE. The annual cost of delivering care was estimated at just over 2,000 Australian dollars (∼2,090 USD) (2012) per person with diabetes.CONCLUSIONSA needs-driven approach to primary care service planning identified a wider range of competencies in the diabetes primary and community care team than typically described. Access to psychosocial competences as well as medical management is required if clinical targets are to be met, especially in disadvantaged groups. 23484958 Unraveling the Role of the Protein Environment for [FeFe]-Hydrogenase: A New Application of Coarse-Graining. Hydrogenase enzymes are natural biocatalysts that might be harnessed to reduce the cost of hydrogen gas production. [FeFe]-hydrogenases are the most effective of three such enzymes at catalyzing H(+) reduction. In this study, we develop and apply a novel combination of all-atom molecular dynamics and coarse-grained (CG) analysis to characterize two important steps of the catalytic cycle of [FeFe]-hydrogenase. The first is the electron transport through FeS clusters to the active site. We use a Marcus formulation to compute the free energy and the reorganization energy of three electron transport steps and decompose these values into contributions from the CG protein sites and the solvent. The three-step transport process is found to be downhill with relative free energies of -11.7 for the first step, -14.8 for the second step, and -17.1 kcal/mol for the third step. The electron-transport process is also found to activate a water channel suggesting a coupled mechanism for proton and electron transport to the active site. The channel opening is orchestrated by three CG sites located in the active-site domain of the protein with one of the sites also contributing a strong attractive electrostatic potential (ESP) to help shuttle protons to the active site. Overall, our CG analysis points to a concerted mechanism of electron and proton delivery to the active site in these proteins thus providing important insight for the development of biomimetic devices. 22372865 Pharmacokinetic and pharmacodynamic evaluation of floating microspheres of metformin hydrochloride. Metformin hydrochloride (MH), a biguanide antidiabetic, is the drug of choice in obese patients. It is well absorbed from the upper part of gastrointestinal tract and has oral bioavailability of 50% to 60%. The objective of this study was to formulate MH into floating microspheres in order to increase its residence time at the site of absorption and thus improve its bioavailability; and to extend the duration of action along with possibilities of dose reduction. Microspheres were prepared by emulsion solvent evaporation method and evaluated for particle size, entrapment efficiency, buoyancy, and in vitro release; and further characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, and differential scanning calorimetry. The pharmacokinetic and pharmacodynamic evaluation of selected formulation was carried out in male Wistar diabetic rats. The data was statistically analyzed by unpaired t-test. A 3.5-fold increase in relative bioavailability was observed. The prolongation of half-life (t(1/2)) from 4.5 ± 2.41 h to 14.12 ± 4.81 h indicated extended duration of action. Oral glucose tolerance test (OGTT) was analyzed by one-way analysis of variance followed by Dunnet multiple comparison test, a significant decrease (p < 0.05) in the blood glucose levels was observed when formulations were compared with control rats. Hence, MH floating microspheres were tested at 50 mg/kg and 100 mg/kg body weight, OGTT data showed nonsignificant difference (p >0.05). In conclusion, an effective oral antidiabetics treatment can be achieved by formulating MH into floating microspheres which results in increase in bioavailability along with extended duration of action resulting in possible reduction in dose. 23313377 Lipopolysaccharide-induced acute lung injury in rats: comparative assessment of intratracheal instillation and aerosol inhalation. Acute lung injury (ALI) has many possible etiopathologies and is characterized by acute diffuse lung damage with poor prognosis. Lipopolysaccharide (LPS) is widely used as septic model of ALI in pharmacological research. This study compares intratracheal bolus instillation (IT) with dose-adjusted aerosol inhalation (IH) of LPS in Wistar rats using both non-invasive and terminal endpoints. The former comprised exhaled nitric oxide (NOE) and 'enhanced pause' (Penh) both measured in spontaneous breathing conscious rats. Terminal endpoints included lung weights, LDH, protein, total cell counts, and cytodifferentiation in bronchoalveolar lavage (BAL). Measurements were made 1, 3, 7, and 14 days after IT instillation (5 mg LPS/kg body weight) or 6-hour directed-flow nose-only inhalation exposure to respirable LPS-aerosol at 100 mg/m(3) (thoracic dose: 2.6 mgLPS/kg body weight). Controls received saline (IT) or air only (IH). LDH and protein were significantly different from the control in the LPS-IH group (days 1 and 3) with a somewhat inconclusive outcome in the LPS-IT group due to the effects occurring in the control. Total cell counts were equally elevated with similar time-course changes in the LPS-IT and -IH groups. Polymorphonuclear neutrophils (PMNs) were indistinguishable amongst LPS-dosed rats. Again, IT-dosed control rats displayed markedly higher background levels than those dosed by inhalation. Similarly NOE was significantly elevated on post-LPS day 1 as was Penh. In summary, the LPS-aerosol dose delivered by nose-only exposure over 6 h was equally potent as the 2-times higher LPS-IT bolus dose on post-LPS day 1 with somewhat faster recovery thereafter. The climax and discriminatory power of the non-invasive endpoints matched those determined terminally. This supports the conclusion that the pharmacological efficacy and side effects of inhalation pharmaceuticals designed to mitigate ALI can better be identified by LPS-aerosol than by LPS-IT. Non-invasive time-course measurements may deliver apt information both on the efficacious dose as well as the dosing intervals required to maintain the targeted efficacy using a minimum of experimental animals. The outcome of this comparative study supports the conclusion that the inhalation route produces a more uniform type of injury at lower, more meaningful dosages. When designing studies for screening of effective drugs this mode of delivery appears to better approximate the human condition with less dosimetric uncertainty, less experimental variability and better characterization of what was actually delivered to the entire respiratory tract. 23255254 Effect of guanidinylation on the properties of poly(2-aminoethylmethacrylate)-based antibacterial materials. The effect of converting ammonium into guanidine moieties, compared to other factors such as molecular weight or hydrophobicity, on the antibacterial activity is investigated for homo- and copolymers of 2-aminoethylmethacrylate in solution or coatings. Polymers are obtained by free radical polymerization, polymer-analogous guanidinylation is conducted with cyanamide; non-leaching immobilization is achieved by LBL assembly of homopolymers or crosslinking of functional sidegroups in copolymers. Antibacterial activity to Escherichia coli or Bacillus subtilis is determined by different standard methods. Guanidinylation improves antibacterial activity and speed as well as cytotoxicity of hydrophilic homo- and copolymers in solution or coatings. 23298862 Methadone N-demethylation by the common CYP2B6 allelic variant CYP2B6.6. The long-acting opioid methadone displays considerable unexplained interindividual pharmacokinetic variability. Methadone metabolism clinically occurs primarily by N-demethylation to 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), catalyzed predominantly by CYP2B6. Retrospective studies suggest that the common allele variant CYP2B6*6 may influence methadone plasma concentrations. The catalytic activity of CYP2B6.6, encoded by CYP2B6*6, is highly substrate-dependent. This investigation compared methadone N-demethylation by CYP2B6.6 with that by wild-type CYP2B6.1. Methadone enantiomer and racemate N-demethylation by recombinant-expressed CYP2B6.6 and CYP2B6.1 was determined. At substrate concentrations (0.25-2 µM) approximating plasma concentrations occurring clinically, rates of methadone enantiomer N-demethylation by CYP2B6.6, incubated individually or as the racemate, were one-third to one-fourth those by CYP2B6.1. For methadone individual enantiomers and metabolism by CYP2B6.6 compared with CYP2B6.1, Vmax was diminished, Ks was greater and the in vitro intrinsic clearance was diminished 5- to 6-fold. The intrinsic clearance for R- and S-EDDP formation from racemic methadone was diminished approximately 6-fold and 3-fold for R- and S-methadone, respectively. Both CYP2B6.6 and CYP2B6.1 showed similar stereoselectivity (S>R-methadone). Human liver microsomes with diminished CYP2B6 content due to a CYP2B6*6 allele had lower rates of methadone N-demethylation. Results show that methadone N-demethylation catalyzed by CYP2B6.6, the CYP2B6 variant encoded by the CYP2B6*6 polymorphism, is catalytically deficient compared with wild-type CYP2B6.1. Diminished methadone N-demethylation by CYP2B6.6 may provide a mechanistic explanation for clinical observations of altered methadone disposition in individuals carrying the CYP2B6*6 polymorphism. 23586737 Study of the microcharacter of ultrastable aqueous foam stabilized by a kind of flexible connecting bipolar-headed surfactant with existence of magnesium ion. In this paper, ultrastable aqueous foam stabilized by a kind of flexible connecting bipolar-headed surfactant alkyl polyoxyethylene sulfate (AE3S) with coexisting Mg(2+) was reported. Detailed molecular behaviors of AE3S in foam film with coexisting divalent cationic Ca(2+) or Mg(2+) were investigated by molecular dynamic simulation, comparing with the traditional surfactant sodium dodecyl sulfate (SDS), to find out how the microcharacter and array behavior of molecules in the foam film determined by molecular interaction effect the foam stability. It was found that the ultrastable foam film obtained by the cooperation of magnesium ions and AE3S was driven from two aspects: one is the favorable arrangement of surfactant molecules, and the other is the increase of capacity of foam films for resolutely holding water molecules deduced by a dipolar pair formed by the flexible connecting head groups of AE3S and hydrated Mg(2+) via intermolecular coactions, both related to the presence of magnesium ions. Foam lamella stability measurement and foam decay method were both used to evaluate the stability of foam. Fourier transform infrared (FT-IR) was used to detect the composition variation of foam film in the drainage process; the vibration peak of OH for water molecule shifted from the 3390 cm(-1) (being assigned to the bulk water integrated by hydrogen bonds) to 3685 cm(-1) (being assigned to the vibration of isolated water molecules) for the ultrastable foam film after complete drainage, which agreed very well with the molecular simulation results. 23495918 Creating "Living" Polymer Surfaces to Pattern Biomolecules and Cells on Common Plastics. Creating patterns of biomolecules and cells has been applied widely in many fields associated with the life sciences, including diagnostics. In these applications it has become increasingly apparent that the spatiotemporal arrangement of biological molecules in vitro is important for the investigation of the cellular functions found in vivo. However, the cell patterning techniques often used are limited to creating 2D functional surfaces on glass and silicon. In addition, in general, these procedures are not easy to implement in conventional biological laboratories. Here, we show the formation of a living poly(ethylene glycol) (PEG) layer that can be patterned with visible light on plastic surfaces. This new and simple method can be expanded to pattern multiple types of biomolecule on either a previously formed PEG layer or a plastic substrate. Using common plastic wares (i.e., polyethylene films and polystyrene cell culture Petri-dishes), we demonstrate that these PEG-modified surfaces have a high resistance to protein adsorption and cell adhesion, while at the same time, being capable of undergoing further molecular grafting with bioactive motifs. With a photomask and a fluid delivery system, we illustrate a flexible way to immobilize biological functions with a high degree of 2D and 3D spatial control. We anticipate that our method can be easily implemented in a typical life science laboratory (without the need for specialized lithography equipment) offering the prospect of imparting desirable properties to plastic products, for example, the creation of functional microenvironments in biological studies or reducing biological adhesion to surfaces. 23579429 The lack of association between components of metabolic syndrome and treatment resistance in depression. RATIONALE: Although a number of studies investigated the link between major depressive disorder (MDD) and metabolic syndrome (MetS), the association between MetS and treatment-resistant depression (TRD) is still not clear. OBJECTIVES: The aim of the study was to investigate the relationship between TRD and MetS and/or components of MetS and cardiovascular risk factors. Given the high prevalence of both conditions, the hypothesis was that TRD would be significantly associated with MetS. METHODS: This cross-sectional study included 203 inpatients with MDD, assessed for the treatment resistance, MetS and its components, and severity of MDD. Diagnoses and evaluations were made with SCID based on DSM-IV, National Cholesterol Education Program Adult Treatment Panel III criteria, and the Hamilton Depression Rating Scale. RESULTS: TRD prior to study entry was found in 26.1 % of patients, while MetS was observed in 33.5 % of patients. The prevalence of MetS did not differ significantly between TRD and non-TRD patients. In addition, the frequency of the altered values of particular components of the MetS or cardiovascular risk factors was not associated with treatment resistance in depressed patients. Patients with TRD were older, had a higher number of lifetime episodes of depression and suicide attempts, and longer duration of MDD compared to non-TRD patients. CONCLUSIONS: The occurrence of either MetS or the particular components of the MetS and other cardiovascular risk factors was similar between TRD and non-TRD patients. Although there is a bidirectional relationship between depression and MetS, neither MetS nor its components appear to influence treatment resistance to antidepressants. 23464805 Two new tri-nor-eudesmanolides from Inula racemosa. Two new tri-nor-eudesmane-type sesquiterpenoids were isolated from the roots of Inula racemosa, and their structures were elucidated as 8-oxo-tri-nor-eudesm-6-en-5α-ol (1) and tri-nor-eudesm-5-en-7β,8β-diol (2). The cytotoxic activity of compound 1 against five human cancer cell lines had been tested, but exhibited no cytotoxic activity. 23454526 Effect of chronic heroin and cocaine administration on global DNA methylation in brain and liver. Drug abuse is associated with epigenetic changes, such as histone modifications and DNA methylation. The purpose of the present study was to examine the effect of chronic cocaine and heroin administration on global DNA methylation in brain and liver. Male, 8 week old, C57BL/6J mice received heroin in a chronic 'intermittent' escalating dose paradigm, or cocaine in a chronic escalating dose 'binge' paradigm, which mimic the human pattern of opioid or cocaine abuse respectively. Following sacrifice, livers and brains were removed and DNA was extracted from them. The extracted DNA was hydrolyzed and 2'-deoxycytidine and 5-methyl-2'-deoxycytidine were determined by HPLC-UV. The % 5-methyl-2'-deoxycytidine content of DNA was significantly higher in the brain compared to the liver. There were no differences between the control animals and the cocaine or heroin treated animals in neither of the tissues examined, which is surprising since cocaine administration induced gross morphological changes in the liver. Moreover, there was no difference in the % 5-methyl-2'-deoxycytidine content of DNA between the cocaine and the heroin treated animals. The global DNA methylation status in the brain and liver of mice chronically treated with cocaine or heroin remains unaffected, but this finding cannot exclude the existence of anatomical region or gene-specific methylation differences. This is the first time that global DNA methylation in the liver and whole brain has been studied following chronic cocaine or heroin treatment. 23414839 3D-QSAR and docking studies of pentacycloundecylamines at the sigma-1 (σ1) receptor. Pentacycloundecylamine (PCU) derived compounds have been shown to be promising lead structures for the development of novel drug candidates aimed at a variety of neurodegenerative and psychiatric diseases. Here we show for the first time a 3D quantitative structure-activity relationship (3D-QSAR) for a series of aza-PCU-derived compounds with activity at the sigma-1 (σ1) receptor. A comparative molecular field analysis (CoMFA) model was developed with a partial least squares cross validated (q(2)) regression value of 0.6, and a non-cross validated r(2) of 0.9. The CoMFA model was effective at predicting the sigma-1 activities of a test set with an r(2) >0.7. We also describe here the docking of the PCU-derived compounds into a homology model of the sigma-1 (σ1) receptor, which was developed to gain insight into binding of these cage compounds to the receptor. Based on docking studies we evaluated in a [(3)H]pentazocine binding assay an oxa-PCU, NGP1-01 (IC50=1.78μM) and its phenethyl derivative (IC50=1.54μM). Results from these studies can be used to develop new compounds with specific affinity for the sigma-1(σ1) receptor. 23574308 Water-Mediated Interactions Influence the Binding of Thapsigargin to Sarco/Endoplasmic Reticulum Calcium Adenosinetriphosphatase. A crystal structure suggests four water molecules are present in the binding cavity of thapsigargin in sarco/endoplasmic reticulum calcium ATPase (SERCA). Computational chemistry indicates that three of these water molecules mediate an extensive hydrogen-bonding network between thapsigargin and the backbone of SERCA. The orientation of the thapsigargin molecule in SERCA is crucially dependent on these interactions. The hypothesis has been verified by measuring the affinity of newly synthesized model compounds, which are prevented from participating in such water-mediated interactions as hydrogen-bond donors. 23429263 Intracellular localization of the BCL-2 family member BOK and functional implications. The pro-apoptotic BCL-2 family member BOK is widely expressed and resembles the multi-BH domain proteins BAX and BAK based on its amino acid sequence. The genomic region encoding BOK was reported to be frequently deleted in human cancer and it has therefore been hypothesized that BOK functions as a tumor suppressor. However, little is known about the molecular functions of BOK. We show that enforced expression of BOK activates the intrinsic (mitochondrial) apoptotic pathway in BAX/BAK-proficient cells but fails to kill cells lacking both BAX and BAK or sensitize them to cytotoxic insults. Interestingly, major portions of endogenous BOK are localized to and partially inserted into the membranes of the Golgi apparatus as well as the endoplasmic reticulum (ER) and associated membranes. The C-terminal transmembrane domain of BOK thereby constitutes a 'tail-anchor' specific for targeting to the Golgi and ER. Overexpression of full-length BOK causes early fragmentation of ER and Golgi compartments. A role for BOK on the Golgi apparatus and the ER is supported by an abnormal response of Bok-deficient cells to the Golgi/ER stressor brefeldin A. Based on these results, we propose that major functions of BOK are exerted at the Golgi and ER membranes and that BOK induces apoptosis in a manner dependent on BAX and BAK. 23646355 Molecular spectroscopy and dynamics: a polyad-based perspective. The efficiency and insight of global, polyad-based modeling in overtone spectroscopy and dynamics is demonstrated. Both vibration and vibration-rotation polyads are considered. The spectroscopic implications of polyad Hamiltonians derive from their ability to account for the detailed line positions and intensities of spectral features and their unique predictive power. The dynamical implications of polyad Hamiltonians include classical bifurcations that lead to the birth of new vibrational modes and intramolecular vibrational-rotational energy redistribution over multiple timescales. The literature is reviewed, with emphasis on acetylene results. 23466331 The two faces of the pharmacological interaction of mGlu2 and 5-HT2A - Relevance of receptor heterocomplexes and interaction through functional brain pathways. Important functional interactions between the metabotropic glutamate 2 (mGlu2) and 5-hydroxytryptamine2A (5-HT2A) neurotransmitter receptors have been established based on electrophysiological, biochemical and behavioral evidence. Over the last several years, dimerization between 5-HT2A and mGlu2 receptors has been proposed to account for the functional cross-talk between these two receptors in the prefrontal cortex. The pros and cons for the existence of a heteromeric complex between 5-HT2A and mGlu2 receptors will be reviewed here. First, the fundamental criteria needing to establish evidence for heteromeric complexes will be reviewed. Then, the in vitro evidence for and against heteromeric complexes between 5-HT2A and mGlu2 receptors will be discussed in regard to physical and functional interactions. Finally, the data with native in situ mGlu2 and 5-HT2A receptors will be discussed with respect to whether heteromeric complexes or a simple functional interaction between two distinct GPCRs based on brain network activity is the more simple explanation for a range of in vivo data. 23561219 Phospholipids in rice: Significance in grain quality and health benefits: A review. Phospholipids (PLs) are a major class of lipid in rice grain. Although PLs are only a minor nutrient compared to starch and protein, they may have both nutritional and functional significance. We have systemically reviewed the literature on the class, distribution and variation of PLs in rice, their relation to rice end-use quality and human health, as well as available methods for analytical profiling. Phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI) and their lyso forms are the major PLs in rice. The deterioration of PC in rice bran during storage was considered as a trigger for the degradation of rice lipids with associated rancid flavour in paddy and brown rice. The lyso forms in rice endosperm represent the major starch lipid, and may form inclusion complexes with amylose, affecting the physicochemical properties and digestibility of starch, and hence its cooking and eating quality. Dietary PLs have a positive impact on several human diseases and reduce the side-effects of some drugs. As rice has long been consumed as a staple food in many Asian countries, rice PLs may have significant health benefits for those populations. Rice PLs may be influenced both by genetic (G) and environmental (E) factors, and resolving G×E interactions may allow future exploitation of PL composition and content, thus boosting rice eating quality and health benefits for consumers. We have identified and summarised the different methods used for rice PL analysis, and discussed the consequences of variation in reported PL values due to inconsistencies between methods. This review enhances the understanding of the nature and importance of PLs in rice and outlines potential approaches for manipulating PLs to improve the quality of rice grain and other cereals. 23500545 Oxysterols in cancer cell proliferation and death. Oxysterols have been shown to interfere with proliferation and cause the death of many cancer cell types, such as leukaemia, glioblastoma, colon, breast and prostate cancer cells, while they have little or no effect on senescent cells. The mechanisms by which oxysterols may influence proliferation are manifold: they control the transcription and the turnover of the key enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl CoA reductase, by binding to Insig-1, Insig-2 and liver X receptors. Oxysterols are thought to be generated in proportion to the rate of cholesterol synthesis. Although there is no consensus about the mechanism by which these oxysterols are generated in vivo, it clearly has to be ubiquitous. The 25- and the 27-cholesterol hydroxylases, present in almost all tissues, are possible candidates. Cholesterol uptake from lipoproteins, intracellular vesicle transport and lipid transfer are also modified by oxysterols. Oxysterols interfere with ERK, hedgehog and wnt pathways of proliferation and differentiation. When administered in vitro to cancer cell lines, oxysterols invariably both slow down proliferation and provoke cell death. Perhaps is it sufficient to stop proliferation of a cancer to provoke its eradication. Therefore, the two facets of oxysterol action that seem important for cancer treatment, cytostaticity and cytotoxicity, will be discussed. 23411269 Structural elucidation and antioxidant activity of a water-soluble polysaccharide from the fruit bodies of Bulgaria inquinans (Fries). The non-lichenized ascomycete Bulgaria inquinans (Fries), growing in the Changbai Mountain of China, has been used as medicinal diet for many years. In a previous study, we have reported that a heteropolysaccharide BIWS-4b from the fruit bodies of B. inquinans (Fries) exhibited markedly antimalarial and immunostimulating activities. In this paper, the structural features and antioxidant activity of BIWS-4b were investigated. The results showed that BIWS-4b contains an α-(1→2), (1→6)-mannan core to which the glucogalactan chains are attached. The glucogalactan chains were composed of (1→6)-, (1→5)- and (1→5,6)-linked β-Galf, (1→4)-linked and non-reducing terminal β-Glcp units, and might be attached to the mannan core at the O-2 positions of α-Manp units. The antioxidant assays showed that BIWS-4b exhibited good activities, including free radicals scavenging effects, ferrous ion-chelating ability and reducing power. Thus, BIWS-4b could be used as a natural antioxidant agent for food and pharmaceutical industries. 23026138 Methamphetamine regulation of sulfotransferase 1A1 and 2A1 expression in rat brain sections. Sulfotransferase catalyzed sulfation regulates the biological activities of various neurotransmitters/hormones and detoxifies xenobiotics. Rat sulfotransferase rSULT1A1 catalyzes the sulfation of neurotransmitters and xenobiotic phenolic compounds. rSULT2A1 catalyzes the sulfation of hydroxysteroids and xenobiotic alcoholic compounds. In this work, Western blot and real-time RT-PCR were used to investigate the effect of methamphetamine on rSULT1A1 and rSULT2A1 protein and mRNA expression in rat cerebellum, frontal cortex, hippocampus, and striatum. After 1-day treatment, significant induction of rSULT1A1 was observed only in the cerebellum; rSULT2A1 was induced significantly in the cerebellum, frontal cortex, and hippocampus. After 7 days of exposure, rSULT1A1 was induced in the cerebellum, frontal cortex, and hippocampus, while rSULT2A1 was induced significantly in all four regions. Western blot results agreed with the real-time RT-PCR results, suggesting that the induction occurred at the gene transcriptional level. Results indicate that rSULT1A1 and rSULT2A1 are expressed in rat frontal cortex, cerebellum, striatum, and hippocampus. rSULT1A1 and rSULT2A1are inducible by methamphetamine in rat brain sections in a time dependable manner. rSULT2A1 is more inducible than rSULT1A1 by methamphetamine in rat brain sections. Induction activity of methamphetamine is in the order of cerebellum>frontal cortex, hippocampus>striatum. These results suggest that the physiological functions of rSULT1A1 and rSULT2A1 in different brain regions can be affected by methamphetamine. 22619007 Silibinin triggers apoptosis and cell-cycle arrest of SGC7901 cells. Silibinin, a flavonoid compound, has shown to be of chemopreventive potential against many cancers. However, its efficacy against gastric cancer has not been well elucidated. Here, we assessed the activity of Silibinin on apoptosis and cell-cycle arrest in human gastric cells culture system using SGC-7901 as the model. Silibinin treatment could inhibit the cell growth and cause a prominent G2 phase arrest and apoptosis in dose- and time-dependent manner. In mechanistic studies, Silibinin decreased the protein level of p34cdc2, which might be the possible molecular mechanism of Silibinin efficacy on the growth inhibition in SGC-7901 cells. In addition, Silibinin caused an increase in p53 and p21 protein level as well as mRNA levels. Interestingly, Silibinin-induced apoptosis in SGC-7901 cells was independent of caspases activation. These results indicated that Silibinin is a cell-cycle regulator and apoptosis inducer in human gastric carcinoma SGC-7901 cells and might be used as a candidate chemopreventive agent for gastric carcinoma prevention and intervention. Copyright © 2012 John Wiley & Sons, Ltd. 23351169 Biosynthesis and characterization of diblock copolymer of p(3-Hydroxypropionate)-block-p(4-hydroxybutyrate) from recombinant Escherichia coli. Poly(4-hydroxybutyrate) (P4HB) is a highly elastic polymer, whereas poly(3-hydroxypropionate) (P3HP) is a polymer with enormous tensile strength. This study aimed to biosynthesize a block copolymer consisting of soft P4HB block with a strong P3HP block to gain unique and excellent material properties. A recombinant Escherichia coli strain that produces homopolymers of P3HP and P4HB was employed for the block copolymer synthesis. When the strain was grown in the presence of 1,4-butanediol (BDO) as a 4HB precursor, P4HB block was formed. Sequential supplementation of 1,3-propanediol (PDO) as a 3HP precursor allowed the strain to produce P3HP block. Thermal, NMR, fractionation, and mechanical characterizations confirmed the resulting polymer as a block copolymer of P3HP-b-P4HB. Two block copolymers were formed from this study, including the P3HP-b-29% P4HB and P3HP-b-37% P4HB, they showed superior properties over random copolymers P(3HP-co-4HB). The block copolymers had two glass transition temperatures (Tg) and two melting temperatures (Tm). In comparison to the homopolymers P3HP and P4HB, incorporation of block microstructure resulted in the lowering of Tm, block copolymers were revealed with higher Young's modulus, yield strengths, and tension strengths much better than the previously reported random copolymers of similar compositions. Block copolymerization of P3HP and P4HB adds a new vision on PHA polymerization by generation of new polymers with superior properties. 23624379 Oxidative damage induced by chlorpyrifos in the hepatic and renal tissue of Kunming mice and the antioxidant role of vitamin E. Chlorpyrifos is a broad-spectrum, chlorinated organophosphate pesticide employed for pest control in various agricultural and animal husbandries. Acute and chronic exposure to CPF can elicit several adverse effects, including oxidative stress. We investigated neurotoxicity of CPF-treated mice, and evaluated the antioxidant effect of vitamin E against oxidative stress and histological changes in the livers and kidneys of CPF-treated mice. Kunming mice were divided randomly into five exposure groups of six: (A) peanut oil; (B) 3mg/kg CPF; (C) 6mg/kg CPF; (D) 12mg/kg CPF; (E) vitamin E (100mg/kg), 3h after administration of CPF (12mg/kg) and used as a post-treatment group. Oral administration of high-dose groups (12mg/kg) CPF led to a significant increase in levels of reactive oxygen species, DNA-protein crosslinks, 8-hydroxy-2-deoxyguanosine and malondialdehyde, decreases in acetylcholinesterase activity and glutathione level, as well as causing hepatic and renal histopathological change. Except for AChE activity levels, administration of vitamin E to CPF-treated mice restored these biochemical parameters to within normal levels, and resulted in overall improvement in damage to livers and kidneys. These data suggest that oxidative stress is involved in CPF-induced toxicity and that vitamin E can protect against the tissue damage induced by CPF. 23146698 Hepatoprotective effects of Gentiana asclepiadea L. extracts against carbon tetrachloride induced liver injury in rats. This study is an attempt to evaluate the hepatoprotective activity of Gentiana asclepiadea L. against carbon tetrachloride-induced liver injury in rats. Methanol extracts of aerial parts (GAA) and roots (GAR) of G. asclepiadea at doses of 100, 200, and 400mg/ kg b.w. were orally administered to Wistar rats once daily for 7 days before they were treated with CCl(4). The hepatoprotective activity of the extracts in this study was compared with the reference drug silymarin. In CCl(4) treated animals, GAA and GAR significantly decreased levels of serum transaminases, alkaline phosphatase and total bilirubin, and increased the level of total protein. Treatment with the extracts resulted in a significant increase in the levels of catalase, superoxide dismutase and reduced glutathione, accompanied with a marked reduction in the levels of malondialdehyde, as compared to CCl(4) treated group. The histopathological studies confirmed protective effects of extracts against CCl(4)-induced liver injuries. No genotoxicity was observed in liver cells after GAA treatment, while GAR showed only slight genotoxic effects by comet assay. Phytochemical analysis revealed the presence of sweroside, swertiamarin and gentiopicrin in high concentrations in both extracts. It could be concluded that the use of G. asclepiadea extracts in the treatment of chemical-induced hepatotoxicity. 23349535 Mineralocorticoid receptor-mediated vascular insulin resistance: an early contributor to diabetes-related vascular disease? Two-thirds of adults in the U.S. are overweight or obese, and another 26 million have type 2 diabetes (T2D). Patients with diabetes and/or the metabolic syndrome have a significantly increased risk of heart attack and stroke compared with people with normal insulin sensitivity. Decreased insulin sensitivity in cardiovascular tissues as well as in traditional targets of insulin metabolic signaling, such as skeletal muscle, is an underlying abnormality in obesity, hypertension, and T2D. In the vasculature, insulin signaling plays a critical role in normal vascular function via endothelial cell nitric oxide production and modulation of Ca(2+) handling and sensitivity in vascular smooth muscle cells. Available evidence suggests that impaired vascular insulin sensitivity may be an early, perhaps principal, defect of vascular function and contributor to the pathogenesis of vascular disease in persons with obesity, hypertension, and T2D. In the overweight and obese individual, as well as in persons with hypertension, systemic and vascular insulin resistance often occur in concert with elevations in plasma aldosterone. Indeed, basic and clinical studies have demonstrated that elevated plasma aldosterone levels predict the development of insulin resistance and that aldosterone directly interferes with insulin signaling in vascular tissues. Furthermore, elevated plasma aldosterone levels are associated with increased heart attack and stroke risk. Conversely, renin-angiotensin-aldosterone system and mineralocorticoid receptor (MR) antagonism reduces cardiovascular risk in these patient populations. Recent and accumulating evidence in this area has implicated excessive Ser phosphorylation and proteosomal degradation of the docking protein, insulin receptor substrate, and enhanced signaling through hybrid insulin/IGF-1 receptor as important mechanisms underlying aldosterone-mediated interruption of downstream vascular insulin signaling. Prevention or restoration of these changes via blockade of aldosterone action in the vascular wall with MR antagonists (i.e., spironolactone, eplerenone) may therefore account for the clinical benefit of these compounds in obese and diabetic patients with cardiovascular disease. This review will highlight recent evidence supporting the hypothesis that aldosterone and MR signaling represent an ideal candidate pathway linking early promoters of diabetes, especially overnutrition and obesity, to vascular insulin resistance, dysfunction, and disease. 23022140 The PNarec method for detection of ancient recombinations through phylogenetic network analysis. Recombinations are known to disrupt bifurcating tree structure of gene genealogies. Although recently occurred recombinations are easily detectable by using conventional methods, recombinations may have occurred at any time. We devised a new method for detecting ancient recombinations through phylogenetic network analysis, and detected five ancient recombinations in gibbon ABO blood group genes [Kitano et al., 2009. Mol. Phylogenet. Evol., 51, 465-471]. We present applications of this method, now named as "PNarec", to various virus sequences as well as HLA genes. 23311883 Virtual walls based on oil-repellent surfaces for low-surface-tension liquids. Manipulating and controlling water-based aqueous solutions with the use of virtual walls is relatively simple compared to that of nonaqueous low-surface-tension liquids, which pose greater challenges to microfluidic devices. This letter reports a novel technique to form a virtual wall for various low-surface-tension liquids. A microfluidic channel with virtual walls has been made to guide low-surface-tension liquids by using a specially designed oil-repellent surface. Unlike generic superoleophobic surfaces, our oil-repellent surface exhibited strong repellency to the lateral flow of low-surface-tension liquids such as hexadecane and dodecane. A plasma-assisted surface micromachining process has been utilized to form the oil-repellent surface. The use of combined features of re-entrant geometries on the surface played an important role in promoting its repellence to the lateral flow of low-surface-tension liquids. We have successfully demonstrated how low-surface-tension liquids can be well confined by the virtual walls. 23078954 An in vitro model using the IPEC-J2 cell line for efficacy and drug interaction testing of mycotoxin detoxifying agents. An in vitro model simulating the intestinal barrier for efficacy and drug interaction testing of mycotoxin detoxifying agents was developed using Transwell® cell culture inserts. Intestinal porcine epithelial cells derived from the jejunum of piglets were exposed to DON and a mycotoxin binder (efficacy testing) or exposed to tylosin and a mycotoxin binder (drug interaction testing). Active carbon and bentonite were used in the efficacy and drug interaction trials, respectively, to validate the developed model. The evaluated parameters were passage of DON and tylosin through the epithelial monolayer, the integrity of the monolayer by measurements of the trans-epithelial electrical resistance and the viability of the monolayer using the neutral red assay. In the efficacy model it was shown that active carbon effectively bound DON at both non-cytotoxic and cytotoxic concentrations of DON, respectively 0.5 and 1 μg/mL. Moreover, the negative effects of DON at cytotoxic concentrations on cellular viability and integrity were completely offset. A commercially available modified gluco-mannan binder was also tested and it was able to partly reduce the negative effects on these latter parameter. Moreover, it reduced the transepithelial passage of DON with 37% to 57% compared to active carbon, at both cytotoxic and non-cytotoxic concentrations of DON. In our drug interaction model, the interaction between tylosin and mycotoxin binders was investigated as some authors suggest binding of macrolide antibiotics to bentonite clays. Indeed, a bentonite clay showed decreased passage of tylosin through the epithelial monolayer, indicating binding of tylosin by bentonite. This indicates that the combined use of bentonite and tylosin in the feed could lead to therapy failure. The modified gluco-mannan binder did not alter the passage of tylosin significantly, indicating safe combined use. 23411188 Thermal-induced changes of kale's antioxidant activity analyzed by HPLC-UV/Vis-online-TEAC detection. Generally, boiling of vegetables is assumed leading to lower nutritional values because of leaching effects and activity loss of bioactive compounds. Kale (Brassica oleracea var. sabellica) reveals a great diversity of flavonoids, which have been shown to be good antioxidants. As Brassica vegetables are mainly consumed cooked, the influence of boiling on kale's flavonoids and their antioxidant activity was investigated. Therefore, three kale cultivars were cooked at 100°C for 2 and 4h prior to analysis. The total phenolic content (TPC) and the total antioxidant activity (TEAC assay and EPR spectrometry) of each cultivar were determined and revealed no change, independent of cooking time, although kale samples visually altered. Using the HPLC-UV/Vis-online-TEAC approach, distinct changes in composition and antioxidant activity of the flavonoids were detectable. Thus, it was observable, that the antioxidant activities of the reaction products compensated the "loss" of the antioxidant activity of the original compounds of the uncooked material. 23395169 Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Bile acids are synthesized from cholesterol in the liver and further metabolized by the gut microbiota into secondary bile acids. Bile acid synthesis is under negative feedback control through activation of the nuclear receptor farnesoid X receptor (FXR) in the ileum and liver. Here we profiled the bile acid composition throughout the enterohepatic system in germ-free (GF) and conventionally raised (CONV-R) mice. We confirmed a dramatic reduction in muricholic acid, but not cholic acid, levels in CONV-R mice. Rederivation of Fxr-deficient mice as GF demonstrated that the gut microbiota regulated expression of fibroblast growth factor 15 in the ileum and cholesterol 7α-hydroxylase (CYP7A1) in the liver by FXR-dependent mechanisms. Importantly, we identified tauro-conjugated beta- and alpha-muricholic acids as FXR antagonists. These studies suggest that the gut microbiota not only regulates secondary bile acid metabolism but also inhibits bile acid synthesis in the liver by alleviating FXR inhibition in the ileum. 23179409 Periphyton responses to nutrient and atrazine mixtures introduced through agricultural runoff. Agricultural runoff often contains pollutants with antagonistic impacts. The individual influence of nutrients and atrazine on periphyton has been extensively studied, but their impact when introduced together and with multiple agricultural pollutants is less clear. We simulated a field-scale runoff pulse into a riverine wetland that mimicked pollutant composition typical of field runoff of the Mississippi River Alluvial Plain. Periphyton biomass and functional responses were measured for 2 weeks along a 500 m section. Additionally, laboratory chamber assays were used to identify potential periphyton changes due to nutrients, atrazine, and their interactions. Generally, nutrients stimulated, and atrazine reduced chlorophyll a (Chl a) in chambers. In the wetland, nutrient and atrazine relationships with periphyton were weaker, and when found, were often opposite of trends in chambers. Total nitrogen (TN) was inversely related to Chl a, and total phosphorus was inversely related to respiration (R) rates. Atrazine (10-20 μg L(-1) in the wetland) had a positive relationship with ash-free dry mass (AFDM), and weakened the relationship between TN and AFDM. Wetland periphyton biomass was better correlated to total suspended solids than nutrients or atrazine. Periphyton function was resilient as periphyton gross primary production (GPP)/R ratios were not strongly impacted by runoff. However, whole-system GPP and R decreased over the 2-week period, suggesting that although periphyton metabolism recovered quickly, whole-system metabolism took longer to recover. The individual and combined impacts of nutrients and atrazine in complex pollutant mixtures can vary substantially from their influence when introduced separately, and non-linear impacts can occur with distance downstream of the pollutant introduction point. 23506209 Contact angle hysteresis on randomly rough surfaces: a computational study. Wetting is important in many applications, and the solid surfaces being wet invariably feature some amount of surface roughness. A free energy-based computational simulation is used to study the effect of roughness on wetting and especially contact angle hysteresis. On randomly rough, self-affine surfaces, it is found that hysteresis depends primarily on the value of the Wenzel roughness parameter r, increasing in proportion with r - 1. Micrometer-level roughness causes hysteresis of a few degrees. 23411294 Effects of blanching on polyphenol stability of innovative paste-like parsley (Petroselinum crispum (Mill.) Nym ex A. W. Hill) and marjoram (Origanum majorana L.) products. Fresh herbs were water- and steam-blanched at 90-100°C and 100°C, respectively, for 1-10 min and 30 s to 7 min for parsley and marjoram, respectively, and subsequently minced to obtain a paste. For the first time, phenolic compounds of unheated marjoram were characterised by high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS). Hereby, 10 phenolics were detected. Among them, apigenin-glucuronide, lucenin-2 and lithospermic acid were tentatively identified for the first time. In unheated parsley, apart from the major compound apiin, 10 further phenolics were characterised including several p-coumaric acid derivatives which were newly detected. Except for apiin, short-time steam- and water-blanching (1 min), respectively, did not cause significant losses of phenolic compounds, and thus proved to be the most suitable measures to ensure polyphenol retention. Consequently, blanching is a recommendable initial operation in the processing of parsley and marjoram into novel paste-like products. 23411344 Transglycosylation of stevioside to improve the edulcorant quality by lower substitution using cornstarch hydrolyzate and CGTase. Stevioside is an abundant sweetener extracted from Stevia rebaudiana leaf with a bitter aftertaste. Enzymatic transglycosylation of stevioside is a solution to improve the edulcorant quality of stevioside, but highly derivatised stevioside coming with high conversion of stevioside is undesired. In this experiment, the transglycosylation of stevioside was investigated by using a commercial cyclodextrin glucanotransferase and cornstarch hydrolyzate. With controlled parameters, the product was mainly composed of mono- and di-glucosylated stevioside while the highest stevioside conversion reached 77.11%. Neither kinetic nor thermodynamic factor stimulated the formation of high substituted steviosides. The simultaneous hydrolysis in the reaction might inhibit the yield of highly substituted steviosides. 23320465 Single-molecule catalysis mapping quantifies site-specific activity and uncovers radial activity gradient on single 2D nanocrystals. Shape-controlled metal nanocrystals are a new generation of nanoscale catalysts. Depending on their shapes, these nanocrystals exhibit various surface facets, and the assignments of their surface facets have routinely been used to rationalize or predict their catalytic activity in a variety of chemical transformations. Recently we discovered that for 1-dimensional (1D) nanocrystals (Au nanorods), the catalytic activity is not constant along the same side facets of single nanorods but rather differs significantly and further shows a gradient along its length, which we attributed to an underlying gradient of surface defect density resulting from their linear decay in growth rate during synthesis (Nat. Nanotechnol.2012, 7, 237-241). Here we report that this behavior also extends to 2D nanocrystals, even for a different catalytic reaction. By using super-resolution fluorescence microscopy to map out the locations of catalytic events within individual triangular and hexagonal Au nanoplates in correlation with scanning electron microscopy, we find that the catalytic activity within the flat {111} surface facet of a Au nanoplate exhibits a 2D radial gradient from the center toward the edges. We propose that this activity gradient results from a growth-dependent surface defect distribution. We also quantify the site-specific activity at different regions within a nanoplate: The corner regions have the highest activity, followed by the edge regions and then the flat surface facets. These discoveries highlight the spatial complexity of catalytic activity at the nanoscale as well as the interplay amid nanocrystal growth, morphology, and surface defects in determining nanocatalyst properties. 23142507 Heteromtoxin (HmTx), a novel heterodimeric phospholipase A(2) from Heterometrus laoticus scorpion venom. Heteromtoxin (HmTx) is a group III phospholipase A(2) produced in Heterometrus laoticus, in Thailand. In this study, HmTx was purified from venom by separation chromatography, and the PLA(2) activity of the fractions was determined by lecithin agar assay. The enzyme is an acidic protein with a pI of 5.6 and an apparent molecular weight of 14018.4 Da. The nucleotide sequence of HmTx contains 649 bp, and the mature protein is predicted to have 131 amino acid residues-104 of which make up the large subunit, and 27 of which make up the small subunit. The subunit structure of HmTx is highly similar to that of the other toxin, Pandinus imperator imperatoxin I (IpTx(i)) and to Mesobuthus tamulus phospholipase A(2) (MtPLA(2)). The 3D-structure of HmTx consists of three conserved alpha-helices: h1 (Lys24-His34), h2 (Cys59-Asp71), and h3 (Ala80-Phe89). The beta-sheet consisted of a single stranded anti-parallel beta-sheet (b1.1 at Glu43-Lys45 and b1.2 at Lys48-Asn50) that was highly similar to the conserved sequences (-CGXG-, -CCXXHDXC- and CXCEXXXXXC-) of Apis mellifera (bee) phospholipases. 23644210 Synthesis and biological characterization of spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] based histone deacetylase inhibitors. Histone Deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies we described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, we report further explorations, which resulted in the discovery of a new class of spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] derivatives. Several compounds showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumour cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumour growth inhibition. In addition, the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogues. 23525512 Modelling the surface free energy parameters of polyurethane coats-part 1. Solvent-based coats obtained from linear polyurethane elastomers. Polyurethane elastomers coating were synthesised by using typical diisocyanates, polyether and polyester polyols and HO-tertiary amines or diols as a chain extenders. Mole fractions of structural fragments (κ exp) responsible for the polar interactions within polyurethane chains were calculated by (1)H NMR method. Obtained results were confronted with the analogous parameter values (κ theor) calculated on the basis of process stoichiometry, considering the stage of the production of isocyanate prepolymers and reaction of their extension for polyurethanes. Trials of linear correlation between the κ exp parameters and surface free energy (SFE) values of investigated coatings were presented. SFE values were determined by Owens-Wendt method, using contact angles measured with the goniometric method. Based on achieved results, another empirical models, allowing for prediction the influence of the kind of polyurethane raw materials on SFE values of received coatings were determined. It was found that it is possible to regulate the SFE in the range millijoules per cubic metre by the selection of appropriate substrates. It has been found that use of 2,2,3,3-tetrafluoro-1,4-butanediol as a fluorinated extender of prepolymer chains is essential to obtain coatings with increased hydrophobicity, applied among others as biomaterials-next to diphenylmethane diisocyanate and polyoxyethylene glycol. 23558679 Drosophila homologues of Adenomatous polyposis coli (APC) and the formin Diaphanous collaborate by a conserved mechanism to stimulate actin filament assembly. Adenomatous polyposis coli (APC) is a large multi-domain protein that regulates the cytoskeleton. Recently, it was shown that vertebrate APC through its Basic domain directly collaborates with the formin mDia1 to stimulate actin filament assembly in the presence of nucleation barriers. However, it has been unclear whether these activities extend to homologues of APC and Dia in other organisms. Drosophila APC and Dia are each required to promote actin furrow formation in the syncytial embryo, suggesting a potential collaboration in actin assembly, but low sequence homology between the Basic domains of Drosophila and vertebrate APC has left their functional and mechanistic parallels uncertain. To address this question, we purified Drosophila APC1 and Dia and determined their individual and combined effects on actin assembly using both bulk fluorescence assays and total internal reflection fluorescence (TIRF) microscopy. Our data show that APC1, similar to its vertebrate homologue, bound to actin monomers and nucleated and bundled filaments. Further, Drosophila Dia nucleated actin assembly, and protected growing filament barbed ends from capping protein. Drosophila APC1 and Dia directly interacted and collaborated to promote actin assembly in the combined presence of profilin and capping protein. Thus, despite limited sequence homology, Drosophila and vertebrate APCs exhibit highly related activities and mechanisms, and directly collaborate with formins. These results suggest that APC-Dia interactions in actin assembly are conserved and may underlie important in vivo functions in a broad range of animal phyla. 23395669 Sophocarpine alleviates hepatocyte steatosis through activating AMPK signaling pathway. Sophocarpine, an effective compound derived from foxtail-like sophora herb and seed, has been reported that it can alleviate non-alcoholic steatohepatitis (NASH) in rats and affect adipocytokine synthesis. Meanwhile, adipocytokines could adjust hepatic lipid metabolism through AMPK signaling pathway. In the work presented here, primary hepatocytes were isolated from specific pathogen-free male SD rats and incubated with 200 μmol/L oleic acid for 24h to induce steatotic model, then treated with sophocarpine for 72 h. Oil red staining was performed to evaluate steatosis, total RNA and protein of primary hepatocytes were extracted for real-time RT-PCR and western blot analysis. A cluster of aberrances were observed in the model group, including hepatocyte steatosis, increased leptin and decreased adiponectin mRNA expressions. While sophocarpine treatment resulted in: significant improvement of steatosis (>50% decrease), decrease of leptin expression (<0.57-fold) and increase of adiponectin expression (>1.48-fold). Moreover, compared with the model group, sophocarpine could significantly increase P-AMPKα (>5.82-fold), AMPKα (>1.29-fold) and ACC (>3.27-fold) protein expressions, and reduce P-ACC (<0.30-fold) and HNF-4α (<0.20-fold) protein expression. The mRNA expression of Srebp-1c was downregulated significantly simultaneously (<0.68-fold). We concluded that sophocarpine could alleviate hepatocyte steatosis and the potential mechanism might be the activated signaling pathway of AMPK. 23577649 Liquid/Gas and Liquid/Liquid Phase Equilibria of the System Water/Bovine Serum Albumin. The thermodynamic behavior of the system H2O/BSA was studied at 25 °C within the entire composition range: vapor pressure measurements via head space sampling gas chromatography demonstrate that the attainment of equilibria takes more than one week. A miscibility gap was detected via turbidity and the coexisting phases were analyzed. At 6 °C the two phase region extends from ca. 34 to 40 wt % BSA; it shrinks upon heating. The polymer rich phase is locally ordered, as can be seen under the optical microscope using crossed polarizers. The Flory-Huggins theory turns out to be inappropriate for the modeling of experimental results. A phenomenological expression is employed which uses three adjustable parameters and describes the vapor pressures quantitatively; it also forecasts the existence of a miscibility gap. 23152191 Δ9-tetrahydrocannabinol impairs the inflammatory response to influenza infection: role of antigen-presenting cells and the cannabinoid receptors 1 and 2. Δ(9)-tetrahydrocannabinol (Δ(9)-THC) has potent immune modulatory properties and can impair pathogen-induced immune defenses, which in part have been attributed to ligation of the cannabinoid receptors 1 (CB(1)) and 2 (CB(2)). Most recently, dendritic cells (DC) were identified for their potential to enhance influenza-induced immunopathology in mice lacking CB(1) and CB(2) (CB(1) (-/-)CB(2) (-/-)). This study focused on the modulation of the inflammatory immune response to influenza by Δ(9)-THC and the role of CB(1) and/or CB(2) as receptor targets for Δ(9)-THC. C57Bl/6 (wild type) and CB(1) (-/-)CB(2) (-/-) mice were administered Δ(9)-THC (75 mg/kg) surrounding the intranasal instillation of A/PR/8/34 influenza virus. Three days post infection (dpi), Δ(9)-THC broadly decreased expression levels of mRNA induced by the innate immune response to influenza, suppressed the percentage of interferon-gamma (IFN-γ)-producing CD4(+) and interleukin-17-producing NK1.1(+) cells, and reduced the influx of antigen-presenting cells (APC), including inflammatory myeloid cells and monocytes/macrophages, into the lung in a CB(1)- and/or CB(2)-dependent manner. Δ(9)-THC had little effect on the expression of CD86, major histocompatibility complex I (MHC I), and MHC II by APC isolated from the lung. In vitro studies demonstrated that lipopolysaccharide (LPS)-induced maturation was suppressed by Δ(9)-THC in bone marrow-derived DC (bmDC). Furthermore, antigen-specific IFN-γ production by CD8(+) T cells after coculture was reduced by Δ(9)-THC treatment of bmDC in a CB(1)- and/or CB(2)-dependent manner. Collectively, these studies suggest that Δ(9)-THC potently suppresses myeloid cell immune function, in a manner involving CB(1) and/or CB(2), thereby impairing immune responses to influenza infection. 23566515 Synthesis and structure-activity relationships of 2-amino-3-carboxy-4-phenylthiophenes as novel atypical protein kinase C inhibitors. Recent evidence suggests atypical protein kinase C (aPKC) isoforms are required for both TNF- and VEGF-induced breakdown of the blood-retinal barrier (BRB) and endothelial permeability to 70kDa dextran or albumin. A chemical library screen revealed a series of novel small molecule phenylthiophene based inhibitors of aPKC isoforms that effectively block permeability in cell culture and in vivo. In an effort to further elucidate the structural requirements of this series of inhibitors, we detail in this study a structure-activity relationship (SAR) built on screening hit 1, which expands on our initial pharmacophore model. The biological activity of our analogues was evaluated in models of bona fide aPKC-dependent signaling including NFκB driven-gene transcription as a marker for an inflammatory response and VEGF/TNF-induced vascular endothelial permeability. The EC50 for the most efficacious inhibitors (6, 32) was in the low nanomolar range in these two cellular assays. Our study demonstrates the key structural elements that confer inhibitory activity and highlights the requirement for electron-donating moieties off the C-4 aryl moiety of the 2-amino-3-carboxy-4-phenylthiophene backbone. These studies suggest that this class has potential for further development into small molecule aPKC inhibitors with therapeutic efficacy in a host of diseases involving increased vascular permeability and inflammation. 23570261 Ion impacts on graphene/ir(111): interface channeling, vacancy funnels, and a nanomesh. By combining ion beam experiments and atomistic simulations we study the production of defects in graphene on Ir(111) under grazing incidence of low energy Xe ions. We demonstrate that the ions are channeled in between graphene and the substrate, giving rise to chains of vacancy clusters with their edges bending down toward the substrate. These clusters self-organize to a graphene nanomesh via thermally activated diffusion as their formation energy varies within the graphene moiré supercell. 23199199 Multiple-time-scale motion in molecularly linked nanoparticle arrays. We explore the transport of electrons between electrodes that encase a two-dimensional array of metallic quantum dots linked by molecular bridges (such as α,ω alkaline dithiols). Because the molecules can move at finite temperatures, the entire transport structure comprising the quantum dots and the molecules is in dynamical motion while the charge is being transported. There are then several physical processes (physical excursions of molecules and quantum dots, electronic migration, ordinary vibrations), all of which influence electronic transport. Each can occur on a different time scale. It is therefore not appropriate to use standard approaches to this sort of electron transfer problem. Instead, we present a treatment in which three different theoretical approaches-kinetic Monte Carlo, classical molecular dynamics, and quantum transport-are all employed. In certain limits, some of the dynamical effects are unimportant. But in general, the transport seems to follow a sort of dynamic bond percolation picture, an approach originally introduced as formal models and later applied to polymer electrolytes. Different rate-determining steps occur in different limits. This approach offers a powerful scheme for dealing with multiple time scale transport problems, as will exist in many situations with several pathways through molecular arrays or even individual molecules that are dynamically disordered. 23231410 Collective proton dynamics at highly charged interfaces studied by ab initio metadynamics. Surface proton conduction is of utmost importance in biology, materials science, and electrochemistry; yet experimental findings of ultrafast proton transport at densely packed arrays of anionic surface groups have remained controversial and unexplained. We present an ab initio molecular dynamics study of proton dynamics at sulfonic-acid terminated surface groups. Results furnish a highly efficient collective mechanism of hydronium ion translocations at a critical surface group separation of ~6.5 Å. Orientational fluctuations of SG trigger hydrogen bond breaking that sets off the hydronium ion motion. The activation free energy of this process is 0.3 eV (±0.1 eV). The soliton-like nature of this mechanism is owed to the trigonal symmetry of sulfonate anions and exceptionally strong interfacial hydrogen bonding. These insights should stimulate surface conductance studies at SG monolayers with sulfonic acid groups, and they bolster efforts in designing proton conducting polymers conducive to fuel cell operation above ~100 °C. 23411270 Effects of different freezing treatments on the biogenic amine and quality changes of bighead carp (Aristichthys nobilis) heads during ice storage. The effects of different freezing treatments on the quality changes of bighead carp heads were evaluated in terms of pH value, TBARS, TVB-N, K-value, biogenic amine, total aerobic counts (TACs), drip loss, cooking loss and electrical conductivity (EC) during ice storage. Fish heads were stored at -40°C (T1), -40°C for 12h and then -18°C (T2), -18°C (T3) for 3months prior to ice storage. No significant differences were observed among T1, T2 and T3 for drip loss, cooking loss and EC (p>0.05). T2 showed lower TACs, pH value, TBARS and TVB-N than T3 did. Significant lower value of spermine and spermidine were observed in T1, T2 and T3 than those of control group (fresh) from 9th to 18th day (p<0.05). Drip loss was significantly correlated with TBARS, pH value, TVB-N, and TACs in groups T1, T2 and T3 (p<0.05). 23606533 Transient, Biocompatible Electronics and Energy Harvesters Based on ZnO. The combined use of ZnO, Mg, MgO, and silk provides routes to classes of thin-film transistors and mechanical energy harvesters that are soluble in water and biofluids. Experimental and theoretical studies of the operational aspects and dissolution properties of this type of transient electronics technology illustrate its various capabilities. Application opportunities range from resorbable biomedical implants, to environmentally dissolvable sensors, and degradable consumer electronics. 23454661 Evaluation of microelectrode array data using Bayesian modeling as an approach to screening and prioritization for neurotoxicity testing. The need to assess large numbers of chemicals for their potential toxicities has resulted in increased emphasis on medium- and high-throughput in vitro screening approaches. For such approaches to be useful, efficient and reliable data analysis and hit detection methods are also required. Assessment of chemical effects on neuronal network activity using microelectrode arrays (MEAs) has been proposed as a screening tool for neurotoxicity. The current study examined a Bayesian data analysis approach for assessing effects of a 30 chemical training set on activity of primary cortical neurons grown in multi-well MEA plates. Each well of the MEA plate contained 64 microelectrodes and the data set contains the number of electrical spikes registered by each electrode over the course of each experiment. A Bayesian data analysis approach was developed and then applied to several different parsings of the data set to produce probability determinations for hit selection and ranking. This methodology results in an approach that is approximately 74% sensitive in detecting chemicals in the training set known to alter neuronal function (23 expected positives) while being 100% specific in detecting chemicals expected to have no effect (7 expected negatives). Additionally, this manuscript demonstrates that the Bayesian approach may be combined with a previously published weighted mean firing rate approach in order to produce a more robust hit detection method. In particular, when combined with the weighted mean firing rate approach, the joint analysis produces a sensitivity of approximately 96% and a specificity of 100%. These results demonstrate the utility of a novel approach to analysis of MEA data and support the use of neuronal networks grown on MEAs as a for neurotoxicity screening approach. 23512732 Epigallocatechin-3-Gallate Inhibits Collagen Production of Nasal Polyp-Derived Fibroblasts. Nasal polyps are chronic inflammatory conditions characterized by myofibroblast differentiation and extracelluar matrix accumulation. The major catechin from green tea is (-)-epigallocatechin-3-gallate (EGCG), which has garnered attention for its potential to prevent oxidative stress-related diseases. The purpose of this study was twofold: (i) to determine the effect of EGCG on fibroblast differentiation into myofibroblasts and extracellular matrix accumulation in transforming growth factor (TGF)-β1-induced nasal polyp-derived fibroblasts (NPDFs) and (ii) to determine if the antioxidative effect of EGCG on reactive oxygen species (ROS) production in TGF-β1-induced NPDFs is involved in the aforementioned processes. TGF-β1-induced NPDFs were treated with or without EGCG. α-smooth muscle actin (α-SMA) and collagen type I mRNA were analyzed by reverse transcription-polymerase chain reaction. α-SMA protein was also detected using immunofluorescent staining. The amount of total soluble collagen was analyzed by Sircol collagen assay. ROS activity was measured by the nitroblue tetrazolium reduction assay and visualized by fluorescent microscopy. EGCG significantly inhibited expressions of α-SMA and collagen type I mRNA and reduced α-SMA and collagen protein levels at concentrations of 10-20 µg/mL. EGCG also inhibited TGF-β1-induced ROS production at the same concentrations. These results suggest the possibility that EGCG may be effective at inhibiting the development of nasal polyps through an anti-oxidant effect. Copyright © 2013 John Wiley & Sons, Ltd. 23344887 The CXCL12/CXCR4/CXCR7 ligand-receptor system regulates neuro-glio-vascular interactions and vessel growth during human brain development. This study investigates glio-vascular interactions in human fetal brain at midgestation, specifically examining the expression and immunolocalization of the CXCL12/CXCR4/CXCR7 ligand-receptor axis and its possible role in the vascular patterning of the developing brain. At midgestation, the telencephalic vesicles are characterized by well developed radial glia cells (RGCs), the first differentiated astrocytes and a basic vascular network mainly built of radial vessels. RGCs have been recognized to contribute to cerebral cortex neuro-vascular architecture and have also been demonstrated to act as a significant source of neural cells (Rakic, Brain Res 33:471-476, 1971; Malatesta et al, Development 127:5253-5263, 2000). According to our hypothesis CXCL12, a potent migration and differentiation chemokine released by RGCs, may act as a linking factor coordinating neuroblast migration with vessel growth and patterning through the activation of different ligand/receptor axes. The obtained results support this hypothesis showing that together with CXCR4/CXCR7-reactive neuroblasts, which migrate in close association with CXCL12 RGCs, layer-specific subsets of CXCL12 RGCs and astrocytes specifically contact the microvessel wall. Moreover, the CXCL12/CXCR4/CXCR7 system appears to be directly involved in microvessel growth, its members being differentially expressed in angiogenically activated microvessels and vascular sprouts. 23403016 Triethylenetetramine prevents insulin aggregation and fragmentation during copper catalyzed oxidation. Metal catalyzed oxidation via the oxidative system Cu(2+)/ascorbate is known to induce aggregation of therapeutic proteins, resulting in enhanced immunogenicity. Hence, inclusion of antioxidants in protein formulations is of great interest. In this study, using recombinant human insulin (insulin) as a model, we investigated the ability of several excipients, in particular triethylenetetramine (TETA), reduced glutathione(GSH) and ethylenediamine tetraacetic acid (EDTA), for their ability to prevent protein oxidation, aggregation, and fragmentation. Insulin (1mg/ml) was oxidized with 40μM Cu(2+) and 4mM ascorbic acid in absence or presence of excipients. Among the excipients studied, 1mM of TETA, EDTA, or GSH prevented insulin aggregation upon metal catalyzed oxidation (MCO) for 3h at room temperature, based on size exclusion chromatography (SEC). At lower concentration (100μM), for 72h at +4°C, TETA was the only one to inhibit almost completely oxidation-induced insulin aggregation, fragmentation, and structural changes, as indicated by SEC, nanoparticle tracking analysis, light obscuration particle counting, intrinsic/extrinsic fluorescence, circular dichroism, and chemical derivatization. In contrast, GSH had a slight pro-oxidant effect, as demonstrated by the higher percentage of aggregates and a more severe structural damage, whereas EDTA offered substantially less protection. TETA also protected a monoclonal IgG1 against MCO-induced aggregation, suggesting its general applicability. In conclusion, TETA is a potential candidate excipient for inclusion in formulations of oxidation-sensitive proteins. 23479387 Quercetin mitochondriotropic derivatives antagonize nitrate tolerance and endothelial dysfunction of isolated rat aorta rings. Chronic use of glyceryl trinitrate is limited by serious side effects, inter alia tolerance and endothelial dysfunction of coronary and resistance arteries. The natural flavonoid quercetin has been shown to counteract the development of glyceryl trinitrate tolerance in vitro. Two mitochondriotropic, 4-O-triphenylphosphoniumbutyl derivatives of quercetin (QTA-3BTPI and Q-3BTPI) were compared to quercetin for protection against glyceryl trinitrate-induced tolerance and endothelial dysfunction of isolated rat aorta rings. Both QTA-3BTPI and Q-3BTPI significantly counteracted the reduced vascular responsiveness to both glyceryl trinitrate and acetylcholine caused by prolonged exposure of the vessel to glyceryl trinitrate itself, their potency being much greater than that of quercetin. QTA-3BTPI, however, turned out to cause endothelial dysfunction per se. Since Q-3BTPI antagonized in vitro nitrate tolerance and endothelial dysfunction of vessels, this encourages assessing whether this effect is displayed also in vivo during long-term glyceryl trinitrate treatment. 23607293 On the association between Hashimoto's thyroiditis and papillary thyroid carcinoma. Looking 100 years back and, hopefully, fewer years ahead to sort out this association. NOT required for a LETTER TO THE EDITOR. 22936348 Carbon nanotube functionalization with carboxylic derivatives: a DFT study. Chemical functionalization of a single-walled carbon nanotube (CNT) with different carboxylic derivatives including -COOX (X=H, CH3, CH2NH2, CH3Ph, CH2NO2, and CH2CN) has been theoretically investigated in terms of geometric, energetic, and electronic properties. Reaction energies have been calculated to be in the range of -0.23 to -7.07 eV. The results reveal that the reaction energy is increased by increasing the electron withdrawing character of the functional groups so that the relative magnitude order is -CH2NO2>-CH2CN>-H>-CH2Ph>-CH3>-CH2NH2. The chemical functionalization leads to an increase in HOMO/LUMO energy gap of CNT by about 0.32 to 0.35 eV (except for -H). LUMO, HOMO, and Fermi level of the CNT are shifted to lower energies especially in the case of -CH2NO2 and -CH2CN functional groups. Therefore, it leads to an increment in work function of the tube, impeding the field electron emission. 22799453 Comparison of antifungal activities of Vietnamese citrus essential oils. Citrus essential oils (EOs) are volatile compounds from citrus peels and widely used in perfumes, cosmetics, soaps and aromatherapy. In this study, inhibition of citrus EOs extracted from Vietnamese orange (Citrus sinensis), mandarin (Citrus reticulata Blanco), pomelo (Citrus grandis Osbeck) and lime (Citrus aurantifolia Swingle) on the growth of plant pathogenic fungi, Mucor hiemalis, Penicillium expansum and Fusarium proliferatum was investigated. The EOs of the citrus peels were obtained by cold-pressing method and the antifungal activity of EOs was evaluated using the agar dilution method. The results show that the EOs had significant antifungal activity. Lime EO was the best inhibitor of M. hiemalis and F. proliferatum while pomelo EO was the most effective against P. expansum. These results indicate that citrus EOs can be used as antifungal natural products in the food, pharmaceutical and cosmetic industries. 23239550 3,14-Bis(p-nitrophenyl)-17,17-dipentyltetrabenzo[a,c,g,i]-fluorene: a new fluorophore displaying both remarkable solvatochromism and crystalline-induced emission. A series of 17,17-dialkyl-3,14-diaryltetrabenzofluorenes were efficiently prepared by using Suzuki-Miyaura cross-coupling reactions of the corresponding 3,14-dibromo derivatives. Studies of the unique fluorescence properties of these compounds showed that they display intense blue to yellow fluorescence with high quantum yields in the solution state and blue to orange fluorescence with moderate quantum yields in the solid state. In addition, the fluorescence wavelength of the bis(p-nitrophenyl) derivative is remarkably solvent-dependent in a manner that correlates with the solvent polarity parameter E(T)(30). The results of density function theory calculations suggest that the intramolecular charge-transfer character of the HOMO-LUMO transition is responsible for the large solvent effect. Moreover, addition of water to a tetrahydrofuran (THF) solution of this compound leads to quenching of the yellow fluorescence owing to an increase in the solvent polarity. However, when the amount of water fraction exceeds 70%, a new fluorescence band appears at the same orange-red emission wavelength as that of the solid-state fluorescence. This observation suggests the occurrence of a crystallization-induced emission (CIE) phenomenon in highly aqueous THF. 23592781 AP-1/Fos-TGase2 axis mediates wounding-induced Plasmodium falciparum killing in Anopheles gambiae. Anopheline mosquitoes are the only vectors of human malaria worldwide. It is now widely accepted that mosquito immune responses play a crucial role in restricting Plasmodium development within the vector, therefore further dissection of the molecular mechanisms underlying these processes should inform new vector control strategies urgently needed to roll back the disease. Here, using genome-wide transcriptional profiling, bioinformatics and functional gene analysis we identify a new axis of mosquito resistance to monoclonal P. falciparum infections that includes the AP-1 transcription factor Fos and the transglutaminase 2 (TGase2), a cross-linking enzyme with known roles in wound responses. We demonstrate that Fos regulates induction of TGase2 expression after wounding but does not affect expression of the components of the well-characterized complement-like system. Silencing of Fos or of TGase2 aborts the wounding-induced mosquito killing of P. falciparum. These results reveal multiple signaling pathways that are required for efficient Plasmodium killing in A. gambiae. 23292170 Marked decline in beta cell function during pregnancy leads to the development of glucose intolerance in Japanese women. The aim of this study is to investigate glucose metabolism longitudinally during pregnancy to explore mechanisms underlying gestational diabetes mellitus (GDM). We reviewed a total of 62 pregnant Japanese women who underwent a 75g oral glucose tolerance test (OGTT) twice during pregnancy (median: early, 13; late, 28 weeks' gestation) because of positive GDM screening. All showed normal OGTT results in early pregnancy. Based on late OGTT, 15 had GDM (late-onset GDM) and 47 normal glucose tolerance (NGT). In early pregnancy, there were no significant differences in insulin sensitivity (insulin sensitivity index derived from OGTT [ISOGTT] and homeostasis model assessment for insulin resistance [HOMA-IR]) and insulin secretion (a ratio of the total area-under-the-insulin-curve to the total area-under-the-glucose-curve [AUCins/glu] and insulinogenic index [IGI]) between the NGT and late-onset GDM groups. In each group, insulin sensitivity significantly decreased from early to late pregnancy, most in the late-onset GDM group (each p < 0.05). The insulin secretion showed no significant changes with advancing pregnancy in both of the groups, although late-onset GDM showed significantly lower IGI compared with NGT in late OGTT (p < 0.05). When assessed beta cell function by OGTT-derived disposition index (i.e. Insulin Secretion-Sensitivity Index-2 and IGI/fasting insulin), the indices significantly decreased from early to late pregnancy in the both groups (each p < 0.05). Women with late-onset GDM showed significantly lower indices compared with NGT (each p < 0.05). The failure of beta cell to compensate for decreased insulin sensitivity could contribute to the development of the late-onset GDM. 23411320 Characterization and identification of gamma-irradiated sauces by electron spin resonance spectroscopy using different sample pretreatments. Tomato ketchup, barbeque sauce, sweet chili sauce, and spaghetti sauce were gamma irradiated at 0, 1, 5, and 10 kGy. Electron spin resonance (ESR) technique was used to characterize the irradiated sauces, targeting radiation-induced cellulose radicals and using a modified sample pretreatment method. The samples were first washed with water, and then the residues were extracted with alcohol. The non-irradiated sauces exhibited the single central signal, whose intensity showed a significant increase on irradiation. The ESR spectra from the radiation-induced cellulose radicals, with two side peaks (g=2.02012 and g=1.98516) equally spaced (± 3 mT) from the central signal, were also observed in the irradiated sauces. The improvements in the central (natural) and radiation-induced (two side peaks corresponding to the cellulose radicals) signal intensities were obvious, when compared with routine freeze-drying and alcoholic-extraction techniques. 23134558 Efficacy of the levonorgestrel intrauterine system (LNG-IUS) in the prevention of the atypical endometrial hyperplasia and endometrial cancer: retrospective data from selected obese menopausal symptomatic women. The aim of this retrospective study was to evaluate the efficacy of levonorgestrel intrauterine system-releasing (LNG-IUS) insertion in preventing atypical endometrial hyperplasia (AH) and endometrial cancer (EC) in symptomatic postmenopausal overweight/obese women. A total of 34 overweight/obese postmenopausal women, presenting abnormal uterine bleeding (AUB) and endometrial hyperplasia (EH), and who were submitted to LNG-IUS insertion, were identified from registry data. Endometrial histology at LNG-IUS insertion showed simple EH in 20 cases (58.8%), complex EH in 14 cases (41.2%). At 36 months, 91% of patients showed no recurrence of AUB and a significant reduction in the mean endometrial thickness (from 8.2 ± 2.2 to 3.2 ± 1.5 mm, p < 0.05) was observed. Histologic regression of EH was observed in 27 (79.4%) and 33 (97.5%) cases at 12 and 36 months, respectively. None of the women in which EH persisted, reported cellular atypia or cancer progression at 12 and 36 months of follow-up. LNG-IUS represents an effective treatment option to manage postmenopausal obese women affected by AUB and EH. The device seems to be able to prevent the onset of AH and EC in women at high risk. Further prospective controlled studies in a well selected group of women are needed. 22056334 Pollutant concentrations in placenta. Unborn children are exposed to environmental pollutants via the placenta, and there is a causal relationship between maternal intake of pollutants and fetal exposure. Placental examination is an effective way for acquiring data for estimating fetal exposure. We analyzed the concentrations of 104 congeners of persistent organic pollutants, seven organotin compounds, five heavy metals, and methylmercury in 130 randomly selected placentas. Additionally, we examined similarities between pollutant concentrations by analyzing correlations between their placental concentrations. Our results yield new information for conducting contaminant risk assessments for the prenatal period. Out of the 117 individual persistent organic pollutants or metals assayed, 46 could be detected in more than half of the placentas. Moreover, dichlorodiphenyldichloroethylene (p,p'-DDE) was found in all placentas. The data indicates that fetal exposure to dioxins and furans (PCDD/Fs), polychlorinated biphenyls (PCBs), p,p'-DDE, and methylmercury depends on the mother's parity, and age. We also conclude that sources of the above four pollutants are similar but differ from the sources of polybrominated diphenyl ethers. 22708724 An antileishmanial prenyloxy-naphthoquinone from roots of Plumbago zeylanica. Leishmania donovani, an obligate intracellular parasite of genus Leishmania causes visceral leishmaniasis that affects millions of people worldwide, especially in the Indian subcontinent and East Africa. Generic pentavalent antimonials have been the mainstay for therapy in the endemic regions due to efficacy and cost effectiveness but the growing incidence of their resistance has seriously hampered their use. This study discloses strong in vitro antileishmanial activity of 2-methyl-5 -(3'-methyl-but-2'-enyloxy)-[1,4]naphthoquinone (1), a prenyloxy-naphthoquinone isolated and characterised from roots of the plant Plumbago zeylanica (family-Plumbaginaceae). The observed EC50 for the compound 1 against promastigote and amastigote forms of L. donovani was significantly (p<0.001) lower than miltefosine, a reference drug. In context to limited treatment options and growing resistance for available drugs, compound 1 offers a greater prospect towards antileishmanial drug discovery and development. 23179349 Iron excess disturbs metabolic status and relative gonad mass in rats on high fat, fructose, and salt diets. The aim of this study was to assess the metabolic and physiological changes in rats fed a diet high in fat, fructose, and salt, and with excess iron level. Mineral status was also estimated. Wistar rats were assigned to groups fed either a standard control diet (C) or a diet high in fat, fructose, and salt. The noncontrol diets contained either normal (M) or high level (MFe) of iron. After 6 weeks, the length and weight of the rats were measured, and the animals were euthanized. The kidneys and gonads were collected, and blood samples were taken. Serum levels of insulin, nitric oxide, and iron were measured. The iron, zinc, copper, and calcium concentrations of tissues were determined. It was found that the M diet led to a significant increase in the relative kidney mass of the rats compared with the control group. Among the rats fed the M diet, markedly higher serum level of iron and lower levels of zinc and copper were observed in tissues, while significantly higher calcium levels were found in the gonads. The MFe diet resulted in decreased obesity index, insulin level, and nitric oxide serum concentration in the rats, when compared with both the M and C diets. The high iron level in the modified diet increased the relative mass of the gonads. The excess iron level in the diet disturbed the zinc, copper, and calcium status of tissues. The decrease in insulin and nitric oxide in rats fed the diet high in iron, fat, fructose, and salt was associated with disorders of zinc, copper, and calcium status, as well as with an increase in the relative mass of the gonads. 23313633 Predictive modeling of insulin release profile from cross-linked chitosan microspheres. Insulin-loaded microspheres composed of chitosan 3% (w/v), and loading 120 IU insulin were produced by emulsion cross-linking method. Cross-linking time was 5 h and glutaraldehyde 3.5% (v/v) was used as cross-linker. Swelling ratio studies were evaluated to predict release of insulin from chitosan microspheres. Bacitracin and sodium taurocholate were incorporated in the formulations as proteolytic enzyme inhibitor and absorption enhancer, respectively. In vitro insulin release studies were performed in phosphate buffer pH 7.4 and also in HCl pH 2 with and without trypsin. Activity of bacitracin was also evaluated. In vitro release showed a controlled profile up to 12 h and the formulation containing 0.15% (w/v) of bacitracin revealed a maximum biological activity of about 49.1 ± 4.1%. Mathematical modeling using Higuchi and Korsmeyer-Peppas suggested a non-Fickian diffusion as the mechanism of insulin release. Insulin-loaded chitosan microspheres for oral delivery showed to be an innovative and reliable delivery system to overcome conventional insulin therapy. 23409959 Protein recognition of the S23906-1-DNA adduct by nuclear proteins: direct involvement of glyceraldehyde-3-phosphate dehydrogenase (GAPDH)1. In a view to develop new DNA alkylating antitumour drugs, evaluating the precise mechanism of action and the molecular/cellular consequences of the alkylation is a point of major interest. The benzo-b-acronycine derivative S23906-1 alkylates guanine nucleobases in the minor groove of the DNA helix and presents an original ability to locally open the double helix of DNA, which appears to be associated with its cytotoxic activity. However, the molecular mechanism linking adduct formation to cellular consequences is not precisely known. The objective of the present study was to identify proteins involved in the recognition and mechanism of action of S23906-DNA adducts. We found that GAPDH (glyceraldehyde-3-phosphate dehydrogenase) is a protein that binds to S23906-alkylated single-stranded, double-stranded and telomeric sequences in a drug-dependent and DNA sequence/structure-dependent manner. We used the CASTing (cyclic amplification of sequence targeting) method to identify GAPDH DNA-binding selectivity and then evaluated its binding to such selected S23906-alkylated sequences. At the cellular level, alkylation of S23906-1 results in an increase in the binding of GAPDH and its protein partner HMG (high-mobility group) B1 to the chromatin. Regarding the multiple roles of GAPDH in apoptosis and DNA repair, the cytotoxic and apoptotic activities of GAPDH were evaluated and present opposite effects in two different cellular models. 23142844 Anesthetics interacting with lipid rafts. The exact mechanism by which anesthetics induce cell membrane-mediated modifications is still an open question. Although the fluidization effect of the anesthetic molecules on the cellular membrane is widely recognized, it is not known if anesthetics show any preference for specific membrane domains, namely the lipid rafts. The importance of these membrane micro-domains derives from the fact that they have been associated with cell signaling pathways, as well as with specific drug interactions. The objective of this work is to contribute for the elucidation of this question through the comparison of the anesthetic interactions with membranes of various lipid compositions. Liposomes prepared with an equimolar mixture of POPC, sphingomyelin and cholesterol, were chosen as models for lipid rafts. The interactions of these liposomes with two local anesthetics, tetracaine and lidocaine, and one general anesthetic, propofol, were studied. The effect of cholesterol was investigated by comparing anesthetic interactions with POPC/SM liposomes and POPC/SM/CHOL liposomes. The following experimental techniques were used: quartz crystal microbalance with dissipation, differential scanning calorimetry and phosphorus nuclear magnetic resonance. Although the liposomes investigated by the different techniques are not in the same conditions, it is possible to assemble the information obtained from all experimental techniques employed to reach a general conclusion. Tetracaine interacts more with raftlike domains, lidocaine induces stronger modifications on POPC/SM liposomes and the results for propofol are not fully conclusive but it seems to be the least prone to lipid interactions. The results were compared with those obtained with DMPC-containing liposomes, reported in a previous work. 23466526 ZEB2 zinc-finger missense mutations lead to hypomorphic alleles and a mild Mowat-Wilson syndrome. Mowat-Wilson syndrome (MWS) is a severe intellectual disability (ID)-distinctive facial gestalt-multiple congenital anomaly syndrome, commonly associating microcephaly, epilepsy, corpus callosum agenesis, conotruncal heart defects, urogenital malformations and Hirschsprung disease (HSCR). MWS is caused by de novo heterozygous mutations in the ZEB2 gene. The majority of mutations lead to haplo-insufficiency through premature stop codons or large gene deletions. Only three missense mutations have been reported so far; none of which resides in a known functional domain of ZEB2. In this study, we report and analyze the functional consequences of three novel missense mutations, p.Tyr1055Cys, p.Ser1071Pro and p.His1045Arg, identified in the highly conserved C-zinc-finger (C-ZF) domain of ZEB2. Patients' phenotype included the facial gestalt of MWS and moderate ID, but no microcephaly, heart defects or HSCR. In vitro studies showed that all the three mutations prevented binding and repression of the E-cadherin promoter, a characterized ZEB2 target gene. Taking advantage of the zebrafish morphant technology, we performed rescue experiments using wild-type (WT) and mutant human ZEB2 mRNAs. Variable, mutation-dependent, embryo rescue, correlating with the severity of patients' phenotype, was observed. Our data provide evidence that these missense mutations cause a partial loss of function of ZEB2, suggesting that its role is not restricted to repression of E-cadherin. Functional domains other than C-ZF may play a role in early embryonic development. Finally, these findings broaden the clinical spectrum of ZEB2 mutations, indicating that MWS ought to be considered in patients with lesser degrees of ID and a suggestive facial gestalt, even in the absence of congenital malformation. 22977167 Effects of ozone and particulate matter on cardiac mechanics: role of the atrial natriuretic peptide gene. A positive association between air pollution exposure and increased human risk of chronic heart disease progression is well established. In the current study, we test two hypotheses: (1) the cardiac compensatory changes in response to air pollution are dependent on its composition and (2) specific cardiac adaptations are regulated by atrial natriuretic peptide (ANP). We address these hypotheses by initially examining the exposure effects of ozone (O(3)) and/or particulate matter (PM) on cardiac function in C57Bl/6J (B6) mice. Subsequently, the results are compared with cardiac functional changes to the same exposures in Nppa (the precursor gene for ANP) knockout (KO) mice. Separate groups of mice underwent 3 consecutive days of the same exposure sequence for 3h each consisting of the following: (1) 6h of filtered air (FAFA), (2) O(3) then FA (O(3)FA), (3) FA then carbon black (FACB), or (4) O(3) then CB. Cardiac function was assessed using a conductance catheter to generate cardiac pressure-volume loops 8-10h following each exposure sequence. As compared with FAFA, each sequence led to a substantial drop (as much as 33%) in stroke volume and cardiac output. However, these losses of cardiac function occurred by different compensatory mechanisms dependent on the pollutant composition. For example, O(3)FA exposure led to reductions in both end-systolic and end-diastolic left ventricular (LV) volumes, whereas FACB exposure led an increase in end-diastolic LV volume. These same cardiac compensatory changes were largely abolished in Nppa KO mice following O(3)FA or FACB exposure. These results suggest that cardiac functional changes in response to air pollution exposure are strongly dependent on the pollutant constituents, especially related to O(3) and/or PM. Furthermore, ANP regulation appears to be crucial to these cardiac compensatory mechanisms induced by air pollution. 22640631 mGlu2/3 and mGlu5 receptors: potential targets for novel antidepressants. Major depressive disorder is among the most prevalent forms of mental illness. All currently available antidepressant medications have stemmed from study of the mechanisms of serendipitously discovered drugs, and only 30-50% of patients exhibit remission and frequently at least 3-4 weeks are required for manifestation of significant therapeutic effects. To overcome these drawbacks, discovering novel neuronal mechanisms of pathophysiology of depression as well as more effective treatments are necessary. This review focuses on the metabotropic glutamate (mGlu) receptors and their potential for drug targets for the treatment of depression. In particular, accumulating evidence has indicated the potential importance and usefulness of agents acting on mGlu2/3 and mGlu5 receptors. Preclinical and clinical evidence of mGlu2/3 receptor ligands and mGlu5 receptor antagonists are described. Moreover, their potential in clinic will be discussed in the context of neuronal mechanisms of ketamine, an agent recently demonstrated a robust effect for patients with treatment-resistant depression. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23414800 Discovery of novel 7-membered cyclic amide derivatives that inhibit 11beta-hydroxysteroid dehydrogenase type 1. A series of novel 5-trans-hydroxyadamantan-2-yl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-ones that inhibit 11beta-hydroxysteroid dehydrogenase type 1 are described. We discovered these 7-membered cyclic amide derivatives by introducing a distinctive linker through pharmacophore analysis of known ligands included in X-ray co-crystal structures. Further optimization using docking studies led to highly potent inhibitors 15b and 27, which furthermore showed the potent efficacy in in vivo studies. 23631463 Design, Synthesis and Biological Evaluation of Aminoalkylindole Derivatives as Cannabinoid Receptor Ligands with Potential for Treatment of Alcohol Abuse. Attenuation of increased endocannabinoid signaling with a CB1R neutral antagonist might offer a new therapeutic direction for treatment of alcohol abuse. We have recently reported that a mono-hydroxylated metabolite of the synthetic aminoalkylindole cannabinoid JHW-073 (3) exhibits neutral antagonist activity at CB1Rs and thus may serve as a promising lead for the development of novel alcohol abuse therapies. In the current study, we show that systematic modification of an aminoalkylindole scaffold identifies two new compounds with dual CB1R antagonist/CB2R agonist activity. Similar to the CB1R antagonist/inverse agonist rimonabant, analogues 27 and 30 decrease oral alcohol self-administration, without affecting total fluid intake and block the development of alcohol-conditioned place preference. Collectively, these initial findings suggest that design and systematic modification of aminoalkylindoles such as 3 may lead to development of novel cannabinoid ligands with dual CB1R antagonist/CB2R agonist activity with potential for use as treatments of alcohol abuse. 23421649 Two new sesquiterpenoids from the fungus Ceriporia alachuana. Two new sesquiterpenoids, tremulenolide D (1) and muurolane-10β,15-diol (2), together with four known sesquiterpenoids, tremulenediol A (3), 2β-hydroxy-α-candinol (4), epicubenol (5), and 3β-hydroxy-δ-candinol (6), were isolated from cultures of the fungus Ceriporia alachuana. The structures of new compounds were determined by extensive spectroscopic analyses. Structurally, compounds 1 and 3 are tremulane-type sesquiterpenoids with an unusual perhydroazulene carbon skeleton. 23414340 Reduction of dimethylarsinic acid to the highly toxic dimethylarsinous acid by rats and rat liver cytosol. Dimethylarsinic acid (DMAs(V)), the major urinary metabolite of inorganic arsenic, is weakly cytotoxic, whereas its reduced form, dimethylarsinous acid (DMAs(III)), is highly toxic. Although glutathione S-transferase omega 1 (GSTO1) and arsenic methyltransferase have been shown or thought to catalyze DMAs(V) reduction, their role in DMAs(V) reduction in vivo, or in cell extracts is uncertain. Therefore, the reduction of DMAs(V) to DMAs(III) in rats and in rat liver cytosol was studied to better understand its mechanism. To assess DMAs(V) reduction in rats, a novel procedure was devised based on following the accumulation of red blood cell (RBC)-bound dimethylarsenic (DMAs), which represents DMAs(III), in the blood of DMAs(V)-injected anesthetized rats. These studies indicated that rats reduced DMAs(V) to DMAs(III) to a significant extent, as in 90 min 31% of the injected 50 μmol/kg DMAs(V) dose was converted to DMAs(III) that was sequestered by the circulating erythrocytes. Pretreatment of rats with glutathione (GSH) depletors (phorone or BSO) delayed the elimination of DMAs(V) and the accumulation of RBC-bound DMAs, whereas the indirect methyltransferase inhibitor periodate-oxidized adenosine was without effect. Assessment of DMAs(V)-reducing activity of rat liver cytosol revealed that reduction of DMAs(V) required cytosolic protein and GSH and was inhibited by thiol reagents, GSSG and dehydroascorbate. Although thioredoxin reductase (TRR) inhibitors (aurothioglucose and Sb(III)) inhibited cytosolic DMAs(V) reduction, recombinant rat TRR plus NADPH, alone or when added to the cytosol, failed to support DMAs(V) reduction. On ultrafiltration of the cytosol through a 3 kDa filter, the reducing activity in the retentate was lost but was largely restored by NADPH. Such experiments also suggested that the reducing enzyme was larger than 100 kDa and was not GSTO1. In summary, reduction of DMAs(V) to the highly toxic DMAs(III) in rats and rat liver cytosol is a GSH-dependent enzymatic process, yet its mechanism remains uncertain. 23574541 Safety evaluation of desloratadine in allergic rhinitis. Introduction: Desloratadine is a biologically active metabolite of second-generation antihistamine loratadine. It is also indicated for the treatment of allergic diseases, including allergic rhinitis. Areas covered: A Medline search was conducted to identify preclinical and clinical studies of desloratadine. This was supplemented with additional articles obtained from online sources. The focus of this review is on the safety profile of desloratadine. Expert opinion: The review of these data indicates that the safety profile of desloratadine is similar to other second-generation antihistamines. Desloratadine is highly selective for histamine H1-receptors, does not cross the blood-brain barrier (BBB), and has minimal adverse events (very low sedation rate), with a better safety and tolerability than first-generation antihistamines. Desloratadine is safe and well tolerated without having central nervous system (CNS) or cardiovascular effects and with low drug interaction. 23358258 Synthesis and biological evaluation of xanthine derivatives on dipeptidyl peptidase 4. A series of xanthine derivatives in which a methylene was inserted at position 8 of xanthine scaffold was synthesized and evaluated as inhibitors of dipeptidyl peptidase 4 (DPP-4) for the treatment of type 2 diabetes. As the results of structure-activity relationship (SAR) study of the series, the compounds with 4-methyl-quinazoline-2-yl-methyl group at N-1 position and 2-aminoethylaminomethyl group gave better activities. Compounds H4 and H9 showed good DPP-4 inhibition and more than 100-fold selectivity over DPP-7 and DPP-8. 23327588 Endometrial thickness in women with ovulatory dysfunction. This study is designed to evaluate the relationship between endometrial thickness and clinical/biochemical parameters in women with chronic anovulation. One hundred and twenty women with ovulatory dysfunction were prospective included, endometrial thickness and endocrine and metabolic parameters were measured. The interval between the examination day and the day of the most recent menstrual bleeding (the anovulatory interval) for the studied subject was an average of 145 ± 186 days. The endometrial thickness averaged 7.1 ± 3.2 mm. Correlation analyses revealed that the endometrial thickness was positively correlated with body mass index but was not correlated with age, serum androgens, or estradiol (E2) levels. We further classified the subjects into two groups based on endometrial thickness: Group A, endometrial thickness <7 mm and Group B, endometrial thickness ≥7 mm. The anovulatory interval, follicle-stimulating hormone, luteinizing hormone, E2 and androgen levels were not significantly different between Groups A and B. Group B had higher body weight and more risk for metabolic syndrome. We concluded that endometrial thickness in women with ovulatory dysfunction is positively correlated with body weight status but is not correlated with serum androgens or E2 levels. 23274889 Fecal microbiota composition differs between children with β-cell autoimmunity and those without. The role of the intestinal microbiota as a regulator of autoimmune diabetes in animal models is well-established, but data on human type 1 diabetes are tentative and based on studies including only a few study subjects. To exclude secondary effects of diabetes and HLA risk genotype on gut microbiota, we compared the intestinal microbiota composition in children with at least two diabetes-associated autoantibodies (n = 18) with autoantibody-negative children matched for age, sex, early feeding history, and HLA risk genotype using pyrosequencing. Principal component analysis indicated that a low abundance of lactate-producing and butyrate-producing species was associated with β-cell autoimmunity. In addition, a dearth of the two most dominant Bifidobacterium species, Bifidobacterium adolescentis and Bifidobacterium pseudocatenulatum, and an increased abundance of the Bacteroides genus were observed in the children with β-cell autoimmunity. We did not find increased fecal calprotectin or IgA as marker of inflammation in children with β-cell autoimmunity. Functional studies related to the observed alterations in the gut microbiome are warranted because the low abundance of bifidobacteria and butyrate-producing species could adversely affect the intestinal epithelial barrier function and inflammation, whereas the apparent importance of the Bacteroides genus in development of type 1 diabetes is insufficiently understood. 23149657 Short duration of diabetes and disuse of sulfonylurea have any association with insulin cessation of the patients with type 2 diabetes in a clinical setting in Japan (JDDM 30). Insulin therapy is often required to achieve good glycemic control for the patients with type 2 diabetes mellitus (T2DM), while protraction of glycemic control without insulin therapy may be preferable for patients. To determine the characteristics of and therapeutic regimen in outpatients with T2DM who were able to stop insulin therapy with satisfactory glycemic control in a real clinical practice setting in Japan by a case-control study. The present study was performed on 928 patients with T2DM who started insulin therapy in 2007. Data regarding age, sex, body mass index, duration of diabetes, HbA1c, postprandial plasma glucose, plasma fasting C-peptide immunoreactivity and treatment modality were compared between patients who were able to stop insulin therapy and those who continued with insulin. Of the 928 patients, 37 had stopped insulin therapy within 1 year. In the patients who stopped insulin therapy, the duration of diabetes was significantly shorter and the daily insulin dosage at initiation and the prevalence of sulfonylurea pretreatment significantly lower compared with patients who continued on insulin. In conclusion, almost 4% of T2DM patients were able to stop insulin therapy with satisfactory glycemic control in a real clinical practice setting in Japan. Shorter duration of diabetes and disuse of sulfonylureas prior to insulin may associate with stopping insulin therapy as a near-normoglycemic remission in outpatients with T2DM in Japan. 22968082 Influence of stimulant-induced hyperactivity on social approach in the BTBR mouse model of autism. Translational research is needed to discover pharmacological targets and treatments for the diagnostic behavioral domains of autism spectrum disorders. Animal models with phenotypic relevance to diagnostic criteria offer clear experimental strategies to test the efficacy and safety of novel treatments. Antagonists of mGluR5 receptors are in clinical trials for Fragile X syndrome and under investigation for the treatment of autism spectrum disorders. However, in preclinical studies of mGluR5 compounds tested in our laboratory and others, increased locomotion following mGluR5 modulation has been observed. Understanding the influence of general activity on sociability and repetitive behaviors will increase the accuracy of interpretations of positive outcomes measured from pharmacological treatment that produces locomotor activating or sedating effects. In the present studies, dose-response curves for d-amphetamine (AMPH)-induced hyperlocomotion were similar in standard B6 mice and in the BTBR mouse model of autism. AMPH produced significant, robust reductions in the high level of repetitive self-grooming that characterizes BTBR, and also reduced the low baseline grooming in B6, indicating that AMPH-induced hyperlocomotion competes with time spent engaged in self-grooming. We then tested AMPH in B6 and BTBR on the 3-chambered social approach task. One component of sociability, the time spent in the chamber with the novel mouse, in B6 mice was reduced, while the sniffing time component of sociability in BTBR mice was enhanced. This finding replicated across multiple cohorts treated with AMPH and saline vehicle. In-depth analysis revealed that AMPH increased the number and decreased the duration of sniffing bouts in BTBR, suggesting BTBR treated with AMPH mostly engaged in brief sniffs rather than true social interactions with the novel mouse during the social approach task. Our data suggest that compounds with stimulant properties may have some direct benefits on reducing repetitive behaviors in autism spectrum disorders, particularly in the subset of autistic individuals with hyperactivity. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. 23323839 Synthesis and antibacterial evaluation of typharin analog: 6,8-dihydroxy-7-methyl-3-styryl-3,4-dihydroisocoumarin. Synthesis of the 6-hydroxy-7-methyl analog of typharin (8-dihydroxy-3-styryl-3,4-dihydroisocoumarin) isolated from the rhizomes of Typha capensis has been described. Direct condensation of 3,5-dimethoxy-4-methylhomophthalic acid (1) with cinnamoyl chloride at elevated temperature under inert conditions afforded 6,8-dihydroxy-7-methyl-3-styrylisocoumarin (2). Hydrolysis of isocoumarin to keto acid (3) followed by reduction and cyclodehydration of hydroxy acid analog (4) afforded ( ± )-6,8-dimethoxy-3-(4-methoxyphenyl)-3,4-dihydroisocoumarin (5). Demethylation of the latter using anhydrous aluminum chloride/ethane thiol furnished the title isocoumarin (6). Compounds (1-6) were screened for in vitro antibacterial activity against a representative panel of Gram-positive and Gram-negative bacteria using levofloxacin as the reference drug. 23238299 Modulation of multidrug resistance in cancer cells by chelidonine and Chelidonium majus alkaloids. Cancer cells often develop multidrug resistance (MDR) which is a multidimensional problem involving several mechanisms and targets. This study demonstrates that chelidonine and an alkaloid extract from Chelidonium majus, which contains protoberberine and benzo[c]phenanthridine alkaloids, has the ability to overcome MDR of different cancer cell lines through interaction with ABC-transporters, CYP3A4 and GST, by induction of apoptosis, and cytotoxic effects. Chelidonine and the alkaloid extract inhibited P-gp/MDR1 activity in a concentration-dependent manner in Caco-2 and CEM/ADR5000 and reversed their doxorubicin resistance. In addition, chelidonine and the alkaloid extract inhibited the activity of the drug modifying enzymes CYP3A4 and GST in a dose-dependent manner. The alkaloids induced apoptosis in MDR cells which was accompanied by an activation of caspase-3, -8,-6/9, and phosphatidyl serine (PS) exposure. cDNA arrays were applied to identify differentially expressed genes after treatment with chelidonine and the alkaloid extract. The expression analysis identified a common set of regulated genes related to apoptosis, cell cycle, and drug metabolism. Treatment of Caco-2 cells with 50 μg/ml alkaloid extract and 50 μM chelidonine for up to 48 h resulted in a significant decrease in mRNA levels of P-gp/MDR1, MRP1, BCRP, CYP3A4, GST, and hPXR and in a significant increase in caspase-3 and caspase-8 mRNA. Thus, chelidonine is a promising model compound for overcoming MDR and for enhancing cytotoxicity of chemotherapeutics, especially against leukaemia cells. Its efficacy needs to be confirmed in animal models. 23466232 A new series of N2-substituted-5-(p-toluenesulfonylamino)phthalimide analogues as α-glucosidase inhibitors. Several members of a new family of non-sugar-type α-glycosidase inhibitors, bearing a 5-(p-toluenesulfonylamino)phthalimide moiety and various substituent at the N2 position, were synthesized and their activities were investigated. The newly synthesized compounds displayed different inhibition profile towards yeast α-glycosidase and rat intestinal α-glycosidase. Almost all the compounds had strong inhibitory activities against yeast α-glycosidase. Regarding rat intestinal α-glycosidase, only analogs with N2-aromatic substituents displayed varying degrees of inhibitory activities on rat intestinal maltase and lactase and nearly all compounds showed no inhibition against rat intestinal α-amylase. Structure-activity relationship studies indicated that 5-(p-toluenesulfonylamino)phthalimide moiety is a favorable scaffold to exert the α-glucosidase inhibitory activity and substituents at the N2 position have considerable influence on the efficacy of the inhibition activities. 23596124 From a Multipotent Stilbene to Soluble Epoxide Hydrolase Inhibitors with Antiproliferative Properties. Inspired by nature: Natural product isopropylstilbene was identified as an inhibitor of soluble epoxide hydrolase exhibiting antiproliferative properties. Following the natural product inspired design approach, a library of (E)-styryl-1H-benzo[d]imidazoles was synthesized and evaluated with recombinant enzyme and on several cancer cell lines. 23464578 Hierarchical or not? Effect of the length scale and hierarchy of the surface roughness on omniphobicity of lubricant-infused substrates. Lubricant-infused textured solid substrates are gaining remarkable interest as a new class of omni-repellent nonfouling materials and surface coatings. We investigated the effect of the length scale and hierarchy of the surface topography of the underlying substrates on their ability to retain the lubricant under high shear conditions, which is important for maintaining nonwetting properties under application-relevant conditions. By comparing the lubricant loss, contact angle hysteresis, and sliding angles for water and ethanol droplets on flat, microscale, nanoscale, and hierarchically textured surfaces subjected to various spinning rates (from 100 to 10 000 rpm), we show that lubricant-infused textured surfaces with uniform nanofeatures provide the most shear-tolerant liquid-repellent behavior, unlike lotus leaf-inspired superhydrophobic surfaces, which generally favor hierarchical structures for improved pressure stability and low contact angle hysteresis. On the basis of these findings, we present generalized, low-cost, and scalable methods to manufacture uniform or regionally patterned nanotextured coatings on arbitrary materials and complex shapes. After functionalization and lubrication, these coatings show robust, shear-tolerant omniphobic behavior, transparency, and nonfouling properties against highly contaminating media. 23494855 Evaporation-Induced Coating of Hydrous Ruthenium Oxide on Mesoporous Silica Nanoparticles to Develop High-Performance Supercapacitors. An efficient evaporation-induced coating method combining microwave-assisted hydrothermal transformation and annealing is developed to fabricate an ideal electrode material from composites with a layer of hydrous RuO2 on mesoporous silica nanoparticles (MSNs), for a high-performance supercapacitor. Total and RuO2 -based specific capacitances are as high as 1125 and 2000 F g(-1) , respectively. 23157632 Abnormal striatal dopamine transmission in schizophrenia. Despite numerous revisions and reformulations, dopamine (DA) hypothesis of schizophrenia remains a pivotal neurochemical hypothesis of this illness. The aim of this review is to expose and discuss findings from positron emission tomography (PET) or single-photon- emission computed tomography (SPECT) studies investigating DA function in the striatum of medicated, drug-naive or drug-free patients with schizophrenia and in individuals at risk compared with healthy volunteers. DA function was studied at several levels: i) at a presynaptic level where neuroimaging studies investigating DOPA uptake capacity clearly show an increase of DA synthesis in patients with schizophrenia; ii) at a synaptic level where neuroimaging studies investigating dopamine transporter availability (DAT) does not bring any evidence of dysfunction; iii) and finally, neuroimaging studies investigating DA receptor density show a mild increase of D2 receptor density in basic condition and, an hyperreactivity of DA system in dynamic condition. These results are discussed regarding laterality, sub-regions of striatum and implications for the at-risk population. Striatal DA abnormalities are now clearly demonstrated in patients with schizophrenia and at risk population and could constitute an endophenotype of schizophrenia. Subtle sub-clinical striatal DA abnormalities in at risk population could be a biomarker of transition from a vulnerability state to the expression of frank psychosis. 23219934 3-(1H-indol-3-yl)-2-[3-(4-nitrophenyl)ureido]propanamide enantiomers with human formyl-peptide receptor agonist activity: molecular modeling of chiral recognition by FPR2. N-formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) that play critical roles in inflammatory reactions, and FPR-specific interactions can possibly be used to facilitate the resolution of pathological inflammatory reactions. Recent studies indicated that FPRs have stereo-selective preference for chiral ligands. Here, we investigated the structure-activity relationship of 24 chiral ureidopropanamides, including previously reported compounds PD168368/PD176252 and their close analogs, and used molecular modeling to define chiral recognition by FPR2. Unlike previously reported 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones, whose R-forms preferentially activated FPR1/FPR2, we found that four S-enantiomers in the seven ureidopropanamide pairs tested preferentially activated intracellular Ca(2+) flux in FPR2-transfected cells, while the R-counterpart was more active in two enantiomer pairs. Thus, active enantiomers of FPR2 agonists can be in either R- or S-configurations, depending on the molecular scaffold and specific substituents at the chiral center. Using molecular modeling approaches, including field point methodology, homology modeling, and docking studies, we propose a model that can explain stereoselective activity of chiral FPR2 agonists. Importantly, our docking studies of FPR2 chiral agonists correlated well with the FPR2 pharmacophore model derived previously. We conclude that the ability of FPR2 to discriminate between the enantiomers is the consequence of the arrangement of the three asymmetric hydrophobic subpockets at the main orthosteric FPR2 binding site with specific orientation of charged regions in the subpockets. 23623904 Developmental immunotoxicity in male rats after juvenile exposure to ethanol. The aim of the present study was to determine the sensitivity of the developing immune system to ethanol (EtOH) after exposure from postnatal day (PND) 10 onward. Adult Wistar dams and litters were exposed to EtOH via drinking water (0, 0.25, 1.5, 2.75, 4, 5.25, or 6.5% (w/v) EtOH ad libitum) and drinking water exposure of the F1 was continued from weaning until sacrifice. Immune assessments were performed at postnatal days (PNDs) 21, 42, and 70. Furthermore, Keyhole Limpet Hemocyanin (KLH) specific immune responses were evaluated following subcutaneous immunizations on PNDs 21 and 35. EtOH exposure affected innate immune responses, such as LPS-induced NO-production by adherent splenocytes, as well as adaptive immune responses as represented by KLH-specific parameters. The most sensitive developmental parameters included effects on maternal and pup bodyweight with calculated BMDs of 4.0% and 4.3% EtOH, respectively. The most sensitive immune parameters were affected at dose levels lower than those affecting developmental parameters and included KLH-specific immune responses, LPS-induced NO production by adherent splenocytes, and IL-10 production by ConA stimulated splenocytes. Calculated BMDs for these parameters were between 0.01% and 0.1% EtOH. A comparison of the results of this juvenile study with an extended one-generation reproductive toxicity study revealed that the juvenile study design may result in a higher sensitivity related to differences in the exposure design. These findings demonstrate the relative sensitivity of the developing immune system for EtOH exposure, the additional value of assessing functional immune parameters, and the importance of the juvenile window in developmental immunotoxicity testing. 23527615 Thiolactone Sulfoxides as New Reactive Metabolites Acting as Bis-Electrophiles: Implication in Clopidogrel and Prasugrel Bioactivation. The antithrombotics of the tetrahydrothienopyridine series, clopidogrel and prasugrel, are prodrugs that must be metabolized in two steps to become pharmacologically active. The first step is the formation of a thiolactone metabolite. The second step is a cytochrome P450 (P450)-dependent oxidation of this thiolactone resulting in the formation of a sulfenic acid that is eventually reduced into the corresponding active thiol. It has been postulated that the sulfenic acid metabolite resulted from a nucleophilic attack of water on a highly reactive thiolactone sulfoxide derived from P450-dependent oxidation of the thiolactone primary metabolite. The data described in the present article are in complete agreement with this proposition as they show that it was possible to trap these thiolactone sulfoxides by a series of nucleophiles such as amines, thiols, or cyclopentane-1,3-dione (CPDH), an equivalent of dimedone that is used as a sulfenic acid trapping agent. HPLC-MS studies showed that various bis-adducts having incorporated two nucleophile molecules were formed in these reactions. One of them that resulted from the oxidation of 2-oxo-prasugrel by human liver microsomes in the presence of ethanolamine and CPDH was isolated and completely characterized by (1)H and (13)C NMR spectroscopy in addition to MS and MS(2) spectrometry. All metabolites derived from an attack of H2O or an amine at the CO carbon of the intermediate thiolactone sulfoxide existed as a mixture of two diastereomers having a cis configuration of the double bond, whereas those formed in the presence of thiols appeared as a mixture of four diastereomers with a cis or trans configuration of the double bond. This led us to propose tentative mechanisms for the previously reported formation of trans isomers of the active thiol metabolite of clopidogrel upon microsomal metabolism of this antithrombotic in the presence of thiols. The results described in this article showed that thiolactone sulfoxides are formed as reactive metabolites during the metabolism of clopidogrel and prasugrel and are able to react as bis-electrophiles with a variety of nucleophiles. The possible implications of the formation of these reactive metabolites in the pharmacological and/or secondary toxic effects of these drugs remain to be studied. 23641693 Immunogenicity assays for antibody-drug conjugates: case study with ado-trastuzumab emtansine. Background: Antibody-drug conjugates (ADCs) such as Kadcyla™ (ado-trastuzumab emtansine [T-DM1]) present covalently bound cytotoxic drugs, which may influence their immunogenicity potential compared with antibody therapies. Therefore, ADCs require assay strategies that allow measurement of responses to all the molecular components. Results: The immunogenicity strategy for T-DM1 used a risk-based, tiered approach that included screening and titration to detect antitherapeutic antibodies; confirmation of positive responses; and characterization to assess whether the immune response is primarily to the antibody or to the linker-drug and/or new epitopes in trastuzumab resulting from conjugation. Conclusion: The tiered immunogenicity assay strategy for T-DM1 allowed detection of antitherapeutic antibodies to all components of the ADC in multiple nonclinical and clinical studies. Characterization strategies implemented in clinical studies provided additional insights into the specificity of the immune response. 23542559 A global toxicogenomic analysis investigating the mechanistic differences between tobacco and marijuana smoke condensates in vitro. Like tobacco smoking, habitual marijuana smoking causes numerous adverse pulmonary effects. However, the mechanisms of action involved, especially as compared to tobacco smoke, are still unclear. To uncover putative modes of action, this study employed a toxicogenomics approach to compare the toxicological pathways perturbed following exposure to marijuana and tobacco smoke condensate in vitro. Condensates of mainstream smoke from hand-rolled tobacco and marijuana cigarettes were similarly prepared using identical smoking conditions. Murine lung epithelial cells were exposed to low, medium and high concentrations of the smoke condensates for 6h. RNA was extracted immediately or after a 4h recovery period and hybridized to mouse whole genome microarrays. Tobacco smoke condensate (TSC) exposure was associated with changes in xenobiotic metabolism, oxidative stress, inflammation, and DNA damage response. These same pathways were also significantly affected following marijuana smoke condensate (MSC) exposure. Although the effects of the condensates were largely similar, dose-response analysis indicates that the MSC is substantially more potent than TSC. In addition, steroid biosynthesis, apoptosis, and inflammation pathways were more significantly affected following MSC exposure, whereas M phase cell cycle pathways were more significantly affected following TSC exposure. MSC exposure also appeared to elicit more severe oxidative stress than TSC exposure, which may account for the greater cytotoxicity of MSC. This study shows that in general MSC impacts many of the same molecular processes as TSC. However, subtle pathway differences can provide insight into the differential toxicities of the two complex mixtures. 23561119 Peach (Prunus persica) extract inhibits angiotensin II-induced signal transduction in vascular smooth muscle cells. Angiotensin II (Ang II) is a vasoactive hormone that has been implicated in cardiovascular diseases. Here, the effect of peach, Prunus persica L. Batsch, pulp extract on Ang II-induced intracellular Ca(2+) mobilization, reactive oxygen species (ROS) production and signal transduction events in cultured vascular smooth muscle cells (VSMCs) was investigated. Pretreatment of peach ethyl acetate extract inhibited Ang II-induced intracellular Ca(2+) elevation in VSMCs. Furthermore, Ang II-induced ROS generation, essential for signal transduction events, was diminished by the peach ethyl acetate extract. The peach ethyl acetate extract also attenuated the Ang II-induced phosphorylation of epidermal growth factor receptor and myosin phosphatase target subunit 1, both of which are associated with atherosclerosis and hypertension. These results suggest that peach ethyl acetate extract may have clinical potential for preventing cardiovascular diseases by interfering with Ang II-induced intracellular Ca(2+) elevation, the generation of ROS, and then blocking signal transduction events. 23411235 Antioxidant activity of phytosteryl phenolates in different model systems. As part of a comprehensive study of the physiochemical and biological properties of phytosteryl phenolates, successfully synthesized chemoenzymatically in our lab, their antioxidant activity was evaluated using three different in vitro model systems, namely bulk oil model system, β-carotene-linoleate model system and low-density lipoprotein cholesterol (LDL-C) oxidation assay. In the bulk oil system, phytosteryl phenolates showed similar or lower antioxidant activity compared with those of phenolic acids. However, in β-carotene-linoleate assay, an emulsion model system, phytosteryl phenolates showed enhanced antioxidant activity except phytosteryl ferulates. Moderate inhibitory effect of LDL-C oxidation by phytosteryl phenolates was observed. These findings demonstrate that use of multidimensional antioxidant activity determinations with differing reaction mechanisms is necessary to provide an overall understanding of the mechanisms of antioxidant action of phytosteryl phenolates. 23631494 Milk-Derived Peptides, Val-Pro-Pro and Ile-Pro-Pro, Attenuate Atherosclerosis Development in Apolipoprotein E-Deficient Mice: A Preliminary Study. Abstract Milk-derived peptides, Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP), have angiotensin I-converting enzyme inhibitory activities and blood pressure-lowering effects. We examined the effects of these peptides on the development of atherosclerosis in apolipoprotein E-deficient [apoE(-/-)] mice. For 31 weeks, six-week-old male apoE(-/-) mice received a diet that included one of the following: fermented milk containing both VPP and IPP; casein hydrolysate containing both of these peptides; synthesized VPP; synthesized IPP; enalapril; captopril; or control diet. At the end of feeding, blood biochemistry, aortic atherogenesis, and gene expression by DNA microarray analysis were evaluated. There were no significant changes in the plasma lipid levels and 8-isoprostane, a marker of oxidative stress. The area ratio of intima to media in the aortic arch was significantly lower in the fermented milk, casein hydrolysate, synthesized VPP, enalapril, and captopril groups than in the control group. As is common with diets containing VPP and/or IPP, we observed reductions in mRNA expression of inflammatory cytokines, such as interleukin (IL)-6 and IL-1β, oxidized low-density lipoprotein receptor, and transcription regulators. These results suggest that a continuous intake of VPP and IPP might be beneficial for preventing atherosclerosis caused by hypercholesterolemia. 23404316 MRI morphometric characterisation of the paediatric cervical spine and spinal cord in children with MPS IVA (Morquio-Brailsford syndrome). Nearly all children with MPS IVA develop skeletal deformities affecting the spine. At the atlanto-axial spine, odontoid hypoplasia occurs. GAG deposition around the dens, leads to peri-odontoid infiltration. Transverse/alar ligament incompetence causes instability. Atlanto-axial instability is associated with cord compression and myelopathy, leading to major morbidity and mortality. Intervention is often required. Does the presence of widened bullet shaped vertebra in platyspondily encroach on the spinal canal and cause spinal stenosis in MPS IVA? So far, there have been no standardised morphometric measurements of the paediatric MPS IVA cervical spine to evaluate whether there is pre-existing spinal stenosis predisposing to compressive myelopathy or whether this is purely an acquired process secondary to instability and compression. This study provides the first radiological quantitative analysis of the cervical spine and spinal cord in a series of affected children. MRI morphometry indicates that the MPS IVA spine is narrower at C1-2 level giving an inverted funnel shape. There is no evidence of a reduction in the Torg ratio (canal-body ratio) in the cervical spine. The spinal canal does not exceed 11 mm at any level, significantly smaller than normal historical cohorts (14 mm). The sagittal diameter and axial surface area of both spinal canal and cord are reduced. C1-2 level cord compression was evident in the canal-cord ratio but the Torg ratio was not predictive of cord compression. In MPS IVA the reduction in the space available for the cord (SAC) is multifactorial rather than due to congenital spinal stenosis. 23604722 Fructose-1,6-bisphosphate ameliorates lipopolysaccharide-induced dysfunction of blood-brain barrier. Fructose-1,6-bisphosphate (FBP), a glycolytic intermediate, has neuroprotective effects in various brain injury models. However, its effects on blood-brain barrier (BBB) are largely unknown. In this study, we investigated the effects of FBP on lipopolysaccharide (LPS)-induced BBB dysfunction in in vitro BBB model comprising co-culture of mouse brain endothelial cell line, bEnd.3 and mouse primary astrocyte and explored its action mechanism therein involved. LPS induced the impairment of endothelial permeability and transendothelial electrical resistance (TEER). The functional changes were confirmed by alterations in immunostaining for junctional proteins occludin, ZO-1 and VE-cadherin, such as the loss of cortical staining pattern and appearance of intercellular gaps in endothelial cells. Co-administration of FBP alleviated the deleterious effects of LPS on BBB permeability and TEER in a dose dependent manner. And also FBP inhibited the LPS-induced changes in the distribution of endothelial junctional proteins, resulting in the better preservation of monolayer integrity. FBP suppressed the production of reactive oxygen species (ROS) but did not affect cyclooxygenase-2 expression and prostaglandin E2 production in endothelial cells stimulated with LPS. Taken together, these data suggest that FBP could ameliorate LPS-induced BBB dysfunction through the maintenance of junctional integrity, which might be mediated by downregulation of ROS production. 23500058 Gene silencing of TNF-alpha in a murine model of acute colitis using a modified cyclodextrin delivery system. Inflammatory bowel disease (IBD) is a chronic relapsing inflammation of the gastrointestinal tract. The cytokine TNF-alpha (TNF-α) plays a pivotal role in mediating this inflammatory response. RNA interference (RNAi) holds great promise for the specific and selective silencing of aberrantly expressed genes, such as TNF-α in IBD. The aim of this study was to investigate the efficacy of an amphiphilic cationic cyclodextrin (CD) vector for effective TNF-α siRNA delivery to macrophage cells and to mice with induced acute-colitis. The stability of CD.siRNA was examined by gel electrophoresis in biorelevant media reflecting colonic fluids. RAW264.7 cells were transfected with CD.TNF-α siRNA, stimulated with lipopolysaccharide (LPS) and TNF-α and IL-6 responses were measured by PCR and ELISA. Female C57BL/6 mice were exposed to dextran sodium sulphate (DSS) and treated by intrarectal administration with either CD.siRNA TNF-α or a control solution. In vitro, siRNA in CD nanocomplexes remained intact and stable in both fed and fasted simulated colonic fluids. RAW264.7 cells transfected with CD.TNF-α siRNA and stimulated with LPS displayed a significant reduction in both gene and protein levels of TNF-α and IL-6. CD.TNF-α siRNA-treated mice revealed a mild amelioration in clinical signs of colitis, but significant reductions in total colon weight and colonic mRNA expression of TNF-α and IL-6 compared to DSS-control mice were detected. This data indicates the clinical potential of a local CD-based TNF-α siRNA delivery system for the treatment of IBD. 22465815 Combination of group I mGlu receptors antagonist with dopaminergic agonists strengthens the synaptic transmission at corticostriatal synapses in culture. Restoring synaptic plasticity in neurodegenerative diseases could prevent neuronal degeneration, as well as motor and cognitive disorders. In Parkinson's disease, synaptic plasticity at corticostriatal synapses is altered. Dendrites of striatal medium spiny neurons (MSNs) receive dopaminergic inputs from the substantia nigra and glutamatergic cortical afferents. Because both glutamate and dopamine are required to induce and sustain MSNs plasticity, the particular molecular mechanisms involved at this synaptic triad are difficult to understand. In the present work, we established a convenient in vitro model of the corticostriatal synapse to study synaptic plasticity. We focused on long-term depression involving group I metabotropic glutamate (mGlu) receptors. We found that in striatal neurons co-cultured with cortical neurons, the absence of dopaminergic stimuli favored the excess of glutamatergic drive from cortical neuron terminals, thus resulting in a constitutive depression of the corticostriatal glutamatergic transmission. Indeed, concomitant blockade of group I mGlu receptors and activation of dopaminergic receptors stably reduced the depression of the synaptic transmission. Thus the dependence on glutamate and dopamine balance of the corticostriatal synapse responsiveness validates the accuracy of this manageable in vitro model to depict the molecular pathways involved in the plasticity at corticostriatal synapses and to test restorative therapeutic approaches in Parkinson's disease. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23305513 Surface transformations of Bioglass 45S5 during scaffold synthesis for bone tissue engineering. In physiological fluid, a layer of hydroxycarbonate apatite, similar to bone mineral, develops on the surface of Bioglass 45S5. Collagen from the surrounding tissue is adsorbed on this layer that attracts osteoblasts, and favors bone regrowth. Bioglass is therefore an osteoinductive material. Still, due to its brittleness, the glass alone cannot be used to heal large bone defects. To overcome this issue, Bioglass is used to form a composite scaffold with poly(D,L-lactide) (PDLLA), a biodegradable polymer. The goal of this work is to understand Bioglass reactivity throughout scaffold fabrication via a low-temperature route, the solvent casting and particulate leaching technique. Changes in Bioglass (especially its surface) are susceptible to occur both while in contact with the processing fluids and potentially through a reaction with the surrounding polymeric matrix. Here we analyzed the surface changes of three different Bioglass samples: (i) as-received, (ii) treated in solutions that parallel those used in scaffold fabrication, and (iii) extracted from the scaffolds. We showed that extracted, just like treated, Bioglass deviates from the as-received, but to a larger extent. X-ray photoelectron and infrared spectroscopy support the theory that Bioglass surface was modified not just through contact with the solutions in scaffold fabrication, but upon an interaction with the polymeric matrix. The polymer network slows down the Na(+)/H(+) exchange between Bioglass and water used to leach salt particles to create pores within the scaffold. Changes in surface properties affect the bioactivity of Bioglass and thus of the composite scaffolds, and are therefore critical to identify. 23499778 The animal's dignity in Swiss Animal Welfare Legislation - Challenges and opportunities. The introduction of the animal's dignity as a concern in animal welfare legislation in Switzerland is unique worldwide. Naturally, this measure has raised hopes and fears in those concerned with animal welfare and animal use. For the past several years, a lively debate has focused on the question of whether the addition is merely a declaration of intent or an explicit demand with, possibly, a profound impact on everyday practice. What the implications may be in the latter case is not clear. In the area of research, it has yet to be seen how this concept may be incorporated feasibly, for example, into the harm-benefit analysis, which is the prerequisite for the approval of an animal experiment. It is foreseeable, therefore, that this addition might have direct implications on research. Unfortunately, in the legislative text, there are some inconsistencies in wording, at least in the German version, that complicate interpretation. This article provides a short overview of some aspects of the controversy, which is far from settled at this time. The commentary will be restricted to the situation of experimental animals in Switzerland. 23216107 Aqueous extracts of Roselle (Hibiscus sabdariffa Linn.) varieties inhibit α-amylase and α-glucosidase activities in vitro. This study sought to investigate the inhibitory effect of aqueous extracts of two varieties (red and white) of Hibiscus sabdariffa (Roselle) calyces on carbohydrate hydrolyzing enzymes (α-amylase and α-glucosidase), with the aim of providing the possible mechanism for their antidiabetes properties. Aqueous extracts were prepared (1:100 w/v) and the supernatant used for the analysis. The extracts caused inhibition of α-amylase and α-glucosidase activities in vitro.The IC(50) revealed that the red variety (25.2 μg/mL) exhibited higher α-glucosidase inhibitory activity than the white variety (47.4 μg/mL), while the white variety (90.5 μg/mL) exhibited higher α-amylase inhibitory activity than the red variety (187.9 μg/mL). However, the α-glucosidase inhibitory activities of both calyces were higher than that of their α-amylase. In addition, the red variety possessed higher antioxidant capacity as exemplified by the (•)OH scavenging abilities, Fe(2+) chelating ability, and inhibition of Fe(2+)-induced pancreatic lipid peroxidation in vitro. The enzyme inhibitory activities and antioxidant properties of the roselle extracts agreed with their phenolic content. Hence, inhibition of α-amylase and α-glucosidase, coupled with strong antioxidant properties could be the possible underlying mechanism for the antidiabetes properties of H. sabdariffa calyces; however, the red variety appeared to be more potent. 23642226 Vibrational Perturbations of W(CO)6 Trapped in a Molecular Lattice Probed by Linear and Non Linear Spectroscopy. Vibrational dynamics of the T1u CO stretching mode of tungsten hexacarbonyl is explored when the molecule is embedded in a nitrogen matrix at low temperature. Experiments combined IR absorption spectroscopy and IR stimulated photon echoes at the femtosecond timescale. W(CO)6 is found to be trapped in two main families of sites differing by their symmetries (called hereafter Oh and D2h ). In Oh sites, the vibrational coherence is strongly temperature dependent, exhibiting a coupling with librational phonons of the nitrogen lattice. Perturbation in D2h sites results in the splitting of the T1u band in three components. Each component is inhomogeneously broadened, with dephasing times in the tens of picoseconds, weakly coupled to the lattice phonons. Experiments in solid krypton are performed to compare the effect of atomic and diatomic host lattices. Dephasing time in Kr does not depend on temperature and remains in the hundreds of picosecond, highlighting the molecular origin of dephasing process in N2 . Additionally, non linear signals show oscillations due to quantum beats and polarization interferences between different frequency components of the induced third order polarization, giving information, in particular, on the overtone vibrational transition. 23507976 Droplet-based microfluidic platform for heterogeneous enzymatic assays. Heterogeneous enzymatic reactions are used in many industrial processes including pulp and paper, food, and biofuel production. Industrially-relevant optimization of the enzymes used in these processes requires assaying them with insoluble substrates. However, platforms for high throughput heterogeneous assays do not exist thereby severely increasing the cost and time of enzyme optimization, or leading to the use of assays with soluble substrates for convenient, but non-ideal, optimization. We present an innovative approach to perform heterogeneous reactions in a high throughput fashion using droplet microfluidics. Droplets provide a facile platform for heterogeneous reactions as internal recirculation allows rapid mixing of insoluble substrates with soluble enzymes. Moreover, it is easy to generate hundreds or thousands of picoliter droplets in a small footprint chip allowing many parallel reactions. We validate our approach by screening combinations of cellulases with real-world insoluble substrates, and demonstrate that the chip-based screening is in excellent agreement with the conventional screening methods, while offering advantages of throughput, speed and lower reagent consumption. We believe that our approach, while demonstrated for a biofuel application, provides a generic platform for high throughput monitoring of heterogeneous reactions. 23536974 Comparison of the Relative Propensities of Isoamyl Nitrite and Sodium Nitrite to Ameliorate Acute Cyanide Poisoning in Mice and a Novel Antidotal Effect Arising from Anesthetics. Isoamyl nitrite has previously been considered acceptable as an inhaled cyanide antidote; therefore, the antidotal utility of this organic nitrite compared with sodium nitrite was investigated. To facilitate a quantitative comparison, doses of both sodium nitrite and isoamyl nitrite were given intraperitoneally in equimolar amounts to sublethally cyanide-challenged mice. Righting recovery from the knockdown state was clearly compromised in the isoamyl nitrite-treated animals, the effect being attributable to the toxicity of the isoamyl alchol produced during hydrolysis of the isoamyl nitrite to release nitrite anion. Subsequently, inhaled aqueous sodium nitrite aerosol was demonstrated to ameliorate sublethal cyanide toxicity, when provided to mice after the toxic dose, by the more rapid recovery of righting ability compared to that of the control animals given only the toxicant. Aerosolized sodium nitrite has thus been shown by these experiments to have promise as a better alternative to organic nitrites for development as an inhaled cyanide antidote. The inhaled sodium nitrite led to the production of NO in the bloodstream as determined by the appearance of EPR signals attributable to nitrosylhemoglobin and methemoglobin. The aerosol delivery was performed in an unmetered inhalation chamber, and in this study, no attempt was made to optimize the procedure. It is argued that administration of an effective inhaled aqueous sodium nitrite dose in humans is possible, though just beyond the capability of current individual metered-dose inhaler designs, such as those used for asthma. Finally, working at slightly greater than LD50 NaCN doses, it was fortuitously discovered that (i) anesthesia leads to significantly prolonged survival compared to that of unanesthetized animals and that (ii) the antidotal activity of nitrite anion was completely abolished under anesthesia. Plausible explanations for these effects in mice and their practical consequences in relation to testing putative cyanide antidotes are discussed. 23323640 Polymorphism of GeSbTe superlattice nanowires. Scaling-down of phase change materials to a nanowire (NW) geometry is critical to a fast switching speed of nonvolatile memory devices. Herein, we report novel composition-phase-tuned GeSbTe NWs, synthesized by a chemical vapor transport method, which guarantees promising applications in the field of nanoscale electric devices. As the Sb content increased, they showed a distinctive rhombohedral-cubic-rhombohedral phase evolution. Remarkable superlattice structures were identified for the Ge(8)Sb(2)Te(11), Ge(3)Sb(2)Te(6), Ge(3)Sb(8)Te(6), and Ge(2)Sb(7)Te(4) NWs. The coexisting cubic-rhombohedral phase Ge(3)Sb(2)Te(6) NWs exhibited an exclusively uniform superlattice structure consisting of 2.2 nm period slabs. The rhombohedral phase Ge(3)Sb(8)Te(6) and Ge(2)Sb(7)Te(4) NWs adopted an innovative structure; 3Sb(2) layers intercalated the Ge(3)Sb(2)Te(6) and Ge(2)Sb(1)Te(4) domains, respectively, producing 3.4 and 2.7 nm period slabs. The current-voltage measurement of the individual NW revealed that the vacancy layers of Ge(8)Sb(2)Te(11) and Ge(3)Sb(2)Te(6) decreased the electrical conductivity. 23281892 A class of 5-nitro-2-furancarboxylamides with potent trypanocidal activity against Trypanosoma brucei in vitro. Recently, the World Health Organization approved the nifurtimox-eflornithine combination therapy for the treatment of human African trypanosomiasis, renewing interest in nitroheterocycle therapies for this and associated diseases. In this study, we have synthesized a series of novel 5-nitro-2-furancarboxylamides that show potent trypanocidal activity, ∼1000-fold more potent than nifurtimox against in vitro Trypanosoma brucei with very low cytotoxicity against human HeLa cells. More importantly, the most potent analogue showed very limited cross-resistance to nifurtimox-resistant cells and vice versa. This implies that our novel, relatively easy to synthesize and therefore cheap, 5-nitro-2-furancarboxylamides are targeting a different, but still essential, biochemical process to those targeted by nifurtimox or its metabolites in the parasites. The significant increase in potency (smaller dose probably required) has the potential for greatly reducing unwanted side effects and also reducing the likelihood of drug resistance. Collectively, these findings have important implications for the future therapeutic treatment of African sleeping sickness. 23578644 Conjugated linoleic acid and calcium co-supplementation improves bone health in ovariectomised mice. Osteoporosis is a significant health concern for the elderly; conjugated linoleic acid (CLA) has been shown to improve overall bone mass when calcium is included as a co-supplement. However, potential effects of CLA and calcium on bone mass during a period of bone loss have not been reported. The purpose of this study was to determine how dietary calcium modulates the effects of conjugated linoleic acid (CLA) in preventing bone loss, using an ovariectomised mouse model. CLA supplementation significantly prevented ovariectomy-associated weight and fat mass gain, compared to non-supplemented controls. CLA significantly increased bone markers without major changes in bone mineral composition in the femur compared to respective controls. CLA treatment increased serum parathyroid hormone (PTH) significantly (p=0.0172), while serum 1,25-dihydroxyvitamin D3 concentration was not changed by CLA. Meanwhile, CLA significantly reduced femur tartrate resistant acid phosphatase (TRAP) activity, suggesting potential reduction of osteoclastogenesis. The data suggest that CLA, along with dietary calcium, has great potential to be used to prevent bone loss and weight gain associated with menopause. 23411216 The influence of cation exchange treatment on the final characteristics of red wines. Ion exchange technology has been applied to adjust the pH of red wine and improve its tartaric and oxidative stability. Ion exchange appears to be a useful technique to achieve these objectives. Regarding the effect of ion exchange on organoleptic characteristics and the quality of the obtained wines, a slight decrease in both anthocyanin and tannin contents was observed along with a small drop in the aromatic content. However, the treated wines had lower hue and higher colour intensity and gave better punctuations in the sensory evaluation. These results confirm that ion exchange is an interesting technique for application in red winemaking. 23477619 DNA Adducts in Aldehyde Dehydrogenase-Positive Lung Stem Cells of A/J Mice Treated with the Tobacco Specific Lung Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Lung cancer is the leading cause of cancer death in the world. Evidence suggests that lung cancer could originate from mutations accumulating in a subpopulation of self-renewing cells, lung stem cells. Aldehyde dehydrogenase (ALDH) is a marker of stem cells. To investigate the presence of DNA modifications in these cells, we isolated ALDH-positive lung cells from A/J mice exposed to the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Using LC-NSI-HRMS/MS-PRM, O(6)-methyl-G, 7-POB-G, and O(2)-POB-dT were positively identified in ALDH-positive cell DNA. This is the first example of detection of carcinogen-DNA adducts in lung stem cells, supporting the hypothesis of their role in lung carcinogenesis. 23537005 Biotransformation of 2,2',4,4'-Tetrabromodiphenyl Ether (BDE-47) by Human Liver Microsomes: Identification of Cytochrome P450 2B6 as the Major Enzyme Involved. Polybrominated diphenyl ethers (PBDEs) were widely used flame retardants that have become persistent environmental pollutants. In the present study, we investigated the in vitro oxidative metabolism of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a major PBDE detected in human tissue and environmental samples. Biotransformation of BDE-47 by pooled and individual human liver microsomes and by human recombinant cytochrome P450 (P450) enzymes was assessed using a liquid chromatography/tandem mass spectrometry-based method. Of the nine hydroxylated metabolites of BDE-47 produced by human liver microsomes, seven metabolites were identified using authentic standards. A monohydroxy-tetrabrominated and a dihydroxy-tetrabrominated metabolite remain unidentified. Kinetic analysis of the rates of metabolite formation revealed that the major metabolites were 5-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (5-OH-BDE-47), 6-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (6-OH-BDE-47), and possibly the unidentified monohydroxy-tetrabrominated metabolite. Among the human recombinant P450 enzymes tested, P450 2B6 was the most active enzyme in the formation of the hydroxylated metabolites of BDE-47. Moreover, the formation of all metabolites of BDE-47 by pooled human liver microsomes was inhibited by a P450 2B6-specific antibody and was highly correlated with P450 2B6-mediated activity in single donor liver microsomes indicating that P450 2B6 was the major P450 responsible for the biotransformation of BDE-47. Additional experiments involving the incubation of liver microsomes with individual monohydroxy-tetrabrominated metabolites in place of BDE-47 demonstrated that 2,4-dibromophenol was a product of BDE-47 and several primary metabolites, but the dihydroxy-tetrabrominated metabolite was not formed by sequential hydroxylation of any of the monohydroxy-tetrabrominated metabolites tested. The present study provides a comprehensive characterization of the oxidative metabolism of BDE-47 by human liver microsomes and P450 2B6. 22964394 Reversal of experimental Laron Syndrome by xenotransplantation of microencapsulated porcine Sertoli cells. Recombinant human IGF-1 currently represents the only available treatment option for the Laron Syndrome, a rare human disorder caused by defects in the gene encoding growth hormone receptor, resulting in irreversibly retarded growth. Unfortunately, this treatment therapy, poorly impacts longitudinal growth (13% in females and 19% in males), while burdening the patients with severe side effects, including hypoglycemia, in association with the unfair chore of taking multiple daily injections that cause local intense pain. In this study, we have demonstrated that a single intraperitoneal graft of microencapsulated pig Sertoli cells, producing pig insulin-like growth factor-1, successfully promoted significant proportional growth in the Laron mouse, a unique animal model of the human Laron Syndrome. These findings indicate a novel, simply, safe and successful method for the cell therapy-based cure of the Laron Syndrome, potentially applicable to humans. 23261526 Cloning, expression and analysis of the olfactory glutathione S-transferases in coho salmon. The glutathione S-transferases (GSTs) provide cellular protection by detoxifying xenobiotics, maintaining redox status, and modulating secondary messengers, all of which are critical to maintaining olfaction in salmonids. Here, we characterized the major coho salmon olfactory GSTs (OlfGSTs), namely omega, pi, and rho subclasses. OlfGST omega contained an open reading frame of 720bp and encoded a protein of 239 amino acids. OlfGST pi and OlfGST rho contained open reading frames of 627 and 681nt, respectively, and encoded proteins of 208 and 226 amino acids. Whole-protein mass spectrometry yielded molecular weights of 29,950, 23,354, and 26,655Da, respectively, for the GST omega, pi, and rho subunits. Homology modeling using four protein-structure prediction algorithms suggest that the active sites in all three OlfGST isoforms resembled counterparts in other species. The olfactory GSTs conjugated prototypical GST substrates, but only OlfGST rho catalyzed the demethylation of the pesticide methyl parathion. OlfGST pi and rho exhibited thiol oxidoreductase activity toward 2-hydroxyethyl disulfide (2-HEDS) and conjugated 4-hydroxynonenal (HNE), a toxic aldehyde with neurodegenerative properties. The kinetic parameters for OlfGST pi conjugation of HNE were K(M)=0.16 ± 0.06mM and V(max)=0.5 ± 0.1μmolmin⁻¹mg⁻¹, whereas OlfGST rho was more efficient at catalyzing HNE conjugation (K(M)=0.022 ± 0.008 mM and V(max)=0.47 ± 0.05μmolmin⁻¹mg⁻¹). Our findings indicate that the peripheral olfactory system of coho expresses GST isoforms that detoxify certain electrophiles and pesticides and that help maintain redox status and signal transduction. 23624352 Pullulan-based nanoparticles as carriers for transmucosal protein delivery. Polymeric nanoparticles have revealed very effective in transmucosal delivery of proteins. Polysaccharides are among the most used materials for the production of these carriers, owing to their structural flexibility and propensity to evidence biocompatibility and biodegradability. In parallel, there is a preference for the use of mild methods for their production, in order to prevent protein degradation, ensure lower costs and easier procedures that enable scaling up. In this work we propose the production of pullulan-based nanoparticles by a mild method of polyelectrolyte complexation. As pullulan is a neutral polysaccharide, sulfated and aminated derivatives of the polymer were synthesized to provide pullulan with a charge. These derivatives were then complexed with chitosan and carrageenan, respectively, to produce the nanocarriers. Positively charged nanoparticles of 180-270nm were obtained, evidencing ability to associate bovine serum albumin, which was selected as model protein. In PBS pH 7.4, pullulan-based nanoparticles were found to have a burst release of 30% of the protein, which maintained up to 24h. Nanoparticle size and zeta potential were preserved upon freeze-drying in the presence of appropriate cryoprotectants. A factorial design was approached to assess the cytotoxicity of raw materials and nanoparticles by the metabolic test MTT. Nanoparticles demonstrated to not cause overt toxicity in a respiratory cell model (Calu-3). Pullulan has, thus, demonstrated to hold potential for the production of nanoparticles with an application in protein delivery. 23604390 The relationship between cocaine self-administration and actigraphy-based measures of sleep in adult rhesus monkeys. RATIONALE: Clinical trials show that chronic cocaine users suffer from sleep disturbances and preclinical research has shown that acute sleep deprivation increases the rate of cocaine self-administration in rats. OBJECTIVE: This study examined the effect of cocaine self-administration on behavioral indices of sleep and alternatively the effect of sleep disruption on cocaine-maintained responding by rhesus monkeys. METHODS: Seven adult rhesus monkeys, fitted with Actical® activity monitors, were trained to respond under a concurrent choice paradigm with food (three 1.0-g pellets) and cocaine (0.003-0.3 mg/kg) or saline presentation. For each monkey, the lowest preferred dose of cocaine (>80 % cocaine choice) was determined. Activity data were analyzed during lights out (2000-0600) to determine sleep efficiency, sleep latency, and total activity counts. Subsequently, the monkeys' sleep was disrupted (every hour during lights-out period) the night prior to food-cocaine choice sessions. RESULTS: Self-administration of the preferred dose of cocaine resulted in a significant decrease in sleep efficiency, with a significant increase in total lights-out activity. Sleep disruption significantly altered behavioral indices of sleep, similar to those seen following cocaine self-administration. However, sleep disruption did not affect cocaine self-administration under concurrent choice conditions. CONCLUSIONS: Based on these findings, cocaine self-administration does appear to disrupt behavioral indices of sleep, although it remains to be determined if treatments that improve sleep measures can affect future cocaine taking. 23639540 Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of Dorsomorphin: The discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe. A structure-activity relationship of the 3- and 6-positions of the pyrazolo[1,5-a]pyrimidine scaffold of the known BMP inhibitors dorsomorphin, 1, LDN-193189, 2, and DMH1, 3, led to the identification of a potent and selective compound for ALK2 versus ALK3. The potency contributions of several 3-position substituents were evaluated with subtle structural changes leading to significant changes in potency. From these studies, a novel 5-quinoline molecule was identified and designated an MLPCN probe molecule, ML347, which shows >300-fold selectivity for ALK2 and presents the community with a selective molecular probe for further biological evaluation. 23415548 Stability of black cohosh triterpene glycosides and polyphenols: Potential clinical relevance. Concurrent to a clinical trial of black cohosh for menopausal hot flashes, the long-term stability of the black cohosh, over the duration of the clinical trial, was examined. Analytical results showed that the major constituents, both triterpene glycosides and polyphenols, were stable over the 3-year period of testing. These results indicate that a black cohosh product stored for several years in a controlled environment does not undergo significant changes in its major constituents. These results have implications not only for clinical research in natural products, but for basic science, as well as the dietary supplements industry. 23440054 The development of synthetic antitumour vaccines from mucin glycopeptide antigens. Based on important cell-biological and biochemical results concerning the structural difference between membrane glycoproteins of normal epithelial cells and epithelial tumour cells, tumour-associated glycopeptide antigens have been chemically synthesised and structurally confirmed. Glycopeptide structures of the tandem repeat sequence of mucin MUC1 of epithelial tumour cells constitute the most promising tumour-associated antigens. In order to generate a sufficient immunogenicity of these endogenous structures, usually tolerated by the immune system, these synthetic glycopeptide antigens were conjugated to immune stimulating components: in fully synthetic two-component vaccines either with T-cell peptide epitopes or with Toll-like receptor2 lipopeptide ligands or in three-component vaccines with both these stimulants. Alternatively, the synthetic glycopeptide antigens were coupled to immune stimulating carrier proteins. In particular, MUC1 glycopeptide conjugates with Tetanus toxoid proved to be efficient vaccines inducing very strong immune responses in mice. The antibodies elicited with the fully synthetic vaccines showed selective recognition of the tumour-associated glycopeptides as was shown by neutralisation and micro-array binding experiments. After booster immunisations, most of the immune responses showed the installation of an immunological memory. Immunisation with fully synthetic three-component vaccines induced immune reactions with therapeutic effects in terms of reduction of the tumour burden in mice or in killing of tumour cells in culture, while MUC1 glycopeptide-Tetanus toxoid vaccines elicited antibodies in mice which recognised tumour cells in human tumour tissues. The results achieved so far are considered to be promising for the development of an active immunisation against tumours. 23564566 Radiolabeled Heterobivalent Peptidic Ligands: an Approach with High Future Potential for in vivo Imaging and Therapy of Malignant Diseases. Two-pronged synergism: We review the recently developed approach of using heterobivalent peptide ligands that interact concomitantly with different receptors on tumor cells. These ligands exhibit highly favorable tumor-targeting properties and pave the way for the development of drugs for specific, sensitive, and noninvasive tumor imaging and therapy. 23561121 μ-Calpain is involved in the postmortem proteolysis of gizzard smooth muscle. Postmortem changes in proteins that have been implicated in affecting muscle integrity were examined in goose (GG) and duck (DG) gizzard smooth muscle stored at 5°C. GG and DG smooth muscles were sampled at 0, 1, 3 and 7day of storage. The pH was approximately 7 in both GG and DG samples during postmortem storage. Casein zymograms showed that 0-day μ-calpain activity was higher (p<0.05) in GG than in DG samples. As postmortem time progressed, μ-calpain was activated and autolyzed more extensively in GG than in DG samples. However, μ/m-calpain remained relatively stable in both samples. Western blots indicated that postmortem desmin degradation was more rapid in GG than in DG samples. In contrast, α-actinin remained nearly unchanged in both samples. Therefore, our results suggest that μ-calpain has an important role in the postmortem proteolysis of gizzard smooth muscle. 23514730 Baseline Markers of Inflammation Are Associated With Progression to Macroalbuminuria in Type 1 Diabetic Subjects. OBJECTIVEThe current study aimed to determine in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications cohort whether or not abnormal levels of markers of inflammation and endothelial dysfunction measured in samples collected at DCCT baseline were able to predict the development of macroalbuminuria.RESEARCH DESIGN AND METHODSLevels of inflammation and endothelial cell dysfunction biomarkers were measured in 1,237 of 1,441 patients enrolled in the DCCT study who were both free of albuminuria and cardiovascular disease at baseline. To test the association of log-transformed biomarkers with albuminuria, generalized logistic regression models were used to quantify the association of increased levels of biomarkers and development of abnormal albuminuria. Normal, micro-, and macroalbuminuria were the outcomes of interest.RESULTSIn the logistic regression models adjusted by DCCT treatment assignment, baseline albumin excretion rate, and use of ACE/angiotensin receptor blocker drugs, one unit increase in the standardized levels of soluble E-selectin (sE-selectin) was associated with an 87% increase in the odds to develop macroalbuminuria and one unit increase in the levels of interleukin-6 (IL-6), plasminogen activator inhibitor 1 (PAI-1; total and active), and soluble tumor necrosis factor receptors (TNFR)-1 and -2 lead to a 30-50% increase in the odds to develop macroalbuminuria. Following adjustment for DCCT baseline retinopathy status, age, sex, HbA1c, and duration of diabetes, significant associations remained for sE-selectin and TNFR-1 and -2 but not for IL-6 or PAI-1.CONCLUSIONSOur study indicates that high levels of inflammatory markers, mainly E-selectin and sTNRF-1 and -2, are important predictors of macroalbuminuria in patients with type 1 diabetes. 23538319 Exposure to 2,4-dichlorophenoxyacetic acid alters glucose metabolism in immature rat Sertoli cells. The purpose of this study was to determine the effects of 2,4-D, an herbicide used worldwide also known as endocrine disruptor, in Sertoli cell (SC) metabolism. Immature rat SCs were maintained 50h under basal conditions or exposed to 2,4-D (100nM, 10μM and 1mM). SCs exposed to 10μM and 1mM of 2,4-D presented lower intracellular glucose and lactate content. Exposure to 10μM of 2,4-D induced a significant decrease in glucose transporter-3 mRNA levels and phosphofructokinase-1 mRNA levels decreased in cells exposed to 100nM and 10μM of 2,4-D. Exposure to 100nM and 10μM also induced a decrease in lactate dehydrogenase (LDH) mRNA levels while the LDH protein levels were only decreased in cells exposed to 1mM of 2,4-D. Exposure to 2,4-D altered glucose uptake and metabolization in SCs, as well as lactate metabolism and export that may result in impaired spermatogenesis. 23412114 Inhibition of Gβγ-subunit signaling potentiates morphine-induced antinociception but not respiratory depression, constipation, locomotion, and reward. Inhibition of Gβγ-subunit signaling to phospholipase C β3 has been shown to potentiate morphine-mediated antinociception while attenuating the development of tolerance and dependence in mice. The objective of this study was to determine the effect of Gβγ-subunit inhibition on antinociception and other pharmacological effects, such as respiratory depression, constipation, and hyperlocomotion, mediated by the μ-opioid receptor. The Gβγ-subunit inhibitor, gallein, was administered to C57BL/6J mice by intraperitoneal injection before morphine, and data were compared with mice treated with vehicle, morphine, or gallein alone. Morphine-induced antinociception was measured using the 55°C warm-water tail-withdrawal test. Pretreatment with gallein produced a dose-dependent potentiation of morphine-mediated antinociception, producing up to a 10-fold leftward shift in the morphine dose-response curve and extending the duration of antinociception induced by a single dose of morphine. Gallein pretreatment also prevented acute antinociceptive tolerance induced by morphine. In contrast, the dose-dependent respiratory depression and hyperlocomotion induced by morphine were not potentiated by gallein pretreatment. Similarly, gallein pretreatment did not potentiate morphine-conditioned place preference responses or morphine-induced constipation, as measured as a reduction in excreta. These results suggest that selectively inhibiting Gβγ-mediated signaling may selectively increase μ-opioid receptor-mediated antinociception without matching increases in adverse physiological effects. 23287708 Sunset yellow FCF, a permitted food dye, alters functional responses of splenocytes at non-cytotoxic dose. Sunset yellow FCF (SY), a permitted food color, is extensively used in various food preparations and quite often exceeds the permissible levels (100-200 mg/kg). Several toxicity studies on SY are reported, however immunomodulatory properties have not been explored yet. To investigate the immunotoxic properties of SY, splenocytes were isolated, cultured and subjected to mitogen stimulated proliferation assay (lipopolysaccharide, LPS or concanavalin A, Con A), mixed lymphocyte reaction (MLR) assay, immunophenotypic analysis of cell surface receptor expression and assay for cytokines release in the culture supernatants were performed in the presence of SY. Since SY did not exhibit any cytotoxicity up to 250 μg/ml, this dose was used for further studies. It was observed that SY (250 μg/ml) significantly (p<0.05) suppressed the mitogen induced proliferation of splenocytes and MLR response. Further, immunophenotypic analysis revealed that SY alters the relative expression of CD3e/CD4/CD8 in T cells and CD19 in B-cells. Consistent with the suppression of T-cell and B-cell responses and altered surface receptor expression, SY also lowered the expression of IL2, IL4, IL6, IL-17, IFN-γ and TNF-α cytokines. These results suggest that non-cytotoxic dose of SY may have immunomodulatory effects. 23411280 Inhibitory activity of Filipendula ulmaria constituents on recombinant human histidine decarboxylase. Histidine decarboxylase (HDC) catalyses the formation of histamine, a bioactive amine. Agents that control HDC activity are beneficial for treating histamine-mediated symptoms, such as allergies and stomach ulceration. We searched for inhibitors of HDC from the ethyl acetate extract of the petal of Filipendula ulmaria, also called meadowsweet. Rugosin D, rugosin A, rugosin A methyl ester (a novel compound), and tellimagrandin II were the main components; these 4 ellagitannins exhibited a non-competitive type of inhibition, with K(i) values of approximately 0.35-1 μM. These K(i) values are nearly equal to that of histidine methyl ester (K(i)=0.46 μM), an existing substrate analogue inhibitor. Our results show that food products contain potent HDC inhibitors and that these active food constituents might be useful for designing clinically available HDC inhibitors. 23265474 Comparative formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in creatinine/phenylalanine and creatinine/phenylalanine/4-oxo-2-nonenal reaction mixtures. The comparative formation of the heterocyclic aromatic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in both creatinine/phenylalanine (CRN/Phe) and creatinine/phenylalanine/4-oxo-2-nonenal (CRN/Phe/ON) systems was studied to analyse the ability of lipid-derived reactive carbonyls to promote PhIP formation. Although PhIP was produced to some extent in the CRN/Phe system, the presence of the oxidized lipid increased considerably the amount of PhIP produced. This increase seemed to be a consequence of the decrease in the E(a) of the reaction when the lipid was present, which diminished from 112.9 to 80.9 kJ/mol. On the other hand, the addition of the lipid did not seem to produce PhIP by an alternative mechanism because PhIP was formed analogously in both CRN/Phe and CRN/Phe/ON systems as a function of pH, creatinine concentration, phenylalanine concentration, time, temperature, oxygen concentration in the reaction atmosphere, and the addition of different amounts of ammonia. All these results suggest that the ability of lipid oxidation products to produce PhIP is related to their capacity to induce the Strecker degradation of phenylalanine to phenylacetaldehyde. Therefore, any other reactive carbonyl compound that can produce the Strecker degradation of phenylalanine should also be considered as a potential inducer of PhIP formation under appropriate conditions. 23109425 Systematic identification of functional residues in mammalian histone H2AX. The histone variant H2AX is a principal component of chromatin involved in the detection, signaling, and repair of DNA double-strand breaks (DSBs). H2AX is thought to operate primarily through its C-terminal S139 phosphorylation, which mediates the recruitment of DNA damage response (DDR) factors to chromatin at DSB sites. Here, we describe a comprehensive screen of 67 residues in H2AX to determine their contributions to H2AX functions. Our analysis revealed that H2AX is both sumoylated and ubiquitylated. Individual residues defective for sumoylation, ubiquitylation, and S139 phosphorylation in untreated and damaged cells were identified. Specifically, we identified an acidic triad region in both H2A and H2AX that is required in cis for their ubiquitylation. We also report the characterization of a human H2AX knockout cell line, which exhibits DDR defects, including p53 activation, following DNA damage. Collectively, this work constitutes the first genetic complementation system for a histone in human cells. Finally, our data reveal new roles for several residues in H2AX and define distinct functions for H2AX in human cells. 22616933 Does the light influence astaxanthin production in Xanthophyllomyces dendrorhous? Astaxanthin (C40H52O4) is an important natural pigment that has considerable promising applications in human health. Until now, many efforts were made aimed to develop economically sustainable bioprocesses alternative to the chemical synthesis, to satisfy the increasing demand of this ketocarotenoid from feed, food and cosmetic industries. The extraction of natural astaxanthin from the yeast Xanthophyllomyces dendrorhous till now seems to be rather expensive if compared with chemically synthesized astaxanthin. In this article, astaxanthin production by Xanthophyllomyces dendrorhous under two different conditions was studied: a first effort was made using a conventional reactor while a second using an enlightened one. This research was aimed also to optimise astaxanthin production by testing the influence of the light and of some nutrient sources. From fermentation tests, an astaxanthin yield ranging about 970 µg g(-1) was obtained after fed batch cultivation in the conventional reactor. In the enlightened reactor lower values, about 930 µg g(-1), were found. 23281044 Hydrosoluble benzo[e]pyridoindolones as potent inhibitors of aurora kinases. Aurora kinases play an essential role in mitotic progression and are potentially druggable targets in cancer therapy. We identified benzo[e]pyridoindoles (BePI) as powerful aurora kinase inhibitors. Their efficiency was demonstrated both in enzymatic inhibition studies and in cell culture assays. New BePI molecules were synthesized, and a structure-activity relationship study was conducted with the aim of improving the activity and solubility of the lead compound. Tetracyclic BePI derivatives are characterized by a particular curved shape, and the presence of an oxo group on the pyridine ring was found to be required for aurora kinase B inhibition. New hydrosoluble benzo[e]pyridoindolones were subsequently designed, and their efficacy was tested by a combination of cell-cycle analysis and time-lapse experiments in live cells. The most active BePI derivative, 13 b, inhibited the cell cycle, drove cells to polyploidy, and eventually induced apoptosis. It exhibited high antiproliferative activity in HeLa cells with an IC(50) value of 63 nM. Relative to compounds tested in clinical trials, this antiproliferative potency places 13 b among the top 10 aurora kinase inhibitors. Our results justify further in vivo evaluation in preclinical animal models of cancer. 23188717 Mechanism of the antiproliferative activity of some naphthalene diimide G-quadruplex ligands. G-quadruplexes are higher-order nucleic acid structures that can form in G-rich telomeres and promoter regions of oncogenes. Telomeric quadruplex stabilization by small molecules can lead to telomere uncapping, followed by DNA damage response and senescence, as well as chromosomal fusions leading to deregulation of mitosis, followed by apoptosis and downregulation of oncogene expression. We report here on investigations into the mechanism of action of tetra-substituted naphthalene diimide ligands on the basis of cell biologic data together with a National Cancer Institute COMPARE study. We conclude that four principal mechanisms of action are implicated for these compounds: 1) telomere uncapping with subsequent DNA damage response and senescence; 2) inhibition of transcription/translation of oncogenes; 3) genomic instability through telomeric DNA end fusions, resulting in mitotic catastrophe and apoptosis; and 4) induction of chromosomal instability by telomere aggregate formation. 23085095 The exposure of highly toxic aconitine does not significantly impact the activity and expression of cytochrome P450 3A in rats determined by a novel ultra performance liquid chromatography-tandem mass spectrometric method of a specific probe buspirone. Aconitum species are widely used to treat rheumatism, cardiovascular diseases, and tumors in China and other Asian countries. The herbs are always used with drugs such as paclitaxel. Aconitine (AC) is one of the main bioactive/high-toxic alkaloids of Aconitum roots. AC is metabolized by cytochrome P450 (CYP) 3A. However, whether AC inhibits/induces CYP3A, which causes drug-drug interaction (DDI) is unclear. Our study aims to explore the potent effects of AC, as a marker component of Aconitum, on CYP3A using the probe buspirone in rats. The effects of oral AC on pharmacokinetics of buspirone were evaluated. CYP3A activity and protein levels in rat liver microsomes pretreated with oral AC were also measured using in vitro buspirone metabolism and Western blot. Buspirone and its major metabolites 1-(2-pyrimidinyl)piperazine and 6'-hydroxybuspirone were determined using a newly validated UPLC-MS/MS method. Single dose and 7-day AC administration at 0.125mg/kg had no effect on CYP3A activity since no change in the formation of 1-(2-pyrimidinyl)piperazine and 6'-hydroxybuspirone. CYP3A activity and protein levels in liver microsomes were also not affected by 7-day AC pretreatment at 0.125mg/kg. Therefore, AC neither inhibits nor induces CYP3A in rats, indicating AC does not cause CYP3A-related DDI in the liver. 23201927 Cardioprotective effect of salvianolic acid B against arsenic trioxide-induced injury in cardiac H9c2 cells via the PI3K/Akt signal pathway. The clinical use of arsenic trioxide (ATO), a potent anti-neoplastic agent, is often limited because of its severe cardiotoxicity. Salviae miltiorrhiza is widely used for the treatment of cardiovascular diseases. One of the most abundant ingredients of S. miltiorrhiza is salvianolic acid B (Sal B). The present study was designed to evaluate whether Sal B protects against ATO-induced cardiac cell injury in vitro. With MTT cell viability assay, LDH release, ROS generation, caspase-3 activity assay and Hoechst 33342/PI staining, we found that Sal B pretreatment provided significantly protection against ATO-induced cell death. The effect was correlated with the activation of the PI3K/Akt signal pathway. Conversely, blocking Akt activation with the PI3K inhibitor LY294002 effectively suppressed the protective effect of Sal B against ATO-induced cell apoptosis. In addition, the PI3K inhibitor partially blocked the effects of Sal B on the upregulation of Bcl-2 and Bcl-xl protein expression, and downregulation of Bax protein expression. Collectively, the results showed that Sal B decreased the apoptosis and necrosis of H9c2 cardiomyocytes caused by ATO treatment, and PI3K played a crucial role in enhancing cell survival during this process. These observations indicate that Sal B has the potential to exert cardioprotective effects against ATO toxicity. 23281180 Practical synthesis of (20S)-10-(3-aminopropyloxy)-7-ethylcamptothecin, a water-soluble analogue of camptothecin. A robust, practical synthesis of (20S)-10-(3-aminopropyloxy)-7-ethylcamptothecin (T-2513, 5), which is a water-soluble analogue of camptothecin, has been developed. The key step in this synthesis is a highly diastereoselective ethylation at the C20 position by using N-arylsulfonyl-(R)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ester as a chiral auxiliary, which affords the key intermediate ethyl-(S)-2-acyloxy-2-(6-cyano-5-oxo-1,2,3,5-tetrahydroindolizin-7-yl)butanoate (8k) in 93% yield and 87% de. Optically pure compound 8k was obtained by a single recrystallization from acetone and its further elaboration through Friedlander condensation afforded compound 5. This synthesis does not require any chromatographic purification steps and can provide compound 5 on a multi-gram scale in 6.3% overall yield (16 steps). 23583903 Effect of bioactive peptide of Carapax Trionycis on TGF-β1-induced intracellular events in hepatic stellate cells. ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicines for hepatic fibrosis therapy, Carapax Trionycis is used usually as an indispensable component and has a long history of medical use in China. Previous studies have demonstrated that extracts of Carapax Trionycis were able to protect liver against fibrosis in CCl4 animal models. AIM OF THE STUDY: The purpose of this study is to verify the inhibitory effect and the underlying mechanisms of Carapax Trionycis extract peptide (CTEP) on activated hepatic stellate cells which play a central role in liver fibrogenesis. MATERIALS AND METHODS: Hepatic stellate cells induced by TGF-β1 were applied to evaluate the anti-fibrotic effect of CTEP in vitro. MTS assay, enzyme-linked immunosorbent assay and western blotting were then used to further investigate the molecular mechanisms. RESULTS: The results show that the contents of collagen I, collagen III and TIMP-1 were significantly inhibited and the level of collagen I, collagen III, p-Smad 3, TIMP-1 and α-SMA proteins decreased significantly in a concentration-dependence manner after treatment with CTEP. Interestingly, the level of Smad 3 protein was not different significantly. CONCLUSIONS: Our data indicate that CTEP efficiently inhibits cultured HSC-T6 cell activation and proliferation via the TGF-β1/Smad pathway as well as by the elimination of the extracellular matrix. 22438091 Effects of sinensetin on lipid metabolism in mature 3T3-L1 adipocytes. Sinensetin is a rare polymethoxylated flavone found in certain citrus fruits. In this study, we investigated the effects of sinensetin on lipid metabolism in mature 3T3-L1 adipocytes. Sinensetin decreased the expression of sterol regulatory element-binding protein 1c (SREBP1c), suggesting its antiadipogeneic property via downreguation of SREBP1c. Also, sinensetin increased the phosphorylation of protein kinase A and hormone-sensitive lipase, indicating its lipolytic property via a cAMP-mediated signaling pathway. Moreover, sinensetin inhibited insulin-stimulated glucose uptake by decreasing the phosphorylation of insulin receptor substrate and Akt. Furthermore, sinensetin increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase. It also upregulated mRNA expression of carnitine palmitoyltransferase-1a, suggesting that sinensetin enhances fatty acid β-oxidation through the AMPK pathway. Taken together, these results suggest that sinensetin may have potential as a natural agent for prevention/improvement of obesity. 23411193 Dispersive liquid-liquid microextraction combined with field-amplified sample stacking in capillary electrophoresis for the determination of non-steroidal anti-inflammatory drugs in milk and dairy products. Dispersive liquid-liquid microextraction (DLLME) was coupled with field-amplified sample stacking in capillary electrophoresis (FASS) for the determination of five non-steroidal anti-inflammatory drugs (NSAIDs) in bovine milk and dairy products. After extraction, the enriched analytes were back-extracted into a basic aqueous solution for injection into CE. Under optimum conditions, enrichment factors were in the range 46-229. Limits of detection of the analytes ranged from 3.0 to 13.1 μg kg(-1) for all matrices analysed. Calibration graphs showed good linearity with coefficients of determination (R(2))≥ 0.9915 and relative standard deviations (RSD%) of the analyses in the range of 0.6-6.2% (n=5). Recoveries of all NSAIDs from bottled milk, raw milk, yogurt and white cheese samples were in the ranges of 86.6-109.3%, 84.3-100.5%, 77.4-107.3%, and 90.9-101.6%, respectively. DLLME-FASS-CE was demonstrated to be a rapid and convenient method for the determination of NSAIDs in milk and dairy products. 22491024 Synergy between L-DOPA and a novel positive allosteric modulator of metabotropic glutamate receptor 4: implications for Parkinson's disease treatment and dyskinesia. Group III metabotropic glutamate (mGlu) receptors are localized in presynaptic terminals within basal ganglia (BG) circuitry that become hyperactive due to dopamine depletion in Parkinson's disease (PD). For this reason, group III mGlu receptors, in particular mGlu4, have been considered as key strategic targets for non-dopaminergic pharmacological treatments aimed at modulating these synapses, without producing the well known side-effects of l-DOPA, in particular the highly disabling l-DOPA-induced dyskinesia (LID). Herein we add physiological and functional support to this hypothesis using Lu AF21934, a novel selective and brain-penetrant mGlu4 receptor positive allosteric modulator (PAM) tool compound. By in vitro electrophysiological recordings we demonstrate that Lu AF21934 inhibits corticostriatal synaptic transmission and enhances the effect of the orthosteric mGlu4 receptor-preferred agonist LSP1-2111. In naïve rats, Lu AF21934 dose-dependently (10 and 30 mg/kg) alleviated haloperidol-induced catalepsy. In hemiparkinsonian rats (unilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta), Lu AF21934 alone did not affect akinesia at the doses tested (10 and 30 mg/kg). However, when Lu AF21934 was combined with sub-threshold doses of l-DOPA (1 and 5 mg/kg), it acted synergistically in alleviating akinesia in a dose-dependent manner and, notably, also reduced the incidence of LID but not its severity. Interestingly, these effects occurred at Lu AF21934 brain free concentrations that showed functional activity in in vitro screens (calcium flux and electrophysiology assays). These results support the potential for antiparkinsonian clinical use of a combined treatment consisting in l-DOPA and a mGlu4 receptor PAM to reduce efficacious l-DOPA doses (generally known as l-DOPA sparing), while maintaining the same benefit on PD motor troubles, and at the same time minimizing the development of LID. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'. 23402861 Elemental composition of dog foods using nitric acid and simulated gastric digestions. Eighteen dry dog foods obtained commercially in the United States were digested using microwave assisted nitric acid digestion and a simulated gastric digestion. Digests were analysed for 23 elements using inductively coupled plasma-mass spectrometry. Data, expressed as dry matter concentrations, were compared to published nitric acid digestion results. Nitric acid data obtained in the present study were not statistically different from published data, with the exception of Mo, Sn, Sb, Tl and Th. However, significant differences in individual intra-sample results were observed between published studies and the present work. Simulated gastric digestions demonstrated lower extraction efficiencies (<50% nitric acid digestions) that were statistically significant. Much lower bioavailability was observed for Al, Ba and Pb. In general, elemental concentrations were determined to be lower than the appropriate Mineral Tolerance Limit or consistent with background concentrations in foodstuffs. Evaluation against Reference Doses (RfDs) showed concentrations for many elements obtained by nitric acid digestion to be above RfD levels. However, the respective simulated gastric digestion data were below or only moderately elevated above RfDs. Only arsenic displayed median and maximum concentrations at factors of five and ten above the relevant RfD. 23500333 DNA barcoding in plants: Evolution and applications of in silico approaches and resources. Bioinformatics has played an important role in the analysis of DNA barcoding data. The process of DNA barcoding initially involves the available data collection from the existing databases. Many databases have been developed in recent years, e.g. MMDBD [Medicinal Materials DNA Barcode Database], BioBarcode, etc. In case of non-availability of sequences, sequencing has to be done in vitro for which a recently developed software ecoPrimers can be helpful. This is followed by multiple sequence alignment. Further, basic sequence statistics computation and phylogenetic analysis can be performed by MEGA and PHYLIP/PAUP tools respectively. Some of the recent tools for in silico and statistical analysis specifically designed for barcoding viz. CAOS (Character Based DNA Barcoding), BRONX (DNA Barcode Sequence Identification Incorporating Taxonomic Hierarchy and within Taxon Variability), Spider (Analysis of species identity and evolution, particularly DNA barcoding), jMOTU and Taxonerator (Turning DNA Barcode Sequences into Annotated OTUs), OTUbase (Analysis of OTU data and taxonomic data), SAP (Statistical Assignment Package), etc. have been discussed and analysed in this review. The paper presents a comprehensive overview of the various in silico methods, tools, softwares and databases used for DNA barcoding of plants. 23435689 Surface-enhanced Raman scattering spectra of adsorbates on Cu₂O nanospheres: charge-transfer and electromagnetic enhancement. Surface-enhanced Raman scattering (SERS) spectra of 4-mercaptobenzoic acid (4-MBA) have been investigated on the surface of Cu2O nanospheres. The SERS signals were believed to originate from the static chemical enhancement, resonant chemical enhancement and electromagnetic enhancement. The coupling between the adsorbates and the semiconductor, evidenced by the shift in absorption spectrum of modified Cu2O and the enhancement of non-totally symmetric modes of the 4-MBA and 4-mercaptopyridine (4-MPY) molecules, were invoked to explain the experimental results. Furthermore, simulations were employed to investigate the nature of the enhancement mechanisms operative between the molecules and the semiconductor. Density functional theory (DFT) calculations suggested a charge transfer (CT) transition process between the molecules and the Cu2O nanospheres. Three-dimensional finite-difference time domain (3D-FDTD) simulations were conducted to map out the electromagnetic field around the Cu2O nanospheres. The experimental and simulation results have revealed the promise of the Cu2O nanospheres as a good SERS substrate and the prospect of using the SERS substrate as a valuable tool for in situ investigation and assay of the adsorption behavior on semiconductor surfaces. 23200735 Effects of quercetin on mRNA expression of steroidogenesis genes in primary cultures of Leydig cells treated with atrazine. The effect of the phytoestrogen, quercetin (QT) on the reproductive toxicity of atrazine (ATZ) was explored in interstitial Leydig cells (ILCs). We measured the mRNA expressions of steroidogenesis genes: steroidogenic acute regulatory protein (StAR), 3β-hydroxysteroid dehydrogenase (3β-HSD), cytochrome-P450 (CYP) 11A1, insulin-like factor 3 (INSL-3), CYP17A1, inhibin-α (INH-α), androgen receptor (AR), estrogen receptor-α (ER-α), and luteinising hormone receptor (LHR) in isolated ILCs by real-time-PCR after cultured cells were treated in vitro with ATZ (232 μM) and QT (50 μM). The mRNA expression of tested genes increased with ATZ treatment and was normalized by quercetin except AR and ER-α expression. Treatment of cells with QT alone (15-50 μM) caused a dose-dependent increase in AR and ER-α mRNA expression. We also found that QT (50 μM) increased the expressions of AR and ER-α in the presence of a sub-threshold level of cyclic-AMP at 1h culture period to the levels seen with maximal stimulation of cyclic-AMP. Furthermore, the expressions of tested genes were unaffected by cyclic-AMP at 6h when the stimulatory effects of ATZ on tested genes were sustained. These findings suggest that ATZ may stimulate the expression of tested steroidogenesis genes in ILCs via a mechanism independent of cyclic-AMP which was partially antagonize by QT. 23602985 Chronic social stress during adolescence: Interplay of paroxetine treatment and ageing. Exposure to chronic stress during developmental periods is a risk factor for a number of psychiatric disorders. While the direct effects of stress exposure have been studied extensively, little is known about the long-lasting effects and the interaction with ageing. The same holds true for the treatment with selective serotonin reuptake inhibitors (SSRIs), which have been shown to prevent or reverse some stress-induced effects. Here, we studied the direct and long-lasting impact of chronic social stress during adolescence and the impact of chronic treatment with the SSRI paroxetine in adulthood and aged animals. Therefore, male CD1 mice at the age of 28 days were subjected to 7 weeks of chronic social stress. Treatment with paroxetine was performed per os with a dosage of 20 mg/g BW. We were able to reverse most of the effects of chronic social stress in adult mice (4 months old) and to some extend in aged animals (15 months old) with the SSRI treatment. Especially the regulation of the HPA axis seems to be affected in aged mice with a shift to the use of vasopressin. Our results demonstrate that chronic stress exposure and antidepressant treatment at the end of the developmental period can have a significant and long-lasting impact, highly relevant for healthy ageing. 23627699 Active Layer-Incorporated, Spectrally-Tuned Au/SiO2 Core/Shell Nanorod-Based Light Trapping for Organic Photovoltaics. We demonstrated that incorporation of octadecyltrimethoxysilane (OTMS) functionalized, spectrally tuned, gold/silica (Au/SiO2) core/shell nanospheres and nanorods into the active layer of an organic photovoltaic (OPV) device led to an in increase photo conversion efficiency (PCE). A silica shell layer was added onto Au core nanospheres and nanorods in order to provide an electrically insulating surface that does not interfere with carrier generation and transport inside the active layer. Functionalization of the Au/SiO2 core/shell nanoparticles with the OTMS organic ligand was then necessary in order to transfer the Au/SiO2 core/shell nanoparticles from an ethanol solution into an OPV polymer-compatible solvent, such as dichlorobenzene (DCB). The OTMS-functionalized Au/SiO2 core/shell nanorods and nanospheres were then incorporated into the active layers of two OPV polymer systems: a poly(3-hexylthiophene):[6,6]-phenyl-C61-butyric acid methyl ester (P3HT:PCB60M) OPV device and a poly[2,6-4,8-di(5-ethylhexylthienyl)benzo[1,2-b;3,4-b]dithiophene-alt-5-dibutyloctyl-3,6-bis(5-bromothiophen-2-yl) pyrrolo[3,4-c]pyrrole-1,4-dione] (PBDTT-DPP:PC60BM) OPV device. For the P3HT:PC60BM polymer with a band edge of ~700 nm, the addition of the core/shell nanorods with an aspect ratio (AR) of ~2.5 (extinction peak ~670 nm) resulted in a 7.1% improvement in PCE, while for the PBDTT-DPP:PC60BM polymer with a band edge ~860 nm, the addition of core/shell nanorods with an AR of ~4 (extinction peak ~830 nm) resulted in a 14.4% improvement in PCE. The addition of Au/SiO2 core/shell nanospheres to the P3HT:PC60BM-polymer resulted in a 2.7% improvement in PCE, while their addition to a PBDTT-DPP:PC60BM polymer resulted in a 9.1% improvement. The PCE and Jsc enhancements were consistent with external quantum efficiency (EQE) measurements and the EQE enhancements spectrally matched the extinction spectra of Au/SiO2 nanospheres and nanorods in both OPV polymer systems. 23557230 Determination of Specific Binding Interactions at l-Cystine Crystal Surfaces with Chemical Force Microscopy. The pathogenesis of l-cystine kidney stones involves four critical steps: nucleation, crystal growth, crystal aggregation, and crystal adhesion to cells. Although inhibition of crystal growth by l-cystine "imposters" at l-cystine crystal surfaces has been suggested as a plausible route for the suppression of stones, understanding the factors that govern crystal-crystal aggregation and adhesion of crystals to epithelial cells also is essential for devising strategies to mitigate l-cystine stone formation. Chemical force microscopy performed with atomic force microscope tips decorated with functional groups commonly found in urinary constituents that likely mediate aggregation and attachment (e.g., COOH, NH2, SH, CH3, OH) revealed signatures that reflect differences in the chemical affinity of these groups for the (001) and {100} faces of the naturally occurring hexagonal form of l-cystine single crystals and the {110} faces of the non-native tetragonal form. These signatures can be explained by the different chemical compositions of the crystal faces, and they reveal a remarkable binding specificity of the thiol group for the sulfur-rich {100} and {110} faces of the hexagonal and tetragonal forms, respectively. Collectively, these observations suggest that alterations of the crystal habit and polymorph by crystal growth inhibitors may not affect crystal aggregation or adhesion to cells significantly. 23060409 Exposures to 1,3-dimethylamylamine-containing products reported to Texas poison centers. 1,3-Dimethylamylamine (DMAA) is an ingredient in a number of weight loss and exercise performance enhancing products. However, information on the safety of DMAA-containing products is limited. Exposures to DMAA-containing products reported to Texas poison centers during 2010-2011 were identified and selected factors were examined. A total of 56 exposures were found, of which 75.0% were reported during 2011. OxyElite Pro™ was the reported product in 80.4% of the exposures. The patients were 51.8% male and 55.4% age ≤5 years. The patient was managed on site (such as at home) in 57.1% of the cases, and the exposure was known or expected to result in an outcome that was classified as not serious in 80.4%. The most frequently reported clinical effects were tachycardia (28.6%), nausea (16.1%), and vomiting (12.5%). The most common treatments were dilution (41.1%), food (19.6%), and activated charcoal (14.3%). It should be noted that the adverse clinical effects may be due to other ingredients in the DMAA-containing products, such as caffeine. 23428403 Cyclopia maculata and Cyclopia subternata (honeybush tea) inhibits adipogenesis in 3T3-L1 pre-adipocytes. The stems, leaves and flowers of Cyclopia have been consumed as a herbal tea 'honeybush tea' to treat various medical ailments since the 19th century. Plant polyphenols are reported to inhibit adipogenesis in cell and animal models of obesity. The aim of this study was to assess the effect of hot water extracts of two Cyclopia species, C. maculata and C. subternata on obesity in an in vitro model. The total polyphenol content of unfermented C. subternata, unfermented C. maculata and fermented C. maculata extracts was 25.6, 22.4 and 10.8g GAE/100g, respectively. The major compounds present in the extracts were: the flavonoid, phloretin-3',5'-di-C-glucoside in C. subternata, the xanthone, mangiferin in unfermented C. maculata and the flavanone, hesperidin in fermented C. maculata. All of the plant extracts inhibited intracellular triglyceride and fat accumulation, and decreased PPARγ2 expression. The higher concentrations of unfermented C. maculata (800 and 1600μg/ml) and C. subternata (1600μg/ml) were cytotoxic in terms of decreased mitochondrial dehydrogenase activity. Both fermented and unfermented C. maculata, at concentrations greater than 100μg/ml, decreased cellular ATP content. Cyclopia maculata and C. subternata inhibit adipogenesis in vitro, suggesting their potential as anti-obesity agents. 23321259 Synthesis and evaluation of antibacterial activity of 7-alkyloxy-4,5-dihydro-imidazo[1,2-a]quinoline derivatives. In this study, a series of 7-alkyloxy-4,5-dihydro-imidazo[1,2-a]quinoline derivatives was synthesized and tested for their antibacterial activity against various bacterial strains. Most of the compounds exhibited potential antibacterial activity against gram-negative and gram-positive bacteria. Compound 7p (7-heptyloxy-4,5-dihydro-imidazo[1,2-a]quinoline) was found to be the most potent inhibitor. The minimum inhibitory concentration (MIC) of compound 7p against Escherichia coli was 0.5 μg/mL, better than that of reference agent ciprofloxacin and amoxicillin. Furthermore, compound 7p exhibited a modest activity against several gram-negative bacterial strains at a dose range of 2-64 μg/mL. 23561223 Impact of pectin type on the storage stability of black currant (Ribes nigrum L.) anthocyanins in pectic model solutions. The effects of different pectins on the stabilisation of black currant anthocyanins in viscous model solutions at pH 3.0 were investigated. For this purpose, low esterified amidated (AM), low (LM) and high (HM) methoxylated citrus and apple pectins and a sugar beet pectin were added to a purified anthocyanin extract (ACN-E) and to an extract containing anthocyanins and non-anthocyanin phenolics (PP-E). Model systems were stored at 20±0.5°C in the dark. Anthocyanin contents were monitored by HPLC analysis over a period of 18weeks, and half-life and destruction values were calculated. In all pectic model solutions anthocyanin stability was significantly improved compared to stability of the extracts without added pectins (blank). Best stabilisation was obtained with AM pectin, followed by LM and HM pectins. In model systems containing citrus pectins, anthocyanin stabilisation was better compared to that of apple pectins having similar degrees of esterification and amidation, respectively. This was primarily due to the strong interaction of delphinidin glycosides with the citrus pectins, whereas stabilisation of cyanidin derivatives was less important. Sugar beet pectin improved anthocyanin stability only to a limited extent. In the presence of non-anthocyanin phenolics (PP-E) the impact of the pectin source was even more pronounced than the effect of the pectin type. Addition of citrate to pectic systems accelerated anthocyanin decay. Stabilising effects of pectins were hardly noticeable when evaluating total phenolic content (TPC, Folin-Ciocalteu) and antioxidant capacity during storage. Highest TPC, TEAC- and FRAP values were observed in systems containing citrus pectin, which was in contrast to sugar beet pectin, where values fell below those of the blank after storage. 23454514 Synthesis, evaluation and absolute configuration assignment of novel dihydropyrimidin-2-ones as picomolar sodium iodide symporter inhibitors. A small library of dihydropyrimidin-2-ones (DHPMs) was synthesized and evaluated for their potency to block iodide entrapment in rat thyroid cells. Synthesis was achieved using the multicomponent Biginelli reaction. Twelve compounds were tested for the inhibition of sodium iodide symporter (NIS) in a cell-based assay. One newly synthesized derivative exhibited a remarkably strong activity, with a half-maximum inhibitory concentration value (IC50) of 65 pM. Three DHPMs were further resolved from racemates using chiral HPLC and absolute configurations were assigned using circular dichroism spectroscopy. Biological evaluation showed that most of the activity against NIS resides in one enantiomer. This study provides new insights for the development of anti-thyroid drugs, as well as for the synthesis of novel pharmacological tools designed to investigate iodide transport mechanisms at cellular and molecular levels. 23267695 Electrical method to quantify nanoparticle interaction with lipid bilayers. Understanding as well as rapidly screening the interaction of nanoparticles with cell membranes is of central importance for biological applications such as drug and gene delivery. Recently, we have shown that "striped" mixed-monolayer-coated gold nanoparticles spontaneously penetrate a variety of cell membranes through a passive pathway. Here, we report an electrical approach to screen and readily quantify the interaction between nanoparticles and bilayer lipid membranes. Membrane adsorption is monitored through the capacitive increase of suspended planar lipid membranes upon fusion with nanoparticles. We adopt a Langmuir isotherm model to characterize the adsorption of nanoparticles by bilayer lipid membranes and extract the partition coefficient, K, and the standard free energy gain by this spontaneous process, for a variety of sizes of cell-membrane-penetrating nanoparticles. We believe that the method presented here will be a useful qualitative and quantitative tool to determine nanoparticle interaction with lipid bilayers and consequently with cell membranes. 23387306 Photoelectron and electron momentum spectroscopy of tetrahydrofuran from a molecular dynamical perspective. The results of experimental studies of the valence electronic structure of tetrahydrofuran employing He I photoelectron spectroscopy as well as Electron Momentum Spectroscopy (EMS) have been reinterpreted on the basis of Molecular Dynamical simulations employing the classical MM3 force field and large-scale quantum mechanical simulations employing Born-Oppenheimer Molecular Dynamics in conjunction with the dispersion corrected ωB97XD exchange-correlation functional. Analysis of the produced atomic trajectories demonstrates the importance of thermal deviations from the lowest energy path for pseudorotation, in the form of considerable variations of the ring-puckering amplitude. These deviations are found to have a significant influence on several outer-valence electron momentum distributions, as well as on the He I photoelectron spectrum. 23561179 Inhibition kinetics of lipid oxidation of model foods by using antioxidant extract of fermented soybeans. Fermentation by using Aspergillus oryzae has been reported to increase antioxidant activity of soybeans significantly. The effectiveness of the extract from fermented soybeans was studied in 3 model foods with different complexities, i.e., linoleic acid emulsion, sunflower oil emulsions and bulk sunflower oil. For the emulsion systems, oxidation at two different pH values (4.5 and 7) was also compared. A reparameterised logistic equation was used to describe and to predict the experimental data. In general, a good agreement between experimental trends and simulated data from the model was found. A crude antioxidant extract (5mg/g) showed a comparable antioxidant activity to 0.26mg/g of butylated hydroxytoluene (BHT) in the linoleic acid emulsions. The extract exhibited a better capability to retard primary products in the linoleic acid systems than the secondary products. The opposite effect was observed in the bulk sunflower oil and its emulsion systems. 23266503 Effects of baicalein on apoptosis, cell cycle arrest, migration and invasion of osteosarcoma cells. Baicalein is a bioactive flavonoid that is widely used in ancient China. However, its effects on the most common primary malignant bone tumor, osteosarcoma, remain unknown. In the present study, we investigated the effects of baicalein in osteosarcoma cells. Our results indicate baicalein might be an efficacious anti-osteosarcoma drug. We found that baicalein could inhibit cell proliferation in a time- and dose-dependent manner. Additionally, we demonstrated that baicalein promotes osteosarcoma cell apoptosis, and our mechanistic studies suggest that this is mediated by caspase activation, especially caspase-3. We also showed that the down-regulation of Bcl-2 and concurrent increase in Bax and Bim levels contribute to the apoptosis induced by baicalein. In addition, we observed that baicalein induces G1 cell cycle arrest by decreasing cyclin D1 and cyclin-dependent kinase 4 (CDK4). Furthermore, our data verifies that baicalein can reduce osteosarcoma cell adhesion, migration and invasion in vitro, which indicates its potential to inhibit osteosarcoma metastasis. The decrease in expression of matrix metalloproteinases (MMP)-2 and MMP-9 may contribute to the effects of baicalein. Taken together, our results provide evidence that baicalein plays important roles in anti-osteosarcoma therapy, and thus may serve as a novel and efficient candidate agent for osteosarcoma treatment. 23499857 Toxicity of thienopyridines on human neutrophil granulocytes and lymphocytes. Thienopyridines can cause neutropenia and agranulocytosis. The aim of the current investigations was to compare cytotoxicity of ticlopidine, clopidogrel, clopidogrel carboxylate and prasugrel for human neutrophil granulocytes with the toxicity for lymphocytes and to investigate underlying mechanisms. For granulocytes, clopidogrel, ticlopidine, clopidogrel carboxylate and prasugrel were concentration-dependently toxic starting at 10μM. Cytotoxicity could be prevented by the myeloperoxidase inhibitor rutin, but not by the cytochrome P450 inhibitor ketoconazole. All compounds were also toxic for lymphocytes, but cytotoxicity started at 100μM and could not be prevented by rutin or ketoconazole. Granulocytes metabolized ticlopidine, clopidogrel, clopidogrel carboxylate and prasugrel, and metabolization was inhibited by rutin, but not by ketoconazole. Metabolism of these compounds by lymphocytes was much slower and could not be inhibited by ketoconazole or rutin. In neutrophils, all compounds investigated decreased the electrical potential across the inner mitochondrial membrane, were associated with cellular accumulation of ROS, mitochondrial loss of cytochrome c and induction of apoptosis starting at 10μM. All of these effects could be inhibited by rutin, but not by ketoconazole. Similar findings were obtained in lymphocytes; but compared to neutrophils, the effects were detectable only at higher concentrations and were not inhibited by rutin. In conclusion, ticlopidine, clopidogrel, clopidogrel carboxylate and prasugrel are toxic for both granulocytes and lymphocytes. In granulocytes, cytotoxicity is more accentuated than in lymphocytes and depends on metabolization by myeloperoxidase. These findings suggest a mitochondrial mechanism for cytotoxicity for both myeloperoxidase-associated metabolites and, at higher concentrations, also for the parent compounds. 23063689 Global slowing of network oscillations in mouse neocortex by diazepam. Benzodiazepines have a broad spectrum of clinical applications including sedation, anti-anxiety, and anticonvulsive therapy. At the cellular level, benzodiazepines are allosteric modulators of GABA(A) receptors; they increase the efficacy of inhibition in neuronal networks by prolonging the duration of inhibitory postsynaptic potentials. This mechanism of action predicts that benzodiazepines reduce the frequency of inhibition-driven network oscillations, consistent with observations from human and animal EEG. However, most of existing data are restricted to frequency bands below ∼30 Hz. Recent data suggest that faster cortical network rhythms are critically involved in several behavioral and cognitive tasks. We therefore analyzed diazepam effects on a large range of cortical network oscillations in freely moving mice, including theta (4-12 Hz), gamma (40-100 Hz) and fast gamma (120-160 Hz) oscillations. We also investigated diazepam effects over the coupling between theta phase and the amplitude fast oscillations. We report that diazepam causes a global slowing of oscillatory activity in all frequency domains. Oscillation power was changed differently for each frequency domain, with characteristic differences between active wakefulness, slow-wave sleep and REM sleep. Cross-frequency coupling strength, in contrast, was mostly unaffected by diazepam. Such state- and frequency-dependent actions of benzodiazepines on cortical network oscillations may be relevant for their specific cognitive effects. They also underline the strong interaction between local network oscillations and global brain states. 23063782 The role of oxygen during fracture healing. Oxygen affects the activity of multiple skeletogenic cells and is involved in many processes that are important for fracture healing. However, the role of oxygen in fracture healing has not been fully studied. Here we systematically examine the effects of oxygen tension on fracture healing and test the ability of hyperoxia to rescue healing defects in a mouse model of ischemic fracture healing. Mice with tibia fracture were housed in custom-built gas chambers and groups breathed a constant atmosphere of 13% oxygen (hypoxia), 21% oxygen (normoxia), or 50% oxygen (hyperoxia). The influx of inflammatory cells to the fracture site, stem cell differentiation, tissue vascularization, and fracture healing were analyzed. In addition, the efficacy of hyperoxia (50% oxygen) as a treatment regimen for fracture nonunion was tested. Hypoxic animals had decreased tissue vascularity, decreased bone formation, and delayed callus remodeling. Hyperoxia increased tissue vascularization, altered fracture healing in un-complicated fractures, and improved bone repair in ischemia-induced delayed fracture union. However, neither hypoxia nor hyperoxia significantly altered chondrogenesis or osteogenesis during early stages of fracture healing, and infiltration of macrophages and neutrophils was not affected by environmental oxygen after bone injury. In conclusion, our results indicate that environmental oxygen levels affect tissue vascularization and fracture healing, and that providing oxygen when fractures are accompanied by ischemia may be beneficial. 23466330 Noradrenergic control of the bed nucleus of the stria terminalis in stress and reward. The bed nucleus of the stria terminalis (BNST) is a group of inter-connected subnuclei that play critical roles in stress-reward interactions. An interesting feature of this brain region is the massive noradrenergic input that it receives. Important roles for norepinephrine in this region have been documented in a number of stress and reward related behaviors. This work has been paralleled over the last several years by efforts to understand the actions of norepinephrine on neuronal function in the region. In this review, we will summarize the current state of these research areas. 23302590 A chemical approach to searching for bioactive ingredients in cigarette smoke. Cigarette smoke, a collection of many toxic chemicals, contributes to the pathogenesis of smoking-related diseases such as chronic obstructive pulmonary disease and cancer. Much work has been done on the chemical analysis of ingredients in cigarette smoke, but there are few reports on the active ingredients that can modify biomolecules. We used a sensitive liquid chromatography-mass spectrometry (LC/MS) and LC/MS/MS method to show that L-tyrosine (Tyr), an amino acid with a highly reactive hydroxyl group, readily reacts with cigarette smoke extract (CSE) at body temperature (37°C) to form various Tyr derivatives. Among these derivatives were N-(3-oxobutyl)-Tyr and two acetylated compounds, N-acetyl-Tyr and O-acetyl-Tyr, which were synthesized by reaction of Tyr with methyl vinyl ketone and acetic anhydride, respectively, at 37°C. The presence of methyl vinyl ketone and acetic anhydride in CSE was confirmed by gas chromatography-mass spectrometry (GC/MS). These results indicate that Tyr can easily react with active ingredients in CSE. The present analytical methods should aid the search for active ingredients in cigarette smoke. 23497865 Lipid components and water soluble metabolites in salted and dried tuna (Thunnus thynnus L.) roes. The salted and dried product of tuna roe (bottarga) is a seafood characteristic of the Mediterranean area and exported all over the world. Samples of bottarga from bluefin tunas (Thunnus thynnus, L.) caught in the southwest Mediterranean sea were analysed. The samples were characterised by high content of marine wax esters (55-67 mol% of lipid classes), of docosahexaenoic (22:6 n-3, 25 w%) and oleic (18:1 n-9, 19 w%) fatty acids. Cholesterol was detected as 7-9 w% of lipids. Free fatty acids, index of lipid hydrolysis, represented 32-39 mol% over total fatty acids. Among metabolites, nutrients as taurine, nicotinamide and β-alanine, were found. The microflora comprised staphylococci, enterococci (2.2 log(10)CFU/g) and lactic acid bacteria (3 log(10) CFU/g). The food-borne pathogens Staphylococcus aureus, Listeria monocytogenes and Salmonella spp. were not detected. These findings indicate tuna bottarga as valuable source of nutrients. 23315598 Paternal Metabolic and Cardiovascular Risk Factors for Fetal Growth Restriction: A case-control study. OBJECTIVEFathers of low-birth weight offspring are more likely to have type 2 diabetes and cardiovascular disease in later life. We investigated whether paternal insulin resistance and cardiovascular risk factors were evident at the time that fetal growth-restricted offspring were born.RESEARCH DESIGN AND METHODSWe carried out a case-control study of men who fathered pregnancies affected by fetal growth restriction, in the absence of recognized fetal disease (n = 42), compared with men who fathered normal-birth weight offspring (n = 77). All mothers were healthy, nonsmoking, and similar in age, BMI, ethnicity, and parity. Within 4 weeks of offspring birth, all fathers had measures of insulin resistance (HOMA index), blood pressure, waist circumference, endothelial function (flow-mediated dilatation), lipid profile, weight, and smoking habit. Comparison was made using multivariable logistical regression analysis.RESULTSFathers of fetal growth-restricted offspring [mean (SD) 1.8th (2.2) customized birth centile] were more likely to have insulin resistance, hypertension, central adiposity, and endothelial dysfunction and to smoke cigarettes compared with fathers of normal grown offspring. After multivariable analysis, paternal insulin resistance and smoking remained different between the groups. Compared with fathers of normal grown offspring, men who fathered pregnancies affected by fetal growth restriction had an OR 7.68 (95% CI 2.63-22.40; P < 0.0001) of having a 1-unit higher log HOMA-IR value and 3.39 (1.26-9.16; P = 0.016) of being a smoker.CONCLUSIONSMen who recently fathered growth-restricted offspring have preclinical evidence of the insulin resistance syndrome and are more likely to smoke than fathers of normal grown offspring. Paternal lifestyle may influence heritable factors important for fetal growth. 23436428 Addition of cilostazol to conventional dual antiplatelet therapy reduces the risk of cardiac events and restenosis after drug-eluting stent implantation: a meta-analysis. This meta-analysis was performed to compare the risk of cardiac events and restenosis between triple antiplatelet therapy (TAT, addition of cilostazol to aspirin and clopidogrel) and conventional dual antiplatelet therapy (DAT, aspirin and clopidogrel) in drug-eluting stents (DES) implantation patients. We performed PUBMED, MEDLINE, EMBASE, and Cochrane CENTRAL searches for randomized clinical trials of TAT versus DAT in patients after DES implantation. Five clinical trials were involved in the study. TAT was associated with a 36% reduction in major adverse cardiac events (MACE; odds ratio (OR) = 0.64; 95% confidence interval (CI) = 0.51-0.81, P < .01), a 40% reduction (OR = 0.60, 95% CI = 0.44-0.80; P < .01) in target vessel revascularization (TVR), a 44% reduction (OR = 0.56, 95% CI = 0.34-0.91; P = .02) in target lesion revascularization (TLR) and a 47%/44% reduction in in-segment/in-stent restenosis (P < .01) and lower in-segment/in-stent late loss (P < .01). As regards to the safety assessment, there was no significant difference about the risk of stent thrombosis and bleeding between TAT and DAT group, while the risk of gastrointestinal trouble was significantly higher in TAT group (OR = 2.46, 95% CI = 1.25-4.86; P < .01). Addition of cilostazol to DAT reduced the incidence of MACE, TVR, and TLR after DES implantation. TAT also reduced the risk of restenosis and late loss in patients after DES implantation. 23253427 Vasorelaxing effects and inhibition of nitric oxide in macrophages by new iron-containing carbon monoxide-releasing molecules (CO-RMs). Carbon monoxide-releasing molecules (CO-RMs) are a class of organometallo carbonyl complexes capable of delivering controlled quantities of CO gas to cells and tissues thus exerting a broad spectrum of pharmacological effects. Here we report on the chemical synthesis, CO releasing properties, cytotoxicity profile and pharmacological activities of four novel structurally related iron-allyl carbonyls. The major difference among the new CO-RMs tested was that three compounds (CORM-307, CORM-308 and CORM-314) were soluble in dimethylsulfoxide (DMSO), whereas a fourth one (CORM-319) was rendered water-soluble by reacting the iron-carbonyl with hydrogen tetrafluoroborate. We found that despite the fact all compounds liberated CO, CO-RMs soluble in DMSO caused a more pronounced toxic effect both in vascular and inflammatory cells as well as in isolated vessels. More specifically, iron carbonyls soluble in DMSO released CO with a fast kinetic and displayed a marked cytotoxic effect in smooth muscle cells and RAW 247.6 macrophages despite exerting a rapid and pronounced vasorelaxation ex vivo. In contrast, CORM-319 that is soluble in water and liberated CO with a slower rate, preserved smooth muscle cell viability, relaxed aortic tissue and exerted a significant anti-inflammatory effect in macrophages challenged with endotoxin. These data suggest that iron carbonyls can be used as scaffolds for the design and synthesis of pharmacologically active CO-RMs and indicate that increasing water solubility and controlling the rate of CO release are important parameters for limiting their potential toxic effects. 23409871 Synthesis and structure-activity relationships of indazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists. A series of indazole arylsulfonamides were synthesized and examined as human CCR4 antagonists. Methoxy- or hydroxyl-containing groups were the more potent indazole C4 substituents. Only small groups were tolerated at C5, C6, or C7, with the C6 analogues being preferred. The most potent N3-substituent was 5-chlorothiophene-2-sulfonamide. N1 meta-substituted benzyl groups possessing an α-amino-3-[(methylamino)acyl]-group were the most potent N1-substituents. Strongly basic amino groups had low oral absorption in vivo. Less basic analogues, such as morpholines, had good oral absorption; however, they also had high clearance. The most potent compound with high absorption in two species was analogue 6 (GSK2239633A), which was selected for further development. Aryl sulfonamide antagonists bind to CCR4 at an intracellular allosteric site denoted site II. X-ray diffraction studies on two indazole sulfonamide fragments suggested the presence of an important intramolecular interaction in the active conformation. 23063623 FoxA1 corrupts the antiandrogenic effect of bicalutamide but only weakly attenuates the effect of MDV3100 (Enzalutamide™). Prostate cancer growth depends on androgens. Synthetic antiandrogens are used in the cancer treatment. However, antiandrogens, such as bicalutamide (BIC), have a mixed agonist/antagonist activity. Here we compare the antiandrogenic capacity of BIC to a new antiandrogen, MDV3100 (MDV) or Enzalutamide™. By reconstitution of a hormone-regulated enhancer in Xenopus oocytes we show that both antagonists trigger the androgen receptor (AR) translocation to the nucleus, albeit with a reduced efficiency for MDV. Once in the nucleus, both AR-antagonist complexes can bind sequence specifically to DNA in vivo. The forkhead box transcription factor A (FoxA1) is a negative prognostic indicator for prostate cancer disease. FoxA1 expression presets the enhancer chromatin and makes the DNA more accessible for AR binding. In this context the BIC-AR antiandrogenic effect is seriously compromised as demonstrated by a significant chromatin remodeling and induction of a robust MMTV transcription whereas the MDV-AR complex displays a more persistent antagonistic character. 23534530 Pickering-Emulsion-Polymerized Polystyrene/Fe2O3 Composite Particles and Their Magnetoresponsive Characteristics. Core-shell-structured magnetic polystyrene (PS)/inorganic particles were fabricated by Pickering emulsion polymerization using nanosized Fe2O3 particles as a solid stabilizer. Scanning electron microscopy and transmission electron microscopy confirmed the synthesized PS/Fe2O3 particles to be comprised of a PS surface coated with Fe2O3 nanoparticles. The chemical structure of the composite nanospheres was characterized by Fourier transform infrared spectroscopy and X-ray diffraction. The thermal properties of composite nanospheres and corresponding pure polymer were examined by thermogravimetric analysis. The rheological properties of the core-shell-structured magnetic PS/inorganic particles dispersed in silicone oil were investigated under an external magnetic field strength using a rotational rheometer. The particles with extremely lower density than common magnetic particles exhibited solid-like magnetorheological phase characteristics, and the flow curves were fitted to the Cho-Choi-Jhon model of the rheological equation of state. 23505325 Synthesis of phenyleneethynylene-doped poly(pphenylenebutadiynylene) s for live cell imaging. We developed a new synthetic approach to high molecular weight poly(p-phenylenebutadiynylene) s (PPBs) by increasing backbone flexibility. The introduction of a small amount of flexible units along the backbone improved both the physical and photophysical properties of the polymers. These materials were successfully fabricated into conjugated polymer nanoparticles (CPNs) and used for fluorescent live cell imaging for the first time. 23403203 Antofine-induced connexin43 gap junction disassembly in rat astrocytes involves protein kinase Cβ. Antofine, a phenanthroindolizidine alkaloid derived from Cryptocaryachinensis and Ficusseptica in the Asclepiadaceae milkweed family, is cytotoxic for various cancer cell lines. In this study, we demonstrated that treatment of rat primary astrocytes with antofine induced dose-dependent inhibition of gap junction intercellular communication (GJIC), as assessed by scrape-loading 6-carboxyfluorescein dye transfer. Levels of Cx43 protein were also decreased in a dose- and time-dependent manner following antofine treatment. Double-labeling immunofluorescence microscopy showed that antofine (10ng/ml) induced endocytosis of surface gap junctions into the cytoplasm, where Cx43 was co-localized with the early endosome marker EEA1. Inhibition of lysosomes or proteasomes by co-treatment with antofine and their respective specific inhibitors, NH4Cl or MG132, partially inhibited the antofine-induced decrease in Cx43 protein levels, but did not inhibit the antofine-induced inhibition of GJIC. After 30min of treatment, antofine induced a rapid increase in the intracellular Ca(2+) concentration and activation of protein kinase C (PKC)α/βII, which was maintained for at least 6h. Co-treatment of astrocytes with antofine and the intracellular Ca(2+) chelator BAPTA-AM prevented downregulation of Cx43 and inhibition of GJIC. Moreover, co-treatment with antofine and a specific PKCβ inhibitor prevented endocytosis of gap junctions, downregulation of Cx43, and inhibition of GJIC. Taken together, these findings indicate that antofine induces Cx43 gap junction disassembly by the PKCβ signaling pathway. Inhibition of GJIC by antofine may undermine the neuroprotective effect of astrocytes in CNS. 23436315 Effect of excipients on acetaminophen metabolism and its implications for prevention of liver injury. Acetaminophen poisoning is the most frequent cause of acute hepatic failure in the US. Toxicity requires reductive metabolism of acetaminophen, primarily via CYP2E1. Liquid acetaminophen preparations contain propylene glycol, a common excipient that has been shown to reduce hepatocellular injury in vitro and in rodents. Children are less susceptible to acetaminophen toxicity for unclear reasons. We conducted a pharmacokinetic single-blinded crossover study of 15 healthy adult volunteers comparing the CYP2E1 and conjugative metabolism of a 15 mg/kg dose of liquid versus solid preparations of acetaminophen. Measured AUC's for the CYP2E1 metabolites were 16-17% lower and extrapolated AUC's were 25-28% lower in the liquid formulation arm while there was no difference in conjugative metabolite production. The formation rate constants for reductive metabolites were equivalent between solid and liquid formulations indicating that enzyme inhibition was competitive. Propylene glycol, an established CYP2E1 competitive antagonist, was detected in the liquid formulation but not solid formulation arm. Since children tend to ingest liquid preparations, the protective effect of this excipient could explain their decreased susceptibility to acetaminophen toxicity. A less hepatotoxic formulation of acetaminophen could potentially be developed if co-formulated with a CYP2E1 inhibitor. 23428794 Serial infusions of low-dose ketamine for major depression. Background: Single infusions of ketamine have been used successfully to achieve improvement in depressed patients. Side effects during the infusions have been common. It is not known whether serial infusions or lower infusion rates result in greater efficacy. Methods: Ten depressed patients were treated with twice weekly ketamine infusions of ketamine 0.5 mg/kg administered over 100 min until either remission was achieved or four infusions were given. Side effects were assessed with the Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS). Patients were followed naturalistically at weekly intervals for four weeks after completion of the infusions. Results: Five of 10 patients achieved remission status. There were no significant increases on the BPRS or YMRS. Two of the remitting patients sustained their improvement throughout the four week follow-up period. Conclusions: Ketamine infusions at a lower rate than previously reported have demonstrated similar efficacy and excellent tolerability and may be more practically available for routine clinical care. Serial ketamine infusions appear to be more effective than a single infusion. Further research to test relapse prevention strategies with continuation ketamine infusions is indicated. 23449198 Self-organizing map analysis using multivariate data from theophylline tablets predicted by a thin-plate spline interpolation. The "quality by design" concept in pharmaceutical formulation development requires the establishment of a science-based rationale and a design space. We integrated thin-plate spline (TPS) interpolation and Kohonen's self-organizing map (SOM) to visualize the latent structure underlying causal factors and pharmaceutical responses. As a model pharmaceutical product, theophylline tablets were prepared based on a standard formulation. The tensile strength, disintegration time, and stability of these variables were measured as response variables. These responses were predicted quantitatively based on nonlinear TPS. A large amount of data on these tablets was generated and classified into several clusters using an SOM. The experimental values of the responses were predicted with high accuracy, and the data generated for the tablets were classified into several distinct clusters. The SOM feature map allowed us to analyze the global and local correlations between causal factors and tablet characteristics. The results of this study suggest that increasing the proportion of microcrystalline cellulose (MCC) improved the tensile strength and the stability of tensile strength of these theophylline tablets. In addition, the proportion of MCC has an optimum value for disintegration time and stability of disintegration. Increasing the proportion of magnesium stearate extended disintegration time. Increasing the compression force improved tensile strength, but degraded the stability of disintegration. This technique provides a better understanding of the relationships between causal factors and pharmaceutical responses in theophylline tablet formulations. 23528363 Protection of glycyrrhizic acid against AGEs-induced endothelial dysfunction through inhibiting RAGE/NF-κB pathway activation in human umbilical vein endothelial cells. ETHNOPHARMACOLOGICAL RELEVANCE: Licorice (Glycyrrhiza uralensis roots) is used as a traditional medicine for the treatment of diabetes mellitus and its vascular complications. Glycyrrhizic acid (GA, also known as Glycyrrhizin), a triterpenoid saponin glycoside, is considered to be a bioactive component in Licorice and is beneficial to diabetic vascular complications. AIM OF STUDY: The present study was conducted to evaluate the potential protective activities on AGEs-induced endothelial dysfunction, including anti-apoptosis, antioxidant stress and anti-proinflammatory responses, and explore the underlying mechanism. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were incubated and pre-treated with GA (10(-9)-10(-6)M) or RAGE-Ab (5μg/ml) in the presence or absence of 200μg/ml AGEs. AO/EB fluorescence staining assay was performed to evaluate anti-apoptosis activity. The superoxide dismutase (SOD) activity and malondialdehyde (MDA) level in cell supernatant were detected by kits while the intracellular reactive oxygen species (ROS) generation was determined by 2,7-dichlorodihydrofluorescin diacetate (DCFH-DA) kit. Immunocytochemistry analysis was designed to determine transforming growth factor beta1(TGF-β1) protein expression while immunofluorescence analysis for RAGE and NF-kB. The protein expressions of TGF-β1, RAGE and NF-kB were analyzed by Western blot analysis. RESULTS: Pretreatment with GA at a concentration of 10(-8)-10(-6)M significantly reduced the AGEs-induced apoptosis in HUVECs. GA significantly increased antioxidant enzyme SOD activity and decreased peroxide degradation product MDA level in a dose-dependent manner. Furthermore, GA also remarkably inhibited the overgeneration of AGEs-induced ROS. Both immunocytochemistry analysis and western blot analysis showed that GA significantly decreased the protein expression of poinflammatory cytokine TGF-β1 in a similar manner which RAGE-Ab did. Additionally, AGEs-induced RAGE and NF-kB protein expressions were down-regulated significantly by the pretreatment with GA or RAGE-Ab. CONCLUSION: These findings provide evidences that GA possesses protective activity on AGEs-induced endothelial dysfunction, including anti-apoptosis, anti-inflammation and antioxidant stress, via inhibiting RAGE/NF-kB pathway. GA might be an alternative for the prevention and treatment of diabetic vascular complications in an appropriate dosage. 23265484 Microwave distillation followed by headspace single drop microextraction coupled to gas chromatography-mass spectrometry (GC-MS) for fast analysis of volatile components of Echinophora platyloba DC. To avoid the traditional and time consuming hydrodistillation, the analyses of volatile components in aerial parts of Echinophora platyloba DC was carried out by a simple microwave distillation followed by headspace single drop microextraction (MD-HS-SDME) coupled to gas chromatography-mass spectrometry (GC-MS). The headspace volatile compounds were collected after irradiation using a single drop of n-heptadecan. The extraction conditions were optimised using the relative peak areas as index. The chemical composition of the MD-HS-SDME extracts was confirmed according to their retention indexes and mass spectra. Fifty-three components were extracted and identified by using the MD-HS-SDME method. E-β-ocimene (53.81%), R-D-decalactone (12.75%), α-pinene (6.43%), n-heptanol (6.27%), β-phellanderne (2.70%) and linalool (1.89%) were the major constituents. 23570612 Adsorption of small organic molecules on graphene. We present a combined experimental and theoretical quantification of the adsorption enthalpies of seven organic molecules (acetone, acetonitrile, dichloromethane, ethanol, ethyl acetate, hexane, and toluene) on graphene. Adsorption enthalpies were measured by inverse gas chromatography and ranged from -5.9 kcal/mol for dichloromethane to -13.5 kcal/mol for toluene. The strength of interaction between graphene and the organic molecules was estimated by density functional theory (PBE, B97D, M06-2X, and optB88-vdW), wave function theory (MP2, SCS(MI)-MP2, MP2.5, MP2.X, and CCSD(T)), and empirical calculations (OPLS-AA) using two graphene models: coronene and infinite graphene. Symmetry-adapted perturbation theory calculations indicated that the interactions were governed by London dispersive forces (amounting to ∼60% of attractive interactions), even for the polar molecules. The results also showed that the adsorption enthalpies were largely controlled by the interaction energy. Adsorption enthalpies obtained from ab initio molecular dynamics employing non-local optB88-vdW functional were in excellent agreement with the experimental data, indicating that the functional can cover physical phenomena behind adsorption of organic molecules on graphene sufficiently well. 23085122 Timing of decontamination and treatment in case of percutaneous VX poisoning: A mini review. Low volatile organophosphorous nerve agents such as VX, will most likely enter the body via the skin. The pharmacokinetics of drugs such as oximes, atropine and diazepam, are not aligned with the variable and persistent toxicokinetics of the agent. Repeated administration of these drugs showed to improve treatment efficacy compared to a single injection treatment. Because of the effectiveness of continuous treatment, it was investigated to what extent a subchronic pretreatment with carbamate (pyridostigmine or physostigmine combined with either procyclidine or scopolamine) would protect against percutaneous VX exposure. Inclusion of scopolamine in the pretreatment prevented seizures in all animals, but none of the pretreatments affected survival time or the onset time of cholinergic signs. These results indicate that percutaneous poisoning with VX requires additional conventional treatment in addition to the current pretreatment regimen. Decontamination of VX-exposed skin is one of the most important countermeasures to mitigate the effects of the exposure. To evaluate the window of opportunity for decontamination, the fielded skin decontaminant Reactive Skin Decontaminant Lotion (RSDL) was tested at different times in hairless guinea pigs percutaneously challenged with 4× LD50 VX in IPA. The results showed that RSDL decontamination at 15min after exposure could not prevent progressive blood cholinesterase inhibition and therefore would still require additional treatment. A similar decontamination regimen with RSDL at 90min showed that it still might effectively increase the time window of opportunity for treatment. In conclusion, the delay in absorption presents a window of opportunity for decontamination and treatment. The continuous release of VX from the skin presents a significant challenge for efficacious therapy, which should ideally consist of thorough decontamination and continuous treatment. 23532940 Highly efficient förster resonance energy transfer in a fast, serum-compatible immunoassay. Highly efficient FRET leads to important enhancements for homogeneous immunoassays. By using the novel phosphorescent dye EuLH and BHQ-10 as a donor-acceptor pair, the FRET efficiency increases to >99.5 %, leading to significantly improved signal-to-background ratio, precision and linear range. The phosphorescence detection enabled full compatibility to serum samples for this fast-responding immunoassay. 23273978 eRNAs are required for p53-dependent enhancer activity and gene transcription. Binding within or nearby target genes involved in cell proliferation and survival enables the p53 tumor suppressor gene to regulate their transcription and cell-cycle progression. Using genome-wide chromatin-binding profiles, we describe binding of p53 also to regions located distantly from any known p53 target gene. Interestingly, many of these regions possess conserved p53-binding sites and all known hallmarks of enhancer regions. We demonstrate that these p53-bound enhancer regions (p53BERs) indeed contain enhancer activity and interact intrachromosomally with multiple neighboring genes to convey long-distance p53-dependent transcription regulation. Furthermore, p53BERs produce, in a p53-dependent manner, enhancer RNAs (eRNAs) that are required for efficient transcriptional enhancement of interacting target genes and induction of a p53-dependent cell-cycle arrest. Thus, our results ascribe transcription enhancement activity to p53 with the capacity to regulate multiple genes from a single genomic binding site. Moreover, eRNA production from p53BERs is required for efficient p53 transcription enhancement. 23032079 The GARD assay for assessment of chemical skin sensitizers. Allergic contact dermatitis is a skin disease caused by an immunologic reaction to low molecular weight compounds, so called haptens. These substances are commonly present in products used by humans in daily life, such as in cosmetics and fragrances, as well as within chemical industry and in pharmaceuticals. The frequent usage of these compounds in different applications has led to increasing incidences of allergic contact dermatitis, which has become a substantial economic burden for society. As a consequence, chemicals are routinely tested for their ability to induce skin sensitization, using animal models such as the murine Local Lymph Node Assay. However, recent legislations regulate the use of animal models within chemical testing. Thus, there is an urgent need for in vitro alternatives to replace these assays for safety assessment of chemicals. Recently, we identified a signature of predictive genes, which are differentially regulated in the human myeloid cell-line MUTZ-3 when stimulated with sensitizing compounds compared to non-sensitizing compounds. Based on these findings, we have formulated a test strategy for assessment of sensitizing compounds, called Genomic Allergen Rapid Detection, GARD. In this paper, we present a detailed method description of how the assay should be performed. 22521210 Effects of estradiol in adult neurogenesis and brain repair in zebrafish. The brain of the adult teleost fish exhibits intense neurogenic activity and an outstanding capability for brain repair. Remarkably, the brain estrogen-synthesizing enzyme, aromatase B, is strongly expressed, particularly in adult fishes, in radial glial cells, which act as progenitors. Using zebrafish, we tested the hypothesis that estrogens affect adult neurogenesis and brain regeneration by modulating the neurogenic activity of radial glial cells. To investigate this, the estrogenic environment was modified through inhibition of aromatase activity, blockade of nuclear estrogen receptors, or estrogenic treatments. Estrogens significantly decreased cell proliferation and migration at the olfactory bulbs/telencephalon junction and in the mediobasal hypothalamus. It also appears that cell survival is reduced at the olfactory bulbs/telencephalon junction. We also developed a model of telencephalic lesion to assess the role of aromatase and estrogens in brain repair. Proliferation increased rapidly immediately after the lesion in the parenchyma of the injured telencephalon, while proliferation at the ventricular surface appeared after 48 h and peaked at 7 days. At this time, most proliferative cells express Sox2, however, none of these Sox2 positive cells correspond to aromatase B-positive radial glial cells. Interestingly, aromatase B expression was significantly reduced 48 h and 7 days after the injury, but surprisingly, at 72 h after lesion, aromatase B expression appeared de novo expressed in parenchyma cells, suggesting a role for this ectopic expression of aromatase in brain repair mechanisms. Altogether these data suggest that estrogens modulate adult, but not reparative neurogenesis, in zebrafish. 23389091 New casbane diterpenoids from a South China Sea soft coral, Sinularia sp. Six new casbane diterpenoids, named as sinularcasbanes A-F (1-6), along with six known analogues 7-12, were isolated from a South China Sea soft coral, Sinularia sp. The structures of the new compounds were elucidated by extensive spectroscopic analysis and by comparison with data reported in the literature. All compounds were evaluated for their cytotoxicity against selected cancer cell lines and the inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in mouse peritoneal macrophages. 23416178 Mutagenicity of the cysteine S-conjugate sulfoxides of trichloroethylene and tetrachloroethylene in the Ames test. The nephrotoxicity and nephrocarcinogenicity of trichloroethylene (TCE) and tetrachloroethylene (PCE) are believed to be mediated primarily through the cysteine S-conjugate β-lyase-dependent bioactivation of the corresponding cysteine S-conjugate metabolites S-(1,2-dichlorovinyl)-l-cysteine (DCVC) and S-(1,2,2-trichlorovinyl)-l-cysteine (TCVC), respectively. DCVC and TCVC have previously been demonstrated to be mutagenic by the Ames Salmonella mutagenicity assay, and reduction in mutagenicity was observed upon treatment with the β-lyase inhibitor aminooxyacetic acid (AOAA). Because DCVC and TCVC can also be bioactivated through sulfoxidation to yield the potent nephrotoxicants S-(1,2-dichlorovinyl)-l-cysteine sulfoxide (DCVCS) and S-(1,2,2-trichlorovinyl)-l-cysteine sulfoxide (TCVCS), respectively, the mutagenic potential of these two sulfoxides was investigated using the Ames Salmonella typhimurium TA100 mutagenicity assay. The results show both DCVCS and TCVCS were mutagenic, and TCVCS exhibited 3-fold higher mutagenicity than DCVCS. However, DCVCS and TCVCS mutagenic activity was approximately 700-fold and 30-fold lower than DCVC and TCVC, respectively. DCVC and DCVCS appeared to induce toxicity in TA100, as evidenced by increased microcolony formation and decreased mutant frequency above threshold concentrations. TCVC and TCVCS were not toxic in TA100. The toxic effects of DCVC limited the sensitivity of TA100 to DCVC mutagenic effects and rendered it difficult to investigate the effects of AOAA on DCVC mutagenic activity. Collectively, these results suggest that DCVCS and TCVCS exerted a definite but weak mutagenicity in the TA100 strain. Therefore, despite their potent nephrotoxicity, DCVCS and TCVCS are not likely to play a major role in DCVC or TCVC mutagenicity in this strain. 23351147 Cytotoxic constituents of ethyl acetate fraction from Dianthus superbus. The ethyl acetate fraction (EE-DS) from Dianthus superbus was found to possess the cytotoxic activity against cancer cells in previous study. To investigate cytotoxic constituents, the bioassay-guided isolation of compounds from EE-DS was performed. Two dianthramides (1 and 2), three flavonoids (3-5), two coumarins (6 and 7) and three other compounds (8-10) were obtained. Structures of isolated compounds were identified by spectroscopic analysis. Cytotoxicity of the compounds against HepG2 cells was evaluated. Compound 1 showed the strongest cytotoxicity, compounds 10, 4, 3 and 5 had moderate cytotoxicity. 23416003 Design and synthesis of bicyclic pyrazinone and pyrimidinone amides as potent TF-FVIIa inhibitors. Bicyclic pyrazinone and pyrimidinone amides were designed and synthesized as potent TF-FVIIa inhibitors. SAR demonstrated that the S2 and S3 pockets of FVIIa prefer to bind small, lipophilic groups. An X-ray crystal structure of optimized compound 9b bound in the active site of FVIIa showed that the bicyclic scaffold provides 5 hydrogen bonding interactions in addition to projecting groups for interactions within the S1, S2 and S3 pockets. Compound 9b showed excellent FVIIa potency, good selectivity against FIXa, Xa, XIa and chymotrypsin, and good clotting activity. 23274698 Effects of water restriction on reproductive physiology and affiliative behavior in an opportunistically-breeding and monogamous songbird, the zebra finch. Wild zebra finches form long-term monogamous pair-bonds that are actively maintained year-round, even when not in breeding condition. These desert finches are opportunistic breeders, and breeding is highly influenced by unpredictable rainfall. Their high levels of affiliation and complex breeding patterns make zebra finches an excellent model in which to study the endocrine regulation of affiliation. Here, we compared zebra finch pairs that were provided with water ad libitum (control) or water restricted. We examined (1) reproductive physiology, (2) pair-maintenance behaviors in several contexts, and (3) circulating and brain steroid levels. In females, water restriction profoundly reduced largest ovarian follicle size, ovary size, oviduct size, and egg laying. In males, water restriction had no effect on testes size but decreased systemic testosterone levels. However, in the hypothalamus, local testosterone and estradiol levels were unaffected by water restriction in both sexes. Systemic and local levels of the androgen precursor dehydroepiandrosterone (DHEA) were also unaffected by water restriction. Lastly, in three different behavioral paradigms, we examined a variety of pair-maintenance behaviors, and none were reduced by water restriction. Taken together, these correlational data are consistent with the hypothesis that local production of sex steroids in the brain promotes the expression of pair-maintenance behaviors in non-breeding zebra finches. 22158333 Pharmacogenetic predictors for EGFR-inhibitor-associated skin toxicity. The aim of this study was to investigate pharmacogenetic determinants of skin rash associated with epidermal growth factor receptor (EGFR) inhibitor treatment. A total of 109 prospectively sampled cancer patients, receiving the first treatment with an EGFR inhibitor, were genotyped for functional EGFR polymorphisms and tagging variants in genes involved in receptor downstream signaling. Skin rash was absent in 26 (23.9%) patients and associated with shorter overall survival compared with patients presenting skin rash (P=0.005). The EGFR polymorphisms, 497G/A (P=0.008), and the haplotypes of the promoter variants, EGFR-216G/T and -191C/A (P=0.029), were associated with the appearance of skin rash. In addition, a common haplotype in the PIK3CA gene was associated with skin rash (P=0.045) and overall survival (P=0.009). In conclusion, genetic variation within the EGFR gene and its downstream signaling partner PIK3CA might predict EGFR-inhibitor-related skin rash. 23561081 Enrichment of two isoflavone aglycones in black soymilk by using spent coffee grounds as an immobiliser for β-glucosidase. Spent coffee grounds, discarded as environmental pollutants, were adopted as enzyme immobilisation solid carriers instead of commercialised solid supports to establish an economical catalytic system. β-Glucosidase was covalently immobilised onto spent coffee grounds for the conversion of isoflavone glycosides into their aglycones in black soymilk. Optimum conditions were determined to be 40°C and pH 6 using 4-nitrophenyl β-d-glucuronide as an indicator. Operational reusability was confirmed for more than 30 batch reactions and the storage stability was capable of sustaining its highest catalytic activity for 20days. The kinetic parameters including rate constant (K), time (τ50) in which 50% of isoflavone deglycosylation was reached, and time (τcomplete) required to achieve complete isoflavone deglycosylation, were0.16±0.02min(-1), 4.54±0.32min, 60min for daidzin and 0.16±0.02min(-1), 2.28±0.11min, 60min for genistin, respectively. The total aglycone content in black soymilk was enriched by 67.14±0.60% in the enzymatic treatment of 60min duration. 23567953 Synthesis of novel 1,3,4-trisubstituted pyrazoles as anti-inflammatory and analgesic agents. Some novel 1,3,4-trisubstituted pyrazoles were synthesized and screened for their anti-inflammatory and analgesic activities as well as their ulcerogenic liability. They showed anti-inflammatory and analgesic activities with better GIT tolerance than the standard drug phenylbutazone. In addition, IC50 values for 5e and 8e were recorded. Compound 5e was found to be the most active one as anti-inflammatory and analgesic agent. On the other hand, COX-1/COX-2 isozyme selectivity was also done which showed equal inhibition to both isoforms. 23402729 New insight into artifactual phenomena during in vitro toxicity assessment of engineered nanoparticles: study of TNF-α adsorption on alumina oxide nanoparticle. Biomolecules can be adsorbed on nanoparticles (NPs) and degraded during in vitro toxicity assays. These artifactual phenomena could lead to misinterpretation of biological activity, such as false-negative results. To avoid possible underestimation of cytokine release after contact between NP and cells, we propose a methodology to account for these artifactual phenomena and lead to accurate measurements. We focused on the pro-inflammatory cytokine tumor necrosis factor TNF-α. We studied well-characterized boehmite engineered NP [aluminum oxide hydroxide, AlO(OH)]. The rate of TNF-α degradation and its adsorption (on boehmite and on the walls of wells) were determined in cell-free conditions by adding a known TNF-α concentration (1500 pg/ml) under various experimental conditions. After a 24-h incubation, we quantified that 7 wt.% of the initial TNF-α was degraded over time, 6 wt.% adsorbed on the walls of 96-well plates, and 13 wt.% adsorbed on the boehmite surface. Finally, boehmite NP were incubated with murine macrophages (RAW 264.7 cell line). The release of TNF-α was assessed for boehmite NP and the experimental data were corrected considering the artifactual phenomena, which accounted for about 20-30% of the total. 23518278 Design, synthesis and structure-activity relationships of 3,5-diaryl-1H-pyrazoles as inhibitors of arylamine N-acetyltransferase. The synthesis and inhibitory potencies of a novel series of 3,5-diaryl-1H-pyrazoles as specific inhibitors of prokaryotic arylamine N-acetyltransferase enzymes is described. The series is based on hit compound 1 3,5-diaryl-1H-pyrazole identified from a high-throughout screen that has been carried out previously and found to inhibit the growth of Mycobacterium tuberculosis. 23425268 Conference Report: Bioanalysis-related topics presented at the International Conference and Exhibition on Biowaivers and Biosimilars. This conference of approximately 30 professionals attracted a diverse group of attendees, whose expertise spanned the broad topics of development, production, testing and regulation of biosimilars. The topics covered during this meeting were varied in scope due to the breadth of knowledge of the attendees. Topics of discussion included: biowaivers for small molecules; patent law and interpretation of the Biologics Price Competition and Innovation Act; analytical tools for the characterization of a biosimilar; novel production methods; bioanalytical methods; immunogenicity considerations; formulation techniques; and the characterization of the glycosylation of biosimilars. 23512538 The Tumor Suppressor Kruppel-Like Factor 6 is a Novel Aryl Hydrocarbon Receptor DNA Binding Partner. The Aryl Hydrocarbon Receptor (AhR) is a ligand mediated basic helix-loop-helix transcription factor of Per/Arnt/Sim family that regulates adaptive and toxic responses to variety of chemical pollutants including polycyclic aromatic hydrocarbons (PAH) and halogenated aromatic hydrocarbons, most notably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Ligand activation leads to AhR nuclear translocation and binding to a xenobiotic response element (XRE) in association with the aryl receptor nuclear translocator (Arnt) to regulate gene expression. Several recent genome-wide transcriptional studies identified numerous AhR target genes that lack the canonical XRE recognition site in the promoter regions. Characterization of one such target gene, the Plasminogen Activator Inhibitor 1 (PAI-1) identified a novel non-consensus XRE (NC-XRE) that confers TCDD responsiveness independently of the Arnt protein. Studies reported here show that the NC-XRE is a recognition site for the AhR and a new binding partner, the Kruppel-like Factor (KLF) family member KLF6. In vivo chromatin immunoprecipitations and in vitro DNA binding studies demonstrate that the AhR and KLF6 proteins form an obligatory heterodimer necessary for NC-XRE binding. Mutational analyzes show that the protein-protein interactions involve the AhR C-terminus and KLF6 N-terminus, respectively. Moreover, NC-XRE binding depends on the 5' basic region in KLF6 rather than the previously characterized zinc finger DNA binding domain. Collectively, the results unmask a novel AhR signaling mechanism distinct from the canonical XRE-driven process that will enrich our future understanding of AhR biology. 23313338 Perturbation of male sexual behavior in mice (Mus musculus) within a discrete range of perinatal bisphenol-A doses in the context of a high- or low-phytoestrogen diet. Differentiation of masculine and feminine behavior in mammals depends on perinatal sex steroids. As bisphenol-A (BPA) can be estrogenic and anti-androgenic, we examined impacts of perinatal exposure upon adult sexual behavior and morphology of male mice. In Experiment 1, dams were fed either a high- or low-phytoestrogen diet and received daily oral doses of 0, 0.175, 1.75, or 17.5μg BPA from gestation day 10 through post-partum day 9. Male offspring from the high-phytoestrogen plus 17.5μg BPA condition showed reduced mass of vesicular-coagulating but not other male glands, and showed increased latency to insemination when paired with females. In Experiment 2, these procedures were replicated but with all animals fed the high-phytoestrogen diet and perinatal BPA doses of 0, 17.5, 175, or 1750μg/day. Adult masses of testes and male-accessory glands and levels of urinary steroids were not significantly affected. When males each encountered a sexually receptive female, there were fewer intromissions among those given 17.5 or 175μg and fewer ejaculations among those given 17.5μg, but the 1750μg dose had no effect. Perinatal BPA dosages thus influenced male sexual behavior non-monotonically, with impairment evident in a discrete dose range among males on a high-phytoestrogen diet. 23386029 Nocapyrones H-J, 3,6-Disubstituted α-Pyrones from the Marine Actinomycete Nocardiopsis sp. KMF-001. Three new 3,6-disubstituted α-pyrones, nocapyrones H-J (1-3), were isolated from the marine actinomycete Nocardiopsis sp. KMF-001. Their structures were assigned to be 3-alkylated 6-(1-methyl-1-propenyl)-2H-pyran-2-ones on the basis of UV, MS, NMR, and high resolution (HR)-FAB-MS analyses. Nocapyrone H (1) reduced the pro-inflammatory factor such as nitric oxide (NO), prostaglandin E2 (PGE2) and interleukin-1β (IL-1β). Moreover, nocapyrone H showed 5.82% stronger inhibitory effect on NO production than chrysin at a concentration of 10 µm in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. 23199996 From fish chemical characterisation to the benefit-risk assessment--part A. Proximate composition, fatty acid profile, cholesterol, α-tocoferol content and essential (K, Na, Cl, S, Mg, Ca, Zn, Cu, Fe, Mn, and Se) and contaminant element (Hg/MeHg, Cd, Pb, and As) levels in silver scabbardfish (Lepidopus caudatus), hake (Merluccius merluccius), and ray (Raja spp.) were investigated. Results showed that these species contain high protein, low cholesterol and energy levels, being its consumption recommended. Polyunsaturated fatty acids (PUFA) were the dominant group of the fatty acids, being 80% of the n-3 family. Attending to the dietary reference intakes (DRIs), these fish species are a good source of Se and the other minerals can give a relevant contribution to the DRIs in a balanced diet. More than one weekly meal of silver scabbardfish has to be avoided due to the organic mercury concentration. More accurate dietary recommendations require a probabilistic assessment, which will be the focus of this study's Part B. 23511715 Population pharmacokinetics of intramuscular artesunate in african children with severe malaria: implications for a practical dosing regimen. Parenteral artesunate (ARS) is the drug of choice for the treatment of severe malaria. Pharmacokinetics data on intramuscular ARS are limited with respect to the main treatment group that carries the highest mortality, namely, critically ill children with severe malaria. A population pharmacokinetic study of ARS and dihydroartemisinin (DHA) was conducted from sparse sampling in 70 Tanzanian children of ages 6 months to 11 years. All the children had been admitted with severe falciparum malaria and were treated with intramuscular ARS (2.4 mg/kg at 0, 12, and 24 h). Venous plasma concentration-time profiles were characterized using nonlinear mixed-effects modeling (NONMEM). A one-compartment disposition model accurately described first-dose population pharmacokinetics of ARS and DHA. Body weight significantly affected clearance and apparent volume of distribution (P < 0.001), resulting in lower ARS and DHA exposure levels in smaller children. An adapted dosing regimen including a practical dosing table per weight band is proposed for young children based on the pharmacokinetic model. 23317165 Recent Developments of p38α MAP Kinase Inhibitors as Antiinflammatory Agents Based on the Imidazole Scaffolds. Rheumatoid arthritis (RA) and other chronic inflammatory diseases are always the major therapeutic challenges. Recent research efforts provided new insights into the molecular basis of these diseases and new opportunities for developing improved anti-inflammatory drugs. The p38 mitogen-activated protein (MAP) kinase plays a central role in the regulation of the biosynthesis and release of several proinflammatory cytokines including tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β). Hence, inhibition of the p38 MAP kinase is regarded as a promising therapeutic strategy for controlling inflammatory diseases. A diverse range of p38α MAP kinase inhibitors have been developed as potential anti-inflammatory agents, and some of them have entered the phase II clinical trials. The imidazole derivatives are known as competitive inhibitors at the ATP binding site of the p38α MAP kinase. Modifications on the imidazole scaffold have led to a large amount of potent p38α MAP kinase inhibitors. This review will summarize the developments of small molecule p38α MAP kinase inhibitors based on the imidazole core scaffolds in recent 10 years. Variations at the N1, C2, C4 and C5 positions of imidazole were introduced, and the structure-activity relationships of these imidazole inhibitors were also discussed. 23546398 Differential propensity of citrate- and polyethylene glycol-coated silver nanoparticles to bovine hemoglobin. Propensity of two different silver nanoparticles (Ag-NPs) to bovine hemoglobin (BHb) was investigated by means of spectroscopic methods. We have combined spectrophotometric and calorimetric methods to show that there is no significant interaction between citrate-coated Ag-NPs and BHb at physiological pH and 20°C. However, our previous results show that polyethylene glycol-coated Ag-NPs strongly bind to Hb and effect on the secondary and tertiary structures of BHb. Thus, a suitable surface coating and modification of surface charge would increase the NPs safety and reduce adverse biological responses. 23406460 A nonionic inhibitor with high specificity for the UDP-Gal donor binding site of human blood group B galactosyltransferase: design, synthesis, and characterization. 9-(5-O-α-D-galactopyranosyl)-D-arabinityl-1,3,7-trihydropurine-2,6,8-trione (1) was designed and synthesized as a nonionic inhibitor for the donor binding site of human blood group B galactosyltransferase (GTB). Enzymatic characterization showed 1 to be extremely specific, as the highly homologous human N-acetylgalactosaminyltransferase (GTA) is not inhibited. The binding epitope of 1 demonstrates a high involvement of the arabinityl linker, whereas the galactose residue is only making contact to the protein via its C-2 site, which is very important for the discrimination between galactose and N-acetylgalactosamine, the substrate transferred by GTA. The approach can generate highly specific glycosyltransferase inhibitors. 23296276 The effect of remelting on the physical properties of borotellurite glass doped with manganese. A systematic set of borotellurite glasses doped with manganese (1-x) [(B(2)O(3))(0.3)(TeO(2))(0.7)]-xMnO, with x = 0.1, 0.2, 0.3 and 0.4 mol%, were successfully synthesized by using a conventional melt and quench-casting technique. In this study, the remelting effect of the glass samples on their microstructure was investigated through density measurement and FT-IR spectra and evaluated by XRD techniques. Initial experimental results from XRD evaluation show that there are two distinct phases of glassy and crystallite microstructure due to the existence of peaks in the sample. The different physical behaviors of the studied glasses were closely related to the concentration of manganese in each phase. FTIR spectra revealed that the addition of manganese oxide contributes the transformation of TeO(4) trigonal bipyramids with bridging oxygen (BO) to TeO(3) trigonal pyramids with non-bridging oxygen (NBO). 23532918 Synthesis and in Vitro Characterisation of Ifenprodil-Based Fluorescein Conjugates as GluN1/GluN2B N-Methyl-D-aspartate Receptor Antagonists. GluN2B-containing NMDA receptors are involved in many important physiological functions and play a pivotal role in mediating pain as well as in several neurodegenerative disorders. We aimed to develop fluorescent probes to target the GluN2B subunit selectively in order to allow better understanding of the relationships between receptor localisation and physiological importance. Ifenprodil, known as the GluNR2B antagonist of reference, was chosen as the template for the elaboration of probes. We had previously reported a fluorescein conjugate that was shown (by confocal microscopy imaging of DS-red-labelled cortical neurons) to bind specifically to GluN2B. To elaborate this probe, we explored the influence of both the nature and the attachment point of the spacer between the fluorophore and the parent compound, ifenprodil. We performed chemical modifications of ifenprodil at the benzylic position and on the phenol ring by introducing secondary amine or amide functions and evaluated alkyl chains from two to 20 bonds either including or not including secondary amide functions as spacers. The previously developed probe was found to display the greatest activity in the inhibition of NMDA-induced Ca(2+) influx by calcium imaging experiments on HEK293 cells transfected with the cDNA encoding for GluN1-1A and GluN2B. Further investigations revealed that this probe had a neuroprotective effect equivalent to that of ifenprodil in a standard test for neurotoxicity. Despite effects of lesser amplitude with these probes relative to ifenprodil, we demonstrated that they displaced [(3) H]ifenprodil in mouse brain slices in a similar manner. 23606503 Receptor-Specific Delivery of Protein Antigen to Dendritic Cells by a Nanoemulsion Formed Using Top-Down Non-Covalent Click Self-Assembly. A new class of targeted and immune-evading nanocarrier made using only biological components and facile processes is assembled in a bottom-up fashion. Simple top-down sequential addition of immune-evading or receptor-specific antibody elements conjugated to biosurfactant protein DAMP4 promotes self-assembly at an interface previously formed in the presence of peptide surfactant AM1, leading to a functional display at the interface through non-covalent molecular self-assembly. 23411290 Quality and antioxidant properties of breads enriched with dry onion (Allium cepa L.) skin. The aim of the study was to investigate the effect on the antioxidant properties and sensory value of bread of adding ground onion skin (OS). For a determination of bioaccessibility and bioavailability in vitro the human gastrointestinal tract model was used. OS contained mastication-extractable quercetin (4.6 mg/g). Quercetin from OS was highly bioaccessible during in vitro conditions, but only approximately 4% of quercetin released during simulated digestion was bioavailable in vitro. The antioxidant potential of bread with OS was significantly higher than the activity noted in the control. In particular, OS addition significantly fortificated bread with bioaccessible lipid oxidation preventers and compounds with reducing and chelating abilities. The 2-3% OS addition caused significant improvement of antioxidant abilities (further increases in the OS supplement did not increase the activity of bread). Sensory evaluation showed that replacement of wheat flour in bread with up to 3% OS powder gave satisfactory consumer acceptability. 23122115 Batch and continuous synthesis of lactulose from whey lactose by immobilized β-galactosidase. In this study, lactulose synthesis from whey lactose was investigated in batch and continuous systems using immobilized β-galactosidase. In the batch system, the optimal concentration of fructose for lactulose synthesis was 20%, and the effect of galactose, glucose and fructose on β-galactosidase activity was determined for hydrolysis of whey lactose and the transgalactosylation reaction for lactulose synthesis. Galactose and fructose were competitive inhibitors, and glucose acted as a noncompetitive inhibitor. The inhibitory effects of galactose and glucose were stronger in the transgalactosylation reaction than they were in the hydrolysis reaction. In addition, when immobilized β-galactosidase was reused for lactulose synthesis, its catalytic activity was retained to the extent of 52.9% after 10 reuses. Lactulose was synthesized continuously in a packed-bed reactor. We synthesized 19.1g/l lactulose during the continuous flow reaction at a flow rate of 0.5 ml/min. 23347001 Biotransformation and pharmacokinetics of inositol hexanicotinate in rats. Abstract 1. Inositol hexanicotinate (IHN) is an ester of the anti-hyperlipidemic drug nicotinic acid (NA). This study assessed the hydrolysis rate of IHN in human and rat plasma, and pharmacokinetics of the drug using a rat animal model. 2. IHN (10 or 50 µg/mL) was incubated in plasma at 37 °C for 72 h. Kinetic parameters were determined based on the disappearance of IHN and the appearance of NA. The mean IHN disappearance and NA appearance half-lives were 1.07 and 3.93 h in human plasma, and 0.152 and 2.68 h in rat plasma. Increasing the initial plasma concentration to 50 µg/mL increased the NA appearance half-life in human and rat plasma to 4.66 and 6.47 h, respectively. 3. After single 50 or 100 mg/kg intravenous dose of IHN to Sprague-Dawley rats, the drug showed statistically significant dose-dependent alterations in systemic clearance, suggesting a non-linear saturable elimination of IHN. Dose-normalized mean plasma levels of NA increased by 30% with increasing IHN dose (p < 0.02). The mean metabolic ratio (i.e. NA/IHN AUC ratio) significantly increased with increasing IHN dose (p < 0.05). 4. The results provide first indication of saturable elimination and rapid disappearance of IHN, while niacin was slowly formed. 22982569 Leptin overexpression in VTA trans-activates the hypothalamus whereas prolonged leptin action in either region cross-desensitizes. High-fat feeding or CNS leptin overexpression in chow-fed rats results in a region-specific cellular leptin resistance in medial basal hypothalamic regions and the ventral tegmental area (VTA). The present investigation examined the effects of targeted chronic leptin overexpression in the VTA as compared with the medial basal hypothalamus on long-term body weight homeostasis. The study also examined if this targeted intervention conserves regional leptin sensitivity or results in localized leptin resistance. Cellular leptin resistance was assessed by leptin-stimulated phosphorylation of signal transducers and activators of transcription 3 (STAT3). Tyrosine hydroxylase was measured in hypothalamus and VTA along with brown adipose tissue uncoupling protein 1. Leptin overexpression in VTA tempered HF-induced obesity, but to a slightly lesser extent than that with leptin overexpression in the hypothalamus. Moreover, the overexpression of leptin in the VTA stimulated cellular STAT3 phosphorylation in several regions of the medial basal hypothalamus, whereas verexpression in the hypothalamus did not activate STAT3 signaling in the VTA. This unidirectional trans-stimulation did not appear to involve migration of either the vector or the gene product. Long-term leptin overexpression in either the medial basal hypothalamus or VTA caused desensitization of leptin signaling in the treated region and cross-desensitization of leptin signaling in the untreated region. These results demonstrate a role of leptin receptors in the VTA in long-term body weight regulation, but the trans-activation of the hypothalamus following VTA leptin stimulation suggests that an integrative response involving both brain regions may account for the observed physiological outcomes. 23341196 Central ghrelin signaling mediates the metabolic response of C57BL/6 male mice to chronic social defeat stress. Chronic stressors promote metabolic disturbances, including obesity and metabolic syndrome. Ghrelin, a peptide that promotes appetite and the accumulation of adipose tissue, is also secreted in response to stressors to protect the brain and peripheral tissues from the effects of these stressors. Here we demonstrate that elevated ghrelin levels produced by chronic exposure to social stress are associated with increased caloric intake and body weight gain in male C57BL mice. In contrast, stressed mice lacking ghrelin receptors (GHSR KO mice) or C57BL mice receiving chronic intracerebroventricular delivery of the ghrelin receptor antagonist [d-Lys(3)]-GHRP-6 show attenuated weight gain and feeding responses under the same social stress paradigm. Interestingly, stressed GHSR KO mice showed depleted sc and intrascapular brown fat depots, whereas stressed young wild-type mice did not. In old wild-type mice, chronic social defeat increased visceral and intrascapular brown fat depots in association with increases in obesity markers like hyperleptinemia and hyperinsulinemia along with increased hypothalamic expression of neuropeptide Y and Agouti related peptide. Importantly, the elevated expression of these peptides persisted least for 2 weeks after cessation of the stressor regimen. In contrast, old GHSR KO mice did not show these alterations after chronic social defeat. These results suggest that ghrelin plays an important role in the metabolic adaptations necessary to meet the energetic demands posed by stressors, but chronic exposure to stress-induced ghrelin elevations ultimately could lead to long lasting metabolic dysfunctions. 23232079 Citalopram at the recommended human doses after long-term treatment is genotoxic for male germ cell. The present study was aimed to examine if multiple oral administration of citalopram, an antidepressant drug, has any genotoxic potential on germ cells of male mice. Mice were treated with citalopram for 4 or 8 weeks at the doses of 6, 12 and 24 mg/kg/day and were sacrificed 24 h after the last dose. Multiple exposures to 12 and 24 mg/kg/day citalopram significantly increased sperm DNA strand breaks (14.0 and 16.0, respectively, compared to the concurrent control of 6.8 at week 4 and 15.2 and 20.7, respectively, compared to the concurrent control of 7.2 at week 8) and aberrant primary spermatocytes (6.6% and 7.6%, respectively, compared to the control of 2.8% at week 4 and 7.4% and 8.4%, respectively, compared to the control of 3.2% at week 8) as well as oxidative DNA damage (2.7 and 3.1, respectively, compared to the control of 1.6 at week 4 and 3.3 and 3.9, respectively, compared to the control of 1.7 at week 8). Overall, this study provides that citalopram at the recommended human doses after long-term treatment is genotoxic for mouse germ cells. Thus, male patients receiving citalopram may stand at higher risk for abnormal reproductive outcomes, particularly in the reproductive ages. 23607484 The Relationship between Charge Density and Polyelectrolyte Brush Profile Using Simultaneous Neutron Reflectivity and In Situ Attenuated Total Internal Reflection FTIR. We report on a novel experimental study of a pH-responsive polyelectrolyte brush at the silicon/D2O interface. A poly[2-(diethylamino)ethyl methacrylate] brush was grown on a large silicon crystal which acted as both a substrate for a neutron reflectivity solid/liquid experiment but also as an FTIR-ATR spectroscopy crystal. This arrangement has allowed for both neutron reflectivities and FTIR spectroscopic information to be measured in parallel. The chosen polybase brush shows strong IR bands which can be assigned to the N-D(+) stretch, D2O, and a carbonyl group. From such FTIR data, we are able to closely monitor the degree of protonation along the polymer chain as well as revealing information concerning the D2O concentration at the interface. The neutron reflectivity data allows us to determine the physical brush profile normal to the solid/liquid interface along with the corresponding degree of hydration. This combined approach makes it possible to quantify the charge on a polymer brush alongside the morphology adopted by the polymer chains. 23202846 Design, synthesis and crystallographic analysis of nitrile-based broad-spectrum peptidomimetic inhibitors for coronavirus 3C-like proteases. Coronaviral infection is associated with up to 5% of respiratory tract diseases. The 3C-like protease (3CL(pro)) of coronaviruses is required for proteolytic processing of polyproteins and viral replication, and is a promising target for the development of drugs against coronaviral infection. We designed and synthesized four nitrile-based peptidomimetic inhibitors with different N-terminal protective groups and different peptide length, and examined their inhibitory effect on the in-vitro enzymatic activity of 3CL(pro) of severe-acute-respiratory-syndrome-coronavirus. The IC(50) values of the inhibitors were in the range of 4.6-49 μM, demonstrating that the nitrile warhead can effectively inactivate the 3CL(pro) autocleavage process. The best inhibitor, Cbz-AVLQ-CN with an N-terminal carbobenzyloxy group, was ~10x more potent than the other inhibitors tested. Crystal structures of the enzyme-inhibitor complexes showed that the nitrile warhead inhibits 3CL(pro) by forming a covalent bond with the catalytic Cys145 residue, while the AVLQ peptide forms a number of favourable interactions with the S1-S4 substrate-binding pockets. We have further showed that the peptidomimetic inhibitor, Cbz-AVLQ-CN, has broad-spectrum inhibition against 3CL(pro) from human coronavirus strains 229E, NL63, OC43, HKU1, and infectious bronchitis virus, with IC(50) values ranging from 1.3 to 3.7 μM, but no detectable inhibition against caspase-3. In summary, we have shown that the nitrile-based peptidomimetic inhibitors are effective against 3CL(pro), and they inhibit 3CL(pro) from a broad range of coronaviruses. Our results provide further insights into the future design of drugs that could serve as a first line defence against coronaviral infection. 23274087 6-OHDA-induced apoptosis and mitochondrial dysfunction are mediated by early modulation of intracellular signals and interaction of Nrf2 and NF-κB factors. 6-Hydroxydopamine (6-OHDA) is a neurotoxin that generates an experimental model of Parkinson's disease in rodents and is commonly employed to induce a lesion in dopaminergic pathways. The characterization of those molecular mechanisms linked to 6-OHDA-induced early toxicity is needed to better understand the cellular events further leading to neurodegeneration. The present work explored how 6-OHDA triggers early downstream signaling pathways that activate neurotoxicity in the rat striatum. Mitochondrial function, caspases-dependent apoptosis, kinases signaling (Akt, ERK 1/2, SAP/JNK and p38) and crosstalk between nuclear factor kappa B (NF-κB) and nuclear factor-erythroid-2-related factor 2 (Nrf2) were evaluated at early times post-lesion. We found that 6-OHDA initiates cell damage via mitochondrial complex I inhibition, cytochrome c and apoptosis-inducing factor (AIF) release, as well as activation of caspases 9 and 3 to induce apoptosis, kinase signaling modulation and NF-κB-mediated inflammatory responses, accompanied by inhibition of antioxidant systems regulated by the Nrf2 pathway. Our results suggest that kinases SAP/JNK and p38 up-regulation may play a role in the early stages of 6-OHDA toxicity to trigger intrinsic pathways for apoptosis and enhanced NF-κB activation. In turn, these cellular events inhibit the activation of cytoprotective mechanisms, thereby leading to a condition of general damage. 23274767 Cationic nanoparticles disrupt cellular signaling in a cholesterol dependent manner. In this study, we investigate the interaction of charged polystyrene particles with respiratory epithelial cells. Experiments were designed to reveal the effect of cellular interaction with particles of varying size and charge and how such interactions could alter cytokine induced cellular processes. A549 cells, containing a stably transfected Interleukin-8 (IL-8) Luciferase promoter construct, were cultured in the presence of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) and polystyrene particles for 4.5h. Several endpoints were measured: IL-8 gene expression, IL-6 protein, IL-8 protein, and NF-кB translocation. At 4.5h, cellular viability was maintained for the particle exposed cells. Interestingly, we found that only the cationic nanoparticles have the ability to disrupt the TNF-α stimulated cellular signaling by reducing the IL-8 promoter activity, IL-6 and IL-8 protein. Cationic nanoparticles reduce these processes through interfering with NF-κB translocation. However, the activity of the cationic nanoparticles on the IL-8 promoter and NF-κB translocation is lost when cholesterol is depleted from A549 cells before particle exposure, which suggests that cationic nanoparticles rely on membrane cholesterol integrity to disrupt cellular signaling. 23311976 Evaluation of Coumarin and Neoflavone Derivatives as HCV NS5B Polymerase Inhibitors. Coumarins and coumestans represent an important family of compounds with diverse pharmacological properties. We recently identified coumestans as novel inhibitors of hepatitis C virus NS5B polymerase and predicted their binding in thumb pocket-1 (TP-1) of NS5B. As the coumarins are structurally related to coumestans by virtue of their common A- and B-rings, we postulated them to also exhibit similar binding interaction with NS5B and inhibit its polymerase function. We therefore investigated 24 coumarin and neoflavone derivatives as candidate NS5B inhibitors and identified 14 compounds inhibiting NS5B polymerase activity with IC50 values between 17 and 63 μm. Of these, the newly synthesized 6,8-diallyl-5,7-dihydroxycoumarin (8a) was produced in three steps in high chemical yield from floroglucinol and found to be the most potent of this series, exhibiting activity similar to the reference coumestan LQB-34. The binding site of 8a was mapped to TP-1 of NS5B by counter screening against P495L NS5B mutant, employed as a screen for TP-1 site binders. NS5B-TP-1-8a interaction map provided insight into 8a binding and offered clues for future SAR optimization. 23551063 A high throughput assay for the glucuronidation of 7-hydroxy-4-trifluoromethylcoumarin by recombinant human UDP-glucuronosyltransferases and liver microsomes. Abstract 1.  UDP-glucuronosyltransferases (UGTs) are versatile and important conjugation enzymes in the metabolism of drugs and other xenobiotics. 2.  We have developed a convenient quantitative multi-well plate assay to measure the glucuronidation rate of 7-hydroxy-4-trifluoromethylcoumarin (HFC) for several UGTs. 3.  We have used this method to screen 11 recombinant human UGTs for HFC glucuronidation activity and studied the reaction kinetics with the most active enzymes. We have also examined the HFC glucuronidation activity of liver microsomes from human, pig, rabbit and rat. 4.  At a substrate concentration of 20 µM, the most active HFC glucuronidation catalysts were UGT1A10 followed by UGT1A6 >UGT1A7 >UGT2A1, whereas at 300 µM UGT1A6 was about 10 times better catalyst than the other recombinant UGTs. The activities of UGTs 1A3, 1A8, 1A9, 2B4 and 2B7 were low, whereas UGT1A1 and UGT2B17 exhibited no HFC glucuronidation activity. UGT1A6 exhibited a significantly higher Vmax and Km values toward both HFC and UDP-glucuronic acid than the other UGTs. 5.  Human, pig and rabbit, but not rat liver microsomes, catalyzed HFC glucuronidation at high rates. 6.  This new method is particularly suitable for fast activity screenings of UGTs 1A6, 1A7, 1A10 and 2A1 and HFC glucuronidation activity determination from various samples. 23232323 New amide alkaloids from Piper longum. Bioassay-guided phytochemical investigation on Piper longum resulted in the isolation of two new compounds. By analyses of the MS, IR, UV, 1D and 2D NMR data, the two new compounds were identified as 3β, 4α-dihydroxy-1-(3-phenylpropanoyl)-piperidine-2-one (1) and (2E, 4E, 14Z)-6-hydroxyl-N-isobutyleicosa-2,4,14-trienamide (2). In vitro anti-HBV bioassay demonstrated compound 1 possessed remarkable activity suppressing the secretion of HBeAg in Hep G2.2.15 cell line, with an IC(50) value of 0.21mM and SI value of 16.4. 23411507 High serum vitamin D levels reduce the risk for nonalcoholic fatty liver disease in healthy men independent of metabolic syndrome. Recent studies suggest an association of vitamin D with obesity, diabetes and cardiovascular diseases. We analyzed the association of serum vitamin D level assessed by 25-hydroxyvitamin D(3) {25(OH)D(3)} with nonalcoholic fatty liver disease (NAFLD) in apparently healthy men. We performed a cross-sectional study of 6,567 Korean men who participated in a health screening program, evaluating the association of serum 25(OH)D(3) levels with the risk of NAFLD assessed by abdominal ultrasonogram. Of the participants, 43.6% had NAFLD and 21.1% had metabolic syndrome. Age, serum calcium, and aspartate aminotransferase levels showed weak but significant positive correlations with 25(OH)D(3) level; total cholesterol, triglycerides, low-density lipoprotein cholesterol and fasting insulin level showed weak but significant negative correlations with 25(OH)D(3) level. The mean 25(OH)D(3) level was significantly lower in participants with NAFLD than in those without (38.7 ± 9.0 vs. 39.7 ± 9.7 nmol/L, p < 0.001). When participants were divided into tertiles based on mean 25(OH)D(3) level, the proportion with NAFLD significantly increased as mean 25(OH)D(3) level decreased (40.0, 45.0 and 45.9%, p for linear trend < 0.001). Multiple logistic regression analyses with NAFLD as the dependent variable showed that the tertiles with lower 25(OH)D(3) levels had a significantly increased risk for NAFLD compared with the highest tertile, even after adjusting for body mass index and metabolic syndrome (OR 1.247 and 1.408 vs. the highest tertile, p < 0.001). Thus, participants with higher serum 25(OH)D(3) showed a significantly reduced risk for NAFLD compared with the low 25(OH)D(3) groups, independent of obesity and metabolic syndrome. 23154533 The onset of antineutrophil cytoplasmic antibody-associated vasculitis immediately after methimazole was switched to propylthiouracil in a woman with Graves' disease who wished to become pregnant. Propylthiouracil (PTU) is recommended as a first-line antithyroid drug (ATD) during first trimester organogenesis in pregnancy because recent evidence suggests that methimazole (MMI) may be associated with congenital anomalies. However, PTU more commonly causes myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, which usually occurs during prolonged treatment, compared with MMI. We report a case of MPO-ANCA-associated vasculitis in a 35-year-old woman with Graves'disease. Although her thyroid function could be maintained euthyroid by MMI, her ATD was switched to PTU because she wished to become pregnant. The patient presented with flu-like symptoms 8 days after starting PTU and developed hemoptysis and dyspnea at 22 days. Her MPO-ANCA titer was 21 ELISA units (EUs) before PTU treatment but increased to 259 EUs at 22 days after PTU treatment. Her clinical condition improved with the discontinuation of PTU and with immunosuppressive therapy. This case indicated that MPO-ANCA vasculitis occurred within several weeks after the initiation of PTU and that this side effect could be caused by the change from MMI to PTU. Thus, our clinical observation suggests that patients treated with PTU should be carefully monitored for MPO-ANCA titers and variable manifestations of MPO-ANCA-associated vasculitis regardless of the period of administration. 23400254 Probing the dielectric response of graphene via dual-band plasmonic nanoresonators. In this article, we use optical transmission spectroscopy to measure the changes in the resonance features of a Au plasmonic nanoresonator array consisting of concentric ring/disc cavity elements, when graphene is introduced as an encapsulating medium. We show that by using finite element modelling to best reproduce our experimental results the dielectric response of the graphene film can be determined. We discuss the potential of such structures for chemical sensing applications. 23497877 PSP activates monocytes in resting human peripheral blood mononuclear cells: immunomodulatory implications for cancer treatment. Polysaccharopeptide (PSP), from Coriolus versicolor, has been used as an adjuvant to chemotherapy, and has demonstrated anti-tumor and immunomodulating effects. However its mechanism remains unknown. To elucidate how PSP affects immune populations, we compared PSP treatments both with and without prior incubation in phytohaemagglutinin (PHA) - a process commonly used in immune population experimentation. We first standardised a capillary electrophoresis fingerprinting technique for PSP identification and characterisation. We then established the proliferative capability of PSP on various immune populations in peripheral blood mononuclear cells, using flow cytometry, without prior PHA treatment. It was found that PSP significantly increased the number of monocytes (CD14(+)/CD16(-)) compared to controls without PHA. This increase in monocytes was confirmed using another antibody panel of CD14 and MHCII. In contrast, proliferations of T-cells, NK, and B-cells were not significantly changed by PSP. Thus, stimulating monocyte/macrophage function with PSP could be an effective therapeutic intervention in targeting tumors. 23010360 A novel, potent, and selective inhibitor of cardiac late sodium current suppresses experimental arrhythmias. Inhibition of cardiac late sodium current (late I(Na)) is a strategy to suppress arrhythmias and sodium-dependent calcium overload associated with myocardial ischemia and heart failure. Current inhibitors of late I(Na) are unselective and can be proarrhythmic. This study introduces GS967 (6-[4-(trifluoromethoxy)phenyl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine), a potent and selective inhibitor of late I(Na), and demonstrates its effectiveness to suppress ventricular arrhythmias. The effects of GS967 on rabbit ventricular myocyte ion channel currents and action potentials were determined. Anti-arrhythmic actions of GS967 were characterized in ex vivo and in vivo rabbit models of reduced repolarization reserve and ischemia. GS967 inhibited Anemonia sulcata toxin II (ATX-II)-induced late I(Na) in ventricular myocytes and isolated hearts with IC(50) values of 0.13 and 0.21 µM, respectively. Reduction of peak I(Na) by GS967 was minimal at a holding potential of -120 mV but increased at -80 mV. GS967 did not prolong action potential duration or the QRS interval. GS967 prevented and reversed proarrhythmic effects (afterdepolarizations and torsades de pointes) of the late I(Na) enhancer ATX-II and the I(Kr) inhibitor E-4031 in isolated ventricular myocytes and hearts. GS967 significantly attenuated the proarrhythmic effects of methoxamine+clofilium and suppressed ischemia-induced arrhythmias. GS967 was more potent and effective to reduce late I(Na) and arrhythmias than either flecainide or ranolazine. Results of all studies and assays of binding and activity of GS967 at numerous receptors, transporters, and enzymes indicated that GS967 selectively inhibited late I(Na). In summary, GS967 selectively suppressed late I(Na) and prevented and/or reduced the incidence of experimentally induced arrhythmias in rabbit myocytes and hearts. 23432062 TRP Channels in Vascular Disorders. In recent years, research on the roles of TRP channels in vascular function and disease has undergone a rapid expansion from tens of reports published in the early 2000s to several hundreds of papers published to date. Multiple TRP subtypes are expressed in vascular smooth muscle cells and endothelial cells, where they form diverse non-selective cation channels permeable to Ca2+. These channels mediate Ca2+ entry following receptor stimulation, Ca2+ store depletion and mechanical stimulation of vascular myocytes and endothelial cells. The complex molecular composition and signalling pathways leading to the activation of various vascular TRP channels and the growing evidence for their involvement in various vascular disorders, including dysregulation of vascular tone and hypertension, impaired endothelium-dependent vasodilatation, increased endothelial permeability, occlusive vascular disease, vascular injury and oxidative stress, are summarised and discussed in this review. 23174748 Anti-inflammatory properties of anthraquinones and their relationship with the regulation of P-glycoprotein function and expression. There is a growing interest in natural products that potentially have anti-inflammatory properties and inhibit P-glycoprotein (P-gp) function. In this report, we assessed the effects of anthraquinone derivatives from rhubarb on LPS-induced RAW 264.7 macrophages to determine their anti-inflammatory potential. The derivatives were also tested in Caco-2 cell lines to evaluate the inhibition of the drug efflux function of P-gp. The transport abilities were examined and the cellular accumulation of rhodamine-123 (R-123) was also measured. Electorphoretic mobility shift assay (EMSA) was performed to check the activator protein-1 (AP-1) DNA binding affinity. Five anthraquinones were tested to determine their inhibitory activities on NO production and the protein and mRNA expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, the level of prostaglandin E(2) (PGE(2)) was determined in LPS-induced RAW264.7 macrophages. Emodin was found to be the most potent inhibitor, and it also reduced paw swelling in the mouse model of carrageenan-induced paw edema. In Caco-2 cells, emodin elevated the accumulation of R-123 and decreased the efflux ratio of R-123, which indicates the inhibition of P-gp function. The inhibition of COX-2 protein by emodin paralleled the decrease in P-gp expression. In addition, mitogen-activated protein kinase (MAPK) expression was decreased through the prevention of AP-1 DNA binding, which leads to downregulation in the expression of P-gp. Our data indicate that the decrease of P-gp expression is caused by the decreased expression of COX-2 through the MAPK/AP-1 pathway. Based on our results, we suggest that anti-inflammatory drugs with COX-2 inhibitory activity might be used to modulate P-gp function and expression. 23350690 In vivo microdialysis for the evaluation of transfersomes as a novel transdermal delivery vehicle for cinnamic acid. Abstract In this study, cinnamic acid-loaded transfersomes were prepared and dermal microdialysis sampling was used in Sprague-Dawley rats to compare the amount of drug released into the skin using transfersomes as transdermal carriers with that released on using conventional liposomes. The formulation of cinnamic acid-loaded transfersomes was optimized by a uniform design through in vitro transdermal permeation studies. Hydration time was confirmed as a significant factor influencing the entrapment efficiency of transfersomes, further affecting their transdermal flux in vitro. The fluxes of cinnamic acid from transfersomes were all higher than those from conventional liposomes, and the flux from the optimal transfersome formulation was 3.01-fold higher than that from the conventional liposomes (p < 0.05). An in vivo microdialysis sampling method revealed that the dermal drug concentrations from transfersomes applied on various skin regions were much lower than those required with conventional liposomes. After the administration of drug-containing transfersomes and liposomes on abdominal skin regions of rats for a period of 10 h, the C(max) of cinnamic acid from the compared liposomes was 3.21 ± 0.25 μg/mL and that from the transfersomes was merely 0.59 ± 0.02 μg/mL. The results suggest that transfersomes can be used as carriers to enhance the transdermal delivery of cinnamic acid, and that these vehicles may penetrate the skin in the complete form, given their significant deformability. 23382458 Characterization of efflux transporters involved in distribution and disposition of apixaban. The studies reported here were conducted to investigate the transport characteristics of apixaban (1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide) and to understand the impact of transporters on apixaban distribution and disposition. In human permeability glycoprotein (P-gp)- and breast cancer resistance protein (BCRP)-cDNA-transfected cell monolayers as well as Caco-2 cell monolayers, the apparent efflux ratio of basolateral-to-apical (PcB-A) versus apical-to-basolateral permeability (PcA-B) of apixaban was >10. The P-gp- and BCRP-facilitated transport of apixaban was concentration- and time-dependent and did not show saturation over a wide range of concentrations (1-100 μM). The efflux transport of apixaban was also demonstrated by the lower mucosal-to-serosal permeability than that of the serosal-to-mucosal direction in isolated rat jejunum segments. Apixaban did not inhibit digoxin transport in Caco-2 cells. Ketoconazole decreased the P-gp-mediated apixaban efflux in Caco-2 and the P-gp-cDNA-transfected cell monolayers, but did not affect the apixaban efflux to a meaningful extent in the BCRP-cDNA-transfected cell monolayers. Coincubation of a P-gp inhibitor (ketoconazole or cyclosporin A) and a BCRP inhibitor (Ko134) provided more complete inhibition of apixaban efflux in Caco-2 cells than separate inhibition by individual inhibitors. Naproxen inhibited apixaban efflux in Caco-2 cells but showed only a minimal effect on apixaban transport in the BCRP-transfected cells. Naproxen was the first nonsteroidal antiinflammatory drug that was demonstrated as a weak P-gp inhibitor. These results demonstrate that apixaban is a substrate for efflux transporters P-gp and BCRP, which can help explain its low brain penetration, and low fetal exposures and high milk excretion in rats. 23643883 Streptococcus pneumoniae ClpP protease induces apoptosis via caspase-independent pathway in human neuroblastoma cells: cytoplasmic relocalization of p53. Streptococcus pneumoniae causes the most severe form of the bacterial meningitis which is the major cause of bacterial meningitis. Virulence factors produced by S. pneumoniae have been known to contribute significantly to the disease process. ClpP protease (ClpP) which is essential for virulence and survival under stress conditions in S. pneumonia was examined for the ability to induce apoptosis and the mechanism of the induction of apoptosis in human neuron-like cells, SK-N-SH neuroblastoma cells. ClpP inhibited cell growth and induced apoptosis in SK-N-SH cells. Treatment with ClpP resulted in hypodiploid DNA contents, increased Bax/ Bcl-2 ratio and induction of reactive oxygen species (ROS) production. The release of cytochrome c from mitochondria into the cytosol, which is an initiator of the activation of caspase cascades, was not observed in ClpP-treated cells. In addition, pretreatment with Z-Val-Ala-Asp-fluoromethylketone (Z-VAD-fmk), a broad spectrum of caspase inhibitor, could not rescue apoptotic cells from ClpP toxicity. Coincidently, caspase-3 and -8 activation and cleavage of PARP were not detected. Moreover, caspase independent apoptosis-inducing factor (AIF) was released from mitochondria and translocated to the nucleus in response to ClpP. We also found that ClpP treatment resulted in the increase of p53 activity and cytoplasmic p53 levels were increased by ClpP, suggesting that functional activation of p53 is intact despite increased cytoplasmic accumulation. Taken together, these data suggest that ClpP contributes to neuronal damage in meningitis and provide further insight into the mechanisms underlying action of pneumococcal virulence factors during bacterial pathogenesis. 23394067 Hyperbranched Polyester Hydrogels with Controlled Drug Release and Cell Adhesion Properties. Hyperbranched polyesters (HPE) have a high efficiency to encapsulate bioactive agents, including drugs, genes, and proteins, due to their globe-like nanostructure. However, the use of these highly branched polymeric systems for tissue engineering applications has not been broadly investigated. Here, we report synthesis and characterization of photocrosslinkable HPE hydrogels with sustained drug release characteristics for cellular therapies. These HPE can encapsulate hydrophobic drug molecules within the HPE cavities due to the presence of a hydrophobic inner structure that is otherwise difficult to achieve in conventional hydrogels. The functionalization of HPE with photocrosslinkable acrylate moieties renders the formation of hydrogels with a highly porous interconnected structure and mechanically tough network. The compressive modulus of HPE hydrogels was tunable by changing the crosslinking density. The feasibility of using these HPE networks for cellular therapies was investigated by evaluating cell adhesion, spreading, and proliferation on hydrogel surface. Highly crosslinked and mechanically stiff HPE hydrogels have higher cell adhesion, spreading, and proliferation compared to soft and complaint HPE hydrogels. Overall, we showed that hydrogels made from HPE could be used for biomedical applications that require spatial control of cell adhesion and controlled release of hydrophobic clues. 23531865 Population structure, migration, and diversifying selection in the Netherlands. Genetic variation in a population can be summarized through principal component analysis (PCA) on genome-wide data. PCs derived from such analyses are valuable for genetic association studies, where they can correct for population stratification. We investigated how to capture the genetic population structure in a well-characterized sample from the Netherlands and in a worldwide data set and examined whether (1) removing long-range linkage disequilibrium (LD) regions and LD-based SNP pruning significantly improves correlations between PCs and geography and (2) whether genetic differentiation may have been influenced by migration and/or selection. In the Netherlands, three PCs showed significant correlations with geography, distinguishing between: (1) North and South; (2) East and West; and (3) the middle-band and the rest of the country. The third PC only emerged with minimized LD, which also significantly increased correlations with geography for the other two PCs. In addition to geography, the Dutch North-South PC showed correlations with genome-wide homozygosity (r=0.245), which may reflect a serial-founder effect due to northwards migration, and also with height (♂: r=0.142, ♀: r=0.153). The divergence between subpopulations identified by PCs is partly driven by selection pressures. The first three PCs showed significant signals for diversifying selection (545 SNPs - the majority within 184 genes). The strongest signal was observed between North and South for the functional SNP in HERC2 that determines human blue/brown eye color. Thus, this study demonstrates how to increase ancestry signals in a relatively homogeneous population and how those signals can reveal evolutionary history.European Journal of Human Genetics advance online publication, 27 March 2013; doi:10.1038/ejhg.2013.48. 22456000 Isolation of a p-hydroxyphenyl anhydride from the leaves of Diphysa carthagenensisw. Diphysidione (1), a new p-hydroxyphenyl anhydride, and vitexin (2) were isolated from the leaves of Diphysa carthagenensis. The structure of the new metabolite was characterised as 4-(4-hydroxy-phenyl)-3H-pyran-2,6-dione using 1D and 2D NMR spectroscopy. 23194569 Field application of farm-food safety risk assessment (FRAMp) tool for small and medium fresh produce farms. The objective of this study was to develop a farm food safety-risk assessment tool (FRAMp) which serves as a self-assessment and educational tool for fresh produce farms. FRAMp was developed in Microsoft® Excel spreadsheet software using standard mathematical and logical functions and utilised a qualitative risk assessment approach for farmers to evaluate their food safety practices. The FRAMp tool has since been tested on 12 fresh produce farms throughout UK. All the farms determined that FRAMp was interesting but 17% found it too long while 25% of the farms felt the tool was too complicated. The instructions on FRAMp usage were revised and farmers were given the options to skip and select specific steps in the farm risk assessment. The end users (farmers/farm managers) determined that developing their own action plans and using it as proof of assessment for future third-party audits were most useful to them. FRAMp tool can be described as an illustrative risk ranking tool to facilitate farms to identify potential risk factors during their crop production. 23422566 Molecular tweezers modulate 14-3-3 protein-protein interactions. Supramolecular chemistry has recently emerged as a promising way to modulate protein functions, but devising molecules that will interact with a protein in the desired manner is difficult as many competing interactions exist in a biological environment (with solvents, salts or different sites for the target biomolecule). We now show that lysine-specific molecular tweezers bind to a 14-3-3 adapter protein and modulate its interaction with partner proteins. The tweezers inhibit binding between the 14-3-3 protein and two partner proteins--a phosphorylated (C-Raf) protein and an unphosphorylated one (ExoS)--in a concentration-dependent manner. Protein crystallography shows that this effect arises from the binding of the tweezers to a single surface-exposed lysine (Lys214) of the 14-3-3 protein in the proximity of its central channel, which normally binds the partner proteins. A combination of structural analysis and computer simulations provides rules for the tweezers' binding preferences, thus allowing us to predict their influence on this type of protein-protein interactions. 23567963 Biological evaluation of bisbenzaldehydes against four Mycobacterium species. A series of bisbenzaldehydes and structurally related analogs, conveniently synthesized via microwave-assisted reactions, were evaluated in vitro against drug susceptible and multi-drug resistant Mycobacterium tuberculosis, against virulent Mycobacterium bovis, against Mycobacterium ulcerans and against two Mycobacterium avium subspecies. Among the 33 substances that were tested, compound 12, i.e. 4,4'-[1,12-dodecanediyl(oxy)]bisbenzaldehyde, emerged as the most promising hit. Its activity was further confirmed in an intracellular growth inhibition assay of M. tb in murine J774 A.1 macrophages. None of the compounds showed significant cytotoxicity on human C3A hepatocytes in a neutral red dye uptake assay and no genotoxicity or mutagenicity was observed as demonstrated by a VITOTOX™ test and confirmed with a comet assay. 23314308 Electrical field stimulation (EFS)-induced relaxations turn into contractions upon removal of extracellular calcium in rat mesenteric artery. In the present study, we aimed to examine the effect of blockade of L-type Ca(2+) channels (LTCC) and in addition the removal of extracellular Ca(2+), on EFS-induced relaxations in rings of rat mesenteric artery. EFS applied to the tissues precontracted with phenylephrine caused relaxations which were markedly inhibited by nifedipine (10(-7)M) and tetraethylammonium (TEA) (1mM). Addition of LTCC opener BAY K 8644 (10(-7)M) failed to enhance the relaxations. Upon removal of Ca(2+), EFS with the same stimulation parameters produced frequency-dependent transient contractions. Tetrodotoxin (10(-6)M), capsaicin (10(-5)M) and removal of endothelium did not alter these contractions suggesting that they were not neural in origin and endothelium-derived contracting factors were unlikely to be involved. However, they were increased by nearly 40% in response to BAY K 8644 (10(-7)M) and were inhibited by nifedipine (10(-7)M), indicating that activation of the LTCCs was essential. Inositol triphosphate (InsP3) receptor antagonist 2-APB (10(-4)M) significantly reduced, and high concentration of caffeine (20mM) almost totally suppressed the contractions. These results suggest that in the absence of extracellular Ca(2+) EFS through membrane depolarization, evokes the opening of the LTCCs which subsequently leads to the release of Ca(2+) from internal stores via InsP3 receptors, a phenomenon known as Ca(2+) channel-induced Ca(2+) release (CCICR), to trigger vasoconstriction. That activation of LTCCs causes arterial relaxation or contraction depending on the Ca(2+) status apparently exemplifies how the same messenger fulfils opposing physiological functions in a given cell. 23418956 Soluble conjugated one-dimensional nanowires prepared by topochemical polymerization of a butadiynes-containing star-shaped molecule in the xerogel state. A star-shaped molecule with three butadiyne moieties attached to a central phenyl core was self-assembled via organogel formation in different solvents and subjected to UV irradiation in its xerogels form to give a soluble conjugated 1D nanowire made of three connected polydiacetylene (PDA) chains. The resulting polymer has a slightly lower optical band gap than its linear counterpart and presents no chromism property, indicative of the rigid nature of the polymer thus obtained. 23157627 Facilitative effect of serotonin(1A) receptor agonists on cognition in patients with schizophrenia. Disturbances of cognitive function are considered to largely affect the outcome in patients with schizophrenia. There is much attention to the role of psychotropic compounds acting on serotonin (5-HT) receptors in ameliorating cognitive deficits of the disease. Among the 5-HT receptor subtypes, the 5-HT(1A) receptor is attracting particular interests as a potential target for enhancing cognition, based on preclinical and clinical evidence. The neural network underlying the ability of 5-HT(1A) agonists to treat cognitive impairments of schizophrenia likely includes dopamine, glutamate, and gamma-aminobutyric acid neurons. Recent advances of electrophysiological measures, such as event-related potentials, have provided insights into facilitative effects on cognition of some atypical antipsychotic drugs or related compounds acting directly or indirectly on 5-HT(1A) receptors. These considerations are expected to promote the development of novel therapeutics for the betterment of functional outcome in people suffering from schizophrenia. 23583495 Interdependency of protein-release completeness and polymer degradation in PLGA-based implants. Release of BSA (model protein) from hot-melt extruded poly(lactide-co-glycolide) (PLGA)-based implants was incomplete. A residual mass of covalent BSA-PLGA adducts was still present after 6months. The objective of this study was to increase the completeness of BSA release. BSA reduced the PLGA degradation and erosion rate as well as the extent of erosion. An increased uptake of release medium in the presence of BSA in addition to the early outflux of PLGA oligomers resulted in a reduction of the matrix acidity and thus reduction of autocatalysis effects. PLGA mass loss was incomplete at 60% and 80% for 10% and 25% BSA-containing implants. The extent of PLGA mass loss was correlated with the total releasable protein. The same release was obtained from implants prepared with pre-degraded PLGA suggesting that the induction phase did not affect the release completeness. Thus, the focus was on the erosion phase to enhance outflux of soluble oligomers. BSA release completeness increased by increasing the porosity of the implants at the onset of erosion phase. This could be obtained with a higher initial porosity, formation of porosity upon higher diffusional release and/or incorporation of pore-formers/plasticizers. Accordingly, the BSA release completeness could be improved by enhancing the outflux of soluble PLGA degradation products. 23467018 Refinement of the ECETOC approach to identify endocrine disrupting properties of chemicals in ecotoxicology. To use and implement an assessment scheme for the evaluation of endocrine disrupting properties of chemicals in ecotoxicology, the types of effect need to be agreed. Effects that merit further consideration in this context should fulfil the following three criteria: caused by an endocrine mode of action, be adverse, and be relevant at the population level to reflect the protection goal of ecotoxicological assessments. Thereafter, a comparison of effect values, regardless of the causative mechanisms, should be made, firstly to determine if endocrine toxicity generates the lowest endpoint within a taxon, and secondly if it is the lowest endpoint compared to that of other taxa living in the same compartment. These comparisons inform on two levels of specificity and determine if endocrine-mediated side-effects determine the ecotoxicological profile of a chemical. Various quantitative measures for the assessment of potency are also presented, which could assist in determining how to handle substances in the risk assessment when a regulatory concern is identified. Finally, derogation criteria should be defined for compounds that were designed as endocrine disruptors for non-vertebrates and those for which there is 'negligible exposure'. This paper discusses and provides proposals on how to apply these concepts for assessment of substances. 23229141 Oxidative folding of peptides with cystine-knot architectures: kinetic studies and optimization of folding conditions. Bioactive peptides often contain several disulfide bonds that provide the main contribution to conformational rigidity and structural, thermal, or biological stability. Among them, cystine-knot peptides-commonly named "knottins"-make up a subclass with several thousand natural members. Hence, they are considered promising frameworks for peptide-based pharmaceuticals. Although cystine-knot peptides are available through chemical and recombinant synthetic routes, oxidative folding to afford the bioactive isomers still remains a crucial step. We therefore investigated the oxidative folding of ten protease-inhibiting peptides from two knottin families, as well as that of an HIV entry inhibitor and of aprotinin, under two conventional sets of folding conditions and by a newly developed procedure. Kinetic studies identified folding conditions that resulted in correctly folded miniproteins with high rates of conversion even for highly hydrophobic and aggregation-prone peptides in concentrated solutions. 23166012 Toxicity evaluation of two typical surfactants to Dunaliella bardawil, an environmentally tolerant alga. Sodium dodecyl benzene sulfonate (SDBS) and cetyl trimethyl ammonium chloride (CTAC) are two kinds of surfactants widely applied in various industries. The tremendous direct discharge of these surfactants into natural waters has posed a significant threat to ecosystems. Dunaliella bardawil was employed in the present research to test the toxic effects of SDBS, CTAC, and their mixture on cell growth, cellular morphology, β-carotene accumulation, and enzymatic activities of superoxide dismutase (SOD) and catalase (CAT). The results showed that SDBS at 200, 550, 900, 1,350, 1,800, and 2,400 mg/L and CTAC at 0.4, 0.7, 1.0, 1.3, 2.8, and 3.5 mg/L inhibited algal growth and β-carotene accumulation, both of which declined and then increased. In particular, CTAC (median inhibitory concentration at 10 days [IC50](10 d)  = 2.8 ± 1.49 mg/L) was more hazardous than SDBS (IC50(10 d)  = 2,044 ± 637.3 mg/L). The additive index (AI) calculated from carotene content data was (-4.10, -1.67) < 0, indicating an antagonistic effect between SDBS and CTAC. Algae cultivated at level 6 of the binary system showed hormesis due to the mitigated toxicity; SDBS at 2,400 mg/L, CTAC at 3.5 mg/L, and combined surfactants at level 6 exerted lethal effects on D. bardawil. Both SOD and CAT activities showed similar associations with varied concentrations of surfactants: SOD was significantly promoted by 550 to 1,800 mg/L SDBS, 0.7 to 1.3 mg/L CTAC, and mixtures at levels 2 to 4; CAT was clearly promoted by 900 mg/L SDBS, 0.4 to 1.3 mg/L CTAC, and mixtures at levels 2 to 4. 23609444 Large lateral movement of transmembrane helix S5 is not required for substrate access to the active site of rhomboid intramembrane protease. Rhomboids represent an evolutionarily ancient protease family. Unlike most other proteases, they are polytopic membrane proteins, and specialize in cleaving transmembrane protein substrates. Rhomboid protease's polar active site is embedded in the membrane, and normally closed. For bacterial rhomboid GlpG, it has been proposed that one of the protease's transmembrane helices (S5) can rotate to open a lateral gate, enabling substrate to enter the protease from inside the membrane. Here we study GlpG's conformational change by solving the cocrystal structure of the protease with a mechanism-based inhibitor. We also examine the lateral gating model by crosslinking S5 to a neighboring helix (S2). The crystal structure shows that inhibitor binding displaces a capping loop (L5) from the active site, but causes only minor shifts of the transmembrane helices. Crosslinking S5 and S2, which not only restricts S5's lateral movement, but also prevents substrate from passing between the two helices, does not hinder the protease's ability to cleave a membrane protein substrate in detergent solution and in reconstituted membrane vesicles. Taken together, these data suggest that a large lateral movement of S5 helix is not required for substrate access to rhomboid protease's active site. 23465048 Protein Targets of Thioacetamide Metabolites in Rat Hepatocytes. Thioacetamide (TA) has long been known as a hepatotoxicant whose bioactivation requires S-oxidation to thioacetamide S-oxide (TASO) and then to the very reactive S,S-dioxide (TASO2). The latter can tautomerize to form acylating species capable of covalently modifying cellular nucleophiles including phosphatidylethanolamine (PE) lipids and protein lysine side chains. Isolated hepatocytes efficiently oxidize TA to TASO but experience little covalent binding or cytotoxicity because TA is a very potent inhibitor of the oxidation of TASO to TASO2. However, hepatocytes treated with TASO show extensive covalent binding to both lipids and proteins accompanied by extensive cytotoxicity. In this work, we treated rat hepatocytes with [(14)C]-TASO and submitted the mitochondrial, microsomal, and cytosolic fractions to 2DGE, which revealed a total of 321 radioactive protein spots. To facilitate the identification of target proteins and adducted peptides, we also treated cells with a mixture of TASO/[(13)C2D3]-TASO. Using a combination of 1DGE- and 2DGE-based proteomic approaches, we identified 187 modified peptides (174 acetylated, 50 acetimidoylated, and 37 in both forms) from a total of 88 nonredundant target proteins. Among the latter, 57 are also known targets of at least one other hepatotoxin. The formation of both amide- and amidine-type adducts to protein lysine side chains is in contrast to the exclusive formation of amidine-type adducts with PE phospholipids. Thiobenzamide (TB) undergoes the same two-step oxidative bioactivation as TA, and it also gives rise to both amide and amidine adducts on protein lysine side chains but only amidine adducts to PE lipids. Despite their similarity in functional group chemical reactivity, only 38 of 62 known TB target proteins are found among the 88 known targets of TASO. The potential roles of protein modification by TASO in triggering cytotoxicity are discussed in terms of enzyme inhibition, protein folding, and chaperone function, and the emerging role of protein acetylation in intracellular signaling and the regulation of biochemical pathways. 23609108 Phytoestrogenic Potential of Cyclopia Extracts and Polyphenols. Cyclopia Vent. species, commonly known as honeybush, are endemic to Southern Africa. The plant is traditionally used as an herbal tea but several health benefits have recently been recorded. This minireview presents an overview of polyphenols found in Cyclopia and focusses on the phytoestrogenic potential of selected polyphenols and of extracts prepared from the plant. 23514973 Biological activity of Pd(II) complexes with mono- and disubstituted pyridines-Experimental and theoretical studies. Due to the similarity between Pd and Pt, the complexes of palladium(II) can be considered as potential anticancer agents. Activity of six PdCl2(X2Py)2 complexes (Py=pyridine, and X=CH3 or Cl) was measured by MTT test using MCF7, CCRF-SB, PC3 and human B-lymphoblastoid cell lines. We found that the effect of PdCl2(XnPy)2 was cell-specific and time-dependent. Obtained results were discussed and compared with the activation parameters calculated for the hydrolysis of PdCl2(XnPy)2, indicating a correlation between viability of MCF7 and CCRF-SB cells and rates of hydrolysis of the Pd(II) complexes. 23228341 Organotins: A review of their reproductive toxicity, biochemistry, and environmental fate. The review purposes are to (1) evaluate the experimental evidence for adverse effects on reproduction and metabolism and (2) identify the current knowledge of analytical procedures, biochemistry and environmental aspects relating to organotins. Organotins are pollutants that are used as biocides in antifouling paints. They produce endocrine-disrupting effects in mollusks, such as imposex. In rodents, organotin exposure induces developmental and reproductive toxicity as well as alteration of metabolic homeostasis through its action as an obesogen. The adverse effects that appear in rodents have raised concerns about organotins' potential health risk to humans in relation to organotin exposure. At present, triorganotin, such as tributyltin, have been demonstrated to produce imposex, and mammalian reproductive and metabolic toxicity. For most mammals, triorganotin exposure predominantly occurs through the ingestion, and this compound can cross the placenta. With these risks in mind, it is important to improve our knowledge of organotins' effects on environmental health. 23093024 Mouse liver protein sulfhydryl depletion after acetaminophen exposure. Acetaminophen (APAP)-induced liver injury is the leading cause of acute liver failure in many countries. This study determined the extent of liver protein sulfhydryl depletion not only in whole liver homogenate but also in the zonal pattern of sulfhydryl depletion within the liver lobule. A single oral gavage dose of 150 or 300 mg/kg APAP in B6C3F1 mice produced increased serum alanine aminotransferase levels, liver necrosis, and glutathione depletion in a dose-dependent manner. Free protein sulfhydryls were measured in liver protein homogenates by labeling with maleimide linked to a near infrared fluorescent dye followed by SDS-polyacrylamide gel electrophoresis. Global protein sulfhydryl levels were decreased significantly (48.4%) starting at 1 hour after the APAP dose and maintained at this reduced level through 24 hours. To visualize the specific hepatocytes that had reduced protein sulfhydryl levels, frozen liver sections were labeled with maleimide linked to horseradish peroxidase. The centrilobular areas exhibited dramatic decreases in free protein sulfhydryls while the periportal regions were essentially spared. These protein sulfhydryl-depleted regions correlated with areas exhibiting histopathologic injury and APAP binding to protein. The majority of protein sulfhydryl depletion was due to reversible oxidation since the global- and lobule-specific effects were essentially reversed when the samples were reduced with tris(2-carboxyethy)phosphine before maleimide labeling. These temporal and zonal pattern changes in protein sulfhydryl oxidation shed new light on the importance that changes in protein redox status might play in the pathogenesis of APAP hepatotoxicity. 23538162 Activating glucocorticoid receptor-ERK signaling pathway contributes to ginsenoside Rg1 protection against β-amyloid peptide-induced human endothelial cells apoptosis. The deposition of β-amyloid (Aβ) in neurons and vascular cells of the brain has been characterized in Alzheimer's disease. Ginsenoside Rg1 (Rg1) is an active components in Panax ginseng, a famous traditional Chinese medicines recorded in Compendium of Materia Medica. Present study attempted to evaluate the potential mechanisms of Aβ-mediated insult and the protective effects of Rg1 on human endothelial cells. Rg1 attenuated the Aβ25-35-associated mitochondrial apoptotic events, accompanied by inhibiting HIF-1α expression followed by intracellular reactive nitrogen species generation, and protein nitrotyrosination. These protective effects were abolished by glucocorticoid receptor (GR) antagonist RU486 or p-ERK inhibitor U0126 rather than estrogen receptor α antagonist ICI 82,780. Taken together, our results suggested that Rg1 protected against Aβ25-35-induced apoptosis at least in part by two complementary GR-dependent ERK phosphorylation pathways: (1) down-regulating HIF-1α initiated protein nitrotyrosination, and (2) inhibiting mitochondrial apoptotic cascades. These data provided a novel insight to the mechanisms of Rg1protective effects on Aβ25-35-induced endothelial cells apoptosis, suggesting that GR-ERK signaling pathway might play an important role in it. 23395156 Conundrum of angiotensin II and TGF-β interactions in aortic aneurysms. Angiotensin II (AngII) has been invoked as a principal mediator for the development and progression of both thoracic and abdominal aortic aneurysms. While there is consistency in experimental and clinical studies that overactivation of the renin angiotensin system promotes aortic aneurysm development, there are many unknowns regarding the mechanistic basis underlying AngII-induced aneurysms. Interactions of AngII with TGF-β in both thoracic and abdominal aortic aneurysms have been the focus of recent studies. While these studies have demonstrated profound effects of manipulating TGF-β activity on AngII-induced aortic aneurysms, they have also led to more questions regarding the interactions between AngII and this multifunctional cytokine. This review compiled the recent literature to provide insights into understanding the potentially complex interactions between AngII and TGF-β in the development of aortic aneurysms. 23238103 Age dependent differences in the regulation of hippocampal steroid hormones and receptor genes: relations to motivation and cognition in male rats. Estrogen and estrogenic functions are age-dependently involved in the modulation of learning, memory and mood in female humans and animals. However, the investigation of estrogenic effects in males has been largely neglected. Therefore, we investigated the hippocampal gene expression of estrogen receptors α and β (ERα, β) in 8-week-old, 12-week-old and 24-week-old male rats. To control for possible interactions between the expression of the estrogen receptor genes and other learning-related steroid receptors, androgen receptors (AR), corticosterone-binding glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) were also measured. Furthermore, the concentrations of the ligands 17β-estradiol, testosterone and corticosterone were measured. The spatial training was conducted in a hole-board. The 8-week-old rats exhibited higher levels of general activity and exploration during the training and performed best with respect to spatial learning and memory, whereas no difference was found between the 12-week-old and 24-week-old rats. The trained 8-week-old rats exhibited increased gene expression of ERα compared with the untrained rats in this age group as well as the trained 12-week-old and 24-week-old rats. The concentrations of estradiol and testosterone, however, were generally higher in the 24-week-old rats than in the 8-week-old and 12-week-old rats. The ERα mRNA concentrations correlated positively with behavior that indicate general learning motivation. These results suggest a specific role of ERα in the age-related differences in motivation and subsequent success in the task. Thus, estrogen and estrogenic functions may play a more prominent role in young male behavior and development than has been previously assumed. 23306944 Effects of silicon on osteoblast activity and bone mineralization of MC3T3-E1 cells. Previous studies have reported that dietary silicon (Si) intake is positively associated with bone health including bone mineral density. Although the amount of Si intake is high among trace elements in humans, how dietary Si affects bone formation at the cellular level is not well addressed. The purpose of this study was to investigate the role of Si in osteoblast activity and bone mineralization. MC3T3-E1 was cultured as mature osteoblasts and treated with sodium metasilicate (0, 1, 5, 10, 25, 50, and 100 μM) as a source of Si. After 7 days of treatment, 5 and 10 μM of sodium metasilicate significantly increased intracellular alkaline phosphatase activity (p < 0.05) when compared to the control. Additionally, all doses of sodium metasilicate (1, 5, 10, 25, 50, and 100 μM) increased mineralized nodule formation at 14 days of differentiation as evidenced by increased Alizarin Red S staining. In the analysis of gene expression, 50 μM of sodium metasilicate upregulated type I collagen (COL-I) compared to the control group. However, the increase of COL-I gene expression as a result of treatment with 1, 10, 25, and 100 μM of sodium metasilicate did not reach statistical significance. mRNA expression of insulin-like growth factor-I and receptor activator of NF-κB ligand was not significantly changed at any dose of sodium metasilicate (0, 1, 5, 10, 25, 50, and 100 μM). In light of the results, we conclude that Si has a positive effect on bone metabolism by enhancing osteoblast mineralization activity. 23384309 Frequency and intensity of pain related to thyroid nodule fine needle aspiration cytology. Background: Quality of life is an important issue in endocrine tumors because of the high prevalence of benign tumors and the indolent course of most malignant tumors. Objective: To evaluate the frequency and the intensity of pain and anxiety in patients undergoing thyroid nodule fine needle aspiration cytology (FNAC), and to identify factors associated with pain. Method: Single center prospective study in the setting of a one-stop outpatient diagnostic clinic for thyroid nodules. Pain was evaluated using a 100-mm visual analogue scale (VAS) immediately following (VAS1) and 30 minutes after (VAS2) FNAC and was considered significant if ≥30. Anxiety symptoms were assessed prior to FNAC using a self-report measure questionnaire: the state form of Spielberger State-Trait Anxiety Inventory (STAI, form Y-A). FNAC was performed with a 25-Gauge needle and a moderate aspiration and two passes for each nodule. Results: 218 consecutive patients (163 females, 55 males; mean age 53 years, range 12-84) undergoing FNAC of 1 to 3 nodules were included. VAS1 was ≥30 in 24% of the patients and VAS2 was 30 in 13% of the patients. Independent significant factors correlated to a VAS1 30 were age under 25 and the number of nodules being biopsied. Independent significant factors correlated to a VAS2 30 were VAS1 30 and female gender. No correlation was found between pain and nodule size or nodule depth, nor the duration of application of the Eutectic Mixture of Local Anesthetics (EMLA patch) prior to FNAC. The mean STAI score for anxiety was 37  12. The average STAI score was significantly higher in women (39) than in men (33) (p=0.01). There was no significant correlation between STAI score and age under 25, previous FNAC, number of nodules biopsied or acetaminophen administration, but the STAI score was significantly correlated to VAS1 and VAS2 Conclusions: FNAC-related pain is frequent and correlates with the number of nodules biopsied, age under 25, female gender and anxiety. 22974972 Green tomato extract attenuates high-fat-diet-induced obesity through activation of the AMPK pathway in C57BL/6 mice. Obesity is a risk factor for numerous metabolic disorders. Recently, natural compounds that may be beneficial for improving obesity have received increasing attention. In this study, we investigated whether red and green tomato extracts attenuate high-fat-diet-induced obesity in C57BL/6 mice. The mice were maintained on a normal diet (ND) or high-fat diet (HFD) for 4 weeks and then fed ND, HFD, HFD plus 2% red tomato extract (RTE) or HFD plus 2% green tomato extract (GTE) for 13 weeks. The weekly food intakes among the groups were not significantly different. Body weight of mice fed HFD plus GTE was significantly decreased to the level of mice fed ND, but the body weight was only slightly reduced in mice fed HFD plus RTE. Epididymal adipose tissue and liver weights were significantly decreased in mice fed HFD plus GTE compared to those in HFD. Serum total cholesterol and low-density lipoprotein cholesterol levels in mice fed GTE were modestly reduced, and liver total cholesterol level was strongly decreased in HFD plus GTE-fed mice compared to that in HFD-fed mice. Adenosine-monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase phosphorylation in liver from HFD plus GTE-fed mice was significantly elevated, and HMG-CoA reductase expression was also significantly decreased. GTE strongly decreased the expression of peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein alpha and perilipin in the adipose tissue of mice fed HFD plus GTE. Our results indicate that the antiobesity effects of GTE may be associated with activation of the AMPK pathway. 23149937 RBFOX2 is an important regulator of mesenchymal tissue-specific splicing in both normal and cancer tissues. Alternative splicing provides a critical and flexible layer of regulation intervening in many biological processes to regulate the diversity of proteins and impact cell phenotype. To identify alternative splicing differences that distinguish epithelial from mesenchymal tissues, we have investigated hundreds of cassette exons using a high-throughput reverse transcription-PCR (RT-PCR) platform. Extensive changes in splicing were noted between epithelial and mesenchymal tissues in both human colon and ovarian tissues, with many changes from mostly one splice variant to predominantly the other. Remarkably, many of the splicing differences that distinguish normal mesenchymal from normal epithelial tissues matched those that differentiate normal ovarian tissues from ovarian cancer. Furthermore, because splicing profiling could classify cancer cell lines according to their epithelial/mesenchymal characteristics, we used these cancer cell lines to identify regulators for these specific splicing signatures. By knocking down 78 potential splicing factors in five cell lines, we provide an extensive view of the complex regulatory landscape associated with the epithelial and mesenchymal states, thus revealing that RBFOX2 is an important driver of mesenchymal tissue-specific splicing. 22720714 A new furolactone-type lignan from Lycium chinense. The phytochemical investigation of extracts from the root barks of Lycium chinense yielded a new furolactone-type lignan, lyciumin (1). Its structure and absolute configurations were established on the basis of spectral data, particularly by the use of 1D NMR, 2D shift-correlated NMR pulse sequences ((1)H-(1)H COSY, HSQC, HMBC and ROESY) and CD spectra. 23177536 Seizure control by ketogenic diet-associated medium chain fatty acids. The medium chain triglyceride (MCT) ketogenic diet is used extensively for treating refractory childhood epilepsy. This diet increases the plasma levels of medium straight chain fatty acids. A role for these and related fatty acids in seizure control has not been established. We compared the potency of an established epilepsy treatment, Valproate (VPA), with a range of MCT diet-associated fatty acids (and related branched compounds), using in vitro seizure and in vivo epilepsy models, and assessed side effect potential in vitro for one aspect of teratogenicity, for liver toxicology and in vivo for sedation, and for a neuroprotective effect. We identify specific medium chain fatty acids (both prescribed in the MCT diet, and related compounds branched on the fourth carbon) that provide significantly enhanced in vitro seizure control compared to VPA. The activity of these compounds on seizure control is independent of histone deacetylase inhibitory activity (associated with the teratogenicity of VPA), and does not correlate with liver cell toxicity. In vivo, these compounds were more potent in epilepsy control (perforant pathway stimulation induced status epilepticus), showed less sedation and enhanced neuroprotection compared to VPA. Our data therefore implicates medium chain fatty acids in the mechanism of the MCT ketogenic diet, and highlights a related new family of compounds that are more potent than VPA in seizure control with a reduced potential for side effects. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'. 23145849 Gender difference of childhood overweight and obesity in predicting the risk of incident asthma: a systematic review and meta-analysis. The aims of our meta-analysis were (i) to quantify the predictability of childhood overweight and obesity on the risk of incident asthma; and (ii) to evaluate the gender difference on this relationship. The selection criteria included prospective cohort paediatric studies which use age- and sex-specific body mass index (BMI) as a measure of childhood overweight and the primary outcome of incident asthma. A total of 1,027 studies were initially identified through online database searches, and finally 6 studies met the inclusion criteria. The combined result of reported relative risk from the 6 included studies revealed that overweight children conferred increased risks of incident asthma as compared with non-overweight children (relative risk, 1.19; 95% confidence interval [CI], 1.03-1.37). The relationship was further elevated for obesity vs. non-obesity (relative risk, 2.02; 95% CI, 1.16-3.50). A dose-responsiveness of elevated BMI on asthma incidence was observed (P for trend, 0.004). Obese boys had a significantly larger effect than obese girls (relative risk, boys: 2.47; 95% CI, 1.57-3.87; girls: 1.25; 95% CI, 0.51-3.03), with significant dose-dependent effect. Proposed mechanisms of gender difference could be through pulmonary mechanics, sleep disordered breathing and leptin. Further research might be needed to better understand the exact mechanism of gender difference on the obesity-asthma relationship. 23429274 Cyclic stretch induces inducible nitric oxide synthase and soluble guanylate cyclase in pulmonary artery smooth muscle cells. In the pulmonary vasculature, mechanical forces such as cyclic stretch induce changes in vascular signaling, tone and remodeling. Nitric oxide is a potent regulator of soluble guanylate cyclase (sGC), which drives cGMP production, causing vasorelaxation. Pulmonary artery smooth muscle cells (PASMCs) express inducible nitric oxide synthase (iNOS), and while iNOS expression increases during late gestation, little is known about how cyclic stretch impacts this pathway. In this study, PASMC were subjected to cyclic stretch of 20% amplitude and frequency of 1 Hz for 24 h and compared to control cells maintained under static conditions. Cyclic stretch significantly increased cytosolic oxidative stress as compared to static cells (62.9 ± 5.9% vs. 33.3 ± 5.7% maximal oxidation), as measured by the intracellular redox sensor roGFP. Cyclic stretch also increased sGCβ protein expression (2.5 ± 0.9-fold), sGC activity (1.5 ± 0.2-fold) and cGMP levels (1.8 ± 0.2-fold), as well as iNOS mRNA and protein expression (3.0 ± 0.9 and 2.6 ± 0.7-fold, respectively) relative to control cells. An antioxidant, recombinant human superoxide dismutase (rhSOD), significantly decreased stretch-induced cytosolic oxidative stress, but did not block stretch-induced sGC activity. Inhibition of iNOS with 1400 W or an iNOS-specific siRNA inhibited stretch-induced sGC activity by 30% and 68% respectively vs. static controls. In conclusion, cyclic stretch increases sGC expression and activity in an iNOS-dependent manner in PASMC from fetal lambs. The mechanism that produces iNOS and sGC upregulation is not yet known, but we speculate these effects represent an early compensatory mechanism to counteract the effects of stretch-induced oxidative stress. A better understanding of the interplay between these two distinct pathways could provide key insights into future avenues to treat infants with pulmonary hypertension. 23457114 Synthesis of Isoidide through Epimerization of Isosorbide using Ruthenium on Carbon. A highly efficient procedure for obtaining resin-grade isoidide through catalytic epimerization of isosorbide using a ruthenium-on-carbon (Ru/C) catalyst is reported. A comprehensive reaction-parameter variation study involving substrate concentration, catalyst (type of metal, support, and loading), initial pH value, hydrogen pressure, solvent, and reaction temperature demonstrates that superior performance and high selectivity can be achieved. Epimerization of isosorbide in water (pH 8) at 220 °C, under 40 bar of hydrogen, and using a Ru/C catalyst (5 % Ru) for 2 h results in a thermodynamic equilibrium mixture containing 55 % isoidide, 40 % isosorbide, and 5 % isomannide. In comparison with previously reported nickel-based catalysts, the Ru/C catalyst is advantageous because it is highly active (as low as 360 ppm Ru) and recyclable. High purity isoidide is obtained by high-vacuum distillation of an equilibrium mixture on a 200 g scale. The high substrate loading (50 wt % in water), high selectivity, and the possibility for substrate reuse makes this procedure highly atom efficient and therefore, highly attractive for industrial use. 23641695 Immunogenicity testing strategy and bioanalytical assays for antibody-drug conjugates. Background: Immunogenicity testing is an important component of clinical development for large-molecule biotherapeutics. New complex types of large molecules, such as antibody-drug conjugates (ADCs), require careful evaluation of the testing strategy and bioanalytical assays used to monitor the development of antitherapeutic antibodies. Results: An electrochemiluminescence-based immunoassay for the detection and epitope characterization of anti-ADC antibodies was validated. Using this assay format, antibodies directed against the monoclonal antibody and linker-drug components of the ADC were successfully detected in a multiple-dose rat toxicity study. Conclusion: Immunogenicity assays incorporating epitope determination may provide additional information about the characteristics of induced antitherapeutic antibodies, including the magnitude and timing of the various types of antibody responses. 23496094 Structural Rearrangement in the Formation of Jet-Cooled Complexes of Chiral (S)-1,2,3,4-Tetrahydro-3-isoquinolinemethanol with Methyl Lactate: Chirality Effect in Conformer Selection. The jet-cooled complexes between the two enantiomers of methyl lactate (ML) and (S)-1,2,3,4-tetrahydro-3-isoquinolinemethanol (THIQM) are studied by double resonance spectroscopy combined with ab initio calculations. Both diastereomer complexes exist in different isomers, involving either direct addition of THIQM on ML with no structural rearrangement of the subunits or formation of very stable structures involving multiple intermolecular hydrogen bonds and extensive deformation of the subunits. Competition between these two processes and its dependence upon chirality are discussed. It is shown that the most stable form of the chromophore (THIQMI with an OH···N hydrogen bond) prefers to directly stick to ML to form the addition complex whereas the second conformer (THIQMII with NH···O hydrogen bond) rearranges to form a strongly bound structure. The two structures are formed for the homochiral as well the heterochiral complex, however with different relative abundance. This shows an enantioselective binding preference of ML for one of the conformers of the chromophore. 23315497 Decreased RB1 mRNA, Protein, and Activity Reflect Obesity-Induced Altered Adipogenic Capacity in Human Adipose Tissue. Retinoblastoma (Rb1) has been described as an essential player in white adipocyte differentiation in mice. No studies have been reported thus far in human adipose tissue or human adipocytes. We aimed to investigate the possible role and regulation of RB1 in adipose tissue in obesity using human samples and animal and cell models. Adipose RB1 (mRNA, protein, and activity) was negatively associated with BMI and insulin resistance (HOMA-IR) while positively associated with the expression of adipogenic genes (PPARγ and IRS1) in both visceral and subcutaneous human adipose tissue. BMI increase was the main contributor to adipose RB1 downregulation. In rats, adipose Rb1 gene expression and activity decreased in parallel to dietary-induced weight gain and returned to baseline with weight loss. RB1 gene and protein expression and activity increased significantly during human adipocyte differentiation. In fully differentiated adipocytes, transient knockdown of Rb1 led to loss of the adipogenic phenotype. In conclusion, Rb1 seems to play a permissive role for human adipose tissue function, being downregulated in obesity and increased during differentiation of human adipocytes. Rb1 knockdown findings further implicate Rb1 as necessary for maintenance of adipogenic characteristics in fully differentiated adipocytes. 23561160 Effect of temperature on the release of intentionally and non-intentionally added substances from polyethylene terephthalate (PET) bottles into water: Chemical analysis and potential toxicity. The purpose of this study was to investigate the impact of temperature on the release of PET-bottle constituents into water and to assess the potential health hazard using in vitro bioassays with bacteria and human cell lines. Aldehydes, trace metals and other compounds found in plastic packaging were analysed in PET-bottled water stored at different temperatures: 40, 50, and 60°C. In this study, temperature and the presence of CO2 increased the release of formaldehyde, acetaldehyde and antimony (Sb). In parallel, genotoxicity assays (Ames and micronucleus assays) and transcriptional-reporter gene assays for estrogenic and anti-androgenic activity were performed on bottled water extracts at relevant consumer exposure levels. As expected, and in accordance with the chemical formulations specified for PET bottles, neither phthalates nor UV stabilisers were present in the water extracts. However, 2,4-di-tert-butylphenol, a degradation compound of phenolic antioxidants, was detected. In addition, an intermediary monomer, bis(2-hydroxyethyl)terephthalate, was found but only in PET-bottled waters. None of the compounds are on the positive list of EU Regulation No. 10/2011. However, the PET-bottled water extracts did not induce any cytotoxic, genotoxic or endocrine-disruption activity in the bioassays after exposure. 23524112 Efficient synthesis of new (R)-2-amino-1-butanol derived ureas, thioureas and acylthioureas and in vitro evaluation of their antimycobacterial activity. The synthesis of 22 structurally diverse urea, thiourea and acylthiourea derivatives containing the (R)-2-amino-1-butanol motif has been performed. The evaluation of their in vitro activity against Mycobacterium tuberculosis (H37Rv and strain 43) showed promising results in the case of the acylthiourea derivatives (MIC range 0.36-7.46 μM for H37Rv strain). 23450220 New directions in thermoresponsive polymers. Interest in thermoresponsive polymers has steadily grown over many decades, and a great deal of work has been dedicated to developing temperature sensitive macromolecules that can be crafted into new smart materials. However, the overwhelming majority of previously reported temperature-responsive polymers are based on poly(N-isopropylacrylamide) (PNIPAM), despite the fact that a wide range of other thermoresponsive polymers have demonstrated similar promise for the preparation of adaptive materials. Herein, we aim to highlight recent results that involve thermoresponsive systems that have not yet been as fully considered. Many of these (co)polymers represent clear opportunities for advancements in emerging biomedical and materials fields due to their increased biocompatibility and tuneable response. By highlighting recent examples of newly developed thermoresponsive polymer systems, we hope to promote the development of new generations of smart materials. 23288051 Influence of DNA repair on nonlinear dose-responses for mutation. Recent evidence has challenged the default assumption that all DNA-reactive alkylating agents exhibit a linear dose-response. Emerging evidence suggests that the model alkylating agents methyl- and ethylmethanesulfonate and methylnitrosourea (MNU) and ethylnitrosourea observe a nonlinear dose-response with a no observed genotoxic effect level (NOGEL). Follow-up mechanistic studies are essential to understand the mechanism of cellular tolerance and biological relevance of such NOGELs. MNU is one of the most mutagenic simple alkylators. Therefore, understanding the mechanism of mutation induction, following low-dose MNU treatment, sets precedence for weaker mutagenic alkylating agents. Here, we tested MNU at 10-fold lower concentrations than a previous study and report a NOGEL of 0.0075 µg/ml (72.8nM) in human lymphoblastoid cells, quantified through the hypoxanthine (guanine) phosphoribosyltransferase assay (OECD 476). Mechanistic studies reveal that the NOGEL is dependent upon repair of O(6)-methylguanine (O(6)MeG) by the suicide enzyme O(6)MeG-DNA methyltransferase (MGMT). Inactivation of MGMT sensitizes cells to MNU-induced mutagenesis and shifts the NOGEL to the left on the dose axis. 22867272 Alteration in plasma protein binding properties of propranolol and flurbiprofen during development of adjuvant-induced arthritis in rats. Adjuvant-induced arthritis (AA) in the rat is used as a model for rheumatoid arthritis. In AA rats, the pharmacokinetics of various drugs is affected due to the alterations of plasma protein binding of drugs. We choose propranolol (PL) and flurbiprofen (FP) as model basic and acidic drugs, respectively, and investigated the effect of AA induction on their plasma protein binding at each developing stage of inflammation. The plasma protein binding of PL and FP was dramatically changed due to reduced albumin and increased α₁-acid glycoprotein levels for at least 21 days after adjuvant treatment. Moreover, we illustrated the differences in protein binding in AA between both the drugs in each developing stage of inflammation. These results suggest that the changed plasma protein levels in AA rats accompanying the altered protein binding of drugs affect the pharmacokinetics of drugs which extensively bind to plasma protein under inflammatory condition. 23244162 Preparation of raspberry-like polymer particles by a heterocoagulation technique utilizing hydrogen bonding interactions between steric stabilizers. Large polystyrene particles stabilized by poly(acrylic acid) (PAA) (L-PS(PAA)) (as the core) and small polystyrene particles stabilized by poly(vinyl pyrrolidone) (PVP) (S-PS(PVP)) (as the corona) were successfully used to prepare raspberry-like particles by a heterocoagulation technique utilizing the hydrogen bonding interaction between PAA and PVP. The coverage of L-PS(PAA) by S-PS(PVP) could be controlled by adding PVP homopolymer to the L-PS(PAA) dispersion and by changing the molecular weight of the stabilizers. Moreover, the heterocoagulation of large poly(methyl methacrylate) particles stabilized by PAA (L-PMMA(PAA)) and S-PS(PVP) particles was also accomplished, resulting in the formation of L-PMMA(PAA)-core/S-PS(PVP)-corona raspberry-like composite particles. These results suggested that the raspberry-like particles composed of various polymer particles could be formed by the heterocoagulation technique utilizing the hydrogen bonding interaction. 23644914 Cortical excitability in smoking and not smoking individuals with and without nicotine. RATIONAL: Activation of nicotinic acetylcholine receptors has a major neuromodulatory impact on central nervous system function. Beyond acute activation, chronic nicotine intake has long-lasting effects on cortical excitability in animal experiments, caused by receptor up- or down-regulation. Knowledge about the impact of nicotine on cortical excitability in humans, however, is limited. OBJECTIVES: We therefore aimed to explore the effect of nicotine intake on cortical excitability in healthy human smokers and non-smokers. METHODS: The primary motor cortex served as model, and cortical excitability was monitored via transcranial magnetic stimulation (TMS). Corticospinal excitability and intracortical excitability were recorded before and after application of nicotine patch in both groups. Corticospinal excitability was explored by motor threshold and input/output curve (I/O curve), and intracortical excitability was explored by means of paired-pulse TMS techniques (intracortical facilitation (ICF), short-latency intracortical inhibition (SICI), I-wave facilitation and short-latency afferent inhibition (SAI)). RESULTS: The results show that smokers during nicotine withdrawal display increased corticospinal excitability with regard to the I/O curve (TMS intensity 150 % of resting motor threshold) compared to non-smokers and furthermore enhanced SAI and diminished ICF at the intracortical circuit level. After administration of nicotine, intracortical facilitation in smokers increased, while in non-smokers, inhibition (SICI, SAI) was enhanced. CONCLUSION: Our results show that chronic nicotine consumption in smokers alters cortical excitability independent from acute nicotine consumption and that acute nicotine has different effects on motor cortical excitability in both groups. 23604205 Thermal and electrical conduction in 6.4 nm thin gold films. For sub-10 nm thin metallic films, very little knowledge is available so far on how electron scattering at surface and grain boundaries reduces the thermal transport. This work reports on the first time characterization of the thermal and electrical conductivities of gold films of 6.4 nm average thickness. The electrical (σ) and thermal (k) conductivities of the Au film are found to be reduced dramatically from their bulk counterparts by 93.7% (σ) and 80.5% (k). Its Lorenz number is measured as 7.44 × 10(-8) W Ω K(-2), almost a twofold increase from the bulk value. The Mayadas-Shatzkes model is used to interpret the experimental results and reveals very strong electron reflection (77%) at grain boundaries. 23452083 Highly enantioselective rhodium-catalyzed [2+2+2] cycloaddition of diynes to sulfonimines. A new asymmetric [2+2+2] cycloaddition of diynes to sulfonimines under rhodium catalysis that provides the corresponding enantioenriched 1,2-dihydropyridines in good yields is described. 23597018 Enhanced Triboelectric Nanogenerators and Triboelectric Nanosensor Using Chemically Modified TiO2 Nanomaterials. Mechanical energy harvesting based on triboelectric effect has been proven to be a simple, cost-effective, and robust method for electricity generation. In this study, we developed a rationally designed triboelectric nanogenerator (TENG) by utilizing the contact electrification between a polytetrafluoroethylene (PTFE) thin film and a layer of TiO2 nanomaterial (nanowire and nanosheet) array. The as-developed TENG was systematically studied and demonstrated as a self-powered nanosensor toward catechin detection. The high sensitivity (detection limit of 5 μM) and selectivity are achieved through a strong interaction between Ti atoms of TiO2 nanomaterial and enediol group of catechin. The output voltage and current density were increased by a factor of 5.0 and 2.9, respectively, when adsorbed with catechin of a saturated concentration, because of the charge transfer from catechin to TiO2. This study demonstrates the possibility of improving the electrical output of TENG through chemical modification. 23561175 Oil composition and characterisation of phenolic compounds of Opuntia ficus-indica seeds. The seed composition of four varieties of Opuntia ficus-indica growing in Algeria was investigated. Seeds ground into a fine powder were first, subjected to oil extraction and fatty acids analysis. The phenolic compounds were then extracted from the defatted powder of seeds in order to be quantified and characterised by liquid chromatography coupled to mass spectrometry (LC-MS(n)) and to nuclear magnetic resonance (LC-NMR) approaches. In addition, an evaluation of the antioxidant activity of the phenolic extracts was investigated. Gas chromatography analysis of the seed oil showed high percentages of linoleic acid in the four varieties ranging from 58% to 63%. The phenolic profile of the Opuntia ficus-indica seeds displayed a high complexity, with more than 20 compounds detected at 330nm after the LC separation. Among them, three isomers of feruloyl-sucrose were firmly identified and another was strongly supposed to be a sinapoyl-diglycoside. High correlations were found between phenolic content in the defatted seed extracts and their antioxidant activity. The data indicate that the defatted cactus seed wastes still contain various components that constitute a source for natural foods. 23448197 Newer insulin analogs: advances in basal insulin replacement. Basal insulin analog therapy is the most common method of introducing insulin replacement therapy for the majority of patients with type 2 diabetes mellitus. Long-acting insulin analogs provide relatively peakless and more physiologic insulin replacement therapy than neutral protaminated Hagedorn insulin. Recently 2 new basal insulin analogs have been developed with superior pharmacokinetic and pharmacodynamics properties; insulin degludec and a pegylated insulin lispro. These agents are generally well tolerated and have been evaluated in both type 1 and type 2 diabetes. In this article we review the results of clinical trials assessing the efficacy, safety and tolerability of these newer longer-acting insulin analogs. In general rates of hypoglycaemia in these trials were low, glucose control was comparable to currently available basal insulin analogs, and rates of nocturnal hypoglycaemia were significantly and substantially lower. While further study will be required, advances in basal insulin replacement may offer important advantages over existing options for starting insulin strategies. 22722774 Alleviation of high salt toxicity-induced oxidative damage by salicylic acid pretreatment in two wheat cultivars. Role of exogenous salicylic acid (SA) in the antioxidative response to salt toxicity of two wheat (Triticum aestivum) cultivars (Gerek-79 and Bezostaya) was investigated. Hydroponic growth environment of 10-day wheat seedlings grown under normal conditions (22/20°C) was adjusted to 0.0, 0.25, 0.50 and 0.75 M of salt (NaCl), and then freshly prepared SA solutions (0.0, 0.01 and 0.1 mM) were once sprayed on leaves of the same seedlings. Activities of superoxide dismutase (SOD), peroxidase (POX) and catalase (CAT) were determined in fresh leaves obtained from 15-day seedlings. Treatment with SA alone increased all the antioxidant activities in Gerek-79. However, the same treatments with SA decreased the activities of CAT and SOD in Bezostaya, while increased that of POX. Salt applications alone increased the activities of POX and SOD, while decreased that of CAT in Bezostaya. The same salt applications increased the POX activity, while decreased the activities of CAT and SOD in Gerek-79. In plants under saline conditions, except 0.75 M NaCl, treatments with SA increased the activities of CAT, POX and SOD in both the varieties compared with plants applied salt alone. In plants applied with 0.75 M NaCl, however, treatments with SA decreased CAT activity. Results showed that salt toxicity caused a derangement in the regulation of antioxidant enzyme activities by decreasing CAT activity especially in both the varieties, but treatments with SA could turn back the derangement in the antioxidative enzymes caused by salt toxicity. SA can involve in increasing salt tolerance by regulating the activities of antioxidant enzymes in wheat cultivars exposed to salt toxicity. 23305776 Three new phenolic compounds from the roots of Glycyrrhiza yunnanensis. Three new phenolic compounds (1-3), together with 16 known compounds (4-19), were isolated from the roots of Glycyrrhiza yunnanensis Cheng f. et L. K. Dai. On the basis of 1D and 2D NMR, HR-ESI-MS, and circular dichroism (CD) spectroscopic analysis, structures of the new compounds were elucidated as 2-(2'-methoxy-4'-hydroxy)-aryl-3-methy-6-hydroxy-benzofuran (1), (2S)-6,7-(2,2-dimethyldihydropyrano)-8-prenyl-4'-hydroxyflavanone (2), and 6-prenyl-7,3',4'-trihydroxyflavone (3). Compounds 1, 3, 5, 12, 14, 15 and 16 showed antioxidant activity by an ABTS-based assay. 23557027 Gravitational drainage of foam films. Gravitational drainage from thick plane vertical soap films and hemispherical bubbles is studied experimentally and theoretically. The experiments involve microinterferometry kindred to the one used in the experiments in the Scheludko cell. The following surfactants were used in the experiments: cationic dodecyltrimethylammonium bromide (DTAB), anionic sodium dodecyl sulfate (SDS), anionic Pantene shampoo which primarily contains sodium lauryl sulfate, nonionic tetraethylene glycol monooctyl ether (C8E4), and nonionic Pluronic (P-123) surfactants at different concentrations. The theoretical results explain the drainage mechanism and are used to develop a new method of measurement of the surface elasticity and to test it on the above-mentioned surfactants. 23585333 Tandem Assays of Protein and Glucose with Functionalized Core/Shell Particles Based on Magnetic Separation and Surface-Enhanced Raman Scattering. Tandem assays of protein and glucose in combination with mannose-functionalized Fe3 O4 @SiO2 and Ag@SiO2 tag particles have promising potential in effective magnetic separation and highly sensitive and selective SERS assays of biomaterials. It is for the first time that tandem assay of glucose is developed using SERS based on the Con A-sandwiched microstructures between the functionalized magnetic and tag particles. 23551535 Hypoxia, energy balance and obesity: from pathophysiological mechanisms to new treatment strategies. High altitude exposure is often accompanied by weight loss. Postulated mechanisms are a reduction of nutritional energy intake, a reduction of intestinal energy uptake from impaired intestinal function and increased energy expenditure. Beyond the field of altitude, there are good reasons for renewed interest in the relationship between hypoxia and energy balance. The increasing prevalence of obesity and associated comorbidities represent a major health concern. Obesity is frequently associated with sleep disorders leading to intermittent systemic hypoxia with deleterious cardiovascular and metabolic consequences. Hypoxic regions may be present within hypertrophic white adipose tissue leading to chronic systemic inflammation. Among the increasing number of people commuting to altitude for work or leisure, obesity is a risk factor for acute mountain sickness. Paradoxically, exposure to intermittent hypoxia might be considered as a means to lose body mass and to improve metabolic risk factors. Daytime exposure to intermittent hypoxia has been used to treat hypertension in former Soviet Union countries and is now being experimented elsewhere. Such intermittent hypoxic exposure at rest or during exercise may lead to improvement in body composition and health status with improved exercise tolerance, metabolism and systemic arterial pressure. Future research should confirm whether hypoxic training could be a new treatment strategy for weight loss and comorbidities in obese subjects and elucidate the underlying mechanisms and signalling pathways. 23631736 Highly Enantioselective Zirconium-Catalyzed Cyclization of Aminoalkenes. Aminoalkenes are catalytically cyclized in the presence of cyclopentadienylbis(oxazolinyl)borato group 4 complexes {PhB(C5H4)(Ox(R))2}M(NMe2)2 (M = Ti, Zr, Hf; Ox(R) = 4,4-dimethyl-2-oxazoline, 4S-isopropyl-5,5-dimethyl-2-oxazoline, 4S-tert-butyl-2-oxazoline) at room temperature and below, affording five-, six-, and seven-membered N-heterocyclic amines with enantiomeric excesses of >90% in many cases and up to 99%. Mechanistic investigations of this highly selective system employed synthetic tests, kinetics, and stereochemistry. Secondary aminopentene cyclizations require a primary amine (1-2 equiv vs catalyst). Aminoalkenes are unchanged in the presence of a zirconium monoamido complex {PhB(C5H4)(Ox(4S-iPr,Me2))2}Zr(NMe2)Cl or a cyclopentadienylmono(oxazolinyl)borato zirconium diamide {Ph2B(C5H4)(Ox(4S-iPr,Me2))}Zr(NMe2)2. Plots of initial rate versus [substrate] show a rate dependence that evolves from first-order at low concentration to zero-order at high concentration, and this is consistent with a reversible substrate-catalyst interaction preceding an irreversible step. Primary kinetic isotope effects from substrate conversion measurements (k'obs((H))/k'obs((D)) = 3.3 ± 0.3) and from initial rate analysis (k2((H))/k2((D)) = 2.3 ± 0.4) indicate that a N-H bond is broken in the turnover-limiting and irreversible step of the catalytic cycle. Asymmetric hydroamination/cyclization of N-deutero-aminoalkenes provides products with higher optical purities than obtained with N-proteo-aminoalkenes. Transition state theory, applied to the rate constant k2 that characterizes the irreversible step, provides activation parameters consistent with a highly organized transition state (ΔS(⧧) = -43(7) cal·mol(-1) K(-1)) and a remarkably low enthalpic barrier (ΔH(⧧) = 6.7(2) kcal·mol(-1)). A six-centered, concerted transition state for C-N and C-H bond formation and N-H bond cleavage involving two amidoalkene ligands is proposed as most consistent with the current data. 23295732 Effect of A and B-site cations on surface exchange coefficient for ABO3 perovskite materials. A novel approach, called isothermal isotope exchange (IIE), was applied to varying A- and B-site lanthanum manganites, ferrites, and cobaltites in the perovskite crystal structure in order to extract accurate surface exchange coefficients (k*). Pure electronic conductors revealed temperature dependent isotope exchange, while for mixed ionic and electronic conductors (MIEC) the extent of exchange was independent of temperature. MIEC materials have higher k* values than pure electronic conductors in the temperature range from 500-850 °C, demonstrating the importance of both electronic species and oxygen vacancies being present for surface exchange. Strontium doped perovskites exhibited opposite temperature dependencies to parent materials. Some perovskites exhibited an apparent negative activation energy for k*, the behavior of which is explained by a precursor-mediated mechanism for dissociative adsorption. The results have significant implications for the improvement of the oxygen reduction reaction for fuel cells, metal-air batteries, and numerous other energy technologies. 23577599 Identification and Characterization of a Cellulose Binding Heptapeptide Revealed by Phage Display. Cellulose nanowhiskers (CNWs) were used in conjunction with phage display technology to identify polypeptides which bind the crystalline region of cellulose. A consensus peptide WHWTYYW was identified to efficiently bind the CNWs. The binding affinities of specific phage particles were assessed using biopanning assays and enzyme-linked immunosorbent assay (ELISA). The WHWTYYW peptide was synthesized and isothermal titration calorimetry (ITC) analysis showed that the peptide exhibited a binding constant of ~10(5) M(-1) toward the crystalline CNWs. In order to understand how the affinity of this peptide differs for non-crystalline cellulose, binding properties were characterized using cello-oligosaccharides as substrates. Binding analysis was performed using UV spectroscopy and fluorescence quenching experiments. The specific molecular interactions of the WHWTYYW peptide with cellohexaose were examined using nuclear magnetic resonance (NMR). Interactions of this peptide with crystalline cellulose were also investigated using computational molecular modeling (MM) studies. The MM and NMR experiments indicate that the WHWTYYW peptide exhibits a bent structure when bound, allowing the Y5 amino acid to form a CH/π stacking interaction and H-bond with the glucose ring of cellulose. 23561127 In vitro antioxidant capacity and anti-inflammatory activity of seven common oats. Oats are gaining increasing scientific and public interest for their purported antioxidant-associated health benefits. Most reported studies focused on specific oat extracts or particular oat components, such as β-glucans, tocols (vitamin E), or avenanthramides. Studies on whole oats with respect to antioxidant and anti-inflammatory activities are still lacking. Here the antioxidant and anti-inflammatory activities from whole oat groats of seven common varieties were evaluated. All oat varieties had very similar oxygen radical absorption capacity compared with other whole grains. In an anti-inflammatory assay, oat variety CDC Dancer inhibited tumor necrosis factor-α induced nuclear factor-kappa B activation by 27.5% at 2mg/ml, whereas variety Deiter showed 13.7% inhibition at a comparable dose. Avenanthramide levels did not correlate with the observed antioxidant and anti-inflammatory activities. Further investigations are needed to pinpoint the specific antioxidant and anti-inflammatory compounds, and potential synergistic and/or matrix effects that may help explain the mechanisms of oat's anti-inflammatory actions. 23411229 Simple, fast, and efficient process for producing and purifying trehalulose. A new property of recombinant trehalose synthase (GTase) from Thermus thermophilus HB-8 (ATCC 27634) was found and described in this study. GTase can act on sucrose and catalyze trehalulose formation without isomaltose, isomaltulose, or isomelezitose, releasing small amounts of glucose and fructose as byproducts. Maximum trehalulose yield (approximately 81%) was obtained at an optimum temperature of 65°C and was independent of substrate concentration. A simple, fast, and efficient method of producing and purifying trehalulose is then described. In the first step, GTase catalyzed trehalulose formation using a 20% sucrose substrate. Miscellaneous sugars were then rapidly removed, while trehalulose was completely preserved by Saccharomyces cerevisiae cells. Finally, the cells were separated by centrifugation, and salt ions were removed by an ion-exchange resin, subsequently obtaining a high-purity trehalulose solution. A trehalulose recovery rate of over 95% was achieved using this process. This method has a simple process, fast separation efficiency, and low investment in production equipment, so greatly to improve production efficiency and reduce production costs. 23453840 2-Substituted-2-amino-6-boronohexanoic acids as arginase inhibitors. Substitution at the alpha center of the known human arginase inhibitor 2-amino-6-boronohexanoic acid (ABH) is acceptable in the active site pockets of both human arginase I and arginase II. In particular, substituents with a tertiary amine linked via a two carbon chain show improved inhibitory potency for both enzyme isoforms. This potency improvement can be rationalized by X-ray crystallography, which shows a water-mediated contact between the basic nitrogen and the carboxylic acid side chain of Asp200, which is situated at the mouth of the active site pocket of arginase II (Asp181 in arginase I). We believe that this is the first literature report of compounds with improved arginase inhibitory activity, relative to ABH, and represents a promising starting point for further optimization of in vitro potency and the identification of better tool molecules for in vivo investigations of the potential pathophysiological roles of arginases. 23578611 Beneficial effects of noni (Morinda citrifolia L.) juice on livers of high-fat dietary hamsters. Polyphenols in noni juice (NJ) are mainly composed of phenolic acids, mainly gentisic, p-hydroxybenoic, and chlorogenic acids. To investigate the beneficial effects of NJ on the liver, hamsters were fed with two diets, normal-fat and high-fat diets. Furthermore, high-fat dietary hamsters were received distilled water, and 3, 6, and 9mL NJ/kg BW, respectively. After a 6-week feeding period, the increased (p<0.05) sizes of liver and visceral fat in high-fat dietary hamsters compared to the control hamsters were ameliorated (p<0.05) by NJ supplementation. NJ also decreased (p<0.05) serum/liver lipids but enhanced (p<0.05) daily faecal lipid/bile acid outputs in the high-fat dietary hamsters. High-fat dietary hamsters supplemented with NJ had higher (p<0.05) liver antioxidant capacities but lowered (p<0.05) liver iNOS, COX-2, TNF-α, and IL-1β expressions, gelatinolytic levels of MMP9, and serum ALT values compared to those without NJ. Hence, NJ protects liver against a high-fat dietary habit via regulations of antioxidative and anti-inflammatory responses. 23611027 Synthesis of Atactic and Isotactic Poly(1,2-glycerol carbonate)s: Degradable Polymers for Biomedical and Pharmaceutical Applications. The synthesis and characterization of atactic and isotactic linear poly(benzyl 1,2-glycerol carbonate)s are reported. The poly(benzyl 1,2-glycerol carbonate)s were obtained via the ring-opening copolymerization of rac-/(R)-benzyl glycidyl ether with CO2 using [SalcyCo(III)X] complexes with high carbonate linkage selectivity and polymer/cyclic carbonate selectivity (>99%). Deprotection of the resultant polymers afforded poly(1,2-glycerol carbonate)s with a functionalizable pendant primary hydroxyl group. Poly(1,2-glycerol carbonate) showed a remarkable increase in degradation rate compared to poly(1,3-glycerol carbonate) with a t1/2 ≈ 2-3 days. These polymers fulfill an unmet need for a readily degradable biocompatible polycarbonate. 23578641 Prooxidative and antioxidative properties of β-carotene in chlorophyll and riboflavin photosensitized oil-in-water emulsions. Effects of β-carotene on the oxidative stability of chlorophyll or riboflavin photosensitized oil-in-water (O/W) emulsions were determined by analysing the depleted headspace oxygen content, lipid hydroperoxides, fluorescence intensity, and headspace volatiles. As the concentration of β-carotene increased from 0 to 10, 100, and 1000μM, the oxidative stability of samples containing chlorophylls decreased in a concentration-dependent manner under light, indicating that β-carotene acted as a prooxidant. However, in riboflavin photosensitized O/W emulsions, 100 and 1000μM β-carotene inhibited lipid oxidation. Although β-carotene protected both photosensitisers in O/W emulsions, β-carotene displayed antioxidative or prooxidative properties, which depended on the polarity of the photosensitisers. The development of t-2-heptenal and 1-octen-3-ol increased greatly in chlorophyll sensitised O/W emulsions with an increase in β-carotene concentration, implying that more singlet oxygen oxidation occurred due to the higher levels of remaining chlorophylls. However, the content of t-2-heptenal and 1-octen-3-ol in the riboflavin sensitised O/W emulsions was not significantly correlated with the β-carotene concentration, which indicates that β-carotene in the lipid particles effectively quenched singlet oxygen. 23327358 A thermoplastic elastomer patch matrix for traditional Chinese medicine: design and evaluation. Abstract Objective: To design and evaluate a novel pressure sensitive adhesive (PSA) patch containing traditional Chinese medicine (TCM) using styrene-isoprene-styrene (SIS) copolymer. Method: A mixture D-optimal design with ternary response surface diagram was employed in the optimization process. The proportions of SIS copolymer, tackifying resin and plasticizer were selected as the independent variables while tack force, peel strength of the patch and skin penetrability of methyl salicylate were selected as the dependent variables. The optimized patch was then evaluated including in vivo absorption, pharmacological activities and skin irritation, by comparing with a commercial patch based on natural rubber. Results: The optimized patch, which comprised 30.0% SIS copolymer, 26.6% tackifying resin and 43.4% plasticizer, was superior to commercial patch in skin permeation, pharmacological activities and skin biocompatibility. Conclusion: SIS copolymer was a suitable substitute to natural rubber in producing patches containing TCM formula. 23567490 The cyclin D1 (CCND1) rs9344 G>A polymorphism predicts clinical outcome in colon cancer patients treated with adjuvant 5-FU-based chemotherapy. Recent evidence indicates a potential prognostic and predictive value for germline polymorphisms in genes involved in cell cycle control. We investigated the effect of cyclin D1 (CCND1) rs9344 G>A in stage II/III colon cancer patients and validated the findings in an independent study cohort. For evaluation and validation set, a total of 264 and 234 patients were included. Patients treated with 5-fluorouracil-based chemotherapy, carrying the CCND1 rs9344 A/A genotype had significantly decreased time-to-tumor recurrence (TTR) in univariate analysis and multivariate analysis (hazard ratio (HR) 2.47; 95% confidence interval (CI) 1.16-5.29; P=0.019). There was no significant association between CCND1 rs9344 G>A and TTR in patients with curative surgery alone. In the validation set, the A allele of CCND1 rs9344 G>A remained significantly associated with decreased TTR in univariate and multivariate analyses (HR 1.94; 95% CI 1.05-3.58; P=0.035). CCND1 rs9344 G>A may be a predictive and/or prognostic biomarker in stage II/III colon cancer patients, however, prospective trials are warranted to confirm our findings.The Pharmacogenomics Journal advance online publication, 9 April 2013; doi:10.1038/tpj.2013.15. 23147692 A practical quantification method for Heinz bodies in birds applicable to rapid response field scenarios. Oil-induced oxidative injury to red blood cells results in Heinz body hemolytic anemia. Here, we evaluated three Heinz body staining techniques in brown pelican (Pelecanus occidentalis) blood. Using a range of in vitro acetylphenylhydrazine incubations, we validated a field-adapted technique against laboratory wet-mounts and verified the stability of this technique for one month following preparation. Employing this technique during petrochemical spill responses allows for delays between sample collection and analysis. 23460265 In vivo binding of the dopamine-1 receptor PET tracers [(11)C]NNC112 and [ (11)C]SCH23390: a comparison study in individuals with schizophrenia. RATIONALE: A deficit in dopamine-1 (D1) receptor function in the prefrontal cortex is suggested to play a role in the cognitive dysfunction observed in patients with schizophrenia. However, the results from positron emission tomography imaging studies of D1 receptor levels in individuals with schizophrenia are mixed. OBJECTIVES: The aim of this investigation was to determine whether the in vivo characteristics of the different D1 receptor tracers used in previous reports, [(11)C]SCH23390 and [(11)C]NNC112, may have contributed to these discrepancies reported in the literature. METHODS: Eight patients with schizophrenia and 12 healthy control subjects were scanned with both [(11)C]SCH23390 and [(11)C]NNC112. RESULTS: [(11)C]SCH23390 and [(11)C]NNC112 binding potentials in both patients and control subjects were compared and no tracer by diagnosis interactions were observed. CONCLUSIONS: The results of this study suggest that differences in the binding of [(11)C]SCH23390 and [(11)C]NNC112 observed in previous studies are not due to differences in the in vivo behavior of these tracers. 23415833 Metabolism of profenofos to 4-bromo-2-chlorophenol, a specific and sensitive exposure biomarker. Profenofos is a direct acting phosphorothioate organophosphorus (OP) pesticide capable of inhibiting β-esterases such as acetylcholinesterase, butyrylcholinesterase, and carboxylesterase. Profenofos is known to be detoxified to the biologically inactive metabolite, 4-bromo-2-chlorophenol (BCP); however, limited data are available regarding the use of urinary BCP as an exposure biomarker in humans. A pilot study conducted in Egyptian agriculture workers, demonstrated that urinary BCP levels prior to application (3.3-30.0μg/g creatinine) were elevated to 34.5-3566μg/g creatinine during the time workers were applying profenofos to cotton fields. Subsequently, the in vitro enzymatic formation of BCP was examined using pooled human liver microsomes and recombinant human cytochrome P-450s (CYPs) incubated with profenofos. Of the nine human CYPs studied, only CYPs 3A4, 2B6, and 2C19 were able to metabolize profenofos to BCP. Kinetic studies indicated that CYP 2C19 has the lowest Km, 0.516μM followed by 2B6 (Km=1.02μM) and 3A4 (Km=18.9μM). The Vmax for BCP formation was 47.9, 25.1, and 19.2nmol/min/nmol CYP for CYP2B6, 2C19, and 3A4, respectively. Intrinsic clearance (Vmax/Km) values of 48.8, 46.9, and 1.02ml/min/nmol CYP 2C19, 2B6, and 3A4, respectively, indicate that CYP2C19 and CYP2B6 are primarily responsible for the detoxification of profenofos. These findings support the use of urinary BCP as a biomarker of exposure to profenofos in humans and suggest polymorphisms in CYP 2C19 and CYP 2B6 as potential biomarkers of susceptibility. 23159330 Behavioural and EEG effects of chronic rapamycin treatment in a mouse model of Tuberous Sclerosis Complex. Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder caused by mutation in either Tsc1 or Tsc2 genes that leads to the hyper activation of the mTOR pathway, a key signalling pathway for synaptic plasticity. TSC is characterized by benign tumors arising in different organs and severe neuropsychiatric symptoms, such as epilepsy, intellectual disability, autism, anxiety and depressive behaviour. Rapamycin is a potent inhibitor of mTOR and its efficacy in treating epilepsy and neurological symptoms remains elusive. In a mouse model in which Tsc1 has been deleted in embryonic telencephalic neural stem cells, we analyzed anxiety- and depression-like behaviour by elevated-plus maze (EPM), open-field test (OFT), forced-swim test (FST) and tail-suspension test (TST), after chronic administration of rapamycin. In addition, spectral analysis of background EEG was performed. Rapamycin-treated mutant mice displayed a reduction in anxiety- and depression-like phenotype, as shown by the EPM/OFT and FST, respectively. These results were inline with EEG power spectra outcomes. The same effects of rapamycin were observed in wild-type mice. Notably, in heterozygous animals we did not observe any EEG and/or behavioural variation after rapamycin treatment. Together these results suggest that both TSC1 deletion and chronic rapamycin treatment might have a role in modulating behaviour and brain activity, and point out to the potential usefulness of background EEG analysis in tracking brain dysfunction in parallel with behavioural testing. 23232060 Discovery of 4-phenyl-2-phenylaminopyridine based TNIK inhibitors. A series of compounds based on a 4-phenyl-2-phenylaminopyridine scaffold that are potent and selective inhibitors of Traf2- and Nck-interacting kinase (TNIK) activity are described. These compounds were used as tools to test the importance of TNIK kinase activity in signaling and proliferation in Wnt-activated colorectal cancer cells. The results indicate that pharmacological inhibition of TNIK kinase activity has minimal effects on either Wnt/TCF4/β-catenin-driven transcription or viability. The findings suggest that the kinase activity of TNIK may be less important to Wnt signaling than other aspects of TNIK function, such as its putative role in stabilizing the TCF4/β-catenin transcriptional complex. 23085382 What is behind the non-antibiotic properties of minocycline? Minocycline is a second-generation, semi-synthetic tetracycline that has been in use in therapy for over 30 years for its antibiotic properties against both Gram-positive and Gram-negative bacteria. It displays antibiotic activity due to its ability to bind to the 30S ribosomal subunit of bacteria and thus inhibit protein synthesis. More recently, it has been described to exert a variety of biological actions beyond its antimicrobial activity, including anti-inflammatory and anti-apoptotic activities, inhibition of proteolysis, as well as suppression of angiogenesis and tumor metastasis, which have been confirmed in different experimental models of non-infectious diseases. There are also many studies that have focused on the mechanisms involved in these non-antibiotic properties of minocycline, including anti-oxidant activity, inhibition of several enzyme activities, inhibition of apoptosis and regulation of immune cell activation and proliferation. This review summarizes the current findings in this topic, mainly focusing on the mechanisms underlying the immunomodulatory and anti-inflammatory activities of minocycline. 23468386 The Role of Surface Chemistry on the Toxicity of Ag Nanoparticles. The role of surface chemistry on the toxicity of Ag nanoparticles is investigated using Saccharomyces cerevisiae yeast as a platform for evaluation. Combining the shape-controlled synthesis of Ag nanoparticles with a comprehensive characterization of their physicochemical properties, an understanding is formed of the correlation between the physicochemical parameters of nanoparticles and the inhibition growth of yeast cells upon the introduction of nanoparticles into the cell culture system. Capping agents, surface facets, and sample stability-the three experimental parameters that are inherent from the wet-chemical synthesis of Ag nanoparticles-have a strong impact on toxicity evaluation. Hence, it is important to characterize surface properties of Ag nanoparticles in the nature of biological media and to understand the role that surface chemistry may interplay to correlate the physicochemical properties of nanoparticles with their biological response upon exposure. This work demonstrates the great importance of surface chemistry in designing experiments for reliable toxicity evaluation and in mitigating the toxicity of Ag nanoparticles for their safe use in future commercialization. 23373701 Dopamine D2 receptor activation leads to an up-regulation of glial cell line-derived neurotrophic factor via Gβγ-Erk1/2-dependent induction of Zif268. Glial cell line-derived neurotrophic factor (GDNF) is a potent growth factor essential to the development, survival, and function of dopaminergic neurons (Airaksinen and Saarma 2002). The molecular mechanisms underlying GDNF expression remain elusive; thus, we set out to identify a signaling pathway that governs GDNF levels. We found that treatment of both differentiated dopaminergic-like SH-SY5Y cells and rat midbrain slices with the dopamine D2 receptor (D2R) agonist, quinpirole, triggered an increase in the expression of GDNF that was temporally preceded by an increase in the levels of zinc-finger protein 268 (Zif268), a DNA-binding transcription factor encoded by an immediate-early gene. Moreover, the D2R inhibitor raclopride blocked the increase of both GDNF and Zif268 expression following potassium-evoked dopamine release in SH-SY5Y cells. We used adenoviral delivery of small hairpin RNA (shRNA) targeting Zif268 to down-regulate its expression and found that Zif268 is specifically required for the D2R-mediated up-regulation of GDNF. Furthermore, the D2R-mediated induction of GDNF and Zif268 expression was dependent on Gβγ-mediated signaling and activation of extracellular signal-regulated kinase 1/2. Importantly, using chromatin immunoprecipitation assay, we identified a direct association of Zif268 with the GDNF promoter. These results suggest that D2R activation induces a Gβγ- and extracellular signal-regulated kinase 1/2-dependent increase in the level of Zif268, which functions to directly up-regulate the expression of GDNF. 23618623 Characterization of the nucleation process of lysozyme at physiological pH: Primary but not sole process. We report on a kinetic study of the heat-induced aggregation process of lysozyme at physiological pH. The time evolution of the aggregation extent and the conformational changes of the protein were followed by dynamic light scattering (DLS) and FTIR spectroscopy, respectively, whereas the morphology of the aggregates was observed by Atomic Force Microscopy (AFM). The conformational changes of the secondary and tertiary structures were simultaneous and distinct in time with respect to the formation of aggregates. Oligomer formation occurred through at least two different aggregation processes: a nucleation process and a homogeneous non-nucleative diffusion-controlled process. FTIR measurements showed that supramolecular aggregation proceeded without the formation of β-aggregated structures and AFM images revealed the presence of oligomers and amorphous aggregates; no fibrillar structures were observed. 23393127 GnRH pulse frequency-dependent stimulation of FSHβ transcription is mediated via activation of PKA and CREB. Expression of pituitary FSH and LH, under the control of pulsatile GnRH, is essential for fertility. cAMP response element-binding protein (CREB) has been implicated in the regulation of FSHβ gene expression, but the molecular mechanisms by which pulsatile GnRH regulates CREB activation remain poorly understood. We hypothesized that CREB is activated by a distinct signaling pathway in response to pulsatile GnRH in a frequency-dependent manner to dictate the FSHβ transcriptional response. GnRH stimulation of CREB phosphorylation (pCREB) in the gonadotrope-derived LβT2 cell line was attenuated by a protein kinase A (PKA) inhibitor, H89. A dominant negative PKA (DNPKA) reduced GnRH-stimulated pCREB and markedly decreased GnRH stimulation of FSHβ mRNA and FSHβLUC activity, but had little effect on LHβLUC activity, indicating relative specificity of this pathway. In perifusion studies, FSHβ mRNA levels and FSHβLUC activities were increased by pulsatile GnRH, with significantly greater increases at low compared with high pulse frequencies. DNPKA markedly reduced these GnRH-stimulated FSHβ responses at both low and high pulse frequencies. Correlating with FSHβ activation, both PKA activity and levels of pCREB were increased to a greater extent by low compared with high GnRH pulse frequencies, and the induction of pCREB was also attenuated by overexpression of DNPKA at both low and high pulse frequencies. Taken together, these data indicate that a PKA-mediated signaling pathway mediates GnRH activation of CREB at low-pulse frequencies, playing a significant role in the decoding of the hypothalamic GnRH signal to result in frequency-dependent FSHβ activation. 23425199 Quantum mechanics/molecular mechanics modeling of fatty acid amide hydrolase reactivation distinguishes substrate from irreversible covalent inhibitors. Carbamate and urea derivatives are important classes of fatty acid amide hydrolase (FAAH) inhibitors that carbamoylate the active-site nucleophile Ser241. In the present work, the reactivation mechanism of carbamoylated FAAH is investigated by means of a quantum mechanics/molecular mechanics (QM/MM) approach. The potential energy surfaces for decarbamoylation of FAAH covalent adducts, derived from the O-aryl carbamate URB597 and from the N-piperazinylurea JNJ1661610, were calculated and compared to that for deacylation of FAAH acylated by the substrate oleamide. Calculations show that a carbamic group bound to Ser241 prevents efficient stabilization of transition states of hydrolysis, leading to large increments in the activation barrier. Moreover, the energy barrier for the piperazine carboxylate was significantly lower than that for the cyclohexyl carbamate derived from URB597. This is consistent with experimental data showing slowly reversible FAAH inhibition for the N-piperazinylurea inhibitor and irreversible inhibition for URB597. 23574435 Detection of Nitrogen-Protonated Nitrous Oxide (HNNO(+)) by Rotational Spectroscopy. The rotational spectrum of nitrogen-protonated nitrous oxide (HNNO(+)), an isomer whose existence was first inferred from kinetic studies more than 30 years ago, has now been detected by Fourier transform microwave spectroscopy, guided by new high-level coupled-cluster calculations of its molecular structure. From high-resolution measurements of the hyperfine splitting in its fundamental rotational transition, the rotational constant (B + C)/2 and the quadrupole tensor element χaa(N) for both nitrogen atoms have been precisely determined. The derived constants agree well with quantum-chemical calculations here and others in the literature. The χaa(N) values for the two isomers of protonated nitrous oxide are qualitatively consistent with the valence bond description of H-N═N(+)═O for the electronic structure of the nitrogen-protonated form and N≡N(+)-O-H for the oxygen-protonated form. HNNO(+) is found to be 2-4 times less abundant than NNOH(+) under a range of experimental conditions, as might be expected because this metastable isomer is known to be only ∼6 kcal mol(-1) less stable than ground-state NNOH(+) from kinetic measurements by Ferguson and co-workers. 23452243 β-Sheet Nanocrystalline Domains Formed from Phosphorylated Serine-Rich Motifs in Caddisfly Larval Silk: A Solid State NMR and XRD Study. Adhesive silks spun by aquatic caddisfly (order Trichoptera) larvae are used to build both intricate protective shelters and food harvesting nets underwater. In this study, we use (13)C and (31)P solid-state NMR and wide angle X-ray diffraction (WAXD) as tools to elucidate molecular protein structure of caddisfly larval silk from the species Hesperophylax consimilis . Caddisfly larval silk is a fibroin protein based biopolymer containing mostly repetitive amino acid motifs. NMR and X-ray results provide strong supporting evidence for a structural model in which phosphorylated serine repeats (pSX)4 complex with divalent cations Ca(2+) and Mg(2+) to form rigid nanocrystalline β-sheet structures in caddisfly silk. (13)C NMR data suggests that both phosphorylated serine and neighboring valine residues exist in a β-sheet conformation while glycine and leucine residues common in GGX repeats likely reside in random coil conformations. Additionally, (31)P chemical shift anisotropy (CSA) analysis indicates that the phosphates on phosphoserine residues are doubly ionized, and are charge-stabilized by divalent cations. Positively charged arginine side chains also likely play a role in charge stabilization. Finally, WAXD results finds that the silk is at least 7-8% crystalline, with β-sheet interplane spacings of 3.7 and 4.5 Å. 23454150 Nitrosylation: An adverse factor in Uremic Hemolytic Syndrome. Antitoxin effect of Ziziphus mistol Griseb. Toxins of Escherichia coli (STEC) causing Uremic Hemolytic Syndrome (UHS) generate oxidative stress in human blood with more production of nitric oxide (NO) than reactive oxygen species (ROS). Shiga toxin (Stx) together with the hemolysin (Hly) increased lipid oxidation, as evaluated by malondialdehyde MDA and oxidation of proteins. The addition of Ziziphus mistol Griseb extracts decreased NO, ROS, MDA and simultaneously caused an increase in the degradation of oxidized proteins to advanced oxidation protein products (AOPPs) in controls and samples with toxins. Furthermore, the nitrosylated proteins/AOPP ratio was reduced, due to the increase of AOPP. Z. mistol Griseb extracts exhibited a high proportion of polyphenols and flavonoids, with evident correlation with ferrous reduction antioxidant potential (FRAP). The plasma of eight children with UHS showed oxidative stress and NO stimulus, comparable to the effect of toxins during the assays in vitro. UHS children presented high levels of nitrosylated proteins respect to control children of similar age. Although the degradation of oxidized proteins to AOPP rose in UHS children, the nitrosylated proteins/AOPP rate increased as a consequence of the elevated nitrosative stress observed in these patients. 23580332 Decursin Exerts Anti-cancer Activity in MDA-MB-231 Breast Cancer Cells Via Inhibition of the Pin1 Activity and Enhancement of the Pin1/p53 Association. The peptidyl-prolyl cis/trans isomerase Pin1 is overexpressed in a wide variety of cancer cells and thus considered as an important target molecule for cancer therapy. This study demonstrates that decursin, a bioactive compound from Angelica gigas, exert the anti-cancer effect against breast cancer cells via regulation of Pin1 and its related signaling molecules. We observed that decursin induced G1 arrest with decrease in cyclin D1 level in Pin1-expressing breast cancer cells MDA-MB-231, but not Pin1-non-expressing breast cancer cells MDA-MB-157. In addition, decursin significantly reduced protein expression and enzymatic activity of Pin1 in MDA-MB-231 cells. Further, we found that decursin treatment enhanced the p53 expression level and failed to down-regulate Pin1 in the cells transfected with p53 siRNA, indicating the importance of p53 in the decursin-mediated Pin1 inhibition in MDA-MB-231 cells. Decursin stimulated association between Pin1 to p53. Moreover, decursin facilitated p53 transcription in MDA-MB-231 cells. Overall, our current study suggests the potential of decursin as an attractive cancer therapeutic agent for breast cancer by targeting Pin1 protein. Copyright © 2013 John Wiley & Sons, Ltd. 23474897 Practical synthesis of a chromene analog for use as a retinoic acid receptor alpha antagonist lead compound. Retinoic acid receptor alpha (RARα) selective compounds may guide the design of drugs that can be used in conjunction with hormonal adjuvant therapy in the treatment of breast cancer. Herein we report a modified synthesis of a known RARα antagonist, 2-fluoro-4-[[[8-bromo-2,2-dimethyl-4-(4-methylphenyl)chroman-6-yl]carbonyl]amino]benzoic acid and a synthesis of its unknown, desfluoro analog, 4-[[[8-bromo-2,2-dimethyl-4-(4-methylphenyl)chroman-6-yl]carbonyl]amino]benzoic acid. The modified route allows for facile reaction workups, increased yields, lower cost and incorporates a green alternative step. Structure-activity relationship studies determined through functional cell-based assays, demonstrated antagonism to RARα for both compounds. Molecular modeling within the RARα binding pocket was used to compare binding interactions of the desfluoro analog to a known RAR antagonist. 22798249 Correlation of high urinary Smad1 level with glomerular hyperfiltration in type 2 diabetes mellitus. The aim of this study was to assess the relationship between urinary Smad1 and glomerular hyperfiltration (GHF) in type 2 diabetes mellitus (T2DM), and to explore the factors related to the urinary Smad1 in T2DM. The reference value of the estimated glomerular filtration rate (eGFR) was determined in 248 healthy individuals. 30 patients with GHF, 58 patients with norm-GFR T2DM, and 24 healthy patients who served as controls were recruited. Urinary Smad1, fasting plasma glucose (FPG), fasting serum C-Peptide (C-P), hemoglobin A1C (HbA1c), cystatin C, and other chemistry laboratory parameters of T2DM participants and controls were measured. Patients with GHF had higher levels of urinary Smad1 than the control group, and those with norm-GFR. For T2DM patients with body mass index, age, and gender adjustments, urinary Smad1 was positively correlated with FPG, HbA1C, and eGFR, but negatively correlated with fasting serum C-P. Multivariate linear regression analysis demonstrated that eGFR, HbA1C, and fasting serum C-P were independently associated with urinary Smad1. High levels of urinary Smad1 were found in GHF patients with T2DM, which may be another potential mechanism of GHF in relation to diabetic nephropathy. 23061622 Progress in synthesis and antitumor activities of estradiol-linked platinum complex. Platinum complexes such as cisplatin and caboplatin are widely used in cancer chemotherapy. However, their clinical applications are substantially limited by unexpected toxic side effects. In this review, we discuss the current progress on the design and synthesis of estradiol-linked platinum complexes as the targeted antitumor drugs. Many of them display a high antitumor activity against the growth of breast cancer cell lines in vitro. The estradiol-linked platinum complexes could be used as target therapeutics for breast cancer. 23421798 Electronic Spectroscopy and Electronic Structure of Copper Acetylide, CuCCH. The optical spectrum of the linear CuCCH molecule has been investigated for the first time, using resonant two-photon ionization spectroscopy employing ArF (193 nm) or F2 (157 nm) excimer radiation for photoionization. Scans over the range 19 400-25 200 cm(-1) were conducted, leading to the observation of three electronic band systems. These are identified as the [20.2] ã1 ← X̃ (1)Σ(+), the [23.1] à (1)Σ(+) ← X̃ (1)Σ(+), and the [24.7] B̃ (1)Π ← X̃ (1)Σ(+) systems, although only the first two have been rotationally resolved. The ã1 state is tentatively assigned as having (3)Π1 symmetry, becoming optically accessible through spin-orbit interaction with the B̃ (1)Π state. Vibrational assignments have provided the frequency of the Cu-C stretching mode, ν3, in the ground and all three excited states, along with both bending modes, ν4 and ν5, in the à (1)Σ(+) and B̃ (1)Π states, and the Cu-C≡C bending mode, ν5, in the ground state. Comparisons are made to the known electronic states of CuF, CuCl, CuBr, and CuI, and it is argued that like these molecules, the CuCCH molecule is essentially ionic in both the ground and excited states, with the ground state correlating diabatically to Cu(+) (3d(10), (1)S) + CCH(-) (X̃ (1)Σ(+)) and the excited states correlating diabatically to Cu(+) (3d(9)4s(1), (1,3)D) + CCH(-) (X̃ (1)Σ(+)). 23327840 Significant interaction between RETN -420 G/G genotype and lower BMI on decreased risk of type 2 diabetes mellitus (T2DM) in Japanese--the J-MICC Study. We examined the association of the RETN (resistin) -420 C>G polymorphism (rs1862513) with risk of diabetes mellitus (DM), considering lifestyle factors, in Japanese. Subjects were participants of J-MICC Study, where 2,651 participants aged 35-69 years provided their blood for genotyping and lifestyle data after informed consent. Odds ratio (OR) of DM for RETN-420 G/G genotype was estimated using unconditional logistic regression model. Statistically significant interaction on risk of DM was observed between RETN-420 G/G genotype and BMI<25 (OR for interaction = 0.12; P = 0.046), and when subjects with RETN-420 C/C+C/G and BMI ≥ 25 (n = 69 for DM and 544 for non-DM) were defined as the reference, the adjusted ORs for subjects with RETN-420 G/G genotype and BMI>25 (n = 10 for DM and 111 for non-DM), RETN-420 C/C+C/G and BMI<25 (n = 81 for DM and 1,605 for non-DM), and RETN-420 G/G and BMI<25 (n = 1 for DM and 230 for non-DM) were demonstrated to be 0.72 (95% confidence interval: 0.36-1.46), 0.40 (0.28-0.56) and 0.03 (0.005-0.25), respectively. The present study revealed the significant interaction of RETN-420 G/G genotype with lower BMI on the decreased risk of DM, but the direction was opposite to the reported ones in Japanese. We should be careful in interpretation of the present study results because of the limited sample sizes. Further investigation of this association as well as of the actual biological roles of RETN in the genesis of human metabolic disorders including DM will be required. 23541674 Identification of metal ion binding peptides containing unnatural amino acids by phage display. The bidentate metal binding amino acid bipyridylalanine (BpyAla) was incorporated into a disulfide linked cyclic peptide phage displayed library to identify metal ion binding peptides. Selection against Ni(2+)-nitrilotriacetic acid (NTA) enriched for sequences containing histidine and BpyAla. BpyAla predominated when selections were carried out at lower pH, consistent with the differential pKa's of histidine and BpyAla. Two peptides containing BpyAla were synthesized and found to bind Ni(2+) with low micromolar dissociation constants. Incorporation of BpyAla and other metal binding amino acids into peptide and protein libraries should enable the evolution of novel binding and catalytic activities. 23303713 Proteomic methods reveal cyclophilin a function as a host restriction factor against rotavirus infection. Rotavirus (RV) infection is the main cause of acute dehydrating diarrhea in infants and young children below 5 years old worldwide. RV infection causes a global shutoff of host proteins as many other viruses do. However, previous studies revealed that RV could selectively upregulated the expression of some host proteins that then played important roles in RV infection. To globally explor such host proteins that were upregulated in early human rotavirus (HRV) infection, proteomic methods were used and a total of ten upregulated host proteins were unambiguously identified. Cyclophilin A (CYPA), a peptidyl-prolyl cis-trans isomerase, was among these upregulated host proteins. Following infection, CYPA was recruited to the viroplasm and interacted with HRV structural protein VP2; CYPA reduced host susceptibility to HRV infection and inhibited replication of HRV by repressing the expression of viral proteins. Furthermore, we found that the increased expression of CYPA in enterocytes of small intestine correlated to the period when BALB/c mice became resistant to RV diarrhea. Together, we identified CYPA as a novel host restriction factor that confered protection against RV infection and might contribute to host susceptibility to RV diarrhea. 23606568 Cell Surface Receptor Targeted Biomimetic Apatite Nanocrystals for Cancer Therapy. Nanosized drug carriers functionalized with moieties specifically targeting tumor cells are promising tools in cancer therapy, due to their ability to circulate in the bloodstream for longer periods and their selectivity for tumor cells, enabling the sparing of healthy tissues. Because of its biocompatibility, high bioresorbability, and responsiveness to pH changes, synthetic biomimetic nanocrystalline apatites are used as nanocarriers to produce multifunctional nanoparticles, by coupling them with the chemotherapeutic drug doxorubicin (DOXO) and the DO-24 monoclonal antibody (mAb) directed against the Met/Hepatocyte Growth Factor receptor (Met/HGFR), which is over-expressed on different types of carcinomas and thus represents a useful tumor target. The chemical-physical features of the nanoparticles are fully investigated and their interaction with cells expressing (GTL-16 gastric carcinoma line) or not expressing (NIH-3T3 fibroblasts) the Met/HGFR is analyzed. Functionalized nanoparticles specifically bind to and are internalized in cells expressing the receptor (GTL-16) but not in the ones that do not express it (NIH-3T3). Moreover they discharge DOXO in the targeted GTL-16 cells that reach the nucleus and display cytotoxicity as assessed in an MTT assay. Two different types of ternary nanoparticles are prepared, differing for the sequence of the functionalization steps (adsorption of DOXO first and then mAb or vice versa), and it is found that the ones in which mAb is adsorbed first are more efficient under all the examined aspects (binding, internalization, cytotoxicity), possibly because of a better mAb orientation on the nanoparticle surface. These multifunctional nanoparticles could thus be useful instruments for targeted local or systemic drug delivery, allowing a reduction in the therapeutic dose of the drug and thus adverse side effects. Moreover, this work opens new perspectives in the use of nanocrystalline apatites as a new platform for theranostic applications in nanomedicine. 23317099 Synthesis and biological evaluation as microtubule-active agents of several tetrahydrofuran and spiroacetal derivatives. The stereoselective preparation of several molecules containing structural fragments of the tetrahydrofuran and spiroacetal type is described. Their degree of cytotoxicity and their interactions with tubulin have been investigated. It has been confirmed that the tetrahydrofuran derivatives are cytotoxic but, in contrast to previous reports, it has been found that the cytoxicity is not due to interactions with the microtubule network. Furthermore, and also in contrast to a previous report on closely related compounds, the spiroacetal derivatives do show interactions with tubulin, even though the precise mechanism and the binding site still remain to be established. 23432662 Discovery of a Novel Selective PPARγ Ligand with Partial Agonist Binding Properties by Integrated in Silico/in Vitro Work Flow. Full agonists to the peroxisome proliferator-activated receptor (PPAR)γ, such as Rosiglitazone, have been associated with a series of undesired side effects, such as weight gain, fluid retention, cardiac hypertrophy, and hepatotoxicity. Nevertheless, PPARγ is involved in the expression of genes that control glucose and lipid metabolism and is an important target for drugs against type 2 diabetes, dyslipidemia, atherosclerosis, and cardiovascular disease. In an effort to identify novel PPARγ ligands with an improved pharmacological profile, emphasis has shifted to selective ligands with partial agonist binding properties. Toward this end we applied an integrated in silico/in vitro workflow, based on pharmacophore- and structure-based virtual screening of the ZINC library, coupled with competitive binding and transactivation assays, and adipocyte differentiation and gene expression studies. Hit compound 9 was identified as the most potent ligand (IC50 = 0.3 μM) and a relatively poor inducer of adipocyte differentiation. The binding mode of compound 9 was confirmed by molecular dynamics simulation, and the calculated free energy of binding was -8.4 kcal/mol. A novel functional group, the carbonitrile group, was identified to be a key substituent in the ligand-protein interactions. Further studies on the transcriptional regulation properties of compound 9 revealed a gene regulatory profile that was to a large extent unique, however functionally closer to that of a partial agonist. 23394550 Reversible sol-to-gel transformation of uracil gelators: specific colorimetric and fluorimetric sensor for fluoride ions. A new type of anthracene organogelator based on uracil was obtained using organic aromatic solvents, cyclohexane, DMSO, ethanol, and ethyl acetate. It was further characterized by field-emission scanning electron microscopy and transmission electron microscopy. Specifically, the resulting organogels were demonstrated to be promising colorimetric and fluorescent sensors toward fluoride ions with high sensitivity and selectivity, accompanying the disruption of the gelators. Spectroscopic study and (1)H NMR titration experiment revealed that the deprotonation of the hydrogen atom on the N position of uracil moiety by fluoride ions is responsible for the recognition events, evidenced by immediate transformation from the sol phase to the gel state upon adding a small amount of a proton solvent, methanol. The process is reversible, with zero loss in sensing activity and sol-to-gel transformation ability even after five runs. 23542343 Tail Tip Proteins Related to Bacteriophage λ gpL Coordinate an Iron-Sulfur Cluster. The assembly of long non-contractile phage tails begins with the formation of the tail tip complex (TTC). TTCs are multi-functional protein structures that mediate host cell adsorption and genome injection. The TTC of phage λ is assembled from multiple copies of eight different proteins, including gpL. Purified preparations of gpL and several homologues all displayed a distinct reddish color, suggesting the binding of iron by these proteins. Further characterization of the gpL homologue from phage N15, which was most amenable to in vitro analyses, showed that it contains two domains. The C-terminal domain was demonstrated to coordinate an iron-sulfur cluster, providing the first example of a viral structural protein binding to this type of metal group. We characterized the iron-sulfur cluster using inductively coupled plasma-atomic emission spectroscopy, absorbance spectroscopy, and electron paramagnetic resonance spectroscopy and found that it is an oxygen-sensitive [4Fe-4S](2+) cluster. Four highly conserved cysteine residues were shown to be required for coordinating the iron-sulfur cluster, and substitution of any of these Cys residues with Ser or Ala within the context of λ gpL abolished biological activity. These data imply that the intact iron-sulfur cluster is required for function. The presence of four conserved Cys residues in the C-terminal regions of very diverse gpL homologues suggest that utilization of an iron-sulfur cluster is a widespread feature of non-contractile tailed phages that infect Gram-negative bacteria. In addition, this is the first example of a viral structural protein that binds an iron-sulfur cluster. 23512496 Hop Extracts and Hop Substances in Treatment of Menopausal Complaints. Hop extract is a long used medicinal product and, regarding hormonal activities, in 1999 a number of prenylflavanones have been identified as its major constituents with 8-prenylnaringenin (8-PN) being the main active estrogenic compound. There have been several in vivo studies performed that demonstrate the potential of hop extract and the single compound 8-PN to alleviate climacteric symptoms like osteoporosis, vasomotoric complaints, and sexual motivation. On the other hand, only a few clinical studies have been performed so far, and these mainly focused on menopausal discomforts, especially hot flushes, yielding rather inconclusive results. Despite preferentially activating estrogen receptor α, 8-PN is only slightly uterotrophic, but it also elucidates estrogenic effects on the mammary gland. In conclusion, although hop extract and especially 8-PN are promising candidates as a relief for climacteric symptoms, data on the safety and efficacy is still scarce. 23298136 Luminol as in situ light source in meso-tetraphenylporphyrin-mediated photodynamic therapy. The light sources used in current photodynamic therapy are mainly lasers or light emitting diodes, which are not suitable to treat large-volume tumors and those located in the inner body. To overcome the limitation, we propose an in situ light source to activate the photosensitizer and kill the cancer cells directly. In the present work, we use luminol as light source and meso-tetraphenylporphyrin as the photosensitizer. According to the results, cells incubated with meso-tetraphenylporphyrin, subsequently triggered by luminol, decreased significantly in assays including cell viability and cytotoxicity, while the other groups showed only minor differences. The flow cytometric and fluorescent microscopy analysis showed similar results as well. In the analysis of cell death pathway, cell shrinkage was noticed after photodynamic therapy treatment, which might refer to apoptosis. Briefly, we suggest that luminol is a promising light source in meso-tetraphenylporphyrin-mediated photodynamic therapy for its greater penetration depth and well matched emission wavelength. 23561114 Synthesis of amino acid conjugates of tetrahydrocurcumin and evaluation of their antibacterial and anti-mutagenic properties. Tetrahydrocurcumin (THC), the hydrogenated and stable form of curcumin, exhibits physiological and pharmacological activities similar to curcumin. A protocol has been developed for the synthesis of novel conjugates of THC with alanine (2a), isoleucine (2b), proline (2c), valine (2d), phenylalanine (2e), glycine (2f) and leucine (2g) in high yields (43-82%). All the derivatives of THC exhibited more potent anti-microbial activity than THC against Bacillus cereus, Staphylococcus aureus, Escherichia coli and Yersinia enterocolitica. The MIC values of the derivatives were 24-37% of those for THC in case of both Gram-positive and Gram-negative bacteria. Derivatives 2g and 2d exhibited maximum anti-mutagenicity against Salmonella typhimurium TA 98 and TA 1538, respectively at a low concentration of 313μg/plate, with comparable activity for THC evident only at 3750μg/plate. These results clearly demonstrated that the conjugation of THC at the phenolic position with amino acids led to significant improvement of its in vitro biological attributes. 23549272 A central role for thiols in plant tolerance to abiotic stress. Abiotic stress poses major problems to agriculture and increasing efforts are being made to understand plant stress response and tolerance mechanisms and to develop new tools that underpin successful agriculture. However, the molecular mechanisms of plant stress tolerance are not fully understood, and the data available is incomplete and sometimes contradictory. Here, we review the significance of protein and non-protein thiol compounds in relation to plant tolerance of abiotic stress. First, the roles of the amino acids cysteine and methionine, are discussed, followed by an extensive discussion of the low-molecular-weight tripeptide, thiol glutathione, which plays a central part in plant stress response and oxidative signalling and of glutathione-related enzymes, including those involved in the biosynthesis of non-protein thiol compounds. Special attention is given to the glutathione redox state, to phytochelatins and to the role of glutathione in the regulation of the cell cycle. The protein thiol section focuses on glutaredoxins and thioredoxins, proteins with oxidoreductase activity, which are involved in protein glutathionylation. The review concludes with a brief overview of and future perspectives for the involvement of plant thiols in abiotic stress tolerance. 23183624 Inhibition of ice nucleation by slippery liquid-infused porous surfaces (SLIPS). Ice repellent coatings have been studied and keenly sought after for many years, where any advances in the durability of such coatings will result in huge energy savings across many fields. Progress in creating anti-ice and anti-frost surfaces has been particularly rapid since the discovery and development of slippery, liquid infused porous surfaces (SLIPS). Here we use SLIPS-coated differential scanning calorimeter (DSC) pans to investigate the effects of the surface modification on the nucleation of supercooled water. This investigation is inherently different from previous studies which looked at the adhesion of ice to SLIPS surfaces, or the formation of ice under high humidity conditions. Given the stochastic nature of nucleation of ice from supercooled water, multiple runs on the same sample are needed to determine if a given surface coating has a real and statistically significant effect on the nucleation temperature. We have cycled supercooling to freezing and then thawing of deionized water in hydrophilic (untreated aluminum), hydrophobic, superhydrophobic, and SLIPS-treated DSC pans multiple times to determine the effects of surface treatment on the nucleation and subsequent growth of ice. We find that SLIPS coatings lower the nucleation temperature of supercooled water in contact with statistical significance and show no deterioration or change in the coating performance even after 150 freeze-thaw cycles. 23159986 Renal biomarker changes associated with hyaline droplet nephropathy in rats are time and potentially compound dependent. Alpha 2u-globulin mediated hyaline droplet nephropathy (HDN) is a male rat specific lesion induced when a compound or metabolite binds to alpha 2u-globulin. The objective of this study was to investigate if the newer and more sensitive renal biomarkers would be altered with HDN as well as be able to distinguish between HDN and oxidative stress-induced kidney injury. Rats were dosed orally for 7 days to determine (1) if HDN (induced by 2-propanol or D-limonene) altered the newer renal biomarkers and not BUN or creatinine, (2) if renal biomarkers could distinguish between HDN and oxidative stress-induced kidney injury (induced by potassium bromate), (3) sensitivity of HDN-induced renal biomarker changes relative to D-limonene dose, and (4) reversibility of HDN and renal biomarkers, using vehicle or 300 mg/kg/day D-limonene with 7 days of dosing and necropsies scheduled over the period of Days 8-85. HDN-induced renal biomarker changes in male rats were potentially compound specific: (1) 2-propanol induced mild HDN without increased renal biomarkers, (2) potassium bromate induced moderate HDN with increased clusterin, and (3) D-limonene induced marked HDN with increased αGST, μGST and albumin. Administration of potassium bromate did not result in oxidative stress-induced kidney injury, based on histopathology and renal biomarkers creatinine and BUN. The compound D-limonene induced a dose dependent increase in HDN severity and renal biomarker changes without altering BUN, creatinine or NAG: (1) minimal induction of HDN and no altered biomarkers at 10 mg/kg/day, (2) mild induction of HDN with increased αGST and μGST at 50 mg/kg/day and (3) marked induction of HDN with increased αGST, μGST and albumin at 300 mg/kg/day. HDN induced by D-limonene was reversible, but with a variable renal biomarker pattern over time: Day 8 there was increased αGST, μGST and albumin; on Day 15 increased clusterin, albumin and Kim-1. In summary, HDN altered the newer and more sensitive renal biomarkers in a time and possibly compound dependent manner. 23544465 Organic selenium resin in solid phase synthesis and its application in constructing medicinally relevant small organic molecules. Heterocyclic compounds are of high importance in constructing active drug intermediates library. The emergence of solid-phase and combinatorial chemistry has led to renewed interest in using organoselenium resins to library drug-like production. In this mini review, we summarize the construction of heterocyclic compounds libraries such as isoxazoles, oxadiazoles, triazoles, pyrimidines, pyrrolines, indolines, benzopyrans, furans etc. using organoselenium resins. And it provided efficient and practical ways for the preparation of a variety of well-defined functional heterocyclic compounds with the advantages of good yields, high purity, straightforward operations, broad range and high diversity of the products, lack of odor, and good stability of the resins, all of these give expression to green chemistry. 23585332 tert-Butylhydroquinone reduces lipid accumulation in C57BL/6 mice with lower body weight gain. tert-Butylhydroquinone (tBHQ) is a commonly used antioxidant additive that is approved for human use by both the Food and Agriculture Organization and the World Health Organization (FAO/WHO). In this study, we examined the effect of tBHQ on body weight gain and found that food supplementation with 0.001 % (w/w) tBHQ inhibited 61.4 % (P < 0.01) of body weight gain in high-fat diet (HFD)-induced C57BL/6 mice, and the oral administration of tBHQ (1.5 mg/kg) reduced 47.5 % (P < 0.05) of body weight gain in normal diet fed db/db mice. The HFD increased lipid deposit in adipocytes, but these were reduced significantly by tBHQ treatment in C57BL/6 mice. tBHQ supplementation significantly lowered the plasma triglyceride and total cholesterol, with reduced size of accumulated fat mass. The rate limiting enzyme of beta-oxidation (ACOX1) was significantly over-expressed in the liver with tBHQ treatment. These results indicate that tBHQ suppresses body weight gain in mice, possibly at least related to the up-regulation of ACOX1 gene expression. 23460509 Replication of genetic effects of MC4R polymorphisms on body mass index in a Korean population. Obesity is associated with a variety of adverse health risks. Several genome-wide association studies of obesity have identified candidate genes, including the fat mass and obesity-associated gene (FTO) and the melanocortin-4 receptor (MC4R) gene. We carried out a replication study of MC4R and FTO variants in a Korean cohort. A total of 2,281 subjects in the Bundang-gu region were analyzed using selected markers. Another 8,826 subjects in the Ansung/Ansan city were used for a meta-analysis. Two single nucleotide polymorphisms (SNPs) in FTO and one SNP in the MC4R gene were genotyped. Multivariate linear regression models were employed to test for genotypic effects on obesity traits while adjusting for age and sex using an additive model. The SNP rs17782313 near the MC4R gene was associated with mean body mass index in the Bundang-gu cohort (effect per allele 0.288 kg/m(2), p = 0.0023). The p value for meta-analysis of rs17782313 in all 11,107 individuals in the Bundang-gu and Ansung/Ansan cohorts was 2.82 × 10(-6) (effect per allele 0.22 kg/m(2)). Two SNPs in FTO were significantly associated with weight (effect per allele 0.969 kg, p = 0.011 for rs9939609; 0.943, p = 0.014 for rs8050136) but not with body mass index. This study demonstrates that genetic variants in MC4R influence obesity traits in Korean adults. 23286606 Multifunctional mesoporous nanocomposites with magnetic, optical, and sensing features: synthesis, characterization, and their oxygen-sensing performance. In this paper, the fabrication, characterization, and application in oxygen sensing are reported for a novel multifunctional nanomaterial of [Ru(bpy)(2)phen-MMS] (bpy, 2,2'-bipyridyl; phen, phenathrolin) which was simply prepared by covalently grafting the ruthenium(II) polypyridyl compounds into the channels of magnetic mesoporous silica nanocomposites (MMS). Scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, N(2) adsorption-desorption, a superconducting quantum interference device, UV-vis spectroscopy, and photoluminescence spectra were used to characterize the samples. The well-designed multifunctional nanocomposites show superparamagnetic behavior and ordered mesoporous characteristics and exhibit a strong red-orange metal-to-ligand charge transfer emission. In addition, the obtained nanocomposites give high performance in oxygen sensing with high sensitivity (I(0)/I(100) = 5.2), good Stern-Volmer characteristics (R(2) = 0.9995), and short response/recovery times (t↓ = 6 s and t↑ = 12 s). The magnetic, mesoporous, luminescent, and oxygen-sensing properties of this multifunctional nanostructure make it hold great promise as a novel multifunctional oxygen-sensing system for chemical/biosensor. 23271002 In vitro and in vivo anti-inflammatory effects of 4-methoxy-5- hydroxycanthin-6-one, a natural alkaloid from Picrasma quassioides. In the present study, we evaluated the anti-inflammatory effect of 4-methoxy-5- hydroxycanthin-6-one (CAN), a natural alkaloid isolated from Picrasma quassioides. CAN significantly inhibited the production of NO and the release of TNF-α induced by LPS in macrophage RAW 264.7. Western blot showed that CAN can downregulate the expression of iNOS protein. After oral administration, CAN (3, 9, and 27 mg/kg) reduced the development of carrageenan-induced paw edema and complete Freund's adjuvant (CFA)-induced chronic arthritis in rats. The observed results indicated that pre-treatment with CAN might be an effective therapeutic intervention against inflammatory diseases including chronic arthritis. 23578300 Synthesis and Self-assembly of Amphiphilic Homoglycopolypeptide. The synthesis of the amphiphilic homoglycopolypeptide was carried out by a combination of NCA polymerization and click chemistry to yield a well-defined polypeptide having an amphiphilic carbohydrate on its side chain. The amphiphilicity of the carbohydrate was achieved by incorporation of an alkyl chain at the C-6 position of the carbohydrate thus also rendering the homoglycopolypeptide amphiphilic. The homoglycopolypeptide formed multimicellar aggregates in water above a critical concentration of 0.9 μM due to phase separation. The multimicellar aggregates were characterized by DLS, TEM, and AFM. It is proposed that hydrophobic interactions of the aliphatic chains at the 6-position of the sugar moieties drives the assembly of these rod-like homoglycopolypeptide into large spherical aggregates. These multimicellar aggregates encapsulate both hydrophilic as well as hydrophobic dye as was confirmed by confocal microscopy. Finally, amphiphilic random polypeptides containing 10% and 20% α-d-mannose in addition to glucose containing a hydrophobic alkyl chain at its 6 position were synthesized by our methodology, and these polymers were also found to assemble into spherical nanostructures. The spherical assemblies of amphiphilic random glycopolypeptides containing 10% and 20% mannose were found to be surface bioactive and were found to interact with the lectin Con-A. 23256708 Iridium-catalyzed enantioselective allylic vinylation. The first example of Ir-catalyzed asymmetric substitution reaction with vinyl trifluoroborates is described. The direct reaction between branched, racemic allylic alcohols and potassium alkenyltrifluoroborates proceeded with high site selectivity and excellent enantioselectivity (up to 99%) mediated by an Ir-(P,olefin) complex. This method allows rapid access to various 1,4-dienes or trienes including the biologically active natural products (-)-nyasol and (-)-hinokiresinol. 23210780 The pentacyclic triterpenoids in herbal medicines and their pharmacological activities in diabetes and diabetic complications. Pentacyclic triterpenoids including the oleanane, ursane and lupane groups are widely distributed in many medicinal plants, such as Glycyrrhiza species, Gymnema species, Centella asiatica, Camellia sinensis, Crataegus species and Olea europaea, which are commonly used in traditional medicine for the treatment of diabetes and diabetic complications. A large number of bioactive pentacyclic triterpenoids, such as oleanolic acid, glycyrrhizin, glycyrrhetinic acid, ursolic acid, betulin, betulinic acid and lupeol have shown multiple biological activities with apparent effects on glucose absorption, glucose uptake, insulin secretion, diabetic vascular dysfunction, retinopathy and nephropathy. The versatility of the pentacyclic triterpenes provides a promising approach for diabetes management. 23008095 Pituitary metastasis of thyroid cancer. Pituitary metastases (PM) from thyroid cancer are rare, but their management can represent a difficult challenge for the endocrinologist. Our aim was to review all reported cases of PM from thyroid cancer. PubMed was consulted and 19 papers reporting 20 cases were found. We moreover discuss two of our own cases, which had come to our attention within a few months of one another. Eleven cases were follicular cancer, eight cases were papillary cancer, two cases were medullary cancer, and one case was an insular cancer. In nine cases, PM was the first sign of the disease. Cranial nerve involvement was the most common sign of its presence, and no neuroradiological imaging could lead to a sure diagnosis of PM. Neurosurgical intervention was performed in almost all cases, and post-surgical treatment comprised radioiodine, external beam radiotherapy, and radiosurgery. Prognosis was poor for larger metastases, cranial nerve palsy disappeared in only one case, and in only one case of intrasellar metastasis was the disease cured. PM from thyroid cancer are rare, but are burdened by a poor prognosis. An early diagnosis appears important, and a comprehensive strategy for treatment (neurosurgery, radioiodine, external radiotherapy, and radiosurgery) appears advisable. 23562060 Discovery of ML326: The first sub-micromolar, selective M5 PAM. This Letter describes the further chemical optimization of the M5 PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M5 PAMs (M5 EC50 >10μM) with a structurally related isatin core that possessed a southern phenethyl ether linkage. While SAR within the HTS series was very shallow and unable to be optimized, grafting the phenethyl ether linkage onto the ML129/ML172 cores led to the first sub-micromolar M5 PAM, ML326 (VU0467903), (human and rat M5 EC50s of 409nM and 500nM, respectively) with excellent mAChR selectivity (M1-M4 EC50s >30μM) and a robust 20-fold leftward shift of the ACh CRC. 23392755 Effects of monocarboxylate transporter inhibition on the oral toxicokinetics/toxicodynamics of γ-hydroxybutyrate and γ-butyrolactone. Respiratory depression and death secondary to respiratory arrest have occurred after oral overdoses of γ-hydroxybutyrate (GHB) and its precursor γ-butyrolactone (GBL). GHB is a substrate for monocarboxylate transporters (MCTs), and increasing GHB renal clearance or decreasing GHB absorption via MCT inhibition represents a potential treatment strategy for GHB/GBL overdose. In these studies, GHB and GBL were administered in doses of 1.92, 5.77, and 14.4 mmol/kg orally with and without MCT inhibition to determine effects of this treatment strategy on the oral toxicokinetics and toxicodynamics of GHB and GBL. The competitive MCT inhibitor l-lactate was administered by intravenous infusion starting 1 hour after GHB and GBL administration. Oral administration of l-lactate and the MCT inhibitor luteolin was also evaluated. Respiratory depression was measured using plethysmography. Intravenous l-lactate, but not oral treatments, significantly increased GHB renal and/or oral clearances. At the low dose of GHB and GBL, i.v. l-lactate increased GHB renal clearance. Due to the increased contribution of renal clearance to total clearance at the moderate dose, increased renal clearance translated to an increase in oral clearance. At the highest GHB dose, oral clearance was increased without a significant change in renal clearance. The lack of effect of i.v. l-lactate on renal clearance after a high oral GHB dose suggests possible effects of i.v. l-lactate on MCT-mediated absorption. The resulting increases in oral clearance improved respiratory depression. Intravenous l-lactate also reduced mortality with the high GBL dose. These data indicate i.v. l-lactate represents a potential treatment strategy in oral overdose of GHB and GBL. 23003213 Effect of surfactant and solvent on spin-lattice relaxation dynamics of magnetic nanocrystals. The effect of varying the surfactant and solvent medium on the dynamics of spin-lattice relaxation in photoexcited Fe3O4 nanocrystals has been investigated by measuring the time-dependent magnetization employing pump-probe transient Faraday rotation technique. The variation of the surfactants having surface-binding functional groups modified not only the static magnetization but also the dynamics of the recovery of the magnetization occurring via spin-lattice relaxation in the photoexcited Fe3O4 nanocrystals. The variation of the polarity and size of the solvent molecules can also influence the spin-lattice relaxation dynamics. However, the effect is limited to the nanocrystals having sufficiently permeable surfactant layer, where the small solvent molecules (e.g., water) can access the surface and dynamically modify the ligand field on the surface. 23584282 A microfluidic D-subminiature connector. Standardized, affordable, user-friendly world-to-chip interfaces represent one of the major barriers to the adoption of microfluidics. We present a connector system for plug-and-play interfacing of microfluidic devices to multiple input and output lines. The male connectors are based on existing standardized housings from electronics that are inexpensive and widely available. The female connectors are fabricated using familiar replica molding techniques that can easily be adopted by microfluidic developers. 23591110 Discovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (Part I). A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays. 23402880 The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 2. Various substituted indazole and benzoxazolone amino acids were investigated as d-tyrosine surrogates in highly potent CGRP receptor antagonists. Compound 3, derived from the 7-methylindazole core, afforded a 30-fold increase in CGRP binding potency compared with its unsubstituted indazole analog 1. When dosed at 0.03mg/kg SC, compound 2 (a racemic mixture of 3 and its (S)-enantiomer) demonstrated robust inhibition of CGRP-induced increases in mamoset facial blood flow up to 105min. The compound possesses a favorable predictive in vitro toxicology profile, and good aqueous solubility. When dosed as a nasal spray in rabbits, 3 was rapidly absorbed and showed good intranasal bioavailability (42%). 23639431 Nedd4 is a specific E3 ubiquitin ligase for the NMDA receptor subunit GluN2D. NMDA receptors are a family of glutamate-gated ion channels that regulate various CNS functions such as synaptic plasticity and learning. However hypo-or hyper-activation of NMDA receptors is critically involved in many neurological and psychiatric conditions such as pain, stroke, epilepsy, neurodegeneration, schizophrenia, and depression. Thus, it is important to identify mechanisms (such as by targeted ubiquitination) that regulate the levels of individual subtypes of NMDA receptors. In this study, we used a series of tagged, carboxy terminal constructs of GluN2D to identify associating proteins from rat brain. Of seven different GluN2D C-terminal fragments used as bait, only the construct containing amino acids 983-1097 associated with an E3 ligase, Nedd4. A direct interaction between GluN2D and Nedd4 was confirmed both in vivo and in vitro. This association is mediated by an interaction between GluN2D's C-terminal PPXY motif and the 2nd and 3rd WW domains of Nedd4. Of the four GluN2 subunits, Nedd4 directly interacted with GluN2D and also weakly with GluN2A. Nedd4 coexpression with GluN2D enhances GluN2D ubiquitination and reduces GluN1/GluN2D NMDA receptor responses. These results identify Nedd4 as a novel binding partner for GluN2D and suggest a mechanism for the regulation of NMDA receptors that contains GluN2D subunit through ubiquitination-dependent downregulation. This article is part of a Special Issue entitled 'GluR-dep synaptic plasticity'. 23623867 Modulation of the peroxiredoxin system by cytokines in insulin-producing RINm5F cells: Down-regulation of PRDX6 increases susceptibility of beta cells to oxidative stress. Peroxiredoxins are a family of six antioxidant enzymes (PRDX1-6), and may be an alternative system for the pancreatic beta cells to cope with oxidative stress. This study investigated whether the main diabetogenic pro-inflammatory cytokines or the anti-inflammatory cytokine IL-4 modulate PRDXs levels and putative intracellular pathways important for this process in the insulin-producing RINm5F cells. RINm5F cells expressed significant amounts of PRDX1, PRDX3 and PRDX6 enzymes. Only PRDX6 was modulated by cytokines, showing both mRNA and protein down-regulation following incubation of RINm5F cells with TNF-alpha and IFN-gamma but not with IL-1beta. Separately IFN-gamma or TNF-alpha decreased PRDX6 protein but not mRNA levels. The blockage of the JNK signalling and of the calpains and proteasome proteolysis systems restored PRDX6 protein levels. IL-4 alone did not modulate PRDXs levels. However, pre/co-incubation with IL-4 substantially prevented the decrease in PRDX6 induced by pro-inflammatory cytokines. Knockdown of PRDX6 increased susceptibility of RINm5F cells to the deleterious effects of pro-inflammatory cytokines and to oxidative stress. These results show that, from the PRDXs significantly expressed in RINm5F cells, only PRDX6 is modulated by the diabetogenic cytokines IFN-gamma and TNF-alpha. This PRDX6 down-regulation depends on the calpain and proteasome systems and JNK signalling. PRDX6 is an important enzyme for protection against oxidative stress and the interaction between pro- and anti-inflammatory cytokines might be important to determine the antioxidant capacity of the cells. 23556338 Interspecies difference of luteolin and apigenin after oral administration of Chrysanthemum morifolium extract and prediction of human pharmacokinetics. The aims of the present study were to study the interspecies difference in the pharmacokinetics of luteolin and apigenin occurring in Chrysanthemum morifolium extract (CME) among rats, beagle dogs, mini-pigs, and humans, and compared the human pharmacokinetic parameters with the data predicted from the above three animals. The plasma concentrations of luteolin and apigenin were determined with a RP-HPLC method. An interspecies difference of pharmacokinetics was found, especially between rats and other species, the plasma concentration of luteolin was much lower than that of apigenin in rats, although the content of luteolin in CME was higherthan that of apigenin, whereas the plasma concentration of luteolin was much higher than that of apigenin in dogs, mini-pigs and humans. Animal scale-up of some pharmacokinetic parameters of luteolin and apigenin were also performed after rats, beagle dogs, mini-pigs and humans were orally given CME at dosages of 400 mg/kg, 102 mg/kg, 90 mg/kg, and 20 mg/kg, respectively. Linear relationships were obtained between log mean retention time (MRT) and log species body weight (W) (kg), and log elimination half-life (t1/2) (h) and logW. The corresponding allometric equations were MRT=9.382W(0.1711) (R2 = 0.9999) and t1/2 = 4.811W(0.1093) (R2 = 0.9013) for luteolin, MRT = 12.53W(0.0356) (R2 = 0.9980) and t1/2 = 7.940W(0.0294) (R2 = 0.9258) for apigenin, respectively. The predicted human pharmacokinetic parameters (MRT and t1/2) by an allometric approach were 18.6 h and 7.46 h for luteolin, 14.3 h and 8.95 h for apigenin, respectively, which were close to the values obtained from humans (20 mg CME/kg) in the present study. The study has demonstrated the possibility to extrapolate the pharmacokinetic behavior of flavonoids from animals to humans. 23178651 Garlic-derived diallyl disulfide modulates peroxisome proliferator activated receptor gamma co-activator 1 alpha in neuroblastoma cells. The peroxisome proliferator activated receptor gamma co-activator 1 alpha (PGC1α) is an inducible transcriptional co-activator with direct function in the induction of mitochondrial biogenesis. In the present report we show that, in SH-SY5Y neuroblastoma cells, garlic-derived diallyl disulfide (DADS) is able to increase PGC1α expression in a ROS-dependent manner and to induce mitochondrial biogenesis at early stage of treatment that precede cell cycle arrest and apoptosis outcome. In particular, we demonstrate that DADS elicits: i) the increase of PGC1α within nuclear compartment; ii) the decrease of PGC1α non-active acetylated form; iii) the induction of nuclear-encoded mitochondrial genes such as TFAM and TFBM1. We also show an accumulation of PGC1α within mitochondria along with an increased association with the regulatory D-Loop region of mtDNA and a concomitant augmented expression of mitochondrial RNA. Such events are related to a prompt elevation of mitochondrial mass, as assessed by evaluating the content of mtDNA. We show that the induction of mitochondrial biogenesis is directed to dampen the cytotoxic effect of DADS. Indeed, PGC1α overexpression or down-regulation prevents or exacerbates mtDNA loss and apoptosis. Overall the data highlight an anti-apoptotic role of PGC1α-mediated mitochondrial biogenesis in neuroblatoma cells and suggest PGC1α as a potential target for enhancing the effectiveness of therapy in aggressive neuroblastoma with high drug-resistance. 23416065 Human serum albumin-based design of a diflunisal prodrug. The cyclooxygenase-2 inhibitor, diflunisal, is used in the clinic for its anti-inflammatory activity. About 99% of a dose of diflunisal is unavailable for reaction with the target enzyme, because diflunisal strongly binds to human serum albumin (HSA). To reduce the binding affinity of diflunisal to albumin, we designed and synthesized the prodrug acetyldiflunisal. The crystal structure of HSA complexed with fatty acid and acetyldiflunisal revealed that acetyldiflunisal binds to the IIA subdomain and that upon binding, it acetylates lysine 199. Mass spectrometry confirmed that acetyldiflunisal acetylates Lys199. The acetylated albumin had twofold weaker binding affinity for diflunisal as demonstrated by fluorescence quenching. Reduced binding affinity means that diflunisal is more easily released from acetylated albumin into the circulation. Therefore, lower doses of acetyldiflunisal compared to diflunisal will be required. Taken together, our results not only provide a template for design of HSA-based prodrugs, but also pave the way toward more effective use of diflunisal in the clinic. 23344855 Theoretical design and experimental implementation of Ag/Au electrodes for the electrochemical reduction of nitrate. The current imbalance in the biogeochemical cycle of nitrogen is as serious as that of carbon. One way to mitigate this problem is through the electrochemical reduction of nitrates under mild conditions, which is an appealing though not fully understood process. Therefore, deeper insight into the electrocatalytic reaction mechanism is needed to optimize this process. Here we thoroughly analyse the adsorption energy of nitrate with DFT calculations on various surface facets of pure Au, Ag, and their near-surface and surface alloys, as the adsorption and subsequent reduction of nitrate are thought to be rate limiting in the electrocatalytic reaction. The observed systematic trends allow prediction of the surface with highest electrocatalytic activity for the reduction of nitrate. This prediction was verified experimentally by depositing sub-monolayer amounts of Ag on polycrystalline Au electrodes. We observe a well-defined volcano curve which correlates the amount of Ag deposited on the surface with the current density at a fixed potential, with the peak activity around 2/3 ML Ag surface coverage. The electrocatalytic activity and stability of the bimetallic Ag-Au systems, found through the interplay of theoretical modelling and empirical observations, serve as a clear example for the rational design of novel catalytic materials and confirm the key role that the adsorption of nitrate plays in the overall nitrate reduction rate. 23381904 A Serum-Resistant Low-Generation Polyamidoamine with PEI 423 Outer Layer for Gene Delivery Vector. A new derivative of polyamidoamine and polyethylenimine, G2.5-PEI 423 or G1.5-PEI 423, is prepared by an amidation reaction of PAMAM G2.5 or PAMAM G1.5 using PEI 423. The polycations show a great ability to combine with pDNA to form complexes, which protect the pDNA from nuclease degradation. The polymers display stronger buffer capacity and lower cytotoxicity. The complexes have particle sizes of 120-180 nm and zeta potentials of 20-40 mV. The G2.5-PEI 423 complexes display much higher transfection efficiencies than PAMAM G5 and Lipo-2k, and the G1.5-PEI 423 complexes display higher transfection efficiencies than PAMAM G4 and PEI-25k. The complexes possess better serum-resistant capacity. The G2.5-PEI 423 has a great potential to be used as a serum-resistant gene vector. 23196805 Mechanistic models describing active renal reabsorption and secretion: a simulation-based study. The objective of the present study was to evaluate mechanistic pharmacokinetic models describing active renal secretion and reabsorption over a range of Michaelis-Menten parameter estimates and doses. Plasma concentration and urinary excretion profiles were simulated and renal clearance (CL(r)) was calculated for two pharmacokinetic models describing active renal reabsorption (R1/R2), two models describing active secretion (S1/S2), and a model containing both processes. A range of doses (1-1,000 mg/kg) was evaluated, and V (max) and K (m) parameter estimates were varied over a 100-fold range. Similar CL(r) values were predicted for reabsorption models (R1/R2) with variations in V (max) and K (m). Tubular secretion models (S1/S2) yielded similar relationships between Michaelis-Menten parameter perturbations and CL(r), but the predicted CL(r) values were threefold higher for model S1. For both reabsorption and secretion models, the greatest changes in CL(r) were observed with perturbations in V (max), suggesting the need for an accurate estimate of this parameter. When intrinsic clearance was substituted for Michaelis-Menten parameters, it failed to predict similar CL(r) values even within the linear range. For models S1 and S2, renal secretion was predominant at low doses, whereas renal clearance was driven by fraction unbound in plasma at high doses. Simulations demonstrated the importance of Michaelis-Menten parameter estimates (especially V (max)) for determining CL(r). K (m) estimates can easily be obtained directly from in vitro studies. However, additional scaling of in vitro V (max) estimates using in vitro/in vivo extrapolation methods are required to incorporate these parameters into pharmacokinetic models. 23292655 Expanding the genetic code in Xenopus laevis oocytes. Heterologous expression of ligand-gated ion channels (LGICs) in Xenopus laevis oocytes combined with site-directed mutagenesis has been demonstrated to be a powerful approach to study structure-function relationships. In particular, introducing unnatural amino acids (UAAs) has enabled modifications that are not found in natural proteins. However, the current strategy relies on the technically demanding in vitro synthesis of aminoacylated suppressor tRNA. We report here a general method that circumvents this limitation by utilizing orthogonal aminoacyl-tRNA synthetase (aaRS)/suppressor tRNA(CUA) pairs to genetically encode UAAs in Xenopus oocytes. We show that UAAs inserted in the N-terminal domain of N-methyl-D-aspartate receptors (NMDARs) serve as photo-crosslinkers that lock the receptor in a discrete conformational state in response to UV photo treatment. Our method should be generally applicable to studies of other LGICs in Xenopus oocytes. 23228651 Quantitative characterization of non-contact microdispensing technologies for the sub-microliter range. This work describes how to effectively compare non-contact dispensing technologies for automated liquid handling under high-throughput screening (HTS) conditions in the range of 0.05-10μl. Exemplarily, we characterize five established technologies and categorize them into valve-based and positive displacement-based technologies. Furthermore we introduce dispensing accuracy and precision in an 'intra-run', 'inter-run' and 'tip-to-tip' context as universally applicable performance parameters. A NIST traceable spectrophotometric measurement method is utilized for experimental characterization. It yields an Intra-Run CV (Inter-Run CV) between 0.4% to 7.7% (0.5 to 10.9%) and a Tip-to-Tip CV between 1.4% and 9.9% for target volumes <1μl. An absolute accuracy of better than 5.0% is generally difficult to achieve in the sub-microliter range. 23421650 Adsorption, organization, and rheology of catanionic layers at the air/water interface. We have investigated the adsorption and organization at the air/water interface of catanionic molecules released from a dispersion of solid-like catanionic vesicles composed of myristic acid and cetyl trimethylammonium chloride at the 2:1 ratio. These vesicles were shown recently to be promising foam stabilizers. Using Brewster angle microscopy, we observed the formation of a catanionic monolayer at the air/water interface composed of liquid-condensed domains in a liquid-expanded matrix. Further adsorption of catanionic molecules forced them to pack, thereby forming a very dense monolayer that prevented further vesicle rupture by avoiding contact of the vesicles with air. Moreover, confocal fluorescence microscopy revealed the presence of layers of intact vesicles that were progressively creaming toward this catanionic monolayer; the surface tension of the vesicle dispersion remained constant upon creaming. The catanionic monolayer behaved as a soft glassy material, an amorphous solid with time- and temperature-dependent properties. Using interfacial oscillatory rheology, we found that the monolayer relaxed mechanical stresses in seconds and melted at a temperature very close to the melting transition temperature of the vesicle bilayers. These results have potential application in the design of smart foams that have temperature-tunable stability. 23020788 A phase I, open-label, single-dose, mass balance study of 14C-labeled abiraterone acetate in healthy male subjects. 1. Metabolic disposition of (14)C-abiraterone acetate (AA), a prodrug of abiraterone was assessed in a phase I, open-label, single-dose (1000 mg, approximately 100 μCi) study in healthy males (18-55 years, N = 8). Blood, urine, and faecal samples were obtained at specified timepoints for determination of abiraterone concentrations in the plasma, total radioactivity (TR), and the metabolite profile. 2. Most plasma AA concentrations were below the limit of quantification. The mean maximum plasma concentration (Cmax) of abiraterone was 10.4 ng/mL, mean area under the plasma concentration-time curve (AUC) from 0 to the last measurable plasma concentration (AUC0-last) was 74.8 ng·h/mL. The exposures for TR in plasma (Cmax = 3429 ng·eq/mL; AUC0-last = 26,683 ng eq·h/mL) and whole blood (Cmax = 1836 ng·eq/mL; AUC0-last = 12,162 ng·eq·h/mL) were >300-fold higher than abiraterone exposure in plasma. The majority of TR resided in the plasma compartment of blood. 3. Main circulating metabolites were abiraterone sulfate and N-oxide abiraterone sulfate. The main metabolite excreted in urine was N-oxide abiraterone sulfate (4.22% of TR). Major components of TR in faeces were unchanged AA (55.3% of TR) and abiraterone (22.3% of TR). Mean recovery of TR in faeces was 87.9%, indicating faeces as primary route of excretion. 23298139 Silver nanoparticles in cancer: therapeutic efficacy and toxicity. In recent years, there has been escalating interest in the biomedical applications of nanoparticles (NPs). In particular, silver nanoparticles (AgNPs) are increasingly being investigated as tools for novel cancer therapeutics, capitalizing on their unique properties to enhance potential therapeutic efficacy. However, questions as to are we able to contain or control the toxicity effects of AgNPs, and how much do we know about the toxicological profile of AgNPs which are commonly used in emerging nanotechnology-based applications, still remain. Hence, serious considerations have to be given to the hazards and risks of toxicity associated with the use of AgNPs. This review focuses on the current applications of AgNPs, their known effects and toxicity, as well as the potential of harnessing them for use in cancer therapy. 23495693 Therapeutic applications of PI3K inhibitors in cardiovascular diseases. PI3Ks are signaling enzymes engaged by different types of membrane receptors and activated in cardiovascular diseases such as hypertension, atherosclerosis, thrombosis and heart failure. Studies performed on genetically modified animals have provided proof-of-concept that general or isoform-specific blockade of these enzymes can modify disease development and progression. Hence, therapeutic inhibition of PI3Ks with novel pharmacological compounds constitutes a promising area of drug development. In particular, inhibitors of PI3Ks have the potential to reduce blood pressure, restrain the development of atherosclerosis and/or stabilize atherosclerotic plaques, blunt platelet aggregation, prevent left ventricular remodeling and preserve myocardial contractility in heart failure. This review summarizes the rationale of PI3K inhibition in the most prevalent cardiovascular diseases, and the available data on the therapeutic effects of PI3K inhibitors in their preclinical models. Implications for future drug development and human therapy are also discussed. 23265537 Biogenic amines formation in Streptococcus thermophilus isolated from home-made natural yogurt. Twelve different biogenic amines formation in 58 isolates of Streptococcus thermophilus from home-made natural yogurt were investigated in histidine (HDB) and lysine decarboxylase broth (LDB). All S. thermophilus isolates had an ability to produce twelve different biogenic amines in HDB and LDB. Most of the S. thermophilus isolates formed low amounts of histamine (1-50 mg/L) from histidine. Apart from one isolate, S. thermophilus produced tyramine at low (47 isolates) and medium (10 isolates) levels. The amount of each specific biogenic amine produced by S. thermophilus was generally lower than 100 mg L(-1). Also, the presence of hdcA gene was investigated using PCR technique and relation between gene and histamine production was conducted in S. thermophilus isolates. This study showed that most of the S. thermophilus isolates have the ability to form biogenic amines, especially histamine, and tyramine, which is an important consideration when selecting strains as starter cultures. 23632310 Immunoregulatory effects of Glycyrrhizic acid exerts anti-asthmatic effects via modulation of Th1/Th2 cytokines and enhancement of CD4(+)CD25(+)Foxp3(+) regulatory T cells in ovalbumin-sensitized mice. ETHNOPHARMACOLOGICAL RELEVANCE: Glycyrrhizic acid (GA) is the main bioactive ingredient of licorice (Glycyrrhiza glabra), and has been found to be associated with multiple therapeutic properties. AIM OF THE STUDY: In this study, we investigated immunoregulatory effects of glycyrrhizic acid on anti-asthmatic effects and underlying mechanisms. MATERIALS AND METHODS: Asthma model was established by ovalbumin-induced. A total of 60 mice were randomly assigned to six experimental groups: control, model, dexamethasone (2mg/kg) and GA (10mg/kg, 20mg/kg, 40mg/kg). Airway resistance (Raw) were measured by the forced oscillation technique, histological studies were evaluated by The hematoxylin and eosin (HE) staining, Th1/Th2 and Th17 cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA), and CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) was evaluated by Flow Cytometry (FCM), the forkhead/winged helix transcription factor (Foxp3) was evaluated by western blotting. RESULTS: Our study demonstrated that, compared with model group, GA inhibited OVA-induced increases in Raw and eosinophil count; interleukin (IL)-4, IL-5, IL-13 levels were recovered in bronchoalveolar lavage fluid compared; increased IFN-γlevel in bronchoalveolar lavage fluid; histological studies demonstrated that GA substantially inhibited OVA-induced eosinophilia in lung tissue and airway tissue compared with model group. Flow cytometry studies demonstrated that GA substantially enhanced Tregs compared with model group. CONCLUSION: These findings suggest that GA may effectively ameliorate the progression of asthma and could be used as a therapy for patients with allergic asthma. 23373869 REMNANT UPTAKE AS A POSTOPERATIVE ONCOLOGIC QUALITY INDICATOR. BACKGROUND: The purpose of this study was to examine the utility of remnant uptake on postoperative radioiodine scans as an oncologic indicator after thyroidectomy for differentiated thyroid cancer (DTC). METHODS: We conducted a retrospective review of patients undergoing total thyroidectomy for DTC and subsequent radioactive iodine (RAI) treatment. Of the eight surgeons included, three were considered high volume, performing at least 20 thyroidectomies per year. Patients with distant metastases at diagnosis or poorly differentiated variants were excluded. To control for the effect of varying RAI doses, the remnant uptake was analyzed as a ratio of the percentage uptake to the dose received (uptake to dose ratio, UDR). Multivariate logistic regression was used to determine the influence of UDR on recurrence. RESULTS: Of the 223 patients who met inclusion criteria, 21 patients (9.42%) experienced a recurrence. Those who recurred had a ten-fold higher UDR compared to those who did not recur (0.030 vs. 0.003, p = 0.001). Similarly, patients with increasing postoperative thyroglobulin measurements (0.339 vs. 0.003, p<0.001) also had significantly greater UDRs compared to those with stable thyroglobulin. The UDRs of high volume surgeons were significantly smaller than low volume surgeons (0.003 vs. 0.025, p = 0.002). When combined with other known predictors for recurrence, UDR (OR 3.71, C.I 1.05 - 13.10, p = 0.041) was significantly associated with recurrence. High volume surgeons maintained a low level of permanent complications across all UDRs whereas low volume surgeons had greater permanent complications associated with higher uptake. 23545706 PD-1, but not PD-L1, expressed by islet-reactive CD4+ T cells suppresses infiltration of the pancreas during Type 1 Diabetes. The inhibitory receptor PD-1 constrains Type 1 Diabetes (T1D) in the non-obese diabetic (NOD) mouse. However, how PD-1 influences diabetogenic CD4(+) T cells during natural diabetes is not fully understood. To address this question we developed a novel model to investigate antigen-specific CD4(+) T cells under physiological conditions in vivo. We transferred a low number of naïve CD4(+) T cells from the BDC2.5 mouse into prediabetic NOD mice to mimic a physiological precursor frequency and allowed the cells to become primed by endogenous autoantigen. Transferred BDC2.5 T cells became activated, differentiated into T-bet(+) IFNγ-producing cells, and infiltrated the pancreas. In this model, loss of PD-1, but not PD-L1, on the antigen-specific CD4(+) T cell resulted in increased cell numbers in the spleen, pancreas-draining lymph node and pancreas. PD-1-deficiency also increased expression of the chemokine receptor CXCR3. Lastly, histological data showed that a loss of PD-1 caused BDC2.5 cells to penetrate deep into the islet core, resulting in conversion from peri-insulitis to destructive insulitis. These data support a model by which PD-1 regulates islet-reactive CD4(+) T cells in a cell intrinsic manner by suppressing proliferation, inhibiting infiltration of the pancreas, and limiting diabetes. 23396206 Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Oncolytic viruses and active immunotherapeutics have complementary mechanisms of action (MOA) that are both self amplifying in tumors, yet the impact of dose on subject outcome is unclear. JX-594 (Pexa-Vec) is an oncolytic and immunotherapeutic vaccinia virus. To determine the optimal JX-594 dose in subjects with advanced hepatocellular carcinoma (HCC), we conducted a randomized phase 2 dose-finding trial (n=30). Radiologists infused low- or high-dose JX-594 into liver tumors (days 1, 15 and 29); infusions resulted in acute detectable intravascular JX-594 genomes. Objective intrahepatic Modified Response Evaluation Criteria in Solid Tumors (mRECIST) (15%) and Choi (62%) response rates and intrahepatic disease control (50%) were equivalent in injected and distant noninjected tumors at both doses. JX-594 replication and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression preceded the induction of anticancer immunity. In contrast to tumor response rate and immune endpoints, subject survival duration was significantly related to dose (median survival of 14.1 months compared to 6.7 months on the high and low dose, respectively; hazard ratio 0.39; P=0.020). JX-594 demonstrated oncolytic and immunotherapy MOA, tumor responses and dose-related survival in individuals with HCC. 23232711 π-Extended isomeric and expanded porphyrins. The phenomenon of π-extension has been widely applied to, and exploited within, the field porphyrin chemistry. The development of reliable synthetic routes to various useful starting materials has facilitated the underlying preparative work. The chemical resemblance between porphyrins and expanded and isomeric porphyrins, as well as the increasing accessibility of the requisite starting materials is giving birth to the hybrid field of π-extended expanded and isomeric porphyrins. This tutorial review is intended to provide an overview of up-to-date published synthetic efforts and to summarize the effect of annulation on the properties of expanded and isomeric porphyrins. 23103224 Mitochondrial fusion: a mechanism of cisplatin-induced resistance in neuroblastoma cells? Cisplatin induces apoptosis through different pathways. The intrinsic apoptotic pathway is mediated by mitochondria, which, as a result of cisplatin treatment, undergo morphological alterations. The aim of this study was to investigate cisplatin-induced mitochondrial functional and morphological long-term effects in neuroblastoma B50 rat cells. To this purpose, we followed evaluated different several apoptotic markers by means of flow cytometry, confocal and electron microscopy and western blotting techniques. We applied different treatment protocols based on the incubation of the neuroblastoma B50 rat cells with 40 μM cisplatin: (i) for 48 h and harvesting of the cells at the end of the treatment; (ii) further recovery in drug-free medium for 7 days post-treatment; (iii) conditions as in (ii) followed by re-seeding in normal medium and growth for a further 4 days. We observed apoptosis induction after the first treatment and after the recovery from cell death after long-term culture in drug-free medium. Interestingly, the latter phenomenon was characterized by mitochondrial elongation and mitochondrial protein rearrangement. In recovered and re-seeded cells, mitochondrial equilibrium moved toward fusion, possibly protecting cells from apoptosis. 23360140 Nonhuman targets in allergic lung conditions. Existing therapies for allergic asthma are far from perfect: the global prevalence of disease increases despite them and they are poorly effective in dealing with the exacerbations that account for hospitalization and asthma deaths. Commercially, there are pressures on these existing medicines too - a growing threat from generics and reluctance by payers to reimburse for increasingly marginal improvements in medicines with precedented mechanisms. Experience shows that attempts to devise selective small-molecule interventions directed at the myriad of downstream effector pathways has not been a fertile ground for the development of effective new medicines. An alternative strategy, exploiting breakthroughs in understanding the molecular basis of allergenicity and the key role of innate immune mechanisms in asthma, is to direct new approaches to the disease triggers themselves: allergens. This raises interesting possibilities for anti-Lipinski drug design (extracellular nonhuman targets, inhaled delivery) and creates unprecedented pharmacological opportunities in the therapeutic area. 23194513 Analysis of total polyphenols in wines by FIA with highly stable amperometric detection using carbon nanotube-modified electrodes. The use of glassy carbon electrodes (GCEs) modified with multi-walled carbon nanotube (CNT) films for the continuous monitoring of polyphenols in flow systems has been examined. The performance of these modified electrodes was evaluated and compared to bare GCE by cyclic voltammetry experiments and by flow injection analysis (FIA) with amperometric detection monitoring the response of gallic, caffeic, ferulic and p-coumaric acids in 0.050 M acetate buffer pH 4.5 containing 100 mM NaCl. The GCE modified with CNT dispersions in polyethyleneimine (PEI) provided lower overpotentials, higher sensitivity and much higher signal stability under a dynamic regime than bare GCEs. These properties allowed the estimation of the total polyphenol content in red and white wines with a remarkable long-term stability in the measurements despite the presence of potential fouling substances in the wine matrix. In addition, the versatility of the electrochemical methodology allowed the selective estimation of the easily oxidisable polyphenol fraction as well as the total polyphenol content just by tuning the detection potential at +0.30 or 0.70 V, respectively. The significance of the electrochemical results was demonstrated through correlation studies with the results obtained with conventional spectrophotometric assays for polyphenols (Folin-Ciocalteu, absorbance at 280 nm index and colour intensity index). 23429907 The interfacial-organized monolayer water film (MWF) induced "two-step" aggregation of nanographene: both in stacking and sliding assembly pathways. A computational investigation was carried out to understand the aggregation of nanoscale graphene with two typical pathways of stacking assembly and sliding assembly in water. The interfacial-organized monolayer water film (MWF) induced "two-step" aggregation of nanographene in both stacking and sliding assembly pathways was reported for the first time. By means of potential mean forces (PMFs) calculation, no energy barrier was observed during the sliding assembly of two graphene nanosheets, while the PMF profiles could be impacted by the contact forms of nanographene and the MWF within the interplate of two graphene nanosheets. To explore the potential physical basis of the "hindering role" of self-organized interfacial water, the dynamical and structural properties as well as the status of hydrogen bonds (H-bonds) for interfacial water were investigated. We found that the compact, ordered structure and abundant H-bonds of the MWF could be taken as the fundamental aspects of the "hindering role" of interfacial water for the hydrophobic assembly of nanographene. These findings are displaying a potential to further understand the hydrophobic assembly which mostly dominate the behaviors of nanomaterials, proteins etc. in aqueous solutions. 23286905 Lipofection and nucleofection of substrate plasmid can generate widely different readings of DNA end-joining efficiency in different cell lines. In vivo plasmid end-joining assays are valuable tools for dissecting important qualitative and quantitative aspects of non-homologous end-joining (NHEJ)--a key mechanism for the repair of DNA double-strand breaks (DSBs) in higher eukaryotes. They enable the use of defined DNA ends as substrates for end-joining and the analysis by sequencing of the resulting junctions to identify the repair pathways engaged. Yet, plasmid assays have generated divergent results of end-joining capacity in the same DSB repair mutants when used under different conditions, which implies contributions from undefined and therefore uncontrolled parameters. To help standardize these assays, we searched for parameters underpinning these variations and identified transfection method as an important determinant. Here, we compare a lipid-based transfection method, lipofection, with an electroporation method, nucleofection, and find large, unanticipated and cell line-dependent differences in percent end-joining without recognizable trends. For example, in rodent cells, transfection using lipofection gives nearly WT end-joining in DNA-PKcs mutants and only mildly inhibited end-joining in Lig4 and Ku mutants. In contrast, transfection using nucleofection shows marked end-joining inhibition in all NHEJ mutants tested as compared to the WT. In human HCT116 cells, end-joining after nucleofection is strongly suppressed even in the WT and the differences to the mutants are small. After lipofection, in contrast, end-joining is high in WT cells and markedly suppressed in the mutants. We conclude that better understanding and control of the physicochemical/biological and analytical parameters underpinning these differences will be required to generate with plasmid assays results with quantitative power comparable to that of well-established methods of DSB analysis such as pulsed-field gel electrophoresis or γ-H2AX foci scoring. Until then, caution is needed in the interpretation of the results obtained - particularly with reference to pathway efficiency and residual damage - and confirmation of critical results with alternative transfection approaches is advisable. 23089153 Redox control of teratogenesis. A number of human teratogens elicit their deleterious effects through mechanisms involving the generation of reactive oxygen species (ROS) and oxidative stress. However, classic definitions of oxidative stress do not fully coincide with basic fundamental principles of teratology. Newer definitions of oxidative stress focus on the targeted redox modification of cysteine/thiol functional groups found in the regulatory domains of critical signaling pathway proteins, suggesting that the targeted disruption of signaling through specific redox couples may account for the specificity of teratogen-induced malformations which previously could not be rationalized. Here, we review examples of teratogens that induce ROS and oxidative injury, describe oxidative stress-related teratogenic mechanisms, and provide rationale for developmental periods of sensitivity and species susceptibility. Understanding how chemicals disrupt redox status, induce oxidative stress leading to dysmorphogenesis becomes important to identify potential teratogens and develop therapeutic interventions for attenuation of harmful chemical effects in utero following exposure. 23148024 Metabolically competent human skin models: activation and genotoxicity of benzo[a]pyrene. The polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (BP) is metabolized into a complex pattern of BP derivatives, among which the ultimate carcinogen (+)-anti-BP-7,8-diol-9,10-epoxide (BPDE) is formed to certain extents. Skin is frequently in contact with PAHs and data on the metabolic capacity of skin tissue toward these compounds are inconclusive. We compared BP metabolism in excised human skin, commercially available in vitro 3D skin models and primary 2D skin cell cultures, and analyzed the metabolically catalyzed occurrence of seven different BP follow-up products by means of liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). All models investigated were competent to metabolize BP, and the metabolic profiles generated by ex vivo human skin and skin models were remarkably similar. Furthermore, the genotoxicity of BP and its derivatives was monitored in these models via comet assays. In a full-thickness skin, equivalent BP-mediated genotoxic stress was generated via keratinocytes. Cultured primary keratinocytes revealed a level of genotoxicity comparable with that of direct exposure to 50-100 nM of BPDE. Our data demonstrate that the metabolic capacity of human skin ex vivo, as well as organotypic human 3D skin models toward BP, is sufficient to cause significant genotoxic stress and thus cutaneous bioactivation may potentially contribute to mutations that ultimately lead to skin cancer. 23122102 Comprehensive analysis of Phyteuma orbiculare L., a wild Alpine food plant. Plants which have been traditionally eaten by the alpine population may provide new opportunities for agricultural development in mountain regions. In this context we have investigated the chemical composition of Phyteuma orbiculare (Campanulaceae), a perennial herb whose leaves have been eaten as salad by rural populations in Valais (Switzerland). Extracts of different polarities were subjected to comprehensive metabolite profiling using a dereplication platform combining HPLC-PDA-MS, and offline NMR analysis. Twenty-three compounds, including various phenolic glycosides, a new dimeric phenylpropanoid glucoside, saponins, and fatty acids were identified online, or after targeted isolation. Selected phenolic constituents were quantitatively assessed by HPLC-PDA analysis. In addition, substances relevant for nutrition, such as β-carotene, fatty acids, ascorbic acid and minerals were quantified in leaves and flowers. The antioxidant capacity was determined with an ORAC assay, and total phenolic compounds were quantified. Finally, the phytochemical profile was compared to that of the related species P. spicatum, P. hemisphaericum and P. ovatum. 23265468 Simultaneous detection of flavonoids and phenolic acids in Herba Lysimachiae and Herba Desmodii Styracifolii using liquid chromatography tandem mass spectrometry. A sensitive liquid chromatography and tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous analysis of 15 flavonoids and 3 phenolic acids in Herba Lysimachiae and Herba Desmodii Styracifolii. Separation was performed using a Diamonsil C(18) column, which was eluted with methanol (A) and 0.1‰ acetic acid (B). The gradient condition was as follows: 0-34 min, 20-34% A; 34-38 min, 34-95% A; maintained 95% A for the next 4 min. Analytes were detected using a hybrid quadrupole linear ion trap mass spectrometer that was equipped with an electrospray ionisation source in the negative ion and multiple-reaction monitoring modes. A full validation of the method was performed, including the linearity, precision, and accuracy, as well as limits of detection and quantification. The results indicated that the developed method was simple, sensitive and reliable. Furthermore, the method was successfully applied to differentiate 16 batches of Herba Lysimachiae and 21 batches of Herba Desmodii Styracifolii. 23150495 Ablation of Egr2-positive cells in male mouse anterior pituitary leads to atypical isolated GH deficiency. In this study, we have investigated the expression and function of the transcription factor early growth response factor 2 (Egr2)/Krox20 in the developing anterior pituitary. Egr2 is initially expressed in all differentiating hormonal cells types, but its expression is mostly restricted to the somatotroph lineage after birth. Egr2 knockout results in anterior pituitary hypoplasia. However, the analysis of a conditional mutant demonstrates that this phenotype does not originate from a lack of Egr2 expression in the pituitary. Using an Egr2 allele driving a Cre-activable toxin gene, we performed a genetic ablation of Egr2-positive cells in the pituitary. During the postnatal period, this ablation leads to specific and progressive depletion of the somatotroph population, creating a novel model of early-onset isolated GH deficiency (GHD). Mutant animals were subjected to a complete metabolic analysis, revealing atypical and expected features. Consistent with an adult-onset isolated GHD model, mutant animals are hypoglycemic and display increased insulin sensitivity and glucose clearance. This latter phenotype is in contrast to the glucose intolerance observed in another early-onset GHD model. Surprisingly, increased insulin sensitivity is not accompanied by a modified balance between fat and lean tissues, but by reduced metabolic adaptability between glucose and lipid oxidation conditions. This suggests that the relationship between these metabolic features and insulin sensitivity should be reconsidered. In conclusion, our mutant may be a valuable genetic model with which to study the effects of long-term GH deficiency, in conditions of normal pancreatic function and unaffected balance between fat and glucose metabolism. 23439480 Ghrelin inhibits sodium metabisulfite induced oxidative stress and apoptosis in rat gastric mucosa. This study aimed to investigate the effect of ghrelin administration on sulfite induced oxidative and apoptotic changes in rat gastric mucosa. Forty male albino Wistar rats were randomized into control (C), sodium metabisulfite (Na2S2O5) treated (S), ghrelin treated (G) and, Na2S2O5+ghrelin treated (SG) groups. Sodium metabisulfite (100mg/kg/day) was given by gastric gavage and, ghrelin (20μg/kg/day) was given intraperitoneally for 5weeks. Plasma-S-sulfonate level was increased in S and SG groups. Na2S2O5 administration significantly elevated total oxidant status (TOS) levels while depleting total antioxidant status (TAS) levels in gastric mucosa. Ghrelin significantly decreased gastric TOS levels in the SG group compared with the S group. Additionally, TAS levels were found to be higher in SG group in reference to S group. Na2S2O5 administration also markedly increased the number of apoptotic cells, cleaved caspase-3 and PAR expression (PARP activity indicator) and, decreased Ki67 expression (cell proliferation index) in gastric mucosal cells. Ghrelin treatment decreased the number apoptotic cells, cytochrome C release, PAR and, caspase-3 expressions while increasing Ki67 expression in gastric mucosa exposed to Na2S2O5. In conclusion, we suggest that ghrelin treatment might ameliorate ingested-Na2S2O5 induced gastric mucosal injury stemming from apoptosis and oxidative stress in rats. 22889582 Can the chemical reactivity of an ultimate carcinogen be related to its carcinogenicity? An application to propylene oxide. In this article we report calculations of the activation free energy for a chemical reaction between propylene oxide and DNA, in particular with the guanine at the N7 position. Calculations were performed using Hartree-Fock and MP2 methods in conjunction with flexible basis sets. The effects of solvation were considered using the Langevin dipoles and solvent reaction field methods. The calculated activation free energies are in good agreement with the experimental value of 25.36 kcal/mol. Moreover, the reactivities of a series of ultimate carcinogens of the epoxy type toward DNA are shown to be related to their carcinogenicities. Higher reactivity is generally associated with higher carcinogenicity, although transport properties, reactions with ultimate carcinogen scavengers, and the DNA correction mechanism are also very important. It is very likely that the window of reactivity rather than a high reactivity value is the relevant measure of carcinogenicity, since highly reactive ultimate carcinogens interact with water and proteins before they reach DNA. 23612369 Unusual glycosaminoglycans from a deep sea hydrothermal bacterium improve fibrillar collagen structuring and fibroblast activities in engineered connective tissues. Biopolymers produced by marine organisms can offer useful tools for regenerative medicine. Particularly, HE800 exopolysaccharide (HE800 EPS) secreted by a deep-sea hydrothermal bacterium displays an interesting glycosaminoglycan-like feature resembling hyaluronan. Previous studies demonstrated its effectiveness to enhance in vivo bone regeneration and to support osteoblastic cell metabolism in culture. Thus, in order to assess the usefulness of this high-molecular weight polymer in tissue engineering and tissue repair, in vitro reconstructed connective tissues containing HE800 EPS were performed. We showed that this polysaccharide promotes both collagen structuring and extracellular matrix settle by dermal fibroblasts. Furthermore, from the native HE800 EPS, a low-molecular weight sulfated derivative (HE800 DROS) displaying chemical analogy with heparan-sulfate, was designed. Thus, it was demonstrated that HE800 DROS mimics some properties of heparan-sulfate, such as promotion of fibroblast proliferation and inhibition of matrix metalloproteinase (MMP) secretion. Therefore, we suggest that the HE800EPS family can be considered as an innovative biotechnological source of glycosaminoglycan-like compounds useful to design biomaterials and drugs for tissue engineering and repair. 23122143 Physico-chemical changes occurring in oil when atmospheric frying is combined with post-frying vacuum application. The aim of this study was to investigate the effect of atmospheric frying followed by drainage under vacuum on the stability of oil, compared to similar frying with drainage at atmospheric pressure. Changes in the oil were assessed by the free fatty acid (FFA) content, p-anisidine value (AnV), colour, viscosity, fatty acid profile and concentration of tocols. The rate of FFA formation in the case of vacuum drainage was found to be about half that of atmospheric drainage. Oil deterioration by oxidation and polymerisation was also reduced by the use of vacuum drainage. The AnV of the oil after vacuum drainage was lower by about 12%, the total colour difference was improved by 14% and viscosity was slightly reduced after 5 days of frying, compared to the values for oil that had been drained at atmospheric pressure. There was a reduction in the loss of polyunsaturated fatty acids in the case of vacuum drainage after 5 days of frying but differences in retention of tocols were only evident in the first two days of frying. 23218401 Ameliorative effect of aspalathin from rooibos (Aspalathus linearis) on acute oxidative stress in Caenorhabditis elegans. Rooibos leaves and fine stems (Aspalathus linearis; Fabaceae) are increasingly enjoyed as herbal tea, largely in fermented (oxidised) red-brown form, but also in unfermented (unoxidised) green form. Rooibos is rich in antioxidant polyphenols, with the dihydrochalcone, aspalathin, as a major active ingredient. We used Caenorhabditis elegans as model organism to investigate the effect of rooibos extracts against oxidative stress in vivo. In a high glucose environment, C. elegans treated with rooibos extract exhibited an extended lifespan. Furthermore, green rooibos was a more potent antioxidant than red rooibos, probably due to its substantially higher aspalathin content. In addition, rooibos decreased acute oxidative damage caused by the superoxide anion radical generator, juglone, with aspalathin playing a major role in improving the survival rate of C. elegans. Quantitative real-time PCR results demonstrated that aspalathin targets stress and ageing related genes, reducing the endogenous intracellular level of ROS. These findings suggest that rooibos increases stress resistance and promotes longevity under stress, probably mediated via a regulation of the DAF-16/FOXO insulin-like signalling pathway, supporting some of the health claims put forward for rooibos tea. 23395171 Tmem64 modulates calcium signaling during RANKL-mediated osteoclast differentiation. Osteoclast maturation and function primarily depend on receptor activator of NF-κB ligand (RANKL)-mediated induction of nuclear factor of activated T cells c1 (NFATc1), which is further activated via increased intracellular calcium ([Ca(2+)](i)) oscillation. However, the coordination mechanism that mediates Ca(2+) oscillation during osteoclastogenesis remains ill defined. Here, we identified transmembrane protein 64 (Tmem64) as a regulator of Ca(2+) oscillation during osteoclastogenesis. We found that Tmem64-deficient mice exhibit increased bone mass due in part to impaired osteoclast formation. Using in vitro osteoclast culture systems, we show here that Tmem64 interacts with sarcoplasmic endoplasmic reticulum Ca(2+) ATPase 2 (SERCA2) and modulates its activity. Consequently, Tmem64 deficiency significantly diminishes RANKL-induced [Ca(2+)](i) oscillation, which results in reduced Ca(2+)/calmodulin-dependent protein kinases (CaMK) IV and mitochondrial ROS, both of which contribute to achieving the CREB activity necessary for osteoclast formation. These data demonstrate that Tmem64 is a positive modulator of osteoclast differentiation via SERCA2-dependent Ca(2+) signaling. 23362262 Transforming growth factor β integrates Smad 3 to mechanistic target of rapamycin complexes to arrest deptor abundance for glomerular mesangial cell hypertrophy. In many renal diseases, transforming growth factor β (TGFβ)-stimulated canonical Smad 3 and noncanonical mechanistic target of rapamycin (mTOR) promote increased protein synthesis and mesangial cell hypertrophy. The cellular underpinnings involving these signaling molecules to regulate mesangial cell hypertrophy are not fully understood. Deptor has recently been identified as an mTOR interacting protein and functions as an endogenous inhibitor of the kinase activity for both TORC1 and TORC2. Prolonged incubation of mesangial cells with TGFβ reduced the levels of deptor concomitant with an increase in TORC1 and TORC2 activity. Sustained TGFβ activation was required to inhibit association of deptor with mTOR, whereas rapid activation had no effect. Using the mTOR inhibitor PP242, we found that TGFβ-induced both early and sustained activation of TORC1 and TORC2 was necessary for deptor suppression. PP242-induced reversal of deptor suppression by TGFβ was associated with a significant inhibition of TGFβ-stimulated protein synthesis and hypertrophy. Interestingly, expression of siRNA against Smad 3 or Smad 7, which blocks TGFβ receptor-specific Smad 3 signaling, prevented TGFβ-induced suppression of deptor abundance and TORC1/2 activities. Furthermore, overexpression of Smad 3 decreased deptor expression similar to TGFβ stimulation concomitant with increased TORC1 and TORC2 activities. Finally, knockdown of deptor reversed Smad 7-mediated inhibition of protein synthesis and mesangial cell hypertrophy induced by TGFβ. These data reveal the requirement of both early and late activation of mTOR for TGFβ-induced protein synthesis. Our results support that TGFβ-stimulated Smad 3 acts as a key node to instill a feedback loop between deptor down-regulation and TORC1/2 activation in driving mesangial cell hypertrophy. 23400848 Pharmacokinetics of intravenous voriconazole in obese patients: implications of CYP2C19 homozygous poor metabolizer genotype. There is a paucity of pharmacokinetic studies describing weight-based dosing of intravenous voriconazole in obese patients. In this case report, we describe the pharmacokinetics of intravenous voriconazole in an obese CYP2C19 homozygous poor metabolizer and review previously reported data regarding the use of intravenous voriconazole in obese patients. A 17-year-old obese Hispanic male patient (body mass index 35 kg/m(2) ) received intravenous voriconazole for the treatment of suspected aspergillosis. After 2.5 days of voriconazole 4 mg/kg intravenously every 12 hours based on adjusted body weight, the voriconazole area under the serum concentration-time curve over the course of a single (12-hr) dosing interval and trough concentration were 86,100 ng · hr/ml and 6.2 µg/ml, respectively. Six days later, the voriconazole dosage was decreased. A trough concentration measured just before the dosage reduction (after 8.5 days of voriconazole 4 mg/kg intravenously every 12 hours based on adjusted body weight) remained elevated at 5.8 µg/ml. Genotyping revealed a CYP2C19 homozygous poor metabolizer (CYP2C19*2/*2). Voriconazole was subsequently discontinued due to QTc prolongation. These data and those from two recent publications suggest that voriconazole does not distribute extensively into human adipose tissue and that obese patients should be dosed on an adjusted body weight basis. If an obese patient dosed on total body weight is also a CYP2C19 poor metabolizer, serum voriconazole concentrations will be further elevated, potentially leading to drug-induced toxicity. 23616352 Selective Bisubstrate Inhibitors with Sub-nanomolar Affinity for Protein Kinase Pim-1. Potent and selective: The unique nature of the ATP binding pocket structure of Pim family protein kinases (PKs) was used for the development of bisubstrate inhibitors and a fluorescent probe with sub-nanomolar affinity. Conjugates of arginine-rich peptides with two ATP mimetic scaffolds were synthesized and tested as inhibitors of Pim-1. Against a panel of 124 protein kinases, a novel ARC-PIM conjugate selectively inhibited PKs of the Pim family. 23279930 Synthesis and Biological Evaluation of [1,2,4]Triazolo[3,4-a]phthalazine and Tetrazolo[5,1-a]phthalazine Derivatives Bearing Substituted Benzylpiperazine Moieties as Positive Inotropic Agents. Two series of [1,2,4]triazolo[3,4-a]phthalazine and tetrazolo[5,1-a]phthalazine derivatives bearing substituted benzylpiperazine moieties have been synthesized and evaluated for their positive inotropic activity by measuring left atrium stroke volume on isolated rabbit heart preparations. The majority of the derivatives exhibited better in vitro activity than the existing drug, milrinone, and 6-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)tetrazolo[5,1-a]phthalazine. 8 m in particular was identified as the most potent with an increased stroke volume of 12.02 ± 0.20% (milrinone: 2.46 ± 0.07%) at a concentration of 3 × 10(-5)  m. The chronotropic effects of the compounds that exhibited good potency were also evaluated. 23523950 Avermectin induces P-glycoprotein expression in S2 cells via the calcium/calmodulin/NF-κB pathway. Avermectin (AVM) is a macrocyclic lactone agent widely used as a nematicide, acaricide and insecticide in veterinary medicine and plant protection. P-glycoprotein (P-gp) is an ATP-dependent drug efflux pump for xenobiotic compounds, and is involved in multidrug resistance. To understand the development of AVM resistance in invertebrates, we investigated the mechanisms by which AVM affected P-gp expression in Drosophila S2 cells. We found that AVM induced upregulation of P-gp protein expression, increased P-gp ATPase activity and enhanced cellular efflux of the P-gp substrate rhodamine 123 from cells. Furthermore, we observed that AVM-induced expression of P-gp was due to elevation of intracellular calcium concentration ([Ca(2+)]i). This occurred both directly, by activating calcium ion channels, and indirectly, by activating chloride ion channels. These results are supported by our observations that verapamil, a Ca(2+) channel blocker, and niflumic acid, a chloride channel antagonist, significantly attenuated AVM-induced [Ca(2+)]i elevation, thereby reducing P-gp expression. Inhibition of P-gp with anti-P-gp antibody or cyclosporine A (a P-gp inhibitor) reduced the AVM-induced elevation of [Ca(2+)]i, implying that P-gp and [Ca(2+)]i regulate each other. Finally, we found that trifluoperazine, a calmodulin inhibitor, and pyrrolidine dithiocarbamic acid, an NF-κB inhibitor, attenuated the AVM-induced expression of P-gp, suggesting that AVM induces P-gp protein expression via the calmodulin/Relish (NF-κB) signaling pathway. 22525272 The autophagy-associated factors DRAM1 and p62 regulate cell migration and invasion in glioblastoma stem cells. The aggressiveness of glioblastoma multiforme (GBM) is defined by local invasion and resistance to therapy. Within established GBM, a subpopulation of tumor-initiating cells with stem-like properties (GBM stem cells, GSCs) is believed to underlie resistance to therapy. The metabolic pathway autophagy has been implicated in the regulation of survival in GBM. However, the status of autophagy in GBM and its role in the cancer stem cell fraction is currently unclear. We found that a number of autophagy regulators are highly expressed in GBM tumors carrying a mesenchymal signature, which defines aggressiveness and invasion, and are associated with components of the MAPK pathway. This autophagy signature included the autophagy-associated genes DRAM1 and SQSTM1, which encode a key regulator of selective autophagy, p62. High levels of DRAM1 were associated with shorter overall survival in GBM patients. In GSCs, DRAM1 and SQSTM1 expression correlated with activation of MAPK and expression of the mesenchymal marker c-MET. DRAM1 knockdown decreased p62 localization to autophagosomes and its autophagy-mediated degradation, thus suggesting a role for DRAM1 in p62-mediated autophagy. In contrast, autophagy induced by starvation or inhibition of mTOR/PI-3K was not affected by either DRAM1 or p62 downregulation. Functionally, DRAM1 and p62 regulate cell motility and invasion in GSCs. This was associated with alterations of energy metabolism, in particular reduced ATP and lactate levels. Taken together, these findings shed new light on the role of autophagy in GBM and reveal a novel function of the autophagy regulators DRAM1 and p62 in control of migration/invasion in cancer stem cells. 23512537 Metabolism of Beclomethasone Dipropionate by Cytochrome P450 3A Enzymes. Inhaled glucocorticoids, such as beclomethasone dipropionate (BDP), are the mainstay treatment of asthma. However, ∼30% of patients exhibit little to no benefit from treatment. It has been postulated that glucocorticoid resistance, or insensitivity, is attributable to individual differences in glucocorticoid receptor-mediated processes. It is possible that variations in cytochrome P450 3A enzyme-mediated metabolism of BDP may contribute to this phenomenon. This hypothesis was explored by evaluating the contributions of CYP3A4, 3A5, 3A7, and esterase enzymes in the metabolism of BDP in vitro and relating metabolism to changes in CYP3A enzyme mRNA expression via the glucocorticoid receptor in lung and liver cells. CYP3A4 and CYP3A5 metabolized BDP via hydroxylation ([M4] and [M6]) and dehydrogenation ([M5]) at similar rates; CYP3A7 did not metabolize BDP. A new metabolite [M6], formed by the combined action of esterases and CYP3A4 hydroxylation, was also characterized. To validate the results observed using microsomes and recombinant enzymes, studies were also conducted using A549 lung and DPX2 liver cells. Both liver and lung cells produced esterase-dependent metabolites [M1-M3], with [M1] correlating with CYP3A5 mRNA induction in A549 cells. Liver cells produced both hydroxylated and dehydrogenated metabolites [M4, M5, and M6], but lung cells produced only the dehydrogenated metabolite [M5]. These studies show that CYP3A4 and CYP3A5 metabolize BDP to inactive metabolites and suggest that differences in the expression or function of these enzymes in the lung and/or liver could influence BDP disposition in humans. 23381641 Differential autophagic cell death under stress with ectopic cytoplasmic and mitochondrial-specific PPP2R2B in human neuroblastoma cells. Protein phosphatase 2A is one of four major classes of serine/threonine phosphatases. Overexpression of brain-specific regulatory subunit PPP2R2 in neuron cells is implicated in pathogenesis. The alternative splicing of PPP2R2B encodes two isoforms. They are subunit of cytoplasmic specific Bβ1 and mitochondria-targeted Bβ2. The two constructs were transfected into human neuroblastoma cells, SK-N-SH, respectively, and the stable clones overexpressing either Bβ1 or Bβ2 established. We have reported that Bβ2 clones are sensitive to reactive oxygen species (ROS) treatment by inducing autophagic cell death. To study more on the onset of neuropathogenesis under strain, both clones were exposed to different environmental stress, e.g. starvation and endoplasmic reticulum (ER) stress. To learn how PPP2R2B overexpression responds to starvation, cells were incubated in Hank's buffered salt solution of deprived nutrient. Cell death was induced in Bβ1 clones after 6 h starvation, but not in Bβ2 clones. The pharmacological inhibitor, Bafilomycin A1, rescued the cell death while suppressing autophagy. On the other hand, to assess how cells respond to ER stress, the cells were treated with 0.1 μM of N-glycosylation inhibitor, tunicamycin (TM). In contrast with Bβ1, the apoptotic cell death appeared in Bβ2 after 48 h treatment. The formation of autophagolysosome was detected in Bβ2 following 12 h treatment with TM as evidenced by lysotracker and GFP-LC3 staining for fluorescence microscopy analysis. The autophagy inhibitor, 3-methyladenine, salvaged the final apoptosis. The stable cell lines with ectopically transfected PPP2R2B genes encoding isoforms of brain-specific regulatory subunit exhibit distinct apoptosis under different stressors. The induced autophagic apoptotic cell death is related to mitochondrial membrane potential drop and ROS generation. Disturbance of autophagy alleviates the induced cell death. The results promised a good model for understanding the onset in pathogenesis under stress in neuron cells with aberrant PPP2R2B expression. 23435915 The characteristics of genistin-induced inhibitory effects on intestinal motility. Genistin belongs to isoflavones. Based on the facts that genistin exerts inhibitory effects on the contractility of vascular smooth muscle,the present study was designed to characterize the effects of genistin on intestinal contractility and evaluate its potential clinical implication. Ex vivo [isolated jejunal segment (IJS) of rat], in vitro, and in vivo assays were used in the study. The results indicated that genistin (5-80 μmol/L) inhibited the contraction of IJS in a dose-dependent manner and inhibited the increased-contractility of IJS induced by acetylcholine (ACh), histamine, high Ca(2+), and erythromycin, respectively. The inhibitory effects of genistin were correlated with the stimulation of alpha adrenergic and beta adrenergic receptors since these inhibitory effects were significantly blocked in the presence of phentolamine and propranolol respectively. No further inhibitory effects of genistin were observed in the presence of verapamil or in Ca(2+)-free condition, indicating genistin-induced inhibitory effects are Ca(2+)-dependent. Genistin decreased myosin light chain kinase (MLCK) protein contents and MLCK mRNA expression in IJS, and inhibited both phosphorylation and Mg(2+)-ATPase activity of purified myosin, implicating that the decrease of MLCK contents and inhibition of MLCK activity are involved in the genistin-induced inhibitory effects. The study suggests the potential clinical implications of genistin in relieving intestinal hypercontractility. 23418068 Superhydrophobic and Superoleophilic PVDF Membranes for Effective Separation of Water-in-Oil Emulsions with High Flux. A superhydrophobic-superoleophilic PVDF membrane is fabricated via an inert solvent-induced phase inversion for effective separation of both micrometer and nanometer-sized surfactant-free and surfactant-stabilized water-in-oil emulsions solely driven by gravity, with high separation efficiency (oil purity in filtrate after separation > 99.95 wt%) and high flux, which is several times higher than those of commercial filtration membranes and reported materials with similar permeation properties. 23323549 The volume of distribution is an indicator of poor in vitro-in vivo extrapolation of clearance for acidic drugs in the rat. Abstract 1. We applied the regression offset approach to predict rat in vivo intrinsic clearance (CLint) for 54 new chemical acid entities with high plasma protein binding values and low renal clearance (CL). The prediction success was correlated to volume of distribution (Vd), molecular weight (Mw) and CL. 2. A correlation between poor in vitro-in vivo extrapolation (IVIVE) and Vd values distinct from the Vd of albumin (0.1-0.2 L/kg) was revealed. For compounds with a Vd value above 0.5 L/kg, 0% of the predictions of in vivo CLint was within twofold of the observed value, compared to 69% for compounds with a Vd value below 0.5 L/kg. 3.  Compounds with a Mw below 450 g/mol demonstrated more accurate in vivo CLint predictions than compounds with a Mw above 450 g/mol, i.e. 63% compared to 21% within twofold. For compounds with in vivo CL below 30% of the liver blood flow (LBF), 53% of the predictions was within twofold of the observed value, compared to 0% for compounds with CL above 30% of the LBF. 4. We show that accurate IVIVE for acidic compounds with high plasma protein binding and low renal CL can be associated with a low Vd (i.e. around the Vd of albumin) and with a low in vivo CL, and that Mw is an important optimization parameter for pharmacokinetic. This study also further demonstrates the advantages of the application of the regression method for identifying cases when metabolic CL is not the single major elimination pathway. 23337040 Paradoxical Sost gene expression response to mechanical unloading in metaphyseal bone. The Sost gene encodes Sclerostin, an inhibitor of Wnt-signaling, generally considered a main response gene to mechanical loading in bone. Several papers describe that unloading leads to upregulation of Sost, which in turn may lead to loss of bone. These studies were based on whole bone homogenates or cortical bone. By serendipity, we noted an opposite response to unloading in the proximal rat tibia. Therefore, we hypothesized that Sost-expression in response to changes in mechanical load is bone site specific. One hind limb of male, 3 month old rats was unloaded by paralyzing the extensors with Botulinium toxin A (Botox) injections. A series of experiments compared the expression of Sost mRNA in the unloaded and contralateral, loaded limbs, after 3 or 10 days, in metaphyseal cancellous bone, metaphyseal cortical bone, and diaphyseal cortical bone. We also conducted μCT to confirm changes in bone volume density related to unloading. Sost mRNA expression in the cancellous metaphyseal bone was downregulated almost 2-fold, both 3 days and 10 days after unloading (P<0.05). A similar tendency was seen in the metaphyseal cortical bone, in which Sost was 1.5-fold downregulated (P<0.05) after 10days, but not significantly changed after 3days. In contrast, diaphyseal cortical Sost expression was instead upregulated 1.4-fold (P<0.05) following 3-day unloading, while there was no significant change after 10days. Cancellous bone volume density was 58% lower (P<0.001, compared to cage controls) in the unloaded limb but not significantly affected in the loaded limb. The results suggest that Sost mRNA expression in metaphyseal bone responds to mechanical unloading in an opposite direction to that observed in diaphyseal cortical bone. This proposes a more complex expression pattern for Sost in response to unloading. Therapeutics that target Sclerostin during altered loading conditions may result in local bone mass changes that are difficult to predict. 23517784 Mesoporous silica-supported lipid bilayers (protocells) for DNA cargo delivery to the spinal cord. Amorphous mesoporous silica nanoparticles ('protocells') that support surface lipid bilayers recently characterized in vitro as carrier constructs for small drug and DNA delivery are reported here as highly biocompatible both in vitro and in vivo, involving the brain and spinal cord following spinal delivery into the lumbosacral subarachnoid space (intrathecal; i.t.). Specifically, positively charged, 1, 2-Dioleoyl-3-Trimethylammonium-Propane (DOTAP)-cholesterol (DOTAP:Chol) liposome-formulated protocells revealed stable in vitro cargo release kinetics and cellular interleukin-10 (IL-10) transgene transfection. Recent approaches using synthetic non-viral vector platforms to deliver the pain-suppressive therapeutic transgene, IL-10, to the spinal subarachnoid space have yielded promising results in animal models of peripheral neuropathy, a condition involving aberrant neuronal communication within sensory pathways in the nervous system. Non-viral drug and gene delivery protocell platforms offer potential flexibility because cargo release-rates can be pH-dependent. We report here that i.t. delivery of protocells, with modified chemistry supporting a surface coating of DOTAP:Chol liposomes and containing the IL-10 transgene, results in functional suppression of pain-related behavior in rats for extended periods. This study is the first demonstration that protocell vectors offer amenable and enduring in vivo biological characteristics that can be applied to spinal gene delivery. 23201452 Acute and sub-chronic (28days) oral toxicity evaluation of hydroethanolic extract of Bridelia ferruginea Benth root bark in male rodent animals. The present investigation was carried out to evaluate the safety of hydro-ethanol extract of Bridelia ferruginea Benth (Euphorbiaceae) root bark. For acute toxicity study, a single dose of 2000 and 5000 mg/kg of the B. ferruginea root bark extract was given orally to healthy male Wistar rats and Balb/c mice. The animals were observed for mortality and clinical signs for 3 h and then daily for 14 days. In the sub-chronic toxicity study, the extract was administered orally at doses of 250, 500 and 1000 mg/kg/day for 28 days to male Wistar rats. Animals were sacrificed to examine their organs, and urine and blood serum were analyzed. In the acute toxicity study, B. ferruginea root bark extract caused neither significant visible signs of toxicity, nor mortality in Wistar rats and Balb/c mice. In sub-chronic toxicity study, administration of the B. ferruginea root bark extract at 250, 500, and 1000 mg/kg for 28 consecutive days to Wistar rats did not produce mortality. No significant differences were found in relative organ weights, biochemical studied parameters in treated groups compared to control group. No obvious histological changes were observed in organs of B. ferruginea extract treated animals compared to controls. 23295385 SKF83959 is a potent allosteric modulator of sigma-1 receptor. SKF83959 (3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine), an atypical dopamine receptor-1 (D(1) receptor) agonist, has shown many D(1) receptor-independent effects, such as neuroprotection, blockade of Na(+) channel, and promotion of spontaneous glutamate release, which resemble the effects of the sigma-1 receptor activation. In the present work, we explored the potential modulation of SKF83959 on the sigma-1 receptor. The results indicated that SKF83959 dramatically promoted the binding of (3)H(+)-pentazocine (a selective sigma-1 receptor agonist) to the sigma-1 receptor in brain and liver tissues but produced no effect on (3)H-progesterone binding (a sigma-1 receptor antagonist). The saturation assay and the dissociation kinetics assay confirmed the allosteric effect. We further demonstrated that the SKF83959 analogs, such as SCH22390 [(R)-(1)-7-chloro-8- hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride] and SKF38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide], also showed the similar allosteric effect on the sigma-1 receptor in the liver tissue but not in the brain tissue. Moreover, all three tested chemicals elicited no significant effect on (3)H-1,3-di(2-tolyl)-guanidine ((3)H-DTG) binding to the sigma-2 receptor. The present data uncovered a new role of SKF83959 and its analogs on the sigma-1 receptor, which, in turn, may reveal the underlying mechanism for the D(1) receptor-independent effect of the drug. 23639249 Indoxyl 3-sulfate stimulates Th17 differentiation enhancing phosphorylation of c-Src and STAT3 to worsen experimental autoimmune encephalomyelitis. Although AhR activation regulates CD4T cell differentiation, how it works has yet to be elucidated. In the present study, using in vitro Th17 differentiation model, we examined effects of AhR activation by indoxyl 3-sulfate (I3S), a uremic toxin, on Th17 differentiation and investigated underlying mechanisms. I3S increased expression of RORγt, the master transcription factor for Th17 differentiation, and stimulated Th17 differentiation, in a comparative manner as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a prototypical AhR ligand. Activation of STAT3, which is phosphorylated by the IL-6 signaling pathways and thus is necessary for Th17 differentiation, was strongly stimulated by I3S and TCDD. Phosphorylation of c-Src, which was shown to be activated by AhR ligands, was also increased by I3S and TCDD, and blocking of c-Src activity by 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d]pyrimidine (PP2) inhibited phosphorylation of both c-Src and STAT3, raising a possibility that stimulatory activities of I3S and TCDD on Th17 differentiation could be exerted via increased phosphorylation of c-Src, which in turn stimulates STAT3 activation. Finally, we found that I3S worsened experimental autoimmune encephalomyelitis (EAE), which is primarily mediated by Th17 cells, enhancing the frequency of IL-17-producing cells in draining lymph nodes. 23225753 Effect of ganglioside GM3 synthase gene knockout on the glycoprotein N-glycan profile of mouse embryonic fibroblast. The structural and clinical significance of cellular glycoproteins and glycosphingolipids (GSLs) are often separately discussed. Considering the biosynthetic pathway of glycoconjugates, glycans of cell-surface glycoproteins and GSLs might partially share functions in maintaining cellular homeostatis. The purpose of this study is to establish a general and comprehensive glycomics protocol for cellular GSLs and N-glycans of glycoproteins. To test the feasibility of a glycoblotting-based protocol, whole glycans released both from GSLs and glycoproteins were profiled concurrently by using GM3 synthase-deficient mouse embryonic fibroblast GM3(-/-). GM3(-/-) cells did not synthesize GM3 or any downstream product of GM3 synthase. Instead, expression levels of o-series gangliosides involving GM1-b and GD1-α increased dramatically, whereas a-/b-series gangliosides were predominantly detected in wild-type (WT) cells. We also discovered that glycoprotein N-glycan profiles of GM3(-/-) cells are significantly altered as compared to WT cells, although GM3 synthase is responsible only for GSLs synthesis and is not associated with glycoprotein N-glycan biosynthesis. The present approach allows for high-throughput profiling of cellular glycomes enriched by different classes of glycoconjugates, and our results demonstrated that gene knockout of the enzymes responsible for GSL biosynthesis significantly influences the N-glycans of glycoproteins. 23423993 Evaluation of phytotoxicity and genotoxicity of nitrobenzene with A battery of Vicia Faba assay system. Nitrobenzene (NB) is an important organic compound intermediate that is used widely in industry. In the present study, to evaluate the phytotoxicity and genotoxicity of NB on plants, Vicia faba was exposed to increasing concentrations of NB (5 mg L(-1) , 10 mg L(-1) , 25 mg L(-1) , 50 mg L(-1) , and 100 mg L(-1) ). The data revealed that germination rate and radicle length of V. faba seedlings were promoted by low NB concentrations and short exposure periods, whereas these parameters were inhibited at greater NB concentrations and longer exposures. When assessed by mitotic index, micronucleus, and chromosomal aberration assays, NB showed dose-dependent genotoxicity at 0 mg L(-1) to 50 mg L(-1) . Environ Toxicol Chem 2013;32:1426-1432. © 2013 SETAC. 23254197 Estradiol negative and positive feedback in a prenatal androgen-induced mouse model of polycystic ovarian syndrome. Gonadal steroid hormone feedback is impaired in polycystic ovarian syndrome (PCOS), a common endocrine disorder characterized by hyperandrogenism and an associated increase in LH pulse frequency. Using a prenatal androgen (PNA)-treated mouse model of PCOS, we aimed to investigate negative and positive feedback effects of estrogens on the hypothalamic-pituitary axis regulation of LH. PNA-treated mice exhibited severely disrupted estrous cycles, hyperandrogenism, significantly reduced fertility, and altered ovarian morphology. To assess the negative feedback effects of estrogens, LH was measured before and after ovariectomy and after estradiol (E2) administration. Compared with controls, PNA-treated mice exhibited a blunted postcastration rise in LH (P < .001) and an absence of LH suppression after E2 administration. To assess E2-positive feedback, control and PNA-treated GnRH-green fluorescent protein transgenic mice were subjected to a standard ovariectomy with E2-replacement regimen, and both plasma and perfusion-fixed brains were collected at the time of the expected GnRH/LH surge. Immunocytochemistry and confocal imaging of cFos and green fluorescent protein were used to assess GnRH neuron activation and spine density. In the surged group, both control and PNA-treated mice had significantly increased LH and cFos activation in GnRH neurons (P < .05) compared with nonsurged animals. Spine density was quantified in cFos-positive and -negative GnRH neurons to examine whether there was an increase in spine density in cFos-expressing GnRH neurons of surged mice as expected. A significant increase in spine density in cFos-expressing GnRH neurons was evident in control animals; however, no significant increase was observed in the PNA-treated mice because spine density was elevated across all GnRH neurons. These data support that PNA treatment results in a PCOS-like phenotype that includes impaired E2-negative feedback. Additionally, although E2-positive feedback capability is retained in PNA mice, elevated GnRH neuron spine density may reflect altered synaptic regulation. 23255101 Capture and stimulated release of circulating tumor cells on polymer-grafted silicon nanostructures. A platform for capture and release of circulating tumor cells is demonstrated by utilizing polymer grafted silicon nanowires. In this platform, integration of ligand-receptor recognition, nanostructure amplification, and thermal responsive polymers enables a highly efficient and selective capture of cancer cells. Subsequently, these captured cells are released upon a physical stimulation with outstanding cell viability. 23298622 In situ forming nimodipine depot system based on microparticles for the treatment of posthemorrhagic cerebral vasospasm. The present study was conducted to examine the feasibility of nimodipine-loaded PLGA microparticles suspended in Tisseel™ fibrin sealant as an in situ forming depot system. This device locally placed can be used for the treatment of vasospasm after a subarachnoid hemorrhage. Microparticles were prepared via spray-drying by using the vibration mesh spray technology of Nano Spray Dryer B-90. Spherically shaped microparticles with different loadings and high encapsulation efficiencies of 93.3-97.8% were obtained. Depending on nimodipine loading (10-40%), the particle diameter ranged from 1.9±1.2μm to 2.4±1.3μm. Thermal analyses using DSC revealed that nimodipine is dissolved in the PLGA matrix. Also, fluorescent dye loaded microparticles were encapsulated in Tisseel™ to examine the homogeneity of particles. 3D-pictures of the in situ forming devices displayed uniform particle homogeneity in the sealant matrix. Drug release was examined by fluorescence spectrophotometry which demonstrated a drug release proportional to the square root of time. A prolonged drug release of 19.5h was demonstrated under in vitro conditions. Overall, the nimodipine in situ forming device could be a promising candidate for the local treatment of vasospasm after a subarachnoid hemorrhage. 23392232 Time-of-flight magnetic flow cytometry in whole blood with integrated sample preparation. Rapid and specific rare cell detection for point-of-care testing requires an integration of the sample preparation for flow cytometry. To achieve such a challenging goal we have developed a magnetic flow cytometry technique which applies magnetophoresis to perform cell enrichment, focusing, and background elimination in a single step. Time-of-flight measurements are performed with integrated magnetic sensors to detect specifically cancer cells and cell diameters in whole blood. 22972752 Estrogen receptor-α is required for the osteogenic response to mechanical loading in a ligand-independent manner involving its activation function 1 but not 2. Estrogen receptor-α (ERα) is crucial for the adaptive response of bone to loading but the role of endogenous estradiol (E2) for this response is unclear. To determine in vivo the ligand dependency and relative roles of different ERα domains for the osteogenic response to mechanical loading, gene-targeted mouse models with (1) a complete ERα inactivation (ERα(-/-) ), (2) specific inactivation of activation function 1 (AF-1) in ERα (ERαAF-1(0) ), or (3) specific inactivation of ERαAF-2 (ERαAF-2(0) ) were subjected to axial loading of tibia, in the presence or absence (ovariectomy [ovx]) of endogenous E2. Loading increased the cortical bone area in the tibia mainly as a result of an increased periosteal bone formation rate (BFR) and this osteogenic response was similar in gonadal intact and ovx mice, demonstrating that E2 (ligand) is not required for this response. Female ERα(-/-) mice displayed a severely reduced osteogenic response to loading with changes in cortical area (-78% ± 15%, p < 0.01) and periosteal BFR (-81% ± 9%, p < 0.01) being significantly lower than in wild-type (WT) mice. ERαAF-1(0) mice also displayed a reduced response to mechanical loading compared with WT mice (cortical area -40% ± 11%, p < 0.05 and periosteal BFR -41% ± 8%, p < 0.01), whereas the periosteal osteogenic response to loading was unaffected in ERαAF-2(0) mice. Mechanical loading of transgenic estrogen response element (ERE)-luciferase reporter mice did not increase luciferase expression in cortical bone, suggesting that the loading response does not involve classical genomic ERE-mediated pathways. In conclusion, ERα is required for the osteogenic response to mechanical loading in a ligand-independent manner involving AF-1 but not AF-2. 23362982 Attitude of German women towards hormone therapy: results of a lay survey. Abstract Objective: Hormone therapy (HT) use has experienced a substantial change since publication of Women's Health Initiative (WHI) controlled trial. We aimed to investigate the attitude towards HT in German women aged 45-60 years. Study design: A questionnaire was sent to 9785 randomly selected women in Germany aged between 45 and 60 years. Results: Response rate was 19.3% (n = 1,893). Of those, 81% experienced climacteric symptoms. Vasomotor symptoms were most frequently reported (71.2%; n = 1332). Of the respondents, 19.7% (n = 369) used HT. The most frequently mentioned benefits of HT were the improvement of climacteric complaints (71.2%; n = 1346), followed by the relief of osteoporosis (37.2%; n = 697) and the "anti-aging" effect (16.3%; n = 305). Breast cancer was stated as the main risk (64.9%; n = 1215), closely followed by weight gain (53.4%; n = 1000) and thromboembolism (48%; n = 898). About 44% of the women who has been advised by gynaecologists choose a HT, whereas this rate dropped down to 14.3% and 11.3% for women who have been advised by friends or media. Conclusion: German women were generally aware of the main risks and benefits of HT. "More informed" women appear to be more likely to use HT compared to "less informed" women. The media produces negative impression of HT. 23336441 Nanoscale mapping of lithium-ion diffusion in a cathode within an all-solid-state lithium-ion battery by advanced scanning probe microscopy techniques. High-resolution real-space mapping of Li-ion diffusion in the LiNi(1/3)Co(1/3)Mn(1/3)O₂ cathode within an all-solid-state thin film Li-ion battery has been conducted using advanced scanning probe microscopy techniques, namely, band excitation electrochemical strain microscopy (BE-ESM) and conductive atomic force microscopy. In addition, local variations of the electrochemical response in the LiNi(1/3)Co(1/3)Mn(1/3)O₂ thin film cathode at different cycling stages have been investigated. This work demonstrates the unique feature and applications of the BE-ESM technique on battery research. The results allow us to establish a direct relationship of the changes in ionic mobility as well as the electrochemical activity at the nanoscale with the numbers of charge/discharge cycles. Furthermore, various factors influencing the BE-ESM measurements, including sample mechanical properties (e.g., elastic and dissipative properties) as well as surface electrical properties, have also been studied to investigate the coupling effects on the electrochemical strain. The study on the relationships between the Li-ion redistribution and microstructure of the electrode materials within thin film Li-ion battery will provide further understanding of the electrochemical degradation mechanisms of Li-ion rechargeable batteries at the nanoscale. 23157419 Protein-polyanion interactions for the controlled release of monoclonal antibodies. The objective of the present study was to investigate ionic interactions between alginate and a monoclonal antibody (mAb1) and to utilize those interactions for the sustained release of mAb1. The existence of ionic interactions between alginate and mAb1 was strongly reflected by their rheological behavior. A 3-4 times increase in storage modulus (G') was observed by addition of 30 mg/mL mAb1 to a 20 mg/mL alginate solution. This increase was strongly dependent on pH and ionic strength. In vitro release studies revealed a marked pH-dependence of release rates and the reversibility of alginate-mAb1 complexation under physiological conditions. Two alginate-mAb1 sustained release formulations were developed by an internal gelation technique using CaCO(3) and CaHPO(4) as calcium sources for physical cross-linking. The CaCO(3) formulation provided a stable pH-environment, optimally suited for pH-sensitive proteins. CaHPO(4) led to a lower pH and stronger alginate-mAb1 interactions. The CaHPO(4) cross-linked alginate released mAb1 over a period of 10-15 days. The long release period and changes in viscoelastic properties of alginate, when being mixed with mAb1, indicate the incorporation of mAb1 molecules into a mixed network with alginate. The results of this study demonstrate that ionic interactions between polyanions and mAb1 are present and that they can be exploited for sustained release delivery of mAb1. 23578993 Effect of N-acetyl cysteine (NAC), an organosulfur compound from Allium plants, on experimentally induced hepatic prefibrogenic events in wistar rat. Aim of present study was to investigate the effect of NAC on experimental chronic hepatotoxicity models induced by carbon tetrachloride (CCl4) and thioacetamide (TAA). CCl4 toxicity was induced by administering 200μl CCl4 (diluted 2:3 in coconut oil)/100g body weight, p.o., twice weekly for 8 weeks. TAA toxicity was induced by administering 150mg/kg b. wt. of TAA i.p., twice weekly for 8 weeks. NAC treatment was started along with toxicants (CCl4 and TAA) for 8 weeks and continued for further 4 weeks. Self reversal group was kept without any treatment for 4 weeks after completion of toxicant treatments. Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), Bilirubin were measured in serum. Hydroxyproline (HP), lipid peroxidation (LPO), catalase (CAT), Glutathione peroxidase (GPx) and Glutathione (GSH) were determined in liver samples by colorimetric methods. Cytochrome P450 2E1 (CYP 450 2E1), activity was determined as hydroxylation of aniline in liver microsomes. General examination and histological analysis were also performed. Serum markers of liver damage (AST, ALT, ALP and Bilirubin) were increased by CCl4 and TAA intoxication (p<0.001), whereas co-treatment with NAC reversed such changes (p<0.001). HP was enhanced in toxicant groups (p<0.001 in CCl4 and TAA), but inhibited by NAC (p<0.001). LPO was increased while as GSH, CAT and GPx decreased by the administration of CCl4 and TAA (p<0.001); co-administration of NAC restored these liver markers to normal levels (p<0.001). Biochemical determinations were corroborated by general and histological findings. Keeping in view the biochemical and histopathological studies, it was concluded that CCl4 and TAA are strong hepatotoxic agents that produce liver fibrosis with close proximity to human etiology (micronodular cirrhosis) and NAC has a significant protective activity against CCl4 and TAA. NAC has also been validated as a model against oxidative burden in chronic liver pathology. 23157625 Effects of antipsychotics on the BDNF in schizophrenia. Brain-derived neurotropic factor (BDNF) is involved in the development of the brain, and likely influences the neuroplasticity in schizophrenia. BDNF is also believed to interact with other neurotransmitter systems implicated in schizophrenia, such as dopamine, glutamate, serotonin and GABA. Therefore, BDNF is a candidate gene for schizophrenia. In past decades, the blood (serum or plasma) BDNF protein levels and BDNF gene alleles and genotypes to the clinical features of schizophrenia, such as age of onset, clinical subtypes, symptom severity, and drug response, have been evaluated among different populations. However, the results are still inconsistent. Further, different drugs have been reported to have different effects on BDNF protein levels. A cross-sectional survey revealed that serum BDNF levels in chronic schizophrenic patients treated with clozapine exceeded those of patients treated with risperidone or with typical antipsychotics. In recent times, BDNF epigenetic studies have also been conducted in clinical studies of schizophrenia to address the question of why patients with the same gene genotype and alleles have different clinical presentations. In addition, the effects of different antipsychotic drugs on gene methylation and protein acetylation have also been reported. In conclusion, more data are needed regarding BDNF in the brain and in peripheral blood, including protein levels, single nucleotide polymorphisms, epigenetic regulation, and clinical data in order to understand the role of BDNF in schizophrenia. 23456850 Rapid cortical bone loss in patients with chronic kidney disease. Chronic kidney disease (CKD) patients may have high rates of bone loss and fractures, but microarchitectural and biochemical mechanisms of bone loss in CKD patients have not been fully described. In this longitudinal study of 53 patients with CKD Stages 2-5D, we used dual energy X-ray absorptiometry (DXA), high resolution peripheral quantitative computed tomography (HRpQCT) and biochemical markers of bone metabolism to elucidate effects of CKD on the skeleton. Median follow-up was 1.5 years (Range 0.9 to 4.3 years); bone changes were annualized and compared to baseline. By DXA, there were significant declines in areal bone mineral density (BMD) of the total hip and ultradistal radius: -1.3% (95% CI: -2.1 to -0.6) and -2.4% (95% CI: -4.0 to -0.9), respectively. By HRpQCT at the distal radius, there were significant declines in cortical area, density and thickness, and increases in porosity: -2.9% (95% CI -3.7 to -2.2), -1.3% (95% CI -1.6 to -0.6), -2.8% (95% CI -3.6 to -1.9), and +4.2% (95% CI 2.0 to 6.4) respectively. Radius trabecular area increased significantly: +0.4% (95% CI 0.2 to 0.6), without significant changes in trabecular density or microarchitecture. Elevated time-averaged levels of parathyroid hormone (PTH) and bone turnover markers predicted cortical deterioration. Higher levels of serum 25-hydroxyvitamin D predicted decreases in trabecular network heterogeneity. These data suggest that significant cortical loss occurs with CKD, which is mediated by hyperparathyroidism and elevated turnover. Future investigations are required to determine whether these cortical losses can be attenuated by treatments that reduce PTH levels and remodeling rates. © 2013 American Society for Bone and Mineral Research. 23200000 Recently introduced foods as new allergenic sources: sensitisation to Goji berries (Lycium barbarum). Goji berries (GB) have been introduced in Western diet. Preliminary reports have demonstrated its allergenic capacity. The objectives of the study were to investigate the frequency of sensitisation and the allergens involved. 566 individuals, with respiratory or cutaneous symptoms were skin-prick tested with GB extract. Thirty three were positive (5.8%). 94% were sensitised to other allergens. Specific IgE to GB, peach, tomato and nut-mix was measured. Thirteen individuals from 24 available sera (54.2%) had positive specific IgE. 92.3% of GB positive patients were positive to peach. Seven individuals recognised 8 bands and six recognised a 7kDa band. This band was identified as a LTP by MS/MS. Cross-reactivity was demonstrated with tomato, tobacco, nutmix, Artemisia pollen and purified Lyc e 3 and Pru p 3. GB are a new allergenic source with high prevalence of sensitisation. LTP seems to be the major allergen involved in sensitisation and cross-reactivity. 22472136 Heavy metals content by ICP-OES in Sarda sarda, Sardinella aurita and Lepidopus caudatus from the Strait of Messina (Sicily, Italy). In this study copper, nickel, lead, cadmium, arsenic, chromium and vanadium content was measured in the muscles and gills of 24 fishes (Sarda sarda, Sardinella aurita and Lepidopus caudatus) caught in the Strait of Messina, by inductively coupled plasma-optical emission spectroscopy with microwave digestion techniques. In general, it was found that arsenic was higher than other analytes in all fish species, particularly its content was much higher in S. aurita than in the other two exemplary species. Lead and cadmium were always detected with values below the legal limits (CE no. 1881/2006 and subsequent modification CE no. 629/2008). 23122122 The importance of amylose and amylopectin fine structures for starch digestibility in cooked rice grains. Statistically and causally meaningful relationships are established between starch molecular structures (obtained by size-exclusion chromatography, proton NMR and multiple-angle laser light scattering) and digestibility of cooked rice grains (measured by in vitro digestion). Significant correlations are observed between starch digestion rate and molecular structural characteristics, including fine structures of the distributions of branch (chain) lengths in both amylose and amylopectin. The in vitro digestion rate tends to increase with longer amylose branches and smaller ratios of long amylopectin and long amylose branches to short amylopectin branches, although the statistical analyses show that further data are needed to establish this unambiguously. These new relationships between fine starch structural features and digestibility of cooked rice grains are mechanistically reasonable, but suggestive rather than statistically definitive. 23332447 Testosterone deficiency induces markedly decreased serum triglycerides, increased small dense LDL, and hepatic steatosis mediated by dysregulation of lipid assembly and secretion in mice fed a high-fat diet. OBJECTIVE: Although low serum testosterone (T) is associated with metabolic disorders, the mechanism of this association is unclear. The objective of the present study was to investigate the combined effects of T deficiency and a high-fat diet (HFD) on hepatic lipid homeostasis in mice. MATERIALS/METHODS: Orchiectomized (ORX) mice and sham-operated (SHAM) mice were randomly divided into five groups: SHAM mice fed a standard diet (SD), SHAM mice fed HFD, ORX mice fed SD, ORX mice fed HFD, and ORX mice fed HFD with T supplementation. After 4weeks of treatment, we investigated the synthesis and secretion of lipids in the liver and detailed serum lipoprotein profiles in each group. RESULTS: ORX mice fed HFD showed increased hepatic steatosis, markedly decreased serum triglyceride (TG) and TG-VLDL content, and increased serum very small-LDL content. Gene expression analysis revealed that ORX mice fed HFD showed significantly decreased expression of microsomal triglyceride transfer protein, lipin-1, peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ coactivator 1-α, and significantly increased sterol regulatory element-binding protein-1, diacylglycerol acyltransferase-2 and fatty acid synthase. Reduction of hepatic AMPK phosphorylation was observed in ORX mice fed HFD. These perturbations in ORX mice fed HFD were normalized to the levels of SHAM mice fed HFD by T supplementation. CONCLUSION: T deficiency is associated with failure of lipid homeostasis mediated by altered expression of genes involved in hepatic assembly and secretion of lipids. 23195751 Reproductive experience modifies the effects of estradiol on learning and memory bias in female rats. Previous studies have shown that estrogen affects whether a hippocampus-mediated place (allocentric) or a striatum-mediated response (egocentric) memory system is employed by female rats when searching for a food reward in a maze. Because it has been suggested that reproductive experience alters some of the responses to E in the brain, two experiments were carried out to investigate whether reproductive experience would also alter the effect of E on place and response learning. In experiment 1, 152 ovariectomized nulliparous (n=77; no reproductive experience) and primiparous (n=74; having had and raised one litter of pups) Wistar rats were trained on an ambiguous t-maze task and tested for memory system bias. In experiment 2, 35 ovariectomized nulliparous (n=16) and primiparous (n=19) Wistar rats were trained on place and response plus-maze tasks. All rats were exposed to no, chronic low or chronic low with pulsatile high 17β-estradiol (E2) replacement. Congruent with previous findings, low E2 nulliparous rats showed predominant use of response memory and faster response learning, whereas high E2 nulliparous rats showed a trend towards predominant place memory use. Interestingly, the facilitatory effect of low E2 on response task learning and memory seen in nulliparous rats was not observed in low E2 primiparous rats in either experiment. In conclusion, E2 levels do dictate the rate at which female rats learn a response task and utilize response memory, but only in those with no reproductive experience. 23601395 Variability in the contents of pork meat nutrients and how it may affect food composition databases. Pork meat is generally recognised as a food with relevant nutritional properties because of its content in high biological value proteins, group B vitamins, minerals especially heme iron, trace elements and other bioactive compounds. But pork meat also contributes to the intake of fat, saturated fatty acids, cholesterol, and other substances that, in inappropriate amounts, may result in negative physiologically effects. However, there are relevant factors affecting the content of many of these substances and somehow such variability should be taken into consideration. So, genetics, age and even type of muscle have a relevant influence on the amount of fat and the contents in heme iron. Also the composition in fatty acids of triacylglycerols is very sensitive to the contents of cereals in the feed; for instance, polyunsaturated fatty acids may range from 10% to 22% in pork meat. The content of other nutrients, like vitamins E and A, are also depending on the type of feed. Some bioactive substances like coenzyme Q10, taurine, glutamine, creatine, creatinine, carnosine and anserine show a large dependence on the type of muscle. This manuscript describes the main factors affecting the composition of pork meat nutrients and how these changes may affect the general food composition databases. 23333907 Cryptotanshinone and dihydrotanshinone I exhibit strong inhibition towards human liver microsome (HLM)-catalyzed propofol glucuronidation. Danshen is one of the most famous herbs in the world, and more and more danshen-prescribed drugs interactions have been reported in recent years. Evaluation of inhibition potential of danshen's major ingredients towards UDP-glucuronosyltransferases (UGTs) will be helpful for understanding detailed mechanisms for danshen-drugs interaction. Therefore, the aim of the present study is to investigate the inhibitory situation of cryptotanshinone and dihydrotanshinone I towards UGT enzyme-catalyzed propofol glucuronidation. In vitro the human liver microsome (HLM) incubation system was used, and the results showed that cryptotanshinone and dihydrotanshinone I exhibited dose-dependent inhibition towards HLM-catalyzed propofol glucuronidation. Dixon plot and Lineweaver-Burk plot showed that the inhibition type was best fit to competitive inhibition type for both cryptotanshinone and dihydrotanshinone I. The second plot using the slopes from the Lineweaver-Burk plot versus the concentrations of cryptotanshinone or dihydrotanshinone I was employed to calculate the inhibition parameters (Ki) to be 0.4 and 1.7μM, respectively. Using the reported maximum plasma concentration (Cmax), the altered in vivo exposure of propofol increased by 10% and 8.2% for the co-administration of dihydrotanshinone I and cryptotanshinone, respectively. All these results indicated the possible danshen-propofol interaction due to the inhibition of dihydrotanshinone I and cryptotanshinone towards the glucuronidation reaction of propofol. 23298614 Polyethylenimine combined with liposomes and with decreased numbers of primary amine residues strongly enhanced therapeutic antiviral efficiency against herpes simplex virus type 2 in a mouse model. The development of antiviral agents that have novel mechanisms of action is urgently required in the topical therapy of herpes simplex virus type 2 (HSV-2) infections. We reported previously that topical application of branched 3610-Da polyethylenimine (PEI) exhibited preventative antiviral activity. In this study, to develop therapeutic anti-HSV-2 agents, the most potent PEI combined with ~200 nm-sized liposomes with or without oleic acid (liposomes/PEI) was selected in vitro and further evaluated using in vivo studies. The mechanism of action in vivo was elucidated using PEIs with decreased numbers of primary amine residues, resulting from ethylene carbonate treatment, and polyallylamine, a linear polyamine consisting of primary amines. Cytotoxicity and antiviral activity in vitro, and the appearance of acute herpetic disease and virus yields in mice intravaginally administered with liposomes/PEI were evaluated in cell culture assays and a mouse genital herpes model, respectively. In addition, the cellular association of liposome/PEI was examined by flow cytometry and confocal microscopy. PEI showed higher antiviral activity postinfection than preinfection in vivo. Liposome/PEI and PEI with decreased numbers of primary amine residues at a dose of 0.2 mg PEI/mouse exhibited more potent therapeutic antiviral activity than acyclovir and PEI alone without acute lesion appearance or toxicity pre- or postinfection, but polyallylamine was moderately effective only preinfection. Liposome concentrations were important for the effectiveness of liposome/PEI. This finding suggests that PEI combined with liposomes and with slightly decreased numbers of primary amines may be an effective vaginally administrated antiviral drug, and secondary and tertiary amine residues of PEI may contribute to the inhibitory efficiency against viral infection. 23567039 Identification of microcystins in a Lake Victoria cyanobacterial bloom using LC-MS with thiol derivatization. Microcystins are cyclic heptapeptides from cyanobacteria which are responsible for poisonings of livestock and humans. Cyanobacteria also produce a range of peptides and other compounds that can result in complex chromatograms when samples are analysed by LC-MS. Thiol derivatization of the α,β-unsaturated amide present in most microcystins was recently shown to simplify analysis of LC-MS chromatograms of a Microcystis culture, making it easier to identify peaks corresponding to microcystins in complex mixtures. This method was applied to analysis of extracts taken from a natural cyanobacteria bloom in Mwanza Gulf, Lake Victoria, Tanzania, in 2010, revealing the presence of numerous putative microcystin analogues in the sample. Results were verified using LC-MS(2), LC-MS/MS with precursor-ion scanning, and LC-HRMS, leading to identification of 8 major and 17 minor microcystins in the sample, including analogues of microcystin-RY, -RL and -RA. Microcystin-YR (2), -RR (3), and -RY (9) were isolated from bloom material from Lake Victoria, and the structure of 9 was confirmed by NMR spectroscopic analysis and NMR spectral comparison with 2 and 3. Confirmation of the structure of MC-RY (9) facilitated detailed analysis of its MS(2) spectrum, thereby supporting the structures of related analogues tentatively established on the basis of MS analyses. 23636640 Enhanced beta cell function and anti-inflammatory effect after chronic treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin in an advanced-aged diet-induced obesity mouse model. AIMS/HYPOTHESIS: Studies have shown that dipeptidyl peptidase-4 (DPP4) inhibitors stimulate insulin secretion and increase beta cell mass in rodents. However, in these models hyperglycaemia has been induced early on in life and the treatment periods have been short. To explore the long-term effects of DPP4 inhibition on insulin secretion and beta cell mass, we have generated a high-fat diet (HFD)-induced-obesity model in mice of advanced age (10 months old). METHODS: After 1 month of HFD alone, the mice were given the DPP4 inhibitor vildagliptin for a further 11 months. At multiple time points throughout the study, OGTTs were performed and beta cell area and long-term survival were evaluated. RESULTS: Beta cell function and glucose tolerance were significantly improved by vildagliptin with both diets. In contrast, in spite of the long treatment period, beta cell area was not significantly different between vildagliptin-treated mice and controls. Mice of advanced age chronically fed an HFD displayed clear and extensive pancreatic inflammation and peri-insulitis, mainly formed by CD3-positive T cells, which were completely prevented by vildagliptin treatment. Chronic vildagliptin treatment also improved survival rates for HFD-fed mice. CONCLUSIONS/INTERPRETATION: In a unique advanced-aged HFD-induced-obesity mouse model, insulin secretion was improved and the extensive peri-insulitis prevented by chronic DPP4 inhibition. The improved survival rates for obese mice chronically treated with vildagliptin suggest that chronic DPP4 inhibition potentially results in additional quality-adjusted life-years for individuals with type 2 diabetes, which is the primary goal of any diabetes therapy. 23425969 Synthesis, in vitro antiplatelet activity and molecular modelling studies of 10-substituted 2-(1-piperazinyl)pyrimido[1,2-a]benzimidazol-4(10H)-ones. The multistep preparation of the new 10-substituted 2-(1-piperazinyl)pyrimido[1,2-a]benzimidazol-4(10H)-ones 6a-o, and of the two isomers 10-ethyl-2-(diethylamino)pyrimido[1,2-a]benzimidazol-4(10H)-one 6p and 10-ethyl-4-(diethylamino)pyrimido[1,2-a]benzimidazol-2(10H)-one 13, as well as the in vitro evaluation of their inhibitory activity on human platelet aggregation induced in platelet-rich plasma by ADP, collagen or the Ca(2+) ionophore A23187 were here described. Nine out of fifteen 2-(1-piperazinyl)derivatives (6g-o) showed good inhibitory properties towards all the platelet aggregation agonists used. Moreover, a molecular modelling study has been performed on two of the best compounds of this series (6i and 6o) to confirm in silico their interactions with the catalytic site of human platelet PDE3, using the X-ray data of the PDE3B isoform in complex with an inhibitor. 23311288 Hypoxia-selective O6-alkylguanine-DNA alkyltransferase inhibitors: design, synthesis, and evaluation of 6-(benzyloxy)-2-(aryldiazenyl)-9H-purines as prodrugs of O6-benzylguanine. O(6)-Alkylguanine-DNA alkyltransferase (AGT) is a DNA repair protein which removes alkyl groups from the O-6 position of guanine, thereby providing strong resistance to anticancer agents which alkylate this position. The clinical usefulness of these anticancer agents would be substantially augmented if AGT could be selectively inhibited in tumor tissue, without a corresponding depletion in normal tissue. We report the synthesis of a new AGT inhibitor (5c) which selectively depletes AGT in hypoxic tumor cells. 23025922 Phospholipases A2: unveiling the secrets of a functionally versatile group of snake venom toxins. Phospholipases A(2) (PLA(2)s) are abundant components of snake venoms, where they play toxic and digestive roles. Despite having a similar three-dimensional structure, venom PLA(2)s exert an amazing variety of toxic and pharmacological effects, which include neurotoxic, myotoxic, hemolytic, edematogenic, hyperalgesic, pro-inflammatory, hypotensive, platelet-aggregation inhibitory, anticoagulant, cytotoxic, and bactericidal activities. Toxinologists have made significant contributions to deciphering the structure, molecular evolution, mechanisms of action, receptors, role of enzymatic activity for toxicity, structural determinants of toxicity and selectivity, and the impact of these enzymes in the overall pathophysiology of snakebite envenoming. The present work highlights some of the most relevant contributions in the study of venom PLA(2)s, including the personal accounts of the authors of these studies. 23152439 Hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism: a systematic review of the literature. Hungry bone syndrome (HBS) refers to the rapid, profound, and prolonged hypocalcaemia associated with hypophosphataemia and hypomagnesaemia, and is exacerbated by suppressed parathyroid hormone (PTH) levels, which follows parathyroidectomy in patients with severe primary hyperparathyroidism (PHPT) and preoperative high bone turnover. It is a relatively uncommon, but serious adverse effect of parathyroidectomy. We conducted a literature search of all available studies reporting a 'hungry bone syndrome' in patients who had a parathyroidectomy for PHPT, to identify patients at risk and address the pitfalls in their management. The severe hypocalcaemia is believed to be due to increased influx of calcium into bone, due to the sudden removal of the effect of high circulating levels of PTH on osteoclastic resorption, leading to a decrease in the activation frequency of new remodelling sites and to a decrease in remodelling space, although there is no good documentation for this. Various risk factors have been suggested for the development of HBS, including older age, weight/volume of the resected parathyroid glands, radiological evidence of bone disease and vitamin D deficiency. The syndrome is reported in 25-90% of patients with radiological evidence of hyperparathyroid bone disease vs only 0-6% of patients without skeletal involvement. There is insufficient data-based evidence on the best means to treat, minimise or prevent this severe complication of parathyroidectomy. Treatment is aimed at replenishing the severe calcium deficit by using high doses of calcium supplemented by high doses of active metabolites of vitamin D. Adequate correction of magnesium deficiency and normalisation of bone turnover are required for resolution of the hypocalcaemia which may last for a number of months after successful surgery. Preoperative treatment with bisphosphonates has been suggested to reduce post-operative hypocalcaemia, but there are to date no prospective studies addressing this issue. 23455059 Platinum(II) complexes with mono-aminophosphonate ester targeting group that induce apoptosis through G1 cell-cycle arrest: Synthesis, crystal structure and antitumour activity. Six new platinum(II) complexes with mono-aminophosphonate ester were synthesized and characterized by elemental analysis, (1)H NMR, ESI-MS as well as single crystal X-ray diffraction analysis. They are mononuclear structures. In all the crystal structures of complexes 1-6, the platinum centre adopts an approximately square-planar geometry, which were found to possess excellent solubility in both organic solvents and water and exhibit considerable cytotoxicity against MG-63, SK-OV-3 and HepG2 cell lines, but low cytotoxicity towards normal human liver cell HL-7702. In contrast to cisplatin, their antitumour activities are achieved through the induction of cell apoptosis by G1 cell-cycle arrest. 23628481 A proteome-wide visual screen identifies fission yeast proteins localizing to DNA double-strand breaks. DNA double-strand breaks (DSBs) are a major threat to genome integrity. Proteins involved in DNA damage checkpoint signaling and DSB repair often relocalize and concentrate at DSBs. Here, we used an ORFeome library of the fission yeast Schizosaccharomyces pombe to systematically identify proteins targeted to DSBs. We found 51 proteins that, when expressed from a strong exogenous promoter on the ORFeome plasmids, were able to form a distinct nuclear focus at an HO endonuclease-induced DSB. The majority of these proteins have known connections to DNA damage response, but few have been visualized at a specific DSB before. Among the screen hits, 37 can be detected at DSBs when expressed from native promoters. We classified them according to the focus emergence timing of the endogenously tagged proteins. Eight of these 37 proteins are yet unnamed. We named these eight proteins DNA-break-localizing proteins (Dbls) and performed preliminary functional analysis on two of them, Dbl1 (SPCC2H8.05c) and Dbl2 (SPCC553.01c). We found that Dbl1 and Dbl2 contribute to the normal DSB targeting of checkpoint protein Rad26 (homolog of human ATRIP) and DNA repair helicase Fml1 (homolog of human FANCM), respectively. As the first proteome-wide inventory of DSB-localizing proteins, our screen result will be a useful resource for understanding the mechanisms of eukaryotic DSB response. 23411327 Determination of tartrazine in beverage samples by stopped-flow analysis and three-way multivariate calibration of non-linear kinetic-spectrophotometric data. The performance of MCR-ALS was studied in the modeling of non-linear kinetic-spectrophotometric data acquired by a stopped-flow system for the quantitation of tartrazine in the presence of brilliant blue and sunset yellow FCF as possible interferents. In the present work, MCR-ALS and U-PCA/RBL were firstly applied to remove the contribution of unexpected components not included in the calibration set. Secondly, a polynomial function was used to model the non-linear data obtained by the implementation of the algorithms. MCR-ALS was the only strategy that allowed the determination of tartrazine in test samples accurately. Therefore, it was applied for the analysis of tartrazine in beverage samples with minimum sample preparation and short analysis time. The proposed method was validated by comparison with a chromatographic procedure published in the literature. Mean recovery values between 98% and 100% and relative errors of prediction values between 4% and 9% were indicative of the good performance of the method. 23411238 A nanosilver-based spectrophotometry method for sensitive determination of tartrazine in food samples. A new method is reported for sensitive determination of tartrazine in the food samples. The method is based on the catalytic effect of silver nanoparticle (AgNPs) on the oxidation reaction of tartrazine by potassium iodate in the acetate buffer medium. The reaction is followed spectrophotometrically by measuring the change in absorbance (ΔA) at 420 nm using a fixed time method (70 s). The reaction variables were optimised in order to achieve the highest sensitivity. The thirty six criterion detection limit was 0.3 ng/mL, and the relative standard deviation for ten replicate measurements of 30 ng/mL of tartrazine was 0.98% (n=10). The method was successfully applied to the determination of tartrazine in lemon, and papaya-flavoured gelatin, candy, and in fruit syrup. 23564645 Detection of Statin Cytotoxicity Is Increased in Cells Expressing the OATP1B1 Transporter. Cytotoxicity of a compound is determined by the intracellular concentration mediated both by passive permeability and active uptake through drug transporters. However, the major liver uptake transporters were either absent or expressed at significantly lower levels in human liver cell lines than in human liver. When comparing cytotoxicity of five statins, the organic anion transporting polypeptide 1B1 (OATP1B1) expressing HEK cells showed a significantly higher sensitivity than the wild-type HEK cells. The IC50 shifts ranged from 9- to >100-fold, and the potency shifts collapsed in the presence of rifampicin, the inhibitor for OATPs. The extent of the IC50 shift correlated with the permeability of the statins with high permeable compounds having smaller shifts and low permeable compounds having larger shifts. The changes in statin potency in transporter transfected cells reflect the active uptake of statins into the cells and the increased intracellular drug concentration lead to increased toxicity. The data suggested that uptake transporters have a significant impact on the outcomes of a cell-based assay and should be considered during the early stages of compound toxicity screening in drug discovery. For compounds with low permeability which are likely to undergo transporter-mediated uptake, it is important to test them in transporter-competent cell models. 23167767 Fabrication of 3-dimensional cellular constructs via microstereolithography using a simple, three-component, poly(ethylene glycol) acrylate-based system. A novel method for the production of inhibitor- and solvent-free resins suitable for three-dimensional (3D) microstereolithography is reported. Using an exemplar poly(ethylene glycol)-based resin, the control of features in the X, Y, and Z planes is demonstrated such that complex structures can be manufactured. Human mesenchymal stem cells cultured on the manufactured scaffolds remained viable during the 7 day assessment period, with proliferation rates comparable to those observed on tissue culture polystyrene. These data suggest that this novel, yet simple, method is suitable for the production of 3D scaffolds for tissue engineering and regenerative medicine applications. 23313794 Effects of 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP) on histopathology, oxidative stress, and expression of c-fos, c-jun and p16 in rat stomachs. 2-Amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP) is one of the most abundant heterocyclic amines (HCAs) generated from overcooking meat at high temperatures. To understand the possible mechanism of PhIP-associated stomach cancer, the effects of PhIP on morphology, oxidative stress, gene expression of c-fos, c-jun and p16 in rat stomachs were investigated. The results showed that (1) 15mg/kg body weight PhIP induced obvious histopathological changes in gastric mucosa; (2) PhIP (10 and/or 15mg/kg) significantly decreased superoxide dismutase (SOD) and glutathioneperoxidase (GPx) activities, while increased catalase (CAT) activity compared with the control. With the elevated doses of PhIP, malondialdehyde (MDA) contents, protein carbonyl (PCO) contents and DNA-protein crosslinks (DPC) coefficients were significantly raised in a dose-dependent manner; (3) PhIP at the doses of 10mg/kg and/or 15mg/kg significantly inhibited p16 mRNA and protein expression, whereas enhanced c-fos and c-jun expression relative to control. The data indicated that PhIP could cause stomach injury, oxidative stress in rat stomachs as well as the activation of c-fos and c-jun and inactivation of p16, which may play a role in the pathogenesis of PhIP-associated stomach cancer. 23454269 A cell-penetrating peptide suppresses the hypoxia inducible factor-1 function by binding to the helix-loop-helix domain of the aryl hydrocarbon receptor nuclear translocator. The heterodimeric hypoxia inducible factor-1 (HIF-1) complex is composed of the hypoxia inducible factor-1 alpha (HIF-1α) and the aryl hydrocarbon receptor nuclear translocator (ARNT). Activation of the HIF-1 function is essential for tumor growth and metastasis. We previously showed that transfection of a plasmid containing an ARNT-interacting peptide (Ainp1) cDNA suppresses the HIF-1 signaling in Hep3B cells. Here we generated TAT fusion of the Ainp1 peptide (6His-TAT-Ainp1) to determine whether and how the Ainp1 peptide suppresses the HIF-1 function. The bacterially expressed 6His-TAT-Ainp1 was purified under denatured condition and then refolded by limited dialysis. The refolded 6His-TAT-Ainp1 interacts with the helix-loop-helix (HLH) domain of ARNT in a similar fashion as the native 6His-Ainp1. 6His-TAT-Ainp1 colocalizes with ARNT in the nucleus of HeLa and Hep3B cells after protein transduction. The transduced protein reaches the maximum intracellular levels within 2h while remains detectable up to 96h in HeLa cells. At 2μM concentration, 6His-TAT-Ainp1 is not cytotoxic in HeLa cells but suppresses the cobalt chloride-activated, hypoxia responsive enhancer-driven luciferase expression in a dose-dependent manner. In addition, it decreases the cobalt chloride-dependent induction of the HIF-1 target genes at both the message (vascular endothelial growth factor and aldolase C) and protein (carbonic anhydrase IX and glucose transporter 1) levels. The protein levels of HIF-1α and ARNT are not altered in the presence of 6His-TAT-Ainp1. In summary, we provided evidence to support that the Ainp1 peptide directly suppresses the HIF-1 function by interacting with the ARNT HLH domain, and in turn interfering with the heterodimerization of HIF-1α and ARNT. 23416004 Efficient synthesis of anacardic acid analogues and their antibacterial activities. Anacardic acid derivatives exhibit a broad range of biological activities. In this report, an efficient method for the synthesis of anacardic acid derivatives was explored, and a small set of salicylic acid variants synthesised retaining a constant hydrophobic element (a naphthyl tail). The naphthyl side chain was introduced via Wittig reaction and the aldehyde installed using directed ortho-metalation reaction of the substituted o-anisic acids. The failure of ortho-metalation using unprotected carboxylic acid group compelled us to use directed ortho-metalation in which a tertiary amide was used as a strong ortho-directing group. In the initial route, tertiary amide cleavage during final step was challenging, but cleaving the tertiary amide before Wittig reaction was beneficial. The Wittig reaction with protected carboxylic group (methyl ester) resulted in side-products whereas using sodium salt resulted in higher yields. The novel compounds were screened for antibacterial activity and cytotoxicity. Although substitution on the salicylic head group enhanced antibacterial activities they also enhanced cytotoxicity. 23353756 Synthesis, pharmacological evaluation and QSAR modeling of mono-substituted 4-phenylpiperidines and 4-phenylpiperazines. A series of mono-substituted 4-phenylpiperidines and -piperazines have been synthesized and their effects on the dopaminergic system tested in vivo. The structure activity relationship (SAR) revealed that the position and physicochemical character of the aromatic substituent proved to be critical for the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) in the brain of freely moving rats. In order to investigate how the structural properties of these compounds affect the response, a set of tabulated and calculated physicochemical descriptors were modeled against the in vivo effects using partial least square (PLS) regression. Furthermore, the binding affinities to the dopamine D2 (DA D2) receptor and monoamine oxidase A (MAO A) enzyme were determined for a chosen subset and QSAR models using the same descriptors as in the in vivo model were produced to investigate the mechanisms leading to the observed DOPAC response. These models, in combination with a strong correlation between the levels of striatal DOPAC and the affinities to DA D2 and MAO A, provides a comprehensive understanding of the biological response for compounds in this class. 23319166 Steady and out-of-equilibrium phase diagram of a complex fluid at the nanolitre scale: combining microevaporation, confocal Raman imaging and small angle X-ray scattering. We engineered specific microfluidic devices based on the pervaporation of water through a PDMS membrane, to formulate continuous and steady concentration gradients of a binary aqueous molecular mixture at the nanolitre scale. In the case of a model complex fluid (a triblock copolymer solution), we demonstrate that such a steady gradient crosses the phase diagram from pure water up to a succession of highly viscous mesophases. We then performed in situ spatially resolved measurements (confocal spectroscopy and small-angle X-ray scattering) to quantitatively measure the concentration profile and to determine the microstructure of the different textures. Within a single microfluidic channel, we thus screen quantitatively and continuously the phase diagram of a complex fluid. Beside, as such a gradient corresponds to an out-of-equilibrium regime, we also extract from the concentration measurement a precise estimate of the collective diffusion coefficient of the mixture as a function of the concentration. In the present case of the triblock copolymer, this transport coefficient features discontinuities at some phase boundaries, which have never been observed before. 23521043 Peak forces in high-resolution imaging of soft matter in liquid. The maximum force exerted by the tip of a force microscope on the sample surface is a critical factor that determines the spatial resolution and the degree of invasiveness of the measurement, in particular, on soft materials. Here we determine the conditions needed to image soft matter in the 30-500 MPa range while applying very small forces. Imaging at sub-50 pN in the elastic regime can only be achieved under strict conditions in terms of force constant values (below 0.1 N/m) and free amplitudes (below 2 nm). The peak force depends on the operational parameters, probe properties, the elastic and/or viscoelastic response of the sample, and the contact mechanics model. Images of heterogeneous samples are never taken at a constant peak force. Under the same operational conditions, smaller forces are obtained on the more compliant materials. We also find that the viscoelastic response reduces the peak force with respect to the purely elastic regions. Our findings are summarized in three-dimensional maps that contain the operational conditions for imaging at low forces. 23530617 Self-assembly of DNA rings from scaffold-free DNA tiles. We report a scaffold-free approach in which four- and six-helix DNA bundle units, assembled from a small number of single stranded DNA oligonucleotides precisely arranged in networks of contiguous and semicrossover strands, are connected into DNA nano rings. Nearly uniform structures with well-defined diameters of 53 ± 7, 81 ± 9, 85 ± 8, and 166 ± 13 nm were achieved by introducing uniform, in-plane curvature to the repeating units. We demonstrate that precise higher order assemblies can be achieved by fine tuning the particular features of the individual building blocks. 23179350 Retraction note to: The effect of lead acetate toxicity on experimental male albino rat. Retraction to: Biol Trace Elem Res 144(1–3):1120–1132, DOI 10.1007/s12011-011-9149-z. Article has been retracted due to duplicate publication. 23311668 Fine Needle Aspiration of Thyroid Nodules with Macrocalcification. Background: The presence of microcalcification is highly suggestive of malignancy; however, the association of macrocalcification with cancer remains unclear and controversial. The purpose of this study was to evaluate the diagnostic yield and accuracy of ultrasound (US)-guided fine needle aspiration (FNA) of thyroid nodules with macrocalcification and to investigate the association between macrocalcification subtype and malignancy risk. Methods: We retrospectively reviewed sonographic findings and pathologic results of thyroid nodules with macrocalcification in patients who underwent US-guided FNA in our hospital from January 2009 through December 2010. Inclusion criteria were as follows: (a) malignant or benign nodules confirmed on histologic examination of surgical specimens after US-guided FNA and (b) nodules not histologically confirmed that were subjected to FNA at least twice and follow-up US examinations for 2 years. Thyroid nodules with macrocalcification were classified into 4 groups: smooth total (eggshell) calcification, smooth partial calcification, irregular calcification, and nodular calcification. Diagnostic yield of FNA for thyroid nodules with macrocalcification was determined by cytology. Sensitivity, specificity, and diagnostic accuracy of preoperative FNA cytology were calculated and compared with those of histologic examination of surgical specimens. Results: There were 188 nodules with macrocalcification in 167 patients; of these, 95 were benign, 80 were malignant, and 13 were nondiagnostic. Diagnostic yield of FNA for thyroid nodules with macrocalcification was 93.08%. Sensitivity, specificity, positive predictive value, and negative predictive value were 98.51%, 90.91%, 95.65%, and 96.77%, respectively. The false-positive value and false-negative value were 9.09% and 1.49%, respectively. The diagnostic accuracy was 96%. There was no statistically significant difference in the association between macrocalcification subtype and malignancy risk (P > 0.05). Conclusions: Macrocalcification associated with thyroid nodules is not a reliable criterion for malignancy. FNA of thyroid nodules with macrocalcification had significantly high diagnostic yield and reliable accuracy. Consistency between FNA and histology was almost perfect. Therefore, FNA is a good screening method for malignancy of thyroid nodules with macrocalcification. 23346856 Controlled synthesis of amino acid-based pH-responsive chiral polymers and self-assembly of their block copolymers. Leucine/isoleucine side chain polymers are of interest due to their hydrophobicity and reported role in the formation of α-helical structures. The synthesis and reversible addition-fragmentation chain transfer (RAFT) polymerization of amino acid-based chiral monomers, namely Boc-L-leucine methacryloyloxyethyl ester (Boc-L-Leu-HEMA, 1a), Boc-L-leucine acryloyloxyethyl ester (Boc-L-Leu-HEA, 1b), Boc-L-isoleucine methacryloyloxyethyl ester (Boc-L-Ile-HEMA, 1c), and Boc-L-isoleucine acryloyloxyethyl ester (Boc-L-Ile-HEA, 1d), are reported. The controlled nature of the polymerization of the said chiral monomers in N, N-dimethylformamide (DMF) at 70 °C is evident from the formation of narrow polydisperse polymers, the molecular weight controlled by the monomer/chain transfer agent (CTA) molar ratio and the linear relationship between molecular weight and monomer conversion. The resulting well-defined polymers were used as macro-CTAs to prepare corresponding diblock copolymers by RAFT polymerization of methyl (meth)acrylate monomers. Deprotection of Boc groups in the homopolymers and block copolymers under acidic conditions produced cationic, pH-responsive polymers with primary amine moieties at the side chains. The optical activity of the homopolymers and block copolymers were studied using circular dichroism (CD) spectroscopy and specific rotation measurements. The self-assembling nature of the block copolymers to produce highly ordered structures was illustrated through dynamic light scattering (DLS) and atomic force microscopy (AFM) studies. The side chain amine functionality instills pH-responsive behavior, which makes these cationic polymers attractive candidates for drug delivery applications, as well as for conjugation of biomolecules. 23202851 Synthesis, antibacterial activity and docking of 14-membered 9-O-(3-arylalkyl) oxime 11,12-cyclic carbonate ketolides. A series of 9-O-(3-aryl-2-propargyl)oxime ketolides 8 was synthesized and evaluated for in vitro antibacterial activity. Among 8, 8b-8d, and 8h-8l displayed dramatically improved potency against inducibly MLS(B)-resistant and efflux-resistant pathogens as compared to clarithromycin and azithromycin. Especially, 8i (Ar=4-isoquinolyl) possessed an MIC of 0.064 μg/mL against constitutively MLS(B)-resistant Streptococcus pneumoniae, and MICs of 0.032-0.064 μg/mL against methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus hominis. The analog 10 with a propyl linker was less effective than both the corresponding 8 and 9 containing propynyl and propenyl linkers. A docking study was performed to gain insight into the binding mode of series 8 and 9 and to rationalize the disparity found in the SAR of 8 and 9. 23541647 Synthesis and biological evaluation of Foscan(®) bile acid conjugates to target esophageal cancer cells. Porphyrins and chlorins such as Foscan® have a natural proclivity to accumulate in cancer cells. This trait has made them good candidates for photosensitizers and as imaging agents in phototherapy. In order to improve on cellular selectivity to lower post-treatment photosensitivity bile acid porphyrin bioconjugates have been prepared and investigated in esophageal cancer cells. Bile acids which are known to selectively bind to, or be readily taken up by cancer cells were chosen as targeting moieties. Synthesis of the conjugates was achieved via selective nucleophilic monofunctionalization of 5,10,15,20-tetrahydroxyphenylporphyrins with propargyl bromide followed by Cu(I) mediated cycloaddition with bile acid azides in good yields. The compounds were readily taken up by esophageal cancer cells but showed no PDT activity. 23561212 Degradation of complex carbohydrate: Immobilization of pectinase from Bacillus licheniformis KIBGE-IB21 using calcium alginate as a support. Pectinases are heterogeneous group of enzymes that catalyse the hydrolysis of pectin substances which is responsible for the turbidity and undesirable cloudiness in fruits juices. In current study, partially purified pectinase from Bacillus licheniformis KIBGE-IB21 was immobilized in calcium alginate beads. The effect of sodium alginate and calcium chloride concentration on immobilization was studied and it was found that the optimal sodium alginate and calcium chloride concentration was 3.0% and 0.2M, respectively. It was found that immobilization increases the optimal reaction time for pectin degradation from 5 to 10min and temperature from 45 to 55°C, whereas, the optimal pH remained same with reference to free enzyme. Thermal stability of enzyme increased after immobilization and immobilized pectinase retained more than 80% of its initial activity after 5days at 30°C as compared with free enzyme which showed only 30% of residual activity. The immobilized enzyme also exhibited good operational stability and 65% of its initial activity was observed during third cycle. In term of pectinase immobilization efficiency and stability, this calcium alginate beads approach seemed to permit good results and can be used to make a bioreactor for various applications in food industries. 23429192 The role of lipid domains in bacterial cell processes. Membranes are vital structures for cellular life forms. As thin, hydrophobic films, they provide a physical barrier separating the aqueous cytoplasm from the outside world or from the interiors of other cellular compartments. They maintain a selective permeability for the import and export of water-soluble compounds, enabling the living cell to maintain a stable chemical environment for biological processes. Cell membranes are primarily composed of two crucial substances, lipids and proteins. Bacterial membranes can sense environmental changes or communication signals from other cells and they support different cell processes, including cell division, differentiation, protein secretion and supplementary protein functions. The original fluid mosaic model of membrane structure has been recently revised because it has become apparent that domains of different lipid composition are present in both eukaryotic and prokaryotic cell membranes. In this review, we summarize different aspects of phospholipid domain formation in bacterial membranes, mainly in Gram-negative Escherichia coli and Gram-positive Bacillus subtilis. We describe the role of these lipid domains in membrane dynamics and the localization of specific proteins and protein complexes in relation to the regulation of cellular function. 23441977 Spur reactions observed by picosecond pulse radiolysis in highly concentrated bromide aqueous solutions. The formation of the well-known product Br3(-), observed in the steady-state radiolysis of highly concentrated Br(-) aqueous solutions, has now been directly observed at ultrashort times corresponding to the relaxation of the spur. The transient absorption induced by picosecond pulse radiolysis of 6 M Br(-) aqueous solution was probed simultaneously at 260 nm with the third harmonic laser wave and from 350 to 750 nm with a supercontinuum generated by the fundamental laser wave. This approach allows several transient radiolytic species to be followed in parallel, particularly the solvated electron, BrOH(-•), Br2(-•), and Br3(-). The kinetics measured within 4 ns at 260 and 370 nm clearly exhibit that the decay of Br2(•-) is correlated with the formation of Br3(-). In highly concentrated Br(-) solutions, the OH(•) radical is fully replaced by Br2(•-), and the spur kinetics of OH(•) radical in pure water is comparable with that of Br2(-•). Model calculations indicate that the main OH(•) radical combination product H2O2 in pure water has formation kinetics similar to that of Br3(-) in 6 M Br(-) solutions. Moreover, they point out that oxidation of Br(-) occurs within the electron pulse both by direct energy absorption and by scavenging of the water radical cation, H2O(•+). 23376356 PI3 k/akt inhibition induces apoptosis through p38 activation in neurons. Accumulating evidence suggests that the PI3K/AKT pathway is a pro-survival signalling system in neurons. Therefore, the inhibition of this pathway may be implicated in the degeneration of neurons in Parkinson's disease (PD), Alzheimer's disease (AD), and other neurological disorders. Here we study the participation of the mitogen-activated protein kinase (MAPK) pathway on apoptosis induced by PI3K/AKT inhibition in cultured cerebellar granule cells (CGCs). LY294002, a specific PI3K/AKT inhibitor, selectively activated the p38 MAPK kinase pathway and enhanced c-Jun phosphorylation, but did not activate JNK. The pharmacological inhibitors SB203580 (p38 inhibitor) and SP600125 (a JNK inhibitor) protected primary cultures of rat CGCs from LY294002-induced apoptosis. Furthermore, both compounds decreased the phosphorylation of c-Jun and lowered mRNA levels of the pro-apoptotic gene dp5, a direct target of c-Jun. Taken together, our data demonstrate that PI3K/AKT inhibition induces neuronal apoptosis, a process that is mediated by the activation of p38 MAPK/c-Jun/dp5. 23202372 A rechargeable room-temperature sodium superoxide (NaO2) battery. In the search for room-temperature batteries with high energy densities, rechargeable metal-air (more precisely metal-oxygen) batteries are considered as particularly attractive owing to the simplicity of the underlying cell reaction at first glance. Atmospheric oxygen is used to form oxides during discharging, which-ideally-decompose reversibly during charging. Much work has been focused on aprotic Li-O(2) cells (mostly with carbonate-based electrolytes and Li(2)O(2) as a potential discharge product), where large overpotentials are observed and a complex cell chemistry is found. In fact, recent studies evidence that Li-O(2) cells suffer from irreversible electrolyte decomposition during cycling. Here we report on a Na-O(2) cell reversibly discharging/charging at very low overpotentials (< 200 mV) and current densities as high as 0.2 mA cm(-2) using a pure carbon cathode without an added catalyst. Crystalline sodium superoxide (NaO(2)) forms in a one-electron transfer step as a solid discharge product. This work demonstrates that substitution of lithium by sodium may offer an unexpected route towards rechargeable metal-air batteries. 23165155 In vitro combined cytotoxic effects of pesticide cocktails simultaneously found in the French diet. Although human populations may be constantly exposed to complex pesticide mixtures through their diet, the human health risk of pesticide exposure is currently assessed on the basis of toxicity data on individual compounds. To investigate the combined toxic effects of pesticide cocktails previously identified in the French diet, we first studied the cytotoxicity induced by seven cocktails composed of two to six pesticides on human hepatic (HepG2) and colon (Caco-2) cell lines using the MTT and neutral red uptake assays. Secondly, we challenged to assess the combined effects of the two most cytotoxic cocktails by comparing the measured effects of the mixtures with the predictions based on additive effects on two concepts-independent action (IA) and concentration addition (CA). For the cocktail composed of dichlorodiphenyltrichloroethane (DDT) and dieldrin, the cytotoxicity of the equimolar cocktail proved greater than the additive effect estimated by the two concepts. Furthermore, apoptosis induction was higher in equimolar cocktail than predicted by summing the effects of DDT and dieldrin. Thus, some supra-additive toxicity was found in the DDT-dieldrin cocktail. Nevertheless, if IA and CA models could reveal combined effects of pesticide cocktails, an accurate evaluation remains challenging. 23569176 Minor Compensatory Changes in SAGE Mdr1a (P-gp), Bcrp, and Mrp2 Knockout Rats do not Detract from their General Utility in the Study of Transporter-mediated Pharmacokinetics. Mdr1a-, Bcrp-, and Mrp2-knockout rats are a more practical species for ADME studies than murine models and previously demonstrated expected alterations in pharmacokinetics of various probe substrates. At present, gene expression and pathology changes were systematically studied in small intestine, liver, kidney, and brain tissue from male SAGE Mdr1a-, Bcrp-, and Mrp2-knockout rats versus wild-type Sprague Dawley controls. Gene expression data supported the relevant knockout genotype. As expected, Mrp2-knockout rats were hyperbilirubinemic and exhibited upregulation of hepatic Mrp3. Overall, few alterations were observed within 112 ADME-relevant genes. The two potentially most consequential changes were upregulation of intestinal carboxylesterase in Mdr1a-knockouts and catechol-O-methyltransferase in all tissues of Bcrp-knockout rats. Previously reported upregulation of hepatic Mdr1b P-glycoprotein in proprietary Wistar Mdr1a-knockout rats was not observed in the SAGE counterpart investigated herein. Relative liver and kidney weights were 22-53% higher in all three knockouts, with microscopic increases in hepatocyte size in Mdr1a- and Mrp2-knockout rats, and glomerular size in Bcrp- and Mrp2-knockouts. Increased relative weight of clearing organs is quantitatively consistent with reported increases in clearance of drugs that are not substrates of the knocked-out transporter. Overall, SAGE knockout rats demonstrated modest compensatory changes, which do not preclude their general application to study transporter-mediated pharmacokinetics. However, until future studies elucidate the magnitude of functional change, caution is warranted in rare instances of extensive metabolism by catechol-O-methyltransferase in Bcrp-knockouts and intestinal carboxylesterase in Mdr1a-knockout rats, specifically for molecules with free catechol groups and esters subject to gut wall hydrolysis. 23419043 Chimera of IL-2 Linked to Light Chain of anti-IL-2 mAb Mimics IL-2/anti-IL-2 mAb Complexes Both Structurally and Functionally. IL-2/anti-IL-2 mAb immunocomplexes were described to have dramatically higher activity than free IL-2 in vivo. We designed protein chimera consisting of IL-2 linked to light chain of anti-IL-2 mAb S4B6 through flexible oligopeptide spacer (Gly4Ser)3. This protein chimera mimics the structure of IL-2/S4B6 mAb immunocomplexes but eliminates general disadvantages of immunocomplexes like possible excess of either IL-2 or anti-IL-2 mAb and their dissociation to antibody and IL-2 at low concentrations. This novel kind of protein chimera is characterized by an intramolecular interaction between IL-2 and binding site of S4B6 mAb similarly as in IL-2/S4B6 mAb immunocomplexes. Our protein chimera has biological activity comparable to IL-2/S4B6 mAb immunocomplexes in vitro, as shown by stimulation of proliferation of purified and activated OT-I CD8(+) T cells. The protein chimera exerts higher stimulatory activity to drive expansion of purified CFSE-labeled OT-I CD8(+) T cells activated by an injection of a low dose of SIINFEKL peptide than IL-2/S4B6 mAb immunocomplexes in vivo. 23353807 Liposomal fasudil, a rho-kinase inhibitor, for prolonged pulmonary preferential vasodilation in pulmonary arterial hypertension. Current pharmacological interventions for pulmonary arterial hypertension (PAH) require continuous infusions, multiple inhalations, or oral administration of drugs that act on various pathways involved in the pathogenesis of PAH. However, invasive methods of administration, short duration of action, and lack of pulmonary selectivity result in noncompliance and poor patient outcomes. In this study, we tested the hypothesis that encapsulation of an investigational anti-PAH molecule fasudil (HA-1077), a Rho-kinase inhibitor, into liposomal vesicles results in prolonged vasodilation in distal pulmonary arterioles. Liposomes were prepared by hydration and extrusion method and fasudil was loaded by ammonium sulfate-induced transmembrane electrochemical gradient. Liposomes were then characterized for various physicochemical properties. Optimized formulations were tested for pulmonary absorption and their pharmacological efficacy in a monocrotaline (MCT) induced rat model of PAH. The entrapment efficiency of optimized liposomal fasudil formulations was between 68.1±0.8% and 73.6±2.3%, and the cumulative release at 37°C was 98-99% over a period of 5 days. Compared to intravenous (IV) fasudil, a ~10 fold increase in the terminal plasma half-life was observed when liposomal fasudil was administered as aerosols. The t1/2 of IV fasudil was 0.39±0.12 h. and when given as liposomes via pulmonary route, the t1/2 extended to 4.71±0.72 h. One h after intratracheal instillation of liposomal fasudil, mean pulmonary arterial pressure (MPAP) was reduced by 37.6±5.7% and continued to decrease for about 3 h, suggesting that liposomal formulations produced pulmonary preferential vasodilation in MCT induced PAH rats. Overall, this study established the proof-of-principle that aerosolized liposomal fasudil is a feasible option for a non-invasive, controlled release and pulmonary preferential treatment of PAH. 23178950 Combination chemotherapy using core-shell nanoparticles through the self-assembly of HPMA-based copolymers and degradable polyester. The preparation of core-shell polymeric nanoparticles simultaneously loaded with docetaxel (DTXL) and doxorubicin (DOX) is reported herein. The self-assembly of the aliphatic biodegradable copolyester PBS/PBDL (poly(butylene succinate-co-butylene dilinoleate)) and HPMA-based copolymers (N-(2-hydroxypropyl)methacrylamide-based copolymers) hydrophobically modified by the incorporation of cholesterol led to the formation of narrow-size-distributed (PDI<0.10) sub-200-nm polymeric nanoparticles suitable for passive tumor-targeting drug delivery based on the size-dependent EPR (enhanced permeability and retention) effect. The PHPMA provided to the self-assembled nanoparticle stability against aggregation as evaluated in vitro. The highly hydrophobic drug docetaxel (DTXL) was physically entrapped within the PBS/PBDL copolyester core and the hydrophilic drug doxorubicin hydrochloride (DOX·HCl) was chemically conjugated to the reactive PHPMA copolymer shell via hydrazone bonding that allowed its pH-sensitive release. This strategy enabled the combination chemotherapy by the simultaneous DOX and DTXL drug delivery. The structure of the nanoparticles was characterized in detail using static (SLS), dynamic (DLS) and electrophoretic (ELS) light scattering besides transmission electron microscopy (TEM). The use of nanoparticles simultaneously loaded with DTXL and DOX provided a more efficient suppression of tumor-cell growth in mice bearing EL-4 T cell lymphoma when compared to the effect of nanoparticles loaded with either DTXL or DOX separately. Additionally, the obtained self-assembled nanoparticles enable further development of targeting strategies based on the use of multiple ligands attached to an HPMA copolymer on the particle surface for simultaneous passive and active targeting and different combination therapies. 23230133 The bovine ATP-binding cassette transporter ABCG2 Tyr581Ser single-nucleotide polymorphism increases milk secretion of the fluoroquinolone danofloxacin. The bovine adenosine triphosphate-binding cassette transporter G2 (ABCG2/breast cancer resistance protein) polymorphism Tyr581Ser (Y581S) has recently been shown to increase in vitro transepithelial transport of antibiotics. Since this transporter has been extensively related to the active secretion of drugs into milk, the potential in vivo effect of this polymorphism on secretion of xenobiotics in livestock could have striking consequences for milk production, the dairy industry, and public health. Our purpose was to study the in vivo effect of this polymorphism on the secretion of danofloxacin, a widely used veterinary antibiotic, into milk. Danofloxacin (1.25 mg/kg) was administered to six Y/Y 581 homozygous and six Y/S 581 heterozygous lactating cows, and plasma and milk samples were collected and analyzed by high-performance liquid chromatography. No differences were found in the pharmacokinetic parameters of danofloxacin in plasma between the two groups of animals. In contrast, Y/S heterozygous cows showed a 2-fold increase in danofloxacin levels in milk. In addition, the pharmacokinetic elimination parameters, mean residence time and elimination half-life, were significantly lower in the milk of the animals carrying the Y/S polymorphism. These in vivo results are in agreement with our previously published in vitro data, which showed a greater capacity of the S581 variant in accumulation assays, and demonstrate, for the first time, an important effect of the Y581S single-nucleotide polymorphism on antibiotic secretion into cow milk. These findings could be extended to other ABCG2 substrates, and may be relevant for the treatment of mastitis and for the design of accurate and novel strategies to handle milk residues. 23165930 Identification, characterization, and isolation of a common progenitor for osteoclasts, macrophages, and dendritic cells from murine bone marrow and periphery. Osteoclasts are specialized bone-resorbing cells that derive from monocyte precursors. We have identified three populations of cells with high osteoclastogenic potential in murine bone marrow, which expressed the phenotype B220(-) CD3(-) CD11b(-/low) CD115(+) and either CD117(hi) , CD117(intermediate) , or CD117(low) . We have evaluated these populations for their ability to also generate macrophages and dendritic cells. At a single-cell level, the population expressing higher CD117 levels was able to generate bone-resorbing osteoclasts, phagocytic macrophages, and antigen-presenting dendritic cells in vitro with efficiencies of more than 90%, indicating that there exists a common developmental pathway for these cell types. Cells with osteoclastogenic potential also exist in blood and peripheral hematopoietic organs. Their functional meaning and/or their relationship with bone marrow progenitors is not well established. Hence, we characterized murine peripheral cell populations for their ability to form osteoclasts, macrophages, and dendritic cells in vitro. The spleen and peripheral blood monocyte progenitors share phenotypic markers with bone marrow progenitors but differ in their expression of CD11b, which was low in bone marrow but high in periphery. We propose that circulating monocyte progenitors are derived from a common bone marrow osteoclasts/macrophage/dendritic cell progenitor (OcMDC), which we have now characterized at a clonal level. However, the lineage relationship between the bone marrow and peripheral monocyte progenitors has yet to be defined. © 2013 American Society for Bone and Mineral Research. 23184572 An artificial neural network approach to improving the correlation between protein energetics and the backbone structure. Computational approaches to modeling protein structures have made significant advances over the past decade. However, the current limitation in modeling protein structures is to produce protein structures consistently below the limit of 6 Å compared to their native structure. Therefore, improvement of protein structures consistently below the 6 Å limit using simulation of biophysical forces is of significant interest. Current protein force fields such as those implemented in CHARMM, AMBER, and NAMD have been deemed complete, yet their use in ab initio approaches to protein structure determination has been unsuccessful. Here, we introduce a new approach in evaluation of protein structures based on analysis of energy profiles produced by the SCOPE software package. The latest version of SCOPE produces a hydrogen bond profile that is substantially more informative than a single hydrogen bond energy value. We demonstrate how analysis of SCOPE's energy profile by an artificial neural network shows a significant improvement compared to the traditional force-based approaches to evaluation of structures. The artificial neural network based analysis of SCOPE's energy profile showed identification of structures to within the range of 1.5-3.0 Å of the native structure. These results have been obtained by testing structures in the same Homology, Topology, Architecture, or Class of the CATH family. 23432060 Transient Receptor Potential (TRP) Channels and Cardiac Fibrosis. Cardiac fibrosis is associated with most cardiac diseases. Fibrosis is an accumulation of excessive extracellular matrix proteins (ECM) synthesized by cardiac fibroblasts and myofibroblasts. Fibroblasts are the most prevalent cell type in the heart, comprising 75% of cardiac cells. Myofibroblasts are hardly present in healthy normal heart tissue, but appear abundantly in diseased hearts. Cardiac fibroblasts are activated by a variety of pathological stimuli, such as myocardial injury, oxidative stress, mechanical stretch, and elevated autocrine-paracrine mediators, thereby undergoing proliferation, differentiation to myofibroblasts, and production of various cytokines and ECM proteins. A number of signaling pathways and bioactive molecules are involved and work in concert to activate fibroblasts and myofibroblasts in the fibrogenesis cascade. Fibroblasts and myofibroblasts are not only principal ECM producers, but also play a central role in fibrogenesis and myocardial remodeling in fibrotic heart disease. Thus, understanding the biological processes of cardiac fibroblasts will provide novel insights into the underlying mechanisms of fibrosis and provide potential targets for developing antifibrotic drugs. Recent studies demonstrate that Ca2+ signal is essential for fibroblast proliferation, differentiation, and ECM-protein production. This review focuses on the recent advances in understanding molecular mechanisms of Ca2+ signaling in cardiac fibrogenesis, and potential role of Ca2+-permeable channels, in particular, the transient potential (TRP) channels in fibrotic heart disease. TRP channels are highly expressed in cardiac fibroblasts. TRPM7 has been shown to be essential in TGFβ1 mediated fibrogenesis, and TRPC3 has been demonstrated to play an essential role in regulating fibroblast function. Thus, the Ca2+-permeable TRP channels may serve as potential novel targets for developing anti-fibrotic drugs. 23276138 Deregulation of HOX B13 expression in urinary bladder cancer progression. Urinary bladder cancer is a common malignancy in industrialized countries. More than 90% of bladder cancer originates in the transitional cells. Bladder transitional cancer prognosis is, according to the most recent definition related to the level of tumor infiltration, characterized by two main phenotypes, Non Muscle Invasive Bladder Transitional Cancer (NMIBC) and Muscle Invasive Bladder Transitional Cancer (MIBC). The genetic profile and the clinical course of the two subtypes are completely different, however among NMIBC the prognosis is not completely predictable, since 20% of the cases experience a relapse, even in the form of MIBC. It has recently been reported that the chromosomal region 12q13-15, containing crucial cancer genes such as MDM2, CDK4, GLI and an entire cluster of HOX genes, is amplified in bladder cancer. HOX genes codify for transcriptionl factor, involved in embryonal development and cancer progression, with main nuclear expression. Particularly it was also described the strong involvement of HOX B13 in several tumors of urogenital system. In this study we have been investigated, by immunohistochemisty and quantitative Real Time PCR, the HOX B13 expression in bladder cancer evolution and progression, evaluating its ability to discriminate between NMIBC and MBCI phenotypes. Cytoplasmic HOX B13 delocalization significantly relates with muscle invasion (p 0.004). In addition in the series of NMIBC nuclear HOX B13 expression loss is significantly associated to shorter disease free survival (p-value=0.038) defining a potential prognostic role. Overexpression of HOX B13 in more aggressive phenotype is also demonstrate at gene level by quantitative RT-PCR. The de-regulation and delocalization of HOX B13 in urinary bladder cancer supports again the important role of HOX genes in tumor evolution and represents a starting point to establish an integrated analysis, in which HOX genes represent important prognostic and predictive markers for bladder cancer. 23337386 The hidden quality gap in discovery. Progress made through technological advances in drug discovery can be undermined by problems with measurement equipment, but it is often difficult to detect the issues without a specific investigation. This article describes the fundamentals of measurement systems analysis and focuses on the issue of precision. Three case studies are given where measurement systems were found to be flawed when subjected to a systematic analysis, and examples of the approaches needed for correction are described. 23505123 Sorting out Semiconducting Single-Walled Carbon Nanotube Arrays by Washing off Metallic Tubes Using SDS Aqueous Solution. Semiconducting single-walled carbon nanotube (s-SWNT) arrays are produced via a procedure analogous to a surfactant-assisted decontamination process. Aligned individual SWNT arrays grow on a quartz surface as a mixture of metallic SWNTs (m-SWNTs) and s-SWNTs. They are immersed in a sodium dodecyl sulfate (SDS) solution, and the SDS molecules selectively adsorb onto m-SWNTs. This SDS coating minimizes the interaction between m-SWNTs and the substrate, thus the m-SWNTs are easily washed off during ultrasonication while the s-SWNT arrays remain on the substrate. The percentage of s-SWNTs in the arrays can be higher than 90%. 23646356 Can mitochondrial dysfunction be initiated by dissociative electron attachment to xenobiotics? Resonance attachment of low-energy electrons to xenobiotic molecules, 2,4-dichlorophenoxyacetic acid (), dichlorodiphenyltrichloroethane () and dichlorodiphenyldichloroethylene (), was investigated under gas-phase conditions by means of complementary experimental techniques. Electron transmission spectroscopy (ETS) and dissociative electron attachment spectroscopy (DEAS), in the 0-6 eV and 0-15 eV energy range, respectively, were applied with the aim of modeling the behavior of these pesticide molecules under reductive conditions in vivo. Formation of long-lived parent molecular anions and fragment negative ions was observed at incident electron energies very close to zero, in agreement with the results of density functional theory calculations. The gas-phase DEA process, analogous to dissociative electron transfer in solution, was considered as a model for the initial step which occurs in the intermembrane space of mitochondria when a xenobiotic molecule captures an electron "leaked" from the respiratory chain. A possible involvement of the fragments produced by DEA to the pesticides under investigation into cellular processes is discussed. It is concluded that the free radicals and potential DNA adducts formed by DEA are expected to be dangerous for mitochondrial functionalities, while several of the products observed could act as messenger molecules, thus interfering with the normal cellular signaling pathways. 23421757 p53-mediated autophagy adjustment is involved in the protection of silibinin against murine dermal inflammation and epidermal apoptosis induced by UVB irradiation. Apoptosis in murine dermal cells is retarded by ultraviolet B (UVB) irradiation-induced autophagic intervention while simultaneously epidermal cells commit apoptosis, during which inflammatory cytokines released from the lost epidermal cells promote immune responses of dermal inflammatory cells, forming morphological symptoms of acute cutaneous diseases. Autophagy is involved in prevention or provocation of apoptosis of dermal or epidermal cells of UVB-irradiated mice via modulation of intracellular metabolism, intervening the balance between cell death and survival in dermis and epidermis. p53 expressed in immune system affects autophagy function through activating or inactivating genes encoding apoptotic factors and inflammatory cytokines. Silibinin protects dermal and epidermal cells of UVB irradiated skin against abnormally autophagy-mediated apoptosis adjustments. In this study, how UVB irradiation intervenes autophagy in dermal and epidermal cells as well as how silibinin protects UVB irradiated skin through physiological recovering of autophagy function in dermis and epidermis are focused and elucidated preliminarily. Silibinin treatment (50 mg/kg/day for 4 days) reversed dermal and epidermal autophagy levels from UVB irradiation-induced improper autophagy intervention, repaired the balance between cell survival and death in dermis and epidermis, and protected skin against damage through mediation of p53 activation in dermal and epidermal cells. 23249625 Pharmacological inhibition of mitochondrial carbonic anhydrases protects mouse cerebral pericytes from high glucose-induced oxidative stress and apoptosis. Diabetes-associated complications in the microvasculature of the brain are caused by oxidative stress, generated by overproduction of reactive oxygen species from hyperglycemia-induced accelerated oxidative metabolism of glucose. Pericytes, essential for the viability of the microvasculature, are especially susceptible to oxidative stress. Mitochondrial carbonic anhydrases, regulators of the oxidative metabolism of glucose, determine the rate of reactive oxygen species production and inhibition of mitochondrial carbonic anhydrases rescues glucose-induced pericyte loss in the diabetic mouse brain. We hypothesized that high glucose induces intracellular oxidative stress and pericyte apoptosis and that inhibition of mitochondrial carbonic anhydrases protects pericytes from oxidative stress-induced apoptosis. To validate our hypothesis, conditionally immortalized cerebral pericyte (IPC) cultures were established from Immortomice to investigate the effect of high glucose on oxidative stress and pericyte apoptosis. The IPCs expressed pericyte markers and induced high transendothelial electrical resistance and low permeability in brain endothelial cell monolayers comparable with pericytes in primary cultures. The IPCs also secreted cytokines constitutively and in response to lipopolysaccharide similar to pericytes. High glucose caused oxidative stress and apoptosis of these cells, with both oxidative stress and apoptosis significantly reduced after mitochondrial carbonic anhydrase inhibition. These results provide the first evidence that pharmacological inhibition of mitochondrial carbonic anhydrases attenuates pericyte apoptosis caused by high glucose-induced oxidative stress. Carbonic anhydrase inhibitors have a long history of safe clinical use and can be immediately evaluated for this new indication in translational research. Thus, mitochondrial carbonic anhydrases may provide a new therapeutic target for oxidative stress-related illnesses of the brain. 23404092 HIV protease inhibitors in pregnancy : pharmacology and clinical use. The impact of antiretroviral therapy (ART) on the natural history of HIV-1 infection has resulted in dramatic reductions in disease-associated morbidity and mortality. Additionally, the epidemiology of HIV-1 infection worldwide is changing, as women now represent a substantial proportion of infected adults. As more highly effective and tolerable antiretroviral regimens become available, and as the prevention of mother-to-child transmission becomes an attainable goal in the management of HIV-infected individuals, more and more HIV-positive women are choosing to become pregnant and have children. Consequently, it is important to consider the efficacy and safety of antiretroviral agents in pregnancy. Protease inhibitors are a common class of medication used in the treatment of HIV-1 infection and are increasingly being used in pregnancy. However, several studies have raised concerns regarding pharmacokinetic alterations in pregnancy, particularly in the third trimester, which results in suboptimal drug concentrations and a theoretically higher risk of virologic failure and perinatal transmission. Drug level reductions have been observed with each individual protease inhibitor and dose adjustments in pregnancy are suggested for certain agents. Furthermore, studies have also raised concerns regarding the safety of protease inhibitors in pregnancy, particularly as they may increase the risk of pre-term birth and metabolic disturbances. Overall, protease inhibitors are safe and effective for the treatment of HIV-infected pregnant women. Specifically, ritonavir-boosted lopinavir- and atazanavir-based regimens are preferred in pregnancy, while ritonavir-boosted darunavir- and saquinavir-based therapies are reasonable alternatives. This paper reviews the use of protease inhibitors in pregnancy, focusing on pharmacokinetic and safety considerations, and outlines the recommendations for use of this class of medication in the HIV-1-infected pregnant woman. CHEMDNER_CORPUS_BIOCREATIVE_4/CHEMDNER_DEVELOPMENT/cdi_ann_development_13-08-18.txt0000644002344200234200000126677312204144742027510 0ustar mkrallingerBioinfoUnix22006095 Serotonin 22006095 serotonin 22006095 venlafaxine XR 22056334 PCBs 22056334 PCDD 22056334 dichlorodiphenyldichloroethylene 22056334 dioxins 22056334 furans 22056334 methylmercury 22056334 p,p'-DDE 22056334 polybrominated diphenyl ethers 22056334 polychlorinated biphenyls 22079313 DHA 22079313 MeHg 22079313 N3-docosahexaenoic acid 22079313 methylmercury 22082827 Cu 22082827 Fe 22082827 Ni 22082827 Pb 22082827 S 22082827 Zn 22082827 copper 22082827 glutathione 22082827 hydrogen peroxide 22082827 iron 22082827 malondialdehyde 22082827 nickel 22082827 superoxide 22082827 zinc 22236017 linalool 22236017 terpineol 22236093 3-methylthio-1-propene 22239172 Diclavatol 22239172 clavatol 22239172 dimethylated tetraketide 22239172 ethyl acetate 22239172 n-butanol 22239172 terrestric acid 22239172 tetronic acids 22239172 viridicatic acid 22273350 1,1-diphenyl-2-picrylhydrazyl 22273350 1,8-cineol 22273350 8S,13-cedran-diol 22273350 caryophyllene oxide 22273350 cubenol 22273350 curcumenol 22273350 ethyl iso-allocholate 22273350 friedeline 22273350 monoterpenes 22273350 o-cymene 22273350 sesquiterpenes 22273350 spathulenol 22273350 triterpenes 22273350 γ-cadinene 22273350 α-cadinol 22273350 β-caryophyllene 22273350 β-cubebene 22273350 β-eudesmol 22273350 β-sitosterol 22273350 α-terpineol 22301814 NaAsO2 22301814 alanine 22301814 arsenic 22301814 aspartate 22301814 bilirubin 22301814 cholesterol 22301814 creatinine 22301814 thiobarbituric acid 22301814 urea 22301815 Cortisol 22301815 Glucose 22301815 S 22301815 carbohydrate 22301815 cortisol 22301815 endosulfan 22301815 glutathione 22301815 organochlorine 22312035 AFM1 22312035 aflatoxin M1 22313530 -amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 22313530 2-amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 22313530 Glutamate 22313530 LY459477 22313530 [(3)H]LY459477 22313530 [³H]LY459477 22313530 amphetamine 22313530 glutamate 22313530 phencyclidine 22335586 ERL 100 22335586 ERS 100 22335586 eudragit RL 100 22335586 eudragit RS 100 22335586 risperidone 22348222 1,8-cineole 22348222 Trans-3(10)-caren-4-ol 22348222 artemisia ketone 22348222 monoterpene hydrocarbons 22348222 monoterpenes 22348222 sesquiterpene hydrocarbons 22348222 α-pinene 22348222 δ-selinene 22348951 GSH 22348951 GSSG 22348951 glutathione 22348951 oxidized GSSG 22348951 oxygen 22348951 reduced GSH 22348951 superoxide 22352409 glucoraphanin 22352409 sulforaphane 22360570 Ser 22360570 Thr 22364642 Serratin 22364642 calcium carbonate 22364642 chloroform 22364642 dextrose 22364642 serratin 22372659 5-allosyloxy-aucubin 22372659 7-β-hydroxy-harpagide 22372659 ajugol 22372659 arbutin 22372659 harpagide 22372659 verbascoside 22372865 Metformin hydrochloride 22372865 biguanide 22372865 glucose 22372865 metformin hydrochloride 22381584 CHPG 22381584 CPA 22381584 Ca(2+) 22381584 Glutamate 22381584 LY379268 22381584 MCPG 22381584 MTEP 22381584 TEA 22381584 TTX 22381584 glutamate 22381584 potassium 22381584 thapsigargin 22391562 AR323 22391562 AR678 22400496 bibenzyls 22400496 flavonoid 22400496 steroids 22400496 terpenoid 22401710 Eudragit RS-30D 22401710 Ketoprofen 22401710 PEG 22401710 PEG 6000 22401710 PVPP 22401710 ketoprofen 22401710 lactose 22401710 mannitol 22401710 polyvinylpyrrolidone 22410775 tyrosine 22410778 ATP 22410778 adenosine triphosphate 22410778 cAMP 22410778 cyclic adenosine monophosphate 22410778 forskolin 22410778 glucose 22410778 oxygen 22424051 5,7-dihydroxy-2 -(hydroxymethyl)-6,8-dimethyl-chromen-4-one 22424051 anthraquinone 22424051 benzene 22424051 chromone 22424051 chromones 22424051 ellagic acids 22424051 flavonoid glycosides 22424051 flavonoids 22424051 melachromone 22424051 terpenes 22426233 Glutamate 22426233 cAMP 22426233 calcium 22426233 glutamate 22426233 histamine 22429027 3-O-β-D-glucopyranosyl (1→6)-[β-D-glucopyranosyl (1→2)]-β-D-glucopyranosyl, 28-O-β-D-glucopyranosyl (1→6)-[α-L-rhamnopyranosyl (1→2)]-β-D-glucopyranosyl 16-deoxybarringtogenol C 22429027 3-O-β-D-glucopyranosyl (1→6)-[β-D-glucopyranosyl (1→2)]-β-D-glucopyranosyl, 28-O-β-D-glucopyranosyl (1→6)-β-D-glucopyranosyl 16-deoxybarringtogenol C 22429027 oleanane 22429027 triterpenoid saponins 22429027 xanthohuskisides 22430206 tyrosine 22438091 AMP 22438091 Sinensetin 22438091 acetyl-CoA 22438091 cAMP 22438091 carnitine 22438091 glucose 22438091 polymethoxylated flavone 22438091 sinensetin 22438091 sterol 22438103 ethanol 22439867 (1)H 22439867 (13)C 22439867 3,5,10,14-O-tetraacetyl-8-O-(2'-methyl butanoyl)-cyclomyrsinol 22439867 3,5,10,14-O-tetracetyl-8-O-isobutanoylcyclomyrsinol 22439867 3,5,10-O-triacetyl-8-O-isobutanoyl-14-O-benzoylcyclomyrsinol 22439867 Aceton 22439867 chloroform 22439867 cyclomyrsinol diterpenes 22439867 diterpenoids 22439867 pentacyclic myrisinane polyester 22440717 17β-estradiol 22440717 estrogen 22443216 Monoterpene 22443216 germacrene D 22443216 sesquiterpene hydrocarbons 22443216 δ-3-carene 22443216 γ-cadinene 22443216 α-pinene 22443683 Ser 22443683 Thr 22443683 leucine carboxyl methyl 22443683 methyl 22443683 rapamycin 22447662 ACh 22447662 Ascorbic acid 22447662 GSH 22447662 acetylcholine 22447662 alanine 22447662 aspartate 22447662 cholesterol 22447662 creatinine 22447662 glucose 22447662 glutathione 22447662 nitric oxide 22447662 reduced glutathione 22447662 superoxide 22447662 urea nitrogen 22447684 Quercetin 22447684 cholesterol 22447684 quercetin 22447684 thiobarbituric acid 22447684 triglyceride 22451331 Triton 22451331 Triton WR1339 22451331 ethanol 22451331 fructose 22451331 triglycerides 22451331 tyloxapol 22455790 Sarmentosamide 22455790 hexadienamide 22455790 sarmentosamide 22455986 MTT 22455986 polyphenolic 22455986 sterols 22455986 γ-sitosterol 22456000 4-(4-hydroxy-phenyl)-3H-pyran-2,6-dione 22456000 Diphysidione 22456000 p-hydroxyphenyl anhydride 22456000 vitexin 22465815 Glutamate 22465815 dopamine 22465815 glutamate 22472136 arsenic 22472136 cadmium 22472136 chromium 22472136 copper 22472136 nickel 22472136 vanadium 22475036 (1)H 22475036 (13)C 22475036 1β,3β-dihydroxy-12-oleanene 22475036 5α,6α-dimethoxy-7,11,14-trioxoabieta-8,12-diene 22475036 H 22475036 abietane diterpenoid 22475036 chloroform 22475036 oleanene triterpenoid 22475036 terpenoid 22475036 xantoquinone 22475047 amide 22475047 monoterpene 22480349 betulinic acid 22480349 lanst-5, 24-dien-3β-yl acetate 22480349 lup-12, 20(29)-dien-3β-ol-26-oic acid 22480349 lup-20(29)-en-3β-ol-27-oic acid 22480349 lupeol 22480349 moruslanosteryl acetate 22480349 moruslupenoic acid A 22480349 moruslupenoic acid B 22480349 pentacyclic triterpenoids 22480349 triterpenoids 22480349 α-amyrin acetate 22480349 β-amyrin-β-D-glucopyranoside 22491024 6-hydroxydopamine 22491024 Glutamate 22491024 L-DOPA 22491024 LSP1-2111 22491024 Lu AF21934 22491024 calcium 22491024 dopamine 22491024 glutamate 22491024 haloperidol 22491024 l-DOPA 22493952 2α,3α-di-O-carbonyl-2α,3α-dihydroxytaraxer-14-en-28-oic acid 22493952 2α,3α-diacetyltaraxer-14-en-28-oic acid 22493952 2α,3α-dihydroxytaraxer-14-en-28-oic acid 22493952 2α,3α-dipropionyltaraxer-14-en-28-oic acid 22493952 3-oxo-taraxer-14-ene 22493952 3α-acetyltaraxer-14-en-28-oic acid acetate 22493952 3α-hydroxytaraxer-14-en-28-oic acid 22493952 3β-hydroxytaraxer-14-en-28-oic acid 22493952 aleuritolic acid 22493952 aleuritolic acid acetate 22493952 carboxylic acid 22493952 isoaleuritolic acid 22493952 maprounic acid 22493952 p-bromobenzyl acetylmaprounate 22493952 pentacyclic triterpenoid 22493952 stigmasterol 22493952 taraxer-14-ene 22493952 taraxerone 22493952 triterpenoids 22493952 β-sitosterol 22494026 (3R)-7,2'-dihydroxy-3',4'-dimethoxyisoflavan 22494026 (3R)-7,3'-dihydroxy-2',4'-dimethoxyisoflavan 22494026 3-O-rhamnocitrin-6-O-benzoyl-β-D-glucopyranoside 22494026 acylated flavonoid 22494026 flavonoids 22494026 flavonol 22494026 isoliquiritigenin 22494026 pratensein 22494026 rhamnocitrin 22495969 20-hydroxyecdysone 22495969 Phytoecdysteroids 22495969 phytoecdysteroids 22499272 STZ 22499272 carbohydrate 22499272 cholesterol 22499272 glucose 22499272 glucose-6 phosphate 22499272 streptozotocin 22499272 triglycerides 22503097 Griseofulvin 22503097 Naproxen 22503097 hydroxypropyl 22503097 nitrogen 22503097 sodium lauryl sulfate 22508482 H(2)O(2) 22511240 NO 22511240 fluorescein isothiocyanate 22511240 nitric oxide 22511240 oxygen 22511286 caffeine 22511286 chlorogenic acid 22511286 hydrogen peroxide 22511286 oxygen 22511286 phenolic 22511286 polyphenols 22511286 xanthine 22511286 xanthines 22511336 eosin 22511336 glucose 22511336 hematoxylin 22519721 poly (ethylene glycol) diacrylate 22519721 rhodamine B 22521210 estradiol 22521210 estrogen 22521210 estrogens 22524504 Fenofibrate 22524504 amino methacrylate 22524504 fenofibrate 22524504 polyvinylpyrrolidone 22524504 sugars 22525271 tyrosine 22525272 ATP 22525272 lactate 22531751 Glutamate 22531751 LY341495 22531751 LY395756 22531751 LY541850 22531751 glutamate 22532499 2-(n-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose 22532499 Glucose 22532499 Vescalagin 22532499 glucose 22532499 vescalagin 22537580 chukrasine F 22537580 chukvelutilide G 22537580 enolic acyl phragmalin 22537580 limonoid orthoesters 22537580 limonoids 22548320 1,4,8-trihydroxyxanthone 22548320 1,7-dihydroxyxanthone 22548320 DPPH 22548320 calothorexanthone 22548320 garbogiol 22548320 globuxanthone 22548320 xanthone 22548320 δ-tocotrienol 22553909 HP-β-CD 22553909 HP-β-cyclodextrin 22553909 ITR 22553909 ITRDNT 22553909 itraconazole 22553909 itraconazolium dinitrate 22553909 β-CD 22553909 β-cyclodextrin 22554350 Vitamin E 22554350 triglycerides 22554350 vitamin E 22564440 5-hydroxymethylcytosine 22564440 5-methylcytosine 22564440 CpG 22564440 clozapine 22564440 glutamic acid 22564440 valproic acid 22564442 (-)baclofen 22564442 (S)-3,4-DCPG 22564442 (S)-3,4-dicarboxyphenylglycine 22564442 (l)-AP4 22564442 3-[[(3,4-Dichlorophenyl)methyl]amino]propyl] diethoxymethyl) phosphinic acid 22564442 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one hydrochloride 22564442 8-Br-cAMP 22564442 AMN082 22564442 CGP52432 22564442 GABA 22564442 K(+) 22564442 KCl 22564442 MDL-12,330A 22564442 MMPIP 22564442 N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride 22564442 [(3)H]D-γ-aminobutyric acid 22564442 [(3)H]GABA 22564442 forskolin 22564442 glutamate 22564442 l-(+)-2-amino-4-phosphonobutyric acid 22577972 ethanol 22577972 pentacyclic triterpene 22577972 pentacyclic triterpenene 22577972 pentacyclic triterpenes 22578098 Ca(2+) 22578098 alanine 22578098 amino acid 22581512 1,8-cineole 22581512 limonene 22581512 p-cymene 22581512 α-pinene 22585412 cinnamic acid 22585412 hydroxy 22585412 p-Coumaric acid 22585412 p-coumaric acid 22591127 C14:0 22591127 C16:0 22591127 C18:1 22591127 C18:2 22591127 C18:3 22591127 FA methyl esters 22591127 FAME 22591127 Fatty acid 22591127 H 22591127 chloroform 22591127 eicosapentaenoic 22591127 fatty acid 22591127 linoleic FA 22591127 methanol 22591127 monounsaturated acid 22591127 myristic 22591127 oleic 22591127 palmitic 22591127 α-linolenic 22591175 2-hydroxypropyl-β-cyclodextrin 22591175 HPCD 22591175 puerarin 22607130 Apigenin 22607130 Capryol 22607130 Transcutol 22607130 apigenin 22610748 SCH 22610748 alanine 22610748 aspartate 22610748 bilirubin 22610748 glutathione 22610748 sesamin 22610748 superoxide 22610748 thiobarbituric acid 22614004 DCA 22614004 H(2)O(2) 22614004 dichloroacetate 22614004 glucose 22614004 prolyl 22614004 pyruvate 22614004 α-ketoglutarate 22614014 cysteine 22616839 Atorvastatin calcium 22616839 Tween 20 22616839 Tween 60 22616839 Tween 80 22616933 Astaxanthin 22616933 C40H52O4 22616933 astaxanthin 22619007 Silibinin 22619007 flavonoid 22640596 5-[(α-D-galactopyranosyloxy) methyl]-1H-pyrrole-2-carbaldehyde 22640596 6-[(α-D-galactopyranosyloxy) methyl]-3-pyridinol 22640596 alkaloid galactosides 22640596 galactose 22640596 pyridinol 22640596 pyrrole 22640631 Glutamate 22640631 glutamate 22640631 ketamine 22646532 glucose 22664304 Glutamate 22664304 glutamate 22664304 l-DOPA 22690834 adefovir 22690834 adefovir dipivoxil 22690834 nucleoside 22691039 2,3,6-tribromo-4,5-dihydroxybenzyl methyl sulphoxide 22691039 EtOH 22691039 bromobenzyl methyl sulphoxide 22691039 bromophenol 22691108 Aromadendrine 22691108 aromadendrine 22691108 dihydroflavonol 22691108 ethyl acetate 22691108 flavonoid 22691108 flavonoidic 22691108 hydroxy-phenyl-ethyl alcohols 22691108 hydroxyl-tyrosol 22691108 tyrosol 22694127 Ibuprofen 22694127 OH(-) 22694127 ibuprofen 22697341 Brij 22697341 Carbomer 22697341 Transcutol 22697341 butyl lactate 22697341 diflunisal 22703292 ABTS 22703292 DPPH 22703292 flavonoid 22703292 linoleic acid 22703292 phenol 22703292 β-carotene 22703341 Feroniellides C-E 22703341 apotirucallane triterpenoids 22703341 feroniellides A-C 22703341 feroniellides C-E 22703341 feroniellides D and E 22703341 isovalerate 22703341 triterpenoids 22705273 chloride 22708546 GFC 22708546 Garcinielliptone FC 22708546 polyisoprenylated benzophenone GFC 22708546 prenylated benzophenone 22708583 13C 22708583 1H 22708583 ABTS 22708583 DPPH 22708583 Flavones 22708583 acylated flavone glycoside 22708583 flavone 22708583 flavones 22708583 luteolin 22708583 ortho-dihydroxy 22708620 1,1-diphenyl-2-picrylhydrazyl 22708620 BHT 22708620 butylated hydroxytoluene 22708620 germacrene D 22708620 hexane 22708620 phytol 22708620 α-caryophyllene 22708620 β-caryophyllene 22708620 γ-elemene 22708620 δ-elemene 22708639 PGE2 22708639 acetylcholine 22708639 oxytocin 22708639 prostaglandin E2 22708657 13C 22708657 1β-methoxycaryol-9-one 22708657 caryolane sesquiterpene 22708724 2-methyl-5 -(3'-methyl-but-2'-enyloxy)-[1,4]naphthoquinone 22708724 miltefosine 22708724 prenyloxy-naphthoquinone 22712554 N-α-methyl-N-δ-hydroxy-N-δ-formylornithine 22712554 N-α-methyl-N-δ-hydroxyornithine 22712554 amino acids 22712554 cyclic N-hydroxyornithine 22712554 iron 22712554 ornithine 22712554 serine 22712554 tsukubachelin B 22717743 triglyceride 22718571 Gentianine 22718571 Swertiamarin 22718571 gentianine 22718571 swertiamarin 22719017 2-(2-benzofuranyl)-2-imidazoline 22719017 2-(4,5-dihydroimidazol-2-yl) quinoline hydrochloride 22719017 2-BFI 22719017 2-styryl-2-imidazoline 22719017 BU-224 22719017 LSL 60101 22719017 LSL 61122 22719017 N-methyl-D-aspartate 22719017 NMDA 22719017 Ser 22719017 idazoxan 22719017 imidazole 22719017 imidazoline 22720714 (1)H 22720714 furolactone 22720714 lignan 22720714 lyciumin 22722027 MDL 11,939 22722027 Serotonin 22722027 TCB-2 22722027 serotonin 22722028 AMN082 22722028 AMPA 22722028 MS-275 22722028 N-methly-d-aspartate 22722028 PEPA 22722028 d-cycloserine 22722028 glutamate 22722028 valproic acid 22722774 NaCl 22722774 salicylic acid 22722774 superoxide 22725249 PLGA 22725249 Poly-(lactide-co-glycolic acid) 22732147 Melamine 22732147 melamine 22732440 6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one 22732440 GABA 22732440 methyl 3,5-diphenylpyridazine-4-carboxylate 22732440 γ-aminobutyric acid 22736625 estrogen 22749926 Nicotine 22749926 acetylcholine 22749926 nicotine 22757667 Geraniol 22757667 p-cymene 22757667 α-cedrene 22761031 7-geranyloxycoumarin 22761031 AUR 22761031 Auraptene 22761031 auraptene 22761031 geranyloxycoumarin 22761031 phospho 22761042 2,2-diphenyl-1-picryhydrazyl 22761042 CHCl3 22761042 DPPH 22761042 MTT 22761042 MeOH 22761042 chloroform 22761042 methanol 22761042 n-hexane 22765351 2H 22765351 Ala-thio-Arg 22765351 Ala-thio-Lys 22765351 AtK 22765351 AtR 22765351 Gly-thio-Lys 22765351 GtK 22765351 N 22765351 N-C(α) 22765351 Thioxodipeptides 22765351 amide 22765351 aminothioketyl 22765351 ammonium 22765351 ammonium cation 22765351 fluoranthene anion-radical 22765351 hydrogen 22765351 lysine 22765351 thioenol anion-radical 22765351 thioxoamide 22766391 JNJ-39393406 22766391 acetylcholine 22788802 CO 22788802 D 22788802 D(+) 22788802 DCO(+) 22788802 DOCO(+) 22788802 H 22788802 H(+) 22788802 HCO(+) 22788802 HOCO(+) 22788802 HOD(+) 22788802 HOD+ 22788802 OD 22788802 OH 22788802 deuteron 22790339 1,3-dimethyl-2-imidazolidinone 22790339 CH3NHC2H4N(CH3)CONH2 22790339 DMEDA 22790339 DMI 22790339 N 22790339 NH 22790339 NH3 22790339 ammonia 22790339 carbon 22790339 dimethylethylenediamine 22790339 ethylenediamine 22790339 imidazolidinone 22790339 secondary ammonia 22790339 urea 22796110 acetylcholine 22796428 AHN 2-005 22796428 benztropine 22796428 dopamine 22796428 norepinephrine 22796429 NMDA 22798249 glucose 22800435 CdSe 22800435 NiAs 22800435 ZnS 22800435 wurtzite 22809709 8-OH-DPAT 22809709 DHβE 22809709 Dopamine 22809709 WAY100635 22809709 acetylcholine 22809709 dihydro-β-erythroidinehydrobromide 22809709 dopamine 22809709 mecamylamine 22809709 methyllycaconitine 22809709 nicotine 22809709 serotonin 22812637 Caesalpinolide F 22812637 Caesalpinolide G 22812637 cassane 22812637 diterpenes 22813627 DiNP 22813627 MCiOP 22813627 MHiNP 22813627 MOiNP 22813627 MiNP 22813627 MiNP-G 22813627 Monoisononyl phthalate 22813627 Testosterone 22813627 diiosononyl phthalate 22813627 diisononyl phthalate 22813627 mono(carboxy-isooctyl) phthalate 22813627 mono(hydroxyl-isononyl) phthalate 22813627 mono(oxo-isononyl) phthalate 22813627 monoisononyl phthalate glucuronide 22813627 testosterone 22815312 bupropion 22815312 carbamazepine 22815312 estradiol 22815312 methadone 22815312 rifampin 22820274 Cholesterol 22830954 clarithromycin 22830954 clopidogrel 22830954 sibutramine 22835278 DHEAS 22835278 androgen 22835278 testosterone 22837389 Estradiol 22837389 estradiol 22837389 estrogen 22837389 progesterone 22847135 MTT 22847135 Naringin 22847135 flavonoid 22847135 naringin 22849377 Na 22849377 Na(+) 22851333 adenosine 22851333 cortisol 22854821 carbon 22856387 TM-25659 22864625 B 22864625 INH 22864625 boron 22864625 carbon 22864625 isoniazid 22864849 Chrysin 22864849 GSH 22864849 apigenin 22864849 chrysin 22864849 cysteine 22864849 flavones 22864849 glutamate 22864849 glutathione 22864849 heme 22864849 hydroxyl 22864849 l-buthionine-S-sulfoximine 22864849 luteolin 22864849 oxidized GSH 22864849 oxygen 22864849 tBHP 22864849 tert-butyl hydroperoxide 22864849 zinc protoporphyrin 22867272 flurbiprofen 22867272 propranolol 22871218 KH2PO4 22871218 ginsenosides 22872142 Hg 22872142 alcohol 22872142 amalgams 22872142 methacrylates 22872606 glutathione 22872606 malondialdehyde 22872606 superoxide 22872606 thymoquinone 22876784 MEG 22876784 Methyleugenol 22876784 methyleugenol 22876943 1, 3-Diphenyl-2-propen-1-one 22876943 1, 3-diphenyl-2-propen-1-one 22876943 Chalcones 22876943 NO 22876943 carbon 22876943 chalcone 22876943 chalcones 22876943 flavonoids 22876943 heme 22876943 isoflavonoids 22876943 nitric oxide 22876943 α, β-unsaturated carbonyl 22876949 Chalcones 22876949 chalcones 22876949 flavonoids 22876949 polyphenolic 22876953 2'-O-AADPR 22876953 2'-O-acetyl-ADP-ribose 22876953 NAD 22876953 Nε-acetyl-lysine 22876953 acetyl 22876953 amide 22876953 nicotinamide 22876953 β-NAD 22876953 β-nicotinamide adenine dinucleotide 22878908 TZD 22878908 TZDs 22878908 Thiazolidinediones 22878908 estradiol 22878908 estrogen 22878908 oleic acid 22878908 pioglitazone 22878908 rosiglitazone 22878908 testosterone 22883213 C 22883213 Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-His-Gly-OH 22883213 H-His-Gly-Val-Ser-Gly-His-Gly-Gln-His-Gly-Val-His-Gly-OH 22883213 N 22883213 Phe 22883213 Phe(p-Cl) 22883213 Phe(p-OMe) 22883213 Trp 22883213 Tyr 22883213 [3-13]-alloferon 22883213 alloferon 22884111 Zn 22884111 ZnO 22884111 ammonia solution 22884111 sodium hydroxide 22884611 Adderall 22884611 amphetamine 22887780 25-OHD 22887780 25-hydroxyvitamin D 22887780 Vitamin D 22887780 lysine 22887780 nucleotide 22887780 threonine 22887780 vitamin D 22889582 epoxy 22889582 guanine 22889582 propylene oxide 22898566 DHA 22898566 EPA 22898566 Omega-3 PUFA 22898566 PUFAs 22898566 docosahexaenoic acid 22898566 eicosapentaenoic acid 22898566 hydroperoxide 22898566 omega-3 polyunsaturated fatty acids 22899102 BP phenols 22899102 BP-7,8-dihydrodiol-9,10-epoxide 22899102 BPDE 22899102 BPDE glutathione 22899102 S 22899102 benzo[a]pyrene 22899102 glutathione 22899102 sulfates 22901687 Oleuropein 22901687 corticosterone 22901687 nitrogen 22901687 noradrenaline 22901687 oleuropein 22901687 phenolic 22901687 testosterone 22902308 metformin 22902308 pravastatin 22905673 Aminofilin 22905673 Carbopol 22905673 Phyllocontin 22905673 aminophylline 22910795 Dihydrorhodamine 22910795 Hg(2+) 22910795 HgCl(2) 22910795 Mercury 22910795 N-acetylcysteine 22910795 Pb(2+) 22910795 Pb(NO(3))(2) 22910795 Rhodamine-123 22910795 mercuric 22910795 oxygen 22918489 ADP 22918489 zinc 22922115 Organophosphorus 22922115 oximes 22922115 serine 22922115 soman 22926007 S 22926007 acetylcholine 22926007 amino acid 22926007 glutathione 22926007 methylcarbamate 22926007 organophosphorus 22931187 PTZ601 22931187 [14C]PTZ601 22931187 [¹⁴C]PTZ601 22931187 di-cysteine 22935038 CORT 22935038 corticosterone 22935511 cocaine 22935610 Ser 22935610 prolyl 22936348 CH2CN 22936348 CH2NH2 22936348 CH2NO2 22936348 CH2Ph 22936348 CH3 22936348 CH3Ph 22936348 COOX 22936348 Carbon 22936348 H 22936348 carbon 22936348 carboxylic 22939001 2-amino-4,8-dihydropyrano[3,2-b]pyran-3-carbonitrile 22939001 aromatic aldehydes 22939001 kojic acid 22939001 malononitrile 22939001 transition metal 22939899 retinal 22940000 Adenosine 22940000 adenosine 22940001 CpG 22940001 methyl 22940575 kainic acid 22940575 pentylenetetrazol 22940575 pilocarpine 22948775 glucose 22948803 2-aminopyridine 22948803 N 22951949 Cu-DEDTC 22951949 DEDTC 22951949 DEDTC-copper 22951949 Diethyldithiocarbamate 22951949 Dithiocarbamates 22951949 N,N-diethyldithiocarbamate 22951949 copper 22951949 dithiocarbamates 22951949 nitrogen 22951949 sulfur 22954533 Neutral red 22954533 Silver 22954533 citrate 22954533 silver 22956628 Arsenic 22956628 Bisulfite 22956628 NaAsO(2) 22956628 arsenic 22956628 methyl 22956632 GDC-0152 22961095 Acrolein 22961095 NO 22961095 RO32-0432 22961095 acrolein 22961095 cyclophosphamide 22961095 nitrate 22961095 nitric oxide 22961095 nitrite 22963497 GnRH 22963497 Phoenixin 22963497 gonadotrophin-releasing hormone 22963497 phoenixin 22965581 Carbon 22965581 TiO(2) 22965581 carbon 22965581 oxide 22965581 titania 22966073 Cysteines 22966073 Lysine 22966073 cysteine 22966073 cysteines 22966073 disulfide 22966073 glutamate 22966073 glutamates 22966073 serine 22966073 tyrosine 22967140 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol 22967140 1H-pyrazole dihydrochloride 22967140 2,3-bis(4-hydroxyphenyl)-propionitrile 22967140 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol 22967140 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol 22967140 DPN 22967140 MPP 22967140 NADPH 22967140 PHTPP 22967140 PPT 22967140 nitric oxide 22967140 oestradiol 22967140 oestrogen 22968082 AMPH 22968082 d-amphetamine 22972752 Estrogen 22972752 estradiol 22972752 estrogen 22974972 Adenosine-monophosphate 22974972 HMG-CoA 22974972 acetyl-CoA 22974972 cholesterol 22977165 Gadodiamide 22977165 Gd 22977165 adenine 22977165 gadobenate 22977165 gadobutrol 22977165 gadodiamide 22977165 gadolinium 22977165 gadopentetate 22977165 gadoterate 22977167 O(3) 22977167 carbon black 22977167 ozone 22981459 HI-6 22981459 atropine 22981459 diazepam 22981459 organophosphorous 22981459 oxime 22981796 Cu 22981796 copper 22981796 lactate 22981796 oxygen 22982007 Mn(3)O(4) 22982007 Mn3O4 22982007 manganese(II) nitrate 22982007 potassium hydroxide 22982007 trimanganese tetraoxide 22982218 PJ34 22982218 radio-iodine 22982218 sodium iodide 22982248 MK-801 22982248 NMDA 22982479 2-aminoimidazoline 22982479 fluoxetine 22982479 guanidine 22982479 mirtazapine 22982479 noradrenaline 22982569 Tyrosine 22982776 histidine 22982776 organophosphorus 22985736 DEHP 22985736 Di 2-ethyl hexyl phthalate 22985736 Di-2-ethyl hexyl phthalate 22986488 1,25(OH)(2)D 22986488 1,25-dihydroxyvitamin D 22986488 25(OH)D 22986488 Twenty five-hydroxyvitamin D 22986488 calcium 22986488 phosphate 22986488 vitamin D 22986947 A438079 22986947 APAP 22986947 Acetaminophen 22986947 GSH 22986947 N 22986947 acetaminophen 22986947 tert-butyl hydroperoxide 22987483 carbon 22987605 carbon 22987605 polystyrene 22989414 ATP 22989414 Ca(2+) 22989414 Ca2+ 22989414 DCFDA 22989414 Fluo3 22989414 N-acetyl-l-cysteine 22989414 Withaferin A 22989414 amiloride 22989414 ceramide 22989414 phosphatidylserine 22989414 triterpenoid 22989414 withaferin 22989414 withaferin A 22989504 curcumin 22989504 resveratrol 22989775 Aryl methylcarbamates 22989775 carbamate 22989775 carbamates 22991293 N 22991293 aspartate 22991293 phosphate 22991293 serine 22991293 zinc 22992332 D-cycloserine 22992332 DCS 22992332 N-methyl-D-aspartate glutamate 22992332 VPA 22992332 Valproic acid 22992332 valproic acid 22992376 caffeine 22995439 Fe(3)O(4) 22995439 iron oxide 22995584 2',7'-dichlorodihydrofluorescein diacetate 22995584 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide 22995584 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine 22995584 DCFH(2)-DA 22995584 Epo A 22995584 Epo B 22995584 Epothilones 22995584 Hoechst 33258 22995584 JC-1 22995584 MTT 22995584 N-acetylcysteine 22995584 NAC 22995584 PTX 22995584 epothilone 22995584 epothilone A 22995584 epothilone A and B 22995584 epothilone B 22995584 epothilones 22995584 oxygen 22995584 paclitaxel 22995584 propidium iodide 22995584 taxane 22995584 taxanes 22998221 cholesterol 22998221 dicetylphosphate 22998221 isradipine 22998221 span20 22998221 span40 22998221 span60 22998221 span80 22998295 MTX 22998295 ethyl oleate 22998295 methotrexate 22998295 propylene glycol 22998295 tween 80 22998295 β-CD 22998295 β-cyclodextrin 23000249 Met 23000249 cysteine 23000249 histidines 23000249 zinc 23000445 Wogonoside 23000445 flavonoid 23000445 rapamycin 23000445 wogonoside 23000446 chlorogenic acid 23000446 methyl-methanesulfonate 23000446 nucleotide 23000446 phenolic 23000446 quercetin 23000446 rutin 23001363 NaCl 23001363 hydrogen 23003213 Fe3O4 23008095 radioiodine 23010360 6-[4-(trifluoromethoxy)phenyl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine 23010360 E-4031 23010360 GS967 23010360 Kr 23010360 Na 23010360 calcium 23010360 clofilium 23010360 flecainide 23010360 methoxamine 23010360 ranolazine 23010360 sodium 23010565 OAM 23010565 PEI 23010565 glyceraldehyde 3-phosphate 23010565 monoolein 23010565 oleylamine 23010565 polyethylenimine 23010670 alanine 23010670 aspartate 23010670 eosin 23010670 ethidium bromide 23010670 hematoxylin 23010670 methylchavicol 23010670 sodium dichromate 23014761 elacridar 23014761 erlotinib 23017390 Gallic acid 23017390 Hydroxytyrosol 23017390 Luteolin 23017390 Phenolic 23017390 Phenolics 23017390 Vanillic acid 23017390 gallic acid 23017390 luteolin 23017390 oleoropein 23017390 p-cumaric acid 23017390 rutin 23017390 sinapinic and apigenin acids 23017390 syringic, p-cumaric, chlorogenic and ferulic acids 23017390 tyrasol 23017390 tyrosol 23017390 vanilic acid 23017392 anthocyanin 23017392 phenolics 23017392 vitamin C 23017398 Ochratoxin A 23017398 ochratoxin A 23017405 2-methyl-3-furanthiol 23017405 amino acids 23017405 bis(2-methyl-3-furyl)disulfide 23017407 BZD 23017407 GABA 23017407 benzodiazepine 23017407 ethanol 23017407 ethyl acetate 23017407 flavonoid 23017407 flavonoids 23017407 flumazenil 23017407 pentobarbital 23017411 (1)H 23017411 (2-hydroxypropyl)-α-cyclodextrin 23017411 (2-hydroxypropyl)-β-cyclodextrin 23017411 (2-hydroxypropyl)-γ-cyclodextrin 23017411 HP-α-CD 23017411 HP-β-CD 23017411 HP-γ-CD 23017411 rutin 23017411 β-CD 23017411 β-cyclodextrin 23017419 oxygen 23017425 flavanones 23017425 flavones 23017425 polymethoxylated flavones 23017425 scoparone 23019138 (6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl) methanone) 23019138 1-(methylpiperidin-2-ylmethyl)-3-(2-iodo-5-nitrobenzoyl)indole 23019138 9β-(hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol 23019138 9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol 23019138 AM1241 23019138 AM2389 23019138 AM404 23019138 AM4054 23019138 AM630 23019138 Methanandamide 23019138 R-(1)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate 23019138 U50-488 23019138 WIN 55,212 23019138 anandamide 23019138 capsazepine 23019138 furosemide 23019138 rimonabant 23019138 trans-(-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide 23019138 vanilloid 23019138 Δ(9)-tetrahydrocannabinol 23020786 6-methoxy-2-naphtylacetic acid 23020786 Nabumetone 23020786 carbonyl 23020786 nabumetone 23020787 Ko143 23020787 MK571 23020787 gemifloxacin 23020787 gemifloxacin mesylate 23020787 quinolone 23020787 verapamil 23020788 (14)C-abiraterone acetate 23020788 14C-labeled abiraterone acetate 23020788 N-oxide abiraterone sulfate 23020788 abiraterone 23020788 abiraterone sulfate 23022048 GABA 23022048 LAG 23022048 glutamic acid 23022048 l-allylglycine 23022048 γ-aminobutyric acid 23022271 CYT 23022271 Ca(2+) 23022271 Cytisine 23022271 N-methyl-d-aspartate 23022271 NMDA 23022324 Arsenic 23022324 NaAsO(2) 23022324 sodium arsenite 23024204 1,12-diamino-3,6,9-triazadodecane 23024204 SpmTrien 23024204 Syprine 23024204 TETA 23024204 Triethylenetetramine 23024204 copper 23024204 polyamine 23024204 spermidine 23024204 spermine 23024204 thialysine 23024204 triethylenetetramine 23025634 Ag 23025634 CdSe 23026138 Methamphetamine 23026138 alcoholic 23026138 hydroxysteroids 23026138 methamphetamine 23026138 phenolic 23030793 polyamine 23036111 (1)H 23036111 (13)C 23036111 acetophenone 23036111 acetophenones 23036111 alkyl 23036111 benzyl 23036111 hymexazol 23036330 formalin 23036330 tyrosine 23040268 C 23041041 4-((5Z)-5-{[5-(4-bromophenyl)-2-furyl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)butanoic acid 23041041 5-(5-Phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one 23041041 6-((5Z)-5-{[5-(4-bromophenyl)-2-furyl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)hexanoic acid 23041042 organophosphorus 23041042 soman 23041232 fatty acid 23042952 (trans-3,5,4'-trihydroxystilbene) glucosides 23042952 2,2-diphenyl-1-picrylhydrazyl 23042952 3G-RSV 23042952 4'G-RSV 23042952 NAD(+) 23042952 RSV 23042952 Resveratrol 23042952 glycosyl RSVs 23042952 piceid 23042952 polydatin 23042952 polyphenol 23042952 resveratrol 23042952 resveratrol-3-O-β-d-glucoside 23042952 resveratrol-4'-O-β-d-glucoside 23042952 superoxide 23042952 trans-3,5,4'-trihydroxystilbene 23043183 O 23043183 Vilanterol 23043183 [(14)C]vilanterol 23043183 vilanterol 23044094 4-aminobenzoic acid 23044094 4-ter-butyl-4-methoxy-dibenzoylmethane, 2-ethylexyl-p-methoxycinnamate 23044094 6-methylcumarin 23044094 8-methoxypsoralen 23044094 MTT 23044094 SDS 23044094 acridine 23044094 benzophenone 23044094 chloropromazine 23044094 chlorpromazine 23044094 ibuprofen 23044094 ketoprofen 23044094 lactic acid 23044094 p-phenilendiamine 23044094 promethazine 23044094 retinoic acid 23044908 Zoledronic acid 23044908 zoledronic acid 23044992 tartrate 23046379 PGE(2) 23046379 prostaglandin E(2) 23046389 2-oxozoniporide 23046389 Aldehyde 23046389 aldehyde 23046389 zoniporide 23046524 paraoxon 23047462 FTO 23047462 TiCl(4) 23047462 TiO(2) 23047462 TiO2 23047462 fluorine-doped tin oxide 23047828 aldosterone 23047828 cortisol 23047828 glucose 23048186 BIM-22493 23048186 LY2112688 23048186 RM-493 23048186 glucose 23052058 fatty acid 23052190 CRM 23052190 MDZ 23052190 MGS 23052190 Magnesium sulfate 23052190 Sarin 23052190 TMB4 23052190 atropine 23052190 caramiphen 23052190 kainate 23052190 midazolam 23052190 organophosphate 23052190 oxime 23052190 sarin 23052191 Melamine 23052191 alanine 23052191 creatinine 23052191 melamine 23052191 nitrogen 23052191 urea 23053666 Cu 23053666 Pt 23053666 cisplatin 23053666 copper 23053666 l-DOPA 23053666 platinum 23054066 3,4- methylenedioxymethamphetamine 23054066 MDMA 23054066 serotonin 23054066 tryptophan 23055445 Al 23055445 Pd 23055445 hydrogen 23055445 hydrogen peroxide 23055445 oxygen 23055540 CVT-510 23055540 INO-8875 23055540 N-[3(R)-tetrahydrofuranyl]-6-aminopurine riboside 23055540 adenosine 23058251 NADPH 23058251 carbamates 23058251 imidacloprid 23058251 organochlorines 23058251 organophosphates 23058251 pyrethroids 23059508 Al 23059508 AlCl(3) 23059508 Aluminum 23059508 N 23059508 NADPH 23059508 aluminum trichloride 23059508 aminopyrin 23059508 aniline 23059509 Cd 23059509 Pb 23059509 zinc 23059538 d-alanyl 23059538 glycosyl 23059655 RGO 23059655 graphene 23059655 graphene oxide 23059655 reduced graphene oxide 23059794 PFOS 23059794 Perfluorooctane sulfonic acid 23060276 cadmium 23060276 chromium 23060276 copper 23060276 nickel 23060276 polycyclic aromatic hydrocarbon 23060276 silver 23060276 zinc 23060409 1,3-Dimethylamylamine 23060409 1,3-dimethylamylamine 23060409 DMAA 23060409 caffeine 23060409 charcoal 23060411 (NaPO(3))6 • H2O 23060411 Na2HPO(4) 23060411 NaH2PO(4) 23060411 PO(4) 23060411 PO4 23060411 Polyphosphates 23060411 monophosphates 23060411 phosphate 23060411 phosphates 23060411 polyphosphates 23060411 pyrophosphates 23060411 sodium metaphosphate 23060524 cholesterol 23060524 streptozotocin 23060524 triglyceride 23060524 triglycerides 23061622 Platinum 23061622 caboplatin 23061622 cisplatin 23061622 estradiol 23061622 platinum 23061623 coumarins 23061623 ellagitannins 23061623 flavonoids 23061623 polyphenols 23061623 xanthones 23063623 BIC 23063623 Enzalutamide 23063623 MDV3100 23063623 androgen 23063623 androgens 23063623 bicalutamide 23063689 Benzodiazepines 23063689 benzodiazepines 23063689 diazepam 23063782 Oxygen 23063782 oxygen 23064325 ITRA 23064325 itraconazole 23064325 polysorbate 23064325 polysorbate 80 23064325 tobramycine 23064722 ATP 23064722 Adenosine 23064722 adenine nucleotides 23064722 adenosine 23064722 nucleoside 23065141 3,4-dichloroaniline 23065141 3,4-dichloropropionanalide 23065141 3,4-dichloropropionanilide 23065141 6-hydroxy 23065141 6-hydroxy-3,4-dichloroaniline 23065141 6OH-DCA 23065141 DCA 23065141 DCPA 23065141 N-hydroxy 23065141 N-hydroxy-3,4-dichloroaniline 23065141 NOH-DCA 23065141 Propanil 23065141 calcium 23065141 chlorine 23065141 chlorines 23065141 fluorine 23065141 fluorines 23065531 DPA-714 23065531 N,N-diethyl-2-(2-(4-(2[(18)F]-fluoroethoxy)phenyl)5,7dimethylpyrazolo[1,5a]pyrimidin-3-yl)acetamide 23065531 N-deethyl 23065531 O 23065531 O-deethyl 23065531 [(18)F]DPA-714 23065531 [(18)F]carboxylic acid 23065531 [(18)F]deethyl 23065531 [(18)F]fluoroacetic acid 23065531 [(18)F]hydroxyl 23065531 carboxylic acid 23065531 hydroxyl 23065592 vitamin D 23066870 alanine 23066996 Alanine 23066996 alanine 23066996 amino acid 23066996 amino acids 23072367 PI(4,5)P(2) 23072367 phosphatidylinositol 4,5-bisphosphate 23072367 phosphoamino acid 23072941 Acyclovir 23072941 O-2,O-3 permethylated O-6 alkylthio- and perfluoroalkyl-propanethio-amphiphilic β-cyclodextrins 23072941 acyclovir 23072941 β-cyclodextrin 23073075 FTY720 23073075 FTY720-P 23073075 Fingolimod 23073075 N-methyl-d-aspartate 23073075 NMDA 23073075 S1P 23073075 W146 23073075 phosphatidylinositol 23073075 sphingosine-1-phosphate 23074095 PEG 23076766 Dox 23076766 doxorubicin hydrochloride 23076766 silica 23078954 DON 23078954 bentonite 23078954 carbon 23078954 macrolide 23078954 neutral red 23078954 tylosin 23079545 ARG 23079545 arginine 23080299 (E)-α-bromoacrylates 23080299 methyl bis(2,2,2-trifluoroethoxy)-bromophosphonoacetate 23080299 methyl bis(2,2,2-trifluoroethoxy)bromophosphonoacetate 23080299 methyl bis(2,2,2-trifluoroethoxy)phosphonoacetate 23080535 C 23080535 H 23080535 MnO(2) 23080535 TiO(2) 23084046 GSH 23084046 K(+) 23084046 Na(+) 23084046 Ti 23084046 TiO(2) 23084046 glutathione 23084046 titanium dioxide 23084047 MC-LR 23084047 S 23084047 glutathione 23084047 malondialdehyde 23084047 microcystin-LR 23084047 microcystins 23084047 oxygen 23084047 superoxide 23084158 Mg(OH)(2) 23084158 magnesium hydroxide 23084158 magnesium nitrate 23084158 potassium hydroxide 23085095 1-(2-pyrimidinyl)piperazine 23085095 6'-hydroxybuspirone 23085095 Aconitine 23085095 Buspirone 23085095 aconitine 23085095 buspirone 23085095 paclitaxel 23085121 organophosphate 23085122 IPA 23085122 atropine 23085122 carbamate 23085122 diazepam 23085122 organophosphorous 23085122 oximes 23085122 physostigmine 23085122 procyclidine 23085122 pyridostigmine 23085122 scopolamine 23085295 4',6'-diamidino-2-phenylindole dihydrochloride 23085295 DAPI 23085295 propidium iodide 23085331 HCl 23085331 TLM 23085331 Telmisartan 23085331 telmisartan 23085382 Minocycline 23085382 minocycline 23085382 tetracycline 23085436 cholesterol 23085436 glucose 23085436 triacylglycerol 23085522 DDE 23085522 HCB 23085522 PCB-153 23085522 dichlorodiphenyldichloroethylene 23085522 hexachlorobenzene 23085522 polychlorinated biphenyl-153 23086037 AMP 23086037 ATP 23086037 fatty acids 23086037 metformin 23086037 monosodium uric acid 23086037 nucleotide 23086037 oxygen 23086141 CORT 23086141 corticosterone 23086182 DDD 23086182 DDT 23086182 dichlorodiphenyldichloroethane 23086182 dichlorodiphenyltrichloroethane 23086182 permethrin 23086182 polydimethylsiloxane 23086747 2,3-dimercaptosuccinic acid 23086747 DMSA 23086747 Fe(3)O(4) 23086747 Fe3O4 23086747 desferrioxamine 23086747 iron 23086747 irons 23089045 tyrosine 23089153 cysteine 23089153 oxygen 23089153 thiol 23089211 Cholesterol ester 23089211 Cholesteryl ester 23089211 cholesterol 23089211 corticosterone 23089211 progesterone 23089211 testosterone 23089211 triacylglycerol 23089250 Hg 23089250 L-selenomethionine 23089250 MeHg 23089250 Se 23089250 SeMet 23089250 Selenium 23089250 mercury 23089250 methylmercury 23089250 selenomethionine 23090760 molybdenum oxide 23090760 α-MoO(3) 23090793 carbon 23091168 diclofenac 23091168 indomethacin 23091168 naproxen 23091188 ATP 23091188 CDCA 23091188 LPV 23091188 Lactate 23091188 RTV 23091188 TCA 23091188 [(14)C]CDCA 23091188 [(14)C]chenodeoxycholic acid 23091188 [(3)H]TCA 23091188 [(3)H]taurocholic acid 23091188 bile acid 23091188 bile acids 23091188 bile salt 23091188 glycochenodeoxycholic acid 23091188 glycocholic acid 23091188 lopinavir 23091188 ritonavir 23091188 taurochenodeoxycholic acid 23091188 α/β-tauromuricholic acid 23092225 PDMS 23092225 TiO(2) 23092225 poly(dimethyl siloxane) 23092225 silicone 23092304 PDMAEMA 23092304 poly(2-(dimethylamino)ethylmethacrylate) 23092880 glucose 23092880 rapamycin 23093023 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenyl}-acetamide 23093023 CO(2) 23093023 O(2) 23093023 OSU-03012 23093024 APAP 23093024 Acetaminophen 23093024 SDS 23093024 acetaminophen 23093024 alanine 23093024 glutathione 23093024 maleimide 23093024 polyacrylamide 23093024 sulfhydryl 23093024 sulfhydryls 23093024 tris(2-carboxyethy)phosphine 23093494 Ca(2+) 23093494 Cl(-) 23093494 Ethanol 23093494 H(+) 23093494 K 23093494 K(+) 23093494 N 23093494 Na(+) 23093494 alcohol 23093494 ethanol 23093496 2'-deoxyribose 23093496 2-(methylthio)-ADP 23093496 2-(methylthio)-ATP 23093496 3'-OH 23093496 ADP 23093496 ATP 23093496 N-Methyl-anthraniloyl 23093496 clopidogrel 23093496 purine 23095245 amisulpride 23095245 aripiprazole 23095245 clozapine 23095245 olanzapine 23097088 CdCl₂ 23097088 tyrosine 23097213 ADL5859 23098878 anthraquinone 23098878 bulgareone A 23098878 bulgareone B 23099319 DOM 23099319 domoic acid 23099319 phosphorylated cAMP 23099502 Deoxynivalenol 23099502 T-2 23099502 T-2 toxin 23099502 deoxynivalenol 23099502 zearalenone 23099503 PMF 23099503 aspartate 23099503 bilirubin 23099503 cholesterol 23099503 creatine 23099503 creatinine 23099503 lactate 23099503 niacin 23099503 polymethoxylated flavones 23099503 urea 23100157 Formaldehyde 23100157 formaldehyde 23103224 Cisplatin 23103224 cisplatin 23103330 estrogen 23103330 steroid 23103351 d-glucose 23103351 l-leucine 23103351 midazolam 23103351 testosterone 23103446 DNR 23103446 Dox 23103446 daunorubicin 23103446 nilotinib 23103566 GW0742 23103566 HFCS-55 23103566 high-fructose corn syrup 23103566 leucine 23103566 nucleotide 23103566 sugar 23103569 CO 23103569 Dithiolethione 23103569 GYY4137 23103569 H2S 23103569 Hydrogen sulfide 23103569 L-DOPA 23103569 N-acetyl cysteine 23103569 NO 23103569 NOSH-aspirin 23103569 S-allyl cysteine 23103569 S-propargyl cysteine 23103569 S-propyl cysteine 23103569 aspirin 23103569 carbon monoxide 23103569 cysteine 23103569 diclofenac 23103569 erucin 23103569 hydrogen sulfide 23103569 iberin 23103569 ibuprofen 23103569 indomethacin 23103569 mesalamine 23103569 naproxen 23103569 nitric oxide 23103569 sildenafil 23103569 sulforaphane 23103600 NAD 23103600 NADP 23104246 As(III) 23104246 As(V) 23104246 arsenate 23104246 arsenic 23104246 arsenite 23106203 glutamate 23106203 nitrogen 23106203 phosphate 23107818 DXR 23107818 bafilomycin A1 23107818 doxorubicin 23107818 oxygen 23107818 rapamycin 23108036 Arsenic 23108036 arsenic 23108036 fatty acid 23108036 troglitazone 23108606 (R)-naphthylethyleneamine 23108606 1,3,5-benzenetricarboxylic acid 23108606 1,8-di((R)-α-methylnaphthyl)-1,3,6,8,10,13-hexaazacyclotetradecane 23108606 BTC(3-) 23108606 Binaphthol 23108606 [Ni(L(R,R))](3) [C(6)H(3)(COO)(3)](2) 23108606 [Ni(L(R,R))](ClO(4))(2) 23108606 nickel(II) 23108606 nickel(II) hexaaza 23108606 rac-1,1'-bi-2-naphthol 23108606 rac-2,2,2-trifluoro-1-(9-anthryl)ethanol 23108727 Ga(In)NAs 23108979 Ethyl acetate 23108979 ethyl acetate 23108979 ethyl ethanoate 23109258 isoproturon 23109258 metsulfuron-methyl 23109258 pentachlorophenol 23109425 C 23110414 modafinil 23110812 EDTA 23111348 CARV 23111348 FLC 23111348 Hoechst 33342 23111348 R6G 23111348 Rhodamine6G 23111348 THY 23111348 Thymol 23111348 azole 23111348 azoles 23111348 carvacrol 23111348 fluconazole 23111348 glucose 23111348 monoterpenes 23111803 Thiram 23111803 difenoconazole 23111803 imidacloprid 23111803 thiram 23111876 8-(3-chlorostyryl) caffeine 23111876 8-cyclopentyl-1,3-dipropylxanthine 23111876 Amitriptyline 23111876 DPCPX 23111876 adenosine 23111876 amitriptyline 23111877 Duloxetine 23111877 duloxetine 23111877 norepinephrine 23111877 serotonin 23111881 TAA 23111881 Thioacetamide 23111881 thioacetamide 23111886 Cisp 23111886 Cisplatin 23111886 alanine 23111886 aspartate 23111886 bilirubin 23111886 cisplatin 23111886 creatinine 23111886 nitrogen 23111886 urea 23111950 Magnesium 23111950 Mg 23111950 MgO 23111950 magnesium 23115221 cotinine 23115221 nicotine 23115221 sodium sulfate 23117151 2,3,7,8-tetrachlorodibenzo-p-dioxin 23117151 5α-dihydrotestosterone 23117151 Androgen 23117151 TCDD 23117151 androgen 23117151 aryl hydrocarbon 23117207 hydrogen 23118486 sulfate 23121886 Ag 23121886 As 23121886 Cd 23121886 Cu 23121886 Pb 23121886 Zn 23122065 A23187 23122065 Ca(2+) 23122065 calcium 23122065 phosphatidylinositol 23122067 Anthraquinone 23122067 anthraquinones 23122067 chrysophanol 23122067 emodin 23122067 flavonoid 23122067 phenolic 23122067 phenols 23122067 physcion 23122070 2-NBDG 23122070 4-hydroxybenzaldehyde 23122070 europetin-3-O-rhamnoside 23122070 glucose 23122070 myricetin-3-O-rhamnoside 23122070 myrigalone-B 23122070 myrigalone-G 23122070 phloretin 23122070 rosiglitazone 23122072 phenolic 23122079 AMP 23122079 Phillyrin 23122079 compound C 23122079 fatty acid 23122079 glucose 23122079 phillyrin 23122079 sterol 23122081 lycopene 23122094 linalool 23122094 terpene alcohols 23122094 terpinen-4-ol 23122094 α-terpineol 23122099 10-formyltetrahydrofolate 23122099 5-formyltetrahydrofolate 23122099 5-methyltetrahydrofolate 23122099 Salicylic acid 23122099 folates 23122099 salicylic acid 23122099 vitamin (B(9)) 23122100 HODE 23122100 dimethylsiloxane 23122100 eicosanoids 23122100 fatty acids 23122100 hydroxyoctadecadienoic acid 23122102 ascorbic acid 23122102 fatty acids 23122102 phenolic 23122102 phenolic glycosides 23122102 phenylpropanoid glucoside 23122102 saponins 23122102 β-carotene 23122111 Ca(2+) 23122111 Neferine 23122111 calcium 23122111 glutathione 23122111 neferine 23122111 oxygen 23122115 Galactose 23122115 Lactulose 23122115 fructose 23122115 galactose 23122115 glucose 23122115 lactose 23122115 lactulose 23122120 Neu5Ac 23122120 sialic acid 23122121 betulinic acid 23122121 betulinic, corosolic, maslinic, oleanolic and ursolic acid 23122121 betulinic, corosolic, maslinic, oleanolic and ursolic acids 23122121 corosolic acid 23122121 maslinic acid 23122121 oleanolic acid 23122121 triterpene pentacyclic acids 23122121 triterpenic acids 23122121 ursolic 23122126 bile salt 23122134 polydextrose 23122143 fatty acid 23122143 p-anisidine 23122143 polyunsaturated fatty acids 23122147 17-hydroxyprogesterone 23122147 cortolone-3-glucuronide 23122147 steroid 23122147 testosterone-glucuronide 23122147 tetrahydroaldosterone-3-glucuronide 23122151 EtOAc 23122151 afzelin 23122151 aldose 23122151 ethyl acetate 23122151 flavonoid rhamnosides 23122151 flavonoids 23122151 kaempferol 23122151 methanol 23122151 myricetin 23122151 myricitrin 23122151 quercetin 23122151 quercitrin 23122157 1,1'-diphenyl-2-picrylhydrazyl 23122157 DPPH 23122157 Gallic acid 23122157 gallic acid 23122161 NO 23122161 PGE(2) 23122161 hexane 23122161 methanol 23122161 nitric oxide 23122161 prostaglandin E(2) 23122166 AMP 23122166 acetyl-CoA 23122166 carnitine 23122166 ethanol 23122166 fatty acid 23122166 palmitoyl 23122166 trigycerides 23122331 (15)N 23122331 C 23122331 lactose 23122331 sugar 23123224 berberine 23123224 ethanol 23123224 jatrorrhizin 23123224 palmatine 23123225 ergosterol 23123225 β-Asarone 23123225 β-asarone 23123249 NEMP 23123249 NIMP 23123249 PIMP 23123249 nitrophenyl ethyl methylphosphonate 23123249 nitrophenyl isopropyl methylphosphonate 23123249 organophosphate 23123249 oxime 23123249 oximes 23123249 phenoxyalkyl pyridinium oximes 23123249 phthalimidyl isopropyl methylphosphonate 23123249 sarin 23123662 carboplatin 23123662 cisplatin 23123662 copper 23123662 oxaliplatin 23123662 platinum 23123662 silver 23123662 zinc 23123664 Cysteine 23123664 GSH 23123664 S-adenosylhomocysteine 23123664 S-adenosylmethionine 23123664 TAM 23123664 Tamoxifen 23123664 amino acid 23123664 buthionine sulfoximine 23123664 cystathionine 23123664 cysteine 23123664 glutathione 23123664 homocysteine 23123664 hypotaurine 23123664 methionine 23123664 propargylglycine 23123664 sulfur 23123664 tamoxifen 23123664 taurine 23123664 γ-glutamylcysteine 23123771 Glu 23123771 His 23123771 Ser 23123771 leucine 23123771 nitrogen 23123771 oxygen 23123771 proline 23124594 rebaudioside A 23124594 steviol glycoside 23124594 steviol glycosides 23124594 stevioside 23125284 oxygen 23126422 2-Amino-4-arylthiazole 23126422 2-amino-4-arylthiazole 23126495 DPPH 23126495 dichloromethane 23126495 oleanolic acid 23126495 oleanolic and ursolic acids 23126495 salvigenin 23126495 sclareol 23126495 ursolic acid 23126495 β-sitosterol 23127499 5-hydroxyuracil 23127499 8-oxoG 23127499 8-oxoguanine 23127540 O(2) 23127540 SO(2) 23127540 Sulfur 23127540 sulfur 23127540 sulfurous acid 23127567 AZT 23127567 Oleandrin 23127567 oleandrin 23127600 STZ 23127600 dimethyldiguanide 23127600 glucose 23127600 polyphenols 23127600 streptozotocin 23127600 sugar 23127820 ethanol 23127820 stauntosides C-K 23127820 steroidal glycosides 23127916 imatinib 23127916 tyrosine 23129783 Sulfur 23129783 propidium iodide 23129783 sulfur 23129806 NAD(+) 23129806 fatty acids 23129806 glucose 23130977 tyrosine 23131595 ATP 23131595 Adenosine 23131595 adenosine 23132629 (15)N 23132629 15N 23132629 3-amino-2-cyanopent-2-enedinitrile 23132629 enaminones 23132866 Ser 23132866 Thr 23132866 androgen 23132909 cholesterol 23132909 triglyceride 23134558 LNG 23134558 levonorgestrel 23135241 Serotonin 23135241 Sibutramine 23135241 agomelatine 23135241 bupropion 23135241 catecholamine 23135241 dopamine 23135241 fluoxetine 23135241 idazoxan 23135241 monoamine 23135241 noradrenaline 23135241 paroxetine 23135241 serotonin 23135241 sibutramine 23135241 venlafaxine 23135549 17-alpha-ethinylestradiol 23135549 Cadmium 23135549 Cd 23135549 CdCl₂ 23135549 EE2 23135549 EE₂ 23135549 aryl hydrocarbon 23135549 cadmium 23135549 estrogen 23135549 estrogens 23135549 ethinyl-estradiol 23136062 (31) P 23136062 (68) Ga 23136062 (68) Ga(3+) 23136062 (68) Ge 23136062 (68)Ga 23136062 (68)Ge 23136062 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid 23136062 1,4,7-triazacyclononane-1,4,7-triacetic acid 23136062 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid]) 23136062 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-hydroxymethyl)phosphinic acid] 23136062 Al(3+) 23136062 Cu(2+) 23136062 DOTA 23136062 Fe(3+) 23136062 Ga(3+) 23136062 NOPO 23136062 NOTA 23136062 Sn(IV) 23136062 TRAP 23136062 Ti(IV) 23136062 Zn(2+) 23136062 Zn(II) 23136062 carboxylate 23136062 phosphinate 23136129 nucleotide 23137956 EGCG 23137956 S 23137956 Se 23137956 Selenium 23137956 catechins 23137956 epigallocatechin-3-gallate 23137956 glutathione 23137956 selenite 23137956 selenium 23137956 sodium selenite 23141426 Hoechst 33258 23141427 5-HT 23141427 5-hydroxytryptamine 23141427 NO 23141427 acetonitrile 23141427 nitric oxide 23141427 phosphoric acid 23142073 STX 23142073 Saxitoxin 23142073 saxitoxin 23142104 retinal 23142105 oxygen 23142327 11-Ketotestosterone 23142327 11-kT 23142327 androgen 23142327 androgens 23142505 PGE2 23142505 nitric oxide 23142507 Ala 23142507 Asn 23142507 Asp 23142507 Cys 23142507 Glu 23142507 His 23142507 Lys 23142507 Phe 23142507 amino acid 23142507 nucleotide 23142547 1,N(6)-ethenoadenine 23142547 C 23142547 N 23142547 amino acid 23142547 dCMP 23142559 4-DAMP 23142559 ACh 23142559 acetylcholine 23142559 physostigmine 23142559 pilocarpine 23142559 tiotropium 23142599 1,2,3,7,8-pentachlorodibenzo-p-dioxin 23142599 17α-ethynylestradiol 23142599 2,3,7,8-TCDD 23142599 2,3,7,8-tetrachlorodibenzo-p-dioxin 23142599 EE2 23142599 aryl hydrocarbon 23142599 dioxin 23142599 estrogen 23142789 17α-ethynylestradiol 23142789 BPA 23142789 Bisphenol A 23142789 Ca 23142789 Octylphenol 23142789 alkylphenol ethoxylates 23142789 bisphenol A 23142789 calcium 23142789 epoxy 23142789 octylphenol 23142789 phenol 23142789 polycarbonate 23142789 vitamin D 23142844 CHOL 23142844 DMPC 23142844 POPC 23142844 Tetracaine 23142844 cholesterol 23142844 lidocaine 23142844 phosphorus 23142844 propofol 23142844 quartz 23142844 sphingomyelin 23142844 tetracaine 23143037 IBU 23143037 S 23143037 arachidonic acid 23143037 glutathione 23143037 ibuprofen 23143037 superoxide 23143415 NiFe 23143415 O(2) 23143415 O2 23143415 nickel-iron 23143619 acetaminophen 23143619 diclofenac 23143619 trovafloxacin 23143802 Alachlor 23143802 testosterone 23143803 pyrene 23143912 Al 23143912 Fe 23143912 Ti 23143912 aluminosilicate 23143912 silicate 23143912 zeolite 23143912 zeolites 23143926 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole lysylamide dihydrochloride 23143926 2-[4-amino-3-methylphenyl]-5-fluorobenzothiazole lysylamide dihydrochloride 23143926 NSC 710305 23143926 Phortress 23145944 polyarginine 23146664 5-ASA 23146664 Mesalamine 23146664 mesalamine 23146691 Emodin-6-O-β-D-glucoside 23146695 CCl(4) 23146695 CCl4 23146695 MDA 23146695 Puerarin 23146695 alanine 23146695 aspartate 23146695 carbon tetrachloride 23146695 isoflavonoid 23146695 malondialdehyde 23146695 nitric oxide 23146695 puerarin 23146695 superoxide 23146698 CCl(4) 23146698 Methanol 23146698 bilirubin 23146698 carbon tetrachloride 23146698 gentiopicrin 23146698 malondialdehyde 23146698 reduced glutathione 23146698 superoxide 23146698 sweroside 23146698 swertiamarin 23146750 BDE47 23146750 BPA 23146750 PCB126 23146750 PCB153 23146750 PFOA 23146750 bisphenol 23146750 dioxin 23146750 perfluorinated alkyl acid 23146750 polychlorinated biphenyl 23146755 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester 23146755 2,5-di-tert-butylhydroquinone 23146755 BAPTA-AM 23146755 BHQ 23146755 Ca(2+) 23146755 Ca2+ 23146755 Carvacrol 23146755 U73122 23146755 carvacrol 23146755 oxygen 23146755 thapsigargin 23146758 2,2',4,4'-tetrabromodiphenyl ether 23146758 5-OH-BDE-47 23146758 6-OH-BDE-47 23146758 CGS 16949A 23146758 androstenedione 23146758 dibenzylfluorescein 23146758 estradiol 23146758 hydroxylated BDE-47 23146758 testosterone 23146761 7α-hydroxy-4-cholesten-3-one 23146761 EGCG 23146761 Epigallocatechin gallate 23146761 bile acid 23146761 epigallocatechin gallate 23146761 ethinylestradiol 23146761 glutathione 23147004 adenine 23147004 methyl 23147004 phosphodiester 23147033 acetate 23147033 butyrate 23147033 carbohydrate 23147033 carbohydrates 23147033 fatty acids 23147033 lactic acid 23147033 propionate 23147639 (19Z)-HCA 23147639 (19Z)-Halichondramide 23147639 (19Z)-halichondramide 23147639 oxazole 23147639 trisoxazole 23147692 acetylphenylhydrazine 23147987 PCB 23147987 PCBs 23147987 polychlorinated biphenyl 23147987 polychlorinated biphenyls 23148024 (+)-anti-BP-7,8-diol-9,10-epoxide 23148024 BPDE 23148024 PAH 23148024 PAHs 23148024 benzo[a]pyrene 23148024 polycyclic aromatic hydrocarbon 23149118 Atrazine 23149118 atrazine 23149118 plastoquinone 23149118 quinones 23149657 glucose 23149657 sulfonylurea 23149657 sulfonylureas 23150067 (1)H 23150067 (13)C 23150067 14-aryl-14H-dibenzo[a,j]xanthenes-3,11-dicarboxylic acid 23150067 As(2)O(3) 23150067 N(3),N(11)-bis(2-hydroxyethyl)-14-aryl-14H-dibenzo[a,j]xanthene-3,11-dimethanamine 23150067 N(3),N(11)-bis(2-hydroxyethyl)-14-aryl-14H-dibenzo[a,j]xanthenes-3,11-dicarboxamide 23150067 carboxamide 23150210 Hoechst 33342 23150210 XR9576 23150210 tariquidar 23150226 S-S 23150226 disulfide 23150428 dextromethorphan 23150428 dextrorphan 23150428 retinoic acid 23150493 N-acetylcysteine 23150493 fatty acid 23150493 fatty acids 23150495 glucose 23150999 cholesterol 23150999 glycerophospholipid 23150999 sphingolipids 23151001 C 23151002 Cholesterol 23151002 cholesterol 23151002 serotonin 23151002 sphingolipids 23151004 cholesterol 23151004 palmytoilated aminoacid 23152189 2,3,7,8-Tetrachlorodibenzo-p-dioxin 23152189 2,3,7,8-tetrachlorodibenzo-p-dioxin 23152189 ATP 23152189 Aryl hydrocarbon 23152189 GSH 23152189 NAD(+) 23152189 NADH 23152189 TCDD 23152189 ceramide 23152189 ceramides 23152189 fatty acids 23152189 glucose 23152189 glutathione 23152189 glutathione disulfide 23152189 hydrogen peroxide 23152189 oxygen 23152189 pyruvate 23152191 Δ(9)-THC 23152191 Δ(9)-tetrahydrocannabinol 23152191 Δ9-tetrahydrocannabinol 23152439 bisphosphonates 23152439 calcium 23152439 magnesium 23152439 vitamin D 23153618 fatty acids 23153618 lopinavir 23153618 poloxamer 23153618 polyethylene glycol 23153618 stearic acid 23153668 PLL 23153668 coumarin-6 23153668 poly-L-lysine 23154194 Amino acid 23154194 Azone 23154194 DDAIP 23154194 DDAK 23154194 Transkarbam 12 23154194 alanine 23154194 amino acids 23154194 ester 23154194 glycine 23154194 l-Pro 23154194 proline 23154194 propylene glycol 23154194 sarcosine 23154194 β-alanine 23154533 MMI 23154533 PTU 23154533 Propylthiouracil 23154533 methimazole 23154533 propylthiouracil 23157419 CaCO(3) 23157419 CaHPO(4) 23157419 calcium 23157625 GABA 23157625 clozapine 23157625 dopamine 23157625 glutamate 23157625 risperidone 23157625 serotonin 23157627 5-HT 23157627 dopamine 23157627 gamma-aminobutyric acid 23157627 glutamate 23157627 serotonin 23157632 DOPA 23157632 dopamine 23157634 (1)H 23157634 GABA 23157634 Gln 23157634 Glu 23157634 N-acetylaspartate 23157634 NAA 23157634 choline 23157634 glutamate 23157634 glutamine 23157634 myo-inositol 23159330 Rapamycin 23159330 rapamycin 23159502 oxygen 23159668 ethyl 23159668 ethyl-hydroxypropyl 23159668 hydroxypropyl 23159791 bradykinin 23159885 Aldehyde 23159885 NAD(P)(+) 23159885 aldehyde 23159885 aldehydes 23159885 carboxylic acids 23159885 nicotinamide adenine dinucleotide (phosphate) 23159886 GSH 23159886 N-acetyl cysteine 23159886 NAC 23159886 S 23159886 alanine 23159886 aspartate 23159886 bilirubin 23159886 glutathione 23159886 nitric oxide 23159886 nitrite 23159886 paraquat 23159886 superoxide 23159986 2-propanol 23159986 D-limonene 23159986 creatinine 23159986 potassium bromate 23160480 alanine 23160480 amino acid 23160480 nucleotide 23160480 phenyalanine 23160480 proline 23160480 serine 23160480 tyrosine 23160481 cAMP 23160481 phosphatidylinositol 23160530 Diazepam 23160530 glucose 23161062 carboxyl 23161484 259F 23161484 LC-95A 23161484 PHOS-CHEK 259F and LC-95A 23161512 oxygen 23161512 selenium 23161521 Hg 23161521 Si 23161521 styrene 23161581 Ag 23161581 Ag-doped PbSe 23161581 PbSe 23161581 silver 23161646 Graphene 23161646 carbon 23161646 graphene 23161646 graphene oxide 23161646 nucleotide 23161844 histamine 23161868 corticosterone 23161873 alanine 23161873 aspartate 23161873 carbohydrate 23161873 fructose 23161873 glucose 23161873 monosaccharides 23161873 sugar 23161873 triglyceride 23161873 uric acid 23163337 Iron 23163337 iron 23163337 nitrate 23163337 nitrite 23164616 ethanol 23164618 Dopamine 23164618 cAMP 23164618 cyclic-AMP 23164618 dopamine 23164618 morphine 23164619 DHβE 23164619 Glucose 23164619 MLA 23164619 acetylcholine 23164619 dihydro-beta-erythroidine 23164619 glucose 23164619 methyllycaconitine 23164713 NA255 23164921 Catalpol 23164921 NO 23164921 catalpol 23164932 3-NP 23164932 3-Nitropropionic acid 23164932 3-nitropropionic acid 23164985 3-cyanopyridine 23165154 Rotigotine 23165154 dopamine 23165154 ergoline 23165154 poly(lactide-co-glycolide) 23165154 rotigotine 23165154 sodium 23165155 DDT 23165155 MTT 23165155 dichlorodiphenyltrichloroethane 23165155 dieldrin 23165155 neutral red 23165858 Ca 23165858 CaCl2 23165858 Co 23165858 CoCl2 23165858 N 23165858 P 23165858 amino acids 23166012 CTAC 23166012 SDBS 23166012 Sodium dodecyl benzene sulfonate 23166012 cetyl trimethyl ammonium chloride 23166012 superoxide 23166012 β-carotene 23167526 gambogic acid 23167526 hydroxyxanthone 23167526 xanthones 23167531 N-demethyl darexaban 23167531 N-oxides 23167531 UDP 23167531 YM150 23167531 [(14)C]Darexaban 23167531 [(14)C]darexaban maleate 23167531 darexaban 23167531 darexaban glucuronide 23167767 poly(ethylene glycol) 23167767 poly(ethylene glycol) acrylate 23167767 polystyrene 23167812 8,8-DDBs 23167812 8,8-dialkylcanadines 23167812 8,8-dialkyldihydroberberines 23167812 8,8-diethyldihydroberberine chloride 23167812 8,8-dimethyldihydroberberine chloride 23167812 poly(dA·dT) 23168114 BDZ 23168114 BZD 23168114 BZDs 23168114 Benzodiazepines 23168114 DZP 23168114 STP 23168114 Stiripentol 23168114 benzodiazepine 23168114 diazepam 23168115 5-HT 23168115 GABA 23168115 GTP-γ-S 23168115 glutamate 23168115 serotonin 23169608 10-Keto-NBP 23169608 10-hydroxy-NBP 23169608 11-hydroxy-NBP 23169608 3-, ω-1-, and ω-carbons 23169608 3-hydroxy-NBP 23169608 3-n-Butylphthalide 23169608 3-n-butylphthalide 23169608 NBP 23169608 NBP-11-oic acid 23169608 alcohol 23169608 aldehyde 23169608 alkyl 23169608 phthalide-3-acetic acid 23169609 PF-04971729 23169609 [(14)C]-ertugliflozin 23169609 des-ethyl ertugliflozin 23169609 ertugliflozin 23169609 ertugliflozin -4-O-β- and -3-O-β-glucuronide 23169609 glucose 23169609 hydroxyl 23169609 sodium 23169610 3-Methylcholanthrene 23169610 3-methylcholanthrene 23169610 NADPH 23169610 aryl hydrocarbon 23170792 aspirin 23170792 clopidogrel 23170792 prasugrel 23170792 thienopyridines 23170792 ticagrelor 23170792 warfarin 23170957 acetyl-CoA 23170957 fatty acid 23170957 malonyl-CoA 23171424 SDS 23171424 amino acid 23171424 iron 23171424 phenol 23171424 propane 23171962 Cu 23171962 CuO 23171962 carbon black 23171962 lithium 23172156 silica 23172156 zirconium 23172726 FR901464 23172726 herboxidiene 23172726 meayamycin B 23172734 2,2',5,5'-polychlorinated biphenyl 23172734 C(60) 23172734 Fullerene 23172734 PCB 23172734 fullerene 23172734 nC(60) 23172734 nC60 23172734 toluene 23173549 androstane 23173549 aryl hydrocarbon 23174031 androgens 23174031 androstenedione 23174144 Cu 23174144 CuSO(4) 23174144 copper 23174144 copper sulphate 23174340 (125)I 23174340 BMS-763534 23174340 BMS-790318 23174340 GABA 23174340 O 23174340 TBOB 23174340 cAMP 23174340 chlordiazepoxide 23174518 2,2-diphenyl-1-picrylhydrazyl 23174518 polyphenol 23174518 superoxide 23174748 Emodin 23174748 NO 23174748 PGE(2) 23174748 R-123 23174748 anthraquinone 23174748 anthraquinones 23174748 nitric oxide 23174748 prostaglandin E(2) 23174748 rhodamine-123 23175103 CO 23175103 CO(2) 23175103 Co(2+) 23175103 Co(3)O(4) 23175103 Co(3+) 23175103 Co3O4 23175103 O 23175103 O(2) 23175103 oxygen 23177260 GSH 23177260 GSSH 23177260 MDA 23177260 Superoxide 23177260 TMT 23177260 Trimethyltin 23177260 acetylcholine 23177260 glutathione 23177260 serotonin 23177260 trimethyltin 23177536 VPA 23177536 Valproate 23177536 fatty acids 23177536 triglyceride 23178198 Etazolate 23178198 etazolate 23178257 1α,25(OH)(2)D(3) 23178257 1α,25-dihydroxyvitamin D(3) 23178257 Vitamin D 23178257 calcium 23178257 phosphorus 23178257 vitamin D 23178323 N 23178323 serine 23178441 cefadroxil 23178441 citric and lactic acids 23178441 quetiapine 23178632 amiodarone 23178651 diallyl disulfide 23178681 H(2)O(2) 23178681 oxygen 23178950 DOX 23178950 DOX·HCl 23178950 DTXL 23178950 HPMA 23178950 N-(2-hydroxypropyl)methacrylamide 23178950 PBDL 23178950 PBS 23178950 PHPMA 23178950 cholesterol 23178950 docetaxel 23178950 doxorubicin 23178950 doxorubicin hydrochloride 23178950 hydrazone 23178950 poly(butylene succinate-co-butylene dilinoleate) 23178950 polyester 23179349 Iron 23179349 calcium 23179349 copper 23179349 fructose 23179349 iron 23179349 nitric oxide 23179349 zinc 23179350 lead acetate 23179409 Atrazine 23179409 Chl a 23179409 atrazine 23179409 chlorophyll a 23179409 nitrogen 23179409 phosphorus 23179753 MeHg 23179753 VPA 23179753 Valproic acid 23179753 methylmercury 23179775 androgens 23179775 cortisol 23179775 cortisone acetate 23179775 hydrocortisone 23180341 EtOAc 23180341 amauroamoienin 23180449 CdSe 23180449 GeSe2 23180684 MeHg 23180684 Methyl mercury 23180684 mercury 23180691 polyethylene glycol 23180693 Bi(3) Fe(2) Mn(2) O(10+δ) 23180693 BiFeO(3) 23180693 BiMnO(3) 23180693 BiRO(3) 23180693 Co 23180693 Cr 23180693 Fe 23180693 Mn 23180693 Ni 23180693 bismuth 23180693 perovskite 23182087 Benzothiazole 23182087 NK0139A 23182087 NK0148 23182087 NK037 23182087 NK041 23182087 NK042 23182087 NKTA 23182087 benzimidazole 23182087 benzothiazole 23182087 phthalimide 23182087 thalidomide 23182739 flavonoids 23182739 phenolic 23182739 phenolic acids 23182739 tannins 23182766 amino acid 23182766 carboxy 23182766 cholesterol 23182766 creatine 23182946 (PhTe)(2) 23182946 Ser 23182946 [(3)H]glutamate 23182946 cAMP 23182946 diphenyl ditelluride 23182946 glutamate 23182946 propidium iodide 23183177 11β-hydroxysteroid 23183177 17β-hydroxysteroid 23183177 C 23183177 N 23183177 NADPH 23183177 digitonin 23183177 glucose-6-phosphate 23183177 hexose-6-phosphate 23183177 nicotinamide adenine dinucleotide phosphate 23183177 pyridine nucleotide 23183177 Δ4-androstene-3,17-dione 23183374 C 23183374 cytidine 23183374 cytosine 23183374 uracil 23183543 2-hydrazinyl-1,3,4-thiadiazole 23183543 ADP 23183543 Schiff bases 23183543 arachidonic acid 23183543 hydrazone 23183624 aluminum 23184149 Ca(2+) 23184149 dopamine 23184149 nucleotide 23184149 oxygen 23184572 hydrogen 23185042 6-MI 23185042 6-methyl isoxanthopterin 23185042 guanine 23186033 RAI 23186033 Romidepsin 23186033 iodine 23186033 radioactive iodine 23186033 romidepsin 23186033 sodium iodide 23186588 A317491 23186588 PGE(2) 23186588 amine 23186588 amines 23186588 dexamethasone 23186588 dopamine 23186588 prostaglandin E(2) 23186588 prostaglandins 23186588 αβmeATP 23187065 FAAS 23187065 fatty acid alkyl esters 23187618 MCM-41 23187618 MCM-48 23187618 Nucleosil 23187618 PMO 23187618 SBA-15 23187618 SBA-16 23187618 ethene 23187618 geminal and vicinal silanols 23187618 organosilicas 23187618 silanes 23187618 silanes. 23187618 silanol 23187618 silanols 23187618 silica 23187618 silicas 23187874 graphene 23187874 pristine graphene 23188391 glucose 23188717 naphthalene diimide 23188819 zinc 23190031 C-glycosylxanthone 23190031 Mangiferin 23190031 aromatic hydroxyl 23190031 hydroxyl 23190031 iron 23190031 mangiferin 23190031 polyphenol 23190031 xanthonoid 23190033 CO(2) 23190033 HCO(3) - 23190033 Phenolic 23190033 bicarbonate 23190033 carbon dioxide 23190033 flavonoids 23190033 phenol 23190033 phenolic 23190033 phenolics 23190033 phenyl 23190035 Quinoline 23190035 quinoline 23190093 (oligo)tyrosine 23190093 N-carboxyanhydride 23190093 NCA 23190093 PEG 23190093 PEG2000-Tyr(6) 23190093 oligo(tyrosine) 23190093 poly(ethylene glycol) 23190093 tyrosine 23190297 2,4-diOH-BP 23190297 2,4-dihydroxybenzophenone 23190297 2,5-Dihydroxy-4-methoxybenzophenone 23190297 2,5-dihydroxy-4-methoxybenzophenone 23190297 2-hydroxy-4-methoxybenzophenone 23190297 3-methylcholanthrene 23190297 5-OH-BP-3 23190297 BP-3 23190297 NADPH 23190297 SKF 525-A 23190297 benzophenone-3 23190297 dexamethasone 23190297 ketoconazole 23190297 phenobarbital 23190297 quinidine 23190297 sulfaphenazole 23190297 α-naphthoflavone 23192339 glucose 23192347 cysteines 23192347 disulfide 23192350 N 23192350 carbohydrates 23192785 (S)-2-phenylglycinol 23192785 Triton X-100 23192785 aldol 23192785 amino acids 23192785 aromatic aldehydes 23192785 chiral β-amino alcohols 23192785 ketones 23192785 β-amino alcohol 23192785 β-amino alcohols 23192785 β-hydroxy ketones 23194076 Androgen 23194076 Orlistat 23194076 Testosterone 23194076 androgens 23194076 glucose 23194156 Safranin-O 23194156 carboxylate 23194156 hydroxyl 23194156 sulfonate 23194280 carbon 23194280 graphene 23194280 hydrogen 23194408 amphetamine 23194408 cocaine 23194408 dopamine 23194506 SDS 23194513 NaCl 23194513 PEI 23194513 acetate 23194513 carbon 23194513 gallic, caffeic, ferulic and p-coumaric acids 23194513 polyethyleneimine 23194513 polyphenol 23194513 polyphenols 23194514 lactokinin 23194515 amino acid 23194515 amino acids 23194529 D-fagomine 23194532 CCl(4) 23194532 GSH 23194532 carbon tetrachloride 23194532 carbonyls 23194532 glutathione 23194532 hydroxyproline 23194532 thiobarbituric acid 23194534 carbonyls 23194537 C 23194537 amino acids 23194537 angiotensin I 23194537 sulphur 23194541 2,2'-diphenyl picrylhydrazyl 23194541 Caffeine 23194541 Catechin 23194541 Cyanidin-3-O-glucoside 23194541 DPPH 23194541 Folin-Ciocalteu phenol 23194541 anthocyanin 23194541 catechin 23194541 catechins 23194541 flavonoid 23194541 phenolic 23194541 polyphenols 23194542 6-BA 23194542 6-benzyl aminopurine 23194542 acetonitrile 23194542 carbendazim 23194542 thiabendazole 23194548 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide 23194548 MTT 23194548 arabinose 23194548 ethanol 23194548 galactose 23194548 glucose 23194548 mannose 23194548 monosaccharides 23194548 rhamnose 23194548 uronic acid 23194548 xylose 23194828 CPF 23194828 Chlorpyrifos 23194828 D-amphetamine 23194828 GABA 23194828 MK-801 23194828 amino acid 23194828 amino acids 23194828 chlorpyrifos 23194828 d-amphetamine 23194828 dizocilpine 23194828 dopamine 23194828 gamma-aminobutyric acid 23194828 glutamate 23194828 ketanserin 23194828 monoamines 23194828 organophosphate 23194828 quinpirole 23195733 (4-aminobutyloxy)quinolines 23195733 4- and 8-(4-aminobutylamino)quinoline 23195733 5-, 6- and 8-(4-aminobutyloxy)quinolines 23195733 chloroquine 23195733 hydroxyquinolines 23195733 oxygen 23195733 quinolines 23195733 rhodium 23195751 17β-estradiol 23195751 estradiol 23195751 estrogen 23195959 phospho 23196670 2,3,7,8-tetrachlorodibenzo-p-dioxin 23196670 PCB 126 23196670 PCBs 23196670 TCDD 23196670 aryl hydrocarbon 23196670 polychlorinated biphenyls 23197401 C(60) 23197401 c(60) 23197401 hydroxyl 23197401 poly(vinyl alcohol) 23197401 poly[(N-vinylpyrrolidone)-co-(vinyl acetate)] 23197401 poly{[poly(ethylene glycol) acrylate]-co-(vinyl acetate)} 23197647 Etoposide 23197647 MK571 23197647 MTX 23197647 [(3)H]MTX 23197647 etoposide 23197647 methotrexate 23197773 (6aR)-5,6,6a,7-tetrahydro-6-propyl-4H-dibenzo[de,g]quinoline-10,11-diol 23197773 (6aR,10aR)-3-(1-adamantyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydrobenzo[c]chromen-1-ol 23197773 (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride 23197773 (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide (methanandamide) 23197773 (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide 23197773 5-(4-alkylphenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide 23197773 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide 23197773 9β-(hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol 23197773 AM4054 23197773 AM411 23197773 AM4113 23197773 R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate 23197773 R-(-)-NPA 23197773 SCH23390 23197773 SKF82958 23197773 SR141716A 23197773 WIN55,212.2 23197773 dopamine 23197773 haloperidol 23197773 methamphetamine 23197773 methanandamide 23197773 morphine 23197773 naltrexone 23197773 Δ(9)-THC 23197773 Δ(9)-tetrahydrocannabinol 23198782 sucrose 23199199 dithiols 23199985 Polyacrylamide 23199985 manganese 23199985 polyacrylamide 23199987 Polyamines 23199987 Putrescine 23199987 Tryptamine 23199987 amines 23199987 cadaverine 23199987 histamine 23199987 phenylethylamine 23199987 putrescine 23199987 spermidine 23199987 spermine 23199987 tryptamine 23199987 tyramine 23199989 (Z)-3-hexen-1-ol 23199989 2,5-dimethyl-4-hydroxy-3(2H)-furanone 23199989 2-phenylethanol 23199989 DMHF 23199989 hexanol 23199989 vanillin 23199989 β-damascenone 23199996 As 23199996 Ca 23199996 Cd 23199996 Cl 23199996 Cu 23199996 Fe 23199996 Hg 23199996 K 23199996 MeHg 23199996 Mg 23199996 Mn 23199996 Na 23199996 PUFA 23199996 Pb 23199996 Polyunsaturated fatty acids 23199996 S 23199996 Se 23199996 Zn 23199996 cholesterol 23199996 fatty acid 23199996 fatty acids 23199996 mercury 23199996 silver 23199996 α-tocoferol 23199998 Amide 23199998 GCB 23199998 STX 23199998 acetonitrile 23199998 formic acid 23200254 4-azaindole 23200254 4-azaindole oxoacetic acid piperazine benzamides 23200254 BMS-378806 23200255 (-)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one 23200255 4,4-dimethylpyrazolone 23200255 6-aryl-4,5-dihydropyridazin-3(2H)-one 23200255 KCA-1490 23200255 N 23200255 dihydropyridazinone 23200255 histamine 23200255 pyrazolopyridine 23200255 pyridazinone 23200732 Estrogens 23200732 estrogen 23200732 estrogens 23200732 steroid 23200735 3β-hydroxysteroid 23200735 ATZ 23200735 androgen 23200735 atrazine 23200735 cyclic-AMP 23200735 estrogen 23200735 quercetin 23200888 Thiazole 23200888 Zn 23200888 thiadiazole 23200888 thiazole 23200942 organophosphate 23200942 sarin 23200942 soman 23200942 tabun 23200943 20α-hydroxysteroid 23200943 3-keto and 20-ketosteroid 23200943 3β-hydroxysteroid 23200943 ketosteroid 23200943 progesterone 23200944 Zn 23200944 alcohol 23201051 Brij-700 23201051 Stearoyl-PEG-polySDM 23201051 amino 23201051 fluorescein 23201051 methacryloyl sulfadimethoxines 23201051 paclitaxel 23201051 stearoyl-PEG-NH2 23201051 stearoyl-PEG-poly-sulfadimethoxine methacrylate 23201051 stearoyl-PEG-polySDM 23201051 sulfadimethoxine methacrylate 23201092 GnIH 23201092 Gonadotrophin-inhibitory hormone 23201179 AVP 23201179 AVT 23201179 arginine vasopressin 23201179 arginine vasotocin 23201179 vasotocin 23201180 (+)-fenamiphos 23201180 (-)-fenamiphos 23201180 Ca(2+) 23201180 Fenamiphos 23201180 ethanol 23201180 ethyl 4-methylthio-m-tolyl isopropylphosphoramidate 23201180 fenamiphos 23201180 hexane 23201180 organophosphorus 23201337 Oxytocin 23201337 estrogen 23201337 oxytocin 23201337 progesterone 23201371 2-acetyl-amino-fluorene 23201371 2-aminoanthracene 23201371 2AA 23201371 2AF 23201371 ENNG 23201371 MNNG 23201371 NLX 23201371 NOR 23201371 Vitamin B1 23201371 Vitamin B12 23201371 Vitamins B 23201371 ethyl-N-nitro-N'- nitrosoguanidine 23201371 methyl-N-nitro-N-nitrosoguanidine 23201371 nalidixic acid 23201371 norfloxacin 23201371 vitamins B 23201371 vitamins B1 and B6 23201371 vitamins B1, B6 and B12 23201441 OFLX 23201441 ofloxacin 23201441 prostaglandin 23201441 quinolone 23201452 ethanol 23201622 PEI 23201622 Polyethyleneimine 23201622 polyethyleneimine 23201927 ATO 23201927 Hoechst 33342 23201927 LY294002 23201927 MTT 23201927 Sal B 23201927 arsenic trioxide 23201927 salvianolic acid B 23202134 MDA 23202134 Pb 23202134 jasmonic acid 23202134 superoxide 23202371 MoS(2) 23202371 MoS2 23202371 graphene 23202371 transition-metal dichalcogenides 23202372 Li(2)O(2) 23202372 Li-O(2) 23202372 Na-O(2) 23202372 NaO(2) 23202372 NaO2 23202372 carbon 23202372 carbonate 23202372 lithium 23202372 oxides 23202372 oxygen 23202372 sodium 23202372 sodium superoxide 23202442 (13)C 23202442 13C 23202442 Cu(II) 23202846 CN 23202846 Cbz 23202846 Cys 23202846 N 23202846 carbobenzyloxy 23202846 nitrile 23202847 Amphotericin-B 23202847 Ampicillin 23202847 Kanamycin 23202847 Nystatin 23202847 bisulfone 23202847 bisulfones 23202847 chalcone 23202847 chalcone sulfides 23202847 m-CPBA 23202847 sodium 23202847 sulfone 23202847 sulfones 23202847 thiophenol 23202848 (E)-5-alkoxy-3-(3-hydroxy-3-phenylprop-1-enyl)-4H-chromen-4-ones 23202848 (E)-5-alkoxy-3-(3-phenyl-3-oxoprop-1-enyl)-4H-chromen-4-ones 23202848 Propenone 23202848 allylic alcohol 23202848 chalcone 23202848 chromenone 23202848 hydrogen 23202848 hydroxyl 23202848 isoflavone 23202848 phenyl 23202851 14-membered 9-O-(3-arylalkyl) oxime 11,12-cyclic carbonate ketolides 23202851 4-isoquinolyl 23202851 9-O-(3-aryl-2-propargyl)oxime ketolides 23202851 azithromycin 23202851 clarithromycin 23202851 methicillin 23202851 propenyl 23202851 propyl 23202851 propynyl 23202852 (E)-2-methyl-N'-(4-phenyl-3-furoxanylmethylidene)-4H-imidazo[1,2-a]pyridine-3-carbohydrazide 23202852 (E)-N'-(4-hydroxy-3-methoxyphenylmethylidene)-3-methylfuroxan-4-carbohydrazide 23202852 (E)-N'-(5-benzofuroxanylmethylidene)benzo[d][1,3]dioxole-5-carbohydrazide 23202852 Furoxanyl N-acylhydrazone 23202852 N'-(4-phenyl-3-furoxanylmethylidene)isoniazide 23202852 N-Acylhydrazone 23202852 furoxan 23202852 furoxanyl N-acylhydrazone 23202852 furoxanyl N-acylhydrazones 23202852 isoniazid 23202986 (1)H(N) 23202986 N-H 23202986 O=C 23202986 hydrogen 23202986 ¹H(N) 23203941 vitamin B(12) 23203941 vitamin-B(12) 23204111 2,3,7,8-tetrachlorodibenzo-p-dioxin 23204111 TCDD 23204111 aryl hydrocarbon 23204517 ATP 23204517 Ca(2+) 23204517 Ca2+ 23205514 9-hydroxyrisperidone 23205514 risperidone 23205567 Nitric Oxide 23205584 perfluoropolyether 23205634 Bile acids 23205634 bile acids 23205634 cholesterol 23205668 InP 23205668 indium 23205668 wurtzite 23205668 zinc-blende 23205727 PZT 23205727 Pb(Zr(0.52)Ti(0.48))O(3) 23205740 Nafion 23205740 calcium 23205740 dimethyl methylphosphonate 23205740 hydrated Nafion 23205740 hydrated sPS 23205740 polyethylene 23205740 polyolefin 23205740 potassium 23205740 sPS 23205740 sarin 23205740 sulfonated polystyrene 23206276 Ag 23206276 Au 23206276 Fe(3)O(4) 23206276 Fe3O4 23206276 RdB 23206276 Rhodamine-b 23206276 SiO(2) 23206276 SiO2 23206310 corticosteroids 23206310 mycophenolic acid 23206865 imide 23206865 naphthalimide 23206865 naphthalimides 23206865 propargyl 23206867 benzamides 23207055 DMP 23207055 dimethyl phthalate 23207055 hydrogen peroxide 23207055 hydroxylated monomethyl phthalates 23207055 hydroxylated phthalic acid 23207056 DHBA 23207056 dihydroxybenzoic acid 23207056 hydroxyl 23207056 salicylic acid 23207323 apomorphine 23207409 chalcones 23207409 chromones 23207409 coumarins 23207409 thiazolylhydrazones 23207679 Triterpene saponins 23207679 epicatechin 23207679 lignan glycoside 23207679 saponins 23207679 triterpene saponins 23208411 graphene 23208411 graphene oxide 23208787 (18) F 23208787 (19) F 23208822 (-)-bengamide E 23208822 Zn(BH(4))(2) 23208822 bengamide E 23208822 bis(dimethylamide) 23208822 polyhydroxy caprolactam amide 23208822 tartaric acid 23208955 GDP 23208955 GTP 23208955 nucleotide 23208955 silica 23209285 Arg 23210482 fusicoccin A 23210639 PNIMAAm 23210639 PNIPAAm 23210639 poly-N-isopropylacrylamide 23210742 (1)H 23210742 4-phenylazo benzoic acid 23210742 ACA 23210742 OHAC 23210742 cis-ACA 23210742 oleyl bis(2-hydroxyethyl)methyl ammonium chloride 23210742 sodium 23210742 trans-ACA 23210774 ATP 23210774 CX-4945 23210777 Taxanes 23210777 Taxol 23210777 methyl jasmonate 23210777 paclitaxel 23210777 taxane 23210777 taxanes 23210780 Pentacyclic triterpenoids 23210780 betulin 23210780 betulinic acid 23210780 glucose 23210780 glycyrrhetinic acid 23210780 glycyrrhizin 23210780 lupane 23210780 lupeol 23210780 oleanane 23210780 oleanolic acid 23210780 pentacyclic triterpenes 23210780 pentacyclic triterpenoids 23210780 ursane 23210780 ursolic acid 23210786 cinnamtannin B1 23210786 crocin 23210786 resveratrol 23210786 thymoquinone 23210852 DCQAs 23210852 cyclohexylidene 23210852 dicaffeoyl and digalloyl esters 23210852 dicaffeoylquinic acids 23210852 digalloyls 23210852 quinic acid 23210854 lysine 23210854 methyl 23211363 (-)-NPA 23211363 ARI 23211363 Dopamine 23211363 ETIC 23211363 R(-)-norpropylapomorphine 23211363 aripiprazole 23211363 cocaine 23211363 dopamine 23211363 eticlopride 23211441 afzelin 23211441 alanine 23211441 aspartate 23211441 glutathione 23211441 quercitrin 23211441 t-BHP 23211441 tert-butyl hydroperoxide 23211707 Estrogen 23211707 Steroid 23211707 estrogen 23211707 estrogens 23211707 propyl pyrazole triol 23211707 steroid 23212047 (ar2)Guo 23212047 ADP 23212047 GMP 23212047 GTP 23212047 N(2)-(ADP-ribos-1-yl)-guanosine 23212047 NAD(+) 23212047 cyclic GMP 23212047 dGMP 23212047 dGTP 23212047 deoxyguanosine 23212047 guanine mononucleotides 23212047 guanosine 23212047 nucleoside 23212107 Vitamin K 23212107 apixaban 23212107 dabigatran 23212107 rivaroxaban 23212107 warfarin 23212238 Br 23212238 CH(2)XO 23212238 CH2XO 23212238 Cl 23212238 F 23212238 NO 23212238 hydrogen 23212912 Val 23212963 1-naphthylamine 23212963 2-naphthol 23212963 Carbon 23212963 Lewis acid 23212963 SDS 23212963 carbon 23212963 phenanthrene 23212963 sodium dodecyl sulfate 23212976 PCBs 23212976 dioxins 23212976 organochlorine 23212976 polychlorinated biphenyls 23212976 polychlorinated dibenzo-p-dioxins 23213044 RGO 23213044 Reduced graphene oxide 23213044 reduced graphene oxide 23213199 17β-Estradiol 23213199 Estradiol 23213199 H(2)O(2) 23213199 acetoxymethylester 23213199 calcein 23213199 cobalt 23213199 estrogen 23213199 steroid 23213199 superoxide 23214973 PVA 23214973 alkynyl 23214973 alkynyl PVA 23214973 alkynyl polyvinyl alcohol 23214973 azide 23214973 sialic acid 23215039 cysteine 23215051 ZnMgSe 23215051 ZnSe 23215051 fluorine 23216107 (•)OH 23216107 Fe(2+) 23216107 carbohydrate 23216107 phenolic 23218401 aspalathin 23218401 dihydrochalcone 23218401 glucose 23218401 juglone 23218401 polyphenols 23218401 superoxide 23218718 curcumin 23218718 doxorubicin 23218718 monocarbonyl 23219324 Metachromins 23219324 amino acid 23219324 metachromins 23219324 metachromins L-Q 23219324 sesquiterpenoid quinones 23219324 tyrosine 23219338 glucose 23219338 streptozotocin 23219338 triglyceride 23219593 4-tert-Octylphenol 23219593 4-tert-octylphenol 23219593 MTT 23219593 estrogen 23219593 steroid 23219683 Fe 23219683 Pb 23219683 iron 23219702 (+)-sattabacin 23219702 sattabacin 23219925 3-Hydroxykynurenine 23219925 3-hydroxykynurenine 23219925 Kynurenine 23219925 tryptophan 23219934 3-(1H-indol-3-yl)-2-[3-(4-nitrophenyl)ureido]propanamide 23219934 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones 23219934 Ca(2+) 23219934 N-formyl 23219934 PD168368 23219934 PD176252 23219934 formyl 23219934 ureidopropanamide 23219934 ureidopropanamides 23220035 BBP 23220035 DBP 23220035 DEHP 23220035 DEP 23220035 Esters 23220035 aryl hydrocarbon 23220035 benzyl butyl phthalate 23220035 di-(2-ethy hexyl) phthalate 23220035 dibutyl phthalate 23220035 diethyl phthalate 23220035 estradiol 23220035 estrogen 23220035 phthalate 23220035 phthalates 23220035 phthalic acid 23220035 steroid 23220037 ATP 23220037 DOX 23220037 Doxorubicin 23220037 MTT 23220037 [³H]-choline 23220037 choline 23220037 doxorubicin 23220037 paraquat 23220041 Capreomycin 23220041 Capreomycin oleate and linoleate 23220041 capreomycin 23220041 capreomycin linoleate and linolenate 23220041 capreomycin linolenate 23220041 capreomycin oleate 23220041 capreomycin sulfate 23220041 linoleate 23220041 linolenate 23220041 oleate 23220145 MTT 23220145 acetone 23220145 phenol 23220145 phenolic 23220145 physodic acid 23220145 pyrocatechol 23220145 superoxide 23220290 FITC 23220290 MTT 23220290 SDC 23220290 bile salt 23220290 bile salts 23220290 sodium deoxycholate 23220340 Cyclosporine A 23220340 d-polylactide 23220340 l-polylactide 23220340 polyethylene glycol 23220340 polyglycolic acid 23220489 H(2)O 23220512 GKB 23220512 azoxymethane 23220512 ethanol 23220512 gymnasterkoreayne B 23220512 polyacetylene 23220512 polyacetylenes 23220512 sodium 23220609 17β-estradiol 23220609 Benzylparaben 23220609 BzP 23220609 benzylparaben 23220609 estrogen 23220609 parabens 23220614 4261-42-1 23220614 ISO 23220614 Isoorientin 23220614 NAC 23220614 SB203580 23220614 SP600125 23220614 U0126 23220614 flavonoid 23220614 isoorientin 23220616 Glutathione 23220616 S-adenosylhomocysteine 23220616 S-adenosylmethionine 23220616 cysteine 23220616 homocysteine 23220616 hypotaurine 23220616 methionine 23220616 polyamine 23220616 putrescine 23220616 spermidine 23220616 sulfur 23220616 sulfur amino acid 23220616 sulfur amino acids 23220616 γ-glutamylcysteine 23220618 IMG 23220618 hyperoside 23220618 isorhamnetin-3-O-galactoside 23220618 methoxy 23220641 AcK 23220641 N(ε)-acetyl-lysine 23220641 NAD(+) 23223020 fructose 23223020 glucose 23223125 fullerene 23223125 phthalocyanine 23223177 AMP 23223177 NH2 23223177 glucose 23223177 metformin 23223499 17β-estradiol 23223499 cortisol 23223499 estrogen 23223499 estrogens 23223499 progesterone 23223802 Cu(2+) 23223802 copper 23223802 silver 23225346 2-Phenoxy-nicotinamides 23225346 bile acid 23225753 ganglioside 23225753 gangliosides 23228341 Organotins 23228341 organotin 23228341 organotins 23228341 tributyltin 23228341 triorganotin 23228472 uracil 23228886 THP 23228886 Tetrahydropapaveroline 23228886 amino acid 23228886 carbonyl 23228886 catechol 23228886 copper 23228886 dityrosine 23228886 glutamate 23228886 l-DOPA 23228886 lysine 23228886 oxygen 23228886 proline 23228886 tetrahydropapaveroline 23229056 11,4″-disubstituted azithromycin 23229056 3,5-dinitrophenyl 23229056 azithromycin 23229056 bisamide 23229056 clarithromycin 23229056 erythromycin 23229056 erythromycin A 23229057 (1)H 23229057 (31)P 23229057 1,3,5-triaza-7-phosphaadamantane 23229057 Copper 23229057 CuCl 23229057 MTT 23229057 N 23229057 O 23229057 PCN 23229057 PTA 23229057 [Cu(CH(3)CN)(4)]BF(4) 23229057 bis(azolyl)borates 23229057 bis(triazolyl)borate 23229057 cisplatin 23229057 copper(I) 23229057 phosphine 23229057 phosphine/scorpionate copper(I) complexes 23229057 phosphines 23229057 poly(pyrazolyl)methanes 23229057 tertiary monodentate phosphine 23229057 tris(cyanoethyl)phosphine 23229057 {[H(2)B(tz(NO2))(2)]Cu[PCN]}(n) 23229136 Cr 23229136 Ni 23229136 platinum 23229141 cystine 23229141 disulfide 23229510 (N-(1-benzyl-piperidin-4-yl)-2-(4-fluoro-phenyl)-benzo[d]imidazo[2,1-b]thiazole-7-carboxamide) 23229510 E235 23229510 N-(1-benzyl-piperidin-4-yl)-2-(4-fluoro-phenyl)-benzo[d]imidazo[2,1-b]thiazole-7-carboxamide 23229510 Ser 23229510 amino acid 23229556 Gln 23229556 carbohydrate 23229556 carbon 23229556 xylose 23229556 α1,6-xylose 23230133 ATP 23230133 Danofloxacin 23230133 adenosine triphosphate 23230133 danofloxacin 23230905 Au 23230905 PEG 23230905 PLA 23231351 Porphyrin 23231351 porphyrin 23231351 porphyrins 23231410 hydrogen 23231410 hydronium 23231410 sulfonate 23231410 sulfonic acid 23231410 sulfonic-acid 23231420 MPTS 23231420 PMPTS 23231420 PSQ 23231420 ethanol 23231420 methacryloxypropylene 23231420 poly(γ-methacryloxypropyl trimethoxysilane) 23231420 polysilsesquioxane 23231420 polystyrene 23231420 styrene 23231420 γ-methacryloxypropyl trimethoxysilane 23232060 4-phenyl-2-phenylaminopyridine 23232079 Citalopram 23232079 citalopram 23232123 amino acid 23232323 (2E, 4E, 14Z)-6-hydroxyl-N-isobutyleicosa-2,4,14-trienamide 23232323 3β, 4α-dihydroxy-1-(3-phenylpropanoyl)-piperidine-2-one 23232323 amide alkaloids 23232711 porphyrin 23232711 porphyrins 23233324 Chlorothalonil 23233324 chlorothalonil 23234271 2,6-diazatricyclo[3.3.1.1∼3,7∼]decane 23234271 3-oxa-7-aza-bicyclo[3.3.1]nonanes 23234271 carbamate 23234271 diazatricyclic 23234271 diazatricyclodecane 23234271 diazatricylic 23234434 3-hydroxypicolinic acid 23234434 6-(1-piperidinyl)pyridine-3-carboxlic acid 23234434 6-methylpyridine-2-carboxylic acid 23234434 DMEC 23234434 LEA 23234434 LLA 23234434 N 23234434 PPCA 23234434 Pd acetate 23234434 bis(acetonitrile)dichloropalladium(II) 23234434 dimethylethynylcarbinol 23234434 dimethylvinylcarbinol 23234434 iron oxide 23234434 isonicotinic acid 23234434 linolenic (LLA) and linoleic (LEA) acids 23234434 pyridine 23235156 Ca(2+) 23235156 calcium 23235690 Fe 23235690 Li 23235690 Si 23235690 Ti 23235690 lithium 23235690 silicon 23235923 calcium 23235923 cyclic adenosine monophosphate 23235923 potassium 23237384 Sulfonylureas 23237384 amino acid 23237384 ethyl 2-(N-((4-iodo-6-methoxypyrimidin-2-yl)carbamoyl)sulfamoyl)benzoate 23237384 sulfonylurea 23237384 sulfonylureas 23237450 Ca(2+) 23237450 Calcium 23237450 calcium 23237450 phosphate 23237733 4-MU 23237733 4-methylumbelliferone 23237733 Isoliquiritigenin 23237733 UDP 23237733 chalcone 23237733 isoliquiritigenin 23237835 EETs 23237835 amide 23237835 epoxide 23237835 epoxyeicosatrienoic acids 23237835 piperidine 23237835 urea 23237860 4-hydroxy-2-ketovalerate 23237860 CoA 23237860 acetaldehyde 23237860 acetyl-CoA 23237860 aldehyde 23237860 aldehydes 23238103 17β-estradiol 23238103 Estrogen 23238103 androgen 23238103 corticosterone 23238103 estradiol 23238103 estrogen 23238103 steroid 23238103 testosterone 23238226 Cr 23238226 Si 23238226 SiGe 23238226 ammonia 23238299 Chelidonine 23238299 chelidonine 23238299 doxorubicin 23238299 phosphatidyl serine 23238299 protoberberine and benzo[c]phenanthridine alkaloids 23238642 Arsenate 23238642 As 23238642 As(3+) 23238642 As(5+) 23238642 Cr(2+) 23238642 Cu(2+) 23238642 Ni(2+) 23238642 arsenate 23238642 arsenic 23238642 arsenite 23238784 DMSO 23238784 UDP 23238784 bile acid 23238784 bile acids 23238784 bile salts 23238784 dimethyl sulfoxide 23238784 dimethylsulfoxide 23238784 rifampicin 23239458 4-N,N-dimethylamino-1,8-naphthalimide 23239550 17,17-dialkyl-3,14-diaryltetrabenzofluorenes 23239550 3,14-Bis(p-nitrophenyl)-17,17-dipentyltetrabenzo[a,c,g,i]-fluorene 23239550 3,14-dibromo 23239550 THF 23239550 bis(p-nitrophenyl) 23239550 tetrahydrofuran 23239602 FePO4 23239602 Li 23239629 DMAPMA 23239629 N-[3-(dimethylamino)propyl] methacrylamide 23240979 OPE 23240979 OPEs 23240979 PPE 23240979 oligo-phenylene ethynylenes 23240979 oxygen 23240979 poly(phenylene ethynylene) 23240995 Al 23240995 GaAs 23240995 In 23240995 In(0.2)Ga(0.8)As 23240995 InGaAs 23240995 Si 23240995 SiN(x) 23240995 SiO(2) 23240995 silicon 23240995 wurtzite 23241082 (31)P 23241082 1-butyl-3-methylimidazolium hexafluorophosphate 23241082 31P 23241082 PF(6)(-) 23241082 PF6(-) 23241082 [C(4)mim]PF(6) 23241082 ammonium salts 23241082 hexafluorophosphate 23243006 Valproic acid 23243006 flusilazole 23243006 methylmercury 23244033 MnO(2) 23244033 Pd 23244033 carbon 23244162 PAA 23244162 PMMA(PAA) 23244162 PS(PAA) 23244162 PS(PVP) 23244162 PVP 23244162 hydrogen 23244162 poly(acrylic acid) 23244162 poly(methyl methacrylate) 23244162 poly(vinyl pyrrolidone) 23244162 polystyrene 23244292 B 23244292 B-doped graphene 23244292 O 23244292 borane 23244292 carbon 23244292 graphene 23244292 graphene oxide 23244292 tetrahydrofuran 23244594 (1)H 23244594 C(12)φ(2)C(12) 23244594 C(12)φC(12) 23244594 O,O'-bis(sodium 2-dodecylcarboxylate)-p-benzenediol 23244594 O,O'-bis(sodium 2-dodecylcarboxylate)-p-dibenzenediol 23244594 alkyl 23244594 carboxylate 23244594 phenyl 23244629 2-aminoethyl methacrylate hydrochloride 23244629 AEMA 23244629 AIBN 23244629 N-isopropylacrylamide 23244629 NIPAAM 23244629 ammonium hydroxide 23244683 Si 23244683 SiO(2) 23244683 graphene 23244683 oxide 23245513 MCND 23245513 N-methoxycarbonyl-2-amino-1,8-naphthyridine 23245513 adenine 23245513 guanine 23245513 hydrogen 23245513 methylcarbamate 23245515 GSK364735 23245515 NTD 23245515 Naphthyridinone 23245515 amide 23245515 methyl 23245515 methyl naphthyridinone 23245695 Cisplatin 23245695 cisplatin 23245695 guanines 23245695 nucleotide 23246460 glufosinate ammonium 23246469 1,2-dipalmitoyl-sn-glycero-3-phosphocholine 23246469 1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol 23246469 1,2-distearoyl-sn-glycero-3-phosphocholine 23246469 DPPG(2) 23246469 Gd 23246469 Gd-BOPTA 23246469 Gd-BT-DO3A 23246469 Gd-DOTA 23246469 Gd-DTPA 23246469 Gd-DTPA-BMA 23246469 Gd-HP-DO3A 23246469 phosphatidyldiglycerol 23246481 H2O2 23246481 Wogonin 23246481 anisomycin 23246481 monoflavonoid 23246481 wogonin 23246578 Boc2 23246578 dexamethasone 23246578 formyl 23246578 indomethacin 23246578 zileuton 23246611 DMSO 23246611 H2O2 23246611 Hydrogen peroxide 23246611 NaHCO3 23246732 Pb 23246732 Pb acetate 23246732 methyl cytosine 23246797 HP-β-CD 23246797 Inegy 23246797 Soluplus 23246797 Tandemact 23246797 ezetimibe 23246797 glimepiride 23246797 hydroxypropyl-β-cyclodextrin 23246797 pioglitazone 23246797 polyethylene glycol 23246797 polyvinyl acetate 23246797 polyvinyl caprolactam 23246797 simvastatin 23246798 Camphor 23246798 PEO 23246798 camphor 23246798 metformin 23247008 acetaldehyde 23247008 aldehydes 23247008 amino acid 23247048 aldosterone 23247407 Au 23247407 CO 23247471 Ga(+) 23247471 TiO(2) 23247471 TiO2 23247545 As 23247545 Cd 23247545 Cr 23247545 Cu 23247545 DDTs 23247545 Hg 23247545 Ni 23247545 PCBs 23247545 Pb 23247545 Se 23247545 Zn 23247722 CDCl(3) 23247722 DMSO-d(6) 23247722 MeOH-d(4) 23247722 chloroform 23247722 dimethyl sulfoxide 23247722 hydrogen 23247722 methanol 23247722 methyl mandelate 23248329 Glycosphingolipids 23248329 cholesterol 23248329 glycosphingolipid 23248329 sphingomyelin 23249265 carbon 23249265 graphene 23249265 silicon 23249276 3-bromo- and 3-chlorodiosmin 23249276 citroflavonoid 23249276 diosmin 23249276 flavone glycosides 23249300 perfluorosulfonic acid 23249300 poly(tetrafluoroethylene) 23249300 sulfonic acid 23249384 1,3-dioxolane, 1,4-dioxane, 1-propanol 23249384 2-propanol 23249384 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid 23249384 HEPES 23249384 THF 23249384 acetone 23249384 acetonitrile 23249384 tert-butanol 23249384 tetrahydrofuran 23249538 amino acid 23249624 Dabrafenib 23249624 dabrafenib 23249624 glutamic acid 23249624 serine 23249624 threonine 23249624 valine 23249624 vemurafenib 23249625 glucose 23249625 oxygen 23249626 sulfate 23249751 2'-O-methyl 23250808 6,7-dihydroxycoumarin 23250808 Azone 23250808 R-(+)-limonene 23250808 decenoic acid 23250808 esculetin 23250808 ethanol 23250808 laurocapram 23250808 oleic acid 23252553 Arg 23252553 Lys 23252553 Ser 23252553 ampicillin 23252553 boronic acid 23252553 clavulanate 23252553 clavulanic acid 23252553 hydrogen 23252553 sulfhydryl 23252613 Li 23252613 LiFePO(4) 23252799 PS-b-P4VP 23252846 Au 23252846 YBCO 23252846 YBa(2)Cu(3)O(7) 23252950 Busulfan 23252950 S 23252950 aldehyde 23252950 busulfan 23252950 chlorambucil 23252950 cyclophosphamide 23252950 glutathione 23252950 melphalan 23253427 CO 23253427 CORM-307 23253427 CORM-308 23253427 CORM-314 23253427 CORM-319 23253427 Carbon monoxide 23253427 DMSO 23253427 carbon monoxide 23253427 dimethylsulfoxide 23253427 hydrogen tetrafluoroborate 23253427 iron 23253427 iron carbonyls 23253427 iron-allyl carbonyls 23253427 iron-carbonyl 23253427 nitric oxide 23253427 organometallo carbonyl 23254197 Estradiol 23254197 androgen 23254197 estradiol 23254197 estrogens 23254197 steroid 23254198 BZA 23254198 bazedoxifene 23254198 estradiol 23254198 estrogen 23254198 estrogens 23254198 progesterone 23254198 progestogen 23254253 Ag 23254253 AgVO(3) 23254253 carbon 23254253 lithium 23254253 silver vanadium oxide 23254341 Ca(2+) 23254341 N 23254573 7-(N,N'-diethylamino)coumarin-3-carboxylic acid 23254573 7-DCCA 23254573 AOT 23254573 isooctane 23255101 silicon 23255236 N 23255254 2-aminoethylmethacrylate 23255254 ammonium 23255254 cyanamide 23255254 guanidine 23255254 poly(2-aminoethylmethacrylate) 23255426 (1)H 23255426 selenium 23256440 norbornene 23256440 polystyrene 23256525 Ag(55) 23256525 Ag(55)-SCH(3) 23256525 Ag55 23256525 SCH(3) 23256525 SCH3 23256525 methyl-thiol 23256525 silver 23256525 thiol 23256531 C(12)G(2) 23256531 C(60) 23256531 CTAB 23256531 CTAC 23256531 Fullerene 23256531 benzene 23256531 butanol 23256531 cetyltrimethylammonium bromide 23256531 cetyltrimethylammonium chloride 23256531 diglycerol monolaurate 23256531 fullerene 23256625 GSK1292263 23256625 rosuvastain 23256625 rosuvastatin 23256625 simvastatin 23256708 (-)-hinokiresinol 23256708 (-)-nyasol 23256708 1,4-dienes 23256708 Ir 23256708 Ir-(P,olefin) 23256708 Iridium 23256708 allylic alcohols 23256708 potassium alkenyltrifluoroborates 23256708 trienes 23256708 vinyl trifluoroborates 23257178 Steroid 23257178 androstenedione 23257178 ergosterol 23257178 steroid 23257178 steroids 23257178 sterol 23257178 testosterone 23257178 tryptophan 23257312 (+)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d]oxazol-4(5H)-one 23257312 2,5-dimethoxy-4-iodoamphetamine 23257312 ADX71743 23257312 L-(+)-2-amino-4-phosphonobutyric acid 23257312 amphetamine 23257312 glutamate 23257627 6-amino-4-(2,4-dimethoxyphenyl)-[1,2]dithiolo[4,3-b]pyrrol-5-ones 23257627 cyclophosphamide 23257735 aldosterone 23257735 cortisol 23257777 graphane 23257777 graphene 23257777 hydrogen 23258121 (4,4')-Bipyridine 23258121 (4,4')-bipyridine 23258121 44BPY 23258121 pyridine 23258548 25HC3S 23258548 5-cholesten-3β,25-diol 3-sulfate 23258548 acetyl-CoA 23258548 cholesterol 23258548 fatty acid 23258548 glucose 23258548 glycerol-3-phosphate 23258566 (18)O 23258566 Al(2)O(3) 23258566 Oxygen 23258566 Y(2)O(3) 23258566 Y2O3 23258566 YSZ 23258566 ZrO(2) 23258566 oxygen 23259487 Fe 23259487 Fe(II) 23259487 Fe(III) 23259487 Iron 23259487 O(2) 23259487 O2 23259487 TpivPP 23259487 [Fe(II)(pfp)(1-MeIm)(2)] 23259487 [Fe(II)(pfp)] 23259487 [Fe(III)(tpp)(ImH)(2)]Cl 23259487 [Fe(pfp)(1-MeIm)O(2)] 23259487 heme 23259487 iron 23259487 meso-tetra(α,α,α,α-o-pivalamidophenyl)porphyrin 23259487 meso-tetraphenylporphyrin 23259487 oxy-pfp 23259487 pfp 23259487 picket fence porphyrin 23259487 porphyrin 23259487 tpp 23259533 Graphene 23259533 Si 23259533 graphene 23259708 Ag 23259708 Au 23259708 silver 23259819 NaBH(4) 23259819 Pd 23259819 Pt 23259819 Sn(2+) 23259819 SnO(2) 23259819 Vulcan XC-72R 23259819 alcohol 23259819 carbon 23259819 graphene 23259819 graphene oxide 23259848 2-(dimethylamino)ethyl methacrylate 23259848 C-H 23259848 DMAEMA 23259848 GMA 23259848 P(DMAEMA) 23259848 P(GMA) 23259848 bromoalkyl 23259848 epoxy 23259848 glycidyl methacrylate 23259848 polypropylene 23260346 carbamate 23260346 darapladib 23260346 serine 23260350 Benzofuran 23260350 LTA(4) 23260350 LTB(4) 23260350 Leukotriene A(4) 23260350 Leukotrienes 23260350 benzofuran 23260350 benzofurans 23260350 leukotriene A(4) 23261051 MMS 23261051 methyl methane sulfonate 23261423 3,4-Methylenedioxy-methamphetamine 23261423 3,4-methylenedioxy-methamphetamine 23261423 MDMA 23261423 NIC 23261423 Nicotine 23261423 [(3)H]epibatidine 23261423 [(3)H]methyllycaconitine 23261423 [(3)H]paroxetine 23261423 acetylcholine 23261423 nicotine 23261423 serotonin 23261526 2-HEDS 23261526 2-hydroxyethyl disulfide 23261526 4-hydroxynonenal 23261526 HNE 23261526 S 23261526 aldehyde 23261526 amino acids 23261526 glutathione 23261526 methyl parathion 23261526 thiol 23261589 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 23261589 LY294002 23261589 MPTP 23261589 SAL 23261589 Sal 23261589 Salsolinol 23261589 catechol isoquinoline 23261643 Neutral Red 23261643 acetylsalicylic acid 23261643 aflatoxin B1 23261643 atropine sulphate monohydrate 23261643 benzo(a)pyrene 23261643 cycloheximide 23261643 sodium lauryl sulphate 23261643 valproic acid 23261672 glufosinate ammonium 23261678 oleuropein 23261679 Monotropein 23261679 monotropein 23261679 nitric oxide 23261679 sodium 23261757 gentamicin 23261757 nitrate 23261757 vitamin D 23262028 streptozotocin 23262035 (1)H 23262035 (13)C 23262035 (E)-3-(Benzo [d]thiazol-2-ylamino) phenylprop-2-en-1-one 23262035 (E)-3-(Benzo [d]thiazol-2-ylamino)phenylprop-2-en-1-one 23262035 1-aryl-3,3-bis- (methylsulfanyl)-2-propen-1-ones 23262035 2-aminobenzothiazole 23262035 THF 23262035 sodium hydride 23262161 PEG 23262161 PVA 23262161 poly(ethylene glycol) 23262161 poly(vinyl alcohol) 23262201 HPMA 23262201 N-(2-hydroxypropyl)methacrylamide 23262201 PTX 23262201 paclitaxel 23262268 C(22)-steroidal lactone glycosides 23262268 chonglouoside SL-7 23262268 chonglouoside SL-8 23262392 Caffeine 23262392 Glutamate 23262392 PMA 23262392 amino acid 23262392 caffeine 23262392 chelerythrine 23262392 glutamate 23262392 l-Glutamate 23262392 phorbol-12-myristate-13-acetate 23262392 staurosporine 23262392 wortmannin 23262562 Ag 23262562 Ag(+) 23262562 H 23262562 H(+) 23262562 H(2) 23262562 [C(4)mim][BF(4)] 23262562 [C(4)mim][NTf(2)] 23262562 [C(4)mim][OTf] 23262562 [C(4)mpyrr][NTf(2)] 23262562 benzoic acid 23262562 bis(benzyloxycarbonyl)-l-lysine 23262562 hydrogen 23262562 platinum 23263362 Fe 23263362 Fe2S2 23263362 Fe3S4 23263362 Fe4S4 23263362 Fe₂S₂ 23263362 Fe₃S₄ 23263362 Fe₄S₄ 23263362 S 23263864 C 23263984 amino acid 23263984 fatty acid 23264019 Lindane 23264019 gamma-HCH 23264019 lindane 23264448 Acyclovir 23264448 Valacyclovir 23264448 [(3)H]valacyclovir 23264448 acyclovir 23264448 amino acids 23264448 aminocephalosporin cefadroxil 23264448 glycylsarcosine 23264448 l-histidine 23264448 l-valine 23264448 p-aminohippurate 23264448 tetraethylammonium 23264448 valacyclovir 23265191 Fe(4)S(4) 23265191 Fe-S 23265191 Fe4S4 23265191 Iron-sulfur 23265191 L-cysteine 23265191 cysteine 23265191 iron 23265191 iron-sulfur 23265191 sulfur 23265312 silicon 23265447 Ca 23265447 CaCl(2) 23265447 K 23265447 KCl 23265447 Mn 23265447 Na 23265447 NaCl 23265447 sodium 23265448 platinum 23265448 potassium triiodide 23265448 triiodide 23265450 hydrogen peroxide 23265450 urea 23265451 antheraxanthin 23265451 epoxy 23265451 furanoxy 23265451 violaxanthin 23265451 β-cryptoxanthin 23265454 FITC 23265454 MTT 23265454 Myricetin 23265454 acridine orange 23265454 flavonoid 23265454 flavonoids 23265454 myricetin 23265454 myricitrin 23265454 quercetin 23265454 quercitrin 23265455 Bromopropylate 23265455 Chlorpyrifos 23265455 Iprodione 23265455 Lambda-Cyhalothrin 23265455 Penconazole 23265455 Procymidone 23265455 cyclohexane 23265455 ethyl acetate 23265455 florosil 23265457 amino acids 23265457 ergothioneine 23265457 nucleotides 23265457 γ-aminobutyric acid 23265460 DON 23265460 deoxynivalenol 23265463 2,3-dehydrosilybin 23265463 CCl(4) 23265463 DHS 23265463 alanine 23265463 aspartate 23265463 carbon tetrachloride 23265463 glutathione 23265463 nitric oxide 23265463 superoxide 23265464 2,2'-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) 23265464 6-hydroxy-2,5,7,8-tetramethychroman-2-carboxylic acid 23265464 ABTS 23265464 ABTS(+) 23265464 Trolox 23265464 superoxide 23265465 (S)-2-(4-hydroxyphenyl)propionic acid 23265465 (S)-2-phenylpropionic 23265465 2-(4-hydroxyphenyl)propionic acid 23265465 2-HPPA 23265465 O-desmethylangolensin 23265465 daidzein 23265465 genistein 23265465 isoflavonoids 23265468 acetic acid 23265468 flavonoids 23265468 methanol 23265468 phenolic acids 23265471 4-hydroxybenzyl alcohol 23265471 anisyl alcohol 23265471 glucovanillin 23265471 phenolics 23265471 vanillin 23265472 Manganese 23265472 Vitamin C 23265472 calcium 23265472 carbohydrate 23265472 carbohydrates 23265472 copper 23265472 iron 23265472 magnesium 23265472 phosphorous 23265472 potassium 23265472 sodium 23265472 vitamin C 23265472 zinc 23265473 1-butyl-3-methylimidazolium bromide 23265473 glycyrrhizic acid 23265473 isoliquiritigenin 23265473 liquiritin 23265474 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine 23265474 4-oxo-2-nonenal 23265474 CRN 23265474 PhIP 23265474 Phe 23265474 ammonia 23265474 carbonyl 23265474 carbonyls 23265474 creatinine 23265474 oxygen 23265474 phenylacetaldehyde 23265474 phenylalanine 23265484 E-β-ocimene 23265484 linalool 23265484 n-heptadecan 23265484 n-heptanol 23265484 β-phellanderne 23265484 α-pinene 23265489 9,10-epoxy-18-hydroxyoctadecanoic acid 23265494 1,5-DCQA 23265494 1,5-dicaffeoylquinic acid 23265494 5-CQA 23265494 acetic acid 23265494 acetonitrile 23265494 caffeoyl esters 23265494 caffeoylquinic acid 23265494 chlorogenic acid 23265496 Tris-HCl 23265496 diethylaminoethyl 23265505 DPPH 23265505 caffeic and benzoic acids 23265505 ethanol 23265505 flavonoids 23265505 methanol 23265505 phenolic acids 23265509 Punicalin 23265509 TFA 23265509 gallic acid 23265509 methanol 23265509 punicalagin 23265509 punicalin 23265509 tannin 23265510 Retinoid 23265510 retinoic acid 23265510 retinoid 23265510 retinoids 23265510 retinol 23265510 vitamin A 23265511 ABTS(·+) 23265511 Lutein 23265511 hydroxyl 23265511 oxygen 23265511 tocopherols 23265511 α-tocopherol 23265515 1-octyl-3-methylimidazolium hexafluorophosphate 23265515 Arsenic 23265515 As(III) 23265515 As(V) 23265515 DDTC 23265515 [C(8)mim][PF(6)] 23265515 arsenic 23265515 arsenite 23265515 organo-arsenic 23265515 sodium diethyldithiocarbamate 23265516 anthocyanin 23265516 anthocyanins 23265516 baicalin 23265516 cyanidin quinoidal base 23265516 flavone 23265516 flavones 23265516 hydrogen 23265522 phenol 23265522 salicylic acid 23265523 Phenolic 23265523 anthocyanins 23265523 oxygen 23265523 phenolic 23265523 sulphorhodamine B 23265524 Glucose 23265524 bisulphite 23265524 fructose 23265524 glucose 23265524 hydrogen 23265524 sucrose 23265524 sugar 23265524 tannin 23265524 urea 23265528 1,1-diphenyl-2-picrylhydrazyl 23265528 DPPH 23265528 Ribose 23265528 anhydroribose 23265528 arabinose 23265528 carbohydrates 23265528 fructose 23265528 galactose 23265528 glucose 23265528 iron 23265528 lactose 23265528 ribose 23265532 2-acetylfurane 23265532 3-hexen-1-yl acetate 23265532 5-methyl furfural 23265532 alcohols 23265532 aldehydes 23265532 benzaldeyhde 23265532 butyl butyrate 23265532 citric acid 23265532 decanal 23265532 esters 23265532 fructose 23265532 furans 23265532 furfural 23265532 isobutyl acetate 23265532 isomaltulose 23265532 mesifurane 23265532 nonanal 23265532 octanal 23265532 propan-2-ol 23265532 sucrose 23265532 sugar 23265534 ABTS 23265534 ABTS radical cation 23265534 ABTS(+) 23265534 ethanol 23265537 amine 23265537 amines 23265537 histamine 23265537 histidine 23265537 lysine 23265537 tyramine 23265539 (E)-2-octenal 23265539 Aliphatic aldehydes 23265539 alcohols 23265539 aldehydes 23265539 aliphatic aldehydes 23265539 hexanal 23265539 nonanal 23265539 peroxide 23265539 pyrazines 23265872 milrinone 23265872 triazole acetamide 23265872 triazole acetamides 23265873 2,5-disubstituted-1,3,4-oxadiazoles 23265873 GABA 23265873 N(4)-(5-(2/3/4-substituted-phenyl)-1,3,4-oxadiazol-2-yl)-N(1)-(2-methyl-5-(prop-1-en-2-yl)cyclohex-2-enylidene)semicarbazide 23265873 N(4)-(5-(2/3/4-substituted-phenyl)-1,3,4-oxadiazol-2-yl)-N(1)-(3,7-dimethylocta-3,6-dienylidene)-semicarbazide 23265873 citral 23265873 limonene 23265873 pentylenetrtrazole 23265873 semicarbazones 23265873 strychnine 23265878 isocytosine 23265878 xanthine 23265884 1,14-spermine-di-(2-hydroxyphenylacetamide) 23265884 1,14-sperminedihomovanillamide 23265884 1,14-sperminediphenylacetamides 23265884 orthidine F 23265884 phenylacetamido-polyamines 23265884 polyamine 23265884 spermine 23265889 aminopyrimidine 23265889 dihydropyrrolopyrimidine 23265889 hydrogen 23265889 phenol 23265889 phenol glucuronic acid 23265893 (125)I 23265893 Tyr 23265893 bombesin 23265895 ST-193 23265895 ST-37 23265895 benzimidazole 23265895 methylamino 23265895 phenyl 23266309 Ca(2+) 23266309 calcium 23266310 cyanide 23266310 nitrate 23266491 Retinol 23266491 phosphate 23266491 retinoic acid 23266491 retinol 23266503 Baicalein 23266503 baicalein 23266503 flavonoid 23266665 H(2)Or(-) 23266665 H(3)Or 23266665 Me 23266665 Ph 23266665 R(2)Sn(H(2)Or)(2) 23266665 R(3)Sn(H(2)Or) 23266665 R(n)Sn(H(2)Or)(m) 23266665 Tri- and diorganotin(IV) 23266665 Tri-and diorganotin(IV) orotates 23266665 n-Bu 23266665 n-Bu(2)Sn(HOr) 23266665 n-Oct 23266665 n-Oct(2)Sn(H(2)Or)(2) 23266665 orotic acid 23266726 ITC 23266726 ITCs 23266726 Isothiocyanates 23266726 glucosinolate 23266726 isothiocyanates 23266726 mercapturic acid 23266733 cytarabine 23266735 5α,6β,7α-7α-acetoxysitosterol 23266735 phytosterol 23266735 sterol 23266735 sterols 23266735 trihydroxysitosterol 23267008 doxorubicin 23267008 ellagic acid 23267008 nucleotide triphosphate 23267008 suramin 23267767 ETB 23267767 MTT 23267767 malate 23267767 ortho-carborane 23267767 ortho-carboranylphenoxyacetanilides 23267840 AMPA 23267840 Curcumin 23267840 N-methyl-D-aspartate 23267840 NMDA 23267840 aspartate 23267840 curcumin 23267840 glutamate 23267840 glutathione 23267840 streptozotocin 23267840 α-amino-3-hydroxy-5-methyl-4-isoxazole propionate 23268106 2-hydroxy-5-(2,3,5,6-tetrafluoro-4 trifluoromethylbenzylamino) benzoic acid 23268106 N-methyl-d-aspartate 23268106 Neu2000 23268106 antimycin 23268106 carbonyl 23268106 glutathione 23268106 hydrogen peroxide 23268106 hydroxyl 23268106 iron(III)-ascorbate 23268106 nitric oxide 23268106 nitrogen 23268106 oxygen 23268106 peroxynitrite 23268106 phenoxy 23268106 superoxide 23268106 tert-butyl hydroperoxide 23268441 Bisulfite 23268441 bisulfite 23268441 nucleotide 23268549 Ethanol 23268549 H(2)O(2) 23268549 cyclosporin A 23268549 ethanol 23268549 nortriptyline 23268549 oxygen 23268987 MGS0028 23268987 glutamate 23270282 Ca 23270282 Ca(2+) 23270282 Calcium 23270282 Cramb816 23270282 CrambA2 23270282 CrambC1 23270282 Crambescidin 816 23270282 Crambescins 23270282 K(+) 23270282 Na 23270282 Na(+) 23270282 NcrambA2 23270282 Potassium 23270282 Sodium 23270282 calcium 23270282 crambescidin 23270282 crambescidin 816 23270282 crambescidins 23270282 crambescin 23270282 crambescin A2 23270282 crambescin C1 23270282 crambescins 23270282 guanidine alkaloids 23270282 nifedipine 23270282 norcrambescin A2 23270282 potassium 23270282 sodium 23270326 CYN 23270326 Cylindrospermopsin 23270326 cylindrospermopsin 23270326 glutathione 23270326 oxygen 23270387 mesityl 23270565 Licochalcone A 23270565 chalcones 23270565 medicagenin 23270565 munchiwarin 23270593 amino acid 23270593 methyl 23270805 anorexigen 23270805 glucose 23270805 oxytocin 23270965 4-allyl-1, 2-methylenedioxybenzene 23270965 SFO 23270965 Safrole-2',3'-oxide 23270965 safrole 23270990 TEA 23270990 Valine 23270990 alanine 23270990 calcium 23270990 phenylalanine 23270990 potassium 23270990 tetraethylammonium 23270990 valine 23271001 Curcumin 23271001 curcumin 23271002 4-methoxy-5- hydroxycanthin-6-one 23271002 CAN 23271002 NO 23271679 (55)Fe 23271679 (59)Fe 23271679 Ca 23271679 Iron 23271679 Zn 23271679 ferrous ascorbate 23271679 ferrous gluconate 23271679 glycine 23271679 iron 23271679 radio iron 23271679 zinc 23273260 CO 23273260 C═O 23273260 NH(3) 23273260 O6 23273260 Pt 23273260 PtAN1 23273260 PtAN3 23273260 adenine 23273260 carbonyl 23273260 carbonyl oxygen 23273260 cis-[Pt(NH(3))(2)(A)Cl](+) 23273260 cis-[Pt(NH(3))(2)(G)Cl](+) 23273260 cisplatin 23273260 guanine 23273260 hydrogen 23273506 1,N(6)-ethenoadenine 23273506 N3- and N7-alkylguanines 23273506 alkylpurine 23273506 amino acid 23273506 serine 23273895 Ca(2+) 23273999 2,5-dimethoxy-4-iodoamphetamine 23273999 3,4-BDB 23273999 3,4-methylenedioxy-α-ethylphenethylamine 23273999 DOI 23273999 N-(1-phenylcyclohexyl)-3-ethoxypropanamine 23273999 N-iso-propyl-1,2-diphenylethylamine 23273999 NPDPA 23273999 PCEPA 23273999 glaucine 23273999 sertraline 23273999 verapamil 23274087 6-Hydroxydopamine 23274087 6-OHDA 23274345 beta-tricalcium phosphate 23274345 dexamethasone 23274345 β-TCP 23274394 methapyrilene 23274413 Gambogic acid 23274413 gambogic acid 23274413 oxygen 23274413 potassium 23274413 steroid 23274570 diterpenoid 23274570 kaurene 23274570 oridonin 23274570 spirolactone 23274698 DHEA 23274698 androgen 23274698 dehydroepiandrosterone 23274698 estradiol 23274698 steroid 23274698 steroids 23274698 testosterone 23274714 Trichothecene 23274714 Trichothecenes 23274714 sesquiterpenoid mycotoxins 23274714 trichothecene 23274714 trichothecenes 23274767 cholesterol 23274767 polystyrene 23274889 butyrate 23274889 lactate 23274893 glucose 23274893 glutamate 23274893 glutamine 23274898 2-NBD-Glucose 23274898 2-NBDG 23274898 AS605240 23274898 ATP 23274898 Glucose 23274898 adenosine-phosphate 23274898 glucose 23274898 suramin 23274907 glucose 23274909 carbachol 23274909 glucose 23274909 sulfonylureas 23274916 TiO2 23274916 polyacrylate 23274916 titanium dioxide 23274950 BaSO4 23274950 mesalamine 23275067 (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one 23275067 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol 23275067 3-aminopropyl (diethoxymethyl)phosphinic acid 23275067 CGP35348 23275067 CGP7930 23275067 GABA 23275067 GHB 23275067 alcohol 23275067 baclofen 23275067 benzodiazepines 23275067 cocaine 23275067 diazepam 23275067 nicotine 23275067 rac-BHFF 23275067 γ-hydroxybutyrate 23275112 calcium 23275112 ethanol 23275112 levofloxacin 23275112 silanol 23275112 silica 23275442 amino 23275442 amino acids 23275442 carboxyl 23275471 calcein 23275571 magnesium 23276134 4(3H)-quinazolinones 23276134 benzo 23276134 polycyclic 4(3H)-quinazolinones 23276134 pyrimidine 23276134 quinazoline 23276134 quinazolinone 23276134 quinazolinone alkaloids 23276150 2-aminoethyl methacrylate 23276150 Boc 23276150 PMMA 23276150 amino 23276150 hydroxyl 23276150 methacrylate 23276150 methyl methacrylate 23276150 p-Toluenesulfonate 23276150 poly(methyl methacrylate) 23276150 tert-butoxycarbonyl 23276229 2-butoxyethanol 23276229 crystal violet 23276229 hydroxide 23276631 progesterone 23277288 erlotinib 23277288 gefitinib 23277288 nilotinib 23277288 pregnane 23277288 sorafenib 23277288 tyrosine 23277288 vandetanib 23277289 AHL 23277289 acyl-homoserine lactone 23277289 acyl-homoserine-lactone 23277289 mannitol 23277289 trehalose 23277358 (R)-β-lysine 23277358 fMet-Lys 23277358 fMet-Phe 23277358 hydroxyl-(β)-lysyl 23277358 lysine 23277358 polyproline 23277358 puromycin 23278281 MAs 23278281 TOL 23278281 Tol 23278281 Toluene 23278281 benzylmercapturic, o-, m- and p-toluylmercapturic acids 23278281 glutathione 23278281 hippuric acid 23278281 mercapturic acids 23278281 o-cresol 23278281 oCre 23278281 toluene 23278394 Estrogen 23278394 Fulvestrant 23278394 Tamoxifen 23278394 estrogen 23278394 gonadotropin-releasing hormone 23278394 tamoxifen 23278396 Tyrosin 23278396 cisplatin 23278396 cyclophosphamide 23278396 estrogen 23278396 poly (ADP-ribose) 23278396 progesterone 23278403 Androgen 23278403 Bicalutamide 23278403 Enzalutamide 23278403 androgen 23279865 anthra[1,2-d]imidazole-6,11-dione 23279867 1,4-naphthoquinones 23279867 2-((8E,11Z)-heptadeca-8,11-dienyl)-3-hydroxynaphthalene-1,4-dione 23279930 6-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)tetrazolo[5,1-a]phthalazine 23279930 Benzylpiperazine 23279930 Tetrazolo[5,1-a]phthalazine 23279930 [1,2,4]Triazolo[3,4-a]phthalazine 23279930 [1,2,4]triazolo[3,4-a]phthalazine 23279930 benzylpiperazine 23279930 milrinone 23279930 tetrazolo[5,1-a]phthalazine 23280488 C 23280488 Chl 23280488 Chlorophyll-a 23280488 N 23280488 Nitrate 23280488 TBA 23280488 carbon 23280488 chlorophyll 23280488 nitrate 23280488 nitrogen 23280488 phosphate 23280488 terbuthylazine 23280489 DHT 23280489 dihydrotestosterone 23280489 dutasteride 23280489 steroid hormone 23280489 testosterone 23280672 mercury 23280672 methylmercury 23280691 4-iso-nonylphenol 23280691 4-iso-nonylphenols 23280691 4-nonylphenols 23280691 estrogen 23280691 estrone 23280691 ethinylestradiol 23280691 steroidal estrogens 23280809 (3) H 23280809 Amitriptyline 23280809 N-desmethyl amitriptyline 23280809 Nortriptyline 23280809 Tritiated amitriptyline 23280809 amitriptyline 23280809 amitriptyline-N-oxide 23280809 nortriptyline 23280831 MeHg 23280831 Mercury 23280831 mercury 23280831 methylmercury 23281020 carbon 23281020 hydrogen 23281044 BePI 23281044 Tetracyclic BePI 23281044 benzo[e]pyridoindoles 23281044 benzo[e]pyridoindolones 23281044 oxo 23281044 pyridine 23281180 (20S)-10-(3-aminopropyloxy)-7-ethylcamptothecin 23281180 N-arylsulfonyl-(R)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ester 23281180 T-2513 23281180 acetone 23281180 camptothecin 23281180 ethyl-(S)-2-acyloxy-2-(6-cyano-5-oxo-1,2,3,5-tetrahydroindolizin-7-yl)butanoate 23281275 PEI 23281275 poly(ethylenimine) 23281657 (1)H 23281657 (13)C 23281657 Chloroform 23281657 acetone 23281657 cyclomyrsinol 23281657 cyclomyrsinol diterpenes 23281657 diterpenes 23281657 diterpenoidal 23281661 silica 23281892 5-nitro-2-furancarboxylamides 23281892 eflornithine 23281892 nifurtimox 23281965 L-thyroxine 23281965 Thyroid hormone 23281965 calcium 23281965 cholesterol 23281965 phosphate 23281965 thyroid hormone 23281965 triglyceride 23282011 4Fe-4S 23282011 Cys 23282011 Met 23282011 SAM 23282011 amino acids 23282011 cysteine 23282011 methionine 23282011 thioether 23282011 α-carbon 23282065 Flavonoids 23282065 Quercetin 23282065 aldehyde 23282065 amino acids 23282065 flavonoids 23282065 genistein 23282065 glycosylated flavonoids 23282065 myricetin 23282065 polyphenolic 23282065 sugar 23282083 Aaptamine 23282083 aaptamine 23282083 ethanol 23283546 OH 23283546 dihydroquercetin 23283546 hydrogen 23283546 phenolic 23283546 quercetin 23283546 taxifolin 23286284 CPT-11 23286284 irinotecan 23286606 2,2'-bipyridyl 23286606 Ru(bpy)(2)phen 23286606 bpy 23286606 oxygen 23286606 phen 23286606 phenathrolin 23286606 ruthenium(II) polypyridyl 23286606 silica 23287046 5-(and 6-)-chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate 23287046 CM-H2DCFDA 23287046 acetyl ester 23287046 oxygen 23287412 Ca(2+) 23287412 calcium 23287539 Cis-hinokiresinol 23287539 Cu 23287539 DPPH 23287539 Zn 23287539 cis-hinokiresinol 23287539 estrogen 23287539 glucose 23287539 hinokiresinols 23287539 nitrotyrosine 23287539 oxygen 23287539 phenylpropanoid 23287539 trans- and cis-hinokiresinols 23287539 trans-hinokiresinol 23287708 Sunset yellow FCF 23287726 N 23287726 amino acid 23287726 cysteine 23287726 nucleotide 23287727 flavonoids 23287727 glycosides phenols 23287727 lignans 23287727 pyridoxine 23287727 saponins 23287727 spermine alkaloids 23287737 2'-deoxy-6-thioguanosines 23287737 4-thiothymidines 23287737 s(4)Ts 23287737 s(6)Gs 23287737 sugar 23287737 thiocarbonyl 23288051 MNU 23288051 O(6)-methylguanine 23288051 O(6)MeG 23288051 ethylmethanesulfonate 23288051 ethylnitrosourea 23288051 guanine 23288051 hypoxanthine 23288051 methyl 23288051 methylnitrosourea 23288053 iodine 23288053 potassium iodate 23288144 SUN 23288144 Sunitinib 23288144 actinomycin D 23288144 aryl hydrocarbon 23288144 tyrosine 23288505 amodiaquine 23288505 artemisinin 23288505 lumefantrine 23288505 mefloquine 23288505 piperaquine 23288505 pyrimethamine 23288505 sulfadoxine 23288867 13-epiestradiol 23288867 13-espiestradiol 23288867 16-OH 23288867 16-epiestriol 23288867 17-OH 23288867 17-epiestriol 23288867 3-OH 23288867 UDP 23288867 estradiol 23288867 estriol 23288867 estriols 23288867 estrogens 23288867 hydroxyl 23288867 hydroxyls 23288867 methyl 23288867 steroid 23288867 steroid hormones 23289503 1-phenylazo-2-hydroxynaphthol 23289503 1-phenylazo-2-naphthol 23289503 NAD(P)H 23289503 NADPH 23289503 Sudan I 23289503 azo 23289503 quinone 23289528 His 23289528 Phe 23289528 Thioflavin T 23289528 heme 23289528 iron 23289528 porphyrin 23289528 protoporphyrin 23289788 cholesterol 23289788 doxorubicin 23289802 Cu 23289802 Ni 23289802 Zn 23289802 oxygen 23289802 silica 23289802 superoxide 23289830 GABA 23289830 Glu 23289830 HU210 23289830 [(35) S]GTPγS 23289830 [³H]CP55,940 23289851 Phosphatidylinositol 3-phosphate 23289851 PtdIns3P 23289851 phosphatidylinositol 23289851 phosphatidylinositol 3-phosphate 23290048 (1)H 23290048 (13)C 23290048 1-methyl-5-(2,4,6-trimethoxy-phenyl)-1H-pyrazole 23290048 benzophenones 23290048 pyrazole 23290051 GUT-70 23290051 tricyclic coumarin 23291047 acebutolol 23291047 hydrocarbon 23291047 phosphatidylcholines 23291047 propranolol 23291050 1- and 2-naphthyl acetate 23291050 AZM 23291050 CPF 23291050 OPs 23291050 acetylthiocholine 23291050 azinphos-methyl 23291050 chlorpyrifos 23291050 organophosphorus 23291050 p-nitrophenyl acetate 23291050 p-nitrophenyl butyrate 23291323 Cl(-) 23291323 F(-) 23291323 H(+) 23291323 OH(-) 23291323 fluoride 23291341 Bombesin 23291341 D-Phe 23291341 Nle 23291341 PD98059 23291341 Phe 23291341 Wortmannin 23291341 bombesin 23291341 glucose 23291341 rapamycin 23291341 β-Ala 23291558 2,3,7,8- tetrachlorodibenzo-p-dioxin 23291558 Aryl hydrocarbon 23291558 BNF 23291558 FSK 23291558 aryl hydrocarbon 23291558 cAMP 23291558 forskolin 23291558 phorbol 12-tetradecanoate 13-acetate 23291558 β-naphthoflavone 23291595 2,6-bis((1H-1,2,3-triazol-1-yl)-methyl)pyridine 23291595 Cu(I) 23291595 Steroid 23291595 cholic acid 23291595 estrone 23291595 etienic acid 23291595 steroid 23292158 PRG 23292158 Pregabalin 23292170 glucose 23292655 N 23292655 N-methyl-D-aspartate 23292655 amino acids 23292747 Ag(+) 23292747 Silver 23292747 silver 23292798 4-Me-UAB30 23292798 4-methyl-UAB30 23292798 Bexarotene 23292798 DMBA 23292798 TRG 23292798 Targretin 23292798 UAB30 23292798 aryl hydrocarbon 23292798 dimethylbenzanthracene 23292798 retinoic acid 23292798 retinoid 23292798 triglyceride 23292798 triglycerides 23292798 vitamin D 23293024 serine 23293024 threonine 23293106 PCB 23293106 PCBs 23293106 polychlorinated biphenyl 23293129 N-methyl-N'-nitro-N-nitrosoguanidine 23293129 acridin 23293129 aflatoxin 23293129 aflatoxin B(1) 23293129 glutathione 23293129 malondialdehyde 23293129 methanol 23293129 superoxide 23293130 Kaun 23293130 glutathione 23293130 hydroperoxide 23293130 malondialdehyde 23293130 reduced glutathione 23293130 superoxide 23293130 trona 23293130 vitamins C and E 23293300 BOC 23293300 UDP 23293300 atorvastatin 23293300 boceprevir 23293300 ketoconazole 23293300 pitavastatin 23293300 rifampin 23293300 sodium 23293300 taurocholate 23293300 telaprevir 23294363 CNV97101 23294363 fluoroquinolone 23294378 Arundinols A-C 23294378 Arundinone B 23294378 Cu 23294378 Rh(2)(OCOCF(3))(4) 23294378 [Rh(2)(OCOCF(3))(4)] 23294378 arundinols A-C 23294378 arundinone A 23294378 arundinone B 23294378 arundinones A and B 23294378 benzofuran-3(2H)-one 23294378 ent-eudesmane sesquiterpenoids 23294378 isochroman-1-one 23294378 polyoxygenated benzofuran-3(2H)-one 23294378 tertiary alcohols 23294700 tyrosine 23295225 1,2-diketo 23295225 1,2-naphthoquinone 23295225 1,4-naphthoquinone 23295225 2,3-hexanedione 23295225 4-benzoylpyridine 23295225 9,10-phenanthrenequinone 23295225 Carbonyl 23295225 Cys 23295225 GSNO 23295225 NADPH 23295225 S-Nitrosoglutathione 23295225 S-glutathionylation 23295225 S-nitrosoglutathione 23295225 carbonyl 23295225 cysteine 23295225 cysteines 23295225 daunorubicin 23295225 disulfide 23295225 isatin 23295225 menadione 23295323 Printex90 23295323 TiO2 23295323 carbon black 23295323 titanium dioxide 23295385 (+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide 23295385 (3)H(+)-pentazocine 23295385 (3)H-1,3-di(2-tolyl)-guanidine 23295385 (3)H-DTG 23295385 (3)H-progesterone 23295385 (R)-(1)-7-chloro-8- hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride 23295385 3-methyl-6-chloro-7,8-hydroxy-1-[3-methylphenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine 23295385 Na(+) 23295385 SCH22390 23295385 SKF38393 23295385 SKF83959 23295385 dopamine 23295385 glutamate 23295386 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine 23295386 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid 23295386 WY14,643 23295386 fatty acid 23295645 NO 23295645 PGE2 23295645 PLGA 23295645 Poly(d,l-lactide-co-glycolide) 23295645 Polymeric triamcinolone acetonide 23295645 prednisolone acetate 23295645 triamcinolone acetonide 23295732 Strontium doped perovskites 23295732 cobaltites 23295732 ferrites 23295732 lanthanum manganites 23295732 oxygen 23295732 perovskite 23295732 perovskites 23296027 C(36)H(12) 23296027 corannulene 23296027 sumanene 23296098 MTT 23296098 OTA 23296098 Ochratoxin A 23296098 androgen 23296098 estradiol 23296098 ochratoxin A 23296098 oestrogen 23296098 progestagen 23296098 steroid 23296098 thiazolyl blue tetrazolium bromide 23296104 CO₂ 23296104 Morphine 23296104 morphine 23296142 BIS 23296142 ICI 182,780 23296142 bisindolylmaleimide 23296142 estradiol 23296142 estrogen 23296276 (1-x) [(B(2)O(3))(0.3)(TeO(2))(0.7)]-xMnO 23296276 TeO(3) 23296276 TeO(4) 23296276 borotellurite 23296276 manganese 23296276 manganese oxide 23296276 oxygen 23296904 ATP 23296904 Ca 23296904 Ca(2+) 23296904 CaCl(2) 23296904 K 23296904 K(+) 23296904 NS1619 23296904 Norepinephrine 23296904 Polyphenol 23296904 Resveratrol 23296904 adenosine 5'-triphosphate 23296904 calcium 23296904 calcium chloride 23296904 norepinephrine 23296904 potassium chloride 23296904 resveratrol 23297162 (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride 23297162 5-hydroxytryptamine 23297162 atipamezole 23297162 milnacipran 23297162 monoamine 23297162 monosodium iodoacetate 23297162 naloxone 23297162 noradrenaline 23297162 serotonin 23297245 Mercury 23297245 mercury 23297250 Ca 23297250 Ca(2+) 23297250 Cl(-) 23297250 K(+) 23297250 Mg 23297250 Mg(2+) 23297250 NO 3- 23297250 Na(+) 23297250 Ni 23297250 Ni(2+) 23297250 SO 42- 23297250 chloride 23297250 nitrate 23297250 sulfate 23297362 PtdIns(3,5)P2 23297362 PtdIns3P 23297362 phosphatidylinositol 3-phosphate 23297676 5-allosyloxy-aucubin 23297676 flavonoids 23297676 iridoids 23297676 melittoside 23297676 phenylethanoids 23297676 scutellarein 23297676 siderol 23297676 verbascoside 23297714 alcohol 23297714 dUTP 23297714 ethanol 23297714 testosterone 23297716 carvacrol 23297716 phenolic monoterpenes 23297716 thymol 23297831 anthracene 23297831 naphthalene 23297831 poly(aryl ether) 23297831 pyrene 23297842 glucose 23297842 α-glucose 23298136 Luminol 23298136 luminol 23298136 meso-tetraphenylporphyrin 23298138 iodo 23298139 Silver 23298139 silver 23298236 GRL-0519 23298236 carbonyl 23298236 hydrogen 23298236 oxygen 23298236 tris-THF 23298236 tris-tetrahydrofuran 23298292 D,L-valine 23298292 amino acid 23298292 polysorbate 23298292 sorbitan ester 23298577 (1)H 23298577 PPI 23298577 ZDV 23298577 carbohydrate 23298577 mannose 23298577 mannosylated PPI 23298577 mannosylated poly(propyleneimine) 23298577 sialic acid 23298577 zidovudine 23298578 Lamivudine 23298578 cholesterol 23298578 deoxycytidine nucleoside 23298578 lamivudine 23298613 DTX 23298613 PCL 23298613 PEO 23298613 Zn(II) 23298613 ZnPc 23298613 docetaxel 23298613 oxygen 23298613 phthalocyanine 23298613 poly(ethylene oxide) 23298613 poly(ε-caprolactone) 23298613 zinc 23298614 PEI 23298614 PEIs 23298614 Polyethylenimine 23298614 acyclovir 23298614 ethylene carbonate 23298614 oleic acid 23298614 polyallylamine 23298614 polyamine 23298614 polyethylenimine 23298614 primary amine 23298614 primary amines 23298614 secondary and tertiary amine 23298622 PLGA 23298622 nimodipine 23298677 LY294002 23298677 PD98059 23298677 SB203580 23298677 SP600125 23298677 creatinine 23298677 ethanol 23298677 heme 23298694 DON 23298694 deoxynivalenol 23298698 PGE2 23298698 Prostaglandin E2 23298698 prostaglandin E2 23298809 benzyloxazoles 23298809 ethyl 23298809 isopropyl 23298809 nucleoside 23298862 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine 23298862 EDDP 23298862 Methadone 23298862 N 23298862 R- and S-EDDP 23298862 R- and S-methadone 23298862 S>R-methadone 23298862 methadone 23298862 racemic methadone 23299080 androstane 23299080 pregnane 23299080 vitamin D 23299193 PBO 23299193 alphacypermethrin 23299193 cypermethrin 23299193 deltamethrin 23299193 piperonyl butoxide 23299193 pyrethroid 23299193 pyrethroids 23299193 tetramethrin 23300130 Hydroxyl 23300130 PEI 23300130 Polyethylenimine 23300130 Tris(hydroxymethyl) acrylamidomethane 23300130 polyethylenimine 23300287 glucose 23301582 quartz 23301592 2-aminoimidazolinium 23301592 Aminoalkyl 23301592 O 23301592 aminoalkyl 23301592 dihydrofolate 23301592 guanidine 23301592 guanidinium 23301655 C 23301655 PEG 23301655 Phenyl 23301655 amyl 23301655 phenyl 23301655 polyethylene glycol 23301655 propyl 23301838 Graphene 23301838 SiO₂ 23301838 boron nitride 23301838 graphene 23301897 2-oxaisodauc-5-en-12-al 23301897 Mo2(AcO)4 23301897 chloroform 23301897 cycloartane triterpenoids 23301897 cyclopenta[b]benzofuran 23301897 cyclopenta[b]benzopyran 23301897 dimolybdenum tetraacetate 23301897 diol 23301897 flavaglines 23301897 methanol 23301897 perviridicin B 23301897 rocaglaol 23301897 rocaglate 23301897 sesquiterpene 23302007 CO(2) 23302007 aluminum 23302007 amino triphenolate 23302007 epoxides 23302007 organic carbonates 23302590 L-tyrosine 23302590 N-(3-oxobutyl)-Tyr 23302590 N-acetyl-Tyr 23302590 O-acetyl-Tyr 23302590 Tyr 23302590 acetic anhydride 23302590 amino acid 23302590 hydroxyl 23302590 methyl vinyl ketone 23302592 Schisphenlignans A-E 23302592 dibenzocyclooctadiene lignans 23302592 schisphenlignans A-E 23303199 hydrogen 23303207 5-HT 23303207 5-hydroxytryptamine 23303207 H2O2 23303207 indoleamine 23303207 kynurenine 23303207 tryptophan 23303314 Pt 23303314 oxide 23303314 oxygen 23303365 Au 23303365 SiO(2) 23303365 benzaldehyde 23303365 benzyl alcohol 23303365 polyvinylpyrrolidone 23303469 FeGaB 23303469 PZN-PT 23303575 Halogen 23303575 halogen 23303575 halogens 23303575 hydrogen 23303713 prolyl 23303717 biotin 23303717 bis-triazole 23303717 copper(II) 23303717 cyclam 23303717 naphthalimide 23303717 zinc(II) 23303727 4-OT 23303727 4-oxalocrotonate 23303727 acetaldehyde 23303727 aldehydes 23303727 octanal 23303727 proline 23303727 trans-β-nitrostyrene 23303727 γ-nitroaldehydes 23303727 β-nitrostyrene 23303733 1-allyl-3-methylimidazolium chloride 23303733 1-allyl-3-methylimidazolium fluoride 23303733 AlMeImF 23303733 DMSO 23303733 F(-) 23303733 acyl fluoride 23303733 carboxylic acid anhydride 23303733 ester 23303733 fluoride 23305495 (1)H 23305495 (±)-wilsonirine 23305495 11-sulfonyl-1,11-anhydroaporphine 23305495 9-sulfonyl-seco 23305495 H2SO4 23305495 N 23305495 N-formylnorglaucine 23305495 N-propylnorglaucine 23305495 Thaliporphine 23305495 aporphine 23305495 laurolitsine 23305495 thaliporphine 23305513 Bioglass 45S5 23305513 H(+) 23305513 Na(+) 23305513 PDLLA 23305513 hydroxycarbonate apatite 23305513 poly(D,L-lactide) 23305550 silver 23305709 3-[9-fluoro-2-(piperidin-1-ylcarbonyl)-1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl]-4-imidazo[1,2-a]pyridin-3-yl-1H-pyrrole-2,5-dione 23305709 LY2090314 23305709 LY2090314 glucuronide 23305709 [(14)C]LY2090314 23305776 (2S)-6,7-(2,2-dimethyldihydropyrano)-8-prenyl-4'-hydroxyflavanone 23305776 2-(2'-methoxy-4'-hydroxy)-aryl-3-methy-6-hydroxy-benzofuran 23305776 6-prenyl-7,3',4'-trihydroxyflavone 23305776 ABTS 23305776 phenolic 23305850 cinnamic aldehyde 23305850 hydrogen peroxide 23305850 sulforaphane 23305850 tert-butylhydroquinone 23305919 3,5-bis(benzylidene)-4-piperidone 23305919 S 23305919 glutathione 23305919 oxygen 23305919 thiol 23305994 apigenin 23305994 flavonoid 23306105 TDCPP 23306105 TPP 23306105 Tris(1,3-dichloro-2-propyl) phosphate 23306105 aryl hydrocarbon 23306105 thyroid hormone 23306105 triphenyl phosphate 23306105 tris(1,3-dichloro-2-propyl) phosphate 23306106 Cd 23306106 Fatty acid 23306106 Fatty acids 23306106 MUFA 23306106 PO(4)(3-) 23306106 PUFA 23306106 PUFAs 23306106 SAFA 23306106 TAG 23306106 acetone 23306106 cadmium 23306106 fatty acid 23306106 hydrocarbon 23306106 monounsaturated FA 23306106 phosphate 23306106 polyunsaturated FA 23306106 saturated fatty acid 23306106 triacylglycerol 23306106 ω3 PUFA 23306206 H(+) 23306206 NAD(+) 23306206 NADH 23306206 ubiquinol 23306206 ubiquinone 23306788 GSH 23306788 alanine 23306788 aspartate 23306788 caffeic acid 23306788 glutathione 23306788 oxidized glutathione 23306788 rosmarinic acid 23306788 superoxide 23306788 t-BHP 23306788 tert-butyl hydroperoxide 23306944 Alizarin Red S 23306944 Si 23306944 silicon 23306944 sodium metasilicate 23307549 Ruxolitinib 23307549 ruxolitinib 23307703 (trimethylsilyl)vinyl 23307703 2-phenylvinyl 23307703 Si 23307703 octyl 23307703 silicon 23311288 6-(benzyloxy)-2-(aryldiazenyl)-9H-purines 23311288 O(6)-Alkylguanine 23311288 O6-alkylguanine 23311288 O6-benzylguanine 23311288 guanine 23311400 DMF 23311400 PS-b-PAA 23311400 dioxane 23311471 (13)C 23311471 PEG 23311471 PEG-PPLG 23311471 alkynyl 23311471 azide 23311471 biotin 23311471 galactose 23311471 poly(ethylene glycol)-block-poly(γ-propargyl-l-glutamate) 23311532 Dopamine 23311532 PDA 23311532 PDMS 23311532 epoxy 23311532 polydimethylsiloxane 23311532 polydopamine 23311883 dodecane 23311883 hexadecane 23311976 6,8-diallyl-5,7-dihydroxycoumarin 23311976 Coumarin 23311976 Coumarins 23311976 LQB-34 23311976 Neoflavone 23311976 coumarin 23311976 coumarins 23311976 coumestan 23311976 coumestans 23311976 floroglucinol 23311976 neoflavone 23312283 TMA 23312283 TMAO 23312283 Trimethylamine-N-oxide 23312283 androgens 23312283 bile acid 23312283 bile acids 23312283 choline 23312283 flavin 23312283 trimethylamine 23312283 trimethylamine-N-oxide 23312474 2,6-dichlorobenzoylamine 23312474 Ethyl ester 23312474 N-Acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine 23312474 N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine 23312474 esters 23312474 ethyl ester 23313270 TCA 23313270 TCAs 23313270 Tricycloalternarenes F-H 23313270 terpenoids 23313270 tricycloalternarenes 23313271 29-nor-cycloart triterpenoid 23313271 Aphagrandinoid A 23313271 Aphagrandinoids A-D 23313271 aphagrandinoid C 23313271 aphagrandinoid D 23313271 aphagrandinoids A-C 23313271 cycloartane triterpenoids 23313271 pentnortriterpenoid 23313336 27-hydroxycholesterol 23313336 3β-hydroxyl 23313336 5α-androstanediol 23313336 Estradiol 23313336 aldosterone 23313336 cortisol 23313336 estriol 23313336 estrogen 23313336 estrogens 23313336 estrone 23313336 ketone 23313336 methyl 23313336 progesterone 23313336 steroids 23313336 testosterone 23313336 Δ(5)-androstenediol 23313338 BPA 23313338 bisphenol-A 23313338 steroids 23313345 3,5,3'-triiodothyronine 23313345 nitric oxide 23313377 nitric oxide 23313378 (-)-Xanthatin 23313378 (-)-xanthatin 23313378 N-acetyl-l-cysteine 23313378 oxygen 23313378 xanthanolide 23313609 Anthocyanins 23313609 DPPH 23313609 anthocyanins 23313609 malvidin 3-O-p-coumaroyl-rutinoside-5-O-glucoside 23313609 petunidin 3-O-p-coumaroyl-rutinoside-5-O-glucoside 23313632 (-)-surinamensin 23313632 (-)-virolin 23313632 8,4'-oxyneolignans 23313632 aldehyde 23313632 ethyl lactate 23313632 surinamensin 23313632 virolin 23313633 Bacitracin 23313633 HCl 23313633 bacitracin 23313633 glutaraldehyde 23313633 phosphate 23313633 sodium taurocholate 23313794 2-Amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine 23313794 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine 23313794 HCAs 23313794 MDA 23313794 PhIP 23313794 carbonyl 23313794 heterocyclic amines 23313794 malondialdehyde 23313794 superoxide 23314050 1,2,3-triazoles 23314050 Azide-Alkyne 23314050 Triazole 23314050 aryl azide 23314050 propargylated α-desmotrosantonin 23314050 triazole 23314050 α-Santonin 23314050 α-santonin 23314275 5-hydroxytryptamine 23314275 Ca(2+) 23314275 Dopamine 23314275 N-methyl-D-aspartate 23314275 TBT 23314275 Tributyltin 23314275 a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid 23314275 amino acid 23314275 cyclic adenosine monophosphate 23314275 dopamine 23314275 glutamate 23314275 norepinephrine 23314308 2-APB 23314308 BAY K 8644 23314308 Ca(2+) 23314308 Inositol triphosphate 23314308 TEA 23314308 Tetrodotoxin 23314308 caffeine 23314308 calcium 23314308 capsaicin 23314308 nifedipine 23314308 phenylephrine 23314308 tetraethylammonium 23315091 PCP 23315091 Pentachlorophenol 23315091 pentachlorophenol 23315277 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide 23315277 SiO(2) 23315277 Silica 23315277 glutathione 23315277 lactate 23315277 oxygen 23315277 silica 23315522 H2O2 23315522 Mn 23315522 Mn(2+) 23315522 divalent Mn 23315522 divalent copper, cadmium, nickel, cobalt, zinc, and iron 23315522 divalent manganese 23315522 glutamate 23315522 hydrogen peroxide 23315522 malate 23315522 manganese 23315522 succinate 23315586 ATP 23315586 Ca(2+) 23315586 calcium 23315644 arachidonic acid 23315644 epoxides 23315644 hydroxy 23315644 linoleic acid 23316011 ESHU 23316011 poly(ethylene glycol)-poly(serinol hexamethylene urethane) 23316015 iron 23316053 imatinib 23316053 tyrosine 23316864 CO(2) 23316864 manoyl oxide 23316864 trans-totarol 23316864 α-acoradiene 23316933 ATP 23316933 adenosine 23316933 cyclic AMP 23316933 nucleoside 23316963 batimastat 23316963 doxycycline 23316963 marimastat 23316963 zinc 23317013 N-methyl-p-aminobenzoic acid 23317013 Solphenazines A-F 23317013 glycosylated phenazines 23317013 paraben 23317013 rhamnosyl 23317013 solphenazines A-F 23317099 spiroacetal 23317099 tetrahydrofuran 23317164 O(2) 23317164 Oxygen 23317164 oxygen 23317165 ATP 23317165 Imidazole 23317165 imidazole 23317370 Au 23317370 H(2) 23317370 Ir 23317370 Pt 23317370 thiol 23317370 thiolate 23317370 thiolates 23317570 carboxylic acid 23317570 pyridine-carboxamide 23317570 pyridine-carboxamides 23318354 graphitic 23318431 oxygen 23318431 tyrosine 23318598 catecholamine 23318598 glucose 23318726 Butein 23318726 H2O2 23318726 NH2 23318726 butein 23318726 heme 23318726 hydrogen peroxide 23318726 oxygen 23318726 polyphenol 23318731 3-NT 23318731 3-nitrotyrosine 23318731 8-Epi-PGF2a 23318731 8-epi-PGF2a 23318731 8-epi-prostaglandin F2 alpha 23318731 BaP 23318731 Pb 23318731 benzo[a]pyrene 23318833 4-hydroxy-2-nonenal 23318833 8-hydroxydeoxyguanosine 23318833 N-diethylnitrosamine 23318833 S 23318833 TAA 23318833 glutathione 23318833 heme 23318833 isoquercitrin 23318833 thioacetamide 23318833 thiobarbituric acid 23319077 CTX-1 23319077 Ciguatoxin 23319077 Ciguatoxins 23319077 ciguatoxin 23319077 sodium 23319147 C(60) 23319147 C60 23319166 PDMS 23319588 N 23319588 amino acids 23319588 leptomycin B 23319588 polyglutamine 23320465 Au 23320542 C 23320732 GSH 23320732 GSH thiol 23320732 GSH thiolate 23320732 Lewis acid 23320732 Mn(2+) 23320732 Tyr 23320732 epoxide 23320732 fosfomycin 23320732 glutathione 23320732 manganese 23320893 carbon 23320893 graphene 23320893 graphite 23321074 tamoxifen 23321159 Morphine 23321216 Glucose 23321216 glucose 23321259 7-alkyloxy-4,5-dihydro-imidazo[1,2-a]quinoline 23321259 7-heptyloxy-4,5-dihydro-imidazo[1,2-a]quinoline 23321259 amoxicillin 23321259 ciprofloxacin 23321396 Androgen 23321560 ISO 23321560 N,α-L-rhamnopyranosyl vincosamide 23321560 TTC 23321560 creatine 23321560 glutamate 23321560 indole alkaloid 23321560 isoproterenol 23321560 lactate 23321560 pyruvate 23321560 tri-phenyl tetrazolium chloride 23321564 (thio)semicarbazones 23321564 5-fluorouracil 23321564 Indenoindolone 23321564 etoposide 23321564 hydrazones 23321564 indenoindolols 23321564 indenoindolone 23321564 indenoindolones 23321564 oximes of indenoindolones 23321689 PNU-120596 23321689 PNU-282987 23321689 WAY-100135 23321689 acetylcholine 23321689 methyllycaconitine 23321689 nicotine 23321689 scopolamine 23322166 LPA 23322166 lysophosphatidic acid 23322284 calcium 23322284 chromium 23322284 copper 23322284 glucose 23322284 magnesium 23322284 manganese 23322284 testosterone 23322284 zinc 23322418 glycerol-1-phosphate 23322418 heptaprenyl diphosphate 23322418 heptaprenylglyceryl phosphate 23322418 triose phosphate 23322537 acetylcholine 23322558 Perfluoroalkyl 23322558 alanine 23322558 cholesterol 23322558 creatinine 23322558 perfluoroalkyl 23322558 perfluoroalkyl sulfonates 23322558 perfluorocarboxylates 23322558 perfluorodecanoic acid 23322558 perfluorooctane sulfonate 23322558 perfluorooctanoic acid 23322558 phosphorus 23322586 aluminum 23322586 titanium 23322586 titanium dioxide 23322633 anilines 23322633 anthranilic esters 23322633 azagrevellin 23322633 azepine 23322633 carboxylic acid 23322633 glutamate 23322633 isatins 23322633 lactam carbonyl 23322633 quinolin-2(1H)-one 23322633 quinoxaline-2,3(1H)-dione 23322633 quinoxaline-2,4(1H)-dione 23322633 α-amino acid 23322633 α-amino acids 23322633 α-ammonium 23322633 α-carboxylate 23322676 Zoledronic Acid 23322676 alendronate 23322676 glucose 23322676 zoledronic acid 23322677 Carbon 23322677 Silicon 23322677 carbon 23322677 hydrofluoric acid 23322677 polyaniline 23322677 silicon 23322677 thionyl chloride 23322705 inositol hexakisphosphate 23322705 inositol polyphosphate 23322705 inositol polyphosphates 23322705 inositol pyrophosphates 23322769 cholesterol 23322769 cholesterol ester 23322769 manumycin A 23323521 ATP 23323521 C 23323521 H 23323521 N 23323521 bis(aryl) ether 23323521 dipeptide 23323600 1,2,18,19-tetradehydro-4-demethyl-3,17-epoxy-7,20(2H,19H)-cyclovobasan 23323600 1,2,18,19-tetradehydro-4-demethyl-4-formaldehyde-3,17-epoxy-7,20(2H,19H)-cyclovobasan 23323600 1,2,4,21,18,19-hexadehydro-4-demethyl-3,17-epoxy-7,20(2H,19H)-cyclovobasan 23323600 1,2,4,21,18,19-hexadehydro-4-demethyl-4-oxy-3,17-epoxy-7,20(2H,19H)-cyclovobasan 23323600 chloroform 23323600 koumine 23323600 phenobarbital 23323640 3Sb(2) 23323640 Ge(2)Sb(1)Te(4) 23323640 Ge(2)Sb(7)Te(4) 23323640 Ge(3)Sb(2)Te(6) 23323640 Ge(3)Sb(8)Te(6) 23323640 Ge(8)Sb(2)Te(11) 23323640 GeSbTe 23323640 Sb 23323647 6-(5-acetyl-2-methoxyphenyl)-apigenin 23323647 6-phenyl 23323647 flavonoid 23323712 All-trans retinoic acid 23323712 retinoic acid 23323808 Au 23323808 GaAs 23323808 In(x)Ga(1-x)As 23323808 InGaAs 23323839 ( ± )-6,8-dimethoxy-3-(4-methoxyphenyl)-3,4-dihydroisocoumarin 23323839 3,5-dimethoxy-4-methylhomophthalic acid 23323839 6,8-dihydroxy-7-methyl-3-styryl-3,4-dihydroisocoumarin 23323839 6,8-dihydroxy-7-methyl-3-styrylisocoumarin 23323839 6-hydroxy-7-methyl 23323839 8-dihydroxy-3-styryl-3,4-dihydroisocoumarin 23323839 aluminum chloride 23323839 cinnamoyl chloride 23323839 ethane thiol 23323839 hydroxy acid 23323839 isocoumarin 23323839 keto acid 23323839 levofloxacin 23323839 typharin 23323873 PLGA 23323873 PVA 23323873 Polyvinyl-alcohol 23323873 acetone 23323873 corticosteroid 23323873 corticosteroids 23323873 dichloromethane 23323873 methylprednisolone 23323873 polyD,L-lactide-co-glycolide 23323890 3-methylenepyridine 23323890 Fasciospyrinadine 23323890 monocyclicfarnesane 23323890 pyridine alkaloid 23323890 sesquiterpene 23323975 CO(2) 23323975 OCS 23324033 (13)C 23324033 20S,24-epoxy-24,25-dihydroxy-3,4-secodammar-4(28)-en-3-oic acid 23324033 Aglinin A 23324033 acetonide 23324033 aglinin A 23324406 N-aryl-3,4-dihydro-3-methyl-4-oxo-1-phthalazineacetamide 23324406 Phthalazinone 23324406 benzofuranamide 23324406 guanine nucleotides 23324406 inosine 5'-monophosphate 23324406 inosine-5'-monophosphate 23324406 phthalazinone 23325363 carbohydrate 23325363 carbohydrates 23325363 cholesterol 23325363 dextrose 23325363 glucose 23325363 triglyceride 23325370 Alcohol 23325370 alcohol 23325372 alcohol 23325372 aripiprazole 23325372 escitalopram 23325437 Losmapimod 23325437 losmapimod 23325562 AMP 23325562 MG132 23325562 SB216763 23325562 Ursolic Acid 23325562 Ursolic acid 23325562 compound C 23325562 dUTP 23325562 ethidium 23325562 poly-ADP-ribose 23325562 serine 23325562 ursolic acid 23325700 1-[(4-Chlorophenyl)(phenyl)methylene]-4-(6-nitrobenzothiazol-2-yl)semicarbazide 23325700 6-nitrobenzothiazole 23325700 hydrogen 23325700 semicarbazones 23325847 C 23325847 GTP 23325847 guanosine triphosphate 23327103 NH(3) 23327103 amine 23327103 carbon 23327103 carboxylic acid 23327103 graphene 23327358 SIS 23327358 methyl salicylate 23327358 styrene-isoprene-styrene 23327445 graphene 23327445 silicon 23327533 ABT-107 23327533 N 23327533 [(14)C]ABT-107 23327533 acetylcholine 23327533 indole 23327533 nitrogen 23327533 quinuclidine 23327546 Ni(111) 23327546 pentacene 23327546 sulfur 23327546 tetrathienoanthracene 23327588 androgen 23327588 androgens 23327588 estradiol 23327691 CJ-15,208 23327691 cocaine 23327691 cyclo[Phe-d-Pro-Phe-Trp] 23327691 macrocyclic tetrapeptide 23327722 carboxy 23327722 lysine 23327735 Embelin 23327735 STZ 23327735 embelin 23327735 hexosamine 23327735 hydroxyproline 23327735 streptozotocin 23327832 Jatropholane 23327832 diterpenes 23327832 jatropholane 23327832 sikkimenoids A-D 23328624 C 23328895 estrogens 23328895 progesterone 23331575 MTM 23331575 Mithramycin 23331575 Mithramycin SA 23331575 carbon 23331575 carboxylic acid 23331575 mithramycin 23331575 mithramycin SA 23331575 mithramycin SDK 23331575 mithramycin SK 23331575 phosphate 23331859 NaCl 23331859 Oxytocin 23331859 Vasotocin 23331859 oxytocin 23331859 sodium 23331859 vasotocin 23332447 Testosterone 23332447 diacylglycerol 23332447 fatty acid 23332447 sterol 23332447 testosterone 23332447 triglyceride 23332447 triglycerides 23333175 aspirin 23333175 warfarin 23333184 aldosterone 23333184 eplerenone 23333184 potassium 23333184 sodium 23333184 spironolactone 23333208 tetrahydroisoquinolines 23333305 N 23333305 phospho 23333424 Ag 23333424 AgNO3 23333424 H2O2 23333424 Silver 23333424 hydrogen peroxide 23333424 oxygen 23333424 silver nitrate 23333503 4-Di-ANNEPS 23333503 K(+) 23333503 NO 23333503 NO(-) 23333503 Nitric oxide 23333503 ODQ 23333503 RuBPY 23333503 SNP 23333503 TEA 23333503 cis-[Ru(bpy)(2)(py)NO(2)](PF(6)) 23333503 guanylyl 23333503 nitric oxide 23333503 radicalar NO 23333503 sodium nitroprusside 23333640 BaP 23333640 arsenite 23333640 benzo(a)pyrene 23333907 Cryptotanshinone 23333907 UDP 23333907 cryptotanshinone 23333907 dihydrotanshinone I 23333907 propofol 23334349 C 23334349 H 23334349 H-C 23334349 H-N 23334349 N 23334349 O 23334349 dipeptide 23334349 dipeptides 23334349 pyrrolysine 23334349 α-carbon 23334800 Cd 23334800 CdTe 23334800 Te 23334800 cadmium telluride 23334800 carbon 23334855 abscisic acid 23334855 methyl jasmonate 23334855 salicylic acid 23334864 2,7-dichlorofluorescin diacetate 23334864 Iron 23334864 ferric 23334864 ferric ammonium citrate 23334864 iron 23334864 oxygen 23335025 estrogen 23335030 Fe 23335030 FePt3 23335030 ZnO 23335106 azo 23335346 Hexaconazole 23335346 acetonitrile 23335346 ammonium acetate 23335346 hexaconazole 23335346 rac-hexaconazole 23335346 triazole 23335398 N-acetylglucosamine 23335398 O 23335398 O-GlcNAc 23335398 dimethylarginine 23335817 CO(2) 23335817 ZnO 23335817 ZnPd 23335817 formaldehyde 23335817 methanol 23336435 (17Z,20Z)-hexacosa-17,20-dien-9-one 23336435 bisindole alkaloid 23336435 gangenoid 23336441 Li 23336441 LiNi(1/3)Co(1/3)Mn(1/3)O₂ 23336441 lithium 23337041 PPi 23337041 PolyP5 23337041 PolyP65 23337041 PolyPs 23337041 Polyphosphates 23337041 hydroxyapatite 23337041 orthophosphates 23337041 phosphate 23337041 phosphoanhydride 23337041 polyphosphates 23337041 pyrophosphate 23337041 β-glycerophosphate 23337256 N-methyl d-aspartate 23337256 estrogen 23337256 ketamine 23337256 progesterone 23337256 rapamycin 23337257 d-amphetamine 23337257 dopamine 23337567 ATO 23337567 Arsenic trioxide 23337567 arsenic 23337567 arsenic trioxide 23337568 3-hydroxychromone 23337568 LiCl 23337568 SB-415286 23337568 isothiazolidine-1,1-dione 23337597 POM 23337597 Polyoxometalate 23337597 amine 23337597 polyoxometalate 23337598 aniline 23337598 aryl chloride 23337598 naphthoquinone 23337602 1,3,4-oxathiazol-2-one 23337602 3H-1,2,4-Dithiazol-3-one 23337602 3H-1,2,4-dithiazol-3-one 23337602 HT1171 23337602 MTT 23337602 oxathiazol-2-one 23337911 17 β-estradiol 23337911 17β-estradiol 23337911 ATR 23337911 DES 23337911 RES 23337911 atrazine 23337911 diethylstilbestrol 23337911 p-NP 23337911 para-nonylphenol 23337911 resveratrol 23338044 [W(10)O(32)](4-) 23338044 [W(10)O(32)](5-) 23338044 [W(10)O(32)](6-) 23338044 [W10O32]4- 23338539 Velcade 23338539 bortezomib 23338843 Au 23338843 ITO 23338843 indium tin oxide 23339052 DOX 23339052 HPMA 23339052 N-(2-hydroxypropyl)methacrylamide 23339052 doxorubicin 23339052 thiol 23339076 Ba 23339076 Ca 23339076 La 23339076 MN2 23339076 Metal-pernitride 23339076 Sr 23339076 Ti 23339076 TiN2 23339076 pernitride 23339076 pernitrides 23339663 CBDP 23339663 H(2)(16)O 23339663 H(2)(18)O 23339663 Phe 23339663 TOCP 23339663 Tri-o-cresyl-phosphate 23339663 cresyl saligenin phosphate 23339663 organophosphate 23339663 oxime 23339742 ATP 23339744 Thyroid hormone 23339744 Triiodothyronine 23339744 thyroid hormone 23339744 thyroid hormones 23339830 SiO(2) 23339830 graphene 23339830 phenyl-diazonium salts 23339966 5-((1-Aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones 23339966 5-((1-aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones 23339966 N 23339966 hydrogen 23339966 naphthoyl 23340093 2-furfural 23340093 2-pentylfuran 23340093 5-hydroxymethylfurfural 23340093 furan 23340093 furanic 23340093 furfuryl alcohol 23340252 Cort 23340252 acetyl-coenzyme A 23340252 corticosterone 23340252 leucine 23340252 phenylsulfamide 23340252 serine 23340252 tolylfluanid 23340305 1H, 1H, 2H, 2H-perfluorodecanol 23340305 2,7-dichlorofluorescin diacetate 23340305 DCFH-DA 23340305 FTOH 8:2 23340305 PFOA 23340305 PFOS 23340305 PFOSA 23340305 fluorotelomer alcohol 23340305 oxygen 23340305 perfluorooctane sulfonylamide 23340305 perfluorooctanoic acid 23340305 perfluorooctyl sulfonate 23340305 polychlorinated biphenyls 23340305 trypan blue 23340494 C 23340494 Carboxy 23340494 amino acids 23340494 cystine 23340653 GGA 23340653 Geranylgeranylacetone 23340653 Ser 23340653 Ther 23340653 acyclic polyisoprenoid 23340653 dUTP 23340653 eosin 23340653 hematoxylin 23340653 oxygen 23340670 (13)C 23340670 L-polylactide 23340670 α-PLLA 23340670 α-poly(L-lactide) 23340689 Al(3)(-) 23340689 Al(4)(-) 23340689 Al(n)(-) 23340689 aluminum 23341183 FK506 23341183 MTX 23341183 acetylene 23341183 azide 23341183 reversine 23341183 tamoxifen 23341191 Silver vanadate 23341191 silver 23341191 silver vanadate 23341191 vanadium 23341196 Lys 23341212 (13) C 23341212 1,8-cineole 23341212 3,3,5,5,8,8-hexamethyl-7-oxabicyclo[4.3.0]non-1(6)-ene-2,4-dione 23341212 limonene 23341212 linalool 23341212 linalyl acetate 23341212 monoterpenes 23341212 myrtenyl acetate 23341212 α-pinene 23341241 Hg 23341241 MeHg 23341241 Mercury 23341241 methylmercury 23341458 Arg 23341458 Gln 23341458 Lys 23341458 N 23343190 Ba(1-x)K(x)Fe(2)As(2) 23343190 Ba(Fe(1-x)Co(x))(2)As(2) 23343190 BaFe(2)(As(1-x)P(x))(2) 23343190 BaFe(2)As(2) 23343190 BaFe2As2 23343190 iron 23343190 iron arsenides 23343308 ibuprofen 23343308 ibuprophen 23343346 1,1'-dibromoferrocene 23343346 Br(2)Fc 23343346 Co(II)(Ch) 23343346 Co(II)(OEP) 23343346 H(2)O(2) 23343346 HClO(4) 23343346 O(2) 23343346 OEP(2-) 23343346 PhCN 23343346 [Co(II)(ChH)](+) 23343346 [Co(III)(Ch)](+) 23343346 [Co(III)(ChH)](2+) 23343346 [Co(III)(OEP)](+) 23343346 benzonitrile 23343346 cobalt chlorin 23343346 cobalt porphyrin 23343346 dioxygen 23343346 ferrocene 23343346 hydrogen peroxide 23343346 octaethylporphyrin 23343346 perchloric acid 23343565 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide 23343565 1-ethyl-3-methylimidazolium dicyanimide 23343565 1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide 23343565 [EMIM][N(CN)2] 23343565 [EMIM][NTf2] 23343565 [HMIM][NTf2] 23343565 acetone 23343565 ethanol 23343565 hydrogen 23344156 phlorotannins 23344433 alstovenine 23344433 aminonitrile 23344433 hydrindanone 23344433 venenatine 23344433 yohimbinoid alkaloids 23344796 hydrogen 23344796 penicillin G 23344796 β-lactam 23344796 β-lactams 23344855 Ag 23344855 Au 23344855 carbon 23344855 nitrate 23344855 nitrates 23344855 nitrogen 23344856 DE-71 23344856 OH-PBDE 23344856 OH-PBDEs 23344856 PBDE 23344856 PBDEs 23344856 hydroxylated PBDEs 23344856 pentabrominated diphenyl ether 23344856 polybrominated diphenyl ethers 23344974 phenylalanine 23344983 Pb 23344983 glutathione 23345067 2-deoxysorbitol 23345067 Ag 23345067 Al 23345067 Au 23345067 Bi 23345067 C 23345067 Cd 23345067 Co 23345067 Cr 23345067 Cu 23345067 Fe 23345067 Hf 23345067 In 23345067 Ir 23345067 Mn 23345067 Mo 23345067 Nb 23345067 Ni 23345067 Pb 23345067 Pd 23345067 Pt 23345067 Re 23345067 Rh 23345067 Ru 23345067 Sb 23345067 Sn 23345067 Ta 23345067 Ti 23345067 V 23345067 We 23345067 Zn 23345067 Zr 23345067 fructose 23345067 glucose 23345067 hydrogen 23345067 platinum 23345067 sorbitol 23345067 transition metals 23345167 NADPH 23345167 diarylheptanoids 23345167 lignans 23345167 oxygen 23346856 Boc 23346856 Boc-L-Ile-HEA 23346856 Boc-L-Ile-HEMA 23346856 Boc-L-Leu-HEA 23346856 Boc-L-Leu-HEMA 23346856 Boc-L-isoleucine acryloyloxyethyl ester 23346856 Boc-L-isoleucine methacryloyloxyethyl ester 23346856 Boc-L-leucine acryloyloxyethyl ester 23346856 Boc-L-leucine methacryloyloxyethyl ester 23346856 DMF 23346856 Leucine 23346856 N, N-dimethylformamide 23346856 amine 23346856 amino acid 23346856 isoleucine 23346856 methyl (meth)acrylate 23346856 primary amine 23346913 Cys 23346913 MPA 23346913 TiO(2) 23346913 cysteine 23346913 mercaptopropionic acid 23346994 amino acid 23347001 IHN 23347001 Inositol hexanicotinate 23347001 inositol hexanicotinate 23347001 niacin 23347001 nicotinic acid 23347043 ATP 23347089 BPA 23347089 DEHP 23347089 MEHP 23347089 PFOA 23347089 PFOS 23347089 androgen 23347089 aryl hydrocarbon 23347089 bisphenol A 23347089 di-(2-ethylhexyl) phthalate 23347089 estrogen 23347089 mono-ethylhexyl phthalate 23347089 perfluorooctane sulfonate 23347089 perfluorooctanoic acid 23347089 pregnane 23347206 DON 23347206 ZEN 23347206 deoxynivalenol 23347206 zearalenone 23347584 diterpenoids 23347584 ent-18-acetoxykaur-16-en-15-one 23347584 ent-kaurane 23347584 ent-kauranes 23347584 kauranes 23347584 superoxide 23347954 GSK429286 23347954 H1152 23347954 Y27632 23347954 polyglutamine 23348005 GSSG 23348005 ORO 23348005 Oil-Red-O 23348005 Quercetin 23348005 TAG 23348005 alanine 23348005 glucose 23348005 glutathione 23348005 oleic acid 23348005 peroxides 23348005 quercetin 23348005 superoxide 23348005 triacyl glycerol 23348005 triacylglycerol 23348005 urea 23348055 BPA 23348055 bisphenol A 23348055 estrogen 23348235 EUDRAGIT 23348235 HCl 23348235 KH(2)PO(4) 23348235 Prednisolone 23348235 bicarbonate 23348235 mesalamine 23348407 coumestrol 23348407 isoflavones 23348407 isoflavonoid 23348407 lignan 23348407 lignans 23348500 2-Methyl-6-(phenylethynyl)pyridine 23348500 CPPHA 23348500 MPEP 23348500 N-(4-chloro-2-((4-fluoro-1,3-dioxoisoindolin-2-yl)methyl)phenyl)picolinamide 23348500 N-(4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl)-2-hydroxybenzamide 23348500 NCFP 23348500 glutamate 23348755 (+)-naloxone 23348755 (-)-naloxone 23348755 DAMGO 23348755 [D-Ala2, N-Me-Phe4, Glycinol5]-Enkephalin 23348755 adenylate 23348755 guanosine-5'-0-(γ-thio)-triphosphate 23349485 AMP 23349489 thymidine 23349493 glucose 23349493 palmitate 23349524 glucose 23349535 Ca(2+) 23349535 Ser 23349535 aldosterone 23349535 eplerenone 23349535 nitric oxide 23349535 spironolactone 23350627 TiO₂ 23350627 TiO₂-graphdiyne 23350627 TiO₂-graphene 23350627 carbon 23350627 graphdiyne 23350627 graphene 23350627 methylene blue 23350690 cinnamic acid 23350692 AMX 23350692 Amoxicillin 23350692 CFX 23350692 amoxicillin 23350692 cefuroxime 23350692 polypropylene 23350733 sivelestat 23350733 symplostatin 5 23350785 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide 23350785 MTT 23350785 bisdemethoxycurcumin 23350785 curcumin 23350785 curcuminoids 23350785 demethoxycurcumin 23350926 1,10-phenanthroline-5,6-dione 23350926 1,10-phenanthroline-6-one-5-diol 23350926 H 23350926 H(2)O 23350926 H(2)O(2+) 23350926 Ru(III) phen-semiquinone 23350926 [(phen)(2)Ru(phenH(2)O)](2+) 23350926 [(phen)(2)Ru(phendione)](2+) 23350926 [Ru(phen)(3)](2+) 23350926 acetonitrile 23350926 carbonyl 23350926 hydrate 23350926 hydrated Ru(II) 1,10-phenanthroline-5,6-dione 23350926 oxygen 23350926 phenH(2)O 23350926 phendione 23350926 quinone 23350926 ruthenium 23350926 ruthenium(II) 23350926 sugar 23351043 COOH 23351043 NaCl 23351043 PAA 23351043 PAH 23351043 PHEMA-g-PAA 23351043 poly(2-hydroxyethyl methacrylate)-graft-poly(acrylic acid) 23351043 poly(acrylic acid) 23351043 poly(allylamine) 23351072 biotin 23351072 streptavidin 23351147 coumarins 23351147 dianthramides 23351147 ethyl acetate 23351147 flavonoids 23351169 1,3-propanediol 23351169 1,4-butanediol 23351169 3HP 23351169 4HB 23351169 BDO 23351169 P(3HP-co-4HB) 23351169 P3HP 23351169 P3HP-b-P4HB 23351169 P4HB 23351169 PDO 23351169 PHA 23351169 Poly(4-hydroxybutyrate) 23351169 p(3-Hydroxypropionate)-block-p(4-hydroxybutyrate) 23351169 poly(3-hydroxypropionate) 23351960 GSH 23351960 MDA 23351960 glutathione 23351960 malondialdehyde 23351960 reduced glutathione 23351960 scopolamine 23351960 superoxide 23351962 Crocin 23351962 MDA 23351962 STZ 23351962 crocin 23351962 glutathione 23351962 malondialdehyde 23351962 streptozotocin 23351962 thiol 23352511 2-aminopyrimidine 23352511 4-fluorophenyl 23352511 PTZ 23352511 cyanopyridine 23352511 cyanopyridone 23352511 imidazo[1,2-a]pyridine 23352511 imidazo[1,2-a]pyridines 23352511 pentylene tetrazole 23352511 pyrazoline 23352511 pyrimidine-2-thione 23352834 sodium 23352909 DOXO 23352909 PSO-PEO 23352909 Pluronic 23352909 Pluronic P85 23352909 Poly(styrene oxide)-poly(ethylene oxide) 23352909 doxorubicin 23352909 poly(styrene oxide)-poly(ethylene oxide) 23352911 PLA 23352911 Poly(Lactic Acid) 23352911 poly(lactic acid) 23352980 ETP-45299 23352980 SGI-1776 23352980 tryptanthrin 23352986 All-trans retinoic acid 23352986 all-trans retinoic acid 23352986 atRA 23352986 retinoic acid 23352986 vitamin A 23353053 1,2,3,4,6 Penta-O-galloyl-β-d-glucose 23353053 1,2,3,4,6 penta-O-galloyl-β-d-glucose 23353053 CBX 23353053 PGG 23353053 carbenoxolone 23353053 corticosterone 23353053 gallotannin 23353053 glucose 23353657 Labdane diterpenoids 23353657 calomacrins A-C 23353657 calomacrol A 23353657 diaryl butyrolactone 23353657 labdane diterpenoids 23353657 lignan 23353657 lignans 23353700 C6-ceramide 23353700 Ceramide 23353700 Tamoxifen 23353700 VX-710 23353700 ceramide 23353700 cyclosporin A 23353700 sphingolipids 23353700 tamoxifen 23353700 verapamil 23353701 3-deazaadenosine 23353701 AdOx 23353701 DAZA 23353701 S-adenosylmethionine 23353701 SAH 23353701 SAM 23353701 adenosine dialdehyde 23353701 adenosylhomocysteine 23353701 methyl 23353736 methyl rosmarinate 23353744 5-arylbenzoxepins 23353744 CA-4 23353744 N-tosylhydrazones 23353744 aryl iodides 23353744 benzoxepin 23353744 benzoxepins 23353744 isoCA-4 23353744 isocombretastatin A-4 23353744 palladium 23353747 1,4-naphthoquinones 23353747 Naphthoquinones 23353747 cisplatin 23353747 lapachol 23353747 naphthoquinone 23353747 α- and β-lapachone 23353747 β-lapachone 23353749 (S)-α-Tfm-proline 23353749 (S)-α-trifluoromethyl-proline 23353749 CF3-(MIF-1) 23353749 HCl. Leu-Gly-NH2 23353749 MIF-1 23353749 NO 23353749 l-Arg 23353749 l-N(G)-nitroarginine ester 23353749 l-NAME 23353749 l-arginine 23353749 naloxone 23353749 nitric 23353749 nitric oxide 23353749 trifluoromethyl 23353749 tripeptide 23353751 (1)H 23353751 (13)C 23353751 1,10-phen 23353751 1,10-phenanthroline 23353751 2,2'-bipy 23353751 2,2'-bipyridine 23353751 N 23353751 N-furfuryl-N-(2-phenylethyl)dithiocarbamate 23353751 Zn 23353751 Zn(fpedtc)2 23353751 Zn(fpedtc)2(1,10-phen) 23353751 Zn(fpedtc)2(2,2'-bipy) 23353751 Zn(fpedtc)2(py) 23353751 bis(N-furfuryl-N-(2-phenylethyl)dithiocarbamato-S,S')zinc(II) 23353751 fpedtc 23353751 nitrogen 23353751 pyridine 23353753 C 23353753 agmatine dipeptide 23353753 agmatine dipeptides 23353753 aldehydes 23353753 serine 23353756 3,4-dihydroxyphenylacetic acid 23353756 4-phenylpiperazines 23353756 4-phenylpiperidines 23353756 4-phenylpiperidines and -piperazines 23353756 DOPAC 23353756 dopamine 23353756 mono-substituted 4-phenylpiperidines and -piperazines 23353756 monoamine 23353805 DOX 23353805 doxorubicin 23353805 iron oxide 23353805 γ-Fe(2)O(3) 23353807 HA-1077 23353807 MCT 23353807 ammonium sulfate 23353807 fasudil 23353807 monocrotaline 23353821 H(2)O(2) 23353821 oxygen 23353821 tyrosine 23353901 1-methylpsilocin 23353901 2,5-dimethoxy-4-iodoamphetamine 23353901 4-phenyl-2-N,N-dimethyl-aminotetralin 23353901 5-HT 23353901 CP 809101 23353901 DOI 23353901 M100907 23353901 PAT 23353901 Ro 60-0175 23353901 SB-206553 23353901 SB-242084 23353901 WAY 161503 23353901 mCPP 23353901 serotonin 23354151 PVP 23354151 TPGS 23354151 d-α-tocopheryl polyethylene glycol 1000 succinate 23354151 hydrocortisone 23354151 phosphatidylcholine 23354151 polyvinylpyrrolidone 23354457 organochlorine 23354457 organophosphate 23354532 CAF 23354532 Caffeine 23354532 caffeine 23354536 3,4 methylenedioxymethamphetamine 23354536 5-HT 23354536 5-HTP 23354536 5-hydroxytryptophan 23354536 8-OHDPAT 23354536 MDMA 23354536 serotonin 23354536 tryptophan 23354542 Ca 23354542 Fe 23354542 Mg 23354542 Na 23354542 P 23354542 S 23354542 Zn 23354542 nitric acid 23354542 perchloric acid 23354728 11-β-hydroxysteroid 23354728 fatty acid 23354728 glucose 23354728 sodium 23354809 piperacillin 23354809 tazobactam 23355192 Iron bisterpyridine 23355192 methacrylates 23355456 NSC 100874 23355456 NSC 104999 23355456 NSC 55158 23355456 NSC 57148 23355456 phenylbenzamide 23357335 cyclic nucleotide 23357335 cyclic nucleotides 23357361 1-propenyl-2,4,5-methoxybenzol 23357361 MTT 23357361 β-Asarone 23357361 β-asarone 23357630 NO 23357630 butyl lucidenate D(2) 23357630 butyl lucidenate E(2) 23357630 butyl lucidenate P 23357630 butyl lucidenate Q 23357630 lanostane triterpenes 23357630 triterpenes 23357951 Glutamate 23357951 glutamate 23357951 rapamycin 23358195 acetaminophen 23358236 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide 23358236 ATP 23358236 Didehydrostemofoline 23358236 MTT 23358236 NH-B6 23358236 NH-D6 23358236 OH-A1 23358236 doxorubicin 23358236 paclitaxel 23358236 stemofoline 23358236 vinblastine 23358249 Baicalein 23358249 EGCG 23358249 PQQ 23358249 epigallocatechin gallate 23358249 pyrroloquinoline quinone 23358249 quinone 23358258 2-aminoethylaminomethyl 23358258 4-methyl-quinazoline-2-yl-methyl 23358258 methylene 23358258 xanthine 23358307 3-phenylpropanamide 23358307 cystodytin 23358307 cystodytin iminoquinone alkaloids 23358307 pyrido[4,3,2-mn]acridin-4-one 23358307 pyrido[4,3,2-mn]acridine 23358307 styelsamine 23358307 styelsamines B and D 23358500 acetylcholine 23358500 nicotine 23358572 polyaniline 23359135 N-phenyl-2-naphthylamine 23359135 norflurazon 23359135 triclosan 23359475 alcohol 23359475 triglycerides 23359599 (125) I 23359599 PEG 23359599 Poly(2-Hydroxyethyl Methacrylate) 23359599 Poly(Glycidyl Methacrylate) 23359599 amino 23359599 carboxyl 23359599 poly(2-hydroxyethyl methacrylate) 23359599 poly(ethylene glycol-co-propylene glycol) 23359599 poly(glycidyl methacrylate) 23359599 α,ω-bis-carboxy poly(ethylene glycol) 23359599 α-methoxy-ω-amino poly(ethylene glycol) 23360082 Ti 23360082 TiO(2) 23360082 poly-N-(isopropylacrylamide) 23360082 polystyrene 23360082 titanium dioxide 23360118 10-hydroxycamptothecin 23360118 2-methoxyestradiol 23360118 2-methoxyestradiol glucosides 23360118 daidzein 23360118 flavones 23360118 flavopiridol 23360118 glucosylate 23360118 indole alkaloids 23360118 isoflavones 23360118 resveratrol 23360118 steroids 23360118 stilbenes 23360211 EGDE 23360211 ethylene glycol diglycidyl ether 23360295 poly(β-amino) esters 23360333 (111)(Si) 23360333 AlN 23360333 Si 23360333 Si (111) 23360333 Si(111) 23360333 aluminum nitride 23360333 silicon 23360443 Posaconazole 23360443 posaconazole 23360443 triazoles 23360452 2,7-dimethyloctane 23360452 alkanes 23360452 carbon 23360452 cyclodecane 23360452 n-decane 23360452 n-hexane 23360452 n-octane 23360475 tryptanthrin 23360475 tryptanthrins 23360513 benzenehexathiol 23360513 nickel bis(dithiolene) 23360513 nickel(II) acetate 23360549 CP-2 23360549 SDS 23360549 cyclic D,L-α-peptide 23360549 cyclic D,L-α-peptides 23360549 thioflavin T 23360676 carbohydrate 23360912 (Ni(0.33)Co(0.67))N 23360912 Co 23360912 Li 23360912 Li(3)N 23360912 Metal nitride 23360912 N(2) 23360912 NH(3) 23360912 Ni 23360912 NiCo(2)O(4) 23360912 cobalt 23360912 cobalt nitride 23361121 CuO 23361121 lithium 23361257 1-ethyl-3-methylimidazolium bis(trifluoro-methylsulfonyl)imide 23361257 EAN 23361257 EMIm 23361257 EMIm TFSI 23361257 ethylammonium nitrate 23361264 CoQ10 23361264 EPI-743 23361264 arginine 23361264 citrulline 23361264 coenzyme Q10 23361264 creatine 23361264 dichloroacetate 23361264 idebenone 23361264 nitric oxide 23361264 phosphocreatine 23361264 pyruvate 23361264 α-lipoate 23361305 ATP 23361305 cardiolipin 23361305 monolysocardiolipin 23361313 Ag 23361313 CO 23361313 H(2)SO(4) 23361313 Pt 23361313 methanol 23361398 Ge 23361398 HClO4 23361398 OOH 23361398 hydrogen 23361398 oxygen 23361398 peroxide 23361398 peroxides 23361398 superoxide 23361398 superoxides 23361404 PDMS 23361404 polydimethylsiloxane 23361586 Glucose 23361586 glucose 23361846 Methadone 23361846 N 23361846 R- and S-methadone 23361846 Ticlopidine 23361846 alfentanil 23361846 deuterium 23361846 methadone 23361846 racemic methadone 23361846 ticlopidine 23361977 Carboxylic acid 23361977 carboxylic acid 23362135 (111) Indium 23362135 (18) fluorodeoxyglucose 23362135 1,25-dihydroxyvitamin D(3) 23362135 1,25D 23362135 C 23362135 phosphate 23362135 phosphorus 23362224 Graphene Oxide 23362224 graphene oxide 23362240 Vemurafenib 23362240 calcium 23362240 glucose 23362240 thapsigargin 23362240 vemurafenib 23362262 PP242 23362262 PP242, 23362262 rapamycin 23362940 Co(2+) 23362940 CoFe(2)O(4) 23362940 Fe(2+) 23362940 FeO 23362940 ferrite 23362940 metal oxide 23363038 PAHs 23363038 polycyclic aromatic hydrocarbons 23363299 Au-Pd 23363299 Fe(III)(C₅H₈O₂)₃ 23363299 FeSe 23363299 O₂ 23363299 Se 23363299 carbon 23363299 iron acetylacetonate 23363299 iron selenide 23363377 Genistein 23363377 androgen 23363377 genistein 23363377 isoflavone 23363377 polyQ 23363377 polyglutamine 23363397 1,3-dioxane 23363397 1,4-butanediol 23363397 2,4:3,5-di-O-methylene-d-mannitol 23363397 bicyclic D-mannitol 23363397 carbohydrate 23363397 dimethyl succinate 23363397 diol 23363397 hydroxyl 23363397 isosorbide 23363397 polyester 23363397 polyesters 23363575 2,3,7,8-Tetrachloro dibenzo-p-dioxin 23363575 TCDD 23363575 corticosterone 23364186 Tetrabenzoporphyrins 23364186 porphyrin 23364186 tetrabenzoporphyrins 23364509 atorvastatin 23364619 petroleum hydrocarbon 23364619 petroleum hydrocarbons 23364619 polyaromatic hydrocarbons 23364814 polyphenols 23364815 Heroin 23364815 Sucrose 23364815 buprenorphine 23364815 methadone 23364815 naltrexone 23364815 sugars 23364886 9,19-cycloartane triterpene glycosides 23364886 Heracleifolinoside B 23364886 Heracleifolinosides A-F 23364886 heracleifolinosides A-F 23364886 norkhelloside 23364886 triterpene glycosides 23364935 p-phenylenevinylene trimers 23367873 ATP 23367873 Jakafi 23367873 Xeljanz 23367873 ruxolitinib 23367873 tofacitinib 23367873 tyrosine 23368280 AAO 23368280 aluminum oxide 23368280 amino acid 23368280 glycine 23368280 α-glycine 23368280 β-glycine 23368710 Reduced graphene oxide 23368710 carbon 23368710 carbonyl 23368710 epoxy 23368710 graphene 23368710 hydroxyl 23368710 oxygen 23368710 rGO 23368710 reduced graphene oxide 23368735 Cl 23368735 I 23368735 M = Ru(II) or Os(II) 23368735 Os(II) 23368735 Ru(II) 23368735 X ═ Cl or I 23368735 [M(p-cymene)(azo/imino-pyridine)X](+) 23368735 chlorido 23368735 chlorido ruthenium 23368735 cisplatin 23368735 glutathione 23368735 iodido 23368735 l-buthionine sulfoxime 23368735 osmium arene azo- and imino-pyridine 23368735 oxaliplatin 23368735 platinum 23368753 Cu(I) 23368753 CuCl 23368753 CuO₄ 23368753 Cu₂Nb₈O₂₁ 23368753 HNbO₃ 23368753 LiOH·H₂O 23368753 Li₃NbO₄ 23368753 Nb(V) 23368753 NbO₇ 23368753 PEG200 23368753 copper(I) 23368753 niobate 23368753 oxides 23368902 PLA 23368902 polylactide 23368902 polynorbornene 23368902 polystyrene 23368996 (-)-petrosynoic acids A-D 23368996 C31-C33 polyacetylenes 23368996 pellynols A (5), C (6), D (7), F (8), and I 23369012 NaOH 23369072 (co)polyesters 23369072 1,4-butanediol 23369072 AzA 23369072 BDO 23369072 DMAz 23369072 P(BS-co-BAz) copolyesters 23369072 P(BS-co-BAz)s 23369072 SuA 23369072 aliphatic copolyesters 23369072 copolyesters 23369072 dimethylazelate 23369072 poly(butylene succinate-co-butylene azelate) 23369072 poly(butylenesuccinate-co-butyleneazelate) 23369072 polyesters 23369072 succinic acid 23369093 CO(2) 23369093 DTZ 23369093 Diltiazem hydrochloride 23369093 PEO 23369093 diltiazem HCl 23369093 polyethylene oxide 23369093 sodium bicarbonate 23369206 flavonoid 23369206 flavonoids 23369206 laninamivir 23369206 oseltamivir 23369206 oseltarmivir 23369206 peramivir 23369206 phenyl-benzopyrane 23369206 phosphonate 23369206 zanamivir 23369791 Thiamine 23369791 Vitamin B1 23369791 alcohol 23369791 alcoholics 23369791 benfotiamine 23369791 ethanol 23369791 phosphate esters 23369791 pro-vitamin B1 23369791 thiamine 23369791 thiamine hydrochloride 23369791 vitamin B1 23369932 bilirubin 23369932 copper 23369932 creatinine 23369932 gamma-glutamyl 23369932 manganese superoxide 23369932 superoxide 23369932 urea 23369932 zinc 23369934 UDCA 23369934 cholesterol 23369934 triglyceride 23369934 ursodeoxycholic acid 23369934 urushiol 23369935 9-Methoxycamptothecin 23369935 FITC 23369935 MCPT 23369935 propidium iodide 23369989 C 23369989 deoxypyridinoline 23369989 sulfate 23370007 Cys 23370007 Pb 23370007 lead acetate 23370007 oxygen 23370194 1,3,4-oxadiazole 23370194 2,5-disubstituted-1,3,4-oxadiazole 23370194 2-substituted thio-5-substituted-1,3,4-oxadiazole 23370194 3-substituted aminomethyl-5-substituted-1,3,4-oxadiazole-2(3H)-thione 23370194 SRB 23370194 Sulfo-Rodamine B 23370194 diphenylamine 23370194 oxadiazole 23370195 Flurbiprofen 23370195 flurbiprofen 23370198 C 23370198 Organosilicon 23370198 Si 23370198 TMN 23370198 silicon 23370198 tetrahydrotetramethylnaphthalene 23370266 Ag 23370266 Ag(+) 23370266 Silver 23370266 glutathione 23370266 silver 23370266 silver glutathionates 23371492 cortisol 23371548 Carbon 23371548 Li 23371548 SnO2 23371548 carbon 23371801 pyrene 23371801 thymine 23372018 Manganese 23372018 Mn 23372018 glucose 23372018 iron 23372018 manganese 23372018 superoxide 23373428 Vitamin D(3) 23373428 acetonitrile 23373428 methanol 23373428 probucol 23373428 vitamin D(3) 23373428 vitamin D(3) or K(1) 23373428 vitamin K(1) 23373428 vitamins 23373428 vitamins D(3) and K(1) 23373513 iron oxide 23373677 AtO(+) 23373677 AtO(OH) 23373677 astatine(III) 23373677 astatine(III) hydroxide 23373696 HPMA 23373696 N-(2-hydroxypropyl)methacrylamide 23373696 doxorubicin 23373701 Dopamine 23373701 dopamine 23373701 potassium 23373701 quinpirole 23373701 raclopride 23373701 zinc 23373704 (13)C 23373704 (15)N 23373704 (2)H 23373704 H 23373704 pentaerythritol tetranitrate 23373819 Arg 23373819 Gly 23373819 Phe 23373819 Pro 23373819 Ser 23373819 alanine 23373819 amino acid 23373819 bradykinin 23373819 proline 23373819 prolines 23373869 iodine 23373869 radioiodine 23374864 (2-fluoro-4-methylsulfonyl)phenylamino 23374864 5-Nitropyrimidine 23374864 5-nitropyrimidine 23374864 azabicyclic 23374864 azabicyclic amines and alcohols 23374864 endo-azabicyclic amines and alcohols 23374864 exo-azabicyclic amines and alcohols 23374864 fluorine 23374873 2'-O,4'-C-methylene-bridged/linked bicyclic ribonucleotides 23374873 methylene 23374873 nucleotides 23375228 quinoxalines 23375813 (1)H 23375813 (13)C 23375813 3'-R/S-Hydroxyvoacamine 23375813 3'-R/S-hydroxyvoacamine 23375813 bisindole alkaloid 23376007 androgens 23376007 dihydrotestosterone 23376007 testosterone 23376097 Ala 23376097 Asp 23376097 Glu 23376097 amino acid 23376097 d-glyceraldehyde-3-phosphate 23376097 glyceraldehyde-3-phosphate 23376097 indole 23376097 indole-3-glycerol phosphate 23376097 tryptophan 23376217 Acyl-CoA 23376217 acyl-CoA 23376217 cAMP 23376247 diclofenac Na 23376247 thieno [2',3':4,5]pyrimido[1,2-b][1,2,4]triazines 23376247 thieno[2',3':4,5]pyrimido[1,2-b][1,2,4]triazines 23376247 thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidine 23376247 thieno[2,3-d][1,2,4]triazolo[1,5-a]pyrimidines 23376247 thienotriazolopyrimidine 23376250 CTM 23376250 cyrtominetin 23376258 ATP 23376258 VIN 23376258 oxygen 23376258 superoxide 23376258 vinclozolin 23376345 (14)C-labeled 8-oxo-GTP 23376345 8-oxo-7,8-dihydroguanine 23376345 8-oxo-GDP 23376345 8-oxo-GMP 23376345 8-oxo-GTP 23376345 CaCl2 23376345 GDP 23376345 GMP 23376345 GTP 23376345 adenine 23376345 adenylate 23376345 cytosine 23376345 guanine nucleotides 23376345 guanylate 23376345 nucleoside-diphosphate 23376345 nucleotides 23376345 oxygen 23376352 ATP 23376352 Bradykinin 23376352 bradykinin 23376355 3,3'-Diindolymethane 23376355 3,3'-diindolymethane 23376355 DIM 23376355 adriamycin 23376356 LY294002 23376356 SB203580 23376356 SP600125 23376546 BUP 23376546 NBUP 23376546 buprenorphine 23376546 norbuprenorphine 23376779 EGCG 23376779 N-acetyl-cysteine 23376779 NAC 23376779 catechins 23376779 epigallocatechin gallate 23376779 polyphenols 23376802 Pb 23376823 DTDP 23376823 DUDP 23376823 dialkyl phthalate esters 23376823 ditridecyl phthalate 23376823 diundecyl and ditridecyl phthalates 23376823 diundecyl phthalate 23376823 phthalate 23376975 Coumarin 23376975 acenocoumarol 23376975 coumarin 23376975 gamma-glutamyl 23376975 phenprocoumon 23376975 vitamin K epoxide 23376975 warfarin 23377024 Alcohol 23377024 Caffeine 23377024 alcohol 23377024 caffeine 23377618 acetaminophen 23377618 glucose 23377618 rosiglitazone 23377618 troglitazone 23378191 tyrosine 23378600 cholesterol 23378600 fatty acid 23378600 sphingolipids 23379472 1,2,5,6-tetrahydropyridine-3-carboxylic acid 23379472 Tetrahydropyridine-3-carboxylate Esters 23379472 [(3)H]DA 23379472 [(3)H]N-methylscopolamine 23379472 acetylcholine 23379472 oxotremorine 23379514 (E)-3-(4-(phenylamino)phenylcarbamoyl)acrylic acid 23379514 (E)-N'-(4-(dimethylamino)benzylidene) diazenecarboximidhydrazide 23379514 CO 23379514 HN 23379514 N 23379514 heme 23379514 iron 23379514 phenoxy 23380374 PEG 23380374 TIBO 23380374 d4T 23380374 d4T-6PEG-TIBO 23380374 nucleoside 23380374 polyethylene glycol 23380374 triphosphate 23380568 cholesterol 23380568 triglyceride 23380916 AMPA 23380916 N-methyl-D-aspartate 23380916 NMDA 23380916 amphetamine 23380916 dopamine 23380916 glutamate 23380916 α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid 23381641 3-methyladenine 23381641 Bafilomycin A1 23381641 N 23381641 oxygen 23381641 serine 23381641 threonine 23381641 tunicamycin 23381727 Carbon 23381727 carbon 23381904 PAMAM 23381904 PEI 23381904 PEI 423 23381904 Polyamidoamine 23381904 polyamidoamine 23381904 polyethylenimine 23381936 Atorvastatin 23381936 atorvastatin 23381936 o-hydroxyatorvastatin 23381968 Clopidogrel 23381968 Sibutramine 23381968 clarithromycin 23381968 clopidogrel 23381968 racemic sibutramine 23381968 sibutramine 23382024 Ir(111) 23382024 graphene 23382024 ir(111) 23382458 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide 23382458 Apixaban 23382458 Ketoconazole 23382458 Ko134 23382458 Naproxen 23382458 apixaban 23382458 cyclosporin A 23382458 digoxin 23382458 ketoconazole 23383648 Gd-DTPA 23383648 Polyethylene glycol 23383648 ruthenium 23383648 silica 23383744 PTU 23383744 propylthiouracil 23383744 thyroid hormone 23384448 4-hydroxytamoxifen 23384448 ADP 23384448 ATP 23384448 Acitretin 23384448 Ca(2+) 23384448 acitretin 23384448 adenine nucleotide 23384448 retinoid 23384448 tamoxifen 23384448 thiol 23384834 Dex 23384834 [(3)H]thymidine 23384834 dexamethasone 23384834 steroid 23384997 Cys-Se-Se-Cys 23384997 Glutathione 23384997 Na2SeO3 23384997 Se 23384997 SeCys 23384997 Selenium 23384997 amino acid 23384997 glutathione 23384997 hydroperoxide 23384997 oxygen 23384997 selenium 23384997 selenocysteine 23384997 sodium selenite 23385032 Floxuridine 23385032 Gemcitabine 23385032 Gemcitabine 5'-mono-, di- and triphosphates 23385032 nucleoside 23385032 phosphorylated 5-FU nucleoside 23385032 polyvinyl alcohol 23385210 Darapladib 23385210 amide 23385210 imidazole 23385210 quaternary ammonium salts 23385210 triazole 23385213 (5R)-[1,2,3]triazolylmethyl and (5R)-[(4-F-[1,2,3]triazolyl)methyl] oxazolidinones 23385213 5(R)-[1,2,3]triazolylmethyl and (5R)-[(4-F-[1,2,3]triazolyl)methyl]oxazolidinones 23385213 exo-cyanoethylidene 23385213 linezolid 23385213 penicillin 23385213 piperidine 23385219 AFB1 23385219 aflatoxin B1 23385325 C 23385325 O 23385325 aspartic acids 23385325 carboxylic acids 23385325 hydrogen 23385960 DXM 23385960 Doxazosin mesylate 23385960 Eudragit 23385960 PEG 6000 23385960 Polymethacrylate 23385960 TEC 23385960 doxazosin mesylate 23385960 polyethylene glycol 6000 23385960 triethyl citrate 23386029 3,6-Disubstituted α-Pyrones 23386029 3,6-disubstituted α-pyrones 23386029 3-alkylated 6-(1-methyl-1-propenyl)-2H-pyran-2-ones 23386029 NO 23386029 Nocapyrone H 23386029 Nocapyrones H-J 23386029 PGE2 23386029 nitric oxide 23386029 nocapyrone H 23386029 nocapyrones H-J 23386029 prostaglandin E2 23386251 glucose 23386251 sodium 23386251 tofogliflozin 23386368 Lithium 23386368 Sn 23386368 SnO(2) 23386368 carbon 23386368 graphene 23386368 iron oxides 23386368 lithium 23386368 metal oxides 23386368 metal-oxide 23386368 tin dioxide 23386368 titanium dioxide 23386390 metformin 23386390 sitagliptin 23386390 sulfonylureas 23386413 17-hydroxyprogesterone 23386413 17OHP 23386413 Androgen 23386702 (R)-naproxen-β-d-glucuronide 23386702 (S)-naproxen-β-d-glucuronide 23386702 4-nitrophenyl acetate 23386702 CGP 47292-β-d-glucuronide 23386702 Diclofenac-β-d-glucuronide 23386702 Uridine 5'-diphosphate 23386702 Valproate-β-d-glucuronide 23386702 acyl glucuronides 23386702 alcohols 23386702 amides 23386702 amines 23386702 carboxylic acids 23386702 clopidogrel-β-d-glucuronide 23386702 diclofenac-β-d-glucuronide 23386702 esters 23386702 ibuprofen-β-d-glucuronide 23386702 ibuprofen-β-d-glucuronide (racemic) 23386702 potassium phosphate 23386702 thioesters 23386702 thiols 23386702 valproate-β-d-glucuronide 23386779 ketamine 23387288 chloroform 23387288 ethyl acetate 23387288 hexane 23387288 iridoids 23387288 loganin 23387288 secoxyloganin 23387288 sweroside 23387306 He 23387306 tetrahydrofuran 23387425 AZA-1 23387425 AZAs 23387425 Azaspiracid-1 23387425 chlorpromazine 23387554 CTAB 23387554 chloroform 23387554 methanol 23387554 silica 23387554 stearic acid 23387824 (E)-15,16-bisnorlabda-8(17),11-dien-13-one 23387824 12-hydroxycurcumenol 23387824 15-hydroxyprocurcumenol 23387824 4,10-epizedoarondiol 23387824 Sesquiterpenes 23387824 aerugidiol 23387824 curcumanolides 23387824 diterpenes 23387824 germacranes 23387824 guaianes 23387824 heyneanone A 23387824 heyneanone C 23387824 heyneanones A-D 23387824 labdane 23387824 procurcumenol 23387824 sesquiterpenes 23387824 spirolactones 23387824 tyrosine 23387824 zerumin A 23388072 (1)H 23388072 DOX 23388072 FITC 23388072 PCL-b-PEO 23388072 cyclic (Arginine-Glycine-Aspartic acid-d-Phenylalanine-Lysine) 23388072 doxorubicin 23388072 fluorescein isothiocyannate 23388072 poly(ε-caprolactone)-b-poly(ethylene oxide) 23388095 DMOG 23388095 NaCl 23388095 NaOCl 23388095 Prolyl 23388095 acetylcholine 23388095 dimethyloxalylglycine 23388095 heme 23388095 hypochlorite 23388095 oxygen 23388095 prolyl 23388705 Tecadenoson 23388705 adenosine 23388705 nitrobenzylmercaptopurine 23388705 nucleoside 23388705 tecadenoson 23389090 (1)H 23389090 (13)C 23389090 sugar 23389091 NO 23389091 casbane diterpenoids 23389091 nitric oxide 23389091 sinularcasbanes A-F 23389324 iron oxide 23389739 H(2)Ti(3)O(7) 23389739 TiO(2) 23389739 oxygen 23389756 BMY-14802 23389756 L-DOPA 23389756 SKF81297 23389756 WAY-100635 23389756 dopamine 23389756 quinpirole 23389830 ACh 23389830 Ca(2+) 23389830 K(+) 23389830 acetylcholine 23389830 noradrenaline 23389852 androgen 23389862 Roflumilast 23389862 fluticasone propionate 23389862 formoterol 23389862 roflumilast 23389878 NH2 23389878 androgen 23390132 nucleotide 23390932 Au102(pMBA)44 23391023 polyacenes 23391037 benzene 23391095 1,5-bis(2,3-dihydroxybenzamido)naphthalene 23391095 Ar-CH2 23391095 DMF 23391095 [Ga4L6](12-) 23391095 benzyl phosphonium 23391095 methanol 23391095 ortho-substituted benzyl phosphonium 23391212 (14)C 23391212 AZD7903 23391273 Cholesterol 23391274 C 23391274 CO 23391274 H 23391274 HCO 23391274 OH 23391280 Glutathione 23391280 N 23391280 O 23391280 clarithromycin 23391280 cysteine 23391280 irgarol 23391280 terbutryn 23391280 tramadol 23391280 valsartan 23391280 venlafaxine 23391336 5-mercapto-1,3,4-thiadiazoles 23391336 CO(2) 23391336 His 23391336 Sulfonamide 23391336 Thiol 23391336 aromatic sulfonamides 23391336 aromatic/heterocyclic sulfonamides 23391336 thiols 23391596 Benzaldehyde semicarbazone 23391596 benzaldehyde semicarbazone 23391596 ethanol 23392120 Li 23392120 Li2MnO3 23392120 LiMn2O4 23392120 LiMnO2 23392120 Mn 23392120 Mn5O8 23392120 MnCO3 23392120 MnCO₃ 23392120 O 23392354 Cl(-) 23392354 GABA 23392354 acetazolamide 23392354 bicarbonate 23392354 dopamine 23392354 furosemide 23392354 morphine 23392354 muscimol 23392755 GBL 23392755 GHB 23392755 l-lactate 23392755 monocarboxylate 23392755 γ-butyrolactone 23392755 γ-hydroxybutyrate 23392757 noradrenaline 23392757 serotonin 23393127 GnRH 23393127 H89 23393127 cAMP 23393213 glucose 23393218 glucose 23393220 5-MEO 23393220 5-MeO-DMT 23393220 5-Methoxy-N,N-Dimethyltryptamine 23393220 5-Methoxy-N,N-dimethyltryptamine 23393220 Harmaline 23393220 Monoamine 23393220 O 23393220 bufotenine 23393220 harmaline 23393220 indolealkylamines 23393220 monoamine 23394067 Polyester 23394067 acrylate 23394067 polyesters 23394134 iron oxide 23394134 zwitterated iron oxide 23394134 zwitterion siloxane 23394134 zwitterionic siloxane 23394284 Tetracyclic diterpenoids 23394284 diterpenoids 23394284 isospongian 23394284 isospongian diterpene 23394284 kravanhin D 23394284 kravanhins A-C 23394284 labdane diterpenes 23394284 labdane diterpenoids 23394284 nitric oxide 23394284 tetracyclic diterpenes 23394392 MTX 23394392 Methotrexate 23394550 (1)H 23394550 DMSO 23394550 N 23394550 anthracene 23394550 cyclohexane 23394550 ethanol 23394550 ethyl acetate 23394550 fluoride 23394550 hydrogen 23394550 methanol 23394550 uracil 23394553 cholesterol 23394555 ATP 23394555 Mg(2+) 23394555 Thymidylate 23394555 dTDP 23394555 dTMP 23394555 dTTP 23394555 doxorubicin 23394555 nucleoside 23394555 nucleoside-diphosphate 23394555 pyrimidine 23394555 thymidine 5'-diphosphate 23394555 thymidine 5'-monophosphate 23394555 thymidine 5'-triphosphate 23394608 amine 23394608 carbodiimide 23394608 carboxylic acid 23394608 glutathione 23394608 lipoic acid 23394608 poly(ethylene glycol) 23394608 polyethylene glycol 23394611 PbS 23395169 Bile acid 23395169 Bile acids 23395169 bile acid 23395169 bile acids 23395169 cholesterol 23395169 cholic acid 23395169 muricholic acid 23395169 tauro-beta-muricholic acid 23395169 tauro-conjugated beta- and alpha-muricholic acids 23395171 Ca(2+) 23395171 calcium 23395172 heme 23395172 iron 23395259 1-butanol 23395259 1-hexanol 23395259 butanoic acid 23395259 butyl acetate 23395259 ethyl 2-methylbutanoate 23395259 ethyl hexanoate 23395259 hexanoic acid 23395259 octanoic acid 23395259 β-damascenone 23395668 bisphosphonates 23395668 hydroxyapatite 23395669 Sophocarpine 23395669 oleic acid 23395669 sophocarpine 23395695 2,4,-dinitrofluorobenzene 23395695 CPDs 23395695 DNFB 23395695 cyclobutane pyrimidine dimers 23395696 Oxysterols 23395696 cholesterol 23395696 oxygen 23395696 oxysterol 23395696 oxysterols 23395804 Ca(2+) 23395804 Cl(-) 23395804 Cl- 23395804 H(+) 23395804 Na(+) 23395804 Na+ 23395821 N 23395821 amino acid 23395821 decapeptide 23395967 (1)H 23395967 CuZn 23395967 Fe 23395967 Glucantime 23395967 Mn 23395967 aza 23395967 meglumine antimoniate 23395981 Alcohol 23395981 CpG 23395981 MG-132 23395981 alcohol 23395981 ethanol 23395981 methyl CpG 23396053 androstane 23396053 aryl hydrocarbon 23396053 pregnane 23396138 BZA 23396138 PAH 23396138 PAHs 23396138 aryl hydrocarbon 23396138 benzanthracene 23396138 polycyclic aromatic hydrocarbons 23396185 H2O2 23396185 NO2(-) 23396185 O2(-) 23396185 ONOO(-) 23396185 Quercetin 23396185 flavonoid 23396185 glutathione 23396185 hydrogen peroxide 23396185 nitrite 23396185 peroxynitrite 23396185 poly ADP ribose 23396185 pyruvate 23396185 superoxide 23396488 BFA 23396488 N 23396488 brefeldin A 23397054 Elacridar 23397054 elacridar 23398051 Co(OH)2 23398051 Co3O4 23398051 Fe2O3 23398051 H2O 23398051 Hematite 23398051 cobalt oxide 23398051 hematite 23398173 C-O 23398173 carbenes 23398173 chlorocarbene 23398173 chloromethanol 23398189 1,2-dimyristoyl-sn-glycero-3-phosphocholine 23398189 1,2-dioleoyl-sn-glycero-3-phosphocholine 23398189 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine 23398189 CTAB 23398189 DMPC 23398189 DOPC 23398189 POPC 23398189 SDS 23398189 SOPC 23398189 cholesterol 23398189 stearoyl-oleoylphosphatidylcholine 23398356 Al(OH)3-PAM 23398356 Al-PAM 23398356 Cationic Al-PAM 23398356 Kaolinite 23398356 MF1011 23398356 PAM 23398356 PAMs 23398356 Quartz 23398356 alumina 23398356 aluminum-hydroxy 23398356 anionic MF1011 23398356 anionic PAM 23398356 hydrogen 23398356 kaolinite 23398356 polyacrylamide 23398356 quartz 23398356 silica 23398572 Pt 23398572 Pt(n) 23398572 Pt(n)(+) 23398572 carbon 23398572 glassy carbon 23398572 oxygen 23399444 Oxygen 23399444 Se 23399444 SeMet 23399444 lactate 23399444 methionine 23399444 oxygen 23399444 selenomethionine 23399444 sterol 23399444 triglycerides 23399444 tyrosine 23399444 β-hydroxyacyl coenzyme A 23400048 C(7)H(14)N(2)O(3) 23400048 H 23400048 amide 23400048 carboxyl 23400048 dialanine 23400048 hydrogen 23400048 methyl-dialanine 23400254 Au 23400254 graphene 23400750 2-butyl acetate 23400750 2-pentyl acetate 23400750 2-pentyl butyrate 23400750 alcohol 23400750 ester 23400750 isopropyl butyrate 23400750 ketone 23400750 tenofovir 23400848 Voriconazole 23400848 voriconazole 23401165 Arsenic 23401165 As[III] 23401165 As[V] 23401165 acetate 23401165 arsenate 23401165 arsenic 23401165 arsenite 23401165 bicarbonate 23401165 iron 23401165 sulfate 23401165 sulfide 23401165 sulfur 23401165 thioarsenic 23401165 uranium 23401165 uranium (IV) 23401165 uranium (VI) 23401173 (-)-Cubebin 23401173 (-)-cubebin 23401173 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one 23401173 Cubebin 23401173 L-NAME 23401173 Lignan 23401173 NO 23401173 Nitric Oxide 23401173 Nω-nitro-L-arginine methyl ester 23401173 ODQ 23401173 Phe 23401173 acetylcholine 23401173 cGMP 23401173 indomethacin 23401173 lignan 23401173 nitric oxide 23401173 phenylephrine 23401173 prostacyclin 23401173 sodium nitroprusside 23401228 H(2) O(2) 23401228 Hydrogen Peroxide 23401228 [6]-Shogaol 23401228 [6]-shogaol 23401228 hydrogen peroxide 23401228 oxygen 23401280 Labdane Diterpenoid 23401280 Otostegindiol 23401280 labdane diterpenoid 23401280 methanol 23401280 otostegindiol 23401298 DMDOA 23401298 Mn 23401298 PPh(4) 23401298 Polyoxometalate 23401298 TBA 23401298 [(MnMo(6) O(18) )((OCH(2) )(3) -C-(CH(2) )(7) CHCH(2) )(2) ](3-) 23401298 [(MnMo(6) O(18) )((OCH(2) )(3) C-(CH(2) )(7) CHCH(2) )(1) ((OCH(2) )(3) C-NHCH(2) C(16) H(9) )(1) ](3-) 23401298 [(MnMo(6) O(18) )((OCH(2) )(3) C-NHC(O)(CH(2) )(x) CH(3) )(2) ] 23401298 [(MnMo(6) O(18) )((OCH(2) )(3) C-NHC(O)(CH(2) )(x) CH(3) )(2) ]) 23401298 [(MnMo(6) O(18) )((OCH(2) )(3) C-NHC(O)CH(2) CHCH(2) )(2) ](3-) 23401298 [(MnMo(6) O(18) )((OCH(2) )(3) C-NHCH(2) C(16) H(9) )(2) ](3-) 23401298 polyoxometalates 23401298 tetraphenylphosphonium 23401474 5-OH-omeprazole 23401474 caffeine 23401474 dextromethorphan-HBr 23401474 midazolam 23401474 omeprazole 23401474 tolbutamide 23402292 (1)H 23402292 1,5,7-triaza-bicyclo[4.4.0]dec-5-ene 23402292 PLA 23402292 PLA-b-PEG 23402292 Poly(lactic acid)-block-poly(ethylene glycol) 23402292 aluminum salan 23402292 aluminum salen 23402292 l- and rac-lactide 23402292 monomethoxy-poly(ethylene glycol) 23402292 poly(lactic acid)-block-poly(ethylene glycol) 23402292 pyrene 23402292 tin(II) bis(2-ethylhexanoate) 23402546 Hcy 23402546 Vitamin B12 23402546 folate 23402546 homocysteine 23402546 metformin 23402546 vitamin B12 23402652 adenine 23402652 thymine 23402729 AlO(OH) 23402729 alumina oxide 23402729 aluminum oxide hydroxide 23402729 boehmite 23402735 CoA 23402735 cholesterol 23402788 Carnitine 23402788 Cys 23402788 DTE 23402788 H2O2 23402788 N-acetylcysteine 23402788 Ser 23402788 Val 23402788 [(3)H]carnitine 23402788 acetylcarnitine 23402788 acylcarnitine 23402788 carnitine 23402788 disulphide 23402788 dithioerythritol 23402788 l-cysteine 23402841 GSH 23402841 STX 23402841 glutathione 23402841 gonyautoxin 23402841 neosaxitoxin 23402841 oxygen 23402841 reduced glutathione 23402841 saxitoxin 23402841 saxitoxins 23402841 superoxide 23402861 Al 23402861 Ba 23402861 Mo 23402861 Nitric acid 23402861 Pb 23402861 Sb 23402861 Sn 23402861 Th 23402861 Tl 23402861 nitric acid 23402862 1,2,4-benzenetriol 23402862 3-methoxycatechol 23402862 EGCG 23402862 Pyrogallol 23402862 apigenin 23402862 benzene 23402862 curcumin 23402862 etoposide 23402862 flavonoids 23402862 gallic acid 23402862 hydroxyls 23402862 pyrogallol 23402862 quercetin 23402862 quinacrine 23402862 tannins 23402880 7-methylindazole 23402880 amino acids 23402880 benzoxazolone 23402880 d-tyrosine 23402880 indazole 23402880 tyrosine 23403012 COU 23403012 DCP 23403012 PRO 23403012 coumarin 23403012 dicalcium phosphate 23403012 lactose 23403012 propranolol hydrochloride 23403014 EUDRAGIT E PO 23403014 PVP K30 23403014 carbamazepine 23403014 celecoxib 23403014 felodipine 23403014 fenofibrate 23403016 Cu(2+) 23403016 EDTA 23403016 GSH 23403016 TETA 23403016 Triethylenetetramine 23403016 ascorbate 23403016 ascorbic acid 23403016 copper 23403016 ethylenediamine tetraacetic acid 23403016 reduced glutathione 23403016 triethylenetetramine 23403058 Iberverin 23403058 cheirolin 23403058 iberin 23403058 iberverin 23403058 isothiocyanates 23403058 sulforaphane 23403058 γ-glutamylcysteine 23403092 DON 23403092 Trichothecenes 23403092 deoxynivalenol 23403203 6-carboxyfluorescein 23403203 Antofine 23403203 BAPTA-AM 23403203 Ca(2+) 23403203 MG132 23403203 NH4Cl 23403203 antofine 23403203 phenanthroindolizidine alkaloid 23404092 atazanavir 23404092 darunavir 23404092 lopinavir 23404092 ritonavir 23404092 saquinavir 23404305 cholesterol 23404305 creatinine 23404505 C 23404505 N 23404733 11,17-DOA 23404733 11,17-dioxoandrostane 23404733 11-KT 23404733 11-KT-3-CMO 23404733 11-Oxoetiocholanolone 23404733 11-ketotestosterone 23404733 17ß-hydroxy 23404733 C19 O3 -androgens 23404733 biotinylated 11-KT 23404733 cortisol 23404733 methanol 23404837 desaspidinol 23404837 formic acid 23404837 hydrogen 23404837 phenolic 23404837 syringaldehyde 23404837 syringol 23404894 amino acid 23406460 9-(5-O-α-D-galactopyranosyl)-D-arabinityl-1,3,7-trihydropurine-2,6,8-trione 23406460 N 23406460 N-acetylgalactosamine 23406460 UDP-Gal 23406460 arabinityl 23406460 galactose 23406497 FK-506 23406515 H2O 23406515 hydroxyl 23406949 GSH 23406949 MDA 23406949 NO(2) 23406949 NO(3) 23406949 malondialdehyde 23406949 methyl esters 23406949 nitrate 23406949 nitrite 23406949 reduced glutathione 23406955 2,3,7,8-tetrachlorodibenzo-p-dioxin 23406955 TCDD 23406955 alanine 23406955 aspartate 23406955 cholesterol 23406955 creatinine 23406955 tocopherol 23406955 urea 23406958 chloroform 23406958 ethyl acetate 23406958 n-hexane 23407741 1,10-phenanthroline 23407741 2,2'-bipyridine 23407741 4-indoleimidazo[4,5-f][1,10]phenanthroline 23407741 4idip 23407741 Ruthenium(II) polypyridyl 23407741 [Ru(bpy)2(4idip)](ClO4)2 23407741 [Ru(phen)2(4idip)](ClO4)2 23407741 bpy 23407741 phen 23407741 ruthenium 23407741 ruthenium(ii) polypyridyl 23407781 (+)-amphetamine 23407781 2,5-dimethoxy-4-iodoamphetamine 23407781 5-HT 23407781 DOI 23407781 LSD 23407781 lisuride 23407781 lysergic acid diethylamide 23408261 Pb 23408261 lead acetate 23408271 Alkamides 23408271 alkamide 23408271 alkamides 23408271 ethanol 23408271 ketone 23408271 ketones 23408421 BDE-209 23408421 Brominated diphenyl ether-209 23408421 Dechlorane Plus 23408421 PBDE 23408421 PBDEs 23408421 TBPH 23408421 bis(2-ethylhexyl)-3,4,5,6-tetrabromophthalate 23408421 polybrominated diphenyl ethers 23408556 Chromones 23408556 chromone 23408556 chromone carboxamide 23408556 chromone-2-carboxamide 23408642 CLOD 23408642 bisphosphonates 23408642 clodronate 23408642 zoledronic acid 23408697 Bisphosphonate 23408697 Bisphosphonates 23408697 bisphosphonate 23408697 bisphosphonates 23408858 uracil 23409714 oxygen 23409720 V4-015 23409720 tyrosine 23409722 Indacaterol 23409722 abediterol 23409722 beclomethasone 23409722 budesonide 23409722 carmoterol 23409722 fenoterol 23409722 fluticasone 23409722 formoterol 23409722 milveterol 23409722 olodaterol 23409722 salbutamol 23409722 salmeterol 23409722 vilanterol 23409763 fatty acid 23409810 dNTP 23409810 deoxynucleoside triphosphate 23409810 nucleotides 23409864 pyrazole 23409871 3-[(methylamino)acyl] 23409871 5-chlorothiophene-2-sulfonamide 23409871 Aryl sulfonamide 23409871 GSK2239633A 23409871 Methoxy 23409871 amino 23409871 benzyl 23409871 hydroxyl 23409871 indazole 23409871 indazole arylsulfonamides 23409871 indazole sulfonamide 23409871 morpholines 23409936 meta-fluoro-N-1-phenyl pyrazolobenzothiazine 23409936 pyrazolobenzothiazine 23409951 20-hydroxyeicosatetraenoic acid 23409951 Arsenic 23409951 As(III) 23409951 DHETs 23409951 EETs 23409951 arachidonic acid 23409951 arsenic 23409951 dihydroxyeicosatrienoic acid 23409951 epoxide 23409951 epoxyeicosatrienoic acids 23409959 S23906 23409959 S23906-1 23409959 benzo-b-acronycine 23409959 glyceraldehyde-3-phosphate 23409959 guanine nucleobases 23410005 5-morpholino-7H-thieno[3,2-b]pyran-7-one 23410005 5-morpholino-7H-thieno[3,2-b]pyran-7-ones 23410005 LY294002 23410005 SF1126 23410094 aldehyde 23410094 hydrazide 23410094 hydrazone 23410094 iron oxide 23410094 pNIPAM 23410094 poly(N-isopropylacrylamide) 23410125 N acyl 23410155 Ala 23410155 Gly 23410155 H 23410155 Trp 23410155 cysteine 23410155 heteroarylnitrile 23410167 galantamine 23410167 physostigmine 23410167 rivastigmine 23410886 CpG 23410886 bisulfite 23411074 Aspulvinones 23411074 aspulvinone E 23411074 butenolide 23411074 butenolides 23411074 isoaspulvinone E 23411074 pulvic acid 23411077 (6R,7R)-8-oxo-7-(2-oxo-2H-chromene-3-carboxamido)-3-((4-(2-oxo-2H-chromene-3-carboxamido)-phenylthio)methyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 23411077 Zn(II) 23411081 MPEG 23411081 MPEGs 23411081 Saturated fatty acids 23411081 cyclotriphosphazene 23411081 fatty acids 23411081 lauric, myristic, palmitic and stearic acids 23411081 methoxy poly(ethylene glycol) 23411081 tyrosine 23411169 SDS 23411169 Sudan I 23411169 carbon 23411169 graphene 23411169 phosphate 23411169 sodium dodecyl sulphonate 23411180 DMN 23411180 Pterostilbene 23411180 dimethyl n-nitrosamine 23411180 dimethylnitrosamine 23411180 pterostilbene 23411188 flavonoids 23411193 steroidal 23411197 AAPH 23411197 GSH 23411197 carnosine 23411197 dioscorin 23411197 hydroxyl 23411197 methylglyoxal 23411197 oxygen 23411197 thiol 23411198 5,7,4'-trihydroxy-3',5'-dimethoxyflavone 23411198 Tricin 23411198 flavone 23411198 tricin 23411201 C13-norisoprenoids 23411201 C6 23411201 alcohols 23411201 phenols 23411201 terpenes 23411204 (1)H 23411204 1H 23411204 4-hydroxyhippuric acid 23411204 creatinine 23411204 dimethylamine 23411204 hippuric acid 23411204 polyphenol 23411205 4,4'[(4-cholorophenyl)methylene] bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) 23411205 CMBPP 23411205 Fe(3+) 23411205 Fe3+ 23411205 Mn(2+) 23411205 Mn2+ 23411205 pyrazol 23411216 anthocyanin 23411216 tannin 23411224 PUFA 23411224 TAG 23411224 acyls 23411224 atty acids 23411224 fatty acid 23411224 fatty acyls 23411224 triglycerides 23411229 fructose 23411229 glucose 23411229 isomaltose 23411229 isomaltulose 23411229 isomelezitose 23411229 sucrose 23411229 sugars 23411229 trehalose 23411229 trehalulose 23411230 Ascorbic acid 23411230 anthocyanin 23411230 anthocyanins 23411230 ascorbic acid 23411230 ascorbic and 23411230 ascorbic and chlorogenic acids 23411230 chlorogenic acid 23411230 glycoalkaloid 23411230 glycoalkaloids 23411230 α-chaconine 23411230 α-chaconine and α-solanine 23411230 α-solanine 23411231 MeCN 23411231 PSA 23411231 acetonitrile 23411231 citrate 23411231 primary secondary amine 23411235 cholesterol 23411235 linoleate 23411235 phenolic acids 23411235 phytosteryl ferulates 23411235 phytosteryl phenolates 23411235 β-carotene 23411238 acetate 23411238 potassium iodate 23411238 silver 23411238 tartrazine 23411240 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane 23411240 3,5 dicaffeoylquinic acid 23411240 DPPH 23411240 caffeic acid 23411240 chlorogenic acid 23411240 furofuran lignan glucosides 23411240 furofuran lignans 23411240 lactuberin A 23411240 lactuberin B 23411240 phenolic 23411241 CCl(4) 23411241 CCl4 23411241 DPPH 23411241 HO 23411241 O(2)(-) 23411241 alanine 23411241 arabinose 23411241 aspartate 23411241 ferric 23411241 galactose 23411241 galacturonic acid 23411241 glutathione 23411241 malondialdehyde 23411241 superoxide 23411245 (-) epicatechin 23411245 EPI 23411245 L-ascorbic acid 23411245 chlorogenic acid 23411245 o-quinones 23411245 oxygen 23411245 phenol 23411245 phenols 23411251 anthocyanidins 23411251 anthocyanins 23411251 flavonoids 23411251 phenolic acids 23411251 polyphenols 23411253 (1)H 23411253 acyl 23411257 ATP 23411257 Lewis acids 23411257 N 23411257 aluminium oxide 23411257 nitrogen 23411257 silica gel 23411259 alcohol 23411259 cholesterol 23411259 flavonoids 23411259 glucose 23411259 naringin 23411260 flavonoid 23411263 Piceatannol 23411263 anthocyanin 23411263 anthocyanins 23411263 flavonols 23411263 gallic acid 23411263 phenolic 23411263 piceatannol 23411263 stilbene 23411263 stilbenes 23411266 cholesterol 23411266 dichloro-methane 23411266 ethyl acetate 23411266 flavonoïd 23411266 flavonoïds 23411266 hexane 23411266 methanol 23411266 phenolic 23411266 superoxide 23411266 thiobarbituric acid 23411266 triglycerides 23411269 ferrous 23411269 β-Galf 23411269 β-Glcp 23411269 α-Manp 23411270 amine 23411270 spermidine 23411270 spermine 23411275 β-carotene 23411280 Histidine 23411280 Rugosin D 23411280 amine 23411280 ethyl acetate 23411280 histamine 23411280 histidine 23411280 histidine methyl ester 23411280 rugosin A 23411280 rugosin A methyl ester 23411280 tellimagrandin II 23411281 DPPH 23411281 Fe(2+) 23411281 ascorbic acid 23411281 phenolics 23411286 Procyanidin B3 23411286 carbohydrates 23411286 polyphenol 23411286 polyphenols 23411286 procyanidin 23411286 procyanidins 23411286 sucrose 23411287 disulphide 23411287 thiol 23411287 β-mercaptoethanol 23411288 cyromazine 23411288 melamine 23411289 AAs 23411289 Ala 23411289 Arg 23411289 Asn 23411289 Asp 23411289 Cys 23411289 Gln 23411289 Glu 23411289 Gly 23411289 Glycine 23411289 His 23411289 Ile 23411289 Leu 23411289 Lys 23411289 Met 23411289 Phe 23411289 Pro 23411289 Ser 23411289 Thr 23411289 Tyrosine 23411289 Val 23411289 amino acid 23411289 ethanol 23411289 nitrogen 23411290 Quercetin 23411290 quercetin 23411293 2,4,6-tri(2'-pyridyl)-1,3,5-triazine 23411293 Fe (II) 23411293 Iron (III) 23411293 N,N-bis(salicylidene)-1,3-propanediamine 23411293 SPDA 23411293 TPTZ 23411293 ascorbic acid 23411293 hydrochloric acid 23411293 iron 23411293 iron (II) 23411293 polyurethane 23411294 apigenin-glucuronide 23411294 apiin 23411294 lithospermic acid 23411294 lucenin-2 23411294 p-coumaric acid 23411294 phenolic 23411294 phenolics 23411294 polyphenol 23411297 2,2-diphenyl-1-picrylhydrazyl 23411297 Ethanol 23411297 Phenolic 23411297 ferrous 23411297 polyphenol 23411297 polyphenols 23411297 tocopherols 23411300 alcohols 23411300 anthocyanin 23411300 dimethyl sulfide 23411300 esters 23411300 ethanol 23411300 glycerol 23411300 hexyl acetate 23411300 isobutyl methoxypyrazine 23411300 phenolics 23411300 tannin 23411303 C-H 23411303 D 23411303 D(2)O 23411303 H 23411303 deuterium 23411303 fatty acids 23411303 hydrogen 23411305 Sulforaphane 23411305 glucoraphanin 23411305 glucosinolate 23411305 sulforaphane 23411305 sulforaphane nitrile 23411317 7-hydroxymatairesinol 23411317 Secoisolariciresinol 23411317 ethanol 23411317 isolariciresinol 23411317 lariciresinol 23411317 lariciresinol monoglycoside 23411317 lignan 23411317 lignans 23411317 pinoresinol 23411317 pinoresinol mono-, di- and triglycoside 23411317 secoisolariciresinol diglycoside 23411317 sesaminol 23411317 sesaminol triglycoside 23411317 sesamolinol 23411317 sesamolinol diglycoside 23411317 sodium methoxide 23411317 syringaresinol 23411318 Ca(2+) 23411318 Leu 23411318 Ser 23411318 calcium 23411320 alcohol 23411327 brilliant blue and sunset yellow FCF 23411327 tartrazine 23411330 FeSO(4) 23411330 Iron 23411330 ferrous sulfate 23411330 iron 23411330 γ-aminobutyric acid 23411336 BA-β-CD 23411336 Betulinic acid 23411336 betulinic acid 23411336 pentacyclic triterpenoid 23411336 β-CD 23411336 β-cyclodextrin 23411344 Stevioside 23411344 mono- and di-glucosylated stevioside 23411344 stevioside 23411344 steviosides 23411507 25(OH)D(3) 23411507 25-hydroxyvitamin D(3) 23411507 aspartate 23411507 calcium 23411507 cholesterol 23411507 triglycerides 23411507 vitamin D 23412112 Cocaine 23412112 cocaine 23412114 Gallein 23412114 Morphine 23412114 gallein 23412114 morphin 23412114 morphine 23412751 HPBCD 23412751 cholesterol 23412751 gangliosides 23412751 hydroxypropyl-β-cyclodextrin 23412751 sphingolipids 23412751 sucrose 23412922 estrogen 23413833 Phosphorus 23413833 silicon 23414209 AAc 23414209 PAAc 23414209 PVP 23414209 Pilocarpine 23414209 acrylic acid 23414209 pilocarpine 23414209 poly(acrylic acid) 23414209 polyvinylpyrrolidone 23414210 PEG 23414214 (99m)Tc(CO)3 23414214 (99m)Tc(CO)3-Pz(1)-βAlaNleCycMSH(hex) 23414214 (99m)Tc(CO)3-Pz(3)-βAlaNleCycMSH(hex) 23414214 (99m)Tc(CO)3-Pz(4)-βAlaNleCycMSH(hex) 23414214 99mTc(CO)3 23414214 azolyl 23414214 carboxylate 23414214 cyclic α-melanocyte stimulating hormone 23414214 cyclized α-melanocyte stimulating hormone 23414214 lactam 23414214 methyl 23414214 pyrazolyl-diamine 23414214 βAlaNleCycMSH(hex) 23414214 βAlaNleCycMSHhex 23414235 Tyrosine 23414235 Vegfrecine 23414235 tyrosine 23414235 vegfrecine 23414340 BSO 23414340 DMAs 23414340 DMAs(III) 23414340 DMAs(V) 23414340 Dimethylarsinic acid 23414340 GSH 23414340 GSSG 23414340 NADPH 23414340 S 23414340 Sb(III) 23414340 adenosine 23414340 arsenic 23414340 aurothioglucose 23414340 dehydroascorbate 23414340 dimethylarsenic 23414340 dimethylarsinic acid 23414340 dimethylarsinous acid 23414340 glutathione 23414340 periodate 23414340 phorone 23414340 thiol 23414527 graphene 23414527 graphene oxide 23414527 graphenes 23414800 11beta-hydroxysteroid 23414800 1beta-hydroxysteroid 23414800 5-trans-hydroxyadamantan-2-yl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-ones 23414800 7-membered cyclic amide 23414805 5-Sulfonyl tetrazole 23414805 5-sulfinyl tetrazole 23414805 5-sulfonyl tetrazole 23414805 Cyclosporine A 23414805 cyclosporine A 23414805 thiol 23414807 CO2 23414807 Halides 23414807 bicarbonate 23414807 bromide 23414807 carbonate 23414807 cyanate 23414807 cyanide 23414807 diethyldithiocarbamate 23414807 hydrogen sulfide 23414807 hydrogen sulfite 23414807 iodide 23414807 phenylarsonic acid 23414807 phenylboronic acid 23414807 sulfamate 23414807 sulfamide 23414807 trithiocarbonate 23414808 C 23414808 N 23414808 fosmidomycin 23414808 hydrogen 23414808 isoprene 23414808 phosphate 23414808 phosphonate 23414808 phosphonohydroxamate 23414808 phosphonohydroxamic acids 23414808 tetrazole 23414808 tetrazoyl 23414839 NGP1-01 23414839 PCU 23414839 Pentacycloundecylamine 23414839 [(3)H]pentazocine 23414839 aza-PCU 23414839 oxa-PCU 23414839 pentacycloundecylamines 23414839 phenethyl 23414844 Aminoglycoside 23414844 NEOF004 23414844 aminoglycoside 23414844 aminoglycosides 23414844 neomycin 23414844 pyranmycin 23414845 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin 23414845 8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide 23414845 N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine 4,4-dioxide 23414845 pyrazolo[4,3-c][2,1]benzothiazines 23415548 polyphenols 23415548 triterpene glycosides 23415833 4-bromo-2-chlorophenol 23415833 BCP 23415833 Profenofos 23415833 creatinine 23415833 organophosphorus 23415833 phosphorothioate 23415833 profenofos 23415902 Org 214444-0 23415902 cAMP 23415902 dihydropyridine 23415902 estradiol 23415903 ATP 23415903 BODIPY 23415903 TMR 23416003 Bicyclic pyrazinone and pyrimidinone amides 23416003 bicyclic pyrazinone and pyrimidinone amides 23416003 hydrogen 23416004 Anacardic acid 23416004 aldehyde 23416004 anacardic acid 23416004 carboxylic 23416004 carboxylic acid 23416004 methyl ester 23416004 naphthyl 23416004 o-anisic acids 23416004 salicylic 23416004 salicylic acid 23416004 sodium 23416004 tertiary amide 23416006 piperidinyl glycine 23416006 piperidinyl glycine 2-cyano-4,5-methano pyrroline 23416006 piperidinyl glycinyl 2-cyano-4,5-methano pyrrolidines 23416007 proline 23416040 acetylcholine 23416040 nicotine 23416065 Lys 23416065 acetyldiflunisal 23416065 diflunisal 23416065 fatty acid 23416065 lysine 23416131 NO 23416143 GSH 23416143 Narirutin 23416143 alcohol 23416143 aspartate 23416143 ethanol 23416143 malondialdehyde 23416143 narirutin 23416173 organophosphates 23416178 AOAA 23416178 DCVC 23416178 DCVCS 23416178 PCE 23416178 S 23416178 S-(1,2,2-trichlorovinyl)-l-cysteine 23416178 S-(1,2,2-trichlorovinyl)-l-cysteine sulfoxide 23416178 S-(1,2-dichlorovinyl)-l-cysteine 23416178 S-(1,2-dichlorovinyl)-l-cysteine sulfoxide 23416178 TCE 23416178 TCVC 23416178 TCVCS 23416178 aminooxyacetic acid 23416178 cysteine 23416178 sulfoxides 23416178 tetrachloroethylene 23416178 trichloroethylene 23416189 3-methyl-1,6-diphenyl-1H-pyrazolo[3,4-b] pyrazine-5-carboxylic acid chloride 23416189 AlCl3 23416189 CS2 23416189 Indenopyrazolopyrazinone 23416189 acid chloride 23416189 indeno[2,1-e]pyrazolo[3,4-b]pyrazin-5-one 23416410 P-25 23416410 TiO2 23416410 titanium dioxide 23416413 11-ketotestosterone 23416413 naphthenic acids 23416413 steroids 23416796 Ag 23416796 carbon 23416797 SDS 23417514 (±)-2,5-dimethoxy-4-iodophenyl-2-aminopropane 23417514 5-HT 23417514 8-OH-DPAT 23417514 8-hydroxy-2-(di-n-propylamino)tetralin 23417514 DOI 23417514 dopamine 23417514 serotonin 23417745 cadmium 23417745 cadmium nitrate 23417745 cadmium selenide 23417745 selenious acid 23417745 selenium 23417974 silicon 23418045 Graphene 23418045 Phthalocyanine 23418045 graphene 23418045 graphite 23418045 oPPV 23418045 zinc phthalocyanine 23418045 zinc phthalocyanines 23418068 PVDF 23418081 diamine 23418081 graphene 23418125 emodin 23418125 hydroxylanthraquinone 23418165 O-acyl 23418165 OH 23418165 beyerane 23418165 diterpenoid glycoside 23418165 diterpenoids 23418165 ent-kaur-16-ene-13,19-diol 19-O-4',4',4'-trifluorocrotonate 23418165 isosteviol 23418165 kaurane 23418165 steviol 23418165 stevioside 23418168 acetylenes 23418168 caryophyllene oxide 23418168 matricaria ester 23418168 sesquiterpenes 23418369 N 23418369 Nicotinamide 23418369 aldehyde 23418369 nicotinamide 23418369 nicotinamide N-oxide 23418369 vitamin B(3) 23418719 Ag 23418719 Au 23418719 Au-Ag 23418719 SiO2 23418719 SiO₂ 23418750 Cu-B 23418750 H2(+) 23418750 Li2(+) 23418750 boron 23418750 copper 23418750 metalloboratrane 23418783 H(2)S 23418783 HNO 23418783 Hydrogen Sulfide 23418783 Hydrogen sulfide 23418783 NO 23418783 Nitroprusside 23418783 Nitroxyl 23418783 SNP 23418783 cyanide 23418783 nitric oxide 23418783 nitroprusside 23418783 nitroxyl 23418783 sodium nitroprusside 23418783 thiocyanate 23418783 thiols 23418815 5β-pregnane-2α,6α,20(S)-triol 23418815 8-hydroxyl-3-methoxyl-2(1H)-quinolone 23418956 PDA 23418956 butadiyne 23418956 butadiynes 23418956 phenyl 23418956 polydiacetylene 23419043 CFSE 23419390 carbonyl 23419390 oxygen 23419685 Mn 23419685 manganese 23419776 BPs 23419776 bisphosphonates 23419812 terbinafine 23419816 COOH 23419816 NH2 23419816 OH 23419816 PAMAM 23419816 Poly(amidoamine) 23419816 amine 23419816 carboxyl 23419816 hydroxyl 23419816 poly(amidoamine) 23419872 DIC 23419872 GSH 23419872 OGC 23419872 antimycin A 23419872 dicarboxylate 23419872 glutathione 23419872 oxoglutarate 23420023 Ag 23420023 Bi 23420023 Bi-Ag-Cu oxide 23420023 Cd 23420023 Co 23420023 Cu 23420023 Cu oxide 23420023 CuBi2O4 23420023 CuO 23420023 Pt 23420023 Sn 23420023 Zn 23420023 copper bismuth oxide 23420023 copper oxide 23420023 hydrogen 23420023 oxide 23420023 oxides 23420214 CoA 23420214 Succinyl-CoA 23420214 acetoacetyl-CoA 23420214 ketone 23420214 succinyl-CoA 23420214 tricarboxylic acid 23420700 Methacrylamide 23420700 methacrylamide 23421374 C60 23421374 CPT 23421374 PEG 23421374 [60]fullerene 23421374 camptothecin 23421374 perylene-bisimide 23421432 3β,15β-dihydroxy-7,11,23-trioxo-lanost-8,16-dien-26-oic acid methyl ester 23421432 3β,7β,15β-trihydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid 23421432 3β,7β,15β-trihydroxy-11,23-dioxo-lanost-8,16-dien-26-oic acid methyl ester 23421432 EtOAc 23421432 lanostanoid triterpenes 23421434 GaP 23421434 Si 23421517 3-(4,5-Dimethylthiazol)-2,5-diphenyl tetrazolium bromide 23421517 Adr 23421517 MTT 23421517 Rh123 23421517 adriamycin 23421517 rhodamine123 23421517 rosmarinic acid 23421585 piperidine alkaloids 23421585 streptazones 23421616 2-amino-naphthothiazole 23421616 naphthothiazoles 23421616 quinoidal 23421616 thiazole 23421620 11,12-dihydroxy-15-drimeneoic acid 23421620 3β,11,12-trihydroxydrimene 23421620 3α,11,15-trihydroxydrimene 23421620 drimane 23421620 sesquiterpenes 23421620 sesquiterpenoids 23421648 Berberine 23421648 berberine 23421648 isoquinoline alkaloid 23421649 2β-hydroxy-α-candinol 23421649 3β-hydroxy-δ-candinol 23421649 carbon 23421649 epicubenol 23421649 muurolane-10β,15-diol 23421649 perhydroazulene 23421649 sesquiterpenoids 23421649 tremulane 23421649 tremulenediol A 23421649 tremulenolide D 23421650 cetyl trimethylammonium chloride 23421650 myristic acid 23421717 (1R)-(3-acetophenyl)-1,2-ethanediol 23421717 (1R)-(3-ethenylphenyl)-1,2-ethanediol 23421717 (1R)-(3-formylphenyl)-1,2-ethanediol 23421717 (3-ethylphenyl)-1,2-ethanediol 23421717 (4-acetophenyl)-1,2-ethanediol 23421717 phenyl-ethanediols 23421757 Silibinin 23421757 silibinin 23421779 5,6,7-trimethoxycoumarin 23421779 calycanthoside 23421779 coumarin glycosides 23421779 d-calycanthine 23421779 nitensosides A-B 23421779 scopoletin 23421779 scopolin 23421779 xeroboside 23421798 ArF 23421798 CCH(-) 23421798 Copper Acetylide 23421798 Cu(+) 23421798 Cu-C 23421798 Cu-C≡C 23421798 CuBr 23421798 CuCCH 23421798 CuCl 23421798 CuF 23421798 CuI 23421798 F2 23421850 NaCl 23421850 mica 23421879 Al 23421879 Co 23421879 Li 23421879 LiNi0.62Co0.14Mn0.24O2 23421879 LiNi0.70Co0.15Mn0.15O2 23421879 LiNiO2 23421879 Li[Ni(1-x)M(x)]O2 23421879 Mn 23421879 Ni 23421879 Ni(2+) 23421879 Ni0.7Co0.15Mn0.15(OH)2 23421879 NiO 23421879 PVP 23421879 lithium nickel metal oxides 23421879 polyvinylpyrrolidone 23421930 5,6,7,5'-tetrahydroxy-4'-methoxyflavone 23421930 5,7,5'-trihydroxy-3',4',6-trimethoxyflavone 23421930 axillaroside 23421930 cirsimaritin 23421930 ethyl acetate 23421930 phenolics 23421930 stenocepflavan 23421930 stenocepflavone 23421930 stenocephol 23422035 deoxynivalenol 23422035 zearalenone 23422073 calcium 23422073 glucose 23422225 (1)H 23422225 (13)C 23422225 2, 2-diphenyl-1-picrylhydrazyl 23422225 DPPH 23422225 catechin 23422225 cyanogenic glycoside 23422225 epicatechin 23422225 epicatechin 3-O-(3,4,5-O-trimethyl)gallate 23422225 epicatechin 3-O-(3,5-O-dimethyl)gallate 23422225 epicatechin 3-O-(3-O-methyl)gallate 23422225 epicatechin 3-O-gallate 23422225 linamarin gallate 23422225 peltatoside 23422225 phenolic glycosides 23422225 polyphenols 23422225 quercetin 3-O-β-d-glucopyranoside 23422225 rutin 23422225 walsuraside B 23422298 KYNA 23422298 Kynurenic acid 23422298 NMDA 23422298 kynurenic acid 23422298 kynurenine 23422298 thiorphan 23422298 tryptophan 23422566 Lys 23422566 lysine 23422569 A23187 23422569 EX527 23422569 NAD(+) 23422569 NADPH 23422569 NO 23422569 acetylcholine 23422569 apocynin 23422569 calcium 23422569 nicotinamide 23422569 oxygen 23422569 resveratrol 23422569 sirtinol 23422569 superoxide 23422727 (PEG)-b-P[Asp(DET)] 23422727 PEG-b-P[Asp(DET)] 23422727 P[Asp(DET)] 23422727 polyethylene glycol 23422727 poly{N'-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} 23423570 dapsone 23423570 glucose 23423570 oxygen 23423711 8-hydroxy-2'-deoxyguanosine 23423711 8-oxo-dGuo 23423904 Ca(2+) 23423904 CaSO4 23423904 Cl(-) 23423904 Mg(2+) 23423904 MgSO4 23423904 Na(+) 23423904 NaCl 23423904 NaHCO3 23423904 Ni 23423904 Nickel 23423904 nickel 23423993 Nitrobenzene 23423993 nitrobenzene 23424203 histidine 23424206 DOX 23424206 N-Acetylcysteine 23424206 N-acetylcysteine 23424206 NAC 23424206 NO 23424206 aspartate 23424206 creatine 23424206 doxorubucine 23424206 lactate 23424206 nitric oxide 23424206 superoxide 23424206 thiobarbituric acid 23424217 Clonazepam 23424217 GABA 23424217 Tiagabine 23424217 clonazepam 23424217 sodium 23424217 tiagabine 23425034 acridine 23425034 acridines 23425125 carvacrol 23425125 p-cymene 23425125 α-pinene 23425125 α-terpineol 23425199 Carbamate 23425199 JNJ1661610 23425199 N 23425199 N-piperazinylurea 23425199 O 23425199 Ser 23425199 URB597 23425199 amide 23425199 carbamic 23425199 carbamoylate 23425199 cyclohexyl carbamate 23425199 fatty acid 23425199 fatty acid amide 23425199 oleamide 23425199 piperazine carboxylate 23425199 urea 23425274 SDS 23425274 carbohydrate 23425274 sarcosyl 23425314 Ag 23425314 Ag(+) 23425314 Silver 23425314 pCBMA 23425314 pSBMA 23425314 poly(carboxybetaine methacrylate) 23425314 poly(sulfobetaine methacrylate) 23425314 silver 23425969 10-ethyl-2-(diethylamino)pyrimido[1,2-a]benzimidazol-4(10H)-one 23425969 10-ethyl-4-(diethylamino)pyrimido[1,2-a]benzimidazol-2(10H)-one 23425969 10-substituted 2-(1-piperazinyl)pyrimido[1,2-a]benzimidazol-4(10H)-ones 23425969 2-(1-piperazinyl) 23425969 A23187 23425969 ADP 23425969 Ca(2+) 23425970 pyranochalcone 23426858 (1)H 23426955 Voriconazole 23426955 eosin 23426955 hematoxylin 23426955 posaconazole 23426955 silver 23426955 voriconazole 23427017 atrazine 23427190 Vardenafil 23427190 vardenafil 23427194 CPZ 23427194 bromperidol 23427194 chlorpromazine 23427194 dopamine 23427194 haloperidol 23427194 olanzapine 23427194 perospirone 23427194 risperidone 23427194 serotonin 23427194 zotepine 23427810 MoS2 23427810 MoS₂ 23427810 SiO2 23427810 TMDC 23427810 TMDCs 23427810 sapphire 23427810 transition metal dichalcogenides 23427825 2-Arylpyrazolo[4,3-d]pyrimidin-7-amino 23427825 2-arylpyrazolo[4,3-d]pyrimidin-7-amines 23427825 2-arylpyrazolo[4,3-d]pyrimidin-7-ones 23427825 2-phenyl 23427825 7-acylamino 23427825 7-amino 23427825 Adenosine 23427825 CH2Ph 23427825 Me 23427825 Ph 23427825 acyl 23427825 adenosine 23427825 carbamoyl 23427825 oxaliplatin 23427825 para-methoxy 23427825 pyrazolo[4,3-d]pyrimidin-7-amides 23427901 Oxysporone 23427901 Phyllostin 23427901 Scytolide 23427901 dihydrofuropyranone 23427901 hexahydro-1,4-benzodioxines 23427901 oxysporone 23427901 phyllostin 23427901 scytolide 23428094 H2SO4 23428109 3-aminopropyl phosphinic acid 23428109 GABA 23428109 alcohol 23428109 baclofen 23428109 difluoromethyl ketone 23428109 difluoromethyl ketones 23428109 fluorines 23428109 hydrogens 23428109 trifluoroacetate 23428109 γ-aminobutyric acid 23428163 CO 23428163 Co 23428163 H2 23428163 Platinum 23428163 Pt 23428163 Pt-Co 23428163 cobalt 23428368 ATP 23428368 Bzf 23428368 bezafibrate 23428368 fatty acid 23428368 triiodothyronine 23428403 ATP 23428403 flavanone 23428403 flavonoid 23428403 mangiferin 23428403 phloretin-3',5'-di-C-glucoside 23428403 polyphenol 23428403 polyphenols 23428403 triglyceride 23428403 xanthone 23428407 TBT 23428407 tributyltin 23428645 (-)-Cannabidiol 23428645 (-)-cannabidiol 23428645 (-)-Δ(9)-Tetrahydrocannabinol 23428645 anandamide 23428645 cannabidiol 23428645 carbachol 23428645 fatty acid amide 23428645 histamine 23428645 phenylmethanesulfonyl fluoride 23428645 virodhamine 23428794 Ketamine 23428794 ketamine 23428833 Pb 23428833 Pb acetate 23428833 calcium 23428833 creatinine 23428833 glutathione 23428833 malondialdehyde 23428833 nimodipine 23428833 nitrogen 23428833 super oxide 23428833 urea 23428833 verapamil 23428959 B[a]P 23428959 EMS 23428959 benzo[a]pyrene 23428959 ethyl methanesulfonate 23428960 cinnamic aldehyde 23428960 citral 23428960 isoeugenol 23428981 CPF 23428981 acetylcholine 23428981 chlorpyrifos 23429263 C 23429263 amino acid 23429263 brefeldin A 23429274 Nitric oxide 23429274 cGMP 23429274 guanylate 23429274 nitric oxide 23429274 superoxide 23429907 H 23429907 graphene 23429907 hydrogen 23429907 nanographene 23429912 2,3,7,8-tetrachlorodibenzo-p- dioxin 23429912 TCDD 23430139 GaAs 23430139 gallium arsenide 23430139 nickel subsulphide 23430139 oxygen 23430410 As 23430410 AsA 23430410 GSH 23430410 GSSG 23430410 H2O2 23430410 MDA 23430410 NO 23430410 Na2HAsO4·7H2O 23430410 Pro 23430410 S 23430410 SNP 23430410 arsenic 23430410 ascorbate 23430410 chl 23430410 chlorophyll 23430410 dehydroascorbate 23430410 glutathione 23430410 glutathione disulfide 23430410 monodehydroascorbate 23430410 nitric oxide 23430410 proline 23430410 sodium nitroprusside 23432060 Ca2+ 23432062 Ca2+ 23432065 Vanilloid 23432090 Manganese-peroxos 23432090 Mn 23432090 Mn(III)-(η(1)-peroxos) 23432090 Mn(III)-OOR 23432090 N(py,quin) 23432090 N-heterocyclic amines 23432090 O-O 23432090 manganese(III)-alkylperoxo complexes 23432090 peroxo O-O 23432093 Fe(2+) 23432093 Fe(3+) 23432093 Fe3O4 23432093 H2O2 23432093 bis(2,4-methylpentadienyl)iron 23432093 iron 23432093 iron oxide 23432093 iron oxides 23432093 oxygen 23432093 α-Fe2O3 23432124 (2R)-IKM-159 23432124 (R)-2-amino-2-(4-methoxyphenyl)ethanol 23432124 (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid 23432124 AMPA 23432124 IKM-159 23432124 Racemic IKM-159 23432124 glutamate 23432134 (24R)- and (24S)-cycloart-25-en-3b,24-diols 23432134 1-octacosanol 23432134 11-epi-8α-hydroxyarborescin 23432134 5αH,6βH,7αH,11αH-guaian-12,6α-olides 23432134 guaianolide 23432134 palmitic acid 23432336 poly(ε-caprolactone) 23432420 Aldehyde 23432420 aldehyde 23432465 1-nitropyrene 23432465 2-acetylaminofluorene 23432465 2-aminoanthracene 23432465 2-aminofluorene 23432465 5-methylchrysene 23432465 7,12-dimethylbenz[a]anthracene 23432465 7,12-dimethylbenz[a]anthracene-5,6-diol 23432465 Aryl and Heterocyclic Amines 23432465 PAHs 23432465 Polycyclic Aromatic Hydrocarbons 23432465 acenaphthene 23432465 acenaphthylene 23432465 aryl- and heterocyclic amines 23432465 benz[a]pyrene-4,5-diol 23432465 benzo[a]pyrene-7,8-diol 23432465 benzo[c]phenanthrene 23432465 fluoranthene 23432465 fluoranthene-2,3-diol 23432465 nitrosamines 23432465 polycyclic aromatic hydrocarbons 23432580 FTS 23432580 Farnesylthiosalisylic acid 23432580 farnesoids 23432580 steroids 23432581 Carbon 23432581 carbon 23432590 Camptothecin 23432590 camptothecin 23432590 camptothecins 23432662 Rosiglitazone 23432662 carbonitrile 23432662 glucose 23432753 F 23432753 Fe 23432753 FeOF 23432753 Li 23432753 O 23432753 iron oxyfluoride 23434031 6-methyl pyridone 23434193 DHA 23434193 EPA 23434193 Omega-3 polyunsaturated fatty acids 23434193 PUFAs 23434193 aspirin 23434193 docosahexaenoic acid 23434193 omega-3 eicosapentaenoic acid 23434193 resolvins 23434223 5-amino-2,7-bis(4-methoxyphenyl)-2,3-dihydrobenzo[b]thiophene-4,6-dicarbonitrile 23434223 5-amino-2,7-diaryl-2,3-dihydrobenzo[b]thiophene-4,6-dicarbonitriles 23434223 5-aryldihydro-3(2H)-thiophenones 23434223 aromatic aldehydes 23434223 dihydrobenzo[b]thiophenes 23434223 malononitrile 23434223 morpholine 23434224 Pyridine 23434224 aniline 23434227 H 23434227 MTT 23434227 oleanolic acid 23434417 2-(Benzothiazol-2-yl)-phenyl-β-d-galactopyranoside 23434506 CoQ10 23434506 Coenzyme Q10 23434506 cisplatin 23434506 coenzyme Q10 23434663 TA-III 23434663 Timosaponin AIII 23434663 ginsenoside Re 23434663 timosaponin AIII 23434829 ATP 23434829 DUN 23434829 Daunomycin 23434829 actinomycin-D 23434829 arginine 23434829 aspartic acid 23434829 doxorubicin 23434829 glycine 23434829 paclitaxel 23434829 rapamycin 23434831 Asperolide A 23434831 Cisplatin 23434831 PD98059 23434831 asperolide A 23434831 tetranorditerpenoid 23434832 glucosamine 23434832 hexaacylated disaccharide 23434832 lipid A 23434832 monophosphoryl lipid A 23434832 pentaacylated monophosphoryl lipid A 23435157 aspirin 23435157 cholesterol 23435160 glucose 23435263 amino acid 23435263 serine 23435358 ALA 23435358 ARA 23435358 DHEA 23435358 DPA 23435358 EPA 23435358 FA methyl esters 23435358 FAMEs 23435358 FAs 23435358 MUFA 23435358 PFOA 23435358 PFOS 23435358 PUFA 23435358 PUFAs 23435358 arachidonic acid 23435358 cholesterol 23435358 cortisol 23435358 dehydroepiandrosterone 23435358 docosapentaenoic acid 23435358 eicosapentaenoic acid 23435358 estrone 23435358 fatty acids 23435358 methanol 23435358 mono- and poly-unsaturated FA 23435358 pentadecenoic MUFA 23435358 perfluorooctane sulfonic or perfluorooctane carboxylic acids 23435358 steroid 23435358 testosterone 23435358 α-linolenic acid 23435367 8Br-cAMP 23435367 cAMP 23435367 iron 23435367 progesterone 23435367 steroid 23435367 steroid hormone 23435367 sulfur 23435541 NADPH 23435541 O2(.-) 23435541 ceramide 23435541 cholesterol 23435541 pravastatin 23435541 simvastatin 23435541 statins 23435541 superoxide 23435614 Aspirin 23435614 acetylsalicylic acid 23435614 aspirin 23435689 4-MBA 23435689 4-MPY 23435689 4-mercaptobenzoic acid 23435689 4-mercaptopyridine 23435689 Cu2O 23435689 Cu₂O 23435915 ACh 23435915 Ca(2+) 23435915 Genistin 23435915 Mg(2+) 23435915 acetylcholine 23435915 erythromycin 23435915 genistin 23435915 histamine 23435915 isoflavones 23435915 phentolamine 23435915 propranolol 23435915 verapamil 23436259 Zaleplon 23436259 zaleplon 23436293 bile acids 23436315 Acetaminophen 23436315 Propylene glycol 23436315 acetaminophen 23436315 propylene glycol 23436428 aspirin 23436428 cilostazol 23436428 clopidogrel 23436437 alanine 23436437 aspartate 23436437 creatinine 23436437 nitrogen 23436437 urea 23436442 H(2)O(2) 23436442 Hydrogen peroxide 23436442 benzyl ether 23436442 boronic ester 23436442 hydrogen peroxide 23436442 oxygen 23436494 Mifepristone 23436494 RU 486 23436494 mifepristone 23436709 Al 23436709 Ga 23436709 SubPc 23436709 SubPz 23436709 aluminum 23436709 boron 23436709 chloroform 23436709 gallium 23436709 subphthalocyanines 23436709 subporphyrazines 23437791 3-O-methyl-D-glucose 23437791 3MG 23437791 AMP 23437791 Gallic acid 23437791 Ser 23437791 Thr 23437791 Tyr 23437791 glucose 23437843 2-(1-benzofuran-3-yl)-N-methylacetamide 23437843 4-N-methylcarboxamidomethylcoumarin 23437843 6'-Sulfonyloxy 23437843 6'-benzyloxy 23437843 6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-alkylacetamide 23437843 6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-methylacetamides 23437843 moclobemide 23437843 monoamine 23438486 acetylcholine 23438486 amino acids 23438486 cysteine 23439078 2-O-sulfo-α-l-iduronic acid 23439078 Pyranose 23439078 Sugar 23439078 carbohydrate 23439078 monosaccharaides 23439078 sulfate 23439240 PEO-PPO-PEO 23439240 PLGA 23439240 irinotecan hydrochloride 23439478 flavonoids 23439478 polyphenolic 23439478 polyphenols 23439479 S 23439479 SH 23439479 arginine 23439479 glutathione 23439479 l-arginine 23439479 malondialdehyde 23439479 silybin 23439479 superoxide 23439480 Na2S2O5 23439480 S 23439480 Sodium metabisulfite 23439480 sodium metabisulfite 23439480 sulfite 23439480 sulfonate 23440512 Vitamin A 23440512 all-trans retinoic acid 23440512 atRA 23440512 retinoic acid 23440512 retinoid 23440512 retinol 23440512 vitamin 23440512 vitamin A 23440577 MTT 23440577 cis-platin 23440577 dihydropyridine 23440577 imidazole 23440577 imidazole-2-yl 23440577 indeno[1,2-b]quinoline-9,11-dione 23440580 glucose 23441017 CrB 23441017 CrB2 23441017 CrB3 23441017 CrB4 23441017 MoB 23441017 TiI 23441017 WB2 23441017 chromium borides 23441102 PEG 23441102 histidine 23441102 methoxy-PEG 23441102 poly(ethylene glycol) 23441686 Diaion HP20SS 23441686 EtOAc 23441686 HP20SS 23441686 Si 23441686 polystyrene 23441686 silica 23441976 1,7,8,12b-tetrahydro-2,2,4-trimethyl-2H-benzo[6,7]cyclohepta [1,2,3-de] [1] benzopyran-5,10,11 triol 23441976 Racemosolone 23441976 cycloheptane 23441976 de-O-methyl racemosol 23441976 eicosanoic acid 23441976 furopyran 23441976 lupeol 23441976 n-tetracosane 23441976 octacosyl ferulate 23441976 pentacyclic phenol 23441976 pentacyclic phenolic 23441976 racemosol 23441976 stigmasterol 23441976 β-sitosterol 23441976 β-sitosteryl stearate 23441977 Br(-) 23441977 Br2(-•) 23441977 Br2(•-) 23441977 Br3(-) 23441977 BrOH(-•) 23441977 H2O(•+) 23441977 H2O2 23441977 OH(•) 23441977 bromide 23442147 carbohydrates 23442161 ATP 23442788 K+ 23442788 Na+ 23442788 OUA 23442788 PLTX 23442788 Palytoxin 23442788 ouabain 23443513 Ag(+) 23443513 Au(3+) 23443513 Cd(2+) 23443513 Cu(2+) 23443513 Hg(2+) 23443513 NaBH4 23443513 Zn(2+) 23443513 cytosine 23443513 silver 23443908 HCl 23443908 He 23443908 hydrogen halide 23444040 Eugenol 23444040 SDS 23444040 crystal violet 23444040 eugenol 23444040 polyacrylamide 23444043 Phenolic 23444043 phenolic 23444043 yunnanensins A-C 23444099 Aminoacyl 23444099 aminoacyl 23444099 lysyl 23444099 lysyl-adenylate 23444274 imidacloprid 23444285 prednisone 23444386 1,1'-azobis(N,N-dimethylformamide 23444386 5,5'-dithiobis(2-nitrobenzoic acid) 23444386 DHEA 23444386 Disulfide 23444386 Hydroxysteroid 23444386 bile acids 23444386 cysteines 23444386 dehydroepiandrosterone 23444386 diamide 23444386 disulfide 23444386 disulfides 23444386 glutathione disulfide 23444386 hydroxysteroids 23444386 nucleotide 23444386 thiol 23444428 Vancomycin 23444779 Honokiol 23444779 honokiol 23445175 C 23445175 N 23445175 acyl-CoA 23445175 amino acids 23445175 ceramidases 23445175 ceramide 23445175 cysteine 23445175 cysteines 23445175 dihydrosphingosine 23445175 disulfide 23445175 fatty acids 23445175 lysine 23445175 phytosphingosine 23445189 alkyl 23445189 alkylated-C60 23445219 BPAP 23445219 bisphenol AP 23445219 carbon 23445219 ethanol 23445219 hydrogen 23445219 sodium hydrate 23448197 glucose 23448247 CH2Cl2 23448247 CO 23448247 CpFe(CO)2P(OMe)3(•) 23448247 CpRu(CO)2(•) 23448247 CpRu(CO)2P(OMe)3(•) 23448247 Fe-C-O 23448247 P(OMe)3 23448247 [CpFe(CO)2]2 23448247 [CpRu(CO)2]2 23448247 [CpRu(CO)]2(μ-CO) 23448247 carbonyl 23448247 ruthenium 23448247 transition metal 23448580 polyhexanide 23449195 acetylcholine 23449195 malondialdehyde 23449195 minocycline 23449195 minocycline hydrochloride 23449195 nitrite 23449195 reduced glutathione 23449195 tween 80 23449197 7-Methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole 23449197 7-methoxy-6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole 23449197 TASP0382088 23449197 benzothiazole 23449197 imidazole 23449197 methoxy 23449197 thiazole 23449198 magnesium stearate 23449198 theophylline 23449199 (R)-dihydro-β-ionol 23449199 dihydro-β-ionol 23449199 β-ionol 23449199 β-ionols 23449199 β-ionone 23449204 1,1-diphenyl-2-picrylhydrazyl 23449204 3-hydroxy-5-methylphenol 23449204 DPPH 23449204 NBT 23449204 cleyeratannin A 23449204 cleyeratannin B 23449204 cleyeratannin C 23449204 nitroblue tetrazolium 23449204 orcinol 23449204 superoxide 23449204 tannins 23449888 Androgen 23449888 C 23449888 N 23449888 androgen 23449981 CDP 23449981 CPE 23449981 Ceramide phosphoethanolamine 23449981 Sphingomyelin 23449981 alcohol 23449981 ceramide 23449981 ceramide phosphoethanolamine 23449981 ethanolamine 23449981 phosphatidylcholine 23449981 phosphocholine 23449981 sphingolipid 23450164 CH3SO3 23450164 CH3SO3H 23450164 H2O 23450164 HO 23450164 MSA 23450164 hydrogen 23450164 hydroxyl 23450164 methane sulfonic acid 23450220 PNIPAM 23450220 poly(N-isopropylacrylamide) 23452037 (13)C 23452037 13C 23452037 BPhe a 23452037 Bacteriopheophytin a 23452037 bacteriopheophytin 23452037 bacteriopheophytin a 23452037 δ-aminolevulinic acid 23452083 1,2-dihydropyridines 23452083 diynes 23452083 rhodium 23452083 sulfonimines 23452185 1,3,4-thiadiazole 23452185 Thiadiazole 23452185 thiadiazole 23452205 GABA 23452205 glutamate 23452237 C 23452237 N 23452237 Trimethylamine N-oxide 23452237 arginine 23452237 molybdenum 23452243 (13)C 23452243 (31)P 23452243 Ca(2+) 23452243 Mg(2+) 23452243 Phosphorylated Serine 23452243 amino acid 23452243 arginine 23452243 glycine 23452243 leucine 23452243 phosphates 23452243 phosphorylated serine 23452243 phosphoserine 23452243 valine 23453003 Hydrocarbons 23453003 hydrocarbon 23453003 hydrocarbons 23453071 2-{1-[1-(6-chloro-5-fluoropyrimidin-4-yl)ethyl]piperidin-4-ylamino}-N-(3-chlorophenyl) pyridine-3-carboxamide 23453071 BRN-103 23453071 BRN-250 23453071 nicotinamide 23453071 tyrosine 23453073 Niclosamide 23453308 C-18 fatty acids 23453308 Jacaric acid 23453308 alpha- and beta-calendic and catalpic acid 23453308 fatty acids 23453308 jacaric acid 23453308 jacaric and punicic acid 23453308 mono-unsaturated C-18 fatty acids 23453308 octadecatrienoic acid 23453308 punicic acid 23453308 trans- and cis-vaccenic acid 23453838 Br 23453838 Et 23453838 F 23453838 I 23453838 Me 23453838 O 23453838 OTs 23453838 R=Et 23453838 R=Me 23453838 R=Me, Et; X=O, S; n=2, 3; Z=halogen, OTs 23453838 R=Me, Z=F, n=2 23453838 S 23453838 Z=Br, I, or OTs 23453838 ethyl phosphonates 23453838 halogen 23453838 methyl phosphonates 23453838 organophosphate 23453838 p-NO(2)PhO-P(X)(R)[(O(CH(2))(n)Z] 23453838 paraoxon 23453838 thionate 23453838 β- and γ-substituted alkoxy organophosphonates 23453838 β-fluoroethoxy methylphosphonate 23453838 β-substituted ethoxy and γ-substituted propoxy phosphonoesters 23453839 N-Alkyldeoxynojirimycin 23453839 N-alkyldeoxynojirimycins 23453839 NADNJ 23453839 NADNJs 23453839 alkyl 23453839 tertiary amide 23453839 tertiary carboxamide 23453840 2-Substituted-2-amino-6-boronohexanoic acids 23453840 2-amino-6-boronohexanoic acid 23453840 ABH 23453840 Asp 23453840 carbon 23453840 carboxylic acid 23453840 nitrogen 23453840 tertiary amine 23454012 (R)-α-lipoic acid 23454012 GSH 23454012 MEM 23454012 Memantine 23454012 N-methyl-d-aspartate 23454012 NMDA 23454012 glutamate 23454012 memantine 23454012 sulfur 23454112 PEG-grafted PLL 23454112 PLL-g-PEG 23454112 Photofrin 23454112 poly(ethylene glycol)-grafted poly(l-lysine) 23454112 porfimer sodium 23454113 TetraN-3,4,3 23454113 cyclic disulfides 23454113 cyclic hexa- and octa-amine disulfides 23454113 cyclic polyamine disulfide 23454113 cyclic polyamine disulfides 23454113 cyclic tetra-amine disulfide 23454113 cyclic tri- and tetra-amine disulfides 23454113 disulfide amino 23454113 hexa- and octa-amine 23454113 polyamine disulfide 23454113 spermine tetra-amine disulfide 23454150 MDA 23454150 NO 23454150 ferrous 23454150 flavonoids 23454150 malondialdehyde 23454150 nitric oxide 23454150 oxygen 23454150 polyphenols 23454207 Rotigotine 23454207 alanine 23454207 aspartate 23454207 dopamine 23454207 ergoline 23454207 poly(lactide-co-glycolide) 23454207 rotigotine 23454207 sodium 23454269 6His 23454269 aryl hydrocarbon 23454269 cobalt chloride 23454269 glucose 23454296 Squalene 23454296 squalene 23454300 polystyrene 23454306 Glyphosate 23454306 Roundup 23454306 glyphosate 23454513 amino acid 23454513 colchicine 23454513 combretastatin A-4 23454513 phosphate 23454513 β-lactam 23454513 β-lactam amides 23454513 β-lactam amino acid amides 23454513 β-lactam combretastatins 23454513 β-lactam phosphate esters 23454514 DHPMs 23454514 dihydropyrimidin-2-ones 23454514 iodide 23454514 sodium iodide 23454526 2'-deoxycytidine 23454526 5-methyl-2'-deoxycytidine 23454526 cocaine 23454526 heroin 23454530 1H-benzimidazol-2-yl 23454530 2-acetyl-1H-benzimidazoles 23454530 2-alkoxy-4-aryl-6-(1H-benzimidazol-2-yl)-3-pyridinecarbonitriles 23454530 3-aryl-1-(1H-benzimidazol-2-yl)-2-propen-1-ones 23454530 3-pyridinecarbonitriles 23454530 alcohol 23454530 malononitrile 23454530 norepinephrine hydrochloride 23454530 prazosin hydrochloride 23454530 sodium alkoxide 23454530 ylidenemalononitriles 23454532 2-heteroarylthio-6-substituted-quinazolin-4-one 23454532 2-heteroarylthio-quinazolin-4-ones 23454532 Arg 23454532 Lys 23454532 amino acid 23454532 gentamicin 23454655 15-acetyldeoxynivalenol 23454655 3-acetyldeoxynivalenol 23454655 HT-2-and T-2-toxin 23454655 HT-2-toxin 23454655 T-2 and HT-2 toxin 23454655 T-2-toxin 23454655 deoxynivalenol 23454655 deoxynivalenol-3-glucoside 23454655 zearalenone 23454655 zearalenone-4-glucoside 23454655 zearalenone-4-sulfate 23454655 α-zearalenol 23454655 β-zearalenol 23454655 α-zearalenol-4-glucoside 23454655 β-zearalenol-4-glucoside 23454672 (24R/S)-24-hydroxy-3α 10α-epoxy-9-eip-cucurbita-25-ene 23454672 triterpenoids 23454831 carbon 23454831 polyamidoamine 23454832 MC-LR 23454832 Microcystins 23454832 microcystin-LR 23454833 silver 23455059 (1)H 23455059 Platinum(II) 23455059 cisplatin 23455059 mono-aminophosphonate ester 23455059 platinum 23455059 platinum(II) 23455313 ATRA 23455313 Cyclic AMP 23455313 Retinoid 23455313 all-trans-retinoic acid 23455313 cAMP 23455313 retinoid 23455594 nicotine 23455594 varenicline 23455599 bupropion 23455599 naltrexone 23455898 Ca 23455898 Cd 23455898 Cr 23455898 Cu 23455898 Fe 23455898 K 23455898 Mg 23455898 Mn 23455898 Ni 23455898 Pb 23455898 Zn 23456363 estrogens 23456363 isoflavones 23456815 aflatoxin B1 23456815 glutathione 23456815 malondialdehyde 23456815 methanol 23456815 superoxide 23456850 25-hydroxyvitamin D 23457022 aspergiloids E-H 23457022 chlorflavonin A 23457022 diterpenoids 23457022 flavonol 23457058 Carbon 23457058 carbon 23457058 graphene 23457114 C 23457114 Carbon 23457114 Isoidide 23457114 Isosorbide 23457114 Ru 23457114 Ruthenium 23457114 carbon 23457114 hydrogen 23457114 isoidide 23457114 isomannide 23457114 isosorbide 23457114 nickel 23457114 ruthenium 23457123 MeHg 23457123 [(18)F]FDG 23457123 methylmercury 23458420 ThT 23458420 Thioflavin T 23458618 Cu 23458618 Pb 23458618 Zn 23458620 PLGA 23458620 poly (D,L-lactide-co-glycolide) 23458894 Crotonaldehyde 23458894 crotonaldehyde 23458894 α, β-unsaturated aldehyde 23458897 PFOA 23458897 perfluorooctanoate 23458950 6-cis-amentadione-1'-methyl ether 23458950 Meroterpenoids 23458950 amentadione-1'-methyl ether 23458950 cystodiones A (1) and B 23458950 cystodiones A-F 23458950 meroterpenes 23458950 meroterpenoids 23458950 usneoidone Z 23458966 ATP 23458966 Zinc oxide 23458966 ZnO 23458966 adenosine-5'-triphosphate 23458966 oxygen 23459107 HEBP 23459107 ammonium 23459107 bisphosphonate 23459107 bisphosphonates 23459107 hydroxyethylenebisphosphonate 23459107 iron oxide 23459107 methylene 23459107 mono-ammonium 23459473 PEG 23459473 PEO 23459473 Polyethylene oxide 23459473 poly(ethylene glycol) 23460265 [ (11)C]SCH23390 23460265 [(11)C]NNC112 23460265 [(11)C]SCH23390 23460265 dopamine 23460644 sulfate 23461628 (+)-Laburnamine 23461628 [(3)H]-dopamine 23461628 nicotine 23461763 (157)Gd(3+) 23461860 FITC 23461860 PLGA 23461860 Rh B 23461860 Rhodamine B 23461860 fluorescein isothiocyanate 23461860 poly lactic-co-glycolic acid 23462105 AF B1 23462105 AF M1 23462105 Aflatoxin M1 23462105 aflatoxin B1 23462105 aflatoxin M1 23462308 Ketamine 23462308 ketamine 23462526 Boron 23462526 boronophenylalanine 23462671 isopropanol 23462671 phosphate 23462671 rapamycin 23462672 PACA 23462672 Polyalkylcyanoacrylates 23462672 diclofenac 23462672 diclofenac sodium 23462672 poly(alkyl-2-cyanoacrylate) 23462672 poly(n-butyl-2-cyanoacrylate) 23462797 cholesterol 23462797 glucose 23462797 triacylglycerol 23462814 SiO2 23462814 graphene 23462814 mica 23464522 DM1 23464522 cabazitaxel 23464522 eribulin 23464522 ixabepilone 23464522 taxanes 23464522 vinca alkaloids 23464578 ethanol 23464629 creatinine 23464629 enalapril 23464629 nitrogen 23464629 stachydrine 23464739 1,1-diphenyl-2-picrylhydrazyl 23464739 Uncinataflavone 23464739 flavonoid 23464739 methyl 3-(5,7-dihydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-6-yl)-4-methoxybenzoate 23464739 methyl benzoate 23464760 7-Hydroxyisoflavone 23464760 7-hydroxyisoflavone 23464805 8-oxo-tri-nor-eudesm-6-en-5α-ol 23464805 sesquiterpenoids 23464805 tri-nor-eudesm-5-en-7β,8β-diol 23464805 tri-nor-eudesmane 23464805 tri-nor-eudesmanolides 23464810 Si 23464810 silicon 23464829 d-galactosamine 23464829 flavanol 23464829 songarin A 23464873 Graphene 23464873 graphene 23465048 S 23465048 S,S-dioxide 23465048 TASO 23465048 TASO2 23465048 Thioacetamide 23465048 Thiobenzamide 23465048 [(13)C2D3]-TASO 23465048 [(14)C]-TASO 23465048 amide 23465048 amidine 23465048 lysine 23465048 phosphatidylethanolamine 23465048 thioacetamide S-oxide 23466229 PF-04859989 23466229 dihydroquinolinone 23466229 pyrazole 23466229 tetrahydropyrazolopyridinone 23466230 dabigatran 23466230 dabigatran etexilate 23466230 methyl (E)-3-(4-hydroxy-2-methoxyphenyl)propenoate 23466230 methyl ferulate 23466232 5-(p-toluenesulfonylamino)phthalimide 23466232 N2-substituted-5-(p-toluenesulfonylamino)phthalimide 23466232 sugar 23466234 (1)H 23466234 (13)C 23466234 1,2,4-triazole 23466234 3-S-β-d-glucosides-4-arylideneamino-5-aryl-1,2,4-triazoles 23466234 5-aryl-1,2,4-triazole-3-thiones 23466234 S-β-d-glucosides 23466234 Schiff base 23466234 glucosides 23466330 norepinephrine 23466331 glutamate 23466342 AMP 23466342 Mollugin 23466342 adriamycin 23466342 mollugin 23466342 rhodamine-123 23466460 Polyphenols 23466460 curcumin 23466460 epigallocatechin gallate 23466460 glucose 23466460 polyphenols 23466460 quercetin 23466500 DDP 23466500 LY 294002 23466500 cisplatin 23466501 calcium 23466501 p-Cresol 23466501 p-cresol 23466501 serine 23466526 zinc 23466565 Isosteviol 23466565 acetate 23466565 acetylcholine 23466565 ent-16β-acetoxybeyeran-19-oic acid 23466565 ent-16β-hydroxybeyeran-19-oic acid 23466565 ent-7α-hydroxy-16-ketobeyeran-19-oic acid 23466565 isosteviol 23466606 STZ 23466606 sodium orthovanadate 23466606 streptozotocin 23466606 vanadium 23466606 vanadium-flavonol 23466742 estrogen 23466742 estrogens 23467017 Abacavir 23467017 N 23467017 abacavir 23467017 aldehyde 23467017 valine 23468100 Alcohol 23468100 alcohol 23468173 2,4-dideoxy-2,4-iminoribonic acid 23468173 3-Hydroxyazetidine carboxylic acids 23468173 3-hydroxyazetidine amides 23468173 3-hydroxyazetidine carboxylic acids 23468173 D-glucose 23468173 N,3-O-dibenzyl-2,4-dideoxy-2,4-imino-D-ribonic acid 23468173 N-methylazetidine amide 23468173 amide 23468173 amino acid 23468173 amino acids 23468173 iminosugar 23468173 sugar amino acid 23468386 Ag 23469760 Au(111) 23469760 CH3S-Au-SPh 23469760 Methylthiolate 23469760 Phenylthiolate 23469760 RS-Au 23469760 RS-Au-(SR)-Au-SR 23469760 RS-Au-SR 23469760 alkanethiols 23469760 hydrocarbon 23469760 methylthiolate 23469760 organometallic 23469760 phenylthiolate 23469760 thiolate 23469760 trithiolate 23469923 dopamine 23469927 Soman 23469927 Tyrosine 23469927 amino acid 23469927 pentapeptide 23469927 pinacolyl 23469927 pinacolyl methylphosphonate 23469927 soman 23469927 tyrosine 23469927 tyrosines 23470166 Cu(2+) 23470166 GSH 23470166 polyphenol 23470166 polyphenols 23470181 CdA 23470181 Si 23470181 SiO2 23470181 cadmium arachidate 23470181 methyl 23470181 rubrene 23470217 3-MB-PP 23470217 3-methyl-benzyl-PP 23470217 Calcium 23470217 Gly 23470217 calcium 23470217 pyrazolo [3,4-d] pyrimidine 23470287 1-Acetyl-sinapic acyl-4-(3'-chlorine-)benzylpiperazine 23470287 2,2-diphenyl-1-picrylhydrazyl 23470287 DPPH(⋅) 23470287 SA9 23470287 Sinapic acid 23470287 hydroxyl 23470287 phenylpropanoid 23470287 sinapic Acid 23470629 3β-Hydroxy-Δ(5)-bile Acids 23470629 3β-hydroxy-Δ(5)-bile acids 23470629 Bile Salt 23470629 bile acids 23470629 bile salt 23470629 glycocholic acid 23470629 taurolithocholic acid 3-sulfate 23470692 oxygen 23471562 PGE2 23471562 indomethacin 23471562 myricitrin 23471562 n-butanol 23471562 oleanane triterpene saponin 23471562 patuletin 7-O-glucopyranoside 23471562 sophradiol 3-O-α-L-(1)C4-rhamnopyranosyl-(1'''→4'')-O-β-D-(4)C1-galactopyranosyl (1''→6')-O-β-D-(4)C1-glucopyranoside 23471562 triterpene saponin 23471562 α-amyrin 3-O-glucopyranoside 23471769 Adenosine 23471769 Regadenoson 23471769 adenosine 23471769 dipyridamole 23471769 nitroglycerin 23471769 regadenoson 23471769 technetium 99 m sestamibi 23471850 Alcohols 23471850 Bi(III) 23471850 C 23471850 N 23471850 O 23471850 S 23471850 alcohol 23471850 alcohols 23471850 bismuth(III) 23471850 carbon 23471850 gold(III) 23471850 iron(III) 23471850 lanthanum(III) 23471850 nitrogen 23471850 oxygen 23471850 palladium(II) 23471850 rhenium(I) 23471850 rhenium(VII) 23471850 sulfur 23471871 Fe2 S2 23471871 Fe2 S2 (-) 23471871 Fe3 S4 23471871 Fe3 S4 (-) 23471871 Fe4 S4 23471871 Fe4 S4 (-) 23471871 FeS 23471871 FeS(-) 23471871 FeS2 23471871 FeS2 (-) 23471970 Ser 23471970 cAMP 23472833 12,12-ionene 23472833 3,3-, 6,9-, 6,12-, and 12,12-ionenes 23472833 3,3-, 6,9-, or 6,12-ionene fluorides and bromides 23472833 Na2SO4 23472833 NaBr 23472833 NaF 23472833 aliphatic 6,12- and 12,12-ionene bromides and fluorides 23472833 alkali halide 23472833 bromide 23472833 fluoride 23472833 iodide 23472833 methylene 23472833 sodium fluoride and bromide 23472833 sodium sulfate 23472857 AOT 23472857 Coumarin-500 23472857 Igepal 23472857 Igepal-520 23472857 cyclohexane 23472952 (R)-2-amino-6-borono-2-(2-(piperidin-1-yl)ethyl)hexanoic acid 23472952 α,α-disubstituted amino acid 23473053 Benzo[de][1,7]naphthyridin-7(8H)-ones 23473053 H2O2 23473053 Temozolomide 23473053 benzo[de][1,7]naphthyridin-7(8H)-ones 23473053 phthalazin-1(2H)-one 23473343 BFO 23473343 BiFeO3 23473343 CFO 23473343 CoFe2O4 23473343 STO 23473343 SrTiO3 23473343 oxide 23473535 (13)N 23473535 (16)O 23473535 Al2O3 23473535 aluminum oxide 23473535 metal oxide 23473568 1H-1,2,4-triazole-3-carboxylate 23473568 Pb3O2Br2 23473568 [Pb(L)(μ2-Br)(H2O)]n 23473568 lead(II) 23473568 lead(II) oxybromide 23473679 (177)Lu-DOTA-GGNle-CycMSHhex 23473679 Lu-177 23473679 lactam 23473682 PAP 23473682 hydrogen 23473682 imatinib 23473682 phenylaminopyrimidine 23473682 tyrosine 23474014 CORT 23474014 corticosterone 23474169 Glufosinate 23474169 Monurol 23474169 Phosacetamycin 23474169 Phosphonic Acid 23474169 fosfomycin 23474169 phosacetamycin 23474169 phosphinate 23474169 phosphinothricin 23474169 phosphonate 23474169 phosphonates 23474218 (1)H 23474218 CO2 23474218 conocarpan 23474218 eupomatenoid-3 23474218 eupomatenoid-5 23474218 neolignans 23474218 sulforhodamine B 23474381 MPT 23474381 behenic acid 23474381 fatty acid 23474381 fatty acids 23474381 metoprolol tartrate 23474381 stearic acid 23474389 3-(benzylthio)-5-(1H-indol-3-yl)-1,2,4-triazol-4-amines 23474389 3-(benzylthio)-5-(1H-indol-3-yl)-4H-1,2,4-triazol-4-amines 23474389 S 23474389 carbon disulfide 23474389 indole-3-carboxylic acid hydrazide 23474389 nitrobenzyl 23474547 C 23474547 N 23474547 Pt 23474547 S 23474547 Sulfur 23474547 carbon 23474547 methanol 23474547 nitrogen 23474547 oxygen 23474547 sulfur-nitrogen co-doped carbon 23474650 (S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate 23474650 (S)-1-pyridin-4-yl-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine 23474650 4-pyrimidone 23474650 AZD3839 23474650 N 23474650 Pyrimidine 23474650 aminoisoindoles 23474650 aryl-pyrimidine 23474650 carbon 23474650 imidazole 23474650 pyridine 23474650 pyrimidine 23474650 pyrimidine-2,4-dione 23474807 NaNO3 23474807 PEG 23474807 cesium chloride 23474807 polyethylene glycol 23474845 (R)-(+)-8-Hydroxy-DPAT 23474845 DOI 23474845 LSP1-2111 23474845 MK-801 23474845 WAY100635 23474845 amphetamine 23474845 glutamate 23474897 2-fluoro-4-[[[8-bromo-2,2-dimethyl-4-(4-methylphenyl)chroman-6-yl]carbonyl]amino]benzoic acid 23474897 4-[[[8-bromo-2,2-dimethyl-4-(4-methylphenyl)chroman-6-yl]carbonyl]amino]benzoic acid 23474897 Retinoic acid 23474897 chromene 23474897 retinoic acid 23474903 (3)C60*[>M(C3N6(+)C3)2] 23474903 (I(-))10 23474903 C60 23474903 C60(-)·[>M(C3N6(+)C3)2] 23474903 C60[>M(C3N6(+)C3)2] 23474903 C60[>M(C3N6(+)C3)2]-(I(-))10 23474903 C60[>M(t-Bu)2] 23474903 O2(-)· 23474903 bis(2,4-dinitrobenzenesulfonyl)tetrafluorofluorescein 23474903 decacationic [60]fullerene decaiodides 23474903 decacationic methano[60]fullerene decaiodides 23474903 fullerene 23474903 hydroxyl 23474903 iodide 23474903 malonato[60]fullerene diester 23474903 oxygen 23474903 quaternary ammonium 23474903 superoxide 23474903 trifluoroacetic acid 23474904 (1)H 23474904 (13)C 23474904 [1,3,4]thiadiazoles 23474904 [1,3,4]thiadiazolo[3,2-a]pyrimidines 23474904 benzo[h][1,3,4]thiadiazolo[2,3-b]quinazolines 23474904 benzothiadiazolotriazocine 23474904 imidazo[2,1-b][1,3,4]thiadiazoles 23474905 (1)H 23474905 (13)C 23474905 2-amino-1,4-naphthoquinone 23474905 2-amino-1,4-naphthoquinones 23474905 N,O-acetals 23474905 N,S-acetals 23475289 Isoflavone 23475289 estradiol 23475289 estrone 23475289 glucose 23475289 isoflavone 23475289 triglyceride 23475307 Ag 23475307 Arsenic 23475307 Arsenite 23475307 As 23475307 As(III) 23475307 As(V) 23475307 AsB 23475307 Cd 23475307 Cu 23475307 DMA 23475307 Hg 23475307 MMA 23475307 Monomethylarsonic acid 23475307 Ni 23475307 Pb 23475307 Zn 23475307 arsenobetaine 23475307 dimethylarsinic acid 23475368 glucose 23475368 tyrosine 23475370 Strontium 23475370 hydroxyproline 23475370 strontium 23475432 Arsenic 23475432 Glutathione 23475432 Nicotine 23475432 S 23475432 arsenic 23475432 nicotine 23475432 sodium arsenite 23475784 17β-estradiol 23475784 FAD 23475784 fadrozole 23475902 1-Hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol 23475902 MJ33 23475902 NADPH 23475902 oxygen 23477372 Gelsil 23477372 sulfur 23477482 ascorbic acid 23477482 capsaicinoids 23477482 flavonoids 23477482 tocopherols 23477482 vitamin C 23477482 vitamin E 23477619 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone 23477619 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone 23477619 7-POB-G 23477619 Aldehyde 23477619 NNK 23477619 O(2)-POB-dT 23477619 O(6)-methyl-G 23477624 C 23477624 Ca 23477624 DPYR 23477624 N 23477624 P 23477624 Polycalcium 23477624 calcium 23477624 calcium lactate-gluconate 23477624 deoxypyridinoline 23477624 phosphorus 23477624 polycalcium 23478148 6-amidinotetrahydroquinoline 23478148 Asp 23478148 BMS-593214 23478148 Lys 23478338 amino-acid 23478338 rapamycin 23478802 2-(trimethylammonium)ethyl methanesulfonate 23478802 Benzoquinone 23478802 Cysteine 23478802 amino 23478802 carvacrol 23478802 cinnamaldehyde 23478802 cysteine 23478802 cysteines 23478802 iodoacetamide 23478802 pBQN 23478802 para-benzoquinone 23478802 serine 23478908 IPTG 23478908 RBG 23478908 Resorufin β-d-galactopyranoside 23478908 isopropyl-β-d-thiogalactopyranoside 23479059 BPA 23479059 Bromodeoxyuridine 23479059 Paraben 23479059 bisphenol A 23479059 butyl paraben 23479059 ethyl paraben 23479059 methyl paraben 23479059 parabens 23479059 propyl paraben 23479059 xenoestrogens 23479079 H2S 23479079 Hydrogen sulfide 23479079 NaHS 23479079 Sulfide 23479079 poly (ADP-ribose) 23479079 sodium hydroxysulfide 23479079 sulfide 23479335 Triglyceride 23479335 cholesterol 23479335 cholesterol ester 23479335 statin 23479335 triglyceride 23479335 triglycerides 23479387 4-O-triphenylphosphoniumbutyl 23479387 Q-3BTPI 23479387 QTA-3BTPI 23479387 Quercetin 23479387 acetylcholine 23479387 glyceryl trinitrate 23479387 nitrate 23479387 quercetin 23479388 2α-O-cis-p-coumaroyl-3β,19α-dihydroxy-urs-12-en-28-oic acid 23479388 2α-O-trans-p-coumaroyl-3β,19α-dihydroxy-urs-12-en-28-oic acid 23479388 pentacyclic triterpenoids 23479388 triterpenoids 23479392 coumestans 23479392 flavanones 23479392 flavonoids 23479392 flavonols 23479392 isoflavones 23479392 isoflavonoids 23479392 lignans 23479392 stilbenoids 23479726 C 23479726 His 23479726 Phosphoserine 23479726 amino acid 23479726 l-phosphoserine 23479726 phosphoglycerate 23479726 phosphoserine 23479726 serine 23480235 8-azapurine 23480235 9-benzyl 23480235 Adenosine 23480235 N-[9-(ortho-Fluorobenzyl)-2-Phenyl-8-Azapurin-6-yl]-Amides 23480235 N-[9-(ortho-fluorobenzyl)-2-phenyl-8-azapurin-6-yl]-amides 23480235 adenosine 23480235 amide 23480235 benzyl 23480235 carbonyl carbon 23480235 fluorine 23480235 meta-fluorophenyl 23480470 3- hydroxyiminomethyl-1-alkylpyridinium bromide 23480470 3-C16 23480470 BNDPP 23480470 CPB 23480470 CnH2n+1 23480470 Di- and Triphosphate Esters 23480470 Oxime 23480470 Oximes 23480470 PNPDPP 23480470 P═O 23480470 alkyl 23480470 bis(2,4-dinitrophenyl) phosphate 23480470 cetylpyridinium bromide 23480470 hexadecyl 23480470 oxime 23480470 oximes 23480470 p-nitrophenyl diphenyl phosphate 23480470 phosphate ester 23480470 phosphate esters 23480470 tri- and diphosphate esters 23480643 C-H 23480643 Pd 23480643 acrolein 23480643 carbazole 23480643 clauraila A 23480643 diarylamine 23480643 exo-2-oxazolidinone diene 23480783 Simvastatin 23480783 cholesterol 23480783 fatty acid 23480783 glucose 23480783 metformin 23480783 retinol 23480783 simvastatin 23480874 1,2-distearoyl-sn-glycero-3-phosphocholine 23480874 1,4-butyndiol 23480874 DSPC 23480874 Zinc Porphyrin 23480874 carboxylphenyl 23480874 zinc porphyrin 23480874 zinc tetraphenyl porphyrin 23481176 Fe(2+) 23481176 Fe(3+) 23481176 TGA 23481176 iron 23481176 iron oxide 23481176 thioglycolic acid 23481256 C 23481256 Dilysine 23481256 carboxylate 23481256 dilysine 23481256 lysine 23481321 hydrogen 23481590 Testosterone 23481590 androgen 23481590 testosterone 23481595 Ribonucleoside 23481595 guanosines 23481595 uridine 23481643 tacrine 23481645 1-pyrazoline 23481645 2-pyrazoline 23481645 Al 23481645 Glutamate 23481645 Hg 23481645 NN 23481645 NaCNBH3 23481645 TMS diazomethane 23481645 azakainoid 23481645 azakaniod 23481645 diazomethane 23481645 glutamate 23481645 iso and azakainoids 23481645 isokainoid 23481645 pyrazolidine 23481645 trans azakainate 23481645 trans-dibenzyl glutaconate 23481651 Gd-DOTA 23481651 alkyne 23481651 azide 23481651 azide-alkyne 23481651 copper(I) 23481651 sucrose 23481676 Diterpenoids 23481676 Eunicellin 23481676 diterpenoids 23481676 eunicellin 23481676 krempfielins E-I 23481678 23-(10-methyl)undecanoic acid demalony lazalomycin F4a ester 23481678 23-(6-methyl)heptanoic acid demalonylazalomycins F3a ester 23481678 23-(9-methyl)decanoic acid demalonylazalomycin F4a ester 23481678 23-valine demalonylazalomycin F5a ester 23481678 25-malonyl demalonylazalomycin F5a monoester 23481678 Azalomycin F 23481678 F4a ester 23481678 F5a ester 23481678 azalomycin F 23481678 azalomycins F3a, F4a and F5a 23482500 MPP(+) 23482500 Na(+) 23482500 Sorafenib 23482500 [(14)C]Sorafenib 23482500 [(14)C]sorafenib 23482500 decynium 22 23482500 ketoprofen 23482500 rifamycin 23482500 rifamycin SV 23482500 sorafenib 23482500 tyrosine 23483083 G-TiO2 23483083 TiO2 23483083 graphene 23483201 CORM-2 23483201 CoPP 23483201 acid acetic 23483201 carbon monoxide 23483201 cobalt protoporphyrin IX 23483201 formalin 23483201 morphine 23483201 nitric oxide 23483201 tricarbonyldichlororuthenium(II) 23484537 Paclitaxel 23484537 boron dipyrromethene 23484593 Embellicine B 23484593 Embellicines A and B 23484593 EtOAc 23484593 embellicine A 23484593 embellicine B 23484593 embellicines 23484593 embellicines A and B 23484633 C 23484633 Na 23484633 Ni 23484633 Sn 23484633 Tin 23484633 carbon 23484633 sodium 23484633 steel 23484901 1-aminoanthracene 23484901 1-azidoanthracene 23484901 Epothilone D 23484901 allopregnanolone 23484901 aminoanthracene 23484901 anthracene 23484901 colchicine 23484901 discodermolide 23484901 epothilone D 23484958 FeS 23484958 H(+) 23484958 [FeFe] 23484958 hydrogen 23485402 N 23485402 Tetrodotoxin 23485474 DMAEMA 23485474 Eudragit 23485474 Eudragit E PO 23485474 Polymethacrylates 23485474 dimethylaminoethyl 23485474 dimethylaminoethyl methacrylate 23485474 isobornyl 23485474 methacrylate 23485474 methyl-methacrylate 23485474 n-butyl 23485474 polymethacrylates 23485474 t-butyl 23485474 terpolymer 23485481 Hg 23485481 Mercury 23485481 mercury 23485559 1-Methylimidazolium hydrogen sulfate 23485559 2,5-dimethyl-N-substituted pyrroles 23485559 2,5-hexanedione 23485559 N-substituted pyrroles 23485559 [HMIM]HSO4 23485559 amines 23485615 DMN 23485615 NAD(P)H 23485615 S 23485615 alanine 23485615 aspartate 23485615 dimethylnitrosamine 23485615 glutathione 23485615 heme 23485615 malondialdehyde 23485615 quinone 23485615 γ-glutamylcysteine 23485618 Ethyl lauroyl arginate 23485618 LAE 23485618 dipropylene glycol methyl ether 23485618 ethanol 23485618 ethyl lauroyl arginate 23485618 ethyl-N-dodecanoyl-L-arginate hydrochloride 23485618 tributyl-o-acetylcitrate 23485651 Cadmium telluride 23485651 CdCl2 23485651 CdTe 23485651 GSH 23485651 GSSG 23485651 N 23485651 S 23485651 cadmium 23485651 cadmium telluride 23485651 glutathione 23485651 oxidized glutathione 23485651 oxygen 23485651 phosphatidylserine 23485651 poly ADP-ribose 23485651 reduced glutathione 23485651 superoxide 23485652 Bezafibrate 23485652 alpha-keto acid 23485652 alpha-ketoacid 23485652 amino acids 23485652 bezafibrate 23486447 Amitriptyline 23486447 clomipramine 23486447 desipramine 23486447 doxepin 23486447 imipramine 23486447 nortriptyline 23486447 trimipramine 23486479 Allolactose 23486479 Asn 23486479 Bis-Tris (2,2-bis(hydroxymethyl)-2,2',2″-nitrilotriethanol) 23486479 Glu 23486479 His 23486479 Lys 23486479 Ser 23486479 Trp 23486479 allolactose 23486479 galactose 23486479 glucose 23486479 l-ribose 23486479 lactose 23487168 Azilsartan 23487168 azilsartan 23487168 candesartan 23487168 eprosartan 23487168 irbesartan 23487168 losartan 23487168 olmesartan 23487168 telmisartan 23487168 valsartan 23487256 OH 23487256 abietic acid 23487256 acetaldehyde 23487256 acetic acid 23487256 formic acid 23487256 glucic acid 23487256 glycolic acid 23487256 levoglucosan 23487256 methanol 23487256 nitric acid 23487256 nitroguaiacol 23489438 glucose 23489627 (1)H 23489627 2-acetylpyridine N(4)-phenylthiosemicarbazone 23489627 2-acetylpyridine N4-phenylthiosemicarbazone 23489627 Bi(L)(NO3)2(CH3CH2OH) 23489627 bismuth(III) 23489627 oxygen 23489627 thiosemicarbazones 23489628 N-(thiophen-2-yl) benzamide 23493819 CF2O 23493819 CF3O 23493819 CF3O2 23493819 CF3OI 23493819 CF3OIO2 23493819 CF3OOI 23493819 CF3OOIO 23493819 CF3OOOI 23493819 CX3O2 23493819 F 23493819 FIO2 23493819 FOIO 23493819 FOOI 23493819 H 23493819 IO 23493819 O 23493819 O2 23493819 OIO 23493819 hydrogen 23494230 DHβE 23494230 Midazolam 23494230 Morphine 23494230 Nicotine 23494230 Varenicline 23494230 acetylcholine 23494230 cytisine 23494230 dihydro-β-erythroidine 23494230 mecamylamine 23494230 midazolam 23494230 morphine 23494230 nicotine 23494230 varenicline 23494236 Nicotine 23494236 nicotine 23494855 Hydrous Ruthenium Oxide 23494855 RuO2 23494855 Silica 23494855 hydrous RuO2 23494855 silica 23494861 methylglyoxal 23494904 FPI 23494904 PCBM 23494904 fullerene 23494904 fullerenes 23494904 fulleropyrrolidinium iodide 23494904 iodide 23494944 (-)-epicatechin 23494944 (-)-epigallocatechin gallate 23494944 AlCl3 23494944 Aluminium 23494944 Aluminium Chloride 23494944 aluminium chloride 23494944 glutathione 23494944 superoxide 23495155 cholic acid 23495155 deoxycholic acid 23495155 polyamine 23495155 spermine 23495155 sterol 23495205 4-{[(4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate 23495205 Br 23495205 Cl 23495205 F 23495205 difluoromethylene 23495205 halogen 23495205 imidazole 23495205 imidazolyl 23495205 methylene 23495205 para-cyanophenyl 23495205 phenol 23495205 steroid 23495205 triazolyl 23495690 nucleotide 23495690 nucleotides 23495771 PU-Ac 23495771 PU-Am 23495771 PU-Su 23495771 acetyl anhydride 23495771 amino 23495771 poly(L-citrulline) 23495771 poly(allylurea) 23495771 succinyl anhydride 23495825 glycine 23495825 proline 23495832 EtOH 23495832 HCl 23495832 NaCl 23495832 carbon dioxide 23495832 carvone 23495832 ethanol 23495832 limonene 23495832 omeprazole 23495918 PEG 23495918 poly(ethylene glycol) 23495918 polyethylene 23495918 polystyrene 23495918 silicon 23496094 (S)-1,2,3,4-Tetrahydro-3-isoquinolinemethanol 23496094 (S)-1,2,3,4-tetrahydro-3-isoquinolinemethanol 23496094 Methyl Lactate 23496094 N 23496094 NH 23496094 O 23496094 OH 23496094 THIQM 23496094 THIQMI 23496094 THIQMII 23496094 hydrogen 23496094 methyl lactate 23496772 CF3 23496772 CH3 23496772 CH3(CH2)20COCH2CF3 23496772 CH3(CH2)20COCH2CH3 23496772 COC 23496772 FEE 23496772 OH 23496772 ethyl ether 23496772 fluorinated ethyl ether 23497861 MTBE 23497861 caffeate 23497861 caffeate esters 23497861 cyanopropyl 23497861 hexane 23497861 p-coumarate 23497861 steroid 23497861 steryl ferulate 23497861 trans-ferulate 23497861 γ-Oryzanol 23497861 γ-oryzanol 23497865 Cholesterol 23497865 docosahexaenoic 23497865 esters 23497865 fatty acids 23497865 lactic acid 23497865 nicotinamide 23497865 oleic 23497865 taurine 23497865 β-alanine 23497868 AMP 23497868 Compound C 23497868 Gly-Sar 23497868 Ile-Phe 23497868 TF 3'-O-gallate 23497868 TFs 23497868 Theaflavins 23497868 Val-Tyr 23497868 di- and tripeptides 23497868 dimeric catechins 23497868 dipeptides 23497868 glycyl-sarcosine 23497868 theaflavins 23497870 unsaturated fatty acids 23497871 2-butanone 23497871 acetaldehyde 23497871 acetoin 23497871 diacetyl 23497871 lactic acid 23497873 SDS 23497873 formaldehyde 23497873 l-cysteine sulphoxide 23497873 γ-glutamyl 23497880 fructosyl-galacto-oligosaccharides 23497880 lactulose 23497880 sugar 23497885 Chrysoeriol 23497885 berberine 23497885 celastrol 23497885 ellagic acid 23497885 flavonoid 23497885 flavonoids 23497885 hippuric acid 23497885 laricitrin 23497885 limonin 23497885 myricetin 3',4',5'-trimethylether 23497885 oleanolic acid 23497885 phenolic acids 23497885 pinocembrin 23497885 propyl gallate 23497885 quercitrin 23497885 sinapic acid 23497885 tamarixetin 23497885 tricetin 23497885 tricetin 3',4',5'-trimethylether 23497885 triterpenes 23497885 ursolic acid 23497888 2-hydroxypropanedialdehyde 23497888 acetic acid 23497888 arabinose 23497888 arabinotriose 23497888 carbon 23497888 formaldehyde 23497888 formic acid 23497888 glyceraldehyde 23497888 glycolaldehyde 23497888 glycolic acid 23497888 glyoxal 23497888 α-(1→5)-l-arabinotriose 23497892 STMP 23497892 amino acid 23497892 amino acids 23497892 phosphorus 23497892 sodium trimetaphosphate 23497895 1-hydroxy-2-propanone 23497895 2-hydroxy-3-pentanone 23497895 cis-2,6-dimethyl-1,4-cyclohexanedione 23497895 monosaccharides 23497895 silica gel 23497895 sugars 23497901 ethanol 23497901 phlorotannins 23497902 CARN 23497902 FAs 23497902 VITE 23497902 carnosic acid 23497902 fatty acid 23497902 phenolic 23497902 vitamin E 23497905 ellagic acid 23497907 5,6-epoxy 23497907 5,8-epoxy 23497907 cis-antheraxanthin 23497907 cis-violaxanthin 23497907 epoxy 23497907 hydroxy 23497907 lutein 23497907 zeaxanthin 23497907 β-cryptoxanthin 23498899 Glucose 23498899 caffeine 23498899 glucose 23499235 6-aryl-3-amino-thieno[2,3-b]pyridine 23499235 NO 23499235 nitric oxide 23499235 thienopyridine 23499661 Naltrexone 23499661 formalin 23499661 naloxonazine 23499661 naltrexone 23499716 [(131)I] iodinated fenofibrate 23499716 [(131)I] labeled fenofibrate 23499716 iodinated fenofibrate 23499716 radiolabeled fenofibrate 23499717 Fe3O4 23499717 carboxylic acid 23499717 doxorubicin 23499717 magnetite 23499717 nitroxide 23499717 triethylene glycol 23499718 PEG12 23499718 PEG40 23499751 Atrazine 23499751 S 23499751 atrazine 23499751 glutathione 23499751 superoxide 23499856 COOH 23499856 PEG 23499857 Thienopyridines 23499857 clopidogrel 23499857 clopidogrel carboxylate 23499857 ketoconazole 23499857 prasugrel 23499857 rutin 23499857 thienopyridines 23499857 ticlopidine 23499954 1,4-diazabicyclo[2.2.2]octane 23499954 DABCO 23499954 HBr 23499954 salpichrolides 23499954 steroids 23499954 vicinal dibromo D-homosteroid 23500040 metoprolol 23500058 sodium sulphate 23500491 AMPPNP 23500491 ATP 23500491 adenylyl imidodiphosphate 23500491 nucleotide 23500491 phosphate 23500545 3-hydroxy-3-methylglutaryl CoA 23500545 Cholesterol 23500545 Oxysterols 23500545 cholesterol 23500545 oxysterol 23500545 oxysterols 23500546 K(+) 23500546 LY294002 23500546 PD98059 23500546 SB203580 23500546 TRAM-34 23500546 calcium 23500659 Androgen 23500659 Estrogen 23500659 Testosterone 23500659 estrogen 23500659 testosterone 23500660 Iron 23500660 Vanadium 23500660 vanadium 23500769 O2 23500769 PUFA 23500769 PUFA n-3 23500769 PUFAs 23500769 cholesterol 23500769 peroxide 23500769 polyunsaturated fatty acids 23500769 thiobarbituric acid 23500775 anthraquinone 23500775 anthraquinones 23500776 EROD 23500776 PAH 23500776 PHH 23500776 benzo(a)pyrene 23500776 halogenated and polycyclic aromatic hydrocarbons 23500776 phenanthrene 23500776 polycyclic aromatic hydrocarbons 23500776 pyrene 23501111 (1)H 23501111 2-ferrocenyl-7-hydroxy-5-phenethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one 23501111 ferrocenylpyrazolo[1,5-a][1,4]diazepin-4-one 23501115 7,8-dehydrorutaecarpine 23501115 Trolox 23501115 curcumin 23503684 Ethanol 23503684 Naltrexone 23503684 alcohol 23503684 dopamine 23503684 ethanol 23503684 morphine 23503684 naltrexone 23503684 β-funaltrexamine 23503701 Lithium 23503701 lithium 23503702 Alcohol 23503702 alcohol 23504441 (E,Z)4-[3-(4-chlorophenyl)-3-(3-4dimethoxyphenyl) acryloyl] morpholine 23504441 Copper 23504441 Cu 23504441 Forum 23504441 copper 23504441 dimethomorph 23505123 Carbon 23505123 SDS 23505123 carbon 23505123 quartz 23505123 sodium dodecyl sulfate 23505224 Au 23505224 Carbon 23505224 Oxygen 23505224 Platinum 23505224 Pt 23505224 copper 23505224 oxygen 23505224 platinum 23505325 PPBs 23505325 phenyleneethynylene 23505325 poly(p-phenylenebutadiynylene) s 23505325 poly(pphenylenebutadiynylene) s 23505396 SDS 23505396 Tris(hydroxymethyl phosphine) 23505396 amino acid 23505396 sodium dodecyl sulfate polyacrylamide gel 23506042 ammonia 23506042 carbon 23506042 nitrogen 23506042 α-Ketoglutarate 23506042 α-ketoglutarate 23506042 αKG 23506253 acetonitrile 23506253 codonopyrrolidum A 23506253 codonopyrrolidum A, B 23506253 codonoside A 23506253 formic acid 23506253 n-butanol 23506316 carbon 23506316 diamond 23506316 silicon 23506316 silicon nitride 23506316 silicon-nitride 23506469 PBD 23506469 Poly(butadiene) 23506469 Thiol-ene 23506469 hydrocarbon 23506469 poly(butadiene) 23506469 thiol-ene 23506559 N2 23506559 glucose 23506559 phosphoric acid 23506857 MC-LR 23506857 ROOHs 23506857 glutathione 23506857 hydroperoxides 23506857 microcystin-LR 23506857 superoxide 23506857 α-tocopherol 23507752 11β-prostaglandin F2α 23507752 15(R)-prostaglandin F2α 23507752 8-iso prostaglandin F2α 23507752 8-iso-15(R)-prostaglandin F2α 23507752 8-iso-PGF2α-d4 23507752 DOX 23507752 Doxorubicin 23507752 Isoprostanes 23507752 TBHP 23507752 Tert-Butyl Hydroperoxide 23507752 arachidonic acid 23507752 doxorubicin 23507752 isoprostane 23507752 isoprostanes 23507752 tert-butyl hydroperoxide 23508306 Glucose 23508306 LPA 23508306 Lysophosphatidic acid 23508306 glucose 23508556 Alcohol 23508556 alcohol 23508963 Sialic Acid 23508963 sialic acid 23509956 N-acetyl-glucosamine 23510389 PAEA90-b-PDLLA40 23510389 PDLLA 23510389 lactic acid 23510389 poly(acrylamidoethylamine)90-block-poly(dl-lactide)40 23510441 Hydrogen Peroxide 23510441 oxygen 23510441 phosphate 23510441 selenide 23510441 selenium 23510441 selenone 23511020 4-substituted ureido-benzene-sulfonamides 23511020 acetazolamide 23511020 sulfamates 23511020 sulfamides 23511020 sulfonamides 23511348 polystyrene 23511715 ARS 23511715 DHA 23511715 artesunate 23511715 dihydroartemisinin 23511945 copper 23512126 Pt 23512126 Ti 23512126 TiO2 23512126 oxygen 23512495 Artemisinin 23512495 artemisinin 23512496 8-PN 23512496 8-prenylnaringenin 23512496 estrogen 23512496 prenylflavanones 23512499 2-deoxyglucose 23512499 Cardamonin 23512499 Glucose 23512499 Ser 23512499 cardamonin 23512499 glucose 23512499 rapamycin 23512501 NAD(P)H 23512501 Quinone 23512501 artemisinin 23512501 deoxyartemisinin 23512501 quinone 23512535 DOX 23512535 DOX-ω-3 FA 23512535 FAs 23512535 GSH 23512535 Glutathione 23512535 MDA 23512535 doxorubicin 23512535 glutathione 23512535 malondialdehyde 23512535 superoxide 23512535 ω-3 FA 23512535 ω-3 FAs 23512535 ω-3 fatty acids 23512537 BDP 23512537 Beclomethasone Dipropionate 23512537 beclomethasone dipropionate 23512538 2,3,7,8-tetrachlorodibenzo-p-dioxin 23512538 Aryl Hydrocarbon 23512538 PAH 23512538 TCDD 23512538 halogenated aromatic hydrocarbons 23512538 polycyclic aromatic hydrocarbons 23512538 zinc 23512732 (-)-epigallocatechin-3-gallate 23512732 EGCG 23512732 Epigallocatechin-3-Gallate 23512732 Sircol 23512732 catechin 23512732 nitroblue tetrazolium 23512732 oxygen 23512787 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 23512787 GSH 23512787 MPTP 23512787 Puerarin 23512787 dopamine 23512787 glutathione 23512787 oxygen 23512787 puerarin 23512804 C 23512804 N 23512804 amino acids 23512804 valine 23514279 H2O2 23514279 [Mn-(TDCPPS)Cl] 23514279 kaolinite 23514279 manganese(III) chloride 23514279 meso-tetra(2,6-dichloro-3-sulfonatophenyl)porphyrinate 23514442 (+)- and (-)-coniine 23514442 (+)-N-methylconiine 23514442 (-)-, (±)-, and (+)-N-methylconiine 23514442 (-)-N-methylconiine 23514442 (±)-N-methylconiine 23514442 N-Methylconiine 23514442 N-methylconiine 23514442 acetylcholine 23514442 coniine 23514442 piperidine alkaloids 23514442 γ-Coniceine 23514442 γ-coniceine 23514447 CZO 23514447 CeO2 23514447 CexZr1-xO2 23514447 KLE 23514447 Oxide 23514447 Oxygen 23514447 ZrO2 23514447 ceria-zirconia 23514447 oxygen 23514537 Cholesterol 23514537 DOPC 23514537 GM1 23514537 Ganglioside GM1 23514537 PSM 23514537 cholesterol 23514537 dioleoylphosphatidylcholine 23514537 ganglioside GM1 23514537 palmitoyl sphingomyelin 23514637 Methyl (3R)-Malonyl-(13S)-hydroxycheilanth-17-en-19-oate 23514637 Sesterterpene 23514637 cheilanthane 23514637 malonate half-ester 23514637 methyl ester 23514637 sesterterpene 23514973 CH3 23514973 Cl 23514973 MTT 23514973 Pd 23514973 Pd(II) 23514973 PdCl2(X2Py)2 23514973 PdCl2(XnPy)2 23514973 Pt 23514973 Py 23514973 mono- and disubstituted pyridines 23514973 palladium(II) 23514973 pyridine 23515287 3β-Diol 23515287 3β-diol 23515287 5α-Androstane-3β,17β-Diol 23515287 5α-androstane-3β,17β-diol 23515287 Androgen 23515287 Estrogen 23515287 Oxytocin 23515287 Testosterone 23515287 androgen 23515287 dihydrotestosterone 23515287 estradiol benzoate 23515287 estrogen 23515287 oxytocin 23515287 testosterone 23515498 Fe(2+) 23515498 MDA 23515498 ascorbate 23515498 malondialdehyde 23515498 vitamin E 23515940 Ca(2+) 23515940 Fluo3 23515940 Zearalenone 23515940 zearalenone 23515941 8-OHdG 23515941 N-acetyl-L-cysteine 23515941 NAC 23515941 OTA 23515941 Ochratoxin A 23515941 ochratoxin A 23515941 oxygen 23516041 adenosine triphosphophate 23517076 Gentamicin 23517076 Oxygen 23517076 gentamicin 23517076 oxygen 23517243 PTU 23517243 iodine 23517243 propylthiouracil 23517243 thyroid hormone 23517243 triiodothyronine 23517381 GdmCl 23517381 guanidinium chloride 23517381 urea 23517437 PAA 23517437 methacrylates 23517437 methacrylic 23517437 poly(acrylic acid) 23517437 polyacrylamide 23517437 pyrene 23517479 (E)-2-[(2S,3S)-3-ethyl-8-methoxy-1,2,3,4,6,7,12,12b-octahydroindolo[3,2-h]quinolizin-2-yl]-3-methoxyprop-2-enoic acid methyl ester 23517479 7-OH-MG 23517479 7-hydroxymitragynine 23517479 9-methoxy coryantheidine 23517479 mitragynine 23517479 morphine 23517479 naloxone 23517558 AMG 221 23517558 [(14)C] AMG 221 23517726 (1)H 23517726 (13)C 23517726 2-thiophenecarboxylic acid hydrazide 23517726 4-substituted-5-(2-thienyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones 23517726 Mannich bases 23517726 aminomethyl 23517726 ethanol 23517726 ethyl alcohol 23517726 formaldehyde 23517726 isothiocyanate 23517726 secondary amines 23517726 sodium hydroxide 23517726 thiosemicarbazides 23517726 triazole 23517728 7-oxyiminomethylcamptothecin 23517728 Platinum 23517728 SN38 23517728 camptothecin 23517728 camptothecins 23517728 cisplatin 23517728 diaminedichloro-platinum (II) 23517728 irinotecan 23517728 oxyiminomethyl 23517728 platinum 23517728 topotecan 23517784 1, 2-Dioleoyl-3-Trimethylammonium-Propane 23517784 Chol 23517784 DOTAP 23517784 cholesterol 23517784 silica 23517910 N-nitrosamines 23517910 nicotine 23518278 1 3,5-diaryl-1H-pyrazole 23518278 3,5-diaryl-1H-pyrazoles 23518278 N 23518278 arylamine 23518413 ATP 23518413 alanine 23518413 glucose 23518413 mitomycin C 23518413 ser 23518413 serine 23518662 n-alkane 23518662 n-alkanes 23518662 n-nonane 23518662 n-octane 23519365 Au 23519365 Au-Ag 23519365 Au-Au 23519392 Amprenavir 23519392 Pregnane 23519392 amprenavir 23519392 cholesterol 23519392 pregnane 23520133 glucose 23520133 sialic acid 23521080 4-PIOL 23521080 5-(4-piperidyl)-3-isoxazolol 23521080 TXA 23521080 lysine 23521080 tranexamic Acid 23521080 tranexamic acid 23521110 Scutellarin 23521110 hydrogen 23521110 scutellarin 23521132 ruthenium(II)tris(bipyridine) 23521132 tripeptide 23522834 dihydropteridinone 23523257 8-OHdG 23523257 THA 23523257 Tacrine 23523257 oxygen 23523257 tacrine 23523545 PLGA 23523545 Poly-lactide-co-glycolide 23523664 GLPG0492 23523664 NAND 23523664 PDN 23523664 androgen 23523664 nandrolone 23523664 steroids 23523664 α-methylprednisolone 23523665 ABTS 23523665 DBM 23523665 DBMs 23523665 Hydrogen peroxide 23523665 N 23523665 dibenzoylmethane 23523665 hydrogen peroxide 23523665 poly(ADP-ribose) 23523665 poly(ADP-ribosyl) 23523950 ATP 23523950 AVM 23523950 Avermectin 23523950 Ca(2+) 23523950 calcium 23523950 chloride 23523950 cyclosporine A 23523950 lactone 23523950 niflumic acid 23523950 pyrrolidine dithiocarbamic acid 23523950 rhodamine 123 23523950 trifluoperazine 23523950 verapamil 23523951 Gefitinib 23523951 gefitinib 23523951 poly (ADP-ribose) 23523951 tyrosine 23523965 BrdU 23523965 Copper 23523965 copper 23523965 oxygen 23524112 (R)-2-amino-1-butanol 23524112 acylthiourea 23524112 acylthioureas 23524112 thiourea 23524112 thioureas 23524112 urea 23524112 ureas 23524238 glutathione 23524238 oxysterols 23524253 P188 23524253 P407 23524253 poloxamers (P407 and P188) 23524255 hydroxyapatite 23524255 phosphate 23524316 N 23524316 cholesterol 23524316 glucose 23524316 quercetin 23524316 triglyceride 23524567 platinum 23524878 bilirubin 23524878 ferrous 23524878 iron 23524878 methanol 23524881 Methyl mercury 23524881 mercury 23525110 MgCl2 23525110 dNTP 23525110 dNTPs 23525110 nucleotide 23525158 4-acetamidophenol 23525158 C 23525158 CO 23525158 Cl(-) 23525158 PPy 23525158 PVP 23525158 Polyvinylpyrrolidone 23525158 Pt 23525158 ascorbic acid 23525158 chloride 23525158 glucose 23525158 methanol 23525158 oxygen 23525158 uric acid 23525221 GnRH 23525221 fatty acids 23525298 CdSe 23525298 CdTe 23525298 ZnS 23525298 lanthanide 23525512 (1)H 23525512 2,2,3,3-tetrafluoro-1,4-butanediol 23525512 HO 23525512 Polyurethane 23525512 diisocyanates 23525512 diols 23525512 diphenylmethane diisocyanate 23525512 isocyanate 23525512 polyester polyols 23525512 polyether 23525512 polyoxyethylene glycol 23525512 polyurethane 23525512 polyurethanes 23525512 tertiary amines 23525522 2-hydroxypropyl methacrylamide 23525522 HPMA 23525522 N, O-dimethacryloyl hydroxylamine 23525522 acrylic acid 23525522 hydroxyapatite 23525522 pHEMA 23525522 phosphate 23525522 poly(2-hydroxyethyl methacrylate) 23525522 β -TCP 23525522 β-tricalcium phosphate 23526664 Nicotinamide 23526664 Nicotinic Acid 23526664 Phosphate 23526664 niacin 23526664 niacinamide 23526664 nicotinamide 23526664 nicotinic acid 23526664 phosphorus 23526725 ICI182780 23526725 Manganese Superoxide 23526725 apigenin 23526725 coumestrol 23526725 daidzein 23526725 estrogen 23526725 genistein 23526725 glycitin 23526725 hydrogen peroxide 23526725 isoliquirtigenin 23526725 kaempferol 23526725 manganese superoxide 23526725 resveratrol 23527529 IPI-926 23527529 cyclopamine 23527529 midazolam 23527529 testosterone 23527615 (1)H 23527615 (13)C 23527615 2-oxo-prasugrel 23527615 CO 23527615 CPDH 23527615 Clopidogrel 23527615 H2O 23527615 Prasugrel 23527615 Thiolactone Sulfoxides 23527615 amine 23527615 amines 23527615 carbon 23527615 clopidogrel 23527615 cyclopentane-1,3-dione 23527615 dimedone 23527615 ethanolamine 23527615 prasugrel 23527615 sulfenic acid 23527615 tetrahydrothienopyridine 23527615 thiol 23527615 thiolactone 23527615 thiolactone sulfoxide 23527615 thiolactone sulfoxides 23527615 thiols 23527691 (18)O 23527691 LSC 23527691 La1-xSrxCoO3-δ 23527691 LaAlO3 23527691 Oxygen 23527691 SrTiO3 23527691 oxides 23527691 oxygen 23528045 2-pyridone 23528296 Arylpiperazines 23528296 arylpiperazine 23528296 fatty acid 23528296 triglyceride 23528298 Arg 23528298 Gln 23528298 H 23528298 Phe 23528298 SC-558 23528298 SO2NH2 23528298 benzenesulfonamide 23528298 celecoxib 23528298 cyclic imides 23528298 diclofenac 23528298 homosulfonamide 23528363 2,7-dichlorodihydrofluorescin diacetate 23528363 DCFH-DA 23528363 Glycyrrhizic acid 23528363 Glycyrrhizin 23528363 MDA 23528363 glycyrrhizic acid 23528363 malondialdehyde 23528363 oxygen 23528363 superoxide 23528363 triterpenoid saponin glycoside 23528740 CHOL-PEG2000 23528740 PEG 23528740 PEG2000 23528740 cholesterol 23528740 prednisolone 23528741 nystatin 23528741 polyene 23529824 Afinitor 23529824 Everolimus 23529824 Exemestane 23529824 anastrozole 23529824 everolimus 23529824 exemestane 23529824 letrozole 23529824 oestrogen 23529824 rapamycin 23529825 BELVIQ 23529825 Lorcaserin 23529825 lorcaserin 23529825 serotonin 23529900 PMMA 23529900 Si 23530003 glucose 23530006 Graphene 23530006 carbon 23530006 graphene 23530012 1,25-dihydroxyvitamin D 23530012 24,25-dihydroxyvitamin D 23530012 25(OH)D 23530012 25-hydroxyvitamin D 23530012 Vitamin D 23530012 calcium 23530012 vitamin D 23530031 CpG 23530031 purmorphamine 23530049 Dileucine 23530049 dileucine 23530596 PEG 23530596 arginine 23530596 aspartic acid 23530596 biotin 23530596 glycine 23530596 poly(ethylene glycol) 23530626 NO2 23530626 Ni(II) 23530626 Nickel(II) Dithiocarbamate 23530626 Nitrogen Dioxide 23530626 Sulforhodamine B 23530626 dithiocarbamate 23530626 nitrogen dioxide 23530626 sulforhodamine B 23530668 Fe 23530668 Magnetite 23530668 ferrihydrite 23530668 magnetite 23530668 phosphorus 23530747 ATP 23530747 Calcium 23530747 calcium 23530747 glycine 23530926 (1)H 23530926 Poly(ester-anhydride) 23530926 Ricinoleic Acid 23530926 fatty acid 23530926 p(SA-RA) 3:7 23530926 ricinoleic acid 23530959 Catechol 23530959 DOPA 23530959 L-DOPA 23530959 catechol 23531154 Met 23531154 TZD 23531154 metformin 23531154 sulphonylurea 23531154 thiazolidinedione 23531536 GSH 23531536 MDA 23531536 Malonaldehyde 23531536 NADPH 23531536 ascorbic acid 23531536 glutathione 23531536 lipoic acid 23531536 superoxide 23531536 vitamin C 23531536 vitamin E 23531536 α-Lipoic Acid 23531536 α-lipoic acid 23531554 glucose 23531554 oxygen 23531555 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide 23531555 MTT 23531555 MTT tetrazolium salt 23531555 P25 TiO2 23531555 TiO2 23531555 formazan 23531555 titania 23531555 titanium dioxide 23532002 P25 TiO2 23532002 Sn(ii) 23532002 TiO2 23532002 hydrogen 23532002 tin 23532057 [Pyrr][NO3] 23532057 aluminum 23532057 carbon 23532057 gamma butyrolactone 23532057 pyrrolidinium nitrate 23532057 γ-BL 23532258 MMF 23532258 everolimus 23532258 mycophenolate mofetil 23532258 sirolimus 23532258 streptozotocin 23532258 tacrolimus 23532634 DHEA 23532634 cortisol 23532634 creatinine 23532634 delta DHEA 23532634 delta cortisol 23532634 ΔCor 23532634 ΔDHEA 23532843 Trp 23532843 Tryptophan 23532843 alanine 23532843 glucose 23532843 tryptophan 23532849 Amino acid 23532849 S-Methylmethionine 23532849 S-adenosyl-[methyl-(3)H]methionine 23532849 S-adenosylmethionine 23532849 aflatoxin 23532849 amino acid 23532849 lovastatin 23532849 methionine 23532849 methyl 23532849 penicillin 23532918 Ca(2+) 23532918 Fluorescein 23532918 Ifenprodil 23532918 N-Methyl-D-aspartate 23532918 NMDA 23532918 [(3) H]ifenprodil 23532918 benzylic 23532918 calcium 23532918 fluorescein 23532918 ifenprodil 23532918 phenol 23532918 secondary amide 23532918 secondary amine or amide 23532940 BHQ-10 23534403 carbon 23534411 batzelladine K 23534411 chloroquine 23534411 methyl 23534411 nonyl 23534411 pentyl 23534411 tricyclic guanidine 23534530 Fe2O3 23534530 Polystyrene 23534530 polystyrene 23534553 PDMS 23534553 polydimethylsiloxane 23534553 silicon 23535327 7-O-p-cyanobenzoyl pyripyropene A 23535327 acyl-CoA 23535327 cholesterol 23535327 di-tert-butylsilylene acetal 23535327 pyripyropene A 23535337 NaCl 23535337 Proline 23535337 lysine 23535337 proline 23535337 sorbitol 23535338 fatty acids 23535338 polyenic fatty acids 23535338 sphingomyelin 23535348 5-HT 23535348 5-hydroxytryptamine 23535348 8-OH-DPAT 23535348 8-hydroxy-2-(di-n-propylamino) tetralin 23535348 GABA 23535348 muscimol 23535348 serotonin 23535348 γ-aminobutyric acid 23535349 olanzapine 23535349 quetiapine 23535349 risperidone 23535361 Iodide 23535361 Perchlorate 23535361 iodide 23535361 perchlorate 23535361 sodium iodide 23535361 thyroxine 23535361 triiodothyronine 23535363 Diisocyanate 23535363 diisocyanate 23535363 methacholine 23535364 2-Amino-3,4-dimethylimidazo[4,5-f]quinoline 23535364 2-Amino-9H-pyrido[2,3-b]indole 23535364 2-amino-3,4-dimethylimidazo[4,5-f]quinoline 23535364 MeIQ 23535364 deoxyguanosine 23535364 heterocyclic aromatic amine 23535393 amino acids 23535393 glycine 23535393 methionine 23535393 proline 23535393 taurine 23535393 threonine 23535828 bicyclic azasugars 23535828 carbasugars 23536264 creatinine 23536264 nitrogen 23536264 urea 23536314 Cilostazol 23536314 cilostazol 23536314 dUTP 23536316 Chrysin 23536316 chrysin 23536316 flavonoid 23536316 flavonoids 23536517 Tau 23536517 glutathione 23536517 malondialdehyde 23536517 sodium taurocholate 23536517 superoxide 23536517 taurine 23536518 DBP 23536518 di-butyl phthalate 23536518 omega-3 23536518 omega-3 fatty acids 23536518 omega-3 polyunsaturated fatty acids 23536518 phthalates 23536518 testosterone 23536519 Resveratrol 23536519 citrate 23536519 glucose 23536519 resveratrol 23536521 3-methyl-1-phenyl-2-(phenylseleno)oct-2-en-1-one 23536521 C21H2HOSe 23536521 NO 23536521 SH 23536521 Se 23536521 Selenium 23536521 adenosine 23536521 nitric oxide 23536521 organoselenium 23536521 selenium 23536521 sodium nitroprusside 23536521 sodium selenate 23536521 thiols 23536974 Cyanide 23536974 Isoamyl Nitrite 23536974 Isoamyl nitrite 23536974 NO 23536974 NaCN 23536974 Sodium Nitrite 23536974 cyanide 23536974 isoamyl alchol 23536974 isoamyl nitrite 23536974 nitrite 23536974 nitrites 23536974 sodium nitrite 23537005 2,2',4,4'-Tetrabromodiphenyl Ether 23537005 2,2',4,4'-tetrabromodiphenyl ether 23537005 2,4-dibromophenol 23537005 5-OH-BDE-47 23537005 5-hydroxy-2,2',4,4'-tetrabromodiphenyl ether 23537005 6-OH-BDE-47 23537005 6-hydroxy-2,2',4,4'-tetrabromodiphenyl ether 23537005 BDE-47 23537005 PBDE 23537005 PBDEs 23537005 Polybrominated diphenyl ethers 23537005 dihydroxy 23537005 monohydroxy 23537094 3',4'-dimethoxywogonin 23537094 4'-hydroxywogonin 23537094 Flavonoids 23537094 desmethylnobiletin 23537094 flavonoids 23537094 gardenin C 23537094 pectolinarigenin 23537094 xanthomicrol 23537160 (1)H 23537160 (13)C 23537160 flavonoids 23537160 kaempferol 23537160 mauritianin 23537160 methanol 23537160 triterpene glycoside 23537160 triterpene saponin 23537160 β-D-glucopyranosyl 3β-hydroxy-olean-12-en-28-oate 23537427 Br 23537427 Bromoform 23537427 C3H5ClO 23537427 CHBr2Cl 23537427 CHBr3 23537427 CHBrCl2 23537427 CHCl2Br 23537427 CHClBr2 23537427 Epichlorohydrin 23537427 OH 23537427 bromoform 23537427 epichlorohydrin 23537427 methanes 23537582 1-naphthol 23537582 1-pyrenol 23537582 1OH-BaP 23537582 3OH-BaP 23537582 4-n-NP 23537582 4-n-nonylphenol 23537582 4-tert-OP 23537582 4-tertoctylphenol 23537582 9-fluorenol 23537582 9-phenantrol 23537582 OH-PAHs 23537582 alkylphenols 23537598 ferulic, sinapinic and gallic acids 23537598 isorhamnetin 23537598 kaempferol 23537598 phenolic 23537598 rutin 23537701 THC 23537701 Tetrahydrocannabinol 23537701 tetrahydrocannabinol 23537702 rapamycin 23537702 retinoic acid) 23537746 Ze 450 23537749 ampicillin 23537749 beta-lactam 23537749 carbenicillin 23537749 cefazolin 23537749 ceftazidime 23537749 cefuroxime 23537749 meropenem 23537749 piperacillin 23537889 1-O-methylglucopyranoside 23537889 3-(N-sulfonylindolyl)-D-lactic acid 23537889 3-O-β-D-glucopyranosyl-β-sitosterol 23537889 5-O-β-D-glucopyranosyl-2-hydroxyphenylacetic acid 23537889 N-sulfonyl-L-tryptophan 23537889 dopamine 23537889 entadamide A 23537889 glutamate 23537889 homogentisic acid 23537889 indolamine 23537889 kynurenine 23537889 serotonin 23537889 tryptophan 23537889 tryptorheedei A 23537889 tryptorheedei B 23538035 GSH 23538035 MC-LR 23538035 MC-RR 23538035 arginine 23538035 cyclic heptapeptides 23538035 leucine 23538035 microcystin-RR 23538035 mycrocistins 23538162 Ginsenoside Rg1 23538162 ICI 82,780 23538162 RU486 23538162 Rg1 23538162 U0126 23538162 estrogen 23538162 ginsenoside Rg1 23538162 nitrogen 23538319 2,4-D 23538319 2,4-dichlorophenoxyacetic acid 23538319 glucose 23538319 lactate 23538397 4-aminothienopyrimidine 23538397 4-chlorothienopyrimidines 23538397 4-substituted phenylamino 23538397 4-thienopyrimidin-4-ones 23538397 Doxorubicin 23538397 N-alkyl thienopyrimidin-4-ones 23538397 hydrogen 23538397 thieno[3,2-d]pyrimidines 23538397 thienopyrimidoquinazolinones 23538844 Cadmium 23538844 cadmium 23538844 phosphate 23539089 Fe(2+) 23539089 ammonium thiocyanate 23539089 hydro peroxide 23539089 β-Carotene 23539089 β-carotene 23539147 Calcium 23539147 calcium 23539147 cholesterol 23539147 triglyceride 23539337 cinnamaldehyde 23539337 sanguinarine 23539337 totarol 23539337 viriditoxin 23539337 zantrin Z1 23540443 14C 23540443 3H-cholesteryl ester 23540443 3H-triglycerides 23540443 cholesterol 23540646 chalcones 23540646 coumarin 23540646 coumarins 23540646 α,β-unsaturated carbonyl 23540737 3-iodine 23540737 3-isopropyl 23540737 6-substituted-4-cycloalkyloxy-pyridin-2(1H)-ones 23540737 Nucleoside 23540737 Pyridinone 23540737 nucleoside 23540737 pyridinone 23540838 Maslinic Acid 23540838 Pentacyclic Triterpenoid 23540838 acetic acid 23540838 capsaicin 23540838 formalin 23540838 maslinic acid 23540838 pentacyclic triterpenoid 23541086 Abacavir 23541086 abacavir 23541086 glutaraldehyde 23541125 3,5-ditert-butylphenol 23541125 HC-030031 23541125 agathic acid 23541125 calcium 23541125 coniferaldehyde 23541125 ethanol 23541125 formaldehyde 23541125 glutathione 23541125 isocupressic acid 23541125 menthol 23541125 perinaphthenone 23541472 5-HIAA 23541472 5-HT 23541472 DOPAC 23541472 HVA 23541472 MHPG 23541472 amitraz 23541472 dopamine 23541472 monoamine 23541472 noradrenaline 23541472 serotonin 23541514 PEG 23541514 PEG400 23541514 PEG600 23541514 PEGs 23541514 PVP 23541514 Tibolone 23541647 5,10,15,20-tetrahydroxyphenylporphyrins 23541647 Bile acids 23541647 Cu(I) 23541647 Foscan 23541647 Porphyrins 23541647 bile acid 23541647 bile acid azides 23541647 bile acid porphyrin 23541647 chlorins 23541647 propargyl bromide 23541649 1-(7-Azabenzobicyclo[2.2.1]heptane)diazen-1-ium-1,2-diolate 23541649 7-azabenzobicyclo[2.2.1]heptane 23541649 HNO 23541649 NO 23541649 diazen-1-ium-1,2-diolate 23541649 nitric oxide 23541649 nitroxyl 23541668 DMPG 23541668 dimyristoylphosphatidylglycerol 23541668 m-phenylenediamine 23541668 metaphenylenediamine 23541668 ureas 23541672 Diclofenac 23541672 PEG 23541672 PEG-400 23541672 fluoro substituted pyrazoline 23541672 polyethylene glycol-400 23541672 pyrazole chalcones 23541674 BpyAla 23541674 NTA 23541674 Ni(2+) 23541674 amino acid 23541674 amino acids 23541674 bipyridylalanine 23541674 disulfide 23541674 histidine 23541674 nitrilotriacetic acid 23541929 poly-vinyl alcohol 23542080 DHPG 23542080 LY341495 23542080 dihydroxyphenylglycine 23542080 glutamate 23542114 ATO 23542114 Arsenic trioxide 23542114 arsenic trioxide 23542166 2-methyl 23542166 2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles 23542166 5-HT 23542166 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole 23542166 5-hydroxytryptamine 23542166 EMD386088 23542166 alkyl 23542166 benzenesulfonyl 23542166 bromo 23542166 chloro 23542166 fluoro 23542166 halogen 23542166 indole 23542166 serotonin 23542210 SLs 23542210 Sesquiterpene lactones 23542210 santonin 23542210 α-santonin 23542230 labetalol 23542230 methyldopa 23542343 Ala 23542343 C 23542343 Cys 23542343 Iron-Sulfur 23542343 Ser 23542343 [4Fe-4S](2+) 23542343 cysteine 23542343 iron 23542343 iron-sulfur 23542343 oxygen 23542494 CurDD 23542494 curcumin 23542494 curcumin didecanoate 23542494 reserpine 23542495 AlClPc 23542495 Chloroaluminium phthalocyanine 23542495 chloroaluminium phthalocyanine 23542495 poly(d,l-lactide) 23542495 poly(d,l-lactide-co-glycolide) 23542495 polyethylene glycol-block-poly(d,l-lactide) 23542815 ATO 23542815 Arsenic trioxide 23542815 As2O3 23542815 LY364947 23542815 MTT 23542816 PEs 23542816 phthalate 23542816 phthalate esters 23542817 GSH 23542817 MDA 23542817 glutathione 23542817 malondialdehyde 23542819 Fe(3+) 23542819 Mancozeb 23542819 ethylene bis-dithiocarbamate 23542819 iron 23542819 manganese 23542819 manganese/zinc ethylene bis-dithiocarbamate 23542819 potassium 23542819 sodium 23542819 zinc ethylene bis-dithiocarbamate 23543013 1-hydroxypyrene 23543013 BPDE 23543013 CpG 23543013 O(6)-methylguanine 23543013 PAH 23543013 PAHs 23543013 bisulfite 23543013 bleomycin 23543013 polycyclic aromatic hydrocarbon 23543013 polycyclic aromatic hydrocarbons 23543426 creatine 23543426 creatinine 23543426 glutamate 23543426 oxalacetate 23543426 pyruvate 23543630 5,7-dihydroxy-6-methoxy-2(4-phenoxyphenyl)-4H-chromene-4-one 23543630 Cl(-) 23543630 DMPC 23543630 MK-801 23543630 N-methyl-D-aspartate 23543630 muscimol 23543630 oroxylin A 23543630 scopolamine 23543630 γ-aminobutyric acid 23543631 NO 23543631 PGE(2) 23543631 Tryptanthrin 23543631 indoloquinazoline alkaloid 23543631 tryptanthrin 23543632 (3,4-dihydro-2H-pyran-2-yl)methanol 23543632 (E/Z)-Goniothalamin 23543632 (Z)-Goniothalamin 23543632 5-(hydroxymethyl)dihydrofuran-2(3H)-one 23543632 Goniothalamin 23543632 lactones 23543632 naphthalene 23543632 phenyl 23543632 pyridine 23543737 ATP 23543737 Calcium 23543737 Glutamate 23543737 N 23543737 calcium 23543737 glutamate 23543864 2-decanone 23543864 2-heptanone 23543864 2-hexanone 23543864 2-nonanone 23543864 2-octanone 23543864 2-pentanone 23543864 Acetate 23543864 Ketone 23543864 Ketones 23543864 ketone 23543864 ketones 23543864 n-alkyl acetate 23543864 n-alkyl acetates 23543864 n-alkyl ketone 23543864 tetrabutylammonium trifluoromethanesulfonate 23544432 2-(Acylamino)thiophene 23544432 2-(acylamino)thiophene 23544432 BHF177 23544432 COR627 23544432 COR628 23544432 GABA 23544432 GS39783 23544432 baclofen 23544459 butenolides 23544459 γ,γ- disubstituted butenolides 23544459 γ,γ-disubstituted butenolides 23544459 γ-Butenolides 23544459 γ-butenolide 23544459 γ-butenolides 23544459 γ-tertiary and quaternary carbon 23544461 H 23544461 Organophosphorus 23544461 P(O)-H 23544461 Transition metal 23544461 carbon 23544461 organophosphorus 23544461 transition metal 23544465 benzopyrans 23544465 furans 23544465 indolines 23544465 isoxazoles 23544465 organoselenium 23544465 oxadiazoles 23544465 pyrimidines 23544465 pyrrolines 23544465 selenium 23544465 triazoles 23544613 1,8-diaminooctane 23544613 diethyl sebacate 23544613 dimethyl terephthalate 23544613 oligo(octamethylene terephthalamide) 23544613 oligo(p-xylylene sebacamide) 23544613 p-xylylenediamine 23544615 polystyrene 23545109 carboxylates 23545109 hydroxamic acids 23545456 gentamycin 23545456 methicillin 23545456 plumbagin 23545568 3Co1 23545568 3Mn1 23545568 3O2 23545568 Li1.05Mn1.95O4 23545568 LiFePO4 23545568 LiNi1 23545568 lithium 23545721 MTX 23545721 Mitoxantrone 23545721 glutathione 23545721 mitoxantrone 23545721 monocarboxylic acid 23545721 naphtoquinoxaline 23546010 gypsophin A-F 23546397 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide 23546397 GSH 23546397 chloroform 23546397 ethanol 23546397 ethyl acetate 23546397 glutathione 23546397 neutral red 23546397 oxygen 23546397 petroleum ether 23546398 Ag 23546398 citrate 23546398 polyethylene glycol 23546398 silver 23546603 DES 23546603 androgen 23546603 androgens 23546603 diethylstilbestrol 23546603 estrogen 23546603 estrogens 23546603 testosterone propionate 23547762 BDS 23547762 Budesonide 23547762 C=O 23547762 HP-β-CD 23547762 Na 23547762 budesonide 23547762 carbonyl 23547762 carboxyl 23547762 hydroxypropyl-β-cyclodextrin 23547762 sodium 23547810 5-HT 23547810 Serotonin 23547810 Tryptophan 23547810 serotonin 23547810 tryptophan 23547844 H2S 23547844 Hydrogen Sulfide 23547844 Hydrogen sulfide 23547844 perthiol 23547844 thiol 23547884 Indotertine B 23547884 Isoprenoids 23547884 N-C(O) 23547884 drimentine C 23547884 drimentine H 23547884 indotertine B 23547884 isoprenoids 23548027 fatty acid 23548055 2,2,2-trifluorodiazoethanes 23548055 Benzamides 23548055 C-H 23548055 Diazo 23548055 O-pivaloyl benzhydroxamic acids 23548055 Rh(III) 23548055 benzhydroxamic acids 23548055 diazo 23548055 isoindolones 23548055 γ-Lactams 23548165 N 23548165 Pazopanib 23548165 Votrient 23548165 [(14)C]pazopanib 23548165 pazopanib 23548165 tyrosine 23548584 MDA 23548584 PRZ 23548584 alanine 23548584 aldehyde 23548584 aspartate 23548584 glutathione 23548584 malondialdehyde 23548584 pyrazole 23548584 superoxide 23548704 quinolone 23548704 thiazolidin-4-ones 23549272 cysteine 23549272 glutathione 23549272 methionine 23549272 thiol 23549272 thiol glutathione 23549272 thiols 23549272 tripeptide 23549985 Asp 23549985 KSCN 23549985 Met 23549985 Pro 23549985 SCN 23549985 SCN(-) 23549985 Ser 23549985 amino acids 23549985 ascorbate 23549985 asparagine 23549985 chlorophyll 23549985 methionine 23549985 potassium thiocyanate 23549985 proline 23549985 serine 23549985 superoxide 23549985 thiocyanate 23550028 2-Hydroxy-3-methylanthraquinone 23550028 2-hydroxy-3-methylanthraquinone 23550028 PD98059 23550028 SB203580 23550028 anthraquinones 23550937 ATP 23550937 Curcumin 23550937 Monocarbonyl Curcumin 23550937 Ser 23550937 Thr 23550937 curcumin 23550966 Triterpenoids 23550966 carinatins A-H 23550966 cycloartane triterpenoids 23550966 dikamaliartane D 23550966 secaubryolide 23551063 7-hydroxy-4-trifluoromethylcoumarin 23551063 HFC 23551063 UDP 23551063 glucuronic acid 23551255 1,2-Dichloroethane 23551255 1,2-dichloroethane 23551255 BTPPA(+) 23551255 BTPPATPFB 23551255 Cs(+) 23551255 CsCl 23551255 Li(+) 23551255 LiCl 23551255 Na(+) 23551255 NaCl 23551255 Rb(+) 23551255 RbCl 23551255 TPFB(-) 23551255 alkali-metal 23551255 alkali-metal chlorides 23551255 bis(triphenylphosphor anylidene) ammonium tetrakis(pentafluorophenyl)borate 23551295 Ar 23551295 Boron Nitride 23551295 Rh 23551295 Rh(111) 23551295 argon 23551295 boron nitride 23551295 graphene 23551295 h-BN 23551295 neon 23551295 noble gases 23551295 ruthenium 23551329 DEX 23551329 Dexamethasone 23551329 corticosterone 23551329 dexamethasone 23551329 poly (ADP-ribose) 23552260 Cisplatin 23552260 cisplatin 23552260 creatinine 23552260 nitrogen 23552260 urea 23552263 ethyl acetate 23552263 flavonoids 23552263 n-butanol 23552263 phenols 23552263 saponins 23552263 tannins 23552263 terpenoids 23552267 Zn 23552267 cadmium 23552267 calcium 23552267 lithium 23552267 magnesium 23552267 manganese 23552267 sodium 23552267 zinc 23552269 Rocuronium 23552269 Sugammadex 23552269 rocuronium 23552269 sodium chloride 23552269 sugammadex 23552831 NDI 23552831 flavin 23552831 naphthalenediimide 23553331 FXeOXeF 23553331 HXeOXeF 23553331 HXeOXeH 23553331 Xe 23553357 sitagliptin 23553497 tenofovir 23553497 vitamin D 23553739 Graphene 23553739 graphene 23553772 Trialkylgermyl 23553797 propranolol 23554428 R,S-lorazepam 23554428 R- and S- Lorazepam 23554428 R- and S- lorazepam 23554428 R- and S-lorazepam 23554428 R-lorazepam 23554428 UDP 23554428 codeine 23554428 fluconazole 23554428 glucuronic acid 23554428 ketamine 23554428 ketoconazole 23554428 lorazepam 23554428 methadone 23554428 morphine 23554428 valproic acid 23554428 zidovudine 23556334 Posaconazole-d4 23556334 acetonitrile 23556334 formic acid 23556334 posaconazole 23556338 apigenin 23556338 flavonoids 23556338 luteolin 23556998 PAMAM 23556998 SDS 23556998 poly(amidoamine) 23556998 silica 23556998 sodium dodecyl sulfate 23557027 C8E4 23557027 DTAB 23557027 Pluronic (P-123) 23557027 SDS 23557027 dodecyltrimethylammonium bromide 23557027 sodium dodecyl sulfate 23557027 sodium lauryl sulfate 23557027 tetraethylene glycol monooctyl ether 23557230 CH3 23557230 COOH 23557230 NH2 23557230 OH 23557230 SH 23557230 l-Cystine 23557230 l-cystine 23557230 sulfur 23557687 17β-estradiol 23557687 BPA 23557687 bisphenol A 23557688 organophosphate 23557688 ornithine 23557843 DFZ 23557843 Deflazacort 23557843 corticosteroids 23557843 methanol 23557843 prednisolone 23558232 Rhodamine 23558232 TSA 23558232 Trichostatin A 23558232 calcium 23558232 cisplatin 23558232 phalloidin 23558232 trichostatin A 23558237 JNJ7777120 23558237 PF-3893787 23558237 histamine 23558237 pyrido[3,2-d]pyrimidine 23558237 pyrido[3,2-d]pyrimidines 23558237 quinazoline 23558295 Calcein AM 23558295 DMSO 23558295 Phorbol-12-myristate-13-acetate 23558295 TPA 23558295 acetoxymethyl 23558295 dimethyl sulfoxide 23558297 Vinclozolin 23558297 androgen 23558297 androgens 23558297 flutamide 23558297 steroid 23558297 vinclozolin 23559222 3-methoxy-4-hydroxyphenylglycol 23559222 HVA 23559222 MHPG 23559222 Norepinephrine 23559222 VMA 23559222 Yohimbine 23559222 catecholamine 23559222 dopamine 23559222 homovanillic acid 23559222 norepinephrine 23559222 vanillylmandelic acid 23559222 yohimbine 23559258 Li 23559258 Li4+xTi5O12 23559258 Li4Ti5O12 23559258 LiPF6 23559258 LixC6 23559258 LixFePO4 23559517 Fe(C10 H15 )2 23559517 I(-) 23559517 I3 (-) 23559517 [Fe(C10 H15 )2 ](+) 23560391 PDMAEMA 23560391 PDMAEMAs 23560391 Poly(2-(dimethylamino)ethyl methacrylate) 23560391 poly(2-(dimethylamino)ethyl methacrylate) 23560438 NO 23560438 Nitric Oxide 23560438 PVA 23560438 Poly(vinyl alcohol) 23560438 nitric oxide 23560438 poly(vinyl alcohol) 23560442 TiO2 23560447 Graphene 23560447 graphene 23560447 silicon 23560504 CdSe 23560571 Au 23560571 Au(3+) 23560571 GSH 23560571 HCl 23560571 MPG 23560571 N-(2-mercapto-propionyl) glycine 23560571 Ti 23560571 Titanium 23560571 glutathione 23560571 thiol 23560571 thiolate 23561071 alcohol 23561071 benzene 23561071 carbohydrate 23561071 ethanol 23561071 galacturonic acid 23561071 hydrochloric acid 23561071 isopropanol 23561080 aspartame 23561081 4-nitrophenyl β-d-glucuronide 23561081 daidzin 23561081 genistin 23561081 isoflavone 23561081 isoflavone aglycones 23561081 isoflavone glycosides 23561082 1,1-diphenyl-2-picrylhydrazyl 23561082 DPPH 23561082 coumarins 23561082 ethyl acetate 23561082 glabranin 23561082 lignan 23561082 linoleic acid 23561082 methanol 23561082 pyranocoumarin 23561082 scopoletin 23561082 sesamin 23561082 umbelliferone 23561082 β-carotene 23561085 Phenolic 23561085 Polyphenol 23561085 amino acid 23561085 nucleotide 23561085 phenolic 23561085 phenolics 23561085 polyphenol 23561092 ethanol 23561092 fatty acids 23561092 linoleic 23561092 methanol 23561092 oleic 23561095 stearin 23561095 stearins 23561095 triacylglycerol 23561096 HCl 23561096 PAs 23561096 bile salts 23561096 flavan-3-ols 23561096 proanthocyanidins 23561098 calcium 23561100 GSH 23561100 Hesperidin 23561100 alcohol 23561100 ethanol 23561100 flavonoids 23561100 malondialdehyde 23561100 narirutin 23561102 1-octanol 23561102 Carbon 23561102 carbamate 23561102 carbon 23561106 MQCA 23561106 QCA 23561106 diethylaminoethylmethacrylate 23561106 ethylene glycol dimethacrylate 23561106 methyl-3-quinoxaline-2-carboxylic acid 23561106 quinoxaline-1,4-dioxides 23561106 quinoxaline-2-carboxylic acid 23561106 tetrahydrofuran 23561114 THC 23561114 Tetrahydrocurcumin 23561114 alanine 23561114 amino acid 23561114 amino acids 23561114 curcumin 23561114 glycine 23561114 isoleucine 23561114 leucine 23561114 phenolic 23561114 phenylalanine 23561114 proline 23561114 tetrahydrocurcumin 23561114 valine 23561115 oleanolic acid 23561115 triterpenoids 23561115 ursanic, oleanic and lupanic pentacyclic triterpenoids 23561115 ursolic acid 23561115 β-damascone 23561117 DPPH 23561117 SDS 23561117 amide 23561117 fructose 23561117 glucose 23561117 lactose 23561117 maltose 23561117 sucrose 23561117 xylose 23561118 ethanol 23561118 ferulic acid 23561118 flavonoid 23561118 oxygen 23561118 phenolic 23561118 poly (ADP-ribose) 23561118 polyphenolics 23561118 quercetin 23561119 Ang II 23561119 Angiotensin II 23561119 Ca(2+) 23561119 angiotensin II 23561119 ethyl acetate 23561119 oxygen 23561123 C16:0 23561123 C18:0 23561123 C18:1n9 23561123 C18:2n6 23561123 C18:3n3 23561123 carbon 23561123 docosahexaenoic acid 23561123 eicosapentaenoic acid 23561123 fatty acid 23561123 fatty acids 23561123 polyunsaturated fatty acids 23561123 saturated fatty acids 23561123 triglycerides 23561123 unsaturated fatty acids 23561125 copper 23561125 iron 23561125 selenium 23561125 sodium chloride 23561127 Avenanthramide 23561127 avenanthramides 23561127 oxygen 23561127 tocols 23561127 vitamin E 23561136 caffeic acid 23561136 chlorogenic acid 23561136 ferulic acid 23561136 ferulic acids 23561136 flavonoid 23561136 flavonoids 23561136 luteolin 7-O-6'malonylglucoside 23561136 luteolin 7-O-malonylglucoside 23561136 myricetin 3-O-galactoside 23561136 naringenin tri glycoside 23561136 ortho- and para-coumaric acids 23561136 p-coumaric acid 23561136 p-hydroxybenzoic acid 23561136 phenolic 23561136 phenolic acids 23561136 protocatechuic acid 23561136 quercetin 3'-O-galactoside 23561136 quercetin 3'-O-glucoside 23561136 quercetin 3'-O-malonylglucoside 23561136 quercetin 3'-O-pentosylhexoside 23561136 quercetin 3'-O-rhamnoside 23561136 quercetin 3-O-6'malonylglucoside 23561136 quercetin 3-O-robinobioside 23561136 quercetin 3-O-rutinoside 23561136 vanillic acid 23561136 vanillin 23561142 carbohydrate 23561142 phenolics 23561142 sodium 23561143 fatty acid 23561143 monounsaturated fatty acids 23561143 omega-3 fatty acids 23561143 α-tocopherol 23561146 DPPH 23561146 Ethyl acetate 23561146 caffeic acid 23561146 chlorogenic acid 23561146 ethanol 23561146 ethyl acetate 23561146 ferulic acid 23561146 flavonoids 23561146 geniposidic acid 23561146 isoquercitrin 23561146 methanol 23561146 n-butanol 23561146 petroleum ether 23561146 quercetin-3-O-sambubioside 23561146 rutin 23561148 ABTS 23561148 Cyanidin 3-glucoside 23561148 DPPH 23561148 Ellagic acid 23561148 ellagic acid 23561148 flavonol 23561148 myricetin 23561148 phenolics 23561148 polyphenols 23561148 proanthocyanidins 23561148 quercetin 23561148 vitamin C 23561150 SDS 23561150 sodium chloride 23561154 Amino acid 23561154 NaCl 23561154 SDS 23561154 acidic amino acids 23561154 arginine 23561154 lysine 23561154 tryptophan 23561154 tyrosine 23561155 (13)C 23561155 (13)C-glucose 23561155 (13)C-lycopene 23561155 acetone 23561155 glucose 23561155 hexane 23561155 lycopene 23561156 polyphenols 23561156 sucrose 23561160 2,4-di-tert-butylphenol 23561160 Aldehydes 23561160 CO2 23561160 PET 23561160 Sb 23561160 acetaldehyde 23561160 antimony 23561160 bis(2-hydroxyethyl)terephthalate 23561160 formaldehyde 23561160 phenolic 23561160 phthalates 23561160 polyethylene terephthalate 23561163 5-hydroxymethylfurfural 23561163 alcohols 23561163 aldehydes 23561163 coniferaldehyde 23561163 esters 23561163 ethanol 23561163 furfural 23561163 gallic, vanilic and syringic acids 23561163 methanol 23561163 sinapaldehyde 23561163 siringaldehyde 23561163 sugar 23561163 syringaldehyde 23561163 vanilic acid 23561163 vanillin 23561166 Fisetin 23561166 fisetin 23561166 glucose 23561166 triglyceride 23561170 ferric 23561170 phloroglucinol 23561170 polyphenol 23561172 dry-ice 23561174 13(2) OH chl a 23561174 15(1) OH lactone chl a 23561174 2,4-DCP 23561174 2,4-dichlorophenol 23561174 Chl 23561174 H2O2 23561174 chl a 23561174 chlorophyll 23561174 chlorophyll a 23561175 fatty acids 23561175 feruloyl-sucrose 23561175 linoleic acid 23561175 phenolic 23561175 sinapoyl-diglycoside 23561179 BHT 23561179 butylated hydroxytoluene 23561179 linoleic acid 23561181 amino acid 23561181 amino acids 23561181 dipeptide 23561181 glucose 23561181 l-isoleucine 23561181 l-isoleucyl-l-leucine dipeptide 23561181 l-leucine 23561181 l-leucyl-l-isoleucine 23561181 l-leucyl-l-isoleucine dipeptide 23561182 2,2-diphenyl-picrylhydrazyl 23561182 CCl4 23561182 DPPH 23561182 Friedelin 23561182 GSH 23561182 friedelin 23561182 glutamate 23561182 glutathione 23561182 hydroxyl 23561182 lactate 23561182 nitric oxide 23561182 oxaloacetate 23561182 pyruvate 23561182 reduced glutathione 23561182 superoxide 23561184 (Methyl)selenocysteine 23561184 Se 23561184 SeMet 23561184 Selenium 23561184 Selenocystine 23561184 oxidized selenium methionine 23561184 selenate 23561184 selenite 23561184 selenium 23561184 selenium methionine 23561184 selenocystine 23561187 anthocyanin 23561187 anthocyanins 23561189 3,3',4',5,5',7-hexahydroxyflavone 23561189 Myricetin 23561189 bioflavonoids 23561189 myricetin 23561195 phenol 23561196 4-methylguaiacol 23561196 PAH 23561196 Polycyclic aromatic hydrocarbons 23561196 eugenol 23561196 guaiacol 23561196 phenolic 23561196 polycyclic aromatic hydrocarbons 23561196 syringol 23561196 trans-isoeugenol 23561204 2-AA 23561204 2-aminoanthracene 23561204 4-NQO 23561204 4-nitroquinoline-N-oxide 23561204 NO 23561204 chlorogenic acid 23561204 kaempferol 23561204 luteolin 23561204 phenolic 23561204 quercetin 23561204 rutin 23561209 benzaldehyde 23561209 benzoic acid 23561209 ethyl vanillate 23561209 guaiacol 23561209 isoamyl alcohols 23561209 phenolic 23561209 sugar 23561211 NO 23561211 dichloromethane 23561211 flavonoids 23561211 hexane 23561211 saponins 23561211 sterols 23561211 triterpenes 23561212 calcium 23561212 calcium chloride 23561212 carbohydrate 23561212 sodium 23561214 desferoxamine 23561214 β-carotene 23561214 α-tocopherol 23561219 Phosphatidylcholine 23561219 phosphatidylethanolamine 23561219 phosphatidylinositol 23561220 pyruvate 23561220 sodium sulphate 23561223 ACN 23561223 Anthocyanin 23561223 anthocyanin 23561223 anthocyanin phenolics 23561223 anthocyanins 23561223 cyanidin 23561223 delphinidin glycosides 23561223 phenolic 23562056 cis-cyclopropane 23562056 cyclopropane 23562056 ethylene 23562056 isocytosine 23562060 ACh 23562060 ML129 23562060 ML172 23562060 ML326 23562060 VU0467903 23562060 isatin 23562060 phenethyl ether 23562063 (S)-3-[4-(1-{3,5-dimethyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}butyl)benzamido]propanoic acid 23562063 glucose 23562072 cholesterol 23562365 EVn-50 23562365 Evn-50 23562365 Lignans 23562365 Ser 23562365 Tyr 23562365 VB1 23562365 lignan 23562376 H(+) 23562376 MPP(+) 23562376 metformin 23562496 2-Hydroxychalcone 23562496 2-hydroxychalcone 23562496 4-methoxychalcone 23562496 Chalcone 23562496 Chalcones 23562496 Neohesperidin dihydrochalcone 23562496 Xanthohumol 23562496 chalcone 23562496 chalcones 23562496 estrogen 23562496 flavonoids 23562496 hesperidin methylchalcone 23562496 progesterone 23562496 xanthohumol 23562534 ITZ 23562534 OH 23562534 OH-ITZ 23562534 Soluplus 23562534 Sporanox 23562534 itraconazole 23562630 Ach 23562630 N-methyl-d-aspartate 23562630 acetylcholine 23562630 asiaticoside 23562630 calcium 23562630 phospho 23562637 PEI 23562637 disulfide 23562637 poly(ethylenimine) 23562637 polyethylenimine 23562637 sodium 23562926 Aconitine 23562926 Cyclosporin A 23562926 Glucose 23562926 MK-571 23562926 Na(+) 23562926 aconitine 23562926 glucose 23562926 sodium 23562926 verapamil 23563104 hydroxypropyl 23563104 lactose 23563248 cAMP 23563248 forskolin 23563672 thyroxine 23563672 triiodothyronine 23563730 PDMS 23563730 polydimethylsiloxane 23563730 sulfobetaine 23564369 TCS 23564369 triclosan 23564596 18F-FDG 23564596 18F-fluorodeoxiglucose 23564596 FDG 23564596 sorafenib 23564645 rifampicin 23564882 epoxide 23564882 epoxides 23564882 polycyclic aromatic hydrocarbons 23564914 Glucose 23564914 Glutamine 23564914 glucose 23564914 glutamine 23564917 CHO 23564917 Carbohydrate 23564917 carbohydrates 23564921 glucose 23564921 sodium 23564921 thiazolidinediones 23565325 hydroxamates 23565644 carbamazepine 23565644 clozapine 23565644 cysteine 23565644 diclofenac 23565644 glutathione 23565644 ketoconazole 23565644 olanzapine 23565644 troglitazone 23565644 voriconazole 23565654 Carbon 23565654 carbon 23565720 diamond 23565720 nitrogen 23565755 androgen 23565759 carbohydrate 23566035 Au 23566035 Palladium 23566035 Pd 23566035 aldehydes 23566035 aromatic alcohols 23566035 benzylamine 23566035 ketones 23566035 palladium 23566035 phenol 23566035 transition metal 23566056 Acetic Acid 23566056 Acetic acid 23566056 Curcumin 23566056 MDA 23566056 N 23566056 acetic acid 23566056 curcumin 23566056 malondialdehyde 23566058 PGE2 23566058 phenolic 23566058 prostaglandin E2 23566058 prostaglandin e2 23566060 Enterolactone 23566060 enterodiol 23566060 enterolactone 23566060 enterolignans 23566060 lignan 23566060 lignans 23566515 2-amino-3-carboxy-4-phenylthiophene 23566515 2-amino-3-carboxy-4-phenylthiophenes 23566515 phenylthiophene 23566515 retinal 23566520 amide 23566520 lomefloxacin 23566884 LY294002 23566884 Tomatidine 23566884 U0126 23566884 cysteine 23566884 pyrrolidine dithiocarbamate 23566884 tomatidine 23566884 tomatine 23567030 DPPH 23567030 SH 23567030 flavonoids 23567030 glucose 23567030 iron 23567030 kaempferol-3-O-(2-rhamnosyl) rutinoside 23567030 kaempferol-3-O-rutinoside 23567030 phenolic 23567030 polyphenols 23567030 quercetin-3-O-(2-rhamnosyl) rutinoside 23567030 quercetin-3-O-rutinoside 23567032 carbohydrate 23567032 ethanol 23567032 glucose 23567032 streptozotocin 23567035 anthraquinones 23567035 ethanol 23567035 flavonoids 23567035 saponins 23567035 tannins 23567039 MC-RY 23567039 Microcystin-YR (2), -RR (3), and -RY (9) 23567039 Microcystins 23567039 Thiol 23567039 cyclic heptapeptides 23567039 microcystin 23567039 microcystin-RY, -RL and -RA 23567039 microcystins 23567039 thiol 23567039 α,β-unsaturated amide 23567043 DEA 23567043 DEtA 23567043 LOX 23567043 LOX-TEtA 23567043 N-(2'-hydroxy-ethanol)-piperdine 23567043 TEA 23567043 TEF 23567043 TEF-TEtA 23567043 TEtA 23567043 acetic acid 23567043 amine salts 23567043 amines 23567043 diethanolamine 23567043 diethylamine 23567043 lornoxicam 23567043 organic amines 23567043 teriflunomide 23567043 triethanolamine 23567043 triethylamine 23567245 NO 23567245 nitric oxide 23567245 nitrotyrosine 23567245 polyphenols 23567316 Rotenone 23567316 [(3)H]dopamine 23567316 dopamine 23567316 rotenone 23567484 1,2-dilinolenoyl-sn-glycero-3-phosphocholine 23567484 DLPC 23567484 Sugar 23567484 ferrous 23567484 sucrose 23567484 sugar 23567484 sugars 23567490 5-FU 23567490 5-fluorouracil 23567948 Hoechst 33258 23567948 MTT 23567948 [Ru(bpy)2(addppn)](ClO4)2 23567948 [Ru(dmb)2(addppn)](ClO4)2 23567948 ruthenium(II) 23567953 1,3,4-trisubstituted pyrazoles 23567953 phenylbutazone 23567956 2- and 3-indolyl carbohydrazides 23567956 2-indolyl carbohydrazides 23567956 3-(1H-indol-3-yl)propanehydrazide 23567956 3-(3-hydrazinylpropyl)-1H-indole 23567956 3-indolyl carbohydrazide 23567956 DMSO 23567956 DPPH 23567956 JL317 23567956 JL34 23567956 JL344 23567956 JL40 23567956 JL418 23567956 JL432 23567956 JL436 23567956 JL71 23567956 JL72 23567956 JL87 23567956 hydroxyl 23567956 indolyl carbohydrazides 23567956 oxygen 23567963 4,4'-[1,12-dodecanediyl(oxy)]bisbenzaldehyde 23567963 bisbenzaldehydes 23567963 neutral red 23568452 methyl 23568452 silicon 23568554 Cyclic AMP 23568554 cyclic AMP 23568554 glucose 23568566 Au 23568627 Chlorogenic Acid 23568627 chlorogenic acid 23568627 glutathione 23568627 silver sulfadiazine 23568627 superoxide 23568773 N 23568773 SB202190 23568773 Thr 23569176 O 23569176 catechol 23569204 N 23569204 histidine 23569204 phospho 23569204 phospho-serine 23569204 phospho-tyrosine 23570232 Adenine 23570232 DB[a,l]P 23570232 Dibenzo[a,l]pyrene 23570232 Guanine 23570232 Nucleotide 23570232 adenine 23570232 dibenzo[a,l]pyrene 23570232 diol epoxides 23570232 guanine 23570232 nucleotide 23570237 Hydrocarbon Radicals and Biradicals 23570237 methylene 23570237 peroxy 23570261 Ir(111) 23570261 Xe 23570261 graphene 23570261 ir(111) 23570284 sorbate 23570284 zeolite 23570284 zeolite L 23570347 Ag 23570347 Silver 23570467 thiopurine 23570469 lithium 23570612 acetone 23570612 acetonitrile 23570612 coronene 23570612 dichloromethane 23570612 ethanol 23570612 ethyl acetate 23570612 graphene 23570612 hexane 23570612 toluene 23570689 formaldehyde 23570790 TSG-8-1 23570790 amide 23570790 amino acid 23570997 GSH 23570997 MDA 23570997 NO 23570997 Pyranocycloartobiloxanthone A 23570997 SH 23570997 ethanol 23570997 glutathione 23570997 malondialdehyde 23570997 nitric oxide 23570997 sulfhydryl 23570997 xanthone 23571493 Na+ 23571493 Potassium 23571495 Sphingomyelin 23571495 cholesterol 23571495 sphingolipid 23571495 sphingomyelin 23571664 PVA 23571664 graphene 23571664 hydroiodic acid 23571664 poly(vinyl alcohol) 23571753 nucleotides 23572389 calcium 23572390 MDA 23572390 malondialdehyde 23572390 super oxide 23572392 aromatic amines and aromatic or hetero-aromatic aldehydes 23572392 bismuth triflate 23572392 bismuth(III) triflate 23572392 cyclohexanone 23572392 β-aminoketone 23572392 β-aminoketones 23572394 2,3,7,8-tetrachlorodibenzo-p-dioxin 23572394 2,3,7,8-tetrachlorodibenzo-pdioxin 23572394 H2O2 23572394 Hydrogen peroxide 23572394 S 23572394 TCDD 23572394 carbonyl 23572394 glutathione 23572394 lycopene 23572394 thiol 23572394 toluene 23572394 uridine 5'-diphospho 23572405 glucose 23572407 nicotine 23572408 Sorafenib 23572408 axitinib 23572408 everolimus 23572408 pazopanib 23572408 rapamycin 23572408 sorafenib 23572408 sunitinib 23572408 temsirolimus 23572408 tivozanib 23573970 2-iminothiolane 23573970 6,6´dithionicotinamide 23573970 disulfide 23573970 mercaptonicotinamide 23573970 thiobutylamidine 23573970 thiol 23574049 Graphene Oxide 23574049 N-cyclohexyl-2-pyrrolidone 23574049 N-dimethylformamide 23574049 acetone 23574049 carbon 23574049 ethanol 23574049 graphene oxide 23574049 tetrahydrofuran 23574259 diphenylvinyl 23574259 o-Quinonoid 23574259 o-quinonoid 23574272 Flavone 23574272 Flavones 23574272 Flavonoids 23574272 flavone 23574272 flavones 23574272 flavonoid 23574272 flavonoids 23574272 nicotinamide 23574308 Calcium 23574308 Thapsigargin 23574308 calcium 23574308 hydrogen 23574308 thapsigargin 23574310 Graphene 23574310 PVP 23574310 dimethyl sulfoxide 23574310 graphene 23574310 graphene oxide 23574310 methanol 23574310 poly(4-vinylpyridine) 23574310 polyvinyl pyrrolidone 23574435 H-N═N(+)═O 23574435 HNNO(+) 23574435 N 23574435 NNOH(+) 23574435 Nitrogen 23574435 N≡N(+)-O-H 23574435 Protonated Nitrous Oxide 23574435 nitrogen 23574435 oxygen 23574435 protonated nitrous oxide 23574541 Desloratadine 23574541 desloratadine 23574541 histamine 23574541 loratadine 23574729 cortisol 23574729 dehydroepiandrosterone sulfate 23574729 dexamethasone 23574807 6-NQ 23574807 6-nitroquipazine 23574807 Alkylnitroquipazines 23574807 Serotonin 23574807 alkyl 23574807 decyl 23574807 dodecyl 23574807 octyl 23574807 serotonin 23575745 BaTiO3 23575800 DCA 23575800 TCA 23575800 TCE 23575800 Trichloroethylene 23575800 dichloroacetate 23575800 fatty acid 23575800 lysophosphatidylcholine 18:0 and 18:1 23575800 phosphatidylcholine 23575800 trichloroacetate 23575800 trichloroethylene 23575901 Boron 23575901 NaB 23575901 boron 23575901 calcium 23575901 sodium pentaborate pentahydrate 23575940 fluconazole 23576111 glutathione 23576111 superoxide 23576175 Emodinol 23576175 Monosodium Urate 23576175 emodinol 23576175 monosodium urate 23576175 triterpene 23576194 polyimide 23576205 azo 23576242 2-(4-benzoylphenyl)-2-phenyl-1-methylenecyclopropane 23576242 TMM 23576242 trimethylenemethane 23576269 Serine 23576269 Threonine 23576269 serine 23576269 threonine 23576424 Hydroxyl 23576424 Methyl 23576424 secondary alcohols 23576424 α-methyl 23577599 CH 23577599 H 23577599 Heptapeptide 23577599 amino acid 23577599 cellohexaose 23577599 glucose 23577636 Esters 23577636 TBAF 23577636 acyl 23577636 esters 23577636 secondary alcohol esters 23577636 tetrabutylammonium fluoride 23577649 H2O 23577871 N-N 23577871 Nitrogen 23577871 nitrogen 23578300 alkyl 23578300 carbohydrate 23578300 glucose 23578300 mannose 23578300 sugar 23578300 α-d-mannose 23578392 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene 23578392 TCPOBOP 23578392 androstane 23578607 6-DHSG 23578607 6-Dehydroshogaol 23578607 6-dehydroshogaol 23578607 6-gingerol 23578607 6-shogaol 23578607 ASC 23578607 GS-6-DHSG 23578607 GSH 23578607 Glutathione 23578607 N-acetyl cysteine 23578607 NAC 23578607 S 23578607 ascorbic acid 23578607 glutathione 23578607 sulfhydryl 23578607 α,β-unsaturated carbonyl 23578611 Polyphenols 23578611 bile acid 23578611 gentisic, p-hydroxybenoic, and chlorogenic acids 23578611 phenolic acids 23578612 disulphide 23578612 sodium dodecyl sulphate 23578612 sodium sulphite 23578614 P25 TiO2 23578614 glycerol 23578614 oxygen 23578614 thionine 23578617 (+)-catechin 23578617 Catechin 23578617 Ethyl butyrate 23578617 catechin 23578617 esters 23578617 ethyl butyrate 23578617 ethyl isobutyrate 23578617 ethyl octanoate 23578617 gallic acid 23578617 isoamyl acetate 23578617 phenolic 23578618 Fe3O4 23578618 SAs 23578618 carbon 23578618 sulfonamides 23578619 geranylgeranyl pyrophosphate 23578619 tocopherol 23578619 tocotrienol 23578619 vitamin E 23578631 3-methyl-2-oxobutyric acid 23578631 3-methyl-2-oxovaleric acid 23578631 4-hydroxyphenylpyruvic acid 23578631 4-methyl-2-oxovaleric acid 23578631 dansylhydrazine 23578631 phenylpyruvic acid 23578631 pyruvic acid 23578631 α-keto acid 23578631 α-keto acids 23578631 α-keto-γ-methylthiobutyric acid 23578631 α-ketoglutaric acid 23578635 Amino acid 23578635 amino acid 23578641 1-octen-3-ol 23578641 chlorophyll 23578641 chlorophylls 23578641 hydroperoxides 23578641 oxygen 23578641 riboflavin 23578641 t-2-heptenal 23578641 β-carotene 23578644 1,25-dihydroxyvitamin D3 23578644 calcium 23578644 linoleic acid 23578647 (+)-platyphyllarin A (1) and B 23578647 (-)-liriopein A (4) and B 23578647 amides 23578647 benzenoids 23578647 butanoate 23578647 chalcone 23578647 dihydrobenzofuroisocoumarins 23578647 ethyltributanoate 23578647 fatty acid 23578647 homoisoflavanones 23578647 homoisoflavonoids 23578647 lignan 23578647 steroids 23578649 Fluoride 23578649 fluoride 23578649 sodium fluoride 23578649 β carotene 23578650 5-feruloylquinic and 5-p-coumaroylquinic acids 23578650 caffeic acid 23578650 dicaffeic acid 23578650 feruloylquinic and caffeoylquinic acid 23578650 phenolic 23578650 phenolics 23578650 polyphenol 23578650 rutin 23578688 BMS-582949 23578688 acyloxymethylene carbamates 23578688 carbamoylmethylene 23578688 fumaric acid 23578688 phosphoryloxymethylene carbamates 23578688 secondary amides 23578688 α-aminoacyloxymethylene carbamates 23578689 3-cycloalkyl substituted indoles 23578689 5-(cis-2-aminomethylcyclopentyl)indoles 23578689 5-(trans-2-aminomethylcyclopentyl) indoles 23578689 Indole-5-cycloalkyl methylamines 23578689 Racemic 5-(trans-2-aminomethylcyclopropyl)indoles 23578689 homotryptamines 23578689 serotonin 23578846 PLGA 23578846 poly (lactic acid-co-glycolic acid) 23578952 2-arachidonoylglycerol 23578952 JZL184 23578952 Monoacylglycerol 23578952 corticosterone 23578952 metyrapone 23578952 monoacylglycerol 23578993 Alanine 23578993 Aspartate 23578993 Bilirubin 23578993 CCl4 23578993 GSH 23578993 Glutathione 23578993 Hydroxyproline 23578993 N-acetyl cysteine 23578993 NAC 23578993 TAA 23578993 aniline 23578993 carbon tetrachloride 23578993 organosulfur 23578993 thioacetamide 23578994 Fatty Acid 23578994 calcium 23578994 cyclic AMP 23578994 glucose 23579392 AsA 23579392 Cu 23579392 Cu(2+) 23579392 GSH 23579392 H2O2 23579392 MDA 23579392 O 2 (•-) 23579392 S 23579392 Salicylic acid 23579392 ascorbate 23579392 ascorbic acid 23579392 copper 23579392 dehydroascorbate 23579392 glutathione 23579392 hydrogen peroxide 23579392 malondialdehyde 23579392 oxygen 23579392 proline 23579392 salicylic acid 23579392 superoxide 23579392 thiol 23579421 carbon 23579421 iron oxide 23579429 Cholesterol 23580001 Metformin 23580001 metformin 23580312 4-pyridoxic acid 23580312 7-methylguanine 23580312 C18-dihydrosphingosine 23580312 Dimethylphosphate 23580312 Organophosphate 23580312 acephate 23580312 cholic acid 23580312 citric acid 23580312 creatinine 23580312 dichlorvos 23580312 dimethoate 23580312 dimethyldithiophosphate 23580312 gentisic acid 23580312 hippuric acid 23580312 indoxyl sulfate 23580312 kynurenine 23580312 organophosphate 23580312 phorate 23580312 phytosphingosine 23580312 ribothymidine 23580312 suberic acid 23580312 tricarboxylic acid 23580312 uric acid 23580316 1-ethoxypentacosane 23580316 MDA 23580316 alcohol 23580316 heptacosan-1-ol 23580316 kampferol 23580316 kampferol-3-galactoside 23580316 kampferol-3-glucoside 23580316 malondialdehyde 23580316 phenolic 23580316 β-sitosterol 23580332 Decursin 23580332 decursin 23580332 prolyl 23580446 PGE2 23580446 prostanoids 23580446 rofecoxib 23580446 β-lactose 23580569 Estrogen 23580569 estrogen 23580611 FSK 23580611 cAMP 23580611 forskolin 23581424 PDMS 23581424 PEG 23581424 Polyethylene glycol 23581424 carboxylic acid 23581424 poly(dimethylsiloxane) 23581424 polyethylene glycol 23581424 primary amine 23581750 1,4-dioxane 23581750 Cholesterol 23581750 ECPS 23581750 N,N'-(ethane-1,2-diyl)-bis(N-(2-(chol-amino)ethyl)pyrene-1-sulfonamide) 23581750 Pyrene 23581750 acetonitrile 23581750 benzene 23581750 cholesterol 23581750 n-hexane 23581750 pyrene 23581964 Graphene 23581964 Si 23581964 SiO2 23581964 graphene 23582019 2-benzothiazoyl 23582019 9,9-diethylfluorene 23582019 Bisphthalimide 23582019 Fluorene 23582019 Ph2N 23582019 bisphthalimide 23582019 bisphthalimides 23582211 deoxyuridine 23582211 nucleotide dimers 23582211 polyamine 23582211 spermidine 23582273 1,3,4-oxadiazole 23582273 1,4-benzodioxan 23582273 Met 23582273 methionine 23582408 berberine 23582408 glucose 23582408 streptozotocin 23583009 CO 23583009 Ethanol 23583009 Quercetin 23583009 carbon monoxide 23583009 ethanol 23583009 heme 23583009 quercetin 23583257 AA-861 23583257 Cys 23583257 NAD(P)H 23583257 NADPH 23583257 Quinone 23583257 disulfide 23583257 duroquinone 23583257 oxygen 23583257 quinone 23583257 quinones 23583257 tBuBHQ 23583257 tBuBQ 23583258 Cholesterol 23583258 NADPH 23583258 Oxysterol 23583258 Phenolic 23583258 cholesterol 23583258 flavonoids 23583258 oxygen 23583258 oxysterol 23583258 oxysterols 23583258 phenolic 23583258 phenolic acids 23583258 phenolics 23583436 5,5-dihydro-pyran 23583436 5-Fluorouracil 23583436 Simonols A and B 23583436 dihydronfuran 23583436 ethanol 23583436 hemiketal carbon 23583436 sesqui-neolignans 23583436 simonol A 23583436 simonol B 23583456 24(S),25-epoxycholesterol 23583456 Cholesterol 23583456 cholesterol 23583456 mevalonate 23583486 DADS 23583486 DAS 23583486 DATS 23583486 ajoene 23583486 diallyl disulfide 23583486 diallyl sulfide 23583486 diallyl trisulfide 23583486 organosulfur 23583495 PLGA 23583495 poly(lactide-co-glycolide) 23583512 d-deoxynucleotide 23583512 l-deoxynucleotide 23583603 Estradiol 23583603 ICI 23583603 ICI 182 780 23583603 ICI 182,780 23583603 Ser 23583603 estrogen 23583603 progesterone 23583736 N-alkylamide 23583736 N-alkylamide spilanthol 23583736 Spilanthol 23583736 T-2 toxin 23583736 aflatoxin B1 23583736 caffeine 23583736 citrinin 23583736 fumonisin B1 23583736 ibuprofen 23583736 ochratoxin A 23583736 spilanthol 23583736 testosterone 23583736 zearalenone 23583802 Ca(2+) 23583802 Hg 23583802 MeHg 23583802 Nimodipine 23583802 calcium 23583802 dihydropryidine 23583802 methylmercury 23583802 nimodipine 23583804 MDA 23583804 triptolide 23583902 Chlorogenic acid 23583902 chlorogenic acid 23583902 phenolic acid 23583902 polyphenol 23583902 polyphenols 23583903 MTS 23583911 tartaric acid 23583911 thieno[1,2,3]triazine 23583911 thieno[3,2-d]pyrimidinone 23583911 thienopyrimidines 23584353 FFA 23584353 Lucifer yellow 23584353 MFA 23584353 Meclofenamic acid 23584353 aspirin 23584353 flufenamic acid 23584353 meclofenamic acid 23584434 arginine 23584543 Acetylacetonate 23584543 Copper(II) 23584543 Fc-MetH 23584543 Fc-TrpH 23584543 Fc-TyrH 23584543 Fc-aa 23584543 Hcur 23584543 N-ferrocenylmethyl-l-amino acids 23584543 [Cu(Fc-aa)(acac)] 23584543 [Cu(Fc-aa)(cur)] 23584543 acac 23584543 copper(II) 23584543 curcumin 23584543 ferrocenylmethyl-l-methionine 23584543 ferrocenylmethyl-l-tryptophan 23584543 ferrocenylmethyl-l-tyrosine 23584895 Diamond 23584895 epirubicin 23584984 Alkane 23584984 L(t) (Bu) 23584984 Ni 23584984 Ni(II) 23584984 NiL2 23584984 Nickel 23584984 Si 23584984 Silica 23584984 [Ni(L(t) (Bu) )(OAc)2 (H2 O)] (L(t) (Bu) /Ni) 23584984 [Ni(L(t) (Bu) )2 ]BF4 (2 L(t) (Bu) /Ni) 23584984 azidopropyl 23584984 bis(2-pyridylmethyl)(1H-1,2,3-triazol-4-ylmethyl)amine 23584984 cyclohexane 23584984 m-chloroperbenzoic acid 23584984 mCPBA 23584984 nickel 23584984 silicas 23585309 glucose 23585332 cholesterol 23585332 tBHQ 23585332 tert-Butylhydroquinone 23585332 triglyceride 23585333 Ag 23585333 Fe3 O4 23585333 Glucose 23585333 SiO2 23585333 glucose 23585333 mannose 23586436 octadecyltrichlorosilane 23586436 silicon oxide 23586470 Histidine 23586470 Ni 23586470 Ni(2)(+) 23586470 S 23586470 histidine 23586669 4-imidazo[2,1-b]thiazole-1,4-DHPs 23586669 4-imidazo[2,1-b]thiazole-1,4-dihydropyridines 23586669 Calcium 23586669 Imidazo[2,1-b]thiazole-1,4-Dihydropyridines 23586669 calcium 23586669 imidazo[2,1-b]thiazole-1,4-DHPs 23586680 alumina 23586680 aluminum oxide 23586680 hydrocarbon 23586680 hydrogen 23586680 hydroiodic acid 23586680 oxide 23586702 graphene 23586702 pristine graphene 23586737 AE3S 23586737 Ca(2+) 23586737 Mg(2+) 23586737 OH 23586737 SDS 23586737 alkyl polyoxyethylene sulfate 23586737 hydrated Mg(2+) 23586737 hydrogen 23586737 magnesium 23586737 sodium dodecyl sulfate 23586757 Heme 23586757 Quinoline 23586757 amodiaquine 23586757 chloroquine 23586757 heme 23586757 quinine 23586757 quinoline 23586849 Fumiquinazoline L 23586849 valine 23586868 FST 23586868 Fostriecin 23586868 PD 113,271 23586868 lactone 23586868 malonyl ester 23586868 unsaturated lactone 23586925 PVA 23586925 polystyrene 23586925 polyvinyl alcohol 23586938 silica 23586938 silicic acid 23586970 Cyclohexapeptides 23586970 Nocardiamides A and B 23586970 cyclic hexapeptides 23586970 d- and one l-valine 23586970 nocardiamides 23587425 imidazo[1,2-a]pyrazine 23587425 imidazo[1,2-a]pyrazines 23587425 imidazo[1,2-c]pyrimidine 23587425 imidazo[1,2-c]pyrimidines 23587503 1,4-benzoquinone 23587503 ATP 23587503 Duroquinone 23587503 carbonyl 23587503 duroquinone 23587503 superoxide 23587526 GABA 23587526 U69593 23587526 ethanol 23587526 nor-binaltorphimine 23587645 docusate sodium 23587645 glibenclamide 23587645 mannitol 23587648 calcium 23587668 2,3,7,8-Tetrachlorodibenzo-p-dioxin 23587668 TCDD 23587668 dioxin 23587849 Dextrose 23587849 ENs 23587849 enniatins A, A1, B, B1 23588096 Methanol 23588096 chloroform 23588096 methanol 23588252 8-OH-dG 23588252 8-oxodeoxyguanosine 23588252 BrO3 (-) 23588252 Bromate 23588252 KBrO3 23588252 bromate 23588252 bromodeoxyuridine 23588252 eosin 23588252 hematoxylin 23588308 cyclosporine 23588308 simvastatin 23588585 Silibinin 23588585 silibinin 23589302 Tyr 23589302 tyrosine 23589404 Hg 23589404 amalgam 23589404 mercury 23589408 aflatoxin 23589499 2-Arylbenzofurans 23589499 2-arylbenzofuran 23589499 2-arylbenzofurans 23589499 3-(4'-Methoxyphenyl)-6-nitrocoumarin 23589499 3-Arylcoumarins 23589499 3-arylcoumarin 23589499 3-arylcoumarins 23589499 3-phenylcoumarin 23589499 5-Nitro-2-(4-methoxyphenyl)benzofuran 23589499 Monoamine 23589499 benzofuran 23589499 coumarin 23589499 trans-stilbene 23589515 MoS2 23589515 Si 23589515 SiO2 23589515 graphene 23590193 TCEP 23590193 disulfide 23590193 thioflavin T 23590193 tris(2-carboxyethyl)phosphine 23590470 6-MP 23590470 6-mercaptopurine 23590470 6-mercaptopurine riboside 23590470 6-thioguanine 23590470 6-thioguanine riboside 23590470 acetonitrile 23590470 azide 23590470 iodine 23590470 sodium azide 23590470 sodium heptane sulfonate 23590470 thiopurine 23590470 thiopurines 23590563 NPHOS 23590563 NPHOS-PEO 23590563 PEO 23590563 Poly[3,5-bis(dimethylaminomethyl)-4-hydroxystyrene]-block-poly(ethylene oxide) 23590563 SDS 23590563 Sodium Dodecyl Sulfate 23590563 dimethylaminomethyl 23590563 poly[3,5-bis(dimethylaminomethyl)-4-hydroxystyrene]-block-poly(ethylene oxide) 23590563 sodium dodecyl sulfate 23590572 Phenylperoxy 23590572 phenylperoxy 23590591 CpG 23590591 pyridyl disulfide 23590591 thiol 23590723 MoS2 23590729 DTBN 23590729 Sodium 23590729 di-tert-butyl nitroxide 23590729 l-Phenyl Alanine 23590729 l-Tyrosine 23590729 lauryl ester 23590729 maleamic acid 23590729 phenyl alanine 23590729 tyrosine 23591110 aryl amides 23591110 aryl ureas 23591110 histamine 23591115 Hg(2+) 23591115 Phenanthroimidazole 23591115 amide 23591115 mercury(II) 23591115 phenanthroimidazole 23591115 thioamide 23591115 thiobenzamide 23591125 alaproclate 23591125 bryostatin-1 23591125 serotonin 23591149 porphyrinoid 23591149 porphyrinoids 23591590 Br(-) 23591590 C8F17I 23591590 Cl(-) 23591590 H2PO4(-) 23591590 HSO4(-) 23591590 I(-) 23591590 NO3(-) 23591590 TsO(-) 23591590 halides 23591590 halogen 23591590 hydrogen 23591590 oxo 23591590 tosylate 23591661 Cremophor 23591661 PGA 23591661 plitidepsin 23591661 polyamino acid 23591661 polyglutamic acid 23591959 Na2SeO3 23591959 NaF 23591959 Selenium 23591959 dUTP 23591959 fluoride 23591959 selenium 23591959 sodium fluoride 23591959 sodium selenite 23591996 5-MCA-NAT 23591996 5-methoxycarbonylamino-N-acetyltryptamine 23591996 Melatonin 23591996 brimonidine 23591996 melatonin 23591996 timolol 23591997 PF-573,228 23592428 prostaglandin E2 23592577 Graphene 23592577 MoS2 23592577 TTF 23592577 Tetrathiafulvalene 23592577 graphene 23592577 tetracyanoethylene 23592745 Wogonin 23592745 flavonoid 23592745 tyrosine 23592745 wogonin 23592780 Glucose 23592780 Lys 23592780 fructose 23592780 glucose 23592780 monosaccharides 23592780 sugar 23592839 rapamycin 23594027 CaO 23594027 Na2O 23594027 P2O5 23594027 SiO2 23594027 orthosilicate 23594047 H 2 23594047 OH (-) 23594047 TiO 2 23594047 titanium hydroxide 23594105 alkylammonium 23594105 montmorillonite 23594210 ND3 23594210 NH3 23594210 Parahydrogen 23594210 pH2 23594210 parahydrogen 23594301 meloxicam 23594304 (1)H 23594304 (13)C 23594304 Phyllanthin 23594304 ethanol 23594304 lignan 23594304 petroleum ether 23594304 phyllanthin 23594342 (1)H 23594342 Genistein 23594342 PDLLA 23594342 PEO 23594342 Poly(d,l-lactic acid) 23594342 Poly(ethylene oxide) 23594342 genistein 23594342 poly(d,l-lactic acid) 23594342 poly(ethylene oxide) 23594396 2,2,6,6-tetramethylpiperidine-1-oxyl 23594396 CO2 23594396 COOH 23594396 H2 23594396 Hydrogen 23594396 N2 23594396 O2 23594396 TEMPO 23594396 carboxyl 23594396 carboxylate 23594396 cesium 23594396 hydrogen 23594396 lithium 23594396 metal carboxylate 23594396 potassium 23594396 sodium 23595058 2-amino-(6E)-octadec-6-en-1,3,4-triol 23595058 2-hydroxytetracosanoic acid 23595058 Axidjiferosides 23595058 axidjiferoside-A 23595058 axidjiferoside-A, -B and -C 23595058 axidjiferosides 23595058 chloroquine 23595058 galactosylceramides 23595058 glycosphingolipids 23595058 β-Galactosylceramides 23595058 β-galactopyranosylceramides 23595911 H-SAPO-34 23595911 H-ZSM-5 23595911 Methanol 23595911 Olefins 23595911 ethene 23595911 methanol 23595911 olefins 23595911 propene 23596058 GTN 23596058 NO 23596058 NOBA 23596058 NOC-5 23596058 Nitrooxybutyl-esters 23596058 ferulic-acid 23596058 flurbiprofen 23596058 glyceryl trinitrate 23596058 nitrate 23596058 nitrates 23596058 nitrite 23596058 nitrooxybutyl-alcohol 23596058 nitrooxybutyl-esters 23596124 (E)-styryl-1H-benzo[d]imidazoles 23596124 Epoxide 23596124 Stilbene 23596124 epoxide 23596124 isopropylstilbene 23596261 Methamidophos 23596261 OPs 23596261 Organophosphates 23596261 choline 23596261 methamidophos 23597018 PTFE 23597018 Ti 23597018 TiO2 23597018 catechin 23597018 polytetrafluoroethylene 23597098 Polypyrrole 23597098 nucleoside 23597098 nucleotide 23597098 nucleotides 23597098 polypyrrole 23597402 bis-homoallylic hydroxylamines 23597402 pyrrolidine 23597402 thiourea 23597443 TiO2 23597443 Titanium dioxide 23597443 titanium dioxide 23597506 Anandamide 23597506 R-flurbiprofen 23597506 amide 23597506 anandamide 23597506 fatty acid 23597511 3,4-methylenedioxypyrovalerone 23597511 MDPV 23597511 METH 23597511 d-methamphetamine 23597790 cAMP 23597790 cGMP 23597790 pyrazolodiazepinone 23598043 Pb 23598363 Trp 23598363 cisplatin 23598363 imatinib 23598363 imatinib mesylate 23598363 platinum 23598364 boron 23598364 diamond 23598364 methyl viologen 23598364 oxygen 23598364 superoxide 23598368 2-cyanopyrrolide 23598368 3-(trifluoromethyl)pyrazolide 23598368 CO2 23598368 N2O 23598368 [2-CNpyr] 23598368 [3-CF3pyra] 23598368 [P66614] 23598368 [P66614][2-CNpyr] 23598368 [P66614][3-CF3pyra] 23598368 [P66614][Pro] 23598368 [Pro] 23598368 phosphonium 23598368 prolinate 23598368 tetraglyme 23598368 trihexyl(tetradecyl)phosphonium 23598400 alcohol 23598442 Melatonin 23598442 cAMP 23598442 melatonin 23600593 6‴-(3-hydroxy-3-methylglutaroyl)-2″-O-β-d-galactopyranosyl orientin 23600593 6‴-(3-hydroxy-3-methylglutaroyl)-2″-O-β-d-galactopyranosyl vitexin 23600593 Flavone C-glycosides 23600593 ethanol 23600593 flavone C-glycosides 23600593 flavonoids 23600748 C 23600748 DOX 23600748 amino acid 23600748 doxorubicin 23600958 5-hydroxy-4'-propargyloxyflavone 23600958 5-hydroxyflavone 23600958 5H4'FPE 23600958 Pyranoflavones 23600958 flavone 23600958 α-Naphthoflavone 23600958 β-naphthoflavone 23601386 Trans fatty acids 23601386 fatty acids 23601386 t9-C18:1 23601386 trans elaidic acid 23601386 trans fatty acid 23601386 trans fatty acids 23601388 folate 23601388 iron 23601388 retinol 23601388 vitamin D 23601388 zinc 23601392 B vitamins 23601392 calcium 23601392 cholesterol 23601392 iron 23601392 magnesium 23601392 phosphorus 23601392 vitamin B1 23601392 vitamin B2 23601392 vitamin B3 23601392 zinc 23601395 anserine 23601395 carnosine 23601395 cholesterol 23601395 coenzyme Q10 23601395 creatine 23601395 creatinine 23601395 fatty acids 23601395 glutamine 23601395 heme 23601395 iron 23601395 polyunsaturated fatty acids 23601395 saturated fatty acids 23601395 taurine 23601395 triacylglycerols 23601395 vitamins E and A 23601410 carbohydrates 23601412 amines 23601412 histamine 23601412 putrescine 23601412 tyramine 23601413 Ca 23601413 Fe 23601413 Na 23601649 camptothecin 23601649 flavonoid 23601649 oxygenated flavonoid 23601700 SDS 23601700 disulphide 23601753 aspartate 23601753 calcium 23601990 cholesterol 23601990 flavonoids 23601990 hydroxyl 23601990 phosphate 23601990 phosphorylated flavonoids 23602474 serotonin 23602515 3'-PG 23602515 3'-phosphoglycolates 23602515 PGs 23602515 thymine glycol 23602864 AHGDM 23602864 DOC 23602864 HPMA 23602864 N-(2-hydroxypropyl)methacrylamide 23602864 aminohexylgeldanamycin 23602864 cisplatin 23602864 docetaxel 23602864 glucose 23602984 ATP 23602984 GABA 23602985 paroxetine 23602985 serotonin 23602985 vasopressin 23602997 octanol 23603023 iron oxide 23603023 maghemite 23603023 ricinoleic acid 23603044 (125)I 23603044 (131)I 23603044 fluorine-18 23603044 iodine-125 23603044 iodine-131 23603045 N 23603045 Triazolothiadiazoles 23603045 triazolothiadiazines 23603045 triazolothiadiazoles 23603058 DON 23603058 bilirubin 23603058 deoxynivalenol 23603103 carbohydrates 23603103 galactose 23603145 Chromium 23603145 chromium 23603145 hexavalent chromium 23603145 hexavalent-chromium 23603191 kojic acid 23603200 gold-thioglucose 23603477 DEAE 23603477 SDS 23603478 2,2',4,4',5,5'-hexachlorobiphenyl 23603478 2,2',4,4'-tetrabrominated diphenyl ether 23603478 2,3,7,8-tetrachlorodibenzo-[p]-dioxin 23603478 BDE-47 23603478 BPA 23603478 DES 23603478 HBCD 23603478 HCB 23603478 PCB-153 23603478 PFOA 23603478 PFOS 23603478 TBT 23603478 TCDD 23603478 bisphenol A 23603478 diethylstilbestrol 23603478 hexabromocyclododecane 23603478 hexachlorobenzene 23603478 perfluorinated octyl acid 23603478 perfluorinated octyl sulfonate 23603478 tributyltin 23603554 diazepam 23603615 DOX 23603615 doxorubicin 23603918 Glucose 23603918 glucose 23604205 Au 23604390 cocaine 23604717 (PG) E2 23604717 4-hydroxynonenal 23604717 GSH 23604717 GSSG 23604717 HNE 23604717 PGE2 23604717 SAL-2 23604717 arachidonic acid 23604717 salicylate 23604717 salicylideneamino-2-thiophenol 23604720 aldose 23604720 caffeoylquinic acids 23604720 galactitol 23604720 glucose 23604720 methyl-3,5-di-O-caffeoylquinate 23604720 phenolic 23604722 FBP 23604722 Fructose-1,6-bisphosphate 23604722 oxygen 23604722 prostaglandin E2 23604723 cAMP 23605048 GSH 23605048 MDA 23605048 NaF 23605048 Superoxide 23605048 glutathione 23605048 malondialdehyde 23605048 sodium fluoride 23605050 Fe 23605050 Glucose 23605050 Iron 23605050 glucose 23605050 glutathione 23605050 iron 23605050 superoxide 23605694 Ospemifene 23605694 Osphena 23605694 estrogen 23605694 ospemifene 23605695 Pasireotide 23605695 Signifor 23605695 cortisol 23605695 glucose 23605695 pasireotide 23605695 somatostatin 23606264 1,6-anhydro-β-L-idonojirimycin 23606264 L-Idonojirimycin 23606334 15-deoxy-delta(12,14) -prostaglandin J2 23606334 15-deoxy-delta12,14-prostaglandin J2 23606334 15d-PGJ2 23606334 PGD2 23606334 biotinylated-15d-PGJ2 23606334 cyclopentenone 23606334 α,β-unsaturated carbonyl 23606349 Colistin 23606349 colistin 23606349 creatinine 23606423 2-methacryloyloxyethyl phosphorylcholine 23606423 MPC 23606423 SEBS 23606423 styrene-block-(ethylene-co-butylene)-block-styrene 23606438 Carbon 23606438 carbon 23606510 Se 23606510 Superoxide 23606510 glutathione 23606510 porphyrin 23606510 superoxide 23606523 Glucose 23606523 glucose 23606533 Mg 23606533 MgO 23606533 ZnO 23606568 Apatite 23606568 DOXO 23606568 MTT 23606568 apatites 23606568 doxorubicin 23606657 Fe3 O4 23606657 Graphene 23606657 Li 23606657 Metal Oxide 23606657 graphene 23607484 D2O 23607484 carbonyl 23607484 poly[2-(diethylamino)ethyl methacrylate] 23607484 silicon 23607568 N-Me-Val-Thr 23607568 Viequeamide A 23607568 viequeamide A 23608189 3-Hydroxy-3-methylglutaryl coenzyme A 23608189 atorvastatin 23608189 oxygen 23608239 ABTS 23608239 ABTS(•+) 23608239 Acetone 23608239 DPPH 23608239 DPPH(•) 23608239 Ethyl acetate 23608239 GSH 23608239 acetone 23608239 ethanol 23608239 ethyl acetate 23608239 glutathione 23608239 phosphomolybdenum 23608239 quercetin 23608239 superoxide 23608240 (-)-epicatechin 23608240 anthraquinones 23608240 cyclopeptid alkaloids 23608240 flavonoids 23608240 kaempferol 23608240 kaempferol-3-O-β-d-(6″-E-p-coumaryl)-glucopyranoside) 23608240 quercetin 23608240 saponins 23608240 sterols 23608240 tannins 23608240 terpenes 23608700 estrogen 23608700 steroid hormones 23608700 β-estradiol 17-valerate 23608737 17β-estradiol 23608737 Cocaine 23608737 DPN 23608737 Estradiol 23608737 PPT 23608737 cocaine 23608737 estradiol 23608737 estrogen 23608764 cycloartane triterpenoids 23608764 estrogen 23609108 Polyphenols 23609108 polyphenols 23609940 GnRH 23609940 estradiol valerate 23609940 estrogen 23609940 gonadotropin-releasing hormone 23610039 Ca(2+) 23610039 CaCO3 23610039 Calcium Carbonate 23610039 PGlu22 -b-PAla8 23610039 calcite 23610039 poly(glutamic acid)22 -block-poly(alanine)8 23610060 fructosamine 23610060 glucose 23610081 Glucose 23610081 glucose 23610123 Aldosterone 23610123 aldosterone 23610123 potassium 23610123 sodium 23611027 CO2 23611027 Poly(1,2-glycerol carbonate) 23611027 Poly(1,2-glycerol carbonate)s 23611027 [SalcyCo(III)X] 23611027 carbonate 23611027 poly(1,2-glycerol carbonate)s 23611027 poly(1,3-glycerol carbonate) 23611027 poly(benzyl 1,2-glycerol carbonate)s 23611027 polycarbonate 23611027 primary hydroxyl 23611027 rac-/(R)-benzyl glycidyl ether 23611039 Tetracyclines 23611039 tetracyclines 23611475 NIM 23611475 PEG 23611475 PEG 2000, 4000 and 6000 23611475 nimodipine 23611475 polyethylene glycol 23611626 Quinazolinone 23611626 miltefosine 23611626 nitric oxide 23611626 quinazolinone 23611733 heterocyclic amines 23611733 quinolone 23611733 trifluoromethyl quinolone 23612318 fatty acids 23612369 sulfate 23612422 MeOH 23612422 chloroquine 23612422 pyrimethamine 23612689 Co 23612689 Co-O 23612689 carbon 23612689 cobalt 23612710 Astrin 23612710 astrin 23612967 Cyclic GMP 23612967 cGMP 23612980 Ca2+ 23612980 N 23612980 methionine 23613084 Azo 23613084 Diazonium Salt 23613084 aniline 23613084 aryldiazonium salt 23613084 azo 23613084 azo-aryldiazonium salt 23613084 sulfanilic acid 23613150 Cd 23613150 Cu 23613150 Fe 23613150 Mg 23613150 Ni 23613150 Zn 23613450 Gd 23613450 Gd(III) 23613450 Gd(III) diethylenetriamine pentaacetate 23613450 Gd-DTPA 23613450 Gd-PSQ 23613450 PSQ 23613450 Polysilsesquioxane 23613450 anisamide 23613450 bis(trialkoxysilyl) 23613450 cysteine 23613450 disulfide 23613450 glutathione 23613450 trialkoxysilanes 23613484 2-(2,6-dichlorobenzylideneamino) benzenethiol 23613484 Co(2+) 23613484 Cu(2+) 23613484 Ni(2+) 23613484 Pb(2+) 23613484 Zn(2+) 23613484 cobalt 23613484 copper 23613484 nickel 23613484 zinc 23614367 tyrosine 23614395 (1)H 23614395 (13)C 23614395 arjunglucoside 23614395 diterpenoid glycoside 23614395 ent-kaurane 23614395 glaucocalyxin G 23614395 kaempferol-3-O-rutinoside 23614395 n-butanol 23614566 2'-deoxycytidine diphosphate 23614566 5-hydroxyindoleacetic acid 23614566 L-carnitine 23614566 N-acetylglucosaminylamine 23614566 acetyl-L-carnitine 23614566 anandamide 23614566 dCDP 23614566 harmaline 23614566 pantothenic acid 23614566 serotonin 23614566 stearoyl-L-carnitine 23614663 Silica 23614663 silica 23614663 silicate 23614730 MDA 23614730 NO 23614730 carbohydrate 23614730 creatine 23614730 malondialdehyde 23614730 nitric oxide 23614730 prallethrin 23614730 pyrethroid 23614730 superoxide 23614896 Novobiocin 23615073 Vitamin C 23615073 vitamin C 23615124 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonate 23615124 2,2-diphenyl-1-picrylhydrazyl 23615124 ABTS 23615124 DPPH 23615124 MeOH 23615124 egallic 23615124 ellagic acid 23615124 flavonoids 23615124 flavonols 23615124 gallic acid 23615124 polyphenols 23615124 tannins 23615471 5-fluorouracil 23615471 CAPE 23615471 Caffeic Acid Phenethyl Ester 23615471 Caffeic acid phenethyl ester 23615471 Ser 23615471 phospho 23615708 flumorph 23615905 NaCl 23615905 TCA 23615905 [1-13C]-, [2-13C]-, [6-13C]- and [U-13C6]-glucose 23615905 acetate 23615905 carbon 23615905 ectoines 23615905 gluconate 23615905 glucose 23615905 pyruvate 23616352 ATP 23616352 arginine 23617223 Paclitaxel 23617223 Pax 23617223 paclitaxel 23617391 2'-O,4'-C-methylene-β-d-ribofuranose 23617391 2'-O,4'-C-methylene-α-l-ribofuranose 23617391 O-CH2 23617391 deoxyribose 23617391 furanose sugar 23617391 sugar 23617426 boron 23617429 Boron 23617429 Velcade 23617429 boron 23617429 bortezomib 23617431 Boron 23617431 Boronated carbohydrate 23617431 boron 23617431 boronated carbohydrate 23617431 carbohydrates 23617431 carborane 23617539 Au 23617539 PEG 23617539 citrate 23617539 polyethylene glycol 23617615 hydrocarbon 23617615 lipid A 23617615 sugars 23617725 Aryl Chloride 23617725 CN 23617725 Cl 23617725 D-Ala-D-Ala 23617725 N-Boc 23617725 OMe 23617725 VanB 23617725 Vancomycin 23617725 aryl chloride 23617725 boronic acid 23617725 chloro substituted vancomycin 23617725 vancomycin 23618899 arsenic 23618899 arsenite 23618901 Nicotine 23618901 SB431542 23619006 2,3,7,8-TCDD 23619006 TCDD 23619006 lithium chloride 23619018 TNBS 23619018 baicalein 23619018 baicalin 23619018 berberine 23619018 coptisine 23619018 emodin 23619018 jatrorrhizine 23619018 palmatine 23619018 rhein 23619018 trinitrobenzene sulfonic acid 23619018 wogonin 23619018 wogonoside 23619020 MTT 23619020 N-acetylcysteine 23619020 NAC 23619020 oxygen 23619020 tyrosine 23619028 apixaban 23619028 dabigatran 23619028 rivaroxaban 23619028 warfarin 23619284 ATP 23619284 CT53518 23619284 MLN518 23619284 Tandutinib 23619284 [H(3)] mitoxantrone 23619284 doxorubicin 23619284 mitoxantrone 23619284 rhodamine 123 23619284 tandutinib 23619284 tyrosine 23619386 Rapamycin 23619386 rapamycin 23619386 seco-rapamycin 23619527 lithium 23620134 1-octanoic acid 23620134 alkyl 23620134 graphite 23620134 meso-5,10,15,20-tetrakis(undecyl)porphyrin copper(ii) 23620134 porphyrin 23620303 C 23620303 C-C 23620303 C-H 23620303 N 23620303 N-H 23620303 N-O 23620303 O 23620303 O-H 23620303 acetone 23620303 carbon tetrachloride 23620303 ethanol 23620303 hexane 23620303 methanol 23620303 silicon 23620303 silicon dioxide 23620303 toluene 23620436 MNU 23620436 testosterone 23620484 AR-67 23620484 Camptothecin 23620484 camptothecin 23620484 camptothecins 23620484 carboxylate 23620484 lactone 23620529 nitrogen 23620529 sodium 23620529 urea 23621317 PEG 23621317 Sugar 23621317 iron oxide 23621317 poly(ethylene glycol) 23621317 sugar 23621381 alogliptin 23621381 glucose 23621381 linagliptin 23621381 saxagliptin 23621381 sitagliptin 23621381 vildagliptin 23621464 microcystin 23621464 microcystins 23621524 (C6H2tBu2-3,5-O-4)2 23621524 2,6-(Me2NCH2)2C6H3 23621524 3,3',5,5'-tetra-tert-butyl-4,4'-diphenoquinone 23621524 Ar'Bi(C6H2tBu2-3,5-O-4) 23621524 Ar'Bi(X)(C6H2tBu2-3,5-OSiR3-4) 23621524 Ar'BiI2 23621524 Ar'BiX2 23621524 Ar'Bi[O2C(C6H2tBu2-3-5-O-4)-κ2O,O'] 23621524 Ar'Bi[OSC(C6H2tBu2-3-5-O-4)-κ2O,S] 23621524 Bi-C 23621524 Bi3+ NCN 23621524 Bismuth NCN 23621524 CN 23621524 CO2 23621524 COS 23621524 Cl 23621524 I2 23621524 Me 23621524 N3 23621524 Oxyaryl 23621524 Ph 23621524 R3Si 23621524 R3SiOC6H3tBu2-2,6 23621524 R3SiX 23621524 Silyl halides 23621524 [2,6-(Me2NCH2)2C6H3]Bi(C6H2tBu2O) 23621524 bismuth 23621524 oxyaryl 23621524 oxyarylcarboxy 23621524 oxyarylthiocarboxy 23621524 oxygen 23621524 pseudohalides 23621524 quinone 23621573 :C=CH2 23621573 Acetylene 23621573 CCH 23621573 H2C=C: 23621573 Vinylidene 23621573 acetylene 23621573 vinyl 23621573 vinylidene 23621647 Fullerene 23621647 P3HT 23621647 PCBM 23621647 PEDOT 23621647 PSS 23621647 [6,6]-phenyl C61 butyric acid methyl ester 23621647 fullerene 23621647 poly(3,4-ethylenedioxythiophene) 23621647 poly(3-hexylthiophene) 23621647 poly(styrenesulfonate) 23621689 Hydrazide 23621689 Hydrazides 23621689 Hydrazones 23621689 hydrazide 23621689 hydrazone 23621768 Chlorpheniramine Maleate 23621768 Eudragit EPO 23621769 PVA 23621769 polyvinyl alcohol 23621769 sodium alginate 23621813 15,16-seco-cimiterpenes A and B 23621813 Triterpenes 23621813 cimilactone C 23621813 triterpene 23621813 yunnanterpenes A-F 23621840 Bisbenzylisoquinoline Alkaloids 23621840 Cepharanthine 23621840 benzylisoquinoline 23621840 bisbenzylisoquinoline N-oxides 23621840 bisbenzylisoquinoline alkaloid 23621840 bisbenzylisoquinoline alkaloids 23621840 cepharanthine 23621840 methylenedioxy 23621840 oxyacanthine 23621840 seco-aristolactam 23623417 daphnane diterpenoids 23623417 daphneresiniferins A (1) and B 23623417 diterpenes 23623417 genkwadaphnin 23623417 genkwanine A 23623417 genkwanine F 23623417 genkwanine H 23623417 methanol 23623417 yuanhuacine 23623417 yuanhuadine 23623417 yuanhuahine 23623491 2-aminobenzothizole 23623491 aminobenzothiazole 23623491 pyrazolo[1,5-a]pyrimidine 23623750 Amino acid 23623750 Flavin 23623750 N 23623750 benzydamine 23623750 flavin 23623750 methimazole 23623750 trimethylamine 23623790 ((2E,4E)-5-(1,3-benzodioxol-5-yl))-N,N-diisobutyl-2,4-pentadienamide) 23623790 GABA 23623790 N-di-isobutyl 23623790 Piperine 23623790 SCT-66 23623790 chloride 23623790 gamma-aminobutyric acid 23623790 piperidine 23623790 piperine 23623823 polyacrylamide 23623838 NIC 23623838 amphetamine 23623838 cocaine 23623838 nicotine 23623904 EtOH 23623904 NO 23623904 ethanol 23624237 ATP 23624237 PPIX 23624237 Porphyrins 23624237 adenosine triphosphate 23624237 propionate 23624237 protoporphyrin IX 23624237 tetrapyrrole macrocycle 23624326 polystyrene 23624352 MTT 23624360 carbon 23624379 8-hydroxy-2-deoxyguanosine 23624379 CPF 23624379 Chlorpyrifos 23624379 chlorinated organophosphate 23624379 chlorpyrifos 23624379 glutathione 23624379 malondialdehyde 23624379 oxygen 23624379 vitamin E 23624422 nickel 23624607 Fullerenes 23624607 c60 23624607 carbon 23624607 fullerene 23624607 fullerenes 23624607 oxygen 23624811 acetylcholine 23624811 nicotine 23625273 Aluminium 23625273 Calcium 23625273 Sevelamer 23625273 calcium 23625273 calcium acetate or carbonate 23625273 lanthanum 23625273 lanthanum carbonate 23625273 magnesium 23625273 phosphate 23625273 phosphorus 23625273 sevelamer 23625455 hydrogen 23625693 apixaban 23625693 edoxaban 23625693 rivaroxaban 23625804 Cu(I) 23625804 Disulfide 23625804 Superoxide 23625804 copper 23625804 copper(I) 23625804 cysteines 23625804 disulfide 23625911 Metoprolol 23625911 Ziprasidone 23625911 diltiazem 23625911 metoprolol 23625911 ziprasidone 23625915 AICAR 23625915 AMP 23625915 Ca2+ 23625915 SB203580 23625915 serine 23626400 PCL 23626400 PDLLA 23626400 PEG 23626400 PLA 23626400 PLLA 23626400 poly (D, L-lactide) 23626400 poly (L-lactide) 23626400 polycaprolactone 23626400 polyethylene glycol 23626400 polylatide 23626400 steroids 23626400 triamcinolone acetonide 23627311 AMPA 23627311 Ca(2+) 23627311 GABA 23627311 N-Methyl-D-Aspartate 23627311 NMDA 23627311 Tetrahydroisoquinoline 23627311 acyclic amides 23627311 glutamate 23627311 glycine 23627311 kainate 23627311 tetrahydroisoquinoline 23627311 tetrahydroisoquinolines 23627352 2,4-diamino-6-bromo-pyrido[2,3-d]pyrimidine 23627352 pivaloyl 23627352 pyrido[2,3-d]pyrimidine 23627352 pyrido[2,3-d]pyrimidines 23627414 Ag 23627414 Au 23627414 AuPCl3 23627414 AuPF3 23627414 AuPH3 23627414 AuSCH3 23627414 Cu 23627414 H2O 23627414 H2S 23627414 Metal-thiol 23627414 NF3 23627414 NH3 23627414 NMe3 23627414 NX3 23627414 OF2 23627414 OMe2 23627414 OX2 23627414 P 23627414 PCl3 23627414 PF3 23627414 PH3 23627414 PMe3 23627414 PX3 23627414 SF2 23627414 SMe2 23627414 SX2 23627637 H2O 23627637 MoS2 23627637 MoSe2 23627637 O2 23627637 WSe2 23627637 transition metal dichalcogenides 23627649 CeO2 23627649 CoxNi1-x 23627649 Ni 23627649 SrTiO3 23627670 N 23627670 amino acid 23627670 amino acids 23627670 carbohydrate 23627670 hydrogen 23627670 nonapeptide 23627670 threonine 23627670 α-O-disaccharide 23627699 Au 23627699 DCB 23627699 OTMS 23627699 P3HT 23627699 PBDTT-DPP 23627699 PC60BM 23627699 PCB60M 23627699 SiO2 23627699 [6,6]-phenyl-C61-butyric acid methyl ester 23627699 dichlorobenzene 23627699 ethanol 23627699 octadecyltrimethoxysilane 23627699 poly(3-hexylthiophene) 23627699 poly[2,6-4,8-di(5-ethylhexylthienyl)benzo[1,2-b;3,4-b]dithiophene-alt-5-dibutyloctyl-3,6-bis(5-bromothiophen-2-yl) pyrrolo[3,4-c]pyrrole-1,4-dione] 23627699 silica 23627743 NaCl 23627743 PEI 23627743 Poly(ethylenimine) 23627743 poly(ethylenimine) 23627804 PPF 23627804 XTT 23627804 ZCF 23627804 poly(propylene fumarate) 23627804 polyethylene 23627804 polyurethane 23627804 zinc diethyldithiocarbamate 23628456 APAP 23628456 Acetaminophen 23628456 GSH 23628456 acetaminophen 23628456 cysteine 23628456 glutamate 23628456 glutathione 23628456 nitric oxide 23628456 nitrotyrosine 23628456 oxygen 23628456 peroxynitrite 23628762 amino 23628791 Mn 23628791 manganese 23628791 manganism 23628841 2,2-bismethylolpropionic acid 23628841 bis-MPA 23629664 H+ 23629664 K+ 23629664 Na+ 23629861 H2O2 23629861 N-formylkynurenine 23629861 ONOO 23629861 ONOO(-) 23629861 ONOO- 23629861 kynurenine 23629861 methionine sulfoxide 23629861 peroxynitrite 23629861 tryptophan 23629923 genistein 23630137 Luteolin 23630137 luteolin 23630301 glucose 23631440 2-mercaptocyclopentane arylsulfonamide 23631440 3-Mercaptopyrrolidine 23631440 3-mercapto-4-arylsulfonamido pyrrolidine 23631440 cyclopentane 23631440 hydroxamates 23631440 mercaptosulfide 23631440 mercaptosulfonamides 23631440 pyrrolidine 23631440 pyrrolidine mercaptosulfide 23631463 Alcohol 23631463 Aminoalkylindole 23631463 JHW-073 23631463 alcohol 23631463 aminoalkylindole 23631463 aminoalkylindoles 23631494 8-isoprostane 23631494 Ile-Pro-Pro 23631494 Val-Pro-Pro 23631494 captopril 23631494 enalapril 23631498 polyphenol 23631528 Glu 23631528 His 23631528 Ser 23631528 amino acids 23631528 organophosphate 23631528 paraoxon 23631539 cidofovir 23631539 poly(ethylene glycol) 23631539 poly(lactic-co-glycolic acid) 23631590 Polystyrene 23631590 polystyrene 23631674 Ag 23631674 Au 23631674 Silver 23631674 citrate 23631736 4,4-dimethyl-2-oxazoline 23631736 4S-isopropyl-5,5-dimethyl-2-oxazoline 23631736 4S-tert-butyl-2-oxazoline 23631736 Aminoalkenes 23631736 C-H 23631736 C-N 23631736 Hf 23631736 N-H 23631736 N-deutero-aminoalkenes 23631736 N-heterocyclic amines 23631736 N-proteo-aminoalkenes 23631736 Ox(R) 23631736 Secondary aminopentene 23631736 Ti 23631736 Zirconium 23631736 Zr 23631736 amidoalkene 23631736 cyclopentadienylbis(oxazolinyl)borato 23631736 cyclopentadienylmono(oxazolinyl)borato zirconium diamide 23631736 primary amine 23631736 zirconium monoamido 23631736 {Ph2B(C5H4)(Ox(4S-iPr,Me2))}Zr(NMe2)2 23631736 {PhB(C5H4)(Ox(4S-iPr,Me2))2}Zr(NMe2)Cl 23631736 {PhB(C5H4)(Ox(R))2}M(NMe2)2 23631744 5-(N-(4-((4-ethylbenzyl)thio)phenyl)sulfamoyl)-2-methyl benzoic acid 23631744 CP-778 875 23631744 atorvastatin 23631744 atorvastatin acid 23631744 ortho- and para-hydroxyatorvastatin 23631760 20(R)- and (S)-25-OCH3-PPD 23631760 20(R)-25-OH-PPD 23631760 20(R,S)-25-OCH3-PPD 23631760 20(R,S)-25-OH-PPD 23631760 20(S)-25-OH-PPD 23631760 25-OCH3-PPD 23631760 25-methoxydammarane-3β,12β,20-triol 23631760 acetonitrile 23631760 ammonium acetate 23631927 Iron 23631927 corticosterone 23631927 iron 23632005 8-Gua 23632005 8-OH Gua 23632005 8-hydroxyl guanine 23632005 Cisplatin 23632005 GSH 23632005 Gua 23632005 TPP 23632005 Thiamine 23632005 cisplatin 23632005 glutathione 23632005 guanine 23632005 superoxide 23632005 thiamine 23632005 thiamine pyrophosphate 23632005 thio barbituric acid 23632006 Ag 23632006 Nanocid 23632006 cortisol 23632006 glucose 23632006 silver 23632099 androgen 23632304 Calcium 23632304 Clothianidin 23632304 acetylcholine 23632304 cAMP 23632304 calcium 23632304 clothianidin 23632304 d-tubocurarine 23632304 imidacloprid 23632304 mecamylamine 23632310 Glycyrrhizic acid 23632310 dexamethasone 23632310 eosin 23632310 glycyrrhizic acid 23632310 hematoxylin 23632340 C-H 23632340 CH 23632340 Fe(IV)oxo 23632340 alkane 23632340 oxyl 23632448 CD4 23632448 CH4 23632448 methane 23633618 4-(4-chlorophenyl)imidazole 23633618 Paroxetine 23633618 amlodipine 23633618 paroxetine 23634668 2-(pyridin-2-yl)quinazoline 23634668 Co(II) 23634668 Methionine 23634668 Mn(II) 23634668 Pyridinylquinazolines 23634668 Zn(II) 23634668 methionine 23634707 metal-oxide 23634759 Anthrapyrazolone 23634759 Indazole 23634759 SP600125 23634759 anthrapyrazolone 23634759 indazole 23635097 silver 23635829 (68)Ga 23635829 (68)Ga labeled bis-DOTA 23635829 3,3'-(benzylidene)-bis-(1H-indole-2-carbohydrazide) 23635829 benzylidene-bis-indole 23635829 bis-DTPA 23636302 Nicotine 23636302 nicotine 23636640 glucose 23636640 vildagliptin 23636685 ([PtCl(en)(ACRAMTU-S)](NO3)2 23636685 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea 23636685 ACRAMTU 23636685 Acridine 23636685 PT-ACRAMTU 23636685 Platinum 23636685 acridine 23636685 ethane-1,2-diamine 23636685 platinum 23637347 cholesterol 23638683 He 23638683 Helium 23638683 alkali metals 23638683 helium 23638960 Methyl tortuoate D 23638960 bis-cembranoid 23638960 bis-cembranoids 23638960 lobophytone K 23638960 methyl tortuoate D 23638960 ximaolide A 23639191 GSH 23639191 H2O2 23639191 cAMP 23639191 calycopterin 23639191 glutamylcysteine 23639191 glutathione 23639233 Amino Acid 23639233 Bpa 23639233 Leu 23639233 Phe 23639233 amino acid 23639233 para-benzoylphenylalanine 23639246 3-hydroxymethylantipyrine 23639246 4-hydroxyantipyrine 23639246 Antipyrine 23639246 Cyfluthrin 23639246 O 23639246 antipyrine 23639246 carnitine 23639246 cyfluthrin 23639246 ethoxyresorufin 23639246 lauric acid 23639246 methoxyresorufin 23639246 norantipyrine 23639246 palmitoyl 23639249 2,3,7,8-tetrachlorodibenzo-p-dioxin 23639249 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d]pyrimidine 23639249 I3S 23639249 Indoxyl 3-sulfate 23639249 TCDD 23639249 indoxyl 3-sulfate 23639363 NO 23639363 PGE2 23639363 glucose 23639363 nitric oxide 23639363 prostaglandin E2 23639431 C 23639431 NMDA 23639431 amino acids 23639431 carboxy 23639431 glutamate 23639452 (C12)2 23639452 C12 23639452 cholesteryl 23639452 cholesteryl-spermine 23639538 (3R)-5,7-dihydroxyl-6,8-dimethyl-3-(4'-hydroxylbenzyl)-chroman-4-one 23639538 (3R)-5,7-dihydroxyl-6-methyl-3-(4'-hydroxylbenzyl)-chroman-4-one 23639538 (3R)-5,7-dihydroxyl-6-methyl-8-methoxyl-3-(4'-hydroxylbenzyl)-chroman-4-one 23639538 AMP 23639538 Adenosine monophosphate 23639538 acetyl-CoA 23639538 adenosine monophosphate 23639538 dihydrochalcone 23639538 homoisoflavonoids 23639538 polygonatone D 23639538 polygonatones A-D 23639540 5-quinoline 23639540 DMH1 23639540 LDN-193189 23639540 ML347 23639540 dorsomorphin 23639540 pyrazolo[1,5-a]pyrimidine 23639540 pyrazolo[1.5-a]pyrimidine 23639541 BODIPY 23639541 alkyne 23639541 azide 23639541 copper 23639798 Rotenone 23639798 rotenone 23639798 superoxide 23639798 thiol 23639798 tyrosine 23639867 S 23639867 biotin 23639867 cysteine 23639867 nitric oxide 23639867 nitroso 23639867 organophosphine 23640034 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether 23640034 BDE209 23640034 PBDEs 23640034 glucose 23640034 polybrominated diphenyl ethers 23640034 reduced glutathione 23640034 superoxide 23640283 Ag 23640283 RhB 23640283 TiO2 23640283 carbon 23640283 graphitic 23640283 phenol 23640884 2-MeSADP 23640884 ADP 23640884 Proline 23640884 TxA2 23640884 thromboxane 23640884 tyrosine 23641693 DM1 23641701 EDTA 23641792 SDS 23641792 SDS sulfate 23641792 Sodium Dodecyl Sulfate 23641792 amine nitrogen 23641792 diethylenetriamine 23641792 hexamine 23641792 pentaethylenehexamine 23641792 pentamine 23641792 sodium dodecyl sulfate 23641792 tetraethylenepentamine 23641792 tetramine 23641792 triamine 23641792 triethylenetetramine 23641901 2-methacryloyloxyethyl phosphorylcholine 23641901 AEC 23641901 Ethylene sulfide 23641901 MPC 23641901 PPC 23641901 PPEGMA 23641901 PPFS 23641901 alkyne 23641901 alkynyl-PHEAA 23641901 alkynyl-PMETA 23641901 amine 23641901 azide 23641901 azido-PPEGMA 23641901 azido-PPFS 23641901 azidoethyl carbonylimidazole 23641901 hydroxyl 23641901 poly(2,3,4,5,6-pentafluorostyrene) 23641901 poly(2-(methacryloyloxy)ethyl trimethylammonium chloride) 23641901 poly(N-hydroxyethyl acrylamide) 23641901 poly(poly(ethylene glycol)methyl ether methacrylate) 23641901 propargyl carbonylimidazole 23641901 thiol 23642004 Esters 23642004 ester 23642004 esters 23642004 hydroxide 23642004 methyl acetate 23642004 methyl trifluoroacetate 23642033 Cu(2+) 23642124 Ag 23642124 Ag-Au 23642226 CO 23642226 Kr 23642226 N2 23642226 W(CO)6 23642226 krypton 23642226 nitrogen 23642226 tungsten hexacarbonyl 23642262 Nucleotides 23642262 guanine 23642262 nucleotide 23642262 phosphate 23642262 sugar 23642287 GTP 23642287 Pyrimidyn 23642287 pyrimidine 23643483 Glutathione 23643483 S 23643483 glutathione 23643631 Melamine 23643631 NADPH 23643631 PGE2 23643631 apocynin 23643631 melamine 23643631 oxygen 23643631 prostaglandin E2 23643682 N 23643682 Val 23643682 estradiol 23643682 estrogen 23643733 Acetylcholine 23643733 acetylcholine 23643746 AMPA 23643746 GABA 23643746 NMDA 23643746 bicuculline 23643747 GABA 23643747 Haloperidol 23643747 PF470867 23643747 Ser 23643747 cAMP 23643747 calyculin A 23643747 dopamine 23643747 haloperidol 23643747 okadaic acid 23643747 rapamycin 23643751 1-methyl-4-phenylpyridinium 23643751 3-methyladenine 23643751 6-OHDA 23643751 6-hydroxydopamine 23643751 Arylpiperazine 23643751 N-{3-[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-picolinamide 23643751 arylpiperazine 23643751 arylpiperazines 23643751 bafilomycin A1 23643751 superoxide 23643752 2-arachidonoylglycerol 23643752 AEA 23643752 AM281 23643752 AM630 23643752 N-arachidonoylethanolamine 23643752 N-arachidonoylglycine 23643752 Retinal 23643752 URB597 23643752 fatty acid amide 23643752 retinal 23643755 CCh 23643755 Carbachol 23643755 Norepinephrine 23643784 C6H14O6(.)0.5H2O 23643784 MHH 23643784 Mannitol 23643784 mannitol 23643784 mannitol hemihydrate 23643798 1H 23643798 Gentian violet 23643798 gentian violet 23643798 triarylmethane 23643808 Prolyl 23643808 prolyl 23643828 Dialkyl 5-(hydroxymethyl)isophthalates 23643828 Gö6976 23643828 isophthalate 23643828 isophthalates 23643828 serine 23643828 threonine 23643831 benzene 23643831 iodiconazole 23643831 triazole 23643837 glucose 23643883 Z-VAD-fmk 23643883 Z-Val-Ala-Asp-fluoromethylketone 23643883 oxygen 23643932 Ca(2+) 23643932 LXA4 23643932 Lipoxin A4 23643932 cAMP 23643932 formyl 23643932 lipoxin A4 23644193 1,2,3-triazole-dithiocarbamate-urea 23644199 carbon 23644199 echinocystic acid 23644199 hydroxyl 23644199 lactone 23644199 oleanane 23644199 triterpene 23644203 N'-(benzofuroxan-5-yl)methylene]benzohydrazides 23644203 benzofuroxan 23644205 2-methylbenzothiazoles 23644205 Amphotericin B 23644205 N 23644205 N-Alkylated 2,3,3-trimethylindolenines 23644205 N-alkylated 2,3,3-trimethylindolenines 23644205 Thiabendazole 23644210 benzoxazines 23644210 hydroxamic acid 23644210 ketone 23644210 potassium 23644210 spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] 23644210 zinc 23644211 2-arylidene-22β-hydroxy-3-oxoolean-12-en-28-oic acids 23644211 22β-hydroxy-3-oxoolean-12-en-28-oic acid 23644211 Lantadene A (1) and B 23644211 aldehydes 23644211 cisplatin 23644211 lantadenes 23644213 1,2,4-oxadiazol-5(4H)-one 23644213 Arg-Gly-Asp 23644213 rivaroxaban 23644219 N-(4-hydroxy-3-mercaptonaphthalen-1-yl)amides 23644219 benzene 23644219 ortho-nitro 23644411 MTT 23644411 NO 23644411 Steroidal glycosides 23644411 furostanol saponin 23644411 glucose 23644411 hydroxy 23644411 methyl thiazole tetrazolium 23644411 nitric oxide 23644411 steroidal glycoalkaloids 23644411 steroidal glycosides 23644914 acetylcholine 23644914 nicotine 23644925 (25S)-5α-cholestane-3β,4β,6α,7α,8,15α,16β,26-octaol 23644925 (25S)-5α-cholestane-3β,6α,7α,8,15α,16β,26-heptaol 23644925 Steroids 23644925 asterosaponin Р1 23644925 distolasterosides D1-D3 23644925 glucose 23644925 oxygen 23644925 polyhydroxysteroids 23644925 steroids 23645630 Oxygen 23645630 oxygen 23646041 doxorubicin 23646355 acetylene 23646356 2,4-dichlorophenoxyacetic acid 23646356 dichlorodiphenyldichloroethylene 23646356 dichlorodiphenyltrichloroethane CHEMDNER_CORPUS_BIOCREATIVE_4/CHEMDNER_DEVELOPMENT/cem_ann_development_13-08-18.txt0000644002344200234200000211131112204144710027462 0ustar mkrallingerBioinfoUnix22006095 A:285:294 22006095 A:498:512 22006095 A:622:636 22006095 T:0:9 22006095 T:79:93 22056334 A:1002:1010 22056334 A:1016:1029 22056334 A:1173:1203 22056334 A:391:404 22056334 A:824:856 22056334 A:858:866 22056334 A:938:945 22056334 A:950:956 22056334 A:958:962 22056334 A:968:993 22056334 A:995:999 22079313 A:107:120 22079313 A:1159:1162 22079313 A:1212:1216 22079313 A:122:126 22079313 A:20:43 22079313 A:321:324 22079313 A:376:379 22079313 A:493:497 22079313 A:54:57 22079313 A:698:702 22079313 A:707:710 22079313 A:848:852 22079313 A:903:906 22082827 A:1076:1093 22082827 A:1098:1113 22082827 A:1130:1141 22082827 A:420:422 22082827 A:425:427 22082827 A:430:432 22082827 A:435:437 22082827 A:440:442 22082827 A:508:510 22082827 A:513:515 22082827 A:517:519 22082827 A:528:530 22082827 A:535:537 22082827 A:570:572 22082827 A:575:577 22082827 A:580:582 22082827 A:585:587 22082827 A:590:592 22082827 A:604:606 22082827 A:609:611 22082827 A:614:616 22082827 A:619:621 22082827 A:624:626 22082827 A:699:703 22082827 A:728:732 22082827 A:786:792 22082827 A:817:823 22082827 A:910:920 22082827 A:942:953 22082827 A:954:955 22082827 A:972:983 22236017 A:297:305 22236017 A:382:390 22236017 A:395:404 22236093 A:197:219 22239172 A:159:167 22239172 A:171:195 22239172 A:318:332 22239172 A:334:350 22239172 A:355:370 22239172 A:381:394 22239172 A:399:408 22239172 A:591:605 22239172 A:721:735 22239172 T:0:10 22239172 T:15:29 22273350 A:216:230 22273350 A:241:253 22273350 A:266:277 22273350 A:323:338 22273350 A:349:358 22273350 A:369:386 22273350 A:396:407 22273350 A:417:427 22273350 A:437:456 22273350 A:469:490 22273350 A:510:520 22273350 A:522:532 22273350 A:534:541 22273350 A:543:553 22273350 A:555:563 22273350 A:565:575 22273350 A:577:588 22273350 A:590:600 22273350 A:605:617 22273350 A:710:739 22301814 A:1042:1049 22301814 A:140:147 22301814 A:149:155 22301814 A:261:268 22301814 A:358:365 22301814 A:384:393 22301814 A:458:467 22301814 A:469:480 22301814 A:482:486 22301814 A:491:501 22301814 A:634:641 22301814 A:709:728 22301814 A:879:886 22301814 T:29:36 22301815 A:1089:1099 22301815 A:15:25 22301815 A:30:44 22301815 A:491:501 22301815 A:631:641 22301815 A:643:650 22301815 A:755:762 22301815 A:774:785 22301815 A:786:787 22301815 A:967:975 22301815 T:11:23 22301815 T:154:164 22301815 T:65:73 22312035 A:241:245 22312035 A:329:333 22312035 A:38:50 22312035 A:500:504 22312035 A:52:56 22312035 A:680:684 22312035 A:893:897 22312035 T:17:29 22313530 A:1103:1116 22313530 A:1120:1131 22313530 A:1167:1181 22313530 A:1703:1717 22313530 A:1936:1945 22313530 A:22:31 22313530 A:306:364 22313530 A:307:364 22313530 A:366:374 22313530 A:526:534 22313530 A:651:659 22313530 A:781:790 22313530 A:890:899 22313530 A:990:998 22313530 T:33:42 22313530 T:82:94 22335586 A:1131:1142 22335586 A:1206:1217 22335586 A:1298:1309 22335586 A:1587:1598 22335586 A:194:205 22335586 A:21:32 22335586 A:333:348 22335586 A:353:368 22335586 A:558:569 22335586 A:759:770 22335586 A:776:783 22335586 A:788:795 22335586 T:79:90 22348222 A:249:271 22348222 A:281:297 22348222 A:307:318 22348222 A:328:338 22348222 A:351:359 22348222 A:404:416 22348222 A:464:490 22348222 A:500:524 22348951 A:1033:1044 22348951 A:1068:1079 22348951 A:1080:1093 22348951 A:1870:1873 22348951 A:1874:1878 22348951 A:499:505 22348951 A:576:586 22352409 A:115:128 22352409 A:163:175 22352409 A:487:500 22352409 A:505:517 22352409 A:636:649 22352409 T:30:43 22352409 T:48:60 22360570 A:0:3 22360570 A:4:7 22364642 A:149:166 22364642 A:167:175 22364642 A:218:226 22364642 A:260:277 22364642 A:327:337 22364642 A:478:486 22364642 T:0:8 22372659 A:270:279 22372659 A:281:302 22372659 A:304:310 22372659 A:312:332 22372659 A:334:346 22372659 A:386:393 22372865 A:0:23 22372865 A:1144:1151 22372865 A:1311:1318 22372865 A:32:41 22372865 T:75:98 22381584 A:1123:1127 22381584 A:1136:1140 22381584 A:1205:1209 22381584 A:1222:1228 22381584 A:1256:1260 22381584 A:1292:1298 22381584 A:1304:1307 22381584 A:1308:1320 22381584 A:1381:1385 22381584 A:1438:1441 22381584 A:1452:1461 22381584 A:1498:1504 22381584 A:1515:1524 22381584 A:1571:1575 22381584 A:1632:1636 22381584 A:2047:2056 22381584 A:2317:2326 22381584 A:2403:2412 22381584 A:2532:2541 22381584 A:391:400 22381584 A:508:517 22381584 A:578:587 22381584 A:755:761 22381584 A:924:928 22381584 A:974:982 22381584 A:999:1002 22381584 T:64:73 22391562 A:317:322 22391562 A:327:332 22400496 A:150:158 22400496 A:170:179 22400496 A:192:201 22400496 A:214:223 22400496 A:298:307 22400496 A:368:377 22401710 A:1174:1184 22401710 A:1287:1297 22401710 A:1416:1420 22401710 A:1566:1576 22401710 A:309:319 22401710 A:466:476 22401710 A:563:573 22401710 A:655:670 22401710 A:688:691 22401710 A:688:696 22401710 A:896:903 22401710 A:905:913 22401710 A:951:971 22401710 A:973:977 22401710 T:49:59 22410775 A:29:37 22410775 T:13:21 22410778 A:1014:1036 22410778 A:1038:1041 22410778 A:1109:1115 22410778 A:1409:1416 22410778 A:1591:1594 22410778 A:332:339 22410778 A:537:567 22410778 A:568:572 22410778 A:599:603 22410778 A:709:713 22410778 A:869:878 22410778 A:950:957 22410778 T:65:69 22410778 T:86:95 22424051 A:141:150 22424051 A:152:165 22424051 A:167:177 22424051 A:16:75 22424051 A:179:199 22424051 A:201:208 22424051 A:222:235 22424051 A:240:248 22424051 A:6:14 22424051 A:83:95 22424051 T:6:14 22426233 A:1167:1176 22426233 A:1184:1191 22426233 A:1312:1319 22426233 A:13:22 22426233 A:1652:1661 22426233 A:379:388 22426233 A:410:419 22426233 A:430:437 22426233 A:585:592 22426233 A:617:626 22426233 A:683:692 22426233 A:746:755 22426233 A:867:871 22429027 A:17:38 22429027 A:188:365 22429027 A:374:523 22429027 A:40:56 22429027 A:8:16 22429027 T:8:29 22430206 A:685:693 22438091 A:0:10 22438091 A:124:134 22438091 A:184:194 22438091 A:21:45 22438091 A:223:229 22438091 A:355:365 22438091 A:486:490 22438091 A:529:539 22438091 A:569:576 22438091 A:670:680 22438091 A:714:717 22438091 A:754:764 22438091 A:817:826 22438091 A:868:878 22438091 A:980:990 22438091 T:11:21 22438103 A:381:388 22439867 A:0:6 22439867 A:127:139 22439867 A:183:215 22439867 A:229:289 22439867 A:295:357 22439867 A:366:417 22439867 A:463:468 22439867 A:474:478 22439867 A:8:18 22439867 T:22:46 22440717 A:372:385 22440717 A:407:415 22440717 A:770:778 22443216 A:290:301 22443216 A:319:345 22443216 A:408:416 22443216 A:429:441 22443216 A:455:465 22443216 A:480:490 22443216 A:761:769 22443216 A:771:783 22443216 A:785:795 22443216 A:800:810 22443683 A:72:75 22443683 A:76:79 22443683 A:819:842 22443683 A:871:877 22443683 A:925:934 22447662 A:1079:1086 22447662 A:1107:1116 22447662 A:1178:1188 22447662 A:1196:1207 22447662 A:1209:1222 22447662 A:1227:1234 22447662 A:308:321 22447662 A:431:442 22447662 A:461:480 22447662 A:482:485 22447662 A:488:499 22447662 A:517:527 22447662 A:705:717 22447662 A:881:894 22447662 A:896:899 22447684 A:1362:1371 22447684 A:288:297 22447684 A:549:560 22447684 A:562:574 22447684 A:580:599 22447684 A:67:76 22447684 A:808:817 22447684 A:862:871 22447684 A:949:958 22447684 T:0:9 22451331 A:1018:1024 22451331 A:1026:1034 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23195733 A:63:69 23195733 A:89:126 23195733 T:49:76 23195751 A:33:41 23195751 A:936:949 23195751 T:48:57 23195959 A:207:214 23195959 T:34:41 23196670 A:120:124 23196670 A:1313:1317 23196670 A:215:231 23196670 A:40:75 23196670 A:526:533 23196670 A:77:81 23196670 A:93:118 23197401 A:112:117 23197401 A:174:179 23197401 A:24:43 23197401 A:44:49 23197401 A:451:459 23197401 A:54:111 23197401 A:644:689 23197401 A:690:695 23197401 A:730:738 23197401 T:63:68 23197647 A:1232:1244 23197647 A:1246:1249 23197647 A:1325:1334 23197647 A:1387:1390 23197647 A:1450:1459 23197647 A:1524:1527 23197647 A:933:942 23197647 A:956:961 23197647 T:102:114 23197647 T:47:56 23197773 A:1072:1080 23197773 A:1083:1177 23197773 A:1179:1187 23197773 A:1190:1261 23197773 A:1263:1272 23197773 A:1275:1286 23197773 A:1300:1308 23197773 A:1310:1320 23197773 A:1539:1544 23197773 A:1615:1625 23197773 A:1786:1791 23197773 A:1793:1807 23197773 A:1823:1829 23197773 A:1831:1842 23197773 A:1844:1852 23197773 A:1979:1988 23197773 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A:692:700 23199989 A:705:742 23199989 A:744:748 23199989 A:779:783 23199996 A:102:103 23199996 A:105:107 23199996 A:109:111 23199996 A:113:115 23199996 A:117:119 23199996 A:121:123 23199996 A:125:127 23199996 A:133:135 23199996 A:162:164 23199996 A:165:169 23199996 A:171:173 23199996 A:175:177 23199996 A:183:185 23199996 A:197:203 23199996 A:23:33 23199996 A:368:379 23199996 A:434:461 23199996 A:43:54 23199996 A:463:467 23199996 A:500:511 23199996 A:56:67 23199996 A:633:635 23199996 A:753:759 23199996 A:810:817 23199996 A:91:92 23199996 A:94:96 23199996 A:98:100 23199998 A:329:341 23199998 A:377:388 23199998 A:412:415 23199998 A:617:622 23199998 A:912:915 23200254 A:12:60 23200254 A:214:224 23200254 A:299:310 23200254 T:95:106 23200255 A:0:104 23200255 A:106:114 23200255 A:234:235 23200255 A:254:266 23200255 A:357:394 23200255 A:412:413 23200255 A:531:550 23200255 A:612:634 23200255 A:657:673 23200255 A:800:809 23200732 A:0:9 23200732 A:1259:1268 23200732 A:1282:1290 23200732 A:211:219 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23200943 A:231:243 23200943 A:564:576 23200943 A:682:699 23200943 A:714:725 23200943 A:998:1010 23200943 T:40:52 23200944 A:19:26 23200944 A:817:819 23200944 T:37:44 23201051 A:119:166 23201051 A:1304:1315 23201051 A:1325:1345 23201051 A:1579:1590 23201051 A:1600:1620 23201051 A:1665:1675 23201051 A:1683:1703 23201051 A:168:188 23201051 A:1838:1848 23201051 A:282:302 23201051 A:375:404 23201051 A:440:445 23201051 A:463:479 23201051 A:515:535 23201051 A:573:603 23201051 A:672:692 23201051 A:985:993 23201092 A:0:32 23201092 A:1091:1095 23201092 A:1157:1161 23201092 A:34:38 23201092 A:526:530 23201092 A:728:732 23201092 A:799:803 23201092 A:819:823 23201092 A:893:897 23201092 A:957:961 23201092 A:969:973 23201092 T:59:63 23201179 A:1012:1015 23201179 A:104:107 23201179 A:1161:1164 23201179 A:137:157 23201179 A:1519:1522 23201179 A:159:162 23201179 A:1718:1721 23201179 A:1722:1725 23201179 A:182:185 23201179 A:186:189 23201179 A:343:346 23201179 A:347:350 23201179 A:496:499 23201179 A:794:797 23201179 A:84:102 23201179 T:51:60 23201180 A:0:10 23201180 A:1086:1096 23201180 A:1298:1314 23201180 A:12:63 23201180 A:279:295 23201180 A:364:374 23201180 A:435:441 23201180 A:442:449 23201180 A:78:94 23201180 A:878:892 23201180 A:928:942 23201180 A:962:968 23201180 T:0:10 23201337 A:1013:1021 23201337 A:1192:1200 23201337 A:1324:1332 23201337 A:1482:1490 23201337 A:158:166 23201337 A:17:25 23201337 A:382:390 23201337 A:684:692 23201337 A:792:800 23201337 A:891:899 23201337 A:943:951 23201337 A:953:965 23201337 T:15:23 23201371 A:1005:1016 23201371 A:1055:1058 23201371 A:1062:1065 23201371 A:1076:1086 23201371 A:1139:1142 23201371 A:1146:1149 23201371 A:1178:1188 23201371 A:123:127 23201371 A:1249:1253 23201371 A:1257:1261 23201371 A:1304:1314 23201371 A:130:164 23201371 A:166:170 23201371 A:193:210 23201371 A:212:215 23201371 A:221:244 23201371 A:246:249 23201371 A:282:293 23201371 A:295:298 23201371 A:304:318 23201371 A:320:323 23201371 A:36:46 23201371 A:439:442 23201371 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A:59:72 23432590 A:677:689 23432590 A:787:799 23432590 T:0:12 23432662 A:1204:1216 23432662 A:309:316 23432662 A:81:94 23432753 A:206:222 23432753 A:878:879 23432753 A:915:916 23432753 A:91:93 23432753 A:927:928 23432753 A:934:935 23432753 A:968:970 23432753 A:976:977 23432753 T:79:83 23434031 A:105:122 23434193 A:0:35 23434193 A:342:371 23434193 A:373:376 23434193 A:37:42 23434193 A:382:402 23434193 A:404:407 23434193 A:417:426 23434193 A:694:701 23434193 T:28:37 23434223 A:181:213 23434223 A:19:86 23434223 A:215:228 23434223 A:233:251 23434223 A:271:281 23434223 A:551:631 23434223 T:66:91 23434224 T:0:8 23434224 T:12:19 23434227 A:206:209 23434227 A:22:36 23434227 A:453:454 23434227 A:493:507 23434227 T:41:55 23434417 A:0:50 23434417 T:0:50 23434506 A:106:118 23434506 A:123:128 23434506 A:155:164 23434506 A:307:312 23434506 A:387:396 23434506 A:504:509 23434506 A:649:658 23434506 A:797:802 23434506 A:833:842 23434506 A:925:930 23434506 T:0:12 23434506 T:38:47 23434663 A:132:148 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A:1122:1134 23435358 A:1179:1187 23435358 A:1192:1203 23435358 A:1244:1248 23435358 A:1253:1257 23435358 A:1280:1284 23435358 A:1289:1296 23435358 A:1304:1308 23435358 A:1319:1323 23435358 A:1332:1336 23435358 A:1379:1383 23435358 A:1394:1401 23435358 A:1403:1407 23435358 A:1525:1541 23435358 A:1543:1548 23435358 A:1551:1580 23435358 A:1582:1586 23435358 A:1591:1595 23435358 A:1623:1627 23435358 A:1642:1646 23435358 A:1651:1655 23435358 A:1688:1706 23435358 A:1723:1728 23435358 A:1729:1745 23435358 A:1747:1750 23435358 A:1765:1786 23435358 A:1788:1791 23435358 A:1811:1815 23435358 A:1817:1833 23435358 A:1835:1838 23435358 A:1850:1871 23435358 A:186:190 23435358 A:1873:1876 23435358 A:1881:1885 23435358 A:1890:1894 23435358 A:195:199 23435358 A:2168:2172 23435358 A:2177:2181 23435358 A:218:226 23435358 A:553:560 23435358 A:571:582 23435358 A:584:587 23435358 A:731:735 23435358 A:740:744 23435358 A:908:912 23435358 A:90:94 23435358 A:98:102 23435358 T:167:227 23435358 T:58:69 23435358 T:74:81 23435367 A:118:125 23435367 A:118:133 23435367 A:39:43 23435367 A:44:50 23435367 A:660:668 23435367 A:808:820 23435367 A:927:931 23435367 A:963:970 23435367 A:963:978 23435541 A:1015:1022 23435541 A:1171:1179 23435541 A:1342:1349 23435541 A:1364:1370 23435541 A:150:157 23435541 A:1531:1538 23435541 A:1695:1702 23435541 A:1815:1826 23435541 A:571:578 23435541 A:590:601 23435541 A:606:617 23435541 A:61:66 23435541 A:641:646 23435541 A:739:746 23435541 A:811:819 23435541 A:863:870 23435541 A:935:945 23435541 A:947:953 23435541 T:15:22 23435614 A:245:252 23435614 A:958:965 23435614 T:20:40 23435689 A:1084:1088 23435689 A:124:128 23435689 A:404:408 23435689 A:467:472 23435689 A:477:495 23435689 A:497:502 23435689 A:52:74 23435689 A:76:81 23435689 A:842:846 23435689 A:993:997 23435689 T:59:63 23435915 A:0:8 23435915 A:1003:1011 23435915 A:1043:1049 23435915 A:1061:1069 23435915 A:1202:1208 23435915 A:1344:1352 23435915 A:1439:1447 23435915 A:201:209 23435915 A:20:31 23435915 A:416:424 23435915 A:559:572 23435915 A:574:577 23435915 A:57:65 23435915 A:580:589 23435915 A:596:602 23435915 A:608:620 23435915 A:662:670 23435915 A:835:847 23435915 A:852:863 23435915 A:911:919 23435915 A:953:962 23435915 A:969:975 23435915 T:23:31 23436259 A:165:173 23436259 A:654:662 23436259 A:72:80 23436259 A:989:997 23436259 T:45:53 23436293 A:443:453 23436315 A:0:13 23436315 A:1245:1258 23436315 A:129:142 23436315 A:1303:1316 23436315 A:173:186 23436315 A:208:224 23436315 A:355:368 23436315 A:598:611 23436315 A:972:988 23436315 T:24:37 23436428 A:1261:1271 23436428 A:140:150 23436428 A:154:161 23436428 A:166:177 23436428 A:228:235 23436428 A:240:251 23436428 T:12:22 23436437 A:563:572 23436437 A:587:594 23436437 A:631:641 23436437 A:652:656 23436437 A:657:665 23436442 A:0:17 23436442 A:197:205 23436442 A:363:371 23436442 A:409:422 23436442 A:42:48 23436442 A:469:481 23436442 A:757:765 23436442 A:879:887 23436442 T:74:91 23436494 A:1224:1236 23436494 A:1420:1432 23436494 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23439078 A:38:50 23439078 A:625:633 23439078 A:662:689 23439078 A:996:1003 23439078 T:17:22 23439240 A:1005:1009 23439240 A:1010:1021 23439240 A:126:130 23439240 A:1302:1313 23439240 A:131:142 23439240 A:1379:1383 23439240 A:1385:1396 23439240 A:1417:1421 23439240 A:1422:1433 23439240 A:1513:1524 23439240 A:363:367 23439240 A:368:379 23439240 A:834:838 23439240 A:839:850 23439240 A:91:115 23439240 T:117:121 23439240 T:122:133 23439478 A:220:231 23439478 A:326:336 23439478 A:905:917 23439478 A:97:109 23439478 T:52:63 23439479 A:1064:1066 23439479 A:1145:1152 23439479 A:262:272 23439479 A:371:381 23439479 A:683:698 23439479 A:755:766 23439479 A:768:779 23439479 A:792:803 23439479 A:815:825 23439479 A:923:938 23439479 A:92:102 23439479 A:961:972 23439479 A:973:974 23439479 T:73:81 23439480 A:1232:1239 23439480 A:1316:1323 23439480 A:207:227 23439480 A:229:236 23439480 A:276:283 23439480 A:313:333 23439480 A:451:452 23439480 A:453:462 23439480 A:503:510 23439480 A:72:79 23439480 A:836:843 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